PMID- 23658516 TI - Behind closed membranes: the secret lives of picornaviruses? PMID- 23658517 TI - The EBV Latent Antigen 3C Inhibits Apoptosis through Targeted Regulation of Interferon Regulatory Factors 4 and 8. AB - Epstein-Barr virus (EBV) is linked to a broad spectrum of B-cell malignancies. EBV nuclear antigen 3C (EBNA3C) is an encoded latent antigen required for growth transformation of primary human B-lymphocytes. Interferon regulatory factor 4 (IRF4) and 8 (IRF8) are transcription factors of the IRF family that regulate diverse functions in B cell development. IRF4 is an oncoprotein with anti apoptotic properties and IRF8 functions as a regulator of apoptosis and tumor suppressor in many hematopoietic malignancies. We now demonstrate that EBNA3C can contribute to B-cell transformation by modulating the molecular interplay between cellular IRF4 and IRF8. We show that EBNA3C physically interacts with IRF4 and IRF8 with its N-terminal domain in vitro and forms a molecular complex in cells. We identified the Spi-1/B motif of IRF4 as critical for EBNA3C interaction. We also demonstrated that EBNA3C can stabilize IRF4, which leads to downregulation of IRF8 by enhancing its proteasome-mediated degradation. Further, si-RNA mediated knock-down of endogenous IRF4 results in a substantial reduction in proliferation of EBV-transformed lymphoblastoid cell lines (LCLs), as well as augmentation of DNA damage-induced apoptosis. IRF4 knockdown also showed reduced expression of its targeted downstream signalling proteins which include CDK6, Cyclin B1 and c-Myc all critical for cell proliferation. These studies provide novel insights into the contribution of EBNA3C to EBV-mediated B-cell transformation through regulation of IRF4 and IRF8 and add another molecular link to the mechanisms by which EBV dysregulates cellular activities, increasing the potential for therapeutic intervention against EBV-associated cancers. PMID- 23658518 TI - DRAM triggers lysosomal membrane permeabilization and cell death in CD4(+) T cells infected with HIV. AB - Productive HIV infection of CD4(+) T cells leads to a caspase-independent cell death pathway associated with lysosomal membrane permeabilization (LMP) and cathepsin release, resulting in mitochondrial outer membrane permeabilization (MOMP). Herein, we demonstrate that HIV infection induces damage-regulated autophagy modulator (DRAM) expression in a p53-dependent manner. Knocking down the expression of DRAM and p53 genes with specific siRNAs inhibited autophagy and LMP. However, inhibition of Atg5 and Beclin genes that prevents autophagy had a minor effect on LMP and cell death. The knock down of DRAM gene inhibited cytochrome C release, MOMP and cell death. However, knocking down DRAM, we increased viral infection and production. Our study shows for the first time the involvement of DRAM in host-pathogen interactions, which may represent a mechanism of defense via the elimination of infected cells. PMID- 23658519 TI - A nucleotide sugar transporter involved in glycosylation of the Toxoplasma tissue cyst wall is required for efficient persistence of bradyzoites. AB - Toxoplasma gondii is an intracellular parasite that transitions from acute infection to a chronic infective state in its intermediate host via encystation, which enables the parasite to evade immune detection and clearance. It is widely accepted that the tissue cyst perimeter is highly and specifically decorated with glycan modifications; however, the role of these modifications in the establishment and persistence of chronic infection has not been investigated. Here we identify and biochemically and biologically characterize a Toxoplasma nucleotide-sugar transporter (TgNST1) that is required for cyst wall glycosylation. Toxoplasma strains deleted for the TgNST1 gene (Deltanst1) form cyst-like structures in vitro but no longer interact with lectins, suggesting that Deltanst1 strains are deficient in the transport and use of sugars for the biosynthesis of cyst-wall structures. In vivo infection experiments demonstrate that the lack of TgNST1 activity does not detectably impact the acute (tachyzoite) stages of an infection or tropism of the parasite for the brain but that Deltanst1 parasites are severely defective in persistence during the chronic stages of the infection. These results demonstrate for the first time the critical role of parasite glycoconjugates in the persistence of Toxoplasma tissue cysts. PMID- 23658520 TI - An extracellular siderophore is required to maintain the mutualistic interaction of Epichloe festucae with Lolium perenne. AB - We have identified from the mutualistic grass endophyte Epichloe festucae a non ribosomal peptide synthetase gene (sidN) encoding a siderophore synthetase. The enzymatic product of SidN is shown to be a novel extracellular siderophore designated as epichloenin A, related to ferrirubin from the ferrichrome family. Targeted gene disruption of sidN eliminated biosynthesis of epichloenin A in vitro and in planta. During iron-depleted axenic growth, DeltasidN mutants accumulated the pathway intermediate N(5)-trans-anhydromevalonyl-N(5) hydroxyornithine (trans-AMHO), displayed sensitivity to oxidative stress and showed deficiencies in both polarized hyphal growth and sporulation. Infection of Lolium perenne (perennial ryegrass) with DeltasidN mutants resulted in perturbations of the endophyte-grass symbioses. Deviations from the characteristic tightly regulated synchronous growth of the fungus with its plant partner were observed and infected plants were stunted. Analysis of these plants by light and transmission electron microscopy revealed abnormalities in the distribution and localization of DeltasidN mutant hyphae as well as deformities in hyphal ultrastructure. We hypothesize that lack of epichloenin A alters iron homeostasis of the symbiotum, changing it from mutually beneficial to antagonistic. Iron itself or epichloenin A may serve as an important molecular/cellular signal for controlling fungal growth and hence the symbiotic interaction. PMID- 23658521 TI - Recombinant monovalent llama-derived antibody fragments (VHH) to rotavirus VP6 protect neonatal gnotobiotic piglets against human rotavirus-induced diarrhea. AB - Group A Rotavirus (RVA) is the leading cause of severe diarrhea in children. The aims of the present study were to determine the neutralizing activity of VP6 specific llama-derived single domain nanoantibodies (VHH nanoAbs) against different RVA strains in vitro and to evaluate the ability of G6P[1] VP6-specific llama-derived single domain nanoantibodies (VHH) to protect against human rotavirus in gnotobiotic (Gn) piglets experimentally inoculated with virulent Wa G1P[8] rotavirus. Supplementation of the daily milk diet with 3B2 VHH clone produced using a baculovirus vector expression system (final ELISA antibody -Ab- titer of 4096; virus neutralization -VN- titer of 256) for 9 days conferred full protection against rotavirus associated diarrhea and significantly reduced virus shedding. The administration of comparable levels of porcine IgG Abs only protected 4 out of 6 of the animals from human RVA diarrhea but significantly reduced virus shedding. In contrast, G6P[1]-VP6 rotavirus-specific IgY Abs purified from eggs of hyperimmunized hens failed to protect piglets against human RVA-induced diarrhea or virus shedding when administering similar quantities of Abs. The oral administration of VHH nanoAb neither interfered with the host's isotype profiles of the Ab secreting cell responses to rotavirus, nor induced detectable host Ab responses to the treatment in serum or intestinal contents. This study shows that the oral administration of rotavirus VP6-VHH nanoAb is a broadly reactive and effective treatment against rotavirus-induced diarrhea in neonatal pigs. Our findings highlight the potential value of a broad neutralizing VP6-specific VHH nanoAb as a treatment that can complement or be used as an alternative to the current strain-specific RVA vaccines. Nanobodies could also be scaled-up to develop pediatric medication or functional food like infant milk formulas that might help treat RVA diarrhea. PMID- 23658522 TI - The production of monokaryotic hyphae by Cryptococcus neoformans can be induced by high temperature arrest of the cell cycle and is independent of same-sex mating. AB - Cryptococcus neoformans is a heterothallic fungal pathogen of humans and animals. Although the fungus grows primarily as a yeast, hyphae are produced during the sexual phase and during a process called monokaryotic fruiting, which is also believed to involve sexual reproduction, but between cells of the same mating type. Here we report a novel monokaryotic fruiting mechanism that is dependent on the cell cycle and occurs in haploid cells in the absence of sexual reproduction. Cells grown at 37 degrees C were found to rapidly produce hyphae (~4 hrs) and at high frequency (~40% of the population) after inoculation onto hyphae-inducing agar. Microscopic examination of the 37 degrees C seed culture revealed a mixture of normal-sized and enlarged cells. Micromanipulation of single cells demonstrated that only enlarged cells were able to produce hyphae and genetic analysis confirmed that hyphae did not arise from alpha-alpha mating or endoduplication. Cell cycle analysis revealed that cells grown at 37 degrees C had an increased population of cells in G2 arrest, with the proportion correlated with the frequency of monokaryotic fruiting. Cell sorting experiments demonstrated that enlarged cells were only found in the G2-arrested population and only this population contained cells able to produce hyphae. Treatment of cells at low temperature with the G2 cell cycle arrest agent, nocodazole, induced hyphal growth, confirming the role of the cell cycle in this process. Taken together, these results reveal a mating-independent mechanism for monokaryotic fruiting, which is dependent on the cell cycle for induction of hyphal competency. PMID- 23658523 TI - Phosphorylation of CDK9 at Ser175 enhances HIV transcription and is a marker of activated P-TEFb in CD4(+) T lymphocytes. AB - The HIV transactivator protein, Tat, enhances HIV transcription by recruiting P TEFb from the inactive 7SK snRNP complex and directing it to proviral elongation complexes. To test the hypothesis that T-cell receptor (TCR) signaling induces critical post-translational modifications leading to enhanced interactions between P-TEFb and Tat, we employed affinity purification-tandem mass spectrometry to analyze P-TEFb. TCR or phorbal ester (PMA) signaling strongly induced phosphorylation of the CDK9 kinase at Ser175. Molecular modeling studies based on the Tat/P-TEFb X-ray structure suggested that pSer175 strengthens the intermolecular interactions between CDK9 and Tat. Mutations in Ser175 confirm that this residue could mediate critical interactions with Tat and with the bromodomain protein BRD4. The S175A mutation reduced CDK9 interactions with Tat by an average of 1.7-fold, but also completely blocked CDK9 association with BRD4. The phosphomimetic S175D mutation modestly enhanced Tat association with CDK9 while causing a 2-fold disruption in BRD4 association with CDK9. Since BRD4 is unable to compete for binding to CDK9 carrying S175A, expression of CDK9 carrying the S175A mutation in latently infected cells resulted in a robust Tat dependent reactivation of the provirus. Similarly, the stable knockdown of BRD4 led to a strong enhancement of proviral expression. Immunoprecipitation experiments show that CDK9 phosphorylated at Ser175 is excluded from the 7SK RNP complex. Immunofluorescence and flow cytometry studies carried out using a phospho-Ser175-specific antibody demonstrated that Ser175 phosphorylation occurs during TCR activation of primary resting memory CD4+ T cells together with upregulation of the Cyclin T1 regulatory subunit of P-TEFb, and Thr186 phosphorylation of CDK9. We conclude that the phosphorylation of CDK9 at Ser175 plays a critical role in altering the competitive binding of Tat and BRD4 to P TEFb and provides an informative molecular marker for the identification of the transcriptionally active form of P-TEFb. PMID- 23658524 TI - Broadly neutralizing antibody PGT121 allosterically modulates CD4 binding via recognition of the HIV-1 gp120 V3 base and multiple surrounding glycans. AB - New broad and potent neutralizing HIV-1 antibodies have recently been described that are largely dependent on the gp120 N332 glycan for Env recognition. Members of the PGT121 family of antibodies, isolated from an African donor, neutralize ~70% of circulating isolates with a median IC50 less than 0.05 ug ml(-1). Here, we show that three family members, PGT121, PGT122 and PGT123, have very similar crystal structures. A long 24-residue HCDR3 divides the antibody binding site into two functional surfaces, consisting of an open face, formed by the heavy chain CDRs, and an elongated face, formed by LCDR1, LCDR3 and the tip of the HCDR3. Alanine scanning mutagenesis of the antibody paratope reveals a crucial role in neutralization for residues on the elongated face, whereas the open face, which accommodates a complex biantennary glycan in the PGT121 structure, appears to play a more secondary role. Negative-stain EM reconstructions of an engineered recombinant Env gp140 trimer (SOSIP.664) reveal that PGT122 interacts with the gp120 outer domain at a more vertical angle with respect to the top surface of the spike than the previously characterized antibody PGT128, which is also dependent on the N332 glycan. We then used ITC and FACS to demonstrate that the PGT121 antibodies inhibit CD4 binding to gp120 despite the epitope being distal from the CD4 binding site. Together, these structural, functional and biophysical results suggest that the PGT121 antibodies may interfere with Env receptor engagement by an allosteric mechanism in which key structural elements, such as the V3 base, the N332 oligomannose glycan and surrounding glycans, including a putative V1/V2 complex biantennary glycan, are conformationally constrained. PMID- 23658525 TI - Yersinia pestis DNA from skeletal remains from the 6(th) century AD reveals insights into Justinianic Plague. AB - Yersinia pestis, the etiologic agent of the disease plague, has been implicated in three historical pandemics. These include the third pandemic of the 19(th) and 20(th) centuries, during which plague was spread around the world, and the second pandemic of the 14(th)-17(th) centuries, which included the infamous epidemic known as the Black Death. Previous studies have confirmed that Y. pestis caused these two more recent pandemics. However, a highly spirited debate still continues as to whether Y. pestis caused the so-called Justinianic Plague of the 6(th)-8(th) centuries AD. By analyzing ancient DNA in two independent ancient DNA laboratories, we confirmed unambiguously the presence of Y. pestis DNA in human skeletal remains from an Early Medieval cemetery. In addition, we narrowed the phylogenetic position of the responsible strain down to major branch 0 on the Y. pestis phylogeny, specifically between nodes N03 and N05. Our findings confirm that Y. pestis was responsible for the Justinianic Plague, which should end the controversy regarding the etiology of this pandemic. The first genotype of a Y. pestis strain that caused the Late Antique plague provides important information about the history of the plague bacillus and suggests that the first pandemic also originated in Asia, similar to the other two plague pandemics. PMID- 23658526 TI - hepatitis c Virus p7 is critical for capsid assembly and envelopment. AB - Hepatitis C virus (HCV) p7 is a membrane-associated ion channel protein crucial for virus production. To analyze how p7 contributes to this process, we dissected HCV morphogenesis into sub-steps including recruitment of HCV core to lipid droplets (LD), virus capsid assembly, unloading of core protein from LDs and subsequent membrane envelopment of capsids. Interestingly, we observed accumulation of slowly sedimenting capsid-like structures lacking the viral envelope in cells transfected with HCV p7 mutant genomes which possess a defect in virion production. Concomitantly, core protein was enriched at the surface of LDs. This indicates a defect in core/capsid unloading from LDs and subsequent membrane envelopment rather than defective trafficking of core to this cellular organelle. Protease and ribonuclease digestion protection assays, rate zonal centrifugation and native, two dimensional gel electrophoresis revealed increased amounts of high-order, non-enveloped core protein complexes unable to protect viral RNA in cells transfected with p7 mutant genomes. These results suggest accumulation of capsid assembly intermediates that had not yet completely incorporated viral RNA in the absence of functional p7. Thus, functional p7 is necessary for the final steps of capsid assembly as well as for capsid envelopment. These results support a model where capsid assembly is linked with membrane envelopment of nascent RNA-containing core protein multimers, a process coordinated by p7. In summary, we provide novel insights into the sequence of HCV assembly events and essential functions of p7. PMID- 23658527 TI - Wnt signaling regulates the lineage differentiation potential of mouse embryonic stem cells through Tcf3 down-regulation. AB - Canonical Wnt signaling plays a rate-limiting role in regulating self-renewal and differentiation in mouse embryonic stem cells (ESCs). We have previously shown that mutation in the Apc (adenomatous polyposis coli) tumor suppressor gene constitutively activates Wnt signaling in ESCs and inhibits their capacity to differentiate towards ecto-, meso-, and endodermal lineages. However, the underlying molecular and cellular mechanisms through which Wnt regulates lineage differentiation in mouse ESCs remain to date largely unknown. To this aim, we have derived and studied the gene expression profiles of several Apc-mutant ESC lines encoding for different levels of Wnt signaling activation. We found that down-regulation of Tcf3, a member of the Tcf/Lef family and a key player in the control of self-renewal and pluripotency, represents a specific and primary response to Wnt activation in ESCs. Accordingly, rescuing Tcf3 expression partially restored the neural defects observed in Apc-mutant ESCs, suggesting that Tcf3 down-regulation is a necessary step towards Wnt-mediated suppression of neural differentiation. We found that Tcf3 down-regulation in the context of constitutively active Wnt signaling does not result from promoter DNA methylation but is likely to be caused by a plethora of mechanisms at both the RNA and protein level as shown by the observed decrease in activating histone marks (H3K4me3 and H3-acetylation) and the upregulation of miR-211, a novel Wnt regulated microRNA that targets Tcf3 and attenuates early neural differentiation in mouse ESCs. Our data show for the first time that Wnt signaling down-regulates Tcf3 expression, possibly at both the transcriptional and post-transcriptional levels, and thus highlight a novel mechanism through which Wnt signaling inhibits neuro-ectodermal lineage differentiation in mouse embryonic stem cells. PMID- 23658528 TI - Neuropeptides function in a homeostatic manner to modulate excitation-inhibition imbalance in C. elegans. AB - Neuropeptides play crucial roles in modulating neuronal networks, including changing intrinsic properties of neurons and synaptic efficacy. We previously reported a Caenorhabditis elegans mutant, acr-2(gf), that displays spontaneous convulsions as the result of a gain-of-function mutation in a neuronal nicotinic acetylcholine receptor subunit. The ACR-2 channel is expressed in the cholinergic motor neurons, and acr-2(gf) causes cholinergic overexcitation accompanied by reduced GABAergic inhibition in the locomotor circuit. Here we show that neuropeptides play a homeostatic role that compensates for this excitation inhibition imbalance in the locomotor circuit. Loss of function in genes required for neuropeptide processing or release of dense core vesicles specifically modulate the convulsion frequency of acr-2(gf). The proprotein convertase EGL-3 is required in the cholinergic motor neurons to restrain convulsions. Electrophysiological recordings of neuromuscular junctions show that loss of egl 3 in acr-2(gf) causes a further reduction of GABAergic inhibition. We identify two neuropeptide encoding genes, flp-1 and flp-18, that together counteract the excitation-inhibition imbalance in acr-2(gf) mutants. We further find that acr 2(gf) causes an increased expression of flp-18 in the ventral cord cholinergic motor neurons and that overexpression of flp-18 reduces the convulsion of acr 2(gf) mutants. The effects of these peptides are in part mediated by two G protein coupled receptors, NPR-1 and NPR-5. Our data suggest that the chronic overexcitation of the cholinergic motor neurons imposed by acr-2(gf) leads to an increased production of FMRFamide neuropeptides, which act to decrease the activity level of the locomotor circuit, thereby homeostatically modulating the excitation and inhibition imbalance. PMID- 23658529 TI - A compendium of nucleosome and transcript profiles reveals determinants of chromatin architecture and transcription. AB - Nucleosomes in all eukaryotes examined to date adopt a characteristic architecture within genes and play fundamental roles in regulating transcription, yet the identity and precise roles of many of the trans-acting factors responsible for the establishment and maintenance of this organization remain to be identified. We profiled a compendium of 50 yeast strains carrying conditional alleles or complete deletions of genes involved in transcriptional regulation, histone biology, and chromatin remodeling, as well as compounds that target transcription and histone deacetylases, to assess their respective roles in nucleosome positioning and transcription. We find that nucleosome patterning in genes is affected by many factors, including the CAF-1 complex, Spt10, and Spt21, in addition to previously reported remodeler ATPases and histone chaperones. Disruption of these factors or reductions in histone levels led genic nucleosomes to assume positions more consistent with their intrinsic sequence preferences, with pronounced and specific shifts of the +1 nucleosome relative to the transcription start site. These shifts of +1 nucleosomes appear to have functional consequences, as several affected genes in Ino80 mutants exhibited altered expression responses. Our parallel expression profiling compendium revealed extensive transcription changes in intergenic and antisense regions, most of which occur in regions with altered nucleosome occupancy and positioning. We show that the nucleosome-excluding transcription factors Reb1, Abf1, Tbf1, and Rsc3 suppress cryptic transcripts at their target promoters, while a combined analysis of nucleosome and expression profiles identified 36 novel transcripts that are normally repressed by Tup1/Cyc8. Our data confirm and extend the roles of chromatin remodelers and chaperones as major determinants of genic nucleosome positioning, and these data provide a valuable resource for future studies. PMID- 23658530 TI - Female bias in Rhox6 and 9 regulation by the histone demethylase KDM6A. AB - The Rhox cluster on the mouse X chromosome contains reproduction-related homeobox genes expressed in a sexually dimorphic manner. We report that two members of the Rhox cluster, Rhox6 and 9, are regulated by de-methylation of histone H3 at lysine 27 by KDM6A, a histone demethylase with female-biased expression. Consistent with other homeobox genes, Rhox6 and 9 are in bivalent domains prior to embryonic stem cell differentiation and thus poised for activation. In female mouse ES cells, KDM6A is specifically recruited to Rhox6 and 9 for gene activation, a process inhibited by Kdm6a knockdown in a dose-dependent manner. In contrast, KDM6A occupancy at Rhox6 and 9 is low in male ES cells and knockdown has no effect on expression. In mouse ovary where Rhox6 and 9 remain highly expressed, KDM6A occupancy strongly correlates with expression. Our study implicates Kdm6a, a gene that escapes X inactivation, in the regulation of genes important in reproduction, suggesting that KDM6A may play a role in the etiology of developmental and reproduction-related effects of X chromosome anomalies. PMID- 23658531 TI - Attachment site selection and identity in Bxb1 serine integrase-mediated site specific recombination. AB - Phage-encoded serine integrases mediate directionally regulated site-specific recombination between short attP and attB DNA sites without host factor requirements. These features make them attractive for genome engineering and synthetic genetics, although the basis for DNA site selection is poorly understood. Here we show that attP selection is determined through multiple proofreading steps that reject non-attP substrates, and that discrimination of attP and attB involves two critical site features: the outermost 5-6 base pairs of attP that are required for Int binding and recombination but antagonize attB function, and the "discriminators" at positions -15/+15 that determine attB identity but also antagonize attP function. Thus, although the attachment sites differ in length and sequence, only two base changes are needed to convert attP to attL, and just two more from attL to attB. The opposing effect of site identifiers ensures that site schizophrenia with dual identities does not occur. PMID- 23658532 TI - Chromosomal organization and segregation in Pseudomonas aeruginosa. AB - The study of chromosomal organization and segregation in a handful of bacteria has revealed surprising variety in the mechanisms mediating such fundamental processes. In this study, we further emphasized this diversity by revealing an original organization of the Pseudomonas aeruginosa chromosome. We analyzed the localization of 20 chromosomal markers and several components of the replication machinery in this important opportunistic gamma-proteobacteria pathogen. This technique allowed us to show that the 6.3 Mb unique circular chromosome of P. aeruginosa is globally oriented from the old pole of the cell to the division plane/new pole along the oriC-dif axis. The replication machinery is positioned at mid-cell, and the chromosomal loci from oriC to dif are moved sequentially to mid-cell prior to replication. The two chromosomal copies are subsequently segregated at their final subcellular destination in the two halves of the cell. We identified two regions in which markers localize at similar positions, suggesting a bias in the distribution of chromosomal regions in the cell. The first region encompasses 1.4 Mb surrounding oriC, where loci are positioned around the 0.2/0.8 relative cell length upon segregation. The second region contains at least 800 kb surrounding dif, where loci show an extensive colocalization step following replication. We also showed that disrupting the ParABS system is very detrimental in P. aeruginosa. Possible mechanisms responsible for the coordinated chromosomal segregation process and for the presence of large distinctive regions are discussed. PMID- 23658533 TI - Distinct translational control in CD4+ T cell subsets. AB - Regulatory T cells expressing the transcription factor Foxp3 play indispensable roles for the induction and maintenance of immunological self-tolerance and immune homeostasis. Genome-wide mRNA expression studies have defined canonical signatures of T cell subsets. Changes in steady-state mRNA levels, however, often do not reflect those of corresponding proteins due to post-transcriptional mechanisms including mRNA translation. Here, we unveil a unique translational signature, contrasting CD4(+)Foxp3(+) regulatory T (T(Foxp3+)) and CD4(+)Foxp3(-) non-regulatory T (TFoxp3-) cells, which imprints subset-specific protein expression. We further show that translation of eukaryotic translation initiation factor 4E (eIF4E) is induced during T cell activation and, in turn, regulates translation of cell cycle related mRNAs and proliferation in both T(Foxp3)- and T(Foxp3+) cells. Unexpectedly, eIF4E also affects Foxp3 expression and thereby lineage identity. Thus, mRNA-specific translational control directs both common and distinct cellular processes in CD4(+) T cell subsets. PMID- 23658534 TI - Diffuse Optical Technology: A Portable and Simple Method for Noninvasive Tissue Pathophysiology. PMID- 23658536 TI - The anterior cingulate cortex: an integrative hub for human socially-driven interactions. PMID- 23658535 TI - Functional mapping of thalamic nuclei and their integration into cortico-striatal thalamo-cortical loops via ultra-high resolution imaging-from animal anatomy to in vivo imaging in humans. AB - The thalamus, a crucial node in the well-described cortico-striatal-thalamo cortical circuits, has been the focus of functional and structural imaging studies investigating human emotion, cognition and memory. Invasive work in animals and post-mortem investigations have revealed the rich cytoarchitectonics and functional specificity of the thalamus. Given current restrictions in the spatial resolution of non-invasive imaging modalities, there is, however, a translational gap between functional and structural information on these circuits in humans and animals as well as between histological and cellular evidence and their relationship to psychological functioning. With the advance of higher field strengths for MR approaches, better spatial resolution is now available promising to overcome this conceptual problem. We here review these two levels, which exist for both neuroscientific and clinical investigations, and then focus on current attempts to overcome conceptual boundaries of these observations with the help of ultra-high resolution imaging. PMID- 23658537 TI - Confocal microscopy for astrocyte in vivo imaging: Recycle and reuse in microscopy. AB - In vivo imaging is one of the ultimate and fundamental approaches for the study of the brain. Two-photon laser scanning microscopy (2PLSM) constitutes the state of-the-art technique in current neuroscience to address questions regarding brain cell structure, development and function, blood flow regulation and metabolism. This technique evolved from laser scanning confocal microscopy (LSCM), which impacted the field with a major improvement in image resolution of live tissues in the 1980s compared to widefield microscopy. While nowadays some of the unparalleled features of 2PLSM make it the tool of choice for brain studies in vivo, such as the possibility to image deep within a tissue, LSCM can still be useful in this matter. Here we discuss the validity and limitations of LSCM and provide a guide to perform high-resolution in vivo imaging of the brain of live rodents with minimal mechanical disruption employing LSCM. We describe the surgical procedure and experimental setup that allowed us to record intracellular calcium variations in astrocytes evoked by sensory stimulation, and to monitor intact neuronal dendritic spines and astrocytic processes as well as blood vessel dynamics. Therefore, in spite of certain limitations that need to be carefully considered, LSCM constitutes a useful, convenient, and affordable tool for brain studies in vivo. PMID- 23658538 TI - The role of automaticity and attention in neural processes underlying empathy for happiness, sadness, and anxiety. AB - Although many studies have examined the neural basis of empathy, relatively little is known about how empathic processes are affected by different attentional conditions. Thus, we examined whether instructions to empathize might amplify responses in empathy-related regions and whether cognitive load would diminish the involvement of these regions. Thirty-two participants completed a functional magnetic resonance imaging session assessing empathic responses to individuals experiencing happy, sad, and anxious events. Stimuli were presented under three conditions: watching naturally, actively empathizing, and under cognitive load. Across analyses, we found evidence for a core set of neural regions that support empathic processes (dorsomedial prefrontal cortex, DMPFC; medial prefrontal cortex, MPFC; temporoparietal junction, TPJ; amygdala; ventral anterior insula, AI; and septal area, SA). Two key regions-the ventral AI and SA were consistently active across all attentional conditions, suggesting that they are automatically engaged during empathy. In addition, watching vs. empathizing with targets was not markedly different and instead led to similar subjective and neural responses to others' emotional experiences. In contrast, cognitive load reduced the subjective experience of empathy and diminished neural responses in several regions related to empathy and social cognition (DMPFC, MPFC, TPJ, and amygdala). The results reveal how attention impacts empathic processes and provides insight into how empathy may unfold in everyday interactions. PMID- 23658539 TI - Is there a semantic system for abstract words? AB - Two views on the semantics of concrete words are that their core mental representations are feature-based or are reconstructions of sensory experience. We argue that neither of these approaches is capable of representing the semantics of abstract words, which involve the representation of possibly hypothetical physical and mental states, the binding of entities within a structure, and the possible use of embedding (or recursion) in such structures. Brain based evidence in the form of dissociations between deficits related to concrete and abstract semantics corroborates the hypothesis. Neuroimaging evidence suggests that left lateral inferior frontal cortex supports those processes responsible for the representation of abstract words. PMID- 23658540 TI - Emotion regulation choice: selecting between cognitive regulation strategies to control emotion. PMID- 23658541 TI - Ipsilateral motor pathways after stroke: implications for non-invasive brain stimulation. AB - In humans the two cerebral hemispheres have essential roles in controlling the upper limb. The purpose of this article is to draw attention to the potential importance of ipsilateral descending pathways for functional recovery after stroke, and the use of non-invasive brain stimulation (NBS) protocols of the contralesional primary motor cortex (M1). Conventionally NBS is used to suppress contralesional M1, and to attenuate transcallosal inhibition onto the ipsilesional M1. There has been little consideration of the fact that contralesional M1 suppression may also reduce excitability of ipsilateral descending pathways that may be important for paretic upper limb control for some patients. One such ipsilateral pathway is the cortico-reticulo-propriospinal pathway (CRPP). In this review we outline a neurophysiological model to explain how contralesional M1 may gain control of the paretic arm via the CRPP. We conclude that the relative importance of the CRPP for motor control in individual patients must be considered before using NBS to suppress contralesional M1. Neurophysiological, neuroimaging, and clinical assessments can assist this decision making and facilitate the translation of NBS into the clinical setting. PMID- 23658542 TI - Detecting global form: separate processes required for Glass and radial frequency patterns. AB - Global processing of form information has been studied extensively using both Glass and radial frequency (RF) patterns. Models, with common early stages, have been proposed for the detection of properties of both pattern types but human performance has not been examined to determine whether the two pattern types interact in the manner this would suggest. The experiments here investigated whether low RF patterns and concentric Glass patterns, which are thought to tap the same level of processing in form-vision, are detected by a common mechanism. Six observers participated in two series of masking experiments. First: sensitivity to the presence of either coherent structure, or contour deformation, was assessed. The computational model predicted that detection of one pattern would be masked by the other. Second: a further experiment examined position coding. The model predicted that localizing the center of form in a Glass pattern would be affected by the presence of an RF pattern: sensitivity to a change of location should be reduced and the apparent location should be drawn toward the center of the masking pattern. However, the results observed in all experiments were inconsistent with the interaction predicted by the models, suggesting that separate neural mechanisms for global processing of signal are required to process these two patterns, and also indicating that the models need to be altered to preclude the interactions that were predicted but not obtained. PMID- 23658543 TI - Nonlinear multiplicative dendritic integration in neuron and network models. AB - Neurons receive inputs from thousands of synapses distributed across dendritic trees of complex morphology. It is known that dendritic integration of excitatory and inhibitory synapses can be highly non-linear in reality and can heavily depend on the exact location and spatial arrangement of inhibitory and excitatory synapses on the dendrite. Despite this known fact, most neuron models used in artificial neural networks today still only describe the voltage potential of a single somatic compartment and assume a simple linear summation of all individual synaptic inputs. We here suggest a new biophysical motivated derivation of a single compartment model that integrates the non-linear effects of shunting inhibition, where an inhibitory input on the route of an excitatory input to the soma cancels or "shunts" the excitatory potential. In particular, our integration of non-linear dendritic processing into the neuron model follows a simple multiplicative rule, suggested recently by experiments, and allows for strict mathematical treatment of network effects. Using our new formulation, we further devised a spiking network model where inhibitory neurons act as global shunting gates, and show that the network exhibits persistent activity in a low firing regime. PMID- 23658544 TI - RipleyGUI: software for analyzing spatial patterns in 3D cell distributions. AB - The true revolution in the age of digital neuroanatomy is the ability to extensively quantify anatomical structures and thus investigate structure function relationships in great detail. To facilitate the quantification of neuronal cell patterns we have developed RipleyGUI, a MATLAB-based software that can be used to detect patterns in the 3D distribution of cells. RipleyGUI uses Ripley's K-function to analyze spatial distributions. In addition the software contains statistical tools to determine quantitative statistical differences, and tools for spatial transformations that are useful for analyzing non-stationary point patterns. The software has a graphical user interface making it easy to use without programming experience, and an extensive user manual explaining the basic concepts underlying the different statistical tools used to analyze spatial point patterns. The described analysis tool can be used for determining the spatial organization of neurons that is important for a detailed study of structure function relationships. For example, neocortex that can be subdivided into six layers based on cell density and cell types can also be analyzed in terms of organizational principles distinguishing the layers. PMID- 23658545 TI - Fractal analyses: statistical and methodological innovations and best practices. PMID- 23658546 TI - Echolocation may have real-life advantages for blind people: an analysis of survey data. AB - Some people can echolocate by making sonar emissions (e.g., mouth-clicks, finger snaps, feet shuffling, humming, cane tapping, etc.) and listening to the returning echoes. To date there are no statistics available about how many blind people use echolocation, but anecdotal reports in the literature suggest that perhaps between 20 and 30% of totally blind people may use it, suggesting that echolocation affords broad functional benefits. Consistent with the notion that blind individuals benefit from the use of echolocation, previous research conducted under controlled experimental conditions has shown that echolocation improves blind people's spatial sensing ability. The current study investigated if there is also evidence for functional benefits of echolocation in real life. To address this question the current study conducted an online survey. Thirty seven blind people participated. Linear regression analyses of survey data revealed that, while statistically controlling for participants' gender, age, level of visual function, general health, employment status, level of education, Braille skill, and use of other mobility means, people who use echolocation have higher salary, and higher mobility in unfamiliar places, than people who do not use echolocation. The majority of our participants (34 out of 37) use the long cane, and all participants who reported to echolocate, also reported to use the long cane. This suggests that the benefit of echolocation that we found might be conditional upon the long cane being used as well. The investigation was correlational in nature, and thus cannot be used to determine causality. In addition, the sample was small (N = 37), and one should be cautious when generalizing the current results to the population. The data, however, are consistent with the idea that echolocation offers real-life advantages for blind people, and that echolocation may be involved in peoples' successful adaptation to vision loss. PMID- 23658547 TI - Reach-to-grasp movements in Macaca fascicularis monkeys: the Isochrony Principle at work. AB - Humans show a spontaneous tendency to increase the velocity of their movements depending on the linear extent of their trajectory in order to keep execution time approximately constant. Termed the isochrony principle, this compensatory mechanism refers to the observation that the velocity of voluntary movements increases proportionally with their linear extension. Although there is a wealth of psychophysical data regarding isochrony in humans, there is none regarding non human primates. The present study attempts to fill that gap by investigating reach-to-grasp movement kinematics in free-ranging macaques. Video footage of monkeys grasping objects located at different distances was analyzed frame-by frame using digitalization techniques. The amplitude of arm peak velocity was found to be correlated with the distance to be covered, and total movement duration remained invariant although target distances varied. Like in humans, the "isochrony principle" seems to be operative as there is a gearing down/up of movement velocity that is proportional to the distance to be covered in order to allow for a relatively constant movement duration. Based on a centrally generated temporal template, this mode of motor programming could be functional in macaques given the high speed and great instability of posture and joint kinematics characterizing their actions. The data presented here take research in the field of comparative motor control a step forward as they are based on precise measurements of spontaneous grasping movements by animals living/acting in their natural environment. PMID- 23658548 TI - The temporal priority principle: at what age does this develop? AB - The temporal priority principle states that all causes must precede their effects. It is widely assumed that children's causal reasoning is guided by this principle from early in development. However, the empirical studies that have examined children's use of the principle, most of which were conducted some decades ago, in fact show inconsistent findings. Some researchers have argued that 3-year-olds reliably use this principle, whereas others have suggested that it is not until 5 years that children properly grasp the inviolability of the principle. To examine this issue, 100 children, 50 three-year-olds, and 50 four year-olds, took part in a study in which they had to judge which of two causes yielded an effect. In the task, children saw one event (A), an effect (E), and then another event (B). The events A and B involved the rolling of balls down runways, and the effect E was a Jack-in-a-box popping up. The extent to which E left a visible trace was also varied, because comparisons across previous studies suggested that this may affect performance. As a group, 3- and 4-year-olds performed at above-chance levels, but performance improved with age. The nature of the effect did not have a significant impact on performance. Although some previous studies suggested that 3-year-olds may be more likely to choose B rather than A as a cause due to a recency effect, we found no evidence of this pattern of performance in the younger group. Potential explanations of the age-related improvement in performance are discussed. PMID- 23658549 TI - Audio-Visual Temporal Recalibration Can be Constrained by Content Cues Regardless of Spatial Overlap. AB - It has now been well established that the point of subjective synchrony for audio and visual events can be shifted following exposure to asynchronous audio-visual presentations, an effect often referred to as temporal recalibration. Recently it was further demonstrated that it is possible to concurrently maintain two such recalibrated estimates of audio-visual temporal synchrony. However, it remains unclear precisely what defines a given audio-visual pair such that it is possible to maintain a temporal relationship distinct from other pairs. It has been suggested that spatial separation of the different audio-visual pairs is necessary to achieve multiple distinct audio-visual synchrony estimates. Here we investigated if this is necessarily true. Specifically, we examined whether it is possible to obtain two distinct temporal recalibrations for stimuli that differed only in featural content. Using both complex (audio visual speech; see Experiment 1) and simple stimuli (high and low pitch audio matched with either vertically or horizontally oriented Gabors; see Experiment 2) we found concurrent, and opposite, recalibrations despite there being no spatial difference in presentation location at any point throughout the experiment. This result supports the notion that the content of an audio-visual pair alone can be used to constrain distinct audio-visual synchrony estimates regardless of spatial overlap. PMID- 23658550 TI - All P's or mixed vegetables? PMID- 23658551 TI - Do personality traits predict individual differences in excitatory and inhibitory learning? AB - Conditioned inhibition (CI) is demonstrated in classical conditioning when a stimulus is used to signal the omission of an otherwise expected outcome. This basic learning ability is involved in a wide range of normal behavior - and thus its disruption could produce a correspondingly wide range of behavioral deficits. The present study employed a computer-based task to measure conditioned excitation and inhibition in the same discrimination procedure. CI by summation test was clearly demonstrated. Additionally summary measures of excitatory and inhibitory learning (difference scores) were calculated in order to explore how performance related to individual differences in a large sample of normal participants (n = 176 following exclusion of those not meeting the basic learning criterion). The individual difference measures selected derive from two biologically based personality theories, Gray's (1982) reinforcement sensitivity theory and Eysenck and Eysenck (1991) psychoticism, extraversion, and neuroticism theory. Following the behavioral tasks, participants completed the behavioral inhibition system/behavioral activation system (BIS/BAS) scales and the Eysenck personality questionnaire revised short scale (EPQ-RS). Analyses of the relationship between scores on each of the scales and summary measures of excitatory and inhibitory learning suggested that those with higher BAS (specifically the drive sub-scale) and higher EPQ-RS neuroticism showed reduced levels of excitatory conditioning. Inhibitory conditioning was similarly attenuated in those with higher EPQ-RS neuroticism, as well as in those with higher BIS scores. Thus the findings are consistent with higher levels of neuroticism being accompanied by generally impaired associative learning, both inhibitory and excitatory. There was also evidence for some dissociation in the effects of behavioral activation and behavioral inhibition on excitatory and inhibitory learning respectively. PMID- 23658552 TI - The scope of usage-based theory. AB - Usage-based approaches typically draw on a relatively small set of cognitive processes, such as categorization, analogy, and chunking to explain language structure and function. The goal of this paper is to first review the extent to which the "cognitive commitment" of usage-based theory has had success in explaining empirical findings across domains, including language acquisition, processing, and typology. We then look at the overall strengths and weaknesses of usage-based theory and highlight where there are significant debates. Finally, we draw special attention to a set of culturally generated structural patterns that seem to lie beyond the explanation of core usage-based cognitive processes. In this context we draw a distinction between cognition permitting language structure vs. cognition entailing language structure. As well as addressing the need for greater clarity on the mechanisms of generalizations and the fundamental units of grammar, we suggest that integrating culturally generated structures within existing cognitive models of use will generate tighter predictions about how language works. PMID- 23658554 TI - The Three-Species Consortium of Genetically Improved Strains Cupriavidus necator RW112, Burkholderia xenovorans RW118, and Pseudomonas pseudoalcaligenes RW120 Grows with Technical Polychlorobiphenyl, Aroclor 1242. AB - Burkholderia xenovorans LB400, Cupriavidus necator H850, and Pseudomonas pseudoalcaligenes KF707 are bacterial strains able to mineralize biphenyl and to co-oxidize many of its halogenated derivatives (PCBs). Only strain LB400 also mineralizes a few mono- and dichlorobiphenyls, due to the presence of a functioning chlorocatechol pathway. Here, we used a Tn5-based minitransposon shuttle system to chromosomically introduce genes tcbRCDEF, encoding the chlorocatechol pathway into KF707, and genes cbdABC encoding a 2-chlorobenzoate 1,2-dioxygenase into KF707 and LB400, as well as transposon Tn4653 from the TOL plasmid, providing genes xylXYZL, encoding a broad-range toluate (methylbenzoate) dioxygenase and its dihydrodiol dehydrogenase, to extend the range for the mineralization of halogenated benzoates in LB400 and in KF707 through co oxidation of halobenzoates into chlorocatechols. The engineered derivatives of LB400 and KF707 thus gained the ability for the mineralization of all isomeric monochloro- and bromobenzoates of the so-called lower pathway which, consequently, also allowed the mineralization of all monochlorobiphenyls and a number of di- and trichlorobiphenyls, thus preventing the accumulation of halobenzoates and of catabolites thereof. LB400 and KF707 also grow with the two commercial PCB formulations, Aroclor 1221 and Aroclor 1232, as the sole carbon and energy sources, but not with higher halogenated PCB mixtures, similar to the already published strain RW112. Repeated exposition of the modified LB400 to short pulses of UV light, over a prolonged period of time, allowed the isolation of a derivative of LB400, termed RW118, capable of growth with Aroclor 1016 still containing only traces of biphenyl, and in co-culture with modified KF707 termed RW120, and modified H850 (RW112) with Aroclor 1242, the commercial mixture already void of biphenyl and monochlorobiphenyls. PMID- 23658555 TI - The pH and pCO2 dependence of sulfate reduction in shallow-sea hydrothermal CO2 - venting sediments (Milos Island, Greece). AB - Microbial sulfate reduction (SR) is a dominant process of organic matter mineralization in sulfate-rich anoxic environments at neutral pH. Recent studies have demonstrated SR in low pH environments, but investigations on the microbial activity at variable pH and CO2 partial pressure are still lacking. In this study, the effect of pH and pCO2 on microbial activity was investigated by incubation experiments with radioactive (35)S targeting SR in sediments from the shallow-sea hydrothermal vent system of Milos, Greece, where pH is naturally decreased by CO2 release. Sediments differed in their physicochemical characteristics with distance from the main site of fluid discharge. Adjacent to the vent site (T ~40-75 degrees C, pH ~5), maximal sulfate reduction rates (SRR) were observed between pH 5 and 6. SR in hydrothermally influenced sediments decreased at neutral pH. Sediments unaffected by hydrothermal venting (T ~26 degrees C, pH ~8) expressed the highest SRR between pH 6 and 7. Further experiments investigating the effect of pCO2 on SR revealed a steep decrease in activity when the partial pressure increased from 2 to 3 bar. Findings suggest that sulfate reducing microbial communities associated with hydrothermal vent system are adapted to low pH and high CO2, while communities at control sites required a higher pH for optimal activity. PMID- 23658553 TI - Alterations in polyadenylation and its implications for endocrine disease. AB - INTRODUCTION: Polyadenylation is the process in which the pre-mRNA is cleaved at the poly(A) site and a poly(A) tail is added - a process necessary for normal mRNA formation. Genes with multiple poly(A) sites can undergo alternative polyadenylation (APA), producing distinct mRNA isoforms with different 3' untranslated regions (3' UTRs) and in some cases different coding regions. Two thirds of all human genes undergo APA. The efficiency of the polyadenylation process regulates gene expression and APA plays an important part in post transcriptional regulation, as the 3' UTR contains various cis-elements associated with post-transcriptional regulation, such as target sites for micro RNAs and RNA-binding proteins. Implications of alterations in polyadenylation for endocrine disease: Alterations in polyadenylation have been found to be causative of neonatal diabetes and IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) and to be associated with type I and II diabetes, pre eclampsia, fragile X-associated premature ovarian insufficiency, ectopic Cushing syndrome, and many cancer diseases, including several types of endocrine tumor diseases. PERSPECTIVES: Recent developments in high-throughput sequencing have made it possible to characterize polyadenylation genome-wide. Antisense elements inhibiting or enhancing specific poly(A) site usage can induce desired alterations in polyadenylation, and thus hold the promise of new therapeutic approaches. SUMMARY: This review gives a detailed description of alterations in polyadenylation in endocrine disease, an overview of the current literature on polyadenylation and summarizes the clinical implications of the current state of research in this field. PMID- 23658556 TI - Finding Missing Interactions of the Arabidopsis thaliana Root Stem Cell Niche Gene Regulatory Network. AB - Over the last few decades, the Arabidopsis thaliana root stem cell niche (RSCN) has become a model system for the study of plant development and stem cell niche dynamics. Currently, many of the molecular mechanisms involved in RSCN maintenance and development have been described. A few years ago, we published a gene regulatory network (GRN) model integrating this information. This model suggested that there were missing components or interactions. Upon updating the model, the observed stable gene configurations of the RSCN could not be recovered, indicating that there are additional missing components or interactions in the model. In fact, due to the lack of experimental data, GRNs inferred from published data are usually incomplete. However, predicting the location and nature of the missing data is a not trivial task. Here, we propose a set of procedures for detecting and predicting missing interactions in Boolean networks. We used these procedures to predict putative missing interactions in the A. thaliana RSCN network model. Using our approach, we identified three necessary interactions to recover the reported gene activation configurations that have been experimentally uncovered for the different cell types within the RSCN: (1) a regulation of PHABULOSA to restrict its expression domain to the vascular cells, (2) a self-regulation of WOX5, possibly by an indirect mechanism through the auxin signaling pathway, and (3) a positive regulation of JACKDAW by MAGPIE. The procedures proposed here greatly reduce the number of possible Boolean functions that are biologically meaningful and experimentally testable and that do not contradict previous data. We believe that these procedures can be used on any Boolean network. However, because the procedures were designed for the specific case of the RSCN, formal demonstrations of the procedures should be shown in future efforts. PMID- 23658557 TI - Current overview of S-nitrosoglutathione (GSNO) in higher plants. PMID- 23658558 TI - Genome-wide association study of personality traits in the long life family study. AB - Personality traits have been shown to be associated with longevity and healthy aging. In order to discover novel genetic modifiers associated with personality traits as related with longevity, we performed a genome-wide association study (GWAS) on personality factors assessed by NEO-five-factor inventory in individuals enrolled in the Long Life Family Study (LLFS), a study of 583 families (N up to 4595) with clustering for longevity in the United States and Denmark. Three SNPs, in almost perfect LD, associated with agreeableness reached genome-wide significance (p < 10(-8)) and replicated in an additional sample of 1279 LLFS subjects, although one (rs9650241) failed to replicate and the other two were not available in two independent replication cohorts, the Baltimore Longitudinal Study of Aging and the New England Centenarian Study. Based on 10,000,000 permutations, the empirical p-value of 2 * 10(-7) was observed for the genome-wide significant SNPs. Seventeen SNPs that reached marginal statistical significance in the two previous GWASs (p-value <10(-4) and 10(-5)), were also marginally significantly associated in this study (p-value <0.05), although none of the associations passed the Bonferroni correction. In addition, we tested age by-SNP interactions and found some significant associations. Since scores of personality traits in LLFS subjects change in the oldest ages, and genetic factors outweigh environmental factors to achieve extreme ages, these age-by-SNP interactions could be a proxy for complex gene-gene interactions affecting personality traits and longevity. PMID- 23658559 TI - Comparison of responses of human melanoma cell lines to MEK and BRAF inhibitors. AB - The NRAS and BRAF genes are frequently mutated in melanoma, suggesting that the NRAS-BRAF-MEK-ERK signaling pathway is an important target for therapy. Two classes of drugs, one targeting activated BRAF and one targeting MEK, are currently undergoing clinical evaluation. We have analysed the NRAS and BRAF mutational status of a series of 44 early passage lines developed from New Zealand patients with metastatic melanoma. 41% of the lines analysed had BRAF mutations, 23% had NRAS mutations, and 36% had neither. We then determined IC50 values (drug concentrations for 50% growth inhibition) for CI-1040, a commonly used inhibitor of MEK kinase; trametinib, a clinical agent targeting MEK kinase; and vemurafenib, an inhibitor of mutant BRAF kinase. Cell lines with activating BRAF mutations were significantly more sensitive to vemurafenib than lines with NRAS mutations or lines lacking either mutation (p < 0.001). IC50 values for CI 1040 and trametinib were strongly correlated (r = 0.98) with trametinib showing ~100-fold greater potency. Cell lines sensitive to vemurafenib were also sensitive to CI-1040 and trametinib, but there was no relationship between IC50 values and NRAS mutation status. A small number of lines lacking a BRAF mutation were sensitive to CI-1040 but resistant to vemurafenib. We used western blotting to investigate the effect on ERK phosphorylation of CI-1040 in four lines, of vemurafenib in two lines and of trametinib in two lines. The results support the view that MEK inhibitors might be combined with BRAF inhibitors in the treatment of melanomas with activated BRAF. The high sensitivity to trametinib of some lines with wildtype BRAF status also suggests that MEK inhibitors could have a therapeutic effect against some melanomas as single agents. PMID- 23658560 TI - Functional polymorphisms of xenobiotics metabolizing enzymes-a research topic. PMID- 23658561 TI - Effects of aerobic exercise and drug therapy on blood pressure and antihypertensive drugs: a randomized controlled trial. AB - BACKGROUND: Although aerobic exercise has been shown to lower blood pressure (BP) in human beings, its additive BP-reducing effect on antihypertensive drug therapy seems to have been investigated in only laboratory animals. OBJECTIVES: This study investigated the effects of aerobic dance combined with antihypertensive drugs on BP and number of antihypertensive drugs in individuals with hypertension. METHODS: This open label randomised-controlled trial involved new diagnosed male and female individuals with mild-to-moderate essential hypertension after at least four weeks of treatment. They were randomly assigned to drug therapy (Normoretic: Hydrochlorothiazide + amiloride hydrochloride, and Amlodipine) (control: n=33) and aerobic dance combined with drug therapy (exercise: n=30) groups. Intervention in each group lasted 12 weeks. BP was measured at baseline and during and pos-intervention. Number of antihypertensive drugs was recorded post-intervention. RESULTS: There were significant reductions in SBP at some periods of the intervention in the exercise group (p=0.000 to 0.002) and control group (p=0.001 to 0.002), and significant difference in DBP at some periods of the intervention in exercise group (p=0.000 to 0.003) and control group (p=0.000 to 0.001). SBP (p=0.066) and DBP (p=0.100) did not differ between the two groups post-12-week intervention. The BP control rates were similar between the exercises (56.7%) and control (35.5%) groups (p=0.075). Similarly, between-group difference in the number of drugs was not significant (p=0.511). CONCLUSION: This preliminary report demonstrates the tendency of aerobic dance to enhance BP control in individuals on two antihypertensive drugs without BP control. PMID- 23658562 TI - Cardio-respiratory fitness markers among Kenyan university students using a 20m shuttle run test (SRT). AB - AIM: To assess Cardio-respiratory fitness (CF) markers among university students using a 20m shuttle run test (SRT). METHODS: Markers of CF were assessed in 80 males aged 21.4+/-1.8 years, randomly selected from Moi University, Kenya. Assessed at different stages of SRT protocol included heart rate (HR), systolic and diastolic blood pressure (SBP & DBP). VO2max was also determined. Data were analyzed using Stata v10. Comparisons were based on subjects exercise regimes. RESULTS: Subjects with either regular or irregular regimes attained lower HR in 4(th) minute of SRT compared to non-exercise group (174.5+/-11.6 and 172.2+/-10.8 vs 182.8+/-6.8 b/m; p=0.04 and p=0.01 respectively). Lower HRs were maintained among irregularly exercising after 5(th) minute (176.5+/-10.1 vs 186.7+/-6.3 b/m; p=0.02). Regularly exercising subjects obtained lowest DBP at exhaustion compared to irregular and non-exercising (58.58+/-15.0, 62.43+/-12.9 and 64.1+/-8.8 mmhg respectively). VO2maxpredictors included year of study (r=-0.40), age (r=-0.41) and weight (r=-0.23). The regularly exercising had higher VO2max than irregular (p<0.01) and non-exercising (p<0.001). No demonstrable difference in VO2max existed between irregular and non-exercise subjects. CONCLUSION: Exercise regimes should be emphasized amongst university students, albeit with less regard to regularity, which should be encouraged for those in higher study years and those with higher DBP at exhaustion. PMID- 23658563 TI - Physical activity and health promotion strategies among physiotherapists in Rwanda. AB - BACKGROUND: Physical inactivity has become a global health concern and is among the 10 leading causes of death and disability. Physiotherapists are in a position to combat inactivity and effectively promote physical activity to their clients. OBJECTIVES: To establish the relationship between physical activity levels of physiotherapists and their physical activity promotion strategies. METHODS: A sequential mixed method design was used by means of a self-administered questionnaire (n=92) and a focus group discussion comprising of 10 purposively selected physiotherapists. Descriptive statistics were employed to summarize demographic information. Inferential statistics was used to test the associations between different categorical variables (p<0.05). Tape recorded interviews were transcribed. Thematic analysis was then done. RESULTS: The findings revealed that 64% of the participants were physically active both within the work and recreation domains and 65% of the participants had good physical activity promoting practices. Discussing physical activity and giving out information regarding physical activity were most common methods used in promotion of physical activity. Policies on physical activity, cultural influence, and nature of work, time management as well as the environment were the barriers highlighted. CONCLUSION: Although physiotherapists experience barriers to promoting physical activity, they have good physical activity promoting practices. PMID- 23658564 TI - Perceived and experienced restrictions in participation and autonomy among adult survivors of stroke in Ghana. AB - BACKGROUND: Many stroke survivors do not participate in everyday life activities. OBJECTIVE: To assess the perceived and experienced restrictions in participation and autonomy among adult stroke survivors in Ghana. METHOD: The "Impact on Participation and Autonomy Questionnaire" (IPAQ) instrument was administered in a survey of 200 adult stroke survivors to assess perceived restrictions in participation and autonomy, followed by in-depth interviews with a sub-sample on the restrictions they experienced in participation. RESULTS: Perceived restrictions in participation were most prevalent in the domains of education and training (3.46+/-0.79), paid or voluntary work (2.68+/-0.89), helping and supporting other people (2.20+/-0.82), and mobility (2.12+/-0.79). There were significant differences in two domains between survivors who received physiotherapy and those who received traditional rehabilitation. Over half of the survivors also perceived they would encounter severe problems in participation in the domains of paid or voluntary work, mobility, and education and training. The sub-sample of stroke survivors (n=7) mostly experienced restrictions in participation and autonomy in going outside the house, working, and in fulfilling family roles. CONCLUSION: If these perceptions and experiences are not addressed during rehabilitation, they could further inhibit the full participation and social integration of stroke survivors. PMID- 23658565 TI - Body size and abnormal lipids among adult patients at the Baptist Medical centre, Ogbomoso, Nigeria. AB - BACKGROUND: In many developing countries overweight, obesity and obesity-related morbidity are becoming a problem of increasing importance. Obese individuals are more likely to have elevated total cholesterol, triglycerides, low density lipoprotein (LDL) cholesterol and decreased high density lipoprotein (HDL) cholesterol. OBJECTIVE: To determine the prevalence of obesity using the measure of body mass index (BMI) and abnormal lipid level and the association between obesity and abnormal lipid level among adults in Ogbomoso, Nigeria. METHODS: A cross-sectional descriptive study of 400 adults aged 18 years and above was carried out at the Baptist Medical Centre, Ogbomoso, Nigeria. Participants were administered a standardized questionnaire and had measurements of weight, height and blood lipids taken. RESULTS: Four hundred subjects were randomly selected (221 females and 179 males) with a mean age of 48.65 +/- 16.56 years. The overall prevalence of obesity was 14.75% (8.9% for males and 19.5% for females p<0.05). The female subjects were significantly more sedentary than the males (50.8% for males, 62.4% for females, p<0.05). Most of the subjects who were obese (88.1%) preferred high calorie food. The overall prevalence of abnormal lipid levels was 28.5% (26.8% for males and 29.9% for females). The prevalence of abnormal lipid levels among the subjects who were obese was 40.7%. CONCLUSION: Obesity in this environment is particularly significant among females and is associated with abnormal lipid level. PMID- 23658566 TI - Nutrition status and associated factors among children in public primary schools in Dagoretti, Nairobi, Kenya. AB - BACKGROUND: Malnutrition among school-age children is due to inadequacies in one or more of the three main preconditions for good nutrition: food, care and health. Children stunted at school age are likely to have been exposed to poor nutrition since early childhood. Interventions for school age children can supplement efforts to reduce levels of stunting in the preschool years. OBJECTIVE: To assess the nutrition status and associated risk factors of children in selected public primary schools in Dagoretti Division, Nairobi. METHODS: Descriptive cross sectional design was used. 208 students aged 4-11years of both gender were randomly selected from four public primary schools in Dagoretti Division. Data was collected from school registers and directly questioning the students, parents /guardians. RESULTS: Among the children surveyed, 24.5% were stunted, 14.9% underweight and 9.7% were wasted. There were more boys than girls who were stunted. Breakfast contributed 10.2% of the daily energy intake. Few children consumed foods from more than four food groups. Incidence of diarrhea, colds/coughs increased the risk of stunting and underweight. CONCLUSION: Consumption of food which is inadequate in required calories and from less than four varieties of food groups by the children were important predictors of malnutrition. PMID- 23658567 TI - Seasonal disease activity and serum vitamin D levels in rheumatoid arthritis, ankylosing spondylitis and osteoarthritis. AB - BACKGROUND: Vitamin D is a steroid hormone that plays essential roles in calcium and phosphorus metabolism, bone formation and mineralization homeostasis, also has a role in the maintenance of immune-homeostasis. OBJECTIVE: We aimed to investigate seasonal serum vitamin D levels and seasonal disease activity in patients with Rheumatoid Arthritis, Ankylosing Spondylitis, and Osteoarthritis. METHODS: Seventy-one Rheumatoid Arthritis patients, 72 Ankylosing Spondylitis patients, 74 knee Osteoarthritis patients and 70 healthy controls were recruited for the study. Bi-seasonal measurements of serum 25(OH)D vitamin were checked in either in July or August or September for summertime and either in December or January or February for wintertime. Disease activity were evaluated by Disease Activity Score-28, Bath Ankylosing Spondylitis Disease Activity Index, and Western Ontario and McMaster Universities Osteoarthritis Index in groups of Rheumatoid Arthritis, Ankylosing Spondylitis, and Osteoarthritis respectively. RESULTS: We did not find any correlation between serum 25(OH)D levels and Disease Activity Score-28, Bath Ankylosing Spondylitis Disease Activity Index, and Western Ontario and McMaster Universities Osteoarthritis Index scores in winter and summer. The difference of Disease Activity Score-28 and Western Ontario and McMaster Universities Osteoarthritis Index scores between winter and summer seasons were not significant in Rheumatoid Arthritis and Osteoarthritis patients (p>0.05). The mean Bath Ankylosing Spondylitis Disease Activity Index score was significantly higher in winter than in summer (p<0.05). Consequently we did not find any correlation between variations of seasonal serum 25(OH)D and the disease activity in the patients with Rheumatoid Arthritis, Ankylosing Spondylitis, and Osteoarthritis. CONCLUSION: These results suggest that vitamin D does not have an important role in the seasonal disease activity of these diseases and that seasonal changes in disease activity may play an important role in evaluating Ankylosing Spondylitis patients rather than Rheumatoid Arthritis and Osteoarthritis patients and should be taken into account when examining these patients. These conclusions need to be validated in multicenter studies with high number of patients. PMID- 23658568 TI - High blood pressure in a semi-urban community in south-south Nigeria: a community based study. AB - BACKGROUND: Non communicable diseases (NCDs) are taking their toll in most low and middle income countries; incidentally, in the same populations that are struggling to deal with communicable diseases, hence presenting a picture of "double tragedy". Most of the researches conducted on NCDs are facility-based; often in urban locations. OBJECTIVE: To determine the prevalence of high BP in a semi-urban community in Nigeria. METHODS: It was a cross-sectional study, where all the adult residents of the community were enrolled. Data was collected using a multi-section questionnaire, including anthropometric measurements. Data entry and analysis was done using SPSS 17.0 for windows and STATA 10. RESULTS: The results showed that 47.0% of the study population had a raised BP >=140/90mmHg. At a univariate level, age, sex, higher income, more people in the household, daily cigarette smoking, daily alcohol intake and BMI, showed increased risk for high BP. However, sleeping for at least 8 hours a day showed protective influence against raised BP among the participants. In the adjusted model, only age, sex and BMI remained statistically significant with Odds Ratio (OR) of 1.04 (95%CI; 1.00, 1.08), 0.45 (95%CI; 0.22, 0.90) and 1.08(95%CI; 1.03, 1.13) respectively. The model had an area under curve of 71.9%. CONCLUSION: It was concluded that there is a high prevalence of raised BP in this semi-urban community, thus the need for intervention and preventive services to curb the looming epidemic of hypertension in this community in particular, and Nigeria as a whole, cannot be overemphasized. PMID- 23658569 TI - Non communicable disease and risky behaviour in an urban university community Nigeria. AB - BACKGROUND: Most developing countries have only limited information on the burden of Non Communicable Diseases (NCDs) even though rapid transitions in these NCDs have been predicted. OBJECTIVES: To describe the burden of selected NCDs and associated risk behaviours in an urban university community in Nigeria. METHODS: A cross-sectional survey of 525 representative staff of a University in a large city in Nigeria was conducted. RESULTS: In all, 27.6% were already diagnosed with at least one NCD (hypertension-21.5%, diabetes-11%, cancer 2.9%) while 67.4% reported at least one risk behaviour (unhealthy diet- 96%, sedentary living- 27.4% excessive alcohol use-5.1% and smoking- 1.9%). Multiple risk behaviours were observed in 29.9% with no significant variation by sex or age. Those 40 years and above had significantly higher prevalence of NCD, particularly for hypertension (p<0.05). Only 7%, considered themselves to be at risk of NCDs. Those whose parents had NCDs OR: 5.9 (2.4-14.5) and those who currently had NCDs OR: 3.9(1.8-8.1) perceived themselves at risk of one or more NCDs, but not those with multiple risk behaviours. CONCLUSION: The high burden of NCDs and risk behaviours in the face of limited self-perceived risk has been demonstrated and calls for urgent intervention. PMID- 23658570 TI - Factors associated with depression and suicide among patients with diabetes mellitus and essential hypertension in a Nigerian teaching hospital. AB - BACKGROUND: Diabetes mellitus (DM) and essential hypertension are chronic medical conditions that place a lot of burden on patients. The presence of depression and suicidal behaviour may worsen the prognosis. OBJECTIVE: To assess the prevalence of depression and suicidal behaviour in subjects with diabetes mellitus and essential hypertension and also determine the socio-demographic correlates. METHODS: Major depressive episode and suicidality modules of Mini-International Neuropsychiatric Interview were used to assess depression and suicidal behaviour respectively. RESULTS: The prevalence of depression for the subjects with DM was 27.8% and 26.7% for essential hypertension. The subjects with DM had prevalence of 6.3% for suicidal behaviour while essential hypertension had 7.8%. Depression was higher in subjects with DM if they were not married or had no education while the subjects with essential hypertension were more likely to have depression if they were not married, had no education or not employed. Suicidal behaviour was higher in subjects with DM if they had no education while in essential hypertension suicidal behaviour was higher in females, those not married and those not educated. CONCLUSION: Depression and suicidal behaviour occur with DM and essential hypertension. PMID- 23658571 TI - Effect of brief training on reliability and applicability of Global Assessment of functioning scale by Psychiatric clinical officers in Uganda. AB - BACKGROUND: The Global Assessment of Functioning (GAF) is the standard method and an essential tool for representing a clinician's judgment of a patient's overall level of psychological, social and occupational functioning. As such, it is probably the single most widely used method for assessing impairment among the patients with psychiatric illnesses. OBJECTIVE: To assess the effects of one-hour training on application of the GAF by Psychiatric Clinical Officers' in a Ugandan setting. METHOD: Five Psychiatrists and five Psychiatric Clinical Officers (PCOs) or Assistant Medical Officers who hold a 2 year diploma in Clinical Psychiatry were randomly selected to independently rate a video-recorded psychiatric interview according to the DSM IV-TR. The PCOs were then offered a one-hour training on how to rate the GAF scale and asked to rate the video case interview again. All ratings were assigned on the basis of past one year, at admission and current functioning. Interclass correlations (ICC) were computed using two-way mixed models. RESULTS: The ICC between the psychiatrists and the PCOs before training in the past one year, at admission and current functioning were +0.48, +0.51 and +0.59 respectively. After training, the ICC coefficients were +0.60, +0.82 and +0.83. CONCLUSION: Brief training given to PCOs improved the applications of their ratings of GAF scale to acceptable levels. There is need for formal training to this cadre of psychiatric practitioners in the use of the GAF. PMID- 23658572 TI - Psychological distress among adults admitted to medical and surgical wards of a Regional Referral Hospital, Uganda. AB - BACKGROUND: Physical illness is commonly associated with psychological distress that may be a direct effect of the illness or an adjustment in coping with the physical illness or its treatment. Little is known about psychological distress of patients on general wards in developing countries. OBJECTIVES: This study aimed to determine the extent and associations of psychological distress among adult in-patients on medical and surgical wards of Mbarara hospital in Uganda. METHODS: It was a cross sectional descriptive study among 258 adult in-patients. The WHO endorsed self report questionnaire (SRQ-25) was used to assess psychological distress with a cut off of 5/6. The MINI International Neuropsychiatric Interview (MINI) was used to identify specific psychiatric disorders. Cross-tabulations and multivariate analysis was used to analyze the relationship between psychological distress and different factors. RESULTS: One hundred and fifty eight individuals (61%) had psychological distress. One hundred and nine (42%) met criteria for at least one major psychiatric diagnosis. Only 6% of these were recognized by the attending health workers. Psychological distress was significantly associated with previous hospitalizations, ward of admission and marital status. CONCLUSIONS: There is a high level of psychological distress among the physically ill and it is often unrecognized and untreated. PMID- 23658573 TI - Psychiatric morbidity among physically ill patients in a Ugandan Regional Referral Hospital. AB - BACKGROUND: Mental illness is a global health burden that remains poorly understood even by health care providers. It is important to get insight of the prevalence, clinical features and management of psychiatric morbidity in general practice in Uganda as it affects treatment outcome. OBJECTIVE: To determine the prevalence, types and associations of psychiatric morbidity as seen among adult in-patients on medical and surgical wards of Mbarara Regional Referral hospital as a prototype Ugandan regional referral hospital. METHODS: This was a cross sectional descriptive study. Psychiatric diagnosis was arrived at by administering the Mini International Neuropsychiatric Interview (MINI) as the diagnostic instrument. RESULTS: Of the 258 participants in this study, 109 (42%) met criteria for at least one DSM IV psychiatric diagnosis. Only 6% of all the psychiatrically diagnosed patients were recognized by their treating doctors as having mental illness. CONCLUSION: The psychiatric disorders on the general medical and surgical wards are highly prevalent and not recognized by staff on these wards despite their common occurrence. There is need for sensitisation of staff on recognition and management of psychiatric disorders in physical illness. PMID- 23658574 TI - Henoch Schonlein Purpura in children: clinical analysis of 120 cases. AB - BACKGROUND: Henoch Schonlein Purpura (HSP) is a systemic vasculitic disease which is common in children. It is very important to understand the clinical features of this disease for doctors and nurses. OBJECTIVES: To study the clinical characteristics of HSP in children. METHODS: Collect the clinical data of the HSP children, and analyze the clinical characteristics of these HSP patients. RESULTS: The ratio of M:F was 1.9:1. The mean age was 6.6 +/- 1.6 years. The typical onset seasons were spring, winter and autumn. Infection and food allergy were the main etiological factors. The first symptom was skin purpura and these purpura mainly concentrated the lower extremities and buttocks. The dominant digestive clinical features were abdominal pains and vomiting. The knee joint and ankle joint were most frequently affected. The typical kidney symptoms were microscopic hematuria and albuminuria. An increased ESR was reported in 68 patients (56.7%). Serum C3 decreased in 13 cases (10.8%). ASO titer was higher in 57 children (47.5%). CONCLUSION: There were gender, season and area differences for the HSP patients. The etiological factors were diverse. HSP patients could have various clinical symptoms and rare complications. PMID- 23658575 TI - Renal insufficiency in Ghanaian HIV infected patients: need for dose adjustment. AB - BACKGROUND: Antiretrovirals (ARVs) could lead to clinically significant nephrotoxicity and as such will require dose adjustments in the presence of renal insufficiency. OBJECTIVE: To explore renal function estimating equations as alternatives for glomerular filtration rate (GFR) measurement in a stable cohort of HIV-infected patients. METHOD: In estimating renal insufficiency in Ghanaian HIV-infected patients, GFR for 276 HAART-naive patients and 166 patients on HAART was estimated with the Cockcroft-Gault, 4v-MDRD and CKD-EPI estimating equations. RESULTS: Females outnumbered males by 3 to 1 in the HAART-naive group and 4 to 1 in subjects on HAART. The prevalence of renal insufficiency calculated with the Cockcroft-Gault, 4v-MDRD and CKD-EPI equations was 8.7%, 9.1% and 8.7% in HAART naive patients; 14.5%, 12.6% and 12.6% in patients on HAART; 7.7%, 11.5% and 11.5% in HAART-naive males; 10.8%, 8.1% and 8.1% in males on HAART; 9.1%, 8.0% and 7.5% in HAART-naive females and 15.5%, 14.0% and 14.0% in females on HAART. The CKD-EPI equation yielded lower bias when compared to the Cockcroft-Gault and 4v-MDRD equations. CONCLUSION: Renal insufficiency is not uncommon among HIV infected Ghanaian patients. A significant proportion (10 to 11%) will require ARV dose adjustment at the time of initiating therapy or sometime during on-going therapy. PMID- 23658576 TI - Helicobacter pylori infection and atrophic gastritis. AB - BACKGROUND: Helicobacter pylori-infection associated gastritis is known to be a significant risk factor of gastric cancer. Serum levels of Gastrin-17 and Pepsinogen1which are respectively biomarkers of gastric antral and corpus mucosal activity are well known parameters of atrophic gastritis. OBJECTIVES: To determine the prevalence of Helicobacter pylori and atrophic gastritis amongst dyspeptic patients and to compare the production of PGI and G-17 in the various atrophic stages. METHODS: A total of 139 dyspeptic patients aged 46.68+/-15.50 years [females 106 aged47.23+/-15.51years, males 33 aged 44.48+/-14.62] were included during the one year period, March 2008-april 2009 at the district hospital Tombel. The degree of atrophy was determined by the levels of serum pepsinogen1, and gastrin-17 and the presence of Helicobacter pylori antibodies detected by an enzyme immunoassay. RESULTS: The prevalence of Helicobacter pylori was 79.82% and that for atrophic gastritis was 6.6%. A decrease in mean serum levels of gastin-17 along with increasing antral atrophy was observed; the mean serum levels of pepsinogen1 were reduced during progression of corpus atrophy. CONCLUSION: A weak reverse correlation(r =-0.036) was found between Gastrin-17 and Helicobacter pylori antibodies. PMID- 23658577 TI - Meningiomas among intracranial neoplasms in Johannesburg, South Africa: prevalence, clinical observations and review of the literature. AB - BACKGROUND: Worldwide there are varying reports on the prevalence of meningiomas among intracranial neoplasms. Different reports state intracranial meningiomas, gliomas or metastatic tumours as the most common tumour among intracranial neoplasms. We present our institutions' experience of patients with intracranial neoplasms and a comparison of our findings with those from the literature. OBJECTIVE: To determine the relative frequency of intracranial meningiomas among intracranial neoplasms in our environment. METHODS: Consecutive patients (151) seen at the CMJAH and CHBAH, Johannesburg, with histologically proven intracranial neoplasms over a 12 month period were analyzed. RESULTS: The commonest histological types were meningiomas, gliomas and pituitary tumours. Forty eight (31.8%) patients had histologically confirmed intracranial meningiomas during the study period, 35 (23.2%) had pituitary adenomas and 32 (21.2%) had gliomas. The mean age of the patients was 43 years with a female-to male ratio of 1.3:1. The peak age range at presentation was in the fifth (27.1%) and sixth (26.5%) decades. CONCLUSION: The study showed that meningioma is the most common tumour among intracranial neoplasms in our environment. PMID- 23658578 TI - Esophageal cancer awareness in Bomet district, Kenya. AB - BACKGROUND: Esophageal cancer is the most common malignancy in Western Kenya and patients present with advanced disease. OBJECTIVE: To determine baseline level of knowledge of esophageal cancer in Bomet District in order to develop targeted and effective educational classes. METHODS: A questionnaire with twelve questions testing knowledge about esophageal cancer and eight questions aimed at determining barriers to healthcare was conducted out of Tenwek Hospital from June to July 2010. RESULTS: Eighty-one questionnaires were completed. 33% thought that cancer is a virus and 35% thought that it is contagious. 47% did not think that family history is a risk factor. 79% accurately claimed dysphagia as the most common symptom for esophageal cancer. 40% thought that herbal therapy is the optimal treatment for esophageal cancer. Cost and fear of diagnosis were cited as the most significant barriers to healthcare. Most participants had a monthly income of less than 3000 Kenyan schillings (37.5 US dollars); for 37% of participants, the cost of transport to the hospital represented a third of their monthly income. CONCLUSION: The questionnaire provided population-specific information on cancer knowledge and aided in targeting barriers to healthcare access. These factors will be incorporated into the cancer education outreach program of Tenwek Hospital. PMID- 23658579 TI - Acute organo-phosphorus pesticide poisoning in North Karnataka, India: oxidative damage, haemoglobin level and total leukocyte. AB - BACKGROUND: Pesticide poisoning is an important cause of morbidity and mortality in India. OBJECTIVES: To assess the oxidative damage, hemoglobin level and leukocyte count in acute organophosphorus pesticide poisoning. METHODS: Plasma cholinesterase was assessed as a toxicity marker. Oxidative damage was assessed by estimating serum malondialdehyde (MDA) levels, plasma total antioxidant capacity (TAC), erythrocyte superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) levels. RESULTS: Progressive and significant decline (p< 0.001) in plasma cholinesterase in correlation with the severity of organophosphorus poisoning was observed. Serum MDA levels significantly increased (p< 0.001) in all grades of organophosphorus poisoning cases as compared to controls. Erythrocyte SOD, CAT and GPx were significantly increased (p< 0.05) in earlier grade and (p< 0.001) in later grades of organophosphorus poisoning cases as compared to controls. While plasma TAC (p<0.001) was significantly decreased in all grades of organophosphorus poisoning cases as compared to controls. Leucocytosis observed in these cases signifies the activation of defense mechanism which could be a positive response for survival. CONCLUSION: Organophosphorus compounds inhibit cholinesterase action leading to cholinergic hyperactivity. Increased MDA level may lead to peroxidative damages deteriorating the structural and functional integrity of neuronal membrane. Increased erythrocyte SOD, CAT and GPx activities suggest an adaptive measure to tackle the pesticide accumulation. Hence it is concluded that cholinesterase inhibition may initiate cellular dysfunction leading to acetylcholine induced oxidative damage. PMID- 23658580 TI - Influence of indoor formaldehyde pollution on respiratory system health in the urban area of Shenyang, China. AB - BACKGROUND: The decoration of interior spaces can lead to dangerous levels of indoor formaldehyde pollution. Exposure to indoor air pollution may be responsible for nearly 2 million deaths per year in developing countries. OBJECTIVES: To assess the prevalence of indoor formaldehyde pollution caused by decoration and resultant respiratory system symptoms exhibited in exposed adults and children, due to indoor formaldehyde pollution caused by decoration. METHODS: Survey sites were chosen and indoor formaldehyde concentrations determined according to the standard of formaldehyde in GB50325-2001. Logistic regression models were used to derive odds ratios (ORs) and 95% confidence intervals (95% CIs) after adjusting for potential confounders for this survey. RESULTS: Formaldehyde concentration was above the standard in 64% of Shenyang City. Some adults surveyed complained of common respiratory system disorders, including coughing (11.8%), nasal irritation (39.2%), Heterosmia (14.51%), and throat irritation (25.27%); 12% of children suffered from asthma. The analysis identified formaldehyde pollution and ventilation frequency as risk factors for respiratory system disorders in both adults (OR=2.603, [95% CI: 1.770-3.828], OR=1.604, [95% CI: 1.146-2.244], respectively) and children (OR=4.250, [2.064 8.753], OR=1.831, [1.006-3.333], respectively). CONCLUSION: The prevalence of common respiratory system disorders was related both to formaldehyde pollution and insufficient ventilation after decorating. PMID- 23658581 TI - Allergy sensitization and asthma among 13-14 year old school children in Nigeria. AB - BACKGROUND: The prevalence of asthma and role of atopy in asthma among children has not been clearly defined in Nigeria. OBJECTIVE: To determine the prevalence of asthma and investigate risk factors related to allergy sensitization among urban and rural school children in southwest Nigeria. METHODS: Validated ISAAC questionnaire was administered to 1736 high school children in randomly selected schools in rural and urban communities. Identified asthma cases were matched to controls. Allergy skin tests, blood eosinophil count, serum IgE and stool examination for parasites were performed. Dust samples from homes were also collected and analyzed for allergens. RESULTS: The prevalence of asthma was 7.5% (95% CI 6.0 to 9.2%) and 8% (95% CI 6.0-10.4%) in the rural and urban communities respectively . Risk factors for asthma included cigarette-smoking, cats in the home and family size. Eosinophil count (109/L) was elevated in asthmatics [0.70 (95% CI 0.48-1.11) vs. 0.32 (95% CI 0.19-0.69); p<0.01], but IgE levels were similar between the two groups (298+/-229 IU/mL vs. 288+/-257; p=0.97). Positive skin tests to cat hair, cockroach, mango blossom and mouse epithelium were more frequent in asthmatics than in healthy controls, especially in the rural communities. There was no correlation between allergens in dust collected from homes and skin test reactivity. CONCLUSION: Asthma prevalence is similar in rural and urban children in Southwest Nigeria and atopy with elevated IgE was not observed to be a major factor for asthma in our cohort of children in both communities. PMID- 23658582 TI - Outcome of cholelithiasis in Sudanese children with Sickle Cell Anaemia (SCA) after 13 years follow-up. AB - BACKGROUND: SCA causes chronic haemolysis which is a risk factor for cholelithiasis. OBJECTIVE: To determine the prevalence and outcome of children with SCA complicated with gallstones treated at the sickle cell clinic at the children emergency hospital Khartoum state. METHODS: 261 patients age 4 months to 16 years were studied. AUS examination was carried out. The 30 patients in whom gall stones were detected followed prospectively from June 1996 to September 2009 when a second AUS examination was obtained. RESULTS: Gall stones occurred in 30 patients of whom four were lost to follow up in the first year. The overall prevalence of cholelithiasis was 11.5% and it increased with age. The youngest patient with cholelithiasis was 2 1/2 years old. Haematological variables, bilirubin and sex did not identify a subgroup of patients at higher risk for gallstones. All the patients were asymptomatic at the time of diagnosis. One patient developed symptoms 3years after the diagnosis and he was submitted to surgery. The 25 remaining asymptomatic patients were followed up for 13 years and none of them presented complications related to cholelithiasis during this period. CONCLUSION: The prevalence of cholelithiasis in Sudanese children and adolescents with SCA was significant. The large majority patients remained asymptomatic over a long period. PMID- 23658583 TI - Chest wall tumor at relapse of multiple myeloma. PMID- 23658584 TI - Giant fibroadenoma presenting like fungating breast cancer in a Nigerian teenager. AB - BACKGROUND: Giant fibroadenoma of the breast is a rare benign breast tumour which seldom grows to a giant size, it is even rarer for this benign tumour to grow rapidly, ulcerate spontaneously and present like a fungating breast tumour in a way mimicking breast cancer. CASE PRESENTATION: This is a presentation of a 14 year old premenarchal girl with a massive ulcerating and fungating left breast mass that was initially thought to be a fungating locally advanced breast carcinoma on clinical examination. Further examination of the morphology of the resected surgical specimen and histological examination confirmed it to be giant fibroadenoma of the breast. It was successfully managed by partial mastectomy and breast reconstruction with an excellent result and a high degree of patient satisfaction was achieved. CONCLUSION: Though a rare clinical entity benign breast tumour can present like a fungating breast cancer and this must be bore in mind especially in young adolescent patients presenting with ulcerating breast tumour. PMID- 23658585 TI - Bilateral giant inguinoscrotal Hernia: psychosocial issues and a new classification. AB - BACKGROUND: Bilateral giant inguinoscrotal hernias pose challenging psychosocial problems to the patient. The engulfed phallus and hernia size are socially embarrassing and may make penetration during coitus increasingly difficult and uncomfortable. This paper presents a classification and the psychosocial aspects of bilateral giant inguinoscrotal hernias. METHODS: A prospective study of patients with bilateral giant inguinoscrotal hernia in which the phallus was completely engulfed by the swelling, managed by this author between 2002 and 2011 in both urban and rural practice in Nigeria and Sierra Leone was reviewed and analyzed using a simple frequency distribution. RESULTS: Eleven patients with bilateral giant inguinoscrotal hernias were reviewed. Age range 63-86 years. Mean age 73.73 (+/- 6.96SD) years. The reason for delayed presentation was financial constraint. Six patients (54.55%) presented due to continuous refusal of coitus by their partners. Sexual satisfaction was poor in all the patients (100.00%). All the patients (100.00%) had poor self-esteem and poor socialization habits as a result of continuous ridicule from peers and colleagues. CONCLUSION: To improve quality of life of the elderly, there is the need for early awareness campaigns and provision of improved access to free surgical health care services particularly in rural African communities. PMID- 23658586 TI - Tardive hip disease diagnosis in a young adult with sickle cell disease. AB - BACKGROUND: Hip disease is a complication of Sickle Cell Disease most commonly occurs during adolescence and early adult life that constitutes from 3.3% to 26.7% % of cases in SCD patients. Damage to mature epiphysis may cause persistent symptoms requiring surgery which may need revision if it becomes loose with wear. CASE PRESENTATION: We report a 27-year-old male who was diagnosed with hip disease following investigations for persistent pain in right hip associated with limp and painful limitation of movement. Avascular necrosis of the right femoral head was identified on a hip X-ray. CONCLUSION: Further investigation will be necessary to identify risk factors in SCD Congolese patient and each SCD patient must be screened for predisposing factors. PMID- 23658587 TI - Evidence for association between paraoxonase-1 activity and diseases. PMID- 23658588 TI - Dr. Hasan Karsen replies. PMID- 23658590 TI - Vaccine-Induced Anti-HBs Level in 5-6 Year-Old Malnourished Children. AB - BACKGROUND: Malnutrition is the most common cause of immune deficiency. It results in reduced secretion of T-cells and B-cell-stimulating factors leading to declining of special immunoglobulins. On the other hand, hepatitis B, as a major world health problem, can be prevented effectively by vaccination. Three doses of hepatitis B virus (HBV) vaccine induce protective levels of anti-hepatitis B surface (anti-HBs) in 95% of healthy children. This level decreases gradually over time. OBJECTIVES: The goal of this study was to assess anti-HBs in malnourished children, who confronted to some degrees of immune deficiency. PATIENTS AND METHODS: This is a cross-sectional study conducted during May to August 2010 in therapeutic clinics of Yazd, Iran. Samples were selected simply and consecutively among 5-6 year-old children with a history of three doses of HBV vaccine in infancy. On the basis of World Health Organization's definition on malnutrition, which considers anthropometric measurements, malnourished children entered the study. Totally 83 cases (37 boys and 46 girls) were gathered and classified into three groups of mild, moderate, and severe malnutrition. One milliliter of venous blood was taken and anti-HBs were tested by enzyme linked immunosorbant assay (ELISA). RESULTS: Overall, seroprotection rate and geometric mean titer (GMT) of anti-HBs were 60.2% and 15.47 +/- 10.92 mIU/mL, respectively. Seroprotection rate was 71.4%, 55.2%, and 72.7% in mild, moderate, and severe malnourished children, respectively. GMT was 30.78 mIU/mL, 12.15 mIU/mL, and 22.95 mIU/mL in these groups, respectively. None of these two indices were significant in these groups (P = 0.471, P = 0.364). Seroprotection rate and GMT were 54.1% and 13.26 +/- 11.59 mIU/mL in boys, and 65.2% and 17.5 +/- 10.59 mIU/mL in girls, respectively, showing no significant relationship with gender (P = 0.302, P = 0.602). Lowest seroprotection rate was in stunted cases (47.1%) and highest in wasted children (77.8%). This difference also was not significant (P = 0.43). CONCLUSIONS: The seroprotection rate and GMT of anti-HBs observed in this study do not show a high level of immunity. These two indices were not related to severity of malnutrition. We conclude that severity of malnutrition does not affect vaccine-induced antibody level and seroprotection rate; however small sample size in each group of study hinders decisive conclusion. Moreover, GMT and seroprotection rate showed no relationship with type of abnormal anthropometric index, including weight for height, weight for age, and height for age. PMID- 23658591 TI - An emerging trend of methamphetamine injection in iran: a critical target for research on blood-borne infection diseases. PMID- 23658592 TI - Three doses of hepatitis B vaccine or four doses in chronic renal failure. PMID- 23658593 TI - Evaluation of Knowledge and Practice of Hairdressers in Women's Beauty Salons in Isfahan About Hepatitis B, Hepatitis C, and AIDS in 2010 and 2011. AB - BACKGROUND: Blood-borne viruses such as hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) have some common epidemiological characteristics, and have infected millions of people throughout the world. Patients infected by acute hepatitis or HIV infections may not be aware of the disease, and thereby cause transmission to others. During haircut, shave, or pedicure, barbers may accidentally expose to their clients' blood, transmit their own infection to them, or transmit the infection from one client to another. Thus the beauty salon staff has a potential role in expansion of infections. OBJECTIVES: As being barbers and barbering are risk factors to some infectious diseases, determining the role of knowledge and awareness of barbers and hairdressers about topics related to AIDS, and hepatitis B and C is important. PATIENTS AND METHODS: This cross-sectional descriptive study was performed in 2010-2011 on 281 women's beauty salons located in eleven urban districts of Isfahan town. A multistage cluster sampling was performed and knowledge assessment questionnaire accompanied by practice checklist regarding hepatitis B and C, and AIDS were completed by trained interviewers. Knowledge and practice scores were determined in 0-20 and 0 10 scales, respectively. The content validity of questionnaire was confirmed by three expert opinions and the test-retest reliability of the questionnaire was determined to be 0.83 in a pilot study on 30 participants. Data were analyzed using Pearson's correlation coefficient and one-way ANOVA test by SPSS software, version 18. RESULTS: In the study, 281 hairdressers participated. There was a statistically significant relationship between education level and knowledge score of hairdressers (P < 0.001). We found a statistically significant relationship between knowledge level and job history of hairdressers according to the Pearson's correlation coefficient (P = 0.004). The results did not show any statistically significant relationship between education level and practice scores (P = 0.5). Furthermore, the job history of hairdressers and their practice score did not show a significant relationship (P = 0.77). CONCLUSIONS: We obtained promising results about the knowledge and practice levels of staffs of women's beauty salons in Isfahan about AIDS, and hepatitis B and C. The target group exhibited an intermediate level of knowledge about the diseases because of important role of barbers in virus transmission; we should provide the best control, evaluation, and continuous teaching programs. PMID- 23658594 TI - Should we rely on the findings of each published randomized controlled study? PMID- 23658595 TI - Reverse transcription complex: the key player of the early phase of HIV replication. PMID- 23658596 TI - RIGOR guidelines: escalating STAIR and STEPS for effective translational research. AB - Stroke continues to be a serious and significant health problem in the USA and worldwide. This article will emphasize the need for good laboratory practices, transparent scientific reporting, and the use of translational research models representative of the disease state to develop effective treatments. This will allow for the testing and development of new innovative strategies so that efficacious therapies can be developed to treat ischemic and hemorrhagic stroke. This article recommends guidelines for effective translational research, most importantly, the need for study blinding, study group randomization, power analysis, accurate statistical analysis, and a conflict of interest statement. Additional guidelines to ensure reproducibility of results and confirmation of efficacy in multiple species are discussed. PMID- 23658597 TI - Suppression of the Rho/Rho-kinase pathway and prevention of cerebral vasospasm by combination treatment with statin and fasudil after subarachnoid hemorrhage in rabbit. AB - The Rho/Rho-kinase pathway is considered important in the pathogenesis of sustained smooth muscle cell contraction during cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). The aims of this study were to investigate whether combination treatment, with pitavastatin as an inhibitor of RhoA and fasudil as an inhibitor of Rho-kinase, prevents the cerebral vasospasm. SAH was simulated using the double-hemorrhage rabbit model, and pitavastatin, or fasudil, or both (combination treatment) were administrated. The basilar artery (BA) cross-sectional area only in the combination treatment group was statistically larger than in the SAH group (p<0.05). BA Rho-kinase, as measured by ELISA, was statistically reduced only in the combination treatment group compared with the SAH group (p<0.05). In the other two treatment groups, pitavastatin or fasudil treatment group showed larger BA cross-sectional areas and lower value for BA Rho-kinase, but there were no statistically significant differences compared with the SAH group. The expression of endothelial nitric oxide synthase (eNOS), evaluated by immunohistochemistry in the pitavastatin group and the combination group, was higher than in the SAH group. Results indicate that combination treatment could extensively prevent cerebral vasospasm due to the synergic effect of combining pitavastatin and fasudil on the Rho/Rho kinase pathway and on eNOS. PMID- 23658598 TI - A Double-Blind Clinical Study to Investigate the Effects of a Fungal Protease Enzyme System on Metabolic, Hepato-renal, and Cardiovascular Parameters Following 30 Days of Supplementation in Active, Healthy Men. AB - Research on the role of digestion in overall health has driven increasing interest in the use of digestive enzymes, which may improve nutrient absorption and reduce gastrointestinal symptoms. Sales of digestive aids and enzymes have grown over 8% in 2009, with enzymes accounting for $69 million of this growing category. Recent clinical research reported that acute dosing of Aminogen(r), a patented blend of digestive protease enzymes isolated from Aspergillus and blended with whey protein concentrate, increased the rate of protein absorption. The results indicated a faster rate of amino acid absorption reflected in significantly higher blood levels of amino acids, increased nitrogen retention, and significantly reduced levels of C-reactive protein. Few studies, however, have examined the safety of repeated dosing of oral enzymes with an appropriate substrate. The purpose of this study, therefore, was to evaluate basic measures of clinical safety during 30 days of continuous, repeated dosing of Aminogen(r) and whey protein supplementation in healthy, active men maintaining a regimen of resistance training. Parameters evaluated include various markers of general physical health, metabolic function, hepato-renal function, and cardiovascular health including fasting blood lipids. Forty healthy, resistance-trained men (27.1 +/- 7.9 years) were recruited for this double-blind, randomized study. Group A ingested two 40-g doses of whey protein per day containing Aminogen(r). Group B ingested two 40-g doses of whey protein per day. No significant changes were noted in measures of general physical health, metabolic function, cardiovascular health, and hepato-renal function within or between groups. However, total cholesterol, LDL cholesterol, and serum calcium significantly increased (P < 0.05) in group B. In group A, whey protein containing Aminogen(r) was well tolerated with no adverse reactions reported. No differences in serum markers of clinical safety and an improved blood lipid profile are also reported. PMID- 23658603 TI - A novel anti-tumor inhibitor identified by virtual screen with PLK1 structure and zebrafish assay. AB - Polo-like kinase 1 (PLK1), one of the key regulators of mitosis, is a target for cancer therapy due to its abnormally high activity in several tumors. Plk1 is highly conserved and shares a nearly identical 3-D structure between zebrafish and humans. The initial 10 mitoses of zebrafish embryonic cleavages occur every~30 minutes, and therefore provide a rapid assay to evaluate mitosis inhibitors including those targeting Plk1. To increase efficiency and specificity, we first performed a computational virtual screen of~60000 compounds against the human Plk1 3-D structure docked to both its kinase and Polo box domain. 370 candidates with the top free-energy scores were subjected to zebrafish assay and 3 were shown to inhibit cell division. Compared to general screen for compounds inhibiting zebrafish embryonic cleavage, computation increased the efficiency by 11 folds. One of the 3 compounds, named I2, was further demonstrated to effectively inhibit multiple tumor cell proliferation in vitro and PC3 prostate cancer growth in Xenograft mouse model in vivo. Furthermore, I2 inhibited Plk1 enzyme activity in a dose dependent manner. The IC50 values of I2 in these assays are compatible to those of ON-01910, a Plk1 inhibitor currently in Phase III clinic trials. Our studies demonstrate that zebrafish assays coupled with computational screening significantly improves the efficiency of identifying specific regulators of biological targets. The PLK1 inhibitor I2, and its analogs, may have potential in cancer therapeutics. PMID- 23658604 TI - Natural variation for lifespan and stress response in the nematode Caenorhabditis remanei. AB - Genetic approaches (e.g. mutation, RNA interference) in model organisms, particularly the nematode Caenorhabditis elegans, have yielded a wealth of information on cellular processes that can influence lifespan. Although longevity mutants discovered in the lab are instructive of cellular physiology, lab studies might miss important genes that influence health and longevity in the wild. C. elegans has relatively low natural genetic variation and high levels of linkage disequilibrium, and thus is not optimal for studying natural variation in longevity. In contrast, its close relative C. remanei possesses very high levels of molecular genetic variation and low levels of linkage disequilibrium. To determine whether C. remanei may be a good model system for the study of natural genetic variation in aging, we evaluated levels of quantitative genetic variation for longevity and resistance to oxidative, heat and UV stress. Heritability (and the coefficient of additive genetic variation) was high for oxidative and heat stress resistance, low (but significant) for longevity, and essentially zero for UV stress response. Our results suggest that C. remanei may be a powerful system for studying natural genetic variation for longevity and oxidative and heat stress response, as well as an informative model for the study of functional relationships between longevity and stress response. PMID- 23658605 TI - Porcine E. coli: virulence-associated genes, resistance genes and adhesion and probiotic activity tested by a new screening method. AB - We established an automated screening method to characterize adhesion of Escherichia coli to intestinal porcine epithelial cells (IPEC-J2) and their probiotic activity against infection by enteropathogenic E. coli (EPEC). 104 intestinal E. coli isolates from domestic pigs were tested by PCR for the occurrence of virulence-associated genes, genes coding for resistances to antimicrobial agents and metals, and for phylogenetic origin by PCR. Adhesion rates and probiotic activity were examined for correlation with the presence of these genes. Finally, data were compared with those from 93 E. coli isolates from wild boars. Isolates from domestic pigs carried a broad variety of all tested genes and showed great diversity in gene patterns. Adhesions varied with a maximum of 18.3 or 24.2 mean bacteria adherence per epithelial cell after 2 or 6 hours respectively. Most isolates from domestic pigs and wild boars showed low adherence, with no correlation between adhesion/probiotic activity and E. coli genes or gene clusters. The gene sfa/foc, encoding for a subunit of F1C fimbriae did show a positive correlative association with adherence and probiotic activity; however E. coli isolates from wild boars with the sfa/foc gene showed less adhesion and probiotic activity than E. coli with the sfa/foc gene isolated from domestic pigs after 6 hour incubation. In conclusion, screening porcine E. coli for virulence associated genes genes, adhesion to intestinal epithelial cells, and probiotic activity revealed a single important adhesion factor, several probiotic candidates, and showed important differences between E. coli of domestic pigs and wild boars. PMID- 23658606 TI - The effect of similarity: non-spatial features modulate obstacle avoidance. AB - The introduction of non-target objects into a workspace leads to temporal and spatial adjustments of reaching trajectories towards a target. If the non-target is obstructing the path of the hand towards the target, the reach is adjusted such that collision with the non-target, or obstacle, is avoided. Little is known about the influence of features which are irrelevant for the execution of the movement on avoidance movements, like color similarity between target and non target objects. In eye movement studies the similarity of non-targets has been revealed to influence oculomotor competition. Because of the tight neural and behavioral coupling between the gaze and reaching system, our aim was to determine the contribution of similarity between target and non-target to avoidance movements. We performed 2 experiments in which participants had to reach to grasp a target object while a non-target was present in the workspace. These non-targets could be either similar or dissimilar in color to the target. The results indicate that the non-spatial feature similarity can further modify the avoidance response and therefore further modify the spatial path of the reach. Indeed, we find that dissimilar pairs have a stronger effect on reaching to-grasp movements than similar pairs. This effect was most pronounced when the non-target was on the outside of the reaching hand, where it served as more of an obstacle to the trailing arm. We propose that the increased capture of attention by the dissimilar obstacle is responsible for the more robust avoidance response. PMID- 23658607 TI - Differential translation of Dazap1 transcripts during spermatogenesis. AB - Deleted in AZoospermia Associated Protein 1 (DAZAP1) is a ubiquitous hnRNP protein that has been implicated in RNA transcription, splicing, and translation. It is highly expressed in testes, predominantly in late stage spermatocytes and post-meiotic spermatids. Dazap1 deficiency in mice results in growth retardation and spermatogenic arrest. The gene produces two major transcripts of 2.4 and 1.8 kb, designated Dazap1-L and Dazap1-S, respectively. Results of our previous RNA in situ hybridization and immunostaining suggested translational regulation of the Dazap1 transcripts during spermatogenesis. The main objectives of the study were to determine the origin of the two Dazap1 transcripts and to investigate whether they were similarly translated. Our Northern and 3' RACE analyses showed that the two transcripts were generated through alternative polyadenylation. In mouse testes, the levels of both transcripts were low at postnatal day 12 (P12), increased significantly at P18, and reached maximum at P27. Sucrose gradient analyses showed that at P12 both transcripts were actively translated. Afterward, an increasing portion of Dazap1-S became associated with the translationally inactive mRNPs, and the translational repression was accompanied by an increase in the length of its poly(A) tail. A much smaller portion of Dazap1-L was also sequestered to mRNPs as testes matured, but there was no changes in its poly(A) tail length. Using RNA pull-down followed by mass spectrometry, we identified DAZL, a germ-cell specific translation regulator, as one of the proteins that bound to the 3'UTR region specific for Dazap1-L. We further showed that DAZL preferentially bound to Dazap1-L in testis lysates and stimulated the translation of a reporter gene carrying Dazap1-L 3'UTR. In summary, our study shows that the translation of the two Dazap1 transcripts is differentially regulated. It also provides a new example of translational repression associated with poly(A) tail elongation during spermatogenesis. PMID- 23658608 TI - Partial altitudinal migration of a Himalayan Forest pheasant. AB - BACKGROUND: Altitudinal migration systems are poorly understood. Recent advances in animal telemetry which enables tracking of migrants across their annual cycles will help illustrate unknown migration patterns and test existing hypotheses. Using telemetry, we show the existence of a complex partial altitudinal migration system in the Himalayas and discuss our findings to help better understand partial and altitudinal migration. METHODOLOGY/PRINCIPAL FINDINGS: We used GPS/accelerometer tags to monitor the migration of Satyr tragopan (Tragopan satyra) in the Bhutan Himalayas. We tagged 38 birds from 2009 - 2011 and found that tragopans are partially migratory. Fall migration lasted from the 3(rd) week of September till the 3(rd) week of November with migrants traveling distances ranging from 1.25 km to 13.5 km over 1 to 32 days. Snowfall did not influence the onset of migration. Return migration started by the 1(st) week of March and lasted until the 1(st) week of April. Individuals returned within 4 to 10 days and displayed site fidelity. One bird switched from being a migrant to a non migrant. Tragopans displayed three main migration patterns: 1) crossing multiple mountains; 2) descending/ascending longitudinally; 3) moving higher up in winter and lower down in summer. More females migrated than males; but, within males, body size was not a factor for predicting migrants. CONCLUSIONS/SIGNIFICANCE: Our observations of migrants traversing over multiple mountain ridges and even of others climbing to higher elevations is novel. We support the need for existing hypotheses to consider how best to explain inter- as well as intra-sexual differences. Most importantly, having shown that the patterns of an altitudinal migration system are complex and not a simple up and down slope movement, we hope our findings will influence the way altitudinal migrations are perceived and thereby contribute to a better understanding of how species may respond to climate change. PMID- 23658609 TI - Changes in cancer cell metabolism revealed by direct sample analysis with MALDI mass spectrometry. AB - Biomarker discovery using mass spectrometry (MS) has recently seen a significant increase in applications, mainly driven by the rapidly advancing field of metabolomics. Instrumental and data handling advancements have allowed for untargeted metabolite analyses which simultaneously interrogate multiple biochemical pathways to elucidate disease phenotypes and therapeutic mechanisms. Although most MS-based metabolomic approaches are coupled with liquid chromatography, a few recently published studies used matrix-assisted laser desorption (MALDI), allowing for rapid and direct sample analysis with minimal sample preparation. We and others have reported that prostaglandin E3 (PGE3), derived from COX-2 metabolism of the omega-3 fatty acid eicosapentaenoic acid (EPA), inhibited the proliferation of human lung, colon and pancreatic cancer cells. However, how PGE3 metabolism is regulated in cancer cells, particularly human non-small cell lung cancer (NSCLC) cells, is not fully understood. Here, we successfully used MALDI to identify differences in lipid metabolism between two human non-small-cell lung cancer (NSCLC) cell lines, A549 and H596, which could contribute to their differential response to EPA treatment. Analysis by MALDI-MS showed that the level of EPA incorporated into phospholipids in H596 cells was 4 fold higher than A549 cells. Intriguingly, H596 cells produced much less PGE3 than A549 cells even though the expression of COX-2 was similar in these two cell lines. This appears to be due to the relatively lower expression of cytosolic phospholipase A2 (cPLA2) in H596 cells than that of A549 cells. Additionally, the MALDI-MS approach was successfully used on tumor tissue extracts from a K-ras transgenic mouse model of lung cancer to enhance our understanding of the mechanism of action of EPA in the in vivo model. These results highlight the utility of combining a metabolomics workflow with MALDI-MS to identify the biomarkers that may regulate the metabolism of omega-3 fatty acids and ultimately affect their therapeutic potentials. PMID- 23658610 TI - The exported protein PbCP1 localises to cleft-like structures in the rodent malaria parasite Plasmodium berghei. AB - Protein export into the host red blood cell is one of the key processes in the pathobiology of the malaria parasite Plasmodiumtrl falciparum, which extensively remodels the red blood cell to ensure its virulence and survival. In this study, we aimed to shed further light on the protein export mechanisms in the rodent malaria parasite P. berghei and provide further proof of the conserved nature of host cell remodeling in Plasmodium spp. Based on the presence of an export motif (R/KxLxE/Q/D) termed PEXEL (Plasmodium export element), we have generated transgenic P. berghei parasite lines expressing GFP chimera of putatively exported proteins and analysed one of the newly identified exported proteins in detail. This essential protein, termed PbCP1 (P. berghei Cleft-like Protein 1), harbours an atypical PEXEL motif (RxLxY) and is further characterised by two predicted transmembrane domains (2TMD) in the C-terminal end of the protein. We have functionally validated the unusual PEXEL motif in PbCP1 and analysed the role of the 2TMD region, which is required to recruit PbCP1 to discrete membranous structures in the red blood cell cytosol that have a convoluted, vesico-tubular morphology by electron microscopy. Importantly, this study reveals that rodent malaria species also induce modifications to their host red blood cell. PMID- 23658611 TI - Novel phylogenetic algorithm to monitor human tropism in Egyptian H5N1-HPAIV reveals evolution toward efficient human-to-human transmission. AB - Years of endemic infections with highly pathogenic avian influenza (HPAI) A subtype H5N1 virus in poultry and high numbers of infections in humans provide ample opportunity in Egypt for H5N1-HPAIV to develop pandemic potential. In an effort to better understand the viral determinants that facilitate human infections of the Egyptian H5N1-HPAIVvirus, we developed a new phylogenetic algorithm based on a new distance measure derived from the informational spectrum method (ISM). This new approach, which describes functional aspects of the evolution of the hemagglutinin subunit 1 (HA1), revealed a growing group G2 of H5N1-HPAIV in Egypt after 2009 that acquired new informational spectrum (IS) properties suggestive of an increased human tropism and pandemic potential. While in 2006 all viruses in Egypt belonged to the G1 group, by 2011 these viruses were virtually replaced by G2 viruses. All of the G2 viruses displayed four characteristic mutations (D43N, S120(D,N), (S,L)129Delta and I151T), three of which were previously reported to increase binding to the human receptor. Already in 2006-2008 G2 viruses were significantly (p<0.02) more often found in humans than expected from their overall prevalence and this further increased in 2009 2011 (p<0.007). Our approach also identified viruses that acquired additional mutations that we predict to further enhance their human tropism. The extensive evolution of Egyptian H5N1-HPAIV towards a preferential human tropism underlines an urgent need to closely monitor these viruses with respect to molecular determinants of virulence. PMID- 23658612 TI - Effective exon skipping and dystrophin restoration by 2'-o-methoxyethyl antisense oligonucleotide in dystrophin-deficient mice. AB - Antisense oligonucleotide (AO)-mediated exon-skipping therapy is one of the most promising therapeutic strategies for Duchenne Muscular Dystrophy (DMD) and several AO chemistries have been rigorously investigated. In this report, we focused on the effect of 2'-O-methoxyethyl oligonucleotides (MOE) on exon skipping in cultured mdx myoblasts and mice. Efficient dose-dependent skipping of targeted exon 23 was achieved in myoblasts with MOE AOs of different lengths and backbone chemistries. Furthermore, we established that 25-mer MOE phosphorothioate (PS) AOs provided the greatest exon-skipping efficacy. When compared with 2'O methyl phosphorothioate (2'OmePS) AOs, 25-mer MOE (PS) AOs also showed higher exon-skipping activity in vitro and in mdx mice after intramuscular injections. Characterization of uptake in vitro corroborated with exon-skipping results, suggesting that increased uptake of 25-mer MOE PS AOs might partly contribute to the difference in exon-skipping activity observed in vitro and in mdx mice. Our findings demonstrate the substantial potential for MOE PS AOs as an alternative option for the treatment of DMD. PMID- 23658613 TI - Impact of nutrient imbalance on wine alcoholic fermentations: nitrogen excess enhances yeast cell death in lipid-limited must. AB - We evaluated the consequences of nutritional imbalances, particularly lipid/nitrogen imbalances, on wine yeast survival during alcoholic fermentation. We report that lipid limitation (ergosterol limitation in our model) led to a rapid loss of viability during the stationary phase of fermentation and that the cell death rate is strongly modulated by nitrogen availability and nature. Yeast survival was reduced in the presence of excess nitrogen in lipid-limited fermentations. The rapidly dying yeast cells in fermentations in high nitrogen and lipid-limited conditions displayed a lower storage of the carbohydrates trehalose and glycogen than observed in nitrogen-limited cells. We studied the cell stress response using HSP12 promoter-driven GFP expression as a marker, and found that lipid limitation triggered a weaker stress response than nitrogen limitation. We used a SCH9-deleted strain to assess the involvement of nitrogen signalling pathways in the triggering of cell death. Deletion of SCH9 increased yeast viability in the presence of excess nitrogen, indicating that a signalling pathway acting through Sch9p is involved in this nitrogen-triggered cell death. We also show that various nitrogen sources, but not histidine or proline, provoked cell death. Our various findings indicate that lipid limitation does not elicit a transcriptional programme that leads to a stress response protecting yeast cells and that nitrogen excess triggers cell death by modulating this stress response, but not through HSP12. These results reveal a possibly negative role of nitrogen in fermentation, with reported effects referring to ergosterol limitation conditions. These effects should be taken into account in the management of alcoholic fermentations. PMID- 23658614 TI - The role and dynamic of strengthening in the reconsolidation process in a human declarative memory: what decides the fate of recent and older memories? AB - Several reports have shown that after specific reminders are presented, consolidated memories pass from a stable state to one in which the memory is reactivated. This reactivation implies that memories are labile and susceptible to amnesic agents. This susceptibility decreases over time and leads to a re stabilization phase usually known as reconsolidation. With respect to the biological role of reconsolidation, two functions have been proposed. First, the reconsolidation process allows new information to be integrated into the background of the original memory; second, it strengthens the original memory. We have previously demonstrated that both of these functions occur in the reconsolidation of human declarative memories. Our paradigm consisted of learning verbal material (lists of five pairs of nonsense syllables) acquired by a training process (L1-training) on Day 1 of our experiment. After this declarative memory is consolidated, it can be made labile by presenting a specific reminder. After this, the memory passes through a subsequent stabilization process. Strengthening creates a new scenario for the reconsolidation process; this function represents a new factor that may transform the dynamic of memories. First, we analyzed whether the repeated labilization-reconsolidation processes maintained the memory for longer periods of time. We showed that at least one labilization-reconsolidation process strengthens a memory via evaluation 5 days after its re-stabilization. We also demonstrated that this effect is not triggered by retrieval only. We then analyzed the way strengthening modified the effect of an amnesic agent that was presented immediately after repeated labilizations. The repeated labilization-reconsolidation processes made the memory more resistant to interference during re-stabilization. Finally, we evaluated whether the effect of strengthening may depend on the age of the memory. We found that the effect of strengthening did depend on the age of the memory. Forgetting may represent a process that weakens the effect of strengthening. PMID- 23658615 TI - Filtration parameters influencing circulating tumor cell enrichment from whole blood. AB - Filtration can achieve circulating tumor cell (CTC) enrichment from blood. Key parameters such as flow-rate, applied pressure, and fixation, vary largely between assays and their influence is not well understood. Here, we used a filtration system, to monitor these parameters and determine their relationships. Whole blood, or its components, with and without spiked tumor cells were filtered through track-etched filters. We characterize cells passing through filter pores by their apparent viscosity; the viscosity of a fluid that would pass with the same flow. We measured a ratio of 5.10(4)?10(2)?1 for the apparent viscosities of 15 um diameter MDA-231 cells, 10 um white cells and 90 fl red cells passing through a 5 um pore. Fixation increases the pressure needed to pass cells through 8 um pores 25-fold and halves the recovery of spiked tumor cells. Filtration should be performed on unfixed samples at a pressure of ~10 mbar for a 1 cm(2) track-etched filter with 5 um pores. At this pressure MDA-231 cells move through the filter in 1 hour. If fixation is needed for sample preservation, a gentle fixative should be selected. The difference in apparent viscosity between CTC and blood cells is key in optimizing recovery of CTC. PMID- 23658616 TI - Accelerating fibre orientation estimation from diffusion weighted magnetic resonance imaging using GPUs. AB - With the performance of central processing units (CPUs) having effectively reached a limit, parallel processing offers an alternative for applications with high computational demands. Modern graphics processing units (GPUs) are massively parallel processors that can execute simultaneously thousands of light-weight processes. In this study, we propose and implement a parallel GPU-based design of a popular method that is used for the analysis of brain magnetic resonance imaging (MRI). More specifically, we are concerned with a model-based approach for extracting tissue structural information from diffusion-weighted (DW) MRI data. DW-MRI offers, through tractography approaches, the only way to study brain structural connectivity, non-invasively and in-vivo. We parallelise the Bayesian inference framework for the ball & stick model, as it is implemented in the tractography toolbox of the popular FSL software package (University of Oxford). For our implementation, we utilise the Compute Unified Device Architecture (CUDA) programming model. We show that the parameter estimation, performed through Markov Chain Monte Carlo (MCMC), is accelerated by at least two orders of magnitude, when comparing a single GPU with the respective sequential single-core CPU version. We also illustrate similar speed-up factors (up to 120x) when comparing a multi-GPU with a multi-CPU implementation. PMID- 23658617 TI - Discovery of trypanosomatid parasites in globally distributed Drosophila species. AB - Microbial parasites of animals include bacteria, viruses, and various unicellular eukaryotes. Because of the difficulty in studying these microorganisms in both humans and disease vectors, laboratory models are commonly used for experimental analysis of host-parasite interactions. Drosophila is one such model that has made significant contributions to our knowledge of bacterial, fungal, and viral infections. Despite this, less is known about other potential parasites associated with natural Drosophila populations. Here, we surveyed sixteen Drosophila populations comprising thirteen species from four continents and Hawaii and found that they are associated with an extensive diversity of trypanosomatids (Euglenozoa, Kinetoplastea). Phylogenetic analysis finds that Drosophila-associated trypanosomatids are closely related to taxa that are responsible for various types of leishmaniases and more distantly related to the taxa responsible for human African trypanosomiasis and Chagas disease. We suggest that Drosophila may provide a powerful system for studying the interactions between trypanosomatids and their hosts. PMID- 23658618 TI - Stability mechanisms of a thermophilic laccase probed by molecular dynamics. AB - Laccases are highly stable, industrially important enzymes capable of oxidizing a large range of substrates. Causes for their stability are, as for other proteins, poorly understood. In this work, multiple-seed molecular dynamics (MD) was applied to a Trametes versicolor laccase in response to variable ionic strengths, temperatures, and glycosylation status. Near-physiological conditions provided excellent agreement with the crystal structure (average RMSD ~0.92 A) and residual agreement with experimental B-factors. The persistence of backbone hydrogen bonds was identified as a key descriptor of structural response to environment, whereas solvent-accessibility, radius of gyration, and fluctuations were only locally relevant. Backbone hydrogen bonds decreased systematically with temperature in all simulations (~9 per 50 K), probing structural changes associated with enthalpy-entropy compensation. Approaching T opt (~350 K) from 300 K, this change correlated with a beginning "unzipping" of critical beta sheets. 0 M ionic strength triggered partial denucleation of the C-terminal (known experimentally to be sensitive) at 400 K, suggesting a general salt stabilization effect. In contrast, F(-) (but not Cl(-)) specifically impaired secondary structure by formation of strong hydrogen bonds with backbone NH, providing a mechanism for experimentally observed small anion destabilization, potentially remedied by site-directed mutagenesis at critical intrusion sites. N glycosylation was found to support structural integrity by increasing persistent backbone hydrogen bonds by ~4 across simulations, mainly via prevention of F(-) intrusion. Hydrogen-bond loss in distinct loop regions and ends of critical beta sheets suggest potential strategies for laboratory optimization of these industrially important enzymes. PMID- 23658619 TI - Changing emergence of Shigella sero-groups in Bangladesh: observation from four different diarrheal disease hospitals. AB - BACKGROUND: Shigellosis continues to be a public health challenge for developing countries, including Bangladesh. The aim of the study is to demonstrate recent changes in Shigella sero-groups and their geographical diversity. METHODS: Data were extracted from data archive of four diarrheal disease surveillance systems. A 2% sub sample from urban Dhaka Hospital (2008-2011; n = 10,650), and 10% from urban Mirpur Treatment Centre (2009-2011; n = 3,585), were enrolled systematically; whereas, all patients coming from the Health and Demographic Surveillance System area in rural Matlab (2008-2011; n = 6,399) and rural Mirzapur (2010-2011; n = 2,812) were included irrespective of age, sex, and disease severity. A fresh stool specimen was collected for identification of Shigella spp. Of them, 315 (3%) were positive for Shigella in Dhaka, 490 (8%) from Matlab, 109 (3%) from Mirpur and 369 (13%) from Mirzapur and considered as analyzable sample size. RESULTS: Among all Shigella isolates regardless of age, significant decreases in percentage of S. flexneri over time was observed in Mirpur (55->29%; p value of chi(2)-for trend = 0.019) and Mirzapur (59->47%; p = 0.025). A non-significant decrease was also seen in Dhaka (58->48%), while in Matlab there was a non-significant increase (73->81%). Similar patterns were observed among under-5 children at all sites. Emergence of S. sonnei was found in Dhaka (8->25%; p<0.001) and Mirpur (10->33%; p = 0.015), whereas it decreased in Mirzapur (32->23%; p = 0.056). The emergence of S. boydii was seen in all ages in Mirzapur [(3->28%; p<0.001); (3->27%; p<0.001)]. On the other hand, we saw non significant percent reductions in S. boydii in Dhaka [overall (25->16%); under-5 (16->9%)]. Decreasing rates of Shigella dysenteriae were observed in Matlab, Mirpur and Mirzapur; whereas, in Dhaka it remained unchanged. CONCLUSION AND SIGNIFICANCE: Emergence of S. sonnei and S. boydii as important infectious diarrhea etiologies and variations in geographical diversity underscore the need for monitoring, with possible implications for vaccine development. PMID- 23658620 TI - Behavioural profiles in captive-bred cynomolgus macaques: towards monkey models of mental disorders? AB - BACKGROUND: To date, experimental and preclinical studies on neuropsychiatric conditions have almost exclusively been performed in experimentally-induced animal models and have only rarely relied upon an ethological approach where animals have been observed in more naturalistic settings. The laboratory species of choice has been the rodent while the potential of more closely-related non human primates have remained largely underexplored. METHODS: The present study, therefore, aimed at investigating the possible existence of spontaneous atypical/abnormal behaviours displayed by 40 cynomolgus macaques in captive conditions using an unbiased ethological scan-sampling analysis followed by multifactorial correspondence analysis and a hierarchical clustering. RESULTS: The study identified five distinct profiles (groups A to E) that significantly differed on several behaviours, body postures, body orientations, gaze directions and locations in the cage environment. We suggest that animals from the low n groups (D and E) present depressive-like and anxious-like symptoms, reminiscent of depressive and generalized anxiety disorders. Inter-individual differences were highlighted through unbiased ethological observations of spontaneous behaviours and associated parameters, although these were not associated with differences in plasma or cerebrospinal fluid levels of either stress-related hormones or monoamines, i.e. in accordance with the human situation. CONCLUSIONS: No interventional behavioural testing was required to discriminate between 3 typical and 2 atypical ethologically-defined behavioural profiles, reminiscent of certain depressive-like and anxiety-like symptoms. The use of unbiased behavioural observations might, thus, allow the identification of animal models of human mental/behavioural disorders and their most appropriate control groups. PMID- 23658621 TI - Altitudinal variations of ground tissue and xylem tissue in terminal shoot of woody species: implications for treeline formation. AB - 1. The terminal shoot (or current-year shoot), as one of the most active parts on a woody plant, is a basic unit determining plant height and is potentially influenced by a variety of environmental factors. It has been predicted that tissues amount and their allocation in plant stems may play a critical role in determining plant size in alpine regions. The primary structure in terminal shoots is a key to our understanding treeline formation. The existing theories on treeline formation, however, are still largely lacking of evidence at the species level, much less from anatomy for the terminal shoot. 2. The primary structures within terminal shoot were measured quantitatively for 100 species from four elevation zones along the eastern slope of Gongga Mountain, southwestern China; one group was sampled from above the treeline. An allometric approach was employed to examine scaling relationships interspecifically, and a principal components analysis (PCA) was performed to test the relation among primary xylem, ground tissue, species growth form and altitude. 3. The results showed that xylem tissue size was closely correlated with ground tissue size isometrically across species, while undergoing significant y- or/and x-intercept shift in response to altitudinal belts. Further, a conspicuous characteristic of terminal shoot was its allocation of contrasting tissues between primary xylem and ground tissues with increasing elevation. The result of the PCA showed correlations between anatomical variation, species growth form/height classes and environment. 4. The current study presents a comparative assessment of the allocation of tissue in terminal shoot across phylogenically and ecologically diverse species, and analyzes tissue, function and climate associations with plant growth forms and height classes among species. The interspecific connection between primary xylem ratio and plant size along an elevation gradient suggests the importance of primary xylem in explaining the treeline formation. PMID- 23658622 TI - GA-responsive dwarfing gene Rht12 affects the developmental and agronomic traits in common bread wheat. AB - Opportunities exist for replacing reduced height (Rht) genes Rht-B1b and Rht-D1b with alternative dwarfing genes, such as the gibberellin-responsive gene Rht12, for bread wheat improvement. However, a comprehensive understanding of the effects and mode of action of Rht12 is lacking. In the present study, the effects of Rht12 were characterized by analyzing its effects on seeding vigour, seedling roots, leaf and stem morphology, spike development and carbohydrate assimilation and distribution. This was carried out in the four genotypes of F2:3 lines derived from a cross between Ningchun45 and Karcagi (12) in two experiments of autumn sowing and spring sowing. Rht12 significantly decreased stem length (43%~48% for peduncle) and leaf length (25%~30% for flag leaf) while the thickness of the internode walls and width of the leaves were increased. Though the final plant stature was shortened (40%) by Rht12, the seedling vigour, especially coleoptile length and root traits at the seedling stage, were not affected adversely. Rht12 elongated the duration of the spike development phase, improved the proportion of spike dry weight at anthesis and significantly increased floret fertility (14%) in the autumn sowing experiment. However, Rht12 delayed anthesis date by around 5 days and even the dominant Vrn-B1 allele could not compensate this negative effect. Additionally, grain size was reduced with the ability to support spike development after anthesis decreased in Rht12 lines. Finally, grain yield was similar between the dwarf and tall lines in the autumn sowing experiment. Thus, Rht12 could substantially reduce plant height without altering seeding vigour and significantly increase spikelet fertility in the favourable autumn sowing environment. The successful utilization of Rht12 in breeding programs will require careful selection since it might delay ear emergence. Nonetheless, the potential exists for wheat improvement by using Rht12. PMID- 23658623 TI - Curcumin inhibits CD4(+) T cell activation, but augments CD69 expression and TGF beta1-mediated generation of regulatory T cells at late phase. AB - BACKGROUND: Curcumin is a promising candidate for a natural medicinal agent to treat chronic inflammatory diseases. Although CD4(+) T cells have been implicated in the pathogenesis of chronic inflammation, whether curcumin directly regulates CD4(+) T cells has not been definitively established. Here, we showed curcumin mediated regulation of CD2/CD3/CD28-initiated CD4(+) T cell activation in vitro. METHODOLOGY/PRINCIPAL FINDINGS: Primary human CD4(+) T cells were stimulated with anti-CD2/CD3/CD28 antibody-coated beads as an in vitro surrogate system for antigen presenting cell-T cell interaction and treated with curcumin. We found that curcumin suppresses CD2/CD3/CD28-initiated CD4(+) T cell activation by inhibiting cell proliferation, differentiation and cytokine production. On the other hand, curcumin attenuated the spontaneous decline of CD69 expression and indirectly increased expression of CCR7, L-selectin and Transforming growth factor-beta1 (TGF-beta1) at the late phase of CD2/CD3/CD28-initiated T cell activation. Curcumin-mediated up-regulation of CD69 at late phase was associated with ERK1/2 signaling. Furthermore, TGF-beta1 was involved in curcumin-mediated regulation of T cell activation and late-phase generation of regulatory T cells. CONCLUSIONS/SIGNIFICANCE: Curcumin not merely blocks, but regulates CD2/CD3/CD28 initiated CD4(+) T cell activation by augmenting CD69, CCR7, L-selectin and TGF beta1 expression followed by regulatory T cell generation. These results suggest that curcumin could directly reduce T cell-dependent inflammatory stress by modulating CD4(+) T cell activation at multiple levels. PMID- 23658625 TI - Metaphor identification in large texts corpora. AB - Identifying metaphorical language-use (e.g., sweet child) is one of the challenges facing natural language processing. This paper describes three novel algorithms for automatic metaphor identification. The algorithms are variations of the same core algorithm. We evaluate the algorithms on two corpora of Reuters and the New York Times articles. The paper presents the most comprehensive study of metaphor identification in terms of scope of metaphorical phrases and annotated corpora size. Algorithms' performance in identifying linguistic phrases as metaphorical or literal has been compared to human judgment. Overall, the algorithms outperform the state-of-the-art algorithm with 71% precision and 27% averaged improvement in prediction over the base-rate of metaphors in the corpus. PMID- 23658624 TI - Differential effects of motor efference copies and proprioceptive information on response evaluation processes. AB - It is well-kown that sensory information influences the way we execute motor responses. However, less is known about if and how sensory and motor information are integrated in the subsequent process of response evaluation. We used a modified Simon Task to investigate how these streams of information are integrated in response evaluation processes, applying an in-depth neurophysiological analysis of event-related potentials (ERPs), time-frequency decomposition and sLORETA. The results show that response evaluation processes are differentially modulated by afferent proprioceptive information and efference copies. While the influence of proprioceptive information is mediated via oscillations in different frequency bands, efference copy based information about the motor execution is specifically mediated via oscillations in the theta frequency band. Stages of visual perception and attention were not modulated by the interaction of proprioception and motor efference copies. Brain areas modulated by the interactive effects of proprioceptive and efference copy based information included the middle frontal gyrus and the supplementary motor area (SMA), suggesting that these areas integrate sensory information for the purpose of response evaluation. The results show how motor response evaluation processes are modulated by information about both the execution and the location of a response. PMID- 23658626 TI - "Self" versus "non-self" connectivity dictates properties of synaptic transmission and plasticity. AB - Autapses are connections between a neuron and itself. These connections are morphologically similar to "normal" synapses between two different neurons, and thus were long thought to have similar properties of synaptic transmission. However, this has not been directly tested. Here, using a micro-island culture assay in which we can define the number of interconnected cells, we directly compared synaptic transmission in excitatory autapses and in two-neuron micronetworks consisting of two excitatory neurons, in which a neuron is connected to one other neuron and to itself. We discovered that autaptic synapses are optimized for maximal transmission, and exhibited enhanced EPSC amplitude, charge, and RRP size compared to interneuronal synapses. However, autapses are deficient in several aspects of synaptic plasticity. Short-term potentiation only became apparent when a neuron was connected to another neuron. This acquisition of plasticity only required reciprocal innervation with one other neuron; micronetworks consisting of just two interconnected neurons exhibited enhanced short-term plasticity in terms of paired pulse ratio (PPR) and release probability (Pr), compared to autapses. Interestingly, when a neuron was connected to another neuron, not only interneuronal synapses, but also the autaptic synapses on itself exhibited a trend toward enhanced short-term plasticity in terms of PPR and Pr. Thus neurons can distinguish whether they are connected via "self" or "non-self" synapses and have the ability to adjust their plasticity parameters when connected to other neurons. PMID- 23658627 TI - Identification of residues of SARS-CoV nsp1 that differentially affect inhibition of gene expression and antiviral signaling. AB - An epidemic of Severe Acute Respiratory Syndrome (SARS) led to the identification of an associated coronavirus, SARS-CoV. This virus evades the host innate immune response in part through the expression of its non-structural protein (nsp) 1, which inhibits both host gene expression and virus- and interferon (IFN) dependent signaling. Thus, nsp1 is a promising target for drugs, as inhibition of nsp1 would make SARS-CoV more susceptible to the host antiviral defenses. To gain a better understanding of nsp1 mode of action, we generated and analyzed 38 mutants of the SARS-CoV nsp1, targeting 62 solvent exposed residues out of the 180 amino acid protein. From this work, we identified six classes of mutants that abolished, attenuated or increased nsp1 inhibition of host gene expression and/or antiviral signaling. Each class of mutants clustered on SARS-CoV nsp1 surface and suggested nsp1 interacts with distinct host factors to exert its inhibitory activities. Identification of the nsp1 residues critical for its activities and the pathways involved in these activities should help in the design of drugs targeting nsp1. Significantly, several point mutants increased the inhibitory activity of nsp1, suggesting that coronaviruses could evolve a greater ability to evade the host response through mutations of such residues. PMID- 23658628 TI - Pepsin digest of wheat gliadin fraction increases production of IL-1beta via TLR4/MyD88/TRIF/MAPK/NF-kappaB signaling pathway and an NLRP3 inflammasome activation. AB - Celiac disease (CD) is a gluten-responsive, chronic inflammatory enteropathy. IL 1 cytokine family members IL-1beta and IL-18 have been associated with the inflammatory conditions in CD patients. However, the mechanisms of IL-1 molecule activation in CD have not yet been elucidated. We show in this study that peripheral blood mononuclear cells (PBMC) and monocytes from celiac patients responded to pepsin digest of wheat gliadin fraction (PDWGF) by a robust secretion of IL-1beta and IL-1alpha and a slightly elevated production of IL-18. The analysis of the upstream mechanisms underlying PDWGF-induced IL-1beta production in celiac PBMC show that PDWGF-induced de novo pro-IL-1beta synthesis, followed by a caspase-1 dependent processing and the secretion of mature IL 1beta. This was promoted by K+ efflux and oxidative stress, and was independent of P2X7 receptor signaling. The PDWGF-induced IL-1beta release was dependent on Nod-like receptor family containing pyrin domain 3 (NLRP3) and apoptosis associated speck like protein (ASC) as shown by stimulation of bone marrow derived dendritic cells (BMDC) from NLRP3(-/-) and ASC(-/-) knockout mice. Moreover, treatment of human PBMC as well as MyD88(-/-) and Toll-interleukin-1 receptor domain-containing adaptor-inducing interferon-beta (TRIF)(-/-) BMDC illustrated that prior to the activation of caspase-1, the PDWGF-triggered signal constitutes the activation of the MyD88/TRIF/MAPK/NF-kappaB pathway. Moreover, our results indicate that the combined action of TLR2 and TLR4 may be required for optimal induction of IL-1beta in response to PDWGF. Thus, innate immune pathways, such as TLR2/4/MyD88/TRIF/MAPK/NF-kappaB and an NLRP3 inflammasome activation are involved in wheat proteins signaling and may play an important role in the pathogenesis of CD. PMID- 23658629 TI - Mechanism of intramembrane cleavage of alcadeins by gamma-secretase. AB - BACKGROUND: Alcadein proteins (Alcs; Alcalpha, Alcbetaand Alcgamma) are predominantly expressed in neurons, as is Alzheimer's beta-amyloid (Abeta) precursor protein (APP). Both Alcs and APP are cleaved by primary alpha- or beta secretase to generate membrane-associated C-terminal fragments (CTFs). Alc CTFs are further cleaved by gamma-secretase to secrete p3-Alc peptide along with the release of intracellular domain fragment (Alc ICD) from the membrane. In the case of APP, APP CTFbeta is initially cleaved at the epsilon-site to release the intracellular domain fragment (AICD) and consequently the gamma-site is determined, by which Abeta generates. The initial epsilon-site is thought to define the final gamma-site position, which determines whether Abeta40/43 or Abeta42 is generated. However, initial intracellular epsilon-cleavage sites of Alc CTF to generate Alc ICD and the molecular mechanism that final gamma-site position is determined remains unclear in Alcs. METHODOLOGY: Using HEK293 cells expressing Alcs plus presenilin 1 (PS1, a catalytic unit of gamma-secretase) and the membrane fractions of these cells, the generation of p3-Alc possessing C terminal gamma-cleavage site and Alc ICD possessing N-terminal epsilon-cleavage site were analysed with MALDI-TOF/MS. We determined the initial epsilon-site position of all Alcalpha, Alcbeta and Alcgamma, and analyzed the relationship between the initially determined epsilon-site position and the final gamma cleavage position. CONCLUSIONS: The initial epsilon-site position does not always determine the final gamma-cleavage position in Alcs, which differed from APP. No additional gamma-cleavage sites are generated from artificial/non-physiological positions of epsilon-cleavage for Alcs, while the artificial epsilon-cleavage positions can influence in selection of physiological gamma-site positions. Because alteration of gamma-secretase activity is thought to be a pathogenesis of sporadic Alzheimer's disease, Alcs are useful and sensitive substrate to detect the altered cleavage of substrates by gamma-secretase, which may be induced by malfunction of gamma-secretase itself or changes of membrane environment for enzymatic reaction. PMID- 23658630 TI - Spaceflight promotes biofilm formation by Pseudomonas aeruginosa. AB - Understanding the effects of spaceflight on microbial communities is crucial for the success of long-term, manned space missions. Surface-associated bacterial communities, known as biofilms, were abundant on the Mir space station and continue to be a challenge on the International Space Station. The health and safety hazards linked to the development of biofilms are of particular concern due to the suppression of immune function observed during spaceflight. While planktonic cultures of microbes have indicated that spaceflight can lead to increases in growth and virulence, the effects of spaceflight on biofilm development and physiology remain unclear. To address this issue, Pseudomonas aeruginosa was cultured during two Space Shuttle Atlantis missions: STS-132 and STS-135, and the biofilms formed during spaceflight were characterized. Spaceflight was observed to increase the number of viable cells, biofilm biomass, and thickness relative to normal gravity controls. Moreover, the biofilms formed during spaceflight exhibited a column-and-canopy structure that has not been observed on Earth. The increase in the amount of biofilms and the formation of the novel architecture during spaceflight were observed to be independent of carbon source and phosphate concentrations in the media. However, flagella-driven motility was shown to be essential for the formation of this biofilm architecture during spaceflight. These findings represent the first evidence that spaceflight affects community-level behaviors of bacteria and highlight the importance of understanding how both harmful and beneficial human-microbe interactions may be altered during spaceflight. PMID- 23658631 TI - MabsBase: a Mycobacterium abscessus genome and annotation database. AB - SUMMARY: Mycobacterium abscessus is a rapidly growing non-tuberculous mycobacterial species that has been associated with a wide spectrum of human infections. As the classification and biology of this organism is still not well understood, comparative genomic analysis on members of this species may provide further insights on their taxonomy, phylogeny, pathogenicity and other information that may contribute to better management of infections. The MabsBase described in this paper is a user-friendly database providing access to whole genome sequences of newly discovered M. abscessus strains as well as resources for whole-genome annotations and computational predictions, to support the expanding scientific community interested in M. abscessus research. The MabsBase is freely available at http://mabscessus.um.edu.my. PMID- 23658633 TI - Trend of urban-rural disparities in hospice utilization in Taiwan. AB - AIMS: The palliative care has spread rapidly worldwide in the recent two decades. The development of hospice services in rural areas usually lags behind that in urban areas. The aim of our study was to investigate whether the urban-rural disparity widens in a country with a hospital-based hospice system. METHODS: From the nationwide claims database within the National Health Insurance in Taiwan, admissions to hospices from 2000 to 2006 were identified. Hospices and patients in each year were analyzed according to geographic location and residence. RESULTS: A total of 26,292 cancer patients had been admitted to hospices. The proportion of rural patients to all patients increased with time from 17.8% in 2000 to 25.7% in 2006. Although the numbers of beds and the utilizations in both urban and rural hospices expanded rapidly, the increasing trend in rural areas was more marked than that in urban areas. However, still two-thirds (898/1,357) of rural patients were admitted to urban hospices in 2006. CONCLUSIONS: The gap of hospice utilizations between urban and rural areas in Taiwan did not widen with time. There was room for improvement in sufficient supply of rural hospices or efficient referral of rural patients. PMID- 23658632 TI - A cryptic cytoplasmic male sterility unveils a possible gynodioecious past for Arabidopsis thaliana. AB - Gynodioecy, the coexistence of hermaphrodites and females (i.e. male-sterile plants) in natural plant populations, most often results from polymorphism at genetic loci involved in a particular interaction between the nuclear and cytoplasmic genetic compartments (cytonuclear epistasis): cytoplasmic male sterility (CMS). Although CMS clearly contributes to the coevolution of involved nuclear loci and cytoplasmic genomes in gynodioecious species, the occurrence of CMS genetic factors in the absence of sexual polymorphism (cryptic CMS) is not easily detected and rarely taken in consideration. We found cryptic CMS in the model plant Arabidopsis thaliana after crossing distantly related accessions, Sha and Mr-0. Male sterility resulted from an interaction between the Sha cytoplasm and two Mr-0 genomic regions located on chromosome 1 and chromosome 3. Additional accessions with either nuclear sterility maintainers or sterilizing cytoplasms were identified from crosses with either Sha or Mr-0. By comparing two very closely related cytoplasms with different male-sterility inducing abilities, we identified a novel mitochondrial ORF, named orf117Sha, that is most likely the sterilizing factor of the Sha cytoplasm. The presence of orf117Sha was investigated in worldwide natural accessions. It was found mainly associated with a single chlorotype in accessions belonging to a clade predominantly originating from Central Asia. More than one-third of accessions from this clade carried orf117Sha, indicating that the sterilizing-inducing cytoplasm had spread in this lineage. We also report the coexistence of the sterilizing cytoplasm with a non sterilizing cytoplasm at a small, local scale in a natural population; in addition a correlation between cytotype and nuclear haplotype was detected in this population. Our results suggest that this CMS system induced sexual polymorphism in A. thaliana populations, at the time when the species was mainly outcrossing. PMID- 23658634 TI - miR-132/212 knockout mice reveal roles for these miRNAs in regulating cortical synaptic transmission and plasticity. AB - miR-132 and miR-212 are two closely related miRNAs encoded in the same intron of a small non-coding gene, which have been suggested to play roles in both immune and neuronal function. We describe here the generation and initial characterisation of a miR-132/212 double knockout mouse. These mice were viable and fertile with no overt adverse phenotype. Analysis of innate immune responses, including TLR-induced cytokine production and IFNbeta induction in response to viral infection of primary fibroblasts did not reveal any phenotype in the knockouts. In contrast, the loss of miR-132 and miR-212, while not overtly affecting neuronal morphology, did affect synaptic function. In both hippocampal and neocortical slices miR-132/212 knockout reduced basal synaptic transmission, without affecting paired-pulse facilitation. Hippocampal long-term potentiation (LTP) induced by tetanic stimulation was not affected by miR-132/212 deletion, whilst theta burst LTP was enhanced. In contrast, neocortical theta burst-induced LTP was inhibited by loss of miR-132/212. Together these results indicate that miR-132 and/or miR-212 play a significant role in synaptic function, possibly by regulating the number of postsynaptic AMPA receptors under basal conditions and during activity-dependent synaptic plasticity. PMID- 23658635 TI - Enhanced production of bovine chymosin by autophagy deficiency in the filamentous fungus Aspergillus oryzae. AB - Aspergillus oryzae has been utilized as a host for heterologous protein production because of its high protein secretory capacity and food-safety properties. However, A. oryzae often produces lower-than-expected yields of target heterologous proteins due to various underlying mechanisms, including degradation processes such as autophagy, which may be a significant bottleneck for protein production. In the present study, we examined the production of heterologous protein in several autophagy (Aoatg) gene disruptants of A. oryzae. We transformed A. oryzae gene disruptants of Aoatg1, Aoatg13, Aoatg4, Aoatg8, or Aoatg15, with a bovine chymosin (CHY) expression construct and found that the production levels of CHY increased up to three fold compared to the control strain. Notably, however, conidia formation by the Aoatg gene disruptants was significantly reduced. As large amounts of conidia are necessary for inoculating large-scale cultures, we also constructed Aoatg gene-conditional expression strains in which the promoter region of the Aoatg gene was replaced with the thiamine-controllable thiA promoter. Conidiation by the resultant transformants was clearly enhanced in the absence of thiamine, while autophagy remained repressed in the presence of thiamine. Moreover, these transformants displayed increased CHY productivity, which was comparable to that of the Aoatg gene disruptants. Consequently, we succeeded in the construction of A. oryzae strains capable of producing high levels of CHY due to defects in autophagy. Our finding suggests that the conditional regulation of autophagy is an effective method for increasing heterologous protein production in A. oryzae. PMID- 23658637 TI - Experimentally simulating paternity uncertainty: immediate and long-term responses of male and female reed warblers Acrocephalus scirpaceus. AB - In many socially monogamous species, both sexes seek copulation outside the pair bond in order to increase their reproductive success. In response, males adopt counter-strategies to combat the risk of losing paternity. However, no study so far has tried to experimentally prove the function of behaviour for paternity assurance. Introducing a potential extra-pair partner during the female fertile period provides a standardised method to examine how pair members respond immediately (e.g. increase mate guarding or copulation frequency) or long term (e.g. later parental investment and paternity uncertainty). In this study on a socially monogamous passerine species, we experimentally confronted pairs of reed warblers with a conspecific male (caged male simulating an intruder) during egg laying. Our results revealed that occurrence of an intruder during that period triggered aggression against the intruder, depending on the presence of the female. The male territory owner also attacked the female partner to drive her away from the intruder. Thus territory defence in reed warblers also serves to protect paternity. The increase in paternity uncertainty did not affect later paternal investment. Paternal investment was also independent of the actual paternity losses. In females, the experiment elicited both, immediate and long term responses. E.g. female copulation solicitations during the intruder experiment were only observed for females which later turned out to have extra pair chicks in their nest. In relation to long term response females faced with an intruder invested later less in offspring feeding, and had less extra-pair chicks in their nests. Extra-pair paternity also seems to be affected by female quality (body size). In conclusion female reed warblers seem to seek extra-pair fertilizations but we could demonstrate that males adopt paternity assurance tactics which seems to efficiently help them to reduce paternity uncertainty. PMID- 23658636 TI - Candidate gene study of TRAIL and TRAIL receptors: association with response to interferon beta therapy in multiple sclerosis patients. AB - TRAIL and TRAIL Receptor genes have been implicated in Multiple Sclerosis pathology as well as in the response to IFN beta therapy. The objective of our study was to evaluate the association of these genes in relation to the age at disease onset (AAO) and to the clinical response upon IFN beta treatment in Spanish MS patients. We carried out a candidate gene study of TRAIL, TRAILR-1, TRAILR-2, TRAILR-3 and TRAILR-4 genes. A total of 54 SNPs were analysed in 509 MS patients under IFN beta treatment, and an additional cohort of 226 MS patients was used to validate the results. Associations of rs1047275 in TRAILR-2 and rs7011559 in TRAILR-4 genes with AAO under an additive model did not withstand Bonferroni correction. In contrast, patients with the TRAILR-1 rs20576-CC genotype showed a better clinical response to IFN beta therapy compared with patients carrying the A-allele (recessive model: p = 8.88*10(-4), pc = 0.048, OR = 0.30). This SNP resulted in a non synonymous substitution of Glutamic acid to Alanine in position 228 (E228A), a change previously associated with susceptibility to different cancer types and risk of metastases, suggesting a lack of functionality of TRAILR-1. In order to unravel how this amino acid change in TRAILR-1 would affect to death signal, we performed a molecular modelling with both alleles. Neither TRAIL binding sites in the receptor nor the expression levels of TRAILR-1 in peripheral blood mononuclear cell subsets (monocytes, CD4+ and CD8+ T cells) were modified, suggesting that this SNP may be altering the death signal by some other mechanism. These findings show a role for TRAILR-1 gene variations in the clinical outcome of IFN beta therapy that might have relevance as a biomarker to predict the response to IFN beta in MS. PMID- 23658638 TI - Magnetic resonance imaging of mouse islet grafts labeled with novel chitosan coated superparamagnetic iron oxide nanoparticles. AB - OBJECT: To better understand the fate of islet isografts and allografts, we utilized a magnetic resonance (MR) imaging technique to monitor mouse islets labeled with a novel MR contrast agent, chitosan-coated superparamagnetic iron oxide (CSPIO) nanoparticles. MATERIALS AND METHODS: After being incubated with and without CSPIO (10 ug/ml), C57BL/6 mouse islets were examined under transmission electron microscope (TEM) and their insulin secretion was measured. Cytotoxicity was examined in alpha (alphaTC1) and beta (NIT-1 and betaTC) cell lines as well as islets. C57BL/6 mice were used as donors and inbred C57BL/6 and Balb/c mice were used as recipients of islet transplantation. Three hundred islets were transplanted under the left kidney capsule of each mouse and then MR was performed in the recipients periodically. At the end of study, the islet graft was removed for histology and TEM studies. RESULTS: After incubation of mouse islets with CSPIO (10 ug/mL), TEM showed CSPIO in endocytotic vesicles of alpha- and beta-cells at 8 h. Incubation with CSPIO did not affect insulin secretion from islets and death rates of alphaTC1, NIT-1 and betaTC cell lines as well as islets. After syngeneic and allogeneic transplantation, grafts of CSPIO labeled islets were visualized on MR scans as persistent hypointense areas. At 8 weeks after syngeneic transplantation and 31 days after allogeneic transplantation, histology of CSPIO-labeled islet grafts showed colocalized insulin and iron staining in the same areas but the size of allografts decreased with time. TEM with elementary iron mapping demonstrated CSPIO distributed in the cytoplasm of islet cells, which maintained intact ultrastructure. CONCLUSION: Our results indicate that after syngeneic and allogeneic transplantation, islets labeled with CSPIO nanoparticles can be effectively and safely imaged by MR. PMID- 23658639 TI - Leaf litter mixtures alter microbial community development: mechanisms for non additive effects in litter decomposition. AB - To what extent microbial community composition can explain variability in ecosystem processes remains an open question in ecology. Microbial decomposer communities can change during litter decomposition due to biotic interactions and shifting substrate availability. Though relative abundance of decomposers may change due to mixing leaf litter, linking these shifts to the non-additive patterns often recorded in mixed species litter decomposition rates has been elusive, and links community composition to ecosystem function. We extracted phospholipid fatty acids (PLFAs) from single species and mixed species leaf litterbags after 10 and 27 months of decomposition in a mixed conifer forest. Total PLFA concentrations were 70% higher on litter mixtures than single litter types after 10 months, but were only 20% higher after 27 months. Similarly, fungal-to-bacterial ratios differed between mixed and single litter types after 10 months of decomposition, but equalized over time. Microbial community composition, as indicated by principal components analyses, differed due to both litter mixing and stage of litter decomposition. PLFA biomarkers a15?0 and cy17?0, which indicate gram-positive and gram-negative bacteria respectively, in particular drove these shifts. Total PLFA correlated significantly with single litter mass loss early in decomposition but not at later stages. We conclude that litter mixing alters microbial community development, which can contribute to synergisms in litter decomposition. These findings advance our understanding of how changing forest biodiversity can alter microbial communities and the ecosystem processes they mediate. PMID- 23658640 TI - The roles of noradrenergic and glucocorticoid activation in the development of intrusive memories. AB - Intrusive memories are a common feature of many psychological disorders. Recent evidence has potentially extended cognitive models of intrusions by identifying the role of biological markers of arousal at the time of consolidation in subsequent memory for emotional events. This study investigated the role of arousal during consolidation in the development of intrusive memories. Seventy eight university students (37 men and 41 women) viewed 20 negative and 20 neutral images. Half the participants then underwent a cold pressor test (High Stress), immersing their hand in ice water, while the remaining participants immersed their hand in warm water (Low Stress). Samples of salivary alpha-amylase (sAA) and cortisol were collected from participants at baseline and following the stressor challenge. Participants completed a delayed free recall test and intrusion questionnaires two days later. Participants in the High Stress condition reported more intrusions of negative images than participants in the Low Stress condition. An interaction variable in a linear regression of increased noradrenergic and cortisol values predicted intrusive memories of emotional stimuli for men but not women. These findings are consistent with recent evidence of the combined effects of noradrenaline and corticoid responses to stress on emotional memories, and also with increasing evidence of gender differences in how stress hormones influence formation of emotional memories. These findings point to possible mechanisms by which development of intrusions may be prevented after consolidation of traumatic experiences. PMID- 23658641 TI - Male-female differences in upregulation of vasoconstrictor responses in human cerebral arteries. AB - BACKGROUND AND PURPOSE: Male-female differences may significantly impact stroke prevention and treatment in men and women, however underlying mechanisms for sexual dimorphism in stroke are not understood. We previously found in males that cerebral ischemia upregulates contractile receptors in cerebral arteries, which is associated with lower blood flow. The present study investigates if cerebral arteries from men and women differ in cerebrovascular receptor upregulation. EXPERIMENTAL APPROACH: Freshly obtained human cerebral arteries were placed in organ culture, an established model for studying receptor upregulation. 5 hydroxtryptamine type 1B (5-HT1B), angiotensin II type 1 (AT1) and endothelin-1 type A and B (ETA and ETB) receptors were evaluated using wire myograph for contractile responses, real-time PCR for mRNA and immunohistochemistry for receptor expression. KEY RESULTS: Vascular sensitivity to angiotensin II and endothelin-1 was markedly lower in cultured cerebral arteries from women as compared to men. ETB receptor-mediated contraction occurred in male but not female arteries. Interestingly, there were similar upregulation in mRNA and expression of 5-HT1B, AT1, and ETB receptors and in local expression of Ang II after organ culture. CONCLUSIONS AND IMPLICATIONS: In spite of receptor upregulation after organ culture in both sexes, cerebral arteries from women were significantly less responsive to vasoconstrictors angiotensin II and endothelin-1 as compared to arteries from men. This suggests receptor coupling and/or signal transduction mechanisms involved in cerebrovascular contractility may be suppressed in females. This is the first study to demonstrate sex differences in the vascular function of human brain arteries. PMID- 23658642 TI - AKAP13 Rho-GEF and PKD-binding domain deficient mice develop normally but have an abnormal response to beta-adrenergic-induced cardiac hypertrophy. AB - BACKGROUND: A-kinase anchoring proteins (AKAPs) are scaffolding molecules that coordinate and integrate G-protein signaling events to regulate development, physiology, and disease. One family member, AKAP13, encodes for multiple protein isoforms that contain binding sites for protein kinase A (PKA) and D (PKD) and an active Rho-guanine nucleotide exchange factor (Rho-GEF) domain. In mice, AKAP13 is required for development as null embryos die by embryonic day 10.5 with cardiovascular phenotypes. Additionally, the AKAP13 Rho-GEF and PKD-binding domains mediate cardiomyocyte hypertrophy in cell culture. However, the requirements for the Rho-GEF and PKD-binding domains during development and cardiac hypertrophy are unknown. METHODOLOGY/PRINCIPAL FINDINGS: To determine if these AKAP13 protein domains are required for development, we used gene-trap events to create mutant mice that lacked the Rho-GEF and/or the protein kinase D binding domains. Surprisingly, heterozygous matings produced mutant mice at Mendelian ratios that had normal viability and fertility. The adult mutant mice also had normal cardiac structure and electrocardiograms. To determine the role of these domains during beta-adrenergic-induced cardiac hypertrophy, we stressed the mice with isoproterenol. We found that heart size was increased similarly in mice lacking the Rho-GEF and PKD-binding domains and wild-type controls. However, the mutant hearts had abnormal cardiac contractility as measured by fractional shortening and ejection fraction. CONCLUSIONS: These results indicate that the Rho-GEF and PKD-binding domains of AKAP13 are not required for mouse development, normal cardiac architecture, or beta-adrenergic-induced cardiac hypertrophic remodeling. However, these domains regulate aspects of beta-adrenergic-induced cardiac hypertrophy. PMID- 23658643 TI - On the origins of signal variance in FMRI of the human midbrain at high field. AB - Functional Magnetic Resonance Imaging (fMRI) in the midbrain at 7 Tesla suffers from unexpectedly low temporal signal to noise ratio (TSNR) compared to other brain regions. Various methodologies were used in this study to quantitatively identify causes of the noise and signal differences in midbrain fMRI data. The influence of physiological noise sources was examined using RETROICOR, phase regression analysis, and power spectral analyses of contributions in the respiratory and cardiac frequency ranges. The impact of between-shot phase shifts in 3-D multi-shot sequences was tested using a one-dimensional (1-D) phase navigator approach. Additionally, the effects of shared noise influences between regions that were temporally, but not functionally, correlated with the midbrain (adjacent white matter and anterior cerebellum) were investigated via analyses with regressors of 'no interest'. These attempts to reduce noise did not improve the overall TSNR in the midbrain. In addition, the steady state signal and noise were measured in the midbrain and the visual cortex for resting state data. We observed comparable steady state signals from both the midbrain and the cortex. However, the noise was 2-3 times higher in the midbrain relative to the cortex, confirming that the low TSNR in the midbrain was not due to low signal but rather a result of large signal variance. These temporal variations did not behave as known physiological or other noise sources, and were not mitigated by conventional strategies. Upon further investigation, resting state functional connectivity analysis in the midbrain showed strong intrinsic fluctuations between homologous midbrain regions. These data suggest that the low TSNR in the midbrain may originate from larger signal fluctuations arising from functional connectivity compared to cortex, rather than simply reflecting physiological noise. PMID- 23658644 TI - Rhinovirus and dsRNA induce RIG-I-like receptors and expression of interferon beta and lambda1 in human bronchial smooth muscle cells. AB - Rhinovirus (RV) infections cause exacerbations and development of severe asthma highlighting the importance of antiviral interferon (IFN) defence by airway cells. Little is known about bronchial smooth muscle cell (BSMC) production of IFNs and whether BSMCs have dsRNA-sensing receptors besides TLR3. dsRNA is a rhinoviral replication intermediate and necrotic cell effect mimic that mediates innate immune responses in bronchial epithelial cells. We have explored dsRNA evoked IFN-beta and IFN-lambda1 production in human BSMCs and potential involvement of TLR3 and RIG-I-like receptors (RLRs). Primary BSMCs were stimulated with 0.1-10 ug/ml dsRNA, 0.1-1 ug/ml dsRNA in complex with the transfection agent LyoVec (dsRNA/LyoVec; selectively activating cytosolic RLRs) or infected with 0.05-0.5 MOI RV1B. Both dsRNA stimuli evoked early (3 h), concentration-dependent IFN-beta and IFN-lambda1 mRNA expression, which with dsRNA/LyoVec was much greater, and with dsRNA was much less, after 24 h. The effects were inhibited by dexamethasone. Further, dsRNA and dsRNA/LyoVec concentration-dependently upregulated RIG-I and MDA5 mRNA and protein. dsRNA and particularly dsRNA/LyoVec caused IFN-beta and IFN-lambda1 protein production (24 h). dsRNA- but not dsRNA/LyoVec-induced IFN expression was partly inhibited by chloroquine that suppresses endosomal TLR3 activation. RV1B dose-dependently increased BSMC expression of RIG-I, MDA5, IFN-beta, and IFN-lambda1 mRNA. We suggest that BSMCs express functional RLRs and that both RLRs and TLR3 are involved in viral stimulus-induced BSMC expression of IFN-beta and IFN-lambda1. PMID- 23658646 TI - Change in fish community structure in the Barents Sea. AB - Change in oceanographic conditions causes structural alterations in marine fish communities, but this effect may go undetected as most monitoring programs until recently mainly have focused on oceanography and commercial species rather than on whole ecosystems. In this paper, the objective is to describe the spatial and temporal changes in the Barents Sea fish community in the period 1992-2004 while taking into consideration the observed abundance and biodiversity patterns for all 82 observed fish species. We found that the spatial structure of the Barents Sea fish community was determined by abiotic factors such as temperature and depth. The observed species clustered into a deep assemblage, a warm water southern assemblage, both associated with Atlantic water, and a cold water north eastern assemblage associated with mixed water. The latitude of the cold water NE and warm water S assemblages varied from year to year, but no obvious northward migration was observed over time. In the period 1996-1999 we observed a significant reduction in total fish biomass, abundance, mean fish weight, and a change in community structure including an increase in the pelagic/demersal ratio. This change in community structure is probably due to extremely cold conditions in 1996 impacting on a fish community exposed to historically high fishing rates. After 1999 the fish community variables such as biomass, abundance, mean weight, P/D ratio as well as community composition did not return to levels of the early 90s, although fishing pressure and climatic conditions returned to earlier levels. PMID- 23658645 TI - HnRNP A1/A2 and SF2/ASF regulate alternative splicing of interferon regulatory factor-3 and affect immunomodulatory functions in human non-small cell lung cancer cells. AB - Heterogeneous nuclear ribonucleoparticule A1/A2 (hnRNP A1/A2) and splicing factor 2/alternative splicing factor (SF2/ASF) are pivotal for precursor messenger RNA (pre-mRNA) splicing. Interferon regulatory factor-3 (IRF-3) plays critical roles in host defense against viral and microbial infection. Truncated IRF-3 proteins resulting from alternative splicing have been identified and characterized as functional antagonists to full-length IRF-3. In this study, we examined the molecular mechanism for splicing regulation of IRF-3 pre-mRNA and first reported the regulatory effect of hnRNP A1/A2 and SF2/ASF on IRF-3 splicing and activation. RNA interference-mediated depletion of hnRNP A1/A2 or SF2/ASF in human non-small cell lung cancer (NSCLC) cells increased exclusion of exons 2 and 3 of IRF-3 gene and reduced expression levels of IRF-3 protein and IRF-3 downstream effector molecules interferon-beta and CXCL10/IP-10. In addition, direct binding of hnRNP A1 and SF2/ASF to specific binding motifs in IRF-3 intron 1 was confirmed by RNA electrophoretic mobility shift assay. Subsequent minigene splicing assay showed that IRF-3 minigenes with mutated hnRNPA 1/A2 or SF2/ASF binding motifs increased exclusion of exons 2 and 3. Moreover, knockdown of hnRNP A1/A2 or SF2/ASF in NSCLC cells reinforced phytohemagglutinin-induced tumor necrosis factor-alpha release by peripheral blood mononuclear cells (PBMC) but suppressed that of interleukin-10 in NSCLC/PBMC co-cultures. Taken together, our results suggest that specific knockdown for hnRNP A1/A2 or SF2/ASF increase exclusion of exons 2 and 3 of IRF-3 pre-mRNA and influence immunomodulatory functions of human NSCLC cells. PMID- 23658647 TI - Effects of regulating positive emotions through reappraisal and suppression on verbal and non-verbal recognition memory. AB - Previous research has suggested that regulating emotions through reappraisal does not incur cognitive costs. However, in those experiments, cognitive costs were often assessed by recognition memory for information that was contextually related to the emotionally evocative stimuli and may have been incorporated into the reappraisal script, facilitating memory. Furthermore, there is little research on the cognitive correlates of regulating positive emotions. In the current experiment, we tested memory for information that was contextually unrelated to the emotional stimuli and could not easily be related to the reappraisal. Participants viewed neutral and mildly positive slides and either reappraised, suppressed their emotions, or viewed the images with no emotion regulation instruction. At the same time, they heard abstract words that were unrelated to the picture stimuli. Subsequent verbal recognition memory was lower after reappraising than viewing, whereas non-verbal recognition memory (of the slides) was higher after reappraising, but only for positive pictures and when participants viewed the positive pictures first. Suppression had no significant effect on either verbal or non-verbal recognition scores, although there was a trend towards poorer recognition of verbal information. The findings support the notion that reappraisal is effortful and draws on limited cognitive resources, causing decrements in performance in a concurrent memory task. PMID- 23658648 TI - Methods for cryopreservation of guinea fowl sperm. AB - Conservation of indigenous poultry species is an important part of the new Hungarian agricultural strategy. Semen cryopreservation is the most practical method for the long term storage of poultry genetic material. The objective was to compare four protocols for cryopreservation of guinea fowl sperm (slow and fast programmable, freezing in nitrogen vapor, and pellet) and three cryoprotectants (10% ethylene glycol, 6% dimethyl-formamide and 6% dimethyl acetamide). The efficiency of the methods was examined by in vitro tests (subjective motility scoring, sperm concentration, morphological and live/dead sperm analysis with eosin-aniline staining). Thereafter, the two most promising methods were tested by artificial insemination of frozen-thawed semen (3 times a week for 3 weeks using 300 million spermatozoa/hen), followed by candling of incubated eggs, assessment of fertilization, embryonic death, and hatching rate. The survival rate of live, intact spermatozoa was greatest (p<=0.05) in pellet method and the slow programmable protocol (with 10% ethylene glycol) (28.6 and 23.5%). The two best protocols (based on in vitro assessment of post-thaw semen quality) were subsequently tested in vivo with artificial insemination. The pellet method yielded a 64% fertility rate compared to slow protocol with only 30% fertility. Regardless, both freezing protocols significantly increased embryonic deaths compared to the control group (16,7; 9,1 and 8,3%, respectively). During the 3-week in vivo trial, fertility increased and early embryonic death decreased over time. According to the results the guinea fowl sperm could tolerate the fast freezing in pellet better than the slower freezing rates and resulted acceptable fertility rate. PMID- 23658649 TI - Peripheral monocyte functions and activation in patients with quiescent Crohn's disease. AB - Recent developments suggest a causal link between inflammation and impaired bacterial clearance in Crohn's disease (CD) due to alterations of intestinal macrophages. Studies suggest that excessive inflammation is the consequence of an underlying immunodeficiency rather than the primary cause of CD pathogenesis. We characterized phenotypic and functional features of peripheral blood monocytes of patients with quiescent CD (n = 18) and healthy controls (n = 19) by analyses of cell surface molecule expression, cell adherence, migration, chemotaxis, phagocytosis, oxidative burst, and cytokine expression and secretion with or without lipopolysaccharide (LPS) priming. Peripheral blood monocytes of patients with inactive CD showed normal expression of cell surface molecules (CD14, CD16, CD116), adherence to plastic surfaces, spontaneous migration, chemotaxis towards LTB4, phagocytosis of E. coli, and production of reactive oxygen species. Interestingly, peripheral blood monocytes of CD patients secreted higher levels of IL1beta (p<.05). Upon LPS priming we found a decreased release of IL10 (p<.05) and higher levels of CCL2 (p<.001) and CCL5 (p<.05). The expression and release of TNFalpha, IFNgamma, IL4, IL6, IL8, IL13, IL17, CXCL9, and CXCL10 were not altered compared to healthy controls. Based on our phenotypic and functional studies, peripheral blood monocytes from CD patients in clinical remission were not impaired compared to healthy controls. Our results highlight that defective innate immune mechanisms in CD seems to play a role in the (inflamed) intestinal mucosa rather than in peripheral blood. PMID- 23658650 TI - Overexpression of CD97 confers an invasive phenotype in glioblastoma cells and is associated with decreased survival of glioblastoma patients. AB - Mechanisms of invasion in glioblastoma (GBM) relate to differential expression of proteins conferring increased motility and penetration of the extracellular matrix. CD97 is a member of the epidermal growth factor seven-span transmembrane family of adhesion G-protein coupled receptors. These proteins facilitate mobility of leukocytes into tissue. In this study we show that CD97 is expressed in glioma, has functional effects on invasion, and is associated with poor overall survival. Glioma cell lines and low passage primary cultures were analyzed. Functional significance was assessed by transient knockdown using siRNA targeting CD97 or a non-target control sequence. Invasion was assessed 48 hours after siRNA-mediated knockdown using a Matrigel-coated invasion chamber. Migration was quantified using a scratch assay over 12 hours. Proliferation was measured 24 and 48 hours after confirmed protein knockdown. GBM cell lines and primary cultures were found to express CD97. Knockdown of CD97 decreased invasion and migration in GBM cell lines, with no difference in proliferation. Gene expression based Kaplan-Meier analysis was performed using The Cancer Genome Atlas, demonstrating an inverse relationship between CD97 expression and survival. GBMs expressing high levels of CD97 were associated with decreased survival compared to those with low CD97 (p = 0.007). CD97 promotes invasion and migration in GBM, but has no effect on tumor proliferation. This phenotype may explain the discrepancy in survival between high and low CD97-expressing tumors. This data provides impetus for further studies to determine its viability as a therapeutic target in the treatment of GBM. PMID- 23658651 TI - Copy Number Change of the NDM-1 sequence in a multidrug-resistant Klebsiella pneumoniae clinical isolate. AB - The genetic features of the antimicrobial resistance of a multidrug resistant Klebsiella pneumoniae strain harboring bla NDM-1 were investigated to increase our understanding of the evolution of NDM-1. The strain, KPX, came from a Taiwanese patient with a hospitalization history in New Delhi. Complete DNA sequencing was performed; and the genes responsible for antimicrobial resistance were systematically examined and isolated by library screening. KPX harbored two resistance plasmids, pKPX-1 and pKPX-2, which are 250-kb and 141-kb in size, respectively, with bla NDM-1 present on pKPX-1. The plasmid pKPX-1 contained genes associated with the IncR and IncF groups, while pKPX-2 belonged to the IncF family. Each plasmid carried multiple antimicrobial resistance genetic determinants. The gene responsible for resistance to carbapenems was found on pKPX-1 and that for resistance to aztreonam was found on pKPX-2. To our surprise, we discovered that bla NDM-1 exists on pKPX-1 as multiple copies in the form of tandem repeats. Amplification of bla NDM-1 was found to occur by duplication of an 8.6-kb unit, with the copy number of the repeat varying from colony to colony. This repeat sequence is identical to that of the pNDM-MAR except for two base substitutions. The copy number of bla NDM-1 of colonies under different conditions was assessed by Southern blotting and quantitative PCR. The bla NDM-1 sequence was maintained in the presence of the antimicrobial selection; however, removal of antimicrobial selection led to the emergence of susceptible bacterial populations with a reduced copy number or even the complete loss of the bla NDM-1 sequence. The dynamic nature of the NDM-1 sequence provides a strong argument for judicious use of the broad-spectrum antimicrobials in order to reduce the development and spread of antimicrobial resistance among pathogens. PMID- 23658652 TI - CO2 mediated interaction in yeast stimulates budding and growth on minimal media. AB - Here we show that carbon dioxide (CO2) stimulates budding and shortens the lag period of Saccharomyces cerevisiae cultures, grown on specific weak media. CO2 can be both exogenous and secreted by another growing yeast culture. We also show that this effect can be observed only in the lag-period, and demonstrate minimal doses and duration of culture exposition to CO2. Opposite to the effects of CO2 sensitivity, previously shown for pathogens, where increased concentration of CO2 suppressed mitosis and stimulated cell differentiation and invasion, here it stimulates budding and culture growth. PMID- 23658653 TI - Changes in the circadian rhythm in patients with primary glaucoma. AB - PURPOSE: The current study was undertaken to investigate whether glaucoma affects the sleep quality and whether there is any difference between patients with primary glaucoma (primary open angle glaucoma, POAG and primary angle-closure glaucoma, PACG) and healthy subjects, using a validated self-rated questionnaire, the Pittsburgh Sleep Quality Index (PSQI). METHODS: The sleep quality of patients with POAG and PACG was tested against normal controls. Subjects were divided into three sub-groups according to age. Differences in the frequency of sleep disturbances (PSQI score >7) were assessed. The differences of sleep quality within the three groups and within the POAG group depending on the patients' intraocular pressure (IOP) and impairment of visual field (VF) were also studied. RESULTS: 92 POAG patients, 48 PACG patients and 199 controls were included. Sleep quality declined with age in control and POAG group (tendency chi-square, P<0.05). The prevalence of sleep disturbances was higher in POAG and PACG group than in the control group, the differences were statistically significant. The prevalence of sleep disturbances was higher in patients with PACG, compared to POAG patients in the age interval of 61-80. In POAG group, the ratio of patients with sleep disorders increased with augmented impairment of VF, but the differences were not statistically significant (chi(2)-test, P>0.05). No significant differences were found in POAG group between patients with a highest IOP in daytime and at nighttime (chi(2)-test, P>0.05). CONCLUSIONS: The prevalence of sleep disorders was higher in patients with POAG and PACG than in controls. PACG patients seemed to have a more serious problem of sleep disorders than POAG patients between 61 to 80 years old. No correlation was found between the prevalence of sleep disorders and impairment of VF or the time when POAG patients showed a highest IOP. PMID- 23658654 TI - Development of a threshold model to predict germination of Populus tomentosa seeds after harvest and storage under ambient condition. AB - Effects of temperature, storage time and their combination on germination of aspen (Populus tomentosa) seeds were investigated. Aspen seeds were germinated at 5 to 30 degrees C at 5 degrees C intervals after storage for a period of time under 28 degrees C and 75% relative humidity. The effect of temperature on aspen seed germination could not be effectively described by the thermal time (TT) model, which underestimated the germination rate at 5 degrees C and poorly predicted the time courses of germination at 10, 20, 25 and 30 degrees C. A modified TT model (MTT) which assumed a two-phased linear relationship between germination rate and temperature was more accurate in predicting the germination rate and percentage and had a higher likelihood of being correct than the TT model. The maximum lifetime threshold (MLT) model accurately described the effect of storage time on seed germination across all the germination temperatures. An aging thermal time (ATT) model combining both the TT and MLT models was developed to describe the effect of both temperature and storage time on seed germination. When the ATT model was applied to germination data across all the temperatures and storage times, it produced a relatively poor fit. Adjusting the ATT model to separately fit germination data at low and high temperatures in the suboptimal range increased the models accuracy for predicting seed germination. Both the MLT and ATT models indicate that germination of aspen seeds have distinct physiological responses to temperature within a suboptimal range. PMID- 23658655 TI - Tissue multicolor STED nanoscopy of presynaptic proteins in the calyx of Held. AB - The calyx of Held, a large glutamatergic terminal in the mammalian auditory brainstem has been extensively employed to study presynaptic structure and function in the central nervous system. Nevertheless, the nanoarchitecture of presynaptic proteins and subcellular components in the calyx terminal and its relation to functional properties of synaptic transmission is only poorly understood. Here, we use stimulated emission depletion (STED) nanoscopy of calyces in thin sections of aldehyde-fixed rat brain tissue to visualize immuno labeled synaptic proteins including VGluT1, synaptophysin, Rab3A and synapsin with a lateral resolution of approximately 40 nm. Excitation multiplexing of suitable fluorescent dyes deciphered the spatial arrangement of the presynaptic phospho-protein synapsin relative to synaptic vesicles labeled with anti-VGluT1. Both predominantly occupied the same focal volume, yet may exist in exclusive domains containing either VGluT1 or synapsin immunoreactivity. While the latter have been observed with diffraction-limited fluorescence microscopy, STED microscopy for the first time revealed VGluT1-positive domains lacking synapsins. This observation supports the hypothesis that molecularly and structurally distinct synaptic vesicle pools operate in presynaptic nerve terminals. PMID- 23658657 TI - Picoinjection enables digital detection of RNA with droplet rt-PCR. AB - The ability to add reagents to drops in a sequential fashion is necessary for numerous applications of microfluidics in biology. An important method for accomplishing this is picoinjection, a technique in which reagents are injected into aqueous drops using an electric field. While picoinjection has been shown to allow the precise addition of reagents to drops, its compatibility with biological reactions is yet to be thoroughly demonstrated. Here, we investigate the compatibility of picoinjection with digital RT-PCR Taqman assays, reactions that incorporate nucleic acids, enzymes, and other common biological reagents. We find that picoinjection is compatible with this assay and enables the detection of RNA transcripts at rates comparable to workflows not incorporating picoinjection. We also find that picoinjection results in negligible transfer of material between drops and that the drops faithfully retain their compartmentalization. PMID- 23658656 TI - Development of autoimmune hair loss disease alopecia areata is associated with cardiac dysfunction in C3H/HeJ mice. AB - Alopecia areata (AA) is a chronic autoimmune hair loss disease that affects several million men, women and children worldwide. Previous studies have suggested a link between autoimmunity, stress hormones, and increased cardiovascular disease risk. In the current study, histology, immunohistology, quantitative PCR (qPCR) and ELISAs were used to assess heart health in the C3H/HeJ mouse model for AA and heart tissue response to adrenocorticotropic hormone (ACTH) exposure. Mice with AA exhibited both atrial and ventricular hypertrophy, and increased collagen deposition compared to normal-haired littermates. QPCR revealed significant increases in Il18 (4.6-fold), IL18 receptor-1 (Il18r1; 2.8-fold) and IL18 binding protein (Il18bp; 5.2-fold) in AA hearts. Time course studies revealed a trend towards decreased Il18 in acute AA compared to controls while Il18r1, Il18bp and Casp1 showed similar trends to those of chronic AA affected mice. Immunohistochemistry showed localization of IL18 in chronic AA mouse atria. ELISA indicated cardiac troponin-I (cTnI) was elevated in the serum and significantly increased in AA heart tissue. Cultures of heart atria revealed differential gene expression between AA and control mice in response to ACTH. ACTH treatment induced significant increase in cTnI release into the culture medium in a dose-dependent manner for both AA and control mice. In conclusion, murine AA is associated with structural, biochemical, and gene expression changes consistent with cardiac hypertrophy in response to ACTH exposure. PMID- 23658658 TI - Acute toxicity of TiO2 nanoparticles to Ceriodaphnia dubia under visible light and dark conditions in a freshwater system. AB - The ever increasing industrial and consumer applications of titanium dioxide nanoparticles (TiO2 NPs) raise concern over the possible risk associated with their environmental exposure. Still, the knowledge regarding nanoparticle behavior in a freshwater ecosystem is lacking. The current study focuses on the toxicity of TiO2 NPs towards Ceriodaphnia dubia (a dominant daphnid isolated from the freshwater) under two different conditions; (1) light and dark photoperiod (16:8 h) and (2) continuous dark conditions, for a period of 48 h. An increase in toxicity was observed with an increase in the concentration, until a certain threshold level (under both photoperiod and dark conditions), and beyond which, reduction was noted. The decrease in toxicity would have resulted from the aggregation and settling of NPs, making them less bioavailable. The oxidative stress was one of the major contributors towards cytotoxicity under both photoperiod and dark conditions. The slow depuration of TiO2 NPs under the photoperiod conditions confirmed a higher NP bioaccumulation and thus a higher bioconcentration factor (BCF) compared to dark conditions. The transmission electron micrographs confirmed the bioaccumulation of NPs and damage of tissues in the gut lining. PMID- 23658660 TI - Dynamics of specific anti-Mycobacterium avium subsp. paratuberculosis antibody response through age. AB - Mycobacterium avium subsp. paratuberculosis (MAP) causes a chronic infection in cattle. MAP infected cattle with humoral immune (HI) reactions with IgG antibodies are usually those where latency of infection has ceased and their infection is progressing towards reduced milk yield, weight loss and significant bacterial excretion in feces. The proportion of detectable infections among all infected animals that will develop disease is often referred to as 'the tip of the iceberg'. The purpose of this study was to estimate this proportion. Test records from 18,972 Danish dairy cows with MAP specific IgG antibodies on their final test-record were used to estimate age-specific sensitivities (Se). These cows were the infected ones considered to develop disease in a population with a representative age-distribution and were defined as cases. The specificity (Sp) of the test was estimated based on test-results from 166,905 cows, which had no MAP IgG antibodies in their final four test-records. The Sp, age-specific Se and maximum Se were used to estimate the probability of having HI at a given age resulting in the proportion of infected cows with HI at a given age. For cows 2 years of age, the proportion of detectable cases was 0.33, while it was 0.94 for cows 5 years of age. Thus, there was a significant shift in the tip of the iceberg with aging. This study provided a model for estimating the proportion of latent chronic infections that would progress to disease, and the results can be used to model infection dynamics. PMID- 23658659 TI - Age-specific signatures of glioblastoma at the genomic, genetic, and epigenetic levels. AB - Age is a powerful predictor of survival in glioblastoma multiforme (GBM) yet the biological basis for the difference in clinical outcome is mostly unknown. Discovering genes and pathways that would explain age-specific survival difference could generate opportunities for novel therapeutics for GBM. Here we have integrated gene expression, exon expression, microRNA expression, copy number alteration, SNP, whole exome sequence, and DNA methylation data sets of a cohort of GBM patients in The Cancer Genome Atlas (TCGA) project to discover age specific signatures at the transcriptional, genetic, and epigenetic levels and validated our findings on the REMBRANDT data set. We found major age-specific signatures at all levels including age-specific hypermethylation in polycomb group protein target genes and the upregulation of angiogenesis-related genes in older GBMs. These age-specific differences in GBM, which are independent of molecular subtypes, may in part explain the preferential effects of anti angiogenic agents in older GBM and pave the way to a better understanding of the unique biology and clinical behavior of older versus younger GBMs. PMID- 23658661 TI - A combination of receptor-based pharmacophore modeling & QM techniques for identification of human chymase inhibitors. AB - Inhibition of chymase is likely to divulge therapeutic ways for the treatment of cardiovascular diseases, and fibrotic disorders. To find novel and potent chymase inhibitors and to provide a new idea for drug design, we used both ligand-based and structure-based methods to perform the virtual screening(VS) of commercially available databases. Different pharmacophore models generated from various crystal structures of enzyme may depict diverse inhibitor binding modes. Therefore, multiple pharmacophore-based approach is applied in this study. X-ray crystallographic data of chymase in complex with different inhibitors were used to generate four structure-based pharmacophore models. One ligand-based pharmacophore model was also developed from experimentally known inhibitors. After successful validation, all pharmacophore models were employed in database screening to retrieve hits with novel chemical scaffolds. Drug-like hit compounds were subjected to molecular docking using GOLD and AutoDock. Finally four structurally diverse compounds with high GOLD score and binding affinity for several crystal structures of chymase were selected as final hits. Identification of final hits by three different pharmacophore models necessitates the use of multiple pharmacophore-based approach in VS process. Quantum mechanical calculation is also conducted for analysis of electrostatic characteristics of compounds which illustrates their significant role in driving the inhibitor to adopt a suitable bioactive conformation oriented in the active site of enzyme. In general, this study is used as example to illustrate how multiple pharmacophore approach can be useful in identifying structurally diverse hits which may bind to all possible bioactive conformations available in the active site of enzyme. The strategy used in the current study could be appropriate to design drugs for other enzymes as well. PMID- 23658662 TI - Evaluation of genetically inactivated alpha toxin for protection in multiple mouse models of Staphylococcus aureus infection. AB - Staphylococcus aureus is a major human pathogen and a leading cause of nosocomial and community-acquired infections. Development of a vaccine against this pathogen is an important goal. While S. aureus protective antigens have been identified in the literature, the majority have only been tested in a single animal model of disease. We wished to evaluate the ability of one S. aureus vaccine antigen to protect in multiple mouse models, thus assessing whether protection in one model translates to protection in other models encompassing the full breadth of infections the pathogen can cause. We chose to focus on genetically inactivated alpha toxin mutant HlaH35L. We evaluated the protection afforded by this antigen in three models of infection using the same vaccine dose, regimen, route of immunization, adjuvant, and challenge strain. When mice were immunized with HlaH35L and challenged via a skin and soft tissue infection model, HlaH35L immunization led to a less severe infection and decreased S. aureus levels at the challenge site when compared to controls. Challenge of HlaH35L-immunized mice using a systemic infection model resulted in a limited, but statistically significant decrease in bacterial colonization as compared to that observed with control mice. In contrast, in a prosthetic implant model of chronic biofilm infection, there was no significant difference in bacterial levels when compared to controls. These results demonstrate that vaccines may confer protection against one form of S. aureus disease without conferring protection against other disease presentations and thus underscore a significant challenge in S. aureus vaccine development. PMID- 23658663 TI - Structural basis of the induced-fit mechanism of 1,4-dihydroxy-2-naphthoyl coenzyme A synthase from the crotonase fold superfamily. AB - 1, 4-Dihydroxy-2-naphthoyl coenzyme A (DHNA-CoA) synthase is a typical crotonase fold enzyme with an implicated role of conformational changes in catalysis. We have identified these conformational changes by determining the structures of its Escherichia coli and Synechocystis sp. PCC6803 orthologues in complex with a product analog. The structural changes include the folding of an active-site loop into a beta-hairpin and significant reorientation of a helix at the carboxy terminus. Interestingly, a new interface is formed between the ordered loop and the reoriented helix, both of which also form additional interactions with the coenzyme A moiety of the ligand. Site-directed mutation of the amino acid residues involved in these ligand-induced interactions significantly diminishes the enzyme activity. These results suggest a catalytically essential induced-fit that is likely initiated by the enzyme-ligand interactions at the active site. PMID- 23658664 TI - Primitive auditory memory is correlated with spatial unmasking that is based on direct-reflection integration. AB - In reverberant rooms with multiple-people talking, spatial separation between speech sources improves recognition of attended speech, even though both the head shadowing and interaural-interaction unmasking cues are limited by numerous reflections. It is the perceptual integration between the direct wave and its reflections that bridges the direct-reflection temporal gaps and results in the spatial unmasking under reverberant conditions. This study further investigated (1) the temporal dynamic of the direct-reflection-integration-based spatial unmasking as a function of the reflection delay, and (2) whether this temporal dynamic is correlated with the listeners' auditory ability to temporally retain raw acoustic signals (i.e., the fast decaying primitive auditory memory, PAM). The results showed that recognition of the target speech against the speech masker background is a descending exponential function of the delay of the simulated target reflection. In addition, the temporal extent of PAM is frequency dependent and markedly longer than that for perceptual fusion. More importantly, the temporal dynamic of the speech-recognition function is significantly correlated with the temporal extent of the PAM of low-frequency raw signals. Thus, we propose that a chain process, which links the earlier-stage PAM with the later-stage correlation computation, perceptual integration, and attention facilitation, plays a role in spatially unmasking target speech under reverberant conditions. PMID- 23658665 TI - Thresholds for phosphatidylserine externalization in Chinese hamster ovarian cells following exposure to nanosecond pulsed electrical fields (nsPEF). AB - High-amplitude, MV/m, nanosecond pulsed electric fields (nsPEF) have been hypothesized to cause nanoporation of the plasma membrane. Phosphatidylserine (PS) externalization has been observed on the outer leaflet of the membrane shortly after nsPEF exposure, suggesting local structural changes in the membrane. In this study, we utilized fluorescently-tagged Annexin V to observe the externalization of PS on the plasma membrane of isolated Chinese Hamster Ovary (CHO) cells following exposure to nsPEF. A series of experiments were performed to determine the dosimetric trends of PS expression caused by nsPEF as a function of pulse duration, tau, delivered field strength, ED, and pulse number, n. To accurately estimate dose thresholds for cellular response, data were reduced to a set of binary responses and ED50s were estimated using Probit analysis. Probit analysis results revealed that PS externalization followed the non-linear trend of (tau*ED (2))(-1) for high amplitudes, but failed to predict low amplitude responses. A second set of experiments was performed to determine the nsPEF parameters necessary to cause observable calcium uptake, using cells preloaded with calcium green (CaGr), and membrane permeability, using FM1-43 dye. Calcium influx and FM1-43 uptake were found to always be observed at lower nsPEF exposure parameters compared to PS externalization. These findings suggest that multiple, higher amplitude and longer pulse exposures may generate pores of larger diameter enabling lateral diffusion of PS; whereas, smaller pores induced by fewer, lower amplitude and short pulse width exposures may only allow extracellular calcium and FM1-43 uptake. PMID- 23658677 TI - Pulmonary Adenocarcinoma in Malignant Pleural Effusion Enriches Cancer Stem Cell Properties during Metastatic Cascade. AB - BACKGROUND: Metastasis occurs in a series of discrete steps involving invasion, angiogenesis, lymphovascular space permeation, and establishment of secondary tumors. Malignant pleural effusion (MPE), a type of tumor metastasis, is usually a poor prognostic sign for patients with pulmonary adenocarcinoma, although its underlying mechanism has received less attention than other types of metastases have. The objective of the current study was to confirm whether cancer stem cells (CSCs) in MPE contribute to the "metastatic cascade" through the epithelial - mesenchymal transition (EMT), anoikis, and adaptation in the microenvironment. METHODS: Pulmonary tissue and corresponding cell blocks of MPE samples from 20 patients with primary adenocarcinoma were analyzed by immunohistochemical staining with CSC-representative markers (CD133, Nanog, and OCT-4) and EMT associated markers (E-cadherin and vimentin). Correlations between these variables and clinico-pathological parameters were analyzed. Primary cultures from eight cases of MPE were investigated to characterize the CSC properties, including marker expression, sphere formation, and differentiation. RESULTS: Expressions of CSC-representative markers for 20 cases of MPE cell blocks were quite diverse and variable ranging from 15% to 90%. Stronger expression of CSC representative markers and alteration of EMT-associated markers were found at the invasive fronts and in MPEs compared with the expression in primary pulmonary tumor tissues. The expression of OCT-4 in MPEs significantly related to distant metastasis and stage, as well as inversely correlated with patient survival. Primary cultures confirmed the CSC properties in MPE. Five of eight cases of MPE yielded adequate cell clusters, which also showed variable expressions of CSC markers in addition to sphere formation and the ability for differentiation and metastasis. CONCLUSION: This pilot study offers a better understanding of the metastatic cascade. Establishing a model of MPE will provide further insight into the role of CSCs in metastasis and may explain the high therapeutic failure rates for patients with MPE. PMID- 23658678 TI - Over-expression of PUMA correlates with the apoptosis of spinal cord cells in rat neuropathic intermittent claudication model. AB - BACKGROUND: Neuropathic intermittent claudication (NIC) is a typical clinical symptom of lumbar spinal stenosis and the apoptosis of neurons caused by cauda equina compression (CEC) has been proposed as an important reason. Whereas, the factors and the mechanism involved in the process of apoptosis induced by CEC remain unclear. METHODOLOGY AND RESULTS: In our modified rat model of NIC, a trapezoid-shaped silicon rubber was inserted into the epidural space under the L5 and L6 vertebral plate. Obvious apoptosis was observed in spinal cord cells after compression by TUNEL assay. Simultaneously, qRT-PCR and immunohistochemistry showed that the expression levels of PUMA (p53 up-regulated modulator of apoptosis) and p53 were upregulated significantly in spinal cord under compression, while the expression of p53 inhibitor MDM2 and SirT2 decreased in the same region. Furthermore, CEC also resulted in the upregulation of Bcl-2 pro apoptotic genes expression and caspase-3 activation. With the protection of Methylprednisolone, the upregulation of PUMA and p53 expression as well as the decrease of MDM2 and SirT2 in spinal cord were partially rescued in western bolt analysis. CONCLUSIONS: These results suggest that over-expression of PUMA correlates with CEC caused apoptosis of spinal cord cells, which is characterized by the increase of p53, Bax and Bad expression. PUMA upregulation might be crucial to induce apoptosis of spinal cord cells through p53-dependent pathway in CEC. PMID- 23658679 TI - Do global diversity patterns of vertebrates reflect those of monocots? AB - Few studies of global diversity gradients in plants exist, largely because the data are not available for all species involved. Instead, most global studies have focussed on vertebrates, as these taxa have historically been associated with the most complete data. Here, we address this shortfall by first investigating global diversity gradients in monocots, a morphologically and functionally diverse clade representing a quarter of flowering plant diversity, and then assessing congruence between monocot and vertebrate diversity patterns. To do this, we create a new dataset that merges biome-level associations for all monocot genera with country-level associations for almost all ~70,000 species. We then assess the evidence for direct versus indirect effects of this plant diversity on vertebrate diversity using a combination of linear regression and structural equation modelling (SEM). Finally, we also calculate overlap of diversity hotspots for monocots and each vertebrate taxon. Monocots follow a latitudinal gradient although with pockets of extra-tropical diversity, mirroring patterns in vertebrates. Monocot diversity is positively associated with vertebrate diversity, but the strength of correlation varies depending on the clades being compared. Monocot diversity explains marginal amounts of variance (<10%) after environmental factors have been accounted for. However, correlations remain among model residuals, and SEMs apparently reveal some direct effects of monocot richness. Our results suggest that collinear responses to environmental gradients are behind much of the congruence observed, but that there is some evidence for direct effects of producer diversity on consumer diversity. Much remains to be done before broad-scale diversity gradients among taxa are fully explained. Our dataset of monocot distributions will aid in this endeavour. PMID- 23658680 TI - Genetic diversity of Mycobacterium tuberculosis isolates from Inner Mongolia, China. AB - BACKGROUND: Tuberculosis (TB) is a serious public health problem in China, and within China, Inner Mongolia has a high prevalence area of TB. Though studies on the genetic diversity of Mycobacterium tuberculosis (MTB) have been reported in many provinces, there are no such studies to date in Inner Mongolia. In this study, we investigated the genetic diversity of MTB in Inner Mongolia. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we analyzed 372 clinical MTB isolates with 22-loci mycobacterial interspersed repetitive unit and variable number tandem repeats (MIRU-VNTR), spoligotyping, large sequence polymorphism (LSP), and NTF region analysis to understand the TB genotypes prevalent in Inner Mongolia. We found that the Beijing family was the most prevalent genotype (85.48%, 318/372), and the "modern" sublineage accounted for 76.73% (244/318) of the isolates. Our data also showed that there was no statistically significant association between the two major nationalities and the Beijing genotype (chi(2) = 3.612, P = 0.057; P>0.05). CONCLUSION/SIGNIFICANCE: The Beijing genotype is the most prevalent family of M. tuberculosis in Inner Mongolia, and we do not find any correlation between the Beijing genotype and the major nationalities. PMID- 23658681 TI - Short- and long-term effects of conscious, minimally conscious and unconscious brand logos. AB - Unconsciously presented information can influence our behavior in an experimental context. However, whether these effects can be translated to a daily life context, such as advertising, is strongly debated. What hampers this translation is the widely accepted notion of the short-livedness of unconscious representations. The effect of unconscious information on behavior is assumed to rapidly vanish within a few hundreds of milliseconds. Using highly familiar brand logos (e.g., the logo of McDonald's) as subliminal and supraliminal primes in two priming experiments, we assessed whether these logos were able to elicit behavioral effects after a short (e.g., 350 ms), a medium (e.g., 1000 ms), and a long (e.g., 5000 ms) interval. Our results demonstrate that when real-life information is presented minimally consciously or even unconsciously, it can influence our subsequent behavior, even when more than five seconds pass between the presentation of the minimally conscious or unconscious information and the behavior on which it exerts its influence. PMID- 23658682 TI - Employment growth through labor flow networks. AB - It is conventional in labor economics to treat all workers who are seeking new jobs as belonging to a labor pool, and all firms that have job vacancies as an employer pool, and then match workers to jobs. Here we develop a new approach to study labor and firm dynamics. By combining the emerging science of networks with newly available employment micro-data, comprehensive at the level of whole countries, we are able to broadly characterize the process through which workers move between firms. Specifically, for each firm in an economy as a node in a graph, we draw edges between firms if a worker has migrated between them, possibly with a spell of unemployment in between. An economy's overall graph of firm-worker interactions is an object we call the labor flow network (LFN). This is the first study that characterizes a LFN for an entire economy. We explore the properties of this network, including its topology, its community structure, and its relationship to economic variables. It is shown that LFNs can be useful in identifying firms with high growth potential. We relate LFNs to other notions of high performance firms. Specifically, it is shown that fewer than 10% of firms account for nearly 90% of all employment growth. We conclude with a model in which empirically-salient LFNs emerge from the interaction of heterogeneous adaptive agents in a decentralized labor market. PMID- 23658683 TI - Remarkable growth of open access in the biomedical field: analysis of PubMed articles from 2006 to 2010. AB - INTRODUCTION: This study clarifies the trends observed in open access (OA) in the biomedical field between 2006 and 2010, and explores the possible explanations for the differences in OA rates revealed in recent surveys. METHODS: The study consists of a main survey and two supplementary surveys. In the main survey, a manual Google search was performed to investigate whether full-text versions of articles from PubMed were freely available. Target samples were articles published in 2005, 2007, and 2009; the searches were performed a year after publication in 2006, 2008, and 2010, respectively. Using the search results, we classified the OA provision methods into seven categories. The supplementary surveys calculated the OA rate using two search functions on PubMed: "LinkOut" and "Limits." RESULTS: The main survey concluded that the OA rate increased significantly between 2006 and 2010: the OA rate in 2010 (50.2%) was twice that in 2006 (26.3%). Furthermore, majority of OA articles were available from OA journal (OAJ) websites, indicating that OAJs have consistently been a significant contributor to OA throughout the period. OA availability through the PubMed Central (PMC) repository also increased significantly. OA rates obtained from two supplementary surveys were lower than those found in the main survey. "LinkOut" could find only 40% of OA articles in the main survey. DISCUSSION: OA articles in the biomedical field have more than a 50% share. OA has been achieved through OAJs. The reason why the OA rates in our surveys are different from those in recent surveys seems to be the difference in sampling methods and verification procedures. PMID- 23658684 TI - Evaluating the quality of colorectal cancer care across the interface of healthcare sectors. AB - BACKGROUND: Colorectal cancer (CRC) has a high prevalence in western countries. Diagnosis and treatment of CRC is complex and requires multidisciplinary collaboration across the interface of health care sectors. In Germany, a new nationwide established program aims to provide quality information of healthcare delivery across different sectors. Within this context, this study describes the development of a set of quality indicators charting the whole pathway of CRC-care including data specifications that are necessary to operationalize these indicators before practice testing. METHODS: Indicators were developed following a systematic 10 step modified 'RAND/UCLA Appropriateness Method' which involved a multidisciplinary panel of thirteen participants. For each indicator in the final set, data specifications relating to sources of quality information, data collection procedures, analysis and feedback were described. RESULTS: The final indicator set included 52 indicators covering diagnostic procedures (11 indicators), therapeutic management (28 indicators) and follow-up (6 indicators). In addition, 7 indicators represented patient perspectives. Primary surgical tumor resection and pre-operative radiation (rectum carcinoma only) were perceived as most useful tracer procedures initiating quality data collection. To assess the quality of CRC care across sectors, various data sources were identified: medical records, administrative inpatient and outpatient data, sickness-funds billing code systems and patient survey. CONCLUSION: In Germany, a set of 52 quality indicators, covering necessary aspects across the interfaces and pathways relevant to CRC-care has been developed. Combining different sectors and sources of health care in quality assessment is an innovative and challenging approach but reflects better the reality of the patient pathway and experience of CRC-care. PMID- 23658685 TI - Generation and analysis of the expressed sequence tags from the mycelium of Ganoderma lucidum. AB - Ganoderma lucidum (G. lucidum) is a medicinal mushroom renowned in East Asia for its potential biological effects. To enable a systematic exploration of the genes associated with the various phenotypes of the fungus, the genome consortium of G. lucidum has carried out an expressed sequence tag (EST) sequencing project. Using a Sanger sequencing based approach, 47,285 ESTs were obtained from in vitro cultures of G. lucidum mycelium of various durations. These ESTs were further clustered and merged into 7,774 non-redundant expressed loci. The features of these expressed contigs were explored in terms of over-representation, alternative splicing, and natural antisense transcripts. Our results provide an invaluable information resource for exploring the G. lucidum transcriptome and its regulation. Many cases of the genes over-represented in fast-growing dikaryotic mycelium are closely related to growth, such as cell wall and bioactive compound synthesis. In addition, the EST-genome alignments containing putative cassette exons and retained introns were manually curated and then used to make inferences about the predominating splice-site recognition mechanism of G. lucidum. Moreover, a number of putative antisense transcripts have been pinpointed, from which we noticed that two cases are likely to reveal hitherto undiscovered biological pathways. To allow users to access the data and the initial analysis of the results of this project, a dedicated web site has been created at http://csb2.ym.edu.tw/est/. PMID- 23658686 TI - Long-term trends in calcifying plankton and pH in the North Sea. AB - Relationships between six calcifying plankton groups and pH are explored in a highly biologically productive and data-rich area of the central North Sea using time-series datasets. The long-term trends show that abundances of foraminiferans, coccolithophores, and echinoderm larvae have risen over the last few decades while the abundances of bivalves and pteropods have declined. Despite good coverage of pH data for the study area there is uncertainty over the quality of this historical dataset; pH appears to have been declining since the mid 1990s but there was no statistical connection between the abundance of the calcifying plankton and the pH trends. If there are any effects of pH on calcifying plankton in the North Sea they appear to be masked by the combined effects of other climatic (e.g. temperature), chemical (nutrient concentrations) and biotic (predation) drivers. Certain calcified plankton have proliferated in the central North Sea, and are tolerant of changes in pH that have occurred since the 1950s but bivalve larvae and pteropods have declined. An improved monitoring programme is required as ocean acidification may be occurring at a rate that will exceed the environmental niches of numerous planktonic taxa, testing their capacities for acclimation and genetic adaptation. PMID- 23658687 TI - Transcriptome of the Lymantria dispar (gypsy moth) larval midgut in response to infection by Bacillus thuringiensis. AB - Transcriptomic profiles of the serious lepidopteran insect pest Lymantria dispar (gypsy moth) were characterized in the larval midgut in response to infection by Bacillus thuringiensis kurstaki, a biopesticide commonly used for its control. RNA-Seq approaches were used to define a set of 49,613 assembled transcript sequences, of which 838, 1,248 and 3,305 were respectively partitioned into high , mid- and low-quality tiers on the basis of homology information. Digital gene expression profiles suggested genes differentially expressed at 24 hours post infection, and qRT-PCR analyses were performed for verification. The differentially expressed genes primarily associated with digestive function, including alpha-amylase, lipase and carboxypeptidase; immune response, including C-type lectin 4; developmental genes such as arylphorin; as well as a variety of binding proteins: cellular retinoic acid binding protein (lipid-binding), insulin related peptide binding protein (protein-binding) and ovary C/EBPg transcription factor (nucleic acid-binding). This is the first study conducted to specifically investigate gypsy moth response to a bacterial infection challenge using large scale sequencing technologies, and the results highlight important genes that could be involved in biopesticide resistance development or could serve as targets for biologically-based control mechanisms of this insect pest. PMID- 23658688 TI - Differential expression profiles in the midgut of Triatoma infestans infected with Trypanosoma cruzi. AB - Chagas disease, or American trypanosomiasis, is a parasitic disease caused by the protozoan Trypanosoma cruzi and is transmitted by insects from the Triatominae subfamily. To identify components involved in the protozoan-vector relationship, we constructed and analyzed cDNA libraries from RNA isolated from the midguts of uninfected and T. cruzi-infected Triatoma infestans, which are major vectors of Chagas disease. We generated approximately 440 high-quality Expressed Sequence Tags (ESTs) from each T. infestans midgut cDNA library. The sequences were grouped in 380 clusters, representing an average length of 664.78 base pairs (bp). Many clusters were not classified functionally, representing unknown transcripts. Several transcripts involved in different processes (e.g., detoxification) showed differential expression in response to T. cruzi infection. Lysozyme, cathepsin D, a nitrophorin-like protein and a putative 14 kDa protein were significantly upregulated upon infection, whereas thioredoxin reductase was downregulated. In addition, we identified several transcripts related to metabolic processes or immunity with unchanged expressions, including infestin, lipocalins and defensins. We also detected ESTs encoding juvenile hormone binding protein (JHBP), which seems to be involved in insect development and could be a target in control strategies for the vector. This work demonstrates differential gene expression upon T. cruzi infection in the midgut of T. infestans. These data expand the current knowledge regarding vector-parasite interactions for Chagas disease. PMID- 23658689 TI - iPad-assisted measurements of duration estimation in psychiatric patients and healthy control subjects. AB - Handheld devices with touchscreen controls have become widespread in the general population. In this study, we examined the duration estimates (explicit timing) made by patients in a major general hospital and healthy control subjects using a custom iPad application. We methodically assessed duration estimates using this novel device. We found that both psychiatric and non-psychiatric patients significantly overestimated time periods compared with healthy control subjects, who estimated elapsed time very precisely. The use of touchscreen-based methodologies can provide valuable information about patients. PMID- 23658690 TI - Within-host evolution of Staphylococcus aureus during asymptomatic carriage. AB - BACKGROUND: Staphylococcus aureus is a major cause of healthcare associated mortality, but like many important bacterial pathogens, it is a common constituent of the normal human body flora. Around a third of healthy adults are carriers. Recent evidence suggests that evolution of S. aureus during nasal carriage may be associated with progression to invasive disease. However, a more detailed understanding of within-host evolution under natural conditions is required to appreciate the evolutionary and mechanistic reasons why commensal bacteria such as S. aureus cause disease. Therefore we examined in detail the evolutionary dynamics of normal, asymptomatic carriage. Sequencing a total of 131 genomes across 13 singly colonized hosts using the Illumina platform, we investigated diversity, selection, population dynamics and transmission during the short-term evolution of S. aureus. PRINCIPAL FINDINGS: We characterized the processes by which the raw material for evolution is generated: micro-mutation (point mutation and small insertions/deletions), macro-mutation (large insertions/deletions) and the loss or acquisition of mobile elements (plasmids and bacteriophages). Through an analysis of synonymous, non-synonymous and intergenic mutations we discovered a fitness landscape dominated by purifying selection, with rare examples of adaptive change in genes encoding surface anchored proteins and an enterotoxin. We found evidence for dramatic, hundred fold fluctuations in the size of the within-host population over time, which we related to the cycle of colonization and clearance. Using a newly-developed population genetics approach to detect recent transmission among hosts, we revealed evidence for recent transmission between some of our subjects, including a husband and wife both carrying populations of methicillin-resistant S. aureus (MRSA). SIGNIFICANCE: This investigation begins to paint a picture of the within host evolution of an important bacterial pathogen during its prevailing natural state, asymptomatic carriage. These results also have wider significance as a benchmark for future systematic studies of evolution during invasive S. aureus disease. PMID- 23658691 TI - Comparative transcriptional profiling of the axolotl limb identifies a tripartite regeneration-specific gene program. AB - Understanding how the limb blastema is established after the initial wound healing response is an important aspect of regeneration research. Here we performed parallel expression profile time courses of healing lateral wounds versus amputated limbs in axolotl. This comparison between wound healing and regeneration allowed us to identify amputation-specific genes. By clustering the expression profiles of these samples, we could detect three distinguishable phases of gene expression - early wound healing followed by a transition-phase leading to establishment of the limb development program, which correspond to the three phases of limb regeneration that had been defined by morphological criteria. By focusing on the transition-phase, we identified 93 strictly amputation-associated genes many of which are implicated in oxidative-stress response, chromatin modification, epithelial development or limb development. We further classified the genes based on whether they were or were not significantly expressed in the developing limb bud. The specific localization of 53 selected candidates within the blastema was investigated by in situ hybridization. In summary, we identified a set of genes that are expressed specifically during regeneration and are therefore, likely candidates for the regulation of blastema formation. PMID- 23658692 TI - Substantial agreement of referee recommendations at a general medical journal--a peer review evaluation at Deutsches Arzteblatt International. AB - BACKGROUND: Peer review is the mainstay of editorial decision making for medical journals. There is a dearth of evaluations of journal peer review with regard to reliability and validity, particularly in the light of the wide variety of medical journals. Studies carried out so far indicate low agreement among reviewers. We present an analysis of the peer review process at a general medical journal, Deutsches Arzteblatt International. METHODOLOGY/PRINCIPAL FINDINGS: 554 reviewer recommendations on 206 manuscripts submitted between 7/2008 and 12/2009 were analyzed: 7% recommended acceptance, 74% revision and 19% rejection. Concerning acceptance (with or without revision) versus rejection, there was a substantial agreement among reviewers (74.3% of pairs of recommendations) that was not reflected by Fleiss' or Cohen's kappa (<0.2). The agreement rate amounted to 84% for acceptance, but was only 31% for rejection. An alternative kappa statistic, however, Gwet's kappa (AC1), indicated substantial agreement (0.63). Concordance between reviewer recommendation and editorial decision was almost perfect when reviewer recommendations were unanimous. The correlation of reviewer recommendations and citations as counted by Web of Science was low (partial correlation adjusted for year of publication: -0.03, n.s.). CONCLUSIONS/SIGNIFICANCE: Although our figures are similar to those reported in the literature our conclusion differs from the widely held view that reviewer agreement is low: Based on overall agreement we consider the concordance among reviewers sufficient for the purposes of editorial decision making. We believe that various measures, such as positive and negative agreement or alternative Kappa values are superior to the application of Cohen's or Fleiss' Kappa in the analysis of nominal or ordinal level data regarding reviewer agreement. Also, reviewer recommendations seem to be a poor proxy for citations because, for example, manuscripts will be changed considerably during the revision process. PMID- 23658693 TI - Mutations disrupting histone methylation have different effects on replication timing in S. pombe centromere. AB - The fission yeast pericentromere comprises repetitive sequence elements packaged into heterchromatin marked by histone H3K9 methylation and Swi6 binding. Transient disruption of Swi6 during S phase allows a period of RNA synthesis which programs the RNAi machinery to maintain histone methylation. However, Swi6 is also required for early replication timing. We show that not only Swi6 but also the chromodomain protein Chp1 are delocalized during S phase. Different from loss of swi6, mutations that disrupt histone methylation in the centromere, chp1Delta and clr4Delta, undergo early DNA replication. However, timing is modestly delayed in RNAi mutants dcr1Delta or rdp1Delta, while hrr1Delta mutants resemble swi6Delta in their replication delay. Finally, we show that recruitment of RNA polymerase II in the centromere occurs independently of replication. These different effects indicate that replication timing is not simply linked to histone methylation. PMID- 23658695 TI - Nondestructive intervention to multi-agent systems through an intelligent agent. AB - For a given multi-agent system where the local interaction rule of the existing agents can not be re-designed, one way to intervene the collective behavior of the system is to add one or a few special agents into the group which are still treated as normal agents by the existing ones. We study how to lead a Vicsek-like flocking model to reach synchronization by adding special agents. A popular method is to add some simple leaders (fixed-headings agents). However, we add one intelligent agent, called 'shill', which uses online feedback information of the group to decide the shill's moving direction at each step. A novel strategy for the shill to coordinate the group is proposed. It is strictly proved that a shill with this strategy and a limited speed can synchronize every agent in the group. The computer simulations show the effectiveness of this strategy in different scenarios, including different group sizes, shill speed, and with or without noise. Compared to the method of adding some fixed-heading leaders, our method can guarantee synchronization for any initial configuration in the deterministic scenario and improve the synchronization level significantly in low density groups, or model with noise. This suggests the advantage and power of feedback information in intervention of collective behavior. PMID- 23658694 TI - Empirically derived dietary patterns and health-related quality of life in the SUN project. AB - OBJECTIVE: The analysis of dietary patterns has become a valuable tool to examine diet-disease relationships but little is known about their effects on quality of life. Our aim was to ascertain the association between major dietary patterns and mental and physical quality of life after 4 years of follow-up. MATERIALS AND METHODS: This analysis included 11,128 participants from the "Seguimiento Universidad de Navarra" (SUN) cohort. Dietary habits were assessed using a validated food-frequency questionnaire. Factor analysis was used to derive dietary patterns. Quality of life was measured with the validated Spanish version of the SF-36 Health Survey. RESULTS: Two major dietary patterns were identified, the 'Western' dietary pattern (rich in red meats, processed pastries and fast food) and the "Mediterranean" dietary pattern (high in fruits, vegetables and olive oil). After controlling for confounders, the Western dietary pattern was associated with quality of life in all domains. The magnitude of these differences between the subjects in the highest (quintile 5) and the lowest quintile of adherence to the Western pattern ranged from -0.8 (for mental health) to -3.5 (for vitality). On the contrary, the Mediterranean dietary pattern was associated with better quality of life domains: differences ranged from +1.3 (for physical functioning) to +3.4 (for vitality) when comparing extreme quintiles of adherence. Additional sensitivity analyses did not change the reported differences. CONCLUSIONS: Whereas baseline adherence to a Western dietary pattern was inversely associated with self-perceived quality of life after 4 years of follow-up, baseline adherence to a Mediterranean dietary pattern was directly associated with better scores in quality of life four years later in the SUN Project. PMID- 23658696 TI - Does presence of a mid-ocean ridge enhance biomass and biodiversity? AB - In contrast to generally sparse biological communities in open-ocean settings, seamounts and ridges are perceived as areas of elevated productivity and biodiversity capable of supporting commercial fisheries. We investigated the origin of this apparent biological enhancement over a segment of the North Mid Atlantic Ridge (MAR) using sonar, corers, trawls, traps, and a remotely operated vehicle to survey habitat, biomass, and biodiversity. Satellite remote sensing provided information on flow patterns, thermal fronts, and primary production, while sediment traps measured export flux during 2007-2010. The MAR, 3,704,404 km(2) in area, accounts for 44.7% lower bathyal habitat (800-3500 m depth) in the North Atlantic and is dominated by fine soft sediment substrate (95% of area) on a series of flat terraces with intervening slopes either side of the ridge axis contributing to habitat heterogeneity. The MAR fauna comprises mainly species known from continental margins with no evidence of greater biodiversity. Primary production and export flux over the MAR were not enhanced compared with a nearby reference station over the Porcupine Abyssal Plain. Biomasses of benthic macrofauna and megafauna were similar to global averages at the same depths totalling an estimated 258.9 kt C over the entire lower bathyal north MAR. A hypothetical flat plain at 3500 m depth in place of the MAR would contain 85.6 kt C, implying an increase of 173.3 kt C attributable to the presence of the Ridge. This is approximately equal to 167 kt C of estimated pelagic biomass displaced by the volume of the MAR. There is no enhancement of biological productivity over the MAR; oceanic bathypelagic species are replaced by benthic fauna otherwise unable to survive in the mid ocean. We propose that globally sea floor elevation has no effect on deep sea biomass; pelagic plus benthic biomass is constant within a given surface productivity regime. PMID- 23658697 TI - Retinal contrast transfer functions in adults with and without ADHD. AB - In previous studies, we found a strong reduction in contrast perception and retinal contrast gain in patients with major depression, which normalized after remission of depression. We also identified a possible role of the dopaminergic system in this effect, because visual contrast perception depends on dopaminergic neurotransmission. Dopamine is also known to play an important role in the pathogenesis of attention deficit hyperactivity disorder (ADHD). Therefore, in order to explore the specificity of retinal contrast gain as a marker of depression in comparison with other psychiatric diseases, we recorded the pattern electroretinogram (PERG) in patients with ADHD. Twenty patients diagnosed with ADHD and 20 matched healthy subjects were studied. Visual pattern electroretinograms were recorded from both eyes. The contrast gain of the patients with attention deficit disorder (ADD) did not differ from the control group, nor did the contrast gain of any ADHD subgroup (predominantly inattentive or combined patients). In the healthy subjects, a significant correlation between depression score and contrast gain was found. As the contrast gain in an earlier study clearly separated the patients with depression from the controls, we assume that retinal contrast gain might be a specific marker in depression. PMID- 23658698 TI - Primary medication non-adherence after discharge from a general internal medicine service. AB - BACKGROUND: Medication non-adherence frequently leads to suboptimal patient outcomes. Primary non-adherence, which occurs when a patient does not fill an initial prescription, is particularly important at the time of hospital discharge because new medications are often being prescribed to treat an illness rather than for prevention. METHODS: We studied older adults consecutively discharged from a general internal medicine service at a large urban teaching hospital to determine the prevalence of primary non-adherence and identify characteristics associated with primary non-adherence. We reviewed electronic prescriptions, electronic discharge summaries and pharmacy dispensing data from April to August 2010 for drugs listed on the public formulary. Primary non-adherence was defined as failure to fill one or more new prescriptions after hospital discharge. In addition to descriptive analyses, we developed a logistical regression model to identify patient characteristics associated with primary non-adherence. RESULTS: There were 493 patients eligible for inclusion in our study, 232 of whom were prescribed new medications. In total, 66 (28%) exhibited primary non-adherence at 7 days after discharge and 55 (24%) at 30 days after discharge. Examples of medications to which patients were non-adherent included antibiotics, drugs for the management of coronary artery disease (e.g. beta-blockers, statins), heart failure (e.g. beta-blockers, angiotensin converting enzyme inhibitors, furosemide), stroke (e.g. statins, clopidogrel), diabetes (e.g. insulin), and chronic obstructive pulmonary disease (e.g. long-acting bronchodilators, prednisone). Discharge to a nursing home was associated with an increased risk of primary non-adherence (OR 2.25, 95% CI 1.01-4.95). CONCLUSIONS: Primary non adherence after medications are newly prescribed during a hospitalization is common, and was more likely to occur in patients discharged to a nursing home. PMID- 23658699 TI - Insulin-mediated activation of the L-arginine nitric oxide pathway in man, and its impairment in diabetes. AB - AIMS/HYPOTHESIS: Impaired L-arginine transport has been reported in cardiovascular diseases, providing a possible mechanism for reduced nitric oxide (NO) production. Given that cardiovascular diseases are also associated with insulin resistance, and insulin is known to induce vasodilation via a NO dependent pathway, we hypothesised that abnormal insulin modulation of L-arginine transport may contribute to vascular dysfunction in diabetes. METHODS: Forearm blood flow (FBF) responses to insulin and sodium nitroprusside (SNP) were measured in control and type 2 diabetic volunteers using venous occlusion plethysmography. Effects of intra-arterial insulin on the forearm veno-arterial flux of arginine and related amino acids were determined by HPLC. The effect of locally delivered insulin on arginine transport was assessed during an intra arterial infusion of [4,5-(3)H] L-arginine. RESULTS: In controls, intrabrachial infusion of 5 mUnits/min insulin lead to a progressive rise in FBF (p<0.001) while this was not evident in diabetics. In support of this observation, we observed a concomitant, significant increase in the flux of N-hydroxy-L-arginine (the NO precursor) in controls (baseline vs. 60 mins insulin: 16.2+/-12.2 vs. 33.0+/-13.1 nmol/100 ml tissue/min; p<0.01), whilst no increase was observed in diabetics. Moreover, insulin augmented the clearance of [(3)H]L-arginine from the forearm circulation in controls (baseline vs insulin: 123+/-22 vs. 150+/-28 ml/min; p<0.05) but not in diabetics. CONCLUSION: These findings suggest that insulin resistance may contribute substantially to the onset and development of cardiovascular disease in type 2 diabetics via abnormal insulin-mediated regulation of L-arginine transport. PMID- 23658700 TI - A-type lamins maintain the positional stability of DNA damage repair foci in mammalian nuclei. AB - A-type lamins encoded by LMNA form a structural fibrillar meshwork within the mammalian nucleus. How this nuclear organization may influence the execution of biological processes involving DNA transactions remains unclear. Here, we characterize changes in the dynamics and biochemical interactions of lamin A/C after DNA damage. We find that DNA breakage reduces the mobility of nucleoplasmic GFP-lamin A throughout the nucleus as measured by dynamic fluorescence imaging and spectroscopy in living cells, suggestive of incorporation into stable macromolecular complexes, but does not induce the focal accumulation of GFP-lamin A at damage sites. Using a proximity ligation assay and biochemical analyses, we show that lamin A engages chromatin via histone H2AX and its phosphorylated form (gammaH2AX) induced by DNA damage, and that these interactions are enhanced after DNA damage. Finally, we use three-dimensional time-lapse imaging to show that LMNA inactivation significantly reduces the positional stability of DNA repair foci in living cells. This defect is partially rescued by the stable expression of GFP-lamin A. Thus collectively, our findings suggest that the dynamic structural meshwork formed by A-type lamins anchors sites of DNA repair in mammalian nuclei, providing fresh insight into the control of DNA transactions by nuclear structural organization. PMID- 23658702 TI - Use of "MGE enhancers" for labeling and selection of embryonic stem cell-derived medial ganglionic eminence (MGE) progenitors and neurons. AB - The medial ganglionic eminence (MGE) is an embryonic forebrain structure that generates the majority of cortical interneurons. MGE transplantation into specific regions of the postnatal central nervous system modifies circuit function and improves deficits in mouse models of epilepsy, Parkinson's disease, pain, and phencyclidine-induced cognitive deficits. Herein, we describe approaches to generate MGE-like progenitor cells from mouse embryonic stem (ES) cells. Using a modified embryoid body method, we provided gene expression evidence that mouse ES-derived Lhx6(+) cells closely resemble immature interneurons generated from authentic MGE-derived Lhx6(+) cells. We hypothesized that enhancers that are active in the mouse MGE would be useful tools in detecting when ES cells differentiate into MGE cells. Here we demonstrate the utility of enhancer elements [422 (DlxI12b), Lhx6, 692, 1056, and 1538] as tools to mark MGE-like cells in ES cell differentiation experiments. We found that enhancers DlxI12b, 692, and 1538 are active in Lhx6-GFP(+) cells, while enhancer 1056 is active in Olig2(+) cells. These data demonstrate unique techniques to follow and purify MGE-like derivatives from ES cells, including GABAergic cortical interneurons and oligodendrocytes, for use in stem cell-based therapeutic assays and treatments. PMID- 23658703 TI - Patterns of warfarin use in subgroups of patients with atrial fibrillation: a cross-sectional analysis of 430 general practices in the United Kingdom. AB - BACKGROUND: Despite the proven efficacy of warfarin, its use in patients with Atrial Fibrillation (AF) is reportedly low. We investigated the underuse and overuse of warfarin in the management of AF in general practices in the United Kingdom (UK) against the National Institute of Clinical Excellence (NICE, UK) guidelines whilst seeking to identify subgroups of AF patients to inform efforts to optimise warfarin use. METHODOLOGY: A retrospective database analysis to determine warfarin prescribing using tree models based on 50,361 patients with AF (classified as low, moderate and high risk of stroke using CHADS2) from 430 general practices in the UK. RESULTS: Over one-third (37.0%, 4573/12,351) of low risk AF patients were on warfarin, compared with 47.1% (8349/17,709) moderate risk AF patients and 54.9% (11,142/20,301) high risk AF patients. Clinical subgroups (n = 15 low risk subgroups, n = 15 medium risk subgroups, n = 22 high risk subgroups) were identified. Several factors not supported by current guidelines (age, BMI, dementia, gender) were associated with the use of warfarin. Gender and BMI were associated with warfarin use in low and medium risk AF patients but not in high risk AF patients. CONCLUSION: Whilst NICE guidelines suggest that all high risk AF patients should be on warfarin, half of those at moderate risk should be on warfarin and none of those at low risk should be on warfarin, we found evidence of over and under use of warfarin. Interventions to optimise warfarin therapy tailored to and targeting specific subgroups of AF patients identified by the tree models are required. PMID- 23658701 TI - Critical role of a survivin/TGF-beta/mTORC1 axis in IGF-I-mediated growth of prostate epithelial cells. AB - Survivin is a unique member of the inhibitor of apoptosis (IAP) proteins that is overexpressed in numerous cancers through poorly defined mechanisms. One such mechanism may be through constitutive activation of the insulin-like growth factor-I (IGF-I) signaling pathway, implicated in the development and progression of prostate cancer. Using the pre-neoplastic NRP-152 rat prostate cell line as a model, we showed that IGF-I induces Survivin expression, and that silencing Survivin by lentiviral-mediated small hairpin RNA (shRNA) represses IGF-I stimulated cell growth, implicating Survivin as a mediator of this growth response. Moreover, our data support that the induction of Survivin by IGF-I occurs through a transcriptional mechanism that is mediated in part by the PI3K/Akt/mTORC1 pathway. Use of various Survivin promoter-luciferase constructs revealed that the CDE and CHR response elements in the proximal region of the Survivin promoter are involved in this IGF-I response. Transforming growth factor (TGF-beta) signaling antagonists similarly activated the Surivin promoter and rendered cells refractory to further promoter activation by IGF-I. IGF-I suppressed levels of phospho-Smads 2 and 3 with kinetics similar to that of Survivin induction. Suppression of TGF-beta signaling, either by TGF-beta receptor kinase inhibitors or by silencing Smads 2 and 3, induced Survivin expression and promoted cell growth similar to that induced by IGF-I. TGF-beta receptor antagonists also rescued cells from down-regulation of Survivin expression and growth suppression by pharmacological inhibitors of PI3K, Akt, MEK and mTOR. Sh-RNA gene silencing studies suggest that mTORC1 induces while mTORC2 represses the expression of Survivin by IGF-I. Taken together, these results suggest that IGF-I signaling through a PI3K/Akt/mTORC1 mechanism elevates expression of Survivin and promotes growth of prostate epithelial cells by suppressing Smad-dependent autocrine TGF-beta signaling. PMID- 23658704 TI - Knockout of CD8 delays reendothelialization and accelerates neointima formation in injured arteries of mouse via TNF-alpha inhibiting the endothelial cells migration. AB - OBJECTIVE: Delayed or impaired reendothelialization is a major cause of stent thrombosis in the interventional treatment of coronary heart disease. T cells are involved in neointima formation of injured arteries. However, the regulated mechanism of reendothelialization and the role of CD8 T cell in reendothelialization are unclear. METHODS AND RESULTS: Immunofluorescence staining showed that CD8 positive cells were increased in wire injured femoral artery of mice. On day 21 after injury, elastin staining showed that knockout of CD8 (CD8(-/-)) significantly increased intimal thickness and a ratio of intima to media by 1.8 folds and 1.9 folds respectively in injured arteries. Evans blue staining showed that knockout of CD8 delayed the reendothelialization area on day 7 after injury (18.8+/-0.5% versus 42.1+/-5.6%, p<0.05). In vitro, a migration assay revealed that CD8(-/-) T cells co-cultured with WT macrophages significantly inhibited the migration of the endothelial cells (ECs); compared to CD4(+) T cells, and CD8(+) T cells could promote the ECs migration. Furthermore, real-time PCR analysis showed that knockout of CD8 increased the level of tumor necrosis factor alpha (TNF-alpha) in injured arteries and cytometric bead cytokine array showed that TNF-alpha was elevated in cultured CD8(-/-) T cells. Finally, a wound-healing assay showed that recombinant TNF-alpha significantly inhibited the migration of ECs. CONCLUSION: Our study suggested that CD8(+) T cells could promote the reendothelialization and inhibit the neointima formation after the artery wire injury, and this effect is at least partly dependent on decreasing TNF-alpha production promoting ECs migration. PMID- 23658705 TI - Tribological and antioxidation synergistic effect study of sulfonate-modified nano calcium carbonate. AB - A middle base number sulphonate-modified nano calcium carbonate (SMC) with an average size of 35 nm was synthesized, and its tribological and antioxidation synergistic behaviors with ashless antioxidant N-phenyl-alpha-naphthylamine (T531) in hydrogenated oil (5Cst) were evaluated. The results demonstrate that adding this synthesized additive even at a low amount (<2.0 wt.%) can evidently improve its load-carrying capacity by 1.5 times and enhance its antiwear performance; in addition, the friction-reducing effect of additive in the high load was better than that in low load. The SMC have a good synergistic antioxidation effect with T531, which verifies the nano calcium carbonate compound was a kind of multifunctional and high-performance additive. The chemical composition of the rubbing surface which formed on the boundary film was analyzed by using scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). The results indicating that the excellent antiwear and load carrying performance could be attributed to the forming of boundary lubrication film which composed of calcium carbonate, oxides, ferrites, sulphide and FeSO4, and so on. Its ability to increase oxidation free energy of base oil is the main reason for increasing its antioxidant collaboration property with ashless antioxidant T531. PMID- 23658706 TI - Identification of metabolic pathways influenced by the G-protein coupled receptors GprB and GprD in Aspergillus nidulans. AB - Heterotrimeric G-protein-mediated signaling pathways play a pivotal role in transmembrane signaling in eukaryotes. Our main aim was to identify signaling pathways regulated by A. nidulans GprB and GprD G-protein coupled receptors (GPCRs). When these two null mutant strains were compared to the wild-type strain, the DeltagprB mutant showed an increased protein kinase A (PKA) activity while growing in glucose 1% and during starvation. In contrast, the DeltagprD has a much lower PKA activity upon starvation. Transcriptomics and (1)H NMR-based metabolomics were performed on two single null mutants grown on glucose. We noted modulation in the expression of 11 secondary metabolism gene clusters when the DeltagprB and DeltagprD mutant strains were grown in 1% glucose. Several members of the sterigmatocystin-aflatoxin gene cluster presented down-regulation in both mutant strains. The genes of the NR-PKS monodictyphenone biosynthesis cluster had overall increased mRNA accumulation in DeltagprB, while in the DeltagprD mutant strain the genes had decreased mRNA accumulation. Principal component analysis of the metabolomic data demonstrated that there was a significant metabolite shift in the DeltagprD strain. The (1)H NMR analysis revealed significant expression of essential amino acids with elevated levels in the DeltagprD strain, compared to the wild-type and DeltagprB strains. With the results, we demonstrated the differential expression of a variety of genes related mainly to secondary metabolism, sexual development, stress signaling, and amino acid metabolism. We propose that the absence of GPCRs triggered stress responses at the genetic level. The data suggested an intimate relationship among different G-protein coupled receptors, fine-tune regulation of secondary and amino acid metabolisms, and fungal development. PMID- 23658707 TI - Genome-wide characterization of transcriptional patterns in high and low antibody responders to rubella vaccination. AB - Immune responses to current rubella vaccines demonstrate significant inter individual variability. We performed mRNA-Seq profiling on PBMCs from high and low antibody responders to rubella vaccination to delineate transcriptional differences upon viral stimulation. Generalized linear models were used to assess the per gene fold change (FC) for stimulated versus unstimulated samples or the interaction between outcome and stimulation. Model results were evaluated by both FC and p-value. Pathway analysis and self-contained gene set tests were performed for assessment of gene group effects. Of 17,566 detected genes, we identified 1,080 highly significant differentially expressed genes upon viral stimulation (p<1.00E(-15), FDR<1.00E(-14)), including various immune function and inflammation-related genes, genes involved in cell signaling, cell regulation and transcription, and genes with unknown function. Analysis by immune outcome and stimulation status identified 27 genes (p<=0.0006 and FDR<=0.30) that responded differently to viral stimulation in high vs. low antibody responders, including major histocompatibility complex (MHC) class I genes (HLA-A, HLA-B and B2M with p = 0.0001, p = 0.0005 and p = 0.0002, respectively), and two genes related to innate immunity and inflammation (EMR3 and MEFV with p = 1.46E(-08) and p = 0.0004, respectively). Pathway and gene set analysis also revealed transcriptional differences in antigen presentation and innate/inflammatory gene sets and pathways between high and low responders. Using mRNA-Seq genome-wide transcriptional profiling, we identified antigen presentation and innate/inflammatory genes that may assist in explaining rubella vaccine-induced immune response variations. Such information may provide new scientific insights into vaccine-induced immunity useful in rational vaccine development and immune response monitoring. PMID- 23658708 TI - Ancestral genome inference using a genetic algorithm approach. AB - Recent advancement of technologies has now made it routine to obtain and compare gene orders within genomes. Rearrangements of gene orders by operations such as reversal and transposition are rare events that enable researchers to reconstruct deep evolutionary histories. An important application of genome rearrangement analysis is to infer gene orders of ancestral genomes, which is valuable for identifying patterns of evolution and for modeling the evolutionary processes. Among various available methods, parsimony-based methods (including GRAPPA and MGR) are the most widely used. Since the core algorithms of these methods are solvers for the so called median problem, providing efficient and accurate median solver has attracted lots of attention in this field. The "double-cut-and-join" (DCJ) model uses the single DCJ operation to account for all genome rearrangement events. Because mathematically it is much simpler than handling events directly, parsimony methods using DCJ median solvers has better speed and accuracy. However, the DCJ median problem is NP-hard and although several exact algorithms are available, they all have great difficulties when given genomes are distant. In this paper, we present a new algorithm that combines genetic algorithm (GA) with genomic sorting to produce a new method which can solve the DCJ median problem in limited time and space, especially in large and distant datasets. Our experimental results show that this new GA-based method can find optimal or near optimal results for problems ranging from easy to very difficult. Compared to existing parsimony methods which may severely underestimate the true number of evolutionary events, the sorting-based approach can infer ancestral genomes which are much closer to their true ancestors. The code is available at http://phylo.cse.sc.edu. PMID- 23658709 TI - Protein complex detection via weighted ensemble clustering based on Bayesian nonnegative matrix factorization. AB - Detecting protein complexes from protein-protein interaction (PPI) networks is a challenging task in computational biology. A vast number of computational methods have been proposed to undertake this task. However, each computational method is developed to capture one aspect of the network. The performance of different methods on the same network can differ substantially, even the same method may have different performance on networks with different topological characteristic. The clustering result of each computational method can be regarded as a feature that describes the PPI network from one aspect. It is therefore desirable to utilize these features to produce a more accurate and reliable clustering. In this paper, a novel Bayesian Nonnegative Matrix Factorization (NMF)-based weighted Ensemble Clustering algorithm (EC-BNMF) is proposed to detect protein complexes from PPI networks. We first apply different computational algorithms on a PPI network to generate some base clustering results. Then we integrate these base clustering results into an ensemble PPI network, in the form of weighted combination. Finally, we identify overlapping protein complexes from this network by employing Bayesian NMF model. When generating an ensemble PPI network, EC-BNMF can automatically optimize the values of weights such that the ensemble algorithm can deliver better results. Experimental results on four PPI networks of Saccharomyces cerevisiae well verify the effectiveness of EC-BNMF in detecting protein complexes. EC-BNMF provides an effective way to integrate different clustering results for more accurate and reliable complex detection. Furthermore, EC-BNMF has a high degree of flexibility in the choice of base clustering results. It can be coupled with existing clustering methods to identify protein complexes. PMID- 23658710 TI - Kif3a guides microtubular dynamics, migration and lumen formation of MDCK cells. AB - The microtubular motor Kinesin-2 and its subunit Kif3a are essential for the formation of primary cilia, an organelle implicated in a wide spectrum of developmental abnormalities. Outside cilia, Kinesin-2 mediated transport has been implicated in vesicle and N-cadherin transport, but it is unknown if and how extraciliary Kif3a affects basic cellular functions such as migration or the formation of multicellular structures. Here we show that tetracycline inducible depletion of Kif3a in MDCK cells slows epithelial cell migration. Microtubules at the leading edge of Kif3a depleted cells failed to grow perpendicularly into the leading edge and microtubular dynamics were dampened in Kif3a depleted cells. Loss of Kif3a retarded lateral membrane specification and completely prevented the formation of three-dimensional spheres in collagen. These data uncover that Kif3a regulates the microtubular cytoskeleton in the cell periphery and imply that extra-ciliary Kif3a has an unexpected function in morphogenesis. PMID- 23658711 TI - Quantitative PCR reveals strong spatial and temporal variation of the wasting disease pathogen, Labyrinthula zosterae in northern European eelgrass (Zostera marina) beds. AB - Seagrass beds are the foundation species of functionally important coastal ecosystems worldwide. The world's largest losses of the widespread seagrass Zostera marina (eelgrass) have been reported as a consequence of wasting disease, an infection with the endophytic protist Labyrinthula zosterae. During one of the most extended epidemics in the marine realm, ~90% of East and Western Atlantic eelgrass beds died-off between 1932 and 1934. Today, small outbreaks continue to be reported, but the current extent of L. zosterae in European meadows is completely unknown. In this study we quantify the abundance and prevalence of the wasting disease pathogen among 19 Z. marina populations in northern European coastal waters, using quantitative PCR (QPCR) with primers targeting a species specific portion of the internally transcribed spacer (ITS1) of L. zosterae. Spatially, we found marked variation among sites with abundances varying between 0 and 126 cells mg(-1) Z. marina dry weight (mean: 5.7 L. zosterae cells mg(-1) Z. marina dry weight +/-1.9 SE) and prevalences ranged from 0-88.9%. Temporarily, abundances varied between 0 and 271 cells mg(-1) Z. marina dry weight (mean: 8.5+/-2.6 SE), while prevalences ranged from zero in winter and early spring to 96% in summer. Field concentrations accessed via bulk DNA extraction and subsequent QPCR correlated well with prevalence data estimated via isolation and cultivation from live plant tissue. L. zosterae was not only detectable in black lesions, a sign of Labyrinthula-induced necrosis, but also occurred in green, apparently healthy tissue. We conclude that L. zosterae infection is common (84% infected populations) in (northern) European eelgrass populations with highest abundances during the summer months. In the light of global climate change and increasing rate of marine diseases our data provide a baseline for further studies on the causes of pathogenic outbreaks of L. zosterae. PMID- 23658712 TI - Detection and characterization of protein interactions in vivo by a simple live cell imaging method. AB - Over the last decades there has been an explosion of new methodologies to study protein complexes. However, most of the approaches currently used are based on in vitro assays (e.g. nuclear magnetic resonance, X-ray, electron microscopy, isothermal titration calorimetry etc). The accurate measurement of parameters that define protein complexes in a physiological context has been largely limited due to technical constrains. Here, we present PICT (Protein interactions from Imaging of Complexes after Translocation), a new method that provides a simple fluorescence microscopy readout for the study of protein complexes in living cells. We take advantage of the inducible dimerization of FK506-binding protein (FKBP) and FKBP-rapamycin binding (FRB) domain to translocate protein assemblies to membrane associated anchoring platforms in yeast. In this assay, GFP-tagged prey proteins interacting with the FRB-tagged bait will co-translocate to the FKBP-tagged anchor sites upon addition of rapamycin. The interactions are thus encoded into localization changes and can be detected by fluorescence live-cell imaging under different physiological conditions or upon perturbations. PICT can be automated for high-throughput studies and can be used to quantify dissociation rates of protein complexes in vivo. In this work we have used PICT to analyze protein-protein interactions from three biological pathways in the yeast Saccharomyces cerevisiae: Mitogen-activated protein kinase cascade (Ste5-Ste11 Ste50), exocytosis (exocyst complex) and endocytosis (Ede1-Syp1). PMID- 23658713 TI - Sex chromosomes regulate nighttime sleep propensity during recovery from sleep loss in mice. AB - Sex differences in spontaneous sleep amount are largely dependent on reproductive hormones; however, in mice some sex differences in sleep amount during the active phase are preserved after gonadectomy and may be driven by non-hormonal factors. In this study, we sought to determine whether or not these sex differences are driven by sex chromosome complement. Mice from the four core genotype (FCG) mouse model, whose sex chromosome complement (XY, XX) is independent of phenotype (male or female), were implanted with electroencephalographic (EEG) and electromyographic (EMG) electrodes for the recording of sleep-wake states and underwent a 24-hr baseline recording followed by six hours of forced wakefulness. During baseline conditions in mice whose gonads remained intact, males had more total sleep and non-rapid eye movement sleep than females during the active phase. Gonadectomized FCG mice exhibited no sex differences in rest-phase sleep amount; however, during the mid-active-phase (nighttime), XX males had more spontaneous non-rapid eye movement (NREM) sleep than XX females. The XY mice did not exhibit sex differences in sleep amount. Following forced wakefulness there was a change in the factors regulating sleep. XY females slept more during their mid-active phase siestas than XX females and had higher NREM slow wave activity, a measure of sleep propensity. These findings suggest that the process that regulates sleep propensity is sex-linked, and that sleep amount and sleep propensity are regulated differently in males and females following sleep loss. PMID- 23658714 TI - Influences of excluded volume of molecules on signaling processes on the biomembrane. AB - We investigate the influences of the excluded volume of molecules on biochemical reaction processes on 2-dimensional surfaces using a model of signal transduction processes on biomembranes. We perform simulations of the 2-dimensional cell-based model, which describes the reactions and diffusion of the receptors, signaling proteins, target proteins, and crowders on the cell membrane. The signaling proteins are activated by receptors, and these activated signaling proteins activate target proteins that bind autonomously from the cytoplasm to the membrane, and unbind from the membrane if activated. If the target proteins bind frequently, the volume fraction of molecules on the membrane becomes so large that the excluded volume of the molecules for the reaction and diffusion dynamics cannot be negligible. We find that such excluded volume effects of the molecules induce non-trivial variations of the signal flow, defined as the activation frequency of target proteins, as follows. With an increase in the binding rate of target proteins, the signal flow varies by i) monotonically increasing; ii) increasing then decreasing in a bell-shaped curve; or iii) increasing, decreasing, then increasing in an S-shaped curve. We further demonstrate that the excluded volume of molecules influences the hierarchical molecular distributions throughout the reaction processes. In particular, when the system exhibits a large signal flow, the signaling proteins tend to surround the receptors to form receptor-signaling protein clusters, and the target proteins tend to become distributed around such clusters. To explain these phenomena, we analyze the stochastic model of the local motions of molecules around the receptor. PMID- 23658715 TI - Inferring genome-wide recombination landscapes from advanced intercross lines: application to yeast crosses. AB - Accurate estimates of recombination rates are of great importance for understanding evolution. In an experimental genetic cross, recombination breaks apart and rejoins genetic material, such that the genomes of the resulting isolates are comprised of distinct blocks of differing parental origin. We here describe a method exploiting this fact to infer genome-wide recombination profiles from sequenced isolates from an advanced intercross line (AIL). We verified the accuracy of the method against simulated data. Next, we sequenced 192 isolates from a twelve-generation cross between West African and North American yeast Saccharomyces cerevisiae strains and inferred the underlying recombination landscape at a fine genomic resolution (mean segregating site distance 0.22 kb). Comparison was made with landscapes inferred for a similar cross between four yeast strains, and with a previous single-generation, intra strain cross (Mancera et al., Nature 2008). Moderate congruence was identified between landscapes (correlation 0.58-0.77 at 5 kb resolution), albeit with variance between mean genome-wide recombination rates. The multiple generations of mating undergone in the AILs gave more precise inference of recombination rates than could be achieved from a single-generation cross, in particular in identifying recombination cold-spots. The recombination landscapes we describe have particular utility; both AILs are part of a resource to study complex yeast traits (see e.g. Parts et al., Genome Res 2011). Our results will enable future applications of this resource to take better account of local linkage structure heterogeneities. Our method has general applicability to other crossing experiments, including a variety of experimental designs. PMID- 23658716 TI - The relationship between online social networking and sexual risk behaviors among men who have sex with men (MSM). AB - Online social networking usage is growing rapidly, especially among at-risk populations, such as men who have sex with men (MSM). However, little research has studied the relationship between online social networking usage and sexual risk behaviors among at-risk populations. One hundred and eighteen Facebook registered MSM (60.1% Latino, 28% African American; 11.9% other) were recruited from online (social networking websites and banner advertisements) and offline (local clinics, restaurants and organizations) venues frequented by minority MSM. Inclusion criteria required participants to be men who were 18 years of age or older, had had sex with a man in the past 12 months, were living in Los Angeles, and had a Facebook account. Participants completed an online survey on their social media usage and sexual risk behaviors. Results from a multivariable regression suggest that number of sexual partners met from online social networking technologies is associated with increased: 1) likelihood of having exchanged sex for food, drugs, or a place to stay within the past 3 months; 2) number of new partners within the past 3 months; 3) number of male sex partners within the past 3 months; and 4) frequency of engaging in oral sex within the past 3 months, controlling for age, race, education, and total number of sexual partners. Understanding the relationship between social media sex-seeking and sexual risk behaviors among at-risk populations will help inform population focused HIV prevention and treatment interventions. PMID- 23658717 TI - A comparison of HAART outcomes between the US military HIV Natural History Study (NHS) and HIV Atlanta Veterans Affairs Cohort Study (HAVACS). AB - INTRODUCTION: The Department of Defense (DoD) and the Department of Veterans Affairs (VA) provide comprehensive HIV treatment and care to their beneficiaries with open access and few costs to the patient. Individuals who receive HIV care in the VA have higher rates of substance abuse, homelessness and unemployment than individuals who receive HIV care in the DoD. A comparison between individuals receiving HIV treatment and care from the DoD and the VA provides an opportunity to explore the impact of individual-level characteristics on clinical outcomes within two healthcare systems that are optimized for clinic retention and medication adherence. METHODS: Data were collected on 1065 patients from the HIV Atlanta VA Cohort Study (HAVACS) and 1199 patients from the US Military HIV Natural History Study (NHS). Patients were eligible if they had an HIV diagnosis and began HAART between January 1, 1996 and June 30, 2010. The analysis examined the survival from HAART initiation to all-cause mortality or an AIDS event. RESULTS: Although there was substantial between-cohort heterogeneity and the 12 year survival of participants in NHS was significantly higher than in HAVACS in crude analyses, this survival disparity was reduced from 21.5% to 1.6% (mortality only) and 26.8% to 4.1% (combined mortality or AIDS) when controlling for clinical and demographic variables. CONCLUSION: We assessed the clinical outcomes for individuals with HIV from two very similar government-sponsored healthcare systems that reduced or eliminated many barriers associated with accessing treatment and care. After controlling for clinical and demographic variables, both 12-year survival and AIDS-free survival rates were similar for the two study cohorts who have open access to care and medication despite dramatic differences in socioeconomic and behavioral characteristics. PMID- 23658718 TI - Pathogens and politics: further evidence that parasite prevalence predicts authoritarianism. AB - According to a "parasite stress" hypothesis, authoritarian governments are more likely to emerge in regions characterized by a high prevalence of disease-causing pathogens. Recent cross-national evidence is consistent with this hypothesis, but there are inferential limitations associated with that evidence. We report two studies that address some of these limitations, and provide further tests of the hypothesis. Study 1 revealed that parasite prevalence strongly predicted cross national differences on measures assessing individuals' authoritarian personalities, and this effect statistically mediated the relationship between parasite prevalence and authoritarian governance. The mediation result is inconsistent with an alternative explanation for previous findings. To address further limitations associated with cross-national comparisons, Study 2 tested the parasite stress hypothesis on a sample of traditional small-scale societies (the Standard Cross-Cultural Sample). Results revealed that parasite prevalence predicted measures of authoritarian governance, and did so even when statistically controlling for other threats to human welfare. (One additional threat-famine-also uniquely predicted authoritarianism.) Together, these results further substantiate the parasite stress hypothesis of authoritarianism, and suggest that societal differences in authoritarian governance result, in part, from cultural differences in individuals' authoritarian personalities. PMID- 23658719 TI - "Whom should I pass to?" the more options the more attentional guidance from working memory. AB - Three experiments investigated the predictions of the biased competition theory of selective attention in a computer based sport task. According to this theory objects held in the circuitry of working memory (WM) automatically bias attention to objects in a visual scene that match or are related to the WM representation. Specifically, we investigated whether certain players that are activated in the circuitry of WM automatically draw attention and receive a competitive advantage in a computer based sport task. In all three experiments participants had to hold an image of a certain player in WM while engaged in a speeded sport task. In Experiment 1 participants had to identify as quickly as possible which player was in possession of the ball. In Experiment 2 and 3 participants had to decide to which player they would pass to in a cartoon team handball situation and a photo picture basketball situation. The results support the biased competition theory of selective attention and suggest that certain decision options receive a competitive advantage if they are associated with the activated contents in the circuitry of WM and that this effect is more pronounced when more decision options compete for attention. A further extension compared to previous research was that the contents of working memory not only biased attention but also actual decisions that can lead to passing errors in sport. We critically discuss the applied implications of the findings. PMID- 23658720 TI - Enhanced IL-6/IL-6R signaling promotes growth and malignant properties in EBV infected premalignant and cancerous nasopharyngeal epithelial cells. AB - Nasopharyngeal carcinoma (NPC) is etiologically associated with Epstein-Barr virus (EBV) infection. However, the exact role of EBV in NPC pathogenesis remains elusive. Activation of signal transducer and activator of transcription 3 (STAT3) is common in human cancers including NPC and plays an important role in the pathogenesis and progression of human cancers. Interleukin-6 (IL-6), a major inflammatory cytokine, is a potent activator of STAT3. In this study, we report that EBV-infected immortalized nasopharyngeal epithelial (NPE) cells often acquire an enhanced response to IL-6-induced STAT3 activation to promote their growth and invasive properties. Interestingly, this enhanced IL-6/STAT3 response was mediated by overexpression of IL-6 receptor (IL-6R). Furthermore, IL-6R overexpression enhanced IL-6-induced STAT3 activation in uninfected immortalized NPE cells in vitro, and promoted growth and tumorigenicity of EBV-positive NPC cell line (C666-1) in vivo. Moreover, it is shown for the first time that IL-6R was overexpressed in clinical specimens of NPC. IL-6 expression could also be strongly detected in the stromal cells of NPC and a higher circulating level of IL-6 was found in the sera of advance-staged NPC patients compared to the control subjects. Therefore, IL-6R overexpression, coupled with enhanced IL-6/STAT3 signaling may facilitate the malignant transformation of EBV-infected premalignant NPE cells into cancer cells, and enhance malignant properties of NPC cells. PMID- 23658721 TI - Synthesis and biological evaluation of novel folic acid receptor-targeted, beta cyclodextrin-based drug complexes for cancer treatment. AB - Drug targeting is an active area of research and nano-scaled drug delivery systems hold tremendous potential for the treatment of neoplasms. In this study, a novel cyclodextrin (CD)-based nanoparticle drug delivery system has been assembled and characterized for the therapy of folate receptor-positive [FR(+)] cancer. Water-soluble folic acid (FA)-conjugated CD carriers (FACDs) were successfully synthesized and their structures were confirmed by 1D/2D nuclear magnetic resonance (NMR), matrix-assisted laser desorption ionization time-of flight mass spectrometer (MALDI-TOF-MS), high performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FTIR), and circular dichroism. Drug complexes of adamatane (Ada) and cytotoxic doxorubicin (Dox) with FACD were readily obtained by mixed solvent precipitation. The average size of FACD-Ada-Dox was 1.5-2.5 nm. The host-guest association constant K a was 1,639 M(-1) as determined by induced circular dichroism and the hydrophilicity of the FACDs was greatly enhanced compared to unmodified CD. Cellular uptake and FR binding competitive experiments demonstrated an efficient and preferentially targeted delivery of Dox into FR-positive tumor cells and a sustained drug release profile was seen in vitro. The delivery of Dox into FR(+) cancer cells via endocytosis was observed by confocal microscopy and drug uptake of the targeted nanoparticles was 8-fold greater than that of non-targeted drug complexes. Our docking results suggest that FA, FACD and FACD-Ada-Dox could bind human hedgehog interacting protein that contains a FR domain. Mouse cardiomyocytes as well as fibroblast treated with FACD-Ada-Dox had significantly lower levels of reactive oxygen species, with increased content of glutathione and glutathione peroxidase activity, indicating a reduced potential for Dox-induced cardiotoxicity. These results indicate that the targeted drug complex possesses high drug association and sustained drug release properties with good biocompatibility and physiological stability. The novel FA-conjugated beta-CD based drug complex might be promising as an anti-tumor treatment for FR(+) cancer. PMID- 23658722 TI - Caspase-3 is involved in the signalling in erythroid differentiation by targeting late progenitors. AB - A role for caspase activation in erythroid differentiation has been established, yet its precise mode of action remains elusive. A drawback of all previous investigations on caspase activation in ex vivo erythroid differentiation is the lack of an in vitro model producing full enucleation of erythroid cells. Using a culture system which renders nearly 100% enucleated red cells from human CD34(+) cells, we investigated the role of active caspase-3 in erythropoiesis. Profound effects of caspase-3 inhibition were found on erythroid cell growth and differentiation when inhibitors were added to CD34(+) cells at the start of the culture and showed dose-response to the concentration of inhibitor employed. Enucleation was only reduced as a function of the reduced maturity of the culture and the increased cell death of mature cells while the majority of cells retained their ability to extrude their nuclei. Cell cycle analysis after caspase-3 inhibition showed caspase-3 to play a critical role in cell proliferation and highlighted a novel function of this protease in erythroid differentiation, i.e. its contribution to cell cycle regulation at the mitotic phase. While the effect of caspase-3 inhibitor treatment on CD34(+) derived cells was not specific to the erythroid lineage, showing a similar reduction of cell expansion in myeloid cultures, the mechanism of action in both lineages appeared to be distinct with a strong induction of apoptosis causing the decreased yield of myeloid cells. Using a series of colony-forming assays we were able to pinpoint the stage at which cells were most sensitive to caspase-3 inhibition and found activated caspase-3 to play a signalling role in erythroid differentiation by targeting mature BFU-E and CFU-E but not early BFU-E. PMID- 23658723 TI - Dispensing processes impact apparent biological activity as determined by computational and statistical analyses. AB - Dispensing and dilution processes may profoundly influence estimates of biological activity of compounds. Published data show Ephrin type-B receptor 4 IC50 values obtained via tip-based serial dilution and dispensing versus acoustic dispensing with direct dilution differ by orders of magnitude with no correlation or ranking of datasets. We generated computational 3D pharmacophores based on data derived by both acoustic and tip-based transfer. The computed pharmacophores differ significantly depending upon dispensing and dilution methods. The acoustic dispensing-derived pharmacophore correctly identified active compounds in a subsequent test set where the tip-based method failed. Data from acoustic dispensing generates a pharmacophore containing two hydrophobic features, one hydrogen bond donor and one hydrogen bond acceptor. This is consistent with X-ray crystallography studies of ligand-protein interactions and automatically generated pharmacophores derived from this structural data. In contrast, the tip based data suggest a pharmacophore with two hydrogen bond acceptors, one hydrogen bond donor and no hydrophobic features. This pharmacophore is inconsistent with the X-ray crystallographic studies and automatically generated pharmacophores. In short, traditional dispensing processes are another important source of error in high-throughput screening that impacts computational and statistical analyses. These findings have far-reaching implications in biological research. PMID- 23658724 TI - (99m)Tc-DTPA renal dynamic imaging method may be unsuitable to be used as the reference method in investigating the validity of CDK-EPI equation for determining glomerular filtration rate. AB - OBJECTIVE: To compare the measurements of glomerular filtration rate (GFR) determined by (99m)Tc-diethylene triamine pentaacetic acid ((99m)Tc-DTPA) renal dynamic imaging with those estimated by Chronic Kidney Disease Epidemiology Collaboration (CDK-EPI) equation and to identify a more accurate measurement of GFR of chronic kidney disease (CKD) patients in clinical practice. METHODS: The GFR was determined simultaneously by 3 methods: (a) dual plasma sample clearance method (tGFR); (b) renal dynamic imaging method (dGFR); (c) CDK-EPI equation (eGFR). The tGFR was employed as the reference method. The correlation, regression, and limit of agreement of dGFR and eGFR were used to demonstrate the validity of the two methods. The comparison of bias, precision, and accuracy between dGFR and eGFR was analyzed to identify the most suitable method. The analysis of bias, precision and accuracy was repeated after stratifying patients by a measured tGFR cutpoint of 60 ml.min(-1).(1.73 m(2))(-1). RESULTS: A total of 149 patients were enrolled. Both dGFR and eGFR correlated well with tGFR and the regression equation of dGFR and eGFR against tGFR was respectively Y = 4.289+0.962X (r = 0.919; RMSE = 14.323 ml.min(-1). (1.73 m(2))(-1); P<0.001) and Y = 2.462+0.914X (r = 0.909; RMSE = 15.123 ml.min(-1). (1.73 m(2))(-1); P<0.001). In addition, Bland-Altman analysis showed preferable agreement between the two methods and the reference method. The comparison revealed that eGFR, compared with dGFR, showed better performance on bias and 50% accuracy and similar performance on other indexes in the whole cohort and the lower-GFR subgroup, whereas in the higher-GFR subgroup the difference of the two methods was not significant in all parameters. CONCLUSIONS: Although both CDK-EPI equation and renal dynamic imaging can be used to determine the GFR of CKD patients, CDK-EPI equation is more accurate than renal dynamic imaging. As a result, (99m)Tc-DTPA renal dynamic imaging may be unsuitable to be used as the reference method in investigating the validity of CDK-EPI equation. PMID- 23658725 TI - Flotillin2 expression correlates with HER2 levels and poor prognosis in gastric cancer. AB - OBJECTIVE: Flotillin gene is known as a tumor promoter or suppressor, depending on the tumor type or tumor stage. We aimed to investigate the clinical significance of flotillin2 protein expression in gastric cancer. METHODS: We examined flotillin2 and erbB2 levels in tissue microarray of 282 gastric cancer samples and analyzed the association between flotillin2 levels, clinicopathologic factors and prognosis. The regulation of erbB2 by flotillin2 was examined with flotillin2 siRNA-transfected gastric cancer cells. RESULTS: Flotillin2 partially co-localized with erbB2 at the plasma membrane as detected by confocal microscopy, levels of erbB2 were reduced after flotillin knockdown in SGC-7901 cancer cells, and the expression of flotillin2 was positively correlated with that of erbB2. In non-neoplastic gastric mucosa, flotillin2 was not expressed in the epithelial compartment. In gastric cancer, positive staining of flotillin2 was shown in 129 (45.7%) of 282 cases, also, it was significantly associated with a Lauren grade, histologic type, lymphovascular invasion and tumor location. Moreover, survival analysis showed that flotillin2 expression was an independent prognostic factor of poor survival (p<0.001). CONCLUSIONS: These results indicate that a positive correlation exists between flotillin2 and erbB2 expression levels, flotillin2 maybe involved in the stabilization of erbB2 at the plasma membrane, flotillin2 is significantly correlated with cancer progression and poor prognosis in gastric cancer. PMID- 23658726 TI - How fire history, fire suppression practices and climate change affect wildfire regimes in Mediterranean landscapes. AB - Available data show that future changes in global change drivers may lead to an increasing impact of fires on terrestrial ecosystems worldwide. Yet, fire regime changes in highly humanised fire-prone regions are difficult to predict because fire effects may be heavily mediated by human activities We investigated the role of fire suppression strategies in synergy with climate change on the resulting fire regimes in Catalonia (north-eastern Spain). We used a spatially-explicit fire-succession model at the landscape level to test whether the use of different firefighting opportunities related to observed reductions in fire spread rates and effective fire sizes, and hence changes in the fire regime. We calibrated this model with data from a period with weak firefighting and later assess the potential for suppression strategies to modify fire regimes expected under different levels of climate change. When comparing simulations with observed fire statistics from an eleven-year period with firefighting strategies in place, our results showed that, at least in two of the three sub-regions analysed, the observed fire regime could not be reproduced unless taking into account the effects of fire suppression. Fire regime descriptors were highly dependent on climate change scenarios, with a general trend, under baseline scenarios without fire suppression, to large-scale increases in area burnt. Fire suppression strategies had a strong capacity to compensate for climate change effects. However, strong active fire suppression was necessary to accomplish such compensation, while more opportunistic fire suppression strategies derived from recent fire history only had a variable, but generally weak, potential for compensation of enhanced fire impacts under climate change. The concept of fire regime in the Mediterranean is probably better interpreted as a highly dynamic process in which the main determinants of fire are rapidly modified by changes in landscape, climate and socioeconomic factors such as fire suppression strategies. PMID- 23658727 TI - Increased risk of dementia in patients with mild traumatic brain injury: a nationwide cohort study. AB - BACKGROUND: It is known that the risk of dementia in patients with moderate to severe traumatic brain injury (TBI) is higher. However, the relationship between mild traumatic brain injury (mTBI) and dementia has never been established. OBJECTIVES: We investigated the incidences of dementia among patients with mTBI in Taiwan to evaluate if there is higher risk compared with general population. METHODS: We utilized a sampled National Health Insurance (NHI) claims data containing one million beneficiaries. We followed all adult beneficiaries from January 1, 2005 till December 31, 2009 to see if they had been diagnosed with dementia. We further identify patients with mTBI and compared their risk of dementia with the general population. RESULTS: We identified 28551 patients with mTBI and 692382 without. After controlled for age, gender, urbanization level, socioeconomic status, diabetes, hypertension, coronary artery disease, hyperlipidemia, history of alcohol intoxication, history of ischemic stroke, history of intracranial hemorrhage and Charlson Comorbidity Index Score, the adjusted hazard ratio is 3.26 (95% Confidence interval, 2.69-3.94). CONCLUSIONS: TBI is an independent significant risk factor of developing dementia even in the mild type. PMID- 23658728 TI - Integrative effect of carvedilol and aerobic exercise training therapies on improving cardiac contractility and remodeling in heart failure mice. AB - The use of beta-blockers is mandatory for counteracting heart failure (HF) induced chronic sympathetic hyperactivity, cardiac dysfunction and remodeling. Importantly, aerobic exercise training, an efficient nonpharmacological therapy to HF, also counteracts sympathetic hyperactivity in HF and improves exercise tolerance and cardiac contractility; the latter associated with changes in cardiac Ca(2+) handling. This study was undertaken to test whether combined beta blocker and aerobic exercise training would integrate the beneficial effects of isolated therapies on cardiac structure, contractility and cardiomyocyte Ca(2+) handling in a genetic model of sympathetic hyperactivity-induced HF (alpha2A/alpha2C- adrenergic receptor knockout mice, KO). We used a cohort of 5-7 mo male wild-type (WT) and congenic mice (KO) with C57Bl6/J genetic background randomly assigned into 5 groups: control (WT), saline-treated KO (KOS), exercise trained KO (KOT), carvedilol-treated KO (KOC) and, combined carvedilol-treated and exercise-trained KO (KOCT). Isolated and combined therapies reduced mortality compared with KOS mice. Both KOT and KOCT groups had increased exercise tolerance, while groups receiving carvedilol had increased left ventricular fractional shortening and reduced cardiac collagen volume fraction compared with KOS group. Cellular data confirmed that cardiomyocytes from KOS mice displayed abnormal Ca(2+) handling. KOT group had increased intracellular peak of Ca(2+) transient and reduced diastolic Ca(2+) decay compared with KOS group, while KOC had increased Ca(2+) decay compared with KOS group. Notably, combined therapies re-established cardiomyocyte Ca(2+) transient paralleled by increased SERCA2 expression and SERCA2:PLN ratio toward WT levels. Aerobic exercise trained increased the phosphorylation of PLN at Ser(16) and Thr(17) residues in both KOT and KOCT groups, but carvedilol treatment reduced lipid peroxidation in KOC and KOCT groups compared with KOS group. The present findings provide evidence that the combination of carvedilol and aerobic exercise training therapies lead to a better integrative outcome than carvedilol or exercise training used in isolation. PMID- 23658729 TI - A site-specific recombinase-based method to produce antibiotic selectable marker free transgenic cattle. AB - Antibiotic selectable marker genes have been widely used to generate transgenic animals. Once transgenic animals have been obtained, the selectable marker is no longer necessary but raises public concerns regarding biological safety. The aim of this study was to prepare competent antibiotic selectable marker free transgenic cells for somatic cell nuclear transfer (SCNT). PhiC31 intergrase was used to insert a transgene cassette into a "safe harbor" in the bovine genome. Then, Cre recombinase was employed to excise the selectable marker under the monitoring of a fluorescent double reporter. By visually tracking the phenotypic switch from red to green fluorescence, antibiotic selectable marker free cells were easily detected and sorted by fluorescence-activated cell sorting. For safety, we used phiC31 mRNA and cell-permeant Cre protein in this study. When used as donor nuclei for SCNT, these safe harbor integrated marker-free transgenic cells supported a similar developmental competence of SCNT embryos compared with that of non-transgenic cells. After embryo transfer, antibiotic selectable marker free transgenic cattle were generated and anti-bacterial recombinant human beta-defensin-3 in milk was detected during their lactation period. Thus, this approach offers a rapid and safe alternative to produce antibiotic selectable marker free transgenic farm animals, thereby making it a valuable tool to promote the healthy development and welfare of transgenic farm animals. PMID- 23658730 TI - Inhibition of enveloped viruses infectivity by curcumin. AB - Curcumin, a natural compound and ingredient in curry, has antiinflammatory, antioxidant, and anticarcinogenic properties. Previously, we reported that curcumin abrogated influenza virus infectivity by inhibiting hemagglutination (HA) activity. This study demonstrates a novel mechanism by which curcumin inhibits the infectivity of enveloped viruses. In all analyzed enveloped viruses, including the influenza virus, curcumin inhibited plaque formation. In contrast, the nonenveloped enterovirus 71 remained unaffected by curcumin treatment. We evaluated the effects of curcumin on the membrane structure using fluorescent dye (sulforhodamine B; SRB)-containing liposomes that mimic the viral envelope. Curcumin treatment induced the leakage of SRB from these liposomes and the addition of the influenza virus reduced the leakage, indicating that curcumin disrupts the integrity of the membranes of viral envelopes and of liposomes. When testing liposomes of various diameters, we detected higher levels of SRB leakage from the smaller-sized liposomes than from the larger liposomes. Interestingly, the curcumin concentration required to reduce plaque formation was lower for the influenza virus (approximately 100 nm in diameter) than for the pseudorabies virus (approximately 180 nm) and the vaccinia virus (roughly 335 * 200 * 200 nm). These data provide insights on the molecular antiviral mechanisms of curcumin and its potential use as an antiviral agent for enveloped viruses. PMID- 23658731 TI - SNP set association analysis for genome-wide association studies. AB - Genome-wide association study (GWAS) is a promising approach for identifying common genetic variants of the diseases on the basis of millions of single nucleotide polymorphisms (SNPs). In order to avoid low power caused by overmuch correction for multiple comparisons in single locus association study, some methods have been proposed by grouping SNPs together into a SNP set based on genomic features, then testing the joint effect of the SNP set. We compare the performances of principal component analysis (PCA), supervised principal component analysis (SPCA), kernel principal component analysis (KPCA), and sliced inverse regression (SIR). Simulated SNP sets are generated under scenarios of 0, 1 and >= 2 causal SNPs model. Our simulation results show that all of these methods can control the type I error at the nominal significance level. SPCA is always more powerful than the other methods at different settings of linkage disequilibrium structures and minor allele frequency of the simulated datasets. We also apply these four methods to a real GWAS of non-small cell lung cancer (NSCLC) in Han Chinese population. PMID- 23658732 TI - The absence of obstructive sleep apnea may protect against non-alcoholic fatty liver in patients undergoing bariatric surgery. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide and its progressive form, steatohepatitis, will be the leading indication for liver transplant by 2020. While risk factors for steatohepatitis have been identified, little work has been performed to identify factors protective against NAFLD development. AIM: This study sought to identify factors predictive of normal liver histology in a bariatric cohort. METHODS: Patients undergoing weight loss surgery with liver biopsies at the time of surgery were included. Patients with other causes of chronic liver disease were excluded. RESULTS: One hundred fifty-nine patients were included. Forty-nine patients had normal liver histology and 110 patients had NAFLD. Several previously identified factors associated with normal liver histology were found. Black race was the strongest predictor of the absence of NAFLD with an odds ratio (OR) of 6.8, 95% confidence interval (CI) 2.4-18.9. Low HOMA-IR was also associated with normal histology (OR 1.4, 95% CI 1.03-1.9). In contrast, low HDL was associated with a decreased chance of normal histology (OR 0.38, 95% CI 0.05 0.83). Interestingly, a novel protective factor, the absence of obstructive sleep apnea (OSA) was strongly associated with normal histology (OR 5.6, 95% CI 2.0 16.1). In multivariate regression controlling for BMI, black race, absence of OSA, low HOMA-IR and low ALT independently predicted normal liver histology with an area under the ROC curve of 0.85. CONCLUSIONS: Our study confirmed several factors associated with normal liver histology, including black race and identified a novel factor, absence of OSA. Further evaluation of these factors will allow for improved understanding of the pathogenesis of NAFLD. PMID- 23658733 TI - Distinct structural features of G protein-coupled receptor kinase 5 (GRK5) regulate its nuclear localization and DNA-binding ability. AB - G protein-coupled receptor kinases (GRKs) act to desensitize G protein-coupled receptors (GPCRs). In addition to this role at the plasma membrane, a nuclear function for GRK5, a member of the GRK4 subfamily of GRKs, has been reported. GRK5 phosphorylates and promotes the nuclear export of the histone deacetylase, HDAC5. Here we demonstrate that the possession of a nuclear localization sequence (NLS) is a common feature of GRK4 subfamily members (GRKs 4, 5 and 6). However, the location of the NLS and the ability of these GRKs to bind DNA in vitro are different. The NLSs of GRK5 and 6 bind DNA in vitro, whilst the NLS of GRK4 does not. Using mutants of GRK5 we identify the regions of GRK5 required for DNA binding in vitro and nuclear localization in cells. The DNA-binding ability of GRK5 requires both the NLS and an N-terminal calmodulin (CaM)-binding site. A functional nuclear export sequence (NES), required for CaM-dependent nuclear export of the kinase, is also identified. Based on our observations we propose a model to explain how nuclear localization of GRK5 may be regulated. Notably, the nuclear localization of GRK5 and 6 is differentially regulated. These results suggest subfamily specific nuclear functions for the GRK4 subfamily members. Identification of GRK specific small molecule inhibitors of nuclear localization and/or function for the GRK4 subfamily may thus be an achievable goal. PMID- 23658734 TI - Effects on immune cells of a new 1,8-naphthyridin-2-one derivative and its analogues as selective CB2 agonists: implications in multiple sclerosis. AB - The efficacy of cannabinoids in the treatment of multiple sclerosis is widely documented; however their use is limited by psychoactivity mainly ascribed to the activation of the cannabinoid receptor CB1. Emerging findings support as alternative strategy in the treatment of neurodegenerative disorders, the application of compounds targeting the CB2 receptor, since likely unrelated to these side effects. Recently, a novel class of compounds, 1,8-naphthyridine, pyridine and quinoline derivatives have been demonstrated to show high CB2 receptor selectivity and affinity versus the CB1 receptor. Considering that the CB2 receptor is mainly expressed in cell and organs of the immune system, in this study we assessed the potential immune-modulatory effects of these compounds in activated lymphocytes isolated from MS patients with respect to healthy controls. These compounds blocked cell proliferation through a mechanism partially ascribed to the CB2 receptor, down-regulated TNF-alpha production and did not induce cell death. They also down-regulated Akt, Erk and NF-kB phosphorylation. Despite comparable effects observed in patients and healthy controls, these compounds, in particular, 1,8-naphthyridine and quinoline derivatives inhibited cell activation markers in MS patient derived lymphocytes more efficiently than in healthy control derived cells. Indeed, 1,8-naphthyridin-2-one derivative reduced the levels of Cox-2 in lymphocytes from patients whereas no effect was observed in control cells. Our findings suggest potential application of these drugs in neuro inflammation, supporting further investigations of the effects of compounds in the therapy of MS, particularly on the aspects regarding activation and inflammation. PMID- 23658735 TI - Differences in dopaminergic modulation to motor cortical plasticity between Parkinson's disease and multiple system atrophy. AB - Dopamine modulates the synaptic plasticity in the primary motor cortex (M1). To evaluate whether the functioning of the cortico-striatal circuit is necessary for this modulation, we applied a paired associative stimulation (PAS) protocol that comprised an electric stimulus to the right median nerve at the wrist and subsequent transcranial magnetic stimulation of the left M1, to 10 patients with Parkinson's disease (PD) and 10 with multiple system atrophy of the parkinsonian type (MSA-P) with and without dopamine replacement therapy (-on/off). To investigate the M1 function, motor-evoked potentials (MEPs) were measured before and after the PAS. In both patient groups without medication, the PAS protocol failed to increase the averaged amplitude of MEPs. The dopamine replacement therapy in PD, but not in MSA-P effectively restored the PAS-induced MEP increase. This suggests that not the existence of dopamine itself but the activation of cortico-striatal circuit might play an important role for cortical plasticity in the human M1. PMID- 23658736 TI - Modes of competition: adding and removing brown trout in the wild to understand the mechanisms of density-dependence. AB - While the prevalence of density-dependence is well-established in population ecology, few field studies have investigated its underlying mechanisms and their relative population-level importance. Here, we address these issues, and more specifically, how differences in body-size influence population regulation. For this purpose, two experiments were performed in a small coastal stream on the Swedish west coast, using juvenile brown trout (Salmo trutta) as a study species. We manipulated densities of large and small individuals, and observed effects on survival, migration, condition and individual growth rate in a target group of intermediate-sized individuals. The generality of the response was investigated by reducing population densities below and increasing above the natural levels (removing and adding large and small individuals). Reducing the density (relaxing the intensity of competition) had no influence on the response variables, suggesting that stream productivity was not a limiting factor at natural population density. Addition of large individuals resulted in a negative density dependent response, while no effect was detected when adding small individuals or when maintaining the natural population structure. We found that the density dependent response was revealed as reduced growth rate rather than increased mortality and movement, an effect that may arise from exclusion to suboptimal habitats or increased stress levels among inferior individuals. Our findings confirm the notion of interference competition as the primary mode of competition in juvenile salmonids, and also show that the feedback-mechanisms of density dependence are primarily acting when increasing densities above their natural levels. PMID- 23658737 TI - A fetal and an intra-amniotic inflammatory response is more severe in preterm labor than in preterm PROM in the context of funisitis: unexpected observation in human gestations. AB - OBJECTIVE: Although intra-amniotic(IA) infection is present in both preterm labor and intact membranes(PTL) and preterm premature rupture of membranes(preterm PROM), it is more common in preterm-PROM than in PTL. Microorganisms and their products in the amniotic-cavity can elicit an inflammatory-response in fetus as well as in amniotic-cavity in the progression of acute histologic chorioamnionitis(acute-HCA). A fundamental question is whether a fetal and an IA inflammatory-response is more severe in preterm-PROM than in PTL, in the same context of acute-HCA with or without fetal-involvement. The purpose of current study was to answer this-question. STUDYDESIGN: Study population consisted of 213 singleton preterm-gestations(<34 weeks) delivered within 4 days of amniocentesis due to PTL(120 cases) or preterm-PROM(93 cases). The intensity of fetal and IA inflammatory-responses was compared between PTL and preterm-PROM, according to placental inflammatory conditions:1)placenta without inflammatory-lesion;2)acute HCA without funisitis;3)acute-HCA with funisitis. IA inflammatory response was assessed by amniotic-fluid(AF) matrix metalloproteinase-8(MMP-8), and fetal inflammatory response(FIR) by umbilical-cord plasma(UCP) C-reactive protein(CRP) at birth. RESULTS: 1) Patients with preterm-PROM had higher rates of IA infection, acute-HCA, and acute-HCA with funisitis than those with PTL did(p<.01 for each);2) there were no significant differences in the intensity of fetal and IA inflammatory-responses and the rate of cervical dilatation>=3 cm or 4 cm between patients with PTL and those with preterm-PROM in the context of both placenta without inflammatory-lesion and acute-HCA without funisitis(p>.05 for each);3) however, acute-HCA with funisitis was associated with a significantly higher median AF MMP-8 and UCP CRP concentration and higher rate of cervical dilatation>=3 cm or 4 cm in PTL than in preterm-PROM(AF MMP-8, 675 ng/mlvs.417 ng/ml; UCP CRP, 969 ng/mlvs.397 ng/ml;each for p<.05), despite less common IA infection in PTL than in preterm-PROM(29%vs.57%;p<.05). CONCLUSIONS: A fetal and an IA inflammatory-response is more severe in PTL than in preterm-PROM in the context of funisitis, despite less common IA infection. This unexpected observation may indicate the fundamental difference in the pathogenesis between PTL and preterm-PROM. PMID- 23658738 TI - Estrogen-dependent dynamic profile of eNOS-DNA associations in prostate cancer. AB - In previous work we have documented the nuclear translocation of endothelial NOS (eNOS) and its participation in combinatorial complexes with Estrogen Receptor Beta (ERbeta) and Hypoxia Inducible Factors (HIFs) that determine localized chromatin remodeling in response to estrogen (E2) and hypoxia stimuli, resulting in transcriptional regulation of genes associated with adverse prognosis in prostate cancer (PCa). To explore the role of nuclear eNOS in the acquisition of aggressive phenotype in PCa, we performed ChIP-Sequencing on chromatin-associated eNOS from cells from a primary tumor with poor outcome and from metastatic LNCaP cells. We found that: 1. the eNOS-bound regions (peaks) are widely distributed across the genome encompassing multiple transcription factors binding sites, including Estrogen Response Elements. 2. E2 increased the number of peaks, indicating hormone-dependent eNOS re-localization. 3. Peak distribution was similar with/without E2 with ~ 55% of them in extragenic DNA regions and an intriguing involvement of the 5' domain of several miRs deregulated in PCa. Numerous potentially novel eNOS-targeted genes have been identified suggesting that eNOS participates in the regulation of large gene sets. The parallel finding of downregulation of a cluster of miRs, including miR-34a, in PCa cells associated with poor outcome led us to unveil a molecular link between eNOS and SIRT1, an epigenetic regulator of aging and tumorigenicity, negatively regulated by miR-34a and in turn activating eNOS. E2 potentiates miR-34a downregulation thus enhancing SIRT1 expression, depicting a novel eNOS/SIRT1 interplay fine tuned by E2-activated ER signaling, and suggesting that eNOS may play an important role in aggressive PCa. PMID- 23658739 TI - Retest reliability of individual p3 topography assessed by high density electroencephalography. AB - BACKGROUND: Some controversy remains about the potential applicability of cognitive potentials for evaluating the cerebral activity associated with cognitive capacity. A fundamental requirement is that these neurophysiological parameters show a high level of stability over time. Previous studies have shown that the reliability of diverse parameters of the P3 component (latency and amplitude) ranges between moderate and high. However, few studies have paid attention to the retest reliability of the P3 topography in groups or individuals. Considering that changes in P3 topography have been related to different pathologies and healthy aging, the main objective of this article was to evaluate in a longitudinal study (two sessions) the reliability of P3 topography in a group and at the individual level. RESULTS: The correlation between sessions for P3 topography in the grand average of groups was high (r = 0.977, p<0.001). The within-subject correlation values ranged from 0.626 to 0.981 (mean: 0.888). In the between-subjects topography comparisons, the correlation was always lower for comparisons between different subjects than for within subjects correlations in the first session but not in the second session. CONCLUSIONS: The present study shows that P3 topography is highly reliable for group analysis (comprising the same subjects) in different sessions. The results also confirmed that retest reliability for individual P3 maps is suitable for follow-up studies for a particular subject. Moreover, P3 topography appears to be a specific marker considering that the between-subjects correlations were lower than the within-subject correlations. However, P3 topography appears more similar between subjects in the second session, demonstrating that is modulated by experience. Possible clinical applications of all these results are discussed. PMID- 23658740 TI - Evidence for gating roles of protein kinase A and protein kinase C in estradiol induced luteinizing hormone receptor (lhcgr) expression in zebrafish ovarian follicle cells. AB - Estradiol (E2) stimulates luteinizing hormone receptor (lhcgr) expression in zebrafish follicle cells via nuclear estrogen receptors (nERs) that are likely expressed on the membrane, and lhcgr responds to E2 in a biphasic manner during 24-h treatment. These observations raise an interesting question on the signaling mechanism underlying E2 regulation, in particular the biphasic response of lhcgr expression. In the present study, we demonstrated that E2 regulation of lhcgr was significantly influenced by the activity of cAMP-PKA pathway. Activation of cAMP PKA pathway by forskolin or db-cAMP suppressed E2-stimulated lhcgr expression in short-term (3 h) but enhanced its effect in long-term (24 h), suggesting differential roles of PKA at these two phases of lhcgr response. PKA inhibitor H89 showed reversed effects. In contrast, PKC pathway had consistent permissive effect on E2-induced lhcgr expression as evidenced by strong inhibition of E2 effect by PKC inhibitors GF109203X and Ro-31-8220 at both 3 and 24 h. One of the mechanisms by which PKA and PKC gated E2 effect might be through regulating nERs, particularly esr2a. Despite the strong influence of PKA and PKC, our data did not suggest direct mediating roles for these two pathways in E2 stimulation of lhcgr expression; yet they likely play critical gating roles in E2 signal transduction. As a follow-up study to our previous report on E2 regulation of gonadotropin receptors in the zebrafish ovary, the present study provides further evidence for the involvement of classical intracellular signal transduction pathways in E2 stimulation of lhcgr expression in the follicle cells. PMID- 23658741 TI - Change in neighborhood traffic safety: does it matter in terms of physical activity? AB - BACKGROUND: There is limited evidence on the causality of previously observed associations between neighborhood traffic safety and physical activity (PA). This study aims to contribute to this evidence by assessing the extent to which changes over time in neighborhood traffic safety were associated with PA. METHODS: Data were accessed from the national survey Netherlands Housing Research for 2006 and 2009. The two samples of in total 57,092 Dutch residents aged 18-84 years lived in 320 neighbourhoods. Using multi-level hurdle models, the authors assessed whether the odds of being physically active and the mean hours of PA among active people (in 2009) were related to the levels of neighborhood traffic safety (in 2006) and changes in the levels of neighborhood traffic safety (between 2006 and 2009). Next, we examined if these associations varied according to gender, age, and employment status. RESULTS: Higher levels of neighborhood traffic safety were associated with higher odds of being active (OR 1.080 (1.025 1.139)). An increase in levels of neighborhood traffic safety was associated with increased odds of being active (OR 1.060 (1.006-1.119)). This association was stronger among women, people aged 35 to 59, and those who were gainfully employed. Neither levels of traffic safety nor changes in these levels were associated with the mean hours of PA among people who were physically active (OR 0.997 (0.975-1.020); OR 1.001 (0.978-1.025), respectively). CONCLUSION: Not only levels of neighborhood traffic safety, but also increases in neighborhood traffic safety were related to increased odds of being active. This relationship supports claims for a causal relationship between neighborhood traffic safety and PA. PMID- 23658742 TI - p63 attenuates epithelial to mesenchymal potential in an experimental prostate cell model. AB - The transcription factor p63 is central for epithelial homeostasis and development. In our model of epithelial to mesenchymal transition (EMT) in human prostate cells, p63 was one of the most down-regulated transcription factors during EMT. We therefore investigated the role of p63 in EMT. Over-expression of the predominant epithelial isoform DeltaNp63alpha in mesenchymal type cells of the model led to gain of several epithelial characteristics without resulting in a complete mesenchymal to epithelial transition (MET). This was corroborated by a reciprocal effect when p63 was knocked down in epithelial EP156T cells. Global gene expression analyses showed that DeltaNp63alpha induced gene modules involved in both cell-to-cell and cell-to-extracellular-matrix junctions in mesenchymal type cells. Genome-wide analysis of p63 binding sites using ChIP-seq analyses confirmed binding of p63 to regulatory areas of genes associated with cell adhesion in prostate epithelial cells. DH1 and ZEB1 are two elemental factors in the control of EMT. Over-expression and knock-down of these factors, respectively, were not sufficient alone or in combination with DeltaNp63alpha to reverse completely the mesenchymal phenotype. The partial reversion of epithelial to mesenchymal transition might reflect the ability of DeltaNp63alpha, as a key co-ordinator of several epithelial gene expression modules, to reduce epithelial to mesenchymal plasticity (EMP). The utility of DeltaNp63alpha expression and the potential of reduced EMP in order to counteract metastasis warrant further investigation. PMID- 23658743 TI - Protein expression of ZEB2 in renal cell carcinoma and its prognostic significance in patient survival. AB - BACKGROUND: ZEB2 has been reportedly shown to mediate the epithelial-to mesenchymal transition (EMT) and disease aggressiveness in human tumors. However, the expression status of ZEB2 in renal cell carcinoma (RCC) and ZEB2's clinicopathologic/prognostic significance are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, tissue microarray, immunohistochemistry (IHC) and western blot analyses were utilized to investigate the ZEB2 expression status in RCC and adjacent renal tissue samples. In our study, samples from 116 RCC patients treated with radical nephrectomy were used as a training set to generate a ZEB2 optimal cut-point for patient outcome by receiver operating characteristic (ROC) analysis. For validation, the correlation of ZEB2 expression with the clinical characteristics and patient outcomes in another set (including 113 patients) was analyzed to validate the obtained cut point. In the training and validation sets, high expression of ZEB2, defined by ROC analysis, predicted a poorer overall survival and progression-free survival, as evidenced by the univariate and multivariate analyses. In different subsets of overall patients, ZEB2 expression was also a prognostic indicator in patients with stage I/II, stage III/IV, grade 1/2 and grade 3/4 disease (P<0.05). Downregulation of ZEB2 by shRNA decreased the migration and invasion ability of 769-P cells in vitro. Furthermore, high ZEB2 expression was positively correlated with vimentin expression and inversely linked to E-cadherin expression in RCC. CONCLUSIONS/SIGNIFICANCE: Our findings provide a basis for the concept that high ZEB2 expression in RCC may be important in the acquisition of an aggressive phenotype. This evidence suggests that ZEB2 overexpression (examined by IHC) is an independent biomarker for the poor prognosis of patients with RCC. PMID- 23658744 TI - Tryptogalinin is a tick Kunitz serine protease inhibitor with a unique intrinsic disorder. AB - BACKGROUND: A salivary proteome-transcriptome project on the hard tick Ixodes scapularis revealed that Kunitz peptides are the most abundant salivary proteins. Ticks use Kunitz peptides (among other salivary proteins) to combat host defense mechanisms and to obtain a blood meal. Most of these Kunitz peptides, however, remain functionally uncharacterized, thus limiting our knowledge about their biochemical interactions. RESULTS: We discovered an unusual cysteine motif in a Kunitz peptide. This peptide inhibits several serine proteases with high affinity and was named tryptogalinin due to its high affinity for beta-tryptase. Compared with other functionally described peptides from the Acari subclass, we showed that tryptogalinin is phylogenetically related to a Kunitz peptide from Rhipicephalus appendiculatus, also reported to have a high affinity for beta tryptase. Using homology-based modeling (and other protein prediction programs) we were able to model and explain the multifaceted function of tryptogalinin. The N-terminus of the modeled tryptogalinin is detached from the rest of the peptide and exhibits intrinsic disorder allowing an increased flexibility for its high affinity with its inhibiting partners (i.e., serine proteases). CONCLUSIONS: By incorporating experimental and computational methods our data not only describes the function of a Kunitz peptide from Ixodes scapularis, but also allows us to hypothesize about the molecular basis of this function at the atomic level. PMID- 23658745 TI - Hydrogen peroxide produced by oral Streptococci induces macrophage cell death. AB - Hydrogen peroxide (H2O2) produced by members of the mitis group of oral streptococci plays important roles in microbial communities such as oral biofilms. Although the cytotoxicity of H2O2 has been widely recognized, the effects of H2O2 produced by oral streptococci on host defense systems remain unknown. In the present study, we investigated the effect of H2O2 produced by Streptococcus oralis on human macrophage cell death. Infection by S. oralis was found to stimulate cell death of a THP-1 human macrophage cell line at multiplicities of infection greater than 100. Catalase, an enzyme that catalyzes the decomposition of H2O2, inhibited the cytotoxic effect of S. oralis. S. oralis deletion mutants lacking the spxB gene, which encodes pyruvate oxidase, and are therefore deficient in H2O2 production, showed reduced cytotoxicity toward THP-1 macrophages. Furthermore, H2O2 alone was capable of inducing cell death. The cytotoxic effect seemed to be independent of inflammatory responses, because H2O2 was not a potent stimulator of tumor necrosis factor-alpha production in macrophages. These results indicate that streptococcal H2O2 plays a role as a cytotoxin, and is implicated in the cell death of infected human macrophages. PMID- 23658746 TI - Associations of PON1 and genetic ancestry with obesity in early childhood. AB - Obesity in children has become an epidemic in the U.S. and is particularly prominent in minority populations such as Mexican-Americans. In addition to physical activity and diet, genetics also plays a role in obesity etiology. A few studies in adults and adolescents suggest a link between obesity and paraoxonase 1 (PON1), a multifunctional enzyme that can metabolize organophosphate pesticides and also has antioxidant properties. We determined PON1192 genotype and arylesterase levels (ARYase, measure of PON1 enzyme quantity), to characterize the relationship between PON1 and obesity in young Mexican-American children (n = 373) living in an agricultural community in California. Since PON1 polymorphisms and obesity both vary between ethnic groups, we estimated proportional genetic ancestry using 106 ancestral informative markers (AIMs). Among children, PON1192 allele frequencies were 0.5 for both alleles, and the prevalence of obesity was high (15% and 33% at ages two and five, respectively). The average proportion of European, African, and Native American ancestry was 0.40, 0.09, and 0.51, yet there was wide inter-individual variation. We found a significantly higher odds of obesity (9.3 and 2.5- fold) in PON1192QQ children compared to PON1192RR children at ages two and five, respectively. Similar relationships were seen with BMI Z-scores at age two and waist circumference at age five. After adjusting for genetic ancestry in models of PON1 and BMI Z-score, effect estimates for PON1192 genotype changed 15% and 9% among two and five year old children, respectively, providing evidence of genetic confounding by population stratification. However even after adjustment for genetic ancestry, the trend of increased BMI Z-scores with increased number of PON1192 Q alleles remained. Our findings suggest that PON1 may play a role in obesity independent of genetic ancestry and that studies of PON1 and health outcomes, especially in admixed populations, should account for differences due to population stratification. PMID- 23658747 TI - Phylogeny, floral evolution, and inter-island dispersal in Hawaiian Clermontia (Campanulaceae) based on ISSR variation and plastid spacer sequences. AB - Previous studies based on DNA restriction-site and sequence variation have shown that the Hawaiian lobeliads are monophyletic and that the two largest genera, Cyanea and Clermontia, diverged from each other ca. 9.7 Mya. Sequence divergence among species of Clermontia is quite limited, however, and extensive hybridization is suspected, which has interfered with production of a well resolved molecular phylogeny for the genus. Clermontia is of considerable interest because several species posses petal-like sepals, raising the question of whether such a homeotic mutation has arisen once or several times. In addition, morphological and molecular studies have implied different patterns of inter-island dispersal within the genus. Here we use nuclear ISSRs (inter-simple sequence repeat polymorphisms) and five plastid non-coding sequences to derive biparental and maternal phylogenies for Clermontia. Our findings imply that (1) Clermontia is not monophyletic, with Cl. pyrularia nested within Cyanea and apparently an intergeneric hybrid; (2) the earliest divergent clades within Clermontia are native to Kauai, then Oahu, then Maui, supporting the progression rule of dispersal down the chain toward progressively younger islands, although that rule is violated in later-evolving taxa in the ISSR tree; (3) almost no sequence divergence among several Clermontia species in 4.5 kb of rapidly evolving plastid DNA; (4) several apparent cases of hybridization/introgression or incomplete lineage sorting (i.e., Cl. oblongifolia, peleana, persicifolia, pyrularia, samuelii, tuberculata), based on extensive conflict between the ISSR and plastid phylogenies; and (5) two origins and two losses of petaloid sepals, or--perhaps more plausibly--a single origin and two losses of this homeotic mutation, with its introgression into Cl. persicifolia. Our phylogenies are better resolved and geographically more informative than others based on ITS and 5S-NTS sequences and nuclear SNPs, but agree with them in supporting Clermontia's origin on Kauai or some older island and dispersal down the chain subsequently. PMID- 23658748 TI - Continuing fragmentation of a widespread species by geographical barriers as initial step in a land snail radiation on crete. AB - The phylogeographic structure of the land snail Xerocrassa mesostena on Crete inferred from AFLP markers and mitochondrial cox1 sequences can be explained by three mechanisms: gene flow restriction, population expansion and leptokurtic dispersal. Gene flow restriction by geographic barriers caused subdivision of the gene pool into distinct clusters. Population expansion was probably facilitated by deforestation of Crete in the postglacial. Newly available areas were colonized by leptokurtic dispersal, i.e. slow active expansion resulting in isolation by distance within the clusters and occasional long distance dispersal events that resulted in departures from the isolation by distance model. Less than one percent of the AFLP markers show correlations with environmental variables. Random phylogeographic breaks in the distribution of the mitochondrial haplotype groups indicate that single locus markers, especially mitochondrial DNA, might result in a misleading picture of the phylogeographic structure of a species. Restriction of gene flow between metapopulations caused by geographical barriers can interact with sexual selection resulting in the differentiation of these metapopulations into separate species without noticeable ecological differentiation. Evidence for gene flow between parapatrically distributed evolutionary units representing different stages of the speciation process suggests that the ongoing process of fragmentation of the X. mesostena complex might be an example for parapatric speciation. The lack of ecological differentiation between these units confirms theoretical predictions that divergent selection for local adaptation is not required for rapid speciation. PMID- 23658749 TI - Quantitatively different, yet qualitatively alike: a meta-analysis of the mouse core gut microbiome with a view towards the human gut microbiome. AB - BACKGROUND: A number of human diseases such as obesity and diabetes are associated with changes or imbalances in the gut microbiota (GM). Laboratory mice are commonly used as experimental models for such disorders. The introduction and dynamic development of next generation sequencing techniques have enabled detailed mapping of the GM of both humans and animal models. Nevertheless there is still a significant knowledge gap regarding the human and mouse common GM core and thus the applicability of the latter as an animal model. The aim of the present study was to identify inter- and intra-individual differences and similarities between the GM composition of particular mouse strains and humans. METHODOLOGY/PRINCIPAL FINDINGS: A total of 1509428 high quality tag-encoded partial 16S rRNA gene sequences determined using 454/FLX Titanium (Roche) pyro sequencing reflecting the GM composition of 32 human samples from 16 individuals and 88 mouse samples from three laboratory mouse strains commonly used in diabetes research were analyzed using Principal Coordinate Analysis (PCoA), nonparametric multivariate analysis of similarity (ANOSIM) and alpha diversity measures. A reliable cutoff threshold for low abundant taxa estimated on the basis of the present study is recommended for similar trials. CONCLUSIONS/SIGNIFICANCE: Distinctive quantitative differences in the relative abundance of most taxonomic groups between the examined categories were found. All investigated mouse strains clustered separately, but with a range of shared features when compared to the human GM. However, both mouse fecal, caecal and human fecal samples shared to a large extent not only representatives of the same phyla, but also a substantial fraction of common genera, where the number of shared genera increased with sequencing depth. In conclusion, the GM of mice and humans is quantitatively different (in terms of abundance of specific phyla and species) but share a large qualitatively similar core. PMID- 23658750 TI - Quantitative analysis of food and feed samples with droplet digital PCR. AB - In this study, the applicability of droplet digital PCR (ddPCR) for routine analysis in food and feed samples was demonstrated with the quantification of genetically modified organisms (GMOs). Real-time quantitative polymerase chain reaction (qPCR) is currently used for quantitative molecular analysis of the presence of GMOs in products. However, its use is limited for detecting and quantifying very small numbers of DNA targets, as in some complex food and feed matrices. Using ddPCR duplex assay, we have measured the absolute numbers of MON810 transgene and hmg maize reference gene copies in DNA samples. Key performance parameters of the assay were determined. The ddPCR system is shown to offer precise absolute and relative quantification of targets, without the need for calibration curves. The sensitivity (five target DNA copies) of the ddPCR assay compares well with those of individual qPCR assays and of the chamber digital PCR (cdPCR) approach. It offers a dynamic range over four orders of magnitude, greater than that of cdPCR. Moreover, when compared to qPCR, the ddPCR assay showed better repeatability at low target concentrations and a greater tolerance to inhibitors. Finally, ddPCR throughput and cost are advantageous relative to those of qPCR for routine GMO quantification. It is thus concluded that ddPCR technology can be applied for routine quantification of GMOs, or any other domain where quantitative analysis of food and feed samples is needed. PMID- 23658751 TI - Self-affirmation improves problem-solving under stress. AB - High levels of acute and chronic stress are known to impair problem-solving and creativity on a broad range of tasks. Despite this evidence, we know little about protective factors for mitigating the deleterious effects of stress on problem solving. Building on previous research showing that self-affirmation can buffer stress, we tested whether an experimental manipulation of self-affirmation improves problem-solving performance in chronically stressed participants. Eighty undergraduates indicated their perceived chronic stress over the previous month and were randomly assigned to either a self-affirmation or control condition. They then completed 30 difficult remote associate problem-solving items under time pressure in front of an evaluator. Results showed that self-affirmation improved problem-solving performance in underperforming chronically stressed individuals. This research suggests a novel means for boosting problem-solving under stress and may have important implications for understanding how self affirmation boosts academic achievement in school settings. PMID- 23658752 TI - Childhood hyperactivity, physical aggression and criminality: a 19-year prospective population-based study. AB - BACKGROUND: Research shows that children with Attention Deficit/Hyperactivity Disorder are at elevated risk of criminality. However, several issues still need to be addressed in order to verify whether hyperactivity in itself plays a role in the prediction of criminality. In particular, co-occurrence with other behaviors as well as the internal heterogeneity in ADHD symptoms (hyperactivity and inattention) should be taken into account. The aim of this study was to assess the unique and interactive contributions of hyperactivity to the development of criminality, whilst considering inattention, physical aggression and family adversity. METHODOLOGY/PRINCIPAL FINDINGS: We monitored the development of a population-based sample of kindergarten children (N = 2,741). Hyperactivity, inattention, and physical aggression were assessed annually between the ages of 6 and 12 years by mothers and teachers. Information on the presence, the age at first charge and the type of criminal charge was obtained from official records when the participants were aged 25 years. We used survival analysis models to predict the development of criminality in adolescence and adulthood: high childhood hyperactivity was highly predictive when bivariate analyses were used; however, with multivariate analyses, high hyperactivity was only marginally significant (Hazard Ratio: 1.38; 95% CI: 0.94-2.02). Sensitivity analyses revealed that hyperactivity was not a consistent predictor. High physical aggression was strongly predictive (Hazard Ratio: 3.44; 95% CI: 2.43 4.87) and its role was consistent in sensitivity analyses and for different types of crime. Inattention was not predictive of later criminality. CONCLUSIONS/SIGNIFICANCE: Although the contribution of childhood hyperactivity to criminality may be detected in large samples using multi-informant longitudinal designs, our results show that it is not a strong predictor of later criminality. Crime prevention should instead target children with the highest levels of childhood physical aggression and family adversity. PMID- 23658753 TI - Evaluating power and type 1 error in large pedigree analyses of binary traits. AB - Studying population isolates with large, complex pedigrees has many advantages for discovering genetic susceptibility loci; however, statistical analyses can be computationally challenging. Allelic association tests need to be corrected for relatedness among study participants, and linkage analyses require subdividing and simplifying the pedigree structures. We have extended GenomeSIMLA to simulate SNP data in complex pedigree structures based on an Amish pedigree to generate the same structure and distribution of sampled individuals. We evaluated type 1 error rates when no disease SNP was simulated and power when disease SNPs with recessive, additive, and dominant modes of inheritance and odds ratios of 1.1, 1.5, 2.0, and 5.0 were simulated. We generated subpedigrees with a maximum bit size of 24 using PedCut and performed two-point and multipoint linkage using Merlin. We also ran MQLS on the subpedigrees and unified pedigree. We saw no inflation of type 1 error when running MQLS on either the whole pedigrees or the sub-pedigrees, and we saw low type 1 error for two-point and multipoint linkage. Power was reduced when running MQLS on the subpedigrees versus the whole pedigree, and power was low for two-point and multipoint linkage analyses of the subpedigrees. These data suggest that MQLS has appropriate type 1 error rates in our Amish pedigree structure, and while type 1 error does not seem to be affected when dividing the pedigree prior to linkage analysis, power to detect linkage is diminished when the pedigree is divided. PMID- 23658754 TI - Neonicotinoid insecticides alter induced defenses and increase susceptibility to spider mites in distantly related crop plants. AB - BACKGROUND: Chemical suppression of arthropod herbivores is the most common approach to plant protection. Insecticides, however, can cause unintended, adverse consequences for non-target organisms. Previous studies focused on the effects of pesticides on target and non-target pests, predatory arthropods, and concomitant ecological disruptions. Little research, however, has focused on the direct effects of insecticides on plants. Here we demonstrate that applications of neonicotinoid insecticides, one of the most important insecticide classes worldwide, suppress expression of important plant defense genes, alter levels of phytohormones involved in plant defense, and decrease plant resistance to unsusceptible herbivores, spider mites Tetranychus urticae (Acari: Tetranychidae), in multiple, distantly related crop plants. METHODOLOGY/PRINCIPAL FINDINGS: Using cotton (Gossypium hirsutum), corn (Zea mays) and tomato (Solanum lycopersicum) plants, we show that transcription of phenylalanine ammonia lyase, coenzyme A ligase, trypsin protease inhibitor and chitinase are suppressed and concentrations of the phytohormone OPDA and salicylic acid were altered by neonicotinoid insecticides. Consequently, the population growth of spider mites increased from 30% to over 100% on neonicotinoid-treated plants in the greenhouse and by nearly 200% in the field experiment. CONCLUSIONS/SIGNIFICANCE: Our findings are important because applications of neonicotinoid insecticides have been associated with outbreaks of spider mites in several unrelated plant species. More importantly, this is the first study to document insecticide mediated disruption of plant defenses and link it to increased population growth of a non-target herbivore. This study adds to growing evidence that bioactive agrochemicals can have unanticipated ecological effects and suggests that the direct effects of insecticides on plant defenses should be considered when the ecological costs of insecticides are evaluated. PMID- 23658755 TI - Endoplasmic reticulum stress-induced resistance to doxorubicin is reversed by paeonol treatment in human hepatocellular carcinoma cells. AB - BACKGROUND: Endoplasmic reticulum stress (ER stress) is generally activated in solid tumors and results in tumor cell anti-apoptosis and drug resistance. Paeonol (Pae, 2-hydroxy-4-methoxyacetophenone), is a natural product extracted from the root of Paeonia Suffruticosa Andrew. Although Pae displays anti neoplastic activity and increases the efficacy of chemotherapeutic drugs in various cell lines and in animal models, studies related to the effect of Pae on ER stress-induced resistance to chemotherapeutic agents in hepatocellular carcinoma (HCC) are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we investigated the effect of the endoplasmic reticulum (ER) stress response during resistance of human hepatocellular carcinoma cells to doxorubicin. Treatment with the ER stress-inducer tunicamycin (TM) before the addition of doxorubicin reduced the rate of apoptosis induced by doxorubicin. Interestingly, co-pretreatment with tunicamycin and Pae significantly increased apoptosis induced by doxorubicin. Furthermore, induction of ER stress resulted in increasing expression of COX-2 concomitant with inactivation of Akt and up regulation of the pro-apoptotic transcription factor CHOP (GADD153) in HepG2 cells. These cellular changes in gene expression and Akt activation may be an important resistance mechanism against doxorubicin in hepatocellular carcinoma cells undergoing ER stress. However, co-pretreatment with tunicamycin and Pae decreased the expression of COX-2 and levels of activation of Akt as well as increasing the levels of CHOP in HCC cells. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that Pae reverses ER stress-induced resistance to doxorubicin in human hepatocellular carcinoma cells by targeting COX-2 mediated inactivation of PI3K/AKT/CHOP. PMID- 23658756 TI - A simple and novel method to monitor breathing and heart rate in awake and urethane-anesthetized newborn rodents. AB - Rodents are most useful models to study physiological and pathophysiological processes in early development, because they are born in a relatively immature state. However, only few techniques are available to monitor non-invasively heart frequency and respiratory rate in neonatal rodents without restraining or hindering access to the animal. Here we describe experimental procedures that allow monitoring of heart frequency by electrocardiography (ECG) and breathing rate with a piezoelectric transducer (PZT) element without hindering access to the animal. These techniques can be easily installed and are used in the present study in unrestrained awake and anesthetized neonatal C57/Bl6 mice and Wistar rats between postnatal day 0 and 7. In line with previous reports from awake rodents we demonstrate that heart rate in rats and mice increases during the first postnatal week. Respiratory frequency did not differ between both species, but heart rate was significantly higher in mice than in rats. Further our data indicate that urethane, an agent that is widely used for anesthesia, induces a hypoventilation in neonates whilst heart rate remains unaffected at a dose of 1 g per kg body weight. Of note, hypoventilation induced by urethane was not detected in rats at postnatal 0/1. To verify the detected hypoventilation we performed blood gas analyses. We detected a respiratory acidosis reflected by a lower pH and elevated level in CO2 tension (pCO2) in both species upon urethane treatment. Furthermore we found that metabolism of urethane is different in P0/1 mice and rats and between P0/1 and P6/7 in both species. Our findings underline the usefulness of monitoring basic cardio-respiratory parameters in neonates during anesthesia. In addition our study gives information on developmental changes in heart and breathing frequency in newborn mice and rats and the effects of urethane in both species during the first postnatal week. PMID- 23658757 TI - Malaria mosquitoes attracted by fatal fungus. AB - Insect-killing fungi such as Beauveria bassiana are being evaluated as possible active ingredients for use in novel biopesticides against mosquito vectors that transmit malaria. Fungal pathogens infect through contact and so applications of spores to surfaces such as walls, nets, or other resting sites provide possible routes to infect mosquitoes in and around domestic dwellings. However, some insects can detect and actively avoid fungal spores to reduce infection risk. If true for mosquitoes, such behavior could render the biopesticide approach ineffective. Here we find that the spores of B. bassiana are highly attractive to females of Anopheles stephensi, a major anopheline mosquito vector of human malaria in Asia. We further find that An. stephensi females are preferentially attracted to dead and dying caterpillars infected with B. bassiana, landing on them and subsequently becoming infected with the fungus. Females are also preferentially attracted to cloth sprayed with oil-formulated B. bassiana spores, with 95% of the attracted females becoming infected after a one-minute visit on the cloth. This is the first report of an insect being attracted to a lethal fungal pathogen. The exact mechanisms involved in this behavior remain unclear. Nonetheless, our results indicate that biopesticidal formulations comprising B. bassiana spores will be conducive to attraction and on-source visitation by malaria vectors. PMID- 23658758 TI - Profiling the secretion of soluble mediators by end stage osteoarthritis synovial tissue explants reveals a reduced responsiveness to an inflammatory trigger. AB - OBJECTIVE: Evidence is accumulating that synovial tissue plays an active role in osteoarthritis (OA), however, exact understanding of its contribution is lacking. In order to further elucidate its role in the OA process, we aimed to identify the secretion pattern of soluble mediators by synovial tissue and to assess its ability to initiate cartilage degeneration. METHODS: Synovial tissue explants (STEs) obtained from donors without history of OA (n = 8) or from end stage OA patients (n = 16) were cultured alone or together with bovine cartilage explants in the absence or presence of IL-1alpha. The secretion of 48 soluble mediators was measured and the effect on glycosaminoglycan (GAG) release and matrix metalloproteinase (MMP) activity was determined. RESULTS: Normal and OA STEs secreted comparable levels of almost all measured soluble mediators. However, in the presence of IL-1alpha these mediators were less secreted by OA than by normal STEs of which 15 differed significantly (p<0.01). No effect of normal or OA STEs on GAG release from the cartilage explants was observed, and no differences in MMP activity between OA and normal STEs were detected. CONCLUSIONS: Unexpectedly, a comparable secretion profile of soluble mediators was found for OA and normal STEs while the reduced responsiveness of OA STEs to an inflammatory trigger indicates a different state of this tissue in OA patients. The effects could be the result of prolonged exposure to an inflammatory environment in OA development. Further understanding of the pro-inflammatory and inflammation resolving mechanisms during disease progression in synovial tissue may provide valuable targets for therapy in the future. PMID- 23658759 TI - The walking-induced transient hack concept is valid & relies on a transient early exercise hypoxemia. AB - BACKGROUND: Decreased arterial oxygen pressure obtained at peak exercise is strong evidence of walking-induced hypoxemia, assuming that the lower pressure occurs just before exercise is stopped. Using empirical predefined models and transcutaneous oximetry, we have shown that some patients reporting exercise intolerance show a minimal value at the onset of walking and a post-exercise overshoot. These changes are referred to as transcutaneous "walking-induced transient hacks". METHODS: In 245 patients, walking-induced transcutaneous oxygen pressure changes in the chest were analyzed using observer-independent clustering techniques. Clustering classes were compared to the profile types previously proposed with the cross-correlation technique. The classifications of patients according to both approaches were compared using kappa statistics. In 10 patients showing a hack on transcutaneous oximetry, we analyzed the results of direct iterative arterial sampling recorded during a new walking treadmill test. RESULTS: Clustering analysis resulted in 4 classes that closely fit the 4 most frequently proposed empirical models (cross-correlation coefficients: 0.93 to 0.97). The kappa between the two classifications was 0.865. In 10 patients showing transcutaneous hacks, the minimal direct arterial oxygen pressure value occurred at exercise onset, and these patients exhibited a recovery overshoot reaching a maximum at two minutes of recovery, confirming the walking-induced transient hypoxemia. CONCLUSIONS: In patients reporting exercise intolerance, transcutaneous oximetry could help to detect walking-induced transient hypoxemia, while peak-exercise arterial oximetry might be normal. PMID- 23658760 TI - Cloning, expression and characterization of 3-hydroxyisobutyrate dehydrogenase from Pseudomonas denitrificans ATCC 13867. AB - The gene encoding an NAD(+)-dependent, 3-hydroxyisobutyrate dehydrogenase (3HIBDH IV) from Pseudomonas denitrificans ATCC 13867 was cloned and expressed in Escherichia coli BL 21 (DE3) and characterized to understand its physiological relevance in the degradation of 3-hydroxypropionic acid (3-HP). The deduced amino acid sequence showed high similarity to other 3-hydroxyisobutyrate dehydrogenase isozymes (3HIBDHs) of P. denitrificans ATCC 13867. A comparison of 3HIBDH-IV with its relevant enzymes along with molecular docking studies suggested that Lys171, Asn175 and Gly123 are important for its catalytic function on 3-hydroxyacids. The recombinant 3HIBDH-IV was purified to homogeneity utilizing a Ni-NTA-HP resin column in high yield. 3HIBDH-IV was very specific to (S)-3-hydroxyisobutyrate, but also catalyzed the oxidation of 3-HP to malonate semialdehyde. The specific activity and half-saturation constant (K m) for 3-HP at 30 degrees C and pH 9.0 were determined to be 17 U/mg protein and 1.0 mM, respectively. Heavy metals, such as Ag(+) and Hg(2+), completely inhibited the 3HIBDH-IV activity, whereas dithiothreitol, 2-mercaptoethanol and ethylenediaminetetraacetic acid increased its activity 1.5-1.8-fold. This paper reports the characteristics of 3HIBDH-IV as well as its probable role in 3-HP degradation. PMID- 23658761 TI - Modular biological function is most effectively captured by combining molecular interaction data types. AB - Large-scale molecular interaction data sets have the potential to provide a comprehensive, system-wide understanding of biological function. Although individual molecules can be promiscuous in terms of their contribution to function, molecular functions emerge from the specific interactions of molecules giving rise to modular organisation. As functions often derive from a range of mechanisms, we demonstrate that they are best studied using networks derived from different sources. Implementing a graph partitioning algorithm we identify subnetworks in yeast protein-protein interaction (PPI), genetic interaction and gene co-regulation networks. Among these subnetworks we identify cohesive subgraphs that we expect to represent functional modules in the different data types. We demonstrate significant overlap between the subgraphs generated from the different data types and show these overlaps can represent related functions as represented by the Gene Ontology (GO). Next, we investigate the correspondence between our subgraphs and the Gene Ontology. This revealed varying degrees of coverage of the biological process, molecular function and cellular component ontologies, dependent on the data type. For example, subgraphs from the PPI show enrichment for 84%, 58% and 93% of annotated GO terms, respectively. Integrating the interaction data into a combined network increases the coverage of GO. Furthermore, the different annotation types of GO are not predominantly associated with one of the interaction data types. Collectively our results demonstrate that successful capture of functional relationships by network data depends on both the specific biological function being characterised and the type of network data being used. We identify functions that require integrated information to be accurately represented, demonstrating the limitations of individual data types. Combining interaction subnetworks across data types is therefore essential for fully understanding the complex and emergent nature of biological function. PMID- 23658762 TI - Proteomic characterization of inbreeding-related cold sensitivity in Drosophila melanogaster. AB - Inbreeding depression is a widespread phenomenon of central importance to agriculture, medicine, conservation biology and evolutionary biology. Although the population genetic principles of inbreeding depression are well understood, we know little about its functional genomic causes. To provide insight into the molecular interplay between intrinsic stress responses, inbreeding depression and temperature tolerance, we performed a proteomic characterization of a well defined conditional inbreeding effect in a single line of Drosophila melanogaster, which suffers from extreme cold sensitivity and lethality. We identified 48 differentially expressed proteins in a conditional lethal line as compared to two control lines. These proteins were enriched for proteins involved in hexose metabolism, in particular pyruvate metabolism, and many were found to be associated with lipid particles. These processes can be linked to known cold tolerance mechanisms, such as the production of cryoprotectants, membrane remodeling and the build-up of energy reserves. We checked mRNA-expression of seven genes with large differential protein expression. Although protein expression poorly correlated with gene expression, we found a single gene (CG18067) that, after cold shock, was upregulated in the conditional lethal line both at the mRNA and protein level. Expression of CG18067 also increased in control flies after cold shock, and has previously been linked to cold exposure and chill coma recovery time. Many differentially expressed proteins in our study appear to be involved in cold tolerance in non-inbred individuals. This suggest the conditional inbreeding effect to be caused by misregulation of physiological cold tolerance mechanisms. PMID- 23658764 TI - Tibet as a potential domestication center of cultivated barley of China. AB - The importance of wild barley from Qinghai-Tibet Plateau in the origin and domestication of cultivated barley has long been underestimated. Population-based phylogenetic analyses were performed to study the origin and genetic diversity of Chinese domesticated barley, and address the possibility that the Tibetan region in China was an independent center of barley domestication. Wild barley (Hordeum vulgare ssp. spontaneum) populations from Southwest Asia, Central Asia, and Tibet along with domesticated barley from China were analyzed using two nuclear genes. Our results showed that Tibetan wild barley distinctly diverged from Southwest Asian (Near East) wild barley, that Central Asian wild barley is related to Southwest Asian wild barley, and that Chinese domesticated barley shares the same haplotypes with Tibetan wild barley. Phylogenetic analysis showed a close relationship between Chinese domesticated barley and the Tibetan wild barley, suggesting that Tibetan wild barley was the ancestor of Chinese domesticated barley. Our results favor the polyphyletic origin for cultivated barley. PMID- 23658763 TI - Brain injury in very preterm children and neurosensory and cognitive disabilities during childhood: the EPIPAGE cohort study. AB - OBJECTIVE: To investigate the association of motor and cognitive/learning deficiencies and overall disabilities in very preterm (VPT) children and their relations to gestational age (GA) and brain lesions. DESIGN SETTING AND PARTICIPANTS: EPIPAGE is a longitudinal population-based cohort study of children born before 33 weeks' gestation (WG) in 9 French regions in 1997-1998. Cumulating data from all follow up stages, neurodevelopmental outcomes were available for 90% of the 2480 VPT survivors at 8 years. Main outcomes were association of motor and cognitive deficiencies and existence of at least one deficiency (motor, cognitive, behavioral/psychiatric, epileptic, visual, and/or hearing deficiencies) in three GA groups (24-26, 27-28, and 29-32WG) and four groups of brain lesions (none, minor, moderate, or severe). RESULTS: VPT had high rates of motor (14%) and cognitive (31%) deficiencies. Only 6% had an isolated motor deficiency, 23% an isolated cognitive one and 8% both types. This rate reached 20% among extremely preterm. Psychiatric disorders and epilepsy were observed in 6% and 2% of children, respectively. The risks of at least one severe or moderate deficiency were 11 and 29%. These risks increased as GA decreased; only 36% of children born extremely preterm had no reported deficiency. Among children with major white matter injury (WMI), deficiency rates reached 71% at 24-26WG, 88% at 27-28WG, and 80% at 29-32WG; more than 40% had associated motor and cognitive deficiencies. By contrast, isolated cognitive deficiency was the most frequent problem among children without major lesions. CONCLUSIONS: In VPT, the lower the GA, the higher the neurodisability rate. Cerebral palsy is common. Impaired cognitive development is more frequent. Its occurrence in case without WMI or early motor disorders makes long-term follow up necessary. The strong association between motor impairments, when they exist, and later cognitive dysfunction supports the hypothesis of a common origin of these difficulties. PMID- 23658765 TI - Similar local and landscape processes affect both a common and a rare newt species. AB - Although rare species are often the focus of conservation measures, more common species may experience similar decline and suffer from the same threatening processes. We tested this hypothesis by examining, through an information theoretic approach, the importance of ecological processes at multiple scales in the great crested newt Triturus cristatus, regionally endangered and protected in Europe, and the more common smooth newt, Lissotriton vulgaris. Both species were similarly affected by the same processes, i.e. suitability of aquatic and terrestrial components of their habitat at different scales, connectivity among breeding sites, and the presence of introduced fish. T. cristatus depended more on water depth and aquatic vegetation than L. vulgaris. The results show that environmental pressures threaten both common and rare species, and therefore the more widespread species should not be neglected in conservation programs. Because environmental trends are leading to a deterioration of aquatic and terrestrial habitat features required by newt populations, populations of the common species may follow the fate of the rarest species. This could have substantial conservation implications because of the numerical importance of common species in ecosystems and because commonness could be a transient state moving towards rarity. On the other hand, in agreement with the umbrella species concept, targeting conservation efforts on the most demanding species would also protect part of the populations of the most common species. PMID- 23658766 TI - Effects of an electric field on white sharks: in situ testing of an electric deterrent. AB - Elasmobranchs can detect minute electromagnetic fields, <1 nV cm(-1), using their ampullae of Lorenzini. Behavioural responses to electric fields have been investigated in various species, sometimes with the aim to develop shark deterrents to improve human safety. The present study tested the effects of the Shark Shield Freedom7TM electric deterrent on (1) the behaviour of 18 white sharks (Carcharodon carcharias) near a static bait, and (2) the rates of attacks on a towed seal decoy. In the first experiment, 116 trials using a static bait were performed at the Neptune Islands, South Australia. The proportion of baits taken during static bait trials was not affected by the electric field. The electric field, however, increased the time it took them to consume the bait, the number of interactions per approach, and decreased the proportion of interactions within two metres of the field source. The effect of the electric field was not uniform across all sharks. In the second experiment, 189 tows using a seal decoy were conducted near Seal Island, South Africa. No breaches and only two surface interactions were observed during the tows when the electric field was activated, compared with 16 breaches and 27 surface interactions without the electric field. The present study suggests that the behavioural response of white sharks and the level of risk reduction resulting from the electric field is contextually specific, and depends on the motivational state of sharks. PMID- 23658767 TI - In-vitro archaeacidal activity of biocides against human-associated archaea. AB - BACKGROUND: Several methanogenic archaea have been detected in the human intestinal microbiota. These intestinal archaea may contaminate medical devices such as colonoscopes. However, no biocide activity has been reported among these human-associated archaea. METHODOLOGY: The minimal archaeacidal concentration (MAC) of peracetic acid, chlorhexidine, squalamine and twelve parent synthetic derivatives reported in this study was determined against five human-associated methanogenic archaea including Methanobrevibacter smithii, Methanobrevibacter oralis, Methanobrevibacter arboriphilicus, Methanosphaera stadtmanae, Methanomassiliicoccus luminyensis and two environmental methanogens Methanobacterium beijingense and Methanosaeta concilii by using a serial dilution technique in Hungates tubes. PRINCIPAL FINDINGS: MAC of squalamine derivative S1 was 0.05 mg/L against M. smithii strains, M. oralis, M. arboriphilicus, M. concilii and M. beijingense whereas MAC of squalamine and derivatives S2-S12 varied from 0.5 to 5 mg/L. For M. stadtmanae and M. luminyensis, MAC of derivative S1 was 0.1 mg/L and varied from 1 to >= 10 mg/L for squalamine and its parent derivatives S2-S12. Under the same experimental conditions, chlorhexidine and peracetic acid lead to a MAC of 0.2 and 1.5 mg/L, respectively against all tested archaea. CONCLUSIONS/SIGNIFICANCE: Squalamine derivative S1 exhibited a 10 200 higher archaeacidal activity than other tested squalamine derivatives, on the majority of human-associated archaea. As previously reported and due to their week corrosivity and their wide spectrum of antibacterial and antifungal properties, squalamine and more precisely derivative S1 appear as promising compounds to be further tested for the decontamination of medical devices contaminated by human-associated archaea. PMID- 23658768 TI - Occurrence of vasospasm and infarction in relation to a focal monitoring sensor in patients after SAH: placing a bet when placing a probe? AB - INTRODUCTION: Vasospastic brain infarction is a devastating complication of aneurysmal subarachnoid hemorrhage (SAH). Using a probe for invasive monitoring of brain tissue oxygenation or blood flow is highly focal and may miss the site of cerebral vasospasm (CVS). Probe placement is based on the assumption that the spasm will occur either at the dependent vessel territory of the parent artery of the ruptured aneurysm or at the artery exposed to the focal thick blood clot. We investigated the likelihood of a focal monitoring sensor being placed in vasospasm or infarction territory on a hypothetical basis. METHODS: From our database we retrospectively selected consecutive SAH patients with angiographically proven (day 7-14) severe CVS (narrowing of vessel lumen >50%). Depending on the aneurysm location we applied a standard protocol of probe placement to detect the most probable site of severe CVS or infarction. We analyzed whether the placement was congruent with existing CVS/infarction. RESULTS: We analyzed 100 patients after SAH caused by aneurysms located in the following locations: MCA (n = 14), ICA (n = 30), A1CA (n = 4), AcoA or A2CA (n = 33), and VBA (n = 19). Sensor location corresponded with CVS territory in 93% of MCA, 87% of ICA, 76% of AcoA or A2CA, but only 50% of A1CA and 42% of VBA aneurysms. The focal probe was located inside the infarction territory in 95% of ICA, 89% of MCA, 78% of ACoA or A2CA, 50% of A1CA and 23% of VBA aneurysms. CONCLUSION: The probability that a single focal probe will be situated in the territory of severe CVS and infarction varies. It seems to be reasonably accurate for MCA and ICA aneurysms, but not for ACA or VBA aneurysms. PMID- 23658769 TI - Early detection of Lewis lung carcinoma tumor control by irradiation using diffusion-weighted and dynamic contrast-enhanced MRI. AB - PURPOSE: To investigate the correlation between diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) derived parameters and radioresponsiveness of Lewis lung carcinoma (LLC) tumor. MATERIALS AND METHODS: LLC tumor growth in C57BL/6 mouse limb was used for the experiment. The tumors were irradiated with 10 Gy*5, or 30 Gy*2 vs. sham irradiation. Fourteen tumors were subjected to DW-MRI and DCE-MRI pre-radiotherapy and weekly imaging after radiotherapy. The temporal changes in apparent diffusion coefficient (ADC) and DCE-MRI derived parameters (K(trans), k(ep), v(e), and v(p)) were correlated with tumor size, and were histologically compared with CD31 staining of resected tumors. RESULTS: The 10 Gy*5 dose inhibited tumor growth for a week, while 30 Gy*2 controlled tumor growth for a 3-week observation period. One week after radiotherapy (week 2), irradiated tumors showed significantly higher values of ADC than untreated ones (10 Gy*5, p = 0.004; 30 Gy*2, p = 0.01). Significantly higher values of v(e) were shown earlier by 30 Gy*2 vs. sham (p = 0.01) and 10 Gy*5 vs. sham irradiation (p = 0.05). Sustained higher v(e) from 10 Gy*5 compared to sham irradiated tumors was evident at week 3 (p = 0.016) and week 4 (p = 0.046). A 13.8% early increase in ADC for 30 Gy*2 tumor group (p = 0.002) and a 16.5% increase for 10 Gy*5 group were noted (p = 0.01) vs. sham irradiation (which showed a 2.2% decrease). No differences were found for K(trans), k(ep), or v(p). Both radiotherapy groups demonstrated significant reduction in microvessel counts. CONCLUSION: Early increase in ADC and v(e) correlated with tumor control by irradiation. PMID- 23658770 TI - Humans as long-distance dispersers of rural plant communities. AB - Humans are known for their capacity to disperse organisms long distances. Long distance dispersal can be important for species threatened by habitat destruction, but research into human-mediated dispersal is often focused upon few and/or invasive species. Here we use citizen science to identify the capacity for humans to disperse seeds on their clothes and footwear from a known species pool in a valuable habitat, allowing for an assessment of the fraction and types of species dispersed by humans in an alternative context. We collected material from volunteers cutting 48 species-rich meadows throughout Sweden. We counted 24,354 seeds of 197 species, representing 34% of the available species pool, including several rare and protected species. However, 71 species (36%) are considered invasive elsewhere in the world. Trait analysis showed that seeds with hooks or other appendages were more likely to be dispersed by humans, as well as those with a persistent seed bank. More activity in a meadow resulted in more dispersal, both in terms of species and representation of the source communities. Average potential dispersal distances were measured at 13 km. We consider humans capable seed dispersers, transporting a significant proportion of the plant communities in which they are active, just like more traditional vectors such as livestock. When rural populations were larger, people might have been regular and effective seed dispersers, and the net rural-urban migration resulting in a reduction in humans in the landscape may have exacerbated the dispersal failure evident in declining plant populations today. With the fragmentation of habitat and changes in land use resulting from agricultural change, and the increased mobility of humans worldwide, the dispersal role of humans may have shifted from providers of regular local and landscape dispersal to providers of much rarer long-distance and regional dispersal, and international invasion. PMID- 23658771 TI - Neoadjuvant chemotherapy induces expression levels of breast cancer resistance protein that predict disease-free survival in breast cancer. AB - Three main xenobiotic efflux pumps have been implicated in modulating breast cancer chemotherapy responses. These are P-glycoprotein (Pgp), Multidrug Resistance-associated Protein 1 (MRP1), and Breast Cancer Resistance Protein (BCRP). We investigated expression of these proteins in breast cancers before and after neoadjuvant chemotherapy (NAC) to determine whether their levels define response to NAC or subsequent survival. Formalin-fixed paraffin-embedded tissues were collected representing matched pairs of core biopsy (pre-NAC) and surgical specimen (post-NAC) from 45 patients with invasive ductal carcinomas. NAC regimes were anthracyclines +/- taxanes. Immunohistochemistry was performed for Pgp, MRP1 and BCRP and expression was quantified objectively using computer-aided scoring. Pgp and MRP1 were significantly up-regulated after exposure to NAC (Wilcoxon signed-rank p = 0.0024 and p<0.0001), while BCRP showed more variation in response to NAC, with frequent up- (59% of cases) and down-regulation (41%) contributing to a lack of significant difference overall. Pre-NAC expression of all markers, and post-NAC expression of Pgp and MRP1 did not correlate with NAC response or with disease-free survival (DFS). Post-NAC expression of BCRP did not correlate with NAC response, but correlated significantly with DFS (Log rank p = 0.007), with longer DFS in patients with low post-NAC BCRP expression. In multivariate Cox regression analyses, post-NAC BCRP expression levels proved to predict DFS independently of standard prognostic factors, with high expression associated with a hazard ratio of 4.04 (95% confidence interval 1.3-12.2; p = 0.013). We conclude that NAC-induced expression levels of BCRP predict survival after NAC for breast cancer, while Pgp and MRP1 expression have little predictive value. PMID- 23658772 TI - Identification of bacterial protein O-oligosaccharyltransferases and their glycoprotein substrates. AB - O-glycosylation of proteins in Neisseria meningitidis is catalyzed by PglL, which belongs to a protein family including WaaL O-antigen ligases. We developed two hidden Markov models that identify 31 novel candidate PglL homologs in diverse bacterial species, and describe several conserved sequence and structural features. Most of these genes are adjacent to possible novel target proteins for glycosylation. We show that in the general glycosylation system of N. meningitidis, efficient glycosylation of additional protein substrates requires local structural similarity to the pilin acceptor site. For some Neisserial PglL substrates identified by sensitive analytical approaches, only a small fraction of the total protein pool is modified in the native organism, whereas others are completely glycosylated. Our results show that bacterial protein O-glycosylation is common, and that substrate selection in the general Neisserial system is dominated by recognition of structural homology. PMID- 23658773 TI - Examination of influenza specific T cell responses after influenza virus challenge in individuals vaccinated with MVA-NP+M1 vaccine. AB - Current influenza vaccines stimulate neutralising antibody to the haemagglutinin antigen but as there is antigenic drift in HA it is difficult to prepare a vaccine in advance against an emergent strain. A potential strategy is to induce CD8(+) and CD4(+) T cells that recognize epitopes within internal proteins that are less subject to antigenic drift. Augmenting humoral responses to HA with T cell responses to more conserved antigens may result in a more broadly protective vaccine. In this study, we evaluate the quality of influenza specific T cell responses in a clinical trial using MVA-NP+M1 vaccination followed by influenza virus challenge. In vaccinated volunteers, the expression of Granzyme A, Perforin and CD57 on influenza HLA A*02 M158-66 antigen specific cells was higher than non vaccinated volunteers before and after challenge despite a similar frequency of antigen specific cells. BCL2 expression was lower in vaccinated volunteers. These data indicate that antigen specific T cells are a useful additional measure for use in human vaccination or immunization studies. PMID- 23658774 TI - Specific IgG response against Mycobacterium avium paratuberculosis in children and adults with Crohn's disease. AB - BACKGROUND AND AIMS: Presence of serum antibodies against Mycobacterium avium paratuberculosis (MAP) in Crohn's Disease (CD) as a disease characteristic remains controversial. In the present work, we assessed antibody reactivity of serum and intestinal fluid against four distinct MAP-antigens, including the recently identified MAP-specific lipopentapeptide (L5P). METHODS: Immunoglobulin concentrations and specificity against 3 non MAP-specific antigens: glycosyl transferase-d (GSD), purified protein derivative from MAP (Johnin-PPD), heparin binding haemagglutinin (MAP-HBHA) and one MAP-specific antigen: synthetic L5P were determined by ELISA in gut lavage fluids from adult controls or patients with CD, and in sera of children or adult controls or patients with CD, ulcerative colitis or celiac disease. RESULTS: Total IgA and IgG concentrations were increased in sera of children with CD but were decreased in sera of adults with CD, thereof specificity against MAP antigens was assessed by normalizing immunoglobulin concentrations between samples. In CD patients, IgG reactivity was increased against the four MAP antigens, including L5P in gut lavage fluids but it was only increased against L5P in sera. By contrast, anti-L5P IgG were not increased in patients with ulcerative colitis or celiac disease. CONCLUSIONS: A significant increase in anti-L5P IgG is observed in sera of children and adults with CD but not in patients with other intestinal inflammatory diseases. Anti-L5P antibodies may serve as serological marker for CD. PMID- 23658775 TI - Stimulation of subthalamic nuclei restores a near normal planning strategy in Parkinson's patients. AB - A fundamental function of the motor system is to gather key information from the environment in order to implement behavioral strategies appropriate to the context. Although several lines of evidence indicate that Parkinson's disease affects the ability to modify behavior according to task requirements, it is currently unknown whether deep brain stimulation (DBS) of the subthalamic nucleus (STN) affects context-related planning. To explore this issue, we asked 12 Parkinson's patients with bilateral STN DBS and 13 healthy subjects to execute similar arm reaching movements in two different paradigms: go-only and countermanding tasks. In the former task patients had to perform speeded reaching movements to a peripheral target. In contrast, in the countermanding task participants had to perform the same reaches unless an infrequent and unpredictable stop-signal was shown during the reaction time (RT) indicating that they should withhold the ongoing action. We compared the performance of Parkinson's patients in different DBS conditions. We found that patients with both DBS-ON behaved similarly to healthy subjects, in that RTs of no-stop trial increased while movement times (MTs) decreased with respect to those of go-only trials. However, when both DBS were off, both RTs and MTs were longer in no-stop trials than in go-only trials. These findings indicate that bilateral DBS of STN can partially restore the appropriate motor strategy according to the given cognitive contexts. PMID- 23658776 TI - No ancient DNA damage in Actinobacteria from the Neanderthal bone. AB - BACKGROUND: The Neanderthal genome was recently sequenced using DNA extracted from a 38,000-year-old fossil. At the start of the project, the fraction of mammalian and bacterial DNA in the sample was estimated to be <6% and 9%, respectively. Treatment with restriction enzymes prior to sequencing increased the relative proportion of mammalian DNA to 15%, but the large majority of sequences remain uncharacterized. PRINCIPAL FINDINGS: Our taxonomic profiling of 3.95 Gb of Neanderthal DNA isolated from the Vindija Neanderthal Vi33.16 fossil showed that 90% of about 50,000 rRNA gene sequence reads were of bacterial origin, of which Actinobacteria accounted for more than 75%. Actinobacteria also represented more than 80% of the PCR-amplified 16S rRNA gene sequences from a cave sediment sample taken from the same G layer as the Neanderthal bone. However, phylogenetic analyses did not identify any sediment clones that were closely related to the bone-derived sequences. We analysed the patterns of nucleotide differences in the individual sequence reads compared to the assembled consensus sequences of the rRNA gene sequences. The typical ancient nucleotide substitution pattern with a majority of C to T changes indicative of DNA damage was observed for the Neanderthal rRNA gene sequences, but not for the Streptomyces-like rRNA gene sequences. CONCLUSIONS/SIGNIFICANCE: Our analyses suggest that the Actinobacteria, and especially members of the Streptomycetales, contribute the majority of sequences in the DNA extracted from the Neanderthal fossil Vi33.16. The bacterial DNA showed no signs of damage, and we hypothesize that it was derived from bacteria that have been enriched inside the bone. The bioinformatic approach used here paves the way for future studies of microbial compositions and patterns of DNA damage in bacteria from archaeological bones. Such studies can help identify targeted measures to increase the relative amount of endogenous DNA in the sample. PMID- 23658777 TI - Equivalent indels--ambiguous functional classes and redundancy in databases. AB - There is considerable interest in studying sequenced variations. However, while the positions of substitutions are uniquely identifiable by sequence alignment, the location of insertions and deletions still poses problems. Each insertion and deletion causes a change of sequence. Yet, due to low complexity or repetitive sequence structures, the same indel can sometimes be annotated in different ways. Two indels which differ in allele sequence and position can be one and the same, i.e. the alternative sequence of the whole chromosome is identical in both cases and, therefore, the two deletions are biologically equivalent. In such a case, it is impossible to identify the exact position of an indel merely based on sequence alignment. Thus, variation entries in a mutation database are not necessarily uniquely defined. We prove the existence of a contiguous region around an indel in which all deletions of the same length are biologically identical. Databases often show only one of several possible locations for a given variation. Furthermore, different data base entries can represent equivalent variation events. We identified 1,045,590 such problematic entries of insertions and deletions out of 5,860,408 indel entries in the current human database of Ensembl. Equivalent indels are found in sequence regions of different functions like exons, introns or 5' and 3' UTRs. One and the same variation can be assigned to several different functional classifications of which only one is correct. We implemented an algorithm that determines for each indel database entry its complete set of equivalent indels which is uniquely characterized by the indel itself and a given interval of the reference sequence. PMID- 23658778 TI - Testing the role of meander cutoff in promoting gene flow across a riverine barrier in ground skinks (Scincella lateralis). AB - Despite considerable attention, the long-term impact of rivers on species diversification remains uncertain. Meander loop cutoff (MLC) is one river phenomenon that may compromise a river's diversifying effects by passively transferring organisms from one side of the river to the other. However, the ability of MLC to promote gene flow across rivers has not been demonstrated empirically. Here, we test several predictions of MLC-mediated gene flow in populations of North American ground skinks (Scincella lateralis) separated by a well-established riverine barrier, the Mississippi River: 1) individuals collected from within meander cutoffs should be more closely related to individuals across the river than on the same side, 2) individuals within meander cutoffs should contain more immigrants than individuals away from meander cutoffs, 3) immigration rates estimated across the river should be highest in the direction of the cutoff event, and 4) the distribution of alleles native to one side of the river should be better predicted by the historical rather than current path of the river. To test these predictions we sampled 13 microsatellite loci and mitochondrial DNA from ground skinks collected near three ancient meander loops. These predictions were generally supported by genetic data, although support was stronger for mtDNA than for microsatellite data. Partial support for genetic divergence of samples within ancient meander loops also provides evidence for the MLC hypothesis. Although a role for MLC-mediated gene flow was supported here for ground skinks, the transient nature of river channels and morphologies may limit the long-term importance of MLC in stemming population divergence across major rivers. PMID- 23658779 TI - A lympho-follicular microenvironment is required for pathological prion protein deposition in chronically inflamed tissues from scrapie-affected sheep. AB - In sheep scrapie, pathological prion protein (PrP(Sc)) deposition occurs in the lymphoreticular and central nervous systems. We investigated PrP(Sc) distribution in scrapie-affected sheep showing simultaneous evidence of chronic lymphofollicular, lymphoproliferative/non-lymphofollicular, and/or granulomatous inflammations in their mammary gland, lung, and ileum. To do this, PrP(Sc) detection was carried out via immunohistochemistry and Western Blotting techniques, as well as through inflammatory cell immunophenotyping. Expression studies of gene coding for biological factors modulating the host's inflammatory response were also carried out. We demonstrated that ectopic PrP(Sc) deposition occurs exclusively in the context of lymphofollicular inflammatory sites, inside newly formed and well-organized lymphoid follicles harboring follicular dendritic cells. On the contrary, no PrP(Sc) deposition was detected in granulomas, even when they were closely located to newly formed lymphoid follicles. A significantly more consistent expression of lymphotoxin alpha and beta mRNA was detected in lymphofollicular inflammation compared to the other two types, with lymphotoxin alpha and beta signaling new lymphoid follicles' formation and, likely, the occurrence of ectopic PrP(Sc) deposition inside them. Our findings suggest that, in sheep co-affected by scrapie and chronic inflammatory conditions, only newly formed lymphoid follicles provide a suitable micro environment that supports the scrapie agent's replication in inflammatory sites, with an increased risk of prion shedding through body secretions/excretions. PMID- 23658780 TI - Calmodulin adopts an extended conformation when interacting with L-selectin in membranes. AB - Calmodulin, an intracellular calcium-binding protein, is thought to regulate ectodomain shedding of many membrane proteins, but the underlying molecular mechanism has remained unclear. Basing on a solution structure of calcium-loaded calmodulin in complex with a L-selectin fragment that contains a portion of its transmembrane domain, Gifford et al. (University of Calgary) recently suggested that calmodulin regulates L-selectin shedding by binding directly to a portion of the L-selectin transmembrane domain in a compact conformation. Using fluorescently labeled calmodulin, we show however that calmodulin adopts a distinctly different and much more extended conformation when it binds to the CLS peptide (i.e. the entire transmembrane and cytoplasmic domains of L-selectin) reconstituted in the phosphatidylcholine liposome with micromolar dissociation constant and in a calcium-independent manner. Calmodulin adopts a similarly extended conformation in a ternary complex with the N-terminal FERM domain of moesin and CLS reconstituted in the phospholipid liposome that mimics the native membrane environment. These results indicate that calmodulin does not bind directly to the transmembrane domain of L-selectin. Understanding the association of calmodulin with L-selectin helps to shed light on the mechanisms underlying regulation of ectodomain shedding. PMID- 23658781 TI - Construction of a stable replicating shuttle vector for Caldicellulosiruptor species: use for extending genetic methodologies to other members of this genus. AB - The recalcitrance of plant biomass is the most important barrier to its economic conversion by microbes to products of interest. Thermophiles have special advantages for biomass conversion and members of the genus Caldicellulosiruptor are the most thermophilic cellulolytic microbes known. In this study, we report the construction of a replicating shuttle vector for Caldicellulosiruptor species based on pBAS2, the smaller of two native C. bescii plasmids. The entire plasmid was cloned into an E. coli cloning vector containing a pSC101 origin of replication and an apramycin resistance cassette for selection in E. coli. The wild-type C. bescii pyrF locus was cloned under the transcriptional control of the regulatory region of the ribosomal protein S30EA (Cbes2105), and the resulting vector was transformed into a new spontaneous deletion mutant in the pyrFA locus of C. bescii that allowed complementation with the pyrF gene alone. Plasmid DNA was methylated in vitro with a recently described cognate methyltransferase, M.CbeI, and transformants were selected for uracil prototrophy. The plasmid was stably maintained in low copy with selection but rapidly lost without selection. There was no evidence of DNA rearrangement during transformation and replication in C. bescii. A similar approach was used to screen for transformability of other members of this genus using M.CbeI to overcome restriction as a barrier and was successful for transformation of C. hydrothermalis, an attractive species for many applications. Plasmids containing a carbohydrate binding domain (CBM) and linker region from the C. bescii celA gene were maintained with selection and were structurally stable through transformation and replication in C. bescii and E. coli. PMID- 23658783 TI - Drought tolerance in wild plant populations: the case of common beans (Phaseolus vulgaris L.). AB - Reliable estimations of drought tolerance in wild plant populations have proved to be challenging and more accessible alternatives are desirable. With that in mind, an ecological diversity study was conducted based on the geographical origin of 104 wild common bean accessions to estimate drought tolerance in their natural habitats. Our wild population sample covered a range of mesic to very dry habitats from Mexico to Argentina. Two potential evapotranspiration models that considered the effects of temperature and radiation were coupled with the precipitation regimes of the last fifty years for each collection site based on geographical information system analysis. We found that wild accessions were distributed among different precipitation regimes following a latitudinal gradient and that habitat ecological diversity of the collection sites was associated with natural sub-populations. We also detected a broader geographic distribution of wild beans across ecologies compared to cultivated common beans in a reference collection of 297 cultivars. Habitat drought stress index based on the Thornthwaite potential evapotranspiration model was equivalent to the Hamon estimator. Both ecological drought stress indexes would be useful together with population structure for the genealogical analysis of gene families in common bean, for genome-wide genetic-environmental associations, and for postulating the evolutionary history and diversification processes that have occurred for the species. Finally, we propose that wild common bean should be taken into account to exploit variation for drought tolerance in cultivated common bean which is generally considered susceptible as a crop to drought stress. PMID- 23658782 TI - The progestin-only contraceptive medroxyprogesterone acetate, but not norethisterone acetate, enhances HIV-1 Vpr-mediated apoptosis in human CD4+ T cells through the glucocorticoid receptor. AB - The glucocorticoid receptor (GR) regulates several physiological functions, including immune function and apoptosis. The HIV-1 virus accessory protein, viral protein R (Vpr), can modulate the transcriptional response of the GR. Glucocorticoids (GCs) and Vpr have been reported to induce apoptosis in various cells, including T-cells. We have previously shown that the injectable contraceptive, medroxyprogesterone acetate (MPA) is a partial to full agonist for the GR, unlike norethisterone acetate (NET-A). We investigated the functional cross talk between the GR and Vpr in inducing apoptosis in CD4(+) T-cells, in the absence and presence of GCs and these progestins, as well as progesterone. By using flow cytometry, we show that, in contrast to NET-A and progesterone, the synthetic GR ligand dexamethasone (Dex), cortisol and MPA induce apoptosis in primary CD4(+) T-cells. Furthermore, the C-terminal part of the Vpr peptide, or HIV-1 pseudovirus, together with Dex or MPA further increased the apoptotic phenotype, unlike NET-A and progesterone. By a combination of Western blotting, PCR and the use of receptor- selective agonists, we provide evidence that the GR and the estrogen receptor are the only steroid receptors expressed in peripheral blood mononuclear cells. These results, together with the findings that RU486, a GR antagonist, prevents Dex-, MPA- and Vpr-mediated apoptosis, provide evidence for the first time that GR agonists or partial agonists increase apoptosis in primary CD4(+) T-cells via the GR. We show that apoptotic induction involves differential expression of key apoptotic genes by both Vpr and GCs/MPA. This work suggests that contraceptive doses of MPA but not NET-A or physiological doses of progesterone could potentially accelerate depletion of CD4(+) T-cells in a GR dependent fashion in HIV-1 positive women, thereby contributing to immunodeficiency. The results imply that choice of progestin used in contraception may be critical to susceptibility and progression of diseases such as HIV-1. PMID- 23658784 TI - Characterization of acid sphingomyelinase activity in human cerebrospinal fluid. AB - BACKGROUND: As a key enzyme in sphingolipid metabolism, acid sphingomyelinase (ASM) is involved in the regulation of cell fate and signaling via hydrolysis of sphingomyelin to form ceramide. While increased activity of the lysosomal form has been associated with various pathological conditions, there are few studies on secretory ASM limited only to cell models, plasma or serum. METHODS: An optimized assay based on a fluorescent substrate was applied to measure the ASM activity in cerebrospinal fluid (CSF) collected from mice and from 42 patients who were classified as controls based on normal routine CSF values. RESULTS: We have detected ASM activity in human CSF, established a sensitive quantitative assay and characterized the enzyme's properties. The enzyme resembles plasmatic ASM including protein stability and Zn(2+)-dependence but the assays differ considerably in the optimal detergent concentration. Significantly increased activities in the CSF of ASM transgenic mice and undetectable levels in ASM knock out mice prove that the measured ASM activity originates from the ASM-encoding gene SMPD1. CSF localized ASM activities were comparable to corresponding serum ASM levels at their respective optimal reaction conditions, but no correlation was observed. The large variance in ASM activity was independent of sex, age or analyzed routine CSF parameters. CONCLUSIONS: Human and mouse CSF contain detectable levels of secretory ASM, which are unrelated to serum ASM activities. Further investigations in humans and in animal models will help to elucidate the role of this enzyme in human disease and to assess its value as a potential biomarker for disease type, severity, progress or therapeutic success. PMID- 23658785 TI - Evaluation of responsiveness of community health services in urban China: a quantitative study in Wuhan City. AB - BACKGROUND: With the objective of the national health services systems reform to move care to the community, community health services (CHS) are becoming the gateways of the health system in China. This study aims to evaluate the levels and distributions of the responsiveness of CHS in urban China and identify the relevant features to provide the government with policy advice on the improvement of CHS responsiveness. METHODS: A total of 872 face-to-face interviews were conducted in community health centers (CHCs) from 2007 to 2009. Indicators of responsiveness that were recommended by the World Health Organization were adopted, and non-conditional logistic regression analysis was performed to explore the factors associated with the levels and distributions of the responsiveness of CHS. RESULTS: The responsiveness scored at a fairly 'good' level of 7.45, 7.45, and 7.46 for CHS in years 2007, 2008, and 2009, respectively. The representative responsiveness inequality indexes were 0.097, 0.101, and 0.109, respectively, indicating the moderately balanced distributions of responsiveness in these three years. During this period, the scores of responsiveness elements were highest at 7.44 to 8.34 in "dignity", "communication", and "social support", while lowest at 6.76 to 7.54 in "autonomy", "confidentiality", and "basic amenities". The results of the logistic regression analysis suggested that five elements (OR value), namely, "dignity" (1.414-3.345), "communication" (1.218-3.655), "basic amenities" (1.251-2.362), "prompt attention" (1.098-1.590), and "autonomy" (1.416-2.173), had significant associations with CHS responsiveness. CONCLUSIONS: The responsiveness of CHS in Wuhan City was fairly good but still requires further improvement, particularly on the working conditions of CHCs and communication skills trainings among CHS workers. PMID- 23658786 TI - Assessment of night vision problems in patients with congenital stationary night blindness. AB - Congenital Stationary Night Blindness (CSNB) is a retinal disorder caused by a signal transmission defect between photoreceptors and bipolar cells. CSNB can be subdivided in CSNB2 (rod signal transmission reduced) and CSNB1 (rod signal transmission absent). The present study is the first in which night vision problems are assessed in CSNB patients in a systematic way, with the purpose of improving rehabilitation for these patients. We assessed the night vision problems of 13 CSNB2 patients and 9 CSNB1 patients by means of a questionnaire on low luminance situations. We furthermore investigated their dark adapted visual functions by the Goldmann Weekers dark adaptation curve, a dark adapted static visual field, and a two-dimensional version of the "Light Lab". In the latter test, a digital image of a living room with objects was projected on a screen. While increasing the luminance of the image, we asked the patients to report on detection and recognition of objects. The questionnaire showed that the CSNB2 patients hardly experienced any night vision problems, while all CSNB1 patients experienced some problems although they generally did not describe them as severe. The three scotopic tests showed minimally to moderately decreased dark adapted visual functions in the CSNB2 patients, with differences between patients. In contrast, the dark adapted visual functions of the CSNB1 patients were more severely affected, but showed almost no differences between patients. The results from the "2D Light Lab" showed that all CSNB1 patients were blind at low intensities (equal to starlight), but quickly regained vision at higher intensities (full moonlight). Just above their dark adapted thresholds both CSNB1 and CSNB2 patients had normal visual fields. From the results we conclude that night vision problems in CSNB, in contrast to what the name suggests, are not conspicuous and generally not disabling. PMID- 23658787 TI - Nicotinic acid receptor GPR109A is down-regulated in human macrophage-derived foam cells. AB - Nicotinic acid (NA) regresses atherosclerosis in human imaging studies and reduces atherosclerosis in mice, mediated by myeloid cells, independent of lipoproteins. Since GPR109A is expressed by human monocytes, we hypothesized that NA may drive cholesterol efflux from foam cells. In THP-1 cells NA suppressed LPS induced mRNA transcription of MCP-1 by 76.6+/-12.2% (P<0.01) and TNFalpha by 56.1+/-11.5% (P<0.01), yet restored LPS-induced suppression of PPARgamma transcription by 536.5+/-46.4% (P<0.001) and its downstream effector CD36 by 116.8+/-19.8% (P<0.01). Whilst direct PPARgamma-agonism promoted cholesterol efflux from THP-1 derived foam cells by 37.7+/-3.1% (P<0.01) and stimulated transcription of LXRalpha by 87.9+/-9.5% (P<0.001) and ABCG1 by 101.2+/-15.5% (P<0.01), NA showed no effect in foam cells on either cholesterol efflux or key RCT genes transcription. Upon foam cell induction, NA lost its effect on PPARgamma and cAMP pathways, since its receptor, GPR109A, was down-regulated by foam cell transformation. This observation was confirmed in explanted human carotid plaques. In conclusion, despite NA's anti-inflammatory effect on human macrophages, it has no effect on foam cells in reverse cholesterol transport; due to GPR109A down-regulation. PMID- 23658788 TI - Enterobacter-activated mosquito immune responses to Plasmodium involve activation of SRPN6 in Anopheles stephensi. AB - Successful development of Plasmodium in the mosquito is essential for the transmission of malaria. A major bottleneck in parasite numbers occurs during midgut invasion, partly as a consequence of the complex interactions between the endogenous microbiota and the mosquito immune response. We previously identified SRPN6 as an immune component which restricts Plasmodium berghei development in the mosquito. Here we demonstrate that SRPN6 is differentially activated by bacteria in Anopheles stephensi, but only when bacteria exposure occurs on the lumenal surface of the midgut epithelium. Our data indicate that AsSRPN6 is strongly induced following exposure to Enterobacter cloacae, a common component of the mosquito midgut microbiota. We conclude that AsSRPN6 is a vital component of the E. cloacae-mediated immune response that restricts Plasmodium development in the mosquito An. stephensi. PMID- 23658789 TI - Neurotoxicity induced by bupivacaine via T-type calcium channels in SH-SY5Y cells. AB - There is concern regarding neurotoxicity induced by the use of local anesthetics. A previous study showed that an overload of intracellular calcium is involved in the neurotoxic effect of some anesthetics. T-type calcium channels, which lower the threshold of action potentials, can regulate the influx of calcium ions. We hypothesized that T-type calcium channels are involved in bupivacaine-induced neurotoxicity. In this study, we first investigated the effects of different concentrations of bupivacaine on SH-SY5Y cell viability, and established a cell injury model with 1 mM bupivacaine. The cell viability of SH-SY5Y cells was measured following treatment with 1 mM bupivacaine and/or different dosages (10, 50, or 100 uM) of NNC 55-0396 dihydrochloride, an antagonist of T-type calcium channels for 24 h. In addition, we monitored the release of lactate dehydrogenase, cytosolic Ca(2+) ([Ca2+]i), cell apoptosis and caspase-3 expression. SH-SY5Y cells pretreated with different dosages (10, 50, or 100 uM) of NNC 55-0396 dihydrochloride improved cell viability, reduced lactate dehydrogenase release, inhibited apoptosis, and reduced caspase-3 expression following bupivacaine exposure. However, the protective effect of NNC 55-0396 dihydrochloride plateaued. Overall, our results suggest that T-type calcium channels may be involved in bupivacaine neurotoxicity. However, identification of the specific subtype of T calcium channels involved requires further investigation. PMID- 23658790 TI - Suspected outbreak of riboflavin deficiency among populations reliant on food assistance: a case study of drought-stricken Karamoja, Uganda, 2009-2010. AB - BACKGROUND: In 2009, a humanitarian response was launched to address a food security and livelihoods crisis in Karamoja, Uganda. During a polio immunization campaign in mid-August 2009, health workers in Nakapiripit District reported a concern about an increase in mouth sores, or angular stomatitis (AS) and gum ulcerations, among children in one village, and an investigation was launched. OBJECTIVE: This article describes the investigation, lessons learned, and provides guidance for monitoring micronutrient deficiencies among populations receiving food assistance. DESIGN: An investigation into a suspected outbreak of riboflavin (vitamin B2) deficiency was initiated, including a rapid assessment, mass screening, a convenience sample collection of blood specimens (n = 58 symptomatic cases and n = 18 asymptomatic individuals), and analysis of the general food ration (70% ration). RESULTS: Findings showed signs of AS in only 399 (0.2%) of 179,172 screened individuals, including adults and children. Biochemical analysis confirmed riboflavin deficiency in 84.5% of specimens from symptomatic individuals and 94.4% of specimens from asymptomatic individuals. Ration distribution data showed that 55% of distributions provided less than half the riboflavin RDA. CONCLUSION: Evidence was insufficient to confirm an actual outbreak of riboflavin deficiency, though the present investigation adds further documentation that micronutrient deficiencies continue to persist among populations in emergency settings. This article describes challenges, lessons learned, and guidance for monitoring micronutrient deficiencies among food assistance recipients, including: ongoing nutrition monitoring and surveillance; training and sensitization about micronutrient deficiencies, sensitization of the population about locally-available food, and identifying ways to improve micronutrient interventions. PMID- 23658791 TI - Enhancement of chemical entity identification in text using semantic similarity validation. AB - With the amount of chemical data being produced and reported in the literature growing at a fast pace, it is increasingly important to efficiently retrieve this information. To tackle this issue text mining tools have been applied, but despite their good performance they still provide many errors that we believe can be filtered by using semantic similarity. Thus, this paper proposes a novel method that receives the results of chemical entity identification systems, such as Whatizit, and exploits the semantic relationships in ChEBI to measure the similarity between the entities found in the text. The method assigns a single validation score to each entity based on its similarities with the other entities also identified in the text. Then, by using a given threshold, the method selects a set of validated entities and a set of outlier entities. We evaluated our method using the results of two state-of-the-art chemical entity identification tools, three semantic similarity measures and two text window sizes. The method was able to increase precision without filtering a significant number of correctly identified entities. This means that the method can effectively discriminate the correctly identified chemical entities, while discarding a significant number of identification errors. For example, selecting a validation set with 75% of all identified entities, we were able to increase the precision by 28% for one of the chemical entity identification tools (Whatizit), maintaining in that subset 97% the correctly identified entities. Our method can be directly used as an add-on by any state-of-the-art entity identification tool that provides mappings to a database, in order to improve their results. The proposed method is included in a freely accessible web tool at www.lasige.di.fc.ul.pt/webtools/ice/. PMID- 23658792 TI - A 3D analysis of flight behavior of Anopheles gambiae sensu stricto malaria mosquitoes in response to human odor and heat. AB - Female mosquitoes use odor and heat as cues to navigate to a suitable landing site on their blood host. The way these cues affect flight behavior and modulate anemotactic responses, however, is poorly understood. We studied in-flight behavioral responses of females of the nocturnal malaria mosquito Anopheles gambiae sensu stricto to human odor and heat. Flight-path characteristics in a wind tunnel (flow 20 cm/s) were quantified in three dimensions. With wind as the only stimulus (control), short and close to straight upwind flights were recorded. With heat alone, flights were similarly short and direct. The presence of human odor, in contrast, caused prolonged and highly convoluted flight patterns. The combination of odor+heat resulted in longer flights with more landings on the source than to either cue alone. Flight speed was greatest (mean groundspeed 27.2 cm/s) for odor+heat. Odor alone resulted in decreased flight speed when mosquitoes arrived within 30 cm of the source whereas mosquitoes exposed to odor+heat maintained a high flight speed while flying in the odor plume, until they arrived within 15 cm of the source. Human odor evoked an increase in crosswind flights with an additive effect of heat at close range (<15 cm) to the source. This was found for both horizontal and vertical flight components. However, mosquitoes nevertheless made upwind progress when flying in the odor+heat generated plume, suggesting that mosquitoes scan their environment intensively while they progress upwind towards their host. These observations may help to improve the efficacy of trapping systems for malaria mosquitoes by (1) optimizing the site of odor release relative to trap entry and (2) adding a heat source which enhances a landing response. PMID- 23658793 TI - Electronic implementation of a repressilator with quorum sensing feedback. AB - We investigate the dynamics of a synthetic genetic repressilator with quorum sensing feedback. In a basic genetic ring oscillator network in which three genes inhibit each other in unidirectional manner, an additional quorum sensing feedback loop stimulates the activity of a chosen gene providing competition between inhibitory and stimulatory activities localized in that gene. Numerical simulations show several interesting dynamics, multi-stability of limit cycle with stable steady-state, multi-stability of different stable steady-states, limit cycle with period-doubling and reverse period-doubling, and infinite period bifurcation transitions for both increasing and decreasing strength of quorum sensing feedback. We design an electronic analog of the repressilator with quorum sensing feedback and reproduce, in experiment, the numerically predicted dynamical features of the system. Noise amplification near infinite period bifurcation is also observed. An important feature of the electronic design is the accessibility and control of the important system parameters. PMID- 23658794 TI - A tale that morphology fails to tell: a molecular phylogeny of Aeolidiidae (Aeolidida, Nudibranchia, Gastropoda). AB - Aeolidida is one of the largest clades of nudibranchs with at least 560 known species. However, its systematics has not been studied in a comprehensive manner. Phylogenetic analyses of larger clades such as Nudibranchia or Cladobranchia have usually included a poor sample of aeolids. Furthermore, phylogenetic studies at the family or generic level in Aeolidida are a few and far between. The first molecular phylogeny of the aeolid family Aeolidiidae is presented here. This study, the most comprehensive for Aeolidida to date, uses new sequences of two mitochondrial (COI and 16S) genes and one nuclear gene (H3). 251 specimens from members of seven families of Aeolidida, including 39 species of Aeolidiidae were studied. Excluding Pleurolidia juliae, Aeolidiidae is monophyletic. Our results resolve the systematic relationships within the Aeolidiidae at a generic level, requiring changes in the systematics of this family. Spurilla, Anteaeolidiella, Limenandra and Aeolidia are well-supported and monophyletic clades. Aeolidiella stephanieae is transferred to Berghia and Aeolidiopsis ransoni and Spurilla salaamica to Baeolidia, to maintain the monophyletic lineages reflected in this study. The systematics of Cerberilla remains unclear. Some species earlier attributed to Aeolidiella are now grouped in a previously unnamed clade that we designate as Bulbaeolidia gen. nov. PMID- 23658795 TI - Total and carboxylated osteocalcin associate with insulin levels in young adults born with normal or very low birth weight. AB - OBJECTIVE: Osteocalcin (OC), a bone-derived protein, has been implicated in the regulation of glucose and energy metabolism. Young adults born with very low birth weight (VLBW) have altered glucose regulation and lower bone mineral density (BMD) compared with those born at term. The aim of this study was to explore the association between bone and glucose metabolism in healthy young adults born prematurely or at term. METHODS: The cohort of this cross-sectional study comprised 332 non-diabetic young adults (age 18 to 27 years) born either preterm with VLBW (n = 163) or at term (n = 169). OC, carboxylated osteocalcin (cOC) and markers of glucose metabolism were measured at fasting and after a 75-g oral glucose tolerance test (OGTT). RESULTS: VLBW adults were shorter, had lower BMD (p<0.001) and higher fasting OC (p = 0.027) and cOC (p = 0.005) than term born subjects. They also had higher 2-hour insulin (p = 0.001) and glucose (p = 0.037) concentrations. OGTT induced a significant reduction in OC (p<0.001), similar in both groups. OC reduction was not associated with OGTT-induced increases in insulin (p = 0.54). However, fasting total OC and cOC correlated negatively with fasting insulin after adjustment for age, gender, BMD and VLBW status (r = -0.182, p = 0.009 and r = -0.283, p<0.001, respectively). CONCLUSION: Adults born with VLBW have higher OC and cOC than their peers born at term. This may in part reflect the mechanisms that underlie their lower BMD and decreased insulin sensitivity. Serum OC appears to be negatively associated with long-term glucose regulation whereas acute changes during OGTT may be mediated via other mechanisms. PMID- 23658796 TI - Direct activation of human dendritic cells by particle-bound but not soluble MHC class II ligand. AB - Dendritic cells (DCs) are key activators of cellular immune responses through their capacity to induce naive T cells and sustained effector T cell responses. This capacity is a function of their superior efficiency of antigen presentation via MHC class I and class II molecules, and the expression of co-stimulatory cell surface molecules and cytokines. Maturation of DCs is induced by microbial factors via pattern recognition receptors such as Toll-like receptors, pro inflammatory cytokines or cognate interaction with CD4(+) T cells. Here we show that, unexpectedly, the PanDR helper T cell epitope PADRE, a generic T helper cell antigen presented by a large fraction of HLA-DR alleles, when delivered in particle-bound form induced maturation of human DCs. The DCs that received the particle-bound PADRE displayed all features of fully mature DCs, such as high expression of the co-stimulatory molecules CD80, CD86, CD83, the MHC-II molecule HLA-DR, secretion of high levels of the biologically active IL-12 (IL-12p70) and induction of vigorous proliferation of naive CD4(+) T cells. Furthermore, the maturation of DCs induced by particle-bound PADRE was shown to involve sphingosine kinase, calcium signaling from internal sources and downstream signaling through the MAP kinase and the p72syk pathways, and finally activation of the transcription factor NF-kappaB. Based on our findings, we propose that particle-bound PADRE may be used as a DC activator in DC-based vaccines. PMID- 23658797 TI - The oxidant-scavenging abilities in the oral cavity may be regulated by a collaboration among antioxidants in saliva, microorganisms, blood cells and polyphenols: a chemiluminescence-based study. AB - Saliva has become a central research issue in oral physiology and pathology. Over the evolution, the oral cavity has evolved the antioxidants uric acid, ascorbate reduced glutathione, plasma-derived albumin and antioxidants polyphenols from nutrients that are delivered to the oral cavity. However, blood cells extravasated from injured capillaries in gingival pathologies, or following tooth brushing and use of tooth picks, may attenuate the toxic activities of H2O2 generated by oral streptococci and by oxidants generated by activated phagocytes. Employing a highly sensitive luminol-dependent chemiluminescence, the DPPH radical and XTT assays to quantify oxidant-scavenging abilities (OSA), we show that saliva can strongly decompose both oxygen and nitrogen species. However, lipophilic antioxidant polyphenols in plants, which are poorly soluble in water and therefore not fully available as effective antioxidants, can nevertheless be solubilized either by small amounts of ethanol, whole saliva or also by salivary albumin and mucin. Plant-derived polyphenols can also act in collaboration with whole saliva, human red blood cells, platelets, and also with catalase-positive microorganisms to decompose reactive oxygen species (ROS). Furthermore, polyphenols from nutrient can avidly adhere to mucosal surfaces, are retained there for long periods and may function as a "slow-release devises" capable of affecting the redox status in the oral cavity. The OSA of saliva is due to the sum result of low molecular weight antioxidants, albumin, polyphenols from nutrients, blood elements and microbial antioxidants. Taken together, saliva and its antioxidants are considered regulators of the redox status in the oral cavity under physiological and pathological conditions. PMID- 23658798 TI - Identification and characterization of the direct interaction between methotrexate (MTX) and high-mobility group box 1 (HMGB1) protein. AB - BACKGROUND: Methotrexate (MTX) is an agent used in chemotherapy of tumors and autoimmune disease including rheumatoid arthritis (RA). In addition, MTX has some anti-inflammatory activity. Although dihydrofolate reductase (DHFR) is a well known target for the anti-tumor effect of MTX, the mode of action for the anti inflammatory activity of MTX is not fully understood. METHODOLOGY/RESULT: Here, we performed a screening of MTX-binding proteins using T7 phage display with a synthetic biotinylated MTX derivative. We then characterized the interactions using surface plasmon resonance (SPR) analysis and electrophoretic mobility shift assay (EMSA). Using a T7 phage display screen, we identified T7 phages that displayed part of high-mobility group box 1 (HMGB1) protein (K86-V175). Binding affinities as well as likely binding sites were characterized using genetically engineered truncated versions of HMGB1 protein (Al G1-K87, Bj: F88-K181), indicating that MTX binds to HMGB1 via two independent sites with a dissociation constants (KD) of 0.50+/-0.03 uM for Al and 0.24 +/- 0.01 uM for Bj. Although MTX did not inhibit the binding of HMGB1 to DNA via these domains, HMGB1/RAGE association was impeded in the presence of MTX. These data suggested that binding of MTX to part of the RAGE-binding region (K149-V175) in HMGB1 might be significant for the anti-inflammatory effect of MTX. Indeed, in murine macrophage like cells (RAW 264.7), TNF-alpha release and mitogenic activity elicited by specific RAGE stimulation with a truncated monomeric HMGB1 were inhibited in the presence of MTX. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that HMGB1 is a direct binding protein of MTX. Moreover, binding of MTX to RAGE-binding region in HMGB1 inhibited the HMGB1/RAGE interaction at the molecular and cellular levels. These data might explain the molecular basis underlying the mechanism of action for the anti-inflammatory effect of MTX. PMID- 23658799 TI - Fatty acid metabolites in rapidly proliferating breast cancer. AB - PURPOSE: Breast cancers that over-express a lipoxygenase or cyclooxygenase are associated with poor survival possibly because they overproduce metabolites that alter the cancer's malignant behaviors. However, these metabolites and behaviors have not been identified. We here identify which metabolites among those that stimulate breast cancer cell proliferation in vitro are associated with rapidly proliferating breast cancer. EXPERIMENTAL DESIGN: We used selective ion monitoring-mass spectrometry to quantify in the cancer and normal breast tissue of 27 patients metabolites that stimulate (15-, 12-, 5-hydroxy-, and 5-oxo eicosatetraenoate, 13-hydroxy-octadecaenoate [HODE]) or inhibit (prostaglandin [PG]E2 and D2) breast cancer cell proliferation. We then related their levels to each cancer's proliferation rate as defined by its Mib1 score. RESULTS: 13-HODE was the only metabolite strongly, significantly, and positively associated with Mib1 scores. It was similarly associated with aggressive grade and a key component of grade, mitosis, and also trended to be associated with lymph node metastasis. PGE2 and PGD2 trended to be negatively associated with these markers. No other metabolite in cancer and no metabolite in normal tissue had this profile of associations. CONCLUSIONS: Our data fit a model wherein the overproduction of 13-HODE by 15-lipoxygenase-1 shortens breast cancer survival by stimulating its cells to proliferate and possibly metastasize; no other oxygenase-metabolite pathway, including cyclooxygenase-PGE2/D2 pathways, uses this specific mechanism to shorten survival. PMID- 23658800 TI - Effects of targeted suppression of glutaryl-CoA dehydrogenase by lentivirus mediated shRNA and excessive intake of lysine on apoptosis in rat striatal neurons. AB - In glutaric aciduria type 1 (GA1), glutaryl-CoA dehydrogenase (GCDH) deficiency has been shown to be responsible for the accumulation of glutaric acid and striatal degeneration. However, the mechanisms by which GA1 induces striatal degeneration remain unclear. In this study, we aimed to establish a novel neuronal model of GA1 and to investigate the effects of GCDH deficiency and lysine-related metabolites on the viability of rat striatal neurons. Thus we constructed a lentiviral vector containing short hairpin RNA targeted against the GCDH gene expression (lentivirus-shRNA) in neurons. A virus containing a scrambled short hairpin RNA construct served as a control. Addition of lysine (5 mmol/L) was used to mimic hypermetabolism. Cell viability was measured using 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Apoptosis was assessed using Hoechst33342 staining and Annexin V-PE/7-AAD staining. The mitochondrial membrane potential (MPP) was monitored using tetramethylrhodamine methyl ester. The expression levels of caspases 3, 8, and 9 were determined by Western blotting. We found that lentivirus-shRNA induced apoptosis and decreased MMP levels in neurons, and addition of 5 mmol/L lysine enhanced this effect markedly. Lentivirus-shRNA upregulated the protein levels of caspases 3 and 9 regardless of the presence of 5 mmol/L lysine. The expression level of caspase 8 was higher in neurons co-treated with lentivirus-shRNA and 5 mmol/L lysine than in control. Benzyloxy-carbonyl-Val-Ala-Asp(OMe)-fluoromethylketone, a pan-caspase inhibitor, blocked the apoptosis induced by lentivirus-shRNA and 5 mmol/L lysine to a great extent. These results indicate that the targeted suppression of GCDH by lentivirus-mediated shRNA and excessive intake of lysine may be a useful cell model of GA1. These also suggest that GA1-induced striatal degeneration is partially caspase-dependent. PMID- 23658801 TI - Comparison of psychological symptoms and serum levels of neurotransmitters in Shanghai adolescents with and without internet addiction disorder: a case-control study. AB - BACKGROUND: Internet addiction disorder (IAD) is now recognized internationally and is known to be linked with academic and social impairment. To date, we know little about its associated main biological factors. This study aimed to collect a carefully defined group of adolescents with IAD and an age- and gender-matched typically developing comparison group. We hypothesized that the young people with IAD would have higher rates of self-reported anxiety and depressive symptoms, have altered levels of peripheral blood dopamine, norepinephrine and serotonin. In addition, we hypothesized the hours spent online are correlated with the severity of depression and anxiety among these young people with IAD. METHODOLOGY/PRINCIPAL FINDING: A cross-sectional study of 20 adolescents who met Beard's criteria for IAD and 15 typically developing adolescents (comparison group) was conducted. All the participants completed the Self Rating Depression Scale (SDS), Self Rating Anxiety Scale (SAS), and the Screen for Child Anxiety Related Emotional Disorders (SCARED). Peripheral blood dopamine, serotonin and norepinephrine were assayed. The mean level of norepinephrine was lower in the IAD group than that in the typically developing participants, while dopamine and serotonin levels did not differ. The SDS, SAS and SCARED symptom scores were increased in the adolescents with IAD. A logistic regression analysis revealed that a higher SAS score and lower level of norepinephrine independently predicted IAD group membership. There was no significant correlation between hours spent online and scores of SAS/SDS in IAD group. CONCLUSIONS/SIGNIFICANCE: Increased self-reported anxiety and lower peripheral blood norepinephrine are independently associated with IAD. PMID- 23658802 TI - Deficiency in serine protease inhibitor neuroserpin exacerbates ischemic brain injury by increased postischemic inflammation. AB - The only approved pharmacological treatment for ischemic stroke is intravenous administration of plasminogen activator (tPA) to re-canalize the occluded cerebral vessel. Not only reperfusion but also tPA itself can induce an inflammatory response. Microglia are the innate immune cells of the central nervous system and the first immune cells to become activated in stroke. Neuroserpin, an endogenous inhibitor of tPA, is up-regulated following cerebral ischemia. To examine neuroserpin-dependent mechanisms of neuroprotection in stroke, we studied neuroserpin deficient (Ns(-/-))mice in an animal model of temporal focal ischemic stroke. Infarct size and neurological outcome were worse in neuroserpin deficient mice even though the fibrinolytic activity in the ischemic brain was increased. The increased infarct size was paralleled by a selective increase in proinflammatory microglia activation in Ns(-/-) mice. Our results show excessive microglial activation in Ns(-/-) mice mediated by an increased activity of tPA. This activation results in a worse outcome further underscoring the potential detrimental proinflammatory effects of tPA. PMID- 23658803 TI - Variations in gene and protein expression in canine chondrodystrophic nucleus pulposus cells following long-term three-dimensional culture. AB - Intervertebral disc (IVD) degeneration greatly affects quality of life. The nucleus pulposus (NP) of chondrodystrophic dog breeds (CDBs) is similar to the human NP, because the cells disappear with age and are replaced by fibrochondrocyte-like cells. However, because IVD develops as early as within the first year of life, we used canines as a model to investigate in vitro the mechanisms underlying IVD degeneration. Specifically, we evaluated the potential of a three-dimensional (3D) culture of healthy NP as an in vitro model system to investigate the mechanisms of IVD degeneration. Agarose hydrogels were populated with healthy NP cells from beagles after performing magnetic resonance imaging, and mRNA expression profiles and pericellular extracellular matrix (ECM) protein distribution were determined. After 25 days of 3D culture, there was a tendency for redifferentiation into the native NP phenotype, and mRNA levels of Col2A1, COMP, and CK18 were not significantly different from those of freshly isolated cells. Our findings suggest that long-term 3D culture promoted chondrodystrophic NP redifferentiation through reconstruction of the pericellular microenvironment. Further, lipopolysaccharide (LPS) induced expression of TNF-alpha, MMP3, MMP13, VEGF, and PGES mRNA in the 3D cultures, creating a molecular milieu that mimics that of degenerated NP. These results suggest that this in vitro model represents a reliable and cost-effective tool for evaluating new therapies for disc degeneration. PMID- 23658804 TI - Critical role of TLR7 signaling in the priming of cross-protective cytotoxic T lymphocyte responses by a whole inactivated influenza virus vaccine. AB - Current influenza vaccines fail to induce protection against antigenically distinct virus strains. Accordingly, there is a need for the development of cross protective vaccines. Previously, we and others have shown that vaccination with whole inactivated virus (WIV) induces cross-protective cellular immunity in mice. To probe the mechanistic basis for this finding, we investigated the role of TLR7, a receptor for single-stranded RNA, in induction of cross-protection. Vaccination of TLR7-/- mice with influenza WIV failed to protect against a lethal heterosubtypic challenge; in contrast, wild-type mice were fully protected. The lack of protection in TLR7-/- mice was associated with high viral load and a relative paucity of influenza-specific CD8+ cytotoxic T lymphocyte (CTL) responses. Dendritic cells (DCs) from TLR7-/- mice were unable to cross-present WIV-derived antigen to influenza-specific CTLs in vitro. Similarly, TLR7-/- DCs failed to mature and become activated in response to WIV, as determined by the assessment of surface marker expression and cytokine production. Plasmacytoid DCs (pDCs) derived from wild-type mice responded directly to WIV while purified conventional DCs (cDCs) did not respond to WIV in isolation, but were responsive in mixed pDC/cDC cultures. Depletion of pDCs prior to and during WIV immunization resulted in reduced numbers of influenza-specific CTLs and impaired protection from heterosubtypic challenge. Thus, TLR7 plays a critical role in the induction of cross-protective immunity upon vaccination with WIV. The initial target cells for WIV appear to be pDCs which by direct or indirect mechanisms promote activation of robust CTL responses against conserved influenza epitopes. PMID- 23658805 TI - The energy expenditure of sedentary behavior: a whole room calorimeter study. AB - It has recently been recommended that sedentary behavior be defined as sitting or reclining activities expending less than 1.5 metabolic equivalents (METs), which is distinct from the traditional viewpoint based on insufficient moderate vigorous activity or formal exercise. This study was designed to determine the energy expenditure associated with common sedentary behaviors. Twenty-five African American adults (BMI 27.8 +/- 5.5) participated in the metabolic chamber study. Participants entered the metabolic chamber in the morning and their basal metabolic rate was estimated. They were fed breakfast and then engaged in four different sedentary behaviors sequentially, lasting 30 minutes each. The activities included reclining, watching TV, reading, and typing on a computer. In the afternoon, the participants were fed lunch and then the activities were repeated. The results show that the energy expenditure values between the morning and afternoon sessions were not significantly different (p = .232). The mean energy expenditure of postprandial reclining (0.97 METs) was slightly, but significantly, lower than postprandial watching TV (p = .021) and typing (p<.001). There were no differences in energy cost (1.03-1.06 METs) between the seated (i.e., reading, typing, watching TV) sedentary activities. The energy expenditure of several common sedentary behaviors was approximately 1.0 METs in the postprandial state. The results support the conclusion that the average energy cost of common sedentary behaviors is narrowly banded around 1.0 METs in the postprandial state. PMID- 23658806 TI - Addition of a novel, protective family history category allows better profiling of cardiovascular risk and atherosclerotic burden in the general population. The Asklepios Study. AB - OBJECTIVES: Whereas the importance of family history (FH) is widely recognized in cardiovascular risk assessment, its full potential could be underutilized, when applied with its current simple guidelines-based definition (cFH): presence of premature cardiovascular disease (CVD) in a first-degree relative. We tested the added value of a new, extended family history definition (eFH), also taking into account later onset of disease, second-degree relatives and number of affected relatives, on profiling cardiovascular risk and atherosclerotic burden in the general population. DESIGN: Longitudinal population study. SETTING: Random, representative population sample from Erpe-Mere and Nieuwerkerken (Belgium, primary care). SUBJECTS: 2524 male/female volunteers, aged 35-55 years, free from overt CVD. MAIN OUTCOME MEASURES: Subjects were extensively phenotyped including presence of atherosclerosis (ultrasound) and a newly developed FH questionnaire (4 generations). RESULTS: Compared to cFH, eFH was superior in predicting an adverse risk profile (glycemic state, elevated blood pressure, lipid abnormalities, presence of metabolic syndrome components) and presence of atherosclerosis (all age & sex-adjusted p<0.05). Unlike cFH, eFH remained a significant predictor of subclinical atherosclerosis after adjusting for confounders. Most relations with eFH were not graded but showed clear informational breakpoints, with absence of CVD (including late onset) in any first-degree relative being a negative predictor of atherosclerosis, and a particularly interesting phenotype for further study. CONCLUSIONS: A novel, extended FH definition is superior to the conventional definition in profiling cardiovascular risk and atherosclerotic burden in the general population. There remain clear opportunities to refine and increase the performance and informational content of this simple, readily-available inexpensive tool. PMID- 23658807 TI - Metabolic turnover of synaptic proteins: kinetics, interdependencies and implications for synaptic maintenance. AB - Chemical synapses contain multitudes of proteins, which in common with all proteins, have finite lifetimes and therefore need to be continuously replaced. Given the huge numbers of synaptic connections typical neurons form, the demand to maintain the protein contents of these connections might be expected to place considerable metabolic demands on each neuron. Moreover, synaptic proteostasis might differ according to distance from global protein synthesis sites, the availability of distributed protein synthesis facilities, trafficking rates and synaptic protein dynamics. To date, the turnover kinetics of synaptic proteins have not been studied or analyzed systematically, and thus metabolic demands or the aforementioned relationships remain largely unknown. In the current study we used dynamic Stable Isotope Labeling with Amino acids in Cell culture (SILAC), mass spectrometry (MS), Fluorescent Non-Canonical Amino acid Tagging (FUNCAT), quantitative immunohistochemistry and bioinformatics to systematically measure the metabolic half-lives of hundreds of synaptic proteins, examine how these depend on their pre/postsynaptic affiliation or their association with particular molecular complexes, and assess the metabolic load of synaptic proteostasis. We found that nearly all synaptic proteins identified here exhibited half-lifetimes in the range of 2-5 days. Unexpectedly, metabolic turnover rates were not significantly different for presynaptic and postsynaptic proteins, or for proteins for which mRNAs are consistently found in dendrites. Some functionally or structurally related proteins exhibited very similar turnover rates, indicating that their biogenesis and degradation might be coupled, a possibility further supported by bioinformatics-based analyses. The relatively low turnover rates measured here (~0.7% of synaptic protein content per hour) are in good agreement with imaging-based studies of synaptic protein trafficking, yet indicate that the metabolic load synaptic protein turnover places on individual neurons is very substantial. PMID- 23658808 TI - Analyzing recent coronary heart disease mortality trends in Tunisia between 1997 and 2009. AB - BACKGROUND: In Tunisia, Cardiovascular Diseases are the leading causes of death (30%), 70% of those are coronary heart disease (CHD) deaths and population studies have demonstrated that major risk factor levels are increasing. OBJECTIVE: To explain recent CHD trends in Tunisia between 1997 and 2009. METHODS: DATA SOURCES: Published and unpublished data were identified by extensive searches, complemented with specifically designed surveys. ANALYSIS: Data were integrated and analyzed using the previously validated IMPACT CHD policy model. Data items included: (i)number of CHD patients in specific groups (including acute coronary syndromes, congestive heart failure and chronic angina)(ii) uptake of specific medical and surgical treatments, and(iii) population trends in major cardiovascular risk factors (smoking, total cholesterol, systolic blood pressure (SBP), body mass index (BMI), diabetes and physical inactivity). RESULTS: CHD mortality rates increased by 11.8% for men and 23.8% for women, resulting in 680 additional CHD deaths in 2009 compared with the 1997 baseline, after adjusting for population change. Almost all (98%) of this rise was explained by risk factor increases, though men and women differed. A large rise in total cholesterol level in men (0.73 mmol/L) generated 440 additional deaths. In women, a fall (-0.43 mmol/L), apparently avoided about 95 deaths. For SBP a rise in men (4 mmHg) generated 270 additional deaths. In women, a 2 mmHg fall avoided 65 deaths. BMI and diabetes increased substantially resulting respectively in 105 and 75 additional deaths. Increased treatment uptake prevented about 450 deaths in 2009. The most important contributions came from secondary prevention following Acute Myocardial Infarction (AMI) (95 fewer deaths), initial AMI treatments (90), antihypertensive medications (80) and unstable angina (75). CONCLUSIONS: Recent trends in CHD mortality mainly reflected increases in major modifiable risk factors, notably SBP and cholesterol, BMI and diabetes. Current prevention strategies are mainly focused on treatments but should become more comprehensive. PMID- 23658809 TI - Mitochondrial dynamics associated with oxygen-glucose deprivation in rat primary neuronal cultures. AB - Our objective was to investigate the mitochondrial dynamics following oxygen glucose deprivation (OGD) in cultured rat cortical neurons. We documented changes in morphology, protein expression, and DNA levels in mitochondria following OGD and examined the roles of mitochondrial fission [dynamin-related protein 1 (Drp1), fission protein-1 (Fis1)] and fusion [mitofusin-1 (Mfn1), mitofusin-2 (Mfn2), and optic atrophy-1 protein (OPA1)] proteins on mitochondrial biogenesis and morphogenesis. We tested the effects of two Drp1 blockers [15-deoxy Delta12,14-Prostaglandin J2 (PGJ2) and Mitochondrial Division Inhibitor (Mdivi 1)] on mitochondrial dynamics and cell survival. One hour of OGD had minimal effects on neuronal viability but mitochondria appeared condensed. Three hours of OGD caused a 60% decrease in neuronal viability accompanied by a transition from primarily normal/tubular and lesser number of rounded mitochondria during normoxia to either poorly labeled or small and large rounded mitochondria. The percentage of rounded mitochondria remained the same. The mitochondrial voltage dependent anion channel, Complex V, and mitoDNA levels increased after OGD associated with a dramatic reduction in Drp1 expression, less reduction in Mfn2 expression, an increase in Mfn1 expression, with no changes in either OPA1 or Fis1. Although PGJ2 increased polymerization of Drp1, it did not reduce cell death or alter mitochondrial morphology following OGD and Mdivi-1 did not protect neurons against OGD. In summary, mitochondrial biogenesis and maintained fusion occurred in neurons along with mitochondrial fission following OGD; thus Mfn1 but not Drp1 may be a major regulator of these processes. PMID- 23658810 TI - Decreased mitochondrial DNA content in association with exposure to polycyclic aromatic hydrocarbons in house dust during wintertime: from a population enquiry to cell culture. AB - Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants that are formed in combustion processes. At the cellular level, exposure to PAHs causes oxidative stress and/or some of it congeners bind to DNA, which may interact with mitochondrial function. However, the influence of these pollutants on mitochondrial DNA (mtDNA) content remains largely unknown. We determined whether indoor exposure to PAHs is associated with mitochondrial damage as represented by blood mtDNA content. Blood mtDNA content (ratio mitochondrial/nuclear DNA copy number) was determined by real-time qPCR in 46 persons, both in winter and summer. Indoor PAH exposure was estimated by measuring PAHs in sedimented house dust, including 6 volatile PAHs and 8 non volatile PAHs. Biomarkers of oxidative stress at the level of DNA and lipid peroxidation were measured. In addition to the epidemiologic enquiry, we exposed human TK6 cells during 24 h at various concentrations (range: 0 to 500 uM) of benzo(a)pyrene and determined mtDNA content. Mean blood mtDNA content averaged (+/- SD) 0.95 +/- 0.185. The median PAH content amounted 554.1 ng/g dust (25(th) 75(th) percentile: 390.7-767.3) and 1385 ng/g dust (25(th)-75(th) percentile: 1000-1980) in winter for volatile and non-volatile PAHs respectively. Independent for gender, age, BMI and the consumption of grilled meat or fish, blood mtDNA content decreased by 9.85% (95% CI: -15.16 to -4.2; p = 0.002) for each doubling of non-volatile PAH content in the house dust in winter. The corresponding estimate for volatile PAHs was -7.3% (95% CI: -13.71 to -0.42; p = 0.04). Measurements of oxidative stress were not correlated with PAH exposure. During summer months no association was found between mtDNA content and PAH concentration. The ability of benzo(a)pyrene (range 0 uM to 500 uM) to lower mtDNA content was confirmed in vitro in human TK6 cells. Based on these findings, mtDNA content can be a target of PAH toxicity in humans. PMID- 23658811 TI - Use of traditional Korean medicine by patients with musculoskeletal disorders. AB - BACKGROUND: South Korea has maintained a dual healthcare delivery system that incorporates both traditional Korean and Western medicine. In this research, we identified the determinants of the frequency of using traditional Korean medicine among musculoskeletal patients, who are known to be the most frequent users of complementary and alternative medicine. METHODS: In this research, we reviewed 2 consecutive years of nationally representative survey data from the 2008 and 2009 Korea Health Panel Survey. We analyzed the utilization of outpatient services by musculoskeletal patients within 12 months of the 2009 survey date. A two-part model was used because some patients did not use traditional Korean medicine and skewness was present in the data on traditional Korean medicine use. In the first part, logistic regression analysis was performed to investigate the use of traditional Korean medicine. In the second part, multiple regression analysis was performed to analyze the frequency of traditional Korean medicine usage among the subjects who visited traditional Korean medical institutions. RESULTS: The frequency of traditional Korean medicine usage was positively associated with ages of 40-49 years and over 60, restrictions on daily life, a greater number of chronic diseases, not being hospitalized, and more frequent visits (more than five times) to conventional hospitals or clinics for musculoskeletal disorders. CONCLUSIONS: The important determinants of the frequency of traditional Korean medicine usage were age, activity restrictions, the number of chronic diseases, hospitalization history, and the number of visits to conventional hospitals for musculoskeletal disorders. The results contribute to our understanding of the characteristics of traditional Korean medicine users and may be used as a basic resource for related policymaking by government officials and medical professionals. PMID- 23658812 TI - Variability of grip kinetics during adult signature writing. AB - Grip kinetics and their variation are emerging as important considerations in the clinical assessment of handwriting pathologies, fine motor rehabilitation, biometrics, forensics and ergonomic pen design. This study evaluated the intra- and inter-participant variability of grip shape kinetics in adults during signature writing. Twenty (20) adult participants wrote on a digitizing tablet using an instrumented pen that measured the forces exerted on its barrel. Signature samples were collected over 10 days, 3 times a day, to capture temporal variations in grip shape kinetics. A kinetic topography (i.e., grip shape image) was derived per signature by time-averaging the measured force at each of 32 locations around the pen barrel. The normalized cross correlations (NCC) of grip shape images were calculated within- and between-participants. Several classification algorithms were implemented to gauge the error rate of participant discrimination based on grip shape kinetics. Four different grip shapes emerged and several participants made grip adjustments (change in grip shape or grip height) or rotated the pen during writing. Nonetheless, intra-participant variation in grip kinetics was generally much smaller than inter-participant force variations. Using the entire grip shape images as a 32-dimensional input feature vector, a K-nearest neighbor classifier achieved an error rate of 1.2+/ 0.4% in discriminating among participants. These results indicate that writers had unique grip shape kinetics that were repeatable over time but distinct from those of other participants. The topographic analysis of grip kinetics may inform the development of personalized interventions or customizable grips in clinical and industrial applications, respectively. PMID- 23658813 TI - The effect of threat on novelty evoked amygdala responses. AB - A number of recent papers have suggested that the amygdala plays a role in the brain's novelty detection circuit. In a recent study, we showed that this role may be specific to certain classes of biologically-relevant stimuli, such as human faces. The purpose of the present experiment was to determine whether other biologically-relevant stimuli also evoke novelty specific amygdala responses. To test this idea, we presented novel and repeated images of snakes and flowers while measuring BOLD. Surprisingly, we found that novel images of snakes and flowers evoke more amygdala activity than repeated images of snakes and flowers. Our results further confirm the robustness of the novelty evoked amygdala responses, even when compared with effects more traditionally associated with the amygdala. In addition, our results suggest that threatening stimuli may prime the amygdala to respond to other types of stimuli as well. PMID- 23658814 TI - Effects of the chromatic defocus caused by interchange of two monochromatic lights on refraction and ocular dimension in guinea pigs. AB - To investigate refractive and axial responses to the shift of focal plane resulting from the interchange of two monochromatic lights separately corresponding to the peak wavelengths of the cones absorption spectrum in retina, fifty 2-week-old pigmented guinea pigs were randomly assigned to five groups based on the mode of illumination: short-wavelength light (SL), middle-wavelength light (ML) and broad-band white light (BL) for 20 weeks, SL for 10 weeks followed by ML for 10 weeks (STM), as well as ML for 10 weeks followed by SL for 10 weeks (MTS). Biometric and refractive measurements were then performed every 2 weeks. After 10 weeks, SL and STM groups became more hyperopic and had less vitreous elongation than BL group. However, ML and MTS groups became more myopic and had more vitreous elongation. After interchange of the monochromatic light, the refractive error decreased rapidly by about 1.93D and the vitreous length increased by 0.14 mm in STM group from 10 to 12 weeks. After that, there were no significant intergroup differences between STM and BL groups. The interchange from ML to SL quickly increased the refractive error by about 1.53D and decreased the vitreous length by about 0.13 mm in MTS group after two weeks. At this time, there were also no significant intergroup differences between MTS and BL groups. The guinea pig eye can accurately detect the shift in focal plane caused by interchange of two monochromatic lights and rapidly generate refractive and axial responses. However, an excessive compensation was induced. Some properties of photoreceptors or retina may be changed by the monochromatic light to influence the following refractive development. PMID- 23658815 TI - The pro-survival role of autophagy depends on Bcl-2 under nutrition stress conditions. AB - Autophagy can be induced under nutrition stress conditions. Bcl-2 is a pro survival protein which inhibits apoptosis and autophagy. However, the role of Bcl 2 in autophagy regulation and cell survival under nutrition deprivation has not been fully understood. This study sought to investigate if Bcl-2 upregulation is essential in limiting autophagic activity and prevent cell death under nutrition deprivation conditions. Autophagic activity was monitored by the changes in GFP LC3 localization and protein levels of Beclin1, LC3-II, cathepsin D and p62 in neuroblastoma SH-SY5Y cells underwent serum deprivation. Manipulation of Bcl-2 function was achieved with siRNAs and small molecular inhibitors. The cell viability and apoptosis were assessed with MTT assay and Annexin V/PI staining. The results showed that serum starvation increased protein levels of LC3-II and Beclin1 but decreased autophagy substrate p62. Autophagy activation induced by serum deprivation and rapamycin was accompanied by an upregulation of Bcl-2 protein levels. When Bcl-2 was knocked down with siRNA or inhibited with HA 14-1 or ABT-737, serum starvation induced profound cell death and enhanced autophagic flux under nutrition deprivation conditions, while knockdown of autophagic gene Beclin1 or autophagy inhibitors (bafilomycin A1 and E64D), rescued cell death. In contrast, overexpression of Bcl-2 inhibited autophagy and blocked cell death in response to serum deprivation. These data suggest that Bcl-2 plays an essential role in limiting autophagy activation and preventing initiation of programmed cell death. Thus Bcl-2 may be an important mechanism for balancing beneficial and detrimental impacts of autophagy on cell survival. PMID- 23658816 TI - Group B Streptococcus hijacks the host plasminogen system to promote brain endothelial cell invasion. AB - Group B Streptococcus (GBS) is the leading cause of meningitis in neonates. We have previously shown that plasminogen, once recruited to the GBS cell surface and converted into plasmin by host-derived activators, leads to an enhancement of bacterial virulence. Here, we investigated whether plasmin(ogen) bound at the GBS surface contributes to blood-brain barrier penetration and invasion of the central nervous system. For that purpose, GBS strain NEM316 preincubated with or without plasminogen plus tissue type plasminogen activator was analyzed for the capacity to adhere to, invade and transmigrate the human brain microvascular endothelial cell (hBMEC) monolayer, and to penetrate the central nervous system using a neonatal mouse model. At earlier times of infection, plasmin(ogen) treated GBS exhibited a significant increase in adherence to and invasion of hBMECs. Later, injury of hBMECs were observed with plasmin(ogen)-treated GBS that displayed a plasmin-like activity. The same results were obtained when hBMECs were incubated with whole human plasma and infected with untreated GBS. To confirm that the observed effects were due to the recruitment and activation of plasminogen on GBS surface, the bacteria were first incubated with epsilon aminocaproic acid (epsilonACA), an inhibitor of plasminogen binding, and thereafter with plasmin(ogen). A significant decrease in the hBMECs injury that was correlated with a decrease of the GBS surface proteolytic activity was observed. Furthermore, plasmin(ogen)-treated GBS infected more efficiently the brain of neonatal mice than the untreated bacteria, indicating that plasmin(ogen) bound to GBS surface may facilitate the traversal of the blood-brain barrier. A higher survival rate was observed in offspring born from epsilonACA-treated mothers, compared to untreated mice, and no brain infection was detected in these neonates. Our findings suggest that capture of the host plasmin(ogen) by the GBS surface promotes the crossing of the blood-brain barrier and contributes to the establishment of meningitis. PMID- 23658817 TI - Physiological and biogeochemical traits of bleaching and recovery in the mounding species of coral Porites lobata: implications for resilience in mounding corals. AB - Mounding corals survive bleaching events in greater numbers than branching corals. However, no study to date has determined the underlying physiological and biogeochemical trait(s) that are responsible for mounding coral holobiont resilience to bleaching. Furthermore, the potential of dissolved organic carbon (DOC) as a source of fixed carbon to bleached corals has never been determined. Here, Porites lobata corals were experimentally bleached for 23 days and then allowed to recover for 0, 1, 5, and 11 months. At each recovery interval a suite of analyses were performed to assess their recovery (photosynthesis, respiration, chlorophyll a, energy reserves, tissue biomass, calcification, delta(13)C of the skeletal, delta(13)C, and delta(15)N of the animal host and endosymbiont fractions). Furthermore, at 0 months of recovery, the assimilation of photosynthetically acquired and zooplankton-feeding acquired carbon into the animal host, endosymbiont, skeleton, and coral-mediated DOC were measured via (13)C-pulse-chase labeling. During the first month of recovery, energy reserves and tissue biomass in bleached corals were maintained despite reductions in chlorophyll a, photosynthesis, and the assimilation of photosynthetically fixed carbon. At the same time, P. lobata corals catabolized carbon acquired from zooplankton and seemed to take up DOC as a source of fixed carbon. All variables that were negatively affected by bleaching recovered within 5 to 11 months. Thus, bleaching resilience in the mounding coral P. lobata is driven by its ability to actively catabolize zooplankton-acquired carbon and seemingly utilize DOC as a significant fixed carbon source, facilitating the maintenance of energy reserves and tissue biomass. With the frequency and intensity of bleaching events expected to increase over the next century, coral diversity on future reefs may favor not only mounding morphologies but species like P. lobata, which have the ability to utilize heterotrophic sources of fixed carbon that minimize the impact of bleaching and promote fast recovery. PMID- 23658818 TI - Deficient reporting and interpretation of non-inferiority randomized clinical trials in HIV patients: a systematic review. AB - OBJECTIVES: Non-inferiority (NI) randomized clinical trials (RCTs) commonly evaluate efficacy of new antiretroviral (ARV) drugs in human immunodeficiency virus (HIV) patients. Their reporting and interpretation have not been systematically evaluated. We evaluated the reporting of NI RCTs in HIV patients according to the CONSORT statement and assessed the degree of misinterpretation of RCTs when NI was inconclusive or not established. DESIGN: Systematic review. METHODS: PubMed, Web of Science, and Scopus were reviewed until December 2011. Selection and extraction was performed independently by three reviewers. RESULTS: Of the 42 RCTs (n = 21,919; range 41-3,316) selected, 23 were in ARV-naive and 19 in ARV-experienced patients. Twenty-seven (64%) RCTs provided information about prior RCTs of the active comparator, and 37 (88%) used 2-sided CIs. Two thirds of trials used a NI margin between 10 and 12%, although only 12 explained the method to determine it. Blinding was used in 9 studies only. The main conclusion was based on both intention-to-treat (ITT) and per protocol (PP) analyses in 5 trials, on PP analysis only in 4 studies, and on ITT only in 31 studies. Eleven of 16 studies with NI inconclusive or not established highlighted NI or equivalence, and distracted readers with positive secondary results. CONCLUSIONS: There is poor reporting and interpretation of NI RCTs performed in HIV patients. Maximizing the reporting of the method of NI margin determination, use of blinding and both ITT and PP analyses, and interpreting negative NI according to actual primary findings will improve the understanding of results and their translation into clinical practice. PMID- 23658819 TI - Effects of different regeneration scenarios and fertilizer treatments on soil microbial ecology in reclaimed opencast mining areas on the Loess Plateau, China. AB - The soil microbial community in reclaimed mining areas is fundamental to vegetative establishment. However, how this community responds to different regeneration scenarios and fertilizer treatments is poorly understood. This research evaluated plant and soil microbial communities from different regeneration scenarios and different fertilizer treatments. Regeneration scenarios significantly influenced soil bacterial, archaeal, and fungal rDNA abundance. The ratios of fungi to bacteria or archaea were increased with fertilizer application. The diversity of both plants and microbes was lowest in Lotus corniculatus grasslands. Regeneration scenario, fertilizer treatment, and their interaction influenced soil microbial richness, diversity and evenness indices. Labile carbon pool 2 was a significant factor affected plant and microbe communities in July, suggesting that plants and microbes may be competing for nutrients. The higher ratios of positive to negative association were found in soil bacteria and total microbe than in archaea and fungi. Stronger clustering of microbial communities from the same regeneration scenario indicated that the vegetative composition of regeneration site may have a greater influence on soil microbial communities than fertilizer treatment. PMID- 23658820 TI - Density-dependent compensatory growth in brown trout (Salmo trutta) in nature. AB - Density-dependence is a major ecological mechanism that is known to limit individual growth. To examine if compensatory growth (unusually rapid growth following a period of imposed slow growth) in nature is density-dependent, one year-old brown trout (Salmo trutta L.) were first starved in the laboratory, and then released back into their natural stream, either at natural or at experimentally increased population density. The experimental trout were captured three times over a one-year period. We found no differences in growth, within the first month after release (May-June), between the starved fish and the control group (i.e. no evidence of compensation). During the summer however (July September), the starved fish grew more than the control group (i.e. compensation), and the starved fish released into the stream at a higher density, grew less than those released at a natural density, both in terms of weight and length (i.e. density-dependent compensation). Over the winter (October-April), there were no effects of either starvation or density on weight and length growth. After the winter, starved fish released at either density had caught up with control fish in body size, but recapture rates (proxy for survival) did not indicate any costs of compensation. Our results suggest that compensatory growth in nature can be density-dependent. Thus, this is the first study to demonstrate the presence of ecological restrictions on the compensatory growth response in free-ranging animals. PMID- 23658821 TI - Expression and functions of galectin-7 in human and murine melanomas. AB - The identification of galectin-7 as a p53-induced gene and its ability to induce apoptosis in many cell types support the hypothesis that galectin-7 has strong antitumor activity. This has been well documented in colon cancer. However, in some cases, such as breast cancer and lymphoma, its high expression level correlates with aggressive subtypes of cancer, suggesting that galectin-7 may have a dual role in cancer progression. In fact, in breast cancer, overexpression of galectin-7 alone is sufficient to promote metastasis to the bone and lung. In the present work, we investigated the expression and function of galectin-7 in melanoma. An analysis of datasets obtained from whole-genome profiling of human melanoma tissues revealed that galectin-7 mRNA was detected in more than 90% of biopsies of patients with nevi while its expression was more rarely found in biopsies collected from patients with malignant melanoma. This frequency, however, was likely due to the presence of normal epidermis tissues in biopsies, as shown our studies at the protein level by immunohistochemical analysis. Using the experimental melanoma B16F1 cell line, we found that melanoma cells can express galectin-7 at the primary tumor site and in lung metastasis. Moreover, we found that overexpression of galectin-7 increased the resistance of melanoma cells to apoptosis while inducing de novo egr-1 expression. Overexpression of galectin-7, however, was insufficient to modulate the growth of tumors induced by the subcutaneous injection of B16F1 cells. It also failed to modulate the dissemination of B16F1 cells to the lung. PMID- 23658822 TI - Intrinsic properties of larval zebrafish neurons in ethanol. AB - The behavioral effects of ethanol have been studied in multiple animal models including zebrafish. Locomotion of zebrafish larvae is resistant to high concentrations of ethanol in bath solution. This resistance has been attributed to a lower systemic concentration of ethanol in zebrafish when compared with bath solution, although the mechanism to maintain such a steep gradient is unclear. Here we examined whether the intrinsic properties of neurons play roles in this resistance. In order to minimize the contribution of metabolism and diffusional barriers, larvae were hemisected and the anterior half immersed in a range of ethanol concentrations thereby ensuring the free access of bath ethanol to the brain. The response to vibrational stimuli of three types of reticulospinal neurons: Mauthner neurons, vestibulospinal neurons, and MiD3 neurons were examined using an intracellular calcium indicator. The intracellular [Ca(2+)] response in MiD3 neurons decreased in 100 mM ethanol, while Mauthner neurons and vestibulospinal neurons required >300 mM ethanol to elicit similar effects. The ethanol effect in Mauthner neurons was reversible following removal of ethanol. Interestingly, activities of MiD3 neurons displayed spontaneous recovery in 300 mM ethanol, suggestive of acute tolerance. Finally, we examined with mechanical vibration the startle response of free-swimming larvae in 300 mM ethanol. Ethanol treatment abolished long latency startle responses, suggesting a functional change in neural processing. These data support the hypothesis that individual neurons in larval zebrafish brains have distinct patterns of response to ethanol dictated by specific molecular targets. PMID- 23658823 TI - Disease-specific survival in de novo metastatic renal cell carcinoma in the cytokine and targeted therapy era. AB - BACKGROUND: Recent phase III studies of targeted agents for metastatic renal cell carcinoma (mRCC) have generated median survival estimates that far exceed those observed during the cytokine era. However, substantial population-based data does not exist to confirm this trend. We sought to determine whether survival has improved for patients with mRCC diagnosed in the era of targeted therapies, as compared to the era of immunotherapy. METHODS: The Surveillance, Epidemiology, and End Results (SEER) Registry was used to identify patients aged 18 and older diagnosed stage IV RCC between 1992 and 2009. Patients had documented clear cell, papillary or chromophobe histology. The Kaplan Meier method and log-rank test were used to compare disease-specific survival (DSS) for patients diagnosed from 1992-2004 (i.e., the cytokine era) and 2005-2009 (i.e., the targeted therapy era). Univariate and multivariate analyses of relevant clinicopathologic characteristics were also performed. RESULTS: Of 5,176 patients identified using the above characteristics, 2,392 patients were diagnosed from 1992-2004 and 2,784 from 2005-2009. Median DSS was improved in those patients diagnosed from 2005 2009 (16 months vs 13 months; P<0.0001). A similar temporal trend towards improving survival was noted in patients with clear cell (P = 0.0006), but not in patients with non-clear cell disease (P = 0.32). Notable findings on multivariate analysis include an association between shorter DSS and the following characteristics: (1) diagnosis from 1992-2004, (2) advanced age (80+), and (3) absence of cytoreductive nephrectomy. CONCLUSIONS: These data reflect progress in the management of mRCC, specifically in the era of targeted therapies. Notably, it was inferred that certain treatment strategies were employed during pre specified time periods, representing a major caveat of the current analysis. Further studies related to the influence of age and race/ethnicity are warranted, as are studies exploring the role of cytoreductive nephrectomy and novel treatments for non-clear cell disease. PMID- 23658824 TI - An impossible journey? The development of Plasmodium falciparum NF54 in Culex quinquefasciatus. AB - Although Anopheles mosquitoes are the vectors for human Plasmodium spp., there are also other mosquito species-among them culicines (Culex spp., Aedes spp.) present in malaria-endemic areas. Culicine mosquitoes transmit arboviruses and filarial worms to humans and are vectors for avian Plasmodium spp., but have never been observed to transmit human Plasmodium spp. When ingested by a culicine mosquito, parasites could either face an environment that does not allow development due to biologic incompatibility or be actively killed by the mosquito's immune system. In the latter case, the molecular mechanism of killing must be sufficiently powerful that Plasmodium is not able to overcome it. To investigate how human malaria parasites develop in culicine mosquitoes, we infected Culex quinquefasciatus with Plasmodium falciparum NF54 and monitored development of parasites in the blood bolus and midgut epithelium at different time points. Our results reveal that ookinetes develop in the midgut lumen of C. quinquefasciatus in slightly lower numbers than in Anopheles gambiae G3. After 30 hours, parasites have invaded the midgut and can be observed on the basal side of the midgut epithelium by confocal and transmission electron microscopy. Very few of the parasites in C. quinquefasciatus are alive, most of them are lysed. Eight days after the mosquito's blood meal, no oocysts can be found in C. quinquefasciatus. Our results suggest that the mosquito immune system could be involved in parasite killing early in development after ookinetes have crossed the midgut epithelium and come in contact with the mosquito hemolymph. PMID- 23658825 TI - Modification of histone acetylation facilitates hepatic differentiation of human bone marrow mesenchymal stem cells. AB - The multi-potentiality of mesenchymal stem cells makes them excellent options for future tissue engineering and clinical therapy, including liver injury. In this study, we investigated the effects of valproic acid (VPA), a direct inhibitor of histone deacetylase (HDAC), on the hepatic differentiation of human bone marrow mesenchymal stem cells (BMMSCs). The cells were found to differentiate into a more homogeneous hepatocyte-like population when pretreated with 5 mM VPA for 72 h. The expression of liver-specific markers was significantly upregulated in the VPA-treated group at the mRNA and protein levels. VPA treatment also significantly enhanced the hepatic functions of the differentiated cells, including glycogen storage, cytochrome P450 activity, AFP and ALB synthesis, and urea production. Further analysis showed that treatment with 5 mM of VPA for 72 h greatly improved the histones H3 and H4 acetylation. These results demonstrated that VPA could considerably improve the hepatic differentiation of human BMMSCs, probably because the chromatin-acetylated state changes upon VPA treatment through its HDAC inhibitory effect. Thus, this study provides a direct research model for producing human hepatocytes for clinical purposes. PMID- 23658826 TI - HMGA1: a master regulator of tumor progression in triple-negative breast cancer cells. AB - Emerging evidence suggests that tumor cells metastasize by co-opting stem cell transcriptional networks, although the molecular underpinnings of this process are poorly understood. Here, we show for the first time that the high mobility group A1 (HMGA1) gene drives metastatic progression in triple negative breast cancer cells (MDA-MB-231, Hs578T) by reprogramming cancer cells to a stem-like state. Silencing HMGA1 expression in invasive, aggressive breast cancer cells dramatically halts cell growth and results in striking morphologic changes from mesenchymal-like, spindle-shaped cells to cuboidal, epithelial-like cells. Mesenchymal genes (Vimentin, Snail) are repressed, while E-cadherin is induced in the knock-down cells. Silencing HMGA1 also blocks oncogenic properties, including proliferation, migration, invasion, and orthotopic tumorigenesis. Metastatic progression following mammary implantation is almost completely abrogated in the HMGA1 knock-down cells. Moreover, silencing HMGA1 inhibits the stem cell property of three-dimensional mammosphere formation, including primary, secondary, and tertiary spheres. In addition, knock-down of HMGA1 depletes cancer initiator/cancer stem cells and prevents tumorigenesis at limiting dilutions. We also discovered an HMGA1 signature in triple negative breast cancer cells that is highly enriched in embryonic stem cells. Together, these findings indicate that HMGA1 is a master regulator of tumor progression in breast cancer by reprogramming cancer cells through stem cell transcriptional networks. Future studies are needed to determine how to target HMGA1 in therapy. PMID- 23658827 TI - Distinguishable in vitro binding mode of monomeric TRBP and dimeric PACT with siRNA. AB - RNA interference (RNAi) is an evolutionally conserved posttranscriptional gene silencing mechanism whereby small interfering RNA (siRNA) triggers sequence specific cleavage of its cognate mRNA. Dicer, Argonaute (Ago), and either TAR-RNA binding protein (TRBP) or a protein activator of PKR (PACT) are the primary components of the RNAi pathway, and they comprise the core of a complex termed the RNA-induced silencing complex (RISC)-loading complex (RLC). TRBP and PACT share similar structural features including three dsRNA binding domains (dsRBDs), and a complex containing Dicer and either TRBP or PACT is considered to sense thermodynamic asymmetry of siRNA ends for guide strand selection. Thus, both TRBP and PACT are thought to participate in the RNAi pathway in an indistinguishable manner, but the differences in siRNA binding mode and the functional involvement of TRBP and PACT are poorly understood. Here, we show in vitro binding patterns of human TRBP and PACT to siRNA using electrophoresis mobility shift analysis and gel filtration chromatography. Our results clearly showed that TRBP and PACT have distinct in vitro siRNA binding patterns from each other. The results suggest that monomeric TRBP binds to siRNA at the higher affinity compared to the affinity for own homodimerization. In contrast, the affinity between PACT and siRNA is lower than that of homodimerization or that between TRBP and siRNA. Thus, siRNA may be more readily incorporated into RLC, interacting with TRBP (instead of PACT) in vivo. PMID- 23658828 TI - Mapping the ligand-binding region of Borrelia hermsii fibronectin-binding protein. AB - Many pathogenic microorganisms express fibronectin-binding molecules that facilitate their adherence to the extracellular matrix and/or entry into mammalian cells. We have previously described a Borrelia recurrentis gene, cihC that encodes a 40-kDa surface receptor for both, fibronectin and the complement inhibitors C4bp and C1-Inh. We now provide evidence for the expression of a group of highly homologues surface proteins, termed FbpA, in three B. hermsii isolates and two tick-borne relapsing fever spirochetes, B. parkeri and B. turicatae. When expressed in Escherichia coli or B. burgdorferi, four out of five proteins were shown to selectively bind fibronectin, whereas none of five proteins were able to bind the human complement regulators, C4bp and C1-Inh. By applying deletion mutants of the B. hermsii fibronectin-binding proteins a putative high-affinity binding site for fibronectin was mapped to its central region. In addition, the fibronectin-binding proteins of B. hermsii were found to share sequence homology with BBK32 of the Lyme disease spirochete B. burgdorferi with similar function suggesting its involvement in persistence and/or virulence of relapsing fever spirochetes. PMID- 23658829 TI - Effect of neuroglobin genetically modified bone marrow mesenchymal stem cells transplantation on spinal cord injury in rabbits. AB - OBJECTIVE: This study aims to investigate the potentially protective effect of neuroglobin (Ngb) gene-modified bone marrow mesenchymal stem cells (BMSCs) on traumatic spinal cord injury (SCI) in rabbits. METHODS: A lentiviral vector containing an Ngb gene was constructed and used to deliver Ngb to BMSCs. Ngb gene modified BMSCs were then injected at the SCI sites 24 hours after SCI. The motor functions of the rabbits were evaluated by the Basso-Beattie-Bresnahan rating scale. Fluorescence microscopy, quantitative real-time PCRs, Western blots, malondialdehyde (MDA) tests, and terminal deoxynucleotidyltransferase-mediated UTP end labeling assays were also performed. RESULTS: Ngb expression in the Ngb BMSC group increased significantly. A more significant functional improvement was observed in the Ngb-BMSC group compared with those in the other groups. Traumatic SCI seemingly led to an increase in MDA level and number of apoptotic cells, which can be prevented by Ngb-BMSC treatment. CONCLUSION: This study demonstrates that Ngb gene-modified BMSCs can strengthen the therapeutic benefits of BMSCs in reducing secondary damage and improving the neurological outcome after traumatic SCI. Therefore, the combined strategy of BMSC transplantation and Ngb gene therapy can be used to treat traumatic SCI. PMID- 23658830 TI - Constitutively active androgen receptor variants upregulate expression of mesenchymal markers in prostate cancer cells. AB - Androgen receptor (AR) signaling pathway remains the foremost target of novel therapeutics for castration-resistant prostate cancer (CRPC). However, the expression of constitutively active AR variants lacking the carboxy-terminal region in CRPC may lead to therapy inefficacy. These AR variants are supposed to support PCa cell growth in an androgen-depleted environment, but their mode of action still remains unresolved. Moreover, recent studies indicate that constitutively active AR variants are expressed in primary prostate tumors and may contribute to tumor progression. The aim of this study was to investigate the impact of constitutively active AR variants on the expression of tumor progression markers. N-cadherin expression was analyzed in LNCaP cells overexpressing the wild type AR or a constitutively active AR variant by qRT-PCR, Western blot and immunofluorescence. We showed here for the first time that N cadherin expression was increased in the presence of constitutively active AR variants. These results were confirmed in C4-2B cells overexpressing these AR variants. Although N-cadherin expression is often associated with a downregulation of E-cadherin, this phenomenon was not observed in our model. Nevertheless, in addition to the increased expression of N-cadherin, an upregulation of other mesenchymal markers expression such as VIMENTIN, SNAIL and ZEB1 was observed in the presence of constitutively active variants. In conclusion, our findings highlight novel consequences of constitutively active AR variants on the regulation of mesenchymal markers in prostate cancer. PMID- 23658831 TI - The protective effects of beta-casomorphin-7 against glucose -induced renal oxidative stress in vivo and vitro. AB - Oxidative stress is implicated in the pathogenesis of diabetic nephropathy. The present study aimed to investigate the effect of beta-casomorphin-7 (BCM7) on the oxidative stress occurring in kidney tissue in streptozotocin (STZ)-induced diabetic rats and proximal tubular epithelial cells (NRK-52E) exposure to high glucose (HG) by using biochemical methods. There is a significant decrease in plasma insulin and a significant increase in plasma glucagon in the rats of diabetic group. Oral administration of BCM7 for 30 days to rats with STZ-induced diabetes resulted in a significant increase in serum level of insulin, and a decrease in the level of glucagon. Moreover, rats with STZ-induced diabetes had lower levels of superoxide dismutase (SOD), glutathione peroxidase (GPx) and total antioxidative capacity (T-AOC), higher levels of malondialdehyde (MDA) and hydrogen peroxide (H2O2) in the kidney than that in the control rats. The administration of BCM7 altered the changes of SOD, GPx, T-AOC, MDA and H2O2 in the kidney of diabetic rats. Furthermore, BCM7 alleviated high glucose-induced decreasement in SOD and GPx activity, increasement in MDA contents in the NRK-52E cells. BCM7 ameliorated the changes of angiotensin converting enzyme (ACE) and ACE2 levels in the kidney of diabetic rats and BCM7 lowered the levels of angiotensin (Ang)II in the kidney of diabetic rats and culture medium for cells. Moreover losartan (antagonist of angiotensin II type I receptor) lowered the high glucose-induced oxidative stress in the NRK-52E cells. Our results suggest that administration of BCM7 would alleviate high glucose-induced renal oxidative stress in vivo and in vitro, which may be associated with down regulation of the concentration of Ang II partly. PMID- 23658832 TI - Population exposure to PM2.5 in the urban area of Beijing. AB - The air quality in Beijing, especially its PM2.5 level, has become of increasing public concern because of its importance and sensitivity related to health risks. A set of monitored PM2.5 data from 31 stations, released for the first time by the Beijing Environmental Protection Bureau, covering 37 days during autumn 2012, was processed using spatial interpolation and overlay analysis. Following analyses of these data, a distribution map of cumulative exceedance days of PM2.5 and a temporal variation map of PM2.5 for Beijing have been drawn. Computational and analytical results show periodic and directional trends of PM2.5 spreading and congregating in space, which reveals the regulation of PM2.5 overexposure on a discontinuous medium-term scale. With regard to the cumulative effect of PM2.5 on the human body, the harm from lower intensity overexposure in the medium term, and higher overexposure in the short term, are both obvious. Therefore, data of population distribution were integrated into the aforementioned PM2.5 spatial spectrum map. A spatial statistical analysis revealed the patterns of PM2.5 gross exposure and exposure probability of residents in the Beijing urban area. The methods and conclusions of this research reveal relationships between long-term overexposure to PM2.5 and people living in high-exposure areas of Beijing, during the autumn of 2012. PMID- 23658833 TI - Elevated circulating levels and tissue expression of pentraxin 3 in uremia: a reflection of endothelial dysfunction. AB - Elevated systemic pentraxin 3 (PTX3) levels appear to be a powerful marker of inflammatory status and a superior outcome predictor in patients with chronic kidney disease (CKD). As previous data imply that PTX3 is involved in vascular pathology and that adipose tissue mass may influence circulating PTX3 levels, we aimed to study the importance of adipose tissue expression of PTX3 in the uremic milieu and its relation to endothelial dysfunction parameters. Plasma PTX3 and abdominal subcutaneous adipose tissue (SAT) PTX3 mRNA levels were quantified in 56 stage 5 CKD patients (median age 57 [range 25-75] years, 30 males) and 40 age and gender matched controls (median age 58 [range 20-79] years, 27 males). Associations between PTX3 measures and an extensive panel of clinical parameters, including surrogate markers of endothelial function, were assessed. Functional ex vivo studies on endothelial status and immunohistochemical staining for PTX3 were conducted in resistance subcutaneous arteries isolated from SAT. SAT PTX3 mRNA expression correlated with plasma PTX3 concentrations (rho = 0.54, p = 0.0001) and was increased (3.7 [0.4-70.3] vs. 1.2 [0.2-49.3] RQ, p = 0.02) in CKD patients with cardiovascular disease (CVD), but was not significantly different between patients and controls. The association to CVD was lost after adjustments. SAT PTX3 mRNA levels were independently correlated to asymmetric dimethylarginine and basal resistance artery tone developed after inhibition with nitric oxide synthase and cyclooxygenase (rho = -0.58, p = 0.002). Apparent positive PTX3 immunoreactivity was observed in both patient and control arteries. In conclusion, fat PTX3 mRNA levels are associated with measures of endothelial cell function in patients with CKD. PTX3 may be involved in adipose tissue orchestrated mechanisms that are restricted to the uremic milieu and modify inflammation and vascular complications in CKD patients. PMID- 23658834 TI - An ensemble prognostic model for colorectal cancer. AB - Colorectal cancer can be grouped into Dukes A, B, C, and D stages based on its developments. Generally speaking, more advanced patients have poorer prognosis. To integrate progression stage prediction systems with recurrence prediction systems, we proposed an ensemble prognostic model for colorectal cancer. In this model, each patient was assigned a most possible stage and a most possible recurrence status. If a patient was predicted to be recurrence patient in advanced stage, he would be classified into high risk group. The ensemble model considered both progression stages and recurrence status. High risk patients and low risk patients predicted by the ensemble model had a significant different disease free survival (log-rank test p-value, 0.0016) and disease specific survival (log-rank test p-value, 0.0041). The ensemble model can better distinguish the high risk and low risk patients than the stage prediction model and the recurrence prediction model alone. This method could be applied to the studies of other diseases and it could significantly improve the prediction performance by ensembling heterogeneous information. PMID- 23658835 TI - Downregulation of OPA3 is responsible for transforming growth factor-beta-induced mitochondrial elongation and F-actin rearrangement in retinal pigment epithelial ARPE-19 cells. AB - Transforming growth factor-beta signaling is known to be a key signaling pathway in the induction of epithelial-mesenchymal transition. However, the mechanism of TGF-beta signaling in the modulation of EMT remains unclear. In this study, we found that TGF-beta treatment resulted in elongation of mitochondria accompanied by induction of N-cadherin, vimentin, and F-actin in retinal pigment epithelial cells. Moreover, OPA3, which plays a crucial role in mitochondrial dynamics, was downregulated following TGF-beta treatment. Suppression of TGF-beta signaling using Smad2 siRNA prevented loss of OPA3 induced by TGF-beta. Knockdown of OPA3 by siRNA and inducible shRNA significantly increased stress fiber levels, cell length, cell migration and mitochondrial elongation. In contrast, forced expression of OPA3 in ARPE-19 cells inhibited F-actin rearrangement and induced mitochondrial fragmentation. We also showed that Drp1 depletion increased cell length and induced rearrangement of F-actin. Depletion of Mfn1 blocked the increase in cell length during TGF-beta-mediated EMT. These results collectively substantiate the involvement of mitochondrial dynamics in TGF-beta-induced EMT. PMID- 23658836 TI - Euphorbia tirucalli L.-comprehensive characterization of a drought tolerant plant with a potential as biofuel source. AB - Of late, decrease in mineral oil supplies has stimulated research on use of biomass as an alternative energy source. Climate change has brought problems such as increased drought and erratic rains. This, together with a rise in land degeneration problems with concomitant loss in soil fertility has inspired the scientific world to look for alternative bio-energy species. Euphorbia tirucalli L., a tree with C3/CAM metabolism in leaves/stem, can be cultivated on marginal, arid land and could be a good alternative source of biofuel. We analyzed a broad variety of E. tirucalli plants collected from different countries for their genetic diversity using AFLP. Physiological responses to induced drought stress were determined in a number of genotypes by monitoring growth parameters and influence on photosynthesis. For future breeding of economically interesting genotypes, rubber content and biogas production were quantified. Cluster analysis shows that the studied genotypes are divided into two groups, African and mostly non-African genotypes. Different genotypes respond significantly different to various levels of water. Malate measurement indicates that there is induction of CAM in leaves following drought stress. Rubber content varies strongly between genotypes. An investigation of the biogas production capacities of six E. tirucalli genotypes reveals biogas yields higher than from rapeseed but lower than maize silage. PMID- 23658837 TI - Secretome analysis defines the major role of SecDF in Staphylococcus aureus virulence. AB - The Sec pathway plays a prominent role in protein export and membrane insertion, including the secretion of major bacterial virulence determinants. The accessory Sec constituent SecDF has been proposed to contribute to protein export. Deletion of Staphylococcus aureus secDF has previously been shown to reduce resistance, to alter cell separation, and to change the expression of certain virulence factors. To analyse the impact of the secDF deletion in S. aureus on protein secretion, a quantitative secretome analysis was performed. Numerous Sec signal containing proteins involved in virulence were found to be decreased in the supernatant of the secDF mutant. However, two Sec-dependent hydrolases were increased in comparison to the wild type, suggesting additional indirect, regulatory effects to occur upon deletion of secDF. Adhesion, invasion, and cytotoxicity of the secDF mutant were reduced in human umbilical vein endothelial cells. Virulence was significantly reduced using a Galleria mellonella insect model. Altogether, SecDF is a promising therapeutic target for controlling S. aureus infections. PMID- 23658838 TI - Anorexia and eating patterns in the elderly. AB - OBJECTIVES: To evaluate the change in eating habits occurring in community dwelling and institutionalized elderly subjects with senile anorexia. DESIGN: Cross-sectional, observational. SETTING: Community, nursing homes and rehabilitation or acute care facilities in four Italian regions. PARTICIPANTS: A random sample of 526 subjects, aged 65 years and older (217 free living individuals, 213 residents in nursing homes, and 93 patients in rehabilitation and acute wards). MEASUREMENTS: All subjects underwent a multidimensional geriatric evaluation of: nutritional status, anthropometric parameters, health and cognitive status, depression, taste, chewing and swallowing function, and some hormones related to appetite. Diet variety was assessed, considering the frequency of consumption of different food groups (milk and dairy products; meat, fish, and eggs; cereals and derivatives; fruit and vegetables). RESULTS: In anorexic elderly subjects the global food intake was reduced, and the eating pattern was characterized by the reduced consumption of certain food groups ("meat, eggs and fish" and "fruit and vegetables") whereas the frequency of consumption of milk and cereals remained almost unchanged. Nutritional parameters were significantly better in normal eating subjects and correlated with diet variety. CONCLUSION: Because of the high prevalence of senile anorexia in the geriatric population and its impact on the nutritional status, further research should be prompted to establish an intervention. protocol allowing the early diagnosis of anorexia of aging, aimed at identifying its causes and at optimizing treatment of anorexic patients. PMID- 23658839 TI - Methyl donor supplementation blocks the adverse effects of maternal high fat diet on offspring physiology. AB - Maternal consumption of a high fat diet during pregnancy increases the offspring risk for obesity. Using a mouse model, we have previously shown that maternal consumption of a high fat (60%) diet leads to global and gene specific decreases in DNA methylation in the brain of the offspring. The present experiments were designed to attempt to reverse this DNA hypomethylation through supplementation of the maternal diet with methyl donors, and to determine whether methyl donor supplementation could block or attenuate phenotypes associated with maternal consumption of a HF diet. Metabolic and behavioral (fat preference) outcomes were assessed in male and female adult offspring. Expression of the mu-opioid receptor and dopamine transporter mRNA, as well as global DNA methylation were measured in the brain. Supplementation of the maternal diet with methyl donors attenuated the development of some of the adverse effects seen in offspring from dams fed a high fat diet; including weight gain, increased fat preference (males), changes in CNS gene expression and global hypomethylation in the prefrontal cortex. Notable sex differences were observed. These findings identify the importance of balanced methylation status during pregnancy, particularly in the context of a maternal high fat diet, for optimal offspring outcome. PMID- 23658840 TI - The connection of monocytes and reactive oxygen species in pain. AB - The interplay of specific leukocyte subpopulations, resident cells and proalgesic mediators results in pain in inflammation. Proalgesic mediators like reactive oxygen species (ROS) and downstream products elicit pain by stimulation of transient receptor potential (TRP) channels. The contribution of leukocyte subpopulations however is less clear. Local injection of neutrophilic chemokines elicits neutrophil recruitment but no hyperalgesia in rats. In meta-analyses the monocytic chemoattractant, CCL2 (monocyte chemoattractant protein-1; MCP-1), was identified as an important factor in the pathophysiology of human and animal pain. In this study, intraplantar injection of CCL2 elicited thermal and mechanical pain in Wistar but not in Dark Agouti (DA) rats, which lack p47(phox), a part of the NADPH oxidase complex. Inflammatory hyperalgesia after complete Freund's adjuvant (CFA) as well as capsaicin-induced hyperalgesia and capsaicin induced current flow in dorsal root ganglion neurons in DA were comparable to Wistar rats. Macrophages from DA expressed lower levels of CCR2 and thereby migrated less towards CCL2 and formed limited amounts of ROS in vitro and 4 hydroxynonenal (4-HNE) in the tissue in response to CCL2 compared to Wistar rats. Local adoptive transfer of peritoneal macrophages from Wistar but not from DA rats reconstituted CCL2-triggered hyperalgesia in leukocyte-depleted DA and Wistar rats. A pharmacological stimulator of ROS production (phytol) restored CCL2-induced hyperalgesia in vivo in DA rats. In Wistar rats, CCL2-induced hyperalgesia was completely blocked by superoxide dismutase (SOD), catalase or tempol. Likewise, inhibition of NADPH oxidase by apocynin reduced CCL2-elicited hyperalgesia but not CFA-induced inflammatory hyperalgesia. In summary, we provide a link between CCL2, CCR2 expression on macrophages, NADPH oxidase, ROS and the development CCL2-triggered hyperalgesia, which is different from CFA induced hyperalgesia. The study further supports the impact of CCL2 and ROS as potential targets in pain therapy. PMID- 23658841 TI - Heat shock protein 90 inhibitors repress latent membrane protein 1 (LMP1) expression and proliferation of Epstein-Barr virus-positive natural killer cell lymphoma. AB - Epstein-Barr virus (EBV) LMP1 is a major oncoprotein expressed in latent infection. It functions as a TNFR family member and constitutively activates cellular signals, such as NFkappaB, MAPK, JAK/STAT and AKT. We here screened small molecule inhibitors and isolated HSP90 inhibitors, Radicicol and 17-AAG, as candidates that suppress LMP1 expression and cell proliferation not only in EBV positive SNK6 Natural Killer (NK) cell lymphoma cells, but also in B and T cells. Tumor formation in immuno-defficient NOD/Shi-scid/IL-2Rgamma(null) (NOG) mice was also retarded. These results suggest that HSP90 inhibitors can be alternative treatments for patients with EBV-positive malignancies. PMID- 23658842 TI - Roles of GSK3beta in odor habituation and spontaneous neural activity of the mouse olfactory bulb. AB - Glycogen synthase kinase 3beta (GSK3beta), a multifaceted kinase, is abundantly expressed in the brain, including the olfactory bulb (OB). In resting cells, GSK3beta is constitutively active, and its over-activation is presumably involved in numerous brain diseases, such as Alzheimer's disease. However, the functions of the constitutively active GSK3beta in the adult brain under physiological conditions are not well understood. Here, we studied the possible functions of GSK3beta activity in the OB. Odor stimulation, or blockade of peripheral olfactory inputs caused by either transgenic knock-out or ZnSO4 irrigation to the olfactory epithelium, all affected the expression level of GSK3beta in the OB. When GSK3beta activity was reduced by a selective inhibitor, the spontaneous oscillatory activity was significantly decreased in the granule cell layer of the OB. Furthermore, local inhibition of GSK3beta activity in the OB significantly impaired the odor habituation ability. These results suggest that GSK3beta plays important roles in both spontaneous neural activity and odor information processing in the OB, deepening our understanding of the potential functions of the constitutively active GSK3beta in the brain under physiological conditions. PMID- 23658843 TI - Characterization of gonadal transcriptomes from Nile tilapia (Oreochromis niloticus) reveals differentially expressed genes. AB - Four pairs of XX and XY gonads from Nile tilapia were sequenced at four developmental stages, 5, 30, 90, and 180 days after hatching (dah) using Illumina Hiseq(TM) technology. This produced 28 Gb sequences, which were mapped to 21,334 genes. Of these, 259 genes were found to be specifically expressed in XY gonads, and 69 were found to be specific to XX gonads. Totally, 187 XX- and 1,358 XY enhanced genes were identified, and 2,978 genes were found to be co-expressed in XX and XY gonads. Almost all steroidogenic enzymes, including cyp19a1a, were up regulated in XX gonads at 5 dah; but in XY gonads these enzymes, including cyp11b2, were significantly up-regulated at 90 dah, indicating that, at a time critical to sex determination, the XX fish produced estrogen and the XY fish did not produce androgens. The most pronounced expression of steroidogenic enzyme genes was observed at 30 and 90 dah for XX and XY gonads, corresponding to the initiation of germ cell meiosis in the female and male gonads, respectively. Both estrogen and androgen receptors were found to be expressed in XX gonads, but only estrogen receptors were expressed in XY gonads at 5 dah. This could explain why exogenous steroid treatment induced XX and XY sex reversal. The XX-enhanced expression of cyp19a1a and cyp19a1b at all stages suggests an important role for estrogen in female sex determination and maintenance of phenotypic sex. This work is the largest collection of gonadal transcriptome data in tilapia and lays the foundation for future studies into the molecular mechanisms of sex determination and maintenance of phenotypic sex in non-model teleosts. PMID- 23658844 TI - The novel ubiquitin ligase complex, SCF(Fbxw4), interacts with the COP9 signalosome in an F-box dependent manner, is mutated, lost and under-expressed in human cancers. AB - Identification of novel proteins that can potentially contribute to carcinogenesis is a requisite venture. Herein, we report the first biochemical characterization of the novel F-box and WD40 containing protein, FBXW4. We have identified interacting protein partners and demonstrated that FBXW4 is part of a ubiquitin ligase complex. Furthermore, the Fbxw4 locus is a common site of proviral insertion in a variety of retroviral insertional mutagenesis murine cancer models and Fbxw4 mRNA is highly expressed in the involuting murine mammary gland. To begin to characterize the biochemical function of Fbxw4, we used proteomic analysis to demonstrate that Fbxw4 interacts with Skp1 (SKP1), Cullin1 (CUL1), Ring-box1 (RBX1) and all components of the COP9 signalosome. All of these interactions are dependent on an intact F-box domain of Fbxw4. Furthermore, Fbxw4 is capable of interacting with ubiquitinated proteins within cells in an F-box dependent manner. Finally, we demonstrate that FBXW4 is mutated, lost and under expressed in a variety of human cancer cell lines and clinical patient samples. Importantly, expression of FBXW4 correlates with survival of patients with non small cell lung cancer. Taken together, we suggest that FBXW4 may be a novel tumor suppressor that regulates important cellular processes. PMID- 23658845 TI - Sulfated polysaccharide, curdlan sulfate, efficiently prevents entry/fusion and restricts antibody-dependent enhancement of dengue virus infection in vitro: a possible candidate for clinical application. AB - Curdlan sulfate (CRDS), a sulfated 1->3-beta-D glucan, previously shown to be a potent HIV entry inhibitor, is characterized in this study as a potent inhibitor of the Dengue virus (DENV). CRDS was identified by in silico blind docking studies to exhibit binding potential to the envelope (E) protein of the DENV. CRDS was shown to inhibit the DENV replication very efficiently in different cells in vitro. Minimal effective concentration of CRDS was as low as 0.1 ug/mL in LLC-MK2 cells, and toxicity was observed only at concentrations over 10 mg/mL. CRDS can also inhibit DENV-1, 3, and 4 efficiently. CRDS did not inhibit the replication of DENV subgenomic replicon. Time of addition experiments demonstrated that the compound not only inhibited viral infection at the host cell binding step, but also at an early post-attachment step of entry (membrane fusion). The direct binding of CRDS to DENV was suggested by an evident reduction in the viral titers after interaction of the virus with CRDS following an ultrafiltration device separation, as well as after virus adsorption to an alkyl CRDS-coated membrane filter. The electron microscopic features also showed that CRDS interacted directly with the viral envelope, and caused changes to the viral surface. CRDS also potently inhibited DENV infection in DC-SIGN expressing cells as well as the antibody-dependent enhancement of DENV-2 infection. Based on these data, a probable binding model of CRDS to DENV E protein was constructed by a flexible receptor and ligand docking study. The binding site of CRDS was predicted to be at the interface between domains II and III of E protein dimer, which is unique to this compound, and is apparently different from the beta-OG binding site. Since CRDS has already been tested in humans without serious side effects, its clinical application can be considered. PMID- 23658846 TI - Immunomodulatory impact of leishmania-induced macrophage exosomes: a comparative proteomic and functional analysis. AB - Released by many eukaryotic cells, the exosomes are 40-100 nm vesicles shown to operate over the complex processes of cell-cell communication. Among the metazoan cell lineages known to generate exosomes is the mononuclear phagocyte lineage, a lineage that parasites such as Leishmania are known to subvert as host cells. We previously reported that mouse macrophage signaling and functions are modified once co-incubated with exoproteome of Leishmania promastigotes. Using mass spectrometry analysis, we were curious to further compare the content of purified exosomes released by the J774 mouse macrophage cell line exposed or not to either LPS or to stationary phase Leishmania mexicana promastigotes. Collectively, our analyses resulted in detection of 248 proteins, ~50-80% of which were shared among the three sources studied. Using exponentially modified protein abundance index (emPAI) and network analyses, we found that the macrophage exosomes display unique signatures with respect to composition and abundance of many functional groups of proteins, such as plasma membrane-associated proteins, chaperones and metabolic enzymes. Moreover, for the first time, L. mexicana surface protease GP63 is shown to be present in exosomes released from J774 macrophages exposed to stationary phase promastigotes. We observed that macrophage exosomes are able to induce signaling molecules and transcription factors in naive macrophages. Finally, using qRT-PCR, we monitored modulation of expression of multiple immune related genes within macrophages exposed to exosomes. We found all three groups of exosomes to induce expression of immune-related genes, the ones collected from macrophages exposed to L. mexicana sharing properties with exosomes collected from macrophage left unexposed to any agonist. Overall, our results allowed depicting that protein sorting into macrophage-derived exosomes depends upon the cell status and how such distinct protein sorting can in turn impact the functions of naive J774 cells. PMID- 23658847 TI - Secondary bacterial infections of buruli ulcer lesions before and after chemotherapy with streptomycin and rifampicin. AB - Buruli ulcer (BU), caused by Mycobacterium ulcerans is a chronic necrotizing skin disease. It usually starts with a subcutaneous nodule or plaque containing large clusters of extracellular acid-fast bacilli. Surrounding tissue is destroyed by the cytotoxic macrolide toxin mycolactone produced by microcolonies of M. ulcerans. Skin covering the destroyed subcutaneous fat and soft tissue may eventually break down leading to the formation of large ulcers that progress, if untreated, over months and years. Here we have analyzed the bacterial flora of BU lesions of three different groups of patients before, during and after daily treatment with streptomycin and rifampicin for eight weeks (SR8) and determined drug resistance of the bacteria isolated from the lesions. Before SR8 treatment, more than 60% of the examined BU lesions were infected with other bacteria, with Staphylococcus aureus and Pseudomonas aeruginosa being the most prominent ones. During treatment, 65% of all lesions were still infected, mainly with P. aeruginosa. After completion of SR8 treatment, still more than 75% of lesions clinically suspected to be infected were microbiologically confirmed as infected, mainly with P. aeruginosa or Proteus miriabilis. Drug susceptibility tests revealed especially for S. aureus a high frequency of resistance to the first line drugs used in Ghana. Our results show that secondary infection of BU lesions is common. This could lead to delayed healing and should therefore be further investigated. PMID- 23658848 TI - Relationship between serum antibodies and Taenia solium larvae burden in pigs raised in field conditions. AB - BACKGROUND: Serological tests have been used for the diagnosis of Taenia solium infection in pigs. However, those serological results do not necessarily correlate with the actual infection burden after performing pig necropsy. This study aimed to evaluate the Electro Immuno Transfer Blot (EITB) seropositivity with infection burden in naturally infected pigs. METHODOLOGY/PRINCIPAL FINDINGS: In an endemic area of Peru, 476 pigs were sampled. Seroprevalence was 60.5 +/- 4.5% with a statistically higher proportion of positive older pigs (>8 months) than young pigs. The logistic model showed that pigs >8 month of age were 2.5 times more likely to be EITB-positive than <= 8 months. A subset of 84 seropositive pigs were necropsied, with 45.2% (38/84) positive to 1-2 bands, 46.4% (39/84) to 3 bands, and 8.3% (7/84) to 4+ bands. 41 out of 84 positive pigs were negative to necropsy (48.8%) and 43 (51%) had one or more cysts (positive predictive value). Older pigs showed more moderate and heavy infection burdens compared to younger pigs. In general, regardless of the age of the pig, the probability of having more cysts (parasite burden) increases proportionally with the number of EITB bands. CONCLUSIONS/SIGNIFICANCE: The probability of being necropsy-positive increased with the number of bands, and age. Therefore, the EITB is a measure of exposure rather than a test to determine the real prevalence of cysticercosis infection. PMID- 23658849 TI - Review of Dengue hemorrhagic fever fatal cases seen among adults: a retrospective study. AB - BACKGROUND: Dengue is a mosquito-borne viral disease endemic in many countries in the tropics and sub-tropics. The disease affects mainly children, but in recent years it is becoming more of an adult disease. Malaysia experienced a large dengue outbreak in 2006 to 2007, involving mostly adults, with a high number of deaths. METHODOLOGY/PRINCIPAL FINDINGS: We undertook a retrospective study to examine dengue death cases in our hospital from June 2006 to October 2007 with a view to determine if there have been changes in the presentation of severe to fatal dengue. Nine of ten fatal cases involved adult females with a median age of 32 years. All had secondary dengue infection. The mean duration of illness prior to hospitalization was 4.7 days and deaths occurred at an average of 2.4 days post-admission. Gastrointestinal pain, vomiting, diarrhea, intravascular leakages and bleeding occurred in the majority of cases. DSS complicated with severe bleeding, multi-organ failure and coagulopathy were the primary causes of deaths. Seven patients presented with thrombocytopenia and hypoalbuminemia, five of which had hemoconcentration and increased ALT and AST indicative of liver damage. Co morbidities particularly diabetes mellitus was common in our cohort. Prominent unusual presentations included acute renal failure, acute respiratory distress syndrome, myocarditis with pericarditis, and hemorrhages over the brain and heart. CONCLUSIONS: In our cohort, dengue fatalities are seen primarily in adult females with secondary dengue infection. The majority of the patients presented with common clinical and laboratory warning signs of severe dengue. Underlying co morbidities may contribute to the rapid clinical deterioration in severe dengue. The uncommon presentations of dengue are likely a reflection of the changing demographics where adults are now more likely to contract dengue in dengue endemic regions. PMID- 23658850 TI - Efficacy of anti-leishmania therapy in visceral leishmaniasis among HIV infected patients: a systematic review with indirect comparison. AB - OBJECTIVE: We conducted a systematic literature review with indirect comparison of studies evaluating therapeutic efficacy and toxicity associated to visceral leishmaniasis (VL) therapy among HIV infected individuals. MAIN OUTCOME MEASUREMENTS: The outcomes of interest were clinical and parasitological cure, mortality, and adverse events. METHODS: PRISMA guidelines for systematic reviews and Cochrane manual were followed. Sources were MEDLINE, LILACS, EMBASE, Web of Knowledge databases and manual search of references from evaluated studies. We included all studies reporting outcomes after VL treatment, regardless of their design. Study quality was evaluated systematically by using the Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Comprehensive Meta-Analysis software v.2.2.048 was used to perform one-group meta analysis of study arms with the same drug to estimate global rates of success and adverse events with each drug. These estimates were used, when possible, to indirectly compare treatment options, adjusted for CD4 count. Direct comparison was pooled when available. RESULTS: Seventeen studies reporting five treatment regimens and outcome of 920 VL episodes occurring in HIV infected individuals were included. The main outstanding difference in outcome among the treatment regimens was observed in mortality rate: it was around 3 times higher with high dose antimony use (18.4%, CI 95% 13.3-25%), indirectly compared to lipid formulations of amphotericin B treatment (6.1%, CI 95% 3.9-9.4%). It was observed, also by indirect comparison, higher rates of clinical improvement in study arms using amphotericin B than in study arms using pentavalent antimonial therapy (Sb(v)). The parasitological cure, an outcome that presented some degree of risk of selection and verification bias, had rates that varied widely within the same treatment arm, with high heterogeneity, hampering any formal comparison among drugs. One direct comparison of amphotericin and antimoniate was possible combining results of two studies and confirming the superiority of amphotericin. CONCLUSIONS: Available evidence suggests that amphotericin is superior to antimony treatment. Death rate using antimoniate high dose is unacceptably high. Randomized controlled trials are necessary to compare different formulations and doses of amphotericin, alternative therapies and drug combinations. PMID- 23658851 TI - Novel low-cost thermotherapy for cutaneous leishmaniasis in Peru. AB - Thermotherapy is an accepted alternative therapy for new-world cutaneous leishmaniasis, but current heat-delivery modalities are too costly to be made widely available to endemic populations. We adapted a low-cost heat pack named the HECT-CL device that delivers safe, reliable, and renewable conduction heat. 25 patients with cutaneous leishmaniasis completed treatment with the device at an initial temperature of 52 degrees C +/- 2 degrees C for 3 minutes to each lesion, repeated daily for 7 days, and were followed up for 6 months by direct observation. The overall definitive clinical cure rate was 60%. Concurrently, 13 patients meeting minimally significant exclusion criteria received identical compassionate use treatment with a cumulative definitive cure rate of 68.4%, 75% for those who had experienced CL relapse after prior antimonial treatment. Therapy was well tolerated. Reversible second-degree burns occurred in two patients and no bacterial super-infections were observed. HECT-CL is a promising treatment and deserves further study to verify its safety and efficacy as adjuvant and mono- therapy. PMID- 23658853 TI - Imported human rabies cases worldwide, 1990-2012. AB - Sixty cases of human rabies in international travelers were reviewed from 1990 2012. A significant proportion of the cases were observed in migrants or their descendants when emigrating from their country of origin or after a trip to visit friends and relatives or for other reasons (43.3%). The cases were not necessarily associated with long-term travel or expatriation to endemic countries; moreover, cases were observed in travelers after short trips of two weeks or less. A predominance of male patients was observed (75.0%). The proportion of children was low (11.7%). Cases from India and Philippines were frequent (16 cases/60). In a significant proportion of cases (51.1%), diagnosis was challenging, with multiple missed diagnoses and transfers from ward to ward before the final diagnosis of rabies. Among the 28 patients whose confirmed diagnosis was obtained ante-mortem, the mean time between hospitalization and diagnosis was 7.7 days (median time: 6.0 days, range 2-30) including four cases with a diagnosis delayed by 15 or more days. In five cases, a patient traveled through one or more countries before ultimately being hospitalized. Three factors played a role in delaying the diagnosis of rabies in a number of cases: (i) a low index of suspicion for rabies in countries where the disease has been eradicated for a long time or is now rare, (ii) a negative history of animal bites or exposure to rabies, and (iii) atypical clinical presentation of the disease. Clinical symptomatology of rabies is complex and commonly confuses physicians. Furthermore, failure in diagnosing imported cases in more developed countries is most likely related to the lack of medical familiarity with even the typical clinical features of the disease. PMID- 23658852 TI - A novel hyaluronidase from brown spider (Loxosceles intermedia) venom (Dietrich's Hyaluronidase): from cloning to functional characterization. AB - Loxoscelism is the designation given to clinical symptoms evoked by Loxosceles spider's bites. Clinical manifestations include skin necrosis with gravitational spreading and systemic disturbs. The venom contains several enzymatic toxins. Herein, we describe the cloning, expression, refolding and biological evaluation of a novel brown spider protein characterized as a hyaluronidase. Employing a venom gland cDNA library, we cloned a hyaluronidase (1200 bp cDNA) that encodes for a signal peptide and a mature protein. Amino acid alignment revealed a structural relationship with members of hyaluronidase family, such as scorpion and snake species. Recombinant hyaluronidase was expressed as N-terminal His-tag fusion protein (~45 kDa) in inclusion bodies and activity was achieved using refolding. Immunoblot analysis showed that antibodies that recognize the recombinant protein cross-reacted with hyaluronidase from whole venom as well as an anti-venom serum reacted with recombinant protein. Recombinant hyaluronidase was able to degrade purified hyaluronic acid (HA) and chondroitin sulfate (CS), while dermatan sulfate (DS) and heparan sulfate (HS) were not affected. Zymograph experiments resulted in ~45 kDa lytic zones in hyaluronic acid (HA) and chondroitin sulfate (CS) substrates. Through in vivo experiments of dermonecrosis using rabbit skin, the recombinant hyaluronidase was shown to increase the dermonecrotic effect produced by recombinant dermonecrotic toxin from L. intermedia venom (LiRecDT1). These data support the hypothesis that hyaluronidase is a "spreading factor". Recombinant hyaluronidase provides a useful tool for biotechnological ends. We propose the name Dietrich's Hyaluronidase for this enzyme, in honor of Professor Carl Peter von Dietrich, who dedicated his life to studying proteoglycans and glycosaminoglycans. PMID- 23658854 TI - Antileishmanial Activity of Liposomal Clarithromycin against Leishmania Major Promastigotes. AB - OBJECTIVES: Cutaneous leishmaniasis is a common parasitic disease which is endemic in some parts of the world. In vitro and in vivo studies have shown azithromycin efficacy on some Leishmania species. Because of structural similarity between clarithromycin and azithromycin and efficacy of clarithromycin against intracellular organisms and due to the absence of previous studies in this respect, we decided to evaluate the efficacy of clarithromycin against promastigotes of L. major in vitro. MATERIALS AND METHOD: First, liposomal and non- liposomal clarithromycin were prepared, then both forms of the drug were incubated with promastigotes for 24 hr in NNN culture media without red phenol in the presence of 5% FCS with different concentrations as follows: 20, 40, 80, 100, 200 and 500 ug/ml. RESULTS: According to the results, clarithromycin in both liposomal and non- liposomal forms has in vitro activity against the promastigotes of L. major. The concentration of drug that killed 50% of parasites (ED 50) was 169 and 253.6 ug/ml for liposomal and non- liposomal forms, respectively which shows that lower concentrations of liposomal drug are required to have the same effect as non- liposomal drug and the liposomal form of the drug is more effective than non- liposomal form. CONCLUSION: Clarithromycin in both liposomal and non- liposomal forms has in vitro activity against the promastigotes of L. major. PMID- 23658856 TI - First Use of Multiple Imputation with the National Tuberculosis Surveillance System. AB - AIMS: The purpose of this study was to compare methods for handling missing data in analysis of the National Tuberculosis Surveillance System of the Centers for Disease Control and Prevention. Because of the high rate of missing human immunodeficiency virus (HIV) infection status in this dataset, we used multiple imputation methods to minimize the bias that may result from less sophisticated methods. METHODS: We compared analysis based on multiple imputation methods with analysis based on deleting subjects with missing covariate data from regression analysis (case exclusion), and determined whether the use of increasing numbers of imputed datasets would lead to changes in the estimated association between isoniazid resistance and death. RESULTS: Following multiple imputation, the odds ratio for initial isoniazid resistance and death was 2.07 (95% CI 1.30, 3.29); with case exclusion, this odds ratio decreased to 1.53 (95% CI 0.83, 2.83). The use of more than 5 imputed datasets did not substantively change the results. CONCLUSIONS: Our experience with the National Tuberculosis Surveillance System dataset supports the use of multiple imputation methods in epidemiologic analysis, but also demonstrates that close attention should be paid to the potential impact of missing covariates at each step of the analysis. PMID- 23658855 TI - Galectins as cancer biomarkers. AB - Galectins are a group of proteins that bind beta-galactosides through evolutionarily conserved sequence elements of the carbohydrate recognition domain (CRD). Proteins similar to galectins can be found in very primitive animals such as sponges. Each galectin has an individual carbohydrate binding preference and can be found in cytoplasm as well as in the nucleus. They also can be secreted through non-classical pathways and function extracellularly. Experimental and clinical data demonstrate a correlation between galectin expression and tumor progression and metastasis, and therefore, galectins have the potential to serve as reliable tumor markers. In this review, we describe the expression and role of galectins in different cancers and their clinical applications for diagnostic use. PMID- 23658857 TI - Impact of an early education multimedia intervention in managing nutrition related chemotherapy side effects: a pilot study. AB - BACKGROUND: The purpose of the educational intervention was to measure changes in knowledge, perceived benefit of nutrition, and perceived self efficacy in handling side effects of chemotherapy before and after viewing a 15 minute DVD among patients with cancer. METHODS: A convenience sample of 14 (4 male, 10 female, 61 +/- 9 years) patients with cancer, early to chemotherapy, participated in the study. Participants completed a survey with demographic, knowledge items, and perceived health belief and self efficacy statements; viewed the DVD; and were then sent home with a one page handout. Two weeks after the nutrition education intervention, a second survey was completed including an item about tips used. Change was measured using paired t-test and wilcoxon signed rank tests. FINDINGS: The mean score on the four knowledge items significantly increased (p < 0.05). No significant differences were noted in statements intended to evaluate changes in perceived health beliefs. However, perceived knowledge and skills related to managing side effects increased (p < 0.05). All participants responded that the DVD was informative and most (n = 11, 79%) responded that it was useful. The majority reported (n = 10, 71%) a tip they used from the DVD. CONCLUSIONS: This short multimedia nutrition education intervention was found primarily to increase knowledge and could form a useful component of counseling services for patients undergoing chemotherapy. PMID- 23658858 TI - Sub-acute administration of (S)-dimethyl 2-(3-(phenyltellanyl) propanamido) succinate induces toxicity and oxidative stress in mice: unexpected effects of N acetylcysteine. AB - The organic tellurium compound (S)-dimethyl 2-(3-(phenyltellanyl) propanamide) succinate (TeAsp) exhibits thiol-peroxidase activity that could potentially offer protection against oxidative stress. However, data from the literature show that tellurium is a toxic agent to rodents. In order to mitigate such toxicity, N acetylcysteine (NAC) was administered in parallel with TeAsp during 10 days. Mice were separated into four groups receiving daily injections of (A) vehicle (PBS 2.5 ml/kg, i.p. and DMSO 1 ml/kg, s.c.), (B) NAC (100 mg/kg, i.p. and DMSO s.c.), (C) PBS i.p. and TeAsp (92.5 MUmol/kg, s.c), or (D) NAC plus TeAsp. TeAsp treatment started on the fourth day. Vehicle or NAC-treated animals showed an increase in body weight whereas TeAsp caused a significant reduction. Contrary to expected, NAC co-administration potentiated the toxic effect of TeAsp, causing a decrease in body weight. Vehicle, NAC or TeAsp did not affect the exploratory and motor activity in the open-field test at the end of the treatment, while the combination of NAC and TeAsp produced a significant decrease in these parameters. No DNA damage or alterations in cell viability were observed in leukocytes of treated animals. Treatments produced no or minor effects on the activities of antioxidant enzymes catalase, glutathione peroxidase and glutathione reductase, whereas the activity of the thioredoxin reductase was decreased in the brain and increased the liver of the animals in the groups receiving TeAsp or TeAsp plus NAC. In conclusion, the toxicity of TeAsp was potentiated by NAC and oxidative stress appears to play a central role in this process. PMID- 23658859 TI - Targeting PI3K in Cancer: Any Good News? AB - The phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates several cellular processes and it's one of the most frequently deregulated pathway in human tumors. Given its prominent role in cancer, there is great interest in the development of inhibitors able to target several members of PI3K signaling pathway in clinical trials. These drug candidates include PI3K inhibitors, both pan- and isoform-specific inhibitors, AKT, mTOR, and dual PI3K/mTOR inhibitors. As novel compounds progress into clinical trials, it's becoming urgent to identify and select patient population that most likely benefit from PI3K inhibition. In this review we will discuss individual PIK3CA mutations as predictors of sensitivity and resistance to targeted therapies, leading to use of novel PI3K/mTOR/AKT inhibitors to a more "personalized" treatment. PMID- 23658860 TI - Surgical Management for Peyronie's Disease. AB - Peyronie's disease is a common debilitating condition for both men and their partners that results in penile deformity and compromises sexual functioning. While there are a myriad of medical therapeutic options, these have not been demonstrated to correct the deformity and restore sexual function definitively. As such, surgery is the mainstay of treatment for this disease, and multiple surgical approaches may be considered depending on disease characteristics, patient co-morbidity, and findings on preoperative diagnostic testing. The purpose of this review is to highlight the different surgical approaches and different procedures within each approach, and to examine important issues for surgeons to consider for administering the best treatment that restores function while reconciling patient expectations. PMID- 23658861 TI - Current issues in varicocele management: a review. AB - The most common cause of male infertility is varicocele, and varicocele is the most common correctable cause of male factor infertility. In this article we reviewed the concept of varicocele in terms of its diagnosis, method of treatment, indications for treatment, treatment outcomes, and prognostic factors. Physical examination is an essential diagnostic tool in the evaluation of a patient with a varicocele. However, as it depends on subjective findings, standardization of the physical examination method is needed. Various methods for treatment of varicocele exist, including open surgical, laparoscopic, microscopic surgical, and radiologic treatment such as embolization. Among these treatment approaches, microscopic inguinal or subinguinal varicocelectomy has superior outcomes, with a low complication rate. The influence of the treatment of varicocele on fertility is still a controversial issue and a difficult question to address, because there are limitations to performing a randomized control study, and previous studies had a heterogeneity of subjects and high dropout rate. However, there is robust evidence that varicocelectomy improves semen parameters as a surrogate marker of the potential for fertility. To date, general indications for treatment of varicocele are limited in patients with proven infertility, clinical palpable varicocele, and abnormal semen characteristics. Recently, it was shown that some symptoms other than infertility could be an indication for varicocelectomy because these symptoms are frequently related to deterioration of semen parameters. Varicocele in the adolescent presents a more difficult decision regarding whether to treat. A testicular size discrepancy of more than 20% is helpful for treatment decisions. Various prognostic factors were noted in several studies without, however, a consistent consensus. PMID- 23658862 TI - The current role of the artificial urinary sphincter in male and female urinary incontinence. AB - The evolution of the artificial urinary sphincter has affected the current surgical options for urinary incontinence. With its unique features, the artificial urinary sphincter (AUS) has been an attractive option for the treatment of urinary incontinence regardless of gender. The current paper discusses the indications, contraindications, types of devices, surgical approaches, outcomes, and complications of the AUS in the treatment of both male and female urinary incontinence. A PubMed review of the available literature was performed and articles reporting implantation of artificial urinary sphincters for urinary incontinence in both male and female patients were evaluated. There was a comparable satisfactory continence rate after the implantation of an AUS (59~97% in males vs. 60~92% in females). In comparison, there were some differences in the indications, contraindications, surgical approaches, outcomes, and complications of the AUS implanted for urinary incontinence in male and female patients. AUS implantation is a safe and effective surgical option for the treatment of urinary incontinence of various etiologies. Continuous evolution of the device has made it an attractive option for the treatment of both male and female urinary incontinence. PMID- 23658863 TI - Treatment Strategy for Non-Responders to PDE5 Inhibitors. AB - Currently, phosphodiesterase type 5 (PDE5) inhibitors are the initial treatment option for erectile dysfunction. The reported efficacy of PDE5 inhibitors is about 70%, although it is significantly lower in difficult-to-treat subpopulations. Treatment failures might be due to the severity of the underlying pathophysiology, improper use of medication, unrealistic patient expectations, difficult relationship dynamics, severe performance anxiety, and other psychological problems. Physicians must address these issues to identify true treatment failures attributable to the drugs. This article discusses factors that might affect the response to PDE5 inhibitors and develops a strategy to maximize the overall efficacy of PDE5 inhibitors in initial non-responders to PDE5 inhibitors. PMID- 23658864 TI - Clinical Significance of Wnt/beta-Catenin Signalling and Androgen Receptor Expression in Prostate Cancer. AB - PURPOSE: To investigate the relationships among the Wnt/beta-catenin pathway, androgen receptor (AR), and clinicopathological factors in hormone-naive prostate cancer. MATERIALS AND METHODS: This study was conducted with132 cases of hormone naive prostate cancer treated by prostatectomy and prostate needle biopsy. An immunohistochemical study using antibodies against beta-catenin, matrix metalloproteinase-7 (MMP-7), and the AR was performed. For the in vitro study, PC 3, LNCaP, 22Rv1, and DU145 cell lines were used. RESULTS: The clinical or pathological stage ware a localized cancer in 36 patients (27.3%), locally advanced cancer in 31 (23.5%), and metastatic cancer in 65 (49.2%). We detected increased beta-catenin, AR, and MMP-7 expression with a high Gleason grade, disease progression, and increasing serum prostate-specific antigen (PSA) levels (p<0.01). In Spearman's rank correlations, the expression of cytoplasmic beta catenin, MMP-7, and the AR were found to be significantly positively correlated. In addition, the expression of beta-catenin, MMP-7, and the AR were significantly correlated with clinicopathological variables indicative of a poor prognosis. Forty-nine patients with primary androgen deprivation had short response durations from hormone therapy to PSA progression with elevated MMP-7 expression on the Kaplan-Meier curve (p=0.0036). CONCLUSIONS: These data show that an activated Wnt/beta-catenin pathway and AR expression in prostate cancer are correlated with metastasis and aggressiveness. In addition, the expression of MMP 7 protein, a target of the Wnt/beta-catenin pathway, is associated with PSA progression in prostate cancer patients undergoing primary hormone therapy. PMID- 23658865 TI - Testosterone replacement alone for testosterone deficiency syndrome improves moderate lower urinary tract symptoms: one year follow-up. AB - PURPOSE: To evaluate the actual impact of testosterone replacement therapy (TRT) on patients with lower urinary tract symptom (LUTS), without benign prostate hyperplasia (BPH) medication. MATERIALS AND METHODS: Two hundreds forty-six patients underwent TRT using intramuscular injection of 3 months bases injection of testosterone 100 mg undecanoate over a year. Among them, 17 patients had moderate LUTS with a maximal flow rate of at least 10 ml/s but did not take any BPH-specific medication during TRT. The changes in prostate specific antigen (PSA), International Prostate Symptom Score (IPSS), and uroflowmetery were measured before and after TRT. RESULTS: After TRT, PSA remained unchanged after a year of treatment (p=0.078). Compared with their counterparts (n=229), the patients without BPH medication had similar baseline prostate characteristics in all variables, including prostate volume, IPSS, maximal flow rate, voiding volume, and PSA, except the median amount of residual urine, which was higher in the patients without BPH medication (21 ml vs. 10 ml). In the no-BPH medication group, the total IPSS score was decreased significantly (p=0.028), both in storage symptoms (questionnaire 2, 4, 7) and voiding symptoms (questionnaire 1, 3, 5, 6), while the maximal flow rate and residual urine amount remained unchanged after a year of TRT. During the median follow up of 15.1 months, no patients experienced urinary retention, BPH-related surgery, or admission for urinary tract infection. CONCLUSIONS: Over a year of TRT for the no-BPH medication patients with moderate LUTS and maintained a relatively high maximal flow rate and improved both storage and voiding symptoms, without the clinical progression of BPH or rising PSA. PMID- 23658866 TI - The Relationship between Clinical Symptoms and Urine Culture in Adult Patients with Acute Epididymitis. AB - PURPOSE: We evaluated adult patients with acute epididymitis to identify the frequency of actual sexual contacts and the causative organism, and compared clinical examinations, degrees of manifested symptoms, and radiological test results. MATERIALS AND METHODS: We reviewed the medical records of 65 patients older than 18 years presenting with acute epididymitis who had been treated between 2002 and 2011. Scrotal ultrasonography, urinalysis, and urine culture were performed to diagnose the acute epididymitis. Patients were divided into negative (n=45) and positive (n=20) urine culture groups. Then the latter groups were subdivided into a sexually transmitted organism (STO) culture group (n=13) and a non-STO (n=7) culture group. Data on any history of sexual contact, scrotal pain and tenderness, symptoms of urethritis (discharge, dysuria, urethral burning, or irritation), and lower urinary tract symptoms (dysuria, frequency, and urgency of urination) were obtained from all of the subjects. RESULTS: Patients in the positive urine culture group were significantly younger than those in the other group (p=0.224) and were more likely to have a history of sexual contact at least two weeks prior to onset of epididymitis (p=0.012). They had also a significantly enlarged epididymal head and significantly more severe complaints of pain or tenderness than those of latter group (p=0.348, p=0.288). However, the difference in these measures between the STO and non-STO group was not significant, except in the case of age (p=0.044). CONCLUSIONS: Patients of the positive urine culture group with acute epididymitis were significantly younger and more sexually active than the others. They also had severe pain or tenderness and an enlarged epididymal head. There was a close association between clinical symptoms, a positive urine culture, and ultrasonographic findings. PMID- 23658867 TI - Preoperative predictors of varicocelectomy success in the treatment of testicular pain. AB - PURPOSE: We performed the present study to evaluate the prognostic factors for the surgical outcome of varicocelectomy in the treatment of a painful varicocele. MATERIALS AND METHODS: A total of 77 patients undergoing varicocelectomy were enrolled. All the patients were examined for body mass index (BMI), varicocele grade, testosterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), semen analysis, maximal vein diameter, and discrepancy of testicular volume. At a follow-up visit 3~6 months after the surgery, the patient response was graded as a complete response, partial response, or no response. The resolution of pain was defined as a complete or partial response. We used logistic regression analyses to determine the preoperative factors for predicting a complete response and the resolution of pain. RESULTS: Ten subjects were lost to follow-up. The remaining 67 patients were included in this study. The pain was completely resolved in 47.8% of patients, partial resolution was observed in 25.4% of patients, and failure was reported in 26.9% of patients. Among the parameters, only a longer duration of pain (>=3 months) was an independent factor related to the complete response of pain (odds ratio, 7.371; p=0.010) and the resolution of pain (odds ratio, 7.209; p=0.042). The parameters of semen analysis results, testosterone, LH, FSH, BMI, grade, ultrasonography results, and the type of surgical approach did not significantly predict the resolution of pain. CONCLUSIONS: The duration of pain (>=3 months) was an independent prognostic factor for the complete response of pain and the resolution of pain. PMID- 23658868 TI - Effect of Transurethral Resection of the Prostate on Storage Symptoms in Patients with Benign Prostatic Hyperplasia of Less than 30 ml. AB - PURPOSE: Many patients with benign prostatic hyperplasia (BPH) have not only voiding symptoms but also storage symptoms. Despite the many types of treatment that have been developed for BPH, storage symptoms persist. We conducted an assessment of the efficacy of transurethral resection of the prostate (TURP) and the change in the International Prostate Symptoms Score (IPSS) storage sub-score after the procedure according to prostate size in patients with BPH. MATERIALS AND METHODS: Men aged 50 years or older who had BPH were enrolled in this study. 186 patients were divided into two groups according to prostate size measuring using transrectal ultrasonography: In group 1, prostate size was less than 30 ml (51 patients), and in group 2, prostate size was greater than 30 ml (135 patients). All of the patients underwent TURP. We examined whether the degree of change in the IPSS, voiding symptoms, storage symptoms, and quality of life (QoL) differed before and after TURP and according to prostate size. RESULTS: After three months of TURP, the subjects in both groups showed significant improvement in the IPSS, voiding symptoms, storage symptoms, QoL, and maximum flow rate (p<0.05). The scores for the IPSS, voiding symptoms, storage symptoms, and QoL of group 1 and 2 after three months of TURP were 16.36, 14.25 (p=0.233), 8.21, 8.24 (p=0.980), 8.11, 5.16 (p=0.014), 2.89, and 2.10 (p=0.030), respectively. CONCLUSIONS: TURP is an effective treatment for patients with BPH, regardless of prostate size. However, while the improvement in the storage symptoms of patients with a prostate size of less than 30 ml was not significant, it was in patients with a prostate size greater than 30 ml. PMID- 23658869 TI - Self-Reported Prevalence of and Attitudes toward Premature Ejaculation in a Community-Based Study of Married Couples. AB - PURPOSE: We evaluated the self-reported prevalence of and attitudes toward premature ejaculation (PE) in a community-based study of married couples. MATERIALS AND METHODS: A community-based cross-sectional study of PE was conducted among married couples in Gwangju, Korea. Self-reported data were collected through the use of questionnaires, which included demographic questions, the Premature Ejaculation Diagnostic Tool (PEDT), the intravaginal ejaculation latency time (IELT), patient-reported outcome (PRO), and the Female Sexual Function Index (FSFI). RESULTS: Of the 290 couples who completed the survey, the prevalence of PEDT-diagnosed PE including probable PE was 23.7% of men. By IELT measure, the prevalence of PE was 21.7% as reported by the men and 23.9% as reported by their partners, respectively. PRO responses indicated that control over ejaculation and severity of PE were not reported significantly differently by the men and their partners. Satisfaction with sexual intercourse was poorer for the men's partners than for the men. Personal distress and interpersonal difficulty were higher for the men than for their partners. The partners of men in the PE group had significantly lower FSFI scores than did the partners of men in the non-PE group. CONCLUSIONS: The reporting of the prevalence of PE did not differ significantly between the men in this study and their partners. However, PE in men tended to impact their partners' sexual function. PMID- 23658870 TI - Stuttering priapism in a patient with neurosyphilis. AB - We recently encountered a case of stuttering priapism in a 41-year-old patient with neurosyphilis. Priapism very rarely has a neurogenic cause, and to our knowledge, priapism caused by neurosyphilis has not been reported previously in the literature. Our aim was to report this case and systematically review the related literature. PMID- 23658871 TI - Multiple intratesticular cysts. AB - Intratesticular cysts, once thought to be a rarity, are now being reported with an increasing prevalence as a result of the wider use of scrotal ultrasound scanning. Despite greater understanding of intratesticular cysts, their management remains unclear. Treatment has included enucleation and even radical orchiectomy over fear of the possibility of an associated malignancy. A more conservative approach with serial ultrasound scanning has been advocated if a clear distinction can be made between neoplastic and non-neoplastic testicular cysts. However, in view of the benign nature of such cysts, even repeated ultrasound scanning may not be necessary and may be considered over-treatment. In this study we present clinical and morphological characteristics of multiple cysts in the right testicle in a 62-year-old patient, where a slightly nodular lesion in the right testicle was detected. PMID- 23658872 TI - Effect of antioxidants and nitric oxide on activity of peritoneal macrophages in albino rats during normal pregnancy. AB - We compared activity of peritoneal macrophages in rats during normal pregnancy and under the action of NO-synthase inhibitor L-NAME, of E. coli LPS, SOD, and alpha-tocopherol analogue trolox. In non-pregnant rats, E. coli LPS stimulated peritoneal macrophages, while L-NAME produced a dose-dependent effect. During pregnancy, E. coli LPS activated phagocytosis, while antioxidants trolox, SOD, and L-NAME produced an inhibitory effect. PMID- 23658873 TI - Involvement of translation and transcription processes into neurophysiological mechanisms of long-term memory reconsolidation. AB - We studied the involvement of translation and transcription processes into behavioral and neuronal mechanisms of reconsolidation of the long-term memory of the conditioned taste aversion in edible snails. Injection of cycloheximide (an inhibitor of protein synthesis) to the snails in 48 h after training combined with subsequent reminder and presentation of the conditional stimulus resulted in the development of persistent amnesia and depression of the responses of the defensive behavior command neurons LPl1 and RPl1 to the conditional stimulus. Injection of mRNA synthesis inhibitors actinomycin D or DRB (5,6-dichloro-1-beta D-ribofuranosylbenzimidasole) in 48 h after conditioning with subsequent reminding procedure produced no effects on memory retention and on the responses of the command neurons to the conditional stimulus. The study suggests that the proteins translated from previously synthesized and stored mRNA were involved in the mechanisms of reconsolidation of the memory responsible for conditioned taste aversion. PMID- 23658874 TI - Involvement of alpha-adrenoceptors to the implementation of the contractile effects in the capsule of mesenteric lymph nodes in response to electrostimulation. AB - We studied changes in the contractile function of smooth muscle cells in bovine mesenteric lymph node capsule caused by electrical stimulation of nerve fibers in vitro. It was found that electrostimulation increased tonic tension and frequency of smooth muscle contractions in the node capsule. Tetrodotoxin prevented the stimulatory effect of electrical stimulation on the smooth muscle cells. Phentolamine, prazosin, and yohimbine significantly reduced the capsule response to electrical stimulation and norepinephrine application. It was concluded that excitation of nerve fibers in the capsule of bovine mesenteric lymph nodes upon electrical stimulation is realized, at least in part, via activation of alpha1 adrenoceptors and, to a lesser extent, via alpha2-adrenoceptors located on the membrane of smooth muscle cells. PMID- 23658875 TI - The role of experimental maternal liver pathology in the development of physiological immaturity in the offspring. AB - We compared the parameters of physiological maturity in the offspring of albino Wistar rats with experimental chronic liver disease of various genesis (toxic, autoimmune, and alcoholic). It was found that chronic liver disease in female rats can be a cause of physiological immaturity of the offspring (increased stillbirth rate, reduced viability, and delayed disappearance of immaturity). PMID- 23658876 TI - Analysis of the application of MMP-9 inhibitor in skin melanoma: experimental study. AB - Experiment on C57Bl/6 mice with modeled skin melanoma showed that selective inhibition of matrix metalloproteinase-9 increased lifetime and reduced the number of PCNA(+) tumor cells and intensity of neoangiogenesis. Inhibition of matrix metalloproteinase-9 prevented tumor necrosis. The results suggest that matrix metalloproteinase-9 is involved not only in the regulation of extracellular matrix degradation, but also in the processes of cell proliferation and neoangiogenesis in skin melanoma. Therefore, this enzyme can be considered as a potential therapeutic target. PMID- 23658877 TI - Role of proinflammatory factors, nitric oxide, and some parameters of lipid metabolism in the development of immediate adaptation to hypoxia and HIF-1alpha accumulation. AB - The development of immediate and delayed long-term resistance to hypoxia during a course of intermittent normobaric hypoxia (15 daily sessions of alternating exposure to 10% O2 and atmospheric air for 1 h) correlated with biphasic expression of HIF-1alpha in neocortex of hypoxia-intolerant rats, which suggests involvement of this protein factor not only in the formation of long-term adaptation, but also in triggering immediate adaptation to hypoxia. Both processes develop under conditions promoting down-regulation of oxidative modification of LDL and increasing tolerance of biological membranes to hypoxia in the absence of activation of the free radical processes, which therefore do not trigger HIF-1alpha expression under these conditions. Neither cytokines nor NO are the inducers of immediate adaptation, and they are not related to HIF 1alpha expression during the early post-hypoxic period. In contrast, long-term adaptation in response to the course of intermittent normobaric hypoxia develops against the background of enhanced NO production, activation of pro- and anti inflammatory factors, and expression of VEGF, the marker of angiogenesis. Therefore, all these factors can promote activation of transcription processes required to form the long-term adaptation. PMID- 23658878 TI - Role of nitric oxide in the pathogenesis of alloxan diabetes. AB - We studied the effects of N(w)-nitro-L-arginine (L-NNA), a nonselective inhibitor of NO synthases, on the severity of type 1 diabetes mellitus induced by subcutaneous injection of 130 mg/kg alloxan in August rats with high activity of NO system and in Wistar rats. Five days after alloxan injection, hyperglycemia levels after overnight fasting in August and Wistar rats were 27.1+/-3.7 and 22.0+/-1.1 mmol/liter, respectively (p<0.03). The mortality over 15 days after alloxan injection in August rats was higher than in Wistar rats (36 and 26%, respectively). L-NNA normalized glucose levels in diabetics of both groups. It completely prevented mortality in August and reduced it to 13% in Wistar rats. Body weight loss and polydipsia after L-NNA injection were also less pronounced in August rats. Plasma nitrite/nitrate concentrations in August rats were 32% higher than in Wistar rats, both in intact and diabetic rats. These data attest to an important role of NO in the pathogenesis of alloxan diabetes. PMID- 23658879 TI - Benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine, a prolyl endopeptidase inhibitor, modulates depression-like behavior of rats in forced swimming test and activities of proline-specific peptidases in the brain structures. AB - High activities of prolyl endopeptidase and dipeptidylpeptidase IV in the striatum and of prolyl endopeptidase in the frontal cortex were recorded in rats with stress-induced depression-like state (behavioral despair) developed in the Porsolt forced swimming test. Acute injection of benzyloxycarbonyl-methionyl-2(S) cyanopyrrolidine (prolyl endopeptidase noncompetitive synthetic inhibitor) in a dose of 1 mg/kg prevented the development of behavioral despair and the increase of prolyl endopeptidase and dipeptidylpeptidase IV activities in the brain structures. In a dose of 2 mg/kg prolyl endopeptidase inhibitor did not modify the development of behavioral despair, but prevented the increase of prolyl endopeptidase and dipeptidylpeptidase IV activities in the striatum. PMID- 23658880 TI - Dysfunction of membrane-receptor system of blood cells and kidney tissue in experimental diabetes mellitus. AB - The effect of streptozotocin-induced diabetes mellitus on some parameters of energy metabolism and functional status of cell membranes was studied in experiments on rats. It was found that the development of diabetes mellitus is associated with dramatic changes in the metabolism of blood cells and kidney tissue: inhibition of aerobic ATP synthesis, accumulation of lactate, uncoupling of oxidative phosphorylation, and development of lactic acidosis. Diabetes mellitus leads to restructuring of membrane lipids, changes in microviscosity, and suppression of insulin receptors and membrane-bound Na(+), K(+)-ATPase, and Ca(2+)-ATPase. Sharply increased levels of LPO products and lactic acidosis during DM indicate an imbalance in the LPO-antioxidant system and development of oxidative stress. PMID- 23658881 TI - Effects of phospholipid hepatoprotectors on apoptosis during experimental liver pathology induced by isoniazid and paracetamol. AB - Phospholipid hepatoprotectors essentiale, eplir, and their combinations with succinic acid decreased the relative content of apoptotic lymphocytes and granulocytes in the blood, content of TNF-alpha, total and indirect bilirubin, and activities of transaminases and alkaline phosphatase and increase the content of IL-10 in rats with experimental intoxication induced by isoniazid and paracetamol. A combination of eplir and succinic acid was most effective in preventing the development of leukocyte apoptosis. PMID- 23658882 TI - Iron-containing proteins lactoferrin and ferritin in biological media of patients with pulmonary tuberculosis. AB - Salivary and serum levels of lactoferrin and ferritin were measured in patients with pulmonary tuberculosis and patients with other nonspecific respiratory diseases. Measurements of lactoferrin in biological media and particularly in the serum of patients with pulmonary tuberculosis proved to be a highly informative test for monitoring the disease course, i.e. for evaluation of inflammatory process activity. Ferritin level can serve as an indicator of tissue destruction during inflammation and of the course of rehabilitation processes. PMID- 23658883 TI - Plasma lipoproteins as a transport form of extracellular DNA. AB - We showed DNA-binding activity of different classes of plasma lipoproteins in rats and humans. Experiments with fluorescent dye Hoechst 33258 showed that about 12% extracellular plasma DNA is present in circulating lipoproteins complexes; 7 8% of them with HDL. Structural HDL protein apoA-I probably plays the major role in the interaction between extracellular DNA and lipoprotein particle. Participation of lipoproteins in the transport of extracellular DNA can be considered as an important mechanism for elimination of nucleic acids from blood plasma. PMID- 23658884 TI - Lipofuscin component A2E does not reduce antioxidant activity of DOPA-melanin. AB - We studied the capacity of DOPA-melanin (natural eumelanin analog) to bind chromophore A2E of retinal pigmented epithelial cell lipofuscin granule into complexes. DOPA-melanin bound up to 200 nm A2E per 1 mg polymer; antioxidant activity of the resultant complexes was evaluated. Luminol chemiluminescence quenching in the presence of hydrogen peroxide showed that the chemiluminescence latency/concentration constants were virtually the same for DOPA-melanin and its A2E complexes. Comparison of the inhibitory effects of DOPA-melanin and DOPA-A2E complexes by rate of UV-induced peroxidation of the outer segments of photoreceptor cells showed higher inhibitory activity of the complexes in comparison with pure DOPA-melanin. Antioxidant activity of DOPA-A2E complexes towards Fe(2+)-ascorbate-induced peroxidation of the outer segments of photoreceptor cells was also higher than that of DOPA-melanin. The results indicated that chromophore A2E of lipofuscin granules in the studied concentrations did not attenuate the antioxidant effects of DOPA-melanin and even potentiated it. This suggested that A2E excess in retinal pigmented epithelium cells could be bound by melanosome melanin and lose its toxicity. PMID- 23658885 TI - Content of vitamins B1 and B2 in germinating grain. AB - The content of vitamin B1 in wheat and rye grain remained at a constant level and that of vitamin B2 gradually increased during germination over 5 days at 20 degrees C (in the dark). Significant difference was observed for rye within 1 day and for wheat in 2 days. By day 5, the content of vitamin B2 in both crops increased by 2.7-2.9 times above the baseline value. PMID- 23658886 TI - The role of mitochondria in the development of radiation-induced oxidative stress in K562 leukemia cells. AB - Radiation-induced accumulation of active oxygen species and the role of the mitochondria in this process were studied on cultured K562 leukemia cells. Intracellular concentrations of active oxygen species in the presence of rotenone and without it and the mitochondrial potential were analyzed 15, 30 min, 1, 4, 8, 12, 24, and 48 h after X-ray exposure in doses of 4 and 12 Gy. Radiation-induced generation of active oxygen species had two time peaks: 30 min and 24 h after the exposure. Addition of rotenone reduced the levels of active oxygen species 24 and 48 h after the exposure. Increase of active oxygen species concentrations was paralleled by an increase of the mitochondrial potential. The mitochondria were responsible for the increase in the concentrations of active oxygen species 12-48 h after irradiation. PMID- 23658887 TI - Nitric oxide level in the rat tissues increases after 30-day hypokinesia: studies by electron paramagnetic resonance (EPR) spectroscopy. AB - Studies by EPR spectroscopy showed that 30-day exposure of rats to augmenting hypokinesia led to a 3-fold increase in nitric oxide (NO) production in the heart and 2-fold in the liver. These results indicated that long-term hypokinesia stimulated NO synthesis. PMID- 23658888 TI - Cold-induced activities of cytochromes P450 1A1 and 1A2 in rat liver: putative role of endogenous compounds in induction mechanism. AB - Adaptation to cold includes adaptive changes at the organism and molecular levels. One of the interesting facts is induction of cytochromes P450 subfamily 1A (CYP1A) in the liver of rats, inducible enzymes participating in biotransformation of procarcinogenic xenobiotics, under the effect of moderate cold exposure. Cold activation of CYP1A can be mediated by adaptive changes and the resultant redistribution or intensification of the synthesis of mediator compounds. This hypothesis is verified in the present study. The role of bilirubin, tocopherol, and corticosterone as mediators of cold induction of CYP1A in the rat liver was evaluated. The results indicate that these compounds can be involved in cold induction of CYP1A, but none of them is the only mediator in this process. PMID- 23658889 TI - Original nerve growth factor mimetic dipeptide GK-2 limits the manifestations of hemorrhagic stroke in rats. AB - The protective effects of a new low-molecular-weight mimetic of nerve growth factor hexamethylene diamide bis-(N-monosuccinyl-L-glutamine-L-lysine; GK-2) were studied on the experimental model of hemorrhagic stroke (intracerebral posttraumatic hematoma) in rats. Intraperitoneal injections of GK-2 in a dose of 1 mg/kg 4 and 24 h after surgery and 24 h before testing the CNS function on days 3, 7, and 14 prevent death of experimental animals, reduce the neurological deficit, and normalized behavior. PMID- 23658890 TI - Evaluation of hepatoprotective activity of water-soluble polysaccharide fraction of Stellaria media L. AB - Therapy of rats with CCl4 hepatitis with Stellaria media L. water-soluble polysaccharide fraction in a dose of 100 mg/kg reduces serum activities of transaminases (ALT and AST), alkaline phosphatase, bilirubin, and the thymol test values. In the liver, the density of inflammatory infiltration of the organ parenchyma, total count of necrotic hepatocytes, fatty and protein degeneration are reducing. Hence, water-soluble polysaccharide fraction, isolated from the terrestrial part of Stellaria media L., is characterized by hepatoprotective activity. PMID- 23658891 TI - Studies of antimutagenic effects of vitamins A and C in humans. AB - We studied antimutagenic effects of vitamins A and C (in recommended daily doses for 30 days) and their effects on the kinetics of human buccal epitheliocytes. Buccal swab specimens were collected in 29 students before and after vitamin course. The cytogenetic parameters (cells with micronuclei and protrusions) and parameters of proliferation (binuclear cells and cells with double nuclei) and nucleus destruction (karyopyknosis, karyorrhexis, karyolysis, etc.) were analyzed. The levels of cells with micronuclei and total level of cytogenetic disorders decreased by 38% after vitamin course, which confirmed their antimutagenic effect. A slight increase in the percentage of apoptotic cells seemed to reflect more active process of elimination of genetically damaged cells. PMID- 23658892 TI - Coexpression of two mRNA isoforms of insulin-like growth factor-1 gene and mRNA of YB-1 gene in patients with multiple myeloma. AB - Coexpression of two mRNA isoforms for insulin-like growth factor-1 (IGF-1A and IGF-1B) and expression of YB-1 mRNA were analyzed in the bone marrow aspirates from 19 patients with multiple myeloma. It was shown that mRNA isoforms for IGF 1A and IGF-1B were mainly expressed in samples with hyperexpression of YB-1 mRNA, and, on the contrary, practically were not expressed (except sporadic cases) in samples with low level of YB-1 mRNA expression. Coexpression of mRNA isoforms for IGF-1A and IGF-1B were observed in 80% patients with multiple myeloma. PMID- 23658893 TI - Preparation of Fab-fragments of GD2-specific antibodies and analysis of their antitumor activity in vitro. AB - Monoclonal antibodies ME361 specific to ganglioside GD2 were isolated from the conditioned medium of hybridoma HB9326 and mouse ascitic fluid by the method of affinity chromatography; their Fab-fragments were obtained by proteolytic cleavage with papain. Evaluation of Fab-fragment specificity by flow cytometry and dot-blot analysis showed that binding effectiveness of fragments with antigens was close to that for the full-length molecule of antigen. It was shown that Fab-fragments and whole antibodies ME361 dose-dependently inhibit the proliferation of cells of mice T-lymphoma EL-4, and induce apoptosis of these cells 24 h after incubation. PMID- 23658894 TI - Mutagenic activation reduces carcinogenic activity of ortho-aminoazotoluene for mouse liver. AB - Pentachlorophenol (aromatic amine and azo stain metabolic stimulation inhibitor) reduced the hepatocarcinogenic activity of 4-aminoazobenzene and reduced that of ortho-aminoazotoluene in suckling mice. Both 4-aminoazobenzene and ortho aminoazotoluene exhibited mutagenic activity in Ames' test in vitro on S. typhimurium TA 98 strain with activation with liver enzymes; this mutagenic activity was similarly suppressed by adding pentachlorophenol into activation medium. Induction of xenobiotic metabolism enzymes, stimulating the mutagenic activity of ortho-aminoazotoluene, suppressed its carcinogenic effect on mouse liver. Hence, ortho-aminotoluene (the initial compound), but not its mutagenic metabolites, was the direct active hepatocarcinogen for mice. PMID- 23658895 TI - The mechanism of cytostatic effect of a new somatostatin analog cifetrelin on in vitro cultured MCF-7 breast carcinoma cells. AB - The mechanisms of antitumor effect of cifetrelin have been studied in vitro on cultured MCF-7 breast carcinoma cells. Cifetrelin exhibits higher cytotoxic activity than native somatostatin. In subthreshold concentrations, cifetrelin boosts the apoptotic effects of drugs, e.g. adriamycin. Cifetrelin-induced apoptosis develops by the p53-independent mechanism and is associated with early suppression of NF-kappaB activity. These data attest to high antitumor activity of cifetrelin. PMID- 23658896 TI - Magnetofection of human somatic cells with magnetite and cobalt ferrospinel nanoparticles. AB - Superparamagnetic nanoparticles varying by their chemical composition and synthesis method were used to transfer DNA into somatic cells under the influence of constant magnetic field (method of magnetofection). Magnetite particles obtained by mechanochemical synthesis ensured higher expression of the marker gene GFP (evaluated by fluorescence intensity of the cell lysate) then particles of ferric oxide obtained by chemical co-precipitation and cobalt ferrospinel particles obtained by the mechanochemical method. PMID- 23658897 TI - Changes in plasma levels of serotonin and 5-hydroxyindoleacetic acid and population of serotonin-secreting cells in small and large intestine of Wistar rats in hypo- and hyperandrogenemia. AB - We studied the effects of hypo- and hyperandrogenemia on the plasma levels of serotonin and its major metabolite 5-hydroxyindoleacetic acid as well as on the size of EC1 cell pool in the small and large intestine of adult male Wistar rats in the control group, after orchiectomy, and after administration of long-acting testosterone Omnadren 250. Orchiectomy did not change the levels of serotonin, 5 hydroxyindoleacetic acid, and the number of AN-1-cells in the epithelium of the small and large intestine. Administration of Omnadren 250 increased serum level of free testosterone and reduced plasma serotonin concentration; the level of 5 hydroxyindoleacetic acid remained unchanged and hence the rate of serotonin metabolism increased. Hyperandrogenemia significantly reduced the number of AN-1- in the jejunum and ileum and did not change this parameter in the duodenum and colon. PMID- 23658898 TI - Effect of peptides Lys-Glu-Asp-Gly and Ala-Glu-Asp-Gly on the morphology of the thymus in hypophysectomized young and old birds. AB - Investigations were carried out on chicks of different age. It was found that the most pronounced changes in the morphology of the thymus occurred after neonatal hypophysectomy. These changes are least pronounced in old chicks. Peptides Lys Glu-Asp-Gly and Ala-Glu-Asp-Gly synthesized on the basis of amino acid composition of peptide complexes of the anterior and posterior pituitary lobes administered to hypophysectomized birds regardless of age promoted recovery of the morphological structures of the thymus. The anterior pituitary peptide (Lys Glu-Asp-Gly) had more pronounced effect on the recovery of thymic structure than posterior pituitary peptide (Ala-Glu-Asp-Gly). PMID- 23658899 TI - Effect of dopamine on Ehrlich ascites carcinoma cells. AB - Morphological studies showed that daily intraperitoneal injections of dopamine in doses of 10(-2)and 10(-1)M down-regulates the general number of cells in the Ehrlich ascites carcinoma in 10 and 30 times and decreases their diameter by 27% and 59%, respectively (as compared to the control animals received physiological saline). According to ultrastructural data these injections were followed by the abnormal changes in microvilluses, forming the specific moire fringes in cytosol, thickening of cortical layer, and a significant increase in filament reticulum density (actin fibers) in tumor cells of treatment group specimens. We concluded that the oncocytotoxic effect of dopamine was related to the induced polymerization of cytosol actin. PMID- 23658900 TI - Morphological study of burn wound healing with the use of collagen-chitosan wound dressing. AB - Experiments on the model of thermal skin burn in rats showed that the use of wound dressing based on collagen-chitosan complex Kollakhit-Bol in local treatment of grade IIIb skin burns increased healing rate by accelerating the formation of granulation and fibrous connective tissues and reducing crust thickness in comparison with Kollakhit coating. Kollakhit-Bol provided targeted stimulation of reparative processes in the treatment of grade IIIb burns by creating favorable conditions for grafting full thickness skin transplant or dermal-epidermal skin equivalent. In the topical treatment of thermal burn, Kollakhit-Bol application shortened the phases of alteration and exudation and accelerated transition to the productive phase of the inflammatory process with phagocytosis and neoangiogenesis activation. PMID- 23658901 TI - Statistic parametric mapping of changes in gene activity in animal brain during acoustic stimulation. AB - We analyzed the expression of transcription factor c-Fos induced by neural activity in the mouse brain after acoustic stimulation. The brain sections of the animals subjected to acoustic stimulation and controls were immunohistochemically stained for c-Fos protein. Statistical parametric mapping (SPM) was used to identify group differences in the acquired images. c-Fos expression was significantly higher in the auditory cortex, amygdala, and hippocampus CA3 area after tone presentation. The proposed combination of SPM with molecular biological approach to visualization of transcription in the nerve cells makes it possible to identify the collaborative activation of distant brain structures assumed to be the components of united functional systems. PMID- 23658902 TI - Neurovisualization of the dynamics of real and simulation biofeedback: functional magnetic resonance imaging study. AB - On-line brain mapping in subjects operating a competitive virtual gameplay was performed using functional magnetic resonance imaging. The interaction between the brain and visceral systems was studied on the model of real and simulated adaptive biofeedback. The immersion into a virtual story leads to a large-scale activation of cortical regions characterized by high values of voxels in the midtemporal, occipital, and frontal areas as well as in cingulate gyrus, cuneus, and precuneus (Brodmann areas 6, 7, 9, 10, 19, 24, 32, 39, 40, 45). The maximum increase in activity was observed during stage 2 of the game biofeedback, when the volumes of activated voxels increased several times in comparison with the starting phase. Qualitative characteristics of real and imitation game periods are discussed. PMID- 23658903 TI - Dynamic mapping of brain and cognitive control of virtual gameplay (study by functional magnetic resonance imaging). AB - Using functional magnetic resonance imaging technique, we performed online brain mapping of gamers, practiced to voluntary (cognitively) control their heart rate, the parameter that operated a competitive virtual gameplay in the adaptive feedback loop. With the default start picture, the regions of interest during the formation of optimal cognitive strategy were as follows: Brodmann areas 19, 37, 39 and 40, i.e. cerebellar structures (vermis, amygdala, pyramids, clivus). "Localization" concept of the contribution of the cerebellum to cognitive processes is discussed. PMID- 23658904 TI - Nociceptive thresholds in rats in response to lipopolysaccharide injection into the specific nuclei of the thalamus of the brain. AB - Microinjections of LPS into the specific nuclei of rat thalamus (ventrobasal thalamic nuclei VPL and VPM) slightly increased perceptual component and significantly decreased emotional component of systemic nociceptive response. PMID- 23658905 TI - Reaction of the adrenal cortex to graded exercise in children with different initial tonus of the autonomic nervous system. AB - It was found that the response of the adrenal cortex to graded bicycle exercise in children depends on the initial autonomic tonus and is adequate to the background excretion level of hormone metabolites. Seven-year-old sympathotonic girls with increased excretion of 17-hydroxycorticosteroids at rest demonstrated the lowest increase in this parameter after exercise in comparison with more pronounced increment in vagotonics with relative low initial level of glucocorticoid metabolites. Enhanced excretion of glucocorticoid metabolites with a decrease in androgens observed in 9-year-old sympathotonic girls attests to predominance of catabolic processes over anabolic ones and low efficiency of switching from muscle exercise to recovery in children. PMID- 23658906 TI - Phenotypic features of the dynamics of HIF-1alpha levels in rat neocortex in different hypoxia regimens. AB - There are tissue-specific and phenotypic differences in the basal levels of HIF 1alpha under normoxic conditions. Induction of short-term adaptation to hypoxia and formation of long-term adaptation are genetically determined. These phenomena are observed only in animals with low resistance to hypoxia and are associated with biphasic expression of HIF-1alpha in the neocortex only during hypoxic preconditioning. Severe hypoxia disorders HIF-1alpha expression and impairs the formation of short-term and long-term resistance. In animals with high resistance to hypoxia, neither short-term nor long-term resistance develops in response to hypoxic exposure, and this correlates with the absence of changes in post-hypoxic HIF-1alpha levels in the neocortex. PMID- 23658907 TI - Anticoagulant effects of arginine-containing peptide Arg-Pro-Gly-Pro under conditions of immobilization stress. AB - Anticoagulant, fibrinolytic, and antiplatelet effects of RPGP peptide were found in animals under stress conditions caused by single or repeated immobilization. The observed properties of the peptide extend the study of agents protecting the organism under conditions of hypercoagulation occurring under stress conditions and help to re-evaluate the role of glyprolines as contributors to the maintenance of adaptation capacities in various pathologies. PMID- 23658908 TI - Lipid peroxidation and antioxidant system in erythrocytes of patients with renal cell carcinoma. AB - For evaluation lipid peroxidation and antioxidant status of red blood cells, 150 patients with locally advanced renal cell carcinoma were examined. The content of conjugated dienes, MDA, and reduced glutathione and activities of SOD, catalase, and glutathione metabolism enzymes were determined. It was found that the balance between pro- and anti-oxidants in patients with kidney cancer differed significantly from that of healthy people and little changed during the observation. PMID- 23658909 TI - Antioxidant potential of the blood in men with obstructive sleep breathing disorders. AB - We studied the state of the LPO-antioxidant defense system in men aged from 46 to 55 years. The main group included patients with obstructive sleep breathing disorders. The state of the antioxidant defense system was assessed by measuring the blood levels of LPO substrates with conjugated double bonds, conjugated dienes, ketodienes and conjugated trienes, MDA, retinol, alpha-tocopherol, reduced and oxidized glutathione, SOD activity, and the level of total antioxidant activity of blood. Calculation of antioxidant potential helps to identify the processes of "oxidative stress" in the main group, which is a pathogenetic substantiation for including antioxidant drugs in the complex therapy of patients with OSBD. PMID- 23658910 TI - Diagnosis of nitrosative stress by quantitative EPR-spectroscopy of epidermal cells. AB - Quantitative assay of nitric oxide (NO) and iron (Fe) was carried out by the electron paramagnetic resonance (EPR) method in epidermal derivative (hair) of 45 liquidators of the Chernobyl accident, 30 employees of radiological institutions having contact with radiation, and 50 students of Vladimir State University, most of which were diagnosed with iron deficiency, namely iron deficiency anemia (4 persons) and latent iron deficiency (34 persons). Measurements were performed on a Radiopan EPR-spectrometer. It was found that the method of quantitative EPR spectroscopy using diethyldithiocarbamate as a trap in vitro could be successfully used to measure NO-radical activity in such a biological substrate as hair. It was found that the intensity of NO-radical signal in the spectrogram depends on the Fe level (not only in the analyzed substrate, but also in the whole organism). PMID- 23658911 TI - Effect of nitric oxide on physical development and erythropoiesis in the offspring of rats with impaired uteroplacental circulation. AB - We evaluated physical development and activity of erythropoiesis in the offspring of rats with experimentally impaired uteroplacental circulation as well as the effect of exogenous nitric oxide donator used during pregnancy, on offspring development. Exogenous NO producing an anti-hypoxic effects contributes to the increase in somatometric parameters of the offspring on postnatal days 15 and 30. The rates of erythropoiesis in the liver and bone marrow did not differ from the normal; hemopoietic organs were not overstrained, which prevented exhaustion and failure of functional reserves of the erythrocyte system. PMID- 23658912 TI - Effect of ultrasonic irradiation on the development of symptoms of depression and anxiety in rats. AB - Behavioral reactions of rats were studied under conditions of constant exposure to ultrasonic irradiation at a frequency of 20-45 kHz for 21 days. In rats subjected to ultrasound, impaired behavior in the social interest test and Porsolt forced swimming test was observed; the development of anhedonia in the sucrose preference test was revealed (manifested in the symptoms of depression). The effects of ultrasonic irradiation were abolished by an antidepressant fluoxetine, a selective serotonin reuptake inhibitor. Our results indicate that chronic exposure to ultrasonic radiation produces a modulatory effect on depressive symptoms in rats. These changes satisfy the requirements for experimental animals, which are used as a model of psychopathological processes. PMID- 23658913 TI - Effect of cholera toxin on ATPase activities in rabbit small intestinal mucosa. AB - Cholera toxin induced the appearance of ATPase activity in rabbit small intestinal mucosa. This enzyme significantly differed from other ATPases, including Na(+),K(+)-ATPase and HCO3(-)-ATPase in the small intestinal epithelium of rabbits, by some properties, in particular, by relation to divalent and monovalent cations and anions, pH optimum, substrate specificity, and inhibitory analysis. PMID- 23658914 TI - Free radical oxidation in rats in the delayed period after combined exposure to dust and radiation. AB - We studied the intensity of free radical processes in organs (liver, spleen, thymus, lymph nodes of the small intestine, and adrenal glands) and cells (lymphocytes) in the delayed period after combined exposure to a sublethal dose of gamma-radiation (6 Gy) and asbestos dust particles. Combined exposure was followed by accumulation of LPO metabolites (diene conjugates and malonic dialdehyde) in homogenates of the studied organs and resulted in antioxidant defense failure in experimental animals. Ionizing radiation have a pivotal role in these processes. PMID- 23658915 TI - Mechanisms underlying modulation of the pharmacological properties of pegylated erythropoietin by pegylated hyaluronate-endo-beta-N-acetylhexosaminidase. AB - Pegylated hyaluronate-endo-beta-N-acetylhexosaminidase was shown to potentiate significantly the hemostimulatory effect of pegylated erythropoietin. It was found that enhanced production of hemopoietin by adherent and non-adherent cells of the hemopoiesis-inducing microenvironment and elevated serum content of endogenous erythropoietin along with increased susceptibility of erythroid precursors to pegylated erythropoietin underlay this phenomenon. PMID- 23658916 TI - Hemorheological effects of complex isoflavonoid preparation in ovariectomized rats. AB - We have shown that rats with simulated hormone deficiency develop the hyperviscosity syndrome. Course intragastric administration (14 days) of the composition of extracts from red clover (100 mg/kg) and alfalfa (100 mg/kg) prevents the development of hyperviscosity syndrome in rats with hormone deficiency. PMID- 23658917 TI - Induction of TNF-alpha production by metal complexes of gamma-globulin fraction proteins and copper and zinc cations. AB - Plasma gamma-globulin fraction proteins, copper and zinc cations, and metal complexes of these cations and human serum gamma-globulin induce the production of TNF-alpha by human blood cells. The protein modified by zinc cations is by 1.4 1.7 times more potent (p<0.001-0.01) than control gamma-globulin in inducing the production of TNF-alpha, while metal complex formed by gamma-globulin and copper is by 1.9-2.2 times more potent that the control protein (p<0.001). Under conditions of experimental induction, TNF-alpha is produced as a typical early response cytokine. During long-term incubation, copper cations lose the ability to induce TNF-alpha production, while in combination with gamma-globulin these cations produce a synergistic effect with the control protein. PMID- 23658918 TI - Effects of specific antibodies and immunocompetent cells on tumor growth in passive transfer experiment. AB - Experiments with passive transfer of immunocompetent cell and serum demonstrated suppression of tumor growth after transfer of splenocytes from animals immunized with Trypanosoma cruzi. The nonspecific constituent of antitumor effect of immunocompetent cells was detected. The previously reported oncoprotective effect of mucins 2 and 3 was not confirmed. PMID- 23658919 TI - Effects of Staphylococcus aureus supernatants on human lymphocyte surface receptors. AB - The effects of Staphylococcus aureus proteolytic enzymes on surface receptors of human lymphocytes were studied. Proteolytic activity was detected in 35 supernatants of 45 S. aureus strains. aur and sspA genes were detected by PCR in 43 strains. Incubation of lymphocytes showed reduced expression of receptors labeled with anti-CD8, anti-CD4, and anti-CD16 antibodies and no changes in the receptors labeled with anti-CD3 and anti-CD19 antibodies in comparison with the control (incubation with sterile nutrient medium). S. aureus enzymes can trigger in vivo one of the mechanisms of early death of lymphocyte subpopulations expressing these receptors. PMID- 23658920 TI - Effects of short-term local warm and cold applications to the chest on immunophysiological parameters of the organism. AB - Applications of cold and warm activated cellular immunity and orientation and exploratory behavior in mice. Application of cold increased the number of turns to the left in the open field, muscle force, and activity of the food instinct, and caused an increase in the total count of peripheral blood leukocytes. Warm applications reduced the food instinct activity and stimulated the humoral immunity. PMID- 23658921 TI - Study of the efficiency of doxorubicin deposited in microparticles from resorbable BioplastotaneTM on laboratory animals with Ehrlich's solid carcinoma. AB - Antitumor efficiency of an experimental form of an experimental form of anthracyclin antibiotic (doxorubicin), resorbable microparticles from Bioplastotane(TM), was studied on laboratory mice with transplanted Ehrlich's solid carcinoma. Use of the experimental form of the cytostatic in polymeric microparticles from resorbable Bioplastotane(TM)in animals with solid tumor led to inhibition of the cancerous process, comparable to that in response to intravenous free doxorubicin, but without negative effects on the blood system. PMID- 23658922 TI - Dynamics of oxidative modification of proteins and specific structural features of blood plasma from animals with Pliss lymphosarcoma. AB - The growth of Pliss lymphosarcoma in experimental animals was followed by accumulation oxidative protein modification products and structural simplification of blood plasma facies pattern in the central and peripheral zones. A correlation was found between the tumor volume, blood content of aldehyde and ketone dinitrophenylhydrazones, and structural characteristics of the peripheral and central facies zone. PMID- 23658923 TI - Effects of modified detonation nanodiamonds on the biochemical composition of human blood. AB - In vitro experiments showed that protein and non-protein components of human blood serum could be absorbed on the surface of modified nanodiamonds obtained by detonation synthesis. The prospects of using nanodiamond as a new absorbent for hemodialysis, plasmapheresis, and laboratory diagnostics are discussed. PMID- 23658924 TI - Spontaneous and mitogen-induced cytokine production in lymphoproliferative diseases. AB - The levels of spontaneous and mitogen-induced production of pro- and anti inflammatory cytokines were studied in patients with chronic lymphoid leukemia, non-Hodgkin's lymphocytic lymphomas, and multiple myeloma during the course of chemotherapy. Cytokine concentrations varied within a great range and did not conform to the normal distribution law. The levels of granulocyte and granulocyte macrophage CSF were high during the debut, progress, and remission of the lymphoproliferative diseases. Imbalance of a wide spectrum of pro- and anti inflammatory cytokines was observed during the debut and progress of the lymphoproliferative diseases, more often in chronic lymphoid leukemia and non Hodgkin's lymphocytic lymphomas than in multiple myeloma. PMID- 23658925 TI - Enzymological evaluation of hepatotropic effect of ozone in a subchronic experiment. AB - Hepatotoxicity of ozone in total systems treatment was evaluated by the functioning of hepatic oxidoreductases. Activities of lactate dehydrogenase and alcohol dehydrogenase were measured in liver homogenates of Wistar rats, injected daily with saline with saturating ozone concentrations of 3000, 10,000, and 40,000 MUg/liter or placebo for 30 days. Systemic ozone treatment had a two-step effect on the hepatic oxidoreductases. Low doses (0.6 MUg) promoted a moderate physiological stimulation of the enzymes, while in doses >2 MUg ozone led to progressive tissue hypoxia and accumulation of toxic products in the liver. PMID- 23658926 TI - Vascular endothelial growth factor and its receptors in the placental villi of pregnant patients with pre-eclampsia. AB - Comparative morphological study of the placentas from women with pre-eclampsia of different severity was carried out. The expression of vascular endothelial growth factor and its receptors (VEGFR-1, VEGFR-2, VEGFR-3) was studied by immunohistochemical methods. Branched angiogenesis processes predominated in the placentas of patients with pre-eclampsia. The syncytiocapillary membranes were thickened, the number of syncytial buds was greater than normally. Immunohistochemical studies showed high expression of VEGF and VEGFR-1 and low expression of VEGFR-2 in the placental villous structures. PMID- 23658927 TI - Effects of space mission factors on the morphology and function of endothelial cells. AB - The structure and functions of endothelial cells after space mission were studied by electron and laser confocal microscopy, image analysis, and MTT test. The endothelial cells changed significantly (proliferative activity, size, contours, shape, distribution of mitochondria and microtubules) in comparison with controls on the Earth. These changes indicated injuries in the cytoskeleton and impairment of the barrier function of the cells, which presumably contributed to the development of endothelial dysfunction. PMID- 23658928 TI - The morphology of the rat ovarian network during reproduction and aging. AB - We studied the morphology of the ovarian network in outbred albino rats of different age. Morphogenetic restructuring of the network during aging were detected. The role of the network in the glandular cystic transformation of the ovaries in aging was discussed. PMID- 23658929 TI - Pancreatic fat necrosis and hemorrhagic necrosis as separate morphological and functional entities. AB - Peculiarities of pathomorphogenesis of two destructive forms of acute pancreatitis were compared using three experimental models. We have shown that the direction of the pathological process is determined by specific combinations of pathogenic factors. Pathological processes caused by common bile duct ligation (ductal hypertension) alone and in combination with injection of phospholipase A2 are characterized by mixed pattern with strong predominance of fat necrosis symptoms (coagulative acinar necrosis, inflammatory demarcation, and sites of lipolysis) and hemorrhagic necrosis, respectively. Trypsin injection into the pancreatic tissue induces rapidly progressing hemorrhagic pancreatic necrosis with massive hemorrhages, extensive acinar necrosis, and weak cell reaction. Considerable differences in pathomorphogenesis and outcome of the pathological process allow us to consider pancreatic fat necrosis and hemorrhagic necrosis as separate morphological and functional entities, which is essential for the prognosis and treatment strategy. PMID- 23658930 TI - Simulation of incomplete obstructive uropathy in rats by injecting an artificial calculus into the bladder. AB - Incomplete varying obstruction of the urinary tract was reproduced by injecting artificial stomatological material into the rat bladder. Inflammatory changes and nephrosclerosis were detected in the renal tissue on days 14 and 21 of the experiment. Urinary concentration of total protein and activity of gamma glutamylaminotransferase increased. A direct positive correlation between the volume percentage of connective tissue and activities of the renal enzymes in the urine was detected. PMID- 23658931 TI - Experimental simulation of radio- and chemoradio stomatitis in rats. AB - Experimental models of stomatitis developing in response to an isolated (radiation) and combined (radiation and chemical) exposure of experimental animals, were created. The severity of radiation-induced stomatitis was determined by the dose of radiation exposure. Additional exposure to a chemical factor (cyclophosphamide) augmented the destructive effect of ionizing radiation on the buccal mucosa of rats. PMID- 23658932 TI - Hydrogen respiratory test: pilot examinations for evaluation of the small intestinal colonization by normal microflora. AB - Respiration hydrogen analyzer H2Rate has been used in pilot examinations of a group of students. This method for noninvasive diagnosis of small intestinal diseases promotes proper interpretation of the results. Free hydrogen level in the exhaled air increases as a result of lactulose (diagnostic agent) cleavage by enteric microflora within about 3 h. Based on the experimental data, the main groups with characteristic curves reflecting the time course of hydrogen concentrations have been distinguished. Excessive bacterial colonization of the intestine can correspond to emergence of characteristic peaks of hydrogen concentrations in the curve. Hydrogen concentrations in exhaled air can also be analyzed to evaluate the rate of the substrate propulsion in the middle compartment of the intestine. PMID- 23658933 TI - Beyond the ridge pattern: multi-informative analysis of latent fingermarks by MALDI mass spectrometry. AB - After over a century, fingerprints are still one of the most powerful means of biometric identification. The conventional forensic workflow for suspect identification consists of (i) recovering latent marks from crime scenes using the appropriate enhancement technique and (ii) obtaining an image of the mark to compare either against known suspect prints and/or to search in a Fingerprint Database. The suspect is identified through matching the ridge pattern and local characteristics of the ridge pattern (minutiae). However successful, there are a number of scenarios in which this process may fail; they include the recovery of partial, distorted or smudged marks, poor quality of the image resulting from inadequacy of the enhancement technique applied, extensive scarring/abrasion of the fingertips or absence of suspect's fingerprint records in the database. In all of these instances it would be very desirable to have a technology able to provide additional information from a fingermark exploiting its endogenous and exogenous chemical content. This opportunity could potentially provide new investigative leads, especially when the fingermark comparison and match process fails. We have demonstrated that Matrix Assisted Laser Desorption Ionisation Mass Spectrometry and Mass Spectrometry Imaging (MALDI MSI) can provide multiple images of the same fingermark in one analysis simultaneous with additional intelligence. Here, a review on the pioneering use and development of MALDI MSI for the analysis of latent fingermarks is presented along with the latest achievements on the forensic intelligence retrievable. PMID- 23658935 TI - Gene therapy. Preface. PMID- 23658999 TI - Final priority. National Institute on Disability and Rehabilitation Research- Traumatic Brain Injury Model Systems Centers Collaborative Research Project. Final priority. AB - The Assistant Secretary for Special Education and Rehabilitative Services announces a priority for the Disability and Rehabilitation Research Projects and Centers Program administered by the National Institute on Disability and Rehabilitation Research (NIDRR). Specifically, we announce a priority for a Disability and Rehabilitation Research Project (DRRP) on Traumatic Brain Injury Model Systems Centers Collaborative Research Project. The Assistant Secretary may use this priority for competitions in fiscal year (FY) 2013 and later years. We take this action to focus research attention on areas of national need. We intend this priority to improve outcomes among individuals with traumatic brain injuries. PMID- 23658934 TI - Double hit, triple hit--look for it. PMID- 23659000 TI - Final priorities; National Institute on Disability and Rehabilitation Research- Rehabilitation Research and Training Centers. Final priorities. AB - The Assistant Secretary for Special Education and Rehabilitative Services announces priorities for the Disability and Rehabilitation Research Projects and Centers Program administered by the National Institute on Disability and Rehabilitation Research (NIDRR). Specifically, we announce priorities for Rehabilitation Research and Training Centers (RRTCs) on Community Living and Participation for Individuals with Physical Disabilities (Priority 1), Employment of Individuals with Physical Disabilities (Priority 2), Health and Function of Individuals with Intellectual and Developmental Disabilities (Priority 3), and Community Living and Participation for Individuals with Intellectual and Developmental Disabilities (Priority 4). If an applicant proposes to conduct research under these priorities, the research must be focused on one of the four stages of research defined in this notice. The Assistant Secretary may use these priorities for competitions in fiscal year (FY) 2013 and later years. We take this action to focus research attention on areas of national need. We intend these priorities to improve outcomes among individuals with disabilities. PMID- 23659001 TI - [Treatment goal of alcohol dependence: reduction in alcohol consumption introduction of the special issue]. PMID- 23659002 TI - [Reduction in alcohol consumption: therapeutic goal in alcohol dependence treatment]. AB - Mean per capita consumption of alcohol for Japanese adults has been gradually decreasing for more than15 years, while it still remains at a high level. It is pointed out that those who consume alcoholic beverages become more diversified and that the proportion of male drinkers tends to gradually decrease. On the other hand, it is estimated that the proportion of female drinkers, especially, young generation, remarkably increases. The existing cross-sectional and longitudinal studies suggest that alcohol consumption causes a variety of health- and social-related problems with accelerating increase over the past few decades except for some exceptions. The results from a patient survey show that the number of patients with alcohol dependence who receive medical treatment tends to increase. However, the percentage of patients who receive medical care is estimated to be only 5% of total number of patients with the disease, which means that there exist many untreated patients or potential patients who undergo treatment for complications only. Treatment for alcohol dependence can be divided into psychosocial and pharmacological treatment. The former is a mainstream of the treatment. Although medications available in Japanese clinical practice are limited to so called anti-alcoholic drugs, disulfiram and cyanamide, pharmacological treatment is expected to become more accessible because many potential patients can benefit from pharmacotherapy. Treatment outcomes for alcohol dependence are not necessarily high in Japan as shown by the fact that abstinence rate 1 - 3 years after treatment is 7% - 30%, while mortality rate is extremely high. However, not a few individuals are able to maintain a reduced alcohol consumption, and some are able to do so for a long period of time. It is shown that many risks of health-related problems including cancer, hypertension and intra cerebral haemorrhage and social-related problems including suicide increase with the increasing alcohol consumption in a dose-dependent manner. A certain types of disease including ischemic heart disease and cerebral infarction are indicated to have a J-shaped relationship with alcohol consumption. On the other hand, once alcohol consumption exceeds a certain level, the risks increase with the amount of alcohol consumed. Thus, reduction in alcohol consumption can lead to decrease in a large number of health-related and social-related problems in general population. Many studies indicate that reduction in alcohol consumption in patients with alcohol dependence can also lead to the improvement of these problems. In recent years, in Japan, there have been some discussions as to whether "harm reduction" approaches that target reduction in alcohol consumption are needed and the approaches should be aggressively introduced into clinical practice, stimulated by requests from clinicians, the established efficacy of novel therapeutic approaches on reduction in alcohol consumption and trend of various countries. The results from a survey on therapeutic goals in alcohol dependence treatment show that many experts in alcohol dependence answered that they could accept reduction in alcohol consumption (controlled drinking) as a stepwise/interim treatment goal for guiding abstinence if the patient rejects abstinence as a therapeutic goal. Regarding effective medications for reduction in alcohol consumption, most experts answered that they found the medications clinical significant and that they would use them for controlled drinking or abstinence form alcohol when available. In Japan, available drugs for alcohol dependence are extremely limited. Comments in the column for unreserved opinions on the survey questionnaire reveals that many experts hope novel agents will be developed to improve the current treatment as much as possible. PMID- 23659003 TI - [Effects of alcohol reduction in patients with alcoholic liver disease]. PMID- 23659004 TI - [Treatment processes of pre-alcoholism and alcohol dependence targeted towards drinking reduction]. AB - Since the 1990s, we have suggested the concept of pre-alcoholism which encompasses patients who have drunk a great deal of alcohol leading to alcohol related problems such as health issues, domestic violence, drunken driving and black-outs. Pre-alcoholism excludes alcohol-dependent patients who have experienced continuous drinking or withdrawal symptoms. We have treated many outpatients with pre-alcoholism for several years. Our regimen demands that the patients must be abstinent for half a year at the beginning of their treatment. After half a year they can choose whether they will continue to be abstinent or they will resume drinking with the aim of reducing their total alcohol consumption. The study clarified the character of pre-alcoholism by investigation of the patients' background and re-diagnosis of the patients based on the International Classification of Diseases, 10th Revision (ICD-10). A remarkable ratio of pre-alcoholic patients was diagnosed with alcohol dependence under ICD 10. We classified pre-alcoholic patients into two groups, one diagnosed as having ICD-10-classed alcohol dependence and the other which did not fulfill the ICD-10 diagnostic criteria of alcohol dependence, and examined the therapeutic processes of the two groups. It was shown that most pre-alcoholic patients could finally take required courses of treatment by themselves without regard to diagnosis under ICD-10, even if they chose any treatment and made alcohol related mistakes on the way. Our findings suggested that pre-alcoholic patients, a portion of whom may have exhibited mild alcohol dependence, could select drinking reduction as a primary goal of treatment after a certain period of abstinence. PMID- 23659005 TI - [Treatment outcome of alcoholics in a general hospital alcoholic clinic: effects of adopting moderation as a practical treatment goal]. AB - It's almost 50 years since medical treatment for alcoholism began to be practiced in Japan in 1960s. Since then, treatment goal for alcohol use disorders has always been absolute abstinence, and only severe cases have been treated. Recently, many people are concerned about lifestyle-related diseases, suicides, depression, and drunken-driving accidents. Reduction in alcohol consumption of heavy drinkers began to draw attention, and brief motivational intervention study was launched at last in 2007 in Japan. In 2009 we set up alcohol clinic in a general hospital in order that the alcoholics may get easier access to their treatments. The basic roles of our alcohol satellite clinicare as follows: 1. Assessment and diagnosis of patient's alcohol-related problem are our primary role. 2. Referral to a specialized hospital is offered in case special treatments for alcohol dependence are needed. 3. Our standard treatment is a brief intervention, not exceeding 3 sessions, to enhance the patients' self-efficacy. 4. Our treatment goal is not limited to total abstinence. Moderation of drinking can also be a goal. We examined the treatment outcome to verify these roles and meanings. Of all the patients visited this hospital from 2009 to 2011, 77 patients were diagnosed as alcohol dependent. Out of those 77 patients, 21 patients set up a moderation of drinking as their temporal treatment goal and 10 achieved good outcome at the inquiry point of 8 to 41 (average: 22) months after intervention. This result suggests that moderation can be a practical treatment goal in some alcoholics. PMID- 23659006 TI - [Reduction in alcohol consumption as a treatment goal of alcohol dependence: actual conditions in Okinawa]. AB - In Japan, abstinence has traditionally been considered the sole method of treatment for alcohol dependence. In recent years there have also been reports that a small percentage of alcoholics are able to regain control of their drinking, but thus far there have been few reports in Japan on reducing the amount of alcohol consumed in alcohol dependence. In the present study we therefore conducted a survey of outpatients who were examined on a certain day at 4 general hospitals in Okinawa Prefecture. Of the 421 examinees, 5% of the males and 4% of the females had a score of 20 or more on the Alcohol Use Disorders Identification Test (AUDIT) and were suspected of alcohol dependence. When those suspected of alcohol dependence were asked if they wanted to decrease their level of alcohol consumption, 90% of the males and 78% of the females replied that they wanted to reduce it. We also conducted a survey of the post-discharge outcome of alcohol-dependent inpatients at the National Hospital Organization Ryukyu Hospital. The Hospital is a psychiatric hospital that has a specialized unit for alcohol dependence, and treatment based on cognitive behavioral therapy is conducted there. The results for the outcome 1 year after their discharge from the Hospital of the 116 patients admitted for the treatment of alcohol dependence showed that 31% were able to remain abstinent, 61% were unable to remain abstinent, and 8% had died. The alcohol-related problems of some of those who were unable to remain abstinent had become mild, i.e., they had been able to return to work, their violent behavior while inebriated had improved, etc. Many alcoholics want to reduce the amount of alcohol they consume as a goal of treatment, and some of them actually are able to reduce their alcohol consumption. The details will be left to future research, but it may be possible for a reduction in alcohol consumption to be the goal of treatment for a certain type of alcoholics. PMID- 23659007 TI - [Survey of physicians and alcohol-dependent patients in regard to the goals of treatment of alcohol dependence]. AB - We conducted a survey of alcohol-dependent patients at the time of their first visit and physicians in regard to the goals of treatment of alcohol dependence. There were 99 replies from patients, and replies from physicians related to 64 of the patients' replies were also received, and in 25.0% of them it was judged possible to make reducing the amount of alcohol consumed a temporary or final goal. Having a mild drinking problem, the absence of a personality disorder or mental retardation, the presence of a strong motivation in regard to treatment, etc., were cited as reasons for the physicians' judgments. In addition, the number of diagnostic criteria of the ICD-10 for dependence syndrome that applied was shown to be significantly related to the judgments regarding treatment goals. However, as for Alcohol Dependence Scale (ADS), there was no significant relationship with the treatment goal. PMID- 23659008 TI - [A survey of alcoholics and their families on controlled drinking as a treatment goal: discussions on new treatment approaches]. AB - INTRODUCTION: To encourage persons with alcoholism to seek treatment or to overcome denial is an important issue to be addressed in the treatment of alcoholism. Recognizing one's own addiction might be the first step in overcoming alcohol abuse. Abstaining from alcohol consumption was found to be the only effective treatment in Japan. Efforts are in place to introduce abstinence therapy as a first step towards overcoming denial. Abstinence therapy is very popular worldwide: however, many people oppose its introduction in Japan. Concern about relapse is the main reason for this apprehension. Therefore, we conducted a survey to assess awareness of sobriety treatment among persons with alcoholism and their families. METHODS: Subjects were 109 patients with a diagnosis of alcohol dependence and their families who attended family therapy. To examine the consideration of alcoholics and their families for sobriety treatment, we administered a questionnaire that measured awareness of sobriety treatment. RESULTS: Based on the results of the survey, 24% of workshop participants and 25% of hospital patients were admitted for sobriety treatment. According to the sobriety treatment, 41% of patients and 53% of family members realized the need "not to drink too much" (patients who have control over their drinking limit), while 67% of patients and 53% of family members acknowledged "not to pull out the healthy problem." For sobriety treatment, the patients' families tended to focus on the "patient's attitude toward sobriety," "social status," and "extent of mental dependence." The results of "liver dysfunction," "history of alcohol abuse," "treatment history," and "extent of mental dependence" are considered important in the decision to initiate sobriety treatment. CONCLUSIONS: Attitude toward sobriety, abstinence of patients, and social stability were found to be important factors in the choice of treatment focus. Further investigation is needed for the successful introduction of new treatment methods. PMID- 23659009 TI - The findings are in. PMID- 23659010 TI - The state of mental health care revisited. PMID- 23659011 TI - Ensuring resources exist so nurses can ask the right questions. PMID- 23659012 TI - Seeing the value in nursing research. PMID- 23659013 TI - From tragedy to opportunity: investing in students' mental health and well-being. PMID- 23659014 TI - Six hospitals earn ANA's award for nursing quality. PMID- 23659015 TI - Using expertise in older adult care to make a difference. PMID- 23659016 TI - [Management of rectal traumatism in the pediatric age]. AB - OBJECTIVE: In pediatrics anorectal injuries are not very common and their management classically includes an intestinal derivation. In selected patients and with favourable conditions, there has been an increased interest in repair the injuries without derivation. We present our experience in the management of this pathology, looking through the literature. The aim of the study is to develop some guidelines to follow in these cases. PATIENTS AND METHODS: Retrospective and descriptive study of patients with anorectal injury admitted in our institution between 2005-2011. Data abstraction included patient demographic data, mechanism of injury, associated injuries, time between injury and treatment, methods of diagnosis, treatment, length of stay and resultant complications. RESULTS: 7 patients were reviewed and classified according to the type of the injury in two groups: iatrogenic injuries (all of them with associated malformations) and non-iatrogenic accidental injuries. A CT was performed in 4 cases. None of them was explored with sigmoidoscopy. We performed colostomy without primary repair in four patients, primary injury repair with colostomy in two patients, and one patient underwent primary repair without colostomy. All patients had a long evolution (mean hospital length of stay was 31,4 days) with many dressings and some of them required relaparotomy. Fecal continence and long term results have been, in all of them, satisfactories. CONCLUSIONS: An early and complete diagnosis of anorectal injuries is basic for an appropriate approach to the treatment. Primary repair of injuries without colostomy could be a safe procedure as a first treatment in selected patients: stables, with no contamination and no associated injuries. It is very important to individualize each patient to minimize the morbidity, reduce the hospital length of stay and reach a full continence. PMID- 23659017 TI - [When should a patient be referred to the pediatric surgeon?]. AB - INTRODUCTION: An incorrect transfer of patients to paediatric surgery clinic results in clinic saturation and both patient and medical staff discomfort. As a consequence the quality of medical care is deteriorated. AIM: 1) To evaluate the transfer of new patients to paediatric surgery clinic from primary paediatric care considering the medical diagnosis and the surgical calendar, looking for the most common mistakes. 2) To analyze the inconvenience of a wrong indication for both our patients and the medical staff. 3) To propose new measures to decrease the rate of patients incorrectly transferred. MATERIAL AND METHOD: An observational retrospective study was performed based on medical records of new patients evaluated in paediatric surgery clinic between september 2010 and january 2012. Age, address, diagnosis, transfer indication and referring centre were collected. RESULTS: Two thousand four hundred thirty medical records were reviewed from new patients finding an incorrect transfer in 44.28% of them (2.37 children/day). From these cases wrong transfer was related to surgical calendar in 18.59% and wrong diagnosis in 81.41% of them. Most common mistakes due to wrong diagnosis were Phimosis (91.45% n= 113) and Cryptorquidism (85.29% n = 122); mistakes related to surgical calendar were Umbilical Hernia (88.46%), Hypospadias (72.22% n= 31) and Hydrocele (70.83% n = 12). Mean distance of transfer for patients wrongly referred outside the metropolitan area was 35.92 km (Range: 7.1-129). CONCLUSIONS: We have detected major mistakes in patient transfer from primary paediatric care. The knowledge of surgical calendar and accurate diagnosis should avoid these problems. These mistakes result in deterioration of medical care quality, patient discomfort and clinic saturation. It is necessary to propose and develop measures that improve the knowledge of surgical calendar and to make more accurate surgical diagnosis in primary paediatric care. PMID- 23659018 TI - [Prognostic factors in hypertrophic pyloric stenosis]. AB - INTRODUCTION: Although the surgical treatment of hypertrophic pyloric stenosis is well established, its management and main complication after surgery, postoperative vomits, are subject to constant revisions. In this study, we sought a prognostic factor that indicates the occurrence of this complication. METHODS: We analyzed different parameters listed in the medical histories of 169 patients treated at a tertiary hospital between 2000 and 2009, both inclusive, ruling out those who suffered some type of complication (n = 17) and those who followed a different pattern of reintroduction of feeding (n = 43). RESULTS: The decrease in the time interval between surgery and the first shot does not influence the outcome of patients. However, we found a negative correlation between the chlorine level in blood measured by the number of postoperative vomits. The time required to reach a correct tolerance, influenced by the degree of metabolic disorder, does influence both the number of vomits and the time required to achieve a proper tolerance. Other parameters analyzed, such as surgical time and ultrasound measurements of the pyloric olive, do not seem to influence the postoperative course of patients. CONCLUSION: Just the degree of metabolic disturbance and blood levels of chlorine seem to influence postoperative outcome, detected by the time required to reach a correct tolerance and the number of postoperative vomits. PMID- 23659019 TI - [Increase of newborns with anorectal malformation in 2011. Is it just by chance?]. AB - OBJECTIVE: In 2011 we have diagnosed 9 anorectal malformations (MAR). This means 13.3 cases/10.000 NB versusu the estimated incidence of 2 cases/10.000 NB. This accumulation of defects can not be due to chance, so we have decided to focus on its research. MATERIAL AND METHODS: The study included all the patients with anorrectal malformations born in 2011. In all of them we analyzed: geographic area, age and health status of parents, pregnancy, exposure to teratogens, especially lorazepam intake, sex, gestational age, weight at birth, exploration of the abdomen and perineum, birth defects associated, imaging studies performed, treatment and current situation. RESULTS: All patients came from our province, and maternal age is under 20 years in 2 patientes and older than 30 in 7; male dominated (8/1); low forms in 4 of 9 patients. 100% of newborns have some type of associated malformation, in genitals, urinary system or costovertebral. Clinical assessment and imaging study provided the right diagnosis in all the cases. It must be noted the absence of difficulties in the surgery treatment and a favorable outcome in all children. CONCLUSIONS: To this accumulation of cases with anorrectal malformation cases it is added a male predominanced, and a high incidence of associatedmalformations and high defects. We have not found an epidemiological explanation for this concentration of patients with anorrectal malformations. This forces us to continue our investigation if detected for some reason, currently not known. PMID- 23659020 TI - [Transumbilical cholecystectomy using hybrid technique: a new promising approach]. AB - OBJECTIVES: The use of magnets in transumbilical cholecystectomy improves triangulation and achieves optimal critical view. However, the attraction between magnets can cause collisions and their management complicates the procedure, and this will become more important in children. In order to simplify the technique, we have developed a hybrid model with a single magnet. MATERIAL AND METHODS: Retrospective review of cholecystectomies performed in our department between June 2011 and July 2012. The technique combines the use of a magnet and a curved grasper. Through transumbilical incision, a 12 mm trocar and another flexible 5 mm are placed. Laparoscope with working channel uses the 12 mm trocar. The magnet is introduced to the abdominal cavity using the working channel to provide cephalad retraction of gallbladder fundus. Curved grasper is run by the assistant to mobilize the infundibulum across flexible trocar. The surgeon operates through the working channel of the laparoscope. RESULTS: Twenty-six patients were operated on with this technique. Mean age was 14 years (4-17) and weight 50 kg (18-90). 65% were girls. The mean operative time was 62 minutes (50-70) and the critical view of safety was achieved in all cases. Instrumental collision or hands crossing were not seen. There were no intraoperative or postoperative complications. The hospital stay was 1.4 +/- 0.6 days and the median follow-up 201 days (42-429). CONCLUSIONS: The hybrid technique, combining magnet and a curved grasper, simplifies transumbilical surgery. It seems a feasible and safe for transumbilical cholecystectomy and potentially reproducible. PMID- 23659021 TI - [Single port video-assisted transumbilical appendectomy. What have we gained and what have we lost after 754 cases]. AB - INTRODUCTION: Single-port transumbilical laparoscopically assisted appendectomy (TULAA) has become the preferred method of treating appendicitis in our Department. At first, it was reserved for noncomplicated cases, and gradually for the rest of them. We have gained experience, and it is time to share it, evaluate the results and raise into new possibilities. MATERIAL AND METHODS: We performed a retrospective statistical analysis of undergone changes over the last years, referring to aspects such as surgical indications, andpostoperative complications, hospital stays and re-admissions. RESULTS: From September 2003 to January 2012, a total of 1,022 appendectomies were performed. Eight hundred and forty-one children underwent TULAA, 89.65% were completed with no problems. In 179 patients, open appendectomy was initially chosen. In those cases, the reasons were complicated appendicitis, obesity or surgeon's preference (43 in the first year and just 3 in the last one). Ninety seven patients had postoperative complications of any kind, fifteen were readmitted to the hospital and 3 were reoperated because of intestinal obstruction. Medical cost savings were estimated around 750.000 Euros. CONCLUSIONS: We think that TULAA is a simple and easy learning procedure, which does not result in any increase in complications, inexpensive and beneficial for patients. However, along these years, our surgical staff may have lost skills and training opportunities in conventional laparoscopic surgery. So although TULAA is still our preferred method in appendicectomy, selected cases will undergo laparoscopic appendectomy. PMID- 23659022 TI - [Treatment of lymphangioma with OK-432 infiltration]. AB - The management of lymphangioma using sclerotherapy has proven to be an effective therapeutic. Our aim was to evaluate the therapeutic efficacy of OK-432 (Picibanil) in patients with lymphagioma. METHODS: The study was performed from November 2010 to July 2011. Fifteen patients of both genders were diagnosed with lymphangioma, 12 days to 12 years old. All patients were infiltrated with OK-432. The studied variables were: previous surgery, localization, type of lymphangioma, number of effective injections, reduction of mass valued as excellent (100% reduction), good (reduction > 50%) and bad (reduction < 50%), presence of recurrence and complications. RESULTS: 40% of pacients had prior surgery and 53.3% were located in the cervical-face region. The type of macrocystic lymphangioma was present in 40% of the series, mixed type in 46.6% and microcystic type in 13.4%. The number of effective infiltrations were 3. In 6 cases (40%) the result was excellent in 5 cases (33.4%) the result was good and in 4 cases (26.6%). We had 1 recurrence (6.6%) and we haven't had complications. CONCLUSION: Injection of OK-432 in macrocystic lymphangioma and mixed had a safe therapeutic modality with satisfactory results. So it is a valid alternative to conventional surgery. PMID- 23659023 TI - [Eosinophilic esophagitis: an underevaluated condition. Our experience]. AB - OBJECTIVES: The aim of this review is to present our experience in this emerging disease and mainly help improve diagnostic suspicion. MATERIAL AND METHODS: We reviewed the literature in order to analyze the epidemiology, pathophysiology, diagnosis and management of eosinophilic esophagitis (EE), we describe 4 cases diagnosed in our hospital during 2011 after an emergency admission by food impaction. RESULTS: The age of our patients was 7-11 years, males in all cases. All patients had a history of allergies, and the impaction had been preceded by episodes of dysphagia. In esophagoscopy we observed nonspecific macroscopic findings. The results of biopsies showed the presence of an infiltration of eosinophils in the mucosa over 15 per high power field. All patients were referred to the gastroenterology section of our hospital. DISCUSSION: Eosinophilic esophagitis is a primary disease of esophagus, defined as the presence of symptoms of esophageal dysfunction (mainly dysphagia and food impaction), associated to at least one esophageal biopsy with more than 15 eosinophils in high-power field and the exclusion of gastroesophageal reflux. The diagnosis is clinical, endoscopic and pathologic. It requires an upper endoscopy to evaluate characteristic findings and biopsies for histology. Current treatments include diet therapy based on avoiding exposure to certain food allergens. PMID- 23659024 TI - [Use of self-expandable prosthesis in esophageal stenosis in children]. AB - OBJECTIVE: Caustic or peptic esophageal strictures in children are the main cause of multiple dilations, which involve an important anesthetic risk and esophageal trauma. The placement of an esophageal stent can be an advance in the treatment of these patients. The objective of our work is to analiyze the efficacy of self expanding stents for the treatment of esophageal strictures in children. MATERIAL AND METHODS: Three patients with esophageal strictures, one due to caustic and two to peptic esophageal injuries have been treated with esophageal stents. Metal stent covered with nitinol has been used in the first patient, and biodegradable material stent in the rest. RESULTS: After a year of serial dilations, we placed two consecutive metal stents in one patient with caustic stricture. After its withdrawal, new dilations have been needed, but with longer asymptomatic period. The other two patients had peptic strictures; biodegradable stents were placed after months of serial dilations, before performing antireflux surgery. None of them needed further dilation. CONCLUSIONS: Esophageal stent placement has solved the problem without further dilation in peptic esophageal strictures. Asymptomatic period was significantly increased in caustic stricture. The results obtained with self-expanding stents are promising. PMID- 23659025 TI - [Ectopic testicular parenchyma in albugineal tunic]. AB - We introduce a male patient with bilateral chryptorchidism submitted to surgery; during the intervention, macroscopically round macules were seen in the outer surface of both testes. In the round macules histological study, groups of seminiferous tubules were observed, including stroma and Leydig's intestitial cells surrounded of tunica albuginea, isolated from the rest of testicular parenchymal tissue; the diagnosis "Ectopic testicular parenchyma tissue" was confirmed by histopathological study. Due to the seminiferous tubules are surrounded by the tunica albuginea, with no apparent connection to the rest of the testicular parenchyma, a long-term assessment is required, both during puberty as well as in adulthood; owing to that can mislead and make unnecessary laparotomies and orchiectomies in the future. PMID- 23659026 TI - [Aggressive fibromatosis of the head and neck in pediatric age. A case report and review of the literature]. AB - BACKGROUND: Desmoid tumor is a rare benign mesenchymal neoplasm in children primarily originated in the muscle connective tissue, fascial sheaths, and musculoaponeurotic structures. It is often misdiagnosed as fibroids, reactive processes or low-grade fibrosarcomas. It is characterized by slow growth, locally aggressive nature, high recurrence rate without metastasize capacity. MATERIAL AND METHODS: 7 year old girl with right paramandibular tumor, a year of evolution. It was characterized by slow and painless growth, trismus and mandibular latero-deviation to the left during mouth opening. Imaging tests showed soft parts tumor in masseteric region with a periosteal reaction in the mandibular body. The biopsy reported a desmoid tumor. RESULTS: Risdon approach was performed for tumor resection and external cortical Split mandibular body, without preserving the marginal branch of CP VII. The pathology reports of aggressive fibromatosis without bone involvement. It currently presents marginal paralysis and free-disease. CONCLUSIONS: Desmoid tumors of head and neck are difficult to treat because of the proximity or involvement in vital structures, infiltrative nature and tendency to local recurrence. Primary surgery with negative surgical margins is the treatment of choice. However, in many cases this involves disfiguring surgery. Therefore, in these cases and in those surgical margins affections, the use of chemotherapy/non-cytotoxic drugs can be an alternative. Because they are low incidence tumors prospective multicenter studies are needed to clarify the role of adjuvant treatment in this tumor. PMID- 23659027 TI - [Editorial Note]. PMID- 23659028 TI - A new year--a new approach. PMID- 23659029 TI - Moving beyond the "perpetual novice": understanding the experiences of novice hemodialysis nurses and cannulation of the arteriovenous fistula. AB - Cannulation of the arteriovenous fistula (AVF) is an essential skill for hemodialysis (HD) nurses. With declining rates of AVFs, opportunities to develop expert cannulation skills have become limited. This study explored the concept of perpetual novice and AVF cannulation from the perspective of the novice cannulator. Nine hemodialysis nurses were interviewed using ethnographic methodology. The study identified the interplay between personal and environmental/contextual factors that hindered skill acquisition. Personal attributes identified by participants included HD nurses' approach to learning and previous experience, emotional reaction to stress, and interpersonal relationships with colleagues. Environmental/contextual factors identified as impediments to cannulation skill development included limited learning opportunities, attitudes and demands from patients, unit flow and time pressures, and limitations imposed by the current model of nursing care. This study will be helpful in directing future educational, operational, and supportive interventions for novice HD nurses around cannulation skill development. PMID- 23659031 TI - ["Morfologiya" journal in 2012]. PMID- 23659030 TI - Understanding pruritis in dialysis patients. PMID- 23659032 TI - [Organization of the projections of the structures of the basal ganglia morpho functional system to the individual substructures of the deep mesencephalic nucleus complex of dog brain]. AB - The method of retrograde axonal transport of horseradish peroxidase was used to study the organization of the projections of the morpho-functional system of the basal ganglia nuclei to the individual substructures of the of deep mesencephalic nucleus complex (DMNC) of dog brain (n = 9). It was found that the nucleus accumbens was the only striatum structure containing the neurons that sent projection fibers to the subcuneate nucleus. The projections of the output structures of the basal ganglia--pallidum, substantia nigra, zona incerta, pedunculopontine nucleus were more numerous in DMNC. It was demonstrated that not all DMNC substructures received projection fibers from the neurons of all the nuclei of the basal ganglia structures mentioned. Thus, the fibers from the neurons of the globus pallidus and the ventral pallidum innervated the cuneiform and the subcuneiform nuclei, while those from the entopeduncular nucleus projected to all the DMNC substructures. The projection fibers from the zona incerta neurons were directed to the subcuneate nucleus and to the deep mesencephalic nucleus, while those from the pedunculopontine nucleus projected to the cuneate and the subcuneate nuclei. The projections from the substantia nigra neurons were directed to all the substructures of DMNC. PMID- 23659033 TI - [The distribution of heme oxygenase-2 in the brainstem nuclei of rats]. AB - Immunocytochemical method was used to determine the distribution of neurons expressing heme oxygenase-2 (HO-2-positive neurons) in the nuclei of various parts of the brainstem of 16 male Wistar rats. The sizes of neurons and the optical density of the product of histochemical reaction in their cytoplasm were determined in the nuclei studied. HO-2-positive neurons, differing in shape, size and numbers, were identified in the nuclei of the medulla oblongata, pons and midbrain. HO-2-positive cells were found 3-5 times more frequently in the sensory nuclei as compared to the motor ones. At the same time, relatively large number of nuclei was detected, which contained either no or a few HO-2-positive neurons. PMID- 23659034 TI - [Synaptogenesis in the dorsal raphe nucleus of rat medulla oblongata in serotonin deficiency]. AB - The purpose of the present study was to examine the synaptogenesis in the dorsal raphe nucleus (DRN) in Wistar rats (n = 8-10 for each time point) in the end of prenatal (days 19 and 20) and early postnatal (days 5 and 20) periods, and to determine the role of serotonin in the formation of synaptic contacts during this period of development. It is shown that at prenatal dayl9 neuropil started to develop in DRN -d, DRN -v and DRN -1 in control (intact) animals, while the synaptic contacts appeared on cell processes. At prenatal day20 synaptic contacts were detected for the first time on neuronal cell body surface. The density of synaptophysin-positive granules on both the cell processes in the neuropil, and neuronal cell bodies was sharply and considerably increased by postnatal day 5. Subsequently, until postnatal day 20, the augmentation of their density was insignificant. Serotonin deficiency in a second half of prenatal development, induced by a single injection of parachlorophenylalanine to female rats at gestational day 16 resulted in a significant delay of synaptogenesis in DRN of their offspring in both prenatal and early postnatal periods. With the increase of postnatal age the density synaptic contacts was unequally augmented in various parts of DRN: in DNR-d it approached the control level, while in DRN-v and DRN-1 it remained significantly reduced. The results received suggest serotonin participation in synaptogenesis in DRN. PMID- 23659035 TI - [Neuron contractile and electrical activities as affected by colchicine]. AB - The purpose of this investigation was to analyze the contractile activity of traumatized nerve cell processes and to try to inhibit their retraction by colchicine solution. Isolated living neurons of mollusks (Lymnaea stagnalis and Planorbis comeus vulgaris) were studied using phase contrast and time-lapse microvideorecording. In the control group, contractile activity of nerve cell processes in Ringers solution was detected in 92% of cases. Application of colchicine resulted in the inhibition of retraction of nerve fibers in 86% of neurons. In the experiments designed to study neuron electrical activity, leech Retzius neurons were used. It was found that ganglion incubation in colchicine solution of increased the frequency of spontaneous pulse activity from 0.22 to 0.75 imp/s. The amplitude of spontaneous potentials decreased from 46.9 to 37 mV, the threshold was reduced by 18%, spontaneous spike duration increased from 4.3 ms to 7.1 ms, while the latent period of the response to irritating stimulus increased from 25.0 to 37.9 ms. During the irritation with a frequency of 7-10 Hz, neuron generated higher frequency of pulse activity, than in norm. Thus, it was possible to show, that cochicine can inhibit the contractive activity of the traumatized nerve cell processes, preserving an electroexcitable membrane in a satisfactory state. These results suggest that it is possible to partially inhibit the nerve fiber retraction in vivo, thus preventing the diastasis increase in the nerves that impedes their contact surgical approximation and promotes the development of a massive scar in severed area. PMID- 23659036 TI - [Morphometric evaluation of the effectiveness of post-traumatic peripheral nerve regeneration after a single and repeated courses of electrostimulation]. AB - Sciatic nerve (SN) transection and microsurgical suture were performed in 41 dogs to assess the effect of electrostimulation (ES) on peripheral nerve regeneration. 23 dogs served as a control group, ES of the spinal cord and SN was made with alternating current of 50-Hz frequency in 18 dogs: in 13 dogs one course of 18 sessions was performed within the period of 1-2.5 months after surgery (ESL1), in 5 dogs two courses were performed: the first one--in a similar time interval, the second one--within 6-7.5 months after surgery (ES2). The mean diameter of myelinated fibers (MF) after 2.5, 4, 6, and 12 postoperational months for ES1 was significantly greater than the control values, mainly due to the increase of axonal diameter. After 12 months, the tendency towards the restoration of MF diameter bimodal distribution was marked in ES2, and, to a lesser degree, in ES1. Thus, it was found that ES effectively activates the regeneration and differentiation of MF, but leads to their relative hypomyelination. PMID- 23659037 TI - [Age-related dynamics of morphometric parameters of tibial nerve in dogs]. AB - The morphometric study of the tibial nerve was performed in 10 mongrel puppies aged 2, 4 and 10-11 months and of 7 adult dogs aged 1-3 years. It was demonstrated that during the process of growth of the animals the numerical density of nerve fibers (NF) and endoneural microvessels decreased, while the proportion of soft-tissue component and the values of all the dimensional characteristics of myelin NF significantly increased. Both the processes of myelin NF differentiation and the appearance of mature large-caliber NF at the age of 10 months resulted in the increase of system heterogeneity accompanied by an increment of entropy. The myelin NF population in adult dogs was characterized by high values of organization and redundancy, and, therefore, it is more deterministic and stable, with greater reliability of information transmission along the nerve trunks as communication channels. PMID- 23659038 TI - [Morphological changes of THP-1 tumor cells exposed to dopamine in vitro]. AB - The effect of dopamine (DA) on the viability and morphology of cultured tumor THP 1 cells (human acute monocytic leukemia) was studied. DA in concentration of 10( 5) M had virtually no effect on the culture, while in concentration of 10(-4) M to 10(-3) M it stopped the growth and caused a sharp increase in cell death after 24 and 48 hours. Incubation with DA reduced the cell diameter, progressively increased their vacuolization and intensity of fluorescence after treatment by Falck method. Electron microscopical study has shown that cells exposed for 1 day to DA in the concentrations starting with 10(-4) M, demonstrated smoothing of their surface with the disappearance of microvilli and clasmatosis vesicles, actin filaments perforating the plasma membrane, the emergence of an increasingly dense network of filaments in the cytosole and karyoplasm and, finally, apoptotic cell death. It is suggested that the oncotherapeutic cellular target for DA is a cytosolic G-actin, which at a certain DA concentration, turns into filaments that damage the cells, break the cell cycle and cause cell death. PMID- 23659039 TI - [Age-related dynamics of morphofunctional state of the lymphoid tissue in the wall of human ureter]. AB - Cellular composition of the lymphoid tissue in the ureteral epithelium and lamina propria was studied morphometrically in human postnatal ontogenesis using autopsy material obtained from 32 males of different age (from the neonatal period to the II period of mature age). Lymphoid tissue was found to be weakly developed in the ureteral wall during the studied period of human life. Processes of lymphocytopoiesis were not expressed, while there was high activity of cellular destruction. The reduction of the plasma cell numbers by the II period of mature age is a manifestation of a general decrease of functional activity of the lymphoid tissue in the wall of the ureter. PMID- 23659040 TI - [Human lung topography in the early fetal period of ontogenesis]. AB - Lung holotopy, skeletotopy and syntopy were studied in 70 human fetuses at developmental weeks 16-24 with N. I. Pirogov method, macro-microscopical preparation and using histotopographical sections in three imutually perpendicular planes. It was found that during weeks 16-18, the apex of the left lung was located posteriorly at the level of I intercostal space, at weeks 22-24- at the level of lower surface of I rib. At the right side, the apex was located at the level of upper surface of I rib during the whole period. The lower margin of the right lung was located at the level of IV rib during the whole period, while that of the left lung was detected at the level of III rib only during the beginning of the period. In the early fetal period, the projection of the root of the right lung extended from the lower margin of T(III) vertebral body toT(VI), while that one of the left lung was located at the level of the upper margins of T(IV)-T(VII) vertebral bodies. In the late period, these projections were found at the level of T(IV) (upper vertebral margin)--T(VII) (lower vertebral margin), and T(IV) (lower vertebral margin)--T(VIII) (upper vertebral margin) respectively. Intraorgan bronchi and pulmonary vessels were most clearly visualized in horizontal sections at T(III) -T(IX) levels. The results obtained should be taken into account when carrying out of diagnostic ultrasound and magnetic resonance studies of the fetus and surgical interventions on fetuses. PMID- 23659041 TI - [Epidermal thickness and keratinocyte proliferation after cutaneous application of vitamin D]. AB - Using light microscopy, morphometry and immunohistochemistry, the epidermis of 72 male and female rats was examined 1 day and 1 month after the completion of daily cutaneous applications of vitamin D3-containing composition lasting for two weeks. It was found that vitamin D3 causes a statistically significant reduction in the thickness of interfollicular epidermis and in the number of Ki-67 positive keratinocytes. The identified effects persisted for 1 month after the last application of the preparation. Modifying influence of vitamin D3 on the morphogenetic processes in the epidermis, which were manifested, in particular, by a decreased proliferative activity of keratinocytes, is discussed in the light of the data on the possibility of the formation of its active metabolite- calcitriol--directly in the skin. PMID- 23659042 TI - [The nucleolus of the cell is the site of iron accumulation in the substantia nigra neurons of the human brain]. AB - Distribution of iron in the substantia nigra of the human brain (10 men and women aged 27-78 years) was studied using Perls' histochemical method. Iron ions were demonstrated in the nigral neuropil and melanin-containing neurons. For the first time the nuclei of some neurons were found to contain iron accumulations. The intranuclear iron inclusions correspond to the nucleolus according to their sharp outline and sizes. Detection of iron in the neuronal nucleolus may contribute to the understanding of mechanisms of iron neurotoxicity for nigral dopaminergic neurons. PMID- 23659043 TI - [Cajal body in the neuroendocrine neurons of the paleoamygdala]. AB - The article demonstrates the ultrastructure of Cajal body (CB) that was detected during the electron microscopic study of nucleoplasm of the neuroendocrine neurons of the paleoamygdala of the adult Wistar rats in the study of the dynamics of their functional states throughout the estrous cycle. CB is located in the nucleoplasm close to the nucleolus and appears as a polygon structure, having the size of 0.4 x 0.5 microm, consisting of twisted strands of 40 to 60 nm thickness, which are separated from each other by the material of low electron density, obviously, a continuation of the nucleoplasm. Structural association of CB with other nuclear domains--nucleoli, interchromatin granule clusters were not noticed. CB was found in neurons only at the stage of "return to the initial state", which characterizes the completion of the functional activity of neurons. The number of these neurons was increased at the stage of metestrus. They are characterized by a segregation of nucleolar components, indicating the blockade of the protein synthesis. This fact is associated with the restructuring of CB modular organization, caused by the functional state of neurons. PMID- 23659044 TI - [The method of the superposition of visual space map on a three-dimensional model of the cortical visual center of the analysis of the object motion]. AB - The aim of the present investigation was to develop an algorithm of superposition of retinotopic map of PMLS (posterior medial part of lateral suprasylvian sulcus) visual area on a 3-D model of brain frontal slices. A step by step description of the algorithm is presented. The suggested algorithm may be used for the solution of the various tasks of the analysis of the organization of interneuronal connections. PMID- 23659045 TI - [Method of selective demonstration of proliferating cells in the structures of developing nervous system based on the detection of phosphorylated H3 histone]. AB - Phosphorylated H3 histone is of interest for the study of proliferative activity of the cells in various tissues. Its detection is used in histopathological tumor diagnosis. The purpose of this study was to develop immunocytochemical protocols for the demonstration of H3 phosphohistone in the cells of the developing nervous system for classical light microscopy and confocal laser microscopy. The protocols presented allow to identify the dividing cells in the structures of developing brain with high selectivity and good reproducibility. Zinc-ethanol formaldehyde is recommended as an optimal fixative for H3 phosphohistone. PMID- 23659046 TI - [Methodological approaches to the complex study of the functional morphology of the tracheal epithelial lining in the experiment]. AB - An algorithm is described for the functional and morphological analysis of the trachea in small laboratory animals, including the consecutive in vivo study of the velocity of mucus movement and in vitro analysis of motor activity of the ciliary apparatus in combination with the histological study of the organ. The proposed methodological approaches permits, during a short period of time (20-30 min per one animal) to supravitally register and document in digital format video files with their subsequent visual estimation and mathematical analysis of the parameters studied. These techniques provide high reproducibility of the results with a maximum efficiency and information value and permit to undertake a comprehensive morpho-functional analysis of the investigated object. PMID- 23659047 TI - [Morphometric evaluation of relative adipose tissue content in the human body]. AB - Analysis of the mathematical models of the human body composition revealed main shortcomings of body mass index (A. Quetelet, 1832). This allowed to offer more accurate body mass index (BMI = M/H3), body build index [BBI = (BMI)1/2] and body fatness index (BFI = M/HC2), where (M), (H) and (C) signified the mass, height and wrist circumference correspondingly. PMID- 23659048 TI - [International anatomical terminology: controversial issues]. AB - The article contains an analysis of problems related to the content of the International anatomical terminology (IAT): the relationship and differences between the terms and concepts as the elements of the professional language of morphologists; forms in which concepts are reflected in IAT; classification of the IAT terms according to the principle of their relationship to the categories of concrete and abstract concepts. PMID- 23659049 TI - [The role of lecture form in teaching the morphological disciplines in the medical university under conditions of remodeling of higher medical education. History and actual problems]. PMID- 23659050 TI - [80-years-long history of teaching anatomy to the future doctors in a city of Vitebsk]. PMID- 23659051 TI - [Fundamental museum of the Department of Anatomy of Rostov State Medical University (1917-2012)]. PMID- 23659052 TI - [Effects of stress factors on adult hippocampus: molecular, cellular mechanisms and dorso-ventral gradient]. AB - Adult hippocampus is one of the brain structures selectively vulnerable to stress factors. In the hippocampus, stress-induced neuroinflammation, neurodegeneration, epileptic activity and disturbances of neurogenesis take place. Stress of different modality specifically affects hippocampal structural and functional plasticity, the primary target of the stress hormones are corticosteroid receptors (glucocorticoid and mineralocorticoid receptors). Different parts of the hippocampus along the septo-temporal axis are functionally different. The dorsal hippocampus is in charge for definite forms of learning and memory, primarily spatial, while the ventral part is involved in stress response and anxiety behavior. Differences in basal and stress-induced molecular and cellular mechanisms of neuronal plasticity underlie this functional differentiation. PMID- 23659053 TI - [Serotonin and its immune and physiological effects]. AB - Now that the neurotransmitter serotonin modulates the immune system cells, and its main sources for antigenpresenting cells and lymphocytes are enterochromaffin cells of the gut, peripheral nerves, platelets and mast cells in case of inflammation. Immune cells uptake serotonin because they express receptors for this monoamine and intracellular serotonin transporters. The dendritic cells have a mechanism to transfer serotonin to T lymphocytes during antigen presentation. The macrophages and T cells have the ability to serotonin synthesis. Serotonin can influence mobility and proliferation of lymphocytes, phagocytosis, cytolytic properties, synthesis of chemokines and cytokines. Diversity of immunomodulating effects of serotonin is determined by heterogeneity of serotoninergic receptors. Immunomodulating action of serotonin is evidence of the close relationship between nervous and immune systems. PMID- 23659054 TI - [Role of spatio-temporal non uniformities in blood coagulation regulation]. AB - This paper reviews some contemporary researches of thrombosis and hemostasis process that consider its spatio-temporal dynamics. Among them, there are platelet distribution in the blood vessel and the dependence of the platelet plug growth on the hematocrit level; influence of the tissue factor density on the blood coagulation onset and on the efficacy of some drugs, designed for the hemostasis improvement; regulation of blood coagulation by the flow rate. Mechanisms controlling the mentioned processes are described. Clinical significance and novel diagnostic and therapeutic approaches are discussed from the position of the spatio-temporal non uniformities of thrombosis and hemosatsis. PMID- 23659055 TI - [Influence of maternal factor on motor behavior and lipid turnover in rats exposed to severe psychoemotional stress]. AB - Adverse condition of rat development during the prenatal period (rearing by mother survived brain injury) or during the early post-natal period (cross fostering), causes impairment of motor behavior and a lipid turnover in adult rats. Such rats under severe stress showed decrease of adaptation (as expressed or low indexes of motor impellent behavior and lipid metabolism) in comparison with rats that were grown up by own mother. The psychoemotional stress caused the most expressed deficient behavior in males that were grown up by mothers with brain injury (decrease in serum level of HC and HDL and depressively - similar behavior). PMID- 23659056 TI - [Modern methods of functional tomographic brain imaging for brain function reseaching in norm and pathology]. AB - For many years the modern methods of functional tomographic brain imaging (fMRI and PET) were actively used not only for the research of basic brain functions, but also in clinical practice. In present paper we described the basic characteristics of the signal registered with fMRI and PET, the principles of image reconstruction, as well as the methodological requirements, which are necessary to obtain reliable results. The advantages and limitations of modem tomographic methods of the brain functions investigation are discussed. The need of the complex approach use in brain study is emphasized and methods for the study of functional integration of the brain are suggested. PMID- 23659057 TI - [Regulation of potential-dependant calcium channels by 5-HT1B serotonin receptors in various populations of hippocampal cells]. AB - Metabotropic serotonin receptors of 5HT1-type in brain neurons participate in regulation of such human emotional states as aggression, fear and dependence on alcohol. Activated presynaptic 5-HT1B receptors suppress the Ca2+ influx through the potential-dependent calcium channels in certain neurons. The Ca2+ influx into the cells has been measured by increase of calcium ions concentration in cytoplasm in reply to the depolarization caused by 35mM KC1. Using system of image analysis in hippocampal cells culture we found out that Ca2+-signals to depolarization oin various populations of neurons differed in form, speed and amplitude. 5HT1B receptor agonists in 86 +/- 3 % of neurons slightly suppressed the activity of potential-dependent calcium channels. Two minor cell populations (5-8 % of cells each) were found out, that strongly differed in Ca2+ signal desensitization. Calcium signal caused by depolarization in one cells population differed in characteristic delay and high rate of decay. 5HT1B receptor agonists strongly inhibited the amplitude of the Ca2+ response on KCl only in this population of neurons. The calcium signal in second cell population differed by absence desensitization and smaller amplitude which constantly increased during depolarization. 5HT 1 B receptor agonists increased the calcium response amplitude to depolarization in this population of neurons. Thus we show various sensitivity of potential-dependent calcium channels of separate neurons to 5HTB1 receptor agonist. PMID- 23659058 TI - [Abnormal tropomyosin function in ATPase cycle in hypertrophic and dilated cardiomyopathies]. AB - Pathogenesis of most myopathies including inherited hypertrophic (HCM) and dilated (DCM) cardiomyopathies is based on modification of structural state of contractile proteins induced by point mutations, such as mutations in alpha tropomyosin (TM). To understand the mechanism of abnormal function of contractile system of muscle fiber due to Glu180Gly, Asp175 or Glu40Lys, Glu54Lys mutations in alpha-TM associated with HCM or DCM, we specifically labeled alpha-TM by fluorescence probe 5-IAF after Cys-190 and examined the position and mobility of the IAF-TM in the ATP hydrolysis cycle using polarized fluorescence technique. Analysis of the data suggested that the point mutations in alpha-TM associated with hypertrophic or dilated cardiomyopathy caused abnormal changes in the affinity ofTM to actin and in the position of this protein on the thin filaments in the ATPase cycle. Mutations in alpha-TM associated with HCM caused a shift of TM strands to the center of the thin filament and increased a range of tropomyosin motion and affinity of this protein to actin in the ATPase cycle. In contrast, mutations in alpha-TM associated with DCM shifted the protein to the periphery of the thin filament, reduced the amplitude of the TM movement and its affinity for actin. It is proposed that anomalous behavior of TM on the thin filaments in ATPase cycle may provoke the dysfunction of the cardiac muscle in patients with HCM and DCM. PMID- 23659059 TI - [Influence of protamine on expression of tight junction proteins in Caco-2]. AB - Action of polycation protein protamine on the expression of tight junction proteins (claudins-1, -2, -3 and occludin) which contribute to paracellular transport function was investigated on cellular models of tight (MDCK I cell line) and leaky (Caco-2 cell line) epithelium. The expression of claudins-1,-3 and occludin was observed in both cell lines by methods of immunocytochemistry. Influence of protamine (100 microg/ml; 30 min; apical) on fluorescence intensity of claudins-1, -3 was different in MDCK I and Caco-2 cells. Addition ofprotamine to the incubation medium of Caco-2 cells resulted in significant increase of claudin-3 expression by 45 % (p <0.01) in comparison with control, whereas claudin-1 and occludin expression did not alter. On the contrary, in MDCK I cells protamine induced the significant decrease ofclaudin-1 and -3 expression by 25 % (p <0.001) and 15 % (p < 0.01) respectively, whereas occludin expression did not alter. It was confirmed by the methods of confocal laser scanning microscopy that protamine alter the expression of claudins-1, -3 directly in the tight junctions. Our results suggest that charged chyme components may alter paracellular permeability of epithelium. PMID- 23659060 TI - [Characterisation of enucleated cells apoptosis: human platelets and erythrocytes]. AB - Apoptosis is a common mechanism of programmed cell death in virtually all nucleated cells. In spite of the fact that platelets and erythrocytes are the only enucleated cells in mammals they contain most of the apoptosis machinery of other cells and undergo similar apoptotic processes as nucleated cells except those connected with nuclear and chromatin transformation. Here we compare the mechanisms of platelet and erythrocytes apoptosis induced by different stimuli namely, stimulation ofthrombin and collagen receptor (T/C), inhibitor of BclX family proteins (ABT-373) for platelets, tert-butylhydroperoxide (tBH) and calcium ionophore (A-23187) for erythrocytes. Induction of platelet apoptosis by both methods (T/C and ABT-373) lead to strong phosphoetydilserine (PS) externalization, loss of the mitochondrial membrane potential (DeltaPsim), proteolytic cleavage of some cytoskeletal and regulatory proteins, and microparticle (MP) formation. However, there are clear differences between mechanisms of platelet apoptosis induced by TC and ABT-373. T/C induced apoptotic reaction is very fast (reach the maximum at 5 min), whereas ABT-373 induced reaction is more prolonged (first apoptotic evidence appears only after 30 min and reach the maximum after 3 hours). MP formation is much more pronounced in T/C than in ABT-373 stimulated platelets, whereas caspase 3 activation is much more stronger in ABT-373 than in T/C stimulated platelets. The main differences between these two apoptotic pathways are connected with aIIbp3 integrin, which activation appears only after T/C stimulation. For tBH experiments on erythrocytes we established optimal conditions (0.25x1012 cells/L, and strong, 1500 RPM stirring) for elucidation of apoptotic processes and found two independent ways of erythrocytes apoptotic processes; calcium independent, connected with met hemoglobin (metHb) formation (tBH stimulation), and calcium dependent pathway (A-23187 stimulation). Erythrocytes apoptosis induced by tBH is characterized by formation ofmetHb, cell shrinkage, fast (95 % during 3 hours) PS externalization, yield of hemoglobin, probably by vesicle (MP) formation. These cells are transformed to stomatocytes, become highly rigid, and could not be lysed even in pure water. All these reactions are calcium independent. Whereas increase of intracellular calcium concentration by A-23187 connected with formation of exinocytes, less pronounced (17 % during 3 h, 35 % during 15 h) PS externalization and rigidity (lysed in 50 mOsm buffer). PMID- 23659061 TI - [Nitric oxide modification of hemoglobin oxygen affinity in different conditions of oxygenation]. AB - The aim of the present study was to investigate the role of nitric oxide (NO) in the regulation of hemoglobin oxygen affinity (HOA) in the presence of different oxygen partial pressure. In this research the effect of NO donors on gas transport, acid-base balance, HOA indexes, metHb, iron-nitrosylhemoglobin amounts, and total nitrite/nitrate concentration was estimated in vitro. Experimentally, positive correlation was found between NO-dependent shift of HOA and hemoglobin oxygen saturation level. In conclusion, NO is a component of autonomous intraerythrocytic system of HOA regulation, which action is determined by oxygen in the blood. We assume that the physiological significance of such NO action is to maintain aerobic metabolism through optimal blood oxygenation in the pulmonary circulation, on the one hand, and, on the other hand, its compensation under low oxygen tension in the working tissues. PMID- 23659062 TI - [Genetic determinants of generating the motor pattern of rhythmic movements in Drosophila melanogaster]. AB - To investigate molecular and cellular mechanisms of central pattern generators (CPG) functioning, we previously selected candidate genes mutations of which are accompanied with deviations in Drosophila melanogaster motor activity. In this research we tested locomotor parameters in lines with post transcriptional silencing of 12 candidate gene in Drosophila central nervous system. Silencing was provided by synthesis of interfering RNA by means of GAL4/UAS system under control of CNS-specific gene promoters (elav, nrv2, appl, tsh). It was found that RNA interference of most genes are accompanied with changes in one or several locomotor parameters. Pattern of revealed deviations under control of different promotors makes it possible to determine the genes that activity in nervous system is necessary for proper functioning of locomotor CPG. PMID- 23659063 TI - [Eubiosis and dysbiosis of gastrointestinal tract: myths and reality]. AB - Current data on eubiosis and dysbiosis of gastrointestinal tract are discussed along with the role of its microflora in human body under normal and pathological conditions. Certain debatable problems are discussed. Classification of colonic dysbiosis is presented with reference to its stages, functions of normal flora, "myths" related to the science of eubiosis and dysbiosis, the authors views of the problem. Diagnostic methods and their informative value are described. The main diseases and syndromes associated with intestinal dysbiosis are discussed. In conjunction with approaches to its correction. PMID- 23659064 TI - [Hyperuricemia and cardiovascular continuum]. AB - Many recent reports suggest the relationship between hyperuricemia, risk and prognosis of arterial hypertension and coronary heart disease. The works on the clinical and prognostic significance in chronic heart failure are few even if this pathology deteriorates prognosis of some cardiovascular diseases. Hyperuricemia is considered to be a component of cardiovascular continuum, risk factor of chronic heart failure and marker of its unfavourable outcome. Prognostic significance of hyperuricemia in patients with chronic heart failure is discussed. PMID- 23659065 TI - [The role of autonomous nervous system in the development of atrial fibrillation]. AB - Atrial fibrillation (AF) is a challenging medical problem accounting for the development of stroke, thromboembolism, and cardiac failure. Disbalance in the autonomous nervous system (ANS) is a leading cause of AF. There is definitive evidence of the relationship between vegetative innervations, initiation and maintenance of AF, the main contributors being hyperactivity of ANS and uncontrolled release of neurotransmitters that shorten atrial refractoriness. The neurotransmitters make up the triggering mechanism of AF. The present review focuses on the role and mechanism of AF in ANS disbalance. PMID- 23659066 TI - [Low and very low density lipoproteins: pathogenetic and clinical significance]. AB - LDLP and VLDLP have different biological functions: phylogenetically older LDLP transfer FA that serve as substrates for intracellular production of energy and ATP while VLDLP transfer FA--precursors of cell membranes and eicosanoids. The cells absorb LDLP via apoB-100 endocytosis and VLDLP through apoE/B-100 receptors. VLDLP consist of palmitic and oleic VLDLP and LDLP of linoleic and linolenic LDLP. The contribution of LDLP to the development of HLP atherosclerosis and atheromatosis is negligible. LDLP form palmitic and oleic VLDLP with hydrated LDLP density. Blockade of LDLP absorption by apoB endocytosis and deficit of poly-FA constitute the etiological basis of atherosclerosis. Its pathogenetic basis is the excess of palmitic VLDLP with LDPL density in the intercellular space that block absorption of linoleic LDLP with all transferred SC poly-FA. Atheromatosis is clinically and prognostically most significant symptom of atherosclerosis associated with accumulation of ligand-free VLDLP and LDLP in arterial intima of the elastic type as the local pool of interstitial tissue for intravascular pool of intercellular medium. Type 2 diabetes mellitus in aged patients is a symptom of atherosclerosis resulting from SC poly-FA deficit and GLUT4 incompetence. Insulin-dependent cells differ in the degree of insulin resistance. Non-alcoholic fatty liver disease, synthesis of a physiological palmitic TG by hepatocytes and excessive formation of palmitic VLDLP in liver integrate pathogenesis of atherosclerosis and hepatic steatosis. The main pathogenetic factor is the excess of palmitic s-FA and palmitic TG. PMID- 23659067 TI - [Methods for the correction of dysregulated erythropoesis in coronary heart disease]. AB - AIM--to develop pathogenetic methods for the correction of dysregulated erythropoesis in coronary heart disease (CHD). 20 patients with myocardial Q infarction and 52 ones with chronic CHD. 26 patients of the CHD group suffered anemia. Ten volunteers without signs of cardiovascular pathology served as controls. Characteristics of peripheral blood and iron metabolism, serum levels of inflammation markers and erythropoietin (EPO) were measured. In most CHD patients elevated levels of TNF-alpha inhibited hepatic synthesis of EPO. Low hepcidin production was associated with increased EPO levels and low iron content in blood. Anemia developing in CHD patients may cause not only inflammation but also depletion of iron reserves. Correction of dysregulated erythropoesis in coronary heart in CHD must be performed with due regard for the above mechanisms on an individual basis. PMID- 23659068 TI - [The results of application of the rapid quantitative assay for fatty acid binding protein at the onset of acute coronary syndrome]. AB - Fatty acid-binding protein (FABP) appearing in blood within a few hours of acute coronary syndrome (ACS) is a marker of myocardial necrosis. We estimated the diagnostic value of rapid immunochromatographic test for FABP in patients with ACS and compared it with other cardiomarkers: troponin 1 (Tn1), myoglobin and creatin phosphokinase-MB (CPK-MB). The study included 100 patients aged 61.3 +/- 12.9 yr hospitalized with ACS within 2 hr after beginning of anginous pain. FABP was detected by CardioFABP test, Tn1, myoglobin and CPK-MB by quantitative assays. Blood samples were taken 2, 6, and 24 hr after the onset of anginous pain. Acute myocardial infarction was diagnosed in 79 patients, unstable angina in 9, FC 3-4 angina of effort in 4, vasospastic angina in 1, non-coronary pathology in 7. Sensitivity of FABP, Tn1, myoglobin and CPK-MB 2 hr after onset of pain was 84.8; 34.2, 65.8; 22.8% respectively: it was 98.7: 92.4; 96.2; 82.3% in 6 hr and 56; 100; n/d; 86.7% in 24 hr. Specificity of FABP was 100% in all time intervals. It is concluded that FABP level determined by rapid qualitative assay within 2-6 hr after onset of ACS is a more sensitive cardiomarker than Tn1, myoglobin and CPK-MB for diagnostics of ACS. PMID- 23659069 TI - [Potential utility of optic aggregometry for identification of patients with coronary heart disease resistant to acetylsalicylic acid]. AB - We estimated potential of optic aggregometry for the identification of patients with coronary heart disease in 271 patients with coronary heart disease (CHD) and 230 ones with FC 2-3 angina of effort. Duration of the study was 24 months. Platelet aggregation in patients given anti-aggregation therapy with acetylsalicylic acid (ASA) was assessed with a Biola laser aggregometer (Russia) from changes in transmissivity in the presence of aggregation agonists. Optic aggregometry permitted to distinguish the forms of CHD producing increased risk of atherothrombotic complications in patients with enhanced platelet functional activity resistant to ASA. The prevalence of ACA resistance was estimated at 10% and did not depend on the form of CHD. It was 11.3 and 9.95% in patients with stable angina and acute coronary syndrome respectively. Resistance to ACA was an independent predictor of atherothrombotic complications in patients with different forms of CHD (OR = 8.25; 95% CI 5.77-11.82; p = 0.05). PMID- 23659070 TI - [Cognitive functions and extracranial circulation in patients with hypertonic crisis]. AB - We studied effects of enalaprilate and infedipine therapy on the cognitive functions and extracranial circulation in 60 patients with chronic AH complicated by acute encephalopathy. 10% of them had predemential disorders on day 1 of hospitalization and 90% mild cognitive problems. Half of the patients suffered reduced circulation in the common carotid artery. The contribution of impaired extracranial circulation to cognitive dysfunction in the acute period of hypertonic crisis was higher than that of high SAD and DAD. Antihypertensive therapy improved bloodflow in extracranial vessels, decreased their systolic and diastolic indices but failed to eliminate mild cognitive disorders in 65% of the patients. Visual-spatial orientation was restored more frequently than verbal auditory memory. Enalaprilate and infedipine had similar angio- and cerebroprotective effects but the latter had more pronounced favourable effect on verbal auditory memory than the former. The degree of recovery of cognitive function 2 weeks after hypertonic crisis depended not only on the form of cognitive disorder and therapeutic modality but also on the patient's age. Hemodynamic parameters and age 2 weeks after antihypertensive therapy are predictors of residual cognitive dysfunction soon (2 weeks) after recovery. PMID- 23659071 TI - [Results of duplex scanning of brachiocephalic arteries and estimation of the lipid spectrum in coronary heart disease and arterial hypertension in indigenous and alien population of Yamalo-Nenetsky Autonomous District]. AB - The work aimed at studying atherosclerotic lesions in brachiocephalic arteries and lipid spectrum in coronary heart disease (CHD) and arterial hypertension (AH) in indigenous and alien population of Yamalo-Nenetsky Autonomous District. It included 200 patients with CHD and AH (men and women aged 21-55 years, mean 48.2 +/- 07 yr). They were allocated to indigenous and alien groups (100 persons each). The patients matched for age and sex were examined by duplex scanning based at an outpatient facility (Salekhard). The indigenous population showed more pronounced thickening of the intima-media complex (IMC) of the common carotid artery (p = 0.001) and more frequent lesions of the main head arteries with stenosis of different severity (especially in internal carotid arteries). Total cholesterol, LDLP and atherogenicity index were similar in both groups and higher than normal. Indigenous subjects had less atherogenic structure of the lipid spectrum due to lower TG and VLDLP but higher HDLP levels. PMID- 23659072 TI - [Profile of autonomous regulation of circulation in patients with severe left ventricular myocardial hypertension]. AB - The possibility of concomitant hypertrophic myopathy (HCMP) and hypertensive disease (HD) in the same patient is debatable. This study aimed at estimating peculiarities of autonomous regulation of circulation and clinic-pathogenetic features of the disease in patients with marked hypertrophy of interventrucular septum (IVS) depending on the presence of arterial hypertension (AH). The patients with manifest left ventricular hypertrophy (MLVH) were divided into those with and without AH. Clinical examination included assessment of the vasomotor cardiopulmonary baroreflex (VM CPBR). Valsalva maneuver, sensitivity of spontaneous arterial baroreflex (ABR), cardiac rhythm variability at rest and orthostasis. Hemodynamic parameters were determined by continuous non-invasive recording using a Finometer arterial pressure monitor. Patients with HCMP showed reduced VM CPBR, preserved ABR, Valsalva and sympatovagal indices. Similar but less pronounced changes were documented in patients with MLVH, AH and HD. Profile of autonomous regulation of circulation in patients with manifest left ventricular myocardial hypertension and AH was significantly different from that in HCMP patients but similar to the profile in the patients with HD. PMID- 23659073 TI - [Predictors of the closure of tuberculosis infiltrate decay cavities during the conservative treatment of infiltrative tuberculosis]. AB - We studied predictors of the closure of tuberculosis infiltrate decay cavities (DC) in the affected regions in patients with infiltrative lung tuberculosis (ILT) by clinical examination. X-ray laboratory and psychological methods 103 patients were under observation for 12 months and received standard therapy. The closure was achieved during the first 4 months in 74 patients but did not occur in 29 ones. Logistic regression analysis showed that the probability of DC closure in the first 4 months decreases in parallel to the initial character of complaints of "chest pain", the size of tuberculosis infiltrates determined in X ray study, results of thymol test, content of lipid peroxides in expirates, depressive "fatigue" and "suicidal thoughts". The probability of DC cavity during 4 months increased with the initial "number of destructions" in the infiltrate (by X-ray) and depressive "loss of working ability". Results of regression analysis permit to predict the closure of DC during the first 4 months with sensitivity 98.3% and specificity 82.4%. PMID- 23659074 TI - [Efficacy of reamberin for the treatment of acute intestinal infections caused by opportunistic bacteria]. AB - Reamberin was shown to improve the efficacy of the treatment of acute intestinal infections caused by opportunistic bacteria. Its introduction into combined therapy accelerated normalization of the patients' general conditions, improved their well-being, eliminated syndrome of infectious toxicosis, diarrheic and abdominal pain syndromes, decreased duration of postinfectious asthenia, had beneficial effect on biochemical and immune parameters. Reamberin reduced the level of medium-sized molecules and malonic dialdehyde to the upper normal value which suggests elimination of endogenous "metabolic" intoxication syndrome, normalization of the level of circulating immune complexes and their fractional composition. The study showed that introduction of reamberin in combined therapy of acute intestinal infections is pathogenetically justified. PMID- 23659075 TI - [Variant form of hepatic lesion: autoimmune hepatitis--primary biliary cirrhosis in patients with Sjogren's syndrome]. AB - Two clinical observations of the variant form of hepatic lesion: autoimmune hepatitis--primary biliary cirrhosis with systemic manifestations are presented in patients with long-standing Sjogren's syndrome, one at the stage of lever cirrhosis, the other at stage F2 of fibrosis. Difficulties encountered in diagnostics and the necessity of changing the entire spectrum of autoimmune markers characteristic of Sjogren's syndrome, autoimmune hepatitis and primary biliary cirrhosis are discussed. The possibility of different forms of hepatic lesions in autoimmune hepatitis--primary biliary cirrhosis is emphasized. PMID- 23659076 TI - [Etinger: a page in the history of cardiology in the USSR]. PMID- 23659077 TI - [D4 family genes in vertebrates: genomic organization and expression]. AB - A family of closely related genes, named the d4 family, has been previously identified in mammals. It comprises three genes encoding structurally related proteins. The hallmark of the family is d4 domain--a double-paired finger motifthat consists of two tandemly arranged PHD finger domains. These genes are expressed in various tissues and at various developmental stages. Two of those, neuro-d4 and cer-d4, are strictly neurospecific and their expression is developmentally regulated. Another gene, ubi-d4/Requiem is ubiquitously expressed in all embryonic and adult tissues at the same levels. d4 family genes are evolutionary conserved. Human, mouse, rat, and chicken d4 genes have been cloned. The only d4-like gene was found in the genome of nematode C. elegans. The sole member of d4 family was identified also in the genome of D. melanogaster. However, d4 genes are not believed to be present in the genomes of prokaryotes and yeast. This review describes genomic organization and expression ofd4family genes in different organisms. PMID- 23659078 TI - [Expression of TGFbeta family factors and FGF2 in mouse and human embryonic stem cells maintained in different culture systems]. AB - Mouse and human embryonic stem cells are in different states of pluripotency (naive/ground and primed states). Mechanisms of signaling regulation in cells with ground and primed states of pluripotency are considerably different. In order to understand the contribution of endogenous and exogenous factors in the maintenance of a metastable state of the cells in different phases ofpluripotency, we examined the expression of TGFbeta family factors (ActivinA, Nodal, Leftyl, TGFbeta1, GDF3, BMP4) and FGF2 initiating the appropriate signaling pathways in mouse and human embryonic stem cells (mESCs, hESCs) and supporting feeder cells. Quantitative real-time PCR analysis of gene expression showed that the expression patterns of endogenous factors studied were considerably different in mESCs and hESCs. The most significant differences were found in the levels of endogenous expression of TGFbeta1, BMP4 and ActivinA. The sources of exogenous factors ActivnA, TGFbeta1, and FGF2 for hESCs are feeder cells (mouse and human embryonic fibroblasts) expressing high levels of these factors, as well as low levels of BMP4. Thus, our data demonstrated that the in vitro maintenance of metastable state of undifferentiated pluripotent cells is achieved in mESCs and hESCs using different schemes of the regulations of ActivinA/Nodal/Lefty/Smad2/3BMP/Smad1/5/8 endogenous branches of TGFbeta signaling. The requirement for exogenous stimulation or inhibition of these signaling pathways is due to different patterns of endogenous expression of TGFbeta family factors and FGF2 in the mESCs and hESCs. For the hESCs, enhanced activity of ActivinA/Nodal/Lefty/Smad2/3 signaling by exogenous factor stimulation is necessary to mitigate the effects of BMP/Smadl/5/8 signaling pathways that promote cell differentiation into the extraembryonic structures. Significant differences in endogenous FGF2 expression in the cells in the ground and primary states of pluripotency demonstrate diverse involvement of this factor in the regulation of the pluripotent cell self-renewal. PMID- 23659079 TI - [Cyclic rejuvenation in the development of shoots of Canary Island pine (Pinus canariensis C. Sm.)]. AB - Age-related changes in the structure of shoots are described for a 6-m Canary Island pine tree (Pinus canariensis C. Sm.) growing in a greenhouse. These changes in the structure of monopodial shoots of the crown have a periodic character and are manifested in the form of a cyclic rejuvenation. PMID- 23659080 TI - [Effect of ectopic expression of NtEXPA5 gene on cell size and growth of organs of transgenic tobacco plants]. AB - We obtained transgenic tobacco plants demonstrating overexpression of NtEXPA5 gene that encodes alpha-expansin of Nicotiana tabacum. The transgenic plants were characterized by increased size of leaves and stems. However, size of flowers remained almost unchanged. The increase of organ sizes was induced by cell stretching only. Moreover, the number of cell divisions was even decreased. The obtained data suggest tight interaction between cell stretching regulation and cell division, which together provide the basic mechanism aimed at the controlling of plant organ sizes. PMID- 23659081 TI - [Functional role for MAP kinase signaling in cell lineage and dorso-ventral axis specification in the basal gastropod Testudinalia testudinalis (Patellogastropoda, Molluska)]. AB - In Spriralia, the specification of cell lines in the course of development is provided by maternal factors. However, recent studies demonstrated the importance of inductive processes whose significant element is cellular signaling. Our data allow us to speak of the dependent specification of a number of cell lines at the early stages of development of the mollusk Testudinalia testudinalis (Testudinalia tessellate, Patellogastropoda), including the period when the determination of the 3D cell takes place, which is accompanied by a change in the shape and establishing of contacts with animal micromeres by one of the macromeres of the third quartet. It is exactly at this moment that activation of MARK was registered in the 3D blastomere-organizer. An analysis of the influence of the U0126 blocker of the MAP-kinase way on the development of Testudinalia showed that the greatest effect of the inhibitor is observed during the cultivation of embryos until the sixth cycle of fragmentation. It should be noted that a scale of correlation of the degree of defects and increase in concentration exists. Absence of the functioning retractor, disorganization of the muscle system, and abnormal structure of the shell (to the extent of complete absence of the shell), as well as velum, foot, and mantle fold, were observed in a considerable part of larvae after a lengthy upkeep of the objects in the U0126 solution. At the same time, none of the experiments showed a complete disruption of the specification of the dorsoventral axis, which produces a larva with a four ray radial symmetry. This attests in favor of the existence of various molecular mechanisms of determination of the secondary body axis among the animals from the group Spiralia. PMID- 23659082 TI - [Graduated change of life expectancy in mice in ontogenesis]. AB - Life expectancy of descendants of a normal female mouse and a male with an inherited growth inhibition mutation discovered in a laboratory population was investigated. The hereditability of the characteristic allows us to consider it a result of mutation. It was shown that, in mice, the curve of dependence of life expectancy on their serial number in a row of increase in life expectancy (curve of rank distribution) has step-like shape for mutant males and females, as well as for males with normal development. The first grade of mice death on the curve of rank distribution was observed at one month after their birth and was characteristic only of males and females with a mutation during the period of maximum lag in weight as compared with their normal relatives. The surviving mutants catch up to the normally developing individuals within two months and externally become indistinguishable from them. The subsequent grades of death in mutants and normal males coincide on the time axis. The steps are absent on the rank curves of life expectancy of normally developing females. The time intervals between the steps are reproduced in parallel groups of mice and, hence, are not casual deviations from theoretical curves and are of a regular nature. The discovered phenomenon is interpreted within the scope of a hypothesis about the realization of the genetic program of ontogenesis, which provides periodic change of vitality stages with stages of sensitivity to external risk factors, which increase the probability of death, by mice. Absence of such stages in the group of normally developing females can be explained by shifts in development, which are produced by the irregular performance of reproductive functions. PMID- 23659083 TI - More heart needed? PMID- 23659084 TI - HPV oropharyngeal cancer: a killer among us. PMID- 23659085 TI - Dental photography. PMID- 23659086 TI - Dr. Goodchild responds. PMID- 23659087 TI - Fracture resistant endodontic and restorative preparations. PMID- 23659088 TI - Dr. Khademi responds. PMID- 23659089 TI - Dr. Herbranson responds. PMID- 23659090 TI - Dr. Clark responds to Dr. Musikant. PMID- 23659091 TI - Endodontics. PMID- 23659092 TI - Dr. Khademi responds. PMID- 23659093 TI - Dr. Clark responds to Dr. Marrone. PMID- 23659094 TI - Robert C. Margeas, DDS, discusses the latest trends in minimally invasive dentistry. PMID- 23659095 TI - The role of cements in dental lant success, Part I. AB - Peri-implant disease can be the result of residual excess cement. While there is no ideal implant restorative cement, the clinician must be aware that the material selection for implant restorations should not be based on properties which are more suited to restoration of the natural dentition. More appropriate criteria would be those unique to implants and the specific challenges these medical devices bring to the restorative dentist. PMID- 23659096 TI - Solving complex full-arch cases with simple solutions. AB - This case report described a new technique for immediately loading an implant supported fixed screw-retained bridge that has flat abutments to achieve a superior passive fit. The definitive prosthetic bridge was placed within 72 hours from surgery and follow-up data over a 5-year period are presented. Good aesthetic results were achieved, and at the end of the follow-up period neither biological nor biomechanical complications were observed. PMID- 23659097 TI - Update on apexogenesis: case reports: achieving predictable root maturation in young patients. PMID- 23659098 TI - The shaping movement: fifth-generation technology. PMID- 23659099 TI - Implant therapy in the aesthetic zone: maintaining gingival margins. PMID- 23659100 TI - Management of occlusion over implants, Part I. Three 10-year case follow-ups and evaluations. PMID- 23659101 TI - The new science of strong endo teeth. PMID- 23659102 TI - Advancing the standard of care with the LANAP protocol. PMID- 23659103 TI - Endoscopic periodontal debridement. PMID- 23659104 TI - [Standards and outcome measures in cardiovascular rehabilitation. Position paper GICR/IACPR]. AB - Despite major improvements in diagnostics and interventional therapies, cardiovascular diseases remain a major health care and socio-economic problem in Italy. Costs and resources required are increasing in close correlation to both the improved quality of care and to the population ageing. There is an overwhelming evidence of the efficacy of cardiac rehabilitation (CR) in terms of reduction in morbidity and mortality after acute cardiac events. CR services are by definition multi-factorial and comprehensive. Furthermore, systematic analysis and monitoring of the process of delivery and outcomes is of paramount importance. The aim of this position paper promoted by the Italian Association for Cardiovascular Prevention and Rehabilitation (GICR-IACPR) is to provide specific recommendations to assist CR staff in the design, evaluation and development of their care delivery organization. The position paper should also assist health care providers, insurers, policy makers and consumers in the recognition of the quality of care requirements, standards and outcome measure, quality and performance indicators, and professional competence involved in such organization and programs. The position paper i) include comprehensive CR definition and indications, ii) describes priority criteria based on the clinical risk for admission to both inpatient or outpatient CR, and iii) defines components and technological, structural and organizing requirements for inpatient or outpatient CR services, with specific indicators and standards, performance measures and required professional skills. A specific chapter is dedicated to the requirements for highly specialized CR services for patients with more advanced cardiovascular diseases. PMID- 23659105 TI - [Cardiovascular risk prediction in the real world. The discouraging evidences coming from literature]. AB - Risk prediction plays a leading role in cardiovascular (CV) prevention. Thus, several risk charts have been developed in different Countries in the attempt to identify subjects at high risk who might benefit from more aggressive and early interventions. However despite the availability of several risk charts, they are underutilized in clinical practice. Indeed risk charts show main limitations: they estimate absolute, but not individual risk; their performance is affected by changes on the incidence of CV diseases; they do not take into account the duration of risk exposure, which is related to the progression of atherosclerosis. Moreover, risk estimate might be less accurate in younger, in women, and in the elderly. Addition of novel risk markers have substantially failed to improve risk charts' discrimination power. Imaging has recently gained relevance in CV risk stratification for its ability to detect subclinical atherosclerosis. Among imaging techniques coronary artery calcium score(CACS) emerged as the most powerful and independent predictor of CV events. Hence, a CACS-based screening strategy have been proposed in all asymptomatic middle-aged people. However since CACS it is still quite expensive and not-radiation free, it is not recommended by most scientific guidelines. Conversely, detecting subclinical organ damage (SOD) like LV hypertrophy, carotid plaque, renal failure, microalbuminuria or the metabolic syndrome in subjects at intermediate risk is pretty cost-effective yielding to reclassification of subjects into higher-risk strata. Thus, merging information coming from different tools (risk scores, biomarkers, and non-invasive imaging) individual risk might be better stratified saving costs. In the next future, an integrated, semi-automated, high reproducible and inexpensive ultrasound approach could represent a key point to approach the individual risk. PMID- 23659106 TI - Multiprofessional and intrahospital experience for diagnosis and treatment of pulmonary arterial hypertension. AB - BACKGROUND: Referral centres for pulmonary hypertension will provide care by a multiprofessional team, which should as a minimum comprise: consultant physicians with a special interest in PH, clinical nurse specialist, radiologist, cardiologist with expertise in echocardiography. AIMS: this study sought to determine whether the experience of the establishment of a clinic for pulmonary arterial hypertension, initially created only for the treatment and diagnosis of heart failure, may be considered positive. METHODS: From 1 July 2008 to January 1, 2012 we evaluated 80 patients in our ambulatory dedicated to the diagnosis and treatment of PAH. All patients were performed to clinical evaluation, ECG, and echocardiography with estimation of the sPAP. Then we evaluated the functional capacity through cardiopulmonary exercise testing or six minute walking test (6MWT). RHC was required to confirm the diagnosis of pulmonary arterial hypertension. RESULTS: 80 patients (mean age: 50.9 +/- 18.68 years, 31 males) were evaluated in our center; the largest groups subjected to screening were thalassemia (21 subjects), rheumatologic patients (18 patients), respirators, suspected of "out-of Proportion" (12 patients) and 4 patients with OSAS. 8 adult congenital heart patients. A diagnosis of PAH after right heart catheterization was possible in 25 cases. In particular, among patients with pulmonary arterial hypertension, 8 had a rheumatic etiology (systemic sclerosis), 2 post thromboembolic disease, 5 patients had congenital heart disease, 1 patient with HIV infection, 1 patient with thalassemia major, 1 chronic lymphocytic leukemia and 1 with myelodysplasia. CONCLUSIONS: The initial experience of our center and network within our hospital may be considered positive, because it permitted to patients easy access to hospital services, to undertake a comprehensive prognostic stratification and to recognize the early signs of worsening in subsequent tests. PMID- 23659107 TI - Anterior mitral valve aneurysm perforation in a patient with preexisting aortic regurgitation. AB - We report the case of a 71-year-old man hospitalized for acute heart failure. Transthoracic and transesophageal echocardiography showed mitral valve aneurysm (MVA) rupture and severe mitral regurgitation. No vegetations but significant aortic regurgitation were also observed. MVA perforation is a rare life threatening condition that typically occurs as a complication of endocarditis but may also be associated with other diseases, in particular connective tissue disorders. In the present case, the absence of such etiology suggests a possible role for of aortic regurgitation in MVA rupture secondary to a "jet lesion" mechanism. PMID- 23659108 TI - Atrioventricular node reentrant tachycardia (AVNRT) after mitral valvuloplasty during cardiac rehabilitation. AB - We descrive a patient who presents palpitations during cardiac rehabilitation after mitral valvuloplasty. ECG showed regular narrow QRS tachycardia compatible with Atrioventricular Node Reentrant Tachycardia. After slow pathway radiofrequency catheter ablation, the patient completed the rehabilitation program remained tachycardia and palpitations-free. PMID- 23659109 TI - [Preventive and rehabilitative cardiology in Sicily]. PMID- 23659110 TI - [Interannual changes in PAR and soil moisture during the warm season may be more important for directing of annual carbon balance in tundra than temperature fluctuations]. AB - A lot of studies on the impact of global climate changes on natural communities deal with cryogenic ecosystems, tundra in particular, since they are delimited by low air temperature and permafrost, thus being extremely sensitive to long-term climate fluctuations. Continuous warming in Northern Hemisphere is unmasking all the more details concerning complex system of direct relationships, feedbacks, and interactions of carbon balance factors as the main response function. While the set of such factors may be viewed as more or less complete, their relative contribution to C-balance, as is becoming clear with accumulating results of field observations, directly depends on temporal scale of observations and is not constant. As the results of field observations and modeling of tundra ecosystems show, any one of significant factors can become the leading one within the boundaries determined by the given scale of observations. Even the least significant factor can become the determining one for direction of carbon annual net flux in an ecosystem, if contributions of more significant factors canceled each other during the period of observations. In the most general situation, the greater is the variation of a significant factor during the period of observations, the larger is its partial contribution. The complete set of independent variables of C-balance is not limited by abiotic factors but should include such an important factor as a stock of plants living top mass, which can be treated as not only the natural product of C-balance but also as its independent parameter. PMID- 23659111 TI - [Solution of trap tube test by hooded crows (Corvus cornix L.)]. AB - Eight hooded crows (Corvus cornix L.) were tested for their ability to use a piston (a stick with two attached clear plates between which the food is enclosed such that moving the stick would move the food) to get the reward out of a transparent tube avoiding a trap. Six out of eight crows learned to use a piston to extract a food reward from a transparent non-trap tube. One out of these six birds successfully performed the task in which it had to avoid a trap to retrieve a reward, in the first trial showing spontaneous comprehending of the task structure. Four crows learned to perform this task using the trial-and-error method. To find out a mechanism these crows used to perform the task, birds were presented with two transfer tasks (tests) in which we changed the relative positions of components in the apparatus. We found out that crows performed transfer tasks using rather concrete rules than immediate estimation of the relative positions of the components in the apparatus. PMID- 23659112 TI - [Temporal variability in model coefficients: Bupalus piniarius as a case study]. AB - Given a population dynamics model and a sufficiently long time series of data, the model parameters can be measured in different segments of this series to get respectively different estimates and a model with time-variable parameters. The variations in model parameters can be caused either by variations in the environmental conditions which affect population size, or by mere demographic stochasticity. As an example, a possible approach to the issue is considered for the data on fluctuations in the population density of pine moth (Bupalus piniarius L.) in Germany. To approximate the data, the well-known Moran-Ricker model is used, which has a rich variety of dynamic regimes. Parameter estimation was carried out by the least squares method (along 12 out of 58 values). The analysis of trends in the two series of model coefficients--the maximal growth rate and the coefficient of self-regulation--reveals that the changes in both indexes are low for quite a long period of time (60 years), and the hypothesis of no directed trends in the environment changes turns out statistically plausible. PMID- 23659113 TI - [Insects at the borderline between the Permian and the early triassic (Urzhum - Olenek age) and the problem of Permian-Triassic biodiversity crisis]. AB - Distribution of 115 insect families is considered in 15 local assemblages of European Russia, Siberia, Australia and South Africa. The assemblage ages embrace the Urzhum stage of the Middle Permian, the Late Permian, and the transitional Permian-Triassic interval. The assemblages are ordered statistically using two criteria. Ordination after the appearance of a fauna, that is, relation of the number of younger vs. older families, is found to be generally consistent with the stratigraphic data. The method of minimizing the gaps (ghost ranges) in distribution of the families is useful in interpreting the results. Urzhum time is characterized by the balance of emergence and extinction of families (counted as their first and latest appearances, respectively). In Severodvinsk and particularly in Vyatka time, the number of first appearances was decreasing resulted in prevailing extinction. In the transitional Permian-Triassic interval, the emergence of new families accelerated. Initially, the appearance of assemblages was typically Paleozoic (with older families prevailed). It changed gradually, so as by the end of Vyatka time it turned to be quite post-Paleozoic. Diversity was the highest in Severodvinsk time, and it halved at Vyatka time and at the transition interval. However, if we consider transitional families (those not found on a particular interval, but known before and after), the extinction rate reduces to one-third. And when normalized after the material volume, the diversity drop decreases up to a quarter. There was no mass extinction found at the end of the Permian, and the less so at the Permian-Triassic boundary and during the Lower Triassic. Structure of the Permian-Triassic diversity crisis is similar to that of the Cretaceous crisis in many respects. Since the Middle Triassic and up to now, the biodiversity kept increasing quickly and continuously. This implies that the Permian-Triassic crisis resulted in profound modification of the biosphere structure, so as its capacity increased manifold. PMID- 23659114 TI - [Molecular criteria in insects systematics: bar-coding gene COI range of variability as a taxonomic criterion for genus, tribe, and subfamily, with Chironominae and Orthocladiinae midges (Chironomidae, Diptera) as a case study]. AB - Contemporary systematics of insects is based mainly on morphological traits. However, their usage is limited both by high variability and complications in comparisons of remote taxa due to low number of common traits. In whole, this leads to a somewhat subjective view when elaborating the system. Unlike morphological ones, molecular traits of taxa, revealed by use of marker genes such as gene cytochrome-c-oxidase I (COI), are less variable and more uniform, which allows them to be used as a criterion of genus, tribe, and subfamily for a wide range of organisms. Application of molecular criteria appears to be all the more important when constructing the system for groups of organisms with high morphological and specific diversity, such as midges (Chironomidae, Diptera). Last years, the DNA-sequence of gene COI is becoming widely used for species identification as a bar-coding one. Its use as a criterion for taxa of super species level is hampered by its high nucleotide variability. We established the bounds of COI nucleotide and aminoacid divergence between midge species of Chironominae subfamily belonging to the same genus, same tribe, different tribes, as well as between species of Chironominae and Orthocladiinae subfamilies. It is shown that the level of aminoacid divergence reflects molecular boundaries of genus and tribe better than nucleotide one. It can be stated that if the level of aminoacid divergence falls within the limits from 0 to 1.7% then a pair of species compared belongs to the same genus; if it falls within the limits from 1.7 to 4.0% then they belong to the same tribe; within the limits from 4.6 to 6.3%--to different tribes; if it exceeds 7.9%--to different subfamilies. The accuracy of identification when using these ranges turns out to be not less than 75%. In this regard, bounds of COI sequence aminoacid divergence may be used as taxonomic criteria for midge genus, tribe or subfamily. PMID- 23659115 TI - [Characteristics of medulloblastoma in children under age of three years]. AB - We present a series of 51 medulloblastoma in children under three years, collected in N.N. Burdenko Neurosurgical Institute from 2000 to 2010. 57% of the tumors showed desmoplastic/nodular histology. Performed fluorescence in situ hybridization (FISH) analysis revealed the MYC oncogene amplification in 4%, the MYCN oncogene amplification - in 8%, isochromosome 17q - in 16% of cases. 9q deletion was found in 8% of desmoplastic/ nodular medulloblastomas. Our results showed that desmoplastic/nodular medulloblastoma has a positive predictive value for progression-free survival. Another feature of a biology of medulloblastomas in children younger than three years is the lack of nuclear accumulation of beta catenin, and 6q deletion. Medulloblastomas with MYCN oncogene amplification often exhibit desmoplastic/nodular histology and a relatively favorable outcome. The most unfavorable prognostic marker is the MYC oncogene amplification, which in our series of 100% combined with the large cell/anaplastic medulloblastoma and isochromosome 17q - such tumors should be included in the "high risk" protocol. PMID- 23659116 TI - [Meningioma challenge: analysis of 80-year experience of Burdenko Neurosurgical institute and future perspectives]. AB - The paper describes the history of meningioma surgery at Burdenko Neurosurgical Institute, analyses of accumulated series of patients and assesses effectiveness of different techniques for meningioma diagnosis and treatment of. We analyzed 15413 patients with meningiomas operated in Burdenko Neurosurgical Institute from 1932 to 2011. Mathematical analysis was performed using Statistica 6.0 program. Mortality rate during World War II reached a disastrous level of 45,8%, in 21st century it is below 1%. Temporary and permanent morbidity has also decreased. While in 1961 Karnofsky performance score was 71, in 2011 it became 83. The probability of postoperative tumour recurrence also diminished, from 40% in 1960 s to 29% in 1996 and presumably to 25% nowadays. Independent factors that influence the risk of recurrence are primary gross total resection, grade of anaplasia and radiation therapy. However, unreasonably aggressive surgery leads to significant increase of morbidity. Further improvement of surgical results in patients with meningiomas depends on implementation of new technologies for neurovisualization, abandoning extensive surgical approaches whenever possible, finding the "balance" between radical removal and expected functional outcome, wider application of radiosurgery and three-dimensional conformal radiation therapy. PMID- 23659117 TI - [Lung cancer metastases to the brain: clinical and morphological prognostic factors]. AB - Brain metastases (BM) are the most frequent intracranial SOL and extremely heterogeneous group of tumours from morphological point of view. Nevertheless, studies devoted to BM up to now paid little attention to the histogenesis of the primary tumour. Lung carcinoma is the most common source of BM; morpologically this is a very heterogeneous group of tumors, and they demostrate different clinical pathway and outcome. The aim of present study was to evaluate clinical and morphological prognostic factors in 126 patients with lung carcinoma metastases to the brain, operated in 2004-2010 at Burdenko Neurosurgical Institute. Statistical analysis demonstrated that age, gender, amount and location of BM, primary operation and even histological tumour type were not significant prognostic factors, meanwhile absence of extracranial metastases and Karnofsky index above 70 were significant factors of the favorable prognosis. PMID- 23659118 TI - [Primary and metastatic Ewing sarcoma of the skull base - case reports and comparative analysis]. AB - The aim of the present study was to evaluate and compare diagnostic/and treatment modalities of primary and metastatic Ewing sarcoma (ES) of the skull base. MATERIAL AND METHODS: We analyzed nine cases of the skull base ES patients operated in Burdenko Neurosurgical Institute from 2003 to 2011. Among them there were five cases of primary ES, the other four were of metastatic origin. Clinical history, neuroimaging and pathology data together with IHC are presented. Treatment options and results are discussed. Seven patients were operated transcranially, in the other two cases endoscopic endonsnasal operations/were performed. Mean follow up was 11-92 months. RESULTS: We did not reveal arW pathological or IHC differences between primary and metastatic tumors. The labeling index Ki-67 was insignificantly higher in the metastatic tumors gro'Vip. In one case the patient developed relapse of the metastatic tumour in the temporal bone; he underwent second surgery and died 7 months after the operation. CONCLUSION: Despite both metastatic and primary ES of the skull base are of maMignant behavior, the long-term relatively good prognosis can be achieved when combined treatment, including surgery, chemotherapy and radiation is applied. PMID- 23659119 TI - [Analysis of anterior cervical spondylodesis using plate cage PCB Evolution for a 2 year period]. AB - The aim of this study was to analyze treatment results of patients who underwent cervical fusion using plate cage PCB Evolution during 2 year period. 37 hybrid cages (titanium plate and PEEK cage) were implanted to 34 patients with degenerative disease of cervical spine. Assessment of results was performed by neurologic examination, neurovisualization data, visual analogue pain scale and Neck Disability Index. Mean duration of surgery was 92 min., blood loss - 42 ml, length of hospital stay - 8 days. Substantial decrease of frequency and intensity of neck and arm pain was observed after surgery in 91% of patients. Single asymptomatic complication occurred due to improper implant position owing to loosening of the upper screw. When properly performed, anterior cervical interbody fusion applying PCB Evolution plate cage is a simple and effective method with low complication rate. PMID- 23659120 TI - [Case report of a "probable" cerebral amyloid angiopathy]. AB - Sixty-two year old man was admitted to the department of neurosurgery after stroke episode. CT-scan revealed non-traumatic, non-hypertensive intracerebral hemorrhage in the left temporal lobe; cerebral amyloid angiopathy was suspected. Initially, according to Boston criteria, intracerebral hematoma was interpreted as a result of a "probable" cerebral amyloid angiopathy. Surgical evacuation of the hematoma lead to the partial recourse of speech and cognitive deficit. Four weeks after stroke onset and 3 weeks after surgery CT was performed, which revealed intracerebral hematoma in the right parietal lobe; this fact let to diagnose "probable" cerebral amyloid angiopathy. The second hematoma was evacuated, and surgical treatment together with medical therapy improved patient's quality of life. Treatment strategy for the intracerebral hematomas resulting from cerebral amyloid angiopathy has not been justified yet, which requires further investigations. PMID- 23659121 TI - [Biology of the craniopharyngioma]. AB - In the recent years a considerable number of different studies devoted to craniopharyngioma morphology were performed. There are more than 35 factors known up to date that could be related to the craniopharyngioma growth (Ki-67, p53, beta-catenin, p63, Retinoid acid receptors, Galectin-3, MIF, MVD, CK et al.). Despite the such a variety of factors, none of them, except for the Ki-67, strongly correlates with the risk of tumour recurrence and none can be associated with a particular tumour type. Most studies, by the way, focused on a very small number of factors and were performed in relatively small groups of patients. Most publications are devoted to the Ki-67, beta-catenin and p53 studies, and the highest number of patients enrolled to the study was 67. This survey made an attempt to review the literature on the craniopharyngioma biology and to identify further areas of research to obtain data that could affect the choice of treatment and outcome in this complex disease. PMID- 23659123 TI - [International conference on neurorehabilitation in neurosurgery]. PMID- 23659122 TI - [Brain tumours: analysis of epidemiology and neuro-oncology service status in the Ul'ianovsk region]. AB - The incidence of brain tumours: analysis of epidemiology figures and neurooncology service status in the Ulyanovsk region during 1996-2005 was investigated. This article demonstrates lack of early brain tumour diagnosis in the region owing to insufficient equipment of medical care facilities and low level of expertise among primary care phycisians. Risk factors for complications development and increase in postoperative mortality are defined. The uniform algorithm of medical care for brain tumour patients will allow considerably improve treatment results. PMID- 23659124 TI - It's no accident. PMID- 23659125 TI - Locked up. PMID- 23659126 TI - Heavy duty. PMID- 23659127 TI - A 'racing heart'. PMID- 23659128 TI - What does 2020 hold? PMID- 23659129 TI - Forecast of the future? JEMS 200-city survey shows recession continues to affect EMS in 2012 & beyond. PMID- 23659130 TI - Putting standards on the map. Oklahoma leaders create comprehensive set of evidence-based protocols. PMID- 23659131 TI - Forced to wait. the effect of the peri-shock pause on automated external defibrillators. PMID- 23659132 TI - Skin deep. Understand common skin infections, how to treat them & how to protect yourself. PMID- 23659133 TI - Bridging adversity. Your EMS organzation can succeed & thrive during turbulent times. PMID- 23659134 TI - Experiential music salvation. PMID- 23659135 TI - [Confidential birth instead of anonymously giving up the child]. PMID- 23659136 TI - [Men in pediatric nursing]. PMID- 23659137 TI - [Experts sound alarm: nursing care for sick children is in danger]. PMID- 23659138 TI - [Hospital visit with clinic clowns]. PMID- 23659139 TI - [Years of dedication to GKiKP: Elfriende Zoller receives the Federal Cross of Merit]. PMID- 23659140 TI - [Brain food for the concentrated work day]. PMID- 23659141 TI - [Babies can already distinguish syllables in the uterus]. PMID- 23659142 TI - ["Time donation by grandmothers and grandfathers" project]. PMID- 23659143 TI - [Nursing in renal replacement therapy exemplified by continuous venovenous hemofiltration (CVVHF)]. PMID- 23659144 TI - [Each child is unique - and therefore a challenge for family and society]. PMID- 23659145 TI - [Lillian Wald opens the gate to health for the poor]. PMID- 23659146 TI - [An overview of supplementary infant food products: an online databank with a scientific background]. PMID- 23659147 TI - [The formation of a nursing association in Schleswig-Holstein is anchored in a coalition agreement]. PMID- 23659149 TI - ["Nurse, you apparently don't understand a joke....!"]. PMID- 23659150 TI - [How to enhance general internal medicine?]. PMID- 23659151 TI - [Impact of red blood cells transfusion on upper gastrointestinal bleeding]. AB - Upper gastrointestinal bleeding is a major digestive emergency. The compensation of hypovolemia represents the cornerstone of the initial treatment, according to international recommendations. In contrast, use of red blood cells transfusion and target hemoglobin vary considerably across different centers. The real impact of blood transfusions on the rate of rebleeding and mortality is still unknown. However, several studies suggest that transfusion may have a deleterious effect in patients with hemodynamically stable condition during upper gastrointestinal bleeding, promoting recurrent bleeding. PMID- 23659152 TI - [Screening for colorectal cancer: recommendations]. AB - Colorectal cancer is Europe's most frequent malignancy with an annual incidence of more than 430000 cases and a mortality approaching 50%. Fecal blood tests (guaiac fecal occult blood tests, fecal immunological tests) are primarily designed for early cancer detection. They lack sensitivity and have to be repeated annually to be effective. Optical colonoscopy allows the detection and endoscopic removal of precancerous lesions and early cancer. Hence, it represents the most comprehensive and complete--albeit invasive and expensive--screening tool available to date. More sensitive DNA-based stool and blood tests are currently under evaluation and may have the potential to influence a future screening programme, yet to be implemented in our country. PMID- 23659153 TI - [Should cardiopulmonary rehabilitation be provided to patients with lung cancer?]. AB - The exercise capacity has a specific importance in patients with non small cell lung cancer (NSCLC) at all stages of the disease. In the preoperative period for the early stages of the disease, low exercise capacity can be improved and thus allow curative surgery for unfit patients with NSCLC. The body of current literature suggests a beneficial effect of cardiopulmonary rehabilitation on exercise capacity, quality of life and length of hospital stay or rate of post operative complications. For patients with advanced disease, exercise capacity, which is a predictor of survival, could be maintained at higher level with adapted cardiopulmonary rehabilitation. Ongoing studies will precise the best programs for patients with NSCLC and help to establish guidelines for clinicians. PMID- 23659154 TI - [Primary glomerulonephritis in focus]. AB - The glomerulonephritis (GN) are responsible for a significant amount of end stage renal disease. They may be secondary to another disease or idiopathic. When a secondary etiology has been excluded, it is called primary glomerulonephritis (PGN). Glomerular damage may have different presentations and there are many way to classify them. It is thus difficult for the non-specialist to understand the terminology used. This article is a summary of the most frequently encountered PGN such as: IgA nephropathy, membranous GN, idiopathic nephrotic syndrome, extracapillary and membranoproliferative GN. A brief description is given for each one of the PGN including epidemiology, semiology, histology and a pathophysiology explanation. PMID- 23659155 TI - ["Less is more"]. AB - After decades of remarkable development, medicine is facing a tough economic reality and new challenges. These challenges include defining the values, objectives and tasks of sustainable medicine. In this context, the concept of "less is more" emerged in North America. "Less is more" is an invitation to recognize the potential risks of overuse of medical care that may result in harm rather than in better health. It is therefore necessary to drive unnecessary and costly practices by streamlining care without rationing. PMID- 23659156 TI - [The bioresorbable coronary stent: a revolution]. AB - Coronary angioplasty has undergone several technological revolutions: starting with balloon angioplasty, then with bare metal stent and finally with drug eluting stent (DES), this technique is now mature. However, once we thought the problem of instent restenosis solved with DES, new concerns arise with late and very late stent thrombosis. Should we therefore proscribe DES? How long should be the duration of dual antiplatelet therapy? And how should we manage the patients who need a surgery and are at high risk of bleeding? Are bioresorbable stents the final solution with their initial mechanical properties, then with their drug eluting effect against intra-stent restenosis, and finally with their complete resorption which leaves the artery free of any foreign material? PMID- 23659157 TI - [Concept of first responders in Western Switzerland: current situation and future perspectives]. AB - The notion of "First Responder" (FR) refers to the system of first-aid volunteers who act to initiate the first-aid care before the classical emergency help arrives. In 2011, the French-speaking Switzerland counts 19 groups, divided up between four cantons (Fribourg, Vaud, Neuchatel, Valais). The geographical distribution of those FR shows the stakes of these peripherical areas, with the accessibility difficulties for the emergency services, and a low demography of ambulances and doctors. The number of interventions carried out by the FR has significantly increased during the last years. The association of a quality formation, an excellent knowledge of the ground and a quick intervention has a positive impact on the survival of the patients with vital emergency or traumatic conditions. PMID- 23659159 TI - [New light on the contagiousness of Mycobacterium abscessus]. PMID- 23659161 TI - [In Europe, often the right to reproduce varies (3)]. PMID- 23659163 TI - [Choices and goals]. PMID- 23659164 TI - [Changes in ingestive behavior during growth affects the functional maturation of temporomandibular joint nociceptive neurons of rats]. AB - Temporomandibular joint (TMJ) loading during development promotes its growth and maintains normal structure/function. Continuous change in diet consistency is related to development and maturation of the peripheral nervous system, including the nociceptive system. However, the functional modulation of TMJ-nociceptive neurons under different ingestive behavior is unclear. We fed growing rats a liquid diet to investigate the effects of low TMJ loading on the response properties of neurons in the trigeminal spinal tract subnucleus caudalis (Sp5C). Forty 2-week-old male rats were used. They were fed chow pellets (n = 20, C group) or a liquid diet (n = 20, LD group) soon after weaning. Firing activities of single sensory units in response to TMJ pressure stimuli were recorded at 4, 5, 7 and 9 weeks. In TMJ-nociceptive neurons, the firing threshold (FT) in the LD group was significantly lower than that in the C group at each recording age. The FT in the C group remained unchanged throughout the recording period, whereas that in the LD group was the highest at 4 weeks, and gradually decreased. On the other hand, the initial firing frequency (IFF) was significantly higher in the LD group than in the C group at each recording age. The IFF in the C group remained unchanged throughout the experimental period, whereas that in the LD group was at its lowest at 4 weeks, and gradually increased. Based on these findings, ingestive behavior that results from continuous changes in the physical consistency of the diet during growth may affect the functional maturation of TMJ nociceptive neurons. PMID- 23659165 TI - [Role of ARID3A in E2F target gene expression and cell growth]. AB - ARID3A is a member of the AT-rich interaction domain (ARID) family of DNA-binding proteins. ARID3A was isolated as proteins binding to E2F1, and stimulates transcription mediated by the E2F transcription factor that plays a central role in regulating cell cycle progression. However, the function of ARID3A in E2F target-gene expression has not been fully understood. METHODS: Gene-silencing and overexpression experiments were carried out using siRNA and recombinant adenoviruses, respectively. E2F responsive gene expression was measured by RT PCR. Effects of ARID3A silencing on DNA synthesis and cell growth were determined by EdU incorporation and colony formation assay, respectively. RESULTS: siRNA mediated gene silencing of ARID3A blocked the transcription of E2F-target genes, such as E2F1, p107, CDC2 and CDC6 in normal human dermal fibroblasts (NHDFs). Although adenoviral-mediated overexpression of ARID3A did not up-regulate the transcription of these E2F-target genes in quiescent NHDFs, E2F1 overexpression was unable to overcome the blockade of CDC6 expression by ARID3A silencing. Furthermore, ARID3A silencing attenuated S phase entry of NHDFs, and suppressed growth of human tumor cell lines. CONCLUSION: These results indicate that ARID3A plays an important role for E2F-mediated transcriptional activation and cell growth. PMID- 23659166 TI - New furanocoumarins and other chemical constituents from Ficus carica root heartwood. AB - Two new furanocoumarins, 5-(1",1"-dimethylallyl)-8-methyl psoralen (1) and 2"-O acetyl oxypeucedanin hydrate-3"-methyl ether (2), were isolated from the root heartwood of Ficus carica Linn. together with three known furanocoumarins, two triterpenoids, two long-chain compounds, and a steroid. Their structures and relative configurations were elucidated by spectroscopic methods (IR, HR-ESI-MS, and NMR) and by comparison of their NMR spectral data with those of related compounds. PMID- 23659167 TI - Comparative study of the volatiles' composition of healthy and larvae-infested Artemisia ordosica. AB - Volatiles emitted by healthy Artemisia ordosica (Asteraceae) and plants infested with larvae of Sphenoptera sp. (Coleoptera: Buprestidae) or Holcocerus artemisiae (Lepidoptera: Cossidae) were obtained using a dynamic headspace method and analysed by automatic thermal desorption/gas chromatography/mass spectrometry (ATD/GC/MS). Twenty-eight major compounds were identified, and qualitative and quantitative differences were compared. The novel green leaf volatiles 2-hexenal, (Z)-3-hexen-1-ol, 2-hexen-1-ol 1-hexanol, and (Z)-3-hexen-1-ol acetate, the terpenoids alpha-copaene, beta-cedrene, and (E,E)-alpha-farnesene, and the ester methyl salicylate were present in all infested plants. Volatiles from healthy plants were dominated by D-limonene (32.14%), beta-pinene (16.63%), beta phellandrene (16.06%), and sabinene (12.88%). Volatiles from Sphenoptera sp. larvae-infested plants were dominated by D-limonene (24.74%), beta-pinene (21.05%), alpha-pinene (19.39%), and sabinene (11.64%), whereas volatiles from H. artemisiae larvae-infested plants were dominated by D-limonene (31.76%), sabinene (18.49%), ocimene (15.93%), and beta-phellandrene (10.59%). In addition to the qualitative variation, a larvae-induced quantitative change in the proportion of terpenoids in the blends was also a noticeable feature. PMID- 23659168 TI - Analysis of the essential oil of Dipsacus japonicus flowering aerial parts and its insecticidal activity against Sitophilus zeamais and Tribolium castaneum. AB - Water-distilled essential oil from the aerial parts of Dipsacus japonicus Miq. (Dipsacaceae) at the flowering stage was analysed by gas chromatography-mass spectrometry (GC-MS). Forty-six compounds, accounting for 96.76% of the total oil, were identified and the main compounds of the essential oil were linalool (11.78%), trans-geraniol (8.58%), 1,8-cineole (7.91%), beta-caryophyllene (5.58%), alpha-terpineol (5.32%), beta-selinene (5.15%), and spathulenol (5.04%). The essential oil of D. japonicus possessed contact toxicity against two grain storage insects, Sitophilus zeamais and Tribolium castaneum adults, with LD50 values of 18.32 microg/ adult and 13.45 microg/adult, respectively. The essential oil of D. japonicus also exhibited pronounced fumigant toxicity against S. zeamais (LC50 = 10.11 mg/l air) and T. castaneum adults (LC50 = 5.26 mg/l air). Of the three major compounds, 1,8-cineole exhibited stronger fumigant toxicity than the crude essential oil against S. zeamais and T. castaneum adults with LC50 values of 2.96 mg/l air and 4.86 mg/l air, respectively. PMID- 23659169 TI - A new flavonoid C-glycoside from Solanum elaeagnifolium with hepatoprotective and curative activities against paracetamol-induced liver injury in mice. AB - A new flavonoid C-glycoside, kaempferol 8-C-beta-galactoside, along with twelve known glycosidic flavonoids was isolated from the aqueous methanolic extract of Solanum elaeagnifolium Cav. (Solanaceae), by conventional chromatographic methods; their structure elucidation was achieved using UV, ESI-MS, and NMR spectral analyses. Groups of six mice were administered S. elaeagnifolium extracts at 25, 50, and 75 mg/kg body weight (BW) prior to or post administration of a single dose of paracetamol (500 mg/kg BW). The extract showed significant hepatoprotective and curative effects against histopathological and histochemical damage induced by paracetamol in liver. The extract also ameliorated the elevation in glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), and alkaline phosphatase (ALP) levels. These findings were accompanied by a nearly normal architecture of the liver in the treated groups, compared to the paracetamol control group. As a positive control, silymarin was used, an established hepatoprotective drug against paracetamol-induced liver injury. This study provides the first validation of the hepatoprotective activity of S. elaeagnifolium. PMID- 23659170 TI - Induction of caspase-8 and death receptors by a new dammarane skeleton from the dried fruits of Forsythia koreana. AB - A new naturally occurring compound based on the dammarane skeleton, i.e. cabralealactone 3-acetate-24-methyl ether, was isolated from the aqueous methanolic extract of Forsythia koreana fruits, along with eight known compounds: cabralealactone 3-acetate, ursolic acid, arctigenin, arctiin, phillyrin, rutin, caffeic acid, and rosmarinic acid. The identification of the isolated compounds was based on their spectral analysis including: HREI-MS, 1D and 2D NMR spectroscopy. The selected compounds and the aqueous methanolic extract were evaluated for their cytotoxic activity against human solid tumour cell lines. Cabralealactone 3-acetate-24-methyl ether and ursolic acid were found to be active against human breast cancer cells (MCF-7). The cytotoxicity was associated with the activation of caspase-8, the induction of the death receptors DR4 and DR5, as well as DNA fragmentation, and was thus due to apoptosis rather than necrosis. PMID- 23659171 TI - Cell death of rice roots under salt stress may be mediated by cyanide-resistant respiration. AB - Treatment with solutions containing high concentrations of NaCl (200 or 300 mM) induced cell death in rice (Oryza sativa L.) roots, as well as the application of exogenous hydrogen peroxide (H2O2). Moreover, the pretreatment with dimethylthiourea (DMTU), a scavenger of H2O2, partially alleviated the root cell death induced by 200 mM NaCl. These observations suggest that the cell death of rice roots under high salt stress is linked to H2O2 accumulation in vivo. NaCl stress increased the level of cyanide-resistant respiration to some extent and enhanced the transcript levels of the alternative oxidase (AOX) genes AOX1a and AOX1b in rice roots. High-salt-stressed (200 mM NaCl) rice roots pretreated with 1 mM salicylhydroxamic acid (SHAM), a specific inhibitor of alternative oxidase, exhibited higher levels of cell death and H2O2 production than roots subjected to either 200 mM NaCl stress or SHAM treatment alone. These results suggest that cyanide-resistant respiration could play a role in mediating root cell death under high salt stress. Furthermore, this function of cyanide-resistant respiration could relate to its ability to reduce the generation of H2O2. PMID- 23659172 TI - Biosurfactant production by Pseudomonas aeruginosa BN10 cells entrapped in cryogels. AB - Production of a rhamnolipid biosurfactant by cells of Pseudomonas aeruginosa strain BN10 immobilized into poly(ethylene oxide) (PEO) and polyacrylamide (PAAm) cryogels was investigated under semicontinuous shake flask conditions and compared to biosurfactant secretion by free cells. The biosurfactant synthesis was followed over 9 cycles of operation of the immobilized system, each cycle comprising 7 days at ambient temperature and neutral pH. Type and quantity of the carrier were optimized for the rhamnolipid production. The highest rhamnolipid yield of 4.6 g l(-1) was obtained in the 6th cycle for the immobilized system with 3 g PEO compared to 4.2 g l(-1) obtained for the free cells, thus immobilization provided physiological stability of the cells. Scanning electron microscopy revealed preservation of the cell shape and regular distribution of the cells under the matrix surface. The polymer matrices possessed chemical and biological stability and very good physico-mechanical characteristics which are a prerequisite for a high life span of these materials for the production of rhamnolipids. PMID- 23659173 TI - Phenol biodegradation by fungal cells immobilized in sol-gel hybrids. AB - The capability of cells of the fungus Aspergillus awamori, either free or immobilized in hybrid sol-gel material cells, for phenol biodegradation was demonstrated. Phenol was present in the reaction mixture as the sole carbon and energy source, and its decomposition was followed in repeated batch degradation experiments. Atomic force microscopy provided information on the development of self-organizing structures in the materials synthesized by the sol-gel method. Phenol biodegradation was mediated only by the fungal cells, and no absorption by the hybrid matrix was observed. Ten cycles of phenol biodegradation using the immobilized cells system were conducted during which up to 2000 mg l(-1) phenol was completely decomposed. Immobilized cells degraded phenol at 8.33 mg h(-1), twice as fast as free cells. The good performance of the immobilized fungal cell system is promising for the development of an efficient technology for treating phenol-containing waste waters. PMID- 23659174 TI - Cloning, expression, and purification of a Cu/Zn superoxide dismutase from Jatropha curcas. AB - We report cDNA cloning, expression, purification, and characterization of a novel Cu/ Zn superoxide dismutase (SOD) from Jatropha curcas leaves. The full-length cDNA of this SOD contained a 496-bp open-reading frame (ORF) encoding 162 amino acid residues. The recombinant plasmid containing the SOD coding sequence was introduced into Escherichia coli, and the SOD was expressed as a fusion protein. The recombinant SOD was purified from a high-density fed-batch culture using a combination of immobilized metal ion affinity chromatography (IMAC) and Sephadex G25 desalting chromatography. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and matrix-assisted laser desorption/ionization time of-flight mass spectrometry (MALDI-TOF MS) analysis indicated that the recombinant SOD was a monomeric protein with a molecular mass of approximately 16.4 kDa. Isoelectric focusing showed that this SOD was a basic protein with pI values of 7.04, 7.33, 8.62, and 8.77. The activity of the SOD was stable at 70 degrees C for 10 min, and in a broad pH range from 4 to 9. The presence of urea (up to 8 M), guanidinium chloride (up to 6 M), and 2-mercaptoethanol (up to 8 mM) had little effect on the activity. The activity decreased gradually with increasing concentrations of imidazole, hydrogen peroxide, and ethylenediaminetetraacetic acid (EDTA). Atomic absorption spectrometry showed the presence of 0.239 copper and 0.258 zinc atoms, respectively, in the SOD polypeptide. PMID- 23659175 TI - A new cytotoxic brominated acetylenic hydrocarbon from the marine sponge Haliclona sp. with a selective effect against human breast cancer. AB - Three acetylenic brominated derivatives were isolated from a Red Sea sponge, Haliclona sp. One of them, 18-bromooctadeca-9(E),17(E)-dien-7,15-diynoic acid (3), is a known metabolite, and the other two are new compounds, (1E,5E,12E,19E) 1,22-dibromodocosa-1,5,12,19-tetraen-3,14,21-triyne (1) and methyl 18 bromooctadeca-9(E),17(E)-dien-7,15-diynoate (2) which was isolated for the first time as a natural metabolite. Structures of all compounds were determined based on extensive spectroscopic measurements [1D (1H, 13C and DEPT) and 2D (HSQC, HMBC and NOESY) NMR, MS, UV, and IR]. All compounds, except 3, were evaluated for their cytotoxicity employing four cancer cell lines, i.e. MCF-7 (human breast cancer), HepG2 (human hepatocellular carcinoma), WI-38 (skin carcinoma), and Vero (African green monkey kidney). Compounds 1 and 2 had potent selective antitumour activity towards MCF-7 cells with IC50 values of 32.5 and 50.8 microM, respectively. PMID- 23659176 TI - Visualizing basins of attraction for different minimization algorithms. AB - We report a study of the basins of attraction for potential energy minima defined by different minimization algorithms for an atomic system. We find that whereas some minimization algorithms produce compact basins, others produce basins with complex boundaries or basins consisting of disconnected parts. Such basins deviate from the "correct" basin of attraction defined by steepest-descent pathways, and the differences can be controlled to some extent by adjustment of the maximum step size. The choice of the most convenient minimization algorithm depends on the problem in hand. We show that while L-BFGS is the fastest minimizer, the FIRE algorithm is also quite fast and can lead to less fragmented basins of attraction. PMID- 23659177 TI - Stereochemistry of reductions catalyzed by methyl-epimerizing ketoreductase domains of polyketide synthases. AB - Ketoreductase (KR) domains from modular polyketide synthases (PKSs) catalyze the reduction of 2-methyl-3-ketoacyl acyl carrier protein (ACP) substrates and in certain cases epimerization of the 2-methyl group as well. The structural and mechanistic basis of epimerization is poorly understood, and only a small number of such KRs been studied. In this work, we studied three recombinant KR domains with putative epimerase activity: NysKR1 from module 1 of the nystatin PKS, whose stereospecificity can be predicted from both the protein sequence and the product structure; RifKR7 from module 7 of the rifamycin PKS, whose stereospecificity cannot be predicted from the protein sequence; and RifKR10 from module 10 of the rifamycin PKS, whose specificity is unclear from both the sequence and the structure. Each KR was individually incubated with NADPH and (2R)- or (2RS)-2 methyl-3-ketopentanoyl-ACP generated enzymatically in situ or via chemoenzymatic synthesis, respectively. Chiral GC-MS analysis revealed that each KR stereospecifically produced the corresponding (2S,3S)-2-methyl-3-hydroxypentanoyl ACP in which the 2-methyl substituent had undergone KR-catalyzed epimerization. Thus, our results have led to the identification of a prototypical set of KR domains that generate (2S,3S)-2-methyl-3-hydroxyacyl products in the course of polyketide biosynthesis. PMID- 23659178 TI - Genotypic and phenotypic characterization of methicillin-resistant Staphylococcus aureus (MRSA) isolated from milk of bovine mastitis. AB - The aim of this study was to evaluate the presence of methicillin-resistant Staphylococcus aureus (MRSA) among a (S. aureus) collection (n = 430) isolated from milk of cows suffering from mastitis in Belgium and to compare their genotypic as well as phenotypic characteristics. Pulsed field gel electrophoresis (PFGE) and PCR-based typing techniques (MLST, spa, SCCmec, and agr typing) have been applied and supplemented by capsule serotyping, biofilm production quantification and antimicrobial susceptibility testing. Nineteen MRSA were isolated. Seven distinct ApaI PFGE patterns were observed. All isolates, except one, were identified as ST398 strains. Three spa types (t011, t567 and t108) and two SCCmec types (IV and V) were identified. All isolates belonged to agr type I and capsule type 5 and were Panton-Valentine leukocidin (PVL) negative. All isolates produced biofilm in TSBglc , whereas the majority did not in milk serum. Twelve resistance patterns were observed, with almost two-thirds of the isolates being resistant to at least six antibiotics, including penicillin and tetracycline. Our study confirms that the emerging ST398 LA-MRSA clone has attained Belgian cattle. With regard to genotypic and phenotypic typing, the 19 MRSA isolated in this study form a homogenous group and do not differ much from one another, neither from what has been previously described. PMID- 23659179 TI - Measuring individual significant change on the Beck Depression Inventory-II through IRT-based statistics. AB - Several researchers have emphasized that item response theory (IRT)-based methods should be preferred over classical approaches in measuring change for individual patients. In the present study we discuss and evaluate the use of IRT-based statistics to measure statistical significant individual change on the Beck Depression Inventory-II (BDI-II, Beck, Steer, & Brown, 1996). We compare results obtained with a simple IRT-based statistical test (Z-test) to those obtained with the Reliable Change Index (RCI) in a sample of clinical outpatients. Mean group differences between the Z-test and the RCI were similar, but for some individuals change classifications differed. Differences were most evident for change scores within the lower range of depression scores. We show that this may have consequences for the measurement of individual change in psychotherapy outcome research and clinical practice. PMID- 23659180 TI - Selected ion flow tube mass spectrometry analysis of exhaled breath for volatile organic compound profiling of esophago-gastric cancer. AB - Exhaled breath analysis of volatile organic compounds (VOCs) has great potential in terms of disease diagnosis and measuring physiological response to treatment. In this study, selected ion flow tube mass spectrometry (SIFT-MS) has been applied for the quantification of VOCs in the exhaled breath from 3 groups of patients, viz., those with esophago-gastric cancer, noncancer diseases of the upper gastro-intestinal tract, and a healthy upper gastrointestinal tract cohort. A total of 17 VOCs have been investigated in this study. The concentrations of 4 VOCs, hexanoic acid, phenol, methyl phenol, and ethyl phenol, were found to be significantly different between cancer and positive control groups using the Mann Whitney U test. Receiver operating characteristics (ROC) analysis was applied for a combination of 4 VOCs (hexanoic acid, phenol, methyl phenol, and ethyl phenol) to discriminate the esophago-gastric cancer cohort from positive controls. The integrated area under the ROC curve (AUC) is 0.91. The results highlight the potential of VOC profiling as a noninvasive test to identify those with esophago gastric cancer. PMID- 23659181 TI - Dexibuprofen for fever in children with upper respiratory tract infection. AB - BACKGROUND: The aim of this study was to investigate the safety and efficacy of dexibuprofen compared to ibuprofen. METHODS: This double-blind, double-dummy study enrolled patients from January 2008 to May 2009 presenting at one of five tertiary care centers in Seoul, Korea with febrile illness who were then given one of three active treatments: one dose of dexibuprofen 2.5 or 5 mg/kg (DEX 1); dexibuprofen 3.5 or 7 mg/kg (DEX 2); or ibuprofen 5 or 10 mg/kg (control) syrup. Those with a temperature <38.5 degrees C were given the lower dose. Temperature was measured every hour for 4 h. Primary study outcome was mean change in temperature 4 h after one dose. RESULTS: A total of 264 children (aged 6 months 14 years) with febrile illness due to upper respiratory tract infection were consecutively sampled and screened, with 260 randomized. No patients withdrew due to adverse effects. Mean temperature change after 4 h (mean +/- SD: DEX 1, 0.99 +/- 0.84 degrees C; DEX 2, 1.12 +/- 0.92 degrees C; control, 1.38 +/- 0.84 degrees C) differed only between DEX 1 and controls (P = 0.007, 95% confidence interval [CI]: -0.61 to -0.15). When groups were subdivided according to initial temperature, there were no significant differences in mean temperature change after 4 h between DEX 2 subgroups (<38.5 degrees C, 0.88 +/- 0.86 degrees C; >=38.5 degrees C, 1.46 +/- 0.90 degrees C) and controls (1.07 +/- 0.84 degrees C and 1.72 +/- 0.91 degrees C, respectively), but there was a significant difference between DEX 1 (>=38.5 degrees C, 1.25 +/- 0.76 degrees C) and controls (P = 0.0222, 95%CI: -0.80 to -0.13). There were no significant differences in adverse events among groups. CONCLUSION: Dexibuprofen (3.5 or 7 mg/kg) is as effective and tolerable as ibuprofen for fever caused by upper respiratory tract infection in children. PMID- 23659182 TI - Effects of the KiVa antibullying program on cyberbullying and cybervictimization frequency among Finnish youth. AB - Cyberbullying among school-aged children has received increased attention in recent literature. However, no empirical evidence currently exists on whether existing school-based antibullying programs are effective in targeting the unique aspects of cyberbullying. To address this important gap, the present study investigates the unique effects of the KiVa Antibullying Program on the frequency of cyberbullying and cybervictimization among elementary and middle school youth. Using data from a group randomized controlled trial, multilevel ordinal regression analyses were used to examine differences in the frequencies of cyberbullying and cybervictimization between intervention (N = 9,914) and control students (N = 8,498). The effects of age and gender on frequencies of cyber behaviors were also assessed across conditions. Results revealed a significant intervention effect on the frequency of cybervictimization; KiVa students reported lower frequencies of cybervictimization at posttest than students in a control condition. The effect of condition on the perpetration of cyberbullying was moderated by age. When student age was below the sample mean, KiVa students reported lower frequencies of cyberbullying than students in the control condition. We also found evidence of classroom level variation in cyberbullying and cybervictimization, suggesting cyberbullying is in part a classroom-level phenomenon. KiVa appears to be an efficacious program to address cyber forms of bullying and victimization. We discuss several unique aspects of KiVa that may account for the significant intervention effects. Results suggest that KiVa is an intervention option for schools concerned with reducing cyberbullying behavior and its deleterious effects on children's adjustment. PMID- 23659183 TI - Bifunctional inhibition of human immunodeficiency virus type 1 reverse transcriptase: mechanism and proof-of-concept as a novel therapeutic design strategy. AB - Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is a major target for currently approved anti-HIV drugs. These drugs are divided into two classes: nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). This study illustrates the synthesis and biochemical evaluation of a novel bifunctional RT inhibitor utilizing d4T (NRTI) and a TMC-derivative (a diarylpyrimidine NNRTI) linked via a poly(ethylene glycol) (PEG) linker. HIV-1 RT successfully incorporates the triphosphate of d4T-4PEG-TMC bifunctional inhibitor in a base-specific manner. Moreover, this inhibitor demonstrates low nanomolar potency that has 4.3-fold and 4300-fold enhancement of polymerization inhibition in vitro relative to the parent TMC-derivative and d4T, respectively. This study serves as a proof-of-concept for the development and optimization of bifunctional RT inhibitors as potent inhibitors of HIV-1 viral replication. PMID- 23659184 TI - Strength and functional deficits in individuals with hip osteoarthritis compared to healthy, older adults. AB - PURPOSE: Hip osteoarthritis (OA) compromises quality of life for many individuals. This study quantified deficits in functional capacity for use in rehabilitation goal setting by combining assessments of muscle strength, function and physical activity in patients with hip OA and healthy adults. METHOD: Twenty six patients with end-stage hip OA and 18 healthy adults participated. Isometric muscle strength around the hip and knee was measured. Function was assessed using stair climbing, five-time-sit-to-stand, timed-up-and-go and 6-minute walk tests. The UCLA activity rating scale assessed physical activity. Analyses of covariance (ANCOVA) were used to assess differences between groups. RESULTS: Patients had 30% less knee extensor (p < 0.001), 38% less knee flexor (p < 0.001), 10% less hip flexor (p = 0.47), 23% less hip extensor (p = 0.24) and 17% less hip abductor strength (p = 0.23) than healthy adults. Hip adductor strength was equal between groups (p = 0.93). Patients were 50% slower on the stair climbing test (p = 0.001), 34% slower on the timed-up-and-go test (p = 0.004), 34% slower on the five-time-sit-to-stand test (p = 0.001), and walked 28% less during the 6-min walk test (p < 0.001). Patients were less physically active (p = 0.001). CONCLUSIONS: Patients had deficits in muscle strength, function and physical activity compared to healthy adults. Quantifying these deficits provides benchmarks for improvement during rehabilitation. IMPLICATIONS FOR REHABILITATION: Hip osteoarthritis (OA) affects up to 28% of adults over the age of 65 and many individuals report functional and activity limitations directly related to their arthritic condition, posing a risk for future morbidity Total hip arthroplasty (THA) is the treatment of choice for decreasing pain and improving function, however, some individuals suffering from end-stage hip OA are not candidates for THA, and effective rehabilitation interventions to improve physical function are crucial Establishing estimates of the deficits in muscle strength, physical function and physical activity in people with and without hip OA can aid rehabilitation professionals in their goal setting and intervention planning Rehabilitation interventions should not only consist of muscle strengthening and functional training, but interventions to improve physical activity levels are required to improve overall physical functioning and to decrease risks for additional health complications. PMID- 23659185 TI - Hypophosphatemia as a prognostic value in acute exacerbation of COPD. AB - BACKGROUND: Phosphorus (P) is an essential element in all living cells, it is extremely important in the process of production of adenosine triphosphate, main element in the structure of nucleic acids. Low levels of phosphorus in blood is very rare, however, it may be caused by unbalance between components participating in phosphorus cycle and affect performances of several systems. A low level of phosphorus in the blood increases the exacerbation and the severity of chronic obstructive pulmonary disease (COPD) and requires prolonged ventilation process. AIM: This study aims to examine the prognostic effects of hypophosphatemia in COPD patients and evaluate the correlation between phosphorus levels and severity, recurrences of attacks, ventilation duration and successful of weaning process. METHODS: Two hundred and fifty-five patients who were admitted because of worsening in COPD, from October 2010-April 2011, were examined. A comparison was made between the group with normal blood phosphorus (2.5-4.5 mg%), group of patients with low phosphorus (2-2.5 mg%) and group with very low phosphorous values (<2.0 mg%). RESULTS: Ninety-five per cent of all admissions had normal blood phosphorus levels, 3.3% had low phosphorus levels, and only 1.7% of all admissions had very low phosphorus levels. 2.4% of patients had both low levels of phosphorus and potassium. All patients (100%) with very low phosphorus needed mechanical ventilation, compared to 62.5% of patients with low phosphorus and 16.9% of patients with normal phosphorus levels. In addition, 16 ventilated patients (33% of all ventilated patients) had low potassium values. SUMMARY: Low blood phosphorus levels contribute to an increase in: COPD flare-up, need for ventilation, duration of hospitalisation, days in intensive care units and finally increased rate of mortality. Accordingly, close monitoring and careful adjustment of disorders correlated to electrolyte such as phosphorus, are crucial and may improve prognosis and also increase the survival rate of patients with COPD. PMID- 23659186 TI - Bowen disease of the palm associated with human papillomavirus 52. AB - Human papillomavirus (HPV) is a well-known risk factor for many human cancers, especially cervical cancers. Among the nonmelanoma skin cancers, Bowen disease (BD) of the genitalia and fingers has also been shown to be closely associated with the high-risk types of HPV, especially HPV16. We report a case of BD of the palm, which is a very rare location for BD. In addition to its rare location, HPV52, which is classified as a mucous high-risk HPV type, was detected in the lesion by PCR restriction fragment length polymorphism analysis. To our knowledge, this is the first reported case of BD associated with HPV52. PMID- 23659187 TI - Ultraviolet nanoplasmonics: a demonstration of surface-enhanced Raman spectroscopy, fluorescence, and photodegradation using gallium nanoparticles. AB - Self-assembled arrays of hemispherical gallium nanoparticles deposited by molecular beam epitaxy on a sapphire support are explored as a new type of substrate for ultraviolet plasmonics. Spin-casting a 5 nm film of crystal violet upon these nanoparticles permitted the demonstration of surface-enhanced Raman spectra, fluorescence, and degradation following excitation by a HeCd laser operating at 325 nm. Measured local Raman enhancement factors exceeding 10(7) demonstrate the potential of gallium nanoparticle arrays for plasmonically enhanced ultraviolet detection and remediation. PMID- 23659188 TI - Rational synthesis of a porous copper(II) coordination polymer bridged by weak Lewis-base inorganic monoanions using an anion-mixing method. AB - The use of divalent Cu(II) ions and an anion-mixing method led to the rational construction of a porous coordination polymer bridged by weak Lewis-base inorganic CF3SO3(-) monoanions. PMID- 23659189 TI - Traditional intracytoplasmic sperm injection provides equivalent outcomes compared with human zona pellucida-bound selected sperm injection. AB - The capability of human zona pellucida (ZP) to bind selectively to normal functional sperm with normal chromatin has been reported widely in the literature. The aim of this study was to evaluate whether ZP-binding sperm selection may represent a method to retrieve superior spermatozoa for intracytoplasmic sperm injection (ICSI). Patients were divided into two groups: a ZP-ICSI and a conventional ICSI group. In the ZP-ICSI group, spermatozoa for injection were selected after ZP-sperm incubation and spermatozoa that were tightly bound to the ZP were used for ICSI (ZP-ICSI). Clinical outcomes of ZP ICSI were compared with the outcomes of traditional scientist-selected sperm injection (conventional ICSI). Results did not show any significant difference in fertilization, pregnancy, implantation and take-home-baby rates between conventional ICSI and ZP-ICSI. However, when data relative to patients who received ZP-ICSI were analyzed, an interesting result was observed: higher sperm concentration and morphology correlated with higher ZP-sperm binding. Additionally, patients with higher ZP-sperm binding seem to have improved pregnancy and take-home-baby rates. In conclusion, this study shows that ZP-ICSI is not a superior method compared with conventional ICSI. However, clinical ICSI outcomes were apparently improved in the presence of good ZP-sperm binding. We therefore speculate that sperm competence to ICSI could be reduced when the sperm's ability to bind the ZP is impaired. PMID- 23659190 TI - Sampling volume in root studies: the pitfalls of under-sampling exposed using accumulation curves. AB - Root systems are important for global models of below-ground carbon and nutrient cycling. Notoriously difficult sampling methods and the fractal distribution of root diameters in the soil make data being used in these models especially susceptible to error resulting from under-sampling. We applied the concept of species accumulation curves to root data to quantify the extent of under-sampling inherent to minirhizotron and soil coring sampling for both root uptake and carbon content studies. Based on differences in sample size alone, minirhizotron sampling missed approximately one third of the root diameters observed by soil core sampling. Sample volumes needed to encounter 90% of root diameters averaged 2481 cm(3) for uptake studies and 5878 cm(3) for root carbon content studies. These results show that small sample volumes encounter a non-representative sample of the overall root pool, and provide future guidelines for determining optimal sample volumes in root studies. PMID- 23659191 TI - Modified hypothermic circulatory arrest for emergent repair of acute aortic dissection type a: a single-center experience. AB - BACKGROUND: Deep hypothermic circulatory arrest (DHCA) with antegrade cerebral perfusion has been historically preferred for organ protection during surgical repair of the acute aortic dissection type A. However, in the past decades, different perfusion-specific strategies with a growing trend to increase the body temperature at circulatory arrest emerged. In this study, we retrospectively analyzed the clinical results of our modified protocol for cardiopulmonary bypass and hypothermia management. METHODS: Between February 2007 and September 2012, 54 consecutive patients suffering from acute aortic dissection type A underwent emergent surgery. All patients received hypothermic circulatory arrest in combination with antegrade cerebral perfusion. The patients were divided into two subsets according to the degree of hypothermia and perfusion strategies: namely the DHCA group and the group of modified hypothermic circulatory arrest (MHCA). RESULTS: The overall 30-day mortality was 27.8% and was not significantly different between groups (DHCA, 33.3%, MHCA, 19%; p=0.253). The requirement for blood product transfusion in MHCA patients was significantly less as as compared with the patients in the DHCA group. No difference occurred in the incidence of temporary neurologic dysfunction, dialysis-dependent renal failure, or reexploration for bleeding between two groups of patients. The use of MHCA was identified as a protective factor against the postoperative composite complications (OR, 0.78; CI, 0.52 to 0.98; p=0.04) and the prolonged intensive care unit stay (OR, 0.8; 95% CI, 0.56 to 0.98; p=0.04). CONCLUSIONS: Moderate hypothermia in combination with selective brain perfusion and systemic retrograde perfusion is associated with adequate cerebral and visceral protection, reduced postoperative complications and shortened intensive care unit stay in our series. This modified perfusion strategy may help in improving perioperative outcomes in this particular group of patients. PMID- 23659198 TI - Is stereotactic radiosurgery under-utilised in the treatment of surgically excisable cerebral metastases? AB - BACKGROUND/OBJECTIVE: Brain metastases are a significant cause of morbidity and mortality. Treatment options included surgery, whole brain radiotherapy and stereotactic radiosurgery alone or in combination. There has been a significant increase in stereotactic radiosurgery (SRS) provision in the UK over the last 5 years. We investigated the proportion of surgically resected brain metastases that would be suitable for SRS. METHODS: We retrospectively collected data on 116 consecutive patients undergoing surgical resection of brain metastases. Suitable radiological targets for SRS were defined as solid tumours < 30 mm maximum diameter with no hydrocephalus and no symptomatic mass effect. RESULTS: One hundred and two cases (88%) were solitary metastasis and fourteen (12%) had multiple metastases. Median maximum tumour diameter was 34 mm (range: 12-70 mm). Approximately one-third of patients (n = 41) had surgically resected brain metastasis suitable for SRS. Median OS was 7.7 months for those suitable for SRS and 5.4 months for those not suitable for SRS (Fig. 3; Log Rank: P = 0.52). CONCLUSIONS: In surgically amenable tumours, day case SRS could also be used in approximately one-third of cases, thereby avoiding craniotomy and reducing length of stay. These data may be useful in planning service provision, and for drawing up business plans for a new SRS services. Nationally agreed guidelines for SRS for brain metastases have been developed and a full health economic analysis warrants further investigation to determine the cost effectiveness of SRS compared to craniotomy. PMID- 23659199 TI - Surgical embolectomy for large vessel occlusion of anterior circulation. AB - OBJECT: The aim of this study was to assess the technical details and the efficacy and safety of surgical embolectomy for occlusion of large vessels in the anterior circulation. METHODS: Twenty-three consecutive patients with acute ischemic stroke attributed to embolic occlusion of large arteries of the anterior circulation who underwent treatment with surgical embolectomy were retrospectively reviewed. Twenty patients were treated based on data from magnetic resonance angiography (MRA)-diffusion weighted imaging (DWI) mismatch, while three other patients had contraindications to magnetic resonance imaging (MRI) and were treated based on computed tomography (CT) and digital subtraction angiography (DSA) findings. Clinical outcomes, including recanalization rate, recanalization time, complications, modified Rankin Scale (mRS) at 3 months, and National Institute of Health Stroke Scale (NIHSS) score improvement at 1 month, were evaluated. RESULTS: Among the 23 patients (median age, 80 years; median presenting NIHSS score, 21 points), the occlusion site was the internal carotid artery (ICA) terminus in six patients, the M1 segment of the middle cerebral artery (MCA) in 10 patients, and the M2 division of the MCA in seven patients. Final recanalization status was thrombolysis in myocardial infarction (TIMI) 3 in 21 patients (91%). Median recanalization time from symptom onset and from start of surgery was 282 min and 70 min, respectively. One patient (4.3%) had symptomatic haemorrhage. Three patients (13%) had brain oedema due to massive infarction of affected vessel area; two of these patients had undergone embolectomy based on CT findings and had successful recanalization, while one patient underwent embolectomy based on MRI findings and did not have successful recanalization. All 18 patients who underwent embolectomy based on MRA-DWI mismatch and had successful recanalization did not develop additional confluent ischaemic lesion on postoperative DWI. At 3 months, seven patients (30%) had a mRS score of 0-2, eight patients (35%) had a mRS score of 3, and none of the patients had died. Sixteen patients (70%) demonstrated NIHSS score improvement of more than eight points at 1 month. CONCLUSION: Surgical embolectomy for occlusion of large vessels in the anterior circulation resulted in a high complete recanalization rate with an acceptable safety profile. Use of MRA-DWI mismatch as an indication for surgical embolectomy was associated with a reduced complication rate. PMID- 23659200 TI - Urinalysis and pre-renal acute kidney injury: time to move on. AB - Urinary indices are classically believed to allow differentiation of transient (or pre-renal) acute kidney injury (AKI) from persistent (or acute tubular necrosis) AKI. However, the data validating urinalysis in critically ill patients are weak. In the previous issue of Critical Care, Pons and colleagues demonstrate in a multicenter observational study that sodium and urea excretion fractions as well as urinary over plasma ratios performed poorly as diagnostic tests to separate such entities. This study confirms the limited diagnostic and prognostic ability of urine testing. Together with other studies, this study raises more fundamental questions about the value, meaning and pathophysiologic validity of the pre-renal AKI paradigm and suggests that AKI (like all other forms of organ injury) is a continuum of injury that cannot be neatly divided into functional (pre-renal or transient) or structural (acute tubular necrosis or persistent). PMID- 23659201 TI - The cost-effectiveness of exenatide once weekly compared with exenatide twice daily and insulin glargine for the treatment of patients with type two diabetes and body mass index >=30 kg/m(2) in Spain. AB - OBJECTIVE: The objective of this analysis was to estimate the cost-effectiveness of exenatide once weekly (EQW) for the treatment of type two diabetes mellitus (T2DM) in Spain. EQW was compared against exenatide twice daily (EBID) and insulin glargine (IG). METHODS: The IMS CORE Diabetes Model was used to project clinical and economic outcomes for patients with T2DM treated with EQW, EBID, and IG. Treatment effects and patient baseline characteristics were taken from the DURATION 3 and pooled DURATION 1 and 5 studies, in the comparison against IG and EBID, respectively. Unit costs and health state utility values were derived from published sources. To reflect diabetes progression, patients started on EQW or EBID, switching to insulin glargine after 3 years. The analysis was conducted from the perspective of the Spanish National Health Service over a time horizon of 35 years with costs and outcomes discounted at 3%. The base case included patients with a BMI > 30 kg/m(2), which is in line with current prescription restrictions in Spain. Uncertainty was addressed through extensive one-way sensitivity analyses around key model parameters and a comprehensive probabilistic sensitivity analysis. RESULTS: When compared with EBID, EQW was the dominant strategy, i.e., less costly and more effective. When compared to IG, the incremental cost-effectiveness ratio was estimated at ?12,084 per QALY gained. Sensitivity analysis indicated that the model projections were robust to the various scenarios tested. LIMITATIONS: Primary limitations of the analysis are common to other T2DM analyses and include the extrapolation of short-term clinical data to the 35 year time horizon and uncertainty around optimum treatment durations. CONCLUSION: The analyses indicate that EQW is a cost effective option for the treatment of T2DM patients in Spain for patients with a BMI > 30 kg/m(2) considering a willingness-to-pay threshold of ?30,000 per QALY gained. PMID- 23659202 TI - Centrifugation on Percoll density gradient enhances motility, membrane integrity and in vitro fertilizing ability of frozen-thawed boar sperm. AB - The effects of Percoll density gradient centrifugation on sperm quality, in vitro fertilizability and developmental capacity of frozen-thawed boar sperm were evaluated. Two-step density gradient centrifugation by Percoll enhanced significantly the motility parameters of sperm compared with a simple centrifugation procedure. Percentages of motile sperm and sperm with intact plasma and acrosome membranes after Percoll separation were significantly greater than those after simple centrifugation. The rates of penetration, cleavage and blastocyst formation after in vitro fertilization were significantly improved by Percoll separation compared with simple centrifugation and were influenced positively by the intactness of sperm head membranes, but not any sperm motility parameters. However, insemination with increased concentrations of sperm prepared by Percoll gradient centrifugation did not improve the success of fertilization and embryo development in vitro. Our results indicate that the integrity of sperm head membranes after Percoll separation is important for successful embryo development in vitro, more so than sperm motility. PMID- 23659203 TI - Resonant tunneling in graphene pseudomagnetic quantum dots. AB - Realistic relaxed configurations of triaxially strained graphene quantum dots are obtained from unbiased atomistic mechanical simulations. The local electronic structure and quantum transport characteristics of y-junctions based on such dots are studied, revealing that the quasi-uniform pseudomagnetic field induced by strain restricts transport to Landau level- and edge state-assisted resonant tunneling. Valley degeneracy is broken in the presence of an external field, allowing the selective filtering of the valley and chirality of the states assisting in the resonant tunneling. Asymmetric strain conditions can be explored to select the exit channel of the y-junction. PMID- 23659204 TI - Biochemical evidence for lead and mercury induced transbilayer movement of phospholipids mediated by human phospholipid scramblase 1. AB - Human phospholipid scramblase 1(hPLSCR1) is a transmembrane protein involved in bidirectional scrambling of plasma membrane phospholipids during cell activation, blood coagulation, and apoptosis in response to elevated intracellular Ca(2+) levels. Pb(2+) and Hg(2+) are known to cause procoagulant activation via phosphatidylserine exposure to the external surface in erythrocytes, resulting in blood coagulation. To explore its role in lead and mercury poisoning, hPLSCR1 was overexpressed in Escherichia coli BL21 (DE3) and purified using affinity chromatography. The biochemical assay showed rapid scrambling of phospholipids in the presence of Hg(2+) and Pb(2+). The binding constant (Ka) was calculated and found to be 250 nM(-1) and 170 nM(-1) for Hg(2+) and Pb(2+), respectively. The intrinsic tryptophan fluorescence and far ultraviolet circular dichroism studies revealed that Hg(2+) and Pb(2+) bind to hPLSCR1 and induce conformational changes. hPLSCR1 treated with protein modifying reagent N-ethylmaleimide before functional reconstitution showed 40% and 24% inhibition in the presence of Hg(2+) and Pb(2+), respectively. This is the first biochemical evidence to prove the above hypothesis that hPLSCR1 is activated in heavy metal poisoning, which leads to bidirectional transbilayer movement of phospholipids. PMID- 23659205 TI - Mechanism and selectivity of rhodium-catalyzed 1:2 coupling of aldehydes and allenes. AB - The rhodium-catalyzed highly regioselective 1:2 coupling of aldehydes and allenes was investigated by means of density functional theory calculations. Full free energy profiles were calculated, and several possible reaction pathways were evaluated. It is shown that the energetically most plausible catalytic cycle is initiated by oxidative coupling of the two allenes, which was found to be the rate-determining step of the overall reaction. Importantly, Rh-allyl complexes that are able to adopt both eta(3) and eta(1) configurations were identified as key intermediates present throughout the catalytic cycle with profound implications for the selectivity of the reaction. The calculations reproduced and rationalized the experimentally observed selectivities and provided an explanation for the remarkable alteration in the product distribution when the catalyst precursor is changed from [RhCl(nbd)]2 (nbd = norbornadiene) to complexes containing noncoordinating counterions ([Rh(cod)2X]; X = OTf, BF4, PF6; cod = 1,5-cyclooctadiene). It turns out that the overall selectivity of the reaction is controlled by a combination of the inherent selectivities of several of the elementary steps and that both the mechanism and the nature of the selectivity-determining steps change when the catalyst is changed. PMID- 23659206 TI - In situ modification of plain liposomes with lipidated coiled coil forming peptides induces membrane fusion. AB - Complementary coiled coil forming lipidated peptides embedded in liposomal membranes are able to induce rapid, controlled, and targeted membrane fusion. Traditionally, such fusogenic liposomes are prepared by mixing lipids and lipidated peptides in organic solvent (e.g., chloroform). Here we prepared fusogenic liposomes in situ, i.e., by addition of a lipidated peptide solution to plain liposomes. As the lipid anchor is vital for the correct insertion of lipidated peptides into liposomal membranes, a small library of lipidated coiled coil forming peptides was designed in which the lipid structure was varied. The fusogenicity was screened using lipid and content mixing assays showing that cholesterol modified coiled coil peptides induced the most efficient fusion of membranes. Importantly, both lipid and content mixing experiments demonstrated that the in situ modification of plain liposomes with the cholesterol modified peptides yielded highly fusogenic liposomes. This work shows that existing membranes can be activated with lipidated coiled coil forming peptides, which might lead to highly potent applications such as the fusion of liposomes with cells. PMID- 23659207 TI - The observation of dianions generated by electrochemical reduction of trans stilbenes in ionic liquids at room temperature. AB - Three highly aprotic bis(trifluoromethylsulfonyl)amide (NTf2(-)) based ionic liquids (ILs) containing the cations trihexyl(tetradecyl)phosphonium (P6,6,6,14(+)), N-butyl-N-methylpyrrolidinium (Pyrr4,1(+)), and (trimethylamine)(dimethylethylammine)dihydroborate ((N111)(N112)BH2(+)) have been examined as media for room temperature voltammetric detection of highly basic stilbene dianions electrochemically generated by the reduction of trans-stilbene (t-Stb) and its derivatives (4-methoxy-, 2-methoxy-, 4,4'-dimethyl-, and 4 chloromethyl-). Transient and steady-state data in the ILs were compared with results obtained in the molecular solvent acetonitrile. In all media examined, the t-Stb(0/*-) process is chemically and electrochemically reversible with a heterogeneous charge transfer rate constant in CH3CN of 1.5 cm s(-1), as determined by Fourier transformed AC voltammetry. However, further reduction to the dianion was always irreversible in this molecular but weakly acidic solvent. On the other hand, a substantial level of chemical reversibility for the reduction of t-Stb(*-) to t-Stb(2-) on the time scale of cyclic voltammetry is achieved when the concentration of trans-stilbene, [t-Stb], appreciably exceeds the concentration of adventitious water or other proton sources. In particular, these conditions are met when [t-Stb] >= 0.1 M in thoroughly dehydrated and purified ILs, while in the presence of CH3CN, t-Stb(2-) still suffers fast irreversible protonation under these stilbene concentration conditions. The E0/* (0) values (vs Fc(0/+)) for substituted trans-stilbenes in acetonitrile and (N111)(N112)BH2-NTf2 do not differ substantially, nor do the E0/*-(0) and E*-/2 (0) differences or other aspects of the voltammetric behavior. PMID- 23659208 TI - Probabilistic approach to the length-scale dependence of the effect of water hydrogen bonding on hydrophobic hydration. AB - We present a probabilistic approach to water-water hydrogen bonding that allows one to obtain an analytic expression for the number of bonds per water molecule as a function of both its distance to a hydrophobic particle and hydrophobe radius. This approach can be used in density functional theory (DFT) and computer simulations to examine particle size effects on the hydration of particles and on their solvent-mediated interaction. For example, it allows one to explicitly identify a water hydrogen bond contribution to the external potential, whereto a water molecule is subjected near a hydrophobe. The DFT implementation of the model predicts the hydration free energy per unit area of a spherical hydrophobe to be sharply sensitive to the hydrophobe radius for small radii and weakly sensitive thereto for large ones; this corroborates the vision of the hydration of small and large length-scale particles as occurring via different mechanisms. On the other hand, the model predicts that the hydration of even apolar particles of small enough radii may become thermodynamically favorable owing to the interplay of the energies of pairwise (dispersion) water-water and water hydrophobe interactions. This sheds light on previous counterintuitive observations (both theoretical and simulational) that two inert gas molecules would prefer to form a solvent-separated pair rather than a contact one. PMID- 23659209 TI - Discovery of potent, selective chymase inhibitors via fragment linking strategies. AB - Chymase plays an important and diverse role in the homeostasis of a number of cardiovascular processes. Herein, we describe the identification of potent, selective chymase inhibitors, developed using fragment-based, structure-guided linking and optimization techniques. High-concentration biophysical screening methods followed by high-throughput crystallography identified an oxindole fragment bound to the S1 pocket of the protein exhibiting a novel interaction pattern hitherto not observed in chymase inhibitors. X-ray crystallographic structures were used to guide the elaboration/linking of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over cathepsin G and that mitigated a number of liabilities associated with poor physicochemical properties of the series it was derived from. PMID- 23659210 TI - A giant left ventricular pseudoaneurysm in Behcet's disease: a case report. AB - Behcet's disease is a chronic autoimmune disease with vascular complications that are most frequently manifested as thromboembolism in veins and pseudoaneurysm in arteries. We report the case of a 13-year-old boy admitted for clinical and biological signs of rheumatic fever associated with chest pain. The clinical examination found heart sounds with a discrete systolic murmur of mitral regurgitation. The electrocardiogram showed a microvoltage with diffuse repolarisation disorder. Biologically, he had inflammatory syndrome. Transthoracic echocardiography showed circumferential pericardial effusion with anterosepto-apical hypokinesia of the left ventricle with systolic dysfunction, and a minimal mitral regurgitation. The patient was treated by corticotherapy and antibiotherapy. The outcome was marked by orogenital aphthous ulceration and decreased visual acuity related to intermediate uveitis. The retinal angiography showed a vasculitis. The late appearance of this symptom led to the right diagnosis of Behcet's syndrome. Transthoracic echocardiography showed a hypokinetic dilated cardiomyopathy left ventricular with septo apical and anterior akinesia and severe systolic dysfunction, with a defect of the inferior septal with a collar communicating the left ventricle with a giant pseudo aneurysm. Magnetic resonance imaging showed a giant pseudoaneurysm communicating with the left ventricle. The coronary computed tomography was normal. The patient had undergone surgical treatment for the pseudoaneurysm with good outcomes. PMID- 23659211 TI - Synthesis, properties, and structures of functionalized peri-xanthenoxanthene. AB - Three types of alkylated peri-xanthenoxanthene (PXX) have been synthesized employing efficient synthetic routes. These heteroaromatic compounds exhibited different electronic and crystal structures according to UV-vis spectra, electrochemical measurements, and X-ray structural analyses. Among them, 1,7 DOPXX has been demonstrated as an active material for organic field-effect transistors with promising mobility and a high on/off ratio simultaneously. PMID- 23659212 TI - Modeling challenges in the synthetic biology of secondary metabolism. AB - The successful engineering of secondary metabolite production relies on the availability of detailed computational models of metabolism. In this brief review we discuss the types of models used for synthetic biology and their application for the engineering of metabolism. We then highlight some of the major modeling challenges, in particular the need to make informative model predictions based on incomplete and uncertain information. This issue is particularly pressing in the synthetic biology of secondary metabolism, due to the genetic diversity of microbial secondary metabolite producers, the difficulty of enzyme-kinetic characterization of the complex biosynthetic machinery, and the need for engineered pathways to function efficiently in heterologous hosts. We argue that an explicit quantitative consideration of the resulting uncertainty of metabolic models can lead to more informative predictions to guide the design of improved production hosts for bioactive secondary metabolites. PMID- 23659213 TI - Single-walled carbon nanotubes do not pierce aqueous phospholipid bilayers at low salt concentration. AB - Because of their unique physical, chemical, and electrical properties, carbon nanotubes are an attractive material for many potential applications. Their interactions with biological entities are, however, not yet completely understood. To fill this knowledge gap, we present experimental results for aqueous systems containing single-walled carbon nanotubes and phospholipid membranes, prepared in the form of liposomes. Our results suggest that dispersed single-walled carbon nanotubes, instead of piercing the liposome membranes, adsorb on them at low ionic strength. Transmission electron microscopy and dye leakage experiments show that the liposomes remain for the most part intact in the presence of the nanotubes. Further, the liposomes are found to stabilize carbon nanotube dispersions when the surfactant sodium dodecylbenezenesulfonate is present at low concentrations. Quantifying the interactions between carbon nanotubes and phospholipid membranes could not only shed light on potential nanotubes cytotoxicity but also open up new research venues for their use in controlled drug delivery and/or gene and cancer therapy. PMID- 23659215 TI - Chameleon behavior of a newly synthesized scandium nitrilimine derivative. AB - The synthesis, structural characterization, and reactivity of the first example of a scandium-substituted nitrilimine are presented. This unique complex exhibits high thermal stability but shows a rich reactivity toward a variety of unsaturated substrates, including aldehyde, ketone, nitrile, and allene derivatives. The versatility of the complex was further highlighted by density functional theory mechanistic studies. PMID- 23659214 TI - Identification of C-2 hydroxyethyl imidazopyrrolopyridines as potent JAK1 inhibitors with favorable physicochemical properties and high selectivity over JAK2. AB - Herein we report on the structure-based discovery of a C-2 hydroxyethyl moiety which provided consistently high levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine series of JAK1 inhibitors. X-ray structures of a C-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed differential ligand/protein interactions between the two isoforms and offered an explanation for the observed selectivity. Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability. This work culminated in the identification of a highly JAK1 selective compound (31) exhibiting favorable oral bioavailability across a range of preclinical species and robust efficacy in a rat CIA model. PMID- 23659216 TI - The design and discovery of T-type calcium channel inhibitors for the treatment of central nervous system disorders. AB - INTRODUCTION: Neuronal T-type calcium channels (T-type channels) are expressed throughout the central nervous system (CNS), regulating neuronal excitability. T type channels in the CNS are involved in various neurophysiological and pathophysiological states, and thus have become a promising therapeutic target. AREAS COVERED: This article discusses T-type channel-related CNS disorders such as epilepsy, neuropathic pain, insomnia and tremor disorders including Parkinson's disease. In addition, the article reviews T-type channel inhibitors showing efficacy in animal models in such CNS disorders, with a focus on classical T-type channel inhibitors with limited specificity for T-type channels as well as novel inhibitors with high specificity. Furthermore, the article also presents and discusses the next generation of T-type channel inhibitor discovery, virtual as well as screening and high-throughput screening techniques. EXPERT OPINION: Although T-type channel-related CNS disorders seem to be diverse, it converges into the one major cause - abnormal hyperactivity of neurons. T-type channel-specific inhibitors could thus be commonly applied for the treatment of such CNS disorders regardless of the complexity of individual disorder. Structural information of inhibitor-binding sites would facilitate the discovery of the next generation of T-type channel-specific inhibitors by stimulating structure-based rational drug designs. PMID- 23659217 TI - Response to: Extraventricular neurocytoma of the sellar region. PMID- 23659218 TI - From the 'King's Speech' to Queen Square. PMID- 23659219 TI - Medication management at home: enhancing nurse's skills and improving patient satisfaction--a longitudinal study. AB - The purpose of this longitudinal study was to improve nurse medication management skills during home care (HC) visits, and thus improve care quality and the related patient ratings of nurse performance. Nurses completed presurveys asking how often they asked to see, taught about, and explained side effects of patient medications. Two focus groups were held with HC nurses to determine barriers to provision of such medication interventions, followed by presentation of a series of 5 medication-related educational sessions. HC nurse's surveys 6 months later reveal an increased frequency of medication skill performance, and patient ratings in these same areas improved statistically significantly, nearing or surpassing national benchmarks. PMID- 23659220 TI - Perceptions of Midwest rural women related to their physical activity and eating behaviors. AB - The study aim was to describe the perceptions of 65 Midwestern rural women related to healthy eating, physical activity, and weight management. A semistructured interview guide was used to elicit data. Theory of planned behavior constructs were used to categorize the data into 4 predominant themes related to healthy lifestyle behaviors, (a) knowledge and attitudes, (b) rural cultural influences, (c) facilitators, and (d) barriers. Analyses revealed that facilitators and barriers consisted of social and environmental factors, and personal life situations. Results suggest key elements for developing and implementing effective physical activity and weight management interventions for Midwestern rural women. PMID- 23659221 TI - Barriers to and interventions for improved tuberculosis detection and treatment among homeless and immigrant populations: a literature review. AB - Tuberculosis (TB) cases worldwide have declined over the last 10 years, but strong barriers to detection and treatment of TB still exist, especially among 2 special subgroups of low-income populations, immigrants and the homeless, where the incidence of TB can be up to 20 times higher than the general population even in affluent countries. A systematic review of literature was performed, aimed at identifying the main (1) barriers to and (2) effective interventions for the improved detection and treatment of TB in homeless and immigrant populations. Data were collected from 22 studies out of 80 potentially relevant citations worldwide published between 1998 and 2012. Key findings show that hard-to-reach groups like immigrants and the homeless seem willing to obtain care if they believe it is important, but any new detection/treatment efforts must go beyond current bio-medical models to bio-psychosocial models of the target populations' cultural values. Preliminary results also suggest that the best interventions for the homeless and immigrant populations will be a combination of, at least, monetary incentive and improved accessibility of care. PMID- 23659222 TI - Family health history and self-rated health: a study from the Turkish countryside. AB - Self-rated health is a good indicator for mortality and morbidity, and many of the factors affecting self-rated health are well known. However, the effect of familial disease history on an individual's health perception has not been investigated. This study examined the effects of chronic and serious diseases in mothers, fathers, and siblings, and familial deaths, on self-rated health. A history of familial cancer or stroke affected men's health perceptions negatively, and the presence of familial heart disease affected women's health perception negatively. PMID- 23659223 TI - A descriptive and comparative study from China on patients with type-2 diabetes with and without depressive symptoms. AB - The aim of this study was to assess the prevalence of depressive symptoms for patients with type-2 diabetes at the population level in China and explore differences in demographic, socioeconomic, and disease-specific parameters between diabetic patients with and without depression. Self-rating depression scale was used to screen for depressive symptoms in 667 patients with type-2 diabetes from 4 communities in Beijing; their quality of life and social support was assessed using appropriate and validated tools. The results indicate that 44.23% of diabetic patients report depressive symptoms; patients with depressive symptoms had a significantly higher rate of diabetic complications, a lower quality of life and less social support than patients without depressive symptoms. PMID- 23659225 TI - The effects of integrating instrumental and affective arguments in rhetorical and testimonial health messages. AB - Recent research highlights the superior influence of affect over cognition in health decision making. The present study examined the independent and combined effects of 2 message characteristics that are thought to tap into the cognition affect distinction: message format (rhetorical vs. testimonial) and argument type (instrumental vs. affective). In this 2 * 2 experiment, 81 college students were randomly assigned to 1 of 4 health messages discouraging binge drinking. The results indicated that messages containing affective arguments were judged more positively and perceived as more effective than were messages containing instrumental arguments. The results further revealed an interaction effect between message format and argument type. Testimonials were more persuasive when they contained affective arguments than when they contained instrumental arguments. Type of arguments did not influence the efficacy of rhetorical messages. Mediation analyses revealed that instrumental arguments reduce the efficacy of testimonials because they prevent individuals from being transported into the story, and increase psychological reactance. In conclusion, testimonial messages more effectively discourage binge drinking among college students when they contain affective, as opposed to instrumental, arguments. PMID- 23659226 TI - Plasma proteins adsorption mechanism on polyethylene-grafted poly(ethylene glycol) surface by quartz crystal microbalance with dissipation. AB - Protein adsorption has a vital role in biomaterial surface science because it is directly related to the hemocompatibility of blood-contacting materials. In this study, monomethoxy poly(ethylene glycol) (mPEG) with two different molecular weights was grafted on polyethylene as a model to elucidate the adsorption mechanisms of plasma protein through quartz crystal microbalance with dissipation (QCM-D). Combined with data from platelet adhesion, whole blood clotting time, and hemolysis rate, the blood compatibility of PE-g-mPEG film was found to have significantly improved. Two adsorption schemes were developed for real-time monitoring of protein adsorption. Results showed that the preadsorbed bovine serum albumin (BSA) on the surfaces of PE-g-mPEG films could effectively inhibit subsequent adsorption of fibrinogen (Fib). Nonspecific protein adsorption of BSA was determined by surface coverage, not by the chain length of PEG. Dense PEG brush could release more trapped water molecules to resist BSA adsorption. Moreover, the preadsorbed Fib could be gradually displaced by high-concentration BSA. However, the adsorption and displacement of Fib was determined by surface hydrophilicity. PMID- 23659227 TI - Increased ischaemia-modified albumin is associated with inflammation in acute rheumatic fever. AB - INTRODUCTION: Ischaemia-modified albumin, a novel biochemical marker for tissue ischaemia, was found to be associated with oxidative stress. The purpose of this study was to assess the role of ischaemia-modified albumin in the diagnosis of acute rheumatic fever and also to evaluate the ischaemia-modified albumin levels in children with heart valve disease. METHODS: The study groups, aged 5-18 years, consisted of 128 individuals - 40 with acute rheumatic fever, 35 with congenital heart valve disease, 33 with chronic rheumatic heart disease, and 20 healthy control subjects. RESULTS: The ischaemia-modified albumin, erythrocyte sedimentation rate, and C-reactive protein levels of the acute rheumatic fever group were significantly higher than those in the chronic rheumatic heart disease, congenital heart valve disease, and control groups, separately (p < 0.001). The ischaemia-modified albumin levels in both carditis and isolated arthritis subgroups of children with acute rheumatic fever were significantly higher than in the control group (p < 0.001, p < 0.01, respectively). However, there was no statistically significant difference between the chorea subgroup and control subjects. In addition, significant correlations were observed between ischaemia-modified albumin and acute phase reactants of patients with acute rheumatic fever (p < 0.001 for both erythrocyte sedimentation rate and C-reactive protein). The ischaemia-modified albumin levels of chronic rheumatic heart disease, congenital heart valve disease, and control subjects were similar. CONCLUSIONS: The increased level of ischaemia-modified albumin in children with acute rheumatic fever seems to be associated with inflammation. However, further studies are needed to provide stronger evidence. PMID- 23659228 TI - Sources of medical error in refractive surgery. AB - PURPOSE: To evaluate the causes of laser programming errors in refractive surgery and outcomes in these cases. METHODS: In this multicenter, retrospective chart review, 22 eyes of 18 patients who had incorrect data entered into the refractive laser computer system at the time of treatment were evaluated. Cases were analyzed to uncover the etiology of these errors, patient follow-up treatments, and final outcomes. The results were used to identify potential methods to avoid similar errors in the future. RESULTS: Every patient experienced compromised uncorrected visual acuity requiring additional intervention, and 7 of 22 eyes (32%) lost corrected distance visual acuity (CDVA) of at least one line. Sixteen patients were suitable candidates for additional surgical correction to address these residual visual symptoms and six were not. Thirteen of 22 eyes (59%) received surgical follow-up treatment; nine eyes were treated with contact lenses. After follow-up treatment, six patients (27%) still had a loss of one line or more of CDVA. Three significant sources of error were identified: errors of cylinder conversion, data entry, and patient identification error. CONCLUSION: Twenty-seven percent of eyes with laser programming errors ultimately lost one or more lines of CDVA. Patients who underwent surgical revision had better outcomes than those who did not. Many of the mistakes identified were likely avoidable had preventive measures been taken, such as strict adherence to patient verification protocol or rigorous rechecking of treatment parameters. PMID- 23659229 TI - Long-term outcomes of photorefractive keratectomy for low to high myopia: 13 to 19 years of follow-up. AB - PURPOSE: To evaluate long-term outcomes after photorefractive keratectomy (PRK). METHODS: A retrospective follow-up study of patients who received PRK at 5.0- to 6.5-mm optical zones, using the Summit broad beam excimer laser (Summit Technology, Inc., Waltham, MA) at Odense University Hospital, Odense, Denmark, between 1992 and 1998. One randomly selected eye of each patient was used in the statistical analyses. Re-treated eyes were excluded. RESULTS: One hundred sixty eyes were included. Mean follow-up time was 16 years (range: 13 to 19 years). Mean preoperative spherical equivalent was -4.84 +/- 2.95 diopters (D) (range: 20.25 to -1.25 D). At last follow-up examination, achieved refraction was -1.00 +/- 1.56 D (range: -10.75 to +1.00 D) from attempted refraction, and the change in mean refractive error from 6 months postoperatively was less than 1.00 D. Results from a subgroup of unilateral treated patients indicated that myopic progression was the main reason for the residual refractive error. For eyes with low myopia (n = 124), the proportion of eyes within +/- 1.0 D of attempted refraction was 72%, and for eyes with high myopia (-6.00 D or more, n = 36) it was 47%. Forty-five percent had uncorrected distance visual acuity of 20/20 or better at last follow-up examination. Three eyes (2%) lost two or more lines and 13 eyes (8%) gained two or more lines of corrected distance visual acuity. Fourteen percent had haze (grade 0.5 to 2). Eighty-one percent were satisfied with the surgery. CONCLUSION: PRK for low degrees of myopia seemed safe and effective up to 19 years after surgery with conventional broad beam laser ablation. Refractive predictability was significantly lower and the occurrence of haze was higher in eyes with high myopia. PMID- 23659230 TI - Comparison of corneal flap morphology using AS-OCT in LASIK with the WaveLight FS200 femtosecond laser versus a mechanical microkeratome. AB - PURPOSE: To evaluate and compare the thickness and the morphology of femtosecond and mechanical microkeratome LASIK flaps using anterior segment optical coherence tomography (AS-OCT). METHODS: Bilateral LASIK was performed in 132 eyes from 61 myopic patients. Flaps were created in 72 eyes using the WaveLight FS200 femtosecond laser (Wave-Light GmbH, Erlangen, Germany) and in 50 eyes using the Moria microkeratome (Moria SA, Antony, France). AS-OCT was used 1 week postoperatively to evaluate the thickness of 17 points across each flap, which were 0, 2, and 3.5 mm to the corneal vertex on the horizontal, vertical, 45 degrees , and 135 degrees meridians. RESULTS: The mean central flap thickness was 105.53 +/- 5.86 MUm in the WaveLight group and 132.96 +/- 13.91 MUm in the Moria group (P < .001). The difference between the achieved and the intended flap thickness (accuracy) was 6.17 +/- 3.98 and 23.60 +/- 12.64 MUm, respectively (P < .001). The standard deviation within individual flap (uniformity) was smaller in the WaveLight group. The symmetry and regularity were also better in the WaveLight group. Flap morphology showed a more regular planar shape in the WaveLight group and a meniscus shape in the Moria group. CONCLUSIONS: AS-OCT showed that the flaps created by the WaveLight femtosecond laser were more accurate, reproducible, and uniform than those created by the Moria microkeratome. PMID- 23659232 TI - Combined surgical management of capsular and iris deficiency with glued intraocular lens technique. AB - PURPOSE: To determine the outcome after glued aniridia intraocular lens (IOL) and glued IOL with iridoplasty in eyes with combined lens capsular and iris deficiency. METHODS: Twenty-seven eyes of 25 patients (6 had congenital aniridia with subluxated cataract and 19 had acquired lens/iris defects) were included. Glued IOL with aniridia IOL (Intra Ocular Care, Gujarat, India) was performed in eyes with total aniridia and iridoplasty with glued IOL with a three-piece foldable IOL (Sofport; Bausch & Lomb, Rochester, NY) was performed in eyes with partial aniridia. The postoperative outcomes were analyzed at follow-up examination (range: 6 to 48 months). RESULTS: Eleven eyes underwent glued aniridia IOL and 16 eyes underwent glued IOL with iridoplasty. There was significant improvement in (spectacle) corrected distance visual acuity (CDVA) (P = .002). Postoperatively, pigment dispersion on the IOL (n = 1) and raised intraocular pressure was seen in the glued aniridia IOL group and chronic uveitis (n = 1), cystoid macular edema (n = 1), and hyphema (n = 1) in the glued IOL with iridoplasty group. The CDVA remained unchanged in 14 eyes (51.8%) and improved in 13 eyes (48.1%). There was a difference in postoperative CDVA (P = .001) between eyes with glued aniridia IOL and glued IOL with iridoplasty. There was no IOL decentration, retinal detachment, corneal decompensation, or endophthalmitis. There was reduction in glare and photophobia. CONCLUSIONS: Both glued aniridia IOL and glued IOL/iridoplasty showed good functional and anatomical results with fewer complications in eyes with lens capsule and iris deficiency. However, long term follow-up is required.[J Refract Surg. 2013;29(5):342-347.]. PMID- 23659231 TI - Biological and biomechanical responses to traditional epithelium-off and transepithelial riboflavin-UVA CXL techniques in rabbits. AB - PURPOSE: To compare the biological effects of riboflavin-ultraviolet A (UVA) corneal cross-linking (CXL) performed with a traditional epithelium-off method to several transepithelial methods in a rabbit model. Preliminary experiments on biomechanical rigidity were also performed. METHODS: Four treatment groups were included: (1) standard epithelium-off, (2) tetracaine transepithelial, (3) benzal konium chloride-ethylenediaminetetraacetic acid (BKC-EDTA) transepithelial, and (4) femtosecond laser-assisted transepithelial riboflavin-UVA CXL. Six eyes from each treatment group and the untreated control group were analyzed at 24 hours and 2 months after treatment in wound healing studies. The TUNEL assay was performed to detect the extent of stromal cell death. Optical density was measured with a Scheimpflug analyzer. The corneal stiffening effect was quantitated in three eyes from each group using optical coherence elastography performed 2 months after treatments. RESULTS: Twenty-four hours after CXL, stromal cell death extended full corneal thickness with both standard epithelium off CXL and femtosecond laser-assisted CXL, but only approximately one-third stromal depth after BKC-EDTA transepithelial CXL. Negligible stromal cell death was detected with tetracaine transepithelial CXL. Cell death results were statistically different between the BKC-EDTA transepithelial CXL and standard epithelium-off CXL groups (P < .0001). Significant corneal opacity differences were noted. Standard epithelium-off CXL had the greatest density and tetracaine transepithelial CXL had the least density compared to the control group after treatment. As measured with optical coherence elastography, a trend toward greater mean stiffening was observed with BKC-EDTA transepithelial CXL than with epithelium-off CXL, femtosecond laser-assisted CXL, or tetracaine transepithelial CXL, but the result did not reach statistical significance. All of the CXL treatment groups exhibited significantly smaller variance of stiffness compared to the control group. CONCLUSION: In the rabbit model, BKC-EDTA transepithelial CXL produced less stromal cell death and less risk of endothelial cell damage than standard epithelium-off CXL or femtosecond laser-assisted CXL. Additional study is needed to determine whether biomechanical stiffness is significantly different between the epithelium-off CXL and transepithelial CXL groups. PMID- 23659233 TI - A new slant on toric intraocular lens power calculation. AB - PURPOSE: The AcrySof Toric intraocular lens (IOL) (Alcon Laboratories, Inc., Fort Worth, TX) is designed to correct corneal astigmatism ranging from 0.67 to 4.11 diopters (D). The authors reviewed the clinical outcomes of this IOL and investigated possible improvements of the online calculator provided by the manufacturer. METHODS: Review of published studies. RESULTS: The AcrySof Toric IOL can provide good results, although a mean overcorrection or undercorrection relative to the intended correction has been found by some authors. Stability over time has been reported to be excellent. Rotation occurs mainly in the first postoperative month and is greater in eyes with a longer axial length due to the larger capsule size. The online calculator of this IOL may be improved by considering the posterior corneal astigmatism and better calculating the conversion of the IOL cylinder from the IOL plane to the corneal plane, which may be inaccurate for two reasons. First, given the variable distance between the IOL and the cornea in short and long eyes, the fixed ratio (1.46) provided by the manufacturer cannot be used to calculate this conversion. Second, the online calculator does not take into account the effect of varying IOL sphere power. CONCLUSION: The AcrySof Toric IOL is a reliable choice to correct corneal astigmatism at the time of cataract surgery. Results will be improved once the online calculator by the manufacturer considers the posterior corneal astigmatism and the variable ratio between the toricity at the IOL and corneal plane. PMID- 23659234 TI - Oral pathologies of the Neolithic Iceman, c.3,300 BC. AB - The famous Iceman 'Otzi' (South Tyrol Museum of Archaeology, Bolzano, Italy), a Neolithic human ice mummy, offers a unique opportunity to study evolutionary aspects of oral disease. The aim of this study was to assess, for the very first time, his oral cavity, which surprisingly had never been examined systematically. Based on several computed tomography (CT) scans from 1991 onwards and on macroscopic investigation, only a few findings, such as a central maxillary diastema, heavy abrasions, and missing wisdom teeth, were known. We re-evaluated the latest CT scans from 2005 and found various oral pathologies. In line with the increase of tooth decay in the Neolithic - because of diet change in this historic transition phase - several carious lesions were found, one of which penetrated into the dental pulp. In accordance with the Iceman's troubled life, as several injuries on his body and his violent death attest, mechanical trauma of one of his upper front teeth is evident. Finally, the poor periodontal condition of the Iceman's dentition (e.g. loss of alveolar bone), indicative of periodontitis, was assessed. These oral pathological findings in the Iceman's dentition provide a unique glimpse into the evolutionary history of oral conditions. PMID- 23659235 TI - Novel RUNX2 frameshift mutations in Chinese patients with cleidocranial dysplasia. AB - Cleidocranial dysplasia (CCD) is a skeletal disorder caused by heterozygous mutations in the runt-related transcription factor 2 (RUNX2) gene. We evaluated the phenotypes of eight Chinese patients with CCD from three unrelated families followed by analysis of the RUNX2 genes. Three different RUNX2 frameshift mutations were identified. Two of the mutations are novel (c.887insC and c.592delA) and one (c.90insC) has been described previously. Surprisingly, the patient with the most severely truncated RUNX2 protein (c.90insC) had the mildest phenotype. The RUNX2 mutations identified were assessed for their effect on the subcellular localization of the mutant RUNX2 proteins because of previously reported inconsistent findings. All three mutant proteins showed at least partially impaired nuclear localization compared with wild-type RUNX2, which was localized exclusively in the nucleus. Our findings support the notion that haploinsufficiency of RUNX2 may be mainly responsible for CCD. However, because the correlation between the severity of the phenotype and the degree of mutational impairment of RUNX2 is not consistent, other factors, such as nonsense mediated mRNA decay and negative dominant effects, may also play a role. In addition, we show that despite the presence of the best characterized nuclear localization signal, nuclear translocation of truncated RUNX2 can be inhibited, possibly as a result of precipitation in the cytoplasm. PMID- 23659237 TI - Effect of metalloporphyrins on red autofluorescence from oral bacteria. AB - The aim of this study was to assess the red autofluorescence from bacterial species related to dental caries and periodontitis in the presence of different nutrients in the growth medium. Bacteria were grown anaerobically on tryptic soy agar (TSA) supplemented with nutrients, including magnesium-porphyrins from spinach and iron-porphyrins from heme. The autofluorescence was then assessed at 405 nm excitation. On the TSA without additives, no autofluorescence was observed from any of the species tested. On the TSA containing sheep blood, red autofluorescence was observed only from Parvimonas micra. When the TSA was supplemented with blood, hemin, and vitamin K, red autofluorescence was observed from Actinomyces naeslundii, Bifidobacterium dentium, and Streptococcus mutans. Finally, on the TSA supplemented with spinach extract, red autofluorescence was observed from Aggregatibacter actinomycetemcomitans, A. naeslundii, Enterococcus faecalis, Fusobacterium nucleatum, Lactobacillus salivarius, S. mutans, and Veillonella parvula. We conclude that the bacteria related to dental caries and periodontal disease exhibit red autofluorescence. The autofluorescence characteristics of the tested strains depended on the nutrients present, such as metalloporphyrins, suggesting that the metabolic products of the oral biofilm could be responsible for red autofluorescence. PMID- 23659236 TI - Characteristics of Streptococcus mutans genotypes and dental caries in children. AB - This longitudinal cohort study evaluated the diversity, commonality, and stability of Streptococcus mutans genotypes associated with dental caries history. Sixty-seven 5- and 6-yr-old children, considered as being at high caries risk, had plaque collected from baseline through 36 months for S. mutans isolation and genotyping using repetitive extragenic palindromic-PCR (4,392 total isolates). Decayed, missing, or filled surfaces (dmfs (primary teeth)/DMFS (secondary teeth)) for each child were recorded at baseline. At baseline, 18 distinct genotypes were found among 911 S. mutans isolates from 67 children (diversity), and 13 genotypes were shared by at least two children (commonality). The number of genotypes per individual was positively associated with the proportion of decayed surfaces (p-ds) at baseline. Twenty-four of the 39 children who were available at follow-up visits maintained a predominant genotype for the follow-up periods (stability) and this was negatively associated with the p-ds. The observed diversity, commonality, and stability of S. mutans genotypes represent a pattern of dental caries epidemiology in this high-caries-risk community, which suggests that fewer decayed surfaces are significantly associated with lower diversity and higher stability of S. mutans genotypes. PMID- 23659238 TI - Porphyromonas gingivalis biofilms persist after chlorhexidine treatment. AB - Chlorhexidine (CHX) gluconate effectively reduces the viability of biofilm forming bacteria, such as Porphyromonas gingivalis. However, it is impossible to completely remove biofilms. The goal of the present study was to assess the potential pathogenicity of residual P. gingivalis biofilms in vitro after treatment with CHX gluconate. Scanning and transmission electron microscopy and confocal laser imaging revealed that treatment with CHX gluconate disrupted individual biofilm-forming P. gingivalis cells but did not destroy the biofilms. The volumes of the protein and carbohydrate constituents in the residual biofilms were not significantly different from those of the controls. The physical resistance of the residual biofilms to ultrasonication was significantly higher than that of controls. The volume of P. gingivalis adherent to the residual biofilms was higher than that to saliva-coated wells. These findings suggest that although CHX gluconate caused disruption of biofilm-forming cells, the constituents derived from disrupted cells were maintained in the biofilms, which sustained their external structures. Moreover, the residual biofilms could serve as a scaffold for the formation of new biofilms. PMID- 23659239 TI - Oral health and welfare state regimes: a cross-national analysis of European countries. AB - Very little is known about the potential relationship between welfare state regimes and oral health. This study assessed the oral health of adults in a range of European countries clustered by welfare regimes according to Ferrera's typology and the complementary Eastern type. We analysed data from Eurobarometer wave 72.3, a cross-sectional survey of 31 European countries carried out in 2009. We evaluated three self-reported oral health outcomes: edentulousness, no functional dentition (<20 natural teeth), and oral impacts on daily living. Age standardized prevalence rates were estimated for each country and for each welfare state regime. The Scandinavian regime showed lower prevalence rates for all outcomes. For edentulousness and no functional dentition, there were higher prevalence rates in the Eastern regime but no significant differences between Anglo-Saxon, Bismarckian, and Southern regimes. The Southern regime presented a higher prevalence of oral impacts on daily living. Results by country indicated that Sweden had the lowest prevalences for edentulousness and no functional dentition, and Denmark had the lowest prevalence for oral impacts. The results suggest that Scandinavian welfare states, with more redistributive and universal welfare policies, had better population oral health. Future research should provide further insights about the potential mechanisms through which welfare state regimes would influence oral health. PMID- 23659240 TI - Inequalities in the use of dental services among adults in inner South East London. AB - Improving access to National Health Service (NHS) dentistry is a public health issue that has been a focus for successive governments and policy makers in the UK. To inform this process, commissioners of services need to understand trends in service use and demands of the local population. This study explored inequalities in dental services use among adults in a socially deprived, ethnically diverse metropolitan area of London; satisfaction with services; and public views for improvement of services. Data from 695 adults were analysed for this study (56% of the eligible sample). Inequalities in dental services use and satisfaction with care according to sociodemographic factors were assessed in unadjusted and fully adjusted models. The proportion of participants who reported attending the dentist in the last 24 months was 69%, with inequalities according to social grade, ethnicity, sex and age but not according to borough of residence. The most common areas identified by respondents for service improvement were availability of dentists, affordability of care, and accommodation of services. Among those who visited the dentist in the last 24 months, 90% were satisfied with the quality of care provided. However, there were inequalities in satisfaction with care according to borough and reason for the last dental visit. PMID- 23659241 TI - Clinical status in adolescents: is its impact on oral health-related quality of life influenced by psychological characteristics? AB - The objective of this study was to examine, using structural equation modelling, the relationships among clinical characteristics (such as caries experience and malocclusion), oral health-related quality of life (OHRQoL), and psychological characteristics (mental health, self-esteem, somatisation, and social perception of body image) in adolescents in New Zealand. Adolescents were examined for malocclusion using the Dental Aesthetic Index (DAI) and for dental caries. Among the 353 (58.8%) 12- and 13-yr-old adolescents who took part in this cross sectional study, the overall mean +/- SD decayed, missing, or filled surfaces (DMFS) value was 1.6 +/- 3.0, with slightly more than 50% of being caries-free; the mean +/- SD DAI was 31.5 +/- 7.6, with one-quarter of subjects having a 'handicapping' malocclusion. The structural equation modelling analysis showed that the structural model was a good fit to the data. As hypothesized, the DAI score significantly predicted OHRQoL. There was no direct relationship between caries experience (DMFS) and OHRQoL, but there was an indirect effect of DMFS on OHRQoL mediated through psychological characteristics. The amount of OHRQoL variance accounted for in the model was substantial, at 62%. It appears that investigating OHRQoL in adolescents is not straightforward; while malocclusion directly affects OHRQoL, the influence of dental caries experience is less direct. PMID- 23659242 TI - Oral Health Impact Profile, EuroQol, and Assessment of Quality of Life instruments as quality of life and health-utility measures of oral health. AB - Oral-specific measures are often preferred to examine outcomes of oral disorders. However, generic measures can add additional information, including health utility. The aim was to assess the Oral Health Impact Profile (OHIP), EuroQol (EQ 5D), and Assessment of Quality of Life (AQoL) instruments in relation to oral health in terms of their discriminative and convergent validities. Data were collected from adults, 30-61 yr of age, in Australia by mailed survey during 2009 and 2010, including the OHIP-14, the EQ-5D, and the AQoL, a range of self reported oral health variables, and by self-rated oral and general health. Responses were collected from 1093 subjects (a response rate of 39.1%). The OHIP, the EQ-5D, and the AQoL were associated with oral health variables, with effect sizes ranging from 0.6 to 1.1 for the OHIP, from 0.3 to 0.5 for the EQ-5D, and from 0.4 to 0.6 for the AQoL. The OHIP tended to be more strongly correlated with self-rated oral health (rho = -0.5) than with general health (rho = -0.3), whilst the EQ-5D and the AQoL were less strongly correlated with oral health (rho = -0.3 and -0.3, respectively) than with general health (rho = -0.4 and -0.5, respectively). Whilst the OHIP was more sensitive to differences in oral health, the generic measures of EQ-5D and AQoL both exhibited discriminative validity and convergent validity in relation to oral health variables, supporting their use in oral health studies. PMID- 23659243 TI - Applying the Cognitive Vulnerability Model to the analysis of cognitive and family influences on children's dental fear. AB - Negative experiences, cognitions, and family variables are involved in the etiology of child dental fear, but previous research has frequently considered them separately. This study uses the Cognitive Vulnerability Model to explore the influence of negative dental experiences and family members on children's dental anxiety. The participants were 185 children who completed a questionnaire comprising measures of dental fear and cognitive vulnerability-related perceptions. Measures were obtained for 88 of the participants' fathers and for 97 of the participants' mothers. Cognitive vulnerability perceptions had the strongest association with children's dental fear (beta = 0.40), explaining 14 21% of the variance in dental fear scores beyond that explained by other variables. Furthermore, vulnerability perceptions mediated the relationship between negative dental experiences and dental fear. Children's dental fear and cognitive vulnerability perceptions were significantly associated with those of their fathers (r = 0.23 and r = 0.40, respectively) and mothers (r = 0.28 and r = 0.35, respectively). Moreover, fathers' (beta = 0.24) and mothers' (beta = 0.31) levels of cognitive vulnerability significantly predicted the children's levels of dental fear. The Cognitive Vulnerability Model offers a framework to understand child dental fear. Furthermore, this cognitive approach may help explain why some children develop dental fear problems after suffering a negative dental experience and how dental anxiety is passed on from parents to children. PMID- 23659244 TI - Effect of pretreatment with calcium-containing desensitizer on the dentine bonding of mild self-etch adhesives. AB - Desensitizing agents are frequently applied to sensitive teeth and may affect subsequent resin bonding. The current study aimed to evaluate the bonding performance of two self-etch adhesives containing functional monomers to dentine pretreated with three new calcium-containing desensitizers. No desensitizer was applied in the control group. Groups 1, 2, and 3 were treated with an arginine calcium carbonate-containing polishing paste, a casein phosphopeptide-amorphous calcium phosphate (CPP-ACP)-containing paste, and an experimental hydroxyapatite paste, respectively. G-Bond and Clearfil S(3) Bond were used for bonding after desensitizer treatments. The microtensile bond strength (MUTBS) was tested (n = 20 beams per group) and failure mode distribution was analyzed. Scanning electron microscopy was used to observe the occlusion of dentinal tubules. The mean (+/ SD) MUTBS values, expressed in MPa, of groups 1, 2, and 3 and the control group were, respectively, 30.81 (7.79), 44.41 (8.02), 31.49 (6.13), and 41.40 (8.67) for G-Bond and 39.63 (9.59), 32.55 (7.86), 37.50 (8.60), 27.90 (6.52) for S3 Bond. Most failures were recorded as adhesive failure (69.375%), instead of cohesive failure or mixed failure. The dentinal tubules were seldom plugged in group 2, but were mostly occluded in groups 1 and 3. Two-way anova indicated that desensitizer application in association with a compatible adhesive system should be used when endeavoring to control hypersensitivity without adverse interference in bonding. PMID- 23659245 TI - Chlorhexidine release from orthodontic adhesives after topical chlorhexidine treatment. AB - This study was designed to investigate the ability of orthodontic adhesives to adsorb and release chlorhexidine (CHX) after periodic treatment with 1% CHX solution. Composite and resin-modified glass-ionomer cement (RM-GIC) adhesive disks were incubated with whole saliva or distilled water for 2 h. Release of CHX was measured using high-performance liquid chromatography after 1, 2, and 5 d of incubation, 1 min after exposure to 1% CHX solution. The CHX measurements were performed in a 5-d cycle, which was repeated four consecutive times (n = 7). The amount of CHX adsorbed and the cumulative amounts of CHX released, with respect to type of adhesive and saliva-coating, were analyzed using repeated-measures anova. Chlorhexidine-adsorbed orthodontic adhesives demonstrated a short-term release of CHX, which rapidly returned to near-baseline levels within 3 d. Saliva coating did not significantly influence CHX release from RM-GIC, but increased the amount of CHX released from the composite. The amount of CHX released from the composite was 20-fold higher than that released from the RM-GIC after saliva coating. The composite adhesive showed a greater adsorption capacity for CHX than did the RM-GIC, which was more evident after saliva-coating. This study suggests that composite adhesives may be a significantly more effective CHX reservoir than RM-GICs in the oral cavity filled with saliva. PMID- 23659247 TI - Probing the interaction of lysozyme with ciprofloxacin in the presence of different-sized Ag nano-particles by multispectroscopic techniques and isothermal titration calorimetry. AB - The binding of ciprofloxacin to lysozyme in the presence of three Ag nano particles of varying sizes was for the first time investigated by multispectroscopic and isothermal titration calorimetry techniques at pH 7.4. The results indicated that ciprofloxacin quenched the fluorescence intensity of lysozyme through a static mechanism but in the presence of size-II Ag nano particles, there were two kinds of interaction behaviors. The interaction between ciprofloxacin and lysozyme occurred via a second type of binding site, whereas in the presence of the Ag nano-particles, some changes occurred. The secondary structure of lysozyme-ciprofloxacin in the presence of Ag nano-particles was determined by circular dichroism. The thermodynamic parameters of the interaction between ciprofloxacin and lysozyme in the presence of Ag nano-particles were measured according to the van't Hoff equation. The enthalpy (DeltaH(?)) and entropy (DeltaS(?)) changes were calculated to be -49.7 (kJ mol(-1)) and -20.1 (J mol(-1) K(-1)), respectively, which indicated that the interaction of ciprofloxacin with lysozyme was driven mainly by van der Waals forces and hydrogen bonding. In the presence of the three different-sized Ag nano-particles, the enthalpic and the entropic changes were both negative which indicated that hydrogen bonding with van der Waals forces played major roles in the binding between ciprofloxacin and lysozyme. Recent developments in nano-materials offer new pathways for controlling the protein behavior through surface interactions. These data indicate that the recent research on nano-particle/protein interactions will emphasize the importance of such interactions in biological systems with applications including the diagnosis and treatment of human diseases. PMID- 23659246 TI - DNA repair variants, indoor tanning, and risk of melanoma. AB - Although ultraviolet radiation (UV) exposure from indoor tanning has been linked to an increased risk of melanoma, the role of DNA repair genes in this process is unknown. We evaluated the association of 92 single nucleotide polymorphisms (SNPs) in 20 DNA repair genes with the risk of melanoma and indoor tanning among 929 patients with melanoma and 817 controls from the Minnesota Skin Health Study. Significant associations with melanoma risk were identified for SNPs in ERCC4, ERCC6, RFC1, XPC, MGMT, and FBRSL1 genes; with a cutoff of P < 0.05. ERCC6 and FBRSL1 gene variants and haplotypes interacted with indoor tanning. However, none of the 92 SNPs tested met the correction criteria for multiple comparisons. This study, based on an a priori interest in investigating the role of DNA repair capacity using variants in base excision and nucleotide excision repair, identified several genes that may play a role in resolving UV-induced DNA damage. PMID- 23659248 TI - Primary cardiovascular prevention by Mediterranean diet - the PREDIMED trial. PMID- 23659249 TI - Spotted Weimaraner dog due to de novo KIT mutation. PMID- 23659250 TI - Multiple recombinant adeno-associated viral vector serotypes display persistent in vivo gene expression in vector-transduced rat stifle joints. AB - Our aim was to investigate serotype-specific cell and tissue-transduction tropisms, transgene expression levels and longevity, and immunogenicity of candidate rAAV serotypes in rat osteochondral cells, tissues, and stifle joints. In vitro, we used six rAAV serotypes and two promoters to transduce synoviocytes and chondrocytes. Serotypes rAAV2/5 and 2/2 yielded the highest transduction efficiency 4 days after transduction. No differences were detected between cytomegalovirus and chicken beta-actin promoters. In vivo, intra-articular injection was used to introduce four rAAV serotypes into 4-month-old rats in the left stifle joint. Eleven months later, serotype 2/5 vector, diluted with saline or surfactant, was injected into the right stifle joint of the same rats. Rats were analyzed up to 12 months after initial injection. Bioluminescence was detected at 7 days and all serotypes tested displayed bioluminescence above controls after 1 year in the left stifle. Gene expression was detected in the right stifle joints of all rats with the exception of rats previously injected with serotype 2/5. We observed no difference irrespective of whether the luciferin was injected subcutaneously or intraperitoneally. However, surfactant diluted vectors led to increased gene expression compared with saline-diluted vectors. Cell- and tissue-specific transduction was observed in rat stifles injected with an nLacZ-containing rAAV. Transduction was greatest in stromal tissues and mesenchymal cell types. Exposure to a specific serotype did not inhibit subsequent transduction with a different serotype at a second vector injection. Including surfactant as a vector diluent increased gene expression within the stifle joint and should be considered for in vivo gene therapy applications. PMID- 23659251 TI - Preoperative risk stratification models fail to predict hospital cost of cardiac surgery patients. AB - BACKGROUND: Preoperative risk stratification models have previously been suggested to predict cardiac surgery unit costs. However, there is a lack of consistency in their reliability in this field. In this study we aim to test the correlation between the values of six commonly known preoperative scoring systems and evaluate their reliability at predicting unit costs of cardiac surgery patients. METHODS: Over a period of 14 months all consecutive adult patients undergoing cardiac surgery on cardiopulmonary bypass were prospectively classified using six preoperative scoring models (EuroSCORE, Parsonnet, Ontario, French, Pons and CABDEAL). Transplantation patients were the only patients we excluded. Total hospital costs for each patient were calculated independently on a daily basis using the bottom up method. The full unit costs were calculated including preoperative diagnostic tests, operating room cost, disposable materials, drugs, blood components as well as costs for personnel and fixed hospital costs. The correlation between hospital cost and the six models was determined by linear regression analysis. Both Spearman's and Pearson's correlation coefficients were calculated from the regression lines. An analysis of residuals was performed to determine the quality of the regression. RESULTS: A total of 887 patients were operated on for CABG (n = 608), valve (n = 142), CABG plus valve (n = 100), thoracic aorta (n = 33) and ventricular assist devices (n = 4). Mean age of the patients was 68.3+/-9.9 years, 27.6% were female. 30-day mortality rate was 4.1%. Correlation between the six models and hospital cost was weak (Pearson's: r < 0.30; Spearman's: r < 0.40). CONCLUSION: The risk stratification models in this study are not reliable at predicting total costs of cardiac surgical patients. We therefore do not recommend their use for this purpose. PMID- 23659252 TI - The First Symposium on Behavioral and Community Dentistry at the University of Gothenburg: Ulf Berggren and dental anxiety. PMID- 23659253 TI - Dental anxiety - a joint interest for dentists and psychologists. AB - This introductory article to the Symposium on Behavioral and Community Dentistry aims to describe the development of research and clinical work on dental anxiety, and includes a discussion of the historical background and the evolution since the 1970s. In view of its pioneering activities in this regard, special focus is placed on research and development at the Institute of Odontology of the University of Gothenburg, Sweden. PMID- 23659254 TI - Psychological treatment of dental anxiety among adults: a systematic review. AB - The aim was to investigate the efficacy of behavioural interventions as treatment of dental anxiety/phobia in adults, by conducting a systematic review of randomized controlled trials (RCTs). The inclusion criteria were defined according to the Patients, Interventions, Controls, Outcome (PICO) methodology. The study samples had documented dental anxiety, measured using validated scales [the Dental Anxiety Scale (DAS) or the Dental Fear Survey (DFS)], or fulfilled the psychiatric criteria for dental phobia. Behavioural interventions included were based on cognitive behavioural therapy (CBT)/behavioural therapy (BT), and control conditions were defined as information, sedation, general anaesthesia, and placebo/no treatment. The outcome variables were level of dental anxiety, acceptance of conventional dental treatment, dental treatability ratings, quality of life and oral health-related quality of life, and complications. This systematic review identified 10 RCT publications. Cognitive behavioural therapy/behavioural therapy resulted in a significant reduction in dental anxiety, as measured using the DAS (mean difference = -2.7), but the results were based on low quality of evidence. There was also some support that CBT/BT improves the patients' acceptance of dental treatment more than general anaesthesia does (low quality of evidence). Thus, there is evidence that behavioural interventions can help adults with dental anxiety/phobia; however, it is clear that more well-designed studies on the subject are needed. PMID- 23659255 TI - On the dynamics of dental fear: dental or mental? AB - This study explored possible predictors of change over time in dental fear. In a population-based sample of 664 women, 38-54 yr of age at first assessment, a self rating of dental fear was recorded on two occasions, 6 yr apart. Whilst the majority of the women maintained their level of fear, two subgroups reported changes at follow up. Of the 99 subjects indicating high fear at baseline, 54 recorded no or minimal fear at follow up and, among the 565 recording minimal fear at baseline, 27 reported increased fear at follow up. We used psychological and odontological findings at baseline to compare the four subgroups with altered or maintained fear ratings at follow up. The women reporting reduced fear at follow up differed significantly in the psychological variables from those reporting unchanged fear; there were no significant differences between these groups in any of the odontological variables. The group indicating increased fear at follow up did not differ from those with a maintained fearlessness in any of the baseline measurements. The results are discussed in terms of a systems oriented understanding of the development of dental fear. PMID- 23659256 TI - Predicting dental avoidance among dentally fearful Australian adults. AB - Dental fear is related to poorer oral health outcomes, and this might be explained by the less frequent dental visiting of many fearful people. The objectives of this study were to investigate differences between dentally fearful people who regularly attend the dentist and fearful people who infrequently visit the dentist. A random sample of 1,082 Australians >= 15 yr of age completed a mailed questionnaire (response rate = 71.6%), and 191 dentate, high-fear adults (>= 18 yr of age) were selected for further analysis. Dental avoidance was recorded if a person was currently avoiding or delaying dental care and if he/she had not been to a dentist in the previous 2 yr. Among the selected dentally fearful adults, dental avoidance was predicted by smoking status, toothbrushing frequency, coping strategy use, perceptions of dental visits as uncontrollable and unpredictable, and by anxiety relating to numbness, not knowing what the dentist is going to do, and cost. In a multivariate logistic regression model, smoking, toothbrushing, coping, and anxiety about numbness and cost remained as statistically significant predictors, with the model accounting for 30% of the variance. While several variables were associated with dental avoidance among fearful adults, the nature and causal directions of these associations remain to be established. PMID- 23659257 TI - Dental fear and sense of coherence among 18-yr-old adolescents in Finland. AB - The aim was to investigate whether dental fear was associated with the sense of coherence (SOC) among 18-yr-old adolescents (n = 777). Cross-sectional data from a prospective cohort of a random sample of families from Finland and their first born children were used. Dental fear was measured using the Modified Dental Anxiety Scale and categorized as high dental fear for scores of 19-25 and as no to moderate dental fear for scores of 5-18. Sense of coherence was measured using a 13-item version of Antonovsky's Sense of Coherence Questionnaire, dichotomized as scores 13-63 for weak SOC and as scores of 64-91 for strong SOC. Gender and education were included as background factors in the logistic regression analyses. The prevalence of high dental fear was 8%. Those reporting high dental fear reported more often a weaker SOC than did those with no to moderate dental fear (69% vs. 31%, OR = 2.5, 95% CI = 1.4-4.4), also when adjusted for gender and education (OR = 2.2, 95% CI = 1.2-3.9). According to the theory of salutogenesis, as proposed by Antonovsky, SOC is a resource instrument especially in situations of tension or strain and hence a strong SOC might protect against high dental fear. PMID- 23659258 TI - General fearfulness, attitudes to dental care, and dental anxiety in adolescents. AB - The etiology of dental anxiety (DA) may involve a spectrum of factors related to past dental experiences, general and specific fears, and other personality factors, but is relatively unexplored in adolescents. The aim of this study was to examine how general fearfulness and attitudes to dental care/personnel were related to DA in 15-yr-old subjects. The sample included 263 randomly selected 15 yr-old adolescents living in the municipality of Jonkoping in southern Sweden. Four questionnaires were used: one general questionnaire regarding background data and three psychometric instruments dealing with DA, general fearfulness, and dental beliefs. Of all participants, 6.5% were classified as having DA. Dental anxiety was moderately to strongly correlated both with attitudes to dental care/personnel and with general fearfulness and indicated the strongest impact for individuals with both high general fearfulness and high dental beliefs in relation to DA. The linear multiple regression analysis showed that the best predictors of DA were general fearfulness and dental beliefs. This suggests that both individual vulnerability in terms of generalized fear and apprehensions about dental staff, which is linked to experiences of dentistry, appear to be important factors for DA and may be considered as risk factors for DA in adolescents. PMID- 23659259 TI - Attention deficit hyperactivity disorder and dental anxiety in adults: relationship with oral health. AB - The aim of the present study was to investigate the presence of attention deficit hyperactivity disorder (ADHD) in adult patients with severe dental anxiety. Specifically, we analysed the relationship among ADHD, oral health, and dental anxiety. The World Health Organization Adult ADHD Self-Report Scale (ASRS) Screener was administered to a consecutive sample of patients referred to a dental fear research and treatment clinic. Patients completed questionnaires measuring dental anxiety (Dental Fear Survey) and self-rated oral health, and underwent a full radiographic examination. Of the total sample (n = 110), 16% scored above the established ASRS cut-off point, which is indicative of having ADHD. The ADHD group showed a higher level of dental anxiety and poorer self rated oral health. There were also indications of poorer clinical oral health in the ADHD group, but these results did not reach statistical significance. In conclusion, the results of this study indicate an increased prevalence of ADHD in highly dentally anxious adults and the need to pay special attention to these patients because of greater treatment needs and increased dental anxiety. PMID- 23659260 TI - Changes over time in adult dental fear and correlation to depression and anxiety: a cohort study of pregnant mothers and fathers. AB - We aimed to evaluate (i) changes in dental fear over time during pregnancy and after delivery among mothers and fathers and (ii) whether these changes inter relate to changes in depression and anxiety. Longitudinal pilot data for the FinnBrain Cohort study were used. Of 254 pregnant families, 80% agreed to participate and 60% returned questionnaires at the first data-collection point. After three data-collection points [weeks 18-20 and 32-34 of pregnancy (H18-20 and H32-34, respectively), and 3 months after childbirth], 99 mothers and 74 fathers had filled out at least two out of three Modified Dental Anxiety Scale questionnaires and were included in this study. Other questionnaires used were the Edinburgh Postnatal Depression Scale, the State Trait Anxiety Inventory, and the Pregnancy Related Anxiety Questionnaire. All scales were analyzed as sum scores. Among mothers, dental fear decreased during late pregnancy and increased slightly after childbirth, but no statistically significant correlations between dental fear and depression or anxiety, except for fear of giving birth, were found. Among fathers dental fear increased and was correlated with depression and anxiety. Dental fear seems to fluctuate among women during pregnancy and could be affected by hormonal changes. PMID- 23659261 TI - Dental coping strategies, general anxiety, and depression among adult patients with dental anxiety but with different dental-attendance patterns. AB - The aim of the present study was to investigate dental coping strategies, general anxiety, and depression in relation to regularity of dental treatment among persons with either regular dental care or phobic avoidance, whilst controlling for sociodemographic factors. Psychometric questionnaires on dental anxiety, dental coping strategies, general anxiety, and depression were delivered to 263 adult patients with dental phobic avoidance behavior who were seeking help from a specialized dental fear clinic and to 141 adult patients with dental anxiety who were receiving regular dental care from various public dental clinics. The results showed that the levels of dental and general anxiety and of depression were significantly higher among irregular attendees compared with regular attendees. Irregular attendees admitted fewer adaptive coping strategies. Predictive of irregular dental care were gender, dental anxiety, general anxiety, and the nonuse of the coping strategy 'optimism'. This study further confirms earlier preliminary results that the use of optimistic thinking is predictive for regular dental attendance habits and that male gender is a risk factor for irregular attendance. Moreover, this study adds that a high level of general anxiety indicates a higher risk for irregular dental care. PMID- 23659262 TI - Validating the dental subscale of the children's fear survey schedule using Rasch analysis. AB - Rasch analysis was used to examine the validity of the Children's Fear Survey Schedule - Dental Subscale (CFSS-DS). Data were collected from parents of children in regular dental care (n = 240) and from parents of children referred to a specialized pediatric dental clinic (n = 200). The Rasch model is a probabilistic model in which estimations are based on the relationship between person ability and item difficulty, and the present study investigated the validity of the CFSS-DS through analysis of person and item fit, dimensionality, ordering of thresholds, local dependency, and differential item functioning. The results show multidimensionality of the original scale, and an adjusted version consisting of six items with good fit to the model is suggested. The adjusted scale makes interval-level analysis possible, and time efficiency and elimination of previously criticized items argue in favor of the adjusted scale. PMID- 23659263 TI - Dentists' skills with fearful patients: education and treatment. AB - The aims were to explore dentists' skills in dental fear, current strategies when treating fearful adult patients, and the possible need for additional education among dentists working in Sweden. A sample of 1,293 members of the Association of Public Health Dentists in Sweden were asked to respond to a Web survey concerning dental fear. The response rate was 69% (n = 889); 91% trained in Sweden and 9% trained in another country. The most frequently used pharmacological anxiety reducing techniques were medication with a midazolame mixture (72%) and benzodiazepine tablets (77%), and the most commonly used psychological techniques were relaxation (68%), distraction (66%), and Tell-Show-Do (86%). A larger proportion of dentists trained in Sweden, compared with dentists who were trained in other countries, reported that they had received undergraduate training in dental fear. Dentists trained in Sweden more often reported competence in pharmacological and psychological anxiety-reducing techniques, compared with dentists who were trained in other countries. Higher levels of self-rated efficacy in treating fearful patients accompanied additional education in dental fear after graduation. In conclusion, Swedish dentists use a variety of techniques to meet the needs of fearful dental patients. Competence in anxiety reducing techniques is associated with self-efficacy and the site of education. PMID- 23659264 TI - Algorithm-based management of bleeding in patients with extracorporeal membrane oxygenation. PMID- 23659265 TI - Prediction of fundamental properties of ionic liquid electrospray thrusters using molecular dynamics. AB - Molecular dynamics (MD) simulations are performed to model an electrospray thruster for the ionic liquid (IL) EMIM-BF4 using two coarse-grained (CG) potentials. Different equilibrium properties were obtained for the two potentials and then both were used to study the electrical extrusion of the IL for different electric field strengths and mass flow rates. The MD simulations provide the first insight into the atomistic modeling of a capillary-tip-extractor system, the basic elements of an electrospray thruster. One of the CG potentials was found to predict the formation of the Taylor cone, the cone-jet, and other extrusion modes for similar electric fields and mass flow rates observed in experiments of a IL fed capillary-tip-extractor system. Current distributions and anion and cation behavior were characterized and estimates of thrust and specific impulse are presented and compare reasonably well with measurements. Moreover, the role of inhomogeneities in the electric field as well as that of the IL space charge most likely will improve agreement between modeling and experiment. PMID- 23659266 TI - Follicle-stimulating hormone receptor expression in soft tissue sarcomas. AB - AIMS: In adult humans, the follicle-stimulating hormone receptor (FSHR) is expressed only in the granulosa cells of the ovary and the Sertoli cells of the testis. Recently, it has been shown that FSHR is expressed selectively on the surface of blood vessels in a wide range of tumours. So far, the expression of FSHR in mesenchymal tumours has not been studied. METHODS AND RESULTS: We performed a semiquantitative evaluation of FSHR protein expression in a large cohort of soft tissue sarcomas (STS; n = 335), including 11 subtypes. FSHR positive vessels were detected in all sarcoma subtypes analysed. Among liposarcomas, significantly more cases of dedifferentiated liposarcomas (28 of 44) showed FSHR expression compared to well-differentiated liposarcomas (WDLS; four of 21; P < 0.001). Vessels in lipomas (n = 9) and non-neoplastic fat were FSHR-negative. FSHR expression was also detected in tumour cells of all sarcoma subtypes examined, with the lowest incidence in WDLS (three of 21; 14.3%) and the highest frequency in undifferentiated high-grade pleomorphic sarcomas (41 of 60; 68.3%). CONCLUSIONS: These data supplement the previously reported results of FSHR expression in endothelial cells of various cancer types and form a solid basis for further studies of FSHR in mesenchymal neoplasms. PMID- 23659267 TI - Temporally separated bilateral anal sac gland carcinomas in four dogs. AB - Anal sac gland carcinoma arising from the apocrine secretory epithelium in the anal sac wall, is locally invasive and highly metastatic. The majority of anal sac gland carcinomas are unilateral on presentation, but bilateral tumours have been identified. This case series presents the outcome of four unique cases of unilateral anal sac gland carcinoma which subsequently developed contralateral anal sac gland carcinoma 50 to 390 days after removal of the initial tumour. Median survival was 1035 days after initial diagnosis and 807 days after diagnosis of the second anal sac gland carcinoma. PMID- 23659268 TI - Cervical cancer screening adherence among Somali immigrants and refugees to the United States. AB - Somali women have lower cervical cancer screening (CCS) rates than non-Somali women in the United States. We examined clinical and administrative data associated with CCS adherence among Somali women seen at a large primary care practice over 2 years. Fifty-one percent of 310 women were adherent to CCS, and adherence was associated with more overall health care system visits. Patients saw male providers 65.8% of the time; however, only 20.4% of the CCS tests were performed by male providers. Future interventions that enhance cancer prevention, health literacy, and patient-provider gender concordance may improve rates of CCS among Somali women. PMID- 23659269 TI - Social media @BJUIjournal--what a start! PMID- 23659277 TI - Brief history of intermolecular and intersurface forces in complex fluid systems. AB - We review the developments of ideas, concepts, and theories of intermolecular and intersurface forces and how these were influenced (or ignored) by observations of nature and, later, systematic experimentation. The emphasis of this review is on the way things gradually changed: experimentation replaced rhetoric, measurement and quantification replaced hand waving, energy replaced force in calculations, discrete atoms replaced the (continuum) aether, thermodynamics replaced mechanistic models, randomness and probability replaced certainty, and delicate experiments on the subnanoscale revealed fascinating self-assembling structures and complex behavior of even the simplest systems. We conclude by discussing today's unresolved challenges: how complex "dynamic" multicomponent--especially living biological--systems that receive a continuous supply of energy can be far from equilibrium and not even in any steady state. Such systems, never static but evolving in both space and time, are still far from being understood both experimentally and theoretically. PMID- 23659278 TI - Morphological and molecular characterization of adult worms of Leucochloridium paradoxum Carus, 1835 and L. perturbatum Pojmanska, 1969 (Digenea: Leucochloridiidae) from the great tit, Parus major L., 1758 and similarity with the sporocyst stages. AB - Unlike the sporocyst stages, adult leucochloridiid digeneans are difficult to differentiate. Sporocyst broodsacs can be identified on the basis of their colour and banding pattern, but in the absence of broodsacs and when experimental infection cannot be performed, tentative morphological identification needs to be verified, and molecular techniques offer a tool to do this. In this study, adult leucochloridiid digeneans were collected from the great tit (Parus major) found dead at three localities at or near the Baltic Sea coast (Hel, Bukowo-Kopan and Szczecin) in northern Poland. On the basis of differences in their morphological characters, Hel specimens were tentatively assigned to Leucochloridium perturbatum, Bukowo-Kopan and Szczecin specimens being identified tentatively as L. paradoxum. Subsequent ribosomal DNA sequence analysis confirmed the identification of these leucochloridiid flukes. Nucleotide sequences discriminating between the two species were identical to those used by earlier authors as characteristic of two distinctly different sporocyst broodsacs representing L. perturbatum and L. paradoxum. PMID- 23659279 TI - Asymmetric cross-dimerization between methyl methacrylate and substituted alkene by Ru(0)-bicyclononadiene complex. AB - New Ru(0)-naphthalene complexes containing a bicyclononadiene ligand catalyze the linear cross-dimerization between methyl methacrylate and substituted alkenes by an oxidative coupling mechanism. The chiral (S,S)-2-methylbicyclo[3.3.1]nona-2,6 diene complex (S,S)-1b catalyzes asymmetric linear cross-dimerization between methyl methacrylate and 2,5-dihydrofuran to give the cross-dimer in 74% yield in 80% ee. PMID- 23659280 TI - Treatment of familial hypercholesterolaemia in children and adolescents in the last three decades. AB - BACKGROUND: This study evaluated the effectiveness of long-term intensive lipid lowering therapy in children and adolescents with familial hypercholesterolaemia. METHODS: The charts of 89 children and adolescents with heterozygous familial hypercholesterolaemia among ~1000 patients treated from 1974 to 2008 were reviewed. Familial hypercholesterolaemia was defined as low-density lipoprotein cholesterol level >90th percentile in individuals with a history of familial hypercholesterolaemia. RESULTS: Of the 89 patients, 51% were male; the mean age at diagnosis was 8 +/- 4 years, and the mean follow-up was 13 +/- 8 years. Baseline and most recent low-density lipoprotein cholesterol levels (mg/dl) under treatment were 250 +/- 50 and 142 +/- 49, respectively, reduced 43% from baseline (p < 0.0001). At the most recent visit, 39 patients received statin monotherapy, mainly atorvastatin or rosuvastatin, and 50 (56%) patients received combination therapy, mainly vytorin or rosuvastain/ezetimibe, 15 patients were >30 years of age, and none developed symptomatic cardiovascular disease or needed revascularisation. CONCLUSIONS: Long-term statin-based therapy can reduce low density lipoprotein cholesterol levels in most children and adolescents with heterozygous familial hypercholesterolaemia and decrease cardiovascular risk significantly. PMID- 23659281 TI - The juvenile alopecia mutation (jal) maps to mouse Chromosome 2, and is an allele of GATA binding protein 3 (Gata3). AB - BACKGROUND: Mice homozygous for the juvenile alopecia mutation (jal) display patches of hair loss that appear as soon as hair develops in the neonatal period and persist throughout life. Although a report initially describing this mouse variant suggested that jal maps to mouse Chromosome 13, our preliminary mapping analysis did not support that claim. RESULTS: To map jal to a particular mouse chromosome, we produced a 103-member intraspecific backcross panel that segregated for jal, and typed it for 93 PCR-scorable, microsatellite markers that are located throughout the mouse genome. Only markers from the centromeric tip of Chromosome 2 failed to segregate independently from jal, suggesting that jal resides in that region. To more precisely define jal's location, we characterized a second, 374-member backcross panel for the inheritance of five microsatellite markers from proximal Chromosome 2. This analysis restricted jal's position between D2Mit359 and D2Mit80, an interval that includes Il2ra (for interleukin 2 receptor, alpha chain), a gene that is known to be associated with alopecia areata in humans. Complementation testing with an engineered null allele of Il2ra, however, showed that jal is a mutation in a distinct gene. To further refine the location of jal, the 374-member panel was typed for a set of four single-nucleotide markers located between D2Mit359 and D2Mit80, identifying a 0.55 Mb interval where jal must lie. This span includes ten genes-only one of which, Gata3 (for GATA binding protein 3)-is known to be expressed in skin. Complementation testing between jal and a Gata3 null allele produced doubly heterozygous, phenotypically mutant offspring. CONCLUSIONS: The results presented indicate that the jal mutation is a mutant allele of the Gata3 gene on mouse Chromosome 2. We therefore recommend that the jal designation be changed to Gata3jal, and suggest that this mouse variant may provide an animal model for at least some forms of focal alopecia that have their primary defect in the hair follicle and lack an inflammatory component. PMID- 23659282 TI - Spirohexenolide A targets human macrophage migration inhibitory factor (hMIF). AB - Spirohexenolides A and B comprise a unique family of spirotetronate natural products. We report on the identification of their binding to and modulation of human macrophage migration inhibitor factor (hMIF). Using an immunoaffinity fluorescent labeling method, the properties of this interaction are detailed and evidence is provided that hMIF plays a key role in the cytostatic activity of the spirohexenolides. PMID- 23659284 TI - "I get angry if he's always drinking and we have no money": exploring motivations for male and female perpetrated intimate partner violence in the Philippines. AB - Our objective was to describe the context of and motivations for female and male perpetrated intimate partner violence (IPV) in Cebu, Philippines, using data from in-depth interviews with 19 married women. We found three categories of IPV motivations-self-defense or retaliation, reactivity, and control. Motivations differed by gender, with women acting out of self-defense more often and men acting out of control more often. Effective IPV prevention and treatment programs should take these gender differences into consideration. Moreover, it is important to look at how IPV occurs within relationships and how this may vary by context and by gender. PMID- 23659286 TI - Neocosmospora sp.-derived resorcylic acid lactones with in vitro binding affinity for human opioid and cannabinoid receptors. AB - Bioassay-guided fractionation of a fungus Neocosmospora sp. (UM-031509) resulted in the isolation of three new resorcylic acid lactones, neocosmosin A (2), neocosmosin B (3), and neocosmosin C (4). Three known resorcylic acid lactones, monocillin IV (1), monocillin II (5), and radicicol (6), were also isolated and identified. The structures of these compounds were established on the basis of extensive 1D and 2D NMR spectroscopic analysis, mass spectrometric (ESIMS) data, and X-ray crystallography. Compounds 4-6 show good binding affinity for the human opioid receptors. These findings have important implications for evaluating the potential psychoactive effects with this class of compounds. PMID- 23659287 TI - Antibacterial activities of almond skins on cagA-positive and-negative clinical isolates of Helicobacter pylori. AB - BACKGROUND: Helicobacter pylori is known to be a gastric pathogen of humans. Eradication regimens for H. pylori infection have some side effects, compliance problems, relapses, and antibiotic resistance. Therefore, the need for alternative therapies for H. pylori infections is of special interest. We have previously shown that polyphenols from almond skins are active against a range of food-borne pathogens. The aim of this study was to evaluate the antibacterial effects of natural almond skins before and after simulated human digestion and the pure flavonoid compounds epicatechin, naringenin and protocatechuic acid against H. pylori. RESULTS: H. pylori strains were isolated from gastric biopsy samples following standard microbiology procedures. Also, cagA and vacA genes were identified using PCR. Susceptibility studies on 34 strains of H. pylori, including two reference strains (ATCC 43504, ATCC 49503), were performed by the standard agar dilution method. CONCLUSIONS: Polyphenols from almond skins were effective in vitro against H. pylori, irrespective of genotype status and could therefore be used in combination with antibiotics as a novel strategy for antibiotic resistance. PMID- 23659288 TI - The use of levosimendan in children with cancer with severe acute cardiac dysfunction: case series and a review of the literature. AB - We report the use of levosimendan in two febrile, neutropenic children with cancer - one post bone marrow transplant - with acute heart failure following chemotherapy. Initial management with epinephrine, milrinone, and diuresis was unsuccessful. Infusion of levosimendan without a loading dose was added to the ongoing heart failure therapy, which resulted in persistent symptomatic and echocardiographic improvement without major side effects. PMID- 23659289 TI - Analysis of a pannexin 2-pannexin 1 chimeric protein supports divergent roles for pannexin C-termini in cellular localization. AB - Pannexins (Panxs) are a three-member family of large pore ion channels permeable to ions and small molecules. Recent elegant work has demonstrated that the Panx1 C-terminus plays an important role in channel trafficking. Panx2, another family member, has a longer and highly dissimilar C-terminus. Interestingly, Panx1 is readily found at the plasma membrane, while Panx2 is mainly present on intracellular membranes. Here we used overlap-extension cloning to create the first chimeric Panx, consisting of Panx2 with the Panx1 C-terminus (Panx2(Panx1CT)), to determine whether the Panx1 C-terminus influences the trafficking of Panx2. We are the first to observe a high level of co-localization between Panx2 and the endolysosomal enriched mannose-6-phosphate receptor. Interestingly this distinct localization of Panx2 is altered by the presence of the Panx1 C-terminus. These novel observations support previous data indicating the importance of the C-terminus in the control of Panx trafficking, and highlight the complexity of molecular signals involved. PMID- 23659290 TI - Overexpression of CXCL12 chemokine up-regulates connexin and integrin expression in mesenchymal stem cells through PI3K/Akt pathway. AB - Mesenchymal stem cells offer several potential advantages over other types of stem cells for cardiac repair. Nevertheless, poor survival of donor cells is one of the major concerns that hampers a better prognosis. Integrins, which involved in cell/extracellular matrix (ECM) interaction and connexins (Cxs), with a dual role as an anti-apoptotic and gap-junctional protein, can effectively resolve this issue. CXCL12, a member of the chemokine CXC subfamily, may play a role in stem cell survival and proliferation. CXCL12 activates several signaling pathways in stem cells, particularly the survival kinase, PI3K/Akt, which is also an important mediator of integrins and Cxs. Based on these characteristics of CXCL12, we investigated the potential of CXCL12 overexpression to induce integrin and connexin expression via PI3K/Akt pathway. Mesenchymal stem cells were transfected with adenovirus for increasing CXCL12 secretion. Membranous integrin and Cx expression as well as Akt expression levels were evaluated using Western blot analysis. Transfection resulted in increased CXCL12 in situ. Increased CXCL12 elevated membrane Cx43, Cx45, and integrin alphaVbeta3 expression, as well as Cx phosphorylaton, which was activated by PI3K/Akt pathway. This mechanism may serve to improve mesenchymal stem cell viability in host tissue. PMID- 23659291 TI - mulPBA: an efficient multiple protein structure alignment method based on a structural alphabet. AB - The increasing number of available protein structures requires efficient tools for multiple structure comparison. Indeed, multiple structural alignments are essential for the analysis of function, evolution and architecture of protein structures. For this purpose, we proposed a new web server called multiple Protein Block Alignment (mulPBA). This server implements a method based on a structural alphabet to describe the backbone conformation of a protein chain in terms of dihedral angles. This 'sequence-like' representation enables the use of powerful sequence alignment methods for primary structure comparison, followed by an iterative refinement of the structural superposition. This approach yields alignments superior to most of the rigid-body alignment methods and highly comparable with the flexible structure comparison approaches. We implement this method in a web server designed to do multiple structure superimpositions from a set of structures given by the user. Outputs are given as both sequence alignment and superposed 3D structures visualized directly by static images generated by PyMol or through a Jmol applet allowing dynamic interaction. Multiple global quality measures are given. Relatedness between structures is indicated by a distance dendogram. Superimposed structures in PDB format can be also downloaded, and the results are quickly obtained. mulPBA server can be accessed at www.dsimb.inserm.fr/dsimb_tools/mulpba/ . PMID- 23659292 TI - A cross-cultural examination of the Aggression Questionnaire-Short Form among Egyptian and Omani adolescents. AB - The psychometric properties of an Arabic version of the Aggression Questionnaire Short Form (AQ-SF) were examined in 2 samples of Egyptian and Omani adolescents. Confirmatory factor analysis (CFA) revealed that the 4-factor model had adequate fit to the data of both samples, whereas the unidimensional and hierarchical models did not. Multigroup CFAs revealed culture invariance for the AQ-SF 4 factor model when the 2 samples were compared for each gender. The analysis also revealed gender invariance for the AQ-SF 4-factor model within the Omani sample. However, the analysis showed partial gender invariance for the AQ-SF 4-factor model within the Egyptian sample. A latent mean analysis showed consistent gender differences on Physical Aggression in the male direction when males and females were compared across and within both samples. The AQ-SF correlated positively and significantly with peer nominations but did not correlate with a measure of social desirability. PMID- 23659293 TI - Novel variants in the KIT and PAX3 genes in horses with white-spotted coat colour phenotypes. AB - Variants in the EDNRB, KIT, MITF, PAX3 and TRPM1 genes are known to cause white spotting phenotypes in horses, which can range from the common white markings up to completely white horses. In this study, we investigated these candidate genes in 169 horses with white spotting phenotypes not explained by the previously described variants. We identified a novel missense variant, PAX3:p.Pro32Arg, in Appaloosa horses with a splashed white phenotype in addition to their leopard complex spotting patterns. We also found three novel variants in the KIT gene. The splice site variant c.1346+1G>A occurred in a Swiss Warmblood horse with a pronounced depigmentation phenotype. The missense variant p.Tyr441Cys was present in several part-bred Arabians with sabino-like depigmentation phenotypes. Finally, we provide evidence suggesting that the common and widely distributed KIT:p.Arg682His variant has a very subtle white-increasing effect, which is much less pronounced than the effect of the other described KIT variants. We termed the new KIT variants W18-W20 to provide a simple and unambiguous nomenclature for future genetic testing applications. PMID- 23659294 TI - The role of vaccination in prisoners' health. PMID- 23659296 TI - Progress in the development of an adenovirus 26 vector platform for HIV vaccines. AB - Evaluation of: Baden LR, Walsh SR, Seaman MS et al. First-in-human evaluation of the safety and immunogenicity of a recombinant adenovirus serotype 26 HIV-1 Env Vaccine (IPCAVD 001). J. Infect. Dis. 207(2), 240-247 (2013). A novel replication deficient recombinant adenovirus serotype 26 vector expressing the envelope protein of a clade A HIV type 1 was evaluated in a group of 60 healthy human volunteers. Three different doses of the recombinant adenovirus vector were used to assess its safety and immunogenicity. The vaccine was found to be generally safe, with no vaccine-related serious adverse events. Although all vaccinated subjects developed neutralizing antibodies against the adenovirus 26 vector, these antibodies did not interfere with the boosting of immune responses against the expressed HIV envelope protein. HIV envelope-specific binding antibodies as well as cellular immune responses were detected in the majority of individuals, persisting for at least 1 year. These results are discussed in the context of previously published protection data in nonhuman primates and of recently published immunological findings with this new vector. Options to proceed to vaccine efficacy trials with this vaccine are reviewed. PMID- 23659297 TI - What next for botulism vaccine development? AB - Botulism is a severe neuroparalytic disease caused by the toxins produced from several Clostridium species. Botulinum neurotoxins (BoNTs) cause flaccid paralysis by inducing a blockade at voluntary motor and autonomic cholinergic junctions that, if not treated, can be fatal. Vaccination to elicit protective circulating antibodies that bind, neutralize and clear toxins before they can be internalized and affect cholinergic neurons remains the most effective form of protection against BoNT. A pentavalent BoNT toxoid vaccine administered in the USA under an Investigational New Drug protocol to at-risk workers was discontinued by the CDC in 2011 due to diminished potency and reactogenic effects. Subsequent research efforts have primarily focused on recombinant protein antigens. This review focuses on the development of a recombinant bivalent vaccine (rBV A/B) composed of purified recombinant BoNT/A and BoNT/B receptor-binding domain proteins, as well as presenting a summary of progress and issues associated with alternative vaccines currently being developed against botulism. PMID- 23659298 TI - Live-attenuated Listeria-based immunotherapy. AB - For decades Listeria monocytogenes has been used as a model of host-disease immunology, and a considerable body of knowledge has been amassed regarding the complex immune response to L. monocytogenes. Attenuated strains of L. monocytogenes are currently being assessed as therapeutic bacterial vectors to present tumor-associated antigens to the immune system for the clinical treatment of cancer. L. monocytogenes immunotherapy utilizes many synchronous and disparate action mechanisms that stimulate innate and cell-mediated adaptive immunity while reducing immunosuppressive influences in the tumor microenvironment. Other effects not typically associated with immunotherapy include the stimulation of myeloid hematopoiesis and vascular changes that enable chemotaxis. Preliminary clinical results using L. monocytogenes bearing the HPV oncogene E7 indicate good tolerability and a strong efficacy signal, warranting further development. This article reviews the current status of L. monocytogenes as a cancer immunotherapeutic and the complex immune responses that underlie L. monocytogenes immunotherapy. PMID- 23659299 TI - Controlling serogroup B invasive meningococcal disease: the Canadian perspective. AB - With publically funded meningococcal immunization programs established in infants, children and adolescents, Canada is at the forefront of invasive meningococcal disease prevention. The advent of two new serogroup B vaccines that may protect against multiple disease-causing strains offers the potential to reduce endemic disease to very low levels in Canada. Canada likely will be one of the first countries with approval to use recombinant serogroup B vaccine. However, inclusion of these new vaccines into public immunization programs will be decided at the provincial/territorial level, rather than nationally, and may result initially in different immunization schedules throughout the country as we have seen with conjugate meningococcal vaccines. Such heterogeneous use and adoption of new vaccines complicates disease control, but may assist in evaluation of effectiveness. Minimally, it requires regionally specific information. In this article, the authors provide an overview of the Canadian epidemiology, serogroup B vaccine characteristics, potential strain coverage, immunization strategies and remaining postmarketing research questions. PMID- 23659300 TI - Immunological assessment of influenza vaccines and immune correlates of protection. AB - Influenza vaccines remain the primary public health tool in reducing the ever present burden of influenza and its complications. In seeking more immunogenic, more effective and more broadly cross-protective influenza vaccines, the landscape of influenza vaccines is rapidly expanding, both in near-term advances and next-generation vaccine design. Although the first influenza vaccines were licensed over 60 years ago, the hemagglutination-inhibition antibody titer is currently the only universally accepted immune correlate of protection against influenza. However, hemagglutination-inhibition titers appear to be less effective at predicting protection in populations at high risk for severe influenza disease; older adults, young children and those with certain medical conditions. The lack of knowledge and validated methods to measure alternate immune markers of protection against influenza remain a substantial barrier to the development of more immunogenic, broadly cross-reactive and effective influenza vaccines. Here, the authors review the knowledge of immune effectors of protection against influenza and discuss assessment methods for a broader range of immunological parameters that could be considered in the evaluation of traditional or new-generation influenza vaccines. PMID- 23659302 TI - Economic evaluation of vaccines: specificities and future challenges illustrated by recent European examples. AB - This study reviews the current challenges in the economic evaluation of vaccines with a focus on European countries. In particular, the type of clinical evidence generally available, the impact of discounting for time preference and the use of modeling to derive valid cost-effectiveness assessments are considered. First, the characteristics of evidence for vaccines are discussed, as well as potential difficulties faced when using evidence-based medicine applied to curative drugs to interpret vaccine evidence. Then, discounting is considered and specific examples illustrating issues with different types of discounting are described, taking HPV as the example. Finally, the need for sometimes complex dynamic models for vaccines is explored, and specific types of models are reviewed, keeping into consideration the adage "complex when needed, straightforward if allowed." PMID- 23659305 TI - Switchable vesicles formed by diblock random copolymers with tunable pH- and thermo-responsiveness. AB - The thermo-responsiveness of polymers in aqueous media can be tuned by the choice of comonomers used in the synthesis of block copolymers made of random sequences of the same comonomers but of different molar ratios. The same synthetic approach may be applied to other stimuli and we have made diblock random copolymers with both pH- and thermo-responsiveness and studied the formation of vesicles whose membrane core and coronas may be inverted in aqueous media. Sequential reversible addition-fragmentation chain transfer (RAFT) polymerization was used to prepare well-defined block copolymers in the form of AnBm-b-ApCq, where A, B, and C are N n-propylacrylamide (nPA), 2-(diethylamino)ethyl methacrylate (DEAEMA), and N ethylacrylamide (EA), respectively. This polymer shows interesting "schizophrenic" behavior in aqueous solutions. Both blocks are thermo-responsive, and one block is pH-responsive in which the tertiary amine group of DEAEMA may be protonated at a lower pH. A molecularly dissolved polymer is obtained at neutral pH and ambient temperature. At pH 7 and 37 degrees C, the polymer self-assembles into vesicles with the poly(nPA0.8-co-EA0.2) block as the membrane core (mean hydrodynamic diameter of the vesicles Dh = 148 nm). In an alkaline medium (pH 10) at 25 degrees C, the membrane core and the coronas of the vesicles are inverted with poly(nPA0.8-co-DEAEMA0.2) block forming the core (Dh = 60 nm). In addition, two-step phase transitions are observed in both alkaline and neutral solutions corresponding to the cloud points of the individual blocks. Here, the random nature of the blocks allows fine-tuning the thermo-responsiveness based solely on lower critical solution temperatures and its combination with pH-sensitivity provides vesicles with switchable membrane core and corona in aqueous solution. PMID- 23659303 TI - Viral vaccines for bony fish: past, present and future. AB - Since 1970, aquaculture production has grown. In 2010, it had an annual average rate of 6.3% with 59.9 million tons of product and soon could exceed capture fisheries as a source of fishery products. However, the occurrence of viral diseases continues to be a significant limiting factor and its control is important for the development of this sector. In aquaculture farms, fish are reared under intensive culture conditions, and the use of viral vaccines has enabled an increase in production. Several types of vaccines and strategies of vaccination have been developed; however, this approach has not reached the expected goals in the most susceptible stage (fingerlings). Currently, there are inactivated and recombinant commercial vaccines, mainly for salmonids and cyprinids. In addition, updated genomic and proteomic technology has expedited the research and expansion of new vaccine models, such as those comprised of subunits or DNA. The objective of this review is to cover the various types of viral vaccines that have been developed and are available for bony fishes, as well as the advantages and challenges that DNA vaccines present for massive administration in a growing aquaculture, possible risks for the environment, the controversy regarding genetically modified organisms and possible acceptance by consumers. PMID- 23659301 TI - Synthetic DNA vaccine strategies against persistent viral infections. AB - The human body has developed an elaborate defense system against microbial pathogens and foreign antigens. However, particular microbes have evolved sophisticated mechanisms to evade immune surveillance, allowing persistence within the human host. In an effort to combat such infections, intensive research has focused on the development of effective prophylactic and therapeutic countermeasures to suppress or clear persistent viral infections. To date, popular therapeutic strategies have included the use of live-attenuated microbes, viral vectors and dendritic-cell vaccines aiming to help suppress or clear infection. In recent years, improved DNA vaccines have now re-emerged as a promising candidate for therapeutic intervention due to the development of advanced optimization and delivery technologies. For instance, genetic optimization of synthetic plasmid constructs and their encoded antigens, in vivo electroporation-mediated vaccine delivery, as well as codelivery with molecular adjuvants have collectively enhanced both transgene expression and the elicitation of vaccine-induced immunity. In addition, the development of potent heterologous prime-boost regimens has also provided significant contributions to DNA vaccine immunogenicity. Herein, the authors will focus on these recent improvements to this synthetic platform in relation to their application in combating persistent virus infection. PMID- 23659306 TI - Comparative host-parasite population genetic structures: obligate fly ectoparasites on Galapagos seabirds. AB - Parasites often have shorter generation times and, in some cases, faster mutation rates than their hosts, which can lead to greater population differentiation in the parasite relative to the host. Here we present a population genetic study of two ectoparasitic flies, Olfersia spinifera and Olfersia aenescens compared with their respective bird hosts, great frigatebirds (Fregata minor) and Nazca boobies (Sula granti). Olfersia spinifera is the vector of a haemosporidian parasite, Haemoproteus iwa, which infects frigatebirds throughout their range. Interestingly, there is no genetic differentiation in the haemosporidian parasite across this range despite strong genetic differentiation between Galapagos frigatebirds and their non-Galapagos conspecifics. It is possible that the broad distribution of this one H. iwa lineage could be facilitated by movement of infected O. spinifera. Therefore, we predicted more gene flow in both fly species compared with the bird hosts. Mitochondrial DNA sequence data from three genes per species indicated that despite marked differences in the genetic structure of the bird hosts, gene flow was very high in both fly species. A likely explanation involves non-breeding movements of hosts, including movement of juveniles, and movement by adult birds whose breeding attempt has failed, although we cannot rule out the possibility that closely related host species may be involved. PMID- 23659307 TI - Facile synthesis of beta- and alpha-arabinofuranosides and application to cell wall motifs of M. tuberculosis. AB - Propargyl 1,2-orthoesters of arabinose are exploited for the synthesis of 1,2 trans furanosides; easily accessible 1,2-trans ribofuranosides are converted to challenging 1,2-cis-arabinofuranosides by oxidoreduction. Utility of these protocols was demonstrated by the successful synthesis of major structural motifs present in the cell surface of Mycobacterium tuberculosis. Key furanosylations were carried out under gold-catalyzed glycosidation conditions. PMID- 23659308 TI - Chemoselective Pd-catalyzed oxidation of polyols: synthetic scope and mechanistic studies. AB - The regio- and chemoselective oxidation of unprotected vicinal polyols with [(neocuproine)Pd(OAc)]2(OTf)2 (1) (neocuproine = 2,9-dimethyl-1,10 phenanthroline) occurs readily under mild reaction conditions to generate alpha hydroxy ketones. The oxidation of vicinal diols is both faster and more selective than the oxidation of primary and secondary alcohols; vicinal 1,2-diols are oxidized selectively to hydroxy ketones, whereas primary alcohols are oxidized in preference to secondary alcohols. Oxidative lactonization of 1,5-diols yields cyclic lactones. Catalyst loadings as low as 0.12 mol % in oxidation reactions on a 10 g scale can be used. The exquisite selectivity of this catalyst system is evident in the chemoselective and stereospecific oxidation of the polyol (S,S) 1,2,3,4-tetrahydroxybutane [(S,S)-threitol] to (S)-erythrulose. Mechanistic, kinetic, and theoretical studies revealed that the rate laws for the oxidation of primary and secondary alcohols differ from those of diols. Density functional theory calculations support the conclusion that beta-hydride elimination to give hydroxy ketones is product-determining for the oxidation of vicinal diols, whereas for primary and secondary alcohols, pre-equilibria favoring primary alkoxides are product-determining. In situ desorption electrospray ionization mass spectrometry (DESI-MS) revealed several key intermediates in the proposed catalytic cycle. PMID- 23659309 TI - Weight of tradition: culture as a rationale for obesity in contemporary U.S. news coverage. AB - In studies of mediated representations of obesity to date, the overwhelming majority have found predominant a personal responsibility frame, specifically as drawn against environmental frames, which are nonetheless gaining ground in recent years. In this essay, I review that extant literature and seek to trouble the binary by isolating national news coverage of obesity in two historically and culturally specific regions of the United States that are regularly referenced in relation to the issue: the South and the Midwest. I evaluate the key characterizations of obesity and obese individuals in these regions in mainstream national news coverage between January 2009 and December 2012 in order to assess whether, how, and to what extent personal responsibility or environmental frames are invoked in this coverage. I argue that 'culture' appears to be gaining traction as an emergent discourse for obesity, which may appear to offer a more complex or nuanced explanation of the issue; however, this analysis suggests that it can be taken up in ways that feature troubling implications and consequences. PMID- 23659310 TI - Cost effective improvement in the protocol for detection of haemoglobin variants a step forward in quality assurance. AB - BACKGROUND: We report the results of a cost effective improvement in the protocol for detection of haemoglobin variants which incorporates the findings of peripheral blood film along with the results of HPLC. FINDINGS: A total of n = 10,844 samples were received from January 2011 till August 2011. Diagnosis of haemoglobinopathy was made in n = 1123 samples while other abnormalities included iron deficiency anaemia, megaloblastic anaemia, malarial parasite, autoimmune haemolytic anaemia and G6PD deficiency (n = 2473). CONCLUSION: We diagnosed 23% of abnormalities other than haemoglobinopathy by reviewing peripheral smear of samples received for detection of haemoglobin variants. This resulted in providing proper diagnosis to the referring physician without increment in cost. PMID- 23659311 TI - HIV prevalence, risk behavior, knowledge, and beliefs among women seeking care at a sexually transmitted infection clinic in Mumbai, India. AB - Three hundred women presenting to a sexually transmitted infection (STI) clinic in Mumbai, India were surveyed and HIV tested. Thirty-nine percent were HIV infected; 80% were current sex workers, and HIV infection was not significantly associated with past-year sex work. Only 44% always used condoms with their noncommercial sex partners. Most believed that condom preparation is a male responsibility (58%); that condom use is a sign that partner trust is lacking (84%); and that if a woman asks her partner to use a condom, he will lose respect for her (65%). All women at STI clinics in India need HIV testing and culturally sensitive risk interventions. PMID- 23659312 TI - Dopexamine: immunomodulatory, hemodynamic, or both? AB - Dopexamine is a dopamine analog that has been used for hemodynamic optimization in a number of clinical settings. This animal investigation showed anti inflammatory effects of dopexamine in a rat endotoxin model without effects on global or regional flow, but it is not time to dispense with hemodynamics altogether just yet. Rather, an integrative approach to the effects of catecholamines, considering both inflammatory and hemodynamic effects, including those on the microcirculation, can help clinicians best understand how to employ them in clinical practice. PMID- 23659315 TI - Asymmetric tonic neck reflex and symptoms of attention deficit and hyperactivity disorder in children. AB - One of the particularly important postnatal developmental reflexes that diminish in later stages of development is asymmetric tonic neck reflex (ATNR), which belongs among the so-called primitive reflexes. According to current evidence, certain later developed functions during ontogenesis of the central nervous system tend to replace the primitive reflexes, and their persistence is related to certain specific neuropsychiatric or neurological disorders. According to current knowledge, there is no evidence to which extent persistence of these reflexes may play a role in attention deficit and hyperactivity disorder (ADHD). With respect to these findings, we have tested a hypothesis to which extent persisting primitive reflex ATNR in 60 children in the school age (8-11 years) will be related to symptoms of ADHD and compared the results with 30 children of the same age. Results of this study show that ADHD symptoms are closely linked to persisting ATNR, which indicates that ADHD symptoms may present a compensation of unfinished developmental stages related to diminishing ATNR. PMID- 23659314 TI - HIV testing practices among men who have sex with men in Buenos Aires, Argentina. AB - The objective of the study was to explore HIV-testing practices among men who have sex with men (MSM) in Buenos Aires, Argentina, in light of current international health guidelines that recommend frequent HIV testing for MSM who engage in high-risk behavior. Participants, who were recruited using respondent driven sampling (RDS), were 500 mostly young, nongay-identified MSM of low socioeconomic status, high levels of unemployment, living mainly in the less affluent areas surrounding Buenos Aires, and lacking health insurance. They provided blood samples for HIV testing and responded to a Computer Assisted Self Interview. Fifty-two percent had never been tested for HIV, and 20% had been tested only once; 17% were found to be HIV infected, of whom almost half were unaware of their status. Main reasons for never having tested previously were: not feeling at risk, fear of finding out results, and not knowing where to get tested. Among those previously tested, men had been tested a median of 2 times with their most recent test having occurred a median of 2.7 years prior to study enrollment. Of those who had not tested positive before entering the study, only 41% returned for their results. HIV testing was infrequent and insufficient for early detection of infection, entry into treatment, and protection of sexual partners. This was particularly the case among nongay-identified MSM. Testing campaigns should aim to help MSM become aware of their risk behavior, decrease fear of testing by explaining available treatment resources and decreasing the stigma associated with HIV, and by publicizing information about free and confidential testing locations. Rapid HIV testing should be made available to eliminate the need for a return visit and make results immediately available to individuals who are tested. PMID- 23659316 TI - Benzophenone glycosides from Hypericum humifusum ssp. austral. AB - Six new benzophenone glycosides, 2,3',4,5',6-pentahydroxybenzophenone 4-O-(6" benzoyl)-beta-d-glucopyranoside (1), 2,3',4,5',6-pentahydroxybenzophenone 4-O beta-d-glucopyranoside (2), 2,3',4,5',6-pentahydroxybenzophenone 2-O-(2"-benzoyl) alpha-l-arabinopyranoside (3), 2,3',4,5',6-pentahydroxybenzophenone 2-O-alpha-l arabinopyranoside (4), 2,3',4,5',6-pentahydroxybenzophenone 2-O-(4"-acetyl)-beta d-xylopyranoside (5), and 2,3',4,5',6-pentahydroxybenzophenone 3-C-(4"-benzoyl) beta-d-glucopyranoside (6), and five known compounds were isolated from the aerial parts of Hypericum humifusum ssp. austral. The structures of 1-6 were elucidated by mass spectrometry and extensive 1D and 2D NMR spectroscopy. PMID- 23659318 TI - The impact of the conjugative IncP-1 plasmid pKJK5 on multispecies biofilm formation is dependent on the plasmid host. AB - Horizontal gene transfer by conjugation has been reported to increase overall biofilm formation. Biofilm is considered a hot spot for plasmid transfer, and it has been found that social interactions during biofilm formation can increase the biomass. In this study, we demonstrate a contrast to previous studies by showing that the conjugative IncP-1 plasmid pKJK5 influences biofilm formation negatively. The results showed that a co-culture (Pseudomonas putida, Kluyvera sp., and Escherichia coli) formed significantly more biofilm than the strains did individually. When pKJK5 was inserted into P. putida, biofilm formation was significantly reduced compared with the co-culture without plasmid. A nonconjugative version of pKJK5 was also used, and the biofilm formation was restored. Visualization with the BioFlux 1000 facility showed that the presence of pKJK5-containing P. putida in the co-culture led to a changed biofilm structure, where the cells showed a higher tendency to attach to other cells rather than surfaces. This study thus indicates that the presence of conjugative plasmids in some species may decrease the surface-associated biofilm formation of a mixed co-culture by facilitating cell-cell attachment with reduced surface attachment as the consequence. PMID- 23659317 TI - Higher rate of skin rash in a phase II trial with weekly nanoparticle albumin bound paclitaxel and cisplatin combination in Chinese breast cancer patients. AB - BACKGROUND: The aim of this sub-study is to explore the incidence of skin rash among advanced breast cancer(ABC) patients in a phase II trial treated with weekly nab-paclitaxel and cisplatin combination. METHODS: Nab-paclitaxel(125 mg/m2) was administered on days 1, 8, 15, followed by cisplatin(75 mg/m2) on day 1 every 28 day cycle until disease progression, intolerable toxicities or the maximum of 6 cycles. Patients who received at least one injection of the study drug were included in this analysis of the incidence of skin rash among Chinese patients. Toxicity was graded using the CTCAE4.0 criteria. Statistical analysis was carried out by using SPSS 16.0 (SPSS Inc, Chicago, IL). RESULTS: Seventy three patients were enrolled and eligible for analysis. A total of 384 cycles were administered at the time of this analysis. Rash was presented in 27 patients (37.0%). The most common sites involved were face (14/27), neck (14/27), limbs (18/27) and frictional parts of the trunk (10/27). Macular and papular rash with pruritus commonly occurred 2 (95% CI: 1-7) days after the first day of chemotherapy. Only one patient developed Grade 3 skin toxicity with generalized erythroderma and disfigurement of the face requiring dose reduction. The rash gradually regressed 2 (95% CI: 1-10) days after antihistamines used, but pigmentation remained in 13/27 cases. The incidence rate of skin rash was significantly higher than what has been described for western patients (approximate 4%, P < 0.0001). CONCLUSION: A higher rate of maculo-papular rash occurred in Chinese breast cancer patients treated with weekly nab-paclitaxel compared to western patients. The albumin component of nab-paclitaxel might be the cause of the skin disorder. TRIAL REGISTRATION: NCT01149798. PMID- 23659319 TI - Viral/plasmid captures in Crenarchaea. AB - tRNA genes are the integration sites of viral/plasmid genomes into their hosts chromosomes by homologous recombination catalyzed by integrases. The crossover between viral/plasmid and host genomes leaves 3'-fractional tRNA motif as tell tale marker of integration on host-chromosome. This 3'-fractional tRNA motif on host genome is our retrenched tRNA (rtRNA). To track integration in Crenarchaea, host rtRNAs, and conserved features in viral/plasmid tRNA motifs and in integrases were identified. The viral-integrase has a conserved 24-nucleotide long motif, GTATTATGTTTACTCAATAGAGAA in the N-terminal region. Upstream of the viral tRNA motif has a conserved poly-cytosine region and a hairpin secondary structure. Corresponding to a host tRNA, we observe up to two rtRNAs on crenarchaeal chromosome. The length of the rtRNA is not random. The fraction of tRNA excised off in rtRNA is either 61.8, or 50, or 38.2, or 23.6%. Thus, the integration fragments the tRNA nonrandomly dividing it approximately in ratios 3:2, or 1:1, or 2:3, or 1:3. More than 79% of rtRNAs have lengths that are excised 38.2% off tRNA. It turns out that 38.2% excision implies that the ratio of the length of tRNA to its rtRNA is just 1.618, the golden ratio. Hence, the vast majority of rtRNAs are at or near the golden ratio. Evidence emerges of new extremophile viral entities. PMID- 23659320 TI - Significant association between SNPs in the superoxide dismutase 3, extracellular (SOD3) gene and resistance to Aeromonas hydrophila in the freshwater mussel Hyriopsis cumingii. AB - Extracellular superoxide dismutase (SOD3) is a major antioxidant enzyme that protects organs from damage by reactive oxygen species (ROS). In this study, the SOD3 gene was identified and characterized from the freshwater mussel Hyriopsis cumingii (Hc-SOD3). The cDNA sequence consists of 763 bp, encoding a protein of 208 amino acids. The amino acid sequence possesses two CuZnSOD signature sequences, and amino acids required for binding of Cu (His-93, -95, -110 and 169) and Zn (His-110, -118, -129 and Asp-132) were conserved in Hc-SOD3. The Hc SOD3 genomic sequence was 9165 bp in length, containing four exons and three introns. Eighteen single nucleotide polymorphisms were detected in the Hc-SOD3 gene from resistant stock (RS) and susceptible stock (SS) of H. cumingii to Aeromonas hydrophila. The genotype and allele distribution were examined in resistant and susceptible stocks. Among them, a C/G substitution at the g.7994C>G locus and G/C substitution at the g.8087G>C locus were significantly associated with resistance/susceptibility of H. cumingii to A. hydrophila, both in genotype (P = 0.017, P = 0.004 respectively) and allele frequency (P = 0.021, P = 0.006 respectively). Linkage disequilibrium analysis revealed that g.7994C>G, g.8001A>G, g.8035G>A, g.8087G>C and g.8191T>A were in linkage disequilibrium. The results suggest that the two polymorphic loci, g.7994C>G and g.8087G>C, could be potential genetic markers for future molecular selection of strains that are resistant to diseases. PMID- 23659321 TI - Injuries and fatalities among emergency medical technicians and paramedics in the United States. AB - INTRODUCTION: Emergency medical services personnel treat 22 million patients a year, yet little is known of their risk of injury and fatality. PROBLEM: Work related injury and fatality rates among US paramedics and emergency medical technicians (EMTs) are higher than the national average for all occupations. METHODS: Data collected by the Department of Labor (DOL) Bureau of Labor Statistics were reviewed to identify injuries and fatalities among EMTs and paramedics from 2003 through 2007. The characteristics of fatal injuries are described and the rates and relative risks of the non-fatal injuries were calculated and compared to the national average. RESULTS: Of the 21,749 reported cases, 21,690 involved non-fatal injuries or illnesses that resulted in lost work days among EMTs and paramedics within the private sector. Of the injuries, 3,710 (17%) resulted in >=31 days of lost work time. A total of 14,470 cases (67%) involved sprains or strains; back injury was reported in 9,290 of the cases (43%); and the patient was listed as the source of injury in 7,960 (37%) cases. The most common events were overexertion (12,146, 56%), falls (2,169, 10%), and transportation-related (1,940, 9%). A total of 530 assaults were reported during the study period. Forty-five percent of the cases occurred among females (females accounted for 27% of employment in this occupation during 2007). In 2007, EMTs and paramedics suffered 349.9 injuries with days away from work per 10,000 full time workers, compared to an average of 122.2 for all private industry occupations (Relative risk = 2.9; 95% CI: 2.7-3.0). During the study period, 59 fatalities occurred among EMTs and paramedics in both the private industry and in the public sector. Of those fatalities, 51 (86%) were transportation-related and five (8%) were assaults; 33 (56%) were classified as "multiple traumatic injuries." CONCLUSIONS: Data from the DOL show that EMTs and paramedics have a rate of injury that is about three times the national average for all occupations. The vast majority of fatalities are secondary to transportation related-incidents. Assaults are also identified as a significant cause of fatality. The findings also indicate that females in this occupational group may have a disproportionately larger number of injuries. Support is recommended for further research related to causal factors and for the development, evaluation and promulgation of evidence-based interventions to mitigate this problem. PMID- 23659322 TI - Ion-specific conformational behavior of polyzwitterionic brushes: exploiting it for protein adsorption/desorption control. AB - The conformation of polyzwitterionic brushes plays a crucial role in the adsorption/desorption of proteins on solid surfaces. By use of quartz crystal microbalance with dissipation (QCM-D) and surface plasmon resonance (SPR), we have systematically investigated the conformational behavior of poly(sulfobetaine methacrylate) (PSBMA) brushes as a function of ionic strength in the presence of different ions. The frequency change demonstrates that the effectiveness of anions to weaken the inter/intrachain association and to enhance the hydration of the grafted chains increases from kosmotrope to chaotrope in the low ionic strength regime, but the ordering of anions is almost reversed at the high ionic strengths. The dissipation change indicates that some heterogeneous structures are formed inside the brushes in the presence of chaotropic anions with the increase of ionic strength. In SPR studies, the change of resonance unit (DeltaRU) with ionic strength is determined by the balance between the increase of thickness and the decrease of refractive index of the brushes. No anion specificity is observed in the SPR measurements because DeltaRU is insensitive to the coupled water molecules inside the brushes. For the control of protein adsorption/desorption, our studies show that the brushes can more effectively resist the protein adsorption in the presence of a more chaotropic anion and a more chaotropic anion can also more effectively induce the protein desorption from the surface of the brushes. In addition, no obvious cation specificity can be observed in the conformational change of the brushes in either QCM-D or SPR measurements. PMID- 23659323 TI - New route to the ergoline skeleton via cyclization of 4-unsubstituted indoles. AB - A new route to the ergoline skeleton has been developed that does not require prior functionalization of the indole 4-position. The indole nucleus is introduced late in the synthesis to allow for eventual efficient introduction of substituents in this region. Key steps include Negishi coupling of a three-carbon chain to a bromonicotinate ester, Fischer indole synthesis to facilitate incorporation of substituents via phenylhydrazines, and Pd-catalyzed cyclization to form the ergoline C ring. PMID- 23659324 TI - Energy expenditure for egg production in arthropod ectoparasites: the effect of host species. AB - We studied the energy cost of egg production in two flea species (Parapulex chephrenis and Xenopsylla ramesis) feeding on principal (Acomys cahirinus and Meriones crassus, respectively) and auxiliary (M. crassus and A. cahirinus, respectively) rodent hosts. We predicted that fleas feeding on principal as compared with auxiliary hosts will (a) expend less energy for egg production; (b) produce larger eggs and (c) live longer after oviposition. Both fleas produced more eggs and spent less energy per egg when exploiting principal hosts. Parapulex chephrenis produced larger eggs after exploiting auxiliary hosts, while the opposite was true for X. ramesis. After oviposition, P. chephrenis fed on the auxiliary hosts survived for a shorter time than those fed on the principal hosts, while in X. ramesis the survival time did not differ among hosts. Our results suggested that one of the proximate causes for lower reproductive performance and subsequent lower abundance of fleas on auxiliary hosts is the higher energy cost of egg production. However, in some species, lower offspring number may be compensated to some extent by their size, although this compensation may also compromise their future reproduction via decreased survival. In addition, the reproductive strategy of exploitation of low profitable (i.e. auxiliary) hosts may differ between flea species. PMID- 23659325 TI - Thermodynamic and structural insights into nanocomposites engineering by comparing two materials assembly techniques for graphene. AB - Materials assembled by layer-by-layer (LBL) assembly and vacuum-assisted flocculation (VAF) have similarities, but a systematic study of their comparative advantages and disadvantages is missing. Such a study is needed from both practical and fundamental perspectives aiming at a better understanding of structure-property relationships of nanocomposites and purposeful engineering of materials with unique properties. Layered composites from polyvinyl alcohol (PVA) and reduced graphene (RG) are made by both techniques. We comparatively evaluate their structure, mechanical, and electrical properties. LBL and VAF composites demonstrate clear differences at atomic and nanoscale structural levels but reveal similarities in micrometer and submicrometer organization. Epitaxial crystallization and suppression of phase transition temperatures are more pronounced for PVA in LBL than for VAF composites. Mechanical properties are virtually identical for both assemblies at high RG contents. We conclude that mechanical properties in layered RG assemblies are largely determined by the thermodynamic state of PVA at the polymer/nanosheet interface rather than the nanometer scale differences in RG packing. High and nearly identical values of toughness for LBL and VAF composites reaching 6.1 MJ/m(3) observed for thermodynamically optimal composition confirm this conclusion. Their toughness is the highest among all other layered assemblies from RG, cellulose, clay, etc. Electrical conductivity, however, is more than 10* higher for LBL than for VAF composites for the same RG contents. Electrical properties are largely determined by the tunneling barrier between RG sheets and therefore strongly dependent on atomic/nanoscale organization. These findings open the door for application oriented methods of materials engineering using both types of layered assemblies. PMID- 23659327 TI - Mothering and self-othering: the impact of uncertain reproductive capability in young women after hematological malignancy. AB - We explored the experiences of uncertain fertility, pregnancy, and motherhood in 12 young women treated for hematological malignancy during their reproductive years. It is demonstrated how, through interpretations of the women's own words, these women lived and coped with a sense of "otherness" in relation to their peers. The concept of otherness is described and discussed in relation to relevant existing literature and it is concluded that, regardless of their cancer history, young women's uncertainty in this context has a broad impact on their psychosocial health and requires sensitive and empathic information, discussion, and support. PMID- 23659326 TI - Inhibition of ADAM-17 more effectively down-regulates the Notch pathway than that of gamma-secretase in renal carcinoma. AB - BACKGROUND: Our study is to research the effect of inhibited ADAM-17 expression through the Notch pathway in renal carcinoma. METHODS: Immunohistochemistry and western blot were used to examine the expression of ADAM-17 protein in renal cancer tissues. Proliferation and cell invasion of 786-o cells, as well as OS-RC 2 cells, after treatment with two different inhibitors of the Notch pathway, were examined by CCK-8 assay and Transwell assay, respectively. 786-o cell apoptosis was measured using the FCM test. RESULTS: ADAM-17 was highly expressed in RCC tissues. Compared with blocking gamma-secretase, a known mechanism of impairing Notch, blockade of ADAM-17 more effectively down-regulated the expressions of Notch1 and HES-1 proteins. Similarly, we found that the ADAM-17 inhibitor, Marimastat, could more efficiently reduce renal cell proliferation and invasive capacity in comparison with the gamma-secretase inhibitor DAPT when used at the same dose. Similar results were obtained when apoptosis of 786-o was measured. CONCLUSION: Compared with gamma-secretase, inhibition of ADAM-17 expression more effectively inhibits Notch pathway-mediated renal cancer cell proliferation and invasion. ADAM-17 may be a new target for future treatment of renal carcinoma. PMID- 23659328 TI - Obesity-driven endometrial cancer: is weight loss the answer? PMID- 23659329 TI - Design and statistical analysis of observational studies. PMID- 23659330 TI - Design and statistical analysis of observational studies. PMID- 23659331 TI - Accuracy of colposcopy-directed punch biopsies. PMID- 23659332 TI - Accuracy of colposcopy-directed punch biopsies. PMID- 23659333 TI - A report from #Blue JC: 'Doctor, when can I have my twins?'. PMID- 23659337 TI - Multitissue molecular, genomic, and developmental effects of the Deepwater Horizon oil spill on resident Gulf killifish (Fundulus grandis). AB - The Deepwater Horizon oil rig disaster resulted in crude oil contamination along the Gulf coast in sensitive estuaries. Toxicity from exposure to crude oil can affect populations of fish that live or breed in oiled habitats as seen following the Exxon Valdez oil spill. In an ongoing study of the effects of Deepwater Horizon crude oil on fish, Gulf killifish ( Fundulus grandis ) were collected from an oiled site (Grande Terre, LA) and two reference locations (coastal MS and AL) and monitored for measures of exposure to crude oil. Killifish collected from Grande Terre had divergent gene expression in the liver and gill tissue coincident with the arrival of contaminating oil and up-regulation of cytochrome P4501A (CYP1A) protein in gill, liver, intestine, and head kidney for over one year following peak landfall of oil (August 2011) compared to fish collected from reference sites. Furthermore, laboratory exposures of Gulf killifish embryos to field-collected sediments from Grande Terre and Barataria Bay, LA, also resulted in increased CYP1A and developmental abnormalities when exposed to sediments collected from oiled sites compared to exposure to sediments collected from a reference site. These data are predictive of population-level impacts in fish exposed to sediments from oiled locations along the Gulf of Mexico coast. PMID- 23659338 TI - Coenzyme Q10 supplementation reduces oxidative stress and increases antioxidant enzyme activity in patients with relapsing-remitting multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease of central nervous system in which a higher oxidative stress may contribute to its pathogenesis. The aim of this study was to investigate the effect of coenzyme Q10 (CoQ10) supplementation on oxidative stress and antioxidant enzyme activity in patients with MS. MATERIALS AND METHODS: We performed a randomized, double blinded, placebo-controlled trail to determine the effect of CoQ10 supplement (500 mg/day, n = 24) versus placebo (controls, n = 24) for 12 weeks. Fasting blood samples were taken before and after a 12-week intervention to analyze malondialdehyde (MDA), total antioxidant capacity (TAC) and antioxidant enzymes [superoxide dismutase (SOD), glutathione peroxidase (GPx)] activity. RESULTS: Forty-five subjects with MS completed intervention study. After 12 weeks, CoQ10 treated patients had significant increase in SOD activity (p = 0.013); and decrease in MDA levels (P=0.003) compared with controls. Despite the significant effect of CoQ10 supplementation on plasma TAC (p = 0.010), no significant differences were found between the two groups. CoQ10 supplementation did not affect GPx activity. CONCLUSION: Present study suggests that CoQ10 supplements at a dose of 500 mg/day can decrease oxidative stress and increase antioxidant enzyme activity in patients with relapsing-remitting MS. PMID- 23659339 TI - Alcohol use and alcohol-use disorders among older adults in India: a literature review. AB - OBJECTIVES: With changing attitudes to alcohol and an increasing life span in India, the prevalence of alcohol use and misuse in successive cohorts of older people is likely to increase. In this paper, we attempt to review the most recent evidence covering alcohol use and alcohol-use disorders in the Indian elderly. METHODS: PubMed, PsycINFO and Indmed databases were searched using relevant keywords. Papers meeting eligibility criteria were selected through a sequential process of screening title, abstract and full text. Data were extracted into Excel sheets. RESULTS: There was a dearth of pan-national studies. There were several methodological issues with many studies especially related to measurement. A substantial proportion of individuals above the age of 50 years are current consumers of alcohol and the prevalence is generally higher in urban compared to rural areas. Older women are generally likely to be alcohol abstainers. The general trend appears to be a reduction in current drinking among successive age cohorts over the age of 50. Alcohol consumption in the older adults is associated with educational status, health status, chronic morbidity, employment status, socioeconomic status, auditory/locomotor impairment and asthma. CONCLUSION: Alcohol use and misuse is a problem among the Indian older adults. With socio-demographic changes that will further increase longevity, this problem is likely to increase and policy-makers need to plan for it. Future research needs to improve validity and reliability in study methodology, as well as add to the current evidence base. PMID- 23659340 TI - Can't buy my love: a typology of female sex workers' commercial relationships in the Mexico-U.S. Border Region. AB - Female sex workers (FSWs) experience elevated risk for HIV and sexually transmitted infections (STIs) through unprotected sex with male clients, yet the complexity of these commercial relationships remains understudied. From 2010 to 2011, we explored FSWs' conceptualizations of various client types and related risk behavior patterns using semistructured interviews with 46 FSWs in Tijuana and Ciudad Juarez, Mexico, where FSWs' HIV/STI prevalence is increasing. Our grounded theory analysis identified four types of commercial relationships: nonregular clients, regular clients and friends, clients who "fell in love" with FSWs, and long-term financial providers who often originated from the United States. As commercial relationships developed, clients' social and emotional connections to FSWs increased, rendering condom negotiation and maintaining professional boundaries more difficult. Drug abuse and poverty also influenced behaviors, particularly in Ciudad Juarez, where lucrative U.S. clients were increasingly scarce. While struggling to cultivate dependable relationships in a setting marked by historical sex tourism from a wealthier country, some FSWs ceased negotiating condom use. We discuss the need for HIV/STI research and prevention interventions to recognize the complexity within FSWs' commercial relationships and how behaviors (e.g., condom use) evolve as relationships develop through processes that are influenced by local sociopolitical contexts and binational income inequality. PMID- 23659341 TI - Competing-risk analysis of death and dialysis initiation among elderly (>=80 years) newly referred to nephrologists: a French prospective study. AB - BACKGROUND: Reasons underlying dialysis decision-making in Octogenarians and Nonagenarians have not been further explored in prospective studies. METHODS: This regional, multicentre, non-interventional and prospective study was aimed to describe characteristics and quality of life (QoL) of elderly (>=80 years of age) with advanced chronic kidney disease (stage 3b-5 CKD) newly referred to nephrologists. Predictive factors of death and dialysis initiation were also assessed using competing-risk analyses. RESULTS: All 155 included patients had an estimated glomerular filtration rate (eGFR) below 45 ml/min/1.73 m2. Most patients had a non anaemic haemoglobin level (Hb) with no iron deficiency, and normal calcium and phosphate levels. They were well-fed and had a normal cognitive function and a good QoL. The 3-year probabilities of death and dialysis initiation reached 27% and 11%, respectively. The leading causes of death were cardiovascular (32%), cachexia (18%), cancer (9%), infection (3%), trauma (3%), dementia (3%), and unknown (32%). The reasons for dialysis initiation were based on uncontrolled biological abnormalities, such as hyperkalemia or acidosis (71%), uncontrolled digestive disorders (35%), uncontrolled pulmonary or peripheral oedema (29%), and uncontrolled malnutrition (12%). No patients with acute congestive heart failure or cancer initiated dialysis. Predictors of death found in both multivariate regression models (Cox and Fine & Gray) included acute congestive heart failure, age, any walking impairment and Hb<10 g/dL. Regarding dialysis initiation, eGFR <23 mL/min/1.73 m2 was the only predictor found in the Cox multivariate regression model whereas eGFR<23 mL/min/1.73 m2 and diastolic blood pressure were both independently associated with dialysis initiation in the Fine & Gray analysis. Such findings suggested that death and dialysis were independent events. CONCLUSIONS: Octogenarians and Nonagenarians newly referred to nephrologists by general practitioners were highly selected patients, without any symptoms of the common geriatric syndrome. In this population, nephrologists' dialysis decision was based exclusively on uremic criteria. PMID- 23659342 TI - Myriocin, a serine palmitoyltransferase inhibitor, blocks cytokinesis in Leishmania (Viannia) braziliensis promastigotes. AB - We studied the effect of myriocin, an inhibitor of serine palmitoyltransferase, on cultured Leishmania (Viannia) braziliensis promastigotes. Myriocin significantly reduced synthesis of inositol phosphorylceramide, the major sphingolipid expressed in promastigotes as characterized by thin layer chromatography and electrospray ionization mass spectrometry. Log-phase promastigotes treated with 1 MUM myriocin showed a 52% reduction in growth rate and morphological alterations such as more rounded shape and shorter flagellum. Promastigotes treated with myriocin also displayed a variety of aberrant cell phenotypes. The percentage of cells with one nucleus and one kinetoplast (1N1K), following treatment with 1 or 5 MUM myriocin, decreased from 89% (control value) to 27% or 3%, respectively. The percentage of cells with two nuclei (2N2K) varied from 7% (control value) to 19% and 6% for 1 or 5 MUM myriocin-treated parasites, respectively. High percentage of myriocin-treated parasites exhibited large atypical cells presenting three or more nucleus (32% and 89% for 1 or 5 MUM myriocin, respectively). Transmission electron microscopy following treatment with 1 MUM myriocin showed the presence of 4N parasites possibly as a result of an incomplete cytokinesis. Addition of 3-ketodihidrosphingosine to myriocin treated promastigotes rescue parasite growth and morphology. Addition of ethanolamine did not rescue the myriocin effect on parasite. Our findings indicate that sphingolipids are essential for the completion of cytokinesis, and may play a major role in cell proliferation in L. (V.) braziliensis, thus, differing from data described for Leishmania major sphingolipid-free mutant, where addition of ethanolamine rescue wild-type parasite characteristics. PMID- 23659343 TI - Prevalence of staphylococcal enterotoxins in Staphylococcus pseudintermedius isolates from dogs with pyoderma and healthy dogs. AB - To investigate the role of staphylococcal enterotoxins (SEs) produced by Staphylococcus pseudintermedius in the pathogenesis of pyoderma, isolates from dogs with pyoderma and healthy dogs were analyzed. According to reverse passive latex agglutination, 14/184 isolates (7.6%) from dogs with pyoderma and 9/87 (10.3%) from healthy dogs produced SEs (SEA, SEC or SED). According to multiplex PCR, 99 isolates (53.7%) from dogs with pyoderma and 97 (90.8%) from healthy dogs possessed one or more se genes. There was no significant difference regarding ses between dogs with pyoderma and healthy dogs. Therefore, SEs may not be a direct virulence factor in pyoderma. PMID- 23659344 TI - Patient perspectives of managing fatigue in Ankylosing Spondylitis, and views on potential interventions: a qualitative study. AB - BACKGROUND: Fatigue is a major component of living with ankylosing spondylitis (AS), though it has been largely over-looked, and currently there are no specific agreed management strategies. METHODS: This qualitative exploratory study involved participants who are members of an existing population-based ankylosing spondylitis (PAS) cohort. Participants residing in South West Wales were invited to participate in a focus group to discuss; (1) effects of fatigue, (2) self management strategies and (3) potential future interventions. The focus groups were audio-recorded and the transcripts were analysed using thematic analysis. RESULTS: Participants consisted of 3 males/4 females (group 1) and 4 males/3 females (group 2), aged between 35 and 73 years (mean age 53 years). Three main themes were identified: (1) The effects of fatigue were multi-dimensional with participants expressing feelings of being 'drained' (physical), 'upset' (emotional) and experiencing 'low-mood' (psychological); (2) The most commonly reported self-management strategy for fatigue was a balanced combination of activity (exercise) and rest. Medication was reluctantly taken due to side effects and worries over dependency; (3) Participants expressed a preference for psychological therapies rather than pharmacological for managing fatigue. Information on Mindfulness-Based Stress Reduction (MBSR) was received with interest, with recommendations for delivery in a group format with the option of distance-based delivery for people who were not able to attend a group course. CONCLUSIONS: Patients frequently try and manage their fatigue without any formal guidance or support. Our research indicates there is a need for future research to focus on psychological interventions to address the multi-faceted aspects of fatigue in AS. PMID- 23659345 TI - Molecular modeling of protein-protein interaction to decipher the structural mechanism of nonhost resistance in rice. AB - Nonhost resistance (NHR) is the most common and durable form of plant resistance to disease-causing organisms. A successful example of NHR is the cloning of a maize R gene Rxo1 in rice and validating its function in conferring bacterial streak resistance in transgenic rice lines. In order to understand the structural mechanism of NHR in rice, we built the model of the protein-protein interaction between the encoded Rxo1 (RXO1) and AvrRXO1 (avirulence protein of rice pathogen, Xanthomonas oryzae pv. oryzicola). Interestingly, although a RXO1 homolog in rice (RHR) is present, it does not interact with AvrRXO1 in nature. We have confirmed that the specificity of RXO1-AvrRXO1 interaction originates from the structured leucine rich repeat (LRR) domain of RXO1, facilitating the recognition process, while the absence of such ordered LRR region makes RHR unfavorable to recognize AvrRXO1. We postulate that the RXO1-AvrRXO1 complex formation is a three step process where electrostatic interactions, shape complementarity and short-range interactions play an important role. The presence of the structural and physicochemical properties essential for the protein-protein recognition process empowers RXO1 to mediate NHR, which the host protein RHR lacks and consequently loses its specificity to bind with AvrRXO1. To the best of our knowledge, this is the first report on the understanding of NHR in rice from the structural perspective of protein-protein interaction. PMID- 23659347 TI - Long-term outcome following pneumatic dilatation as initial therapy for idiopathic achalasia: an 18-year single-centre experience. AB - BACKGROUND: Relapse after treatment for idiopathic achalasia is common and long term outcome data are limited. AIM: To determine the cumulative relapse rate and long-term outcome after pneumatic dilatation (PD) for achalasia in a tertiary referral centre. METHODS: A retrospective study of 301 patients with achalasia treated with PD as first-line therapy. Short-term outcome was measured at 12 months. Long-term outcome was assessed in those who were in remission at 12 months by cumulative relapse rate and cross-sectional analysis of long-term remission rate regardless of any interval therapy, using a validated achalasia specific questionnaire. RESULTS: Eighty-two percent of patients were in remission 12 months following initial PD. Relapse rates thereafter were 18% by 2 years; 41% by 5 years and 60% by 10 years. Whilst 43% patients underwent additional treatments [PD (29%), myotomy (11%) or botulinum toxin (3%)] beyond 12 months, 32% of those who had not received interval therapy had relapsed at cross sectional analysis. After a mean follow-up of 9.3 years, regardless of nature, timing or frequency of any interval therapy, 71% (79/111) patients were in remission. The perforation rate from PD was 2%. Chest pain had a poor predictive value (24%) for perforation. CONCLUSIONS: Long-term relapse is common following pneumatic dilatation. While on-demand pneumatic dilatation for relapse yields a good response, one-third of relapsers neither seek medical attention nor receive interval therapy. Close follow-up with timely repeat dilatation is necessary for a good long-term outcome. Given the poor predictive value of chest pain for perforation, routine gastrografin swallow is recommended postdilatation. PMID- 23659346 TI - Integrative toxicoproteomics implicates impaired mitochondrial glutathione import as an off-target effect of troglitazone. AB - Troglitazone, a first-generation thiazolidinedione of antihyperglycaemic properties, was withdrawn from the market due to unacceptable idiosyncratic hepatotoxicity. Despite intensive research, the underlying mechanism of troglitazone-induced liver toxicity remains unknown. Here we report the use of the Sod2(+/-) mouse model of silent mitochondrial oxidative-stress-based and quantitative mass spectrometry-based proteomics to track the mitochondrial proteome changes induced by physiologically relevant troglitazone doses. By quantitative untargeted proteomics, we first globally profiled the Sod2(+/-) hepatic mitochondria proteome and found perturbations including GSH metabolism that enhanced the toxicity of the normally nontoxic troglitazone. Short- and long term troglitazone administration in Sod2(+/-) mouse led to a mitochondrial proteome shift from an early compensatory response to an eventual phase of intolerable oxidative stress, due to decreased mitochondrial glutathione (mGSH) import protein, decreased dicarboxylate ion carrier (DIC), and the specific activation of ASK1-JNK and FOXO3a with prolonged troglitazone exposure. Furthermore, mapping of the detected proteins onto mouse specific protein centered networks revealed lipid-associated proteins as contributors to overt mitochondrial and liver injury when under prolonged exposure to the lipid normalizing troglitazone. By integrative toxicoproteomics, we demonstrated a powerful systems approach in identifying the collapse of specific fragile nodes and activation of crucial proteome reconfiguration regulators when targeted by an exogenous toxicant. PMID- 23659348 TI - Delusional versus nondelusional body dysmorphic disorder: recommendations for DSM 5. AB - The core feature of body dysmorphic disorder (BDD) is distressing or impairing preoccupation with nonexistent or slight defects in one's physical appearance. BDD beliefs are characterized by varying degrees of insight, ranging from good (ie, recognition that one's BDD beliefs are not true) through "absent insight/delusional" beliefs (ie, complete conviction that one's BDD beliefs are true). The Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., rev. (DSM-III-R) and The Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) classified BDD's nondelusional form in the somatoform section of the manual and its delusional form in the psychosis section, as a type of delusional disorder, somatic type (although DSM-IV allowed double-coding of delusional BDD as both a psychotic disorder and BDD). However, little or no evidence on this issue was available when these editions were published. In this article, we review the classification of BDD's delusional and nondelusional variants in earlier editions of DSM and the limitations of their approaches. We then review empirical evidence on this topic, which has become available since DSM-IV was developed. Available evidence indicates that across a range of validators, BDD's delusional and nondelusional variants have many more similarities than differences, including response to pharmacotherapy. Based on these data, we propose that BDD's delusional and nondelusional forms be classified as the same disorder and that BDD's diagnostic criteria include an insight specifier that spans a range of insight, including absent insight/delusional BDD beliefs. We hope that this recommendation will improve care for patients with this common and often-severe disorder. This increased understanding of BDD may also have implications for other disorders that have an "absent insight/delusional" form. PMID- 23659349 TI - RDC-based determination of the relative configuration of the fungicidal cyclopentenone 4,6-diacetylhygrophorone A12.. AB - The hygrophorones, a class of cyclopentenones isolated from fruiting bodies of the genus Hygrophorus (basidiomycetes), show promising antifungal activity. While the constitution of 4,6-diacetylhygrophorone A(12) (3) and the relative configuration of the stereogenic centers in the cyclopentenone ring were elucidated using standard NMR and MS techniques, the relative configuration of the exocyclic stereogenic center could not be assigned. By introducing a sample of 3 into an alignment medium and measuring anisotropic NMR parameters, namely, residual dipolar couplings, we were able to unambiguously determine the relative configuration of all three stereogenic centers in 4,6-diacetylhygrophorone A(12) simultaneously by fitting several structure proposals to the experimental data. PMID- 23659350 TI - Tiny grains give huge gains: nanocrystal-based signal amplification for biomolecule detection. AB - Nanocrystals, despite their tiny sizes, contain thousands to millions of atoms. Here we show that the large number of atoms packed in each metallic nanocrystal can provide a huge gain in signal amplification for biomolecule detection. We have devised a highly sensitive, linear amplification scheme by integrating the dissolution of bound nanocrystals and metal-induced stoichiometric chromogenesis, and demonstrated that signal amplification is fully defined by the size and atom density of nanocrystals, which can be optimized through well-controlled nanocrystal synthesis. Further, the rich library of chromogenic reactions allows implementation of this scheme in various assay formats, as demonstrated by the iron oxide nanoparticle linked immunosorbent assay (ILISA) and blotting assay developed in this study. Our results indicate that, owing to the inherent simplicity, high sensitivity and repeatability, the nanocrystal based amplification scheme can significantly improve biomolecule quantification in both laboratory research and clinical diagnostics. This novel method adds a new dimension to current nanoparticle-based bioassays. PMID- 23659351 TI - Synthesis of the C4-epi-lomaiviticin B core reveals subtle stereoelectronic effects. AB - An efficient synthesis of the C4-epi-lomaiviticin B core is reported. The synthesis features a diastereoselective anionic formal furan Diels-Alder reaction and a stereoselective oxidative enolate dimerization. During the investigation, subtle yet critical stereoelectronic effects imparted by the C4-stereocenter were observed. PMID- 23659352 TI - Rickettsia felis in Rhipicephalus sanguineus from two distant Chilean cities. AB - INTRODUCTION: Rickettsia felis is an emerging agent considered a human threat; although its natural reservoir and agent of transmission is the cat flea, it has been also found in other vectors. R. felis has been identified in Chile in cat fleas and in one specimen of Rhipicephalus sanguineus collected in the Metropolitan Region. The objective of this study was to detect the presence of Rickettsia spp. in R. sanguineus from dogs of two different and distant geographical areas in Chile. MATERIAL AND METHODS: We performed a domiciliary sampling in urban and rural localities of two distant areas of the country-the Metropolitan Region in the center and the northern city of Arica. A total of 460 households were visited; one dog per household was included in the study and ectoparasites were collected from them. RESULTS: R. sanguineus was found in 50% of the 460 dogs. R. felis was identified by amplification and sequencing of gltA, ompA, and ompB genes in R. sanguineus from both regions, with predominance in Arica. DISCUSSION: The presence of R. felis in R. sanguineus from two distant regions of Chile suggests that this rickettsial agent is well established in the country. Considering that no human spotted fever group infections have been recognized in the country, the results should alert clinicians about such possible cases. The role of R. sanguineus in the epidemiology and transmission of R. felis should be further investigated. PMID- 23659353 TI - The emergence of echinococcosis in central Asia. AB - SUMMARY Following the collapse of the Soviet Union in 1991, there was an increase in the number of cases of human echinococcosis recorded throughout central Asia. Between 1991 and 2001 incidence rates of cystic echinococcosis (CE) increased by 4 fold or more. There also appeared to be increases in prevalence of CE in livestock and prevalences of Echinococcus granulosus reported in dogs. The increase in human echinococcosis was associated with changes in livestock husbandry, decline in veterinary public health services, increases in dog populations and increased poverty, all of which served to promote transmission of E. granulosus. A few years after reports of increased transmission of E. granulosus, the first reports of E. multilocularis infection in dogs were recorded. Further studies indicated that in both Kazakhstan and Kyrgyzstan prevalences of up to 18% were present. Recently there has been a dramatic increase in the number of cases of human alveolar echinococcosis recorded in Kyrgyzstan with over 60 cases reported in 2011. PMID- 23659354 TI - Anxiety genetics - findings from cross-species genome-wide approaches. AB - Anxiety disorders are complex diseases, which often occur in combination with major depression, alcohol use disorder, or general medical conditions. Anxiety disorders were the most common mental disorders within the EU states in 2010 with 14% prevalence. Anxiety disorders are triggered by environmental factors in genetically susceptible individuals, and therefore genetic research offers a great route to unravel molecular basis of these diseases. As anxiety is an evolutionarily conserved response, mouse models can be used to carry out genome wide searches for specific genes in a setting that controls for the environmental factors. In this review, we discuss translational approaches that aim to bridge results from unbiased genome-wide screens using mouse models to anxiety disorders in humans. Several methods, such as quantitative trait locus mapping, gene expression profiling, and proteomics, have been used in various mouse models of anxiety to identify genes that regulate anxiety or play a role in maintaining pathological anxiety. We first discuss briefly the evolutionary background of anxiety, which justifies cross-species approaches. We then describe how several genes have been identified through genome-wide methods in mouse models and subsequently investigated in human anxiety disorder samples as candidate genes. These studies have led to the identification of completely novel biological pathways that regulate anxiety in mice and humans, and that can be further investigated as targets for therapy. PMID- 23659355 TI - Estimates of the burden of foodborne illness in Canada for 30 specified pathogens and unspecified agents, circa 2006. AB - Estimates of foodborne illness are important for setting food safety priorities and making public health policies. The objective of this analysis is to estimate domestically acquired, foodborne illness in Canada, while identifying data gaps and areas for further research. Estimates of illness due to 30 pathogens and unspecified agents were based on data from the 2000-2010 time period from Canadian surveillance systems, relevant international literature, and the Canadian census population for 2006. The modeling approach required accounting for under-reporting and underdiagnosis and to estimate the proportion of illness domestically acquired and through foodborne transmission. To account for uncertainty, Monte Carlo simulations were performed to generate a mean estimate and 90% credible interval. It is estimated that each year there are 1.6 million (1.2-2.0 million) and 2.4 million (1.8-3.0 million) episodes of domestically acquired foodborne illness related to 30 known pathogens and unspecified agents, respectively, for a total estimate of 4.0 million (3.1-5.0 million) episodes of domestically acquired foodborne illness in Canada. Norovirus, Clostridium perfringens, Campylobacter spp., and nontyphoidal Salmonella spp. are the leading pathogens and account for approximately 90% of the pathogen-specific total. Approximately one in eight Canadians experience an episode of domestically acquired foodborne illness each year in Canada. These estimates cannot be compared with prior crude estimates in Canada to assess illness trends as different methodologies were used. PMID- 23659356 TI - Implant survival after preparation of the implant site using a single bur: a case series. AB - BACKGROUND: Implant site preparation usually consists of several consecutive drilling steps, performed using different burs with increasing diameter. PURPOSE: The purpose of the present study was to report the clinical outcomes of edentulous patients that underwent implant treatment, in which a special bur that allows preparation of the implant site in a single drilling step was used. MATERIAL AND METHODS: One hundred forty-nine patients (79 males, 70 females, mean age 51.8 +/- 12.2 [SD] years, range 20-80 years) have been rehabilitated using different oral surgery procedures. A total of 350 implants were inserted (171 in the maxilla and 179 in the mandible). A barrier membrane was used for covering a total of 126 implants. Fifteen implants were placed by using the osteotome technique and 52 by using the lateral sinus lift procedure. Eighty-nine implants were placed in postextraction sockets. Thirty-six implants underwent immediate loading. Implant survival, peri-implant bone level change, and patients' satisfaction were the main variables assessed. RESULTS: No patient dropout occurred. The mean follow-up on a patient basis was 21.5 +/- 3.1 months (range 12 27 months). A total of seven implant failures were recorded in six patients, leading to a mean implant survival of 98.0% (96.0% on a patient basis). The mean peri-implant bone loss after 1 year was 0.58 +/- 0.44 mm (n = 282). Apart from implant failures, no biological nor mechanical complications occurred. All patients demonstrated full satisfaction. CONCLUSIONS: The use of a single bur for implant site preparation allows the reduction of the time needed for the surgical procedure, without compromising the clinical outcomes. Further, long-term comparative studies are needed to confirm the results of this study. PMID- 23659357 TI - Sexuality examined through the lens of attachment theory: attachment, caregiving, and sexual satisfaction. AB - Attachment researchers have proposed that the attachment, caregiving, and sexual behavioral systems are interrelated in adult love relationships (Mikulincer & Shaver, 2007 ). This study examined whether aspects of partners' caregiving (proximity, sensitivity, control, compulsive caregiving) mediated the association between their attachment insecurities (anxiety and avoidance) and each other's sexual satisfaction in two samples of committed couples (Study 1: 126 cohabiting or married couples from the general community; Study 2: 55 clinically distressed couples). Partners completed the Experiences in Close Relationships measure (Brennan, Clark, & Shaver, 1998 ), the Caregiving Questionnaire (Kunce & Shaver, 1994 ), and the Global Measure of Sexual Satisfaction (Lawrance & Byers, 1998 ). Path analyses based on the actor-partner interdependence model (APIM) revealed that caregiving proximity mediated the association between low attachment avoidance and partners' sexual satisfaction in distressed and nondistressed couples. Sensitivity mediated this association in nondistressed couples only. Control mediated the association between men's insecurities (attachment-related avoidance and anxiety) and their partners' low sexual satisfaction in nondistressed couples. Attachment anxiety predicted compulsive caregiving, but this caregiving dimension was not a significant mediator. These results are discussed in light of attachment theory and their implications for treating distressed couples. PMID- 23659358 TI - Molecular dynamics study of water transfer at supercooled sulfuric acid solution surface covered with butanol. AB - The evaporation and condensation mechanisms of water through a butanol film on sulfuric acid solution are elucidated by molecular dynamics simulation. A previous experiment by Nathanson et al. reported the mass accommodation coefficient alpha to be almost unity, whereas MD simulation of water scattering on the butanol film on water predicted a value of alpha significantly smaller than unity. This discrepancy is elucidated by considering the protonated butanol at the sulfuric acid solution surface, which roughens the surface layer, and the low temperature at the supercooled condition. PMID- 23659359 TI - Cancer-associated missense mutations of caspase-8 activate nuclear factor-kappaB signaling. AB - Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with a 5 year survival rate of ~50%. With the use of a custom cDNA-capture system coupled with massively parallel sequencing, we have now investigated transforming mechanisms for this malignancy. The cDNAs of cancer-related genes (n = 906) were purified from a human HNSCC cell line (T3M-1 Cl-10) and subjected to high throughput resequencing, and the clinical relevance of non-synonymous mutations thus identified was evaluated with luciferase-based reporter assays. A CASP8 (procaspase-8) cDNA with a novel G-to-C point mutation that results in the substitution of alanine for glycine at codon 325 was identified, and the mutant protein, CASP8 (G325A), was found to activate nuclear factor-kappaB (NF-kappaB) signaling to an extent far greater than that achieved with the wild-type protein. Moreover, forced expression of wild-type CASP8 suppressed the growth of T3M-1 Cl 10 cells without notable effects on apoptosis. We further found that most CASP8 mutations previously detected in various epithelial tumors also increase the ability of the protein to activate NF-kappaB signaling. Such NF-kappaB activation was shown to be mediated through the COOH-terminal region of the second death effector domain of CASP8. Although CASP8 mutations associated with cancer have been thought to promote tumorigenesis as a result of attenuation of the proapoptotic function of the protein, our results now show that most such mutations, including the novel G325A identified here, separately confer a gain of function with regard to activation of NF-kappaB signaling, indicating another role of CASP8 in the transformation of human malignancies including HNSCC. PMID- 23659361 TI - Direct measurement of the surface tension of a soft elastic hydrogel: exploration of elastocapillary instability in adhesion. AB - An adhesively stressed thin film of a soft hydrogel confined between two rigid flat substrates autoroughens with its dominant wavelength (lambda) exhibiting pronounced dependence on the film thickness (H). A linear stability analysis confirmed that this long wavelength instability (lambda ~ 7H) is due to an elastocapillary effect, the implementation of which required direct measurements of the surface tension and the elasticity of the gel. The surface tension of the gel was estimated from the fundamental spherical harmonic of a hemispherical cap of the gel that was excited by an external noise. The shear modulus (MU) of the gel was determined from its resonant shear mode in a confined geometry. During the course of this study, it was found that a high density steel ball submerges itself inside the gel by balancing its excess weight with the accumulated strain induced elastic force that allows another estimation of its elastic modulus. The large ratio (1.8 mm) of the surface tension to its elasticity ascertains the role of elastocapillarity in the adhesion-induced pattern formation with such gels. Experimental results are in accord with a linear stability analysis that predicts that the rescaled wavelength lambda(MUH/gamma)(0.27) is linear with H, which also modifies the conventional stress to pull a flat rigid object out of a very soft film by a multiplicative factor: (gamma/MUH)(1/4). The analysis also suggests some new results related to the role of the finite dilation of a material in interfacial pattern formation that may have nontrivial consequences in the adhesive delamination of very thin and/or soft elastic films via self-generated cracks. PMID- 23659360 TI - Clinical gains from including both dextroamphetamine and methylphenidate in stimulant trials. AB - OBJECTIVE: The purpose of this study was to investigate clinical gains from including both dextroamphetamine and methylphenidate in stimulant trials. METHOD: Thirty-six medication-naive children ages 9-14 years diagnosed with attention deficit/hyperactivity disorder (ADHD) were enrolled for 6 weeks in a crossover trial, with 2 weeks of methylphenidate, dextroamphetamine, and placebo, in a randomly assigned, counterbalanced sequence. Outcome measures constituted a computer-based continuous performance test combined with a motion tracking system (Qb Test) and an ADHD questionnaire rated by parents and teachers. RESULTS: Group analyses found significant treatment effects of similar size for the two stimulants on both outcome measures. Single-subject analyses revealed that each stimulant produced a favourable response in 26 children; however, an individual child frequently responded qualitatively or quantitatively differently to the two stimulants. By including both stimulants in the trial, the number of favorable responders increased from 26 (72%) to 33 (92%). In children with favorable responses of unequal strength to the two stimulants, a shift from inferior drug to best drug was associated with a 64% mean increase in the overall response strength score, as measured by the ADHD questionnaire. CONCLUSIONS: The likelihood of a favorable response and optimal response strength is increased by including both stimulants in the stimulant trial. The study was first registered in clinical trials 28 September 2010. Clinical Trials.gov Identifier: NCT01220440. PMID- 23659362 TI - Three-dimensional speckle tracking echocardiography-derived left atrial strain parameters are reduced in patients with atrial fibrillation (results from the MAGYAR-path study). AB - OBJECTIVE: Three-dimensional (3D) speckle tracking echocardiography (3DSTE) is a novel imaging modality for assessing cardiac function. We aimed to analyze left atrial (LA) function using 3DSTE in patients with atrial fibrillation (AF). METHODS: 3DSTE was performed in 20 patients prior to their pulmonary vein isolation for AF. Every patient underwent a complete two-dimensional echocardiographic study at the same time. 3DSTE-derived circumferential (CS), longitudinal (LS), radial (RS), 3D (3DS), and area strain (AS) values were measured in the basal (b), mid (m), and superior (s) regions of the LA. 3DSTE defined maximal (LAmax ) and minimal LA volumes (LAmin ) and LA total emptying fraction were calculated automatically. Eleven randomly selected age- and gender matched healthy volunteers served as controls. RESULTS: Patients with AF had significantly larger LAmax and LAmin and reduced LS, RS and CS.3DS and AS were significantly lower throughout the LA in cases with AF (3DS-b, -m, -s [AF patients vs. controls]: -18 +/- 8% vs. -29 +/- 8%, P = 0.001; -14 +/- 6% vs. -22 +/- 7%, P = 0.002; -10 +/- 7% vs. -20 +/- 9%, P = 0.002; AS-b, -m, -s [AF patients vs. controls]: 35 +/- 15% vs. 52 +/- 13%, P = 0.004; 50 +/- 21% vs. 72 +/- 19%, P = 0.009; 31 +/- 21% vs. 65 +/- 27%, P < 0.0001, respectively). CONCLUSIONS: 3DSTE-derived "uni-dimensional" LS, RS, CS, as well as novel strain parameters (3DS, AS) are significantly reduced in patients with AF compared to matched controls. 3DS and AS might be new strain parameters providing further insights into the alterations of LA function in patients developing AF. PMID- 23659363 TI - Dimensions of racism and their impact on partner selection among men of colour who have sex with men: understanding pathways to sexual risk. AB - While many studies have established the relationship between experiences of racism and sexual risk among men of colour who have sex with men, the pathways by which this occurs are underdeveloped. To address this gap, we must better investigate the lived realities of racism in the gay community. In this study, we had the unique opportunity to examine experiences of racism among African American, Asian/Pacific Islander and Latino men who have sex with men living in Los Angeles through focus groups and individual in-depth interviews. We found three themes of racism: exclusion from West Hollywood and the mainstream gay community, sexual rejection based on race/ethnicity and sexual stereotypes. There were differences across the three racial groups in the experiences of each theme, however. We then considered how racism impacted partner selection and found that race played a salient role in determining power differentials within mixed-race partnerships. Finally, we discussed several future areas for research that can better establish pathways between racism and sexual risk. PMID- 23659364 TI - Brain circuitry of compulsivity and impulsivity. AB - Impulsivity and compulsivity have been considered opposite poles of a continuous spectrum, but their relationship appears to be more complex. Disorders characterized by impulsivity often have features of compulsivity and vice versa. The overlaps of the constructs of compulsivity and impulsivity warrant additional investigation, not only to identify the similarities and differences, but also to examine the implications for prevention and treatment strategies of both compulsive and impulsive behaviors. PMID- 23659365 TI - Controlling molecular self-assembly on an insulating surface by rationally designing an efficient anchor functionality that maintains structural flexibility. AB - Molecular self-assembly on surfaces is dictated by the delicate balance between intermolecular and molecule-surface interactions. For many insulating surfaces, however, the molecule-surface interactions are weak and rather unspecific. Enhancing these interactions, on the other hand, often puts a severe limit on the achievable structural variety. To grasp the full potential of molecular self assembly on these application-relevant substrates, therefore, requires strategies for anchoring the molecular building blocks toward the surface in a way that maintains flexibility in terms of intermolecular interaction and relative molecule orientation. Here, we report the design of a site-specific anchor functionality that provides strong anchoring toward the surface, resulting in a well-defined adsorption position. At the same time, the anchor does not significantly interfere with the intermolecular interaction, ensuring structural flexibility. We demonstrate the success of this approach with three molecules from the class of shape-persistent oligo(p-benzamide)s adsorbed onto the calcite(10.4) surface. These molecules have the same aromatic backbone with iodine substituents, providing the same basic adsorption mechanism to the surface calcium cations. The backbone is equipped with different functional groups. These have a negligible influence on the molecular adsorption on the surface but significantly change the intermolecular interaction. We show that distinctly different molecular structures are obtained that wet the surface due to the strong linker while maintaining variability in the relative molecular orientation. With this study, we thus provide a versatile strategy for increasing the structural richness in molecular self-assembly on insulating substrates. PMID- 23659366 TI - Identification of indicator proteins associated with flooding injury in soybean seedlings using label-free quantitative proteomics. AB - Flooding injury is one of the abiotic constraints on soybean growth. An experimental system established for evaluating flooding injury in soybean seedlings indicated that the degree of injury is dependent on seedling density in floodwater. Dissolved oxygen levels in the floodwater were decreased by the seedlings and correlated with the degree of injury. To understand the molecular mechanism responsible for the injury, proteomic alterations in soybean seedlings that correlated with severity of stress were analyzed using label-free quantitative proteomics. The analysis showed that the abundance of proteins involved in cell wall modification, such as polygalacturonase inhibitor-like and expansin-like B1-like proteins, which may be associated with the defense system, increased dependence on stress at both the protein and mRNA levels in all organs during flooding. The manner of alteration in abundance of these proteins was distinct from those of other responsive proteins. Furthermore, proteins also showing specific changes in abundance in the root tip included protein phosphatase 2A subunit-like proteins, which are possibly involved in flooding induced root tip cell death. Additionally, decreases in abundance of cell wall synthesis-related proteins, such as cinnamyl-alcohol dehydrogenase and cellulose synthase-interactive protein-like proteins, were identified in hypocotyls of seedlings grown for 3 days after flooding, and these proteins may be associated with suppression of growth after flooding. These flooding injury-associated proteins can be defined as indicator proteins for severity of flooding stress in soybean. PMID- 23659368 TI - Enantioselective nickel-catalyzed Michael additions of 2-acetylazaarenes to nitroalkenes. AB - 2-Acetylazaarenes undergo catalytic enantioselective Michael additions to nitroalkenes in the presence of a chiral Ni(II)-bis(oxazoline) complex. The process is tolerant of a range of azines or azoles in the pronucleophilic component, resulting in Michael products in moderate to high enantioselectivities. PMID- 23659367 TI - Postprandial regulation of growth- and metabolism-related factors in zebrafish. AB - Zebrafish (Danio rerio) have been proposed as a possible model organism for nutritional physiology. However, this potential has not yet been realized and studies on the field remain scarce. In this work, we investigated in this species the effect of a single meal as well as that of an increase in the ratio of dietary carbohydrates/proteins on the postprandial expression of several hepatic and muscle metabolism-related genes and proteins. Fish were fed once either a commercial diet (experiment 1) or one of two experimental diets (experiment 2) containing different protein and carbohydrate levels after 72 h of starvation. Refeeding induced the postprandial expression of genes of glycolysis (GK, HK1) and lipogenesis (FAS, G6PDH, ACCa) and inhibited those of gluconeogenesis (cPEPCK) and beta-oxidation (CPT1b) in the viscera. In the muscle, refeeding increased transcript levels of myogenesis (Myf5, Myogenin), inhibited those of Ub proteasomal proteolytic system (Atrogin1, Murf1a, Murf1b), and induced the activation of key signaling factors of protein synthesis (Akt, 4EBP1, S6K1, S6). However, diet composition had a low impact on the studied factors. Together, these results highlight some specificity of the zebrafish metabolism and demonstrate the interest and the limits of this species as a model organism for nutritional physiology studies. PMID- 23659369 TI - Details acquired from medical history and patients' experience of empathy--two sides of the same coin. AB - BACKGROUND: History taking and empathetic communication are two important aspects in successful physician-patient interaction. Gathering important information from the patient's medical history is needed for effective clinical decision making while empathy is relevant for patient satisfaction. We wanted to investigate whether medical students near graduation are able to combine both skills as required in daily medical practice. METHODS: Thirty near graduates from Hamburg Medical School participated in an assessment for clinical competences including a consultation hour with five standardized patients. Each patient interview was videotaped and standardized patients rated participants with the CARE questionnaire for consultation and relational empathy. All videotaped interviews were rated with a checklist based on the number of important medical aspects for each case. Data were analysed with the linear mixed model to correct for random effects. Regression analysis was performed to look for correlations between the number of questions asked by a participant and their respective empathy rating. RESULTS: Of the 123 aspects that could have been gathered in total, students only requested 56.4% (95% CI 53.5-59.3). While no difference between male and female participants was found, a significant difference (p<.001) was observed between the two parts of the checklist with 61.1% (95% CI 57.9-64.3) of aspects asked for in part 1 (patient's symptoms) versus 52.0 (95 47.4-56.7) in part 2 (further history). All female standardized patients combined rated female participants (mean score 14.2, 95% CI 12.3-16.3) to be significantly (p<.01) more empathetic than male participants (mean score 19.2, 95% CI 16.3-22.6). Regression analysis revealed no correlation between the number of medical aspects gathered by a participant and his or her respective empathy score given by the standardized patient in the CARE questionnaire. CONCLUSION: Gathering sufficient medical data from a patient's history and empathetic communication are two completely separate sides of the coin of history taking. While both skills have to be acquired during medical school training with particular focus on their respective learning objectives, medical students need to be provided with additional learning and feedback opportunities where they can be observed exercising both skills combined as required in physicians' daily practice. PMID- 23659370 TI - Clinical features, STAT3 gene mutations and Th17 cell analysis in nine children with hyper-IgE syndrome in mainland China. AB - Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency disease characterized by eczema, recurrent staphylococcal aureus skin abscesses, pneumonia with pneumatocele formation, remarkably high serum IgE levels, eosinophilia and involvement of skeleton and connective tissues. Heterozygous signal transducer and activator of transcription 3 (STAT3) mutations were shown to be the cause of autosomal dominant HIES (AD-HIES). In this study, we diagnosed nine patients with HIES from 9 unrelated families on the basis of a National Institutes of Health (NIH) score of >=40 points, sequenced the STAT3 gene of all nine patients, and quantified Th17 cells in peripheral blood of seven patients by flow cytometry in mainland China. All nine patients had characteristic manifestation of HIES with the range of NIH scores 45-77 points. STAT3 hot mutations V637M or R382W/Q were identified in five patients. We identified two novel heterozygous missense mutations (T620S and R609G) located in Src homology 2 (SH2) domain in two patients, respectively. In two other patients, no STAT3 mutations were found. Quantified Th17 cell numbers were markedly decreased or absent (0-0.28% of CD4(+) T cells) in six patients with STAT3 mutations and almost normal (0.53% of CD4(+) T cells) in one wild-type STAT3 patient compared with healthy controls (0.40-2.25% of CD4(+) T cells). These results suggest that not all patients with HIES who had NIH scores over 40 points carry STAT3 mutations, those whose Th17 cell numbers strikingly decreased probably had AD HIES with STAT3 mutations. PMID- 23659371 TI - Antiproliferative Homoisoflavonoids and Bufatrienolides from Urginea depressa. AB - Investigation of the South African plant Urginea depressa Baker (Asparagaceae Juss.) for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of the six new homoisoflavonoids urgineanins A-F (1-6), the two known bufatrienolides 7 and 9, and the new bufatrienolides urginins B and C (8 and 10). Structures were elucidated based on analysis of their 1D and 2D NMR spectra, electronic circular dichroism, and mass spectrometric data. Five of the six new homoisoflavonoids had good antiproliferative activity against the A2780 ovarian cancer, A2058 melanoma, and H522-T1 human non-small-cell lung cancer cells, and urgineanin A (1) had submicromolar activity against all three cell lines. The four bufatrienolides 7-10 had strong antiproliferative activity against the same cell line, with IC50 values of 24.1, 11.2, 111, and 40.6 nM, respectively. PMID- 23659372 TI - A virtual reality system combined with biofeedback for treating pediatric chronic headache--a pilot study. AB - OBJECTIVE: Pediatric headache is highly widespread and is associated with distress and reduced quality of life. Pharmacological treatment of chronic headache in children has been only partially effective and, as in medication overuse headache, can sometimes be counterproductive. Therefore, there is a substantial need to develop other effective methods of treatment. Here we present the rationale, feasibility, and preliminary results of a pilot study applying a novel system, combining virtual reality and biofeedback, aimed as an abortive treatment of pediatric chronic headache. DESIGN: A prospective single-arm open label, pilot study. Ten children attending an outpatient pediatric neurology clinic were treated by the proposed system. Participants practiced relaxation with biofeedback and learned to associate successful relaxation with positive pain-free virtual images of themselves. RESULTS: Nine patients completed the 10 session intervention. Ratings of pain, daily functioning, and quality of life improved significantly at 1 and at 3 months posttreatment. Most patients reported applying their newly acquired relaxation and imagery skills to relieve headache outside the lab. CONCLUSION: This novel system, combining biofeedback and virtual reality, is feasible for pediatric use. Randomized controlled studies in larger populations are needed in order to determine the utility of the system in reducing headache, improving daily functioning, and elevating quality of life. PMID- 23659373 TI - Cognitive subtypes in non-affected siblings of schizophrenia patients: characteristics and profile congruency with affected family members. AB - BACKGROUND: Although cognitive subtypes have been suggested in schizophrenia patients, similar analyses have not been carried out in their non-affected siblings. Subtype classification may provide more insight into genetically driven variation in cognitive function. We investigated cognitive subtypes in siblings. METHOD: Cluster analyses were performed in 654 non-affected siblings, on a cognitive battery that included tests of attention, intellectual function and episodic memory. Resulting subtypes in the siblings were analyzed for cognitive, demographic and clinical characteristics and compared with those of their probands. RESULTS: Three sibling subtypes of cognitive function were distinguished: 'normal', 'mixed' and 'impaired'. Normal profile siblings (n = 192) were unimpaired on cognitive tests, in contrast to their proband (n = 184). Mixed profile siblings (n = 228) and their probands (n = 222) had a more similar performance pattern. Impaired profile siblings had poorer functional outcomes (n = 234) and their profile was almost identical to that of their proband (n = 223). Probands with cognitively impaired siblings could be distinguished from other schizophrenia patients by their own cognitive performance. They also had poorer clinical characteristics, including achievement of symptomatic remission. CONCLUSIONS: Unaffected siblings of patients with schizophrenia are heterogeneous with respect to cognitive function. The poorer the cognitive profile of the sibling, the higher the level of correspondence with the proband. The sibling's cognitive subtype was predictive for disease course in the proband. Distinguishing cognitive subtypes of unaffected siblings may be of relevance for genetic studies. PMID- 23659374 TI - Arterial blood gas parameters in pet rabbits anaesthetized using a combination of fentanyl-fluanisone-midazolam-isoflurane. AB - OBJECTIVES: Blood gas analysis is a well-recognized method to monitor pulmonary function, blood oxygenation, ventilation and acid-base status during general anaesthesia. The aim of this study was to report blood gas analysis results in pet rabbits (Oryctolagus cuniculus) obtained during general anaesthesia using a portable clinical analyser. METHODS: Thirty-two rabbits were premedicated with 0.2 mL/kg fentanyl and fluanisone. Anaesthesia was induced with 0.2 mg/kg midazolam and maintained with 2% isoflurane in oxygen via endotracheal tube. Arterial blood samples were taken from the central ear artery 10 minutes after induction of anaesthesia. RESULTS: Respiratory acidaemia was observed during anaesthesia. Mean +/-sd (range) arterial blood pH was 7.33 +/-0.08 (7.15 to 7.48). PaCO2 and PaO2 were, respectively, 55.02 +/-10.5 (37.7 to 92.1) mmHg and 370.0 +/-120.5 (67 to 561) mmHg. Base excess was 2.8 +/-3.6 (-3 to 11) mmol/L, HCO3 was 28.73 +/-3.07 (23.7 to 35.4) mmol/L and TCO2 was 30.4 +/-3.2 (25 to 37) mmol/L. None of the rabbits developed haematoma during arterial blood collection or ischaemia of the pinna during the hospitalization period. CLINICAL SIGNIFICANCE: Arterial blood gas analysis is a safe and easy to perform diagnostic technique that can contribute to improved safety of rabbit anaesthesia, by providing information on the respiratory and metabolic status of the patient. PMID- 23659375 TI - Influence of pellet diameter and length on the quality of pellets and performance, nutrient utilisation and digestive tract development of broilers fed on wheat-based diets. AB - 1. The influence of pellet diameter and length on the quality of pellets and performance, nutrient utilisation and digestive tract development of broilers given wheat-based diets was examined from 10 to 42 d of age. The experimental design was a 2 * 2 factorial arrangement of treatments evaluating two pellet diameters (3 and 4.76 mm) and two pellet lengths (3 and 6 mm). From 0 to 9 d of age, all birds were offered a common starter diet pelleted with a 3-mm diameter die and 3-mm length. Broiler grower (d 10 to 21) and finisher (d 22 to 42) diets, based on wheat, were formulated and then subjected to the 4 different treatments. 2. In grower diets, increasing pellet diameter and pellet length reduced the gelatinised starch (GS) content of the diets. In finisher diets, GS content of 3 mm diameter pellets did not change with increasing pellet length but decreased in 4.76-mm diameter pellets. 3. In grower and finisher diets, increments in intact pellet weight, pellet durability index and pellet hardness with increasing pellet length were greater in 3-mm diameter pellets than those with 4.76-mm diameter. 4. Increasing pellet length from 3 to 6 mm increased apparent metabolisable energy values. Neither the interaction nor main effects were significant for the ileal digestibility of nitrogen and starch. 5. During the grower period (d 10 to 21), birds given pellets of 6-mm length had greater body-weight gain than those given 3-mm length pellets. Feeding 6-mm length pellets decreased feed per body-weight gain compared to 3-mm length pellets. During the finisher (d 22 to 42) and whole grow-out (d 10 to 42) periods, while different pellet lengths had no effect on feed per body-weight gain values at 3-mm pellet diameter, increasing the pellet length decreased feed per body-weight gain at 4.76-mm pellet diameter. 6. Increasing pellet diameter and pellet length reduced the relative length of duodenum. Birds given 3-mm diameter pellets had heavier proventriculus compared to those given 4.76-mm diameter pellets. 7. Overall, the data suggest that increasing the pellet length from 3 to 6 mm improved the body-weight gain and feed per body-weight gain during the grower period (d 10 to 21). While the positive effect on body-weight gain disappeared as the birds grew older, improvements in feed per body-weight gain were maintained over the finisher and whole grow-out periods only in 4.76-mm diameter pellets. Small diameter die holes and longer pellet lengths may be considered as potential manipulations to manufacture high-quality pellets under low conditioning temperatures. PMID- 23659376 TI - Cytotoxic activity of Pulsatilla chinensis saponins and their structure-activity relationship. AB - The cytotoxic activity of 36 saponins isolated from roots of Pulsatilla chinensis (Bunge) Regel against the human cancer cell lines (A549, SGC-7901) and the human hepatic cell line (HL-7702) was tested by 3-(4,5-dimethylthiazole-2-yl)-2,5 diphenyltetrazolium bromide assay. Saponins 1-14 showed considerable cytotoxic activity, whereas saponins 15-36 showed no significant activity, which suggested that a free carboxylic group located at C-28 of aglycon is essential for their cytotoxic activity. Moreover, the analysis of structure-activity relationships also suggested that the oleanane-type saponins showed better cytotoxic activity than lupane-type saponins, and the length and linkage of glycolic chain attached to C-3 of aglycon displayed an important effect to the potent cytotoxicity. In conclusion, oleanolic acid 3-O-alpha-l-rhamnopyranosyl-(1 -> 2)-[beta-d glucopyranosyl-(1 -> 4)]-alpha-l-arabinopyranoside (5) exhibited the most significant cytotoxic activity. PMID- 23659377 TI - Global atmospheric emissions of polycyclic aromatic hydrocarbons from 1960 to 2008 and future predictions. AB - Global atmospheric emissions of 16 polycyclic aromatic hydrocarbons (PAHs) from 69 major sources were estimated for a period from 1960 to 2030. Regression models and a technology split method were used to estimate country and time specific emission factors, resulting in a new estimate of PAH emission factor variation among different countries and over time. PAH emissions in 2007 were spatially resolved to 0.1 degrees * 0.1 degrees grids based on a newly developed global high-resolution fuel combustion inventory (PKU-FUEL-2007). The global total annual atmospheric emission of 16 PAHs in 2007 was 504 Gg (331-818 Gg, as interquartile range), with residential/commercial biomass burning (60.5%), open field biomass burning (agricultural waste burning, deforestation, and wildfire, 13.6%), and petroleum consumption by on-road motor vehicles (12.8%) as the major sources. South (87 Gg), East (111 Gg), and Southeast Asia (52 Gg) were the regions with the highest PAH emission densities, contributing half of the global total PAH emissions. Among the global total PAH emissions, 6.19% of the emissions were in the form of high molecular weight carcinogenic compounds and the percentage of the carcinogenic PAHs was higher in developing countries (6.22%) than in developed countries (5.73%), due to the differences in energy structures and the disparities of technology. The potential health impact of the PAH emissions was greatest in the parts of the world with high anthropogenic PAH emissions, because of the overlap of the high emissions and high population densities. Global total PAH emissions peaked at 592 Gg in 1995 and declined gradually to 499 Gg in 2008. Total PAH emissions from developed countries peaked at 122 Gg in the early 1970s and decreased to 38 Gg in 2008. Simulation of PAH emissions from 2009 to 2030 revealed that PAH emissions in developed and developing countries would decrease by 46-71% and 48-64%, respectively, based on the six IPCC SRES scenarios. PMID- 23659378 TI - Aquaporin-4 expression in the cerebrospinal fluid in congenital human hydrocephalus. AB - BACKGROUND: Aquaporin-4 (AQP4) is a water channel mainly located in the ventricular ependymal cells (brain-CSF barrier), the sub-ependymal glia, glia limitans and in end-feet of astrocytes in at the blood-brain barrier (BBB). METHODS: In the present work, the expression of AQP4 in the cerebrospinal fluid (CSF) in control and congenital human hydrocephalus infants (obstructive and communicating), was analysed by Western-blot and enzyme immunoassay (ELISA). RESULTS: AQP4 was found to be high compared to the control in the CSF in congenital hydrocephalus patients. Western-blot showed higher values for AQP4 than controls in communicating hydrocephalus (communicating: 38.3%, control: 6.9% p < 0.05) although the increase was not significant in obstructive hydrocephalus (obstructive: 14.7%). The AQP4 quantification by ELISA also showed that, the mean concentration of AQP4 in CSF was significantly higher in communicating hydrocephalus (communicating: 11.32 +/- 0.69 ng/ml, control: 8.61 +/- 0.31 ng/ml; p < 0.05). However, there was no increase over control in obstructive hydrocephalus (obstructive: 8.65 +/- 0.80 ng/ml). CONCLUSIONS: AQP4 has a modulatory effect on ependyma stability and acts in CSF production and reabsorption. Therefore, the increase of AQP4 in the CSF in congenital hydrocephalus could be due to the fact that AQP4 passes from the parenchyma to the CSF and this AQP4 movement may be a consequence of ependyma denudation. PMID- 23659379 TI - The cross-talk between spinal cord stimulators and the ConfirmTM cardiac monitor. AB - INTRODUCTION: Spinal cord stimulators (SCS) function by transmission of electrical impulses to electrode contacts placed within the epidural space depending on the painful area to be treated. Because of the electrical nature of the SCS, there has been concern about the interaction between these devices and devices that monitor or augment the cardiac system. Implantable loop recorders help to identify the causes of syncope or palpitation by continuously evaluating and recording portions of an electrocardiograph in patients being evaluated for cardiac conduction arrhythmias. The purpose of the study is to simulate the possible effects of spinal cord stimulation on a Confirm cardiac monitor (St. Jude Medical, St. Paul, MN, USA). METHODS: Twenty patients without preexisting cardiac disease, who were successfully being treated with SCS, were enrolled. Confirm loop recorders (St. Jude Medical) were placed on their chest wall in a noninvasive manner, with all programmed at identical settings. Multiple stimulation settings were adjusted on the stimulators and the recordings from the Confirm loop recorder were analyzed for evidence of interference. RESULTS: Fifteen of the patients had no electrical noise detected at any of the tested combinations of stimulation. Five patients had some electrical "noise" detected by the loop recorder, but it did not inhibit the cardiologist evaluating the recording from analyzing the electrocardiograph for diagnostic purposes. At no point with any of the patients at any tested setting was there an appearance of a life-threatening arrhythmia. CONCLUSION: Our study demonstrates that spinal cord stimulation is unlikely to interfere with the data collected by the Confirm loop recorder, and the presence of an SCS should not interfere with the ability to use a loop recorder for diagnostic purposes. PMID- 23659380 TI - Buoyancy of a thin plate pressing a floating oil film on water. AB - Because of the superhydrophobicity of their legs, water striders and many other aquatic creatures can stand and walk effortlessly on water. Because of pollution, an oil film may exist on water in some practical situations. To date, however, it remains unclear how the presence of an oil film would affect the wetting behavior of an object floating on water. In this work, we investigated, both theoretically and experimentally, the buoyancy of a thin plate pressing the surface of a bilayered liquid system. In particular, the effect of the oil layer on the buoyancy force was examined. The critical depth and the corresponding buoyancy at the penetration of the plate into the liquids were obtained analytically. For a plate vertically pressing the liquid surface, the force-displacement loop during a complete advancing-receding cycle was analyzed. Experiments were also performed to verify the theoretical results. PMID- 23659381 TI - Association between serum 25-hydroxyvitamin D concentration and symptoms of respiratory tract infection in a Norwegian population: the Tromso Study. AB - OBJECTIVE: Previous studies have suggested anti-infection effects of vitamin D, although the associations reported between vitamin D (serum 25-hydroxyvitamin D (25(OH)D) concentration) and respiratory tract infection (RTI) are conflicting. The main aim of the present study was to explore this association in a Norwegian population. DESIGN: We examined the association between serum 25(OH)D and recent RTI symptoms in 6350 middle-aged and elderly participants in the Tromso Study 6. The main outcome measurement was self-reported RTI symptoms in the previous week. SETTING: Tromso, Norway, 69 degrees N. SUBJECTS: Six thousand three hundred and fifty middle-aged and elderly residents of Tromso. RESULTS: Of the 6350 included, 791 (12.5%) reported RTI symptoms in the previous week. We classified serum 25(OH)D concentrations into quartiles and adjusted the data for current smoking habit and month of attendance. The prevalence of RTI symptoms did not increase with decreasing serum 25(OH)D level, was highest in quartile 3 (15.0%) followed by quartile 4 (12.4%), and was lowest in quartiles 1 and 2 (11.1% and 11.4%). There was no trend for increasing duration of illness with decreasing serum 25(OH)D. The prevalence of RTI symptoms was not significantly associated with the intake of fish, n-3 capsules or vitamin and/or mineral supplements, or sun exposure. Only use of cod-liver oil or fish oil capsules daily or sometimes was significantly associated with fewer RTI symptoms during the preceding 7 d (P = 0.04). CONCLUSIONS: Low serum 25(OH)D was not associated with increased prevalence of recent RTI symptoms. Our findings do not support the idea that vitamin D supplementation can reduce the incidence of RTI in Norway. PMID- 23659383 TI - Modification of interdomain interfaces within the A3C1C2 subunit of factor VIII affects its stability and activity. AB - Factor (F)VIII consists of a heavy chain [A1(a1)A2(a2)B domains] and a light chain [(a3)A3C1C2 domains]. Several reports have shown significant changes in FVIII stability and/or activity following selected mutations at the A1-A2, A1-A3, A2-A3, and A1-C2 domain interfaces. In this study, the remaining inter-FVIII subunit interfaces (A3-C1 and C1-C2) were examined for their contributions to the stability and activity of FVIII and FVIIIa. We prepared FVIII mutants with nascent disulfide bridges between A3 and C1 domains (Gly1750Cys/Arg2116Cys and Ala1866Cys/Ser2119Cys) or C1 and C2 domains (Ser2029Cys/Pro2292Cys). We also prepared mutants via replacement of Arg2116 with hydrophobic residues (Ala and Val) because this C1 domain residue appears to face a pocket of positive electrostatic potential in the A3 domain. Stability was assessed following the rates of loss of FVIII activity at 55 degrees C and the spontaneous loss of FVIIIa activity from A2 subunit dissociation. FVIII Gly1750Cys/Arg2116Cys showed a marked increase in thermal stability (~3.7-fold) compared with that of wild type (WT) FVIII, while the stability of FVIII Ala1866Cys/Ser2119Cys was reduced (~4.7-fold). Although the Ser2029Cys/Pro2292Cys variant showed a modest loss of FVIII stability, the specific activity and thrombin generation potential of this variant were increased (up to 1.2-fold) compared with those of WT. Furthermore, this variant demonstrated an ~2-fold reduced Km for FX. Mutation of Arg2116 to hydrophobic residues resulted in variable decreases in stability and thrombin generation parameters, suggesting a role of this Arg residue contributing to FVIII structure. Taken together, selective modification of the contiguous domain interfaces in the FVIII light chain may improve FVIII stability and/or cofactor function. PMID- 23659384 TI - High levels of CD20 expression predict good prognosis in chronic lymphocytic leukemia. AB - Heterogeneity of CD20 expression exists in chronic lymphocytic leukemia (CLL), therefore, we explored the prognostic significance of CD20 expression in Chinese patients with CLL. Multiparameter flow cytometry was used to detect the expression of CD20 in CD5(+) CD19(+) cells. In 172 CLL patients, the median expression percent of CD20 was 97.82% (range, 0-100), and the median mean fluorescence intensity (MFI) of CD20 in CLL cells was 731.45 (range, 0.00 9071.90). The percentage of CD20(+) cells in the patient group with mutated variable region of immunoglobulin genes (IGHV) was higher than in the non-mutant IGHV group (mean, 92.1% vs 80.4%, P < 0.001). There were no differences in the MFI of CD20(+) cells in all prognostic factor groups. Representation of the data using a receiver operating characteristic plot reflected separation between the two IGHV groups, with an area under the curve of 0.661 (95% confidence interval, 0.569-0.753). At the cut-off value of 60.3% for percentage of CD20, the sensitivity and specificity were 90.00% and 38.46%, respectively. Patients whose percentage of CD20 antigen was above 60.3% had longer treatment-free survival (hazard ratio, 0.452; 95% confidence interval, 0.232-0.884, P = 0.020). Percentage and MFI of CD20 were the variables not associated with treatment-free survival by multivariate Cox regression analysis (P < 0.05). High level of CD20 expression in de novo CLL appears to be associated with a good prognosis. PMID- 23659385 TI - 17beta-estradiol confers protection after traumatic brain injury in the rat and involves activation of G protein-coupled estrogen receptor 1. AB - Abstract Traumatic brain injury (TBI) is a significant public health problem in the United States. Despite preclinical success of various drugs, to date all clinical trials investigating potential therapeutics have failed. Recently, sex steroid hormones have sparked interest as possible neuroprotective agents after traumatic injury. One of these is 17beta-estradiol (E2), the most abundant and potent endogenous vertebrate estrogen. The goal of our study was to investigate the acute potential protective effects of E2 or the specific G protein-coupled estrogen receptor 1 (GPER) agonist G-1 when administered in an intravenous bolus dose 1 hour post-injury in the lateral fluid percussion (LFP) rodent model of TBI. The results of this study show that, when assessed at 24 hours post-injury, E2 or G-1 confers protection in adult male rats subjected to LFP brain injury. Specifically, we found that an acute bolus dose of E2 or G-1 administered intravenously 1 hour post-TBI significantly increases neuronal survival in the ipsilateral CA 2/3 region of the hippocampus and decreases neuronal degeneration and apoptotic cell death in both the ipsilateral cortex and CA 2/3 region of the hippocampus. We also report a significant reduction in astrogliosis in the ipsilateral cortex, hilus, and CA 2/3 region of the hippocampus. Finally, these effects were observed to be chiefly dose-dependent for E2, with the 5 mg/kg dose generating a more robust level of protection. Our findings further elucidate estrogenic compounds as a clinically relevant pharmacotherapeutic strategy for treatment of secondary injury following TBI, and intriguingly, reveal a novel potential therapeutic target in GPER. PMID- 23659386 TI - Relation of coronary flow reserve and diastolic function to fractional pulse pressure in hypertensive patients. AB - Fractional pulse pressure (PPf), is thought to more directly reflect arterial stiffness than pulse pressure. Our aim was to evaluate the relationship between coronary flow reserve (CFR), left ventricular diastolic function (LVDf) and PPf in hypertensive patients with normal coronary arteries. Out of 109 hypertensive patients (aged 52.8 +/- 9.4 years), with normal coronary angiography, CFR was calculated successfully in 106 patients. CFR was calculated using transthoracic echo Doppler assessment with hyperemia induced by infusion of dipyridamole at a rate of 0.56 mg/kg over 4 minutes, while diastolic function was evaluated by means of transmitral flow and tissue Doppler imaging. PPf was calculated as pulse pressure divided by mean arterial pressure [Systolic blood pressure - Diastolic blood pressure/Mean arterial pressure (SBP - DBP/MAP)], Hypertensive patients with low CFR (n = 54) compared with those with normal CFR (n = 52) exhibited significantly increased PPf (75.2 +/- 11.4 vs. 61.5 +/- 6.7 P < 0.001). Moreover, patients with higher PPf had significantly decreased transmitral E/A ratio (P < 0.01), as well as increased E/Em ratio (P < 0.01). In hypertensives with low CFR, PPf was negatively correlated with CFR (r = -0.815, P < 0.0001). After applying multivariate linear regression analysis, PPf turned out to be a powerful independent predictor of CFR. Receiver operating characteristic (ROC) analysis revealed that a PPf of >=0.63 was the best cutoff value for prediction of CFR <2.0 and E/Em >= 8 (AUC = 0.916 and 0.929 respectively; P < 0.001). Increased PPf was associated with impaired CFR and diastolic dysfunction in hypertensive patients with normal coronary arteries. PPf could be used as a simple non invasive index for assessment of coronary microcirculation in hypertensives with normal coronary arteries. PMID- 23659387 TI - 'My culture haunts me no matter where I go': Iranian-American women discussing sexual and acculturation experiences. AB - Iranian-American womens' perceptions of their sexual-selves and gender roles are influenced both by the cultural context of their life experience in Iran and their acculturation in the USA. In a qualitative study, using narrative as methodology and a feminist theoretical framework, individual interviews were conducted with 24 first-generation Iranian-American women in southern California. The narratives revealed that these Iranian-American women felt attached to their home culture while also having a desire to distinguish themselves from it. In so doing, they realised that their individual sexual-selves and gender roles stemmed from their life experiences, such as home culture memories and new cultural exposures. The degrees of adjustment during the acculturation process provided women with challenges in dealing with the consequences of new experiences and the shame and guilt of shedding old cultural norms. Acculturation offered these Iranian-American women a fuller understanding of their gender role and sexual self perceptions. An understanding of cultural impact on women's life experiences may assist healthcare professionals in their efforts to assist women in determining innovative intervention where the needs of gender role and sexual self-concept are concerned. PMID- 23659388 TI - Efficient access to 1,4-benzothiazine: palladium-catalyzed double C-S bond formation using Na2S2O3 as sulfurating reagent. AB - A novel Pd-catalyzed double C-S bond formation coupling reaction has been developed. This protocol, in which Na2S2O3 was used as sulfurating reagent in metal-catalyzed reactions, provides an efficient method for the synthesis of substituted 1,4-benzothiazine derivates, which are structural elements of numerous bioactivity molecules rendering this protocol attractive to both synthetic and medicinal chemistry. PMID- 23659389 TI - National anaesthesia mortality reporting in Australia from 1985-2008. AB - This article summarises the Australian national anaesthesia mortality data from 1985-2008, previously published in eight consecutive triennial reports and covering an estimated 50 million anaesthetics. The data were obtained using consistent definitions and methodology over a 24-year period. Anaesthesia-related mortality in Australia fell from about 1:36,000 anaesthetics in the 1985-1987 triennium to about 1:55,000 for the most recent reported 2006-2008 triennium. The percentage of the deaths considered anaesthesia-caused fell from about 50% of all anaesthesia-related deaths in the 1985-1987 triennium to about 15% of all anaesthesia-related deaths in the 2006-2008 triennium. The percentage of anaesthesia-related deaths considered non-preventable (no correctable anaesthetic factor identified) increased from about 4% in the 1991-1993 triennium to about 50% in the 2006-2008 triennium. There was also an increase in the proportion of deaths in which the patient's medical condition was considered a significant factor in the death over this period. While the trends are encouraging, they nevertheless suggest that additional efforts are required to further reduce 'preventable' anaesthetic deaths, and that continuing research and development into safer agents, techniques and approaches are required to reduce the incidence of deaths currently considered 'non-preventable'. PMID- 23659390 TI - Primary anaesthetic deaths in Western Australia from 1985-2008: causation and preventability. AB - This paper reports on the causes and preventability of primary anaesthetic deaths in Western Australia between 1985 and 2008. In Western Australia, it is a legal requirement to report all deaths that occur within 48 hours of an anaesthetic and later deaths if an anaesthetic complication is implicated. A committee assesses whether an anaesthetic factor caused the death (a primary anaesthetic death) or contributed to the death (an anaesthesia-related death). Of the 2361 deaths reported to the Committee over the 24-year period, 102 were considered anaesthesia-related and of these, 53 were considered a primary anaesthetic death. There were six main causes of primary anaesthetic death: failure to oxygenate; aspiration of gastric contents; adverse drug reaction; dose-related drug effect leading to an adverse cardiovascular event; intravascular injection of local anaesthetic; and injury related to an anaesthetic procedure or invasive monitoring. The most common cause was a dose-related drug effect leading to an adverse cardiovascular event. The medical condition of the patient was considered a significant contributing factor in 69% of the deaths and 72% were considered preventable. In the second 12-year period, there were fewer deaths overall (15 vs 38), proportionately fewer deaths related to failure to oxygenate (one vs six) and proportionately more deaths related to aspiration of gastric contents (four vs two). However, the percentage of deaths considered preventable was similar. These findings can be used to advise patients on anaesthetic risks, to educate anaesthetists about preventable deaths and to encourage the development of even safer anaesthetic drugs and techniques. PMID- 23659391 TI - The association between sedation practices and duration of mechanical ventilation in intensive care. AB - Choice of sedation agent may influence duration of mechanical ventilation in the intensive care unit (ICU). We conducted a retrospective observational analysis of 2102 consecutive mechanically ventilated ICU patients over an eight-year period at a Melbourne metropolitan hospital with a ten-bed general ICU to determine if propofol was associated with shorter duration of mechanical ventilation (MV) than midazolam. Data were extracted from the hospital administrative database, pharmacy supply order records and ICU database, to calculate rates of MV and tracheostomy, length-of-stay, propofol and midazolam infusion doses, illness severity and casemix and use of 'sedation scores' and 'sedation break' respectively. The primary end-points were duration of MV, tracheostomy rate and hospital outcome. Negative binomial regression and logistic regression were used to identify temporal trends. From 1 July 2002 to 30 June 2010 there were 5751 ICU admissions including 2102 (36.6%) with MV. Over this period there was a 70% decline in annual midazolam use and a greater than fivefold rise in propofol use. 'Sedation scoring' and 'sedation break' procedures were introduced from 2006. Over the eight-year observation period there were significant increases in the numbers of annual MV admissions and long-term (>96 hours) MV patients, but a decline in median duration of MV, tracheostomy rate, median ICU length-of-stay and median hospital length-of-stay. All temporal trends were significant (P <0.05). The temporal association with changes in sedation management practice, including primary sedative agent choice during MV, may explain these findings. PMID- 23659392 TI - The prevalence of anaemia, hypochromia and microcytosis in preoperative cardiac surgical patients. AB - This retrospective study aimed to determine the prevalence of preoperative anaemia, hypochromia and microcytosis in cardiac surgery patients. Data was analysed for 943 patients (over a two-year period) undergoing coronary artery bypass graft, valve or combined coronary artery bypass graft and valve surgery at a tertiary hospital in South Australia. Overall prevalence of preoperative anaemia was 25.2%, greater in males than females (27.6 vs 19.9%, P <0.01). Of patients with preoperative anaemia, 19.3% had reduced red cell indices (mean corpuscular haemoglobin and/or mean corpuscular volume) compared to 4% of patients without anaemia. The proportion of anaemic patients with low red cell indices was significantly higher in women <50 years and 50-65 years, compared to those >65 years of age (P=0.003). Anaemic patients with low red cell indices had lower preoperative haemoglobin than anaemic patients without low red cell indices (median haemoglobin 112 vs 120 g/l, P=0.008). Compared to non-anaemic patients, anaemic patients had higher transfusion rates (79.8 vs 46.4%, P <0.0001), which were greater in those with reduced red cell indices compared to those with normal red cell indices (93.5 vs 76.6%, P=0.01). This study demonstrated a high prevalence of preoperative anaemia, microcytosis and hypochromia in cardiac surgical patients. PMID- 23659393 TI - Can the presence of significant coagulopathy be useful to exclude symptomatic acute pulmonary embolism? AB - Thrombocytopenia or an abnormal coagulation profile is not rare in hospitalised patients who have symptoms consistent with acute pulmonary embolism (PE). Theoretically, coagulopathy is more likely to occur in patients with pneumonia than acute PE. This study aimed to assess whether the presence of coagulopathy could be used to exclude acute PE in patients with symptoms and signs consistent with acute PE. In this study, a significant coagulopathy was defined as a platelet count <100*10(9)/l, an international normalised ratio >1.5, or activated partial thromboplastin time >50 seconds. Patients treated with systemic anticoagulants prior to computed tomography pulmonary angiography were excluded. Of the 986 consecutive patients who required computed tomography pulmonary angiography to exclude acute PE over a four-month period in five hospitals in Western Australia, acute PE was confirmed in 149 patients (15.1%). The incidence of coagulopathy was not significantly different between those with and without acute PE (4 vs 7%, respectively; P=0.161) and between those with and without pneumonia (8 vs 7%, respectively; P=0.505). Positive and negative likelihood ratios of coagulopathy in differentiating acute PE or pneumonia were both unsatisfactory. As a continuous predictor, platelet counts, international normalised ratio, activated partial thromboplastin time and plasma fibrinogen concentrations were also not useful in differentiating between acute PE and other pulmonary pathologies (areas under the receiver operating characteristic curve were all close to 0.5). In conclusion, the presence of significant acquired coagulopathy cannot be used to suggest pneumonia or exclude symptomatic acute PE when the prevalence or pre-test probability of acute PE is not low. PMID- 23659394 TI - Effects of dexmedetomidine infusion on laryngeal mask airway removal and postoperative recovery in children anaesthetised with sevoflurane. AB - We investigated the effects of dexmedetomidine infusion on the end-tidal concentration of sevoflurane required for smooth removal of the laryngeal mask airway (LMA) and on the incidence of respiratory complications during postoperative recovery in paediatric patients anaesthetised with sevoflurane. Eighty-seven patients (ASA 1 or 2, aged 3-7 years) were randomly allocated to receive saline (Group C), 0.5 ug/kg dexmedetomidine (Group D(1)), or 1 ug/kg dexmedetomidine (Group D(2)) after LMA insertion. A predetermined end-tidal sevoflurane concentration for each patient was determined using the Dixon's up and-down method (starting at 2.2% and step was 0.2%). The LMA was removed after the predetermined concentration had been maintained stable for five minutes. Sevoflurane minimum alveolar concentration for smooth LMA removal and postoperative recovery were assessed. The end-tidal concentration of sevoflurane required for smooth LMA removal in 50% of children (MAC(LMA-RM)) in Group D(2) (0.84+/-0.15%) was significantly lower than in Group D(1) (1.39+/-0.20%; P=0.003), the latter being significantly lower than in Group C (1.73+/-0.14%; P <0.001). The incidence of breath-holding was significantly lower in Group D(2) (3%) than in Group C (27%; P=0.009), but comparable between Groups D(1) (17%) and C (P=0.385). The incidence of severe coughing was significantly lower in Groups D(1) (14%) and D(2) (6%) as compared to Group C (39%; P=0.005), but comparable between Groups D(1) and D(2) (P=0.323). In conclusion, dexmedetomidine infusion produced a dose-dependent decrease in the end-tidal concentration of sevoflurane required for smooth LMA removal in children and was associated less agitation in the post-anaesthetic care unit. PMID- 23659395 TI - How do anaesthetists in New Zealand disseminate critical airway information? AB - The communication of information concerning patients with difficult airways is universally recognised as an important component in avoiding future airway management difficulties. A range of options is available to impart this information; little is known however, about the follow-up patterns of anaesthetists following the identification and management of a difficult airway. In this study, 158 anaesthetists were contacted and asked to comment on their follow-up patterns regarding a number of difficult airway scenarios. This was followed by a retrospective survey of 124 patients with known difficult airways. A wide discrepancy was found between stated follow-up preferences by anaesthetists and the actual use of options such as postoperative visits, notes in the clinical record, letters to the patient and family doctor, and entries in hospital, national and MedicAlertTM databases. Of the patients with an airway difficulty noted on their anaesthetic record, only 14% of them also had a pertinent comment on their clinical record; even fewer were referred to hospital warning systems (12%) or national (6%) and MedicAlert (7%) databases. Comments from our survey were critical of multiple difficult airway databases and alert systems, which are not linked and do not lead automatically to a single source of information. We suggest that a custom-designed MedicAlert New Zealand difficult airway/intubation registry could be established, with easy access for medical practitioners and patients. This registry could be accessed through the National Health Index database and linked to the MedicAlert international registry and their nine international affiliates. PMID- 23659396 TI - Validating a process-of-care checklist for intensive care units. AB - Early evidence suggests that checklists are one way of ensuring required processes of care are delivered to intensive care unit patients. Evidence to date however, has not explicitly detailed methods of checklist validation in these settings. This study aimed to test the validity of a 'process-of-care' checklist for measuring and ensuring daily care delivery in an intensive care unit. A retrospective audit of a random selection of patient medical records was undertaken to compare with checklist data completed during the same time frame. Documentation in the patients' medical records was used as a proxy measure for actual completion of care. A specific audit tool extracted information from both the checklist and the medical record on the following processes of care: nutrition, weaning from ventilation, pain, glucose control, sit out of bed, bowel management, deep vein thrombosis and stress ulcer prophylaxis. These two data sources were compared using the Spearman's rho correlation coefficient. The two forms of documentation were significantly correlated (P=0.01) for all but one of the checklist items (pain). Findings provided support for the concurrent validity of an intensive care unit process-of-care checklist. Further research is required for checklist validity and reliability testing prior to, or in conjunction with, a planned prospective intervention study. PMID- 23659397 TI - Bench performance of ventilators during simulated paediatric ventilation. AB - This study compares the accuracy and capabilities of various ventilators using a paediatric acute respiratory distress syndrome lung model. Various compliance settings and respiratory rate settings were used. The study was done in three parts: tidal volume and FiO2 accuracy; pressure control accuracy and positive end expiratory pressure (PEEP) accuracy. The parameters set on the ventilator were compared with either or both of the measured parameters by the test lung and the ventilator. The results revealed that none of the ventilators could consistently deliver tidal volumes within 1 ml/kg of the set tidal volume, and the discrepancy between the delivered volume and the volume measured by the ventilator varied greatly. The target tidal volume was 8 ml/kg, but delivered tidal volumes ranged from 3.6-11.4 ml/kg and the volumes measured by the ventilator ranged from 4.1 20.6 ml/kg. All the ventilators maintained pressure within 20% of the set pressure, except one ventilator which delivered pressures of up to 27% higher than the set pressure. Two ventilators maintained PEEP within 10% of the prescribed PEEP. The majority of the readings were also within 10%. However, three ventilators delivered, at times, PEEPs over 20% higher. In conclusion, as lung compliance decreases, especially in paediatric patients, some ventilators perform better than others. This study highlights situations where ventilators may not be able to deliver, nor adequately measure, set tidal volumes, pressure, PEEP or FiO2. PMID- 23659398 TI - Has the middle-level anaesthesia manpower training program of the West African College of Surgeons fulfilled its objectives? AB - An audit of the West African College of Surgeons' middle-level Diploma in Anaesthesia program was carried out to determine the current status of the diplomates. Using the West African College of Surgeons' database, social media and personal communications, the current status of Diploma in Anaesthesia graduates spanning 20 years was determined. A total of 303 (97%) out of 311 of graduates were traced. Eighty percent were still practising anaesthesia, while 5% were now in other disciplines. Two hundred and four (67.3%) still resided in West Africa (183 in Nigeria, 50 in Ghana, one in Sierra Leone), while 69 (22.7%) were abroad: 35 (11.5%) in the United Kingdom, 21 (6.9%) in the United States of America and four (1.3%) in Canada. More Ghanaian than Nigerian graduates had emigrated (41 vs 14%, respectively). Only 9% of diplomates remained in rural communities (as originally envisaged), while 31% were now consultants (as fellows) and 30% were registrars in fellowship training. These findings indicate that most diplomates moved on to acquire further qualifications and a significant proportion migrated. The program did not appear to have achieved the objectives of meeting rural middle-level manpower needs in anaesthesia as envisaged. It has, however, boosted the recruitment drive for residency training in anaesthesia. Perhaps a less migrant cadre such as nurses may better serve this function if recruited into a suitably designed training program in countries desiring to use middle-level manpower in anaesthesia. PMID- 23659399 TI - Outcomes in critical care delivery at Jimma University Specialised Hospital, Ethiopia. AB - The aim of this study was to assess outcomes following intensive care unit (ICU) admissions at Jimma University Specialised Hospital, Ethiopia. This was a retrospective observational study. Data were collected regarding all ICU admissions and discharges during a 12-month period beginning August 2011. Demographic data and information regarding diagnosis, length-of-stay and outcome were gathered and data analysed. There were 370 admissions to the ICU during the study period. Median age (interquartile range) was 32.0 (22.0-47.0) years and 56.2% were males. The median length-of-stay (interquartile range) was 3.0 (1.0 7.0) days. The overall ICU mortality rate was 50.4% and major causes included trauma, cardiac disease, acute abdominal presentations, septic shock, tetanus and hysterectomy secondary to uterine rupture. Medical diagnoses accounted for 50.1% of admissions followed by surgery (43.2%) and obstetrics (5.8%). Corresponding mortality rates were 53.6, 48.0 and 42.9%, respectively. The main cause for surgical admission was trauma, with head injury carrying a mortality of 52.1%. The principal cause for medical admission was cardiac disease. In children, trauma, upper airway obstruction and communicable diseases were most common. Critical care mortality rates at this Ethiopian university hospital reflect the challenges facing critical care delivery in the developing world. Delayed presentation to hospital secondary to poor access to healthcare plays a predominant role. This is confounded by inadequate staffing, training, diagnostic and interventional limitations. Despite resource restraints, simple cost effective measures may improve morbidity and mortality. PMID- 23659400 TI - A survey of patient understanding and expectations of sedation/anaesthesia for colonoscopy. AB - One hundred and fifty-nine adult patients undergoing elective colonoscopy in a major regional hospital were surveyed regarding their perceptions and expectations of sedation/anaesthesia for this procedure. The survey was undertaken on the day of the procedure, but before their assessment by the anaesthetist. Most of our patients expected to be completely unconscious and few understood that there was any chance of being aware during any part of their colonoscopy procedure. The perception (level of knowledge) of patients about their sedation/anaesthesia was highly variable, and was influenced both by having had a prior colonoscopy and by having had a discussion with an anaesthetist prior to the day of procedure. Of a range of potential adverse outcomes, procedural awareness generated the highest level of concern. However, those patients who recognised the potential for procedural awareness reported significantly less concern about this potential occurrence than patients who were unaware of the possibility. Our findings suggest that explicit discussion of the possibility of procedural awareness during colonoscopy should be considered by clinicians who administer sedation or anaesthesia for colonoscopy. Knowledge of this potential source of patient confusion and anxiety may enable clinicians to better target the pre-procedural discussion, in order to more appropriately inform patient expectations. PMID- 23659401 TI - A survey of the management of neuromuscular blockade monitoring in Australia and New Zealand. AB - This survey of anaesthetists in Australia and New Zealand aimed to investigate their attitudes and practice relating to the management of neuromuscular blockade monitoring. All medical practitioner members (3188) of the Australian and New Zealand Societies of Anaesthetists were invited to complete an anonymous survey, which was available online for two months. A total of 678 survey questionnaires were completed (response rate 21%). Most respondents (71.4%) underestimated the incidence of residual neuromuscular blockade and 63.2% believed this to be a significant clinical problem. Objective monitoring of neuromuscular function was used routinely only by 17% of respondents, although 70% believed routine monitoring would reduce the incidence of residual neuromuscular blockade. Only 25% of respondents correctly indicated that quantitative train-of-four counts of greater than 90% were the accepted criteria for safe extubation, with 52% using clinical judgement only. Only 29% of respondents believed neuromuscular function monitors should be part of minimum monitoring standards; quantitative neuromuscular function monitors were not available in 42% of the hospitals in which the respondents practiced. Despite the low response rate, the large sample size and heterogeneity of respondents make the findings of this survey concerning. There is a need for more education, availability of appropriate monitoring equipment and evidence-based guidelines for management of neuromuscular blockade in Australia and New Zealand. PMID- 23659402 TI - Donation after cardiac death in non-survivable burns. AB - Major burns have previously been considered a contraindication to solid organ donation. We present two cases of successful organ donation and transplantation, after Maastricht category III cardiac death in adult patients with non-survivable burns injury. The implications of the outcome of these cases are that major burns should not be considered a contraindication to organ donation, and that cardiac death provides opportunity for patients with non-survivable burns to contribute to the pool of potential organ donors. PMID- 23659403 TI - Post-cardiac surgery thrombotic thrombocytopenic purpura with digital ischaemia. AB - We report a case of thrombotic thrombocytopenic purpura in a woman post mitral valve repair who presented with unexplained thrombocytopenia, intermittent fever, acute renal failure and severe digital ischaemia. The diagnosis of thrombotic thrombocytopenic purpura was confirmed after exclusion of many of the aetiological factors of postoperative digital ischaemia, a positive haemolytic screen and blood film examination which showed schistocytes and fragmented red cells. Plasma ADAMTS-13 activity measured by enzyme-linked immunosorbent assay was reduced. Treatment of thrombotic thrombocytopenic purpura with exchange plasmapheresis and methylprednisolone was of paramount importance and the patient was discharged home on day 30 with complete recovery of haematological, neurological and renal function. In order to increase the awareness of this rare multisystem process, we report our experience in managing this life-threatening condition. Our discussion covers the diagnostic challenges, theories on aetiology, pathogenesis and treatment of this condition in the context of cardiac surgery. PMID- 23659404 TI - Intraoperative awake tracheal intubation using the Airway ScopeTM in caesarean section. AB - The Airway ScopeTM, a novel videolaryngoscope used for tracheal intubation, is minimally invasive and can be used in conscious patients. The parturient with a potentially difficult airway should sometimes be intubated while awake, without anaesthesia or neuromuscular block. Two pregnant women who experienced massive postpartum haemorrhage during caesarean section underwent unscheduled intraoperative tracheal intubation using the Airway Scope. They were conscious and were intubated with minimal local anaesthesia so as to prevent cardiovascular compromise. We believe the Airway Scope is useful for anaesthetic procedures in the parturient who has haemodynamic instability. PMID- 23659405 TI - Spontaneous intracranial hypotension and epidural blood patch: a report involving seven cases. AB - Spontaneous intracranial hypotension is a rare condition caused by spontaneous cerebrospinal fluid leak. It is characterised by orthostatic headache, diffuse pachymeningeal enhancement on brain imaging and low cerebrospinal fluid pressure. Seven patients with spontaneous intracranial hypotension were treated conservatively: of these, four responded to drug treatment and three underwent a lumbar autologous epidural blood patch (EBP). A complete response was obtained in two patients after a single EBP; one patient underwent a second EBP and then became asymptomatic. Clinical improvement coincided with a dramatic reduction of pachymeningeal enhancement. The aetiology and brain imaging findings, and the technique and effectiveness of EBP are discussed. PMID- 23659406 TI - Pre-admission processes and opportunities for improvement. PMID- 23659407 TI - Pre-admission processes and opportunities for improvement - reply. PMID- 23659408 TI - Failed intubation and oxygenation in a child. PMID- 23659409 TI - Failed intubation and oxygenation in a child - reply. PMID- 23659410 TI - Anaesthesia training in a private healthcare facility. PMID- 23659411 TI - Dynamic ultrasound-guided, short axis, out-of-plane radial artery cannulation: the 'follow the tip' technique. PMID- 23659412 TI - Accidental intra-arterial dexmedetomidine injection in postoperative ward. PMID- 23659413 TI - C-MACTM Storz(r) videolaryngoscope for checking vocal cord mobility following thyroidectomy. PMID- 23659414 TI - Digoxin prescription in the critically ill: an unpredictably loaded problem? PMID- 23659415 TI - Sugammadex and general anaesthesia in a patient with Brugada syndrome. PMID- 23659416 TI - Serum lactate dehydrogenase as an early marker of posterior reversible encephalopathy syndrome: keep your eyes open on the score of severity brain oedema. PMID- 23659417 TI - Delirium and Takotsubo cardiomyopathy following cardiac surgery. PMID- 23659418 TI - Recycled and simplified anaesthesia machines for medical missions. PMID- 23659419 TI - Acute renal failure during the "off" period after sunitinib administration: possible mechanism of vascular endothelial growth factor cascade hyperactivation. PMID- 23659420 TI - Validation of antibiotic efficacy on in vitro subgingival biofilms. AB - BACKGROUND: Systemic antibiotics are often used as adjunctive treatment modalities for periodontal diseases. Testing of antimicrobial efficacy can be relevant only if the bacteria are in the form of biofilms rather than the planktonic state, and at concentrations of physiologic relevance, i.e., reachable in the periodontal pocket. The aim of the present study is to test the antimicrobial efficacy of five common antibiotic schemes at physiologically relevant concentrations on a multispecies in vitro biofilm model. METHODS: A 10 species in vitro subgingival biofilm model was exposed to metronidazole (15 MUg/mL), amoxicillin (15 MUg/mL), metronidazole and amoxicillin in combination, doxycycline (2 MUg/mL), and azithromycin (10 MUg/mL) over 24 hours. Species specific bacterial numbers were determined by culture on selective agar media or by epifluorescence microscopy. RESULTS: Metronidazole alone did not affect biofilm composition. Total bacterial counts were significantly reduced by doxycycline, azithromycin, and amoxicillin alone or in combination with metronidazole, albeit by less than 1 log. On the species-specific level, these regimens significantly reduced the numbers of Streptococcus anginosus, Porphyromonas gingivalis, and Fusobacterium nucleatum, as well as Campylobacter rectus (except for amoxicillin alone). The strongest effects were displayed by the combination of amoxicillin and metronidazole. CONCLUSION: Antibiotics at concentrations detectable in gingival crevicular fluid do not dramatically reduce total bacterial loads in this in vitro biofilm model, but cause species-specific reductions, which may disrupt the biofilm unity. PMID- 23659421 TI - Gingival crevicular fluid matrix metalloproteinase-8 levels predict treatment outcome among smokers with chronic periodontitis. AB - BACKGROUND: Molecular biomarkers are needed for diagnostic use in periodontal diseases. The aim of this study is to explore different gingival crevicular fluid (GCF) matrix metalloproteinase-8 (MMP-8) patterns in smokers and non-smokers with chronic periodontitis (CP) and test the utility of baseline GCF MMP-8 levels in predicting categorically assessed treatment outcomes. METHODS: The study population comprised 15 patients with CP (five non-smokers and 10 smokers). GCF sampling of five to seven periodontal sites per patient was done at baseline, post-treatment, and bimonthly during the maintenance period from 8 to 12 months. GCF MMP-8 levels were measured with an immunofluorometric assay. MMP-8 response patterns were explored by cluster analysis. The ability of baseline MMP-8 levels to predict categorical treatment outcomes was analyzed with receiver operating characteristic curves. RESULTS: GCF MMP-8 response patterns could be clustered into two different site profiles among both smokers and non-smokers. Smoker site profiles 1 and 2 had significantly different clinical attachment level and gingival recession changes by the end of the maintenance period. In smoker sites, baseline MMP-8 levels significantly predicted the categorical treatment outcome. CONCLUSIONS: Baseline GCF MMP-8 levels strongly predict how MMP-8 levels behave during the maintenance period. In smoker sites, high baseline MMP-8 levels indicate weak treatment response. PMID- 23659422 TI - Effect of glycemic control on self-perceived oral health, periodontal parameters, and alveolar bone loss among patients with prediabetes. AB - BACKGROUND: The effect of glycemic control on severity of periodontal inflammatory parameters in patients with prediabetes is unknown. The aim of the present study is to assess the effects of glycemic control on self-perceived oral health, periodontal parameters, and marginal bone loss (MBL) in patients with prediabetes. METHODS: A total of 303 individuals were included. Hemoglobin A1c (HbA1c) and fasting blood glucose levels (FBGLs) were recorded. Participants were divided into three groups: 1) group A: 75 patients with prediabetes (FBGLs = 100 to 125 mg/dL [HbA1c >=5%]); 2) group B: 78 individuals previously considered prediabetic but having FBGLs <100 mg/dL (HbA1c <5%) resulting from dietary control; and 3) control group: 150 medically healthy individuals. Self-perceived oral health, socioeconomic status, and education status were determined using a questionnaire. Plaque index (PI), bleeding on probing (BOP), probing depth (PD), and clinical attachment loss (AL) were recorded. Premolar and molar MBLs were measured on panoramic radiographs. RESULTS: Periodontal parameters (PI, BOP, PD, and AL) (P <0.01) and MBL (P <0.01) were worse among individuals in group A than those in group B. Self-perceived gingival bleeding (P <0.001), pain on chewing (P <0.001), dry mouth (P <0.001), and oral burning sensations (P <0.05) were worse among patients in group A than those in group B. There was no difference in periodontal parameters, MBL, and self-perceived oral symptoms among patients with prediabetes in group B and healthy controls. CONCLUSIONS: Self-perceived oral health, severity of periodontal parameters, and MBL are worse in patients with prediabetes than controls. Glycemic control significantly reduces the severity of these parameters as well as the state of prediabetes in affected individuals. PMID- 23659423 TI - Soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) in gingival crevicular fluid: association with clinical and microbiologic parameters. AB - BACKGROUND: Soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) belongs to the immunoglobulin superfamily and is involved in amplification of the inflammatory response to bacterial infection. This cross-sectional study aims to investigate the levels of sTREM-1 in gingival crevicular fluid (GCF) of individuals without periodontitis and with chronic periodontitis (CP) or generalized aggressive periodontitis (GAgP) and their association with the levels of key periodontal pathogens in subgingival plaque. METHODS: GCF and subgingival plaque samples were obtained from healthy sites of participants without periodontitis (n = 20) and periodontitis sites of patients with CP (n = 22) and GAgP (n = 20). sTREM-1 levels in GCF were measured by enzyme-linked immunosorbent assay. Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, and Aggregatibacter actinomycetemcomitans levels in subgingival plaque were analyzed by quantitative real-time polymerase chain reaction. RESULTS: sTREM-1 levels in GCF were higher in CP and GAgP than healthy sites by 3.6- and 4.4-fold, respectively, with no significant differences between the two forms of periodontitis. Moreover, sTREM-1 levels in GCF were positively correlated with site-specific clinical periodontal parameters and levels of P. gingivalis, T. denticola, and T. forsythia, but not A. actinomycetemcomitans, in subgingival plaque. CONCLUSION: Increased GCF levels of sTREM-1 at diseased sites and their positive correlation with clinical and microbiologic parameters strengthen the association of this inflammatory marker with periodontitis. PMID- 23659424 TI - Toll-like receptor 4 expression in trigeminal neurons is increased during ligature-induced periodontitis in rats. AB - BACKGROUND: Periodontitis, activated by oral bacteria and orchestrated by innate immune response, is regulated by primary nociceptive neurons, which are generally considered to have small- to medium-sized perikaryons. Bacterial byproducts (e.g., lipopolysaccharides) activate primary nociceptive neurons directly through Toll-like receptors (TLRs). Therefore, this study aims to morphometrically characterize rat trigeminal neurons, which express TLR4, and to investigate the changes in the TLR4 expression in neurons during periodontal inflammation. METHODS: Trigeminal neurons innervating gingivomucosa were identified by application of the retrograde tracer hydroxystilbamidine into the gingival sulcus of the maxillary molar in 14 rats. Periodontitis was induced by ligature around the same molar in seven rats. TLR4 expression was investigated by immunohistochemistry on paraffin sections of the trigeminal ganglia (TG). Semiquantitative method was used to identify the intensity of TLR4 expression. RESULTS: In the control group without the ligatures, TLR4 was detected in 19% of the neurons in the maxillary region of TG and in 29% of neurons innervating gingivomucosa. Expression of TLR4 was more frequent and intensive in small- to medium-sized neurons than in large-sized neurons. One week after ligature-induced periodontitis, the percentage of TLR4-positive neurons in the maxillary region and among the neurons innervating inflamed gingivomucosa significantly increased statistically to 32% and 41%, respectively. CONCLUSIONS: TLR4 is predominantly, but not exclusively, expressed in smaller trigeminal nociceptive neurons in the rat. Experimental periodontitis upregulates TLR4 expression in the trigeminal neurons. The hypothesis that bacterial byproducts regulate the pathogenesis of periodontitis by activation of trigeminal nociceptors through TLR4 should be explored. PMID- 23659425 TI - Antimicrobial resistance and prevalence of resistance genes of obligate anaerobes isolated from periodontal abscesses. AB - BACKGROUND: This study attempts to determine the antimicrobial resistance profiles of obligate anaerobic bacteria that were isolated from a periodontal abscess and to evaluate the prevalence of resistance genes in these bacteria. METHODS: Forty-one periodontal abscess samples were cultivated on selective and non-selective culture media to isolate the oral anaerobes. Their antibiotic susceptibilities to clindamycin, doxycycline, amoxicillin, imipenem, cefradine, cefixime, roxithromycin, and metronidazole were determined using the agar dilution method, and polymerase chain reaction assays were performed to detect the presence of the ermF, tetQ, nim, and cfxA drug resistance genes. RESULTS: A total of 60 different bacterial colonies was isolated and identified. All of the isolates were sensitive to imipenem. Of the strains, 6.7%, 13.3%, 16.7%, and 25% were resistant to doxycycline, metronidazole, cefixime, and amoxicillin, respectively. The resistance rate for both clindamycin and roxithromycin was 31.7%. Approximately 60.7% of the strains had the ermF gene, and 53.3% of the amoxicillin-resistant strains were found to have the cfxA gene. Two nim genes that were found in eight metronidazole-resistant strains were identified as nimB. CONCLUSIONS: In the present study, the Prevotella species are the most frequently isolated obligate anaerobes from periodontal abscesses. The current results show their alarmingly high resistance rate against clindamycin and roxithromycin; thus, the use of these antibiotics is unacceptable for the empirical therapy of periodontal abscesses. A brief prevalence of four resistance genes in the anaerobic bacteria that were isolated was also demonstrated. PMID- 23659426 TI - Differences in peri-implant microflora between fully and partially edentulous patients: a systematic review. AB - BACKGROUND: The current evidence suggests that the oral microflora differs between individuals who are fully edentulous (FES) and those who are partially edentulous (PES). It is unknown whether this leads to differences in peri-implant microflora when implants are installed. The aim of the study is to compare the submucosal peri-implant microflora between FES and PES. METHODS: A systematic review was conducted. The MEDLINE, Embase, and Cochrane databases were searched for publications up to September 1, 2012. To reduce methodologic variations, only studies reporting in the same article about the submucosal peri-implant microflora of FES and PES were selected. RESULTS: Eleven publications describing 10 studies were selected. Because of numerous differences among the selected studies, no meta-analysis could be performed. Six of 10 studies showed a significant difference in the composition of the submucosal peri-implant microflora in healthy and peri-implant mucositis conditions between FES and PES, with the latter showing a potentially more pathogenic composition. However, microbiologic results were not unanimous among the studies. CONCLUSIONS: In healthy and peri-implant mucositis conditions, PES harbor a potentially more pathogenic peri-implant microflora than FES. The current data are insufficient for a clear conclusion regarding peri-implantitis cases. Overall, because of the lack of a meta-analysis, the variability in microbiologic outcomes and the limited number of studies available, the current evidence seems not to be robust. PMID- 23659428 TI - Scaffold-divergent synthesis of ring-fused indoles, quinolines, and quinolones via iodonium-induced reaction cascades. AB - N-(2-Iodophenyl)imines A are readily formed from Schiff's base condensation of 2 iodoanilines with carbonyls and ketals. These imines provide useful substrates in scaffold-divergent synthesis through the attachment of an alkyne (Songashira coupling or acyl substitution of a Weinreb amide) followed by an iodonium-induced reaction cascade to give ring-fused indoles B, quinolines C, or quinolones D depending on the reaction conditions employed. PMID- 23659427 TI - Role of Kir6.2 subunits of ATP-sensitive potassium channels in endotoxemia induced cardiac dysfunction. AB - BACKGROUND: Cardiac dysfunction is well-described in endotoxemia and diagnosed in up to 60% of patients with endotoxic shock. ATP-sensitive potassium (KATP) channels are critical to cardiac function. This study investigates the role of Kir6.2 subunits of KATP channels on cardiac dysfunction in lipopolysaccharide (LPS)-induced endotoxemia. METHODS: Kir6.2 subunits knockout (Kir6.2-/-) and wild type (WT) mice were injected with LPS to induce endotoxemia. Cardiac function was monitored by echocardiography. Left ventricles were taken for microscopy (both light and electron) and TUNEL examination. Serum lactate dehydrogenase (LDH) and creatine kinase (CK) activities, and tumor necrosis factor-alpha (TNF-alpha) levels in both serum and left ventricular tissues were determined. RESULTS: Compared to WT, Kir6.2-/- mice showed significantly declined cardiac function 360 min after LPS administration, aggravated myocardial damage and elevated serum LDH and CK activities. Apoptotic cells were obviously increased in heart tissues from Kir6.2-/- mice at 90, 180 and 360 min. TNF-alpha expression in both serum and heart tissues of Kir6.2-/- mice was significantly increased. CONCLUSIONS: We conclude that Kir6.2 subunits are critical in resistance to endotoxemia-induced cardiac dysfunction through reducing myocardial damage by inhibition of apoptosis and inflammation. KATP channels blockers are extensively used in the treatment of diabetes, their potential role should therefore be considered in the clinic when patients treated with antidiabetic sulfonylureas are complicated by endotoxemia. PMID- 23659429 TI - Riboflavin requirements of white Pekin ducks from hatch to 21 d of age. AB - 1. A 2 * 8 factorial experiment containing different sexes (female and male) and 8 dietary riboflavin concentrations (1.2, 3.2, 5.2, 7.2, 9.2, 11.2, 13.2 and 15.2 mg/kg) was conducted to evaluate the riboflavin requirements of male and female White Pekin ducks from hatch to 21 d of age. 2. A total of 640 1-d-old Pekin ducks including 320 male and 320 female birds were randomly distributed into 80 wire-floor pens of 8 birds, sexed separately and with each treatment group containing 5 replicate pens. The birds were raised from hatch to 21 d of age. At 21 d of age, the weight gain, feed intake, feed conversion ratio and plasma and liver riboflavin were measured. 3. Growth depression, high mortality and low plasma and liver riboflavin were observed in riboflavin-deficient ducks, and these ill effects could be reduced by increasing dietary riboflavin concentrations. Weight gain, feed intake and riboflavin concentration in plasma and liver increased as dietary riboflavin increased. 4. According to broken-line regression analysis, the riboflavin requirements of modern breed of White Pekin ducks from hatch to 21 d of age for weight gain, feed conversion ratio, plasma riboflavin and liver riboflavin were 3.31, 5.20, 3.85 and 3.91 mg/kg for male and 3.27, 3.33, 3.84 and 3.28 mg/kg for female, respectively. Compared with female birds, more riboflavin was needed by male ducks, which may be because of significantly greater weight gain and liver riboflavin content of male ducks. PMID- 23659431 TI - Transgenerational effects of plant sex and arbuscular mycorrhizal symbiosis. AB - In gynodioecious plants, females are predicted to produce more and/or better offspring than hermaphrodites in order to be maintained in the same population. In the field, the roots of both sexes are usually colonized by arbuscular mycorrhizal (AM) fungi. Transgenerational effects of mycorrhizal symbiosis are largely unknown, although theoretically expected. We examined the maternal and paternal effects of AM fungal symbiosis and host sex on seed production and posterior seedling performance in Geranium sylvaticum, a gynodioecious plant. We hand-pollinated cloned females and hermaphrodites in symbiosis with AM fungi or in nonmycorrhizal conditions and measured seed number and mass, and seedling survival and growth in a glasshouse experiment. Females produced more seeds than hermaphrodites, but the seeds did not germinate, survive or grow better. Mycorrhizal plants were larger, but did not produce more seeds than nonmycorrhizal plants. Transgenerational parental effects of AM fungi were verified in seedling performance. This is the first study to show transgenerational mycorrhiza-mediated parental effects in a gynodioecious species. Mycorrhizal symbiosis affects plant fitness mainly through female functions with enduring effects on the next generation. PMID- 23659430 TI - Three-dimensional hierarchical plasmonic nano-architecture enhanced surface enhanced Raman scattering immunosensor for cancer biomarker detection in blood plasma. AB - A three-dimensional (3D) hierarchical plasmonic nano-architecture has been designed for a sensitive surface-enhanced Raman scattering (SERS) immunosensor for protein biomarker detection. The capture antibody molecules are immobilized on a plasmonic gold triangle nanoarray pattern. On the other hand, the detection antibody molecules are linked to the gold nanostar@Raman reporter@silica sandwich nanoparticles. When protein biomarkers are present, the sandwich nanoparticles are captured over the gold triangle nanoarray, forming a confined 3D plasmonic field, leading to the enhanced electromagnetic field in intensity and in 3D space. As a result, the Raman reporter molecules are exposed to a high density of "hot spots", which amplifies the Raman signal remarkably, improving the sensitivity of the SERS immunosensor. This SERS immunosensor exhibits a wide linear range (0.1 pg/mL to 10 ng/mL) and a low limit of detection (7 fg/mL) toward human immunoglobulin G protein in the buffer solution. This biosensor has been successfully used for detection of the vascular endothelial growth factor in the human blood plasma from clinical breast cancer patient samples. PMID- 23659432 TI - Concentrations of aroma compounds and odor activity values of odorant series in different olive cultivars and their oils. AB - Olives from Picual, Arbequina, Manzanilla de Sevilla, and Local cultivars together with their corresponding oils were analyzed in terms of odor activity values (OAVs) to establish the relationship between the aromatic profile of both olives and oils. The OAVs for the different compounds were classified in nine odorant series: grass, leaf, wood, bitter, sweet, pungent, olive fruit, apple, and banana. The total intensities for every aromatic series were calculated as the sum of the OAVs of each compound associated with this series. As a result, olives had characteristic profiles. Picual cultivar had not a clear sensory characterization from the volatile compounds. Arbequina cultivar was mainly characterized by apple and bitter odorant series; Manzanilla de Sevilla by apple, bitter, and grass odorant series; and Local variety by banana and olive fruit. However, in the oils obtained from those olives, these differences disappeared, and all oils showed the same profile with pungent, bitter, and wood odorant series most strongly contributing. PMID- 23659433 TI - Anomalous location of the vertebral artery in relation to the neural foramen. Implications for cervical transforaminal epidural steroid injections. AB - OBJECTIVES: Evaluate the prevalence of an anomalous posterior vertebral artery (VA) in the neural foramen and to see if any factors might correlate with proximity of the VA to needle location in a cervical transforaminal epidural steroid injection (CTFESI). METHODS: A radiologist with subspecialty training in neuroradiology documented VA location in relation to the neural foramen on axial views of 198 consecutive computed tomography angiograms done for various reasons, 11 were excluded because of poor imaging or occluded VA. The levels of C2-3 through C6-7 were evaluated, where the VA courses within the foramen. The distance was measured from VA to ideal needle location for a CTFESI. Other data were collected including severity of foraminal stenosis, loss of disc height, and medical history. Analysis was done to see if any factor correlated with anomalous VA location. RESULTS: The VA was in the posterior foramen and within 2 mm of ideal needle location in at least one location in 29% of patients. When looking at the more commonly injected levels of C4-5 through C6-7, the prevalence was 18%. Severity of foraminal stenosis and loss of disc height correlated with VA proximity to typical needle location (both with P < 0.0001). CONCLUSION: The VA can sometimes be in close proximity to the typical target location of a CTFESI. This proximity correlates with severity of foraminal stenosis and loss of disc height. Physicians should be mindful of this and evaluate the T2 axial magnetic resonance imaging before doing CFTESIs. PMID- 23659434 TI - Cytotoxic constituents from Psoralea corylifolia. AB - Bioassay directed isolation of the EtOAc extract from a traditional Chinese medicine Psoralea corylifolia resulted in the purification of two isoflavonoids, corylifols D (1) and E (2), along with four known ones. The structures of 1 and 2 were determined by extensive 1D and 2D NMR and MS data analyses. When tested against HepG2 and Hep3B hepatocellular carcinoma cell lines, corylifol A (4) displayed IC50 values of 4.6 and 13.5 MUg/ml, respectively. PMID- 23659435 TI - Screening houses for vapor intrusion risks: a multiple regression analysis approach. AB - The migration of chlorinated volatile organic compounds from groundwater to indoor air-known as vapor intrusion-can be an important exposure pathway at hazardous waste sites. Because sampling indoor air at every potentially affected home is often logistically infeasible, screening tools are needed to help identify at-risk homes. Currently, the U.S. Environmental Protection Agency (EPA) uses a simple screening approach that employs a generic vapor "attenuation factor," the ratio of the indoor air pollutant concentration to the pollutant concentration in the soil gas directly above the groundwater table. At every potentially affected home above contaminated groundwater, the EPA assumes the vapor attenuation factor is less than 1/1000--that is, that the indoor air concentration will not exceed 1/1000 times the soil-gas concentration immediately above groundwater. This paper reports on a screening-level model that improves on the EPA approach by considering environmental, contaminant, and household characteristics. The model is based on an analysis of the EPA's vapor intrusion database, which contains almost 2,400 indoor air and corresponding subsurface concentration samples collected in 15 states. We use the site data to develop a multilevel regression model for predicting the vapor attenuation factor. We find that the attenuation factor varies significantly with soil type, depth to groundwater, season, household foundation type, and contaminant molecular weight. The resulting model decreases the rate of false negatives compared to EPA's screening approach. PMID- 23659436 TI - gammadelta T cell receptor deficiency attenuated cardiac allograft vasculopathy and promoted regulatory T cell expansion. AB - gammadelta T cell comprises about 5% of the overall T cell population, and they differ from conventional alphabeta T cells. Previous studies have indicated the contribution of gammadelta T cell to acute allograft rejection, but the role of gammadelta T cell in cardiac allograft vasculopathy (CAV) is not investigated. Hearts of adult B6.C-H-2(bm12) KhEg were heterotopically transplanted into major histocompatibility complex (MHC) class II-mismatched C57BL/6 mice (wild-type, gammadelta TCR(-/-)), which is an established murine model of chronic allograft rejection without immunosuppression. The survival of grafts was monitored daily by abdominal palpation until the complete cessation of cardiac contractility. Our current study demonstrated that gammadelta T cell receptor (TCR) deficiency significantly attenuated CAV, and this effect coincides with low expression of Hmgb1, IFN-gamma and IL-17 while increased number of CD4(+) CD25(+) Foxp3(+) regulatory T cells, and depletion of regulatory T cells abrogated the prolonged allograft survival induced by gammadelta TCR deficiency. gammadelta TCR deficiency resulted in attenuated CAV and prolonged graft survival in murine models of cardiac transplantation, and this effect was associated with enhanced expansion of regulatory T cells. PMID- 23659437 TI - Prosocial peer affiliation suppresses genetic influences on non-aggressive antisocial behaviors during childhood. AB - BACKGROUND: Available research has suggested that affiliation with prosocial peers reduces child and adolescent antisocial behavior. However, the etiologic mechanisms driving this association remain unclear. The current study sought to evaluate whether this association takes the form of a gene-environment interaction (G * E) in which prosocial peer affiliation acts to reduce the consequences of genetic risk for non-aggressive antisocial behavior during childhood. METHOD: Our sample consisted of 500 twin pairs aged 6-10 years from the Michigan State University Twin Registry (MSUTR). RESULTS: The results robustly support moderation by prosocial peer affiliation. Genetic influences on non-aggressive antisocial behavior were observed to be several times larger in those with lower levels of prosocial peer affiliation than in those with higher levels of prosocial peer affiliation. This pattern of results persisted even after controlling for gene-environment correlations and deviant peer affiliation, and when restricting our analyses to those twins who shared all or nearly all of their friends. CONCLUSIONS: Such findings not only suggest that prosocial peer affiliation moderates genetic influences on non-aggressive antisocial behaviors during childhood but also provide support for the theoretical notion that protective environmental experiences may exert their influence by promoting resilience to genetic risk. PMID- 23659438 TI - A loss in cellular protein partners promotes alpha-synuclein aggregation in cells resulting from oxidative stress. AB - There is a consensus that oxidative stress promotes neurodegeneration and may be linked to plaque formation. alpha-Synuclein is the main component of neurodegenerative plaques. We have found that alpha-synuclein binds strongly to the enzyme phospholipase Cbeta1 (PLCbeta1) in vitro and in cells affecting both its G protein activation and its degradation. Because PLCbeta1 binds to alpha synuclein in cells, we tested whether decreasing its level would promote alpha synuclein aggregation and whether overproducing PLCbeta1 would inhibit aggregation. By imaging fluorescent alpha-synuclein in living HEK293, PC12, and SK-H-SH cells, we find that alpha-synuclein aggregation is directly related to the level of PLCbeta1. Importantly, we found that oxidative stress does not affect the cellular levels of alpha-synuclein but results in the down-regulation of PLCbeta1 thereby promoting alpha-synuclein aggregation. A peptide that mimics part of the alpha-synuclein binding site to PLCbeta prevents aggregation. Our studies indicate that PLCbeta1 can reduce cell damage under oxidative stress and offers a potential site that might be exploited to prevent alpha-synuclein aggregation. PMID- 23659439 TI - Effects of the hierarchical structure of rough solid surfaces on the wetting of microdroplets. AB - We used the lattice Boltzmann method to investigate how the hierarchical structure of a rough solid surface, which in this work is modeled as the microstructure (micropillars) covered with nanostructures (nanopillars), affects the contact angle of microdroplets atop of the solid surface and the wetting transition between the Wenzel and Cassie states. Our simulation results show that the Wenzel-to-Cassie state transition can be achieved by decreasing the fluid solid attraction, increasing the micropillar spacing, or coating the microstructures with nanostructures. For the effect of the hierarchical structure on the contact angle, we find that the micropillars show a negligible effect on the contact angle, but they may affect the sliding angle. In contrast, it is the nanostructure that determines the contact angle. The contact angle increases with the nanopillar length until reaching a maximal value, but its dependence on the nanopillar spacing becomes more complicated. The contact angle may first increase with the nanopillar spacing and then decreases, or decreases monotonously, depending on whether the liquid enters the nanostructure or not. In this work, we also demonstrate in the presence of contact line pinning, that the pinning effect affects the apparent contact angle. PMID- 23659440 TI - Socio-cultural predictors of injuries: life-course experience of hospitalised injuries during the past century in the Velestino study. AB - Retrospective reviews provide unique opportunity to assess changing approaches to trauma in recent history and identify modifiable behaviours through the lessons of the past. The objective of this paper is to depict the nearly one-century long, life-course injury experience of seniors residing in Velestino, an agricultural Greek town, and comment on neglected determinants and transitional patterns following historical and socio-cultural events in the area. The life course experience of non-fatal injuries, requiring hospitalisation, has been reported by N = 643 study participants, aged 65-102 years. Injuries were grouped and assessed in three ways: chronologically, by body part and by type. Overall, 124 injuries have been recorded over the past 70 years; the majority sustained by men (58.6%), and the highest number of injuries occurred during the recent decades, 1980s-1990s. For the age groups 26-45 and 46-65 years old, traffic (37.5% and 22.2%) and occupational (25.0% and 22.2%) events have been the commonest cause of injury, whereas injuries occurring at home were primary hazard (25.8%) for the elderly. Moreover, meaningful historical connections with warfare and migration movements were made. In retrospect, socio-cultural factors emerge as important predictors of certain injuries, pointing to the number of factors that should be taken into account when designing injury-prevention programmes. PMID- 23659441 TI - Influences on loneliness, depression, sexual-risk behaviour and suicidal ideation among Thai transgender youth. AB - This study examined the influence of age, education level and number of sex partners on levels of loneliness, depression, suicidal ideation and sexual-risk behaviour in Thai male-to-female transgender youth. A total of 190 participants filled in the study's questionnaire, designed to tap the primary variables of age, level of education, number of sex partners, loneliness, depression, suicidal ideation and sexual-risk behaviour. Results reveal that level of education has a significant influence on depression and loneliness, the number of sex partners has a significant influence on sexual-risk behaviour and suicidal ideation and age has a significant influence on sexual-risk behaviour and suicidal ideation. Participants with higher levels of education reported more loneliness than participants who did not graduate from high school. In addition, participants who did not graduate from high school reported more depression than participants with some university credit. Furthermore, participants aged 15 to 19 years, compared with those of 20 to 25 years, reported higher level of sexual-risk behaviour and higher levels of suicidal ideation. PMID- 23659442 TI - Combined administration of FVIII and rFVIIa improves haemostasis in haemophilia A patients with high-responding inhibitors--a thrombin generation-guided pilot study. AB - Treatment of haemophilia A patients with inhibitors is challenging, and may require individually tailored regimens. Whereas low titre inhibitor patients may respond to high doses of factor VIII (FVIII), high-responding inhibitor patients render replacement therapy ineffective and often require application of bypassing agents. Thrombin generation (TG) assays may be used to monitor haemostasis and/or predict patients' response to bypass agents. In this study we defined by TG, the potential contribution of FVIII to recombinant activated factor VII (rFVIIa) induced haemostasis in inhibitor plasma. Based upon results, prospectively designed individual regimens of coadministration of rFVIIa and FVIII were applied. Plasma samples from 14 haemophilia patients with inhibitors (including high titre inhibitors) were tested. The response to increasing concentrations of FVIII, rFVIIa or both was assayed by TG. Eight patients, chosen following consent and at physician's discretion, comprised the combined FVIII-rFVIIa therapy clinical study cohort. Combined spiking with FVIII/rFVIIa improved TG induced by rFVIIa alone in all inhibitor plasmas. Combined rFVIIa and FVIII therapy was applied during bleeding or immune tolerance to eight patients, for a total of 393 episodes. Following a single combined dose, 90% haemostasis was documented and neither thrombosis nor any complications evolved. During study period decline of inhibitor levels and bleeding frequency were noted. Pre-analytical studies enabled us to prospectively tailor individual therapy regimens. We confirmed for the first time that the in vitro advantage of combining FVIII and rFVIIa, indeed accounts for improved haemostasis and may safely be applied to inhibitor patients. PMID- 23659443 TI - In vivo and in vitro antineoplastic actions of caffeic acid phenethyl ester (CAPE): therapeutic perspectives. AB - Cancer prevention and treatment strategies have attracted increasing interest. Caffeic acid phenethyl ester (CAPE), an active component of propolis extract, specifically inhibits NF-kappaB at MUM concentrations and shows ability to stop 5 lipoxygenase-catalyzed oxygenation of linoleic acid and arachidonic acid. Previous studies have demonstrated that CAPE exhibits antioxidant, antiinflammatory, antiproliferative, cytostatic, antiviral, antibacterial, antifungal, and, most improtantly, antineoplastic properties. The primary goal of the present review is to summarize and critically evaluate the current knowledge regarding the anticancer effect of CAPE in different cancer types. PMID- 23659445 TI - Egg consumption and risk of bladder cancer: a meta-analysis. AB - The findings of epidemiologic studies on the association between egg consumption and bladder cancer risk remain conflicting. We conducted a meta-analysis to clarify the potential association between egg consumption and bladder cancer risk. Four cohort studies and 9 case-control studies in the PubMed database through February 2012 were identified on egg consumption and risk of bladder cancer involving 2715 cases and 184,727 participants. Random-effects models were used to calculate the summary relative risk estimates (SRRE) based on the highest compared with the lowest category of egg consumption. In addition, we performed stratified analyses and sensitivity and dose-response analyses to examine the association. Overall, no significant association was observed between egg consumption and bladder cancer (SRRE = 1.11 95% CI: 0.90-1.35). However, increased risk of bladder cancer was detected in North/South America (SRRE = 1.40 95% CI: 1.05-1.86) and, moreover, fried egg intake positively associated with bladder cancer as well (SRRE = 2.04, 95% CI: 1.41-2.95). In conclusion, our findings suggest no significant association between egg consumption and bladder cancer risk, except for a possible positive relationship with the intake of fried eggs based on the limited number of studies. Additional studies, especially large prospective cohort studies, are warranted to confirm these findings. PMID- 23659444 TI - The effects of soy consumption before diagnosis on breast cancer survival: the Multiethnic Cohort Study. AB - This study tested the hypothesis that prediagnostic soy intake was inversely associated with all-cause and breast cancer-specific mortality. The analyses included 3842 women in the Multiethnic Cohort (MEC) study of African Americans, Native Hawaiians, Japanese Americans, Latinos, and Caucasians, who completed a quantitative food frequency questionnaire, aged >=50 yr at cohort entry, and diagnosed with primary invasive breast cancer following cohort entry (1993-2007). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated from Cox proportional hazards regression with adjustment for known clinical and lifestyle factors. During a mean follow-up after diagnosis of invasive breast cancer of 6.2 +/- 3.8 yr, there were 804 deaths including 376 breast cancer-specific deaths. The HR (95%CI) for all-cause and breast cancer-specific morality comparing the highest versus lowest tertiles were 1.03 (0.81-1.33) and 1.03 (0.71-1.50) for soy products and 0.99 (0.82-1.20) and 0.95 (0.71-1.28) for total isoflavones, respectively (Ptrend > 0.60 for all). There was limited evidence of differences by hormone receptor status, tumor stage, or ethnic group. Prediagnostic soy intake was unrelated to mortality in postmenopausal women. Our findings are consistent with the literature that soy consumption does not adversely affect breast cancer survival in women. PMID- 23659446 TI - Dietary quality, caloric intake, and adiposity of childhood cancer survivors and their siblings: an analysis from the cardiac risk factors in childhood cancer survivors study. AB - Childhood cancer survivors are at increased risk of cardiovascular disease, in part because of adiposity. Whether survivors have healthy diets and whether dietary quality is associated with adiposity among survivors are not known. Survivors and siblings from the Cardiac Risk Factors in Childhood Cancer Survivors Study completed 3-day food records that were used to estimate daily caloric intake relative to recommended and dietary quality using the Healthy Eating Index-2005 (HEI). Medical records were reviewed for cancer therapies. Body composition was measured by dual-energy x-ray absorptiometry. Of 91 childhood cancer survivors and 30 sibling controls, there were no marked differences in mean daily caloric intakes (98% vs. 100% of recommended) or HEI total scores (55.5 vs. 53.3), respectively, with both groups scoring worst for the consumption of dark green vegetables and whole grains. Survivors exposed to cranial irradiation had lower total HEI scores (-6.4, P = 0.01). Among survivors, better dietary quality, as reflected by the total HEI score, was associated with decreasing percent body fat (beta = -0.19, P = 0.04). Survivors consume diets similar to their siblings although these diets are only moderately adherent to current guidelines. Decreased dietary quality is associated with higher body fat and receipt of cranial irradiation in survivors. PMID- 23659447 TI - A low dietary ratio of omega-6 to omega-3 Fatty acids may delay progression of prostate cancer. AB - Prostate cancer (PCa) is the second leading cause of cancer-related deaths in men. Studies show that consumption of polyunsaturated fatty acids (PUFA) modulates the development and progression of prostate cancer. High amounts of omega-6 fatty acids have been linked with increased prostate cancer risk, whereas omega-3 fatty acids have been shown to inhibit PCa growth. However, because omega 3 and omega-6 are both essential fatty acids and part of a complete diet, it is more relevant to determine the ideal ratio of the two that would allow patients to benefit from the therapeutic properties of omega-3 fatty acids. LNCaP prostate cancer cells were treated with dietary-based ratios of omega-6 to omega-3 fatty acids under hormone-deprivation conditions, and effects on various cellular processes were determined. A low omega-6 to omega-3 PUFA ratio can delay the progression of cells toward castration-resistance by suppressing pathways involved in prostate cancer progression, such as the Akt/mTOR/NFkappaB axis. It also suppresses the expression of cyclin D1, and activation of caspase-3 and annexin V staining shows induction of proapoptotic events. Taken together, our data demonstrates that maintaining a low omega-6 to omega-3 fatty acids ratio can enhance efficacy of hormone ablation therapy. PMID- 23659448 TI - Supplementation with selenium-enriched yeast attenuates brain metastatic growth. AB - Metastases are the leading cause of cancer mortality and their development may be affected by diet. The aim of this study was to compare the effects of dietary supplementation with different selenium (Se) compounds on the dynamics of brain metastasis development in a novel mouse model. Mice were fed experimental diets enriched (1 mg/kg) with sodium selenite (Se-S), seleno-1-methionine (Se-Meth), a yeast-derived organic form of selenium (Se-Yeast), or a control diet (Se < 0.05 mg/kg) for 20 wk. At the end of the feeding period, animals were injected with luciferase-tagged K1735 (K1735-Luc) melanoma cells into the brain vasculature. The development of brain metastatic tumors was monitored for 2 wk following injection. Mice bearing brain metastatic tumors and fed Se-Yeast- or Se-S enriched diets displayed a higher survival rate compared with other experimental and control groups. Importantly, Se-Yeast supplementation decreased the growth of brain metastatic tumors as determined by the measurement of the intensity of the bioluminescent signal emitted by K1735-Luc cells upon reaction with luciferin. Different chemical forms of Se have distinct effects on the development of brain metastases. Organic Se in the form of Se-Yeast may be a valuable agent in suppression of brain metastatic disease. PMID- 23659449 TI - Lack of protective effects of zinc gluconate against rat colon carcinogenesis. AB - Zinc has been proposed as a promising chemopreventive candidate against colon cancer. However, few studies on the potential beneficial effects of this trace element on cancer chemoprevention are available. The present study was designed to investigate the potential modifying influence of zinc gluconate (ZnGly) on the initiation step of colon carcinogenesis induced by 1,2-dimethylhydrazine (DMH). Male Wistar rats received orally ZnGly (15 mg elemental zinc/kg, 3 times per wk) 2 wk before and during DMH treatment (3 * 40 mg/kg, once a wk). The animals were euthanized at the end of 4th and 16th wk. Colons were analyzed for aberrant crypt foci (ACF) and tumor development. Blood and colon zinc levels, cell proliferation, and apoptosis indexes in colonic crypts were analyzed 24 h after the last DMH administration. Oral treatment with ZnGly did neither alter the number of ACF nor the indexes of cell proliferation and apoptosis in the colonic mucosa. The incidence and multiplicity of colon tumors induced by DMH and their histopathological patterns were not modified by previous treatment with ZnGly. These findings indicate a lack of chemopreventive action of zinc gluconate supplementation on the initiation step of rat colon carcinogenesis induced by DMH. PMID- 23659450 TI - Inhibitory effects of isoflavones on tumor growth and cachexia in newly established cachectic mouse models carrying human stomach cancers. AB - Cachexia, a negative prognostic factor, worsens a patient's quality of life. We established 2 novel cachexia models with the human stomach cancer cell line MKN 45, which was subcloned to produce potent cachexia-inducing cells by repeating the xenografts in immune-deficient mice. After subsequent xenografts, we isolated potent cachexia-inducing cells (MKN45cl85 and 85As2mLuc). Xenografts of MKN45cl85 cells in mice led to substantial weight loss and reduced adipose tissue and musculature volumes, whereas xenografts of 85As2mLuc cells resulted in highly metastatic and cachectic mice. Surgical removal of tumor tissues helped the mice regain body-weight in both mouse models. In vitro studies using these cells showed that isoflavones reduced their proliferation, implying that the isoflavones possess antiproliferative effects of these cancer cell lines. Isoflavone treatment on the models induced tumor cytostasis, attenuation of cachexia, and prolonged survival whereas discontinuation of the treatment resulted in progressive tumor growth and weight loss. The inhibitory effects of tumor growth and weight loss by isoflavones were graded as soy isoflavone aglycone AglyMax > daidzein > genistein. These results demonstrated that the 2 novel cachectic mouse models appear useful for analyzing the mechanism of cancer cachexia and monitoring the efficacy of anticachectic agents. PMID- 23659451 TI - Multitargeting and antimetastatic potentials of silibinin in human HepG-2 and PLC/PRF/5 hepatoma cells. AB - Hepatocellular carcinoma (HCC) is the most common sort of primary liver malignancy with poor prognosis. This study aimed at examining the effects of silibinin (a putative antimetastatic agent) on some transcriptional markers mechanistically related to HCC recurrence and metastasis in HepG-2 [hepatitis B virus (HBV)-negative and P53 intact) and PLC/PRF/5 (HBV-positive and P53 mutated) cells. The expression of 27 genes in response to silibinin was evaluated by real time RT-PCR. The MMP gelatinolytic assay and microculture tetrazolium test (MTT) were tested. Silibinin was capable of suppressing the transcriptional levels of ANGPT2, ATP6L, CAP2, CCR6, CCR7, CLDN-10, cortactin, CXCR4, GLI2, HK2, ID1, KIAA0101, mortalin, PAK1, RHOA, SPINK1, and STMN1 as well as the enzymatic activity of MMP-2 but promoted the transcripts of CREB3L3, DDX3X, and PROX1 in both cells. Some significant differences between the cells in response to silibinin were detected that might be related to the differences of the cells in terms of HBV infection and/or P53 mutation, suggesting the possible influence of silibinin on HCC through biological functions of these 2 prognostic factors. In conclusion, our findings suggest that silibinin could potentially function as a multitargeting antimetastatic agent and might provide new insights for HCC therapy particularly for HBV-related and/or P53-mutated HCCs. PMID- 23659452 TI - beta-ionone induces cell cycle arrest and apoptosis in human prostate tumor cells. AB - 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase is the rate-limiting activity in the mevalonate pathway that provides essential intermediates for posttranslational modification of growth-associated proteins. Assorted dietary isoprenoids found in plant foods suppress HMG CoA reductase and have cancer chemopreventive activity. beta-Ionone, a cyclic sesquiterpene and an end-ring analog of beta-carotene, induced concentration-dependent inhibition of the proliferation of human DU145 (IC50 = 210 MUmol/L) and LNCaP (IC50 = 130 MUmol/L) prostate carcinoma cells and PC-3 prostate adenocarcinoma cells (IC50 = 130 MUmol/L). Concomitantly, beta-ionone-induced apoptosis and cell cycle arrest at the G1 phase in DU145 and PC-3 cells were shown by fluorescence microscopy, flow cytometry, and TUNEL reaction, and downregulation of cyclin-dependent kinase 4 (Cdk4) and cyclin D1 proteins. Growth suppression was accompanied by beta-ionone induced downregulation of reductase protein. A blend of beta-ionone (150 MUmol/L) and trans, trans-farnesol (25 MUmol/L), an acyclic sesquiterpene that putatively initiates the degradation of reductase, suppressed the net growth of DU145 cells by 73%, an impact exceeding the sum of those of beta-ionone (36%) and farnesol (22%), suggesting a synergistic effect. beta-ionone, individually or in combination with other HMG CoA reductase suppressors, may have potential in prostate cancer chemoprevention and/or therapy. PMID- 23659453 TI - Role of di-allyl disulfide, a garlic component in NF-kappaB mediated transient G2 M phase arrest and apoptosis in human leukemic cell-lines. AB - Diallyl disulfide (DADS), the major organosulfur component of processed garlic is very effective in chemoprevention of several types of cancers; however, its detailed mechanism is yet to be divulged. Present study shows antiproliferative activity of DADS against human leukemic cell-lines, mainly U937. DADS induced transient G2/M phase arrest, which is evident from FACS analysis. The results revealed that a significant transcriptional induction of p21 happened in early hours of treatment, which is due to increased nuclear translocation of NF-kappaB and its specific binding to p21 promoter. However, in the later hours, G2/M arrest is lost leading to apoptosis via intrinsic mitochondria-mediated pathway through generation of reactive oxygen species followed by changes in mitochondrial membrane potential. Western blots indicate release of cytochrome-c, activation of caspase-3, cleavage of PARP1, and finally decrease in bcl-2 levels. In addition, inactivation of NF-kappaB by its inhibitor BAY 11-7085 causes early onset of apoptosis without any transient G2/M arrest. Thus, in conclusion, DADS induces reversible G2/M arrest through NF-kappaB mediated pathway in human leukemic cell lines, like U937, K562, and Jurkat, lacking wild type p53. However, G2/M arrest is lost owing to the incapability of the damage repair system that leads to apoptosis. PMID- 23659454 TI - Emerging antineoplastic effects of garcinol besides role in inhibiting growth in pancreatic carcinomas. PMID- 23659455 TI - Liquid-phase gallium-indium alloy electronics with microcontact printing. AB - Liquid-phase electronic circuits are patterned on an elastomer substrate with a microcontact printer. The printer head dips into a pool of a liquid-phase gallium indium alloy, e.g., eutectic gallium-indium (EGaIn) or gallium-indium-tin (Galinstan), and deposits a single drop on a silicone elastomer substrate. After patterned deposition, the liquid-phase circuit is sealed with an additional layer of silicone elastomer. We also demonstrate patterned deposition of the liquid phase GaIn alloy with a molded polydimethylsiloxane stamp that is manually inked and pressed into an elastomer substrate. As with other liquid-phase electronics produced through needle injection or masked deposition, the circuit is elastically deformable and can be stretched to several times its natural length without losing electronic functionality. In contrast to existing fabrication techniques, microcontact printing and stamp lithography can be used to produce circuits with any planar geometric feature, including electrodes with large planar area, intersecting and closed-loop wires, and combs with multiple terminal electrodes. In air, the surface of the coalesced droplets oxidize to form a thin oxide skin that preserves the shape of the circuit during sealing. This first demonstration of soft-lithography fabrication with liquid-phase GaIn alloy expands the space of allowable circuit geometries and eliminates the need for mold or mask fabrication. PMID- 23659456 TI - Elevated CSF histamine levels in multiple sclerosis patients. AB - BACKGROUND: Histamine is an ubiquitous inflammatory mediator of numerous physiological processes. Histamine and its receptors have been implicated in multiple sclerosis (MS) disease pathogenesis. We prospectively enrolled 36 MS patients and 19 age and gender-matched healthy volunteers for cerebrospinal fluid (CSF) histamine analysis. FINDINGS: CSF HISTAMINE LEVELS IN MS PATIENT SAMPLES WERE SIGNIFICANTLY HIGHER (MEDIAN: 35.6 pg/ml) than in controls (median: 5.5 pg/ml; Beta = 0.525, p < 0.001). In addition, histamine increased with age (Pearson's correlation, p < 0.003). CONCLUSIONS: Histamine may be an important factor for both the initiation and maintenance of chronic inflammatory diseases of the central nervous system. Our observation encourages a deeper investigation of the role of histamine in MS. PMID- 23659457 TI - INDQ/NO, a bioreductively activated nitric oxide prodrug. AB - The design, synthesis, and development of INDQ/NO, a novel nitric oxide (NO) prodrug targeted by a bioreductive trigger, are described. INDQ/NO, an indolequinone-diazeniumdiolate is found to be metabolized to produce NO by DT diaphorase, a bioreductive enzyme that is overexpressed in certain cancers and hypoxic tumors. Cell-based assays revealed that INDQ/NO induces DNA damage and is a potent inhibitor of cancer cell proliferation. PMID- 23659460 TI - Staff perspectives on the provision of end-of-life care in a community residence for older adults with developmental disabilities. AB - OBJECTIVE: The purpose of the study was to describe the perceptions of community residence (CR) staff who have cared for older adults with developmental disabilities (ADDs) that are at the end of life. DESIGN: This exploratory, descriptive study utilized qualitative methods that involved semistructured interviews with CR staff members. SETTING: The setting was a CR that was also an intermediate care facility (ICF) that provided 24-hour residential treatment for medical and/or behavioral needs. At least one registered nurse was present at all times. A CR with at least one resident who was over the age of 40 and had a diagnosis of a life-limiting illness was chosen. PARTICIPANTS: Participants included three frontline workers, four managers, and one registered nurse. METHODS: In-person interviews included open-ended questions about end-of-life care for older ADDs. Demographics such as age, length of time working with ADDs, and education were analyzed using descriptive statistics. Descriptive statistics were used to analyze demographics such as age, and length of time working with ADDs. Interviews were digitally recorded, transcribed, and analyzed using grounded theory techniques. RESULTS: Four themes illuminated unique elements of the provision of end-of-life care in a CR: (1) influence of relationships, (2) expression of individuality, (3) contribution of hospice, (4) grief and bereavement, and (5) challenges to end-of-life care. CONCLUSION: The results provided insight into the unique needs of older ADDs at the end of life and how this influences their care. Emphasis was also placed on the importance of specialized care that involved collaborations with hospice for older ADDs who remain in a CR at the end of life. PMID- 23659459 TI - Latent classes of prognosis conversations in palliative care: a mixed-methods study. AB - BACKGROUND: Prognosis conversations are complex phenomena of substantial importance to palliative care (PC), yet these remain poorly understood. This study empirically identifies and describes major types of prognosis conversations that occur in the natural setting of PC consultation. METHODS: We audio-recorded and coded 71 inpatient "goals of care" PC consultations at a large academic medical center in the northeastern United States. We used quantitative Latent Class Analyses for identifying discrete prognosis conversation types and qualitative Dimensional Analyses for more fully describing the process and content of the latent classes. RESULTS AND CONCLUSIONS: We observed three discrete types of prognosis conversations, each placing different communication demands upon all participants for achieving goal-concordant care: Navigating Options & Goals (56% of consultations), Facilitating New Goals (23%) and Preparing for End-of-Life (21%). This study provides the first step for developing educational and clinical prognosis communication interventions that are tailored to common decision-making contexts facing seriously ill patients, their families, and PC clinicians. PMID- 23659458 TI - Urinary C-peptide creatinine ratio detects absolute insulin deficiency in Type 2 diabetes. AB - AIMS: To determine the prevalence and clinical characteristics of absolute insulin deficiency in long-standing Type 2 diabetes, using a strategy based on home urinary C-peptide creatinine ratio measurement. METHODS: We assessed the urinary C-peptide creatinine ratios, from urine samples taken at home 2 h after the largest meal of the day, in 191 insulin-treated subjects with Type 2 diabetes (diagnosis age >=45 years, no insulin in the first year). If the initial urinary C-peptide creatinine ratio was <=0.2 nmol/mmol (representing absolute insulin deficiency), the assessment was repeated. A standardized mixed-meal tolerance test with 90-min stimulated serum C-peptide measurement was performed in nine subjects with a urinary C-peptide creatinine ratio <= 0.2 nmol/mmol (and in nine controls with a urinary C-peptide creatinine ratio >0.2 nmol/mmol) to confirm absolute insulin deficiency. RESULTS: A total of 2.7% of participants had absolute insulin deficiency confirmed by a mixed-meal tolerance test. They were identified initially using urinary C-peptide creatinine ratio: 11/191 subjects (5.8%) had two consistent urinary C-peptide creatinine ratios <= 0.2 nmol/mmol; 9 of these 11 subjects completed a mixed-meal tolerance test and had a median stimulated serum C-peptide of 0.18 nmol/l. Five of these 9 had stimulated serum C peptide <0.2 nmol/l and 9/9 subjects with urinary C-peptide creatinine ratio >0.2 had endogenous insulin secretion confirmed by the mixed-meal tolerance test. Compared with subjects with a urinary C-peptide creatinine ratio >0.2 nmol/mmol, those with confirmed absolute insulin deficiency had a shorter time to insulin treatment (median 2.5 vs. 6 years, P=0.005) and lower BMI (25.1 vs. 29.1 kg/m(2) , P=0.04). Two out of the five patients with absolute insulin deficiency were glutamic acid decarboxylase autoantibody-positive. CONCLUSIONS: Absolute insulin deficiency may occur in long-standing Type 2 diabetes, and cannot be reliably predicted by clinical features or autoantibodies. Absolute insulin deficiency in Type 2 diabetes may increase the risk of hypoglycaemia and ketoacidosis, as in Type 1 diabetes. Its recognition should help guide treatment, education and management. The urinary C-peptide creatinine ratio is a practical non-invasive method to aid detection of absolute insulin deficiency, with a urinary C-peptide creatinine ratio > 0.2 nmol/mmol being a reliable indicator of retained endogenous insulin secretion. PMID- 23659461 TI - Determination of in vivo behavior of mitomycin C-loaded o/w soybean oil microemulsion and mitomycin C solution via gamma camera imaging. AB - In this study, a microemulsion system was evaluated for delivery of mitomycin C (MMC). To track the distribution of the formulated drug after intravenous administration, radiochemical labeling and gamma scintigraphy imaging were used. The aim was to evaluate a microemulsion system for intravenous delivery of MMC and to compare its in vivo behavior with that of the MMC solution. For microemulsion formulation, soybean oil was used as the oil phase. Lecithin and Tween 80 were surfactants and ethanol was the cosurfactant. To understand the whole body localization of MMC-loaded microemulsion, MMC was labeled with radioactive technetium and gamma scintigraphy was applied for visualization of drug distribution. Radioactivity in the bladder 30 minutes after injection of the MMC solution was observed, according to static gamma camera images. This shows that urinary excretion of the latter starts very soon. On the other hand, no radioactivity appeared in the urinary bladder during the 90 minutes following the administration of MMC-loaded microemulsion. The unabated radioactivity in the liver during the experiment shows that the localization of microemulsion formulation in the liver is stable. In the light of the foregoing, it is suggested that this microemulsion formulation may be an appropriate carrier system for anticancer agents by intravenous delivery in hepatic cancer chemotherapy. PMID- 23659462 TI - A review of 5434 percutaneous pediatric central venous catheters inserted by anesthesiologists. AB - OBJECTIVE: To review the results of an anesthesiologist led pediatric percutaneous central venous access service. METHODS: Prospective data on percutaneous pediatric central venous catheter (CVC) insertions were collected over 22 years. Data included age, gender, weight, previous central CVCs, venous thromboses, investigations for great vein patency, type of CVC, external diameter, previous CVC insertions, intended use, operator identity, and the vein into which the CVC was inserted. The default technique was internal jugular vein cannulation using landmark technique (LT). Complication was defined as the following: failure to cannulate any vein, hemothorax, pneumothorax, right atrial perforation, extravenous wire positioning or CVC position and whether the patient was taken back to theater for CVC repositioning. RESULTS: Five thousand four hundred and thirty-four percutaneous CVC insertion procedures were performed on 3954 patients. One-third involved children <1 year of age (n = 1823: 34%). Five thousand one hundred and twenty-five CVCs (95.3%) were inserted into internal jugular veins. The majority were tunneled CVCs (n = 5190: 96.2%). The perioperative complication rate was 1.3%. Successful cannulation occurred in 99.5% of patients. Failure was more likely in children <3 kg, during large bore hemodialysis CVC insertions and during the first 4 years of the service - the latter suggesting a learning curve. Ninety-nine percent of CVCs were inserted using LTs. CONCLUSION: This study demonstrates a high success rate and low complication rate during pediatric percutaneous internal jugular vein CVC insertions by trained anesthesiologists using LTs. Smaller children, hemodialysis CVCs, and the team's learning curve were identified as risk factors for insertion failure. PMID- 23659463 TI - Chemical gradients on graphene to drive droplet motion. AB - This work demonstrates the production of a well-controlled, chemical gradient on the surface of graphene. By inducing a gradient of oxygen functional groups, drops of water and dimethyl-methylphosphonate (a nerve agent simulant) are "pulled" in the direction of increasing oxygen content, while fluorine gradients "push" the droplet motion in the direction of decreasing fluorine content. The direction of motion is broadly attributed to increasing/decreasing hydrophilicity, which is correlated to high/low adhesion and binding energy. Such tunability in surface chemistry provides additional capabilities in device design for applications ranging from microfluidics to chemical sensing. PMID- 23659464 TI - Effects of molecular structure on kinetics and dynamics of the trolox equivalent antioxidant capacity assay with ABTS(+*). AB - Reaction kinetics in the Trolox equivalent antioxidant capacity (TEAC) assay between ABTS(+*) [2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) cation radical] and compounds with different structure, molecular weight, number of OH groups, and redox potential were investigated by recording loss of ABTS(+*) absorbance (734 nm) continuously over time. Curves showed six distinguishable kinetic patterns, including both immediate and extended reaction components. Radical quenching rates in the immediate component most relevant to reactions in foods and tissues depended on phenol structure and steric accessibility to the hindered radical, while reaction stoichiometry correlated with the number of phenol groups (>0.81) but not redox potential. Current assay procedures measure antioxidant capacity under conditions not relevant to actual applications and do not determine radical quenching rates. Results raise serious questions regarding the ability of reactions with the hindered ABTS(+*) to rank actual radical quenching by compounds with different structures and invalidate reporting antioxidant activity as Trolox equivalents. PMID- 23659465 TI - Enhanced vapor-phase processing in fluorinated Fe4 single-molecule magnets. AB - A new tetrairon(III) single-molecule magnet with enhanced volatility and processability was obtained by partial fluorination of the ancillary beta diketonato ligands. Fluorinated proligand Hpta = pivaloyltrifluoroacetone was used to assemble the bis(alkoxido)-bridged dimer [Fe2(OEt)2(pta)4] (1) in crystalline form, from which the new tetranuclear complex [Fe4(L)2(pta)6] (2) was synthesized in a one-pot reaction with H3L = 2-hydroxymethyl-2-phenylpropane-1,3 diol, NaOEt, and FeCl3 in a Et2O:EtOH solvent mixture. The structure of compound 2 was inferred from (1)H NMR, mass spectrometry, magnetic measurements, and DFT calculations. Direct current magnetic data are consistent with the expected metal centered triangular topology for the iron(III) ions, with an antiferromagnetic coupling constant J = 16.20(6) cm(-1) between the central iron and the peripheral ones and consequent stabilization of an S = 5 spin ground state. Alternating current (ac) susceptibility measurements in 0 and 1 kOe static applied fields show the presence of a thermally activated process for magnetic relaxation, with tau0 = 2.3(1) 10(-7) s and U(eff)/kB = 9.9(1) K at zero static field and tau0 = 2.0(2) 10(-7) s and U(eff)/kB = 13.0(2) K at 1 kOe. At a pressure of 10(-7) mbar, compound 2 sublimates at (440 +/- 5) K vs (500 +/- 10) K for the nonfluorinated variant [Fe4(L)2(dpm)6] (Hdpm = dipivaloylmethane). According to XPS, ToF-SIMS, and ac susceptibility studies, the chemical composition, fragmentation pattern, and slow magnetic relaxation of the pristine material are retained in sublimated samples, suggesting that the molecular structure remains totally unaffected upon vapor-phase processing. PMID- 23659466 TI - Sociodemographic determinants of diet quality of the EU elderly: a comparative analysis in four countries. AB - OBJECTIVE: To investigate the sociodemographic determinants of diet quality of the elderly in four EU countries. DESIGN: Cross-sectional study. For each country, a regression was performed of a multidimensional index of dietary quality v. sociodemographic variables. SETTING: In Finland, Finnish Household Budget Survey (1998 and 2006); in Sweden, SNAC-K (2001-2004); in the UK, Expenditure & Food Survey (2006-07); in Italy, Multi-purpose Survey of Daily Life (2009). SUBJECTS: One- and two-person households of over-50s (Finland, n 2994; UK, n 4749); over-50 s living alone or in two-person households (Italy, n 7564); over-60 s (Sweden, n 2023). RESULTS: Diet quality among the EU elderly is both low on average and heterogeneous across individuals. The regression models explained a small but significant part of the observed heterogeneity in diet quality. Resource availability was associated with diet quality either negatively (Finland and UK) or in a non-linear or non-statistically significant manner (Italy and Sweden), as was the preference for food parameter. Education, not living alone and female gender were characteristics positively associated with diet quality with consistency across the four countries, unlike socio professional status, age and seasonality. Regional differences within countries persisted even after controlling for the other sociodemographic variables. CONCLUSIONS: Poor dietary choices among the EU elderly were not caused by insufficient resources and informational measures could be successful in promoting healthy eating for healthy ageing. On the other hand, food habits appeared largely set in the latter part of life, with age and retirement having little influence on the healthiness of dietary choices. PMID- 23659467 TI - Pure transvaginal natural orifice translumenal endoscopic surgery for renal cyst decortication: report of initial five cases. AB - OBJECTIVE: To present our initial experience with pure transvaginal natural orifice translumenal endoscopic surgery renal cyst decortication. METHODS: From December 2010 to July 2011, five female patients with symptomatic renal cyst in the anterior portion and lower pole of the kidney were submitted to pure transvaginal natural orifice translumenal endoscopic surgery renal cyst decortication in our center. Under general anesthesia, the patients were placed in the lithotomy position with the affected side elevated by 60 degrees . A 3-cm incision was made at the posterior vaginal fornix and a modified three-channel port was deployed across the vaginal incision. The cyst was dissected and the cyst fluid was aspirated using a suction device. The cyst wall was circumferentially excised. RESULTS: All five procedures were successfully carried out without additional transabdominal trocars. The median operative time was 80 min (range 60-90 min). The median estimated blood loss was 25 mL (range 25-50 mL). The median visual analog scale score was 1 on postoperative day 1. None of the patients required narcotic pain medications beyond postoperative day 2. Intestinal function recovered on postoperative day 1-3. There was no intraoperative or postoperative complication in any of the patients. During the follow-up visits, all the patients were in good condition. All the patients reported unaltered sexual function after surgery by the Female Sexual Function Index questionnaire. CONCLUSION: Our initial experience suggests that pure transvaginal natural orifice translumenal endoscopic surgery renal cyst decortication is feasible and safe in selected patients. PMID- 23659468 TI - Reactive centre loop mutants of alpha-1-antitrypsin reveal position-specific effects on intermediate formation along the polymerization pathway. AB - The common severe Z mutation (E342K) of alpha1-antitrypsin forms intracellular polymers that are associated with liver cirrhosis. The native fold of this protein is well-established and models have been proposed from crystallographic and biophysical data for the stable inter-molecular configuration that terminates the polymerization pathway. Despite these molecular 'snapshots', the details of the transition between monomer and polymer remain only partially understood. We surveyed the RCL (reactive centre loop) of alpha1-antitrypsin to identify sites important for progression, through intermediate states, to polymer. Mutations at P14P12 and P4, but not P10P8 or P2P1', resulted in a decrease in detectable polymer in a cell model that recapitulates the intracellular polymerization of the Z variant, consistent with polymerization from a near-native conformation. We have developed a FRET (Forster resonance energy transfer)-based assay to monitor polymerization in small sample volumes. An in vitro assessment revealed the position-specific effects on the unimolecular and multimolecular phases of polymerization: the P14P12 region self-inserts early during activation, while the interaction between P6P4 and beta-sheet A presents a kinetic barrier late in the polymerization pathway. Correspondingly, mutations at P6P4, but not P14P12, yield an increase in the overall apparent activation energy of association from ~360 to 550 kJ mol(-1). PMID- 23659469 TI - Homologous overexpression of RfaH in E. coli K4 improves the production of chondroitin-like capsular polysaccharide. AB - BACKGROUND: Glycosaminoglycans, such as hyaluronic acid, heparin, and chondroitin sulfate, are among the top ranked products in industrial biotechnology for biomedical applications, with a growing world market of billion dollars per year. Recently a remarkable progress has been made in the development of tailor-made strains as sources for the manufacturing of such products. The genetic modification of E. coli K4, a natural producer of chondroitin sulfate precursor, is challenging considering the lack of detailed information on its genome, as well as its mobilome. Chondroitin sulfate is currently used as nutraceutical for the treatment of osteoarthritis, and several new therapeutic applications, spanning from the development of skin substitutes to live attenuated vaccines, are under evaluation. RESULTS: E. coli K4 was used as host for the overexpression of RfaH, a positive regulator that controls expression of the polysaccharide biosynthesis genes and other genes necessary for the virulence of E. coli K4. Various engineering strategies were compared to investigate different types of expression systems (plasmid vs integrative cassettes) and integration sites (genome vs endogenous mobile element). All strains analysed in shake flasks on different media showed a capsular polysaccharide production improved by 40 to 140%, compared to the wild type, with respect to the final product titer. A DO stat fed-batch process on the 2L scale was also developed for the best performing integrative strain, EcK4r3, yielding 5.3 g ? L(-1) of K4 polysaccharide. The effect of rfaH overexpression in EcK4r3 affected the production of lipopolysaccharide and the expression of genes involved in the polysaccharide biosynthesis pathway (kfoC and kfoA), as expected. An alteration of cellular metabolism was revealed by changes of intracellular pools of UDP-sugars which are used as precursors for polysaccharide biosynthesis. CONCLUSIONS: The present study describes the identification of a gene target and the application of a successful metabolic engineering strategy to the unconventional host E. coli K4 demonstrating the feasibility of using the recombinant strain as stable cell factory for further process implementations. PMID- 23659470 TI - Improving access to care for women veterans suffering from chronic pain and depression associated with trauma. AB - OBJECTIVE: Access to care has become a priority for the Veterans Administration (VA) health care system as a significant number of veterans enrolled in the VA health care system reside in rural areas. The feasibility and effects of a novel clinical intervention that combined group therapy and biofeedback training was evaluated on women veterans living in rural areas. METHODS: The study was conducted at selected community-based outpatient clinics (CBOCs) in Texas. Thirty four women veterans with chronic pain and comorbid depression and/or posttraumatic stress disorder (PTSD) were recruited. Five sessions of education/therapy were delivered via telemedicine in combination with daily home practice of a portable biofeedback device (Stress Eraser(r), Helicor, New York, NY, USA). Participants responded to self-report questionnaires at baseline, at posttreatment, and at 6-week follow-up. Daily practice logs were also maintained by participants. RESULTS: The clinical protocol was acceptable, easy to administer, and associated with statistically significant decreases in self reported pain unpleasantness, pain interference, depressive symptoms, PTSD symptoms, and sleep disturbance at posttreatment. Improvements were maintained at 6-week follow-up. Qualitative analyses indicated that many participants 1) wished to continue to meet as a support group in their respective CBOCs and 2) felt less isolated and more empowered to cope with their problems of daily living as a result of the treatment. CONCLUSIONS: It is feasible to provide treatment to women veterans living in rural areas by utilizing video-teleconferencing technology between larger VA medical centers and facilities at CBOCs in more rural settings. A controlled trial of the intervention is warranted. PMID- 23659471 TI - Obesity in haemophilia patients: effect on bleeding frequency, clotting factor concentrate usage, and haemostatic and fibrinolytic parameters. AB - The prevalence of obesity in patients with haemophilia (PWH) is increasing. We investigated the effect of obesity on bleeding frequency and clotting factor concentrate (CFC) usage in PWH and assessed whether prothrombotic changes observed in obesity differ between controls and PWH. Number of bleeds and CFC usage were compared between obese (N = 51) and non-obese (N = 46) haemophilia A patients. Markers of haemostasis and fibrinolysis were compared between PWH, and gender-, age- and body mass index (BMI)-matched non-haemophilic controls (N = 91). Median number of bleeds/patient-month was comparable between obese and non obese patients with severe haemophilia (P = 0.791). Obese patients with severe haemophilia used 1.4 times more CFC/patient-month than non-obese patients (P = 0.036). When adjusting for weight this difference disappeared (P = 0.451). von Willebrand factor plasma concentration (VWF:Ag), factor VIII activity and endogenous thrombin potential were higher in obese than in non-obese controls. Obesity did not influence these markers in PWH. Plasminogen activator inhibitor type 1 levels were higher in obese vs. non-obese PWH (P < 0.001), whereas levels were comparable between PWH and controls (P = 0.912). Plasmin-alpha2-antiplasmin complex (PAP) levels appeared to be lower in obese vs. non-obese subjects, both within controls (P = 0.011) and PWH (P = 0.008). However, in PWH, PAP levels were higher than in controls (P < 0.001). Obesity is associated with an increase in net CFC usage in PWH, but has no effect on bleeding frequency. In addition, obesity attenuates hyperfibrinolysis in PWH. Future research investigating whether obese PWH need CFC treatment dosed on weight or whether a lower dosage would suffice to prevent and treat bleedings is needed. PMID- 23659472 TI - Reversal of the substrate specificity of CMP N-glycosidase to dCMP. AB - MilB is a CMP hydrolase involved in the early steps of biosynthesis of the antifungal compound mildiomycin. An enzyme from the bacimethrin biosynthetic pathway, BcmB, is closely related to MilB in both sequence and function. These two enzymes belong to the nucleoside 2'-deoxyribosyltransferase (NDT) superfamily. NDTs catalyze N-glycosidic bond cleavage of 2'-deoxynucleosides via a covalent 2-deoxyribosyl-enzyme intermediate. Conservation of key active site residues suggests that members of the NDT superfamily share a common mechanism; however, the enzymes differ in their substrate preferences. Substrates vary in the type of nucleobase, the presence or absence of a 2'-hydroxyl group, and the presence or absence of a 5'-phosphate group. We have determined the structures of MilB and BcmB and compared them to previously determined structures of NDT superfamily members. The comparisons reveal how these enzymes differentiate between ribosyl and deoxyribosyl nucleotides or nucleosides and among different nucleobases. The 1.6 A structure of the MilB-CMP complex reveals an active site feature that is not obvious from comparisons of sequence alone. MilB and BcmB that prefer substrates containing 2'-ribosyl groups have a phenylalanine positioned in the active site, whereas NDT family members with a preference for 2'-deoxyribosyl groups have a tyrosine residue. Further studies show that the phenylalanine is critical for the specificity of MilB and BcmB toward CMP, and mutation of this phenylalanine residue to tyrosine results in a 1000-fold reversal of substrate specificity from CMP to dCMP. PMID- 23659474 TI - Improving the in vivo persistence, distribution and function of cytotoxic T lymphocytes by inhibiting the tumor immunosuppressive microenvironment. AB - Adoptive cell transfer immunotherapy of malignant tumors has the problem of symbiosis between effector cells and tumor cells, a short in vivo residence time, and a poor killing efficiency of effector cells. Thus, releasing effector cells from the cancer immunosuppressive microenvironment and improving their effective time and functional status in vivo would seem to be ideal strategies for facilitating immunotherapy. Low-dose cyclophosphamide administration can effectively break immunotolerance by inhibiting regulatory T cells. In the present study, in order to verify whether the persistence, distribution and function of effector cells can be improved by inhibiting immunosuppressive microenvironment, low-dose cyclophosphamide was previously intraperitoneally injected into melanoma-bearing C57BL/6 mice, thereafter, CFSE-labeled cytotoxic T lymphocytes were transfused intravenously, and their effective time, distributive pattern, and killing efficiency in different groups were observed by measuring the fluorescence intensity and cell cycle of cytotoxic T lymphocytes distributed in various organs, in comparison with tumor growth. We found down-regulating Tregs in vivo can simultaneously reduce the levels of interleukin-10 and transforming growth factor-beta. Migration and distribution of cytotoxic T lymphocytes in vivo was found to vary with time. Inhibition of immunotolerance can significantly improve the persistence, distribution, and function of cytotoxic T lymphocytes. Correspondingly, significantly higher secretion of perforin, granzyme B, IL-2, and IFN-gamma in tumor tissues with decreased tumor growth was seen in the cyclophosphamide injection group than in the control group. Our study may provide useful information on the cyclophosphamide-mediated mechanism for facilitating tumor immunotherapy by inhibiting the immunosuppressive tumor microenvironment. PMID- 23659473 TI - Reduced parahippocampal cortical thickness in subjects at ultra-high risk for psychosis. AB - BACKGROUND: Grey matter volume and cortical thickness represent two complementary aspects of brain structure. Several studies have described reductions in grey matter volume in people at ultra-high risk (UHR) of psychosis; however, little is known about cortical thickness in this group. The aim of the present study was to investigate cortical thickness alterations in UHR subjects and compare individuals who subsequently did and did not develop psychosis. METHOD: We examined magnetic resonance imaging data collected at four different scanning sites. The UHR subjects were followed up for at least 2 years. Subsequent to scanning, 50 UHR subjects developed psychosis and 117 did not. Cortical thickness was examined in regions previously identified as sites of neuroanatomical alterations in UHR subjects, using voxel-based cortical thickness. RESULTS: At baseline UHR subjects, compared with controls, showed reduced cortical thickness in the right parahippocampal gyrus (p < 0.05, familywise error corrected). There were no significant differences in cortical thickness between the UHR subjects who later developed psychosis and those who did not. CONCLUSIONS: These data suggest that UHR symptomatology is characterized by alterations in the thickness of the medial temporal cortex. We did not find evidence that the later progression to psychosis was linked to additional alterations in cortical thickness, although we cannot exclude the possibility that the study lacked sufficient power to detect such differences. PMID- 23659476 TI - Three new triterpene saponins from Clematis chinensis. AB - Three new triterpene saponins, clematochinenosides H-J (1-3), were isolated from the roots and rhizomes of Clematis chinensis. Their structures were elucidated on the basis of spectroscopic means including 1D and 2D NMR experiments and hydrolysis products. PMID- 23659475 TI - Cell-penetrating peptide enhanced intracellular Raman imaging and photodynamic therapy. AB - We present the application of a theranostic system combining Raman imaging and the photodynamic therapy (PDT) effect. The theranostic nanoplatform was created by loading the photosensitizer, protoporphyrin IX, onto a Raman-labeled gold nanostar. A cell-penetrating peptide, TAT, enhanced intracellular accumulation of the nanoparticles in order to improve their delivery and efficacy. The plasmonic gold nanostar platform was designed to increase the Raman signal via the surface enhanced resonance Raman scattering (SERRS) effect. Theranostic SERS imaging and photodynamic therapy using this construct were demonstrated on BT-549 breast cancer cells. The TAT peptide allowed for effective Raman imaging and photosensitization with the nanoparticle construct after a 1 h incubation period. In the absence of the TAT peptide, nanoparticle accumulation in the cells was not sufficient to be observed by Raman imaging or to produce any photosensitization effect after this short incubation period. There was no cytotoxic effect observed after nanoparticle incubation, prior to light activation of the photosensitizer. This report shows the first application of combined SERS imaging and photosensitization from a theranostic nanoparticle construct. PMID- 23659477 TI - Epidemiology of blindness attributable to diabetes in Scotland: change over 20 years in a defined population. AB - AIMS: To establish the incidence and prevalence of blindness attributable to diabetes in a defined population in Scotland during the period 2000-2009, and to compare these figures with published data from the previous decade in the same population. METHODS: All blind registrations during 2000-2009 in Fife, Scotland, UK were examined and included if diabetic retinopathy/maculopathy was the main cause of blindness. The annual incidence and point prevalence on 31 December 2009 of registered blindness attributable to diabetes were calculated in both the total population and the population with diabetes. These data were compared with figures for the period 1990-1999, using a two-tailed t-test, and subjected to Poisson regression analysis. RESULTS: In the population with diabetes, the mean incidence of blindness attributable to diabetes was 42.7 (sd 24.2, 95% CI 25- 60) per 100 000 per year for 2000-2009, compared with 64.3 for 1990-1999 (P = 0.062). The relative risk of developing blindness per year was 0.894 (95% CI 0.811- 0.988, P = 0.028) for 2000- 2009. The point prevalence on 31 December 2009 was 167 per 100 000 in the population with diabetes, vs 210 on 31 December 1999. CONCLUSION: Compared with the previous decade, the prevalence of blindness attributable to diabetes has decreased in the population with diabetes, with a trend towards a decrease in its incidence. This may be a consequence of an increased denominator population, resulting from better recording of diabetes and changes to the diagnostic criteria. Over the decade 2000-2009, the incidence of blindness attributable to diabetes fell by a mean of 10.6% per year in the population with diabetes. PMID- 23659479 TI - Production of ethanol and arabitol by Debaryomyces nepalensis: influence of process parameters. AB - Debaryomyces nepalensis, osmotolerant yeast isolated from rotten apple, is known to utilize both hexoses and pentoses and produce industrially important metabolites like ethanol, xylitol and arabitol. In the present study, the effect of different growth substrates, trace elements, nitrogen concentration and initial pH on growth and formation of ethanol and arabitol were examined. Optimum conditions for maximizing the product yields were established: glucose as carbon source, an initial pH of 6.0, 6 g/L of ammonium sulphate and addition of micronutrients. Under these best suited conditions, a concentration of 11g/L of arabitol and 19 g/L of ethanol was obtained in shake flask fermentations. The fermentation was scaled up to 2.5 L bioreactor and the influence of aeration, agitation and initial substrate concentration was also determined. Under optimal conditions (150 g/L glucose, 400 rpm and 0.5 vvm) ethanol concentration reached 52 g/L, which corresponds to a yield of 0.34 g/g and volumetric productivity of 0.28 g/L/h, whereas arabitol production reached a maximum of 14 g/L with a yield and volumetric productivity of 0.1 g/g and 0.07 g/L/h respectively. PMID- 23659478 TI - Striking difference in antiproliferative activity of ruthenium- and osmium nitrosyl complexes with azole heterocycles. AB - Ruthenium nitrosyl complexes of the general formulas (cation)(+)[cis RuCl4(NO)(Hazole)](-), where (cation)(+) = (H2ind)(+), Hazole = 1H-indazole (Hind) (1c), (cation)(+) = (H2pz)(+), Hazole = 1H-pyrazole (Hpz) (2c), (cation)(+) = (H2bzim)(+), Hazole = 1H-benzimidazole (Hbzim) (3c), (cation)(+) = (H2im)(+), Hazole = 1H-imidazole (Him) (4c) and (cation)(+)[trans RuCl4(NO)(Hazole)](-), where (cation)(+) = (H2ind)(+), Hazole = 1H-indazole (1t), (cation)(+) = (H2pz)(+), Hazole = 1H-pyrazole (2t), as well as osmium analogues of the general formulas (cation)(+)[cis-OsCl4(NO)(Hazole)](-), where (cation)(+) = (n-Bu4N)(+), Hazole =1H-indazole (5c), 1H-pyrazole (6c), 1H-benzimidazole (7c), 1H-imidazole (8c), (cation)(+) = Na(+); Hazole =1H-indazole (9c), 1H benzimidazole (10c), (cation)(+) = (H2ind)(+), Hazole = 1H-indazole (11c), (cation)(+) = H2pz(+), Hazole = 1H-pyrazole (12c), (cation)(+) = (H2im)(+), Hazole = 1H-imidazole (13c), and (cation)(+)[trans-OsCl4(NO)(Hazole)](-), where (cation)(+) = n-Bu4N(+), Hazole = 1H-indazole (5t), 1H-pyrazole (6t), (cation)(+) = Na(+), Hazole = 1H-indazole (9t), (cation)(+) = (H2ind)(+), Hazole = 1H indazole (11t), (cation)(+) = (H2pz)(+), Hazole = 1H-pyrazole (12t), have been synthesized. The compounds have been comprehensively characterized by elemental analysis, ESI mass spectrometry, spectroscopic techniques (IR, UV-vis, 1D and 2D NMR) and X-ray crystallography (1c.CHCl3, 1t.CHCl3, 2t, 3c, 6c, 6t, 8c). The antiproliferative activity of water-soluble compounds (1c, 1t, 3c, 4c and 9c, 9t, 10c, 11c, 11t, 12c, 12t, 13c) in the human cancer cell lines A549 (nonsmall cell lung carcinoma), CH1 (ovarian carcinoma), and SW480 (colon adenocarcinoma) has been assayed. The effects of metal (Ru vs Os), cis/trans isomerism, and azole heterocycle identity on cytotoxic potency and cell line selectivity have been elucidated. Ruthenium complexes (1c, 1t, 3c, and 4c) yielded IC50 values in the low micromolar concentration range. In contrast to most pairs of analogous ruthenium and osmium complexes known, they turned out to be considerably more cytotoxic than chemically related osmium complexes (9c, 9t, 10c, 11c, 11t, 12c, 12t, 13c). The IC50 values of Os/Ru homologs differ by factors (Os/Ru) of up to ~110 and ~410 in CH1 and SW480 cells, respectively. ESI-MS studies revealed that ascorbic acid may activate the ruthenium complexes leading to hydrolysis of one M Cl bond, whereas the osmium analogues tend to be inert. The interaction with myoglobin suggests nonselective adduct formation; i.e., proteins may act as carriers for these compounds. PMID- 23659481 TI - Dyslipidemia, risk factors, and the prevention of cardiovascular disease in women. PMID- 23659480 TI - Bone-marrow-derived mesenchymal stem cells promote proliferation and neuronal differentiation of Niemann-Pick type C mouse neural stem cells by upregulation and secretion of CCL2. AB - Niemann-Pick type C (NP-C) disease is a neurodegenerative disorder characterized neuropathologically by ballooned neurons distended with lipid storage and widespread neuronal loss. Neural stem cells (NSC) derived from NP-C disease models have decreased ability for self-renewal and neuronal differentiation. Investigation of neurogenesis in the adult brain has suggested that NP-C disease can be overcome, or at least ameliorated, by the generation of new neurons. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are regarded as potential candidates for use in the treatment of neurodegenerative disorders because of their ability to promote neurogenesis. The underlying mechanisms of BM-MSC induced promotion of neurogenesis, however, have not been resolved. The aim of the present study was to examine the mechanism of neurogenesis by BM-MSCs in NP-C disease. Coculture of embryonic NSCs from NP-C mice that exhibit impaired ability for self-renewal and decreased rates of neuronal differentiation with BM-MSCs resulted in an enhanced capacity for self-renewal and an increased ability for differentiation into neurons or oligodendrocytes. In addition, results of in vivo studies have demonstrated that transplantation of intracerebral BM-MSCs resulted in stimulated proliferation and neuronal differentiation of NSCs within the subventricular zone. Of particular interest, enhanced proliferation and neuronal differentiation of endogenous NP-C mouse NSCs showed an association with elevated release of the chemokine (C-C motif) ligand 2 (CCL2) from BM-MSCs. These effects suggest that soluble CCL2 derived from BM-MSCs can modulate endogenous NP-C NSCs, resulting in their improved proliferation and neuronal differentiation in mice. PMID- 23659482 TI - Positive association between 25-hydroxyvitamin D and C-reactive protein is confounded by hormonal contraceptive use. AB - BACKGROUND: Studies of the relationship between vitamin D and inflammation are equivocal. This may be due to unaccounted confounding. Hormonal contraceptive (HC) use is associated with elevated circulating 25-hydroxyvitamin D [25(OH)D] in Caucasians and African-Americans, but its effects on 25(OH)D in other ethnicities are unclear. HC use is associated with elevated C-reactive protein (CRP), an inflammatory biomarker. Our objectives were to assess the effect of HC use on 25(OH)D across ethnic groups, and to examine the association between HC, 25(OH)D and CRP in an ethnically diverse population of young adults. METHODS: We recruited Caucasian, East Asian, and South Asian individuals (n=1,403) from Toronto, Canada. Fasting blood measures of 25(OH)D and CRP were obtained. RESULTS: Across ethnic groups, women HC users (n=280) had higher 25(OH)D and CRP than women HC non-users (n=695) and men (n=428) (p<0.008 and p<0.0001, respectively). Circulating 25(OH)D was positively associated with CRP in the entire population in models not accounting for HC use (beta=0.010+/-0.003; p<0.0001). There was no association when men and women HC non-users were examined separately. Among women HC users, there was no association after accounting for hormone dose. A positive association between 25(OH)D and CRP among individuals above the median 25(OH)D (>=51.9 nmol/L) was not significant after adjustment for HC use. No association was observed among individuals below the median. CONCLUSIONS: HC use and 25(OH)D were positively associated across ethnic groups. We found no association between 25(OH)D and CRP when HC use was accounted for. HC use confounds the association between 25(OH)D and CRP. PMID- 23659483 TI - Racial and ethnic differences in the association between obesity and depression in women. AB - BACKGROUND: It is generally accepted that obesity and depression are positively related in women. Very little prior research, however, has examined potential variation in this relationship across different racial/ethnic groups. This paper examines the association between obesity and depression in non-Hispanic White, non-Hispanic Black, and Mexican American women. METHODS: The sample included women aged 20 years and older in the 2005-2008 National Health and Nutrition Examination Surveys (n=3666). Logistic regression was used to assess the relationship between obesity and depression syndrome (assessed using the Patient Health Questionnaire-9), after adjusting for covariates. We then investigated whether this association varied by race/ethnicity. RESULTS: Overall, obese women showed a 73% greater odds of depression (odds ratio [OR]=1.73; 95% confidence interval [CI]=1.19, 2.53) compared with normal weight women. This association varied significantly, however, by race/ethnicity. The obesity-depression associations for both Black and Mexican American women were different from the positive association found for White women (ORBlack*obese=0.24; 95% CI=0.10,0.54; ORMexican American*obese=0.42; 95% CI=1.04). Among White women, obesity was associated with significantly greater likelihood of depression (OR=2.37; 95% CI=1.41, 4.00) compared to normal weight. Among Black women, although not statistically significant, results are suggestive that obesity was inversely associated with depression (OR=0.56; 95% CI=0.28, 1.12) relative to normal weight. Among Mexican American women, obesity was not associated with depression (OR=1.01; 95% CI=0.59, 1.72). CONCLUSIONS: The results reveal that the association between obesity and depression varies by racial/ethnic categorization. White, but not Black or Mexican American women showed a positive association. Next research steps could include examination of factors that vary by race/ethnicity that may link obesity to depression. PMID- 23659485 TI - Drospirenone-related venous thromboembolism risk: "the rest of the story". PMID- 23659484 TI - Breastfeeding status and maternal cardiovascular variables across the postpartum. AB - BACKGROUND: There have been recent reports that lactational history is associated with long-term women's health benefits. Most of these studies are epidemiological. If particular cardiometabolic changes that occur during lactation ultimately influence women's health later is unknown. METHODS: Seventy one healthy women participated in a prospective postpartum study that provided an opportunity to study anthropometric, endocrine, immune, and behavioral variables across time. Variables studied were heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), C-reactive protein, body mass index (BMI), perceived stress, and hormones. A cohort of women without a change in breastfeeding (N=22) or formula feeding (N=23) group membership for 5 months was used for analysis of effects of feeding status. The data were analyzed using factorial repeated measures analysis of variance and analysis of covariance. RESULTS: SBP and HR declined across the postpartum and were significantly lower in breastfeeding compared to formula feeding mothers (p<0.05). These differences remained statistically significant when BMI was added to the model. Other covariates of income, stress, marital status, and ethnicity were not significantly associated with these variables over time. DBP was also lower, but the significance was reduced by the addition of BMI as a covariate. Stress also was lower in breastfeeders, but this effect was reduced by the addition of income as a covariate. CONCLUSIONS: These data suggest that there are important physiological differences in women during months of breastfeeding. These may have roles in influencing or programming later risks for a number of midlife diseases. PMID- 23659488 TI - Sentinel lymph node dissection in more than 1200 prostate cancer cases: rate and prediction of lymph node involvement depending on preoperative tumor characteristics. AB - OBJECTIVES: To stratify the rate and prediction of lymph node involvement in prostate cancer patients undergoing sentinel-lymphadenectomy depending on preoperative tumor characteristics, and to compare the outcome with the European Association of Urology Guideline indication for lymphadenectomy. METHODS: A total of 1229 patients (median age 66 years) were treated with open sentinel lymphadenectomy and prostatectomy between 2005 and 2009. Median preoperative prostate-specific antigen was 7.4 ng/mL. The rate of lymph node involvement was analyzed for D'Amico risk groups. Multivariable logistic regression was used to estimate the probability of lymph node involvement. Predictor variables included preoperative prostate-specific antigen, clinical T-category and biopsy Gleason sum. Predictive accuracy has been quantified (area under the curve) and lymph node positive patients were verified under consideration of the recommended European threshold for lymphadenectomy (nomogram-predicted lymph node invasion risk of >7%). RESULTS: The median number of lymph nodes removed was 10 (interquartile range 7-13). Overall, 17.1% of patients had lymph node involvement; 3.2% in low-, 14.8% in intermediate- and 37.4% in high-risk disease. The predicted risk for lymph node involvement ranged from 2% (prostate-specific antigen <=4 ng/mL, T1, Gleason sum <=6) to 87% (prostate-specific antigen >20 ng/mL, T3, Gleason sum >=8). The predictive accuracy was 82.1%. According to the European guidelines, 15.9% of all lymph node involved cases would not have been detected. CONCLUSIONS: The rate of lymph node involvement seems to be higher in the examined sentinel collective than expected according to the European Guideline nomogram. The first sentinel-based lymph node involvement prediction model can assist in deciding on the indication for sentinel-lymphadenectomy. The validation of a corresponding sentinel-based nomogram is still missing. PMID- 23659489 TI - Heart rate variability parameters do not correlate with pain intensity in healthy volunteers. AB - OBJECTIVE: When patients cannot indicate pain, physiological parameters may be useful. We tested whether heart rate variability (HRV) parameters, as reflection of sympathetic and vagal tone, can be used to quantify pain intensity. DESIGN: Prospective study. SUBJECTS AND SETTING: A standardized heat stimulus was applied to the forearm in 75 healthy volunteers during three study periods of 2 minutes. METHODS: Before and after each application, pain intensity was measured by a visual analog scale (VAS) and inter beat interval (IBI) was recorded. Standard deviation of normal to normal beat intervals (SDNN) of the IBI, the power of the low (LF, 0.07-0.14 Hz) and high frequency (HF, 0.15-0.50 Hz) band, and LF/HF ratio were calculated. Log transformation resulted in normal distribution. Correlation between HRV parameters and pain intensity was assessed by Pearson's correlation coefficient. RESULTS: Data from 73 volunteers (44 women) could be analyzed. The mean age was 30 +/- 11 years. Compared with baseline, during all heat periods, pain intensity measured by VAS increased from 2 +/- 3 mm, 3 +/- 5 mm, and 2 +/- 4 mm, to 40 +/- 20 mm, 42 +/- 21 mm, and 44 +/- 22 mm, respectively. Log transformed SDNN (lnSDNN) and LF (lnLF) decreased; lnSDNN from 4.0 +/- 0.4 to 3.9 +/- 0.5, P = 0.002; 4.0 +/- 0.4 to 3.9 +/- 0.5, P = 0.016; and 4.1 +/- 0.4 to 3.9 +/- 0.4, P = 0.004, respectively; lnLF from 6.3 +/- 1.0 to 6.1 +/- 1.2, P = 0.001; 6.4 +/- 1.0 to 6.2 +/- 1.1, P = 0.019; and 6.5 +/- 1.0 to 6.2 +/- 1.1, P = 0.020, respectively. No correlation of any HRV parameter with VAS score was found. CONCLUSION: HRV parameters may detect responses to heat pain, but are not suitable to assess pain intensity. PMID- 23659490 TI - Organocatalytic aryl-aryl bond formation: an atroposelective [3,3]-rearrangement approach to BINAM derivatives. AB - Herein we disclose an organocatalytic aryl-aryl bond-forming process for the regio- and atroposelective synthesis of 2,2'-diamino-1,1'-binaphthalenes (BINAMs). In the presence of catalytic amounts of axially chiral phosphoric acids, achiral N,N'-binaphthyl hydrazines undergo a facile [3,3]-sigmatropic rearrangement to afford enantiomerically enriched BINAM derivatives in good to excellent yield. This transformation represents the first example of a metal free, catalytic C(sp(2))-C(sp(2)) bond formation between two aromatic rings with concomitant de novo atroposelective installation of an axis of chirality. Density functional calculations reveal that, in the transition state for C-C bond formation, the phosphoric acid proton of the catalyst is fully transferred to one of the N-atoms of the substrate, and the resulting phosphate acts as a chiral counterion. PMID- 23659491 TI - Iodine status during pregnancy in India and related neonatal and infant outcomes. AB - OBJECTIVE: To document iodine status in Indian pregnancies, associations with maternal diet and demographics, and offspring developmental measures. DESIGN: Longitudinal study following mothers through pregnancy and offspring up to 24 months. SETTING: Rural health-care centre (Vadu) and urban antenatal clinic (Pune) in the Maharashtra region of India. SUBJECTS: Pregnant mothers at 17 (n 132) and 34 weeks' (n 151) gestation and their infants from birth to the age of 24 months. RESULTS: Median urinary iodine concentration (UIC) was 203 and 211 MUg/l at 17 and 34 weeks of pregnancy, respectively (range 26-800 MUg/l). Using the UIC distribution adjusted for within-person variation, extreme UIC quartiles were compared for predictors and outcomes. There was no correlation between UIC at 17 and 34 weeks, but 24 % of those with UIC in the lowest quartile at 17 weeks had UIC in the same lowest quartile at 34 weeks. Maternal educational, socio economic status and milk products consumption (frequency) were different between the lowest and highest quartile of UIC at 34 weeks. Selected offspring developmental outcomes differed between the lowest and highest UIC quartiles (abdominal circumference at 24 months, subscapular and triceps skinfolds at 12 and 24 months). However, UIC was only a weak predictor of subscapular skinfold at 12 months and of triceps skinfold at 24 months. CONCLUSIONS: Median UIC in this pregnant population suggested adequate dietary provision at both gestational stages studied. Occasional high results found in spot samples may indicate intermittent consumption of iodine-rich foods. Maternal UIC had limited influence on offspring developmental outcomes. PMID- 23659492 TI - Partner- and planning-based interventions to reduce fat consumption: randomized controlled trial. AB - OBJECTIVE: The research tested the efficacy of partner- and planning-based interventions to reduce dietary fat intake over a 6-month period. DESIGN: Randomized controlled, blinded, parallel trial. METHODS: A computer randomization feature was used to allocate council employees (N = 427, of which 393 completed baseline measures) to one of four conditions (partner + implementation intentions, partner-only, implementation intentions, and control group) before they completed measures at baseline and follow-ups at 1, 3, and 6 months post baseline. Outcome measures were comprised of validated self-report measures of dietary fat intake (saturated fat intake, fat intake, ratio of 'good' fats to 'bad' fats); psychosocial mediators (enjoyment, intention, self-efficacy, social influence, partner support); weight and waist size (baseline and 6 months only). RESULTS: Data from 393 participants were analysed in accordance with intention-to treat analyses. All intervention groups reported greater reductions in fat intake than the control group at 3 months. The partner-based groups increased the ratio of 'good' fats to 'bad' fats at 3 and 6 months and lost more inches on their waist, versus the non-partner groups. The impacts of the partner-based manipulations on outcomes were partially mediated by greater perceived social influences, partner support, and enjoyment of avoiding high-fat foods. The partner-based interventions also increased intention and self-efficacy. However, the effects in this study were typically small and generally marginally significant. CONCLUSIONS: Partner-based interventions had some positive benefits on dietary-related outcomes at 3 and 6 months. Support for implementation intentions was more limited. PMID- 23659493 TI - A comparison of efficacy and safety of 2-year telbivudine and entecavir treatment in patients with chronic hepatitis B: a match-control study. AB - There are limited data comparing the clinical outcomes between telbivudine and entecavir. We consecutively enrolled 115 telbivudine-naive and 115 entecavir naive chronic hepatitis B patients, who were matched for age, sex, hepatitis B e antigen (HBeAg) status and cirrhosis, and treated for at least 2 years or less than 2 years but had developed resistance. Except for the rate of HBeAg seroconversion, which was similar, patients in the entecavir group had better clinical outcomes than those in the telbivudine group for alanine aminotransferase normalization (85.2% vs 78.4%, p <0.048), undetectable HBV DNA (96.5% vs 74.8%, p <0.001), and viral resistance (0.9% vs 21.7%, p <0.001) after 2 years of treatment, After applying roadmap or super-responders concepts, entecavir still had better outcomes than telbivudine in undetectable HBV DNA and viral resistance. The cumulative incidence of hepatocellular carcinoma development was similar between telbivudine-naive and entecavir-naive patients (p 0.565). In renal function analysis, there were significantly more patients with estimated glomerular filtration rate (eGFR) category improvement in both the telbivudine and entecavir groups at year 1 (p 0.006 and p 0.047, respectively). The rate of virological improvement was significantly higher with entecavir than with telbivudine after 2 years of treatment, whether applying the concepts of roadmap or super-responders. The incidence of hepatocellular carcinoma was similar between telbivudine and entecavir. Both telbivudine and entecavir were associated with eGFR improvement, especially in patients with renal insufficiency. PMID- 23659494 TI - Modulation of (Na,K)-ATPase activity by membrane fatty acid composition: therapeutic implications in human hypertension. AB - Abstract Oxidative stress (OS) plays a key role in the pathophysiology of essential hypertension and is associated with changes in the cell membrane fatty acid composition and fluidity. As (Na,K)-ATPase is modulated by the surrounding lipid microenvironment, lipid peroxidation could alter the interactions of this enzyme with the membrane components. Thus, modifications in the membrane fatty acid profile will translate into effects on (Na,K)-ATPase activity. Accordingly, a decrease in this enzyme activity has been reported in hypertensive patients. The aim of this study was to evaluate the relationship between membrane fluidity and fatty acid composition and (Na,K)-ATPase activity in erythrocytes of essential hypertensive patients supplemented with antioxidant vitamins C and E. A double-blind, randomized, placebo-controlled study was conducted in 120 men with essential hypertension assigned to receive vitamin C (1 g/day) +E (400 IU/day) or placebo for 8 weeks. Measurements included OS related parameters: GSH/GSSG ratio, F2-isoprostanes and antioxidant capacity of plasma, (Na,K)-ATPase activity and erythrocytes membrane fatty acid composition (PUFA, polyunsaturated fatty acids; SAFA, saturated fatty acids). Associations were assessed by Pearson correlation and the differences by Student t-test (p<0.05). Supplemented hypertensive patients showed higher activity of (Na,K)-ATPase and proportion of PUFA, and lower blood pressure, OS markers and proportion of SAFA, versus placebo. The activity of (Na,K)-ATPase correlated negatively with the proportion of SAFA, but positively with that of PUFA in both groups. Supplementation with vitamins C+E resulted in decreased OS and increased fluidity and PUFA proportion in the membrane, both of which positively modulate (Na,K)-ATPase activity, accounting for the blood pressure reduction. PMID- 23659495 TI - Lipidomic analysis of brain tissues and plasma in a mouse model expressing mutated human amyloid precursor protein/tau for Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD), the most common cause of dementia among neurodegenerative diseases, afflicts millions of elderly people worldwide. In addition to amyloid-beta (Abeta) peptide and phosphorylated tau, lipid dysregulation is suggested to participate in AD pathogenesis. However, alterations in individual lipid species and their role in AD disease progression remain unclear. METHODS: We performed a lipidomic analysis using brain tissues and plasma obtained from mice expressing mutated human amyloid precursor protein (APP) and tau protein (Tg2576*JNPL3) (APP/tau mice) at 4 (pre-symptomatic phase), 10 (early symptomatic) and 15 months (late symptomatic). RESULTS: Levels of docosahexaenoyl (22:6) cholesterol ester (ChE) were markedly increased in APP/tau mice compared to controls at all stages examined. Several species of ethanolamine plasmalogens (pPEs) and sphingomyelins (SMs) showed different levels between brains from APP/tau and control mice at various stages of AD. Increased levels of 12-hydroxyeicosatetraenoic acid (12-HETE) during the early symptomatic phase were consistent with previous reports using human AD brain tissue. In addition, 19,20 dihydroxy-docosapentaenoic acid (19,20-diHDoPE) and 17,18-dihydroxy eicosatetraenoic acid (17,18-diHETE), which are produced from docosahexaenoic acid and eicosapentaenoic acid via 19,20-epoxy-docosapentaenoic acid (19,20 EpDPE) and 17,18-epoxy-eicosatetraenoic acid (17,18-EpETE), respectively, were significantly increased in APP/tau brains during the pre-symptomatic phase, and concomitant increases occurred in plasma. Several arachidonic acid metabolites such as prostaglandin D2 (PGD2) and 15-hydroxyeicosatetraenoic acid (15-HETE), which have potential deteriorating and protective actions, respectively, were decreased in the early symptomatic phase of APP/tau mice. Significant decreases in phosphatidylcholines and PEs with polyunsaturated fatty acids were also detected in the late symptomatic phase, indicating a perturbation of membrane properties. CONCLUSION: Our results provide fundamental information on lipid dysregulation during various stages of human AD. PMID- 23659496 TI - Psychological characteristics and motivation of women seeking labiaplasty. AB - BACKGROUND: Labiaplasty is an increasingly popular surgical intervention but little is known about the characteristics and motivation of women who seek the procedure or the psychosexual outcome. METHOD: A total of 55 women seeking labiaplasty were compared with 70 women who did not desire labiaplasty. Various general measures of psychopathology as well as specific measures (Genital Appearance Satisfaction; Cosmetic Procedure Screening for labiaplasty) were used. Labia measurements of the women seeking labiaplasty were also obtained. RESULTS: Women seeking labiaplasty did not differ from controls on measures of depression or anxiety. They did, however, express increased dissatisfaction towards the appearance of their genitalia, with lower overall sexual satisfaction and a poorer quality of life in terms of body image. Women seeking labiaplasty reported a significantly greater frequency of avoidance behaviours on all the domains assessed, and greater frequency of safety-seeking behaviours for most of the domains. Key motivations reported for labiaplasty were categorized as cosmetic, functional or sexual. Of the 55 women seeking labiaplasty, 10 met diagnostic criteria for body dysmorphic disorder. CONCLUSIONS: This is the first controlled study to describe some of the characteristics and motivations of women seeking labiaplasty. We identified a wide range of avoidance and safety-seeking behaviours, which occurred more frequently in the labiaplasty group than the control group. These could be used clinically as part of a psychological intervention for women seeking labiaplasty. PMID- 23659497 TI - Five new flavonoid glycosides from Nervilia fordii. AB - Five new flavonoid glycosides, namely nervilifordins F-J (1-5), were isolated from the 60% EtOH extract of the aerial parts of Nervilia fordii, along with three first isolated flavonoids (7, 8, and 13) and five known flavonoids (6, 9 12). The structures of new compounds were elucidated on the basis of 1D and 2D NMR and MS studies. Their anti-inflammatory activities were tested by measuring their inhibitory effects on nitric oxide production in lipopolysaccharide activated RAW264.7 macrophages. Compounds 2 and 5 showed interesting inhibition effects with their EC50 values of 15.15 MUM and 14.80 MUM, respectively. PMID- 23659498 TI - A strategy for the improvement of the bioavailability and antiosteoporosis activity of BCS IV flavonoid glycosides through the formulation of their lipophilic aglycone into nanocrystals. AB - Epimedium-derived flavonoid glycosides are widely used for the prevention of osteoporosis, but these compounds generally exhibit poor membrane permeability and oral absorption. To address these limitations, the bioactive lipophilic aglycone icaritin (ICT) was selected and successfully developed into nanocrystals (ICTN) through the antisolvent-precipitation method. After the parameters in the preparation of ICTN were optimized, the morphology, crystallinity, adsorption of the stabilizers on the ICT surface, and the dissolution of the resulting nanocrystals were characterized. The pharmacokinetics in rat and the in vitro antiosteoporosis activity of serum withdrawn after the oral administration of ICTN to rats on mouse osteoblastic cells were evaluated. Consistent with its good performance in stabilizing the ICT nanosuspension, atomic force microscopy showed that hydroxypropyl methylcellulose (HPMC) exhibits better adsorption on the ICT surface compared with other stabilizers. Needle-shaped crystals (~ 220 nm in diameter) with a high drug loading (~ 90%) were generated when 0.16 mL of the ICT acetone solution (10 mg/mL) was injected quickly into 2 mL of the HPMC solution (0.02%, w/w) under ultrasonication for 10 s at room temperature. The thermal analysis demonstrated that the majority of the particles are in their crystalline forms, similarly to the unformulated ICT. After oral administration, ICTN exhibited a faster dissolution rate and significantly faster absorption, as supported by the increased AUC0-36h and Cmax and the reduced Tmax of these nanocrystals compared with the raw suspension (p < 0.05). Compared with blank serum, enhanced proliferation and differentiation activities were observed when serum withdrawn after the oral administration of ICTN in rat was incubated with osteoblast MC3T3-E1 cells. The present delivery system could provide a new promising strategy for BCS IV glycoside of flavonoids or other natural products by formulation of their bioactive lipophilic aglycone forms to enhance oral absorption and in vivo bioactivity. PMID- 23659499 TI - Port wine oxidation management: a multiparametric kinetic approach. AB - Port wine is a flagship fortified wine of Portugal, which undergoes a particularly long aging period, developing a dynamic sensory profile over time, responsible for several wine categories, which is dependent upon the type of aging (bottle or barrel). Therefore, the quality of the product is dependent upon the chemical mechanisms occurring during the aging process, such as oxidation or Maillard reactions. To attain the desired quality management, it is necessary to understand how technological parameters, such as temperature or oxygen exposure, affect the kinetics of the formation of key odorants, such as sotolon. There is a lack of information about the impact of the storage conditions (oxygen and temperature) on Port wine quality. In this study, the effect of these two parameters were investigated to increase the knowledge database concerning aging management of Port wines. It was found that sotolon formation is highly dependent upon oxygen and temperature. There is however a synergistic effect between these two parameters that could significantly increase the concentration. The kinetic parameters of oxygen, sotolon, and other compounds related to Port aging (cis- and trans-5-hydroxy-2-methyl-1,3-dioxan, 2-furfural, 5-hydroxy-methyl-furfural, and 5-methyl-furfural) are also reported. Kinetic models with Monte Carlo simulations, where the oxygen permeability dispersion and temperature are the parameters under evaluation, were applied. On the basis of the modeling predictions, it would seem that the temperature of a cellar would have a more significant impact on the Port wines stored in containers where the oxygen intake is higher (barrels) when compared to containers with low oxygen permeability (bottles using cork stoppers). PMID- 23659500 TI - Amiodarone inhibits the entry and assembly steps of hepatitis C virus life cycle. AB - HCV (hepatitis C virus) infection affects an estimated 180 million people in the world's population. Adverse effects occur frequently with current standard treatment of interferon and ribavirin, while resistance of new direct anti-viral agents, NS3 protease inhibitors, is a major concern because of their single anti HCV mechanism against the viral factor. New anti-viral agents are needed to resolve the problems. Amiodarone, an anti-arrhythmic drug, has recently been shown to inhibit HCV infection in vitro. The detailed mechanism has yet to be clarified. The aim of the present study was to elucidate the molecular mechanism of the inhibitory effect of amiodarone on HCV life cycle. The effect of amiodarone on HCV life cycle was investigated in Huh-7.5.1 cells with HCVcc (cell culture-derived HCV), HCVpp (HCV pseudoviral particles), sub-genomic replicons, IRES (internal ribosomal entry site)-mediated translation assay, and intracellular and extracellular infectivity assays. The administration of amiodarone appeared to inhibit HCV entry independent of genotypes, which was attributed to the down-regulation of CD81 receptor expression. The inhibitory effect of amiodarone also manifested in the HCV assembly step, via the suppression of MTP (microsomal triacylglycerol transfer protein) activity. Amiodarone revealed no effects on HCV replication and translation. With the host factor-targeting characteristics, amiodarone may be an attractive agent for the treatment of HCV infection. PMID- 23659501 TI - Protomagalhaensia richardsoni n. sp. (Apicomplexa: Eugregarinida: Blabericolidae): a new gregarine parasitizing the giant lobster cockroach, Henschoutedenia flexivitta (Dictyoptera: Blaberidae). AB - Protomagalhaensia richardsoni n. sp. (Apicomplexa: Eugregarinida: Blabericolidae) is described from the giant lobster cockroach, Henschoutedenia flexivitta (Dictyoptera: Blattaria: Blaberidae: Oxyhaloinae: Nauphoetini). Oocysts within the genus are dolioform with polar plates. Those of Protomagalhaensia granulosae, Protomagalhaensia wolfi, and Protomagalhaensia blaberae possess distinct apical spines and a sagittal depression that are absent or reduced in P. richardsoni and Protomagalhaensia cerastes. Oocysts of P. richardsoni are significantly longer with larger sporozoite-bearing cavities than those of P. blaberae, P. cerastes, P. granulosae, and P. wolfi (external oocyst length 8.07 MUm vs. 7.42 MUm, 7.50 MUm, 6.87 MUm, 7.56 MUm, respectively; internal oocyst length 6.94 MUm vs. 6.44 MUm, 6.77 MUm, 6.09 MUm, 6.72 MUm, respectively). All 5 species are also distinguished by unique oocyst length/width ratios. No unique morphological structure distinguishes among the gametocysts of Protomagalhaensia species, but gametocysts of P. richardsoni are significantly shorter than those of P. blaberae, P. cerastes, P. granulosae, and P. wolfi (gametocyst length 184.3 MUm vs. 325.15 MUm, 253.27 MUm, 273.63 MUm, 218.3 MUm, respectively). No structurally unique morphological gamont feature distinguishes among species of Protomagalhaensia. Rather, species distinctions are morphometric in nature. In general, gamonts of P. richardsoni are readily distinguished from those of P. cerastes and P. wolfi based on size alone: the latter species being roughly half the size of P. richardsoni. Gamonts of P. richardsoni are most similar to those of P. granulosae and P. blaberae but with relatively smaller primites and more slender satellites. PMID- 23659503 TI - ERCP in a low volume hospital. Arguments "for" and "against" this type of practice. PMID- 23659502 TI - One-step preparation and assembly of aqueous colloidal CdS(x)Se(1-x) nanocrystals within mesoporous TiO2 films for quantum dot-sensitized solar cells. AB - In the field of quantum dots (QDs)-sensitized solar cells, semiconductor QDs sensitizer with a moderate band gap is required in order to sufficiently match the solar spectrum and achieve efficient charge separation. At present, changing the size of QDs is the main method used for adjusting their band gap through quantum size effect, however, the pore sizes of mesoporous TiO2 film set a limit on the allowed size of QDs. Therefore, the tuning of electronic and optical properties by changing the particle size could be limited under some circumstances. In this paper, high-quality aqueous CdS(x)Se(1-x) QDs sensitizer is successfully synthesized and effectively deposited on a mesoporous TiO2 film by a one-step hydrothermal method. In addition to size, alloy QDs provide composition as an additional dimension for tailoring their electronic properties. The alloy composition and band gap can be precisely controlled by tuning the precursor (Se/Na2S.9H2O) ratio while maintaining the similar particle size. By using such CdS(x)Se(1-x) sensitized TiO2 films as photoanodes for solar cell, a maximum power conversion efficiency of 2.23% is achieved under one sun illumination (AM 1.5 G, 100 mW cm(-2)). PMID- 23659504 TI - Efficacy and safety of ERCP in a low-volume hospital. AB - BACKGROUND AND AIMS: there is little scientific evidence on the outcomes of endoscopic retrograde cholangiopancreatography (ERCP) performed in low-volume hospitals; however, in our country, it is growing up its implementation. The objectives of our study were to evaluate the efficacy and safety of this technique performed by two endoscopists with basic training in a center of this nature and analyze the learning curve in the first procedures. PATIENTS AND METHODS: single-center retrospective study of the first 200 ERCP performed in our hospital (analyzing the evolution between the first 100 and 100 following procedures), comparing them with the quality standards proposed in the literature. RESULTS: from February 2009 to April 2011, we performed 200 ERCP in 169 patients, and the most common indications were: Choledocholithiasis (77 %), tumors (14.5 %) and other conditions (8.5 %). The cannulation rate rose from 85 % in the first 100 ERCPto 89 % in the next 100 procedures, clinical success from 81 % to 87 %, decreasing the post-ERCP acute pancreatitis rate from 11 % to 4 %, upper gastrointestinal bleeding (UGIB) from 3 % to 2 % and acute cholangitis from 4 % to 1 %. There was a death from a massive UGIB in a cirrhotic patient in the first group of patients and a case of biliary perforation resolved by surgery in the second one. CONCLUSIONS: the results obtained after performing 200 procedures support the ability to practice ERCP in low-volume hospitals obtaining levels of efficacy and safety in accordance with published quality standards. PMID- 23659505 TI - Primary lymphoma of the colon. AB - BACKGROUND: primary colorectal lymphoma is a very rare disease, representing less than 0.5 % of all primary colorectal neoplasms. The gastrointestinal tract is the most frequently involved site of all extranodal lymphomas, the most common type of that is non-Hodgkin s lymphoma. Early diagnosis is often difficult because of unspecific symptoms. Therapeutic approaches have classically included radical resection, chemotherapy and radiotherapy. MATERIALS AND METHODS: we present our experience in the management of primary colorectal lymphomas over a 17-year period (1994-20011). RESULTS: in this period 7 cases of primary colorectal lymphoma were diagnosed in our institution. Abdominal pain and change in bowel habit were the most frequent symptoms. Five patients underwent emergency surgery because of bleeding or bowel obstruction. All primary intestinal lymphomas studied were of the Bcell phenotype. Patients were followed up for a median of 59 months (range 1-180). Three of them are alive with no evidence of recurrence. CONCLUSION: combination treatment with chemotherapy and surgery can obtain good remission rate. Surgery can resolve complications such bleeding or intestinal perforation that are implicated in lymphoma mortality. PMID- 23659506 TI - Diagnostic accuracy of lugol chromoendoscopy in the oesophagus in patients with head and neck cancer. AB - BACKGROUND AND AIM: patients with head and neck squamous cell malignancies have a higher risk of oesophageal squamous cell carcinomas. Lugol chromoendoscopy in oesophagus is a simple technique with a high diagnostic yield in premalignant lesions. The objective was to analyze its diagnostic accuracy in dysplasia and carcinoma of the oesophagus in high-risk patients. METHODS: prospective study from April/2008 to January/2012 using lugol chromoendoscopy with biopsies of suspicious lugol voiding areas > or = 5 mm. Patients with head and neck malignancies were included, except the ones with iodine allergy, oesophageal varices and contra-indications to standard endoscopy. The reference method was histopathology. RESULTS: 89 patients were enrolled (mean age 62.8 + or - 13.3 years, 87 % men). Primary tumour was located in oropharynx in 37 (41.6 %), in oral cavity in 29 (32.6 %) and in the larynx in 23 (25.8 %) cases. 40.4 % patients had previous treatments and 87 % reported alcohol or tobacco addition. All exams performed without anaesthesia or complications. Nine suspicious lugol voiding areas were observed and biopsied. Histopathological analysis revealed high-grade dysplasia in 2 (2.2 %) and inflammation or normal findings in the others. The sensitivity and specificity for detecting high-grade dysplasia were 100 % and 92 % (95 % CI: 87-97), respectively. Diagnostic accuracy of the test was 92 % (95 % CI: 86-98). CONCLUSION: lugol staining of the oesophagus during endoscopy seems to be a feasible, safe and justified procedure in high-risk populationas it enhances the detection of premalignant lesions. PMID- 23659507 TI - Factors related to length of hospital admission in mild interstitial acute pancreatitis. AB - OBJECTIVES: to describe the clinical practice and the factors associated with length of hospital stay in mild acute pancreatitis. METHODS: we present a retrospective observational study that includes a series of patients admitted to our hospital between January 2007 and December 2009 due to mild acute pancreatitis. Baseline data, treatments and examinations were collected. Variables associated with the length of hospital were determined using a Cox proportional hazards model. RESULTS: 232 patients were included (median age 74.3 years, bedside index for severity in acute pancreatitis score 1, comorbidity Charlson score 1, 52.6 % male). 75.9 % were admitted to the gastroenterology department. Oral diet was reintroduced at 3 (0-11) days and 28 patients (12 %) were intolerant to oral re-feeding. Abdominal ultrasound, a magnetic resonance cholangiopancreatography, endoscopic ultrasound, a computed tomographic scan, and endoscopic retrograde cholangiopancreatography were performed in 92.2, 34.5, 9.5, 28.4 and 14.7 % of admissions, respectively. The length of hospital stay was 8 (1 31) days. The variables independently associated with length of admission were: Charlson index > or = 2 (hazard ratio-HR-1.4, 95 % confidence interval-CI- 1.06 1.84; p: 0.017), admission in gastroenterology department (HR 0.67, 95 % CI 0.49 to 0.93; p: 0.016), fasting period > or = 3 days (HR 1.37, 95 % CI 1.05-1.78; p: 0.02), intolerance to oral re-feeding (HR 1.8, 95 % CI 1.17-2.77; p: 0.007), performance of computed tomographic scan (HR 2.05, 95 % CI 1.49-2.82; p < 0.001), magnetic resonance cholangiopancreatography (HR 1.87, 95 % CI 1.42-2.49; p < 0.001) and endoscopic retrograde cholangiopancreatography (HR 2.23, 95 % CI 1.51 3.3; p < 0.001). CONCLUSIONS: the variables associated with length of hospital stay were comorbidity, department in charge, fasting period, food intolerance and complementary explorations. PMID- 23659508 TI - Vaccination of patients with inflammatory bowel disease. Practical recommendations. AB - Patients with inflammatory bowel disease (IBD) have a greater risk of infection associated with the endogenous immunosuppression brought about by their underlying disease as well as the exogenous immunosuppression resulting from their therapies. In the last few years guidelines and consensus papers have been issued on the indication of vaccines for these patients as primary prevention of infection. However, vaccine coverage is low, likely because the risk for infection and both safety and efficacy concerns regarding vaccines are scarcely perceived in such cases. The available scientific evidence shows that immunization is safe for most preparations, and bears no association with an increased risk for disease activity. This paper reviews the available scientific literature, and provides recommendations on the vaccination of adults with IBD. PMID- 23659509 TI - Trichotillomania and trichophagia: the causes of Rapunzel syndrome. PMID- 23659510 TI - Abdominal pain and intestinal malrotation in adults. PMID- 23659511 TI - An endoscopic technique for treating symptomatic distal jejunum obstruction by leaving the overtube in place. AB - Double balloon enteroscopy has a limitation for positioning an enteral stent in the distal jejunum through its long, narrow biopsy channel. When the distal end of its overtube is left in place close to the neoplasia with the enteroscope removed, if we push an enteral stent introduction system, it tends to form loops so the techniquecannot be performed with this instrument. However, the double balloon colonoscope has a shorter overtube length and using the same push-and pull technique we can reach the distal jejunum with this instrument by inserting the delivery stent system without loops through its overtube. We present a patient with neoplastic obstruction in the distal jejunum with resolution of his symptoms after positioning an enteral stent. PMID- 23659512 TI - Cholangitis and multiple liver abscesses after percutaneous ethanol injection (PEI) for recurrent hepatocellular carcinoma (HCC). AB - Percutaneous ablation procedures are minimally invasive treatments for unresectable early stage hepatocellular carcinoma (HCC). These techniques are usually safe, but rare and even fatal complications have been described. We present a fatal result after percutaneous ethanol injection (PEI) for the treatment of a recurrent HCC in a non-cirrhotic liver, with subsequent development of diffuse cholangitis and multiple liver abscesses. Although percutaneous drainage and intensive antibiotic treatment were employed, the patient finally died. We discuss about the etiology and the physiopathology of this rare complication in which the therapeutic options are limited and usually unsuccessful. PMID- 23659513 TI - [Percutaneous liver biopsy]. PMID- 23659514 TI - Computed tomography angiography (CTA) in the diagnosis of an infrequent cause of gastrointestinal bleeding. PMID- 23659515 TI - Severe perianal disease degenerated to adenocarcinoma. Is close monitoring of long-term perianal disease necessary? PMID- 23659516 TI - Gastric outlet obstruction after the insertion of a fully filled intragastric balloon. PMID- 23659517 TI - Gastrointestinal stromal tumor associated with a different malignant neoplasia. PMID- 23659518 TI - Severe colitis due to indomethacin suppository. PMID- 23659519 TI - Progressive myoclonus epilepsy: extraneuronal brown pigment deposition and system neurodegeneration in the brains of Japanese patients with novel SCARB2 mutations. AB - AIMS: Mutations in the SCARB2 gene cause a rare autosomal recessive disease, progressive myoclonus epilepsy (PME) with or without renal failure, the former also being designated action myoclonus-renal failure syndrome. Although reported cases have been accumulating, only a few have described its neuropathology. We studied two Japanese patients with PME without renal failure, in whom the ages at onset and disease durations were 45 and 20 years, and 14 and 8.5 years respectively. METHODS: Sequencing and restriction analysis of the SCARB2 gene and neuropathological examination with immunohistochemistry were performed. RESULTS: Gene analyses revealed novel homozygous frameshift and nonsense mutations in the SCARB2 gene. Both cases exhibited deposition of brown pigment in the brain, especially the cerebellar and cerebral cortices. Ultrastructurally, the pigment granules were localized in astrocytes. Neuronal loss and gliosis were also evident in the brain, including the pallidoluysian and cerebello-olivary systems. The spinal cord was also affected. Such changes were less severe in one patient with late-onset disease than in the other patient with early-onset disease. In brain and kidney sections, immunostaining with an antibody against the C-terminus of human SCARB2 revealed decreased levels and no expression of the protein respectively. CONCLUSIONS: The frameshift mutation detected in the patient with late-onset disease is a hitherto undescribed, unique type of SCARB2 gene mutation. The present two patients are the first reported to have clearly demonstrated both extraneuronal brown pigment deposition and system neurodegeneration as neuropathological features of PME with SCARB2 mutations. PMID- 23659520 TI - 'Migrants from over there' or 'racial minority here'? Sexual networks and prevention practices among sub-Saharan African migrants in France. AB - Migrants from sub-Saharan Africa bear a disproportionate burden of HIV infection in Europe, with an increasing proportion of them acquiring HIV after migration. This transformation in the epidemic pattern has raised concerns about the sexual mixing and preventive behaviours of migrants. This paper aims at exploring how racial boundaries shape sexual networks and structure prevention practices among migrants from sub-Saharan Africa. Analyses are based on a French survey carried out among 1874 individuals born in sub-Saharan Africa, aged 18-49 and living in Paris and its surroundings. Our results provide evidence of the existence of African sexual networks, over and beyond those of national origin. The intra African segregation of these sexual networks leads to sexual contacts between migrants from low- and high-HIV prevalence countries, which probably contribute to the development of the epidemic amongst these migrants. Moreover, racially based perceptions of HIV-related risk seem to produce a specific attitude toward prevention practices as shown by higher rates of condom use among migrant women from sub-Saharan Africa with a partner born outside sub-Saharan Africa. As a consequence, community-based approaches to HIV prevention should take into account the identification of migrants from sub-Saharan Africa as a racial minority and not only focus on national borders. PMID- 23659521 TI - Advances in blood-based protein biomarkers for Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative disorder that accounts for the majority of dementia cases. While research over the past decades has made advances into understanding disease pathology, definite AD diagnosis currently relies on confirmation by autopsy. The anticipated dramatic rise in affected individuals over the next decades necessitates the development of diagnostic tests applicable to living individuals, which depends on identification of disease biomarkers. Diagnostics based on blood protein biomarkers are particularly desired since these would allow for economical, rapid and non invasive analysis of individual biomarker profiles. Research is actively ongoing in this field and has led to the identification of autoantibodies and various proteins in the blood that may represent a disease-specific blood signature of AD. This review provides an overview on the progress in the field of identification of AD-specific blood protein biomarkers. PMID- 23659522 TI - Nocturia and sleep quality after transurethral resection of the prostate. AB - OBJECTIVES: To evaluate the clinical efficacy of transurethral resection of the prostate on nocturia and sleep disorders in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. METHODS: A prospective multicenter study including lower urinary tract symptoms suggestive of benign prostatic obstruction patients with nocturia (twice or more) undergoing transurethral resection of the prostate was carried out. All patients were assessed using the International Prostate Symptom Score and the Pittsburgh Sleep Quality Index at baseline, and 6 months after transurethral resection of the prostate. RESULTS: Overall, 49 patients were included in the study. A total of 20 of them (41%) had a sleep disorder defined as a score of 5.5 or more on the Pittsburgh Sleep Quality Index global score. The nocturia score significantly correlated with component 4 of the Pittsburgh Sleep Quality Index (habitual sleep efficiency). Nocturia significantly decreased after transurethral resection of the prostate from 3.0 +/- 1.2 to 1.9 +/- 0.8, whereas the global Pittsburgh Sleep Quality Index score did not. In 20 patients with a sleep disorder before transurethral resection of the prostate, subjective sleep quality (component 1) and habitual sleep efficiency (component 4) significantly decreased after transurethral resection of the prostate, but this was not the case for the global Pittsburgh Sleep Quality Index score. In 16 patients with a persistent sleep disorder after transurethral resection of the prostate, International Prostate Symptom Score, voiding and storage symptoms score were higher than those of patients without a sleep disorder, although the nocturia score improved equivalently in both groups. CONCLUSIONS: Transurethral resection of the prostate diminishes nocturnal urinary frequency and partly improves sleep quality in patients with nocturia and lower urinary tract symptoms suggestive of benign prostatic obstruction. A persistent sleep disorder after transurethral resection of the prostate is associated with persistent voiding and storage symptoms. PMID- 23659523 TI - Overview of environmental and occupational vanadium exposure and associated health outcomes: an article based on a presentation at the 8th International Symposium on Vanadium Chemistry, Biological Chemistry, and Toxicology, Washington DC, August 15-18, 2012. AB - Vanadium (V) has a variety of applications that make it suitable for use in ceramic production and decoration, production of pigments for a variety of products, an accelerator for drying paint, production of aniline black dye, and as a mordant in coloring textiles. Taking advantage of its hardness, resilience, ability to form alloys, and its resistance to corrosion, V is also used in the production of tools, steel, machinery, and surgical implants. V is employed in producing photographic developers, batteries, and semi-conductors, and in catalyst-based recycling processes. As technologies have evolved, the use of V has increased in jet aircraft and space technology, as well as in manufacture of ultraviolet filter glass to prevent radiation injury. Due to these myriad uses, the potential for occupational exposure to V is ever-evident. Similarly, there is an increased risk for environmental contamination by V agents themselves or as components of by-products released into the environment. For example, the use of V in sulfuric acid production results in the release of soot and/or fly ash rich in vanadium pentoxide. Petroleum refinery, smelting, welding, and cutting of V rich steel alloy, the cleaning and repair of oil-fired boilers, and catalysis of chemical productions are other sources of increased airborne V-bearing particles in local/distant environments. Exposure of non-workers to V is an increasing health concern. Studies have demonstrated associations between exposure to airborne V-bearing particles (as part of air pollution) and increased risks of a variety of pathologies like hypertension, dysrhythmia, systemic inflammation, hyper-coagulation, cancers, and bronchial hyper-reactivity. This paper will provide a review of the history of V usage in occupational settings, documented exposure levels, environmental levels of V associated with pollution, epidemiologic data relating V exposure(s) to adverse health outcomes, and governmental responses to protect both workers and non-workers from exposure to this metal. PMID- 23659524 TI - Photoelectron spectra of some important biological molecules: symmetry-adapted cluster configuration interaction study. AB - In this work, the valence vertical ionization energies (up to 5) of some important biologically active molecules including 2,4-dinitrophenol, 2,4 dinitroanisole, nicotinic acid, nicotinic acid methyl ester, nicotinamide, N,N diethylnicotinamide, barbituric acid, uric acid, cytosine, beta-carotene, and menadione were calculated in the gas phase and compared with the experimental data reported in the literature. The symmetry-adapted-cluster configuration interaction (SAC-CI) general-R method was used to calculate the ionization energies. The intensity of each ionization band was evaluated using the monopole approximation. Comparison of the calculated photoelectron spectrum of each molecule with its corresponding experimental spectra allowed for assigning the photoelectron bands by natural bonding orbital (NBO) calculations even though some of the associated bands were significantly overlapped for some molecules. Among the considered molecules, there was no agreement between the experimental and calculated photoelectron spectrum of beta-carotene. The reason for this disagreement was theoretically investigated and attributed to the degradation and decomposition of beta-carotene. The calculated first ionization energies of the considered molecules were correlated with their Huckel k-index to obtain Coulomb (alpha) and resonance (beta) integrals of the Huckel molecular orbital theory for the biomolecules considered in this study. A linear correlation was found between the first ionization energy and the Huckel k-index. PMID- 23659525 TI - Blood pressure levels but not hypertensive complications have increased in Type 1 diabetes pregnancies during 1989-2010. AB - AIMS: The pre-pregnancy BMI and the third trimester HbA(1c) levels increased in Finnish parturients with Type 1 diabetes during 1989-2008. The aim of the present study was to investigate whether these trends have been accompanied by increases in blood pressure or hypertensive complications. Hypertension trends were analysed using the definitions of hypertension of both the American College of Obstetricians and Gynecologists and the American Diabetes Association. The associations of hypertension, as defined by the latter criteria, with perinatal complications were also studied. METHODS: The records of a cohort of 1007 consecutive patients with Type 1 diabetes with a singleton live childbirth during 1989-2010 at the Helsinki University Central Hospital were studied. RESULTS: The frequencies of hypertensive pregnancy complications did not change, but the mean diastolic blood pressure increased in normotensive parturients in all trimesters. The proportion of patients with systolic blood pressure > 130 mmHg or diastolic blood pressure > 80 mmHg in the first, second and third trimesters of pregnancy increased from 25 to 33%, from 26 to 35% and from 57 to 71%, respectively. Systolic blood pressure of 131-139 mmHg or diastolic blood pressure of 81-89 mmHg in the third trimester was associated with umbilical artery pH < 7.15. CONCLUSIONS: Blood pressure of patients with Type 1 diabetes during pregnancy is increasing. A growing proportion of women with Type 1 diabetes exceed the American Diabetes Association's definition of hypertension during pregnancy. PMID- 23659526 TI - Antibodies of undetermined significance: nuisance or near miss? PMID- 23659527 TI - Single-page reports of new alleles or antigens. PMID- 23659528 TI - Therapy with fibrinogen concentrate: clinical and ethical considerations. PMID- 23659529 TI - In reply. PMID- 23659530 TI - Neonatal alloimmunization: a rare case of multiple alloantibody formation in a patient with disseminated histoplasmosis. PMID- 23659531 TI - Absence of evidence of parvovirus B19 transmission by plasma-derived clotting concentrates derived from B19V nucleic acid technology-tested plasma and including effective steps for the inactivation or removal of nonenveloped viruses. PMID- 23659533 TI - Intermittent leukocytosis in an asymptomatic platelet donor. PMID- 23659532 TI - Evidence for the continued transmission of parvovirus B19 in patients with bleeding disorders treated with plasma-derived factor concentrates. PMID- 23659534 TI - Systemic hypersensitivity reaction mimicking anaphylaxis after first filgrastim administration in a healthy donor. PMID- 23659535 TI - Reduced oxide sites and surface corrugation affecting the reactivity, thermal stability, and selectivity of supported Au-Pd bimetallic clusters on SiO2/Si(100). AB - The morphology and surface elemental composition of Au-Pd bimetallic nanoclusters are reported to be sensitive to and affected by reduced silicon defect sites and structural corrugation on SiO2/Si(100), generated by argon ion sputtering under ultrahigh vacuum (UHV) conditions. Metastable structures of the bimetallic clusters, where Au atoms are depleted from the top surface upon annealing, are stabilized by the interaction with the reduced silica sites, as indicated from CO temperature programmed desorption (TPD) titration measurements. Acetylene conversion to ethylene and benzene has been studied as a probe reaction, revealing the modification of selectivity and reactivity enhancement in addition to improved thermal stability on substrates rich in reduced-silica sites. These observations suggest that these unique sites play an important role in anchoring thermodynamically metastable conformations of supported Au-Pd bimetallic catalysts and dictate their high-temperature activity. PMID- 23659536 TI - A trigonal-prismatic hexanuclear technetium(II) bromide cluster: solid-state synthesis and crystallographic and electronic structure. AB - The compound Na{[Tc6Br12]2Br} has been obtained from the decomposition of TcBr4 under vacuum in a Pyrex ampule at 450 degrees C. The stoichiometry of the compound has been confirmed by energy-dispersive X-ray spectroscopy and its structure determined by single-crystal X-ray diffraction. The compound contains a trigonal-prismatic hexanuclear [Tc6Br12] cluster. The cluster is composed of two triangular Tc3Br6 units linked by multiple Tc-Tc bonds. In the Tc3Br6 unit, the average Tc-Tc distance [2.6845(5) A] is characteristic of Tc-Tc single bonds, while the average Tc-Tc distance between the two triangular units [2.1735(5) A] is characteristic of Tc=Tc triple bonds. The electronic structure of the [Tc6Br12] cluster was studied by first-principles calculations, which confirm the presence of single and triple Tc-Tc bonds in the cluster. PMID- 23659537 TI - Association of vitamin D insufficiency with adiposity and metabolic disorders in Brazilian adolescents. AB - OBJECTIVE: The present study aimed to evaluate the frequency of deficiency/insufficiency of vitamin D in adolescents and its relationship to overweight and metabolic disorders. DESIGN: Cross-sectional study. Nutritional status was assessed by BMI according to WHO recommendations. Dietary intake was evaluated using a 3 d dietary record. The biochemical evaluation comprised measurements of serum lipids, lipoproteins, glucose, insulin, calcidiol (25(OH)D) and parathyroid hormone. Insulin resistance was calculated using the homeostasis model assessment. Body composition and blood pressure were assessed. SETTING: Fifteen schools (eight public and seven private) in the central city of Juiz de Fora, Brazil. SUBJECTS: The analysis included a study population of 160 adolescents (seventy-seven eutrophic and eighty-three overweight) aged 15 to 17 years. RESULTS: Vitamin D deficiency and insufficiency was observed in 1.25 and 70.6 % of adolescents, respectively. Serum 25(OH)D levels were statistically lower in adolescents with weight excess, abdominal obesity, hypercholesterolaemia, higher levels of parathyroid hormone, insulin resistance, hyperinsulinaemia and hypertension (P < 0.05). Lower BMI and waist circumference were observed in the third (highest) tertile of vitamin D intake for all adolescents. The high prevalence of vitamin D insufficiency is primarily nutritional and reflects a low vitamin D intake. CONCLUSIONS: Our results support the negative association among serum 25(OH)D levels and vitamin D intake with non skeletal outcomes in Brazilian adolescents. Vitamin D fortification of foods and/or the use of vitamin D supplements need to be considered to raise vitamin D intake in the adolescent population, even in a sunny country like Brazil. PMID- 23659538 TI - Klebsiella pneumoniae harbouring OXA-48 carbapenemase in a Libyan refugee in Italy. AB - A carbapenem-resistant Klebsiella pneumoniae was isolated from a blood-culture of an inpatient from Libya, hospitalized in the intensive-care unit of Negrar Hospital, Italy. The clinical isolate carried the following beta-lactamase genes, bla(TEM -1), bla(SHV -11), bla(OXA -1), bla(CTX -M-15) and bla(OXA -48), respectively. The bla(OXA -48) gene was inserted in the Tn1999.2 transposon type, carried on a conjugative, 60-kilobase plasmid, that presented an L/M backbone, hosted by a multidrug-resistant ST 101 K. pneumoniae strain. Our report highlights the international transfer of bla(OXA -48) gene and the importance of screening measures of multidrug-resistant Enterobacteriaceae. PMID- 23659539 TI - Provision of bednets and water filters to delay HIV-1 progression: cost effectiveness analysis of a Kenyan multisite study. AB - OBJECTIVE: To estimate the effectiveness, costs and cost-effectiveness of providing long-lasting insecticide-treated nets (LLINs) and point-of-use water filters to antiretroviral therapy (ART)-naive HIV-infected adults and their family members, in the context of a multisite study in Kenya of 589 HIV-positive adults followed on average for 1.7 years. METHODS: The effectiveness, costs and cost-effectiveness of the intervention were estimated using an epidemiologic-cost model. Model epidemiologic inputs were derived from the Kenya multisite study data, local epidemiological data and from the published literature. Model cost inputs were derived from published literature specific to Kenya. Uncertainty in the model estimates was assessed through univariate and multivariate sensitivity analyses. RESULTS: We estimated net cost savings of about US$ 26 000 for the intervention, over 1.7 years. Even when ignoring net cost savings, the intervention was found to be very cost-effective at a cost of US$ 3100 per death averted or US$ 99 per disability-adjusted life year (DALY) averted. The findings were robust to the sensitivity analysis and remained most sensitive to both the duration of ART use and the cost of ART per person-year. CONCLUSIONS: The provision of LLINs and water filters to ART-naive HIV-infected adults in the Kenyan study resulted in substantial net cost savings, due to the delay in the initiation of ART. The addition of an LLIN and a point-of-use water filter to the existing package of care provided to ART-naive HIV-infected adults could bring substantial cost savings to resource-constrained health systems in low- and middle-income countries. PMID- 23659540 TI - Intricacies of the contralateral oblique view for interlaminar epidural access. PMID- 23659541 TI - Chicken meat nutritional value when feeding red palm oil, palm oil or rendered animal fat in combinations with linseed oil, rapeseed oil and two levels of selenium. AB - Chicken meat nutritional value with regard to fatty acid composition and selenium content depends on the choice of dietary oil and selenium level used in the chickens' feed. The objective of this study was to investigate the effect of replacing commonly used rendered animal fat as a dietary source of saturated fatty acids and soybean oil as a source of unsaturated fatty acids, with palm oil and red palm oil in combinations with rapeseed oil, linseed oil and two levels of selenium enriched yeast on chicken breast meat nutritional value. The study also wished to see whether red palm oil had a cholesterol lowering effect on chicken plasma.204 male, newly hatched broiler chickens were randomly divided into twelve dietary treatment groups, and individually fed one out of six dietary fat combinations combined with either low (0.1 mg Se /kg feed) or high (1 mg Se/kg feed) dietary selenium levels. Linseed oil, independent of accompanying dietary fat source, lead to increased levels of the n-3 EPA, DPA and DHA and reduced levels of the n-6 arachidonic acid (AA). The ratio between AA/EPA was reduced from 19/1 in the soybean oil dietary groups to 1.7/1 in the linseed oil dietary groups. Dietary red palm oil reduced total chicken plasma cholesterol levels. There were no differences between the dietary groups with regard to measured meat antioxidant capacity or sensory evaluation. Chicken meat selenium levels were clearly influenced by dietary selenium levels, but were not influenced by feed fatty acid composition. High dietary selenium level lead to marginally increased n-3 EPA and higher meat fat % in breast muscle but did not influence the other LC PUFA levels. Chicken breast meat nutritional value from the soybean oil and low selenium dietary groups may be regarded as less beneficial compared to the breast meat from the linseed oil and high selenium dietary groups. Replacing rendered animal fat with palm oil and red palm oil had no negative effects on chicken muscle nutritional value with regard to fatty acid composition. Red palm oil decreased total chicken plasma cholesterol, confirming the cholesterol reducing effect of this dietary oil. PMID- 23659542 TI - Vitamin E reduces TGF-beta2-induced changes in human trabecular meshwork cells. AB - AIM: To determine the effects of vitamin E on transforming growth factor-beta2 (TGF-beta2)-induced cellular changes in cultured human trabecular meshwork (TM) cells. MATERIALS AND METHODS: Human TM cells were pre-treated with different concentrations of vitamin E. Afterwards, cells were exposed to 1.0 ng/ml TGF beta2 for 24 h. Expressions of the heat shock protein alphaB-crystallin, the extracellular matrix (ECM) component fibronectin and the ECM-degrading enzyme matrix metalloproteinase-2 (MMP-2) were examined by real-time polymerase chain reaction (PCR) analyses. The cytoskeleton was investigated by phalloidin staining. RESULTS: TGF-beta2 increased the expressions of alphaB-crystallin and fibronectin and reduced the levels of MMP-2. TGF-beta2 induced the formation of actin stress fibers and cross-linked actin networks. Pre-treatment with different concentrations of vitamin E reversed the TGF-beta2-induced cellular changes in cultured human TM cells. CONCLUSIONS: TGF-beta2-mediated changes in human TM cells could be reduced by pre-treatment with vitamin E. Therefore, it may be speculated that increasing the antioxidative capacity may help to lower the incidence of characteristic glaucomatous changes in the TM. PMID- 23659543 TI - Trajectories of functioning after remission from anxiety disorders: 2-year course and outcome predictors. AB - BACKGROUND: Anxiety disorders are associated with substantial functional limitations but the course of functioning following symptom remission remains largely unknown. METHOD: Using data from the Netherlands Study of Depression and Anxiety (NESDA), we examined the 2-year trajectories of functioning in participants with chronic (n = 586) or remitting anxiety disorders (n = 385) and in healthy controls (n = 585). In participants with remitting anxiety disorders, we identified predictors of functioning from among sociodemographic, clinical and vulnerability variables. Data were analysed using linear mixed models (LMMs). Functioning was assessed with the World Health Organization Disability Assessment Schedule II (WHO DAS II). RESULTS: At baseline, participants with remitting anxiety disorders functioned significantly better than those with chronic anxiety disorders, but significantly worse than controls. In both anxiety disorder groups, most impairment was reported in social functioning, occupational functioning and cognition. During the follow-up, functioning improved in both groups, probably due to treatments received. Participants who achieved symptom remission experienced moderate improvements in social functioning and cognition but not in occupational functioning. Of those who remitted, 45.8% reported functioning scores similar to healthy controls whereas 28.5% still functioned at the level of those with chronic anxiety disorders. Worse functioning was predicted by severe anxiety disorders, use of psychological treatment, co-morbid depressive disorders and maladaptive personality traits. CONCLUSIONS: In anxiety disorders, symptom remission is accompanied by improvements in functioning but significant functional impairments may persist because of co-morbid disorders, lower functioning prior to the onset of the anxiety disorder or residual subthreshold anxiety symptoms. PMID- 23659544 TI - Prediction of the active layer nanomorphology in polymer solar cells using molecular dynamics simulation. AB - Active layer nanomorphology is a major factor that determines the efficiency of bulk heterojunction polymer solar cells (PSCs). Synthesizing diblock copolymers in which acceptor and donor materials are the constituent blocks is the most recent method to control the structure of the active layer. In the current work, a computational method is proposed to predict the nanomorphology of the active layer consisting of a diblock copolymer. Diblock copolymers have a tendency to self-organize and form well-defined nanostructures. The shape of the structure depends on the Flory-Huggins interaction parameter (i.e., chi), the total degree of polymerization (N) and volume fractions of the constituent blocks (phii). In this work, molecular dynamics (MD) simulations were used to calculate chi parameters for two different block copolymers used in PSCs: P3HT-b-poly(S8A2)-C60 and P3HT-b-poly(n-butyl acrylate-stat-acrylate perylene) also known as P3HT-b PPerAcr. Such calculations indicated strong segregation of blocks into cylindrical structure for P3HT-b-poly(S8A2)-C60 and intermediate segregation into cylindrical structure for P3HT-b-PPerAcr. Experimental results of P3HT-b poly(S8A2)-C60 and P3HT-b-PTP4AP, a diblock copolymer having very similar structure to P3HT-b-PPerAcr, validate our predictions. PMID- 23659545 TI - Finger taps and constipation are closely related to symptoms of overactive bladder in male patients with Parkinson's disease. AB - OBJECTIVES: To assess which motor and non-motor symptoms are closely related to overactive bladder severity in male patients with Parkinson's disease. METHODS: A total of 160 male patients (mean age 71.4 +/- 8.2 years) diagnosed with Parkinson's disease were included in the present study at Osaka University and affiliated hospitals. The severity of Parkinson's disease was classified as stage 3, 4 or 5 based on the Hoehn and Yahr staging system. Disease duration was 8.9 +/ 5.1 years. Age, seven items from the Unified Parkinson's Disease Rating Scale motor section part III and three non-motor symptoms were assessed by multivariate analysis for their impact on the overactive bladder symptom score, a specific questionnaire for overactive bladder. RESULTS: Overactive bladder symptom score was significantly higher in the group with severe motor symptoms related to finger taps and gait than in the group with mild motor symptoms related to these two factors. Furthermore, overactive bladder symptom score of patients with erectile dysfunction and constipation was significantly higher than that in patients without these symptoms. Multivariate analysis identified only finger taps and constipation as factors independently associated with overactive bladder symptom score. CONCLUSIONS: Although a study on a larger scale is required to further assess the association of Parkinson's disease symptoms with overactive bladder symptom score, information on finger taps and severity of constipation should be obtained when assessing urological patients with Parkinson's disease. PMID- 23659547 TI - Two new cholinesterase inhibitors asiatoates A and B from Buddleja asiatica. AB - Two new benzoates, asiatoate A (1) and asiatoate B (2), have been isolated from the ethyl acetate soluble fraction of Buddleja asiatica whole plant. Their structures were elucidated with the help of spectroscopic data. Both showed significant inhibitory effect on acetylcholinesterase (AChE) and butylcholinesterase (BChE) in a dose-dependent manner. The IC50 values of compounds 1-2 were 5.54 and 8.34 MUM against AChE while 30.94 and 35.94 MUM against BChE, respectively. PMID- 23659548 TI - Sorption equilibria of ethanol on cork. AB - We report here for the first time a thermodynamic study of gaseous ethanol sorption on raw cork powder and plate. Our study aims at a better understanding of the reactivity of this material when used as a stopper under enological conditions, thus in close contact with a hydroethanolic solution, wine. Sorption desorption isotherms were accurately measured by thermogravimetry at 298 K in a large range of relative pressures. Sorption enthalpies were determined by calorimetry as a function of loading. Sorption-desorption isotherms exhibit a hysteresis loop probably due to the swelling of the material and the absorption of ethanol. Surprisingly, the sorption enthalpy of ethanol becomes lower than the liquefaction enthalpy as the filling increases. This result could be attributed to the swelling of the material, which would generate endothermic effects. Sorption of SO2 on cork containing ethanol was also studied. When the ethanol content in cork is 2 wt %, the amount of SO2 sorbed is divided by 2. Thus, ethanol does not enhance the sorption rate for SO2 but, on the contrary, decreases the SO2 sorption activity onto cork, probably because of competitive sorption mechanisms. PMID- 23659546 TI - Racial/ethnic differences in hepatic steatosis in a population-based cohort of post-menopausal women: the Michigan Study of Women's Health Across the Nation. AB - AIMS: The prevalence of hepatic steatosis may differ between post-menopausal African-American women and non-Hispanic white women and by sex hormone binding globulin level. We examined prevalence of hepatic steatosis by race/ethnicity and associations with sex hormone binding globulin. METHODS: Participants included post-menopausal women who underwent hepatic ultrasound (n = 345) at the Michigan site of the Study of Women's Health Across the Nation, a population-based study. We examined hepatic steatosis prevalence by race/ethnicity and used logistic regression models to calculate the odds of hepatic steatosis with race/ethnicity and sex hormone binding globulin, after adjustment for age, alcohol use, waist circumference, high density lipoprotein cholesterol, triglycerides, systolic blood pressure and use of medications reported to lower intrahepatic fat. RESULTS: Fewer African-American women than non-Hispanic white women had hepatic steatosis (23 vs. 36%, P = 0.01). African-American women had lower triglyceride and low-density lipoprotein cholesterol levels, but higher blood pressure and follicle-stimulating hormone levels (P < 0.05). In the optimal-fitting multivariable models, women in the highest tertile of sex hormone binding globulin (60.2-220.3 nmol/l) had a lower odds of hepatic steatosis (odds ratio 0.43, 95% CI 0.20-0.93) compared with women in the lowest tertile of sex hormone binding globulin (10.5-40.3 nmol/l). There was an interaction between race/ethnicity and medication use whereby non-Hispanic white women using medications had three times higher odds of hepatic steatosis compared with African-American women not using medications (odds ratio 3.36, 95% CI 1.07 10.58). Interactions between race/ethnicity and other variables, including sex hormone levels, were not significant. CONCLUSIONS: Hepatic steatosis on ultrasound may be more common in post-menopausal non-Hispanic white women than African-American women and was associated with lower levels of sex hormone binding globulin. PMID- 23659550 TI - Cerebrotendinous xanthomatosis with the c.379C>T (p.R127W) mutation in the CYP27A1 gene associated with premature age-associated limbic tauopathy. PMID- 23659551 TI - Crystal growth, structure, polarization, and magnetic properties of cesium vanadate, Cs2V3O8: a structure-property study. AB - Cesium vanadate, Cs2V3O8, a member of the fresnoite-type structure, was synthesized via a hydrothermal route and structurally characterized by single crystal X-ray diffraction. Cs2V3O8 crystallizes in a noncentrosymmetric polar space group, P4bm, with crystal data of a = 8.9448(4) A, c = 6.0032(3) A, V = 480.31(4) A(3), and Z = 2. The material exhibits a two-dimensional layered crystal structure consisting of corner-shared V(5+)O4 and V(4+)O5 polyhedra. The layers are separated by the cesium cations. The alignment of the individual polyhedra results in a macroscopic polarity for Cs2V3O8. Frequency-dependent polarization measurements indicate that the material is not ferroelectric. A pyroelectric coefficient of -2.0 MUC m(-2) K(-1) was obtained from pyroelectric measurements taken as a function of the temperature. The magnetic susceptibility data were measured as a function of the temperature and yielded an effective magnetic moment of 1.78 MUB for the V(4+) cation. Short-range magnetic ordering was observed around 7 K. The susceptibility data were fit to the Heisenberg square-lattice model supporting that the short-range magnetic interactions are antiferromagnetic and two-dimensional. IR and thermal properties were also characterized. PMID- 23659552 TI - Do Dutch nutrition and dietetics students meet nutritional requirements during education? AB - OBJECTIVES: To compare the dietary intakes of Dutch nutrition and dietetics students with the Dutch RDA and the Dutch National Food Consumption Survey (DNFCS), and to assess whether dietary intake changes during education. DESIGN: Cross-sectional and longitudinal research (2004-2010). SETTING: Data collection by 7 d dietary record and questionnaire. SUBJECTS: Dutch nutrition and dietetics students. RESULTS: Three hundred and fifty-two first-year and 216 fourth-year students were included. One hundred and thirty-three students in three cohorts were assessed twice. Of first-year students, >80 % met the RDA for all macronutrients. Of these students only 37 % met the RDA for fibre and in 43 % intake of saturated fat was too high. Fourth-year students more often met the RDA for fruits (55 %) and vegetables (74 %) compared with first-year students (32 % and 40 %, respectively). Intake of fruits and vegetables of both first- and fourth-year students was much higher than that of DNFCS participants (where 2 % and 7 %, respectively, met the corresponding RDA). Only <25 % of fourth-year students met the RDA for Fe, Se and vitamin D. In the cohorts, dietary intake for all macronutrients stabilised from the first to the fourth year (>80 %). Intakes of dietary fibre, Ca, Mg, Se, riboflavin, niacin, fruits, vegetables and fish improved significantly during education. CONCLUSIONS: Dietary intake of nutrition and dietetics students is much better than that of DNFCS participants and improved during education. However, there is still a gap between actual dietary intake and the RDA, especially for Fe, Se and vitamin D. PMID- 23659554 TI - Silymarin protects from varicocele-induced damages in testis and improves sperm quality: evidence for E2f1 involvement. AB - This study was designed to evaluate the protective effect of silymarin (SMN) on varicocele-induced damage in testis and its effects on sperm parameters and on antioxidant status. Wistar rats were divided into three groups: control-sham, varicocele-induced, and SMN-treated varicocelized (50mg/kg, orally) rats. The sperm count, DNA integrity, and histone-protamine transition was evaluated after 42 days. The antioxidant status was analyzed by determining testicular malondialdehyde (MDA) and total thiol molecules (TTM). The endocrine status of the testicular tissue was estimated by counting the normal Leydig cell distribution/mm(2) and by determination of serum testosterone. The expression of E2f1 mRNA was analyzed using RT-PCR. Carbohydrate depletion and lipid foci replacement in germinal cells were examined by histochemical analyses. Silymarin rehabilitated the varicocele-induced Leydig cell degeneration and testosterone reduction. In addition, SMN recovered the varicocele-induced reduction of TTM and lowered significantly (P < 0.05) the varicocele-elevated content of MDA. The SMN treatment resulted in a significant (P < 0.05) down-regulation of the VCL-up regulated E2f1 mRNA. Silymarin-treated animals were protected from varicocele induced testicular atrophy and these animals showed a significant (P < 0.05) increase in the percentage of seminiferous tubules with positive tubular differentiation, repopulation, and spermiogenesis indices. Furthermore, SMN improved the varicocele-induced carbohydrate reduction in germinal cells. Our data suggest that in addition to oxidative stress, alteration in the testicular endocrine function plays a crucial role in the pathogenesis of varicocele. Moreover, the protective effects of SMN on varicocele-induced damage may reflect its antioxidant property, which may be mediated via the E2f1 transcription factor. PMID- 23659555 TI - Prognostic value of human papillomavirus types 16 and 18 DNA physical status in cervical intraepithelial neoplasia. AB - The aim of this work was to assess the value of the physical status of human papillomavirus (HPV) DNA as a disease marker for cervical cancer development in a set of 248 DNA samples previously genotyped as HPV 16 or 18, by calculating the E2/E6 ratio through real-time PCR. There was a significant difference in integration status according to disease grade for both genotypes (p <0.001). Furthermore, especially for HPV 18, determining the DNA physical status could be a useful biomarker in predicting cervical cancer risk development, with a lower E2/E6 ratio clinically associated with the development of a precancerous lesion. PMID- 23659556 TI - 'Once the stuff's left my body, it's not me': service users' views on unlinked anonymous testing of blood for HIV. AB - This paper reports on the qualitative component of a mixed-methods study on unlinked anonymous testing for HIV in genitourinary medicine (GUM) clinics in two English cities. Unlinked anonymous testing is a system of monitoring population prevalence by testing residual blood samples taken for diagnostic purposes after they have been unlinked and anonymised from their source. Little is known about how individuals feel about their blood being tested in this way without their explicit consent, nor is it clear whether the process of unlinking blood affects how people feel about the use of their bodily material for public health surveillance purposes. We report participants' views on these issues, drawing on in-depth interviews with 20 GUM clinic users. The majority thought it preferable for blood samples to be used for population surveillance rather than being discarded. For most, blood and bodily tissue were not seen to represent personal identity even though participants understood that information about them could be gleaned from their analysis. The provision of information, rather than a strict consent process, was advocated as many felt that transactions between health professionals and patients should be as transparent as possible. PMID- 23659557 TI - A comparison of four different approaches to measuring health utility in depressed patients. AB - BACKGROUND: A variety of instruments are used to measure health related quality of life. Few data exist on the performance and agreement of different instruments in a depressed population. The aim of this study was to investigate agreement between, and suitability of, the EQ-5D-3L, EQ-5D Visual Analogue Scale (EQ-5D VAS), SF-6D and SF-12 new algorithm for measuring health utility in depressed patients. METHODS: The intraclass correlation coefficient (ICC) and Bland and Altman approaches were used to assess agreement. Instrument sensitivity was analysed by: (1) plotting utility scores for the instruments against one another; (2) correlating utility scores and depressive symptoms (Beck Depression Inventory (BDI)); and (3) using Tukey's procedure. Receiver Operating Characteristic (ROC) analysis assessed instrument responsiveness to change. Acceptability was assessed by comparing instrument completion rates. RESULTS: The overall ICC was 0.57. Bland and Altman plots showed wide limits of agreement for each pair wise comparison, except between the SF-6D and SF-12 new algorithm. Plots of utility scores displayed 'ceiling effects' in the EQ-5D-3L index and 'floor effects' in the SF-6D and SF-12 new algorithm. All instruments showed a negative monotonic relationship with BDI, but the EQ-5D-3L index and EQ-5D VAS could not differentiate between depression severity sub-groups. The SF-based instruments were better able to detect changes in health state over time. There was no difference in completion rates of the four instruments. CONCLUSIONS: There was a lack of agreement between utility scores generated by the different instruments. According to the criteria of sensitivity, responsiveness and acceptability that we applied, the SF-6D and SF-12 may be more suitable for the measurement of health related utility in a depressed population than the EQ-5D-3L, which is the instrument currently recommended by NICE. PMID- 23659558 TI - Antipsychotic drug-treated patients best suited for metformin therapy. PMID- 23659559 TI - Clinical response at Day 3 of therapy and economic outcomes in hospitalized patients with acute bacterial skin and skin structure infection (ABSSSI). AB - OBJECTIVE: The FDA recently issued guidance for the types of infections that should be included in trials to support an indication for antibacterial treatment. The latest FDA guidance recommends assessing response to drug therapy at 48 to 72 hours as the primary endpoint in clinical trials. This study evaluated clinical and economic outcomes among acute bacterial skin and skin structure infections (ABSSSI) patients hospitalized at a 3000-bed healthcare system in New Jersey. RESEARCH DESIGN AND METHODS: In this retrospective cohort analysis, adult ABSSSI patients hospitalized between July 2010 and December 2011 were stratified based on infection type: cellulitis/erysipelas and major cutaneous abscess, wound infection, and all ABSSSI. Initial antibiotic therapy was assessed by individual agent, regimen, and MRSA coverage. Day 3 response to initial antibiotic therapy was evaluated based on temperature and lesion cessation outcomes; clinical response rates were assessed by initial therapy and pathogen for each cohort. The impact of response on length of stay (LOS), cost of care, and antibiotic treatment duration were also evaluated. RESULTS: Commonly used antibiotics included vancomycin, cefazolin, piperacillin-tazobactam, and ampicillin-sulbactam; over 40% of patients received empiric therapy with activity against MRSA. Clinical non-response to initial antimicrobial therapy at Day 3 was 39.9%, 30.3%, and 60.7%, for all ABSSSI, cellulitis/abscess, and wound infection patients, respectively. The cost of care among non-responders was over 1.5 times that of responders (p < 0.0001). Non-response to initial therapy was associated with a 3.7 day increase in duration of antibiotic treatment (p < 0.0001). CONCLUSIONS: Results of this study demonstrate that a significant percentage of ABSSSI patients, particularly those with wound infection, were not achieving clinical response at Day 3 of therapy. Failure to respond to drug therapy is associated with substantial increases in LOS, antibiotic treatment duration, and cost of care. LIMITATIONS: This had the inherent limitations associated with a retrospective chart review; because data was initially collected for clinical rather than research purposes, certain information may have been absent, incomplete, or missed by data abstractors. PMID- 23659560 TI - Consensus guidelines for the use of bowel preparation prior to colonic diagnostic procedures: colonoscopy and small bowel video capsule endoscopy. AB - BACKGROUND: Adequate bowel preparation prior to colonic diagnostic procedures is essential to ensure adequate visualisation. SCOPE: This consensus aims to provide guidance as to the appropriate use of bowel preparation for a range of defined clinical circumstances. A consensus group from across Europe was convened and met to discuss appropriate bowel preparation. The use of polyethylene glycol (PEG), sodium picosulphate and sodium phosphate (NaP), together with other agents, prokinetics and simethicone, in colonoscopy and small bowel video capsule endoscopy were considered. A systematic review of the literature was carried out and additional unpublished data was obtained from the members of the consensus group where required. Recommendations were graded according to the level of evidence. FINDINGS: PEG-based regimens are recommended first line for both procedures, since their use is supported by good efficacy and safety data. Sodium picosulphate-based regimens are recommended second line as their cleansing efficacy appears less than PEG-based regimens. NaP is not recommended for bowel cleansing due to the potential for renal damage and other adverse events. However, the use of NaP is acceptable in patients in whom PEG or sodium picosulphate is ineffective or not tolerated. NaP should not be used in patients with chronic kidney disease, pre-existing electrolyte disturbances, congestive heart failure, cirrhosis or a history of hypertension. The timing of the dose, dietary restrictions, use in special patient groups and recording of the quality of bowel preparation are also considered for patients undergoing colonoscopy. During the development of the guidelines the European Society of Gastrointestinal Endoscopy (ESGE) issued guidance on bowel preparation for colonoscopy. The ESGE guidelines and these consensus guidelines share many recommendations; differences between the guidelines are reviewed. CONCLUSION: The use of bowel preparation should be tailored to the individual patient and their specific clinical circumstances. PMID- 23659561 TI - Treatment adherence with vildagliptin compared to sulphonylurea as add-on to metformin in Muslim patients with type 2 diabetes mellitus fasting during Ramadan. AB - OBJECTIVE: To assess treatment adherence to dipeptidyl peptidase-4 inhibitor vildagliptin compared with sulphonylureas (SU) in Muslim patients with type 2 diabetes mellitus who were fasting during Ramadan in the UK. RESEARCH DESIGN AND METHODS: This prospective, observational cohort study was conducted in four UK centres. Patients already taking vildagliptin (50 mg twice a day) or an SU as add on therapy to metformin were followed up for <=16 weeks. They were asked to record all missed doses of anti-diabetes medications. RESULTS: Of the 72 patients enrolled (vildagliptin, n = 30; SU, n = 41; not allocated to treatment, n = 1), 59 (81.9%) completed the study (vildagliptin, n = 23; SU, n = 36), including one patient in the SU arm who completed but failed to provide information on missed doses; all patients in the SU arm were taking gliclazide. In the vildagliptin arm one patient (4.3%) missed a total of four doses while in the SU arm 10 patients (27.8%) missed a total of 266 doses (mean [SD] number of doses missed per patient: 26.6 [16.5]). The mean (SD) proportions of doses missed during fasting were 0.2% (0.9) and 10.4% (21.7) in the vildagliptin and SU arms, respectively, with a significant mean between-group difference of -10.2% (95% CI: -19.3%, 1.1%; p = 0.0292). There were no patients in the vildagliptin arm who missed more than 20% of OAD doses compared with 19.4% in the SU arm (p = 0.0358). Of the patients receiving an SU, 15 (42%) collectively reported 34 hypoglycaemic events (HEs) and one grade 2 HE; of these, fewer were non-adherent (n = 6, 40%) than adherent (n = 9, 60%). No patients reported HEs in the vildagliptin arm. CONCLUSION: During Ramadan fasting, treatment with vildagliptin resulted in better treatment adherence compared with SU in Muslim patients with type 2 diabetes mellitus. Study limitations are the sample size and the lack of diet and exercise data. PMID- 23659562 TI - The efficacy and tolerability of perampanel and other recently approved anti epileptic drugs for the treatment of refractory partial onset seizure: a systematic review and Bayesian network meta-analysis. AB - OBJECTIVES: This paper compares the efficacy and tolerability of perampanel (PER) relative to other recently approved anti-epileptic drug (AEDs) - lacosamide (LCS), retigabine (RTG), and eslicarbazepine (ESL) for the adjunctive treatment of partial onset seizures with or without secondary generalization and specifically in the secondary generalization subgroup. MATERIALS AND METHODS: A systematic literature review of all RCTs of PER and selected AEDs in EMBASE, Medline, and the Cochrane Central from 1998 to January 2011 with an update in PubMed in March 2013 was performed. A network meta-analysis was conducted for 50% responder rate for overall seizures; withdrawal due to adverse events; seizure freedom; and 50% responder rate for secondary generalized seizures. RESULTS: Twelve RCTs (three PER, three LCS, three RTG and three ESL) were included. PER performed significantly better than placebo for 'responder rate' (OR 2.151, 95% CrI 1.348-3.472) and 'seizure freedom' (OR 2.507, 95% CrI 1.067-7.429). When compared to other agents, PER was found to be equally effective. For 'withdrawal due to adverse events', PER had the lowest odds ratio vs. placebo compared with other AEDs. In the analysis for the subgroup of patients with secondary generalization, only four RCTs (three PER and one LCS) met the inclusion criteria for one outcome (responder rate) for LCS. In this subgroup, PER was statistically significantly better than placebo (OR 2.448, 95% CrI 1.088-5.828). CONCLUSION: PER was statistically significantly superior to placebo in responder rate, seizure freedom, and responder rate in the secondary generalization population. Though PER had statistically significant greater withdrawal compared to placebo, it had the lowest ORs vs. placebo, suggesting a superior safety profile among the comparators included in this analysis. In patients with partial onset seizure with secondary generalization, PER had a statistically significant effect on responder rate compared to placebo. PMID- 23659563 TI - Clostridium difficile infection in children: a comprehensive review. AB - OBJECTIVE: To provide a comprehensive review of the literature relating to Clostridium difficile (C. difficile) infection (CDI) in the pediatric population. METHODS: Two investigators conducted independent searches of PubMed, Web of Science, and Scopus until March 31st, 2013. All databases were searched using the terms 'Clostridium difficile infection', 'Clostridium difficile associated diarrhea' 'antibiotic associated diarrhea', 'C. difficile', in combination with 'pediatric' and 'paediatric'. Articles which discussed pediatric CDI were reviewed and relevant cross references also read and evaluated for inclusion. Selection bias could be a possible limitation of this approach. FINDINGS: There is strong evidence for an increased incidence of pediatric CDI. Increasingly, the infection is being acquired from the community, often without a preceding history of antibiotic use. The severity of the disease has remained unchanged. Several medical conditions may be associated with the development of pediatric CDI. Infection prevention and control with antimicrobial stewardship are of paramount importance. It is important to consider the age of the child while testing for CDI. Traditional therapy with metronidazole or vancomycin remains the mainstay of treatment. Newer antibiotics such as fidaxomicin appear promising especially for the treatment of recurrent infection. Conservative surgical options may be a life saving measure in severe or fulminant cases. CONCLUSIONS: Pediatric providers should be cognizant of the increased incidence of CDI in children. Early and judicious testing coupled with the timely institution of therapy will help to secure better outcomes for this disease. PMID- 23659564 TI - Clinical outcomes after 24 months of insulin therapy in patients with type 2 diabetes in five countries: results from the TREAT study. AB - OBJECTIVE: To assess factors associated with insulin regimens at initiation, changes in treatment and metabolic control over 2 years of insulin therapy in patients with type 2 diabetes in five countries. RESEARCH DESIGN AND METHODS: TREAT was a prospective, 24 month, observational study in patients with type 2 diabetes initiating insulin in clinical practice. Patient characteristics were collected at baseline and metabolic outcomes at 3, 6, 12, 18 and 24 months after initiation. RESULTS: A total of 985 patients were enrolled, 886 assessed at baseline and 734 (82.8%) at 24 months. Baseline characteristics varied between countries: 52.8% of patients were men; mean age was 60.4 years; body mass index, 29.7 kg/m2; time since diagnosis, 10.1 years; HbA1c, 9.6%. Less than 25% of patients met ADA/IDF targets for blood pressure/LDL cholesterol. Overall, 50.1% of patients were initiated on long/intermediate insulin, 39.3% on mixture and 7.8% on basal-bolus; distribution varied between countries. Patients on long/intermediate were more likely to have lower baseline HbA1c and be intensified to other regimens (19.4%). No oral antidiabetic medication was used for 16.4% initiating on long/intermediate, 47.4% on mixture and 62.3% with basal bolus. Overall, mean HbA1c decreased from 9.6% to 7.6%, with little difference between regimens at endpoint. The percentage of patients with hypoglycaemia was highest at 6 months and with basal-bolus. LIMITATIONS: Sites were not selected at random. Drop-out of patients prior to 24 months may have introduced a bias that favoured responders. CONCLUSIONS: Mean baseline HbA1c was high, indicating delayed initiation of insulin treatment. Blood pressure and lipids were suboptimally controlled. Insulin regimens varied between countries, changed little and resulted in similar HbA1c levels after 24 months. PMID- 23659565 TI - Interest of confocal laser scanning microscopy for the diagnosis and treatment monitoring of demodicosis. PMID- 23659566 TI - Single incision laparoscopic cholecystectomy: for what benefit? AB - BACKGROUND: A single-incision laparoscopic cholecystectomy (SILC) was developed to improve outcomes as compared with the four-port classic laparoscopic cholecystectomy (CLC). Any potential benefits associated with a SILC have been suggested by previous studies reporting few patients with different surgical techniques. The aim of this study was to describe the experience with a standardized SILC as compared with CLC. METHODS: From June 2010 to January 2012, 40 patients underwent a SILC [median age: 47.5 years (25-92)] and operative and peri-operative data were prospectively collected. Over the same period, 37 patients underwent a CLC. A 10-point visual analogue scale (VAS) was used for qualitative data. The costs of SILC and CLC were also compared. RESULTS: For those patients undergoing a SILC the median operating time was 70 min (24-110). There were no conversions. An additional trocar was necessary in 16 patients. Four patients developed post-operative complications. The median immediate post operative pain score was 5 (0-10). The median quality of life and cosmetic satisfaction at the initial post-operative visit were 10 (6-10) and 10 (5-10), respectively (VAS). Although the surgical results of both groups were similar, post-operative complications were exclusively reported in the SILC group (two incisional hernias). CONCLUSION: Standardization of SILC is possible but associated with an important rate of additional trocar placement and a disturbing rate of incisional hernias. PMID- 23659567 TI - Evaluation of the seventh edition of the American Joint Committee on Cancer tumour-node-metastasis (TNM) staging system for patients undergoing curative resection of hepatocellular carcinoma: implications for the development of a refined staging system. AB - OBJECTIVES: This study aimed to evaluate the seventh edition of the American Joint Committee on Cancer (AJCC) tumour-node-metastasis (TNM) staging system and to compare its efficacy with those of the fifth and sixth editions of the AJCC staging system and the TNM staging system defined by the Liver Cancer Study Group of Japan. METHODS: Data for 754 patients submitted to hepatectomy for hepatocellular carcinoma (HCC) between 1989 and 2005 were reviewed. Tumour-free survival was estimated using the Kaplan-Meier method and compared between subgroups using the log-rank test. Prognostic factors for tumour-free survival were identified by multivariable analysis. The accuracy of these staging systems was evaluated using the Cox regression model and a refined staging system was developed based on the drawbacks of the respective systems. RESULTS: According to the criteria defined by the seventh AJCC TNM staging system, 5-year survival was 50.6% in patients with T1 tumours, 21.0% in patients with T2 tumours, 14.6% in patients with T3a tumours, 12.1% in patients with T3b tumours, and 12.9% in patients with T4 tumours. There was no survival difference between patients with T3a and T3b tumours (P = 0.073), nor between those with T3b and T4 tumours (P = 0.227). Significant prognostic tumour factors were microvascular invasion, tumour multiplicity, bilobar disease and a tumour size of >=5.0 cm. The fifth and sixth editions of the AJCC TNM staging system were found to be more accurate in prognosis than the seventh. CONCLUSIONS: The seventh edition of the AJCC TNM staging system is able to adequately stratify patients with early HCC only. A refined staging system is therefore proposed. PMID- 23659568 TI - Vascular inflow control during hemi-hepatectomy: a comparison between intrahepatic pedicle ligation and extrahepatic vascular ligation. AB - BACKGROUND: Intrahepatic pedicle ligation (IPL) is an alternative to extrahepatic portal dissection (EPD). Although IPL has been well described, concern has arisen over a possible association with increased complication rates. METHODS: Patients who underwent hemi-hepatectomy during January 1995 to December 2010 were reviewed and the inflow control technique (IPL versus EPD) documented. Patient, tumour, treatment and outcome variables were compared. RESULTS: A total of 798 patients underwent hemi-hepatectomy, 568 (71.2%) of the right and 230 (28.8%) of the left liver. In univariate analysis, factors associated with the choice of IPL included surgeon, right hepatectomy, preoperative portal vein embolization, diagnosis of colorectal cancer liver metastasis, and smaller tumour size (P < 0.011). In multivariate analysis, right hepatectomy [versus left: hazard ratio (HR) 3.878, 95% confidence interval (CI) 1.15-13.14; P = 0.029] and smaller tumour size (median of 4.5 cm versus 5.5 cm: HR 0.72, 95% CI 0.59-0.88; P = 0.002) were associated with IPL. Pringle manoeuvre time was longer in IPL procedures (40 min versus 29 min; P < 0.001). Complication rates (49.8% in IPL versus 48.4% in EPD; P = 0.706) were similar in both groups, as was the severity of complications; 17.6% of EPD and 22.3% of IPL patients experienced complications of grade >=3 (P = 0.225). CONCLUSIONS: Patients with small tumours undergoing right hepatectomy were more likely to undergo IPL. In selected patients, IPL was not associated with an increased complication rate and thus it should be considered a safe approach. PMID- 23659569 TI - The issue contains a healthy mix of reviews, original fundamental and clinical articles, and letters to the editor covering the full spectrum of thrombosis and hemostasis that our readership is accustomed to expect. PMID- 23659570 TI - Optimization of aerosol jet printing for high-resolution, high-aspect ratio silver lines. AB - Aerosol jet printing requires control of a number of process parameters, including the flow rate of the carrier gas that transports the aerosol mist to the substrate, the flow rate of the sheath gas that collimates the aerosol into a narrow beam, and the speed of the stage that transports the substrate beneath the beam. In this paper, the influence of process parameters on the geometry of aerosol-jet-printed silver lines is studied with the aim of creating high resolution conductive lines of high current carrying capacity. A systematic study of process conditions revealed a key parameter: the ratio of the sheath gas flow rate to the carrier gas flow rate, defined here as the focusing ratio. Line width decreases with increasing the focusing ratio and stage speed. Simultaneously, the thickness increases with increasing the focusing ratio but decreases with increasing stage speed. Geometry control also influences the resistance per unit length and single pass printing of low-resistance silver lines is demonstrated. The results are used to develop an operability window and locate the regime for printing tall and narrow silver lines in a single pass. Under optimum conditions, lines as narrow as 20 MUm with aspect ratios (thickness/width) greater than 0.1 are obtained. PMID- 23659571 TI - Human beta-defensin-3 structure motifs that are important in CXCR4 antagonism. AB - Previously, we reported that human beta-defensin (hBD)-3 can both antagonize CXCR4 function on T cells and promote receptor internalization in the absence of activation. In the present study, we explored the important structural elements of hBD-3 that are involved in blocking CXCR4 activation by its natural ligand, stromal-derived factor 1alpha (SDF-1alpha; CXCL12). Results from site-directed mutagenesis studies suggest that the ability of hBD-3 to inhibit SDF-1alpha-CXCR4 interaction, as assayed either by blocking SDF-1 binding to CXCR4 or antagonizing SDF-1-induced Ca(2+) mobilization, is correlated with the presence of hBD-3 cysteine residues, specific surface-distributed cationic residues, and the electrostatic properties and availability of both hBD-3 termini. Specifically, hBD-3 activity against CXCR4 is reduced by: (a) replacing all six cysteines; (b) replacing the cationic residues with acidic ones in the N-terminus and C- terminus; (c) removal of the first 10 N-terminal residues; and (d) replacing the surface-exposed basic residues Lys8, Lys32 and Arg36 with neutral ones. The hBD-3 CXCR4 interaction has potentially wide-ranging implications for HIV-related biology, as well as for a host of CXCR4-dependent activities, including hematopoiesis, neurogenesis, angiogenesis, carcinogenesis, and immune cell trafficking. CXCR4 is highly expressed on T cells, monocytes, and epithelial cells. Therefore, understanding the structure-function relationship between hBD-3 and CXCR4 that accounts for the antagonistic interaction between the two molecules may provide new insights into HIV/highly active antiretroviral therapy related pathology, as well as novel insights into the interaction between innate and adaptive immunity at mucosal sites. PMID- 23659572 TI - Pre-diabetes in adults 45 years and over in Ireland: the Survey of Lifestyle, Attitudes and Nutrition in Ireland 2007. AB - OBJECTIVES: Pre-diabetes is an important indicator of future diabetes burden and many countries are reporting prevalence estimates of pre-diabetes. To date in Ireland, estimates of the prevalence of pre-diabetes were unavailable. Our objectives were to estimate the prevalence of pre-diabetes in a nationally representative sample of Irish adults and to explore determinants of pre diabetes. METHODS: The Survey of Lifestyle Attitudes and Nutrition 2007 was a cross-sectional survey on health and lifestyle in a nationally representative sample of Irish adults. Analysis was performed on a subsample of 1132 participants >= 45 years who provided blood samples. Determination of pre diabetes was based on American Diabetes Association HbA1c cut points of 39-46 mmol/mol (5.7-6.4%). To explore determinants, we modelled pre-diabetes prevalence as a function of a set of health system and socio-demographic variables using logistic regression. RESULTS: The overall weighted prevalence estimate of pre diabetes in participants >= 45 years was 19.8% (95% CI 16.4-23.9). There was no significant difference between age or gender-specific prevalence rates. Obesity was significantly associated with pre-diabetes on univariate and multivariate analysis. Population attributable fraction estimates for excess BMI, physical inactivity and poor diet as causes of pre-diabetes were 31.3% (95% CI -3.9 to 54.5), 10.0% (95% CI -2.7 to 21.3) and 6.1% (95% CI -4.9 to 15.9), respectively. CONCLUSIONS: The high levels of pre-diabetes detected in this study are worrying. Population level interventions to address diet and lifestyle factors are needed urgently to prevent progression to diabetes in high-risk individuals. PMID- 23659573 TI - Electrochemiluminescent quenching of quantum dots for ultrasensitive immunoassay through oxygen reduction catalyzed by nitrogen-doped graphene-supported hemin. AB - A hemin functionalized graphene sheet was prepared via the noncovalent assembly of hemin on nitrogen-doped graphene. The graphene sheet could act as an oxygen reduction catalyst to produce sensitive electrochemiluminescent (ECL) quenching of quantum dots (QDs) due to the annihilation of dissolved oxygen, the ECL coreactant, by its electrocatalytic reduction. With the use of the catalyst with high loading of hemin as a signal tag of the secondary antibody, a novel ultrasensitive immunoassay method for biomarker detection was proposed. In an air saturated pH 8.0 buffer, the immunosensor constructed by a stepwise immobilization of bidentate-chelated CdTe QDs and capture antibody showed an intensive cathodic ECL irradiation, which could be scavenged upon the formation of the catalyst-bound sandwich immunocomplex. With the use of the carcinoembryonic antigen as a model analyte, the immunoassay method showed a linear range from 0.1 pg mL(-1) to 10 ng mL(-1) and a detection limit of 24 fg mL(-1). The immunosensor exhibited good stability, acceptable fabrication reproducibility, and practicability. The electrocatalytic reduction-based ECL quenching strategy provided a powerful avenue for the design of the ultrasensitive detection method, showing great promise for clinical application. PMID- 23659574 TI - Effect of interferon-alpha on cortical glutamate in patients with hepatitis C: a proton magnetic resonance spectroscopy study. AB - BACKGROUND: The development of depressive symptomatology is a recognized complication of treatment with the cytokine interferon-alpha (IFN-alpha) and has been seen as supporting inflammatory theories of the pathophysiology of major depression. Major depression has been associated with changes in glutamatergic activity and recent formulations of IFN-induced depression have implicated neurotoxic influences that could also lead to changes in glutamate function. The present study used magnetic resonance spectroscopy (MRS) to measure glutamate and its major metabolite glutamine in patients with hepatitis C who received treatment with pegylated IFN-alpha and ribavirin. METHOD: MRS measurements of glutamate and glutamine were taken from a 25 * 20 * 20 mm voxel including the pregenual anterior cingulate cortex in 12 patients before and after 4-6 weeks of treatment with IFN. RESULTS: IFN treatment led to an increase in cortical levels of glutamine (p = 0.02) and a significant elevation in the ratio of glutamine to glutamate (p < 0.01). Furthermore, changes in glutamine level correlated significantly with ratings of depression and anxiety at the time of the second scan. CONCLUSIONS: We conclude that treatment with IFN-alpha is associated with MRS-visible changes in glutamatergic metabolism. However, the changes seen differ from those reported in major depression, which suggests that the pathophysiology of IFN-induced depression may be distinct from that of major depression more generally. PMID- 23659576 TI - Design, synthesis, and vasorelaxation activity of novel imperatorin derivatives. AB - In this study, a series of novel imperatorin derivatives 7a-7e were designed and synthesized. Their vasorelaxation activities were evaluated by the pharmacological experiments in vitro. Most of the tested compounds exhibited better water solubility and vasorelaxation activity in different degrees, especially 7b and 7c with EC50 values of 2.29 and 2.63 MUM, respectively on mesenteric artery, 7d and 7e with EC50 values of 1.04 and 2.65 MUM, respectively on brain artery. The results indicated that these novel compounds have a potential interest for the development of novel and potent vasorelaxant agents for different kinds of arteries. PMID- 23659575 TI - Delivery of gene silencing agents for breast cancer therapy. AB - The discovery of RNA interference has opened the door for the development of a new class of cancer therapeutics. Small inhibitory RNA oligos are being designed to specifically suppress expression of proteins that are traditionally considered nondruggable, and microRNAs are being evaluated to exert broad control of gene expression for inhibition of tumor growth. Since most naked molecules are not optimized for in vivo applications, the gene silencing agents need to be packaged into delivery vehicles in order to reach the target tissues as their destinations. Thus, the selection of the right delivery vehicles serves as a crucial step in the development of cancer therapeutics. The current review summarizes the status of gene silencing agents in breast cancer and recent development of candidate cancer drugs in clinical trials. Nanotechnology-based delivery vectors for the formulation and packaging of gene silencing agents are also described. PMID- 23659577 TI - Axonal expression of sodium channels and neuropathology of the plaques in multiple sclerosis. AB - AIMS: Although demyelination is an important cause of neurological deficits in multiple sclerosis (MS), recently axonal pathology and concomitant involvement of sodium channels (Nav) became a focus of major interest. Studies in experimental autoimmune encephalomyelitis (EAE) and MS have shown diffuse expression of Nav1.6 and Nav1.2 along demyelinated axons. However, the relation between this expression by the axon and its environment is not yet known. The aim of this exploratory study was to identify the neuropathological characteristics of the plaque associated with the changes of sodium channel axonal expression. METHODS: We analysed by immunohistochemistry the expression of Nav1.6 and Nav1.2 along demyelinated axons in 64 plaques from 12 MS cases. To characterize the plaques, we used Luxol fast blue staining and immunohistochemistry for myelin basic protein, microglia/macrophages, T and B cells, reactive astrocytes and axonal lesions performed on sections of formalin-fixed, paraffin-embedded tissue. RESULTS: The presence of diffuse axonal expression of Nav1.6 was equally distributed between active demyelinating and inactive not demyelinating plaques based on presence or absence of myelin laden macrophages respectively. However, presence of diffuse axonal expression of Nav1.6 was more frequent within plaques with T cells infiltrate and microglial hyperplasia. On the other hand, Nav1.2 diffuse axonal expression seemed to be independent of the neuropathological environment of the plaque. CONCLUSIONS: The cellular environment of the axon influences the differential expression of Nav channels. A better understanding of the influence of the inflammation on sodium channels mediated axonal degeneration could offer therapeutic perspectives. PMID- 23659578 TI - Classification of dynamic facial expressions of emotion presented briefly. AB - A number of studies have shown an impact of speed of a developing facial expression of emotion on its recognition and perceived naturalness. Still, the impact of speed at constant, short presentation times, as normally used in many experiments is unclear. In the present study participants classified faces displaying facial expressions of six basic emotions in static and dynamic presentation modes and three different types of neutral movements. Stimuli were created with computer software that allows fine-grained control over action units and dynamic features. Rise times in dynamic expressions varied between 200 and 900 ms. Results replicated classical findings showing better performance for expressions of happiness, and frequent confusions among morphologically similar expressions, and a general dynamic facilitation for most expressions. Importantly, dynamic presentation as such facilitated a more accurate classification, but variations in speed at the fast range studied here had no noticeable effect for expressions of anger, fear, happiness, and surprise. The main exception was sadness, which was best recognised at slow speed and in static pictures, and disgust, which was most unambiguously categorised at fast to moderate speed. PMID- 23659579 TI - Investigation of alternative organic solvents and methods for the preparation of long-circulating and pH-sensitive liposomes containing cisplatin. AB - Recent studies using long-circulating and pH-sensitive liposomes containing cisplatin (SpHL-CDDP) have resulted in a formulation with improved pharmacokinetic, toxicity and tumor localization properties. In this study, SpHL CDDP were prepared in both laboratory and pilot scales. This study evaluated the possibility of using the dehydration-rehydration method, as well as using alternative organic solvents (ethyl acetate/ethanol mixtures at 2:1 and 1:1 volume ratios), for the preparation of liposomes by the reverse-phase evaporation (REV) method. The influence of different concentrations of cisplatin (CDDP) (2.0, 1.0, 0.5 and 0.25 mg/mL) on the entrapment percentage and size of SpHL-CDDP was also investigated. In addition, carbohydrates were tested as cryoprotectants in a freeze-thaw study as a pretest to screen the type to be used in the freeze-drying process. A decrease in the encapsulation percentage of CDDP and an increase in the vesicle diameter could be observed for both liposome formulations prepared with ethyl acetate:ethanol mixtures, as compared with REV liposomes prepared with ethyl ether. It is important to note that after applying either quick or slow cooling, the mean diameter of SpHL (empty liposomes) proved to be similar when in the presence of cryoprotectants. In sum, the optimal processing conditions were achieved when using a 0.5 mg/mL CDDP solution, ethyl ether and the REV method, resulting in liposomal dispersions of mean diameters and homogeneities that were deemed suitable for intravenous administration. PMID- 23659580 TI - Dietary patterns and the risk of non-Hodgkin lymphoma. AB - OBJECTIVE: Previous studies examining the role of single foods or nutrients in the aetiology of non-Hodgkin lymphoma (NHL) have produced inconsistent findings. Few studies have examined associations for dietary patterns, which may more accurately reflect patterns of consumption and the complexity of dietary intake. The objective of the present study was to examine whether dietary patterns identified by factor analysis were associated with NHL risk. DESIGN: Case control. SETTING: Population-based sample residing in Nebraska from 1999 to 2002. SUBJECTS: A total of 336 cases and 460 controls. RESULTS: Factor analysis identified two major dietary patterns: (i) a 'Meat, Fat and Sweets' dietary pattern characterized by high intakes of French fries, red meat, processed meat, pizza, salty snacks, sweets and desserts, and sweetened beverages; and (ii) a 'Fruit, Vegetables and Starch' dietary pattern characterized by high intakes of vegetables, fruit, fish, and cereals and starches. In multivariable logistic regression models, the 'Meat, Fat and Sweets' dietary pattern was associated with an increased risk of overall NHL (ORQ4 v. Q1 = 3.6, 95 % CI 1.9, 6.8; P trend = 0.0004), follicular lymphoma (ORQ4 v. Q1 = 3.1, 95 % CI 1.2, 8.0; P trend = 0.01), diffuse large B-cell lymphoma (ORQ4 v. Q1 = 3.2, 95 % CI 1.1, 9.0; P trend = 0.09) and marginal zone lymphoma (ORQ4 v. Q1 = 8.2, 95 % CI 1.3, 51.2; P trend = 0.05). No association with overall or subtype-specific risk was detected for the 'Fruit, Vegetables and Starch' dietary pattern. No evidence of heterogeneity was detected across strata of age, sex, BMI, smoking status or alcohol consumption. CONCLUSIONS: Our results suggest that a dietary pattern high in meats, fats and sweets may be associated with an increased risk of NHL. PMID- 23659581 TI - A series of tetrathiafulvalene-based lanthanide complexes displaying either single molecule magnet or luminescence-direct magnetic and photo-physical correlations in the ytterbium analogue. AB - The reaction between (4,5-bis(2-pyridyl-N-oxidemethylthio)-4',5') ethylenedithiotetrathiafulvene (L(1)) or -methyldithiotetrathiafulvene (L(2)) ligands and Ln(hfac)3.nH2O precursors (Ln(III) = Pr, Tb, Dy, Er, and Yb) leads to the formation of seven dinuclear complexes of formula [Ln2(hfac)6(H2O)x(L(y))2] (x = 2 and y = 1 for Ln(III) = Pr (1); x = 0 and y = 1 for Ln(III) = Tb (2), Dy (3), Er (4) and Yb (5); x = 0 and y = 2 for Ln(III) = Tb (6) and Dy (7)). Their X ray structures reveal that the coordination environment of each Ln(III) center is filled by two N-oxide groups coming from two different ligands L(y). UV-visible absorption properties have been experimentally measured and rationalized by TD DFT calculations. The temperature dependences of static magnetic measurements have been fitted. The ground state corresponds to the almost pure |M(J) = +/ 13/2> while the first excited state (+/-0.77|+/-11/2> +/- 0.50|+/-3/2> +/- 0.39|+/-5/2>) is located at 19 cm(-1) and 26.9 cm(-1) respectively for 3 and 7. Upon irradiation at 77 K and at room temperature, in the range 25,000-20,835 cm( 1), both compounds 4 and 5 display a metal-centered luminescence attributed to (4)I(13/2) -> (4)I(15/2) (6660 cm(-1)) and (2)F(5/2) -> (2)F(7/2) (9972 cm(-1)) transitions, respectively. Emission spectroscopy provides a direct probe of the |+/-5/2> ground state multiplet splitting, which has been confronted to magnetic data. The energy separation of 225 cm(-1) between the ground state and the first excited level (M(J) = +/-3/2) fits exactly the second emission line (234 cm(-1)). While no out-phase-signal is detected for 3, the change of ligand L(1) -> L(2) induces a change of coordination sphere symmetry around the Dy(III) increasing the energy splitting between the ground and first excited states, and 7 displays a single molecule magnet behavior. PMID- 23659582 TI - 'They were about to take out their guns on us': accessing rural Afar communities in Ethiopia with HIV-related interventions. AB - Although pastoralists are a significant proportion of the rural population in many African countries, they are often underserved with regard to health-related interventions. This paper presents data on an effort to provide information about HIV prevention and treatment to Afar people living in remote, northeastern Ethiopia. Using an evidence-based approach, we worked together with the National Network of Positive Women Ethiopians to build relations with Afar communities to design and test an intervention to improve HIV awareness. In this study we observed how multi-directional, local level perceptions--of Afar regarding HIV and existing health-related interventions, of staff from organisations regarding Afar and of the researchers conducting this study regarding Afar--shape the ways in which health-related interventions are offered to Afar and how these are understood by them. While the Afar people express a desire for culturally appropriate HIV-related interventions, few such initiatives have reached them to date. Organisations working in the area often believed that Afar people did not want to accept HIV and were therefore not responsive to their interventions. We argue that the specific history of the Afar people and how this affects their understanding of HIV needs to be better understood and integrated into HIV interventions. PMID- 23659584 TI - Venous thromboembolism management: where do novel anticoagulants fit? AB - OBJECTIVE: To review novel oral anticoagulant (NOAC) trials in the treatment of venous thromboembolism (VTE) and the possible use of risk-stratification tools to guide their use in practice. SCOPE: MEDLINE and Cochrane databases were searched to identify relevant journal articles published from January 1982 to February 2013. Additional references were obtained from articles extracted during the database search. FINDINGS: NOACs have been developed to optimize VTE management and overcome the limitations of heparin and vitamin K antagonists (VKA). The AMPLIFY and EINSTEIN trials of apixaban and rivaroxaban, respectively, investigated single-drug management of VTE, whereas the edoxaban Hokusai-VTE trial and dabigatran RE-COVER and RE-COVER II trials investigated the use of NOACs with a heparin lead-in. The AMPLIFY and Hokusai-VTE trials are ongoing but the EINSTEIN and RE-COVER trials have demonstrated that rivaroxaban and dabigatran, respectively, are non-inferior to parenteral anticoagulants and warfarin in the management of VTE. Differences in study design complicate the application of study results to clinical practice. There are multiple validated DVT protocols that effectively and safely treat patients in outpatient settings. The pulmonary embolism (PE) severity index (PESI), simplified PESI (sPESI), and other prognostic tools have been used to risk stratify patients with PE by estimating mortality risk to guide outpatient eligibility. CONCLUSIONS: NOACs provide physicians with new therapeutic options in the management of VTE. While heparin and VKAs compose the current standard treatment for VTE, their use will likely disappear as physicians grow comfortable with the adoption of NOACs. As studies have not clearly defined the efficacy of these agents in certain patient populations, further data in special patient populations and risk stratification through the use of VTE severity scores could potentially be adapted to guide anticoagulant management and outpatient treatment eligibility. PMID- 23659585 TI - Elevated circulating cytotoxic T lymphocyte-associated antigen-4 levels are related to lung function and inflammation in chronic obstructive pulmonary disease. AB - Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is involved in immune and inflammation regulation. The present study aimed to investigate the association between CTLA-4 and COPD. Data revealed that serum levels of CTLA-4 were elevated in COPD patients, inversely correlated with lung function and positively correlated with serum C-reactive protein levels in the COPD group. These findings suggest that CTLA-4 may play a role in COPD. PMID- 23659586 TI - Estimation of vitamin D levels in patients with pemphigus vulgaris. AB - BACKGROUND: Keratinocyte acantholysis as a result of pathogenic Dsg3-antibodies production by B cells leads to Pemphigus vulgaris (PV). Vitamin D, through its participation in several immune modulatory functions including B cells apoptosis, Th2 cell differentiation, apoptotic enzyme regulation and Tregs functions, may be actively involved in the immune regulation of PV. OBJECTIVE: To evaluate Vitamin D status in PV patients in comparison to controls in an attempt to determine its role in this autoimmune disease. METHODS: Using ELISA technique, 25 hydroxyvitamin D (25OHD) was determined for 34 pemphigus vulgaris patients and 20 healthy volunteers. Phosphorus and parathormone were also determined in the patient group. RESULTS: 25OHD was significantly lower in patients than controls (P = 0.008). There was a statistically significant difference between both groups regarding suboptimal Vit. D levels (P = 0.007). CONCLUSION: Patients with PV have significantly lower serum vitamin D levels in comparison to controls and that these low levels were not related to age, BMI or pattern of sun exposure. The associated Vitamin D insufficiency in patients with PV may possibly exacerbate their disease through various immune related mechanisms. PMID- 23659587 TI - Propranolol-resistant infantile haemangiomas. AB - BACKGROUND: Propranolol is now widely used to treat severe infantile haemangiomas (IHs). Very few cases of propranolol-resistant IH (PRIH) are mentioned in the literature. OBJECTIVES: To describe the characteristics of PRIHs. METHODS: A national, multicentre, retrospective, observational study was conducted from February 2011 to December 2011. All patients with PRIH evaluated by the members of the Groupe de Recherche Clinique en Dermatologie Pediatrique from 1 January 2007 to 1 December 2011 were eligible. RESULTS: Among 1130 patients treated with propranolol for infantile haemangioma, 10 (0.9%) had PRIHs. Haemangioma propranolol resistance was observed at all ages during early childhood and at any proliferation stage. CONCLUSIONS: PRIH is a rare phenomenon that raises questions and merits further investigation. PMID- 23659588 TI - Facile synthesis of superparamagnetic Fe3O4@polyphosphazene@Au shells for magnetic resonance imaging and photothermal therapy. AB - Multifunctional nanoparticles were prepared by directly welding superparamagnetic Fe3O4 nanoparticles and Au shells together with highly cross-linked polyphosphazene as "glue" in a facile but effective way. The as-prepared particles can simultaneously take advantages of both magnetization of Fe3O4 core for magnetic resonance imaging diagnosis and strong near-infrared absorption of Au nanoshell for photothermal therapy. PMID- 23659589 TI - Munc13-4-mediated secretion is essential for infarct progression but not intracranial hemostasis in acute stroke. PMID- 23659590 TI - Diabetes care provision: barriers, enablers and service needs of young adults with Type 1 diabetes from a region of social disadvantage. AB - AIMS: To determine the barriers to and enablers of engaging with specialist diabetes care and the service requirements of young adults with Type 1 diabetes mellitus from a low socio-economic, multicultural region. METHODS: A cross sectional survey targeted 357 young adults with Type 1 diabetes, aged 18-30 years. Participants completed questions about barriers/enablers to accessing diabetes care and service preferences, self-reported HbA(1c), plus measures of diabetes-related distress (Problem Areas in Diabetes), depression/anxiety (Hospital Anxiety and Depression Scale), and illness perceptions (Brief Illness Perceptions Questionnaire). RESULTS: Eighty-six (24%) responses were received [55 (64%) female; mean +/- sd age 24 +/- 4 years; diabetes duration 12 +/- 7 years; HbA(1c) 68 +/- 16 mmol/mol (8.4 +/- 1.5%)]. Logistical barriers to attending diabetes care were reported; for example, time constraints (30%), transportation (26%) and cost (21%). However, 'a previous unsatisfactory diabetes health experience' was cited as a barrier by 27%. Enablers were largely matched to overcoming these barriers. Over 90% preferred a multidisciplinary team environment, close to home, with after-hours appointment times. Forty per cent reported severe diabetes-related distress, 19% reported moderate-to-severe depressive symptoms and 50% reported moderate-to-severe anxiety. CONCLUSIONS: Among these young adults with Type 1 diabetes, glycaemic control was suboptimal and emotional distress common. They had identifiable logistical barriers to accessing and maintaining contact with diabetes care services, which can be addressed with flexible service provision. A substantial minority were discouraged by previous unsatisfactory experiences, suggesting health providers need to improve their interactions with young adults. This research will inform the design of life-stage-appropriate diabetes services targeting optimal engagement, access, attendance and ultimately improved healthcare outcomes in this vulnerable population. PMID- 23659591 TI - Two approaches to the aromatic core of the aminonaphthoquinone antibiotics. AB - Two complementary approaches are presented for the synthesis of the quinone chromophores of the naphthoquinone ansamycins and related natural products. The first involves the use of an improved protocol for the manganese(III) acetate mediated cyclization of 5-aryl-1,3-dicarbonyl compounds to beta-naphthols, leading to the simple, scalable preparation of building blocks suitable for the synthesis of naturally occurring aminonaphthoquinones. The second approach involves the Diels-Alder reaction of a series of new, ester-containing Danishefsky-type dienes with N-protected aminobenzoquinones to allow more expeditious access to similar intermediates. PMID- 23659592 TI - In vitro and in vivo models of Huntington's disease show alterations in the endocannabinoid system. AB - In this study, we analyzed the components of the endocannabinoid system (ECS) in R6/2 mice, a widely used model of Huntington's disease (HD). We measured the endogenous content of N-arachidonoylethanolamine and 2-arachidonoylglycerol and the activity of their biosynthetic enzymes (N-acyl-phosphatidylethanolamine hydrolyzing phospholipase D and diacylglycerol lipase, respectively) and hydrolytic enzymes [fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase, respectively] and of their target receptors (type 1 cannabinoid receptor, type 2 cannabinoid receptor, and transient receptor potential vanilloid-1) in the brains of wild-type and R6/2 mice of different ages, as well as in the striatum and cortex of 12-week-old animals. In addition, we measured FAAH activity in lymphocytes of R6/2 mice. In the whole brains of 12-week-old R6/2 mice, we found reductions in N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D activity, diacylglycerol lipase activity and cannabinoid receptor binding, mostly associated with changes in the striatum but not in the cortex, as well as an increase in 2-arachidonoylglycerol content as compared with wild-type littermates, without any other change in ECS elements. Then, our analysis was extended to HD43 cells, an inducible cellular model of HD derived from rat ST14A cells. In both induced and noninduced conditions, we demonstrated a fully functional ECS. Overall, our data suggest that the ECS is differently affected in mouse and human HD, and that HD43 cells are suitable for high-throughput screening of FAAH-oriented drugs affecting HD progression. PMID- 23659593 TI - Mn-doped ZnS quantum dot imbedded two-fragment imprinting silica for enhanced room temperature phosphorescence probing of domoic acid. AB - A novel strategy was presented to construct the enhanced molecularly imprinted polymer (MIP)-based room temperature phosphorescence (RTP) probe by combining the RTP of Mn-doped ZnS quantum dots (Mn-ZnS QDs) and two-fragment imprinting. Two fragments or structurally similar parts of the target analytes were used as the dummy templates. Polyethyleneimine capped Mn-ZnS (PEI-Mn-ZnS) QDs, offering the binding sites to interact with the carboxyl groups of templates, were imbedded into MIPs by the hydrolysis of tetraethoxysilane. The rebinding of the target analytes to their fragments' cavities (recognition sites) modulated the selective aggregation of Mn-ZnS QDs in QDs-MIPs and resulted in the RTP enhancement. This new method was suitable for the selective enhanced RTP detection of nonphosphorescent analytes without any derivatization and inducers. The proposed methodology was applied to construct the high selective enhanced MIP-based RTP probe for domoic acid (DA) detection. The RTP enhancement of two-fragment imprinting silica was about 2 times of one-fragment imprinting silica and 4 times of the nonimprinting silica. The two-fragment imprinting silica exhibited the linear RTP enhancement to DA in the range of 0.25-3.5 MUM in buffer and 0.25-1.5 MUM in shellfish sample. The precision for 11 replicate detections of 1.25 MUM DA was 0.65% (RSD), and the limit of detection was 67 nM in buffer and 2.0 MUg g(-1) wet weight (w/w) in shellfish sample. PMID- 23659594 TI - Early word segmentation in infants acquiring Parisian French: task-dependent and dialect-specific aspects. AB - Six experiments explored Parisian French-learning infants' ability to segment bisyllabic words from fluent speech. The first goal was to assess whether bisyllabic word segmentation emerges later in infants acquiring European French compared to other languages. The second goal was to determine whether infants learning different dialects of the same language have partly different segmentation abilities, and whether segmenting a non-native dialect has a cost. Infants were tested on standard European or Canadian French stimuli, in the word passage or passage-word order. Our study first establishes an early onset of segmentation abilities: Parisian infants segment bisyllabic words at age 0;8 in the passage-word order only (revealing a robust order of presentation effect). Second, it shows that there are differences in segmentation abilities across Parisian and Canadian French infants, and that there is a cost for cross-dialect segmentation for Parisian infants. We discuss the implications of these findings for understanding word segmentation processes. PMID- 23659595 TI - Role of imatinib in the treatment of pediatric onset indolent systemic mastocytosis: a case report. AB - BACKGROUND: Mastocytosis is a sporadic disease characterized by an abnormal accumulation of mast cells (MCs) in single or multiple organs. It has a heterogeneous clinical picture which is a reflection of underlying tissue MC burden, mediators released and the organs involved. Here, the authors report significant symptomatic, cutaneous and systemic response to imatinib in a case of childhood onset indolent D816V KIT unmutated systemic mastocytosis (SM). CASE REPORT: A 19-year-old female presented with a history of itchy skin lesions over the face, trunk and extremities since 6 months of age associated with recurrent bouts of angioedema. The skin and bone marrow examination were consistent with mastocytosis. No pathogenic mutations were detected in exons 8 and 17. In view of the severity of cutaneous symptoms and evidence of bone marrow involvement, she was treated with imatinib which resulted in marked improvement. CONCLUSION: Imatinib has a therapeutic role in the presence of an imatinib-sensitive KIT mutation or in KIT816-unmutated patients with aggressive SM. Its role in the treatment of indolent and cutaneous mastocytosis is less well established. However, the authors have demonstrated the usefulness of imatinib in the treatment of c-KIT-negative indolent SM with extensive cutaneous involvement. PMID- 23659596 TI - Pregnancy protection of breast cancer: new insights reveal unanswered questions. AB - The recent paper by Meier-Abt and colleagues on pregnancy protection of breast cancer development takes a different approach to the problem and focused on the effect of parity on the cell subpopulations of the mouse mammary gland. Their results demonstrate that parity decreases the cell number of the hormone receptor positive luminal cells (that is, luminal Sca1+) but not the basal stem/progenitor cells (CD24lo/CD49hi). Additionally, microarray studies demonstrate that wnt4 expression from the luminal Sca1+ cells is markedly reduced as is the wnt signaling pathway in basal cells. One important implication from these results is that targeting the wnt signaling pathway might be a feasible prevention approach in humans. PMID- 23659597 TI - Significant morbidity and mortality attributable to rothia mucilaginosa infections in children with hematological malignancies or following hematopoietic stem cell transplantation. AB - Rothia mucilaginosa is a gram-positive coccus that poses a diagnostic challenge and often requires DNA pyrosequencing for diagnosis as it can be easily mistaken for coagulase-negative staphylococci on initial culture results. While it is often times normal human oral and upper respiratory tract microbiota, it can be a virulent pathogen in immunocompromised patients. Most commonly, it causes bacteremia (catheter and non-catheter related) and meningitis in these patients. Our objective was to report the incidence of R. mucilaginosa infections in neutropenic children with hematological malignancies or following hematopoietic stem cell transplantation at a major children's hospital. We report 11 patients in this cohort who developed clinically significant R. mucilaginosa infections, including three deaths directly attributable to this microorganism. Three patients developed significant neurological involvement, accounting for two of the deaths, and one patient died of disseminated infection. Except for one, all patients had severe neutropenia, central line catheters, and mucosal breakdown at the time of infection. Patients who succumbed never achieved neutrophil recovery. In conclusion, R. mucilaginosa can lead to life-threatening infections in immunocompromised hosts, especially in profoundly neutropenic patients. PMID- 23659598 TI - Two new neuroprotective phenolic compounds from Gastrodia elata. AB - Two new phenolic compounds 4-(4'-hydroxybenzyl) phenyl glucoside (gastrodin B, 1) and 1'-hydroxymethyl-phenyl 4-hydroxy-3-(4"-hydroxybenzyl) benzyl ether (gastrol B, 2) were isolated from the rhizomes of Gastrodia elata. Their structures were elucidated on the basis of spectroscopic data and chemical reaction. All compounds exhibited potent neuroprotective activity against H2O2-induced PC12 cell damage. PMID- 23659599 TI - Clinico-pathological description of three paediatric medulloblastoma cases with MLL2/3 gene mutations. PMID- 23659600 TI - Whole-genome sequencing reveals a link between beta-lactam resistance and synthetases of the alarmone (p)ppGpp in Staphylococcus aureus. AB - The overwhelming majority of methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates exhibit a peculiar heterogeneous resistance to beta-lactam antibiotics: in cultures of such strains, the majority of cells display only a low level of methicillin resistance--often close to the MIC breakpoint of susceptible strains. Yet, in the same cultures, subpopulations of bacteria exhibiting very high levels of resistance are also present with variable frequencies, which are characteristic of the particular MRSA lineage. The mechanism of heterogeneous resistance is not understood. We describe here an experimental system for exploring the mechanism of heterogeneous resistance. Copies of the resistance gene mecA cloned into a temperature-sensitive plasmid were introduced into the fully sequenced methicillin-susceptible clinical isolate S. aureus strain 476. Transductants of strain 476 expressed methicillin resistance in a heterogeneous fashion: the great majority of cells showed only low MIC (0.75 MUg/ml) for the antibiotic, but a minority population of highly resistant bacteria (MIC >300 MUg/ml) was also present with a frequency of ~10( 4). The genetic backgrounds of the majority and minority cells were compared by whole-genome sequencing: the only differences detectable were two point mutations in relA of the highly resistant minority population of bacteria. The relA gene codes for the synthesis of (p)ppGpp, an effector of the stringent stress response. Titration of (p)ppGpp showed increased amounts of this effector in the highly resistant cells. Involvement of (p)ppGpp synthesis genes may explain some of the perplexing aspects of beta-lactam resistance in MRSA, since many environmental and genetic changes can modulate cellular levels of (p)ppGpp. PMID- 23659601 TI - In vitro activity of doripenem in combination with various antimicrobials against multidrug-resistant Acinetobacter baumannii: possible options for the treatment of complicated infection. AB - AIMS: The aim of this study was to evaluate the in vitro activity of doripenem (DOR) alone and in combination with a variety of commonly used anti-Acinetobacter chemotherapeutic agents against 22 primary multidrug-resistant (MDR) Acinetobacter baumannii isolates (including 17 isolates that were resistant to DOR) from Intensive Care Unit patients. Antibiotic interactions were evaluated using the chequerboard method and the time-kill assay. RESULTS: Considering all antimicrobials in combination with DOR, chequerboard analysis showed synergy in 13 A. baumannii strains (54.2%). Seven strains (29.2%) showed >=2 synergistic interactions. DOR showed synergy in combination with tigecycline (TIG) (eight strains), colistin (COL) (eight strains), amikacin (AMK) (four strains), ampicillin/sulbactam (two strains), and rifampicin (one strain). Remarkably, synergistic effects were detected only in DOR nonsusceptible strains. Time-kill assays confirmed synergy in eight isolates (giving 10 synergistic interactions) for DOR in combination with TIG (n=4), COL (n=5), and AMK (n=1). No antagonistic interactions were observed with both methods. CONCLUSIONS: This study demonstrates the in vitro synergistic activity of DOR in combination with TIG, COL, and AMK against DOR-resistant A. baumannii strains, opening the way to in vivo assessment of novel combination therapies for treatment of infections caused by MDR A. baumannii. PMID- 23659602 TI - The role of flies in spreading the extended-spectrum beta-lactamase gene from cattle. AB - The spreading of antimicrobial-resistant bacteria and genes from food-producing animals to humans has been a subject of increasing concern. To clarify the role of flies in spreading the extended-spectrum beta-lactamase (ESBL) gene from food producing animals to humans, we isolated and characterized a third-generation cephalosporin-resistant Escherichia coli strain from flies and cattle feces from a cattle barn. Cephalosporin-resistant strains were isolated from 14.3% (13/91) of houseflies, 10.3% (7/68) of false stable flies, and 7.5% (7/93) of cattle feces. Twenty-seven cephalosporin-resistant strains were tested for the presence of antimicrobial resistance genes. Of the 27 samples, 22 isolates from 11 houseflies, 5 false stable flies, and 6 cattle feces samples harbored the blaCTX M-15 gene. All blaCTX-M-15-harboring isolates belonged to phylogenetic group D and the ST38 clonal group. Analysis of pulsed-field gel electrophoresis showed that these isolates were divided into two clusters, indicating that flies carried several of the same clones that were detected in cattle feces. All blaCTX-M-15 gene-harboring plasmids were transferable and were members of incompatibility group FIB. These results suggest that transferable plasmids encoding ESBL were prevalent among flies and cattle. As vectors, flies may play an important role in spreading ESBL-producing bacteria from food-producing animals to humans. PMID- 23659603 TI - Subnanometer local temperature probing and remotely controlled drug release based on azo-functionalized iron oxide nanoparticles. AB - Local heating can be produced by iron oxide nanoparticles (IONPs) when exposed to an alternating magnetic field (AMF). To measure the temperature profile at the nanoparticle surface with a subnanometer resolution, here we present a molecular temperature probe based on the thermal decomposition of a thermo-sensitive molecule, namely, azobis[N-(2-carboxyethyl)-2-methylpropionamidine]. Fluoresceineamine (FA) was bound to the azo molecule at the IONP surface functionalized with poly(ethylene glycol) (PEG) spacers of different molecular weights. Significant local heating, with a temperature increase up to 45 degrees C, was found at distances below 0.5 nm from the surface of the nanoparticle, which decays exponentially with increasing distance. Furthermore, the temperature increase was found to scale linearly with the applied field at all distances. We implemented these findings in an AMF-triggered drug release system in which doxorubicin was covalently linked at different distances from the IONP surface bearing the same thermo-labile azo molecule. We demonstrated the AMF triggered distance-dependent release of the drug in a cytotoxicity assay on KB cancer cells. PMID- 23659604 TI - Novel role for cystic fibrosis transmembrane conductance regulator in alveolar fluid clearance in lipopolysaccharide-induced acute lung injury in mice. AB - BACKGROUND AND OBJECTIVE: Alveolar fluid clearance (AFC) is important for the resolution of acute lung injury (ALI). The role of cystic fibrosis transmembrane conductance regulator (CFTR) in AFC has not been entirely elucidated in animal models of ALI. The aim of this study was to investigate the role of CFTR and its mechanisms in AFC in normal and ALI mice. METHODS: Seventy mice were randomly divided into 14 groups and ALI was established by intratracheal instillation of lipopolysaccharide (LPS). After 48 h, CFTR activator CFTRact-16 or inhibitor CFinh-172 with or without beta-agonist was instillated intratracheally and AFC was measured with radioisotopic tracer. RESULTS: Although there was no effects of CFTRact-16 on AFC in mice with or without isoproterenol, CFinh-172 markedly decreased isoproterenol-stimulated AFC in both normal (P < 0.01) and LPS-induced ALI mice (P < 0.01) and there was significantly decreased basal AFC in ALI mice (P < 0.05). CONCLUSIONS: These results provide direct functional evidence for CFTR in cAMP-mediated AFC in both normal and ALI mice. PMID- 23659605 TI - On the origin of POU5F1. AB - BACKGROUND: Pluripotency is a fundamental property of early mammalian development but it is currently unclear to what extent its cellular mechanisms are conserved in vertebrates or metazoans. POU5F1 and POU2 are the two principle members constituting the class V POU domain family of transcription factors, thought to have a conserved role in the regulation of pluripotency in vertebrates as well as germ cell maintenance and neural patterning. They have undergone a complex pattern of evolution which is poorly understood and controversial. RESULTS: By analyzing the sequences of POU5F1, POU2 and their flanking genes, we provide strong indirect evidence that POU5F1 originated at least as early as a common ancestor of gnathostomes but became extinct in a common ancestor of teleost fishes, while both POU5F1 and POU2 survived in the sarcopterygian lineage leading to tetrapods. Less divergent forms of POU5F1 and POU2 appear to have persisted among cartilaginous fishes. CONCLUSIONS: Our study resolves the controversial evolutionary relationship between teleost pou2 and tetrapod POU2 and POU5F1, and shows that class V POU transcription factors have existed at least since the common ancestor of gnathostome vertebrates. It provides a framework for elucidating the basis for the lineage-specific extinctions of POU2 and POU5F1. PMID- 23659606 TI - Remineralization of demineralized enamel by toothpastes: a scanning electron microscopy, energy dispersive X-ray analysis, and three-dimensional stereo micrographic study. AB - Remineralization of hard dental tissues is thought to be a tool that could close the gap between prevention and surgical procedures in clinical dentistry. The purpose of this study was to examine the remineralizing potential of different toothpaste formulations: toothpastes containing bioactive glass, hydroxyapatite, or strontium acetate with fluoride, when applied to demineralized enamel. Results obtained by scanning electron microscopy (SEM) and SEM/energy dispersive X-ray analyses proved that the hydroxyapatite and bioactive glass-containing toothpastes were highly efficient in promoting enamel remineralization by formation of deposits and a protective layer on the surface of the demineralized enamel, whereas the toothpaste containing 8% strontium acetate and 1040 ppm fluoride as NaF had little, if any, remineralization potential. In conclusion, the treatment of demineralized teeth with toothpastes containing hydroxyapatite or bioactive glass resulted in repair of the damaged tissue. PMID- 23659608 TI - Tumor treating fields: a new frontier in cancer therapy. AB - Tumor treating fields (TTFields) is a noninvasive, regional antimitotic treatment modality that has been approved for the treatment of recurrent glioblastoma by the U.S. FDA and has a CE mark in Europe. TTFields therapy delivers low-intensity (1-3 V/cm), intermediate-frequency (100-300 kHz), alternating electric fields to the tumor using transducer arrays placed on the skin around the region of the body containing the tumor. TTFields therapy affects metaphase, by disrupting mitotic spindle formation, and anaphase, by dielectrophoretic dislocation of intracellular constituents, resulting in apoptosis. TTFields therapy is frequency tuned to specific cancer cell types. The antimitotic effect of TTFields therapy has been demonstrated in multiple cell lines when the appropriate frequency was utilized. A phase III trial of TTFields monotherapy compared to active chemotherapy in recurrent glioblastoma patients established that TTFields therapy is associated with minimal toxicity, better quality of life, and comparable efficacy to chemotherapy. Ongoing and future trials will evaluate TTFields in newly diagnosed glioblastoma, solid tumor brain metastases, nonsmall cell lung cancer, and ovarian and pancreatic cancers. PMID- 23659607 TI - Peripheral nerve repair in rats using composite hydrogel-filled aligned nanofiber conduits with incorporated nerve growth factor. AB - Repair of peripheral nerve defects with current synthetic, tubular nerve conduits generally shows inferior recovery when compared with using nerve autografts, the current gold standard. We tested the ability of composite collagen and hyaluronan hydrogels, with and without the nerve growth factor (NGF), to stimulate neurite extension on a promising aligned, nanofiber poly-L-lactide-co-caprolactone (PLCL) scaffold. In vitro, the hydrogels significantly increased neurite extension from dorsal root ganglia explants. Consistent with these results, the addition of hydrogels as luminal fillers within aligned, nanofiber tubular PLCL conduits led to improved sensory function compared to autograft repair in a critical-size defect in the sciatic nerve in a rat model. Sensory recovery was assessed 3 and 12 weeks after repair using a withdrawal assay from thermal stimulation. The addition of hydrogel did not enhance recovery of motor function in the rat model. The NGF led to dose-dependent improvements in neurite out-growth in vitro, but did not have a significant effect in vivo. In summary, composite collagen/hyaluronan hydrogels enhanced sensory neurite outgrowth in vitro and sensory recovery in vivo. The use of such hydrogels as luminal fillers for tubular nerve conduits may therefore be useful in assisting restoration of protective sensation following peripheral nerve injury. PMID- 23659609 TI - Identifying nanoscale M13 clusters in the solid state and aqueous solution: vibrational spectroscopy and theoretical studies. AB - Raman spectroscopy, infrared spectroscopy, and quantum mechanical computations were used to characterize and assign observed spectral features, highlight structural characteristics, and investigate the bonding environments of [M13(MU3 OH)6(MU2-OH)18(H2O)24](NO3)15 (M = Al or Ga) nanoscale clusters in the solid phase and aqueous solution. Solid-phase Raman spectroscopy was used to reveal that the metal-oxygen (M-O) symmetric stretch (breathing mode) for the Al13 cluster is observed at 478 cm(-1), whereas this same mode is seen at 464 cm(-1) in the Ga13 cluster. The hydroxide bridges in each cluster are weakly Raman active but show slightly stronger infrared activity. The breathing modes associated with the clusters in the solid state are not clearly visible in aqueous solution. This change in behavior in the solution phase may indicate a symmetry breaking of the cluster or exchange events between protons on the ligands and the protic solvent. Overall, each cluster has several unique vibrational modes in the low wavenumber region (<1500 cm(-1)) that are distinct from the parent nitrate salt and other polymeric species with similar structure, which allows for unambiguous identification of the cluster in solution and solid phases. PMID- 23659610 TI - Towards an in vivo morphologic classification of melanocytic nevi. AB - BACKGROUND: Nevi are common benign neoplasms and the main diagnostic entity in the differential diagnosis of melanoma. Reflectance confocal microscopy (RCM), a novel technique for skin imaging at cellular-level magnification, has been shown to be useful for differentiating nevi from melanoma. However, systematic studies of the specific RCM features of nevi are still lacking. OBJECTIVE: To describe the characteristic RCM features of common melanocytic nevi and to correlate them with histopathology. METHODS: A total of 180 biopsy-proven nevi were imaged with RCM prior to excision. RCM images were evaluated for the overall nevus pattern and presence of specific RCM criteria. Upon histopathology, nevi were analysed for thickness using adapted Breslow depth and Clark's level grading. RESULTS: Observed RCM patterns varied according to anatomic depth of nevi. Junctional nevi were mainly characterized on RCM by a Ringed pattern, indicating a predominantly single cell proliferation of melanocytes; in contrast, the junctional component of compound nevi appeared on RCM as a Meshwork pattern, indicating a predominantly nested-proliferation. In compound nevi, the size of dermal nests was related to the thickness of nevi. Moreover, nevi extending deeper into the dermis were more likely to display a junctional component that extended laterally beyond the dermal component and appeared on RCM as either Ringed or Meshwork pattern. Intradermal nevi showed on RCM, in almost all cases, large clods. CONCLUSIONS: The possibility for in vivo histopathological classification of nevi may help in attaining a better understanding of the origin of nevi and of nevus related melanoma risk. PMID- 23659611 TI - Hemolytic uremic syndrome: sound minds, sick kidneys. PMID- 23659612 TI - Fabrication of novel silicone capsules with tunable mechanical properties by microfluidic techniques. AB - A novel approach for the synthesis of silicone capsules using double W/O/W emulsions as templates is introduced. The low viscosity of the silicone precursors enables the use of microfluidic techniques to accurately control the size and morphology of the double emulsion droplets, which after cross-linking result in the desired monodisperse silicone capsules. Their shell thickness can be finely tuned, which in turn allows control over their permeability and mechanical properties; the latter are particularly important in a variety of practical applications where the capsules are subjected to large external forces. The potential of these capsules for controlled release is also demonstrated using a model hydrophilic substance. PMID- 23659613 TI - Three new monoterpene glycosides from the roots of Paeonia lactiflora. AB - Three new monoterpene glycosides, 2'-O-benzoylpaeoniflorin, albiflorin R2, and albiflorin R3 (1-3) were isolated from the roots of Paeonia lactiflora. Their structures were elucidated on the basis of spectroscopic means including one- and two-dimensional NMR experiments. PMID- 23659614 TI - Impact of double-blind vs. open study design on the observed treatment effects of new oral anticoagulants in atrial fibrillation: a meta-analysis. AB - BACKGROUND: The prospective, randomized, open, blinded endpoint evaluation (PROBE) design has been proposed as a valid alternative to the double-blind (DB) design for trials comparing new oral anticoagulants (NOAs) with INR-adjusted vitamin K antagonists in patients with non-valvular atrial fibrillation (NVAF). OBJECTIVES: To determine whether the observed treatment effects of NOAs in patients with NVAF differ between PROBE/open-label trials and DB trials. METHODS: All phase II or III trials were eligible. The main efficacy and safety outcomes were stroke/systemic embolism (SSE) and major bleeding, respectively. Other outcomes included ischemic SSE, hemorrhagic stroke, intracranial and extracranial bleeding, myocardial infarction, and all-cause and cardiovascular mortality. Interaction (Cochran's chi-squared test) between PROBE and DB designs was tested. RESULTS: Thirteen studies (61 620 patients) were included. For SSE, a greater treatment effect of NOAs vs. INR-adjusted warfarin was observed in PROBE trials (RR 0.76, CI 0.65-0.89) compared with DB trials (RR 0.88, CI 0.78-0.98), but the interaction test was non-significant (P = 0.16). A significant 67% enhancement of treatment effect was found with PROBE/open-label trials compared with DB trials (interaction test, P = 0.05) for hemorrhagic stroke. No other interaction was significant. A non-significant interaction (P = 0.07) between oral direct thrombin inhibitors (RR 0.33; 0.22-0.51) and factor Xa inhibitors (RR 0.54; 0.40 0.72) was seen. No heterogeneity was found for any outcome. CONCLUSIONS: Our meta analysis showed no significant interaction of study design for the main efficacy and safety outcomes. However, the non-significantly exaggerated reduction in SSE suggests interdependence of treatment effect and PROBE design, especially for hemorrhagic stroke. PMID- 23659615 TI - Dynamics of carbon nanotube tipped atomic force microscopy in liquid. AB - Carbon nanotubes (CNT) are proper tips for atomic force microscopes (AFMs) as a result of their small tip diameter, high aspect ratio, and high flexibility. For nanoscale imaging of soft biological specimens, a CNT tipped AFM is an ideal tool. In this article we review the application of CNTs as AFM tips and present related research about the forces applied from liquids on nanotubes. Then a dynamic mode CNT tipped AFM in liquid is modeled and simulated. The simulation results are compared with experimental results. For modeling and simulation, a continuous beam model and a forward-time simulation method are used. The simulation results show that when a CNT tip vibrates in liquid, the oscillation amplitude and resonance frequency are changed compared to the state of oscillation in air. The small structure of CNTs reduces the hydrodynamic forces, and the liquid environment reduces the adhesive forces between the CNT tip and the sample. These two factors make CNTs a good choice as an AFM tip. PMID- 23659616 TI - Objectively measured activity in 8-10-year-old Turkish children: relationship to health-related fitness. AB - BACKGROUND: No objective data regarding the physical activity (PA) levels of young Turkish children currently exist. Furthermore, whether habitual PA is associated with the components of health-related fitness among children is unclear. The aim of this study was to evaluate the patterns and levels of objectively measured PA in prepubertal Turkish children and its relationship with body fatness, aerobic and anaerobic fitness. METHODS: Eighty-nine 8-10-year-old children (47 boys and 42 girls) participated in this study. The intensity, duration and frequency of PA were assessed from 4 days of heart rate monitoring with 15 s sampling intervals. Body fatness was determined by measuring skinfold thickness. Anaerobic fitness was evaluated using the Wingate test. All the children performed the shuttle run test to assess aerobic fitness. RESULTS: The PA of boys was significantly higher than that of girls (P < 0.05). Gender difference is more marked for vigorous PA. Instead of sustained PA, short bouts of PA, lasting up to 1 min, were characteristic of PA patterns of children. The duration and frequency of PA were positively related to aerobic fitness and negatively related to fatness for both gender groups (P < 0.05). These relationships were more prominent for accumulated PA than for other measures of PA. No relationship was obtained between PA and anaerobic fitness in either gender group (P > 0.05). CONCLUSIONS: Intermittent, accumulated moderate intensity PA may be more important than sustained vigorous intensity PA in influencing children's fitness and fatness levels. Detailed studies are needed to clarify which dimension of PA is more beneficial for health-related fitness in children. PMID- 23659617 TI - Synthesis and stabilization of gold nanoparticles induced by denaturation and renaturation of triple helical beta-glucan in water. AB - We report on a green procedure for the synthesis and stabilization of gold nanoparticles (AuNPs) from chlorauric acid (HAuCl4) with the use of a beta-glucan known as Lentinan (LNT) without external reducing or stabilizing agents in aqueous medium. LNT adopted triple helical conformation in water, which was first denatured into single chains (s-LNT) at a high temperature of 140 degrees C before mixing with HAuCl4. Results from UV-vis absorption spectroscopy, transmission electron microscopy (TEM), and energy dispersive X-ray (EDX) spectra suggested that AuCl4(-) was rapidly reduced to AuNPs by s-LNT. Moreover, the as prepared AuNPs could be converted into nanobelt, spherical nanoparticles, and nanowire morphology simply by controlling the s-LNT concentration, reaction time, and temperature. In particular, the AuNPs nanowire was confirmed as the most stable shape in water, which was predominately ascribed to the hydrophobic cavity in the helical center of the renatured triple helical LNT (r-LNT) from s-LNT. Namely, AuNPs were entrapped in the hydrophobic cavity of r-LNT to form nanowire with an outer layer of water-soluble r-LNT, leading to stable dispersion of AuNPs. All the data demonstrated that the beta-glucan of s-LNT can be used as a reducing and stabilizing agent to synthesize and disperse AuNPs in water. The whole process of reduction and stabilization was free of organic solvent and thus very safe, which is important for the potential application of AuNPs in biotechnology and biomedicine. PMID- 23659618 TI - Maternal and perinatal factors associated with subsequent meningococcal, Haemophilus or enteroviral meningitis in children: database study. AB - We used a database of 248 659 births, with follow-up to subsequent disease, in the Oxford record linkage archive (1979-1999) to study the influence of family, maternal, and perinatal factors on subsequent hospital admission for meningococcal, Haemophilus, and enteroviral meningitis in the children. In this summary, we report key findings that were significant in multivariate analysis. Meningococcal meningitis was significantly associated with maternal smoking [odds ratio (OR) 2.1, 95% confidence interval (CI) 1.2-3.7]. Haemophilus meningitis was associated with having older siblings (e.g. second child compared to first-born, OR 3.3, 95% CI 2.0-5.6). Enteroviral meningitis was associated with low birth weight (OR 2.2, 95% CI 1.3-3.6) and male sex (OR 1.7, 95% CI 1.2-2.3). The mothers of six of the 312 children with enteroviral meningitis had previously had enteroviral meningitis themselves. We concluded that several maternal characteristics influence the risk of these types of meningitis. PMID- 23659619 TI - The activity of valproic Acid in the treatment of refractory hyperleukocytosis in a child with acute lymphoblastic leukemia. AB - Hyperleukocytosis may be associated with an early morbidity and mortality due to leukostasis. Cytoreductive therapies-such as steroids, hydroxiurea, exchange transfusion, and leukapheresis-have been used for the prevention of leukostasis. Herein, the valproic acid used for the treatment of the hyperleukocytosis did not respond to known therapies in a child; lymphoblastic lymphoma developed bone marrow relapse under the treatment is discussed. PMID- 23659622 TI - Newly qualified doctors' perceptions of informal learning from nurses: implications for interprofessional education and practice. AB - Newly qualified doctors spend much of their time with nurses, but little research has considered informal learning during that formative contact. This article reports findings from a multiple case study that explored what newly qualified doctors felt they learned from nurses in the workplace. Analysis of interviews conducted with UK doctors in their first year of practice identified four overarching themes: attitudes towards working with nurses, learning about roles, professional hierarchies and learning skills. Informal learning was found to contribute to the newly qualified doctors' knowledge of their own and others' roles. A dynamic hierarchy was identified: one in which a "pragmatic hierarchy" recognising nurses' expertise was superseded by a "normative structural hierarchy" that reinforced the notion of medical dominance. Alongside the implicit learning of roles, nurses contributed to the explicit learning of skills and captured doctors' errors, with implications for patient safety. The findings are discussed in relation to professional socialisation. Issues of power between the professions are also considered. It is concluded that increasing both medical and nursing professions' awareness of informal workplace learning may improve the efficiency of education in restricted working hours. A culture in which informal learning is embedded may also have benefits for patient safety. PMID- 23659623 TI - The assistant medical officer in Sri Lanka: mid-level health worker in decline. AB - The history of Assistant Medical Officers (AMOs) in Sri Lanka can be traced back to the 1860s. Their training from the beginning followed an allopathic, 'evidence based' model. AMOs have played a key role in rural and peripheral health care, through staffing of government central dispensaries and maternity homes and may have contributed to Sri Lanka's favorable health outcomes. While there are currently approximately 2000 AMOs, their training course was discontinued in 1995. It was argued that the quality of care provided by the AMOs is substandard relative to that of physicians. The success, rapid expansion and integration of physician assistant programs into the US health care system have recently spurred other countries to introduce similar programs. This paper reviews Sri Lanka's move in the opposite direction, phasing out the AMO profession, without any research into their contributions to access to interprofessional primary health care and positive health outcomes. PMID- 23659624 TI - The role of cytokines in skin aging. AB - Cutaneous aging is one of the major noticeable menopausal complications that most women want to fight in their quest for an eternally youthful skin appearance. It may contribute to some maladies that occur in aging which, despite not being life threatening, affect the well-being, psychological state and quality of life of aged women. Skin aging is mainly affected by three factors: chronological aging, decreased levels of estrogen after menopause, and environmental factors. Aged skin is characterized by a decrease in collagen content and skin thickness which result in dry, wrinkled skin that is easily bruised and takes a longer time to heal. Cytokines play a crucial role in the manifestation of these features of old skin. The pro-inflammatory cytokine tumor necrosis factor-alpha inhibits collagen synthesis and enhances collagen degradation by increasing the production of MMP 9. It also lowers the skin immunity and thus increases the risk of cutaneous infections in old age. Deranged levels of several interleukins and interferons also affect the aging process. The high level of CCN1 protein in aged skin gives dermal fibroblasts an 'age-associated secretory phenotype' that causes abnormal homeostasis of skin collagen and leads to the loss of the function and integrity of skin. Further research is required especially to establish the role of cytokines in the treatment of cutaneous aging. PMID- 23659628 TI - Neuropsychological indicators of preclinical Alzheimer's disease among depressed older adults. AB - Older adults with major depressive disorder (MDD) may also have preclinical Alzheimer's disease (AD). Differential diagnosis is quite challenging due to the overlapping symptoms of MDD and AD. In the current study, we predicted that impaired long-term memory (an area most affected in early AD), but not executive function (an area affected in MDD and AD), would distinguish older depressed patients who developed AD from those who did not. Patients (N = 120) assessed as having MDD but not dementia at baseline were administered tests of cognitive function and followed longitudinally for subsequent diagnosis of AD. Using structural equation modeling we found a latent construct of long-term memory to be associated with AD to a greater extent than executive functioning. Additional analyses to enhance clinical utility of findings indicated that individual tests of episodic memory were most predictive of AD status. Tests of long-term memory can be utilized by the clinician when assessing for preclinical AD among depressed elderly. PMID- 23659630 TI - Origin of attraction in chalgogen-nitrogen interaction of 1,2,5-chalcogenadiazole dimers. AB - Intermolecular interaction in the 1,2,5-chalcogenadiazole dimers was studied by ab initio molecular orbital calculations. Estimated CCSD(T) interaction energies for the thia-, selena- and tellura-diazole dimers are -3.14, -5.29, and -12.42 kcal/mol, respectively. The electrostatic and dispersion interactions are the major sources of the attraction in the dimers, although it was claimed that the orbital mixing (charge-transfer interaction) was the most prominent contribution to the stabilization. The induction (induced polarization) interaction also contributes largely to the attraction in the telluradiazole dimer. The large electrostatic and induction interactions are responsible for the strong attraction in the telluradiazole dimer. The short-range (orbital-orbital) interaction (sum of the exchange-repulsion and charge-transfer interactions) is repulsive. The directionality of the interactions increases in order of S < Se < Te. The electrostatic interaction is mainly responsible for the directionality. The strong directionality suggests that the chalcogen-nitrogen interaction plays important roles in controlling the orientation of molecules in those organic crystals. The nature of the chalcogen-nitrogen interaction in the chalcogenadiazole dimers is similar to that of the halogen bond, which is an electrostatically driven noncovalent interaction. PMID- 23659631 TI - Dumbbell-shaped DNA analytes amplified by polymerase chain reaction for robust single-nucleotide polymorphism genotyping by affinity capillary electrophoresis. AB - A sample preparation method was developed for single-nucleotide polymorphism (SNP) genotyping based on hybridization between a single-stranded DNA (ssDNA) analyte and an allele-specific oligonucleotide (ASO) probe. When the SNP site is located in the stable secondary structure, the folding of this analyte imposes kinetic penalties on the hybridization with the ASO probe. To address this issue, the sequence of the ssDNA analyte was converted from the original one so that the analyte exhibited a clear dumbbell-shaped structure composed of two stem-loop moieties and an unfolded probe-binding site. The as-prepared analyte was structurally favorable for hybridization with the ASO probe, irrespective of the original sequence and secondary structure of the analyte. The sequence conversion was easily achieved by polymerase chain reaction using forward and reverse primers having an additional sequence at the 5'-terminus. These ssDNA analytes were subjected to affinity capillary electrophoresis using a diblock copolymer probe composed of an ASO segment and a poly(ethylene glycol) segment. The 70-base dumbbell-shaped analytes with a single-base difference were clearly separated within 12 min, although the original ones exhibited almost no separation due to the undesired folding of the probe-binding site. This sample preparation method should open up a wide range of applications for the ASO probes in genetic analysis. PMID- 23659629 TI - A possible role for CCR5 in the progression of atherosclerosis in HIV-infected patients: a cross-sectional study. AB - BACKGROUND: Chemokines can block viral entry by interfering with HIV co-receptors and are recognised mediators of atherosclerosis development. A number of experimental drugs that inhibit HIV entry arrest the development of atherosclerosis in animal models. We hypothesised that the expression of chemokine receptors in circulating leukocytes is associated with the rate of atherosclerosis progression in HIV-infected patients. METHODS: The increase in intima-media thickness during a 2-year follow-up was used to classify HIV infected patients (n = 178) as progressors (n = 142) or non-progressors (n = 36) with respect to atherosclerosis. Logistic regression was used to assess variables associated with atherosclerosis progression. Mutations in the CCR5Delta32, CCR2 64I, and CX3CR1 (T280M and V249I) co-receptors as well as the levels of CCR5, CXCR4, CX3CR1, and CCR2 mRNA expression in circulating leukocytes were analysed as independent variables. RESULTS: Among the baseline variables, only genetic variants explained the dichotomous outcome. The expression of CCR2 and CXCR4 did not discriminate between progressors and non-progressors. Conversely, CCR5 and CX3CR1 expression was higher in not only progressors but also patients with detectable viral load. The logistic regression, however, demonstrated a significant role for CCR5 expression as a predictor of atherosclerosis progression (B = 2.1, OR = 8.1, p = 0.04) and a negligible effect for CXC3R1 and CCR2 expression. CONCLUSIONS: Available CCR5 antagonists should be investigated for their potential to delay the course of atherosclerosis in HIV-infected patients. PMID- 23659632 TI - Structural characterization of human histidine triad nucleotide-binding protein 2, a member of the histidine triad superfamily. AB - The histidine triad proteins (HITs) constitute a large and ubiquitous superfamily of nucleotide hydrolases. The human histidine triad nucleotide-binding proteins (hHints) are a distinct class of HITs noted for their acyl-AMP hydrolase and phosphoramidase activity. The first high-resolution crystal structures of hHint2 with and without bound AMP are described. The differences between hHint2 and previously known HIT family protein structures are discussed. HIT family enzymes have historically been divided into five classes based on their catalytic specificity: Hint, fragile HIT protein, galactose-1-phosphate uridylyltransferase, DcpS and aprataxin. However, although several structures exist for the enzymes in these classes, the endogenous substrates of many of these enzymes have not been identified or biochemically characterized. To better understand the structural relationships of the HIT enzymes, a structure-based phylogeny was constructed that resulted in the identification of several new putative HIT clades with potential acyl-AMP hydrolase and phosphoramidase activity. PMID- 23659633 TI - Serial changes in adipocytokines and cardiac function in a rat model of the metabolic syndrome. AB - Obesity is associated with high chronic cardiac workload due to the need to supply more blood to peripheral tissue, and frequently leads to left ventricular (LV) dysfunction. The present study examined serial changes in cardiac function in the SHR/NDmcr-cp (SHR/cp) strain, an experimental model of obesity plus hypertension and metabolic syndrome. Transthoracic echocardiography was used to define cardiac dimensions and function in male spontaneously hypertensive rats (SHR/lean), SHR/cp and Wistar-Kyoto rats. We also assessed age-related changes in plasma and LV adipocytokine levels in this model. Although there were no significant differences in LV end-diastolic diameter and end-systolic diameter among the three rat strains until 24 weeks of age, these parameters were significantly higher and LV fractional shortening (%FS) was significantly lower in SHR/cp compared with SHR/lean at 32 weeks of age. At the same age, pronounced interstitial fibrosis and infiltration of macrophages and T lymphocytes into the LV was noted in SHR/cp relative to the other strains. In the myocardium, adiponectin levels were significantly lower and resistin levels and the expression of proinflammatory cytokines (tumour necrosis factor-alpha and interleukin-6) were significantly higher in SHR/cp than SHR/lean at 32 weeks of age. Using echocardiography, we demonstrated reduced systolic function in 32-week old SHR/cp. Changes in myocardial cytokine concentrations could be involved in worsening of cardiac function in our animal model of metabolic syndrome. PMID- 23659634 TI - Towards zero rate in healthcare-associated infections: one size shall not fit all... AB - ICU patients are identified as targets for quality of care and patient safety improvement strategies. Critically ill patients are at high risk for complications due to the complex and invasive nature of critical care. Several reports in the literature describe initiatives aiming to zero the healthcare associated infection rate. We discuss the results of a study assessing a systematic team approach with very aggressive interventions surrounding the Institute for Healthcare Improvement Central Line-associated Blood Stream Infection bundle, which obtained a successful reduction of the rates. In addition, we discuss why some healthcare-associated infections are not fully preventable and the different reasons for this, the identification of which would be a cornerstone of quality improvement and safety promotion initiatives in critically ill patients. PMID- 23659635 TI - Highly enantioselective Simmons-Smith fluorocyclopropanation of allylic alcohols via the halogen scrambling strategy of zinc carbenoids. AB - Highly enantio- and diastereoenriched monofluorocyclopropanes were accessed via the Simmons-Smith fluorocyclopropanation of allylic alcohols using difluoroiodomethane and ethylzinc iodide as the substituted carbenoid precursors. The scrambling of halogens at the zinc carbenoid led to the formation of the fluorocyclopropanating agent (fluoroiodomethyl)zinc(II) fluoride. This strategy circumvented the ongoing limitation in Simmons-Smith fluorocyclopropanations relying on the use of the relatively inaccessible and expensive carbenoid precursor fluorodiiodomethane. PMID- 23659636 TI - Application of combined omics platforms to accelerate biomedical discovery in diabesity. AB - Diabesity has become a popular term to describe the specific form of diabetes that develops late in life and is associated with obesity. While there is a correlation between diabetes and obesity, the association is not universally predictive. Defining the metabolic characteristics of obesity that lead to diabetes, and how obese individuals who develop diabetes different from those who do not, are important goals. The use of large-scale omics analyses (e.g., metabolomic, proteomic, transcriptomic, and lipidomic) of diabetes and obesity may help to identify new targets to treat these conditions. This report discusses how various types of omics data can be integrated to shed light on the changes in metabolism that occur in obesity and diabetes. PMID- 23659637 TI - Complex transcriptional and post-transcriptional regulation of an enzyme for lipopolysaccharide modification. AB - The PhoQ/PhoP two-component system activates many genes for lipopolysaccharide (LPS) modification when cells are grown at low Mg(2+) concentrations. An additional target of PhoQ and PhoP is MgrR, an Hfq-dependent small RNA that negatively regulates expression of eptB, also encoding a protein that carries out LPS modification. Examination of LPS confirmed that MgrR effectively silences EptB; the phosphoethanolamine modification associated with EptB is found in DeltamgrR::kan but not mgrR(+) cells. Sigma E has been reported to positively regulate eptB, although the eptB promoter does not have the expected Sigma E recognition motifs. The effects of Sigma E and deletion of mgrR on levels of eptB mRNA were independent, and the same 5' end was found in both cases. In vitro transcription and the behaviour of transcriptional and translational fusions demonstrate that Sigma E acts directly at the level of transcription initiation for eptB, from the same start point as Sigma 70. The results suggest that when Sigma E is active, synthesis of eptB transcript outstrips MgrR-dependent degradation; presumably the modification of LPS is important under these conditions. Adding to the complexity of eptB regulation is a second sRNA, ArcZ, which also directly and negatively regulates eptB. PMID- 23659639 TI - Exploring the color of transition metal ions in irregular coordination geometries: new colored inorganic oxides based on the spiroffite structure, Zn(2 x)M(x)Te3O8 (M = Co, Ni, Cu). AB - We describe the synthesis, crystal structures, and optical absorption spectra of transition metal-substituted spiroffite derivatives, Zn(2-x)M(x)Te3O8 (M(II) = Co, Ni, Cu; 0 < x <= 1.0). The oxides are readily synthesized by solid state reaction of stoichiometric mixtures of the constituent binaries at 620 degrees C. Reitveld refinement of the crystal structures from powder X-ray diffraction (XRD) data shows that the Zn/MO6 octahedra are strongly distorted, as in the parent Zn2Te3O8 structure, consisting of five relatively short Zn/M(II)-O bonds (1.898-2.236 A) and one longer Zn/M(II)-O bond (2.356-2.519 A). We have interpreted the unique colors and the optical absorption/diffuse reflectance spectra of Zn(2-x)M(x)Te3O8 in the visible, in terms of the observed/irregular coordination geometry of the Zn/M(II)-O chromophores. We could not however prepare the fully substituted M2Te3O8 (M(II) = Co, Ni, Cu) by the direct solid state reaction method. Density Functional Theory (DFT) modeling of the electronic structure of both the parent and the transition metal substituted derivatives provides new insights into the bonding and the role of transition metals toward the origin of color in these materials. We believe that transition metal substituted spiroffites Zn(2-x)M(x)Te3O8 reported here suggest new directions for the development of colored inorganic materials/pigments featuring irregular/distorted oxygen coordination polyhedra around transition metal ions. PMID- 23659638 TI - Factor XII promotes blood coagulation independent of factor XI in the presence of long-chain polyphosphates. AB - BACKGROUND: Inorganic polyphosphates (polyP), which are secreted by activated platelets (short-chain polyP) and accumulate in some bacteria (long-chain polyP), support the contact activation of factor XII (FXII) and accelerate the activation of FXI. OBJECTIVES: The aim of the present study was to evaluate the role of FXI in polyP-mediated coagulation activation and experimental thrombus formation. METHODS AND RESULTS: Pretreatment of plasma with antibodies that selectively inhibit FXI activation by activated FXII (FXIIa) or FIX) activation by activated FXI (FXIa) were not able to inhibit the procoagulant effect of long or short chain polyP in plasma. In contrast, the FXIIa inhibitor, corn trypsin inhibitor, blocked the procoagulant effect of long and short polyP in plasma. In a purified system, long polyP significantly enhanced the rate of FXII and prekallikrein activation and the activation of FXI by thrombin but not by FXIIa. In FXI deficient plasma, long polyP promoted clotting of plasma in an FIX-dependent manner. In a purified system, the activation of FXII and prekallikrein by long polyP promoted FIX activation and prothombin activation. In an ex vivo model of occlusive thrombus formation, inhibition of FXIIa with corn trypsin inhibitor but not of FXI with a neutralizing antibodies abolished the prothrombotic effect of long polyP. CONCLUSIONS: We propose that long polyP promotes FXII-mediated blood coagulation bypassing FXI. Accordingly, some polyp-containing pathogens may have evolved strategies to exploit polyP-initiated FXII activation for virulence, and selective inhibition of FXII may improve the host response to pathogens. PMID- 23659640 TI - Structural features of a polysaccharide from Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao. AB - A polysaccharide Astragalus polysaccharide (APS) was obtained from the boiling water extract of Astragalus membranaceus (Fisch.) Bge. var. mongholicus (Bge.) Hsiao. The results of gas chromatography (GC) indicated that APS consisted of l rhamnose (l-Rha), d-xylose (d-Xyl), d-glucose (d-Glc), and d-galactose (d-Gal) in the molar ratio of 1:4:5:1.5. Its molecular weight was determined to be 3.01 * 10(5) by high-performance gel filtration chromatography. The results of (1)H NMR and (13)C NMR spectral analysis indicated that APS had a linear backbone mainly consisting of 1,3-linked beta-d-Gal residues with insertion of beta-Glc, 1,6 linked alpha-Gal, 1,5-linked beta-Xyl, 1,4-linked beta-Gal, beta-d-Gal, 1,2 linked alpha-Rha, 1,2,4-linked alpha-Rha residues. HSQC spectrum indicated that C 2 and C-6 may link with H. PMID- 23659641 TI - Insight into the compositional and structural nano features of AlN/GaN DBRs by EELS-HAADF. AB - III-V nitride (AlGa)N distributed Bragg reflector devices are characterized by combined high-angle annular dark-field (HAADF) and electron energy loss spectroscopy (EELS) in the scanning transmission electron microscope. Besides the complete structural characterization of the AlN and GaN layers, the formation of AlGaN transient layers is revealed using Vegard law on profiles of the position of the bulk plasmon peak maximum. This result is confirmed by comparison of experimental and simulated HAADF intensities. In addition, we present an advantageous method for the characterization of nano-feature structures using low loss EELS spectrum image (EEL-SI) analysis. Information from the materials in the sample is extracted from these EEL-SI at high spatial resolution.The log-ratio formula is used to calculate the relative thickness, related to the electron inelastic mean free path. Fitting of the bulk plasmon is performed using a damped plasmon model (DPM) equation. The maximum of this peak is related to the chemical composition variation using the previous Vegard law analysis. In addition, within the context of the DPM, information regarding the structural properties of the material can be obtained from the lifetime of the oscillation. Three anomalous segregation regions are characterized, revealing formation of metallic Al islands. PMID- 23659642 TI - A framework for performing workplace hazard and risk analysis: a participative ergonomics approach. AB - Despite the unanimity among researchers about the centrality of workplace analysis based on participatory ergonomics (PE) as a basis for preventive interventions, there is still little agreement about the necessary of a theoretical framework for providing practical guidance. In an effort to develop a conceptual PE framework, the authors, focusing on 20 studies, found five primary dimensions for characterising an analytical structure: (1) extent of workforce involvement; (2) analysis duration; (3) diversity of reporter role types; (4) scope of analysis and (5) supportive information system for analysis management. An ergonomics analysis carried out in a chemical manufacturing plant serves as a case study for evaluating the proposed framework. The study simultaneously demonstrates the five dimensions and evaluates their feasibility. The study showed that managerial leadership was fundamental to the successful implementation of the analysis; that all job holders should participate in analysing their own workplace and simplified reporting methods contributed to a desirable outcome. PRACTITIONER SUMMARY: This paper seeks to clarify the scope of workplace ergonomics analysis by offering a theoretical and structured framework for providing practical advice and guidance. Essential to successfully implementing the analytical framework are managerial involvement, participation of all job holders and simplified reporting methods. PMID- 23659643 TI - Brain magnetic resonance imaging pattern and outcome in children with haemolytic uraemic syndrome and neurological impairment treated with eculizumab. AB - AIM: The aim of this study was to describe the magnetic resonance imaging (MRI) findings and the neurological and neuropsychological outcomes in paediatric, diarrhoea-associated haemolytic-uraemic syndrome (D+HUS) with central nervous system impairment treated with eculizumab, a monoclonal antibody. METHOD: The 14 month single-centre prospective study included seven children (three males, four females; age range 16 mo-7 y 8 mo; median age 3 y 7 mo) with typical D+HUS and acute neurological impairment. In the acute phase of the disease, neurological assessment and brain magnetic resonance imaging (MRI), including measurement of the apparent diffusion coefficient (ADC), were performed, and neuropsychological evaluation and brain MRI were also carried out 6 months after disease onset. RESULTS: In the acute phase, basal ganglia and white matter abnormalities with ADC restriction were a common and reversible MRI finding. In all the surviving patients (5/7), follow-up MRI after 6 months was normal, indicating reversible lesions. Clinical and neuropsychological evaluations after 6 months were also normal. INTERPRETATION: This specific brain MRI pattern consisting of an ADC decrease in basal ganglia and white matter without major T2/fluid-attenuated inversion recovery (FLAIR) injury may be a key finding in the acute phase of the disease in favour of a vasculitis hypothesis. These reversible lesions were associated with a good neurological outcome. These results call for further evaluation of the potential role of eculizumab in the choice of treatment for severe D+HUS, particularly in the case of early neurological signs. PMID- 23659644 TI - Taking the long view: exploring the development of interprofessional education. AB - Interprofessional education (IPE) in health and social care has been well documented regarding student outcomes. Less has been written from the perspective of those who actually developed IPE. This study explores IPE within the context of a university partnership working with service providers in Southwest London (UK). We focused on the experiences and perspectives of 19 key players who were interviewed about the inception, implementation and development of IPE over 15 years. Our aim was to understand their views of IPE and its evolution over time. Interviewees provided different understandings of IPE, as well as contrasting views regarding its purpose and optimum delivery. Problems such as lack of central planning and the logistics of implementation were also discussed. Paradoxically, however, the participants highlighted positive outcomes and conveyed optimistic messages for the future. Despite various challenges and setbacks, a strong belief in the importance of IPE and a commitment to carrying it through were strong motivators contributing to finding solutions, as were building trust and positive relationships across professional and disciplinary boundaries. PMID- 23659645 TI - Diarrhoea-related knowledge and practice of physicians in urban slums of Kolkata, India. AB - Diarrhoeal management practices are unsatisfactory in India especially in the slum areas. Dearth of information regarding physicians' diarrhoea-related knowledge and practice in India necessitated this cross-sectional study of allopathic practitioners in the slums of Kolkata, to assess the distribution and interrelationship between physicians' characteristics, knowledge and practice regarding diarrhoea. A total of 264 randomly selected consenting practitioners were interviewed using a field-tested questionnaire. Nineteen percent had good overall knowledge, 49% and 80% prescribed antibiotics to diarrhoea and cholera patients, respectively, and 55% advised stool examination for every case. Qualified and Government physicians had better knowledge regarding diarrhoea [MBBS: odds ratio (OR) 5.96, P < 0.001; postgraduates: OR 9.33, P < 0.001; Government physicians: OR 11.49, P < 0.0001] and were less likely to prescribe antibiotics for all diarrhoea cases (MBBS: OR 0.30, P = 0.002; postgraduates: OR 0.20, P < 0.001; Government physicians OR 0.24, P < 0.029). Better knowledge was associated with a lower likelihood of prescribing antibiotics for diarrhoea (OR 0.72, P < 0.001), cholera (OR 0.78, P = 0.027) and investigative procedure (OR 0.85, P = 0.028). In the slums of Kolkata, diarrhoea-related knowledge and practice were poor with the exception of qualified physicians, hence an improvement in the knowledge of pharmacists and unqualified practitioners is necessary for the overall improvement of diarrhoeal management in these slums. PMID- 23659646 TI - Mechanisms of prebiotic adenine synthesis from HCN by oligomerization in the gas phase. AB - We explored the potential energy surfaces for adenine synthesis by oligomerizations of HCN or HNC from CBS-QB3 calculations. The pathways have been obtained for the formation of the covalently bound HCN dimer, trimer, tetramer, and pentamer (adenine) by sequential additions of HCN or HNC. The activation energies of the individual oligomerization stages are a few hundred kilojoules per mole, which prevent efficient adenine synthesis in interstellar space or in the atmosphere of Titan. On the other hand, when the oligomerizations start from HCNH(+), the activation energies of sequential HCN or HNC additions are significantly reduced. Kinetic analyses results suggest that adenine synthesis by proton-catalyzed oligomerizations cannot occur efficiently in interstellar space or in the atmosphere of Titan, even though some oligomerization stages can occur under the latter condition. PMID- 23659647 TI - Habitability in different Milky Way stellar environments: a stellar interaction dynamical approach. AB - Every Galactic environment is characterized by a stellar density and a velocity dispersion. With this information from literature, we simulated flyby encounters for several Galactic regions, numerically calculating stellar trajectories as well as orbits for particles in disks; our aim was to understand the effect of typical stellar flybys on planetary (debris) disks in the Milky Way Galaxy. For the solar neighborhood, we examined nearby stars with known distance, proper motions, and radial velocities. We found occurrence of a disturbing impact to the solar planetary disk within the next 8 Myr to be highly unlikely; perturbations to the Oort cloud seem unlikely as well. Current knowledge of the full phase space of stars in the solar neighborhood, however, is rather poor; thus we cannot rule out the existence of a star that is more likely to approach than those for which we have complete kinematic information. We studied the effect of stellar encounters on planetary orbits within the habitable zones of stars in more crowded stellar environments, such as stellar clusters. We found that in open clusters habitable zones are not readily disrupted; this is true if they evaporate in less than 10(8) yr. For older clusters the results may not be the same. We specifically studied the case of Messier 67, one of the oldest open clusters known, and show the effect of this environment on debris disks. We also considered the conditions in globular clusters, the Galactic nucleus, and the Galactic bulge-bar. We calculated the probability of whether Oort clouds exist in these Galactic environments. PMID- 23659649 TI - Recent advances in catalytic sequential reactions involving hydroelement addition to carbon-carbon multiple bonds. PMID- 23659648 TI - Effects of low-volume walking programme and vitamin E supplementation on oxidative damage and health-related variables in healthy older adults. AB - BACKGROUND: Both exercise and vitamin E supplementation have been shown to reduce oxidative stress and cardiovascular disease risk in older adults, and when combined there is evidence suggesting that they act synergistically. The currently recommended amount of exercise for older adults is 150 min/week of moderate-intensity exercise; however, the minimum amount of exercise necessary to achieve health benefits is not known. The purpose of this study was to investigate the effects of 12 weeks of participation in a low-volume walking exercise programme (i.e. 90 min/week) combined with daily vitamin E supplementation on thiobarbituric acid reactive substances (TBARS) and oxidised low-density lipoprotein (LDL) concentrations in older adults. METHODS: The participants were recruited from the following four groups separately: 1) control (CG, n = 14), 2) vitamin E supplementation (SG, n = 10), 3) walking (WG, n = 7), or 4) walking + supplementation (WSG, n = 7). In the CG, participants were advised to maintain their normal lifestyle during the study. Participants in both the SG and WSG received 450 IU (300 mg) /day of alpha-tocopherol for 12 weeks. The exercise programme for the WG and WSG consisted of two 30-60 minute sessions weekly for 12 weeks (average walking time was 44.5 +/- 1.6 min/session). Blood samples were collected at baseline and at 12 weeks. RESULTS: Delta plasma oxidised LDL concentrations did not differ among four groups (One-factor ANOVA, P = 0.116). However, negative delta plasma TBARS, a marker of oxidative damage, concentrations were observed in the WG, WSG and SG relative to the CG at the end of the study period (One-factor ANOVA, P = 0.001; post hoc tests; CG compared with WG, WSG and SG, P = 0.005; P = 0.021; P = 0.024, respectively). CONCLUSION: These findings suggest that a low-volume of physical activity and/or vitamin E supplementation may be an effective intervention strategy for reducing TBARS concentrations of older adults. TRIAL REGISTRATION: UMIN000008304. PMID- 23659650 TI - Edinburgh Handedness Inventory - Short Form: a revised version based on confirmatory factor analysis. AB - While the Edinburgh Handedness Inventory has been widely used, there have been few studies assessing its factorial validity. There is evidence that the original instructions and response options are difficult to understand. Using simplified instructions and response options, the Edinburgh Handedness Inventory was administered on a sample of 1514 participants using an online questionnaire. In accordance with previous research, a model of the 10-item inventory had poor fit for the data. This study also detected model misspecification in the previously proposed 7-item modification. A 4-item Edinburgh Handedness Inventory - Short Form had good model fit with items modelled as both continuous and ordinal. Despite its brevity, it showed very good reliability, factor score determinacy, and correlation with scores on the 10-item inventory. By eliminating items that were modelled with considerable measurement error, the short form alleviates the concern of the 10-item inventory over-categorising mixed handers. Evidence was found for factorial invariance across level of education, age groups, and regions (USA and Australia/New Zealand). There generally appeared to be invariance across genders for the 4-item inventory. The proposed Edinburgh Handedness Inventory - Short Form measures a single handedness factor with an inventory that has brief and simple instructions and a small number of items. PMID- 23659651 TI - Utility of whole-blood aggregometry for evaluating anti-platelet therapy for Kawasaki disease. AB - BACKGROUND: Anti-platelet therapy for Kawasaki disease (KD) is often done without monitoring drug efficacy. The aim of this study was to investigate the utility of whole-blood aggregometry to evaluate the efficacy of anti-platelet therapy for KD. METHODS: Of 37 late-phase KD patients included in the present study, 20 were prescribed anti-platelet drugs. Platelet-rich plasma (PRP) aggregation with collagen as the stimulus was measured using an optical aggregometer. The area under the curve of small and large size aggregations was calculated, and categorized into five classes: -2, -1, 0, 1, and 2. Whole-blood aggregation with collagen or adenosine 5'-diphosphate (ADP) as stimulus was evaluated using the platelet aggregation threshold index (PATI), which is the concentration of stimulus that induces a whole-blood aggregation rate of 50%. RESULTS: In both collagen- and ADP-induced aggregation, there was a negative correlation between PATI and class determination using the PRP technique (collagen, rs = -0.870, P < 0.0001; ADP, rs = -0.620, P < 0.0001). Moreover, the PATI in collagen- and ADP induced aggregation was significantly higher in the anti-platelet drug therapy group than in the untreated group (collagen, P < 0.0001; ADP, P = 0.0002). The serum thromboxane B2 level in the anti-platelet drug therapy group was also significantly lower than that in the untreated group (P < 0.0001). PATI was significantly higher in those treated with thienopyridine drug combinations than those without drug therapy (P = 0.0036). CONCLUSIONS: Whole-blood aggregometry is useful for monitoring the efficacy of anti-platelet therapy for KD. PMID- 23659653 TI - Biotinylated cyclen-contained cationic lipids as non-viral gene delivery vectors. AB - A series of 1, 4, 7, 10-tetraazacyclododecane (cyclen)-based cationic lipids, namely 5a-c bearing a biotin moiety and a variety of end groups (cholesterol, diosgenin, and alpha-tocopherol) via biodegradable carbamate bond linkage were prepared and applied as non-viral gene delivery vectors. The liposomes formed from 5 and dioleoylphosphatidylethanolamine could bind and condense plasmid DNA into nanoparticles with appropriate size and zeta potentials. All biotinylated cyclen cationic lipids showed higher cell viability than commercially available lipofectamine 2000 even at high N/P ratios, while their transfection efficiency was relatively lower. Further, results indicate that among the three lipids, alpha-tocopherol-containing compound 5c has higher DNA-binding ability, lower cytotoxicity, and higher transfection efficiency. Transfection in two different cell lines revealed that these lipoplexes have higher gene delivery efficiency toward tumor cells. PMID- 23659652 TI - Three human cell types respond to multi-walled carbon nanotubes and titanium dioxide nanobelts with cell-specific transcriptomic and proteomic expression patterns. AB - The growing use of engineered nanoparticles (NPs) in commercial and medical applications raises the urgent need for tools that can predict NP toxicity. Global transcriptome and proteome analyses were conducted on three human cell types, exposed to two high aspect ratio NP types, to identify patterns of expression that might indicate high versus low NP toxicity. Three cell types representing the most common routes of human exposure to NPs, including macrophage-like (THP-1), small airway epithelial and intestinal (Caco-2/HT29-MTX) cells, were exposed to TiO2 nanobelts (TiO2-NB; high toxicity) and multi-walled carbon nanotubes (MWCNT; low toxicity) at low (10 ug/mL) and high (100 ug/mL) concentrations for 1 and 24 h. Unique patterns of gene and protein expressions were identified for each cell type, with no differentially expressed (p < 0.05, 1.5-fold change) genes or proteins overlapping across all three cell types. While unique to each cell type, the early response was primarily independent of NP type, showing similar expression patterns in response to both TiO2-NB and MWCNT. The early response might, therefore, indicate a general response to insult. In contrast, the 24 h response was unique to each NP type. The most significantly (p < 0.05) enriched biological processes in THP-1 cells indicated TiO2-NB regulation of pathways associated with inflammation, apoptosis, cell cycle arrest, DNA replication stress and genomic instability, while MWCNT-regulated pathways indicated increased cell proliferation, DNA repair and anti-apoptosis. These two distinct sets of biological pathways might, therefore, underlie cellular responses to high and low NP toxicity, respectively. PMID- 23659654 TI - What do Spaniards read about the prudent use of anti-microbial agents and what do they really do? AB - OBJECTIVES: The prudent use of antibiotics (PUA) is promoted not only by public information campaigns, but also in the printed media and on websites. This study assesses the correspondence between PUA information in the Spanish printed media and on websites and the messages put out by national campaigns. Spaniards' use of antibiotics following the campaigns was also analysed. METHODS: A two-phase descriptive study was carried out. First, antibiotics-related news in the Spanish printed media (January 2007-May 2009) and institutional and news media websites (March-May 2009) were systematically reviewed using a data collection tool. In addition, a telephone survey on antibiotics-related knowledge and behaviours was carried out with a random sample of 1526 people living in Spain who had recently received medical care. RESULTS: In total, 29 news items containing nine different messages were identified. All the messages were similar to those promoted by the campaigns. The survey showed that even after the campaigns, relevant gaps in knowledge about the PUA persist, particularly among men (p = .005), those living in rural areas (p = .02) and the elderly (p < .001). Keeping left-over antibiotics was associated with ignorance about the association between antibiotic use and resistance (OR 3.1, 95% CI 2.3-4.2). Also, patients who ask their doctor about drug interactions are less likely to self-medicate (p = .04). CONCLUSIONS: The information reaching the Spanish public via the media seems to be similar to the messages transmitted by public information campaigns. Nevertheless, there appears to be considerable room for improvement. Promoting an active role in patients might reduce self-medication. PMID- 23659655 TI - Toward organic photohydrides: excited-state behavior of 10-methyl-9-phenyl-9,10 dihydroacridine. AB - The excited-state hydride release from 10-methyl-9-phenyl-9,10-dihydroacridine (PhAcrH) was investigated using steady-state and time-resolved UV/vis absorption spectroscopy. Upon excitation, PhAcrH is oxidized to the corresponding iminium ion (PhAcr(+)), while the solvent (acetonitrile/water mixture) is reduced (52% of PhAcr(+) and 2.5% of hydrogen is formed). The hydride release occurs from the triplet excited state by a stepwise electron/hydrogen-atom transfer mechanism. To facilitate the search for improved organic photohydrides that exhibit a concerted mechanism, a computational methodology is presented that evaluates the thermodynamic parameters for the hydride ion, hydrogen atom, and electron release from organic hydrides. PMID- 23659656 TI - Optimizing safe, comfortable ICU care through multi-professional quality improvement: just DO it. AB - Translating research to the bedside can present significant challenges in the complex ICU environment. In this issue of Critical Care, de Jong and colleagues report on a quality improvement project (NURSE-DO) that led to a decrease in severe pain and serious adverse events during nursing care procedures in their ICU. In this commentary we describe three aspects of this quality improvement study that we think contributed to the overall success of the NURSE-DO project: the hospital environment and culture; multi-professional partnerships; and an evidence-based structured approach. PMID- 23659657 TI - Ulcerated plaque in the nasal dorsum in a patient with multiple myeloma. PMID- 23659658 TI - Enantioselective bromoaminocyclization of allyl N-tosylcarbamates catalyzed by a chiral phosphine-Sc(OTf)3 complex. AB - An effective enantioselective bromoaminocyclization of allyl N-tosylcarbamates catalyzed by a chiral phosphine-Sc(OTf)3 complex is described. A wide variety of optically active oxazolidinone derivatives containing various functional groups can be obtained with high enantioselectivities. PMID- 23659660 TI - Histopathology as a simple and reliable method to detect 17beta-oestradiol illegal treatment in male calves. AB - 17beta-Oestradiol is a steroid hormone banned as a growth promoter in food producing animals all over Europe because of its carcinogenicity. Despite mandatory monitoring of illegal treatment all over Europe, official analytical methods in use test negative a few days after 17beta-oestradiol administration, requiring new sensitive tools to ensure a high level of protection for consumers. The aim of this work was the evaluation of the accuracy of histopathology and immunohistochemistry for progesterone receptor (PR) as a screening method for the detection of low-dosage illegal treatments with 17beta-oestradiol. Fresian male calves (153) were farmed under controlled conditions, and 89 of them were treated with 17beta-oestradiol (5 mg/animal once a week for 4 weeks). After 15 days of suspension, all animals were slaughtered and sexual accessory glands (prostate and bulbo-urethral glands) were sampled for histological examination and immunohistochemical staining with anti-PR antibody (clone hPRa 2). Microscopically 86 out of 89 bulbo-urethral glands showed mild to severe metaplasia, while mild metaplasia was observed only in 1 control. Eighteen out of 89 samples of prostate did not show metaplastic lesions. Immunopositivity for PR characterised all treated animals, while no signal was detected in controls. These findings show that metaplasia of the sexual accessory glands is a sensitive and specific parameter for illegal 17beta-oestradiol treatment in calves at the slaughterhouse, while the appliance of immunohistochemistry for PR can improve to 100% the accuracy of this highly reliable histological approach. PMID- 23659662 TI - Intrinsic structural defects in monolayer molybdenum disulfide. AB - Monolayer molybdenum disulfide (MoS2) is a two-dimensional direct band gap semiconductor with unique mechanical, electronic, optical, and chemical properties that can be utilized for novel nanoelectronics and optoelectronics devices. The performance of these devices strongly depends on the quality and defect morphology of the MoS2 layers. Here we provide a systematic study of intrinsic structural defects in chemical vapor phase grown monolayer MoS2, including point defects, dislocations, grain boundaries, and edges, via direct atomic resolution imaging, and explore their energy landscape and electronic properties using first-principles calculations. A rich variety of point defects and dislocation cores, distinct from those present in graphene, were observed in MoS2. We discover that one-dimensional metallic wires can be created via two different types of 60 degrees grain boundaries consisting of distinct 4-fold ring chains. A new type of edge reconstruction, representing a transition state during growth, was also identified, providing insights into the material growth mechanism. The atomic scale study of structural defects presented here brings new opportunities to tailor the properties of MoS2 via controlled synthesis and defect engineering. PMID- 23659661 TI - Uncoupling of mRNA synthesis and degradation impairs adaptation to host temperature in Cryptococcus neoformans. AB - The pathogenic fungus Cryptococcus neoformans must overcome multiple stressors to cause disease in its human host. In this study, we report that C. neoformans rapidly and transiently repressed ribosomal protein (RP) transcripts during a transition from 30 degrees C to host temperature. This repression was accompanied by accelerated mRNA degradation mediated by the major deadenylase, Ccr4, and influenced by the dissociable RNA polymerase II subunit, Rpb4. Destabilization and deadenylation of RP transcripts were impaired in an rpb4Delta mutant, suggesting that Rpb4 may be involved in host temperature-induced Ccr4-mediated decay. Accelerated decay of ER stress transcripts 1 h following a shift to host temperature was also impaired in the rpb4Delta mutant. In response to host temperature, Rpb4 moved from the nucleus to the cytoplasm, supporting a role for Rpb4 in coupling transcription and degradation. The PKH signalling pathway was implicated as a regulator of accelerated degradation of the RP transcripts, but not of the ER stress transcripts, revealing a further level of specificity. When transcription and degradation were uncoupled by deletion of Rpb4, growth at host temperature was impaired and virulence was attenuated. These data suggest that mRNA synthesis and decay are coupled in C. neoformans via Rpb4, and this tight coordination promotes host-temperature adaptation and pathogenicity. PMID- 23659663 TI - An approach for separation and complete structural sequencing of heparin/heparan sulfate-like oligosaccharides. AB - As members of the glycosaminoglycan (GAG) family, heparin and heparan sulfate (HS) are responsible for mediation of a wide range of essential biological actions, most of which are mediated by specific patterns of modifications of regions of these polysaccharides. To fully understand the regulation of HS modification and the biological function of HS through its interactions with protein ligands, it is essential to know the specific HS sequences present. However, the sequencing of mixtures of HS oligosaccharides presents major challenges due to the lability of the sulfate modifications, as well as difficulties in separating isomeric HS chains. Here, we apply a sequential chemical derivatization strategy involving permethylation, desulfation, and trideuteroperacetylation to label original sulfation sites with stable and hydrophobic trideuteroacetyl groups. The derivatization chemistry differentiates between all possible heparin/HS sequences solely by glycosidic bond cleavages, without the need to generate cross-ring cleavages. This derivatization strategy combined with LC-MS/MS analysis has been used to separate and sequence five synthetic HS-like oligosaccharides of sizes up to dodecasaccharide, as well as a highly sulfated Arixtra-like heptamer. This strategy offers a unique capability for the sequencing of microgram quantities of HS oligosaccharide mixtures by LC MS/MS. PMID- 23659664 TI - Long-term survival in elderly patients with stable coronary disease. AB - BACKGROUND: This study aimed to assess long-term prognosis of stable coronary artery disease (sCAD) in patients aged >= 75 years and to identify clinical predictors of cardiovascular and overall mortality. MATERIALS AND METHODS: From February 2000 to January 2007, 391 outpatients aged >= 75 years (median 78 years, interquartile range [IQR] 76-81 years, 66% male) with sCAD were recruited in this prospective cohort study. Associations of baseline variables with long-term cardiovascular and all-cause death were investigated. RESULTS: After up to 11 years of follow-up (median 4 years, IQR 2-6 years), 89 patients died (23%, 5.45%/year), 35 from cardiovascular causes (9%, 2.14%/year). Multivariate analysis identified family history of coronary disease (HR 4.28, 95% CI 1.22 15.02, P = 0.02), baseline atrial fibrillation (HR 3.18, 95% CI 1.37-7.39, P = 0.007), age (HR 1.61 per 5 year increase, 95% CI 1.04-2.50, P = 0.03), resting heart rate (HR 1.26 per 5 bpm increase, 95% CI 1.09-1.47, P = 0.003) and previous revascularization (HR 0.17, 95% CI 0.04-0.77, P = 0.02) as independent predictors of cardiovascular death, and previous acute coronary syndrome (HR 4.93, 95% CI 1.49-16.30, P = 0.009), baseline atrial fibrillation (HR 1.96, 95% CI 1.12-3.43, P = 0.02), tobacco use (HR 1.69, 95% CI 1.00-2.84, P = 0.049 for ex-smoking and HR 6.78, 95% CI 0.89-51.47, P = 0.06 for active smoking), age (HR 1.58 per 5 year increase, 95% CI 1.18-2.11, P = 0.002), resting heart rate (HR 1.10 per 5 bpm increase, 95% CI 1.00-1.22, P = 0.05) and diastolic blood pressure (HR 0.97, 95% CI 0.94-0.99, P = 0.01) as independent predictors of overall mortality. CONCLUSIONS: In this study, 4-years overall mortality was 23% among elderly patients with sCAD. Simple clinical variables can identify patients at higher risk of mortality. PMID- 23659665 TI - Cytotoxic monacolin analogs from Monascus purpureus-fermented rice. AB - Two new monacolin analogs, monacolins O (1) and P (2), along with three known analogs, have been isolated from the ethanolic extract of Monascus purpureus fermented rice. Their structures and absolute configurations were elucidated by spectroscopic methods, especially 2D NMR and CD spectral analyses as well as chemical method. Both 1 and 2 were tested against five tumor cell lines, and compound 1 exhibited selective cytotoxic activity against A2780 and A549 cell lines, with IC50 values of 3.7 and 8.0 MUM, respectively. PMID- 23659666 TI - High-dose phenobarbital or erythropoietin for the treatment of perinatal asphyxia in term newborns. AB - BACKGROUND: The aim of this study was to compare two neuroprotective strategies to supportive care in the treatment of perinatal asphyxia. METHODS: A total of 67 term newborns with perinatal asphyxia were included and randomized into three groups: one group received supportive treatment; another group received a single dose of 40 mg/kg phenobarbital; and the third received three daily doses of 1000 IU/kg erythropoietin. The following parameters were analyzed: gestational age, birthweight, Apgar scores, cord blood pH, total serum antioxidant status (TAS), superoxide dismutase (SOD), glutathione peroxidase (GPx) and malondialdehyde (MDA). The newborns were included in the follow-up program and examined up to 18 months of age. RESULTS: TAS was higher in the erythropoietin group than in the other groups. SOD and GPx were lower for infants treated with phenobarbital or erythropoietin compared to control infants. MDA was lower in the erythropoietin group compared to the other groups, although the difference was not statistically significant (P > 0.05). The mortality rate was lower in the phenobarbital and erythropoietin groups (both 4.6%) than in the control group (17.4%). Long-term neurologic follow up showed a high incidence of sequelae in the control group compared to the phenobarbital and erythropoietin groups. Follow-up results were better in the phenobarbital group than in the erythropoietin group for motor and cognitive function at 3 and 6 months and worse for expressive language. At 18 months, however, the differences between these two groups were not significant. CONCLUSION: High-dose phenobarbital or erythropoietin along with supportive treatment has a positive influence on the outcome of newborns with perinatal asphyxia. Phenobarbital has the advantage of low cost and simplicity. PMID- 23659667 TI - Clinico- pathological profile of patients with breast diseases. AB - BACKGROUND: To evaluate the spectrum of breast diseases and their association with presenting complains of patients. METHODOLOGY: It was a cross sectional study conducted from 1st January 2010 - 30th December 2012. A total of 254 breast specimens of patients, who were admitted in Civil Hospital Karachi with breast complaints, were included. Specimens were collected either from mastectomy, lumpectomy or needle biopsy from the admitted patients. Informed written consent was taken from all the patients. All patients with primary breast diseases were included. Patients undergoing chemotherapy or with secondary breast disease and slides with insufficient specimen were excluded. All data was entered and analyzed through SPSS 19. RESULT: There were 254 breast lesions, histologically diagnosed in 3 year review period. The overall mean age of patients with breast lesion was 25.18, SD +/- 11.73 with a wide age range of 12-74 years. Most common cases identified are benign 191(75.3%), followed by inflammatory 30(11.8%) and malignant lesions 30(11.8%). Most patients presenting with the complain of pain have diagnosis of fibroadenoma 24 (63.2%) while patient with complain of lump also have the most common diagnosis of fibroadenoma 147 (72.8%). CONCLUSIONS: Study shows that in Pakistani females, mostly encountered breast lesion was fibroadenoma. Due to lack of awareness breast diseases present lately. Awareness must be created among women to reduce the mortality and morbidity with breast lesions. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1037059088969395. PMID- 23659668 TI - What liver transplant outcomes can be expected in the uninsured who become insured via the Affordable Care Act? AB - Our study objective is to measure the survival impact of insurance status following liver transplantation in a cohort of uninsured "charity care" patients. These patients are analogous to the population who will gain insurance via the Affordable Care Act. We hypothesize there will be reduced survival in charity care compared to other insurance strata. We conducted a retrospective study of 898 liver transplants from 2000 to 2010. Insurance cohorts were classified as private (n = 640), public (n = 233) and charity care (n = 23). The 1, 3 and 5 year survival was 92%, 88% and 83% in private insurance, 89%, 80% and 73% in public insurance and 83%, 72% and 51% in charity care. Compared to private insurance, multivariable regression analyses demonstrated charity care (HR 3.11, CI 1.41-6.86) and public insurance (HR 1.58, CI 1.06-2.34) had a higher 5-year mortality hazard ratio. In contrast, other measures of socioeconomic status were not significantly associated with increased mortality. The charity care cohort demonstrated the highest incidence of acute rejection and missed clinic appointments. These data suggest factors other than demographic and socioeconomic may be associated with increased mortality. Further investigations are necessary to determine causative predictors of increased mortality in liver transplant patients without private insurance. PMID- 23659669 TI - Rapid interferon-gamma release from natural killer cells induced by a streptococcal commensal. AB - Interferon-gamma (IFN-gamma) is a critical cytokine for the initiation of immune responses against a variety of infectious agents and malignancies. We found that a range of Gram-positive and Gram-negative bacteria stimulated the rapid release (<24 h) of IFN-gamma from murine leukocytes. Using fluorescence activated cell sorting and cd1d(-/-) and rag1(-/-) mice, we determined that dendritic cells (DCs) and natural killer (NK) cells were primarily responsible for IFN-gamma release by Streptococcus salivarius, a Gram-positive commensal, previously noted to possess potent interleukin-12 (IL-12)-inducing potential. IFN-gamma release from NK cells required DC:NK membrane contact and IL-12/IL-18 expression, but was independent of lymphocyte function-associated antigen-1-mediated interactions. IFN-gamma release in response to bacteria was maintained in mice deficient for Toll-like receptor (TLR)-2 and TLR-4, suggesting that bacteria activate antigen presenting cells via multiple, redundant pathways. Together, our results suggest that Gram-positive bacteria may be useful in driving NK cell activation and T helper 1 polarization and have the potential for development as effective adjuvants. PMID- 23659670 TI - A polymorphism of interleukin-22 receptor alpha-1 is associated with the development of childhood IgA nephropathy. AB - Recent studies suggest that dysregulated innate immunity plays an important role in the pathogenesis of immunoglobulin A nephropathy (IgAN). The interleukin-20 subfamily and its receptor, interleukin-22 receptor alpha-1 (IL-22R1), were recently identified as immunomodulators in human diseases, acting as mediators of mucosal host defense. However, the potential role of IL-22R1 in the pathogenesis of IgAN has not been explored. In the current study, 194 patients with IgAN and 287 normal controls were genotyped for coding polymorphisms of the IL-22R1 gene and the association between the polymorphisms and IgAN was investigated. Local expression of IL-22R1 was examined in patients with IgAN and healthy controls using immunohistochemistry. Our case-control analysis showed that genotypes of rs3795299 were associated with childhood IgAN. Individuals with the CC genotype of rs3795299 had about 3-fold reduced risk of IgAN compared with those with the GG genotype in the codominant model (P=0.0028) and those with the genotypes containing the G allele (GG or GC) in the recessive model (P=0.002). After Bonferroni correction, the association between the rs3795299 CC genotype and reduced risk of developing IgAN remained significant. Furthermore, the renal expression of IL-22R1 was significantly higher in healthy controls compared with subjects with IgAN. Our data suggest that the CC genotype of rs3795299 polymorphism in the IL-22R1 gene is associated with the reduced risk of IgAN, and this genetic association was supported by the higher renal expression of IL-22R1 in healthy controls compared with patients with IgAN. PMID- 23659671 TI - Administration of amiodarone during resuscitation is associated with higher tumor necrosis factor-alpha levels in the early postarrest period in the swine model of ischemic ventricular fibrillation. AB - To compare the early postarrest inflammatory cytokine response between animals administered amiodarone (AMIO) and lidocaine (LIDO) intra-arrest during resuscitation from ventricular fibrillation (VF). Domestic swine (n=32) were placed under general anesthesia and instrumented before spontaneous VF was induced by balloon occlusion of the left anterior descending coronary artery. After 7 min of VF, standard ACLS resuscitation was performed and animals were randomized to either bolus AMIO (5 mg/kg, n=13) or LIDO (1 mg/kg, n=14) for recurrent or refractory VF. A non-antiarrhythmic (n=5) was also used for comparison. Following return of spontaneous circulation (ROSC), tumor necrosis factor (TNF)-alpha levels were drawn at 30 and 60 min. Groups were comparable with respect to prearrest hemodynamics and resuscitation variables. In the postarrest period, the LIDO and non-antiarrhythmic group demonstrated virtually identical TNF-alpha response trajectories. However, TNF-alpha levels were significantly higher in AMIO- than LIDO-treated animals at 30 min (geometric mean 539 versus 240 pg/mL, 2.2-fold higher, 95% confidence interval [CI] 1.3-3.8-fold higher, P=0.003) and at 60 min (geometric mean 570 versus 204 pg/mL, 2.8-fold higher, 95% CI 1.1-7.0-fold higher, P=0.03). Significant differences in the postarrest TNF-alpha levels were observed between animals treated with AMIO as compared to those treated with LIDO. Improved rates of ROSC seen with AMIO may come at the expense of a heightened proinflammatory state in the postcardiac arrest period. PMID- 23659672 TI - Pediatric reference ranges for proinflammatory and anti-inflammatory cytokines in cerebrospinal fluid and serum by multiplexed immunoassay. AB - To define cytokine concentrations and detectability in children with noninflammatory neurological disorders (NIND). The multiplex bead assay technology was used for simultaneous measurement of 34 soluble cytokines/chemokines in cerebrospinal fluid (CSF) from 73 NIND. Sera from 36 healthy children and 37 NIND also were analyzed. In CSF, CXCL10 had the highest concentration; CCL2, CXCL10, and interleukin (IL)-6 were detectable in all samples, and CXCL8, CCL22, CXCL1, IL-16, and IL-1 receptor antagonist were found in >=50% of the samples. In serum, CXCL1 had the highest concentration; sIL-2Ra, CXCL1, CXCL10, and CCL22 were detectable in all samples, and CCL2, IL-12, CCL5, and granulocyte monocyte colony-stimulating factor (GM-CSF) were found in >=50% of the samples. The mean CSF:serum ratio for CCL2 was several-fold higher than the rest, with the CXCL10 and CXCL8 ratios also >1. Intercorrelations between CSF cytokines included CCL2 versus CXCL8 and IL-6, and CXCL1 versus CCL22, reflecting both T-helper-1 (Th1)/Th1 and Th1/Th2 relations. Serum correlations included CCL11 versus CCL2, GM-CSF, and IL-4. For serum cytokines, the agreement between healthy children and NIND was good, with the exception of higher CCL4 in NIND. Cytokines in children varied greatly in concentration and detectability, with chemokines predominating in the CSF. These data allow investigators to select their own kit cytokines, instead of manufacturer-selected cytokines, for greater cost-effectiveness and interpretability. PMID- 23659674 TI - Association between IL1B (+3954) polymorphisms and IL-1beta levels in blood and saliva, together with acute graft-versus-host disease. AB - Graft-versus-host disease (GVHD) is associated with morbidity and mortality in the recipients of allogeneic hematopoietic stem cell transplants (allo-HSCTs). Interleukin-1beta (IL-1beta) is a potent inflammatory mediator involved in different inflammatory conditions. Therefore, we aimed to investigate the association of IL1B gene polymorphism in recipients and donors in cases in which acute GVHD (aGVHD) has been reported and the impact of this gene polymorphism on the level of cytokines in the blood and saliva. Fifty-eight consecutive allo-HSCT recipients and their donors were prospectively studied. Saliva and/or blood samples were obtained from the recipients and donors to identify the IL1B gene polymorphism, and cytokine levels were assessed by ELISA. Samples were collected weekly from 7 days before transplantation (day -7) to 100 days after allo-HSCT (day+100), for a total of 16 weeks or until death. aGVHD occurred in 27 individuals evaluated. A significant association was identified between the IL1B polymorphism in the donor and aGVHD development in the corresponding recipients. However, no significant association was detected between the IL1B polymorphism in recipients and the development of aGVHD. In the recipients who were diagnosed with aGVHD, the level of IL-1beta in the saliva and blood were increased. In the saliva, IL-1beta levels increased progressively from the time before the diagnosis of aGVHD until weeks after the diagnosis, whereas in the blood, IL 1beta peak levels could be observed within the time allotted for diagnosis, followed by a decrease in the levels. In addition, we observed a significant association between the IL1B genotype of the recipient (CC) and high IL-1beta levels in the saliva at week 13. In conclusion, IL-1beta could be considered a useful predictor of aGVHD development. PMID- 23659673 TI - Induction of TRIM22 by IFN-gamma Involves JAK and PC-PLC/PKC, but Not MAPKs and pI3K/Akt/mTOR Pathways. AB - Tripartite motif (TRIM) 22 plays an important role in interferons (IFNs)-mediated antiviral activity. We previously demonstrated that interferon regulatory factor 1 (IRF-1) played a central role in IFN-gamma-induced TRIM22 expression via binding to a special cis-element named 5' extended IFN-stimulating response element (5'eISRE). In this study, we sought to identify the signaling pathways involved in TRIM22 induction by IFN-gamma. By using various pharmacological inhibitors, it was found that the activity of tyrosine kinase and phosphatidylcholine-phospholipase C (PC-PLC), but not phosphatidylinositol phospholipase C (PI-PLC) and phospholipase D (PLD), was required for IFN-gamma induced TRIM22 expression in HepG2 cells. Tyrosine kinase Janus kinase (JAK), not SRC and PYK2, played an indispensable role in TRIM22 induction. Inhibition of protein kinase C (PKC) activity also significantly attenuated IFN-gamma induction of TRIM22. Although treatment with IFN-gamma resulted in the stimulation of mitogen-activated protein kinases (MAPKs) (p38, ERK, and JNK) and pI3K/Akt/mTOR pathways in HepG2 cells, the inhibition of their activity did not affect IFN gamma-stimulated TRIM22 expression. Further studies showed that overexpression of JAK1 and PKCalpha activated TRIM22 promoter activity in a 5'eISRE-dependent manner, and inhibition of not only JAK but also PC-PLC/PKC pathways significantly attenuated IFN-gamma-induced IRF-1 expression in HepG2 cells. Taken together, these data indicated that IFN-gamma induced TRIM22 expression via activation of JAK and PC-PLC/PKC signaling pathways, which involved the cis-element 5'eISRE and the transactivator IRF-1. PMID- 23659675 TI - Subclinical infection and asymptomatic carriage of gastrointestinal zoonoses: occupational exposure, environmental pathways, and the anonymous spread of disease. AB - Asymptomatic carriage of gastrointestinal zoonoses is more common in people whose profession involves them working directly with domesticated animals. Subclinical infections (defined as an infection in which symptoms are either asymptomatic or sufficiently mild to escape diagnosis) are important within a community as unknowing (asymptomatic) carriers of pathogens do not change their behaviour to prevent the spread of disease; therefore the public health significance of asymptomatic human excretion of zoonoses should not be underestimated. However, optimal strategies for managing diseases where asymptomatic carriage instigates further infection remain unresolved, and the impact on disease management is unclear. In this review we consider the environmental pathways associated with prolonged antigenic exposure and critically assess the significance of asymptomatic carriage in disease outbreaks. Although screening high-risk groups for occupationally acquired diseases would be logistically problematical, there may be an economic case for identifying and treating asymptomatic carriage if the costs of screening and treatment are less than the costs of identifying and treating those individuals infected by asymptomatic hosts. PMID- 23659676 TI - Prioritizing health disparities in medical education to improve care. AB - Despite yearly advances in life-saving and preventive medicine, as well as strategic approaches by governmental and social agencies and groups, significant disparities remain in health, health quality, and access to health care within the United States. The determinants of these disparities include baseline health status, race and ethnicity, culture, gender identity and expression, socioeconomic status, region or geography, sexual orientation, and age. In order to renew the commitment of the medical community to address health disparities, particularly at the medical school level, we must remind ourselves of the roles of doctors and medical schools as the gatekeepers and the value setters for medicine. Within those roles are responsibilities toward the social mission of working to eliminate health disparities. This effort will require partnerships with communities as well as with academic centers to actively develop and to implement diversity and inclusion strategies. Besides improving the diversity of trainees in the pipeline, access to health care can be improved, and awareness can be raised regarding population-based health inequalities. PMID- 23659677 TI - Amylase enzyme from Bacillus subtilis S8-18: a potential desizing agent from the marine environment. AB - The present study is aimed at developing an economical medium for the production of alpha-amylase from Bacillus subtilis S8-18, a marine sediment isolate from Palk Bay, with various agricultural by-products that are cheap and rich in starch. These products include wheat bran, wheat husk, rice bran, rice husk, and potato peel and are used to replace soluble starch present in the Luria Bertani (LB) broth (synthetic medium). The rice husk was found to be the best to influence enzyme production significantly (61,186 IU mL-1) when compared with the yield of 30,026 IU mL-1 obtained by commercial starch. Hence, LB broth containing rice husk was considered an economical medium. In addition, the effect of various nutritional and physiological factors on enzyme production was also investigated. Furthermore, the desizing efficiency of alpha-amylases produced by synthetic and economical media was evaluated through various assays like reducing sugar estimation, weight loss assay, drop absorbency assay, scanning electron microscopy, and Fourier transform infrared analyses. In addition, a commercial alpha-amylase from B. subtilis was also used in desizing analyses for comparative purposes. It revealed that the alpha-amylase from the economical medium was as effective in desizing the cotton fabrics as that of the commercial enzyme and much superior to the enzyme produced through the synthetic medium. PMID- 23659678 TI - Chromatic aberration-corrected tilt series transmission electron microscopy of nanoparticles in a whole mount macrophage cell. AB - Transmission electron microscopy (TEM) in combination with electron tomography is widely used to obtain nanometer scale three-dimensional (3D) structural information about biological samples. However, studies of whole eukaryotic cells are limited in resolution and/or contrast on account of the effect of chromatic aberration of the TEM objective lens on electrons that have been scattered inelastically in the specimen. As a result, 3D information is usually obtained from sections and not from whole cells. Here, we use chromatic aberration corrected TEM to record bright-field TEM images of nanoparticles in a whole mount macrophage cell. Tilt series of images are used to generate electron tomograms, which are analyzed to assess the spatial resolution that can be achieved for different vertical positions in the specimen. The uptake of gold nanoparticles coated with low-density lipoprotein (LDL) is studied. The LDL is found to assemble in clusters. The clusters contain nanoparticles taken up on different days, which are joined without mixing their nanoparticle cargo. PMID- 23659679 TI - Examination of biologically active nanocomplexes by nanoparticle tracking analysis. AB - Nanoparticle tracking analysis (NTA) was first applied to biologically active nanocomplexes to obtain concurrent information on their size, state of aggregation, concentration, and antigenic specificity in liquid. The subject of the NTA was an immunogenic complex (a candidate nanovaccine) comprised of spherical particles (SPs) generated by thermal remodeling of the tobacco mosaic virus and Rubella virus tetraepitopes exposed on the surface of SP. PMID- 23659681 TI - Is automated peritoneal lavage a better way than an endovascular device to induce mild therapeutic hypothermia after resuscitated cardiac arrest? PMID- 23659680 TI - Short pathways to complexity generation: fungal peptidyl alkaloid multicyclic scaffolds from anthranilate building blocks. AB - Complexity generation in naturally occurring peptide scaffolds can occur either by posttranslational modifications of nascent ribosomal proteins or through post assembly line tailoring of nonribosomal peptides. Short enzymatic pathways utilizing bimodular and trimodular nonribosomal peptide synthetase (NRPS) assembly lines, followed by tailoring oxygenases and/or prenyltransferases, efficiently construct complex fungal peptidyl alkaloid scaffolds in Aspergilli, Neosartorya, and Penicillium species. Use of the nonproteinogenic amino acid anthranilate as chain-initiating building block and chain-terminating intramolecular nucleophile leads efficiently to peptidyl alkaloid scaffolds with two to seven fused rings. PMID- 23659682 TI - Changes in parents' time use and its relationship to child obesity. AB - OBJECTIVE: The aim was to explore any change in parents' time use together with their children, changes in their perceived occupational value, and its relationship to children's body mass index (BMI) over the course of a one-year occupation-focused family intervention. METHOD: The study sample consisted of participants in one arm of a randomized controlled trial, involving mothers and fathers (n = 30) of 17 children aged 4-6 years who were considered obese. Data were collected by time-geographical diaries during the intervention and by measuring the parents' occupational value and the children's BMI before and after the intervention. RESULTS: At the end of the intervention, an increase was shown in the amount of time parents spent together with their children during weekdays (p = .042) and the parents perceived occupational value (p = .013). Children's BMI z-score changed with -0.11 units. CONCLUSION: Collaboration with parents may be useful in interventions aiming at facilitating a normal weight development among children. PMID- 23659683 TI - A nonhealing nodule in an adolescent. PMID- 23659684 TI - How soon they forget: changes to beliefs after learning about tobacco. AB - University students' beliefs about tobacco and nicotine were assessed before an educational intervention aimed at correcting tobacco-related misinformation. Beliefs were again measured immediately after the intervention, and then again after a 2-, 4-, 6-, or 8-week retention interval. Initially, participants showed significantly more accurate beliefs about tobacco than pre-intervention, but this improvement decreased after the retention interval. Results suggest that methods currently used in an attempt to alleviate tobacco misinformation in the public may be effective for short-term, but not long-term retention. The current study accents the need to design tobacco programs that optimize retention of belief change so that people may use that knowledge confidently in future health-related decisions. PMID- 23659685 TI - Deletion mutation in BSCL2 gene underlies congenital generalized lipodystrophy in a Pakistani family. AB - BACKGROUND: Congenital generalized lipodystrophy (CGL) also known as Berardinelli Seip Congenital Lipodystrophy (BSCL) is a genetically heterogeneous disorder characterized by loss of adipose tissues, Acanthosis nigricans, diabetes mellitus, muscular hypertrophy, hepatomegaly and hypertriglyceridemia. There are four subclinical phenotypes of CGL (CGL1-4) and mutations in four genes AGPAT2, BSCL2, CAV1 and PTRF have been assigned to each type. METHODS: The study included clinical and molecular investigations of CGL disease in a consanguineous Pakistani family. For mutation screening all the coding exons including splice junctions of AGPAT2, BSCL2, CAV1 and PTRF genes were PCR amplified and sequenced directly using an automated DNA sequencer ABI3730. RESULTS: Sequence analysis revealed a single base pair deletion mutation (c.636delC; p.Tyr213ThrfsX20) in exon 5 of BSCL2 gene causing a frame shift and premature termination codon. CONCLUSION: Mutation identified here in BSCL2 gene causing congenital generalized lipodystrophy is the first report in Pakistani population. The patients exhibited characteristic features of generalized lipodystrophy, Acanthosis nigricans, diabetes mellitus and hypertrophic cardiomyopathy. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1913913076864247. PMID- 23659687 TI - Design, synthesis, and biological evaluation of novel 3,5-disubstituted-1,2,6 thiadiazine-1,1-dione derivatives as HIV-1 NNRTIs. AB - On the basis of structural features, binding mode, and structure-activity relationship studies of two pyrimidine-derived non-nucleoside reverse transcriptase inhibitors, DABOs, and diaryl pyrimidines, a novel class of 1,2,6 thiadiazine-1,1-dione derivatives were rationally designed using the strategies of bioisosterism and molecular hybridization, synthesized, and evaluated for their anti-HIV activity in MT4 cell cultures. Three compounds were found to have moderate activity against HIV-1 replication with EC50 values ranging from 23 to 32 MUm. To further confirm the binding target, compound IIg was selected to conduct an HIV-1 reverse-transcriptase inhibitory assay. In addition, preliminary structure-activity relationship analysis among the newly synthesized compounds was discussed, and the binding mode of the active compound IIg was rationalized by molecular docking and physicochemical studies. PMID- 23659688 TI - Influence of boundary condition types on unstable density-dependent flow. AB - Boundary conditions are required to close the mathematical formulation of unstable density-dependent flow systems. Proper implementation of boundary conditions, for both flow and transport equations, in numerical simulation are critical. In this paper, numerical simulations using the FEFLOW model are employed to study the influence of the different boundary conditions for unstable density-dependent flow systems. A similar set up to the Elder problem is studied. It is well known that the numerical simulation results of the standard Elder problem are strongly dependent on spatial discretization. This work shows that for the cases where a solute mass flux boundary condition is employed instead of a specified concentration boundary condition at the solute source, the numerical simulation results do not vary between different convective solution modes (i.e., plume configurations) due to the spatial discretization. Also, the influence of various boundary condition types for nonsource boundaries was studied. It is shown that in addition to other factors such as spatial and temporal discretization, the forms of the solute transport equation such as divergent and convective forms as well as the type of boundary condition employed in the nonsource boundary conditions influence the convective solution mode in coarser meshes. On basis of the numerical experiments performed here, higher sensitivities regarding the numerical solution stability are observed for the Adams-Bashford/Backward Trapezoidal time integration approach in comparison to the Euler-Backward/Euler-Forward time marching approach. The results of this study emphasize the significant consequences of boundary condition choice in the numerical modeling of unstable density-dependent flow. PMID- 23659689 TI - An accessible protocol for solid-phase extraction of N-linked glycopeptides through reductive amination by amine-functionalized magnetic nanoparticles. AB - In light of the significance of glycosylation for wealthy biological events, it is important to prefractionate glycoproteins/glycopeptides from complex biological samples. Herein, we reported a novel protocol of solid-phase extraction of glycopeptides through a reductive amination reaction by employing the easily accessible 3-aminopropyltriethoxysilane (APTES)-functionalized magnetic nanoparticles. The amino groups from APTES, which were assembled onto the surface of the nanoparticles through a one-step silanization reaction, could conjugate with the aldehydes from oxidized glycopeptides and, therefore, completed the extraction. To the best of our knowledge, this is the first example of applying the reductive amination reaction into the isolation of glycopeptides. Due to the elimination of the desalting step, the detection limit of glycopeptides was improved by 2 orders of magnitude, compared to the traditional hydrazide chemistry-based solid phase extraction, while the extraction time was shortened to 4 h, suggesting the high sensitivity, specificity, and efficiency for the extraction of N-linked glycopeptides by this method. In the meantime, high selectivity toward glycoproteins was also observed in the separation of Ribonuclease B from the mixtures contaminated with bovine serum albumin. What's more, this technique required significantly less sample volume, as demonstrated in the successful mapping of glycosylation of human colorectal cancer serum with the sample volume as little as 5 MUL. Because of all these attractive features, we believe that the innovative protocol proposed here will shed new light on the research of glycosylation profiling. PMID- 23659690 TI - Maternal thyroid function at gestational weeks 11-13 in twin pregnancies. AB - BACKGROUND: Thyroid disease during pregnancy may be associated with increased risk of various pregnancy complications. It is known that serum thyrotropin (TSH) is suppressed because of the increased hormone production induced by human chorionic gonadotrophin (hCG) in early pregnancy, and that higher hCG levels in twin pregnancies may cause a more pronounced physiologic suppression. The recognition of this phenomenon is important in order to avoid unnecessary concerns and to correctly establish the diagnosis of overt thyroid disease in twin pregnancies. The aim of this study was to establish reference ranges of maternal serum TSH and free thyroxine (FT4) at gestational weeks 11-13 in twin pregnancies. METHODS: This is a case series of 177 dichorionic and 58 monochorionic twin pregnancies with normal outcomes, and 19 monochorionic pregnancies complicated by severe twin-twin transfusion syndrome. Maternal serum concentrations of TSH, FT4, antithyroperoxidase, and antithyroglobulin antibodies were measured at gestational weeks 11-13. The measured TSH and FT4 were converted to multiple of median (MoM) of normal singleton pregnancies and MoM values in the different groups were compared. RESULTS: In the antibody-negative twin pregnancies with normal outcomes, compared to singletons, serum TSH MoM was lower (median 0.62 [interquartile range [IQR 0.16-1.18] vs. 1.01 [IQR 0.61-1.51]; p < 0.0001), FT4 MoM was not significantly different (median 0.98 [IQR 0.91-1.08] vs. 0.99 [IQR 0.91-1.09]; p = 0.975), and free beta-hCG MoM was higher (median 1.91 [IQR 1.33-2.59] vs. 0.98 [IQR 0.66-1.50]; p < 0.0001). In the antibody-positive group (n = 37), compared to the negative group (n = 198), the median TSH was higher, but FT4 and free beta-hCG were not significantly different. In the twin twin transfusion syndrome group, compared to normal twin pregnancies, TSH, FT4, and free beta-hCG were not significantly different. CONCLUSION: In twins, compared to singleton pregnancies, TSH is lower but FT4 is not significantly different. These reference ranges of thyroid hormones in twins can form the basis for the study of early thyroid function in pathological pregnancies and the investigation of the consequences of overt and subclinical hypothyroidism on twin pregnancy outcome. PMID- 23659692 TI - Post-self-assembly cross-linking to integrate molecular nanofibers with copolymers in oscillatory hydrogels. AB - We study the use of post-self-assembly cross-linking to combine molecular nanofibers of hydrogelators with copolymers to generate oscillatory materials using the Belousov-Zhabotinsky reaction. The formation of nanofibers from designed hydrogelators provides multiple polymerizable sites for copolymerizing with N-isopropylacrylamide and for attaching a catalytic ruthenium bipyridine complex on the copolymer. The combination of supramolecular self-assembly with copolymerization offers a versatile and facile approach for generating soft materials that have large pores in the gel network and robust mechanical integrity. These larger pores facilitate the diffusion of the reactants and accelerate the chemical oscillation by about a factor of 4 relative to a poly(NIPAAm-Ru) gel that contains no molecular nanofibers. PMID- 23659691 TI - RNA-Seq facilitates a new perspective on signal transduction and gene regulation in important plant pathogens. AB - RNA-Seq is opening new doors for the functional understanding of microorganisms. Advances in RNA-Seq technology are allowing investigators to focus their studies on specific functional questions. An interesting example is presented by An et al. (2013) in this issue of Molecular Microbiology. New genes were identified for proteins and ncRNAs when the authors concentrated on the role of the rpf genes, which code for key components of a signal transduction hub in the plant pathogen Xanthomonas campestris pv. campestris. Although rpf gene products were already known to be involved in controlling transcription of many genes, including those encoding several important virulence factors, novel and unexpected properties of this signal transduction system emerged from the RNA-Seq analysis. In addition to identifying new target genes influenced by the rpf genes, the study found that the regulons of RpfC and RpfG, the sensor and response regulator of the master two-component regulatory system, only partially overlapped, indicating that the Rpf signalling system is even more complex than previously appreciated. PMID- 23659693 TI - Moments of induced spawning and embryonic development of Brycon amazonicus (Teleostei, Characidae). AB - Based on the economic and ecological relevance of Brycon amazonicus, the goal of this work was to describe the diameter of oocytes and eggs of this species, as well as the chronological embryonic development. The material was provided by Buriti fish farm, Nova Mutum - MT, Brazil. Samples of both oocytes and eggs were obtained from extrusion to hatching. The material was fixed and measured under stereomicroscope, and the samples were divided for light microscopy or scanning electron microscopy (SEM) analyses. At extrusion, the oocytes were bluish green. The frequency distribution of oocytes revealed that 87.7% of them ranged from 1.11-1.30 mm in diameter. During incubation, the total diameter of the eggs increased from 1.22 +/- 0.04 mm to 3.06 +/- 0.46 mm in the first 60 min post fertilization (PF), and growth ceased at 180 min PF. Between 10-30 s PF, most eggs were fertilized and fertilization cones were observed from 10 s onwards after gamete activation. The main fertilization events took place asynchronically and spermatozoa were visualized in the micropyle vestibule up to 90 s PF. The first cell was formed in the centre of the blastodisc 20 min PF. The morula stage was identified 2 h PF and, 3 h later, 70% of the yolk was covered by the blastoderm; the blastopore was almost entirely closed at 6 h PF. The cephalic and caudal regions of the embryo could be defined 8 h PF and hatching occurred after 13 h of embryonic development. The larvae hatched with undifferentiated organic systems and with a large yolk sac, free from swimming abilities or visual acuity. PMID- 23659694 TI - A separate structured conversation with relatives of patients enrolled for advanced palliative home care: a care development project. AB - OBJECTIVE: One prerequisite for palliative home care is the relatives' participation in the care. The relatives' situation in palliative home care is unique, as they support the sick person and also have a great need for support themselves. The aim of this care development project was to develop and implement separate structured conversations (SSC) with relatives of patients of an advanced palliative home care team (APHCT). METHOD: During the project, 61 conversations were held and 55 relatives answered a questionnaire. The questionnaire, eight semistructured interviews with relatives, and three focus-group discussions with nurses constitute the material for the evaluation. RESULTS: Relatives have difficulties separating the SSC from the APHCT's care as a whole. They underline that the SSC was a part of an ongoing process. They also emphasize the value of having a conversation of their own in which the patient was absent, and in which the focus was on the relative's situation. For some, the conversation took place at the APHCT premises. The advantages of that were more privacy and the opportunity to walk around the inpatient palliative care units. The main problem during the project was conducting the SSC soon after the patient was enrolled with the APHCT. SIGNIFICANCE OF RESULTS: Routinely offering one separate structured conversation with relatives with the intention of answering questions, talking about their willingness to provide care in the home, and mapping out their situation and social network, is a way to support both the relatives and the patients. The common structure of the conversations facilitated the assessment of the relatives' situation but did not hinder individualization according to the relatives' needs. The assumption is that all relatives should be offered a conversation. PMID- 23659695 TI - Risk factors for poor outcome in congenital cytomegalovirus infection and neonatal herpes on the basis of a nationwide survey in Japan. AB - BACKGROUND: Congenital cytomegalovirus (CMV) infection and neonatal herpes are major mother-to-child infections, and analyses of the important clinical issues, including risk factors for prognosis, are essential. METHODS: A secondary survey of congenital CMV infection and neonatal herpes was performed using questionnaires for cases reported in the primary survey between 2006 and 2008. RESULTS: Univariate analysis of 71 cases of congenital CMV infection showed that intrauterine growth restriction (IUGR) or other specific findings on fetal ultrasonography (US), microcephaly, intracranial calcification, disseminated intravascular coagulation, abnormal findings on computed tomography, and the use of i.v. gammaglobulin were all significantly correlated with poor outcome (death or severe sequelae). Multivariate analysis showed that only IUGR was significantly associated with poor outcome. Hearing impairment is one of the major abnormalities associated with congenital CMV infection. Automatic auditory brainstem response (automatic ABR) appeared to be useful for detection of hearing impairment in comparison with conventional ABR. Moreover, univariate analysis showed that specific fetal US or abnormal magnetic resonance imaging findings were correlated with sensorineural hearing loss. In 24 cases of neonatal herpes, fever and seizure were correlated with poor outcome on univariate analysis. All patients received acyclovir treatment, although substantial numbers of patients in severe clinical categories (disseminated or central nervous system diseases) received a low dose of acyclovir (<60 mg/kg per day). CONCLUSIONS: This secondary survey has identified the risk factors associated with outcome and important issues in diagnosis and treatment of two mother-to-child infections: congenital CMV and neonatal herpes, in Japan. PMID- 23659696 TI - Genomic and chromosomal distribution patterns of various repeated DNA sequences in wheat revealed by a fluorescence in situ hybridization procedure. AB - Wheat (Triticum aestivum L.) is an allohexaploid, in which each of the three genomes has a high 1C content. This indicates the presence of multiple tandemly repeated sequences, which should be detectable using in situ hybridization. Some repeats have already been described, but others remain to be recognized. To discover others, 2000 plasmid wheat clones were examined for signal presence after fluorescence in situ hybridization and microscopic signal observation. Among them, 47 clones produced strong discrete signals on wheat chromosomes. Two of the newly identified clones (pTa-535 and pTa-713) were determined to have especially valuable sequences for chromosome identification. In combination with pTa-86 (the pSc119 homologous sequence), these probes enable unambiguous discrimination of all wheat chromosomes including orientation. Four newly identified sequences (pTa-465, pTa-k566, pTa-s120, and pTa-s126) were useful in that they produced discrete signals on various wheat chromosome arms. Two other clones (pTa-k288 and pTa-k229) produced GISH-like (genomic in situ hybridization) signals because they allowed the A, B, and D genomes to be distinguished simultaneously. In addition, centromere, centromere-related, and ribosomal DNA clones were identified. Also described are improvements on slide preparation and reprobing procedures. To enhance discrete signal detection, a new direct fluorescent-labeling procedure, namely the VentR (exo-) terminal extension method, was employed. PMID- 23659698 TI - Finding of IFNgamma gene enhancers and their core sequences. AB - DNA segmentation methods were used to study which fragments of the human IFNgamma gene possess enhancer activity. The human IFNgamma gene was divided into 240-bp fragments, which were inserted between the GFP gene and the Alu tandem sequence to determine whether the inserted sequences eliminate the inhibition induced by the Alu tandem sequence. We found that five different 240-bp fragments (FUIFN3F3R, IFN4F4R, IFN6F6R, IFN21F21R, and IFN22F22R) and two 60-bp core sequences (IFN6-2F2R and IFN21-3-4F3-4R) derived from the IFNgamma gene contain enhancers that can activate the GFP reporter gene. These enhancers may be targets of IFNgamma gene expression regulation. PMID- 23659697 TI - Transmission electron microscopy and serial reconstructions reveal novel meiotic phenotypes for the ahp2 mutant of Arabidopsis thaliana. AB - We have found novel phenotypes for the previously studied Arabidopsis thaliana (L.) Heynh. meiotic mutant ahp2. These phenotypes were revealed by analysis of reconstructions of normal and ahp2 nuclei that were imaged using transmission electron microscopy. Previous studies of the ahp2 mutant demonstrated that it has a general failure to form synaptonemal complexes, except for the nucleolus organizing regions, and it fails to complete reciprocal genetic exchange. Here, we show that even though the ahp2 chromosome axes have only 5% of the normal amount of synaptonemal complex formation, it nonetheless has slightly more than 40% of the axes involved in close alignment. We also observed two striking nuclear envelope associated abnormalities. Wild type nuclei contain two nucleoli, one nucleolus-like structure, and nuclear envelope associated structures that we refer to as nuclear envelope associated disks. The ahp2 nuclei have the two nucleoli, but they lack the third nucleolus-like structure and instead have a previously uncharacterized structure that spans the nuclear envelope. Additionally, ahp2 meiocytes have nuclear envelope associated disks that are narrower and more numerous (~2*) than those seen in wild type, and unlike the wild type disks, they are in direct contact with the nuclear envelope. PMID- 23659699 TI - Cytogenetic characterization by in situ hybridization techniques and molecular analysis of 5S rRNA genes of the European hazelnut (Corylus avellana). AB - The European hazelnut (Corylus avellana L.) is widespread in Europe, where it has been cultivated for centuries. Despite progress in genetics, most of the cytogenetic aspects of this species have been overlooked. The aim of this study was to fill in this gap and obtain basic information on the chromosome structure of this species. Karyomorphological analysis confirmed the chromosome number 2n = 22 and showed that, despite their apparent uniformity, the chromosomes could be separated into three groups of different size: large (L), medium (M), and small (S). As a first step towards the physical mapping of the hazelnut chromosomes, we applied FISH to localize the position of rRNA genes (rDNA). The sites of 45S and 5S rDNA enabled us to identify two chromosome pairs belonging, respectively, to the L and S groups. The self-GISH procedure revealed that repetitive DNA is concentrated in the pericentromeric regions of the chromosomes, as with other species with rather small genomes. The analysis of 5S rDNA repeats offered additional information on the hazelnut genome by obtaining the whole sequence of the transcribed region so far unpublished. The overall results constitute a substantial advance in hazelnut cytogenetics. Further investigation of other species of Corylus could be an effective approach to understanding the phylogenesis of the genus and resolving taxonomic problems. PMID- 23659701 TI - Generation and identification of Brassica alboglabra-Brassica campestris monosomic alien addition lines. AB - Four monosomic alien addition lines (MAALs) for Brassica alboglabra-Brassica campestris were developed through digenomic triploid (ACC) backcrossing with the recurrent parent B. alboglabra (CC). The objectives of this study were to compare morphological traits, microsatellite markers (simple sequence repeats), chromosomal karyotypes, and meiotic behaviors. Based on the new chromosome nomenclature system established for Brassica, we preliminarily identified these MAALs as CC+A1, CC+A3, CC+A6, and CC+A7. Their alien chromosomes were transmittable through both female and male gametes at rates of 11.46%-26.53% and 4.88%-12.90%, respectively. PMID- 23659700 TI - Genome-wide analysis of microRNAs expression profiling in patients with primary IgA nephropathy. AB - The aim of this study was to investigate the differential expression characteristics and the roles of the genome-wide microRNAs (miRNAs) in immunoglobulin A nephropathy (IgAN) kidney tissues. We used Illumina high throughput sequencing technology to evaluate the miRNAs expression of six biopsy tissues from IgAN and six normal renal cortex specimens from patients with renal cell carcinoma. We observed a total of 85 miRNAs that were differentially expressed in the six IgAN patients, of which 11 miRNAs were up-regulated and 74 miRNAs were down-regulated in patients' tissues compared with control tissues. Additionally, we identified 55 candidate novel miRNAs in our study, which comprised seven candidates who were detected in the IgAN group and 49 candidates who were detected in the control group. Only one candidate (miR-n-9) was expressed in both groups. The bioinformatics showed that the regulated target genes of differentially expressed miRNAs were associated with immune and renal pathological changes. The identification of specific tissue miRNAs in our study not only helped clarify the genetics or immunology mechanisms involved in the pathogenesis of IgAN but also helped explain the pathological changes in the kidney tissues. We hypothesize that some significant miRNAs might potentially serve as novel diagnostic biomarkers in IgAN patients. PMID- 23659702 TI - The B-hordein prolamin family of barley. AB - The spectrum of B-hordein prolamins and genes in the single barley cultivar Barke is described from an in silico analysis of 1452 B-hordein ESTs and available genomic DNA. Eleven unique B-hordein proteins are derived from EST contigs. Ten contigs encode apparent full-length B-hordeins and the eleventh contains a premature stop codon that will lead to a truncated B-hordein. The 11 sequences are placed within the two previously described classes, i.e., the B1- and B3-type B-hordeins. The number of ESTs assigned to each sequence is used as an estimate of relative gene transcription and expression. Three of the sequences account for 79% of the total ESTs, with one sequence comprises 32% of the total ESTs and has a variant C-terminus caused by an undefined sequence change history near the 3' coding terminus. The 70* difference in EST distribution among sequences points to the importance of understanding differential rates of expression within closely related gene families. Analysis of available genomic sequences confirms the EST assembly and reveals one full-length and two partial sequences of pseudogenes as evidenced by no matching ESTs for the sequences and premature stop codons and frame shifts. PMID- 23659703 TI - Development of everolimus, a novel oral mTOR inhibitor, across a spectrum of diseases. AB - Everolimus is a potent, oral inhibitor of the mammalian target of rapamycin (mTOR) that has been investigated in multiple clinical development programs since 1996. A unique collaboration between academic and pharmaceutical experts fostered research that progressed rapidly, with simultaneous indication findings across numerous tumor types. Initially developed for the prophylaxis of organ transplant rejection, everolimus has demonstrated efficacy and safety for the treatment of patients with various types of cancer (renal cell carcinoma, neuroendocrine tumors of pancreatic origin, and breast cancer) and for adult and pediatric patients with tuberous sclerosis complex. The FDA approval of everolimus for these diseases has addressed several unmet medical needs and is widely accepted by the medical community where treatment options may be limited. An extensive clinical development program is ongoing to establish the role of everolimus as monotherapy, or in combination with other agents, in the treatment of a broad spectrum of malignancies. PMID- 23659704 TI - Delirium and cardiac surgery: progress - and more questions. AB - Post-operative delirium is a common and dangerous complication of cardiac surgery. Many risk factors for delirium have been identified, but its pathogenesis remains largely elusive. A study by Kazmierski and colleagues investigates a more recently considered risk factor for delirium: perturbations in the hypothalamic pituitary axis and depression. This and further work may help define novel prevention and treatment strategies for delirium. PMID- 23659705 TI - Cortical plasticity induced by different degrees of peripheral nerve injuries: a rat functional magnetic resonance imaging study under 9.4 Tesla. AB - BACKGROUND: Major peripheral nerve injuries not only result in local deficits but may also cause distal atrophy of target muscles or permanent loss of sensation. Likewise, these injuries have been shown to instigate long-lasting central cortical reorganization. METHODS: Cortical plasticity changes induced after various types of major peripheral nerve injury using an electrical stimulation technique to the rat upper extremity and functional magnetic resonance imaging (fMRI) were examined. Studies were completed out immediately after injury (acute stage) and at two weeks (subacute stage) to evaluate time affect on plasticity. RESULTS: After right-side median nerve transection, cortical representation of activation of the right-side ulnar nerve expanded intra-hemispherically into the cortical region that had been occupied by the median nerve representation After unilateral transection of both median and ulnar nerves, cortical representation of activation of the radial nerve on the same side of the body also demonstrated intra-hemispheric expansion. However, simultaneous electrical stimulation of the contralateral uninjured median and ulnar nerves resulted in a representation that had expanded both intra- and inter-hemispherically into the cortical region previously occupied by the two transected nerve representations. CONCLUSIONS: After major peripheral nerve injury, an adjacent nerve, with similar function to the injured nerve, may become significantly over-activated in the cortex when stimulated. This results in intra-hemispheric cortical expansion as the only component of cortical plasticity. When all nerves responsible for a certain function are injured, the same nerves on the contralateral side of the body are affected and become significantly over-activated during a task. Both intra- and inter-hemispheric cortical expansion exist, while the latter dominates cortical plasticity. PMID- 23659706 TI - Use of glycosylated hemoglobin increases diabetes screening for at-risk adolescents in primary care settings. AB - OBJECTIVE: To examine rates of diabetes screening in obese adolescents in an ethnically diverse primary care health care system before and after an internal recommendation to use HbA1c-based screening. RESEARCH DESIGN AND METHODS: Adolescents 12-18-years old with BMI > 95% were identified through electronic medical record review during two 18-month periods in 8 community health clinics and 13 school-based health centers: period 1 (P1, 19 April 2008 to 19 October 2009) and period 2 (P2, 3 May 2010 to 3 November 2011). Testing for diabetes in the 2 yr preceding the most recently elevated BMI was reviewed. RESULTS: A total of 2870 obese adolescents were identified in P1 and 3940 in P2. Ethnicity was primarily Hispanic, with smaller populations of Black and White youth. The percent of obese teens screened for diabetes increased from 40% in P1 to 47% in P2. Use of HbA1c increased 493% during P2. Older teens (>15 yr), those seen during P2, and those with BMI >= 30 kg/m2 were more likely to be screened. Record review confirmed equal rates of type 2 diabetes in the two periods: 8 incident (0.7%) cases in P1 and 13 (0.7%) in P2. CONCLUSIONS: The use of HbA1c, a non fasting and logistically simpler test, was associated with increased diabetes screening in primary care. The percentage of screened patients with confirmed type 2 diabetes remained unchanged. Thus, despite potential pitfalls, the use of HbA1c for screening appears to be as successful as previous approaches in identifying adolescents with diabetes. PMID- 23659707 TI - What constitutes competence? That depends on the task. PMID- 23659708 TI - Sickness absence, marginality, and medically unexplained physical symptoms: a focus-group study of patients' experiences. AB - PURPOSE: Medically unexplained physical symptoms (MUPS) form a major cause of sickness absence. The purpose of this study was to explore factors which may influence further marginalization among patients with MUPS on long-term sickness absence. METHODS: Two focus-group discussions were conducted with a purposive sample of 12 participants, six men and six women, aged 24-59 years. Their average duration of sickness absence was 10.5 months. Participants were invited to share stories about experiences from the process leading to the ongoing sickness absence, with a focus on the causes being medically unexplained. Systematic text condensation was applied for analysis. Inspired by theories of marginalization and coping, the authors searched for knowledge of how patients' positive resources can be mobilized to counteract processes of marginality. RESULTS: Analysis revealed how invisible symptoms and lack of objective findings were perceived as an additional burden to the sickness absence itself. Factors that could counteract further marginalization were a supportive social network, positive coping strategies such as keeping to the daily schedule and physical activity, and positive attention and confidence from professionals. CONCLUSIONS: Confidence from both personal and professional contacts is crucial. GPs have an important and appreciated role in this aspect. PMID- 23659709 TI - Antibiotic prescribing in patients with acute rhinosinusitis is not in agreement with European recommendations. AB - OBJECTIVE: To assess the potential overprescribing in patients with acute rhinosinusitis across six countries with different antibiotic prescribing rates and different prevalence of antibiotic resistance. DESIGN, SETTING AND SUBJECTS: A cross-sectional study including GPs from two Nordic countries, two Baltic countries and two Hispano-American countries registered patients with respiratory tract infections (RTIs) during three weeks in January 2008 as part of the EU funded project "Health Alliance for Prudent Prescribing, Yield And Use of antimicrobial Drugs In the Treatment of respiratory tract infections" (HAPPY AUDIT). MAIN OUTCOME MEASURES: Use of antibiotics for acute rhinosinusitis based on the recommendations in the European Position Paper on Rhinosinusitis and Nasal Polyps 2007 (EP3OS). RESULTS: In total, 618 participating GPs registered 33 273 patients with RTI of whom 1150 (3.46%) were considered to have acute rhinosinusitis. Over 50% of the patients with acute rhinosinusitis had symptoms for < 5 days and 81% were prescribed antibiotics. In total, 68% of the patients included were not prescribed antibiotics according to guidelines; 45% had symptoms < 5 days or no fever (possible overprescribing) and 23% had symptoms < 5 days and no fever (probable overprescribing). CONCLUSION: A considerable number of patients with symptoms of acute rhinosinusitis were not managed according to European recommendations (EP3OS guidelines). To prevent overprescribing, efforts should be made to implement the recommendations in daily practice. PMID- 23659710 TI - No identifiable Hb1Ac or lifestyle change after a comprehensive diabetes programme including motivational interviewing: a cluster randomised trial. AB - OBJECTIVE: To study the effectiveness of a comprehensive diabetes programme in general practice that integrates patient-centred lifestyle counselling into structured diabetes care. Design and setting. Cluster randomised trial in general practices. INTERVENTION: Nurse-led structured diabetes care with a protocol, record keeping, reminders, and feedback, plus training in motivational interviewing and agenda setting. SUBJECTS: Primary care nurses in 58 general practices and their 940 type 2 diabetes patients with an HbA1c concentration above 7%, and a body mass index (BMI) above 25 kg/m2. Main outcome measures. HbA1c, diet, and physical activity (medical records and patient questionnaires). RESULTS: Multilevel linear and logistic regression analyses adjusted for baseline outcomes showed that despite active nurse participation in the intervention, the comprehensive programme was no more effective than usual care after 14 months, as shown by HbA1c levels (difference between groups = 0.13; CI 20.8-0.35) and diet (fat (difference between groups = 0.19; CI 20.82-1.21); vegetables (difference between groups = 0.10; CI-0.21-0.41); fruit (difference between groups = 20.02; CI 20.26-0.22)), and physical activity (difference between groups = 21.15; CI 212.26-9.97), or any of the other measures of clinical parameters, patient's readiness to change, or quality of life. CONCLUSION: A comprehensive programme that integrated lifestyle counselling based on motivational interviewing principles integrated into structured diabetes care did not alter HbA1c or the lifestyle related to diet and physical activity. We thus question the impact of motivational interviewing in terms of its ability to improve routine diabetes care in general practice. PMID- 23659711 TI - Study of binding thermodynamics in the optimization of BH3 mimetics. AB - The use of small molecule B-cell lymphoma 2 homology domain 3 mimetics to neutralize the B-cell lymphoma 2 protein is an attractive strategy for cancer treatment due to its ability to cause targeted cell apoptosis. We have previously reported the design and optimization of a series of B-cell lymphoma 2 homology domain 3-mimetics, called compounds 1-6. In this study, we evaluated the optimization of B-cell lymphoma 2 homology domain 3-mimetics from a thermodynamic perspective. Understanding the thermodynamic parameters of B-cell lymphoma 2 homology domain 3-mimetics plays a critical role in the development of B-cell lymphoma 2 small-molecule inhibitors. The thermodynamic parameters for the interactions of these compounds with the myeloid cell leukemia sequence 1 protein were obtained using isothermal titration calorimetry. Owing to compounds 1-6 overcoming enthalpy-entropy compensation, the affinities of them improved gradually. Toward binding to the myeloid cell leukemia sequence 1 protein, compound 6 was deemed optimal with an obtained Kd value of 238 nm, which is a 10(4) -fold improvement compared with 1. Analysis of the enthalpy and -TDeltaS efficiencies showed that ligand efficiencies with respect to molecular size are correlated with the enthalpic efficiencies. Notably, an enthalpy gain of 4.65 kcal/mol identified that an additional hydrogen bond is formed by 2 with myeloid cell leukemia sequence 1 compared with compound 1. For the first time, hydrogen bonding between a small-molecule inhibitor of B-cell lymphoma 2 was demonstrated experimentally. PMID- 23659712 TI - Solid state structure of Bi(N3)3, Bi(N3)3.solvates and the structural dynamics in the [Bi(N3)6]3- anion. AB - The highly explosive bismuth triazide, Bi(N3)3, was obtained in pure form by the reaction of BiF3 with Me3SiN3 in acetonitrile under solvothermal conditions at temperatures between 90 and 100 degrees C. X-ray, (14)N NMR, infrared, and Raman spectra are discussed along with the data for the acetonitrile, acetone, and dmso adducts. The influence of the solvent on the purity of the azide products is studied in detail for Bi(N3)3 and the [Bi(N3)6](3-) ion. Moreover, temperature dependent structural dynamics in the [Bi(N3)6](3-) ion, which is caused by small changes in the local environment around the [Bi(N3)6](3-) ion in the solid state, was studied by temperature variable single crystal X-ray and Raman studies. The azido-chlorido ligand back exchange was studied in detail by NMR techniques in [Bi(N3)6](3-) and Bi(N3)3 when chlorinated solvents such as CH2Cl2 were utilized leading to the formation of CH2(N3)Cl and/or HN3 along with partially chlorinated bismuth azides. PMID- 23659713 TI - How should hepatitis E virus infection be defined in organ-transplant recipients? PMID- 23659714 TI - Natural killer cell-mediated contact sensitivity develops rapidly and depends on interferon-alpha, interferon-gamma and interleukin-12. AB - Natural killer (NK) cell-mediated contact sensitivity was recently described in mice. Here, we confirm NK cell-mediated contact sensitivity (CS) in SCID and RAG1(-/-) mice but not in SCIDbeige mice, which have non-functional NK cells that lack NK cell granules. NK cell-mediated CS was transferred by liver mononuclear cells and the DX5(+) fraction of liver cells, confirming that NK cells mediate CS in the absence of T and B cells. Participation of NKT cells and B-1 cells was ruled out using Jalpha18(-/-) and JH(-/-) mice, respectively. Remarkably, NK cell mediated CS was observed just 1 hr after immunization and was detectable as early as 30 min after challenge. Further, we examined cytokine requirements for NK cell mediated CS, and found that liver mononuclear cells from interleukin-12(-/-) , interferon-gamma(-/-) and interferon-alpha receptor(-/-) donors fail to transfer NK cell-mediated CS to naive hosts. Our studies clearly show that dinitrofluorobenzene sensitized NK cells mediate very rapid, antigen-specific cell-mediated immunity, with features of both innate and acquired immune responses. PMID- 23659715 TI - Identifying appropriate effect measures for analgesic therapies in companion animals. PMID- 23659716 TI - Placebo effects in the caregiver assessment of lameness. PMID- 23659717 TI - Association between this SPINK1 variant and clinically detectable pancreatitis. PMID- 23659718 TI - Genetic study design and the misinterpretation of our own study. PMID- 23659719 TI - A potential role for substance P and interleukin-6 in the cerebrospinal fluid of Cavalier King Charles Spaniels with neuropathic pain. AB - BACKGROUND: Neuropathic pain can be a clinical sign in Cavalier King Charles Spaniels (CKCS) with syringomyelia. The pathophysiology of this pain is not fully understood. HYPOTHESIS: Neuropathic pain in CKCS is a result of a neuroinflammatory process. ANIMALS: Twenty-six client-owned dogs: 15 dogs with clinical signs of cervical hyperesthesia (group 1), and 11 dogs without of clinical signs (group 2). METHODS: Dogs were examined by magnetic resonance imaging (MRI). Interleukin-6, tumor necrosis factor alpha, and substance P were measured in CSF and compared with morphological findings on MRI and clinical pain scores. RESULTS: All dogs without clinical signs had symmetrical syringomyelia, whereas in the group with pain, 6 dogs had symmetrical and 9 dogs had asymmetrical syringomyelia. Pain and syringomyelia asymmetry were correlated, and a strong association between pain and dorsal horn involvement of syringomyelia was observed. There was no significant difference between the mean width of the syringomyelia in dogs with or without pain. The concentrations of interleukin-6 and substance P were significantly higher in dogs with neuropathic pain. Tumor necrosis factor alpha was not detected in either group. Concentrations of substance P were significantly higher in dogs with asymmetrical syringomyelia or dorsal horn involvement, whereas interleukin-6 concentrations were not significantly different between groups. CONCLUSION: Release of interleukin-6 and substance P may initiate proinflammatory effects leading to development of persistent pain in CKCSs with syringomyelia. PMID- 23659721 TI - YouTube as a research tool: three approaches. AB - The present paper provides empirical data to support the use of social media as research environment. YouTube was chosen as a most appropriate format to target adolescents in experimental and cross-sectional designs given its popularity as well as its plasticity. We uniquely applied the YouTube format as (a) an environment to present manipulated media materials in controlled experimental designs; (b) an environment to study effects of peer feedback on various media contents; (c) a format to design a media-based questionnaire, specifically, the Media, Morals and Youth Questionnaire (MMaYQue). Various studies have been conducted that demonstrate the appropriateness of our YouTube transformations for each of these three purposes. The focus in the present paper is on the methodology of these studies to illustrate how we effectively transformed YouTube as a research tool. PMID- 23659723 TI - Information sharing and relationships on social networking sites. AB - This article investigates the relationship between sharing personal information and relationship development in the context of social networking sites (SNSs). Information disclosed on these sites could affect relationships in a different manner compared to more traditional interactions, such as instant messaging or face-to-face interaction. Respondents in the age range of 12 to 83 were surveyed about experiences of relationship development as a consequence of contact through Facebook or Hyves-the most popular Dutch SNSs. Results showed a primarily positive effect of information sharing on SNSs on our relationships. Furthermore, relationship development mainly occurs among acquaintances and friends, and public posts are most strongly related to relationship development. These findings suggest that SNSs might affect relationships in a distinct fashion as acquaintances and friends gain access to public self-disclosures that might normally only be reserved for close friends and family. Overall, this study provides an insight into some of the positive aspects of the public nature of SNSs in contrast with the general negative associations. PMID- 23659722 TI - Virtual environments using video capture for social phobia with psychosis. AB - A novel virtual environment (VE) system was developed and used as an adjunct to cognitive behavior therapy (CBT) with six socially anxious patients recovering from psychosis. The novel aspect of the VE system is that it uses video capture so the patients can see a life-size projection of themselves interacting with a specially scripted and digitally edited filmed environment played in real time on a screen in front of them. Within-session process outcomes (subjective units of distress and belief ratings on individual behavioral experiments), as well as patient feedback, generated the hypothesis that this type of virtual environment can potentially add value to CBT by helping patients understand the role of avoidance and safety behaviors in the maintenance of social anxiety and paranoia and by boosting their confidence to carry out "real-life" behavioral experiments. PMID- 23659724 TI - Giving and receiving peer advice in an online breast cancer support group. AB - People have access to experiential information and advice about health online. The types of advice exchanged affect the nature of online communities and potentially patient decision making. The aim of this study was to examine the ways in which peers exchange advice within an online health forum in order to better understand online groups as a resource for decision making. Messages collected over a one-month period from an online breast cancer support forum were analyzed for examples of advice exchange. The majority of the messages solicited advice through problem disclosure or requests for information and opinion. A novel form of advice solicitation-"anyone in the same boat as me"-was noted as was the use of personal experience as a form of advice giving. Women construct their advice requests to target like-minded people. The implications in terms of decision making and support are discussed. PMID- 23659725 TI - Peer and professional parenting support on the Internet: a systematic review. AB - The Internet offers many opportunities to provide parenting support. An overview of empirical studies in this domain is lacking, and little is known about the design of web based parenting resources and their evaluations, raising questions about its position in the context of parenting intervention programs. This article is a systematic review of empirical studies (n=75), published between 1998 and 2010, that describe resources of peer and professional online support for parents. These studies generally report positive outcomes of online parenting support. A number of recent experimental studies evaluated effects, including randomized controlled trials and quasi-experimental designs (totaling 1,615 parents and 740 children). A relatively large proportion of the studies in our sample reported a content analysis of e-mails and posts (totaling 15,059 coded messages). The results of this review show that the Internet offers a variety of opportunities for sharing peer support and consulting professionals. The field of study reflects an emphasis on online resources for parents of preschool children, concerning health topics and providing professional support. A range of technologies to facilitate online communication is applied in evaluated Web sites, although the combination of multiple components in one resource is not very common. The first generation of online resources has already changed parenting and parenting support for a large group of parents and professionals. Suggestions for future development and research are discussed. PMID- 23659726 TI - Lipid bilayer-integrated optoelectronic tweezers for nanoparticle manipulations. AB - Remotely manipulating a large number of microscopic objects is important to soft condensed matter physics, biophysics, and nanotechnology. Optical tweezers and optoelectronic tweezers have been widely used for this purpose but face critical challenges when applied to nanoscale objects, including severe photoinduced damages, undesired ionic convections, or irreversible particle immobilization on surfaces. We report here the first demonstration of a lipid bilayer-integrated optoelectronic tweezers system for simultaneous manipulation of hundreds of 60 nm gold nanoparticles in an arbitrary pattern. We use a fluid lipid bilayer membrane with a ~5 nm thickness supported by a photoconductive electrode to confine the diffusion of chemically tethered nanoparticles in a two-dimensional space. Application of an external a.c. voltage together with patterned light selectively activates the photoconducting electrode that creates strong electric field localized near the surface. The field strength changes most significantly at the activated electrode surface where the particles tethered to the membrane thus experience the strongest dielectrophoretic forces. This design allows us to efficiently achieve dynamic, reversible, and parallel manipulation of many nanoparticles. Our approach to integrate biomolecular structures with optoelectronic devices offers a new platform enabling the study of thermodynamics in many particle systems and the selective transport of nanoscale objects for broad applications in biosensing and cellular mechanotransductions. PMID- 23659727 TI - Advanced solid-state NMR approaches for structure determination of membrane proteins and amyloid fibrils. AB - Solid-state NMR (SSNMR) spectroscopy has become an important technique for studying the biophysics and structure biology of proteins. This technique is especially useful for insoluble membrane proteins and amyloid fibrils, which are essential for biological functions and are associated with human diseases. In the past few years, as major contributors to the rapidly advancing discipline of biological SSNMR, we have developed a family of methods for high-resolution structure determination of microcrystalline, fibrous, and membrane proteins. Key developments include order-of-magnitude improvements in sensitivity, resolution, instrument stability, and sample longevity under data collection conditions. These technical advances now enable us to apply new types of 3D and 4D experiments to collect atomic-resolution structural restraints in a site-resolved manner, such as vector angles, chemical shift tensors, and internuclear distances, throughout large proteins. In this Account, we present the technological advances in SSNMR approaches towards protein structure determination. We also describe the application of those methods for large membrane proteins and amyloid fibrils. Particularly, the SSNMR measurements of an integral membrane protein DsbB support the formation of a charge-transfer complex between DsbB and ubiquinone during the disulfide bond transfer pathways. The high resolution structure of the DsbA-DsbB complex demonstrates that the joint calculation of X-ray and SSNMR restraints for membrane proteins with low resolution crystal structure is generally applicable. The SSNMR investigations of alpha-synuclein fibrils from both wild type and familial mutants reveal that the structured regions of alpha-synuclein fibrils include the early-onset Parkinson's disease mutation sites. These results pave the way to understanding the mechanism of fibrillation in Parkinson's disease. PMID- 23659728 TI - An unusual case of genital swelling. PMID- 23659729 TI - A dietary survey of patients with irritable bowel syndrome. AB - BACKGROUND: Food is one of the most commonly reported triggers of irritable bowel syndrome (IBS) symptoms. However, the role of diet in the aetiology and management of IBS has not been clearly established. The present study aimed to examine the dietary practices of Irish patients with IBS and to determine whether these practices increased their vulnerability to nutritional inadequacies. METHODS: A questionnaire was completed by 135 IBS patients on their perceptions of the role of diet in their symptoms and whether they restrict their diet according to the symptoms experienced. A similar questionnaire was used to investigate the perceptions of 111 healthy subjects to the gastrointestinal symptoms experienced on the consumption of food. RESULTS: Food was considered to cause or worsen their gastrointestinal symptoms in 89.6% of IBS patients compared to 55% of healthy subjects (P < 0.001). Cereal-based foods, predominantly bread or its components, were the most frequently cited (53.3%), and spicy foods (39.3%), vegetables and fatty foods (35.6% for both) also featured prominently. A significantly greater number of patients with IBS reported changing their diet to minimise symptoms compared to healthy controls (91.9% versus 45.5%, P < 0.001). In relation to whole food groups, milk products (9.6%), fruit (7.4%) and vegetables (5.2%) were those most commonly restricted, with only a small number of IBS patients seeking professional healthcare advice. CONCLUSIONS: The majority of IBS patients consider their symptoms to be related to food, and change their diet by limiting the foods that they perceive as problematic, with some restricting whole food groups. Few patients sought professional healthcare advice when implementing dietary change, possibly exposing a considerable number to an increased risk of nutritional deficiency. PMID- 23659730 TI - Method development and analysis of free HS and HS in proteoglycans from pre- and postmenopausal women: evidence for biosynthetic pathway changes in sulfotransferase and sulfatase enzymes. AB - Heparan sulfate (HS) is one of the most complex and informative biopolymers found on the cell surface or in the extracellular matrix as either free HS fragments or constituents of HS proteoglycans (HSPGs). Analysis of free HS and HSPG sugar chains in human serum at the disaccharide level has great potential for early disease diagnosis and prognosis; however, the low concentration of HS in human serum, together with the complexity of the serum matrix, limits the information on HS. In this study, we present and validate the development of a new sensitive method for in-depth compositional analysis of free HS and HSPG sugar chains. This protocol involved several steps including weak anion exchange chromatography, ultrafiltration, and solid-phase extraction for enhanced detection prior to LC MS/MS analysis. Using this protocol, a total of 51 serum samples from 26 premenopausal and 25 postmenopausal women were analyzed. Statistically significant differences in heparin/HS disaccharide profiles were observed. The proportion of N-acetylation and N-sulfation in both free HS and HSPG sugar chains were significantly different between pre- and postmenopausal women, indicating changes in N-deacetylase/N-sulfotransferases (NDSTs), the enzymes involved in the initial step of the biosynthetic pathway. Differences in the proportion of 6-O sulfation suggest that 6-O-sulfotransferase and/or 6-O-sulfatase enzymes may also be implicated. PMID- 23659732 TI - Expression of polypeptide N-acetylgalactosaminyl transferase-3 and its association with clinicopathological factors in thyroid carcinomas. AB - BACKGROUND: Polypeptide N-acetylgalactosaminyl transferase-3 (GalNAc-T3) has been reportedly expressed in several human adenocarcinomas and is associated with clinicopathological features of tumors. We investigated the clinicopathological significance of GalNAc-T3 in thyroid cancer. METHODS: We evaluated the expression of GalNAc-T3 in 167 patients with thyroid cancer using a specific antibody and analyzed the association between its expression and clinicopathological features. RESULTS: GalNAc-T3 was expressed in 85.8% of normal follicular epithelial cells. In papillary carcinomas, positive staining was observed in 101 (73.7%) cases. Well-differentiated components (papillary and follicular) of papillary carcinomas were significantly more frequently positive than poorly differentiated components (trabecular and solid) (p<0.01), and GalNAc-T3 was highly expressed in papillary carcinomas that had invaded beyond the thyroid capsule (p=0.026). GalNAc-T3 was expressed in 40% and 20% of well and poorly differentiated components of follicular carcinomas, respectively. Thirteen of 15 anaplastic carcinomas were negative for GalNAc-T3 and thyroglobulin. Positive staining for GalNAc-T3 was not observed in any of the medullary carcinomas. CONCLUSIONS: Our data suggest that GalNAc-T3 expression may be a useful indicator of tumor differentiation in thyroid carcinomas. PMID- 23659731 TI - 2D IR cross peaks reveal hydrogen-deuterium exchange with single residue specificity. AB - A form of chemical exchange, hydrogen-deuterium exchange (HDX), has long been used as a method for studying the secondary and tertiary structure of peptides and proteins using mass spectrometry and NMR spectroscopy. Using two-dimensional infrared (2D IR) spectroscopy, we resolve cross peaks between the amide II band and a (13)C(18)O isotope-labeled amide I band, which we show measures HDX with site-specific resolution. By rapidly scanning 2D IR spectra using mid-IR pulse shaping, we monitor the kinetics of HDX exchange on-the-fly. For the antimicrobial peptide ovispirin bound to membrane bilayers, we find that the amide II peak decays with a biexponential with rate constants of 0.54 +/- 0.02 and 0.12 +/- 0.01 min(-1), which is a measure of the overall HDX in the peptide. The cross peaks between Ile-10-labeled ovispirin and the amide II mode, which specifically monitor HDX kinetics at Ile-10, decay with a single rate constant of 0.36 +/- 0.1 min(-1). Comparing this exchange rate to theoretically determined exchange rates of Ile-10 for ovispirin in a solution random coil configuration, the exchange rate at Ile-10 is at least 100 times slower, consistent with the known alpha-helix structure of ovispirin in bilayers. Because backbone isotope labels produce only a very small shift of the amide II band, site-specific HDX cannot be measured with FTIR spectroscopy, which is why 2D IR spectroscopy is needed for these measurements. PMID- 23659734 TI - Disparities in cancer care: perspectives from the front line. AB - OBJECTIVE: The purpose of this qualitative study was to investigate how frontline healthcare professionals witness and understand disparity in cancer care. METHOD: Six healthcare providers from a range of care settings, none with < 15 years of frontline experience, engaged with researchers in an iterative process of identifying and reflecting on equity and disparity in cancer care. This knowledge exchange began with formal interviews. Thematic analysis of the interviews form the basis of this article. RESULTS: Participants drew attention to health systems issues, the meaning and experience of discontinuities in care for patients at personal and community levels, and the significance of social supports. Other concerns raised by participants were typical of the literature on healthcare disparities. SIGNIFICANCE OF RESULTS: Providers at the front lines of care offer a rich source of insight into the operation of disparities, pointing to mechanisms rarely identified in traditional quantitative studies. They are also well positioned to advocate for more equitable care at the local level. PMID- 23659735 TI - Expression levels of mRNA for insulin-like growth factors 1 and 2, IGF receptors and IGF binding proteins in in vivo and in vitro grown bovine follicles. AB - This study investigated mRNA levels for insulin-like growth factors (IGFs) IGF1 (IGF-I) and IGF2 (IGF-II), IGF receptors (IGF1R and IGF2R), and binding proteins (IGFBP-1, IGFBP-2. IGFBP-3, IGFBP-4, IGFBP-5 and IGFBP-6) in bovine follicles of 0.2, 0.5 or 1.0 mm in diameter. mRNA expression levels in in vitro cultured follicles that reached approximately 0.5 mm were compared with that of in vivo grown follicles. IGF1R and IGF2R expression levels in 0.5 mm in vivo follicles were higher than in 1.0 or 0.2 mm follicles, respectively. IGFBP-1, IGFBP-2. IGFBP-3, IGFBP-4, IGFBP-5 and IGFBP-6 showed variable expression in the follicular size classes analyzed. In vitro grown follicles had significantly reduced expression levels for IGF1, IGF1R, IGFBP-3, IGFBP-5 and IGFBP-6 mRNA when compared with 0.2 mm follicles, but, when compared with in vivo grown follicles (0.5 mm), only IGFBP-1, IGFBP-2, IGFBP-3 and IGFBP-6 showed a reduction in their expression. In conclusion, IGFs, their receptors and IGFBPs showed variable expression of mRNA levels in the follicular size classes analyzed. PMID- 23659737 TI - Simple screening statistical tools to detect reporting bias: when should we ask for raw data? PMID- 23659736 TI - Glucocorticoid synthesis-related genes: HSD11B1 and HSD11B2 in hypertensive disorders in pregnancy. AB - OBJECTIVE: To determine whether polymorphisms of the maternal glucocorticoid related genes (HSD11B1 and HSD11B2) are associated with pregnancy-induced hypertension (PIH) in a haplotype-based case-control study. METHODS: A total of 166 PIH patients and 222 age-matched controls were genotyped, with two single nucleotide polymorphisms (SNPs) for the HSD11B1 gene (rs2235543 and rs846910) and three SNPs for the HSD11B2 gene (rs12920590, rs45483293 and rs3743729) used as genetic markers. After separation into preeclampsia (PE) and gestational hypertension (GH) subgroups, PIH patients were assessed. RESULTS: Significant differences were noted between PE and control groups (p = 0.022, p = 0.034, respectively) for the frequency of genotypes and alleles for rs846910 of HSD11B1. The frequency of the AA genotype of rs846910 was significantly higher in PIH and PE groups compared to controls. Logistic regression analyses showed that this genotype was a risk factor for PIH and PE (adjusted OR 2.9, 95% CI 1.3-6.5 and adjusted OR 3.2, 95% CI 1.4-7.4, respectively). The frequency of the T-A haplotype established by rs2235543-rs846910 was also significantly higher in PIH and PE groups (p = 0.045, p = 0.042, respectively). CONCLUSION: rs846910 in the HSD11B1 gene could be a marker for hypertensive disorders during pregnancy. The T A haplotype constructed by rs2235543-rs846910 was also a useful susceptibility marker for PIH and PE. PMID- 23659738 TI - Toward an efficient approach to identify molecular scaffolds possessing selective or promiscuous compounds. AB - The concept of a recurrent scaffold present in a series of structures is common in medicinal drug discovery. We present a scaffold analysis of compounds screened across 100 sequence-unrelated proteins to identify scaffolds that drive promiscuity or selectivity. Selectivity and promiscuity play a major role in traditional and poly-pharmacological drug design considerations. The collection employed here is the first publicly available data set containing the complete screening profiles of more than 15 000 compounds from different sources. In addition, no scaffold analysis of this data set has been reported. The protocol described here employs the Molecular Equivalence Index tool to facilitate the selection of Bemis-Murcko frameworks in the data set, which contain at least five compounds and Scaffold Hunter to generate a hierarchical tree of scaffolds. The annotation of the scaffold tree with protein-binding profile data enabled the successful identification of mostly highly specific compounds, due to data set constraints. We also applied this approach to a public set of 1497 small molecules screened non-uniformly across a panel of 172 protein kinases. The approach is general and can be applied to any other data sets and activity readout. PMID- 23659739 TI - Feeding choice has a gender-associated effect on infant growth. AB - BACKGROUND: Appropriate nutrition during childhood is important for preventing future development of lifestyle-related diseases. The effect of feeding choice on infant growth in Japan is not known. METHODS: Data from 204 healthy schoolchildren (age, 6-9 years) were obtained retrospectively from their parents by questionnaires. Breast-fed (BF) and formula-fed (FF) groups were defined as those fed only breast milk or formula milk at 4 months of age, respectively. There were 71 children (M/F, 31/40) in BF and 30 (M/F, 19/11) in FF. Anthropometric data at birth, and at 1, 4, 7, 10, 18, and 36 months of age in male and female infants were compared between the groups. RESULTS: In male infants, height was significantly lower at 4 months, bodyweight was lower from 4 to 18 months, and body mass index (BMI) was lower from 10 to 36 months in BF than in FF. The standard deviation scores (SDS) for height, weight and BMI had a similar pattern. No significant differences were observed for these variables for female infants in BF compared with FF. Multiple regression analysis showed that birthweight, mother's pre-pregnancy weight, and infant feeding choice were significant factors associated with weight-SDS at 18 and 36 months. Feeding choice was the only factor associated with BMI-SDS at 18 months. CONCLUSIONS: Infant feeding choice had a gender-associated effect on growth during infancy. When evaluating infant growth, not only birthweight and mother's pre-pregnancy weight, but also infant feeding choice and gender should be considered. PMID- 23659733 TI - Pacemaker or defibrillator surgery without interruption of anticoagulation. AB - BACKGROUND: Many patients requiring pacemaker or implantable cardioverter defibrillator (ICD) surgery are taking warfarin. For patients at high risk for thromboembolic events, guidelines recommend bridging therapy with heparin; however, case series suggest that it may be safe to perform surgery without interrupting warfarin treatment. There have been few results from clinical trials to support the safety and efficacy of this approach. METHODS: We randomly assigned patients with an annual risk of thromboembolic events of 5% or more to continued warfarin treatment or to bridging therapy with heparin. The primary outcome was clinically significant device-pocket hematoma, which was defined as device-pocket hematoma that necessitated prolonged hospitalization, interruption of anticoagulation therapy, or further surgery (e.g., hematoma evacuation). RESULTS: The data and safety monitoring board recommended termination of the trial after the second prespecified interim analysis. Clinically significant device-pocket hematoma occurred in 12 of 343 patients (3.5%) in the continued warfarin group, as compared with 54 of 338 (16.0%) in the heparin-bridging group (relative risk, 0.19; 95% confidence interval, 0.10 to 0.36; P<0.001). Major surgical and thromboembolic complications were rare and did not differ significantly between the study groups. They included one episode of cardiac tamponade and one myocardial infarction in the heparin-bridging group and one stroke and one transient ischemic attack in the continued-warfarin group. CONCLUSIONS: As compared with bridging therapy with heparin, a strategy of continued warfarin treatment at the time of pacemaker or ICD surgery markedly reduced the incidence of clinically significant device-pocket hematoma. (Funded by the Canadian Institutes of Health Research and the Ministry of Health and Long Term Care of Ontario; BRUISE CONTROL ClinicalTrials.gov number, NCT00800137.). PMID- 23659740 TI - Minor structural abnormalities in the infant face disrupt neural processing: a unique window into early caregiving responses. AB - Infant faces elicit early, specific activity in the orbitofrontal cortex (OFC), a key cortical region for reward and affective processing. A test of the causal relationship between infant facial configuration and OFC activity is provided by naturally occurring disruptions to the face structure. One such disruption is cleft lip, a small change to one facial feature, shown to disrupt parenting. Using magnetoencephalography, we investigated neural responses to infant faces with cleft lip compared with typical infant and adult faces. We found activity in the right OFC at 140 ms in response to typical infant faces but diminished activity to infant faces with cleft lip or adult faces. Activity in the right fusiform face area was of similar magnitude for typical adult and infant faces but was significantly lower for infant faces with cleft lip. This is the first evidence that a minor change to the infant face can disrupt neural activity potentially implicated in caregiving. PMID- 23659741 TI - Feline cutaneous nerve sheath tumours: histological features and immunohistochemical evaluations. AB - Feline cutaneous nerve sheath tumours (CNSTs) are uncommonly reported in the skin, since they are underestimated relative to the more common spindle cell tumours of soft tissue. In this study, 26 nerve sheath tumours selected from 337 skin neoplasms of cats were examined. Histologically, they were classified into malignant (MPNSTs) and benign tumours (BPNSTs) based on degree of cellular atypia and polymorphism as well as mitotic rate and diffuse necrosis. CPNSTs were tipically characterised by Antoni A pattern, in some cases associated with Antoni B pattern. In the malignant peripheral nerve sheath tumours (MPNSTs) the polymorphism was marked, while it was mild to moderate in the benign forms (BPNSTs). In the MPNSTs the mitotic activity was generally higher than in the BPNSTs. In five cases, including three MPNSTs and two BPNSTs, there were multinucleated giant cells. Necrotic foci occurred in a BPNST and in two MPNSTs, while osseous/chondroid metaplasia was found in two cases. Immunohistochemically, all the tumours showed a marked diffuse vimentin expression. S-100 protein was expressed in 17 cases, including 81.8% of BPNSTs and 57.14% of MPNSTs. Twenty five tumours expressed NSE and twenty-four cases showed immunoreaction for laminin. Thirteen tumours were positive for GFAP, while five tumours were positive for SMA. PGP 9.5 expression was detected in all cases, except for two MPNSTs. NGFR was expressed in eleven cases, including four MPNSTs and seven BPNSTs. Ki67 was expressed in twenty tumours without any relationship with morphologic malignancy of the neoplasm. In this case series we confirmed neoplastic spindloid cells with wavy cytoplasm arranged in compact areas, with occasional nuclear palisading or whirls, and interchanged with loosely arranged areas, as the morphological features supporting a diagnosis of CPNST. A constant concurrent expression of vimentin, NSE, and laminin might confirm the diagnosis of PNST in the absence of clear S-100 protein positivity, especially in the malignant forms. In this study, conclusive data were not obtained on the diagnostic relevance of NGFR- and PGP 9.5-expression in feline CPNSTs. PMID- 23659742 TI - Bovine neosporosis: clinical and practical aspects. AB - Neospora caninum is a protozoan parasite with a wide host range but with a preference for cattle and dogs. Since the description of N. caninum as a new genus and species in 1988, bovine neosporosis has become a disease of international concern as it is among the main causes of abortion in cattle. At present there is no effective treatment or vaccine. This review focuses on the epidemiology of the disease and on prospects for its control in cattle. Finally, based on the implications of clinical findings reported to date, a set of recommendations is provided for veterinarians and cattle farmers. PMID- 23659743 TI - Immunogenicity and safety of a natural rough mutant of Brucella suis as a vaccine for swine. AB - The objective of the current study was to evaluate the safety, immunogenicity and clearance of the natural rough mutant of Brucella suis strain 353-1 (353-1) as a vaccine in domestic swine. In three studies encompassing 105 animals, pigs were inoculated with 353-1 by conjunctival (5 * 10(7) CFU) or IM (1-2 * 10(10) CFU) routes. Clearance, tissue distribution, and pathology of the vaccine strain were determined by periodic blood culture, collection of tissues at periodic necropsy times after vaccination, and histologic evaluation of tissue samples. The B. suis 353-1 strain was nonpathogenic, cleared from most vaccinates by 10-12 weeks after vaccination, and did not induce significant histologic lesions in tissues examined. The vaccine strain appears to be phenotypically stable as all isolates recovered from vaccinates retained their rough phenotype. Vaccination induced significant humoral responses, peripheral blood mononuclear cell proliferation, and interferon-gamma (IFN-gamma) production after inoculation as compared to responses of control pigs. The vaccine strain did not appear to be shed from vaccinates as co-housed sentinel animals demonstrated no serologic or microbiologic evidence of lateral transmission. Our data demonstrates that B. suis 353-1 is a stable, rough mutant that does not induce adverse clinical effects or tissue localization, but does induce significant humoral and cellular immune responses after vaccination of swine. PMID- 23659744 TI - JMIG video articles. PMID- 23659745 TI - Electrosurgery and minimally invasive gynecology. PMID- 23659746 TI - Physical properties of electricity. AB - Electricity is the flow of electrons through a conductor. The amount of current (amps) is related to the voltage (volts) pushing the electrons and the degree of resistance to flow (ohms). During their flow around a circuit, electrons can be used to create a number of useful byproducts such as heat and light. As electrons flow, they alter the charge of the matter they flow through, which may also generate electromagnetic effects. PMID- 23659747 TI - History of power sources in endoscopic surgery. AB - The history of energy sources used in surgery is inextricably linked to the history of electricity. Milestones include identification of safe electrical waveforms that can be used in the human body, patient isolation to prevent alternate-site burns, bipolar energy sources to negate capacitance injuries, laser energy, and the combination vessel sealing devices commonly used today. Engineering efforts to eliminate many of the hazards of electrosurgery are critical to how we practice modern gynecologic surgery. The introduction of bipolar instruments, increasing the safety of monopolar electrosurgery by not using hybrid trocars, and introduction of active shielding of the instruments from stray radiofrequency energy using intelligent secondary conductors have led to the re-emergence of electrosurgery as the universal surgical energy source. The low ongoing costs and the presence of electrosurgical generators in all hospitals readily enables electrosurgery to be the mainstay. Expensive lasers are confined to specialized centers, where they continue to be used, but for a long while filled a gap created by complications of electrosurgery. Sophisticated power sources continue to be introduced and include the ultrasonic scalpel, plasma surgery, and various devices for sealing vessels, all of which have advantages and disadvantages that are recognized as they begin to be subjected to scientific validation in randomized trials. PMID- 23659748 TI - Electrosurgical generators and monopolar and bipolar electrosurgery. AB - Electrosurgery is the most commonly used and misunderstood technology by all surgical and medical disciplines. A lack of basic knowledge or ignorance of principles of electrosurgery and equipment among obstetricians and gynecologists is reported. As a result, thermal injuries during laparoscopic electrosurgery occur, which frequently lead to significant morbidity and mortality and medicolegal actions. Surveys indicate that up to 90% of general surgeons and gynecologists use monopolar radiofrequency (RF) during laparoscopy, 18% have experienced visceral burns, and 13% admitted 1 or more ongoing cases of litigations associated with such burns. This article describes the basics of electrosurgery beginning with the generation of electrons and their physical characteristics and governing laws before their arrival in the operating room where they are fed to an electrosurgical unit (ESU) to boost their frequency with step-up transformers from 60 Hz to >500 000 Hz. This RF creates heat, resulting in dissection, desiccation, coagulation, and fulguration of tissues without neuromuscular stimulation, pain, or burn to the patient. The ESU delivers power (wattage = volts * amps) in monopolar or bipolar (1 vs 2 high-density electrodes) configuration. Because of RF, monopolar electrosurgery compared with other energy sources is associated with unique characteristics, inherent risks, and complications caused by the requirement of a return/dispersive electrode, inadvertent direct and/or capacitive coupling, or insulation failure of instruments. These dangers become particularly important with the popular and frequent use of monopolar electrodes (hook, needle, and scissors) during cholecystectomy; robot-assisted surgeries; and the re-emergence of single-port laparoscopy, which requires close proximity and crossing of multiple intraabdominal instruments outside the surgeon's field of view. Presently, we identify all these potential risks and complications associated with the use of electrosurgery and provide suggestions and solutions to mitigate/minimize these risks based on good clinical practice and sound biophysical principles. PMID- 23659749 TI - Surgical complications specific to monopolar electrosurgical energy: engineering changes that have made electrosurgery safer. AB - Monopolar electrosurgical energy is the most commonly used energy source during laparotomic and laparoscopic surgery. The clinical application of monopolar energy is not without risk. Monopolar electrosurgical energy was introduced into surgical practice at the turn of the 20th century. Alternate site burns during laparotomic application were the most common complication for the first half century (i.e., ground point burns and dispersive electrode burns [1920-1970]). The aims of this article were to discuss historic design flaws associated with the most common alternate site burns, ground point burns, and dispersive electrode burns and the technological advancements introduced to mitigate these risks to the patient and to discuss current design flaws associated with stray energy burns during laparoscopy because of insulation failure and capacitive coupling and the technological advancements introduced to eliminate these risks to the patient. Today, insulation failure and capacitive coupling are the most common reasons for electrosurgical injury during laparocopic procedures. There is a need for advanced technology such as active electrode monitoring to address these invisible risks to the surgeon and their patients. In addition, the laparoscopic surgeon should be encouraged to study the basic biophysics involved in electrosurgery. PMID- 23659750 TI - Laparoscopic vessel sealing technologies. AB - Laparoscopic vessel sealing devices have revolutionized modern laparoscopy. These devices fall into 2 major categories: advanced bipolar and ultrasonic instruments. The range of tissue effects available with these technologies is more limited than with conventional monopolar electrosurgery; however, both advanced bipolar and ultrasonic devices efficiently seal vessels (<=7-mm and <=5 mm diameter, respectively), and most also have built-in tissue transection capabilities. These technologies have been the subject of a range of comparative studies on their relative advantages and disadvantages, and, to date, neither advanced bipolar or ultrasonic devices has been proven to be superior. PMID- 23659751 TI - Comparative studies of energy sources in gynecologic laparoscopy. AB - Energy sources incorporating "vessel sealing" capabilities are being increasingly used in gynecologic laparoscopic surgery although conventional monopolar and bipolar electrosurgery remain popular. The preference for one device over another is based on a combination of factors, including the surgeon's subjective experience, availability, and cost. Although comparative clinical studies and meta-analyses of laparoscopic energy sources have reported small but statistically significant differences in volumes of blood loss, the clinical significance of such small volumes is questionable. The overall usefulness of the various energy sources available will depend on a number of factors including vessel burst pressure and seal time, lateral thermal spread, and smoke production. Animal studies and laboratory-based trials are useful in providing a controlled environment to investigate such parameters. At present, there is insufficient evidence to support the use of one energy source over another. PMID- 23659752 TI - Economics and energy sources. AB - Energy-based instrumentation has not only facilitated the rapid adoption of laparoscopic surgery, but could be considered essential for the completion of abdominal and pelvic procedures under endoscopic guidance. For decades, relatively simple and generic reusable monopolar and bipolar systems were the only options available. More recently, the available options for energy-based surgical instrumentation have become more crowded with the introduction of ultrasound-based cutting and sealing instruments and proprietary, impedance monitoring radiofrequency coagulation devices. Such instrumentation is presented as being easier to use as well as providing greater safety and efficacy. However, these new instruments typically require the expenditure of capital for proprietary energy generators and are usually designed to be for single use, a circumstance that increases per case costs, a circumstance that begs the question of value. Do the additional costs expended for the more expensive devices translate into reduced complications, faster operating time, or even wider access to minimally invasive procedures because they enable more surgeons to offer the service? Herein is explored the complex economic issues associated with the use of energy-based surgical devices as they apply to minimal access surgery in general and to laparoscopic procedures specifically. PMID- 23659753 TI - A new technique of laparoscopic intracorporeal anastomosis for transrectal bowel resection with transvaginal specimen extraction. AB - STUDY OBJECTIVE: To show a new technique of laparoscopic intracorporeal anastomosis for transrectal bowel resection with transvaginal specimen extraction, a technique particularly suited for treatment of bowel endometriosis. DESIGN: Step-by-step explanation of the technique using videos and pictures (educative video). SETTING: Endometriosis may affect the bowel in 3% to 37% of all endometriosis cases. Bowel endometriosis affects young women, without any co morbidities and in particular without any vascular disorders. In addition, affected patients often express a desire for childbearing. Radical excision is sometimes required because of the impossibility of conservative treatment such as shaving, mucosal skinning, or discoid resection. Bowel endometriosis should not be considered a cancer, and consequently maximal resection is not the objective. Rather, the goal would be to achieve functional benefit. As a result, resection must be as economic and cosmetic as possible. The laparoscopic approach has proved its superiority over the open technique, although mini-laparotomy is generally performed to prepare for the anastomosis. INTERVENTIONS: Total laparoscopic approach in patients with partial bowel stenosis, using the vagina for specimen extraction. CONCLUSION: This technique of intracorporeal anastomosis with transvaginal specimen extraction enables a smaller resection and avoidance of abdominal incision enlargement that may cause hernia, infection, or pain. When stenosis is partial, this technique seems particularly suited for treatment of bowel endometriosis requiring resection. If stenosis is complete, the anvil can be inserted above the lesion transvaginally. PMID- 23659754 TI - Laparoscopic transvesical approach for vesicovaginal fistula repair. AB - STUDY OBJECTIVE: To access the technical feasibility of performing laparoscopic repair of vesicovaginal fistula. MATERIAL AND METHODS: We attempted a laparoscopic repair of vesicovaginal fistula in five women with a history of urinary leakage via the vagina after vaginal hysterectomy. Five pelvic ports were used. The surgical procedure was performed using the same principles as for open surgery, i.e., separation of the vaginal wall from the bladder wall, repair of the fistula, and interposition of the omentum. RESULTS: There was early recovery of the patients in terms of continence, with less chance of recurrence. Results were comparable to those with the vaginal approach. CONCLUSION: The use of minimally invasive surgery for vesicovaginal fistula repair helps to ease the suturing deep in the pelvis, and the magnification facilitates good identification of tissues planes and thus better mobilization of the vaginal and bladder walls and decreases postoperative morbidity. PMID- 23659755 TI - Sotrastaurin in calcineurin inhibitor-free regimen using everolimus in de novo kidney transplant recipients. AB - Sotrastaurin, a novel selective protein-kinase-C inhibitor, inhibits early T cell activation via a calcineurin-independent pathway. Efficacy and safety of sotrastaurin in a calcineurin inhibitor-free regimen were evaluated in this two stage Phase II study of de novo kidney transplant recipients. Stage 1 randomized 131 patients (2:1) to sotrastaurin 300 mg or cyclosporine A (CsA). Stage 2 randomized 180 patients (1:1:1) to sotrastaurin 300 or 200 mg or CsA. All patients received basiliximab, everolimus (EVR) and prednisone. Primary endpoint was composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, death or lost to follow-up. Main safety assessment was estimated glomerular filtration rate (eGFR) by MDRD-4 at Month 12. Composite efficacy failure rates at 12 months were higher in sotrastaurin arms (Stage 1: 16.5% and 10.9% for sotrastaurin 300 mg and CsA; Stage 2: 27.2%, 34.5% and 19.4% for sotrastaurin 200 mg, 300 mg and CsA). eGFR was significantly better in sotrastaurin groups versus CsA at most time points, except at 12 months. Gastrointestinal and cardiac adverse events were more frequent with sotrastaurin. Higher treatment discontinuation, deaths and graft losses occurred with sotrastaurin 300 mg. Sotrastaurin combined with EVR showed higher efficacy failure rates and some improvement in renal allograft function compared to a CsA based therapy. PMID- 23659756 TI - Prevalence and features of generalized anxiety disorder in Department of Veteran Affairs primary care settings. AB - Generalized anxiety disorder (GAD) is a highly prevalent distressing condition for individuals in both community and community primary care settings. However, despite the high prevalence of GAD identified in epidemiological studies, little is known about GAD and its related symptoms and impairments in veteran populations. The present study investigated the prevalence, comorbidity, physical and mental health impairment, and healthcare utilization of veteran participants with GAD, as well as comparing symptoms of GAD and posttraumatic stress disorder (PTSD). Veterans (N=884) participated in a cross-sectional investigation in primary care clinics in four Veteran Affairs Medical Centers (VAMCs) and completed diagnostic interviews and self-report questionnaires; a chart review was conducted to assess their VAMC healthcare utilization. A large number of participants (12%) met diagnostic criteria for GAD, reporting significantly worse emotional health, pain, and general health, in addition to increased mental healthcare utilization and antidepressant medications. In addition, GAD was found in 40% of participants with PTSD, resulting in more severe symptoms and impairment than in patients with GAD alone. These findings provide evidence of high prevalence and severe impairment associated with GAD in veterans and highlight the need for improved recognition, assessment, and treatments for GAD. PMID- 23659757 TI - Oral terbinafine as an alternative treatment for Hailey-Hailey disease. PMID- 23659758 TI - Harvesting of Chlorella sp. KR-1 using a cross-flow membrane filtration system equipped with an anti-fouling membrane. AB - The purpose of the present study is to reduce fouling formation, a fatal problem of membrane technology by means of surface-coating with a functional coating material, i.e., hydrophilic polyvinyl alcohol (PVA) polymer. The PVA coating caused the membrane surface to become more hydrophilic and it was confirmed by decreased contact angles up to 64% compared to the un-modified membranes. The surface-coated membrane found to exhibit substantially enhanced performance: a maximum flux increase of 36% and almost 100% recovery rate. Maximum concentration factor of 77 also was modeled in the present study. These results show that the membrane performance can be improved simply by applying a surface-active coating, even to the level of economic feasibility. PMID- 23659759 TI - Enhanced biological phosphorus removal and its modeling for the activated sludge and membrane bioreactor processes. AB - A modified activated sludge process (ASP) for enhanced biological phosphorus removal (EBPR) needs to sustain stable performance for wastewater treatment to avoid eutrophication in the aquatic environment. Unfortunately, the overall efficiency of the EBPR in ASPs and membrane bioreactors (MBRs) is frequently hindered by different operational/system constraints. Moreover, although phosphorus removal data from several wastewater treatment systems are available, a comprehensive mathematical model of the process is still lacking. This paper presents a critical review that highlights the core issues of the biological phosphorus removal in ASPs and MBRs while discussing the inhibitory process requirements for other nutrients' removal. This mini review also successfully provided an assessment of the available models for predicting phosphorus removal in both ASP and MBR systems. The advantages and limitations of the existing models were discussed together with the inclusion of few guidelines for their improvement. PMID- 23659760 TI - Metabolic flux network analysis of fermentative hydrogen production: using Clostridium tyrobutyricum as an example. AB - This study applies metabolic flux network analysis (MFA) to evaluate the metabolic flux of fermentative hydrogen production (FHP) with the use of Clostridium tyrobutyricum fed with either glucose or lactate/acetate as substrates. The MFA results suggest that hydraulic retention time (HRT) presents significant impact on hydrogen production from glucose. At HRT between 4 and 18 h, increase of HRT increased hydrogen production but decreased lactate production, while at HRT below 4 h decrease of HRT increased hydrogen production but decreased lactate production. The flux for lactate, butyrate and acetate seemed to affect H2 production, due presumably to their impacts on the balance of NADH, ferredoxin and ATP. It is suggested that the MFA can be a useful tool to provide valuable information for optimization and design of the fermentative hydrogen production process. PMID- 23659761 TI - Achieving nitritation and phosphorus removal in a continuous-flow anaerobic/oxic reactor through bio-augmentation. AB - The feasibility of achieving nitritation and phosphorus removal using bio augmentation was investigated in a continuous-flow anaerobic/oxic (A/O) reactor treating sewage. The results indicated that nitritation could be quickly start up, and reconstructed with an increase in the nitrite accumulation rate (NAR) from 1% to 89% within 15 days by using bio-augmentation and controlling DO at 0.96 mg/L. Biological phosphorus removal could be achieved with the average phosphorus removal efficiency of 96.43% when the NAR was maintained above 78.60%. Meanwhile, sludge settleablity was good with a sludge volume index (SVI) of between 62 and 102 mL/g even under high NAR. After nitritation and biological phosphorus removal were achieved, this A/O reactor has the potential to supply appropriate influent for the anammox UASB reactor. PMID- 23659762 TI - Vascular function and glucose variability improve transiently following initiation of continuous subcutaneous insulin infusion in children with type 1 diabetes. AB - OBJECTIVE: The effect of continuous subcutaneous insulin infusion (CSII) and glucose variability on vascular health in type 1 diabetes (T1D) is not known. We aimed to determine whether initiation of CSII improves vascular function and reduces glucose variability, independent of changes in HbA1c. METHODS: Twenty-two children with T1D (12.5 +/- 2.9 yr) were reviewed immediately prior, 3 wk, and 12 months after initiation of CSII. Vascular function [flow-mediated dilatation (FMD), glyceryl trinitrate-mediated dilatation (GTN)], glucose variability [mean of daily differences (MODD), mean amplitude of glycaemic excursions (MAGE) and continuous overlapping net glycaemic action (CONGA)], and clinical and biochemical data were measured at each visit. Results for the first two visits were compared to a previously studied cohort of 31 children with T1D who remained on multiple daily injections (MDI). RESULTS: FMD, GTN, blood pressure, HbA1c, fructosamine, and glucose variability significantly improved 3 wk after CSII commencement (all p < 0.05), but there was no change in the MDI control group. At 3 wk, vascular function related to glucose variability [(FMD: MODD, r = -0.62, p = 0.002) and (GTN: MAGE, r = -0.59, p = 0.004; CONGA-4, r = -0.51, p = 0.01; MODD, r = -0.62, p = 0.002)] but not to blood pressure, HbA1c, or fructosamine. At 12 months, FMD, GTN, blood pressure, and glucose variability returned to baseline levels, while HbA1c deteriorated. Carotid intima media thickness was unchanged over 12 months. CONCLUSIONS: Initiation of CSII rapidly improves vascular function in association with decreased glucose variability; however, the effects are not sustained with deterioration of metabolic control and glucose variability. PMID- 23659763 TI - Overexpression of PLCE1 in Kazakh esophageal squamous cell carcinoma: implications in cancer metastasis and aggressiveness. AB - Three recent large-scale genome-wide association studies (GWAS) in Chinese Han populations have identified an esophageal squamous cell carcinoma (ESCC) susceptibility locus within phospholipase C epsilon 1 (PLCE1) gene, which encodes a phospholipase involved in intracellular signaling. The expressed PLCE1 in ESCC, however, are inconsistent. This study examined PLCE1 expression by immunohistochemistry (IHC) from 110 ethnic Kazakh ESCC patients and 50 from adjacent normal esophageal tissues (NETs). The expressed PLCE1 was localized in cytoplasm, especially in the peripheral layers of cancer cell nests, which was significantly higher in tumors than in NETs (p < 0.001). Increased expression of PLCE1 was correlated with advanced tumor-node-metastasis (TNM) stages (p = 0.015) and lymph node metastasis (p = 0.003) in patients with ESCC. Of the 110 patients, we examined 50 paired ESCC tissues and corresponding NETs by quantitative RT-PCR (polymerase chain reaction) and the mean mRNA level of PLCE1 in ESCC was 1.85 fold higher compared with those in corresponding NETs (p = 0.0012). Meanwhile, 4 of 5 ESCC cell lines also showed elevated expression of PLCE1 mRNA. Furthermore, elevated expression of PLCE1 mRNA in Kazakh ESCC was associated with its immunoreactivity (rho = 0.297, p = 0.040), lymph node metastasis (p < 0.001), and advanced TNM stages of ESCC (p = 0.013). To our knowledge, this study demonstrates for the first time that PLCE1 overexpression correlates with lymph node metastasis and advanced TNM stages of Kazakh ESCC, implicating a role of PLCE1 in cancer metastasis and aggressiveness in ethnic Kazakh patients with ESCC. Furthermore, the current findings may warrant investigations into whether inhibiting PLCE1 could be a strategy for targeted anticancer therapy particularly for Kazakh ESCC. PMID- 23659764 TI - Association of methylenetetrahydrofolate reductase polymorphisms with susceptibility to Alzheimer's disease. AB - BACKGROUND: Genetic risk factors play an important role in the pathogenesis of Alzheimer's disease (AD). In this case-control study, we examined the C677T and A1298C polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene and their correlation with this pathology. OBJECTIVE: To verify the association between MTHFR C677T and A1298C polymorphisms and Alzheimer's disease. METHOD: This work was conducted as a case-control study. Cases consisted of thirty-eight patients and 100 individuals without dementia constituted the control group. Genotyping of MTHFR polymorphisms was performed on patients and controls. RESULT: Genetic analyses did not indicate a significant association between the MTHFR C677T mutation and AD (C/T: 63.15% versus 39%, p=0.087). However, the genotype prevalence of the missense variant MTHFR A1298C was significantly different between patients and controls (A/C: 55% versus 7%, p<10(-3)). Our data suggest an association between the MTHFR A1298C mutation and AD; however, the MTHFR C677T mutation did not contribute to susceptibility for AD. CONCLUSION: The MTHFR A1298C polymorphism is a possible risk factor for Alzheimer's disease. PMID- 23659765 TI - Primary cerebellar haemorrhage: complications, treatment and outcome. AB - Given its anatomical proximity to the brainstem and the ventricular system, cerebellar haemorrhage may lead to immediate life-threatening complications such as brainstem compression and hydrocephalus, or to herniation through the foramen magnum or the tentorium. This situation mandates fast diagnosis and precise emergency treatment strategies. However, the treatment protocols in current use are based on little evidence and the indication criteria for surgical intervention are unclear. Early suboccipital decompressive surgery may be life saving, but the potential risk involved is unnecessary if the haemorrhage is benign and can be managed conservatively or with insertion of an external ventricular drain. Deterioration of the patients' state of consciousness has often been used as an indication for surgery, but clinical decline can be a fulminant process leading to death within a short time. Research on cerebellar haemorrhage so far has focused on identifying outcome predictors from which treatment algorithms can be derived. Large randomised controlled trials (RCTs) are lacking. However, RCTs are urgently needed, in order to improve the level of evidence, treatment decisions may be based on. Here, we review the available literature on complications, treatment and outcome of primary cerebellar haemorrhage (PCH). Finally we propose the design of a potential RCT. PMID- 23659766 TI - Are we following a restrictive red cell transfusion practice? A multi-centre audit of paediatric transfusion practice in PICU. PMID- 23659767 TI - Intratympanic manganese administration revealed sound intensity and frequency dependent functional activity in rat auditory pathway. AB - The cochlear plays a vital role in the sense and sensitivity of hearing; however, there is currently a lack of knowledge regarding the relationships between mechanical transduction of sound at different intensities and frequencies in the cochlear and the neurochemical processes that lead to neuronal responses in the central auditory system. In the current study, we introduced manganese-enhanced MRI (MEMRI), a convenient in vivo imaging method, for investigation of how sound, at different intensities and frequencies, is propagated from the cochlear to the central auditory system. Using MEMRI with intratympanic administration, we demonstrated differential manganese signal enhancements according to sound intensity and frequencies in the ascending auditory pathway of the rat after administration of intratympanic MnCl2.Compared to signal enhancement without explicit sound stimuli, auditory structures in the ascending auditory pathway showed stronger signal enhancement in rats who received sound stimuli of 10 and 40 kHz. In addition, signal enhancement with a stimulation frequency of 40 kHz was stronger than that with 10 kHz. Therefore, the results of this study seem to suggest that, in order to achieve an effective response to high sound intensity or frequency, more firing of auditory neurons, or firing of many auditory neurons together for the pooled neural activity is needed. PMID- 23659768 TI - Noise correction for HARDI and HYDI data obtained with multi-channel coils and sum of squares reconstruction: an anisotropic extension of the LMMSE. AB - Parallel magnetic resonance imaging (MRI) yields noisy magnitude data, described in most cases as following a noncentral chi distribution when the signals received by the coils are combined as the sum of their squares. One well-known case of this noncentral chi noise model is the Rician model, but it is only valid in the case of single-channel acquisition. Although the use of parallel MRI is increasingly common, most of the correction methods still perform Rician noise removal, yielding an erroneous result due to an incorrect noise model. Moreover, the existence of noise correlations in phased array systems renders noise nonstationary and further modifies the noise description in parallel MRI. However, the noncentral chi model has been demonstrated to work as a good approximation as long as effective voxelwise parameters are used. A good correction step, adapted to the right noise model, is of paramount importance, especially when working with diffusion-weighted MR data, whose signal-to-noise ratio is low. In this paper, we present a noise removal technique designed to be fast enough for integration into a real-time reconstruction system, thus offering the convenience of obtaining corrected data almost instantaneously during the MRI scan. Our method employs the noncentral chi noise model and uses a simplified method to account for noise correlations; this leads to an efficient and rapid correction. The method consists of an anisotropic extension of the Linear Minimum Mean Square Error estimator (LMMSE) that is a far better edge-preserving method than the traditional LMMSE and addresses noncentral chi distributions along with empirically computed global effective parameters. The results on simulated and real data demonstrate that this anisotropic extended LMMSE outperforms the original LMMSE on images corrupted by noncentral chi noise. Moreover, in comparison with the existing LMMSE technique incorporating the estimation of voxelwise effective parameters, our method yields improved results. PMID- 23659769 TI - White matter maturation in the brains of Long Evans shaker myelin mutant rats by ex-vivo QSI and DTI. AB - The brains of Long Evans shaker (les) rats, a model of dysmyelination, and their age- matched controls were studied by ex-vivo q-space diffusion imaging (QSI) and diffusion tensor imaging (DTI). The QSI and DTI indices were computed from the same acquisition. The les and the control brains were studied at different stages of maturation and disease progression. The mean displacement, the probability for zero displacement and kurtosis were computed from QSI data while the fractional anisotropy (FA) and the eigenvalues were computed from DTI. It was found that all QSI indices detect the les pathology, at all stages of maturation, while only some of the DTI indices could detect the les pathology. The QSI mean displacement was larger in the les group as compared with their age-matched controls while the probability for zero displacement and the kurtosis were both lower all indicating higher degree of restriction in the control brains. Since all the DTI eigenvalues were higher in the les brains as compared to controls, the less efficient DTI measure for discerning the les pathology was found to be the FA. Clearly, the most sensitive DTI parameter to the les pathology is lambda3, i.e., the minimal diffusivity. Since the QSI and DTI data were obtained from the same acquisition, despite the somewhat higher SNR of the QSI data compared to the DTI data, it seems that the higher diagnostic capacity of the QSI data in this experimental model of dysmyelination, originates mainly from the higher diffusing weighting of the QSI data. PMID- 23659770 TI - Computerized MRS voxel registration and partial volume effects in single voxel 1H MRS. AB - Partial volume effects in proton magnetic resonance spectroscopy in the brain have been studied previously in terms of proper water concentration calculations, but there is a lack of disclosure in terms of voxel placement techniques that would affect the calculations. The purpose of this study is to facilitate a fully automated MRS voxel registration method which is time efficient, accurate, and can be extended to all imaging modalities. A total of thirteen healthy adults underwent single voxel 1H-MRS scans in 3.0T MRI scanners. Transposition of a MRS voxel onto an anatomical scan is derived along with a full calculation of water concentration with a correction term to account for the partial volume effects. Five metabolites (tNAA, Glx, tCr, mI, and tCho) known to yield high reliability are studied. Pearson's correlation analyses between tissue volume fractions and metabolite concentrations were statistically significant in parietal (tCr, Glx, and tNAA) lobe and occipital lobe (tNAA). MRS voxel overlaps quantified by dice metric over repeated visits yielded 60%~70% and coefficients of variance in metabolites concentration were 4%~10%. These findings reiterate an importance of considering the partial volume effects when tissue water is used as an internal concentration reference so as to avoid misinterpreting a morphometric difference as a metabolic difference. PMID- 23659771 TI - Early to bed: how sleep benefits children's memory. AB - Children learn differently than adults: they have smaller knowledge bases and thus must rely more on rote learning. Incomplete development of cortical circuits and other cognitive systems leads to additional differences. Now a study argues that differences in sleep-dependent memory processing may be another important source of these differences. PMID- 23659772 TI - Cabazitaxel in patients with metastatic castration-resistant prostate cancer: results of a compassionate use program in the Netherlands. AB - BACKGROUND: Cabazitaxel has been reimbursed as a second-line therapy for patients with metastatic castrate-resistant prostate cancer (mCRPC) in the Netherlands since 2011. Before reimbursement was available, cabazitaxel was provided through a Compassionate Use Program (CUP). We report the results of the Dutch CUP, detailing the safety and efficacy of cabazitaxel in a routine clinical practice setting. PATIENTS AND METHODS: Safety and efficacy data of all 5 Dutch centers participating in the cabazitaxel CUP were collected. Safety data were collected prospectively using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3.0. Overall survival (OS) and progression-free survival (PFS), time to PSA progression (TTPP), and best clinical response were evaluated retrospectively. RESULTS: Fifty-one patients were registered in the CUP; 49 received cabazitaxel. Forty-two of 49 patients [85.7%], 42 patients had >= 2 metastatic sites. Patients received on average 6 cabazitaxel cycles (range, 1 21). A dose reduction or dose delay occurred in 13 and 20 patients [26.5% and 40.9%] respectively. Prophylactic granulocyte colony-stimulating factor (G-CSF) was used in 8 patients [16.3%]. Grade >= 3 adverse events were observed in 25 patients [51.0%]; 16 patients [32.7%] discontinued treatment because of treatment emergent adverse events (TEAEs). Serious adverse events (SAEs) occurred in 16 (32.7%) patients; the most frequent SAEs were hematuria (4 patients [8.3%]) and urosepsis (3 patients [6.3%]). Febrile neutropenia occurred twice; no patient had grade >= 3 neuropathy. No toxicity-related mortality occurred. Median follow-up was 24.1 months. Median OS was 8.7 months (interquartile range [IQR], 6.0-15.9 months); median TTPP was 2.8 months (IQR, 1.7-5.9 months). CONCLUSION: In the Dutch CUP, patients with advanced mCRPC had delayed tumor progression with acceptable toxicities using cabazitaxel treatment. PMID- 23659773 TI - Cumulative risk impact of five genetic variants associated with papillary thyroid carcinoma. AB - BACKGROUND: Two recent genome-wide association studies (GWASs) identified five single nucleotide polymorphisms (SNPs; rs965513, rs944289, rs966423, rs2439302, and rs116909374) associated with papillary thyroid carcinoma (PTC). Each variant showed highly significant but moderate to low disease risk. Here we assessed the cumulative risk and predictive value of the five SNPs. METHODS: We genotyped two cohorts of individuals, 747 PTC cases and 1047 controls from Ohio and 1795 PTC cases and 2090 controls from Poland. Cumulative genetic risk scores were calculated using unweighted and weighted approaches. RESULTS: All five SNPs showed significant association with PTC. The average cumulative risk score in cases was significantly higher than in controls (p<2.2*10(-16)). Each additional risk allele increased the risk of having PTC by 1.51 [95% confidence interval (CI) 1.4, 1.64] in Ohio and by 1.35 [95% CI 1.27, 1.44] in Poland. An analysis was performed weighing risk alleles by effect size and assigning individuals to three weighted risk score groups, low (<=2), medium (2-5), and high (>5). Individuals in the high group were significantly more susceptible to PTC compared with individuals in the low group with an odds ratio of 8.7 [95% CI 5.8, 13.3] in Ohio and 4.24 [95% CI 3.10, 5.84] in Poland. Almost identical results were obtained when follicular variant PTCs and microPTCs were omitted. These five SNPs explained 11% of the familial risk of thyroid cancer in the Ohio cohort and 6% in the Polish cohort. CONCLUSION: As the genetic risk score increases, the risk of having PTC increases. However, the predictive power of the cumulative effect of these five variants is only moderately high and clinical use may not be feasible until more variants are detected. PMID- 23659775 TI - Lowering blood pressure limits in patients with type 2 diabetes: is it still warranted? PMID- 23659774 TI - The influence of subclinical cardiovascular disease and related risk factors on cognition in type 2 diabetes mellitus: The DHS-Mind study. AB - We hypothesized that measures of coronary artery calcified plaque (CAC) collected at baseline from the Diabetes Heart Study (DHS) would explain associations between cognition and diabetes collected at follow-up approximately 7 years later. The DHS is a sibling study of cardiovascular disease (CVD) in a cohort with a high prevalence of type 2 diabetes (~80%). Associations between baseline CAC and cognitive performance were tested using generalized estimating equations and mixed effects models to adjust for familial relationships. Diabetes status was associated (p<0.05) with poorer performance on tests of verbal memory, processing speed, and semantic fluency adjusting for age, sex, education, and hypertension status. As hypothesized, including CAC in the statistical model attenuated this association. Additionally, CAC and fasting glucose predicted performance in tasks not associated with diabetes status in this study (Stroop Task, Phonemic Fluency). These results confirm work attributing the heterogeneity of cognitive outcomes in type 2 diabetes to subclinical risk factors that combine to affect different aspects of brain function. Importantly, these results imply that risk factor intervention should begin before comorbidities, particularly CVD, become clinically apparent. PMID- 23659776 TI - Irisin in obesity and type 2 diabetes. PMID- 23659777 TI - Are diabetes risk scores useful for the prediction of cardiovascular diseases? Assessment of seven diabetes risk scores in the KORA S4/F4 cohort study. AB - AIM: To evaluate the utility of diabetes prediction models for CVD prediction as stated in two earlier studies. METHODS: 845 subjects from the population based German KORA (Cooperative Health Research in the Region of Augsburg) S4/F4 cohort study (aged 55 to 74 years, without diabetes, former stroke, and former myocardial infarction at baseline) were followed for up to ten years for incident stroke and myocardial infarction. Seven diabetes risk scores developed from four different studies were applied to the KORA cohort to assess their predictive ability for CVD. RESULTS: Areas under the receiver-operating curve (AROCs) for the prediction of CVD ranged from 0.60 to 0.65 when diabetes risk scores were applied to the KORA cohort. When diabetes risk scores were used to predict CVD and type 2 diabetes, respectively, AROCs for the prediction of CVD were 0.09 to 0.24 lower than AROCs for the prediction of type 2 diabetes. Furthermore, we used KORA data to develop prediction models for either diabetes or CVD, and found that they differed widely in selected predictor variables. CONCLUSION: In the older population, diabetes risk scores are not useful for the prediction of CVD, and prediction models for diabetes and CVD, respectively, require different parameters. PMID- 23659778 TI - A national approach to improving adolescent and young adult (AYA) oncology psychosocial care: the development of AYA-specific psychosocial assessment and care tools. AB - OBJECTIVE: Age-based screening tools and assessment measures are crucial to the provision of best practice care for adolescent and young adult (AYA) cancer patients. Unfortunately, there are limited psychosocial tools developed for this age group and pediatric or adult measures are often distributed with the assumption that they are "close enough." We describe a collaborative Australian project that strives to improve what currently exists for the psychosocial assessment of and planning for the 15-25-year-old age group. METHOD: Using the National Comprehensive Cancer Network's Distress Thermometer and the HEADSS Assessment as a foundation, the tools were developed in consultation with Australia's leading AYA clinicians, AYAs currently undergoing medical treatment, and a group of AYA survivors through a process of discussion groups and clinical interviews. RESULTS: The result is the first available AYA-specific screening tool, care plan pro forma, and psychosocial assessment measure developed for use within the oncology sector. These new tools will assist clinicians working with this population group to support psychosocial coping during active treatment and promote healthy post-treatment survivorship. SIGNIFICANCE OF RESULTS: Over time, further validation procedures will add to the veracity of the measures. Until then, these measures represent the best available in Australia. They highlight a clinically recognized minimum standard of care that all young cancer patients, regardless of treatment location, have the right to receive. PMID- 23659779 TI - Association of sodium and potassium intake with ventricular arrhythmic burden in patients with essential hypertension. AB - BACKGROUND: Hypertensive populations suffer from an increased susceptibility to ventricular arrhythmias and sudden cardiac death. A high-salt diet appears to be a major factor involved in cardiovascular complications in hypertension. We examined the relationship between dietary salt and potassium, as indicated by urinary sodium (UNa), urinary potassium (UK), and urinary sodium/potassium ratio (UNa/K), and the arrhythmic burden in patients with essential hypertension. METHODS: We included 255 consecutive adult patients with well-controlled hypertension who were being followed in the hypertension outpatient clinic of a university tertiary hospital and complained of episodes of atypical chest pain and/or palpitations. All underwent 24-hour ambulatory electrocardiograph monitoring and their UNa, UK, and UNa/K ratio from 24-hour urinary excretion specimens were evaluated. RESULTS: No significant correlation was found between premature supraventricular contractions and the parameters that were examined. However, the percentage of premature ventricular contractions (PVC%) showed a weak positive association with UNa (r = 0.2; P = .001) and a moderate negative association with UK (r = -0.396; P < .001). The partial correlation coefficient of PVC% with the UNa/UK ratio remained significant even after controlling for left ventricular mass index (r = 0.437; P < .001). CONCLUSIONS: A higher UNa/UK excretion ratio is significantly associated with PVCs, indicating an increased susceptibility to ventricular arrhythmias even among hypertensives with well controlled blood pressure. Our findings reinforce recommendations for dietary interventions in those populations. PMID- 23659780 TI - Effect of body weight on the pharmacokinetics of flunixin meglumine in miniature horses and quarter horses. AB - In most species, large variations in body size necessitate dose adjustments based on an allometric function of body weight. Despite the substantial disparity in body size between miniature horses and light-breed horses, there are no studies investigating appropriate dosing of any veterinary drug in miniature horses. The purpose of this study was to determine whether miniature horses should receive a different dosage of flunixin meglumine than that used typically in light-breed horses. A standard dose of flunixin meglumine was administered intravenously to eight horses of each breed, and three-compartmental analysis was used to compare pharmacokinetic parameters between breed groups. The total body clearance of flunixin was 0.97 +/- 0.30 mL/min/kg in miniature horses and 1.04 +/- 0.27 mL/min/kg in quarter horses. There were no significant differences between miniature horses and quarter horses in total body clearance, the terminal elimination rate, area under the plasma concentration versus time curve, apparent volume of distribution at steady-state or the volume of the central compartment for flunixin (P > 0.05). Therefore, flunixin meglumine may be administered to miniature horses at the same dosage as is used in light-breed horses. PMID- 23659781 TI - Intravitreal bevacizumab monotherapy for retinopathy of prematurity. AB - BACKGROUND: The aim of this study was to evaluate the treatment outcomes of intravitreal bevacizumab (IVB) injections, used as a monotherapy in type 1 retinopathy of prematurity (ROP). METHODS: A retrospective chart review was performed for 17 type 1 ROP patients (34 eyes), who had IVB injection between July 2011 and June 2012. Birthweight, gestational age at birth, stage and location of ROP, IVB injection time, time of complete retinal vascularization, and additional treatments if needed, were noted. A total of 0.625 mg (0.025 mL) bevacizumab was injected intravitreally. RESULTS: Thirty eyes of 17 patients with type 1 ROP enrolled in the study were treated with IVB injection. Of them seven had aggressive posterior-ROP, six had stage 2 ROP, and four had stage 3 ROP. The mean gestational age was 28.44 weeks (range, 26-31 weeks); and the mean birthweight was 1151.88 g (range, 600-1600 g). The mean age for IVB injection was 35.47 weeks. The mean full retinal vascularization time was 136.6 +/- 26.6 days. The mean follow-up time was 285.3 +/- 70 days. ROP was regressed and retinal vascularization was completed in all cases except one eye, which had threshold disease. CONCLUSION: IVB injection, used as a monotherapy, is an effective treatment approach in patients with type 1 ROP. Timely treatment of stage 2 and early stage 3 ROP in which disease progression was observed, prevents vitreoretinal membrane formation in posterior disease. Further studies need to be performed to determine the safety of IVB injection. PMID- 23659782 TI - Akt/PKB plays role of apoptosis relay on entry into first mitosis of mouse embryo. AB - The cell-cycle regulators that control meiotic divisions also regulate the events that accompany the oocyte-to-zygote transition. Thus, the meiotic machinery functions as an internal pacemaker that propels the oocyte toward embryogenesis. The preimplantation embryo expresses a number of receptors that are important for initial activity of the phosphatidylinositol 3-kinase-protein kinase B (PI3K Akt/PKB) pathway. The complete PI3K-Akt/PKB-CDK1 cascade is implicated as a key regulator of a number of cellular functions. Selective inhibition of protein kinase B (Akt/PKB) with inhibitor SH6 and cyclin-dependent kinase 1 (CDK1) with inhibitor roscovitine arrest development of the 1-cell preimplantation mouse embryo before entry into the first mitosis. The pronuclei of these inhibited embryos migrate to one another, but do not progress to pronuclei envelope breakdown and pronuclear fusion running immediately before the onset of mitosis. SH6-treated 1-cell mouse embryos showed a high occurrence of apoptosis features (nuclear fragmentation, positive terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL), active caspase-3 in both cytoplasm and nucleoplasm). In the Akt/PKB-inhibited embryos, the active phosphorylated form Ser473Akt/PKB was not detected in pronuclear areas when compared with inhibitor-free controls. Although CDK1-inhibited 1-cell embryos also failed to enter into the first mitosis, the presence of apoptotic cell death features was not observed. In the roscovitine-treated embryos, Ser473Akt/PKB was detected in the pronuclei independently of CDK1 activity. We conclude that Akt/PKB plays an important role during entry of the 1-cell mouse embryo into the first mitosis, and probably functions as a relay in the cell-cycle stage. We assume that Akt/PKB is the primary target responsible for mediating anti-apoptotic signals in the 1-cell mouse embryo. PMID- 23659783 TI - Candida and severe acute pancreatitis: we won't be fooled again. AB - Several studies have suggested a role of candida in infected cases of severe acute pancreatitis. This commentary reports high incidence and mortality rates of candida infection in this setting and demonstrates the value of the colonization index to detect patients at risk for fungal infection. These findings indicate the need to review the place of antifungal therapy and prophylaxis. PMID- 23659785 TI - Morphophysiological characterization of the embryonic development of Melanotaenia praecox (Weber & de Beaufort, 1922). AB - Dwarf rainbowfish (Melanotaenia praecox) are an ornamental fish with a high added value and considerable commercial interest. However, little information is known about the organism's reproductive biology, especially the early stages of embryonic development (initial ontogeny). Melanotaenia praecox embryos were examined throughout development to describe the dwarf rainbowfish initial ontogeny. Eggs were incubated at 28 degrees C, and observations were recorded at pre-determined times. Development stages were identified and classified according to morphophysiological characteristics. The initial size of the eggs ranged between 0.99 and 1.04 mm. Oil droplets were observed in the eggs, and fixing filaments for adhesion were observed in the corium. Embryonic development was similar to that of other species in the genus Melanotaenia, in which hatching begins 119.50 h post-fertilisation or 3405.75 degree-h post-fertilisation. The main features of the newly hatched larvae were excellent swimming activity, a reduced yolk sac, mouth movement and an apparently functional digestive system. PMID- 23659786 TI - Dermatological features identifying a new family with the cancer-prone Birt-Hogg Dube syndrome. PMID- 23659789 TI - New procedure for epidermal cell isolation using kiwi fruit actinidin, and improved culture of melanocytes in the presence of leukaemia inhibitory factor and forskolin. AB - OBJECTIVES: Conventional isolation of epidermis from the dermis and disruption of epidermal sheets to liberate the cells, are performed using proteolytic enzymes such as thermolysin or collagenase. Selective population expansion of melanocytes is achieved by suppressing proliferation of keratinocytes and fibroblasts in epidermal cell suspensions, using phorbol esters and cholera toxin. Here, we introduce a new procedure for isolation of epidermal cells, using proteolytic activity of kiwi fruit actinidin, and also an improved growth medium for melanocytes in the presence of leukaemia inhibitory factor (LIF) and forskolin. MATERIALS AND METHODS: Dermo-epidermal separation and epidermal sheet cell dispersion were performed using actinidin compared to conventional proteases including collagenase, thermolysin or trypsin. Thereafter, melanocyte culture was performed in two common media and one modified medium to discover optimization for these cells. RESULTS: We found that dermo-epidermal separation and epidermal sheet cell dispersion using kiwi fruit actinidin were considerably better than previously used methods, both from the aspect of less fibroblast and keratinocyte contamination, and of more viable native cells. Also, melanocytes proliferated better in phorbol ester- and cholera toxin-free proliferation medium supplemented with LIF and forskolin. CONCLUSION: Less contamination and higher numbers of viable cells were actinidin preferential for separation of epidermis and isolation of epidermal cells. Supplementation of LIF and forskolin to new medium increased proliferation potential of melanocytes in comparison to exogenous mitogens. PMID- 23659787 TI - Development of M1 mAChR allosteric and bitopic ligands: prospective therapeutics for the treatment of cognitive deficits. AB - Since the cholinergic hypothesis of memory dysfunction was first reported, extensive research efforts have focused on elucidating the mechanisms by which this intricate system contributes to the regulation of processes such as learning, memory, and higher executive function. Several cholinergic therapeutic targets for the treatment of cognitive deficits, psychotic symptoms, and the underlying pathophysiology of neurodegenerative disorders, such as Alzheimer's disease and schizophrenia, have since emerged. Clinically approved drugs now exist for some of these targets; however, they all may be considered suboptimal therapeutics in that they produce undesirable off-target activity leading to side effects, fail to address the wide variety of symptoms and underlying pathophysiology that characterize these disorders, and/or afford little to no therapeutic effect in subsets of patient populations. A promising target for which there are presently no approved therapies is the M1 muscarinic acetylcholine receptor (M1 mAChR). Despite avid investigation, development of agents that selectively activate this receptor via the orthosteric site has been hampered by the high sequence homology of the binding site between the five muscarinic receptor subtypes and the wide distribution of this receptor family in both the central nervous system (CNS) and the periphery. Hence, a plethora of ligands targeting less structurally conserved allosteric sites of the M1 mAChR have been investigated. This Review aims to explain the rationale behind allosterically targeting the M1 mAChR, comprehensively summarize and critically evaluate the M1 mAChR allosteric ligand literature to date, highlight the challenges inherent in allosteric ligand investigation that are impeding their clinical advancement, and discuss potential methods for resolving these issues. PMID- 23659788 TI - Immunohistochemical detection of Helicobacter pylori without association of TLR5 expression in oral squamous cell carcinoma. AB - BACKGROUND: Approximately 15% of human deaths from cancer are associated with chronic viral or bacterial infections. Helicobacter pylori (HP), a flagellated, Gram-negative, spiral, microaerophilic bacteria is considered to be the most common chronic bacterial infection in humans. Toll-like receptor 5 (TLR5) is involved in recognition of bacterial flagella and is thought to promote tumour growth through inflammation-dependent mechanisms in epithelial cells. METHODS: Expression of HP and TLR5 was analysed in OSCC specimen (n = 191) by immunohistochemistry. TLR5 expression specificity was conducted by Western blotting in cancer cell lines (BICR3, BICR56). TLR5-stained sections were scanned and digitally analysed using ImageJ and the immunomembrane plug-in. HP expression and TLR5 expression were associated with clinicopathological characteristics and impact on survival. RESULTS: Helicobacter pylori detection was significantly associated with recurrence of the tumour, whereas TLR5 expression was not. Multivariate analysis demonstrated HP expression as an independent prognostic factor (P = 0.0260). TLR5 specificity was confirmed by Western blot analysis. CONCLUSIONS: For the first time, this study provides evidence that immunohistochemically detected HP expression in OSCC is associated with reduced disease-free survival in a large patient cohort. Although TLR5 was not associated with any clinicopathological characteristics or impact on survival, investigation of the TLR family seems to be reasonable due to the possible existence of other pathogenic bacterial or viral compounds in oral cavity cancer. PMID- 23659790 TI - Structure analysis of archaeal AMP phosphorylase reveals two unique modes of dimerization. AB - AMP phosphorylase (AMPpase) catalyzes the initial reaction in a novel AMP metabolic pathway recently found in archaea, converting AMP and phosphate into adenine and ribose 1,5-bisphosphate. Gel-filtration chromatography revealed that AMPpase from Thermococcus kodakarensis (Tk-AMPpase) forms an exceptionally large macromolecular structure (>40-mers) in solution. To investigate its unique multimerization feature, we determined the first crystal structures of Tk AMPpase, in the apo-form and in complex with substrates. Structures of two truncated forms of Tk-AMPpase (Tk-AMPpaseDeltaN84 and Tk-AMPpaseDeltaC10) clarified that this multimerization is achieved by two dimer interfaces within a single molecule: one by the central domain and the other by the C-terminal domain, which consists of an unexpected domain-swapping interaction. The N terminal domain, characteristic of archaeal enzymes, is essential for enzymatic activity, participating in multimerization as well as domain closure of the active site upon substrate binding. Moreover, biochemical analysis demonstrated that the macromolecular assembly of Tk-AMPpase contributes to its high thermostability, essential for an enzyme from a hyperthermophile. Our findings unveil a unique archaeal nucleotide phosphorylase that is distinct in both function and structure from previously known members of the nucleoside phosphorylase II family. PMID- 23659792 TI - Selectivity of CDC25 homology domain-containing guanine nucleotide exchange factors. AB - The Ras family of small G-proteins plays an essential role in the regulation of a variety of signal transduction processes, ranging from cell cycle control to the regulation of exocytosis. Signalling by the Ras G-proteins is initiated by the CDC25 homology domain (CDC25-HD) containing guanine nucleotide exchange factors (GEFs); each GEF, with its specific selectivity profile towards G-proteins, commonly acts on only a small subset of the Ras family members. Thus, GEFs play a pivotal part in establishing the activation of the downstream signalling routes. The structural basis for the establishment of selectivity in the GEF-G-protein interaction is only partially understood, and several controversies on the selectivity of GEFs are discussed in the literature. In the present study, we undertook a systematic approach to determine the selectivity of CDC25-HD for members of the Ras family. We generated a data set of 126 pairs using a standardised in vitro approach encompassing purified recombinant proteins, and a comprehensive mutational study analysed the basis of the selectivity. Together, these data highlight the distinct selectivity of various GEFs and allow for predictions of untested combinations of GEFs and G-proteins. PMID- 23659793 TI - Quantitative analysis of SecYEG-mediated insertion of transmembrane alpha-helices into the bacterial inner membrane. AB - Most integral membrane proteins, both in prokaryotic and eukaryotic cells, are co translationally inserted into the membrane via Sec-type translocons: the SecYEG complex in prokaryotes and the Sec61 complex in eukaryotes. The contributions of individual amino acids to the overall free energy of membrane insertion of single transmembrane alpha-helices have been measured for Sec61-mediated insertion into the endoplasmic reticulum (ER) membrane (Nature 450:1026-1030) but have not been systematically determined for SecYEG-mediated insertion into the bacterial inner membrane. We now report such measurements, carried out in Escherichia coli. Overall, there is a good correlation between the results found for the mammalian ER and the E. coli inner membrane, but the hydrophobicity threshold for SecYEG mediated insertion is distinctly lower than that for Sec61-mediated insertion. PMID- 23659794 TI - Electrochemical induced dissolution of fragments of nickel-titanium endodontic files and their removal from simulated root canals. AB - AIM: To improve the dissolution process of NiTi endodontic rotary files aiming at fragment removal and the recovery of the original path of the root canal during a clinically acceptable period of time. METHODOLOGY: Anodic polarization curves and redox curves were obtained to determine the conditions necessary for the dissolution of endodontic files. Anodic polarization of K3 files was performed, and analysis of variance (P < 0.05) was used to compare different test times in relation to weight loss, length loss and electrical charge generated in each solution. The polarization of fragments in simulated root canals was undertaken to evaluate the dissolution process. After the tests, a size 10 K-file was used to verify the possibility to bypass the fragment. The total electrical charge of each test was obtained from the corresponding graph area. Radiographic analysis of the simulated canals was used before and after the tests to verify fragment dissolution. RESULTS: The weight loss values, the length loss values and the total values of electrical charge in each period of time were significantly higher (P < 0.05) in the tests using the selected solution compared with the solution previously proposed. A progressive consumption of the K3 file tip was observed up to 30 min. The anodic polarization of file fragments in simulated root canals for 60 min resulted in their partial dissolution and enabled the recovery of the original canal pathway with size 10 K-files. CONCLUSIONS: Increasing fluoride concentration resulted in greater active dissolution of NiTi files. The dissolution of fractured files in simulated root canals enabled the recovery of its original path during a clinically acceptable period of time. PMID- 23659795 TI - Balancing accountable care with risk aversion: transplantation as a model--we cannot forget the outcomes. PMID- 23659791 TI - A key hydrophobic patch identified in an AAA+ protein essential for its in trans inhibitory regulation. AB - Bacterial enhancer binding proteins (bEBPs) are a subclass of the AAA(+) (ATPases Associated with various cellular Activities) protein family. They are responsible for sigma(54)-dependent transcription activation during infection and function under many stressful growth conditions. The majority of bEBPs are regulated in their formation of ring-shaped hexameric self-assemblies via an amino-terminal domain through its phosphorylation or ligand binding. In contrast, the Escherichia coli phage shock protein F (PspF) is negatively regulated in trans by phage shock protein A (PspA). Up to six PspA subunits suppress PspF hexamer action. Here, we present biochemical evidence that PspA engages across the side of a PspF hexameric ring. We identify three key binding determinants located in a surface-exposed 'W56 loop' of PspF, which form a tightly packed hydrophobic cluster, the 'YLW' patch. We demonstrate the profound impact of the PspF W56 loop residues on ATP hydrolysis, the sigma(54) binding loop 1, and the self association interface. We infer from single-chain studies that for complete PspF inhibition to occur, more than three PspA subunits need to bind a PspF hexamer with at least two binding to adjacent PspF subunits. By structural modelling, we propose that PspA binds to PspF via its first two helical domains. After PspF binding-induced conformational changes, PspA may then share structural similarities with a bEBP regulatory domain. PMID- 23659796 TI - Breathlessness in everyday life from a patient perspective: a qualitative study using diaries. AB - OBJECTIVE: Breathlessness is a subjective symptom, which makes it difficult to define and understand. The aim of the present study was to illuminate how patients suffering from breathlessness experience their everyday life. METHOD: The study was a qualitative study, and the focus of the analysis was the patients' descriptions of their experiences of breathlessness using a diary with two unstructured questions for a period of 7 consecutive days. Sixteen participants: 7 men, mean age 65 +/- 7 (range 55-73 years old), and 9 women, mean age 65 +/- 9 (range 50-72 years old) participated in the study. RESULTS: Two themes emerged from the analysis: 1) Impaired quality of life and 2) symptom tolerance and adaptation. The theme "impaired quality of life" included the categories limited physical ability, psychological burdens, and social life barriers. The theme "symptom tolerance and adaptation" included importance of health care, social support, hobbies and leisure activities, and coping strategies. SIGNIFICANCE OF RESULTS: The findings in our study showed that patients, in spite of considerable difficulties with shortness of breath, found relief in several types of activities, in addition to drug therapy. The result indicates that the "biopsychosocial model" is an appealing approach that should be discussed further to gain a better understanding of breathlessness. PMID- 23659797 TI - Measuring impacts of community forestry program through repeat photography and satellite remote sensing in the Dolakha district of Nepal. AB - During the 1990's community-based forest management gained momentum in Nepal. This study systematically evaluates the impacts that this had on land cover change and other associated aspects during the period 1990-2010 using repeat photography and satellite imagery in combination with interviews with community members. The results of the study clearly reflect the success of community-based forest management in the Dolakha district of the mid-hills of Nepal: during the study period, the rate of conversion of sparse forest into dense forest under community-based management was found to be between 1.13% and 3.39% per year. Similarly, the rate of conversion of non-forest area into forest was found to be between 1.11% and 1.96% per year. Community-based forest management has resulted in more efficient use of forest resources, contributed to a decline in the use of slash-and-burn agricultural practices, reduced the incidence of forest fires, spurred tree plantation, and encouraged the conservation and protection of trees on both public and private land. The resulting reclamation of forest in landside areas and river banks and the overall improvement in forest cover in the area has reduced flash floods and associated landslides. PMID- 23659798 TI - River rehabilitation for the delivery of multiple ecosystem services at the river network scale. AB - This paper presents a conceptual framework and methodology to assist with optimising the outcomes of river rehabilitation in terms of delivery of multiple ecosystem services and the benefits they represent for humans at the river network scale. The approach is applicable globally, but was initially devised in the context of a project critically examining opportunities and constraints on delivery of river rehabilitation in Scotland. The spatial-temporal approach highlighted is river rehabilitation measure, rehabilitation scale, location on the stream network, ecosystem service and timescale specific and could be used as initial scoping in the process of planning rehabilitation at the river network scale. The levels of service delivered are based on an expert-derived scoring system based on understanding how the rehabilitation measure assists in reinstating important geomorphological, hydrological and ecological processes and hence intermediate or primary ecosystem function. The framework permits a "total long-term (>25 years) ecosystem service score" to be calculated which is the cumulative result of the combined effect of the number of and level of ecosystem services delivered over time. Trajectories over time for attaining the long-term ecosystem service score for each river rehabilitation measures are also given. Scores could also be weighted according to societal values and economic valuation. These scores could assist decision making in relation to river rehabilitation at the catchment scale in terms of directing resources towards alternative scenarios. A case study is presented of applying the methodology to the Eddleston Water in Scotland using proposed river rehabilitation options for the catchment to demonstrate the value of the approach. Our overall assertion is that unless sound conceptual frameworks are developed that permit the river network scale ecosystem services of river rehabilitation to be evaluated as part of the process of river basin planning and management, the total benefit of river rehabilitation may well be reduced. River rehabilitation together with a 'vision' and framework within which it can be developed, is fundamental to future success in river basin management. PMID- 23659799 TI - Comparative proteome analysis of lung tissue from patients with idiopathic pulmonary fibrosis (IPF), non-specific interstitial pneumonia (NSIP) and organ donors. AB - Among the idiopathic interstitial pneumonias (IIP), the two entities IPF and NSIP seem to be clinically related, but NSIP has a better outcome. The proteomic signatures which distinguish NSIP from IPF remain still elusive. We therefore performed comparative proteomic analysis of peripheral lung tissue from patients with sporadic IPF (n=14) and fibrotic NSIP (fNSIP, n=8) and organ donors (Controls, n=10), by using the 2-dimensional DIGE technique and MALDI-TOF-MS. The study revealed that the proteomic profiles of IPF and fNSIP were quite similar. Among the upregulated proteins in IPF and fNSIP were stress-induced genes involved in the ER stress-pathway, whereas downregulated proteins in IPF and fNSIP included antiapoptotic factors and antifibrotic molecules. The comparison fNSIP versus IPF indicated upregulation of subunits of the proteasome activator complex and antioxidant enzymes of the peroxiredoxin family. We conclude, that only few protein expression changes exist between IPF and fNSIP, and that epithelial ER- and oxidative stress play a major role in the pathogenesis of both diseases. In contrast to IPF, intracellular clearance of ROS and misfolded protein carbonyls seem to be enhanced in fNSIP due to enhanced expression of antioxidant acting proteins, and may explain the better outcome and survival in patients with fNSIP. BIOLOGICAL SIGNIFICANCE: IPF and fibrotic NSIP (fNSIP) belong to the idiopathic interstitial pneumonias and are usually fatal, but fNSIP has a better outcome. In order to identify molecular mechanisms and differences between IPF and fNSIP, we herein present results of a comparative proteome analysis of IPF, fNSIP and control lung tissue. Our data including validation experiments suggest that ER stress and a general stress-response as well as the decline of antioxidant capacity in alveolar epithelium is key in the pathogenesis of IPF and fNSIP. In addition, we could observe a signature of an increased alveolar epithelial protection against oxidative and ER-stress in fNSIP as compared to IPF, which could help to explain the better outcome of fNSIP patients. PMID- 23659800 TI - Cross-linked enzyme aggregates of Mung bean epoxide hydrolases: a highly active, stable and recyclable biocatalyst for asymmetric hydrolysis of epoxides. AB - A highly active and stable cross-linked enzyme aggregates (CLEAs) of epoxide hydrolases (EHs) from Mung bean, which plays a crucial role in synthesis of valuable enantiopure diols, were successfully prepared and characterized. Under the optimum preparation conditions, the activity recovery of CLEAs recorded 92%. The CLEAs were more efficient than the free enzyme in catalyzing asymmetric hydrolysis of styrene oxide to (R)-1-phenyl-1,2-ethanediol in organic solvent containing biphasic system. The biocatalytic reaction performed in n hexane/buffer biphasic system had a clearly faster initial reaction rate, much higher product yield and product e.e. value than that in aqueous medium. Moreover, the optimal volume ratio of n-hexane to buffer, reaction temperature, buffer pH value and substrate concentration for the enzymatic hydrolysis were found to be 1:1, 40 degrees C, 7.5 and 30 mM, respectively, under which the initial reaction rate, product yield and product e.e. value were 13.26 mM/h, 46% and 93.5%, respectively. The CLEAs retained more than 50% of their initial activity after 8 batches of re-use in phosphate buffer and maintained 53% of their original activity after 8 reaction cycle in biphasic system. The efficient biocatalytic process with CLEAs proved to be feasible on a 250-mL preparative scale, exhibiting great potential for asymmetric synthesis of chiral diols. PMID- 23659801 TI - Equilibrium and release properties of hyaluronic acid-drug complexes. AB - With the aim to provide more rational basis about the potentiality of hyaluronic acid (or hyaluronan) as drug carrier a set of ionic complexes of its acid form (HA) and its sodium salt (NaHA) with three model drugs (D) (atenolol, propranolol and lidocaine) were prepared. Besides NaHA subjected to hyalurodinase depolimerization (NaHA(d)) was also used. Transparent dispersions were obtained. They exhibited negative electrokinetic potential and a high degree of counterionic condensation with affinity constants (log Kcc) in the range of 5.8 6.1 for propranolol complexes (pK(a) 9.45) and 4.0-4.6 for lidocaine ones (pK(a) 7.92). Delivery rates of D from the complexes were measured in a Franz-type bicompartimental device. Loaded D were slowly released from the three types of complexes, even when a neutral salt was added to the dispersion placed in the donor compartment, revealing the high affinity between the protonated drugs and the ionisable groups of the polymer. Complex dispersions based on HA or on NaHA(d) exhibited lower viscosity than those of NaHA but their complexing ability remained unaltered. The results reported on equilibrium and release properties of Hyaluronan-model D complexes contribute to expand the use of HA and NaHA as drug carriers for different routes of administration. PMID- 23659802 TI - Labeling lysine acetyltransferase substrates with engineered enzymes and functionalized cofactor surrogates. AB - Elucidating biological and pathological functions of protein lysine acetyltransferases (KATs) greatly depends on the knowledge of the dynamic and spatial localization of their enzymatic targets in the cellular proteome. We report the design and application of chemical probes for facile labeling and detection of substrates of the three major human KAT enzymes. In this approach, we create engineered KATs in junction with synthetic Ac-CoA surrogates to effectively label KAT substrates even in the presence of competitive nascent cofactor acetyl-CoA. The functionalized and transferable acyl moiety of the Ac CoA analogs further allowed the labeled substrates to be probed with alkynyl or azido-tagged fluorescent reporters by the copper-catalyzed azide-alkyne cycloaddition. The synthetic cofactors, in combination with either native or rationally engineered KAT enzymes, provide a versatile chemical biology strategy to label and profile cellular targets of KATs at the proteomic level. PMID- 23659803 TI - The "bicipital aponeurosis flex test": evaluating the integrity of the bicipital aponeurosis and its implications for treatment of distal biceps tendon ruptures. AB - BACKGROUND: One mitigating factor in the accurate diagnosis of complete distal biceps tendon ruptures (DBTR) is the integrity of the bicipital aponeurosis (BA). Current orthopedic literature lacks a descriptive means of evaluating the integrity of the BA in the presence of distal biceps injury. METHODS: A consecutive cohort of 17 patients with suspected DBTR was examined. The hook test, passive forearm pronation test, and the biceps crease interval (BCI) test were performed as part of the overall clinical examination to assess the integrity of the distal tendon. The biceps crease ratio (BCR), a component of the BCI test, was used as an objective measure of distal tendon retraction. Integrity of the BA was assessed using the "BA flex test." The status of the distal tendon and BA were confirmed intraoperatively. RESULTS: Sixteen patients had complete rupture of the distal biceps tendon. One had a high-grade partial thickness tear. The BA remained intact in 59%. Application of the BA flex test resulted in 100% sensitivity and 90% specificity, with overall diagnostic accuracy of 94%. Despite complete DBTR, there was a significant difference in the amount of distal tendon retraction (P = .012) between those with the BA intact (median BCR, 1.5, interquartile range, 1.3-1.9) and those where the BA was absent (median BCR, 2.2, interquartile range, 1.7-2.6). CONCLUSION: Evaluating the integrity of the BA can help to inform evaluation and treatment of DBTR, especially when visible or palpable alterations in biceps contour and proximal tendon migration are absent or equivocal. PMID- 23659804 TI - Value-based shoulder surgery: practicing outcomes-driven, cost-conscious care. AB - BACKGROUND: Pathology of the shoulder contributes significantly to the increasing burden of musculoskeletal disease. Currently, there exists high variability in the nature and quality of shoulder care, and outcomes and cost reporting are not uniform. Value-based practice aims to simultaneously maximize outcomes and minimize costs for given disease processes. METHODS: The current state of the shoulder care literature was examined with regards to cost and outcomes data, initiatives in streamlining care delivery, and evidence-based practice improvements. This was synthesized with value-based care theory to propose new avenues to improve shoulder care in the future. CONCLUSION: The treatment of shoulder disorders is ideal for the value-based model but has been slow to adopt its principles thus far. We can begin to advance value-based practices through (1) the universal reporting of outcomes and costs, (2) integrating shoulder care across provider specialties, and (3) critically analyzing data to formulate best practices. PMID- 23659805 TI - Scapular fractures after reverse shoulder arthroplasty: evaluation of risk factors and the reliability of a proposed classification. AB - BACKGROUND: The aims were to determine the sensitivity of plain radiographs to detect scapular fractures after reverse shoulder arthroplasty (RSA), to test the reliability of a proposed classification, and to evaluate risk factors. MATERIALS AND METHODS: We matched 53 patients with scapular fractures after RSA to 212 control patients. Clinical risk factors were assessed by correlating comorbidities. Independent observers reviewed radiographs to assess fracture detection accuracy and test the reliability of a proposed classification. Radiographic risks were evaluated by measuring acromial thickness, acromial tilt, glenoid-to-tuberosity distance, and acromion-to-tuberosity (AT) distance. RESULTS: Independent reviewers accurately diagnosed 78.8% of fractures and 97.4% of controls with good inter-rater reliability (kappa = 0.782) and excellent intrarater reliability (kappa = 0.862). Inter-rater reliability of the classification was moderate (kappa = 0.422). Osteoporosis significantly increased the risk of fracture (odds ratio, 1.97; 95% confidence interval, 1.00-3.91); however, no difference was found for other comorbidities or between preoperative and postoperative radiographic parameters. A significant difference occurred between groups from the postoperative radiographs to the most recent radiographs for AT distance (0.4 +/- 5.5 mm for control group and 8.3 +/- 7.6 mm for fracture group, P < .001) and acromial tilt (1.8 degrees +/- 6.3 degrees for control group and 14 degrees +/- 15 degrees for fracture group, P < .001). Of 16 scapular spine fractures, 14 occurred from a screw tip; however, screw orientation and length were not different between groups. CONCLUSION: Osteoporosis is a significant risk factor for scapular fractures after RSA. The current classification has only moderate reliability, suggesting that an alternative classification method is needed. Decreasing AT distance and increasing acromial tilt on consecutive radiographs may improve fracture detection. Advanced imaging may be needed to confirm the diagnosis. Whereas most scapular spine fractures occurred from a screw, the surgical technique did not increase the relative risk. PMID- 23659806 TI - Clinical and radiographic comparisons of two different radial head implant designs. AB - BACKGROUND: There is little comparative data to guide implant choice for radial head replacements. The purpose of this study was to evaluate the clinical and radiographic results between patients who received a smooth-stemmed bipolar radial head implant and patients who received an in-growth monopolar prosthesis. METHODS: Twenty-seven patients requiring a metallic radial head implant in the management of acute or chronic elbow trauma were evaluated. Fourteen patients received a smooth-stemmed bipolar prosthesis and 13 patients received a press-fit monopolar prosthesis. Patients returned for follow-up at an average of 33 months (range, 18-57). Outcome assessments included joint motion, elbow stability, grip strength, pain, the Mayo Elbow Performance Index, and the Disability of Arm, Shoulder and Hand questionnaire. Radiographs were reviewed for joint congruence, ectopic bone, periprosthetic osteolysis, degenerative arthritis, and capitellar wear, and selected patients were tested for inflammatory markers and metal ion levels. RESULTS: The differences between patient groups for elbow flexion and forearm pronation averaged 10 degrees or less. There were no other pertinent differences between groups for standardized patient and examiner-determined outcomes. There was a trend for ectopic bone to develop more commonly around the smooth-stemmed implants, while periprosthetic osteolysis was more pronounced in cases with the press-fit design. Inflammatory markers were normal, and metal ion levels did not exceed values reported for a well-functioning hip arthroplasty. CONCLUSION: Outcomes at short- to mid-term follow-up were similar with either implant design. Loosening of a press-fit prosthesis may lead to extensive osteolysis, but of undetermined clinical consequence. PMID- 23659808 TI - Childhood bullying: a review and implications for health care professionals. AB - Childhood bullying continues to be a serious threat to the physical and emotional health of children and adolescents in the United States. This article provides the prevalence and general information about bullying as well as the common characteristics of bullies and victims, the short- and long-term consequences of bullying, and the recommendations of various organizations, which can help health care providers to assess and provide interventions to children affected by bullying. PMID- 23659807 TI - Pediatric abusive head trauma. AB - Pediatric abusive head trauma is a significant contributor to pediatric morbidity and mortality in the United States. Signs and symptoms can be vague, nonspecific, and difficult to recognize. This article increases the healthcare provider's level of suspicion and ability to recognize early warning signs of abuse. It also addresses evidence-based prevention strategies. This information is useful to nurses, advanced practice nurses, and physicians who work with children and families in any capacity. PMID- 23659809 TI - College sorority members' knowledge and behaviors regarding human papillomavirus and cervical cancer. AB - The incidence of human papillomavirus (HPV) is higher in college students than in many other populations. HPV puts young women at risk for developing cervical cancer. The relationship between HPV and risky sexual behaviors has been well established. This study describes female college students' knowledge regarding HPV and cervical cancer, identifies sexual risk behaviors in this group, and assesses whether there is any relationship between knowledge of HPV and cervical cancer and the sexual risk behaviors in this population. Health care providers need to be aware of this health issue and actively promote appropriate prevention strategies. PMID- 23659810 TI - Psychosocial effects of disaster in children and adolescents: significance and management. AB - This article provides a synthesis of the literature addressing the psychological and social effects on children and adolescents after disasters, and the factors that contribute to protecting this population from experiencing related symptoms. Clinical implications are presented for health care providers to reduce the possibility of long-term psychopathologies based on the National Commission on Children and Disasters 2010 Report. PMID- 23659812 TI - Pediatric obesity and asthma quality of life. AB - Widely researched as separate entities, our understanding of the comorbid effects of childhood obesity and asthma on quality of life is limited. This article discusses the effects of childhood obesity and asthma on self-reported quality of life in low-income African American teens with asthma. When controlling for the influence of symptom frequency, asthma classification, asthma self-efficacy, and asthma self-care levels, body mass index remains a most important factor in determining self-reported quality of life among teens with asthma. Although overweight and obesity did not change the effectiveness of the asthma intervention program, obesity did affect participants quality of life scores. PMID- 23659811 TI - Challenges in providing preventive care to inner-city children with asthma. AB - Although the scientific understanding of the pathophysiology of asthma and the quality of asthma therapies have significantly improved over the past 30 years, asthma morbidity remains high and preventive care low for inner-city children. This article focuses on 4 major challenges to providing preventive care (family and patient attitudes and beliefs, lack of access to quality medical care, psychosocial factors, environmental factors) based on prior evidence and the authors' observation of these challenges in research with inner-city children with asthma over the past decade. Cost issues related to preventive care are addressed, and recommendations provide for pediatric nurses. PMID- 23659813 TI - Developing an interactive story for children with asthma. AB - Despite advancements in asthma treatment and diagnosis, asthma still remains the number 1 cause for hospitalizations in school-aged children. This usability study aimed to develop a child-friendly interactive narrative, Okay with Asthma v2.0, based on the Biopsychosocial Family Model using feedback from children. This fun and kid-friendly program encourages children to manage their own asthma with the help of peers, families, communities, and health care services. With these support structures, children can identify and avoid triggers, monitor their asthma, manage their condition with medications based on an action plan, and learn to live happily with asthma. PMID- 23659814 TI - Therapeutic conversations intervention in pediatrics: are they of benefit for families of children with asthma? AB - This article reports a quasiexperimental family level intervention study to measure effectiveness of a theory-based family therapeutic conversation intervention (FAM-TC) for families of children with asthma on perceived family support and asthma-related quality of life (QOL). Perceived family support increased significantly for mothers in the experimental group. The children of the parents in the experimental group reported significantly lower problems with asthma treatment on the treatment problems subscale of the asthma QOL scale after the intervention. These results highlight the benefit of therapeutic conversations for families of children and adolescent with asthma to support or enhance QOL. PMID- 23659815 TI - Health care autonomy in children with chronic conditions: implications for self care and family management. AB - Health care autonomy typically occurs during late adolescence but health care providers and families often expect children with chronic health conditions to master self-care earlier. Few studies have examined the development of health care autonomy as it pertains to self-care and family management. This review links the 3 concepts and discusses the implications for families and health care providers. Case studies are provided as exemplars to highlight areas where intervention and research is needed. PMID- 23659816 TI - Promoting normal development and self-efficacy in school-age children managing chronic conditions. AB - Chronic conditions can affect school-age children in more ways than just physically. Normal childhood maturation is critical at this age, yet daily management of chronic symptoms can be challenging. This article describes 4 common childhood chronic illnesses (asthma, seizure disorders, diabetes, and cystic fibrosis), and the impact these conditions have on the developing child. Self-efficacy, the belief that one can effectively perform necessary skills, is essential to self-management of chronic conditions and contributes in a positive way to the child's normal development. Implications for clinical practice and future research are discussed. PMID- 23659817 TI - Developmental mastery of diabetes-related tasks in children. AB - The goal of managing diabetes in childhood is to assist the child in becoming a physically healthy and emotionally mature adult, free from complications associated with diabetes. Gradual achievement of self-care independence occurs as developmental changes evolve during childhood. Inappropriate expectations related to self-care competence may lead to impaired diabetes control. It is important to have an understanding of child development and cognitive development in order ensure adequate expectations of self-care skill acquisition and the appropriate transition of self-care skills. Numerous steps can be taken to assist the child with diabetes in attaining developmentally appropriate, self-management skills. PMID- 23659818 TI - Implementation of a clinical practice guideline for identification of microalbuminuria in the pediatric patient with type 1 diabetes. AB - Evidence-based practice is a shift in the health care culture from basing decisions on consensus opinion, past practice, and precedent toward the use of rigorous analysis of scientific evidence using outcomes research and clinical evidence to guide clinical decision making. The development of evidence-based clinical practice guidelines (CPG) is critical to guide the assessment and management of children with diabetes. This article provides an overview of the infrastructure and processes that are crucial to providing evidence-based care in a large urban pediatric diabetes center. Development of a CPG to identify microalbuminuria in children with type 1 diabetes is discussed. PMID- 23659819 TI - Strategies from bedside nurse perspectives in conducting evidence-based practice projects to improve care. AB - This article presents the bedside nurses' perspectives on their experience with conducting an evidence based practice project. This is especially important in the climate of hospitals working to achieve Magnet Recognition. The facilitators and barriers to project design and completion are discussed in detail. Strategies to overcome barriers are presented. Facilitators for bedside nurses include motivation and professional development. Most common barriers were lack of time and limited knowledge about the process. Interventions aimed at research utilization can be successful when mindful of commonly understood barriers to project completion with steps taken to resolve those barriers. PMID- 23659820 TI - Current challenges in pediatrics. PMID- 23659821 TI - Was the economic crisis of 2008 good for Icelanders? Impact on health behaviors. AB - This study uses the 2008 economic crisis in Iceland to identify the effects of a macroeconomic downturn on a range of health behaviors. We use longitudinal survey data that include pre- and post-reports from the same individuals on a range of health-compromising and health-promoting behaviors. We find that the crisis led to large and significant reductions in health-compromising behaviors (such as smoking, drinking alcohol or soft drinks, and eating sweets) and certain health promoting behaviors (consumption of fruits and vegetables), but to increases in other health-promoting behaviors (consumption of fish oil and recommended sleep). The magnitudes of effects for smoking are somewhat larger than what has been found in past research in other contexts, while those for alcohol, fruits, and vegetables are in line with estimates from other studies. Changes in work hours, real income, financial assets, mortgage debt, and mental health, together, explain the effects of the crisis on some behaviors (such as consumption of sweets and fast food), while the effects of the crisis on most other behaviors appear to have operated largely through price increases. PMID- 23659822 TI - An investigation into the effect of type I and type II diabetes duration on employment and wages. AB - Using data from the National Longitudinal Survey of Youth 1979, the current study examines the effect of type I and type II diabetes on employment status and wages. The results suggest that both the probability of employment and wages are negatively related to the number of years since the initial diagnosis of diabetes. Moreover, the effect of diabetes duration on the probability of employment appears to be nonlinear, peaking around 16 years for females and 10 years for males. A similar negative effect on wages is found only in male diabetics. Finally, the results suggest that failure to distinguish between type I and type II diabetics may lead to some counterintuitive results. PMID- 23659823 TI - Assessing motivation to move and its relationship to motor development in infancy. AB - Motivation to move has typically been a post hoc explanation for infants' discovery of new patterns of behavior. As a first step to studying motivation to move directly, we qualitatively assessed motivation to move and measured its relationship to motor development in infancy. We observed 27 infants longitudinally from ages 7 to 12 months. Every 3 weeks we assessed infants' motor motivation based on persistence, activity level, activity preference, and stimulus strength needed to elicit movement. We documented the onset of sitting, pulling-to-stand, crawling and cruising, as well as infants' overall motor development as measured with the Alberta Infant Motor Scale (AIMS). Motor motivation increased over the course of the study and we identified two distinct motivation profiles. Strongly motivated infants had earlier onsets for all four motor milestones than weakly motivated infants (all p-values <0.05). Infants' motivation to move score was positively correlated with their AIMS percentile at the same and subsequent sessions. These findings provide empirical evidence for a motivational cascade whereby motivation to move and motor development enjoy a reciprocal relationship. These findings have important clinical implications for children with motor delay, suggesting that evaluation of motivation could be included as part of the assessment procedure so that both treatment and expectations can be tailored appropriately. PMID- 23659824 TI - Maternal naming of object wholes versus parts to preverbal infants: a fine grained analysis of scaffolding at 6-8 months. AB - Maternal naming of object wholes versus parts was examined during interactive free-play. Forty-two Caucasian- and Hispanic-American mothers and their preverbal infants of 6-8 months were video-taped interacting naturally during toy play. For the purpose of fine-grained analyses, maternal naming of object wholes versus parts were coded for bimodal naming (e.g., temporal synchrony) and object motion (e.g., shaking) to examine any differences in these measures across the two word types. The results revealed that during naming, mothers simultaneously moved object wholes more often than they did object parts to highlight the object wholes in their infants' visual field. To further highlight object wholes during naming, mothers predominantly shook or loomed object wholes in synchrony with their naming more often than object parts. These empirical findings suggest that very early during infants' word-mapping development, maternal scaffolding is manifold and assists in infants' disambiguation of names for object wholes versus parts. PMID- 23659825 TI - Effect of the intraoperative wake-up test in sevoflurane-sufentanil combined anesthesia during adolescent idiopathic scoliosis surgery: a randomized study. AB - STUDY OBJECTIVE: To investigate the effect of the intraoperative wake-up test on sevoflurane-sufentanil anesthesia for adolescent idiopathic scoliosis (AIS) surgery. DESIGN: Randomized, double-blind, parallel trial. SETTING: Operating room. PATIENTS: 30 ASA physical status 1 patients, aged 13 to 20 years, scheduled for AIS surgery. INTERVENTIONS: Patients were randomized to two groups: Group W patients received sevoflurane-sufentanil combined anesthesia and underwent the intraoperative wake-up test; Group NW received sevoflurane-sufentanil combined anesthesia without the wake-up test. Anesthesia was induced with an intravenous (IV) injection of midazolam, propofol, and sufentanil and maintained with sevoflurane inhalation, a target-controlled infusion (TCI) of sufentanil, and IV infusion of cisatracurium besylate. MEASUREMENTS: The primary outcome was postoperative delirium. Secondary outcomes were duration of surgery, duration of anesthesia, intraoperative blood loss and transfusion, exposure of drugs administered, time to eye opening, extubation, and consciousness. MAIN RESULTS: Postoperative delirium occurred in one patient from each group (P > 0.05). There were no significant differences between the two groups in duration of surgery (322 +/- 65 min vs 336 +/- 72 min), duration of anesthesia (356 +/- 76 min vs 368 +/- 81 min), intraoperative blood loss (1847 +/- 423 mL vs 1901 +/- 451 mL) and transfusion (1663 +/- 398 mL vs 1649 +/- 382 mL), average exposure of drugs (72 +/- 13 mg vs 75 +/- 15 mg for propofol, 116 +/- 28 MUg vs 109 +/- 25 MUg for sufentanil, and 22 +/- 5 vs 23 +/- 4 mg for cisatracurium), time to eye opening (4.7 +/- 1.5 min vs 4.8 +/- 1.4 min), extubation (7.5 +/- 2.0 min vs 7.3 +/- 2.2 min), and consciousness (8.9 +/- 1.8 min vs 9.1 +/- 2.1 min) (all P > 0.05). CONCLUSIONS: Sevoflurane-sufentanil combined anesthesia provides hemodynamic stability and rapid recovery from AIS surgery. There is no correlation between the intraoperative wake-up test and postoperative delirium after sevoflurane sufentanil combined anesthesia. PMID- 23659826 TI - Effects of surgery, general anesthesia, and perioperative epidural analgesia on the immune function of patients with non-small cell lung cancer. AB - STUDY OBJECTIVE: To assess preoperative and postoperative immune function in patients undergoing surgical resection of non-small cell lung cancer during general anesthesia and postoperative epidural analgesia. DESIGN: Observational single-center study. SETTING: University-affiliated academic center. PATIENTS: 24 adult, ASA physical status 3 and 4 patients with stage 1, 2, or 3 non-small cell lung cancer. No study patient received preoperative chemotherapy or radiation. INTERVENTIONS: Patients underwent thoracotomy with general anesthesia and postoperative epidural analgesia. MEASUREMENTS: Bispectral index monitoring, sevoflurane requirements, and intraoperative transfusions were recorded. Total fentanyl consumption and pain (verbal numeric rating scale) were recorded 24 hours after surgery. Preoperative and 24-hour postoperative natural killer cell percentage and function and percentages of natural killer T cells, T helper cells (CD4+), and cytotoxic T lymphocytes (CD8+) were measured. Plasma concentrations of the TH1 cytokine interleukin-2 and interferon-gamma and the TH2 cytokines interleukin-4 were measured at the same time points. RESULTS: The percentage (preoperative, 13.07 +/- 9.81% vs postoperative, 9.6 +/- 6.57%, P < 0.001) and function (preoperative, 31.61 +/- 21.96%; postoperative, 13.61 +/- 9.36%; P < 0.001) of natural killer cells was significantly decreased after surgery, but the percentage of natural killer T cells, T helper cells (CD4+), and cytotoxic T lymphocytes (CD8+) remained unchanged postoperatively; thus, the CD4/CD8 ratio remained unchanged. Postoperative plasma concentrations of the three cytokines were similar to preoperative levels; therefore, the TH1/TH2 ratio also remained unchanged. CONCLUSIONS: Innate immunity is depressed in patients with non-small cell lung cancer after surgical resection, and immunity is not preserved by the use of postoperative epidural analgesia. PMID- 23659827 TI - Intravenous extension sets: when more is less. PMID- 23659828 TI - Perioperative angioedema: background, diagnosis, and management. AB - Angioedema is a potentially life-threatening condition that may present at any point in the perioperative care of patients. It requires prompt recognition and diagnosis; the primary concern during acute attacks is airway management. The pathophysiology, various causes of angioedema, and treatment strategies according to underlying etiology are presented. PMID- 23659829 TI - Trends in Klebsiella pneumoniae carbapenemase-positive K. pneumoniae in US hospitals: report from the 2007-2009 SENTRY Antimicrobial Surveillance Program. AB - We report the prevalence of carbapenemase-positive Klebsiella pneumoniae among clinical isolates collected from US medical centers (n = 42) from 2007-2009 through the SENTRY Antimicrobial Surveillance Program. Isolates with imipenem or meropenem MIC >= 2 MUg/mL were screened by PCR for various carbapenemase genes. Of 2049 K. pneumoniae isolates, 126 (6.1%) were non-susceptible to imipenem or meropenem. blaKPC was identified in 113 isolates (5.5%). No other carbapenemase genes were identified. For US regions combined, prevalence of K. pneumoniae carbapenemase (KPC)-positive isolates were 5.9% in 2007, 4.9% in 2008, and 5.7% in 2009. Rates were highest in the Mid-Atlantic region (28.6% overall), with fluctuation over time (29%, 23%, and 33% from 2007-2009), followed by the East North Central region (2.4% overall), with a slightly increasing trend (nil, 3.1%, 3.8% from 2007-2009). All KPC-positive organisms were carbapenem non-susceptible according to updated CLSI breakpoints, although all but one was similarly classified according to previous breakpoints. PMID- 23659830 TI - Variation of the mineral density in cortical bone may serve to keep strain amplitudes within a physiological range. AB - Within-bone variation in mineral density could be functional. A heterogeneous mineral-density distribution might serve to maintain habitual amplitudes of bone strain within a non-harmful, i.e., physiological range. Regions of a bone that would be strained the most on the basis of architecture alone might have a higher mineral density to make them more stiff and resistant to strain. We hypothesised that the cortical bone of the rabbit mandible contains such a functional distribution of mineral density. We thereby expected similar mineral-density patterns in the mandibles of different individuals due to the shared masticatory function. Secondly, we hypothesised that the highest mineral densities occur in mandibular regions predicted to be exposed to the largest amplitudes of strain when taking into account bone architecture only. Mineral-density maps of the cortical bone of rabbit mandibles were obtained using micro-computed tomography (MUCT). The MUCT scans of two rabbits were converted into finite-element models (FEMs). To predict mandibular deformation during biting, these models were loaded by muscle forces and reaction forces. The forces acted on the condyles and on either the incisal or molar bite point. The FEMs were assigned a homogeneous material stiffness to calculate the strain amplitudes that would occur when only the architecture of the mandibular bone would be of influence. We found the cortical bone-mineral density patterns to be similar in all six mandibles. The mineral density of the corpus was higher than that of the ramus. A second consistent feature of the mandibular mineral-density distribution was that the medial ridge of the temporal-muscle insertion groove contained more mineral than its surrounding regions. The strain amplitudes calculated with the FEMs were variable and did not feature clear corpo-ramal differences. However, specific mandibular bone sites calculated to be exposed to the largest amplitudes of strain, including the medial ridge of the temporal-muscle insertion groove, did correspond with high-mineral-density regions. We conclude that, in the rabbit mandible, the heterogeneous mineral-density distribution might serve to suppress bone-strain amplitudes in regions architecturally susceptible to the largest deformations during loading. PMID- 23659831 TI - Fracture history of healthy premenopausal women is associated with a reduction of cortical microstructural components at the distal radius. AB - OBJECTIVES: The objective of this study is to determine in healthy premenopausal women with a history of fracture which bone structural components of the distal radius are the most closely associated with a risk of fracture. METHODS AND PARTICIPANTS: The method was as follows: measurement of radial areal bone mineral density (aBMD) by DXA, microstructural components by high-resolution quantitative peripheral computerized tomography (HR-pQCT) and strength variables by micro Finite Element Analysis (MUFEA) in 196 healthy premenopausal women aged 45.9 +/- 3.7 (+/- SD) years with (FX, n = 96) and without (NO-FX, n = 100) a history of fracture. We evaluated differences in T-scores between FX and NO-FX and risk of fracture by Odds ratios (OR with 95% confidence intervals, CI) per one SD decrease, using logistic regression analysis after adjustment for age, height, weight, menarcheal age, calcium and protein intakes, and physical activity. RESULTS: In the whole group the mean radial metaphysis aBMD T-score was not significantly different from zero. In the FX as compared to the NO-FX group, the differences in T-scores were as follows: for radial metaphysis: aBMD, -0.24 (P = 0.005); for distal radius microstructure components: cortical volumetric BMD, 0.38 (P = 0.0009); cortical thickness, -0.37 (P = 0.0001); cross-sectional area (CSA), +0.24 (P=0.034); and endosteal perimeter, +0.28 (P = 0.032); and for strength estimates: stiffness, -0.15 (P = 0.030); failure load, -0.14 (P = 0.044); and apparent modulus, -0.28 (P = 0.006). T-scores of trabecular volumetric BMD and thickness did not significantly differ between the FX and the NO-FX group. Accordingly, the risk of fracture (OR, 95% CI) for 1 SD decrease in radius bone parameters was as follows: radial metaphysis aBMD: 1.70 (1.18-2.44), P = 0.004; cortical volumetric BMD: 1.86 (1.28-2.71), P = 0.001; and cortical thickness: 2.36 (1.53-3.63), P = 0.0001. The corresponding fracture risk for the strength estimates was as follows: stiffness: 1.66 (1.06-2.61), P = 0.028; failure load: 1.59 (1.02-2.47), P = 0.041; and apparent modulus: 1.76 (1.17 2.64), P = 0.006. CONCLUSIONS: In healthy premenopausal women, a history of fracture is associated with reduced T-scores in the distal radius, with the cortical components showing the greatest deficit. A reduction of one SD in cortical thickness is associated with a nearly three-fold increased risk of fracture. This finding strengthens the notion that, in healthy women, a certain degree of bone structural fragility contributes to fractures before the menopause and therefore should be taken into consideration in the individual prevention strategy of postmenopausal osteoporosis. PMID- 23659832 TI - Production of advanced biofuels in engineered E. coli. AB - Commercial fermentation processes have long taken advantage of the synthetic power of living systems to rapidly and efficiently transform simple carbon sources into complex molecules. In this regard, the ability of yeasts to produce ethanol from glucose at exceptionally high yields has served as a key feature in its use as a fuel, but is also limited by the poor molecular properties of ethanol as a fuel such as high water miscibility and low energy density. Advances in metabolic engineering and synthetic biology allow us to begin constructing new high-flux pathways for production of next generation biofuels that are key to building a sustainable pipeline for liquid transportation fuels. PMID- 23659833 TI - Iatrogenic kwashiorkor developing after bypass surgery. PMID- 23659834 TI - The efficacy, safety and cost-effectiveness of hydrotalcite versus esomeprazole in on-demand therapy of NERD: A multicenter, randomized, open-label study in China. AB - OBJECTIVE: The aim of the study was to investigate whether hydrotalcite was comparable to esomeprazole, a proton pump inhibitor, in on-demand therapy for non erosive reflux disease (NERD). METHODS: This was a multicenter, randomized, open label clinical trial with initial and on-demand therapy. Patients who had complete symptom relief in the initial therapy were randomized to either hydrotalcite or esomeprazole in the on-demand therapy. The percentage of patients who quit on-demand therapy in the two groups and the cost-effectiveness of the treatment were evaluated as primary end points. The rate of symptom relief and the improvement of symptom score for initial therapy and the weekly average symptom score and weekly average number of days on treatment for on-demand therapy were evaluated as secondary end points. RESULTS: In total, 398 patients were recruited in the initial therapy group, among whom 253 were included in on demand therapy, with 127 patients in the hydrotalcite group and the remaining 126 in the esomeprazole group. 14 (11.0%) patients in the hydrotalcite group and six (4.8%) in the esomeprazole group quit the on-demand therapy due to unsatisfactory symptom control (P = 0.065). Cost-effectiveness calculated as the ratio of the cost of hydrotalcite to that of esomeprazole (per person/day) was 35.3% in the on demand therapy. Similar number of patients achieved symptom relief in both groups. CONCLUSION: Hydrotalcite is a good option of on-demand therapy for NERD patients due to its cost-effectiveness and speed of action. PMID- 23659835 TI - [Neurological complications associated with ultrasound-guided interscalene and supraclavicular block in elective surgery of the shoulder and arm. Prospective observational study in a university hospital]. AB - OBJECTIVES: The incidence of postoperative neurological symptoms after performing interscalene block varies between 4 and 16%. The majority of cases are resolved spontaneously within a year, but some patients have their symptoms permanently. Our objective was to assess the incidence of postoperative neurological symptoms after performing the ultrasound-assisted interscalene and supraclavicular anaesthetic blocks. MATERIAL AND METHODS: A prospective and observational study was conducted on consecutive patients who had undergone upper extremity surgery with an interscalene or supraclavicular block as an isolated technique, or as a complement to general anaesthesia. Seven days after the intervention, a telephone interview was conducted that focused on the detection of neurological symptoms in the operated limb. Further serial interviews were conducted on patients with symptoms (after the first, the third and the sixth month, and one year after surgery) until resolution of symptoms. Neurological evaluation was offered to those patients with persistent symptoms after one year. RESULTS: A total of 121 patients were included, on whom 96 interscalene blocks and 22 supraclavicular blocks were performed. Postoperative neurological symptoms were detected in 9.9% (95% CI, 5-15%) of patients during the first week. No significant differences were observed between interscalene (9%) and supraclavicular block (14%). After 3 months the symptoms persisted in 9 patients (7.4%), with symptoms remaining in 4 patients (3.3%) after 1.5 years. Electromyogram was performed on 3 patients who tested positive for nerve damage. CONCLUSIONS: A high incidence of postoperative neurological symptoms was observed, and a worrying percentage of permanence of them. There were no significant differences in incidence according to the type of block, or any features of the patient or the anaesthesia technique that were associated with the incidence of these symptoms, except a marginal relationship with age. These complications must be clearly explained to the patients before performing these blocks. PMID- 23659836 TI - Stable adaptive PI control for permanent magnet synchronous motor drive based on improved JITL technique. AB - In this paper, a stable adaptive PI control strategy based on the improved just in-time learning (IJITL) technique is proposed for permanent magnet synchronous motor (PMSM) drive. Firstly, the traditional JITL technique is improved. The new IJITL technique has less computational burden and is more suitable for online identification of the PMSM drive system which is highly real-time compared to traditional JITL. In this way, the PMSM drive system is identified by IJITL technique, which provides information to an adaptive PI controller. Secondly, the adaptive PI controller is designed in discrete time domain which is composed of a PI controller and a supervisory controller. The PI controller is capable of automatically online tuning the control gains based on the gradient descent method and the supervisory controller is developed to eliminate the effect of the approximation error introduced by the PI controller upon the system stability in the Lyapunov sense. Finally, experimental results on the PMSM drive system show accurate identification and favorable tracking performance. PMID- 23659837 TI - Opioid addiction agonist therapy and the QT prolongation phenomenon: state of the science and evolving research questions. PMID- 23659839 TI - Parsing peak provoked craving. PMID- 23659840 TI - Will peak provoked craving prove superior to cue-reactivity? PMID- 23659841 TI - Measuring craving for cigarettes: should we measure more than just craving? PMID- 23659842 TI - Peak-provoked craving deserves a seat at the research table. PMID- 23659843 TI - Commentary on Kerr et al. (2013): The 'French Paradox' versus binge drinking. PMID- 23659844 TI - Commentary on de Vos et al. (2013): can ecological trends in HIV or HCV incidence be used to assess intervention impact? PMID- 23659845 TI - Commentary on Dawkins et al. (2013): the current legislation on nicotine causes millions of deaths--it has to change. PMID- 23659846 TI - Commentary on Gustafson et al. (2013): can we know that addiction treatment has been improved without evidence of better patient outcomes? PMID- 23659847 TI - A critique of Minozzi et al.'s pain relief and dependence systematic review. PMID- 23659848 TI - The future of drug and alcohol libraries. PMID- 23659849 TI - Managing opioid dependence treatment and controlling for HIV incidence among injecting drug users in Greece: a case study of optimism in the face of adversity. PMID- 23659850 TI - New findings in ATP supply in rod outer segments: insights for retinopathies. AB - BACKGROUND INFORMATION: The rod outer segment (OS) is the specialised organelle where phototransduction takes place. Our previous proteomic and biochemical analyses on purified rod disks showed the functional expression of the respiratory chain complexes I-IV and F1 Fo -ATP synthase in OS disks, as well as active soluble tricarboxylic acid cycle enzymes. Here, we focussed our study on the whole OS that contains the cytosol and plasma membrane and disks as native flattened saccules, unlike spherical osmotically intact disks. RESULTS: OS were purified from bovine retinas and characterised for purity. Oximetry, ATP synthesis and cytochrome c oxidase (COX) assays were performed. The presence of COX and F1F0-ATP synthase (ATP synthase) was assessed by semi-quantitative Western blotting, immunofluorescence or confocal laser scanning microscopy on whole bovine retinas and bovine retinal sections and by immunogold transmission electron microscopy (TEM) of purified OS or bovine retinal sections. Both ATP synthase and COX are catalytically active in OS. These are able to consume oxygen (O2) in the presence of pyruvate and malate. CLSM analyses showed that rhodopsin autofluorescence and MitoTracker Deep Red 633 fluorescence co-localise on rod OS. Data are confirmed by co-localisation studies of ATP synthase with Rh in rod OS by immunofluorescence and TEM in bovine retinal sections. CONCLUSIONS: Our data confirm the expression and activity of COX and ATP synthase in OS, suggestive of the presence of an extra-mitochondrial oxidative phosphorylation in rod OS, meant to supply ATP for the visual transduction. In this respect, the membrane rich OS environment would be meant to absorb both light and O2. The ability of OS to manipulate O2 may shed light on the pathogenesis of many retinal degenerative diseases ascribed to oxidative stress, as well as on the efficacy of the treatment with dietary supplements, presently utilised as supporting therapies. PMID- 23659851 TI - Immune response to a pathogen in corals. AB - The sea fan coral (Gorgonia ventalina), one of the most abundant gorgonians in the tropical and subtropical Atlantic waters, have suffered several diseases that have diminished its abundance throughout their range. In this study, we present a model that analyzes the capacity of G. ventalina to eradicate a micro-pathogen under three immune responses: strong, moderate, and very weak. The model assumes that: (1) polyps are the main unit of the coral; (2) the population of polyps is homogeneously distributed; and (3) the immune system is activated by a signal. When an endosymbiont exceeds a density threshold, it becomes pathogenic, increasing polyp mortality. As a consequence, the colony emits a signal to its stem cells to differentiate into phagocytic and humoral cells, both of which combat the pathogen. Given a strong immune response, the pathogen is rapidly eradicated by the immune cells, and the coral polyp population returns to an equilibrium state. With a moderate immune response, polyps and pathogen coexist, but the maximum capacity of polyp density is never reached. An immunologically compromised colony offering a weak immune response is unable to stop pathogen growth, and the colony dies. This analysis suggests an alternative explanation for the spatial and temporal variability in disease incidence and mortality, which is based on the strength of the immune system of hosts rather than the virulence of the pathogen. PMID- 23659852 TI - Emerging role for astroglial networks in information processing: from synapse to behavior. AB - Astrocytes contribute to neurotransmission through a variety of mechanisms ranging from synapse isolation to active signaling. Astroglial involvement in neurophysiology has been mostly investigated at the single-cell level. However, a unique feature of astrocytes is their high level of intercellular connectivity mediated by connexins, the proteins forming gap junction (GJ) channels. These astroglial GJ circuits enable the rapid intercellular exchange of ions, metabolites, and neuroactive substances. Recent findings have suggested that, despite their extensity, astroglial networks are also selective, preferential as well as plastic, and can regulate synapses, neuronal circuits, and behavior. The present review critically discusses the impact of astroglial networks on normal and pathological neuronal information processing as well as the underlying mechanisms. PMID- 23659853 TI - A longitudinal investigation of the associations among parenting, deviant peer affiliation, and externalizing behaviors: a monozygotic twin differences design. AB - Non-shared parenting and deviant peer affiliation are linked to differences in externalizing behaviors between twins. However, few studies have examined these two non-shared environments simultaneously. The present study examined the transactional roles of differential parenting (i.e., warmth and hostility) and deviant peer affiliation on monozygotic (MZ) twin differences in externalizing behaviors using a two-wave longitudinal study of twins and their parents. The sample consisted of 520 pairs of MZ twins (46.5% males, 53.5% females), with a mean age of 13.86 years (SD = 2.10) at the T1 assessment, residing in Beijing, China. The association between non-shared hostility in parenting and adolescent externalizing behaviors was mainly explained by a child-driven effect whereby the twin with a higher level of externalizing behaviors than his or her co-twin was more likely to receive more hostility from the parents. Similarly, the relationship between deviant peer affiliation and adolescent externalizing behaviors supported the selection effect whereby the twin with a higher level of externalizing behaviors than his or her co-twin was more likely to affiliate with deviant peers. The theoretical and practical implications of these findings are discussed. PMID- 23659855 TI - Design, synthesis and structure activity relationships of spirocyclic compounds as potent CCR1 antagonists. AB - A series of CCR1 antagonists based upon spirocyclic compounds 1b and 2b were synthesised in which substituted aniline moiety was replaced with substituted benzamides. In vitro data revealed that CCR1 potency could be retained in such compounds. PMID- 23659854 TI - Impact of anti-PLK1 siRNA-containing F3-targeted liposomes on the viability of both cancer and endothelial cells. AB - We have previously described the development of novel sterically stabilized F3 targeted pH-sensitive liposomes, which exhibited the ability to target both cancer and endothelial cells. Herein, the therapeutic potential of those liposomes was assessed upon encapsulation of a siRNA against a well-validated molecular target, PLK1. Treatment of prostate cancer (PC3) and angiogenic endothelial (HMEC-1) cells with F3-targeted liposomes containing anti-PLK1 siRNA resulted in a significant decrease in cell viability, which was mediated by a marked PLK1 silencing, both at the mRNA and protein levels. Furthermore, pre treatment of PC3 cells with F3-targeted liposomes containing anti-PLK1 siRNA enabled a 3-fold reduction of paclitaxel IC50 and a 2.5-fold augment of the percentage of cancer cells in G2/mitosis arrest, which ultimately culminated in cell death. Overall, the F3-targeted nanocarrier containing an anti-PLK1 siRNA might constitute a valuable system for prostate cancer treatment, either applied in a single schedule or combined with conventional chemotherapy. PMID- 23659856 TI - Phosphorylation of chloramphenicol by a recombinant protein Yhr2 from Streptomyces avermitilis MA4680. AB - Although phosphorylation of chloramphenicol has been shown to occur in the chloramphenicol producer, Streptomyces venezuelae, there are no reports on the existence of chloramphenicol phosphorylase in other Streptomyces species. In the present study, we report the modification of chloramphenicol by a recombinant protein, designated as Yhr2 (encoded by SAV_877), from Streptomyces avermitilis MA4680. Recombinant Yhr2 was expressed in Escherichia coli BL21 (DE3) and the cells expressing this recombinant protein were shown to phosphorylate chloramphenicol to a 3'-O-phosphoryl ester derivative, resulting in an inactivated form of the antibiotic. Expression of yhr2 conferred chloramphenicol resistance to E. coli cells up to 25 MUg/mL and in an in vitro reaction, adenosine triphosphate (ATP), guanosine triphosphate (GTP), adenosine diphosphate (ADP) and guanosine diphosphate (GDP) were shown to be the phosphate donors for phosphorylation of chloramphenicol. This study highlights that antibiotic resistance conferring genes could be easily expressed and functionalized in other organisms that do not produce the respective antibiotic. PMID- 23659857 TI - Synthesis and evaluation of phenoxyoxazaphospholidine, phenoxyoxazaphosphinane, and benzodioxaphosphininamine sulfides and related compounds as potential anti malarial agents. AB - A series of phenoxyoxazaphospholidine, phenoxyoxazaphosphinane and benzodioxaphosphininamine sulfides and related cyclic organophosphorus compounds based on the lead anti-tubulin herbicides amiprophos methyl and butamifos were synthesised and evaluated for anti-malarial activity. Of these compounds, while none of the phenoxyoxazaphospholidines, phenoxyoxazaphosphinanes or benzodioxaphosphininamine sulphides were more potent than APM, phosphorothioamidate 30, a dual compound also bearing an aminoquinoline motif, showed promising activity against Plasmodium falciparum (IC50 0.038 MUM) and warrants further study. PMID- 23659858 TI - Evaluation of selective inhibitors of 11beta-HSD1 for the treatment of hypertension. AB - In an effort to understand the origin of blood-pressure lowering effects observed in recent clinical trials with 11beta-HSD1 inhibitors, we examined a set of 11beta-HSD1 inhibitors in a series of relevant in vitro and in vivo assays. Select 11beta-HSD1 inhibitors reduced blood pressure in our preclinical models but most or all of the blood pressure lowering may be mediated by a 11beta-HSD1 independent pathway. PMID- 23659859 TI - Synthesis and antimycobacterial evaluation of N-substituted 5-chloropyrazine-2 carboxamides. AB - To develop new potential antimycobacterial drugs, a series of pyrazinamide derivatives was designed, synthesized and tested for their ability to inhibit the growth of selected mycobacterial strains (Mycobacterium tuberculosis H37Rv, Mycobacterium kansasii and two strains of Mycobacterium avium). This Letter is focused on binuclear pyrazinamide analogues containing the -CONH-CH2- bridge, namely on N-benzyl-5-chloropyrazine-2-carboxamides with various substituents on the phenyl ring and their comparison with some analogously substituted 5-chloro-N phenylpyrazine-2-carboxamides. Compounds from the N-benzyl series exerted lower antimycobacterial activity against M. tuberculosis H37Rv then corresponding anilides, however comparable with pyrazinamide (12.5-25 MUg/mL). Remarkably, 5 chloro-N-(4-methylbenzyl)pyrazine-2-carboxamide (8, MIC=3.13 MUg/mL) and 5-chloro N-(2-chlorobenzyl)pyrazine-2-carboxamide (1, MIC=6.25 MUg/mL) were active against M. kansasii, which is naturally unsusceptible to PZA. Basic structure-activity relationships are presented. PMID- 23659860 TI - Aromatic glycosyl disulfide derivatives: evaluation of their inhibitory activities against Trypanosoma cruzi. AB - Aromatic oligovalent glycosyl disulfides and some diglycosyl disulfides were tested against three different Trypanosoma cruzi strains. Di-(beta-D galactopyranosyl-dithiomethylene) benzenes 2b and 4b proved to be the most active derivatives against all three strains of cell culture-derived trypomastigotes with IC50 values ranging from 4 to 11 MUM at 37 degrees C. The inhibitory activities were maintained, although somewhat lowered, at a temperature of 4 degrees C as well. Three further derivatives displayed similar activities against at least one of the three strains. Low cytotoxicities of the active compounds, tested on confluent HeLa, Vero and peritoneal macrophage cell cultures, resulted in significantly higher selectivity indices (SI) than that of the reference drug benznidazole. Remarkably, several molecules of the tested panel strongly inhibited the parasite release from T. cruzi infected HeLa cell cultures suggesting an effect against the intracellular development of T. cruzi amastigotes as well. PMID- 23659861 TI - Data collection and processing tools for naturalistic study of powered two wheelers users' behaviours. AB - Instrumented vehicles are key tools for in-depth understanding of drivers' behaviours, thus for the design of scientifically based countermeasures to reduce fatalities and injuries. The instrumentation of Powered Two-Wheelers (PTW) has been less widely implemented that for vehicles, in part due to the technical challenges involved. The last decade has seen the development in Europe of several tools and methodologies to study motorcycle riders' behaviours and motorcycle dynamics for a range of situations, including crash events involving falls. Thanks to these tools, a broad-ranging research programme has been conducted, from the design and tuning of real-time falls detection to the study of riding training systems, as well as studies focusing on naturalistic riding situations such as filtering and line splitting. The methodology designed for the in-depth study of riders' behaviours in naturalistic situations can be based upon the combination of several sources of data such as: PTW sensors, context-based video retrieval system, Global Positioning System (GPS) and verbal data on the riders' decisions making process. The goals of this paper are: (1) to present the methodological tools developed and used by INRETS-MSIS (now Ifsttar-TS2/Simu) in the last decade for the study of riders' behaviours in real-world environment as well as on track for situations up to falls, (2) to illustrate the kind of results that can be gained from the conducted studies, (3) to identify the advantages and limitations of the proposed methodology to conduct large scale naturalistic riding studies, and (4) to highlight how the knowledge gained from this approach will fill many of the knowledge gaps about PTW-riders' behaviours and risk factors. PMID- 23659862 TI - Relationship between plasma copeptin levels and complications of community acquired pneumonia in preschool children. AB - High plasma copeptin level has been associated with clinical outcomes after acute illness. The present study was undertaken to investigate the plasma copeptin concentrations in preschool children with community-acquired pneumonia (CAP) and to analyze the correlations of copeptin with CAP-related complications and pleural effusion. Plasma copeptin concentrations of 100 healthy children and 165 preschool children with CAP were measured. 35 children (21.2%) presented with complicated CAP and 28 children (17.0%) presented with pleural effusion. The admission copeptin levels were significantly increased in all patients (49.7 +/- 21.4 pmol/L), children with complicated CAP (73.0 +/- 16.9 pmol/L), those with uncomplicated CAP (43.4 +/- 17.8 pmol/L), those with pleural effusion (70.9 +/- 17.4 pmol/L) and those without pleural effusion (45.3 +/- 19.5 pmol/L) compared with healthy control individuals (9.0 +/- 2.7 pmol/L, all P<0.001). Multivariate logistic regression analysis showed that plasma copeptin levels were independently related to CAP-related complications (odds ratio 1.214, 95% confidence interval 1.104-1.872, P<0.001) and pleural effusion (odds ratio 1.226, 95% confidence interval 1.109-1.917, P<0.001). A receiver operating characteristic curve analysis showed plasma copeptin level better predicted CAP related complications (area under curve 0.876, 95% confidence interval 0.815 0.922) and pleural effusion (area under curve 0.831, 95% confidence interval 0.765-0.885). Thus, plasma copeptin level may represent a novel biomarker for predicting CAP-related complications in preschool children. PMID- 23659863 TI - Plasma leptin level predicts hematoma growth and early neurological deterioration after acute intracerebral hemorrhage. AB - Higher plasma leptin levels have been associated with poor clinical outcomes after intracerebral hemorrhage. Nevertheless, their links with hematoma growth and early neurological deterioration are unknown. Therefore, we aimed to investigate the relationship between plasma leptin levels, hematoma growth, and early neurological deterioration in patients with acute intracerebral hemorrhage. We prospectively studied 102 consecutive patients with acute spontaneous basal ganglia hemorrhage presenting within 6h from symptoms onset. Significant hematoma growth was defined as hematoma enlargement >33% at 24h. Early neurological deterioration was defined as an increase of >=4 points in National Institute of Health Stroke Scale score at 24h from symptoms onset. We measured plasma leptin levels on admission using an enzyme-linked immunosorbent assay in a blinded fashion. In multivariate logistic regression analysis, plasma leptin level emerged as the independent predictor of hematoma growth (odds ratio, 1.182; 95% confidence interval, 1.061-2.598; P=0.008) and early neurological deterioration (odds ratio, 1.193; 95% confidence interval, 1.075-2.873; P=0.004). Using receiver operating characteristic curves, we calculated areas under the curve for hematoma growth (area under curve, 0.844; 95% confidence interval, 0.759-0.908) and early neurological deterioration (area under curve, 0.857; 95% confidence interval, 0.774-0.918). The predictive performance of leptin was similar to, but did not obviously improve that of hematoma volume. Thus, leptin may help in the prediction of hematoma growth and early neurological deterioration after intracerebral hemorrhage. PMID- 23659864 TI - Is oxytocin a therapeutic factor for ischemic heart disease? AB - Ischemic heart disease (IHD) is among the most important and top ranked causes of death in the world, and its preventive and interventional mechanisms are actively being investigated. Preconditioning may still be beneficial in some situations such as IHD. Development of cardioprotective agents to improve myocardial function, to decrease the incidence of arrhythmias, to delay the onset of necrosis, and to limit the total extent of infarction during IHD is of great clinical importance. In order to reduce morbidity, a new treatment modality must be developed, and oxytocin may indeed be one of the candidates. There is increasing experimental evidence indicating that oxytocin may have cardioprotective effects either by decreasing the extent of reperfusion injury or by pharmacologic preconditioning activity. This review shows that in the presence of oxytocin, the cardioprotective effects may be increased to some extent. The presented board of evidence focuses on the valuable effects of oxytocin on myocardial function and candidates it for future clinical studies in the realm of ischemic heart diseases. PMID- 23659865 TI - Driving avoidance by older adults: is it always self-regulation? AB - Self-regulation shows promise as a means by which older adults can continue to drive at some level without having to stop altogether. Self-regulation is generally described as the process of modifying or adjusting one's driving patterns by driving less or intentionally avoiding driving situations considered to be challenging, typically in response to an awareness that driving skills have declined. However, most studies asking older adults whether they avoid certain driving situations or have reduced the amount of driving they do under certain circumstances have not delved deeper into the motivations for such avoidance or driving reduction. There are many reasons for modifying driving that have nothing to do with self-regulation, such as no longer needing to take trips at certain times of day because of changes in preferences or lifestyles. The purpose of this study was to examine self-regulatory practices among older adults at multiple levels of driver performance and decision making, taking into account the specific motivations for avoiding particular driving situations or engaging in other driving practices. Study participants completed a computer-based questionnaire on driving self-regulation. Results suggest that self-regulation is a complex process that cannot be defined simply by the reported driving modifications made by drivers. Understanding the motivations for these behaviors is necessary and the study showed that they are varied and differ considerably across driving situations. Reasons for driving avoidance or other practices were often more closely related to lifestyle or preferences than to self-regulation. Based on these findings, three distinct groups were identified with regard to whether and for what reasons participants modified their driving. PMID- 23659866 TI - An innovative bioremediation strategy using a bacterial consortium entrapped in chitosan beads. AB - This aim of this work was to develop a bioremediation strategy for oil contaminated mangrove sediments using chitosan beads containing an immobilised hydrocarbonoclastic bacterial consortium. The consortium composed of 17 isolates was obtained from an enrichment culture. The isolates were identified by 16S rDNA sequencing, which revealed 12 different genera. Thirteen isolates showed resistance to chitosan and were thus able to be trapped in chitosan beads for microcosm evaluation. The data revealed that entrapped consortium grew in the microcosms until day 15, which is when the beads disintegrated and released their biomass into the sediments. Bacterial bioaugmentation within the sediments was confirmed by cell counts; additionally, the dynamics of the bacterial populations were analysed through denaturing gradient gel electrophoresis. The chitosan showed a prebiotic effect on the autochthonous bacterial communities. Therefore, chitosan beads containing selected immobilised bacteria attain two bioremediation purposes, bioaugmentation and biostimulation, and thus represent an emergent approach. PMID- 23659867 TI - Internet access and use in adults with hearing loss. AB - BACKGROUND: The future rehabilitation of adults with hearing loss is likely to involve online tools used by individuals at home. Online tools could also be useful for people who are not seeking professional help for their hearing problems. Hearing impairment is a disability that increases with age, and increased age is still associated with reduced use of the Internet. Therefore, to continue the research on online audiological rehabilitative tools for people with hearing loss, it is important to determine if and to what extent adults with hearing loss use the Internet. OBJECTIVE: To evaluate the use of the Internet and email in a group of adults with hearing loss and to investigate if their use of Internet and email differed between genders, among different age groups, and how it compared with the general population in Sweden. METHODS: Questionnaires containing multiple-choice questions about Internet access, email use, and educational level were mailed to individuals with hearing loss, who were registered as patients at a hearing aid clinic. Out of the 269 invited participants, 158 returned a completed questionnaire, which was a response rate of 58.7%. RESULTS: The results showed that 60% (94/158) of the participants with hearing loss used computers and the Internet. The degree of hearing loss in the group of participants did not explain the level of Internet usage, while factors of age, gender, and education did (P<.001). More men than women used the Internet (OR 2.54, 95% CI 1.32-4.91, P<.001). Use of the Internet was higher in the youngest age group (25-64 years) compared to the oldest age group (75-96 years, P=.001). A higher usage of the Internet was observed in the participants with hearing loss, especially the elderly, when compared with the general population of Sweden (OR 1.74, 95% CI 1.23-3.17, P=.04). CONCLUSIONS: We conclude that the use of computers and the Internet overall is at least at the same level for people with hearing loss as for the general age-matched population in Sweden, but that this use is even higher in specific age groups. These results are important for the future work in developing and evaluating rehabilitative educational online tools for adults with hearing loss. PMID- 23659868 TI - Severe orthopnea is not always due to heart failure: a case of bilateral diaphragm paralysis. PMID- 23659869 TI - Innate receptors for adaptive immunity. AB - Pattern recognition receptors (PRRs) are commonly known as sensor proteins crucial for the early detection of microbial or host-derived stress signals by innate immune cells. Interestingly, some PRRs are also expressed and functional in cells of the adaptive immune system. These receptors provide lymphocytes with innate sensing abilities; for example, B cells express Toll-like receptors, which are important for the humoral response. Strikingly, certain other NOD-like receptors are not only highly expressed in adaptive immune cells, but also exert functions related specifically to adaptive immune system pathways, such as regulating antigen presentation. In this review, we will focus particularly on the current understanding of PRR functions intrinsic to B and T lymphocytes; a developing aspect of PRR biology. PMID- 23659870 TI - Common variants in and near IRS1 and subclinical cardiovascular disease in the Framingham Heart Study. AB - OBJECTIVE: Common variants at the 2q36.3-IRS1 locus are associated with insulin resistance (IR), type 2 diabetes (T2D) and coronary artery disease (CAD) in large scale association studies. We tested the hypothesis that variants at this locus are associated with subclinical atherosclerosis traits. METHODS: We studied 2740 Framingham Heart Study participants (54.9% women; mean age 57.8 years) with measures of coronary artery or abdominal aortic calcium, internal and common carotid intima-media thickness, and ankle-brachial index (ABI). We tested 1) four SNPs previously shown to be associated with IR (rs2972146, rs2943650), T2D (rs2943641) or CAD (rs2943634) and 2) any SNP at 2q36.3-IRS1, for association with subclinical atherosclerosis traits, adjusting for atherosclerosis risk factors. We set type 1 error rate for test 1) as 0.05/5 traits = P < 0.01, and for test 2) as 0.05 divided by the effective number of independent tests, divided by 5 for the number of traits analyzed. RESULTS: We found no association between the four known SNPs and subclinical atherosclerosis, but identified one SNP (rs10167219, r(2) with rs2943634 = 0.07) at 2q36.3 that was significantly associated with ABI (corrected P = 0.009). However, rs10167219 was not associated with ABI (P = 0.70) in 35,404 participants in a published ABI association study. CONCLUSION: Common variants at the 2q36.3-IRS1 locus were not associated with subclinical atherosclerosis traits in this study which was adequately powered to find associations with moderate effect size. Although IR and T2D may be mechanistically linked to CAD via subclinical atherosclerosis, an alternate mechanism for the IR-T2D-CAD associations at 2q36.3-IRS1 must be postulated. PMID- 23659871 TI - Hypertension in pregnancy is a risk factor for peripheral arterial disease decades after pregnancy. AB - BACKGROUND: An ankle-brachial index (ABI) (the ratio of ankle to brachial artery systolic blood pressure) value <=0.9 identifies patients with peripheral arterial disease (PAD) and elevated cardiovascular event risk. This study examined whether women with a history of hypertension in pregnancy are more likely to have an ABI <=0.9 decades after pregnancy. METHODS AND RESULTS: ABI was measured in nulliparous women (n = 144), and women with a history of normotensive (n = 1272) or hypertensive (n = 281) pregnancies who participated in the Genetic Epidemiology Network of Arteriopathy (GENOA) study [non-Hispanic white (39%) and black (61%) women, 60 (mean) +/- 10 (SD) years of age]. Relationships between PAD and pregnancy history were examined by logistic regression. Compared to women with a history of normotensive pregnancy, women with a history of hypertensive pregnancy had greater odds of PAD (1.61 (odds ratio); 1.04-2.49 (95% confidence interval), p = 0.03, adjusted for age, race, height and heart rate). Additional adjustment for ever smoking, hypertension, diabetes, dyslipidemia, a family history of hypertension or coronary heart disease, body mass index and education did not attenuate this relationship (1.63; 1.02-2.62, p = 0.04). PAD risk did not differ between women with a history of normotensive pregnancy and nulliparous women (1.06; 0.52-2.14, p = 0.87). CONCLUSIONS: Hypertension in pregnancy is an independent risk factor for PAD decades after pregnancy after adjusting for race, age, height, heart rate, ever smoking, hypertension, diabetes, dyslipidemia, a family history of hypertension or coronary heart disease, body mass index and education. PMID- 23659872 TI - A novel lamin A/C mutation in a Dutch family with premature atherosclerosis. AB - OBJECTIVE: We report a novel lamin A/C (LMNA) mutation, p.Glu223Lys, in a family with extensive atherosclerosis, diabetes mellitus and steatosis hepatis. METHODS: Sequence analysis of LMNA (using Alamut version 2.2), co-segregation analysis, electron microscopy, extensive phenotypic evaluation of the mutation carriers and literature comparison were used to determine the loss of function of this mutation. RESULTS: The father of three siblings died at the age of 45 years. The three siblings and the brother and sister of the father were referred to the cardiovascular genetics department, because of the premature atherosclerosis and dysmorphic characteristics observed in the father at autopsy. The novel LMNA mutation, p.Glu223Lys, was identified in the proband and his two sons. Clinical evaluation revealed atherosclerosis, insulin resistance and hypertension in the proband and dyslipidemia and hepatic steatosis in all the patients with the mutation. CONCLUSION: Based on the facts that in silico analysis predicts a possibly pathogenic mutation, the mutation co-segregates with the disease, only fibroblasts from mutation carriers show nuclear blebbing and a similar phenotype was reported to be due to missense mutations in LMNA we conclude that we deal with a pathogenic mutation. We conclude that the phenotype is similar to Dunnigan type familial partial lipodystrophy. PMID- 23659874 TI - Imaging of contact acoustic nonlinearity using synthetic aperture technique. AB - The angle beam incidence and reflection technique for the evaluation of contact acoustic nonlinearity (CAN) at solid-solid contact interfaces (e.g., closed cracks) has recently been developed to overcome the disadvantage of accessing both the inner and outer surfaces of structures for attaching pulsing and receiving transducers in the through-transmission of normal incidence technique. This paper proposes a technique for B-mode imaging of CAN based on the above reflection technique, which uses the synthetic aperture focusing technique (SAFT) and short-time Fourier transform (STFT) to visualize the distribution of the CAN induced second harmonic magnitude as well as the nonlinear parameter. In order to verify the usefulness of the proposed method, a solid-solid contact interface was tested and the change of the contact acoustic nonlinearity according to the increasing contact pressure was visualized in images of the second harmonic magnitude and the relative nonlinear parameter. The experimental results showed good agreement with the previously developed theory identifying the dependence of the scattered second harmonics on the contact pressure. This technique can be used for the detection and improvement of the sizing accuracy of closed cracks that are difficult to detect using the conventional linear ultrasonic technique. PMID- 23659873 TI - Discordance: can we capitalize on it to better personalize atherosclerosis treatment? PMID- 23659875 TI - On the coupling of resonance and Bragg scattering effects in three-dimensional locally resonant sonic materials. AB - Three-dimensional (3D) locally resonant sonic materials (LRSMs) are studied theoretically for purpose of optimising their sub-wavelength performance by coupling resonance and Bragg scattering effects together. Through the study of effective sound speeds of LRSMs, we find that the starting frequency of Bragg scattering can be shifted to sub-wavelength region by softening coats of resonators when the matrix is a low shear-velocity medium. A similar result can be achieved by compressing the lattice constant. By using a layer-multiple scattering method, we investigate the complex band structure and the transmission spectrum of an LRSM whose Bragg gap is already close to the resonance gap in frequency. The wave fields of the composite simulated by COMSOL are further analysed at several typical frequencies. The result shows that the approaching of two kinds of gaps not only broadens the bandwidth of the resonance gap, but also increases the depth of the Bragg gap since the interaction between resonant modes and scattering waves are enhanced. By varying the shear velocity of coats, we obtain a coupled gap, which exhibits a broad transmission gap in the sub wavelength region. When the loss of coats is considered, the coupled gap can not only maintain a good sound blocking performance, but also perform an efficient absorption in the low frequency region. PMID- 23659876 TI - Correlation of ultrasound contrast agent derived blood flow parameters with immunohistochemical angiogenesis markers in murine xenograft tumor models. AB - PURPOSE: In this study we used temporal analysis of ultrasound contrast agent (UCA) estimate blood flow dynamics and demonstrate their improved correlation to angiogenesis markers relative to previously reported, non-temporal fractional vascularity estimates. MATERIALS AND METHODS: Breast tumor (NMU) or glioma (C6) cells were implanted in either the abdomen or thigh of 144 rats. After 6, 8 or 10 days, rats received a bolus UCA injection of Optison (GE Healthcare, Princeton, NJ; 0.4 ml/kg) during power Doppler imaging (PDI), harmonic imaging (HI), and microflow imaging (MFI) using an Aplio ultrasound scanner with 7.5 MHz linear array (Toshiba America Medical Systems, Tustin, CA). Time-intensity curves of contrast wash-in were constructed on a pixel-by-pixel basis and averaged to calculate maximum intensity, time to peak, perfusion, and time integrated intensity (TII). Tumors were then stained for four immunohistochemical markers (bFGF, CD31, COX-2, and VEGF). Correlations between temporal parameters and the angiogenesis markers were investigated for each imaging mode. Effects of tumor model and implant location on these correlations were also investigated. RESULTS: Significant correlation over the entire dataset was only observed between TII and VEGF for all three imaging modes (R=-0.35, -0.54, -0.32 for PDI, HI and MFI, respectively; p<0.0001). Tumor type and location affected these correlations, with the strongest correlation of TII to VEGF found to be with implanted C6 cells (R=-0.43, -0.54, -0.52 for PDI, HI and MFI, respectively; p<0.0002). CONCLUSIONS: While UCA-derived temporal blood flow parameters were found to correlate strongly with VEGF expression, these correlations were also found to be influenced by both tumor type and implant location. PMID- 23659877 TI - Early detection of prostate cancer: AUA Guideline. AB - PURPOSE: The guideline purpose is to provide the urologist with a framework for the early detection of prostate cancer in asymptomatic average risk men. MATERIALS AND METHODS: A systematic review was conducted and summarized evidence derived from over 300 studies that addressed the predefined outcomes of interest (prostate cancer incidence/mortality, quality of life, diagnostic accuracy and harms of testing). In addition to the quality of evidence, the panel considered values and preferences expressed in a clinical setting (patient-physician dyad) rather than having a public health perspective. Guideline statements were organized by age group in years (age <40; 40 to 54; 55 to 69; >= 70). RESULTS: Except prostate specific antigen-based prostate cancer screening, there was minimal evidence to assess the outcomes of interest for other tests. The quality of evidence for the benefits of screening was moderate, and evidence for harm was high for men age 55 to 69 years. For men outside this age range, evidence was lacking for benefit, but the harms of screening, including over diagnosis and overtreatment, remained. Modeled data suggested that a screening interval of two years or more may be preferred to reduce the harms of screening. CONCLUSIONS: The Panel recommended shared decision-making for men age 55 to 69 years considering PSA-based screening, a target age group for whom benefits may outweigh harms. Outside this age range, PSA-based screening as a routine could not be recommended based on the available evidence. PMID- 23659878 TI - Massive left atrial calcification, tracheobronchopathia osteoplastica and mitral paravalvular leak associated with cardiac rheumatic disease and previous mitral valve replacement. PMID- 23659879 TI - Unusual papillary muscle rupture occurring over two weeks after myocardial infarction associated with late reperfusion of infarct-related artery. PMID- 23659880 TI - Resistant hypertension: multivariate predictors of blood pressure response to renal denervation. PMID- 23659881 TI - Baseline hypertension: new insight into the potential predictors of survival in patients with hepatocellular carcinoma. PMID- 23659882 TI - National trends in case fatality based on anatomical location of ST elevation myocardial infarction, 1993 - 2010. PMID- 23659883 TI - Non-invasive mechanical ventilation for sleep disordered breathing and cardiac function in chronic heart failure. More CPAP or more ASV? That is the question. PMID- 23659884 TI - Erdheim-Chester disease with cardiac involvement successfully treated with anakinra. PMID- 23659885 TI - No surprising forward jump when deploying a self-expandable stent: two cases exploiting the combination of Emboshield Nav6 BareWire and Stentys devices. PMID- 23659886 TI - A primary pericardial liposarcoma mimicking intracardiac neoplasm on echocardiography: role of computed tomography and magnetic resonance imaging in the differential diagnosis. PMID- 23659887 TI - Why South Africa's proposed advertising ban matters. PMID- 23659888 TI - Genotoxicity assessment of beta-caryophyllene oxide. AB - beta-caryophyllene oxide is a biciclic sesquiterpene, occurring naturally in essential oils from various medicinal and edible plants and used as a flavouring agent. Due to its potential hazardous chemical structure, the European Food Safety Authority reported to be pending a safety assessment for this compound. Here, this flavouring agent was tested for its mutagenic effect in the Ames test and micronucleus assay. Furthermore, considering that the penetration of a substance through phospholipid bilayers is determinant for its activity, the ability of beta-caryophyllene oxide to be absorbed into cells was evaluated by differential scanning calorimetry (DSC) using multilamellar vesicles of dimyristoylphosphatidylcholine as a biomembrane model. beta-caryophyllene oxide was found to be devoid of mutagenic effect, both at gene level (frameshift or base-substitution mutations), and on chromosome (clastogenicity and aneuploidogenicity). Results of DSC analysis highlighted that the substance was strongly absorbed through the membrane bilayer. Present results show that beta caryophyllene oxide, although absorbed through cell membranes and in spite of its potentially reactive chemical structure, is devoid of genotoxic effects, inducing neither point mutations nor chromosomal damages. These negative genotoxic findings will be critical to the safety assessment of beta-caryophyllene oxide as used as a flavouring/fragrance ingredient. PMID- 23659889 TI - Scientific reasoning in early and middle childhood: the development of domain general evidence evaluation, experimentation, and hypothesis generation skills. AB - According to Klahr's (2000, 2005; Klahr & Dunbar, 1988) Scientific Discovery as Dual Search model, inquiry processes require three cognitive components: hypothesis generation, experimentation, and evidence evaluation. The aim of the present study was to investigate (a) when the ability to evaluate perfect covariation, imperfect covariation, and non-covariation evidence emerges, (b) when experimentation emerges, (c) when hypothesis generation skills emerge, and (d), whether these abilities develop synchronously during childhood. We administered three scientific reasoning tasks referring to the three components to 223 children of five age groups (from age 4.0 to 13.5 years). Our results show that the three cognitive components of domain-general scientific reasoning emerge asynchronously. The development of domain-general scientific reasoning begins with the ability to handle unambiguous data, progresses to the interpretation of ambiguous data, and leads to a flexible adaptation of hypotheses according to the sufficiency of evidence. When children understand the relation between the level of ambiguity of evidence and the level of confidence in hypotheses, the ability to differentiate conclusive from inconclusive experiments accompanies this development. Implications of these results for designing science education concepts for young children are briefly discussed. PMID- 23659890 TI - Preschoolers' social information processing and early school success: the challenging situations task. AB - As part of a larger longitudinal project on the assessment of preschoolers' social-emotional development, children's social information processing (SIP) responses to unambiguous hypothetical situations of peer provocation were assessed for 298 four-year-olds from Head Start and private childcare settings. Measurement focused on emotions children would feel during these situations, and their behaviour response decisions. Participants most often chose sad and angry emotions, and socially competent and passive behaviours. Relations were found between sad emotion and socially competent behaviour choices, as well as between angry emotion and aggressive behaviour choices. Sad emotion and socially competent behaviour responses contributed to variance in contemporaneous and later school adjustment and kindergarten academic readiness. There was evidence that the contributions of sad emotion responses were mediated by those of socially competent behaviour choices. Results bolstered calls to include emotion in SIP measures, supported predictive validity for this SIP measure in a large representative sample of preschoolers, and pointed to fruitful pathways for future research. PMID- 23659891 TI - Revealing children's implicit spelling representations. AB - Conceptualizing the underlying representations and cognitive mechanisms of children's spelling development is a key challenge for literacy researchers. Using the Representational Redescription model (Karmiloff-Smith), Critten, Pine and Steffler (2007) demonstrated that the acquisition of phonological and morphological knowledge may be underpinned by increasingly explicit levels of spelling representation. However, their proposal that implicit representations may underlie early 'visually based' spelling remains unresolved. Children (N = 101, aged 4-6 years) were given a recognition task (Critten et al., 2007) and a novel production task, both involving verbal justifications of why spellings are correct/incorrect, strategy use and word pattern similarity. Results for both tasks supported an implicit level of spelling characterized by the ability to correctly recognize/produce words but the inability to explain operational strategies or generalize knowledge. Explicit levels and multiple representations were also in evidence across the two tasks. Implications for cognitive mechanisms underlying spelling development are discussed. PMID- 23659892 TI - Head and eye movements affect object processing in 4-month-old infants more than an artificial orientation cue. AB - This study investigates the effects of attention-guiding stimuli on 4-month-old infants' object processing. In the human head condition, infants saw a person turning her head and eye gaze towards or away from objects. When presented with the objects again, infants showed increased attention in terms of longer looking time measured by eye tracking and an increased Nc amplitude measured by event related potentials (ERP) for the previously uncued objects versus the cued objects. This suggests that the uncued objects were previously processed less effectively and appeared more novel to the infants. In a second condition, a car instead of a human head turned towards or away from objects. Eye-tracking results did not reveal any significant difference in infants' looking time. ERPs indicated only a marginally significant effect in late slow-wave activity associated with memory encoding for the uncued objects. We conclude that human head orientation and gaze direction affect infants' object-directed attention, whereas movement and orientation of a car have only limited influence on infants' object processing. PMID- 23659893 TI - The Kids' Empathic Development Scale (KEDS): a multi-dimensional measure of empathy in primary school-aged children. AB - Empathy is an essential building block for successful interpersonal relationships. Atypical empathic development is implicated in a range of developmental psychopathologies. However, assessment of empathy in children is constrained by a lack of suitable measurement instruments. This article outlines the development of the Kids' Empathic Development Scale (KEDS) designed to assess some of the core affective, cognitive and behavioural components of empathy concurrently. The KEDS assesses responses to picture scenarios depicting a range of individual and interpersonal situations differing in social complexity. Results from 220 children indicate the KEDS measures three related but distinct aspects of empathy that are also related to existing measures of empathy and cognitive development. Scores on the KEDS show age and some gender-related differences in the expected direction. PMID- 23659894 TI - Attention in Williams syndrome and Down's syndrome: performance on the new early childhood attention battery. AB - Attentional problems are commonly reported as a feature of the behavioural profile in both Williams syndrome (WS) and Down's syndrome (DS). Recent studies have begun to investigate these impairments empirically, acknowledging the need for an approach that considers cross-syndrome comparisons and developmental changes across the different component functions of attention. The present study assessed children with WS and DS using a new preschool attention battery (ECAB: early childhood attention battery), designed to be suitable for mental age 3-6 years including groups with developmental disorders. The ECAB has the advantage of giving an individual profile of attentional abilities for each child, covering different components of attention. In relation to test norms for their mental age, both groups showed a profile of strengths and weaknesses in the attention domain. Both syndrome groups performed relatively well on tests of sustained attention and poorly on aspects of selective attention and attentional control (executive function). The DS group showed a specific strength in auditory sustained attention, whilst the WS group showed a particular deficit in visuo spatial response control. There was also evidence for considerable differences in the developmental trajectory of these abilities across the two groups. The results provide evidence for syndrome-specific patterns of impairment, and distinct profiles of strengths and weaknesses that may be useful in understanding the nature of everyday attention difficulties in these groups and tailoring interventions to meet these needs. PMID- 23659895 TI - Neuronal morphology in MeCP2 mouse models is intrinsically variable and depends on age, cell type, and Mecp2 mutation. AB - Rett Syndrome (RTT), a progressive neurological disorder characterized by developmental regression and loss of motor and language skills, is caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MECP2). Neurostructural phenotypes including decreased neuronal size, dendritic complexity, and spine density have been reported in postmortem RTT brain tissue and in Mecp2 animal models. How these changes in neuronal morphology are related to RTT-like phenotype and MeCP2 function, and the extent to which restoration of neuronal morphology can be used as a cellular readout in therapeutic studies, however, remain unclear. Here, we systematically examined neuronal morphology in vivo across three Mecp2 mouse models representing Mecp2 loss-of-function, partial loss-of-function, and gain-of-function mutations, at developmental time points corresponding to early- and late-symptomatic RTT-like behavioral phenotypes. We found that in Mecp2 loss-of-function mouse models, dendritic complexity is reduced in a mild, age-dependent, and brain region-specific manner, whereas soma size is reduced consistently throughout development. Neither phenotype, however, is altered in Mecp2 gain-of-function mice. Our results suggest that, in the cell types we examined, the use of dendritic morphology as a cellular readout of RTT phenotype and therapeutic efficacy should be cautioned, as it is intrinsically variable. In contrast, soma size may be a robust and reliable marker for evaluation of MeCP2 function in Mecp2 loss-of-function studies. PMID- 23659898 TI - Hospitalization in adolescence and young adulthood among twins and singletons: a Swedish cohort study of subjects born between 1973 and 1983. AB - Children born with non-optimal birth characteristics - that is, are small for gestational age and/or preterm - have an increased risk for several long-term effects such as neurological sequelae and chronic disease. The purpose of this study was to examine whether twins exhibited a different outcome, compared with singletons, in terms of hospitalization during adolescence and early adulthood, and to what extent differences remain when considering the divergence in birth characteristics between singletons and twins. Persons born between 1973 and 1983 in Sweden and surviving until age 13 were included and followed until the end of 2006. Data on birth characteristics, parental socio-demographic factors, and hospitalizations were collected from national registers. Adjusting for parental socio-demographic factors, twins had a higher risk of being hospitalized than singletons (odds ratio, OR = 1.17, 95% confidence interval, CI = 1.10-1.25) and more often due to 'Congenital anomalies' (OR = 1.18, 95% CI = 1.06-1.28), 'Infections' (OR = 1.14; 95% CI = 1.08-1.20), 'External causes of illness' (OR = 1.10, 95% CI = 1.06-1.15), and 'Diseases of the nervous system' (OR = 1.18, 95% CI = 1.10-1.26). Stratifying for birth characteristics, this difference diminishes, and for some diagnoses non-optimal twins seem to do slightly better than non-optimal singletons. Thus, twins with non-optimal birth characteristics had a lower risk of hospitalization than non-optimal singletons on, for example, 'Congenital anomalies' and 'Diseases of the nervous system' (OR = 0.86, 95% CI = 0.77-0.96; OR = 0.88, 95% CI = 0.81-0.97, respectively) and Total (any) hospitalization (OR = 0.87, 95% CI = 0.83-0.92). Among those with optimal birth characteristics, twins had an increased hospitalization due to 'External causes of illness' (OR = 1.07, 95% CI = 1.02-1.13) compared with optimal singletons. Twins have higher hospitalization rates than singletons. In stratifying for birth characteristics, this difference diminishes, and for some diagnoses, non-optimal twins seem to do less poorly than non-optimal singletons. PMID- 23659896 TI - Restoring endoplasmic reticulum homeostasis improves functional recovery after spinal cord injury. AB - The endoplasmic reticulum (ER) stress response (ERSR) is activated to maintain protein homeostasis or induce apoptosis in the ER in response to distinct cellular insults including hypoxia, inflammation, and oxidative damage. Recently, we showed ERSR activation in a mouse model of a contusive spinal cord injury (SCI) and an improved hindlimb locomotor function following SCI when the pro apoptotic arm of ERSR was genetically inhibited. The objective of the current study was to explore if the pharmacological enhancement of the homeostatic arm of the ERSR pathway can improve the functional outcome after SCI. Salubrinal enhances the homeostatic arm of the ERSR by increasing phosphorylation of eIF2alpha. Salubrinal significantly enhanced the levels of phosphorylated eIF2alpha protein and modulated the downstream ERSR effectors assessed at the lesion epicenter 6h post-SCI. Hindlimb locomotion showed significant improvement in animals treated with salubrinal. Treadmill-based-gait assessment showed a significant increase in maximum speed of coordinated walking and a decrease in rear stance time and stride length in salubrinal-treated animals. This improved functional recovery corresponded with increased white matter sparing and decreased oligodendrocyte apoptosis. In addition, salubrinal protected cultured mouse oligodendrocyte progenitor cells against the ER stress-inducing toxin tunicamycin. These data suggest that boosting the homeostatic arm of the ERSR reduces oligodendrocyte loss after traumatic SCI and support the contention that pharmacological targeting of the ERSR after CNS trauma is a therapeutically viable approach. PMID- 23659897 TI - Ataxin-3 protein modification as a treatment strategy for spinocerebellar ataxia type 3: removal of the CAG containing exon. AB - Spinocerebellar ataxia type 3 is caused by a polyglutamine expansion in the ataxin-3 protein, resulting in gain of toxic function of the mutant protein. The expanded glutamine stretch in the protein is the result of a CAG triplet repeat expansion in the penultimate exon of the ATXN3 gene. Several gene silencing approaches to reduce mutant ataxin-3 toxicity in this disease aim to lower ataxin 3 protein levels, but since this protein is involved in deubiquitination and proteasomal protein degradation, its long-term silencing might not be desirable. Here, we propose a novel protein modification approach to reduce mutant ataxin-3 toxicity by removing the toxic polyglutamine repeat from the ataxin-3 protein through antisense oligonucleotide-mediated exon skipping while maintaining important wild type functions of the protein. In vitro studies showed that exon skipping did not negatively impact the ubiquitin binding capacity of ataxin-3. Our in vivo studies showed no toxic properties of the novel truncated ataxin-3 protein. These results suggest that exon skipping may be a novel therapeutic approach to reduce polyglutamine-induced toxicity in spinocerebellar ataxia type 3. PMID- 23659899 TI - Psychiatric disorders and pain treatment in community nursing homes. AB - OBJECTIVE: Effective pain assessment and pain treatment are key goals in community nursing homes, but residents' psychiatric disorders may interfere with attaining these goals. This study addressed whether (1) pain assessment and treatment obtained by nursing home residents with psychiatric disorders differs from that obtained by residents without psychiatric disorders; (2) this difference is found consistently across the four types of psychiatric disorder most prevalent in nursing homes (dementia, depression, serious mental illness, and substance use disorder); and (3) male gender, non-white, and longer length of stay add to psychiatric disorders to elevate risk of potentially adverse pain ratings and pain treatments. METHODS: In this cross-sectional study, we examined relationships among National Nursing Home Survey 2004 residents' demographic, diagnostic, pain, and pain treatment characteristics. RESULTS: Compared with residents without psychiatric disorders, those with psychiatric disorders were less likely to be rated as having pain in the last 7 days and had lower and more "missing" or "don't know" pain severity ratings. They also were less likely to obtain opioids and more likely to be given only nonopioid pain medications, even after statistically adjusting for demographic factors, physical functioning, and pain severity. These effects generally held across all four types of psychiatric disorders most prevalent in nursing homes and were compounded by male, non-white, and longer-stay status. CONCLUSION: Psychiatric disorders besides dementia may impact pain assessment and treatment in nursing homes. Nursing home residents with psychiatric disorders, especially male, non-white, and longer-stay residents, should be targeted for improved pain care. PMID- 23659901 TI - Histological and histochemical alterations in liver of chronic hepatitis C patients with Helicobacter pylori infection. AB - Hepatitis C is an infectious disease affecting the liver. Chronic infection can progress fibrosis and cirrhosis, liver failure or liver cancer. Helicobacter pylori (H. pylori) is a spiral bacterium infects the stomach of more than 50% of the human population worldwide. H. pylori DNA has been identified in human livers and has been implicated in chronic liver disease and liver cancer. The present work was aimed to study the histological and histochemical alterations in liver of HCV patients with or without H. pylori infection. Immunohistochemical detection of H. pylori showed positive reactivity in 62 biopsies out of 100 biopsies (38% HCV patients and 62% HCV patients coinfected with H. pylori). Histological examination of liver of HCV patients showed microvesicular and macrovesicular steatosis, lymphocytic infiltrations, fibrosis and cirrhosis. Cirrhotic nodules and impairment of hepatic parenchyma were common in HCV patients coinfected with H. pylori. HCV patients coinfected with H. pylori recorded higher NIC score and pronounced fibrosis stages than HCV patients. Glycogen and total proteins decreased in hepatocytes and cirrhotic nodules in HCV patients. Such decrease was marked in liver of HCV patients coinfected with H. pylori. So it is recommended to perform a complete analysis for H. pylori in HCV patients suggesting that it will help in therapy of this disease. PMID- 23659900 TI - Does preoperative risk for delirium moderate the effects of postoperative pain and opiate use on postoperative delirium? AB - OBJECTIVES: To investigate whether preoperative risk for delirium moderates the effect of postoperative pain and opioids on the development of postoperative delirium. DESIGN: Prospective cohort study. SETTING: University medical center. PARTICIPANTS: Patients 65 years of age or older scheduled for major noncardiac surgery. MEASUREMENTS: A structured interview was conducted preoperatively and postoperatively to determine the presence of delirium, defined using the Confusion Assessment Method. We first developed a prediction model to determine which patients were at high versus low risk for the development of delirium based on preoperative patient data. We then computed a logistic regression model to determine whether preoperative risk for delirium moderates the effect of postoperative pain and opioids on incident delirium. RESULTS: Of 581 patients, 40% developed delirium on days 1 or 2 after surgery. Independent preoperative predictors of postoperative delirium included lower cognitive status, a history of central nervous system disease, high surgical risk, and major spine and joint arthroplasty surgery. Compared with the patients at low preoperative risk for developing delirium, the relative risk for postoperative delirium for those in the high preoperative risk group was 2.38 (95% confidence interval: 1.67-3.40). A significant three-way interaction indicates that preoperative risk for delirium significantly moderated the effect of postoperative pain and opioid use on the development of delirium. Among patients at high preoperative risk for development of delirium who also had high postoperative pain and received high opioid doses, the incidence of delirium was 72%, compared with 20% among patients with low preoperative risk, low postoperative pain, and those who received low opioid doses. CONCLUSIONS: High levels of postoperative pain and using high opioid doses increased risk for postoperative delirium for all patients. The highest incidence of delirium was among patients who had high preoperative risk for delirium and also had high postoperative pain and used high opioid doses. PMID- 23659902 TI - Age differences in the control of postural stability during reaching tasks. AB - Reaching tasks are commonly performed during daily activities and require anticipatory postural adjustments (APAs) to ensure a stable posture during movement execution. Age-related changes in APAs may impact dynamic balance and cause postural instability during reaching tasks made from standing. The present study examined age differences in postural control during reaching to targets located at different heights. Fourteen young adults (aged 20.0+/-1.5 yrs) and 16 community-dwelling older adults (aged 73.4+/-5.3 yrs) participated in the study. The task involved reaching forward to grasp a cylinder, and returning to an upright position as fast and accurately as possible. Postural control was analyzed using the center of pressure (COP) during four phases of the task: COP displacement during APA production, COP trajectory smoothness during the reach and return phases, and COP path length during the recovery phase following movement. APA amplitude measured by COP displacement and COP path length during the recovery phase was larger in older compared to young adults. Dynamic balance represented by COP trajectory smoothness was reduced with age. In both age groups, APA amplitude was largest and COP trajectory smoothness the least during low target reaches. The results demonstrate that, while older adults can alter APAs in order to maintain postural stability, control of COP during movement execution, particularly during low target reaches, is compromised with aging. These findings have clinical implications for both the assessment of dynamic balance and the development of balance training programs. PMID- 23659904 TI - Physiologic time: a hypothesis. AB - The scaling of respiratory metabolism with body size in animals is considered by many to be a fundamental law of nature. One apparent consequence of this law is the scaling of physiologic time with body size, implying that physiologic time is separate and distinct from clock time. Physiologic time is manifest in allometry relations for lifespans, cardiac cycles, blood volume circulation, respiratory cycle, along with a number of other physiologic phenomena. Herein we present a theory of physiologic time that explains the allometry relation between time and total body mass averages as entailed by the hypothesis that the fluctuations in the total body mass are described by a scaling probability density. PMID- 23659905 TI - Unformed minds: juveniles, neuroscience, and the law. AB - Recently, the question of adolescent culpability has been brought before the Supreme Court of the United States for reconsideration. Neuroscience, adolescent advocates claim, is teaching us that young people cannot be found fully responsible for their actions. The reason: their brains are not fully formed. Here I consider the history of the use of scientific evidence in the courtroom, a number of adolescent murder cases, and the data now emerging from neuroscience, and argue that when it comes to brains, judges, just like the rest of us, are unnecessarily impressed. Ultimately, how we determine culpability should rest on normative and ethical considerations rather than on scientific ones. PMID- 23659903 TI - Capitalizing on the teachable moment: osteoarthritis physical activity and exercise net for improving physical activity in early knee osteoarthritis. AB - BACKGROUND: Practice guidelines emphasize the use of exercise and weight reduction as the first line of management for knee osteoarthritis (OA). However, less than half of the people with mild OA participate in moderate intensity physical activity. Given that physical activities have been shown to reduce pain, improve quality of life, and have the potential to reduce the progression of joint damage, many people with OA are missing the benefits of this inexpensive intervention. OBJECTIVE: The objectives of this study are (1) to develop a behavioral theory-informed Internet intervention called Osteoarthritis Physical Activity & Exercise Net (OPEN) for people with previously undiagnosed knee OA, and (2) to assess the efficacy of the OPEN website for improving physical activity participation through a proof-of-concept study. METHODS: OPEN was developed based on the theory of planned behavior. Efficacy of this online intervention is being assessed by an ongoing proof-of-concept, single-blind randomized controlled trial in British Columbia, Canada. We are currently recruiting participants and plan to recruit a total of 252 sedentary people with previously undiagnosed knee OA using a set of validated criteria. Half of the participants will be randomized to use OPEN and receive an OA education pamphlet. The other half only will receive the pamphlet. Participants will complete an online questionnaire at baseline, 3 months, and 6 months about their participation in physical activities, health-related quality of life, and motivational outcomes. In addition, we will perform an aerobic fitness test in a sub-sample of participants (n=20 per study arm). In the primary analysis, we will use logistic regression to compare the proportion of participants reporting being physically active at or above the recommended level in the 2 groups, adjusting for baseline measurement, age, and sex. RESULTS: This study evaluates a theory informed behavioral intervention at a time when people affected with OA tend to be more motivated to adopt an active lifestyle (ie, at the early stage of OA). Our approach, which consisted of the identification of early knee OA followed immediately by an online intervention that directly targets physical inactivity, can be easily implemented across communities. CONCLUSIONS: Our online intervention directly targets physical inactivity at a time when the joint damage tends to be mild. If OPEN is found to be effective in changing long-term physical activity behaviors, it opens further opportunities to promote early diagnosis and to implement lifestyle interventions. TRIAL REGISTRATION: Clinicaltrial.gov: NCT01608282; http://clinicaltrials.gov/ct2/show/NCT01608282 (Archived by WebCite at http://www.webcitation.org/6G7sBBayI). PMID- 23659906 TI - Figures of merit of a SERS method for Sudan I determination at traces levels. AB - A substrate for Surface-Enhanced Raman Scattering spectroscopy (SERS), electropolished Al, is proposed as a tool for a rapid and low cost determination of Sudan I. This dye has been used as an additive in some foodstuffs but it is now banned because of the health risk associated with its carcinogenic and mutagenic properties. Despite the presence of fluorescence, Raman spectra of Sudan I can be obtained using excitation lasers at 633 and 785 nm. To get rid of the spectral noise and fluorescence background, Savitzky-Golay smoothing and polynomial corrections were applied, respectively. The Raman signal was proved to be enhanced. A linear dependence was found between the logarithmic intensity at 1598 cm(-1) peak versus the logarithmic concentration. The figures of merit were studied obtaining high sensitivity and low detection limits (10(-7) M). A multivariate exploratory analysis (PCA) was used to study the ability of SERS to distinguish Sudan I from other similar compounds. Therefore, results show that SERS is a potential tool to determine Sudan I quickly and effectively. PMID- 23659907 TI - Vibrational studies of benzene, pyridine, pyridine-N-oxide and their cations. AB - IR and Raman spectra of pyridine and pyridine-N-oxide have been recorded and analyzed. The optimized molecular geometries, APT charges and vibrational characteristics for benzene, pyridine, pyridine-N-oxide and their cations have been computed using DFT method. Due to attachment of O atom at N site or removal of electron all the modes are affected in magnitudes. However, significant changes are noticed in their IR intensities, Raman activities and depolarization ratios of the Raman bands in going from pyridine to its N-oxide or in going from neutrals to their cations. It is interesting to note that in going from benzene to benzene cation charge redistribution takes place to reduce the symmetry from D6h to D2h. The calculated frequencies have been correlated with the experimental frequencies for the pyridine and pyridine-N-oxide molecules. PMID- 23659908 TI - IR spectroscopic analysis of the new organic silver complex C13H13N4OAg. AB - IR analysis in the frequency range 400-4000 cm(-1) is used here to investigate the changes in different modes of thermally treated new metal complex (diphenyl carbazide silver complex DPCAg, C13H13N4OAg) during the glass transition at 91 degrees C and the high temperature phase transition at 167 degrees C. These two phase transitions in this new metal compound are studied here by detecting the changes in some IR spectroscopic parameters (e.g., mode shift, band contour, peak height and peak intensity) during the elevation of temperature. All of the vibrations of DPCAg were found to be due to ionic fundamentals 3311 cm(-1), 3097 cm(-1), 3052 cm(-1), 1677 cm(-1), 1602 cm(-1), 1492 cm(-1), 1306 cm(-1), 1252 cm( 1), 887 cm(-1) and 755 cm(-1). The results obtained can be considered as the first spectroscopic analysis of this new metal complex. These results strongly confirmed that the thermally treated DPCAg transverse a glass transition at 91 degrees C and a high temperature phase transition at 167 degrees C. Anomalous spectroscopic changes near the glass transition temperature Tg could be recorded. A temperature dependence of peak intensity of the two modes 810 cm(-1) and 3440 cm(-1) could be observed beyond Tg. Also, the high temperature phase modification at 167 degrees C showed anomalous change in the spectroscopic parameters before and after the phase transition process. A proposed silver position in the new silver complex DPCAg has been presented. PMID- 23659909 TI - Identification of adenovirus-encoded small RNAs by deep RNA sequencing. AB - Using deep RNA sequencing, we have studied the expression of adenovirus-encoded small RNAs at different times after infection. Nineteen small RNAs which comprised more than 1% of the total pool of small RNAs at least one time point were identified. These small RNAs were between 25 and 35 nucleotides long and mapped in the region of the VA RNAI and RNAII genes. However, the overlap was incomplete and some contained a few extra nucleotides at the 3' end. This finding together with the observation that some of the small RNAs were detected before VA RNA expression had started might indicate that they are derived from other precursors than VA RNAI and II. Interestingly, the small RNAs displayed different expression profiles during the course of the infection suggesting that they have different functions. An effort was made to identify their mRNA targets by using computer prediction and deep cDNA sequencing. The most significant targets for the earliest small RNAs were genes involved in signaling pathways. PMID- 23659910 TI - 6-Acetonyl-5,6-dihydrosanguinarine (ADS) from Chelidonium majus L. triggers proinflammatory cytokine production via ROS-JNK/ERK-NFkappaB signaling pathway. AB - Chelidonium majus L. is an herbal plant that is commonly used in Western phytotherapy and traditional Chinese medicine for diuretic, antitussive, eye regenerative, anti-osteoporotic, and radioprotective purposes. In this study, we purified 6-acetonyl-5,6-dihydrosanguinarine (ADS) from C. majus and investigated its immune-stimulatory effect. We found that ADS has the potential to induce the inflammatory cytokines TNF-alpha, IL-6, and IL-8 in macrophages and dendritic cells (DCs), that NFkappaB activation is a critical mediator of ADS-induced cytokine production, and that the activation of NFkappaB was dependent on reactive oxygen species (ROS). ADS induced phosphorylation of ERK and JNK, which was also associated with NFkappaB activation; phosphorylarion and cytokine production were inhibited by ROS scavenger and by specific MAPK inhibitors. Taken together, the results suggest that ADS from C. majus, as a positive immune modulator, induces inflammatory cytokines that might improve immunity, via the ROS-ERK/JNK-NFkappaB pathway. PMID- 23659912 TI - Does total disc arthroplasty in C3/C4-segments change the kinematic features of axial rotation? AB - We analyze how kinematic properties of C3/C4-segments are modified after total disc arthroplasty (TDA) with PRESTIGE((r)) and BRYAN((r)) Cervical Discs. The measurements were focused on small ranges of axial rotation (<0.8 degrees ) in order to investigate physiologic rotations, which frequently occur in vivo. Eight human segments were stimulated by triangularly varying, axially directed torque. By using a 6D-measuring device with high resolution the response of segmental motion was characterised by the instantaneous helical axis (IHA). Position, direction, and migration rate of the IHA were measured before and after TDA. External parameters: constant axially directed pre-load, constant flexional/extensional and lateral-flexional pre-torque. The applied axial torque and IHA-direction did not run parallel. The IHA-direction was found to be rotated backwards and largely independent of the rotational angle, amount of axial pre load, size of pre-torque, and TDA. In the intact segments pre-flexion/extension hardly influenced IHA-positions. After TDA, IHA-position was shifted backwards significantly (BRYAN-TDA: ~8mm; PRESTIGE-TDA: ~6mm) and in some segments laterally as well. Furthermore it was significantly shifted ventrally by pre flexion and dorsally by pre-extension. The rate of lateral IHA-migration increased significantly after BRYAN-TDA during rightward or leftward rotations. In conclusion after the TDA the IHA-positions shifted backwards with significant increase in variability of the IHA-positions after the BRYAN-TDA more than in PRESTIGE-TDA. The TDA-procedure altered the segment kinematics considerably. TDA causes additional translations of the vertebrae, which superimpose the kinematics of the adjacent levels. The occurrence of adjacent level disease (ALD) is not excluded after the TDA for kinematical reasons. PMID- 23659911 TI - Influence of neuromuscular noise and walking speed on fall risk and dynamic stability in a 3D dynamic walking model. AB - Older adults and those with increased fall risk tend to walk slower. They may do this voluntarily to reduce their fall risk. However, both slower and faster walking speeds can predict increased risk of different types of falls. The mechanisms that contribute to fall risk across speeds are not well known. Faster walking requires greater forward propulsion, generated by larger muscle forces. However, greater muscle activation induces increased signal-dependent neuromuscular noise. These speed-related increases in neuromuscular noise may contribute to the increased fall risk observed at faster walking speeds. Using a 3D dynamic walking model, we systematically varied walking speed without and with physiologically-appropriate neuromuscular noise. We quantified how actual fall risk changed with gait speed, how neuromuscular noise affected speed-related changes in fall risk, and how well orbital and local dynamic stability measures predicted changes in fall risk across speeds. When we included physiologically appropriate noise to the 'push-off' force in our model, fall risk increased with increasing walking speed. Changes in kinematic variability, orbital, and local dynamic stability did not predict these speed-related changes in fall risk. Thus, the increased neuromuscular variability that results from increased signal dependent noise that is necessitated by the greater muscular force requirements of faster walking may contribute to the increased fall risk observed at faster walking speeds. The lower fall risk observed at slower speeds supports experimental evidence that slowing down can be an effective strategy to reduce fall risk. This may help explain the slower walking speeds observed in older adults and others. PMID- 23659913 TI - Comparison of arthrodesis, resurfacing hemiarthroplasty, and total joint replacement in the treatment of advanced hallux rigidus. AB - The purpose of the present study was to compare the functional results of arthrodesis, resurfacing hemiarthroplasty, and total joint replacement in hallux rigidus. The data from patients treated from 2006 to 2010 for advanced stage hallux rigidus were retrospectively reviewed. A total of 38 patients who had at least 2 years (range 24 to 66 months, mean 31.1) of follow-up were included in the present study. Of the 38 patients, 12 were included in the total joint replacement group (group A), 14 in the resurfacing hemiarthroplasty group (group B), and 12 in the arthrodesis group (group C). At the last follow-up visit, the functional outcomes were evaluated using the American Orthopaedic Foot and Ankle Society-Hallux Metatarsophalangeal Interphalangeal (AOFAS-HMI) scale, visual analog scale (VAS), and metatarsophalangeal range of motion. Significant improvements were seen in the AOFAS-HMI score, with a decrease in the VAS score in all 3 groups. According to the AOFAS-HMI score, no significant difference was found between groups A and B. However, in group C, the AOFAS-HMI scores were significantly lower than in the other groups owing to the lack of motion. According to the final VAS scores, no significant difference was found between groups A and B; however, the VAS score had decreased significantly more in group C than in the other groups. No major complications occurred in any of the 3 groups. After 2 years of follow-up, all the groups had good functional outcomes. Although arthrodesis is still the most reliable procedure, implant arthroplasty is also a good alternative for advanced stage hallux rigidus. PMID- 23659914 TI - Rerupture rate after early weightbearing in operative versus conservative treatment of Achilles tendon ruptures: a meta-analysis. AB - Whether Achilles tendon rupture benefits from surgery or conservative treatment remains controversial. Moreover, the outcome can be influenced by the rehabilitation protocol. The goal of the present meta-analysis was to compare the rerupture rate after surgical repair of the Achilles tendon followed by weightbearing within 4 weeks versus conservative treatment with weightbearing within 4 weeks. In addition, a secondary analysis was performed to compare the rerupture rates in patients who started weightbearing after 4 weeks. Seven randomized controlled trials published from 2001 to 2012, with 576 adult patients, were included. The primary outcome measure was the rerupture rate. The secondary outcomes were minor and major complications other than rerupture. In the early weightbearing group, 7 of 182 operatively treated patients (4%) experienced rerupture versus 21 of 176 of the conservatively treated patients (12%). A secondary analysis of the patients treated with late weightbearing showed a rerupture rate of 6% (7 of 108) for operatively treated patients versus 10% (11 of 110) for conservatively treated patients. The differences concerning the rerupture rate in both groups were not statistically significant. No differences were found in the occurrence of minor or major complications after early weightbearing in both patient groups. In conclusion, we found no difference in the rerupture rate between the surgically and nonsurgically treated patients followed by early weightbearing. Weightbearing after 4 weeks also resulted in no differences in the rupture rate in the surgical versus conservatively treated patients. However, surgical treatment was associated with a twofold greater complication rate than conservative treatment. PMID- 23659915 TI - Chronic pain and cognitive function. PMID- 23659916 TI - [Detainees in police custody in Seine-Saint-Denis (France): Medical data and high risk situations, a descriptive study]. AB - OBJECTIVES: The number of detainees held in police custody in France increased up to 792,000 yearly in 2009. Medical examination is a right for every detainee. Our objective was to assess medical characteristics and addictive behaviours of arrestees. METHODS: In this study, we systematically evaluated arrestees detained in police custody in Seine-Saint-Denis, a suburban area near Paris over one year (June 1, 2010-May 31, 2011). RESULTS: A total of 22,379 medical examinations were performed. Males accounted for 94% of detainees. Median age was 23 (range: 13 78). In 2968 of 18,466 cases (16%), the detainee had at least one chronic somatic disease. Asthma, diabetes, and arterial hypertension were the most commonly encountered. A history of psychiatric disorder was reported in 819 of 16,697 cases (5%). Daily alcohol consumption was reported by 14% of detainees and 77% smoked tobacco. Drug use was reported by 40% of detainees, cannabis in most cases (38%), infrequently cocaine or crack (4%) or heroine (1%). Assaults were reported by 20% of detainees, at the time of arrest in most cases (11%). PERSPECTIVES: The present study showed the high frequency of addictive behaviours and reported assaults or traumatic injuries in arrestees. Attending physicians should pay particular attention to addictive disorders and recent traumatic lesions in arrestees, both for immediate care and for prevention. PMID- 23659917 TI - [Evaluating the total incapacity to work: implementing French National Authority for Health guidelines in clinical practice]. AB - Total incapacity to work (TIW) is a legal concept that allows magistrates to assess the severity of violence against persons. The TIW is the duration of the victims' inability to fulfil their usual activities and is determined by physicians. Professional guidelines from the French National Authority for Health indicate that TIW applies both to physical and psychological problems. The law of 9 July 2010 makes explicit reference to TIW in cases of psychological violence and intimate partner harassment. Prosecutors base criminal penalties on the duration of TIW in cases of assault and battery. Whatever the physician, they should describe the mental state of the victim and identify the signs that may indicate the mental impact of reported assaults. Identifying combinations of symptoms can be useful in deciding whether the duration of TIW should be increased because of the psychic state. In case of stalking, assessment of TIW can allow prosecutors to link the reported facts to a criminal offence. In complex situations, the physician may be unable to assess a duration of TIW and can suggest expert assessment. In all cases, the duration of TIW needs to be based on functional criteria. The extent of harm to the life of relationships results from suffered violence, from the victim's reaction, and from the perception of their family and friends. In this area, we suggest to limit the first assessment of TIW to a few days and to reassess it later, according to real information reported by the victims, to careful observation of their behaviour, and to results of a questioning that should be as little suggestive as possible. At either end of the age scale and in case of preexisting functional impairment, assessment of TIW should take into account the actual and global capacity of the person before the assault. PMID- 23659918 TI - Thermotolerance responses in ripening berries of Vitis vinifera L. cv Muscat Hamburg. AB - Berry organoleptic properties are highly influenced by ripening environmental conditions. In this study, we used grapevine fruiting cuttings to follow berry ripening under different controlled conditions of temperature and irradiation intensity. Berries ripened at higher temperatures showed reduced anthocyanin accumulation and hastened ripening, leading to a characteristic drop in malic acid and total acidity. The GrapeGen GeneChip(r) combined with a newly developed GrapeGen 12Xv1 MapMan version were utilized for the functional analysis of berry transcriptomic differences after 2 week treatments from veraison onset. These analyses revealed the establishment of a thermotolerance response in berries under high temperatures marked by the induction of heat shock protein (HSP) chaperones and the repression of transmembrane transporter-encoding transcripts. The thermotolerance response was coincident with up-regulation of ERF subfamily transcription factors and increased ABA levels, suggesting their participation in the maintenance of the acclimation response. Lower expression of amino acid transporter-encoding transcripts at high temperature correlated with balanced amino acid content, suggesting a transcriptional compensation of temperature effects on protein and membrane stability to allow for completion of berry ripening. In contrast, the lower accumulation of anthocyanins and higher malate metabolization measured under high temperature might partly result from imbalance in the expression and function of their specific transmembrane transporters and expression changes in genes involved in their metabolic pathways. These results open up new views to improve our understanding of berry ripening under high temperatures. PMID- 23659919 TI - The Arabidopsis DUF231 domain-containing protein ESK1 mediates 2-O- and 3-O acetylation of xylosyl residues in xylan. AB - Xylan, a major polysaccharide in plant lignocellulosic biomass, is acetylated at O-2 and/or O-3 and its acetylation impedes the use of biomass for biofuel production. Currently, it is not known what genes encode acetyltransferases that are responsible for xylan O-acetylation. In this report, we demonstrate an essential role for the Arabidopsis gene ESKIMO1 (ESK1) in xylan O-acetylation during secondary wall biosynthesis. ESK1 expression was found to be regulated by the secondary wall master regulator SND1 (secondary wall-associated NAC domain protein1) and specifically associated with secondary wall biosynthesis. Its encoded protein was localized in the Golgi, the site of xylan biosynthesis. The esk1 mutation caused reductions in secondary wall thickening and stem mechanical strength. Chemical analyses of cell walls revealed that although the esk1 mutation did not cause apparent alterations in the xylan chain length and the abundance of the reducing end sequence, it resulted in a significant reduction in the degree of xylan acetylation. The reduced acetylation of esk1 xylan rendered it more accessible and digestible by endoxylanase, leading to generation of shorter xylooligomers compared with the wild type. Further structural analysis of xylan showed that the esk1 mutation caused a specific reduction in 2-O- and 3-O monoacetylation of xylosyl residues but not in 2,3-di-O-acetylation or 3-O acetylation of xylosyl residues substituted at O-2 with glucuronic acid. Consistent with ESK1's involvement in xylan O-acetylation, an activity assay revealed that the esk1 mutation led to a significant decrease in xylan acetyltransferase activity. Together, these results demonstrate that ESK1 is a putative xylan acetyltransferase required for 2-O- and 3-O-monoacetylation of xylosyl residues and indicate the complexity of the biochemical mechanism underlying xylan O-acetylation. PMID- 23659920 TI - Can concreteness training buffer against the negative effects of rumination on PTSD? An experimental analogue study. AB - BACKGROUND AND OBJECTIVES: Trauma-related rumination has been found to be an important maintaining factor for PTSD. On the background of the processing mode account of ruminative thinking, this study tested whether the relationship between rumination and analogue PTSD symptoms can be modified by training participants in a concrete mode of processing. METHODS: Healthy participants were trained in either an abstract or a concrete style of processing. Afterwards, they watched a stressful film. The interactive effect of training condition and trait rumination on intrusive memories of the film was examined. RESULTS: Following abstract training, a positive relationship between trait rumination and intrusive memories of the film emerged. As hypothesized, this relationship disappeared following concrete training. LIMITATIONS: include the lack of a no-training control group and the analogue paradigm used. CONCLUSIONS: The study provides preliminary evidence that the relationship between trait rumination and analogue PTSD symptoms can be modified. If replicated in future studies, it may be promising to examine the value of concreteness training for prevention and/or treatment of PTSD. PMID- 23659922 TI - CNV analysis in monozygotic twin pairs discordant for urorectal malformations. AB - Early post-twinning mutational events can account for discordant phenotypes in monozygotic (MZ) twin pairs. Such mutational events may comprise genomic alterations of different sizes, ranging from single nucleotides to large copy number variations (CNVs). Anorectal malformations (ARM) and the bladder exstrophy epispadias complex (BEEC) represent the most severe end of the urorectal malformation spectrum. Recently, CNV studies in patients with sporadic ARM and the BEEC have identified de novo events that occur in specific chromosomal regions. We hypothesized that early arising, post-twinning CNVs might contribute to discordance in MZ twin pairs with ARM or the BEEC; knowledge of such CNVs might help to identify additional chromosomal regions involved in the development of these malformations. We investigated four discordant MZ twin pairs (three ARM and one BEEC) using molecular karyotyping arrays comprising 1,140,419 markers with a median marker spacing of 1.5 kb. Filtering the coding regions for possible disease-causing post-twinning de novo CNVs present only in the affected twin, but not in the unaffected twin or the parents, identified a total of 136 CNVs. These 136 CNVs were then filtered against publicly available databases and finally re evaluated visually. No potentially causative CNV remained after applying these filter criteria. Our results suggest that post-twinning CNV events that affect coding regions of the genome did not contribute to the discordant phenotypes in MZ twin pairs that we investigated. Possible causes for the discordant phenotypes include changes in regulatory elements or smaller genetic changes within coding regions which may be detectable by whole-exome sequencing. PMID- 23659921 TI - Differential role of Dok1 and Dok2 in TLR2-induced inflammatory signaling in glia. AB - Accumulating evidence continues to underpin the role of the innate immune system in pathologies associated with neuroinflammation. Innate immunity is regulated by pattern recognition receptors that detect pathogens, and in the case of Gram positive bacteria, binding of bacterial lipopeptides to toll-like receptor (TLR)2 is emerging as an important mechanism controlling glial cell activation. In the present study, we employed the use of the synthetic bacterial lipoprotein and a selective TLR2 agonist, Pam3CSK4, to induce inflammatory signaling in microglia and astrocytes. The adaptor proteins, downstream of kinase (Dok)1 and Dok2, are known to have a role in negatively regulating the Ras-ERK signaling cascade, with downstream consequences on pro-inflammatory cytokine expression. Data presented herein demonstrate that TLR2 enhanced the tyrosine phosphorylation of Dok1 and Dok2 in astrocytes and microglia, and that knockdown of these adaptors using small interfering RNA robustly elevated TLR2-induced ERK activation. Importantly, TLR2-induced NF-kappaB activation, and IL-6 production was exacerbated in astrocytes transfected with Dok1 and Dok2 siRNA, indicating that both Dok proteins negatively regulate TLR2-induced inflammatory signaling in astrocytes. In contrast, Dok1 knockdown attenuated TLR2-induced NF-kappaB activation and IL-6 production in microglia, while Dok2 siRNA failed to affect TLR2-induced NF-kappaB activity and subsequent cytokine expression in this cell type. Overall, this indicates that Dok1 and Dok2 are novel adaptors for TLR2 in glial cells and importantly indicates that Dok1 and Dok2 differentially regulate TLR2-induced pro inflammatory signaling in astrocytes and microglia. PMID- 23659924 TI - Continuous publication: ready, set, cite! PMID- 23659923 TI - Deoxyribonucleic acid damage-associated biomarkers of ionising radiation: current status and future relevance for radiology and radiotherapy. AB - Diagnostic and therapeutic radiation technology has developed dramatically in recent years, and its use has increased significantly, bringing clinical benefit. The use of diagnostic radiology has become widespread in modern society, particularly in paediatrics where the clinical benefit needs to be balanced with the risk of leukaemia and brain cancer increasing after exposure to low doses of radiation. With improving long-term survival rates of radiotherapy patients and the ever-increasing use of diagnostic and interventional radiology procedures, concern has risen over the long-term risks and side effects from such treatments. Biomarker development in radiology and radiotherapy has progressed significantly in recent years to investigate the effects of such use and optimise treatment. Recent biomarker development has focused on improving the limitations of established techniques by the use of automation, increasing sensitivity and developing novel biomarkers capable of quicker results. The effect of low-dose exposure (0-100 mGy) used in radiology, which is increasingly linked to cancer incidences, is being investigated, as some recent research challenges the linear no-threshold model. Radiotherapy biomarkers are focused on identifying radiosensitive patients, determining the treatment-associated risk and allowing for a tailored and more successful treatment of cancer patients. For biomarkers in any of these areas to be successfully developed, stringent criteria must be applied in techniques and analysis of data to reduce variation among reports and allow data sets to be accurately compared. Newly developed biomarkers can then be used in combination with the established techniques to better understand and quantify the individual biological response to exposures associated with radiology tests and to personalise treatment plans for patients. PMID- 23659925 TI - Percutaneous ablation of lymph node metastases using CT-guided high-dose-rate brachytherapy. AB - OBJECTIVE: To assess the technical feasibility, safety and clinical outcome of CT guided high-dose-rate brachytherapy (CT-HDRBT) for achieving local tumour control (LTC) in isolated lymph node metastases. METHODS: From January 2008 to December 2011, 10 patients (six males and four females) with isolated nodal metastases were treated with CT-HDRBT. Five lymph node metastases were para-aortic, three were at the liver hilum, one at the coeliac trunk and one was a left iliac nodal metastasis. The mean lesion diameter was 36.5 mm (range 12.0-67.0 mm). Patients were followed up by either contrast-enhanced CT or MRI 6 weeks and then every 3 months after the end of treatment. The primary end point was LTC. Secondary end points included primary technical effectiveness rate, adverse events and progression-free survival. RESULTS: The first follow-up examination after 6 weeks revealed complete coverage of all nodal metastases treated. There was no peri interventional mortality or major complications. The mean follow-up period was 13.2 months (range 4-20 months). 2 out of 10 patients (20%) showed local tumour progression 9 and 10 months after ablation. 5 out of 10 patients (50%) showed systemic tumour progression. The mean progression-free interval was 9.2 months (range 2-20 months). CONCLUSION: CT-HDRBT is a safe and effective technique for minimally invasive ablation of nodal metastases. ADVANCES IN KNOWLEDGE: CT-HDRBT of lymph node metastases is feasible and safe. CT-HDRBT might be a viable therapeutic alternative to obtain LTC in selected patients with isolated lymph node metastases. PMID- 23659926 TI - Acute pulmonary injury: high-resolution CT and histopathological spectrum. AB - Acute lung injury usually causes hypoxaemic respiratory failure and acute respiratory distress syndrome (ARDS). Although diffuse alveolar damage is the hallmark of ARDS, other histopathological patterns of injury, such as acute and fibrinoid organising pneumonia, can be associated with acute respiratory failure. Acute eosinophilic pneumonia can also cause acute hypoxaemic respiratory failure and mimic ARDS. This pictorial essay reviews the high-resolution CT findings of acute lung injury and the correlative histopathological findings. PMID- 23659927 TI - First evaluation of unfermented and fermented rooibos (Aspalathus linearis) in preventing lipid oxidation in meat products. AB - This study consisted of two trials aiming to evaluate, for the first time, the antioxidant potential of rooibos in meat products. With this purpose, the first trial evaluated three unfermented (green) rooibos forms (dried leaves, water extract, freeze-dried extract) added at 2% inclusion level to ostrich meat patties on an 8-day shelf-life trial. A Control group without green rooibos inclusion was also considered. The second trial evaluated the addition of different concentrations (0%, 0.25%, 0.5% and 1%) of a fermented rooibos extract to nitrite-free ostrich salami. The 2% green rooibos inclusion considerably lowered the TBARS content of ostrich patties, in this way extending their shelf life. The fermented form (0.5% and 1%) was also effective in delaying lipid oxidation in ostrich salami until 15 days of ripening. The antioxidant potential of both green and fermented forms of rooibos in meat products was confirmed, even if its effect on lipid oxidation requires further study and long-term effects are not yet fully understood. PMID- 23659928 TI - Usefulness of the coherence entrainment test for deep brain stimulation for a patient with atypical tremor. AB - A 40-year-old man with an anxiety disorder developed sudden-onset right-hand tremor after a fixation wire for a tibial bone fracture was removed. He manifested a resting and action tremor with an irregular pattern. A coherence entrainment test (CET) revealed that the peak power spectral frequency of the right finger tremor was not entrained by simultaneous voluntary left finger tapping, which indicated a non-psychogenic origin. Deep brain stimulation to the left thalamic ventral intermediate nucleus abolished the tremor. We concluded that CET can determine the surgical indications for an unusual tremor that must be differentiated from that of psychogenic origin. PMID- 23659929 TI - Significant dermatological side effects of intravenous immunoglobulin. AB - Intravenous immunoglobulin (IVIg) is an essential treatment for many neurological, immunological and haematological conditions. However, the severity of its rare adverse effects is often underrecognised. We report a series of 15 patients receiving IVIg for neurological and immunological disorders who developed severe skin reactions. Despite pre-medication, nearly all patients ceased IVIg due to the severity of the adverse response. Interestingly, the majority of patients were male and two-thirds were receiving treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) or another inflammatory or demyelinating neuropathy. This marked propensity for male patients with CIDP to develop significant dermatological reactions following IVIg administration has not previously been described. Mechanisms involving the underlying autoimmunity inherent to this condition may play a role. PMID- 23659930 TI - [TALE nuclease engineering and targeted genome modification]. AB - Artificial designer nucleases targeting specific DNA sequences open up a new field for reverse genetics study. The rapid development of engineered endonucleases (EENs) enables targeted genome modification theoretically in any species. The construction of transcription activator-like effector nucleases (TALENs) is simpler with higher specificity and less toxicity than zinc-finger nucleases (ZFNs). Here, we summarized the recent progresses and prospects of TALEN technology, with an emphasis on its structure, function, and construction strategies, as well as a collection of species and genes that have been successfully modified by TALENs, especially the application in zebrafish. PMID- 23659931 TI - [A brief history of zebrafish research--toward biomedicine]. AB - Ever since George Streisinger pioneered his research using zebrafish (Danio rerio), at the University of Oregon in 1972, the zebrafish not only has become a unique animal model in basic research, due to its fine embryonic and (molecular) genetics technique/tool developed globally, but it is also a favorite model of choice in the biomedical research, i.e., used for establishing human disease models and discovering lead drug/small chemical in the past decade. In this review, we will briefly describe the history of zebrafish research, emphasizing the well-recognized milestones, and stress how the models of leukemia, melanoma, immunity/infectious diseases and neuronal defects/neuro-degeneration diseases have been established and how pharmaceutical industry and research scientists make use of zebrafish to obtain potential therapeutic drugs. We believe that this direction of zebrafish research will lead to a better understanding of some nasty human diseases and their pathogenic mechanisms, and eventually help to achieve a better health of human beings. PMID- 23659932 TI - [Zebrafish as the model system to study organogenesis and regeneration]. AB - Zebrafish (Danio rerio) is becoming more and more popular as a model organism to study vertebrate organogenesis and regeneration, taking the advantage of its extra-uterine development, transparency, strong regeneration ability and suitability for the large scale genetic screen. In the past decades, a series of useful methods have been established in zebrafish, which allows studies of important questions in developmental biology including cell fate determination, differentiation, morphogenesis, and regeneration after tissue/organ injury. Recently, using large scale mutagenesis screen and improved live imaging techniques, many questions that had not been well understood in mice have been successfully investigated in zebrafish. Therefore, we are confident that the zebrafish model system will further help decipher the cellular and molecular mechanisms of organogenesis and regeneration in the future, providing valuable references for the treatment of related clinical diseases. This review just summarized the progress in the studies of the important organs development using zebrafish, such as central nervous system(CNS), liver and pancreas, blood and vessel, recently. Meanwhile, the updated informations about the regeneration of tail fin, heart, liver, retina and so on in zebrafish were also included in this paper. PMID- 23659933 TI - [Nuclear transfer and reprogramming in fish]. AB - As an important sub-field in the study of animal cloning, fish nuclear transfer was first established in the early 1960s by Chinese embryologists. Due to its advantages, zebrafish has become a unique animal model to study the mystery of reprogramming in nuclear transfer. This article summarizes the history and current situation in fish nuclear transfer technology and discusses the factors that may influence the development of the cloned embryos. A comprehensive understand-ing of the mechanism for epigenetic modification following nuclear transfer, such as genomic DNA methylation and histone acetylation and/or methylation, will likely increase the success rate and eventually lead to the future freedom of cloning technique. PMID- 23659934 TI - [Zebra fish cell movements during gastrulation]. AB - During zebrafish gastrulation, large cellular rearrangements create the formation of the three germ layers, ectoderm, mesoderm, and endoderm. This process includes three types of conserved morphogenetic movement: epiboly, involution, and convergent extension. Specially, the anterior movement of prechordal plate progenitors is essential for the location and differentiation of mesendoderm progenitors, and the pechordal plate progenitors'coherent migration is thought to be a good model to study the mechanism of cell movement in vivo. Gastrulation migration is known to be controlled by many signaling pathways such as Wnt/planar cell polarity signaling; however, the underlying molecular mechanism for cellular behavior remains unknown. At present, it is generally agree that cell adhesion and cytoskeletal rearrangement are critical factors during zebrafish gastrulation cell migration. In addition, the role of extraembryonic tissue (yolk syncytial layer) during gastrulation is concerned increasingly. Here, we described the essential factors for controlling cellular behaviors and highlighted the major issues and questions that require further investigation during zebra fish gastrular cell migration in order to provide a complete map containing all the factors for regulating gastrulation cell migration and their interactions on a cellular level. PMID- 23659935 TI - [Lumen morphogenesis and molecular mechanisms in tubular organs during zebrafish embryonic development]. AB - A network tubular system is an important structure in the body and organ of metazoa. The lumen of tube is fundamental units in the structure, which serve to transport material, divide the organ into different functional compartments and separate the organ from the environment. The defects of lumen formation will lead to abnormalities of the organ morphogenesis and disorder of the function. Zebrafish (Danio rerio)is an important model for development research. Meanwhile easy observation of tubular organ, the relevant mutants, and transgene linages make zebrafish to become an excellent model to study the formation of lumen in the tubular organs, including the blood vessels, neural tube, gut, exocrine pancreas, and pronephric duct, which undergo the typical morphogenesis of lumen that is involved in the organs' development. The process of lumen formation is mainly consisted of induction of extracellular signals, polarization of epithelial cell, directional transportation in the polar cells, the aggregation and transportation of fluid in the lumen, and the reconstruction of cytoskeleton in polar cells and controlled by the precise and complicated molecular networks during embryonic development. This review will summarize our current knowledge on lumen morphogenesis in four kinds of typical tubular organs during zebrafish embryonic development and the related molecular mechanisms as well as to supply helpful reference to the future studies. PMID- 23659936 TI - [G protein-coupled receptors in vascular development]. AB - The vascular development consists of two continuous processes: vasculogenesis and angiogenesis. Some researches showed that G protein-coupled receptors (GPCRs) play important roles in these processes, including the regulation of differentiation, migration and coalescence of angioblasts, fate decision of tip and stalk cells, proliferation and migration of endothelial cells and tube formation. For the key events of vasculogenesis and angiogenesis, we summarize the recent advance of GPCRs, especially Class A and F. In particular, the advantages, of zebrafish, which has been widely used in developmental biology as a vertebrate model, are introduced. Using zebrafish will bring the great potential and prospect to demonstrate the role of GPCRs in vascular development in the future. PMID- 23659937 TI - [Visual system and prey capture behavior of larval zebrafish]. AB - Studying neural circuits is a crucial step for understanding neural mechanisms underlying animal behaviors. Larval zebrafish is a low vertebrate animal model with incomparable advantages in neural circuit study. In this review, we describe the zebrafish visual system and its downstream targets, with special emphasis on their possible roles in prey capture behavior. Prey capture is executed mainly through the visual system and its downstream circuits, including reticulospinal commanding neurons, motor-controlling circuits within the spinal cord, and other un-identified functional units. With the development of approaches in monitoring and manipulating neuronal activity and behavioral assays, we will get deep insights about neural basis for prey capture in near future, which will shed light on elucidating neural circuit mechanisms of behavior. PMID- 23659939 TI - [mir122 deficiency inhibits differentiation of zebrafish hepatoblast into hepatocyte]. AB - As one of the largest internal organs in the body, liver is very important for metabolism, detoxification and homeostasis. It's reported that liver development is accurately regulated by a gene regulating network consists of FGF, BMP, WNT signal pathways and a lot of transcription factors. However, the functions of microRNA are poorly understood during liver formation. In recent years, it has been reported that mir122 is highly expressed in hepatocytes, and plays a vital role in the metabolic processes of the liver, but its function in liver development remains unclear. In this study, we report that mir122 is specifically expressed in zebrafish (Danio rerio) embryonic liver, and its expression level is notably increased during the differentiation process of hepatoblast into hepatocyte. mir122 inactivation by an antisense morpholino has no influence on the specification, budding and outgrowth of hepatoblast. However, zbrafish hepatoblast can not differentiate into hepatocyte without mir122. Therefore, mir122 is not only involved in liver metabolic functions, but also indispensable for hepatoblast differentiation. PMID- 23659938 TI - [Rbb4l enhances TGF-beta/Nodal signaling and promotes zebrafish embryonic dorsolization]. AB - The TGF-beta/Nodal signaling pathway plays an important role in the zebrafish dorsoventral patterning process. To further explore the function and mechanism of this signaling pathway, we identified a set of Smad2/3a interacting proteins by the yeast two-hybrid screen. Rbb4l (Retinoblastoma binding protein 4, like) is one of the identified proteins. Human RBBP4 (Retinoblastoma binding protein 4), the homolog of zebrafish Rbb4l, has been shown to form complexes with other chromatin modifiers, but its roles in embryonic development remain unknown. In this study, we showed that Rbb4l directly interacted with Smad3a and enhances TGF beta/Nodal signaling. In zebrafish embryos, rbb4l overexpression resulted in an expanded expression of dorsal markers with a reduction of ventral markers expression, suggesting a dorsalizing function. On the contrary, rbb4l knockdown caused ventralized phenotype of the embryos at 24 hours post-fertilization (hpf). Furthermore, a series of rescue experiments showed that rbb4l failed to cause embryonic dorsalization in the absence of Nodal signal. Together, our data suggested that Rbb4l acts as an enhancer of Nodal/Smad2/3 signaling during embryogene-sis, and depends on the existence of Nodal signaling. PMID- 23659940 TI - [Expression of gdnf and nos in adult zebrafish brain during the regeneration after spinal cord injury]. AB - Recently, it is unclear about the mechanism of notable regenerated ability of adult zebrafish after spinal cord injury. To investigate the effects of brain on restoration from spinal cord injury, adult zebrafish spinal cord injury model was built and brain samples were dissected at different time points after the injury. Real-time quantitative PCR and in situ hybridization were applied to reveal the dynamics of glial cell line-derived neurotrophic factor (gdnf) and nitric oxide synthases (nos) mRNA expression in various regions of zebrafish brain. The results showed that, compared to sham group at each time points separately, the expression of gdnf mRNA in adult zebrafish brain during both acute phase (4 h and 12 h) and chronic phase of neuroregeneration (6 d and 11 d) increased significantly (P<0.05). The expression of nos mRNA in zebrafish brain enhanced during acute phase, and then reduced to the level lower than the sham group during the chronic phase of neuroregeneration (11 d) (P<0.05). This suggests that brain may promote neural axons regeneration in spinal cord via a more beneficial microenvironment which retains higher level of gdnf and lower level of nos. PMID- 23659941 TI - [Effect of horizontal rotary culture on zebrafish vascular development]. AB - With the development of space life science, a study on the influence of microgravity on organism has been an increasingly concerned topic. Lots of studies indicate that microgravity plays an important role in the early development of embryos. The vascular system as the first-function system of embryos provides an interesting topic for many researchers. However, those studies were mostly carried out in vitro by rotary cell culture system (RCCS), while few experiments were done in vivo. Using zebrafish as a model, this research investigated the effects of horizontal rotary culture on the vascular development in vivo. Zebrafish embryos at 24 hpf (hour post-fertilization) were selected and divided into two groups. One group was cultured by the shaker, and the other was cultured normally as the control. After 12 h, all the embryos were collected and detected. The phenotype of zebrafish was observed by stereo microscope. Then, the expression of vascular specific expression factor, flk1, flt4, and ephrinB2 was compared by RT-PCR, qPCR, and in situ hybridization, respectively. Cell apoptosis and proliferation in situ were observed using TUNEL assay and bromodeoxyuridine incorporation. The results demonstrated that horizontal rotary culture at 90 r/min decreased the hatching of embryos (10.3+/ 0.41 vs. 0.0, P<0.05), accelerate the heart rate (223.5+/-2.32 vs. 185.0+/-3.23, P<0.05) and increased the content of melanin in zebrafish significantly. At the same time, we found some differences in the vascular system of zebrafish after horizontal rotary culture which caused a down regulation of flk1, flt4, and ephrinB2. On the other hand, horizontal rotary culture accelerated the apoptosis of cells in zebrafish, but showed no significance in proliferation. In conclusion, horizontal rotary culture has a significant influence on the vascular development in zebrafish. PMID- 23659942 TI - [Construction and assessment of heart-specific green fluorescence zebrafish line]. AB - Using the promoter for cardiac myosin light chain 2 (cmlc2) gene, an expression vector pTol2-cmlc2-IRES- EGFP for making heart-specific expression of exogenous gene in transgenic zebrafish was generated previously. Here, we reported the construction of a transgenic zebrafish line which stably expresses EGFP using this vector, and the effects of EGFP on the heart development and cardiac function of this transgenic zebrafish line were preliminarily analyzed. The results showed that the green fluorescence signal of cmlc2:EGFP line under fluorescence microscopy specifically expressed in heart and faithfully recapitulated both the spatial and temporal expression patterns of endogenous cmlc2 gene revealed by in situ hybridization in the early developmental stages. The cardiac morphology and development of this transgenic zebrafish line remained to be normal. Furthermore, the heart morphology and physiological function of this transgenic line have been analyzed using M-mode analysis. The results showed that there was no significant difference between the cmlc2:EGFP and the wild type lines with respect to heart period, heart rate, diastolic surface area and systolic surface area, and fractional area change. No tachyarrhythmia was observed in the embryos from either line. Thus, the excessive expression of EGFP in this transgenic line seemed to exert no detrimental effects on the function and development of zebrafish hearts during early stages. Our study laid a foundation for the construction of exogenous gene transgenic line using pTol2 cmlc2-IRES-EGFP vector to study the function of genes that expressed in heart. PMID- 23659943 TI - [A brief protocol for high-resolution whole mount in situ hybridization in zebrafish]. AB - Whole mount in situ hybridization (WISH) is a popular technique that is used to study temporal-spatial gene expression at mRNA level in model systems. Sensitive and high-resolution WISH is important for every laboratory that uses this technique to study expression pattern of genes in wildtype and perturbed embryos. Based on the commonly used protocols in fish community, our lab optimizes them to get more sensitive and specific results. Here, we briefly summarize the history of this technology using zebrafish as an example, describe a detailed experimental protocol, and provide troubleshooting for imperfect results and their solution. PMID- 23659944 TI - [A surgery protocol to construct zebrafish heart damage and regeneration model]. AB - In recent years, zebrafish has been found to be strikingly capable of heart regeneration at adult stage, which sheds lights on cardiac regenerative medicine, and has also become an important direction for the study of vertebrate genetic and developmental mechanisms. Dissecting the regeneration process and unraveling the underlying molecular and cellular mechanisms might help recover the regeneration capacity of the mammalian heart and further provide instructions to potential therapies for certain cardiac diseases such as myocardial infarction. Here, we introduced a simple surgical method to construct heart injury and regeneration model in zebrafish through amputation of ~20% ventricle. The main procedure includes anaesthetization of adult zebrafish, exposure of the heart by dissecting the nearby abdominal skin and opening the pericardium, and amputation of certain fraction of the ventricle at the cardiac apex under a stereo microscope. Over 90% success rate and easy handling with high reproducibility enable this method to be the most commonly used one for the study of zebrafish heart regeneration. PMID- 23659945 TI - [A protocol for TALEN construction and gene targeting in zebrafish]. AB - TALEN (Transcription activator-like effector nuclease) is a newly developed family of artificially engineered sequence-specific endonucleases, which consists of a highly specific and repetitive DNA-binding domain derived from TALE (Transcription activator-like effector) and fused with the non-specific endonuclease domain of FokI. TALENs have been reported to be able to induce site specific genome modification in quite a few species and in vitro cultured cells. Here, we introduced the principles for target site selection and confirmation and described a brief experimental protocol for the easy construction of customized TALENs using unit assembly (UA) method and also for generation of and screening for TALEN-mediated targeted zebrafish mutants through microinjection of TALEN mRNAs into zebrafish embryos. Theoretically, the principles and methods we described here are also applicable to gene targeting in other species. PMID- 23659946 TI - The biopsy-proven benign thyroid nodule: is long-term follow-up necessary? AB - BACKGROUND: Thyroid nodules are common, and of those biopsied by fine-needle aspiration (FNA), the majority will be benign colloid nodules (BCN). Current guidelines suggest these BCN should be followed by ultrasonographic examination (US) every 3 years, with no endpoint specified. This study evaluated if long-term follow-up of benign thyroid nodules was associated with change in treatment or improvement in diagnosing a missed malignancy compared with short-term follow-up. STUDY DESIGN: All patients with FNA-based diagnosis of BCN at our institution from 1998 to 2009 were identified. Patients observed after the diagnosis were divided into short-term follow-up (<3 years) and long-term follow-up (>=3 years). Rates of repeat FNA, thyroidectomy, and malignancy detection were compared. RESULTS: Of 738 patients with BCN, 92 patients underwent thyroid resection after the initial US. Six hundred forty-six patients were observed, of which 366 returned for 1 or more follow-up US: 226 in the short-term group (median 13 months) and 140 in the long-term group (median 57 months). There were more follow up US in long-term vs short-term (medians 4 vs 2, p < 0.01), more repeat FNAs in the long-term group (18 of 140 vs 8 of 226, p < 0.01); but no difference in interval thyroidectomies (13 of 140 vs 31 of 226, p = 0.25) or malignant final pathology (0 of 13 vs 2 of 31, p > 0.99). For all patients undergoing surgery, pathology was malignant in 2 of 136 (1.5%). CONCLUSIONS: Long-term follow-up of patients with BCN is associated with increased repeat FNA and US without improvement in the malignancy detection rate. After 3 years of follow-up, consideration should be given to ceasing long-term routine follow-up of biopsy proven BCN. PMID- 23659947 TI - Predicting lymph node metastases in early esophageal adenocarcinoma using a simple scoring system. AB - BACKGROUND: Endoscopic resection is an organ-sparing option for early esophageal adenocarcinoma, but should be used only in patients with a negligible risk of lymph node metastases (LNM). The objective was to develop a simple scoring system to predict LNM in T1 esophageal adenocarcinoma. STUDY DESIGN: All primary esophagectomies performed for T1 esophageal adenocarcinoma without neoadjuvant therapy at 5 university institutions from 2000 to 2011 were analyzed. Patient and pathologic characteristics were compared between patients with LNM at the time of surgical resection and those without. Univariate and multivariate analyses were performed to establish a simple scoring system that estimated the risk of LNM, using variables from the final surgical pathology. RESULTS: A total of 258 patients were included for analysis (mean age 65.2 years [SD 10.3 years], 88% male). The incidence of LNM was 7% (9 of 122) for T1a and 26% (35 of 136) for T1b. Tumor size (odds ratio [OR] 1.35 per cm, 95% CI 1.07 to 1.71) and lymphovascular invasion (OR 7.50, 95% CI 3.30 to 17.07) were the strongest independent predictors of LNM. A weighted scoring system was devised from the final multivariate model and included size (+1 point per cm), depth of invasion (+2 for T1b), differentiation (+3 for each step of dedifferentiation), and lymphovascular invasion (+6 if present). Total number of points estimated the probability of LNM (low risk [0 to 1 point], <= 2%; moderate risk [2 to 4 points], 3% to 6%; and high risk [5+ points], >= 7%). CONCLUSIONS: We devised a simple scoring system that accurately estimates the risk of LNM to aid in decision-making in patients with T1 esophageal adenocarcinoma undergoing endoscopic resection. PMID- 23659948 TI - Investigation on the adsorption characteristics of anserine on the surface of colloidal silver nanoparticles. AB - The surface-enhanced Raman scattering (SERS) studies of anserine (beta-alanyl-N methylhistidine) was carried out on colloidal silver nanoparticles to understand its adsorption characteristics. The experimentally observed Raman bands were assigned based on the results of DFT calculations. The studies suggest that the interaction of anserine is primarily through the carboxylate group with the imidazole ring in an upright position with respect to the silver surface. Concentration dependent SERS studies suggest a change in orientation at sub monolayer concentration. PMID- 23659949 TI - Simultaneous monitoring of photocatalysis of three pharmaceuticals by immobilized TiO2 nanoparticles: chemometric assessment, intermediates identification and ecotoxicological evaluation. AB - In this study, the photocatalytic degradation of a mixture of three pharmaceuticals, Metronidazole (MET), Atenolol (ATL) and Chlorpromazine (CPR), was quantified simultaneously during the UV/TiO2 process. The investigated TiO2 was Millennium PC-500 immobilized on ceramic plates by sol-gel based method. The partial least squares modeling was successfully applied for the multivariate calibration of the spectrophotometric data. The central composite design was applied to model and optimize the UV/TiO2 process. Predicted values of removal efficiency were found to be in good agreement with experimental values for MET, ATL and CPR (R(2)=0.947 and Adj-R(2)=0.906, R(2)=0.977 and Adj-R(2)=0.960 and R(2)=0.982 and Adj-R(2)=0.969, respectively). The optimum initial concentration of pharmaceuticals, reaction time and UV light intensity was found to be 10 mg L( 1), 150 min and 38.45 W m(-2), respectively. The main degradation intermediates of pharmaceuticals produced in this process were identified by GC-MS technique. The chronic ecotoxicity of pharmaceuticals was evaluated using aquatic species Spirodela polyrrhiza prior to and after photocatalysis. The TOC results (90% removal after 16 h) and ecotoxicological experiments revealed that the photocatalysis process could effectively mineralize and reduce the ecotoxicity of the pharmaceuticals from their aqueous solutions. PMID- 23659950 TI - Synthesis of highly active thin film based on TiO2 nanomaterial for self-cleaning application. AB - Highly active self-cleaning surfaces were prepared from hydrothermally treated TiO2 nanomaterials for different times (0, 12, 24 and 36 h) under acidic condition. TiO2 thin films were characterized by X-ray diffraction (XRD), transmission electron microscope (TEM) and scanning electron microscope (SEM). TiO2 thin film (hydrothermal 24h) exhibited hybrid morphology from accumulated plates, clusters, rods and spheres. The photo self-cleaning activity in term of quantitative determination of the active oxidative species (OH) produced on the thin film surfaces was evaluated using fluorescent probe method. The results show that, the highly active thin film is the hydrothermally treated for 24 h at 200 degrees C. The structural, morphology and photoactivity properties of nano-TiO2 thin films make it promising surfaces for self-cleaning application. Mineralization of commercial textile dye (Remazol Red RB-133, RR) from highly active TiO2 thin film surface was applied. Moreover, the durability of this nano TiO2 thin film (hydrothermal 24h) was studied. PMID- 23659951 TI - The spectroscopic (FTIR, FT-Raman and UV-Vis spectra), DFT and normal coordinate computations of m-nitromethylbenzoate. AB - A combined experimental and theoretical study on molecular structure, vibrational spectra, NBO and UV-spectral analysis of m-nitromethylbenzoate (MNMB) has been reported in the present work. The FT-IR solid phase (4000-400 cm(-1)) and FT Raman spectra (3500-100 cm(-1)) of MNMB was recorded. The molecular geometry, harmonic vibrational frequencies and bonding features of MNMB in the ground-state have been calculated by using the density functional method B3LYP with 6-31G (d,p) and 6-31+G(d,p) basis sets. The assignments of the vibrational spectra have been carried out with the help of normal co-ordinate analysis (NCA) following the Scaled Quantum Mechanical Force Field Methodology (SQMFF). Stability of the molecule arising from hyperconjugative interactions, charge delocalization has been analyzed using natural bond orbital (NBO) analysis. The results show that charge in electron density (ED) in the sigma* antibonding orbitals and E(2) energies confirms the occurrence of ICT (Intra-molecular Charge Transfer) within the molecule. The UV spectrum was measured in ethyl acetate solution. The energy and oscillator strength calculated by Time-Dependent Density Functional Theory (TD-DFT) result complements the experimental findings. The calculated HOMO and LUMO energies show that charge transfer occurs within the molecule. Finally the calculation results were applied to simulated infrared and Raman spectra of the title compound which show good agreement with observed spectra. PMID- 23659952 TI - Quantum mechanical study of the structure and spectroscopic, first order hyperpolarizability, Fukui function, NBO, normal coordinate analysis of phenyl-N (4-methyl phenyl) nitrone. AB - The title compound, Phenyl-N-(4-Methyl Phenyl) Nitrone (PN4MPN) was synthesized and characterized by FT-IR, FT-Raman and (1)HNMR, (13)CNMR spectral analysis. The molecular geometry, harmonic vibrational frequencies and bonding features of the title compound in the ground state are computed at the Hartree-Fock/6-311++G(d,p) and three parameter hybrid functional Lee-Yang-Parr/6-311++G(d,p) levels of theory. The calculated results show that the predicted geometry can well reproduce the structural parameters. The assignments of the vibrational spectra have been carried out with the help of normal co-ordinate analysis (NCA) following the scaled quantum mechanical force field methodology (SQMF). The calculated HOMO and LUMO energies confirm that charge transfer occurs within the molecule. The dipole moment (MU), polarizability (alpha) and hyperpolarizability (beta) of the investigated molecule is calculated by using HF/6-311++G(d,p) and B3LYP/6-311++G(d,p) methods on the finite field approach. Besides, Molecular Electrostatic Potential (MEP), Natural Bond Orbital analysis (NBO) and thermodynamical properties are described from the computational process. The electron density-based local reactivity descriptor such as Fukui functions are calculated to explain the chemical selectivity or reactivity site in PN4MPN. Finally, the calculations are applied to simulated FT-IR and FT-Raman spectra of the title compound which show good agreement with observed spectra. PMID- 23659954 TI - Reinvestigation of growth of urea thiosemicarbazone monohydrate crystal. AB - The reaction of urea with thiosemicarbazide in 1:1 mole ratio in aqueous solution does not result in the formation of urea thiosemicarbazone monohydrate crystal, as reported by Hanumantharao, Kalainathan and Bhagavannarayana [Spectrochim. Acta A91 (2012) 345-351]. A reinvestigation of the reported reaction reveals that the crystal obtained is the starting material namely thiosemicarbazide, which has been unambiguously confirmed with the aid of infrared and (1)H NMR spectra and single crystal X-ray structure determination. Analysis of (1)H NMR spectrum reveals that thiosemicarbazide exhibits thione-thiol tautomerism in solution. In contrast, thiosemicarbazide exists as the thione tautomer in the solid state. PMID- 23659953 TI - Molecular spectroscopic studies on the interaction of ferulic acid with calf thymus DNA. AB - The interaction between ferulic acid and calf thymus deoxyribonucleic acid (ctDNA) under physiological conditions (Tris-HCl buffer solutions, pH 7.4) was investigated by UV-Vis spectroscopy, fluorescence spectroscopy, DNA melting techniques, and viscosity measurements. Results indicated that a complex of ferulic acid with ctDNA was formed with a binding constant of K(290K)=7.60*10(4) L mol(-1) and K(310K)=4.90*10(4) L mol(-1). The thermodynamic parameters enthalpy change (DeltaH degrees ), entropy change (DeltaS degrees ) and Gibbs free energy (DeltaG degrees ) were calculated to be -1.69*10(4) J mol(-1), 35.36 J K(-1) mol( 1) and -2.79*10(4) J mol(-1) at 310 K, respectively. The acting forces between ferulic acid and DNA mainly included hydrophobic interaction and hydrogen bonds. Acridine orange displacement studies revealed that ferulic acid can substitute for AO probe in the AO-DNA complex which was indicative of intercalation binding. Thermal denaturation study suggested that the interaction of ferulic acid with DNA could result in the increase of the denaturation temperature, which indicated that the stabilization of the DNA helix was increased in the presence of ferulic acid. Spectroscopic techniques together with melting techniques and viscosity determination provided evidences of intercalation mode of binding for the interaction between ferulic acid and ctDNA. PMID- 23659955 TI - Vibrational spectroscopic characterization of the sulphate mineral leightonite K2Ca2Cu(SO4)4.2H2O--implications for the molecular structure. AB - The mineral leightonite, a rare sulphate mineral of formula K2Ca2Cu(SO4)4.2H2O, has been studied using a combination of electron probe and vibrational spectroscopy. The mineral is characterized by an intense Raman band at 991 cm(-1) attributed to the SO4(2-) nu1 symmetric stretching mode. A series of Raman bands at 1047, 1120, 1137, 1163 and 1177 cm(-1) assigned to the SO4(2-) nu3 antisymmetric stretching modes. The observation of multiple bands shows that the symmetry of the sulphate anion is reduced. Multiple Raman and infrared bands in the OH stretching region shows that water in the structure of leightonite is in a range of molecular environments. PMID- 23659956 TI - Vibrational spectroscopic characterization of growth bands in Porites coral from South China Sea. AB - A series of samples from different growth bands of Porites coral skeleton were studied using Raman, infrared reflectance methods. The Raman spectra proved that skeleton samples from different growth bands have the same mineral phase as aragonite, but a band at 133 cm(-1) for the top layer shows a transition from ~120 cm(-1) for vaterite to ~141 cm(-1) for aragonite. It is inferred that the vaterite should be the precursor of aragonite of coral skeleton. The positional shift in the infrared spectra of the skeleton samples from growth bands correlate significantly to their minor elements (Li, Mg, Sr, Mn, Fe and U) contents. Mg, Sr and U especially have significant negative correlations with the positions of the antisymmetric stretching band nu3 at ~1469 cm(-1). And Li shows a high negative correlation with nu2 band (~855 cm(-1)), while Sr and Mn show similar negative correlation with nu4 band (~712 cm(-1)). And Mn also shows a negative correlation with nu1 band (~1082 cm(-1)). A significantly negative correlation is observed for U with nu1+nu4 band (~1786 cm(-1)). However, Fe shows positive correlation with nu1, nu2, nu3, nu4 and nu1+nu4 bands shifts, especially a significant correlation with nu1 band (~1082 cm(-1)). New insights into the characteristics of coral at different growth bands of skeleton are given in present work. PMID- 23659957 TI - Bidentate coordinating behaviour of chalcone based ligands towards oxocations: VO(IV) and Mo(V). AB - We synthesized and studied the coordinating behaviour of chalcone based ligands derived from DHA and n-alkoxy benzaldehyde and their complexes of VO(IV) and MoO(V). The chalcone ligands are characterized by elemental analyses, UV-visible, IR, (1)H NMR, and mass spectra. The resulting oxocation complexes are also characterized by elemental analyses, IR, (1)H NMR, electronic, electron spin resonance spectra, magnetic susceptibility measurement and molar conductance studies. The IR and (1)H NMR spectral data suggest that the chalcone ligands behave as a monobasic bidentate with O:O donor sequence towards metal ion. The molar conductivity data show them to be non-electrolytes. From the electronic, magnetic and ESR spectral data suggest that all the chalcone ligand complexes of VO(IV) and MoO(V) have distorted octahedral geometry. PMID- 23659958 TI - Photoelectron spectroscopy of non-steroidal anti-inflammatory drugs. AB - The electronic structures of eight non-steroidal anti-inflammatory drugs (NSAIDs) had been studied by UV photoelectron spectroscopy (UPS) and high-level Green's function (GF) calculations. Our UPS data show that the electronic structure influences the measured biological activity of NSAID, but that it is not the dominating factor. The role of electronic structure needs to be considered in conjunction with other factors like steric properties of the COX active site and orientation of relevant residues in the same site. PMID- 23659959 TI - A highly selective fluorescent sensor for Fe3+ based on covalently immobilized derivative of naphthalimide. AB - In this paper, the fabrication and analytical characteristics of fluorescence based ferric ion-sensing glass slides were described. To fabricate the sensor, a naphthalimide derivative (compound 1) with a terminal double bond was synthesized and copolymerized with 2-hydroxyethyl methacrylate (HEMA) on the activated surface of glass slides by UV irradiation. Upon the addition of Fe(3+) in 0.05 mol/L Tris/HCl (pH 6.02) at 25 degrees C, the fluorescence intensity of the resulting optical sensor decrease, which has been utilized as the basis for the selective detection of Fe(3+). The sensor can be applied to the quantification of Fe(3+) with a linear range covering form 1.0*10(-5) to 1.0*10(-3) M and a detection limit of 4.5*10(-6) M. The experiment results show that the response behavior of the sensor to Fe(3+) is pH-independent in medium condition (pH 5.00 8.00) and exhibits high selectivity for Fe(3+) over a large number of cations such as alkali, alkaline earth and transitional metal ions. Moreover, satisfactory reproducibility, reversibility and a rapid response were realized. The sensing membrane was found to have a lifetime at least 2 months. The accuracy and the precision of the method were evaluated by the analysis of the standard reference material, iron in water (1.0 mol/L HNO3). The developed sensor is applied for the determination of iron in pharmaceutical preparation samples with satisfactory results. PMID- 23659960 TI - Immunological changes of chronic oral exposure to depleted uranium in mice. AB - Direct ingestion of contaminated soil by depleted uranium (DU) might lead to internal exposure to DU by local populations through hand contamination. The purpose of this study was to assess the immunological changes of long-term exposure to various doses of DU in mice. Three-week-old Kunming mice were divided into the following 4 groups based on the various feeding doses (containing DU): 0 (control group), 3 (DU3 group), 30 (DU30 group), and 300 mg/kg feed (DU300 group). After 4 months of exposure, in the DU300 group, the innate immune function decreased, manifesting as decreased secretion of nitric oxide, interleukin (IL)-1beta, IL-18, and tumour necrosis factor (TNF)-alpha in the peritoneal macrophages, as well as reduced cytotoxicity of the splenic natural killer cells. Moreover, the cellular and humoral immune functions were abnormal, as manifested by decreased proliferation of the splenic T cells, proportion of the cluster of differentiation (CD) 3(+) cells, ratio of CD4(+)/CD8(+) cells and delayed-type hypersensitivity, and increased proliferation of the splenic B cells, total serum immunoglobin (Ig) G and IgE, and proportion of splenic mIgM(+)mIgD(+) cells. Through stimulation, the secretion levels of interferon (IFN)-gamma and TNF-alpha in the splenic cells were reduced, and the levels of IL 4 and IL-10 were increased. By comparison, in the DU30 and DU3 groups, the effects were either minor or indiscernible. In conclusions, chronic intake of higher doses of DU (300 mg/kg) had a significant impact on the immune function, most likely due to an imbalance in T helper (Th) 1 and Th2 cytokines. PMID- 23659961 TI - A note on the security of IS-RFID, an inpatient medication safety. AB - OBJECTIVE: In this paper we investigate the security level of a comprehensive RFID solution to enhance inpatient medication safety, named IS-RFID, which has been recently proposed by Peris-Lopez et al. METHOD: We analyses the security of the protocol against the known attacks in the context. The main target of this paper is to determine whether the new protocol provides the confidentiality property, which is expected to be provided by such a protocol. RESULTS: It was found that IS-RFID has critical weaknesses. The presented security investigations show that a passive adversary can retrieve secret parameters of patient's tag in cost of O(2(16)) off-line PRNG evaluations. Given the tag's secret parameters, any security claims are ruined. CONCLUSIONS: In this paper we presented an efficient passive secret disclosure attack which retrieves the main secret parameters related to the patient which shows that IS-RFID may put the patient safety on risk. The proposed attacking technique is in light of two vulnerabilities of the protocol: (1) the short length of the used PRNG, which is urged by the target technology, EPC C1 Gen2 ; (2) the message-generating mechanism utilizing PRNG was not carefully scrutinized. While the later point can be fixed by careful designing of the transferred messages between the protocol's party, the earlier point, i.e., the short length of the available PRNG for EPC C1 Gen2 tags, is a limitation which is forced by the technology. In addition, over the last years, schemes based solely on using simple operations or short PRNG (such as IS-RFID) have been shown to offer very low or no security at all. Recent advances in lightweight ciphers, such as PRESENT or Grain , seem a much more appropriate solution rather than relying on short PRNGs. However, such solutions breaks the EPC C1 Gen2 compatibility. PMID- 23659963 TI - Determination of low levels of polycyclic aromatic hydrocarbons in soil by high performance liquid chromatography with tandem fluorescence and diode-array detectors. AB - Risk assessment of polycyclic aromatic hydrocarbons (PAHs) contaminated soil and source apportionment require accurate analysis of the concentration of each PAH congener in the soil. However, determination of low level PAH congeners in soil is difficult because of similarity in the chemical properties of 16 PAHs and severe matrix interferences due to complex composition of soils. It is therefore imperative to develop a sensitive and accurate method for determination of low level PAHs in soil. In this work, high performance liquid chromatography equipped with fluorescence and diode-array detectors (HPLC-FLD-DAD) was used to determine the concentration of 16 PAHs in soil. The separation of the 16 PAHs was achieved by optimization of the mobile phase gradient elution program and FLD wavelength switching program. Qualitative analysis of the 16 PAHs was based on the retention time (RT) and each PAH specific spectrum obtained from DAD. In contrast, the quantitative analysis of individual PAH congeners was based on the peak areas at the specific wavelength with DAD and FLD. Under optimal conditions the detection limit was in the range 1.0-9.5 MUg L(-1) for 16 PAHs with DAD and 0.01-0.1 MUg L( 1) for 15 PAHs with FLD, and the RSD of PAHs was less than 5% with DAD and 3% with FLD. The spiked recoveries were in the range 61-96%, with the exception of NaP (<40%). The results show that HPLC-FLD-DAD can provide more accurate and reliable analysis of low level PAH congeners in soil samples. PMID- 23659962 TI - Enrichment map profiling of the cancer invasion front suggests regulation of colorectal cancer progression by the bone morphogenetic protein antagonist, gremlin-1. AB - The cancer invasion front (CIF), a spatially-recognized area due to the frequent presence of peritumoral desmoplastic reaction, represents a cancer site where many hallmarks of cancer metastasis occur. It is now strongly suggested that the desmoplastic microenvironment holds crucial information for determining tumor development and progression. Despite extensive research on tumor-host cell interactions at CIFs, the exact paracrine molecular network that is hardwired into the proteome of the stromal and cancer subpopulations remains partially understood. Here, we interrogated the signaling pathways and the molecular functional signatures across the proteome of a desmoplastic coculture model system of colorectal cancer progression. We discovered a group of bone morphogenetic protein (BMP) antagonists that coordinates major biological programs in CIFs, including cell proliferation, invasion, migration and differentiation processes. Using a mathematical model of cancer cell progression, coupled to in vitro cell migration assays, we demonstrated that the prominent BMP antagonist gremlin-1 (GREM1) may trigger motility of cancer cell cohorts. Our data collectively demonstrate that the desmoplastic CIFs deploy a microenvironmental signature, based on BMP antagonism, in order to regulate the motogenic fates of cancer cell cohorts invading the adjacent stroma. PMID- 23659965 TI - Removal characteristics of engineered nanoparticles by activated sludge. AB - Environmental release of engineered nanoparticles (NPs) has been on the rise due to the increased use of NPs in commercial products. In addition, the fate of NPs in sewage treatment processes may play an important role in determining the environmental release pathway of NPs. In this study, we investigated the removal of engineered NPs (AgNPs, TiO2NPs, and SiO2NPs) using activated sludge by evaluating the effects of several important factors of the NPs, including physicochemical properties, contact time between NPs and activated sludge, aquatic chemistry of sewage, and the presence of extracellular polymeric substances (EPS) in the activated sludge. For all three types of NPs tested, a considerable amount of NPs were removed after exposure to activated sludge in a time-dependent manner; nevertheless, the removal efficiencies depended on the type of NPs and seemed to be affected by the NP stability relative to the hydrodynamic diameter (HDD) and zeta potential. In addition, the presences of both ionic compounds and EPS significantly enhanced the NP removal efficiency, indicating that the instability of the NPs resulting from the ionic strength in sewage and entrapment of NP by EPS played an important role in NP removal by activated sludge. These results suggest that the removal efficiencies can be affected by the operating conditions of the activated sludge process and the conditions of the activated sludge; therefore, these factors should be considered when developing approaches to sufficiently remove NPs from sewage treatment plants. PMID- 23659964 TI - Comparison of response indices to toxic microcystin-LR in blood of mice. AB - In order to investigate the response indices to toxic microcystin-LR (MC-LR) in blood of mice, concentrations of free and total MC-LR in blood and tissues, accompanied by serous parameters in series including some enzymatic activities, hematology and the function of leukocytes, were determined in mice exposed to the toxin ranging from 3.125 to 25.000 MUg kg(-1)day(-1) by intraperitoneal injection for 7 days. On the 7th day, the ratios of mass of free MC-LR in serum to the mass of MC-LR in given dose were 3.843-4.555%, while the ratios of total MC-LR in liver were 34.465-38.567%. Comparing the overall experimental results, the three most sensitive indices are total MC-LR in the liver, the phagocytic index and reactive oxygen species (ROS) which have shown significant differences between the lowest dose group and the control group. Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and lactate dehydrogenase had proportional correlations with the MC-LR exposure doses, and the hematology of the majority of blood cells and the volume of erythrocytes were also influenced by the toxin. The alterations of some cytokines and the ROS of leukocytes were observed. The results of the studies suggest that measurement of MC-LR in blood is powerful and clear evidence to indicate that subjects have been exposed to MC-LR and can be used to discriminate from other causes leading to hepatic lesions although it is not as sensitive as other indices that are usually as useful complements to reflect the liver function. PMID- 23659966 TI - Trace metals in fugitive dust from unsurfaced roads in the Viburnum Trend resource mining District of Missouri--implementation of a direct-suspension sampling methodology. AB - Fugitive dust from 18 unsurfaced roadways in Missouri were sampled using a novel cyclonic fugitive dust collector that was designed to obtain suspended bulk samples for analysis. The samples were analyzed for trace metals, Fe and Al, particle sizes, and mineralogy to characterize the similarities and differences between roadways. Thirteen roads were located in the Viburnum Trend (VT) mining district, where there has been a history of contaminant metal loading of local soils; while the remaining five roads were located southwest of the VT district in a similar rural setting, but without any mining or industrial process that might contribute to trace metal enrichment. Comparison of these two groups shows that trace metal concentration is higher for dusts collected in the VT district. Lead is the dominant trace metal found in VT district dusts representing on average 79% of the total trace metal concentration, and was found moderately to strongly enriched relative to unsurfaced roads in the non-VT area. Fugitive road dust concentrations calculated for the VT area substantially exceed the 2008 Federal ambient air standard of 0.15MUgm(-3) for Pb. The pattern of trace metal contamination in fugitive dust from VT district roads is similar to trace metal concentrations patterns observed for soils measured more than 40years ago indicating that Pb contamination in the region is persistent as a long-term soil contaminant. PMID- 23659967 TI - Influence of a municipal waste landfill on the spatial distribution of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs/Fs) in the natural environment. AB - The paper presents the influence of a municipal waste landfill on the pollution of soil, plants and groundwater by polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs/Fs). Analysis of their migration in the environment was made in relation to the direction of groundwater flow in the study area. Determination of PCDDs/Fs was performed by isotope dilution high resolution chromatography/tandem mass spectrometry (ID-HRGC/MS-MS) on a Thermo Scientific GCQ-1100/Trace2000 system equipped with an Xcalibur data acquisition and analysis software. The content in soil was in the range of 0.04-27.3pg I-TEQg(-1) of soil dry mass and decreased with depth. Similar values were obtained for plants: in Solidago virgaurea L. there were 0.13-1.9pg I-TEQg(-1) dry mass and in grass from the Family Poaceae - 0.12-3.18pg I-TEQg(-1) dry mass. The concentration in groundwater reached 1.16-6.6pg I-TEQdm(-3); the highest concentration was obtained in water samples collected from a ditch collecting leachates from the landfill. The study has shown that the analyzed object is not responsible for PCDDs/Fs emission to the environment. The increased concentration of these compounds in the topsoil may be influenced by processes linked with waste management (transportation and unloading) and other localized sources of low emission located beyond the landfill. PMID- 23659970 TI - Tumor heterogeneity and permeability as measured on the CT component of PET/CT predict survival in patients with non-small cell lung cancer. AB - PURPOSE: We prospectively examined the role of tumor textural heterogeneity on positron emission tomography/computed tomography (PET/CT) in predicting survival compared with other clinical and imaging parameters in patients with non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: The feasibility study consisted of 56 assessed consecutive patients with NSCLC (32 males, 24 females; mean age 67 +/ 9.7 years) who underwent combined fluorodeoxyglucose (FDG) PET/CT. The validation study population consisted of 66 prospectively recruited consecutive consenting patients with NSCLC (37 males, 29 females; mean age, 67.5 +/- 7.8 years) who successfully underwent combined FDG PET/CT-dynamic contrast-enhanced (DCE) CT. Images were used to derive tumoral PET/CT textural heterogeneity, DCE CT permeability, and FDG uptake (SUVmax). The mean follow-up periods were 22.6 +/ 13.3 months and 28.5+/- 13.2 months for the feasibility and validation studies, respectively. Optimum threshold was determined for clinical stage and each of the above biomarkers (where available) from the feasibility study population. Kaplan Meier analysis was used to assess the ability of the biomarkers to predict survival in the validation study. Cox regression determined survival factor independence. RESULTS: Univariate analysis revealed that tumor CT-derived heterogeneity (P < 0.001), PET-derived heterogeneity (P = 0.003), CT-derived permeability (P = 0.002), and stage (P < 0.001) were all significant survival predictors. The thresholds used in this study were derived from a previously conducted feasibility study. Tumor SUVmax did not predict survival. Using multivariable analysis, tumor CT textural heterogeneity (P = 0.021), stage (P = 0.001), and permeability (P < 0.001) were independent survival predictors. These predictors were independent of patient treatment. CONCLUSIONS: Tumor stage and CT derived textural heterogeneity were the best predictors of survival in NSCLC. The use of CT-derived textural heterogeneity should assist the management of many patients with NSCLC. PMID- 23659969 TI - A multicenter, first-in-pediatrics, phase 1, pharmacokinetic and pharmacodynamic study of ridaforolimus in patients with refractory solid tumors. AB - PURPOSE: Ridaforolimus (MK-8669, AP23573) is a potent and selective mammalian target of rapamycin (mTOR) inhibitor. Preclinically, ridaforolimus displays antiproliferative activity against a variety of human tumors in vitro and tumor xenograft models in vivo, with additive or synergistic activity when combined with other anticancer agents. Antitumor activity has been confirmed in adults. This phase I study determined the safety, pharmacological, biologic, and toxicity profiles of ridaforolimus in pediatric patients with refractory malignancies. EXPERIMENTAL DESIGN: Eligible children ages 1 to 18 years with advanced solid tumors were enrolled in a 3 + 3 dose escalation design, to determine the safety, tolerability, and maximum tolerated dose (MTD)/dose-limiting toxicity (DLT) of ridaforolimus. Toxicities, pharmacokinetics, and pharmacodynamics were characterized. RESULTS: Fifteen patients were treated. No DLT was observed at any dose level tested; therefore, an MTD was not identified. Most adverse events were mild to moderate; the most common grades 3 and 4 adverse events were hematologic, including thrombocytopenia and anemia. Nonhematologic adverse events were mostly electrolyte disturbances. The observed pharmacokinetic profile of ridaforolimus in children was consistent with that previously showed in adults. Pharmacodynamic confirms that the dose range tested has pharmacological/pharmacodynamic activity. Forty percent of patients achieved stable disease including four of six with central nervous system tumors and two of eight with sarcomas. CONCLUSIONS: This first-in-pediatrics study shows that the second-generation mTOR inhibitor ridaforolimus is well tolerated in heavily pretreated children with refractory solid tumors. No DLTs were observed over the dose range tested. Ridaforolimus may represent a therapeutic option for use in pediatric malignancies. PMID- 23659968 TI - ETS2 mediated tumor suppressive function and MET oncogene inhibition in human non small cell lung cancer. AB - PURPOSE: The ETS2 transcription factor is an evolutionarily conserved gene that is deregulated in cancer. We analyzed the transcriptome of lung adenocarcinomas and normal lung tissue by expression profiling and found that ETS2 was significantly downregulated in adenocarcinomas. In this study, we probed the yet unknown functional role of ETS2 in lung cancer pathogenesis. EXPERIMENTAL DESIGN: Lung adenocarcinomas (n = 80) and normal lung tissues (n = 30) were profiled using the Affymetrix Human Gene 1.0 ST platform. Immunohistochemical (IHC) analysis was conducted to determine ETS2 protein expression in non-small cell lung cancer (NSCLC) histologic tissue specimens (n = 201). Patient clinical outcome, based on ETS2 IHC expression, was statistically assessed using the log rank and Kaplan-Meier tests. RNA interference and overexpression strategies were used to assess the effects of ETS2 expression on the transcriptome and on various malignant phenotypes. RESULTS: ETS2 expression was significantly reduced in lung adenocarcinomas compared with normal lung (P < 0.001). Low ETS2 IHC expression was a significant predictor of shorter time to recurrence in NSCLC (P = 0.009, HR = 1.89) and adenocarcinoma (P = 0.03, HR = 1.86). Moreover, ETS2 was found to significantly inhibit lung cancer cell growth, migration, and invasion (P < 0.05), and microarray and pathways analysis revealed significant (P < 0.001) activation of the HGF pathway following ETS2 knockdown. In addition, ETS2 was found to suppress MET phosphorylation and knockdown of MET expression significantly attenuated (P < 0.05) cell invasion mediated by ETS2-specific siRNA. Furthermore, knockdown of ETS2 augmented HGF-induced MET phosphorylation, cell migration, and invasion. CONCLUSION(S): Our findings point to a tumor suppressor role for ETS2 in human NSCLC pathogenesis through inhibition of the MET proto-oncogene. PMID- 23659971 TI - A phase I, open-label study of siltuximab, an anti-IL-6 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma, multiple myeloma, or Castleman disease. AB - PURPOSE: To evaluate the safety and pharmacokinetics of siltuximab, an anti interleukin-6 chimeric monoclonal antibody (mAb) in patients with B-cell non Hodgkin lymphoma (NHL), multiple myeloma, or Castleman disease. EXPERIMENTAL DESIGN: In an open-label, dose-finding, 7 cohort, phase I study, patients with NHL, multiple myeloma, or symptomatic Castleman disease received siltuximab 3, 6, 9, or 12 mg/kg weekly, every 2 weeks, or every 3 weeks. Response was assessed in all disease types. Clinical benefit response (CBR; composite of hemoglobin, fatigue, anorexia, fever/night sweats, weight, largest lymph node size) was also evaluated in Castleman disease. RESULTS: Sixty-seven patients received a median of 16 siltuximab doses for a median of 8.5 (maximum 60.5) months; 29 were treated 1 year or longer. There was no dose-limiting toxicity, antibodies to siltuximab, or apparent dose-toxicity relationship. The most frequently reported possible drug-related adverse events were thrombocytopenia (25%), hypertriglyceridemia (19%), neutropenia (19%), leukopenia (18%), hypercholesterolemia (15%), and anemia (10%). None of these events led to dose delay/discontinuation except for neutropenia and thrombocytopenia (n = 1 each). No treatment-related deaths occurred. C-reactive protein (CRP) suppression was most pronounced at 12 mg/kg every 3 weeks. Mean terminal-phase half-life of siltuximab ranged 17.73 to 20.64 days. Thirty-two of 37 (86%) patients with Castleman disease improved in 1 or more CBR component; 12 of 36 evaluable Castleman disease patients had radiologic response [complete response (CR), n = 1; partial response (PR), n = 11], including 8 of 19 treated with 12 mg/kg; 2 of 14 (14%) evaluable NHL patients had PR; 2 of 13 (15%) patients with multiple myeloma had CR. CONCLUSION: No dose related or cumulative toxicity was apparent across all disease indications. A dose of 12 mg/kg every 3 weeks was recommended on the basis of the high response rates in Castleman disease and the sustained CRP suppression. Randomized studies are ongoing in Castleman disease and multiple myeloma. PMID- 23659973 TI - Correction of lower lid retraction using tarSys bioengineered grafts for graves ophthalmopathy. AB - PURPOSE: To investigate the efficacy of decellularized porcine-derived membrane (tarSys; IOP Inc), a bioengineered eyelid spacer graft, for lower lid retraction correction in patients with Graves ophthalmopathy. DESIGN: Retrospective observational case series study. METHODS: This was a retrospective review of patients with Graves ophthalmopathy undergoing lower eyelid retraction surgery using decellularized porcine-derived membrane bioengineered eyelid spacer grafts from 2008 through 2011. Outcome measures included lower eyelid height (measured from the corneal light reflex to the lower eyelid margin, or marginal reflex distance-2 [MRD2]), reduction of lagophthalmos, cosmetic appearance, complications, and need for further surgery. Presurgery and postreconstruction photographs were reviewed for functional and cosmetic outcome. RESULTS: A total of 32 Graves patients and 37 eyelids underwent lower eyelid retraction surgery using decellularized porcine-derived membrane. There were 10 male and 22 female patients with mean age of 41.8 +/- 8.6 years. Mean improvement in MRD2 was 1.4 +/ 0.4 mm. Mean reduction of lagophthalmos was 1.3 +/- 0.4 mm. There are statistically significant differences between preoperative and postoperative MRD2 and lagophthalmos (paired t test, both P < .0001). No evidence of infection and corneal erosion was noted and none of the patients needed further surgeries. Prolonged lower lid swelling and slight puffy appearance were noted for 6 patients. The swelling and puffy appearance resolved completely 3 months after surgery. Conjunctival granuloma formation was found in 1 patient. The cosmetic result was satisfactory in all cases. CONCLUSIONS: Decellularized porcine-derived membrane, a bioengineered graft, is effective for the management of lower lid retraction in patients with Graves ophthalmopathy. It can offer an alternate graft for eyelid reconstruction. PMID- 23659974 TI - Determinations of gas-liquid partition coefficients using capillary chromatographic columns. Alkanols in squalane. AB - This study focused on an investigation into the experimental quantities inherent in the determination of partition coefficients from gas-liquid chromatographic measurements through the use of capillary columns. We prepared several squalane - (2,6,10,15,19,23-hexamethyltetracosane) - containing columns with very precisely known phase ratios and determined solute retention and hold-up times at 30, 40, 50 and 60 degrees C. We calculated infinite dilution partition coefficients from the slopes of the linear regression of retention factors as a function of the reciprocal of the phase ratio by means of fundamental chromatographic equations. In order to minimize gas-solid and liquid-solid interface contributions to retention, the surface of the capillary inner wall was pretreated to guarantee a uniform coat of stationary phase. The validity of the proposed approach was first tested by estimating the partition coefficients of n-alkanes between n-pentane and n-nonane, for which compounds data from the literature were available. Then partition coefficients of sixteen aliphatic alcohols in squalane were determined at those four temperatures. We deliberately chose these highly challenging systems: alcohols in the reference paraffinic stationary phase. These solutes exhibited adsorption in the gas-liquid interface that contributed to retention. The corresponding adsorption constant values were estimated. We fully discuss here the uncertainties associated with each experimental measurement and how these fundamental determinations can be performed precisely by circumventing the main drawbacks. The proposed strategy is reliable and much simpler than the classical chromatographic method employing packed columns. PMID- 23659972 TI - Correction of ocular shape in retinal optical coherence tomography and effect on current clinical measures. AB - PURPOSE: To address the misrepresentation of the eye in retinal optical coherence tomography (OCT) images and to examine the effect of this misrepresentation on retinal thickness measurements. DESIGN: Prospective case series. METHODS: Five subjects with recent orbital magnetic resonance imaging (MRI) scans and normal eye examinations were consented from the clinics of the Duke Eye Center. Each subject had both eyes imaged using a retinal spectral-domain OCT system and ocular biometry measured. Two types of individualized optical models of the subject eyes-numerical and analytical-were used to determine the spatial paths of the OCT A-scans. These paths were used to reorient the A-scans in the associated retinal OCT images and generate corrected images. Using curvature as a general measure of shape, the radii of curvature of the retinal pigment epithelium in the original and corrected OCT images were compared to the ocular radii of curvature in the MRI images. Differences between the retinal thickness maps derived from the original and corrected OCT images were then determined. RESULTS: The retinal curvatures were substantially flatter in the original OCT than in the MRI images (mean paired difference: 52.8 +/- 41.8 mm, P < .001). Correcting the OCT images decreased the paired differences between OCT and MRI (numerical: 1.6 +/- 2.3 mm, P = .091; analytical: 1.9 +/- 4.3 mm, P = .278). Retinal thickness measurements between the corrected and uncorrected images differed, with a root mean square difference of 5.61 MUm over the entire 6-mm extent of the image; this difference was greater peripherally (6.02 MUm) than centrally (2.54 MUm). CONCLUSIONS: Optically based algorithms can be used to correct the shape of the retina as represented in OCT; this correction makes OCT more consistent with other clinical imaging techniques. Resultant retinal thickness maps were minimally affected by the change in shape. Ocular shape correction should be considered in future development of posterior segment OCT-based morphologic measurements. PMID- 23659975 TI - Developments in injection port derivatization. AB - Derivatization is conducted to increase the volatility, thermal stability and detectability of the analytes to make them appropriate for gas chromatographic (GC) analysis. The injection port derivatization (IPD), on-line derivatization in nature, occurs in the high-temperature GC injection port. It is demonstrated to be superior to the off-line derivatization with its simplicity, high reaction efficiency and less consumption of potential poisonous reagents. To further encourage applications of this technology, developments in IPD are well highlighted in the present review. The primary types of derivatization reactions involved in IPD are based on silylation, alkylation and acylation. The parameters influential to IPD reactions, such as injection port temperature, purge off time and the amount of derivatization reagents, are elaborated. Furthermore, applications in environmental, biological and food analyses are overviewed. Finally, an outlook on the future of this technique is given. PMID- 23659976 TI - Two-dimensional gas chromatographic analysis of ambient light hydrocarbons. AB - Ambient level hydrocarbons lighter than C6 were analyzed by the Deans switch modulated comprehensive two-dimensional gas chromatography (GC*GC) method with flame ionization detection (FID). A thermal desorption (TD) device built in-house connects the GC*GC system to pre-concentrate the target compounds at ambient levels prior to GC analysis. Because the conventional orthogonality based on polarity difference for normal GC*GC separation does not provide sufficient retention for the target compounds of extremely high volatility, the orthogonality of non-polar vs. adsorptive force was adopted instead. The system employed a 100% polydimethyl siloxane column serving as the first-dimension column to provide separation based on dispersive interaction, with a short PLOT column serving as the second-dimension column to provide the needed retention based on gas-solid adsorption interactions. The shortest possible length of the PLOT column was tested to minimize the modulation period (PM) and wraparound and, at the same time, to maintain the desired resolution. The tests led to the final optimal parameters of 1.1m for the PLOT column length, 9s for the PM, 0.013 for the modulation duty cycle (DC) and a modulation ratio (MR) of 3.7 with minimal wraparound. Important criteria for quality assurance of precision and linearity are reported. The low cost and ease of construction and operation make the in house Deans switch TD-GC*GC-FID system practical and useful for the analysis of light hydrocarbons in urban or industrial environments. PMID- 23659977 TI - A new liquid chromatography-tandem mass spectrometry method using atmospheric pressure photo ionization for the simultaneous determination of azaarenes and azaarones in Dutch river sediments. AB - A new method for the analysis of azaarenes and their degradation products (azaarones) was developed, optimized and validated using liquid chromatography coupled with atmospheric pressure photo ionization tandem mass spectrometric detection (LC-APPI/MS/MS). Seventeen compounds including 4 PAHs (naphthalene, anthracene, phenanthrene, benz[a]anthracene), 7 azaarenes (quinoline, acridine, phenanthridine, 5,6-benzoquinoline and 7,8-benzoquinoline, benzo[a]acridine, benzo[c]acridine), and 6 azaarones (2-OH-quinoline, 4-OH-quinoline, 5-OH quinoline, 6-OH-quinoline, 9(10H)-acridone, 6(5H)phenanthridinone) were analyzed in sediment samples from Dutch rivers. All compounds were analyzed simultaneously in multi reaction monitoring (MRM) mode. Soxhlet extraction was used for the extraction of analytes from sediments. The limits of quantification of azaarenes and azaarones varied from 0.21 to 1.12MUg/l and from 0.23 to 1.58MUg/l, respectively. The limits of quantification for PAHs varied from 32 to 769MUg/l. Matrix-independent recoveries of sediment samples were in the range 85-110%; matrix-dependent recoveries were in the range 73-148%, respectively. The method was tested on real sediment samples and the results were compared with a previous study in which GC/MS/MS was used for the simultaneous measurement of azaarenes and azaarones. 4-, 5- and 6-OH-quinolines and naphthalene, anthracene and phenanthrene were not present or below detection limits in some samples. All other analytes were present in samples in the concentration range 0.2-1200ng/g (dw). To our knowledge, this is the first report showing the possibility of measurement non-polar polyaromatic hydrocarbons together with polar azaarenes and their degradation products azaarones simultaneously with sufficient sensitivity and accuracy using LC/MS/MS. PMID- 23659978 TI - Quick, easy, cheap, effective, rugged and safe method with magnetic graphitized carbon black and primary secondary amine as adsorbent and its application in pesticide residue analysis. AB - By using magnetic graphitized carbon black and primary secondary amine (GCB/PSA/MNPs) as adsorbent, a modified quick, easy, cheap, effective, rugged and safe (QuEChERS) method was proposed for pesticide residue analysis in vegetables. The magnetic adsorbent was fabricated via simple co-mixing method based on an "aggregate warp" mechanism. To achieve the optimum conditions of modified QuEChERS toward target analytes, several parameters, including the composition of analyte protectants and the amount of the adsorbents were investigated. Under the optimized conditions, a simple, rapid and effective method for the determination of 10 pesticide residues in vegetables was established by coupling modified QuEChERS to gas chromatography/mass spectrometry analysis. The detection limits of the proposed method for 10 pesticides ranged from 0.39 to 8.6ng/g. Good linearity (R value>=0.990) was achieved at concentration levels of 10-200ng/g, and acceptable method reproducibility was found as intra- and inter-day precisions, yielding the relative standard deviations less than 10.7% and 13.4%, respectively. The recoveries were in the range of 69.9-125.0% at different concentrations for real samples. Compared with the reported methods for the determination of a large number of samples, the proposed method has the advantage of less time-consuming in clean-up procedure. PMID- 23659979 TI - Fully automated determination of nine ultraviolet filters and transformation products in natural waters and wastewaters by on-line solid phase extraction liquid chromatography-tandem mass spectrometry. AB - This paper describes the development and validation of the first fully automated method, based on on-line solid phase extraction-liquid chromatography-tandem mass spectrometry (on line-SPE-LC-MS/MS), for the determination of UV filters (UV F) and transformation products, with a wide range of physicochemical properties. The developed method was validated and applied to the analysis of the selected compounds in river water (RW), groundwater (GW), influent and effluent wastewater (IWW and EWW). Comparing with the off-line methodologies published so far the presented method provides several advantages including a shorter extraction time, lower sample volume and minimum manipulation. Low limits of detection were achieved for all the studied matrices, <3ng/L (GW), <3.5ng/L (RW), <4ng/L (EWW) and <10ng/L (IWW), allowing a reliable and accurate quantification of the analytes at trace level. SPE optimization and critical aspects associated with the trace level determination of the target compounds (e.g. matrix effects) have been also considered and discussed. The method was successfully applied to the analysis of the UV F in five real water samples of each considered matrix, being the first time that these compounds were determined in GW. PMID- 23659980 TI - Investigations on the calculation of the third moments of elution peaks: II linear flow speed dependence of external mass transfer coefficient. AB - This work is a systematic investigation of the linear velocity dependence of the external mass transfer coefficient provided by fitting experimental results to the solution of the GR (General Rate) model that was previously derived. The second and third statistical moments of eluted peaks were measured at different flow rates, under different experimental conditions and analyzed. The results of this analysis confirm the validity of this dependence under our current experimental conditions. The other mass transfer parameters provided by the GR model were determined. The variations of these parameters with the experimental conditions were measured. The results are discussed and interpreted. PMID- 23659981 TI - A general liquid chromatography tandem mass spectrometry method for the quantitative determination of diquaternary ammonium gemini surfactant drug delivery agents in mouse keratinocytes' cellular lysate. AB - Development of a simple and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the quantification of diquaternary ammonium gemini surfactants, utilized as gene deliver agents, is required for the evaluation of their post transfection fate. The continued development of efficient and safe gene delivery agents will benefit directly from an understanding of their rate of uptake, metabolism and excretion. A method is reported that is specific for the quantification of twenty-nine individual diquaternary ammonium gemini surfactant molecules and was validated for N,N-bis(dimethylhexadecyl)-1,3-propane-diammonium dibromide (G16-3) within PAM212 cell lysate according to USFDA bioanalytical method validation guidelines. The 10min chromatographic separation procedure utilized an Agilent Zorbax CN column (100mm*2.1mm with 3MU particles) with LC-MS grade water and acetonitrile, both containing 0.3% (v:v) formic acid and 1mM triethylamine. Extraction of the gemini surfactant from PAM212 keratinocyte cell lysate was performed using octanol and 10MUL aliquots were injected onto the column. The standard curve was linear from 0.30MUg/mL to 220MUg/mL (r(2)>=0.999) for G16-3 and precision and accuracy were within USFDA specified limits. G16-3 analyte was assessed as stable during storage in the auto-injector, bench-top, freeze-thaw cycling and long-term (60 days) storage at -20 degrees C. Evaluation of the cellular uptake and fate of G16-3, during both the incubation and post incubation periods, has established the potential of the application of the LC MS/MS quantification method for monitoring diquaternary ammonium gemini surfactants in transfection studies. PMID- 23659982 TI - Ionic liquids modified dummy molecularly imprinted microspheres as solid phase extraction materials for the determination of clenbuterol and clorprenaline in urine. AB - New ionic liquid modified dummy molecularly imprinted microspheres (DMIMs) were synthesized by aqueous suspension polymerization using phenylephrine as dummy template and 1-allyl-3-ethylimidazolium bromide as co-functional monomer. The obtained DMIMs were characterized by Fourier transform infrared (FT-IR) and scanning electron microscopy (SEM), and empolyed as the special sorbent of solid phase extraction for isolation of clenbuterol (CLB) and clorprenaline (CLP) from urine sample. The results indicated that the ionic liquid modified polymers were monodispersed microspheres and had high selectivity and adsorbability to CLB and CLP, and the matrix interferences could be efficiently eliminated from the samples. Meanwhile, the effect of template leakage of DMIMs on quantitative analysis was avoided. Compared with other commercial sorbents (HLB, PCX, C18 and SCX), the DMIMs exhibited higher affinity and purification ability to CLP and CLB. Under the optimized conditions, good linearity was observed in a range of 0.90-400MUgL(-1) (r(2)=0.9999) with LOD of 0.19 and 0.070MUgL(-1) for CLP and CLB, respectively. The recoveries at three spiked levels were ranged from 93.3% to 106% with RSD<=5.6% (n=3). PMID- 23659983 TI - Poly(ethylene oxide)-bonded stationary phase for separation of inorganic anions in capillary ion chromatography. AB - A tosylated-poly(ethylene oxide) (PEO) reagent was reacted with primary amino groups of an aminopropylsilica packing material (TSKgel NH2-60) in acetonitrile to form PEO-bonded stationary phase. The reaction was a single and simple step reaction. The prepared stationary phase was able to separate inorganic anions. The retention behavior of six common inorganic anions on the prepared stationary phase was examined under various eluent conditions in order to clarify its separation/retention mechanism. The elution order of the tested anions was iodate, bromate, bromide, nitrate, iodide, and thiocyanate, which was similar as observed in common ion chromatography. The retention of inorganic anions could be manipulated by ion exchange interaction which is expected that the eluent cation is coordinated among the PEO chains and it works as the anion-exchange site. Cations and anions of the eluent therefore affected the retention of sample anions. We demonstrated that the retention of the analyte anions decreased with increasing eluent concentration. The repeatability of retention time for the six anions was satisfactory on this column with relative standard deviation values from 1.1 to 4.3% when 10mM sodium chloride was used as the eluent. Compared with the unmodified TSKgel NH2-60, the prepared stationary phase retained inorganic anions more strongly and the selectivity was also improved. The present stationary phase was applied for the determination of inorganic anions contained in various water samples. PMID- 23659984 TI - Vaginal cuff closure during total laparoscopic hysterectomy: a new technique has been performed 100 times with very few complications. AB - A concern of vaginal cuff dehiscence and other complications after total laparoscopic hysterectomy has been voiced by numerous surgeons. We have developed a simple and easy to learn technique for cuff closure that is associated with no cases of cuff dehiscence and a low complication rate. Our technique is described with an accompanying video. PMID- 23659985 TI - Maternal metformin treatment decreases fetal inflammation in a rat model of obesity and metabolic syndrome. AB - OBJECTIVE: Obesity and metabolic syndrome are associated with systemic inflammation and increased perinatal morbidity. Metformin improves metabolic and inflammatory biomarkers in nonpregnant adults. Using in vivo and in vitro models, we examined the effect of metformin on maternal and fetal inflammation. STUDY DESIGN: Female Wistar rats (6-7 weeks old) were fed a normal diet (NORM) or a high-fat/high-sugar diet (HCAL) for 5-6 weeks to induce obesity/metabolic syndrome. After mating with NORM-fed male rats, one-half of the HCAL-fed female rats received metformin (300 mg/kg, by mouth daily). All dams continued their respective diets until gestational day 19, at which time maternal and fetal outcomes were assessed. Maternal and fetal plasma and placentas were analyzed for metabolic and inflammatory markers. Cultured human placental JAR cells were pretreated with vehicle or metformin (10 MUmol/L-2.5 mmol/L) before tumor necrosis factor alpha (TNF-alpha; 50 ng/mL), and supernatants were assayed for interleukin-6 (IL-6). RESULTS: HCAL rats gained more prepregnancy weight than NORM rats (P = .03), had higher levels of plasma insulin and leptin, and exhibited dyslipidemia (P < .05). Fetuses that were exposed to the HCAL diet had elevated plasma IL-6, TNF-alpha, and chemokine (C-C motif) ligand 2 levels (P < .05) and enhanced placental TNF-alpha levels (P < .05). Maternal metformin did not impact maternal markers but significantly decreased diet-induced TNF-alpha and chemokine (C-C motif) ligand 2 in the fetal plasma. Finally, metformin dose dependently reduced TNF-alpha-induced IL-6 and IkappaBalpha levels in cultured placental JAR cells. CONCLUSION: Diet induced-obesity/metabolic syndrome during pregnancy significantly enhanced fetal and placental cytokine production; maternal metformin reduced fetal cytokine levels. Similarly, metformin treatment of a placental cell line suppressed TNF-alpha-induced IL-6 levels by NFkappaB inhibitor. PMID- 23659986 TI - The association between polycystic ovary syndrome and ectopic pregnancy after in vitro fertilization and embryo transfer. AB - OBJECTIVE: We sought to assess the association between polycystic ovary syndrome (PCOS) and ectopic pregnancy after in vitro fertilization-embryo transfer (ET). STUDY DESIGN: In this retrospective cohort study, we included 5339 women who had clinical pregnancies after in vitro fertilization treatment (PCOS, 205 women; non PCOS, 5134 women) at Nanjing Medical University (China) between 2007 and 2011. Fresh and cryo-thawed ET cycles were analyzed respectively. The primary outcome measure was the occurrence of ectopic pregnancy. Multivariate logistic regression analysis was used to adjust for important confounders. RESULTS: In fresh ET cycles of women who were undergoing controlled ovarian hyperstimulation (COH; n = 3303), women with PCOS had 3.06 times higher risk of ectopic pregnancy compared with those without PCOS (7.0% vs 2.4%; adjusted odds ratio [aOR], 3.06; 95% confidence interval [CI], 1.34-6.96). In the stratified analysis, for women without PCOS, the high estradiol group (>4085 pg/mL) had higher ectopic pregnancy rates compared with the low estradiol group (<=4085 pg/mL; 3.4% vs 2.0%; aOR, 1.99; 95% CI, 1.19-3.35); however, for women with PCOS, both high and low estradiol groups had high ectopic pregnancy rates (5.6% vs 7.7%; aOR, 0.92; 95% CI, 0.15-5.67). In cryo-thawed ET cycles without COH (n = 2036), the ectopic rates between women with and without PCOS were similar (2.2% vs 2.0%; aOR, 0.94; 95% CI, 0.22-4.07). CONCLUSION: PCOS was associated with an increased risk of ectopic pregnancy after COH in fresh ET cycles, but not in cryo-thawed ET cycles. A possible explanation is that, compared with women without PCOS, women with PCOS appear to hold a lower threshold of hyperphysiologic estradiol level that triggers the occurrence of ectopic pregnancy after COH. PMID- 23659987 TI - Long-term efficacy and safety of questionnaire-based initiation of urgency urinary incontinence treatment. AB - OBJECTIVE: The objective of the study was to determine the longer-term efficacy and safety of initiating treatment for urgency-predominant urinary incontinence (UUI) in women diagnosed using a simple questionnaire rather than an extensive evaluation. STUDY DESIGN: Women completing a 12 week randomized controlled trial of fesoterodine therapy for UUI diagnosed by questionnaire were invited to participate in a 9 month, open-label continuation study. UUI and voiding episodes were collected using voiding diaries. Participant satisfaction was measured by questionnaire. Safety was assessed by the measurement of postvoid residual volume and adverse event monitoring; if necessary, women underwent a specialist evaluation. The longitudinal changes in UUI and voiding episodes were evaluated using linear mixed models adjusting for baseline. RESULTS: Of the 567 women completing the randomized trial, 498 (87.8%) took at least 1 dose of medication during this open-label study. Compared with the baseline visit in the randomized trial, fesoterodine was associated with a reduction in total incontinence episodes per day and urgency incontinence episodes per day at the end of the open label study (adjusted mean [SE], 4.6 [0.12] to 1.2 [0.13] and 3.9 [0.11] to 0.9 [0.11], respectively, P < .0001 for both). Most women were satisfied with treatment (89%, 92%, and 93% at 3, 6, and 9 months, respectively). Twenty-six women experienced 28 serious adverse events, 1 of which was considered possibly treatment related. Twenty-two women had a specialist evaluation: 5 women's incontinence was misclassified by the 3 Incontinence Questions; none experienced harm because of misclassification. CONCLUSION: Using a simple validated questionnaire to diagnose and initiate treatment for UUI in community-dwelling women is safe and effective, allowing timely treatment by primary care practitioners. PMID- 23659989 TI - The global epidemiology of bacterial vaginosis: a systematic review. AB - Bacterial vaginosis (BV) enhances the acquisition and transmission of a range of sexually transmitted infections including human immunodeficiency virus. This has made it more important to uncover the reasons why some populations have very high BV prevalences and others not. This systematic review describes the global epidemiology of BV. It summarizes data from peer-reviewed publications detailing the population prevalence of BV as diagnosed by a standardized and reproducible methodology-Nugent scoring system. BV variations between countries, and between ethnic groups within countries, are described. We evaluated 1692 English- and non English-language articles describing the prevalence of BV using MEDLINE and the Web of Science databases. A total of 86 articles met our inclusion criteria. BV prevalences were found to vary considerably between ethnic groups in North America, South America, Europe, the Middle East, and Asia. Although BV prevalence is, in general, highest in parts of Africa and lowest in much of Asia and Europe, some populations in Africa have very low BV prevalences and some in Asia and Europe have high rates. PMID- 23659988 TI - Progress of labor in women induced with misoprostol versus the Foley catheter. AB - OBJECTIVE: To estimate and compare the duration and progress of labor in women induced with misoprostol vs Foley catheter plus oxytocin. STUDY DESIGN: We performed a retrospective cohort study of labor progress among 617 consecutive term pregnancies induced with misoprostol (n = 503) or Foley catheter plus oxytocin (n = 114) who completed the first stage of labor. Labor duration and progress in the entire cohort, and stratified by parity, were compared in multivariable interval-censored regression models adjusting for maternal obesity and birthweight. Repeated-measures analysis with 9th degree polynomial modeling was used to construct average labor curves. RESULTS: Total duration of labor was not significantly different in women induced with misoprostol compared with the Foley catheter (median duration from 1 to 10 cm: 12 vs 14.2 hours, P = .19). Progress from 1 to 4 cm was more rapid with the Foley catheter (median: 3.4 vs 5.6 hours, P < .01), although progress from 4 to 10 cm was slower (median: 6.3 vs 3.6 hours, P < .01). Labor curves demonstrated transition from latent to active labor at about 4 cm cervical dilatation with misoprostol and at 6 cm for the Foley catheter. Similar general patterns were noted for nulliparous and multiparous women, except for a shorter duration of labor with the Foley catheter among multiparous women. CONCLUSION: Induction of labor with the Foley catheter is associated with more rapid initial cervical dilation, but transition to active labor occurs later compared with misoprostol. These differences should be considered in the management of induced labor. PMID- 23659991 TI - Time from consent to cesarean delivery during labor. AB - OBJECTIVE: The objective of the study was to describe the time from consent to incision (consent time) when informed consent (IC) for cesarean delivery (CD) is obtained during labor and identify risk factors for especially short consent times. STUDY DESIGN: The study was a retrospective chart review of 90 cases of CD during labor. Medians and interquartile ranges for times were reported. Multivariable linear and logistic regressions were used to adjust for confounders. A Kaplan-Meier survival analysis was performed to compare consent time among women undergoing CD for fetal heart rate (FHR) indications with other women. RESULTS: The median consent time was 48 minutes (interquartile range, 25 72); 28.9% of patients delivered less than 30 minutes after consent. When adjusted for potential confounders, the odds of delivering less than 30 minutes after consent were 4.7 times higher (95% confidence interval, 1.4-15.2, P = .01) among women who underwent CD for FHR indications than for women who underwent CD for other indications. CONCLUSION: This study demonstrates that when IC for CD is obtained during labor, consent time is brief, particularly among women undergoing CD for FHR indications. Although time is not necessarily a proxy for quality, an especially short consent time is likely to reduce the quality of the conversation and limit a patient's opportunity to understand and recall information. Additional research regarding the optimal approach to IC for CD in labor is needed; however, this study suggests that the practice of obtaining IC at the time the decision for CD is reached is unlikely to provide optimal time for a complete IC discussion. PMID- 23659990 TI - Factors associated with persistent urinary incontinence. AB - OBJECTIVE: Many women with urinary incontinence (UI) have symptoms that continue over many years; however, virtually nothing is known about factors that are associated with persistent UI. STUDY DESIGN: We studied 36,843 participants of the Nurses' Health Study, aged 54-79 years at baseline for the UI study, who provided UI information on biennial questionnaires from 2000 through 2008; follow up in the Nurses' Health Study is 90%. In total, 18,347 women had "persistent UI," defined as urine leakage >=1/mo reported on all 5 biennial questionnaires during this 8-year period; 18,496 women had no UI during this period. Using multivariable-adjusted logistic regression, we estimated odds ratios (ORs) of persistent UI vs no UI across various demographic, lifestyle, and health-related factors, which were derived from reports in 2000. RESULTS: Increasing age group, white race, greater parity, greater body mass index (BMI), and lower physical activity levels were each associated with greater odds of persistent UI, as were several health-related factors (ie, stroke, type 2 diabetes, and hysterectomy). Associations with persistent UI were particularly strong for increasing age group (P trend < .0001; OR, 2.75; 95% confidence interval [CI], 2.54-2.98 comparing women aged >=75 vs <60 years) and greater BMI (P trend < .0001; OR, 3.14; 95% CI, 2.95-3.33 comparing women with BMI >=30 vs <25 kg/m(2)); moreover, black women had much lower odds of persistent UI compared to white women (OR, 0.27; 95% CI, 0.21-0.34). CONCLUSION: Factors associated with persistent UI were generally consistent with those identified in previous studies of UI over shorter time periods; however, older age, white race, and obesity were particularly strongly related to persistent UI. PMID- 23659992 TI - Nebulized salbutamol for asthma: effects on serum potassium and phosphate levels at the 60 min. AB - OBJECTIVE: We conducted this prospective study to expand available information in relation to serum phosphate levels in treatment of acute asthma. A beta adrenergic agonist, salbutamol, was used for this purpose. MATERIAL AND METHODS: Twenty-six patients who met the inclusion criteria as; age over 16 years, asthma history, and an acute exacerbation were included. Serum blood urea nitrogen, creatinine, glucose were within normal limits in all the patients. None of the patients were on chronic theophylline therapy. Baseline serum phosphate and potassium levels were measured. Nebulized salbutamol (2.5mg) was used three times at every hour. After 60 min, serum phosphate and potassium levels were measured. RESULTS: Serum phosphate levels decreased from 3.7+/-0.9 mg/dL (baseline) to 3.6+/-0.9 mg/dL at 60 min. This decrease was not statistically significant (p=0.373). Serum potassium levels decreased significantly (p<0.001) from 4.6+/ 0.7 mmol/L (baseline) to 4.3+/-0.7 mmol/L (60 min). CONCLUSION: Administration of nebulized salbutamol during the emergency treatment of acute exacerbation of asthma is not associated with a statistical decrease in serum phosphate. There was significant hypokalemia. This study indicates that a further study is needed to elucidate the clinical significance of nebulized salbutamol on serum phosphate. PMID- 23659993 TI - Trastuzumab in small tumours and in elderly women. AB - Results of trials assessing the role of trastuzumab in the adjuvant setting in early breast cancer have brought a new standard of treatment to clinical practice. Nevertheless, some groups of patients are underrepresented in these trials and thus therapy should be planned based on incomplete information or lack of solid data. Two of these groups are high-risk HER2+ small tumours (<1cm) and elderly patients. In this review we aimed at addressing the most relevant data about these two populations underrepresented in clinical trials. HER2 overexpression or amplification confers a bad prognosis in patients with small breast tumours. Mammographic screening is increasing the early diagnosis. Taking into account that specific targeted adjuvant treatment can avoid relapses in 50% of HER2-positive patients, about 2 to 7% of relapses from small tumours could be avoided with the use of this treatment. Randomized and non-randomized trials support the idea that adjuvant therapies could improve clinical outcomes of ?1cm tumours. Adding a HER2-targeted treatment to chemotherapy may improve efficacy. Some recent data in the neo-adjuvant context suggest that, in some patients, aggressive chemotherapy treatment could be properly substituted by HER2-targeted therapy. In elderly women with HER2+ breast cancer, trastuzumab should be considered for adjuvant-treatment, particularly in those at higher risk of relapse, lack of extra risk factors for trastuzumab-associated cardiotoxicity, and having a prolonged estimated life expectancy. In addition to traditional anthracycline-based combinations commonly used in younger women, other options are the use of sequential chemotherapy, non-anthracycline containing regimes plus anti-HER2 therapies, combinations with hormonotherapy, or even anti-HER2 agents alone. PMID- 23659994 TI - Characterization of the orientation and isometry of Humphrey's ligament. AB - OBJECTIVES/PURPOSE: The purpose of this study was to examine the effect of flexion angle on isometry and fiber obliquity of the anterior meniscofemoral ligament (Humphrey's ligament (HL)). METHODS: Following a medial parapatellar arthrotomy on 7 fresh frozen cadavers, the insertion points of the anterolateral (AL) and posteromedial (PM) bundles of the PCL, and HL were identified. Using a 9mm circular software tool, virtual fibers were created. Within each virtual graft, a central fiber was calculated and used to generate anisometry profiles for the AL and PM bundles and HL at flexion angles of 0 degrees , 30 degrees , 60 degrees , 90 degrees , and 120 degrees . Previously validated computer navigation software was used to re-create three dimensional bundles to measure fiber obliquity in the sagittal, frontal, and axial planes. RESULTS: HL length increased with knee flexion from 0 to 120 degrees , and underwent similar length changes as the PCL bundles. In full extension and at 90 degrees , the average length of the PM and AL bundles were not statistically different (p=0.13 and p=0.85 respectively). From 0 to 120 degrees , the PM bundle was the most isometric, but the anisometry profile was statistically similar to the AL bundle and HL. In general, HL and the PM bundle had similar graphic trends in terms of fiber obliquity in all planes. CONCLUSIONS: Using computer navigation, we have demonstrated that HL has similar isometry profiles as the PM and AL bundles of the PCL, and "mirrored" the obliquity of the PM bundle in all planes throughout flexion to 120 degrees . PMID- 23659995 TI - Functional characterization of a short peptidoglycan recognition protein, PGRP5 in grass carp Ctenopharyngodon idella. AB - Peptidoglycan recognition proteins (PGRPs), which are evolutionarily conserved from insects to mammals, recognize bacterial peptidoglycan (PGN) and function in antibacterial innate immunity. In this study, a short-form PGRP, designated as gcPGRP5 was identified from grass carp Ctenopharyngodon idella. The deduced amino acid sequence of gcPGRP5 is composed of 180 residues with a conserved PGRP domain at the C-terminus. The gcPGRP5 gene consists of four exons and three introns, spacing approximately 2.3 kb in genomic sequence. Phylogenetic analysis demonstrated that the gcPGRP5 is clustered with other PGRP-S identified in teleost fish. The gcPGRP5 is constitutively expressed in all organs/tissues examined, and its expression was significantly induced in CIK cells treated with lipoteichoic acid (LTA), polyinosinic polycytidylic acid (Poly I:C) and PGN. Fluorescence analysis showed that gcPGRP5 is distributed in cytoplasm of CIK cells, and cell lysates from CIK cells transfected with pTurbo-gcPGRP5-GFP and ptGFP1-gcPGRP5 plasmids display the binding activity and peptidoglycan-lytic amidase activity toward Lys-PGN from Staphylococcus aureus and Dap-PGN from Bacillus subtilis. Furthermore, heat-shock protein70 (Hsp70), and MyD88, an adaptor molecule in Toll-like receptor pathway, had an increased expression in CIK cells overexpressed with gcPGRP5. It is thus indicated that gcPGRP5 exhibits amidase activity, and also possesses roles in anti-stress, and in Toll-like receptor signaling pathway. PMID- 23659996 TI - Vaccination efficiency of surface antigens and killed whole cell of Pseudomonas putida in large yellow croaker (Pseudosciaena crocea). AB - Large yellow croaker (Pseudosciaena crocea), a major marine fish aquacultured in the southeastern coastal region of China, has become endangered by the pathogen Pseudomonas putida in recent years. P. putida infections occur in low water temperatures when fish reduce food intake, thus oral antibiotic administration is not practical. Therefore, vaccination may be the only method to prevent the infection. In the present study, main surface antigens of P. putida, including lipopolysaccharide (LPS), outer membrane proteins (OMP), extracellular biofilm polysaccharide (EPS), and formalin-killed cell (FKC) bacterin, were prepared and the fish vaccinated. On post-immunization day 28, serum antibody titers, phagocytic responses of leukocytes, and lysozyme activities of the fish were evaluated. The efficiency of vaccination was tested by artificial challenge via intraperitoneal injection of live bacteria on post-immunization day 28 and 35, respectively. The results showed that although significant humoral and innate immune responses were elicited in all vaccination groups, the challenge produced similar poor protection in both tests, with a relative percent survival (RPS) of 0-40%. Although the EPS group showed a complete lack of protection, LPS reached the highest RPS value (40%), suggesting that LPS may be involved in protection immunity against the pathogen. Further analysis of the ultra-structures of tissues from infected fish via TEM revealed macrophage survival and intracellular replication ability of the pathogen. New strategies for development might put more emphasis on efficient clearance of intracellular bacteria. The present study is the first to report vaccination against the fish pathogen P. putida and the first investigation of intracellular survival of this pathogen in host macrophages. PMID- 23659997 TI - New roles for Nanos in neural cell fate determination revealed by studies in a cnidarian. AB - Nanos is a pan-metazoan germline marker, important for germ cell development and maintenance. In flies, Nanos also acts in posterior and neural development, but these functions have not been demonstrated experimentally in other animals. Using the cnidarian Hydractinia we have uncovered novel roles for Nanos in neural cell fate determination. Ectopic expression of Nanos2 increased the numbers of embryonic stinging cell progenitors, but decreased the numbers of neurons. Downregulation of Nanos2 had the opposite effect. Furthermore, Nanos2 blocked maturation of committed, post-mitotic nematoblasts. Hence, Nanos2 acts as a switch between two differentiation pathways, increasing the numbers of nematoblasts at the expense of neuroblasts, but preventing nematocyte maturation. Nanos2 ectopic expression also caused patterning defects, but these were not associated with deregulation of Wnt signaling, showing that the basic anterior posterior polarity remained intact, and suggesting that numerical imbalance between nematocytes and neurons might have caused these defects, affecting axial patterning only indirectly. We propose that the functions of Nanos in germ cells and in neural development are evolutionarily conserved, but its role in posterior patterning is an insect or arthropod innovation. PMID- 23659998 TI - Molecular mechanisms of Tau binding to microtubules and its role in microtubule dynamics in live cells. AB - Despite extensive studies, the molecular mechanisms of Tau binding to microtubules (MTs) and its consequences on MT stability still remain unclear. It is especially true in cells where the spatiotemporal distribution of Tau-MT interactions is unknown. Using Forster resonance energy transfer (FRET), we showed that the Tau-MT interaction was distributed along MTs in periodic hotspots of high and low FRET intensities. Fluorescence recovery after photobleaching (FRAP) revealed a two-phase exchange of Tau with MTs as a rapid diffusion followed by a slower binding phase. A real-time FRET assay showed that high FRET occurred simultaneously with rescue and pause transitions at MT ends. To further explore the functional interaction of Tau with MTs, the binding of paclitaxel (PTX), tubulin acetylation induced by trichostatin A (TSA), and the expression of non-acetylatable tubulin were used. With PTX and TSA, FRAP curves best fitted a single phase with a long time constant, whereas with non-acetylatable alpha tubulin, curves best fitted a two phase recovery. Upon incubation with PTX and TSA, the number of high and low FRET hotspots decreased by up to 50% and no hotspot was observed during rescue and pause transitions. In the presence of non acetylatable alpha-tubulin, a 34% increase in low FRET hotspots occurred, and our real-time FRET assay revealed that low FRET hotspots appeared with MTs recovering growth. In conclusion, we have identified, by FRET and FRAP, a discrete Tau-MT interaction, in which Tau could induce conformational changes of MTs, favoring recovery of MT self-assembly. PMID- 23660000 TI - Histone H3 phosphorylation and elimination of paternal X chromosomes at early cleavages in sciarid flies. AB - In sciarid flies (Diptera, Sciaridae), one or two paternally derived X chromosomes are discarded from the soma at early cleavages to determine the sex of the embryo (XX, females; X0, males). X chromosome(s) elimination is achieved by an abnormal anaphase segregation so that X sister chromatids do not reach the poles and are not included in the daughter nuclei. A cis-acting locus (CE) within the heterochromatin proximal to the centromere is known to regulate X chromosome elimination. By immunofluorescence analysis in early embryos from Sciara ocellaris and Sciara coprophila, we investigated histone H3 phosphorylation at Ser10, Ser28 and Thr3 prior to, and during, the X elimination process. We found that the regular syncytial nuclear divisions are characterized by a gradual loss of H3S10 phosphorylation along the chromosome arms at anaphase. Importantly, the eliminating X chromosomes show a retardation in anaphase chromatid segregation and high levels of H3S10 phosphorylation in the chromosome arms. In the present study, we provide the first evidence linking the hyper-phosphorylated H3 status of the X chromosome with a delay in sister chromatid separation at anaphase. Our findings support the idea that the CE induces a deficiency in H3 dephosphorylation in the paternal X chromosomes to be eliminated. PMID- 23659999 TI - Biased inheritance of mitochondria during asymmetric cell division in the mouse oocyte. AB - A fundamental rule of cell division is that daughter cells inherit half the DNA complement and an appropriate proportion of cellular organelles. The highly asymmetric cell divisions of female meiosis present a different challenge because one of the daughters, the polar body, is destined to degenerate, putting at risk essential maternally inherited organelles such as mitochondria. We have therefore investigated mitochondrial inheritance during the meiotic divisions of the mouse oocyte. We find that mitochondria are aggregated around the spindle by a dynein mediated mechanism during meiosis I, and migrate together with the spindle towards the oocyte cortex. However, at cell division they are not equally segregated and move instead towards the oocyte-directed spindle pole and are excluded from the polar body. We show that this asymmetrical inheritance in favour of the oocyte is not caused by bias in the spindle itself but is dependent on an intact actin cytoskeleton, spindle-cortex proximity, and cell cycle progression. Thus, oocyte-biased inheritance of mitochondria is a variation on rules that normally govern organelle segregation at cell division, and ensures that essential maternally inherited mitochondria are retained to provide ATP for early mammalian development. PMID- 23660003 TI - Molecular dynamics study of carbohydrate binding module mutants of fungal cellobiohydrolases. AB - The present study reports the systematic survey of binding free energies at the interface between a carbohydrate-binding module (CBM) and a cellulose Ialpha crystal model using molecular dynamics' calculations. The two wild type CBMs (Cel7A CBM and Cel6A CBM) have been studied, as well as seven mutants of Cel7A CBM. A comparison of the experimental data for the two wild type and the four mutants CBMs (i.e., Y5A, Y5W, N29A, and Q34A) revealed that the interaction energies of Y5W and Q34A were larger than that of the wild type Cel7A CBM, whereas Y5A and N29A gave smaller values. These predicted values of the interaction energies were compared with the results observed for the adsorbing behaviors of the CBMs. PMID- 23660002 TI - A heteropolysaccharide from an edible hybrid mushroom pfle 1p: structural and immunostimulating studies. AB - A water-soluble heteropolysaccharide (PS-I) having molecular weight ~2.1*10(5) Da was isolated from hot aqueous extract of the fruit bodies of hybrid mushroom pfle 1p. The hybrid mushroom pfle 1p was obtained through intergenic protoplast fusion between Pleurotus florida and Lentinula edodes. The heteropolysaccharide contained D-glucose, D-galactose, and D-mannose in a molar ratio of nearly 4:2:1. The structural investigation of PS-I has been carried out using sugar and methylation analyses as well as 1D/2D NMR experiments ((1)H, (13)C, DEPT-135, DQF COSY, TOCSY, NOESY, ROESY, HSQC, and HMBC). Based on the results of these experiments, the repeating unit of the PS-I was established as: [structure: see text]. PS-I showed in vitro macrophage activation by NO production and also stimulated splenocytes and thymocytes. PMID- 23660001 TI - Pbx1 restrains myeloid maturation while preserving lymphoid potential in hematopoietic progenitors. AB - The capacity of the hematopoietic system to promptly respond to peripheral demands relies on adequate pools of progenitors able to transiently proliferate and differentiate in a regulated manner. However, little is known about factors that may restrain progenitor maturation to maintain their reservoirs. Conditional knockout mice for the Pbx1 proto-oncogene have a significant reduction in lineage restricted progenitors in addition to a profound defect in hematopoietic stem cell (HSC) self-renewal. Through analysis of purified progenitor proliferation, differentiation capacity and transcriptional profiling, we demonstrate that Pbx1 regulates the lineage-specific output of multipotent and oligopotent progenitors. In the absence of Pbx1 multipotent progenitor (MPP) and common myeloid progenitor (CMP) pools are reduced due to aberrantly rapid myeloid maturation. This is associated with premature expression of myeloid differentiation genes and decreased maintenance of proto-oncogene transcriptional pathways, including reduced expression of Meis1, a Pbx1 dimerization partner, and its subordinate transcriptional program. Conversely, Pbx1 maintains the lymphoid differentiation potential of lymphoid-primed MPPs (LMPPs) and common lymphoid progenitors (CLPs), whose reduction in the absence of Pbx1 is associated with a defect in lymphoid priming that is also present in CMPs, which persistently express lymphoid and HSC genes underlying a previously unappreciated lineage promiscuity that is maintained by Pbx1. These results demonstrate a role for Pbx1 in restraining myeloid maturation while maintaining lymphoid potential to appropriately regulate progenitor reservoirs. PMID- 23660004 TI - Comparison between DFT- and NMR-based conformational analysis of methyl galactofuranosides. AB - Galactofuranose (Galf) residues are found in a number of microbial polysaccharides, and knowledge of their conformation is key for developing a molecular-level understanding of their biological roles. To this end, we studied 180 conformations of methyl alpha- and beta-Galf in aqueous solution (COSMO solvation model) using density functional theory (DFT). We compare the calculated low energy conformations to those determined from the program PSEUROT using (1)H NMR data. The lowest energy ring conformation for methyl alpha-Galf is (2)E, and this conformer is also the major solution conformation obtained by NMR spectroscopy. For methyl beta-Galf, (4)E is the lowest energy ring conformation; however, DFT results do not agree with the solution NMR spectroscopic results. Additionally, we developed Galf-specific Karplus-like equations from these conformations. PMID- 23660006 TI - [Practical guidelines for diagnosis and treatment of acromegaly. Grupo de Neuroendocrinologia de la Sociedad Espanola de Endocrinologia y Nutricion]. PMID- 23660007 TI - [Improvement in functional capacity after levothyroxine treatment in patients with chronic heart failure and subclinical hypothyroidism]. AB - AIM: To assess whether levothyroxine treatment improves functional capacity in patients with chronic heart failure (New York Heart Association class i-iii) and subclinical hypothyroidism. METHODS: One hundred and sixty-three outpatients with stable chronic heart failure followed up for at least 6 months were enrolled. A physical examination was performed, and laboratory tests including thyroid hormone levels, Doppler echocardiogram, radionuclide ventriculography, and Holter monitoring were requested. Functional capacity was assessed by of the 6-min walk test. Patients with subclinical hypothyroidism were detected and, after undergoing the s6-min walk test, were given replacement therapy. When they reached normal thyrotropin (TSH) levels, the 6-min walk test was performed again. The distance walked in both tests was recorded, and the difference in meters covered by each patient was analyzed. RESULTS: Prevalence of subclinical hypothyroidism in patients with heart failure was 13%. These patients walked 292+/-63m while they were hypothyroid and 350+/-76m when TSH levels returned to normal, a difference of 58+/-11m (P<.011). Patients with normal baseline TSH levels showed no significant difference between the 2 6-min walk tests. CONCLUSIONS: Patients with chronic heart failure and subclinical hypothyroidism significantly improved their physical performance when normal TSH levels were reached. PMID- 23660008 TI - [Normocalcemic primary hyperparathyroidism: recommendations for management and follow-up]. AB - OBJECTIVE: To provide practical recommendations for evaluation and follow-up of patients with normocalcemic primary hyperparathyroidism. PARTICIPANTS: Members of the Bone Metabolism Working Group of the Spanish Society of Endocrinology. METHODS: A systematic search was made in MEDLINE (PubMed), using the terms normocalcemic primary hyperparathyroidism and primary hyperparathyroidism, for articles in English published before 22 November 2012. Literature was reviewed by 2 members of the Bone Metabolism Working Group of the Spanish Society of Endocrinology, and after development of recommendations, the manuscript was reviewed by all other members of the Group, and their suggestions were incorporated. CONCLUSIONS: The document provides practical recommendations for evaluation and follow-up of patients with normocalcemic primary hyperparathyroidism. There is however little evidence available about different aspects of this disease, mainly progression rate and clinical impact. More data are therefore needed before definite recommendations may be made. PMID- 23660010 TI - Transient paralysis during acupuncture therapy: a case report of an adverse event. AB - A patient with apparently well-controlled epilepsy with a painful musculoskeletal condition was treated successfully with two sessions of acupuncture. However, 4 h after the first treatment and during the second, an adverse event involving impairment of consciousness occurred. The patient subsequently experienced an increased frequency of complex partial seizures resulting in the loss of his driving licence. A detailed retrospective review of the past medical history indicated that the patient probably had comorbidities in the form of rapid eye movement sleep behaviour disorder and dysfunctional somatosensory/vestibular processing. Acupuncture may have triggered the adverse event via shared neurosubstrates. This adverse event raises possible implications regarding safe clinical acupuncture practice. PMID- 23660009 TI - Individual EEG differences in affective valence processing in women with low and high neuroticism. AB - OBJECTIVE: In this study, individual differences in brain electrophysiology during positive and negative affective valence processing in women with different neuroticism scores are quantified. METHODS: Twenty-six women scoring high and low on neuroticism participated on this experiment. A support vector machine (SVM) based classifier was applied on the EEG single trials elicited by high arousal pictures with negative and positive valence scores. Based on the accuracy values obtained from subject identification tasks, the most distinguishing EEG channels among participants were detected, pointing which scalp regions show more distinct patterns. RESULTS: Significant differences were obtained, in the EEG heterogeneity between positive and negative valence stimuli, yielding higher accuracy in subject identification using negative pictures. Regarding the topographical analysis, significantly higher accuracy values were reached in occipital areas and in the right hemisphere (p < 0.001). CONCLUSIONS: Mainly, individual differences in EEG can be located in parietooccipital regions. These differences are likely to be due to the different reactivity and coping strategies to unpleasant stimuli in individuals with high neuroticism. In addition, the right hemisphere shows a greater individual specificity. SIGNIFICANCE: An SVM-based classifier asserts the individual specificity and its topographical differences in electrophysiological activity for women with high neuroticism compared to low neuroticism. PMID- 23660012 TI - Incidence of pseudotumor and acute lymphocytic vasculitis associated lesion (ALVAL) reactions in metal-on-metal hip articulations: a meta-analysis. AB - We systematically reviewed the peer-reviewed literature to determine a pooled estimate of the incidence of pseudotumor and acute lymphocytic vasculitis associated lesions (ALVAL) in adult patients with primary metal-on-metal (MoM) total hip arthroplasty or resurfacing. Fourteen eligible articles were identified, with a total of 13,898 MoM hips. The incidence of pseudotumor/ALVAL ranged from 0% to 6.5% of hips with a mean follow-up ranging from 1.7 to 12.3 years across the studies. The pooled estimated incidence of pseudotumor/ALVAL is 0.6% (95% CI: 0.3% to 1.2%). The rate of revision for any reason ranged from 0% to 14.3% of hips, with a pooled estimate of 3.9% (95% CI: 2.7% to 5.3%). PMID- 23660013 TI - Assay for peptidoglycan O-acetyltransferase: a potential new antibacterial target. AB - The O-acetylation of peptidoglycan occurs at the C-6 hydroxyl group of muramoyl residues in many human pathogens, both gram positive and gram negative, such as Staphylococcus aureus and species of Campylobacter, Helicobacter, Neisseria, and Bacillus, including Bacillus anthracis. The process is a maturation event being catalyzed either by integral membrane O-acetylpeptidoglycan transferase (Oat) of gram-positive bacteria or by a two-component peptidoglycan O-acetyltransferase system (PatA/PatB) in gram-negative cells. Here, we describe the development of the first in vitro assay for any peptidoglycan O-acetyltransferase using PatB from Neisseria gonorrhoeae as the model enzyme. This assay is based on the use of chromogenic p-nitrophenyl acetate as the donor substrate and chitooligosaccharides as model acceptor substrates in place of peptidoglycan. The identity of the O-acetylated chitooligosaccharides was confirmed by matrix assisted laser desorption/ionization time-of-flight mass spectrometry. Rates of transacetylations were determined spectrophotometrically by monitoring p nitrophenol release after accounting for both spontaneous and enzyme-catalyzed hydrolysis of the acetate donor. Conditions were established for use of the assay in microtiter plate format, and its applicability was demonstrated by determining the first Michaelis-Menten kinetic parameters for PatB. The assay is readily amenable for application in the high-throughput screening for potential inhibitors of peptidoglycan O-acetyltransferases that may prove to be leads for novel classes of antibiotics. PMID- 23660014 TI - Rapid and sensitive detection of maize chlorotic mottle virus using surface plasmon resonance-based biosensor. AB - We report a biosensor based on surface plasmon resonance (SPR) for the selective detection of maize chlorotic mottle virus (MCMV). 11-Mercaptoundecanoic acid was applied on a gold surface to form a self-assembled monolayer, and a layer of anti MCMV antibody was crosslinked on the surface for specific recognition of MCMV. The effects of coupling reaction time and antibody concentration on detection sensitivity were studied. The coverage mass change is a function of the concentration of MCMV with a dynamic range from 1 to 1000 ppb. The detection limit is approximately 1 ppb, which is approximately two orders of magnitude higher than that of the existing enzyme-linked immunosorbent assay (ELISA) method. The developed SPR sensor showed highly specific recognition for both purified MCMV and crude extracts from real-world samples. PMID- 23660011 TI - STAT5A/B gene locus undergoes amplification during human prostate cancer progression. AB - The molecular mechanisms underlying progression of prostate cancer (PCa) to castrate-resistant (CR) and metastatic disease are poorly understood. Our previous mechanistic work shows that inhibition of transcription factor Stat5 by multiple alternative methods induces extensive rapid apoptotic death of Stat5 positive PCa cells in vitro and inhibits PCa xenograft tumor growth in nude mice. Furthermore, STAT5A/B induces invasive behavior of PCa cells in vitro and in vivo, suggesting involvement of STAT5A/B in PCa progression. Nuclear STAT5A/B protein levels are increased in high-grade PCas, CR PCas, and distant metastases, and high nuclear STAT5A/B expression predicts early disease recurrence and PCa specific death in clinical PCas. Based on these findings, STAT5A/B represents a therapeutic target protein for advanced PCa. The mechanisms underlying increased Stat5 protein levels in PCa are unclear. Herein, we demonstrate amplification at the STAT5A/B gene locus in a significant fraction of clinical PCa specimens. STAT5A/B gene amplification was more frequently found in PCas of high histologic grades and in CR distant metastases. Quantitative in situ analysis revealed that STAT5A/B gene amplification was associated with increased STAT5A/B protein expression in PCa. Functional studies showed that increased STAT5A/B copy numbers conferred growth advantage in PCa cells in vitro and as xenograft tumors in vivo. The work presented herein provides the first evidence of somatic STAT5A/B gene amplification in clinical PCas. PMID- 23660005 TI - Functional activity maps based on significance measures and Independent Component Analysis. AB - The use of functional imaging has been proven very helpful for the process of diagnosis of neurodegenerative diseases, such as Alzheimer's Disease (AD). In many cases, the analysis of these images is performed by manual reorientation and visual interpretation. Therefore, new statistical techniques to perform a more quantitative analysis are needed. In this work, a new statistical approximation to the analysis of functional images, based on significance measures and Independent Component Analysis (ICA) is presented. After the images preprocessing, voxels that allow better separation of the two classes are extracted, using significance measures such as the Mann-Whitney-Wilcoxon U-Test (MWW) and Relative Entropy (RE). After this feature selection step, the voxels vector is modelled by means of ICA, extracting a few independent components which will be used as an input to the classifier. Naive Bayes and Support Vector Machine (SVM) classifiers are used in this work. The proposed system has been applied to two different databases. A 96-subjects Single Photon Emission Computed Tomography (SPECT) database from the "Virgen de las Nieves" Hospital in Granada, Spain, and a 196-subjects Positron Emission Tomography (PET) database from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Values of accuracy up to 96.9% and 91.3% for SPECT and PET databases are achieved by the proposed system, which has yielded many benefits over methods proposed on recent works. PMID- 23660016 TI - Metformin, aging and cancer. PMID- 23660015 TI - Functional consequences of retro-inverso isomerization of a miniature protein inhibitor of the p53-MDM2 interaction. AB - Peptide retro-inverso isomerization is thought to be functionally neutral and has been widely used as a tool for designing proteolytically stable d-isomers to recapitulate biological activities of their parent l-peptides. Despite success in a wide range of applications, exceptions amply exist that clearly defy this rule of thumb when parent l-peptides adopt an alpha-helical conformation in their bound state. The detrimental energetic effect of retro-inverso isomerization of an alpha-helical l-peptide on its target protein binding has been estimated to be 3.0-3.4kcal/mol. To better understand how the retro-inverso isomer of a structured protein works at the molecular level, we chemically synthesized and functionally characterized the retro-inverso isomer of a rationally designed miniature protein termed stingin of 18 amino acid residues, which adopts an N terminal loop and a C-terminal alpha-helix stabilized by two intra-molecular disulfide bridges. Stingin emulated the transactivation peptide of the p53 tumor suppressor protein and bound with high affinity and via its C-terminal alpha helix to MDM2 and MDMX-the two negative regulators of p53. We also prepared the retro isomer and d-enantiomer of stingin for comparative functional studies using fluorescence polarization and surface plasmon resonance techniques. We found that retro-inverso isomerization of l-stingin weakened its MDM2 binding by 720 fold (3.9kcal/mol); while enantiomerization of l-stingin drastically reduced its binding to MDM2 by three orders of magnitude, sequence reversal completely abolished it. Our findings demonstrate the limitation of peptide retro-inverso isomerization in molecular mimicry and reinforce the notion that the strategy works poorly with biologically active alpha-helical peptides due to inherent differences at the secondary and tertiary structural levels between an l-peptide and its retro-inverso isomer despite their similar side chain topologies at the primary structural level.(1.) PMID- 23660018 TI - Proteomic and metabolomic responses of clam Ruditapes philippinarum to arsenic exposure under different salinities. AB - Arsenic (As) contamination is a severe problem in the intertidal zones of the Bohai Sea (China) with wide salinity variation. In the present study, we combined proteomics and metabolomics to characterize the differential responses of arsenic in clam Ruditapes philippinarum under different salinities (31.1, 23.3 and 15.6 psu). Both proteomic and metabolomic responses indicated that varying salinities could significantly affect the toxicological responses of clams to As. Metabolic biomarkers revealed that the environmentally relevant arsenic (20 MUg L(-1)) exposure induced disturbance in energy metabolism and/or osmotic regulation under different salinities, whereas protein biomarkers indicated oxidative stress, cellular injury and apoptosis and disturbance in energy metabolism. In addition, the up-regulated proteins including ATP synthase, succinyl-CoA synthetase and nucleoside diphosphate kinase were validated by related metabolites, succinate and ATP, which confirmed the disturbance in energy metabolism in clam gills at low salinity (15.6 psu). These findings provide important insights into toxicological effects of environmental contaminant at molecular levels using combined proteomics and metabolomics. PMID- 23660017 TI - Differential induction of enzymes and genes involved in lipid metabolism in liver and visceral adipose tissue of juvenile yellow catfish Pelteobagrus fulvidraco exposed to copper. AB - The present study was conducted to determine the mechanism of waterborne Cu exposure influencing lipid metabolism in liver and visceral adipose tissue (VAT) of juvenile yellow catfish Pelteobagrus fulvidraco. Yellow catfish were exposed to four waterborne copper (Cu) concentrations (2 (control), 24 (low), 71 (medium), 198 (high) MUg Cu/l, respectively) for 6 weeks. Waterborne Cu exposure had a negative effect on growth and several condition indices (condition factor, viscerosomatic index, hepatosomatic index and visceral adipose index). In liver, lipid content, activities of lipogenic enzymes (6-phosphogluconate dehydrogenase (6PGD), glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME), isocitrate dehydrogenase (ICDH), and fatty acid synthase (FAS)) as well as mRNA levels of 6PGD, G6PD, FAS and sterol-regulator element-binding protein-1 (SREBP-1) genes decreased with increasing Cu concentrations. However, activity and mRNA level of lipoprotein lipase (LPL) gene in liver increased. In VAT, G6PD, ME and LPL activities as well as the mRNA levels of FAS, LPL and PPARgamma genes decreased in fish exposed to higher Cu concentrations. The differential Pearson correlations between transcription factors (SREBP-1 and peroxisome proliferators activated receptor-gamma (PPARgamma)), and the activities and mRNA expression of lipogenic enzymes and their genes were observed between liver and VAT. Thus, our study indicated that reduced lipid contents in liver and VAT after Cu exposure were attributable to the reduced activities and mRNA expression of lipogenic enzymes and their genes in these tissues. Different response patterns of several tested enzymes and genes to waterborne Cu exposure indicated the tissue-specific regulatory effect of lipid metabolism following waterborne Cu exposure. To our knowledge, the present study provides, for the first time, evidence that waterborne chronic Cu exposure can disturb the normal processes of lipid metabolism at both the enzymatic and molecular levels, and in two tissues (the liver and adipose tissue), which serves to increase our understanding of the mechanisms underlying lipid metabolism during Cu exposure. PMID- 23660019 TI - Honeycomb-patterned fluorescent films fabricated by self-assembly of surfactant assisted porphyrin/polymer composites. AB - A novel honeycomb-patterned fluorescent film was fabricated by self-assembly of polystyrene (PS)/poly(ethylene glycol) (PEG)/meso-tetra (N-methy-4-pyridyl) porphinetetratosylate (TMPyP) blend system, at the assistance of diisooctyl sodium sulfosuccinate (AOT). Ordered microporous PS/PEG/TMPyP/AOT blend films were prepared by the breath figure method. The condensed water droplets acted as the sacrificial templates, which were stabilized by strong hygroscopic PEG and amphiphilic surfactant AOT. Relative humidity and evaporation conditions considered as critical factors were investigated to control the morphologies of the films. The introduction of surfactant AOT greatly promoted the dissolution of the TMPyP in PS/PEG polymer solution according to the UV-vis spectra data, which led to the fluorescence enhancement of ordered porous blend films. The unique "internal ring" structures were formed during phase separation and confirmed by scanning electron microscopy images and fluorescence micrographs. PMID- 23660020 TI - Vitamin E-enriched nanoemulsions formed by emulsion phase inversion: factors influencing droplet size and stability. AB - There is considerable interest in using nanoemulsions as delivery systems for lipophilic bioactive ingredients, such as oil-soluble vitamins. Nanoemulsions can be fabricated using either high-energy or low-energy methods, but the latter offer advantages in terms of low cost, higher energy efficiency, and simplicity of implementation. In this study, the emulsion phase inversion (EPI) method was used to produce food-grade nanoemulsions enriched with vitamin E acetate. The EPI method simply involves titrating water into a mixture containing oil and surfactant, which initially leads to the formation of a water-in-oil emulsion that then inverts into an oil-in-water emulsion. Oil composition, surfactant type, and surfactant-to-oil ratio (SOR) were all found to influence the particle size distribution of the systems produced. Nanoemulsions with a mean particle diameter of 40 nm could be produced at a final system composition of 2 wt% MCT, 8 wt%vitamin E acetate, and 20 wt% Tween 80. The EPI method was shown to be unsuitable for producing nanoemulsions from label-friendly surfactants, such as Quillaja saponin, whey protein, casein, and sucrose monoesters. The EPI method was more effective at producing nanoemulsions at high SOR than microfluidization, but much less effective at low SOR. PMID- 23660021 TI - The adsorption kinetics of a fluorinated surfactant--heptadecafluoro-1-nonanol. AB - The adsorption kinetics of heptadecafluoro-1-nonanol (C8F17CH2OH) onto a clean air-water interface were studied. Video-enhanced pendant (emerging) bubble tensiometry was employed to measure the equation of state and the dynamic/equilibrium surface tensions. Relaxation profiles of the surface tension for heptadecafluoro-1-nonanol molecules absorbing onto a freshly created air water interface were obtained and simulated from theory. The adsorption of the fluoroalcohol C8F17CH2OH was found to be cooperative from the comparison of the equilibrium surface tension data at gamma(C)>65 mN/m to the prediction of the Frumkin model. The comparison was made for the entire relaxation period of the tension data and the model predictions. The controlling mechanism of the adsorption process was found to be mixed diffusive-kinetic control. Values of the adsorption/desorption rate constants of C8F17CH2OH were estimated from these dynamic surface tension profiles with a diffusivity of 5.93*10(-6) cm(2)/s, which was evaluated from the Wilke-Chang equation for C8F17CH2OH. PMID- 23660022 TI - Effects of temperature on micellar-assisted bimolecular reaction of methylnaphtalene-2-sulphonate with bromide and chloride ions. AB - Reactivity of methyl naphthalene-2-sulphonate, MeONs, with H2O, Br(-) and Cl(-) in water and in cationic micelles of cetyltrialkylammonium surfactants, n C16H33N(+)R3X(-), R=Me (CTA(+)), n-Pr (CTPA(+)), X=Br, Cl, CH3SO3, has been investigated in the temperature range 25-45 degrees C. Micellar rate effects were analysed by using the pseudophase treatment, and the second-order rate constants in the micellar pseudophase were evaluated at the various temperatures. Values of these rate constants increase with temperature, and the effect is less important in micelles than in water and more important for chloride than for bromide ions. Micelles lead to an ion behaviour discrimination, whose extent depends on surfactant type and on temperature, with maximum effect in CTPA(+) at 25 degrees C and with bromide being always more reactive than chloride. Quantitative analysis of the temperature effect by the Eyring equation showed that micelles speed up reaction of MeONs with halide ions by decreasing the activation enthalpies, which is partially offset by decreases in the activation entropies. The rate acceleration by increase in surfactant head group size has only enthalpic origin for bromide and only entropic origin for chloride: this different behaviour was rationalised taking into account both solvation of anions and the hydrophobic effect. PMID- 23660023 TI - New surfactant for hydrate anti-agglomeration in hydrocarbon flowlines and seabed oil capture. AB - Anti-agglomeration is a promising solution for gas hydrate risks in deepsea hydrocarbon flowlines and oil leak captures. Currently ineffectiveness at high water to oil ratios limits such applications. We present experimental results of a new surfactant in rocking cell tests, which show high efficiency at a full range of water to oil ratios; there is no need for presence of the oil phase. We find that our surfactant at a very low concentration (0.2 wt.% of water) keeps the hydrate particles in anti-agglomeration state. We propose a mechanism different from the established water-in-oil emulsion theory in the literature that the process is effective without the oil phase. There is no need to emulsify the water phase in the oil phase for hydrate anti-agglomeration; with oil-in water emulsion and without emulsion hydrate anti-agglomeration is presented in our research. We expect our work to pave the way for broad applications in offshore natural gas production and seabed oil capture with very small quantities of an eco-friendly surfactant. PMID- 23660024 TI - Patterning of wettability for controlling capillary-driven flow in closed channels. AB - Glass capillaries are prepared with well-defined regions of tuneable wettability on the interior walls using an inexpensive and simple approach. A homogeneous layer of hydrophilic TiO2 nanoparticles is adsorbed on the capillary wall and chemically hydrophobized using octadecyltrihydrosilane (OTHS). The hydrophobic OTHS monolayer is then patterned by spatially-selective removal of the OTHS via TiO2-catalysed decomposition by ultraviolet irradiation. By patterning the capillaries with hydrophilic-hydrophobic rings, modulated penetration of a liquid (glycerol, in this study) can be achieved. For given wettability contrast, the penetration dynamics and equilibrium rise heights are very sensitive to the characteristic length-scale of the pattern, and may offer greater, time-dependent sampling control in fluidic devices. PMID- 23660025 TI - Anisotropic photoelectric film assembled from mesoporous silica (MS)@CuO@FeS2 composite microspheres for improving photoelectric conversion. AB - We report a novel strategy for the fabrication of mesoporous silica (MS)@CuO@FeS2 composite microsphere-based anisotropic films that combine the advantages of the CuO and FeS2 materials to improve photoelectric conversion. This was achieved by aligning MS@CuO@FeS2 composite microspheres in a cross-linked gel under a homogeneous magnetic field. The MS@CuO@FeS2 composite microspheres, which were synthesized by a simple layer-by-layer (LbL) self-assembly technique together with a solvothermal method, can absorb a wide range of light and exhibit ferromagnetic properties. In addition, the resulting MS@CuO@FeS2 composite microsphere-based anisotropic film shows photoelectric anisotropy. Such systems are promising for improving the performance of solar cells. PMID- 23660026 TI - Very-low-frequency oscillations of cerebral hemodynamics and blood pressure are affected by aging and cognitive load. AB - Spontaneous slow oscillations occur in cerebral hemodynamics and blood pressure (BP), and may reflect neurogenic, metabolic or myogenic control of the cerebral vasculature. Aging is accompanied by a degeneration of the vascular system, which may have consequences for regional cerebral blood flow and cognitive performance. This degeneration may be reflected in a reduction of spontaneous slow oscillations of cerebral hemodynamics and BP. Therefore, we aimed to establish the dependency of slow oscillations of cerebral hemodynamics and BP on the factors age and cognitive load, by using functional near-infrared spectroscopy (fNIRS). Fourteen healthy young (23-32 years) and 14 healthy older adults (64-78 years) performed a verbal n-back working-memory task. Oxygenated and deoxygenated hemoglobin concentration changes were registered by two fNIRS channels located over left and right prefrontal cortex. BP was measured in the finger by photoplethysmography. We found that very-low-frequency oscillations (0.02-0.07 Hz) and low-frequency oscillations (0.07-0.2 Hz) of cerebral hemodynamics and BP were reduced in the older adults compared to the young during task performance. In young adults, very-low-frequency oscillations of cerebral hemodynamics and BP reduced with increased cognitive load. Cognitive load did not affect low frequency oscillations of the cerebral hemodynamics and BP. Transfer function analysis indicated that the relationship between BP and cerebral hemodynamic oscillations does not change under influence of age and cognitive load. Our results suggest aging-related changes in the microvasculature such as declined spontaneous activity in microvascular smooth muscle cells and vessel stiffness. Moreover, our results indicate that in addition to local vasoregulatory processes, systemic processes also influence cerebral hemodynamic signals. It is therefore crucial to take the factors age and BP into consideration for the analysis and interpretation of hemodynamic neuroimaging data. PMID- 23660027 TI - Visualizing the human connectome. AB - Innovations in data visualization punctuate the landmark advances in human connectome research since its beginnings. From tensor glyphs for diffusion weighted imaging, to advanced rendering of anatomical tracts, to more recent graph-based representations of functional connectivity data, many of the ways we have come to understand the human connectome are through the intuitive insight these visualizations enable. Nonetheless, several unresolved problems persist. For example, probabilistic tractography lacks the visual appeal of its deterministic equivalent, multimodal representations require extreme levels of data reduction, and rendering the full connectome within an anatomical space makes the contents cluttered and unreadable. In part, these challenges require compromises between several tensions that determine connectome visualization practice, such as prioritizing anatomic or connectomic information, aesthetic appeal or information content, and thoroughness or readability. To illustrate the ongoing negotiation between these priorities, we provide an overview of various visualization methods that have evolved for anatomical and functional connectivity data. We then describe interactive visualization tools currently available for use in research, and we conclude with concerns and developments in the presentation of connectivity results. PMID- 23660028 TI - Inhibitory control and trait aggression: neural and behavioral insights using the emotional stop signal task. AB - Deficits in response inhibition and heightened impulsivity have been linked to psychiatric disorders and aggression. They have been investigated in clinical groups as well as individuals with trait characteristics, yielding insights into the underlying neural and behavioral mechanisms of response inhibition and impulsivity. The motor inhibition tasks employed in most studies, however, have lacked an emotional component, which is crucial given that both response inhibition and impulsivity attain salience within a socio-emotional context. For this fMRI study, we selected a group with high trait aggression (HA, n=17) and one with low trait aggression (LA, n=16) from 550 males who had completed an Aggression Questionnaire. Neural activation was compared to an emotional version (including angry and neutral faces) of the stop signal task. Behavioral results revealed impaired response inhibition in HA, associated with higher motor impulsivity. This was accompanied by attenuated activation in brain regions involved in response inhibition, including the pre-supplementary motor area (SMA) and motor cortex. Together, these findings offer evidence that a reduced inhibition capacity is present in HA. Notably, response inhibition improved during anger trials in both groups, suggesting a facilitation effect through heightened activation in the related brain regions. In both groups, inclusion of the anger stimuli enhanced the activation of the motor and somatosensory areas, which modulate executive control, and of limbic regions including the amygdala. In summary, the investigation of response inhibition in individuals with high and low trait characteristics affords useful insights into the underlying distinct processing mechanisms. It can contribute to the investigation of trait markers in a clinical context without having to deal with the complex mechanisms of a clinical disorder itself. In contrast, the mechanisms of emotional response inhibition did not differ between groups. Hence, the specific emotional influence is not interacting with trait aggression. PMID- 23660029 TI - Scalp and skull influence on near infrared photon propagation in the Colin27 brain template. AB - Near-infrared neuromonitoring (NIN) is based on near-infrared spectroscopy (NIRS) measurements performed through the intact scalp and skull. Despite the important effects of overlying tissue layers on the measurement of brain hemodynamics, the influence of scalp and skull on NIN sensitivity are not well characterized. Using 3555 Monte Carlo simulations, we estimated the sensitivity of individual continuous-wave NIRS measurements to brain activity over the entire adult human head by introducing a small absorption perturbation to brain gray matter and quantifying the influence of scalp and skull thickness on this sensitivity. After segmenting the Colin27 template into five tissue types (scalp, skull, cerebrospinal fluid, gray matter and white matter), the average scalp thickness was 6.9 +/- 3.6 mm (range: 3.6-11.2mm), while the average skull thickness was 6.0 +/- 1.9 mm (range: 2.5-10.5mm). Mean NIN sensitivity - defined as the partial path length through gray matter divided by the total photon path length - ranged from 0.06 (i.e., 6% of total path length) at a 20mm source-detector separation, to over 0.19 at 50mm separations. NIN sensitivity varied substantially around the head, with occipital pole exhibiting the highest NIRS sensitivity to gray matter, whereas inferior frontal regions had the lowest sensitivity. Increased scalp and skull thickness were strongly associated with decreased sensitivity to brain tissue. Scalp thickness always exhibited a slightly larger effect on sensitivity than skull thickness, but the effect of both varied with SD separation. We quantitatively characterize sensitivity around the head as well as the effects of scalp and skull, which can be used to interpret NIN brain activation studies as well as guide the design, development and optimization of NIRS devices and sensors. PMID- 23660030 TI - Sex matters: Neural correlates of voice gender perception. AB - The basis for different neural activations in response to male and female voices as well as the question, whether men and women perceive male and female voices differently, has not been thoroughly investigated. Therefore, the aim of the present study was to examine the behavioral and neural correlates of gender related voice perception in healthy male and female volunteers. fMRI data were collected while 39 participants (19 female) were asked to indicate the gender of 240 voice stimuli. These stimuli included recordings of 3-syllable nouns as well as the same recordings pitch-shifted in 2, 4 and 6 semitone steps in the direction of the other gender. Data analysis revealed a) equal voice discrimination sensitivity in men and women but better performance in the categorization of opposite-sex stimuli at least in men, b) increased responses to increasing gender ambiguity in the mid cingulate cortex and bilateral inferior frontal gyri, and c) stronger activation in a fronto-temporal neural network in response to voices of the opposite sex. Our results indicate a gender specific processing for male and female voices on a behavioral and neuronal level. We suggest that our results reflect higher sensitivity probably due to the evolutionary relevance of voice perception in mate selection. PMID- 23660031 TI - Fast in vivo imaging of amyloid plaques using MU-MRI Gd-staining combined with ultrasound-induced blood-brain barrier opening. AB - Amyloid plaques are one of the major microscopic lesions that characterize Alzheimer's disease. Current approaches to detect amyloid plaques by using magnetic resonance imaging (MRI) contrast agents require invasive procedures to penetrate the blood-brain barrier (BBB) and to deliver the contrast agent into the vicinity of amyloid plaques. Here we have developed a new protocol (US-Gd staining) that enables the detection of amyloid plaques in the brain of an APP/PS1 transgenic mouse model of amyloidosis after intra-venous injection of a non-targeted, clinically approved MRI contrast agent (Gd-DOTA, Dotarem(r)) by transiently opening the BBB with unfocused ultrasound (1 MHz) and clinically approved microbubbles (Sonovue(r), Bracco). This US-Gd-staining protocol can detect amyloid plaques with a short imaging time (32 min) and high in-plane resolution (29 MUm). The sensitivity and resolution obtained is at least equal to that provided by MRI protocols using intra-cerebro-ventricular injection of contrast agents, a reference method used to penetrate the BBB. To our knowledge this is the first study to demonstrate the ability of MR imaging to detect amyloid plaques by using a peripheral intra-venous injection of a clinically approved NMR contrast agent. PMID- 23660032 TI - Isolated tubal torsion in a postmenarchal adolescent. PMID- 23660033 TI - Open access. PMID- 23660034 TI - Motor vehicle accidents in pregnancy: implications and management. PMID- 23660035 TI - Prenatal genetic screening: do not pass "go". PMID- 23660036 TI - Prenatal genetic screening: do not pass "go". Author reply. PMID- 23660037 TI - The use of a quality indicator to reduce elective repeat Caesarean section for low-risk women before 39 weeks' gestation: the Eastern Ontario experience. AB - OBJECTIVE: Elective repeat Caesarean section (ERCS) for low-risk women at < 39 weeks' gestation has consistently been associated with increased risks to the neonate, including respiratory morbidity, NICU admission, and lengthier hospital stays than ERCS at 39 to 40 weeks' gestation. The objective of this quality improvement project was to reduce high rates of ERCS < 39 weeks across the Eastern Ontario region. METHODS: All hospitals within the region providing care during labour and birth (n = 10) were asked to participate. Representatives from each hospital received information about their site-specific rates and knowledge translation resources to assist them with the project. A benchmark rate for ERCS < 39 weeks was set at 30%. The rates of ERCS < 39 weeks were calculated for two different times (the 2009-2010 and 2010-2011 fiscal years) and the relative difference and 95% confidence intervals were calculated to quantify the magnitude and statistical significance of any change. Qualitative interviews were completed with key informants from each hospital. RESULTS: The proportion of ERCS at < 39 weeks' gestation across the region in the fiscal year 2010-2011 (n = 197/497; 39.6%) was significantly decreased (relative difference: -21%; 95% CI -31% to 8%, P = 0.002) from the previous fiscal year 2009-2010 (n = 229/459; 49.9%). A number of barriers to, and facilitators of, practice change were identified. CONCLUSION: A reduction in the rate of ERCS < 39 weeks among low-risk women was achieved across the region. Awareness of the issue, possession of site-specific data, and agreement about the evidence and the need for change are critical first steps to improving practice. PMID- 23660038 TI - Occurrence and predictors of vacuum and forceps used sequentially for vaginal birth. AB - BACKGROUND: Sequential use of vacuum and obstetric forceps for vaginal delivery is associated with increased risks of adverse maternal and infant outcomes. METHODS: We conducted a retrospective cohort study to estimate the frequency of sequential use of vacuum and forceps for planned vaginal delivery and to identify predictors, using data collected in Ontario between 2004 and 2007. Multivariate logistic regression models were used to estimate the adjusted odds ratios and 95% confidence intervals of predictors of sequential use of vacuum and forceps. RESULTS: Of 186 988 pregnant women with a singleton, vertex presentation at term and a planned vaginal birth, 1062 (0.57%) required the sequential use of vacuum and forceps for delivery. The major predictors for sequential use of vacuum and forceps were mother's primary language being other than English or French, nulliparity, a history of Caesarean section, dystocia, use of epidural or other pain relief, labour induction, labour augmentation, fetal macrosomia, and advanced gestational age. CONCLUSION: In this population-based study we found that 0.57% of planned vaginal births were delivered with sequential use of vacuum and obstetric forceps. Abnormal labour, fetal macrosomia, language barriers, and advanced gestational age are significant predictors of requiring this sequential use. PMID- 23660039 TI - Maternal and neonatal outcomes in pregnancies complicated by systemic lupus erythematosus: a population-based study. AB - OBJECTIVE: To determine maternal and neonatal outcomes in pregnancies complicated by systemic lupus erythematosus (SLE). METHODS: In a retrospective cohort study using the Nova Scotia Atlee Perinatal Database, 97 pregnancies in women with SLE, with 99 live births, were compared with 211 355 pregnancies in women without SLE and their 214 115 babies. All were delivered in Nova Scotia between 1988 and 2008. RESULTS: In women with SLE, gestational age at birth and mean neonatal birth weight were lower (P < 0.001) than in women without SLE. On bivariate analysis, severe preeclampsia, Caesarean section, newborn resuscitation for > 3 minutes, respiratory distress syndrome, assisted ventilation, bronchopulmonary dysplasia, patent ductus arteriosus, mild to moderate intraventricular hemorrhage, retinopathy of prematurity, and congenital heart block in neonates were significantly more frequent in the women with SLE. Logistic regression analysis identified that having SLE increased the risks of Caesarean section (OR 1.8; 95% CI 1.1 to 2.8, P = 0.005), postpartum hemorrhage (OR 2.4; 95% CI 1.3 to 4.3, P = 0.003), need for blood transfusion (OR 6.9; 95% CI 2.7 to 17, P = 0.001), postpartum fever (OR 3.2; 95% CI 1.7 to 6.1, P = 0.032), small for gestational age babies (OR 1.7; 95% CI 1.005 to 2.9, P = 0.047), and gestational age <= 37 weeks (OR 2.1; 95% CI 1.3 to 3.4, P = 0.001). Neonatal death was not shown to be more common in women with SLE (RR 3.05; CI 0.43 to 21.44, P = 0.28). CONCLUSION: Mothers with SLE have an increased risk of Caesarean section, postpartum hemorrhage, and blood transfusion. They are more likely to deliver premature babies, smaller babies, and babies with congenital heart block. PMID- 23660040 TI - Survey on uterine closure and other techniques for Caesarean section among Quebec's obstetrician-gynaecologists. AB - OBJECTIVE: To evaluate the preferred types of uterine closure at Caesarean section among Quebec's obstetrician-gynaecologists. METHODS: An anonymous survey with multiple-choice and open questions was sent by email to all members of the Association des Obstetriciens-Gynecologues du Quebec in clinical practice. The primary response of interest was the type of uterine closure that would be favoured for a primigravida undergoing an elective CS at term for a breech fetus. Secondary responses of interest included type of uterine closure for CS performed for other indications, and methods of closure for the bladder flap, parietal peritoneum, rectus abdominis muscle, subcutaneous tissue, and skin. Results were stratified according to the number of years in practice. RESULTS: Of 454 persons targeted, 176 (39%) responded. Responders were more likely to have fewer years in practice than the targeted population in general. The closures for a primigravida undergoing an elective CS at term for a breech presentation were, in order of preference: (1) a double-layer closure combining a first locked layer and an imbricating second layer (61%), (2) a double-layer closure combining a first unlocked layer and an imbricating second layer (28%), (3) a locked single layer (5%), (4) an unlocked single layer (5%), and (5) other techniques (1%). A locked single-layer closure was more frequently used for repeat CS (29%), and it was the favoured technique (40%) when tubal ligation was performed at the time of CS (P < 0.05). CONCLUSION: Double-layer closure is the type of uterine closure most preferred by obstetricians in Quebec. However, the first layer is locked by two thirds of obstetricians and unlocked by the remainder. PMID- 23660041 TI - Web-based education for placental complications of pregnancy. AB - OBJECTIVE: The objective of this study was to determine whether a web-based education strategy could improve maternal knowledge of placental complications of pregnancy and reduce maternal anxiety in high risk-pregnancies. METHODS: Prospective study in the Placenta Clinic at Mount Sinai Hospital, Toronto, Ontario. Maternal demographics and Internet usage were recorded at the patient's baseline appointment. Placental knowledge was determined using structured verbal and illustrative assessments. The six-item State-Trait Anxiety Inventory (STAI) was administered to assess baseline maternal anxiety. Women were asked to visit the Placenta Clinic website for a minimum of 15 minutes before their follow-up appointment, at which time their placental knowledge and STAI assessments were repeated. RESULTS: Eighteen women were included in the study. Patient knowledge at the baseline appointment was generally poor (median score 10.5 out of a maximum score of 27, range 1 to 22), with major deficits in basic placental knowledge, placenta previa/increta, and preeclampsia. At the follow-up appointment, placental knowledge was significantly improved (median score 23, range 10 to 27; P < 0.001). Educational status (high school or less vs. college or more) had no effect on either baseline knowledge or knowledge improvement. Maternal anxiety at baseline (median score 12 out of a maximum score of 24, range 6 to 23) was significantly reduced at the follow-up appointment (median score 8.5, range 6 to 20; P = 0.005). CONCLUSION: Deficits in maternal knowledge of placental complications of pregnancy in high-risk pregnant women were substantial but easily rectified with a disease-targeted web-based educational resource. This intervention significantly improved patient knowledge and significantly reduced maternal anxiety. PMID- 23660042 TI - A retrospective review of tension-free vaginal tape/transobturator tape procedures done concomitantly with prolapse repair. AB - OBJECTIVE: Midurethral slings have become the standard of care for women with stress urinary incontinence; prolapse repair is often also required. The primary objective of our study was to compare voiding dysfunction rates and the need for reoperation between patients having midurethral sling procedures alone versus those having midurethral sling procedures with concomitant prolapse repair. METHODS: We performed a retrospective chart review over a two-year period in a tertiary urogynaecology clinic. Of 108 charts, 93 had complete data for analysis. RESULTS: Patients having concomitant prolapse repair had a longer operating time, a longer hospital stay, and a longer time to resume normal voiding in the immediate postoperative period. CONCLUSION: Although tension-free vaginal tape or transobturator tape procedures with concomitant prolapse repair have a higher incidence of voiding dysfunction in the immediate postoperative period, we found that this did not persist to the six-week follow-up visit. There appeared to be no greater risk of lasting voiding dysfunction or need for reoperation after concomitant procedures. PMID- 23660043 TI - A triage assessment strategy for the management of women with endometrial cancer. AB - OBJECTIVE: This study examined a risk-factor-based assignment to either a subspecialist or a general gynaecologist for the management of women with endometrial cancer. METHODS: At diagnosis, all women with a diagnosis of endometrial cancer in four community hospitals were referred to a central cancer centre and stratified into low- and high-risk groups. Risk stratification was based primarily on central pathology review, with low-risk disease defined as grade 1, clinical stage 1. Women with low-risk disease were triaged back to the referring gynaecologist for surgery. Women with high-risk disease were managed at the cancer centre. The main outcome measures included risk status and pathology review, treatment and treatment location, and acceptability to patients and gynaecologists. RESULTS: Seventy-three women participated in this pilot study between November 2009 and 2010. Risk stratification was performed in all women: 37 were classified as high risk and 36 as low risk. Ninety-seven percent of women with high-risk disease were managed at the cancer centre, and 83% of these women underwent surgical staging compared with 8% for women with low-risk disease. This approach was acceptable to both patients and gynaecologists. CONCLUSION: This structured pattern of care for women with endometrial cancer resulted in a shift in management, with more women managed in accordance with oncologic guidelines, meaning that women at high risk for metastases had a lymphadenectomy performed. PMID- 23660044 TI - Validating a self-confidence scale for surgical trainees. AB - OBJECTIVE: Self-confidence is a feeling of trust in one's abilities, qualities, and judgement. It is one of the cognitive mechanisms underlying behavioural change. Variations in self-confidence influence motivation and predict performance success. We sought to validate a new tool for measuring self confidence in surgical residents. METHODS: A self-confidence rating scale was developed and consisted of six questions about the attitudes of gynaecology residents while performing a vaginal hysterectomy. The residents were participants in a randomized controlled trial (2008 to 2011) and performed a vaginal hysterectomy before and after an educational intervention. They rated their own surgical performance on a validated global rating scale (GRS) of surgical skill and their self-confidence on the new rating scale. Supervising surgeons concurrently rated the residents' performance on the GRS. Correlations were sought between self-confidence scale scores and measures of competence. RESULTS: There was no difference in self-confidence scores between intervention and control residents at baseline. The number of vaginal hysterectomies performed before the educational intervention was associated with a significantly higher confidence level (P = 0.024). Other demographic variables such as age and gender did not influence confidence levels. Internal consistency between the individual scale items was good (Cronbach alpha 0.85). Self-confidence scores were significantly higher after the educational intervention (P = 0.04). Self confidence was positively correlated with both self-assessed and supervising surgeon-assessed GRS scores in both intervention and control residents. CONCLUSION: The self-confidence scale is a psychometrically valid tool to measure residents' self-confidence during surgical learning. More research is needed to establish the role of this scale for feedback, to channel self-confidence, and to optimize surgical skill acquisition. PMID- 23660045 TI - The fetal safety of fluoxetine: a systematic review and meta-analysis. AB - OBJECTIVE: Fluoxetine is the selective serotonin reuptake inhibitor (SSRI) with the longest clinical use. Published reports regarding its fetal safety are contradictory. We aimed to establish the fetal safety of the drug. METHODS: We performed a systematic review of the literature, searching PubMed, Medline, and Embase from inception to August 31, 2012, for cohort and case-control studies in which women were exposed to fluoxetine during the first trimester and compared outcomes with those of unexposed control subjects. RESULTS: Twenty-one studies met the inclusion criteria. The odds ratio for major malformations associated with maternal fluoxetine use in cohort studies was 1.12 (95% CI 0.98 to 1.28). The studies included were homogeneous. Fifteen cohort studies evaluated cardiac malformations and yielded an overall odds ratio of 1.6 (95% CI 1.31 to 1.95). These studies also were homogeneous. In contrast, two case-control studies assessing cardiac malformations yielded a combined odds ratio of 0.63 (95% CI 0.39 to 1.03). CONCLUSION: The apparent increased risk of fetal cardiac malformations associated with maternal use of fluoxetine has recently been shown also in depressed women who deferred SSRI therapy in pregnancy, and therefore most probably reflects an ascertainment bias. Overall, women who are treated with fluoxetine during the first trimester of pregnancy do not appear to have an increased risk of major fetal malformations. PMID- 23660046 TI - The role of surgery in endometrial cancer. AB - OBJECTIVE: To review current practice and make recommendations for the management and treatment of endometrial cancer. OUTCOMES: This guideline makes recommendations with respect to extended surgical staging, which provides important prognostic information and aids in determining the need for adjuvant treatments. EVIDENCE: Published literature was retrieved through searches of PubMed, CINAHL, and The Cochrane Library, using appropriate controlled vocabulary (e.g., endometrial neoplasms) and key words (e.g., endometrium cancer, endometrial carcinoma). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to December 31, 2011. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, national and international medical specialty societies, and recent conference abstracts BENEFITS, HARMS, AND COSTS: This guideline reviews the benefit of extended surgical staging compared with the potential harm of a limited surgery in grade 2 and 3 disease. VALUES: The quality of evidence is rated and recommendations are made using the criteria described by the Canadian Task Force on Preventive Health Care (Table). PMID- 23660048 TI - The role of adjuvant therapy in endometrial cancer. AB - OBJECTIVE: To review the evidence relating to the use of adjuvant therapy after surgical treatment for endometrial cancer. OPTIONS: Women with endometrial cancer can be given the option of receiving adjuvant radiotherapy and/or chemotherapy according to pathologic findings at time of surgery. OUTCOMES: The outcomes measured are postoperative progression-free and overall survival in endometrial cancer patients. EVIDENCE: Published literature was retrieved through searches of PubMed, CINAHL, and The Cochrane Library, using appropriate controlled vocabulary (e.g., endometrial neoplasms) and key words (e.g., endometrium cancer, endometrial carcinoma). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to December 31, 2011. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, national and international medical specialty societies, and recent conference abstracts. VALUES: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). BENEFITS, HARMS, AND COSTS: This guideline is intended to help standardize postoperative treatment of endometrial cancer and minimize undertreatment and overtreatment. VALIDATION: The guideline was reviewed for accuracy by content experts in pathology, radiation oncology, and medical oncology. Guideline content was also compared with relevant documents from the American Congress of Obstetricians and Gynecologists. PMID- 23660050 TI - Epidemiology and investigations for suspected endometrial cancer. AB - OBJECTIVE: To review the evidence relating to the epidemiology of endometrial cancer and its diagnostic workups. OPTIONS: Women with possible endometrial cancer can undergo an endometrial evaluation by office biopsy, hysteroscopy, or dilatation and curettage. To assist in treatment planning, pelvic ultrasound, CT scan, or MRI may be considered. OUTCOMES: The identification of optimal diagnostic tests to evaluate patients with possible endometrial cancer. EVIDENCE: Published literature was retrieved through searches of PubMed, CINAHL, and The Cochrane Library, using appropriate controlled vocabulary (e.g., endometrial neoplasms) and key words (e.g., endometrium cancer, endometrial carcinoma). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to December 31, 2011. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, national and international medical specialty societies, and recent conference abstracts. VALUES: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). BENEFITS, HARMS, AND COSTS: This document is intended to guide the development of a standardized cost-effective investigation of patients with suspected endometrial cancer. VALIDATION: The guideline was reviewed for accuracy by experts in pathology, radiation oncology, and medical oncology. Guideline content was also compared with relevant documents from the American Congress of Obstetricians and Gynecologists. PMID- 23660053 TI - Tendon healing, edema, and resistance to flexor tendon gliding: clinical implications. AB - Early flexor tendon healing is characterized by peak cellular apoptosis of both inflammatory and tendon cells in the first week, followed by progressively greater tenocyte proliferation in the second and third weeks. Tenocyte apoptosis is a predominant event, but proliferation of tenocytes is minimal in the middle and late healing periods. Edematous subcutaneous tissues, edema of the tendon, the intact annular pulleys, and extensor tendons all greatly contribute to the resistance. Careful consideration of the contributing factors and dynamics offers insight into strategies to reduce repair rupture and maximize tendon gliding through surgery and postoperative motion protocols. PMID- 23660054 TI - Current practice of primary flexor tendon repair: a global view. AB - In this article, a group of international leaders in tendon surgery of the hand provide details of their current methods of primary flexor tendon repair. They are from recognized hand centers around the world, from which major contributions to the development of methods for flexor tendon repair have come over the past 2 decades. Changes made since the early 1990s regarding surgical methods and postoperative care for the flexor tendon repair are also discussed. Current practice methods used in the leading hand centers are summarized, and key points in providing the best possible clinical outcomes are outlined. PMID- 23660052 TI - Gliding resistance and modifications of gliding surface of tendon: clinical perspectives. AB - The smooth gliding of the normal human digital flexor is maintained by synovial fluid lubrication and lubricants bound to the tendon surface. This system can be disrupted by degenerative conditions such as trigger finger, or by trauma. The resistance to tendon gliding after surgical repair of the lacerated digital flexor tendon relates to location of suture knots, exposure of suture materials, and type of surgical repair and materials. Restoration of a functioning gliding surface after injury can be helped by using low-friction, high-strength suture designs, therapy that enables gliding, and the addition of lubricants to the tendon surface. PMID- 23660055 TI - Primary flexor tendon surgery: the search for a perfect result. AB - Repair of the divided flexor tendon to achieve normal, or near normal, function is an unsolved problem, with each result still uncertain. The authors believe the way forward in primary flexor tendon surgery clinically is by use of strengthened but simpler sutures, appropriate venting of the pulley system, and maintaining early rehabilitation. However, there needs also be consideration of patient factors and other aspects. Research needs to continue more widely, in both the laboratory and the clinical environment, to find ways of better modifying adhesions after surgical repair of the tendon. PMID- 23660056 TI - Wide-awake flexor tendon repair and early tendon mobilization in zones 1 and 2. AB - The wide-awake approach to flexor tendon repair has decreased our rupture and tenolysis rates and permitted us to get consistently good results in cooperative patients. The wide-awake surgery allows the repair of gaps of the surgical repair site revealed with intraoperative active movement testing of the repair We are now doing midrange active movement after primary tendon repair. After tenolysis, full-range active motion is possible even before skin closure. We no longer perform flexor tendon repair with the tourniquet, sedation, and muscle paralysis of general or block (Bier or axillary) anesthesia. PMID- 23660057 TI - Uncommon methods of flexor tendon and tendon-bone repairs and grafting. AB - The conventional practices used in flexor tendon repair have remained unchanged in many units. Because clinical cases vary considerably, some situations may merit more unusual methods. Here the author describes a few methods that have been used in flexor tendon repair. This article discusses a few methods that are clinically useful in treating some patients but are not commonly described. The newer tendon-bone junction methods exemplified here would likely replace the pull out suture. Late direct repair and lengthening plasty require the accumulation of clinical experience. Allograft tendon reconstruction has shown successful midterm results, but long-term follow-up is certainly necessary. PMID- 23660058 TI - Two-stage reconstruction with the modified Paneva-Holevich technique. AB - Flexor tendon reconstruction poses both a technical challenge to the hand surgeon and a rehabilitative challenge to the patient and therapist. The modified Paneva Holevich technique, using a pedicled intra-synovial graft, is a safe and reliable means of staged flexor tendon reconstruction, offering a number of theoretical advantages over classic free-tendon grafting techniques. Clinical outcomes are at the least comparable, if not superior, to those achieved following free-tendon techniques with most authors reporting a low requirement for third stage tenolysis. PMID- 23660059 TI - Flexor pulley reconstruction. AB - Flexor pulley reconstruction is a challenging surgery. Injuries often occur after traumatic lacerations or forceful extension applied to an acutely flexed finger. Surgical treatment is reserved for patients with multiple closed pulley ruptures, persistent pain, or dysfunction after attempted nonoperative management of a single pulley rupture, or during concurrent or staged flexor tendon repair or reconstruction. If the pulley cannot be repaired primarily, pulley reconstruction can be performed using graft woven into remnant pulley rim or looping graft around the phalanx. Regardless of the reconstructive technique, the surgeon should emulate the length, tension, and glide of the native pulley. PMID- 23660060 TI - Tendon reconstruction with adjacent finger hand tendon. AB - Whether it is a primary or a delayed flexor digitorum profundus (FDP) repair, no general consent has been found, and no perfect treatment has been imposed. The authors utilize 2 new techniques for FDP reconstruction that allow immediate postoperative mobilization and excellent functional outcome. Harvesting of the donor hemi tendon, both FDP and flexor digitorum superficialis, is the closest match in terms of muscle agonism and excursion, and does not result in an imbalance of forces across the donor joint with the potential complications that this may create. PMID- 23660061 TI - Outcomes and evaluation of flexor tendon repair. AB - This article reviews recent reports of outcomes of flexor tendon repair and discusses the problems associated with such surgeries. Reports of no repair rupture in individual case series have emerged recently. Their results move toward the clinical goal of primary repair without repair rupture. The Strickland method remains the most common to record the outcomes. Outcomes should be provided by subzones of the tendon injuries, and the level of expertise of the surgeons expertise should be reported to allow comparisons of the results. PMID- 23660062 TI - Current methods and biomechanics of extensor tendon repairs. AB - Extensor tendon injuries occur frequently. An in-depth understanding of the intricate anatomy of the extensor mechanism is necessary to guide management. Careful counseling is helpful in ensuring patient compliance and optimal outcomes for nonoperative and surgical treatments. For distal lacerations in Zones II-V, we prefer the running-interlocked horizontal mattress technique. Prolonged immobilization or inadvertent shortening of the extensor mechanism can create the unintended consequence of joint stiffness. While clinical outcomes have improved with modern repairs and rehabilitation, patients should be advised that a slight extensor lag may persist and full flexion may not be possible despite seemingly successful treatment. PMID- 23660063 TI - Diagnosis and treatment of finger deformities following injuries to the extensor tendon mechanism. AB - Injuries to the finger extensor apparatus are very common and may produce chronic deformity and loss of function. Diagnosis is contingent on an understanding of the complex anatomy of this region as well as the ability to perform a careful physical examination. Immobilization is usually the most effective treatment of acute problems. Surgery is often necessary for chronic conditions, but the results are much less predictably corrective. PMID- 23660064 TI - Complex flexor and extensor tendon injuries. AB - Complex hand injuries are those that involve significant soft-tissue loss with variable exposure of bones and/or joints, lacerated tendons, and neurovascular structures. Management of these injuries is optimally accomplished through the restoration of thin, pliable, ideally sensate tissue with reliable vascularity and a gliding surface to facilitate restoration of motion after repair. Unfortunately, optimal restoration may require complex surgical reconstruction and/or staged surgical procedures. This article presents an overview of some of the more commonly used options available to the reconstructive surgeon willing to tackle these difficult clinical cases. PMID- 23660065 TI - Current flexor and extensor tendon motion regimens: a summary. AB - This article summarizes select multinational early motion protocols. Included are flexor and extensor protocols for digital tendon repair in many forms. Custom orthosis design, exercise regimens, and advanced techniques are examples of what to expect. The goal of the article is to expose the reader to new ideas, educate regarding advanced techniques in tendon rehabilitation, and stimulate independent study to further the reader's skill set. PMID- 23660066 TI - Intrinsic tendon healing and staged tendon reconstruction: reflection of legends. PMID- 23660067 TI - Tendon repair and reconstruction. Preface. PMID- 23660069 TI - The tissue inhibitor of metalloproteinases-1 improves migration and adhesion of hematopoietic stem and progenitor cells. AB - Homing and engraftment of hematopoietic stem and progenitor cells (HSPCs) during bone marrow transplantation are critically dependent on integrins such as beta1 integrin. In the present study, we show that beta1-integrin and the tetraspanin CD63 form a cell surface receptor complex for the soluble serum protein tissue inhibitor of metalloproteinases-1 (TIMP-1) on human CD34+ HSPCs. Through binding to this receptor complex, TIMP-1 activates beta1-integrin, increases adhesion and migration of human CD34+ cells, and protects these cells from induced apoptosis. TIMP-1 stimulation in murine bone marrow mononuclear cells also promotes migration and adhesion; this is associated with augmented homing of murine mononuclear cells and of murine LSK+ cells during bone marrow transplantation. These results not only indicate that TIMP-1 is conducive to HSPC homing; they also identify CD63 and beta1-integrin as a TIMP-1 receptor complex on HSPCs. PMID- 23660068 TI - Novel mTOR inhibitory activity of ciclopirox enhances parthenolide antileukemia activity. AB - Ciclopirox, an antifungal agent commonly used for the dermatologic treatment of mycoses, has been shown recently to have antitumor properties. Although the exact mechanism of ciclopirox is unclear, its antitumor activity has been attributed to iron chelation and inhibition of the translation initiation factor eIF5A. In this study, we identify a novel function of ciclopirox in the inhibition of mTOR. As with other mTOR inhibitors, we show that ciclopirox significantly enhances the ability of the established preclinical antileukemia compound, parthenolide, to target acute myeloid leukemia. The combination of parthenolide and ciclopirox demonstrates greater toxicity against acute myeloid leukemia than treatment with either compound alone. We also demonstrate that the ability of ciclopirox to inhibit mTOR is specific to ciclopirox because neither iron chelators nor other eIF5A inhibitors affect mTOR activity, even at high doses. We have thus identified a novel function of ciclopirox that might be important for its antileukemic activity. PMID- 23660070 TI - Burst-forming unit-erythroid assays to distinguish cellular bone marrow failure disorders. AB - Patients with cytopenias and a cellular bone marrow can be a diagnostic and therapeutic challenge. Previous reports suggested a role for progenitor assays for diagnosis and predicting response to therapy. We report the results of Burst forming unit-erythroid (BFU-E) assays in 48 consultative cases of single or multilineage cytopenias with cellular marrows. The final diagnoses included 17 patients with myelodysplastic syndrome, 9 patients with pure red cell aplasia (non-large granular lymphocytosis [LGL] in etiology], 15 patients with LGL (eight of whom had a single-lineage cytopenia only, whereas the other seven had multilineage cytopenias), and 7 patients with cytopenias associated with systemic inflammation from autoimmune conditions. In this cohort, nonmalignant diseases were well-distinguished from myelodysplastic syndrome by BFU-E growth. Our data suggest that low BFU-E growth (less than 10 BFU-E per 10(5) marrow mononuclear cells) helps to exclude LGL, pure red cell aplasia, or cytopenias associated with systemic inflammation as a cause of pancytopenia with a sensitivity of 96.8%, specificity of 76.5%, and a predictive value of 88.2% (p = 0.0001). BFU-E growth also was examined to predict treatment response. Of the 29 patients in this cohort treated with immunosuppressive therapy, there was an 86% response rate with 25 responders (11 partial responses and 14 complete responses) and 4 nonresponders. This result correlated with higher BFU-E growth. Our results suggest that BFU-E assays are a useful adjunct in the diagnosis and management of cytopenias in the setting of a normocellular or hypercellular marrows. PMID- 23660071 TI - A unique PML-RARalpha rearrangement involving chromosomes 11, 15, and 17 in a patient with acute promyelocytic leukemia. PMID- 23660072 TI - Comparative decomposition kinetics of neutral monosaccharides by microwave and induction heating treatments. AB - The stabilities of five neutral monosaccharides (glucose, galactose, mannose, arabinose, and xylose) were kinetically compared after the molecules were submitted to microwave heating (internal heating) and induction heating (external heating) under completely identical thermal histories by employing PID (proportional, integral, and derivative) temperature controlled ovens and homogeneous mixing. By heating in water at 200 degrees C, the rate constants for the decomposition reactions varied from 2.13*10(-4) to 3.87*10(-4)s(-1) for microwave heating; however, the values increased by 1.1- to 1.5-fold for induction heating. Similarly, in a dilute (0.8%) sulfuric acid solution, the decomposition rate constants varied from 0.61*10(-3) to 2.00*10(-3)s(-1) for microwave heating; however, the values increased by 1.5- to 2.2-fold for induction heating. The results show that microwave heating imparts greater stability to neutral monosaccharides than does induction heating. The undesirable decomposition of monosaccharides at the surface boundary of reactor walls may have increased the probability of monosaccharide decomposition during induction heating. PMID- 23660073 TI - Estimating sensitivity and specificity for technology assessment based on observer studies. AB - RATIONALE AND OBJECTIVES: The goal of this study was to determine the accuracy and precision of using scores from a receiver operating characteristic rating scale to estimate sensitivity and specificity. MATERIALS AND METHODS: We used data collected in a previous study that measured the improvements in radiologists' ability to classify mammographic microcalcification clusters as benign or malignant with and without the use of a computer-aided diagnosis scheme. Sensitivity and specificity were estimated from the rating data from a question that directly asked the radiologists their biopsy recommendations, which was used as the "truth," because it is the actual recall decision, thus it is their subjective truth. By thresholding the rating data, sensitivity and specificity were estimated for different threshold values. RESULTS: Because of interreader and intrareader variability, estimated sensitivity and specificity values for individual readers could be as much as 100% in error when using rating data compared to using the biopsy recommendation data. When pooled together, the estimates using thresholding the rating data were in good agreement with sensitivity and specificity estimated from the recommendation data. However, the statistical power of the rating data estimates was lower. CONCLUSIONS: By simply asking the observer his or her explicit recommendation (eg, biopsy or no biopsy), sensitivity and specificity can be measured directly, giving a more accurate description of empirical variability and the power of the study can be maximized. PMID- 23660074 TI - Large-scale purification of pharmaceutical-grade plasmid DNA using tangential flow filtration and multi-step chromatography. AB - The demand for pharmaceutical-grade plasmid DNA in vaccine applications and gene therapy has been increasing in recent years. In the present study, a process consisting of alkaline lysis, tangential flow filtration, purification by anion exchange chromatography, hydrophobic interaction chromatography and size exclusion chromatography was developed. The final product met the requirements for pharmaceutical-grade plasmid DNA. The chromosomal DNA content was <1 MUg/mg plasmid DNA, and RNA was not detectable by agarose gel electrophoresis. Moreover, the protein content was <2 MUg/mg plasmid DNA, and the endotoxin content was <10 EU/mg plasmid DNA. The process was scaled up to yield 800 mg of pharmaceutical grade plasmid DNA from approximately 2 kg of bacterial cell paste. The overall yield of the final plasmid DNA reached 48%. Therefore, we have established a rapid and efficient production process for pharmaceutical-grade plasmid DNA. PMID- 23660076 TI - Comments on "The effects of vaccination on serum hormone concentrations and conception rates in synchronized naive beef heifers". PMID- 23660075 TI - Proapoptotic and TRAIL-sensitizing constituents isolated from Salvia militiorrhiza (Danshen). AB - Natural compounds isolated from medicinal plants are invaluable resources for drug discovery. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent unique by its cancer cell-specific proapoptotic action, but its potential is heavily curbed by acquired resistance. We herein reported for the first time the identification of cytotoxic and TRAIL-sensitizing components of Salvia miltiorrhiza (Danshen), a traditional medicinal plant effective for treating cardiovascular disorders. Specifically, we found that the ethanol extract and its group 5 fraction of S. miltiorrhiza showed evident cytotoxicity against the human lung adenocarcinoma cell line A549 and ovarian adenocarcinoma cell line TOV-21G in a concentration-dependent manner. Likewise, a dose-dependent cytotoxicity was exerted by the standard solutions of cryptotanshinone, tanshinone I and tanshinone IIA, the major components of the group 5 fraction, where tanshinone IIA were most potent and displayed an IC50 of 2.00 +/- 0.36 MUM and 2.75 +/- 0.23 MUM for A549 and TOV-21G, respectively. Induction of apoptosis represents an essential mechanism underlying tanshinone IIA-mediated cytotoxic action, as evidenced by the proteolytic processing of PARP upon tanshinone IIA stimulation and, importantly, a marked rescue of the viability of tanshinone IIA-treated cells when co-treatment with the pan-caspase inhibitor z-VAD-fmk. Noteworthy, stimulation with cryptotanshinone, tanshinone I or tanshinone IIA all effectively potentiated TRAIL to reduce viability and inhibit the colony formation capacity of TRAIL-resistant TOV-21G and SKOV3. Collectively, we revealed the proapoptotic and TRAIL-sensitizing components of S. miltiorrhiza and further implicated the potential of developing these active compounds as monotherapeutic agent or TRAIL-based therapy for cancer chemoprevention or chemotherapy. PMID- 23660077 TI - Liver resection is a therapeutic option for highly selected BCLC C patients in the context of an expert multidisciplinary setting. PMID- 23660078 TI - Longitudinal assessment of liver stiffness in patients undergoing antiviral treatment for hepatitis C. AB - BACKGROUND: Liver stiffness has been suggested as a parameter of fibrosis progression/regression in hepatitis C virus (HCV) patients. AIM: To evaluate stiffness before and after peginterferon-ribavirin treatment. METHODS: Stiffness was prospectively measured in 74 HCV patients, 32 genotypes 1/4 (43.25%) and 42 genotypes 2/3 (56.75%), before, at end of treatment, and after 3 years of follow up (49 patients). On the same study day, 21 patients underwent liver biopsy. RESULTS: In 55 patients with sustained virological response (74.32%), liver stiffness decreased significantly at end of therapy (6.8+/-4.9kPa) vs. baseline (9.5+/-6.9kPa, p=0.04). The decrease vs. baseline was maintained in 30 sustained virological response patients after 3 years follow-up (6.8+/-4.6kPa vs. 10.8+/ 8.5kPa, p=0.0141). No difference was found at end of treatment vs. baseline (10.1+/-4.7kPa vs. 9.7+/-4.2kPa, p=0.825) and after 3 years of follow-up vs. baseline (10.2+/-3.4kPa vs. 9.7+/-4.2kPa, p=0.765) in null responders. Similar results were found in relapsers at end of treatment vs. baseline (13.7+/-7.7kPa vs. 15.2+/-8.2kPa, p=0.74), and after 3 years of follow-up vs. baseline (16.9+/ 10.0kPa vs. 15.2+/-8.2kPa, p=0.734). Pre-treatment stiffness >12kPa was significantly associated with no SVR (p<0.025), RR=2.44 (95%C.I. 1.17-5.07). CONCLUSION: Liver stiffness may be useful to assess long-term antiviral treatment response. PMID- 23660080 TI - Physical exercise ameliorates the toxic effect of fluoride on the insulin-glucose system. AB - Daily intake of water with fluoride concentrations >1.5 mg/l produces insulin resistance (IR). On the other hand, physical activity increases insulin sensitivity in the muscle. Therefore, the aim of this study was to evaluate the effect of physical activity on IR in rats treated with sodium fluoride (NaF) in drinking water. Sprague-Dawley rats were divided into three groups (n=10/group): Control (drinking water without NaF), NaF (drinking water with NaF 15 mg/l for 30 days), and Exercise (daily running on a treadmill for 60 min at 2.25 m/min and drinking water with NaF 15 mg/l for 30 days). IR was evaluated with the homeostasis model assessment-IR (HOMA-IR) index using fasting plasma levels of glucose and insulin. IR increased in rats treated with 15 mg/l NaF in drinking water. A decrease in IR was observed in rats that performed physical activity and drank water with 15 mg/l NaF; the Exercise group also showed an increase in the amounts of bone fluoride. The variation in the HOMA-IR values could be the consequence of variation in the sensitivity of tissues to insulin or decrease in plasma fluoride levels due to bone fluoride intake. These findings indicate that the performance of daily physical activity could reduce the negative effects of the chronic ingestion of NaF on glucose homeostasis. PMID- 23660081 TI - Patient perceptions and barriers to epilepsy surgery: evaluation in a large health region. AB - PURPOSE: Despite evidence that carefully selected patients with refractory focal epilepsy benefit from epilepsy surgery, significant delays remain. We examined patient knowledge and perceptions regarding epilepsy surgery. METHODS: A 5-minute questionnaire was administered to consecutive adults with focal epilepsy seen in the epilepsy clinic in a large Canadian health region. Survey items assessed the following: (1) knowledge of surgical options, (2) perceptions about the risks of surgery vs. ongoing seizures, (3) disease disability, (4) treatment goals, and (5) demographic and socioeconomic variables. Patient responses were compiled to calculate a "Barriers to Epilepsy Surgery Composite" (BESC) score. RESULTS: Of 129 eligible patients, 107 completed the questionnaire (response rate: 83%). The average BESC score was 60/100. Apprehension about epilepsy surgery was less likely among patients who had previously undergone epilepsy surgery and those born in Canada. DISCUSSION: People with epilepsy often have hindering perceptions that can contribute to delays in surgical care. PMID- 23660079 TI - Nanotechnology in diagnostics and therapeutics for gastrointestinal disorders. AB - This review describes the state of the art in nanoparticle and nanodevice applications for medical diagnosis and disease treatment. Nanodevices, such as cantilevers, have been integrated into high-sensitivity disease marker diagnostic detectors and devices, are stable over long periods of time, and display reliable performance properties. Nanotechnology strategies have been applied to therapeutic purposes as well. For example, nanoparticle-based delivery systems have been developed to protect drugs from degradation, thereby reducing the required dose and dose frequency, improving patient comfort and convenience during treatment, and reducing treatment expenses. The main objectives for integrating nanotechnologies into diagnostic and therapeutic applications in the context of intestinal diseases are reviewed. PMID- 23660082 TI - Human performance in a multiple-task environment: effects of automation reliability on visual attention allocation. AB - Diagnostic automation has been posited to alleviate the high demands of multiple task environments; however, mixed effects have been found pertaining to performance aid success. To better understand these effects, attention allocation must be studied directly. We developed a multiple-task environment to study the effects of automation on visual attention. Participants interacted with a system providing varying levels of automation and automation reliability and then were transferred to a system with no support. Attention allocation was measured by tracking the number of times each task was viewed. We found that participants receiving automation allocated their time according to the task frequency and that tasks that benefited most from automation were most harmed when it was removed. The results suggest that the degree to which automation affects multiple task performance is dependent on the relative attributes of the tasks involved. Moreover, there is an inverse relationship between support and cost when automation fails. PMID- 23660083 TI - Designing for designers: insights into the knowledge users of inclusive design. AB - Over the last twenty years, research on inclusive design has delivered a wealth of publications and initiatives, forming an emerging knowledge base for inclusive design. The inclusive design knowledge base breaks down into two discrete areas - understanding end users from many different perspectives, and understanding the information needs of the knowledge users (e.g. designers) who are involved in promoting and delivering inclusive design solutions. Much research has focused on the end users, but in recent years, understanding the needs and the characteristics of knowledge users has added a new dimension to the research task. This paper focuses on the knowledge users of inclusive design. It discusses the different types of knowledge users and their knowledge needs. The research programmes undertaken by the Inclusive Design Research Group (IDRG) are used to illustrate the process of understanding knowledge needs of designers, developing different types of tools to meet those needs and evaluating their effectiveness. The paper concludes with a discussion on how to adopt an inclusive design research methodology to effectively engage the knowledge users in the development of inclusive design tools. PMID- 23660084 TI - Absorption and backscatter of internal conversion electrons in the measurements of surface contamination of 137Cs. AB - We measured 4pi and 2pi counting efficiencies for internal conversion electrons (ICEs), gross beta-particles and also beta-rays alone with various source conditions regarding absorber and backing foil thickness using e-X coincidence technique. Dominant differences regarding the penetration, attenuation and backscattering properties among ICEs and beta-rays were revealed. Although the abundance of internal conversion electrons of (137)Cs-(137)Ba is only 9.35%, 60% of gross counts may be attributed to ICEs in worse source conditions. This information will be useful for radionuclide metrology and for surface contamination monitoring. PMID- 23660085 TI - Comparison of ramosetron with combined ramosetron and midazolam for preventing postoperative nausea and vomiting in patients at high risk following laparoscopic gynaecological surgery. AB - OBJECTIVES: This randomized, double-blind study compared the antiemetic efficacy of ramosetron with that of ramosetron combined with midazolam, and investigated whether the timing of midazolam administration affected the incidence of postoperative nausea and vomiting (PONV). METHODS: Nonsmoking female patients undergoing laparoscopic gynaecological surgery were randomized to three groups: group R received intravenous (i.v.) normal saline at induction of anaesthesia and 30 min before the end of surgery; group RM1 received midazolam i.v. at induction of anaesthesia and normal saline i.v. 30 min before the end of surgery; group RM2 received normal saline i.v. at induction of anaesthesia and midazolam i.v. 30 min before the end of the surgery. All patients received 0.3 mg ramosetron i.v. at the end of surgery. Incidence of PONV and need for rescue antiemetics were assessed during the 48-h postoperative period. RESULTS: A total of 126 patients were included in the analyses. There was no significant difference in the incidence of severe nausea, emetic episodes or use of antiemetics among the three groups. The incidence of complete response (no PONV and no rescue antiemetics) was significantly higher in the RM1 (30/41; 73%) and RM2 (30/42; 71%) groups compared with group R (19/43; 44%). CONCLUSIONS: Midazolam given at induction of anaesthesia or at the end of the surgery, combined with ramosetron, was more effective than ramosetron alone in reducing the incidence of PONV. PMID- 23660086 TI - Electromyographic response of facial nerve stimulation under different levels of neuromuscular blockade during middle-ear surgery. AB - OBJECTIVE: To investigate facial nerve monitoring in patients receiving the partial nondepolarizing neuromuscular blocking agents (NMBAs), remifentanil and propofol. METHODS: Patients with normal facial function and advanced middle-ear disease were enrolled. For total intravenous anaesthesia (TIVA), propofol and remifentanil were infused as induction/maintenance anaesthesia. Stimulation thresholds and amplitudes were recorded at each train-of-four (TOF) nerve stimulation level. Time differences between start of TOF and electromyographic (EMG) amplitude decreases (Ti), and between complete recovery of TOF and EMG amplitudes (Tr), were calculated. RESULTS: Fifteen patients were enrolled. Mean +/- SD Ti was 3.4 +/- 1.28 min; Tr was 18.7 +/- 4.41 min. Amplitude of stimulation was apparent mostly at TOF level 1. In most cases, no or a weak response (<100 uV) was observed at TOF 0. Mean +/- SD threshold of electrical stimulation was 0.31 +/- 0.10 mA at TOF 1. At TOF > 2, all cases showed EMG response on electrical stimulation. CONCLUSIONS: Induction of TIVA using propofol and remifentanil provided reliable conditions for delicate microsurgery. Minimal NMBA use, considered as producing TOF levels >1, was sufficient for facial nerve monitoring in neuro-otological surgery. PMID- 23660087 TI - Analysis of the levonorgestrel-releasing intrauterine system in women with endometriosis. AB - OBJECTIVES: To compare the efficacy, safety and other clinical benefits of the levonorgestrel-releasing intrauterine system (LNG-IUS) and gonadotropin-releasing hormone analogues (GnRH-a) in women with endometriosis. METHODS: A systematic search was carried out using the Cochrane Central Register of Controlled Trials, PubMed, MEDLINETM and EMBASE databases for all randomized controlled trials (RCTs) that evaluated the use of the LNG-IUS and GnRH-a in premenopausal women with endometriosis. RESULTS: Five RCTs studies were identified. A meta-analysis showed that, in women with endometriosis, both the LNG-IUS and GnRH-a reduced pain visual analogue scale scores (weighted mean difference [WMD] 0.03 [95% confidence interval [CI] -0.53, 0.59]), serum levels of CA125 (WMD -12.29 [95% CI -29.90, 3.32]), and American Society of Reproductive Medicine staging scores (WMD 1.10 [95% CI -27.98, 30.18]). Psychological and general wellbeing index scores were increased (WMD 1.50 [95% CI -6.19, 9.19]). Levels of low-density lipoprotein cholesterol were also significantly reduced in patients treated with the LNG-IUS (WMD 39.30 [95% CI 6.74, 71.86]). CONCLUSIONS: The LNG-IUS had clinical efficacy equivalent to that of GnRH-a but may have some clinical advantages over GnRH-a in the treatment of endometriosis-associated symptoms. These observations will require further verification in additional studies employing larger patient populations. PMID- 23660088 TI - Unusual features in four canine meningiomas. AB - Several subtypes of canine meningioma are recognized. This report describes four canine meningiomas with previously unreported features. The four affected dogs were of different breeds. Three of the affected dogs were male and aged 7-10 years. In one dog, age and gender were not recorded. Meningiomas were located intracranially (three dogs) or within the vertebral canal (one dog). Two meningiomas resembled gemistocytic astrocytomas, while one had focal features of a rhabdoid tumour; these three meningiomas also contained amyloid deposits. The fourth tumour, a secretory meningioma, was rich in amianthoid fibres (i.e. unusual collagen deposits containing giant collagen fibres). All of these features are also described in human meningiomas. PMID- 23660089 TI - Comparative pathogenicity of three Korean and one Lelystad type 1 porcine reproductive and respiratory syndrome virus (pan-European subtype 1) isolates in experimentally infected pigs. AB - The aim of this study was to compare the pathogenicity of three type 1 porcine reproductive and respiratory syndrome virus (PRRSV) isolates that originated from Korean herds with varying severity of respiratory disease with one Lelystad virus. An experimental infection model was used to study virus distribution, sites of viral replication, viraemia, gross and microscopical lesions and the humoural immune response. Each virus isolate was given intranasally to 3-week-old pigs. Differences were found in the severity of gross and microscopical pulmonary lesions and the distribution of virus-labelled cells in lung and lymph nodes (LNs). The gross and microscopical pulmonary lesion scores were significantly greater in pigs inoculated with the SNUVR100744 isolate. The distribution of PRRSV-labelled cells within tissues and organs was similar for the different virus isolates; however, significantly more PRRSV-positive cells were detected in the lung and LNs of pigs inoculated with the SNUVR100744 isolate than were detected in the same tissues of pigs inoculated with Lelystad virus. The results of the present study demonstrate that type 1 PRRSV isolates differ in their ability to induce viral replication in tissues and induce interstitial pneumonia in pigs. PMID- 23660090 TI - [Consensus by experts on applying traditional Chinese Medicine combining with western medicine in the diagnosis and treatment of sepsis (protocol)]. PMID- 23660091 TI - [The clinical implication of sepsis-associated liver injury should be further recognized]. PMID- 23660092 TI - [Mergence and innovation should be emphasized in the development of emergency medicine]. PMID- 23660093 TI - [Integration, communication, improvement, and adaption of critical care medicine for healthcare reform: impressions of 42nd SCCM annual congress]. PMID- 23660094 TI - [Amelioration of inflammatory reaction in patients with severe sepsis with inosine]. AB - OBJECTIVE: To evaluate the therapeutic effect of inosine in patients with severe sepsis. METHODS: A prospective study was conducted. Eighty-five severe sepsis patients hospitalized in intensive care unit (ICU) from March 2011 to August 2012 were included and randomized into three groups: 25 cases as conventional therapy group, who were treated with routine treatments; 28 patients were given inosine within 6 hours besides routine treatments; 32 patients were given inosine after 6 hours together with routine treatments. Inosine was given in the latter two groups by intravenous infusion (600 mg twice a day) for 10-14 days or to the end of the research when patients died or discharged from ICU. Before or after the treatment, venous blood was collected for determination of pro-inflammatory factors and organ function parameters. Average duration of stay in ICU and mortality rate were analyzed. RESULTS: Compared with conventional therapy group, the levels of pro-inflammatory factors, such as tumor necrosis factor-alpha (TNF alpha), interleukin-6 (IL-6), and C-reactive protein (CRP) were decreased in inosine in both within 6-hour and after 6-hour groups (TNF-alpha: 9.6 +/- 4.1 ng/L, 10.8 +/- 2.8 ng/L vs. 18.2 +/- 3.3 ng/L, IL-6: 123.0 +/- 10.1 ng/L, 132.0 +/- 18.4 ng/L vs. 172.0 +/- 17.9 ng/L, CRP: 42.0 +/- 10.3 mg/L, 45.0 +/- 8.6 mg/L vs. 61.0 +/- 12.7 mg/L, all P<0.05), but there was no statistical significance in the content of IL-10 (53.0 +/- 9.4 ng/L, 56.0 +/- 10.8 ng/L vs. 58.0 +/- 11.2 ng/L, both P>0.05). The lowering of alanine transaminase (ALT), total bilirubin, B-type natriuretic peptide (BNP), oxygenation index was more marked in inosine within 6-hour and after 6-hour groups than those of conventional therapy group (ALT: 42.0 +/- 10.8 U/L, 46.0 +/- 7.9 U/L vs. 63.0 +/- 9.4 U/L, total bilirubin: 16.3 +/- 6.7 MUmol/L, 18.3 +/- 7.3 MUmol/L vs. 28.1 +/- 8.5 MUmol/L, BNP: 322.0 +/- 28.7 ng/L, 347.0 +/- 31.4 ng/L vs. 428.0 +/- 43.2 ng/L, oxygenation index: 210.0 +/- 23.8 mm Hg, 198.0 +/- 21.4 mm Hg vs. 163.0 +/- 15.2 mm Hg, all P<0.05). However, the difference of these values showed no significant difference between the two inosine groups (all P>0.05). There was no statistical significance in ICU stay days (22.4 +/- 6.3 days, 19.8 +/- 4.6 days, 23.1 +/- 5.2 days) and mortality rate (36.0%, 32.1%, 34.4%) among three groups (all P>0.05). CONCLUSION: For severe sepsis patients, on the base of routine treatments, normal dose of inosine can lower the level of pro-inflammatory factors and ameliorate organ function, but it cannot decrease average ICU stay days and mortality rate. PMID- 23660095 TI - [Clinical research of timing of application of antibiotics in septic shock of pediatric patients]. AB - OBJECTIVE: To investigate the value of timing of antibiotics in pediatric septic shock. METHODS: Eighty children with septic shock treated with bundle treatment in Department of Critical Care Medicine were retrospectively analyzed. Eighty children with septic shock were divided into observation group (n=40, anti infection therapy within 1 hour after admission) and control group (n=40, anti infection therapy 1-6 hours after admission). The contents of lactate, C-reaction protein (CRP) and procalcitonin (PCT) were compared between two groups at admission and 24 hours and 72 hours after admission. RESULTS: Lactate in the observation group was significantly lower than that of the control group within the first 24 hours after admission (8.65 +/- 2.84 mmol/L vs. 11.75 +/- 3.20 mmol/L, P<0.01). CRP in the observation group was significantly lower than that of the control group 24 hours and 72 hours after admission (66.25 +/- 8.55 mg/L vs. 91.77 +/- 7.71 mg/L, 22.03 +/- 7.46 mg/L vs. 50.11 +/- 7.30 mg/L, both P<0.01). PCT in the observation group was significantly lower than that of the control group 72 hours after admission (0.67 +/- 0.31 MUg/L vs. 1.16 +/- 0.25 MUg/L, P<0.01). Time for shock recovery in the observation group was significantly shorter than that of the control group (6.80 +/- 3.70 hours vs. 12.80 +/- 3.63 hours, P<0.05), but no statistical difference in mortality rate between groups was found [5% (2/40) vs. 10% (4/40), P>0.05]. CONCLUSION: With the early empirical anti-infection treatment in pediatric septic shocked patients, time for recovery from shock can be shortened and successful rate of resuscitation can be improved. PMID- 23660096 TI - [Prognostic value of arterial lactate content combined with base excess in patients with sepsis: a retrospective study]. AB - OBJECTIVE: To study the prognostic value of arterial lactate combined with base excess (BE) in sepsis patients. METHODS: Clinical data of patients admitted to intensive care unit (ICU) from July 2009 to December 2012 were retrospectively analyzed. Patients were divided into survivor group and non-survivor group, and the arterial blood lactate and BE concentrations were compared between groups. The receiver operating characteristic curve (ROC curve) was drawn and area under the ROC curve (AUC) was calculated to analyze the function of arterial lactate, BE and their combination in judging the prognosis of sepsis. The best cut-off values of arterial lactate and BE for sepsis prognosis were searched. RESULTS: One hundred and eighteen patients were enrolled with 75 in survivor group and 43 in non-survivor group. There were significant differences in arterial lactate [1.20(0.90) mmol/L, 2.30(1.90) mmol/L] and BE (0.44 +/- 5.13 mmol/L, -4.35 +/- 4.86 mmol/L) between two groups (both P=0.000). The AUC for mortality prediction was 0.805, 0.755 and 0.822 for arterial blood lactate, BE, and their combination respectively. Using arterial lactate higher than 1.7 mmol/L and BE lower than -3 mmol/L as cut-off values, a better sensitivity (79.1% and 69.8%) and positive predictive value (3.955 and 2.493) can be obtained. CONCLUSION: Combination of arterial lactate and BE can be a better indicator of prognosis in sepsis patients. PMID- 23660097 TI - [Distribution and antibiotic resistance of bacteria causing bloodstream infections in patients in intensive care unit]. AB - OBJECTIVE: To investigate the distribution and antibiotic resistance of bacteria causing bloodstream infections in intensive care unit (ICU) patients and to provide a basis for rational clinical use of antibiotics. METHODS: The data of positive specimens, including whole blood, catheter blood and bone marrow samples, were isolated from ICU patients from January 2010 to December 2012. Disc diffusion method, micro-dilution and Etest method were used to test drug sensitivity. Distribution and antibiotic resistance of bacteria were analyzed retrospectively. RESULTS: A total of 1077 strains were isolated from 903 patients with bloodstream infection during 3 years. Gram-positive (G+) bacteria and Gram negative (G-) bacteria accounted for 59.33% (639 isolates) and 40.67% (438 isolates) respectively. The 5 most frequently isolated bacteria were Staphylococcus epidermidis (20.06%, 216 isolates) followed in order by Escherichia coli (13.93%, 150 isolates), Acinetobacter baumannii (10.03%, 108 isolates), Klebsiella pneumonia (7.80%, 84 isolates) and Staphylococcus aureus (6.96%, 75 isolates). There was no significant difference in distribution of bacteria during 3 years. The resistance rate of Staphylococcus epidermidis was higher than that of Staphylococcus aureus to most of the tested drugs. The resistance rate of Staphylococcus epidermidis to quinoline/dalfopristin (4.2%) and nitrofurazone (15.3%) was relatively low, while resistance to penicillin (94.4%), linezolid (93.1%), piperacillin/tazobactam (90.3%), cefoperazone/sulbactam (87.5%) and oxacillin (83.3%) was over 80%. The resistance rate of Staphylococcus aureus to penicillin (96.0%), cefoperazone/sulbactam (84.0%), linezolid (76.0%) and oxacillin (76.0%) was over 70%, and resistance to the other common antibacterial drugs was below 70%. The resistance rate of Acinetobacter baumannii to amikacin (38.9%), nitrofurazone (91.7%), cefotetan (88.9%), ceftazidime (88.9%), ampicillin (88.9%), ceftriaxone (86.1%), the cefepime (86.1%), aztreonam (80.6%) and cefazolin (80.6%), and overall above 80%. The resistance rate of Escherichia coli to amikacin (30.0%), cefotetan (24.0%) and imipenem (16.0%) was below 30%, while resistance to ampicillin/sulbactam (94.0%), levofloxacin (84.0%), ampicillin (84.0%) and ceftriaxone (80.0%) was over 80%. CONCLUSIONS: Among the bacteria causing bloodstream infection as isolated from ICU patients, G(+) and G(-) bacteria accounted for 59.33% and 40.67%, respectively. The resistance rate of G(-) was higher than that of G(+), and resistance rate of majority of bacteria was higher than 60% on average. Before obtaining the susceptibility test Results, both G(-) and G(+) should be taken into account on choosing antimicrobial drugs in the treatment of ICU patients. PMID- 23660098 TI - [The effect of ulinastatin on disbalance of inflammation and immune status in patients with severe sepsis]. AB - OBJECTIVE: To investigate the effect of ulinastatin (UTI) on the levels of immune regulatory cells,pro-inflammatory mediators, and the expression of human leukocyte antigen-DR (HLA-DR) in CD14+ monocytes. METHODS: A total of sixty patients with severe sepsis who were admitted to intensive care unit (ICU) during October 2011 to October 2012 were enrolled. The patients were randomly divided into two groups: routine treatment group (n=30, received routine bundle treatment) and UTI group (n=30, received 30 kU UTI three times per day in addition to routine bundle treatment). A course of treatment consisted of 5 days in both groups. The peripheral blood was collected, and the expression of CD4+CD25+- regulatory T cell (Treg), help T cell 17 (Th17), interleukin (IL-17, IL-6, IL-10) and HLA-DR were determined before and 5 days after treatment, in order to observe the effect of UTI. RESULTS: There was no significant difference in all indexes before treatment between two groups. Compared with routine treatment group, UTI could reduce the abnormal expression of Treg and Th17 in patients with severe sepsis [Treg: (9.05 +/- 1.27)% vs. (11.83 +/- 1.30)%, Th17:(3.20 +/- 0.33)% vs. (4.42 +/- 0.35)%, both P<0.01], and decrease the ratio of Treg/Th17 (2.22 +/- 0.28 vs. 2.82 +/- 0.29, P<0.01) more effectively. UTI could also reduce the abnormal expression of IL-17, IL-6 and IL-10 compared with routine treatment group (IL-17: 98.35 +/- 12.23 ng/L vs. 118.20 +/- 15.97 ng/L, IL-6: 24.17 +/- 6.72 ng/L vs. 29.27 +/- 8.13 ng/L, IL-10: 33.17 +/- 7.24 ng/L vs. 37.34 +/- 8.49 ng/L, P<0.05 or P<0.01). In addition UTI could ameliorate the immune status, improve the expression of HLA-DR compared with routine treatment group [(49.34 +/- 11.34)% vs. (36.44 +/- 8.14)%, P<0.01]. The 28-day mortality in UTI group showed a tendency of lowering compared with routine treatment group, but the difference between two groups was not significant(18.2% vs. 20.1%, P>0.05). CONCLUSIONS: UTI can decrease in the expression of Treg and Th17, inverse the ratio of Treg/Th17, decrease in the expression of IL-17, IL-6 and IL 10, ameliorate the immune status, and improve the expression of HLA-DR. UTI is expected to improve the prognosis of patients with severe sepsis. PMID- 23660099 TI - [The effects of early enteral nutrition with addition of probiotics on the prognosis of patients suffering from severe acute pancreatitis]. AB - OBJECTIVE: To investigate the curative effect of early enteral nutrition (EN) supplemented with probiotics (bifidobacterium) in patients with severe acute pancreatitis (ASP). METHODS: Seventy SAP cases admitted from January 2005 to October 2012 were randomly assigned into parenteral nutrition (PN) group (n=22), EN group (n=25) and bifidobacterium added EN (P+EN) group (n=23). In P+EN group, patients were given their nutrition the same as that of EN, and also probiotics (bifidobacterium, 4 capsules every 12 hours, given through nasal gastric tube, each capsule weighing 210 mg). The routine treatment including anti-infection and anti-acid agents, and that of inhibition of pancreatic secretion were given, except for the different nutritional interventions in all groups. The blood samples were collected for e same measurements of interleukin-8 (IL-8) and tumor necrosis factor (TNF-alpha) by enzyme linked immunosorbent assay (ELISA), and for the C-reactive protein (CRP), lactic acid dehydrogenase (LDH), white blood cell (WBC) count, amylase and lipase by biochemistry assay 1 day before intervention of nutrition, and 7 days and 14 days after intervention. Changes in organ function and outcome were also recorded at the same time points. RESULTS: The plasma levels of IL-8, TNF-alpha, CRP, LDH, WBC count, amylase and lipase were significantly reduced after nutritional intervention compared with their levels on day 1 before intervention in all three groups. The plasma IL-8, TNF-alpha, CRP, lipase, LDH at 14 days after intervention of nutrition in P+EN group were significantly lower than those in PN group and EN group (IL-8: 21.00 +/- 7.07 MUg/L vs. 48.00 +/- 10.32 MUg/L, 32.00 +/- 9.30 MUg/L; TNF-alpha: 44.3 +/- 10.9 ng/L vs. 132.1 +/- 34.1 ng/L, 67.8 +/- 22.3 ng/L; CRP: 35.0 +/- 12.4 mg/L vs. 103.2 +/- 49.2 mg/L, 63.0 +/- 29.2 mg/L; lipase: 269 +/- 79 U/L vs. 670 +/- 145 U/L, 310 +/- 78 U/L; LDH: 21.8 +/- 10.3 U/L vs. 78.1 +/- 37.4 U/L, 37.9 +/- 25.1 U/L, P<0.05 or P<0.01). The WBC count in P+EN group was significantly lower than that in PN group (5.9 +/- 3.0 * 109/L, 6.3 +/- 3.2 * 109/L vs. 9.6 +/- 3.0 *109/L, both P<0.05), but there was no significant difference in amylase between P+EN group and PN group (211 +/- 49 U/L, 236 +/- 52 U/L vs. 298 +/- 71 U/L, P>0.05). The gastrointestinal dysfunction score in P+EN, EN, PN groups 14 days after nutritional intervention was 0.28 +/- 0.05, 0.43 +/- 0.09, 0.71 +/- 0.11, respectively, with statistically significant differences (all P<0.01). Compared with PN and EN groups, the incidence of upper gastrointestinal bleeding (1 vs. 9, 2), infection and abscess (2 vs. 12, 5) was lower (all P<0.01), and hospital day was significantly shortened in P+EN group (10.4 +/- 3.9 days vs. 25.8 +/- 6.4 days, 13.4 +/- 5.2 days, both P<0.01). There was no significant statistical difference in mortality rate among three groups. CONCLUSION: Our results indicated that early EN with addition of probiotics (bifidobacterium) resulted in significant lowering of the level of pro-inflammatory cytokines, earlier restoration of gastrointestinal function, decrease of complications such as infection, and shortening of hospital day in patients with SAP. PMID- 23660100 TI - [The initial CT findings in patients suffering from invasive pulmonary aspergillosis]. AB - OBJECTIVE: To approach the initial CT findings of invasive pulmonary aspergillosis (IPA) in patients with immunosuppression. METHODS: All consecutive adult patients who met the diagnostic criteria of the 2008 European Organization for Research and Treatment of Cancer/ Mycoses Study Group (EORTC/MSG) for proven or probable IPA were included as of January 2005 to June 2011. The patients were divided into two groups according to patients with or without hematological malignancy. The initial CT findings in our study were retrospectively reviewed by two thoracic radiologists, while patients' demographics and clinical outcomes were blinded. The pattern and number of abnormalities were recorded. RESULTS: A total of 65 IPA patients were eligible, with 34 hematological malignancy patients and 31 non-hematological patients. Among all IPA patients, the pattern of ground glass opacity and consolidation or mass formation was most commonly seen (56.9%), followed by macronodules (46.2%); halo sign (32.3%) was relatively uncommon. Ground-glass opacity and consolidation or mass formation were more commonly identified in non-hematological patients than in hematological malignancy patients (54.8%, 45.2% vs. 8.8%, both P<0.05), but macronodules, infarct-shaped macronodules and halo signs were less frequently identified in the non hematological group (16.1%, 3.2%, 12.9%, respectively) than in the hematological malignancy group (73.5%, 23.5% and 50.0%, respectively, P<0.05 or P<0.01). The airway-invasive form of IPA was more frequently seen in non-hematological patients (67.8%), whereas the angioinvasive form was more common in hematological malignancy patients (64.7%, P<0.01). CONCLUSION: Our data indicate that CT findings of IPA in non-hematological patients more commonly present as the airway invasive form, manifesting ground-glass opacity and consolidation or mass formation, whereas in patients with hematological malignancy it more likely shows evidence of the angioinvasive form with macronodules and halo signs. PMID- 23660101 TI - [Clinical study of prognostic value of interleukin-6 in severe acute pancreatitis]. AB - OBJECTIVE: To investigate the value of serum interleukin-6 (IL-6) level as a prognostic indicator in severe acute pancreatitis (SAP) patients. METHODS: Data of 62 cases of SAP admitted to Department of Critical Care Medicine from January 2006 to September 2012 were retrospectively analyzed. They were divided into two groups: non-survivor group (n=15) and survivor group (n=47). Serum levels of IL-6 at 24, 48, 72 hours after admission were compared between two groups. Correlation between IL-6 value and acute physiology and chronic health evaluation II (APACHE II) score and CT severity index (CTSI) at 48 hours were analyzed. The receiver operating characteristic curve (ROC curve) was plotted at 48 hours to analyze the accuracy of IL-6 value as a prognostic indicator in the initial stage of SAP. RESULTS: The IL-6 values were elevated obviously followed by a lowering in non survivor group. However, it continued to decrease gradually in survivor group. The IL-6 values of non-survivor group were significantly higher than those of survivor group at 48 hours and 72 hours after admission (545.5 +/- 265.7 ng/L vs. 147.2 +/- 107.0 ng/L, 243.0 +/- 133.6 ng/L vs. 119.0 +/- 69.5 ng/L, both P<0.01). IL-6 ROC had an area under curve (AUC) of 0.930 at 48 hours. In both groups, IL-6 values and APACHEII score showed a positive correlation (r=0.930, P=0.003; r=0.964, P=0.000), and also between IL-6 values and CTSI (r=0.915, P=0.000; r=0.921, P=0.005) at 48 hours. CONCLUSION: IL-6 can be a useful indicator of the prognosis in the initial stage of SAP (48 hours). PMID- 23660102 TI - [Change in peripheral blood CD4+CD25+ regulatory T cell in patients with sepsis and its clinical implication]. PMID- 23660103 TI - [Advance in the study of the role of macrophages in the pathogenesis of sepsis]. PMID- 23660104 TI - [Advances in the study of myeloid-derived suppressor cells in sepsis]. PMID- 23660105 TI - [Sepsis and mitochondrial dysfunction]. PMID- 23660106 TI - Demand for smokeless tobacco: role of advertising. AB - While the prevalence of smokeless tobacco (ST) is low relative to smoking, the distribution of ST use is highly skewed with consumption concentrated among certain segments of the population (rural residents, males, whites, low-educated individuals). Furthermore, there is suggestive evidence that use has trended upwards recently for groups that have traditionally been at low risk of using ST, and thus started to diffuse across demographics. This study provides the first estimates, at the national level, of the effects of magazine advertising on ST use. The focus on magazine advertising is significant given that ST manufacturers have been banned from using other conventional media since the 1986 Comprehensive ST Act and the 1998 ST Master Settlement Agreement. This study is based on the 2003-2009 waves of the National Consumer Survey (NCS), a unique data source that contains extensive information on the reading habits of individuals, matched with magazine-specific advertising information over the sample period. This allows detailed and salient measures of advertising exposure at the individual level and addresses potential bias due to endogeneity and selective targeting. We find consistent and robust evidence that exposure to ST ads in magazines raises ST use, especially among males, with an estimated elasticity of 0.06. There is suggestive evidence that both ST taxes and cigarette taxes reduce ST use, indicating contemporaneous complementarity between these tobacco products. Sub analyses point to some differences in the advertising and tax response across segments of the population. The effects from this study inform the debate on the cost and benefits of ST use and its potential to be a tool in overall tobacco harm reduction. PMID- 23660107 TI - Reprint of: Iron/sulfur proteins biogenesis in prokaryotes: formation, regulation and diversity. AB - Iron/sulfur centers are key cofactors of proteins intervening in multiple conserved cellular processes, such as gene expression, DNA repair, RNA modification, central metabolism and respiration. Mechanisms allowing Fe/S centers to be assembled, and inserted into polypeptides have attracted much attention in the last decade, both in eukaryotes and prokaryotes. Basic principles and recent advances in our understanding of the prokaryotic Fe/S biogenesis ISC and SUF systems are reviewed in the present communication. Most studies covered stem from investigations in Escherichia coli and Azotobacter vinelandii. Remarkable insights were brought about by complementary structural, spectroscopic, biochemical and genetic studies. Highlights of the recent years include scaffold mediated assembly of Fe/S cluster, A-type carriers mediated delivery of clusters and regulatory control of Fe/S homeostasis via a set of interconnected genetic regulatory circuits. Also, the importance of Fe/S biosynthesis systems in mediating soft metal toxicity was documented. A brief account of the Fe/S biosynthesis systems diversity as present in current databases is given here. Moreover, Fe/S biosynthesis factors have themselves been the object of molecular tailoring during evolution and some examples are discussed here. An effort was made to provide, based on the E. coli system, a general classification associating a given domain with a given function such as to help next search and annotation of genomes. This article is part of a Special Issue entitled: Metals in Bioenergetics and Biomimetics Systems. PMID- 23660109 TI - Emotional, endocrine and brain anandamide response to social challenge in infant male rats. AB - Individual response to stress is orchestrated by hypothalamus-pituitary axis corticosteroids, although critically modulated by the central endocannabinoid (eCB) system. Whilst the role of the eCB system in stress response and emotional homeostasis in adult animals has been extensively studied, it has only been scarcely investigated in developing animals. Herein, we aimed to investigate the participation of eCB ligands in the stress responses of neonate rats. Twelve days old Wistar male rats were exposed to a social challenge (repeated brief isolations from dam and littermates), which resulted in a significant increase in serum corticosterone levels. This stressful social challenge also decreased spontaneous rat pups' behaviours and augmented isolation-induced ultrasonic vocalizations. Notably, a specific decrease in anandamide content (not 2-AG) was observed within the hippocampus (not in the striatum). However, the enhancement of eCB signalling by URB597 administration (0.1mg/kg) did not affect the adrenocortical and behavioural responses to this postnatal social challenge. The influence of gestational stress was also evaluated in the infant offspring of rats dams exposed to restraint stress (PRS, three episodes/day, on gestation days 14 till delivery); however, PRS did not modify neonate responses to this postnatal challenge. Present findings provide evidence for the participation of the eCB system in the acute response to a social challenge in infant male rats. However, the lack of evidences from the pharmacological study encourages the investigation of alternative and/or indirect mechanisms that may participate in the behavioural and endocrine response to stress in developing animals. Further experiments are still needed to clarify the interactions between the HPA axis and the eCB system in stress reactivity at early postnatal stages. PMID- 23660111 TI - Vaccination rates and related factors among health care workers in South Korea, 2009. PMID- 23660110 TI - Living on the mountains: patterns and causes of diversification in the springsnail subgenus Pseudamnicola (Corrosella) (Mollusca: Caenogastropoda: Hydrobiidae). AB - Hydrobiidae is one of the largest families of freshwater gastropods comprised of approximately 400 genera and 1000 species. Despite this high level of diversity, most hydrobiid species inhabit fragile ecosystems in restricted distribution areas. In this work, we analyze modes of speciation and causes of diversification in the hydrobiid springsnail subgenus Pseudamnicola (Corrosella). Species of this group typically live in nutrient poor springs and streams and are restricted to mountainous regions of the Iberian Peninsula (Spain) and Southern France. Previous morphological and molecular (based only on the cytochrome c oxidase subunit I (COI) gene) studies revealed 11 nominal Corrosella species. In this study, we enhance published molecular results by generating new data from mitochondrial (16S rRNA and COI) and nuclear ribosomal regions (18S and 28S rRNA) from 50 Corrosella populations. As a result of this study we have identified one new species, making a total of twelve recognized species in the subgenus Corrosella. Our phylogenetic results also reveal the existence of three lineages within the subgenus, and the estimation of time divergence indicates the occurrence of three main speciation events during the upper Miocene to Pleistocene. We test the influence of several geographical and ecological variables and observe that diversification patterns are related to habitat fragmentation rather than environmental conditions. This result suggests that the high level of diversity observed within the subgenus may have resulted from a non adaptive radiation. The formation of the Iberian Peninsula mountain ranges (the Pyrenees in the north and the Betic Cordillera in the south) and the configuration of the Iberian current hydrographic system played important roles in Corrosella speciation. Additionally, during the Miocene the Iberian Peninsula experienced a gradient of increasing temperature and dryness from north to south, which together with a high level of tectonic activity, may have caused the majority of the diversity found in the southern Iberian Peninsula. PMID- 23660112 TI - Disinfection of iPad to reduce contamination with Clostridium difficile and methicillin-resistant Staphylococcus aureus. PMID- 23660113 TI - The polymorphism in the let-7 targeted region of the Lin28 gene is associated with increased risk of type 2 diabetes mellitus. AB - Genetic polymorphisms in the miRNAs pathway of the pathogenesis of disease might contribute to the risk of disease. However, it is unclear whether these polymorphisms about miRNAs are associated with the risk of type 2 diabetes mellitus (T2DM). We performed a case-control study to investigate two polymorphisms in the let-7/Lin28 pathway based on 588 T2DM patients and 588 age and sex matched controls. The results showed that the rs3811463 polymorphism was associated with increased risk of T2DM (odds ratio (OR)=1.47, 95% confidence inference (95%CI)=1.13-1.93, P=0.005), while the rs3811464 not (OR=1.04, 95%CI=0.79-1.36, P=0.78). For the rs3811463 polymorphism, the variant genotypes were associated with increased risk of disease in females; statistically differences were observed in the clinical features of age at diagnosis, hypertension and peripheral neuropathy for the variant and wild genotype of the rs3811463 in T2DM. In summary, the results indicated that the rs3811463 polymorphism in the let-7/Lin28 pathway could significantly increase the risk of T2DM. PMID- 23660114 TI - Perturbation of nucleotide metabolism--the driving force of oncogene-induced senescence. PMID- 23660115 TI - Bidi and hookah use among Canadian youth: findings from the 2010 Canadian Youth Smoking Survey. AB - INTRODUCTION: Although cigarette use among Canadian youth has decreased significantly in recent years, alternative forms of tobacco use are becoming increasingly popular. Surveillance of youth tobacco use can help inform prevention programs by monitoring trends in risk behaviors. We examined the prevalence of bidi and hookah use and factors associated with their use among Canadian youth by using data from the 2010-2011 Youth Smoking Survey (YSS). METHODS: We analyzed YSS data from 28,416 students (2006-2007) and 31,396 students (2010-2011) in grades 9 through 12 to examine prevalence of bidi and hookah use. We conducted multivariate logistic regression analyses of 2010-2011 YSS data to examine factors associated with bidi and hookah use. RESULTS: From 2006 through 2010, prevalence of hookah use among Canadian youth increased by 6% (P = .02). Marijuana use emerged as a consistent predictor of bidi and hookah use. Males, youth of black, Latin, or other descent, and youth of Asian descent were more likely to use bidis (odds ratio [OR], 1.5; OR, 15.6; OR, 14.9) or hookah (OR, 1.3; OR, 2.4; OR, 1.5). Current cigarette smokers were more likely than nonsmokers to be current users of bidis (OR, 6.7) and hookahs (OR, 3.0), and occasional and frequent alcohol drinkers were also more likely than nondrinkers to be current hookah users (OR, 2.8; OR, 3.6). CONCLUSION: Although bidi use has not changed significantly among Canadian youth, the increase in hookah use warrants attention. Understanding the factors associated with use of bidis and hookahs can inform the development of tobacco use prevention programs to address emerging at-risk youth populations. PMID- 23660116 TI - Using current smoking prevalence to project lung cancer morbidity and mortality in Georgia by 2020. AB - INTRODUCTION: Tobacco use is the leading preventable cause of disease and premature death in the United States. In Georgia, approximately 18% of adults smoke cigarettes, and 87% of men's lung cancer deaths and 70% of women's lung cancer deaths are due to smoking. From 2004-2008, the age-adjusted lung cancer incidence rate in Georgia was 112.8 per 100,000 population, and the mortality rate was 88.2 per 100,000 population. METHODS: The Georgia Behavioral Risk Factor Surveillance System Survey was used to estimate trends in current adult smoking prevalence (1985-2010). Georgia smoking-attributable cancer mortality was estimated using a method similar to the Centers for Disease Control and Prevention's Smoking-Attributable Morbidity, Mortality, and Economic Costs application. Data on cancer incidence (1998-2008) were obtained from the Georgia Comprehensive Cancer Registry, and data on cancer deaths (1990-2007) were obtained from the Georgia Department of Public Health Vital Records Program. RESULTS: From 1985 through 1993, the prevalence of smoking among Georgians declined by an average of 3% per year in men and 0.2% in women. From 2001 through 2008, lung cancer incidence rates declined in men and increased in women. Lung cancer mortality rates declined in men and women from 2000 through 2007. By 2020, Georgia lung cancer incidence rates are projected to decrease for men and increase for women. Lung cancer mortality is projected to decrease for both men and women. CONCLUSION: The lung cancer mortality rates projected in this study are far from meeting the Healthy People 2020 goal (46 per 100,000 population). Full implementation of comprehensive tobacco-use control programs would significantly reduce tobacco-use-related morbidity and mortality. PMID- 23660117 TI - Recruiting women for a study on perceived risk of cancer: influence of survey topic salience and early versus late response. AB - INTRODUCTION: Understanding the characteristics of early and late survey responders has implications for recruitment efforts and for informing potential response bias. The main objective of this analysis was to examine survey responder status (ie, early vs late response) by sociodemographic characteristics and by salience of study variables among respondents. METHODS: We analyzed data from a survey on family cancer history and perceived cancer risk among women at a large managed health-care organization. For baseline and 12-month follow-up surveys, we defined early versus late responder status according to the 95th percentile of the number of days it took to obtain completed interviews. RESULTS: We found no significant associations between responder status and sociodemographic characteristics at baseline or follow-up. At baseline, early responders were significantly more likely than late responders to have a personal history of breast cancer (5.2% vs 3.4%, P = .04) and to have been referred for genetic counseling (4.6% vs 2.0%, P = .004). The association between personal history of breast cancer and responder status persisted at follow-up; only 3.5% of late responders at baseline were also late responders at follow-up. Follow-up survey nonresponse rates did not vary by baseline responder status. CONCLUSION: Survey topic salience is associated with early response and is important for recruitment. However, once recruited, late responders do not remain late responders at follow-up, suggesting that extra efforts made to recruit late responders are worthwhile. Health-related agencies that conduct surveys should consider survey salience in survey administration and recruitment strategies. PMID- 23660118 TI - Survey of New York City resident physicians on cause-of-death reporting, 2010. AB - INTRODUCTION: Death certificates contain critical information for epidemiology, public health research, disease surveillance, and community health programs. In most teaching hospitals, resident physicians complete death certificates. The objective of this study was to examine the experiences and opinions of physician residents in New York City on the accuracy of the cause-of-death reporting system. METHODS: In May and June 2010, we conducted an anonymous, Internet-based, 32-question survey of all internal medicine, emergency medicine, and general surgery residency programs (n = 70) in New York City. We analyzed data by type of residency and by resident experience in reporting deaths. We defined high-volume respondents as those who completed 11 or more death certificates in the last 3 years. RESULTS: A total of 521 residents from 38 residency programs participated (program response rate, 54%). We identified 178 (34%) high-volume respondents. Only 33.3% of all respondents and 22.7% of high-volume residents believed that cause-of-death reporting is accurate. Of all respondents, 48.6% had knowingly reported an inaccurate cause of death; 58.4% of high-volume residents had done so. Of respondents who indicated they reported an inaccurate cause, 76.8% said the system would not accept the correct cause, 40.5% said admitting office personnel instructed them to "put something else," and 30.7% said the medical examiner instructed them to do so; 64.6% cited cardiovascular disease as the most frequent diagnosis inaccurately reported. CONCLUSION: Most resident physicians believed the current cause-of-death reporting system is inaccurate, often knowingly documenting incorrect causes. The system should be improved to allow reporting of more causes, and residents should receive better training on completing death certificates. PMID- 23660119 TI - Beta-blocker use and clinical outcomes after primary vascular surgery: a nationwide propensity score-matched study. AB - OBJECTIVE: To explore the associations between beta-blocker use and clinical outcomes (death, hospitalisation with myocardial infarction (MI) or stroke, major amputation and recurrent vascular surgery) after primary vascular reconstruction. METHODS: Patients who had primary vascular surgical or endovascular reconstruction due to symptomatic peripheral arterial disease, in Denmark between 1996 and 2007 were included. We obtained data on filled prescriptions, clinical outcomes and confounding factors from population-based healthcare registries. Beta-blocker users were matched to non-users by propensity score, and Cox regression was performed. All medications were included as time-dependent variables. RESULTS: We studied 16,945 matched patients (7828 beta-blocker users and 9117 non-users) with a median follow-up period of 582 days (range, 30-4379 days). The cumulative risks were as follows: all-cause mortality, 17.9%; MI, 5.3%; stroke, 5.6%; major amputation, 9.1%; and recurrent vascular surgery, 23.1%. When comparing beta-blocker users with non-users: adjusted hazard ratio: MI, 1.52 (95% CI, 1.31-1.78); stroke, 1.21 (95% CI, 1.03-1.43); and major amputation, 0.80 (95% CI, 0.70-0.93). CONCLUSION: Beta-blocker use after primary vascular surgery was associated with a lower risk of major amputation but an increased risk of hospitalisation with MI and stroke. No associations were found between beta-blocker use and all-cause mortality or the risk of recurrent vascular surgery. However, our results are not sufficient to alter the indication for beta-blocker use among symptomatic peripheral arterial disease patients. PMID- 23660120 TI - Acute meningitis in Behcet's disease. PMID- 23660121 TI - Guy de Maupassant and his account of sleep paralysis in his tale, "The Horla". PMID- 23660122 TI - First-in-human trial of Dz13 for nodular basal-cell carcinoma. PMID- 23660124 TI - Oral lichen planus: focus on etiopathogenesis. AB - Lichen planus is a chronic mucocutaneous inflammatory disease, which frequently affects the oral mucosa of white females over 40 years old. Its aetiology remains uncertain and the pathogenesis is still the object of much speculation. The present paper presents the most well known antigens, and describes the action of different cells and proteins associated with the development of that disease, as well as the possible agents involved with its malignant transformation. Different external agents, especially virus, and internal agents, like stress, and the heat shock protein antigen expression, associated or not, can alter the basal keratinocytes of the oral mucosa making them susceptible to apoptosis by CD8(+) cytotoxic T cell as well as activate matrix metalloproteinase and mast cell degranulation, which produce a great range of inflammatory mediators and cytokines determining the clinical onset of the disease. Regarding carcinogenesis, since it is a complex process and presents multifactorial origin, it is believed that there may be a synergism between intrinsic, such as inflammation mediators, and extrinsic agents (tobacco, alcohol, viral infections) for the OLP malignant transformation to occur. However, further studies are needed to better understand the origin, pathogenesis and process of malignant transformation of OLP. PMID- 23660123 TI - Safety and tolerability of an intratumorally injected DNAzyme, Dz13, in patients with nodular basal-cell carcinoma: a phase 1 first-in-human trial (DISCOVER). AB - BACKGROUND: The nuclear transcription factor c-Jun is preferentially expressed in basal-cell carcinoma. Dz13 is a deoxyribozyme that targets JUN messenger RNA and has inhibited the growth of a range of tumours in mice. We did a phase 1 study to assess safety and tolerability in human beings. METHODS: Adults with nodular basal-cell carcinoma were recruited from Royal Prince Alfred Hospital, Sydney, Australia, between September, 2010, and October, 2011. Patients were assigned to receive one intratumoral injected dose of 10, 30, or 100 MUg Dz13, in a 50 MUL volume of lipid carrier, and were assessed for adverse effects in the first 24 h then at 7, 14, and 28 days after injection. Treated tumours were surgically excised 14 days after injection and compared with the baseline biopsy samples for expression of c-Jun and tumorigenesis markers. FINDINGS: Nine patients were recruited, of whom three received each dose of Dz13. All patients completed the study with no drug-related serious adverse events. No systemic Dz13 exposure was detected. c-Jun expression was reduced in the excised tumours of all nine (100%) patients, compared with baseline, and histological tumour depth had decreased in five (56%) of nine. Proportions of cells positive for caspases 3, 8, and 9 and P53 were increased, but those of cells positive for Bcl-2 and MMP-9 were decreased. Infiltration by inflammatory and immune cells was stimulated. INTERPRETATION: Dz13 was safe and well tolerated after single intratumoral injections at all doses. FUNDING: Cancer Institute NSW, Cancer Council Australia, and National Health and Medical Research Council. PMID- 23660125 TI - Effects of tyrosine kinase inhibitors on rat isolated heart function and protein biomarkers indicative of toxicity. AB - INTRODUCTION: Cardiac toxicity, manifested as diminished contractility, ischemic heart disease, and heart failure is a major issue in drug safety. Concerns revolve around targeted drugs (TKIs) where contractility effects were not anticipated. The ability to predict cardiac toxicity early would help to de-risk drugs in development and prepare physicians to manage risk in the clinic. Issues with current preclinical studies include insufficient testing with informative, translatable models, and predictive biomarkers. The isolated heart model is amenable to multiple assessments which can be combined with current technologies to assess toxicity on a multi-scale level. METHODS: Rat isolated heart model was used to assess changes in left ventricular (LV) contractility and protein biomarkers BNP, IL6, TNFalpha, and cardiac troponins T (TnT) and I (TnI). Responses were assessed during perfusion with modified Henseleit Krebs (MHK), and 20 min concentration escalations of verapamil, carbonyl cyanide 4 (trifluoromethoxy)phenylhydrazone (FCCP), isoproterenol, or 20 min escalations bracketing clinical blood concentrations of sunitinib, sorafenib, and erlotinib. LV parameters and effluent for biomarkers were collected before and during escalating drug concentrations. RESULTS: Verapamil reduced inotropy with no change in biomarkers, FCCP and isoproterenol reduced and increased heart function respectively and increased TnT and TNFalpha. Erlotinib had no significant effects on function or biomarkers. Sunitinib diminished function, increased TNFalpha at 0.1 MUM, and increased TnT at higher concentrations. Sorafenib dose dependently increased TNFalpha beginning at 0.1 MUM, reducing contractility and flow rate at 0.6 MUM. DISCUSSION: The ex-vivo assay is a sensitive and predictive model for assessing changes in heart function and biomarkers of toxicity and injury. This assay demonstrates the potential for sunitinib and sorafenib to cause cardiac toxicity in humans. Also, TNFalpha appears to be a biomarker in the heart prior to injury. Due to its versatility, the isolated heart assay has potential to fill gaps in cardiac safety testing early in drug development. PMID- 23660126 TI - Pharmacology of intravenous sedative/anesthetic medications used in oral surgery. AB - This article provides an overview of historical and current sedative agents available to the dentist anesthetist. The surgeon is given rational choices for sedation and the individualization of drug selection for each patient. Total intravenous anesthesia is becoming increasingly popular for dental sedation because of the availability of ultra-short-acting drugs and computerized infusion technology. Levels of sedation are more easily achieved and maintained, and recovery is enhanced, which gives the operator extreme, moment-to-moment control of the anesthetic experience and improves patient outcomes. PMID- 23660127 TI - Pharmacology of local anesthetics used in oral surgery. AB - This article provides a comprehensive review of the pharmacology of local anesthetics as a class, and provides details of the individual drugs available in dental cartridges. Maximum recommended doses of local anesthetics and vasoconstrictors are presented for healthy adult and pediatric patients, and for patients with cardiovascular system impairments. Various complications and reasons for failure of local anesthesia effectiveness are discussed, and current and future trends in local anesthesia are presented to provide an overview of current research in local anesthesia. PMID- 23660128 TI - The plant cytoskeleton controls regulatory volume increase. AB - The ability to adjust cell volume is required for the adaptation to osmotic stress. Plant protoplasts can swell within seconds in response to hypoosmotic shock suggesting that membrane material is released from internal stores. Since the stability of plant membranes depends on submembraneous actin, we asked, whether this regulatory volume control depends on the cytoskeleton. As system we used two cell lines from grapevine which differ in their osmotic tolerance and observed that the cytoskeleton responded differently in these two cell lines. To quantify the ability for regulatory volume control, we used hydraulic conductivity (Lp) as readout and demonstrated a role of the cytoskeleton in protoplast swelling. Chelation of calcium, inhibition of calcium channels, or manipulation of membrane fluidity, did not significantly alter Lp, whereas direct manipulation of the cytoskeleton via specific chemical reagents, or indirectly, through the bacterial elicitor Harpin or activation of phospholipase D, was effective. By optochemical engineering of actin using a caged form of the phytohormone auxin we can break the symmetry of actin organisation resulting in a localised deformation of cell shape indicative of a locally increased Lp. We interpret our findings in terms of a model, where the submembraneous cytoskeleton controls the release of intracellular membrane stores during regulatory volume change. PMID- 23660129 TI - Positional abnormalities during sleep in children affected by obstructive sleep apnea syndrome: the putative role of kinetic muscular chains. AB - Sleep-related breathing disorders (SRBD) are disorders of breathing during sleep characterized by prolonged partial upper airway obstruction, intermittent complete or partial obstruction (obstructive apnea or hypopnea), or both prolonged and intermittent obstruction that disrupts normal ventilation during sleep, normal sleep patterns, or both. Children with OSAS may sleep in unusual positions, such as seated or with neck hyperextended, even if the neck position is not the only unusual posture or the special sleeping positions that is possible to detect in children with SRBD. We have hypothesized that the assumption of unusual posture during sleep, in particular legs retracting or crossing during sleep, could be a way to enlarge the diaphragmatic excursion and promoting the alveolar gas exchanges avoiding the stress of the antero-lumbar and prevertebral muscular chains in SRBD subjects. We have hypothesized that the assumption of unusual posture during sleep, in particular legs retracting or crossing during sleep, could be a way to enlarge the diaphragmatic excursion and promoting the alveolar gas exchanges avoiding the stress of the antero-lumbar and prevertebral muscular chains in SRBD subjects. We can postulate that the prevertebral and antero-lumbar muscular chains could be oversolicited during the apnoic events, and the assumption of abnormal posture could be interpreted as a way to relax or diminish the strain or muscular stress caused by the apneas. The consequence of this hypothesis could be summarized in the concept that a specific rehabilitation or muscular program to improve the tone of this kinetic chain, could be useful to limit the effect nocturnal or diurnal of this so impacting syndrome. PMID- 23660130 TI - Implicit Association Test: a possible tool for screening patients for orthognathic surgery. AB - In orthognathic surgery, many serious medical disputes and postsurgical dissatisfactions are not caused by the doctors' reasons, but due to the patients' psychological problems. These adverse events obsess not only surgeons, but also patients to a great extent. An effective method is expected to screen patients for orthognathic surgery. So far, most selecting approaches in orthognathic surgery are based on explicit cognition, which inevitably include the following faults: patients' intentional concealment, uncertain errors, and imprecise subjective judgment from the doctors. However, these errors can be avoided by the tests based on implicit cognition, i.e., Implicit Association Test (IAT). Avoiding the faults of explicit cognition, IAT is an objective, quantitative, and easily applicable mental measurement method. We hypothesized that all the patients for orthognathic purpose should have an IAT screening before treatment. By IAT method, the right patients for orthognathic surgery can be picked out. As a result, postoperative dissatisfaction, medical dispute, and even violent conflict can be avoided to a great extent. To the best of our knowledge, there is no relevant report on the use of IAT as a tool to select the right orthognathic patients to avoid postsurgical dissatisfaction, medical disputes and violent conflict events. PMID- 23660131 TI - Is PFAPA syndrome really a sporadic disorder or is it genetic? AB - Periodic fever syndromes are a group of disorders sharing similar symptoms, characterized primarily by regularly recurring fevers. PFAPA syndrome, one of the members of this group of disorders, is a clinical entity of unknown etiology which is frequently seen in the early childhood. Currently, the pathogenesis and the genetic basis of most of the disorders in the periodic fever spectrum are known, other than that of PFAPA syndrome. Although, classically PFAPA syndrome is known as a sporadic disease, we propose that it is not sporadic. We think that PFAPA syndrome may be an inherited disease and this hypothesis is supported by the clinical mimicry of PFAPA syndrome with other periodic fever syndromes with well-known genetic transmissions, frequent occurrence of the condition in members of the same family and emergence of common genetic mutations in the periodic fever syndrome spectrum. Moreover, our clinical observation that most of the patients diagnosed with PFAPA syndrome were of the same families strongly suggest a probable genetic transmission of this disorder. We have decided to discuss this hypothesis to contribute to the literature and assist our colleagues who are dealing with this commonly overlooked and often misdiagnosed disorder. PMID- 23660132 TI - A proposed model of the response of the anophthalmic socket to prosthetic eye wear and its application to the management of mucoid discharge. AB - Mucoid discharge associated with prosthetic eye wear can be a distressing condition that affects the quality of life of people who have lost an eye. Discharge is the second highest concern of experienced prosthetic eye wearers after health of the companion eye and is prevalent in anophthalmic populations. Specific causes of mucoid discharge such as infections and environmental allergens are well understood, but non-specific causes are unknown and an evidence based protocol for managing non-specific discharge is lacking. Current management is based on prosthesis removal and cleaning, and professional re polishing of the prosthesis. Tear protein deposits accumulate on prosthetic eyes. These deposits mediate the response of the socket to prosthetic eye wear and their influence (good and bad) is determined by differing cleaning regimes and standards of surface finish. This paper proposes a three-phase model that describes the response of the socket to prosthetic eye wear. The phases are: An initial period of wear of a new (or newly-polished) prosthesis when homeostasis is being established (or re-established) within the socket; a second period (equilibrium phase) where beneficial surface deposits have built up on the prosthesis and wear is safe and comfortable, and a third period (breakdown phase) where there is an increasing likelihood of harm from continued wear. The proposed model provides a rationale for a personal cleaning regime to manage non-specific mucoid discharge. Professional care of prosthetic eyes is also important for the management of discharge and evidence for effective surface finishing is reported in this study. Taken together, the proposed regimes for personal and professional care comprise a protocol for managing discharge associated with prosthetic eye wear. The protocol describes prosthetic eye cleaning methods and frequency, and suggests minimum standards for professional polishing. If confirmed, the protocol has the potential to resolve the current varied and contradictory opinions about the management of discharge, and to clarify advice given to patients about how to personally care for their prosthetic eyes. PMID- 23660133 TI - Annexin A1: a new biomarker for predicting nasopharyngeal carcinoma response to radiotherapy. AB - Radiotherapy is the primary treatment for nasopharyngeal carcinoma (NPC), but radioresistance remains a serious obstacle to successful treatment in many cases. Therefore, the biomarkers for predicting NPC response to radiotherapy are very important for targeted therapy and individualized radiotherapy of NPC. Accumulating evidences have shown that Annexin A1 was correlated with NPC radioresistance. First, Annexin A1 is a potential tumor suppressor gene, and can regulate tumor cell proliferation and apoptosis, thus abnormal expression of Annexin A1 in NPC affects apoptosis of tumor cells induced by ionizing radiation and radiotherapeutic efficacy. Second, Annexin A1 is one of the proteins that are involved in p53-mediated radioresponse in NPC, and it might be related to NPC radioresistance. Third, the expression level of Annexin A1 is down-regulated in NPC, and is correlated with metastasis, recurrence and poor prognosis of NPC, thus Annexin A1 downregulation may increase NPC radioresistance, leading to poor prognosis. Last but not the least, Annexin A1 is closely related with tumor chemoresistance, whereas radioresistance is similar to chemoresistance in many aspects, thus Annexin A1 may also be involved in NPC radioresistance. Based on the above mentions, we hypothesize that Annexin A1 is closely correlated with NPC radioresistance and is an important new biomarker for predicting NPC response to radiotherapy. PMID- 23660134 TI - Cancer as a carcinogenic hyper-cycle and a RNA world progress. AB - Carcinogenesis is regarded as a mutagenesis, a process of continuous generation of mutations in a cancerous cell. The basis of this process contains a carcinogenic hyper-cycle as one of the forms of the RNA world progress. On the one side, this hyper-cycle ensures self-reproduction, on the other side, generation of mutations of DNA oligo-nucleotides, which, on its part, leads to its re-programming and a cancerous transformation of the cell. Carcinogenic hyper cycle is generated at the beginning as an autonomous process of RNA replication in the cytoplasm of a cell which has stopped the cooperation with the DNA replication. Under influence of different factors, it gets the ability for concurrence with the DNA replication, becomes a new organizer of the order in the cell, and gradually supersedes and represses the latter one (DNA replication). In the article, the structure of a carcinogenic hyper-cycle is mentioned, factors which lead to its generation and development, and new possibilities of cancer treatment resulting from this. PMID- 23660135 TI - Regions-based illustrative visualization of multimodal datasets. AB - We present as novel method for the exploration of multiple overlapping volumes that provides flexibility to merge data in different ways in different regions. In each region, either one of the modalities is rendered alone or the fusion of two modalities is shown. In the regions where data is fused, the relative weights of each modality are defined with a 2D transfer function depending on the voxel's pair of property values. The regions can be defined interactively by painting on the volume. Alternatively, when one of the modalities has been pre-classified, a graph representation of the dataset is constructed, and regions can be defined as sets of voxels fulfilling a specific combination of classification criteria. In both cases, a different fusion and shading function can be defined for each region. In this way, illustrative images of the dataset can be easily generated applying effects of cutting away, ghosting and modality enhancement. PMID- 23660136 TI - Capsicum annuum enhances L-lactate production by Lactobacillus acidophilus: implication in curd formation. AB - Lactobacillus acidophilus is commonly used lactic acid bacteria for producing fermented milk products. In general household practice, curdling is known to occur faster in the presence of red chili. Herein we analyzed the enhanced effect of red chili (Capsicum annuum) and its major component, capsaicin, on Lactobacillus acidophilus (ATCC 4356) in the production of L-lactate in de Man, Rogosa, and Sharpe medium at various temperatures (15, 20, 25, 30, and 37 degrees C). The addition of red chili showed significant increase in the amount of L lactate produced by L. acidophilus compared with the control at all temperatures. Similar results were observed with addition of capsaicin alone. This was accompanied by an increase in the consumption of d-glucose. Capsazepine, a known antagonist of capsaicin, inhibited the production of L-lactate by L. acidophilus in the presence of both capsaicin and red chili. Because no increase occurred in the growth of L. acidophilus in the presence of red chili, the enhanced production of L-lactate in the presence of red chili or capsaicin is due to increased metabolic activity. PMID- 23660137 TI - Model comparison on genomic predictions using high-density markers for different groups of bulls in the Nordic Holstein population. AB - This study compared genomic predictions based on imputed high-density markers (~777,000) in the Nordic Holstein population using a genomic BLUP (GBLUP) model, 4 Bayesian exponential power models with different shape parameters (0.3, 0.5, 0.8, and 1.0) for the exponential power distribution, and a Bayesian mixture model (a mixture of 4 normal distributions). Direct genomic values (DGV) were estimated for milk yield, fat yield, protein yield, fertility, and mastitis, using deregressed proofs (DRP) as response variable. The validation animals were split into 4 groups according to their genetic relationship with the training population. Groupsmgs had both the sire and the maternal grandsire (MGS), Groupsire only had the sire, Groupmgs only had the MGS, and Groupnon had neither the sire nor the MGS in the training population. Reliability of DGV was measured as the squared correlation between DGV and DRP divided by the reliability of DRP for the bulls in validation data set. Unbiasedness of DGV was measured as the regression of DRP on DGV. The results indicated that DGV were more accurate and less biased for animals that were more related to the training population. In general, the Bayesian mixture model and the exponential power model with shape parameter of 0.30 led to higher reliability of DGV than did the other models. The differences between reliabilities of DGV from the Bayesian models and the GBLUP model were statistically significant for some traits. We observed a tendency that the superiority of the Bayesian models over the GBLUP model was more profound for the groups having weaker relationships with training population. Averaged over the 5 traits, the Bayesian mixture model improved the reliability of DGV by 2.0 percentage points for Groupsmgs, 2.7 percentage points for Groupsire, 3.3 percentage points for Groupmgs, and 4.3 percentage points for Groupnon compared with GBLUP. The results showed that a Bayesian model with intense shrinkage of the explanatory variable, such as the Bayesian mixture model and the Bayesian exponential power model with shape parameter of 0.30, can improve genomic predictions using high-density markers. PMID- 23660138 TI - Short communication: insulin responsiveness is affected by the level of milk replacer offered to young calves. AB - Eight male Holstein calves (40.6+/-2.9kg of BW and 7.8+/-1.6 d of age) were individually housed and allocated to either a low milk replacer (MR) allowance of 2 daily doses of 2 L each (478.5g/d of dry matter from MR), or to a high allowance of 2 daily allotments of 4 L (957.0g/d of dry matter from MR). In addition all calves had ad libitum access to the same starter feed and water. At d 7, 30, and 60 of experiment all calves were submitted to a glucose tolerance test (GTT) that consisted on an i.v. infusion of 180mg/kg of BW of glucose at 4h after the morning MR feeding. Blood was harvested at -15, -5, 0, 4, 8, 12, 18, 25, 35, 45, and 60 min relative to glucose infusions. Blood samples collected at 15, -5, and 0 relative to glucose infusion were used as baseline concentrations of glucose and insulin. Then, the area under the curve (concentration/min) for glucose and insulin was calculated as the increase with respect to the baseline. Next, the clearance rates of insulin (%/min), glucose (%/min), as well as insulin sensitivity were computed. The increase in blood glucose following the GTT (assessed as area under the curve) was similar in both low and high calves, which indicates that all animals were able to control glycemia effectively. Similarly, clearance rates of glucose and insulin were not different between low and high calves. However, calves in the high group needed a substantially greater serum insulin concentration (98.7+/-13.2uU/mL) than low calves (41.5+/-13.2uU/mL) to control glycemia. Furthermore, as age increased, the rise in serum insulin elicited by the GTT continued to increase in high but not in low calves. Insulin to glucose ratio was greater in high (157.5+/-7.8uU/mg) than in low (46.7+/ 7.8uU/mg) calves. This ratio increased with age and in a more pronounced fashion in high than in low calves and the same pattern was observed for insulin sensitivity. We concluded that offering 8L of MR/d in 2 separate meals decreases insulin sensitivity of young calves. Further research is needed to assess whether the impaired glucose responsiveness of calves can be minimized by feeding milk more frequently. PMID- 23660139 TI - Intravenous infusions of glucose stimulate key lipogenic enzymes in adipose tissue of dairy cows in a dose-dependent manner. AB - The present study was investigated whether increasing amounts of glucose supply have a stimulatory effect on the mRNA abundance and activity of key lipogenic enzymes in adipose tissue of midlactation dairy cows. Twelve Holstein-Friesian dairy cows in midlactation were cannulated in the jugular vein and infused with either a 40% glucose solution (n=6) or saline (n=6). For glucose infusion cows, the infusion dose increased by 1.25%/d relative to the initial net energy for lactation (NEL) requirement until a maximum dose equating to a surplus of 30% NEL was reached on d 24. This maximum dose was maintained until d 28 and stopped thereafter (between d 29-32). Cows in the saline infusion group received an equivalent volume of 0.9% saline solution. Samples of subcutaneous adipose tissue were taken on d 0, 8, 16, 24, and 32 when surplus glucose reached 0, 10, 20, and 30% of the NEL requirement, respectively. The mRNA abundance of fatty acid synthase, cytoplasmic acetyl-coenzyme A synthetase, cytoplasmic glycerol 3 phosphate dehydrogenase-1, and glucose 6-phosphate dehydrogenase showed linear treatment * dose interactions with increasing mRNA abundance with increasing glucose dose. The increased mRNA abundance was paralleled by a linear treatment * dose interaction for fatty acid synthase and acetyl-coenzyme A synthetase enzymatic activities. The mRNA abundance of ATP-citrate lyase showed a tendency for linear treatment * dose interaction with increasing mRNA abundance with increasing glucose dose. The mRNA abundance of all tested enzymes, as well as the activities of fatty acid synthase and acetyl-coenzyme A synthetase, correlated with plasma glucose and serum insulin levels. In a multiple regression model, the predictive value of insulin was dominant over that of glucose. In conclusion, gradual increases in glucose supply upregulate key lipogenic enzymes in adipose tissue of midlactating dairy cows with linear dose dependency. Insulin appears to be critically involved in this regulation. PMID- 23660140 TI - Reducing sperm concentration is critical to limiting the oxidative stress challenge in liquid bull semen. AB - Because of the short breeding season, the use of liquid bull semen is a viable option in seasonal grass-based dairy systems such as Ireland. Currently in Ireland, liquid bull semen contains approximately 5 million sperm per insemination dose and is used within 2.5d of collection. The hypothesis of this study was that reducing the sperm number per insemination dose would enable bull sperm to be stored for longer. Semen was collected at a commercial AI center and diluted to 1 (T1), 2 (T2), 3 (T3), 4 (T4), and 5 (T5) million sperm per 0.25-mL dose in caprogen diluent. On d 0.25 (6 h postcollection), 1, 2, 3, 4, and 5 postcollection, viability, oxidative stress, and mitochondrial activity were assessed using flow cytometry and the fluorescent probes propidium iodide, CM H2DCFDA, and rhodamine 123, respectively. On the same days, glucose consumption, total antioxidant capacity, and progressive linear motility were assessed. We observed an effect of day and treatment on sperm cell viability, with the highest percentage live found in T 0005 and the lowest in T 0025 on all days. Oxidative stress in live sperm increased with duration of storage and was affected by treatment, being highest in T 0025 and lowest in T 0005 on all days (d 5: 56.4+/ 2.76% and 28.8+/-1.22%, respectively; mean +/- SEM). Both the total antioxidant capacity and percentage of live sperm positive for rhodamine 123 were unaffected by treatment. The concentration of glucose in caprogen declined with time and was lowest in T 0025 and highest in T 0005 on d 5. In conclusion, higher concentrations of sperm have detrimental effects on sperm cell viability and increase oxidative stress but have no effect on the mitochondrial activity of sperm. PMID- 23660141 TI - Development and implementation of a training program to ensure high repeatability of body condition scoring of dairy cows. AB - A body condition score (BCS) in dairy cattle is a subjective assessment of the proportion of body fat that she possesses and is a common measure used in animal welfare assessment. The objectives of our study were to develop and implement a training program to produce highly repeatable BCS by many assessors as part of a cross-Canada epidemiological study on dairy cow comfort and welfare. In preliminary studies, we established that without any proper standard operating procedures (SOP) to describe the practical steps of the process and good standard reference for each score, assessors provided with a BCS chart scored with each other only with substantial agreement within 0.5 points and moderate agreement on exact score (mean weighted kappa coefficient=0.79 and 0.46, respectively). Detailed SOP were developed to assess BCS in 4 locations on a dairy farm. Assessing BCS presented more challenges in some locations (when cows exited the milking parlor, when the assessor was located outside the freestall pen) than others (when cows were headlocked at the feed bunk, when assessor was located inside the freestall pen). Additionally, training material and a training procedure were developed to ensure that future assessors would achieve almost perfect repeatability with the trainer within 0.5 points (weighted kappa coefficient >0.80). Twelve trainees followed this training and their repeatability was assessed using photographs in classroom sessions and live observations on farm over a 1-wk period. Repeatability was maintained above target agreement at periodic checks over the 6 mo of on-farm data collection. Two trainers were used as a reference standard to which all trainees were compared. This study demonstrates that to obtain reliable measures, a training program must include validated procedures to help assessors cope with a variety of farm setups. Regular repeatability checks are essential to ensure that the reference standard is maintained over time and to secure high data quality. This method to develop a training program as well as the training program implemented can be used as a model to successfully train on-farm assessors. PMID- 23660142 TI - Life cycle assessment of milk production from commercial dairy farms: the influence of management tactics. AB - Little consideration has been given to how farm management, specifically tactics used to implement the management strategy, may influence the carbon footprint (CF) and land use for milk produced on commercial farms. In this study, the CF and land use of milk production from 18 Irish commercial dairy farms were analyzed based on foreground data from a 12-mo survey capturing management tactics and background data from the literature. Large variation was found in farm attributes and management tactics; for example, up to a 1.5-fold difference in fertilizer nitrogen input was used to support the same stocking density, and up to a 3.5-fold difference in concentrate fed for similar milk output per cow. However, the coefficient of variation for milk CF between farms only varied by 13% and for land use by 18%. The overall CF and overall land use of the milk production from the 18 dairy farms was 1.23+/-0.04kg of CO2 Eq and 1.22+/-0.05 m(2) per kilogram of energy-corrected milk. Milk output per cow, economic allocation between exports of milk and liveweight, and on-farm diesel use per ha were found to be influential factors on milk CF, whereas the fertilizer N rate, milk output per cow, and economic allocation between exports of milk and liveweight were influential on land use. Effective sward management of white clover within a few farms appeared to lower the CF but increased on-farm land use. It was concluded that a combination of multiple tactics determines CF and land use for milk production on commercial dairy farms and, although these 2 measures of environmental impact are correlated, a farm with a low CF did not always have low land use and vice versa. PMID- 23660143 TI - Short communication: planning considerations for on-farm dairy processing enterprises. AB - Across the world, more dairy producers are considering on-farm dairy processing to add value to the milk produced on their farms. Dairy producers may bottle milk or process their milk into cheese, ice cream, butter, yogurt, or cream. The primary objective of this research was to establish a series of sound factors or indicators of success for those considering on-farm processing. A survey was employed to collect opinions and advice from managers of on-farm processing enterprises. Surveys were distributed online (n=120), with 31 surveys returned, accounting for a 25.8% response rate. Most (64%) respondents had been involved in on-farm dairy processing for less than 10 yr. Sixty-one percent of respondents attained a positive cash flow in 1 to 3 yr. The primary products manufactured were cheese (69%), milk (59%), ice cream (31%), yogurt (25%), and butter (21%). Factors influencing the decision to start an on-farm dairy processing enterprise included commodity milk prices (61%), desire to work with the public (41%), an opportunity to promote the dairy industry (39%), a desire to maintain or expand a small family operation (29%), and product differentiation (16%). Respondents cited dealing with regulations (26%), product marketing (19%), manufacturing technicalities (19%), and securing funding (17%) as the most difficult parts of starting the business. Open-ended responses provided by the respondents of this survey were also documented to give future dairy producers advice. The most common advice to future on-farm processors was to work on realistic business plans, develop and follow realistic budgets, and observe and use market surveys within the industry. These results provide a useful array of information for future on-farm dairy processing enterprises. PMID- 23660144 TI - Associations between herd-level feeding management practices, feed sorting, and milk production in freestall dairy farms. AB - The challenges associated with group-housed dairy cows include within-herd variability in nutrient consumption and milk production, which may be related to feeding management. The objective of this observational study was to examine the association of herd-level feeding management factors, feed sorting, and milk production. Twenty-two freestall herds with an average lactating herd size of 162+/-118 cows, feeding total mixed rations, were each studied for 7 consecutive days in summer and winter. In cases of multiple feeding groups within a herd, the highest producing group of cows with an even distribution of days in milk and parity was selected for this study. The average group size studied was 83+/-31 cows. The average study group consisted of cows 187+/-47 days in milk, with a parity of 2.3+/-0.6, consuming 24.3+/-2.6kg of dry matter, with an average group level yield of 34.3+/-6kg of milk/d, 3.7+/-0.3% milk fat, and 3.2+/-0.18% milk protein. Milk production parameters, including yield, fat, and protein, were recorded through regular Dairy Herd Improvement milk testing. A survey of feeding management practices and barn characteristics was administered on each farm. The amounts of feed offered and refused were recorded and sampled daily to assess dry matter intake (DMI) and particle size distribution. Feeding twice per day compared with once per day was associated with an average increase of 1.42kg of DMI, 2.0kg of milk yield, and less sorting against long ration particles (>19mm). Every 2% group-level selective refusal (sorting) of long particles was associated with 1kg/d of reduction in milk yield. A 10cm/cow increase in feed bunk space was associated with a 0.06-percentage-point increase in group-average milk fat and a 13% decrease in group-average somatic cell count. These results support that herd level management practices to promote feed access, such as increased feeding frequency and bunk space, may improve DMI and promote more balanced nutrient intake and greater milk production. PMID- 23660145 TI - Effect of inorganic or organic copper fed without or with added sulfur and molybdenum on the performance, indicators of copper status, and hepatic mRNA in dairy cows. AB - The effect of inorganic (INORG) or organic (ORG) Cu, fed without (-) or with (+) additional S and Mo on Cu status and performance was examined using 56 early lactation dairy cows in a 2*2 factorial study design. Supplementary Cu was added as either CuSO4 or BioplexCu (Alltech Inc., Nicholasville, KY) to provide an additional 10mg of Cu/kg of dry matter (DM), with S added at 1.5g/kg of DM and Mo at 6.8mg/kg of DM to reduce Cu bioavailability. The basal ration was composed of corn and grass silages (2:1 respectively, DM basis) and straight feeds. Cows commenced the study at wk 7 of lactation and remained on treatment for 16 wk. An interaction existed between Cu source and added S and Mo on DM intake, with cows offered INORG- Cu having an increased intake compared with those offered INORG+ or ORG- Cu. Milk yield averaged 35.4kg/d, and was 5% higher with milk fat content 6% lower in cows fed INORG compared with ORG Cu, but milk fat yield, energy corrected milk yield, and milk protein content did not differ between treatments. A trend existed for cows to have a higher body weight gain when offered ORG compared with INORG Cu. Cows fed diets containing INORG Cu had a higher milk concentration of C17:0 and C18:3n-3 compared with those fed diets containing ORG Cu. Cows fed added S and Mo had a lower milk concentration of C17:0 and C18:0 compared with those that were not supplemented. No effect was observed of dietary treatment on plasma Cu concentration, which averaged 13.1 umol/L, except during wk 12 when cows receiving added S and Mo had a lower concentration. No effect was observed of Cu source on mean plasma Mo concentrations, but during wk 16 cows offered INORG Cu had a higher concentration than those offered ORG Cu. Hepatic Cu levels decreased by approximately 0.9mg/kg of DM per day when fed additional S and Mo, but no effect of Cu source was observed. A trend existed for hepatic ATPase, Cu++ transporting, beta polypeptide (ATP7B) to be upregulated in cows when fed S and Mo along with ORG but not INORG Cu. In conclusion, the inclusion of an ORG compared with an INORG source of Cu reduced milk yield but increased milk fat concentration and body weight gain, with no effect on energy-corrected milk yield. Little effect was observed of dietary Cu supply on plasma mineral concentration, liver mRNA abundance, or milk fatty acid profile, whereas the addition of S and Mo reduced hepatic Cu concentrations. PMID- 23660146 TI - Effect of abomasal ferrous lactate infusion on phosphorus absorption in lactating dairy cows. AB - The objective of this study was to evaluate the effect of ferrous lactate infusion on postruminal P absorption in lactating dairy cows. Four ruminally cannulated lactating cows were used in a 4*4 Latin square design with 14 d per period. Cows were fed a basal diet containing 0.39% P, providing 100% of the calculated P requirement. On d 8 to 14 of each period, each cow was infused with 0, 200, 500, or 1,250mg of Fe/d in the form of ferrous lactate solution (ferrous lactate in 1L of double-distilled water) into the abomasum. Infusate was formulated to approximate 0, 2, 5, or 12.5mg of Fe/L in drinking water with 100L of water intake/d. Total fecal collection was conducted in the last 4 d of each period to measure nutrient digestion and excretion. Dry matter intake, milk yield, and milk composition were not affected by treatment. Digestibility of DM, NDF, and nitrogen decreased linearly with increasing ferrous lactate infusion. Infusion of ferrous lactate did not affect intake and digestibility of total P, inorganic P, or phytate P. In lactating cows, P absorption was not negatively influenced by abomasally infused ferrous lactate up to 1,250mg of Fe/d. PMID- 23660147 TI - Effects of weekly regrouping of prepartum dairy cows on metabolic, health, reproductive, and productive parameters. AB - The objectives of the current experiment were to determine the effect of 2 prepartum grouping strategies on the health, metabolic, reproductive, and productive parameters of dairy cows. Jersey cows enrolled in the experiment at 253+/-3 d of gestation (d 0=calving) were balanced for parity and projected 305-d mature equivalent and assigned to 1 of 2 treatments. Cows assigned to the traditional (TRD; n=6 replicates with a total of 308 cows) treatment were moved to the study pen as a group of 44 cows and weekly thereafter groups of 2 to 15 cows were moved to the study pen to reestablish stocking density. Cows assigned to the all-in-all-out (AIAO; n=6 replicates with a total of 259 cows) treatment were moved to the study pen in groups of 44 cows, but no new cows entered the AIAO pen until the end of the replicate. At the end of each replicate, a new TRD and AIAO group started but pens were switched. Cows were milked thrice daily and monthly milk yield, fat and protein contents, and somatic cell count data were recorded up to 305 d postpartum. Plasma nonesterified fatty acid concentration was measured weekly from d -18+/-3 to 24+/-3 and plasma beta-hydroxybutyrate was measured weekly from d 3+/-3 to 24+/-3. Cows were examined on d 1, 4+/-1, 7+/-1, 10+/-1, and 13+/-1 for diagnosis of uterine diseases and had their ovaries scanned by ultrasound on d 39+/-3 and 53+/-3 to determine resumption of ovarian cycles. Average stocking density was reduced for the AIAO (71.9%) treatment compared with the TRD (86.9%) treatment. Treatment did not affect the incidences of retained fetal membranes (TRD=10.9, AIAO=11.6%), metritis (TRD=16.7, AIAO=19.8%), and acute metritis (TRD=1.7, AIAO=3.6%). Concentrations of nonesterified fatty acids (TRD=80.4+/-8.2, AIAO=62.9+/-8.5 umol/L) and beta hydroxybutyrate (TRD=454.4+/-10.9, AIAO=446.1+/-11.1 umol/L) were not different between treatments. Percentages of cows that resumed ovarian cycles by d 39+/-3 (TRD=70.8, AIAO=63.1%) and 53+/-3 (TRD=90.1, AIAO=90.2%) were not different between treatments. Similarly, treatment had no effect on rate of removal from the herd {TRD=referent, AIAO [(adjusted hazard ratio (95% confidence interval)]=0.85 (0.63, 1.15)} or rate of pregnancy [TRD=referent, AIAO=1.07 (0.88, 1.30)]. Finally, treatment did not affect energy-corrected milk yield (TRD=34.4+/-0.6, AIAO=34.3+/-0.7 kg/d). In conditions of adequate feed bunk space, the AIAO treatment did not improve health, metabolic, reproductive, or productive parameters compared with the TRD treatment. PMID- 23660148 TI - The responsiveness of subclinical endometritis to a nonsteroidal antiinflammatory drug in pasture-grazed dairy cows. AB - The objective of this study was to determine if the inflammation associated with subclinical endometritis (SCE) is a part of the mechanism by which reproductive performance is reduced in cows with this disease. If it is, reducing inflammation associated with SCE with a nonsteroidal antiinflammatory drug (NSAID) should reduce the severity [as measured by average polymorphonuclear cell (PMN) percentage] of uterine pathology and improve reproductive performance. It was also investigated whether the NSAID treatment reduced metabolic indicators of systemic inflammation previously reported to be altered in cows with SCE. Holstein-Friesian and Friesian-Jersey cross dairy cows (n=213) were paired by calving date and d-14 uterine PMN percentage and randomly assigned to 3 injections at intervals of 3 d of an NSAID (1.4 mg of carprofen/kg; n=104) between 21 and 31 d postpartum or left as untreated controls (n=109). Cows with >=14% PMN (upper quartile of PMN percentage) in the cytological sample collected at d 14 postpartum were defined as having SCE. The average d-14 PMN percentage was low (9.9%) and a high self-cure rate of SCE (>90%) at d 42 was observed. Treatment with an NSAID reduced plasma concentrations of aspartate aminotransferase and increased pregnancy rate in SCE cows. However, no effect of the NSAID treatment was observed on PMN percentage at d 42, postpartum anovulatory interval, or milk production. Compared with cows without SCE, cows with SCE had lower plasma albumin concentration, albumin:globulin ratio, and body condition score, but higher nonesterified fatty acids on the day of calving. These results indicate that cows with SCE are experiencing a physiological dysfunction, including lower body condition, liver dysfunction, and greater metabolic challenge during the periparturient period. Further research is required to determine the effect of NSAID on SCE and to evaluate the influence of timing of drug application on treatment effectiveness. PMID- 23660149 TI - Prevalence and duration of PTSD in survivors 6 years after a natural disaster. AB - The present study aimed to examine the prevalence of posttraumatic stress disorder (PTSD) in survivors with low levels of risk factors for PTSD. The sample included 142 adults (58% women, 54% university education, 93% employed/students/retired) on vacation in Southeast Asia during the 2004 Indian Ocean disaster. Semi-structured clinical interviews (SCID-I) were performed after 6 years including PTSD, depression, specific phobia, and alcohol abuse. The 6 year prevalence of PTSD was 11.3% and the current prevalence was 4.2%, with onset mainly within 1 month and remission within 3 years post-disaster. Suicidal ideation and comorbidity were common in PTSD cases. Lifetime prevalence of depression was 19%, specific phobia 7%, and alcohol abuse 4%. The findings suggest elevated levels of PTSD but not other disorders as compared with general population samples, but still lower levels than other disaster samples. Despite benign circumstances, however, the course and burden of PTSD were comparable to similar studies. PMID- 23660150 TI - Intraspecific trait variation and its effects on food chains. AB - Traits such as skill at foraging and investment in anti-predator defense may vary among individuals within a species population. This intraspecific variation has implications for community dynamics. The implications of intraspecific variation of a consumer in the intermediate level of a tritrophic food chain are explored for the case in which two different phenotypes exist within the consumer population having tradeoffs in traits with respect to foraging for resources and resisting predation. The topology of such a web is similar to that of the diamond shaped food web. An important result of prior studies on diamond-shaped webs is that conditions for equilibrium coexistence of two competing consumer species can be found, but the transient oscillations would make it likely for one competing species to become extinct. In the case of two phenotype subpopulations within a single consumer species, however, switching between the two subpopulations can occur, which is stabilizing. As a result, it is feasible for two distinct phenotype subpopulations of the consumer to exist between resources and predators in a tritrophic chain. The occurrence of two stably coexisting phenotype populations changes the nature of the bottom-up and top-down effects in the chain. The predator exerts a top-down effect on the resource, not the consumer subpopulations, and changes in the resource carrying capacity causes changes in the consumer subpopulations, but not the populations of the predators or the resources themselves. PMID- 23660151 TI - Competition for one nutrient with internal storage and toxin mortality. AB - This study presents a mathematical model of two species competing in a chemostat for one resource that is stored internally, and who also compete through allelopathy. Each species produces a toxin to that increases mortality rate of its competitor. The two species system and its single species subsystem follow mass conservation constraints characteristic of chemostat models. Persistence of a single species occurs if the nutrient supply of an empty habitat allows it to acquire a threshold of stored nutrient quota, sufficient to overcome loss to outflow after accounting for the cost of toxin production. For the two-species system, a semitrivial equilibrium with one species resident is unstable to invasion by the missing species according to a similar threshold condition. The invader increases if acquires a stored nutrient quota sufficient to overcome loss to outflow and toxin-induced mortality, after accounting for the cost of the invader's own toxin production. If both semitrivial equilibria for the two species system are invasible then there is at least one coexistence equilibrium. Numerical analyses indicate another possibility: bistability in which both semitrivial equilibria are stable against invasion. In such a case there is competitive exclusion of one species, whose identity depends on initial conditions. When there is a tradeoff between abilities to compete for the nutrient and to compete through toxicity, the more toxic species can dominate only under nutrient-rich conditions. Bistability under such conditions could contribute to the unpredictability of toxic algal blooms. PMID- 23660152 TI - Do the parent-child relationship and parenting behaviors differ between families with a child with and without chronic illness? A meta-analysis. AB - OBJECTIVE: The present meta-analysis compared the quality of the parent-child relationship as well as parenting behaviors and styles of families with a child with chronic physical illness with families of healthy children or test norms. METHODS: Empirical studies were identified with the help of electronic databases and cross-referencing. Based on 325 included studies, random-effects meta analysis was performed. RESULTS: Although most effect sizes were small or very small, the parent-child relationship tended to be less positive if a child had a chronic physical illness (g = -.16 standard deviation units). In addition, lower levels of parental responsiveness (emotional warmth; g = -.22) as well as higher levels of demandingness (control, monitoring; g = .18) and overprotection (g = .39) were observed in these families. However, effect sizes were heterogeneous and only significant for a limited number of diseases. There was also some evidence for higher levels of authoritarian (g = .24) and neglectful parenting (g = .51) as well as lower levels of authoritative parenting compared with families with healthy children (g = -.13). Effect sizes varied, in part, by length of illness, child age, rater, assessment method, and target of comparison. CONCLUSIONS: We conclude that most families with a child with chronic physical illness adapt well with regard to the parent-child relationship and parenting behaviors/styles. Nonetheless, some families of children with specific diseases such as epilepsy, hearing impairment, and asthma-may have difficulties finding appropriate levels of protective behaviors, control, and parental warmth and building positive mutual relationships between parents and children. PMID- 23660154 TI - Evolution of radiological findings detected in the limbs of 321 young horses between the ages of 6 and 18 months. AB - The objective of this study was to evaluate the spontaneous evolution of radiological findings (RF) indicative of juvenile osteochondral conditions (JOCC) in a field study. A radiographic survey was performed at the age of 6 and 18months in 321 young horses from three breeds (French Trotter Standardbred, Selle-Francais Warmblood and Thoroughbred). Each RF identified at 6months was re evaluated at 18months, and classified as (1) disappeared, (2) improved, (3) stable, (4) deteriorated or (5) new when it was not identified at 6months. Only 32.3% of all RF identified at the age of 6months were stable, while at 18months 46.6% had disappeared and 38.7% were new radiological abnormalities. Evolution of RF varied according to the joint involved and the type of lesion. In the stifle, 85.7% of the RF of osteochondral fragmentation (OCF) of the lateral ridge of the femoral trochlea regressed (disappeared or improved). In the hock, 53.1% of the RF of OCD of the intermediate ridge of the tibial cochlea were stable. In the fetlock, dorsal and plantar OCF were frequently observed as new radiological abnormalities at 18months (51% of the dorsal RF and 45.8% of the plantar). As many lesions develop or change after 6months, a definitive radiographic assessment of the JOCC status is more reliable at 18months. Knowing the spontaneous healing capacity of some lesions is useful in helping to decide the appropriate management. PMID- 23660155 TI - Microdialysis in equine research: a review of clinical and experimental findings. AB - Microdialysis is a method for sampling compounds from extracellular fluid with minimal tissue trauma. Small hollow probes that are 0.2-0.5mm in diameter are inserted into the tissue and slowly perfused. The probe membrane is semi permeable and a flux of the solutes occurs exclusively according to the concentration gradients. The recovered dialysate reflects changes in the composition of the extracellular water phase with a minor time delay. Because microdialysis is a continuous sampling method, it differs from point sample methods, such as blood sampling. The ability to obtain local measurements in the tissues has led to important discoveries in the detection of tissue changes within the areas of pharmacokinetics, pharmacodynamics, pathology and pathophysiology. New technological solutions, such as transportable pumps, fluid collectors and bedside analysers, have made microdialysis an indispensable tool for the surveillance of critically ill human patients, such as after brain injuries and reconstructive surgeries. The use of microdialysis in equine medicine has been sparingly described with only 14 published studies within muscle, pulmonary and hoof lamellar tissue, nasal mucosa, intestinal wall, uterine, allantoic and cerebrospinal fluid and blood. Only a few papers have been published within each area, indicating that few equine researchers are aware of the unique opportunities provided by the technique. This review discusses the theory and applications of microdialysis with a special emphasis on clinical and experimental equine studies, which may be useful to veterinary experimental and clinical researchers. PMID- 23660156 TI - Efficacy of therapeutic fluoroscopy-guided lumbar spine interventional procedures. AB - PURPOSE: To evaluate the benefit of fluoroscopy-guided lumbar spine interventional procedures in treatment of low back pain. METHODS: This prospective descriptive study was performed on 60 patients with back/radicular pain after showing no improvement with conservative treatment. RESULTS: One hundred and two injection sessions were done (average 1.7 injection per patient). Caudal and lumbar transforaminal injections were effective in 55.9% and 78.5%, respectively. Facet and sacroiliac interventions were effective in 28.3% and 10%, respectively. Complications occurred in 20% of the procedures. CONCLUSION: Lumbar injections improved pain/disability related to discogenic lumbar spinal diseases. Efficacy of facet and sacroiliac injections is limited. PMID- 23660158 TI - When environmental chemicals act like uncontrolled medicine. AB - In the same way as medicines are delivered to produce effects in the endocrine system, environmental chemicals can be similarly delivered to produce unwanted endocrine effects, resulting in a staggering increase in several diseases. These effects on endocrine and other physiological systems can have significant population-level impacts and thus require public health approaches to disease control. PMID- 23660157 TI - Gardening for the mental well-being of homeless women. AB - PURPOSE: To explore the perceptions of homeless women regarding their experience in a shelter-based garden project to promote mental wellness. Participants planted and tended the vegetable garden and prepared and ate the fruits of their labor. DESIGN: A qualitative descriptive design with a conventional content analysis of narrative data. METHOD: Data were gathered in semistructured interviews. Participants were homeless daytime shelter guests who had participated in at least eight gardening sessions over 4 weeks. The project was started in the fall of 2010 and the interviews were conducted over 2 months in the summer of 2011. FINDINGS: Two polarized themes were identified in the narratives, clustering around negative and positive thoughts. The "dark" theme centered on marginalization and the oppressiveness of shelter life. The "light" theme centered on stress relief, feeling socially included, and personal change. CONCLUSION: The gardening experience interrupted the participants' negative ruminations, offering stress relief and elements of social inclusion and self actualization. Gardening is an inexpensive and positive intervention for a population with a high incidence of mental illness and distress. PMID- 23660153 TI - Detection of superoxide anion and hydrogen peroxide production by cellular NADPH oxidases. AB - BACKGROUND: The recent recognition that isoforms of the cellular NADPH-dependent oxidases, collectively known as the NOX protein family, participate in a wide range of physiologic and pathophysiologic processes in both the animal and plant kingdoms has stimulated interest in the identification, localization, and quantitation of their products in biological settings. Although several tools for measuring oxidants released extracellularly are available, the specificity and selectivity of the methods for reliable analysis of intracellular oxidants have not matched the enthusiasm for studying NOX proteins. SCOPE OF REVIEW: Focusing exclusively on superoxide anion and hydrogen peroxide produced by NOX proteins, this review describes the ideal probe for analysis of O2(-) and H2O2 generated extracellularly and intracellularly by NOX proteins. An overview of the components, organization, and topology of NOX proteins provides a rationale for applying specific probes for use and a context in which to interpret results and thereby construct plausible models linking NOX-derived oxidants to biological responses. The merits and shortcomings of methods currently in use to assess NOX activity are highlighted, and those assays that provide quantitation of superoxide or H2O2 are contrasted with those intended to examine spatial and temporal aspects of NOX activity. MAJOR CONCLUSIONS: Although interest in measuring the extracellular and intracellular products of the NOX protein family is great, robust analytical probes are limited. GENERAL SIGNIFICANCE: The widespread involvement of NOX proteins in many biological processes requires rigorous approaches to the detection, localization, and quantitation of the oxidants produced. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn. PMID- 23660159 TI - Unilateral synchronous breast tumors. Rare association of myofibroblastoma and osteosarcoma. AB - The authors describe the case of a patient with two particularly rare contiguous tumors, myofibroblastoma and osteosarcoma, in the same breast. Rare does not mean untreatable, and the chance of recovery is no less than with more common tumors. However, rare tumors do present a significant problem for pathologists due to diagnostic difficulties, and so an exact prognosis is not always possible. PMID- 23660160 TI - Twenty years experience in oncologic surgery for primary cardiac tumors. AB - INTRODUCTION: Primary cardiac tumors are uncommon in cardiac surgery. To investigate the clinical presentation, surgical results and long-term follow-up we retrospectively analyzed our experience in the treatment of primary cardiac tumors. PATIENTS AND METHODS: Ninety-one patients with primary cardiac tumors underwent surgery in our department in the last 20 years. Fifty-one patients were female, the mean age was 62,2 years. Sixty-three had myxomas, 22 had papillary fibroelastoma, 4 had malignant neoformations and 2 had other benign tumors. RESULTS: All myxomas, fibroelastomas and angiomyolipoma were radically removed. Only a palliative treatment was possible in malignant disease. In-hospital mortality was 1.2%. The mean follow-up time was 78.5 months. Three patients had recurrence of myxoma, all patients with malignant disease dead during the follow up. DISCUSSION: Primary benign cardiac tumors can be treated with low morbidity and mortality. The follow-up demonstrates that radical surgery is curative in case of benign tumors. The prognosis of malignant tumors is still poor. Palliative procedures have small impact on survival in these patients. PMID- 23660161 TI - Sternal wound dehiscence from intense coughing in a cardiac surgery patient: could it be prevented? AB - This case report is on a obese patient who underwent a coronary artery bypass. The immediate postoperative phase, on the 8th day, was characterized by sternal dehiscence with diastasis, from intense coughing. At present, for obese patients there are not any guidelines aimed to prevent the sternal diastasis. The use of a sternum support vest after median sternotomy could be a valuable tool in the postoperative care of our patients, in order to avoid chest wall hyperexpansion and to prevent sternal wound dehiscence and diastasis. PMID- 23660162 TI - Ectopic thyroid carcinoma. Case report. AB - INTRODUCTION: Ectopic thyroid tissue can be found in many sites, including the tongue, thyroglossal duct, mediastinum, trachea, lung, aorta and abdomen. Ectopic thyroid tissue may also be involved in the same processes as normal, orthotopic thyroid gland. These processes include tumors, inflammation and hyperplasia. The appearance of such tissue in rare locations may lead to diagnostic and therapeutic dilemmas. CASE REPORT: We report a rare case of ectopic thyroglossal thyroid carcinoma in a 63-year-old Caucasian male with a normal orthotopic thyroid gland. CONCLUSION: Although 99% of thyroid cancers develop within the thyroid itself, in rare cases a carcinoma can arise in ectopic thyroid tissue located in the neck or in other areas of the body. Though rare, the possibility of an ectopic thyroid carcinoma must always be considered by the surgeon in cases of a pathological mass in the neck. PMID- 23660163 TI - Whipple's disease infection surgical treatment: presentation of a rare case and literature review. AB - The Whipple' Disease (W.D.) is a very rare disease with an incidence of 1 per 1.000.000 inhabitants; it is a systemic infection that may mimic a wide spectrum of clinical disorders, which may have a fatal outcome and affects mainly male 40 50 years old. The infective agent is an actinomycete, Tropheryma Whipplei (T.W.) that was isolated 100 years after first description by Wipple, and identified in macrophages of mucosa of the small intestine by biopsy which is characterized by periodic acid-Schiff-positive, products of the inner membrane of his polysaccharide bacterial cell wall. The multisystemic clinical manifestations evolve rapidly towards an organic decay characterized by weight loss, malabsorption, diarrhea, polyathralgia, opthalmoplegia, neuro-psychiatric disorders and sometimes associated to endocarditis. Early antibiotic treatment with trimethoprim and sulfometathaxazole reduces the fatal evolution of the disease. The authors present a rare experience about a female subject in which the clinical gastrointestinal signs were preceded by neuro-psychiatric disorders, and evolved into obstruction and intestinal perforation which required an emergency surgery with temporary ileostomy, recanalized only after adequate medical treatment with a full dose of antibiotic and resolution of clinical disease for the high risks of fistulae for the edema and lymphadenopathy of mucosa. The diagnosis was histologically examined by intestinal biopsy performed during surgery, which showed PAS-positive histiocytes, while PRC polymerase RNA was negative, which confirms the high sensibility of PAS positive and low specificity of RNA polymerase for T.W. PMID- 23660164 TI - Delayed presentation of blunt duodenal injuries in children. Case report and review of literature. AB - BACKGROUND: Duodenal injuries are rare in children and classically present following a fall over the handle bar. Retroperitoneal location of the duodenum may lead to delay in diagnosis, and missed injuries are associated with increased morbidity and mortality. CASE REPORT: A 5-year-old child was admitted to the National Trauma Center, in Tirana (Albania), 28 hours after a Motor Vehicle Crash (MVC), complaining of mild abdominal pain. He was febrile (39 degrees C) and had a white blood cells count of 18,000 mm3. On physical exam he had mild tenderness. Plain abdominal X-rays and Focused Abdominal Sonography for Trauma (FAST) were negative for free air or free fluid. The CT scan of the abdomen demonstrated free air and fluid in the retroperitoneal space. At laparatomy, a perforation of the second portion of the duodenum was found. A single layer suture repair of the duodenum with wide drainage was performed. The patient was discharged from the hospital tolerating oral feeding 8 days later. CONCLUSION: Duodenal injuries in children are rare. Most duodenal hematomas are managed non-operatively. This is a case of MCV with delayed presentation that was treated surgically for perforation successfully. PMID- 23660165 TI - Secretory breast cancer. Case report. AB - Secretory carcinoma of the breast is a rare tumor initially described in children but occurring equally in adult population. This unusual breast cancer subtype has a generally favorable prognosis, although several cases have been described in adults with increased aggressiveness and a risk of metastases. However, surgery is still considered the most appropriate treatment for this pathology. We describe the case of a 50 -year-old woman who has undergone a breast conservative surgery for a little tumor, preoperatively diagnosticated by a fine needle aspiration biopsy (FNAB) as a well differentiated infiltrating carcinoma. PMID- 23660166 TI - Successful management of evisceration occurred after exploratory laparotomy for bilateral ovarian micropapillary serous borderline tumors. AB - Micropapillary serous borderline tumor of the ovary is characterized by a more frequent association with extraovarian, especially invasive, implants. The aim of this study was to report the clinicopathological findings of a rare case of micropapillary serous borderline tumor of the ovary since there are less than 100 similar cases in the published literature. Additionally, the successful management of evisceration that complicated the postoperative stay of the patient is analyzed. The incidence of this severe complication is estimated between 0.29 2.3%. There are four main causes: suture tearing through the fascia, knot failure, suture failure, and extrusion of abdominal contents between sutures placed too far apart. At least 50% of the cases are due to technical error with a potentially lethal result. PMID- 23660167 TI - One-stage laparoscopic procedure for a patient with bilateral colorectal tumours and renal carcinoma. AB - We describe a case of a patient with synchronous bilateral colorectal tumours and renal carcinoma who underwent one-stage laparoscopic surgery procedure with right transperitoneal nefrectomy, right hemicolectomy and sigmoidectomy. One-stage laparoscopic procedure can be used safely and successfully for a patient with multiple primary tumours. PMID- 23660168 TI - NRAS mutant melanoma--undrugable? AB - Mutations in the three rat sarcoma (RAS) family members NRAS (neuroblastoma-RAS), HRAS (Harvey-RAS) and KRAS (Kirsten-RAS) are found in one third of human cancers. Among the first oncogenes discovered in cutaneous melanoma was NRAS, which is mutant in up to 20% of tumors causing aberrant signaling in several downstream cascades. Despite, being a highly relevant therapeutic target, design of small molecules selectively inhibiting mutant NRAS in melanoma, to date, remains an unsolved challenge. The end? PMID- 23660169 TI - Short-term folinic acid supplementation improves vascular reactivity in HIV infected individuals: a randomized trial. AB - OBJECTIVE: HIV-infected individuals present a cluster of conditions that activate or injure the vascular endothelium. The administration of folates may exert beneficial effects on endothelial function in different populations at risk for cardiovascular disease. The aim of this study was to determine the effects of 4 wk of folinic acid supplementation on forearm vascular responses during reactive hyperemia in HIV-infected patients under highly active antiretroviral therapy. METHODS: This was a prospective, randomized, double-blind, placebo-controlled trial to compare the effects of 4 wk of daily ingestion of 5 mg of folinic acid (n = 15) or placebo (n = 15). Participants had to have been on antiretroviral therapy (ART) for at least 6 mo before enrollment, with undetectable viral load, and CD4 cell count >200 cells/mm(3). Vascular function was evaluated with venous occlusion plethysmography at baseline and after 4 wk, for the determination of brachial artery reactive hyperemia, and after isosorbide dinitrate administration. RESULTS: The groups were comparable. The mean age of patients was 45 y; there were eight women in each group. There was no difference regarding ART regimen. The supplementation of folinic acid produced a significant improvement in reactive hyperemia (from 14.9 to 21.2 mL*min*100 mL). The same was not observed in placebo group (from 15.3 to 14.6 mL*min*100 mL; group P, 0.017; time P < 0.001; interaction P < 0.001). Endothelium-independent responses remained unchanged. CONCLUSIONS: Short-term folinic acid supplementation improved vascular reactivity in HIV-infected individuals enrolled in the studied. As folate supplementation is safe and relatively inexpensive, long-term clinical trials should be conducted. PMID- 23660170 TI - Food frequency questionnaires: Small associations and large errors. PMID- 23660172 TI - Trends in use of and survival after autologous hematopoietic cell transplantation in North America, 1995-2005: significant improvement in survival for lymphoma and myeloma during a period of increasing recipient age. AB - Autologous hematopoietic cell transplantation (auto-HCT) is performed to treat relapsed and recurrent malignant disorders and as part of initial therapy for selected malignancies. This study evaluated changes in use, techniques, and survival in a population-based cohort of 68,404 patients who underwent first auto HCT in a US or Canadian center between 1994 and 2005 and were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). The mean annual number of auto-HCTs performed was highest during 1996-1999 (6948), and decreased subsequently 2000-2003 (4783), owing mainly to fewer auto-HCTs done to treat breast cancer. However, the mean annual number of auto-HCTs increased from 5278 annually in 1994-1995 to 5459 annually in 2004-2005, reflecting increased use for multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma. Despite an increase in the median recipient age from 44 to 53 years, there has been a significant improvement in overall survival (OS) from 1994 to 2005 in patients with chemotherapy-sensitive relapsed non-Hodgkin lymphoma (day +100 OS, from 85% to 96%; 1-year OS, from 68% to 80%; P < .001) and chemotherapy-sensitive multiple myeloma (day +100 OS, from 96% to 98%; 1-year OS, from 83% to 92%; P < .001). This improvement in OS was most pronounced in middle-aged (>40 years) and older (>60 years) individuals. PMID- 23660171 TI - Nonrelapse mortality and mycophenolic acid exposure in nonmyeloablative hematopoietic cell transplantation. AB - We evaluated the pharmacodynamic relationships between mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and outcomes in 308 patients after nonmyeloablative hematopoietic cell transplantation. Patients were conditioned with total body irradiation +/- fludarabine, received grafts from HLA matched related (n = 132) or unrelated (n = 176) donors, and received postgrafting immunosuppression with MMF and a calcineurin inhibitor. Total and unbound MPA pharmacokinetics were determined to day 25; maximum a posteriori Bayesian estimators were used to estimate total MPA concentration at steady state (Css). Rejection occurred in 9 patients, 8 of whom had a total MPA Css less than 3 MUg/mL. In patients receiving a related donor graft, MPA Css was not associated with clinical outcomes. In patients receiving an unrelated donor graft, low total MPA Css was associated with increased grades III to IV acute graft-versus-host disease and increased nonrelapse mortality but not with day 28 T cell chimerism, disease relapse, cytomegalovirus reactivation, or overall survival. We conclude that higher initial oral MMF doses and subsequent targeting of total MPA Css to greater than 2.96 MUg/mL could lower grades III to IV acute graft-versus-host disease and nonrelapse mortality in patients receiving an unrelated donor graft. PMID- 23660173 TI - New developments in shockwave technology intended for meat tenderization: Opportunities and challenges. A review. AB - Meat tenderness is an important quality parameter determining consumer acceptance and price. Meat tenderness is difficult to ensure in the global meat chain because the production systems are not always aiming at this purpose (ex.: cattle derived from milk production) and by the existence within the carcass of "tough" primals. Different methods can be used by the meat industry to improve meat tenderness each with its advantages and drawbacks. The application of hydrodynamic pressure or shockwaves has showed outstanding improvements by reducing the Warner Bratzler Shear Force by 25% or more. However, the technology has not penetrated into the market as first systems were based on the use of explosives and further developments seemed to lack the robustness to fulfill industrial requirements. The present paper describes the main challenges to construct a prototype for the continuous treatment of meat by shockwaves based on electrical discharges under water. Finally, improvements on the tenderness of meat by using the novel prototype are presented. PMID- 23660174 TI - Toxicological issues associated with production and processing of meat. AB - Meat is a very complex and continuously changing ex vivo system of various high- and low-molecular substances that can be used for satisfying needs of the human organism for metabolic energy, building material and fulfilling of the other vital functions. A great majority of these substances are useful and safe for the consumer. Yet, meat and meat products may always contain substances exerting detrimental effects to the consumer's organism. The present paper is a literature review of the most important potentially toxic substances found in meat and meat products; their classification, ways of getting into the meat or formation during meat processing, undesirable physiological outcomes and biochemical mechanisms of their toxic effects, and methods for reduction of these responses. PMID- 23660175 TI - Bacterial sRNAs: regulation in stress. AB - Bacteria are often exposed to a hostile environment and have developed a plethora of cellular processes in order to survive. A burgeoning list of small non-coding RNAs (sRNAs) has been identified and reported to orchestrate crucial stress responses in bacteria. Among them, cis-encoded sRNA, trans-encoded sRNA, and 5' untranslated regions (UTRs) of the protein coding sequence are influential in the bacterial response to environmental cues, such as fluctuation of temperature and pH as well as other stress conditions. This review summarizes the role of bacterial sRNAs in modulating selected stress conditions and highlights the alliance between stress response and clustered regularly interspaced short palindromic repeats (CRISPR) in bacterial defense. PMID- 23660176 TI - Priming children's and adults' analogical problem solutions with true and false memories. AB - We investigated priming of analogical problem solutions with true and false memories. Children and adults were asked to solve nine verbal proportional analogies, three of which had been primed by Deese-Roediger-McDermott (DRM) lists where the critical lure (and problem solution) was presented as the initial word in the list (true memory priming), three of which were primed by DRM lists whose critical lures were the solution to the verbal proportional analogies (false memory priming), and three of which were unprimed. We controlled for age differences in solution rates (knowledge base) in order to examine developmental differences in speed of processing. As anticipated, the results showed that adults completed the problems significantly faster than children. Furthermore, both children and adults solved problems primed with false memories significantly faster than either those primed with true memories or unprimed problems. For both age groups, there was no significant difference between solution times for unprimed and true primed problems. These findings demonstrate that (a) priming of problem solutions extends to verbal proportional analogies, (b) false memories are more effective at priming problem solutions than true memories, and (c) there are clear positive consequences to the production of false memories. PMID- 23660177 TI - Development of the deontic advantage in reasoning: reply to Cummins. AB - In response to Cummins's report that comments on our article (Dack & Astington, Journal of Experimental Child Psychology, 2011, Vol. 110, pp. 94-114), this article clarifies our perspective on what constitutes the deontic advantage, and notes similarities and differences between Cummins's perspective and our own. Like Cummins, we believe that young children are capable of deontic reasoning and that methodological factors alone cannot explain this ability. However, we maintain that it is important to be precise about methodology in order to facilitate investigation of how the deontic advantage changes over developmental time, and this question is our main interest, although as yet incompletely answered. Contrary to Cummins, we do not think that existing data can speak to the issue of the potential innateness of deontic reasoning. We also disagree with Cummins's perspective on norm versus normative proposition and with some of her comparisons between deontic and epistemic phenomena. PMID- 23660178 TI - Infants understand the referential nature of human gaze but not robot gaze. AB - Infants can acquire much information by following the gaze direction of others. This type of social learning is underpinned by the ability to understand the relationship between gaze direction and a referent object (i.e., the referential nature of gaze). However, it is unknown whether human gaze is a privileged cue for information that infants use. Comparing human gaze with nonhuman (robot) gaze, we investigated whether infants' understanding of the referential nature of looking is restricted to human gaze. In the current study, we developed a novel task that measured by eye-tracking infants' anticipation of an object from observing an agent's gaze shift. Results revealed that although 10- and 12-month olds followed the gaze direction of both a human and a robot, only 12-month-olds predicted the appearance of objects from referential gaze information when the agent was the human. Such a prediction for objects reflects an understanding of referential gaze. Our study demonstrates that by 12 months of age, infants hold referential expectations specifically from the gaze shift of humans. These specific expectations from human gaze may enable infants to acquire various information that others convey in social learning and social interaction. PMID- 23660179 TI - Estimated GFR and fracture risk: a population-based study. AB - BACKGROUND AND OBJECTIVES: Although patients with ESRD have a higher fracture risk than the general population, there is conflicting evidence regarding fracture incidence in those with CKD. This study sought to determine the association between estimated GFR (eGFR) and fracture rates. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study identified 1,815,943 community-dwelling adults who had at least one outpatient serum creatinine measurement between 2002 and 2008. Patients with eGFR <15 ml/min per 1.73 m(2) and those who required dialysis were excluded. Incident fractures of the hip, wrist, and vertebrae were identified using diagnostic and procedure codes. Poisson regression was used to determine adjusted rates of each fracture type by eGFR, age, and sex. RESULTS: The median age of the cohort was 47 years (interquartile range, 24), and 7.1% had eGFR <60 ml/min per 1.73 m(2). Over a median follow-up of 4.4 years, fracture rates increased with age at all sites. Within each age stratum, unadjusted rates increased with declining eGFR; however, adjusted rates were similar across eGFR categories. For example, among women aged 65-74 years, adjusted hip fracture rates were 3.41 per 1000 person-years (95% confidence interval, 2.30 to 4.53) and 4.58 per 1000 person-years (95% confidence interval, 0.02 to 9.14) in those with eGFR >=90 and 15-29 ml/min per 1.73 m(2), respectively. Similar results were observed for wrist and vertebral fractures. CONCLUSIONS: In contrast to earlier studies, patients with eGFR<60 ml/min per 1.73 m(2) do not appear to have increased rates of hip, wrist, and vertebral fractures independent of age and sex. PMID- 23660180 TI - Prevention of contrast-induced AKI: a review of published trials and the design of the prevention of serious adverse events following angiography (PRESERVE) trial. AB - Contrast-induced AKI (CI-AKI) is a common condition associated with serious, adverse outcomes. CI-AKI may be preventable because its risk factors are well characterized and the timing of renal insult is commonly known in advance. Intravenous (IV) fluids and N-acetylcysteine (NAC) are two of the most widely studied preventive measures for CI-AKI. Despite a multitude of clinical trials and meta-analyses, the most effective type of IV fluid (sodium bicarbonate versus sodium chloride) and the benefit of NAC remain unclear. Careful review of published trials of these interventions reveals design limitations that contributed to their inconclusive findings. Such design limitations include the enrollment of small numbers of patients, increasing the risk for type I and type II statistical errors; the use of surrogate primary endpoints defined by small increments in serum creatinine, which are associated with, but not necessarily causally related to serious, adverse, patient-centered outcomes; and the inclusion of low-risk patients with intact baseline kidney function, yielding low event rates and reduced generalizability to a higher-risk population. The Prevention of Serious Adverse Events following Angiography (PRESERVE) trial is a randomized, double-blind, multicenter trial that will enroll 8680 high-risk patients undergoing coronary or noncoronary angiography to compare the effectiveness of IV isotonic sodium bicarbonate versus IV isotonic sodium chloride and oral NAC versus oral placebo for the prevention of serious, adverse outcomes associated with CI-AKI. This article discusses key methodological issues of past trials investigating IV fluids and NAC and how they informed the design of the PRESERVE trial. PMID- 23660182 TI - Temporal trends in the incidence, treatment, and outcomes of hip fracture in older patients initiating dialysis in the United States. AB - BACKGROUND AND OBJECTIVES: Patients with ESRD experience a fivefold higher incidence of hip fracture than the age- and sex-matched general population. Despite multiple changes in the treatment of CKD mineral bone disorder, little is known about long-term trends in hip fracture incidence, treatment patterns, and outcomes in patients on dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Fourteen annual cohorts (1996-2009) of older patients (>=67 years) initiating dialysis in the United States were studied. Eligible patients had Medicare fee for-service coverage for >=2 years before dialysis initiation and were followed for <=3 years for a first hip fracture. Type of treatment (internal fixation or partial or total hip replacement) was ascertained along with 30-day mortality. Cox and modified Poisson regressions were used to describe trends in study outcomes. RESULTS: This study followed 409,040 patients over 607,059 person years, during which time 17,887 hip fracture events were recorded (29.3 events/1000 person-years). Compared with patients incident for ESRD in 1996, adjusted hip fracture rates increased until the 2004 cohort (+41%) and declined thereafter. Surgical treatment included internal fixation in 56%, partial hip replacement in 29%, and total hip replacement in 2%, which remained essentially unchanged over time; 30-day mortality after hip fracture declined from 20% (1996) to 16% (2009). CONCLUSIONS: Hip fracture incidence rates remain higher today than in patients reaching ESRD in 1996, despite multiple purported improvements in the management of CKD mineral bone disorder. Although recent declines in incidence and steady declines in associated short-term mortality are encouraging, hip fractures remain among the most common and consequential noncardiovascular complications of ESRD. PMID- 23660181 TI - Parathyroidectomy and heart rate variability in patients with stage 5 CKD. AB - BACKGROUND AND OBJECTIVES: Lower heart rate variability implies increased risk of cardiovascular disease. This study aimed to evaluate the relationship between mineral metabolism and heart rate variability and longitudinal changes of heart rate variability after parathyroidectomy in stage 5 CKD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This cross-sectional study included 118 stage 5 CKD patients, 87 controls, and a prospective study in two subgroups classified as successful (n=17) and unsuccessful (n=4) parathyroidectomy follow up enrolled from March of 2011 to December of 2012. Blood examination and 24-hour Holter for heart rate variability were measured. RESULTS: Most heart rate variability indices were lower in stage 5 CKD patients. In multivariate stepwise regression models, serum intact parathyroid hormone was correlated with mean normal-to-normal R-R intervals, mean heart rate, and very low frequency, serum calcium was correlated with SD of 5-minute average of normal R-R intervals, and serum phosphorus was correlated with very low frequency and low frequency/high frequency. Compared with baseline, the successful parathyroidectomy subgroup had significant improvements in mean normal-to-normal R-R intervals, mean heart rate, SD of normal-to-normal R-R intervals, SD of 5-minute average of normal R-R intervals, very low frequency, high frequency, and low frequency/high frequency. There was no significant change of heart rate variability in patients after unsuccessful parathyroidectomy. CONCLUSIONS: Disorders of mineral metabolism are associated with decreased heart rate variability in stage 5 CKD. Successful parathyroidectomy may contribute to reverse this cardiovascular disease risk in severe secondary hyperparathyroidism patients. PMID- 23660183 TI - Cardiac resynchronization therapy in CKD: a systematic review. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) confers morbidity and mortality benefits to selected patients with heart failure. This systematic review examined effects of CRT in CKD patients (estimated GFR [eGFR] <60 ml/min per 1.73 m(2)). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: MEDLINE and Scopus (from 1990 to December 2012) and conference proceedings abstracts were searched for relevant observational studies and randomized controlled trials (RCTs). Studies comparing the following outcomes were included: (1) CKD patients with and without CRT and (2) CKD patients with CRT to non-CKD patients with CRT. Mortality, eGFR, and left ventricular ejection fraction data were extracted and pooled when appropriate using a random-effects model. RESULTS: Eighteen studies (14 observational studies and 4 RCTs) were included. There was a modest improvement in eGFR with CRT among CKD patients (mean difference 2.30 ml/min per 1.73m(2); 95% confidence interval, 0.33 to 4.27). Similarly, there was a significant improvement in left ventricular ejection with CRT in CKD patients (mean difference 6.24%; 95% confidence interval, 3.46 to 9.07). Subgroup analysis of three RCTs reported lower rates of death or hospitalization for heart failure with CRT (versus other therapy) in the CKD population. Survival outcomes of CKD patients (compared with the non-CKD population) with CRT differed among observational studies and RCTs. CONCLUSIONS: CRT improves left ventricular and renal function in the CKD population with heart failure. Given the increasing use of cardiac devices, further studies examining the effects of CRT on mortality in CKD patients, particularly those with advanced kidney disease, are warranted. PMID- 23660184 TI - Urbanised beaches of the Ligurian coastal area (NW Mediterranean): a classification based on organic-matter characteristics and hydrolytic enzymatic activities. AB - The beaches of Liguria have been intensively affected by human activities for over a century, transforming nearly the entire coastline from natural to urbanised and significantly upsetting beach ecological properties. The present study aims to investigate 9 Ligurian beaches characterised by different degree of urbanisation, to test if and to what extent the organic-matter (OM) recycling processes can be linked to the human activity. Swash zone sediment, sampled during the spring-summer-autumn period, when the anthropogenic influence is at its maximum due to tourism, was analysed for OM features and recycling processes. Multivariate statistical analyses showed that huge amounts of detrital OM accumulated in the more urbanised sites, where the anthropogenic influence was at its peak, deriving from higher inhabitant number and density, from the presence of crowded roads very near to the swash zone and sewage treatment plants. The presence of torrent outlets on the beaches provided further OM accumulation. Lipids, carbohydrates and degraded autotrophic pigments were the OM fractions mainly responsible of the differentiation, and rather constant, high labile phosphorus contents were found in the more urbanised sites. The high activity values of the hydrolytic enzymes indicate the response of the microbial system to the OM accumulation in the urban sites. However, a decoupling of the trends of some enzymatic activities (namely glucosidase and lipase) and their target OM was observed in the highly urbanised conditions. PMID- 23660185 TI - [Macrophage activation syndrome as the presenting manifestation of intravascular lymphoma]. AB - INTRODUCTION: Intravascular large B cell lymphoma is a neoplastic cell proliferation leading to the occlusion of the lumen of small vessels. This is a rare haematological malignancy, which is difficult to diagnose because of a heterogeneous clinical presentation. CASE REPORT: We report a 62-year-old man who presented a macrophage activation syndrome as the presenting manifestation of an intravascular lymphoma. This association is frequently marked by a greater severity and clinical care requires an early and appropriate treatment. CONCLUSION: Due to the polymorphism and the systemic presentation of intravascular large B cell lymphoma, the internist may be confronted with this disease, which is considered to be more severe if associated with a macrophage activation syndrome. Awareness of the intravascular large B cell lymphoma is important because the prognosis depends on the rapidity of the initiation of chemotherapy associated with rituximab. PMID- 23660187 TI - Molecular cloning and functional characterization of a novel cotton CBL interacting protein kinase gene (GhCIPK6) reveals its involvement in multiple abiotic stress tolerance in transgenic plants. AB - Plant CIPKs were specific Ser/Thr protein kinases, which were activated through interaction with calcineurin B-like protein (CBL) containing four EF hands for Ca(2+) binding. The CBL/CIPK complexes play an important role in signal transduction in biotic and abiotic stresses, as well as developmental processes. Here a Ser/Thr protein kinase gene (defined as GhCIPK6), which was isolated from RNA-Seq profile during cotton somatic embryogenesis in our previous research was characterized. The GhCIPK6 gene contains an ORF of 1296 bp that putatively encodes a polypeptide of 431 amino acids with a predicted molecular mass of 48.46 kDa and isoelectric point of 9.12. Sequence alignment analysis confirmed that GhCIPK6 has no intron, and it was homologous to AtCIPK6. Expression analysis of the GhCIPK6 suggested that they might function in diverse tissues, including styles and anthers but not fibers. In addition, expression of the GhCIPK6 gene was induced by salt, drought and ABA treatments. Overexpression of GhCIPK6 significantly enhances the tolerance to salt, drought and ABA stresses in transgenic Arabidopsis, indicating that GhCIPK6 acts as a positive regulator in response to salt and drought stress, and is supposed to be a potential candidate gene to improve stress tolerance by genetic manipulation in cotton and other crops. PMID- 23660186 TI - Platelet rich plasma extract promotes angiogenesis through the angiopoietin1-Tie2 pathway. AB - Development and regeneration of tissues and organs require precise coordination among endothelial, epithelial and mesenchymal morphogenesis. Angiogenesis plays key roles in normal development, wound healing, recovery from ischemic disease, and organ regeneration. It has been recognized that the combination of various angiogenic factors in an appropriate physiological ratio is critical for long term functional blood vessel formation. Here we show that mouse soluble platelet rich-plasma (PRP) extract, which includes abundant angiopoetin-1 (Ang1) and other angiogenic factors, stimulates endothelial cell growth, migration and differentiation in cultured human dermal microvascular endothelial cells in vitro and neonatal mouse retinal angiogenesis in vivo. Mouse platelet rich fibrin (PRF) matrix, the three-dimensional fibrin matrix that releases angiogenic factors with similar concentrations and proportions to the PRP extract, also recapitulates robust angiogenesis inside the matrix when implanted subcutaneously on the living mouse. Inhibition of Ang1-Tie2 signaling suppresses PRP extract-induced angiogenesis in vitro and angiogenic ability of the PRF matrix in vivo. Since human PRP extract and PRF matrix can be prepared from autologous peripheral blood, our findings may lead to the development of novel therapeutic interventions for various angiogenesis-related diseases as well as to the improvement of strategies for tissue engineering and organ regeneration. PMID- 23660188 TI - Kdx1 regulates RCK1 gene expression by interacting with Rlm1 in Saccharomyces cerevisiae. AB - Kdx1 is known as a stress-responsive protein. To better understand the function of Kdx1, we performed microarray analysis in KDX1 overexpressing cells and found that the overexpression of KDX1 dramatically induced the expression of RCK1, a stress-responsive gene. This result was confirmed by northern blot analysis. Furthermore, the overexpression of RCK1 partially rescued the growth defect caused by zymolyase stress. The expression of RCK1 was regulated independently by Slt2 and Hog1, and Kdx1 failed to induce the expression of RCK1 in a HOG1 deletion strain. The transcriptional factors Smp1, Sko1, Msn2, Msn4, and Hot1, which are regulated by Hog1, did not affect RCK1 expression, but Rlm1 did. Furthermore, the mutation of certain phosphorylation sites in RLM1 inhibited the induction of RCK1 expression by Kdx1. We found a conserved Rlm1 binding site in the 5' untranslated region (UTR) of RCK1, and the mutation of these Rlm1 binding sites also inhibited the induction of RCK1 expression by Kdx1. Finally, we showed that Kdx1 physically interacts with Rlm1 and that this interaction affects the ability of Rlm1 to bind to the RCK1 5' UTR. Taken together, these data suggest that Kdx1 interacts with Rlm1 to activate RCK1 gene expression in response to stress in Saccharomyces cerevisiae. PMID- 23660189 TI - Loss of beta-arrestin2 mediates pancreatic-islet dysfunction in mice. AB - Insulin resistance and defective insulin secretion are two major factors contributing to the pathogenesis of type 2 diabetes. beta-Arrestin2 is known to interact with numerous signaling molecules. Our previous study demonstrated that beta-arrestin2 regulates insulin sensitivity in both skeletal muscle and liver, yet its role in insulin secretion remains elusive. In this study, we found that beta-arrestin2 was abundantly expressed in mouse pancreatic beta cells, while its expression was significantly decreased in obese and diabetic mouse models. Hyperglycemic clamp study showed that the acute and late phase of insulin secretion were impaired in beta-arrestin2 knockout mice. Ex vivo study showed that beta-arrestin2 deficient pancreatic islets exhibited blunted glucose stimulated insulin secretion. Further analysis demonstrated the number of docked insulin granules in beta-arrestin2 deficient islets was markedly decreased compared to wild-type islets, while insulin content and beta cell mass remained unchanged. Our study establishes a new role for beta-arrestin2 in beta-cell functions, and suggests that the down regulation of beta-arrestin2 may contribute to impaired insulin secretion in type 2 diabetes. PMID- 23660190 TI - PI3K-delta mediates double-stranded RNA-induced upregulation of B7-H1 in BEAS-2B airway epithelial cells. AB - Airway viral infection disturbs the health-related quality of life. B7-H1 (also known as PD-L1) is a coinhibitory molecule associated with the escape of viruses from the mucosal immunity, leading to persistent infection. Most respiratory viruses generate double-stranded (ds) RNA during replication. The stimulation of cultured airway epithelial cells with an analog of viral dsRNA, polyinosinic polycytidylic acid (poly IC) upregulates the expression of B7-H1 via activation of the nuclear factor kappaB(NF-kappaB). The mechanism of upregulation was investigated in association with phosphatidylinositol 3-kinases (PI3Ks). Poly IC induced upregulation of B7-H1 was profoundly suppressed by a pan-PI3K inhibitor and partially by an inhibitor or a small interfering (si)RNA for PI3Kdelta in BEAS-2B cells. Similar results were observed in the respiratory syncytial virus infected cells. The expression of p110delta was detected by Western blot and suppressed by pretreatment with PI3Kdelta siRNA. The activation of PI3Kdelta is typically induced by oxidative stress. The generation of reactive oxygen species was increased by poly IC. Poly IC-induced upregulation of B7-H1 was attenuated by N-acetyl-L-cysteine, an antioxidant, or by oxypurinol, an inhibitor of xanthine oxidase. Poly IC-induced activation of NF-kappaB was suppressed by a pan-PI3K inhibitor but not by a PI3Kdelta inhibitor. These results suggest that PI3Kdelta mediates dsRNA-induced upregulation of B7-H1 without affecting the activation of NF-kappaB. PMID- 23660191 TI - Curcumin stimulates glucagon-like peptide-1 secretion in GLUTag cells via Ca2+/calmodulin-dependent kinase II activation. AB - Glucagon-like peptide-1 (GLP-1) is a hormone secreted from enteroendocrine L cells. Enhancing GLP-1 action is an important target for prevention and treatment of type 2 diabetes. Several approaches (GLP-1 analogs, dipeptidyl peptidase IV inhibitors) are being used to develop therapeutic agents using GLP-1 action for the treatment of diabetes. However, an alternative approach is to increase endogenous GLP-1 secretion through modulation of the secretory mechanism in intestinal L cells by pharmaceutical agents or dietary ingredients. In the present study, we demonstrate that curcumin, a yellow pigment isolated from the rhizomes of Curcuma longa L, significantly increases GLP-1 secretion in GLUTag cells, and we clarified the structure-activity relationship using curcumin derivatives. Also, concerning the secretory mechanism, the significant increase in GLP-1 secretion by curcumin involved the Ca(2+)-Ca(2+)/calmodulin-dependent kinase II pathway, and was independent of extracellular signal-regulated kinase, PKC, and the cAMP/PKA-related pathway. These findings provide a molecular mechanism for GLP-1 secretion mediated by foods or drugs, and demonstrate a novel biological function of curcumin in regards to GLP-1 secretion. PMID- 23660192 TI - Effects of IV iron isomaltoside-1000 treatment on regional brain iron status in an iron-deficient animal. AB - BACKGROUND: Iron deficiency has been documented to affect human cognitive function and conditions with brain iron compromise such as the restless legs syndrome (RLS). Intravenous (IV) iron treatment is used to reduce iron deficiency but its effects on brain iron are not known. It is not known if IV iron is effective in correcting regional brain iron deficiencies nor if it poses a risk of producing iron overload in some brain regions. Preclinical study of IV iron in the iron-deficient (ID) murine model is needed to evaluate and develop IV iron treatments for brain iron deficiency. METHODS: Response to tail vein injections of iron (iron isomaltoside-1000, dose equivalent to 1000 mg for 75 kg adult) or vehicle were evaluated for ID mice by microdialysis assessing non-transferrin bound (NTB) iron in the ventral midbrain (VMB) and autopsy at 3 and 10 days post injection assessing iron content in critical brain regions. RESULTS: The ID mice showed marked circadian variation in NTB extracellular iron. After iron injection, NTB iron was rapidly increased in the VMB and then decreased over 12h to the levels observed for vehicle. Regional brain iron content at 3 and 10 days post-injection in the iron- compared to vehicle-treated group showed significantly more iron for the VMB and nucleus accumbens but not for the other regions (i.e. prefrontal cortex, caudate-putamen, cerebellum, and pons), which also did not show decreased iron content with the ID diet. CONCLUSION: Iron isomaltoside-1000 given IV corrects the regional brain iron deficiency in these ID mice without producing iron overload in any of the brain regions studied. This is the first demonstration of effects of IV iron in the brain and it provides a useful preclinical model for this assessment, particularly relevant for developing iron treatments for conditions with problematic iron deficiency, e.g. RLS. PMID- 23660193 TI - Repeated restraint stress exerts different impact on structure of neurons in the lateral and basal nuclei of the amygdala. AB - Chronic stress exacerbates and can induce symptoms of depression and anxiety disorders. Chronic stress causes amygdala hyperactivity, which may contribute to these detrimental effects. One potential mechanism for amygdala hyperactivity is an increase of excitatory drive after stress. Excitatory inputs to the amygdala predominantly synapse upon dendritic spines, and repeated stress has been demonstrated to increase dendritic spines in the basolateral amygdala (BLA). However, the BLA is comprised of several nuclei, including the lateral nucleus (LAT) and the basal nucleus (BA), which exert functionally distinct roles in amygdala-dependent behaviors. Furthermore, while an increase of dendritic spines can impart significant functional ramifications, a shift of spine distribution can also exert significant impact. However, differences in the effects of repeated stress on LAT and BA have not been examined, nor differential effects on spine distribution. This study examined the effects of repeated restraint stress on dendritic structure of principal neurons from the LAT and BA in Golgi-stained tissue. This study found that repeated stress increased spine number in LAT and BA, but in very distinct patterns, with proximal increases in LAT neurons and non proximal increases in BA neurons. Furthermore, repeated stress increased dendritic length in the BA, but not the LAT, leading to a global change of spine density in BA, but a focal change in LAT. These distinct effects of repeated stress in the LAT and BA may exert significant functional effects on fear behavior, and may underlie differences in the effects of repeated stress on acquisition, contextual modulation and extinction of fear behavior. PMID- 23660196 TI - Acute hemicerebellitis in children: case report and review of literature. AB - Acute hemicerebellitis in childhood is an extremely rare unilateral presentation of cerebellitis mimicking a tumour. Its aetiology is unknown, although an inflammatory or postinfectious origin is presumed. Its clinical outcome is generally good and a self-limited evolution, in the absence of specific treatment, is usually expected. MRI findings can be misunderstood leading to erroneous diagnosis and invasive treatments. Clinical improvement and regression of the pathological findings in serial MRI will help differentiate acute hemicerebellitis from a neoplastic process. Surgical procedures should be performed only in case of clinical deterioration. We present a case of pseudotumoral hemicerebellitis in an eight-year-old girl, presenting with severe headache. This paper provides a review on hemicerebellitis and highlights the clinical, diagnostic, therapeutic features and outcome of this entity. PMID- 23660195 TI - Long-lasting effects of minocycline on behavior in young but not adult Fragile X mice. AB - Fragile X Syndrome (FXS) is the most common single-gene inherited form of intellectual disability with behaviors characteristic of autism. People with FXS display childhood seizures, hyperactivity, anxiety, developmental delay, attention deficits, and visual-spatial memory impairment, as well as a propensity for obsessive-compulsive disorder. Several of these aberrant behaviors and FXS associated synaptic irregularities also occur in "fragile X mental retardation gene" knock-out (Fmr1 KO) mice. We previously reported that minocycline promotes the maturation of dendritic spines - postsynaptic sites for excitatory synapses - in the developing hippocampus of Fmr1 KO mice, which may underlie the beneficial effects of minocycline on anxiolytic behavior in young Fmr1 KO mice. In this study, we compared the effectiveness of minocycline treatment in young and adult Fmr1 KO mice, and determined the dependence of behavioral improvements on short term versus long-term minocycline administration. We found that 4- and 8-week long treatments significantly reduced locomotor activity in both young and adult Fmr1 KO mice. Some behavioral improvements persisted in young mice post treatment, but in adults the beneficial effects were lost soon after minocycline treatment was stopped. We also show, for the first time, that minocycline treatment partially attenuates the number and severity of audiogenic seizures in Fmr1 KO mice. This report provides further evidence that minocycline treatment has immediate and long-lasting benefits on FXS-associated behaviors in the Fmr1 KO mouse model. PMID- 23660197 TI - Apoptosis in adhesions and the adhesion-tendon gliding interface: relationship to adhesion-tendon gliding mechanics. AB - PURPOSE: Adhesion formation is closely related to tendon-gliding function. We aimed to investigate apoptosis (programmed cell death) in adhesions and tendons and study its relationship to the mechanics of adhesions and healing tendons. METHODS: The flexor digitorum profundus tendons of 30 long toes in 15 chickens were completely transected and repaired surgically. At postoperative weeks 4, 6, and 8, tendon-gliding excursions were tested and adhesion scores were recorded. Tendons and surrounding adhesions were then harvested for analysis of apoptosis using in situ terminal deoxynucleotidyl transferase dUTP (deoxyuridine triphosphate) nick end labeling assay. Three-dimensional image reconstruction was used to provide an overall view of cellular distribution in tendons and adhesions. Finally, we analyzed the correlation between the apoptotic index measured at the adhesions and the gliding excursions. Ten uninjured tendons served as normal controls. RESULTS: Apoptosis was found to be a dominant cellular event in the adhesion tissues at both the adhesion-tendon gliding interface and the adhesion core. The apoptotic index in the adhesions was generally above 20% to 50%. The apoptotic index was significantly higher in the adhesions than in the junction region of the cut tendon ends at weeks 4, 6, and 8. A higher apoptotic index in the adhesions significantly correlated to lower tendon excursions at week 6. CONCLUSIONS: Apoptosis in adhesions and at the adhesion-tendon interface is a prominent event in the tendon-healing process. The tendons exhibiting a lower tendon-gliding amplitude, meaning more severe adhesions, tended to have a greater apoptotic index in their adhesions during a certain period of the tendon remodeling process. CLINICAL RELEVANCE: Apoptosis in the adhesions and at the adhesion-tendon interface may contribute remarkably to the fate of adhesions and the restoration of the tendon gliding surface, which may be closely related to the tendon function. PMID- 23660194 TI - Modeling of grid cell activity demonstrates in vivo entorhinal 'look-ahead' properties. AB - Recent in vivo data show ensemble activity in medial entorhinal neurons that demonstrates 'look-ahead' activity, decoding spatially to reward locations ahead of a rat deliberating at a choice point while performing a cued, appetitive T Maze task. To model this experiment's look-ahead results, we adapted previous work that produced a model where scans along equally probable directions activated place cells, associated reward cells, grid cells, and persistent spiking cells along those trajectories. Such look-ahead activity may be a function of animals performing scans to reduce ambiguity while making decisions. In our updated model, look-ahead scans at the choice point can activate goal associated reward and place cells, which indicate the direction the virtual rat should turn at the choice point. Hebbian associations between stimulus and reward cell layers are learned during training trials, and the reward and place layers are then used during testing to retrieve goal-associated cells based on cue presentation. This system creates representations of location and associated reward information based on only two inputs of heading and speed information which activate grid cell and place cell layers. We present spatial and temporal decoding of grid cell ensembles as rats are tested with perfect and imperfect stimuli. Here, the virtual rat reliably learns goal locations through training sessions and performs both biased and unbiased look-ahead scans at the choice point. Spatial and temporal decoding of simulated medial entorhinal activity indicates that ensembles are representing forward reward locations when the animal deliberates at the choice point, emulating in vivo results. PMID- 23660198 TI - MRI of wrist ligaments. AB - The optimal imaging protocols for magnetic resonance imaging (MRI) of the wrist ligaments are discussed, including the use of magnetic resonance arthrography, and 3 Tesla (T) versus 1.5 T magnetic field strength. The normal MRI appearance of the triangular fibrocartilage complex, capsular, and interosseous wrist ligaments is briefly covered to point out potential diagnostic pitfalls. Numerous examples of common ligamentous pathology discernible on MRI are provided, along with the latest estimates of diagnostic sensitivity and specificity provided by the literature. PMID- 23660199 TI - Acute fight bite. PMID- 23660200 TI - Split flexor pollicis longus tendon transfer to A1 pulley for correction of paralytic Z deformity of the thumb. AB - PURPOSE: To test the hypothesis that split flexor pollicis longus (FPL) transfer to the A1 pulley will correct a thumb paralytic Z deformity and that the transfer can be subjected to early postoperative active mobilization protocol. METHODS: In a prospective trial, 19 consecutive thumbs with ulnar or combined ulnar and median nerve paralysis received split FPL transfer to the thumb A1 pulley and active mobilization of transfer after 48 hours. Outcomes were assessed by correction of Z deformity during pinch, tendon transfer insertion pullout during early active mobilization, range of motion at the thumb metacarpophalangeal and interphalangeal joints, and postoperative treatment time. Data from historical records of 20 thumbs with split FPL to extensor pollicis longus (EPL) and 3 weeks' immobilization, treated before the prospective trial in the same institution, were used for comparison. RESULTS: All 19 thumbs with split FPL to A1 pulley achieved Z deformity correction at discharge from rehabilitation. There was no incidence of transfer insertion pullout during active mobilization, and patients were discharged 22 days earlier than the controls who received transfer of FPL to EPL insertion. Seventeen thumbs were available for follow-up more than 1 year after the index procedure. Fifteen thumbs retained deformity correction, and 2 had recurrence of Z deformity. The interphalangeal joint had considerably greater active motion following split FPL to A1 pulley compared with transfer of split FPL to EPL insertion. CONCLUSIONS: This study supports the hypothesis. Split FPL tendon transfer to thumb A1 pulley can correct paralytic thumb Z deformities and be mobilized early for transfer re-education. Improved interphalangeal joint active motion and reduced treatment time are added advantages over FPL transfer to the EPL insertion. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 23660201 TI - [Make efforts to continuously improve the use of antibacterial drugs in hospital acquired infection in neurosurgical patients-introduction of "consensus statement on the application of antibacterial drugs for hospital-acquired infection in neurosurgical patients"]. PMID- 23660202 TI - [Prevalence and surgical status of cataract among adults aged 50 years or above in rural Jiangsu Province]. AB - OBJECTIVE: To survey the prevalence, operative status, surgical coverage rate and social burden rate of cataract blindness among older adults aged 50 years or above in 2 typical counties (district) of Jiangsu Province, China in 2010. METHODS: Cluster sampling was used in randomly selected 12 867 individuals aged 50 years or above in 58 clusters in Funing County of Northern Jiangsu and Binhu District of Southern Jiangsu. Among them, 12 053 individuals received visual acuity and eye examinations (response rate 93.8%). Lens and cataract operative status were evaluated by slit-lamp biomicroscope. Data bank was established by Epidata3.0 Software. Statistical analyses were performed with Stata/SE Statistical Software, version 10.0. Confidence intervals and P values (significant at P < 0.05) for prevalence of cataract, surgical coverage rate of cataract, social burden rate and surgical outcomes of cataract blindness were calculated with adjustment for clustering effects and stratification associated with the sampling design. RESULTS: Among 12 503 individuals, there were 2208 cases of cataract with a prevalence of 18.3%. The prevalence of cataract was higher in the aged, female and lower-income persons (P < 0.05). Among 2208 cataract patients, cataract surgery was performed in 263 cases (11.9%). The surgical coverage rate of cataract was 59.7% and the social burden rate of cataract blindness 1.93%. The social burden rate of cataract blindness was higher in the aged persons (P < 0.01). In 357 eyes with cataract surgery, the rate of intraocular lens implantation was 85.7%. At Binhu, 71.0% of eyes with cataract surgery underwent phacoemulsification. At Funing, 73.6% of eyes underwent modern extra-capsular surgery respectively. Post-operative presenting and best corrected visual acuity over 0.7 was 11.2% and 19.6% of operated eyes respectively. The main causes of post-operative eyes with worse visual acuity (< 0.3) were post capsular opacity and retinal disorders. CONCLUSION: Cataract is the most common and important eye disease that may lead into blindness and severe visual impairment among older adults aged 50 years or above. The coverage rate of cataract surgery is higher in Jiangsu province than in other provinces. The visual outcomes of surgery is less than ideal. An important task in blindness prevention of Jiangsu province still is the elimination of cataract blindness and the improvement of visual outcomes for cataract surgery in the future. PMID- 23660203 TI - [Demethylation pattern of PD-1 gene in promoter region is associated with the PD 1 expression on peripheral blood mononuclear cells in chronic hepatitis B patients]. AB - OBJECTIVE: To observe the expression variations and influencing factors of programmed death one (PD-1) and DNA demethylation of PD-1 promoter on peripheral blood mononuclear cells (PBMCs) in chronic hepatitis B (CHB) patients and further investigate the relationship between the demethylation pattern of PD-1 gene in promoter region and the PD-1 expression on PBMC in CHB patients. METHODS: A total of 162 subjects, including 144 CHB patients and 18 healthy blood donors, were enrolled. The expression of PD-1 on PBMCs was detected by flow cytometry. And the serum HBV markers, HBV DNA load and liver function were also measured. DNA of PBMCs was treated with sodium bisulfite; the PD-1 promoter fragments were amplified by polymerase chain reaction (PCR) and then transformed into Escherichia coli. Positive clones were selected for sequencing and the methylation status of fragments of PD-1 promoter was examined. RESULTS: With the PD-1 expression in normal controls (10.8% +/- 4.4%) as a baseline level, the expression of PD-1 in CHB patients significantly increased. In CHB patients, the serum expression of PD-1 in PBMCs from patients with positive HBeAg (27.1% +/- 18.4%) was much higher than that from those with negative HBeAg (19.6% +/- 15.6%). And the expression level of PD-1 was not correlated with serum HBV DNA load and serum level of alanine aminotransferase. The results of bisulfite genomic sequencing showed that demethylation probability of some CG points in PD 1 promoter region (-601, -553, -538, -483, -463, -317 bp) were significantly correlated with PD-1 expression level (P < 0.05). CONCLUSION: The demethylation pattern of PD-1 gene in promoter region is associated with the PD-1 expression on PBMC in CHB patients. PMID- 23660204 TI - [Prognostic significance of serum level of vascular endothelial growth factor receptor-2 in hepatocellular carcinoma patients after transcatheter arterial chemoembolization]. AB - OBJECTIVE: To explore the prognostic significance of serum vascular endothelial growth factor receptor-2 (VEGFR-2) in patients with hepatocellular carcinoma (HCC) after transcatheter arterial chemoembolization (TACE). METHODS: A total of 69 HCC patients undergoing TACE from October 2008 to April 2012 were recruited and examined. Their serum level of VEGFR-2 level was measured by enzyme-linked immunosorbent assay (ELISA). The relationship between VEGFR-2 and their clinicopathologic features were observed. Prognostic significance of VEGFR-2 was assessed for their survival. RESULTS: Significant differences existed when the serum level of VEGFR-2 was categorized by tumor number and liver cirrhosis (P = 0.021, P = 0.049). The post-treatment serum level of VEGFR-2 was significant higher than that at pre-treatment (P = 0.045). When the mean pre-treatment serum level of VEGFR-2 (8709 ng/L) was used as a cut-off point, the patients with a low serum level of VEGFR-2 had better overall and progression-free survival than those with a high serum level of VEGF (17 vs. 28 months, P = 0.001 and 10 vs. 15 months P = 0.031 respectively). As revealed by multivariate Cox analysis, the pre treatment serum level of VEGFR-2 was an independent and significant prognostic factor of survival for HCC patients at post-TACE. CONCLUSION: The pre-treatment serum level of VEGFR-2 may predict the post-TACE prognosis in HCC patients. PMID- 23660205 TI - [Electrophysiological features of patients with myotonic dystrophy type 1]. AB - OBJECTIVE: To explore the electromyography (EMG) and nerve conduction (NC) features of patients with myotonic dystrophy type 1 (DM1). METHODS: Routine PCR and triplet primed-PCR (TP-PCR) were performed for 33 clinically diagnosed DM1 cases at our clinic from June 2009 to June 2012. The EMG and NC results of 30 patients with a genetic diagnosis of DM1 were collected and analyzed. RESULTS: Myotonic discharges were found in all patients and EMG revealed myogenic changes in 29 patients. Among all 123 muscles examined, the incidence of myotonic discharges was, a little higher than that of myogenic changes (91.87% vs 90.24%). The rate of myotonic discharges in distal muscles was higher than that of myotonic discharges in proximal muscles (100% vs 83.61%). And the difference was statistically significant. No difference existed in myogenic changes between distal and proximal muscles.(87.10% vs 93.44%) Nerve conduction was all normal. CONCLUSIONS: Myotonic discharges and myogenic changes are important EMG features in DM1. In early stage of DM1, myotonic discharges may be the isolated EMG abnormality. Myotonic discharges are predominantly detected in distal muscles. The involved regions detected by EMG are wider than those of clinical findings. EMG is an important screening tool for subclinical or early atypical DM1 patients. PMID- 23660206 TI - [Differences in risk factors between anterior and posterior circulation affecting young ischemic stroke onset and prognosis]. AB - OBJECTIVE: To explore different risk factors between anterior and posterior circulation affecting onset and prognosis in the North Chinese young ischemic stroke patients. METHODS: This study included 446 cases of young ischemic stroke patients in northern China. All patients were recruited from our department from 2001 to 2010, Among them, the lesion sites were anterior circulation infarction (n = 353), posterior circulation infarction (n = 56) and both anterior and posterior circulation infarction (n = 37). Non-conditional Logistic regression analysis was used to determine the risk factors of predicting the onset of either anterior or posterior or mixed stroke and their short-term prognosis. RESULTS: Advanced age and a higher white blood cell count (WBC) increased the risk of non anterior circulation lesions (OR 0.951, P = 0.030; OR 0.876, P = 0.014). Patients with a history of alcohol drinking had an increased risk for simple posterior circulation lesions (OR 1.856, P = 0.047); Both high National Institute of Health stroke scale (NIHSS score) and high total cholesterol (TC) predicted a poor short term prognosis for simple anterior circulation lesions (OR 1.884, P = 0.000; OR 1.792, P = 0.008). CONCLUSION: Age, WBC count, alcohol intake, NIHSS score and TC are closely correlated with different lesions of northern Chinese young patients with ischemic stroke and their poor short-term prognosis. PMID- 23660207 TI - [Clinical characteristics and early effective treatment for pulmonary infection after acute cervical spinal cord injury]. AB - OBJECTIVE: To explore the clinical characteristics and early effective treatment for pulmonary infection after acute cervical spinal cord injury. METHODS: A total of 215 inpatients with acute cervical spinal cord injury were retrospectively analyzed. Their chest radiological films and blood profiles at discharge were analyzed. The fourth generation cephalosporin was used to treat pulmonary infection as soon as admission and the antibiotics switched according to the results of sputum culture and drug sensitive test. Incision of trachea was performed and breath supported by breath machine according to respiratory condition and blood gas analysis. All patients were turned over and slapped on the back in order to excrete phlegm in time. Sometimes bronchial lavage was used to excrete phlegm. The chest radiological examinations and sputum culture were performed twice one week. Once fungal infection was definite, specific antibiotic was used to treat infection. Three-liter bas and nasal feeding were used to improve the nutrition condition. Incision of trachea was closed as soon as possible. RESULTS: Pulmonary infection of 214 patients was finally cured. Among them, 43 suffered from pulmonary closure. One patient died from severe infection of Klebsiella pneumoniae. Pulmonary infection appeared upon admission and was mostly accompanied with hyperpyrexia. The result of sputum culture revealed baumannii and the pathogen of hemoculture was Pseudomonas aeruginosa. At 3 - 4 weeks later, mycotic infection appeared. And 17 patients suffered from Klebsiella pneumoniae and one died. CONCLUSION: Pulmonary infection after acute cervical spinal cord injury is severe and occurs early. Effective antibiotics according to the result of sputum culture, turnover & back-slapping for excreting phlegm in time, expectoration training and strengthening overall nutrition are effective therapeutic measures. PMID- 23660208 TI - [Trend analysis of rapid shallow breathing indices during spontaneous breathing trial may improve predictive accuracy of extubation success]. AB - OBJECTIVE: To determine the respiratory indices capable of improving predictive accuracy of extubation success through serial measurements of during spontaneous breathing trial (SBT) in automatic tube compensation (ATC) pattern of mechanical ventilation. METHODS: For this prospective observational study, patients ventilated over 48 hours were enrolled according to the weaning criterion and underwent a 60 minutes spontaneous breathing trial (SBT) in ATC pattern (ATC = 100%, FiO2 = 0.4, PEEP = 0 cm H2O, PS = 0 cm H2O). During SBT, heart rate (HR) and mean artery pressure (MAP) were monitored continuously and minute volume (VE), respiratory rate (RR), tidal volume of spontaneous breath (VT), rapid shallow breathing index (RSBI), change and rate of change (DeltaRSBI60_1 and DeltaRSBI60_1/RSBI1, etc.) were recorded or calculated at the first, 30(th) and 60(th) minute of SBT. Patients tolerating the trial were extubated immediately. Clinical data and respiratory indices during SBT were compared between patients in extubation success group and those in extubation failure group. Predictive accuracy of extubation success was assessed by area under the receiver operating characteristic (ROC) curve (AUC) for each index. RESULTS: The duration of mechanical ventilation was longer in patients of extubation failure group than that of extubation success group (10.75 +/- 2.73: 7.47 +/- 5.11, P = 0.035) and extubation failure rate was 17.14%. During SBT, RSBI increased initially and then decreased in patients of extubation success group, but increased continuously in patients of extubation failure group. There were significant difference of DeltaRSBI60_1 and DeltaRSBI60_1/RSBI1 in patients between extubation success and failure groups (-11.5 +/- 16.6: 12.1 +/- 38.9, P = 0.001 and -17 +/- 26: 13 +/- 39, P = 0.028). AUCs of RSBI60, DeltaRSBI60_1 and DeltaRSBI60_1/RSBI1 were 0.75, 0.73 and 0.72 and the sensitivity, specificity and diagnostic accuracy 81.0%, 66.7% and 78.5% respectively. CONCLUSION: It is important to observe change of various respiratory indices dynamically during SBT in patients ventilated in ATC pattern. DeltaRSBI60_1 and DeltaRSBI60_1/RSBI1 have greater predictive value for extubation success. Stable or decreased RSBI60 means higher extubation success rate. PMID- 23660209 TI - [Selection of suitable procedure in the treatment of degenerative lumbar scoliosis based upon imaging studies]. AB - OBJECTIVE: To compare the clinical efficacies of two different procedures in the treatment of degenerative lumbar scoliosis. METHODS: From August 2008 to August 2011, 28 patients of lumbar degenerative scoliosis were divided into one group (n = 14) undergoing modified transforaminal lumbar interbody fusion (TLIF) instrumented surgery and another group (n = 14) undergoing posterolateral fusion (PLF) instrumented surgery. There were 12 males and 16 females with a mean age of 66.2 years (range: 54-79). The operative durations and bleeding volumes of two groups were recorded. The post-operative efficacy was evaluated with VAS (visual analogue scale) for low back pain, ODI (Oswestry disability index), Cobb' angle and lumbar lordosis angle on plain film. RESULTS: The mean follow-up period was 25.9 months. The operative duration was 192.0 +/- 44.7 min in modified TLIF group versus 163.0 +/- 39.0 min in PLF group. The bleeding volume was 718.0 +/- 197.2 ml in modified TLIF group versus 546.0 +/- 226.6 ml in PLF group. All operated lumbar intervertebral achieved bony fusion in modified TLIF group by the last follow-up. Two cases had no bony fusion and there was one case of pseudarthrosis in PLF group. Significant differences existed between two groups in pre-operative and post-operative values of VAS, ODI, Cobb' s angle and lumbar lordosis angle (P < 0.05). There were significant differences between two groups in the values of pre-operative and post-operative VAS and lumbar lordosis angle (P < 0.05) but not in the values of pre-operative and post-operative ODI and Cobb' s angle (P > 0.05). CONCLUSION: As an alternative, safe and effective procedure, modified TLIF instrumented is superior to PLF instrumented in the treatment of lumbar degenerative scoliosis. PMID- 23660210 TI - [Post-traumatic stress disorder in convalescent patients of severe acute respiratory syndrome: (1)H-MRS study]. AB - OBJECTIVE: To ascertain the metabolic changes in patients of severe acute respiratory syndrome (SARS) and SARS-related post-traumatic stress disorder (PTSD) and elucidate the relationship between PTSD, SARS and brain metabolism. METHODS: A total of 58 convalescent SARS patients were evaluated by the scores of impact of event scale (IES), self-rating anxiety scale (SAS) and self-rating depression scale (SDS), etc. And 44 of them participated in (1)H-MRS study. There were 18 patients (M:F = 6:12) with SARS-related PTSD and 26 convalescent SARS patients without PTSD. And the procedures were repeated in 18 age, gender and education-matched normal control subjects. In all patients and controls, the regions of interest on magnetic resonance spectroscopy (MRS) were anterior cingulate gyrus (ACG), posterior cingulate gyrus (PCG), left anterior periventricular white matter (LAPWM) and left posterior periventricular white matter (LPPWM). And the correlations between MRS findings and the scores of SAS, SDS and IES were evaluated. RESULTS: In comparisons with the control subjects (n = 18) and convalescent SARS patients without PTSD (n = 26), the SARS-related PTSD group (n = 18) had significantly lower N-acetylaspartate/creatine (NAA/Cr) in 4 regions of interest while the NAA/Cr of the convalescent SARS patients was significantly lower than controls in 3 regions of interest (ACG, PCG and LAPWM). The ratios of NAA/Cr showed no close correlation with the scores of IES, SAS and SDS in convalescent SARS patients. CONCLUSION: The changes of brain metabolism in PTSD are caused by SARS. But their exact relationship awaits further explorations. SARS may also lead to the changes of brain metabolism. PMID- 23660211 TI - [Clinical efficacies of scleral tunnel sutureless trabeculectomy plus phacoemulsification and intraocular lens implantation]. AB - OBJECTIVE: To explore the clinical efficacies of scleral tunnel sutureless trabeculectomy plus phacoemulsification and intraocular lens implantation in the treatment of glaucoma and cataract. METHODS: A total of 49 cataract patients with glaucoma (52 eyes) from our hospital during the period of February 2009 to June 2012. Their visual acuities were < 0.3 and intraocular pressure was not desirable or in need of various ocular hypotensive drugs. A phaco tunnel knife was employed to prepare a 4 mm * 4 mm scleral tunnel flap with 1/2-2/3 whole layer of sclera depth. Phacoemulsification instrument was used to emulsify cataracts. Foldable intraocular lens was implanted. A trabecular cut of 2 mm * 1.5 mm was made under the scleral tunnel. Tile scleral flap was not sutured and conjunctival flap tightly closed. RESULTS: After a 12-month follow-up, > 0.5 in 42 eyes (80.8%). The intraocular pressure was 11.32 - 17.63 mm Hg (1 mm Hg = 0.133 kPa) and the mean intraocular pressure (13.59 +/- 4.26) mm Hg. There was a mean pressure reduction of 11.2 mm Hg from (24.53 +/- 5.71) mm Hg pre-operation. Statistical significance existed (t' = 11.073, P < 0.01). The filtering blebs of type I-II was 43 eyes (82.6%) and the mean central anterior chamber 3.28 mm +/- 0.42 mm. There was statistical difference (t' = 20.486, P < 0.01) with (1.79 +/- 0.31) mm at pre-operation. On 52 eyes, the mean postoperative astigmatism was (1.01 +/- 0.62) D versus (1.13 +/- 0.74) D at pre-operation. There was no statistical significance (F = 2.0673, P > 0.05). No severe complication occurred in all cases. CONCLUSION: Compared with traditional trabeculectomy and triple procedure, this improved and updated procedure lowers intraocular pressure, improves visual acuity and decreases the occurrences of complications. It is a safe, reasonable, quick and effective treatment for cataract patients with glaucoma. PMID- 23660212 TI - [The MRI findings in chordoid glioma of the third ventricle]. AB - OBJECTIVE: To study the features of chordoid glioma of the third ventricle. METHODS: The MRI findings of five cases of chordoid glioma of the third ventricle pathologically proved were reviewed and correlated with operative and pathologic reports. RESULTS: The patients were 3 women and 2 men, 30 - 50 years old in age. The main symptoms were progressive headache, and usually erratic irregular menstruation in women.Five cases of chordoid glioma were located in the third ventricles. Grossly, the 5 tumors size range were 2 - 4 cm in diameter, and were well-circumscribed mass with rounded or irregular morphological features on standard MRI. They were isointense to slightly hypointense relative to normal white matter in T1WI, slightly hyperintense in T2WI and hypointense in DWI on MR. The significant contrast enhancement of this tumour on postcontrast T1WI result from a breakdown of the blood-brain barrier and extravasation of contrast medium, as confirmed by the absence of vascular proliferation on histological examination.4 tumors were enhanced equivalently and 1 tumor had central nonenhancing components representing small cysts, because of its large size (4 cm in diameter). CONCLUSIONS: Chordoid glioma of the third ventricle is rare and the MR appearances possess unique features which are very helpful in diagnosis of chordoid glioma, but to make a definite diagnosis is based on clinical and histopathological features and immunohistochemical staining. PMID- 23660213 TI - [Values of magnetic resonance spectrum imaging in the diagnosis of hepatic fibrosis of rats]. AB - OBJECTIVE: To explore the values of magnetic resonance spectrum (MRS) in early diagnosis, quantization analysis and staging of hepatic fibrosis. METHODS: A rat model of hepatic fibrosis was established by the method of carbon tetra carbon (CCl4). A total of 47 SD rats were divided into model (n = 40) and control (n = 7) groups. 1H-MRS was performed. The model rats of hepatic fibrosis were grouped according to their pathological stages. The ratio of peak height and peak area of metabolites and lipid (Cho/Lip, Glx/Lip, Lac/Lip and Cr/Lip) were calculated and compared respectively. RESULTS: The ratios of peak height of metabolites and lipid were as follows: ratio of Cho and Lip: significant differences existed between control and grades 3 and 4 model groups (P < 0.05); ratio of Glx and Lip: significant differences existed between control and grades 2, 3 and 4 model groups (P < 0.05); ratio of Cr and Lip: significant differences existed between control and grade 3 model groups (P < 0.05). The peak area ratio of main metabolites and lipid of liver were as follows: ratio of Cho and Lip: significant differences existed between control and grade 4 model groups (P < 0.05); ratio of Glx and Lip: significant differences existed between control and other groups (P < 0.05); ratio of Cr and Lip: significant differences existed between control and grade 4 model groups (P < 0.05); ratio of Lac and Lip: no significant differences existed between these groups (P > 0.05). CONCLUSION: The ratios of peak height and peak area of Cho/Lip, Glx/Lip and Cr/Lip are important for the staging of hepatic fibrosis. PMID- 23660214 TI - [Application of computational fluid dynamics in hemodynamic research of aortic arch]. AB - OBJECTIVE: To evaluate the application of computational fluid dynamics (CFD) on a patient-specific hemodynamic model of aortic arch. METHODS: The original Dicom format image data of a patient were acquired by computed tomographic angiography (CTA). A 3-dimensional (3D) model based on CFD was constructed through the right amount of boundary conditions and hemodynamic parameters related with flow velocity, shear force and wall stress on lumen were analyzed accordingly. RESULTS: The 3D model based on CFD could reflect the characteristic of flow velocity, shear force and wall stress on lumen in vitro. (1) The distributions of hemodynamic variables during cardiac cycle were spatiotemporally different. The unidirectional high-speed systolic current was replaced by diastolic eddy current and reversed flow. The distribution of flow velocity and shear stress gradually increased from outer wall of aortic artery to inner wall under the influences of such anatomical factors as vascular branching and distortions of descending aorta; (2) the magnitude and volatility of wall stress in ascending aorta were greater than those of aortic arch and descending aorta, but the least results were at the lateral wall of descending aorta area. In addition, the wall stress of external wall was higher than the lateral wall in the same section. CONCLUSION: The hemodynamic research of aortic arch based on CFD may actually simulate the characteristics of blood flow and wall stress so as to become a new reliable and convenient application tool in etiological diagnosis and surgical planning. PMID- 23660215 TI - [Pro-apoptotic effects of curcumin associated with CIK cells against ovarian carcinoma cells]. AB - OBJECTIVE: To observe the pro-apoptotic effects of Curcumin associated with CIK cells against SKOV3 cells of ovarian carcinoma and discusses the possible molecular mechanisms. METHODS: CIK cells were induced from umbilicus cord blood. The apoptotic morphology of SKOV3 cells was observed under electron microscope after treated with Cur, CIK cells and Cur associated with CIK cells. The levels of Fas protein on surface of ovarian cancer cells and FasL protein on surface of CIK cells after Curcumin treatment were determined by Western blot. The inhibition rates on proliferation of CIK cells and Cur associated with CIK cells after addition of FasL monoclonal antibody were detected by (thiazolyl blue tetrazolium bromide) MTT. RESULTS: The changes of apoptotic morphology in the group of Cur associated with CIK cells were most obvious compared with that in the group of Cur or CIK cells alone. Cur could promote the expression of Fas on surface of SKOV3 cells and FasL on membranes of CIK cells. The inhibition rates on proliferation in the group of CIK cells and Cur associated with CIK cells could be restrained obviously after an addition of anti-FasmAb. CONCLUSION: The pro-apoptotic effects of SKOV3 cells increase with the combined use of Cur and CIK cells. The mechanism may be that Cur can promote the expression of Fas protein on cell surface of SKOV3 cells and FasL protein on cell membrane of CIK cells so as to up-regulate the expression of Fas protein in SKOV3 cells and lead ultimately to the a higher expression of Caspase3. PMID- 23660216 TI - Interleukin-18 is up-regulated in infectious pleural effusions. AB - The aim of this study was to investigate the pleural and systemic expression of interleukin-18 (IL-18) in patients with pleural effusions (PEs), and the effects of the cytokine in mouse pleural space. One hundred and sixty patients, 23 with pleural effusions (PEs) due to heart failure, 60 malignant, 25 parapneumonic/empyemas, 15 tuberculous and 37 with exudates of miscellaneous etiologies were included in the study. Pleural fluid (PF) and serum IL-18 content was determined using ELISA. IL-18 was injected intrapleurally in mice and pleural inflammation was assessed using pleural lavage. The highest PF IL-18 levels were observed in parapneumonic PEs and the lowest PF IL-18 levels in patients with exudates of miscellaneous aetiologies and transudates. PF IL-18 levels were significantly higher in patients with empyemas compared to those with uncomplicated (p=0.009) or complicated (p=0.028) parapneumonic effusions, while serum levels did not differ significantly among the three groups. Pleural IL-18 content was higher than that of blood only in patients with empyemas. In patients with pleural exudates of all etiologies and in those with parapneumonic PEs/empyema, PF IL-18 levels were correlated with markers of acute pleural inflammation such as the percentage of PF neutrophils, PF LDH and PF/serum LDH ratio, low PF glucose and PF/serum glucose ratio and low PF pH. In mice, intrapleural IL-18 caused neutrophil-predominant pleural inflammation. In conclusion, IL-18 is linked to the intensity of neutrophilic pleural inflammation in patients with PEs, it is up-regulated in the pleural space of patients with empyema and it stimulates the accumulation of neutrophils in mouse pleura. PMID- 23660217 TI - Meta-analysis is victim to Chinese academic and educational systems. PMID- 23660219 TI - Transverse and sagittal angulations of proximal segment after sagittal split and vertical ramus osteotomies and their influence on the stability of distal segment. AB - BACKGROUND/PURPOSE: This study aimed at comparing the transverse and sagittal angulations of proximal segment after sagittal split ramus osteotomy (SSRO) and intraoral vertical ramus osteotomy (IVRO), and examining their influences on the stability of distal segment. METHODS: Patients who received SSRO (n = 21) or IVRO (n = 11) for mandibular setback were included. Lateral and posteroanterior cephalograms taken within 1 month before surgery (T1), within 1 week after surgery (T2), and at least 6 months after surgery (T3) were analyzed. The angulation of each proximal segment relative to the upper orbital margin line was measured on posteroanterior cephalogram and the sum of both angles (total ramus angle, TRA) was obtained. On lateral radiograph, ramus inclination angle (RIA) relative to a horizontal reference line 7 degrees to the sella-nasion was assessed and B-point position was measured. RESULTS: From T1 to T2, more increases in TRA and RIA were noted after IVRO than after SSRO. From T2 to T3, TRA and RIA significantly decreased in IVRO group but remained relatively stable in SSRO group. DeltaTRA(T1-T2) positively related to upward rotation of distal segment for SSRO and downward rotation for IVRO from T2 to T3. For SSRO only, DeltaRIA(T1-T2) significantly related to forward movement of distal segment during remodeling. CONCLUSION: TRA and RIA increase significantly after IVRO and then regress, whereas they increase mildly after SSRO and remain stable. Increase in TRA significantly relates to distal segment rotation during remodeling for both surgeries, but increase in RIA relates to forward relapse of the distal segment only for SSRO. The reasons underlying the correlations are not certain and deserve future investigations. PMID- 23660218 TI - MicroRNAs as potential therapeutic targets in kidney disease. AB - One cornerstone of chronic kidney disease (CKD) is fibrosis, as kidneys are susceptible due to their high vascularity and predisposition to ischemia. Presently, only therapies targeting the angiotensin receptor are used in clinical practice to retard the progression of CKD. Thus, there is a pressing need for new therapies designed to treat the damaged kidney. Several independent laboratories have identified a number of microRNAs that are dysregulated in human and animal models of CKD. This review will explore the evidence suggesting that by blocking the activity of such dysregulated microRNAs, new therapeutics could be developed to treat the progression of CKD. PMID- 23660220 TI - Increased placenta growth factor mRNA level is significantly associated with progression, recurrence and poor prognosis of oral squamous cell carcinoma. AB - BACKGROUND/PURPOSE: Expression of placenta growth factor (PlGF) mRNA is shown to correlate with the progression and prognosis of several human cancers. In this study, we assessed whether the PlGF mRNA level in oral squamous cell carcinoma (OSCC) tissue could be used to predict the progression and prognosis of OSCCs in Taiwan. METHODS: This study used quantitative real-time reverse transcription polymerase chain reaction (quantitative RT-PCR) to detect the PlGF mRNA levels in 63 paired OSCC and adjacent normal-looking oral mucosa (non-OSCC) tissues. Threshold cycle (CT) was defined as the PCR cycle number needed to generate a pre determined amount of DNA (threshold). For a chosen threshold, a smaller starting copy number of mRNA results in a higher CT value. In this study, the relative expression level of tissue PlGF mRNA in each OSCC patients was expressed as DeltaCT = -(OSCC CT - non-OSCC CT). Thus, the higher the -DeltaCT, the greater the copy number of PlGF mRNA in tissues. RESULTS: We found that the higher mean PlGF mRNA -DeltaCT value was significantly associated with OSCCs with larger tumor size (p = 0.03), positive lymph node metastasis (p = 0.003), more advanced clinical stages (p = 0.013) or the presence of loco-regional recurrence (p = 0.039). Positive lymph node metastasis (p = 0.019) and PlGF mRNA -DeltaCT value >2 (p = 0.016) were identified as two independent unfavorable prognosis factors by multivariate analyses with Cox regression model. Moreover, Kaplan-Meier curve showed that OSCC patients with a PlGF mRNA -DeltaCT value >2 had a significantly poorer recurrence-free survival than those with a PlGF mRNA -DeltaCT value <=2 (log-rank test, p = 0.017). CONCLUSION: The OSCC tissue PlGF mRNA level can be used to predict the progression and prognosis of OSCCs in Taiwan. PMID- 23660221 TI - Intrathecal glutamate release during hindlimb tourniquet inflation and femoral artery occlusion in rats. AB - BACKGROUND/PURPOSE: A tourniquet is commonly used in limb surgery. Tourniquet inflation after a period of time may produce painful sensation. While the mechanisms of tourniquet-induced pain are still unknown, two components, pressure and ischemia, have been proposed. In this study, in vivo microdialysis was used to detect changes in intrathecal glutamate, an excitatory amino acid highly relevant to pain transmission, following hindlimb tourniquet application and femoral artery occlusion in the rat. METHODS: Male Wistar rats were used. For the tourniquet study, 6 rats of the study group received 30 minutes right hindlimb tourniquet inflation and another 6 rats as the control group received only tourniquet application without inflation. In the femoral artery occlusion study, 6 rats of the study group received 30 minutes right femoral artery occlusion and another 6 rats as the control group received only sham operation without femoral artery occlusion. Cerebrospinal fluid dialysates were collected prior to, during, and after tourniquet application or femoral artery occlusion. Glutamate was measured by HPLC. RESULTS: A significant increase in intrathecal glutamate release was found during the tourniquet inflation period, and it returned to baseline after tourniquet deflation. No change of glutamate release was noted during femoral artery occlusion or after femoral artery reperfusion. CONCLUSION: The intrathecal glutamate release was increased by the hindlimb tourniquet inflation, but not influenced by femoral artery occlusion in the rat. PMID- 23660222 TI - In-hospital case management to increase anticoagulation therapy for stroke patients with atrial fibrillation: a hospital-based registry. AB - BACKGROUND/PURPOSE: Anticoagulation is underused for stroke patients with atrial fibrillation in Taiwan. An effective preventive measure is in great need of improvement. METHODS: In-hospital case management was implemented to monitor the diagnosis of atrial fibrillation and the use of warfarin. Timely feedback to treating physicians was made. Change in performance after the implementation was analyzed. RESULTS: A total of 2754 patients hospitalized for acute ischemic stroke or transient ischemic attack were included, 1216 before and 1538 after the intervention. The percentage of patients without electrocardiography examination decreased from 8.7% to 2.9% (p < 0.001). The diagnosis of atrial fibrillation increased from 11.5% (n = 140) to 15.9% (n = 244) (p = 0.001). The use of warfarin at discharge increased from 36.9% to 54.7% (p = 0.001). In-hospital case management was significantly related to the use of warfarin (odds ratio = 2.47, p < 0.001). The percentage of warfarin use was still significantly higher in the intervention group at 3 months of follow-up (45.9% vs. 27.8%, p = 0.002) and at 6 months of follow up (49.2% vs. 28.6%, p = 0.004). More patients' international normalized ratio was within the recommended range in the intervention group at 6 months' follow-up (30.5% vs. 9.1%, p = 0.039). CONCLUSION: Our study indicates that in-hospital case management may be an effective strategy to improve anticoagulation for eligible stroke patients. PMID- 23660223 TI - Multidrug-resistant Salmonella enterica serovar Panama carrying class 1 integrons is invasive in Taiwanese children. AB - BACKGROUND/PURPOSE: An increase in group D Salmonella isolates with high antimicrobial resistant rates is being seen in Taiwan. This study aimed to determine the multidrug-resistant (MDR, more than three antibiotics) phenotype, genotype, and the correlation between the presence of class 1 integrons and its invasiveness of Salmonella panama and Salmonella enteritidis isolated from children. METHODS: Twenty S. panama and 59 S. enteritidis isolates were examined for minimal inhibitory concentrations of ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline by agar dilution method. The presence of blaPSE-1, floR, aadA2, sul1, and tet(G) resistance genes, class 1 integrons, and Salmonella genomic island 1 (SGI1) was identified by polymerase chain reaction. The adhesion and invasion assays of S. panama to Caco-2 cells were determined using the pour plate method. RESULTS: All S. panama and 15 (25.4%) of the S. enteritidis isolates displayed MDR phenotype. Furthermore, MDR genotype was present in 70.0% of S. panama and 6.8% of S. enteritidis. Class 1 integrons were present in 40.0% of S. panama and 11.9% of S. enteritidis. None contained SGI1 or SGI1 variants. Strains carrying class 1 integrons were more frequently isolated from bacteria with MDR (73.3% vs. 37.5%; odds ratio, 4.6; 95% confidence interval, 1.3-16.0; p=0.01) and isolated from blood and cerebrospinal fluid (46.7% vs. 21.9%; odds ratio, 3.1; 95% confidence interval, 1.0-10.1; p=0.05) than noncarriers. S. panama carrying class 1 integrons were more invasive to Caco-2 cells than those without (p=0.01). CONCLUSION: S. panama and S. enteritidis with class 1 integrons are significantly related to the presence of MDR phenotype. Moreover, S. panama with class 1 integrons may present more invasiveness than those without. PMID- 23660224 TI - Development and validation of the Chinese Overactive Bladder Symptom Score for assessing overactive bladder syndrome in a RESORT study. AB - BACKGROUND/PURPOSE: This study aimed to develop and validate the Chinese Overactive Bladder Symptom Score (OABSS) for assessing overactive bladder (OAB) symptoms and compare it with a 3-day bladder diary. METHODS: The Chinese OABSS was developed by linguistic validation of the original version. Its reliability and validity and correlations with a 3-day bladder diary were tested on patients with OAB in a multicenter study conducted in Taiwan (the RESORT study). RESULTS: A total of 60 patients with OAB, either incontinent (OAB wet, n=31) or continent (OAB dry, n=29), were enrolled consecutively in this study. The test-retest reliability of the Chinese OABSS was moderate to good, with weighted kappa coefficients of 0.515-0.721 for each symptom score and 0.610 for the total symptom score. Each symptom score correlated positively with the total OABSS (Spearman's rho 0.365-0.793) and was internally consistent (Cronbach's alpha 0.674). The distribution of the OABSS showed a clear separation between OAB wet (average 11.4, range 7-15) and OAB dry (average 7.97, range 4-10) subgroups (Wilcoxon exact test, p<0.05). In addition, the OABSS items correlated positively with the corresponding bladder diary variables (Spearman's rho 0.504-0.879) and the degrees of agreement improved with study visits except for nighttime frequency. The Chinese OABSS tended to underestimate the frequency of nighttime voiding. CONCLUSION: The Chinese OABSS has been developed and validated as a reliable instrument for assessing OAB symptoms. OABSS can be an alternative to, but not a replacement for, a 3-day bladder diary for assessing patients. PMID- 23660225 TI - Cigarette smoking might impair memory and sleep quality. AB - Although nicotine can enhance some cognitive functions, cigarette smoking may impair memory and sleep quality. Our aim was to investigate the impact of cigarette smoking on memory and sleep quality in healthy smokers. Sixty-eight healthy participants (34 smokers and 34 controls) completed the Wechsler Memory Scale-Revised and a Chinese version of the Pittsburgh Sleep Quality Index. The Wilcoxon signed ranks test was performed, and Hochberg's Sharpened Bonferroni correction was applied for multiple comparisons. The results show that current smokers had a worse visual memory compared to nonsmokers. There was no significant correlation between the index of Wechsler Memory Scale-Revised and Fagerstrom test for nicotine dependence. Moreover, smokers had poorer sleep quality. Cigarette smoking might impair memory and adversely influence sleep quality. PMID- 23660226 TI - Blunt abdominal trauma induced splenic and pancreatic rupture--did prior splenorrhaphy make them vulnerable? PMID- 23660227 TI - Secular trends of ADHD and developmental delay in Taiwanese children with epilepsy: a 13-year National Health Insurance data retrospective analysis. PMID- 23660228 TI - Dr Tsai and colleagues' reply. PMID- 23660231 TI - Ethics and data protection in human biomarker studies in environmental health. AB - Human biomarker studies in environmental health are essential tools to study the relationship between health and environment. They should ultimately contribute to a better understanding of environmentally induced adverse health effects and to appropriate preventive actions. To ensure the protection of the rights and dignity of study participants a complex legal and ethical framework is applied, consisting of several international directives, conventions, and guidelines, whether or not translated in domestic laws. Main characteristics of ethics and data protection in studies using biomarkers in the field of environmental health are summarized and current discussions on related questions and bottlenecks highlighted. In the current regulatory context, dominated by the protection of the individual study participant, difficulties are reported due to the different interpretation and implementation of the regulations of concern within and across borders. Advancement of consistency and compatibility is recommended and efforts are ongoing. An increasing demand for secondary use of data and samples poses additional challenges in finding a right balance between the individual rights of the study participants on the one hand and the common interest of, and potential benefit for the public or community at large on the other. Ethics committees could play a key role in assessing problems originating from the sometimes competing needs at individual and societal level. Building trust in science amongst (potential) study participants and within the community allows the inclusion of arguments from the societal perspective. This requires increased attention for respectful communication efforts. Striving for public participation in decision making processes may promote policy relevant research and the related translation of study results into action. PMID- 23660230 TI - Differential regulation of BDNF, synaptic plasticity and sprouting in the hippocampal mossy fiber pathway of male and female rats. AB - Many studies have described potent effects of BDNF, 17beta-estradiol or androgen on hippocampal synapses and their plasticity. Far less information is available about the interactions between 17beta-estradiol and BDNF in hippocampus, or interactions between androgen and BDNF in hippocampus. Here we review the regulation of BDNF in the mossy fiber pathway, a critical part of hippocampal circuitry. We discuss the emerging view that 17beta-estradiol upregulates mossy fiber BDNF synthesis in the adult female rat, while testosterone exerts a tonic suppression of mossy fiber BDNF levels in the adult male rat. The consequences are interesting to consider: in females, increased excitability associated with high levels of BDNF in mossy fibers could improve normal functions of area CA3, such as the ability to perform pattern completion. However, memory retrieval may lead to anxiety if stressful events are recalled. Therefore, the actions of 17beta-estradiol on the mossy fiber pathway in females may provide a potential explanation for the greater incidence of anxiety-related disorders and post traumatic stress syndrome (PTSD) in women relative to men. In males, suppression of BDNF-dependent plasticity in the mossy fibers may be protective, but at the 'price' of reduced synaptic plasticity in CA3. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'. PMID- 23660232 TI - Discovering metric temporal constraint networks on temporal databases. AB - OBJECTIVE: In this paper, we propose the ASTPminer algorithm for mining collections of time-stamped sequences to discover frequent temporal patterns, as represented in the simple temporal problem (STP) formalism: a representation of temporal knowledge as a set of event types and a set of metric temporal constraints among them. To focus the mining process, some initial knowledge can be provided by the user, also expressed as an STP, that acts as a seed pattern for the searching procedure. In this manner, the mining algorithm will search for those frequent temporal patterns consistent with the initial knowledge. BACKGROUND: Health organisations demand, for multiple areas of activity, new computational tools that will obtain new knowledge from huge collections of data. Temporal data mining has arisen as an active research field that provides new algorithms for discovering new temporal knowledge. An important point in defining different proposals is the expressiveness of the resulting temporal knowledge, which is commonly found in the bibliography in a qualitative form. METHODOLOGY: ASTPminer develops an Apriori-like strategy in an iterative algorithm where, as a result of each iteration i, a set of frequent temporal patterns of size i is found that incorporates three distinctive mechanisms: (1) use of a clustering procedure over distributions of temporal distances between events to recognise similar occurrences as temporal patterns; (2) consistency checking of every combination of temporal patterns, which ensures the soundness of the resultant patterns; and (3) use of seed patterns to allow the user to drive the mining process. RESULTS: To validate our proposal, several experiments were conducted over a database of time-stamped sequences obtained from polysomnography tests in patients with sleep apnea-hypopnea syndrome. ASTPminer was able to extract well known temporal patterns corresponding to different manifestations of the syndrome. Furthermore, the use of seed patterns resulted in a reduction in the size of the search space, which reduced the number of possible patterns from 2.1*107 to 1219 and reduced the number of frequent patterns found from 1167 to 340, thereby increasing the efficiency of the mining algorithm. CONCLUSIONS: A temporal data mining technique for discovering frequent temporal patterns in collections of time-stamped event sequences is presented. The resulting patterns describe different and distinguishable temporal arrangements among sets of event types in terms of repetitive appearance and similarity of the dispositions between the same events. ASTPminer allows users to participate in the mining process by introducing domain knowledge in the form of a temporal pattern using the STP formalism. This knowledge constrains the search to patterns consistent with the provided pattern and improves the performance of the procedure. PMID- 23660229 TI - The use of the reinstatement model to study relapse to palatable food seeking during dieting. AB - Excessive consumption of unhealthy foods is a major public health problem. While many people attempt to control their food intake through dieting, many relapse to unhealthy eating habits within a few months. We have begun to study this clinical condition in rats by adapting the reinstatement model, which has been used extensively to study relapse to drug seeking. In our adaptation of the relapse model, reinstatement of palatable food seeking by exposure to food-pellet priming, food-associated cues, or stress is assessed in food-restricted (to mimic dieting) rats after operant food-pellet self-administration training and subsequent extinction of the food-reinforced responding. In this review, we first outline the clinical problem and discuss a recent study in which we assessed the predictive validity of the reinstatement model for studying relapse to food seeking during dieting by using the anorexigenic drug fenfluramine. Next, we summarize results from our initial studies on the role of several stress- and feeding-related peptides (corticotropin-releasing factor, hypocretin, melanin concentrating hormone, peptide YY3-36) in reinstatement of palatable food seeking. We then present results from our studies on the role of dopamine and medial prefrontal cortex in stress-induced reinstatement of food seeking. We conclude by discussing potential clinical implications. We offer two main conclusions: (1) the food reinstatement model is a simple, reliable, and valid model to study mechanisms of relapse to palatable food seeking during dieting, and to identify medications to prevent this relapse; (2) mechanisms of relapse to food seeking are often dissociable from mechanisms of ongoing food intake. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23660233 TI - Quantitative imaging of subcellular metabolism with stable isotopes and multi isotope imaging mass spectrometry. AB - Multi-isotope imaging mass spectrometry (MIMS) is the quantitative imaging of stable isotope labels in cells with a new type of secondary ion mass spectrometer (NanoSIMS). The power of the methodology is attributable to (i) the immense advantage of using non-toxic stable isotope labels, (ii) high resolution imaging that approaches the resolution of usual transmission electron microscopy and (iii) the precise quantification of label down to 1 part-per-million and spanning several orders of magnitude. Here we review the basic elements of MIMS and describe new applications of MIMS to the quantitative study of metabolic processes including protein and nucleic acid synthesis in model organisms ranging from microbes to humans. PMID- 23660235 TI - Persulfate injection into a gasoline source zone. AB - One pore volume of unactivated sodium persulfate was delivered into an emplaced gasoline residual source zone at CFB Borden. Concentrations of inorganic species (S2O8(2-), SO4(2-), Na(+), dissolved inorganic carbon (DIC)) and selected gasoline compounds (benzene, toluene, ethylbenzene, xylenes, trimethylbenzenes and naphthalene) were monitored across a transect equipped with 90 multilevel sampling points for >10months post-injection. Mass loading (M) of compounds constructed from the transect data was used for assessment purposes. Breakthrough of inorganic species was observed when the injection slug crossed the monitoring transect. An increase in [Formula: see text] indicated persulfate consumption during oxidation of gasoline compounds or degradation due to the interaction with aquifer materials. MDIC increased by >100% suggesting some mineralization of gasoline compounds during treatment. Mass loading for all the monitored gasoline compounds reduced by 46 to 86% as the inorganic slug crossed the monitoring transect. The cumulative mass discharge across the monitoring transect was 19 to 58% lower than that expected without persulfate injection. After the inorganic injection slug was flushed from the source zone a partial rebound (40 to 80% of baseline levels) of mass discharge of the monitored gasoline compounds was observed. The ensemble of data collected provides insight into the fate and transport of the injected persulfate solution, and the accompanying treatment of a gasoline the source zone. PMID- 23660236 TI - "We remain very much the second sex": the constructions of prostate cancer in popular news magazines, 2000-2010. AB - Informed by social constructionism, biomedicalization, and a feminist framework, a discourse analysis was performed on 31 popular news articles published in North America between 2000 and 2010. The magazines construct prostate cancer in a gendered manner. Its construction is rooted in themes that are related to discussions of biology, prostate cancer as a heterosexual problem, the responsibilization of health and masculinity. Through these constructions, the popular news articles reinforce dominant ideals and performances of hegemonic masculinity and male sexuality, traditional femininity, and heteronormativity. While reinforcing such ideals, the prevention, treatment, and knowledge of prostate cancer is constructed as the responsibility of individual men. This study reveals that the articles favor discussions of heteronormativity and hegemonic masculinity over racism, rendering health inequalities silent. PMID- 23660234 TI - Making connections in the inner ear: recent insights into the development of spiral ganglion neurons and their connectivity with sensory hair cells. AB - In mammals, auditory information is processed by the hair cells (HCs) located in the cochlea and then rapidly transmitted to the CNS via a specialized cluster of bipolar afferent connections known as the spiral ganglion neurons (SGNs). Although many anatomical aspects of SGNs are well described, the molecular and cellular mechanisms underlying their genesis, how they are precisely arranged along the cochlear duct, and the guidance mechanisms that promote the innervation of their hair cell targets are only now being understood. Building upon foundational studies of neurogenesis and neurotrophins, we review here new concepts and technologies that are helping to enrich our understanding of the development of the nervous system within the inner ear. PMID- 23660238 TI - Jak2V617F myeloproliferative neoplasm stem cells and interferon-alpha. PMID- 23660237 TI - Multiplex newborn screening for Pompe, Fabry, Hunter, Gaucher, and Hurler diseases using a digital microfluidic platform. AB - PURPOSE: New therapies for lysosomal storage diseases (LSDs) have generated interest in screening newborns for these conditions. We present performance validation data on a digital microfluidic platform that performs multiplex enzymatic assays for Pompe, Fabry, Hunter, Gaucher, and Hurler diseases. METHODS: We developed an investigational disposable digital microfluidic cartridge that uses a single dried blood spot (DBS) punch for performing a 5-plex fluorometric enzymatic assay on up to 44 DBS samples. Precision and linearity of the assays were determined by analyzing quality control DBS samples; clinical performance was determined by analyzing 600 presumed normal and known affected samples (12 for Pompe, 7 for Fabry and 10 each for Hunter, Gaucher and Hurler). RESULTS: Overall coefficient of variation (CV) values between cartridges, days, instruments, and operators ranged from 2 to 21%; linearity correlation coefficients were >=0.98 for all assays. The multiplex enzymatic assay performed from a single DBS punch was able to discriminate presumed normal from known affected samples for 5 LSDs. CONCLUSIONS: Digital microfluidic technology shows potential for rapid, high-throughput screening for 5 LSDs in a newborn screening laboratory environment. Sample preparation to enzymatic activity on each cartridge is less than 3h. PMID- 23660239 TI - Emotional intelligence: an admission criterion alternative to cumulative grade point averages for prelicensure students. AB - BACKGROUND: Predicting potential student success is of great interest to nursing educators and academic administrators alike. Cumulative grade point average (CGPA) has traditionally been used to screen nursing program candidates, but CGPA itself has shown to have no statistically significant predictive value and may in fact screen out individuals who possess social intelligence attributes that are essential for success in nursing practice. The purpose of this study is to determine if students whose emotional intelligence characteristics meet or exceed those of successful staff nurses are more likely to be successful in a baccalaureate nursing program. METHODS: A descriptive, correlational design was used to compare the emotional intelligence attributes of 116 potential nursing students and 42 successful staff nurses using the Emotional Quotient Inventory (EQ-i). RESULTS: Nursing students who remained in the nursing program were found to have significantly higher levels of total emotional intelligence, interpersonal capacity, and stress tolerance. Students who dropped from the nursing program were not significantly different from successful staff nurses in terms of emotional intelligence. CONCLUSION: Emotional intelligence presents a compelling adjunct to current selection criteria for nursing students. However, the lack of research prevents widespread adoption of this criterion. This study suggests that students with higher levels of emotional intelligence, particularly intrapersonal capacity and stress tolerance, are more likely to be successful in a baccalaureate nursing program than students with lower levels. Further research is needed to determine the usefulness of EI as a predictor of student success in nursing programs. PMID- 23660240 TI - Korean nursing students' intention to migrate abroad. AB - BACKGROUND: Migration of Korean nurses has continued with changing patterns and reasons. However, detailed studies of migration among Korean nursing students are limited. OBJECTIVES: This study examined the intention, reasons, and preferences of migration among Korean nursing students. This study also identified priorities and barriers to the decision of nursing students to migrate and work abroad. DESIGN: A descriptive study using a questionnaire was used for this study. PARTICIPANTS AND SETTINGS: A total of 717 nursing students from four BSN programs and three diploma programs at nursing schools in D city and K province of South Korea were included in the analysis. RESULTS: According to the results, 69.8% of respondents intended to migrate abroad, if possible, or absolutely in the future. The score for females who answered "yes, if possible" regarding the intention to migrate was significantly higher, compared to males. More than 64% of respondents eventually want to return to Korea after migration. The two most common reasons for migration were economic reason (salary) (29.7%) and "professional development (28.2%)". Half of all respondents preferred the US as the destination country of migration (50.5%). "Working condition" was the most prevalent reason for the decision regarding the destination and the place to work. More than 71% of respondents selected "the lack of language proficiency" as a barrier to migration. CONCLUSIONS: Economic reason was not as strong as in the past to explain migration of Korean nursing students. Most Korean nursing students want to return back with professional development and higher degree. Even permanent migration and return migration of nurses are an inevitable part of globalization, positive and negative aspects of migration between donor as well as destination countries should be investigated. PMID- 23660241 TI - Evaluation of nurses' knowledge and understanding of obstacles encountered when administering resuscitation medications. AB - AIM: The aim of the study was to develop and validate an instrument to evaluate nurses' knowledge and to understand the obstacles that they encounter when administering resuscitation medications. BACKGROUND: Insufficient knowledge is a major factor in nurses' drug administration errors. Resuscitation involves situations in which doctors issue oral orders, and is inherently highly stressful. Sufficient knowledge is vital for nurses if they are to respond quickly and accurately when administering resuscitation medications. METHODS: A cross-sectional study was conducted. A questionnaire (20 true-false questions) developed from literature and expert input, and validated by subject experts and one pilot study, was used to evaluate nurses' knowledge of resuscitation medications. Stratified sampling and descriptive statistics were applied. RESULTS: A total of 188 nurses participated. The overall correct answer rate was 70.5% and the greater the nurse's work experience the higher the score. Only 8% of nurses considered themselves to have sufficient knowledge and 73.9% hoped to gain more training about resuscitation medications. The leading obstacle reported was "interruption of the drug administration procedure on resuscitation" (62.8%). Seventeen out of 20 questions achieved a discriminatory power of over 0.36, indicating good to excellent questions. In the study, a total of 16 resuscitation medication errors were reported by the participants, in which the errors involved atropine (five cases), epinephrine (three cases) and others (eight cases). The errors mainly involved misinterpretation of orders, insufficient knowledge and confusing certain drugs for other look-alike drugs. CONCLUSION: Evidence-based results strongly suggest that nurses have insufficient knowledge and could benefit from longer working experience and additional training about resuscitation medications. Further research to validate the instrument is needed and the education of nurses regarding resuscitation medications is recommended. PMID- 23660243 TI - Alcohol problems as a signal for sensitivity to nicotine dependence and future smoking. AB - BACKGROUND: Alcohol use is a well-documented risk factor for the emergence of chronic smoking behavior. Very little is known, however, about the mediating pathways through which alcohol and/or alcohol-related problems influence future smoking. METHODS: Data were drawn from the longitudinal Social and Emotional Contexts of Adolescent Smoking Patterns Study (SECASPS). Adolescents who had smoked under 100 cigarettes in their lifetime (n=898; experimenters) and adolescents who had smoked over 100 cigarettes, but fewer than 5 cigarettes per day (n=152: current smokers) were examined separately (grouping variable). Path analysis was performed to investigate the association between alcohol related problems at baseline (primary predictor) and smoking regularity at the 48 month follow-up (primary outcome), both directly and through mediating variables of smoking quantity and frequency, and nicotine dependence (averaged across these measures at 6-, 15-, and 24-month assessment waves). RESULTS: Among experimenters, after controlling for smoking and alcohol use, the association between alcohol-related problems at baseline and smoking frequency 48 months later was fully mediated by nicotine dependence symptoms. Among current smokers, only past smoking behavior was associated with 48-month smoking frequency. CONCLUSIONS: Alcohol-related problems are a risk factor for future smoking among novice adolescent smokers above and beyond drinking or smoking per se. By signaling sensitivity to nicotine dependence symptoms, alcohol related problems represent an easily measureable risk factor that can be used to identify and intervene with adolescents before more chronic smoking behaviors emerge. PMID- 23660245 TI - ent-Atisane and ent-kaurane diterpenoids from Isodon rosthornii. AB - A new ent-atisanoid (1) and three new ent-kauranoids (2-4) belonging to different types, along with four known compounds were isolated from Isodon rosthornii. Their structures were established by means of extensive spectroscopic analysis. The absolute configuration of 1 was further determined by X-ray diffraction. Compounds 1 and 5 are the first example of atisane-type diterpenoid from this plant. PMID- 23660244 TI - Chemical constituents of Thai propolis. AB - Phytochemical investigation on the constituents of Thai propolis led the isolation of a new phenylallylflavanone, (7"S)-8-[1-(4'-hydroxy-3' methoxyphenyl)prop-2-en-1-yl]-(2S)-pinocembrin (1) and (E)-cinnamyl-(E) cinnamylidenate (2) from methanolic extract of Thai propolis. Their structures were determined on the basis of extensive NMR spectroscopic analysis. In addition to this, 19 compounds (3-21) belonging to flavonoids and phenolic esters were isolated and identified. PMID- 23660242 TI - Validity of the Adult ADHD Self-Report Scale (ASRS) as a screener for adult ADHD in treatment seeking substance use disorder patients. AB - BACKGROUND: To detect attention deficit hyperactivity disorder (ADHD) in treatment seeking substance use disorders (SUD) patients, a valid screening instrument is needed. OBJECTIVES: To test the performance of the Adult ADHD Self Report Scale V 1.1(ASRS) for adult ADHD in an international sample of treatment seeking SUD patients for DSM-IV-TR; for the proposed DSM-5 criteria; in different subpopulations, at intake and 1-2 weeks after intake; using different scoring algorithms; and different externalizing disorders as external criterion (including adult ADHD, bipolar disorder, antisocial and borderline personality disorder). METHODS: In 1138 treatment seeking SUD subjects, ASRS performance was determined using diagnoses based on Conner's Adult ADHD Diagnostic Interview for DSM-IV (CAADID) as gold standard. RESULTS: The prevalence of adult ADHD was 13.0% (95% CI: 11.0-15.0%). The overall positive predictive value (PPV) of the ASRS was 0.26 (95% CI: 0.22-0.30), the negative predictive value (NPV) was 0.97 (95% CI: 0.96-0.98). The sensitivity (0.84, 95% CI: 0.76-0.88) and specificity (0.66, 95% CI: 0.63-0.69) measured at admission were similar to the sensitivity (0.88, 95% CI: 0.83-0.93) and specificity (0.67, 95% CI: 0.64-0.70) measured 2 weeks after admission. Sensitivity was similar, but specificity was significantly better in patients with alcohol compared to (illicit) drugs as the primary substance of abuse (0.76 vs. 0.56). ASRS was not a good screener for externalizing disorders other than ADHD. CONCLUSIONS: The ASRS is a sensitive screener for identifying possible ADHD cases with very few missed cases among those screening negative in this population. PMID- 23660246 TI - Isolation of anti-tumor compounds from the stem bark of Zanthoxylum ailanthoides Sieb. & Zucc. by silica gel column and counter-current chromatography. AB - Silica gel column chromatography combined with high performance counter-current chromatography (HPCCC) was employed for the separation of potential anti-tumor compounds from a petroleum ether fraction of a crude extract of Zanthoxylum ailanthoides Sieb. & Zucc. This traditional Chinese medicine was recently found to display high inhibitory activity against A-549 human cancer cells in vitro and Lewis lung cancer in vivo. A 75% aqueous ethanol extract of the stem bark of Z. ailanthoides was fractionated with petroleum ether, ethyl acetate and n-butanol. In this paper, the petroleum ether fraction was pre-separated by silica gel column chromatography with a petroleum ether-ethyl acetate gradient. Two fractions were further separated and purified by HPCCC using n-hexane-ethyl acetate-methanol-water (3:1:2:1, v/v) and petroleum-ethyl acetate-methanol-water (8:6:7:7, v/v). Finally, coumarins and lignans including luvangetin, xanthyletin, hinokinin and asarinin were isolated and identified by MS, (1)H and (13)C NMR. In total, 56mg of xanthyletin (1), 140mg of hinokinin (2), 850mg of luvangetin (3) and 74mg of asarinin (4) were obtained from approximately 50g of petroleum ether extract, in 96.0%, 94.0%, 99.0% and 94.0% purity, respectively, as determined by HPLC. The separation method proved to be efficient, especially for those minor components. PMID- 23660247 TI - A new LC-MS/MS method for the clinical determination of reduced and oxidized glutathione from whole blood. AB - Reduced levels of glutathione (gamma-glutamylcysteinylglycine, GSH) and the ratio of GSH to glutathione disulfide (GSSG) can serve as important indicators of oxidative stress and disease risk. Measured concentrations of GSH and GSSG vary widely between laboratories, largely due to the instability of GSH during sample handling and variables arising from different analytical methods. We have developed a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for measuring whole blood GSH and GSSG that minimizes preanalytic and analytic variability, reliably eliminates interference from ion suppression, and can easily be implemented in clinical laboratories. Samples were deproteinized with sulfosalicylic acid (SSA) and derivatized with N ethylmaleimide (NEM) in a single preparative step, and the resulting supernatants combined with stable-isotope internal standards (GSH-(13)C, (15)N-NEM and GSSG (13)C,(15)N), subjected to chromatographic separation using a Hypercarb column, and analyzed by MS/MS in the positive-ion mode. Results showed excellent linearity for both GSH and GSSG over the ranges of physiologic normal, with inter and intra-assay CV's of 3.1-4.3% and accuracy between 95% and 101%. The lower limits of detection (LLOD) were 0.4MUM for GSH and 0.1MUM for GSSG and the lower limits of quantitation (LLOQ) were 1.5MUM for GSH and 0.1MUM for GSSG. Derivatized samples are stable for at least 3 years when stored at -80 degrees C, and underivatized samples for at least 24h at either 4 degrees C or room temperature. Reference intervals were determined for 59 control samples, and were (mean+/-SD): GSH 900+/-140MUM; GSSG 1.17+/-0.43MUM; GSH/GSSG 880+/-370. PMID- 23660248 TI - A rapid and sensitive LC-MS/MS assay for the determination of berbamine in rat plasma with application to preclinical pharmacokinetic study. AB - Berbamine (BBM), a natural compound from Chinese herb Berberis amurensis, has recently received a great deal of attention due to its anti-leukemia activity. In this study, a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of BBM in rat plasma was developed for the first time. Caffeine was used as an internal standard. Chromatographic separation was performed on an ODS column with gradient elution using methanol-1% formic acid as mobile phase at a flow rate of 0.3mL/min. Quantification was through tandem mass spectrometry with positive electrospray ionization (ESI) and multiple reaction monitoring (MRM) at m/z 305.2->566.3 and 195.1->138.0 for BBM and IS, respectively. The lower limit of quantification was 1ng/mL with a linear range of 1-1000ng/mL. The intra- and inter-day assay precision (RSD) ranged from 2.0-6.4% to 2.5-5.5%, respectively, and the intra- and inter-day assay accuracy (RE) was between -5.8-6.0% and -6.5-1.4%, respectively. The validated method was successfully applied to the preclinical pharmacokinetic studies of BBM in rats. The elimination half-lives (t1/2) were (472.4+/-66.1), (509.6+/-97.0) and (486.2+/-94.6) min after single intravenous administration of 2, 4 and 8mg/kg BBM, respectively. The area under the plasma concentration versus time curve (AUC0-24h) and initial plasma concentration (C0) were linearly related to dose. PMID- 23660249 TI - Mechanical modulation of nascent stem cell lineage commitment in tissue engineering scaffolds. AB - Taking inspiration from tissue morphogenesis in utero, this study tests the concept of using tissue engineering scaffolds as delivery devices to modulate emergent structure-function relationships at early stages of tissue genesis. We report on the use of a combined computational fluid dynamics (CFD) modeling, advanced manufacturing methods, and experimental fluid mechanics (micro-piv and strain mapping) for the prospective design of tissue engineering scaffold geometries that deliver spatially resolved mechanical cues to stem cells seeded within. When subjected to a constant magnitude global flow regime, the local scaffold geometry dictates the magnitudes of mechanical stresses and strains experienced by a given cell, and in a spatially resolved fashion, similar to patterning during morphogenesis. In addition, early markers of mesenchymal stem cell lineage commitment relate significantly to the local mechanical environment of the cell. Finally, by plotting the range of stress-strain states for all data corresponding to nascent cell lineage commitment (95% CI), we begin to "map the mechanome", defining stress-strain states most conducive to targeted cell fates. In sum, we provide a library of reference mechanical cues that can be delivered to cells seeded on tissue engineering scaffolds to guide target tissue phenotypes in a temporally and spatially resolved manner. Knowledge of these effects allows for prospective scaffold design optimization using virtual models prior to prototyping and clinical implementation. Finally, this approach enables the development of next generation scaffolds cum delivery devices for genesis of complex tissues with heterogenous properties, e.g., organs, joints or interface tissues such as growth plates. PMID- 23660250 TI - The molecular mechanism of mediation of adsorbed serum proteins to endothelial cells adhesion and growth on biomaterials. AB - To explore molecular mechanism of mediation of adsorbed proteins to cell adhesion and growth on biomaterials, this study examined endothelial cell adhesion, morphology and viability on bare and titanium nitride (TiN) coated nickel titanium (NiTi) alloys and chitosan film firstly, and then identified the type and amount of serum proteins adsorbed on the three surfaces by proteomic technology. Subsequently, the mediation role of the identified proteins to cell adhesion and growth was investigated with bioinformatics analyses, and further confirmed by a series of cellular and molecular biological experiments. Results showed that the type and amount of adsorbed serum proteins associated with cell adhesion and growth was obviously higher on the alloys than on the chitosan film, and these proteins mediated endothelial cell adhesion and growth on the alloys via four ways. First, proteins such as adiponectin in the adsorbed protein layer bound with cell surface receptors to generate signal transduction, which activated cell surface integrins through increasing intracellular calcium level. Another way, thrombospondin 1 in the adsorbed protein layer promoted TGF-beta signaling pathway activation and enhanced integrins expression. The third, RGD sequence containing proteins such as fibronectin 1, vitronectin and thrombospondin 1 in the adsorbed protein layer bound with activated integrins to activate focal adhesion pathway, increased focal adhesion formation and actin cytoskeleton organization and mediated cell adhesion and spreading. In addition, the activated focal adhesion pathway promoted the expression of cell growth related genes and resulted in cell proliferation. The fourth route, coagulation factor II (F2) and fibronectin 1 in the adsorbed protein layer bound with cell surface F2 receptor and integrin, activated regulation of actin cytoskeleton pathway and regulated actin cytoskeleton organization. PMID- 23660253 TI - [Promoting recognition of sleep disorders in the elderly in China]. PMID- 23660252 TI - An ex-vivo multiple sclerosis model of inflammatory demyelination using hyperbranched polymer. AB - Multiple sclerosis (MS) is characterized by the presence of inflammatory demyelinating foci throughout the brain and spinal cord, accompanied by axonal and neuronal damage. Although inflammatory processes are thought to underlie the pathological changes, the individual mediators of this damage are unclear. In order to study the role of pro-inflammatory cytokines in demyelination in the central nervous system, we have utilized a hyperbranched poly(2-dimethyl aminoethylmethacrylate) based non-viral gene transfection system to establish an inflammatory demyelinating model of MS in an ex-vivo environment. The synthesized non-viral gene transfection system was optimized for efficient transfection with minimal cytotoxicity. Organotypic brain slices were then successfully transfected with the TNF or IFNgamma genes. TNF and IFNgamma expression and release in cerebellar slices via non-viral gene delivery approach resulted in inflammation mediated myelin loss, thus making it a promising ex-vivo approach for studying the underlying mechanisms of demyelination in myelin-related diseases such as MS. PMID- 23660251 TI - Enhanced function of immuno-isolated islets in diabetes therapy by co encapsulation with an anti-inflammatory drug. AB - Immuno-isolation of islets has the potential to enable the replacement of pancreatic function in diabetic patients. However, host response to the encapsulated islets frequently leads to fibrotic overgrowth with subsequent impairment of the transplanted grafts. Here, we identified and incorporated anti inflammatory agents into islet-containing microcapsules to address this challenge. In vivo subcutaneous screening of 16 small molecule anti-inflammatory drugs was performed to identify promising compounds that could minimize the formation of fibrotic cell layers. Using parallel non-invasive fluorescent and bioluminescent imaging, we identified dexamethasone and curcumin as the most effective drugs in inhibiting the activities of inflammatory proteases and reactive oxygen species in the host response to subcutaneously injected biomaterials. Next, we demonstrated that co-encapsulating curcumin with pancreatic rat islets in alginate microcapsules reduced fibrotic overgrowth and improved glycemic control in a mouse model of chemically-induced type I diabetes. These results showed that localized administration of anti-inflammatory drug can improve the longevity of encapsulated islets and may facilitate the translation of this technology toward a long-term cure for type I diabetes. PMID- 23660254 TI - [New approaches for the management of sleep disordered breathing]. PMID- 23660255 TI - [Continuous positive airway pressure titration in the treatment of obstructive sleep apnea]. PMID- 23660256 TI - [Impact of chronic intermittent hypoxia upon rat liver lipid metabolism and interventional effect of Tempol]. AB - OBJECTIVE: To explore the impact of chronic intermittent hypoxia (CIH) upon rat liver lipid metabolism and effect of anti-oxidant Tempol. METHODS: Male Wistar rats (n = 80) were randomly divided into intermittent hypoxia group (10, 20, 30, 40 times/h), intermittent hypoxia Tempol treatment group, intermittent hypoxia normal saline treatment group, intermittent air mimic group (IA) and blank control group (CG). Sections of liver were stained with hematoxylin and eosin. Serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured. Levels of liver homogenate triglyceride (TG), total cholesterol (TC), free fatty acids (FFA) and serum TG, TC, adiponectin (ADP) were measured. RESULTS: Liver histology: IH group exhibited hepatocellular swelling, hyperchromatosis, disrupted hepatocellular membrane. With the increase of frequency, there were local necrosis and infiltration of inflammatory cells. But no steatosis was seen. Tempol early treatment and IA groups exhibited no hepatocellular swelling or inflammatory cell infiltration. The activities of ALT and AST increased along with the increased frequency in IH group (all P < 0.01). The levels of ALT and AST in IH group ((48.6 +/- 3.6), (25.4 +/- 2.6) U/L) were higher than those in IA group ((20.3 +/- 3.1), (18.7 +/- 1.3) U/L) and CG group ((17.5 +/- 2.4), (18.8 +/- 1.3) U/L) (all P < 0.01). It decreased in Tempol treatment group, and more obviously when early intervention was applied (all P < 0.01). Liver homogenate TG, TC and FFA had no difference among IH, IA and CG groups (all P > 0.05), and no difference in different frequencies in IH group (all P > 0.05). The levels of serum TG, TC in IH groups were higher than those in IA and CG groups while ADP was lower (all P < 0.01). It changed more obviously in different frequencies in IH group (all P < 0.01). In Tempol treatment group, serum TG, TC decreased while ADP increased and changed more obviously when early intervention was applied (all P < 0.01). CONCLUSIONS: CIH causes the morphologic changes of liver and the elevations of ALT and AST, but results not in lipid deposition in liver cells. Anti-oxidation of Tempol can block intermittent hypoxia associated with liver injury. PMID- 23660257 TI - [Neural respiratory drive and nocturnal hypoventilation in patients with chronic obstructive pulmonary disease]. AB - OBJECTIVE: To explore the effects of neural respiratory drive on ventilation in patients with chronic obstructive pulmonary disease (COPD) during sleep. METHODS: Diaphragm electromyogram (EMG) from a multipair esophageal electrodes and airflow derived from pneumotachography were recorded during overnight polysomnography in 13 patients with stable COPD recruited from outpatient clinic of First Affiliated Hospital of Guangzhou Medical College from May 2010 to May 2011. Changes in diaphragm EMG and ventilation during wakefulness and different sleep stages were observed. RESULTS: Diaphragm EMG decreased by 26% in non-rapid eye movement sleep (NREM) stage and 39% in rapid eye movement (REM) as compared with wakefulness. Coinciding with change in diaphragm EMG, ventilation (VE) (ml*min(-1)*kg(-1)) significantly decreased from wakefulness (156 +/- 53) ml*min(-1)*kg(-1) to steady NREM stage (112 +/- 35) ml*min(-1)*kg(-1) (P < 0.05) and further decreased from NREM stage to REM stage (95 +/- 27) ml*min(-1)*kg(-1) (P < 0.05). Oxygen saturation also decreased significantly from 97.1% +/- 1.8% in wakefulness to REM stage (94.0% +/- 3.9%) (P < 0.01). CONCLUSION: Reduced neural respiratory drive contributes to nocturnal hypoventilation in COPD patients. PMID- 23660258 TI - [Utility of portable monitoring device with airflow, oxygen saturation and respiratory effort in the diagnosis of sleep apnea hypopnea syndrome]. AB - OBJECTIVE: To validate the values of monitoring airflow, oxygen saturation and respiratory effort in the diagnosis of sleep apnea-hypopnea syndrome (SAHS). METHODS: A total of 70 subjects with suspected SAHS underwent the tests of polysomnography (PSG) and portable monitoring device (PMD) separately at our sleep lab. The portable monitoring device recorded nasal airflow, oxygen saturation and respiratory effort. Apnea-hypopnea index (AHI) or respiratory disturbed index (RDI), lowest oxygen saturation (LSaO2), oxygen desaturation index (ODI4) and percentage of different types of sleep breathing events (central/obstructive/mixed hypopnea) accounting for the total numbers of sleep disordered breathing were also analyzed. The data of AHI and ODI4 showed skew distribution undergoing log transformation to approximate to normal distribution. Pair t test was used for the comparisons of different parameters. The agreement between two methods was analyzed by Bland-Altman plot. RESULTS: Fifty-eight subjects were diagnosed as SAHS with an AHI (RDI) over 5 on PSG. The sensitivity and specificity of portable monitoring device were 94.8% and 75.0% respectively. The mean AHI derived from PSG and RDI derived from PMD were (27 +/- 25) and (29 +/- 27) times per hour respectively and those after log transformation were (1.2 +/- 0.5) and (1. 2 +/- 0.5) times per hour (P = 0.411). The mean ODI4 derived from PSG and PMD were (23 +/- 25) and (21 +/- 24) and those after log transformation (0.9 +/- 0.7) and (1.1 +/- 0.5) times per hour respectively (P = 0.042). The mean values of LSaO2 were 79% +/- 13% and 79% +/- 12% respectively (P = 0.550). No significant differences existed between AHI derived from PSG and RDI derived from PMD. Bland-Altman plot also showed a high agreement between AHI derived from PSG and RDI derived from PMD. PMD could also identify major part of different events so as to aid clinical decision-making. CONCLUSION: Portable monitoring device recording airflow, oxygen saturation and respiratory effort shows a great agreement with PSG with regards to AHI (RDI) and the identification of different types of respiratory events. PMID- 23660259 TI - [Prevalence of central sleep apnea in different age groups of children with sleep apnea-hypopnea]. AB - OBJECTIVE: To explore the prevalence of central sleep apnea in different age groups of children with sleep apnea-hypopnea (SAH). METHODS: A total of 431 children with SAH diagnosed by overnight polysomnography at our Sleep Center were retrospectively studied. They were divided into 3 groups based on their ages: toddler group (1 - < 3 years old), preschool group (3 - < 6 years old) and school group (6 - < 13 years old). The relationship between age and different types of apnea-hyponea index (AHI) was analyzed. And the prevalence of central sleep apnea and sleep structure were compared between the groups. RESULTS: A negative correlation existed between age and central sleep apnea index (r = -0.322, P < 0.01). However, there was no correlation between age and obstructive apnea index (P > 0.05). AHI was similar in different age groups, but the medians of central sleep apnea index for toddler, preschool and school groups were 2.35, 1.50 and 0.90 events/h respectively (all P < 0.01). Sleep structure was similar between the groups (P > 0.05). CONCLUSIONS: Central sleep apnea is common in children with sleep disordered breathing. The younger their ages, a higher prevalence of central sleep apnea. PMID- 23660260 TI - [Pathological effects and clinical significance of eosinophils in autoimmune related hematocytopenia]. AB - OBJECTIVE: To observe the pathological effects induced by eosinophils (EOS) in the process of cellular damage in immune-related hematocytopenia (IRH) and elucidate the immunologic mechanism and clinical significance of EOS. METHODS: Enzyme-linked immunosorbent assay (ELISA) was performed to determine the serum concentrations of interleukins (IL)-2, IL-4, IL-5, IL-6, IL-12 and IL-17 in 117 IRH patients from February 2008 to February 2012 in our hospital. Their quantity, activity, peroxidase (POX) and HLA-DR expression of EOS were observed and analyzed. Immunofluorescent staining was used for detecting anti-human immunoglobulin (IgG) on the surface of hematopoietic cell and the expressions of intercellular adhesion molecule-1 (ICAM-1), Fcgamma receptor II (FcgammaRII), mannose receptor (MR), IL-5 receptor (IL-5R), IL-12, IL-12 receptor (IL-12R), IL 17A and IL-17 A receptor (IL-17RA) on EOS. TdR incorporation method was employed to determine the capability of antigen presentation and IL-17 mRNA expression examined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The serum levels of IL-4, IL-5, IL-6, IL-12 and IL-17 were (170.9 +/- 14.7), (112.9 +/- 8.2), (131.8 +/- 13.8), (339.2 +/- 26.1) and (42.5 +/- 2.2) ng/L in patient group versus (60.3 +/- 11.0), (34.1 +/- 2.2), (91.0 +/- 12.3), (94.0 +/- 3.3) and (20.0 +/- 1.1) ng/L in control group respectively. All incremental percentages of IL-5, IL-12 and IL-17 were 100% (117/117) and they were correlated with disease. Diastrophic EOS could be found in marrow of patient with decreased leucocyte with HLA-B27(+). Hematopoietic cells were adhered, captured and phagocytized actively by activated EOS. Activated EOS showed strongly positive POX while POX of neutrophils attacked by EOS became weakened. Activated EOS could express HLA-DR and played a role in antigen presentation. EOS could secrete cytokine IL-17 through a transcription of IL-17 mRNA. And EOS could also express ICAM-1, FcgammaRII, MR, IL-5R and IL-12, IL-17A, IL-17RA. CONCLUSIONS: Capable of expressing or secreting various cytokines and molecules, EOS have immunological functions of adhering, capturing and phagocytizing pathological hemocytes. It also participates in pathogenic process of IRH. Thus EOS is probably an important immune effector cell in the process of in situ marrow damage. PMID- 23660261 TI - [Robotic internal thoracic artery harvesting and the mid-term follow up of arterial graft patency]. AB - OBJECTIVE: To summarize our experience of robotic internal thoracic artery (ITA) skeletonized harvesting in Asian patients and evaluate the learning curves of robotic ITA harvesting and ITA graft patency. METHODS: A total of 200 patients underwent totally robotic ITA takedown at our department from April 2007 to August 2012. ITA was harvested in a skeletonized fashion and learning curve estimated. Coronary artery bypass grafting was completed in minimally invasive direct coronary artery bypass graft (MIDCAB) or totally endoscopic coronary bypass graft on beating heart (BH-TECAB) manners after robotic ITA harvesting. The coronary angiography or 64-MSCT was performed to evaluate the patency of ITA graft before discharge and at Year 1-5 postoperatively. RESULTS: One patient underwent median sternotomy for severe plural adhesion. Left ITA (LITA, n = 190), right ITA (RITA, n = 5) and double-ITA (n = 4) were harvested. The mean duration of single ITA harvesting was 18-70 (35.8 +/- 10.7) min. A significant learning curve was observed: y (min) = 58.0 - 5.3*ln(x) (r(2) = 0.33, P < 0.01). ITA patency was 98.1% at Year 1 and 97.8% at Year 2 postoperatively respectively. And there was no recurrence of ITA occlusion at Years 3-5. CONCLUSIONS: Robotic ITA takedown is a prerequisite for totally endoscopic coronary bypass graft and can be performed safely and within an acceptable time after overcoming a learning curve. ITA graft patency has comparable outcomes of conventional surgery. PMID- 23660262 TI - [Diagnostic accuracy of adenosine triphosphate stress echocardiography derived coronary flow reserve for detecting significant coronary stenosis]. AB - OBJECTIVE: To assess the diagnostic accuracy of coronary flow reserve measured by transthoracic Doppler echocardiography (TTDE) associated with adenosine triphosphate (ATP) stress for detecting coronary stenosis in patients with chest pain. METHODS: A total of 125 patients scheduled for elective coronary angiography (CAG) due to chest pain were recruited. ATP stress echocardiography were performed to measure CFR in left anterior descending (LAD) by TTDE with 2 days pre-CAG. Coronary flow reserve (CFR) was calculated as peak diastolic velocity during maximum hyperemia (PDV2) divided by baseline (PDV1). According to the coronary angiography results, all patients were divided into group A (stenosis < 50% in LAD, n = 57), group B (stenosis of 50% - 75% in LAD, n = 20) and group C (stenosis > 75% in LAD, n = 48). Then CFR was compared among three groups. The receiver operating characteristic curve (ROC) was used to assess the value of CFR for detecting LAD stenosis. RESULTS: CFR was significantly different among three groups (group A: 3.02 +/- 0.85, group B: 2.49 +/- 0.65, group C: 1.82 +/- 0.56; all P < 0.01). With ROC analysis, CFR < 2.2 was the best cut-off value for diagnosing significant LAD stenosis (area under curve: 0.86 (95% CI 0.80 to 0.93)), with sensitivity of 81%, specificity of 83% and accuracy of 82%; CFR < 2.2 for diagnosing LAD stenosis > 50% (area under curve: 0.81 (95%CI 0.74 - 0.89, P < 0.01)), with a sensitivity of 59%, a specificity of 82% and an accuracy of 70%. CONCLUSIONS: CFR measured by TTDE associated with ATP stress is a valuable tool for screening significant stenosis in patients with chest pain. Its advantages are non-invasiveness, easy availability, safety and inexpensiveness. PMID- 23660263 TI - [Correlation between lipoprotein(a) and fibrinogen in elderly patients with coronary heart disease]. AB - OBJECTIVE: To explore the effects of lipoprotein(a) (Lp(a)) and fibrinogen (Fib) in senior patients with coronary heart disease (CHD) and examine the relationship of Lp(a) and Fib. METHODS: Based upon the results of coronary artery angiography (CAG), 784 subjects aged over 65 years were divided into control (n = 116) group, one-vessel (n = 106) group, two-vessel (n = 120) and three-vessel (n = 442) groups. And the levels of Lp(a) and Fib were measured. RESULTS: (1) With increasing number of involved branches, the level of Lp(a) gradually rose in male group ((0.22 +/- 0.16), (0.28 +/- 0.23), (0.32 +/- 0.19), (0.34 +/- 0.21) g/L; F = 9.22, P < 0.01); (2) whether for males or females, with increasing number of involved branches, the levels of Fib gradually rose in male group ((3.24 +/- 0.82), (3.41 +/- 0.82), (3.45 +/- 0.89), (3.61 +/- 0.90) g/L; F = 3.09, P < 0.05) and in female group ((3.58 +/- 0.97), (3.69 +/- 1.20), (3.77 +/- 0.88), (4.09 +/- 1.05) g/L; F = 4.34, P < 0.01); (3) the level of Lp(a) had a positive correlation with Fib in male group (r = 0.15, P < 0.01); (4) multi-Logistic regression analysis showed that Lp(a) and Fib were influencing factors of CHD (OR = 0.31, 1.32, both P < 0.05). CONCLUSION: There are significant correlations between Lp(a), Fib and the severity of CHD in senior male patients. PMID- 23660265 TI - [Clinical manifestations, therapeutic response to tyrosinase inhibitor and RET gene activating mutation in a patient with multiple endocrine neoplasia 2B]. AB - OBJECTIVE: To explore the clinical manifestations, therapeutic response and RET gene mutation in a patient with multiple endocrine neoplasia 2B (MEN2B) characterized by medullary thyroid carcinoma (MTC), bilateral adrenal pheochromocytoma and multiple mucosal neuromas. METHODS: The clinical features, laboratory data and radiological manifestations of this patient were collected. Genomic DNA was extracted from her peripheral blood leukocytes and her parents. Tenth to sixteenth exons of RET proto-oncogene, including the flanking regions of introns, were amplified by polymerase chain reaction (PCR). And the mutations of RET proto-oncogene were identified by direct sequencing. RESULTS: MEN-2B was diagnosed by the clinical presentations, laboratory tests and radiological findings. Gene analysis confirmed heterozygous mis-sense mutation at codon 918 in exon 16 of RET proto-oncogene in which thymine was replaced by cytosine (ATG >ACG). Her thyroid medullary carcinoma was treated by radical operations and radiotherapy. Tyrosinase inhibitor sorafenib was administered for 2 months and watery diarrhea and cough were alleviated. The drug was withdrawn because of such intolerant side effects as hair loss and painful rashes. She had a survival time of over 14 years with multiple system tumor metastases. CONCLUSIONS: The mutation analysis of RET proto-oncogene confirmed the diagnosis of MEN2B in respect of molecular genetics. For patients with advanced MTC, tyrosinase inhibitors may relieve the symptoms and provide a new therapeutic choice. PMID- 23660264 TI - [Clinical diagnosis and treatment of familial medullary thyroid carcinoma caused by a p.C618Y RET proto-oncogene mutation in a Chinese pedigree]. AB - OBJECTIVE: To explore the clinical characteristics, therapeutic and clinical significance for RET proto-oncogene screening in a pedigree with familial medullary thyroid carcinoma. METHODS: Comprehensive medical history was obtained from 19 members in a 4-generate southern Chinese family. Systemic clinical investigations including biochemical testing, imaging examinations and germline RET screening. RESULTS: RET screening showed heterozygous missense mutations of TGC to TAC at codon 618 on exon 10 in 8 cases (p.C618Y) completely consistent with the clinical manifestations. The clinical data of 7 patients with medullary thyroid carcinoma (MTC) and 2 carriers of asymptomatic RET mutation from were analyzed. Single/bilateral multi-centric MTC with lymph node metastases was confirmed in 6 cases by histopathology and 1 case by clinical examination. There were 1 male and 6 females with an initial mean diagnostic age was 49.6 years (range: 24 - 78). All had palpable neck masses. And the mean maximum diameter of MTC was 2.6 cm (range 1.4 - 4.4). Seven patients underwent thyroidectomy except a 78-year-old female patient: right total and left subtotal thyroidectomy (n = 1), right total thyroidectomy (previous left total thyroidectomy for benign mass) (n = 1) and total thyroidectomy (n = 4) were performed. All procedures were accompanied by at least bilateral level VI lymph node dissection and/or with modified single/bilateral neck dissection. After the first operation, 6 patients still presented a high value of calcitonin: 1 patient died of metastasis 64 months postoperatively; 3 patients underwent reoperation at 6 months after initial operation, the calcitonin levels dropped to normal in 2/3 cases and stayed higher in 1 case; another two cases presented bilateral thyroid gland residua, local lymph node enlargement on imaging examination and elevated levels of calcitonin at 214 and 60 months postoperation respectively. However, 1/2 asymptomatic with elevated pre-operative calcitonin subjects underwent total thyroidectomy and histopathological examination showed bilateral C cell hyperplasia. The other carriers, without surgery, with normal neck images, close monitoring and a 10-month follow-up, still presented undetectable calcitonin. CONCLUSIONS: Based on family survey, integrated RET screening and serum levels of calcitonin facilitate an early diagnosis and normalize surgery to improve the prognosis. For asymptomatic RET mutation carriers, their levels of calcitonin shall guide the individualized regimen of prophylactic thyroidectomy or strict monitoring and follow-ups. PMID- 23660266 TI - [Clinical analysis of 20 cases of synchronous multi-primary esophageal carcinomas]. AB - OBJECTIVE: To explore the clinicopathologic findings, endoscopic features and preoperative diagnostic rates of synchronous multi-primary esophageal carcinomas. METHODS: A total of 602 inpatients were diagnosed as esophageal carcinomas from January 1990 to April 2012. According to Warren's criteria, 20 cases of synchronous multi-primary esophageal carcinomas were enrolled. There were 13 males and 7 females with a mean age of (62 +/- 11) years at the onset of diagnosis. Clinicopathologic features and diagnostic methods were studied retrospectively. RESULTS: There were a total of 45 synchronous multi-primary esophageal carcinomas. Most lesions occurred in middle and lower thoracic esophagus (40 lesions, 88.9%) and were of fungating type (27 lesions, 60.0%) under endoscopy. Histologically the most common type was squamous cell carcinoma (36 lesions, 80.0%). Eleven cases of upper gastro-enterography (n = 15) and 6 cases of endoscopy (n = 11) were miss-diagnosed respectively. CONCLUSIONS: Because of a high rate of missed diagnosis, a clinician should be aware of multi esophageal carcinomas. It is important to perform upper gastro-enterography, abdominal computed tomography and endoscopy conscientiously to improve the diagnosis. PMID- 23660267 TI - [A retrospective study of 22 years endoscopic follow-up in elderly patients with gastrointestinal submucosal tumors]. AB - OBJECTIVE: To observe the occurrence characteristics, dynamic variations and potential risks of smaller gastrointestinal submucosal tumor (SMT) in elderly patients. METHODS: A total of 54 SMT patients were retrospectively recruited from January 1981 to September 2010. There were 51 males (94.4%) and 3 females (5.6%) with an average age of (74 +/- 1) years. During each visit, all the relevant data were collected, including symptoms, number of lesion, lesion location, shape, size (maximum transverse diameter under endoscope or endoscopic ultrasonography (EUS), morphology of mucosa, frequency and duration of follow-ups, treatment and pathological results. And the data were analyzed to examine the characteristics of SMT in elderly patients and their dynamic variations. Further more, according to lesion diameter, they were divided into two groups: a diameter <= 1 cm (n = 36) and a diameter > 1 cm and <= 3 cm (n = 16). Then the change of two groups were observed and compared during the follow-ups. RESULTS: Two cases were not under surveillance after direct surgical resection. The other 52 patients received a follow-up of 22 years. Among them, 5 patients underwent surgical resection for fast-growing tumor and mucosal ulcer. And all their pathologic diagnoses were malignant. Only 1 patient (2.8%) in the diameter <= 1 cm group and 4 in the diameter > 1 cm and <= 3 cm group turned malignant at 6 years. But, among 4 patients, the shortest interval was merely 14 months. Therefore, compared with the diameter > 1 cm group, the diameter <= 1 cm group had a lower rate of malignancy (P < 0.05). CONCLUSIONS: The incidence of smaller SMT (especially diameter <= 1 cm) is high in elderly patients, but the malignant potential remains low. Therefore, for elderly patients whose diameters of SMT are no bigger than 3 cm and without obvious malignancy under endoscope or EUS, we may plan an appropriate surveillance interval based on the size of tumor during a long follow up period. PMID- 23660268 TI - [Comparison of operative techniques in single-incision laparoscopic cholecystectomy: suture-suspension versus three-device method]. AB - OBJECTIVE: To compare the operative techniques of single-incision laparoscopic cholecystectomy (SILC) via suture-suspension versus three-device method. METHODS: Retrospective analysis was performed for a total of 300 patients undergoing umbilical single-incision laparoscopic cholecystectomy from June 2008 to November 2011 at our hospital. The procedures were of suture-suspension (n = 200) and three-device (n = 100). Operative duration, estimated intra-operative blood loss, exposure extent of Calot's triangle, postoperative pain score, hospital stay and complications were compared respectively between two groups. Both groups were matched for age, gender, body mass index (BMI), diagnoses and American Society of Anesthesiology (ASA) class. RESULTS: All procedures were completed by the same surgeon. Comparison between two groups showed insignificant differences in blood loss (mean: (15.6 +/- 9.5) vs (16.8 +/- 7.4) ml; t = 1.266, P = 0.207), postoperative complications (number of case, incision contusion:4 vs 2, P = 1.000;incision hemorrhage:2 vs 2, P = 0.603) and hospitalization duration (mean: (1.6 +/- 0.5) vs (1.6 +/- 0.5) d; t = 0.653, P = 0.514), but significant differences in operative duration (mean:(40.5 +/- 16.0) vs (51.5 +/- 18.0) min; t = 5.381, P = 0.000), postoperative pain (mean: 2.0 +/- 1.7 vs 3.7 +/- 1.6; t = 8.324, P = 0.000) and exposure of Calot's triangle (number of case, 197 vs 68; chi(2) = 60.178, P = 0.000). Thus the suture-suspension method was superior to the three-device counterpart. CONCLUSION: The suture-suspension method of SILC is safe, economic and easy-to-handle in clinical practice. PMID- 23660269 TI - [Effects of methane on proximal colon motility of rats and ion channel mechanisms]. AB - OBJECTIVE: To explore the effects of methane on proximal colon motility and elucidate its ion channel mechanisms. METHODS: The circular muscle and longitudinal muscle strips of proximal colon were isolated from rats. An isometric force transducer and a biology signal collection system were employed to observe the effects of methane on spontaneous contractile activity of muscle strips. The effects of methane on longitudinal muscle strips were observed after pre-treatment of these strips with tetrodotoxin (TTX) or N-nitro-L-arginine methylester (L-NAME). Single cell of colonic smooth muscle was isolated by collagenase and then whole-cell patch clamp technique was used to record voltage dependent potassium current (IKV) and large conductance Ca(2+)-activated K(+) current (IBKca) in the absence or presence of methane. RESULTS: Methane significantly attenuated the contractile amplitude of longitudinal muscle strips (from (1.12 +/- 0.27) to (0.99 +/- 0.31) g, n = 19, P = 0.013) whereas there were no changes in some longitudinal muscle strips (n = 6) in the presence of methane. The inhibitory effect of methane persisted after the pre-treatment of longitudinal muscle strips with TTX or L-NAME. Methane had no effects on the contractile cycle time of longitudinal muscle strips and contractile activity of circular muscle strips. And 3% methane solution significantly increased the density of IKV (from (13.3 +/- 1.0) pA/pF to (18.5 +/- 1.4) pA/pF, at +60 mV, n = 11, P = 0.001) versus the control group whereas methane had no effect on IBKca (all P > 0.05). CONCLUSION: Methane can inhibit contractile activity of proximal colonic longitudinal muscle by activating voltage dependent potassium channel and increasing IKV. PMID- 23660270 TI - [Study of apoptosis related factors regulatory mechanism of resveratrol to human skin squamous cell carcinoma A431 xenograft in nude mice]. AB - OBJECTIVE: To explore the anti-tumor effects of resveratrol (Res) upon human skin squamous cell carcinoma A431 xenograft in nude mice and elucidate the regulatory mechanisms of survivin and caspase-3. METHODS: The model of human skin squamous cell carcinoma (A431) xenograft in nude mice was established. And the animals were randomly divided into saline-negative control, cyclophosphamide (CTX) positive control, Res high-, medium- and low-dosage and blank control groups (n = 10 each). After drug intervention, tumor-bearing mice were sacrificed. The tumor growth curve was plotted and the Res inhibition rate calculated by terminal tumor weight. The morphological changes of tumor cell among groups were observed by hematoxylin and eosin staining; cell apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling TUNEL; the impact of Res upon the protein expressions of survivin and caspase-3 in tumor issues was observed by Western blot. Analysis of variance and Pearson's correlation were employed for statistical analyses. RESULTS: (1) By the end of treatment, the tumor volume of CTX, Res high-, medium-, low-dosage, saline-negative control and blank control groups were (1154 +/- 255), (1002 +/- 115), (1207 +/- 176), (1342 +/- 211), (1642 +/- 226), (1564 +/- 156) mm(3) respectively, and tumor weight of CTX, Res high-, medium-, low-dosage, saline-negative control and blank control groups (1.84 +/- 0.30), (1.72 +/- 0.39), (1.96 +/- 0.40), (2.67 +/- 0.73), (3.16 +/- 0.52), (3.33 +/- 0.59) g respectively. Through analysis of variance, the tumor volume and weight of Res high-, medium-, low-dosage groups were smaller than those of saline negative control and blank control groups (all P < 0.05). The inhibition rate of Res high-, medium- and low-dosage groups were 45.57%, 37.97% and 15.51% respectively. (2) The apoptosis index of the above groups were 36.79% +/- 8.86%, 33.15% +/- 6.00%, 18.09% +/- 3.92%, 10.53% +/- 4.20%, 3.87% +/- 1.63%, 2.73% +/- 1.61%. Through analysis of variance, the apoptosis index of Res groups were higher than those of saline-negative control and blank control groups (all P < 0.05). (3) The protein expression of survivin/beta-actin of each group were 0.48 +/- 0.20, 0.19 +/- 0.11, 0.22 +/- 0.12, 0.28 +/- 0.24, 0.98 +/- 0.41, 0.85 +/- 0.34. The protein expression of caspase-3/beta-actin of each group were 0.42 +/- 0.09, 0.31 +/- 0.10, 0.31 +/- 0.07, 0.22 +/- 0.08, 0.14 +/- 0.04, 0.13 +/- 0.05 respectively. Through analysis of variance, the protein expression of survivin of Res groups was lower than those of the saline-negative control and blank control groups (all P < 0.05). And the protein expression of caspase-3 of Res groups were higher than those of the saline-negative control and blank control group (all P < 0.05). Through Pearson's analysis, the protein expression of survivin and caspase 3 had no correlation (r = -0.279, P > 0.05). CONCLUSIONS: Res inhibits the growth of human skin squamous cell carcinoma A431 xenograft in nude mice. And its mechanism may be associated with the apoptosis of tumor cell through the depression of survivin and the activation of caspase-3. PMID- 23660271 TI - [Effects of qishenyiqi gutta pills on calcium/calmodulin dependent protein kinase II in rats with renal hypertension]. AB - OBJECTIVE: To explore the effects of qishenyiqi gutta pills on myocardial hypertrophy of left ventricle and calcium/calmodulin dependent protein kinase II (CAMK II) in rats with renal hypertension and elucidate its intervention mechanism for myocardial hypertrophy. METHODS: A total of 50 Wistar rats were randomly divided into 5 groups of sham-operation, control, high-dose qishenyiqi gutta pills, low-dose qishenyiqi gutta pills and valsartan (n = 10 each). The rat model of myocardial hypertrophy with renal hypertension was established by the 2 kidney 1-clip (2K1C) method. The experimental animals were divided into control, high-dose, low-dose and valsartan groups. At Week 5 postoperation, valsartan group received an oral dose of valsartan (30 mg*kg(-1)*d(-1)), high-dose and low dose groups took qishenyiqi gutta pills (250 and 125 mg*kg(-1)*d(-1)) while sham operation and control groups had the same dose of normal saline solution. Tail arterial pressure was detected weekly and continued for 8 weeks. At the end of Week 12, the animals were sacrificed to harvest myocardial tissue of left ventricle for detecting left ventricular mass index (LVMI). The collagen volume fraction (CVF) of myocardium was examined by Van Gieson staining, the activities of superoxide dismutase (SOD) and reactive oxygen species (ROS) were detected by enzyme-linked immunosorbent assay (ELISA) and the expression of CAMK II was detected by immunohistochemistry and Western blot. RESULTS: (1) Blood pressures were significantly higher in high-dose, low-dose and control groups than those in sham-operation and valsartan groups ((167.66 +/- 11.48), (166.72 +/- 13.51), (174.34 +/- 14.52) vs (119.57 +/- 6.30), (131.80 +/- 12.49) mm Hg, P < 0.01). The changes of blood pressure had no significant difference between high-dose and low dose groups. (2) LVMI and CVF increased significantly in high-dose, low-dose and valsartan groups versus sham-operation group (LVMI: (1.98 +/- 0.16), (2.09 +/- 0.14), (1.97 +/- 0.17) vs (1.74 +/- 0.17) g/kg; CVF: 0.94% +/- 0.22%, 2.53% +/- 0.61%, 0.81% +/- 0.20% vs 0.45% +/- 0.13%) (P < 0.01, P < 0.05), but decreased significantly versus control group (LVMI: (1.98 +/- 0.16), (2.09 +/- 0.14), (1.97 +/- 0.17) vs (2.28 +/- 0.28) g/kg; CVF: 0.94% +/- 0.22%, 2.53% +/- 0.61%, 0.81% +/- 0.20% vs 4.73% +/- 1.04%) (P < 0.01, P < 0.05). (3) The expression of CAMK II was significantly higher in high-dose, low-dose, valsartan and control groups than that in sham-operation group (65.9%, 95.3%, 84.8%, 160.1% vs 67.7%). And it was significantly lower in high-dose, low-dose and valsartan groups than that in control group (65.9%, 95.3%, 84.8% vs 160.1%). There was no statistical difference among high-dose, low-dose and valsartan groups. CONCLUSIONS: Qishenyiqi gutta pills may retard myocardial hypertrophy of left ventricle in rats with renal hypertension. And the mechanism is probably be correlated with its antioxidant activity and inhibited expression of myocardial CAMK II. PMID- 23660273 TI - Analysis of the effect of various decalcification agents on the quantity and quality of nucleic acid (DNA and RNA) recovered from bone biopsies. AB - Molecular studies are part of standard care for cancer patients. Bone, a common and sometimes sole site of metastasis, requires decalcification for morphological examination. Many commonly used decalcification agents contain strong acids that degrade nucleic acids. The paradigm shift in oncology, with biomarker targeted therapy and gene expression profiling analysis, requires sufficient nucleic acid recovery from bone biopsy specimens. We systematically studied the effects of a spectrum of decalcification agents on the quantity and quality of RNA and DNA recovered from bone biopsies. Multiple bone biopsies of similar size and cellularity were fixed in 10% neutral-buffered formalin, randomized to various decalcification agents for 2 hours then processed, and embedded. Tissue lysates were obtained from unstained sections and nucleic acid isolated. DNA and RNA were quantified. Assessment of DNA and RNA integrity was accomplished by comparison of the average cycle threshold by polymerase chain reaction of selected housekeeping genes for each agent. Results were then analyzed by 2-sample t test. There was a significant decrease in both DNA and RNA yield and integrity with strong acids (hydrochloric, nitric) vs 14% EDTA and formic acid. DNA yield was (mean nanograms) 6.15 vs 68.68 (P<.001) and RNA was (mean nanograms) 121.53 vs 288.89 (P=.003), respectively. DNA integrity (mean cycle threshold) was 35.79 vs 30.16 (P<.001), and RNA was 33.03 vs 26.5 (P<.001), respectively. Decalcification of bone biopsies with EDTA or formic acid agents was associated with a significant improvement in recovered nucleic acid quantity and quality. PMID- 23660272 TI - A test of the cognitive self-medication hypothesis of tobacco smoking in schizophrenia. AB - BACKGROUND: Heavier tobacco smoking among people with schizophrenia (SCZ) has been suggested to reflect self-medication of cognitive deficits. The idea that cognitive-enhancing effects of nicotine are a primary motivator of tobacco consumption in SCZ and that abstinence would deprive SCZ of such beneficial effects might explain hesitation among providers to pursue smoking cessation in SCZ. This study tested predictions of the cognitive self-medication hypothesis. METHODS: In three counterbalanced sessions, 17 SCZ and 17 healthy control subjects (HCS), all smokers, were tested under ad libitum smoking or 3.5 hours after abstaining and receiving a nicotine (14 mg/24 hours) or placebo patch. RESULTS: Attention task performance was improved by transdermal nicotine relative to placebo, with intermediate performance by ad libitum smoking. These effects were of similar size in SCZ and HCS and did not reflect remediation of functions disproportionately impaired in SCZ. Although more SCZ reported that the need to concentrate influenced their smoking, this was not reflected by the actual behavior of these patients. Self-reported ability to concentrate changed with nicotine status in HCS but not SCZ, suggesting insensitivity of SCZ to nicotine derived performance benefits. Nicotine plasma concentrations after ad libitum smoking were not associated with performance benefits but instead with the propensity to experience nicotine withdrawal upon abstinence. This association was seen selectively in SCZ, suggesting a possible reason for heavier smoking. CONCLUSIONS: These findings suggest that subjective or objective attentional benefits are unlikely the primary driving force of tobacco consumption in SCZ and should not discourage providers from supporting quit attempts. PMID- 23660274 TI - Longitudinal comparison of quality of life after real-time tumor-tracking intensity-modulated radiation therapy and radical prostatectomy in patients with localized prostate cancer. AB - The purpose of this study was to compare the quality of life (QOL) in patients with localized prostate cancer (PC) after intensity-modulated radiation therapy assisted with a fluoroscopic real-time intensity-modulated radiation therapy (RT IMRT) tumor-tracking system versus the QOL after radical prostatectomy (RP). Between 2003 and 2006, 71 patients were enrolled in this longitudinal prospective study. Each patient was allowed to decide which treatment modality they would receive. Of the 71 patients, 23 patients underwent RT-IMRT, while 48 opted for RP. No patient received neo-adjuvant or adjuvant hormone therapy. The global QOL and disease-specific-QOL were evaluated before treatment and again at 1, 3 and 5 years after treatment. There was no significant difference in the background characteristics between the two groups. The 5-year biochemical progression-free survival was 90% in the RT-IMRT and 79% in the RP group. In the RT-IMRT group, there was no significant deterioration of the global QOL or disease-specific QOL through 5 years post-treatment. In the RP group, the urinary function, sexual function, and sexual bother indicators significantly deteriorated after treatment. Urinary and sexual function was significantly better in the RT-IMRT group at 1, 3 and 5 years post-treatment compared to the RP group. RT-IMRT may be a preferable treatment for localized PC because of similar efficacy to RP but better post-treatment QOL. PMID- 23660275 TI - X-ray-induced bystander responses reduce spontaneous mutations in V79 cells. AB - The potential for carcinogenic risks is increased by radiation-induced bystander responses; these responses are the biological effects in unirradiated cells that receive signals from the neighboring irradiated cells. Bystander responses have attracted attention in modern radiobiology because they are characterized by non linear responses to low-dose radiation. We used a synchrotron X-ray microbeam irradiation system developed at the Photon Factory, High Energy Accelerator Research Organization, KEK, and showed that nitric oxide (NO)-mediated bystander cell death increased biphasically in a dose-dependent manner. Here, we irradiated five cell nuclei using 10 * 10 um(2) 5.35 keV X-ray beams and then measured the mutation frequency at the hypoxanthine-guanosine phosphoribosyl transferase (HPRT) locus in bystander cells. The mutation frequency with the null radiation dose was 2.6 * 10(-)(5) (background level), and the frequency decreased to 5.3 * 10(-)(6) with a dose of approximately 1 Gy (absorbed dose in the nucleus of irradiated cells). At high doses, the mutation frequency returned to the background level. A similar biphasic dose-response effect was observed for bystander cell death. Furthermore, we found that incubation with 2-(4 carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO), a specific scavenger of NO, suppressed not only the biphasic increase in bystander cell death but also the biphasic reduction in mutation frequency of bystander cells. These results indicate that the increase in bystander cell death involves mechanisms that suppress mutagenesis. This study has thus shown that radiation induced bystander responses could affect processes that protect the cell against naturally occurring alterations such as mutations. PMID- 23660276 TI - Dose-volume analysis for respiratory toxicity in intrathoracic esophageal cancer patients treated with definitive chemoradiotherapy using extended fields. AB - PURPOSE: We evaluated the relationship between dosimetric parameters (DPs) and the incidence of radiation pneumonitis (RP) and investigated the feasibility of a proposed treatment planning technique with the potential of reducing RP in esophageal cancer patients treated with definitive chemoradiotherapy using extended fields. PATIENTS AND METHODS: A total of 149 patients with locally advanced esophageal cancer were prospectively enrolled for extended-field radiotherapy (EFRT) to three-field regional lymphatics between September 2004 and June 2009. We retrospectively reviewed 86 consecutive patients who were treated with a total dose of 50.4 Gy (plus an optional 9 Gy boost) and were available for dose-volume analysis. Lung DPs of patients in the Grade 0-1 RP (RPG<=1) group and the Grade 2-5 RP (RPG>=2) group were compared. We compared the proposed plan with the conventional plan to 50.4 Gy on DPs for each case. RESULTS: Of these 86 patients, 10 (12%) developed RPG>=2 (Grade 2, n = 2 patients; Grade 3, n = 3; Grade 4, n = 3; Grade 5, n = 2). The patients in the RPG<=1 group showed significantly lower (P < 0.05) V5 and V10 values for the whole lung compared with those in the RPG>=2 group. There were two advantages gained from the proposed plan for V5 (<55%) and V10 (< 37%) values and the conformity of the PTV. CONCLUSION: The increase in the volume of the lung exposed to low doses of EFRT was found to be associated with the incidence of RP. Our proposed plan is likely to reduce the incidence of RP. PMID- 23660277 TI - Multiple effects of circadian dysfunction induced by photoperiod shifts: alterations in context memory and food metabolism in the same subjects. AB - Humans exposed to shiftwork conditions have been reported to have increased susceptibility to various health problems including various forms of dementia, cancer, heart disease, and metabolic disorders related to obesity. The present experiments assessed the effects of circadian disruption on learning and memory function and various food related processes including diet consumption rates, food metabolism, and changes in body weight. These experiments utilized a novel variant of the conditioned place preference task (CPP) that is normally used to assess Pavlovian associative learning and memory processes produced via repeated context-reward pairings. For the present experiments, the standard CPP paradigm was modified in that both contexts were paired with food, but the dietary constituents of the food were different. In particular, we were interested in whether rats could differentiate between two types of carbohydrates, simple (dextrose) and complex (starch). Consumption rates for each type of carbohydrate were measured throughout training. A test of context preference without the food present was also conducted. At the end of behavioral testing, a fasting glucose test and a glucose challenge test were administered. Chronic photoperiod shifting resulted in impaired context learning and memory processes thought to be mediated by a neural circuit centered on the hippocampus. The results also showed that preferences for the different carbohydrate diets were altered in rats experiencing photoperiod shifting in that they maintained an initial preference for the simple carbohydrate throughout training. Lastly, photoperiod shifting resulted in changes in fasting blood glucose levels and elicited weight gain. These results show that chronic photoperiod shifting, which likely resulted in circadian dysfunction, impairs multiple functions of the brain and/or body in the same individual. PMID- 23660278 TI - Introduction to the 2012 SSIB special issue. PMID- 23660279 TI - Commentary to 'primary breast augmentation clinical trial outcomes stratified by surgical incision, anatomical placement and implant device type'. PMID- 23660280 TI - Cold-induced vasodilatation in cold-intolerant rats after nerve injury. AB - PURPOSE: Cold-induced vasodilatation (CIVD) is a cyclic regulation of blood flow during prolonged cooling of protruding body parts. It is generally considered to be a protective mechanism against local cold injuries and cold intolerance after peripheral nerve injury. The aim of this study was to determine the role of the sympathetic system in initiating a CIVD response. METHODS: Eight rats were operated according to the spared nerve injury (SNI) model, eight underwent a complete sciatic lesion (CSL) and six underwent a sham operation. Prior to operation, 3, 6 and 9 weeks postoperatively, both hind limbs were cooled and the skin temperature was recorded to evaluate the presence of CIVD reactions. Cold intolerance was determined using the cold plate test and mechanical hypersensitivity measured using the Von Frey test. RESULTS: No significant difference in CIVD was found comparing the lateral operated hind limb for time (preoperatively and 3, 6 and 9 weeks postoperatively; p = 0.397) and for group (SNI, CSL and Sham; p = 0.695). SNI and CSL rats developed cold intolerance and mechanical hypersensitivity. CONCLUSION: Our data show that the underlying mechanisms that initiate a CIVD reaction are not affected by damage to a peripheral nerve that includes the sympathetic fibres. We conclude that the sympathetic system does not play a major role in the initiation of CIVD in the hind limb of a rat. CLINICAL RELEVANCE: No substantial changes in the CIVD reaction after peripheral nerve injury imply that the origin of cold intolerance after a traumatic nerve injury is initiated by local factors and has a more neurological cause. This is an important finding for future developing treatments for this common problem, as treatment focussing on vaso-regulation may not help diminish symptoms of cold-intolerant patients. PMID- 23660281 TI - Reconstruction of vaginal agenesis with pudendal thigh flaps thinned with liposuction. AB - AIM: The aim of this study is to describe a technique for and data from vaginoplasty surgeries performed using a pudendal thigh flap (PTF) thinned with liposuction. METHOD: A total of six patients diagnosed with Mullerian agenesis underwent vaginoplasty procedures using this technique between January 2009 and April 2012. The age range of the patients was 19-24 years. In the first stage, the subcutaneous fat tissue under the planned skin flap islands was thinned with liposuction. After 3 months, the second stage of the procedure was carried out and the PTFs were elevated. RESULTS: Complications such as infection, dehiscence of the suture line and haematoma were not observed in any of the patients. Although a partial flap loss was observed at the distal aspect of a flap in one patient, total healing was achieved through debridement and local wound care. Mean tissue flap thickness was found to be thinner, and adequate vaginal depth was achieved in all patients on average 13 months following surgery. CONCLUSION: We are of the opinion that PTFs thinned with liposuction enable both a thinner tissue flap and a vaginal reconstruction that more closely resembles natural anatomy. PMID- 23660282 TI - Ten-year experience with one-step correction of constriction rings by complete circular resection and linear circumferential skin closure. AB - BACKGROUND: In amniotic band syndrome (ABS) constriction rings affecting the limbs are regularly seen at birth. Circular resection and closure with multiple Z plasties has been described as the treatment of choice. However, direct circular closure creating linear circumferential scars might replace multiple Z- or W plasties to reduce scars and improve aesthetic outcome. METHODS: From 2000 to 2009 we treated 160 patients with ABS. In 43 cases release of isolated constriction rings was performed by circular excision and closure. Constriction rings were completely resected and skin closure could be performed without Z plasty in all cases. Data from follow-up of all cases were reviewed and photographs and recordings reassessed. The median age at operation was 14.3 months (range 2-32). Constriction rings were localised on the upper arm in five patients, the lower arm in five, the wrist in two and at the metacarpal level in five. At the lower extremity the thigh was affected in three and the lower leg in 23 patients. RESULTS: In the 16 cases of the first treatment period from 2000 to 2004, average follow-up was 6.5 years (range 5.1-10.3). We observed two minor complications following 43 operations (wound dehiscence and secondary healing). No formation recurrence of banding was seen. Aesthetic outcome was overall good. CONCLUSIONS: We found excellent aesthetical and functional results following change of treatment from multiple Z-plasties to linear circumferential closure. Scars were generally less noticeable and no recurrence or scar constriction could be detected with growth. However, radical excision of all constricting tissues prior to wound closure is mandatory. PMID- 23660283 TI - Reversal of hand peripheral ischaemia due to extravasation of adrenaline during cardiopulmonary resuscitation. AB - A 63 year old woman sustained an extravasation of vasopressor during a successful in hospital cardiopulmonary resuscitation resulting in an acutely ischaemic hand. This was treated with multiple washouts of the hand due to incipient recurrence of the ischaemia. Extravasation of vasopressor is exceedingly rare and potentially devastating. This case highlights the specific problems associated with extravasation of vasopressor. We present an algorithm for treatment of these and identify the potential need to use specific antidotes for the vasoconstriction caused by adrenaline extravasation. PMID- 23660284 TI - dbWFA: a web-based database for functional annotation of Triticum aestivum transcripts. AB - The functional annotation of genes based on sequence homology with genes from model species genomes is time-consuming because it is necessary to mine several unrelated databases. The aim of the present work was to develop a functional annotation database for common wheat Triticum aestivum (L.). The database, named dbWFA, is based on the reference NCBI UniGene set, an expressed gene catalogue built by expressed sequence tag clustering, and on full-length coding sequences retrieved from the TriFLDB database. Information from good-quality heterogeneous sources, including annotations for model plant species Arabidopsis thaliana (L.) Heynh. and Oryza sativa L., was gathered and linked to T. aestivum sequences through BLAST-based homology searches. Even though the complexity of the transcriptome cannot yet be fully appreciated, we developed a tool to easily and promptly obtain information from multiple functional annotation systems (Gene Ontology, MapMan bin codes, MIPS Functional Categories, PlantCyc pathway reactions and TAIR gene families). The use of dbWFA is illustrated here with several query examples. We were able to assign a putative function to 45% of the UniGenes and 81% of the full-length coding sequences from TriFLDB. Moreover, comparison of the annotation of the whole T. aestivum UniGene set along with curated annotations of the two model species assessed the accuracy of the annotation provided by dbWFA. To further illustrate the use of dbWFA, genes specifically expressed during the early cell division or late storage polymer accumulation phases of T. aestivum grain development were identified using a clustering analysis and then annotated using dbWFA. The annotation of these two sets of genes was consistent with previous analyses of T. aestivum grain transcriptomes and proteomes. Database URL: urgi.versailles.inra.fr/dbWFA/ PMID- 23660285 TI - PhenoDigm: analyzing curated annotations to associate animal models with human diseases. AB - The ultimate goal of studying model organisms is to translate what is learned into useful knowledge about normal human biology and disease to facilitate treatment and early screening for diseases. Recent advances in genomic technologies allow for rapid generation of models with a range of targeted genotypes as well as their characterization by high-throughput phenotyping. As an abundance of phenotype data become available, only systematic analysis will facilitate valid conclusions to be drawn from these data and transferred to human diseases. Owing to the volume of data, automated methods are preferable, allowing for a reliable analysis of the data and providing evidence about possible gene disease associations. Here, we propose Phenotype comparisons for DIsease Genes and Models (PhenoDigm), as an automated method to provide evidence about gene disease associations by analysing phenotype information. PhenoDigm integrates data from a variety of model organisms and, at the same time, uses several intermediate scoring methods to identify only strongly data-supported gene candidates for human genetic diseases. We show results of an automated evaluation as well as selected manually assessed examples that support the validity of PhenoDigm. Furthermore, we provide guidance on how to browse the data with PhenoDigm's web interface and illustrate its usefulness in supporting research. Database URL: http://www.sanger.ac.uk/resources/databases/phenodigm PMID- 23660286 TI - RiceSRTFDB: a database of rice transcription factors containing comprehensive expression, cis-regulatory element and mutant information to facilitate gene function analysis. AB - Rice is one of the most important crop plants, representing the staple food for more than half the world's population. However, its productivity is challenged by various stresses, including drought and salinity. Transcription factors (TFs) represent a regulatory component of the genome and are the most important targets for engineering stress tolerance. Here, we constructed a database, RiceSRTFDB, which provides comprehensive expression information for rice TFs during drought and salinity stress conditions and various stages of development. This information will be useful to identify the target TF(s) involved in stress response at a particular stage of development. The curated information for cis regulatory elements present in their promoters has also been provided, which will be important to study the binding proteins. In addition, we have provided the available mutants and their phenotype information for rice TFs. All these information have been integrated in the database to facilitate the selection of target TFs of interest for functional analysis. This database aims to accelerate functional genomics research of rice TFs and understand the regulatory mechanisms underlying abiotic stress responses. Database URL: http://www.nipgr.res.in/RiceSRTFDB.html PMID- 23660287 TI - Morning glory disc anomaly: characteristic MR imaging findings. AB - SUMMARY: Establishing the diagnosis of morning glory disc anomaly is crucial to appropriate patient treatment. Although typically made clinically, the diagnosis is not always straightforward, especially in circumstances where physical examination is limited. The goal of this study was to define the spectrum and frequency of orbital findings in a series of patients with funduscopically confirmed morning glory disc anomaly by using MR imaging. MR imaging demonstrated 3 findings in all patients: 1) funnel-shaped morphologic pattern of the posterior optic disc with elevation of the adjacent retinal surface; 2) abnormal tissue associated with the distal intraorbital segment of the ipsilateral optic nerve, with effacement of the regional subarachnoid spaces; and 3) discontinuity of the uveoscleral coat. These findings were not observed in any of the unaffected globes of the study patients. In summary, these consistent and characteristic findings of morning glory disc anomaly should allow for accurate differentiation from other ocular anomalies and have the potential to guide appropriate management of this patient population. PMID- 23660288 TI - Radiation dose for 345 CT-guided interlaminar lumbar epidural steroid injections. AB - BACKGROUND AND PURPOSE: CT guidance is increasingly being used to localize the epidural space during epidural steroid injections. A common concern is that CT may be associated with significantly higher radiation doses compared with conventional fluoroscopy. The goal of this retrospective study was to determine the average dose-length product and effective dose delivered while interlaminar epidural steroid injections are performed and allow comparison with other modalities. MATERIALS AND METHODS: A total of 281 patients who had undergone 345 consecutive CT-guided epidural steroid injections of the lumbar spine were evaluated for radiation exposure. The dose-length product for each scan was derived from the CT dose index volume and scan length. Effective dose was then calculated from the dose-length product and a kappa coefficient of 0.015. Procedure time was calculated from the PACS time stamp on the scout image to the last CT image of the last image series. RESULTS: The average dose-length product across all procedures was 89.6 +/- 3.33 mGy.cm, which represents an effective dose of 1.34 +/- 0.05 mSv. No complications from the procedure were observed, and average procedure time was 8 minutes. CONCLUSIONS: The use of a stationary table and an intermittent scanning technique allow for short procedures and doses that are significantly lower than those of conventional diagnostic CT scans. Furthermore, because CT dose index overestimates radiation dose in stationary table procedures, the actual radiation dose may be even lower than stated here. PMID- 23660289 TI - Intra-arterial infusion of a glycoprotein IIb/IIIa antagonist for the treatment of thromboembolism during coil embolization of intracranial aneurysm: a comparison of abciximab and tirofiban. AB - BACKGROUND AND PURPOSE: Abciximab and tirofiban are commonly used for the treatment of thromboembolisms that form during coiling of intracranial aneurysms; however, it is not known which of these inhibitors is safer and more effective. We report the safety and the recanalization rates for intra-arterial abciximab and intra-arterial tirofiban infusion for the treatment of thromboembolisms that form during coiling. MATERIALS AND METHODS: Between March 2004 and April 2011, 346 intracranial aneurysms were treated with coiling. Thromboembolisms developed in 22 of these patients and were treated by use of intra-arterial tirofiban (n = 11) or abciximab (n = 11) infusion. RESULTS: In the abciximab group, the thromboembolisms were completely (n = 1) or partially (n = 7) resolved in 8 cases (72.7%) at the time of the final control angiography. Complete (n = 9) or partial (n = 2) resolution was achieved in all cases at the time of follow-up angiography (<3 days after the procedure). In the tirofiban group, thromboembolisms were completely (n = 4) or partially (n = 6) resolved in 10 cases (90.9%) at the time of the final control angiography. Complete (n = 9) or partial (n = 2) resolution was observed in all cases at the time of the follow-up angiography. There were no statistically significant differences between the 2 groups with respect to thrombus resolution (final angiography, P = .311; follow-up angiography, P = .707). No hemorrhagic complications developed in either group. CONCLUSIONS: These results suggest that tirofiban is more effective than abciximab for the immediate resolution of thromboembolisms, with no statistical significance. Both intra arterial tirofiban and abciximab exhibited similar safety and recanalization rates. PMID- 23660290 TI - Coil type does not affect angiographic follow-up outcomes of cerebral aneurysm coiling: a systematic review and meta-analysis. AB - BACKGROUND AND PURPOSE: Previous studies varied in their conclusions about the superiority of second-generation coils compared with bare platinum. In this systematic review and meta-analysis, we assessed differences in reported unfavorable angiographic outcomes of cerebral aneurysms treated with coil embolization as a function of coil type. MATERIALS AND METHODS: This systematic review covered 1999-2011 through the use of Ovid MEDLINE and EMBASE. Search terms were "subarachnoid hemorrhage," "intracranial aneurysms," "endovascular treatment," and "coiling." Inclusion criteria were studies reporting >50 aneurysms with imaging follow-up. We defined "unfavorable angiographic outcome" as either "recanalization," <90% occlusion, or "incomplete occlusion" at follow up. Rates of unfavorable outcomes were pooled through the use of random effects models and compared across various coil types. Multivariate random effects meta regression models were used to further explore the differences in outcomes related to coil type. RESULTS: We included 82 studies, comprising 90 patient cohorts, among which, 65 (72%) used bare platinum coils, 8 (8.9%) used Matrix, 11 (12%) used HydroCoil, and 6 (6.7%) used Cerecyte. The overall unfavorable outcome rate was 19% (95% CI: 17%,21%). Unfavorable outcome rates were 20% (95% CI: 17%, 22%) for bare platinum coils, 23% (95% CI: 16%, 29%) for Matrix, 15% (95% CI: 9%, 21%) for HydroCoil, and 15% (95% CI: 7%, 23%) for Cerecyte, respectively. The difference in unfavorable outcome rates among the various coil types was not statistically significant after adjusting for baseline characteristics, including aneurysm size, rupture status, and follow-up duration. CONCLUSIONS: The rate of unfavorable angiographic outcomes was not statistically different across the major approved coil types. The quality of the evidence, however, remains low because of high heterogeneity, small sample size, and potential publication bias. PMID- 23660292 TI - Stent-assisted coil embolization of posterior communicating artery aneurysms. AB - BACKGROUND AND PURPOSE: Use of protective stents may not be effective in coil embolization of wide-neck aneurysms involving the posterior communicating artery. Successful implementation depends on the caliber of the vessel, its angle of origin, and the manner in which its orifice is incorporated into the aneurysm. Presented here are the results (clinical and radiographic) of coil embolization in aneurysms of the ICA-posterior communicating artery junction, variably aided by stents. The primary focus is angiographic configurations that impact stent placement. MATERIALS AND METHODS: From a prospective data repository, we retrieved records of 32 consecutive patients with 33 posterior communicating artery aneurysms, all of which were treated by stent-assisted coil embolization between June 2008 and August 2012. Outcomes were analyzed in terms of aneurysm configuration and clinical status. RESULTS: Stents were positioned entirely in the ICA (n = 26), from the ICA to the posterior communicating artery (n = 2), in the posterior communicating artery only (n = 3), and retrograde from the posterior communicating artery to the ICA terminus (n = 2). Procedure-related complications occurred in 3 patients (9.1%), but only 1 (3.0%) had mild neurologic sequelae (Glasgow Outcome Score 4). Using coil embolization, we achieved successful occlusion in 24 aneurysms (72.7%), and in 9 others, subtotal occlusion was conferred. During a mean follow-up of 15.7 +/- 10.7 months, imaging of 27 aneurysms documented stable occlusion in 19 (70.4%), whereas angiography of 15 aneurysms (39.5%) disclosed 2 instances of in-stent stenosis (13.3%) and a solitary occurrence of stent migration (6.7%). CONCLUSIONS: In posterior communicating artery aneurysms, stent protection during coil embolization is feasible by adjusting the procedural strategy to accommodate differing configurations of the aneurysm and its vascular source. PMID- 23660291 TI - Differences in imaging characteristics of HPV-positive and HPV-Negative oropharyngeal cancers: a blinded matched-pair analysis. AB - BACKGROUND AND PURPOSE: Human papillomavirus-positive oropharyngeal cancers typically have younger age of onset, limited tobacco exposure, and more favorable prognosis than HPV-negative oropharyngeal cancers. We assessed whether HPV positive and HPV-negative oropharyngeal cancers have consistent differences in pretreatment imaging characteristics. MATERIALS AND METHODS: A retrospective review of 136 pretreatment CT examinations of paired HPV-positive and HPV negative oropharyngeal cancers matched for T stage, tumor subsite, and smoking status was performed with the reviewing radiologist blinded to HPV status and clinical stage. Demographic/clinical characteristics and imaging characteristics of primary lesions and metastatic nodal disease were compared by use of Fisher exact testing. The McNemar chi(2) test was used for the matched-pair analysis. RESULTS: By imaging, HPV-negative tumors were more likely to demonstrate invasion of adjacent muscle (26% versus 6%, P = .013). HPV-positive primary tumors were more likely to be enhancing and exophytic with well-defined borders, whereas HPV negative primary tumors were more likely to be isoattenuated and demonstrate ill defined borders, though these results were not statistically significant. HPV positive tumors were more likely to demonstrate cystic nodal metastases than HPV negative tumors (36% versus 9%, P = .002). CONCLUSIONS: In this matched and blinded analysis of the imaging differences between HPV-positive and HPV-negative oropharyngeal cancers, HPV-positive carcinomas often had primary lesions with well-defined borders and cystic nodal metastases, whereas HPV-negative primaries more often had poorly defined borders and invasion of adjacent muscle. PMID- 23660293 TI - Tentorial dural fistulas: endovascular management and description of the medial dural-tentorial branch of the superior cerebellar artery. AB - BACKGROUND AND PURPOSE: TDAVFs are uncommon causes of spontaneous intracranial hemorrhage. A retrospective review of their management was performed after repeatedly observing a previously under-recognized medial dural-tentorial branch of the SCA. MATERIALS AND METHODS: Thirteen patients were diagnosed with TDAVFs by CT/MR imaging and DSA during a 5.8-year period. Seven patients presented after intracranial hemorrhage. Twelve patients were treated endovascularly, and one, surgically. RESULTS: Eleven TDAVFs were located in the midline (7 at the falx cerebelli and 4 at the torcular), and 2 were petrotentorial. All torcular TDAVFs were associated with sinus thrombosis and showed bidirectional drainage relative to the tentorium. No sinus thrombosis was seen in the falx cerebelli subtype, which drained infratentorially only, except in 1 patient who had had unrelated surgery previously. Venous drainage was directly to cortical veins except for 1 petrotentorial and 2 torcular TDAVFs. A branch of the SCA, the medial dural tentorial artery, was observed in 5 midline TDAVFs. Its anatomy was defined with selective angiography. Endovascular therapy resulted in a cure in 5 and subtotal occlusion in 6, and staged treatment is ongoing in 1 patient. One patient was cured after surgery. CONCLUSIONS: TDAVFs frequently cause intracranial hemorrhage and therefore warrant treatment. Endovascular therapy proved effective in this series, and arteriography was essential for understanding the various fistula subtypes and for treatment planning. We emphasize the importance of recognizing the medial dural-tentorial artery of the SCA with its characteristic course along the tentorium on angiography. This artery should be included in future anatomic descriptions of the cranial blood supply. PMID- 23660294 TI - Dual role of cyclic GMP in cardiac cell survival. AB - It is well known that cyclic guanosine 3',5'-monophosphate plays an important role in cardioprotection against ischemia/reperfusion injury through activation of protein kinase G (PKG). We found that cGMP prevents the mitochondrial permeability transition pore (mPTP) opening by inactivating glycogen synthase kinase 3beta (GSK-3beta) via protein kinase G (PKG) in cardiac H9c2 cells. While GSK-3beta and its major upstream regulator phosphoinositide 3-kinase (PI3K)/Akt are critical for acute cardioprotection, an excessive activation of PI3K/Akt or GSK-3beta inactivation can also lead to cardiac hypertrophy. Here, we show that cGMP not only inactivates GSK-3beta through PKG (this leads to acute cardioprotection) but also negatively regulates Akt activity (this may lead to prevention of hypertrophy and heart failure, and the regulation of NO synthesis) in cardiac cells. We further found that the negative regulatory effect of cGMP on Akt activity is not mediated by PKG but may be through up-regulation of protein phosphatase PP2A activity. We propose that cGMP is a versatile signal with dual beneficial role in cardiac cell survival. PMID- 23660295 TI - The orphan nuclear receptor TR3/Nur77 regulates ER stress and induces apoptosis via interaction with TRAPgamma. AB - The orphan nuclear receptor TR3 (also known as Nur77) belongs to the steroid/thyroid/retinoid nuclear receptor superfamily and plays important roles in regulating cell proliferation, differentiation and apoptosis. No physiological ligand for TR3 has been found thus far; the determination of its binding partners is therefore important to clarify the biological functions of TR3. Here, we identified translocon-associated protein subunit gamma (TRAPgamma) as a novel TR3 binding partner using a tandem affinity purification method. This interaction between TR3 and TRAPgamma was further confirmed, and the interacting regions were mapped. The ligand-binding domain of TR3 was required for TRAPgamma binding, and the C terminus of TRAPgamma was responsible for its interaction with TR3. When stimulated with 12-O-tetradecanoylphorbol 13-acetate (TPA) or CD437, this TR3 TRAPgamma interaction not only induced Ca(2+) depletion in the endoplasmic reticulum (ER) but also promoted the expression of the proapoptotic transcriptional regulator CHOP. Notably, both TR3 and TRAPgamma were required for ER stress-induced apoptosis in HepG2 cells. Overall, this study demonstrated a novel, TR3-initiated signaling pathway in which TR3 regulates ER stress and induces apoptosis of hepatoma cells through its interaction with TRAPgamma. PMID- 23660296 TI - Anti-inflammatory mechanisms of bioactive milk proteins in the intestine of newborns. AB - The human newborn infant is susceptible to gut inflammatory disorders. In particular, growth-restricted infants or infants born prematurely may develop a severe form of intestinal inflammation known as necrotizing enterocolitis (NEC), which has a high mortality. Milk provides a multitude of proteins with anti inflammatory properties and in this review we gather together some recent significant advances regarding the isolation and proteomic identification of these minor constituents of both human and bovine milk. We introduce the process of inflammation, with a focus on the immature gut, and describe how a multitude of milk proteins act against the inflammatory process according to both in vitro and in vivo studies. We highlight the effects of milk proteins such as caseins, and of whey proteins such as alpha-lactalbumin, beta-lactoglobulin, lactoferrin, osteopontin, immunoglobulins, trefoil factors, lactoperoxidase, superoxide dismutase, platelet-activating factor acetylhydrolase, alkaline phosphatase, and growth factors (TGF-beta, IGF-I and IGF-II, EGF, HB-EGF). The effects of milk fat globule proteins, such as TLR-2, TLR-4, sCD14 and MFG-E8/lactadherin, are also discussed. Finally, we indicate how milk proteins could be useful for the prophylaxis and therapy of intestinal inflammation in infants and children. PMID- 23660298 TI - Reproducibility of performance and fatigue in trail running. AB - OBJECTIVES: This study aimed to test the reproducibility of running performance, neuromuscular fatigue markers and indirect muscle damage indicators in a field based trail time-trial. DESIGN: Running performance and changes in classical physiological parameters were analysed in 11 experienced trail runners before and in the days following four bouts of outdoor trail running (15.6 km), 7 days apart. METHODS: Heart rate, running time and lactate concentration were monitored in each running bout. Maximal voluntary contraction torque, counter movement jump height, plasma creatine kinase activity and muscle soreness were assessed before and 1, 24 and 48 h post-race. Within-bout changes were elucidated using a two-way repeated measures ANOVA. Inter-repetition reproducibility was examined using an intraclass correlation coefficient (R) and the mean intra-subject coefficient of variation at each measurement time point. RESULTS: Running time was longer (p<0.05) for the first bout compared with the other three bouts. Magnitude and time course of changes in counter movement jump height, creatine kinase activity and muscle soreness were similar among all four bouts (overall peak means: -17%, +35% and 54/100mm respectively). The acute reduction in maximal voluntary contraction torque (peak mean: -17%) was attenuated exclusively in the fourth bout (p<0.05). The two middle bouts showed good reproducibility (intraclass correlation coefficient and coefficient of variation) for running time, maximal voluntary contraction torque and counter movement jump height, but low to moderate for creatine kinase activity, muscle soreness, blood lactate and rate of perceived exertion. CONCLUSIONS: A short outdoor trail run is a reliable model for investigations of fatigue and muscle damage, but certain methodological precautions should be respected. PMID- 23660297 TI - Transcription factor AP-2alpha regulates acute myeloid leukemia cell proliferation by influencing Hoxa gene expression. AB - Transcription factor AP-2alpha mediates transcription of a number of genes implicated in mammalian development, cell proliferation and carcinogenesis. In the current study, we identified Hoxa7, Hoxa9 and Hox cofactor Meis1 as AP-2alpha target genes, which are involved in myeloid leukemogenesis. Luciferase reporter assays revealed that overexpression of AP-2alpha activated transcription activities of Hoxa7, Hoxa9 and Meis1, whereas siRNA of AP-2alpha inhibited their transcription activities. We found that AP-2 binding sites in regulatory regions of three genes activated their transcription by mutant analysis and AP-2alpha could interact with AP-2 binding sites in vivo by chromatin immunoprecipitation (ChIP). Further results showed that the AP-2alpha shRNA efficiently inhibited mRNA and protein levels of Hoxa7, Hoxa9 and Meis1 in AML cell lines U937 and HL60. Moreover, decreased expression of AP-2alpha resulted in a significant reduction in the growth and proliferation of AML cells in vitro. Remarkably, AP 2alpha knockdown leukemia cells exhibit decreased tumorigenicity in vivo compared with controls. Finally, AP-2alpha and target genes in clinical acute myeloid leukemia samples of M5b subtype revealed variable expression levels and broadly paralleled expression. These data support a role of AP-2alpha in mediating the expression of Hoxa genes in acute myeloid leukemia to influence the proliferation and cell survival. PMID- 23660299 TI - Highly-sensitive troponin I is increased in patients with gynecological cancers. AB - OBJECTIVES: To investigate troponin I (TnI) in patients with gynecological cancers. METHODS: Highly-sensitive (HS) and conventional TnI were measured in 25 patients with untreated ovarian cancer, 25 with endometriosis and 25 with benign masses. RESULTS: Both HS and conventional TnI were increase in cancer patients. Values above the cut-off were found in 44% and 16% cancer patients using HS and conventional TnI methods, respectively. CONCLUSIONS: Cardiac involvement is frequent in patients with gynecological cancers and should be preferably assessed using HS troponin immunoassays. PMID- 23660300 TI - The future of systemic therapies for localised prostate cancer. AB - In the last decade, many systemic therapies have become available to improve survival in the setting of castration-resistant prostate cancer. Once effective treatments for advanced and incurable disease have been established, these agents are generally explored in the adjuvant and neoadjuvant settings to evaluate their role in increasing the chance of cure for localised disease. Clinical trials evaluating new therapies in high-risk prostate cancer can broadly be divided into two categories. Phase III (and some phase II) trials generally evaluate treatments that have already been shown to provide clinical benefit in the advanced disease setting; whereas smaller phase I (and some phase II) trials often serve as proof-of-principle assessments in the development of novel agents. The goal of this review is to provide an overview of present and ongoing clinical trials of both of these categories, evaluating the promise of systemic therapies in the setting of high-risk localised prostate cancer. We undertook a search of Ovid Medline, Embase and clinicaltrials.gov for prospective clinical studies assessing systemic therapy for early stage prostate cancer, either before or after definitive local treatment (surgery or radiation) from 2000 onwards. This resulted in 53 studies, of which 29 were deemed worthy of this overview and are presented herein, broadly divided by mechanism of action. Clearly, the arena evaluating the future of systemic therapies for localised prostate cancer will be a very active one. PMID- 23660301 TI - The extrapituitary prolactin promoter polymorphism is associated with rheumatoid arthritis and anti-CCP antibodies in Mexican population. AB - Prolactin (PRL) is a hormone-cytokine that has been involved in autoimmunity due to its immunoregulatory and lymphoproliferative effects. It is produced by various extrapituitary sites including immune cells, under control of a superdistal promoter that contains a single nucleotide polymorphism -1149 G/T previously associated with rheumatoid arthritis (RA) susceptibility in European population. The aim of this study was to investigate the association of the extrapituitary PRL -1149 G/T promoter polymorphism with clinical parameters, clinical activity and disability indices in RA patients from Western Mexico and to analyze the PRL mRNA expression according to the PRL -1149 G/T promoter polymorphism in total leucocytes from RA patients and controls. We conducted a case-control study that included 258 RA patients and 333 control subjects (CS). The DNA samples were genotyped using the PCR-RFLP method and the PRL mRNA expression was determined by quantitative real time PCR. PRL serum levels and antibodies to cyclic citrullinated peptides (anti-CCP) were measured with ELISA. We found significant differences in the genotype (p=0.022) and allelic (p=0.046) distribution of the polymorphism between RA patients and control subjects. According to the dominant genetic model, there is an association between the T allele (GT+TT genotypes) and decreased RA susceptibility in comparison to the G allele carriers (GG genotype) (OR 0.64, 95% CI 0.45-0.92; p=0.011). The T allele carriers (GT+TT genotypes) had lower titers of anti-CCP antibodies in comparison to the G allele carriers (GG genotype) (median, 66 U/mL vs. 125 U/mL; p=0.03). Furthermore, the GG homozygotes had higher PRL mRNA expression in comparison to the GT heterozygotes, and this latter with respect to the TT homozygotes, in both groups (RA: 1>0.72>0.19; CS: 1>0.54>0.28). However, PRL serum levels were similar in both groups. Our results suggest that the PRL -1149 T allele is a genetic marker for decreased RA susceptibility and is associated with lower titers of anti-CCP antibodies in Mexican population. We also suggest influence of genotype upon PRL mRNA expression. PMID- 23660302 TI - Pain and depression predict self-reported fatigue/energy in lupus. AB - This study examined the contribution of pain and psychological distress to fatigue. METHODS: One-hundred and twenty-five adult Caucasian and Hispanic lupus patients participated in this study. Demographic data, patient- and physician reported disease activity, as well as psychological functioning, were collected. Fatigue, pain, and vitality were measured using visual analogue scales as well as a subscale of the SF-36 questionnaire. Linear and hierarchical regression analyses were conducted. In the regression analysis, ethnicity was entered at the first step, followed by age, income and education at step 2, pain and disease activity measures at step 3, and psychological measurements at step 4. RESULTS: In the linear regression analysis, Caucasians reported more fatigue. Fatigue positively correlated with income, education, pain, patient-reported disease activity, helplessness, and depression, and negatively with internality, and the energy analysis mirrored the results of the fatigue analysis. In the first regression analysis, fatigue was the dependent variable. At step 1, Caucasians reported more fatigue. At step 2, no other demographic variables were significant. At step 3, pain and disease activity measures were significant when entered as a block; however, pain independently explained a large amount of variance. At step 4, psychological factors were significant as a block, with depression being the strongest predictor. In the second analysis, energy was the dependent variable. At step 1, Hispanics reported more energy. At step 2, demographic variables were not significant. At step 3, pain and disease activity were significant when entered as a block; however, only pain uniquely predicted energy. At step 4, psychological factors were significant as a block, with depression as the major contributor. CONCLUSIONS: Both pain and depression were found to be strong predictors of fatigue, and negatively correlated with energy. Disease activity did not appear to play a significant role in lupus fatigue. These findings support the importance of managing depression and pain in order to reduce fatigue in patients with systemic lupus erythematosus. PMID- 23660303 TI - A new multiscale model for the mechanical behavior of vein walls. AB - The purpose of the present work is to propose a new multiscale model for the prediction of the mechanical behavior of vein walls. This model is based on one of our previous works which considered scale transitions applied to undulated collagen fibers. In the present work, the scale below was added to take the anisotropy of collagen fibrils into account. One scale above was also added, modeling the global reorientation of collagen fibers inside the vessel wall. The model was verified on experimental data from the literature, leading to a satisfactory agreement. The proposed multiscale approach also allows the extraction of local stresses and strains at each scale. This approach is presented here in the case of vein walls, but can easily be extended to other tissues which contain similar constituents. PMID- 23660304 TI - Thoracolumbar spinal ligaments exhibit negative and transverse pre-strain. AB - The present work represents the first reported bi-axial spinal ligament pre strain data for the thoracic and lumbar spine. Ligament pre-strain (in-situ strain) is known to significantly alter joint biomechanics. However, there is currently a lack of comprehensive data with regards to spinal ligament pre strain. The current work determined the pre-strain of 71 spinal ligaments (30 anterior longitudinal ligaments, 27 supraspinous ligaments and 14 interspinous ligaments). The interspinous ligament and the anterior longitudinal ligament exhibited bi-axial pre-strain distributions, demonstrating they are not uniaxial structures. The supraspinous ligament frequently exhibited large amounts of negative pre-strain or laxity suggesting it makes no mechanical contribution to spinal stability near the neutral posture. Upon implementing multi-axial pre strain results into a finite element model of the lumbar spine, large differences in spinal biomechanics were observed. These results demonstrate the necessity of accounting for ligament pre-strain in biomechanical models. In addition, the authors present a unique experimental method for obtaining ligament pre-strain that presents a number of advantages when compared to standard techniques. PMID- 23660305 TI - Dynamic compressive properties of articular cartilages in the porcine temporomandibular joint. AB - The mandibular condylar and temporal cartilages in the temporomandibular joint (TMJ) play an important role as a stress absorber during function. However, relatively little information is available on its viscoelastic properties in dynamic compression, particularly in a physiological range of frequencies. We hypothesized that these properties are region-specific and depend on loading frequency. To characterize the viscoelastic properties of both cartilages, we performed dynamic indentation tests over a wide range of loading frequencies. Nine porcine TMJs were used; the articular surface was divided into five regions: anterior; central; posterior; medial and lateral. Sinusoidal compressive strain was applied with an amplitude of 1.0% and a frequency range between 0.01 and 10 Hz. In both cartilages, the dynamic storage modulus increased with frequency, and the value was the highest in the lateral region. These values of E' in the temporal cartilage were smaller than those in the mandibular condylar cartilage in all five regions except the lateral region. The Loss tangent values were higher in the temporal cartilage (0.35-0.65) than in the mandibular condylar one (0.2-0.45), which means that the temporal cartilage presents higher viscosity. The present results suggest that the dynamic compressive moduli in both cartilages are region-specific and dependent on the loading frequency, which might have important implications for the transmission of load in the TMJ. PMID- 23660306 TI - Selenium supplementation protects trophoblast cells from mitochondrial oxidative stress. AB - INTRODUCTION: Oxidative stress plays an important role in the pathogenesis of preeclampsia, a placental disorder affecting approximately 7% of pregnancies. Trophoblast cells are susceptible to oxidative stress which causes increased cell death and placental turnover. In this study, inhibitors of the mitochondrial respiratory chain were utilised to induce oxidative stress and the effect that selenium supplementation had on trophoblast viability was investigated. METHODS: Trophoblast cells (BeWo, JEG-3 and Swan-71) were treated with Na Selenite (100 nM) or Selenomethionine (500 nM) to increase the biological activity of antioxidants Glutathione Peroxidase and Thioredoxin Reductase. The cells were then oxidatively stressed with the addition of increasing doses of Antimycin C and Rotenone and the Resazurin end point assay was used to assess cellular activity. RESULTS: There was a significant dose dependent decrease in the cellular activity in BeWo, JEG-3 and Swan-71 when treated for 4 h with increasing concentrations of Antimycin (40-320 MUM) and Rotenone (100-800 nM). Prior incubation with Na Selenite and Selenomethionine was able to protect trophoblast cells from oxidative stress at Rotenone concentrations of 200 and 400 nM (P < 0.001) and Antimycin concentrations of 80-240 MUM (P < 0.001). DISCUSSION: These data suggest that selenoproteins such as Glutathione Peroxidase and Thioredoxin Reductase have an important role in protecting trophoblast mitochondria from oxidative stress. CONCLUSIONS: This study emphasises the importance of maintaining an adequate selenium supply during pregnancy and especially in pregnancies complicated by conditions such as preeclampsia. PMID- 23660308 TI - Physicochemical and biological evaluation of poly(ethylene glycol) methacrylate grafted onto poly(dimethyl siloxane) surfaces for prosthetic devices. AB - Poly(dimethyl siloxane) (PDMS) was surface-polymerized with poly(ethylene glycol)methacrylate (PEGMA) by surface-initiated atom transfer radical polymerization (SI-ATRP) in aqueous media at room temperature. Modification of the PDMS surface followed a three-step procedure: (i) PDMS surface hydroxylation by UV/ozone exposure, immediately followed by (ii) covalent attachment of the initiator, 1-trichlorosilyl-2-(chloromethylphenyl)ethane, onto the hydroxylated PDMS, via chemical vapor deposition; finally (iii) PDMS surface-polymerization of PEGMA by ATRP. Modified PDMS was characterized by water contact angle measurement, SEM, FTIR-ATR, and XPS. Results showed that modified surfaces had a hydrophilic character, given the water contact angles around 60 degrees ; FTIR ATR and XPS analysis confirmed the presence of polymerized PEGMA on the surface of PDMS and the adhesion of Staphylococcus aureus GB 2/1 and Streptococcus salivarius GB 24/9 onto the modified surfaces was inhibited 94% and 81%, respectively. Finally, the modified PDMS showed no evidence of cytotoxic effects in in vitro assays using human skin fibroblasts. PMID- 23660309 TI - The solvothermal synthesis of magnetic iron oxide nanocrystals and the preparation of hybrid poly(L-lactide)-polyethyleneimine magnetic particles. AB - We report a simple and green procedure for the preparation of magnetic iron oxide nanocrystals via solvothermal synthesis. The nanocrystal synthesis was carried out under mild conditions in the water-ethanol-oleic acid solvent system with the use of the oleate anion as a surface modifier of nanocrystals and glucose as a reducing agent. Specific conditions for homogenous precipitation achieved in such a reaction system lead to the formation of uniform high-quality nanocrystals down to 5 nm in diameter. The obtained hydrophobic nanocrystals can easily be converted to hydrophilic magnetic nanoparticles by being immobilized in a poly(L lactide)-polyethyleneimine polymeric matrix. These hybrid nano-constructs may find various biomedical applications, such as magnetic separation, gene transfection and/or magnetic resonance imaging. PMID- 23660310 TI - Investigation of Paenibacillus alvei ARN63 ability for biodemulsifier production: medium optimization to break heavy crude oil emulsion. AB - The demulsifying performance of Paenibacillus alvei ARN63 (P. alvei), as a biodemulsifier-producing bacterium, for breaking water-in-heavy crude oil emulsion has been investigated. The produced lipopeptide biodemulsifier showed the potential to be used in the petroleum industry as an environmentally friendly and non-toxic material. To optimize the biodemulsifier production, the impacts of parameters such as temperature, pH, carbon source and carbon concentration at a constant agitation speed of 180 rpm and with ammonium sulfate as the sole nitrogen source (1.0 g/l) were studied in detail. Several normal paraffin compounds, vegetable oils and motor oil revealed the ability to be used as the carbon source for synthesis of biodemulsifier. The best biodemulsifier production was obtained employing motor oil as the carbon source with a concentration of 42.5 g/l at 37 degrees C and pH 7.0 after 72 h of incubation. Under these conditions, the surface tension of the medium reduced from 58 mN/m to 24.7 mN/m and the biodemulsifier yield reached a value of 2.1 g/l. The demulsification ratio approached 77% and the produced biodemulsifier by P. alvei strain effectively broke water-in-heavy crude oil emulsion. According to biodemulsifier production and growth time course profiles, the biosynthesis was growth associated. Besides, the produced biodemulsifier had good stability during exposure to salinities up to 20%, temperatures up to 80 degrees C and a wide pH range of 2-12. PMID- 23660311 TI - [Focus on the spino-pelvic sagittal balance in the surgical treatment of spinal deformity]. PMID- 23660312 TI - [Effects of wide posterior release on the correction of severe and rigid thoracic scoliosis in sagittal plane]. AB - OBJECTIVE: To explore the effects of wide posterior release on the correction of severe and rigid thoracic scoliosis in sagittal plane. METHODS: A total of 37 idiopathic scoliosis patients (26 females and 11 males) with severe and rigid thoracic curves corrected with posterior pedicle screw system between 2006 and 2009 were recruited. Their average age was 17.3 years (range: 14 - 22) at operation and the thoracic Cobb angle was between 70 - 100 degrees . They were separated into 2 groups: group A (n = 15) with wide posterior release and group B (n = 22) with posterior soft tissue release alone. The preoperative, postoperative and latest standing posteroanterior and lateral radiographs during follow-ups were reviewed. RESULTS: All patients were operated successfully. No statistic difference existed in the average operative duration between two groups (P > 0.05). The average volume of blood loss was 874 ml in Group A versus 712 ml in Group B (P < 0.05). The average coronal Cobb angle on postoperative standing photograph was 27.4 degrees (68.1% correction) in Group A and 35.6 degrees (56.9% correction) in Group B. For comparing sagittal correction results in patients with similar thoracic sagittal deformities, we distinguished subgroup A1 (preoperative TKA < 40 degrees ) from subgroup A2 (preoperative TKA > 40 degrees ) in group A and subgroup B1 (preoperative TKA < 40 degrees ) from subgroup B2 (preoperative TKA > 40 degrees ) in group B. The postoperative TKA was 26.8 degrees (> 9.2 degrees than preoperation) in subgroup A1 and 12.5 degrees (3.1 degrees < preoperation) in subgroup B1 (P < 0.05). The postoperative TKA was 28.4 degrees (24.9 degrees < preoperation) in subgroup A2 and 39.1 degrees (10.3 degrees < preoperation) in subgroup B2 (P < 0.05). There was one case of dural leakage in group A. A leakage of cerebrospinal fluid was cured with a prone position and wound compression. One case of infection in superficial part of wound in group B was cured after debridement. No nerve system injury, deep infection or instrumentation failure was found. During a follow-up period of 2 years, there was no obvious correction loss or trunk decompensation. CONCLUSION: In idiopathic scoliosis patients with severe and rigid thoracic curves, wide posterior release via a posterior approach may help to correct the deformity in sagittal plan and achieve more coronal correction in these curves. PMID- 23660313 TI - [Features of pelvic parameters in adolescent idiopathic scoliosis and their relationships with spinal sagittal parameters]. AB - OBJECTIVE: To explore the features of pelvic parameters in patients with adolescent idiopathic scoliosis (AIS) and the relationships with spinal sagittal parameters and evaluate their roles in sagittal balance. METHODS: A total of 112 AIS patients from March 2007 to February 2011 were recruited. Six parameters were evaluated from lateral standing radiographs:pelvic incidence (PI), sacral slope (SS), pelvic tilt (PT), lumbar lordosis (LL), thoracic kyphosis (TK) and sagittal vertical axis (SVA). Pearson's correlation was used to determine the relationship between the above parameters and t-test applied to compare the differences between the subgroups: (1) by the major curve types in coronal plane (primary thoracic curve vs. primary lumbar curve); (2) by the value of SVA (positive vs. negative). RESULTS: The values of PI and SS in our cohort were 47.2 degrees and 39.4 degrees and they were lower than those in Caucasians as previously reported. PI was correlated with SS, PT and LL (r = 0.562, 0.773 and 0.278 respectively); TK not correlated with pelvic parameters (PI, PT and SS). SVA correlated with both spinal (TK, LL) and pelvic parameters (PI, PT). In the subgroup analyses, the values of PI and SS were significantly higher in the primary thoracic curve subgroup than those in the primary lumbar curve subgroup (49.4 degrees vs 45.1 degrees , 41.0 degrees vs 38.0 degrees ). The values of PI and PT were distinctively higher in the positive SVA subgroup than those in the negative SVA subgroup (54.6 degrees vs 45.6 degrees , 14.3 degrees vs 6.2 degrees ). CONCLUSION: Ethnic differences exist in the main pelvic parameters and their values are lower in Chinese than in Caucasians. There are also differences among different types of AIS. The values of main pelvic parameters are higher in AIS patients with a primary thoracic curve than in those with a primary lumbar curve. Pelvic parameters play an important role in maintaining a sagittal balance. The main pelvic parameters have influences on sagittal lumbar configuration but little on thoracic segment. A high PI value leads to a forward lean in torso with an increased PT as a result of compensation and vice versa. The alteration of PT is a major compensatory pattern of pelvis. The features of pelvic parameters should be considered during surgical planning. PMID- 23660314 TI - [Osteotomy for severe thoracolumbar kyphosis in advanced ankylosing spondylitis: skipping two-level pedicle subtraction osteotomy]. AB - OBJECTIVE: To explore the feasibility of single-stage skipping two-level pedicle subtraction osteotomy (PSO) for severe thoracolumbar kyphosis (Cobb > 100 degrees ) in advanced ankylosing spondylitis (AS). METHODS: Ten AS patients with thoracolumbar kyphosis undergoing skipping two-level PSO were retrospectively reviewed. The most frequent levels of osteotomy was L1 and L4 (n = 7), followed by T12 and L3 (n = 2) and L2 and L5 (n = 1). All patients were males with a mean age of 28.5 +/- 9.1 years (range: 17 - 47). The pre- and post-operative values of thoracic kyphosis (TK), lumbar lordosis (LL), globe kyphosis (GK), local kyphosis of osteotomized vertebra (LK1, LK2) and sagittal imbalance (SVA) were measured. RESULTS: Significant differences were observed with respects to the improvements of LL, GK, LK1, LK2 and SVA (P < 0.01). LL, GK, LK1, LK2 and SVA improved from 41.9 degrees , 113.4 degrees , 40.5 degrees , -0.3 degrees and 25.2 cm preoperatively to -44.1 degrees , 71.6 degrees , 13.5 degrees ,-26.8 degrees and 5.8 cm postoperatively respectively. The mean operative duration was 370 minutes (range: 290 - 420) and the estimated volume of blood loss 2600 ml (range: 1700 - 3800). Dural tear occurred intra-operatively in 1 patient. One had a transient brachial plexus paralysis and resolved after 1 week postoperatively. One had transient radiculopathy in right lower extremity and recovered completely 3 weeks postoperatively. CONCLUSION: As a safe and effective technique for correction of severe thoracolumbar kyphosis (Cobb > 100 degrees ) secondary to AS, single-stage skipping two-level PSO osteotomy can achieve larger correction and better sagittal alignment with a mean correction of 86 degrees in terms of LL. PMID- 23660315 TI - [A random control study of indomethacin-containing MYCu intrauterine contraceptive device for 60 months]. AB - OBJECTIVE: To explore the clinical efficacy and safety of MYCu intrauterine contraceptive device (IUD) containing indomethacin. METHODS: From October 1 to December 31, 2004, women of child-bearing age requiring IUD for contraception were chosen from the Outpatient Departments of China-Japan Friendship Hospital of Jilin University, Peking University First Hospital, Peking University Third Hospital, Jilin University Second Hospital and Affiliated Shengjing Hospital of China Medical University. They were randomly inserted with MYCuIUD and control TCu380A IUD each for 1000 cases and followed up at 1, 3, 6, 12, 24, 36, 48 and 60 months post-insertion. RESULTS: When MYCu IUD group and TCu380A group 60 months post-insertion were compared, the cumulative pregnancy rates with IUD in situ were 2.38/100 women per year and 2.84/100 women per year respectively. And the difference had no statistical significance (P > 0.05); the cumulative expulsion rates, mostly of partial expulsion and downward movement, were 0.87/100 women per year and 2.94/100 women per year respectively. And the difference had statistical significance (P < 0.05); the cumulative termination rates due to bleeding/pain were 3.57/100 women per year and 4.83/100 women per year respectively. And the difference had no statistical significance (P > 0.05); Side effects in MYCu group were less pronounced than those in TCu group. And the inter-group differences had statistical significance (P < 0.05). CONCLUSION: As a comparatively ideal medicated medical device, MYCu IUD has an excellent contraceptive efficacy, a low rate of expulsion and side effects and good reversibility. Particularly a low occurrence rate of bleeding and pain during early insertion is recommended. Its life expectancy is 15 years. And its contraceptive effectiveness and safety after 5 years should be examined during further follow-ups. PMID- 23660316 TI - [Etiological study of pelvic organ prolapse and stress urinary incontinence with collagen status and metabolism]. AB - OBJECTIVE: To explore the alteration of collagen ultrastructure and content in uterine ligaments and paraurethral tissue and explore whether the alteration may contribute to stress urinary incontinence (SUI) and pelvic organ prolapse (POP). METHODS: The cardinal ligament, uterosacral ligament and paraurethral tissue samples were obtained from 90 subjects undergoing hysterectomy. Collagen ultrastructure was examined with transmission electron microscopy. And collagen content and expression of vasoactive intestinal peptide (VIP) were examined with immunohistochemistry. RESULTS: The smooth muscle fascicles were thinner in the patients of SUI and POP. Arrangement of smooth muscle fascicles was disorderly. Fibroblast was metabolically active. The mean collagen fibril diameters in the SUI and POP groups were larger than that in the control group (P < 0.01). The mean contents of collagen I and III in the SUI and POP groups were lower than that in the control group (P < 0.01). The expression of VIP was lower (P < 0.05). CONCLUSION: Predominance of collagen degradation during tissue repair may contribute to and promote POP and SUI. The decrease of VIP might be related with nerve damage or degeneration to cause or accelerate the progress of pelvic organ prolapse. PMID- 23660317 TI - [Long-term efficacy and safety of adjuvant trastuzumab for HER2-positive early breast cancer]. AB - OBJECTIVE: To explore the long-term efficacy and safety of adjuvant trastuzumab for HER2-positive early breast cancer. METHODS: The clinicopathological data were collected 31 HER2-positive early breast cancer patients on the 1/2-year adjuvant therapy of trastuzumab at our hospital from October 2001 to October 2003. And the disease-free survival, recurrence-free survival, overall survival and safety were respectively analyzed. SPSS 13.0 software was used for statistical analysis. RESULTS: During a median follow-up period of 9.3 years, 6 cases had recurrence, there were 5 cases of second primary cancer and 4 patients died. In total, the 5 and 10-year recurrence-free survival rates were 83.3% and 80.0%, the 5 and 10 year disease-free survival rates 80.6% and 57.3% and the 5 and 10-year overall survival rates 96.8% and 87.1% respectively. The 10-year recurrence-free survival rate of 13 patients with ER and/or PR positive and 18 ER/PR negative patients were 100.0% and 64.7% (chi2 = 5.44, P = 0.019) and 10-year overall survival rate 100% and 77.8% respectively (chi2 = 3.163, P = 0.075). Trastuzmab was well tolerated when used as adjuvant treatment. There was no occurrence of cardiac events. CONCLUSION: Adjuvant trastuzmab has definite efficacies and excellent safety in the treatment of HER2-positive breast cancer patients. And there was no long-term cumulative cardiac toxicity. PMID- 23660318 TI - [Correlation of muscular impairment rating scale with myopathological changes in myotonic dystrophy type 1]. AB - OBJECTIVE: To explore the relationship between muscular impairment rating scale (MIRS) and myopathological changes of myotonic dystrophy type 1 (DM1). METHODS: A total of 46 patients at our hospital from May 2003 to June 2011 were diagnosed as DM1. There were 30 males and 16 females. The age of onset ranged from 10 to 57 years old. The major symptoms included distal extremity weakness and myotonia. They were assessed with MIRS and muscle biopsies. The relationship was examined between MIRS and the variation of fiber size, central nuclear, ragged red fibers, proliferation of connective tissue, sarcoplasmic mass. Statistic analysis of pathological changes was made between the groups of MIRS >= 4 and <= 3. RESULTS: The scores of MIRS were 2 (n = 8), 3 (n = 14), 4 (n = 23) and 5 (n = 1). MIRS had significant correlations with variations of fiber size (P = 0.039, r = 0.305), degree of nuclear translocation (P = 0.002, r = 0.451) and ragged red fibers (P = 0.013, r = 0.364). But there was no significant correlation with the proliferation of connective tissue and sarcoplasmic mass. There were significant differences in nuclear translocation and ragged red fibers. But no significant difference existed in variations of fiber size between the groups of MIRS >= 4 and <= 3. CONCLUSION: The rating scale of MIRS has a certain myopathological basis, especially with regards to the changes in nuclear translocation and ragged red fibers. PMID- 23660319 TI - [Effects of entacapone on plasma homocysteine in Parkinson's disease patients on levodopa]. AB - OBJECTIVE: To explore the effects of entacapone on the plasma level of homocysteine (Hcy) in Parkinson's disease (PD) patients on levodopa. METHODS: This cross-sectional study was made up of 4 groups, i.e. 'L + E' group (primary PD patients on levodopa and entacapone), 'L' group (primary PD patients on levodopa alone), 'L(-)' group (primary PD patients never on levodopa) and control group (people without PD or any other nervous system diseases). They were randomly selected from the PD patient database of our department in September 2012. At the beginning, 60 cases were selected for each group. The C677T genotypes of methylenetetrahydrofolate reductase (MTHFR) were identified and the plasma concentrations of Hcy, folic acid and vitamin B12 detected in each subject. Then group t test, single factor analysis of variance and chi(2) test were used for statistical analysis by SPSS 11.5 software. RESULTS: Among 240 early subjects, 98 cases with CC genotype at 677 site of MTHFR gene were finally recruited. Statistical analysis revealed no differences in age, gender, plasma concentrations of folic acid and vitamin B12 among the groups. The PD duration of 'L + E' group (96 +/- 21 months) were the longest among 3 groups, followed by those of 'L' group (51 +/- 17 months) and 'L(-)' group (21 +/- 6 months). The treatment duration and daily dose of levodopa in 'L + E' group (77 +/- 22 months, 765 +/- 110 mg) were all higher than those in 'L' group (42 +/- 14 months, 673 +/ 73 mg). The plasma Hcy concentrations of 'L + E' group (15.1 +/- 3.1 umol/L) were lower than those of 'L' group (20.4 +/- 4.7 umol/L), but still higher than those of 'L(-)' group (12.2 +/- 2.4 umol/L) and control group (9.1 +/- 2.2 umol/L). The Hcy concentrations of 'L(-)' group were also higher than those of control group. CONCLUSION: Entacapone increases the bioavailability of levodopa and simultaneously alleviates partially its resulting hyperhomocysteinemia. PMID- 23660320 TI - [Complications and clinical outcomes of microwave ablation for liver metastatic cholangiocarcinoma after bilioenteric anastomosis]. AB - OBJECTIVE: To explore the complications and clinical outcome of liver metastatic cholangiocarcinoma after microwave ablation (MWA) in patients with a history of pancreatoduodenectomy or liver resection with bilioenteric anastomosis. METHODS: Retrospective study was made on 10 lesions of intra-hepatic metastatic cholangiocarcinoma undergoing MWA (range: 1.5 - 3.6 cm, mean: 3.3 +/- 1.3 cm) in 6 patients (5 males and 1 female) from February 2008 to October 2011. All had a history of surgical resection for primary neoplasm and bilioenteric anastomosis. Four cases had intrahepatic biliary dilatation pneumatosis. RESULTS: All lesions were completely ablated according to the results of contrast-enhanced ultrasound (CEUS) or contrast-enhanced computed tomography/magnetic resonance imaging (CT/MRI) at Month 1 post-MWA. Liver abscess and fistula occurred in 5 ablation zones (5/10) of 4 patients. Three cases were satisfactorily cured with antibiotic dosing, catheter drainage and supportive care. One case died 13 days after MWA. The overall 1, 2, 3-year survival rates of were 64.8%, 21.6% and 21.0% respectively (median: 15.7 months). CONCLUSION: A high technical success rate of MWA is obtained in the treatment of intrahepatic metastatic cholangiocarcinoma with bilioenteric anastomosis. However, the incidence of abscess formation remains high due to a coexistence of multiple risk factors. PMID- 23660321 TI - [Values of computed tomography angiogram in non-cardiac surgery planning and cardiac risk assessment of coronary atherosclerosis during perioperative period]. AB - OBJECTIVE: To explore the values of detecting coronary atherosclerosis by computed tomography angiogram (CTA) on non-cardiac surgery planning and cardiac risk assessment of coronary atherosclerosis during perioperative period. METHODS: A total of 89 patients with suspected coronary heart disease (CHD) scheduled for non-cardiac surgery underwent coronary CTA to evaluate luminal stenosis and calculate calcification score. There were 56 males and 33 females with a mean age of 65.1 years. Operative sites included chests (n = 29), abdomens and pelvis (n = 26), large vessels (n = 3), bones and joints (n = 19) and other regions (n = 12). Reasons of abandoned or postponed surgery were documented to analyze the influence of CTA results on surgery planning. Cardiac events were recorded to assess the correlation with coronary atherosclerosis. RESULTS: Among them, 75 patients (84.27%) were diagnosed as atherosclerosis while 10 patients (11.24%) were negative; 2 patients had coronary artery bypass and another 2 had stent implantation. According to the results of CTA, 12 operations (13.48%) were canceled and 8 (8.98%) postponed after interventions. Severe stenosis of coronary lumen had significant effects on surgery planning (P = 0.003) while calcification score did not. In patients undergoing surgery as scheduled or after intervention, 1 had atrial fibrillation at post-operation. CONCLUSION: For the patients with suspected CHD scheduled for non-cardiac surgery, severity of coronary stenosis may greatly influence surgery planning. Preoperative coronary CTA may decrease the incidence of cardiac events during perioperative period. PMID- 23660322 TI - [Relationship between macular morphology and visual function in diabetic macular edema]. AB - OBJECTIVE: To investigate the changes and relation between macular morphology and macular visual function in different degrees of diabetic macular edema. METHODS: Seventy-eight eyes of 41 diabetic retinopathy patients were included and graded for diabetic macular edema as follows:31 were graded as no macular edema (NE), 26 as non-clinically significant macular edema (NCSME), and 21 as clinically significant macular edema (CSME). Best corrected visual acuity, macular sensitivity, and macular thickness of all included eyes were examed and quantified. Macular sensitivity and retinal fixation were investigated with MP-1 microperimetry. Optical coherence tomography (OCT) was used to quantify macular thickness. RESULTS: Macular thickness significantly increased and macular sensitivity markedly decreased from the NE to the CSME group (P < 0.01), Visual acuity obviously decreased in the CSME group (P < 0.01) compared to the NE and NCSME group, but there was no statistical difference between the NE group and NCSME group. Retinal fixation type was not significantly different among three groups. Visual acuity and macular sensitivity correlated significantly in these three groups (r = -0.751, P < 0.01; r = -0.583, P < 0.01; r = -0.679, P < 0.01). The correlations were noted between retinal sensitivity and macular thickness as well as between visual acuity and macular thickness in the CSME group (r = 0.465, P < 0.05; r = 0.599, P < 0.01), but not in the NE group or in the NCSME group. CONCLUSIONS: Patients will have retinal morphologic and functional changes in early stage of DME, both of which are significantly related as the disease develops. MP-1 microperimetry proved to be consistent with VA in the evaluation of visual function, and may be more sensitive to investigate the changes of macular visual function in the early stage of macular edema. PMID- 23660323 TI - [Anesthetic management for patients undergoing total thoracoabdominal aorta replacement without cardiopulmonary bypass]. AB - OBJECTIVE: To summarize the experience in anesthetic management for total thoracoabdominal aorta replacement without cardiopulmonary bypass. METHODS: From October 2009 to September 2010, 10 patients of Fuwai Hospital received off-pump total thoracoabdominal aorta replacement. Of these patients, 5 were subjected to Standford B aortic dissection, 2 were Standford A aortic dissection received total aortic arch replacement combined with transaortic stented graft implantation into the descending aorta.1 were Marfan's syndrome, and 2 were thoracoabdominal aorta. All operations used the technique which preserved blood was transfused back by pump via the femoral artery. RESULTS: The average surgery time was (7.4 +/- 1.2) h and extubation time was (14.1 +/- 2.5) h, the descending thoracic aorta cross clamp time was (11.5 +/- 3.6) min, the intercostal artery reconstruction time was (16.4 +/- 5.5) min, the required amount of blood products was fresh frozen plasma (600.5 +/- 542.8) ml, platelet(1.7 +/- 0.8) U, red blood cell (4.3 +/- 2.4) U, auto blood salvage (465.7 +/- 242.3) ml. Three patients occurred atelectasis and one patient occurred sero peritoneum postoperation. All of the 10 patients were discharged from hospital without any neurologic complications. CONCLUSION: The anesthetic management for total thoracoabdominal aorta replacement without cardiopulmonary bypass is feasible. It can reduce the side effects of deep hypothermia circulatory arrest and had a good effect. PMID- 23660324 TI - [Contrast of curative effect and complications between peripheral venous thrombolysis and catheter-direct thrombolysis for acute deep venous thrombosis in lower limbs]. AB - OBJECTIVE: To evaluate the effects of catheter-direct thrombolysis in acute deep venous thrombosis (DVT). METHODS: A total of 86 cases were divided into 2 groups of peripheral venous thrombolysis (group A, n = 33) and catheter-direct thrombolysis (group B, n = 53). The curative effect of two groups was compared by swelling rate and vascular potency. RESULTS: No significant difference existed in swelling rate between two groups (P > 0.05). Vascular patency rates of group B was significantly better than those of group A (P < 0.01). The incidence of bleeding had no significant difference (P > 0.05) and there was no asymptomatic pulmonary embolism in two groups. CONCLUSION: Both treatments of acute DVT are effective in improving symptoms. But catheter-directed thrombolysis results in significant vascular patency rate and does not increase the risk of thrombolytic bleeding. PMID- 23660325 TI - [Risk factors of predicting residual disease in women with stage I a1 squamous cervical carcinoma after conization]. AB - OBJECTIVE: To evaluate the prevalence and influencing factors of residual disease in women with stage I a1 squamous cervical carcinoma after conization. METHODS: The medical records and histopathologic slides of 83 women diagnosed with stage I a1 squamous cervical carcinoma after cervical conization undergoing subsequent hysterectomy at our hospital between January 2003 and December 2007 were reviewed. The correlations between the presence of residual lesions and clinicopathological features were analyzed. RESULTS: Among them, 31 (37.3%) had residual disease in hysterectomy specimens, including CIN1 (n = 5), CIN2-3 (n = 10), microinvasive carcinoma (n = 11) and invasive carcinoma (n = 5). In univariate analysis, menopause, procedure of conization, and status of cone margins were associated with the prevalence of residual disease in stage I a1 cervical carcinoma after conization. However, Logistic regression analysis revealed status of cone margins as an independent risk factor for residual disease in stage I a1 cervical carcinoma after conization. CONCLUSION: Status of cone margins is an independent risk factor for residual disease in stage I a1 cervical carcinoma after conization. Further treatment should be performed in patients with positive or nearing cone margins. PMID- 23660326 TI - [Local adenosine A1 receptors of baihui acupoint mediate cerebral ischemia tolerance induced by Electroacupuncture]. AB - OBJECTIVE: To investigate whether local A1R of Baihui acupoint mediate cerebral ischemia tolerance induced by electro-acupuncture (EA). METHODS: Sixty SD rats were randomly divided into five groups, i.e., the sham-operation (S) group, the model group (M), the electroacupuncture (E) group, the CCPA group and the DMSO group. The focal cerebral ischemia/reperfusion model was established by middle cerebral artery occlusion (MCAO) in rats. Rats in the E group were received EA pretreatment baihui acupoint at 2 h before established MCAO. The rats in DMSO group and the CCPA group were injected with DMSO (20 ul) and CCPA (0.1 mmol/L) 20 ul into Baihui, respectively, at 2 h before established MCAO. After 24 h reperfusion, the rats' behavior, cerebral infarct volume, the cerebral Bcl-2 protein expression were assessed. RESULTS: Compared with M group, the rats' behavior was improved, the cerebral infarct volume was decreased and the Bcl-2 protein expression was up-regulated (P < 0.05) in the E group. Compared with M and DMSO group, the rats' behavior was improved, the cerebral infarct volume was decreased and the Bcl-2 protein expression was up-regulated (P < 0.05) in the CCPA group. There were no statistical differences between CCPA and E group. CONCLUSIONS: EA induced cerebral ischemia tolerance. Local A1R of Baihui acupoint possible mediate cerebral ischemia tolerance induced by Electroacupuncture. PMID- 23660327 TI - [Study on the association between genetic variation of gag gene and HLA restricted CTL response in HIV-1 B' infected Chinese people]. AB - OBJECTIVE: To identify the genetic variation of Gag gene in HIV-1 B' subtype infected Chinese people and to evaluate the association between the positive selection sites and HLA restricted CTL response. METHODS: We downloaded all HIV-1 B' subtype gag gene sampled from China from the LANL HIV database. The sequences were grouped by years of collection and the mean intra-subtype diversity and divergence were examined by MEGA 5.0 software. The sites under positive selection were estimated by using Hyphy software. Then analyzed the association between positively selected sites and HLA restricted CTL epitopes. RESULTS: A set of 122 B' subtype HIV-1 gag sequences were collected from Henan, Hubei, Liaoning and Yunnan provinces, grouped by sampling year as < 2001, 2001 - 2003, 2004 - 2006 and 2007 - 2010. The mean intra-subtype diversity and divergence increased over time (r(1) = 0.497, P1 < 0.001; r(2) = 0.593, P2 < 0.001). This analysis revealed 34 positively selected sites and 97.1% of these sites were located within 47 known CTL epitopes. The most frequent HLA was HLA-A*02 (21.6%) followed by A*11(9.8%), B*35(9.8%) and B*57(5.9%). The percentages of HLA-A/B/C limited CTL epitopes were 43.1%, 49.0% and 7.9%, respectively. CONCLUSION: The mean intra subtype diversity and divergence of B' subtype gag sequences increased over time. B' subtype HIV-1 virus has accumulated adaptations to HLA restricted CTL responses in HIV-1 infected Chinese. PMID- 23660328 TI - [Effect of mild hypothermia on the expression of acid-sensing ion channels 1a and 2a following global cerebral ischemia-reperfusion in rats]. AB - OBJECTIVE: To investigate the effects of mild hypothermia on the expression of ASIC1a and ASIC2a in the rat hippocampus following global cerebral ischemia reperfusion, so as to speculate the underlying mechanisms of neuroresuscitation. METHODS: Ninety five male SD rats were randomly divided into five groups (n = 19): sham operation group (I), model group (II), mild hypothermia group (III), PcTX1 group (IV), mild hypothermia combined PcTX1 group (V). Transient (15 min) global cerebral ischemia was induced by the four-vessel occlusion. PcTX1 (500 ng/ml) 6 ul were injected into lateral cerebral ventricle immediately after reperfusion in group IV and V, while the equal volume of normal saline was injected into lateral cerebral ventricle immediately after reperfusion in the other three groups. At the same time, mild hypothermia after reperfusion was performed and lasted for 6 hours in group III and V, the rectal temperature was reduced to 32 - 33 degrees C within 15 min, while it was maintained at 36 - 37 degrees C by lamp in other three groups. Determination the expression of ASIC1a and ASIC2a protein at 6 h and 24 h of reperfusion, and the expression of ASIC1a and ASIC2a mRNA at 24 h of reperfusion. Observe the pathomorphological changes of hippocampal CA1 neurons at 24 h of reperfusion. Detect the brain water content at 72 h of reperfusion. RESULTS: The difference in the expression of ASIC1a mRNA and protein among the groups was not changed significantly (P > 0.05). Compared with group I, the expression of ASIC2a mRNA and ASIC2a protein was up-regulated in other groups (P < 0.05). It was significantly higher in group III and V than in group II and IV (P < 0.05). Compared to 6 h of reperfusion, the expression of ASIC2a protein was higher in group II, III, IV and V respectively after 24 h of reperfusion. Compared to group I, the number of pyramidal cells in CA1 region of hippocampus in group II, III, IV and V were decreased at 24 h of reperfusion (P < 0.01). Compared to group II, the number of pyramidal cells in CA1 region of hippocampus in group III, IV and V were increased at 24 h of reperfusion (P < 0.01); and compared to group III and IV, the number of pyramidal cells at 24 h of reperfusion in group V was significantly higher (P < 0.01). Compared to group I, the content of brain water in II, III and IV group were increased at 72 h of reperfusion (P < 0.01). Compared to group II, the content of brain water in group III, IV and V were decreased at 72 h of reperfusion (P < 0.01). Giving mild hypothermia or PcTX1 could alleviate the damage in CA1 region of hippocampus, with the best effect in group V, which administers PcTX1 combined mild hypothermia. CONCLUSION: Mild hypothermia attenuates global cerebral ischemia reperfusion of rat, which may up-regulate the expression of ASIC2a mRNA and protein. Mild hypothermia combined by PcTX1 could induce neuroresuscitation. PMID- 23660329 TI - [The effects of low-frequency electric stimulus on hippocampal of Effects of low frequency electric stimulus on hippocampal of alpha5 subunit of extra synapse GABAA receptor in kainic acid-induced epilepsy rats]. AB - OBJECTIVE: To explore the effects of low-frequency electric stimulus (LFS) on hippocampal of alpha5 subunit of extrasynaptic GABAA receptor in kainic acid induced epilepsy rats and explore the possible mechanism of LFS on hippocampus to treat epilepsy. METHODS: A total of 32 male Sprague-Dawley rats were divided randomly into 4 groups:epileptic, pseudo-surgery, LFS treatment and control. The expression of alpha5 subunit of extrasynaptic GABAA receptor and the association with the curative effects of LFS were evaluated by behavioristics, real-time fluorogenic quantitative polymerase chain reaction (PCR) and Western blot. RESULT: After treatment, the number of seizures in LFS group were significantly lower than that in the epileptic and pseudo-surgery groups (2.88 +/- 0.83 vs 8.50 +/- 0.93 and 8.88 +/- 0.83) (P < 0.01). The results of real-time PCR demonstrated that the expression of mRNA of alpha5 subunits in LFS treatment group was obviously higher than that in epileptic and pseudo-surgery groups (0.74 +/- 0.20 vs 0.30 +/- 0.16 and 0.31 +/- 0.16) (P < 0.01), but was lower than 1.10 +/- 0.23 in control group. Western blot demonstrated that the protein expression of alpha5 subunits in LFS (0.75 +/- 0.09) and control (0.88 +/- 0.09) groups were dramatically higher than that in epileptic (0.22 +/- 0.08) and pseudo-surgery (0.26 +/- 0.08) groups (P < 0.01). CONCLUSION: Low-frequency electric stimulus on hippocampus is effective in controlling epileptic seizures. And the mechanism may be related with the expression level of alpha5 subunits of extrasynaptic GABAA receptor. PMID- 23660330 TI - Linking beta-methylamino-L-alanine exposure to sporadic amyotrophic lateral sclerosis in Annapolis, MD. AB - Most amyotrophic lateral sclerosis (ALS) cases occur sporadically. Some environmental triggers have been implicated, including beta-methylamino-L-alanine (BMAA), a cyanobacteria produced neurotoxin. This study aimed to identify environmental risk factors common to three sporadic ALS patients who lived in Annapolis, Maryland, USA and developed the disease within a relatively short time and within close proximity to each other. A questionnaire was used to identify potential risk factors for ALS among the cohort of patients. One common factor among the ALS patients was the frequent consumption of blue crab. Samples of blue crab from the patients' local fish market were tested for BMAA using LC-MS/MS. BMAA was identified in these Chesapeake Bay blue crabs. We conclude that the presence of BMAA in the Chesapeake Bay food web and the lifetime consumption of blue crab contaminated with BMAA may be a common risk factor for sporadic ALS in all three patients. PMID- 23660331 TI - Six-monthly diabetes monitoring of well-controlled patients: experiences of primary care providers. AB - AIMS: To examine experiences of primary care providers with six-monthly diabetes monitoring of well-controlled patients. METHODS: This study was part of the EFFIMODI study, examining whether six-monthly monitoring of well-controlled (HbA1c <=58 mmol/mol, systolic blood pressure <=145 mmHg and total cholesterol <=5.2 mmol/l) type 2 diabetes patients results in equivalent cardiometabolic control compared to three-monthly monitoring. Primary care providers completed a questionnaire about their experiences with six-monthly diabetes monitoring, whether they want to continue six-monthly monitoring and for which type of patients six-monthly monitoring is sufficient. RESULTS: Of 163 questionnaires, 157 (96.3%) were completed and returned. Only 14 (8.9%) primary care providers were negative about the six-monthly monitoring and 102 (65.0%) would like to continue six-monthly monitoring. Primary care providers disagreed about patients' ability to determine their own monitoring frequency and whether six-monthly monitoring was suitable for all well-controlled type 2 diabetes patients. Practical concerns emerged such as the inability to declare healthcare costs and the unsuitability of electronic health record systems. CONCLUSIONS: Almost two out of three primary care providers would like to continue six-monthly monitoring of well-controlled type 2 diabetes patients. However, some diabetes care providers should be convinced and some practical concerns should be solved. PMID- 23660332 TI - Comparison of treatments of peripheral arterial disease with mesenchymal stromal cells and mesenchymal stromal cells modified with granulocyte and macrophage colony-stimulating factor. AB - BACKGROUND AIMS: Granulocyte macrophage-colony stimulating factor (GM-CSF) promotes vessel formation through several molecular signaling pathways. Mesenchymal stromal cells (MSCs) have an important role in neovasculogenesis during ischemia because they release pro-angiogenic paracrine factors, pro survival and immunomodulatory substances and can differentiate into endothelial cells. The objective of this study was to evaluate whether there is synergy between GM-CSF and MSCs in recovering ischemic limbs. METHODS: MSCs from mouse bone marrow were transduced with a lentiviral vector expressing GM-CSF and injected into animals with surgically induced limb ischemia, with unmodified MCSs used as control. The evolution of limb necrosis was evaluated for 1 month. Muscle strength was assessed on the 30th day, and the animals were euthanized to determine the muscle mass and to perform histological analyses to determine the degree of cellular infiltration, capillary and microvessel densities, fibrosis, necrosis and tissue regeneration. RESULTS: Both treatments were able to ameliorate ischemia, decrease the areas of fibrosis, necrosis, adipocytes and leukocyte infiltrates and increase the number of capillaries. The addition of GM CSF promoted the formation of larger vessels, but it also resulted in more fibrosis and less muscle mass without affecting muscle force. CONCLUSIONS: Both treatments resulted in a remarkable amelioration of ischemia. More fibrosis and less muscle mass produced by the overexpression of GM-CSF did not affect muscle functionality significantly. Importantly, MSCs overexpressing GM-CSF produced larger vessels, which is an important long-term advantage because larger vessels are more efficient in the reperfusion of ischemic tissues physiologically. PMID- 23660333 TI - Opposite effects of JNK and p38 MAPK signaling pathways on furazolidone stimulated S phase cell cycle arrest of human hepatoblastoma cell line. AB - Furazolidone (FZD), a synthetic nitrofuran with a broad spectrum of antimicrobial actions, is known to induce genotoxicity and potential carcinogenicity in several types of cells, but little is known about its p38 mitogen-activation protein kinase (p38 MAPK) and c-Jun N-terminal protein kinase (JNK) pathways in human hepatoblastoma cell line (HepG2). Given the previously described essential roles of p38 MAPK and JNK pathways in HepG2 cells, we undertook the present study to investigate the roles of p38 MAPK and JNK pathways in cell cycle arrest of HepG2 cells stimulated with FZD. Here we reported that FZD could obviously induce S phase cell cycle arrest, suppress cell growth, increase the activity of phosphorylated p38 (p-p38), and decrease the activity of phosphorylated JNK (p JNK) in HepG2 cells. Simultaneously, inhibition of p38 MAPK pathway could significantly reduce FZD-stimulated S phase cell cycle arrest, active cell growth, decrease the activity of p-p38, and increase the activity of p-JNK. To the opposite, inhibition of JNK pathway could significantly increase FZD stimulated S phase cell cycle arrest, suppress cell growth, decrease the activity of p-JNK, and increase the activity of p-p38. These results demonstrate that JNK and p38 MAPK pathways have opposite roles in FZD-stimulated S phase cell cycle arrest of HepG2 cells. FZD induces S phase cell cycle arrest and suppresses cell proliferation of HepG2 cells via activating the pathway from p38 to p-p38 and inhibiting the pathway from JNK to p-JNK. PMID- 23660334 TI - Sanguinarine induces apoptosis in human colorectal cancer HCT-116 cells through ROS-mediated Egr-1 activation and mitochondrial dysfunction. AB - We examined the effects of sanguinarine, a benzophenanthridine alkaloid, on reactive oxygen species (ROS) production and the association of these effects with apoptotic cell death in a human colorectal cancer HCT-116 cell line. Sanguinarine generated ROS, which was followed by a decrease in the mitochondrial membrane potential (MMP), the activation of caspase-9 and -3, and the down regulation of anti-apoptotic proteins, such as Bcl2, XIAP and cIAP-1. Sanguinarine also promoted the activation of caspase-8 and truncation of Bid (tBid). However, the quenching of ROS generation by N-acetyl-l-cysteine, a scavenger of ROS, reversed the sanguinarine-induced apoptosis effects via inhibition of the MMP collapse, tBid expression, and activation of caspases. Sanguinarine also markedly induced the expression of the early growth response gene-1 (Egr-1) during the early period, after which expression level was decreased. In addition, HCT-116 cells transfected with Egr-1 siRNA displayed significant blockage of sanguinarine-induced apoptotic activity in a ROS dependent manner. These observations clearly indicate that ROS, which are key mediators of Egr-1 activation and MMP collapse, are involved in the early molecular events in the sanguinarine-induced apoptotic pathway acting in HCT-116 cells. PMID- 23660335 TI - Attenuation of subchronic formaldehyde inhalation toxicity with oral administration of glutamate, glycine and methionine. AB - Inhalation exposure of outbred female white rats (initial age about 4 months) to formaldehyde vapours (12.8 +/- 0.69 mg/m(3)) 4h per day, 5 days per week during 10 weeks induced statistically significant changes in some indices characterizing differential WBC count, functional status of the central nervous system and liver, redox and porphyrin metabolisms, bone marrow micronuclei count as well as free amino acid spectrum of the blood serum. The development of intoxication was accompanied by increased urinary excretion of formaldehyde, formic acid and methanol. Daily oral administration of glutamate (150-180 mg), glycine (12 mg) and methionine (50mg) in combination rendered all of the formaldehyde's toxic effects reduced. This administration also caused a significant increase in the ratio between the rates of excretion of formic acid and non-metabolized formaldehyde. This shift supposedly reflects activation of oxidative detoxifying biotransformation of formaldehyde. Taking into consideration that the combination of amino acids used in this study proved innocuous in protectively effective doses, the administration in this combination may be recommended to humans exposed to high levels of formaldehyde in workplace or ambient air. PMID- 23660336 TI - Protein binding modulates the cellular uptake of silver nanoparticles into human cells: implications for in vitro to in vivo extrapolations? AB - Nanoparticles (NP) absorbed in the body will come in contact with blood proteins and form NP/protein complexes termed protein coronas, which may modulate NP cellular uptake. This study quantitated human epidermal keratinocyte (HEK) uptake of silver (Ag) NP complexed to different human serum proteins. Prior to HEK dosing, AgNP (20nm and 110nm citrate BioPureTM; 40nm and 120nm silica-coated) were preincubated for 2h at 37 degrees C without (control) or with physiological levels of albumin (44mg/ml), IgG (14.5mg/ml) or transferrin (3mg/ml) to form protein-complexed NP. HEK were exposed to the protein incubated AgNP for 3h, rinsed and incubated for 24h, rinsed in buffer and lysed. Ag was assayed by inductively-coupled plasma optical emission spectrometry. Uptake of Ag in HEK was <4.1% of applied dose with proteins suppressing citrate, but not silica coated Ag uptake. IgG exposure dramatically reduced 110nm citrate AgNP uptake. In contrast, greatest uptake of 20nm silica AgNP was seen with IgG, while 110nm silica AgNP showed minimal protein effects. Electron microscopy confirmed cellular uptake of all NP but showed differences in the appearance and agglomeration state of the NP within HEK vacuoles. This work suggests that NP association with different serum proteins, purportedly forming different protein coronas, significantly modulates Ag uptake into HEK compared to native NP uptake, suggesting caution in extrapolating in vitro uptake data to predict behavior in vivo where the nature of the protein corona may determine patterns of cellular uptake, and thus biodistribution, biological activity and toxicity. PMID- 23660337 TI - Differential stage-dependent regulation of prostatic epithelial morphogenesis by Hedgehog signaling. AB - Published studies of Hh (Hedgehog) signaling in the developing prostate have reported varying and discrepant effects on epithelial proliferation, ductal morphogenesis and growth. We report here that these differing observations accrue from stage-specific effects of Hh signaling in the developing prostate. Using in vitro organ cultures of the E16 UGS and P1 prostate, we show that ectopic Hh pathway activation stimulates epithelial proliferation prenatally, but inhibits epithelial proliferation postnatally. Extrapolating from previously published observations that Hh target gene expression is altered in the reactive stroma of prostate cancer, we examined and found discordant regulation of a subset of target genes by Hh signaling in the prenatal and postnatal prostate. Cell based studies and recombination assays show that these changes are not simply attributable to the age of the mesenchyme or the epithelium, but more likely reflect a complex regulation by the cellular microenvironment. To determine the in vivo relevance of these observations, we examined the effect of transgenic activation of Hh signaling on epithelial proliferation in the prenatal and postnatal prostate and confirmed the operation of stage-specific effects. These observations demonstrate stage-specific differences in the effect of Hh signaling on epithelial proliferation in the developing prostate and suggest that these are a product of complex interactions determined by the cellular microenvironment. PMID- 23660338 TI - Neonatal mesenchymal-like cells adapt to surrounding cells. AB - Hematopoietic cord blood (CB) transplantations are performed to treat patients with life-threatening diseases. Besides endothelial cells, the neonatal multipotent stromal cell subpopulations CDSCs (CB-derived stromal cells) and USSCs (unrestricted somatic stromal cells) are like bone marrow (BM) SCs interesting candidates for clinical applications if detailed knowledge is available. Clonal USSC compared to CDSC and BMSC lines differ in their developmental origin reflected by a distinct HOX expression. About 20 (out of 39) HOX genes are expressed in CDSCs (HOX+), whereas native USSCs reveal no HOX gene expression (HOX-). Moreover, USSCs display a lineage-specific absence of the adipogenic differentiation potential. As the specific HOX code can be ascribed to topographic bodysites it may be important to match the HOX code of transplanted cells to the tissue of interest. Herein co-culture experiments were performed, presenting a novel approach to modulate the differentiation potency of USSCs towards HOX positive stromal cells. After co-culturing native USSCs with CDSCs and BMSCs, USSCs adapt a positive HOX code and gain the adipogenic differentiation capacity. These results present for the first time modulation of a lineage-specific differentiation potential by co-culture. Finally, USSCs can be claimed as potential candidates to substitute unique progenitor cell populations in clinical approaches. PMID- 23660339 TI - Hemokinin-1 competitively inhibits substance P-induced stimulation of osteoclast formation and function. AB - Hemokinin-1 (HK-1) is a novel member of the tachykinin family that is encoded by preprotachykinin 4 (TAC4) and shares the neurokinin-1 receptor (NK1-R) with substance P (SP). Although HK-1 is thought to be an endogenous peripheral SP-like endocrine or paracrine molecule in locations where SP is not expressed, neither the distribution of HK-1 in the maxillofacial area nor the role HK-1 in bone tissue have been examined. In this study, we investigated the distribution of HK 1 in trigeminal ganglion (TG) and maxillary bone, and assessed the expression of HK-1 during osteoclast differentiation. In vivo, rat molars were loaded for 5 days using the Waldo method. In vitro, rat osteoclast-like cells were induced from bone marrow cells. HK-1 distribution and expression were examined by immunofluorescence staining and reverse transcription polymerase chain reaction (RT-PCR). In vivo, HK-1 was localized in rat TG neurons; however, the number of HK-1-positive neurons was less than that of SP-positive neurons. In the maxillary bone, nerve fibers, blood vessels, and osteocytes were immunopositive for HK-1. Furthermore, HK-1-positive immunoreactivity was found in osteoclasts on the pressure side. In vitro, PCR showed that TAC4 and NK1-R mRNA was expressed in osteoclasts as well as in bone marrow cells. Although SP (10-7 M) treatment led to an increased number of osteoclasts, HK-1 (10-7 M) treatment did not. The numbers of biotin-labeled HK-1 peptides bound osteoclasts significantly decreased upon incubation with unlabeled SP and biotin-labeled HK-1 compared with biotin labeled HK-1 alone. These results suggest that HK-1 may not stimulate the differentiation and function of osteoclasts. SP-stimulated osteoclast formation is competitively regulated by peripheral HK-1 through NK1-Rs. PMID- 23660340 TI - Bio-microfluidic platform for gold nanoprobe based DNA detection--application to Mycobacterium tuberculosis. AB - We have projected and fabricated a microfluidic platform for DNA sensing that makes use of an optical colorimetric detection method based on gold nanoparticles. The platform was fabricated using replica moulding technology in PDMS patterned by high-aspect-ratio SU-8 moulds. Biochips of various geometries were tested and evaluated in order to find out the most efficient architecture, and the rational for design, microfabrication and detection performance is presented. The best biochip configuration has been successfully applied to the DNA detection of Mycobacterium tuberculosis using only 3 ul on DNA solution (i.e. 90 ng of target DNA), therefore a 20-fold reduction of reagents volume is obtained when compared with the actual state of the art. PMID- 23660341 TI - Fabrication of a highly sensitive adenosine aptasensor based on covalent attachment of aptamer onto chitosan-carbon nanotubes-ionic liquid nanocomposite. AB - The present study describes the fabrication of a novel electrochemical aptasensor for the label-free determination of adenosine. The immobilization surface is prepared by the modification of a glassy carbon (GC) electrode with a robust nanocomposite containing multiwalled carbon nanotubes, ionic liquid and chitosan(MWCNTs-IL-CHIT). Amine-terminated 12-mer capture probe(ssDNA1) is covalently attached onto the nanocomposite using glutaraldehyde (GA) as the linking agent, a 32-mer adenosine-specific aptamer (ssDNA2) immobilized onto the electrode surface through hybridization with the ssDNA1 and methylene blue (MB) used as the redox probe. The peak current of MB decreased linearly with increasing adenosine concentration due to the formation of aptamer-adenosine complex and displacement of the aptamer from the modified electrode surface. The aptasensor showed a low detection limit of 150 pM and high sensitivity of 0.67 MUAnM-1 at a concentration range of up to 0.4 MUM. Through the control experiments performed by using some other nucleosides such as guanosine, cytidine and uridine, the excellent specificity of this sensor toward adenosine detection is demonstrated. The potential applicability of the aptasensor is successfully applied for measuring adenosine concentration in blood serum and drug formulation samples.The herein described methodology may hold great promise for fabrication of other aptasensors and immunosensors. PMID- 23660342 TI - Tissue distribution, ontogeny, and chemical induction of aldo-keto reductases in mice. AB - Aldo-keto reductases (Akrs) are a conserved group of NADPH-dependent oxido reductase enzymes. This study provides a comprehensive examination of the tissue distribution of the 16 substrate-metabolizing Akrs in mice, their expression during development, and whether they are altered by chemicals that activate distinct transcriptional factor pathways. Akr1c6, 1c14, 1c20, and 1c22 are primarily present in liver; Akr1a4, 1c18, 1c21, and 7a5 in kidney; Akr1d1 in liver and kidney; Akr1b7 in small intestine; Akr1b3 and Akr1e1 in brain; Akr1b8 in testes; Akr1c14 in ovaries; and Akrs1c12, 1c13, and 1c19 are expressed in numerous tissues. Liver expression of Akr1d1 and Akr1c is lowest during prenatal and postnatal development. However, by 20 days of age, liver Akr1d1 increases 120 fold, and Akr1c mRNAs increase as much as 5-fold (Akr1c19) to 1000-fold (Akr1c6). Treatment of mice with chemical activators of transcription factors constitutive androgen receptor (CAR), pregnane X receptor (PXR), and the nuclear factor erythroid-2 (Nrf2) transcription factor alters liver mRNAs of Akrs. Specifically, CAR activation by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) increases mRNAs of Akr1b7, Akr1c6, Akr1c19, and Akr1d1, whereas PXR activation by 5 pregnenolone-16alpha-carbonitrile (PCN) increases the mRNA of Akr1b7 and suppresses mRNAs of Akr1c13 and Akr1c20. The Nrf2 activator 2-cyano-3,12 dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) induces mRNAs of Akr1c6 and Akr1c19. Moreover, Nrf2-null and Nrf2 overexpressing mice demonstrate that this induction is Nrf2-dependent. PMID- 23660343 TI - Sclerotherapy of face and oral cavity low flow vascular malformations: our experience. AB - We have reviewed our experience (15 patients during the period 2008-2012) in the treatment of low flow vascular malformations (LFVMs) of the face and oral cavity with polidocanol foam sclerotherapy. They were diagnosed clinically and with the help of Doppler ultrasound and magnetic resonance imaging. The maximum dose recommended for each session was 20mg/day and the minimum interval between sessions was 4 weeks. Embolisation was repeated as many times as needed until the size of the lesions and the symptoms had been reduced sufficiently. Patients were followed up 1, 6, and 12 months after treatment had finished, and the size of the lesions was assessed objectively. The 8 men and 7 women were aged between 18 and 71 (mean 44) years. The lesions had reduced and symptoms had improved in all cases. During the follow-up period, one patient relapsed and developed further symptoms. The pain and postoperative inflammation were successfully controlled with an analgesic and an anti-inflammatory drug. There was only one complication (superficial necrosis), which healed completely by second intention. Direct puncture and sclerosis with polidocanol foam are an effective treatment for LFVM of the face and oral cavity. PMID- 23660344 TI - Sex differences in revascularization interventions after acute ischemic stroke. AB - BACKGROUND: Studies suggest that women are less likely than men to receive intravenous (IV) tissue plasminogen activator (tPA) for acute ischemic stroke (AIS). Relatively little is known about whether this sex disparity in AIS management extends beyond IV tPA use, reflects national practice patterns, or is changing. METHODS: Data from the Nationwide Inpatient Sample from 1997 to 2006 were used to identify adults (>=18 years of age) who were discharged with a primary diagnosis of AIS (n = 4,453,207) in the United States. Of 605,960 individuals admitted to 1056 hospitals that performed reperfusion/revascularization procedures, sex-specific rates of cerebrovascular reperfusion (e.g., IV tPA, intra-arterial therapy, angioplasty, stent, or carotid endarterectomy [CEA]), and cardiac reperfusion (e.g., catheterization, angioplasty, stent, or bypass graft) were determined before and after adjustment for sociodemographic, clinical, and hospital factors. RESULTS: Men were more likely than women to receive IV tPA (prevalence ratio [PR] 1.37, 95% confidence interval [CI] 1.32-1.42), catheter angiography (PR 1.36, 95% CI 1.33-1.38), intracranial or extracranial angioplasty/stent (PR 1.73, 95% CI 1.49-2.01), CEA (PR 1.79, 95% CI 1.72-1.86), or any cardiac reperfusion therapy (PR 1.62, 95% CI 1.53-1.71). Multivariable adjustment slightly attenuated the sex disparity. Use of all procedures except CEA rose from 1997 to 2006 in both sexes, but IV tPA use increased at a higher rate for women (compared to men); by 2006, there was no sex difference. CONCLUSIONS: Over the last decade, women hospitalized for AIS in the United States were less likely than men to receive cerebrovascular and cardiac reperfusion therapies. However, the IV tPA treatment sex disparity may have been eliminated. PMID- 23660345 TI - A case of sinus arrest and post-hiccup cough syncope in medullary infarction. AB - We describe asymptomatic sinus arrest and post-hiccup cough syncope in a patient with medullary infarction. A 78-year-old woman developed arrhythmia, hiccup, and cough syncope attacks. Neurological examination was not remarkable. Cough syncope occurs after hiccup attacks. Bradycardia and decreased blood pressure were also present after the beginning cough. Holter 24-hour electrocardiography monitor exhibited 65 episodes of asymptomatic sinus arrest more than 3 seconds. Magnetic resonance imaging disclosed acute infarction in the bilateral medial regions and the right tegmentum of the upper and middle medulla oblongata. Cerebral angiography showed severe atherosclerotic changes in the vertebral arteries. These clinicoradiological findings suggested that a distinct topography of medullary lesions could cause a series of cardiovascular and respiratory dysfunction. Thus, physicians should pay more attention to the medullary lesion in patients with arrhythmia and syncope. PMID- 23660346 TI - An approach to define potential radon emission level maps using indoor radon concentration measurements and radiogeochemical data positive proportion relationships. AB - The aim of this paper is to present the first step of a new approach to make a map of radonprone areas showing different potential radon emission levels in the Quebec province. This map is a tool intended to assist the Quebec government in identifying populations with a higher risk of indoor radon gas exposure. This map of radon-prone areas used available radiogeochemical information for the province of Quebec: (1) Equivalent uranium (eU) concentration from airborne surface gamma ray surveys; (2) uranium concentration measurements in sediments; and (3) bedrock and surficial geology. Positive proportion relationships (PPR) between each individual criterion and the 1417 available basement radon concentrations were demonstrated. It was also shown that those criteria were reliable indicators of radon-prone areas. The three criteria were discretized into 3, 2 and 2 statistically significant different classes respectively. For each class, statistical heterogeneity was validated by Kruskal-Wallis one way analyses of variance on ranks. Maps of radon-prone areas were traced down for each criterion. Based on this statistical study and on the maps of radon-prone areas in Quebec, 18% of the dwellings located in areas with an equivalent uranium (eU) concentration from airborne surface gamma-ray surveys under 0.75 ppm showed indoor radon concentrations above 150 Bq/m3. This percentage increases to 33% when eU concentrations are between 0.75 ppm and 1.25 ppm and exceeds 40% when eU concentrations are above 1.25 ppm. A uranium concentration in sediments above 20 ppm showed an indoor radon concentration geometric mean of 215 Bq/m3 with more than 69% of the dwellings exceeding 150 Bq/m3 or more than 50% of dwellings exceeding the Canadian radon guideline of 200 Bq/m3. It is also shown that the radon emission potential is higher where a uranium-rich bedrock unit is not covered by a low permeability (silt/clay) surficial deposit. PMID- 23660347 TI - Chordotonal organs. PMID- 23660348 TI - Dermal fin rays and scales derive from mesoderm, not neural crest. PMID- 23660349 TI - Scales of fish arise from mesoderm. PMID- 23660350 TI - Plant venation: from succulence to succulents. AB - Succulent plants dominate certain semi-arid habitats. A new study shows independent origins of 3D venation reflect hydraulic advantages for tissue succulence, and has implications for the molecular development of venation and tissue differentiation, as well as the evolution of crassulacean acid metabolism. PMID- 23660351 TI - Mother-infant communication: carrying understanding to a new level. AB - A recent study has found that carrying - not just holding - by human mothers has a specific calming effect on crying infants, inducing a coordinated physiological response that includes a reduction in heart rate. A similar response in mice has opened the door to elucidating the underlying neural mechanisms. PMID- 23660352 TI - Microbial evolution: regulatory design prevents cancer-like overgrowths. AB - Mutant lineages may cause cancer-like overgrowths in microbial populations. Theory predicts that microbial regulatory controls may be designed to limit the origin and competitive potential of rogue lineages. A new study shows how a Salmonella species protects itself against overgrowths. PMID- 23660353 TI - Chemical communication: a jewel sheds light on signal evolution. AB - When others show sexy tails or sing elaborate songs, many animals use the language of chemistry to attract potential mates. A study provides insights into the evolutionary conundrum of how new chemical signals can evolve in an established communication system. PMID- 23660354 TI - Mechanosensation: tethered ion channels. AB - Two new studies show that the Drosophila transient receptor potential (TRP) family member NOMPC forms both a mechanically gated ion channel and a fine filament that, by tethering the protein to microtubules, might act as a gating spring. PMID- 23660356 TI - The evolution of human nutrition. PMID- 23660355 TI - Marine ecology: reaping the benefits of local dispersal. AB - A central question of marine ecology is, how far do larvae disperse? Evidence is accumulating that the probability of dispersal declines rapidly with distance. This provides an incentive for communities to manage their own fish stocks and cooperate with neighbors. PMID- 23660357 TI - Olives. PMID- 23660358 TI - Multisensory flavour perception. PMID- 23660359 TI - Nutrient sensors. PMID- 23660360 TI - Better fruits and vegetables through sensory analysis. AB - The flavor quality of many fresh fruits available to consumers today is generally believed to have deteriorated. While agricultural and postharvest practices certainly contribute to poor flavor, a large part of the problem is the challenge of breeding for and accurately assessing such a complex, multigenic trait in a natural product such as a fruit. Here we address the parallel challenges linked to measurement of flavor and human preferences, particularly as it applies to a complex, whole food in which many chemicals and sensations are synthesized into a distinct and recognizable flavor profile. What is flavor? What contributes to the pleasure evoked by flavors? We examine interactions between taste and olfaction as well as psychophysical measurement limitations that confound efforts to understand human flavor preferences. The ability to address these questions in a whole food presents exciting opportunities to understand the basic principles of how we select the foods that we eat. PMID- 23660363 TI - Early influences on the development of food preferences. AB - The ability to perceive flavors begins in utero with the development and early functioning of the gustatory and olfactory systems. Because both amniotic fluid and breast milk contain molecules derived from the mother's diet, learning about flavors in foods begins in the womb and during early infancy. This early experience serves as the foundation for the continuing development of food preferences across the lifespan, and is shaped by the interplay of biological, social, and environmental factors. Shortly after birth, young infants show characteristic taste preferences: sweet and umami elicit positive responses; bitter and sour elicit negative responses. These taste preferences may reflect a biological drive towards foods that are calorie- and protein-dense and an aversion to foods that are poisonous or toxic. Early likes and dislikes are influenced by these innate preferences, but are also modifiable. Repeated exposure to novel or disliked foods that occurs in a positive, supportive environment may promote the acceptance of and eventually a preference for those foods. Alternatively, children who are pressured to eat certain foods may show decreased preference for those foods later on. With increasing age, the influence of a number of factors, such as peers and food availability, continue to mold food preferences and eating behaviors. PMID- 23660361 TI - Integration of satiety signals by the central nervous system. AB - Individual meals are products of a complex interaction of signals related to both short-term and long-term availability of energy stores. In addition to maintaining the metabolic demands of the individual in the short term, levels of energy intake must also maintain and defend body weight over longer periods. To accomplish this, satiety pathways are regulated by a sophisticated network of endocrine and neuroendocrine pathways. Higher brain centers modulate meal size through descending inputs to caudal brainstem regions responsible for the motor pattern generators associated with ingestion. Gastric and intestinal signals interact with central nervous system pathways to terminate food intake. These inputs can be modified as a function of internal metabolic signals, external environmental influences, and learning to regulate meal size. PMID- 23660362 TI - Mucosal immunology of food allergy. AB - Food allergies are increasing in prevalence at a higher rate than can be explained by genetic factors, suggesting a role for as yet unidentified environmental factors. In this review, we summarize the state of knowledge about the healthy immune response to antigens in the diet and the basis of immune deviation that results in immunoglobulin E (IgE) sensitization and allergic reactivity to foods. The intestinal epithelium forms the interface between the external environment and the mucosal immune system, and emerging data suggest that the interaction between intestinal epithelial cells and mucosal dendritic cells is of particular importance in determining the outcome of immune responses to dietary antigens. Exposure to food allergens through non-oral routes, in particular through the skin, is increasingly recognized as a potentially important factor in the increasing rate of food allergy. There are many open questions on the role of environmental factors, such as dietary factors and microbiota, in the development of food allergy, but data suggest that both have an important modulatory effect on the mucosal immune system. Finally, we discuss recent developments in our understanding of immune mechanisms of clinical manifestations of food allergy. New experimental tools, particularly in the field of genomics and the microbiome, are likely to shed light on factors responsible for the growing clinical problem of food allergy. PMID- 23660365 TI - Inter- and intra-breed comparative study of sperm motility and viability in Iberian and Duroc boar semen during long-term storage in MR-A and XCell extenders. AB - During boar semen liquid preservation, extender is one of the factors that influence storage tolerance of spermatozoa. However, there are few studies about intra-breed variation in the preservation of semen quality during storage in different extenders. Similarly, boar breed is generally not considered a possible factor influencing variation in the semen storage tolerance in a particular extender. The aim of this study was to compare boar semen storage potential, in terms of the ability to maintain sperm viability and motility, of two currently used long-term extenders, MR-A and XCell. Extended semen from two breeds, Iberian and Duroc that had been stored at 17 degrees C for up to 7 days was used. Intra- and inter-breed effect was studied. On Days 1, 4 and 7 (Day 0=day of semen collection), motility parameters and the percentage of total motile sperm and progressively motile sperm using a CASA system was evaluated. Viability (SYBR 14/PI) was evaluated by flow cytometry. Within each breed and for each storage day, there were differences between extenders, although semen tolerance to preservation was more influenced by the extender in the Iberian than in the Duroc breed. Neither breed nor extender influenced the percentage of viable spermatozoa during the storage time. Moreover, differences in motility parameters were observed between breeds, although the differences were greater when the XCell extender was used. In conclusion, both extender and breed influence motility characteristics of liquid-stored boar semen, so both aspects have to be considered in the design of comparative studies about stored boar semen quality from different breeds or with different extenders. Further studies are needed to corroborate these findings. PMID- 23660364 TI - An evolutionary perspective on food and human taste. AB - The sense of taste is stimulated when nutrients or other chemical compounds activate specialized receptor cells within the oral cavity. Taste helps us decide what to eat and influences how efficiently we digest these foods. Human taste abilities have been shaped, in large part, by the ecological niches our evolutionary ancestors occupied and by the nutrients they sought. Early hominoids sought nutrition within a closed tropical forest environment, probably eating mostly fruit and leaves, and early hominids left this environment for the savannah and greatly expanded their dietary repertoire. They would have used their sense of taste to identify nutritious food items. The risks of making poor food selections when foraging not only entail wasted energy and metabolic harm from eating foods of low nutrient and energy content, but also the harmful and potentially lethal ingestion of toxins. The learned consequences of ingested foods may subsequently guide our future food choices. The evolved taste abilities of humans are still useful for the one billion humans living with very low food security by helping them identify nutrients. But for those who have easy access to tasty, energy-dense foods our sensitivities for sugary, salty and fatty foods have also helped cause over nutrition-related diseases, such as obesity and diabetes. PMID- 23660366 TI - Development and evaluation of deep intra-uterine artificial insemination using cryopreserved sexed spermatozoa in bottlenose dolphins (Tursiops truncatus). AB - Since its development in bottlenose dolphins, widespread application of AI with sex-selected, frozen-thawed (FT) spermatozoa has been limited by the significant expense of the sorting process. Reducing the total number of progressively motile sperm (PMS) required for an AI would reduce the sorting cost. As such, this research compared the efficacy of small-dose deep uterine AI with sexed FT spermatozoa (SEXED-SMALL; ~50*10(6)PMS, n=20), to a moderate dose deposited mid horn (SEXED-STD, ~200*10(6)PMS; n=20), and a large dose of FT non-sexed spermatozoa deposited in the uterine body (NONSEXED-LARGE, 660*10(6)PMS, n=9). Ten of the 11 calves resulting from use of sexed spermatozoa were of the predetermined sex. Similar rates of conception (NONSEXED-LARGE: 78%, SEXED-STD: 60%, SEXED-SMALL: 57%) and total pregnancy loss (TPL: NONSEXED-LARGE: 28.6%; SEXED-STD: 41.0%; SEXED-SMALL: 63.6%) were observed across groups, but early pregnancy loss (EPL, =25y, SEXED-SMALL (15.4%) had a tendency for having reduced calving rates compared to NONSEXED-LARGE (50.0%; P=0.08), while SEXED-STD did not differ (40.0%, 4/10; P=0.341). Current findings indicate that acceptable conception and calving rates using sexed FT spermatozoa are achieved after mid-horn deposition of 200*10(6) PMS, when used with females aged less than 25 y. PMID- 23660368 TI - Taxanes: old drugs, new oral formulations. AB - Oral administration of anticancer drugs is most often preferred over intravenous administration, as it is convenient for patients, prevents hospitalisation and reduces costs of the therapy. However, the oral route is often hampered by low oral bioavailability, for instance of the taxanes paclitaxel and docetaxel. Limited oral bioavailability can be due to pharmaceutical as well as pharmacological reasons. Taxanes are poorly water-soluble drugs and do not sufficiently dissolve when administered in their crystalline form. Furthermore, affinity for drug transporters highly expressed in the epithelial layer of the gastro-intestinal tract, such as the drug efflux pump P-glycoprotein (P-gp, ABCB1), and presystemic elimination by the cytochrome P450 (CYP) metabolic enzymes, especially CYP3A4, present in liver and gut wall, further hamper oral application of these important anticancer drugs. Preclinical studies with knockout mice lacking functional Pgp and CYP3A4 metabolic enzymes show a significant increase in the bioavailability of orally applied taxanes. Enhancement of oral bioavailability of both taxanes was shown also in wild-type mice using P-gp and CYP3A4 blockers such as cyclosporine A (CsA) and ritonavir (RTV). Subsequently, in clinical studies enhancement of the oral bioavailability of paclitaxel and docetaxel was established when administered orally in combination with CsA or ritonavir. Initially, in preclinical and clinical studies drinking solutions based on the intravenous formulations were applied for oral administration of taxanes. Because these solutions had several disadvantages, solid pharmaceutical formulations of paclitaxel and docetaxel were developed. Clinical studies with these novel formulations in combination with ritonavir are currently ongoing at our Institute. PMID- 23660370 TI - Differentiating stage I epithelial ovarian cancer from benign disease in women with adnexal tumours using biomarkers or the ROMA algorithm. PMID- 23660367 TI - Aberrant expression of Igf2/H19 in porcine parthenogenetic fetuses and placentas. AB - The aberrant expression of imprinted genes induces parthenogenetic fetal and placental dysplasia, thus leading to failures in embryonic development. Igf2 and H19 are co-expressed in endoderm and mesoderm-derived tissues and play an important role in normal embryo and extraembryonic development. In this study, the expression and methylation of Igf2/H19 in porcine parthenogenetic fetuses and placentas which had grown 28 days was examined first time to further characterize mammalian parthenogenesis. Weight and morphological comparisons were conducted between parthenogenetic embryos on Day 28 and normal fertilized embryos (control). The results indicated that parthenogenetic fetuses and placentas had smaller weights and volumes than those of the control. In addition, quantitative RT-PCR (qRT-PCR) analysis was performed to determine Igf2/H19 expression levels, showing that the expression of H19 was up-regulated, while Igf2 expression was almost undetectable in both parthenogenetic fetuses and placentas. As a potential mechanism underlying this disrupted expression, the methylation of Igf2/H19 DMR3 was detected using bisulfite sequencing PCR analysis, which revealed the significant hypomethylation of DMR3 in parthenogenetic fetuses and placentas. These results suggest that disruption of Igf2/H19 expression in parthenogenetic fetuses and placentas contributes to implantation failure and/or abortion in swine parthenogenesis, which might be associated with differential methylation patterns in the imprinting control region of imprinted genes. PMID- 23660369 TI - alpha4beta2* neuronal nicotinic receptor ligands (agonist, partial agonist and positive allosteric modulators) as therapeutic prospects for pain. AB - alpha4beta2* neuronal nicotinic acetylcholine receptor are ligand-gated ion channels and widely expressed throughout the central and peripheral nervous system. alpha4beta2* neuronal nicotinic acetylcholine receptor play crucial role in pain signaling via modulation of multiple neurotransmitters like acetylcholine, dopamine, gamma-amino butyric acid (GABA) and norepinephrine. Both spinal and supraspinal pathways are involved in the mechanisms by which alpha4beta2* neuronal nicotinic acetylcholine receptor ligands modulate the neuropathic and inflammatory pain. Selective alpha4beta2* neuronal nicotinic acetylcholine receptor ligands are being developed for the treatment of neuropathic and inflammatory pain as they show considerable efficacy in a wide range of preclinical pain models. Agonists/partial agonists of alpha4beta2* neuronal nicotinic acetylcholine receptor show efficacy in animal models of pain and their anti-nociceptive properties are blocked by nicotinic antagonists. Positive allosteric modulators are being developed with the aim to increase the potency or therapeutic window of agonists/partial agonists. Accumulating evidences suggest that anti-nociceptive effects of nicotinic acetylcholine receptor ligands may not be mediated solely by alpha4beta2* neuronal nicotinic acetylcholine receptor. We have also reviewed the stage of clinical development of various alpha4beta2* neuronal nicotinic acetylcholine receptor ligands. PMID- 23660371 TI - Interaction of bioactive glass with clodronate. AB - Bone tissue engineering is a rapidly growing area of research involving the use of bioactive glass (BG) alone and in combination with different materials. The objective of this study was to investigate the interaction of BG with clodronate. Characterisation of the interaction between BG and clodronate was undertaken using; scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), Fourier transform Raman spectroscopy and Fourier transform infrared spectroscopy (FTIR). The interaction was examined in vitro with respect to the ion exchange and surface modification on the surface of the bioactive glass in the combination product. The results showed clear ion exchange enhancement by clodronate. Additionally, this ion exchange was more extensive and long lasting in the combination product than in BG alone. Clodronate promotes the activity of the BG and a calcium clodronate precipitation is formed. It can be assumed that this solid combination could be used in clinical applications. Therefore, it can be concluded that clodronate makes a beneficial environment for BG and could enhance also the apatite formation of BG. PMID- 23660372 TI - Metabolic alterations in patients who develop traumatic brain injury (TBI) induced hypopituitarism. AB - OBJECTIVE: Hypopituitarism is associated with metabolic alterations but in TBI induced hypopituitarism data are scanty. The aim of our study was to evaluate the prevalence of naive hypertension, dyslipidemia, and altered glucose metabolism in TBI-induced hypopituitarism patients. DESIGN: Cross-sectional retrospective study in a tertiary care endocrinology center. 54 adult patients encountering a moderate or severe TBI were evaluated in the chronic phase (at least 12 months after injury) after-trauma. Presence of hypopituitarism, BMI, hypertension, fasting blood glucose and insulin levels, oral glucose tolerance test (if available) and a lipid profile were evaluated. RESULTS: The 27.8% of patients showed various degrees of hypopituitarism. In particular, 9.3% had total, 7.4% multiple and 11.1% isolated hypopituitarism. GHD was present in 22.2% of patients. BMI was similar between the two groups. Hypopituitaric patients presented a higher prevalence of dyslipidemia (p<0.01) and altered glucose metabolism (p<0.005) with respect to non hypopituitaric patients. In particular, triglycerides (p<0.05) and HOMA-IR (p<0.02) were higher in hypopituitaric TBI patients. CONCLUSIONS: We showed that long-lasting TBI patients who develop hypopituitarism frequently present metabolic alterations, in particular altered glucose levels, insulin resistance and hypertriglyceridemia. In view of the risk of premature cardiovascular death in hypopituitaric patients, major attention has to been paid in those who encountered a TBI, because they suffer from the same comorbidities and may present other deterioration factors due to complex pharmacological treatments and restriction in participation in life activities and healthy lifestyle. PMID- 23660374 TI - Targeting the HIF pathway in inflammation and immunity. AB - Oxygen deprivation (hypoxia) is a frequently encountered condition in both health and disease. Metazoans have evolved an elegant and direct cellular mechanism by which to sense local oxygen levels and mount an adaptive transcriptional response to hypoxia which is mediated by a transcription factor termed the hypoxia inducible factor (HIF). In normoxia, HIF is repressed primarily through the action of a family of hydroxylases, which target HIFalpha subunits for degradation in an oxygen-dependent manner. In hypoxia, HIF is rapidly stabilized in cells thus allowing it to regulate the expression of hundreds of genes which promote an adaptive response including genes expressing regulators of angiogenesis, metabolism, growth and survival. Initial studies into the HIF pathway focused mainly on its role in supporting tumor adaptation through enhancing processes such as angiogenesis, glycolytic metabolism and cell survival. More recently however, it has become clear that the HIF pathway also plays a key role in the regulation of immunity and inflammation. In fact, conditional knockout of the HIF-1alpha subunit has identified key immune roles in T-cells, dendritic cells, macrophages, neutrophils and epithelial cells. In this review, we will consider the role for HIF in the regulation of the immune response and its possible contribution to inflammation. Furthermore, we will consider potential therapeutic strategies, which target the HIF pathway in chronic inflammatory and infectious disease. PMID- 23660375 TI - Talon noir. PMID- 23660373 TI - Omega-3 fatty acids are related to abnormal emotion processing in adolescent boys with attention deficit hyperactivity disorder. AB - BACKGROUND: In addition to the core symptoms, attention deficit hyperactivity disorder (ADHD) is associated with poor emotion regulation. There is some evidence that children and young adults with ADHD have lower omega-3 levels and that supplementation with omega-3 can improve both ADHD and affective symptoms. We therefore investigated differences between ADHD and non-ADHD children in omega 3/6 fatty acid plasma levels and the relationship between those indices and emotion-elicited event-related potentials (ERPs). METHODS: Children/adolescents with (n=31) and without ADHD (n=32) were compared in their plasma omega-3/6 indices and corresponding ERPs during an emotion processing task. RESULTS: Children with ADHD had lower mean omega-3/6 and ERP abnormalities in emotion processing, independent of emotional valence relative to control children. ERP abnormalities were significantly associated with lower omega-3 levels in the ADHD group. CONCLUSIONS: The findings reveal for the first time that lower omega-3 fatty acids are associated with impaired emotion processing in ADHD children. PMID- 23660376 TI - 22q11.2 deletion syndrome with life-threatening adenovirus infection. AB - Adenovirus causes significant morbidity and mortality in immunocompromised children. We report how an infusion of HLA-matched sibling donor T lymphocytes rapidly eradicated life-threatening, high-level adenoviremia in a child with complete DiGeorge syndrome (22q11.2 deletion) who went on to reconstitute a diverse, donor-derived, postthymic T-cell repertoire. PMID- 23660377 TI - Parental perception of functional status following tracheostomy in infancy: a single center study. AB - OBJECTIVE: To examine the functional outcomes of children who underwent a tracheostomy in the initial hospitalization after birth and to determine their correlates. STUDY DESIGN: We administered the validated 43-item Functional Status II (FS-II) questionnaire by Stein and Jessop over the telephone to caregivers of surviving children. The FS-II items generated a total score, age-specific: (1) total; (2) general health (GH); and (3) responsiveness, activity, or interpersonal functioning (IPF) scores in specific age group categories. RESULTS: FS-II was administered to 51/62 (82.2%) survivors at a median (range) age of 5 (1 10) years; 27% children were on the ventilator and 43% required devices. About 40% of children had a median of 1 (1-4) hospitalization in the previous 6 months. Scores were >2 SD below means in 55%, 24%, and 55% cases for age-specific T, GH, and R/A/IPF scores respectively. The T and R/A/IPF scales were significantly higher in those with private, rather than public, maternal insurance, as were T and R/A/IPF scores for children >= 4 years, compared with younger children. On regression analysis, FS-II T, GH, and R/A/IPF scores were independently associated with maternal private insurance (P = .02). R/A/IPF scores were also significantly associated with corrected age at FS-II administration. CONCLUSIONS: One-third of surviving children who underwent tracheostomy during their initial hospitalization remained technology-dependent. The parental FS-II questionnaires revealed low R/A/IPF scores, especially at younger ages and in those with maternal public insurance. Further research on family-level interventions to improve functional outcomes in this population is warranted. PMID- 23660378 TI - Safety and efficacy of early parenteral lipid and high-dose amino acid administration to very low birth weight infants. AB - OBJECTIVE: To assess the efficacy and safety of early parenteral lipid and high dose amino acid (AA) administration from birth onwards in very low birth weight (VLBW, birth weight <1500 g) infants. STUDY DESIGN: VLBW infants (n = 144; birth weight 862 +/- 218 g; gestational age 27.4 +/- 2.2 weeks) were randomized to receive 2.4 g of AA kg(-1) . d(-1) (control group), or 2.4 g AA kg(-1) . d(-1) plus 2-3 g lipids kg(-1) . d(-1) (AA + lipid group), or 3.6 g AA kg(-1) . d(-1) plus 2-3 g lipids kg(-1) . d(-1) (high AA + lipid group) from birth onwards. The primary outcome was nitrogen balance. The secondary outcomes were biochemical variables, urea rate of appearance, growth rates, and clinical outcome. RESULTS: The nitrogen balance on day 2 was significantly greater in both intervention groups compared with the control group. Greater amounts of AA administration did not further improve nitrogen balance compared with standard AA dose plus lipids and was associated with high plasma urea concentrations and high rates of urea appearance. No differences in other biochemical variables, growth, or clinical outcomes were observed. CONCLUSIONS: In VLBW infants, the administration of parenteral AA combined with lipids from birth onwards improved conditions for anabolism and growth, as shown by improved nitrogen balance. Greater levels of AA administration did not further improve the nitrogen balance but led to increased AA oxidation. Early lipid initiation and high-dose AA were well tolerated. PMID- 23660379 TI - Pruritus ani with white threads in a school-aged girl. PMID- 23660380 TI - Changes of the reactor performance and the properties of granular sludge under tetracycline (TC) stress. AB - In this study, the response of nitrifying granules (NG) and conventional granules (CG) to tetracycline (TC) was compared. The presence of TC made granules break down into small fractions and led to nitrite accumulation in nitrifying system; while it had little toxic effect on CG system. Specific oxygen uptake rate tests showed 3.3% inhibition of ammonium oxidizing bacteria and 25.7% inhibition of nitrite oxidizing bacteria in the NG system. Granules produced more extracellular polymeric substances (EPS) to protect themselves from the TC stress, with higher production of proteins compared to polysaccharides. FTIR data also revealed significant changes of protein functional groups, while only small changes in polysaccharides functional groups were found. Three dimensional excitation emission matrix fluorescence spectroscopy showed a decrease of peak intensity, indicating quenching effect of TC on EPS fluorescence, and also a blue shift of peak position, indicating chemical changes of EPS components. PMID- 23660381 TI - Lutein recovery from Chlorella sp. ESP-6 with coagulants. AB - Production of algal lutein included cell cultivation, biomass harvesting, cell wall disruption, and subsequent purification if needed. This work cultivated Chlorella sp. ESP-6 cells in photobioreactor to a biomass content of 1.1 gl(-1) and then the freezing-grinding, ultrasonic treatment (20 and 42kHz) and microwave treatment were used to disrupt the cell walls for recover intracellular lutein. The grinding recovered more lutein than ultrasound or microwave pretreatment. Single coagulation using >30 mgl(-1) chitosan or dual-conditioning using 10 mg l( 1) polyaluminum chloride and 10 mgl(-1) chitosan effectively enhance sedimentation and membrane filtration efficiency of algal suspensions. However, the presence of coagulants lowers the lutein yield from algal biomass in the subsequent 20 kHz ultrasound treatment and purification process. Simulation results revealed affine adsorption of lutein onto chitosan molecules via hydroxyl amine interaction. The possible drawback by pre-treatment stage should be considered together with the subsequent recovery stage in whole process assessment. PMID- 23660382 TI - Aerated swine lagoon wastewater: a promising alternative medium for Botryococcus braunii cultivation in open system. AB - To understand the potential of using swine lagoon wastewater to cultivate Botryococcus braunii for biofuel production, growth characteristics of B. braunii 765 cultivated in aerated swine lagoon wastewater (ASLW) without sterilization and pH adjustment were investigated. The results showed that the alga strain could maintain competitive advantage over the 26-day cultivation. The highest dry biomass of alga grown in ASLW was 0.94 mg L(-1) at day 24, which was 1.73 times that grown in BG11 medium, an artificial medium normally used for B. braunii cultivation. And the algal hydrocarbon content was 23.8%, being more than twice that in BG11 medium. Additionally, after the 26-day cultivation, about 40.8% of TN and 93.3% of TP in ASLW were removed, indicating also good environmental benefits of algal bioremediation. PMID- 23660383 TI - Gait evaluation of new powered knee-ankle-foot orthosis in able-bodied persons: a pilot study. AB - BACKGROUND: Knee-ankle-foot orthoses are utilized for walking by patients with lower limb weakness. However, they may be rejected by patients due to the lack of knee flexion available when using them for walking activities. AIM: The aim of this study was to perform a pilot study investigating the effect of a new powered knee-ankle-foot orthosis on walking in healthy persons before testing with patients with lower limb weakness. METHODS: Walking evaluation was performed on five healthy subjects (mean age: 26 +/- 5.6 years). Walking trials were randomly performed in three test conditions: normal walking without an orthosis, walking with a conventional knee-ankle-foot orthosis unilaterally, and also with a new powered knee-ankle-foot orthosis applied to the same leg. RESULTS: The means of walking speed, cadence, and knee flexion during swing and step length were all decreased. Compensatory motions were increased by both orthoses compared to normal walking. More knee flexion was observed in both swing and stance phases when walking with the powered knee-ankle-foot orthosis compared to the conventional knee-ankle-foot orthosis. CONCLUSION: The results demonstrated the potential of a powered orthosis in providing improvements in gait parameters compared to a conventional device in healthy subjects but are yet untested in subjects with lower limb weakness. CLINICAL RELEVANCE: The results of this study demonstrated that a powered knee-ankle-foot orthosis could lock the knee during stance and provide active knee flexion during swing to potentially reduce the tripping during ambulation. PMID- 23660384 TI - Emergency medical care and the older adult. PMID- 23660385 TI - Nurses' experiences and expectations of family and carers of older patients in the emergency department. AB - BACKGROUND: Older people are often accompanied by family/carers to the emergency department (ED). Few studies investigate nurses' experiences of interacting with these family/carers. AIM: This study was an exploration of the experiences and expectations that ED nurses have of family and carers accompanying the older adult patient. METHOD: Focus group interviews (four, n = 27) were conducted and interviews were audio-taped, transcribed and then thematically analysed. RESULTS: Three themes emerged relating to the way nurses judged family/carers of the older person, with the main theme the importance of time. Family/carers were evaluated as supportive and helpful when they saved nurses time and demanding and obstructive when they cost nurses time. A second theme was the family/carer as a knowledge resource. Nurses evaluated family/carers according to whether they could provide timely and useful information on the older patient. The third theme centred on nurses' evaluations of family/carers getting in the way of assessing or treating the patient, by their physical presence and demands and by limiting open communication with the patient. CONCLUSION: Emergency nurses have clear expectations of older patients' families and/or carers. Future research must determine how nursing roles can sustain positive interactions with older patients' families and/or carers in the ED. PMID- 23660386 TI - Epigenetic action of decitabine (5-aza-2'-deoxycytidine) is more effective against acute myeloid leukemia than cytotoxic action of cytarabine (ARA-C). AB - Treatment of elderly patients with acute myeloid leukemia (AML) with standard cytarabine (ARA-C) chemotherapy can achieve some complete responses (CR), but the median overall survival is less than one year. New approaches should be investigated. The inhibitor of DNA methylation, 5-aza-2'-deoxycytidine (decitabine, DAC), shows effectiveness in these patients, but was not approved by the US Federal Drug Administration. This decision was based on a clinical trial where DAC showed a median survival of 7.0 months as compared to standard ARA-C therapy or supportive care of 5.0 months. However, the difference was not statistically significant. Preclinical data indicate that DAC is much more effective against human AML than ARA-C. The key question is should these preclinical data also be used in the evaluation of new drugs for the clinical treatment of AML? The delayed epigenetic action of DAC is very different than the acute cytotoxic action of ARA-C and should be taken into account in the design clinical trials and evaluation of the response. PMID- 23660387 TI - Epigenetic control of endothelin-1 axis affects invasiveness of breast carcinoma cells with bone tropism. AB - Here, we report a complex regulation of endothelin-1 (ET-1) axis driven by epigenetic reactions in 1833-bone metastatic cells, emphasizing the importance in skeletal metastasis from breast carcinoma. Inhibitors of histone deacetylases, trichostatin A (TSA), and of DNA methylases, 5'-Azacytidine (Aza), caused, respectively, reduction and increase in 1833 cell invasiveness, without affecting the basal migration of parental MDA-MB231 cells. Of note, in the two cell lines exposed to Aza the blockade of the ET-1 receptor ETAR with BQ-123 oppositely changed invasive properties. Even if in MDA-MB231 cells the ET-1 axis was scarcely influenced by epigenetic reactions, ETAR remarkably decreased after Aza. In contrast, in 1833 cells Aza exposure enhanced ET-1 coupled to ETAR wild type, being also ETAR truncated form increased, and invasiveness was stimulated. Under demethylation, the increase in ET-1 steady state protein level in 1833 clone seemed regulated at transcriptional level principally via Ets1 transcription factor. In fact, actinomycin D almost completely prevented ET-1 mRNA induction due to Aza. Only in 1833 cells, TSA exposure inactivated ET-1 axis, with reduction of the expression of ET-1 and ETAR mutated form, in agreement with Matrigel invasion decrease. This treatment favoured the ET-1 repressional control, taking place at the level of mRNA stability due to the 3'-untranslated region in the ET-1 gene, and also decreased transcription via NF-kB. Environmental conditions that alter the balance between epigenetic reactions might, therefore, affect metastasis migratory mode influencing ET-1 axis. PMID- 23660389 TI - How to use: transcutaneous bilirubinometry. AB - The National Institute for Health and Clinical Excellence neonatal jaundice guidelines recommend checking the bilirubin level in all infants with visible jaundice. The gold standard for this measurement is total serum bilirubin (TSB). Transcutaneous bilirubinometry (TcB) is an alternative to TSB that has been validated for clinical use through extensive study. TcB provides many advantages over TSB including instantaneous measurements without requiring a painful lab draw. For infants >35 weeks gestation, TcB can reliably identify infants at risk for severe hyperbilirubinaemia and can decrease the number of TSB measurements obtained. However, paediatric providers should be aware of limitations in clinical use of TcB including decreasing accuracy at higher bilirubin levels, lack of independently validated nomograms for interpretation and limited research regarding its use during phototherapy. PMID- 23660388 TI - Exposure-dose-response of Tellina deltoidalis to metal-contaminated estuarine sediments: 1. Cadmium spiked sediments. AB - Cadmium is a ubiquitous environmental metal contaminant with an affinity for biological membranes; it can enter cells by facilitated transport and it binds therein to various biomolecules and affects membrane system function. The relationship between cadmium exposure, dose and response was investigated in the benthic, deposit feeding, marine bivalve Tellina deltoidalis, using 28 day microcosm spiked cadmium exposures. Tissue cadmium reached steady state with the exposure concentration. Half the accumulated cadmium was detoxified and with increased exposure more was converted into metal rich granules. Most biologically active cadmium was in the mitochondrial fraction, with up to 7320-fold cadmium increases in exposed organisms. Cadmium exposed T. deltoidalis generally had reduced glutathione peroxidase enzyme activity. An increase in total glutathione concentrations, due to a build up of oxidised glutathione, was indicated by the reduced to oxidised glutathione ratio. All cadmium exposed T. deltoidalis had reduced total antioxidant capacity that corresponded with increased lipid peroxidation, lysosomal destabilisation and micronuclei frequency. Clear exposure dose-response relationships have been demonstrated for T. deltoidalis exposed to cadmium-spiked sediments, supporting this organism's suitability for laboratory or in situ evaluation of sediment cadmium toxicity. PMID- 23660390 TI - Thyroid hormone and seasonal regulation of reproduction. AB - Organisms living outside the tropics use changes in photoperiod to adapt to seasonal changes in the environment. Several models have contributed to an understanding of this mechanism at the molecular and endocrine levels. Subtropical birds are excellent models for the study of these mechanisms because of their rapid and dramatic response to changes in photoperiod. Studies of birds have demonstrated that light is perceived by a deep brain photoreceptor and long day-induced thyrotropin (TSH) from the pars tuberalis (PT) of the pituitary gland causes local thyroid hormone activation within the mediobasal hypothalamus (MBH). The locally generated bioactive thyroid hormone, T3, regulates seasonal gonadotropin-releasing hormone (GnRH) secretion, and hence gonadotropin secretion. In mammals, the eyes are the only photoreceptor involved in photoperiodic time perception and nocturnal melatonin secretion provides an endocrine signal of photoperiod to the PT to regulate TSH. Here, I review the current understanding of the hypothalamic mechanisms controlling seasonal reproduction in mammals and birds. PMID- 23660391 TI - Benign oesophageal diseases: a review of the CT findings. AB - A variety of benign conditions can affect the oesophagus, both primarily and secondarily. Traditionally fluoroscopic oesophagography and endoscopy have formed the mainstay for investigating oesophageal diseases. Increasing use of cross sectional imaging means that many such diseases and their thoracic complications are now detected at computed tomography (CT), which is very often the first imaging tool. This review describes the CT manifestations of a range of benign oesophageal conditions and discusses the role of CT in their evaluation. PMID- 23660393 TI - Reply: lung toxicity of hydroxyl-beta-cyclodextrin infusion. PMID- 23660394 TI - Biochemical, molecular, and clinical diagnoses of patients with cerebral creatine deficiency syndromes. AB - Cerebral creatine deficiency syndromes (CCDS) are a group of inborn errors of creatine metabolism that involve AGAT and GAMT for creatine biosynthesis disorders and SLC6A8 for creatine transporter (CT1) deficiency. Deficiencies in the three enzymes can be distinguished by intermediate metabolite levels, and a definitive diagnosis relies on the presence of deleterious mutations in the causative genes. Mutations and unclassified variants were identified in 41 unrelated patients, and 22 of these mutations were novel. Correlation of sequencing and biochemical data reveals that using plasma guanidinoacetate (GAA) as a biomarker has 100% specificity for both AGAT and GAMT deficiencies, but AGAT deficiency has decreased sensitivity in this assay. Furthermore, the urine creatine:creatinine ratio is an effective screening test with 100% specificity in males suspected of having creatine transporter deficiency. This test has a high false-positive rate due to dietary factors or dilute urine samples and lacks sensitivity in females. We conclude that biochemical screening for plasma GAA and measuring of the urine creatine:creatinine ratio should be performed for suspected CCDS patients prior to sequencing. Also, based on the results of this study, we feel that sequencing should only be considered if a patient has abnormal biochemical results on repeat testing. PMID- 23660392 TI - MyD88 and its divergent toll in carcinogenesis. AB - Toll-like and interleukin-1 (IL-1) family receptors recognize microbial or endogenous ligands and inflammatory mediators, respectively, and with the exception of Toll-like receptor 3 (TLR3), signal via the adaptor molecule myeloid differentiation factor 88 (MyD88). MyD88 is involved in oncogene-induced cell intrinsic inflammation and in cancer-associated extrinsic inflammation, and as such MyD88 contributes to skin, liver, pancreatic, and colon carcinogenesis, as well as sarcomagenesis. MyD88 is also protective, for example in oncogenic virus carcinogenesis or, acting downstream of IL-18R to strengthen mucosal repair, in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colon carcinogenesis. Here, we discuss the mechanisms of the divergent effects of MyD88 and the balance of its protumor role in cancer-enhancing inflammation and immunity and its antitumor role in tissue homeostasis, repair, and immunity against the tumor or oncogenic pathogens. PMID- 23660395 TI - Age- and gender-related accumulation of perfluoroalkyl substances in captive Chinese alligators (Alligator sinensis). AB - Fourteen perfluoroalkyl substances (PFASs) were measured in serum of the highly endangered captive Chinese alligators, whole body homogenates of six kinds of fish (alligator prey species), and pond water (alligator habitat) in the Anhui Research Center for Chinese Alligator Reproduction. Six PFASs, including PFOS and five perfluorinated carboxylates, were detected in all alligator samples. The most dominant PFAS was PFUnDA, with a mean value of 31.4 ng/mL. Significant positive correlations were observed among the six PFASs, suggesting that they shared similar sources of contamination. Significantly higher PFOS and PFUnDA levels were observed in males, but the other four PFCAs did not differ between genders. An age related PFAS bioaccumulation analysis showed a significant negative correlation of the concentrations for five PFCAs to age, which means that higher concentrations were found in younger animals. Bioaccumulation factors (BAF) in fish for PFASs ranged from 21 to 28,000, with lower BAF for PFOA than that for longer carbon chain PFCAs, including PFUnDA, PFDA, and PFNA. PMID- 23660396 TI - Mortality differences among hospitalized patients with community-acquired pneumonia in three world regions: results from the Community-Acquired Pneumonia Organization (CAPO) International Cohort Study. AB - BACKGROUND: Community-acquired pneumonia (CAP) causes considerable worldwide mortality, but limited data compare the mortality in different regions of the world. Our objective was to determine if there was a difference in mortality among hospitalized patients with CAP in three continental regions of the world. METHODS: This was a cohort study of patients hospitalized for CAP between November 2001 and December 2011 from 70 institutions in 16 countries in US/Canada, Europe and Latin America; the Community-Acquired Pneumonia Organization (CAPO) international database. The primary outcome was mortality, and factors of interest included world region, processes of care, severity of disease, associated pathogen, specific comorbidities, and antimicrobial therapy. Multivariable logistic regression was performed to adjust for confounding effects on differences in mortality between regions. Patients were analyzed separately based on their intensive care unit admission status. RESULTS: A total of 6371 patients were reviewed. Latin America had the highest mortality (13.3%) followed by Europe (9.1%) and the USA/Canada (7.3%) (P < 0.001 for differences between regions). Important confounding variables included comorbidities (i.e., congestive heart failure, cerebrovascular disease), elevated blood urea nitrogen level, antimicrobial therapy (macrolide or fluoroquinolone use), and whether the patient had prior vaccinations (influenza, pneumococcal). After adjustment for confounding variables, estimated differences in mortality between the three regions were significantly reduced for both patients in the ICU and the ward. CONCLUSIONS: There was an observed discrepancy in CAP mortality between three world regions. Identified factors that contributed to these differences included incidence of H1N1 infection, elevated BUN, cerebrovascular disease, macrolide use, fluoroquinolone use, and vaccinations. Treatment regimen (fluoroquinolone and macrolide use) and preventive measures (vaccinations) were variables that may be modified to help alleviate the differences. PMID- 23660397 TI - Marine lipid fraction PCSO-524 (lyprinol/omega XL) of the New Zealand green lipped mussel attenuates hyperpnea-induced bronchoconstriction in asthma. AB - PURPOSE: Evaluate the effect of the marine lipid fraction of the New Zealand green-lipped mussel (Perna canaliculus) PCSO-524 (Lyprinol/Omega XL), rich in omega-3 fatty acids, on airway inflammation and the bronchoconstrictor response to eucapnic voluntary hyperpnea (EVH) in asthmatics. METHODS: Twenty asthmatic subjects, with documented HIB, participated in a placebo controlled double-blind randomized crossover trial. Subjects entered the study on their usual diet and were then placed on 3 weeks of PCSO-524 or placebo supplementation, followed by a 2 week washout period, before crossing over to the alternative diet. Pre- and post-eucapnic voluntary hyperpnea (EVH) pulmonary function, fraction of exhaled nitric oxide (FENO), asthma symptom scores, medication use, exhaled breath condensate (EBC) pH, cysteinyl leukotrienes (cyst-LT), 8-isoprostane and urinary 9alpha, 11beta-prostaglandin (PG)F2 and Clara (CC16) protein concentrations were assessed at the beginning of the trial and at the end of each treatment period. RESULTS: The PCSO-524 diet significantly reduced (p < 0.05) the maximum fall in post-EVH FEV1 (-8.4 +/- 3.2%) compared to usual (-19.3 +/- 5.4%) and placebo diet (-22.5 +/- 13.7%). Pre- and post- EVH EBC cyst-LT and 8-isoprostane, and urinary 9alpha, 11beta-PGF2 and CC16 concentrations were significantly reduced (p < 0.05) on the PCSO-524 diet compared to the usual and placebo diet. EBC pH and asthma symptom scores were significantly improved (p < 0.05) and rescue medication use significantly reduced (p < 0.05) on the PCSO-524 diet compared to the usual and placebo diet. CONCLUSION: PCSO-524 (Lyprinol)/Omega XL) may have beneficial effects in HIB and asthma by serving as a pro-resolving agonist and/or inflammatory antagonist. PMID- 23660398 TI - Biomarkers from bronchoalveolar lavage fluid in systemic sclerosis patients with interstitial lung disease relate to severity of lung fibrosis. AB - OBJECTIVES: Decision on treatment of systemic sclerosis (SSc) related interstitial lung disease (ILD) largely relies on the findings on high resolution computed tomography (HRCT) and there is a need for improvement in assessment of the fibrotic activity. The objectives of this study were to study biomarkers in bronchoalveolar lavage fluid (BALF) from SSc patients with ILD and to relate the findings to the severity and activity of lung fibrosis. METHODS: Fifteen patients with early SSc and 12 healthy controls were subjected to BAL. Cell counts and analyses of CXCL5, CXCL8 and S100A8/A9 were performed in BALF and serum. COMP and KL-6 were measured in serum. HRCT of lungs was quantified for ground glass opacities (GGO), reticulation and traction bronchiectases. RESULTS: BALF concentrations of CXCL8 (p < 0.001), CXCL5 (p = 0.002) and S100A8/A9 (p = 0.016) were higher in patients than controls. Serum KL-6 (p < 0.001) was increased in SSc patients and correlated with BALF concentration of eosinophils (rS = 0.57, p = 0.027). Patients with more widespread GGO on HRCT were characterised in BALF by a higher eosinophil count (p = 0.002) and in serum by higher KL-6 (p = 0.008). Patients with more fibrosis were characterised in BALF by higher eosinophil count (p = 0.014), higher CXCL8 (p = 0.005) and S100A8A/A9 (p = 0.014) concentration and in serum by a higher serum COMP (p = 0.023). CONCLUSIONS: In SSc related ILD, biomarkers from BALF and serum correlate to findings on HRCT suggesting usefulness as markers of presence and extent of lung fibrosis. PMID- 23660399 TI - Effect of monopolar and bipolar electric stimulation on survival and size of human spiral ganglion cells as studied by postmortem histopathology. AB - The spiral ganglion cell (SGC) is the target of electrical stimulation in cochlear implants. This study is designed to test the hypothesis that chronic electrical stimulation tends to preserve SGCs in implanted hearing-impaired ears. A total of 26 pairs of temporal bones were studied from 26 individuals who in life suffered bilateral profound hearing impairment that was symmetric (in degree of impairment and etiology) across ears and then underwent unilateral cochlear implantation. The subjects were divided in two groups by stimulus configuration: bipolar (n = 16) or monopolar (n = 10). The temporal bones were prepared for histological review by standard methods and two measures of SGC status were made by cochlear segment: count and maximal cross-sectional area. Within-subject comparison of the measures between the implanted-stimulated and the unimplanted ears showed: (1) for both stimulus configurations, the mean (across subjects and segments) of the count difference (implanted ear - unimplanted ear) was significantly less than zero; (2) the mean (across subject) count difference for cochlear segments I, II and III (segments with electrode contacts in the implanted ear) was significantly less negative than the mean difference for cochlear segment IV (no electrode in implanted ear) for bipolar but not for monopolar stimulation; (3) neither implantation-stimulation nor stimulus configuration significantly influenced the measures of maximum cross-sectional cell area. The SGC count results are consistent with the hypothesis that implantation results in a propensity across the whole cochlea for SGCs to degenerate and with chronic bipolar stimulation ameliorating this propensity in those cochlear segments with electrodes present. PMID- 23660400 TI - RNA analysis of inner ear cells from formalin fixed paraffin embedded (FFPE) archival human temporal bone section using laser microdissection--a technical report. AB - OBJECTIVE: Molecular analysis using archival human inner ear specimens is challenging because of the anatomical complexity, long-term fixation, and decalcification. However, this method may provide great benefit for elucidation of otological diseases. Here, we extracted mRNA for RT-PCR from tissues dissected from archival FFPE human inner ears by laser microdissection. METHODS: Three human temporal bones obtained at autopsy were fixed in formalin, decalcified by EDTA, and embedded in paraffin. The samples were isolated into spiral ligaments, outer hair cells, spiral ganglion cells, and stria vascularis by laser microdissection. RNA was extracted and heat-treated in 10 mM citrate buffer to remove the formalin-derived modification. To identify the sites where COCH and SLC26A5 mRNA were expressed, semi-nested RT-PCR was performed. We also examined how long COCH mRNA could be amplified by semi-nested RT-PCR in archival temporal bone. RESULTS: COCH was expressed in the spiral ligament and stria vascularis. However, SLC26A5 was expressed only in outer hair cells. The maximum base length of COCH mRNA amplified by RT-PCR was 98 bp in 1 case and 123 bp in 2 cases. CONCLUSION: We detected COCH and SLC26A5 mRNA in specific structures and cells of the inner ear from archival human temporal bone. Our innovative method using laser microdissection and semi-nested RT-PCR should advance future RNA study of human inner ear diseases. PMID- 23660401 TI - Single left coronary ostium and an anomalous prepulmonic right coronary artery in 2 dogs with congenital pulmonary valve stenosis. AB - A coronary artery anomaly characterized by the presence of a single left coronary ostium with absence of the right coronary ostium and an anomalous prepulmonic right coronary artery course was observed in two dogs with concurrent congenital pulmonary valve stenosis. This unique coronary artery anatomy is similar to the previously described single right coronary ostium with anomalous prepulmonic left coronary artery, the so-called type R2A anomaly, in that an anomalous coronary artery encircles the pulmonary valve annulus. Both dogs of this report, a boxer and an English bulldog, were of breeds known to be at risk for the type R2A anomaly. As such, veterinarians should be aware that the echocardiographic presence of a left coronary ostium in a dog with pulmonary valve stenosis does not exclude the possibility of a prepulmonic coronary artery anomaly that may enhance the risk of complications during balloon pulmonary valvuloplasty. A descriptive naming convention for coronary artery anomalies in dogs is also presented, which may be preferable to the older coding classification scheme. PMID- 23660402 TI - An Arabidopsis R2R3-MYB transcription factor, AtMYB20, negatively regulates type 2C serine/threonine protein phosphatases to enhance salt tolerance. AB - We have characterized the function of a plant R2R3-MYB transcription factor, Arabidopsis thaliana MYB20 (AtMYB20). Transgenic plants overexpressing AtMYB20 (AtMYB20-OX) enhanced salt stress tolerance while repression lines (AtMYB20-SRDX) were more vulnerable to NaCl than wild-type plants. Following NaCl treatment, the expressions of ABI1, ABI2 and AtPP2CA, which encode type 2C serine/threonine protein phosphatases (PP2Cs) that act as negative regulators in abscisic acid (ABA) signaling, were suppressed in AtMYB20-OX but induced in AtMYB20-SRDX. The electrophoretic mobility shift assay results revealed that AtMYB20 binds to the promoter regions containing the MYB recognition sequence (TAACTG) and an ACGT core element of ABI1 and AtPP2CA. These findings suggest that AtMYB20 down regulates the expression of PP2Cs, the negative regulator of ABA signaling, and enhances salt tolerance. PMID- 23660403 TI - Mitochondrial degradation during starvation is selective and temporally distinct from bulk autophagy in yeast. AB - Selective degradation of mitochondria is a fundamental process that depends on formation of autophagy-related double-membrane vesicles exclusive to mitochondria, and is thus termed mitophagy. In yeast, mitophagy is induced by a shift from respiration to starvation, or prolonged respiratory growth. Here we show that mitochondrial degradation in yeast also occurs selectively under starvation conditions even without respiration. Induction of mitophagy takes place much later than that of bulk autophagy, requiring Atg11 and Atg32 essential for mitophagy as well as Atg17, Atg29, and Atg31 specific for bulk autophagy. We propose that these two discrete protein complexes cooperatively activate starvation-induced mitophagy. PMID- 23660404 TI - Secretion of miraculin through the function of a signal peptide conserved in the Kunitz-type soybean trypsin inhibitor family. AB - Miraculin, a glycoprotein that modifies sour tastes into sweet ones, belongs to the Kunitz-type soybean trypsin inhibitor (STI) family. To clarify the functional relation of miraculin with Kunitz-type STIs, we investigated its subcellular localization and trypsin inhibitory activity. In transgenic Arabidopsis thaliana, miraculin, fused to yellow fluorescent protein, localized to and outside the plasma membrane depending on the putative secretion signal peptide. When transgenic seedlings were cultured in liquid medium, miraculin was present in the supernatant only after cellulase treatment. No trypsin inhibitory activity was detected in native or recombinant miraculin. In conclusion, miraculin is secreted outside the plasma membrane through the function of a signal peptide, conserved in Kunitz-type STIs, whereas its trypsin inhibitory activity may be lost during its evolution. PMID- 23660405 TI - The guanylate cyclase signaling system in zebrafish photoreceptors. AB - Zebrafish express in the retina a large variety of three different membrane-bound guanylate cyclases and six different guanylate cyclase-activating proteins (zGCAPs) belonging to the family of neuronal calcium sensor proteins. Although these proteins are predominantly localized in rod and cone photoreceptor cells of the retina, they differ in their spatial-temporal expression profiles. Further, each zGCAP has a different affinity for Ca(2+) and displays different Ca(2+) sensitivities of guanylate cyclase activation. Thus, zGCAPs operate as cytoplasmic Ca(2+)-sensors that sense incremental changes of cytoplasmic Ca(2+) concentration in rod and cone cells and control the activity of their target guanylate cyclases in a Ca(2+)-relay mode fashion. PMID- 23660406 TI - MiR-365b-3p, down-regulated in retinoblastoma, regulates cell cycle progression and apoptosis of human retinoblastoma cells by targeting PAX6. AB - PAX6 contributes to the development and progression of retinoblastoma (RB), but the molecular mechanism underlying the regulation of PAX6 expression is unclear. Here we found that microRNA-365b-3p (miR-365b-3p) is downregulated in human RB tissues. Ectopic expression of miR-365b-3p significantly attenuates cell growth, induces cell cycle arrest in G1 phase and cell apoptosis through inhibiting the expression of PAX6 by directly binding its 3' untranslated regions. Furthermore, overexpression of miR-365b-3p upregulates p21 and p27 but downregulates cdc2 and Cyclin D1 protein levels. Elucidating the regulatory mechanism of PAX6 by microRNAs may give new clues to the therapy against RB. PMID- 23660407 TI - Solvent isotope and viscosity effects on the steady-state kinetics of the flavoprotein nitroalkane oxidase. AB - The flavoprotein nitroalkane oxidase catalyzes the oxidative denitrification of a broad range of primary and secondary nitroalkanes to yield the respective aldehydes or ketones, hydrogen peroxide and nitrite. With nitroethane as substrate the D2O(k(cat)/K(M)) value is 0.6 and the D2Ok(cat) value is 2.4. The k(cat) proton inventory is consistent with a single exchangeable proton in flight, while the k(cat)/K(M) is consistent with either a single proton in flight in the transition state or a medium effect. Increasing the solvent viscosity did not affect the k(cat) or k(cat)/K(M) value significantly, establishing that nitroethane binding is at equilibrium and that product release does not limit k(cat). PMID- 23660408 TI - Interplay of static and dynamic features in biomimetic smart ears. AB - Horseshoe bats (family Rhinolophidae) have sophisticated biosonar systems with outer ears (pinnae) that are characterized by static local shape features as well as dynamic non-rigid changes to their overall shapes. Here, biomimetic prototypes fabricated from elastic rubber sheets have been used to study the impact of these static and dynamic features on the acoustic device characteristics. The basic shape of the prototypes was an obliquely truncated horn augmented with three static local shape features: vertical ridge, pinna-rim incision and frontal flap (antitragus). The prototype shape was deformed dynamically using a one-point actuation mechanism to produce a biomimetic bending of the prototype's tip. In isolation, the local shape features had little impact on the device beampattern. However, strong interactions were observed between these features and the overall deformation. The further the prototype tip was bent down, the stronger the beampatterns associated with combinations of multiple features differed from the upright configuration in the prominence of sidelobes. This behavior was qualitatively similar to numerical predictions for horseshoe bats. Hence, the interplay between static and dynamic features could be a bioinspired principle for affecting large changes through the dynamic manipulations of interactions that are sensitive to small geometrical changes. PMID- 23660410 TI - The devil is in the specificity: the negative effect of prediction specificity on prediction accuracy. AB - In the research reported here, we proposed and demonstrated the prediction specificity effect, which states that people's prediction of the general outcome of an event (e.g., the winner of a soccer match) is less accurate when the prediction question is framed in a more specific manner (e.g., guessing the score) rather than in a less specific manner (e.g., guessing the winner). We demonstrated this effect by examining people's predictions on actual sports games both in field and laboratory studies. In Study 1, the analysis of 19 billion bets from a commercial sports-betting business provided evidence for the effect of prediction specificity. This effect was replicated in three controlled laboratory studies, in which participants predicted the outcomes of a series of soccer matches. Furthermore, the negative effect of prediction specificity was mediated by participants' underweighting of important holistic information during decision making. PMID- 23660409 TI - Family risk as a predictor of initial engagement and follow-through in a universal nurse home visiting program to prevent child maltreatment. AB - OBJECTIVE: As nurse home visiting to prevent child maltreatment grows in popularity with both program administrators and legislators, it is important to understand engagement in such programs in order to improve their community-wide effects. This report examines family demographic and infant health risk factors that predict engagement and follow-through in a universal home-based maltreatment prevention program for new mothers in Durham County, North Carolina. METHODS: Trained staff members attempted to schedule home visits for all new mothers during the birthing hospital stay, and then nurses completed scheduled visits three to five weeks later. Medical record data was used to identify family demographic and infant health risk factors for maltreatment. These variables were used to predict program engagement (scheduling a visit) and follow-through (completing a scheduled visit). RESULTS: Program staff members were successful in scheduling 78% of eligible families for a visit and completing 85% of scheduled visits. Overall, 66% of eligible families completed at least one visit. Structural equation modeling (SEM) analyses indicated that high demographic risk and low infant health risk were predictive of scheduling a visit. Both low demographic and infant health risk were predictive of visit completion. CONCLUSIONS: Findings suggest that while higher demographic risk increases families' initial engagement, it might also inhibit their follow-through. Additionally, parents of medically at-risk infants may be particularly difficult to engage in universal home visiting interventions. Implications for recruitment strategies of home visiting programs are discussed. PMID- 23660411 TI - PmSERPIN3 from black tiger shrimp Penaeus monodon is capable of controlling the proPO system. AB - Serpin or serine proteinase inhibitor is a family of protease inhibitors that are involved in controlling the proteolytic cascade in various biological processes. In shrimp, several serpins have been identified but only a few have been characterized. Herein, the PmSERPIN3 gene identified from Penaeus monodon EST database was studied. By using the 5'- and 3'-Rapid Amplification of cDNA Ends (RACE) techniques, the full-length of PmSERPIN3 cDNA was obtained. The cDNA contained an open reading frame of 1233 bp encoding for 410 amino acid residue protein. Genome sequence analysis revealed that the PmSERPIN3 was an intronless gene. RT-PCR analysis revealed that it was constitutively expressed in all developmental stages, all shrimp tissues tested, and upon pathogen infections. The recombinant mature PmSERPIN3 protein (rPmSERPIN3) produced in Escherichia coli exhibited inhibitory activity against subtilisin. The rPmSERPIN3 also inhibited the shrimp prophenoloxidase system activation in vitro. Injecting the rPmSERPIN3 along with Vibrio harveyi into the shrimp decreased the clearance rate of bacteria in the hemolymph. Potentially, the PmSERPIN3 functions as a regulator of the proPO activating system. PMID- 23660412 TI - Adolescent Purchasing Behavior at McDonald's and Subway. AB - PURPOSE: To assess whether adolescents purchasing food at a restaurant marketed as "healthy" (Subway) purchase fewer calories than at a competing chain (McDonald's). METHODS: We studied 97 adolescents who purchased a meal at both restaurants on different days, using each participant as his or her control. We compared the difference in calories purchased by adolescents at McDonald's and Subway in a diverse area of Los Angeles, CA. RESULTS: Adolescents purchased an average of 1,038 calories (standard error of the mean [SEM]: 41) at McDonald's and 955 calories (SEM 39) at Subway. The difference of 83 calories (95% confidence interval [CI]: -20 to 186) was not statistically significant (p = .11). At McDonald's, participants purchased significantly more calories from drinks (151 vs. 61, p < .01) and from side dishes (i.e., French fries or potato chips; 201 at McDonald's vs. 35 at Subway, p < .01). In contrast, they purchased fewer cups of vegetables at McDonald's (.15 vs. .57 cups, p < .01). CONCLUSIONS: We found that, despite being marketed as "healthy," adolescents purchasing a meal at Subway order just as many calories as at McDonald's. Although Subway meals had more vegetables, meals from both restaurants are likely to contribute to overeating. PMID- 23660413 TI - Envisioning migration: mathematics in both experimental analysis and modeling of cell behavior. AB - The complex nature of cell migration highlights the power and challenges of applying mathematics to biological studies. Mathematics may be used to create model equations that recapitulate migration, which can predict phenomena not easily uncovered by experiments or intuition alone. Alternatively, mathematics may be applied to interpreting complex data sets with better resolution- potentially empowering scientists to discern subtle patterns amid the noise and heterogeneity typical of migrating cells. Iteration between these two methods is necessary in order to reveal connections within the cell migration signaling network, as well as to understand the behavior that arises from those connections. Here, we review recent quantitative analysis and mathematical modeling approaches to the cell migration problem. PMID- 23660414 TI - Simulation: a shared learning experience for child and mental health pre registration nursing students. AB - Learning through the use of simulation is perceived as an innovative means to help manage some of the contemporary challenges for pre-registration nurse education. Mental health and child nurses need to have the knowledge and skills to effectively address the holistic needs of service users. This article reports on a pilot simulated learning experience that was designed with key stakeholders for pre-registration child and mental health nursing students. This involved young actors playing the role of someone who had self-harmed to help students develop their skills for working with young people who experience emotional distress. Focus groups and a questionnaire were used to evaluate the pilot. Students valued the practical approach that simulation entailed and identified the benefits of the shared learning experience across the different fields of practice of nursing. However, some students reported anxiety performing in front of peers and indicated they would perform differently in practice. The pilot identified simulation as a potentially useful approach to help child and mental health student nurses develop skills for caring for young people. However, there is a need for caution in the claims to be made regarding the impact of simulation to address gaps in nursing skills. PMID- 23660415 TI - Differences in detection rates of adenomas and serrated polyps in screening versus surveillance colonoscopies, based on the new hampshire colonoscopy registry. AB - BACKGROUND & AIMS: The adenoma detection rate (ADR) is an important quality indicator originally developed for screening colonoscopies. However, it is unclear whether the ADR should be calculated using data from screening and surveillance examinations. The recommended benchmark ADR for screening examinations is 20% (15% for women and 25% for men >=50 y). There are few data available to compare ADRs from surveillance vs screening colonoscopies. We used a population-based registry to compare ADRs from screening vs surveillance colonoscopies. The serrated polyp detection rate (SDR), a potential new quality indicator, also was examined. METHODS: By using data from the statewide New Hampshire Colonoscopy Registry, we excluded incomplete and diagnostic colonoscopies, and those performed in patients with inflammatory bowel disease, familial syndromes, or poor bowel preparation. We calculated the ADR and SDR (number of colonoscopies with at least 1 adenoma or serrated polyp detected, respectively, divided by the number of colonoscopies) from 9100 colonoscopies. The ADR and SDR were compared by colonoscopy indication (screening, surveillance), age at colonoscopy (50-64 y, >=65 y), and sex. RESULTS: The ADR was significantly higher in surveillance colonoscopies (37%) than screening colonoscopies (25%; P < .001). This difference was observed for both sexes and age groups. There was a smaller difference in the SDR of screening (8%) vs surveillance colonoscopies (10%; P < .001). CONCLUSIONS: In a population-based study, we found that addition of data from surveillance colonoscopies increased the ADR but had a smaller effect on the SDR. These findings indicate that when calculating ADR as a quality measure, endoscopists should use screening, rather than surveillance colonoscopy, data. PMID- 23660416 TI - Coffee reduces risk for hepatocellular carcinoma: an updated meta-analysis. AB - BACKGROUND & AIMS: Coffee consumption has been suggested to reduce the risk for hepatocellular carcinoma (HCC). We performed a meta-analysis of epidemiological studies to provide updated information on how coffee drinking affects HCC risk. METHODS: We performed a PubMed/MEDLINE search of the original articles published in English from 1966 through September 2012, on case-control or cohort studies that associated coffee consumption with liver cancer or HCC. We calculated the summary relative risk (RR) for any, low, and high consumption of coffee vs no consumption. The cut-off point for low vs high consumption was set to 3 cups per day in 9 studies and 1 cup per day in 5 studies. RESULTS: The summary RR for any coffee consumption vs no consumption was 0.60 from 16 studies, comprising a total of 3153 HCC cases (95% confidence interval [CI], 0.50-0.71); the RRs were 0.56 from 8 case-control studies (95% CI, 0.42-0.75) and 0.64 from 8 cohort studies (95% CI, 0.52-0.78). Compared with no coffee consumption, the summary RR was 0.72 (95% CI, 0.61-0.84) for low consumption and 0.44 (95% CI, 0.39-0.50) for high consumption. The summary RR was 0.80 (95% CI, 0.77-0.84) for an increment of 1 cup of coffee per day. The inverse relationship between coffee and HCC risk was consistent regardless of the subjects' sex, alcohol drinking, or history of hepatitis or liver disease. CONCLUSIONS: From this meta-analysis, the risk of HCC is reduced by 40% for any coffee consumption vs no consumption. The inverse association might partly or largely exist because patients with liver and digestive diseases reduce their coffee intake. However, coffee has been shown to affect liver enzymes and development of cirrhosis, and therefore could protect against liver carcinogenesis. PMID- 23660417 TI - Limited evidence for the existence of postdiverticulitis irritable bowel syndrome. PMID- 23660418 TI - Diagnosis and treatment of choledochoceles. AB - Choledochoceles are cystic dilatations of the intraduodenal portion of the common bile duct. Although often classified as Type III biliary cysts, choledochoceles have distinctive demographic and anatomic features and a lower risk of malignancy than other types of choledochal cysts. Type A choledochoceles are cystic dilatations of a segment of the intra-ampullary bile duct and are located proximal to the ampullary orifice. Type B choledochoceles are diverticula of the intra-ampullary common channel and are located distal to the ampullary orifice; they can be distinguished from duodenal duplication cysts both anatomically and histologically. Both types of choledochocele may present with pancreatitis, biliary obstruction, or nonspecific gastrointestinal symptoms. Cross-sectional imaging, endoscopic ultrasound, and endoscopic retrograde cholangiopancreatography are useful for diagnosis. Choledochoceles may be drained or resected endoscopically. Surveillance for dysplasia should be considered for lesions that are not resected. PMID- 23660419 TI - Management of hepatitis B: our practice and how it relates to the guidelines. AB - Seven drugs have been approved for the treatment of chronic hepatitis B. Antiviral treatment has been shown to be effective in suppressing hepatitis B virus replication, decreasing inflammation and fibrosis in the liver, and preventing progression of liver disease. However, current medications do not eradicate hepatitis B virus; therefore, a key question is which patients need to start treatment and which patients can be monitored. Professional societies have developed guidelines to assist physicians in recognition, diagnosis, and optimal management of patients with chronic hepatitis B. These guidelines suggest preferred approaches, and physicians are expected to exercise clinical judgment to determine the most appropriate management based on the circumstances of the individual patient. This article reviews recommendations in hepatitis B guidelines and the basis for those recommendations, and we discuss what we do in our practice to illustrate factors that may influence decisions regarding hepatitis B management. PMID- 23660420 TI - Colon cancer screening models: lessons and challenges. PMID- 23660421 TI - Bisphosphonate use and risk of colorectal cancer. PMID- 23660422 TI - Fragile X screening by quantification of FMRP in dried blood spots by a Luminex immunoassay. AB - Fragile X is the most common inherited cause of intellectual disability and is frequently associated with autism. The syndrome is due to mutations of the FMR1 gene that result in the absence of fragile X mental retardation protein (FMRP). We have developed a rapid, highly sensitive method for quantifying FMRP from dried blood spots and lymphocytes. This assay uses two new antibodies, a bacterially expressed abbreviated FMRP standard, and a Luminex platform to quantify FMRP. The assay readily distinguished between samples from males with fragile X full mutations and samples from normal males. It also differentiated mosaic from nonmosaic full-mutation male samples. This assay, because of its methodology and minimal cost, could be the basis for newborn or population screening. PMID- 23660423 TI - Contribution and limitations of the FRAX(r) tool. PMID- 23660424 TI - Primary lymphoma of bone infected with Staphylococcus aureus. PMID- 23660425 TI - Apolipoprotein m (APOM) levels and APOM rs805297 G/T polymorphism are associated with increased risk of rheumatoid arthritis. AB - OBJECTIVE: To examine whether the apolipoprotein M (APOM) rs805297 G/T polymorphism is associated with risk of rheumatoid arthritis (RA) in a Chinese population. METHODS: We studied APOM rs805297 G/T gene polymorphism in 520 RA patients, and 520 controls in a Chinese population. Genotyping was done by matrix assisted laser desorption/ionization time-of-flight mass spectrometry. The blood plasma concentration of APOM was measured by an enzyme-linked immunosorbent assay in 84 RA patients and 84 controls. RESULTS: When the APOM rs805297 G/T GG homozygote genotype was used as the reference group, the TT or GT/TT genotype was associated with an increased risk for RA (TT vs. GG, adjusted odds ratio 1.76, 95% CI 1.11-2.77, P=0.016; GT + TT vs. GG, adjusted odds ratio 1.30, 95% CI 1.02 1.67, P=0.037). The average concentration of APOM in plasma was significantly higher in RA patients compared to controls. Stratification analysis found a significantly increased risk for RA associated with the APOM rs805297 TT genotype among male patients, C-reactive protein (CRP)-positive patients, anticitrullinated protein/peptide antibodies (ACPA) - positive patients, rheumatoid factor (RF) - positive patients, patients with higher levels of the erythrocyte sedimentation rate (ESR), patients with higher DAS28 score and patients with higher functional class compared to the APOM rs805297 GG genotype. CONCLUSION: These findings suggest that the functional single-nucleotide polymorphism APOM rs805297 G/T variant allele was associated with RA risk. PMID- 23660427 TI - Reversible stenosis of the saphenous vein graft compressed by giant coronary aneurysm in Kawasaki disease. PMID- 23660428 TI - A heart with extra rooms. PMID- 23660429 TI - Receipt of cervical cancer screening in female veterans: impact of posttraumatic stress disorder and depression. AB - PURPOSE: We evaluated receipt of cervical cancer screening in a national sample of 34,213 women veterans using Veteran Health Administration facilities between 2003 and 2007 and diagnosed with 1) posttraumatic stress disorder (PTSD), or 2) depression, or 3) no psychiatric illness. METHODS: Our study featured a cross sectional design in which logistic regression analyses compared receipt of recommended cervical cancer screening for all three diagnostic groups. RESULTS: Cervical cancer screening rates varied minimally by diagnostic group: 77% of women with PTSD versus 75% with depression versus 75% without psychiatric illness were screened during the study observation period (p < .001). However, primary care use was associated with differential odds of screening in women with versus without psychiatric illness (PTSD or depression), even after adjustment for age, income and physical comorbidities (Wald Chi-square (2): 126.59; p < .0001). Specifically, among low users of primary care services, women with PTSD or depression were more likely than those with no psychiatric diagnoses to receive screening. Among high users of primary care services, they were less likely to receive screening. CONCLUSION: Psychiatric illness (PTSD or depression) had little to no effect on receipt of cervical cancer screening. Our finding that high use of primary care services was not associated with comparable odds of screening in women with versus without psychiatric illness suggests that providers caring for women with PTSD or depression and high use of primary care services should be especially attentive to their preventive healthcare needs. PMID- 23660430 TI - At what cost? Payment for abortion care by U.S. women. AB - BACKGROUND: Most U.S. abortion patients are poor or low-income, yet most pay several hundred dollars out of pocket for these services. This study explores how women procure these funds. METHODS: iPad-administered surveys were implemented among 639 women obtaining abortions at six geographically diverse healthcare facilities. Women provided information about insurance coverage, payment for service, acquisition of funds, and ancillary costs incurred. FINDINGS: Only 36% of the sample lacked health insurance, but at least 69% were paying out of pocket for abortion care. Women were twice as likely to pay using Medicaid (16% of abortions) than private health insurance (7%). The most common reason women were not using private insurance was because it did not cover the procedure (46%), or they were unsure if it was covered (29%). Among women who did not use insurance for their abortion, 52% found it difficult to pay for the procedure. One half of patients relied on someone else to help cover costs, most commonly the man involved in the pregnancy. Most women incurred ancillary expenses in the form of transportation (mean, $44), and a minority also reported lost wages (mean, $198), childcare expenses (mean, $57) and other travel-related costs (mean, $140). Substantial minorities also delayed or did not pay bills such as rent (14%), food (16%), or utilities and other bills (30%) to pay for the abortion. CONCLUSIONS: Public and private health insurance plan coverage of abortion care services could ease the financial strain experienced by abortion patients, many of whom are low income. PMID- 23660431 TI - Health indicators, social support, and intimate partner violence among women utilizing services at a community organization. AB - PURPOSE: Intimate partner violence (IPV) against women is a significant public health concern. This study examines the physical and mental health status and relationship to social support for women seeking services to end IPV at a walk-in community organization that serves the community at large, including a shelter for abused women. METHODS: One hundred seventeen (117) English-speaking women between the ages of 18 and 61 years participated in a self-administered survey. Physical, mental, and oral health, social support, and IPV homicide lethality were measured using standardized instruments. RESULTS: Social support was the most important factor related to better health. The participants who had more social support reported better physical (p < .05), mental (p < .01), and oral health (p < .05), and a lower level of psychological distress (p < .01) and depression (p < .01) compared with participants who reported less social support. The participants living in the shelter reported worse physical health (p < .05) but better mental health (p < .05) than the participants not living in a shelter. Older age and low income were related to oral health problems, whereas older age, low education level, and unemployment were related to poor mental health. CONCLUSION: The present study adds to the evidence that social support contributes to improving physical and mental health for women who experience IPV. The findings also suggest the importance of providing or referring women to mental health services. PMID- 23660432 TI - Use of a prenatal risk screen to predict maternal traumatic pregnancy-associated death: program and policy implications. AB - BACKGROUND: Motor vehicle crashes, homicide, suicide, and drug abuse are among the leading causes of pregnancy-associated deaths. To prevent such deaths, identifying women for intervention is required. The universally offered Florida Healthy Start Prenatal Risk Screen was evaluated to identify women at increased risk for traumatic pregnancy-associated death. METHODS: Florida's Enhanced Maternal Mortality Reporting Database for 1999 through 2005 was linked with Florida's Healthy Start Prenatal Risk Screen to identify traumatic pregnancy associated death as the outcome. Distribution of Healthy Start risk scores among women who died were compared with the screened population. Traumatic death estimates per 100,000 births were drawn for each risk score, along with estimates of the relative risk (RR) of traumatic death for each score. The RR of women with scores greater than or equal to 4 were compared with the risk of women scoring 0 to 3. FINDINGS: Almost 20% of the 620,959 women who did not die of traumatic death had a risk score of 0, compared with only 3% of the 144 women who did die of traumatic death. As risk scores increased, the chance of traumatic deaths sharply increased. A woman with a score of 4 had 11.78 times (confidence interval [CI], 4.63-29.69) the risk of traumatic death compared with a woman with a risk score of 0. CONCLUSIONS: The implementation of prenatal risk screening to identify women at increased risk for traumatic pregnancy-associated death would help to ensure that policies to reduce infant risk factors also address maternal risk factors. PMID- 23660433 TI - Musical groove modulates motor cortex excitability: a TMS investigation. AB - Groove is often described as a musical quality that can induce movement in a listener. This study examines the effects of listening to groove music on corticospinal excitability. Musicians and non-musicians listened to high-groove music, low-groove music, and spectrally matched noise, while receiving single pulse transcranial magnetic stimulation (TMS) over the primary motor cortex either on-beat or off-beat. We examined changes in the amplitude of the motor evoked potentials (MEPs), recorded from hand and arm muscles, as an index of activity within the motor system. Musicians and non-musicians rated groove similarly. MEP results showed that high-groove music modulated corticospinal excitability, whereas no difference occurred between low-groove music and noise. More specifically, musicians' MEPs were larger with high-groove than low-groove music, and this effect was especially pronounced for on-beat compared to off-beat pulses. These results indicate that high-groove music increasingly engages the motor system, and the temporal modulation of corticospinal excitability with the beat could stem from tight auditory-motor links in musicians. Conversely, non musicians' MEPs were smaller for high-groove than low-groove music, and there was no effect of on- versus off-beat pulses, potentially stemming from suppression of overt movement. In sum, high-groove music engages the motor system, and previous training modulates how listening to music with a strong groove activates the motor system. PMID- 23660434 TI - The effects of clinical motor variables and medication dosage on working memory in Parkinson's disease. AB - In this study, we investigate the interrelationship between clinical variables and working memory (WM) in Parkinson's disease (PD). Specifically, the aim of the study was to investigate the relationship between disease duration, dopaminergic medication dosage, and motor disability (UPDRS score) with WM in individuals with PD. Accordingly, we recruited three groups of subjects: unmedicated PD patients, medicated PD patients, and healthy controls. All subjects were tested on three WM tasks: short-delay WM, long-delay WM, and the n-back task. Further, PD encompasses a spectrum that can be classified either into akinesia/rigidity or resting tremor as the predominant motor presentation of the disease. In addition to studying medication effects, we tested WM performance in tremor-dominant and akinesia-dominant patients. We further correlated WM performance with disease duration and medication dosage. We found no difference between medicated and unmedicated patients in the short-delay WM task, but medicated patients outperformed unmedicated patients in the long-delay WM and n-back tasks. Interestingly, we also found that akinesia-dominant patients were more impaired than tremor-dominant patients at various WM measures, which is in agreement with prior studies of the relationship between akinesia symptom and basal ganglia dysfunction. Moreover, the results show that disease duration inversely correlates with more demanding WM tasks (long-delay WM and n-back tasks), but medication dosage positively correlates with demanding WM performance. In sum, our results show that WM impairment in PD patients depend on cognitive domain (simple vs. demanding WM task), subtype of PD patients (tremor- vs. akinesia dominant), as well as disease duration and medication dosage. Our results have implications for the interrelationship between motor and cognitive processes in PD, and for understanding the role of cognitive training in treating motor symptoms in PD. PMID- 23660435 TI - Inter-hemispheric remapping between arm proprioception and vision of the hand is disrupted by single pulse TMS on the left parietal cortex. AB - Parietal cortical areas are involved in sensori-motor transformations for their respective contralateral hemifield/body. When arms of the subjects are crossed while their gaze is fixed straight ahead, vision of the hand is processed by the hemisphere ipsilateral to the arm position and proprioception of the arm by the contralateral hemisphere. It induces interhemispheric transfer and remapping. Our objective was to investigate whether a single pulse TMS applied to the left parietal cortical area would disturb interhemispheric remapping in a similar case, and would increase a simple reaction time (RT) with respect to a control single pulse TMS applied to the frontal cortical area. Two LED were superimposed and located in front of the subjects on the saggital axis. Subjects were asked to carefully fixate on these LED during each trial. The lighting of the red LED was used as a warning signal. Following the green one was illuminated after a variable delay and served as a go-signal. The hand for the response was determined before the start of each trial. TMS was applied to the left parietal, the left frontal cortical areas, or not applied to the subject. Results revealed that: (1) Irrespective of its location, single pulse TMS induced a non-specific effect similar to a startle reflex and reduced RT substantially (15ms on average) with respect to a control condition without TMS (mean value=153ms). (2) Irrespective of TMS, RT were shorter when the right or the left hand was positioned in the right visual hemi-field (i.e. normal and crossed positions respectively). (3) Finally, RT increased when single pulse TMS was applied to the left parietal area and when hands were crossed irrespective of which hand was used. We concluded that interhemispheric sensori-motor remapping was disrupted by a single pulse TMS that was applied to the left parietal cortex. This effect was also combined with some visual attention directed towards the hand located on the right visual hemi-field. PMID- 23660436 TI - Task-load manipulation in the Symbol Digit Modalities Test: an alternative measure of information processing speed. AB - OBJECTIVE: To evaluate the utility of an oral fMRI-adapted version of the Symbol Digit Modalities Test (SDMT) to assess information processing speed (IPS) using three different interstimulus intervals (ISI). METHODS: Nineteen right-handed healthy controls performed the adapted version of the SDMT, consisting of a block design that had a total of 6 control/activation block pairs with 3 different ISIs (1.5, 2 and 2.5s) presented in two different runs: in ascending and descending orders. The brain activation patterns during different ISIs were assessed by effective functional connectivity analysis based on independent component analysis. RESULTS: As expected, all conditions yielded activations in the fronto parietal networks (FPNs) related to attention processes. Shorter ISIs (1.5 and 2s) not only yielded greater patterns of connectivity within fronto-parietal and occipital regions such as the FPN and fronto-occipital network (FON), but also recruited more functional networks overall. Task performance at the shortest ISI was negatively correlated with connectivity at the FPN and activity of the pre supplementary motor area extending to the cingulate gyrus. CONCLUSION: Increasing IPS demands due to shorter ISIs resulted in an increased level and number of functional networks required, increased connectivity within the FPN and FON, and enhancement of the prefrontal cortex. IPS does not arise from activity of a single b area but from affective information transfer among distant cortical regions of the frontal and parietal cortices. This adapted version of the SDMT may be useful for studying alterations of IPS in clinical and nonclinical populations. PMID- 23660438 TI - A comparative photochemical study on the behavior of 3,3'-dihydroxyflavone and its complex with La(III) as generators and quenchers of reactive oxygen species. AB - A 1:1 complex between 3,3'-dihydroxyflavone (DHF) and La(III) (DHF-La(III)) is formed in methanolic solution with the relatively high apparent stability constant value of 2.3*10(6) and a calculated standard entropy change of 88.2 J mol(-1) K(-1), both at 25 degrees C. The photophysical properties of the complex and the free flavonoid are discussed in comparison to the well known related compound 3-hydroxyflavone. The ligand photogenerates O2((1)Deltag) by energy transfer from its excited triplet state ((3)DHF(*)) to dissolved ground state oxygen, with a quantum yield of 0.13. (3)DHF(*) is quenched by La(III) with a rate constant close to the diffusion-controlled value. The respective abilities of the free flavonoid and DHF-La(III) as quenchers of the riboflavin photogenerated reactive oxygen species singlet molecular oxygen (O2((1)Deltag)) and superoxide radical anion (O2(-)) have been investigated. Both individual compounds were photoirradiated with visible light in the presence of the flavin as the only light-absorbing compound. A detailed kinetics and mechanistic study employing polarographic monitoring of oxygen uptake and time resolved detection of O2((1)Deltag) phosphorescence indicates that DHF and the complex react with O2((1)Deltag) and O2(-) by a non simple mechanism. The former deactivates O2((1)Deltag) in a predominant physical fashion, a fact that constitutes a desirable property for antioxidants. It was found that metal chelation greatly enhances the ability of DHF as an overall O2((1)Deltag) quencher. PMID- 23660439 TI - pH-insensitive electrostatic interaction of carmoisine with two serum proteins: a possible caution on its uses in food and pharmaceutical industry. AB - Here we have investigated the binding of carmoisine, a water-soluble azo food colorant, with serum proteins (HSA and BSA) by fluorescence and UV-VIS spectroscopy, circular dichroism and molecular docking studies. Results indicate that fluorescence quenching of protein has been due to site-specific binding of the dye with biomacromolecules. Site marker competitive binding and molecular docking explorations show that interaction occurs in the sub-domain IIA of HSA and the sub-domains IIA and IB in the case of BSA. Conformational investigation indicates that dye binding modifies the secondary structure of proteins and this also alters the microenvironment of the tryptophan(s). The interaction is found to be pH-insensitive which can have relevance to the toxicological profiles of the dye, and ionic strength dependence of binding can be exploited in protein purification mediated by such food colorants. PMID- 23660437 TI - Dissociable fronto-striatal effects of dopamine D2 receptor stimulation on cognitive versus motor flexibility. AB - Genetic and pharmacological studies suggest an important role of the dopamine D2 receptor (DRD2) in flexible behavioral adaptation, mostly shown in reward-based learning paradigms. Recent evidence from imaging genetics indicates that also intentional cognitive flexibility, associated with lateral frontal cortex, is affected by variations in DRD2 signaling. In the present functional magnetic resonance imaging (MRI) study, we tested the effects of a direct pharmacological manipulation of DRD2 stimulation on intentional flexibility in a task-switching context, requiring switches between cognitive task rules and between response hands. In a double blind, counterbalanced design, participants received either a low dose of the DRD2 agonist bromocriptine or a placebo in two separate sessions. Bromocriptine modulated the blood-oxygen-level-dependent (BOLD) signal during rule switching: rule-switching-related activity in the left posterior lateral frontal cortex and in the striatum was increased compared to placebo, at comparable performance levels. Fronto-striatal connectivity under bromocriptine was slightly increased for rule switches compared to rule repetitions. Hand switching-related activity, in contrast, was reduced under bromocriptine in sensorimotor regions. Our results provide converging evidence for an involvement of DRD2 signaling in fronto-striatal mechanisms underlying intentional flexibility, and indicate that the neural mechanisms underlying different types of flexibility (cognitive vs motor) are affected differently by increased dopaminergic stimulation. PMID- 23660440 TI - Analysis of the bacterial community in the two typical intertidal sediments of Bohai Bay, China by pyrosequencing. AB - For full understanding of the bacterial community in the intertidal zones of Bohai Bay, China, we used pyrosequencing-based approach to analyze the 16S rRNA gene of bacteria in the sediments from the two typically intertidal zones - Qikou (Qi) and Gaoshaling (Ga). Results showed that, at a 0.03 distance, the sequences from the Qi sediment were assigned to 3252 operational taxonomic units (OTUs) which belong to 34 phyla, 69 classes and 119 genera, while the 3740 OTUs from the Ga sediment were affiliated with 33 phyla, 66 classes and 146 genera. Comparing the bacterial communities inhabiting in the two intertidal sediments, we observed significant difference in the dominant composition and distribution at phylum, class and genus levels. Canonical correspondence analysis (CCA) showed that the median grain size and DO were the most important factors regulating the bacterial abundance and diversity, while the other environmental factors have effects with different degree. PMID- 23660442 TI - Marine debris in mangroves and on the seabed: largely-neglected litter problems. PMID- 23660441 TI - Habitat degradation correlates with tolerance to climate-change related stressors in the green mussel Perna viridis from West Java, Indonesia. AB - It is unclear whether habitat degradation correlates with tolerance of marine invertebrates to abiotic stress. We therefore tested whether resistance to climate change-related stressors differs between populations of the green mussel Perna viridis from a heavily impacted and a mostly pristine site in West Java, Indonesia. In laboratory experiments, we compared their oxygen consumption and mortality under lowered salinity (-13 and -18 units, both responses), hypoxia (0.5 mg/l, mortality only) and thermal stress (+7 degrees C, mortality only). Mussels from the eutrophied and polluted Jakarta Bay showed a significantly smaller deviation from their normal oxygen consumption and higher survival rates when stressed than their conspecifics from the unaffected Lada Bay. This shows that human induced habitat degradation correlates with mussel tolerance to environmental stress. We discuss possible mechanisms - e.g. the selection of tolerant genotypes or habitat-specific differences in the nutritional status of the mussels - that could explain our observation. PMID- 23660443 TI - Evaluation of autochthonous bioaugmentation and biostimulation during microcosm simulated oil spills. AB - Oil spills are treated as a widespread problem that poses a great threat to any ecosystem. Following first response actions, bioremediation has emerged as the best strategy for combating oil spills and can be enhanced by the following two complementary approaches: bioaugmentation and biostimulation. Bioaugmentation is one of the most controversial issues of bioremediation. Studies that compare the relative performance of bioaugmentation and biostimulation suggest that nutrient addition alone has a greater effect on oil biodegradation than the addition of microbial products because the survival and degradation ability of microbes introduced to a contaminated site are highly dependent on environmental conditions. Microbial populations grown in rich media under laboratory conditions become stressed when exposed to field conditions in which nutrient concentrations are substantially lower. There is increasing evidence that the best approach to overcoming these barriers is the use of microorganisms from the polluted area, an approach proposed as autochthonous bioaugmentation (ABA) and defined as a bioaugmentation technology that exclusively uses microorganisms indigenous to the sites (soil, sand, and water) slated for decontamination. In this work, we examined the effectiveness of strategies combining autochthonous bioaugmentation with biostimulation for successful remediation of polluted marine environments. Seawater was collected from a pristine area (Agios Onoufrios Beach, Chania) and was placed in a bioreactor with 1% v/v crude oil to facilitate the adaptation of the indigenous microorganism population. The pre-adapted consortium and the indigenous population were tested in combination with inorganic or lipophilic nutrients in the presence (or absence) of biosurfactants (rhamnolipids) during 90 day long experiments. Chemical analysis (gas chromatography-mass spectrometry) of petroleum hydrocarbons confirmed the results of previous work demonstrating that the biodegradation processes were enhanced by the addition of lipophilic fertilizers (uric acid and lecithin) in combination with biosurfactants (rhamnolipids), resulting in increased removal of petroleum hydrocarbons as well as reduction of the lag phase within 15 days of treatment. Considering this outcome and examining the results, the use of biostimulation additives in combination with naturally pre-adapted hydrocarbon-degrading consortia (bioaugmentation) has proved to be an effective treatment and is a promising strategy that could be applied specifically when an oil spill approaches near a shore line and an immediate hydrocarbon degradation effort is needed. PMID- 23660444 TI - Cortisol treatment of prespawning female cod affects cytogenesis related factors in eggs and embryos. AB - A stable supply of viable eggs and embryos is crucial for successful farming of Atlantic cod. Stress during broodstock rearing can have negative effects on offspring, but little is known about the molecular mechanisms that cause abnormal development. Maternally transferred mRNAs have been shown to be essential for normal development, and stress may therefore influence their expression and the subsequent embryonic development. We investigated if mimicked stress in cod females affects mRNA concentrations in eggs/embryos, and if this can be linked to viability of embryos. Three weeks before peak spawning, 20 fish were intraperitoneally implanted with either cortisol-containing or cortisol-free (sham) osmotic pumps. At peak spawning all individuals were stripped and eggs were fertilized and incubated until hatching. Samples were collected from unfertilized eggs and embryos for analysis of gene expression (microarray), viability, steroids and vitellogenin. Plasma concentration of cortisol (ng/ml) in treated females was significantly higher at spawning (127.1+/-20.9) than that of sham control (11.3+/-6.7). This difference was also reflected in eggs and embryos. Percent fertilization, asymmetric cell division and hatching were not affected. However, numerous genes were differentially expressed in eggs and embryos in response to elevated cortisol, especially in maternal (oocyte and blastula) stages. Among these differentially expressed genes, some were found to be linked to cytogenesis (stxbp6, fbxw2, capn12, thbs4, sytl2, coro1c, sel1l3), induction of mesodermal fate (fgfrl1) and import of the glucocorticoid receptor to the cell nucleus (ipo7). Gene ontology overrepresentation analysis on the whole set of differentially expressed genes at maternal stages (539 genes) revealed enriched activity in membrane associated regions, which largely corresponds to cytogenesis related processes. These results suggest that despite no visible phenotypic effects in early embryos, broodstock stress affects the egg/embryonic transcriptome, especially in relation to cytogenesis. Furthermore, effects related to egg/embryo phenotypes are difficult to measure at early stages of development, and instead might become apparent at later life stages. PMID- 23660445 TI - Changes in the content of sex steroid hormone receptors in the growing and regressing ovaries of Gallus domesticus during development. AB - Sex steroids participate in the regulation of reproduction in female chickens. In this work, we determined the content of androgen receptor (AR), intracellular progesterone receptor isoforms (PR-A and PR-B), membrane progesterone receptor gamma (mPRgamma) and estrogen receptor alpha (ER-alpha) in the left growing and right regressing ovaries of Gallus domesticus from 13-day-old chicken embryos to 1-month-old chickens by western blot analysis. A marked difference in the morphological characteristics of the left and the right ovaries during development was observed. Results show a higher content of AR in the left ovary than in the right one in all ages. In the left ovary, the highest content of AR was observed on day 13 of embryonic development, and diminished with age. In the right ovary, AR was expressed from day 13 of embryonic development to 1-day-old, and became undetectable at 1-week and 1-month-old. In the left ovary, PR isoforms were not detected on day 13 of embryonic development, but they presented a marked expression after hatching. In the right ovary, the highest expression of both PR isoforms was found on 1-day-old, and significantly decreased with age. PR-B was the predominant isoform on 1-day and 1-month old in the left ovary, whereas PR-A was the predominant one on day 13 of embryonic development in the right ovary. Interestingly, mPRgamma was detected at 1-week and 1-month-old in the left ovary meanwhile in the right ovary, it was detected from day 13 of embryonic development to 1-day-old. ER-alpha was only detected in the left ovary from day 13 to 1-week-old, while in 1-month-old chickens, it was expressed in both ovaries. In the left ovary, ER-alpha content was lower from 1-day to 1-month-old as compared with day 13 of embryonic development. Our results demonstrate a differential expression of sex steroid hormone receptors between the left growing and the right regressing ovary, and throughout chickens' age; and this is the first report about mPR expression in birds. PMID- 23660446 TI - Functional characterization of two melanin-concentrating hormone genes in the color camouflage, hypermelanosis, and appetite of starry flounder. AB - To investigate the involvement of two melanin-concentrating hormones (MCHs) in skin color change and appetite in flatfish, we isolated two forms of prepro melanin concentrating hormone (pMCHs) mRNA in the starry flounder Platichthys stellatus and compared their amino acid structures to those of other animals. Then, we examined the relationship of the two starry flounder pMCH (sf-pMCH) with physiological color change, blind-side malpigmentation, and feeding by quantifying mRNA expression level. Sf-pMCH1 cDNA had a 387-bp open reading frame (ORF) that encoded a protein consisting of 129 amino acid residues. The sf-pMCH1 protein included a signal peptide composed of 24 amino acid residues; MCH1 encoded a protein consisting of 17 amino acids. The sf-pMCH2 cDNA had a 450-bp ORF that encoded a protein consisting of 150 amino acid residues, which included a signal peptide comprising 23 amino acid residues; MCH2 encoded a protein consisting of 23 amino acids that was structurally similar to mammalian MCH. Reverse transcription-polymerase chain reaction (RT-PCR) revealed that the strongest sf-pMCHs gene expression was observed in the brain and pituitary, but weak or no amplification was detected in other tissues. The expression of sf pMCH1 was relatively high compared to that of sf-pMCH2 in the brain. The relative levels of mRNA were significantly lower in dark background-reared and hypermelanic fish, indicating that the two pMCHs and background color are related to the physiological and morphological color changes of skin. In term of feeding regulation, we found an obvious functional role of pMCH1 in appetite, whereas the pMCH2 gene was not found to play a role in feeding. PMID- 23660448 TI - Social dominance in tilapia is associated with gonadotroph hyperplasia. AB - Tilapias are emerging as one of the most important fish in worldwide aquaculture and are also widely used as model fish in the study of reproduction and behavior. During the reproductive season, male tilapia are highly territorial and form spawning pits in which the dominant males court and spawn with available females. Non-territorial males stand a much lower chance of reproducing. Using transgenic tilapia in which follicle stimulating hormone (FSH) gonadotrophs were fluorescently labeled with enhanced green fluorescent protein (EGFP), we studied the effect of social dominance on the hormonal profile and pituitary cell populations in dominant and non-dominant males. Immunofluorescence studies showed that FSH-EGFP-transgenic fish reliably express EGFP in FSH-secreting cells. EGFP expression pattern differed from that of luteinizing hormone. Dominant males had larger gonads as well as higher levels of androgens and gonadotropins in the plasma. Pituitaries of dominant males exhibited higher gonadotropin content and gene expression. Flow cytometry revealed pituitary hyperplasia as well as FSH cell hyperplasia and increased granulation. Taken together, these findings suggest that gonadotroph hyperplasia as well as increased production by individual cells underlie the increased reproductive activity of dominant tilapia males. PMID- 23660447 TI - Photoperiod-dependent regulation of gonadotropin-releasing hormone 1 messenger ribonucleic acid levels in the songbird brain. AB - Annual changes in day length induce marked changes in reproductive function in temperate zone vertebrates. In many avian species, in contrast to other seasonally breeding animals, plasticity in hypothalamic gonadotropin-releasing hormone - 1 (GnRH1) expression rather than (or in addition to) release governs changes in pituitary-gonadal activity. Investigations of the cellular and molecular mechanisms that govern GnRH1 plasticity were previously hindered by a collective inability of scientists in the field to characterize the gnrh1 cDNA in songbirds. We finally overcame this roadblock after data from the zebra finch (Taeniopygia guttata) genome project enabled us to rapidly clone the gnrh1 cDNA from hypothalamic RNA of zebra finches and European starlings (Sturnus vulgaris). Here, we review the original data that identified GnRH1 protein plasticity in the songbird brain and discuss earlier failed attempts to clone gnrh1 in these animals. Then, we present recent efforts, including our own, that successfully characterized gnrh1 in zebra finch and starling, and demonstrated dynamic regulation of gnrh1 mRNA expression, particularly in sub-populations of preoptic area neurons, in the latter. Overall, this paper highlights GnRH1 plasticity in the avian brain, and weaves into the narrative the previously untold story of the challenges to sequencing gnrh1 in songbirds. PMID- 23660449 TI - The effect of experimentally induced chronic hyperglycaemia on serum and pancreatic insulin, pancreatic islet IGF-I and plasma and urinary ketones in the domestic cat (Felis felis). AB - Like in humans, diabetes mellitus is on the rise in cats. Feline diabetes is a suitable model for human type-2 diabetes. We investigated magnitude and timing of insulin suppression with induced hyperglycaemia and its relationship to plasma and urinary ketones and to pancreatic islet insulin. IGF-I is under discussion as a protective mechanism but little is known about its role in diabetes in general and its distinct localisation in feline pancreatic islets in particular. Thirteen healthy, adult cats were allocated to 2 groups and infused with glucose to maintain their blood glucose at a high or moderate concentration for 42 days resulting in insulin secretion suppression. After initial increase, insulin levels declined to baseline but were still detectable in the blood at a very low level after 6 weeks of glucose infusion and then increased after a 3 week recovery period. While IGF-I in healthy cats was primarily located in glucagon cells, in hyperglycaemia-challenge IGF-I was pronounced in the beta-cells 3 weeks after ceasation of infusion. Six/8 cats developing glucose toxicity became ketonuric after 3-4 weeks. Gross lipaemia occurred approx 1 week prior to ketonuria. Ketonuric cats required 1-2 weeks of insulin therapy after-infusion until beta-cell recovery. In conclusion, ketosis and hyperlipidaemia are likely to occur in diabetic cats with glucose at 30 mmol/L, especially after >=2 weeks. Three weeks after ceasation of infusions, clinical and morphological recovery occurred. We propose a local protective effect of IGF-I to support survival and insulin production in the hyperglycaemic state and recovery period. PMID- 23660452 TI - A coincidental anterior interosseous nerve palsy after volar plate fixation of a distal radius fracture diagnosed by 3D-CT. AB - A case presented dysfunctional flexion of the thumb and index fingers after volar plate fixation for of distal radius fractures was diagnosed anterior interosseous nerve palsy and confirmed by 3D-CT. 3D-CT was useful to confirm the continuities of tendons, which excluded the most common complication of tendon ruptures after volar plate fixation. Also, it was superior to needle electromyography which is unreliable due to the accompanying damage of the pronator quadratus following volar plate fixation. PMID- 23660451 TI - An open-label, prospective clinical study to evaluate the efficacy of prophylactic antibiotics after diagnostic bronchoscopy. AB - The aim of this study was to prospectively examine the effect of prophylactic antibiotic use on the development of respiratory infections and on the worsening of symptoms after diagnostic fiberoptic bronchoscopy procedures. This study was an open-label, multicenter, controlled, clinical trial. Patients were alternately assigned to a group given prophylactic antibiotics after bronchoscopy (prophylaxis(+) group) and a group not given antibiotic prophylaxis after bronchoscopy (prophylaxis(-) group), and they were followed-up for 1 week. 158 patients were assigned to the prophylaxis(-) group and 153 to the prophylaxis(+) group. Therapeutic antibiotic administration was needed in 3 patients (1.90%) in the prophylaxis(-) group and 5 patients (3.27%) in the prophylaxis(+) group (risk ratio 1.014, 95% confidence interval 0.978-1.052; p=0.446). Worsening of symptoms after bronchoscopy occurred in 57.6% of all patients by day 7, but no significant differences were observed between the 2 study groups. Prophylactic antibiotic use after bronchoscopy did not prevent the development of infectious events and worsening of symptoms, suggesting that prophylactic antibiotics might not be necessary for routine diagnostic bronchoscopic procedures. PMID- 23660450 TI - Genetic influence on the relation between exhaled nitric oxide and pulse wave reflection. AB - Nitric oxide has an important role in the development of the structure and function of the airways and vessel walls. Fractional exhaled nitric oxide (FE(NO)) is inversely related to the markers and risk factors of atherosclerosis. We aimed to estimate the relative contribution of genes and shared and non-shared environmental influences to variations and covariation of FE(NO) levels and the marker of elasticity function of arteries. Adult Caucasian twin pairs (n = 117) were recruited in Hungary, Italy and in the United States (83 monozygotic and 34 dizygotic pairs; age: 48 +/- 16 SD years). FE(NO) was measured by an electrochemical sensor-based device. Pulse wave reflection (aortic augmentation index, Aix(ao)) was determined by an oscillometric method (Arteriograph). A bivariate Cholesky decomposition model was applied to investigate whether the heritabilities of FE(NO) and Aix(ao) were linked. Genetic effects accounted for 58% (95% confidence interval (CI): 42%, 71%) of the variation in FE(NO) with the remaining 42% (95%CI: 29%, 58%) due to non-shared environmental influences. A modest negative correlation was observed between FE(NO) and Aix(ao) (r = -0.17; 95%CI:-0.32,-0.02). FE(NO) showed a significant negative genetic correlation with Aix(ao) (r(g) = -0.25; 95%CI:-0.46,-0.02). Thus in humans, variations in FE(NO) are explained both by genetic and non-shared environmental effects. Covariance between FE(NO) and Aix(ao) is explained entirely by shared genetic factors. This is consistent with an overlap among the sets of genes involved in the expression of these phenotypes and provides a basis for further genetic studies on cardiovascular and respiratory diseases. PMID- 23660453 TI - Comparison of menopause healthcare considerations between Japanese and Filipino women living in local communities. AB - To investigate the involvement of psychological/social factors in the condition of climacteric disturbance in Japan and the Philippines, we examined the menopausal symptoms and psychological/social factors in menopausal women living in local communities and compared among both countries whether differences in culture, lifestyle, etc. affected the condition of climacteric disturbance. High percentages of Japanese women reported mental symptoms, while relatively high percentages of Filipino women also experienced motor neurological symptoms in addition to psychoneurological symptoms. Japanese and Filipino women were found to have different stressors: a high percentage of the Japanese women had problems involving human relationships, such as providing nursing care, while a high percentage of the Filipino women had household problems, including husband's health and financial problems. Stress severity was associated with SMI scores in both countries. A poorer marital relationship in Japan than in the Philippines and an association between marital relationship and SMI scores were found. The present study suggests the association of differences in psychological/social factors between Japanese and Filipino women with differences in menopausal symptoms. PMID- 23660454 TI - Associated factors of psychological distress among Japanese pediatricians in supporting the bereaved family who has lost a child. AB - PURPOSE: The psychological distress of pediatricians is a major problem in bereavement care. In this study, the primary factor related to distress is clarified and the future directions of bereavement care provided by pediatricians are examined. METHOD: A questionnaire was mailed to Japanese pediatricians belonging to the High-risk Infant Follow-up Association and the Society of Child Neurology. Doctors who actually experienced bereavement care were divided into high and low distress groups. We conducted a comparison of the variables for the two groups using a logistic regression analysis, and the primary factor related to psychological distress was analyzed by the odds ratio (OR) and 95% confidence intervals. RESULTS: The primary factors related to psychological distress were found to be the following 4 items: "gender," "years of experience," "acquisition of coping method," and "feelings of helplessness." In the high distress group, most pediatricians were women, lacked experience, had no coping methods, and felt helplessness. CONCLUSION: Countermeasures are required for people feeling strong psychological distress. It is necessary to let pediatricians know that their support is helping the bereaved families and to strive to improve their feelings of helplessness. Education for appropriate coping methods and self-care is required for pediatricians desiring to study bereavement care. Consideration is particularly required for doctors who are female and those who lack experience. PMID- 23660455 TI - Chemobrain: a systematic review of structural and functional neuroimaging studies. AB - Nowadays, chemotherapy-induced cognitive impairment or 'chemobrain' is a well established clinical syndrome, consisting of moderate to subtle cognitive changes across various domains, especially working memory, executive function and episodic verbal memory that persist only in a subgroup of long-term cancer survivors. In recent years, several studies using neuroimaging techniques have reported structural and functional neural changes associated with chemotherapy. This review provides an overview of the relevant advances that neuroimaging techniques have added to the understanding of the underlying mechanisms of chemotherapy-induced cognitive impairment. In summary, our review showed: (i) a pre-treatment (prior to chemotherapy) widespread decrease in white matter (WM) volume as well as an increased level of activation of the frontoparietal attentional network of cancer patients compared to controls; (ii) an early diffuse decrease of gray matter (GM) and WM volume together with a decrease of the overactivation in frontal regions in chemotherapy-treated patients compared to controls and (iii) a long-term persisting decrease in GM and WM volumes together with a predominantly frontal cortex hypoactivation in only a subgroup of chemotherapy-treated patients. PMID- 23660456 TI - MDMA, serotonergic neurotoxicity, and the diverse functional deficits of recreational 'Ecstasy' users. AB - Serotonergic neurotoxicity following MDMA is well-established in laboratory animals, and neuroimaging studies have found lower serotonin transporter (SERT) binding in abstinent Ecstasy/MDMA users. Serotonin is a modulator for many different psychobiological functions, and this review will summarize the evidence for equivalent functional deficits in recreational users. Declarative memory, prospective memory, and higher cognitive skills are often impaired. Neurocognitive deficits are associated with reduced SERT in the hippocampus, parietal cortex, and prefrontal cortex. EEG and ERP studies have shown localised reductions in brain activity during neurocognitive performance. Deficits in sleep, mood, vision, pain, psychomotor skill, tremor, neurohormonal activity, and psychiatric status, have also been demonstrated. The children of mothers who take Ecstasy/MDMA during pregnancy have developmental problems. These psychobiological deficits are wide-ranging, and occur in functions known to be modulated by serotonin. They are often related to lifetime dosage, with light users showing slight changes, and heavy users displaying more pronounced problems. In summary, abstinent Ecstasy/MDMA users can show deficits in a wide range of biobehavioral functions with a serotonergic component. PMID- 23660457 TI - The shared role of oxidative stress and inflammation in major depressive disorder and nicotine dependence. AB - Nicotine dependence is common in people with mood disorders; however the operative pathways are not well understood. This paper reviews the contribution of inflammation and oxidative stress pathways to the co-association of depressive disorder and nicotine dependence, including increased levels of pro-inflammatory cytokines, increased acute phase proteins, decreased levels of antioxidants and increased oxidative stress. These could be some of the potential pathophysiological mechanisms involved in neuroprogression. The shared inflammatory and oxidative stress pathways by which smoking may increase the risk for development of depressive disorders are in part mediated by increased levels of pro-inflammatory cytokines, diverse neurotransmitter systems, activation the hypothalamic-pituitary-adrenal (HPA) axis, microglial activation, increased production of oxidative stress and decreased levels of antioxidants. Depressive disorder and nicotine dependence are additionally linked imbalance between neuroprotective and neurodegenerative metabolites in the kynurenine pathway that contribute to neuroprogression. These pathways provide a mechanistic framework for understanding the interaction between nicotine dependence and depressive disorder. PMID- 23660458 TI - Multiplex PCR for the detection and differentiation of Vibrio parahaemolyticus strains using the groEL, tdh and trh genes. AB - Vibrio parahaemolyticus is a significant cause of human gastrointestinal disorders worldwide, transmitted primarily by ingestion of raw or undercooked contaminated seafood. In this study, a multiplex PCR assay for the detection and differentiation of V. parahaemolyticus strains was developed using primer sets for a species-specific marker, groEL, and two virulence markers, tdh and trh. Multiplex PCR conditions were standardised, and extracted genomic DNA of 70 V. parahaemolyticus strains was used for identification. The sensitivity and efficacy of this method were validated using artificially inoculated shellfish and seawater. The expected sizes of amplicons were 510 bp, 382 bp, and 171 bp for groEL, tdh and trh, respectively. PCR products were sufficiently different in size, and the detection limits of the multiplex PCR for groEL, tdh and trh were each 200 pg DNA. Specific detection and differentiation of virulent from non virulent strains in shellfish homogenates and seawater was also possible after artificial inoculation with various V. parahaemolyticus strains. This newly developed multiplex PCR is a rapid assay for detection and differentiation of pathogenic V. parahaemolyticus strains, and could be used to prevent disease outbreaks and protect public health by helping the seafood industry maintain a safe shellfish supply. PMID- 23660459 TI - Development of rapid, sensitive and non-radioactive tissue-blot diagnostic method for the detection of citrus greening. AB - Citrus huanglongbing (HLB or citrus greening) is one of the most devastating diseases of citrus worldwide. The disease is caused by Gram-negative, phloem limited alpha-proteobacterium, 'Candidatus Liberibacter asiaticus', vectored by the psyllid, Diaphorina citri Kuwayama. Citrus plants infected by the HLB bacterium may not show visible symptoms sometimes for years following infection and non-uniform distribution within the tree makes the detection of the pathogen very difficult. Efficient management of HLB disease requires rapid and sensitive detection early in the infection followed by eradication of the source of pathogen and the vector. The polymerase chain reaction (PCR) based method is most commonly employed for screening the infected/suspected HLB plants and psyllids. This is time consuming, cumbersome and not practical for screening large number of samples in the field. To overcome this, we developed a simple, sensitive, non radioactive, tissue-blot diagnostic method for early detection and screening of HLB disease. Digoxigenin labeled molecular probes specific to 'Ca. L. asiaticus' nucleotide sequences have been developed and used for the detection of the pathogen of the HLB disease. The copy number of the target genes was also assessed using real-time PCR experiments and the optimized real-time PCR protocol allowed positive 'Ca. L. asiaticus' detection in citrus samples infected with 'Ca. L. asiaticus' bacterium. PMID- 23660460 TI - The biomolecular corona is retained during nanoparticle uptake and protects the cells from the damage induced by cationic nanoparticles until degraded in the lysosomes. AB - Nanoparticles have unique capacities of interacting with the cellular machinery and entering cells. To be able to exploit this potential, it is essential to understand what controls the interactions at the interface between nanoparticles and cells: it is now established that nanoparticles in biological media are covered by proteins and other biomolecules forming a "corona" on the nanoparticle surface, which confers a new identity to the nanoparticles. By labelling the proteins of the serum, using positively-charged polystyrene, we now show that this adsorbed layer is strong enough to be retained on the nanoparticles as they enter cells and is trafficked to the lysosomes on the nanoparticles. There, the corona is degraded and this is followed by lysosomal damage, leading to cytosolic release of lysosomal content, and ultimately apoptosis. Thus the corona protects the cells from the damage induced by the bare nanoparticle surface until enzymatically cleared in the lysosomes. FROM THE CLINICAL EDITOR: This study investigates the effects of protein corona that normally forms on the surface of nanoparticles during in vivo use, describing the steps of intracellular processing of such particles, to enhance our understanding of how these particles interact with the cellular machinery. PMID- 23660461 TI - Structural issues affecting creation of a community action and advocacy board. AB - The most effective woman-initiated method to prevent HIV/sexually transmitted infections is the female condom (FC). Yet, FCs are often difficult to find and denigrated or ignored by community health and service providers. Evidence increasingly supports the need to develop and test theoretically driven, multilevel interventions using a community-empowerment framework to promote FCs in a sustained way. We conducted a study in a midsized northeastern US city (2009 2013) designed to create, mobilize and build capacity of a community group to develop and implement multilevel interventions to increase availability, accessibility and support for FCs in their city. The Community Action and Advocacy Board (CAAB) designed and piloted interventions concurrently targeting community, organizational and individual levels. Ethnographic observation of the CAAB training and intervention planning and pilot implementation sessions documented the process, preliminary successes, challenges and limitations of this model. The CAAB demonstrated ability to conceptualize, plan and initiate multilevel community change. However, challenges in group decision-making and limitations in members' availability or personal capacity constrained CAAB processes and intervention implementation. Lessons from this experience could inform similar efforts to mobilize, engage and build capacity of community coalitions to increase access to and support for FCs and other novel effective prevention options for at-risk women. PMID- 23660462 TI - Impact of targeted health promotion on cardiovascular knowledge among American Indians and Alaska Natives. AB - The National Heart, Lung, and Blood Institute developed the Honoring the Gift of Heart Health (HGHH) curriculum to promote cardiovascular knowledge and heart healthy lifestyles among American Indians and Alaska Natives (AI/ANs). Using data from a small randomized trial designed to reduce diabetes and cardiovascular disease (CVD) risk among overweight/obese AI/ANs, we evaluated the impact of an adapted HGHH curriculum on cardiovascular knowledge. We also assessed whether the curriculum was effective across levels of health literacy (defined as the 'capacity to obtain, process and understand basic health information and services needed to make appropriate health decisions'). We examined change in knowledge from baseline to 3 months for two groups: HGHH (N = 89) and control (N = 50). Compared with controls, HGHH participants showed significant improvement in heart attack knowledge and marginally significant improvement in stroke and general CVD knowledge. HGHH participants attending >=1 class showed significantly greater improvement than controls on all three measures. Although HGHH participants with inadequate health literacy had worse heart attack and stroke knowledge at baseline and 3 months than did participants with adequate skills, the degree of improvement in knowledge did not differ by health literacy level. HGHH appears to improve cardiovascular knowledge among AI/ANs across health literacy levels. PMID- 23660469 TI - Thrombelastographic evaluation of the influence of 2-RBC apheresis on donor's coagulation system. AB - Rotation thrombelastogram (ROTEM(r)/TEG(r)) assays allow rapid global assessment of hemostatic function using whole blood. Since published data about the effects of automated red cell collection on coagulation system are scarce, we aimed to investigate the effects of 2-RBC apheresis on donor's coagulation system using ROTEM(r) assays. In INTEM assay, CFT was significantly shortened 24h after apheresis compared with baseline value (p<0.05) and MCF was significantly prolonged immediately after apheresis and 24h after apheresis compared with baseline value (p<0.05 and p<0.01, respectively). In EXTEM assay, CFT was significantly prolonged immediately after apheresis and 24h after apheresis compared with baseline value (p=0.001 and p<0.001, respectively) and MCF was significantly prolonged 24h after apheresis compared with baseline value (p<0,001). Our results demonstrate thromboelastographic signs of hypercoagulability in donors undergoing 2-RBC apheresis. PMID- 23660470 TI - Editorial. PMID- 23660463 TI - The impact of web-based approaches on psychosocial health in chronic physical and mental health conditions. AB - Chronic conditions such as cancer, cardiovascular disease and mental illness are increasingly prevalent and associated with considerable psychosocial burden. There is a need to consider population health approaches to reducing this burden. Web-based interventions offer an alternative to traditional face-to-face interventions with several potential advantages. This systematic review explores the effectiveness, reach and adoption of web-based approaches for improving psychosocial outcomes in patients with common chronic conditions. A systematic review of published work examining web-based psychosocial interventions for patients with chronic conditions from 2001 to 2011. Seventy-four publications were identified. Thirty-six studies met the criteria for robust research design. A consistent significant effect in favour of the web-based intervention was identified in 20 studies, particularly those using cognitive behavioural therapy for depression. No positive effect was found in 11 studies, and mixed effects were found in 5 studies. The role of sociodemographic characteristics in relation to outcomes or issues of reach and adoption was explored in very few studies. Although it is possible to achieve positive effects on psychosocial outcomes using web-based approaches, effects are not consistent across conditions. Robust comparisons of the reach, adoption and cost-effectiveness of web-based support compared with other options such as face-to-face and print-based approaches are needed. PMID- 23660471 TI - Comparative proteomics of Thellungiella halophila leaves from plants subjected to salinity reveals the importance of chloroplastic starch and soluble sugars in halophyte salt tolerance. AB - Thellungiella halophila, a close relative of Arabidopsis, is a model halophyte used to study plant salt tolerance. The proteomic/physiological/transcriptomic analyses of Thellungiella plant leaves subjected to different salinity levels, reported herein, indicate an extraordinary ability of Thellungiella to adapt to large concentrations of exogenous saline by compartmentalizing Na(+) into cell vacuoles and accumulating proline and soluble sugars as organic osmolytes. Salinity stress stimulated the accumulation of starch in chloroplasts, which resulted in a greatly increased content of starch and total sugars in leaves. Comparative proteomics of Thellungiella leaves identified 209 salt-responsive proteins. Among these, the sequences of 108 proteins were strongly homologous to Arabidopsis protein sequences, and 30 had previously been identified as Thellungiella proteins. Functional classification of these proteins into 16 categories indicated that the majority are involved in carbohydrate metabolism, followed by those involved in energy production and conversion, and then those involved in the transport of inorganic ions. Pathway analysis revealed that most of the proteins are involved in starch and sucrose metabolism, carbon fixation, photosynthesis, and glycolysis. Of these processes, the most affected were starch and sucrose metabolism, which might be pivotal for salt tolerance. The gene expression patterns of the 209 salt-responsive proteins revealed through hierarchical clustering of microarray data and the expression patterns of 29 Thellungiella genes evaluated via quantitative RT-PCR were similar to those deduced via proteomic analysis, which underscored the possibility that starch and sucrose metabolism might play pivotal roles in determining the salt tolerance ability of Thellungiella. Our observations enabled us to propose a schematic representation of the systematic salt-tolerance phenotype in Thellungiella and suggested that the increased accumulation of starch, soluble sugars, and proline, as well as subcellular compartmentalization of sodium, might collectively denote important mechanisms for halophyte salt tolerance. PMID- 23660472 TI - Privileged incorporation of selenium as selenocysteine in Lactobacillus reuteri proteins demonstrated by selenium-specific imaging and proteomics. AB - An analytical approach was developed to study the incorporation of selenium (Se), an important trace element involved in the protection of cells from oxidative stress, into the well-known probiotic Lactobacillus reuteri Lb2 BM-DSM 16143. The analyses revealed that about half of the internalized Se was covalently incorporated into soluble proteins. Se-enriched proteins were detected in 2D gels by laser ablation inductively coupled plasma mass spectrometry imaging (LA-ICP MSI) and identified by capillary HPLC with the parallel ICP MS ((78)Se) and electrospray Orbitrap MS/MS detection. On the basis of the identification of 10 richest in selenium proteins, it was demonstrated that selenium was incorporated by the strain exclusively as selenocysteine. Also, the exact location of selenocysteine within the primary sequence was determined. This finding is in a striking contrast to another common nutraceutical, Se-enriched yeast, which incorporates Se principally as selenomethionine. PMID- 23660473 TI - Quantitative measurement of phosphoproteome response to osmotic stress in arabidopsis based on Library-Assisted eXtracted Ion Chromatogram (LAXIC). AB - Global phosphorylation changes in plants in response to environmental stress have been relatively poorly characterized to date. Here we introduce a novel mass spectrometry-based label-free quantitation method that facilitates systematic profiling plant phosphoproteome changes with high efficiency and accuracy. This method employs synthetic peptide libraries tailored specifically as internal standards for complex phosphopeptide samples and accordingly, a local normalization algorithm, LAXIC, which calculates phosphopeptide abundance normalized locally with co-eluting library peptides. Normalization was achieved in a small time frame centered to each phosphopeptide to compensate for the diverse ion suppression effect across retention time. The label-free LAXIC method was further treated with a linear regression function to accurately measure phosphoproteome responses to osmotic stress in Arabidopsis. Among 2027 unique phosphopeptides identified and 1850 quantified phosphopeptides in Arabidopsis samples, 468 regulated phosphopeptides representing 497 phosphosites have shown significant changes. Several known and novel components in the abiotic stress pathway were identified, illustrating the capability of this method to identify critical signaling events among dynamic and complex phosphorylation. Further assessment of those regulated proteins may help shed light on phosphorylation response to osmotic stress in plants. PMID- 23660474 TI - Heterogeneity in neutrophil microparticles reveals distinct proteome and functional properties. AB - Altered plasma neutrophil microparticle levels have recently been implicated in a number of vascular and inflammatory diseases, yet our understanding of their actions is very limited. Herein, we investigate the proteome of neutrophil microparticles in order to shed light on their biological actions. Stimulation of human neutrophils, either in suspension or adherent to an endothelial monolayer, led to the production of microparticles containing >400 distinct proteins with only 223 being shared by the two subsets. For instance, postadherent microparticles were enriched in alpha-2 macroglobulin and ceruloplasmin, whereas microparticles produced by neutrophils in suspension were abundant in heat shock 70 kDa protein 1. Annexin A1 and lactotransferrin were expressed in both microparticle subsets. We next determined relative abundance of these proteins in three types of human microparticle samples: healthy volunteer plasma, plasma of septic patients and skin blister exudates finding that these proteins were differentially expressed on neutrophil microparticles from these samples reflecting in part the expression profiles we found in vitro. Functional assessment of the neutrophil microparticles subsets demonstrated that in response to direct stimulation neutrophil microparticles produced reactive oxygen species and leukotriene B4 as well as locomoted toward a chemotactic gradient. Finally, we investigated the actions of the two neutrophil microparticles subsets described herein on target cell responses. Microarray analysis with human primary endothelial cells incubated with either microparticle subset revealed a discrete modulation of endothelial cell gene expression profile. These findings demonstrate that neutrophil microparticles are heterogenous and can deliver packaged information propagating the activation status of the parent cell, potentially exerting novel and fundamental roles both under homeostatic and disease conditions. PMID- 23660475 TI - Early replacement therapy in a first Japanese case with autosomal recessive guanosine triphosphate cyclohydrolase I deficiency with a novel point mutation. AB - Autosomal recessive guanosine triphosphate cyclohydrolase I (GTPCH) deficiency is an inborn error of tetrahydrobiopterin (BH4) synthesis from GTP. GTPCH deficiency causes severe reduction of BH4, resulting in hyperphenylalaninemia (HPA) and decreased dopamine and serotonin synthesis. Without treatment, a patient with GTPCH deficiency develops complex neurological dysfunctions, including dystonia and developmental delays. The first Japanese patient with GTPCH deficiency was discovered by HPA during asymptomatic newborn screening. The phenylalanine level at the age of 5days was 1273MUmol/L (cutoff value, 180.0MUmol/L). The high serum phenylalanine level was decreased to normal after adequate BH4 oral supplementation. Serum and urinary pteridine examination revealed very low levels of neopterin and biopterin. Sequence analysis of GCH1 revealed compound heterozygous point mutations, including a novel point mutation (p.R235W). Replacement therapy with BH4 and L-dopa/carbidopa were started at the age of 1month, and 5-hydroxytryptophan (5-HTP) was started at the age of 5months. At 10months of age, the patient showed slight dystonia but no obvious developmental delay. Cerebrospinal fluid should be examined to determine the appropriate dosage of supplement drugs. In conclusion, it is important to control the serum phenylalanine level and perform early replacement of neurotransmitters to prevent neurological dysfunction. PMID- 23660476 TI - Serum miR-210 and miR-30a expressions tend to revert to fetal levels in Chinese adult patients with chronic heart failure. AB - BACKGROUND: MicroRNAs (miRNAs) are widely involved in the process of chronic heart failure (HF), which is characterized by reactivation of the fetal gene program. Here, we examined whether the serum expression levels of some HF-related miRNAs in adult HF patients would tend to revert to fetal levels. METHODS AND RESULTS: Serum was obtained from the peripheral venous blood of 22 HF patients, 18 asymptomatic controls, and the umbilical venous blood of 9 fetuses from 9 independent parturitions. Serum pools of the three groups were initially screened against 40 known HF-associated miRNAs via quantitative reverse transcriptase polymerase chain reaction. Twenty-seven miRNAs were stably expressed in the serum pools. Nine miRNAs showed similar expression levels in the HF and fetus groups compared to the controls, two of which (miR-210, miR-30a) were significantly up regulated in both groups. These miRNAs showed high diagnostic accuracy and correlations with blood N-terminal prohormone of brain natriuretic peptide, identifying them as potential biomarkers for HF. Putative targets of the miRNAs were predicted with online software programs, and the Kyoto Encyclopedia of Genes and Genomes pathway analysis was employed to identify miRNA-regulated functional modules. In particular, miR-210 seemed to be more closely related than miR-30a to the pathological mechanisms of HF, including the calcium signaling, vascular smooth muscle contraction, transforming growth factor-beta signaling, and aldosterone-regulated sodium reabsorption pathways. CONCLUSION: The serum expression levels of some HF-related miRNAs in HF patients tended towards fetal levels. Among them, miR-210 and miR-30a were elevated in the HF and fetus groups. PMID- 23660477 TI - Impulsivity, self-control, and hypnotic suggestibility. AB - Hypnotic responding might be due to attenuated frontal lobe functioning after the hypnotic induction. Little is known about whether personality traits linked with frontal functioning are associated with responsiveness to hypnotic suggestions. We assessed whether hypnotic suggestibility is related to the traits of self control and impulsivity in 154 participants who completed the Brief Self-Control Scale, the Self-Regulation Scale, the Barratt Impulsiveness Scale (BIS-11), and the Harvard Group Scale of Hypnotic Susceptibility (HGSHS:A). BIS-11 non-planning impulsivity correlated positively with HGSHS:A (Bonferroni-corrected). Furthermore, in the best model emerging from a stepwise multiple regression, both non-planning impulsivity and self-control positively predicted hypnotic suggestibility, and there was an interaction of BIS-11 motor impulsivity with gender. For men only, motor impulsivity tended to predict hypnotic suggestibility. Hypnotic suggestibility is associated with personality traits linked with frontal functioning, and hypnotic responding in men and women might differ. PMID- 23660478 TI - Rac1 mediates cytokine-stimulated hemocyte spreading via prostaglandin biosynthesis in the beet armyworm, Spodoptera exigua. AB - Cell spreading is an integral component of insect hemocytic immune reactions to infections and invasions. Cell spreading is accomplished by cytoskeleton rearrangement, which is activated by three major immune mediators, biogenic monoamines, plasmatocyte-spreading peptide (PSP), and eicosanoids, particularly prostaglandin E2 (PGE2). However, little is known about how these immune mediators activate hemocyte spreading at the intra-cellular level. A small G protein, Rac1, acts in cytoskeleton arrangements in mammalian cells. Based on this information, we identified a Rac1 transcript (SeRac1) in hemocytes prepared from Spodoptera exigua. SeRac1 was expressed in most developmental stages and in the two main immunity-conferring tissues, hemocytes and fat body, in larvae. In response to bacterial challenge, its expression was up-regulated by >37-fold at 2h post-injection and returned to a basal level about 2h later. Silencing SeRac1 expression inhibited hemocyte spreading in response to three immune mediators, octopamine, 5-hydroxytryptamine, and PSP. Addition of PGE2 to SeRac1-silenced larvae rescued the influence of these three mediators on hemocyte spreading. These compounds also increased phospholipase A2 activity via SeRac1, which leads to prostaglandin biosynthesis. We infer that SeRac1 transduces OA, 5-HT, and PSP signaling via activating biosynthesis of prostaglandins and possibly other eicosanoids. PMID- 23660480 TI - [Iatrogenic endometriosis during reproductive age: main issues?]. AB - Among endometriotic lesions a small proportion is secondary to various medical activities, and may be considered as iatrogenic. Any medical or surgical procedure increasing the menstrual flow or the retrograde flow bears a potential risk: conization, hydrotubation or copper intra-uterine device. Surgical procedures, by laparotomy or laparoscopic approach, are able to favor transport and cutaneous seeding of endometrial tissue, especially when a hysterotomy has been performed. Diagnosis and treatment of these lesions are today standardized. Few preventive measures are available, besides adequate surgical procedure, but none has been properly evaluated, mainly because these lesions are not frequent. PMID- 23660479 TI - [Segmentary rectal resection and rectal shaving by laparoscopy for endometriosis: peri-operative morbidity]. AB - OBJECTIVE: A comparative study of the peri-operative complications between two surgical methods used in the treatment of bowel endometriosis: shaving versus segmentary colorectal resection. PATIENTS AND METHODS: Forty-one patients, who were treated by laparoscopic treatment of bowel endometriosis between January, 2010 and November, 2011 were included in a retrospective, unicenter series. Twenty patients had a "shaving" while 21 had a segmentary rectal resection. RESULTS: The average follow-up was of 13.6+/-6.7 months. No recurrence was observed during the study. The duration of surgery and the length of stay were significantly longer in the resection group, respectively 485.5+/-85min and 9.6+/ 6.5 days against 259.3+/-104min and 4+/-1.3 days in the shaving group. The rates of early and late complications (Dindo classification) were respectively 71.4% and 33.3% in the resection group against 20% and 0% in the shaving group (P<0.05). Our rate of vaginal fistula was null; this is to put in connection with the fact that an ileostomy of discharge was realized in 95.2% of the resections, as well as an epiplooplasty, when it was technically possible, in the case of a concomitant vaginal opening. DISCUSSION AND CONCLUSION: The peri-operative morbidity was higher after partial bowel resection. Our study underlines that these two techniques are probably not addressed to the same patients. Considering the significant morbidity, it would be interesting to define in a consensual way, who the surgery should be propose to and by which procedure. PMID- 23660481 TI - New aspects of the diagnosis of celiac disease in children, adolescents, and adults. PMID- 23660482 TI - Prion-resistant or prion-susceptible species, this is the question. PMID- 23660483 TI - Antiferromagnetic ordering in Sr2CrO4. AB - The magnetic ground state of Sr2CrO4 with a distorted honeycomb lattice was investigated by means of measurements of the magnetic susceptibility, high-field magnetization process, and electron spin resonance (ESR). Antiferromagnetic ordering was observed clearly below TN = 3.2 K, while the magnetic ground state had been thought to be a spin-singlet state. A two-sublattice model with biaxial anisotropy was applicable for the observed ESR modes. Plateau-like behavior and a sharp kink were detected in the magnetization curve. PMID- 23660484 TI - Automated subtyping of HIV-1 genetic sequences for clinical and surveillance purposes: performance evaluation of the new REGA version 3 and seven other tools. AB - BACKGROUND: To investigate differences in pathogenesis, diagnosis and resistance pathways between HIV-1 subtypes, an accurate subtyping tool for large datasets is needed. We aimed to evaluate the performance of automated subtyping tools to classify the different subtypes and circulating recombinant forms using pol, the most sequenced region in clinical practice. We also present the upgraded version 3 of the Rega HIV subtyping tool (REGAv3). METHODOLOGY: HIV-1 pol sequences (PR+RT) for 4674 patients retrieved from the Portuguese HIV Drug Resistance Database, and 1872 pol sequences trimmed from full-length genomes retrieved from the Los Alamos database were classified with statistical-based tools such as COMET, jpHMM and STAR; similarity-based tools such as NCBI and Stanford; and phylogenetic-based tools such as REGA version 2 (REGAv2), REGAv3, and SCUEAL. The performance of these tools, for pol, and for PR and RT separately, was compared in terms of reproducibility, sensitivity and specificity with respect to the gold standard which was manual phylogenetic analysis of the pol region. RESULTS: The sensitivity and specificity for subtypes B and C was more than 96% for seven tools, but was variable for other subtypes such as A, D, F and G. With regard to the most common circulating recombinant forms (CRFs), the sensitivity and specificity for CRF01_AE was ~99% with statistical-based tools, with phylogenetic based tools and with Stanford, one of the similarity based tools. CRF02_AG was correctly identified for more than 96% by COMET, REGAv3, Stanford and STAR. All the tools reached a specificity of more than 97% for most of the subtypes and the two main CRFs (CRF01_AE and CRF02_AG). Other CRFs were identified only by COMET, REGAv2, REGAv3, and SCUEAL and with variable sensitivity. When analyzing sequences for PR and RT separately, the performance for PR was generally lower and variable between the tools. Similarity and statistical-based tools were 100% reproducible, but this was lower for phylogenetic-based tools such as REGA (~99%) and SCUEAL (~96%). CONCLUSIONS: REGAv3 had an improved performance for subtype B and CRF02_AG compared to REGAv2 and is now able to also identify all epidemiologically relevant CRFs. In general the best performing tools, in alphabetical order, were COMET, jpHMM, REGAv3, and SCUEAL when analyzing pure subtypes in the pol region, and COMET and REGAv3 when analyzing most of the CRFs. Based on this study, we recommend to confirm subtyping with 2 well performing tools, and be cautious with the interpretation of short sequences. PMID- 23660485 TI - Phages of Staphylococcus aureus and their impact on host evolution. AB - Most of the dissimilarity between Staphylococcus aureus strains is due to the presence of mobile genetic elements such as bacteriophages or pathogenicity islands. These elements provide the bacteria with additional genes that enable them to establish a new lifestyle that is often accompanied by a shift to increased pathogenicity or a jump to a new host. S. aureus phages may carry genes coding for diverse virulence factors such as Panton-Valentine leukocidin, staphylokinase, enterotoxins, chemotaxis-inhibitory proteins, or exfoliative toxins. Phages also mediate the transfer of pathogenicity islands in a highly coordinated manner and are the primary vehicle for the horizontal transfer of chromosomal and extra-chromosomal genes. Here, we summarise recent advances regarding phage classification, genome organisation and function of S. aureus phages with a particular emphasis on their role in the evolution of the bacterial host. PMID- 23660486 TI - Whole-genome, deep pyrosequencing analysis of a duck influenza A virus evolution in swine cells. AB - We studied the sub-population level evolution of a duck influenza A virus isolate during passage in swine tracheal cells. The complete genomes of the A/mallard/Netherlands/10-Nmkt/1999 strain and its swine cell-passaged descendent were analysed by 454 pyrosequencing with coverage depth ranging from several hundred to several thousand reads at any point. This allowed characterization of defined minority sub-populations of gene segments 2, 3, 4, 5, 7, and 8 present in the original isolate. These minority sub-populations ranged between 9.5% (for segment 2) and 46% (for segment 4) of their respective gene segments in the parental stock. They were likely contributed by one or more viruses circulating within the same area, at the same period and in the same or a sympatric host species. The minority sub-populations of segments 3, 4, and 5 became extinct upon viral passage in swine cells, whereas the minority sub-populations of segments 2, 7 and 8 completely replaced their majority counterparts. The swine cell-passaged virus was therefore a three-segment reassortant and also harboured point mutations in segments 3 and 4. The passaged virus was more homogenous than the parental stock, with only 17 minority single nucleotide polymorphisms present above 5% frequency across the whole genome. Though limited here to one sample, this deep sequencing approach highlights the evolutionary versatility of influenza viruses whereby they exploit their genetic diversity, predilection for mixed infection and reassortment to adapt to a new host environmental niche. PMID- 23660488 TI - Combinational effects of ketamine and amphetamine on behaviors and neurotransmitter systems of mice. AB - The combined ingestion of ketamine (Ket) and amphetamine (Amph) by drug-users has been rampant and produced more severe behavioral abnormality. However, the interactive consequences of the two drugs are still unclear. In this study, we treated adult male mice with a single i.p. injection of saline, Amph (5 mg/kg), low Ket (LK, 10 mg/kg), high Ket (HK, 50 mg/kg), or Amph and LK or HK (ALK or AHK) and examined their behavioral and neurochemical changes at 0.5 and 2 h post injection. Compared with saline, Amph, LK or HK treatment alone increased the levels of motor activities such as locomotion, stereotypy or ataxia of mice. Notably, at combined treatments, LK and HK differentially exacerbated Amph induced locomotion and stereotypy, whereas Amph worsened LK or HK-produced ataxia. The higher striatal dopamine levels of A, ALK and AHK groups correlated with their greater motor activities. The prolonged increase of dopamine in the motor cortex of ALK and AHK mice may associate with the longer duration of behavioral hyperactivity and greater peak score of locomotion; the greater dopamine level in the somatosensory cortex probably contributes to the more severe ataxia. Furthermore, in the striatum of all drug-treated groups, the expression of GAD67 mRNA and GAD67-positive punctates was higher than respective saline controls, indicating the involvement of GABAergic system in the drug induced behavioral changes. Our results demonstrate the acute interplay between Amph and Ket in both behavioral and neurochemical aspects for the first time. Dopaminergic and GABAergic systems were affected differentially by the drugs in the striatum. PMID- 23660487 TI - The effect of perinatal exposure to ethinyl oestradiol or a mixture of endocrine disrupting pesticides on kisspeptin neurons in the rat hypothalamus. AB - Early life exposure to endocrine disruptors is considered to disturb normal development of hormone sensitive parameters and contribute to advanced puberty and reduced fecundity in humans. Kisspeptin is a positive regulator of the hypothalamic-pituitary-gonadal axis, and plays a key role in the initiation of puberty. In the adult, Kiss1 gene expression occurs in two hypothalamic nuclei, namely the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC), which are differentially regulated by peripheral sex steroid hormones. In this study we determined the effects on puberty onset and Kiss1 mRNA levels in each of the two nuclei after long-term perinatal exposure of rats to ethinyl oestradiol (EE2) or to five different pesticides, individually and in a mixture. Rat dams were per orally administered with three doses of EE2 (5, 15 or 50 MUg/kg/day) or with the pesticides epoxiconazole, mancozeb, prochloraz, tebuconazole, and procymidone, alone or in a mixture of the five pesticides at three different doses. Kiss1 mRNA expression was determined in the AVPV and in the ARC of the adult male and female pups in the EE2 experiment, and in the adult female pups in the pesticide experiment. We find that perinatal EE2 exposure did not affect Kiss1 mRNA expression in this study designed to model human exposure to estrogenic compounds, and we find only minor effects on puberty onset. Further, the Kiss1 system does not exhibit persistent changes and puberty onset is not affected after perinatal exposure to a pesticide mixture in this experimental setting. However, we find that the pesticide mancozeb tends to increase Kiss1 expression in the ARC, presumably through neurotoxic mechanisms rather than via classical endocrine disruption, calling for increased awareness that Kiss1 expression can be affected by environmental pollutants through multiple mechanisms. PMID- 23660489 TI - May you never forget what is worth remembering: the relation between recall of medical information and medication adherence in patients with inflammatory bowel disease. AB - BACKGROUND: Nurses play an important role in educating patients with inflammatory bowel disease (IBD) about immunosuppressive or biological therapy during prescribing consultations. The education for immunosuppressive or biological therapy often contains complex information. Poor medication intake behavior can be a result of poor information recall, which is often caused by complex information. OBJECTIVES: The aim of this study is to measure information recall by IBD patients, and to investigate the relationship between recall and medication intake behavior. METHODS: Data collection took place from September 2009 until March 2012. Eight nurses at six Dutch hospitals and 68 IBD patients participated in this study. Prescribing consultations were videotaped and patients completed surveys immediately after the consultation and after three weeks. Information recall was based on the actual communication in video recordings of the consultations. Medication intake behavior was measured by self report. RESULTS: Issues most frequently discussed were side effects and how patients had to administer their medication. IBD patients could reproduce half of the information. Recall of medical information was a significant predictor for self-reported medication intake behavior (beta=0.37, p=0.007), indicating that higher recall of medical information relates to improved self-reported medication intake behavior. CONCLUSIONS: This study revealed a significant relation between IBD patients' recall and self-reported medication intake behavior. When educating IBD patients about their newly prescribed medication, providers should consider recall-promoting techniques to increase medication intake behavior. PMID- 23660490 TI - Potential of Hydrocotyle vulgaris for phytoremediation of a textile dye: Inducing antioxidant response in roots and leaves. AB - The potential of Hydrocotyle vulgaris as an aquatic plant species was evaluated for phytoremediation of C.I. Basic Red 46 (BR46) from nutrient solution. Under the optimized experimental conditions, BR46 was removed up to 95% from incubation medium by H. vulgaris. The ability of the plant in consecutive removal under long term repetitive experiments confirmed the biodegradation process. Accordingly, a number of produced intermediate compounds were identified. An artificial neural network (ANN) model was developed to predict the biodegradation efficiency. A predictive performance (R(2)=0.974) was obtained based on the network results. Interestingly, dye stress enhanced the activity of antioxidant enzymes including superoxide dismutase, peroxidase and catalase in H. vulgaris roots and leaves. Enzymatic responses found to be highly depended on the plant organ and dye concentration in the liquid medium. Overall, the increase in the activity of antioxidant enzymes was much higher in the roots than in the leaves. Nevertheless, no significant increase in the malondialdehyde (MDA) content was detected in both roots and leaves which reflects the high efficiency of antioxidant system in the elimination of reactive oxygen species. PMID- 23660491 TI - Electrophysiologic evaluation of cremasteric reflex in experimental orchitis. AB - AIM: Absent cremasteric reflex (CR) is a well known but not reliable sign of testicular torsion. We hypothesized that CR can also be altered in other causes of acute scrotum in children. An experimental study was performed to evaluate the clinical and electrophysiological features of CR in orchitis. METHOD: Eighteen Wistar albino rats were allocated into three groups: control (CG), sham (SG) and orchitis (OG). In CG, after anesthetization with ketamine hydrochloride, the medial site of the anterior superior iliac spine was stimulated to obtain CR electrophysiologically, and latency and duration were recorded with a needle electrode placed in the cremasteric muscle. Electrophysiologic evaluations were performed 24 h after injection of 0.1 ml of 10(6) cfu/ml Escherichia coli (0:6 strain) in 1 ml of physiologic saline into the right testicle in OG, and 1 ml of saline only in SG. All testicles were sampled to check for orchitis after the electrophysiologic evaluations. RESULTS: CR was obtained in all rats in CG and in 83.3% and 66.6% in SG and OG respectively (p < 0.05). The latency of CR was significantly higher in OG (15.1 +/- 0.9 ms) and SG (15.5 +/- 1.2 ms) than CG (10.5 +/- 0.7 ms) (p < 0.017). The duration of CR was 15.1 +/- 3.2 ms in CG, 16.2 +/- 4.9 ms in SG and 18.5 +/- 3 ms in OG (p > 0.05). Histopathologic confirmation of orchitis was obtained in all testicle samples in OG, and number of neutrophils and total orchitis score was significantly higher in OG than the other groups (p < 0.05). CONCLUSION: Electrophysiologic parameters of CR may be altered in orchitis. Prolonged latency of CR in orchitis may be due to inflammation of the genitofemoral nerve or cremasteric muscle. PMID- 23660492 TI - Use of holmium:YAG laser in posterior urethral valves: another method of fulguration. AB - OBJECTIVE: To evaluate the use of holmium:YAG laser for posterior urethral valve (PUV) fulguration and compare with electro-fulguration. METHODS: Forty boys underwent primary fulguration of PUV using 20-25 W holmium laser (Group 1) from January 2009 to December 2011. Data of last 40 boys (retrospective cohort: January 2005 to December 2008) who underwent electro-fulguration (Group 2) for PUV were compared with group 1. Ultrasonography was done at 2 weeks and 3 months and voiding cystourethrography at 3 and 6 months respectively after fulguration and as needed thereafter. DTPA scan and urodynamic study were performed during follow-up in select patients, as required. RESULTS: Pre-operative parameters were comparable between groups. Improvement in voiding occurred in 38 and 34 boys in group 1 and 2, respectively. Hydroureteronephrosis and vesico-ureteric reflux resolved in 53% and 60% in group 1 and 51% and 53% in group 2, respectively. Boys in group 1 had statistically significant greater success in voiding after catheter removal (40 vs 32), shorter period of catheterization (1 vs 1.8 days), lower mean operative time (15 vs 20 min), needed re-fulguration less commonly (2 vs 6), and were less likely to develop urethral stricture (0 vs 2) and urinary incontinence (0 vs 1). CONCLUSION: PUV fulguration using holmium:YAG laser is a feasible, safe and effective alternative for endoscopic transurethral ablation with similar success, and appears to have fewer complications than electro fulguration. PMID- 23660493 TI - Biopotentiality as an index of environmental compensation for composting plants. AB - The Biopotentiality Index is a landscape ecology indicator, which can be used to estimate the latent energy of a given land and to assess the environmental impacts due to the loss of naturalness on a landscape scale. This indicator has been applied to estimate the effectiveness of the measures put in place to provide an environmental compensation for the revamping of a composting plant. These compensation measures are represented by a green belt with a minimum width of 25 m all around the plant, representing both a windbreak and a buffer zone, and by two wide wooded zones acting as core natural areas. This case-study shows that the compensation index could be used as a key tool in order to negotiate the acceptance of waste treatment plant with the population. PMID- 23660494 TI - Energy implications of mechanical and mechanical-biological treatment compared to direct waste-to-energy. AB - Primary energy savings potential is used to compare five residual municipal solid waste treatment systems, including configurations with mechanical (MT) and mechanical-biological (MBT) pre-treatment, which produce waste-derived fuels (RDF and SRF), biogas and/or recover additional materials for recycling, alongside a system based on conventional mass burn waste-to-energy and ash treatment. To examine the magnitude of potential savings we consider two energy efficiency levels (state-of-the-art and best available technology), the inclusion/exclusion of heat recovery (CHP vs. PP) and three different background end-use energy production systems (coal condensing electricity and natural gas heat, Nordic electricity mix and natural gas heat, and coal CHP energy quality allocation). The systems achieved net primary energy savings in a range between 34 and 140 MJprimary/100 MJinput waste, in the different scenario settings. The energy footprint of transportation needs, pre-treatment and reprocessing of recyclable materials was 3-9.5%, 1-18% and 1-8% respectively, relative to total energy savings. Mass combustion WtE achieved the highest savings in scenarios with CHP production, nonetheless, MBT-based systems had similarly high performance if SRF streams were co-combusted with coal. When RDF and SRF was only used in dedicated WtE plants, MBT-based systems totalled lower savings due to inherent system losses and additional energy costs. In scenarios without heat recovery, the biodrying MBS-based system achieved the highest savings, on the condition of SRF co-combustion. As a sensitivity scenario, alternative utilisation of SRF in cement kilns was modelled. It supported similar or higher net savings for all pre treatment systems compared to mass combustion WtE, except when WtE CHP was possible in the first two background energy scenarios. Recovery of plastics for recycling before energy recovery increased net energy savings in most scenario variations, over those of full stream combustion. Sensitivity to assumptions regarding virgin plastic substitution was tested and was found to mostly favour plastic recovery. PMID- 23660496 TI - Changes of calcium binding proteins, c-Fos and COX in hippocampal formation and cerebellum of Niemann-Pick, type C mouse. AB - Niemann-Pick disease, type C (NPC) is an intractable disease that is accompanied by ataxia, dystonia, neurodegeneration, and dementia due to an NPC gene defect. Disruption of calcium homeostasis in neurons is important in patients with NPC. Thus, we used immunohistochemistry to assess the expression levels of calcium binding proteins (calbindin D28K, parvalbumin, and calretinin), c-Fos and cyclooxygenase-1,2 (COX-1,2) in the hippocampal formation and cerebellum of 4 and 8 week old NPC+/+, NPC+/-, and NPC-/- mice. General expression of these proteins decreased in the hippocampus and cerebellum of NPC-/- compared to that in both young and adult NPC+/+ or NPC+/- mice. Parvalbumin, COX-1,2 or c-Fos immunoreactive neurons were widely detected in the CA1, CA3, and DG of the hippocampus, but the immunoreactivities were decreased sharply in all areas of hippocampus of NPC-/- compared to NPC+/+ and NPC+/- mice. Taken together, reduction of these proteins may be one of the strong phenotypes related to the neuronal degeneration in NPC-/- mice. PMID- 23660495 TI - [Sclerotherapy for recurrent glomus tumors]. AB - We report the cases of two women aged 28 and 34 years who presented recurrent glomus tumors of the hand after surgery for marginal resection of the tumor mass. The pathological study of the surgical specimen confirmed the diagnosis of recurrent glomus tumor. Due to the vascular origin of this tumor, sclerotherapy was delivered. The functional outcomes were good with dramatic pain relief within a few days. At 3-year mean follow-up, the cosmetic and functional results were very satisfactory. PMID- 23660497 TI - Deep brain stimulation of the mediodorsal thalamic nucleus yields increases in the expression of zif-268 but not c-fos in the frontal cortex. AB - This study explores the regions activated by deep brain stimulation of the mediodorsal thalamic nucleus through examination of immediate early genes as markers of neuronal activation. Stimulation was delivered unilaterally with constant current 100 MUs duration pulses at a frequency of 130 Hz delivered at an amplitude of 200 MUA for 3h. Brains were removed, sectioned and radio-labelled for the IEGs zif-268 and c-fos. In anaesthetised rats, deep brain stimulation of mediodorsal thalamic nucleus produced robust increases in the expression of zif 268 but not c-fos localised to regions that are reciprocally connected with the mediodorsal thalamic nucleus, including the prelimbic and orbitofrontal cortices, and the premotor cortex indicating an increase in synaptic activity in these regions. These findings map those brain regions that are persistently, rather than transiently, activated by high frequency electrical stimulation of the mediodorsal thalamic nucleus by a putatively antidromic mechanism which may be relevant to neuropsychiatric disorders such as schizophrenia in which thalamocortical systems are disrupted and in which DBS protocols are being considered. PMID- 23660498 TI - Exploring the process of women's infant feeding decisions in the early postbirth period. AB - Research indicates that multiple factors are associated with decisions women make about infant feeding, yet few studies have explored the decision-making process. In this article, we present the analysis that produced the core category "deconstructing best," previously reported as part of a grounded theory exploring 37 Australian women's infant feeding experiences and decisions in the first 6 weeks postbirth. We expand on the previous article by detailing and discussing the phases of the infant feeding decision-making process in relation to decision making theory. Analysis demonstrates the importance of these early weeks in shaping women's infant feeding trajectories. Findings illustrate that information gathering encompassing multiple factors occurred at this time, and that complex and often competing goals were involved in the women's decisions. We suggest that acknowledging and assisting women to meet alternate goals in the postbirth period might help them meet their breastfeeding goals. PMID- 23660499 TI - Potential motivations for and perceived risks in research participation: ethics in health research. AB - In a South African urban-township-based ethnographic study with adult 19 women and 7 men, we explored people's motivations for and experiences of research participation and perceptions of being asked about sensitive experiences, including gender-based violence. We also explored the implications of participation. Several informants were motivated by self-interest to participate in research, whereas others were more altruistic; yet with many there was a complex overlap. We found that altruism, as a motivation to participate in research, is a muddled and multifaceted issue that needs careful unpacking and nuanced discussion to understand. Breach of confidentiality was perceived as a main risk, and gender differences were apparent in reporting feared consequences, with women primarily fearing possible violent reprisals from partners. We conclude that the decision to participate in research seems to be a balanced and conditional process wherein individuals assess the potential benefits and risks to themselves and the potential contribution to others. PMID- 23660500 TI - SOX9 directly regulates IGFBP-4 in the intestinal epithelium. AB - SOX9 regulates cell lineage specification by directly regulating target genes in a discrete number of tissues, and previous reports have shown cell proliferative and suppressive roles for SOX9. Although SOX9 is expressed in colorectal cancer, only a few direct targets have been identified in intestinal epithelial cells. We previously demonstrated increased proliferation in Sox9-deficient crypts through loss-of-function studies, indicating that SOX9 suppresses cell proliferation. In this study, crypt epithelial cells isolated from Sox9-deficient mice were used to identify potential target genes of SOX9. Insulin-like growth factor (IGF)-binding protein 4 (IGFBP-4), an inhibitor of the IGF/IGF receptor pathway, was significantly downregulated in Sox9-deficient intestinal epithelial cells and adenoma cells of Sox9-deficient ApcMin/+ mice. Immunolocalization experiments revealed that IGFBP-4 colocalized with SOX9 in mouse and human intestinal epithelial cells and in specimens from patients with primary colorectal cancer. Reporter assays and chromatin immunoprecipitation demonstrated direct binding of SOX9 to the IGFBP-4 promoter. Overexpression of SOX9 attenuated cell proliferation, which was restored following treatment with a neutralizing antibody against IGFBP-4. These results suggest that SOX9 regulates cell proliferation, at least in part via IGFBP-4. Furthermore, the antiproliferative effect of SOX9 was confirmed in vivo using Sox9-deficient mice, which showed increased tumor burden when bred with ApcMin/+ mice. Our results demonstrate, for the first time, that SOX9 is a transcriptional regulator of IGFBP-4 and that SOX9 induced activation of IGFBP-4 may be one of the mechanisms by which SOX9 suppresses cell proliferation and progression of colon cancer. PMID- 23660501 TI - Morphological, immunocytochemical, and functional characterization of esophageal enteric neurons in primary culture. AB - The enteric nervous system of the esophagus plays an important role in its sensory and motor functions. Although the esophagus contains enteric neurons, they have never been isolated and characterized in primary culture. We isolated and cultured enteric neurons of the rat esophagus and determined their morphological appearance, chemical coding for neurotransmitters, and functional characteristics. After primary culture for 2 wk, dendrites and axons appeared in the enteric neurons, which usually have one axon and several dendrites. Although the size of neuronal bodies varied from Dogiel type I to type II, their average size was 39 +/- 1.8 MUm in length and 23 +/- 1.4 MUm in width. Immmunocytochemical studies revealed that over 95% of these cells were positively stained for two general neuronal markers, PGP 9.5 or Milli-Mark Fluoro. Chemical coding showed that the neurons were positively stained for choline acetyltransferease (53 +/- 6%) or nNOS (66 +/- 13%). In functional studies, membrane depolarization and stimulation of several G protein-coupled receptors (GPCRs) induced Ca2+ signaling in the esophageal enteric neurons. The GPCR stimulation was found to induce both intracellular Ca2+ release and extracellular Ca2+ entry. The functional expressions of Ca2+ channels (voltage-gated Ca2+ channels and store-operated channels) and Ca2+ pump (sarcoplasmic reticulum Ca2+ ATPase) were also demonstrated on these neurons. We have grown, for the first time, esophageal enteric neurons in primary culture, and these contain excitatory and inhibitory neurotransmitters. The functional integrity of GPCRs, Ca2+ channels, and Ca2+ pump in these neurons makes them a useful cell model for further studies. PMID- 23660502 TI - Paneth cells expand from newly created and preexisting cells during repair after doxorubicin-induced damage. AB - Paneth cell numbers increase following intestinal damage, but mechanisms driving this process are not understood. We hypothesized that the increase in Paneth cell numbers is due to recruitment of cells from a preexisting pool of secretory progenitors. Mice were given a single injection of doxorubicin (Dox), and intestinal tissue was collected 0-168 h after treatment. Paneth, goblet, and intermediate cells were counted and evaluated for cell morphology. Quantitative RT-PCR was used to measure expression of various genes associated with Paneth cell allocation and maturation. Paneth cells were birth dated using incorporation of thymidine analogs given before or after Dox. Staining revealed "intermediate" cells, which were rarely observed in control crypts but increased significantly in number 96 and 120 h after Dox treatment. Birth dating of intermediate cells 5 days after Dox treatment revealed that 24% of these cells took up thymidine analog given prior to Dox treatment and 36% took up thymidine analog given after Dox treatment. Quantitative RT-PCR demonstrated a significant increase in Spdef, Atoh1, Sox9, EphB3, Mist, Wnt5a, FGF-9, and FGF-18 mRNAs and a significant decrease in Indian hedgehog mRNA. Expansion of the Paneth cell compartment after Dox treatment is due to generation of new cells and recruitment of cells from an existing pool. These cells express Paneth and goblet biomarkers and are found only during repair. Expansion of these cells correlates temporally with reduced Indian hedgehog and increased FGF and Wnt mRNA. These findings are significant, as they provide a first step in understanding mechanisms of Paneth cell expansion during mucosal repair. PMID- 23660505 TI - The peptide transporter PEPT1 is expressed in distal colon in rodents and humans and contributes to water absorption. AB - The peptide transporter PEPT1, expressed in the brush border membrane of enterocytes, mediates the uptake of di- and tripeptides from luminal protein digestion in the small intestine. PEPT1 was proposed not to be expressed in normal colonic mucosa but may become detectable in inflammatory states such as Crohn's disease or ulcerative colitis. We reassessed colonic expression of PEPT1 by performing a systematic analysis of PEPT1 mRNA and protein levels in healthy colonic tissues in mice, rats, and humans. Immunofluorescence analysis of different mouse strains (C57BL/6N, 129/Sv, BALB/c) demonstrated the presence of PEPT1 in the distal part of the colon but not in proximal colon. Rat and human intestines display a similar distribution of PEPT1 as found in mice. However, localization in human sigmoid colon revealed immunoreactivity present at low levels in apical membranes but substantial staining in distinct intracellular compartments. Functional activity of PEPT1 in colonic tissues from mice was assessed in everted sac preparations using [14C]Gly-Sar and found to be 5.7-fold higher in distal compared with proximal colon. In intestinal tissues from Pept1-/ mice, no [14C]Gly-Sar transport was detectable but feces samples revealed significantly higher water content than in wild-type mice, suggesting that PEPT1 contributes to colonic water absorption. In conclusion, our studies unequivocally demonstrate the presence of PEPT1 protein in healthy distal colonic epithelium in mice, rats, and humans and proved that the protein is functional and contributes to electrolyte and water handling in mice. PMID- 23660506 TI - Development of ELISA methodologies for the direct determination of 17beta estradiol and 17alpha-ethinylestradiol in complex aqueous matrices. AB - This study comprises the development of enzyme-linked immunosorbent assays (ELISAs) for the quantification of 17beta-estradiol (E2) and 17alpha ethinylestradiol (EE2) in complex aqueous matrices without any sample clean-up procedures. Salinity and dissolved organic matter were selected as potential interfering agents in the analysis of E2 and EE2. The optimization was performed in order to (i) overcome matrix effects, and to (ii) increase sensitivity. The addition of a sample buffer containing bovine serum albumin (BSA) prior to the sample was found to decrease the influence of matrix effects. Moreover, adjustments of this buffer's pH together with the optimization of tracer (T) dilution and incubation time were undertaken in order to lower the quantification range. The optimized methods allowed the quantification of E2 and EE2 in the ranges 0.03-200 MUg L(-1) and 0.02-10 MUg L(-1), respectively. The assays were applied to real aqueous samples. It was possible to do a first approach to the levels of E2 in Portuguese surface and waste waters; however, it was not feasible to detect EE2 in the samples tested. PMID- 23660503 TI - Role for intestinal CYP2E1 in alcohol-induced circadian gene-mediated intestinal hyperpermeability. AB - We have shown that alcohol increases Caco-2 intestinal epithelial cell monolayer permeability in vitro by inducing the expression of redox-sensitive circadian clock proteins CLOCK and PER2 and that these proteins are necessary for alcohol induced hyperpermeability. We hypothesized that alcohol metabolism by intestinal Cytochrome P450 isoform 2E1 (CYP2E1) could alter circadian gene expression (Clock and Per2), resulting in alcohol-induced hyperpermeability. In vitro Caco-2 intestinal epithelial cells were exposed to alcohol, and CYP2E1 protein, activity, and mRNA were measured. CYP2E1 expression was knocked down via siRNA and alcohol-induced hyperpermeability, and CLOCK and PER2 protein expression were measured. Caco-2 cells were also treated with alcohol or H2O2 with or without N acetylcysteine (NAC) anti-oxidant, and CLOCK and PER2 proteins were measured at 4 or 2 h. In vivo Cyp2e1 protein and mRNA were also measured in colon tissue from alcohol-fed mice. Alcohol increased CYP2E1 protein by 93% and enzyme activity by 69% in intestinal cells in vitro. Alcohol feeding also increased mouse colonic Cyp2e1 protein by 73%. mRNA levels of Cyp2e1 were not changed by alcohol in vitro or in mouse intestine. siRNA knockdown of CYP2E1 in Caco-2 cells prevented alcohol-induced hyperpermeability and induction of CLOCK and PER2 proteins. Alcohol-induced and H2O2-induced increases in intestinal cell CLOCK and PER2 were significantly inhibited by treatment with NAC. We concluded that our data support a novel role for intestinal CYP2E1 in alcohol-induced intestinal hyperpermeability via a mechanism involving CYP2E1-dependent induction of oxidative stress and upregulation of circadian clock proteins CLOCK and PER2. PMID- 23660507 TI - Imbalance of serum IL-10 and TGF-beta in patients with pollen food syndrome. AB - BACKGROUND: Pollen food syndrome is one of the main causes of food allergies in adults. However, the intrinsic immunological mechanisms remain unclear. METHODS: Forty pollinosis sufferers [23 with a food allergy (PSFA) and 17 without a food allergy (PS)] and 17 non-atopic healthy controls were included in this study. The PSFA group was subdivided into an oral allergy syndrome group, a systemic reaction group, and an anaphylactic reaction group according to their symptoms after eating the suspected foods. Serum IL-10 and TGF-beta levels of all participants were determined by ELISA. Clinical characteristics of the patients were also evaluated. RESULTS: There were no significant differences in age, sex, pollen-associated symptoms, duration of respiratory disease, and positive parental history of atopy between the PSFA and PS groups. Compared to healthy controls, serum IL-10 levels of both the PSFA group and PS group were significantly lower (p<=0.01), but TGF beta levels were significantly higher in the PSFA group (35.3+/-5.6ng/ml vs. 31.2+/-6.6ng/ml, respectively; p=0.037). Within the PSFA group, IL-10 levels in the anaphylactic reaction subgroup were significantly lower compared to oral allergy syndrome subgroup (1.87+/-0.47pg/ml vs. 1.40+/-0.30pg/ml, respectively; p=0.027). More severe food allergy symptoms were associated with lower serum IL-10 levels. In contrast, the highest serum levels of TGF-beta were found in patients from the anaphylactic reaction subgroup. CONCLUSIONS: With the exception of a defect in regulatory cells represented by the reduction of IL-10, other potential immunological mechanisms (e.g., Th17 or IL-23 together with TGF-beta) may be involved in the development of pollen food syndrome. PMID- 23660504 TI - Sulfate secretion and chloride absorption are mediated by the anion exchanger DRA (Slc26a3) in the mouse cecum. AB - Inorganic sulfate (SO42-) is essential for a multitude of physiological processes. The specific molecular pathway has been identified for uptake from the small intestine but is virtually unknown for the large bowel, although there is evidence for absorption involving Na+-independent anion exchange. A leading candidate is the apical chloride/bicarbonate (Cl-/HCO3-) exchanger DRA (down regulated in adenoma; Slc26a3), primarily linked to the Cl- transporting defect in congenital chloride diarrhea. The present study set out to characterize transepithelial 35SO42- and 36Cl- fluxes across the isolated, short-circuited cecum from wild-type (WT) and knockout (KO) mice and subsequently to define the contribution of DRA. The cecum demonstrated simultaneous net SO42- secretion ( 8.39 +/- 0.88 nmol.cm-2.h-1) and Cl- absorption (10.85 +/- 1.41 MUmol.cm-2.h-1). In DRA-KO mice, SO42- secretion was reversed to net absorption via a 60% reduction in serosal to mucosal SO42- flux. Similarly, net Cl- absorption was abolished and replaced by secretion, indicating that DRA represents a major pathway for transcellular SO42- secretion and Cl- absorption. Further experiments including the application of DIDS (500 MUM), bumetanide (100 MUM), and substitutions of extracellular Cl- or HCO3-/CO2 helped to identify specific ion dependencies and driving forces and suggested that additional anion exchangers were operating at both apical and basolateral membranes supporting SO42- transport. In conclusion, DRA contributes to SO42- secretion via DIDS-sensitive HCO3-/SO42- exchange, in addition to being the principal DIDS-resistant Cl-/HCO3- exchanger. With DRA linked to the pathogenesis of other gastrointestinal diseases extending its functional characterization offers a more complete picture of its role in the intestine. PMID- 23660509 TI - Nicorandil protects pial arterioles from endothelial dysfunction induced by smoking in rats. AB - BACKGROUND: Our aims are to investigate the effect of nicorandil, which is used for angina prevention and treatment, on the endothelial dysfunction induced by acute smoking and to clarify the underlying mechanism. MATERIALS AND METHODS: A closed cranial window preparation was used to measure changes in pial vessel diameters in Sprague-Dawley rats. The responses of arterioles were examined to an endothelium-dependent vasodilator acetylcholine (ACh) before smoking. After intravenous nicorandil (200 MUg/kg bolus infusion and then 60 MUg/kg/min continuous infusion; n=6) or saline (control; n=6) pretreatment, the pial vasodilator response to topical 10 M ACh infusion was reexamined both before and 1 hour after 1-minute cigarette smoking. Thereafter, either glibenclamide or N omega-nitro-L-arginine methyl ester (L-NAME) was infused 20 minutes before nicorandil infusion. In the glibenclamide (n=6) or L-NAME; n=6 pretreatment group, the pial vasodilator response to topical ACh was examined before and after smoking. Percentage changes in pial vessel diameters were used for the statistical analysis. RESULTS: Cerebral arterioles were dilated during topical ACh infusion. After smoking, 10 M ACh constricted cerebral arterioles (-7.7+/ 1.8%). After smoking, in the nicorandil-pretreatment group, 10 M ACh dilated cerebral pial arterioles by 10.5+/-3.0%. When given before nicorandil infusion, glibenclamide, but not L-NAME, abolished the preventive effects of nicorandil against smoking-induced endothelial dysfunction in pial vessels. CONCLUSIONS: Acute cigarette smoking causes dysfunction of endothelium-dependent pial vasodilatation, and nicorandil prevents this effect of smoking. The mechanism underlying this protective effect may depend mainly on adenosine triphosphate sensitive potassium-channel activation. PMID- 23660510 TI - Subarachnoid anesthesia in a patient with lateral ventricle tumor. PMID- 23660513 TI - Geographic distribution of wolbachial infections in mosquitoes from Thailand. AB - Members of the genus Wolbachia are inherited intracellular bacterial endosymbionts that infect a diverse range of arthropods. Here I report the results of a survey of these endosymbionts in different mosquito species from six geographic regions of Northern, Northeastern, Western, Central, Eastern and Southern Thailand. Using gene amplification assays with wsp and groE gene primers, wolbachiae were detected in 999 mosquitoes representing 28 species of 1622 specimens collected representing 74 species of wild-caught mosquitoes from all regions of Thailand. Results using wsp primers were similar to those using groE primers in all cases. Wolbachiae had not been reported previously from five of the species tested, namely, Aedes lineatopennis, Aedes vexans, Aedes vittatus, Culex pallidothorax and Culex whitmorei. Infections were found in all major disease vector genera except Anopheles. These results indicate that wolbachial infections are distributed throughout many mosquito species in Thailand. PMID- 23660512 TI - The association of elective hormone therapy with changes in lipids among glucose intolerant postmenopausal women in the diabetes prevention program. AB - OBJECTIVE: It is unclear how lipids change in response to lifestyle modification or metformin among postmenopausal glucose intolerant women using and not using hormone therapy (HT). We examined the one-year changes in lipids among postmenopausal, prediabetic women in the Diabetes Prevention Program (DPP), and whether changes were mediated by sex hormones. MATERIALS/METHODS: We performed a secondary analysis of a randomized controlled trial of 342 women who used HT at baseline and year 1 and 382 women who did not use HT at either time point. Interventions included intensive lifestyle (ILS) with goals of weight reduction of at least 7% of initial weight and 150 minutes per week of moderate intensity exercise, or metformin or placebo administered 850 mg up to twice a day. Women were not randomized to HT. Main outcome measures were changes between baseline and study year 1 in low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. RESULTS: Compared to placebo, both ILS and metformin significantly reduced LDL-C and raised HDL-C among HT users, changes partially explained by change in estradiol and testosterone but independent of changes in waist circumference and 1/fasting insulin. In contrast, DPP interventions had no effect on LDL-C and HDL-C among non-HT users. ILS significantly lowered triglycerides among non-users but did not significantly change triglycerides among HT users. Metformin did not significantly change triglycerides among non-users but increased triglycerides among HT users. CONCLUSIONS: The beneficial effects of ILS and metformin on lowering LDL-C and raising HDL-C differ depending upon concurrent HT use. PMID- 23660514 TI - Ultrasound pretreatment of wheat dried distiller's grain (DDG) for extraction of phenolic compounds. AB - Wheat Dried distiller's grain (DDG), a coproduct from the ethanol production process, is rich in potentially health-promoting phenolic compounds. In the extraction of phenolic compounds from DDG, the DDG cell wall is an important barrier for mass transfer from the inside to the outside of the cell. The effect of high-power ultrasound pretreatment on destruction of DDG cell walls and extraction yield and rate was investigated. Direct sonication by an ultrasound probe horn at 24 kHz was applied and factors such as ultrasound power and treatment time were investigated. The method of nitrogen (N2) adsorption at 77K was used as a means to determine and compare the changes in physical properties (specific surface area, pore volume and pore size) of the treated samples at different levels of ultrasound power and treatment time. Increasing specific surface area, pore volume and pore size caused by ultrasonic treatment implied development of new or larger pores and damaged cell walls. Also, it was observed that the ultrasound pretreatment of DDG particles increased the extraction yield and rate of phenolic compounds from DDG by 14.29%. Among tested ultrasound conditions, 100% ultrasound power for 30s was evaluated as the best pretreatment condition. PMID- 23660516 TI - Dyskeratosis congenita mutations in dyskerin SUMOylation consensus sites lead to impaired telomerase RNA accumulation and telomere defects. AB - Mutations in the dyskerin gene (DKC1) cause X-linked dyskeratosis congenita (DC), a rare and fatal premature aging syndrome characterized by defective telomere maintenance. Dyskerin is a highly conserved nucleolar protein, and a component of the human telomerase complex that is essential for human telomerase RNA (hTR) stability. However, its regulation remains poorly understood. Here, we report that dyskerin can be modified by small ubiquitin-like modifiers (SUMOs). We find that human DC-causing mutations in highly conserved dyskerin SUMOylation consensus sites lead to impaired hTR accumulation, telomerase activity and telomere maintenance. Finally, we show that modification of dyskerin by SUMOylation is required for its stability. Our findings provide the first evidence that dyskerin stability is regulated by SUMOylation and that mutations altering dyskerin SUMOylation can lead to defects in telomere maintenance that are characteristics of DC. PMID- 23660518 TI - Why shared decision making is not good enough: lessons from patients. AB - A closer look at the lived illness experiences of medical professionals themselves shows that shared decision making is in need of a logic of care. This paper underlines that medical decision making inevitably takes place in a messy and uncertain context in which sharing responsibilities may impose a considerable burden on patients. A better understanding of patients' lived experiences enables healthcare professionals to attune to what individual patients deem important in their lives.This will contribute to making medical decisions in a good and caring manner, taking into account the lived experience of being ill. PMID- 23660517 TI - Progressive impairment of muscle regeneration in muscleblind-like 3 isoform knockout mice. AB - The muscleblind-like (MBNL) genes encode alternative splicing factors that are essential for the postnatal development of multiple tissues, and the inhibition of MBNL activity by toxic C(C)UG repeat RNAs is a major pathogenic feature of the neuromuscular disease myotonic dystrophy. While MBNL1 controls fetal-to-adult splicing transitions in muscle and MBNL2 serves a similar role in the brain, the function of MBNL3 in vivo is unknown. Here, we report that mouse Mbnl3, which encodes protein isoforms that differ in the number of tandem zinc-finger RNA binding motifs and subcellular localization, is expressed primarily during embryonic development but also transiently during injury-induced adult skeletal muscle regeneration. Mbnl3 expression is required for normal C2C12 myogenic differentiation and high-throughput sequencing combined with cross linking/immunoprecipitation analysis indicates that Mbnl3 binds preferentially to the 3' untranslated regions of genes implicated in cell growth and proliferation. In addition, Mbnl3DeltaE2 isoform knockout mice, which fail to express the major Mbnl3 nuclear isoform, show age-dependent delays in injury-induced muscle regeneration and impaired muscle function. These results suggest that Mbnl3 inhibition by toxic RNA expression may be a contributing factor to the progressive skeletal muscle weakness and wasting characteristic of myotonic dystrophy. PMID- 23660519 TI - Runoff concentration and load of nitrogen and phosphorus from a residential area in an intensive agricultural watershed. AB - To evaluate the runoff load of nitrogen (N) and phosphorus (P) in a rural residential area with high N deposition and few wastewater treatment systems in East China, we monitored the concentrations of N and P during 21 rainfall events in a typical village catchment in Jiangsu Province, China. The results showed that the average event mean concentrations (EMC, mg L(-1)) were 6.20 for dissolved nitrogen (DN), 4.18 for nitrate nitrogen (NO3(-)), 0.26 for ammonium nitrogen (NH4(+)), 1.76 for dissolved organic nitrogen (DON), 0.40 for dissolved phosphorus (DP) and 0.32 for phosphate (PO4(3-)). In addition, the annual loads (kg ha(-1)year(-1)) were 24.1 for DN, 16.3 for NO3(-), 1.01 for NH4(+), 6.83 for DON, 1.56 for DP, and 1.25 for PO4(3-). Concentrations of DN and DP in runoff water were 2.57 and 4.06 times higher than those in rainfall, indicating that waste produced by anthropogenic activity was the dominant pollution source of receiving water in rural residential areas. The average discharged concentrations of DN and DP exceeded the Class V surface water quality standard promulgated by the Ministry of Environmental Protection of China, suggesting that the surface runoff should be dealt with for controlling N and P during rainfall events. The runoff characteristics differed among pollutant species, as DP, PO4(3-) and NH4(+) showed medium mass first-flush, whereas that of DN, NO3(-) and DON was weak. These differences should be considered when planning mitigation measures and developing water quality models. PMID- 23660515 TI - The impact of ageing on natural killer cell function and potential consequences for health in older adults. AB - Forming the first line of defence against virally infected and malignant cells, natural killer (NK) cells are critical effector cells of the innate immune system. With age, significant impairments have been reported in the two main mechanisms by which NK cells confer host protection: direct cytotoxicity and the secretion of immunoregulatory cytokines and chemokines. In elderly subjects, decreased NK cell activity has been shown to be associated with an increased incidence and severity of viral infection, highlighting the clinical implications that age-associated changes in NK cell biology have on the health of older adults. However, is an increased susceptibility to viral infection the only consequence of these age-related changes in NK cell function? Recently, evidence has emerged that has shown that in addition to eliminating transformed cells, NK cells are involved in many other biological processes such as immune regulation, anti-microbial immune responses and the recognition and elimination of senescent cells, novel functions that involve NK-mediated cytotoxicity and/or cytokine production. Thus, the decrease in NK cell function that accompanies physiological ageing is likely to have wider implications for the health of older adults than originally thought. Here, we give a detailed description of the changes in NK cell biology that accompany human ageing and propose that certain features of the ageing process such as: (i) the increased reactivation rates of latent Mycobacterium tuberculosis, (ii) the slower resolution of inflammatory responses and (iii) the increased incidence of bacterial and fungal infection are attributable in part to an age-associated decline in NK cell function. PMID- 23660520 TI - Ecosystem services in Mediterranean river basin: climate change impact on water provisioning and erosion control. AB - The Mediterranean basin is considered one of the most vulnerable regions of the world to climate change and such changes impact the capacity of ecosystems to provide goods and services to human society. The predicted future scenarios for this region present an increased frequency of floods and extended droughts, especially at the Iberian Peninsula. This paper evaluates the impacts of climate change on the water provisioning and erosion control services in the densely populated Mediterranean Llobregat river basin of. The assessment of ecosystem services and their mapping at the basin scale identify the current pressures on the river basin including the source area in the Pyrenees Mountains. Drinking water provisioning is expected to decrease between 3 and 49%, while total hydropower production will decrease between 5 and 43%. Erosion control will be reduced by up to 23%, indicating that costs for dredging the reservoirs as well as for treating drinking water will also increase. Based on these data, the concept for an appropriate quantification and related spatial visualization of ecosystem service is elaborated and discussed. PMID- 23660521 TI - Impact of protein-, lipid- and cellulose-containing complex substrates on biogas production and microbial communities in batch experiments. AB - In the present study, nine complex organic substrates from three classes (protein , lipid-, and cellulose-rich) were investigated in batch experiments and compared with a control in order to evaluate their potential for utilisation as substrates for biogas production. High methane production was observed from protein-rich substrates; problems arose from lipid-containing, lactose and cellulose fermentation. Using DGGE analysis it could be shown that different classes of substrate resulted in different microbial communities, whereupon similar substrates tended to show a similar microbial structure. By means of qPCR Methanoculleus sp., a hydrogenotrophic methanogen was found to be the most abundant organism in the batch experiments. Additionally, it could be demonstrated that methanogenic organisms withstood adverse environmental conditions for at least an incubation period of 55 days, pointing to a high stability of the archaeal community even in times of decreasing or even failing fermenter performance. PMID- 23660522 TI - Stereotactic body radiotherapy in patients with stage I non-small-cell lung cancer aged 75 years and older: retrospective results from a multicenter consortium. AB - BACKGROUND: This study was a retrospective analysis of elderly patients treated with stereotactic body radiotherapy (SBRT) in the setting of a multi institutional consortium. PATIENTS AND METHODS: Three institutions pooled data on patients aged >= 75 years who received SBRT for stage I non-small-cell lung cancer (NSCLC). Forty-seven tumors in 46 patients were analyzed in patients aged 75 to 92 years (median, 82 years). Treatment was delivered during 2007 to 2009, with a median follow-up of 12.4 months. All patients underwent staging positron emission tomography-computed tomography (PET-CT), and 87% of tumors were confirmed by biopsy results. Total doses were 35 to 60 Gy, mainly in 3 to 5 fractions. All tumors were treated using a linear accelerator, with 96% of patients receiving 3-dimensional (3D) conformal RT and 4% undergoing intensity modulated RT (IMRT). RESULTS: At the time of analysis, the local failure rate was 2% (1 of 47). The regional failure rate was 9% (4 of 47). The distant failure rate was 6% (3 of 47). The combined failure rate was 15% (7 of 47) because 1 patient experienced both regional and distant failure. Among 20 tumors with any acute toxicity, there were no >= grade 3 toxicities. Pneumonitis (n = 10) grades 1 (n = 3) and 2 (n = 2) was seen in 15% and 10% of patients, respectively; these data were missing for 25% of patients. CONCLUSION: SBRT in patients aged >= 75 years with stage I NSCLC proved tolerable, with toxicity rates comparable to those in younger patients. Excellent rates of local, regional, and distant control were achieved at a median follow-up of 12.4 months. This patient population represents a rapidly growing segment of the early lung cancer population, and SBRT appears to be a safe and effective treatment option for patients who are not optimal candidates for surgery. PMID- 23660523 TI - Feasibility of automated analysis and inter-examiner variability of cortical silent period induced by transcranial magnetic stimulation. AB - Cortical silent period (cSP) is a short interruption in electromyography (EMG) during active muscle contraction induced with transcranial magnetic stimulation (TMS). The cSP is a measure of cortical inhibition and is believed to represent inhibitory interneuron effects on excited motor cortical areas. Several pathological conditions and pharmacological manipulations induce changes to cSP duration indicating alterations in intracortical inhibition. At present, it is common to manually analyse the cSP duration from measured EMG. However, to avoid inter-examiner effects on cSP interpretation and detection, as well as to allow for quick measurement online, automated routine would be preferable. In this study, we evaluate the feasibility of a straight-forward cSP detection routine based on analysing the rectified first derivative of the EMG signal following TMS. Previously measured cSPs of 54 healthy subjects were reanalysed manually by two of the authors and using the automated routine. Furthermore, we recruited one subject for whom the cSPs were induced with several stimulation intensities, and those cSPs were analysed manually by two of the authors as well as using the automated routine. We found that cSPs were detected correctly by the automated cSP detection routine, and agreement with manually analysed subject-specific mean cSPs was excellent (ICC=0.992, p<0.001). The inter-examiner variability was similar to the variability between manual and automated analysis. Hence, we believe the introduced cSP detection routine would be feasible for online cSP detection, in such a way that is presently used to detect the motor evoked potentials. PMID- 23660525 TI - The cell injury device: a high-throughput platform for traumatic brain injury research. AB - A novel, automated system for delivering controlled scratch-induced trauma to brain cells cultured in multi-well plates was created and characterized. The system is equipped with high-throughput imaging and analysis capabilities, enabling quantitative measurements of cell migration. The scratch-area coefficient of variation of the device was between 3.9% and 8.4%, a significant improvement over traditional manual methods, which provided a scratch-area coefficient of variation of between 10.7% and 19.6%. The device's inexpensive imaging and analysis capabilities were comparable to a well-known system, the Discovery-1 (Molecular Devices), with no significant difference found between the two. When used for drug screening, the gap area of Neuro2a cells after 72h was significantly larger in samples containing UO126 (20MUM), averaging 0.89mm(2)+/ 0.21mm(2); compared with an average vehicle control gap area of 0.42mm(2)+/ 0.1mm(2). A gradient response could also be detected among samples with increasing UO126 concentrations (0-20MUM), due to decreased migration and/or proliferation of cells into the gap over the time period. Our device provides an inexpensive method for delivering a standardized, closely controlled pressure/scratch to brain cells cultured in multi-well plates. The system provides more consistent patterns of scratch-induced trauma to cultured cells when compared to traditional methods. This device is an effective platform for quantifying the injury response of cells, and has applications in testing the effectiveness of drugs on cell migration and proliferation which might potentially treat traumatic brain injury. PMID- 23660526 TI - A portable experimental apparatus for human olfactory fMRI experiments. AB - Human olfactory perception can be measured using psychophysical tools or more complex odor generating devices systems, namely olfactometers. The present paper is aimed at presenting a new inexpensive, non-voluminous portable olfactometer adapted for human fMRI experiments. The system adjusts odorant stimulus presentation to human nasal respiration and records behavioral responses in the same experimental device. Validation by psychophysical measures and photo ionization detection showed a linear increase in both odor intensity perception and vapor concentration as a function of odorant concentration. Further validation by brain imaging revealed neural activation in typical olfactory areas. In summary, the system represents a new low-cost, easy-use, easy maintenance portable olfactometry tool for brain imaging, opening up new possibilities for investigating neural response to odors using event-related fMRI designs. PMID- 23660524 TI - A vibrotactile behavioral battery for investigating somatosensory processing in children and adults. AB - The cortical dynamics of somatosensory processing can be investigated using vibrotactile psychophysics. It has been suggested that different vibrotactile paradigms target different cortical mechanisms, and a number of recent studies have established links between somatosensory cortical function and measurable aspects of behavior. The relationship between cortical mechanisms and sensory function is particularly relevant with respect to developmental disorders in which altered inhibitory processing has been postulated, such as in ASD and ADHD. In this study, a vibrotactile battery consisting of nine tasks (incorporating reaction time, detection threshold, and amplitude- and frequency discrimination) was applied to a cohort of healthy adults and a cohort of typically developing children to assess the feasibility of such a vibrotactile battery in both cohorts, and the performance between children and adults was compared. These results showed that children and adults were both able to perform these tasks with a similar performance, although the children were slightly less sensitive in frequency discrimination. Performance within different task-groups clustered together in adults, providing further evidence that these tasks tap into different cortical mechanisms, which is also discussed. This clustering was not observed in children, which may be potentially indicative of development and a greater variability. In conclusion, in this study, we showed that both children and adults were able to perform an extensive vibrotactile battery, and we showed the feasibility of applying this battery to other (e.g., neurodevelopmental) cohorts to probe different cortical mechanisms. PMID- 23660527 TI - Examining the inflammatory response to nanopatterned polydimethylsiloxane using organotypic brain slice methods. AB - A long-term effect of chronically implanted neural electrodes is the formation of a glial scar made up of reactive astrocytes, microglia and the matrix proteins they generate. Studies have shown glial fibrillary acidic protein (GFAP) and cytokines interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), and transforming growth factor beta 1 (TGFbeta1) are involved with the initial and modulation phases of reactive astrogliosis. In the present study, nanopatterning of polydimethylsiloxane (PDMS) was attempted as a method for reducing the inflammatory response of glial cells. A unique feature of this study is the use of in vitro brain slice cultures (organotypic cultures) in order to more accurately depict the native response. The aim of the study was to determine whether nanotopography could reduce inflammatory signals typically resultant from neural electrode implantation. Specifically, observation of cell alignment and surveillance of GFAP, IL-1beta, TNFalpha, and TGFbeta1 gene expression around the PDMS pins was performed. Results of this study confirm nanopatterning not only influences cell morphology, but some of the molecular signals as well. These results collectively indicate nanopatterning improves the biocompatibility of PDMS by reducing inflammatory markers such as GFAP, IL-1beta, TGFbeta1 and TNFalpha compared to the non-patterned PDMS pins. PMID- 23660528 TI - Effect of strain on the evolution of magnetic multi-vortices in ferromagnetic nano-platelets. AB - The effect of external strain on the evolution of magnetic multi-vortices in nanoscale ferromagnetic platelets is investigated by a phase field model that explicitly includes the coupling between the magnetization and deformation. Phase field simulations show that a compressive strain makes the magnetic vortex antivortex pair stable in rectangular ferromagnetic platelets, which is unstable in the absence of an external magnetic field and strain. The magnetic clockwise (CW) and counterclockwise (CCW) vortex pairs disappear in ferromagnetic platelets under an external magnetic field through the annihilation of the vortex and antivortex, or through expulsion when external strain is absent. In the presence of tensile strain, the expulsion of CW and CCW vortices is suppressed in ferromagnetic platelets. However, external strain has less effect on the annihilation of CW and CCW vortices. For ferromagnetic platelets with triple vortices, both tensile strain and a magnetic field induce the annihilation and expulsion of vortices. The effect of strain on the evolution of magnetic vortices suggests a new way to control them by strain engineering. PMID- 23660529 TI - Self-reported reproductive health in women with tuberous sclerosis complex. AB - PURPOSE: Little is known about sex-specific manifestations of tuberous sclerosis complex. Inactivating mutations in the TSC1 and TSC2 genes cause tuberous sclerosis complex, and recent evidence points to a crucial role for these genes in maintaining appropriate ovarian function. The main objective of this study was to estimate reproductive dysfunction in a sample of women with tuberous sclerosis complex. METHODS: We designed a three-part questionnaire that included demographic information, reproductive history, and tuberous sclerosis complex history, and developed strict criteria to assess patterns in menstrual cyclicity; we analyzed 182 responses from female adult members of the Tuberous Sclerosis Alliance. RESULTS: More than one-third of women in our sample displayed some degree of menstrual irregularity, and their reported miscarriage rate was 41%. More than 4% of women had reproductive histories suggestive of premature ovarian insufficiency, higher than the general population estimate of 1%. CONCLUSION: Our data reveal an underappreciated aspect of tuberous sclerosis complex in affected women, suggesting that a further exploration of the role the tuberous sclerosis complex genes play in reproductive function is warranted. PMID- 23660530 TI - Public preferences regarding informed consent models for participation in population-based genomic research. AB - PURPOSE: Some large population biobanks that house biospecimens and health information for research seek broad consent from participants, whereas others reconsent for specific new studies. Understanding research participants' attitudes and preferences about broad and narrow consent may improve recruitment, retention, and public support. METHODS: An online survey was conducted among a representative sample of 4,659 US adults to examine relationships between consent preferences and demographic factors, beliefs about privacy and the value of research, and the perceived trustworthiness of researchers. RESULTS: Participants preferred broad consent (52%) over study-by-study consent models (48%). Higher preferences for study-by-study consent observed among black non-Hispanic respondents and respondents with lower income and education were explained by differences in the prevalence of one or more beliefs about the study. Respondents with fears about research and those who would feel respected if asked for permission for each research use preferred study-by-study consent. Preference for broad consent was related to the desire not to be bothered with multiple requests and the belief that the study could lead to improved treatments, cures, and lives saved. CONCLUSION: These data suggest that support for broad consent is contingent on sufficient information about data use. Work with research participants and community leaders to understand, respond to, and influence opinions about a given, ongoing study may improve uptake of broad consent. PMID- 23660533 TI - Cost-effective conservation planning: lessons from economics. AB - Economists advocate that the billions of public dollars spent on conservation be allocated to achieve the largest possible social benefit. This is "cost-effective conservation"-a process that incorporates both monetized benefits and costs. Though controversial, cost-effective conservation is poorly understood and rarely implemented by planners. Drawing from the largest publicly financed conservation programs in the United States, this paper seeks to improve the communication from economists to planners and to overcome resistance to cost-effective conservation. Fifteen practical lessons are distilled, including the negative implications of limiting selection with political constraints, using nonmonetized benefit measures or benefit indices, ignoring development risk, using incomplete cost measures, employing cost measures sequentially, and using benefit indices to capture costs. The paper highlights interrelationships between benefits and complications such as capitalization and intertemporal planning. The paper concludes by identifying the challenges at the research frontier, including incentive problems associated with adverse selection, additionality, and slippage. PMID- 23660531 TI - Efficient nitrosation of glutathione by nitric oxide. AB - Nitrosothiols are increasingly regarded as important participants in a range of physiological processes, yet little is known about their biological generation. Nitrosothiols can be formed from the corresponding thiols by nitric oxide in a reaction that requires the presence of oxygen and is mediated by reactive intermediates (NO2 or N2O3) formed in the course of NO autoxidation. Because the autoxidation of NO is second order in NO, it is extremely slow at submicromolar NO concentrations, casting doubt on its physiological relevance. In this paper we present evidence that at submicromolar NO concentrations the aerobic nitrosation of glutathione does not involve NO autoxidation but a reaction that is first order in NO. We show that this reaction produces nitrosoglutathione efficiently in a reaction that is strongly stimulated by physiological concentrations of Mg(2+). These observations suggest that direct aerobic nitrosation may represent a physiologically relevant pathway of nitrosothiol formation. PMID- 23660532 TI - Extracellular matrix proteins regulate epithelial-mesenchymal transition in mammary epithelial cells. AB - Mouse mammary epithelial cells undergo transdifferentiation via epithelial mesenchymal transition (EMT) upon treatment with matrix metalloproteinase-3 (MMP3). In rigid microenvironments, MMP3 upregulates expression of Rac1b, which translocates to the cell membrane to promote induction of reactive oxygen species and EMT. Here we examine the role of the extracellular matrix (ECM) in this process. Our data show that the basement membrane protein laminin suppresses the EMT response in MMP3-treated cells, whereas fibronectin promotes EMT. These ECM proteins regulate EMT via interactions with their specific integrin receptors. alpha6-integrin sequesters Rac1b from the membrane and is required for inhibition of EMT by laminin. In contrast, alpha5-integrin maintains Rac1b at the membrane and is required for the promotion of EMT by fibronectin. Understanding the regulatory role of the ECM will provide insight into mechanisms underlying normal and pathological development of the mammary gland. PMID- 23660534 TI - Stakeholder analysis combined with social network analysis provides fine-grained insights into water infrastructure planning processes. AB - Environmental policy and decision-making are characterized by complex interactions between different actors and sectors. As a rule, a stakeholder analysis is performed to understand those involved, but it has been criticized for lacking quality and consistency. This lack is remedied here by a formal social network analysis that investigates collaborative and multi-level governance settings in a rigorous way. We examine the added value of combining both elements. Our case study examines infrastructure planning in the Swiss water sector. Water supply and wastewater infrastructures are planned far into the future, usually on the basis of projections of past boundary conditions. They affect many actors, including the population, and are expensive. In view of increasing future dynamics and climate change, a more participatory and long-term planning approach is required. Our specific aims are to investigate fragmentation in water infrastructure planning, to understand how actors from different decision levels and sectors are represented, and which interests they follow. We conducted 27 semi-structured interviews with local stakeholders, but also cantonal and national actors. The network analysis confirmed our hypothesis of strong fragmentation: we found little collaboration between the water supply and wastewater sector (confirming horizontal fragmentation), and few ties between local, cantonal, and national actors (confirming vertical fragmentation). Infrastructure planning is clearly dominated by engineers and local authorities. Little importance is placed on longer-term strategic objectives and integrated catchment planning, but this was perceived as more important in a second analysis going beyond typical questions of stakeholder analysis. We conclude that linking a stakeholder analysis, comprising rarely asked questions, with a rigorous social network analysis is very fruitful and generates complementary results. This combination gave us deeper insight into the socio-political-engineering world of water infrastructure planning that is of vital importance to our well-being. PMID- 23660535 TI - Potential for control of harmful cyanobacterial blooms using biologically derived substances: problems and prospects. AB - Water blooms of cyanobacteria have posed a worldwide environmental threat and a human health hazard in recent decades. Many biologically derived (but non antibiotic) bioactive substances are known to inhibit the growth of aquatic bloom forming cyanobacteria. Some of these biologically derived substances (BDSs) have no or low toxicity to aquatic animals and humans. Most BDSs are easily biodegradable in aquatic environments. These characteristics indicate that they may have potential for control and removal of harmful algae. However, BDSs also have the disadvantages of high cost of preparation, and possible damage to non target aquatic organisms, and sometimes, low efficiency of algae removal. The ecological risks of most BDSs are still unknown. Here, we review recent research progress relative to the inhibitory effects of BDSs on cyanobacteria, and critically analyze the potential of BDSs as algicides with an emphasis on possible problems during the process of controlling harmful cyanobacteria. We suggest avenues of study to enhance effective use of BDSs in controlling of cyanobacterial blooms; these include guidelines for isolation and characterization of new effective BDSs, exploiting the synergistic effects of BDSs, the merits of controlling harmful cyanobacteria at the early stages of proliferation and evaluation of ecological risks of BDSs. PMID- 23660536 TI - Invasive riparian vegetation response to flow regimes and flood pulses in a braided river floodplain. AB - This study evaluated flow regimes and flood pulse characteristics, and their influences on invasive riparian vegetation, in a free-flowing braided river in the Southern Alps, South Island, New Zealand. A 46-year gauged flow record was used to evaluate 67 flow metrics for the Ahuriri River, and five sets of colour aerial photographs over 20 years (1991-2011) were analysed to quantify temporal and spatial changes in vegetation (crack willow, Russell lupin, and grassland). The correlation between flow metrics and vegetation class cover for each aerial photo interval was analysed, and multiple regression models were developed. Significant changes in different invasive vegetation classes were found, including cover, number and sizes of patches, and distances from patches to primary channels. In addition to infrequent large floods, specific characteristics of small floods, high flows, low/baseflows, and extreme low flows had influences on different vegetation classes. Key metrics that appear to drive changes in cover and provide a useful multiple regression model include the largest flood peak, frequency of floods, and the time since the last flood for each air photo interval. Up to 25% of invasive vegetation cover was removed and bare substrate increased after the largest flood on record (approximately 50-year flood), and the amount of vegetation cover is highly variable over time and space. Within approximately six years, however, the proportion of vegetation recovered to pre-flood levels. The study reach appears to demonstrate the "shifting-mosaic steady state" conceptual model of riverine floodplains, where the total proportion of substrate, vegetation and water remain relatively constant over long time periods. PMID- 23660537 TI - Trace element contamination in the arms of the Danube Delta (Romania/Ukraine): current state of knowledge and future needs. AB - This paper provides the first critical synopsis of contamination by selected trace elements in the whole Danube Delta (Romania/Ukraine) to: identify general patterns of contamination by trace elements across the Delta, provide recommendations to refine existing monitoring networks and discuss the potential toxicity of trace elements in the whole Delta. Sediment samples were collected between 2004 and 2007 in the three main branches of the Delta (Chilia, Sulina and Sfantu Gheorghe) and in the secondary delta of the Chilia branch. Samples were analyzed for trace elements (Cd, Co, Cr, Cu, Ni, Pb, V, and Zn) and TiO2, Fe2O3, MnO, CaCO3 and total organic carbon. Cluster analysis (CA) and Principal Component Analysis (PCA) showed that levels of Cd, Cu, Pb, and Zn were influenced by anthropogenic activities. At the opposite, concentrations of Cr and Ni largely originated from the weathering of rocks located in the Romanian part of the Danube catchment and naturally rich in these elements. Data analysis using Self Organizing Maps confirmed the conclusions of CA/PCA and further detected that the contamination tended to be higher in the Chilia and Sulina arms than in the Sfantu Gheorghe arm. The potential ecological risks due to trace element contamination in the Danube Delta could be identified as moderate and localized, provided that the presence of the natural sources of Cr and Ni was properly considered. The available results suggest that monitoring sediment quality at the mouths of Sulina and Sfantu Gheorghe arms is probably enough to get a picture of the sediment quality along their entire lengths. However, a larger network of monitoring points is necessary in the Chilia and secondary Chilia delta to account for the presence of local point sources and for the more complex hydrodynamic of this part of the Danube Delta. PMID- 23660538 TI - Associations among perinatal factors and age of achievement of full oral feeding in very preterm infants. AB - BACKGROUND: Progress to full oral feeding from a tube or parenteral feeding is a complex process for very preterm infants born before 32 weeks of gestation. The influence of infant characteristics and medical complications on feeding progression has not been studied thoroughly. The aim of this study was to constitute a regression model to estimate the postmenstrual age (PMA) of full oral feeding and the length of transition time from the initiation to completion of oral feeding. METHODS: A chart review was conducted on very preterm infants born between 2005 and 2010 in one medical center in Taiwan. All enrolled infants were able to take all nutrition by mouth before discharge. RESULTS: A total of 117 infants fulfilling the criteria were included. The mean PMAs for the initiation and completion of oral feeding were 33.9 +/- 1.7 and 35.1 +/- 2.0 weeks, respectively. Infants required 7.5 +/- 6.6 days from initiation to full oral feeding. The results of a stepwise regression revealed that the reciprocal of birth weight (beta coefficient = 3.81, p < 0.001), moderate-severe bronchopulmonary dysplasia (beta coefficient = 1.21, p < 0.001), necrotizing enterocolitis (beta coefficient = 0.84, p < 0.005), and patent ductus arteriosus (beta coefficient = 0.69, p < 0.01) were predictors for the PMA of full oral feeding. The regression model incorporating those factors explained 62.5% of the variation in the feeding outcome (p < 0.001). Gender, multiple gestations, mild bronchopulmonary dysplasia, intraventricular hemorrhage, and sepsis had no effect on the feeding outcome. None of the explored factors were significantly correlated with transition time. CONCLUSION: A regression model incorporating significant predictors to estimate the PMA of full oral feeding in very preterm infants was suggested. It could enhance communication between health professionals and parents about the feeding progress of infants born very prematurely. PMID- 23660540 TI - [Measles vaccination campaign among vulnerable populations during the peak of the 2011 epidemic in Marseilles]. AB - BACKGROUND: From 2008 to the end of 2011, Europe experienced a major outbreak of measles. The outbreak hit France especially hard, with measles hotspots in the South-East of France. It is known that people living in precarious socio-economic conditions are more exposed to infectious diseases. Regarding the local situation, the NGO "MdM-Marseille" decided to conduct a vaccination campaign among the Roma community living in camps. METHODS: The campaign was planned with two injections of a combined measles, mumps and rubella vaccine (MMR) in a one month interval for all young people born since 1980 and over the age of one year, regardless of antecedents. Twenty-four camps were selected. The target population was estimated at 720 people. Each site was the subject of an information visit. A letter was sent to the Prefecture to inform them and ask for a moratorium on evictions for the identified camps. RESULTS: Between May 15th and September 15th 2011, 326 primary immunizations were performed during 34 visits (covering 45.3% of the target population). Over the same period, almost all the camps were evacuated, forcing teams to stop the vaccination campaign. The second injection campaign covered only 37 persons. CONCLUSION: The vaccination campaign among Roma populations in Marseilles was organized in a context of a major national outbreak of measles in the general population. Although the Prefecture was informed, camp evictions were not interrupted. This highlights the discrepancy between public health policy and security policy. In the context of an epidemic, innovative actions should be focused on vulnerable populations in partnership with health authorities. The main objective is to find procedures that can protect populations at risk in the event of a health crisis but which are also useful for routine prevention. PMID- 23660539 TI - Future research directions for understanding neighborhood contributions to health disparities. AB - This paper proposes several promising future directions for neighborhood research to address health inequalities. First, there is a need to apply a Geography of Opportunity framework to understand how vast spatial (neighborhood, regional) inequality translates into health inequality. Such a framework highlights inequality that unfolds across an entire region, as well as the continuing significance of race/ethnicity for producing disparities in health and in the social determinants of health. The Geography of Opportunity framework also points to some of the methodological limitations of current neighborhood-health studies, given the structure of neighborhood racial inequality in the US for estimating how important neighborhoods are for producing racial health disparities. Second, there is a need to incorporate life-course concepts, data, and methods, including to model residential histories, neighborhood temporal change and residential mobility, starting early in life. A life-course focus would help inform when in life neighborhoods matter most for health and health inequalities, as well as improve exposure assessment of residential contexts. Third, we must model mechanisms linking neighborhoods and health, including the role of individual and household socioeconomic status. Lastly, we need to more meaningfully integrate social determinants of health, including drawing on policy evaluations that aim to improve neighborhood environments or that aim to expand household neighborhood choice. Doing so would inform how specific modifiable neighborhood exposures stimulated by policy may influence health and health disparities. PMID- 23660541 TI - [Editorial]. PMID- 23660542 TI - Angiographic CT: in vitro comparison of different carotid artery stents using two different angiography systems. AB - BACKGROUND AND PURPOSE: Our aim was to evaluate the in vitro visualization of different carotid artery stents on Angiographic CT (ACT). Of particular interest was the measurement of artificial lumen narrowing (ALN) caused by the stent material within the stented vessel segment to determine whether ACT can be used to detect restenosis within the stent. MATERIAL AND METHODS: ACT appearances of 17 carotid artery stents of different designs and sizes (4.0 to 11.0 mm) were investigated in vitro. All stents were imaged on two different angiography systems. For each stent, artificial lumen narrowing (ALN) was calculated. RESULTS: The ALN on the two different angiography systems did not significantly differ. With standard algorithm image reconstruction, ALN ranged from 19.1 to 46.6%. With stent-optimized algorithm image reconstruction, ALN was significantly lower and ranged from 7.6 to 17.2%. Different stents showed significantly different degree of ALN. Stent struts could be visualized in all stents. CONCLUSION: In our in vitro model, ACT evaluation of vessel patency after stent placement is possible but is impaired by ALN. Stent-optimized algorithm image reconstruction decreases ALN but further research is required to define the visibility of in-stent stenosis depending on image reconstruction. PMID- 23660543 TI - The effects of silent cerebral ischemic lesions on the prognosis of idiopathic Parkinson's disease. AB - INTRODUCTION: Recent studies have shown that the presence of cerebrovascular lesions may play an important role in determining the presence and severity of neurodegenerative disease. However, the relationship between cerebrovascular disease and idiopathic Parkinson's disease (IPD) has received little attention. Several reports on the impact of cerebrovascular disease on the clinical status of patients with IPD remain controversial. We conducted a 2-year follow-up study to evaluate whether or not silent cerebral ischemic lesions (SIL) contribute to the progression of IPD. METHODS: Thirty IPD patients without SIL (only-IPD) and twenty-six IPD patients with SIL (IPDS) were enrolled in this study. All patients underwent brain magnetic resonance imaging (MRI) twice, once at baseline and again at 2-years, to evaluate brain lesions including SIL. The progression of motor severity between the two groups was compared and analyzed. RESULTS: Two years after the first visit, there was no significant difference in the daily dose of dopamine agonist and levodopa between only-IPD and IPDS patients. Changes in motor severity during the 2-year period were not significantly different between the only-IPD and IPDS group. CONCLUSIONS: The results of our study suggest that minor cerebral ischemic changes in patients with IPD do not have significant effects on the progression of motor severity in IPD. However, to verify and strengthen these findings, brain MRI and clinicopathological studies involving a large cohort of IPD patients to explore further the relative contribution of vascular and neurodegenerative factors to the prognosis of IPD. PMID- 23660544 TI - Movement disorders and the osmotic demyelination syndrome. AB - With the advent of MRI, osmotic demyelination syndromes (ODS) are increasingly recognised to affect varied sites in the brain in addition to the classical central pontine lesion. Striatal involvement is seen in a large proportion of cases and results in a wide variety of movement disorders. Movement disorders and cognitive problems resulting from ODS affecting the basal ganglia may occur early in the course of the illness, or may present as delayed manifestations after the patient survives the acute phase. Such delayed symptoms may evolve over time, and may even progress despite treatment. Improved survival of patients in the last few decades due to better intensive care has led to an increase in the incidence of such delayed manifestations of ODS. While the outcome of ODS is not as dismal as hitherto believed - with the acute akinetic-rigid syndrome associated with striatal myelinolysis often responding to dopaminergic therapy - the delayed symptoms often prove refractory to medical therapy. This article presents a review of the epidemiology, pathophysiology, clinical features, imaging, and therapy of movement disorders associated with involvement of the basal ganglia in ODS. A comprehensive review of 54 previously published cases of movement disorders due to ODS, and a video recording depicting the spectrum of delayed movement disorders seen after recovery from ODS are also presented. PMID- 23660545 TI - FUS in familial essential tremor - the search for common causes is still on. AB - The genetic etiology of essential tremor remains unknown despite the significant proportion of familial cases. The search for monogenic causes has repeatedly failed until recent identification of three disease-causing mutations in FUS (fused in sarcoma), a gene previously linked to a rare forms of familial amyotrophic lateral sclerosis with frontotemporal dementia. The genetic epidemiology of FUS in ET is unknown. Herein, we screened 104 patients from 52 pedigrees for mutations in the coding sequence of FUS. Two of the most genetically distant affected individuals from each pedigree were selected for Sanger sequencing to potentially increase the success of genetic analysis. We did not identify a single pathogenic mutation. Our data suggest that FUS mutations are a rare cause of familial ET. PMID- 23660546 TI - The "floating door sign" in Parkinson's disease. AB - Individuals with Parkinson's disease (PD) display micrographia. We report a new method to elicit micrographic drawing in individuals with PD and compare this to drawing in individuals with essential tremor (ET). We asked 81 individuals with PD and 19 individuals with ET to draw a house and write a sentence. We examined house height and whether vertical lines of the door connected to the house floor. If both vertical door lines failed to reach the floor by more than 1mm we designated this a "floating door sign". House height of <5 cm and letter height of <5 mm were considered micrographic drawing and writing. 45 of 81 PD patients displayed a "floating door sign" compared with only 4 of 19 ET patients (p = 0.0103). 24 of 81 PD patients compared with 1 of 19 ET patients had micrographic writing (p = 0.0224). 60 of 81 PD patients compared with 9 of 19 ET patients had micrographic drawing (p = 0.00526). The "floating door sign" correlated with micrographic writing (p = 0.0275) but not micrographic drawing. The "floating door sign" had a positive predictive value for PD but not ET. We believe it correlates with hypometeric hand movements which cause inadequate stroke size, a phenomenon described in PD. PMID- 23660547 TI - Reduction biodegradable brushed PDMAEMA derivatives synthesized by atom transfer radical polymerization and click chemistry for gene delivery. AB - Novel reducible and degradable brushed poly(2-(dimethylamino) ethyl methacrylate) (PDMAEMA) derivatives were synthesized and evaluated as non-viral gene delivery vectors. First, alkyne-functionalized poly(aspartic acid) with a disulfide linker between the propargyl group and backbone poly([(propargyl carbamate)-cystamine] alpha,beta-aspartamide) (P(Asp-SS-AL)) was synthesized. Second, linear low molecular weight (LMW) monoazido-functionalized PDMAEMAs synthesized via atom transfer radical polymerization were conjugated to the polypeptide side-chains of P(Asp-SS-AL) via click chemistry to yield high molecular weight (HMW) polyaspartamide-based disulfide-containing brushed PDMAEMAs (PAPDEs). The PAPDEs were able to condense plasmid DNA to form 100 to 200nm polyplexes with positive zeta-potentials. Moreover, in the presence of dithiothreitol the PAPDEs degraded into LMW PDAMEMA, resulting in disintegration of the PAPDE/DNA polyplexes and subsequent release of plasmid DNA. In vitro experiments revealed that the PAPDEs were less cytotoxic and more effective in gene transfection than control 25kDa poly(ethyleneimine) and HMW linear PDMAEMA. In conclusion, reducible and degradable polycations composed of LMW PDMAEMAs coupled to a polypeptide backbone via reduction-sensitive disulfide bonds are effective gene vectors with an excellent cytocompatibility. PMID- 23660548 TI - Catheter-based renal denervation in the treatment of resistant hypertension. AB - Clinical trials have shown that catheter-based renal denervation (RD), i.e. interruption of afferent and efferent sympathetic nerves supplying the kidney, can reduce systolic blood pressure (BP) by approximately 30 mm Hg. This technology is currently being tested as a therapeutic option for patients with resistant hypertension, a condition in which BP remains elevated despite adherence to a rational medication regimen. This novel treatment approach was developed on the basis of a wealth of animal and human research demonstrating the importance of the sympathorenal axis in the pathogenesis of hypertension. Sympathetic efferent signals to the kidneys raise BP by stimulating sodium retention and renin release, and the kidneys influence central sympathetic drive via afferent nerves. But as is true with many therapeutic advances, RD has shown benefit in clinical studies long before the mechanisms are fully understood. Additional research is needed to understand the contribution of afferent sympathetic nerve interruption to BP reductions observed with RD; to examine the degree and significance of re-innervation following RD; to elucidate factors that may lead to a lack of response to RD in some patients; to determine whether the modulation of the sympathetic nervous system via RD can have beneficial effects independent of BP reduction; and to develop methods to measure the effectiveness of RD in real time. PMID- 23660549 TI - Limb salvage treatment for Gollop-Wolfgang complex (femoral bifurcation, complete tibial hemimelia, and hand ectrodactyly). AB - We reported the findings from three patients with Gollop-Wolfgang complex and demonstrated the results of five limb salvage treatments for this condition. All three femoral bifurcations were accompanied by ipsilateral complete tibial hemimelia. Two patients showed contralateral complete or partial tibial hemimelia, and one patient had hand ectrodactyly. The five limb salvage treatments included resection of the anteromedial bifurcated femur in three limbs, foot centralization in five limbs, tibiofibular fusion in one limb with partial tibial hemimelia, fibular transfer (Brown's procedure) in three limbs with complete tibial hemimelia, and callus distraction lengthening in one limb. The duration from the first operation to the final follow-up ranged from 3.5 to 5.4 years. None of the three knees treated by fibular transfer achieved a successful functional result, but all of the knees were ultimately able to withstand weight bearing. Early knee disarticulation and resection of the protruded bifurcated femur, followed by fitting of a modern prosthesis is likely to be the best treatment for patients with Gollop-Wolfgang syndrome. We note that limb salvage treatment is an alternative in patients who opt to retain their feet and refuse amputation. PMID- 23660550 TI - Unequal sexual health--differences between detained youth and their same aged peers. AB - PURPOSE: To describe sexual health risks in an understudied group, youth in detention, and compare these to sexual health risks among non-detained youth. In addition, variables predicting adverse sexual health outcomes are sought and compared. METHODS: In 2009, a self-administered questionnaire on sexuality was conducted amongst youth in Sweden. In 2010, the same Internet-based questionnaire was applied in a study at Swedish detention centres. In this article, sexually active youth aged 15-20 years in the two groups are compared and bivariate logistic regression analyses are conducted in order to find predictors of adverse sexual health outcomes, among detainees and non-detainees respectively. RESULTS: Major differences between the detained and the non-detained concerning a majority of risk-taking variables exist. CONCLUSIONS: Although detained youth display several risky sexual behaviors, no specific risk factors are found in a logistic regression analysis. However, this is a vulnerable group. The mere fact that an adolescent is placed at a detention centre should be an imperative for professionals to address the subject of sexual health and safer sex. Furthermore, the results will be used in a forthcoming sex education curriculum tailored especially at detained youth. This is one, but by far not the only way to minimize the health inequalities that are presented in this study. PMID- 23660551 TI - Early and mid-term outcomes of combined aortic valve replacement and coronary artery bypass grafting in elderly patients. AB - OBJECTIVES: Although the number of elderly patients undergoing combined aortic valve replacement (AVR) and coronary artery bypass grafting (CABG) is increasing, the early and mid-term outcomes of this combined procedure remain to be determined. We sought to elucidate the early and mid-term outcomes of elderly (>=75 years) vs non-elderly (<75 years) patients who underwent combined AVR and CABG. METHODS: Between September 2004 and September 2011, 259 patients underwent combined AVR and CABG at our institute, including 155 elderly patients (59.8%; Elderly group) with a mean age of 79.8 +/- 3.6 years and 104 non-elderly patients (40.2%; Non-elderly group) with a mean age of 67.3+/-5.8 years. Early and mid term outcomes were compared, and multivariate analyses were performed to determine the risk factors for morbidity and mortality. The mean follow-up times were 33.1+/-21.7 and 37.4+/-22.2 months in the Elderly and Non-elderly groups, respectively. RESULTS: The mean number of anastomoses and the frequency of use of the internal thoracic artery were similar between the two groups. The use of a mechanical valve was less frequent in the Elderly group than in the Non-elderly group (11.6 vs 60.6%, P<0.001). The Elderly and Non-elderly groups had similar rates of operative death (1.9 vs 1.0%, P=0.651), early stroke (2.6 vs 1.0%, P=0.651), 5-year overall survival (83.1+/-4.8 vs 87.2+/-5.2%, P=0.358), 5-year freedom from cardiac death (92.3+/-2.7 vs 94.8+/-3.4%, P=0.570) and 5-year freedom from stroke (94.0+/-2.6 vs 99.0+/-1.0%, P=0.097). Cox proportional hazards analyses identified diabetes, creatinine level and EuroSCORE II, but not age, as independent predictors of overall mortality rate. CONCLUSIONS: Early and mid-term outcomes of combined AVR and CABG were similar between elderly and non elderly patients. Older age was not a risk factor for mortality in patients undergoing combined AVR plus CABG, and this procedure should be recommended in properly selected elderly patients. PMID- 23660552 TI - Outcomes of Damus-Kaye-Stansel anastomosis at time of cavopulmonary connection in single ventricle patients at risk of developing systemic ventricular outflow tract obstruction. AB - OBJECTIVES: Children with various single ventricle anomalies are at risk of developing systemic ventricular outflow tract obstruction (SVOTO) following volume unloading with cavopulmonary connection (CPC). We aim to evaluate the value of Damus-Kaye-Stansel (DKS) anastomosis at the time of CPC in eliminating late SVOTO risk. METHODS: Retrospective review of single ventricle patients who underwent DKS concurrent with CPC between 1997 and 2012 was performed. Clinical, echocardiographic and angiographic outcomes were analysed. RESULTS: Thirty-six children with single ventricle underwent DKS at the time of Glenn bidirectional CPC (n = 29) or Fontan total CPC (n = 7). The underlying anatomy was double inlet left ventricle (n = 18), double outlet right ventricle (n = 8), unbalanced atrioventricular septal defect (n = 4) and other (n = 6). Prior palliation included pulmonary artery band (n = 35), coarctation/arch repair (n = 11) and atrial septectomy (n = 8). Median age at the time of DKS was 8.9 months (range 3.6 months-9.1 years) and the median weight was 6.7 kg (range 5-27 kg). At the time of DKS, 17 patients (47%) had no SVOT gradient and 19 (53%) had SVOT gradient (mean 23.4 +/- 18.7 mmHg). Overall survival was 89 and 83% at 1 month and 5 years, respectively. None of the deaths were related to SVOTO or DKS complications. When present, SVOT gradient decreased from 23.4 +/- 18.7 mmHg preoperatively to 0 after DKS (P < 0.001). At the last follow-up, none of the patients developed any SVOT gradient; 78% of them had zero or trivial aortic/neoaortic valve regurgitation while 22% had mild regurgitation. None of the patients had evidence of compression of the left pulmonary artery or bronchus. Eighty-one percent of patients have reached or are suitable candidates awaiting final palliative surgery. CONCLUSIONS: DKS can be safely performed in conjunction with CPC without added mortality risk. It is very effective in mitigating SVOTO risk, with sustainable good semilunar valves function. Our data support an aggressive approach to performing DKS concurrent with CPC in children with single ventricle pathologies at risk of developing SVOTO. PMID- 23660553 TI - Reply to Eggebrecht et al. PMID- 23660554 TI - Antiplatelet therapy at the time of coronary artery bypass grafting: a multicentre cohort study. AB - OBJECTIVES: The purpose of this multicentre cohort study was to examine the relationship between antiplatelet therapy (APT) at the time of coronary artery bypass grafting (CABG) and postoperative bleeding complications, transfusion requirements and adverse cardiovascular events. METHODS: A matched-pair analysis was carried out on 6350 consecutive patients undergoing CABG at the three university hospitals in Western Denmark. Patients exposed to aspirin or clopidogrel within 5 days before surgery were compared with those not exposed to these drugs. The data used in the study were retrieved from the Western Denmark Heart Registry. RESULTS: Of the 6350 patients enrolled, 1846 (29%) had been exposed to aspirin or clopidogrel within 5 days prior to CABG (the APT group). Matching with the remaining 4504 (71%) patients of the control group resulted in 1132 pairs of patients. Patients in the APT group had greater mean chest tube drainage volumes (946 vs 775 ml; P < 0001) and greater transfusion requirements (ranging from 37.4-57.5 vs 29.8%; P < 0.0001) than control group patients. Preoperative aspirin therapy was not associated with greater reoperation rates (4.0 vs 3.9%; P = 0.005); nor was it an independent risk factor for severe postoperative bleeding >1000 ml (odds ratio [OR]: 1.07, 95% confidence interval [CI]: 0.55-1.34). Preoperative clopidogrel use, on the other hand, was associated with greater reoperation rates (10.2 vs 3.9% in the control group; P = 0.005) and was an independent predictor of severe postoperative bleeding (OR: 2.08, 95% CI: 1.55-2.80). Overall, preoperative APT had no significant effect on postoperative 30-day mortality, incidence of myocardial infarction, stroke or need for dialysis. CONCLUSIONS: Preoperative APT is associated with increased bleeding and greater transfusion requirements after CABG. Clopidogrel exposure is associated with greater reoperation rates and is an independent risk factor for severe postoperative bleeding. PMID- 23660555 TI - Out-of-hours intensive care unit cover by nurse practitioners: does this have a detrimental effect towards critical care exposure to the cardiothoracic trainee? PMID- 23660556 TI - Total aortic arch replacement with the frozen elephant trunk technique: 10-year follow-up single-centre experience. AB - OBJECTIVES: Since August 2001, the frozen elephant trunk (FET) technique has been used at our institution to treat degenerative or dissecting aneurysms involving the aortic arch and descending aorta as a potential 'single-stage' procedure. The aim of this study was to review our FET experience and to present the 10-year results. METHODS: Between August 2001 and January 2012, 131 patients underwent FET implant with three different prostheses: the custom-made Chavan-Haverich (n = 66), the Jotec E-vita (n = 30) and the Vascutek Thoraflex (n = 35) prostheses. Concomitant procedures included aortic valve-sparing operations (David, n = 17) and aortic root replacement (Bentall, n = 25). Patient records and the first postoperative and last available computer tomography (CT) were retrospectively reviewed. RESULTS: Incidence of rethoracotomy for bleeding, stroke, spinal cord injury, prolonged ventilatory support (>96 h) and acute renal failure requiring dialysis were 18, 11, 1, 41 and 16%, respectively. In-hospital mortality was 15%. The mean follow-up was 42 +/- 37 (range 1-134 months). At 1, 5 and 10 years, survivals were 82 +/- 3, 72 +/- 5 and 58 +/- 8%, respectively. Freedoms from distal aortic operation were 81 +/- 4, 67 +/- 5 and 43 +/- 13%, respectively. Thirty-six patients underwent 40 distal aortic operations, either open surgical (n = 22, 55%) or endovascular (n = 18, 45%). Chronic aortic dissection was identified as an independent risk factor for distal aortic operation (odds ratio = 3.8; 95% confidence interval 1.5-9.3; P = 0.004). At last CT control, false lumen thrombosis rates up to 93% were achieved around the stent graft. CONCLUSIONS: An FET concept adds to the armament of the surgeon in the treatment of complex and diverse aortic arch pathologies. The preoperative patient risk profile explains the postoperative morbidity and in-hospital mortality. The FET can potentially be still a 'one-stage' procedure in selected patients. However, the extension of FET to patients with extensive aortic aneurysms has led to an increase in second-stage procedures. PMID- 23660557 TI - Why do we need IgM memory B cells? AB - Immunological memory is our reservoir of ready-to-use antibodies and memory B cells. Because of immunological memory a secondary infection will be very light or not occur at all. Antibodies and cells, generated in the germinal center in response to the first encounter with antigen, are highly specific, remain in the organism virtually forever and are mostly of IgG isotype. Long lived plasma cells homing to the bone marrow ensure the constant production of protective antibodies, whereas switched memory B cells proliferate and differentiate in response to secondary challenge. IgM memory B cells represent our first-line defense against infections. They are generated by a T-cell independent mechanism probably triggered by Toll-like receptor-9. They produce natural antibodies with anti-bacterial specificity and the spleen is indispensable for their maintenance. We will review the characteristics and functions of IgM memory B cells that explain their importance in the immediate protection from pathogens. IgM memory B cells, similar to mouse B-1a B cells, may be a remnant of a primitive immune system that developed in the spleen of cartilaginous fish and persisted throughout evolution notwithstanding the sophisticated tools of the adaptive immune system. PMID- 23660558 TI - Constraining the astrophysical origin of the p-nuclei through nuclear physics and meteoritic data. AB - A small number of naturally occurring, proton-rich nuclides (the p-nuclei) cannot be made in the s- and r-processes. Their origin is not well understood. Massive stars can produce p-nuclei through photodisintegration of pre-existing intermediate and heavy nuclei. This so-called gamma-process requires high stellar plasma temperatures and occurs mainly in explosive O/Ne burning during a core collapse supernova. Although the gamma-process in massive stars has been successful in producing a large range of p-nuclei, significant deficiencies remain. An increasing number of processes and sites has been studied in recent years in search of viable alternatives replacing or supplementing the massive star models. A large number of unstable nuclei, however, with only theoretically predicted reaction rates are included in the reaction network and thus the nuclear input may also bear considerable uncertainties. The current status of astrophysical models, nuclear input and observational constraints is reviewed. After an overview of currently discussed models, the focus is on the possibility to better constrain those models through different means. Meteoritic data not only provide the actual isotopic abundances of the p-nuclei but can also put constraints on the possible contribution of proton-rich nucleosynthesis. The main part of the review focuses on the nuclear uncertainties involved in the determination of the astrophysical reaction rates required for the extended reaction networks used in nucleosynthesis studies. Experimental approaches are discussed together with their necessary connection to theory, which is especially pronounced for reactions with intermediate and heavy nuclei in explosive nuclear burning, even close to stability. PMID- 23660560 TI - Exact helical polymer synthesis by directionally fixed connection of a C2-chiral 9,9'-spirobifluorene unit with a C2- or C(s)-symmetric unit. AB - Two types of exact helical polymers, screw-shaped and coil-shaped, consisting of right-angled C2-chiral 9,9'-spirobifluorene skeletons were selectively synthesized based on a two-point-connection protocol by controlling the connecting direction between the monomers. PMID- 23660561 TI - Robotic-assisted partial nephrectomy: excellent intermediate results for those who follow up. PMID- 23660559 TI - Molecular and chemical genetic approaches to developmental origins of aging and disease in zebrafish. AB - The incidence of diseases increases rapidly with age, accompanied by progressive deteriorations of physiological functions in organisms. Aging-associated diseases are sporadic but mostly inevitable complications arising from senescence. Senescence is often considered the antithesis of early development, but yet there may be factors and mechanisms in common between these two phenomena over the dynamic process of aging. The association between early development and late onset disease with advancing age is thought to come from a consequence of developmental plasticity, the phenomenon by which one genotype can give rise to a range of physiologically and/or morphologically adaptive states in response to different environmental or genetic perturbations. On the one hand, we hypothesized that the future aging process can be predictive based on adaptivity during the early developmental period. Modulating the thresholds of adaptive plasticity by chemical genetic approaches, we have been investigating whether any relationship exists between the regulatory mechanisms that function in early development and in senescence using the zebrafish (Danio rerio), a small freshwater fish and a useful model animal for genetic studies. We have successfully conducted experiments to isolate zebrafish mutants expressing apparently altered senescence phenotypes during embryogenesis ("embryonic senescence"), subsequently showing shortened lifespan in adulthoods. We anticipate that previously uncharacterized developmental genes may mediate the aging process and play a pivotal role in senescence. On the other hand, unexpected senescence-related genes might also be involved in the early developmental process and regulation. The ease of manipulation using the zebrafish system allows us to conduct an exhaustive exploration of novel genes and small molecular compounds that can be linked to the senescence phenotype, and thereby facilitates searching for the evolutionary and developmental origins of aging in vertebrates. This article is part of a Special Issue entitled: Animal Models of Disease. PMID- 23660562 TI - Endoscopic in vivo cellular imaging of superficial squamous cell carcinoma of the head and neck by using an integrated endocytoscopy system (with video). AB - BACKGROUND: Recently, some patients have been found to have superficial squamous cell carcinoma (SCC) of the head and neck region during GI endoscopy; however, endoscopic biopsy from a lesion in the head and neck region is troublesome. An endocytoscopy system has been reported to enable optical biopsy of an esophageal lesion. OBJECTIVE: To evaluate the feasibility of in vivo cellular imaging with an integrated endocytoscopy system for patients with superficial SCC of the head and neck. DESIGN: Experimental pilot study. SETTING: University hospital. PATIENTS: This study involved 12 patients who were found to have superficial SCC of the head and neck during GI endoscopy. INTERVENTION: Endocytoscopic images were taken of each lesion and of the surrounding mucosa. The images were later reviewed by 1 pathologist and 2 endoscopists who were unaware of any other findings. MAIN OUTCOME MEASUREMENTS: Correlation between endocytoscopy diagnosis and histologic diagnosis. RESULTS: Adequate endocytoscopic images could be obtained in 11 of the 12 patients (15 of 16 lesions). For endocytoscopic images of 15 lesions and 12 areas of surrounding mucosa, the overall accuracy of endocytoscopic diagnosis in differentiating between nonmalignant and malignant histopathology by the pathologist, endoscopist 1, and endoscopist 2 were 96%, 96%, and 96%, respectively. The kappa value for interobserver agreement was 0.77. LIMITATIONS: Single-center experience, small number of patients. CONCLUSION: An endocytoscopy system has the potential to be used as an optical biopsy for superficial head and neck lesions. PMID- 23660563 TI - The role of K-ras gene mutation analysis in EUS-guided FNA cytology specimens for the differential diagnosis of pancreatic solid masses: a meta-analysis of prospective studies. AB - BACKGROUND: Differential diagnosis of pancreatic solid masses with EUS-guided FNA (EUS-FNA) is still challenging in about 15% of cases. Mutation of the K-ras gene is present in over 75% of pancreatic adenocarcinomas (PADC). OBJECTIVE: To assess the accuracy of K-ras gene mutation analysis for diagnosing PADC. DESIGN: We systematically searched the electronic databases for relevant studies published. Data from selected studies underwent meta-analysis by use of a bivariate model providing a pooled value for sensitivity, specificity, diagnostic odds ratio, and summary receiver operating characteristic curve. SETTING: Meta-analysis of 8 prospective studies. PATIENTS: Total of 931 patients undergoing EUS-FNA for diagnosis of pancreatic solid masses. INTERVENTION: K-ras mutation analysis. MAIN OUTCOME MEASUREMENTS: Diagnostic accuracy of K-ras mutation analysis and of combined diagnostic strategy by using EUS-FNA and K-ras mutation analysis in the diagnosis of PADC. RESULTS: The pooled sensitivity of EUS-FNA for the differential diagnosis of PADC was 80.6%, and the specificity was 97%. Estimated sensitivity and specificity were 76.8% and 93.3% for K-ras gene analysis, respectively, and 88.7% and 92% for combined EUS-FNA plus K-ras mutation analysis. Overall, K-ras mutation testing applied to cases that were inconclusive by EUS-FNA reduced the false-negative rate by 55.6%, with a false-positive rate of 10.7%. Not repeating EUS-FNA in cases in which mutation testing of the K-ras gene is inconclusive would reduce the repeat-biopsy rate from 12.5% to 6.8%. LIMITATIONS: Small number of studies and between-study heterogeneity. CONCLUSION: K-ras mutation analysis can be useful in the diagnostic work-up of pancreatic masses, in particular when tissue obtained by EUS-FNA is insufficient, and the diagnosis inconclusive. PMID- 23660564 TI - Do breaks in gastroenterology fellow endoscopy training result in a decrement in competency in colonoscopy? AB - BACKGROUND: Skills decay without practice, but the degree is task specific. Some experts believe that it is essential to teach endoscopy longitudinally to build and maintain endoscopic skills. OBJECTIVE: To determine whether breaks in gastroenterology fellow endoscopy training are associated with a decrement in competency in independent intubation of the cecum. DESIGN: Observational cohort of colonoscopies performed by gastroenterology fellows. SETTING: Academic fellowship program from July 2010 to March 2012. SUBJECTS: Twenty-four fellows. MAIN OUTCOME MEASUREMENTS: The adjusted change in the slope of cumulative summation learning curves for cecal intubation after breaks in training and the slope at the end of the subsequent endoscopy rotation. RESULTS: A total of 6485 colonoscopies were performed by 24 fellows with 87 breaks in training. The average break was 6 weeks (range 2-36 weeks). Seventy-five percent of the breaks were 8 weeks or less. For every additional 4 weeks, the slope after the break worsened by 0.022 (P = .06, maximum possible change = -1.0 to +1.0). By the end of the subsequent rotation, there was no association between the slope of the learning curve and the length of the break (P = .68). LIMITATIONS: This was an observational study of only 24 fellows with relatively few long breaks. Cecal intubation is only 1 component of overall competency in colonoscopy. CONCLUSIONS: There may be a very small decrement in fellows' abilities to intubate the cecum after a break in endoscopy training. Because these changes are so small, teaching endoscopy in blocks is probably adequate, if necessary to balance other clinical and research experience. However, further research is needed to determine whether a longitudinal endoscopy experience is superior for attaining and maintaining competency, to evaluate the effects of breaks longer than 8 weeks, and to determine whether the effects of breaks depend on the previous volume of experience with colonoscopy. PMID- 23660565 TI - Radiofrequency ablation for refractory gastric antral vascular ectasia (with video). AB - BACKGROUND: Gastric antral vascular ectasia (GAVE) is a cause of upper GI bleeding and chronic anemia. Although upper endoscopy with argon plasma coagulation (APC) is an accepted therapy for GAVE, many patients continue to bleed and remain transfusion dependent after therapy. Radiofrequency ablation (RFA) may provide an alternative therapeutic option for GAVE. OBJECTIVE: To determine the efficacy and safety of RFA for patients with GAVE who remain transfusion dependent after APC treatment. DESIGN: Open-label prospective cohort study of patients with GAVE refractory to APC. SETTING: Academic tertiary referral center. PATIENTS: GAVE patients with previous failed APC therapy, chronic anemia, and transfusion dependence. INTERVENTIONS: Endoscopic RFA to the gastric antrum using the HALO(90) ULTRA ablation catheter until transfusion independence is achieved or a maximum of 4 sessions are performed. MAIN OUTCOME MEASUREMENTS: Transfusion requirements before and after RFA. Secondary outcomes are hemoglobin before and 6 months after RFA completion, number of RFA sessions, and complications. RESULTS: Twenty-one patients underwent at least 1 RFA session with ablation of GAVE lesions. At 6 months after completion of the course of RFA therapy, 18 of 21 patients (86%) were transfusion independent. Mean hemoglobin increased from 7.8 to 10.2 in responders (n = 18). Two adverse events occurred (minor acute bleeding and superficial ulceration); both resolved without intervention. LIMITATIONS: Single-center, single-operator, and nonrandomized design. CONCLUSIONS: RFA is safe and effective for treating patients with refractory GAVE after attempted APC. PMID- 23660566 TI - Outcomes of EUS-guided drainage of debris-containing pancreatic pseudocysts by using combined endoprosthesis and a nasocystic drain. AB - BACKGROUND: The presence of debris within a pseudocyst may impair success of endoscopic drainage. OBJECTIVE: To compare the clinical outcomes and adverse event rates of EUS-guided pseudocyst drainage with and without a nasocystic drain for the management of pancreatic pseudocysts with viscous solid debris-laden fluid. DESIGN: Retrospective study. SETTING: Single, tertiary-care referral center. PATIENTS: Consecutive patients with pancreatic pseudocysts managed by EUS guided drainage: those with solid debris who underwent drainage via nasocystic drains alongside stents (n = 63) and those with solid debris who underwent drainage via transmural stents only (n = 24). INTERVENTION: Drainage via nasocystic drains alongside stents or drainage via transmural stents only. MAIN OUTCOME MEASUREMENTS: The primary outcomes were short-term success and long-term success of the procedures. The secondary outcomes were procedure-related adverse events and reintervention. RESULTS: The patients with viscous solid debris-laden fluid whose pseudocysts were drained by both stents and nasocystic tubes had a 3 times greater short-term success rate compared with those who had drainage by stents alone (P = .03). On 12-month follow-up, complete resolution of pseudocysts with debris drained via stents alone was less (58%) compared with those with debris who underwent drainage via nasocystic drains alongside stents (79%; P = .059). The rate of stent occlusion was higher in cysts with debris drained by stents alone (33%) compared with those drained via nasocystic drains alongside stents (13%; P = .03). LIMITATIONS: Retrospective design; limited sample size. CONCLUSION: In patients with pseudocysts with viscous debris-laden fluid, EUS guided drainage by using a combination of a nasocystic drain and transmural stents improves clinical outcomes and lowers the stent occlusion rate compared with those who underwent drainage via stents alone. PMID- 23660567 TI - Temperature-induced responses of xylem structure of Larix sibirica (Pinaceae) from the Russian Altay. AB - PREMISE OF THE STUDY: Xylem structure determines the hydraulic and mechanical properties of a stem, and its plasticity is fundamental for maintaining tree performance under changing conditions. Unveiling the mechanism and the range of xylem adjustment is thus necessary to anticipate climate change impacts on vegetation. METHODS: To understand the mechanistic process and the functional impact of xylem responses to warming in a cold-limited environment, we investigated the relationship between temperature and tracheid anatomy along a 312-yr tree-ring chronology of Larix sibirica trees from the Altay Mountains in Russia. KEY RESULTS: Climate-growth analyses indicated that warming favors wider earlywood cell lumen, thicker latewood walls, denser maximum latewood, and wider rings. The temperature signal of the latewood was stronger (r > 0.7) and covered a longer and more stable period (from June to August) than that of earlywood and tree-ring width. Long-term analyses indicated a diverging trend between lumen and cell wall of early- and latewood. CONCLUSIONS: Xylem anatomy appears to respond to warming temperatures. A warmer early-growing season raises water conduction capacity by increasing the number and size of earlywood tracheids. The higher performing earlywood tracheids promote more carbon fixation of the latewood cells by incrementing the rate of assimilation when summer conditions are favorable for growth. The diverging long-term variation of lumen and cell wall in earlywood vs. latewood suggests that xylem adjustments in latewood increase mechanical integrity and support increasing tree size under the ameliorated growing conditions. PMID- 23660568 TI - Long-term trends mask variation in the direction and magnitude of short-term phenological shifts. AB - PREMISE OF THE STUDY: Plants are flowering earlier in response to climate change. However, substantial interannual variation in phenology may make it difficult to discern and compare long-term trends. In addition to providing insight on data requirements for discerning such trends, phenological shifts within subsets of long-term records will provide insight into the mechanisms driving changes in flowering over longer time scales. METHODS: To examine variation in flowering shifts among temporal subsets of long-term records, we used two data sets of flowering phenology from snow-dominated habitats: subalpine meadow in Gothic, Colorado, USA (38 yr), and arctic tundra in Zackenberg, Greenland (16 yr). Shifts in flowering time were calculated as 10-yr moving averages for onset, peak, and end of flowering. KEY RESULTS: Flowering advanced over the course of the entire time series at both sites. Flowering shifts at Gothic were variable, with some 10 yr time frames showing significant delays and others significant advancements. Early-flowering species were more responsive than later-flowering species, while the opposite was true at Zackenberg. Flowering shifts at Zackenberg were less variable, with advanced flowering across all 10-yr time frames. At both sites, long-term advancement seemed to be primarily driven by strong advancements in flowering in the 1990s and early 2000s. CONCLUSIONS: Analysis of long-term trends can mask substantial variation in phenological shifts through time. This variation in the direction and magnitude of phenological shifts has implications for the evolution of flowering time and for interspecific interactions with flowering plants and can provide more detailed insights into the dynamics of phenological responses to climate change. PMID- 23660569 TI - Diagnostic value of color Doppler ultrasonography and MDCT angiography in complications of hemodialysis fistulas and grafts. AB - PURPOSE: The purpose of the study was to compare the diagnostic value of color Doppler ultrasonography (CDUS) and multidetector computed tomography (MDCT) angiography against that of digital subtraction angiography (DSA) or surgery in the evaluation of failing hemodialysis arteriovenous fistulas (AVFs). MATERIALS AND METHODS: CDUS and MDCT angiography were performed with 41 patients (24 men, 17 women; mean age 55.8) with dysfunctional hemodialysis fistulas. The presence of stenosis, thrombosis, aneurysm, pseudoaneurysm and seroma were recorded. The sensitivity, specificity, positive and negative predictive values (PPV and NPV) and accuracy of CDUS and MDCT angiography were calculated both individually and in combination for the detection of vascular segments with significant stenosis, thrombosis, aneurysms, pseudoaneurysms, perivascular complications and stenosis subgroups. RESULTS: Sixty-four segmental lesions were diagnosed by DSA or surgery. Sensitivity, specificity, PPV, NPV and accuracy of CDUS for all vascular tree lesions were 85.9%, 99.2%, 96.4%, 96.7% and 94.5%, respectively. For MDCT angiography the figures were 96.8%, 99.6%, 98.4%, 99.2% and 98.5%, respectively. When both tests were used in combination, sensitivity, specificity, PPV, NPV and accuracy for all vascular tree lesions rose to 100%. CONCLUSION: Combined use of MDCT and CDUS for diagnosis of AVF dysfunctions is of equivalent value to surgery or DSA, a gold standard technique. PMID- 23660570 TI - Non-coding RNAs: novel players in chromatin-regulation during viral latency. AB - Chromatin structure plays an essential role during gene expression regulation not only in the case of the host cellular genome, but also during the viral life cycle. Epigenetic chromatin marks thereby define, whether a gene promoter is accessible for the transcription machinery or whether a repressive heterochromatin state is established. The heterochromatin-mediated repression of lytic viral genes results in viral latency, enabling the virus to persist dormant without being recognized by the host immune system, but keeping the potential for reactivation. Arising new systems biology approaches are starting to uncover an unexpected multiplicity and variety of non-coding (nc)RNAs playing important roles during chromatin structure control, likely constituting a novel layer in epigenetic regulation. In this review we give an overview of chromatin-regulatory viral and host cellular ncRNAs and their links to viral latency. PMID- 23660571 TI - Effect of lactate supplementation and sodium bicarbonate on 40-km cycling time trial performance. AB - The use of nutritional supplements to improve sporting performance and increase training adaptations is commonplace among athletes and is an expanding market in terms of product choice and availability. The purpose of this study was to examine the effects of 2 ergogenic aids with extracellular blood buffering potential, namely sodium bicarbonate (NaHCO3) and a lactate supplement, during a 40-km cycling time trial. Seven recreationally active men (age, 22.3 +/- 3.3 years; height, 182.5 +/- 6.5 cm; body mass, 79.2 +/- 6.3 kg) completed five 40-km cycling time trials, including a familiarization trial in a randomized, blind, double placebo-controlled design. Subjects ingested (a) 300 mg.kg-1 body mass NaHCO3 (BICARB), (b) 45 mg.kg-1 body mass sodium chloride (PL-BICARB) as the placebo for the NaHCO3 trial, (c) 1115 mg lactate (LACTATE), or (d) plain flour as the placebo for the lactate trial (PL-LACTATE) 60 minutes before exercise. There was no significant difference in performance between the 4 conditions (p > 0.05). Although NaHCO3 ingestion induced significant changes in all the acid-base variables (all p < 0.05), no significant change was seen following lactate ingestion (p > 0.05). Subjects in the LACTATE condition did have a significantly higher heart rate (p < 0.05) without experiencing any greater perceived exertion (p > 0.05) than the other 3 conditions. Neither NaHCO3 nor lactate supplementation seem to improve 40-km cycling time trial performance. However, the potential benefits following LACTATE regarding perceived exertion require further research. PMID- 23660572 TI - Effect of specific short-term physical training on fitness measures in conditioned men. AB - Physical training programs that enhance battlefield-related fitness needs have been increasingly advocated as operational demands on the US military have increased, but few studies have evaluated program effectiveness. The purpose of this study was to compare a novel 7-week physical training program with traditional army physical fitness training in improving the selected measures of physical fitness and military task performance. One hundred and eighty subjects performed a 30-m rush wearing a fighting load, a simulated casualty recovery wearing a fighting load, a 1-repetition maximum bench press, a maximum repetition pull-up test, a medicine ball put, a vertical jump, and a T-test agility drill to establish test-retest reliability and normative reference values. One hundred thirty-three subjects were assigned by block randomization to either traditional Army physical training (TT) of calisthenics and running or a novel program (NT) of calisthenics, resistance, aerobic, speed, power, and agility training. The results indicated that between-day reliability was high (intraclass correlation coefficients [ICCs] 3,1; 0.87-0.98) for all measures except for the casualty recovery (ICC 3,1; 0.67). Reliability improved for all the measures that were averaged over 3 trials (ICC 3,3; 0.93-0.95). The NT was superior to TT in improving bench press (8 vs. 3%; p < 0.01), medicine ball put (7 vs. 1%; p < 0.01), 30-m rush times (5 vs. 1%; p < 0.01), and casualty recovery times (17 vs. 15%; p < 0.01). These findings suggest that a short-term physical training program is effective in improving strength, power, and speed among previously conditioned men. Future studies should determine if similar training programs mitigate the injury risk in this population. PMID- 23660573 TI - The importance of maximal leg strength for female athletes when performing drop jumps. AB - A common suggestion is that a predetermined level of maximal leg strength is required before drop jump (DJ) training can begin. This study sought to examine the relationship between maximal squat strength (1 repetition maximum [RM]) and DJ performance in 15 female rugby players (n = 15). The subjects were tested for 1RM, countermovement jump, squat jump, and DJs from 0.24, 0.36, 0.48, 0.60, 0.72, and 0.84 m. Jump height (JH) was calculated for all jumps and relative peak eccentric force, relative peak concentric force, ground contact time (GCT), and reactive strength index were also calculated for DJs. Pearson correlations were used to examine the relationship between 1RM relative to body mass (BM) (1RM/BM) and JHs, reactive strength index, and GCT during DJs. The subjects were placed in a high strength (HS) or low strength (LS) group depending on whether or not their 1RM/BM was >1 or <1. The T-tests and 2-way analysis of variance (ANOVA) were used to compare the groups. A Fishers post hoc test was used for the ANOVA with significance set at p < 0.05. A large correlation between JH and 1RM/BM was shown at the 0.84-m dropping height (r = 0.56). A significant overall difference was found between the HS and LS groups for DJ JH with a post hoc analysis revealing a significant difference at the 0.84-m drop height (p = 0.029). It is likely beneficial for female athletes to achieve high levels of maximal leg strength if they are going to use high (>0.8-m) drop heights when performing DJs. PMID- 23660574 TI - Cardiovascular and affective outcomes of active gaming: using the nintendo wii as a cardiovascular training tool. AB - Active-video gaming is purported to produce similar cardiovascular responses as aerobic fitness activities. This study compared the emotional and cardiovascular effects of Wii games with those of traditional exercise in college-aged adults with different exercise backgrounds. Specifically, the percentage of heart rate reserve, rate of perceived exertion (RPE), level of enjoyment, and Positive and Negative Affect Schedule scores were compared between subjects who reported exercising frequently at high intensities (high-intensity exerciser group: age = 20.18 years [0.87]; Height = 165.23 cm [9.97]; Mass = 62.37 kg [11.61]), N = 11 and those who exercise more often at lower intensities (low-intensity exercisers group: age = 20.72 years [1.19]; Height = 164.39 cm [8.05]; Mass = 68.04 kg [10.71]), N = 11. The subjects completed six 20-minute exercises sessions: treadmill walking, stationary cycling, and Wii's Tennis, Boxing, Cycling, and Step. The low-intensity exerciser group achieved a greater percentage of heart rate reserve (a) during traditional exercise compared with that during Wii boxing, (b) playing Wii boxing compared with that for Wii tennis, and (c) playing Wii boxing compared with that when the high-intensity exercisers group played any Wii games (p < 0.05). The RPE was greater for boxing and cycling compared with that for tennis and step (p < 0.05). Ratings of enjoyment and the increase in positive emotion were greater for boxing and for tennis compared with those for traditional exercises (p < 0.05). Results suggest that Wii boxing shows the greatest potential as a cardiovascular fitness tool among the Wii games, particularly for individuals who typically exercise at lower intensities. PMID- 23660575 TI - Hormonal contraception decreases bacterial vaginosis but oral contraception may increase candidiasis: implications for HIV transmission. AB - OBJECTIVE: A 2012 WHO consultation concluded that combined oral contraception (COC) does not increase HIV acquisition in women, but the evidence for depot medroxyprogesterone acetate (DMPA) is conflicting. We evaluated the effect of COC and DMPA use on the vaginal microbiome because current evidence suggests that any deviation from a 'healthy' vaginal microbiome increases women's susceptibility to HIV. METHODS: We conducted a systematic review and reanalysed the Hormonal Contraception and HIV Acquisition (HC-HIV) study. Vaginal microbiome outcomes included bacterial vaginosis by Nugent scoring, vaginal candidiasis by culture or KOH wet mount and microbiome compositions as characterized by molecular techniques. RESULTS: Our review of 36 eligible studies found that COC and DMPA use reduce bacterial vaginosis by 10-20 and 18-30%, respectively. The HC-HIV data showed that COC and DMPA use also reduce intermediate microbiota (Nugent score of 4-6) by 11% each. In contrast, COC use (but not DMPA use) may increase vaginal candidiasis. Molecular vaginal microbiome studies (n=4) confirm that high oestrogen levels favour a vaginal microbiome composition dominated by 'healthy' Lactobacillus species; the effects of progesterone are less clear and not well studied. CONCLUSION: DMPA use does not increase HIV risk by increasing bacterial vaginosis or vaginal candidiasis. COC use may predispose for vaginal candidiasis, but is not believed to be associated with increased HIV acquisition. However, the potential role of Candida species, and vaginal microbiome imbalances other than bacterial vaginosis or Candida species, in HIV transmission cannot yet be ruled out. Further in-depth molecular studies are needed. PMID- 23660576 TI - The burden of HIV: insights from the Global Burden of Disease Study 2010. AB - OBJECTIVES: To evaluate the global and country-level burden of HIV/AIDS relative to 291 other causes of disease burden from 1980 to 2010 using the Global Burden of Disease Study 2010 (GBD 2010) as the vehicle for exploration. METHODS: HIV/AIDS burden estimates were derived elsewhere as a part of GBD 2010, a comprehensive assessment of the magnitude of 291 diseases and injuries from 1990 to 2010 for 187 countries. In GBD 2010, disability-adjusted life years (DALYs) are used as the measurement of disease burden. DALY estimates for HIV/AIDS come from UNAIDS' 2012 prevalence and mortality estimates, GBD 2010 disability weights and mortality estimates derived from quality vital registration data. RESULTS: Despite recent declines in global HIV/AIDS mortality, HIV/AIDS was still the fifth leading cause of global DALYs in 2010. The distribution of HIV/AIDS burden is not equal across demographics and regions. In 2010, HIV/AIDS was ranked as the leading DALY cause for ages 30-44 years in both sexes and for 21 countries that fall into four distinctive blocks: Eastern and Southern Africa, Central Africa, the Caribbean and Thailand. Although a majority of the DALYs caused by HIV/AIDS are in high-burden countries, 20% of the global HIV/AIDS burden in 2010 was in countries where HIV/AIDS did not make the top 10 leading causes of burden. CONCLUSION: In the midst of a global economic recession, tracking the magnitude of the HIV/AIDS epidemic and its importance relative to other diseases and injuries is critical to effectively allocating limited resources and maintaining funding for effective HIV/AIDS interventions and treatments. PMID- 23660577 TI - Zidovudine impairs immunological recovery on first-line antiretroviral therapy: collaborative analysis of cohort studies in southern Africa. AB - OBJECTIVES: Zidovudine (ZDV) is recommended for first-line antiretroviral therapy (ART) in resource-limited settings. ZDV may, however, lead to anemia and impaired immunological response. We compared CD4+ cell counts over 5 years between patients starting ART with and without ZDV in southern Africa. DESIGN: Cohort study. METHODS: Patients aged at least 16 years who started first-line ART in South Africa, Botswana, Zambia, or Lesotho were included. We used linear mixed effect models to compare CD4+ cell count trajectories between patients on ZDV containing regimens and patients on other regimens, censoring follow-up at first treatment change. Impaired immunological recovery, defined as a CD4+ cell count below 100 cells/MUl at 1 year, was assessed in logistic regression. Analyses were adjusted for baseline CD4+ cell count and hemoglobin level, age, sex, type of regimen, viral load monitoring, and calendar year. RESULTS: A total of 72,597 patients starting ART, including 19,758 (27.2%) on ZDV, were analyzed. Patients on ZDV had higher CD4+ cell counts (150 vs.128 cells/MUl) and hemoglobin level (12.0 vs. 11.0 g/dl) at baseline, and were less likely to be women than those on other regimens. Adjusted differences in CD4+ cell counts between regimens containing and not containing ZDV were -16 cells/MUl [95% confidence interval (CI) -18 to -14] at 1 year and -56 cells/MUl (95% CI -59 to -52) at 5 years. Impaired immunological recovery was more likely with ZDV compared to other regimens (odds ratio 1.40, 95% CI 1.22-1.61). CONCLUSION: In southern Africa, ZDV is associated with inferior immunological recovery compared to other backbones. Replacing ZDV with another nucleoside reverse transcriptase inhibitor could avoid unnecessary switches to second-line ART. PMID- 23660578 TI - Altered T-cell subsets in HIV-1 natural viral suppressors (elite controllers) with hepatitis C infection. AB - We have established a cohort of 64 Natural Viral Suppressors (NVS) (similar to Elite Controllers/Elite Suppressors), 30 of which have chronic hepatitis C virus (HCV). We investigated T-cell phenotypic changes in association with HCV infection. NVS without HCV and normal controls had similar T-cell phenotypes. However, NVS with HCV had lower naive cell proportions (CD4 and CD8) compared with NVS without HCV (P = 0.0008 and P = 0.02) or normal controls (P = 0.0163 and P = 0.017). These results and previously reported data suggest that HCV coinfection increases immune activation and T-cell disturbances. Any associated T cell functional changes or potential clinical consequences need further study. PMID- 23660580 TI - Synthesis and acid catalysis of zeolite-templated microporous carbons with SO3H groups. AB - Microporous carbon catalysts with large surface areas (800-1100 m(2) g(-1)) and high densities of SO3H groups (ca. 1.1 mmol g(-1)) were synthesized by sulfonation of zeolite-templated microporous carbon. The resulting SO3H-bearing microporous carbon catalysts exhibited higher catalytic performance for the hydrolysis of cellobiose and the Beckmann rearrangement than conventional solid acid catalysts and non-porous amorphous carbon with SO3H groups. The high catalytic activity of these reusable heterogeneous catalysts can be attributed to the high surface area and microporous structure, which enhance the efficient incorporation and diffusion of reactant molecules from solution to the SO3H groups on the catalysts. PMID- 23660579 TI - Oral serum-derived bovine immunoglobulin improves duodenal immune reconstitution and absorption function in patients with HIV enteropathy. AB - OBJECTIVES: To examine the impact of serum-derived bovine immunoglobulin, an oral medical food known to neutralize bacterial antigen and reduce intestinal inflammation, on restoration of mucosal immunity and gastrointestinal function in individuals with HIV enteropathy. DESIGN: Open-label trial with intensive 8-week phase of bovine serum immunoglobulin (SBI) 2.5 g twice daily with a 4-week washout period and an optional 9-month extension study. METHODS: HIV enteropathy was defined as chronic gastrointestinal symptoms including frequent loose or watery stools despite no identifiable, reversible cause. Upper endoscopy for tissue immunofluorescent antibody assay and disaccharide gut permeability/absorption studies were performed before and after 8 weeks of SBI to test mucosal immunity and gastrointestinal function. Blood was collected for markers of microbial translocation, inflammation, and collagen kinetics. A validated gastrointestinal questionnaire assessed changes in symptoms. RESULTS: All eight participants experienced profound improvement in symptoms with reduced bowel movements/day (P = 0.008) and improvements in stool consistency (P = 0.008). Gut permeability was normal before and after the intervention, but D xylose absorption increased in seven of eight participants. Mucosal CD4 lymphocyte densities increased by a median of 139.5 cells/mm2 from 213 to 322 cells/mm2 (P = 0.016). Intestinal-fatty acid binding protein (I-FABP), a marker of enterocyte damage, initially rose in seven of eight participants after 8 weeks (P = 0.039), and then fell below baseline in four of five who continued receiving SBI (P = 0.12). Baseline serum I-FABP levels were negatively correlated with subsequent rise in mucosal CD4 lymphocyte densities (r = -0.74, P = 0.046). CONCLUSION: SBI significantly increases intestinal mucosal CD4 lymphocyte counts, improves duodenal function, and showed evidence of promoting intestinal repair in the setting of HIV enteropathy. PMID- 23660582 TI - Prevalence and risk factors of problematic Internet use: a cross-national comparison of Japanese and Chinese university students. AB - The aim of the present study was to compare risk factors for problematic Internet use (PIU) among Japanese and Chinese university students. A sample of 267 Japanese and 236 Chinese first year university students responded to questionnaires on the severity of PIU, depression, self-image/image of others, and perceived parental child-rearing styles. The results indicated that Japanese participants were more likely to demonstrate PIU than their Chinese counterparts. Compared to Chinese students, Japanese students reported more negative self image, lower parental care, greater overcontrol, and higher depression scores. The PIU group had a higher depression score compared to the normal Internet use group. Compared with the non-PIU group, the PIU group consisted of more male and Japanese participants. Further, they tended to have more negative self-images, saw their mothers to be less caring, and perceived their mothers and fathers as more overcontrolling. PIU is strongly associated with depression, negative self image, and parental relations. Finally, mediation analysis revealed that such national differences in PIU between Japanese and Chinese were clarified in depression and perceived mother's care. This cross-national study indicated that depression and perceived mother's care were both significant risk factors that were associated with the national difference in PIU between Japanese and Chinese participants. PMID- 23660581 TI - Longitudinal neurodevelopmental and neuromotor outcome in congenital diaphragmatic hernia patients in the first 3 years of life. AB - OBJECTIVE: The objective of this study was to longitudinally evaluate the neurodevelopmental (ND) outcome in congenital diaphragmatic hernia (CDH) survivors during the first 3 years of life. STUDY DESIGN: The study cohort consists of 47 CDH survivors that were enrolled in our prospective, follow-up program between July 2004 and September 2010, and underwent serial ND evaluations during the first 3 years of life. ND outcomes were evaluated using the Bayley Scales of Infant Development (BSID)-II or BSID-III. Persistent ND impairment was defined as a score that remained ?79 for the cognitive, language and psychomotor domains at the most recent follow-up visit compared with the first assessment. RESULT: The median age at first and last evaluation was 8 (range, 5 to 15) and 29 (range, 23 to 36) months, respectively. During the follow-up, ND scores improved to average in 17%, remained average in 60%, remained delayed in 10%, improved from severely delayed to mildly delayed in 2% and deteriorated from average to delayed in 15%. Motor scores improved to average in 26%, remained average in 55%, remained delayed in 8% and improved from severely delayed to mildly delayed in 11%. Intrathoracic liver position (P=0.004), preterm delivery (P=0.03), supplemental O2 requirement at day of life 30 (P=0.007), age at discharge (P=0.03), periventricular leukomalacia (PVL; P=0.004) and initial neuromuscular hypotonicity (P=0.01) were associated with persistent motor delays. No relationship was found between patient's characteristics and the risk of persistent cognitive and language delays. CONCLUSION: (1) The majority of children with CDH are functioning in the average range by early preschool age, (2) most children who had early delays showed improvement in their ND outcome, (3) children showing delays in all the three domains were the least likely to show improvement and (4) CDH severity appears to be predictive of persistent psychomotor delays. PMID- 23660583 TI - Simultaneous and sensitive detection of human immunodeficiency virus type 1 (HIV) drug resistant genotypes by multiplex oligonucleotide ligation assay. AB - Oligonucleotide ligation assay (OLA) is a highly specific and relatively simple method to detect point mutations encoding HIV-1 drug-resistance, which can detect mutants comprising >=2-5% of the viral population. Nevirapine (NVP), tenofovir (TDF) and lamivudine (3TC) are antiretroviral (ARV) drugs used worldwide for treatment of HIV infection and prevention of mother-to-child-transmission. Adapting the OLA to detect multiple mutations associated with HIV resistance to these ARV simultaneously would provide an efficient tool to monitor drug resistance in resource-limited settings. Known proportions of mutant and wild type plasmids were used to optimize a multiplex OLA for detection of K103N, Y181C, K65R, and M184V in HIV subtypes B and C, and V106M and G190A in subtype C. Simultaneous detection of two mutations was impaired if probes annealed to overlapping regions of the viral template, but was sensitive to >=2-5% when testing codons using non-overlapping probes. PCR products from HIV-subtype B- and C-infected individuals were tested by multiplex-OLA and compared to results of single-codon OLA. Multiplex-OLA detected mutations at codon pairs 103/181, 106/190 and 65/184 reliably when compared to singleplex-OLA in clinical specimens. The multiplex-OLA is sensitive and specific and reduces the cost of screening for NVP, TDF and/or 3TC resistance. PMID- 23660584 TI - Optical and terahertz spectra analysis by the maximum entropy method. AB - Phase retrieval is one of the classical problems in various fields of physics including x-ray crystallography, astronomy and spectroscopy. It arises when only an amplitude measurement on electric field can be made while both amplitude and phase of the field are needed for obtaining the desired material properties. In optical and terahertz spectroscopies, in particular, phase retrieval is a one dimensional problem, which is considered as unsolvable in general. Nevertheless, an approach utilizing the maximum entropy principle has proven to be a feasible tool in various applications of optical, both linear and nonlinear, as well as in terahertz spectroscopies, where the one-dimensional phase retrieval problem arises. In this review, we focus on phase retrieval using the maximum entropy method in various spectroscopic applications. We review the theory behind the method and illustrate through examples why and how the method works, as well as discuss its limitations. PMID- 23660585 TI - Mechanochemical organic synthesis. AB - Recently, mechanical milling using a mixer mill or planetary mill has been fruitfully utilized in organic synthesis under solvent-free conditions. This review article provides a comprehensive overview of various solvent-free mechanochemical organic reactions, including metal-mediated or -catalyzed reactions, condensation reactions, nucleophilic additions, cascade reactions, Diels-Alder reactions, oxidations, reductions, halogenation/aminohalogenation, etc. The ball milling technique has also been applied to the synthesis of calixarenes, rotaxanes and cage compounds, asymmetric synthesis as well as the transformation of biologically active compounds. PMID- 23660586 TI - Cetuximab therapy in the treatment of metastatic colorectal cancer: the future frontier? AB - BACKGROUND: To review the outcomes following cetuximab therapy in patients with metastatic colorectal cancer. METHODS: Relevant articles were reviewed from the published literature using the Medline database. The search was performed using the keywords "colorectal cancer", "cetuximab", "liver metastases", "liver resection" and "hepatectomy". RESULTS: Cetuximab was first used in the palliative setting and an increase in response rates were seen, however with no improvement in overall survival. Published data have observed that cetuximab may be beneficial as part of a down-staging programme. The addition of cetuximab to chemotherapy regimens in patients with KRAS wild-type colorectal cancer has been shown to increase the response rates and the number of patients being down-staged and offered potentially curative resection. The OPUS and CRYSTAL trials observed good response rates following the addition of cetuximab but low resection rates. The CELIM and POCHER studies reported higher resection rates due to better patient selection and study design. However, the majority of published studies tend to report minimal surgical data and lack short- and long-term outcomes. CONCLUSION: The use of cetuximab to conventional chemotherapy regimens may improve the efficacy of down-staging programmes, leading to more patients being offered potentially curative resection. PMID- 23660587 TI - A review of the interplay between tuberculosis and mental health. AB - AIMS: Tuberculosis and mental illness share common risk factors including homelessness, HIV positive serology, alcohol/substance abuse and migrant status leading to frequent comorbidity. We sought to generate a comprehensive literature review that examines the complex relationship between tuberculosis and mental illness. METHODS: A literature search was conducted in MedLine, Ovid and Psychinfo, with further examination of the references of these articles. In total 316 articles were identified. It was not possible to conduct a formal meta analysis due to the absence of randomised controlled data. RESULTS: Rates of mental illness of up to 70% have been identified in tuberculosis patients. Medications used in the treatment of common mental illnesses, such as depression, may have significant interactions with anti-tuberculosis agents, especially isoniazid and increasingly linezolid. Many medications used in the treatment of tuberculosis can have significant adverse psychiatric effects and some medications such as rifampicin may reduce the effective doses of anti-psychotics y their enzyme induction actions. Treatment with agents such as cycloserine has been associated with depression, and there have been reported cases of psychosis with most anti-tuberculous agents. Mental illness and substance abuse may also affect compliance with treatment, with attendant public health concerns. CONCLUSIONS: As a result of the common co-morbidity of mental illness and tuberculosis, it is probable that physicians will encounter previously undiagnosed mental illness among patients with tuberculosis. Similarly, psychiatrists are likely to meet tuberculosis among their patients. It is important that both psychiatrists and physicians are aware of the potential for interactions between the drugs used to treat tuberculosis and psychiatric conditions. PMID- 23660588 TI - In between breeding systems: neither dioecy nor androdioecy explains sexual polymorphism in functionally dioecious worms. AB - Related species share genetic and developmental backgrounds. Therefore, separate sex species that share recent common ancestors with hermaphroditic species may have hidden genetic variation for sex determination that causes some level of lability of expression of gender. Worms of the polychaete species Ophryotrocha labronica have separate, dimorphic sexes and their ancestor was hermaphroditic. Ophryotrocha labronica has a worldwide distribution and populations may differ in the degree of gender specialization. We analyzed the extent to which O. labronica had fixed or labile expression of gender. We found that there were up to four different sexual phenotypes, namely, pure males, males with oocytes, pure females, and females with sperm; the relative frequency of these sexual phenotypes varied in three geographically-distant populations. These sexual morphs had either male or female morphology. However, populations differed in the extent to which worms were sexually dimorphic. In the less dioecious-like population (in which pure males and females were virtually absent, all worms had both oocytes and sperm and sexual dimorphism was relatively weak), males with oocytes had slightly plastic female allocation that depended on mating opportunities-a clearly hermaphroditic trait. Males with oocytes and females with sperm were not functional hermaphrodites. They only used one type of gametes to reproduce and in this respect they probably differed from many cases of inconstancy of gender described in the literature. We consider these populations as novel examples of intermediate states between androdioecy and dioecy. This study contributes to our understanding of breeding systems as continuous gradients rather than as distinct clear-cut alternatives. PMID- 23660589 TI - Vertebrate land invasions-past, present, and future: an introduction to the symposium. AB - The transition from aquatic to terrestrial habitats was a seminal event in vertebrate evolution because it precipitated a sudden radiation of species as new land animals diversified in response to novel physical and biological conditions. However, the first stages of this environmental transition presented numerous challenges to ancestrally aquatic organisms, and necessitated changes in the morphological and physiological mechanisms that underlie most life processes, among them movement, feeding, respiration, and reproduction. How did solutions to these functional challenges evolve? One approach to this question is to examine modern vertebrate species that face analogous demands; just as the first tetrapods lived at the margins of bodies of water and likely moved between water and land regularly, many extant fishes and amphibians use their body systems in both aquatic and terrestrial habitats on a daily basis. Thus, studies of amphibious vertebrates elucidate the functional demands of two very different habitats and clarify our understanding of the initial evolutionary challenges of moving onto land. A complementary approach is to use studies of the fossil record and comparative development to gain new perspectives on form and function of modern amphibious and non-amphibious vertebrate taxa. Based on the synthetic approaches presented in the symposium, it is clear that our understanding of aquatic-to-terrestrial transitions is greatly improved by the reciprocal integration of paleontological and neontological perspectives. In addition, common themes and new insights that emerged from this symposium point to the value of innovative approaches, new model species, and cutting-edge research techniques to elucidate the functional challenges and evolutionary changes associated with vertebrates' invasion of the land. PMID- 23660590 TI - Multiple physiological responses to multiple environmental challenges: an individual approach. AB - The injection of anthropogenically-produced CO2 into the atmosphere will lead to an increase in temperature and a decrease in pH at the surface of the oceans by 2100. Marine intertidal organisms possess the ability to cope in the short term with environmental fluctuations exceeding predicted values. However, how they will cope with chronic exposure to elevated temperature and pCO2 is virtually unknown. In addition, individuals from the same species/population often show remarkable levels of variation in their responses to complex climatic changes: in particular, variation in metabolic rates often is linked to differences in individuals' performances and fitness. Despite its ecological and evolutionary importance, inter-individual variation has rarely been investigated within the context of climatic changes, and most investigations have typically employed orthogonal experimental designs paired to analyses of independent samples. Although this is undoubtedly a powerful and useful approach, it may not be the most appropriate for understanding all alterations of biological functions in response to environmental changes. An individual approach arguably should be favored when trying to describe organisms' responses to climatic change. Consequently, to test which approach had the greater power to discriminate the intensity and direction of an organism's response to complex climatic changes, we investigated the extracellular osmo/iono-regulatory abilities, upper thermal tolerances (UTTs), and metabolic rates of individual adults of an intertidal amphipod, Echinogammarus marinus, exposed for 15 days to combined elevated temperature and pCO2. The individual approach led to stronger and different predictions on how ectotherms will likely respond to ongoing complex climatic change, compared with the independent approaches. Consequently, this may call into question the relevance, or even the validity, of some of the predictions made to date. Finally, we argue that treating individual differences as biologically meaningful can lead to a better understanding of the physiological responses themselves and the selective processes that will occur with complex climatic changes; selection will likely play a crucial role in defining species' responses to future environmental changes. Individuals with higher metabolic rates were also characterized by greater extracellular osmo/iono-regulative abilities and higher UTTs, and thus there appeared to be no evolutionary trade offs between these functions. However, as individuals with greater metabolic rates also have greater costs for maintenance and repair, and likely a lower fraction of energy available for growth and reproduction, trade-offs between life history and physiological performance may still arise. PMID- 23660591 TI - Effects of chronic ankle instability on energy dissipation in the lower extremity. AB - PURPOSE: This study aimed to investigate the influence of chronic ankle instability (CAI) on lower extremity joint energy dissipation patterns during a stop-jump task. METHODS: Nineteen participants with self-reported CAI and 19 healthy control participants volunteered. Participants performed five double-leg vertical stop-jump tasks onto a force plate. Lower extremity kinetics and kinematics were examined with an electromagnetic tracking system interfaced with a nonconductive force plate. Lower extremity joint energy dissipations were calculated for the hip, knee, and ankle in the sagittal plane during 50, 100, 150, and 200 ms after initial contact with the force plate. Energy dissipation values were normalized to the product of body mass and height [J . (N . m)(-1)]. Individual joint contribution to total lower extremity energy dissipation by the ankle, knee, and hip was reported as the percentage of energy dissipation by each joint over the total energy dissipation of all three joints. Independent t-tests and standard mean differences were conducted to assess differences in each dependent variable between the CAI and the control groups. Significance was set a priori at P < 0.05. RESULTS: The CAI group demonstrated significantly less percentage of knee energy dissipation (P = 0.04) and higher percentage of ankle energy dissipation (P = 0.035) of the total energy dissipation during the 100 ms immediately after initial contact compared with the control group. CONCLUSIONS: We found altered energy dissipation patterns at the knee and ankle during a stop jump task in the CAI group. These findings may provide insight into kinetic alterations that may be associated with CAI. Future research should consider this information as it may be used to develop more effective interventions to target these potentially modifiable energy dissipation patterns in those with CAI. PMID- 23660592 TI - Evaluation of the age of landfill gas methane in landfill gas-natural gas mixtures using co-occurring constituents. AB - At a municipal solid waste landfill in southern California (USA) overlying a natural gas reservoir, methane was detected at concentrations of up to 40% (by volume) in perimeter soil gas probes. Stable isotope and (14)C values of methane together with gas composition (major components and volatile organic compounds) data were evaluated to assess the relative contributions of landfill gas and natural gas to the measured methane concentrations. The data was further used to estimate the residence time of the landfill gas in the probes. Results showed that up to 37% of the measured methane was derived from landfill gas. In addition, the landfill gas in the probe samples has undergone extensive alteration due to dissolution of carbon dioxide in pore water. Data further indicates that the measured methane was released from the waste approximately 1.2 to 9.4 years ago, rather than representing evidence of an ongoing release. PMID- 23660593 TI - Research resource: small RNA-seq of human granulosa cells reveals miRNAs in FSHR and aromatase genes. AB - The granulosa cells in the mammalian ovarian follicle respond to gonadotropin signaling and are involved in the processes of folliculogenesis and oocyte maturation. Studies on gene expression and regulation in human granulosa cells are of interest due to their potential for estimating the oocyte viability and in vitro fertilization success. However, the posttranscriptional gene expression studies on micro-RNA (miRNA) level in the human ovary have been scarce. The current study determined the miRNA profile by deep sequencing of the 2 intrafollicular somatic cell types: mural and cumulus granulosa cells (MGCs and CGCs, respectively) isolated from women undergoing controlled ovarian stimulation and in vitro fertilization. Altogether, 936 annotated and 9 novel miRNAs were identified. Ninety of the annotated miRNAs were differentially expressed between MGCs and CGCs. Bioinformatic prediction revealed that TGFbeta, ErbB signaling, and heparan sulfate biosynthesis were targeted by miRNAs in both granulosa cell populations, whereas extracellular matrix remodeling, Wnt, and neurotrophin signaling pathways were enriched among miRNA targets in MGCs. Two of the nine novel miRNAs found were of intronic origin: one from the aromatase and the other from the FSH receptor gene. The latter miRNA was predicted to target the activin signaling pathway. In addition to revealing the genome-wide miRNA signature in human granulosa cells, our results suggest that posttranscriptional regulation of gene expression by miRNAs could play an important role in the modification of gonadotropin signaling. miRNA expression studies could therefore lead to new prognostic markers in assisted reproductive technologies. PMID- 23660594 TI - Transcriptional repression of AIB1 by FoxG1 leads to apoptosis in breast cancer cells. AB - The oncogene nuclear receptor coactivator amplified in breast cancer 1 (AIB1) is a transcriptional coactivator that is overexpressed in various types of human cancers. However, the molecular mechanisms controlling AIB1 expression in the majority of cancers remain unclear. In this study, we identified a novel interacting protein of AIB1, forkhead-box protein G1 (FoxG1), which is an evolutionarily conserved forkhead-box transcriptional corepressor. We show that FoxG1 expression is low in breast cancer cell lines and that low levels of FoxG1 are correlated with a worse prognosis in breast cancer. We also demonstrate that transient overexpression of FoxG1 can suppress endogenous levels of AIB1 mRNA and protein in MCF-7 breast cancer cells. Exogenously expressed FoxG1 in MCF-7 cells also leads to apoptosis that can be rescued in part by AIB1 overexpression. Using chromatin immunoprecipitation, we determined that FoxG1 is recruited to a region of the AIB1 gene promoter previously characterized to be responsible for AIB1 induced, positive autoregulation of transcription through the recruitment of an activating, multiprotein complex, involving AIB1, E2F transcription factor 1, and specificity protein 1. Increased FoxG1 expression significantly reduces the recruitment of AIB1, E2F transcription factor 1 and E1A-binding protein p300 to this region of the endogenous AIB1 gene promoter. Our data imply that FoxG1 can function as a pro-apoptotic factor in part through suppression of AIB1 coactivator transcription complex formation, thereby reducing the expression of the AIB1 oncogene. PMID- 23660595 TI - Chaperone properties of pdia3 participate in rapid membrane actions of 1alpha,25 dihydroxyvitamin d3. AB - Protein disulfide isomerase family A, member 3 (Pdia3) mediates many of the plasma membrane (PM)-associated rapid responses to 1alpha,25-dihydroxyvitamin D3 (1alpha,25[OH]2D3). It is not well understood how Pdia3, which is an endoplasmic reticulum (ER) chaperone, functions as a PM receptor for 1alpha,25(OH)2D3. We mutated 3 amino acids (K214 and R282 in the calreticulin interaction site and C406 in the isomerase catalytic site), which are important for Pdia3's ER chaperone function, and examined their role in responses to 1alpha,25(OH)2D3. Pdia3 constructs with and without the ER retention signal KDEL were used to investigate the PM requirement for Pdia3. Finally, we determined whether palmitoylation and/or myristoylation were required for Pdia3-mediated responses to 1alpha,25(OH)2D3. Overexpressing the Pdia3 R282A mutant in MC3T3-E1 cells increased PM phospholipase A2-activating protein, Rous sarcoma oncogene (c-Src), and caveolin-1 but blocked increases in 1alpha,25(OH)2D3-stimulated protein kinase C (PKC) seen in cells overexpressing wild-type Pdia3 (Pdia3Ovr cells). Cells overexpressing Pdia3 with K214A and C406S mutations had PKC activity comparable to untreated controls, indicating that the native response to 1alpha,25(OH)2D3 also was blocked. Overexpressing Pdia3[-KDEL] increased PM localization and augmented baseline PKC, but the stimulatory effect of 1alpha,25(OH)2D3 was comparable to that seen in wild-type cultures. In contrast, 1alpha,25(OH)2D3 increased prostaglandin E2 in Pdia3[+/-KDEL] cells. Although neither palmitoylation nor myristoylation was required for PM association of Pdia3, myristoylation was needed for PKC activation. These data indicate that both the chaperone functional domains and the subcellular location of Pdia3 control rapid membrane responses to 1alpha,25(OH)2D3. PMID- 23660597 TI - Stereotactic body radiation therapy for unbiopsied early-stage lung cancer: a multi-institutional analysis. AB - OBJECTIVES: Medically inoperable lung cancer patients often have comorbidities that preclude pathologic diagnosis from being attained. We perform a multi institutional analysis to determine if unbiopsied early-stage lung carcinoma can be safely and effectively treated with stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS: Thirty-four patients with unbiopsied lung cancer were treated with SBRT at the University of Louisville or University of Virginia. Patients had computed tomography (CT) and positron emission tomography (PET) imaging clinically consistent with lung malignancy. Median SBRT dose was 50 Gy (range, 30 to 55 Gy) in a median of 5 fractions (range, 3 to 10 fractions) with static field SBRT or volumetric modulated arc therapy. RESULTS: Median follow-up is 16.7 months. Primary tumors had a median longest dimension on the original CT of 1.6 cm (range, 0.5 to 3.3 cm) and posttreatment CT scan of 1.25 cm (range, 0.0 to 4.5 cm) (P=0.025). Median pretreatment standard uptake value on initial PET scan is 4.6 mg/mL (range, 0.0 to 16.2 mg/mL), and at a median of 7.6 months after SBRT, decreased to 2.25 mg/mL (range, 0.0 to 10.9 mg/mL) on posttreatment PET (P=0.002). Crude local control is 97.1%. The estimated 2-year regional control is 80%, distant control 85%, and overall survival 85%. There were no grade 3 or greater acute toxicities and only 3 grade 3 chronic treatment-related toxicitities. DISCUSSION: In medically inoperable patients with unbiopsied lung cancer, local control can be achieved with minimal toxicity with the use of SBRT. The use of SBRT for unbiopsied early-stage lung cancer patients should be performed in a multidisciplinary setting and after detailed discussion with the patient about the risks and benefits of SBRT. PMID- 23660596 TI - Preventing p38 MAPK-mediated MafA degradation ameliorates beta-cell dysfunction under oxidative stress. AB - The reduction in the expression of glucose-responsive insulin gene transcription factor MafA accompanies the development of beta-cell dysfunction under oxidative stress/diabetic milieu. Humans with type 2 diabetes have reduced MafA expression, and thus preventing this reduction could overcome beta-cell dysfunction and diabetes. We previously showed that p38 MAPK, but not glycogen synthase kinase 3 (GSK3), is a major regulator of MafA degradation under oxidative stress. Here, we examined the mechanisms of this degradation and whether preventing MafA degradation under oxidative stress will overcome beta-cell dysfunction. We show that under oxidative and nonoxidative conditions p38 MAPK directly binds to MafA and triggers MafA degradation via ubiquitin proteasomal pathway. However, unlike nonoxidative conditions, MafA degradation under oxidative stress depended on p38 MAPK-mediated phosphorylation at threonine (T) 134, and not T57. Furthermore the expression of alanine (A) 134-MafA, but not A57-MafA, reduced the oxidative stress-mediated loss of glucose-stimulated insulin secretion, which was independent of p38 MAPK action on protein kinase D, a regulator of insulin secretion. Interestingly, the expression of proteasomal activator PA28gamma that degrades GSK3-phosphorylated (including T57) MafA was reduced under oxidative stress, explaining the dominance of p38 MAPK over the GSK3 pathway in regulating MafA stability under oxidative stress. These results identify two distinct pathways mediating p38 MAPK-dependent MafA degradation under oxidative and nonoxidative conditions and show that inhibiting MafA degradation under oxidative stress ameliorates beta-cell dysfunction and could lead to novel therapies for diabetes. PMID- 23660598 TI - Israeli Dying Patient Act: physician knowledge and attitudes. AB - OBJECTIVES: The recently enacted Israeli Dying Patient Act was designed to strike balance between enhancing patient autonomy in end-of-life decision making and cultural/religious norms that are in opposition to active euthanasia and physician-assisted suicide (PAS). The current study evaluated physician attitudes regarding active and passive euthanasia, and their knowledge of specific aspects of the law. METHODS: A survey was administered to a convenience sample of hospital-based physicians treating terminal patients. Physicians were queried about their attitudes regarding euthanasia and PAS. Physicians were also queried about specific aspects of the law and whether they had sufficient resources to uphold the law. RESULTS: Surveys were distributed to 270 physicians and 100 were returned and evaluated (37%). Nearly all physicians supported passive euthanasia (withholding treatment), whereas over 40% maintained that active forms of euthanasia should be allowed for terminal patients in severe physical pain. Multivariate analysis showed a negative relationship between support for more active forms of euthanasia and physicians' self-reported religiosity. Physicians cited lack of time as a reason for not complying with the new law. Physicians had a familiarity with the general aspects of the new legislation, but a large proportion was not aware of the specifics of the law. CONCLUSIONS: Compared with previous surveys, a larger number of physicians support passive euthanasia. A sizable percentage of physicians would be willing to participate in active euthanasia and even PAS. Attitudes toward euthanasia are influenced by religious factors. PMID- 23660599 TI - N-(guanidinoethyl)-2'-deoxy-5-methylisocytidine exhibits selective recognition of a CG interrupting site for the formation of anti-parallel triplexes. AB - The development of novel nucleoside analogues for the formation of triplex DNA containing pyrimidine-purine inversion sites has been a challenging field. In this paper, we describe the design and synthesis of non-natural nucleoside analogues, N-substituted-2'-deoxy-5-methylisocytidine derivatives, and their evaluation for triplex formation. It has been shown that N-(guanidinoethyl)-2' deoxy-5-methylisocytidine exhibits selective recognition of a CG interrupting site and potentiates the formation of anti-parallel triplexes. PMID- 23660600 TI - Time-dependent effects of haloperidol on glutamine and GABA homeostasis and astrocyte activity in the rat brain. AB - RATIONALE: Schizophrenia is a severe, persistent, and fairly common mental illness. Haloperidol is widely used and is effective against the symptoms of psychosis seen in schizophrenia. Chronic oral haloperidol administration decreased the number of astrocytes in the parietal cortex of macaque monkeys (Konopaske et al., Biol Psych 63:759-765, 2008). Since astrocytes play a key role in glutamate metabolism, chronic haloperidol administration was hypothesized to modulate astrocyte metabolic function and glutamate homeostasis. OBJECTIVES: This study investigated the effects of chronic haloperidol administration on astrocyte metabolic activity and glutamate, glutamine, and GABA homeostasis. METHODS: We used ex vivo 13C magnetic resonance spectroscopy along with high-performance liquid chromatography after [1-13C]glucose and [1,2-13C]acetate administration to analyze forebrain tissue from rats administered oral haloperidol for 1 or 6 months. RESULTS: Administration of haloperidol for 1 month produced no changes in 13C labeling of glutamate, glutamine, or GABA, or in their total levels. However, a 6-month haloperidol administration increased 13C labeling of glutamine by [1,2 13C]acetate. Moreover, total GABA levels were also increased. Haloperidol administration also increased the acetate/glucose utilization ratio for glutamine in the 6-month cohort. CONCLUSIONS: Chronic haloperidol administration in rats appears to increase forebrain GABA production along with astrocyte metabolic activity. Studies exploring these processes in subjects with schizophrenia should take into account the potential confounding effects of antipsychotic medication treatment. PMID- 23660602 TI - RNA-DNA hybrid origami: folding of a long RNA single strand into complex nanostructures using short DNA helper strands. AB - Quick folding of a long RNA strand using short DNA staple strands (at a 1 : 1 ratio) into various pre-designed nanostructures in high yields has been demonstrated. PMID- 23660603 TI - Quantum dot self-decorated TiO2 nanosheets. AB - Quantum dot (TiO2) self-decorated and defect-free anatase nanosheets were fabricated by a long-time hydrothermal strategy and subsequent defect healing. Such decoration provides a new and effective charge transfer pathway over the nanosheet surface, leading to remarkably high photoactivity. PMID- 23660601 TI - Influence of polymorphisms in genes SLC1A1, GRIN2B, and GRIK2 on clozapine induced obsessive-compulsive symptoms. AB - RATIONALE: Clinical observations indicate that atypical antipsychotics, especially clozapine, induce obsessive-compulsive (OC) symptoms in schizophrenia patients. Recent data from neuroimaging and clinical trials suggest a role for altered glutamate neurotransmission in the etiology of OC disorder (OCD), and SLC1A1, GRIN2B, and GRIK2 have all been reported to regulate glutamate transmission and affect OCD pathophysiology. OBJECTIVES: This study aimed to determine whether SLC1A1, GRIN2B, and GRIK2 are associated with clozapine-induced OC symptoms. METHODS: A total of 250 clinically stable schizophrenia patients receiving clozapine treatment were recruited. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was used to evaluate the severity of OC symptoms. Based on their Y BOCS scores, 250 patients were divided into the OC and non-OC groups (patients with or without OC symptoms, respectively). Additionally, three reported OCD susceptibility polymorphisms, SLC1A1 (rs2228622), GRIN2B (rs890), and GRIK2 (rs1556995), were genotyped. RESULTS: Trends of association with OC symptoms were observed in rs2228622A and rs890T alleles. SLC1A1 and GRIN2B interaction was found in the significant two-locus gene-gene interaction model (p = 0.0021), using the multifactor dimensionality reduction method. Further analysis showed a significant interaction between SLC1A1 and GRIN2B on the Y-BOCS score (F 6, 137 = 7.650, p < 0.001), and individuals with AA/TT genotypes had a significantly higher mean Y-BOCS score than those with other genotypes, except AG/TT. CONCLUSIONS: These results suggest that SLC1A1, GRIN2B, and interactions between the two may potentially confer a susceptibility to OC symptoms in schizophrenia patients receiving clozapine. PMID- 23660604 TI - A Brazilian experience in assisted automated peritoneal dialysis: reliable option or just a palliative therapy? PMID- 23660605 TI - Peritoneal dialysis and the process of modality selection. AB - The process of modality selection and how it works is a critical determinant of peritoneal dialysis (PD) utilization. This very complex process has not been well analyzed. Here, we break it down into 6 steps and point out how problems at each step can significantly reduce the proportion of endstage renal disease patients initiating PD. It is important that any program wishing it to grow its use of PD understand the steps and the points at which problems may be arising. Examples are presented. PMID- 23660606 TI - A Brazilian experience in assisted automated peritoneal dialysis: a reliable and effective home care approach. AB - INTRODUCTION: Automated assisted peritoneal dialysis (AAPD) has been shown to be successful as renal replacement therapy for elderly and physically incapable end stage renal disease (ESRD) patients. In early 2003, a pioneer AAPD program was initiated at GAMEN Renal Clinic in Rio de Janeiro, Brazil. ? OBJECTIVE: We evaluated the results of an AAPD program offered as an option to elderly ESRD patients with physical or cognitive debilities or as last resort to patients with vascular access failure or hemodynamic instability during hemodialysis. ? METHODS: A cohort of 30 consecutive patients started AAPD from January 2003 to March 2008 and was followed to July 2009. Demographics, clinical and laboratory parameters, causes of death, and patient and technique survival were analyzed. ? RESULTS: Median age of the patients was 72 years (range: 47 - 93 years), with 60% being older than 65. The Davies score was greater than 2 in 73% of patients, and the Karnofsky index was less than 70 in 40%. The overall peritonitis rate was 1 episode in 37 patient-months. The total duration of AAPD ranged from 3 to 72 months. Patient survival was 80% at 12 months, 60% at 24 months, and 23.3% at 48 months. The most common cause of death was cardiovascular problems (70%). ? CONCLUSIONS: In this clinical observational study, AAPD fulfilled its expected role, offering an opportune, reliable, and effective homecare alternative for ESRD patients with no other renal replacement therapy options. PMID- 23660607 TI - Peritoneal cocoon capsulotomy--an alternative surgical approach in treating encapsulating peritoneal sclerosis. PMID- 23660608 TI - Peritoneal dialysis: the great savior during disasters. PMID- 23660609 TI - Unusual exit site of a migrated peritoneal dialysis catheter. PMID- 23660610 TI - Rhizobium radiobacter peritonitis revisited: catheter removal is not mandatory. PMID- 23660611 TI - Chylous ascites because of intravenous infusion of long-chain fatty acids. PMID- 23660612 TI - Chyloperitoneum in pediatric peritoneal dialysis: rapid remission after introduction of medium-chain triglyceride-based formula. PMID- 23660613 TI - Peritoneal dialysis peritonitis caused by Enterococcus avium. PMID- 23660614 TI - Citrobacter youngae and Pantoea agglomerans peritonitis in a peritoneal dialysis patient. PMID- 23660615 TI - First documented case of endometrial carcinoma in a patient treated with tamoxifen for encapsulating peritoneal sclerosis. PMID- 23660616 TI - Sterile peritonitis because of splenic infarction in a patient on peritoneal dialysis: an unusual presentation. PMID- 23660617 TI - An unusual case of peritoneal dialysis catheter extrusion. PMID- 23660619 TI - The relationship between postpartum depression, domestic violence, childhood violence, and substance use: epidemiologic study of a large community sample. AB - The objective of this study was to determine the contribution of interpersonal violence and substance use to the prediction of postpartum depressive symptomatology. A community-based sample of 634 women in British Columbia, Canada was screened for interpersonal violence and substance use using the Antenatal Psychosocial Health Assessment (ALPHA) form. Of these women, 497 (78%) subsequently completed questionnaires at 8 weeks postpartum to assess for depressive symptomatology using the Edinburgh Postnatal Depression Scale (EPDS). A predictive model for postpartum depressive symptomatology (EPDS > 9) was developed using regression analysis. Findings suggest that women who experience past or current interpersonal violence or personal or partner substance use problems should be considered for targeted screening for postpartum depression (PPD). PMID- 23660618 TI - Trichosporon mucoides peritonitis in a continuous ambulatory peritoneal dialysis patient. PMID- 23660620 TI - Increased leukocyte Rho-kinase activity in a population with acute coronary syndrome. AB - Accumulating evidence suggests that Rho-associated kinase (ROCK) may be important in the pathogenesis of atherosclerosis and coronary vasospasm. In the present study, we investigated whether ROCK activity is increased in acute coronary syndrome (ACS) patients. Twenty-one patients with ACS (12 males, mean age 58.0+/ 8.0 years) and 20 control subjects (10 males, mean age 55.0+/-6.0 years) were enrolled. Blood samples were obtained and demographics were recorded. Peripheral leukocyte ROCK activity was determined by the ratio of phospho-myosin-binding subunit (P-MBS) on myosin light-chain phosphatase to total MBS. Compared with the control subjects, ROCK activity was significantly increased in ACS patients (0.69+/-0.07 vs. 0.45+/-0.04, P<0.001). There was no apparent correlation between the lipid levels (total cholesterol and low-density lipoprotein) and ROCK activity (r=0.17, P>0.05; r=0.08, P>0.05; respectively). However, ROCK activity correlated with mean arterial pressure (r=0.58; P<0.01). ROCK activity is increased in ACS patients indicating that this may be a novel serological marker of ACS. PMID- 23660621 TI - Reversed crystal growth of ZnO microdisks. AB - Hexagonal ZnO microdisks are grown and then selectively dissolved to form microstadiums. Analysis of the growth and dissolution of the microdisks revealed that they follow a reversed crystal growth mechanism, i.e. aggregation of precursors followed by surface crystallization and extension of crystallization from the surface to the core. PMID- 23660622 TI - Control of molecular orientations of poly(3-hexylthiophene) on self-assembled monolayers: molecular dynamics simulations. AB - We theoretically investigate the energetically favorable orientation of poly(3 hexylthiophene) (P3HT) on self-assembled monolayers (SAMs) using molecular dynamics simulations. The effects of different kinds of SAMs are studied by examining a CH3-terminated SAM with a hydrophobic surface and an NH2-terminated SAM with a hydrophilic surface. We also investigate dynamic behavior of the systems with limited numbers of P3HT molecules on the SAM surfaces. The important factors in controlling the molecular orientation are elucidated from these results. We demonstrate that the edge-on orientation is more energetically favorable than the face-on orientation on both SAMs. On the other hand, the face on orientation gains more intermolecular interaction energy between the P3HT molecules and the SAMs. This energy gain is larger in the NH2-terminated SAM than the CH3-terminated SAM. A limited number of P3HT molecules prefer to take the face-on orientation rather than the edge-on orientation. Our theoretical results suggest that the molecular orientation of P3HT is controllable by tuning the conditions of the film formation process and the intermolecular interactions between the P3HT molecules and SAMs. PMID- 23660624 TI - Cutaneous T cell lymphoma cells are targets for immune checkpoint ligand PD-L1 specific, cytotoxic T cells. PMID- 23660623 TI - Development of a multiplex phenotypic cell-based high throughput screening assay to identify novel hepatitis C virus antivirals. AB - Hepatitis C virus (HCV) infection is a global health concern with chronic liver damage threatening 3% of the world's population. To date, the standard of care is a combination of pegylated interferon-alpha with ribavirin, and recently two direct acting antivirals have entered the clinics. However, because of side effects, drug resistance and viral genotype-specific differences in efficacy current and potentially also future therapies have their limitations. Here, we describe the development of a phenotypic high-throughput assay to identify new cross-genotype inhibitors with novel mechanism of action, by combining a genotype (gt) 1 replicon with the infectious HCV gt2 cell culture system. To develop this phenotypic multiplex assay, HCV reporter cells expressing RFP-NLS-IPS and gt1b replicon cells expressing NS5A-GFP were co-plated and treated with compounds followed by inoculation with gt2a HCV. At 72h post treatment, RFP translocation as a marker for HCV infection and GFP fluorescence intensity as a marker for gt1 RNA replication were measured. Additionally, the total cell number, which serves as an indicator of cytotoxicity, was determined. This phenotypic strategy supports multi-parameter data acquisition from a single well to access cross genotypic activity, provides an indication of the stage of the viral life cycle targeted, and also assesses compound cytotoxicity. Taken together, this multiplex phenotypic platform facilitates the identification of novel compounds for drug development and chemical probes for continuing efforts to understand the HCV life cycle. PMID- 23660625 TI - Penetration of projectiles into granular targets. AB - Energetic collisions of subatomic particles with fixed or moving targets have been very valuable to penetrate into the mysteries of nature. But the mysteries are quite intriguing when projectiles and targets are macroscopically immense. We know that countless debris wandering in space impacted (and still do) large asteroids, moons and planets; and that millions of craters on their surfaces are traces of such collisions. By classifying and studying the morphology of such craters, geologists and astrophysicists obtain important clues to understand the origin and evolution of the Solar System. This review surveys knowledge about crater phenomena in the planetary science context, avoiding detailed descriptions already found in excellent papers on the subject. Then, it examines the most important results reported in the literature related to impact and penetration phenomena in granular targets obtained by doing simple experiments. The main goal is to discern whether both schools, one that takes into account the right ingredients (planetary bodies and very high energies) but cannot physically reproduce the collisions, and the other that easily carries out the collisions but uses laboratory ingredients (small projectiles and low energies), can arrive at a synergistic intersection point. PMID- 23660626 TI - Application of mass spectrometric techniques to delineate the modes-of-action of anticancer metallodrugs. AB - Mass spectrometry (MS) has emerged as an important tool for studying anticancer metallodrugs in complex biological samples and for characterising their interactions with biomolecules and potential targets on a molecular level. The exact modes-of-action of these coordination compounds and especially of next generation drug candidates have not been fully elucidated. Due to the fact that DNA is considered a crucial target for platinum chemotherapeutics, metallodrug DNA binding studies dominated the field for a long time. However, more recently, alternative targets were considered, including enzymes and proteins that may play a role in the overall pharmacological and toxicological profile of metallodrugs. This review focuses on MS-based techniques for studying anticancer metallodrugs in vivo, in vitro and in situ to delineate their modes-of-action. PMID- 23660627 TI - B7-H4 enhances oncogenicity and inhibits apoptosis in pancreatic cancer cells. AB - B7-H4 is expressed in a variety of tumor cells and functions as a negative regulator of T cells. However, clarification is needed as to whether B7-H4 mediates tumorigenesis through mechanisms, such as apoptosis, in addition to mediating tumor immune escape. We investigate the mechanisms involved in enhanced oncogenicity and the inhibition of apoptosis by B7-H4 in pancreatic cancer cells. Short interfering RNAs (siRNAs) specific for B7-H4 were evaluated for their ability to knockdown B7-H4 mRNA and protein expression in pancreatic cancer cells and the most effective siRNA was selected for investigating the effect of B7-H4 gene silencing in a number of functional assays. The inhibition of B7-H4 increased cell-cell adhesion and decreased the formation of pseudopodia. It also increased the expression of E-cadherin and decreased the expression of vimentin and CD44. B7-H4 siRNA inhibited cell proliferation, colony formation and migration of pancreatic cancer cells. Moreover, increased apoptosis in pancreatic cancer cells following B7-H4 silencing was demonstrated in vitro by using flow cytometry and in a xenograft tumor model and was associated with increased caspase activity and decreased Erk1/2 phosphorylation both in vitro and in vivo. Loss of B7-H4 function thus prevents tumor growth through many processes, including the induction of apoptosis and inhibition of the Erk1/2 signaling pathway indicating that B7-H4 is a cancer promoter and a potentially important therapeutic target. B7-H4 inhibition might offer an exciting opportunity to inhibit the progression of human pancreatic cancers. PMID- 23660628 TI - Correlation between eight-gene expression profiling and response to therapy of newly diagnosed multiple myeloma patients treated with thalidomide-dexamethasone incorporated into double autologous transplantation. AB - We performed a molecular study aimed at identifying a gene expression profile (GEP) signature predictive of attainment of at least near complete response (CR) to thalidomide-dexamethasone (TD) as induction regimen in preparation for double autologous stem cell transplantation in 112 younger patients with newly diagnosed multiple myeloma. A GEP supervised analysis was performed on a training set of 32 patients, allowing to identify 157 probe sets differentially expressed in patients with CR versus those failing CR to TD. We then generated an eight-gene GEP signature whose performance was subsequently validated in a training set of 80 patients. A correct prediction of response to TD was found in 71 % of the cases analyzed. The eight genes were downregulated in patients who achieved CR to TD. Comparisons between post-autotransplantation outcomes of the 44 non-CR predicted patients and of the 36 CR-predicted patients showed that this latter subgroup had a statistically significant benefit in terms of higher rate of CR after autotransplant(s) and longer time to progression, event-free survival, and overall survival. These results can be an important first step to identify at diagnosis those patients who will respond more favourably to a particular treatment strategy. PMID- 23660629 TI - The clinical importance of moderate/severe bone marrow fibrosis in patients with therapy-related myelodysplastic syndromes. AB - The presence of moderate to severe bone marrow (BM) fibrosis has been shown to be an adverse feature in patients with primary myelodysplastic syndromes (MDS). However, the clinical importance of BM fibrosis is not clear in therapy-related MDS. We retrieved all therapy-related MDS (t-MDS) cases (n = 266) diagnosed at our hospital over a 10-year period (2003-2012). Reticulin and trichrome stains were performed in cases in which BM fibrosis was suspected on initial evaluation of hematoxylin and eosin-stained slide. BM fibrosis was graded according to European consensus guidelines, and a score of MF2/MF3 was defined as moderate/severe fibrosis. Moderate/severe BM fibrosis was found in 47 (17%) patients. Compared to 219 patients with no/mild BM fibrosis, the patients with moderate/severe fibrosis presented with severer thrombocytopenia (p = 0.039) and higher numbers of circulating blasts (p = 0.051) but with similar degrees of anemia and neutropenia, transfusion requirements, and similar incidences of hepatosplenomegaly and constitutional symptoms. Histological examination revealed a comparable BM cellularity and BM blast percentage, but markedly increased megakaryocytes (p < 0.001) in the fibrotic group. Although the risk distribution of cytogenetic data was similar according to the New Comprehensive Cytogenetic Scoring criteria, -5 and -17 were more frequently observed in t-MDS with moderate/severe BM fibrosis (p = 0.031 and p = 0.043, respectively). With a median follow-up of 11.5 months, patients with moderate/severe BM fibrosis showed a similar risk of acute myeloid leukemia transformation and a comparable overall survival in univariate and multivariate analyses. Moderate/severe BM fibrosis in patients with t-MDS is associated with certain clinicopathological and genetic features. However, unlike the situation in patients with primary MDS, moderate/severe BM fibrosis does not add additional risk to patients with therapy related MDS. PMID- 23660630 TI - Musical expertise affects attention as reflected by auditory-evoked gamma-band activity in human EEG. AB - Musical expertise has been shown to induce widespread structural and functional alterations in the brain, even-handedly affecting top-down and bottom-up factors. At the same time, it is known that the early evoked gamma-band response (GBR) can be modulated by top-down as well as bottom-up factors such as attention and sound intensity. In this study, we examined the effects of musicianship and attention on the intensity modulation of the auditory-evoked GBR. We compared the electroencephalogram of 17 professional musicians with that of 17 musical laymen obtained during either a forced-choice discrimination task (active) or a passive listening condition. Pure 1000 Hz sine tones were presented at three systematically varied sound intensities (40, 60, and 80 dB sound pressure levels). The results of auditory-evoked potentials and evoked GBRs obtained in the active condition predominantly corresponded to the findings of previous studies. Besides the already known augmentation of the early evoked GBR because of enhanced intertrial phase coherence with increasing sound intensity, we also observed stronger GBRs and enhanced phase locking under the active condition compared with passive listening, whereas the general shape of intensity modulation was comparable between the two conditions. In addition, phase locking to stimulus onset was increased for stimuli of all three intensities when attended, whereas in musicians, only stimuli of the highest intensity (80 dB) induced significantly increased phase locking under the active condition. Taken together, our results suggest that musical expertise influences attention effects on the intensity-modulated early auditory-evoked GBR with respect to intertrial phase coherence. PMID- 23660631 TI - Influence of stimulation intensity on paired-pulse suppression of human median nerve somatosensory evoked potentials. AB - Paired-pulse stimulation, the application of two stimuli in close succession, is a useful tool to investigate cortical excitability. Suppression of the second response after short interstimulus intervals characterizes paired-pulse behavior. Although paired-pulse suppression is often studied as a marker of cortical excitability in humans, little is known about the influence of stimulation intensity on paired-pulse suppression. To systematically explore the effect of stimulus intensity on paired-pulse suppression of median nerve somatosensory evoked potentials (MNSEPs), we recorded single-pulse or paired-pulse MNSEPs in healthy volunteers using stimulation intensities ranging from the sensory threshold to 1.2 times the motor threshold using interstimulus intervals of 10, 30, and 100 ms. Of the various somatosensory evoked potential components, only the N20-P25 component showed an effect of intensity, where higher intensities resulted in stronger paired-pulse suppression. However, when only intermediate intensities were considered, paired-pulse suppression was not or only weakly influenced. Our data suggest that stimulation intensity in contrast to single pulse-evoked MNSEPs has only a weak influence on the paired-pulse suppression of early MNSEPs. Paired-pulse suppression is believed to arise from inhibition generated by intracortical networks. The lack of intensity dependence within the range tested can be considered as a step toward creating invariance against fluctuations of stimulus intensity. Thus, intracortical computations as apparent in paired-pulse behavior might be characterized by different properties compared with feed-forward processing. PMID- 23660632 TI - Sex matters: n-back modulates emotional mismatch negativity. AB - This work investigates the impact of task load on irrelevant emotional voice processing between the sexes. The working memory task was manipulated by asking participants to evaluate the position of a visual stimulus (0-back) and compare the position of the current stimulus with the one or two trials before (1-back and 2-back). We recorded auditory event-related potentials while presenting the emotionally spoken syllables 'dada' and acoustically matched nonvocal sounds to healthy adults. Women, not men, showed larger amplitudes of emotional mismatch negativity (MMN), presumed to reflect preattentive auditory change detection, during the 1-back task than the 0-back and 2-back tasks. Among women only weaker emotional MMN amplitudes were associated with a higher 2-back accuracy. Neither task difficulty nor sex had any effect on MMN when responding to nonvocal sounds. Our findings suggest that there are sex differences in preattentive emotional voice processing under varying levels of task load. PMID- 23660633 TI - No association of SORT1 gene polymorphism with sporadic Alzheimer's disease in the Chinese Han population. AB - Increasing evidence shows that sortilin (encoded by SORT1 gene), a member of the vacuolar protein sorting 10 family of sorting receptors, can modulate amyloid beta peptides (Abeta) metabolism and clearance, as well as mediate the neurotoxicity of the Abeta oligomer and proneurotrophins, thus playing diverse roles in the pathogenesis of Alzheimer's disease. To assess the association between single nucleotide polymorphism (SNP) of the SORT1 gene and sporadic Alzheimer's disease (sAD) in the Chinese Han population, a case-control study was carried out including 220 sAD patients and 245 controls. One tag SNP was selected from the entire SORT1 gene through construction of linkage disequilibrium blocks, and three SNPs located in the vicinity of SORT1 that affect its expression were also selected. The four target SNPs were genotyped using a multiplex PCR-ligase detection reaction method, yielding no significant association between them or haplotypes containing three of them, and the risk of sAD. The results of this study indicate that polymorphisms of the SORT1 gene are unlikely to confer the risk of sAD in the Chinese Han population. PMID- 23660634 TI - Pertussis toxin attenuates experimental autoimmune encephalomyelitis by upregulating neuronal vascular endothelial growth factor. AB - We have reported earlier that pertussis toxin (PTx) attenuates the motor deficits in experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis. PTx protects neurons from inflammatory insults. Vascular endothelial growth factor (VEGF) is also neuroprotective. However, the effect of PTx on VEGF has never been studied. We investigated whether PTx modulates neuronal VEGF expression and how it affects the pathogenesis of EAE. EAE was induced by injecting myelin oligodendrocyte glycoprotein 35-55 peptides with adjuvants into C57BL/6 mice. Clinical scores of EAE were evaluated daily for 19 days. Brain and spinal cord samples were collected and assessed for inflammation and demyelination. VEGF, NeuN for neurons, and Caspase-3 for apoptosis were stained for localization using immunohistochemistry techniques, followed by western blot analysis for quantification. Primary neurons were cultured to assess the direct effect of PTx on neuronal VEGF expression. PTx treatment increases neuronal VEGF expression by up to ~75% in vitro and ~60% in vivo, preventing neurons from apoptosis. This leads to resolution in inflammation and remyelination and amendment in motor deficits. Our findings suggest that upregulation of endogenous neuronal VEGF by PTx protects motor deficits in EAE and it is a potential therapeutic option for multiple sclerosis. PMID- 23660635 TI - The developmental regulation of glutamate receptor-mediated calcium signaling in primary cultured rat hippocampal neurons. AB - We have studied the developmental changes of glutamate-induced calcium (Ca2+) response in primary cultured hippocampal neurons at three different stages of cultures, 3, 7-8, and 14-16 days in vitro (DIV), using fura-2 single-cell digital micro-fluorimetry. We found that glutamate-induced Ca2+ signaling was altered during development, and that two different ionotropic glutamate receptors, alpha amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPARs) and N-methyl-D aspartate receptors (NMDARs), were differently involved in the modulation of calcium response at different stages of neuronal culture. In the stages of culture at 3 and 8 DIV, glutamate-induced Ca2+ influx was mostly because of AMPAR activation and subsequent opening of voltage-dependent calcium channels, as Ca2+ response can be largely reduced by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and by nifedipine. In the advanced culture (14-17 DIV), glutamate-induced Ca2+ response was less sensitive to 6-cyano-7-nitroquinoxaline-2,3-dione and nifedipine. Furthermore, AMPA-induced Ca2+ response increased in a time-dependent manner during the cultures of 3-8 DIV and then reduced in the advanced culture of 14-17 DIV. NMDA-induced Ca2+ influx increased in a time-dependent manner, with a marked increase in the advanced culture (14-17 DIV). These results suggest that glutamate-induced Ca2+ signaling switched from AMPA-voltage-dependent calcium channel to NMDA-calcium signaling during development. PMID- 23660637 TI - Livedo and ischemic strokes: diagnostic hints of a rare condition. PMID- 23660636 TI - Percutaneous transluminal angioplasty for chronic cerebrospinal venous insufficiency in multiple sclerosis: dichotomy between subjective and objective outcome scores. AB - Some multiple sclerosis (MS) patients reported an improvement after percutaneous transluminal angioplasty (PTA) for chronic cerebrospinal venous insufficiency (CCSVI), despite the lack of correspondence with objective outcome scores. The objective was to assess neurologic and quality of life scores before and after PTA for CCSVI in an observational study after a self-decided approach. 44 consecutive MS patients (21/23 M/F; median age 43 years, SD 9.8) who underwent PTA were evaluated before endovascular treatment for CCSVI and after 12 months. Neurologic outcome was assessed with EDSS, the annualized relapse rate (ARR) and frequency of new lesions at MRI after PTA. Quality of life was evaluated through the MSQoL-54 questionnaire. No modification in the ARR (p = 0.829), worsening of disability status (p = 0.002) and new lesions at MRI in 29.6 % of patients were found, in contrast to an improvement both in physical and mental domains of MSQoL 54 (p = 0.003). Multiple logistic regression showed EDSS score before PTA to be predictor of an increase of >10 points in MSQoL-54 mental domain (OR 0.52, 95 % CI, 0.31-0.89, p = 0.018). Spontaneously performed approach to CCSVI does not improve clinical and MRI parameters, despite frequent subjective perception of quality of life improvement. PMID- 23660638 TI - Near fixation of 374l allele frequencies of the skin pigmentation gene SLC45A2 in Africa. AB - The L374F polymorphism of the SLC45A2 gene, encoding the membrane-associated transporter protein that plays an important role in melanin synthesis, has been suggested to be associated with skin color in human populations. In this study, the detailed distribution of the 374f and 374l alleles has been investigated in 2,581 unrelated subjects from 36 North, East, West, and Central African populations. We found once more the highly significant (p < 0.001) correlation coefficient (r = 0.957) cline of 374f frequencies with degrees of latitude in European and North African populations. Almost all the African populations located below 16 degrees of latitude are fixed for the 374l allele. Peul, Toucouleur, and Soninke populations have 374l allele frequencies of 0.06, 0.03, and 0.03, respectively. PMID- 23660639 TI - Advanced in vivo applications of blue light photoreceptors as alternative fluorescent proteins. AB - The ultimate ambition in cell biology, microbiology and biomedicine is to unravel complex physiological and pathophysiological processes within living organisms. To conquer this challenge, fluorescent proteins (FPs) are used as versatile in vivo reporters and biosensors to study gene regulation as well as the synthesis, localization and function of proteins in living cells. The most widely used FPs are the green fluorescent protein (GFP) and its derivatives and relatives. Their use as in vivo reporter proteins, however, is sometimes restricted by different environmental and cellular factors. Consequently, a whole range of alternative, cofactor-dependent reporter proteins have been developed recently. In this perspective, we summarize the advantages and limitations of the novel class of cyan-green fluorescent flavoproteins in comparison to members of the GFP family and discuss some correlated consequences for the use of FPs as in vivo reporters. PMID- 23660640 TI - Effect of polyunsaturated fatty acids on tight junctions in a model of the human intestinal epithelium under normal and inflammatory conditions. AB - Owing to their immune-modulatory action on the intestinal mucosa immune cells, the n-3 and n-6 polyunsaturated fatty acids (PUFA) have been suggested to modulate the risk and development of inflammatory bowel diseases. Failure in the intestinal barrier is an important hallmark of inflammatory bowel diseases. This study aimed at evaluating the impact of dietary PUFA on tight junction protein localisation and on the modulation of epithelial permeability under physiological conditions or under an inflammatory stress. For this purpose, we first confirmed the accumulation of PUFA in phospholipid fractions of Caco-2 cells upon 7 days of incubation with specific PUFA. Thereafter, Caco-2 cells were cultured in inserts, which provide a model of the human intestinal barrier. Accumulation of dietary n 3 PUFA in phospholipids did not affect the presence of occludin in tight junction complexes, while that of dietary n-6 PUFA decreased it. Whatever the PUFA, at 30 MUM, no distortion of the Caco-2 barrier function was observed. Otherwise, 150 MUM of docosahexaenoic acid (DHA) affected ZO-1 intensity under normal conditions, but not occludin or the barrier function parameters. Finally, to simulate an inflammatory state, cells were exposed for 24 h to interleukin-1beta, tumor necrosis factor-alpha, interferon-gamma at their basolateral side and to lypopolysaccharides at both sides. DHA limited the effect of inflammatory stimulus on occludin, ZO-1 and barrier function. In conclusion, this study has evidenced the specific effect of individual PUFA to modulate occludin and ZO-1 localization, according to the inflammatory status of this in vitro model of the intestinal barrier. PMID- 23660641 TI - Effects of medical therapies for acromegaly on glucose metabolism. AB - OBJECTIVE: Abnormalities of glucose metabolism are common findings of acromegaly. However, robust evidence on whether therapy with somatostatin analogs (SSAs) or pegvisomant (PEG) differently affects glucose metabolism is lacking. The purpose of this study was to evaluate the effects of therapy with SSAs, PEG, or their combination on glucose metabolism in a large series of acromegalic patients. DESIGN: This was a historical-prospective study. Among 50 consecutive acromegalic patients under SSA therapy, acromegaly in 19 patients was controlled. PEG used in combination with SSA therapy allowed the control of acromegaly in the remaining 31 patients and was then continued as monotherapy in 18 patients. METHODS: The following parameters were evaluated at the diagnosis of acromegaly and during DIFFERENT TREATMENTS: fasting plasma glucose (FPG) and insulin concentrations, insulin sensitivity (QUICK-I), homeostasis model assessment of insulin resistance (HOMA2-IR), and plasma glucose and insulin concentrations during the oral glucose tolerance test (OGTT). Comparison was made using analysis for paired data. RESULTS: Insulin resistance improved when acromegaly was controlled with therapy with SSAs, PEG, or SSA+PEG. However, FPG concentrations were higher during SSA therapy (alone or combined with PEG) than at the diagnosis of acromegaly, even when corrected for disease activity, whereas they were reduced during PEG therapy. Mean glucose concentrations during the OGTT were higher in patients receiving SSA therapy than in those receiving PEG therapy. In addition, the prevalence of diabetes or impaired glucose tolerance was higher during SSA therapy than at diagnosis or during PEG therapy and was not influenced by disease control. CONCLUSIONS: Medical therapies for acromegaly reduce insulin resistance and increase insulin sensitivity; on the contrary, glucose indexes may be differently affected by SSA or PEG therapy. PMID- 23660642 TI - Simultaneous expression analysis of vitamin D receptor, calcium-sensing receptor, cyclin D1, and PTH in symptomatic primary hyperparathyroidism in Asian Indians. AB - BACKGROUND: To explore underlying molecular mechanisms in the pathogenesis of symptomatic sporadic primary hyperparathyroidism (PHPT). MATERIALS AND METHODS: Forty-one parathyroid adenomas from patients with symptomatic PHPT and ten normal parathyroid glands either from patients with PHPT (n=3) or from euthyroid patients without PHPT during thyroid surgery (n=7) were analyzed for vitamin D receptor (VDR), calcium-sensing receptor (CASR), cyclin D1 (CD1), and parathyroid hormone (PTH) expressions. The protein expressions were assessed semiquantitatively by immunohistochemistry, based on percentage of positive cells and staining intensity, and confirmed by quantitative real-time PCR. RESULTS: Immunohistochemistry revealed significant reductions in VDR (both nuclear and cytoplasmic) and CASR expressions and significant increases in CD1 and PTH expressions in adenomatous compared with normal parathyroid tissue. Consistent with immunohistochemistry findings, both VDR and CASR mRNAs were reduced by 0.36- and 0.45-fold change (P<0.001) and CD1 and PTH mRNAs were increased by 9.4- and 17.4-fold change respectively (P<0.001) in adenomatous parathyroid tissue. PTH mRNA correlated with plasma PTH (r=0.864; P<0.001), but not with adenoma weight, while CD1 mRNA correlated with adenoma weight (r=0.715; P<0.001). There were no correlations between VDR and CASR mRNA levels and serum Ca, plasma intact PTH, or 25-hydroxyvitamin D levels. In addition, there was no relationship between the decreases in VDR and CASR mRNA expressions and the increases in PTH and CD1 mRNA expressions. CONCLUSIONS: The expression of both VDR and CASR are reduced in symptomatic PHPT in Asian Indians. In addition, CD1 expression was greatly increased and correlated with adenoma weight, implying a potential role for CD1 in adenoma growth and differential clinical expression of PHPT. PMID- 23660643 TI - Mortality outcomes of different sulphonylurea drugs: the results of a 14-year cohort study of type 2 diabetic patients. AB - OBJECTIVE: Available data about mortality of type 2 diabetic patients treated with different sulphonylureas are scarce and contradictory. DESIGN: We evaluated the associations between all-cause and cause-specific mortality and treatments with different sulphonylureas in a retrospective cohort of type 2 diabetic patients from a diabetes clinic. METHODS: All 1277 patients treated with sulphonylureas during 19961997 were enrolled: 159 patients were treated with tolbutamide, 977 glibenclamide and 141 gliclazide. The baseline data (centralised laboratory parameters, anthropometric data and presence of chronic complications) were abstracted from the clinical records. Information on vital status was collected from demographic files after 14-year follow-up. Adjusted hazard ratios (HR) were estimated with Cox (all-cause mortality) or Fine and Gray models (cause specific mortality), including several potential confounders. RESULTS: Five hundred and fifty-six patients died during the follow-up: 262 from cardiovascular causes, 158 from cancer and 136 from other causes. When compared with the glibenclamide users, the gliclazide and tolbutamide users showed a significantly lower cancer mortality (HR=0.30; 95% CI 0.16-0.55, and HR=0.48; 95% CI 0.29-0.79 respectively). These results were strongly confirmed in the 555 patients on sulphonylurea monotherapy. None of the patients who were treated with gliclazide monotherapy died from cancer during the follow-up, and the patients on tolbutamide treatment exhibited a lower cancer mortality than the glibenclamide users (HR=0.40; 95% CI 0.22-0.71). Data did not change after stratification for the duration of sulphonylurea treatment from diabetes diagnosis to the study enrollment. CONCLUSIONS: Cancer mortality was markedly reduced in the patients on gliclazide and tolbutamide treatment. These results suggest additional benefits for these drugs beyond their blood glucose-lowering effect and strongly advocate for further investigation. PMID- 23660645 TI - Enantioselective pharmacodynamics of propranolol in HUVEC cells: a study using chiral 2D gel electrophoresis and mass spectrometry. AB - Propranolol (PRO), a nonselective beta-adrenergic receptor (beta-AR) antagonist, has two enantiomers, R(+)-PRO and S(-)-PRO, which have diverse biological effects. For example, S(-)-PRO blocks the beta-receptor ~100 times more strongly than R(+)-PRO. However, the signaling pathway that causes this difference remains unclear. This pathway may affect the expression of numerous proteins, some of which play key roles during the drug action process. Therefore, we treated human umbilical vein endothelial cells (HUVECs) with R(+)-PRO and S(-)-PRO in order to identify differentially expressed proteins and to determine their functions in the drug action process. Of the 22 differentially expressed protein spots investigated, 14 demonstrated higher expression levels in the R(+)-PRO-treated cells, while 8 demonstrated lower expression levels in the same cells. Mass spectrometry identified 10 of the differentially expressed proteins: 4 signaling molecules, 2 metabolic enzymes, 3 heat shock proteins and 1 cytoskeleton protein. Our results suggest that these differentially expressed proteins, particularly guanine nucleotide-binding protein subunit beta-2-like 1 (GBLP), are the key biomacromolecules underlying the mechanism by which PRO enantiomers induce stereoselective cellular responses. The results aid in clarifying the role of PRO in the treatment of arrhythmia and angina. PMID- 23660646 TI - Collective efficacy and HIV prevention in South African townships. AB - South African townships have high HIV prevalence and a strong need for collective action to change normative sexual risk behaviors. This study investigated the relationship between perceptions of individuals about collective efficacy in the community's ability to prevent HIV and their personal HIV risk behaviors. Men (n = 1,581) and women (n = 718) completed anonymous surveys within four Black African Townships in Cape Town, South Africa from June 2008 to December 2010. Measures included demographics, alcohol use, attitudinal and behavioral norms, sexual health communications, and sexual risk behaviors. In multivariate logistic regressions, men were more likely to endorse collective efficacy if they were married, drank less often in alcohol serving establishments, believed that fewer men approve of HIV risk behaviors, talk more with others about HIV/AIDS, and had more sex partners in the past month. Women were more likely to endorse collective efficacy if they drank alcohol less often, talked more with others about HIV/AIDS, had more sex partners in the past month, but reported fewer unprotected sex acts in the past month. Community level interventions that strengthen collective efficacy beliefs will have to consider both protective and risk behaviors associated with believing that the community is ready and capable of preventing HIV. PMID- 23660647 TI - Structure of matrix metalloproteinase-3 with a platinum-based inhibitor. AB - An X-ray investigation has been performed with the aim of characterizing the binding sites of a platinum-based inhibitor (K[PtCl3(DMSO)]) of matrix metalloproteinase-3 (stromelysin-1). The platinum complex targets His224 in the S1' specificity loop, representing the first step in the selective inhibition process (PDB ID code 4JA1). PMID- 23660648 TI - A physicochemical mechanism of chemical gas sensors using an AC analysis. AB - Electrical modeling of the chemical gas sensors was successfully applied to TiO2 nanofiber gas sensors by developing an equivalent circuit model where the junction capacitance as well as the resistance can be separated from the comparable stray capacitance. The Schottky junction impedance exhibited a characteristic skewed arc described by a Cole-Davidson function, and the variation of the fit and derived parameters with temperature, bias, and NO2 gas concentration indicated definitely a physicochemical sensing mechanism based on the Pt|TiO2 Schottky junctions against the conventional supposition of the enhanced sensitivity in nanostructured gas sensors with high grain boundary/surface area. Analysis on a model Pt|TiO2|Pt structure also confirmed the characteristic impedance response of TiO2 nanofiber sensors. PMID- 23660649 TI - Reduced cytochrome oxidase activity in the retrosplenial cortex after lesions to the anterior thalamic nuclei. AB - The anterior thalamic nuclei (ATN) make a critical contribution to hippocampal system functions. Growing experimental work shows that the effects of ATN lesions often resemble those of hippocampal lesions and both markedly reduce the expression of immediate-early gene markers in the retrosplenial cortex, which still appears normal by standard histological means. This study shows that moderate ATN damage was sufficient to produce severe spatial memory impairment as measured in a radial-arm maze. Furthermore, ATN rats exhibited reduced cytochrome oxidase activity in the most superficial cortical layers of the granular retrosplenial cortex, and, to a lesser extent, in the anterior cingulate cortex. By contrast, no change in cytochrome oxidase activity was observed in other limbic cortical regions or in the hippocampal formation. Altogether our results indicate that endogenous long-term brain metabolic capacity within the granular retrosplenial cortex is compromised by even limited ATN damage. PMID- 23660650 TI - Withdrawal from chronic nicotine and subsequent sensitivity to nicotine challenge on contextual learning. AB - Nicotine withdrawal is associated with numerous symptoms including impaired hippocampus-dependent learning. Theories of nicotine withdrawal suggest that nicotinic acetylcholine receptors (nAChRs) are hypersensitive during withdrawal, which suggests enhanced sensitivity to nicotine challenge. Research indicates that prior exposure to nicotine enhances sensitivity to nicotine challenge, but it is unclear if this is due to prior nicotine exposure or specific to nicotine withdrawal. Therefore, the present experiments examined if prior nicotine exposure or nicotine withdrawal altered the effects of nicotine challenge on hippocampus-dependent learning. C57BL/6J mice were trained and tested in contextual conditioning following saline or nicotine challenge either during (24h after cessation) or after (14 days after cessation) a period of nicotine withdrawal symptoms. Nicotine challenge produced a greater enhancement of contextual conditioning relative to control withdrawal state in mice withdrawn from chronic nicotine for 24h compared to 14 days and corresponding saline controls. These experiments support the suggestion that during periods of abstinence, smokers may perceive tobacco providing a large boost in cognition. PMID- 23660651 TI - Brachial artery aneurysm with "blue finger syndrome" after ligation of a remote brachial artery-cephalic vein fistula. AB - Upper extremity aneurysms are relatively infrequent when compared to other vessels in the body. However, a combination of factors occurring following arteriovenous fistula (AVF) ligation can lead to dilation of the brachial artery. Periodic follow-up after AVF creation can help prevent complications. We report a case of an immunosuppressed, patient with renal transplant who presented with delayed onset digital ischemia following ligation of a remotely created brachial artery-cephalic vein fistula. PMID- 23660652 TI - There is no common ground between science and religion. PMID- 23660653 TI - On toxic effects of scientific journals. AB - The advent of online publishing greatly facilitates the dissemination of scientific results. This revolution might have led to the untimely death of many traditional publishing companies, since today's scientists are perfectly capable of writing, formatting and uploading files to appropriate websites that can be consulted by colleagues and the general public alike. They also have the intellectual resources to criticize each other and organize an anonymous peer review system. The Open Access approach appears promising in this respect, but we cannot ignore that it is fraught with editorial and economic problems. A few powerful publishing companies not only managed to survive, but also rake up considerable profits. Moreover, they succeeded in becoming influential 'trendsetters' since they decide which papers deserve to be published. To make money, one must set novel trends, like Christian Dior or Levi's in fashion, and open new markets, for example in Asia. In doing so, the publishers tend to supplant both national and transnational funding agencies in defining science policy. In many cases, these agencies tend simply to adopt the commercial criteria defined by the journals, forever eager to improve their impact factors. It is not obvious that the publishers of scientific journals, the editorial boards that they appoint, or the people who sift through the vast numbers of papers submitted to a handful of 'top' journals are endowed with sufficient insight to set the trends of future science. It seems even less obvious that funding agencies should blindly follow the fashion trends set by the publishers. The perverse relationships between private publishers and public funding agencies may have a toxic effect on science policy. PMID- 23660654 TI - Natural history in India during the 18th and 19th centuries. PMID- 23660655 TI - What history tells us XXXI. The replicon model: between molecular biology and molecular cell biology. PMID- 23660656 TI - Candidate gene markers for Candidatus Liberibacter asiaticus for detecting citrus greening disease. AB - Citrus Huanglongbing (HLB) also known as citrus greening is one of the most devastating diseases of citrus worldwide. The disease is caused by Candidatus Liberibacter bacterium, vectored by the psyllid Diaphorina citri Kuwayama and Trioza erytreae Del Guercio. Citrus plants infected by the HLB bacterium may not show visible symptoms sometimes for years following infection. The aim of this study was to develop effective gene-specific primer pairs for polymerase chain reaction based method for quick screening of HLB disease. Thirty-two different gene-specific primer pairs, across the Ca. Liberibacter asiaticus genome, were successfully developed. The possibility of these primer pairs for cross-genome amplification across 'Ca. Liberibacter africanus' and 'Ca. Liberibacter americanus' were tested. The applicability of these primer pairs for detection and differentiation of Ca Liberibacter spp. is discussed. PMID- 23660657 TI - Identification of bifidobacteria isolated from Asian elephant (Elephas maximus). AB - Bifidobacteria are considered as one of the key genera in intestinal tracts of animals, and their species composition vary depending on the host. The aim of this study was to identify faecal bifidobacteria from Asian elephants (Elephas maximus), housed in Zoological gardens (Ostrava, Czech Republic). Using culturing, bifidobacteria were found in counts 7.60+/-0.56 log CFU/g. Twenty-six pure strains were isolated from faeces of Asian elephant. The isolates were clustered into two groups according to fingerprinting profiles and fermentation characteristic. Bacteria were identified by a combination of MALDI-TOF MS, PCR methods and sequencing as B. boum (12 isolates) and B. adolescentis (14 isolates). Elephant strains showed different fingerprinting profiles than type and collection strains. Since these two species are frequently isolated from gastrointestinal tract of herbivores, they seem to be typical of animals fed plant diets. PMID- 23660658 TI - A mini-IRES sequence for stringent selection of high producers. AB - Internal Ribosome Entry Site (IRES) sequences have been widely used to link the expression of two independent proteins on the same mRNA transcript. Genes encoding fluorescent proteins or drug-resistance enzymes are usually placed downstream of IRES, serving as expression indicators or selection markers. In biological applications where the upstream gene-of-interest is to be expressed at extremely high levels, it is often desirable to purposely reduce IRES downstream gene expression to economize the cellular resources and/or to generate more stringent selection pressure. Here we describe a miniature IRES mutant sequence (IRESmut3) with dramatically diminished co-translational efficiency to fulfill these purposes. PMID- 23660659 TI - Bioluminescent bioreporter for assessment of arsenic contamination in water samples of India. AB - In the present study the most efficient R-factor controlling the ars operon was selected after screening of 39 Escherichia coli isolates by minimum inhibitory concentration test (MIC) studies from water samples of different geographical locations of India. Among all, strain isolated from Hooghly River (West Bengal) was found to have maximum tolerance towards arsenic and was further used for the development of bioreporter bacteria. Cloning of the ars regulatory element along with operator-promotor and luxCDABE from Photobacteria into expression vector has been accomplished by following recombinant DNA protocols. The bioreporter sensor system developed in this study can measure the estimated range of 0.74-60 mu g of As/L and is both specific and selective for sensing bioavailable As. The constructed bacterial biosensor was further used for the determination of arsenic ion concentration in different environmental samples of India. PMID- 23660660 TI - Role of amylase, mucin, IgA and albumin on salivary protein buffering capacity: a pilot study. AB - It has been suggested that proteins serve as major salivary buffers below pH5. It remains unclear, however, which salivary proteins are responsible for these buffering properties. The aim of this pilot study was to evaluate the correlation between salivary concentration of total protein, amylase, mucin, immunoglobulin A (IgA), albumin and total salivary protein buffering capacity at a pH range of 4 5. In addition, the buffering capacity and the number of carboxylic acid moieties of single proteins were assessed. Stimulated saliva samples were collected at 9:00, 13:00 and 17:00 from 4 healthy volunteers on 3 successive days. The buffering capacities were measured for total salivary protein or for specific proteins. Also, the concentration of total protein, amylase, mucin, IgA and albumin were analysed. Within the limits of the current study, it was found that salivary protein buffering capacity was highly positively correlated with total protein, amylase and IgA concentrations. A weak correlation was observed for both albumin and mucin individually. Furthermore, the results suggest that amylase contributed to 35 percent of the salivary protein buffering capacity in the pH range of 4-5. PMID- 23660661 TI - A unique DNA repair and recombination gene (recN) sequence for identification and intraspecific molecular typing of bacterial wilt pathogen Ralstonia solanacearum and its comparative analysis with ribosomal DNA sequences. AB - Ribosomal gene sequences are a popular choice for identification of bacterial species and, often, for making phylogenetic interpretations. Although very popular, the sequences of 16S rDNA and 16-23S intergenic sequences often fail to differentiate closely related species of bacteria. The availability of complete genome sequences of bacteria, in the recent years, has accelerated the search for new genome targets for phylogenetic interpretations. The recently published full genome data of nine strains of R. solanacearum, which causes bacterial wilt of crop plants, has provided enormous genomic choices for phylogenetic analysis in this globally important plant pathogen. We have compared a gene candidate recN, which codes for DNA repair and recombination function, with 16S rDNA/16-23S intergenic ribosomal gene sequences for identification and intraspecific phylogenetic interpretations in R. solanacearum. recN gene sequence analysis of R. solanacearum revealed subgroups within phylotypes (or newly proposed species within plant pathogenic genus, Ralstonia), indicating its usefulness for intraspecific genotyping. The taxonomic discriminatory power of recN gene sequence was found to be superior to ribosomal DNA sequences. In all, the recN sequence-based phylogenetic tree generated with the Bayesian model depicted 21 haplotypes against 15 and 13 haplotypes obtained with 16S rDNA and 16-23S rDNA intergenic sequences, respectively. Besides this, we have observed high percentage of polymorphic sites (S 23.04%), high rate of mutations (Eta 276) and high codon bias index (CBI 0.60), which makes the recN an ideal gene candidate for intraspecific molecular typing of this important plant pathogen. PMID- 23660662 TI - Identification of a premature termination of DNA polymerization in vitro by Klenow fragment mutants. AB - DNA polymerization products by Klenow fragment (KF) are blunt-ended. In the present study, we found that the Klenow fragment mutants with partial deletions of thumb subdomain were unable to extend primers to the 5' terminal of templates, thus creating 5' overhanging sticky ends 2 nt long. We termed this phenomenon as PmTP (premature termination of polymerization). The KF mutants produced homogenous sticky-ended products only under mild reaction conditions, whereas under vigorous reaction conditions, the sticky ends were prone to be blunt-ended. It was also identified that deletions of more than four residues of KF thumb subdomain could induce PmTP, and tworesidue deletion of KF thumb subdomain only induced PmTP in a lower-concentration situation. Structure modelling analysis suggested that shortening or destruction of alpha helix H1 at the tip of the thumb subdomain was crucial to PmTP, while the conserved residues in front of alpha helix was less important. PmTP might be caused by the reduced DNAbinding affinity of the mutants. The sticky ends made by PmTP have potential applications in gene splicing and molecular cloning techniques. PMID- 23660663 TI - Spo0A positively regulates epr expression by negating the repressive effect of co repressors, SinR and ScoC, in Bacillus subtilis. AB - Bacillus subtilis under nutritional deprivation exhibits several physiological responses such as synthesis of degradative enzymes, motility, competence, sporulation, etc. At the onset of post-exponential phase the global response regulator, Spo0A, directly or indirectly activates the expression of genes involved in the above processes. These genes are repressed during the exponential phase by a group of proteins called transition state regulators, e.g. AbrB, ScoC and SinR. One such post-exponentially expressed gene is epr, which encodes a minor extracellular serine protease and is involved in the swarming motility of B. subtilis. Deletion studies of the upstream region of epr promoter revealed that epr is co-repressed by transition state regulators, SinR and ScoC. Our study shows that Spo0A positively regulates epr expression by nullifying the repressive effect of co-repressors, SinR and ScoC. We demonstrate via in vitro mobility shift assays that Spo0A binds to the upstream region of epr promoter and in turn occludes the binding site of one of the co-repressor, SinR. This explains the mechanism behind the positive regulatory effect of Spo0A on epr expression. PMID- 23660664 TI - Transcriptome analysis of Anopheles stephensi embryo using expressed sequence tags. AB - Germ band retraction (GBR) stage is one of the important stages during insect development. It is associated with an extensive epithelial morphogenesis and may also be pivotal in generation of morphological diversity in insects. Despite its importance, only a handful of studies report the transcriptome repertoire of this stage in insects. Here, we report generation, annotation and analysis of ESTs from the embryonic stage (16-22 h post fertilization) of laboratoryreared Anopheles stephensi mosquitoes. A total of 1002 contigs were obtained upon clustering of 1140 high-quality ESTs, which demonstrates an astonishingly low transcript redundancy (12.1 percent). Putative functions were assigned only to 213 contigs (21 percent), comprising mainly of transcripts encoding protein synthesis machinery. Approximately 78 percent of the transcripts remain uncharacterized, illustrating a lack of sequence information about the genes expressed in the embryonic stages of mosquitoes. This study highlights several novel transcripts, which apart from insect development, may significantly contribute to the essential biological complexity underlying insect viability in adverse environments. Nonetheless, the generated sequence information from this work provides a comprehensive resource for genome annotation, microarray development, phylogenetic analysis and other molecular biology applications in entomology. PMID- 23660665 TI - Identification of two genes potentially associated in iron-heme homeostasis in human carotid plaque using microarray analysis. AB - Classic characteristics are poor predictors of the risk of thromboembolism. Thus, better markers for the carotid atheroma plaque formation and symptom causing are needed. Our objective was to study by microarray analysis gene expression of genes involved in homeostasis of iron and heme in carotid atheroma plaque from the same patient. mRNA gene expression was measured by an Affymetrix GeneChip Human Gene 1.0 ST arrays (Affymetrix, Santa Clara, CA, USA) using RNA prepared from 68 specimens of endarteriectomy from 34 patients. Two genes involved in iron heme homeostasis, CD163 and heme oxygenase (HO-1), were analysed in 34 plaques. CD163 (2.18, p01.45E-08) and HO-1 (fold-change 2.67, p02.07E-09) mRNAs were induced. We suggest that atheroma plaques show a more pronounced induction of CD163 and HO-1. Although further evidence is needed, our results support previous data. To our knowledge, this is the first report comparing gene expression between intact arterial tissue and carotid plaque using microarray analysis. PMID- 23660666 TI - Changes in leaf proteome profile of Arabidopsis thaliana in response to salicylic acid. AB - Salicylic acid (SA) has been implicated in determining the outcome of interactions between many plants and their pathogens. Global changes in response to this phytohormone have been observed at the transcript level, but little is known of how it induces changes in protein abundance. To this end we have investigated the effect of 1 mM SA on soluble proteins of Arabidopsis thaliana leaves by proteomic analysis. An initial study at transcript level has been performed on temporal landscape, which revealed that induction of most of the SA responsive genes occurs within 3 to 6 h post treatment (HPT) and the expression peaked within 24 HPT. Two-dimensional gel electrophoresis (2-DE) coupled with MALDI-TOF MS/MS analysis has been used to identify differentially expressed proteins and 63 spots have been identified successfully. This comparative proteomic profiling of SA treated leaves versus control leaves demonstrated the changes of many defence related proteins like pathogenesis related protein 10a (PR10a), diseaseresistance- like protein, putative late blight-resistance protein, WRKY4, MYB4, etc. along with gross increase in the rate of energy production, while other general metabolism rate is slightly toned down, presumably signifying a transition from 'normal mode' to 'defence mode'. PMID- 23660668 TI - Development of rapid phenotypic system for the identification of Gram-negative oxidase-positive bacilli in resource-limited settings. AB - Rapid and accurate identification of bacterial pathogens is a fundamental goal of clinical microbiology. The diagnosis and surveillance of diseases is dependent, to a great extent, on laboratory services, which cannot function without effective reliable reagents and diagnostics. Despite the advancement in microbiology diagnosis globally, resourcelimited countries still struggle to provide an acceptable diagnosis quality which helps in clinical disease management and improve their mortality and morbidity data. During this study an indigenous product, Quick Test Strip (QTS) NE, was developed for the rapid identification of biochemically slower group of Gram-negative oxidase-positive bacilli that covers 19 different bacterial genera. Some of the members belonging to these groups are well-established human pathogens, e.g. various species of Vibrio, Pseudomonas, Burkholderia, Aeromonas, Achromobacter and Stenotrophomonas. This study also evaluates the performance of QTS-NE by comparing with genotypic characterization methods. A total of 232 clinical and reference bacterial isolates were tested by three different methods. QTSNE provides 100 percent concordant results with other rapid identification and molecular characterization methods and confirms the potential to be used in clinical diagnosis. PMID- 23660669 TI - Dietary diversification and variations in the number of labrum sensilla in grasshoppers: which came first? AB - The diversity of the diet of grasshoppers (Acrididae, Orthoptera) is related to multiple factors, including the chemoreceptors on the antennae, palps and on the epipharyngeal face of the labrum. In the present study, we sought to understand the nature of the diet of 12 Moroccan acridian species and to try to relate various aspects of their diet to the number of labrum sensilla. If the effect of the labrum size on the number of sensilla is removed, four groups of species are recorded: (i) polyphagous species with a broad diet and numerous sensilla; (ii) polyphagous species with a graminivorous diet and numerous sensilla; (iii) oligophagous species feeding exclusively on Poaceae and with a medium number of sensilla; and (iv) strictly monophagous species feeding on a single plant species and with the smallest number of sensilla. These observations show the close relationship between the diet and the number of labrum sensilla. However, Sphingonotus rubescens, a polyphagous species, is an exception to this trend as it harbours a medium number of sensilla. We propose that the modification in the number of labrum sensilla is a result of a progressive adaptation to a different diet and does not represent its cause. PMID- 23660670 TI - Inactivation of Tor proteins affects the dynamics of endocytic proteins in early stage of endocytosis. AB - Tor2 is an activator of the Rom2/Rho1 pathway that regulates alpha-factor internalization. Since the recruitment of endocytic proteins such as actin binding proteins and the amphiphysins precedes the internalization of alpha factor, we hypothesized that loss of Tor function leads to an alteration in the dynamics of the endocytic proteins. We report here that endocytic proteins, Abp1 and Rvs167, are less recruited to endocytic sites not only in tor2 but also tor1 mutants. Furthermore, we found that the endocytic proteins Rvs167 and Sjl2 are completely mistargeted to the cytoplasm in tor1 delta tor2ts double mutant cells. We also demonstrate here that the efficiency of endocytic internalization or scission in all tor mutants was drastically decreased. In agreement with the Sjl2 mislocalization, we found that in tor1 delta tor2ts double mutant cells, as well as other tor mutant cells, the overall PIP2 level was dramatically increased. Finally, the cell wall chitin content in tor2ts and tor1 delta tor2ts mutant cells was also significantly increased. Taken together, both functional Tor proteins, Tor1 and Tor2, are essentially required for proper endocytic protein dynamics at the early stage of endocytosis. PMID- 23660671 TI - Short-term hypoxia/reoxygenation activates the angiogenic pathway in rat caudate putamen. AB - In response to hypoxia, tissues have to implement numerous mechanisms to enhance oxygen delivery, including the activation of angiogenesis. This work investigates the angiogenic response of the hypoxic caudate putamen after several recovery times. Adult Wistar rats were submitted to acute hypoxia and analysed after 0 h, 24 h and 5 days of reoxygenation. Expression of hypoxia-inducible factor-1 alfa (HIF-1 alpha) and angiogenesis-related genes including vascular endothelial growth factor (VEGF), adrenomedullin (ADM) and transforming growth factor-beta 1 (TGF- beta 1) was determined by both RT-PCR and ELISA. For vessel labelling, lectin location and expression were analysed using histochemical and image processing techniques (fractal dimension). Expression of Hif-1 alpha, Vegf, Adm and Tgf- beta 1 mRNA rose immediately after hypoxia and this increase persisted in some cases after 5 days post-hypoxia. While VEGF and TGF-beta 1 protein levels increased parallel to mRNA expression, ADM remained unaltered. The quantification of the striatal vessel network showed a significant augmentation at 24 h of reoxygenation. These results reveal that not only short-term hypoxia, but also the subsequent reoxygenation period, up-regulate the angiogenic pathway in the rat caudate putamen as a neuroprotective mechanism to hypoxia that seeks to maintain a proper blood supply to the hypoxic tissue, thereby minimizing the adverse effects of oxygen deprivation. PMID- 23660672 TI - Physiological responses to acute experimental hypoxia in the air-breathing Indian catfish, Clarias batrachus (Linnaeus, 1758). AB - With an aim to study the mechanism of adaptation to acute hypoxic periods by hypoxia-tolerant catfish, Clarias batrachus, the mass-specific metabolic rate (VO2) along with its hematological parameters, metabolic response and antioxidant enzyme activities were studied. During progressive hypoxia, C. batrachus was found to be an oxyconformer and showed a steady decline in its aquatic oxygen consumption rate. When C. batrachus was exposed for different periods at experimental hypoxia level (0.98 +/- 0.1 mg/L, DO), hemoglobin and hematocrit concentrations were increased, along with decrease in mean cellular hemoglobin concentration, which reflected a physiological adaptation to enhance oxygen transport capacity. Significant increase in serum glucose and lactate concentration as well as lactate dehydrogenase activity was observed. Antioxidant enzymes were found to operate independently of one another, while total glutathione concentration was unaffected in any of the tissues across treatments. These observations suggested that hypoxia resulted in the development of oxidative stress and C. batrachus was able to respond through increase in the oxygen carrying capacity, metabolic depression and efficient antioxidant defense system to survive periods of acute hypoxia. PMID- 23660673 TI - Altered DNA repair, oxidative stress and antioxidant status in coronary artery disease. AB - Coronary artery disease (CAD) is a multifactorial disease caused by the interplay of environmental risk factors with multiple predisposing genes. The present study was undertaken to evaluate the role of DNA repair efficiency and oxidative stress and antioxidant status in CAD patients. Malonaldehyde (MDA), which is an indicator of oxidative stress, and mean break per cell (b/c) values, which is an indicator of decreased DNA repair efficiency, were found to be significantly increased in patients compared to normal controls (P less than 0.05) whereas ascorbic acid and GSH were found to be lower among patients than the control group. It has been found that elevated oxidative stress decreased antioxidant level and decreased DNA repair efficiency can contribute to the development of CAD. This study also showed that high MDA, low ascorbic acid and GSH were significantly associated with high b/c value. PMID- 23660674 TI - Allometric scaling relationship between frequency of intestinal contraction and body size in rodents and rabbits. AB - This study aimed to establish an allometric scaling relationship between the frequency of intestinal contractions and body mass of different mammalian species. The frequency of intestinal contractions of rabbit, guinea pig, rat and mouse were measured using an isolated organ system. The isolated rings were prepared from proximal segments of jejunums and the frequency of contractions was recorded by an isometric force procedure. The coefficients of the obtained allometric equation were ascertained by computation of least squares after logarithmic transformation of both body mass and frequency. Significant differences (p less than 0.001) were shown in the frequency of contractions between different species. The highest frequency that corresponded to the mice was 57.7 min-1 and the 95 percent confidence interval (CI) ranged from 45.4 to 70, while rabbits showed the lowest frequency (12.71 min-1, CI: 8.6-16.8). Logarithms of frequency were statistically proportional to logarithms of body mass (r00.99; p less than 0.001). The data fitted an equation F 1/4 18:51B 0:31 and the 95 percent confidence interval of the exponent ranged from -0.30 to 0.32. The results of this study suggest that it is probably possible to extrapolate the intestinal contraction frequency of other mammalian species by the means of allometry scaling. PMID- 23660675 TI - Metabolism in bacteria at low temperature: a recent report. AB - The adaptability of bacteria to extreme cold environments has been demonstrated from time to time by various investigators. Metabolic activity of bacteria at subzero temperatures is also evidenced. Recent studies indicate that bacteria continue both catabolic and anabolic activities at subzero temperatures. Implications of these findings are discussed. PMID- 23660676 TI - UV-screening of grasses by plant silica layer? AB - UV-screening by terrestrial plants is a crucial trait since colonization of terrestrial environments has started. In general, it is enabled by phenolic substances. Especially for grasses it remains unclear why plants grown under the absence of UV-B-radiation exhibit nonetheless a high UV-B-screening potential. But this may be explained by the UV-screening effect of the silicon double layer. It was shown for seedlings of soybeans (Glycine max L.) and wheat (Triticum aestivum L.) that enhanced silicon supply reduces stress induced by UV-radiation. Even more important is a direct correlation between silicon content in the epidermis near area (intercellular spaces) and the absorption of UV-radiation in this area shown in other papers. The silicon double layer may act like a glass layer and decreases the transmission of UV-radiation at the epidermis near area. In summary, the absorbance/reflection of ultraviolet radiation is dependent on the characteristics of the epidermis near area of leaves, particularly the occurrence (qualitatively and quantitatively) of phenolic substances and/or a silicon double layer in this area. Consequently, UV-screening by plant silicon double layer should get more attention in future research with emphasis on effects of UV-radiation on plant physiology. PMID- 23660677 TI - The multiple faces of calcineurin signaling in Caenorhabditis elegans: development, behaviour and aging. AB - Calcineurin, a well-conserved protein phosphatase 2B (PP2B), is a Ca2+-calmodulin dependent serine/threonine protein phosphatase that is known to be involved in a myriad of cellular processes and signal transduction pathways. The biological role of calcineurin has been extensively studied in diverse groups of organisms. Homologues of mammalian and Drosophila calcineurin subunits exist in the nematode, Caenorhabditis elegans. The C. elegans counterpart of the catalytic subunit, calcineurin A, cna-1/tax-6, and the regulatory subunit, calcineurin B, cnb-1, are known to express ubiquitously in multiple tissues including neurons. The characterization of C. elegans calcineurin mutants facilitates identification of its physiological functions and signaling pathways. Genetic interactions between cna-1/tax-6 and cnb-1 mutants with a number of mutants involved in several signaling pathways have exemplified the pivotal role of calcineurin in regulating nematode development, behaviour and lifespan (aging). The present review has been aimed to provide a succinct summary of the multiple functions of calcineurin in C. elegans relating to its development, fertility, proliferation, behaviour and lifespan. Analyses of cna-1/tax-6 and cnb-1 interacting proteins and regulators of the phosphatase in this fascinating worm model have an immense scope to identify potential drug targets in various parasitic nematodes, which cause many diseases inflicting huge economic loss; and also for many human diseases, particularly neurodegenerative and myocardial diseases. PMID- 23660679 TI - From brain topography to brain topology: relevance of graph theory to functional neuroscience. AB - Although several brain regions show significant specialization, higher functions such as cross-modal information integration, abstract reasoning and conscious awareness are viewed as emerging from interactions across distributed functional networks. Analytical approaches capable of capturing the properties of such networks can therefore enhance our ability to make inferences from functional MRI, electroencephalography and magnetoencephalography data. Graph theory is a branch of mathematics that focuses on the formal modelling of networks and offers a wide range of theoretical tools to quantify specific features of network architecture (topology) that can provide information complementing the anatomical localization of areas responding to given stimuli or tasks (topography). Explicit modelling of the architecture of axonal connections and interactions among areas can furthermore reveal peculiar topological properties that are conserved across diverse biological networks, and highly sensitive to disease states. The field is evolving rapidly, partly fuelled by computational developments that enable the study of connectivity at fine anatomical detail and the simultaneous interactions among multiple regions. Recent publications in this area have shown that graph based modelling can enhance our ability to draw causal inferences from functional MRI experiments, and support the early detection of disconnection and the modelling of pathology spread in neurodegenerative disease, particularly Alzheimer's disease. Furthermore, neurophysiological studies have shown that network topology has a profound link to epileptogenesis and that connectivity indices derived from graph models aid in modelling the onset and spread of seizures. Graph-based analyses may therefore significantly help understand the bases of a range of neurological conditions. This review is designed to provide an overview of graph-based analyses of brain connectivity and their relevance to disease aimed principally at general neuroscientists and clinicians. PMID- 23660680 TI - Benevolent sexism alters executive brain responses. AB - Benevolence is widespread in our societies. It is defined as considering a subordinate group nicely but condescendingly, that is, with charity. Deleterious consequences for the target have been reported in the literature. In this experiment, we used functional MRI (fMRI) to identify whether being the target of (sexist) benevolence induces changes in brain activity associated with a working memory task. Participants were confronted by benevolent, hostile, or neutral comments before and while performing a reading span test in an fMRI environment. fMRI data showed that brain regions associated previously with intrusive thought suppression (bilateral, dorsolateral, prefrontal, and anterior cingulate cortex) reacted specifically to benevolent sexism compared with hostile sexism and neutral conditions during the performance of the task. These findings indicate that, despite being subjectively positive, benevolence modifies task-related brain networks by recruiting supplementary areas likely to impede optimal cognitive performance. PMID- 23660681 TI - Motor and perceptual sequence learning: different time course of parallel processes. AB - The aim was to determine the extent and time course of motor and perceptual learning in a procedural learning task, and the relation of these two processes. Because environmental constraints modulate the relative impact of different learning mechanisms, we chose a simple learning task similar to real-life exercise. Thirty-four healthy individuals performed a visuomotor serial reaction time task. Learning blocks with high stimulus-response compatibility were practiced repeatedly; in between these, participants performed test blocks with the same or a different (mirror-inverted, or new) stimulus sequence and/or with the same or a different (mirror-inverted) stimulus-response allocation. This design allowed us to measure the progress of motor learning and perceptual learning independently. Results showed that in the learning blocks, a steady reduction of the reaction times indicated that - as expected - participants improved their skills continuously. Analysis of the test blocks indicated that both motor learning and perceptual learning were significant. The two mechanisms were correlated (r=0.62, P<0.001). However, their time course was different: the impact of motor learning increased strongly from earlier to later intervals, whereas the progress of perceptual learning was more stable but slower. In conclusion, in a simple visuomotor learning task, participants can learn the motor sequence and the stimulus sequence in parallel. The positive correlation of motor and perceptual learning suggests that the two mechanisms act in synergy and are not alternative opposing strategies. The impact of these two learning mechanisms changes over time: motor learning sets in later and becomes relevant only in the course of training. PMID- 23660682 TI - Investigation of APOE isoforms and the association between APOE E3 and E4 with migraine in the Australian Caucasian population. AB - Migraine is a debilitating neurovascular disease that is associated with pulsating head pain accompanied by nausea, vomiting, photophobia, phonophobia and sometimes visual sensory disturbances. Because of its role in nitric oxide regulation and interleukin release, apolipoprotein E (APOE) has been suggested to play a role in the migraine pathogenesis pathway. This study evaluated the potential role of three APOE variants in an Australian population and the role that they may play in susceptibility to migraine. The study found no significant association between the tested variants and migraine for any of the APOE variants investigated. PMID- 23660683 TI - Metformin inhibits glioma cell U251 invasion by downregulation of fibulin-3. AB - Fibulin-3 has been considered as a regulator of glioma cell invasion, but little is known about the molecules regulating fibulin-3 expression. Metformin, an oral antidiabetic drug in the biguanide class, is known to inhibit proliferation and metastasis in a variety of cancer cells. In the present study, we determined the effect of metformin on the expression of fibulin-3 in U251 Human glioma cells. Metformin potently suppressed U251 cell adhesion and invasion. Metformin inhibited the expression of fibulin-3 at the transcriptional level. Moreover, metformin abolished the protein expression of fibulin-3 in a concentration dependent manner. Furthermore, this compound suppressed the expression of matrix metalloproteinase-2, a key effector of glioma cell invasion, regulated by fibulin 3. Taken together, our results suggest that metformin abolishes fibulin-3 expression and subsequently inhibits invasion of glioma cells. PMID- 23660678 TI - Plant innate immunity: an updated insight into defense mechanism. AB - Plants are invaded by an array of pathogens of which only a few succeed in causing disease. The attack by others is countered by a sophisticated immune system possessed by the plants. The plant immune system is broadly divided into two, viz. microbial-associated molecular-patterns-triggered immunity (MTI) and effector-triggered immunity (ETI). MTI confers basal resistance, while ETI confers durable resistance, often resulting in hypersensitive response. Plants also possess systemic acquired resistance (SAR), which provides long-term defense against a broad-spectrum of pathogens. Salicylic-acid-mediated systemic acquired immunity provokes the defense response throughout the plant system during pathogen infection at a particular site. Trans-generational immune priming allows the plant to heritably shield their progeny towards pathogens previously encountered. Plants circumvent the viral infection through RNA interference phenomena by utilizing small RNAs. This review summarizes the molecular mechanisms of plant immune system, and the latest breakthroughs reported in plant defense. We discuss the plant-pathogen interactions and integrated defense responses in the context of presenting an integral understanding in plant molecular immunity. PMID- 23660684 TI - Human cytomegalovirus infection modulates thrombospondins 1 and 2 in primary fetal astrocytes. AB - Transmission of human cytomegalovirus (HCMV) to the fetus is the most common type of intrauterine infection; the mechanism of HCMV pathogenesis in the developing central nervous system remains unclear. Thrombospondins 1 and 2 (TSP1, TSP2) produced by immature astrocytes are critical for fetal synaptogenesis. To examine the effect of HCMV on fetal astrocytes, human fetal astrocytes were isolated and cultured with HCMV AD169. Cells were harvested at different time points. Protein and mRNA expressions of TSP1 and TSP2 were determined using RT-qPCR, western blotting analysis, and enzyme-linked immunosorbent assay. The results showed that HCMV infection induced time-dependent decreases in mRNA and protein expressions of both TSP1 and TSP2 in astrocytes. Flow cytometry was used to detect apoptosis of HCMV-infected astrocytes, and the result indicated that there was no linkage between cell apoptosis and the decrease in TSP1 and TSP2 expressions induced by HCMV infection. When ganciclovir treatment was performed on HCMV-infected astrocytes, results showed that ganciclovir treatment inhibited the reduction of TSP1 and TSP2 expression in astrocytes. In the further study, pEGFP-N3-IE1 was transfected into astrocytes to identify that it was not IE1 but active viral replication that was essential in the continuous decrease of TSP1 and TSP2 expressions in HCMV-infected astrocytes. PMID- 23660685 TI - Toward personalized therapy in AML: in vivo benefit of targeting aberrant epigenetics in MLL-PTD-associated AML. PMID- 23660686 TI - Switching therapy to bedtime for uncontrolled hypertension with a nondipping pattern: a prospective randomized-controlled study. AB - OBJECTIVE: Uncontrolled hypertension is present in most patients treated with only a single morning dose or fixed dose drug combination; usually a third of them have a high prevalence of a nondipper blood pressure pattern, especially patients with chronic illness. In most cases, nondipping is related partly to the absence of 24-h therapeutic coverage of the single morning doses. We have investigated the usefulness of shifting therapy to evening instead of the morning. AIM: The aim of the study was to better control blood pressure and convert patients with a nondipping pattern to a dipper pattern without the need to increase the dose of their drugs or the addition of any other family of drugs. METHODS: Among 200 hypertensive patients, we investigated the impact of treatment time on the blood pressure pattern in 60 patients (33.3%) with uncontrolled hypertension with a nondipper pattern on the basis of clinic measurements who were studied by 24-h ambulatory monitoring during 2 and 4 months of follow-up; all of them received their treatment in the morning. This group of patients was divided randomly into two groups of 30 patients each; one group continued to receive the medication on awakening and the other took their medication at bedtime. Most of the treatment involved calcium channel blockers and other angiotensin-converting-enzyme inhibitors (ACEI), and 20 patients were taking one tablet of combined treatment (calcium blocker with ACEI). RESULTS: The percentage of patients with controlled ambulatory blood pressure was 0.86 among patients taking the drug at bedtime (P=0.005). Twenty-six patients with uncontrolled hypertension, receiving one drug or combined therapy at bedtime, showed a significant reduction in the 24-h mean systolic and diastolic blood pressure (6.2 and 2.6 mmHg, respectively; P<0.009). This reduction was more prominent during night-time (8.3 and 5.0 mmHg; P<0.001). In addition, all 26 patients showed normal blood pressure less than 140/90 during clinic measurement at daytime. Only four patients treated with monotherapy in the morning were unresponsive to the switching, and their blood pressure was controlled by the addition of a second drug at bedtime. The control group (who continued taking therapy in the morning) showed no reduction in blood pressure during night-time and remained with uncontrolled hypertension as they were at the beginning of the study. CONCLUSION: In patients with uncontrolled hypertension, switching of therapy to bedtime should be considered to improve control and to avoid the nondipper pattern before any attempt is made to increase the dose or add more drugs. We need other research studies with long time follow-up to verify the efficacy of switching therapy. PMID- 23660687 TI - An aptamer-gated silica mesoporous material for thrombin detection. AB - An aptamer-capped mesoporous material for the selective and sensitive detection of alpha-thrombin in human plasma and serum has been prepared and characterised. PMID- 23660688 TI - Synthesis of vanadium(V) hydrazido complexes with tris(2-hydroxyphenyl)amine ligands. AB - The reaction of the oxidovanadium(V) complexes with N,N-dimethylhydrazine was demonstrated to afford the corresponding vanadium(V) dimethylhydrazido complexes. The substituent at the 3-position of the tris(2-hydroxyphenyl)amine ligand was found to influence the electronic environment of the vanadium center. The crystal structure of the non-substituted vanadium(V) dimethylhydrazido complex exhibited a distorted trigonal bipyramidal geometry with phenolate oxygen atoms in equatorial positions and the near-linear V(1)-N(2)-N(3) angle. The vanadium(V) diphenylhydrazido complexes could be obtained by the reaction of the oxidovanadium(V) complexes with N,N-diphenylhydrazine. A distorted trigonal bipyramidal geometry with phenolate oxygen atoms in equatorial positions was also observed in the crystal structure of the non-substituted vanadium(V) diphenylhydrazido complex. PMID- 23660689 TI - Artificial selection on brain-expressed genes during the domestication of dog. AB - Domesticated dogs have many unique behaviors not found in gray wolves that have augmented their interaction and communication with humans. The genetic basis of such unique behaviors in dogs remains poorly understood. We found that genes within regions highly differentiated between outbred Chinese native dogs (CNs) and wolves show high bias for expression localized to brain tissues, particularly the prefrontal cortex, a specific region responsible for complex cognitive behaviors. In contrast, candidate genes showing high population differentiation between CNs and German Shepherd dogs (GSs) did not demonstrate significant expression bias. These observations indicate that these candidate genes highly expressed in the brain have rapidly evolved. This rapid evolution was probably driven by artificial selection during the primary transition from wolves to ancient dogs and was consistent with the evolution of dog-specific characteristics, such as behavior transformation, for thousands of years. PMID- 23660690 TI - Alarmingly high prevalence of smoking and symptoms of bronchitis in young women in Sweden: a population-based questionnaire study. AB - BACKGROUND: After 10 years of a decrease in smoking among young people in Sweden, we now have indications of increased smoking. AIMS: To provide up-to-date information on the prevalence of smoking and smoke-associated respiratory symptoms in young adults in Sweden, with a special focus on possible gender differences. METHODS: In the West Sweden Asthma Study, a detailed postal questionnaire focusing on asthma, respiratory symptoms, and possible risk factors was mailed to 30,000 randomly selected subjects aged 16-75 years. The analyses are based on responses from 2,702 subjects aged 16-25 years. RESULTS: More young women than men were smokers (23.5% vs. 15.9%; p<0.001). Women started smoking earlier and smoked more. Symptoms such as longstanding cough, sputum production, and wheeze were significantly more common in smokers. In the multiple logistic regression analysis, smoking significantly increased the risk of recurrent wheeze (odds ratio (OR) 2.0 (95% CI 1.4 to 3.0)) and sputum production, (OR 2.4 (95% CI 1.9 to 3.1)). CONCLUSIONS: The alarmingly high prevalence of smoking among young women was parallel to a similarly high prevalence of bronchitis symptoms. This is worrisome, both in itself and because maternal smoking is a risk factor for illness in the child. Adverse respiratory effects of smoking occur within only a few years of smoking initiation. PMID- 23660691 TI - A phase II study of modified dose-dense paclitaxel and every 4-week carboplatin for the treatment of advanced-stage primary epithelial ovarian, fallopian tube, or peritoneal carcinoma. AB - PURPOSE: Traditional dose-dense chemotherapy regimens for advanced stage ovarian cancer incorporate weekly paclitaxel on a 21-day cycle and are associated with favorable efficacy but high rates of neutropenia, thrombocytopenia, and anemia. The purpose of this phase II study was to assess the response rate and toxicity of modified dose-dense paclitaxel and every 4-week carboplatin for the treatment of advanced-stage ovarian, fallopian tube, and primary peritoneal carcinoma. METHODS: All eligible patients were treated with 6 cycles of intravenous dose dense paclitaxel (80 mg/m2) days 1, 8, and 15 and carboplatin (AUC 5 or 6) Day 1 during a 28-day cycle in accordance with an IRB-approved protocol. Patients who had clinically defined stable disease or better with a CA-125 <= 35 U/ml following the completion of primary induction therapy were subsequently administered a planned 12 cycles of paclitaxel (135 mg/m2; every 21 days) consolidation therapy. RESULTS: Eighty-eight patients received at least 3 cycles of induction dose-dense chemotherapy, of whom 76 completed 6 cycles of chemotherapy; the overall response rate was 84.2 % (56.6 % complete response). Fifty-three patients received an aggregate 473 cycles (median = 9; range 1-12) of consolidation chemotherapy. Grade 3-4 hematological toxicity included neutropenia (22.7 %), thrombocytopenia (7.9 %), and anemia (1.1 %). Further, grade 3 neuropathy developed in one (1.1 %) patient. The patients' median disease-free survival and overall survival were 22.5 and 31.5 months, respectively. CONCLUSIONS: This phase II study suggests that first-line treatment comprising modified dose-dense paclitaxel and monthly carboplatin chemotherapy with paclitaxel consolidation therapy preserves the efficacy of traditional dose-dense chemotherapy, while minimizing hematologic toxicity. PMID- 23660692 TI - Metrology for metalloproteins--where are we now, where are we heading? AB - The use of the amount of certain proteins in biological samples as markers for distinguishing between a healthy and a diseased state has become increasingly important in clinical diagnosis. As about 30% of all proteins contain metals in one form or another, either as a cofactor or covalently bound as part of the protein, some of these proteins are regularly analyzed in clinical laboratories. With the increasing number of measurements of those proteins performed all over the world, the necessity of obtaining reliable and comparable results is becoming a focal point for scientists and politicians. Directives such as the EC directive covering in vitro diagnostic medical devices (Directive 98/79/EC) and standards such as EN ISO 17511:2003 demand the traceability of the results obtained for analytes in samples of human origin. However, no reference measurement procedures with results traceable to the SI exist for many metalloproteins. In this article, the situation for a few important metalloproteins, such as hemoglobin, transferrin, superoxide dismutase, ceruloplasmin, and C-reactive protein, for which specific efforts have been made in recent years to achieve comparable and traceable results worldwide, is discussed. These proteins also serve as examples of the difficulties scientists face when they wish to quantify proteins and the pitfalls they should avoid to achieve reliable results. PMID- 23660693 TI - Validation of a novel derivatization method for GC-ECD determination of acrylamide in food. AB - This paper proposes a new method for quantitative analysis of acrylamide in cereal-based foods and potato chips. The method uses reaction with trifluoroacetic anhydride, and analyses the resulting derivative by use of gas chromatography with electron-capture detection (GC-ECD). The effects of derivatization conditions, including temperature, reaction time, and catalyst, on the acylation reaction were evaluated. Chromatographic analysis was performed on an SE-54 capillary column. Under the optimum conditions, good retention and peak response were achieved for the acrylamide derivative. The analytical method was fully validated by assessment of LODs and LOQs (1 ng g(-1) and 25 ng g(-1), with relative standard deviations (RSD) 2.1 and 3.6, respectively), linearity (R = 0.9935 over the range 0.03-10 MUg g(-1)), and extraction recovery (>96%, with RSD below 2.0, for acrylamide spiked at 1, 20, 50, and 100 ng g(-1); 99.8% for acrylamide content >1000 ng g(-1)). The method requires no clean-up of the acrylamide derivative before injection. The method has been successfully used to determine acrylamide levels in different commercial cereal-based foods, French fries, and potato chips. PMID- 23660694 TI - Modulation of direct electron transfer of cytochrome c by use of a molecularly imprinted thin film. AB - We describe the preparation of a molecularly imprinted polymer film (MIP) on top of a self-assembled monolayer (SAM) of mercaptoundecanoic acid (MUA) on gold, where the template cytochrome c (cyt c) participates in direct electron transfer (DET) with the underlying electrode. To enable DET, a non-conductive polymer film is electrodeposited from an aqueous solution of scopoletin and cyt c on to the surface of a gold electrode previously modified with MUA. The electroactive surface concentration of cyt c was 0.5 pmol cm(-2). In the absence of the MUA layer, no cyt c DET was observed and the pseudo-peroxidatic activity of the scopoletin-entrapped protein, assessed via oxidation of Ampliflu red in the presence of hydrogen peroxide, was only 30% of that for the MIP on MUA. This result indicates that electrostatic adsorption of cyt c by the MUA-SAM substantially increases the surface concentration of cyt c during the electrodeposition step, and is a prerequisite for the productive orientation required for DET. After template removal by treatment with sulfuric acid, rebinding of cyt c to the MUA-MIP-modified electrode occurred with an affinity constant of 100,000 mol(-1) L, a value three times higher than that determined by use of fluorescence titration for the interaction between scopoletin and cyt c in solution. The DET of cyt c in the presence of myoglobin, lysozyme, and bovine serum albumin (BSA) reveals that the MIP layer suppresses the effect of competing proteins. PMID- 23660695 TI - Preparation of a portable point-of-care in vitro diagnostic system, for quantification of canine C-reactive protein, based on a magnetic two-site immunoassay. AB - In this study, characterization of the binding kinetics and optimization of a magnetic permeability based point-of-care (POC) immunoassay system for quantification of canine C-reactive protein (cCRP) is described. The reagent is based on a two-site heterogeneous immunoassay system utilizing conjugated superparamagnetic nanoparticles (SPION) and silica particles, both particles carrying covalently linked antibodies directed to the cCRP analyte. Detection is carried out using a magnetic permeability-based small instrument, adjusted in order to apply it in a POC setting near the patients. The kinetic parameters are characterized and applied in the final design of the assay system. In the cCRP system studied, 90% of the binding between immobilized solid-phase silica antibody and cCRP is complete after only 15 s, and 30 s for the binding between the antibody on the SPION and the bound cCRP on the silica particle. Additionally, the binding rate constants are determined to be 149 and 30 M(-1)s( 1), respectively. The analytical sensitivity, clinical sensitivity, and imprecision verifies the clinical usefulness of the system. Also, quantification of cCRP, using the system described, in dog clinical samples from mixed breeds shows a high correlation to a commercially available comparative cCRP ELISA system (y = 0.98 * +3.2, R(2) = 0.98, n = 47). The immunoassay system described can thus provide the veterinarian a valuable tool for rapid diagnosis and monitoring of inflammatory diseases in dogs in a setting near the patients. PMID- 23660696 TI - C60 fullerene aggregation in aqueous solution. AB - In the present work we develop a novel approach for quantification of the energetics of C60 fullerene aggregation in aqueous media in terms of equilibrium aggregation constant KF. In particular, it is shown that the experimental determination of the magnitude of KF is possible only within the framework of the 'up-scaled aggregation model', considering the C60 fullerene water solution as a solution of fullerene clusters. Using dynamic light scattering (DLS) data we report the value, K(F) = 56,000 M(-1), which is in good agreement with existing theoretical estimates and the results of energetic analyses. It is suggested that the proposed 'up-scaled model' may be used in any instances of non-specific aggregation resulting in formation of large spherical particles. The measurement of the translational diffusion coefficient and the dimensions of the light scattering particles using a DLS approach with respect to C60 fullerene aggregates is found to contain significant systematic errors originating from the interaction effect that is well-known for micellar solutions. As a result, corrections to the equations associated with DLS data are proposed. PMID- 23660697 TI - Association between IL8 haplotypes and pathogen levels in chronic periodontitis. AB - Chronic periodontitis (CP) is considered to be a multifactorial disease influenced by microbial and genetic factors. The aim of the present study was to investigate whether the genetic susceptibility to CP in individuals with the IL8 ATC/TTC haplotype is associated with subgingival levels of periodontopathogens. Sixty-five individuals, grouped according to the presence (n = 28) or absence (n = 37) of the IL8 haplotype, were evaluated. After clinical periodontal evaluation, each group was subdivided according to the presence (CP) or absence (H) of periodontitis. Four subgingival samples were obtained from CP and two samples per subject from H patients. The levels and proportions of Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola were analyzed using quantitative real-time polymerase chain reaction (q-PCR). No differences were found in the proportion of periodontopathogenic bacteria between groups with the presence or absence of the IL8 haplotype. However, in the CP groups, the levels of periodontopathogens were significantly higher in the individuals without the IL8 haplotype than in the individuals with the IL8 haplotype. These results suggest that periodontal destruction may occur in patients who are considered to be genetically susceptible to CP with a lower microbial challenge because of the presence of the IL8 ATC/TTC haplotype than in patients without this haplotype. PMID- 23660699 TI - Ketamine attenuates the lipopolysaccharide-induced inflammatory response in cultured N2a cells. AB - The use of ketamine is recommended in patients with sepsis undergoing surgery due to its anti-inflammatory effects. However, a paucity of data exists with regard to the anti-inflammatory effects of ketamine in the central nervous system. Therefore, the present study aimed to investigate the effect of ketamine on lipopolysaccharide (LPS)-induced inflammatory responses in cultured Neuro2a (N2a) cells and to elucidate its potential mechanism of action. N2a cells were randomly divided into the following 3 groups (n=6): The DMEM culture solution administration alone group, the 0.5 umol/l LPS administration alone group and the 1 umol/l ketamine plus 0.5 umol/l LPS administration group. The expression levels of interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, nuclear factor (NF)-kappaB and inducible nitric oxide synthase (iNOS) were determined. LPS-treated N2a cells exhibited a significant increase in the expression levels of IL-1beta, IL-6, TNF-alpha, NF-kappaB and iNOS, while the administration of ketamine eliminated the LPS-induced production of IL-1beta, IL-6, TNF-alpha, NF kappaB and iNOS. Based on our data, we hypothesized that the anti-inflammatory effect exerted by ketamine on N2a cells was potentially due to the inhibition of NF-kappaB and iNOS. PMID- 23660698 TI - Diagnostic accuracy and effectiveness of the Xpert MTB/RIF assay for the diagnosis of HIV-associated lymph node tuberculosis. AB - Xpert MTB/RIF (Xpert) is recommended for human immunodeficiency virus (HIV) associated pulmonary tuberculosis but not extrapulmonary tuberculosis. We assessed the performance of Xpert for HIV-associated lymph node tuberculosis (LNTB), the most common type of extrapulmonary tuberculosis. Among HIV-infected adults suspected of LNTB presenting for fine needle aspirate (FNA) at a South African hospital, we assessed the diagnostic accuracy of Xpert using either FNA culture or a composite of microscopy, culture, and cytology as the reference standard, and evaluated the impact of different diagnostics on patient management. Among 344 adults with valid FNA culture and Xpert results, 84 (24 %) were positive on microscopy, 149 (43 %) on culture, 152 (53 %) on Xpert, and 181 (57 %) had a cytology result suggestive of tuberculosis. Using liquid culture as the reference standard, the specificity of a single Xpert was suboptimal (88.2 %) but the sensitivity was high [93.3 %, 95 % confidence interval (CI) 87.6-96.6] and increased with decreasing CD4 count (from 87.0 % for CD4 >250 to 98.6 % for CD4 <100 cells/mm(3)). Using a composite reference standard reduced the sensitivity to 79.2 % but increased the specificity to 98.6 %. All Xpert-positive patients initiated treatment within one day, compared to 70 % of culture-positive but Xpert-negative and 13 % of culture- and Xpert-negative but cytology-positive patients. Xpert is accurate and effective and could be endorsed as the initial diagnostic for HIV-associated LNTB. PMID- 23660700 TI - Electron microscopy and composition of raw acorn starch in relation to in vivo starch digestibility. AB - The structure and composition of starch play an important role as co-factors affecting raw starch digestibility: such features were investigated in raw acorn starch from the most diffused oak trees in the Mediterranean basin. A total of 620 whole ripe acorns from Holm (Quercus ilex L., n = 198), Downy (Quercus pubescens Willd., n = 207) and Cork (Quercus suber L., n = 215) oaks sampled on the Sardinia Isle (40 degrees 56' 0'' N; 9 degrees 4' 0'' E; 545 m above the mean sea level) in the same geographical area, were analyzed for their chemical composition. The starch contents ranged between 51.2% and 53.5% of dry matter. The starch granules displayed a spheroid/ovoid and cylindrical shape; on scanning electron microscopic (SEM) analyses, a bimodal distribution of starch granule size was observed both for Holm and Cork oak acorns, whereas the starch granules of Downy oak acorns showed diameters between 10.2 and 13.8 MUm. The specific amylose to amylopectin ratio of acorn starch was 25.8%, 19.5% and 34.0% in the Holm, Downy and Cork oaks, respectively. The (13)C Nuclear Magnetic Resonance (NMR) signal analysis displayed a pivotal spectrum for the identification of the amylose peaks in raw acorn starch, as a basis for the amylose to amylopectin ratio determination. PMID- 23660701 TI - Earlier Arctic springs cause phenological mismatch in long-distance migrants. AB - An uneven change in climate across the Northern Hemisphere might severely affect the phenology of migrating animals, and especially long-distance migrating birds relying on local climatic cues to regulate the timing of migration. We examine the forward displacement of spring in both staging areas and breeding grounds of one such population, the East Atlantic light-bellied brent goose Branta bernicla hrota, and evaluate to what extent their migration has made a proportional response. On the breeding grounds in Svalbard the onset of spring advanced 2 weeks during the 24-year period, whereas no significant trend was found in the temperate staging areas. The timing of migration was constant throughout the study period, mirroring the static climatic conditions in the spring staging areas. These findings indicate a global warming-induced phenological mismatch in light-bellied brent geese, as these might arrive on their breeding grounds well beyond optimal breeding conditions. Our data indicated that productivity was negatively influenced by phenological delay and positively influenced by prolonged snow cover. We argue that both these effects might be representative of a negative influence of the growing phenological mismatch, because years with later thaw might partly offset the effects of increasingly earlier Svalbard springs. During the study period reproduction fell below annual mortality, and the population declined in recent years. The wider implications of these findings may extend to many migrating species, and highlight the urgent need to clarify how global change may influence cues and the associated timing of important life history activities. PMID- 23660702 TI - Wnt-signalling in the embryonic mammary gland. AB - The first member of the Wnt-family ligands was identified 30 years ago as a factor in mouse mammary tumours whose expression was deregulated due to the promoter activity emanating from the proximal integration of the Mouse Mammary Tumour Virus genome (Nusse and Varmus, Embo J 31:2670-84, 2012). The Wnt-ligands invoke a number of molecular-genetic signalling cascades fundamental to the patterning of developing tissues and organs during embryogenesis as well as during postnatal development. The Wnt-signalling cascade that controls the activities of beta-catenin and the T-cell Factor (Tcf)/Lympoid enhancer factor (Lef1) plays a fundamental role in control of all stages of embryonic mammary gland development. We provide here a brief overview of the known aspects of Wnt signalling activities in the embryonic mammary gland and its interactions with other signalling cascades in this developing tissue. PMID- 23660703 TI - Characterization of a D-psicose-producing enzyme, D-psicose 3-epimerase, from Clostridium sp. AB - The gene coding for D-psicose 3-epimerase (DPEase) from Clostridium sp. BNL1100 was cloned and expressed in Escherichia coli. The recombinant enzyme was purified by Ni-affinity chromatography. It was a metal-dependent enzyme and required Co(2+) as optimum cofactor. It displayed catalytic activity maximally at pH 8.0 and 65 degrees C (as measured over 5 min). The optimum substrate was D-psicose, and the K m, turnover number (k cat), and catalytic efficiency (k cat/K m) for D psicose were 227 mM, 32,185 min(-1), and 141 min(-1 )mM(-1), respectively. At pH 8.0 and 55 degrees C, 120 g D-psicose l(-1) was produced from 500 g D-fructose l(-1) after 5 h. PMID- 23660704 TI - Trait pessimism predicts vulnerability to stress-induced anhedonia in rats. AB - Depressive disorder is often associated with cognitive biases. In this study, we took a unique opportunity to investigate whether trait pessimism could predict vulnerability to stress-induced anhedonia in an animal model of depression. In a series of ambiguous-cue interpretation (ACI) tests, we identified animals displaying 'pessimistic' and 'optimistic' traits. Subsequently, the rats were subjected to chronic restraint, and the trait differences in response to stress were investigated using sucrose preference and ACI tests before, during and after the stress regime. Although stress resulted in anhedonia in both subgroups, it occurred faster and lasted longer in the 'pessimistic' compared with the 'optimistic' animals. Chronic stress exposure also increased the negative judgment bias in rats, although this effect was not dependent on the 'pessimistic' trait. For the first time, we demonstrated a link between cognitive judgment bias and vulnerability to stress-induced anhedonia in an animal model. We also introduced a cognitive biomarker, which may be of value for etiological depression studies. PMID- 23660705 TI - Adenovirus capsid-based anti-cocaine vaccine prevents cocaine from binding to the nonhuman primate CNS dopamine transporter. AB - Cocaine addiction is a major problem for which there is no approved pharmacotherapy. We have developed a vaccine to cocaine (dAd5GNE), based on the cocaine analog GNE linked to the capsid proteins of a serotype 5 adenovirus, designed to evoke anti-cocaine antibodies that sequester cocaine in the blood, preventing access to the CNS. To assess the efficacy of dAd5GNE in a large animal model, positron emission tomography (PET) and the radiotracer [(11)C]PE2I were used to measure cocaine occupancy of the dopamine transporter (DAT) in nonhuman primates. Repeat administration of dAd5GNE induced high anti-cocaine titers. Before vaccination, cocaine displaced PE2I from DAT in the caudate and putamen, resulting in 62+/-4% cocaine occupancy. In contrast, dAd5GNE-vaccinated animals showed reduced cocaine occupancy such that when anti-cocaine titers were >4 * 10(5), the cocaine occupancy was reduced to levels of <20%, significantly below the 47% threshold required to evoke the subjective 'high' reported in humans. PMID- 23660707 TI - Social stress engages opioid regulation of locus coeruleus norepinephrine neurons and induces a state of cellular and physical opiate dependence. AB - Stress is implicated in diverse psychiatric disorders including substance abuse. The locus coeruleus-norepinephrine (LC-NE) system is a major stress response system that is also a point of intersection between stress neuromediators and endogenous opioids and so may be a site at which stress can influence drug-taking behaviors. As social stress is a common stressor for humans, this study characterized the enduring impact of repeated social stress on LC neuronal activity. Rats were exposed to five daily consecutive sessions of social stress using the resident-intruder model or control manipulation. LC discharge rate recorded 2 days after the last manipulation was decreased in stressed rats compared with controls. By 10 days after the last manipulation, LC rates were comparable between groups. Systemic administration of the opiate antagonist, naloxone, robustly increased LC discharge rate in a manner suggestive of opiate withdrawal, selectively in stressed rats when administered 2 or 10 days after the last manipulation. This was accompanied by behavioral signs of mild opiate withdrawal. Western blot and electron microscopic studies indicated that repeated social stress decreased corticotropin-releasing factor type 1 receptor and increased MU-opioid receptor levels in the LC. Together, the results suggest that repeated social stress engages endogenous opioid modulation of LC activity and induces signs of cellular and physical opiate dependence that endure after the stress. These cellular effects may predispose individuals with a history of repeated social stress to substance abuse behaviors. PMID- 23660708 TI - A novel agar formulation for isolation and direct enumeration of Vibrio vulnificus from oyster tissue. AB - A new selective and differential medium, Vibrio vulnificus X-Gal (VVX), was developed for direct enumeration of V. vulnificus (Vv) from oyster samples. This agar utilizes cellobiose and lactose as carbon sources, and the antibiotics colistin and polymyxin B as selective agents. Hydrolysis of 5-bromo-4-chloro-3 indolyl- beta-d-galactopyranoside (x-gal), used in the agar as a lactose analog, produces an insoluble blue dye that makes lactose positive colonies easily distinguishable from any non-lactose fermenting bacteria. Various bacterial species were spot plated onto thiosulfate-citrate-bile salts-sucrose agar (TCBS), and CHROMagar Vibrio, two vibrio-specific selective agars, non-selective agar, and VVX to compare selectivity of VVX to other widely used media. A V. vulnificus pure culture was serially diluted on VVX and non-selective agar to determine the VVX percent recovery. Water and oyster samples were spread plated on VVX agar and allowed to incubate for 16-18 h at 33 degrees C. Blue and white colonies from VVX agar were picked and screened by end point PCR for the Vv hemolysin vvhA. VVX agar showed a significant improvement over TCBS and CHROMagar at preventing non target growth. There was an 87.5% recovery compared to non-selective plating and a 98% positivity rate of blue colonies picked from oyster tissue plating. The findings suggest that this new agar is a fast, distinctive, and accurate method for enumeration of V. vulnificus from the environment. PMID- 23660706 TI - Effects of ketamine on context-processing performance in monkeys: a new animal model of cognitive deficits in schizophrenia. AB - Cognitive deficits are at the crux of why many schizophrenia patients have poor functional outcomes. One of the cognitive symptoms experienced by schizophrenia patients is a deficit in context processing, the ability to use contextual information stored in working memory to adaptively respond to subsequent stimuli. As such, context processing can be thought of as the intersection between working memory and executive control. Although deficits in context processing have been extensively characterized by neuropsychological testing in schizophrenia patients, they have never been effectively translated to an animal model of the disease. To bridge that gap, we trained monkeys to perform the same dot pattern expectancy (DPX) task, which has been used to measure context-processing deficits in human patients with schizophrenia. In the DPX task, the first stimulus in each trial provides the contextual information that subjects must remember in order to appropriately respond to the second stimulus in the trial. We found that administration of ketamine, an N-methyl-D-aspartate receptor antagonist, in monkeys caused a dose-dependent failure in context processing, replicating in monkeys the same specific pattern of errors committed by patients with schizophrenia when performing the same task. Therefore, our results provide the first evidence that context-processing dysfunction can be modeled in animals. Replicating a schizophrenia-like behavioral performance pattern in monkeys performing the same task used in humans provides a strong bridge to better understand the biological basis for this psychiatric disease and its cognitive manifestations using animal models. PMID- 23660709 TI - Systematic study on the structures of salen type lanthanide complexes tuned by lanthanide contraction and corresponding luminescence. AB - Two types of N,N'-bis(salicylidene)-1,3-propanediamine (H2L) lanthanide complexes, viz. [Ln(NO3)3(H2L)2].0.2CH3OH [Ln = La (1), Ce (2) and Pr (3)] and [Ln(NO3)3(H2L)2]2.CH2Cl2.CH3OH [Ln = Nd (4), Sm (5), Eu (6), Gd (7), Tb (8) and Yb (9)], have been isolated by reactions of H2L with Ln(NO3)3.6H2O. X-ray crystallographic and PXRD analysis reveal that 1-3 are isomorphic possessing a novel one-dimensional (1D) ladder-like double-chain structure. Complexes 4-9 are isostructural exhibiting a discrete dinuclear structure. Luminescent analysis reveals the lanthanide ion and ligand-centered co-luminescence for 5, 6 and 8, which are attributed to the incomplete energy transfer from the triplet state of H2L to the resonance energy level of the corresponding Ln(iii) ion. Further, the characteristic near infrared (NIR) luminescence of Nd(iii) and Yb(iii) ions for complexes 4 and 9 have been revealed. PMID- 23660710 TI - Master clinician: Richard P. McLaughlin, DDS. Interviewed by Dr Peter M. Sinclair. PMID- 23660711 TI - Second-molar correction with a modified vacuum-formed retainer. PMID- 23660712 TI - Precise direct lingual bonding with the KommonBase. PMID- 23660713 TI - Corticotomy-enhanced intrusion of an overerupted molar using skeletal anchorage and ultrasonic surgery. PMID- 23660714 TI - Correction of dental asymmetry using miniscrew-supported sliding jigs. PMID- 23660715 TI - Corticotomy-assisted orthodontics. PMID- 23660716 TI - Is there a shortage of neurosurgeons in the United States? AB - BACKGROUND: Neurosurgical workforce decision-making is typically driven by the 1 neurosurgeon per 100,000 population ratio proposed in 1977 in the Study on Surgical Services for the United States report. The actual ratio has always been higher than suggested. OBJECTIVE: We evaluated whether the 1:100,000 ratio from the Study on Surgical Services for the United States report is still valid, whether there are enough neurosurgeons in the United States to meet patient needs, and whether demand is driven by patient need. METHODS: For our analysis, the distribution of practicing US neurosurgeons was merged with census data to yield density indices of neurosurgeons by state; a survey assessing practice characteristics was e-mailed to practicing neurosurgeons; and a compilation of job advertisements for US neurosurgeons was evaluated. RESULTS: Multivariant statistical analyses yielded inconclusive results regarding patient demand because existing data sets are not designed to establish patient demand and many neurosurgeons are subspecialized. The data indicated that the ratio of neurosurgeons to total US population is 1:65,580. In the survey responses, neurosurgeon-to-patient ratios varied dramatically by state and were inconsistently correlated with whether neurosurgeons indicated they were overworked or underworked. The 305 job advertisements may indicate a shortage. Twenty-four percent of advertising practices indicated that they are recruiting only for emergency department coverage, and an additional 26% indicated that they might not be recruiting if not for the need for emergency coverage. CONCLUSION: Demand ratios should be reevaluated by region and subspecialty to consider changes in neurosurgery practice. A "shortage" in the employment market may reflect factors other than patient need. PMID- 23660717 TI - Rembrandt's anatomy lesson of Dr. Deijman of 1656 dissected. AB - More than 350 years ago, Rembrandt painted Anatomy Lesson of Dr. Deijman. This group portrait, featuring important members of the Amsterdam Guild of Surgeons, belongs to the series of paintings of the guild. Rembrandt's masterpiece is one of the most famous historical images of a dissection of the brain. Unfortunately, a large part of the original painting was destroyed by a fire. Still visible, however, is how Dr Deijman, doctor of medicine and reader in anatomy, performs a dissection of the cerebral membranes in the corpse of the executed criminal Joris Fonteijn. Because there is no consensus about the nature, accuracy, and symbolic significance of the anatomic structures depicted in the painting, we compared the painting with a real anatomic dissection of the skull of a cadaver to unravel the hidden messages behind this anatomy lesson. PMID- 23660718 TI - Cost analysis comparing ultrasonic fundus-first and conventional laparoscopic cholecystectomy using electrocautery. AB - BACKGROUND: Costs associated with laparoscopic fundus-first cholecystectomy using ultrasonic dissection versus a conventional laparoscopic cholecystectomy has not been compared. METHODS: Adult patients subjected to elective laparoscopic cholecystectomy between June 2002 and March 2004 were randomized to either an ultrasonic fundus-first dissection or dissection from the triangle of Calot with electrocautery. Differences in direct and indirect costs related to either technique were studied. RESULTS: The duration of the operation and hospitalization was longer when dissection was with the conventional technique. With the ultrasonic fundus-first technique, the direct cost was 1,190 SEK lower, and the total cost, taking also the cost for sick leave into account, was 5,370 SEK lower. CONCLUSIONS: Both direct and indirect costs are lower with a laparoscopic fundus-first cholecystectomy using ultrasonic dissection than conventional laparoscopic cholecystectomy using electrocautery. PMID- 23660719 TI - Effectiveness and safety of n-butyl-2-cyanoacrylate medical adhesive for noninvasive patch fixation in laparoscopic inguinal hernia repair. AB - BACKGROUND: Our purpose was to compare the recurrence rate and other clinical outcomes of laparoscopic (LS) transabdominal preperitoneal (TAPP) inguinal hernia repair using n-butyl-2-cyanoacrylate (NBCA) for mesh fixation with those of no mesh fixation and mesh fixation with titanium spiral tacks (ST). METHODS: The medical records of patients who received LS TAPP inguinal hernia repair between 2009 and 2012 at our institution were reviewed. Patients were included if the received LS TAPP with either no mesh fixation, mesh fixation with NBCA only, fixation with ST only, or fixation with NBCA + ST. Outcome measures were operation time, postoperative length of stay, visual analogue scale (VAS) pain score 24 h after surgery, postoperative complications, and hernia recurrence. RESULTS: A total of 1,027 TAPP cases were included. In 552 cases, meshes were fixed with NBCA only, in 89 cases only ST were used, in 47 cases ST and NBCA were used, and in 339 cases meshes were not fixed. The groups were comparable with respect to demographic and clinical characteristics. No surgical complications occurred in any group. VAS pain scores were significantly lower in the nonfixation and NBCA only groups (1.4 +/- 0.6 and 1.3 +/- 0.6, respectively) than in the ST and NBCA + ST groups (2.2 +/- 0.9 and 2.2 +/- 0.7, respectively; P = 0.001). The mean follow-up duration was ~19 months. At the final follow-up, no wound infections or hernia recurrences had occurred in any of the groups. No occurrence of chronic pain was noted in the nonfixation and NBCA only groups, whereas two cases (2.2%) were noted in the ST group and one case (2.1%) in the NBCA + ST group (P = 0.005). CONCLUSIONS: The use of NBCA medical adhesive for noninvasive patch fixation in laparoscopic hernia repair (TAPP) is effective and safe. PMID- 23660720 TI - Minimally invasive surgery: national trends in adoption and future directions for hospital strategy. AB - BACKGROUND: Surgeons have rapidly adopted minimally invasive surgical (MIS) techniques for a wide range of applications since the first laparoscopic appendectomy was performed in 1983. At the helm of this MIS shift has been laparoscopy, with robotic surgery also gaining ground in a number of areas. METHODS: Researchers estimated national volumes, growth forecasts, and MIS adoption rates for the following procedures: cholecystectomy, appendectomy, gastric bypass, ventral hernia repair, colectomy, prostatectomy, tubal ligation, hysterectomy, and myomectomy. MIS adoption rates are based on secondary research, interviews with clinicians and administrators involved in MIS, and a review of clinical literature, where available. Overall volume estimates and growth forecasts are sourced from The Advisory Board Company's national demand model which provides current and future utilization rate projections for inpatient and outpatient services. The model takes into account demographics (growth and aging of the population) as well as non demographic factors such as inpatient to outpatient shift, increase in disease prevalence, technological advancements, coverage expansion, and changing payment models. RESULTS: Surgeons perform cholecystectomy, a relatively simple procedure, laparoscopically in 96 % of the cases. Use of the robot as a tool in laparoscopy is gaining traction in general surgery and seeing particular growth within colorectal surgery. Surgeons use robotic surgery in 15 % of colectomy cases, far behind that of prostatectomy but similar to that of hysterectomy, which have robotic adoption rates of 90 and 20 %, respectively. CONCLUSIONS: Surgeons are using minimally invasive surgical techniques, primarily laparoscopy and robotic surgery, to perform procedures that were previously done as open surgery. As risk-based pressures mount, hospital executives will increasingly scrutinize the cost of new technology and the impact it has on patient outcomes. These changing market dynamics may thwart the expansion of new surgical techniques and heighten emphasis on competency standards. PMID- 23660721 TI - Maintenance training for laparoscopic suturing: the quest for the perfect timing and training model: a randomized trial. AB - BACKGROUND: Although excellent training programs exist for acquiring the challenging skill required in laparoscopic suturing, without subsequent reinforcement, performance is prone to decay. Therefore, maintenance training is proposed to ensure better skill retention. This study aimed to elucidate the ideal timing and frequency of maintenance training as well as the best model to be used for this training. METHODS: After completing a proficiency-based laparoscopic suturing training, 39 medical students attended different maintenance programs represented by four groups: a control group without additional training (group 1), a massed training group with one supervised training session (150 min) after 2.5 months (group 2), and two distributed training groups with five monthly unsupervised training sessions of 30 min on a box trainer (group 3) or the LapMentor((r)) (group 4). Retention testing, after 5 months, included suturing on a box trainer and on a cadaver porcine Nissen model. Performance scores (time and errors) were expressed in seconds. Afterward, time needed to regain proficiency was measured. RESULTS: On the box trainer, the median performance scores were 233 s (interquartile range [IQR] 27 s) for group 1, 180 s (IQR 55 s) for group 2, 169 s (IQR 26 s) for group 3, and 226 s (IQR 66 s) for group 4 (p = 0.03). No difference was seen between groups 2 and 3, both of which significantly outperformed groups 1 and 4. On the porcine Nissen model, no differences were detected between the groups (p = 0.53). Group 3 reached proficiency more quickly than the other groups. CONCLUSIONS: Maintenance training is a valuable and necessary addendum to proficiency-based training programs for laparoscopic suturing. A maintenance-training interval of 1 month with unsupervised training sessions on simple box trainers seems ideal. The LapMentor((r)) did not show any benefit. Performance differences between groups did not translate to a clinically relevant model, indicating that transfer of training is not perfect. PMID- 23660722 TI - Optimization of sympathectomy to treat palmar hyperhidrosis. PMID- 23660723 TI - Laparoscopic total gastrectomy and gastric cancer genome architecture: lessons, cautions, and promises. PMID- 23660724 TI - Clipping for endoscopic perforations: initial success but late complication requiring surgery. AB - INTRODUCTION: This response discusses the article by Kim and colleagues entitled "endoscopic clip closure versus surgery for the treatment of iatrogenic colon perforations developed during diagnostic colonoscopy: a review of 115,285 patients". Iatrogenic colonoscopic perforation, although uncommon, implies serious management problems for endoscopists and surgeons. Nonoperative treatment currently is recommended under certain conditions, and endoscopic clips can primarily close iatrogenic perforations, helping to avoid surgery. Of the 27 colonoscopic perforation cases presented in the article by Kim and colleagues, 16 were managed by endoscopic clipping closure and 11 by primary surgery. Conservative treatment failed for three patients. Only perforation size obtained statistical significance among the nine variables contrasted between the 11 cases with primary surgery and the 13 cases with successful endoscopic clipping. The results for the three patients whose endoscopic closure failed are not reported. AUTHORS' OPINION: The authors of this letter think it would have been interesting if these three patients had been included in the analysis due to the high importance of discovering factors that can predict failure of endoscopic clipping for perforations. CONCLUSIONS: To call attention to possible late complications requiring surgery even when initial conservative management of endoscopic perforation succeeds, the authors of this letter present a case of a colocutaneous (actually, sigmoid-scrotal) fistula in a patient 2 weeks after an apparently successful closure of colonoscopic perforation with an "over-the scope" clip. PMID- 23660725 TI - Reversibility in protein folding: effect of beta-cyclodextrin on bovine serum albumin unfolded by sodium dodecyl sulphate. AB - The mechanism by which the protein bovine serum albumin undergoes unfolding induced by the anionic surfactant sodium dodecyl sulphate (SDS) and then the subsequent refolding brought in by beta-Cyclodextrin (beta-CD) was studied by steady-state fluorescence, time resolved measurements and Circular Dichroism (CD) spectroscopy. The prominent findings of this investigation are (i) SDS unfolds the protein in a sequential manner passing through three different phases of binding of SDS followed by a saturation phase; (ii) the refolding process is initiated through inclusion/removal of SDS molecules by beta-CD and hence this also seems to happen in a phased manner; (iii) the process of refolding seems to be reversible to the unfolding process but the protein does not regain all its structure on refolding; (iv) however, CD results reveal almost 100% recovery of the secondary structure lost during SDS induced unfolding. We have conclusively proved that there is a marginal structural gain of the native protein at low surfactant concentration and beta-CD also induces a marginal structural loss to the native protein. The unfolding process induced by SDS seems to be spontaneous and the binding of SDS to BSA is rather strong, as revealed by thermodynamic parameters. PMID- 23660726 TI - Organocatalytic visible light mediated synthesis of aryl sulfides. AB - Photo-sensitized synthesis of arylsulfides from arenediazonium salts in the presence of eosin Y has been developed. This protocol exhibits high functional group tolerance and a wide substrate scope and is an attractive alternative to the thermal reaction that involves explosive intermediates. PMID- 23660727 TI - The effect of emotion and physician communication behaviors on surrogates' life sustaining treatment decisions: a randomized simulation experiment. AB - OBJECTIVE: Surrogate decision makers for critically ill patients experience strong negative emotional states. Emotions influence risk perception, risk preferences, and decision making. We sought to explore the effect of emotional state and physician communication behaviors on surrogates' life-sustaining treatment decisions. DESIGN: 5 * 2 between-subject randomized factorial experiment. SETTING: Web-based simulated interactive video meeting with an intensivist to discuss code status. SUBJECTS: Community-based participants 35 and older who self-identified as the surrogate for a parent or spouse recruited from eight U.S. cities through public advertisements. INTERVENTIONS: Block random assignment to emotion arousal manipulation and each of the four physician communication behaviors. MEASUREMENTS AND MAIN RESULTS: Surrogate's code status decision (cardiopulmonary resuscitation vs do not resuscitate/allow natural death). Two hundred fifty-six of 373 respondents (69%) logged-in and were randomized: average age was 50; 70% were surrogates for a parent; 63.5% were women; 76% were white, 11% black, and 9% Asian; and 81% were college educated. When asked about code status, 56% chose cardiopulmonary resuscitation. The emotion arousal manipulation increased the score on depression-dejection scale (beta = 1.76 [0.58 - 2.94]) but did not influence cardiopulmonary resuscitation choice. Physician attending to emotion and framing the decision as the patient's rather than the surrogate's did not influence cardiopulmonary resuscitation choice. Framing no cardiopulmonary resuscitation as the norm rather than cardiopulmonary resuscitation resulted in fewer surrogates choosing cardiopulmonary resuscitation (48% vs 64%, odds ratio, 0.52 [95% CI, 0.32-0.87]), as did framing the alternative to cardiopulmonary resuscitation as "allow natural death" rather than do not resuscitate (49% vs 61%, odds ratio, 0.58 [95% CI, 0.35 0.96]). CONCLUSIONS: Experimentally induced emotional state did not influence code status decisions, although small changes in physician communication behaviors substantially influenced this decision. PMID- 23660728 TI - Mechanical versus manual chest compressions in out-of-hospital cardiac arrest: a meta-analysis. AB - OBJECTIVE: The objective of this study was to conduct a meta-analysis of literature examining rates of return of spontaneous circulation from load distributing band and piston-driven chest compression devices as compared with manual cardiopulmonary resuscitation. DATA SOURCES: Searches were conducted in MEDLINE, the ClinicalTrials.gov registry, and bibliographies on manufacturer websites for studies written in English. STUDY SELECTION: Selection criteria for the meta-analysis required that studies must be human controlled (randomized, historical, or case-control) investigations with confirmed out-of-hospital cases. DATA EXTRACTION: A total of 12 studies (load-distributing band cardiopulmonary resuscitation versus manual cardiopulmonary resuscitation = 8, piston-driven cardiopulmonary resuscitation versus manual cardiopulmonary resuscitation = 4), comprising a total of 6,538 subjects with 1,824 return of spontaneous circulation events, met the selection criteria. DATA SYNTHESIS: Random effects models were used to assess the relative effect of treatments on return of spontaneous circulation. Compared with manual cardiopulmonary resuscitation, load distributing band cardiopulmonary resuscitation had significantly greater odds of return of spontaneous circulation (odds ratio, 1.62 [95% CI, 1.36, 1.92], p < 0.001). The treatment effect for piston-driven cardiopulmonary resuscitation was similar to manual cardiopulmonary resuscitation (odds ratio, 1.25 [95% CI, 0.92, 1.68];p = 0.151). The corresponding difference in percentages of return of spontaneous circulation rates from cardiopulmonary resuscitation was 8.3% for load-distributing band cardiopulmonary resuscitation and 5.2% for piston-driven cardiopulmonary resuscitation. Compared with manual cardiopulmonary resuscitation, combining both mechanical cardiopulmonary resuscitation devices produced a significant treatment effect in favor of higher odds of return of spontaneous circulation with mechanical cardiopulmonary resuscitation devices (odds ratio, 1.53 [95% CI, 1.32, 1.78], p < 0.001). CONCLUSION: The ability to achieve return of spontaneous circulation with mechanical chest compression devices is significantly improved when compared with manual chest compressions. In the case of load-distributing band cardiopulmonary resuscitation, it was superior to manual cardiopulmonary resuscitation as the odds of return of spontaneous circulation were over 1.6 times greater. The robustness of these findings should be tested in large randomized clinical trials. PMID- 23660729 TI - A new severity of illness scale using a subset of Acute Physiology And Chronic Health Evaluation data elements shows comparable predictive accuracy. AB - OBJECTIVES: Severity of illness scores have gained considerable interest for their use in predicting outcomes such as mortality and length of stay. The most sophisticated scoring systems require the collection of numerous physiologic measurements, making their use in real-time difficult. A severity of illness score based on a few parameters that can be captured electronically would be of great benefit. Using a machine-learning technique known as particle swarm optimization, we attempted to reduce the number of physiologic parameters collected in the Acute Physiology, Age, and Chronic Health Evaluation IV system without losing predictive accuracy. DESIGN: Retrospective cohort study of ICU admissions from 2007 to 2011. SETTING: Eighty-six ICUs at 49 U.S. hospitals where an Acute Physiology, Age, and Chronic Health Evaluation IV system had been installed. PATIENTS: 81,087 admissions, of which 72,474 did not have any missing values. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Machine-learning algorithms were used to come up with the minimal set of variables that were capable of yielding an accurate severity of illness score: the Oxford Acute Severity of Illness Score. Predictive models of ICU mortality using Oxford Acute Severity of Illness Score were developed on admissions during 2007-2009 and validated on admissions during 2010-2011. The most parsimonious Oxford Acute Severity of Illness Score consisted of seven physiologic measurements, elective surgery, age, and prior length of stay. Predictive models of ICU mortality using Oxford Acute Severity of Illness Score achieved an area under the receiver operating characteristic curve of 0.88 and calibrated well. CONCLUSIONS: A reduced severity of illness score had discrimination and calibration equivalent to more complex existing models. This was accomplished in large part using machine-learning algorithms, which can effectively account for the nonlinear associations between physiologic parameters and outcome. PMID- 23660731 TI - Predictive ability of the stability and workload index for transfer score to predict unplanned readmissions after ICU discharge. AB - OBJECTIVE: Unplanned readmission of hospitalized patients to an ICU is associated with an increased mortality and hospital length of stay. The ability to identify patients at risk, who would benefit from prolonged ICU treatment, is limited. The aim of this study is to validate a previously published numerical index named the Stability and Workload Index for Transfer in a heterogeneous group of ICU patients. DESIGN: In this retrospective data analysis, the Stability and Workload Index for Transfer score was calculated for all patients, and the ability of the score to predict readmission was compared with the original publication. SETTING: Four ICUs, one intermediate care unit, and one postanesthesia care unit of the department of anesthesia and intensive care of a university hospital. PATIENTS: All consecutive patients treated in one of the units. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Unplanned ICU readmissions or unexpected death within 7 days of ICU discharge. The data of 7,175 patients were included in the analysis. Five hundred ninety-six patients were readmitted or died within 7 days of discharge. The patients who are readmitted to the ICU are significantly older and have significantly higher scores that define the severity of disease at the time of admission and discharge of their first ICU stay. The source of admission for the initial ICU stay did not differ (p = 0.055), and the last Glasgow Coma Scale and the last PaO2/FIO2 ratio before discharge from the ICU were higher in patients who did not need a readmission to the ICU. The performance of the Stability and Workload Index for Transfer score is poor with an area under the receiver operator curve of 0.581 (95% CI, 0.556-0.605; p < 0.001). CONCLUSIONS: Based on the data from our patients, the proposed Stability and Workload Index for Transfer score by Gajic et al is not ideal in aiding the clinician in the decision, if a patient can be discharged safely from the ICU and further research is necessary to define the patients at risk for readmission. PMID- 23660732 TI - Views of pediatric intensive care physicians on the ethics of organ donation after cardiac death. AB - OBJECTIVE: Donation after cardiac death has been endorsed by professional organizations, including the American Academy of Pediatrics as a means of increasing the supply of transplantable organs. However, ethical concerns have been raised about donation after cardiac death, especially in children. This study explores the views of pediatric intensive care physicians on the ethics of pediatric donation after cardiac death. DESIGN: Internet survey. SUBJECTS: Physician members of the American Academy of Pediatrics Section of Critical Care. INTERVENTIONS: Physicians were emailed an anonymous survey consisting of four demographic items and 16 items designed to assess their views on the ethics of pediatric donation after cardiac death. Responses to ethics items were rated on a 5-point scale ranging from strongly disagree to strongly agree. Physicians were also given the opportunity to provide free-text comments regarding their views. MEASUREMENTS AND MAIN RESULTS: Of the 598 eligible physicians, 264 (44.1%) responded to the survey. Of these, 193 (73.4%) were practicing in a transplant center and 160 (60.6%) participated in at least one donation after cardiac death procedure at the time of survey completion. Two hundred twenty (83.4%) agreed or strongly agreed that regarding donation after cardiac death, parents should be able to make decisions based on the best interests of their child. Two hundred twenty-two (84.1%) agreed or strongly agreed that it is not acceptable to harvest organs from a child before the declaration of death, consistent with the Dead Donor Rule. However, only 155 (59.1%) agreed or strongly agreed that the time of death in donation after cardiac death can be conclusively determined. Twenty-nine (11.0%) agreed or strongly agreed that the pediatric donation after cardiac death donor may feel pain or suffering during the harvest procedure. CONCLUSIONS: Most pediatric intensive care physicians agree that the Dead Donor Rule should be applied for donation after cardiac death and that donation after cardiac death can be consistent with the best interest standard. However, concerns about the ability to determine time of death for the purpose of organ donation and the possibility of increasing donor pain and suffering exist. PMID- 23660730 TI - The influence of prehospital systemic corticosteroid use on development of acute respiratory distress syndrome and hospital outcomes. AB - OBJECTIVE: The role of systemic corticosteroids in pathophysiology and treatment of acute respiratory distress syndrome is controversial. Use of prehospital systemic corticosteroid therapy may prevent the development of acute respiratory distress syndrome and improve hospital outcomes. DESIGN: This is a preplanned retrospective subgroup analysis of the prospectively identified cohort from a trial by the U.S. Critical Illness and Injury Trials Group designed to validate the Lung Injury Prediction Score. SETTING: Twenty-two acute care hospitals. PATIENTS: : Five thousand eighty-nine patients with at least one risk factor for acute respiratory distress syndrome at the time of hospitalization. INTERVENTION: Propensity-based analysis of previously recorded data. MEASUREMENTS AND MAIN RESULTS: Three hundred sixty-four patients were on systemic corticosteroids. Prevalence of acute respiratory distress syndrome was 7.7% and 6.9% (odds ratio, 1.1 [95% CI, 0.8-1.7]; p = 0.54) for patients on systemic corticosteroid and not on systemic corticosteroids, respectively. A propensity for being on systemic corticosteroids was derived through logistic regression by using all available covariates. Subsequently, 354 patients (97%) on systemic corticosteroids were matched to 1,093 not on systemic corticosteroids by their propensity score for a total of 1,447 patients in the matched set. Adjusted risk for acute respiratory distress syndrome (odds ratio, 0.96 [95% CI, 0.54-1.38]), invasive ventilation (odds ratio, 0.84 [95% CI, 0.62-1.12]), and in-hospital mortality (odds ratio, 0.97 [95% CI, 0.63-1.49]) was then calculated from the propensity-matched sample using conditional logistic regression model. No significant associations were present. CONCLUSIONS: Prehospital use of systemic corticosteroids neither decreased the development of acute respiratory distress syndrome among patients hospitalized with at one least risk factor, nor affected the need for mechanical ventilation or hospital mortality. PMID- 23660733 TI - Clinical features of critically ill patients with Shiga toxin-induced hemolytic uremic syndrome. AB - OBJECTIVE: In Spring 2011, an unprecedented outbreak of Shiga toxin-producing Escherichia coli serotype O104:H4-associated hemolytic uremic syndrome occurred in Northern Germany. The aim of this study was to describe the clinical characteristics, treatments, and outcomes of critically ill patients with Shiga toxin-producing E. coli-associated hemolytic uremic syndrome during this outbreak. DESIGN, SETTING, AND PATIENTS: Multicenter, retrospective, observational study of critically ill adult patients with Shiga toxin-producing E. coli-associated hemolytic uremic syndrome in six hospitals in Hamburg, Germany, between May 2011 and August 2011. MEASUREMENTS AND MAIN RESULTS: During the study period, 106 patients with Shiga toxin-producing E. coli-associated hemolytic uremic syndrome were admitted to eight ICUs. The median age was 40 years (range, 18-83) with a female:male ratio of 3:1. The median time from onset of clinical symptoms to hospital admission was 3 days and from hospital to ICU admission an additional 3 days. A total of 101 patients (95.3%) had acute renal failure and 78 (73.6%) required renal replacement therapy. Intubation and mechanical ventilation were required in 38 patients (35.8%) and noninvasive ventilation was required in 17 patients (16.0%). The median duration of invasive ventilation was 7 days (range, 1-32 days) and the median ICU stay was 10 days (range, 1-45 days). Fifty-one patients (48.1%) developed sepsis; of these 51 patients, 27 (25.4%) developed septic shock. Seventy patients (66.0%) developed severe neurological symptoms. Ninety-seven patients (91.5%) were treated with plasma exchange and 50 patients (47.2%) received eculizumab (monoclonal anti-C5 antibody). The mortality rate was 4.7%. Mild residual neurological symptoms were present in 21.7% of patients at ICU discharge, and no patient required renal replacement therapy 6 months after ICU admission. CONCLUSIONS: During the 2011 Shiga toxin-producing E. coli-associated hemolytic uremic syndrome outbreak in Germany, critical illness developed rapidly after hospital admission, often in young women. The infection was associated with severe neurological and renal symptoms, requiring mechanical ventilation and renal replacement therapy in a substantial proportion of patients. Overall, recovery was much better than expected. PMID- 23660734 TI - Energy loss and coronary flow simulation following hybrid stage I palliation: a hypoplastic left heart computational fluid dynamic model. AB - OBJECTIVES: The theoretical differences in energy losses as well as coronary flow with different band sizes for branch pulmonary arteries (PA) in hypoplastic left heart syndrome (HLHS) remain unknown. Our objective was to develop a computational fluid dynamic model (CFD) to determine the energy losses and pulmonary-to-systemic flow rates. This study was done for three different PA band sizes. METHODS: Three-dimensional computer models of the hybrid procedure were constructed using the standard commercial CFD softwares Fluent and Gambit. The computer models were controlled for bilateral PA reduction to 25% (restrictive), 50% (intermediate) and 75% (loose) of the native branch pulmonary artery diameter. Velocity and pressure data were calculated throughout the heart geometry using the finite volume numerical method. Coronary flow was measured simultaneously with each model. Wall shear stress and the ratio of pulmonary-to systemic volume flow rates were calculated. Computer simulations were compared at fixed points utilizing echocardiographic and catheter-based metric dimensions. RESULTS: Restricting the PA band to a 25% diameter demonstrated the greatest energy loss. The 25% banding model produced an energy loss of 16.76% systolic and 24.91% diastolic vs loose banding at 7.36% systolic and 17.90% diastolic. Also, restrictive PA bands had greater coronary flow compared with loose PA bands (50.2 vs 41.9 ml/min). Shear stress ranged from 3.75 Pascals with restrictive PA banding to 2.84 Pascals with loose banding. Intermediate PA banding at 50% diameter achieved a Qp/Qs (closest to 1) at 1.46 systolic and 0.66 diastolic compared with loose or restrictive banding without excess energy loss. CONCLUSIONS: CFD provides a unique platform to simulate pressure, shear stress as well as energy losses of the hybrid procedure. PA banding at 50% provided a balanced pulmonary and systemic circulation with adequate coronary flow but without extra energy losses incurred. PMID- 23660735 TI - Multidetector computed tomography evaluation of cavernous haemangioma of the azygous vein. AB - Giant cavernous haemangioma of azygous arch is extremely rare. We present the multidetector computed tomography (MDCT) features of a mediastinal cavernous haemangioma in an asymptomatic child detected in a follow-up examination. MDCT features with multiple venous lakes filling from the periphery, focal specks of calcification, low-density soft tissue mass along with tortuous varicose veins and large feeding veins from the abdomen are suggestive of cavernous haemangioma. PMID- 23660736 TI - Pectus tunneloscopy: making Nuss procedure for pectus excavatum safe. AB - OBJECTIVES: The Nuss procedure for pectus excavatum involves the risk of cardiac injury during the creation of the retrosternal tunnel and during bar introduction or removal across the tunnel. A modified novel real-time technique for the safe introduction of the Nuss bar across the crucial retrosternal tunnel blind spot during introduction and removal is described. METHODS: In 2012, we devised a technique for real-time endovision-guided introduction of the Nuss bar called pectus tunneloscopy. Between February 2012 and December 2012, 6 patients with pectus excavatum had their bar introduced across the tunnel using this technique. RESULTS: This technique provided safe introduction and removal of the bar during the multiple times the bar is remodelled before final fixation. CONCLUSIONS: Pectus tunneloscopy is a real-time endovision surgical technique, providing safe introduction of the bar across the crucial retrosternal tunnel blind spot. PMID- 23660737 TI - Effects of low-power LED and therapeutic ultrasound in the tissue healing and inflammation in a tendinitis experimental model in rats. AB - This work evaluated the anti-inflammatory response of low-power light-emitting diode (LED) and ultrasound (US) therapies and the quality and rapidness of tendon repair in an experimental model of tendinitis, employing histomorphometry and Raman spectroscopy. Tendinitis was induced by collagenase into the right tendon of 35 male Wistar rats with an average weight of 230 g. The animals were randomly separated into seven groups of five animals each: tendinitis without treatment control (TD7 and TD14, where 1 and 2 indicated sacrifice on the 7th and 14th day, respectively), tendinitis submitted to US therapy (US7 and US14) and tendinitis submitted to LED therapy (LED7 and LED14). Contralateral tendons of the TD group at the 14th day were used as the healthy group (H). US treatment was applied in pulsed mode at 10 %, 1 MHz frequency, 0.5 W/cm(2), 120 s. LED therapy parameters were 4 J/cm(2), 120 s, daily dose at the same time and same point. Sacrifice was performed on the 7th or 14th day. Histomorphometric analysis showed lower number of fibroblasts on the 14th day of therapy for the US-treated group, compared to the TD and LED, indicating lower tissue inflammation. Raman showed that the LED group had an increase in the amount of collagen I and III from the 7th to the 14th day, which would indicate more organized fibers and a better quality of the healing, and US showed lower collagen I synthesis in the 14th day compared to H, indicating a lower tissue reorganization. PMID- 23660739 TI - A unique embossed carbon layer from induced domain alignment in a block copolymer thin film under an electric field. AB - A unique embossed carbon surface with regionally heterogeneous properties is constructed via carbonization of a polyacrylonitrile-b-poly(methyl methacrylate) (PAN-b-PMMA) block copolymer thin film precursor self-assembled under an external electric field. The PAN-b-PMMA block copolymer generates a thin surface having microdomains with alternating PAN-PMMA compositions different from that of the matrix when the microdomain alignment is induced under an electric field due to the difference in dielectric susceptibilities between two blocks. PMID- 23660738 TI - Single or repeated antimicrobial photodynamic therapy as adjunct to ultrasonic debridement in residual periodontal pockets: clinical, microbiological, and local biological effects. AB - This study aims to assess in residual periodontal pockets the clinical, microbiological, and local biological effects of antimicrobial photodynamic therapy (PDT), delivered after ultrasonic instrumentation either once or twice in a 1-week interval. A single center, three-arm randomized longitudinal study was carried out for 6 months. Twenty-eight systemically healthy patients on periodontal maintenance with residual pockets (pocket depth (PD) >=5 mm, clinical attachment loss >=2 mm, and bleeding upon probing (BOP+)) were included. Residual pockets on three teeth, separated from each other by at least two other teeth, served as study sites. After ultrasonic debridement, they were randomly assigned to either PDT delivered twice within 1 week (group A), PDT delivered only once (group B), or sham treatment without activating the laser (group C). Methylene blue was applied with a blunt irrigator tip into the pockets. Sites were irradiated with laser light at a wavelength of 670 nm using a light-diffusing tip introduced into the pocket. Initial PD was 5.9 +/- 0.9, 6.3 +/- 1.3, and 6.3 +/- 1.5 mm in groups A, B, and C, respectively, differences being nonsignificant. PD was significantly reduced in all groups. At month 3, PD was significantly lower in groups A (2.9 +/- 1.1 mm; p = 0.04) and B (2.8 +/- 1.1 mm; p = 0.03) compared to group C (3.5 +/- 1.2 mm). At month 6, none of the sites in group A had persisting pockets PD >4 mm and BOP+, whereas two sites in group B and four sites in group C stayed in this category. Detection frequencies of the studied microorganisms at >1,000 and >100.000 cells/ml did not change significantly from baseline to months 3 or 6 in any group. A significant overall decrease was observed from baseline to month 6 for C-reactive protein, serum amyloid A, fibrinogen, procalcitonin, and alpha-2 macroglobulin. When looking at the groups separately, C-reactive protein was significantly lower only if the laser had been activated twice (p < 0.05). Other differences between groups were not significant. A single or double episodes of PDT had some additional benefit over ultrasonic instrumentation alone. PMID- 23660740 TI - The effects of attentional load on saccadic task switching. AB - Everyday life requires the ability to flexibly switch between tasks. Often, task switching is accompanied by concurrent cognitive activities that compete for limited attentional resources. This study aimed to characterize the effects of attentional load on task switching. In experiment 1, participants performed an interleaved pro-saccade and anti-saccade task. In experiment 2, participants performed an interleaved pro-saccade and anti-saccade task simultaneously with a rapid serial visual presentation task that has been shown to create an attentional load. Error rates and reaction times of pro-saccades and anti saccades were analysed for both experiments separately and together. Overall, error rates and reaction times increased with attentional load. With attentional load, switches to pro-saccades were associated with increased error rates and reaction times, whereas switches to anti-saccades were only associated with increased error rates. We propose that attentional load interferes with neural task-set representation and that the resulting executive control is different for the dominant and non-dominant task. PMID- 23660741 TI - Decreasing perceived optic flow rigidity increases postural sway. AB - Optic flow simulating self-motion through the environment can induce postural adjustments in observers. Some studies investigating this phenomenon have used optic flow patterns increasing in speed from center to periphery, whereas others used optic flow patterns with a constant speed. However, altering the speed gradient of an optic flow stimulus changes the perceived rigidity of such a stimulus. Optic flow stimuli that are perceived as rigid can be expected to provide a stronger sensation of self-motion than non-rigid optic flow, and this may well be reflected in the amount of postural sway. The current study, therefore, examined, by manipulating the speed gradient, to what extent the rigidity of an optic flow stimulus influences posture along the anterior posterior axis. We used radial random dot expanding or contracting optic flow patterns with three different speed profiles (single-speed, linear speed gradient or quadratic speed gradient) that differentially induce the sensation of self motion. Interestingly, most postural sway was observed for the non-rigid single speed optic flow pattern, which contained the least self-motion information of the three profiles. Moreover, we found an anisotropy in that contracting optic flow produced more postural sway than expanding optic flow. In addition, the amount of postural sway increased with increasing stimulus speed, but for contracting optic flow only. Taken together, the results of the current study support the view that visual and sensorimotor systems appear to be tailored toward compensating for rigid optic flow stimulation. PMID- 23660742 TI - Fast-ball sports experts depend on an inhibitory strategy to reprogram their movement timing. AB - The purpose of our study was to clarify whether an inhibitory strategy is used for reprogramming of movement timing by experts in fast-ball sports when they correct their movement timing due to unexpected environmental changes. We evaluated the influence of disruption of inhibitory function of the right inferior frontal gyrus (rIFG) on reprogramming of movement timing of experts and non-experts in fast-ball sports. The task was to manually press a button to coincide with the arrival of a moving target. The target moved at a constant velocity, and its velocity was suddenly either increased or decreased in some trials. The task was performed either with or without transcranial magnetic stimulation (TMS), which was delivered to the region of the rIFG. Under velocity change conditions without TMS, the experts showed significantly smaller timing errors and a higher rate of reprogramming of movement timing than the non experts. Moreover, TMS application during the task significantly diminished the expert group's performance, but not the control group, particularly in the condition where the target velocity decreases. These results suggest that experts use an inhibitory strategy for reprogramming of movement timing. In addition, the rIFG inhibitory function contributes to the superior movement correction of experts in fast-ball sports. PMID- 23660743 TI - Imitation behavior is sensitive to visual perspective of the model: an fMRI study. AB - Imitation behavior and accompanying brain activity can be affected by the perspective of the model adopted. The present study was designed to understand the effect of a model's perspective in terms of the view (1st person vs. 3rd person) and the anatomical congruency of the limb between the model and the performer (congruent vs. incongruent). Eighteen young participants observed video clips of a model's finger-lifting behavior and lifted the same finger on their right hand as quickly as possible. Half of the video clips were filmed from the view of the participant (the 1st person view), whereas the other half were filmed from the perspective of facing a mirror (the 3rd person view). Each video clip depicted the finger lifting of the model's right (congruent) or left (incongruent) hand. Comparisons of the latency to imitate among the four perspective conditions showed significantly shorter latency for the 1st person congruent and 3rd person-incongruent conditions. Hemodynamic measurements with functional magnetic resonance imaging showed that shorter latency was explained with less involvement of the brain areas that are activated when a task is relatively complex. The brain areas considered to be a part of neural substrates of imitation were significantly activated under the 1st person view conditions regardless of the hand congruency. These findings suggest that, although the latency to imitate finger lifting was determined by the complexity of the task induced with the model's perspective, imitation behavior seemed to be more effectively guided with the models filmed from the 1st person view. PMID- 23660745 TI - A secure and efficient uniqueness-and-anonymity-preserving remote user authentication scheme for connected health care. AB - Connected health care has several applications including telecare medicine information system, personally controlled health records system, and patient monitoring. In such applications, user authentication can ensure the legality of patients. In user authentication for such applications, only the legal user/patient himself/herself is allowed to access the remote server, and no one can trace him/her according to transmitted data. Chang et al. proposed a uniqueness-and-anonymity-preserving remote user authentication scheme for connected health care (Chang et al., J Med Syst 37:9902, 2013). Their scheme uses the user's personal biometrics along with his/her password with the help of the smart card. The user's biometrics is verified using BioHashing. Their scheme is efficient due to usage of one-way hash function and exclusive-or (XOR) operations. In this paper, we show that though their scheme is very efficient, their scheme has several security weaknesses such as (1) it has design flaws in login and authentication phases, (2) it has design flaws in password change phase, (3) it fails to protect privileged insider attack, (4) it fails to protect the man-in-the middle attack, and (5) it fails to provide proper authentication. In order to remedy these security weaknesses in Chang et al.'s scheme, we propose an improvement of their scheme while retaining the original merit of their scheme. We show that our scheme is efficient as compared to Chang et al.'s scheme. Through the security analysis, we show that our scheme is secure against possible attacks. Further, we simulate our scheme for the formal security verification using the widely-accepted AVISPA (Automated Validation of Internet Security Protocols and Applications) tool to ensure that our scheme is secure against passive and active attacks. In addition, after successful authentication between the user and the server, they establish a secret session key shared between them for future secure communication. PMID- 23660744 TI - Ledge and wedge: younger and older adults' perception of action possibilities. AB - The current study investigated whether younger (college-age) and older adults (60+ years) differ in their ability to perceive safe and unsafe motor actions. Participants decided whether to walk through openings varying in width in two penalty conditions: In the doorway condition, if participants attempted to squeeze through impossibly narrow openings, the penalty for error was entrapment. In the ledge condition, if participants attempted to inch along impossibly narrow ledges, the penalty for error was falling. Results showed that across the lifespan, people consider falling to be a more severe penalty than getting stuck: Both younger and older adults made more conservative decisions when the penalty for error was falling, and older women were especially leery of falling. In both age groups, abilities and decisions were based on dynamic properties of the body, such as compressed body size in the doorway condition and balance in the ledge condition. Findings indicate that failure to perceive possibilities for action is unlikely to be the cause of the increased prevalence of falling in older adults. PMID- 23660746 TI - Effect of bortezomib in combination with cisplatin and 5-fluorouracil on 4T1 breast cancer cells. AB - Bortezomib is a highly selective and reversible inhibitor of the 26S proteasome. It has been approved for the treatment of patients with relapsed and refractory multiple myeloma. A number of studies have been conducted to evaluate the activity and safety of bortezomib either alone or in combination with several cytotoxic agents and radiation. In the current study, the efficacy of bortezomib alone or in combination with cisplatin and 5-fluorouracil was evaluated in 4T1 breast cancer cells, a highly metastatic murine cancer cell line. Using MTT assay, IC50 values of cisplatin and 5-fluorouracil were determined to be 14.2 and 8.9 uM for cisplatin and 5-fluorouracil, respectively. The effects of different concentrations of cisplatin and 5-fluorouracil in combination with two different concentrations of bortezomib were examined in the 4T1 cells. Statistically significant differences were found when 1 or 5 uM cisplatin was combined with 10 or 50 nM bortezomib. Similarly, 1 uM 5-fluorouracil or 5 uM 5-fluorouracil in combination with 10 nM bortezomib caused significant cell death as compared to treatment with single agents. However, 1 or 5 uM 5-fluorouracil did not potentiate the effects of higher concentrations of bortezomib (50 nM). The effect of the combination of cisplatin, 5-fluorouracil and bortezomib was determined by soft agar assay. It was confirmed that a combination of cisplatin and bortezomib was more effective than each drug as a monotherapy. Therefore, the combination of cisplatin and bortezomib should be tested further in clinical settings. PMID- 23660748 TI - Landfill monitoring using remote sensing: a case study of Glina, Romania. AB - Landfill monitoring is one of the most important components of waste management. This article presents a case study on landfill monitoring using remote sensing technology. The study area was the Glina landfill, one of the largest municipal waste disposal sites in Romania. The methodology consisted of monitoring the differences of temperature computed for several distinct waste disposal zones with respect to a ground reference area, all of them located within the landfill site. The remote sensing data used were Landsat satellite multi-temporal data. The differences of temperature were computed using Landsat thermal infrared data. The study confirmed the use of multi-temporal Landsat imagery as a complementary data source. PMID- 23660747 TI - Lack of release of bound anthocyanins and phenolic acids from carrot plant cell walls and model composites during simulated gastric and small intestinal digestion. AB - Separately, polyphenols and plant cell walls (PCW) are important contributors to the health benefits associated with fruits and vegetables. However, interactions with PCW which occur either during food preparation or mastication may affect bioaccessibility and hence bioavailability of polyphenols. Binding interactions between anthocyanins, phenolic acids (PAs) and PCW components, were evaluated using both a bacterial cellulose-pectin model system and a black carrot puree system. The majority of available polyphenols bound to PCW material with 60-70% of available anthocyanins and PAs respectively binding to black carrot puree PCW matter. Once bound, release of polyphenols using acidified methanol is low with only ~20% of total anthocyanins to ~30% of PAs being released. Less than 2% of bound polyphenol was released after in vitro gastric and small intestinal (S.I.) digestion for both the model system and the black carrot puree PCW matter. Confocal laser scanning microscopy shows localised binding of anthocyanins to PCW. Very similar patterns of binding for anthocyanins and PAs suggest that PAs form complexes with anthocyanins and polysaccharides. Time dependent changes in extractability with acidified methanol but not the total bound fraction suggests that initial non-specific deposition on cellulose surfaces is followed by rearrangement of the bound molecules. Minimal release of anthocyanins and PAs after simulated gastric and S.I. digestion indicates that polyphenols in fruits and vegetables which bind to the PCW will be transported to the colon where they would be expected to be released by the action of cell wall degrading bacteria. PMID- 23660749 TI - Evaluation of the association between Hispanic ethnicity and disease activity and severity in a large cohort of patients with juvenile idiopathic arthritis. AB - To examine the association between ethnicity and disease activity in patients with juvenile idiopathic arthritis (JIA), and to determine the association of ethnicity with disease severity and disability in this population. CARRAnet, a US database containing information (collected between May 2010 and June 2011) on almost 3,000 subjects with JIA, was used. Demographic variables were compared between Hispanic patients and non-Hispanic patients. Mann-Whitney and chi-square tests were used to compare indicators of disease activity, as well as imaging evidence of joint damage, and Childhood Health Assessment Questionnaire (CHAQ) scores between ethnicities. Two linear regression models were used to determine the association of ethnicity with number of active joints in JIA, and the association between ethnicity and disability (CHAQ scores). A total of 2,704 patients with JIA (277 Hispanic; 2,427 non-Hispanic) were included. Income and health insurance coverage were higher in non-Hispanics. RF-positive polyarticular JIA, positive RF and anti-CCP, as well as use of systemic steroids were more frequent in Hispanics. Imaging evidence of joint damage was present in 32 % of the Hispanic patients compared to 24 % of the non-Hispanic patients (p = 0.008). In multivariate linear regression analyses, the number of active joints was significantly higher in Hispanics than in non-Hispanics (p = 0.03), as well as CHAQ scores (p = 0.003), after adjusting for confounders. Hispanic patients with JIA had higher disease activity than non-Hispanic patients, as well as higher disease severity and disability. Since ethnicity influences disease activity, severity, and disability, different management and treatment plans should be planned accordingly. PMID- 23660750 TI - Added prognostic value of myocardial blood flow quantitation in rubidium-82 positron emission tomography imaging. AB - AIMS: We studied the respective added value of the quantitative myocardial blood flow (MBF) and the myocardial flow reserve (MFR) as assessed with (82)Rb positron emission tomography (PET)/CT in predicting major adverse cardiovascular events (MACEs) in patients with suspected myocardial ischaemia. METHODS AND RESULTS: Myocardial perfusion images were analysed semi-quantitatively (SDS, summed difference score) and quantitatively (MBF, MFR) in 351 patients. Follow-up was completed in 335 patients and annualized MACE (cardiac death, myocardial infarction, revascularization, or hospitalization for congestive heart failure or de novo stable angor) rates were analysed with the Kaplan-Meier method in 318 patients after excluding 17 patients with early revascularizations (<60 days). Independent predictors of MACEs were identified by multivariate analysis. During a median follow-up of 624 days (inter-quartile range 540-697), 35 MACEs occurred. An annualized MACE rate was higher in patients with ischaemia (SDS >2) (n = 105) than those without [14% (95% CI = 9.1-22%) vs. 4.5% (2.7-7.4%), P < 0.0001]. The lowest MFR tertile group (MFR <1.8) had the highest MACE rate [16% (11-25%) vs. 2.9% (1.2-7.0%) and 4.3% (2.1-9.0%), P < 0.0001]. Similarly, the lowest stress MBF tertile group (MBF <1.8 mL/min/g) had the highest MACE rate [14% (9.2-22%) vs. 7.3% (4.2-13%) and 1.8% (0.6-5.5%), P = 0.0005]. Quantitation with stress MBF or MFR had a significant independent prognostic power in addition to semi quantitative findings. The largest added value was conferred by combining stress MBF to SDS. This holds true even for patients without ischaemia. CONCLUSION: Perfusion findings in (82)Rb PET/CT are strong MACE outcome predictors. MBF quantification has an added value allowing further risk stratification in patients with normal and abnormal perfusion images. PMID- 23660751 TI - Biodegradation of ballast tank coating investigated by impedance spectroscopy and microscopy. AB - This research paper addresses the biodegradation process for ballast tank coatings in marine environments. As part of this new approach, a commercially available ballast tank coating was exposed to bacteria obtained from a culture collection and to a natural bacterial community isolated from a real ballast tank. The natural community was chosen to explore the interaction of natural biofilms with the coating, an aspect, which is not covered in standard procedures. It is shown that biological activity significantly affects the coating properties. Micro-cracks and holes have been identified using AFM. Acidic bacteria generated holes with 0.2-0.9 MUm in depth and 4-9 MUm in width. Whereas the natural community additionally caused cracks of 2-8 MUm in depth and 1 MUm in length. The overall effect of this degradation was examined using the EIS technique. However, the bacterial affected coatings (exposed to acid producing bacteria and a natural community) show a decrease in corrosion resistance. Impedance IZI values decreased over time from 1.18 * 10(9) to 1.87 * 10(7) Omega for acidic bacteria and from 1.71 * 10(9) to 2.24 * 10(7) Omega for the natural community, indicating a clear loss in coating resistance over time. It is also revealed that the coating corrosion resistance declines after 40 days of exposure for the natural community, leading to the formation of blisters. Bacterial settling could be linked to some specific biofilm patterns affecting different types of coating attack. It can be concluded that it is necessary to include natural communities in coating degradation studies to identify possible degradation mechanisms and the severity of the attack over time. PMID- 23660753 TI - A hexaicosametallic copper(II) phosphonate. AB - Structure and characterization of [Cu26{2,3,5,6-(Me)4C6H-CH2-PO3}18(MU2-OH)4(MU3 OH)6(MU4-Cl)6(MU-OH2)2(OH2)2(MeCN)4].6MeCN.15H2O (1) is reported. Complex 1 is the largest discrete molecular homometallic transition metal phosphonate assembly. Remarkably, this gigantic molecular phosphonate has been prepared at room temperature using a normal solution synthetic method. PMID- 23660752 TI - The impact of titanium dioxide nanoparticles on biological nitrogen removal from wastewater and bacterial community shifts in activated sludge. AB - The potential impact of titanium dioxide nanoparticles (TiO2 NPs) on nitrogen removal from wastewater in activated sludge was investigated using a sequencing batch reactor. The addition of 2-50 mg L(-1) of TiO2 NPs did not adversely affect nitrogen removal. However, when the activated sludge was exposed to 100-200 mg L( 1) of TiO2 NPs, the effluent total nitrogen removal efficiencies were 36.5 % and 20.3 %, respectively, which are markedly lower than the values observed in the control test (80 %). Further studies showed that the decrease in biological nitrogen removal induced by higher concentrations of TiO2 NPs was due to an inhibitory effect on the de-nitrification process. Denaturing gradient gel electrophoresis profiles showed that 200 mg L(-1) of TiO2 NPs significantly reduced microbial diversity in the activated sludge. The effect of light on the antibacterial activity of TiO2 NPs was also investigated, and the results showed that the levels of TiO2-dependent inhibition of biological nitrogen removal were similar under both dark and light conditions. Additional studies revealed that different TiO2 concentrations had a significant effect on dehydrogenase activity, and this effect was most likely the result of decreased microbial activity. PMID- 23660754 TI - Synthesis and DFT calculations of spirooxaphosphirane complexes. AB - In situ formed Li/Cl phosphinidenoid complexes [Li(12-crown-4)][M(CO)5(ClPC5Me5)] 3a-c (M = Cr, Mo, W) reacted with cyclobutanone (4), cyclopentanone (5) and cyclohexanone (6) in Et2O to yield the first P-C5Me5 substituted C(3)-spirofused oxaphosphirane complexes 7a-c, 8a and 9a,a'. In the case of cyclopentanone and 1a the outcome of the reaction in THF was different: here the formation of 8a along with (anionic) phosphinoate complexes 14a and 15a was observed, the latter possess an unusual ring-opened oxaphosphirane and 2 cyclopentylidenecyclopentanone as co-ligands to the lithium cation. NMR, IR and MS data as well as single-crystal X-ray structures in the case of 7a-c, 8a, 9a and 15a are reported. DFT calculations on the parent 1-oxa-2 phosphaspiro[2.n]alkane pentacarbonylchromium(0) complexes 10 (a: n = 2; b: n = 3; c: n = 4; d: n = 5) revealed that both ring strain energies and G(r) values decrease significantly as the spiroring size increases. This is caused by an increase in the exocyclic alpha bond angle at the oxaphosphirane C(3) atom, hence decreasing the s-character of the corresponding orbitals involved in endocyclic bonds at C(3) and thus becoming better suited for accommodation of small ring angles. PMID- 23660755 TI - Measurement of phosphoinositides in the zebrafish Danio rerio. AB - Phosphoinositides represent a minor fraction of the total glycerolipids in cells. Despite the fact that phosphoinositides are present in small quantities, they have crucial roles during cell signaling and in regulating numerous intracellular processes. Measuring changes in the levels of different phosphoinositides in animals is difficult, but it is essential in order to define the important functions of specific members of the phosphoinositide family. Here we detail procedures for measuring phosphoinositides in 2-days-postfertilization (2-d.p.f.) embryos in zebrafish (Danio rerio). Both in vivo radiolabeling (using [(32)P]orthophosphate) followed by thin-layer or high-performance liquid chromatography (TLC or HPLC) analysis and specific in vitro phosphorylation assays (using [(32)P]gammaATP) permit the quantitative measurement of phosphoinositides. Normalization of both measurements can be achieved by the determination of total lipid phosphate in embryos. All the techniques described are relatively inexpensive and accessible to most laboratories with an interest in studying the effect of gene manipulation on phosphoinositide metabolism in zebrafish. All the procedures described herein will take up to 10 working days. PMID- 23660756 TI - Enzyme-linked immunospot assays for direct ex vivo measurement of vaccine-induced human humoral immune responses in blood. AB - The enzyme-linked immunospot (ELISPOT) assay was originally developed to enumerate antigen-specific antibody-secreting cells (ASCs), and has subsequently been adapted for various applications, including the detection cytokine-secreting cells. Owing to its exceptionally high sensitivity, the ELISPOT has proven to be especially useful for detecting discrete populations of active cells (e.g., antigen-specific cells). Because of its versatility, the ELISPOT assay is used for a wide range of applications, including clonal analyses of immune responses after vaccination or after immunotherapy. Here we describe standard protocols for the detection of human ASCs specific to virtually any vaccine antigen after enrichment of circulating plasmablasts. In addition, a protocol is described for the measurement of mucosal ASC responses after prior immunomagnetic enrichment of mucosally derived blood lymphocytes. The protocols described allow rapid (~6-8 h) detection of specific ASCs in small (1-2 ml) samples of blood and can be performed in resource-poor settings. PMID- 23660758 TI - Asymmetric amplification in the catalytic enantioselective 1,2-addition of Grignard reagents to enones. AB - Large asymmetric amplification originating from solubility differences between the enantiopure and the racemic catalyst is observed in the addition of Grignard reagents to enones. This behaviour is not reaction or catalyst specific and is observed for metal complexes of a variety of chiral diphosphine ligands, extensively used in asymmetric catalysis. PMID- 23660757 TI - FACS purification of Drosophila larval neuroblasts for next-generation sequencing. AB - Elegant tools are available for the genetic analysis of neural stem cell lineages in Drosophila, but a methodology for purifying stem cells and their differentiated progeny for transcriptome analysis is currently missing. Previous attempts to overcome this problem either involved using RNA isolated from whole larval brain tissue or co-transcriptional in vivo mRNA tagging. As both methods have limited cell type specificity, we developed a protocol for the isolation of Drosophila neural stem cells (neuroblasts, NBs) and their differentiated sibling cells by FACS. We dissected larval brains from fly strains expressing GFP under the control of a NB lineage-specific GAL4 line. Upon dissociation, we made use of differences in GFP intensity and cell size to separate NBs and neurons. The resulting cell populations are over 98% pure and can readily be used for live imaging or gene expression analysis. Our method is optimized for neural stem cells, but it can also be applied to other Drosophila cell types. Primary cell suspensions and sorted cell populations can be obtained within 1 d; material for deep-sequencing library preparation can be obtained within 4 d. PMID- 23660759 TI - The role of single-photon emission computed tomography/computed tomography in localizing parathyroid adenoma. AB - With hybrid imaging playing an increasingly important role in nuclear medicine, this article reviews the literature on single-photon emission computed tomography/computed tomography (SPECT/CT) in parathyroid scintigraphy. An understanding of parathyroid and neck anatomy is important for accurate reporting of these scans, as this can have an impact on the surgical approach used. The contribution of SPECT/CT over and above SPECT alone is greatest in terms of localization, particularly for ectopic tumours. There remains controversy on the role of SPECT/CT in eutopic tumours, especially when considering such factors as imaging time and the additional radiation dose. PMID- 23660760 TI - Prevalence and risk factors of intraoperative identification failure of sentinel lymph nodes in patients affected by breast cancer. AB - INTRODUCTION: Sentinel lymph node biopsy (SLNB) has progressively replaced complete axillary lymph node dissection in the evaluation of breast cancer patients with clinically node-negative disease. Our study investigates the rate of and risk factors involved in sentinel node identification failure. MATERIALS AND METHODS: We collected data on SLNBs performed during 2002-2010, focusing on tumor, patient, and breast characteristics, radioactivity parameters, and operators' experience. Data were analyzed by R (v2.14.2), considering significance at P values lower than 0.05. RESULTS: Among 1050 women who underwent an SLNB, the rate of identification failure was 2% (23/1050), which, on bivariate analysis, was seen to be significantly influenced (P<0.05) by the preoperative and intraoperative low radiotracer uptake (axilla/lesion radiotracer uptake ratio<1%), low level of experience of the specialist in nuclear medicine, luminal A subtype, and radiotracer uptake localization in internal mammary lymph nodes. On multivariate analysis, significant risk factors for sentinel node identification failure were found to be: axilla/lesion radiotracer uptake ratio less than 1%, radiotracer uptake localization in internal mammary lymph nodes, and luminal A subtype. Considering only the preoperative variables in our multivariate analysis, axilla/lesion radiotracer uptake ratio less than 1%, negative lymph node scintiscan, and radiotracer uptake localization in internal mammary lymph nodes had an area under the curve (receiver operating characteristic curve) of 96% (95% confidence interval 92-100%). Further, we built a nomogram based on these simple parameters for counseling the patient about the probability of not finding the sentinel lymph node during the surgical procedure. CONCLUSION: The relatively low prevalence of SLNB failure (2%) is indicative of the accuracy of the procedure when performed by experienced surgeons. The sentinel node identification failure in our population seemed to be related to biological tumor factors (luminal A subtype) and probably to physiological or pathological variations in the lymphatic drainage (axilla/lesion radiotracer uptake ratio<1% and radiotracer uptake localization in internal mammary lymph nodes). PMID- 23660761 TI - An audit of manufacturers' implementation of reconstruction filters in single photon emission computed tomography. AB - AIM: The Nuclear Medicine Software Quality Group of the Institute of Physics and Engineering in Medicine has conducted an audit to compare the ways in which different manufacturers implement the filters used in single-photon emission computed tomography. The aim of the audit was to identify differences between manufacturers' implementations of the same filter and to find means for converting parameters between systems. METHODS: Computer-generated data representing projection images of an ideal test object were processed using seven different commercial nuclear medicine systems. Images were reconstructed using filtered back projection and a Butter worth filter with three different cutoff frequencies and three different orders. RESULTS: The audit found large variations between the frequency-response curves of what were ostensibly the same filters on different systems. The differences were greater than could be explained simply by different Butter worth formulae. Measured cutoff frequencies varied between 40 and 180% of that expected. There was also occasional confusion with respect to frequency units. CONCLUSION: The audit concluded that the practical implementation of filtering, such as the size of the kernel, has a profound effect on the results, producing large differences between systems. Nevertheless, this work shows how users can quantify the frequency response of their own systems so that it will be possible to compare two systems in order to find filter parameters on each that produce equivalent results. These findings will also make it easier for users to replicate filters similar to other published results, even if they are using a different computer system. PMID- 23660762 TI - Preventing delays in Forsus treatment after canine bracket failure. PMID- 23660763 TI - Aligner treatment in the teenage patient. PMID- 23660764 TI - Nonsurgical treatment of facial asymmetry in a growing patient. PMID- 23660765 TI - The challenge of asymmetry. PMID- 23660766 TI - Corticotomy-assisted space closure in adult patients with missing lower molars. PMID- 23660767 TI - The TopJet for routine bodily molar distalization. PMID- 23660768 TI - In situ/operando studies for the production of hydrogen through the water-gas shift on metal oxide catalysts. AB - In this perspective article, we show how a series of in situ techniques {X-ray diffraction (XRD), pair-distribution-function analysis (PDF), X-ray absorption fine structure (XAFS), environmental transmission electron microscopy (ETEM), infrared spectroscopy (IR), ambient-pressure X-ray photoelectron spectroscopy (AP XPS)} can be combined to perform detailed studies of the structural, electronic and chemical properties of metal oxide catalysts used for the production of hydrogen through the water-gas shift reaction (WGS, CO + H2O -> H2 + CO2). Under reaction conditions most WGS catalysts undergo chemical transformations that drastically modify their composition with respect to that obtained during the synthesis process. Experiments of time-resolved in situ XRD, XAFS, and PDF indicate that the active phase of catalysts which combine Cu, Au or Pt with oxides such as ZnO, CeO2, TiO2, CeOx/TiO2 and Fe2O3 essentially involves nanoparticles of the reduced noble metals. The oxide support undergoes partial reduction and is not a simple spectator, facilitating the dissociation of water and in some cases modifying the chemical properties of the supported metal. Therefore, to optimize the performance of these catalysts one must take into consideration the properties of the metal and oxide phases. IR and AP-XPS have been used to study the reaction mechanism for the WGS on metal oxide catalysts. Data of IR spectroscopy indicate that formate species are not necessarily involved in the main reaction path for the water-gas shift on Cu-, Au- and Pt based catalysts. Thus, a pure redox mechanism or associative mechanisms that involve either carbonate-like (CO3, HCO3) or carboxyl (HOCO) species should be considered. In the last two decades, there have been tremendous advances in our ability to study catalytic materials under reaction conditions and we are moving towards the major goal of fully understanding how the active sites for the production of hydrogen through the WGS actually work. PMID- 23660769 TI - Analysis of 5-HT(2A) receptor binding with [(11)C]MDL 100907 in rats: optimization of kinetic modeling. AB - PURPOSE: Preclinical positron emission tomography studies are important to follow disease progression and develop new pharmacological agents. We investigated whether kinetic modeling of 5-HT2A tracer [(11)C]MDL 100907 is possible in rats. PROCEDURES AND RESULTS: Kinetic modeling with either metabolite-corrected plasma curve or with the cerebellum as a reference tissue resulted in a good correlation of nondisplaceable binding potential (BPND) calculated from a two-tissue compartment model (2TCM) or different reference tissue models. Injecting the tracer by a slower bolus decreases the variation in 2TCM outcome parameters and results in a good correlation between k3/k4 and the other models. Application of 0.2 mg/kg cold MDL 100907 resulted in almost complete occupancy of 5-HT2A receptors. CONCLUSIONS: A reference tissue model can be used for [(11)C]MDL kinetic modeling in rats, which is preferable in pharmacological or longitudinal studies. PMID- 23660770 TI - Clinical Pharmacology in European health care-outcome of a questionnaire study in 31 countries. AB - INTRODUCTION: In order to discover how well the discipline of clinical pharmacology (CP) has developed in Europe, a questionnaire survey was undertaken in 31 countries. METHODS: The senior delegate of each of the 31 countries on the Council of the European Association for Clinical Pharmacology and Therapeutics (EACPT) was approached personally. This study was not an official EACPT survey. RESULTS: Based on the results of the completed survey forms, CP is recognized as an academic discipline in teaching and research fields in 28 of the 31 participating countries, but as a medical specialty in only 22 of these 31 countries. Surprisingly, France and Italy were two of the nine countries where CP was not recognized as a medical specialty. In 50 % of the countries where CP was recognized as a medical specialty, this recognition had occurred more than 30 years ago. The training of clinical pharmacologists in terms of years after internship varied between the countries. In eight countries the training was predominantly in internal medicine with shorter periods in pharmacology. In 11 countries the training was predominantly in CP, and in six countries there was dual training in pharmacology and clinical medicine. The training played a decisive role in terms of the clinical functions undertaken in health care. There was considerable variation in the numbers of clinical pharmacologists in each country, with the total figure varying between <= 10 to 600. In terms of the number of clinical pharmacologists per million inhabitants, nine countries have <= 1 (Belgium, Bulgaria, France, Greece, Italy, Lithuania, Poland, Turkey and UK) while four have >= 10 (Hungary, Norway, Slovakia and Sweden). Stumbling blocks which inhibit the development of CP as a discipline in health care are the lack of defined functions and consultant posts for clinical pharmacologists in health care in many countries and the underrepresentation of CP in pre- and postgraduate curricula. CONCLUSION: The majority of the responding countries suggested that EACPT should prioritize that CP becomes recognized and accredited as a European medical specialty. PMID- 23660771 TI - Ineffectiveness and adverse events of nitrofurantoin in women with urinary tract infection and renal impairment in primary care. AB - PURPOSE: To determine whether treatment with nitrofurantoin in women with urinary tract infection (UTI) and renal impairment in primary care is associated with a higher risk of ineffectiveness and/or serious adverse events than in women without renal impairment. METHODS: A cohort of 21,317 women treated with nitrofurantoin and a cohort of 7,926 women treated with trimethoprim, identified from the Pharmo Record Linkage System, were analysed. The primary outcome was ineffectiveness of treatment of nitrofurantoin defined as the start of a second antibacterial within 1 month after the start of nitrofurantoin. The secondary outcome was the occurrence of serious adverse events of nitrofurantoin leading to hospitalization within 90 days. A cohort of trimethoprim users was used to determine if the associations found for nitrofurantoin were mainly related to nitrofurantoin itself. The association between renal impairment and the risk of these outcomes was determined with Cox regression and expressed as hazard ratios (HRs). RESULTS: Overall, the incidence density for ineffectiveness was 5.4 per 1,000 person-days, and moderate renal impairment was not associated with ineffective treatment [HR 1.1, 95 % confidence interval (CI) 0.74-1.51]. The overall incidence density for adverse events was 0.02 per 1,000 person-days. In patients with renal impairment (<50 ml/min/1.73 m2) the risk of pulmonary adverse events leading to hospitalization was significantly increased (HR 4.1, 95 % CI 1.31-13.09) CONCLUSIONS: Nitrofurantoin treatment was not associated with a higher risk of ineffectiveness in women with UTI and moderate renal impairment (30-50 ml/min/1.73 m2). However, we did find a significant association between renal impairment (<50 ml/min/1.73 m2) and pulmonary adverse events leading to hospitalization. PMID- 23660772 TI - Methotrexate binds to recombinant thiopurine S-methyltransferase and inhibits enzyme activity after high-dose infusions in childhood leukaemia. AB - PURPOSE: Important drugs in the treatment of childhood acute lymphoblastic leukaemia (ALL) are 6-mercaptopurine (6-MP) and methotrexate (MTX). Thiopurine methyltransferase (TPMT) is a polymorphic enzyme causing variability in 6-MP response and toxicity. The aim of this study was to investigate the fluctuation in TPMT enzyme activity over time and the effect of high-dose MTX infusions on TPMT enzyme activity and 6-MP metabolites in paediatric ALL patients. METHODS: Fifty-three children with ALL treated according to the NOPHO-ALL 2000 protocol were included in the study. TPMT enzyme activity was measured at six different times starting from diagnosis until after the end of maintenance treatment. TPMT and 6-MP metabolites were measured before the initiation of high-dose MTX (HD MTX) infusions and at 66 h post-infusion. The interaction between MTX and TPMT was investigated in vitro using recombinant TPMT protein and a leukaemic cell line. RESULTS: Forty percent of TPMT wild-type individuals had deceptively low TPMT enzyme activity according to genotype at the time of diagnosis. TPMT activity had decreased significantly 66 h after the start of HD-MTX infusions ( 9.2 %; p = 0.013). MTX bound to recombinant TPMT protein severely inhibiting TPMT enzyme activity (remaining activity 16 %). CONCLUSIONS: Our results show that TPMT genotyping should be performed in children with ALL, since 40 % of the children in our study who carried the wild-type TPMT gene were at risk of initial underdosing of 6-MP in cases where only TPMT enzyme activity was determined. MTX inhibits the TPMT enzyme activity after HD-MTX infusions due to protein binding. PMID- 23660773 TI - CT perfusion technique for assessment of early kidney allograft dysfunction: preliminary results. AB - OBJECTIVES: To assess the benefit of quantitative computed tomography (CT) perfusion for differentiating acute tubular necrosis (ATN) and acute rejection (AR) in kidney allografts. METHODS: Twenty-two patients with acute kidney allograft dysfunction caused by either AR (n = 6) or ATN (n = 16) were retrospectively included in the study. All patients initially underwent a multiphase CT angiography (CTA) protocol (12 phases, one phase every 3.5 s) covering the whole graft to exclude acute postoperative complications. Multiphase CT dataset and dedicated software were used to calculate renal blood flow. Renal biopsy or clinical course of disease served as the standard of reference. Mean effective radiation dose and mean amount of contrast media were calculated. RESULTS: Renal blood flow values were significantly lower (P = 0.001) in allografts undergoing AR (48.3 +/- 21 ml/100 ml/min) compared with those with ATN (77.5 +/- 21 ml/100 ml/min). No significant difference (P = 0.71) was observed regarding creatinine level with 5.65 +/- 3.1 mg/dl in AR and 5.3 +/- 1.9 mg/dl in ATN. The mean effective radiation dose of the CT perfusion protocol was 13.6 +/- 5.2 mSv; the mean amount of contrast media applied was 34.5 +/- 5.1 ml. All examinations were performed without complications. CONCLUSION: CT perfusion of kidney allografts may help to differentiate between ATN and rejection. KEY POINTS: * Quantitative CT perfusion of renal transplants is feasible. * CT perfusion could help to non-invasively differentiate AR from ATN. * CT perfusion might make some renal biopsies unnecessary. PMID- 23660774 TI - Severe aortic arch calcification depicted on chest radiography strongly suggests coronary artery calcification. AB - OBJECTIVE: To evaluate the association between aortic arch calcifications (AAC) on chest radiography and coronary artery calcium (CAC) score determined by CT. METHODS: A total of 128 patients (75 men; 69.3 +/- 14.7 years) who underwent chest radiography and CAC scoring at CT were included in this retrospective analysis. The extent of AAC on chest radiography was evaluated independently by two blinded observers using a semi-quantitative four-point scale (0-3). Intra- and interobserver agreement was assessed by weighted K statistics. Amount of AAC determined on radiography was correlated with CAC and ROC analyses performed to characterise the diagnostic performance of AAC grading. RESULTS: Excellent intraobserver (K = 0.82) and good interobserver (K = 0.75) agreement of AAC grading was noted. Moderate agreement (K = 0.46, 95 % CI 0.36-0.56) with a linear trend (P < 0.0001) between AAC grades and CAC scores was found. Cut-off between AAC grades 0-2 and 3 had a sensitivity of 38.6 %, specificity of 96.4 %, PPV of 85.0 %, NPV of 75.0 % and accuracy of 76.6 % for the correct identification of CAC scores greater than 400. CONCLUSION: Semi-quantitative AAC grading on chest radiography is reliable and positively associated with CAC scoring. We propose to report the extent of AAC in comprehensive radiological reports as "not present", "moderate" or "severe", as severe AAC strongly suggests coronary artery calcification. KEY POINTS: * Semi-quantitative aortic arch calcification (AAC) grading on plain chest radiography appears reliable. * AAC grading is positively associated with CT coronary artery calcium scoring. * AAC grading has a high specificity for ruling out CAC scores greater than 400. * We propose the reporting of the extent of AAC grade in chest X-ray (CXR) reports. PMID- 23660775 TI - Diverticular disease severity score based on CT colonography. AB - OBJECTIVE: We propose a diverticular disease severity score (DDSS) based on CT colonography (CTC) findings. METHODS: Seventy-nine patients (62 +/- 14.5 years) underwent CTC after recovering from an episode of acute diverticulitis. Two independent readers classified each case using a four-point scale (DDSS), based on maximum sigmoid colon wall thickness (MSCWT) and minimum lumen diameter at CTC: 1 = MSCWT <3 mm, lumen diameter >=15 mm; 2 = MSCWT 3-8 mm, lumen diameter >=5 mm; 3 = MSCWT >=8 mm, lumen diameter >=5 mm; 4 = MSCWT >=8 mm, lumen diameter <5 mm. Intra- and interobserver reproducibility was evaluated. Of 79 patients, 32 (40 %) underwent surgery after CTC; MSCWT was directly measured on the pathological specimen. RESULTS: Intra- and interobserver reproducibility of DDSS were almost perfect (k = 0.90-0.84). DDSS significantly correlated with the probability of surgery (P = 0.001). After surgery, histopathology revealed acute/chronic diverticular inflammation only in 29 cases, and superimposed sigmoid cancer (n = 2) or Crohn's disease (n = 1) in 3 patients with a DDSS of 4. MSCWT at histopathology correlated with DDSS (P = 0.008). CONCLUSION: DDSS is highly reproducible and correlates with pathological MSCWT. Nearly 1 in 3 patients with a DDSS of 4 had significant superimposed histopathology. CTC with DDSS can provide colorectal surgeons with valuable information. KEY POINTS: * A diverticular disease severity score (DDSS) based on CT colonography is proposed. * This DDSS is based on sigmoid colon wall thickness and lumen diameter. * High scores may be associated with relevant coexisting lesions. * A CTC-based DDSS may influence therapeutic decision-making. PMID- 23660776 TI - Plasmid- and chromosome-encoded siderophore anguibactin systems found in marine vibrios: biosynthesis, transport and evolution. AB - Vibrio anguillarum is a marine pathogen that causes vibriosis, a hemorrhagic septicemia in aquatic invertebrate as well as vertebrate animals. The siderophore anguibactin system is one of the most important virulence factors of this bacterium. Most of the anguibactin biosynthesis and transport genes are located in the 65-kb pJM1 virulence plasmid although some of them are found in the chromosome of this fish pathogen. Over 30 years of research unveiled the role numerous chromosomal and pJM1 genes play in the synthesis of anguibactin and the transport of cognate ferric complexes into the bacterial cell. Furthermore, these studies showed that pJM1-carrying strains might be originated from pJM1-less strains producing the chromosome-mediated siderophore vanchrobactin. Additionally, we recently identified a chromosome-mediated anguibactin system in V. harveyi suggesting the possible evolutional origin of the V. anguillarum anguibactin system. In this review, we present our current understanding of the mechanisms and evolution hypothesis of the anguibactin system that might have occurred in these pathogenic vibrios. PMID- 23660777 TI - Association of NAT1 and NAT2 genes with nonsyndromic cleft lip and palate. AB - Nonsyndromic cleft lip and palate (NSCLP) is a common congenital deformity, often associated with environmental risk factors, including alcohol, smoking, drugs and radiation exposure. N-acetyltransferase (NAT)1 and NAT2 genes are involved in the detoxification and metabolic activation of numerous drugs and chemicals. The aim of the present study was to investigate whether genetic variations in these two genes and gene-gene interactions are associated with NSCLP. We investigated eight NAT1 tag single nucleotide polymorphisms (SNPs) and five NAT2 tag SNPs, selected from HapMap data. These SNPs were examined for associations with NSCLP in 204 patients and 226 controls. Strong evidence of an association with NSCLP was identified for rs4921580 in the NAT1 gene, and haplotype analysis supported these findings. We also found a significant difference between NSCLP and control groups for rs1041983 in the NAT2 gene. The results of gene-gene interaction analyses also indicated that the combination of rs4921580 (Cg+gg) x rs1041983 (Ct+tt) increased the risk of NSCLP. Thus, the present study provides evidence for the role of NAT1 and NAT2 variations in NSCLP, and indicates that interactions between the NAT1 and NAT2 genes may be important in susceptibility to NSCLP. PMID- 23660779 TI - Aryl 5-substitution of a phenyl-pyridine based ligand as a viable way to influence the opto-electronic properties of bis-cyclometalated Ir(III) heteroleptic complexes. AB - This manuscript reports on the synthesis, the photophysical study and the electroluminescent properties of a series of heteroleptic cyclometalated iridium(III) complexes based on 2,5-diaryl-pyridines as C^N cyclometalating ligands and acetylacetonate as ancillary ligand. The complexes were characterised by elemental analysis, ESI-MS, multinuclear NMR, TGA and electrochemistry. Their optical properties were investigated by UV-Vis and photoluminescence. DFT and TD DFT calculations provided further insights into the effects of the 5-aryl substitution on the electronic and photophysical properties of the new complexes. The presence of suitable pi-extended ligands exerts a beneficial effect on the performances of the corresponding solution-processed light-emitting diodes, leading to a maximum brightness of 10,620 cd m(-2) at a current efficiency of 10.0 cd A(-1). PMID- 23660780 TI - Repairing thymic function. AB - PURPOSE OF REVIEW: Maintenance of T-cell function and modulation of tolerance are critical issues in organ transplantation. The thymus is the primary organ for T cell generation, and a preserved thymic function is essential for a self-tolerant diverse T-cell repertoire. Transplant procedures and related immunosuppressive drugs may hinder thymic integrity and function. We review here the recent advances in understanding the regulation of the unique thymic microenvironment with relevance for the field of transplantation. RECENT FINDINGS: Recent studies have assigned a role for IL-22 in the regeneration of thymic epithelium, and for microRNAs in the modulation of its survival and function. The interplay of key molecules in the cross-talk between thymic epithelial cells and thymocytes was depicted, opening new perspectives for the in-vitro recapitulation of T-cell development and for thymic transplantation. Additionally, the thymus was shown to be able to sustain thymocyte progenitor renewal. SUMMARY: These findings open new venues of research toward therapeutic interventions in the endogenous thymus to modulate or reconstitute the immune system; thymic transplantation; and the future development of artificial thymus, which would represent an important tool to achieve tolerance across the histocompatibility barriers. PMID- 23660781 TI - Current world literature. Liver transplantation. PMID- 23660778 TI - Modeling of PET data in CNS drug discovery and development. AB - Positron emission tomography (PET) is increasingly used in drug discovery and development for evaluation of CNS drug disposition and for studies of disease biomarkers to monitor drug effects on brain pathology. The quantitative analysis of PET data is based on kinetic modeling of radioactivity concentrations in plasma and brain tissue compartments. A number of quantitative methods of analysis have been developed that allow the determination of parameters describing drug pharmacokinetics and interaction with target binding sites in the brain. The optimal method of quantification depends on the properties of the radiolabeled drug or radioligand and the binding site studied. We here review the most frequently used methods for quantification of PET data in relation to CNS drug discovery and development. The utility of PET kinetic modeling in the development of novel CNS drugs is illustrated by examples from studies of the brain kinetic properties of radiolabeled drug molecules. PMID- 23660783 TI - Therapeutic resistance: two steps ahead. PMID- 23660784 TI - Targeting allosteric disulphide bonds in cancer. AB - Protein action in nature is generally controlled by the amount of protein produced and by chemical modification of the protein, and both are often perturbed in cancer. The amino acid side chains and the peptide and disulphide bonds that bind the polypeptide backbone can be post-translationally modified. Post-translational cleavage or the formation of disulphide bonds are now being identified in cancer-related proteins and it is timely to consider how these allosteric bonds could be targeted for new therapies. PMID- 23660785 TI - Human epidermal growth factor receptor-2 expression in primary and metastatic gastric cancer. AB - BACKGROUND: Amplification and overexpression of human epidermal growth factor receptor-2 (HER-2) has been shown in subgroups of gastric cancer, correlated to more aggressive disease and predictive for the treatment with HER-2 antibodies. In this study, we examined the prognostic value of HER-2 expression in primary gastric cancer and in associated lymph node metastases and confirmed the role of HER-2 in tumor angiogenesis by examining vascular endothelial growth factor (VEGF) expression. METHODS: Immunohistochemistry was used to detect HER-2 and VEGF expression in 110 gastric cancer specimens and associated lymph node metastases and in 96 specimens of normal gastric mucosa. RESULTS: The expression level of HER-2 in gastric tissues was significantly higher than in normal tissues (19.1 % vs. 8.3 %; P < 0.05). HER-2 overexpression was homogeneous in primary gastric cancer and metastatic lymph nodes (P = 0.607). There was a significant positive correlation of HER-2 expression and VEGF expression (P = 0.007). HER-2 overexpression in primary tumor correlated with lymph node metastasis, distant metastasis, and American Joint Committee on Cancer (AJCC) stage. Cox regression multivariate analyses confirmed that tumor size, histological grade, lymph node ratio, AJCC stage, chemotherapy, and HER-2 expression were all prognostic factors. Patients with HER-2 positivity in both primary and metastatic tissues (+/+) had the poorest survival (OS, 12.5 months; DFS, 11.0 months) (P < 0.01). CONCLUSIONS: HER-2 was significantly overexpressed in gastric cancer versus normal tissue and correlated with VEGF expression. HER-2 in tumor or lymph nodes was an independent negative prognostic factor. PMID- 23660786 TI - Idiopathic pulmonary fibrosis as a prognostic factor in non-small cell lung cancer. AB - BACKGROUND: We investigated the postoperative mortality and long-term survival of lung cancer patients with underlying idiopathic pulmonary fibrosis (IPF). METHODS: The data of 387 primary lung cancer patients treated by surgical resection at our hospital between 1995 and 2008 were retrospectively reviewed. Clinicopathological characteristics such as age, gender, survival, presence/absence of underlying IPF, atypical adenomatous hyperplasia (AAH), and the associations among these factors were examined. RESULTS: Among the 387 patients, 65 (16.8 %) had underlying IPF as detected by histopathology of the resected specimen (IPF group). The percentages of men and squamous cell carcinomas were significantly higher in the IPF group. None of our patients showed concomitant presence of AAH and IPF. Four of the 65 patients showed acute exacerbation of the IPF postoperatively, and all 4 of these patients died in hospital. In patients with non-small cell lung carcinoma, the postoperative survival tended to be lower in the IPF group than in the non-IPF group. Analysis using a Cox proportional hazards model by disease stage revealed that presence of underlying IPF was a risk factor for postoperative mortality in patients with pathological stage I/II but not for stage III/IV. Respiratory failure was the second main cause of death in the stage I/II lung cancer patients of the IPF group. CONCLUSION: Histopathological evidence of IPF was a risk factor for postoperative mortality and poor long-term survival, especially in patients with stage I/II non-small cell lung cancer, with postoperative respiratory failure representing the major cause of death. PMID- 23660787 TI - Magnetic anisotropy and exchange coupling in a family of isostructural Fe(III)2Ln(III)2 complexes. AB - The reaction of [Fe3O(O2CPh)6(H2O)3](O2CPh) with lanthanide/rare earth nitrate salts in the presence of triethanolamine (H3tea) in acetonitrile/methanol solution yields a series of compounds with isostructural tetranuclear core motifs [Fe(III)2Ln(III)2(MU3-OH)2(teaH)2(O2CCPh)6].3MeCN (Ln = Ce (1), Pr (2), Nd (3), Sm (4), Eu (5), Gd (6), Tb (7), Dy (8), Ho (9), Er (10), Tm (11), Yb (12), Y (13)). In all cases the core topology is a defect-dicubane planar or "butterfly" Fe2Ln2 motif. Compounds 1-13 were investigated using a combination of experimental techniques and theoretical studies. Magnetic susceptibility measurements were carried out on all compounds. The magnetic coupling between the two Fe(III) centres is antiferromagnetic, with J(FeFe) ca.-6.71(4) cm(-1), while the Fe-Ln couplings are much weaker, e.g. J(FeGd) = 0.18(1) cm(-1). Compounds 6, 7, 8 and 13 were selected for Mossbauer studies in order to investigate the influence of isotropic (Gd(III)), highly anisotropic non-Kramers and Kramers (Tb(III) and Dy(III)) and diamagnetic (Y(III)) rare earth ions on the local environment of the Fe(III) centres. Compounds 3, 6, 8 and 13 were also studied using X-Band EPR spectroscopy. For 13, with the diamagnetic Y(III) ion, this made it possible to obtain the D, E, J(FeFe) and g parameters for the iron centres. It is shown that the low-temperature spectra of compounds 3, 6 and 8 are determined by magnetic properties of rare-earth ions and the dipole-dipole interactions between the Ln(III) ions. The Fe-Ln interactions were confirmed as very weak and dipolar in nature by the temperature dependence of EPR spectra at T > 20 K. PMID- 23660788 TI - Space closure and anchorage control. PMID- 23660789 TI - The hot seat: retention. PMID- 23660790 TI - Palatally anchored maxillary molar mesialization using the mesialslider. PMID- 23660791 TI - Non-compliance space closure in patients with missing lateral incisors. PMID- 23660792 TI - Occlusion management in orthodontic anchorage control. PMID- 23660793 TI - Glass ionomer splint remover. PMID- 23660794 TI - Autotransplantation of a fully developed maxillary premolar to a missing mandibular premolar site. PMID- 23660795 TI - Socioeconomic factors in childhood and the risk of multiple sclerosis. AB - In a national cohort comprising 1.5 million Danes born from 1966 to 1992, we studied the association between childhood socioeconomic status (SES) and the risk of multiple sclerosis (MS) from 1981 to 2007 using information about household income and parental educational levels at the person's 15th birthday. The association between childhood SES and MS was evaluated using MS incidence rate ratios with 95% confidence intervals obtained in log-linear Poisson regression analyses. We found no strong association between childhood SES and MS but did observe a tendency toward a reduced risk of MS among children from households with more highly educated parents, particularly mothers. Children whose mothers had a secondary (rate ratio = 0.95, 95% confidence interval: 0.86, 1.04) or higher (rate ratio = 0.86, 95% confidence interval: 0.76, 0.97) education had reduced risks of MS (5% and 14%, respectively) compared with children of mothers with a basic education (P for trend = 0.02). Results were practically unchanged in an analysis restricted to persons aged 15-29 years, among whom the possible effect of own SES on MS risk is considered limited. Overall, SES in childhood seems of no major importance for the subsequent risk of MS; however, offspring of well-educated mothers may be at a slightly reduced risk of MS. PMID- 23660796 TI - Internal validation of risk models in clustered data: a comparison of bootstrap schemes. AB - Internal validity of a risk model can be studied efficiently with bootstrapping to assess possible optimism in model performance. Assumptions of the regular bootstrap are violated when the development data are clustered. We compared alternative resampling schemes in clustered data for the estimation of optimism in model performance. A simulation study was conducted to compare regular resampling on only the patient level with resampling on only the cluster level and with resampling sequentially on both the cluster and patient levels (2-step approach). Optimism for the concordance index and calibration slope was estimated. Resampling of only patients or only clusters showed accurate estimates of optimism in model performance. The 2-step approach overestimated the optimism in model performance. If the number of centers or intraclass correlation coefficient was high, resampling of clusters showed more accurate estimates than resampling of patients. The 3 bootstrap schemes also were applied to empirical data that were clustered. The results presented in this paper support the use of resampling on only the clusters for estimation of optimism in model performance when data are clustered. PMID- 23660797 TI - A modeling framework for the evolution and spread of antibiotic resistance: literature review and model categorization. AB - Antibiotic-resistant infections complicate treatment and increase morbidity and mortality. Mathematical modeling has played an integral role in improving our understanding of antibiotic resistance. In these models, parameter sensitivity is often assessed, while model structure sensitivity is not. To examine the implications of this, we first reviewed the literature on antibiotic-resistance modeling published between 1993 and 2011. We then classified each article's model structure into one or more of 6 categories based on the assumptions made in those articles regarding within-host and population-level competition between antibiotic-sensitive and antibiotic-resistant strains. Each model category has different dynamic implications with respect to how antibiotic use affects resistance prevalence, and therefore each may produce different conclusions about optimal treatment protocols that minimize resistance. Thus, even if all parameter values are correctly estimated, inferences may be incorrect because of the incorrect selection of model structure. Our framework provides insight into model selection. PMID- 23660799 TI - The co-seasonality of pneumonia and influenza with Clostridium difficile infection in the United States, 1993-2008. AB - Seasonal variations in the incidence of pneumonia and influenza are associated with nosocomial Clostridium difficile infection (CDI) incidence, but the reasons why remain unclear. Our objective was to consider the impact of pneumonia and influenza timing and severity on CDI incidence. We conducted a retrospective cohort study using the US National Hospital Discharge Survey sample. Hospitalized patients with a diagnosis of CDI or pneumonia and influenza between 1993 and 2008 were identified from the National Hospital Discharge Survey data set. Poisson regression models of monthly CDI incidence were used to measure 1) the time lag between the annual pneumonia and influenza prevalence peak and the annual CDI incidence peak and 2) the lagged effect of pneumonia and influenza prevalence on CDI incidence. CDI was identified in 18,465 discharges (8.52 per 1,000 discharges). Peak pneumonia prevalence preceded peak CDI incidence by 9.14 weeks (95% confidence interval: 4.61, 13.67). A 1% increase in pneumonia prevalence was associated with a cumulative effect of 11.3% over a 6-month lag period (relative risk = 1.113, 95% confidence interval: 1.073, 1.153). Future research could seek to understand which mediating pathways, including changes in broad-spectrum antibiotic prescribing and hospital crowding, are most responsible for the associated changes in incidence. PMID- 23660798 TI - Epidemiologic approaches to evaluating the potential for human papillomavirus type replacement postvaccination. AB - Currently, 2 vaccines exist that prevent infection by the genotypes of human papillomavirus (HPV) responsible for approximately 70% of cervical cancer cases worldwide. Although vaccination is expected to reduce the prevalence of these HPV types, there is concern about the effect this could have on the distribution of other oncogenic types. According to basic ecological principles, if competition exists between >=2 different HPV types for niche occupation during natural infection, elimination of 1 type may lead to an increase in other type(s). Here, we discuss this issue of "type replacement" and present different epidemiologic approaches for evaluation of HPV type competition. Briefly, these approaches involve: 1) calculation of the expected frequency of coinfection under independence between HPV types for comparison with observed frequency; 2) construction of hierarchical logistic regression models for each vaccine-targeted type; and 3) construction of Kaplan-Meier curves and Cox models to evaluate sequential acquisition and clearance of HPV types according to baseline HPV status. We also discuss a related issue concerning diagnostic artifacts arising when multiple HPV types are present in specific samples (due to the inability of broad-spectrum assays to detect certain types present in lower concentrations). This may result in an apparent increase in previously undetected types postvaccination. PMID- 23660800 TI - Plasma vitamin D biomarkers and leukocyte telomere length. AB - Vitamin D may reduce telomere shortening through anti-inflammatory and anti-cell proliferation mechanisms. In the present study, we examined the association between vitamin D and relative leukocyte telomere length by using both plasma 25 hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) biomarkers. Vitamin D biomarker levels and leukocyte telomere length were measured using plasma samples collected in 1989-1990 from participants of the Nurses' Health Study, a study of nurses from 11 US states. In total, 1,424 participants had their 25(OH)D levels assessed and 837 had their 1,25(OH)2D levels assessed. Genotyping was performed on 480 participants on 12 single nucleotide polymorphisms in vitamin D-related genes. Linear and logistic regression models were used. Higher 25(OH)D levels were significantly associated with longer telomere length (P for trend = 0.05), and the odds ratio increased from 1.07 (P = 0.65) when comparing the second lowest quartile of 25(OH)D with the lowest to 1.59 (P = 0.01) when comparing the highest quartile with the lowest. Vitamin D related single nucleotide polymorphisms and 1,25(OH)2D levels were not significantly associated with telomere length. Total calcium intake significantly modified the association between 25(OH)D and telomere length (P for interaction = 0.05). Higher plasma 25(OH)D levels may be associated with longer telomeres, and this association may be modified by calcium intake. PMID- 23660801 TI - Ultrafast spectroscopy of linear carbon chains: the case of dinaphthylpolyynes. AB - The dynamics of excited states in alpha,omega-dinaphthylpolyyne, a class of linear sp-carbon chains, has been investigated by ultrafast transient absorption spectroscopy and DFT//TDDFT calculations. We show that the role of molecular conformers, in which end-capped naphthalene rings are planar or perpendicular to the polyyne plane, is fundamental for understanding both the steady state properties, such as UV-Vis absorption spectra and vibronic transitions, and the ultrafast transient absorption features. In particular, we observed in one of the conformers the ultrafast formation of a narrow photo-induced absorption band rising within 30 ps. This band can be assigned to an inter-system crossing event leading to the formation of triplet excited states. PMID- 23660802 TI - Microarray testing for the presence of toxic algae monitoring programme in Galicia (NW Spain). AB - Rapid and reliable detection of harmful algae in coastal areas and shellfish farms is an important requirement of monitoring programmes. Monitoring of toxic algae by means of traditional methods, i.e., light microscopy, can be time consuming when many samples have to be routinely analysed. Reliable species identification requires expensive equipment and trained personnel to carry out the analyses. However, all techniques for the monitoring of harmful algae usually require transportation of samples to specialised laboratories. In many monitoring laboratories, results are usually obtained within five working days after receiving the sample and therefore preventative measures are not always possible. Molecular technologies are rapidly improving the detection of phytoplankton and their toxins and the speed at which the results can be obtained. Assays are based on the discrimination of the genetic differences of the different species and species-specific probes can be designed. Such probes have been adapted to a microarray or phylochip format and assessed in several EU monitoring sites. Microarray results are presented for 1 year of field samples validated with cell counts from concentrated samples taken during toxic events from the weekly sampling of the Galician Monitoring Programme done by INTECMAR. The Galician monitoring laboratory does their own counting and their results are posted on their web site within 24 h. There was good correlation between cells present and microarray signals. In the few cases of false negatives, these can be attributed to poor RNA extraction of the target species, viz. Prorocentrum or Dinophysis. Where potential false positives were encountered, the smaller volume taken for cell counts as compared to the upto 300 times more volume taken for RNA extraction for the microarray is likely the cause for these differences, making the microarray more sensitive. The microarray was able to provide better species resolution in Alexandrium and Pseudo-nitzschia. In all cases, the toxins recovered by the toxin array were matched by target species in the array or in the cell counts. PMID- 23660803 TI - Mechanism of aflatoxin uptake in roots of intact groundnut (Arachis hypogaea L.) seedlings. AB - Aflatoxins are one of the most potent toxic substances that occur naturally, which enter agricultural soils through the growth of aflatoxigenic fungi in rhizhosphere and nonrhizhosphere soils. Though several reports regarding the uptake of aflatoxin by plants are available, the mechanism of aflatoxin uptake remains unknown. This study characterized the aflatoxin uptake mechanism by in vitro hydroponic experiments under variable conditions. The uptake reached saturation after 48 h of incubation for AFB1 and B2 and 60 h for AFG1 and G2. A linear increase in uptake with increasing aflatoxin concentrations was observed, and it fits both linear and nonlinear regression. AFB1 uptake was directly proportional to transpiration rate, and blocking aquaporin activity using mercuric chloride revealed its involvement in the uptake. None of the metabolic inhibitors used to block active transport had any effect on aflatoxin uptake except for sodium azide. From the present study, it could be concluded that aflatoxin uptake by groundnut roots followed mainly a passive way and is facilitated through aquaporins. The involvement of active component should be studied in detail. PMID- 23660804 TI - Expression and relationship of proinflammatory chemokine RANTES/CCL5 and cytokine IL-1beta in painful human intervertebral discs. AB - STUDY DESIGN: Laboratory study. OBJECTIVE: To evaluate expression of chemokine regulated and normal T cell expressed and secreted (RANTES)/C-C motif ligand 5 (CCL5) and interleukins in intervertebral discs (IVDs) specimens from patients with discogram-proven painful degeneration. SUMMARY OF BACKGROUND DATA: Discogenic back pain results in tremendous costs related to treatment and lost productivity. The relationship between inflammation, degeneration (IVD), and cytokine upregulation is well established, but other mediators of the inflammatory cascade are not well characterized. METHODS: Painful IVDs were taken from 18 patients undergoing surgery for discogenic pain with positive preoperative discogram. Painless control tissue was taken at autopsy from patients without back pain/spinal pathology or spinal levels with negative discograms resected for deformity.Quantitative real time polymerase chain reaction (qRT-PCR) was performed to evaluate RANTES, IL-1beta, IL-6, and IL-8 expression in painful and control discs. RANTES and interleukin expression were analyzed on the basis of Pfirrmann grade.Disc cells were cultured in alginate beads using 2 groups: an untreated group and a group treated with 10 ng/mL IL 1beta, 10 ng/mL TNF-alpha, and 1% fetal bovine serum to induce a degenerative phenotype. RESULTS: Nine painless IVD specimens and 7 painful IVD specimens were collected. RANTES expression demonstrated a 3.60-fold increase in painful discs versus painless discs, a significant difference (P = 0.049). IL-1beta expression demonstrated significantly higher expression in painful discs (P = 0.03). RANTES expression data demonstrated significant upregulation with increasing Pfirrmann grade (P = 0.045). RANTES expression correlated significantly with IL-1beta expression (rho = 0.67, P < 0.0001). RANTES expression increased more than 200 fold in the alginate culture model in cells treated with IL-1beta/TNF-alpha, 1% fetal bovine serum (P < 0.001). CONCLUSION: RANTES and IL-1beta expression was significantly elevated in painful IVDs after careful selection of painless versus painful IVD tissue. RANTES expression was found to correlate significantly with expression of IL-1beta. RANTES was upregulated by IL-1beta/TNF-alpha/1% fetal bovine serum an in vitro treatment to induce a degenerative phenotype. PMID- 23660805 TI - Re: Feng G, Hong Y, Li L, et al. Anterior decompression and nonstructural bone grafting and posterior fixation for cervical facet dislocation with traumatic disc herniation. Spine (Phila Pa 1976). 2012;37:2082-8. PMID- 23660806 TI - Re: Macedo LG, Wang Y, Battie MC. The sedimentation sign for differential diagnosis of lumbar spinal stenosis. [published online ahead of print November 28, 2012.] Spine. doi:10.1097/BRS.0b013e31827e8ecd. PMID- 23660807 TI - In response. PMID- 23660809 TI - The impracticality of MRI for the diagnosis of atypical penile fracture in the emergency setting. AB - We report the case of a patient who presented to the emergency department with a history suspicious for penile fracture without typical physical exam findings. A small penile fracture was present on MRI, but the diagnosis was missed, and surgery was withheld owing to this misinformation. Despite its technical accuracy, MRI may be impractical for the diagnosis of penile fracture in the emergency setting. PMID- 23660811 TI - Detection of hydrodynamic stimuli by the Florida manatee (Trichechus manatus latirostris). AB - Florida manatees inhabit the coastal and inland waters of the peninsular state. They have little difficulty navigating the turbid waterways, which often contain obstacles that they must circumnavigate. Anatomical and behavioral research suggests that the vibrissae and associated follicle-sinus complexes that manatees possess over their entire body form a sensory array system for detecting hydrodynamic stimuli analogous to the lateral line system of fish. This is consistent with data highlighting that manatees are tactile specialists, evidenced by their specialized facial morphology and use of their vibrissae during feeding and active investigation/manipulation of objects. Two Florida manatees were tested in a go/no-go procedure using a staircase method to assess their ability to detect low-frequency water movement. Hydrodynamic vibrations were created by a sinusoidally oscillating sphere that generated a dipole field at frequencies from 5 to 150 Hz, which are below the apparent functional hearing limit of the manatee. The manatees detected particle displacement of less than 1 MUm for frequencies of 15-150 Hz and of less than a nanometer at 150 Hz. Restricting the facial vibrissae with various size mesh openings indicated that the specialized sensory hairs played an important role in the manatee's exquisite tactile sensitivity. PMID- 23660812 TI - Inactivation of Pseudomonas putida by pulsed electric field treatment: a study on the correlation of treatment parameters and inactivation efficiency in the short pulse range. AB - An important issue for an economic application of the pulsed electric field treatment for bacterial decontamination of wastewater is the specific treatment energy needed for effective reduction of bacterial populations. The present experimental study performed in a field amplitude range of 40 > E > 200 kV/cm and for a suspension conductivity of 0.01 = kappa(e) > 0.2 S/m focusses on the application of short pulses, 25 ns > T > 10 MUs, of rectangular, bipolar and exponential shape and was made on Pseudomonas putida, which is a typical and widespread wastewater microorganism. The comparison of inactivation results with calculations of the temporal and azimuthal membrane charging dynamics using the model of Pauly and Schwan revealed that for efficient inactivation, membrane segments at the cell equator have to be charged quickly and to a sufficiently high value, on the order of 0.5 V. After fulfilling this basic condition by an appropriate choice of pulse field strength and duration, the log rate of inactivation for a given suspension conductivity of 0.2 S/m was found to be independent of the duration of individual pulses for constant treatment energy expenditure. Moreover, experimental results suggest that even pulse shape plays a minor role in inactivation efficiency. The variation of the suspension conductivity resulted in comparable inactivation performance of identical pulse parameters if the product of pulse duration and number of pulses was the same, i.e., required treatment energy can be linearly downscaled for lower conductivities, provided that pulse amplitude and duration are selected for entire membrane surface permeabilization. PMID- 23660810 TI - Mixture and odorant processing in the olfactory systems of insects: a comparative perspective. AB - Natural olfactory stimuli are often complex mixtures of volatiles, of which the identities and ratios of constituents are important for odor-mediated behaviors. Despite this importance, the mechanism by which the olfactory system processes this complex information remains an area of active study. In this review, we describe recent progress in how odorants and mixtures are processed in the brain of insects. We use a comparative approach toward contrasting olfactory coding and the behavioral efficacy of mixtures in different insect species, and organize these topics around four sections: (1) Examples of the behavioral efficacy of odor mixtures and the olfactory environment; (2) mixture processing in the periphery; (3) mixture coding in the antennal lobe; and (4) evolutionary implications and adaptations for olfactory processing. We also include pertinent background information about the processing of individual odorants and comparative differences in wiring and anatomy, as these topics have been richly investigated and inform the processing of mixtures in the insect olfactory system. Finally, we describe exciting studies that have begun to elucidate the role of the processing of complex olfactory information in evolution and speciation. PMID- 23660813 TI - Molecular dynamic simulation of transmembrane pore growth. AB - A molecular dynamic approach was applied for simulation of dynamics of pore formation and growth in a phospholipid bilayer in the presence of an external electric field. Processing the simulation results permitted recovery of the kinetic coefficients used in the Einstein-Smoluchowski equation describing the dynamics of pore evolution. Two different models of the bilayer membrane were considered: membrane consisting of POPC and POPE lipids. The simulations permitted us to find nonempirical values of the pore energy parameters, which are compared with empirical values. It was found that the parameters are sensitive to membrane type. PMID- 23660816 TI - To bend or not to bend. PMID- 23660814 TI - Molecular dynamics simulation and molecular docking studies of Angiotensin converting enzyme with inhibitor lisinopril and amyloid Beta Peptide. AB - Angiotensin converting enzyme (ACE) cleaves amyloid beta peptide. So far this cleavage mechanism has not been studied in detail at atomic level. Keeping this view in mind, we performed molecular dynamics simulation of crystal structure complex of testis truncated version of ACE (tACE) and its inhibitor lisinopril along with Zn(2+) to understand the dynamic behavior of active site residues of tACE. Root mean square deviation results revealed the stability of tACE throughout simulation. The residues Ala 354, Glu 376, Asp 377, Glu 384, His 513, Tyr 520 and Tyr 523 of tACE stabilized lisinopril by hydrogen bonding interactions. Using this information in subsequent part of study, molecular docking of tACE crystal structure with Abeta-peptide has been made to investigate the interactions of Abeta-peptide with enzyme tACE. The residues Asp 7 and Ser 8 of Abeta-peptide were found in close contact with Glu 384 of tACE along with Zn(2+). This study has demonstrated that the residue Glu 384 of tACE might play key role in the degradation of Abeta-peptide by cleaving peptide bond between Asp 7 and Ser 8 residues. Molecular basis generated by this attempt could provide valuable information towards designing of new therapies to control Abeta concentration in Alzheimer's patient. PMID- 23660817 TI - The Tandem Archwire technique in lingual orthodontics. PMID- 23660815 TI - Uniform magnesium silicate hollow spheres as high drug-loading nanocarriers for cancer therapy with low systemic toxicity. AB - Resulting from their versatile functionality, nanomaterials with low systemic toxicity have offered high-performance diagnostic and therapeutic capabilities. Here, we designed and synthesized uniform magnesium silicate hollow spheres as high drug-loading nanocarriers for cancer therapy. Through a classical Stober method and a hydrothermal process, well-defined MgSiO3 hollow spheres were prepared in a facile route with inexpensive inhesion. Compared with routinely used mesoporous silica nanoparticles, our MgSiO3 hollow spheres with larger void space and mesoporous shell endowed the structures with a much higher storage capacity of guest molecules (2140 mg DOX g(-1)) and a much more sustained release of anticancer drugs. In detail, the release property and therapeutic efficacy of DOX-loaded nanoparticles were evaluated in vitro and in vivo. In vitro experiments revealed that these nanoparticles were mostly accumulated in lysosome, which facilitated continual drug release and efficient cancer cell destruction. We further demonstrated that these DOX-loaded nanoparticles could effectively suppress tumor growth compared to free DOX in vivo, as DOX-loaded nanoparticle-treated mice survived over 15 days without obvious detectable tumor growth. Otherwise, long-term toxicity study was also evaluated, indicating their overall safety and great potential in biomedical applications. PMID- 23660818 TI - Design improvements in the modified C-palatal plate for molar distalization. PMID- 23660819 TI - Posterior intrusion using skeletal anchorage in a patient with severe acid erosion. PMID- 23660820 TI - An uprighting auxiliary for deeply impacted mandibular molars. PMID- 23660821 TI - A landmark for monitoring the progress of a bonded palatal expander. PMID- 23660822 TI - Clinical effectiveness and efficiency of customized vs. conventional preadjusted bracket systems. PMID- 23660823 TI - Entangled communities and spatial synchronization lead to criticality in urban traffic. AB - Understanding the relation between patterns of human mobility and the scaling of dynamical features of urban environments is a great importance for today's society. Although recent advancements have shed light on the characteristics of individual mobility, the role and importance of emerging human collective phenomena across time and space are still unclear. In this Article, we show by using two independent data-analysis techniques that the traffic in London is a combination of intertwined clusters, spanning the whole city and effectively behaving as a single correlated unit. This is due to algebraically decaying spatio-temporal correlations, that are akin to those shown by systems near a critical point. We describe these correlations in terms of Taylor's law for fluctuations and interpret them as the emerging result of an underlying spatial synchronisation. Finally, our results provide the first evidence for a large scale spatial human system reaching a self-organized critical state. PMID- 23660824 TI - Salidroside protects against hydrogen peroxide-induced injury in HUVECs via the regulation of REDD1 and mTOR activation. AB - Antioxidative therapy is considered an effective strategy for treating oxidative stress-induced apoptosis in cardiovascular diseases. Salidroside has been used as an antioxidative therapy for oxidative injury in cardiac diseases. However, the mechanism underlying its antioxidant effect is poorly understood. The present study aimed to investigate the pharmacological effects of salidroside on cultured human umbilical vein endothelial cells (HUVECs) under conditions of oxidative injury induced by hydrogen peroxide (H2O2) and the underlying mechanisms in vitro. HUVECs pretreated with or without salidroside for 24 h were exposed to H2O2-induced oxidative stress conditions for 6 h and then cell viability, apoptosis, HIF-1alpha, regulated in development and DNA damage responses-1 (REDD1) and the PI3K/Akt/mTOR pathway were investigated. The results demonstrated that salidroside effectively attenuated H2O2-impaired cell viability and the production of reactive oxygen species (ROS) in a concentration-dependent manner. Reduced H2O2-induced apoptosis and activation of the cellular PI3K/Akt/mTOR pathway were demonstrated in HUVECs pretreated with salidroside. Furthermore, the level of REDD1, a direct regulator of mitochondrial metabolism, significantly increased in parallel with the level of HIF-1alpha following pretreatment with salidroside. The antioxidative effect of salidroside was abrogated in REDD1 knockdown cells. However, LY294002, a PI3K inhibitor, attenuated the anti apoptotic effect of salidroside and blocked the increase of Akt and mTOR; however, did not affect the antioxidative effect of salidroside. These findings suggested that salidroside was capable of protecting HUVECs against H2O2-induced apoptosis by activating the PI3K/Akt/mTOR-dependent pathway and inhibiting ROS production by activating REDD1. PMID- 23660825 TI - Hydrochlorothiazide compared to chlorthalidone in reduction of urinary calcium in patients with kidney stones. AB - Prevention of recurrent calcium stone disease includes treatment with thiazide and thiazide-type diuretics to reduce urinary calcium (UCa) levels, with the reduction in UCa correlating with risk of stone recurrence. There has been a recent trend of using lower doses of these medications and change from chlorthalidone (CTL) use to hydrochlorothiazide (HCTZ) use. It is unknown whether low doses of HCTZ are effective in lowering UCa levels to target levels. We hypothesize that HCTZ is associated with less reduction in UCa than is CTL when comparing currently used doses. Retrospective observational study of stone formers was seen in metabolic stone clinic during a 3 years period. Data included patient demographics, co-morbidities, and 24 h urine electrolyte composition. Primary outcome was the change in 24 h UCa. 322 patients were identified with 112 meeting criteria and used in analysis. The majority were placed on HCTZ (n = 42) or CTL (n = 47) 25 mg QD. Patients on CTL 25 mg had a greater reduction in UCa (164 mg; 41 %) than those on HCTZ (85 mg; 21 %), p = 0.01. Neither CTL nor HCTZ at 12.5 mg QD significantly lowered UCa. There was a decrease in serum [K] of 0.5 Meq/L (p = 0.001) in patients on CTL 25 mg daily, but no significant difference in severe hypokalemia or arrhythmia compared to HCTZ. Our data show that CTL is associated with greater reduction in 24 h UCa compared to similarly dosed HCTZ. PMID- 23660826 TI - The skin of fish as a transport epithelium: a review. AB - The primary function of fish skin is to act as a barrier. It provides protection against physical damage and assists with the maintenance of homoeostasis by minimising exchange between the animal and the environment. However in some fish, the skin may play a more active physiological role. This is particularly true in species that inhabit specialised environmental niches (e.g. amphibious and air breathing fish such as the lungfish), those with physiological characteristics that may subvert the need for the integument as a barrier (e.g. the osmoconforming hagfish), and/or fish with anatomical modifications of the epidermis (e.g. reduced epithelial thickness). Using examples from different fish groups (e.g. hagfishes, elasmobranchs and teleosts), the importance of fish skin as a transport epithelium for gases, ions, nitrogenous waste products, and nutrients was reviewed. The role of the skin in larval fish was also examined, with early life stages often utilising the skin as a surrogate gill, prior to the development of a functional branchial epithelium. PMID- 23660829 TI - Adsorption and diffusion in thin films of nanoporous metal-organic frameworks: ferrocene in SURMOF Cu2(ndc)2(dabco). AB - The adsorption and diffusion of ferrocene (FC) in thin MOF films of type Cu2(ndc)2(dabco) were studied by X-ray diffraction and using a quartz-crystal microbalance (QCM) at different temperatures. A quantitative analysis of the uptake curves in the QCM during loading with FC from the gas phase yields 0.19 FC compounds per pore at a temperature of 305 K and of 0.06 at 335 K, respectively. From an analysis of this temperature dependence we obtain an adsorption enthalpy of -30 kJ mol(-1). A quantitative analysis of the time dependence of the QCM uptake curves yields very small diffusivities on the order of 10(-19) to 10(-17) m(2) s(-1), while the activation energy for diffusion amounts to +90 kJ mol(-1). These results show that using a quartz crystal microbalance for uptake studies in SURMOFs is a valuable tool for investigating very slowly diffusing compounds in nanoporous materials. PMID- 23660830 TI - G-quadruplex formation of entirely hydrophobic DNA in organic solvents. AB - We report herein a novel hydrophobic G-quadruplex DNA consisting of dodecyl phosphotriester linkages. The 6-mer hydrophobic DNA having a TG4T sequence binds to monovalent cations to form a tetramolecular G-quadruplex in low polarity organic solvents. PMID- 23660827 TI - Strategies for hypoxia adaptation in fish species: a review. AB - Aquatic environments exhibit wide temporal and spatial variations in oxygen levels compared to terrestrial environments. Fish are an excellent model for elucidating the underlying mechanisms of hypoxia adaptation. Over the past decade, several hypoxia-related proteins have been reported to act in concert to convey oxygen change information to downstream signaling effectors. Some signaling pathways, such as redox status, AMPK, MAPK and IGF/PI3K/Akt, are known to play a central role in hypoxia adaptation. These networks regulate oxygen sensitive transcription factors which, in turn, affect the expression of hypoxia adaptation-related genes. This review summarizes current insights into hypoxia adaptation-related proteins and signaling pathways in fish. PMID- 23660828 TI - Effect of the administration of Solanum nigrum fruit on blood glucose, lipid profiles, and sensitivity of the vascular mesenteric bed to phenylephrine in streptozotocin-induced diabetic rats. AB - BACKGROUND: Solanum nigrum fruit is traditionally used in Asia to manage, control, and treat diabetes but there is no scientific evidence of the efficacy of Solanum nigrum fruit in treatment of diabetes. We designed this study to investigate the effect of the administration of oral doses of aqueous extract from Solanum nigrum fruit on plasma glucose, lipid profiles, and the sensitivity of the vascular mesenteric bed to Phenylephrine in diabetic and non-diabetic rats. MATERIAL AND METHODS: Animals were divided into 5 groups (n=10): 2 groups served as non-diabetic controls (NDC), and the other groups had diabetes induced with a single injection of streptozotocin (STZ). Solanum nigrum-treated chronic diabetic (CD-SNE) and Solanum nigrum-treated controls (ND-SNE) received 1g/l of Solanum nigrum added to drinking water for 8 weeks. The mesenteric vascular beds were prepared using the McGregor method. RESULTS: Administration of Solanum nigrum caused Ca/Mg ratio, plasma glucose, high-density lipoprotein (HDL), low density lipoprotein (LDL), very low-density lipoprotein (VLDL), total cholesterol, and triglyceride concentrations to return to normal levels, and was shown to decrease alteration in vascular reactivity to vasoconstrictor agents. CONCLUSIONS: Our results support the hypothesis that Solanum nigrum could play a role in the management of diabetes and the prevention of vascular complications in STZ-induced diabetic rats. PMID- 23660831 TI - Peer influences on moral disengagement in late childhood and early adolescence. AB - Moral disengagement processes are cognitive self-justification processes of transgressive actions that have been hypothesized to be learned and socialized within social contexts. The current study aimed at investigating socialization of moral disengagement by friends in two developmentally different age groups, namely late childhood (age: 9-10 years; n = 133, 42.9% girls) and early adolescence (age: 11-14 years; n = 236, 40.6% girls) over a 1-year period. Specifically, the current study examined whether similarity in moral disengagement between friends was the result of friends' influence or friend selection. Moreover, gender (42% girls), individual bullying behavior, and perceived popularity status were examined as potential moderators of socialization for moral disengagement within friendship networks. Self-report measures were used to assess moral disengagement, sociometric questions and a peer-nomination scale for friendship networks and bullying behavior, respectively. Longitudinal social network analysis (RSiena) was used to study change of moral disengagement in friendship networks during a 1-year interval. In early adolescence, friends were more likely to be similar to each other over time and this was explained only by influence processes and not by selection processes. Gender, bullying, and perceived popularity did not moderate the friends' influence on moral disengagement over time. Results indicate that self justification processes change over time already in late childhood, but only in early adolescence this change is likely to be dependent upon peers' moral disengagement. PMID- 23660832 TI - The immune pathogenesis of multiple sclerosis. AB - Multiple sclerosis is an autoimmune disease of the central nervous system (CNS) that leads to changes of nerve conduction due to damage of CNS- resident cells, primarily oligodendrocytes and neurons. CD4+ T cells are of primary importance in the immune cascades leading to tissue damage, but also CD8+ T cells, NK cells and B cells and antibodies contribute to tissue damage. In addition, the innate immune response and mainly microglial cells participate in the events leading to lesions. There are different types of MS and possibly this is due to different underlying immune mechanisms. The current treatment options mainly affect the immune response but have not much influence on secondary signaling changes in astrocytes and neurons which contribute to constant disease progression. The immune response in MS must be seen in the systemic context and there are strong indications that the gut and lung immunity affect MS disease precipitation. The strongest genetic influence in MS is mediated by the HLA class II genes and in Western Europeans and North Americans the disease is associated with HLA-DR2b. Possibly this is due to presentation of a set of specific antigens in context of this HLA allele. Novel data indicates that the immune response in MS is not only focused on certain myelin proteins like myelin basic protein (MBP) but to additional astrocytic and neuronal proteins, which is also mirrored in the pathology. While in the past the disease has been considered as mainly a white matter disease, nowadays it is clear that also grey matter is affected by the aberrant immune response. Still much needs to be learned regarding the underlying events in MS. This expanded knowledge is important to finally discover curative therapies. PMID- 23660833 TI - Enhancement of NMDA receptor-mediated excitatory postsynaptic currents by gp120 treated macrophages: implications for HIV-1-associated neuropathology. AB - A plethora of prior studies has linked HIV-1-infected and immune activated brain mononuclear phagocytes (MP; blood borne macrophages and microglia) to neuronal dysfunction. These are modulated by N-methyl-D-aspartate receptor (NMDAR) antagonists and supporting their relevance for HIV-1-associated nervous system disease. The role of NMDAR subsets in HIV-1-induced neuronal injury, nonetheless, is poorly understood. To this end, we investigated conditioned media from HIV 1gp120-treated human monocyte-derived-macrophages (MDM) for its abilities to affect NMDAR-mediated excitatory postsynaptic currents (EPSC(NMDAR)) in rat hippocampal slices. Bath application of gp120-treated MDM-conditioned media (MCM) produced an increase of EPSC(NMDAR). In contrast, control (untreated) MCM had limited effects on EPSC(NMDAR). Testing NR2A NMDAR (NR2AR)-mediated EPSC (EPSC(NR2AR)) and NR2B NMDAR (NR2BR)-mediated EPSC (EPSC(NR2BR)) for MCM showed significant increased EPSC(NR2BR) when compared to EPSC(NR2AR) enhancement. When synaptic NR2AR-mediated EPSC was blocked by bath application of MK801 combined with low frequency stimulations, MCM retained its ability to enhance EPSC(NMDAR) evoked by stronger stimulations. This suggested that increase in EPSC(NMDAR) was mediated, in part, through extra-synaptic NR2BR. Further analyses revealed that the soluble factors with low (<3 kD) to medium (3-10 kD) molecular weight mediated the observed increases in EPSC(NMDAR). The link between activation of NR2BRs and HIV-1gp120 MCM for neuronal injury was demonstrated by NR2BR but not NR2AR blockers. Taken together, these results indicate that macrophage secretory products induce neuronal injury through extra-synaptic NR2BRs. PMID- 23660834 TI - Whole-genome mapping of agronomic and metabolic traits to identify novel quantitative trait Loci in bread wheat grown in a water-limited environment. AB - Drought is a major environmental constraint responsible for grain yield losses of bread wheat (Triticum aestivum) in many parts of the world. Progress in breeding to improve complex multigene traits, such as drought stress tolerance, has been limited by high sensitivity to environmental factors, low trait heritability, and the complexity and size of the hexaploid wheat genome. In order to obtain further insight into genetic factors that affect yield under drought, we measured the abundance of 205 metabolites in flag leaf tissue sampled from plants of 179 cv Excalibur/Kukri F1-derived doubled haploid lines of wheat grown in a field experiment that experienced terminal drought stress. Additionally, data on 29 agronomic traits that had been assessed in the same field experiment were used. A linear mixed model was used to partition and account for nongenetic and genetic sources of variation, and quantitative trait locus analysis was used to estimate the genomic positions and effects of individual quantitative trait loci. Comparison of the agronomic and metabolic trait variation uncovered novel correlations between some agronomic traits and the levels of certain primary metabolites, including metabolites with either positive or negative associations with plant maturity-related or grain yield-related traits. Our analyses demonstrate that specific regions of the wheat genome that affect agronomic traits also have distinct effects on specific combinations of metabolites. This approach proved valuable for identifying novel biomarkers for the performance of wheat under drought and could facilitate the identification of candidate genes involved in drought-related responses in bread wheat. PMID- 23660835 TI - Involvement of AtPollambda in the repair of high salt- and DNA cross-linking agent-induced double strand breaks in Arabidopsis. AB - DNA polymerase lambda (Pol lambda) is the sole member of family X DNA polymerase in plants and plays a crucial role in nuclear DNA damage repair. Here, we report the transcriptional up-regulation of Arabidopsis (Arabidopsis thaliana) AtPollambda in response to abiotic and genotoxic stress, including salinity and the DNA cross-linking agent mitomycin C (MMC). The increased sensitivity of atpollambda knockout mutants toward high salinity and MMC treatments, with higher levels of accumulation of double strand breaks (DSBs) than wild-type plants and delayed repair of DSBs, has suggested the requirement of Pol lambda in DSB repair in plants. AtPollambda overexpression moderately complemented the deficiency of DSB repair capacity in atpollambda mutants. Transcriptional up-regulation of major nonhomologous end joining (NHEJ) pathway genes KU80, X-RAY CROSS COMPLEMENTATION PROTEIN4 (XRCC4), and DNA Ligase4 (Lig4) along with AtPollambda in Arabidopsis seedlings, and the increased sensitivity of atpollambda-2/atxrcc4 and atpollambda-2/atlig4 double mutants toward high salinity and MMC treatments, indicated the involvement of NHEJ-mediated repair of salinity- and MMC-induced DSBs. The suppressed expression of NHEJ genes in atpollambda mutants suggested complex transcriptional regulation of NHEJ genes. Pol lambda interacted directly with XRCC4 and Lig4 via its N-terminal breast cancer-associated C terminus (BRCT) domain in a yeast two-hybrid system, while increased sensitivity of BRCT deficient Pol lambda-expressing transgenic atpollambda-2 mutants toward genotoxins indicated the importance of the BRCT domain of AtPollambda in mediating the interactions for processing DSBs. Our findings provide evidence for the direct involvement of DNA Pol lambda in the repair of DSBs in a plant genome. PMID- 23660836 TI - Dynamic adaption of metabolic pathways during germination and growth of lily pollen tubes after inhibition of the electron transport chain. AB - Investigation of the metabolome and the transcriptome of pollen of lily (Lilium longiflorum) gave a comprehensive overview of metabolic pathways active during pollen germination and tube growth. More than 100 different metabolites were determined simultaneously by gas chromatography coupled to mass spectrometry, and expressed genes of selected metabolic pathways were identified by next-generation sequencing of lily pollen transcripts. The time-dependent changes in metabolite abundances, as well as the changes after inhibition of the mitochondrial electron transport chain, revealed a fast and dynamic adaption of the metabolic pathways in the range of minutes. The metabolic state prior to pollen germination differed clearly from the metabolic state during pollen tube growth, as indicated by principal component analysis of all detected metabolites and by detailed observation of individual metabolites. For instance, the amount of sucrose increased during the first 60 minutes of pollen culture but decreased during tube growth, while glucose and fructose showed the opposite behavior. Glycolysis, tricarbonic acid cycle, glyoxylate cycle, starch, and fatty acid degradation were activated, providing energy during pollen germination and tube growth. Inhibition of the mitochondrial electron transport chain by antimycin A resulted in an immediate production of ethanol and a fast rearrangement of metabolic pathways, which correlated with changes in the amounts of the majority of identified metabolites, e.g. a rapid increase in gamma-aminobutyric acid indicated the activation of a gamma-aminobutyric acid shunt in the tricarbonic acid cycle, while ethanol fermentation compensated the reduced ATP production after inhibition of the oxidative phosphorylation. PMID- 23660837 TI - Structural determinants at the interface of the ARC2 and leucine-rich repeat domains control the activation of the plant immune receptors Rx1 and Gpa2. AB - Many plant and animal immune receptors have a modular nucleotide-binding-leucine rich repeat (NB-LRR) architecture in which a nucleotide-binding switch domain, NB ARC, is tethered to a LRR sensor domain. The cooperation between the switch and sensor domains, which regulates the activation of these proteins, is poorly understood. Here, we report structural determinants governing the interaction between the NB-ARC and LRR in the highly homologous plant immune receptors Gpa2 and Rx1, which recognize the potato cyst nematode Globodera pallida and Potato virus X, respectively. Systematic shuffling of polymorphic sites between Gpa2 and Rx1 showed that a minimal region in the ARC2 and N-terminal repeats of the LRR domain coordinate the activation state of the protein. We identified two closely spaced amino acid residues in this region of the ARC2 (positions 401 and 403) that distinguish between autoactivation and effector-triggered activation. Furthermore, a highly acidic loop region in the ARC2 domain and basic patches in the N-terminal end of the LRR domain were demonstrated to be required for the physical interaction between the ARC2 and LRR. The NB-ARC and LRR domains dissociate upon effector-dependent activation, and the complementary-charged regions are predicted to mediate a fast reassociation, enabling multiple rounds of activation. Finally, we present a mechanistic model showing how the ARC2, NB, and N-terminal half of the LRR form a clamp, which regulates the dissociation and reassociation of the switch and sensor domains in NB-LRR proteins. PMID- 23660840 TI - Design and test of a MEMS strain-sensing device for monitoring artificial knee implants. AB - This paper describes the development of a polyimide-based MEMS strain-sensing device. Finite element analysis was used to investigate an artificial knee implant and assist on device design and to optimize sensing characteristics. The sensing element of the device was fabricated using polyimide micromachining with embedded thin-metallic wires and placed into a knee prosthesis. The device was evaluated experimentally in a mechanical knee simulator using static and dynamic axial load conditions similar to those encountered in vivo. Results indicates the sensor is capable of measuring the strain associated to the total axial forces in the range of approximately 4 times body weight with a good sensitivity and accuracy for events happening within 1 s time window. PMID- 23660838 TI - Cervical characteristics of Noonan syndrome. AB - BACKGROUND/OBJECTIVES A short neck and low posterior hairline are characteristics of Noonan syndrome (NS) and are hallmarks of basilar invagination/impression. However, it is seldom that NS has been directly linked with this symptom. Thus, this study aimed to investigate basilar impression in NS subjects compared with control subjects and individuals exhibiting Turner Syndrome (TS). SUBJECTS/METHODS The degree of basilar impression and vertical positional differences of the third and fourth cervical vertebrae and hyoid bone in NS (n = 9, mean age: 12.1 years), TS (n = 9, mean age: 12.1 years), and control subjects (n = 9, mean age: 12.0 years) were investigated using lateral cephalometric radiographs. Differences between the three groups were compared using the Steel Dwass test. Vertical positional differences in the anatomical structures within each group were compared using the Wilcoxon signed-rank test accompanied by a Bonferroni-Holm correction. RESULTS The distance by which the odontoid tip extended past McGregor's line in subjects with NS was significantly greater compared with TS and control subjects. The third and fourth cervical vertebrae were positioned significantly superiorly in subjects with NS compared with TS and control subjects and, in NS, were also significantly superior to the hyoid bone. There was no difference in the position of the hyoid bone itself between the groups. CONCLUSION/IMPLICATION These results suggest that basilar impression may be a frequently found symptom of NS. PMID- 23660841 TI - Flexible probe for in vivo quantification of corneal epithelium permeability through non-invasive tetrapolar impedance measurements. AB - Studies concerning the functional status of the corneal epithelium are of special interest due to its key role in preventing ocular surface disease and corneal infections. In particular, quantitative measurements of the epithelium permeability translayer electrical resistance (TER) have been proven as a sensitive in vitro test for evaluation of the corneal barrier function. In a recent work from the authors (Guimera et al. Biosens. Bioelectron. 31:55-61, 2012), a novel method to non-invasively assess the corneal epithelial permeability by using tetrapolar impedance measurements, based on the same TER theoretical principles, was presented and validated using a rigid sensing device. In this work, the usability of this method has been dramatically improved by using SU-8 photoresist as a substrate material. The flexibility of this novel sensing device makes no need to apply pressure on the cornea to ensure the electrical contact between the electrodes and the corneal surface. The feasibility of this flexible sensor has been evaluated in vivo by increasing the permeability of rabbit corneal epithelium. For that, different concentrations of benzalkonium chloride (BAC) solution were instilled on different rabbit corneas. The obtained results have been compared with measurements of the permeability to sodium fluorescein of different excised corneas, a well-known method used to evaluate the corneal barrier function, to demonstrate the feasibility of this novel flexible sensor for quantifying the corneal epithelium permeability in vivo in a non-invasive way. PMID- 23660842 TI - High expression of microRNA-155 is associated with the aggressive malignant behavior of gallbladder carcinoma. AB - The prognosis of gallbladder cancer (GBC) remains poor despite recent advances in diagnostics and therapeutic strategies. Although the role of microRNAs (miRs) in GBC have not been well documented, miR-155 is known to be associated with inflammation-associated carcinogenesis in various types of cancers. The aim of this study was to investigate the clinical significance of miR-155 expression and the biological functions of miR-155 in GBC. The expression levels of miR-155 in surgically resected GBCs and gallbladders with pancreaticobiliary maljunction (PBM) were assessed by quantitative reverse transcription-polymerase chain reaction. The relationship between the expression levels of miR-155 and clinicopathological features of GBCs was analyzed. Human GBC cell lines were transfected with miR-155 inhibitors or mimics, and the effects on proliferation and invasion were assessed. miR-155 was significantly overexpressed in GBCs when compared with that in gallbladders with PBM (p=0.007) and normal gallbladders (p=0.04). The high expression level of miR-155 in GBCs was significantly associated with the presence of lymph node metastasis (p=0.01) and a poor prognosis (p=0.02). In vitro assays showed that aberrant expression of miR-155 significantly enhanced GBC cell proliferation and invasion. In conclusion, high miR-155 expression correlates with the aggressive behavior of GBCs, and miR-155 may become a prognostic marker and therapeutic target for GBC. PMID- 23660843 TI - An electrochemical Lab-on-a-CD system for parallel whole blood analysis. AB - Lab-on-a-CD, as a main branch of Lab-on-a-chip technology, has led to several very successful commercial products. Most of these existing Lab-on-a-CD systems present complex system designs and thus are relatively expensive. In this work, we have developed a simple but robust Lab-on-a-CD system for parallel whole blood analyses. This Lab-on-a-CD system incorporates electrochemical bioanalysis and a simple blood sample separation mechanism into the centrifugal platform, and thus reduces the system's complexity. To demonstrate the applicability, the system was applied to perform basic metabolic panel tests, for example, the concentrations of glucose, lactate and uric acids of whole blood samples. Using only 16 MUL of whole blood, within a few minutes, the Lab-on-a-CD system could produce results that agreed in general with the data by a conventional system. Therefore, this proof-of-concept Lab-on-a-CD system has demonstrated the potential to become a robust and simple-to-use device for parallel blood analyses. PMID- 23660845 TI - Incidence of first stroke: a population study in Iceland. AB - BACKGROUND AND PURPOSE: Iceland is an island in the North Atlantic with ~319 000 inhabitants. The study determines the incidence of first stroke in the adult population of Iceland during 12 months, which has not been previously reported in the entire Icelandic population. METHODS: The study population consisted of all residents of Iceland, aged >= 18 years, during the 12-month study period. Cases were identified by multiple overlapping approaches. Medical records were reviewed to verify diagnosis, to determine stroke subtype and to determine selected risk factors. RESULTS: A total of 343 individuals, aged >= 18 years, had a first stroke during the study period. Incidence was 144 per 100 000 person years; 81% ischemic infarction; 9% intracerebral hemorrhage; 7% subarachnoid hemorrhage; and 3% unknown. Fifty percent of the individuals were men. Mean age for ischemic infarction and intracerebral hemorrhage was 71 years for men and 73 years for women. Atrial fibrillation was previously known in 18% with first ischemic stroke or intracerebral hemorrhage and another 6% were diagnosed on routine admission ECG. Long-term ECG study (24 hours) found that 12% (18/154) of the remaining individuals had paroxysmal atrial fibrillation. CONCLUSIONS: Incidence of first stroke in Iceland is similar to other Western countries. The high number of paroxysmal atrial fibrillation found during the 24-hour ECG suggests that atrial fibrillation may be underdiagnosed in patients with stroke. PMID- 23660844 TI - Combined meningococcal serogroup A and W135 outer-membrane vesicles activate cell mediated immunity and long-term memory responses against non-covalent capsular polysaccharide A. AB - Outer-membrane vesicles (OMVs) have inherent adjuvant properties, and many vaccines use OMV as vaccine components. Utilizing the adjuvant properties of OMV could lead to the formulation of vaccines that are less expensive and potentially more immunogenic than covalently conjugated polysaccharide vaccines. We evaluated the adjuvant effect in Balb/c mice of combinations of OMV from Neisseria meningitidis serogroup A and W135 as compared to that of the non-covalently conjugated capsular polysaccharide A. Both antigens were adsorbed onto aluminum hydroxide. The mice were given a booster dose of plain polysaccharide A to stimulate an immunologic memory response. Subclasses determination and cytokine assays demonstrated the capacity of OMV to induce a IgG2a/IgG2b isotype profile and IFN-gamma production, suggesting the induction of a Th1 pattern immune response. Lymphoproliferative responses to OMVs were high, with affinity maturation of antibodies observed. Bactericidal titers after the booster dose were also observed. Memory B cells and long-term memory T cells were also detected. The results of this study indicate that combined meningococcal serogroup A and W135 OMV can activate cell-mediated immunity and induce a long term memory response. PMID- 23660846 TI - Transcranial laser therapy and infarct volume. AB - BACKGROUND AND PURPOSE: Two randomized trials suggested that transcranial laser therapy (TLT) may benefit patients with acute ischemic stroke, although efficacy has not been confirmed. Supportive proof of concept could be demonstrated if TLT reduces the volume of cortical infarction. METHODS: The NeuroThera Efficacy and Safety Trial-2 (NEST-2) was a randomized trial of TLT versus sham in patients with acute ischemic stroke treated within 24 hours of onset. Infarct volumes were measured quantitatively and semiquantitatively on all protocol-required computed tomography (or MRI, if clinically indicated) scans performed on day 5 (+/-2). Two approaches assessed treatment effects on cortex: (1) indirectly, by analyzing total infarct volume among patients with clinical presentations suggesting cortical involvement; and (2) directly, by assessing the cortical Alberta Stroke Program Early CT Score (cASPECTS) components (M1-M6, anterior, posterior) on a 0- to 8-point modified scale. RESULTS: A total of 640 subjects had scans (576 computed tomography, 64 MRI) on day 5. The reliability of ASPECTS (intraclass correlation coefficient=0.85) and cASPECTS (intraclass correlation coefficient=0.82) was excellent, and total ASPECTS was correlated with total infarct volume (r=0.71). In the overall study population, there was no impact of TLT on total infarct volume (P=0.30), total ASPECTS (P=0.85), or cASPECTS (P=0.89). Similarly, no effect was seen in any of the following prespecified subgroups selected to indicate cortical involvement: baseline National Institutes of Health Stroke Scale score >10, Oxfordshire Total Anterior Circulation Syndrome, subjects with aphasia or extinction at baseline, or subjects with radiographic involvement of cortex. CONCLUSIONS: TLT was not associated with a reduction in overall or cortical infarct volume as measured on computed tomography in the subacute phase. PMID- 23660847 TI - Trends in risk factor prevalence and management before first stroke: data from the South London Stroke Register 1995-2011. AB - BACKGROUND AND PURPOSE: Vascular risk factors are suboptimally managed internationally. This study investigated time trends in risk factors diagnosed before stroke and their treatment, and factors associated with appropriate medication use. METHODS: A total of 4416 patients with a first stroke were registered in the population-based South London Stroke Register from 1995 to 2011. Previously diagnosed risk factors and usual medications were collected from patients' primary care and hospital records. Trends and associations were assessed using multivariate logistic regression. RESULTS: Seventy-two percent of patients were diagnosed previously with 1 or more risk factors; 30% had diagnosed risk factors that were untreated. Hypercholesterolemia increased significantly during the study period; myocardial infarction and transient ischemic attack prevalences decreased. Antiplatelet prescription increased in atrial fibrillation (AF), myocardial infarction, and transient ischemic attack (AF, 37%-51%, P<0.001; myocardial infarction, 48%-69%, P<0.001; transient ischemic attack, 49%-61%, P=0.015). Anticoagulant prescription for AF showed a nonsignificant increase (12% 23%; P=0.059). Fewer older patients with AF were prescribed anticoagulants (age, >85 versus <65 years; adjusted relative risk, 0.19; 95% confidence interval, 0.08 0.41). Black ethnicity (adjusted relative risk, 1.17; 95% confidence interval, 1.10-1.23) and female sex (adjusted relative risk, 1.09; 95% confidence interval, 1.03-1.15) were associated with increased antihypertensive drug prescription; other medications did not vary by ethnicity or sex. CONCLUSIONS: Antiplatelet and cholesterol-lowering treatment prescribing have improved significantly over time; however, only a minority with AF received anticoagulants, and this did not improve significantly. Overall, 30% of strokes occurred in patients with previously diagnosed but untreated risk factors. PMID- 23660849 TI - Effects of candesartan in acute stroke on cognitive function and quality of life: results from the Scandinavian Candesartan Acute Stroke Trial. AB - BACKGROUND AND PURPOSE: High blood pressure is common in the acute phase of stroke and is associated with poor outcome. We examined whether blood pressure lowering treatment with candesartan in the acute phase affects long-term cognitive function and quality of life. METHODS: Scandinavian Candesartan Acute Stroke Trial was a randomized-controlled and placebo-controlled trial of candesartan in 2029 patients with acute stroke and raised blood pressure. At 6 months, cognitive function was assessed by the Mini Mental State Examination and quality of life by the EuroQol instrument. We used ordinal logistic and multiple linear regression for statistical analysis, adjusting for predefined key variables. RESULTS: Median Mini Mental State Examination score was 28 in both groups, and there was no significant difference between the distribution of Mini Mental State Examination scores in the 2 groups (common odds ratio, 1.11; 95% confidence interval, 0.91-1.34; P=0.32). Median EuroQol-5D index were 0.74 and 0.78 (P=0.034), and the mean EuroQol-visual analogue scale scores were 66.0 and 67.3 in the candesartan and placebo groups, respectively (P=0.11). CONCLUSIONS: Candesartan did not improve cognitive function or quality of life. Rather, there were signs of harmful effects. These findings support the conclusion from our previous report that there is no indication for routine blood pressure-lowering treatment with candesartan in the acute phase of stroke. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov. Unique identifier: NCT00120003. PMID- 23660848 TI - Cardiovascular biomarkers and subclinical brain disease in the atherosclerosis risk in communities study. AB - BACKGROUND AND PURPOSE: Cerebrovascular and cardiovascular disease share common risk factors. Our goal was to determine whether levels of N-terminal brain natriuretic peptide (NT-proBNP) and cardiac troponin T measured with a highly sensitive assay (hs-cTnT) are associated with silent brain infarcts (BIs) and white matter lesions (WMLs) on MRI in the Atherosclerosis Risk in Communities (ARIC) study. METHODS: At ARIC visit 3 (1993-1995), 1920 participants had brain MRI. NT-proBNP and hs-cTnT were measured in all individuals at ARIC visit 4 (1996 1998). Of 1920 individuals, 1112 had a follow-up MRI [2004-2006]). We analyzed the association of NT-proBNP and hs-cTnT with MRI-defined BI and WML on the initial MRI and incident BI and WML progression on the follow-up MRI in participants without heart failure, coronary heart disease, or stroke. RESULTS: In the adjusted model, individuals in the highest NT-proBNP quartile had significantly more BI (odds ratio, 3.50; 95% confidence interval, 2.03-6.20), and WML (beta-coefficient, 0.09; SE, 0.03) on the baseline MRI and more incident BI (odds ratio, 2.18; 95% confidence interval, 1.38-3.47) and WML progression (beta coefficient, 0.22; SE, 0.10) on the follow-up MRI. Individuals in the highest hs cTnT category had more BI (odds ratio, 3.03; 95% confidence interval, 1.57-5.82) and WML (beta-coefficient, 0.11; SE, 0.04) on the initial MRI and more WML progression (beta-coefficient, 0.43; SE, 0.17) on the follow-up MRI. CONCLUSIONS: NT-proBNP and hs-cTnT are independently associated with silent MRI-defined BI and WML, suggesting that cardiovascular biomarkers may be useful to identify individuals with subclinical cerebral injury. PMID- 23660851 TI - A novel, efficient synthesis of N-aryl pyrroles via reaction of 1-boronodienes with arylnitroso compounds. AB - A one-pot hetero-Diels-Alder/ring contraction cascade is presented from the reaction of 1-boronodienes and arylnitroso derivatives to derive N-arylpyrroles in moderate to good yields (up to 82%). PMID- 23660850 TI - Crossed pulmonary arteries: a report on 20 cases with an emphasis on the clinical features and the genetic and cardiac abnormalities. AB - Crossed pulmonary arteries (CPAs) are a rare abnormality in which the ostium of the left pulmonary artery originates superior to the right pulmonary artery and to its right. Recognition of this rare pathology is important because it generally is accompanied by other congenital heart defects, extracardiac anomalies, and certain genetic problems. To date, only a few cases have been reported, and most of these cases have been associated with complex cardiac abnormalities. The authors detected 20 cases of CPA between June 2009 and November 2012 through their increasing awareness of this anomaly. Approximately 9,250 echocardiograms were performed during this period, and all of them also were checked for this anomaly. This report describes 20 cases of this CPA, with an emphasis on the clinical features and the genetic and cardiac abnormalities. The patients ranged in age from 1 day to 13 years at the time of the initial diagnosis. Four patients had complex cardiac pathologies such as tetralogy of Fallot, truncus arteriosus, transposition of the great arteries, and complete atrioventricular septal defect. Of the 20 patients, 11 had ventricular septal defects, and 12 had atrial septal defects. Pulmonary artery stenosis was detected in 12 (55 %) of the 20 patients. Aortic arch abnormalities such as interrupted aortic arch, right aortic arch, and coarctation of the aorta were detected in six patients. One patient had a left persistent superior vena cava. In 45 % of the cases, an associated genetic syndrome (DiGeorge-, Noonan-, Holt-Oram syndromes, vertebral, anal, cardiac, tracheal, esophageal, renal, limb anomalies [VACTERL] anomalies) was present. These syndromes were diagnosed based on their clinical features. Karyotype and fluorescent in situ hybridization (FISH) analyses for a 22q11 deletion were performed for 11 patients, with 10 patients found to have normal karyotype and FISH results. Only one patient had a 22q11 deletion. Six patients underwent successful operations. During the follow-up period, 3 of the 20 patients died. At this writing, the remaining patients are clinically stable and being followed without surgery. The authors believe that CPA is not a rare anomaly. If careful echocardiographic examination is performed, CPA will be diagnosed more frequently. Although this pathology usually is associated with genetic syndromes and other cardiac abnormalities, patients with CPA generally are asymptomatic. PMID- 23660853 TI - beta2-integrin activity: the role of thiols. PMID- 23660852 TI - Convergent dysregulation of frontal cortical cognitive and reward systems in eating disorders. AB - A substantive literature has drawn a compelling case for the functional involvement of mesolimbic/prefrontal cortical neural reward systems in normative control of eating and in the etiology and persistence of severe eating disorders that affect diverse human populations. Presently, we provide a short review that develops an equally compelling case for the importance of dysregulated frontal cortical cognitive neural networks acting in concert with regional reward systems in the regulation of complex eating behaviors and in the presentation of complex pathophysiological symptoms associated with major eating disorders. Our goal is to highlight working models of major eating disorders that incorporate complementary approaches to elucidate functionally interactive neural circuits defined by their regulatory neurochemical phenotypes. Importantly, we also review evidence-based linkages between widely studied psychiatric and neurodegenerative syndromes (e.g., autism spectrum disorders and Parkinson's disease) and co-morbid eating disorders to elucidate basic mechanisms involving dopaminergic transmission and its regulation by endogenously expressed morphine in these same cortical regions. PMID- 23660854 TI - The ongoing conundrum of MLL-AF4 driven leukemogenesis. PMID- 23660855 TI - Survival of the weak (signalers): anergy in CLL. PMID- 23660856 TI - To shrink or not to shrink. PMID- 23660857 TI - F8 gene and phenotype: single player in a team? PMID- 23660858 TI - Better BMT for Hurler syndrome--on the level? PMID- 23660860 TI - Components of the revised International Prognostic Scoring System and outcome after hematopoietic cell transplantation for myelodysplastic syndrome. PMID- 23660859 TI - The myelodysplastic syndrome as a prototypical epigenetic disease. AB - The myelodysplastic syndrome (MDS) is a clonal disorder characterized by increased stem cell proliferation coupled with aberrant differentiation resulting in a high rate of apoptosis and eventual symptoms related to bone marrow failure. Cellular differentiation is an epigenetic process that requires specific and highly ordered DNA methylation and histone modification programs. Aberrant differentiation in MDS can often be traced to abnormal DNA methylation (both gains and losses of DNA methylation genome wide and at specific loci) as well as mutations in genes that regulate epigenetic programs (TET2 and DNMT3a, both involved in DNA methylation control; EZH2 and ASXL1, both involved in histone methylation control). The epigenetic nature of MDS may explain in part the serendipitous observation that it is the disease most responsive to DNA methylation inhibitors; other epigenetic-acting drugs are being explored in MDS as well. Progression in MDS is characterized by further acquisition of epigenetic defects as well as mutations in growth-controlling genes that seem to tip the proliferation/apoptosis balance and result in the development of acute myelogenous leukemia. Although MDS is clinically and physiologically heterogeneous, a case can be made that subsets of the disease can be largely explained by disordered stem cell epigenetics. PMID- 23660861 TI - TCF-1 mediates repression of Notch pathway in T lineage-committed early thymocytes. PMID- 23660862 TI - Low frequency of H3.3 mutations and upregulated DAXX expression in MDS. PMID- 23660863 TI - SRSF2 mutation is present in the hypercellular and prefibrotic stage of primary myelofibrosis. PMID- 23660864 TI - Complement factor H mutations are present in ADAMTS13-deficient, ticlopidine associated thrombotic microangiopathies. PMID- 23660866 TI - The impairment of the parasympathetic modulation is involved in the age-related change in mitral E/A ratio. AB - The mitral early to late diastolic flow velocity ratio (E/A ratio) is age dependent. It has been considered that its age dependency reflects the age related lengthening of left ventricular (LV) relaxation; however, the change in E/A ratio is far larger than that expected from those in LV relaxation. We hypothesized that an age-related reduction of the parasympathetic activity increases left atrial (LA) contractility, and that this accounts for the age related change in E/A ratio. (1) Exercise stress test was performed in 61 normal subjects (age range, 8-80 years, mean, 40 years) to assess heart rate (HR) recovery because slowed HR recovery indicates lowered parasympathetic activity. There were good interrelations among age, E/A ratio, and HR recovery. Among those aged <=30 years, the age no longer correlated with E/A ratio or HR recovery, but there was a significant correlation between HR recovery and E/A ratio (r = 0.44, p < 0.05). (2) Pulsed Doppler and two-dimensional speckle tracking echocardiography (2DSTE) were performed before and after administration of parasympathetic blockade (atropine) in ten young healthy subjects. LA booster pump function was assessed with LA emptying index calculated by 2DSTE. LA emptying index was calculated from ([LA volume before the atrial contraction - minimal LA volume]/LA volume before the atrial contraction) * 100. Atropine increased mitral A velocity (p < 0.001) and LA emptying index (p < 0.05) along with a decrease in E/A ratio (p < 0.001). Parasympathetic withdrawal enhances LA contraction and increases mitral A velocity, which likely cause a reciprocal decrease in mitral E velocity and E/A ratio. Thus, parasympathetic deactivation with aging should be closely involved in the age-related change in mitral E/A ratio. PMID- 23660865 TI - The Prolo Scale: history, evolution and psychometric properties. AB - BACKGROUND: The Prolo Scale (PS) is a widely accepted assessment tool for lumbar spinal surgery results. Nevertheless, in the literature there is a dearth of consensus about its application, interpretation and accuracy. The purpose of this review is to investigate the evolution of the PS from its introduction in 1986 to the present, including an analysis of different versions of the scale and research on the existing studies investigating its psychometric properties. MATERIALS AND METHODS: PubMed, Cochrane Library and PEDro databases were searched. Studies in English, Italian, French, Spanish and German published from 1986 to December 2012 were analyzed. RESULTS: The original lumbar surgery outcome scale consisted of two Likert-type scales (economic and functional). There are three more versions of the scale: Schnee proposed one consisting of 10 items, Brantigan made one with 20 items and introduced 2 more subscales (pain and medication), and Davis adapted the scale for the cervical spine. PS is often mentioned without any specific reference to the version used; therefore, a homogeneous comparison of studies is difficult to achieve. Several authors agree on the need to embrace a multidimensional measuring system to evaluate low back pain (LBP), but there is still no consensus regarding the most reliable tool. To date, PS has been mostly used as secondary outcome measure in association with validated primary measures for LBP. CONCLUSIONS: The Prolo Scale has been adopted for clinical examination for 20 years because it is easy to administer and useful to compare significant amounts of data from surgical studies carried out at different times. Although several authors demonstrated the scale sensitivity among a battery of tests, no thorough validation study was found in the current literature. PMID- 23660868 TI - Low-dose 1,25-dihydroxyvitamin D(3) combined with arsenic trioxide synergistically inhibits proliferation of acute myeloid leukemia cells by promoting apoptosis. AB - Arsenic trioxide (As(2)O(3)) has shown substantial efficacy in the treatment of patients with acute promyelocytic leukemia, a specific subtype of acute myeloid leukemia (AML). However, since not all patients can achieve remission after treatment, it is necessary to develop a novel method to overcome this problem. We investigated the anti-leukemic effect of low-dose 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) in combination with As(2)O(3) on the human AML cell lines HL-60 and K562. The cell viability was in reverse proportion to As(2)O(3) or 1,25(OH)(2)D(3) concentration. In both HL-60 and K562 cells, after the combination treatment with As(2)O(3) and 1,25(OH)(2)D(3) at a 10:1 ratio, the combination index (CI) values were <1 in all treatment groups. In the RT-PCR and western blot analysis, the combination treatment decreased Bcl-2 expression and increased Bax and caspase-3 expression more prominently than the single treatment. In the flow cytometric analysis performed in HL-60 cells, the proportion of late apoptotic cells was 4.9% in the control, 30.0% in cells treated with 1.0 uM As(2)O(3), 8.1% in cells treated with 100 nM 1,25(OH)(2)D(3), and 64.3% in cells treated with 1.0 uM As(2)O(3) plus 100 nM 1,25(OH)(2)D(3). In conclusion, low-dose 1,25(OH)(2)D(3) combined with As(2)O(3) synergistically inhibited proliferation of HL-60 and K562 cells. In addition, this combination activated the apoptosis pathway more prominently than the single-drug treatment. PMID- 23660867 TI - Concurrent sunitinib and stereotactic body radiotherapy for patients with oligometastases: final report of a prospective clinical trial. AB - Preliminary results demonstrated that concurrent sunitinib and stereotactic body radiation therapy (SBRT) is an active regimen for metastases limited in number and extent. This analysis was conducted to determine the long-term survival and cancer control outcomes for this novel regimen. Forty-six patients with oligometastases, defined as five or fewer clinical detectable metastases from any primary site, were treated on a phase I/II trial from February 2007 to September 2010. The majority of patients were treated with 37.5 mg sunitinib (days 1-28) and SBRT 50 Gy (days 8-12 and 15-19) and maintenance sunitinib was used in 39 % of patients. Median follow up for surviving patients is 3.6 years. The 4-year estimates for local control, distant control, progression-free and overall survival were 75 %, 40 %, 34 % and 29 %, respectively. At last follow-up, 26 % of patients were alive without evidence of disease, 7 % were alive with distant metastases, 48 % died from distant metastases, 2 % died from local progression, 13 % died from comorbid illness, and 4 % died from treatment-related toxicities. Patients with kidney and prostate primary tumors were associated with a significantly improved overall survival (hazard ratio = 0.25, p = 0.04). Concurrent sunitinib and SBRT is a promising approach for the treatment of oligometastases and further study of this novel combination is warranted. PMID- 23660870 TI - Independent sources of spontaneous BOLD fluctuation along the visual pathway. AB - In resting-state functional magnetic resonance imaging (fMRI) experiments, correlation analysis can be used to identify clusters of cortical regions that may be functionally connected. Although such functional connectivity is often assumed to reflect cortico-cortical connections, a potential confound is the contribution of subcortical brain regions, many of which have strong anatomical connectivity to cortical regions and may also enable cortico-cortical interactions through trans-thalamic pathways. To investigate this, we performed resting state fMRI of the human visual system, including cortical regions and subcortical nuclei of the pulvinar and lateral geniculate. Regression analysis was used to investigate the dependence of the measured inter-regional correlations upon afferents from specific retinal, thalamic and cortical regions as well as systemic global signal fluctuation. A high level of inter-hemispheric correlation (cc = 0.95) was found in the visual cortex that could not be explained by activity in the subcortical nuclei investigated; in addition a relatively low level of inter-hemispheric correlation (cc = 0.39-0.42) was found in vision-related thalamic nuclei that could not be explained by direct anatomical connections or their cortical inputs. These findings suggest that spontaneous fMRI signal correlations within the human visual system originate from a mixture of independent signal sources that may be transmitted through thalamo-cortical, cortico-thalamic, and cortico-cortical connections either trans callosal or trans-thalamic in origin. Our findings thus call for more cautious interpretation of resting state functional connectivity in terms of any single type of anatomical connectivity. PMID- 23660871 TI - Cortical signature of neurological soft signs in recent onset schizophrenia. AB - Motor symptoms such as neurological soft signs (NSS) are characteristic phenomena of schizophrenia at any stage of the illness. Neuroimaging studies in schizophrenia patients have shown regional thinning of the cortical mantle, but it is unknown at present whether NSS are related to cortical thickness changes. Whole brain high-resolution magnetic resonance imaging at 3 Tesla was used to investigate cortical thickness in 28 patients with recent-onset schizophrenia. Cortical reconstruction was performed with the Freesurfer image analysis suite. NSS were examined on the Heidelberg Scale and related to cortical thickness. Age, education, and medication were considered as potential confounders. Higher NSS scores were associated with morphological changes of cortical thickness in multiple areas comprising paracentral gyrus, postcentral lobule, precuneus, inferior parietal lobule and temporal lobe. Our results confirm the hypothesis of a significant relationship between cortical thickness changes and the extent of NSS in schizophrenia. Investigation of cortical thickness may help to explain subtle motor symptoms such as NSS in schizophrenia. PMID- 23660869 TI - Pan-neuronal maturation but not neuronal subtype differentiation of adult neural stem cells is mechanosensitive. AB - Most past studies of the biophysical regulation of stem cell differentiation have focused on initial lineage commitment or proximal differentiation events. It would be valuable to understand whether biophysical inputs also influence distal endpoints more closely associated with physiological function, such as subtype specification in neuronal differentiation. To explore this question, we cultured adult neural stem cells (NSCs) on variable stiffness ECMs under conditions that promote neuronal fate commitment for extended time periods to allow neuronal subtype differentiation. We find that ECM stiffness does not modulate the expression of NeuroD1 and TrkA/B/C or the percentages of pan-neuronal, GABAergic, or glutamatergic neuronal subtypes. Interestingly, however, an ECM stiffness of 700 Pa maximizes expression of pan-neuronal markers. These results suggest that a wide range of stiffnesses fully permit pan-neuronal NSC differentiation, that an intermediate stiffness optimizes expression of pan-neuronal genes, and that stiffness does not impact commitment to particular neuronal subtypes. PMID- 23660872 TI - Integrative analysis of miRNA and mRNA expression profiles in pheochromocytoma and paraganglioma identifies genotype-specific markers and potentially regulated pathways. AB - Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine neoplasias of neural crest origin that can be part of several inherited syndromes. Although their mRNA profiles are known to depend on genetic background, a number of questions related to tumor biology and clinical behavior remain unanswered. As microRNAs (miRNAs) are key players in the modulation of gene expression, their comprehensive analysis could resolve some of these issues. Through characterization of miRNA profiles in 69 frozen tumors with germline mutations in the genes SDHD, SDHB, VHL, RET, NF1, TMEM127, and MAX, we identified miRNA signatures specific to, as well as common among, the genetic groups of PCCs/PGLs. miRNA expression profiles were validated in an independent series of 30 composed of VHL-, SDHB-, SDHD-, and RET-related formalin-fixed paraffin embedded PCC/PGL samples using quantitative real-time PCR. Upregulation of miR 210 in VHL- and SDHB-related PCCs/PGLs was verified, while miR-137 and miR-382 were confirmed as generally upregulated in PCCs/PGLs (except in MAX-related tumors). Also, we confirmed overexpression of miR-133b as VHL-specific miRNAs, miR-488 and miR-885-5p as RET-specific miRNAs, and miR-183 and miR-96 as SDHB specific miRNAs. To determine the potential roles miRNAs play in PCC/PGL pathogenesis, we performed bioinformatic integration and pathway analysis using matched mRNA profiling data that indicated a common enrichment of pathways associated with neuronal and neuroendocrine-like differentiation. We demonstrated that miR-183 and/or miR-96 impede NGF-induced differentiation in PC12 cells. Finally, global proteomic analysis in SDHB and MAX tumors allowed us to determine that miRNA regulation occurs primarily through mRNA degradation in PCCs/PGLs, which partially confirmed our miRNA-mRNA integration results. PMID- 23660873 TI - Insights into the polymorphism of glycine: membrane crystallization in an electric field. AB - In this work we studied glycine crystallization with two main objectives: (i) to get improved control of crystal growth and polymorphic selectivity of organic molecules; (ii) to achieve additional insights into the nucleation mechanisms of glycine polymorphs. To reach these goals, membrane crystallization technology, a tool which allows improved control of supersaturation in solution crystallization, was used under different operating conditions: the variable solvent removal rate, acidic and almost neutral pH, the presence of a pulsed electric field. The traditional explanation for the crystallization of alpha and gamma glycine polymorphs from aqueous solution is based on the general cyclic dimer hypothesis and the self-poisoning mechanism. In contrast with both the conventional theories, experimental results suggest that the relative nucleation rates with respect to the relative growth kinetics of the two forms under the different conditions play a dominant role in determining the polymorphic outcome. Our results instead support a molecular nucleation route where open chain dimers can behave as building units for both gamma- and alpha-glycines in the rate determining structuring step of the two-step nucleation mechanism. PMID- 23660874 TI - A copula model for marked point processes. AB - Many chronic diseases feature recurring clinically important events. In addition, however, there often exists a random variable which is realized upon the occurrence of each event reflecting the severity of the event, a cost associated with it, or possibly a short term response indicating the effect of a therapeutic intervention. We describe a novel model for a marked point process which incorporates a dependence between continuous marks and the event process through the use of a copula function. The copula formulation ensures that event times can be modeled by any intensity function for point processes, and any multivariate model can be specified for the continuous marks. The relative efficiency of joint versus separate analyses of the event times and the marks is examined through simulation under random censoring. An application to data from a recent trial in transfusion medicine is given for illustration. PMID- 23660875 TI - Outstanding luminescence from neutral copper(I) complexes with pyridyl tetrazolate and phosphine ligands. AB - Strongly luminescent, neutral copper(I) complexes bearing 5-(2 pyridyl)tetrazolate and various phosphine ligands were synthesized. While the cationic copper(I) precursors 1b-4b do not exceed photoluminescence quantum yields (PLQY) of 4-46%, the neutral complexes 1a-4a show PLQYs of up to 89%. PMID- 23660876 TI - Percutaneous thrombin injection in an infant to treat hepatic artery pseudoaneurysm after failed embolization. AB - Percutaneous thrombin injection has been described in case reports as an alternative to surgical intervention for the treatment of hepatic artery pseudoaneurysms associated with high-grade liver lacerations in adults. However, there is limited description in the literature of this technique being applied in children, particularly in preadolescents, and no published literature describes its use in infants. The procedure can be performed by pediatric radiologists and pediatric interventional radiologists skilled in ultrasound-guided aspiration techniques. We report successful application of percutaneous thrombin injection in an infant to treat a pseudoaneurysm of a left hepatic arterial branch in an 11 month-old girl with a grade IV liver laceration after superselective transcatheter arterial embolization failed to achieve thrombosis. PMID- 23660877 TI - Facile synthesis of hexagonal Sb2Te3 nanoplates using Ph2SbTeR (R = Et, Ph) single source precursors. AB - Two new antimony telluride single source precursors (SSPs), Ph2SbTeR (R = Et, Ph), have been used to synthesise pure and defect free hexagonal Sb2Te3 nanoplates by thermal decomposition in an organic solvent. The chemical composition of the SSPs plays an important role in the formation of antimony telluride nanocrystals. PMID- 23660878 TI - Significance of halo, reversed halo and air crescent signs in lymphomatoid granulomatosis and pulmonary fungal infections. PMID- 23660879 TI - Oral health professionals and social determinants. PMID- 23660880 TI - Shiny concrescence. PMID- 23660881 TI - Footpath quacks. PMID- 23660882 TI - Hatching a smile. PMID- 23660883 TI - Engaging fully. PMID- 23660884 TI - Anticoagulant guidelines. PMID- 23660885 TI - Contrary to aspiration. PMID- 23660886 TI - Dental guidance for all. PMID- 23660887 TI - Fresh extraction sites. PMID- 23660888 TI - Grossly deformed bodies. PMID- 23660889 TI - Ideally placed. PMID- 23660890 TI - Brush bus rolls out hygiene programme in schools. PMID- 23660891 TI - First lady of dentistry commemorated with plaque. PMID- 23660900 TI - Resorption: part 1. Pathology, classification and aetiology. AB - This paper will explore the pathological process involved in dental resorption as well as its classifications and aetiology. The second subsequent paper will look at its diagnosis and management. PMID- 23660905 TI - Summary of: the Scottish dental practitioner's role in managing child abuse and neglect. PMID- 23660906 TI - Summary of: can audit improve patient care and treatment outcomes in endodontics? PMID- 23660907 TI - Why do general dental practitioners become involved in clinical teaching? A pilot study exploring the views of part-time practitioner teachers, King's College London. AB - INTRODUCTION: Dental schools in the United Kingdom are becoming increasingly reliant on the services of part-time teachers to deliver the clinical educational component of the dental course. Their background is predominantly from general dental practice but the opportunities to progress in the system are limited. The aim of this study was to ascertain the views and perceptions of such teachers at a dental school. MATERIALS AND METHODS: An anonymous, non-incentivised online survey was used to obtain both qualitative and quantitative views of the part timers. RESULTS: The department has n = 40 part-time teachers and there was a response rate of 78%. Overall 73% were satisfied with their current teaching position, whereas the remaining 27% of teachers were seeking higher rewards both in terms of recognition and status. CONCLUSIONS: This study demonstrated the need for formal teaching skills and training to be made available to part-time clinical teachers. Allied to this is the requirement for a clearly defined and achievable career pathway. PMID- 23660908 TI - Future prospects of systemic host modulatory agents in periodontal therapy. AB - Periodontitis is an inflammatory disease caused by microbial infection that leads to destruction of supporting tissues of the teeth. The periodontal tissue destruction is a result of both microbial activity as well as host response. The best chance for clinical improvement may come from implementing complementary treatment strategies that target different aspects of the periodontal balance. Host response modulation, in combination with conventional treatment, offers to restore the balance between health and disease progression in the direction of a healing response. Various host modulatory therapies (HMT) have been developed or proposed to block pathways responsible for periodontal tissue break down. The newer drugs like bortezomib, infliximb, etanercept, vasoactive intestinal peptide, nitric oxide synthase inhibitors and denosumab are developed as a result of better understanding of pathogenesis of inflammatory tissue destruction and may represent the future of periodontal therapy. This review article focuses on the potential systemic host modulatory agents that target cell signalling pathways, cytokines and enzymes. PMID- 23660928 TI - The Scottish dental practitioner's role in managing child abuse and neglect. AB - BACKGROUND: In 2005 Cairns et al. published a paper ( 2005; 15: 310-318) examining the role of the general dental practitioner (GDP) in child protection (CP) in Scotland. This involved a questionnaire sent out to Scottish GDPs in 2003. Subsequently in 2006 all UK dental practices were sent Child protection and the dental team, a manual detailing roles and responsibilities with regard to CP. During this time the profile of CP within dentistry increased. There has been no published research since 2006 investigating whether the gap between the proportion of GDPs who suspect child abuse/neglect in their patients and those who refer cases has changed. AIM: The aim of this research was to investigate whether this gap has changed between 2003 and 2010.Method A postal questionnaire based on that used by Cairns et al. was sent to 50% of GDPs in Scotland in March 2010. RESULTS: The response rate was 52% (53% male). Some 29% and 55% of respondents had received undergraduate or postgraduate training in child protection respectively. Over two thirds (37%) had suspected child abuse/neglect in one or more of their paediatric patients but only 11% had referred a case. The most common factor affecting the decision to refer was 'lack of certainty of the diagnosis' (74%). Some 77% thought that abused/neglected children had an increased caries increment and 73% of dentists were willing to get involved in detecting neglect. CONCLUSION: Dentists in Scotland appear to be suspecting and referring more cases of child abuse/neglect than previously. The vast majority are willing to get involved in detecting neglect. PMID- 23660929 TI - Can audit improve patient care and treatment outcomes in endodontics? AB - Clinical audit is part of the NHS clinical governance framework for dentistry and is recommended as a quality improvement process for patient care, yet there is very mixed evidence supporting audit's ability to produce change in practice. Findings show evidence of changes following audit which improved patient care and practice efficiency. However, there is a general lack of dissemination of audit results, little useful feedback provided to participants, limited use of formal re-auditing of a particular topic and little reported on whether audit improves outcomes for patients. As part of its clinical governance responsibility, the Community Dental Service (CDS) is committed to ensuring that its clinical audit is robust, strategic and measures patient outcomes in its evaluation. The aim of this paper is to present a complete endodontic audit cycle; its recommendations and effects on the process and on outcomes of clinical patient endodontic care; and to evaluate if audit was a useful tool in this case. PMID- 23660930 TI - Detection of left ventricular hypertrophy by the R-wave voltage in lead aVL: population-based study. AB - BACKGROUND: According to hypertension guidelines, the recommended electrocardiographic (ECG) diagnostic criteria for left ventricular hypertrophy (LVH) are the Sokolow-Lyon and Cornel voltage criteria, both with general acceptance by primary care physicians. However, it was recently reported that the R-wave voltage in lead aVL (RaVL) was as good as other more complicated and time consuming ECG criteria to detect LVH in hypertensive patients. Therefore, our aim was to investigate if the ability of the RaVL to identify echocardiographic left ventricular hypertrophy (ECHO-LVH) could be translated to the general population, a more realistic assessment of its utility in a nonreferral setting. METHODS: 682 participants (43.5 % males), aged between 27 and 72 years from the urban population of Vitoria, ES, Brazil, were enrolled. We investigated the association of ECHO-LVH (LV mass >51 g/Ht(2.7)) with several ECG voltage measurements: Sokolow-Lyon and Cornel criteria, S-wave voltage in lead V3 (SV3) and RaVL. RESULTS: The RaVL showed the best positive correlation with LV mass indexed to Ht(2.7), superior to both Cornell and Sokolow-Lyon criteria and was not influenced by gender. Analysis of the ROC curves showed that the RaVL depicted a significant superior performance in relation to all the other measurements in the ability to detect ECHO-LVH. SV3 was not correlated with LV mass. Thus, it seems that most of Cornell's performance depends on its simplified version, that is, RaVL. CONCLUSION: We have shown that the simple and single assessment of RaVL presented a greater diagnostic ability in detecting ECHO-LVH in the general population, signaling its value mainly as a screening tool. PMID- 23660931 TI - Human hsp70 and HPV16 oE7 fusion protein vaccine induces an effective antitumor efficacy. AB - The persistent infection by human papilloma virus (HPV) is considered to be the major risk factor of cervical cancer, which is one of the most common cancers in women worldwide. Millions of women are currently infected with high-risk HPV. Thus, it is urgent to develop therapeutic vaccines to eliminate established infection or HPV-related diseases. In the present study, we constructed a very promising therapeutic HPV16 protein vaccine of optimized E7 (oE7)/huhsp70 using human hsp70 linked to HPV16 oE7. Our results demonstrated that vaccination with the oE7/huhsp70 protein vaccine induced a very strong E7-specific CD8(+) T cell immune response and resulted in a significant therapeutic effect against E7 expressing tumor cells. Our study verifies that huhsp70 is an effective immune adjuvant in the development of tumor therapeutic protein vaccines, and emphasizes that homologous huhsp70 is a promising tool in future human clinical applications. PMID- 23660932 TI - Effects of health care decentralization in Spain from a citizens' perspective. AB - The aim of this article is to analyze the impact of the decentralization of the public national health system in Spain on citizens' satisfaction with different dimensions of primary and hospital care. Using micro-data from the Health Barometer 1996-2009 and taking advantage of the exogeneity of the different pace of decentralization across Spain using a difference-in-differences strategy, we find that, in general, decentralization has not improved citizens' satisfaction with different features of the health services. In our base model, we find that there are even some small negative effects on a subset of variables. Sensitivity analysis confirms that there is no empirical evidence for supporting that decentralization has had a positive impact on citizens' satisfaction with health care. We outline several possible reasons for this. PMID- 23660933 TI - Relationship between prostate-specific antigen levels and ambient temperature. AB - We examined the association between prostate-specific antigen (PSA) and daily mean ambient temperature on the day of the test in healthy men who had three annual checkups. We investigated 9,694 men who visited a hospital for routine health checkups in 2007, 2008, and 2009. Although the means and medians of ambient temperature for the three years were similar, the mode in 2008 (15.8 degrees C) was very different from those in 2007 and 2009 (22.4 degrees C and 23.2 degrees C). After controlling for age, body mass index, and hematocrit, a multiple regression analysis revealed a U-shaped relationship between ambient temperature and PSA in 2007 and 2009 (P<0.001 and P=0.004, respectively), but not in 2008 (P=0.779). In 2007, PSA was 13.5% higher at 5 degrees C and 10.0% higher at 30 degrees C than that at 18.4 degrees C (nadir). In 2009, PSA was 7.3% higher at 5 degrees C and 6.8% at 30 degrees C compared with the level at 17.7 degrees C (nadir). In logistic regression analysis, a U-shaped relationship was found for the prevalence of a higher PSA (>2.5 ng/mL) by ambient temperature, with the lowest likelihood of having a high PSA at 17.8 degrees C in 2007 (P=0.038) and 15.5 degrees C in 2009 (P=0.033). When tested at 30 degrees C, there was a 57% excess risk of having a high PSA in 2007 and a 61% higher risk in 2009 compared with those at each nadir temperature. We found a U-shaped relationship between PSA and ambient temperature with the lowest level of PSA at 15-20 degrees C. PMID- 23660935 TI - Patients' perception of colonoscopy: patients with inflammatory bowel disease and irritable bowel syndrome experience the largest burden. AB - BACKGROUND: Colonoscopy is a frequently performed procedure worldwide with a negative perception, leading to reluctance to undergo the procedure. Perceptions could differ depending on the specific indication for the colonoscopy. AIMS: To compare patient satisfaction with the colonoscopy procedure between five different patient groups: inflammatory bowel disease (IBD), familial predisposition for cancer, adenoma/carcinoma surveillance, symptoms suggestive of cancer, and irritable bowel syndrome (IBS). METHODS: A prospective questionnaire study was carried out in two regional hospitals and two tertiary teaching hospitals in the Netherlands. A total of 797 consecutive patients scheduled for colonoscopy between October 2009 and June 2010, 146 (18%) IBD, 153 (19%) adenoma or carcinoma surveillance, 104 (13%) familial predisposition, 280 (35%) symptoms suggestive of cancer, and 114 (14%) IBS-like symptoms, were included. Two questionnaires were administered: one on the day of the procedure and another 6 weeks after the procedure. The main outcome measurements were embarrassment, pain, burden, most burdensome aspect, and overall level of satisfaction. RESULTS: Patients with IBD and IBS reported significantly more embarrassment and burden from the bowel preparation phase (P=0.040 and 0.018, respectively) and more pain during the colonoscopy procedure (P=0.018). This difference in pain was also observed when adjusting for volume of sedation administered, familiarity with the endoscopist, duration of the colonoscopy, or whether or not an intervention was performed. All patient groups were less satisfied with the procedure at 6 weeks than directly after the colonoscopy; they recalled more embarrassment and burden, but less pain. CONCLUSION: Patient groups, defined by indication for colonoscopy, experience the colonoscopy procedure differently. PMID- 23660934 TI - Heterozygous alpha1-antitrypsin Z allele mutation in presumed healthy donor livers used for transplantation. AB - OBJECTIVES: The Z allele (Glu342Lys) in alpha1-antitrypsin (AAT) deficiency is a combined deficiency and dysfunctional allele. Carrying one Z allele induces a risk of a more aggressive evolution in patients with a chronic liver disease. As most of the carriers of Z allele do not have overt liver disease, it is likely that Z allele-containing livers have been used previously for liver transplantation. We analyzed the incidence, epidemiology, and clinical features of AAT accumulation in the hepatocytes after liver transplantation. METHODS: Follow-up biopsies of liver transplant recipients were analyzed with periodic acid Schiff staining until 2006 (n=486); from 2006 on (n=303), all biopsies were stained with a specific monoclonal antibody against mutated AATZ protein. Genotyping of both recipient and donor was performed in the case of positive staining. RESULTS: Of 789 liver transplantation patients, six patients (0.8%) showed mutated AATZ accumulation in the transplanted liver. Mutation analysis confirmed the presence of the Z allele in all donor organs including one transplanted organ with the SZ phenotype. There was a clear concordance between the isoelectrical focusing of the recipient AAT after transplantation and the genotype of the donor. CONCLUSION: Presumed healthy donor organs containing the Z allele were used for transplantation in 0.8% of cases in our series. As the presence of a Z allele is an independent risk factor of aggravation of chronic liver disease, AATZ accumulation in biopsies after liver transplantation should be actively looked for. PMID- 23660936 TI - Endoscopic submucosal dissection for nonpedunculated submucosal invasive colorectal cancer: is it feasible? AB - BACKGROUND/AIMS: There have been no definite indications for additional surgical resection after endoscopic submucosal dissection (ESD) of submucosal invasive colorectal cancer (SICC). The aims of this study were to evaluate the feasibility of ESD for nonpedunculated SICC and to determine the need for subsequent surgery after ESD. PATIENTS AND METHODS: A total of 150 patients with nonpedunculated SICC in resected specimens after ESD were analyzed. Among them, 75 patients underwent subsequent surgery after ESD. Clinical outcomes of ESD and histopathological risk factors for lymph node (LN) metastasis were evaluated. RESULTS: The en-bloc resection and complete resection (R0) rates of ESD were 98% (147/150) and 95.3% (143/150), respectively. None of the patients had delayed bleeding after ESD. Perforations occurred in seven patients (4.7%), which were successfully treated by endoscopic clipping. After subsequent surgery for 75 patients, LN metastases were found in 10 cases (13.3%). The incidence of LN metastasis was significantly higher in tumors featuring submucosal invasion of at least 1500 MUm, lymphovascular invasion, and tumor budding. Multivariate analysis showed that lymphovascular invasion (P=0.034) and tumor budding (P=0.015) were significantly associated with LN metastasis. Among the 150 patients, no local recurrence or distant metastasis was detected, except one patient with risk factors and who refused subsequent surgery, during the overall median follow-up of 34 months (range, 5-63 months). CONCLUSION: ESD is feasible and may be considered as an alternative treatment option for carefully selected cases of nonpedunculated SICC, provided that the appropriate histopathological curative criteria are fulfilled in completely resectable ESD specimens. PMID- 23660937 TI - Noninvasive detection of hepatic steatosis in patients without ultrasonographic evidence of fatty liver using the controlled attenuation parameter evaluated with transient elastography. AB - OBJECTIVE: Although ultrasound is a useful technique for detecting hepatic steatosis, it cannot provide a precise determination of hepatic fat content. A novel attenuation parameter named controlled attenuation parameter (CAP) has been developed to process the raw ultrasonic signals acquired by Fibroscan. The aim of this study was to determine the percentage of hepatic steatosis in apparently healthy Turkish individuals using the proposed diagnostic cut-off points for CAP. In addition, we sought to investigate the association of CAP with the traditional risk factors for nonalcoholic fatty liver disease in a screening setting. MATERIALS AND METHODS: In the present study, 102 Turkish individuals without evidence of fatty liver on ultrasound and normal aminotransferase levels underwent CAP measurements by means of Fibroscan. RESULTS: The mean (SD), median (minimum-maximum), and 5th and 95th percentile values of CAP values in this cohort of 102 individuals were 206.99 (48.12), 210.5 (100.0-314.0), 113.4 and 280.2 dB/m, respectively. Using the cut-offs of 222, 238, and 283 dB/m for CAP, there were 39 (38.2%), 23 (22.5%), and five (4.9%) individuals out of 102 who had at least 10% steatosis despite normal liver findings on ultrasound. After allowance for potential confounders, CAP was independently associated with BMI (beta=0.39, t=3.5, P<0.001) and the number of metabolic syndrome criteria (beta=0.24, t=2.1, P<0.05). CONCLUSION: These results hold promise for early noninvasive detection of hepatic steatosis on the basis of CAP assessment. PMID- 23660938 TI - Ultra-slow dynamics in low density amorphous ice revealed by deuteron NMR: indication of a glass transition. AB - The postulated glass-liquid transition of low density amorphous ice (LDA) is investigated with deuteron NMR stimulated echo experiments. Such experiments give access to ultra-slow reorientations of water molecules on time scales expected for structural relaxation of glass formers close to the glass-liquid transition temperature. An involved data analysis is necessary to account for signal contributions originating from a gradual crystallization to cubic ice. Even if some ambiguities remain, our findings support the view that pressure amorphized LDA ices are of glassy nature and undergo a glass-liquid transition before crystallization. PMID- 23660939 TI - Relationship between low free testosterone levels and loss of muscle mass. AB - We assessed longitudinal relationships between baseline testosterone and muscle mass changes in Japanese men. Data were collected from community-dwelling 957 adult men who participated in a longitudinal study of ageing biennially from 1997 2010. Appendicular muscle mass (AMM) was measured with dual-energy X-ray absorptiometry at baseline and follow-up examinations. The cut-off point of sarcopenia was defined as a skeletal muscle index (AMM/height(2)) < 6.87 kg/m(2). Total testosterone (TT) and free testosterone (FT) were measured with a radioimmunoassay. The calculated FT (cFT) was determined with a formula using albumin, TT, and sex hormone-binding globulin levels. We analyzed 4,187 or 2,010 cumulative data points using generalized estimating equations. Low TT was not associated with sarcopenia. Low cFT (odds ratio = 2.14, 95% confidence interval: 1.06-4.33) and FT (odds ratio = 1.83, 95% confidence interval: 1.04-3.22) were associated with sarcopenia. Low FT may be a predictor of risk for muscle loss in Japanese men. PMID- 23660940 TI - Differential expression and methylation of brain developmental genes define location-specific subsets of pilocytic astrocytoma. AB - Pilocytic astrocytomas (PAs) are the most common brain tumors in pediatric patients and can cause significant morbidity, including chronic neurological deficiencies. They are characterized by activating alterations in the mitogen activated protein kinase pathway, but little else is known about their development. To map the global DNA methylation profiles of these tumors, we analyzed 62 PAs and 7 normal cerebellum samples using Illumina 450K microarrays. These data revealed two subgroups of PA that separate according to tumor location (infratentorial versus supratentorial), and identified key neural developmental genes that are differentially methylated between the two groups, including NR2E1 and EN2. Integration with transcriptome microarray data highlighted significant expression differences, which were unexpectedly associated with a strong positive correlation between methylation and expression. Differentially methylated probes were often identified within the gene body and/or regions up- or downstream of the gene, rather than at the transcription start site. We also identified a large number of differentially methylated genes between cerebellar PAs and normal cerebellum, which were again enriched for developmental genes. In addition, we found a significant association between differentially methylated genes and SUZ12 binding sites, indicating potential disruption of the polycomb repressor complex 2 (PRC2). Taken together, these data suggest that PA from different locations in the brain may arise from region-specific cells of origin, and highlight the potential disruption of key developmental regulators during tumorigenesis. These findings have implications for future basic research and clinical trials, as therapeutic targets and drug sensitivity may differ according to tumor location. PMID- 23660942 TI - Long noncoding RNAs and the genetics of cancer. AB - Cancer is a disease of aberrant gene expression. While the genetic causes of cancer have been intensively studied, it is becoming evident that a large proportion of cancer susceptibility cannot be attributed to variation in protein coding sequences. This is highlighted by genome-wide association studies in cancer that reveal that more than 80% of cancer-associated SNPs occur in noncoding regions of the genome. In this review, we posit that a significant fraction of the genetic aetiology of cancer is exacted by noncoding regulatory sequences, particularly by long noncoding RNAs (lncRNAs). Recent studies indicate that several cancer risk loci are transcribed into lncRNAs and these transcripts play key roles in tumorigenesis. We discuss the epigenetic and other mechanisms through which lncRNAs function and how they contribute to each stage of cancer progression, understanding of which will be crucial for realising new opportunities in cancer diagnosis and treatment. Long noncoding RNAs play important roles in almost every aspect of cell biology from nuclear organisation and epigenetic regulation to post-transcriptional regulation and splicing, and we link these processes to the hallmarks and genetics of cancer. Finally, we highlight recent progress and future potential in the application of lncRNAs as therapeutic targets and diagnostic markers. PMID- 23660943 TI - Model-based patterns in prostate cancer mortality worldwide. AB - BACKGROUND: Prostate cancer mortality has been decreasing in several high income countries and previous studies analysed the trends mostly according to geographical criteria. We aimed to identify patterns in the time trends of prostate cancer mortality across countries using a model-based approach. METHODS: Model-based clustering was used to identify patterns of variation in prostate cancer mortality (1980-2010) across 37 European, five non-European high-income countries and four leading emerging economies. We characterised the patterns observed regarding the geographical distribution and gross national income of the countries, as well as the trends observed in mortality/incidence ratios. RESULTS: We identified three clusters of countries with similar variation in prostate cancer mortality: pattern 1 ('no mortality decline'), characterised by a continued increase throughout the whole period; patterns 2 ('later mortality decline') and 3 ('earlier mortality decline') depict mortality declines, starting in the late and early 1990s, respectively. These clusters are also homogeneous regarding the variation in the prostate cancer mortality/incidence ratios, while are heterogeneous with reference to the geographical region of the countries and distribution of the gross national income. CONCLUSION: We provide a general model for the description and interpretation of the trends in prostate cancer mortality worldwide, based on three main patterns. PMID- 23660944 TI - Descriptive epidemiology of ependymal tumours in the United States. AB - BACKGROUND: Ependymomas are rare primary gliomas that commonly affect both children and adults, but unique as survival is worse in children. METHODS: Data on brain and central nervous system primary malignant and non-malignant ependymal tumours from the Central Brain Tumor Registry of the United States analytic data set and primary malignant ependymal tumours from the SEER 13 registries research data file were used to evaluate incidence and survival, respectively. RESULTS: The 2004-2009 average annual age-adjusted incidence rate of ependymal tumours was 0.41/100,000. Spinal cord/cauda equina was the primary site at diagnosis for 50 60% of ependymal tumours in adult age groups in contrast to about 20% in children and adolescents. Ependymoma was the most frequent histology in all age groups; however, anaplastic ependymoma comprised about 30% in cases 0-19 years of age compared with about 3-5% in adult age groups. Overall, relative survival was favourable with rates at ~85% and 75% at 3 and 10 years post diagnosis, respectively. However, children and adolescents, the oldest adult age group, cases diagnosed with anaplastic ependymoma and/or tumour location in a brain site had lowest survival rates. CONCLUSION: Paediatric cases had worse outcomes compared with adults for numerous reasons including having a higher percentage of anaplastic ependymomas and greater percentage of cases of intracranial disease. PMID- 23660945 TI - Prevalence of the metabolic syndrome and cardiovascular disease risk in chemotherapy-treated testicular germ cell tumour survivors. AB - BACKGROUND: Testicular cancer patients have an increased risk for cardiovascular disease (CVD), which might be related to the increased prevalence of the metabolic syndrome (MetS) in this group of patients. METHODS: We assessed the prevalence of MetS and calculated the 10-year CVD risk in a cohort of 255 testicular germ cell tumour survivors (median age, 38.7 years; interquartile range, 31-48) at a mean of 7.8 years after anti-cancer treatment, and compared these with data obtained from 360 healthy men. RESULTS: Survivors had an age adjusted increased risk for MetS of 1.9 compared with that of healthy controls. The risk for MetS was highest in survivors treated with combination chemotherapy (CT) 2.3 (Adult Treatment Panel of the National Cholesterol Education Program classification) and 2.2 (International Diabetes Federation classification). The risk of MetS was especially increased in survivors with testosterone levels in the lowest quartile (OR, 2.5). Ten-year cardiovascular risk as assessed by the Framingham Risk Score (3.0%) and Systemic Coronary Risk Evaluation (1.7%) algorithms was low, independent of treatment, and was comparable to controls. CONCLUSION: Testicular germ cell tumour survivors have an increased prevalence of MetS, with hypogonadism and CT treatment being clear risk factors for the development of the syndrome. The increased prevalence of MetS was not associated with an increased 10-year cardiovascular risk. PMID- 23660946 TI - ARID1B, a member of the human SWI/SNF chromatin remodeling complex, exhibits tumour-suppressor activities in pancreatic cancer cell lines. AB - BACKGROUND: The human ATP-dependent SWItch/sucrose nonfermentable (SWI/SNF) complex functions as a primary chromatin remodeler during ontogeny, as well as in adult life. Several components of the complex have been suggested to function as important regulators of tumorigenesis in various cancers. In the current study, we have characterised a possible tumour suppressor role for the largest subunit of the complex, namely the AT-rich interaction domain 1B (ARID1B). METHODS: We performed Azacytidine and Trichostatin A treatments, followed by bisulphite sequencing to determine the possible DNA methylation-induced transcription repression of the gene in pancreatic cancer (PaCa) cell lines. Functional characterisation of effect of ARID1B ectopic expression in MiaPaCa2 PaCa cell line, which harboured ARID1B homozygous deletion, was carried out. Finally, we evaluated ARID1B protein expression in pancreatic tumour samples using immunohistochemistry on a tissue microarray. RESULTS: ARID1B was transcriptionally repressed due to promoter hypermethylation, and ectopic expression severely compromised the ability of MiaPaCa2 cells to form colonies in liquid culture and soft agar. In addition, ARID1B exhibited significantly reduced/loss of expression in PaCa tissue, especially in samples from advanced stage tumours, when compared with normal pancreas. CONCLUSION: The results therefore suggest a possible tumour-suppressor function for ARID1B in PaCa, thus adding to the growing list of SWI/SNF components with a similar function. Given the urgent need to design efficient targeted therapies for PaCa, our study assumes significance. PMID- 23660947 TI - The prognostic role of KRAS, BRAF, PIK3CA and PTEN in colorectal cancer. AB - BACKGROUND: Mutations in KRAS, BRAF, PIK3CA and PTEN expression have been in focus to predict the effect of epidermal growth factor receptor-blocking therapy in colorectal cancer (CRC). Here, information on these four aberrations was collected and combined to a Quadruple index and used to evaluate the prognostic role of these factors in CRC. PATIENTS: We analysed the mutation status in KRAS, BRAF and PIK3CA and PTEN expression in two separate CRC cohorts, Northern Sweden Health Disease Study (NSHDS; n=197) and Colorectal Cancer in Umea Study (CRUMS; n=414). A Quadruple index was created, where Quadruple index positivity specifies cases with any aberration in KRAS, BRAF, PIK3CA or PTEN expression. RESULTS: Quadruple index positive tumours had a worse prognosis, significant in the NSHDS but not in the CRUMS cohort (NSHDS; P=0.003 and CRUMS; P=0.230) in univariate analyses but significance was lost in multivariate analyses. When analysing each gene separately, only BRAF was of prognostic significance in the NSHDS cohort (multivariate HR 2.00, 95% CI: 1.16-3.43) and KRAS was of prognostic significance in the CRUMS cohort (multivariate HR 1.48, 95% CI: 1.02-2.16). Aberrations in PIK3CA and PTEN did not add significant prognostic information. CONCLUSIONS: Our results suggest that establishment of molecular subgroups based on KRAS and BRAF mutation status is important and should be considered in future prognostic studies in CRC. PMID- 23660948 TI - Postdiagnosis supplement use and breast cancer prognosis in the After Breast Cancer Pooling Project. AB - Vitamin supplement use after breast cancer diagnosis is common, but little is known about long-term effects on recurrence and survival. We examined postdiagnosis supplement use and risk of death or recurrence in the After Breast Cancer Pooling Project, a consortium of four cohorts of 12,019 breast cancer survivors from the United States and China. Post-treatment supplement use (vitamins A, B, C, D, E, and multivitamins) was assessed 1-5 years postdiagnosis. Associations with risk of recurrence, breast cancer-specific mortality, or total mortality were analyzed in Cox proportional hazards models separately by cohort. Individual cohort results were combined using random effects meta-analysis. Interactions with smoking, treatment, and hormonal status were examined. In multivariate models, vitamin E was associated with a decreased risk of recurrence (RR: 0.88; 95 % CI 0.79-0.99), and vitamin C with decreased risk of death (RR: 0.81; 95 % CI 0.72-0.92). However, when supplements were mutually adjusted, all associations were attenuated. There were no statistically significant associations with breast cancer mortality. The use of antioxidant supplements (multivitamins, vitamin C, or E) was not associated with recurrence, but was associated with a 16 % decreased risk of death (95 % CI 0.72-0.99). In addition, vitamin D was associated with decreased risk of recurrence among ER positive, but not ER negative tumors (p-interaction = 0.01). In this large consortium of breast cancer survivors, post-treatment use of vitamin supplements was not associated with increased risk of recurrence or death. Post-treatment use of antioxidant supplements was associated with improved survival, but the associations with individual supplement were difficult to determine. Stratification by ER status and considering antioxidants as a group may be more clinically relevant when evaluating associations with cancer risk and mortality. PMID- 23660949 TI - Umbilical cord blood transplant for malignancies: a hope or hype. AB - Cord blood is a rich and unlimited source of hematopoietic stem cells for allogeneic stem cell transplant to treat a variety of oncologic, genetic, hematologic, and immunodeficiency disorders. Since the first successful cord blood transplant in 1988, a large number of cord blood banks have been established world over for collection and storage of cord blood for future use. Majority of such transplants are performed in children, however, the number in adults have been growing steadily in recent years. Results from various transplant registries reveals that a single cord blood provides enough stem cells to provide short and long term engraftment, and has low incidence and less severity of graft versus host disease. With a high booming birth rate and a large genetic diversity, India has potential to become the largest supplier of cord blood stem cells in world. To meet the future transplant need of the country sincere efforts from various institutes and government agencies are needed to increase the number of public cord blood banks in the country. In this article the author will focus on the issue of public and private cord blood banking; the role of physicians in educating and counseling families with regard to the utility of cord blood for donor itself as well as the future of umbilical cord blood transplant in India. PMID- 23660950 TI - Copper-mediated electrophilic imination of alkenylzirconocenes with O-benzoyl ketoximes and aldoximes. AB - Copper-mediated electrophilic imination of alkenylzirconocenes generated in situ from alkynes and zirconocenes is accomplished under mild reaction conditions. The reaction can be used to prepare various 2-azadienes. PMID- 23660951 TI - Diffusion of finite-size particles in confined geometries. AB - The diffusion of finite-size hard-core interacting particles in two- or three dimensional confined domains is considered in the limit that the confinement dimensions become comparable to the particle's dimensions. The result is a nonlinear diffusion equation for the one-particle probability density function, with an overall collective diffusion that depends on both the excluded-volume and the narrow confinement. By including both these effects, the equation is able to interpolate between severe confinement (for example, single-file diffusion) and unconfined diffusion. Numerical solutions of both the effective nonlinear diffusion equation and the stochastic particle system are presented and compared. As an application, the case of diffusion under a ratchet potential is considered, and the change in transport properties due to excluded-volume and confinement effects is examined. PMID- 23660952 TI - miR-30a downregulation aggravates pressure overload-induced cardiomyocyte hypertrophy. AB - miRNAs play an important role in the pathogenesis of cardiac hypertrophy and dysfunction. However, little is known about how miR-30a regulates cardiomyocyte hypertrophy. In the study, Male C57BL/6 mice were subjected to thoracic aortic constriction, and hearts were harvested at 3 weeks. We assayed miR-30a expression level by real-time PCR and defined the molecular mechanisms of miR-30a-mediated cardiomyocyte hypertrophy. We found that myocardial expression of miR-30a was decreased in mouse models of hypertrophy and in H9c2 cells treated with phenylephrine. MiR-30a inhibition markedly increased mRNA expression of cardiac hypertrophy markers such as atrial natriuretic factor and brain natriuretic peptide in H9c2, and cell size was increased after miR-30a inhibitor treatment. Downregulated miR-30a activated autophagy by inhibiting beclin-1 expression in H9c2 cell. More important, autophagy inhibition suppressed miR-30a inhibitor induced cardiomyocyte hypertrophy. Together, our data demonstrated that downregulated miR-30a aggravates pressure overload-induced cardiomyocyte hypertrophy by activating autophagy, thus offering a new target for the therapy of cardiomyocyte hypertrophy. PMID- 23660953 TI - (-)-Epigallocatechin-3-gallate alleviates spatial memory impairment in APP/PS1 mice by restoring IRS-1 signaling defects in the hippocampus. AB - Alzheimer's disease (AD) fundamentally represents a metabolic disease associated with brain insulin resistance. TNF-alpha/c-Jun N-terminal kinase (JNK) signaling plays a central role in serine phosphorylation of insulin receptor substrate-1 (IRS-1). (-)-Epigallocatechin-3-gallate (EGCG), a potent antioxidant, has been verified to attenuate peripheral insulin resistance by reducing IRS-1 signaling blockage. This study aimed to investigate the effects and possible mechanisms of EGCG on central IRS-1 signaling in vivo. APP/PS1 mice were treated with EGCG, and spatial memory was assessed by the Morris water maze test. Levels of soluble and insoluble Abeta42 in the hippocampus were determined by ELISA. The activation of NF-alpha/JNK and IRS signaling was detected by immunohistochemistry and Western blot analysis. Our results showed that EGCG ameliorated the impaired learning and memory in APP/PS1 mice. Notably, we found a significant reduction of IRS-1pS636 level accompanied with decreased Abeta42 levels in the hippocampus of 13-month old female APP/PS1 mice after treatment with EGCG (2 or 6 mg/kg/day) for 4 weeks. Furthermore, EGCG treatment inhibited TNF-alpha/JNK signaling and increased the phosphorylation of Akt and glycogen synthase kinase-3beta in the hippocampus of APP/PS1 mice. In conclusion, our study provides evidence that long-term consumption of EGCG may alleviate AD-related cognitive deficits by effectively attenuating central insulin resistance. PMID- 23660954 TI - AP-2alpha suppresses invasion in BeWo cells by repression of matrix metalloproteinase-2 and -9 and up-regulation of E-cadherin. AB - Preeclampsia complicates 5-10% of pregnancies and is a leading cause of maternal/fetal morbidity and mortality. Although the cause is unknown, the reduced migration/invasion of extravillous trophoblasts is generally regarded as a key feature of preeclampsia genesis. The present study examined the expression of activator protein-2alpha (AP-2alpha), tissue inhibitor of metalloproteinase 2 (TIMP-2), matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and E-cadherin in severe preeclamptic placentas and normal placentas using real time PCR and immunohistochemistry. The expression levels of AP-2alpha, TIMP-2, and E-cadherin were elevated, while MMP-2 and MMP-9 levels were decreased in severe preeclamptic placentas when compared with normal placentas. To explore the underlying molecular mechanisms, BeWo cells were transfected with an AP-2alpha expression construct as well as a siRNA against AP-2alpha. The over-expression of AP-2alpha decreased the invasive abilities of BeWo cells. AP-2alpha induction was followed by the induction of TIMP-2 and E-cadherin and a significant reduction of MMP-2 and MMP-9. Whereas in AP-2alpha-silencing BeWo cells, we observed the decreased expression of TIMP-2 and E-cadherin and the increased expression of MMP 2 and MMP-9. We presume that AP-2alpha may suppress trophoblast invasion by repression of MMP-2 and MMP-9 and up-regulation of E-cadherin, thus leading to shallow placentation in severe preeclampsia. PMID- 23660956 TI - Chronoamperometric study of membrane electrode assembly operation in continuous flow photoelectrochemical water splitting. AB - Water splitting was performed in a photoelectrochemical cell (PEC) with water oxidation and hydrogen formation reactions in two separate compartments. A photoanode consisting of carbon paper loaded with TiO2 and a cathode made of Pt dispersed on carbon black spread also on carbon paper were fixed on both sides of a Nafion(r) membrane and electrically coupled via an external circuit. Anode and cathode compartments with serpentine flow field were operated either in the liquid or vapour phase. Electrical current was monitored with chronoamperometry and D2 formation from deuterated water using mass spectrometry. Mapping the photocurrent under a variety of reaction conditions enabled identification of the limiting factors related to proton and photocarrier transport and reaction product evacuation. This comprehensive research approach to the operation of a PEC will assist future optimisation of cell design and development of membrane electrode assemblies. PMID- 23660955 TI - Exogenous hydrogen sulfide prevents cardiomyocyte apoptosis from cardiac hypertrophy induced by isoproterenol. AB - Oxidative stress is a crucial factor inducing cardiomyocyte apoptosis due to cardiac hypertrophy. Additional evidence has revealed that H2S plays an antioxidant role and is cytoprotective. Hence, we aimed to elucidate whether H2S prevents cardiomyocyte apoptosis due to cardiac hypertrophy via its antioxidant function. The cardiac hypertrophy model was obtained by injecting a high dose of isoproterenol (ISO) subcutaneously, and the hemodynamic parameters were measured in groups that received either ISO or ISO with the treatment of NaHS. TUNEL (terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling) and EM (electron microscopy) experiments were performed to determine the occurrence of apoptosis in heart tissues. The expression of caspase-3 protein in the cytoplasm and NADPH oxidase 4 (NOX4), and cytochrome c (cyt c) proteins in the mitochondria were analyzed using Western blotting. In contrast, to determine whether ISO induced apoptosis in the cultured cardiomyocytes may be related to oxidative stress, JC-1 and MitoSOX assays were performed to detect the mitochondrial membrane potential and reactive oxygen species (ROS) production in the mitochondria. Exogenous H2S was found to ameliorate cardiac function. The histological observations obtained from TUNEL and EM demonstrated that treatment with NaHS inhibited the occurrence of cardiac apoptosis and improved cardiac structure. Moreover, H2S reduced the expression of the cleaved caspase-3, NOX4 and the leakage of cyt c from the mitochondria to the cytoplasm. We also observed that exogenous H2S could maintain the mitochondrial membrane potential and reduce ROS production in the mitochondria. Therefore, H2S reduces oxidative stress due to cardiac hypertrophy through the cardiac mitochondrial pathway. PMID- 23660957 TI - Tumor suppressor genes associated with drug resistance in ovarian cancer (review). AB - Ovarian cancer is a fatal gynecological cancer and a major cause of cancer related mortality worldwide. The main limitation to a successful treatment for ovarian cancer is the development of drug resistance to combined chemotherapy. Tumor suppressor genes (TSGs) are wild-type alleles of genes which play regulatory roles in diverse cellular activities, and whose loss of function contributes to the development of cancer. It has been demonstrated that TSGs contribute to drug resistance in several types of solid tumors. However, an overview of the contribution of TSGs to drug resistance in ovarian cancer has not previously been reported. In this study, 15 TSGs responding to drug resistance in ovarian cancer were reviewed to determine the relationship of TSGs with ovarian cancer drug resistance. Furthermore, gene/protein-interaction and bio-association analysis were performed to demonstrate the associations of these TSGs and to mine the potential drug resistance-related genes in ovarian cancer. We observed that the 15 TSGs had close interactions with each other, suggesting that they may contribute to drug resistance in ovarian cancer as a group. Five pathways/processes consisting of DNA damage, apoptosis, cell cycle, DNA binding and methylation may be the key ways with which TSGs participate in the regulation of drug resistance. In addition, ubiquitin C (UBC) and six additional TSGs including the adenomatous polyposis coli gene (APC), death associated protein kinase gene (DAPK), pleiomorphic adenoma gene-like 1 (PLAGL1), retinoblastoma susceptibility gene (RB1), a gene encoding an apoptosis-associated speck-like protein (PYCARD/ASC) and tumor protein 63 (TP63), which had close interactions with the 15 TSGs, are potential drug resistance-related genes in ovarian cancer. PMID- 23660958 TI - PET-CT staging of DLBCL accurately identifies and provides new insight into the clinical significance of bone marrow involvement. AB - We investigated whether positron emission tomography combined with computed tomography (PET-CT) identifies clinically important bone marrow involvement by diffuse large B-cell lymphoma (DLBCL) with sufficient accuracy to replace routine staging bone marrow biopsy. All patients from a single centre diagnosed as DLBCL since 2005 had data extracted from staging PET-CT, marrow biopsy, and treatment records. Of 130 patients, 35 (27%) were judged to have marrow involvement; 33 were identified by PET-CT compared with 14 by marrow histology. PET identified all clinically important marrow lymphoma, while biopsy did not upstage any patient. Sensitivity and specificity were 94% and 100% for PET-CT and 40% and 100% for marrow biopsy. As a secondary aim, we compared the prognosis of marrow involvement, as detected by PET-CT or biopsy. Cases with marrow deposits identified by PET-CT but not biopsy had progression-free survival (PFS) and overall survival similar to stage IV disease without involved marrow. Positive biopsy conferred significantly inferior PFS (P = .003); these cases frequently had other markers of poor-risk disease. These data confirm that in experienced hands PET-CT has a high level of accuracy for identifying marrow disease in DLBCL, and provide new insight into the nature and clinical significance of marrow involvement. PMID- 23660959 TI - Adult T-cell leukemia cells overexpress Wnt5a and promote osteoclast differentiation. AB - Adult T-cell leukemia/lymphoma (ATL) is etiologically linked to infection with the human T-cell leukemia/lymphoma virus type 1 (HTLV-I). ATL is classified into 4 distinct clinical diseases: acute, lymphoma, chronic, and smoldering. Acute ATL is the most aggressive form, representing 60% of cases and has a 4-year survival of < 5%. A frequent complication and cause of death in acute ATL patients is the presence of lytic bone lesions and hypercalcemia. We analyzed the Wnt/beta catenin pathway because of its common role in cancer and bone remodeling. Our study demonstrated that ATL cells do not express high levels of beta-catenin but displayed high levels of LEF-1/TCF genes along with elevated levels of beta catenin (LEF-1/TCF target genes) responsive genes. By profiling Wnt gene expression, we discovered that ATL patient leukemia cells shifted expression toward the noncanonical Wnt pathway. Interestingly, ATL cells overexpressed the osteolytic-associated genes-Wnt5a, PTHLH, and RANKL. We further show that Wnt5a secreted by ATL cells favors osteoclast differentiation and expression of RANK. Our results suggest that Wnt5a is a major contributing factor to the increase in osteolytic bone lesions and hypercalcemia found in ATL patients. Anti-Wnt5a therapy may prevent or reduce osteolytic lesions found in ATL patients and improve therapy outcome. PMID- 23660960 TI - Perforin deficiency impairs a critical immunoregulatory loop involving murine CD8(+) T cells and dendritic cells. AB - Humans and mice with impaired perforin-dependent cytotoxic function may develop excessive T-cell activation and the fatal disorder hemophagocytic lymphohistiocytosis (HLH) after infection. Though cytotoxic lymphocytes can kill antigen-presenting cells, the physiological mechanism of perforin-mediated immune regulation has never been demonstrated in a disease-relevant context. We used a murine model of HLH to examine how perforin controls immune activation, and we have defined a feedback loop that is critical for immune homeostasis. This endogenous feedback loop involves perforin-dependent elimination of rare, antigen presenting dendritic cells (DCs) by CD8(+) T cells and has a dominant influence on the magnitude of T-cell activation after viral infection. Antigen presentation by a minor fraction of DCs persisted in T-cell- or perforin-deficient animals and continued to drive T-cell activation well beyond initial priming in the latter animals. Depletion of DCs or transfer of perforin-sufficient T cells dampened endogenous DC antigen presentation and T-cell activation, demonstrating a reciprocal relationship between perforin in CD8(+) T cells and DC function. Thus, selective cytotoxic "pruning" of DC populations by CD8(+) T cells limits T-cell activation and protects against the development of HLH and potentially other immunopathological conditions. PMID- 23660961 TI - Understanding pancreatic cancer genomes. AB - Pancreatic cancer is the fourth leading cause of cancer death in our society, with a mortality that virtually parallels its incidence, a median survival of <12 months even with maximal therapy, and a 5-year survival rate of <5 %. The diversity of clinical outcomes and the molecular heterogeneity of histopathologically similar cancer types, incomplete knowledge of the genomic aberrations that drive carcinogenesis and the lack of therapeutics that specifically target most known genomic aberrations necessitates large-scale detailed analysis of cancer genomes to identify novel potential therapeutic strategies. As part of the International Cancer Genome Consortium (ICGC), the Australian Pancreatic Cancer Genome Initiative (APGI) used exomic sequencing and copy number analysis to define genomic aberrations that characterize a large, clinically focused, prospectively accrued cohort of patients with pancreatic cancer. The cohort consisted of early (clinical stages I and II) non-pre-treated patients with pancreatic ductal adenocarcinoma who underwent operative resection with curative intent. We devised approaches to adjust for low epithelial content in primary tumours and to define the genomic landscape of pancreatic cancer to identify novel candidate driver genes and mechanisms. We aim to develop stratified, molecular phenotype-guided therapeutic strategies using existing therapeutics that are either rescued, repurposed, in development, or are known to be effective in an undefined subgroup of PC patients. These are then tested in primary patient-derived xenografts and cell lines from the above deeply characterized cohort. In addition, we return information to treating clinicians that influences patient care and are launching a clinical trial called IMPaCT (Individualized Molecular Pancreatic Cancer Therapy). This umbrella design trial randomizes patients with metastatic disease to either standard first-line therapy with gemcitabine, or a molecular phenotype-guided approach using next-generation sequencing strategies to screen for actionable mutations defined through the ICGC effort. PMID- 23660963 TI - Synthesis of phase pure praseodymium barium copper iron oxide. AB - The control of crystallization of praseodymium barium copper iron oxide, an intermediate temperature solid oxide fuel cell cathode material, has been demonstrated for the first time using a biotemplated sol-gel synthesis technique. The results obtained showed significant improvement in purity, synthesis time, surface area and simplicity over that previously reported. PMID- 23660962 TI - Role of adjuvant surgery for patients with initially unresectable pancreatic cancer with a long-term favorable response to non-surgical anti-cancer treatments: results of a project study for pancreatic surgery by the Japanese Society of Hepato-Biliary-Pancreatic Surgery. AB - PURPOSE: A multicenter survey was conducted to explore the role of adjuvant surgery for initially unresectable pancreatic cancer with a long-term favorable response to non-surgical cancer treatments. METHODS: Clinical data including overall survival were retrospectively compared between 58 initially unresectable pancreatic cancer patients who underwent adjuvant surgery with a favorable response to non-surgical cancer treatments over 6 months after the initial treatment and 101 patients who did not undergo adjuvant surgery because of either unchanged unresectability, a poor performance status, and/or the patients' or surgeons' wishes. RESULTS: Overall mortality and morbidity were 1.7 and 47 % in the adjuvant surgery group. The survival curve in the adjuvant surgery group was significantly better than in the control group (p < 0.0001). The propensity score analysis revealed that adjuvant surgery was a significant independent prognostic variable with an adjusted hazard ratio (95 % confidence interval) of 0.569 (0.36 0.89). Subgroup analysis according to the time from initial treatment to surgical resection showed a significant favorable difference in the overall survival in patients who underwent adjuvant surgery over 240 days after the initial treatment. CONCLUSION: Adjuvant surgery for initially unresectable pancreatic cancer patients can be a safe and effective treatment. The overall survival rate from the initial treatment is extremely high, especially in patients who received non-surgical anti-cancer treatment for more than 240 days. PMID- 23660964 TI - Complications following palmar plate fixation of distal radius fractures: a review of 665 cases. AB - INTRODUCTION: Palmar plate fixation of unstable distal radial fractures is quickly becoming the standard treatment for this common injury. The literature reporting complications consists mainly of isolated case reports or small case series. METHOD: Between February 2004 and December 2009 palmar plate fixation was performed in 665 cases. The overall complication rate was 11.3 % (75 complications). Revision surgery was necessary in 10 % (65 procedures). RESULTS: The reasons for revision surgery were: postoperative median nerve compression (22 patients) and secondary dislocation (9 patients). An ulna shortening osteotomy for ulnar impingement syndrome was necessary in eight cases. Intraarticular screw placement occurred in three patients. There were two flexor pollicis longus, one finger flexor and three extensor pollicis longus tendon ruptures. Posttraumatic compartment syndrome of the forearm requiring fasciotomy occurred in four cases. There were three cases of infection. Nonoperative treatment was necessary in nine patients, who developed a complex regional pain syndrome. Hardware failure occurred in three cases. Hardware removal was performed in 232 (34 %) cases. CONCLUSION: Palmar plate fixation of distal radius fractures is a safe and effective procedure. Nevertheless, complications necessitating a second intervention are relatively common. A proportion of these complications is iatrogenic and can be avoided by improving the surgical technique. PMID- 23660965 TI - Magnetic characteristics of copper ion-modified DNA thin films. AB - We developed a new method of fabricating a divalent copper ion (Cu(2+)) modified DNA thin film on a glass substrate and studied its magnetic properties. We evaluated the coercive field (Hc), remanent magnetization (Mr), susceptibility (chi), and thermal variation of magnetization with varying Cu(2+) concentrations [Cu(2+)] resulting in DNA thin films. Although thickness of the two dimensional DNA thin film with Cu(2+) in dry state was extremely thin (0.6 nm), significant ferromagnetic signals were observed at room temperature. The DNA thin films with a [Cu(2+)] near 5 mM showed the distinct S-shape hysteresis with appreciable high Hc, Mr and chi at low field (<=600 Oe). These were primarily caused by the presence of small magnetic dipoles of Cu(2+) coordination on the DNA molecule, through unpaired d electrons interacting with their nearest neighbors and the inter-exchange energy in the magnetic dipoles making other neighboring dipoles oriented in the same direction. PMID- 23660966 TI - Intrinsic disorder of the bacterial cell division protein ZipA: coil-to-brush conformational transition. AB - The full-length ZipA protein from Escherichia coli, one of the essential elements of the cell division machinery, was studied in a surface model built as adsorbed monolayers. The interplay between lateral packing and molecular conformation was probed using a combined methodology based on the scaling analysis of the surface pressure isotherms and ellipsometry measurements of the monolayer thickness. The observed behavior is compatible with the one expected for an intrinsically disordered and highly flexible protein that is preferentially structured in a random coil conformation. At low grafting densities, ZipA coils organize in a mushroom-like regime, whereas a coil-to-brush transition occurs on increasing lateral packing. The structural results suggest a functional scenario in which ZipA acts as a flexible tether anchoring bacterial proto-ring elements to the membrane during the earlier stages of division. PMID- 23660967 TI - Multiple coagulation factor deficiency protein 2 contains the ability to support stem cell self-renewal. AB - Defects in multiple coagulation factor deficiency protein 2 (MCFD2) are a cause of factor V and factor VIII combined deficiency type 2 (F5F8D). MCFD2 was also suggested to play an important role as an autocrine/paracrine factor in maintaining neural stem cell potential. The current work provided direct evidence that both amphibian and human MCFD2 can maintain stem cell pluripotency or stemness of rhesus monkey embryonic stem cells (rESCs) as basic fibroblast growth factor 2 (FGF-2) does. In most cases, MCFD2 had identical effects on stem cells as FGF-2. We investigated the possible mechanism of MCFD2 to support stem cell pluripotency by highlighting the effects of MCFD2 and FGF-2 on several signaling pathways in rESCs, namely MAPK, TGF-beta, Wnt, and Akt, and 3 core transcriptional factors (Oct4, Nanog, and Sox2). In addition, some features of signaling pathways (MAPK and Akt), which are different from human embryonic stem cells (hESCs) and mouse embryonic stem cells (mESCs), are found in rESCs, indicating that primate ESCs have unique signaling mechanisms. These results may shed light on the biological roles of MCFD2, the conserved protein family distributed in both vertebrates and invertebrates. The ability to support stem cell self-renewal may be the general function of the conserved protein family. PMID- 23660968 TI - The current state of the empirical evidence for psychoanalysis: a meta-analytic approach. AB - LEARNING OBJECTIVES: After participating in this educational activity, the reader should be better able to evaluate the empirical evidence for pre/post changes in psychoanalysis patients with complex mental disorders, and assess the limitations of the meta-analysis. BACKGROUND: The effectiveness of psychoanalysis is still a controversial issue, despite increasing research efforts. OBJECTIVE: To investigate the empirical evidence for psychoanalysis by means of a systematic review of the literature and a meta-analysis of the research data. METHOD: A systematic literature search was undertaken to find studies regarding the effectiveness of psychoanalysis, published between 1970 and 2011. A meta-analysis was performed. RESULTS: Fourteen studies (total n = 603) were included in the meta-analysis. All but one were pre/post cohort studies. At treatment termination, the mean pre/post effect size across all outcome measures was 1.27 (95% confidence interval [CI], 1.03-1.50; p < .01). The mean pre/post effect size for symptom improvement was 1.52 (95% CI, 1.20-1.84; p < .01), and for improvement in personality characteristics 1.08 (95% CI, 0.89-1.26; p < .01). At follow-up the mean pre/follow-up effect size was 1.46 across all outcome measures (95% CI, 1.08-1.83; p < .01), 1.65 for symptom change (95% CI, 1.24-2.06; p < .01), and 1.31 for personality change (95% CI, 1.00-1.62; p < .01). CONCLUSIONS: A limited number of mainly pre/post studies, presenting mostly completers analyses, provide empirical evidence for pre/post changes in psychoanalysis patients with complex mental disorders, but the lack of comparisons with control treatments is a serious limitation in interpreting the results. Further controlled studies are urgently needed. PMID- 23660969 TI - Quality of life in borderline personality disorder. AB - OBJECTIVE: To review the literature on quality of life (QoL) in borderline personality disorder (BPD) by examining the use of QoL instruments, the extent of QoL impairments in BPD, and the impact of treatment on QoL in BPD. METHODS: Studies were identified through PubMed and PsycINFO searches for articles from 1980 to 2011 using the following keywords: quality of life OR health-related quality of life OR QOL OR HRQOL AND borderline personality disorder. We focused our search on studies that actually measured QoL. Two authors agreed independently on including 25 studies that met specific selection criteria. RESULTS: The data on QoL in BPD are still sparse, with high heterogeneity in the instruments used to measure QoL, which decreases the comparability of existing studies. EQ-5D, WHOQOL, SF-36, Satisfaction Profile, and Q-LESQ have been utilized as QoL measures in BPD research. The reviewed studies uniformly demonstrated grave impairments in QoL of BPD patients. The available evidence indicates that BPD treatments improve not only psychiatric symptoms but also QoL, as shown by psychotherapy and pharmacotherapy studies. Nevertheless, it remains unclear whether current treatments are able to restore QoL to community norms. CONCLUSIONS: QoL is gaining more importance as an outcome measure of psychiatric interventions. Research evidence confirms that QoL is seriously impaired in BPD and that QoL improves with treatment. Further research is needed to build a consensus on the utilization of QoL measures and to improve their validity in BPD. More importantly, future studies need to develop and test interventions to improve QoL in BPD. PMID- 23660970 TI - Areas of the brain modulated by single-dose methylphenidate treatment in youth with ADHD during task-based fMRI: a systematic review. AB - OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric disorder affecting 5% of children. Methylphenidate (MPH) is a common medication for ADHD. Studies examining MPH's effect on pediatric ADHD patients' brain function using functional magnetic resonance imaging (fMRI) have not been compiled. The goals of this systematic review were to determine (1) which areas of the brain in pediatric ADHD patients are modulated by a single dose of MPH, (2) whether areas modulated by MPH differ by task type performed during fMRI data acquisition, and (3) whether changes in brain activation due to MPH relate to clinical improvements in ADHD-related symptoms. METHODS: We searched the electronic databases PubMed and PsycINFO (1967-2011) using the following terms: ADHD AND (methylphenidate OR MPH OR ritalin) AND (neuroimaging OR MRI OR fMRI OR BOLD OR event related), and identified 200 abstracts, 9 of which were reviewed based on predefined criteria. RESULTS: In ADHD patients the middle and inferior frontal gyri, basal ganglia, and cerebellum were most often affected by MPH. The middle and inferior frontal gyri were frequently affected by MPH during inhibitory control tasks. Correlation between brain regions and clinical improvement was not possible due to the lack of symptom improvement measures within the included studies. CONCLUSIONS: Throughout nine task-based fMRI studies investigating MPH's effect on the brains of pediatric patients with ADHD, MPH resulted in increased activation within frontal lobes, basal ganglia, and cerebellum. In most cases, this increase "normalized" activation of at least some brain areas to that seen in typically developing children. PMID- 23660971 TI - Managing non-epileptic seizures and psychogenic dystonia in an adolescent girl with preterm brain injury. PMID- 23660973 TI - Supporting universal prevention programs: a two-phased coaching model. AB - Schools are adopting evidence-based programs designed to enhance students' emotional and behavioral competencies at increasing rates (Hemmeter et al. in Early Child Res Q 26:96-109, 2011). At the same time, teachers express the need for increased support surrounding implementation of these evidence-based programs (Carter and Van Norman in Early Child Educ 38:279-288, 2010). Ongoing professional development in the form of coaching may enhance teacher skills and implementation (Noell et al. in School Psychol Rev 34:87-106, 2005; Stormont et al. 2012). There exists a need for a coaching model that can be applied to a variety of teacher skill levels and one that guides coach decision-making about how best to support teachers. This article provides a detailed account of a two phased coaching model with empirical support developed and tested with coaches and teachers in urban schools (Becker et al. 2013). In the initial universal coaching phase, all teachers receive the same coaching elements regardless of their skill level. Then, in the tailored coaching phase, coaching varies according to the strengths and needs of each teacher. Specifically, more intensive coaching strategies are used only with teachers who need additional coaching supports, whereas other teachers receive just enough support to consolidate and maintain their strong implementation. Examples of how coaches used the two-phased coaching model when working with teachers who were implementing two universal prevention programs (i.e., the PATHS curriculum and PAX Good Behavior Game [PAX GBG]) provide illustrations of the application of this model. The potential reach of this coaching model extends to other school based programs as well as other settings in which coaches partner with interventionists to implement evidence-based programs. PMID- 23660972 TI - Culturally sensitive risk behavior prevention programs for African American adolescents: a systematic analysis. AB - The current review conducted a systematic assessment of culturally sensitive risk prevention programs for African American adolescents. Prevention programs meeting the inclusion and exclusion criteria were evaluated across several domains: (1) theoretical orientation and foundation; (2) methodological rigor; (3) level of cultural integration; (4) program target or domain (e.g., schools, communities, families); (5) outcome change level assessed (e.g., addressing change in beliefs/values or behaviors); and (6) program effects on risk behaviors. Thirteen studies (N = 13) with adolescent participants ranging from 10 to 18 years were identified and evaluated. Analyses suggested that more effective culturally sensitive risk prevention programs included the following: (1) a clearly articulated theoretical orientation, which utilized both universal (e.g., behavioral theories) and culturally specific (e.g., Africultural theories) frameworks; (2) a rigorous methodological design (e.g., inclusion of control group, utilization of program manuals, valid and reliable study measures); (3) an integration of culture at multiple levels (e.g., accessibility, delivery, and content) of programming; (4) consideration of the influence of multiple contexts and domains (e.g., family, community, school); (5) multiple behavior change outcomes (e.g., behaviors, relationships, values); and (6) sustained program effects over time. Recommendations for increasing the effectiveness and efficacy of culturally sensitive prevention programs are discussed. PMID- 23660974 TI - Individual differences in reproductive strategy are related to views about recreational drug use in Belgium, The Netherlands, and Japan. AB - Individual differences in moral views are often explained as the downstream effect of ideological commitments, such as political orientation and religiosity. Recent studies in the U.S. suggest that moral views about recreational drug use are also influenced by attitudes toward sex and that this relationship cannot be explained by ideological commitments. In this study, we investigate student samples from Belgium, The Netherlands, and Japan. We find that, in all samples, sexual attitudes are strongly related to views about recreational drug use, even after controlling for various ideological variables. We discuss our results in light of reproductive strategies as determinants of moral views. PMID- 23660975 TI - Red, yellow, and super-white sclera : uniquely human cues for healthiness, attractiveness, and age. AB - The sclera, the eye's tough outer layer, is, among primates, white only in humans, providing the ground necessary for the display of colors that vary in health and disease. The current study evaluates scleral color as a cue of socially significant information about health, attractiveness, and age by contrasting the perception of eyes with normal whites with copies of those eyes whose whites were reddened, yellowed, or further whitened by digital editing. Individuals with red and yellow sclera were rated to be less healthy, less attractive, and older than individuals with untinted control sclera. Individuals with whitened, "super-white" sclera were rated as younger, although not more healthy or attractive, than controls. In humans, clear, white sclera may join such traits as smooth skin and long, lustrous hair as signs of health, beauty, and reproductive fitness. The evolution of a white sclera may have contributed to the emergence of humans as a social species. PMID- 23660977 TI - The whole and the art of medical dialectic: a platonic account. AB - The aim of this paper is to investigate Plato's conception of the whole in the Phaedrus and the theory of medical dialectic underlying this conception. Through this analysis Plato's conception of kairos will also be adressed. It will be argued that the epistemological holism developed in the dialogue and the patient typology emerging from it provides us with a way of perceiving individual situations of medical discourse and decision-making that makes it possible to bridge the gap between observations of a professional nature, i.e. of diagnostics and therapy--of whom to treat and in what magnitude--and individual patients' perceptions of their situation. Besides, it will be argued that such a patient typology represents a conceptual framework to assess and deal normatively with patients' ailments and needs that is more robust than the current standards in use, i.e. the Subjective Standard, the Reasonable Person Standard and the Professional Practice Standard. Finally, it will be argued that the possession of kairos, which according to Plato is the hallmark of a true physician, represents a normative conception of time that today's medicine is in need of revisiting. PMID- 23660976 TI - Genetic disruption of Abl nuclear import reduces renal apoptosis in a mouse model of cisplatin-induced nephrotoxicity. AB - DNA damage activates nuclear Abl tyrosine kinase to stimulate intrinsic apoptosis in cancer cell lines and mouse embryonic stem cells. To examine the in vivo function of nuclear Abl in apoptosis, we generated Abl-MUNLS (MU, mutated in nuclear localization signals) mice. We show here that cisplatin-induced apoptosis is defective in the renal proximal tubule cells (RPTC) from the Abl(MU/MU) mice. When injected with cisplatin, we found similar levels of platinum in the Abl(+/+) and the Abl(MU/MU) kidneys, as well as similar initial inductions of p53 and PUMAalpha expression. However, the accumulation of p53 and PUMAalpha could not be sustained in the Abl(MU/MU) kidneys, leading to reductions in renal apoptosis and tubule damage. Co-treatment of cisplatin with the Abl kinase inhibitor, imatinib, reduced the accumulation of p53 and PUMAalpha in the Abl(+/+) but not in the Abl(MU/MU) kidneys. The residual apoptosis in the Abl(MU/MU) mice was not further reduced in the Abl(MU/MU); p53(-/-) double-mutant mice, suggesting that nuclear Abl and p53 are epistatic to each other in this apoptosis response. Although apoptosis and tubule damage were reduced, cisplatin-induced increases in phospho Stat-1 and blood urea nitrogen were similar between the Abl(+/+) and the Abl(MU/MU) kidneys, indicating that RPTC apoptosis is not the only factor in cisplatin-induced nephrotoxicity. These results provide in vivo evidence for the pro-apoptotic function of Abl, and show that its nuclear localization and tyrosine kinase activity are both required for the sustained expression of p53 and PUMAalpha in cisplatin-induced renal apoptosis. PMID- 23660987 TI - MAPK inhibitors augment gallic acid-induced A549 lung cancer cell death through the enhancement of glutathione depletion. AB - Gallic acid (GA) is involved in various biological processes such as cell growth inhibition and apoptosis through changes in reactive oxygen species (ROS). In the present study, we investigated the effects of MAPK (MEK, JNK or p38) inhibitors on cell death in GA-induced A549 lung cancer cells in relation to ROS and glutathione (GSH). Treatment with 100 uM GA inhibited the growth of A549 cells and induced apoptosis and/or necrosis, which was accompanied by the loss of mitochondrial membrane potential (MMP; ?Psi(m)). GA increased ROS levels as well as GSH depletion in A549 cells at 24 h. MEK inhibitor seemed to enhance cell growth inhibition by GA. This inhibitor also increased cell death, MMP (?Psi(m)) loss and GSH depletion in GA-treated A549 cells. Both JNK and p38 inhibitors intensified growth inhibition, cell death, MMP (?Psi(m)) loss and GSH depletion by GA. However, none of the MAPK inhibitors significantly altered ROS levels in GA-treated A549 cells. In conclusion, MAPK inhibitors enhanced growth inhibition and death in GA-treated A549 cells, which were correlated with GSH depletion rather than ROS levels. PMID- 23660989 TI - Adjunctive immunotherapy with alpha-crystallin based DNA vaccination reduces Tuberculosis chemotherapy period in chronically infected mice. AB - By employing modified Cornell model, we have evaluated the potential of adjunctive immunotherapy with DNA vaccines to shorten the tuberculosis chemotherapy period and reduce disease reactivation. We demonstrate that alpha crystallin based DNA vaccine (DNAacr) significantly reduced the chemotherapy period from 12 weeks to 8 weeks when compared with the chemotherapy alone. Immunotherapy with SodA based DNA vaccine (DNAsod) reduced the pulmonary bacilli only as much as DNAvec. Both DNAacr and DNAsod, although significantly delayed the reactivation in comparison to the chemotherapy alone, this delay was associated with the immunostimulatory sequences present in the vector backbone and was not antigen specific. Both DNA vaccines resulted in the production of significantly higher number of TEM cells than the chemotherapy alone, however, only in the case of DNAsod, this enhancement was significant over the DNAvec treatment. Overall, our findings emphasize the immunotherapeutic potential of DNAacr in shortening the duration of TB chemotherapy. PMID- 23660990 TI - The interaction of antiemetic dose of droperidol with propofol on QT interval during anesthetic induction. AB - PURPOSE: We investigated the effect of low-dose droperidol on heart rate corrected QT (QTc) interval and interaction with propofol. METHODS: Seventy-two patients undergoing upper limb surgery were included in this study. Patients were randomly allocated to one of three groups: group S (n = 24), which received 1 ml saline; group D1 (n = 24), which received 1.25 mg droperidol; or group D2 (n = 24), which received 2.5 mg droperidol. One minute later, fentanyl (3 MUg/kg) was administered. Two minutes after fentanyl administration, anesthesia was induced using propofol (1.5 mg/kg) and vecronium. Tracheal intubation was performed 3 min after the administration of propofol. Heart rate, mean arterial pressure, bispectral index, and QTc interval were recorded at the following time points: immediately before the droperidol injection (baseline); 3 min after the saline or droperidol injection; 3 min after the propofol injection; and 2 min after tracheal intubation. RESULTS: Compared to baseline, the QTc interval in group S and group D1 was significantly shorter after propofol injection, but recovered after tracheal intubation. In group D2, the QTc interval was significantly prolonged after droperidol injection, but recovered after propofol injection, and was significantly prolonged after tracheal intubation. CONCLUSIONS: We found that saline or 1.25 mg droperidol did not prolong QTc interval, whereas 2.5 mg droperidol prolonged the QTc interval significantly, and that propofol injection counteracted the prolongation of the QTc interval induced by 2.5 mg droperidol. PMID- 23660988 TI - Intramolecular hydrogen-bonding in aqueous carbohydrates as a cause or consequence of conformational preferences: a molecular dynamics study of cellobiose stereoisomers. AB - It is often assumed that intramolecular hydrogen-bonding (H-bonding) exerts a significant influence on the conformational properties of aqueous (bio-)polymers. To discuss this statement, one should, however, distinguish between solvent exposed and buried H-bonds, and between their respective roles in promoting stability (i.e., as a driving force) and specificity (for which the term steering force is introduced here). In this study, the role of solvent-exposed H-bonding in carbohydrates as a driving or steering force is probed using explicit-solvent molecular dynamics simulations with local elevation umbrella sampling in the simple context of cellobiose stereoisomers. More specifically, four beta(1->4) linked D-aldohexopyranose disaccharides are considered, which present a different stereochemisty of the potentially H-bonding groups neighboring the glycosidic linkage. Although the epimerization may largely alter the intramolecular trans glycosidic H-bonding pattern, it is found to have only very limited influence on the Ramachandran free-energy map of the disaccharide, a loss of intramolecular H bonding being merely compensated for by an enhancement of the interaction with the solvent molecules. This finding suggests that solvent-exposed trans glycosidic H-bonding (and in particular the HO'(3)->O5 H-bond) is not the cause of the 21-helical secondary structure characteristic of cellooligosaccharides, but rather the opportunistic consequence of a sterically and stereoelectronically dictated conformational preference. In other words, for these compounds, solvent exposed H-bonding appears to represent a minor (possibly adverse) conformational driving as well as steering force. PMID- 23660991 TI - Successful tracheal intubation with the GlideScope(r) in a patient with CHARGE syndrome. PMID- 23660992 TI - Unusual anti-selective asymmetric conjugate addition of aldehydes to nitroalkenes catalyzed by a biphenyl-based chiral secondary amine. AB - Unusual anti-selectivity was observed in the conjugate addition of aldehydes to nitroalkenes, when a biphenyl-based chiral secondary amine was used as catalyst. PMID- 23660993 TI - The behavior and origin of the excess wing in DEET (N,N-diethyl-3 methylbenzamide). AB - Broadband dielectric spectroscopy along with a high pressure technique and quantum-mechanical calculations are employed to study in detail the behavior and to reveal the origin of the excess wing (EW) in neat N,N-diethyl-3 methylbenzamide (DEET). Our analysis of dielectric spectra again corroborates the idea that the EW is a hidden beta-relaxation peak. Moreover, we found that the position frequency of the beta peak corresponds to the position of the primitive relaxation of the Coupling Model. We also studied the possible intramolecular rotations in DEET by means of DFT calculation. On that basis we were able to describe the EW as the JG beta-relaxation and find the possible origin of the gamma-relaxation visible in DEET dielectric spectra at very low temperatures. PMID- 23660994 TI - Establishment of a mammalian cell line suitable for industrial production of recombinant protein using mutations induced by high-energy beam radiation. AB - Mammalian cells are extensively used for production of biopharmaceuticals. Most cells used in industry have infinite proliferative capacity, which provides a high number of cells and corresponding productivity. However, infinite cells will continue to multiply even after cell density reaches sufficient levels. This excess proliferation aggravates the culture environment and induces low productivity. Therefore, after cell density reaches sufficient levels, downregulation of proliferation would prevent such aggravation and extend the culture period and improve productivity. To realize such suitable proliferation, we aimed to establish a novel cell line whose proliferation was spontaneously downregulated after reaching a sufficient population level. Mutagenesis using high-energy beam irradiation was used. CHO-DP12 cells were irradiated with 2.5 Gy X-rays and screened with hydroxyurea and 5-fluorouracil to eliminate any cells multiplying after confluence and to concentrate desired mutants. One clone was established and named CHO-M1. Cell cycle analysis indicated that CHO-M1 cells had a similar cell cycle profile in the exponential growth phase, but cells rapidly accumulated in G1 phase just before confluence and did not progress through the cell cycle. This suggested that until confluence, proliferation of CHO-M1 was similar to parental CHO, but after confluence, it was inhibited and under G1 arrest. The specific antibody production rate of CHO-M1 was kept high, even after confluence, while that of parental CHO was drastically decreased in stationary phase. These results suggest that the desired cell line was successfully established and that high-energy beam irradiation could be an efficient mutagenic technique for breeding industrial cells. PMID- 23660995 TI - Effect of the systemic use of methotrexate on the oxidative stress and paraoxonase enzyme in psoriasis patients. AB - Previous studies have indicated that oxidative stress contributes in the efficacy and toxicity of methotrexate (MTX) treatment. The present study aims to investigate the systemic MTX treatments impact on the total oxidant and antioxidant status of the patients with psoriasis. A total of 26 psoriasis patients were included in the study. Serum total oxidant status (TOS), total antioxidant status (TAS), and serum paraoxonase enzyme (PON) levels were measurement of all patients, and Oxidative Stress Index (OSI) were calculated before and after 8 weeks of MTX therapy. Psoriasis Area Severity Index scores of the patients decreased significantly after MTX treatment. While the serum concentrations of total cholesterol, low density lipoprotein, and high density lipoprotein decreased significantly, the serum ALT levels of the patients increased significantly after MTX treatment. There was no statistically significant alteration in serum levels of PON, TAS, TOS, and OSI after the MTX therapy. The oxidative stress emerging with 8-week MTX treatment is not significantly increased in the patients. In parallel with the decreasing inflammation by MTX treatment in patients with psoriasis, a decrease in oxidative stress (OS) is also expected. However, the expected reduction in OS might have been precluded by MTX-induced OS, which resulted in no significant difference between pre- and post-treatment values of OS parameters in our study. There is a possibility that the 8-week results may change with longer treatment durations and higher cumulative doses. PMID- 23660996 TI - The presence of primary sclerosing cholangitis is protective for ileal pouch from Crohn's disease. AB - BACKGROUND: Primary sclerosing cholangitis (PSC) has been shown to increase the risk for chronic pouchitis. However, the association between PSC and Crohn's disease (CD) of the pouch has not been studied. METHODS: Consecutive inflammatory bowel disease patients undergoing proctocolectomy with ileal pouch-anal anastomosis in our Pouchitis Registry from 2002 to 2012 were studied. Cases consisted of patients with CD of the pouch. Both univariable and multivariable analyses were performed. RESULTS: A total of 1425 patients met the inclusion criteria, including 265 (18.6%) with CD of the pouch and 78 (5.5%) with PSC. In the whole cohort, 799 patients (56.1%) were male and the mean ages at the time of diagnosis of inflammatory bowel disease and at pouch surgery were 25.5 +/- 12.3 years and 35.4 +/- 13.9 years, respectively. Patients with PSC had a longer duration from inflammatory bowel disease diagnosis to pouch construction (P < 0.001). Fewer patients with PSC had toxic megacolon at the time of colectomy (P = 0.009), but more patients with PSC had neoplasia as the indication for colectomy (P < 0.001), concurrent autoimmune disorders (P < 0.001), and liver transplantation (P = 0.001). In the multivariate analysis, the presence of PSC was shown to be inversely associated with the risk for the development of CD of the pouch, with a hazard ratio of 0.39 (95% confidence interval: 0.16 to 0.95, P = 0.038). However, no significant difference in terms of the distribution of phenotypes of CD of the pouch between patients with and without PSC was identified (P = 0.59). CONCLUSIONS: The presence of PSC is inversely associated with the development of CD of the pouch. PMID- 23660997 TI - Cumulative incidence and risk factors for hospitalization and surgery in a population-based cohort of ulcerative colitis. AB - BACKGROUND: We sought to identify clinical and demographic features influencing hospitalization and colectomy in a population-based inception cohort of ulcerative colitis. METHODS: Between 1970 and 2004, a total of 369 patients (58.5% males) from Olmsted County, MN, were followed from diagnosis for 5401 person-years. The cumulative probability of hospitalization and colectomy were estimated using the Kaplan-Meier method. Cox proportional hazards regression was used to identify factors associated with hospitalization and colectomy. RESULTS: The cumulative probability of first hospitalization was 29.4% at 5 years (95% confidence interval [CI], 24.5%-34.1%), 38.7% at 10 years (33.1%-43.8%), 49.2% at 20 years (42.7%-55.2%), and 52.3% at 30 years (45.1%-59.7%). The incidence rate of hospitalizations decreased over the last 4 decades, although cumulative probability of first hospitalization increased with successive decades of diagnosis. Early need for corticosteroids (hazard ratio [HR], 1.8; 95% CI, 1.1% 2.7%) and early need for hospitalization (HR, 1.5; 95% CI, 1.02-2.4) were independent predictors of hospitalization after 90 days of illness. The cumulative probability of colectomy from the time of diagnosis was 13.1% at 5 years (95% CI, 9.4%-16.6%), 18.9% at 10 years (95% CI, 14.4%-23.2%), and 25.4% at 20 years (95% CI, 19.8%-30.8%). Male gender (HR, 2.1; 95% CI, 1.3-3.5), diagnosis in the 1990s (HR, 2.0; 95% CI, 1.01-4.0), and diagnosis in 2000 to 2004 (HR, 3.7; 95% CI, 1.7-8.2) were significantly associated with colectomy risk. CONCLUSIONS: Colectomy rates were comparable to reports from northern Europe. The numbers of hospitalizations show a decreasing trend. Male gender and being diagnosed in the 2000 to 2004 period predicted colectomy while extensive colitis predicted future hospitalizations. PMID- 23660998 TI - Assessment of beta-carotene content, cell physiology and morphology of the yellow yeast Rhodotorula glutinis mutant 400A15 using flow cytometry. AB - Flow cytometry was used to assess beta-carotene content, cell membrane permeability, cell size and granularity in Rhodotorula glutinis mutant 400A15 grown under different oxygen transfer coefficients (k L a) and carbon to nitrogen ratios (C/N). A Doehlert distribution was used in order to select the best conditions that induced the highest carotenoids production. The highest beta carotene content (0.79 mg g(-1) DCW) at the lowest k L a and C/N (5 * 10(-3) s( 1) and 11.3 respectively). Under these conditions, the biomass concentration attained 18.60 g L(-1). The highest ratio of cells with permeabilised membranes (2.6 %), and the highest cell size and granularity were also obtained under these conditions. It was observed that C/N showed a stronger influence than the k L a on the measured cell parameters. PMID- 23660999 TI - Highly valuable microalgae: biochemical and topological aspects. AB - The past decade has seen a surge in the interest in microalgae culture for biodiesel production and other applications as renewable biofuels as an alternative to petroleum transport fuels. The development of new technologies for the culture of these photosynthetic microorganisms and improved knowledge of their biochemical composition has spurred innovation in the field of high-value biomolecules. These developments are only economically viable if all the microalgae fractions are valorized in a biorefinery strategy. Achieving this objective requires an understanding of microalgae content and the cellular localization of the main biomolecular families in order to develop efficient harvest and sequential recovery technologies. This review summarizes the state of the art in microalgae compositions and topologies using some examples of the main industrially farmed microalgae. PMID- 23661001 TI - Amyloid-beta and Alzheimer's disease type pathology differentially affects the calcium signalling toolkit in astrocytes from different brain regions. AB - The entorhinal-hippocampal circuit is severely affected in Alzheimer's disease (AD). Here, we demonstrate that amyloid-beta (Abeta) differentially affects primary cultured astrocytes derived from the entorhinal cortex (EC) and from the hippocampus from non-transgenic controls and 3xTg-AD transgenic mice. Exposure to 100 nM of Abeta resulted in increased expression of the metabotropic glutamate receptor type 5 (mGluR5) and its downstream InsP3 receptor type 1 (InsP3R1) in hippocampal but not in EC astrocytes. Amplitudes of Ca(2+) responses to an mGluR5 agonist, DHPG, and to ATP, another metabotropic agonist coupled to InsP3Rs, were significantly increased in Abeta-treated hippocampal but not in EC astrocytes. Previously we demonstrated that senile plaque formation in 3xTg-AD mice triggers astrogliosis in hippocampal but not in EC astrocytes. The different sensitivities of the Ca(2+) signalling toolkit of EC versus hippocampal astrocytes to Abeta may account for the lack of astrogliosis in the EC, which in turn can explain the higher vulnerability of this region to AD. PMID- 23661000 TI - Identification and validation of risk factors for postoperative infectious complications following hepatectomy. AB - Postoperative infectious complications (PICs) are associated with significant morbidity after abdominal surgery. Using multivariate analysis of data from a prospective database, our study focused on the risk factors for PICs and the prevention of these complications after hepatectomy, with the goal of improving outcomes and reducing the length of hospital stays. BACKGROUND: PICs following surgery are associated with significant morbidity, increase the length of hospital stays, and have a negative impact on long-term oncological outcome. The aim of this study was to determine the risk factors for PICs following partial hepatectomy and to validate these results with an external database. METHODS: Between January 2006 and December 2009, 555 patients underwent elective partial hepatectomy. We prospectively collected and retrospectively analyzed demographic data, pathological variables, associated pathological conditions, and preoperative, intraoperative, and postoperative variables. The dependent variables studied were the occurrence of PICs, defined as development of one or more of the following conditions: pneumonia, sepsis, Central line-associated bloodstream infection, urinary tract infection, wound infection, and infected intra-abdominal fluid collection. PICs were devised in medical (PIMCs) and surgical (PISCs) complications. The incidence of PICs and validation of the predictive score were determined using an external prospective database of 342 patients. RESULTS: The multivariate analysis identified three independent risk factors for PICs: the presence of a nasogastric tube (OR = 1.8), blood transfusion (OR = 1.9), and diabetes (OR = 2.4). The multivariate analysis identified only one independent risk factor for PISCs: an associated portal venous resection (OR = 5.5). The multivariate analysis identified four independent risk factors for PIMCs: presence of a biliary drainage (OR = 1.9), blood transfusion (OR = 2.1), diabetes (OR = 2.9), and presence of atrial fibrillation (OR = 3.6). According to the three predictive factors, the observed rates of PICs ranged from 18.8 % to 77.8 % and ranged from 24.2 % to 100 % in the external database. Predicted and observed risks of PICs were not statistically different. CONCLUSIONS: The correction of modifiable risk factors among the identified factors could reduce the incidence of PICs and, as a consequence, improve patient outcomes and reduce the length of hospital stays. PMID- 23661003 TI - FoxO3a is activated and executes neuron death via Bim in response to beta amyloid. AB - The molecules that mediate death of selective neurons in Alzheimer's disease (AD) are mostly unknown. The Forkhead transcription factor FoxO3a has emerged as an important mediator of cell fate including apoptosis. When phosphorylated by Akt, it is localized in the cytosol as an inactive complex bound with 14-3-3 protein. For activation and localization of FoxO3a in the nucleus, further modifications are required, such as phosphorylation by mammalian sterile 20-like kinase 1 (MST1) and arginine methylation by protein arginine methyltransferase1. We report here that Akt-mediated phosphorylation of FoxO3a is diminished in neurons exposed to oligomeric beta-amyloid (Abeta), in vitro and in vivo. We also find that oligomeric Abeta activates FoxO3a by MST1 phosphorylation and arginine methylation in primary cultures of hippocampal and cortical neurons. Moreover, FoxO3a translocates from the cytosol to nucleus in cultured neurons in response to Abeta. Most importantly, the nuclear redistribution of FoxO3a is significantly increased in Abeta-overexpressing AbetaPPswe-PS1dE9 mice and Abeta-infused rat brains. We further find that FoxO3a is essential for loss of neurons and neural networks in response to Abeta. Recent reports implicate Bim, a pro-apoptotic member of Bcl-2 family, in neuron death in AD, as a key target of this transcription factor. We show that Bim is a direct target of FoxO3a in Abeta treated neurons. Our findings thus indicate that FoxO3a is activated, translocated to the nucleus and mediates neuron death via Bim in response to Abeta toxicity. PMID- 23661004 TI - Protein tyrosine phosphatase 1B modulates GSK3beta/Nrf2 and IGFIR signaling pathways in acetaminophen-induced hepatotoxicity. AB - Acute hepatic failure secondary to acetaminophen (APAP) poisoning is associated with high mortality. Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of tyrosine kinase growth factor signaling. In the liver, this pathway confers protection against injury. However, the involvement of PTP1B in the intracellular networks activated by APAP is unknown. We have assessed PTP1B expression in APAP-induced liver failure in humans and its role in the molecular mechanisms that regulate the balance between cell death and survival in human and mouse hepatocytes, as well as in a mouse model of APAP-induced hepatotoxicity. PTP1B expression was increased in human liver tissue removed during liver transplant from patients for APAP overdose. PTP1B was upregulated by APAP in primary human and mouse hepatocytes together with the activation of c-jun (NH2) terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK), resulting in cell death. Conversely, Akt phosphorylation and the antiapoptotic Bcl2 family members BclxL and Mcl1 were decreased. PTP1B deficiency in mouse protects hepatocytes against APAP-induced cell death, preventing glutathione depletion, reactive oxygen species (ROS) generation and activation of JNK and p38 MAPK. APAP-treated PTP1B(-/-) hepatocytes showed enhanced antioxidant defense through the glycogen synthase kinase 3 (GSK3)beta/Src kinase family (SKF) axis, delaying tyrosine phosphorylation of the transcription factor nuclear factor erythroid 2-related factor (Nrf2) and its nuclear exclusion, ubiquitination and degradation. Insulin-like growth factor-I receptor-mediated signaling decreased in APAP-treated wild-type hepatocytes, but was maintained in PTP1B(-/-) cells or in wild-type hepatocytes with reduced PTP1B levels by RNA interference. Likewise, both signaling cascades were modulated in mice, resulting in less severe APAP hepatotoxicity in PTP1B(-/-) mice. Our results demonstrated that PTP1B is a central player of the mechanisms triggered by APAP in hepatotoxicity, suggesting a novel therapeutic target against APAP-induced liver failure. PMID- 23661006 TI - Scalable analysis of movement data for extracting and exploring significant places. AB - Place-oriented analysis of movement data, i.e., recorded tracks of moving objects, includes finding places of interest in which certain types of movement events occur repeatedly and investigating the temporal distribution of event occurrences in these places and, possibly, other characteristics of the places and links between them. For this class of problems, we propose a visual analytics procedure consisting of four major steps: 1) event extraction from trajectories; 2) extraction of relevant places based on event clustering; 3) spatiotemporal aggregation of events or trajectories; 4) analysis of the aggregated data. All steps can be fulfilled in a scalable way with respect to the amount of the data under analysis; therefore, the procedure is not limited by the size of the computer's RAM and can be applied to very large data sets. We demonstrate the use of the procedure by example of two real-world problems requiring analysis at different spatial scales. PMID- 23661005 TI - The novel c-Met inhibitor cabozantinib overcomes gemcitabine resistance and stem cell signaling in pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignancies. Cancer stem cells (CSCs), which are not targeted by current therapies, may be the reason for pronounced therapy resistance. A new treatment option in phase II trials is cabozantinib that inhibits the pancreatic CSC surface marker and tyrosine kinase receptor c-Met. The purpose of this study was to evaluate the effect of cabozantinib to stem-like features and therapy resistance. Established PDA cell lines, a gemcitabine-resistant subclone, non-malignant pancreatic ductal cells and primary spheroidal cultures from patient tumors were analyzed by MTT assay, flow cytometry, colony and spheroid formation assays, western blotting, qRT-PCR, antibody protein array, immunohistochemistry and morphological features. Cabozantinib inhibited viability and spheroid formation and induced apoptosis in malignant cells with minor effects in non-malignant cells. After long-term cabozantinib treatment, PDA cells had altered anti- and pro-apoptotic signaling, but still responded to cabozantinib, as apoptosis only slightly decreased and viability only slightly increased suggesting a low resistance-inducing potential of cabozantinib. In parallel, c-Met expression and the pluripotency transcription factor SOX2 were downregulated, which might counteract development of full therapy resistance in long-term treated subclones. In single-treatment studies, cabozantinib increased efficacy of gemcitabine. Most importantly, cabozantinib strongly induced apoptosis and reduced viability in PDA cell lines, which are completely resistant toward gemcitabine. In primary, CSC-enriched spheroidal cultures cabozantinib downregulated CSC markers SOX2, c-Met and CD133 and induced apoptosis. These findings suggest that the clinical use of cabozantinib may be more effective than current chemotherapeutics. PMID- 23661007 TI - The longitudinal use of SaNDVis: visual social network analytics in the enterprise. AB - As people continue to author and share increasing amounts of information in social media, the opportunity to leverage such information for relationship discovery tasks increases. In this paper, we describe a set of systems that mine, aggregate, and infer a social graph from social media inside an enterprise, resulting in over 73 million relationships between 450,000 people. We then describe SaNDVis, a novel visual analytics tool that supports people-centric tasks like expertise location, team building, and team coordination in the enterprise. We provide details of a 22-month-long, large-scale deployment to over 2,300 users from which we analyze longitudinal usage patterns, classify types of visual analytics queries and users, and extract dominant use cases from log and interview data. By integrating social position, evidence, and facets into SaNDVis, we demonstrate how users can use a visual analytics tool to reflect on existing relationships as well as build new relationships in an enterprise setting. PMID- 23661008 TI - How visualization layout relates to locus of control and other personality factors. AB - Existing research suggests that individual personality differences are correlated with a user's speed and accuracy in solving problems with different types of complex visualization systems. We extend this research by isolating factors in personality traits as well as in the visualizations that could have contributed to the observed correlation. We focus on a personality trait known as "locus of control” (LOC), which represents a person's tendency to see themselves as controlled by or in control of external events. To isolate variables of the visualization design, we control extraneous factors such as color, interaction, and labeling. We conduct a user study with four visualizations that gradually shift from a list metaphor to a containment metaphor and compare the participants' speed, accuracy, and preference with their locus of control and other personality factors. Our findings demonstrate that there is indeed a correlation between the two: participants with an internal locus of control perform more poorly with visualizations that employ a containment metaphor, while those with an external locus of control perform well with such visualizations. These results provide evidence for the externalization theory of visualization. Finally, we propose applications of these findings to adaptive visual analytics and visualization evaluation. PMID- 23661009 TI - Generalized anisotropic stratified surface sampling. AB - We introduce a novel stratified sampling technique for mesh surfaces that gives the user control over sampling density and anisotropy via a tensor field. Our approach is based on sampling space-filling curves mapped onto mesh segments via parametrizations aligned with the tensor field. After a short preprocessing step, samples can be generated in real time. Along with visual examples, we provide rigorous spectral analysis and differential domain analysis of our sampling. The sample distributions are of high quality: they fulfil the blue noise criterion, so have minimal artifacts due to regularity of sampling patterns, and they accurately represent isotropic and anisotropic densities on the plane and on mesh surfaces. They also have low discrepancy, ensuring that the surface is evenly covered. PMID- 23661010 TI - Interactive applications for sketch-based editable polycube map. AB - In this paper, we propose a sketch-based editable polycube mapping method that, given a general mesh and a simple polycube that coarsely resembles the shape of the object, plus sketched features indicating relevant correspondences between the two, provides a uniform, regular, and user-controllable quads-only mesh that can be used as a basis structure for subdivision. Large scale models with complex geometry and topology can be processed efficiently with simple, intuitive operations. We show that the simple, intuitive nature of the polycube map is a substantial advantage from the point of view of the interface by demonstrating a series of applications, including kit-basing, shape morphing, painting over the parameterization domain, and GPU-friendly tessellated subdivision displacement, where the user is also able to control the number of patches in the base mesh by the construction of the base polycube. PMID- 23661011 TI - Pairwise harmonics for shape analysis. AB - This paper introduces a simple yet effective shape analysis mechanism for geometry processing. Unlike traditional shape analysis techniques which compute descriptors per surface point up to certain neighborhoods, we introduce a shape analysis framework in which the descriptors are based on pairs of surface points. Such a pairwise analysis approach leads to a new class of shape descriptors that are more global, discriminative, and can effectively capture the variations in the underlying geometry. Specifically, we introduce new shape descriptors based on the isocurves of harmonic functions whose global maximum and minimum occur at the point pair. We show that these shape descriptors can infer shape structures and consistently lead to simpler and more efficient algorithms than the state-of the-art methods for three applications: intrinsic reflectional symmetry axis computation, matching shape extremities, and simultaneous surface segmentation and skeletonization. PMID- 23661012 TI - Registration of 3D point clouds and meshes: a survey from rigid to nonrigid. AB - Three-dimensional surface registration transforms multiple three-dimensional data sets into the same coordinate system so as to align overlapping components of these sets. Recent surveys have covered different aspects of either rigid or nonrigid registration, but seldom discuss them as a whole. Our study serves two purposes: 1) To give a comprehensive survey of both types of registration, focusing on three-dimensional point clouds and meshes and 2) to provide a better understanding of registration from the perspective of data fitting. Registration is closely related to data fitting in which it comprises three core interwoven components: model selection, correspondences and constraints, and optimization. Study of these components 1) provides a basis for comparison of the novelties of different techniques, 2) reveals the similarity of rigid and nonrigid registration in terms of problem representations, and 3) shows how overfitting arises in nonrigid registration and the reasons for increasing interest in intrinsic techniques. We further summarize some practical issues of registration which include initializations and evaluations, and discuss some of our own observations, insights and foreseeable research trends. PMID- 23661013 TI - Visualizing natural image statistics. AB - Natural image statistics is an important area of research in cognitive sciences and computer vision. Visualization of statistical results can help identify clusters and anomalies as well as analyze deviation, distribution, and correlation. Furthermore, they can provide visual abstractions and symbolism for categorized data. In this paper, we begin our study of visualization of image statistics by considering visual representations of power spectra, which are commonly used to visualize different categories of images. We show that they convey a limited amount of statistical information about image categories and their support for analytical tasks is ineffective. We then introduce several new visual representations, which convey different or more information about image statistics. We apply ANOVA to the image statistics to help select statistically more meaningful measurements in our design process. A task-based user evaluation was carried out to compare the new visual representations with the conventional power spectra plots. Based on the results of the evaluation, we made further improvement of visualizations by introducing composite visual representations of image statistics. PMID- 23661014 TI - Water surface modeling from a single viewpoint video. AB - We introduce a video-based approach for producing water surface models. Recent advances in this field output high-quality results but require dedicated capturing devices and only work in limited conditions. In contrast, our method achieves a good tradeoff between the visual quality and the production cost: It automatically produces a visually plausible animation using a single viewpoint video as the input. Our approach is based on two discoveries: first, shape from shading (SFS) is adequate to capture the appearance and dynamic behavior of the example water; second, shallow water model can be used to estimate a velocity field that produces complex surface dynamics. We will provide qualitative evaluation of our method and demonstrate its good performance across a wide range of scenes. PMID- 23661015 TI - Inhibition of endogenous phosphodiesterase 7 promotes oligodendrocyte precursor differentiation and survival. AB - During the development of the central nervous system (CNS), oligodendrocyte precursors (OPCs) are generated in specific sites within the neural tube and then migrate to colonize the entire CNS, where they differentiate into myelin-forming oligodendrocytes. Demyelinating diseases such as multiple sclerosis (MS) are characterized by the death of these cells. The CNS reacts to demyelination and by promoting spontaneous remyelination, an effect mediated by endogenous OPCs, cells that represent approximately 5-7 % of the cells in the adult brain. Numerous factors influence oligodendrogliogenesis and oligodendrocyte differentiation, including morphogens, growth factors, chemotropic molecules, extracellular matrix proteins, and intracellular cAMP levels. Here, we show that during development and in early adulthood, OPCs in the murine cerebral cortex contain phosphodiesterase-7 (PDE7) that metabolizes cAMP. We investigated the effects of different PDE7 inhibitors (the well-known BRL-50481 and two new ones, TC3.6 and VP1.15) on OPC proliferation, survival, and differentiation. While none of the PDE7 inhibitors analyzed altered OPC proliferation, TC3.6 and VP1.15 enhanced OPC survival and differentiation, processes in which ERK intracellular signaling played a key role. PDE7 expression was also observed in OPCs isolated from adult human brains and the differentiation of these OPCs into more mature oligodendroglial phenotypes was accelerated by treatment with both new PDE7 inhibitors. These findings reveal new roles for PDE7 in regulating OPC survival and differentiation during brain development and in adulthood, and they may further our understanding of myelination and facilitate the development of therapeutic remyelination strategies for the treatment of MS. PMID- 23661016 TI - Association between GSTP1, GSTM1 and GSTT1 polymorphisms involved in xenobiotic metabolism and head and neck cancer development. AB - Polymorphisms in the glutathione S-transferase superfamily genes that encodes enzymes involved in the phase II xenobiotic metabolism may lead head and neck cancer development. In this study we investigate the association of A313G and C341T GSTP1 polymorphisms, GSTM1 and GSTT1 null genotypes in the head and neck cancer development, interactions between these polymorphisms,the tumor histopathologic parameters and risk factors (smoking and drinking) were also evaluated in the case-control study. 775 individuals (261 patients/514 controls) were included in the study. Molecular analyzes were performed by PCR and PCR RFLP; and statistical analyzes by Chi square and multiple logistic regression. Chi square test showed that only the genotype frequencies for GSTM1 and GSTT1 were in Hardy-Weinberg disequilibrium in both groups. Significant results with p <= 0.05 showed that age >= 48 years (OR = 11.87; 7.55-18.65), smoking (OR = 4.25; 2.70-6.69), drinking (OR = 1.59; 1.02-2.46) were possible predictors for the head and neck cancer development and the presence of A313G GSTP1 polymorphism (OR = 0.62; 0.42-0.92) decreased the risk for this disease. Individuals with the 313AG/GG GSTP1 and age >= 48 years (OR = 0.59; 0.38-0.91), male gender (OR = 0.54; 0.35-0.83), smokers (OR = 0.63; 0.40-0.99) and drinkers (OR = 0.57; 0.35 0.95); the GSTM1 null genotype and age < 48 years (OR = 2.46; 1.09-5.55); the GSTT1 null genotype and primary anatomical sites of pharynx (OR = 0.37; 0.17 0.79) and larynx (OR = 3.60; 1.93-6.72), can modulate the risk for the disease development. The variables age >= 48 years, smoking and drinking can be predictors for head and neck cancer development; moreover, A313G GSTP1 polymorphism, GSTM1 and GSTT1 null genotypes can modulate the risk for this disease. PMID- 23661017 TI - Induction of differentiation by down-regulation of Nanog and Rex-1 in cord blood derived unrestricted somatic stem cells. AB - Stem cells with high self-renewal and tissue regeneration potentials are the core components of regenerative medicine. Adult stem cells with many available sources, high repairing ability, and also possessing no ethical issues are popular candidates in the clinical field. In this study we looked upon the effects of two transcription factors Nanog and Rex-1 in self-renewal and differentiation abilities of a subpopulation of cord blood stem cells known as unrestricted somatic stem cells (USSCs). USSCs were expanded and transfected in vitro with siRNAs targeting either Nanog, Rex-1, and in combination. Gene suppressions were achieved at both transcript and proteome level. Differentiations were evaluated by specific Real time PCR and differentiating staining. Nanog knock down revealed a significant increase in osteogenic markers, Osteocalcin and Osteopontin expression as well as a positive Alizarin Red staining, which proposes Osteogenesis. This treatment also became positive for Oil Red staining, implying adipogenic differentiation as well. In contrast, Rex-1 knock down showed an increase in MAP II and Nestin expression, which is a hall mark of neural differentiation. Surprisingly, treatment with both siRNAs did not express any changes in any of the assessed markers. Therefore, our results indicated a bilateral mesenchymal differentiation for Nanog and a neural lineage fate for Rex-1 suppression. Considering that both transcription factors are core activators of self-renewal and also are orchestrating with other factors, our results imply a positive feedback in response to changes in the regulatory network of self-renewal. PMID- 23661018 TI - Identification of single nucleotide polymorphisms in the agouti signaling protein (ASIP) gene in some goat breeds in tropical and temperate climates. AB - The agouti-signaling protein (ASIP) plays a major role in mammalian pigmentation as an antagonist to melanocortin-1 receptor gene to stimulate pheomelanin synthesis, a major pigment conferring mammalian coat color. We sequenced a 352 bp fragment of ASIP gene spanning part of exon 2 and part of intron 2 in 215 animals representing six goat breeds from Nigeria and the United States: West African Dwarf, predominantly black; Red Sokoto, mostly red; and Sahel, mostly white from Nigeria; black and white Alpine, brown and white Spanish and white Saanen from the US. Twenty haplotypes from nine mutations representing three intronic, one silent and five missense (p.S19R, p.N35K, p.L36V, p.M42L and p.L45W) mutations were identified in Nigerian goats. Approximately 89 % of Nigerian goats carry haplotype 1 (TGCCATCCG) which seems to be the wild type configuration of mutations in this region of the gene. Although we found no association between these polymorphisms in the ASIP gene and coat color in Nigerian goats, in-silico functional analysis predicts putative deleterious functional impact of the p.L45W mutation on the basic amino-terminal domain of ASIP. In the American goats, two intronic mutations, g.293G>A and g.327C>A, were identified in the Alpine breed, although the g.293G>A mutation is common to American and Nigerian goat populations. All Sannen and Sahel goats in this study belong to haplotypes 1 of both populations which seem to be the wild-type composite ASIP haplotype. Overall, there was no clear association of this portion of the ASIP gene interrogated in this study with coat color variation. Therefore, additional genomic analyses of promoter sequence, the entire coding and non-coding regions of the ASIP gene will be required to obtain a definite conclusion. PMID- 23661019 TI - Ewing Sarcoma: influence of TP53 Arg72Pro and MDM2 T309G SNPs. AB - The Ewing Sarcoma is an important tumor of bone and soft tissue. The SNPs Arg72Pro of TP53 and T309G of MDM2 have been associated with many cancer types and have been differently distributed among populations worldwide. Based on a case-control design, this study aimed to assess the role of these SNPs in 24 Ewing Sarcoma patients, compared to 91 control individuals. DNA samples were extracted from blood and genotyped for both SNPs by PCR-RFLP and confirmed by DNA sequencing. The results showed an association between the G allele of the T309G and Ewing Sarcoma (P=0.02). Comparing to the TT carriers, the risk of G allele carriers was 3.35 (95% CI=1.22-9.21) with P=0.02. At the genotypic level, an association of the TT genotype with the control group (P=0.03) was found. Comparing to the TT genotype, the risk of TG and GG was 2.97 (95% CI=1.03-8.58) with P=0.04 and 5.00 (95% CI=1.23-20.34) with P=0.02, respectively. No associations regarding the Arg72Pro SNP were found. Considering that the T309G has been associated with several types of cancer, including sarcomas, our results indicate that this SNP may also be important to Ewing Sarcoma predisposition. PMID- 23661020 TI - Gender specificity of a genetic variant of angiotensin-converting enzyme and risk of coronary artery disease. AB - Etiological factors for coronary artery disease (CAD) involve a wide range of gene and environmental interactions. One of the systems being implicated in the pathophysiology of CAD is the renin-angiotensin system (RAS). However, the genetic polymorphisms of this system have not been widely studied in Iranian patients diagnosed with CAD. The aim of this study was to assess the relationship between six gene polymorphisms of RAS components and CAD in a sample of Iranian population. A total of 374 participants were enrolled in a case/control study. The presence of CAD was determined by coronary angiography. Genotyping of six RAS gene polymorphisms was performed using a modified PCR-RFLP method. Our results revealed, for the first time, a significant independent association of angiotensin-converting enzyme (ACE) A-240T polymorphism and incidence of CAD among Iranian women (P=0.005, OR=20.4, 95% CI=2.49-41.2). There has also been a significant difference in genotype distribution of ACE A-240T (P=0.008) and angiotensin II receptor type 2 C3123A polymorphism (P=0.032) in Iranian female participants. In conclusion, TT genotype of ACE A-240T seems to be a genetic risk factor for CAD in Iranian women. PMID- 23661021 TI - MMP-2 -1306C>T polymorphism in breast cancer: a case-control study in a South European population. AB - This case control study aims to investigate the role of MMP-2 -1306C>T polymorphism as a potential risk factor and possible prognostic marker for breast cancer in a South European population. 113 consecutive incident cases of histologically confirmed ductal breast cancer and 124 healthy controls were recruited. MMP-2 -1306C>T polymorphism was genotyped; multivariate logistic regression as well as Cox regression analysis were performed. MMP-2 -1306C>T status was not associated with breast cancer risk either at the total sample or at the subanalyses on premenopausal and postmenopausal women. At the survival analysis, a trend towards a favorable association between MMP-2 -1306C>T allele and disease-free survival as well as overall survival was observed. Regarding subanalyses on ER-negative and ER-positive cases, the favorable association implicating MMP-2 -1306C>T allele was particularly evident among ER-positive cases; no significant associations emerged among ER-negative cases. MMP-2 1306C>T polymorphism does not seem to be a risk factor for breast cancer in South European population; however, a trend towards a favorable association with survival has been observed. PMID- 23661022 TI - The (TTTA)n polymorphism in intron 4 of CYP19 and the polycystic ovary syndrome risk in a Chinese population. AB - Polycystic ovary syndrome (PCOS) is a heterogeneous disease with a strong genetic origin, but the specific determinants are still unknown. The aim of this study was to investigate the association between the (TTTA) n polymorphism in intron 4 of CYP19 and the PCOS risk in a Chinese population. We performed a case-control study which involved 222 PCOS patients and 281 controls. The fluorescent-labeled target DNA fragments containing the (TTTA)n short tandem repeats were obtained by PCR, thereafter genotyped via capillary electrophoresis. Representative alleles were directly sequenced to confirm their repeat numbers. Genotype analysis revealed seven different alleles including 7-3(?)-, 7-, 8-, 10-, 11-, 12- and 13 TTTA-repeats. The most common allele in a Chinese population is (TTTA) 11 in our study (0.354 for PCOS and 0.390 for controls). PCOS patients showed a higher frequency of short alleles compared with controls (0.47 vs. 0.41, OR=1.245, 95% CI 0.97-1.60). The overall allelic distributions of this polymorphism did not show any significant differences between PCOS patients and the control group. No statistical differences were found in the clinical parameters or serum steroid hormone levels among PCOS patients with different genotypes. In conclusion, PCOS patients had a higher frequency of short alleles, albeit this might not strongly affect the risk of PCOS. PMID- 23661024 TI - Effects of a single nucleotide polymorphism in the leptin gene on the productive traits of dairy buffaloes (Bubalus bubalis). AB - The gene responsible for coding the leptin hormone has been associated with productive and reproductive traits in cattle. In dairy cattle, different polymorphisms found in the leptin gene have been associated with several traits of economic interest, such as energy balance, milk yield and composition, live weight, fertility and dry matter consumption. The aim of this study was to detect genetic variability in the leptin gene of buffaloes and to test possible associations with milk yield, fat and protein percentages, age at first calving and first calving interval. Three genotypes (AA, AG and GG) were identified by polymerase chain reaction-restriction fragment length polymorphism, which presented genotypic frequencies of 0.30, 0.54 and 0.16, respectively. The allele frequencies were 0.57 for the A allele and 0.43 for the G allele. No significant effects were found in the present study, but there is an indicative that leptin gene affects lipid metabolism. PMID- 23661023 TI - Functional divergence and catalytic properties of dehydroascorbate reductase family proteins from Populus tomentosa. AB - Dehydroascorbate reductase (DHAR) is a key enzyme in the ascorbate-glutathione cycle that maintains reduced pools of ascorbic acid and serves as an important antioxidant. In this study, to investigate functional divergence of plant DHAR family and catalytic characteristics of the glutathione binding site (G-site) residues of DHAR proteins, we cloned three DHAR genes (PtoDHAR1/2/3) from Populus tomentosa and predicted the G-site residues. PtoDHAR1 protein was localized in chloroplast, while PtoDHAR2/3 proteins showed cytosolic localizations. Three DHAR proteins showed different enzymatic activities, apparent kinetic characteristics, optimum T m and pH profiles, indicating their functional divergence. Cys20, Lys8, Pro61, Asp72 and Ser73 of PtoDHAR2 were predicted as G-site residues based on their N-terminal amino acid sequence identity and the available crystal structures of glutathione S-transferases. The biochemical functions of these residues are examined in this study through site-directed mutagenesis. The aforementioned five residues are critical components of active sites that contribute to the enzyme's catalytic activity. Cys20, Pro61 and Asp72 of PtoDHAR2 are also responsible for maintaining proper protein structure. This study provides new insights into the functional divergence of the plant DHAR family and biochemical properties of the G-site residues in plant DHAR proteins. PMID- 23661025 TI - Helicobacter pylori infection and antioxidants can modulate the genotoxic effects of heterocyclic amines in gastric mucosa cells. AB - Helicobacter pylori (H. pylori) infection plays an important role in gastric carcinogenesis. This bacterium may induce cancer transformation and change the susceptibility of gastric mucosa cells to various exogenous dietary irritants. The aim of the study was to evaluate the influence of H. pylori infection on the reaction of the stomach cells to a genotoxic effect of heterocyclic amines (HCAs). These well-known mutagens are formed during cooking of protein-rich foods, primarily meat. Taking into account that persons consuming a mixed-western diet are exposed to these compound nearly an entire lifetime and more than half of human population is infected with H. pylori, it is important to assess the combined effect of H. pylori infection and HCAs in the context of DNA damage in gastric mucosa cells, which is a prerequisite to cancer transformation. We employed 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethyl imidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5 b]pyridine (PhIP) because these substances are present in a great amount in cooked and fried meat. Using alkaline comet assay, we showed that the extent of the DNA damage induced by HCAs was significantly higher in H. pylori infected gastric mucosa cells than in non-infected counterparts. We did not observed any difference in the efficiency of repair of DNA lesions induced by HCAs in both type of cells. Vitamin C reduced the genotoxic effects of HCAs in H. pylori infected and non-infected gastric mucosa cells. Melatonin more effectively decreased DNA damage caused by HCAs in H. pylori infected gastric mucosa cells as compared with control. Our results suggest that H. pylori infection may influence the susceptibility of gastric mucosa cells to HCAs and dietary antioxidative substances, including vitamin C and melatonin may inhibit the genotoxic effects of HCAs on gastric mucosa cells and may reduce the risk of carcinogenesis caused by food borne mutagens and H. pylori infection. PMID- 23661026 TI - Overexpression of Smad7 suppressed ROS/MMP9-dependent collagen synthesis through regulation of heme oxygenase-1. AB - We previously reported that AngiotensinII receptor blocker effectively inhibited TGF-beta1-mediated epithelial-to-mesenchymal transition progress through regulating Smad7. However, the underlying mechanism by which Smad7 exerted in regulating MMP9 and fibrogenic response has not been fully elucidated. In the current study, we proved that NADPH p47(phox)-dependent reactive oxygen species (ROS) production contributed to MMP9 activation and collagen expression, which was suppressed by transfecting pcDNA3-Smad7 in cardiac fibroblasts. The effect of Smad7 overexpression on MMP9 activity and collagen expression was further reversed by adding H2O2 (10 MUmol/L). In contrast, knockdown of Smad7 caused the enhanced collagen synthesis in cardiac fibroblasts, which was also reversed by treating cells with a ROS inhibitor, YCG063 (2 MUmol/L). Further investigation showed that Smad7 regulated NADPH-mediated ROS production through activating Heme oxygenase-1 (HO-1). Meanwhile, the intercellular level of bilirubin (product of hemin) and nitric oxide (NO) in cell supernatant were not significantly increased in cells treated with AngII or transfected with Smad7. Knockdown of HO-1 in Smad7 overexpressed cardiac fibroblasts or cells pretreated with SnPP IX, a competitive inhibitor of HO-1 activity, resulted in increased productions of ROS and NADPH p47(phox), and abolished the inhibitory effects of Smad7 on MMP9 activity and collagen expression. Our results indicated that HO-1 might be critically involved in Smad7-mediated regulation of MMP9 activity and fibrogenic genes expression via antagonizing the enhanced myocardial oxidative stress. PMID- 23661027 TI - Antigenically intact hemagglutinin in circulating avian and swine influenza viruses and potential for H3N2 pandemic. AB - The 2009 swine-origin H1N1 influenza, though antigenically novel to the population at the time, was antigenically similar to the 1918 H1N1 pandemic influenza, and consequently was considered to be "archived" in the swine species before reemerging in humans. Given that the H3N2 is another subtype that currently circulates in the human population and is high on WHO pandemic preparedness list, we assessed the likelihood of reemergence of H3N2 from a non human host. Using HA sequence features relevant to immune recognition, receptor binding and transmission we have identified several recent H3 strains in avian and swine that present hallmarks of a reemerging virus. IgG polyclonal raised in rabbit with recent seasonal vaccine H3 fail to recognize these swine H3 strains suggesting that existing vaccines may not be effective in protecting against these strains. Vaccine strategies can mitigate risks associated with a potential H3N2 pandemic in humans. PMID- 23661028 TI - A novel feeding behaviour in wild redfronted lemurs (Eulemur rufifrons): depletion of spider nests. AB - Reports on behavioural innovations in wild primate populations as well as on their transmission are rare. Here, we report observations suggesting that redfronted lemurs (Eulemur rufifrons) invent new behaviours in the wild. We observed a novel feeding behaviour in redfronted lemurs in Kirindy Forest, western Madagascar. The feeding behaviour consisted of depletion of nests of a social spider species (Stegodyphus sp.). The behaviour was observed in only one out of four study groups, although spider nests were present in the home ranges of all four groups. The behaviour was exhibited in three different years (2009, 2011, 2012) and appears to be re-invented from time to time. Interestingly, in 2011 this behaviour was shown by four individuals and probably spread within the group. This feeding behaviour has only been observed between the middle of June and early August (i.e. the early dry season), and nests were found to be empty later on, suggesting that these nests are available as a food source only seasonally. Our observation contributes a rare case of behavioural innovations in a wild primate population. PMID- 23661029 TI - Primate abundance and habitat preferences on the lower Urubamba and Tambo rivers, central-eastern Peruvian Amazonia. AB - We report information on population density, group size, and habitat preferences of primates along the lower Rio Urubamba and in the Rio Urubamba-Rio Tambo interfluvium, in central-eastern Peruvian Amazonia, an area that has been little explored with regard to its primate fauna. During 425 km of transect walks in October-November 2008 and April-May 2009 totally 174 groups of nine primate species were encountered, the most common being Callicebus brunneus (45 groups), Saguinus imperator (41 groups), and Aotus nigriceps (26 groups). Group sizes were smallest for A. nigriceps and C. brunneus (mean of 2.8 and 2.9, respectively) and largest for Saimiri boliviensis (mean 15.6). Population densities were lowest for Lagothrix cana (3.3 individuals/km(2)) and highest for A. nigriceps (31.1 individuals/km(2)). Groups of C. brunneus, S. imperator, S. boliviensis, Cebus albifrons, and Cebus apella were most frequently (83 % of sightings) encountered in semi-dense or in open primary forest that included stands of bamboo (Guadua sarcocarpa) or where bamboo was a very common species. PMID- 23661030 TI - Sperm exposure during menses is a risk factor for developing antisperm antibody (ASA) in female. AB - PURPOSE: Intercourse during menses is a sexual behavior practiced by 3-30 % of sexually active women. Defense responses of mucosal immunity in the female genital tract regulated by sex hormones would be impaired during menses. The present study seeks to clarify whether unprotected sexual activity during menses will increase the risk for antisperm antibody (ASA) production in female. METHODS: In this prospective study, 27 women who had a usual practice of vaginal intercourse during menses admitted in the First Affiliated Hospital of Jinan University with infertility were included, while 30 age-matched infertile women without this practice were set as controls. Indirect immunobead test (I-IBT) performed according to the World Health Organization (WHO) manual was used to measure the ASA levels. RESULTS: No case was revealed to develop significant ASA level. 6 of 27 women (22.2 %) in the case group and 1 of 30 women (3.3 %) in the control group were detected to be ASA subpositive, and a significant difference was found in the subpositive incidence between these two groups (P < 0.05). Among these 6 subpositive cases, 3 became pregnant in the subsequent 2-year follow-up after condom therapy for 6 months. CONCLUSIONS: Sperm exposure during menses is a risk factor for ASA production in female. Although a precisely causal linkage between ASA and infertility in these women cannot be drawn from the present data, the potential disadvantages of sexual activity during menses should still be given importance. PMID- 23661031 TI - Semaphorin 5A promotes gastric cancer invasion/metastasis via urokinase-type plasminogen activator/phosphoinositide 3-kinase/protein kinase B. AB - BACKGROUND: Semaphorin 5A, a member of the semaphorin family, was originally identified as an axonal guidance factor functioning during neuronal development. Previously, we showed that the expression of semaphorin 5A might contribute to the metastasis of gastric cancer. However, less information is currently available as to the involvement of uPA in the semaphorin 5A-induced metastasis and invasion of gastric cancer cells. AIM: The present study was designed to test whether semaphorin 5A mediates the invasion and metastasis of gastric cancer via PI3K/Akt/uPA signaling. METHODS: The semaphorin 5A-overexpressing cell was established from the gastric cancer cell line AGS. The effect of semaphorin 5A on the expression of uPA was evaluated by ELISA and Western blotting as well as RT PCR assays, respectively. Synthetic or natural inhibitors and dominant-negative mutants were used to determine the hierarchical relationship between semaphorin 5A, PI3K/Akt and uPA in the invasion and metastasis of gastric cancer. RESULTS: Overpression of semaphorin 5A enhanced the expression of uPA, and synthetic or natural inhibitors of uPA abolished semaphorin 5A-induced cell migration and invasion. Semaphorin 5A overexpression promoted the phosphorylation of Akt. Blocking effects of PI3K/Akt using pharmacologic inhibitors, dominant-negative mutants abolished the ability of semaphorin 5A to induce uPA expression and cell invasion and migration. CONCLUSION: Semaphorin 5A could promote invasion and metastasis of gastric cancer through the PI3K/Akt/uPA signal transduction pathway. Semaphorin 5A and its regulated molecules could be the potential targets for cancer therapy. PMID- 23661032 TI - Puerarin-induced immune hemolytic anemia. AB - Drug-induced immune hemolytic anemia (DIIHA) is a relatively uncommon condition characterized by a sudden drop in hemoglobin, putatively following exposure to drugs. Severe forms of hemolysis characterized by rapidly falling hemoglobin levels and hemoglobinuria are extremely rare. Here we report the case of a patient who exhibited severe DIIHA due to puerarin. Direct antiglobulin testing and drug-dependent antibody testing indicated that the antibodies were drug dependent and reacted only with RBCs in the presence of the drug. Puerarin is the major isoflavonoid derived from the Chinese medical herb Radix puerariae, and has not yet been widely reported as associated with DIIHA. These results suggest that puerarin may be a cause of severe hemolysis and should be used with caution. PMID- 23661033 TI - IgM anti-recipient ABO antibodies predict acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. AB - Passenger lymphocyte syndrome (PLS) presents as transient immune hemolysis due to anti-recipient ABO antibodies produced by donor B-lymphocytes accompanying minor or bidirectional ABO incompatible allogeneic hematopoietic stem cell transplantation (HSCT). We monitored both IgM and IgG type anti-recipient ABO antibodies in 18 consecutive HSCT recipients with hematological malignancies. Five of these patients (28%) developed transient immune hemolysis due to PLS after a median of 19 days post-HSCT. This response was associated with the detection of IgM and IgG anti-recipient ABO antibodies after a median of 16 and 22 days post-HSCT, respectively. All five patients subsequently developed acute graft-versus-host disease (GVHD) grades II-IV, and three died due to transplant related mortality (TRM) within 1 year after HSCT, while in contrast, of the 13 patients without PLS, three (23%) developed grades II-IV acute GVHD (p < 0.01) and the 1-year TRM was 8% (p = 0.03). Thus, patients with PLS had a significantly lower 1-year overall survival than those without PLS (20 vs. 75%, p = 0.03). These findings suggest that the IgM anti-recipient ABO antibody may be an early predictor of acute GVHD and poor survival after minor or bidirectional ABO incompatible HSCT. PMID- 23661034 TI - An anatomic consideration of C2 vertebrae artery groove variation for individual screw implantation in axis. AB - STUDY DESIGN: Retrospective case series. OBJECTIVES: To identify the variation of C2 vertebral artery groove (VAG) based on the thin-slice computed tomography (CT) scan and choose an individual screw placement method to decrease risk of malposition. BACKGROUND: C2 pedicle screws can be successful anchors for a variety of cervical disorders. However, variations of VAG may cause malposition and breach when C2 transpedicle screw was inserted. Recognizing the variations of vertebrae artery groove (VAG) in C2 and choosing an individual screw placement method (transpedicle or translaminar) may be helpful for avoiding violation and decreasing the operation risk in upper cervical surgery. METHODS: From January 2009 to December 2010, a total 45 patients with upper cervical disorders underwent 1-mm-thin-slice CT scans along the C2 pedicle direction to obtain the consecutive spectrum of C2 VAG were included in this study. The C2 VAG (types I, II, III, and IV) was subgrouped based on parameter e (the vertical distance from the apex of VAG to the upper facet joint surface) and parameter a (horizontal distance from the entrance of VAG to the vertebrae canal). Subsequently, individual strategy was used to avoid the VAG violation. RESULTS: The variations of C2 VAG in these 45 patients include the following: type I 53 (58.9%), type II 16 (17.8%) type III 13 (14.4%), and type IV 8 (8.9%). Transpedicle screws of C2 were used in types I, III, and IV VAGs (n = 74); translaminar screws were inserted in type II subgroup (n = 16). Postoperative CT scans showed that there were two pedicle screws violated into the artery groove, and no translaminar screw breached into the vertebrae canal. All the other screws were in right position. None of the 45 patients had severe complications such as spinal cord injury, dura tear, and infection. CONCLUSION: Thin-slice CT scan along the C2 pedicle direction to analysis the variations of C2 VAG can help choose an individual screw placement method (transpedicle or translaminar) with minimal complication for C2 screw fixation. PMID- 23661035 TI - How do low back pain patients conceptualize their expectations regarding treatment? Content analysis of interviews. AB - PURPOSE: The purpose of this study was to gain insight into how low back pain (LBP) patients conceptualize the construct of expectations regarding treatment. METHODS: This study was nested within a mixed-method randomized clinical trial comparing three primary care interventions for LBP. A total of 77 participants with LBP lasting longer than 6 weeks were included; semi-structured interviews were conducted querying patients about their expectations for treatment. Also factors influencing their expectations were explored. Interviews were administered following enrollment into the study, but prior to study treatment. Two researchers independently conducted a content analysis using NVIVO 9 software. RESULTS: LBP patients' expectations could be categorized in two main domains: outcome and process expectations, each with subdomains. Patients expressed expectations in all subdomains both as values (what they hoped) and probabilities (what they thought was likely). In multiple subdomains, there were differences in the nature (positive vs. negative) and frequency of value and probability expectations. Participants reported that multiple factors influenced their expectations of which past experience with treatment appeared to be of major influence on probability expectations. CONCLUSION AND RECOMMENDATIONS: This study showed that LBP patients' expectations for treatment are multifaceted. Current measurement instruments do not cover all domains and subdomains of expectations. Therefore, we recommend the development of new or improved measures that make a distinction between value and probability expectations and assess process and/or outcome expectations covering multiple subdomains. Some of the influencing factors found in this study may be useful targets for altering patients' treatment expectations and improving health outcomes. PMID- 23661037 TI - Heartsink hotel, or "Oh no, look who's on my schedule this afternoon!". PMID- 23661038 TI - Bedside rounding strategies used by bedside teachers. PMID- 23661039 TI - Synthesis and structures of hypervalent organoantimony and organobismuth chlorides containing asymmetric C,E,C-chelating (E = O, S) ligands. AB - Two asymmetric tridentate C,E,C-chelating ligand precursors, 1-Br-2-[(2' BrC6H4CH2E)CH2]C10H6 (E = O (1), E = S (2), were prepared in good yield. Lithiation of the two precursors was achieved by a reaction with n-BuLi, and was followed by treatment with SbCl3 or BiCl3 in a 1: 1molar ratio to give four air stable hypervalent organoantimony and organobismuth chlorides with an asymmetric C,E,C-chelating ligand (E = O, S), i.e. (C6H4CH2OCH2C10H6)SbCl (3), (C6H4CH2SCH2C10H6)SbCl (4), (C6H4CH2OCH2C10H6)BiCl (5) and (C6H4CH2SCH2C10H6)BiCl (6). These compounds were characterized by NMR spectroscopy, elemental analysis and melting point determination. X-ray structure analysis of compounds 3-6 revealed that the donor atoms (O, S) are strongly coordinated to the metal atoms (Sb, Bi). Compounds 3-6 exhibit chirality and crystallize as racemic mixtures. PMID- 23661040 TI - Genome-wide scan on total serum IgE levels identifies no common variants in a healthy Chinese male population. AB - Immunoglobulin E (IgE) provides important information on the humoral immune status, and the IgE level is routinely detected in clinical practice. There are many diseases associated with IgE, such as atopic disease, autoimmune diseases, and so on. IgE is a genetically complex trait, but comprehensive genetic assessment of the variability in serum IgE levels is lacking. Previous genome wide association studies (GWAS) on total serum IgE levels have identified FCER1A as the susceptibility locus; however, the candidate gene association study in southern Chinese patients reported no association. Given the genetic difference in different populations, we firstly conducted this two-stage GWAS in a Chinese population of 3,495 men, including 1,999 unrelated subjects in the first stage and 1,496 independent individuals replicated in the second stage. In the first stage, we totally identified three single nucleotide polymorphisms (SNPs) which reached a P value of 1.0 * 10-5. Rs17090302 on chromosome 3 and Rs28708846 on chromosome 13 are intergenic. Rs432085 from chromosome 3p28 is located in the gene CCDC50. When the two-stage data was combined, none of the SNPs reached the genome-wide significant level. Collectively, we did not identify novel loci associated with the serum IgE level in Chinese males, but we hypothesized that CCDC50 was a candidate gene in regulation on IgE level. PMID- 23661041 TI - An eye on the future of inflammasomes and drug development in AMD. AB - Age-related macular degeneration (AMD) is the leading cause of central vision loss worldwide. While activation of the immune system has been implicated in disease progression, the pathways involved remain relatively unclear. Typically, inflammatory responses are caused as a result of pathogenic infection. However, in chronic conditions, like AMD, a form of 'sterile' inflammation can exist in localised areas of the body in response to modified host-derived elements and particulate matter accumulation, due to the activation of a complex termed the 'inflammasome'. Inflammasomes control the activity of two major pro-inflammatory cytokines, namely, interleukin (IL)-1beta and IL-18, by allowing for their cleavage from inactive pro-forms into mature cytokines. The major pathological hallmark common to both 'dry' and 'wet' AMD is the presence of extracellular deposits, known as drusen, below the retinal pigment epithelium in the macula of the eye. Past studies have shown that host-derived particulate matter such as amyloid deposits and atherosclerotic plaques can be 'sensed' by the NLRP3 inflammasome causing cleavage of pro-IL-1beta and pro-IL-18. We have recently reported that the NLRP3-inflammasome can also 'sense' drusen isolated from human AMD donor eyes and that IL-18 protects against the development of choroidal neovascularisation in a model that mimics 'wet' AMD. In fact, since then, a number of studies have reported roles for the NLRP3-inflammasome in AMD. This review will focus on describing, comparing and contrasting these reports and analyzing the potential for manipulating the NLRP3-inflammasome as a therapy for AMD. PMID- 23661044 TI - Role of subconjunctival bevacizumab as an adjuvant to primary trabeculectomy: a prospective randomized comparative 1-year follow-up study. AB - PURPOSE: To compare the safety and efficacy of primary trabeculectomy with adjunctive subconjunctival bevacizumab with that of primary trabeculectomy with mitomycin C (MMC). MATERIALS AND METHODS: Forty-two patients with primary open angle glaucoma were studied. Randomly, subject's eyes underwent primary trabeculectomy with either subconjunctival bevacizumab (2.5 mg/0.1 mL) or topical MMC (0.2 mg/mL for 3 min). The intraocular pressure (IOP) was the primary outcome measure. Secondary outcome measures included the corrected distance visual acuity, number of antiglaucoma medications, postoperative interventions and complications, bleb evaluation (on the basis of Moorfields Bleb Grading System), and the percentage of eyes achieving target pressure of 21, 18, 15, and 12 mm Hg at 6 and 12 months postoperatively. RESULTS: Of the 42 eyes, 21 treated with subconjunctival bevacizumab while 21 were treated with MMC. The mean preoperative IOP in the bevacizumab group improved from 23.9 +/- 2.7 mm Hg with 2.6 +/- 0.7 antiglaucoma medications to 13.9 +/- 2.8 mm Hg with 0.6 +/- 0.9 antiglaucoma medications at 12 months (P<0.001 and P<0.001, respectively). The mean preoperative IOP in MMC group improved from 22.9 +/- 2.6 mm Hg with 2.7 +/- 0.8 antiglaucoma medications to 12.2 +/- 3.2 mm Hg with 0.1 +/- 0.5 antiglaucoma medications at 12 months (P<0.001 and P<0.001, respectively). At 12 months, 15 of 21 (71%) eyes in the MMC group met a target IOP of 12 mm Hg without antiglaucoma medication while 7 of 21 (33%) eyes in the bevacizumab group did (P=0.02). Encapsulated bleb was seen in 2 (10%) patients in MMC group and in 6 (29%) patients in bevacizumab group (P=0.23). CONCLUSIONS: Although subconjunctival bevacizumab is effective and safe in primary trabeculectomy, IOP control appears to be superior with MMC, in terms of complete success with a target IOP<12 mm Hg and number of antiglaucoma medications required postoperatively. PMID- 23661042 TI - Inhibitors of C5 complement enhance vaccinia virus oncolysis. AB - Genetically engineered tumor-selective vaccinia virus (VV) has been demonstrated to be a highly effective oncolytic agent, but immune clearance may limit its therapeutic potential. As previously demonstrated, immunosuppression can lead to significant enhancement of viral recovery and therapeutic effect, but the magnitude of complement-mediated viral inactivation has not been fully elucidated and warrants further investigation. Using fluorescent microscopy and quantitative plaque assays, we have determined complement's key role in viral clearance and its multi-faceted means to pathogen destruction. Complement can lead to direct viral destruction and inhibition of viral uptake into cells, even in the absence of anti-vaccinia antibodies. Our data demonstrate C5 to be integral to the clearance pathway, and its inhibition by Staphylococcal superantigen-like protein leads to a 90-fold and 150-fold enhancement of VV infectivity in both the presence and absence of anti-VV antibodies, respectively. This study suggests that complement inhibition may reduce vaccinia viral neutralization and may be critical to future in vivo work. PMID- 23661043 TI - Idebenone prevents human optic nerve head astrocytes from oxidative stress, apoptosis, and senescence by stabilizing BAX/Bcl-2 ratio. AB - PURPOSE: Oxidative stress plays an important role in the pathogenesis of several neurodegenerative diseases including glaucoma. Astrocytes are supposed to play a role in glaucoma pathogenesis. This study investigates the antiapoptotic and cytoprotective effects of idebenone on optic nerve head astrocytes (ONHA) under oxidative stress. METHODS: ONHA were treated with 1 to 150 uM idebenone. Cell viability (MTT assay and live-dead assay), induction of intracellular reactive oxygen species, senescence-associated beta-galactosidase activity were investigated. In addition, apoptosis (detection of histone-associated DNA fragmentation), and expression of BAX and Bcl-2, and their mRNA were determined after 48 hours and after hydrogen peroxide (H2O2) treatment. RESULTS: Idebenone concentrations from 1 to 50 uM showed no effects on ONHA viability. Pretreatment with 10 uM idebenone led to an increase in viability of ONHA after H2O2 treatment. In addition, idebenone pretreatment significantly attenuated the increase of histone-associated DNA fragmentation, induction of senescence associated beta-galactosidase, and intracellular reactive oxygen species after treatment with H2O2. When ONHA cells were treated with idebenone and H2O2, real time polymerase chain reaction and Western blot analysis yielded an increased expression of Bcl-2 and a decrease of BAX compared with those cells that were treated with H2O2 only. CONCLUSIONS: Idebenone reduced senescence, oxidative stress, and apoptotic cell death in cultured ONHA in vitro. Our results suggest that idebenone may help to protect ONHA in vivo, and therefore might be helpful in preventing the progression of glaucomatous degeneration. PMID- 23661045 TI - Illuminated microcatheter-facilitated 360-degree trabeculotomy for refractory aphakic and juvenile open-angle glaucoma. AB - BACKGROUND: Aphakic and juvenile open-angle glaucoma (JOAG) cases often prove to be challenging to manage, frequently requiring surgical intervention. Angle surgery has some reported success in these cases. PURPOSE: The purpose of this study was to evaluate 360-degree trabeculotomy, facilitated by iTrack, for refractory aphakic glaucoma and JOAG. PATIENTS AND METHODS: This study was conducted to evaluate the success and complication rates of illuminated microcatheter-assisted 360-degree trabeculotomy for aphakic glaucoma and JOAG (2 surgeons/2 sites, 2008 to 2011). The success of this surgery was defined as intraocular pressure <=22 mm Hg with >30% reduction, without disease progression, oral glaucoma medications, or additional glaucoma surgery. One eye per subject was analyzed. All had gonioscopically open angles preoperatively. RESULTS: A total of 23 eyes status post iTrack-facilitated 360-degree trabeculotomy, 13 aphakic glaucoma cases (mean age 3.1 y at surgery), and 10 JOAG cases (mean age, 18.6 y) were included in the study. Complete cannulation/opening of the Schlemm canal occurred intraoperatively in 8 aphakic and in all JOAG cases. Success rates achieved at last follow-up were as follows: 8/13 (62%) aphakic glaucoma cases and 9/10 (90%) JOAG cases. Preoperative versus final intraocular pressure decreased for all surgically successful eyes (35.5+/-3.9 vs. 17.3+/-4.6 mm Hg for aphakic glaucoma, P<0.0001, after mean 30 mo and 30.7+/-7.4 vs. 13.4+/-2.8 mm Hg for JOAG, P=0.0001, after mean 10 mo). All trabeculotomy failures (n=5) occurred within 5 months. Complications included vitreous hemorrhage (2 aphakic eyes) and transient choroidal effusion (1 aphakic eye). CONCLUSIONS: iTrack-facilitated 360 degree trabeculotomy shows early promise for initial surgical treatment of medically refractory aphakic glaucoma and JOAG, with few complications and without affecting future surgical options. PMID- 23661046 TI - Correlation of macular thickness with visual fields in glaucoma patients and suspects. AB - PURPOSE: To provide a quantitative comparison of the retinal thickness in the macula, with Humphrey visual field (HVF) parameters and circumpapillary retinal nerve fiber layer (RNFL) defects, in glaucoma patients and suspects. PATIENTS AND METHODS: Retrospective statistical analysis of spectral domain optical coherence tomography (SD-OCT) compared with HVF mean deviation (MD) and pattern standard deviation (PSD) in 73 subjects who met the study criteria. Bivariate statistical analysis was performed. RESULTS: Macular thickness correlates with HVF deficits, with much worse MD (-6.8) and PSD (5.8) scores in subjects with average macular thickness <270 MUm, compared with those >300 MUm, (MD +0.4, PSD 1.7). Both the MD (P=0.0001) and PSD (P<0.0001) correlated with average macular thickness. In subjects with a difference of 3 or greater in the MD between the 2 eyes, there was a difference of 11 to 13 MUm in average macular thickness. Asymmetry within the same eye, between the superior macula and inferior macula, correlated with a larger PSD in that eye. There was a strong correlation between RNFL defects and retinal thinning in the macula. CONCLUSIONS: SD-OCT measurements of retinal thickness in the macula correlate with HVF parameters and RNFL parameters in glaucoma patients and suspects. This correlation between visual field defects and macular thickness can help in confirming the existence and extent of the visual field defect. PMID- 23661047 TI - Late acute myopia syndrome induced by combination of sulfonamide drugs. AB - We present a case of late acute myopia syndrome following discontinuation of treatment with a combination of sulphonamide drugs. To the best of our knowledge, this is the first reported case with such a presentation, and suggests that the pathophysiological basis for the acute myopia syndrome is a rapid decrease in serum carbonic anhydrase inhibitors levels which may lead to a rebound increase in the production of aqueous humor and accumulation of suprachoroidal fluid. It is further postulated that there may be a cumulative effect of sulphonamide drug use on carbonic anhydrase activity in the ciliary body epithelium of susceptible individuals. PMID- 23661048 TI - Lower limits of intraocular pressure in glaucoma clinical trials. AB - PURPOSE: To determine the association of the lower limit of intraocular pressure (IOP) specified in the inclusion criteria to baseline and active treatment visit IOPs for monotherapy treatments. METHODS: A review of clinical trial articles evaluating currently used topical glaucoma medicines. Articles were published between January 1995 and December 2011. RESULTS: This study included 37 monotherapy treatment arms from 15 studies. There were 18 prostaglandin analogs, 8 beta-blockers, 8 carbonic anhydrase inhibitors, 2 alpha-agonists, and 1 unoprostone. For all studies included generally there was a stepwise increase in the baseline 8 AM and diurnal IOP of approximately 1 mm Hg for each 1 mm Hg increase in entry criteria. This was true for all treatment arms together, with or without a PM entry criterion (P<0.0001). However, the inclusion of an afternoon entry criterion time point did not seem to affect average IOP at baseline for the 8 AM and diurnal IOP. The treated reductions from baseline were not statistically different based on morning or afternoon entry criteria for either the 8 AM or diurnal IOPs (P>=0.07). CONCLUSIONS: Progressively higher 8 AM entry criteria IOPs at untreated baseline may influence, depending on design, in a linear manner the 8 AM and diurnal baseline IOPs of glaucoma studies at baseline. However, this effect was not observed in the treated reductions from baseline. Further, the addition of an afternoon entry criterion time point does not seem to change baseline 8 AM and diurnal IOPs. PMID- 23661050 TI - Perforation of the nasal septum as the first sign of histoplasmosis associated with AIDS and review of published literature. AB - Disseminated histoplasmosis in South America is associated with AIDS in 70-90 % of cases. It is visceral and cutaneous, compromising the oral, pharynx, and laryngeal mucous membranes. The involvement of the nasal mucosa is unusual. Two patients with perforation of the nasal septum as the only sign of their disease were clinically and histopathologically diagnosed as leishmaniasis. The revision of the biopsies and the culture of nasal discharge secretions showed that the pathogens seen were not amastigotes but Histoplasma capsulatum. Other mycotic lesions were not detected, nor there was history of cutaneous leishmaniasis. The leishmanin skin test, available only for the male patient, was negative. The PCR and immunofluorescence antibody titers for Leishmania were negative in both patients. They were HIV positive; in the male, his CD4+ T cell count was 60/mm(3) and in the female 133/mm(3). The nasal ulcer was the only manifestation of histoplasmosis and the first of AIDS in both patients. The male patient recovered with amphotericin B and itraconazole treatment. The female has improved with itraconazole. Both patients received antiretroviral treatment. Nasal mucous membrane ulcers should include histoplasmosis among the differential diagnosis. In conclusion, two patients had perforation of their nasal septum as the only manifestation of histoplasmosis, a diagnosis confirmed by nasal mucosa biopsy and by culture of H. capsulatum, findings which demonstrated that both patients had AIDS. PMID- 23661051 TI - Magnetic separation of colloidal nanoparticle mixtures using a material specific peptide. AB - A material specific peptide bound to Fe2O3 facilitates the selective sequestration of Au from a colloidal mixture of Au and CdS nanoparticles; the Au Fe2O3 precipitate can then be magnetically separated from the colloidal CdS, and the Au nanoparticles can be recovered upon release from the Fe2O3. PMID- 23661049 TI - Differential adherence and expression of virulence traits by Candida albicans and Candida parapsilosis in mono- and dual-species cultures in artificial saliva. AB - AIMS: To evaluate specific virulence factors of Candida albicans and Candida parapsilosis clinical oral isolates in mono- and dual-species culture in the presence of artificial saliva. METHODS AND RESULTS: Two of the strains used in this study were isolated from co-infection (C. albicans AM and C. parapsilosis AM2), and the other two were isolated from single infection (C. albicans AC and C. parapsilosis AD). The number of adhered yeast cells was measured and their enzymatic activity was determined simultaneously. In mono-species culture, C. parapsilosis strains adhered to a higher extent to the surface in comparison with the C. albicans strains. In dual-species culture, the C. parapsilosis strains adhered more in the presence of C. albicans AM. Interestingly, C. albicans AM and C. parapsilosis AD adhered to a higher extent when compared with all other co cultures. In dual-species culture, the enzymatic activity of C. parapsilosis strains in the presence of C. albicans AC was higher than in the presence of C. albicans AM. CONCLUSIONS: The virulence factors of C. albicans and C. parapsilosis differ from strain to strain and are influenced by the presence of other species in culture. SIGNIFICANCE AND IMPACT OF THE STUDY: To understand the expression of virulence factors in Candida dual-species systems. PMID- 23661052 TI - NMR self-diffusion study of a phosphonium bis(mandelato)borate ionic liquid. AB - Newly synthesised halogen-free boron based ionic liquids (hf-BILs) composed of chelated orthoborate anions and phosphonium cations have hydrolytic stability, low melting point and outstanding wear and friction reducing properties. We report here the peculiarities of self-diffusion in one representative from this class, trihexyltetradecylphosphonium bis(mandelato)borate, [P6,6,6,14][BMB], in the temperature range of its practical interest, 20-100 degrees C. NMR techniques demonstrated complicated diffusional behaviour - the ionic liquid can exist in one or two liquid "phases". In the low-temperature range (20-50 degrees C), two phases coexist where the cations, [P6,6,6,14], are contained mainly in the phase with slower diffusion coefficients while the anions, [BMB], are in the phase with faster diffusion coefficients. Cations have lower diffusion coefficients with a factor of 20 as compared with the anions, an effect which is caused by aggregation of cations into domains due to so-called "hydrophobic interaction" of their hydrocarbon chains. As the temperature rises above 60 degrees C, the two phases merge into one where both ions have equal diffusion coefficients. This is caused by thermal motion making the cation domains smaller in size and more easily interacting with anions. As a result, anions and cations diffuse in this high-temperature range as a pair. PMID- 23661053 TI - Nonselective access of English phonology in bi-scriptal Chinese-Korean visual word recognition. AB - This study investigated the phonological processes with bilingual readers of Korean and Chinese. Three types of same-different matching between the prime and target were compared. The critical point was on whether the phonological information of English was activated automatically in a semantic judgment task involving only Korean and Chinese. The results showed that the latency of the conditions (S+P-, S-P- and S-P+) was significantly different; latencies in the S P+ condition where there is no semantic but with phonological relations were slower than in the S-P- condition where there are neither semantic nor phonological relations. The implication for phonological recoding was discussed. PMID- 23661054 TI - No evidence of continuously advanced green-up dates in the Tibetan Plateau over the last decade. PMID- 23661055 TI - Solution coating around ice particles of incipient cirrus clouds. PMID- 23661056 TI - Vaccine-induced plasma IgA specific for the C1 region of the HIV-1 envelope blocks binding and effector function of IgG. AB - Analysis of correlates of risk of infection in the RV144 HIV-1 vaccine efficacy trial demonstrated that plasma IgG against the HIV-1 envelope (Env) variable region 1 and 2 inversely correlated with risk, whereas HIV-1 Env-specific plasma IgA responses directly correlated with risk. In the secondary analysis, antibody dependent cellular cytotoxicity (ADCC) was another inverse correlate of risk, but only in the presence of low plasma IgA Env-specific antibodies. Thus, we investigated the hypothesis that IgA could attenuate the protective effect of IgG responses through competition for the same Env binding sites. We report that Env specific plasma IgA/IgG ratios are higher in infected than in uninfected vaccine recipients in RV144. Moreover, Env-specific IgA antibodies from RV144 vaccinees blocked the binding of ADCC-mediating mAb to HIV-1 Env glycoprotein 120 (gp120). An Env-specific monomeric IgA mAb isolated from an RV144 vaccinee also inhibited the ability of natural killer cells to kill HIV-1-infected CD4(+) T cells coated with RV144-induced IgG antibodies. We show that monomeric Env-specific IgA, as part of postvaccination polyclonal antibody response, may modulate vaccine induced immunity by diminishing ADCC effector function. PMID- 23661058 TI - Methanol incorporation in clathrate hydrates and the implications for oil and gas pipeline flow assurance and icy planetary bodies. AB - One of the best-known uses of methanol is as antifreeze. Methanol is used in large quantities in industrial applications to prevent methane clathrate hydrate blockages from forming in oil and gas pipelines. Methanol is also assigned a major role as antifreeze in giving icy planetary bodies (e.g., Titan) a liquid subsurface ocean and/or an atmosphere containing significant quantities of methane. In this work, we reveal a previously unverified role for methanol as a guest in clathrate hydrate cages. X-ray diffraction (XRD) and NMR experiments showed that at temperatures near 273 K, methanol is incorporated in the hydrate lattice along with other guest molecules. The amount of included methanol depends on the preparative method used. For instance, single-crystal XRD shows that at low temperatures, the methanol molecules are hydrogen-bonded in 4.4% of the small cages of tetrahydrofuran cubic structure II hydrate. At higher temperatures, NMR spectroscopy reveals a number of methanol species incorporated in hydrocarbon hydrate lattices. At temperatures characteristic of icy planetary bodies, vapor deposits of methanol, water, and methane or xenon show that the presence of methanol accelerates hydrate formation on annealing and that there is unusually complex phase behavior as revealed by powder XRD and NMR spectroscopy. The presence of cubic structure I hydrate was confirmed and a unique hydrate phase was postulated to account for the data. Molecular dynamics calculations confirmed the possibility of methanol incorporation into the hydrate lattice and show that methanol can favorably replace a number of methane guests. PMID- 23661057 TI - Viral DNA tethering domains complement replication-defective mutations in the p12 protein of MuLV Gag. AB - The p12 protein of murine leukemia virus (MuLV) group-specific antigen (Gag) is associated with the preintegration complex, and mutants of p12 (PM14) show defects in nuclear entry or retention. Here we show that p12 proteins engineered to encode peptide sequences derived from known viral tethering proteins can direct chromatin binding during the early phase of viral replication and rescue a lethal p12-PM14 mutant. Peptides studied included segments of Kaposi sarcoma herpesvirus latency-associated nuclear antigen (LANA)(1-23), human papillomavirus 8 E2, and prototype foamy virus chromatin-binding sequences. Amino acid substitutions in Kaposi sarcoma herpesvirus LANA and prototype foamy virus chromatin-binding sequences that blocked nucleosome association failed to rescue MuLV p12-PM14. Rescue by a larger LANA peptide, LANA(1-32), required second-site mutations that are predicted to reduce peptide binding affinity to chromosomes, suggesting that excessively high binding affinity interfered with Gag/p12 function. This is supported by confocal microscopy of chimeric p12-GFP fusion constructs showing the reverted proteins had weaker association to condensed mitotic chromosomes. Analysis of the integration-site selection of these chimeric viruses showed no significant change in integration profile compared with wild type MuLV, suggesting release of the tethered p12 post mitosis, before viral integration. PMID- 23661060 TI - Species richness can decrease with altitude but not with habitat diversity. PMID- 23661059 TI - Robust measurement of telomere length in single cells. AB - Measurement of telomere length currently requires a large population of cells, which masks telomere length heterogeneity in single cells, or requires FISH in metaphase arrested cells, posing technical challenges. A practical method for measuring telomere length in single cells has been lacking. We established a simple and robust approach for single-cell telomere length measurement (SCT pqPCR). We first optimized a multiplex preamplification specific for telomeres and reference genes from individual cells, such that the amplicon provides a consistent ratio (T/R) of telomeres (T) to the reference genes (R) by quantitative PCR (qPCR). The average T/R ratio of multiple single cells corresponded closely to that of a given cell population measured by regular qPCR, and correlated with those of telomere restriction fragments (TRF) and quantitative FISH measurements. Furthermore, SCT-pqPCR detected the telomere length for quiescent cells that are inaccessible by quantitative FISH. The reliability of SCT-pqPCR also was confirmed using sister cells from two cell embryos. Telomere length heterogeneity was identified by SCT-pqPCR among cells of various human and mouse cell types. We found that the T/R values of human fibroblasts at later passages and from old donors were lower and more heterogeneous than those of early passages and from young donors, that cancer cell lines show heterogeneous telomere lengths, that human oocytes and polar bodies have nearly identical telomere lengths, and that the telomere lengths progressively increase from the zygote, two-cell to four-cell embryo. This method will facilitate understanding of telomere heterogeneity and its role in tumorigenesis, aging, and associated diseases. PMID- 23661063 TI - Fluorescein-guided surgery for grade IV gliomas with a dedicated filter on the surgical microscope: preliminary results in 12 cases. AB - BACKGROUND: Fluorescein is widely used as a fluorescent tracer for many applications. Its capability to accumulate in cerebral areas with blood-brain barrier damage makes it an ideal dye for intraoperative visualization of malignant gliomas (MG). We report our preliminary experience in fluorescein guided removal of grade IV gliomas using a dedicated filter on the surgical microscope. METHODS: In September 2011 we started a prospective phase II trial (FLUOGLIO) to evaluate the safety and obtain initial indications about the efficacy of fluorescein-guided surgery for MG. Patients with suspected MG amenable to complete resection of contrast-enhancing areas were eligible to participate in this study. This report is based on a preliminary analysis of the results of 12 patients with grade IV gliomas out of 15 consecutive cases (age range 48-72 years) enrolled since September 2011. Fluorescein was injected intravenously (i.v.) after intubation (5-10 mg/kg). The tumor was removed using a microsurgical technique and fluorescence visualization by BLU 400 or YELLOW 560 filters on a Pentero microscope (Carl Zeiss, Germany). The study was approved by our ethics committee and registered on the European Regulatory Authorities website (EudraCT no. 2011-002527-18). RESULTS: Histological analysis confirmed grade IV gliomas in 12/15 cases. Median preoperative tumor volume was 33.15 cm(3) (9.6-87.8 cm(3)). No adverse reaction related to the administration of fluorescein was registered. Contrast-enhanced tumor was completely removed in 75 % of the patients. CONCLUSION: This preliminary analysis suggested that the use of intravenous fluorescein during surgery on grade IV gliomas is safe and allows a high rate of complete resection of contrast-enhanced tumor at the early postoperative MRI. PMID- 23661062 TI - Trans-oral resection of large parapharyngeal space tumours. AB - The aim of this study is to describe minimally invasive trans-oral approach for resection of parapharyngeal space (PPS) tumours and to demonstrate surgical technique, resection, repair and outcomes. Five cases were prospectively included in the study. The data collected include age, sex, site, size, pathology, radiological investigations, surgical excision, complications and outcomes. Three females and two male patients underwent trans-oral resection of PPS tumours sized 4-8 cm. The pathology included two deep lobe parotid tumours, one schwannoma, one hibernoma and one primary adenocarcinoma arising form the minor salivary gland. All tumours were resected completely without any technical difficulty. The healing was quick and by primary intention. Patients resumed oral feeding on recovery from general anaesthesia and did not require any significant analgesia beyond the first 2 days. Patient with adenocarcinoma received postoperative radiotherapy and remained disease-free during 4 years post-treatment. No recurrences were observed in patients with benign tumours. No neurovascular injury occurred during surgery and no secondary bleeding was observed. We have demonstrated successful and safe execution of trans-oral resection of large PPS tumours. There were no intra and post-operative complications and there has been no recurrence during the follow-up period. In our experience, it appears to be efficient, safe and minimally invasive compared to the established techniques. PMID- 23661064 TI - The medial loop of the V2 segment of the vertebral artery and the importance of this variation in correlation with the resection safe zone and technical characteristics of spinal cages during anterior cervical approaches. PMID- 23661061 TI - Outcome after elective neck dissection and observation for the treatment of the clinically node-negative neck (cN0) in squamous cell carcinoma of the oropharynx. AB - Optimal elective neck treatment in node-negative (cN0) oropharyngeal squamous cell carcinoma (OPSCC) patients is still controversially discussed. Retrospective chart review of 49 cT1-3 cN0 cM0 OPSCC patients, who had undergone surgical resection of the primary and either elective neck dissection (END) (n = 32) or observation (OBS) (n = 17) of the neck was performed. For systematic review of literature, Pubmed and EMBASE were searched for clinical studies including data on both END and OBS of the neck in cN0 OPSCC patients. Estimated 5-year overall survival (OS) rate was 82 % for END and 76 % for OBS [hazard ratio (HR) = 1.01]. Estimated 5-year disease-free survival (DFS) rate was 78 % for END and 67 % for OBS (HR = 1.79); 5-year DSS rate was 97 % (END) and 81 % (OBS) (HR = 2.22). None of the primary outcome variables (OS, DFS, DSS) revealed statistically significant effects for the treatment assignments. Hazard ratios implied an advantage for END. Systematic review of literature yielded only retrospective chart reviews and no data meeting our selection criteria for further data analysis. Due to lack of high-level evidence, the decision for END in cN0 OPSCC remains a diagnostic and therapeutic challenge. The demonstrated clinical equipoise would provide a solid basis for a multicentric, randomized trial. PMID- 23661065 TI - An update on cobalt-chromium toxic retinopathy. PMID- 23661066 TI - No-go theorem for ground state cooling given initial system-thermal bath factorization. AB - Ground-state cooling and pure state preparation of a small object that is embedded in a thermal environment is an important challenge and a highly desirable quantum technology. This paper proves, with two different methods, that a fundamental constraint on the cooling dynamic implies that it is impossible to cool, via a unitary system-bath quantum evolution, a system that is embedded in a thermal environment down to its ground state, if the initial state is a factorized product of system and bath states. The latter is a crucial but artificial assumption included in numerous tools that treat system-bath dynamics, such as master equation approaches and Kraus operator based methods. Adopting these approaches to address ground state and even approximate ground state cooling dynamics should therefore be done with caution, considering the fundamental theorem exposed in this work. PMID- 23661067 TI - Sexual functioning after traumatic brain injury. (Preface). PMID- 23661068 TI - Sexual changes in individuals with traumatic brain injury: a control comparison. AB - BACKGROUND: Previous research has suggested that sexuality is compromised following traumatic brain injury (TBI), but there has been limited comparison with healthy samples. OBJECTIVES: The aim of the current study was to compare sexuality in individuals with TBI with that in healthy controls matched for age and gender. In doing this, the current study aimed to characterize those individuals who reported a decrease in sexuality relative to those reporting an increase according to certain demographic and injury variables. METHOD: A total of 865 participants with predominantly moderate to severe TBI and 142 controls completed the Brain Injury Questionnaire of Sexuality (BIQS), the Hospital Anxiety and Depression Scale, and the Rosenberg Self-Esteem Scale on one occasion. RESULTS: The results indicated that there was a significant difference between participants with TBI and controls on all the BIQS subscales as well as the total score. Age, depression, anxiety, and self-esteem levels significantly differentiated participants with TBI who reported decreased sexuality from those who reported increased sexuality. Participants with TBI attributed sexual changes to various causes-most commonly, fatigue, low confidence, pain, decreased mobility, and feeling unattractive. CONCLUSIONS: Further research examining the factors contributing to sexual changes is warranted. PMID- 23661069 TI - Changes in sexual functioning from 6 to 12 months following traumatic brain injury: a prospective TBI model system multicenter study. AB - OBJECTIVE: To investigate longitudinal changes in sexual functioning during the first year following moderate to severe traumatic brain injury (TBI). DESIGN: Prospective cohort study. SETTING: Community. PARTICIPANTS: 182 persons (53 women and 129 men) with moderate to severe TBI who were admitted to 1 of 6 participating TBI Model System centers and followed in the community at 6 and 12 months after injury. MAIN MEASURES: Derogatis Interview for Sexual Functioning Self-Report (DISF-SR); Global Sexual Satisfaction Index (GSSI). RESULTS: Mean T scores on the DISF-SR Arousal subscale demonstrated marginal improvement over time, with a 2.59-point increase (P = .05) from 6 to 12 months after injury. There were no significant differences over this 6-month period on the remaining DISF-SR subscales, including sexual cognition/fantasy, sexual behavior/experience, and orgasm. There was no significant change in satisfaction with sexual functioning on the GSSI from 6 months (72% satisfied) to 12 months (71% satisfied). CONCLUSIONS AND IMPLICATIONS: Sexual function and satisfaction appears to be stable in those with moderate to severe TBI from 6 to 12 months after injury, with the exception of minimal improvement in arousal. These findings, to our knowledge, reflect the first evidence regarding prospective changes in sexual functioning in this population. Future research can go far to assist clinicians in treatment planning and managing patient expectations of recovery of sexual functioning after TBI. PMID- 23661070 TI - Predictors of sexual functioning and satisfaction 1 year following traumatic brain injury: a TBI model systems multicenter study. AB - OBJECTIVE: To investigate predictors of sexual functioning 1 year following traumatic brain injury (TBI). DESIGN: Prospective cohort study. SETTING: Community. PARTICIPANTS: A total of 255 persons with TBI (187 males; 68 females) who had been treated at 1 of 6 TBI Model Systems inpatient rehabilitation units and were living in the community. MAIN MEASURES: Derogatis Interview for Sexual Functioning-Self-Report (DISF-SR); Global Satisfaction With Sexual Functioning (Global Sexual Satisfaction Index); Participation Assessment With Recombined Tools-Objective; Patient Health Questionnaire-9. RESULTS: Older age, female gender, and more severe injury were associated with greater sexual dysfunction 1 year following injury. As age increased from 24 to 49 years, the odds of sexual impairment increased more than 3-fold (95% confidence interval: 1.82-5.88). Females had a 2.5 increase in odds of sexual impairment compared with males (95% confidence interval: 1.23-5.26). Greater social participation was predictive of better sexual functioning. Dissatisfaction with sexual functioning was predicted by older age and depression. CONCLUSIONS AND IMPLICATIONS: Older persons and females appear to be at greater risk for sexual dysfunction after TBI and may benefit from specialized assessment and treatment services. Relationships were identified between social participation and sexual function and between depression and sexual satisfaction that may serve as clinical indicators for further assessment and intervention. Further research is needed to elucidate these relationships and identify effective clinical approaches. PMID- 23661071 TI - Factors associated with sexuality following traumatic brain injury. AB - BACKGROUND: Previous research has demonstrated that sexuality is compromised following traumatic brain injury (TBI). OBJECTIVES: The aim of this study was to determine the association between sexuality following TBI and demographic, injury related, and postinjury variables (age, gender, time since injury, posttraumatic amnesia duration, independence in activities of daily activities (ADL), antidepressant use, depression, and self-esteem). METHODS: Participants included 986 individuals with predominantly moderate to severe TBI, who completed the Brain Injury Questionnaire of Sexuality (BIQS), the Hospital Anxiety and Depression Scale, and the Rosenberg Self-Esteem Scale and an ADL assessment on 1 or more occasions, providing a total of 1673 assessments across 1, 2, 3, 5, 10, and 20 years postinjury. RESULTS: Being depressed, older in age, at shorter time postinjury, and less independent in ADL significantly predicted poorer overall BIQS scores as well as the Sexual Functioning subscale score. Poorer Relationship Quality and Self-esteem scores on the BIQS were predicted by older age at injury and higher levels of depression. Lower Mood score on the BIQS was associated with shorter posttraumatic amnesia duration, younger age, and higher levels of depression. Self-esteem was associated positively with sexuality outcome. CONCLUSIONS: Therapeutic interventions for sexuality need to focus on depression where indicated and self-esteem and address specific barriers to social participation and opportunities for sexual contact in individuals who are less independent in ADL. PMID- 23661072 TI - Prevalence, clinical features, and correlates of inappropriate sexual behavior after traumatic brain injury: a multicenter study. AB - OBJECTIVE: Investigate the prevalence and clinical features of inappropriate sexual behavior (ISB) among a community-based cohort of clients of the New South Wales Brain Injury Rehabilitation program. SETTING: All 11 community-based rehabilitation services of the statewide network. PARTICIPANTS: Five hundred seven clients with severe traumatic brain injury. DESIGN: Cross-sectional multicentre study. MAIN MEASURES: Overt Behavior Scale, Disability Rating Scale, Sydney Psychosocial Reintegration Scale-2, Health of the Nation Outcome Scale Acquired Brain Injury, Care and Needs Scale. RESULTS: The point prevalence rate of ISBs was 8.9% (45/507) over the previous 3 months. Inappropriate sexual talk comprised 57.9% of all ISBs, followed by genital and nongenital touching behaviors (29.8%) and exhibitionism/public masturbation (10.5%). In 43 of 45 cases, ISBs were accompanied by other challenging behaviors, most often inappropriate social behavior, and/or aggression. Individuals who sustained more severe injuries and who were younger were significantly more likely to display ISBs. People displaying ISBs were more likely to display higher levels of challenging behaviors overall, lower levels of social participation, and more neuropsychiatric sequelae than 2 other groups: people displaying no challenging behaviors and people displaying challenging behaviors but no ISBs respectively. CONCLUSIONS: ISBs pose a complex clinical challenge among a minority of individuals with severe TBI. PMID- 23661073 TI - Screening for a remote history of mild traumatic brain injury: when a good idea is bad. AB - BACKGROUND: Both the Departments of Defense and Veterans Health Administration have developed and implemented screening procedures for identification of possible deployment-related traumatic brain injury (TBI). OBJECTIVE: To review population-based screening procedures for TBI, particularly mild TBIs, and discuss potential harms/costs versus benefits of such TBI screening. METHODS: The principles commonly used in population-based screening for various medical conditions are identified. These principles are applied to screening for TBI. The potential harms and costs are compared with potential benefits of screening for mild TBI. RESULTS: The core conditions essential for beneficial medical screening progressive disease, symptoms related to the identified disease, suitable tests or examinations for accurate diagnosis, and accepted and effective treatment-are not present within the context of TBI screening. Potential harms/costs outweigh any potential benefits of population-based screening for TBI. CONCLUSION: On the basis of generally accepted medical screening principles and assumptions, population screening for mild TBI is unnecessary at best and potentially harmful at worst. Because nonspecific, postconcussion-like symptoms can be effectively treated in a symptom-specific manner, tying them to concussion through a screening and evaluation process is wasteful and potentially harmful. PMID- 23661074 TI - Department of Veterans Affairs's traumatic brain injury screening and evaluation program: promoting individualized interdisciplinary care for symptomatic veterans. PMID- 23661075 TI - Screening for TBI and persistent symptoms provides opportunities for prevention and intervention. PMID- 23661076 TI - Rehabilitation research: 30 years later; 30 years hence. PMID- 23661077 TI - Reconceptualizing brain injury rehabilitation in the future: a peek over the horizon. PMID- 23661078 TI - Fine mapping TaFLW1, a major QTL controlling flag leaf width in bread wheat (Triticum aestivum L.). AB - INTRODUCTION: Flag leaf width (FLW) is directly related to photosynthetic capacity and yield potential in wheat. In a previous study, Qflw.nau-5A controlling FLW was detected on chromosome 5A in the interval possessing Fhb5 for type I Fusarium head blight (FHB) resistance using a recombinant inbred line population derived from Nanda2419 * Wangshuibai. MATERIALS AND METHODS: Qflw.nau 5A near-isogenic line (NIL) with the background of Mianyang 99-323 and PH691 was developed and evaluated. FLW inheritance was investigated using two F2 populations developed from crossing the Qflw.nau-5A NILs with their recurrent parents. One hundred ten and 28 recombinants, which included 10 and 5 types of recombinants, were identified from 2816 F2 plants with Mianyang 99-323 background and 1277 F2 plants with PH691 background, respectively, and phenotyped in field trials for FLW and type I FHB resistance. Deletion bin mapping was applied to physically map Qflw.nau-5A. RESULTS AND CONCLUSIONS: The introduction of Wangshuibai Qflw.nau-5A allele reduced the FLW up to 3 mm. In the F2 populations, Qflw.nau-5A was inherited like a semi-dominant gene, and was therefore designated as TaFLW1. The FLW of the recombinant lines displayed a distinct two-peak distribution. Recombinants with wider leaves commonly have Mianyang 99-323 or PH691 chromatin in the 0.2 cM Xwmc492-Xwmc752 interval that resided in the 5AL12 0.35-0.57 deletion bin, and recombinants with narrow leaves were Wangshuibai genotype in this interval. Phenotypic recombination between FLW and type I FHB resistance was identified, implying TaFLW1 was in close linkage with Fhb5. These results should aid wheat breeders to break the linkage drag through marker assisted selection and assist in the map-based cloning of TaFLW1. PMID- 23661079 TI - Evaluation of linkage disequilibrium in wheat with an L1-regularized sparse Markov network. AB - Linkage disequilibrium (LD) is defined as a stochastic dependence between alleles at two or more loci. Although understanding LD is important in the study of the genetics of many species, little attention has been paid on how a covariance structure between many loci distributed across the genome should be represented. Given that biological systems at the cellular level often involve gene networks, it is appealing to evaluate LD from a network perspective, i.e., as a set of associated loci involved in a complex system. We applied a Markov network (MN) to study LD using data on 1,279 markers derived from 599 wheat inbred lines. The MN attempts to account for association between two markers, conditionally on the remaining markers in the network model. In this study, the recovery of the structure of a LD network was done through two variants of pseudo-likelihoods subject to an L1 penalty on the MN parameters. It is shown that, while the L1 regularized Markov network preserves features of a Bayesian network (BN), the nodes in the resulting networks have fewer links. The resulting sparse network, encoding conditional independencies, provides a clearer picture of association than marginal LD metrics, and a sparse graph eases interpretation markedly, since it includes a smaller number of edges than a BN. Thus, an L1-regularized sparse Markov network seems appealing for representing conditional LD with high dimensional genomic data, where variables, e.g., single nucleotide polymorphism markers, are expected to be sparsely connected. PMID- 23661081 TI - Macroautophagy--friend or foe of viral replication? PMID- 23661080 TI - Enhanced microRNA accumulation through stemloop-adjacent introns. AB - MicroRNAs (miRNAs) originate from stemloop-forming precursor RNAs found in longer primary transcripts that often contain introns. We show that in plants, those introns, when located 3' of the stemloop, can promote mature miRNA accumulation, through a mechanism that likely operates at the level of miRNA processing or stability. Reversely, when miRNA production is reduced such as in dicer-like 1 mutants, splicing of introns that promote miRNA processing is considerably increased, pointing to a tight physical and temporal coordination of intron splicing and miRNA processing in plants. Our findings further suggest that miRNA transcripts without introns generated through alternative polyA-site usage might contribute to the differential adjustment of miRNA levels, possibly at a tissue specific level. PMID- 23661082 TI - Antibacterial and photocatalytic activity of TiO2 and ZnO nanomaterials in phosphate buffer and saline solution. AB - We studied antibacterial and photocatalytic activity of anatase TiO2 and ZnO in phosphate buffer and saline solution. We found that the different anions in the suspension medium (chloride and phosphate) significantly affected the following suspension properties: the stability of nanoparticle suspension, the release of metal ions from the nanoparticles, and the production of the reactive oxygen species by the nanoparticles. As a result, antibacterial activity and photocatalytic dye degradation were also affected. However, the effect of the suspension medium was different for ZnO and TiO2. Obtained results are discussed. PMID- 23661083 TI - Efficient synthesis of D-branched-chain amino acids and their labeled compounds with stable isotopes using D-amino acid dehydrogenase. AB - D-Branched-chain amino acids (D-BCAAs) such as D-leucine, D-isoleucine, and D valine are known to be peptide antibiotic intermediates and to exhibit a variety of bioactivities. Consequently, much effort is going into achieving simple stereospecific synthesis of D-BCAAs, especially analogs labeled with stable isotopes. Up to now, however, no effective method has been reported. Here, we report the establishment of an efficient system for enantioselective synthesis of D-BCAAs and production of D-BCAAs labeled with stable isotopes. This system is based on two thermostable enzymes: D-amino acid dehydrogenase, catalyzing NADPH dependent enantioselective amination of 2-oxo acids to produce the corresponding D-amino acids, and glucose dehydrogenase, catalyzing NADPH regeneration from NADP(+) and D-glucose. After incubation with the enzymes for 2 h at 65 degrees C and pH 10.5, 2-oxo-4-methylvaleric acid was converted to D-leucine with an excellent yield (>99 %) and optical purity (>99 %). Using this system, we produced five different D-BCAAs labeled with stable isotopes: D-[1 (13)C,(15)N]leucine, D-[1-(13)C]leucine, D-[(15)N]leucine, D-[(15)N]isoleucine, and D-[(15)N]valine. The structure of each labeled D-amino acid was confirmed using time-of-flight mass spectrometry and nuclear magnetic resonance analysis. These analyses confirmed that the developed system was highly useful for production of D-BCAAs labeled with stable isotopes, making this the first reported enzymatic production of D-BCAAs labeled with stable isotopes. Our findings facilitate tracer studies investigating D-BCAAs and their derivatives. PMID- 23661084 TI - Donor substrate promiscuity of the N-acetylglucosaminyltransferase activities of Pasteurella multocida heparosan synthase 2 (PmHS2) and Escherichia coli K5 KfiA. AB - The biological activities of heparan sulfate (HS) and heparin (HP) are closely related to their molecular structures. Both Pasteurella multocida heparosan synthase 2 (PmHS2) and Escherichia coli K5 KfiA have been used for enzymatic and chemoenzymatic synthesis of HS and HP oligosaccharides and their derivatives. We show here that cloning using the pET15b vector and expressing PmHS2 as an N-His6 tagged fusion protein improve its expression level in E. coli. Investigation of the donor substrate specificity of the N-acetylglucosaminyltransferase activities of P. multocida heparosan synthase 2 (PmHS2) and E. coli K5 KfiA indicates the substrate promiscuities of PmHS2 and KfiA. Overall, both PmHS2 and KfiA can use uridine 5'-diphosphate-N-acetylglucosamine (UDP-GlcNAc) and some of its C2'- and C6'-derivatives as donor substrates for their alpha1-4-GlcNAcT activities. Nevertheless, PmHS2 has a broader tolerance towards substrate modifications. Other than the UDP-sugars that can be used by KfiA, additional C6'-derivatives of UDP-GlcNAc, UDP-glucose, and UDP-N-acetylgalactosamine (UDP-GalNAc) are tolerable substrates for the alpha1-4-GlcNAcT activity of PmHS2. The substrate promiscuities of PmHS2 and KfiA will allow efficient chemoenzymatic synthesis of diverse HS and HP oligosaccharide derivatives which may have improved or altered activities compared to their natural counterparts. PMID- 23661085 TI - Structure and magnetism of a Mn(III)-Mn(II)-Mn(II)-Mn(III) chain complex. AB - A novel tetranuclear manganese(II/III) complex with anions of pyridine-2,6 dicarboxylic acid (dipicolinic acid) has been synthesised and magneto structurally characterised. The crystal structure of [Mn(II)2Mn(III)2(dipic)6(H2O)4].2CH3OH.4H2O has been determined by single-crystal X-ray diffraction. The tetranuclear complex molecule [Mn(II)2Mn(III)2(dipic)6(H2O)4] is centrosymmetric and two manganese(II) and two manganese(III) atoms are bridged by four dipicolinate ligands. The complex molecules and uncoordinated water and methanol molecules are connected through hydrogen bonds and they form a 3D supramolecular hydrogen-bonding network. PMID- 23661086 TI - SPARC is involved in the maintenance of mitotically inactivated mouse embryonic fibroblast cells. AB - Mitotically inactivated feeder cells such as mouse embryonic fibroblast (MEFs) cells have been widely applied for physical and physiological support in the pluripotency maintenance of human pluripotent stem cells (hPSCs). However, accurate supporting mechanism or factors of feeder cells are poorly understood. Here, we isolated differentially expressed genes between wild-type MEFs and mitotically inactivated MEFs (miMEFs) by employing annealing control primer-based GeneFishing polymerase chain reaction. We identified a secreted protein acidic cysteine-rich glycoprotein (SPARC) gene that is upregulated in miMEFs. Suppression of SPARC expression in miMEFs using small interference RNA (siRNA) displayed gradual detachment of miMEFs. Furthermore, we found a significant reduction of OCT4- and SSEA3-positive hPS cell population maintained on SPARC siRNA-miMEFs compared to on miMEFs by flow cytometrical analysis. These findings suggest that SPARC plays a critical role in the maintenance of miMEFs without loss of cell number and might be a key component for supporting the culture of hPSCs. PMID- 23661087 TI - Derivation and characterization of cell cultures from the skin of the Indo Pacific humpback dolphin Sousa chinensis. AB - The marine mammalian Indo-Pacific humpback dolphin, once widely lived in waters of the Indian to western Pacific oceans, has become an endangered species. The individual number of this dolphin has significantly declined in recent decades, which raises the concern of extinction. Direct concentration on laboratorial conservation of the genetic and cell resources should be paid to this marine species. Here, we report the successful derivation of cell lines form the skin of Indo-Pacific humpback dolphin. The cell cultures displayed the characteristics of fibroblast in morphology and grew rapidly at early passages, but showed obvious growth arrest at higher passages. The karyotype of the cells consisted of 42 autosomes and sex chromosomes X and Y. The immortalized cell lines obtained by forced expression of the SV40 large T-antigen were capable of proliferation at high rate in long-term culture. Immortalization and long-term culture did not cause cytogenetically observable abnormality in the karyotype. The cell type of the primary cultures and immortalized cell lines were further characterized as fibroblasts by the specific expression of vimentin. Gene transfer experiments showed that exogenetic genes could be efficiently delivered into the cells by both plasmid transfection and lentivirus infection. The cells derived from the skin of the Indo-Pacific humpback dolphin may serve as a useful in vitro system for studies on the effects of environmental pollutants and pathogens in habitats on the dolphin animals. More importantly, because of their high proliferation rate and susceptibility to lentivirus, these cells are potential ideal materials for generation of induced pluripotent stem cells. PMID- 23661088 TI - B16/F10 tumors in aged 3D collagen in vitro simulate tumor growth and gene expression in aged mice in vivo. AB - Although the incidence of cancer rises with age, tumor growth is often slowed in older hosts. The B16/F10 melanoma cell line is commonly used in murine models of age-related tumor growth suppression. We wished to determine if the growth pattern and gene expression of B16/10 tumors grown in aged mice could be simulated in 3D collagen matrices derived from aged mice. Outcome measures were tumor size in vitro and gene expression of the key growth regulatory molecules: growth hormone receptor (GHR), IL-10Rbeta, IL-4Ralpha, and IL-6. B16/F10 tumors were grown in 20-25-mo-old C57/BL6 male mice. Tumor sizes ranged from 30 to 4,910 mg in vivo. Tumors from a subset of mice were removed after euthanasia, and equivalent amounts of each tumor were placed in aged 3D collagen and grown for 5 d. Tumor sizes in aged 3D collagen correlated highly with their original tumor size in vivo. Gene expression changes noted in vivo were also maintained during tumor growth in aged 3D collagen in vitro. The relative expression of GHR was increased, IL-10Rbeta was unchanged, and IL-4Ralpha and IL-6 were decreased in the larger tumors relative to the smaller tumors in vitro, in a pattern similar to that noted in vivo. We propose that 3D matrices from aged mice provide an in vitro model of tumor growth that correlates highly with tumor size and expression of key regulatory molecules in vivo. PMID- 23661089 TI - Genomic analysis reveals epistatic silencing of "expensive" genes in Escherichia coli K-12. AB - A barrier for horizontal gene transfer is high gene expression, which is metabolically expensive. Silencing of horizontally-acquired genes in the bacterium Escherichia coli is caused by the global transcriptional repressor H NS. The activity of H-NS is enhanced or diminished by other proteins including its homologue StpA, and Hha and YdgT. The interconnections of H-NS with these regulators and their role in silencing gene expression in E. coli are not well understood on a genomic scale. In this study, we use transcriptome sequencing to show that there is a bi-layered gene silencing system - involving the homologous H-NS and StpA - operating on horizontally-acquired genes among others. We show that H-NS-repressed genes belong to two types, termed "epistatic" and "unilateral". In the absence of H-NS, the expression of "epistatically controlled genes" is repressed by StpA, whereas that of "unilaterally controlled genes" is not. Epistatic genes show a higher tendency to be non-essential and recently acquired, when compared to unilateral genes. Epistatic genes reach much higher expression levels than unilateral genes in the absence of the silencing system. Finally, epistatic genes contain more high affinity H-NS binding motifs than unilateral genes. Therefore, both the DNA binding sites of H-NS as well as the function of StpA as a backup system might be selected for silencing highly transcribable genes. PMID- 23661090 TI - Speciation of adsorbed CO2 on metal oxides by a new 2-dimensional approach: 2D infrared inversion spectroscopy (2D IRIS). AB - A new methodology based on the inversion of adsorption isotherms obtained using infrared spectroscopy has been developed. It provides a description of coexisting surface species in terms of their individual IR spectra and surface affinities in a new two dimensional, 2D IR spectroscopic technique. When implemented with simultaneous gravimetric analysis, it further provides the quantification of adsorbed species. The adsorption of CO2 on monoclinic ZrO2 was investigated using this technique with temperature and pressure ranges of 353-673 K and 10(-4)-0.4 bar, respectively. The sets of spectra obtained at constant temperature and variable pressures (spectroscopic isotherms) were inverted assuming they obey a generalized Langmuir isotherm. This procedure yields a 2D map in which the IR spectra of the prominent surface species formed upon CO2 adsorption are resolved in one dimension - hydrogen carbonates, bidentate carbonates and polydentate carbonates - while these species are resolved according to their surface adsorption affinities (logarithm of adsorption equilibrium constants, ln K) on the other dimension. This technique also allows for the unambiguous determination of the thermodynamic stabilities of the various adsorbed species. The inversion of the gravimetric isotherms recorded simultaneously with the infrared spectra leads to a quantitative distribution function of CO2 adsorption sites whose components match those of the 2D infrared map and allows for a straightforward quantification of the corresponding sites, namely (i) weakly basic sites leading to bridged carbonates, hydrogen carbonates and bidentate carbonates (~0.7 MUmol m(-2), Delta(ads)H = -70 to 90 kJ mol(-1)), (ii) mild basic sites leading to a second type of bidentate carbonates (~0.8 MUmol m(-2), Delta(ads)H = -110 to 120 kJ mol(-1)) and (iii) strong basic sites leading to polydentate carbonate species (~0.1 MUmol m(-2), Delta(ads)H < -120 kJ mol(-1)). Finally, the advantages and limitations of the present methodology are discussed. Because this technique is not limited to a particular spectroscopy or physical process, it should find other applications in the field of spectroscopic characterization of surfaces. PMID- 23661092 TI - Forster resonance energy transfer by formation of a mechanically interlocked [2]rotaxane. AB - A [2]rotaxane has been constructed from a di-pyrene appended pillar[5]arene wheel, a pyridinium axle, and a perylene stopper. It shows efficient Forster resonance energy transfer from pyrene to perylene by formation of a mechanically interlocked [2]rotaxane. PMID- 23661091 TI - mTOR pathway and Ca2+ stores mobilization in aged smooth muscle cells. AB - Aging is considered to be driven by the so called senescence pathways, especially the mTOR route, although there is almost no information on its activity in aged tissues. Aging also induces Ca2+ signal alterations, but information regarding the mechanisms for these changes is almost inexistent. We investigated the possible involvement of the mTOR pathway in the age-dependent changes on Ca2+ stores mobilization in colonic smooth muscle cells of young (4 month old) and aged (24 month old) guinea pigs. mTORC1 activity was enhanced in aged smooth muscle, as revealed by phosphorylation of mTOR and its direct substrates S6K1 and 4E-BP1. Mobilization of intracellular Ca2+ stores through IP3R or RyR channels was impaired in aged cells, and it was facilitated by mTOR and by FKBP12, as indicated by the inhibitory effects of KU0063794 (a direct mTOR inhibitor), rapamycin (a FKBP12-mediated mTOR inhibitor) and FK506 (an FKBP12 binding immunosuppressant). Aging suppressed the facilitation of the Ca2+ mobilization by FKBP12 but not by mTOR, without changing the total expression of FKBP12 protein. In conclusion, or study shows that in smooth muscle aging enhances the constitutive activity of mTORC1 pathway and impairs Ca2+ stores mobilization by suppression of the FKBP12-induced facilitation of Ca2+ release. PMID- 23661093 TI - Relationship between obesity and serum reactive oxygen metabolites in adolescents. AB - OBJECTIVES: Various cross-sectional studies have revealed a significant positive relationship between systemic oxidative stress and obesity-related indices such as body mass index (BMI, kg/m2). However, little is known of the role of oxidative stress during adolescence. The aim of this study was to determine the association between obesity and serum reactive oxygen metabolites (ROM) in adolescents. METHOD: A total of 595 healthy junior high school students from northern Japan were enrolled in the study. Oxidative stress was evaluated by measuring serum levels of ROM. Obesity indices included BMI and percentage body fat (PBF). The analyses were stratified by sex and controlled for age and menarche. Partial correlation coefficients and analysis of covariance were also analyzed. RESULTS: In female students, ROM levels increased with increasing BMI and PBF. Therefore, ROM levels were significantly higher in the underweight group than in the BMI-classified overweight-obese (P < 0.001) and normal weight groups (P < 0.05). ROM levels were significantly higher in the high PBF group than in the underweight (P < 0.05) and normal groups (P < 0.001). CONCLUSION: The results of this study show that, regardless of menarche, obesity indicators such as BMI and PBF are correlated with the level of oxidative stress in female adolescents. PMID- 23661094 TI - Plasticity in offspring contaminant tolerance traits: developmental cadmium exposure trumps parental effects. AB - Parental effects are non-genotypic influences on offspring phenotype that occur via parental phenotypes or environments, while developmental plasticity is phenotypic variation that arises during development in response to environmental cues. We evaluated the relative contribution of these two sources of phenotypic variation on offspring toxicant tolerance in Physa pomilia snails exposed to cadmium. We exposed adult snails to 0, 2, or 20 MUg/L cadmium for 7 days, then exposed egg masses collected from these adults to 0 or 2 MUg/L cadmium in a factorial design (adult cadmium exposure * egg mass cadmium exposure). Starting at 2 days old, we recorded time to death for hatchlings exposed to 150 MUg/L cadmium for 72 h at 8 h intervals. Juveniles hatched from cadmium-exposed egg masses displayed higher cadmium tolerance than juveniles from unexposed egg masses. Among juveniles from egg masses not exposed to cadmium, offspring of parents exposed to 20 MUg/L cadmium had higher cadmium tolerance than offspring of parents exposed to 0 or 2 MUg/L cadmium. Our results show that both parental effects and developmental plasticity can impact offspring toxicant tolerance and point to the potential importance of both processes in understanding how offspring respond to chemical contaminants. When both parents and offspring are exposed to a toxicant, our results showed that the effects of parental exposure on offspring toxicant tolerance may be eclipsed by the effects of offspring exposure during development. PMID- 23661095 TI - Linking sub-individual and population level toxicity effects in Daphnia schoedleri (Cladocera: Anomopoda) exposed to sublethal concentrations of the pesticide alpha-cypermethrin. AB - Synthetic pyrethroids are classified as moderately toxic to mammals and birds; nevertheless, they are highly toxic to non-target aquatic organisms such as fish and zooplankters. Chemical pollutants produce different effects in exposed organisms, ranging from biochemical to population responses. Cladocerans can modify the energy content of their offspring according to the surrounding medium as a way to improve their odds in case they have to cope with stressful conditions at birth. In this study, the effect of a synthetic pesticide on two levels of response in a Daphnia species different from those traditionally used as test organisms was evaluated. With this aim, Daphnia schoedleri neonates (<24 h) were exposed for 21 days to three sublethal concentrations of alpha cypermethrin, 0.54, 5.4, and 54 ng L(-1), which correspond to 48-h EC1/100, EC1/10, and EC1, respectively. Effects were measured through a life table analysis for fecundity and survivorship. For effects on progeny, protein, carbohydrates, and lipids were determined and then transformed to caloric content. Biomarkers (BM) were expected to be the most sensitive evaluated response; nevertheless, population parameters such as survivorship and net reproductive rate (R0) were more sensitive since they presented significant differences with respect to controls at the lowest tested concentration. Neonates' caloric content varied during the reproductive period assessed and was negatively correlated to fecundity: as more neonates were born, less energy was provided by the adult females. Macromolecules concentration and caloric content values in cypermethrin-exposed adults were not different from those recorded in the control at the end of exposure time. The results herein presented suggest that stressed daphnids allocate more energy reserves to their offspring, although this strategy can vary depending on the number of reproductive events during the lifecycle, and on the toxicant's concentration. Sub-individual approaches to assess toxicant effects should be accompanied by demographic studies, which support population effect predictions inferred from BMs assessment. PMID- 23661096 TI - Pesticide exposure impacts not only hatching of dormant eggs, but also hatchling survival and performance in the water flea Daphnia magna. AB - Laboratory ecotoxicity tests and biomonitoring in aquatic systems are currently based on the active component of invertebrate communities. Even though dormant egg banks are crucial for the long term survival and community dynamics of many aquatic organisms, the effects of anthropogenic activities on dormant egg bank dynamics have rarely been studied. In this study we investigated the effects of two pesticides with a different mode of action (carbaryl and fenoxycarb) on hatching of Daphnia magna dormant eggs (ephippia) as well as on survival, growth and reproduction of the hatched neonates. Dormant eggs were exposed to the pesticides simultaneously to incubation under conditions that induce hatching (long daylight and 20 degrees C). Carbaryl had no negative effects on embryonic development or hatching rate up to concentrations almost 1,000 times the median effect concentration (EC50) of neonate survival in acute tests. Fenoxycarb, however, had a significant dose-related effect by delaying or completely stopping the hatching process and caused severe abnormalities in developing individuals. Both pesticides had significant negative effects on survival and reproduction of the hatchlings. These results indicate that, in addition to inducing mortality of active individuals, pesticides can affect zooplankton communities by altering hatching dynamics and life history traits of hatched individuals. We briefly discuss how such pollution induced changes in the benthic-pelagic coupling could translate into trans-generational effects impacting ecological and evolutionary dynamics. PMID- 23661097 TI - Different phenotypes of the appearance of the outer plexiform layer on optical coherence tomography. AB - PURPOSE: To present a selected case series of different phenotypes of the normal outer plexiform layer (OPL) visualized by optical coherence tomography (OCT). METHODS: Five cases were selected to represent the spectrum of appearances of the OPL in this case series. Categorical descriptions of each manifestation were then developed. Additional SD-OCT scans were obtained from a normal volunteer to further support the hypothesis. RESULTS: The inner one-third of the OPL typically appears hyperreflective on OCT, while the outer two-thirds (Henle fiber layer) may have a more varied appearance. Six different phenotypes of Henle fiber layer reflectivity were noted in this series, and classified as: bright, columnar, dentate, delimited, indistinct, and dark. The brightness of the Henle fiber layer appears to depend on the geometric angle between the OCT light beam and the axonal fibers in this portion of the OPL. This angle appears to be a function of the natural orientation of the Henle fiber layer tissue (thetaN), the existence of subretinal pathology that alters the angle of the neurosensory retina (theta(P)), and the tilt angle of the tissue on the B-scan (theta(T)) due to decentered OCT acquisition. CONCLUSIONS: Since accurate interpretation of the OPL/ONL boundary is of vital importance to study the thickness of ONL, location of cystoid lesions, hyperreflective crescents over drusen, et al., our case series may aid better understanding of the OPL appearance in SD-OCT. In the absence of clear delineation, it may be most correct to refer to indistinct OPL and ONL together as the photoreceptor nuclear axonal complex (PNAC). PMID- 23661098 TI - Visual outcome and histological findings following femtosecond laser-assisted versus microkeratome-assisted DSAEK. AB - BACKGROUND: The aim of this study was to compare the visual outcome of femtosecond laser-assisted Descemet stripping automated endothelial keratoplasty (DSAEK) to microkeratome-assisted DSAEK as well as to contrast precut versus surgeon-cut grafts. Histologic characterization of failed DSAEK grafts was performed in order to correlate ultrastructural changes with graft failures. METHODS: In this case control study, 47 cases of DSAEK were investigated in terms of visual acuity, keratometric astigmatism, spherical equivalent, endothelial cell count, and postoperative complications. We formed three groups: the femtosecondlaser-assisted DSAEK with precut grafts, the microkeratome-assisted DSAEK with precut and with surgeon-cut grafts. Mean follow-up was 6 months. In the case of graft failure, penetrating keratoplasty was performed, and the excised corneal buttons were investigated by light and electron microscopy. RESULTS: Microkeratome-assisted DSAEK lead to better visual outcome than femtosecond laser-assisted DSAEK. Keratometric astigmatism, spherical equivalent and endothelial cell count did not differ significantly between both methods. Precut and surgeon-cut grafts in microkeratome-assisted DSAEK did not show any significant difference regarding all upraised parameters. No definite histological correlate for graft failure following femtosecond laser-assisted DSAEK was found. CONCLUSIONS: Femtosecond laser-assisted DSAEK is not the method of choice, and needs further technical improvement. However, failed femtosecondlaser-assisted DSAEK grafts did not show significant histological changes related to the technique to explain reduced visual acuity. In microkeratome-assisted DSAEK, the preparation time point of the graft does not seem to influence the visual and optical outcome. PMID- 23661099 TI - The dopamine receptor D1 gene is associated with the length of interval between first heroin use and onset of dependence in Chinese Han heroin addicts. AB - Previous researches showed that the dopamine receptor D1 (DRD1) may play a critical role in drug dependence. This research aimed to determine whether DRD1 played a role in development of heroin dependence in Chinese heroin-dependent patients. 465 Chinese Han heroin-dependent subjects and 379 healthy controls were recruited in the Shanghai region. Five single-nucleotide-polymorphisms (SNPs) of the DRD1 gene were genotyped in all subjects. The results found that the frequencies of DRD1 SNP genotypes or haplotypes were not different between heroin dependent patients and controls. Among heroin-dependent patients, subjects with rs5326CC and/or rs6882300AA genotypes develop to heroin-dependent more rapidly than those without rs5326CC and/or rs6882300AA genotypes. The results indicated that DRD1 gene polymorphism may not play an important role in the susceptibility of heroin dependence in the Chinese Han population, but it may be associated with the rapidity of heroin dependence development from first drug use. PMID- 23661101 TI - The efficacy and limitations of stereotactic radiosurgery as a salvage treatment after failed whole brain radiotherapy for brain metastases. AB - The aim of the present study was to evaluate the efficacy and limitations of repeat stereotactic radiosurgery (SRS) salvage for patients with recurrence of brain metastases (BM) after whole brain radiotherapy (WBRT). This is a retrospective, observational, single-center trial analyzing 77 consecutive patients with recurrent BM who were treated primarily with WBRT. All patients underwent SRS as salvage treatment. Median age was 62 years, and median Karnofsky performance status (KPS) was 80. The median interval between the starting date of WBRT and radiosurgery was 10.6 months. One, two and more than two SRS sessions were required in 42, 13 and 22 patients, respectively. The median total planning target volume (PTV) was 8.1 mL and the median dose prescribed was 20 Gy. The median follow-up was 7.7 months. 1- and 2-year neurological death-free survival (NS) rates were 87 and 78 %, respectively. Competing risk analysis demonstrated active extra-central nervous system (CNS) disease [Hazard ratio (HR) 0.236, P = 0.041] and total PTV on initial SRS (>= 5 mL) (HR 4.22, P = 0.033) to be associated with the NS rate. 1- and 2-year overall survival (OS) rates were 41 and 11 %, respectively. The median OS time was 8.2 months. Active extra-CNS disease (HR 1.94, P = 0.034) and high KPS (>= 90) (HR 0.409, P = 0.006) were associated with the OS rate. In total, 798 tumors (75 %) in 66 patients (86 %) with sufficient radiological follow-up data were evaluated. 1- and 2-year metastasis local control rates were 76.6 and 57.9 %, respectively. Prescribed dose (>= 20 Gy) (HR 0.326, P < 0.001), tumor volume (>= 2 mL) (HR 1.98, P = 0.007) and metastases from breast cancer (HR 0.435, P < 0.001) were independent predictive factors for local tumor control. Repeat salvage SRS for recurrent BM after WBRT appeared to be a safe and effective treatment. In the majority of patients, even those with numerous BM, neurological death could be delayed or even prevented. PMID- 23661100 TI - Autophagic failure promotes the exocytosis and intercellular transfer of alpha synuclein. AB - The accumulation of abnormal protein aggregates is a major characteristic of many neurodegenerative disorders, including Parkinson's disease (PD). The intracytoplasmic deposition of alpha-synuclein aggregates and Lewy bodies, often found in PD and other alpha-synucleinopathies, is thought to be linked to inefficient cellular clearance mechanisms, such as the proteasome and autophagy/lysosome pathways. The accumulation of alpha-synuclein aggregates in neuronal cytoplasm causes numerous autonomous changes in neurons. However, it can also affect the neighboring cells through transcellular transmission of the aggregates. Indeed, a progressive spreading of Lewy pathology among brain regions has been hypothesized from autopsy studies. We tested whether inhibition of the autophagy/lysosome pathway in alpha-synuclein-expressing cells would increase the secretion of alpha-synuclein, subsequently affecting the alpha-synuclein deposition in and viability of neighboring cells. Our results demonstrated that autophagic inhibition, via both pharmacological and genetic methods, led to increased exocytosis of alpha-synuclein. In a mixed culture of alpha-synuclein expressing donor cells with recipient cells, autophagic inhibition resulted in elevated transcellular alpha-synuclein transmission. This increase in protein transmission coincided with elevated apoptotic cell death in the recipient cells. These results suggest that the inefficient clearance of alpha-synuclein aggregates, which can be caused by reduced autophagic activity, leads to elevated alpha-synuclein exocytosis, thereby promoting alpha-synuclein deposition and cell death in neighboring neurons. This finding provides a potential link between autophagic dysfunction and the progressive spread of Lewy pathology. PMID- 23661102 TI - Sluggish cognitive tempo in survivors of pediatric brain tumors. AB - The presence of neurocognitive late effects in survivors of pediatric brain tumors is well established. However, there remains some debate about how best to conceptualize these deficits. Sluggish cognitive tempo (SCT) is a proposed conceptual framework that has been used to describe a subset of children with ADHD who exhibit a particular profile characterized by lethargy, day dreaming and staring, and poor organization. Previous work has suggested that survivors of leukemia exhibit a similar profile, but it has not yet been examined in survivors of pediatric brain tumors. A sample of 65 survivors of pediatric brain tumors, 25 survivors of leukemia and 50 community controls completed the Child Behavior Checklist, with four items used to measure SCT. Survivors completed additional measures of neurocognitive functioning. Survivors of brain tumors demonstrated significantly greater symptoms of SCT than survivors of leukemia or controls. SCT was associated with attention problems and working memory deficits and the presence of a VP-shunt. Results provided conditional support for the presence of SCT in survivors of brain tumors, with further research needed to determine the clinical utility of the framework. PMID- 23661104 TI - Gelatinases and their tissue inhibitors in a group of subjects with metabolic syndrome. AB - AIM: To evaluate matrix metalloproteases (MMP)-2 and MMP-9 and tissue inhibitor of metalloproteases (TIMP)-1 and TIMP-2 in a group of subjects with metabolic syndrome (MS) subdivided according to the presence or absence of diabetes mellitus. METHODS: We examined in 90 subjects (51 men and 39 women) with MS, defined following the International Diabetes Federation criteria, and subsequently subdivided into diabetic subjects (22 men and 11 women) and nondiabetic subjects s (29 men and 28 women), the plasma concentrations of MMP-2 and MMP-9 and of TIMP-1 and TIMP-2 using specific enzyme-linked immunosorbent assay kits. RESULTS: We found a significant increase in plasma concentrations of MMP-2, MMP-9, TIMP-1, and TIMP-2 in the whole group of MS subjects (P < 0.001) and in both subgroups of MS subjects with diabetes mellitus (P < 0.001) and without diabetes mellitus (P < 0.001) in comparison with healthy controls. We also noted higher concentrations of all the examined parameters in the MS subjects with diabetes mellitus in comparison with the MS subjects without diabetes mellitus. Matrix metalloproteases and TIMPs showed some significant correlations with body mass index and waist circumference and with metabolic parameters in the whole group of MS subjects. CONCLUSION: An altered pattern of MMPs and their inhibitors is demonstrated in MS; the presence of diabetes mellitus strongly influences the concentration of MMP and TIMP, contributing probably to the increased cardiovascular risk of MS subjects. PMID- 23661103 TI - Natriuretic peptides as biomarkers in heart failure. AB - Following the initial discovery of a natriuretic and diuretic peptide factor present in atrial myocardial tissue homogenates, subsequent elucidation of the natriuretic peptide (NP) family has led to substantial advances in the understanding of the autocrine, paracrine, and endocrine regulation of the cardiovascular system. Furthermore, with the development of assays for the measurement of the NPs, these important biomarkers have gone from being regarded as biological mediators of the cardiovascular system to now represent important clinical tools for the diagnostic and prognostic evaluation of patients with heart failure and may have potential as a therapeutic target in this setting as well. An historical perspective on the NPs from bench to bedside translation will be discussed. PMID- 23661105 TI - EpiDOCK: a molecular docking-based tool for MHC class II binding prediction. AB - Cellular peptide vaccines contain T-cell epitopes. The main prerequisite for a peptide to act as a T-cell epitope is that it binds to a major histocompatibility complex (MHC) protein. Peptide MHC binder identification is an extremely costly experimental challenge since human MHCs, named human leukocyte antigen, are highly polymorphic and polygenic. Here we present EpiDOCK, the first structure based server for MHC class II binding prediction. EpiDOCK predicts binding to the 23 most frequent human, MHC class II proteins. It identifies 90% of true binders and 76% of true non-binders, with an overall accuracy of 83%. EpiDOCK is freely accessible at http://epidock.ddg-pharmfac.net. PMID- 23661106 TI - Type 2 diabetes, socioeconomic status and risk of cancer in Scotland 2001-2007. AB - AIMS/HYPOTHESIS: The objective of this study was to use Scottish national data to assess the influence of type 2 diabetes on the risk of cancer at 16 different sites, while specifically investigating the role of confounding by socioeconomic status in the diabetes-cancer relationship. METHODS: All people in Scotland aged 55-79 years diagnosed with any of the cancers of interest during the period 2001 2007 were identified and classified by the presence/absence of co-morbid type 2 diabetes. The influence of diabetes on cancer risk for each site was assessed via Poisson regression, initially with adjustment for age only, then adjusted for both age and socioeconomic status. RESULTS: There were 4,285 incident cancers in people with type 2 diabetes. RR for any cancers (adjusted for age only) was 1.11 (95% CI 1.05, 1.17) for men and 1.33 (1.28, 1.40) for women. Corresponding values after additional adjustment for socioeconomic status were 1.10 (1.04, 1.15) and 1.31 (1.25, 1.38), respectively. RRs for individual cancer sites varied markedly. CONCLUSIONS/INTERPRETATION: Socioeconomic status was found to have little influence on the association between type 2 diabetes and cancer. PMID- 23661107 TI - Constant communities in complex networks. AB - Identifying community structure is a fundamental problem in network analysis. Most community detection algorithms are based on optimizing a combinatorial parameter, for example modularity. This optimization is generally NP-hard, thus merely changing the vertex order can alter their assignments to the community. However, there has been less study on how vertex ordering influences the results of the community detection algorithms. Here we identify and study the properties of invariant groups of vertices (constant communities) whose assignment to communities are, quite remarkably, not affected by vertex ordering. The percentage of constant communities can vary across different applications and based on empirical results we propose metrics to evaluate these communities. Using constant communities as a pre-processing step, one can significantly reduce the variation of the results. Finally, we present a case study on phoneme network and illustrate that constant communities, quite strikingly, form the core functional units of the larger communities. PMID- 23661108 TI - One-step assembly of Re(I) tricarbonyl 2-pyridyltetrazolato metallacalix[3]arene with aqua emission and reversible three-electron oxidation. AB - The reaction of 2-pyridyltetrazolate with [Re(CO)5X] (X = Cl, Br) yielded the formation of an unexpected cyclic metallacalix[3]arene, as revealed by X-ray structural studies, characterised by aqua emission and reversible three-electron oxidation. PMID- 23661109 TI - Current status of minimally invasive esophagectomy for patients with esophageal cancer. AB - Technical advancements and development of endoscopic equipment in thoracoscopic surgery have resulted in increase in the popularity of minimally invasive esophagectomy (MIE). However, advantages with regard to short-term outcome and oncological feasibility of MIE have not been adequately established. To date, a number of single-institution studies and several meta-analyses have demonstrated acceptable short-term outcomes of thoracoscopic esophagectomy for esophageal cancer, and the outcomes are comparable to those of conventional open esophagectomy (OE). A study group recently reported the results of the first multicenter randomized controlled trial (RCT) that compared MIE and OE. The incidence of pulmonary infection after surgery was markedly lower in the MIE group than in the OE group. Additional benefits of MIE included less operative blood loss, better postoperative patients' quality of life, and shorter hospital stay. However, the oncological benefit to patients undergoing MIE has not been scientifically proven because there have been no RCTs to verify the equivalency in long-term survival of patients undergoing MIE compared with that of patients undergoing OE. If future prospective studies indicate oncological benefits, MIE could truly become the standard care for patients with esophageal cancer. PMID- 23661111 TI - Investigating hypocalcaemia. PMID- 23661112 TI - Cost effectiveness of the NHS breast screening programme: life table model. AB - OBJECTIVE: To assess the overall cost effectiveness of the NHS breast screening programme, based on findings of the Independent UK Panel on Breast Cancer Screening and taking into account the uncertainty of associated estimates of benefits, harms, and costs. DESIGN: A life table model comparing data from two cohorts. SETTING: United Kingdom's health service. PARTICIPANTS AND INTERVENTIONS: 364,500 women aged 50 years-the population of 50 year old women in England and Wales who would be eligible for screening-were followed up for 35 years without screening, compared with a similar cohort who had regular mammographic screening between ages 50 and 70 years and were then followed for another 15 years. MAIN OUTCOME MEASURES: Between the cohorts, we compared the number of breast cancer diagnoses, number of deaths from breast cancer, number of deaths from other causes, person years of survival adjusted for health quality, and person years of survival with breast cancer. We also calculated the costs of treating primary and end stage breast cancer, and the costs of screening. Probabilistic sensitivity analysis explored the effect of uncertainty in key input parameters on the model outputs. RESULTS: Under the base case scenario (using input parameters derived from the Independent Panel Review), there were 1521 fewer deaths from breast cancer and 2722 overdiagnosed breast cancers. Discounting future costs and benefits at a rate of 3.5% resulted in an additional 6907 person years of survival in the screened cohort, at a cost of 40,946 additional years of survival after a diagnosis of breast cancer. Screening was associated with 2040 additional quality adjusted life years (QALYs) at an additional cost of L42.5m (?49.8m; $64.7m) in total or L20,800 per QALY gained. The gain in person time survival over 35 years was 9.2 days per person and 2.7 quality adjusted days per person screened. Probabilistic sensitivity analysis showed that this incremental cost effectiveness ratio varied widely across a range of plausible scenarios. Screening was cost effective at a threshold of L20,000 per QALY gained in 2260 (45%) scenarios, but in 588 (12%) scenarios, screening was associated with a reduction in QALYs. CONCLUSION: The NHS breast screening programme is only moderately likely to be cost effective at a standard threshold. However, there is substantial uncertainty in the model parameter estimates, and further primary research will be needed for cost effectiveness studies to provide definitive data to inform policy. PMID- 23661113 TI - The Ottawa Statement on the ethical design and conduct of cluster randomised trials: precis for researchers and research ethics committees. PMID- 23661114 TI - A man with bilateral loin pain. PMID- 23661115 TI - "Research passports" could reduce misconduct, conference hears. PMID- 23661116 TI - Evidence does not support routine PSA testing, say experts. PMID- 23661117 TI - Researchers thrash out guidelines for working with partners. PMID- 23661118 TI - Copper modulates the large dense core vesicle secretory pathway in PC12 cells. AB - Copper (Cu) is an essential biometal involved in a number of cell functions. Abnormal Cu homeostasis has been identified as a major factor in a number of neurodegenerative disorders. However, little is known about how cells of brain origin maintain Cu homeostasis and in particular, how they respond to an elevated Cu environment. Understanding these processes is essential to obtaining a greater insight into the pathological changes in neurodegeneration and ageing. Although previous studies have shown that Cu in neurons can be associated with synaptic function, there is little understanding of how Cu modulates the regulated secretory vesicle pathways in these cells. In this study, we examined the effect of elevated intracellular Cu on proteins associated with the regulated secretory vesicle pathway in NGF-differentiated PC12 cells that exhibit neuronal-like properties. Increasing intracellular Cu with a cell-permeable Cu-complex (Cu(II)(gtsm)) resulted in increased expression of synaptophysin and robust translocation of this and additional vesicular proteins from synaptic-like microvesicle (SLMV) fractions to chromogranin-containing putative large dense core vesicle (LDCV) fractions in density gradient preparations. The LDCV fractions also contained substantially elevated Cu levels upon treatment of cells with Cu(II)(gtsm). Expression of the H(+) pump, V-ATPase, which is essential for vesicle maturation, was increased in Cu-treated cells while inhibition of V ATPase prevented translocation of synaptophysin to LDCV fractions. Cu treatment was found to inhibit release of LDCVs in chromaffin cells due to reduced Ca(2+) mediated vesicle exocytosis. Our findings demonstrate that elevated Cu can modulate LDCV metabolism potentially resulting in sequestration of Cu in this vesicle pool. PMID- 23661119 TI - Complex organic molecules are released during thermal reduction of graphite oxides. AB - Thermal exfoliation and deoxygenation of graphite oxide is one of the major routes for the preparation of large quantities of graphene-based materials. It is commonly believed that thermal exfoliation leads to the release of H2O, CO and CO2 gases. Here we show for the first time that in addition to these small simple molecules, there is a wide variety of complex organic molecules that are released from graphite oxide during the exfoliation process, such as alkanes, substituted polycyclic aromatic hydrocarbons and heterocyclic molecules. The compositions of the released volatile compounds depend on the exfoliation atmosphere (Ar, H2), pressure and the preparation methods of graphite oxide (such as Hofmann, Staudenmaier or Hummers). The structures of the decomposition products reflect the characters of graphite oxide precursors and are also directly related to the defects in the graphene products. As such, these findings have profound influences on our understanding on the structural defects of reduced graphenes, which consequently provide further insights into their properties. PMID- 23661120 TI - High-performance Brillouin spectroscopy of phonons induced by a piezoelectric thin film with a coaxial microwave resonator. AB - To overcome the low accuracy of acoustic velocity measurements based on Brillouin scattering from thermal phonons, we attempted to utilize induced coherent phonons, which cause intense Brillouin scattering. A ZnO piezoelectric film was used to induce gigahertz-range coherent phonons in a silica glass block sample. An evanescent electromagnetic wave leaked from a coaxial resonator was applied into the film to excite phonons. The scattered light obtained using this simple system was much more intense than that obtained from thermal phonons. This technique will improve the accuracy and reduce the measurement time. PMID- 23661121 TI - Influence of microbubble size on postexcitation collapse thresholds for single ultrasound contrast agents using double passive cavitation detection. AB - For the first time, and using an acoustical method, it has been shown experimentally that the inertial cavitation threshold pressure of an albumin shelled microbubble is significantly correlated with its initial size. PMID- 23661122 TI - Broadband dielectric characterization of sapphire/TiOx/Ba0.3Sr0.7TiO3 (111) oriented thin films for the realization of a tunable interdigitated capacitor. AB - A complete microwave characterization up to 67 GHz using specific coplanar waveguides was performed to determine the dielectric properties (permittivity, losses, and tunability) of sapphire/TiOx/Ba0.3Sr0.7TiO3 (BST) (111)-oriented thin films. To that end, BaxSr1-xTiO3 thin films were deposited by RF magnetron sputtering on sapphire (0001) substrate. To control the preferred (111) orientation, a TiOx buffer layer was deposited on sapphire. According to the detailed knowledge of the material properties, it has been possible to conceive, fabricate, and test interdigitated capacitors, the basic element for future microwave tunable applications. Retention of capacitive behavior up to 67 GHz and a tunability of 32% at 67 GHz at an applied voltage of 30 V (150 kV/cm) were observed. The Q-factor remains greater than 30 over the entire frequency band. The possibility of a complete characterization of the material for the realization of high-performance interdigitated capacitors opens the door to microwave device fabrication. PMID- 23661124 TI - Two-dimensional blood flow velocity estimation using ultrasound speckle pattern dependence on scan direction and A-line acquisition velocity. AB - We have previously investigated the change of apparent lateral speckle size caused by the direction and spatial rate of scanner A-line acquisition (scan velocity). An algorithm which measures the lateral component of blood flow velocity was developed based on the increase in speckle size resulting from relative motion between moving scatterers and the scan velocity. In this paper, the change of the apparent dominant angle of the speckle pattern in a straight vessel was investigated and a new method of two-dimensional blood flow velocity estimation is introduced. Different scan velocities were used for data acquisition from blood flow traveling at an angle relative to the ultrasound beam. The apparent angle of the speckle pattern changes with different scan velocities because of misregistration between the ultrasound beam and scatterers. The apparent angle of the speckle pattern was resolved by line-to-line cross correlation in the fast-time (axial) direction on a region-of-interest (ROI) in each blood flow image and used to spatially align the ROI. The resulting lateral speckle size within the aligned ROI was calculated. The lateral component of the blood flow is shown to be closest to the scan velocity which gives the maximum speckle size and the apparent angle of speckle pattern collected by this scan velocity is the best estimate for the actual angle of blood flow. These two components produce two-dimensional blood flow velocity estimations. This method was studied through both computer simulation and experiments with a blood flow phantom. Nine scan velocities were used to collect blood flow data with velocities ranging from 33 to 98 cm/s and four beam-to-flow angles. In simulated plug blood flow, the mean bias of angle estimation is below 2% with an average standard deviation of 3.6%. In simulated parabolic blood flow, the angle of blood flow is overestimated because of speckle decorrelation caused by flow gradients and the estimation bias increases with decreasing beam-to-flow angle, which has an average value of 8.8% and standard deviation of 10%. Because of the complexity of flow profiles in the blood flow phantom, the angle of blood flow is also overestimated and the mean bias is increased by a factor of two compared with simulated parabolic flow. For the velocity estimation results, the mean bias is below 5% with an average standard deviation of 4.6% in the simulated plug blood flow. In the simulated parabolic flow and blood flow phantom, the velocity is underestimated because of speckle decorrelation. The mean bias of velocity estimation in the simulated parabolic flow is -6% with an average standard deviation of 11.2%. In the blood flow phantom, the mean bias of the velocity estimation is -5% with a higher average standard deviation of 21.5%. This method can resolve the angle and amplitude of two-dimensional blood flow simultaneously. The accuracy of the estimation can be further improved by using more scanning velocities. PMID- 23661123 TI - Development and initial application of a fully integrated photoacoustic micro ultrasound system. AB - Photoacoustic (PA) imaging for biomedical applications has been under development for many years. Based on the many advances over the past decade, a new photoacoustic imaging system has been integrated into a micro-ultrasound platform for co-registered PA-ultrasound (US) imaging. The design and implementation of the new scanner is described and its performance quantified. Beamforming techniques and signal processing are described, in conjunction with in vivo PA images of normal subcutaneous mouse tissue and selected tumor models. In particular, the use of the system to estimate the spatial distribution of oxygen saturation (sO2) in blood and co-registered with B-mode images of the surrounding anatomy are investigated. The system was validated in vivo against a complementary technique for measuring partial pressure of oxygen in blood (pO2). The pO2 estimates were converted to sO2 values based on a standard dissociation curve found in the literature. Preliminary studies of oxygenation effects were performed in a mouse model of breast cancer (MDA-MB-231) in which control mice were compared with mice treated with a targeted antiangiogenic agent over a 3 d period. Treated mice exhibited a >90% decrease in blood volume, an 85% reduction in blood wash-in rate, and a 60% decrease in relative tissue oxygenation. PMID- 23661125 TI - Phase shift variance imaging - a new technique for destructive microbubble imaging. AB - The detection of microbubble contrast agents with ultrasound imaging techniques is the subject of ongoing research. Commonly, the nonlinear response of the agent is employed for detection. The performance of these techniques is, however, affected by nonlinear sound propagation. As an alternative, the change in echo response resulting from microbubble destruction can be employed to detect the agent. In this work, we propose a novel criterion for microbubble destruction detection that allows the rejection of tissue at a defined significance level even for highly echogenic structures in the presence of nonlinear propagation. Most clinical systems provide the hardware requirements for acquisitions consisting of multiple pulses transmitted at the same position, as used in Doppler imaging. Therefore, we develop a processing strategy that distinguishes contrast agent from other stationary or moving structures using these sequences. The proposed criterion is based on the variance of the phase shift of consecutive echoes in the sequence, which, in addition to tissue rejection, permits the distinction of motion from agent disruption. Phantom experiments are conducted to show the validity of the criterion and demonstrate the performance of the new method for contrast detection. Each detection series consists of 20 identical pulses at 9.5 MHz (4.7 MPa peak negative pressure) transmitted at a pulse repetition frequency of 5 kHz. The sequence is applied to phantoms under varied motion and flow conditions. As a first step toward molecular imaging, the technique is applied to microbubbles targeted to vascular endothelial growth factor receptor 2 (VEGFR2) in vitro. The results show a uniform rejection of the background signal while maintaining a contrast enhancement by more than 40 dB. The area under the receiver operating characteristics (ROC) curve is used as the performance metric for the separation of contrast agent and tissue signals, and values larger than 97% demonstrate that an excellent separation was achieved. PMID- 23661126 TI - Dual concentric-sectored HIFU transducer with phase-shifted ultrasound excitation for expanded necrotic region: a simulation study. AB - In high-intensity focused ultrasound (HIFU) surgery, it is desirable to produce a large necrotic area per sonication for reduced treatment time. It has been well known that the conventional split-focus scheme capable of generating multiple foci can increase a necrotic region in the lateral or elevational direction. To treat a deep-seated target, it is necessary to generate an expanded necrotic region in the axial direction. In this paper, a novel sonication scheme capable of producing an expanded coagulated region in the both lateral and axial directions is presented. The proposed method can generate multi-focal spots in the lateral and axial directions by using a dual concentric-sectored (DCS) HIFU transducer based on phase-shifted ultrasound excitation. A sound field simulation was employed for this investigation. Four electrical signals with identical center frequencies and different phases activated the DCS transducer, composed of a disc and an annular element with a confocal point. Four 4-MHz ultrasound signals with different phases were transmitted to the target simultaneously, resulting in generation of dual-focal spots in the lateral and axial directions. The sound field simulation results showed that the 0-6-dB lateral and axial beamwidths of the DCS transducer were maximally 79% and 91% broader than the single-element transducer. Subsequently, bio-heat transfer and thermal dose simulation results were matched to the sound field simulation. Hence, the DCS HIFU transducer combined with phase-shifted excitation may be a promising approach to treat a deep-seated target and to reduce treatment time for HIFU surgery. PMID- 23661127 TI - A statistical model for the ultrasonic backscattered echo from tissue containing microcalcifications. AB - Microcalcifications, generally seen in B-mode breast images as bright spots, often point to the presence of malignancies. Currently, statistical models to describe the signal strengths from tissue containing microcalcifications rely on the Rician or Nakagami densities. Because the Nakagami density requires the existence of randomly located scatterers with random cross sections, microcalcifications manifesting as isolated strong scatterers in the scattering volume makes it less suitable. Additionally, the absence of any regularly spaced scatterers also makes the Rician density less suitable. In this work, it is proposed that a 3-parameter McKay density with heavier tails than the Nakagami density, and hence more severe intensity fluctuations (speckle), might be a better fit to describe echo from tissue containing microcalcifications. This density is developed using a physical description of scattering and its characteristics are explored through random number simulation. Results demonstrate that the McKay densities have higher levels of speckle quantified through the speckle factor than the corresponding gamma densities (Nakagami for the envelope). Some preliminary analysis of tissue-mimicking phantoms modified to include microcalcification-like regions shows that higher speckle factors (seen with the McKay density) can be used to isolate and display microcalcifications. It is expected that this novel approach based on the McKay density will lead to newer and simpler means to detect and identify microcalcifications in ultrasonic B-scans. PMID- 23661128 TI - Evaluation of the transmission line model for couplant layer corrections in pulse echo measurements. AB - An acoustic couplant layer plays an integral role in many ultrasonic nondestructive testing and material characterization applications. It is important to account for this layer for accurate time-delay measurements. In pulse-echo measurements, the couplant layer can be accounted for by modeling the frequency dependence of phase delay. In this paper, two such models are evaluated for robustness in determining an accurate phase velocity: a simple linear relationship and the acoustic transmission line with its associated nonlinear expression. For this evaluation, measurements of acoustic phase delay in an aluminum sample were made by the pulse-echo method using tone bursts of 1800 different carrier frequencies between 35 and 125 MHz. The transmission line model was fit to the measured data using an unconstrained nonlinear least squares fitting routine with two free parameters: the acoustic phase velocity in the sample and the couplant thickness. It was found that this nonlinear model was extremely sensitive to the initial parameter guesses and could not unambiguously determine both the couplant layer thickness and acoustic phase velocity. In contrast, the faster and simpler linear least squares fit to the delay data determines a unique phase velocity in agreement with resonant ultrasound spectroscopy, an independent measurement technique. PMID- 23661129 TI - Iterative reconstruction of the transducer surface velocity. AB - Ultrasound arrays used for medical imaging consist of many elements placed closely together. Ideally, each element vibrates independently. However, because of mechanical coupling, crosstalk between neighboring elements may occur. To quantify the amount of crosstalk, the transducer velocity distribution should be measured. In this work, a method is presented to reconstruct the velocity distribution from far-field pressure field measurements acquired over an arbitrary surface. The distribution is retrieved from the measurements by solving an integral equation, derived from the Rayleigh integral of the first kind, using a conjugate gradient inversion scheme. This approach has the advantages that it allows for arbitrary transducer and pressure field measurement geometries, as well as the application of regularization techniques. Numerical experiments show that measuring the pressure field along a hemisphere enclosing the transducer yields significantly more accurate reconstructions than measuring along a parallel plane. In addition, it is shown that an increase in accuracy is achieved when the assumption is made that all points on the transducer surface vibrate in phase. Finally, the method has been tested on an actual transducer with an active element of 700 * 200 MUm which operates at a center frequency of 12.2 MHz. For this transducer, the velocity distribution has been reconstructed accurately to within 50 MUm precision from pressure measurements at a distance of 1.98 mm (=16lambda0) using a 200-MUm-diameter needle hydrophone. PMID- 23661130 TI - Drive-level dependence of doubly rotated langasite resonators with different configurations. AB - The miniaturization of crystal resonators and filters toward the micro electromechanical systems (MEMS) and nano-structured scales demands improvement of nonlinear piezoelectricity theory and a better understanding of the nonlinear behavior of new crystal materials. The nonlinearities affect the quality factor and acoustic behavior of MEMS and nano-structured resonators and filters. Among these nonlinear effects, drive-level dependence (DLD), which describes the instability of the resonator frequency resulting from voltage level and/or power density, is a potentially significant problem for miniaturized resonators. Langasite, a promising new piezoelectric material, is of current interest for a variety of applications because of its good temperature behavior, good piezoelectric coupling, low acoustic loss, and high Q-factor. It has been recently used to make high-temperature MEMS. In this paper, we report experimental measurements of the DLD of langasite resonators with different resonator configurations (plano-plano, single bevel, and double bevel). The results show that the resonator configuration affects the DLD of the langasite resonator. The DLD measurement results for langasite are compared with literature values for quartz, langaniste, and langatate, and with additional new measurements for a GaPO4 resonator of type R-30 (-11.1 degrees rotated Y-cut). Uncertainty analysis for the measured drive-level sensitivity is performed as well. PMID- 23661131 TI - Experimental measurement of the electroelastic effect in thickness-mode langasite resonators. AB - The electroelastic effect describes the shift in resonant frequency that a resonator experiences as a result of the application of a dc electrical field. We report on experimental measurements of the electroelastic effect observed in fourteen plano-plano configuration thickness-mode langasite (La3Ga5SiO14) resonators. The orientations of the fourteen samples provide a sufficient data set to extract all eight of the third-order piezoelectric constants of this material. The role of this type of measurement in determining third-order piezoelectric constants is discussed. We compare the experimentally observed behavior to that predicted when using the langasite material constants currently available in the literature. PMID- 23661132 TI - Analysis of contributions of nonlinear material constants to stress-induced velocity shifts of quartz and langasite surface acoustic wave resonators. AB - Stress-induced surface acoustic wave velocity shifts are analyzed for langasite (LGS) SAW resonators. The analytical methodology has been verified by comparing experimental results and analytical results for quartz resonators. LGS SAW resonators with Euler angles which are most sensitive and least sensitive to diametrical forces are determined and their applications in force sensors and resonators with minimum acceleration sensitivity are discussed. Sensitivity of the analytical results to different groups of nonlinear material constants is discussed; it was found that for specific configurations, failure to include the third-order piezoelectric constants, dielectric constants and electrostrictive constants may lead to a significant calculation error. Surface acoustic waves propagating on an LGS square plate subject to bending moment along the propagation direction and normal to the propagation direction are analyzed; it was found that the average momentinduced velocity shift of LGS resonators are comparable to quartz resonators. Analyses of the sensitivity of the results to different groups of nonlinear material constants shows that for some specific wave propagation directions, failure to include the third-order piezoelectric constants, dielectric constants, and electrostrictive constants may lead to large errors. PMID- 23661133 TI - Low propagation loss in a one-port SAW resonator fabricated on single-crystal diamond for super-high-frequency applications. AB - Diamond has the highest known SAW phase velocity, sufficient for applications in the gigahertz range. However, although numerous studies have demonstrated SAW devices on polycrystalline diamond thin films, all have had much larger propagation loss than single-crystal materials such as LiNbO3. Hence, in this study, we fabricated and characterized one-port SAW resonators on single-crystal diamond substrates synthesized using a high-pressure and high-temperature method to identify and minimize sources of propagation loss. A series of one-port resonators were fabricated with the interdigital transducer/ AlN/diamond structure and their characteristics were measured. The device with the best performance exhibited a resonance frequency f of 5.3 GHz, and the equivalent circuit model gave a quality factor Q of 5509. Thus, a large fQ product of approximately 2.9 * 10(13) was obtained, and the propagation loss was found to be only 0.006 dB/wavelength. These excellent properties are attributed mainly to the reduction of scattering loss in a substrate using a single-crystal diamond, which originated from the grain boundary of diamond and the surface roughness of the AlN thin film and the diamond substrate. These results show that single-crystal diamond SAW resonators have great potential for use in low-noise super-high frequency oscillators. PMID- 23661134 TI - Correlation between propagation loss and silicon dioxide film properties for surface acoustic wave devices. AB - The correlation between the propagation loss and SiO2 film properties has been studied for temperature-compensated SAW devices using the SiO2/LiNbO3 structure. The SAW devices were prepared under different deposition temperatures for SiO2 film. Although they possessed excellent temperature coefficient of elasticity characteristics, devices prepared at lower temperature showed lower Q-factors. The SiO2 films were also deposited on a Si substrate under the same deposition conditions used for the SAW device preparation. Optical characterization was performed with Fourier transform infrared spectroscopy (FT-IR), spectrometer measurement, and Raman spectroscopy. IR absorbance spectra were almost same in the FT-IR measurement. However, optical attenuation in the UV region decreased with the deposition temperature in the spectrometer measurement. The optical attenuation is caused by the increase of the extinction coefficient in the SiO2 layer, and its optical wavelength dependence indicated that observed excess attenuation is caused by Rayleigh scattering. The Raman scattering also decreased with the deposition temperature in the Raman spectroscopy. The scattering is caused by the distortion of the SiO2 network. These results indicate that the Rayleigh scattering caused by the distortion of the SiO2 network is the main contributor to the excess SAW propagation loss in this case. PMID- 23661135 TI - Transducer characterization by sound field measurements. AB - The paper discusses different methods for characterizing an ultrasonic transducer by sound field measurements and introduces a novel easy-to-implement method besides the commonly known point reflector and hydrophone measurement methods. The characterization methods that are presented are particularly suited to measuring the actual transducer element size and determining fabrication details and asymmetries, where the necessary information is derived from the position of the ultrasonic focus and the structure of the sound field. The procedure is discussed on the basis of the following practical problems: measurement of the acoustically relevant element size of a planar 3-MHz annular array made of lead zirconate titanate (PZT) using a single point reflector; visualization of inaccuracies, asymmetries, and fabrication details for different setups with transducer frequencies between 3 and 50 MHz; determination of the element sizes of the single elements of a spherically curved 9-MHz sparse annular array and examination of the transducer?s focusing characteristics in a fluid containing scattering particles; and determination of the focus position of a 9-MHz single element transducer with acoustic lens and comparison between two lens materials. PMID- 23661136 TI - High-temperature (>500 degrees C) ultrasonic transducers: an experimental comparison among three candidate piezoelectric materials. AB - High-temperature piezoelectric crystals, including YCa4O(BO3)3, LiNbO3, and AlN, have been studied for use in ultrasonic transducers under continuous operation for 55 h at 550 degrees C. Additionally, thermal ratcheting tests were performed on the transducers by subjecting the crystals to heat treatments followed by ultrasonic performance testing at room temperature and 500 degrees C. The changes resulting from the heat treatments were less than the statistical spread obtained in repeated experiments and were thus considered negligible. Finally, in situ measurements of the pulse-echo response of YCa4O(BO3)3 were performed at temperatures up to 950 degrees C for the first time, showing stable characteristics up to these high temperatures. PMID- 23661137 TI - Equivalent circuit-based analysis of CMUT cell dynamics in arrays. AB - Capacitive micromachined ultrasonic transducers (CMUTs) are usually composed of large arrays of closely packed cells. In this work, we use an equivalent circuit model to analyze CMUT arrays with multiple cells. We study the effects of mutual acoustic interactions through the immersion medium caused by the pressure field generated by each cell acting upon the others. To do this, all the cells in the array are coupled through a radiation impedance matrix at their acoustic terminals. An accurate approximation for the mutual radiation impedance is defined between two circular cells, which can be used in large arrays to reduce computational complexity. Hence, a performance analysis of CMUT arrays can be accurately done with a circuit simulator. By using the proposed model, one can very rapidly obtain the linear frequency and nonlinear transient responses of arrays with an arbitrary number of CMUT cells. We performed several finite element method (FEM) simulations for arrays with small numbers of cells and showed that the results are very similar to those obtained by the equivalent circuit model. PMID- 23661138 TI - Waveform design for high-resolution damage detection using lamb waves. AB - Dispersion is encountered very often in ultrasonic guided waves, and may decrease the performance for damage detection significantly. For this reason, many signal processing methods have been proposed to obtain each mode under serious dispersion. In this paper, a new scheme is established for waveform design to suppress the dispersion such that each wave packet can be separated clearly. In this method, the dispersion effect of the guided wave is pre-compensated for a particular distance as it propagates through the structure. The relationship between the resolvable resolution and the waveform parameters is discussed; this relationship is employed as a guide to separately identify the wave packets caused by different structural features. Subsequently, an experiment is carried out to compare the performance of the proposed method with the time-reversal method. By using the proposed method, closely distributed structural features can be recognized with ease in the time domain. PMID- 23661139 TI - Numerical investigation of reflection properties of fast and slow longitudinal waves in cancellous bone. AB - The basic reflection properties of fast and slow waves propagating in cancellous bone were numerically investigated using finite-difference time-domain (FDTD) simulations with 18 microcomputed tomographic (uCT) models of bovine cancellous bone. The simulated results showed that both reflection coefficients of the fast and slow waves linearly increased with porosity. PMID- 23661141 TI - Innominate artery perforation during placement of hemodialysis catheter. PMID- 23661140 TI - Vascular access versus the effect of statins on inflammation and fibrinolysis in renal dialysis patients. AB - PURPOSE: The aim of this work was to assess the effect of statin therapy on inflammatory and fibrinolytic/endothelial (dys)function markers in end-stage renal disease (ESRD) patients under hemodialysis (HD), according to the type of vascular access. METHODS: This transversal study includes 191 ESRD patients under regular HD, divided into four groups according to vascular access and statin therapy: 87 patients with arteriovenous fistula (AVF) and no statins (AVF-NS), 61 with AVF and statins (AVF-S), 27 with central venous dialysis catheter (CVC) and no statins (CVC-NS) and 16 with CVC and statins (CVC-S). The basic lipid profile and fibrinolytic/endothelial cell function markers were assessed. RESULTS: Patients with CVC presented significantly higher levels of D-dimers compared with AVF groups. CVC-NS patients also presented the highest IL-6 values, which were significantly higher than those presented by CVC-S patients. AVF-S patients presented significantly higher t-PA and PAI-1 values and lower adiponectin levels compared with AVF-NS. CONCLUSIONS: Our results demonstrate that patients with CVC, particularly those not under statin therapy, present a higher production and turnover of fibrin. We also found that statin therapy decreases inflammation in CVC patients but is associated with a reduction of adiponectin and increased endothelial function marker levels in AVF patients. PMID- 23661142 TI - Acute cardiorenal syndrome by high flow arteriovenous fistula after kidney transplantation. AB - PURPOSE: The aim of this work was to increase recognition of high flow arteriovenous fistulas in kidney transplant patients. CASE: Here, we report the case of a 22-year-old man with repeated hospitalizations for cardiomegaly and chronic pericardial effusion after kidney transplantation. Eventually, high flow of his arteriovenous fistula was recognized 5.5 years after transplantation when he developed acute cardiorenal syndrome. Access flow reduction markedly improved kidney graft function along with reversion of cardiomegaly, which was impressively demonstrated by follow-up chest-x-rays. CONCLUSION: Arteriovenous fistulas should be monitored regularly after kidney transplantation to avoid congestive heart failure and other serious complications. PMID- 23661143 TI - Duplex ultrasound volumetric flow analysis before and after hemodialysis in patients with brachio-cephalic fistulae. AB - PURPOSE: The United Kingdom Renal Association recommends duplex ultrasound to monitor arteriovenous fistula (AVF) flow rates during surveillance. Significant flow rate changes should prompt further investigation or treatment to avoid a failing fistula. Hemodialysis is known to alter the hemorrheologic and physiologic factors with a potential impact on measured flow rates. The aim of this study was to determine the difference in flow rate measured with duplex ultrasound before and after a single hemodialysis session in patients with brachial-cephalic fistulae. METHODS: Patients with brachial-cephalic AVFs in our dialysis populations who were undergoing regular hemodialysis without recent intervention (less than six weeks) were invited to participate. Flow measurements were made pre-and post-hemodialysis using a Zonare ultrasound machine. The vascular scientist was always blinded to the pre-hemodialysis flow. RESULTS: A total of 157 patients were identified with brachial-cephalic fistulae. Following exclusions, 119 patients were eligible. However, a further 58 were excluded because they declined or did not attend leaving 61 patients in the study. Paired t test showed a statistically significant reduction in flow rate of 105 mL/min (P=0.026) post-hemodialysis which equates to a -6.9% change in flow (95% C.I. 12.7 to -0.8%). Bland-Altman analysis showed limits of flow rate agreement between -599 mL/min and +810 mL/min (+/-1.96 s.d.). CONCLUSIONS: Whilst we have shown a statistically significant change in flow rate post-hemodialysis, this is small and should be taken in the context of previously accepted interobserver variability. Therefore, the practical and financial considerations of implementing an AVF surveillance programme are likely to outweigh the minimal benefit of consistency that would be enabled by strict protocol of pre hemodialysis flow measurements. PMID- 23661145 TI - Toward the establishment of standardized in vitro tests for lipid-based formulations, part 3: understanding supersaturation versus precipitation potential during the in vitro digestion of type I, II, IIIA, IIIB and IV lipid based formulations. AB - PURPOSE: Recent studies have shown that digestion of lipid-based formulations (LBFs) can stimulate both supersaturation and precipitation. The current study has evaluated the drug, formulation and dose-dependence of the supersaturation - precipitation balance for a range of LBFs. METHODS: Type I, II, IIIA/B LBFs containing medium-chain (MC) or long-chain (LC) lipids, and lipid-free Type IV LBF incorporating different doses of fenofibrate or tolfenamic acid were digested in vitro in a simulated intestinal medium. The degree of supersaturation was assessed through comparison of drug concentrations in aqueous digestion phases (APDIGEST) during LBF digestion and the equilibrium drug solubility in the same phases. RESULTS: Increasing fenofibrate or tolfenamic acid drug loads (i.e., dose) had negligible effects on LC LBF performance during digestion, but promoted drug crystallization (confirmed by XRPD) from MC and Type IV LBF. Drug crystallization was only evident in instances when the calculated maximum supersaturation ratio (SR(M)) was >3. This threshold SR(M) value was remarkably consistent across all LBF and was also consistent with previous studies with danazol. CONCLUSIONS: The maximum supersaturation ratio (SR(M)) provides an indication of the supersaturation 'pressure' exerted by formulation digestion and is strongly predictive of the likelihood of drug precipitation in vitro. This may also prove effective in discriminating the in vivo performance of LBFs. PMID- 23661144 TI - The effects of angiotensin-converting enzyme-inhibitory peptide LAP on the left common carotid artery remodeling in spontaneously hypertensive rats. AB - OBJECTIVE: To investigate the protective effect of angiotensin-converting enzyme (ACE)-inhibitory peptide LAP on the left common carotid artery remodeling in spontaneously hypertensive rats (SHRs). METHODS: A cohort of male SHRs were randomly divided into three groups (n = 10 for each group): pseudo-experimental group, enalapril-treated group as a positive control group, ACE-inhibitory peptide LAP-treated group. After the experiment, the left common carotid artery from each rat was removed for morphological evaluation. RESULTS: It was observed that the vascular medial thickness, media thickness/lumen diameter, medial cross sectional area and mean nuclear area of smooth muscle cells of the left common carotid artery in the LAP group or enalapril group were significantly lower than those in the pseudo-experimental group, while there was no significant difference in these parameters observed between the LAP group and enalapril group. Additionally, the vascular area percentage of collagen fibers of the left common carotid artery in the LAP group and enalapril group was significantly lower than that of the pseudo-experimental group. CONCLUSIONS: The protective vessel remodeling effect in SHRs was observed with ACE-inhibitory peptide LAP in SHRs by decreasing blood pressure, inhibiting smooth muscle cell hypertrophy and reducing the proliferation of collagen fibers. PMID- 23661146 TI - Effects of cerium oxide nanoparticles on PC12 neuronal-like cells: proliferation, differentiation, and dopamine secretion. AB - PURPOSE: Oxidative stress has been found to play a key role in several diseases, that range from cancer to neurodegenerative disorders. Besides traditional anti oxidant agents, in recent years much attention has been focused on nanotechnological solutions, including cerium oxide nanoparticles (nanoceria). METHODS: Thanks to its extraordinary catalytic properties, nanoceria mimics the activity of superoxide dismutase and of catalase, therefore acting as a reactive oxygen species (ROS) scavenger in many biological contexts. In this paper, we report on nanoceria interactions with PC12 cell line, that represents a valuable model for many features of central dopaminergic neurons. RESULTS: Nanoceria confirmed a strong anti-ROS action but, most interestingly, also showed beneficial effects on both cell differentiation and dopamine production. CONCLUSIONS: Even if deeper examinations will be necessary in order to better clarify the mechanisms at the base of the documented effects, nanoceria demonstrated a significant potential as pharmacological agent in the treatment of neurological disorders. PMID- 23661147 TI - Neuromuscular function, hormonal and redox status and muscle damage of professional soccer players after a high-level competitive match. AB - The main aim was to analyse the impact of an official match on hormonal and redox status, muscle damage and inflammation and neuromuscular function. Seven high level male soccer players from the same team performed an official match and data were collected 72 h before, 24, 48 and 72 h post-match. Plasma testosterone/cortisol ratio (T/C), creatine kinase (CK), superoxide dismutase (SOD), glutathione peroxidase (GPX) and reductase (GR) activities, myoglobin (Mb), C-reactive protein (CRP), uric acid (UA), protein sulfhydryls (-SH), malondialdehyde (MDA) concentrations and total antioxidant status (TAS) were measured. Sprint, jump and change of direction performance, and maximal isokinetic knee extension and flexion were obtained as neuromuscular functional parameters. Cortisol increased and T/C decreased until 48 h recovery (P < 0.05). Mb, CRP and -SH (P < 0.05) increased at 24 h and CK, TAS, SOD and MDA (P < 0.05) increased up to 48 h recovery. GR increased and GPX decreased at 24 h recovery (P < 0.05). Jump performance decreased 24 h post-match (P < 0.05), but no significant alterations in sprint, change of direction and muscle strength were observed. In conclusion, an official match resulted in changes in plasma biomarkers until 48 h of recovery period, without major impact on performance. PMID- 23661148 TI - Parents' education and the risk of major depression in early adulthood. AB - BACKGROUND: Early-life low socioeconomic position (SEP) increases the risk of adult major depression; however, associations vary according to the measure of SEP and adults' life stage. Although maternal education often predicts offspring health better than other SEP indicators, including paternal education, it is unclear how maternal and paternal education differentially influence early-adult depression, and how early-life and adult risk factors may mediate the association. METHODS: Longitudinal data come from the Canadian National Population Health Survey from 1994/1995 to 2006/2007, restricted to a sample (N = 1,267) that was aged 12-24 years in 1994/1995. Past-year major depressive episode (MDE) was assessed in 2004/2005 and 2006/2007 using the Composite International Diagnostic Interview Short Form for Major Depression. Logistic regression models were used to estimate odds ratios (OR) and 95 % confidence intervals (CI) for the association between both maternal and paternal education and MDE, adjusting for respondent's demographics, early-life adversities, adult SEP, psychosocial factors, and physical health. RESULTS: Offsprings of mothers with less than secondary school education had higher odds of MDE (adjusted OR 2.04, 95 % CI 1.25 3.32) relative to those whose mothers had more education. Paternal education was not associated with MDE. Although adult income, student status, psychosocial stress, and several early-life adversities remained associated with MDE in the fully adjusted model, the estimate for maternal education was not reduced. CONCLUSIONS: Maternal education was associated with MDE in early adulthood, independent of paternal education and other early-life and early-adult risk factors. PMID- 23661149 TI - Perceived emotional support in remission: results from an 18-month follow-up of patients with early episode psychosis. AB - PURPOSE: Serious mental illness is known for the damage that it inflicts on the social network and social support of patients. Although many studies have used relapse and rehospitalisation as outcomes, recent research has emphasized the importance of a fuller definition of recovery that includes social function. In this study, our goal is to investigate the association of social support with sustained remission in patients with early episode psychosis. METHODS: A secondary analysis of remission and social support was performed with 123 of 144 patients enrolled in the Lambeth Early Onset randomized clinical trial who ever achieved symptom-free status in 18 months of follow-up. Social support was measured by hours of family contact, perceived support, and network size at 6 months into an early intervention treatment program. Consensus judgments made by clinicians on symptom status at each of 18 months of follow-up were analyzed for consecutive months spent in remission. Direct and mediated effects of social support on remission were calculated using Poisson regression and path analysis, respectively. RESULTS: 114 of 123 patients achieved remission after about 7 months on average [mean 6.81 (SD 4.17)]. In univariate models, perceived emotional support predicted longer time spent in remission, while moderate family contact predicted shorter remission duration. Perceived practical support was not associated with remission. Perceived emotional support mediated the association between family contact and remission and between network size and remission. These results are not totally attributable to a specialized early intervention treatment. CONCLUSION: Structural measures of support probably contribute to the maintenance of remission through the patient's perception of emotional support. PMID- 23661151 TI - Large spin splitting of metallic surface-state bands at adsorbate-modified gold/silicon surfaces. AB - Finding appropriate systems with a large spin splitting of metallic surface-state band which can be fabricated on silicon using routine technique is an essential step in combining Rashba-effect based spintronics with silicon technology. We have found that originally poor structural and electronic properties of the Au/Si(111) ?3 x ?3 surface can be substantially improved by adsorbing small amounts of suitable species (e.g., Tl, In, Na, Cs). The resultant surfaces exhibit a highly-ordered atomic structure and spin-split metallic surface-state band with a momentum splitting of up to 0.052 A(-1) and an energy splitting of up to 190 meV at the Fermi level. The family of adsorbate-modified Au/Si(111) ?3 x ?3 surfaces, on the one hand, is thought to be a fascinating playground for exploring spin-splitting effects in the metal monolayers on a semiconductor and, on the other hand, expands greatly the list of material systems prospective for spintronics applications. PMID- 23661150 TI - Serious psychological distress among non-Hispanic whites in the United States: the importance of nativity status and region of birth. AB - PURPOSE: Serious psychological distress (SPD) is an understudied health topic. When studied, estimates for minority groups are compared to that of non-Hispanic whites. Non-Hispanic whites are heterogeneous, and comprise individuals from Europe, North Africa or the Middle East. The objectives of this study are to estimate and compare the sex- and age-adjusted prevalence of SPD first by nativity status and then by region of birth (Europe, Middle East and Russia) while controlling for potential confounders. METHODS: The sample consisted of 196,483 participants, 18 years of age or older in the National Health Interview Survey (2000-2010). To measure SPD, Kessler's K6 Likert scale was used. Individuals with scores greater than or equal to 13 were considered to have SPD. RESULTS: The age- and sex- adjusted prevalence of SPD was 3 % for foreign-born non-Hispanic whites. Of this, estimates were 6 % for those from the Middle East, 3 % for Europe and 2 % for Russia (p = 0.00). In the fully adjusted multivariable model, foreign-born non-Hispanic whites from the Middle East were more likely (OR = 1.76; 95 % CI = 1.01, 3.04) to report SPD when compared to US-born non-Hispanic whites. Within the foreign-born population, non-Hispanic whites from the Middle East were more than twice as likely to report SPD (OR = 2.43; 95 % CI = 1.15, 5.14) compared to foreign-born non-Hispanic whites from Europe after controlling for confounders. CONCLUSIONS: This study's findings will help researchers understand which subgroups within non-Hispanic whites suffer most from SPD, which will facilitate tailored prevention intervention efforts. PMID- 23661152 TI - High life in the sky? Mortality by floor of residence in Switzerland. AB - Living in high-rise buildings could influence the health of residents. Previous studies focused on structural features of high-rise buildings or characteristics of their neighbourhoods, ignoring differences within buildings in socio-economic position or health outcomes. We examined mortality by floor of residence in the Swiss National Cohort, a longitudinal study based on the linkage of December 2000 census with mortality and emigration records 2001-2008. Analyses were based on 1.5 million people living in buildings with four or more floors and 142,390 deaths recorded during 11.4 million person-years of follow-up. Cox models were adjusted for age, sex, civil status, nationality, language, religion, education, professional status, type of household and crowding. The rent per m2 increased with higher floors and the number of persons per room decreased. Mortality rates decreased with increasing floors: hazard ratios comparing the ground floor with the eighth floor and above were 1.22 [95% confidence interval (CI) 1.15-1.28] for all causes, 1.40 (95% CI 1.11-1.77) for respiratory diseases, 1.35 (95% CI 1.22 1.49) for cardiovascular diseases and 1.22 (95% CI 0.99-1.50) for lung cancer, but 0.41 (95% CI 0.17-0.98) for suicide by jumping from a high place. There was no association with suicide by any means (hazard ratio 0.81; 95% CI 0.57-1.15). We conclude that in Switzerland all-cause and cause-specific mortality varies across floors of residence among people living in high-rise buildings. Gradients in mortality suggest that floor of residence captures residual socioeconomic stratification and is likely to be mediated by behavioural (e.g. physical activity), and environmental exposures, and access to a method of suicide. PMID- 23661153 TI - Naringenin (citrus flavonone) induces growth inhibition, cell cycle arrest and apoptosis in human hepatocellular carcinoma cells. AB - Search for new substances with antiproliferative activity and apoptosis inducing potential towards HepG2 cells is important since HCC is notoriously resistant to conventional chemotherapy. Dietary phytochemicals with significant anti proliferative and apoptosis inducing potential are considered as agents promising for cancer therapy. Naringenin, a common dietary flavonoid abundantly present in fruits and vegetables, is believed to possess strong cytotoxic activity in numerous types of cancer cells. However, the detailed molecular mechanisms of its antiproliferative effects and apoptosis induction are still unclear. In this study, we investigated antiproliferative and apoptosis-inducing effect of naringenin in human hepatocellular carcinoma HepG2 cells. Naringenin was shown to inhibit the proliferation of HepG2 cells resulted partly from an accumulation of cells in the G0/G1 and G2/M phase of the cell cycle. Naringenin induced a rapid accumulation of p53, which might account for the naringenin-induced G0/G1 and G2/M phase arrests in Hep G2 cells. In addition, naringenin have been shown to induce apoptosis as evidenced by nuclei damage and increased proportion of apoptotic cells detected by flow cytometry analysis. Naringenin triggered the mitochondrial-mediated apoptosis pathway as shown by an increased ratio of Bax/Bcl-2, subsequent release of cytochrome C, and sequential activation of caspase-3. Our results showed that naringenin had inhibitory effect on the growth of HepG2 cell line through inhibition of cell proliferation and apoptosis induction. The elucidation of the drug targets of naringenin on inhibition of tumor cells growth should enable further development of naringenin for liver cancer therapy. PMID- 23661154 TI - There is no significant association between death receptor 4 (DR4) gene polymorphisms and lung cancer in Turkish population. AB - Death receptor 4 (DR4) gene is a candidate tumor suppressor gene that has a role in apoptotic pathway. It was reported in literature that polymorphisms in DR4 gene lead to susceptibility to many cancers. In accordance with this information, we aimed to investigate the association between G422A, C626G, A683C and A1322G polymorphisms in DR4 gene and lung cancer. We selected 60 patients with lung cancer (LC) and 30 healthy, sex and age matched volunteers randomly. Four polymorhisms, G422A, C626G, A683C and A1322G, in DR4 gene were analyzed with Polymerase Change Reaction (PCR)--Restriction Fragment Lenght Polymorphism (RFLP) and Amplification Refractory Mutation System (ARMS) techniques in both groups. Our results showed that there are no statistically significances between the patients and controls in terms of the G422A, C626G, A683C and A1322G polymorphisms in DR4 gene (p > 0,05). Our findings showed no role of DR4 gene polymorphisms in susceptibility to LC and provide a plausible explanation for DR4 genetic heterogeneity in LC susceptibility. PMID- 23661155 TI - Correlation between microRNA-34a levels and lens opacity severity in age-related cataracts. AB - PURPOSE: MicroRNA 34a (miR-34a) is involved in regulating tissue senescence. However, the role of miR-34a in age-related cataracts is unclear. In this study, we evaluated the correlations among the severity of lens opacity, patient age, and miR-34a expression level in the lens epithelium of age-related cataracts for clarifying the role of miR-34a in the lens senescence. METHODS: This study was carried as a case control study in the Department of Ophthalmology, Taipei Veterans General Hospital, Taiwan. We recorded age of each patient at the time of their cataract surgery and information regarding lens opacity according to a modified version of the Lens Opacities Classification System III. Correlations among age, lens opacity, and miR-34a expression levels were evaluated. RESULTS: This study evaluated 110 patients with a mean age of 73.19 years (SD+/-10.2). Older patients had higher nuclear cataract (NC), cortical (C), and posterior subcapsular cataract (P) scores (one-way analysis of variance (ANOVA), P<0.05). miR-34a expression levels were significantly different between each age group (ANOVA post hoc Bonferroni's test, P<0.001), and there were moderate correlations between high NC, C, and P cataract scores and high miR-34a levels (Pearson correlation coefficient; R=0.606, 0.575, and 0.515, respectively). CONCLUSIONS: The current study demonstrated positive correlations between high miR-34a levels and high lens opacity severity in NC, C, or P cataracts. These results suggest that miR-34a expression has a role in lens senescence. PMID- 23661156 TI - Retinal video recordings at different compression levels: a novel video-based imaging technology for diabetic retinopathy screening. AB - BACKGROUND: To evaluate the optimal compression level of retinal color digital video recordings, a novel video-based imaging technology, in screening for diabetic retinopathy (DR). DESIGN: Evaluation of a diagnostic technique. METHODS: A total of 36 retinal videos, captured using EyeScan (Ophthalmic Imaging System), were compressed from original uncompressed file size of 1 GB (gigabyte) to four different compression levels-100 MB (megabyte) (Group 1); 30 MB (Group 2); 20 MB (Group 3); and 5 MB (Group 4). The videos were subsequently interpreted by an ophthalmologist and a resident using the International Clinical Diabetic Retinopathy Severity Scales. MAIN OUTCOME MEASURES: The sensitivity, specificity and kappa coefficient for DR grading detected by were calculated for each compression level (Groups 1-4), with reference to the original uncompressed retinal videos. RESULTS: Groups 1, 2, and 3 graded by both readers had sensitivity and specificity >90% in detecting DR, whereas for group 4, the sensitivity and specificity were 70.6% and 94.7% for ophthalmologist and 80.0% and 72.2% medical officer, respectively. The kappa correlation in detecting DR for groups 1, 2, and 3 were >0.95, whereas for Group 4, the kappa was 0.76 and 0.66 for ophthalmologist and medical officer, respectively. CONCLUSION: Retinal video recording is a novel and effective DR screening technique with high sensitivity, specificity and kappa correlation. With its compressibility, this is a potential effective technique that can be widely implemented in a routine, mobile, and tele-ophthalmology setting for DR screening services. PMID- 23661157 TI - Serum YKL-40 levels as a novel marker of inflammation and endothelial dysfunction in patients with pseudoexfoliation syndrome. AB - PURPOSE: To evaluate serum levels of YKL-40 in patients with pseudoexfoliation syndrome (PEX) in comparison with those of age- and sex-matched healthy subjects. METHODS: Forty patients with PEX (PEX group) and 40 age- and sex-matched control subjects (control group) were enrolled in the study. An enzyme immunoassay method using the commercially available test MicroVue YKL-40 was used to measure serum YKL-40 concentration. Systolic and diastolic blood pressures, serum levels of high sensitivity C-reactive protein (hsCRP), total cholesterol, low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglycerides were also examined. RESULTS: The mean age was 54.4+/-7.6 (ranging 41-65) years in each group. The mean serum YKL-40 level of the PEX group was significantly higher than that of the control group (P<0.001). In addition, the mean serum HsCRP, total cholesterol, LDL, and triglycerides levels were significantly higher, and mean serum HDL level was significantly lower in the PEX group than in the control group (all P<0.001, excluding both P=0.002 for triglycerides and HDL levels). Further, the mean systolic and diastolic blood pressures were significantly higher in the PEX group than in the control group (P1=0.001 and P2=0.01, respectively). CONCLUSION: We have shown a relationship between PEX and elevated serum levels of YKL-40. We imply that a better understanding of the role of YKL-40 in the pathogenesis of endothelial dysfunction and atherosclerosis is necessary to develop new therapies for preventing or treating PEX. Further studies are warranted to clarify the clinical relevance of these findings. PMID- 23661158 TI - Mutual information, perceptual independence, and holistic face perception. AB - The concept of perceptual independence is ubiquitous in psychology. It addresses the question of whether two (or more) dimensions are perceived independently. Several authors have proposed perceptual independence (or its lack thereof) as a viable measure of holistic face perception (Loftus, Oberg, & Dillon, Psychological Review 111:835-863, 2004; Wenger & Ingvalson, Learning, Memory, and Cognition 28:872-892, 2002). According to this notion, the processing of facial features occurs in an interactive manner. Here, I examine this idea from the perspective of two theories of perceptual independence: the multivariate uncertainty analysis (MUA; Garner & Morton, Definitions, models, and experimental paradigms. Psychological Bulletin 72:233-259, 1969), and the general recognition theory (GRT; Ashby & Townsend, Psychological Review 93:154-179, 1986). The goals of the study were to (1) introduce the MUA, (2) examine various possible relations between MUA and GRT using numerical simulations, and (3) apply the MUA to two consensual markers of holistic face perception(-)recognition of facial features (Farah, Wilson, Drain, & Tanaka, Psychological Review 105:482-498, 1998) and the composite face effect (Young, Hellawell, & Hay, Perception 16:747-759, 1987). The results suggest that facial holism is generated by violations of several types of perceptual independence. They highlight the important theoretical role played by converging operations in the study of holistic face perception. PMID- 23661159 TI - What makes an event: temporal integration of stimuli or actions? AB - In this article, we ask what serves as the "glue" that temporarily links information to form an event in an active observer. We examined whether forming a single action event in an active observer is contingent on the temporal presentation of the stimuli (hence, on the temporal availability of the action information associated with these stimuli), or on the learned temporal execution of the actions associated with the stimuli, or on both. A partial-repetition paradigm was used to assess the boundaries of an event for which the temporal properties of the stimuli (i.e., presented either simultaneously or temporally separate) and the intended execution of the actions associated with these stimuli (i.e., executed as one, temporally integrated, response or as two temporally separate responses) were manipulated. The results showed that the temporal features of action execution determined whether one or more events were constructed; the temporal presentation of the stimuli (and hence the availability of their associated actions) did not. This suggests that the action representation, or "task goal," served as the "glue" in forming an event in an active observer. These findings emphasize the importance of action planning in event construction in an active observer. PMID- 23661163 TI - Study proposes antibiotics as possible new treatment for some types of chronic low back pain. PMID- 23661160 TI - Intratumoral treatment of smaller mouse neuroblastoma tumors with a recombinant protein consisting of IL-2 linked to the hu14.18 antibody increases intratumoral CD8+ T and NK cells and improves survival. AB - Hu14.18-IL2 is an immunocytokine (IC) consisting of human IL-2 linked to hu14.18 mAb, which recognizes GD2 disialoganglioside. Phase II clinical trials of intravenous-hu14.18-IL2 (IV-IC) in neuroblastoma and melanoma are underway, and have already demonstrated activity in neuroblastoma. In our Phase II trial, lower neuroblastoma burden at the time of treatment was associated with a greater likelihood of clinical response to IV-IC. We have previously shown that intratumoral-hu14.18-IL2 (IT-IC) compared to IV-IC results in enhanced local and systemic antitumor activity in tumor-bearing mice. We utilized a mouse model to investigate the impact of tumor burden on hu14.18-IL2 treatment efficacy in IV- versus IT-treated animals. Studies presented here describe the analyses of tumor burden at the initiation of treatment and its effects on treatment efficacy, survival, and tumor-infiltrating leukocytes in A/J mice bearing subcutaneous NXS2 neuroblastoma. We show that smaller tumor burden at treatment initiation is associated with increased infiltration of NK and CD8+ T cells and increased overall survival. NXS2 tumor shrinkage shortly after completion of the 3 days of hu14.18-IL2 treatment is necessary for long-term survival. This model demonstrates that tumor size is a strong predictor of hu14.18-IL2-induced lymphocyte infiltration and treatment outcome. PMID- 23661161 TI - Structure of the UreD-UreF-UreG-UreE complex in Helicobacter pylori: a model study. AB - The molecular details of the protein complex formed by UreD, UreF, UreG, and UreE, accessory proteins for urease activation in the carcinogenic bacterium Helicobacter pylori, have been elucidated using computational modeling. The calculated structure of the complex supports the hypothesis of UreF acting as a GTPase activation protein that facilitates GTP hydrolysis by UreG during urease maturation, and provides a rationale for the design of new drugs against infections by ureolytic bacterial pathogens. PMID- 23661164 TI - Heteroleptic tris-cyclometalated iridium(III) complexes supported by an o carboranyl-pyridine ligand. AB - Heteroleptic tris-cyclometalated Ir(III) complexes supported by the o-carboranyl pyridine (CBpy) as a novel C^N chelating ligand were synthesized and characterized. While the CBpy ligand contributes to the electronic stabilization of complexes, their photophysical properties are dominated by 2-arylpyridine ligands. PMID- 23661165 TI - Fluorescent silver(I) and gold(I)-N-heterocyclic carbene complexes with cytotoxic properties: mechanistic insights. AB - Silver(I) and gold(I)-N-heterocyclic carbene (NHC) complexes bearing a fluorescent anthracenyl ligand were examined for cytotoxicity in normal and tumor cells. The silver(I) complex exhibits greater cytotoxicity in tumor cells compared with normal cells. Notably, in cell extracts, this complex determines a more pronounced inhibition of thioredoxin reductase (TrxR), but it is ineffective towards glutathione reductase (GR). Both gold and silver complexes lead to oxidation of the thioredoxin system, the silver(I) derivative being particularly effective. In addition, the dimerization of peroxiredoxin 3 (Prx3) was also observed, demonstrating the ability of these compounds to reach the mitochondrial target. The fluorescence microscopy visualization of the subcellular distribution of the complexes shows a larger diffusion of these molecules in tumor cells with respect to normal cells. PMID- 23661166 TI - Raman spectral characteristics of 4-aminobenzenethiol adsorbed on ZnO nanorod arrays. AB - Interest in the surface-enhanced Raman scattering (SERS) of 4-aminobenzenethiol (4-ABT) has surged recently. The SERS spectral features are highly dependent on the measurement conditions; a notable example is the appearance of b2-type bands that are not evident in the normal Raman (NR) spectrum. In an effort to discover new information and make any necessary corrections, we measured the Raman spectrum of 4-ABT adsorbed on a semiconducting material that would only enable the chemical enhancement mechanism; accordingly, the Raman spectrum of 4-ABT adsorbed on ZnO nanorods grown on an indium tin oxide substrate was measured for the first time. In the NR spectrum of the zinc salt of 4-ABT, which was taken as a reference, only the a1-type bands of 4-ABT were identified. However, in the surface Raman spectrum of 4-ABT on ZnO, the b2-type bands were also clearly evident, suggesting that the b2-type bands arose owing to its adsorption onto ZnO. The b2-type bands were also observed for 4-ABT analogs adsorbed on ZnO; this confirms that the b2-type bands were not a result of a surface-catalyzed photoreaction. Based on electric-potential and excitation-wavelength dependence studies, the a1- and b2-type bands were attributed to a charge-transfer (CT) transition from the surface defect levels of ZnO to the unoccupied La and Lb states (in Platt's notation) of 4-ABT, respectively; the bands gained intensity via the Herzberg-Teller coupling terms. The enhancement factor associated with the CT transition was estimated to be around 22, suggesting that it is, at best, a moderately effective process. PMID- 23661167 TI - Metal ion selectivity of the vanadium(V)-reductase Vanabin2. AB - In a previous study, Vanabin2, a member of a family of V(IV)-binding proteins, or Vanabins, was shown to act as a V(V)-reductase. The current study assesses the ability of Vanabin2 to reduce various transition metal ions in vitro. An NADPH coupled oxidation assay yielded no evidence of reduction activity with the hexavalent transition metal anions, Mo(VI)O4(2-) and W(VI)O4(2-), or with three divalent cations, Mn(II), Ni(II), and Co(II). Although Cu(II) is readily reduced by glutathione and is gradually oxidized in air, this process was not affected by the presence of Vanabin2. In the experiments conducted thus far, Vanabin2 acts only as a V(V)-reductase. This high selectivity may account for the metal ion selectivity of vanadium accumulation in ascidians. PMID- 23661168 TI - Acute toxicity of heavy metals to Tetrahymena in an in vitro experiment and envelope damage study. AB - The toxicity of Cr3+, Cu2+ and Cd2+ to Tetrahymena growth metabolism was studied by microcalorimetry at 28 degrees C, and the growth constant (k), peak time (T) and generation times (T(G)) were calculated. The metal ion concentrations that resulted in 50% inhibition (IC50) of population growth were obtained through the dynamic parameters. The results indicated that the order of toxicity was Cd2+> Cr3+> Cu2+. Inductively coupled plasma-atomic emission spectrometry results suggested that the metal ions affected the permeability of the cell membrane. Observations of the Cd-exposed organisms by scanning electron microscopy revealed damage to the cell membrane in the form of an altered surface appearance. The cells suffered serious damage after sufficient acting time. Attenuated total reflection Fourier transform infrared spectra revealed that amide groups and PO2- of the phospholipid phospho-diester, both located in the hydrophobic end of the outer layer of the cell membrane, were most readily affected. PMID- 23661169 TI - "High rate of recurrent adenomatosis during endoscopic surveillance after duodenectomy in patients with familial adenomatous polyposis". AB - Advanced duodenal adenomatosis in patients with familial adenomatous polyposis (FAP) is associated with a significant risk of duodenal carcinoma. Duodenectomy is sometimes indicated to prevent malignant transformation or to resect established carcinomas. Advanced recurrent adenomatosis and cancer formation in the neo-duodenum after duodenectomy in FAP have been reported. The aim of this study was to describe findings during endoscopic follow-up in a cohort of FAP patients after duodenectomy, to assess the indication and whether recommendations can be made for endoscopic surveillance. All FAP patients with a history of duodenectomy performed at a single tertiary referral centre between January 2000 and July 2011 were identified. Patient characteristics and postoperative upper endoscopic procedures were reviewed retrospectively. 19 patients, with a mean age of 49 years at the time of duodenectomy were identified. One patient was lost to follow-up. The majority of patients underwent prophylactic pancreas preserving duodenectomy (95%). Mean duration of postoperative follow-up in 18 patients was 78 months with 4 postoperative endoscopies on average. An increase in neo Spigelman stage was seen in 9 patients, after an average interval of 35 months. Overall, newly formed adenomas in the neo-duodenum were found in 14 of 18 patients (78%), after a mean of 46 months after duodenectomy. Recurrent adenomas were mostly located in close proximity to the neo-papilla. This included advanced adenomas in 7 patients, warranting enteric re-resection in 2 patients. Continued intensive endoscopic surveillance is indicated after duodenectomy in FAP, especially of the area around the bilio- and pancreatico-enteric anastomoses. PMID- 23661170 TI - Foreword for "100 years of Lynch syndrome". PMID- 23661172 TI - Community pharmacy practice in China: past, present and future. AB - BACKGROUND: In 2009, China launched a new healthcare system, with reform of the primary healthcare system as its foundation and focus, to enable residents to access primary healthcare for simple health problems instead of seeking help at hospitals. Community pharmacies and pharmacists were to have increased responsibility in primary healthcare by delivering pharmaceutical care services in China in addition to their traditional roles of dispensing prescriptions and selling medicines. AIM OF THE REVIEW: To describe the current status of Chinese community pharmacy education and practice, and discuss future directions. METHOD: A literature search was conducted using MEDLINE and International Pharmaceutical Abstracts. Additional articles were identified through the cross-referencing of articles and books. Additional data were found from relevant websites. RESULTS: From the 313 publications identified, 98 were included. China currently has 388,000 retail pharmacies, corresponding to one pharmacy per 3,532 population. All pharmacies provide prescription and over-the-counter products, as well as prescription dispensing and patient counselling. However, the lack of reimbursement mechanisms reduces the willingness of pharmacists to offer high quality dispensing and counselling services. There is a shortage of qualified pharmacists to meet increasing patient needs. This, coupled with a shortage of pharmacist training, has resulted in pharmaceutical care being a low priority for delivery in routine pharmacy practice. To meet the increasing demand for pharmacists, 25 universities have been allowed to offer BS, MS and PhD degrees (3 7 years in length) in clinical pharmacy since 2008. The adoption of Good Pharmacy Practice as a recommended standard for community pharmacy practice provides pharmacists with a framework to aid them in service delivery. CONCLUSION: A number of undertakings still require development, including the enactment of the Chinese Pharmacist Law, development of a standard for pharmaceutical care activities, development of the pharmacy workforce, increasing public awareness of pharmacists, and proper reimbursement for care provision. Although pharmaceutical care services are underdeveloped in China, they will become an integral part of the professional work of all pharmacists in the future, particularly in community pharmacy settings. PMID- 23661173 TI - Potentially inappropriate prescribing among older residents in a geriatric hospital in Israel. AB - BACKGROUND: STOPP/START ("screening tool of older persons potentially inappropriate prescriptions"/"screening tool to alert doctors to right treatment") criteria were formulated to identify potentially inappropriate prescriptions (PIP) and potential prescription omissions (PPO) in older people. OBJECTIVE: To determine the prevalence of PIP and PPO using STOPP/START criteria and to identify associated risk factors. METHOD: Data were prospectively collected from 382 residents' records in an Israeli geriatric hospital. The study population included subjects >= 65 years of age who were taking at least one medication. Data on demographics, medical histories, current diagnoses, current medications and biochemistry results were collected and analyzed. STOPP/START criteria were applied to each medical file. RESULTS: A total of 359 residents comprised the study group (mean age [+/- SD] 82.7 +/- 8.7, 66.6 % females). STOPP identified 430 instances of PIP in 243 (67.7 %) residents, and START identified 151 PPO in 122 (34 %) residents. The number of medications (OR: 1.2, 95 % CI 1.11 1.3), falls (OR: 1.16, 95 % CI 1.021-1.32) and hospitalizations (OR: 1.25, 95 % CI 1.025-1.53) were identified as predictors for STOPP-defined PIP. The Charlson Comorbidity Index (OR: 1.4, 95 % CI 1.17-1.7) was associated with START-defined PPO. CONCLUSION: A high prevalence of PIP/PPO was found among geriatric patients and was associated with number of medications, falls, hospitalizations and Charlson Comorbidity Index score. PMID- 23661171 TI - CYP2C19 genotypes and their impact on clopidogrel responsiveness in percutaneous coronary intervention. AB - BACKGROUND: Cytochrome P450 2C19 (CYP2C19) loss-of-function polymorphisms are more common in Asian populations and have been associated with diminished antiplatelet response to clopidogrel. In this era of 'personalised medicine', combining genotyping and phenotyping as a strategy to personalise antiplatelet therapy warrants further exploration. OBJECTIVE: This study aimed to investigate the prevalence and impact of CYP2C19*2, *3 and *17 genotypes on clopidogrel responsiveness in a multiethnic Malaysian population planned for percutaneous coronary intervention. SETTING: Between October 2010 and March 2011, a total of 118 consecutive patients planned for percutaneous coronary intervention were enrolled in Sarawak General Hospital, Borneo. All patients received at least 75 mg aspirin daily for at least 2 days and 75 mg clopidogrel daily for at least 4 days prior to angiography. METHOD: Genotyping for CYP2C19*2 (rs4244285, 681G > A), *3 (rs4986893, 636G > A) and *17 (rs11188072, -3402C > T) alleles were performed by polymerase chain reaction-restriction fragment linked polymorphism method. Whole blood ADP-induced platelet aggregation was assessed with multiple electrode platelet aggregometry (MEA) using the Multiplate Analyzer. MAIN OUTCOME MEASURES: The distribution of CYP2C19*2, *3 and *17 among different ethnic groups and the association between genotype, clopidogrel responsiveness and clinical outcome were the main outcome measures. RESULTS: The highest prevalence of poor metabolisers (carriers of at least one copy of the *2 or *3 allele) was among the Chinese (53.7 %), followed by the Malays (26.9 %), Ibans (16.4 %) and other races (3.0 %). Poor metabolisers (PMs) had the highest mean MEA (303.6 AU*min), followed by normal metabolisers (NMs) with 270.5 AU*min and extensive metabolisers (EMs) with 264.1 AU*min (p = 0.518). Among poor responders to clopidogrel, 65.2 % were PMs and NMs, respectively, whereas none were EMs (p = 0.350). Two cardiac-related deaths were reported. CONCLUSION: There was a diverse inter-ethnic difference in the distribution of CYP2C19 polymorphism. The findings of this study echo that of other studies where genotype appears to have a limited impact on clopidogrel responsiveness and clinical outcome in low-risk patients. PMID- 23661175 TI - Asymmetric synthesis of gem-diaryl substituted cyclic sulfamidates and sulfamides by rhodium-catalyzed arylation of cyclic ketimines. AB - Asymmetric addition of arylboronates to aryl-substituted cyclic ketimines proceeded in the presence of a rhodium catalyst coordinated with a chiral diene ligand to give high yields of sulfamidates and sulfamides with high enantioselectivity (up to 99% ee). PMID- 23661174 TI - A six-plex proteome quantification strategy reveals the dynamics of protein turnover. AB - MS1 full scan based quantification is one of the most popular approaches for large-scale proteome quantification. Typically only three different samples can be differentially labeled and quantified in a single experiment. Here we present a two stages stable isotope labeling strategy which allows six different protein samples (six-plex) to be reliably labeled and simultaneously quantified at MS1 level. Briefly in the first stage, isotope lysine-d0 (K0) and lysine-d4 (K4) are in vivo incorporated into different protein samples during cell culture. Then in the second stage, three of K0 and K4 labeled protein samples are digested by lysine C and in vitro labeled with light (2CH3), medium (2CD2H), and heavy (2(13)CD3) dimethyl groups, respectively. We demonstrated that this six-plex isotope labeling strategy could successfully investigate the dynamics of protein turnover in a high throughput manner. PMID- 23661176 TI - Familial risk of childhood cancer and tumors in the Li-Fraumeni spectrum in the Utah Population Database: implications for genetic evaluation in pediatric practice. AB - We used the Utah Population Database to examine risk of cancer in relatives of 4,482 pediatric cancer cases (<=18 years old) diagnosed from 1966 to 2009 compared to matched population controls. We quantified cancer risk in relatives of children with cancer to determine evidence of familial aggregation and to inform risk assessment and counseling for families. Odds ratios that reflect risk were obtained using conditional logistic regression models adjusting for number of biological relatives, their degree of genetic relatedness and their person years at risk. First-degree relatives (primarily siblings) of pediatric cases faced a twofold increased risk of a cancer diagnosis before age 19, which extended to their second-degree relatives (p < 10(-4), respectively). Furthermore, first-degree relatives of children diagnosed before age 5 had a 3.6 fold increased risk of developing pediatric cancer (p < 10(-7)), second-degree relatives of very young (under age 5) cases were at 2.5-fold risk (p < 10(-4)) and third-degree relatives were at twofold risk (P < 10(-3)) of childhood cancer. Although first-degree relatives of pediatric cases have a slight increased risk of adult tumors, when they do develop cancer they have a 1.7-fold risk of developing a tumor in the Li-Fraumeni spectrum. Our findings support the hypothesis of familial aggregation in pediatric cancer and suggest that a higher percent of childhood cancers may be related to hereditary syndromes than are adult cancers. We encourage the collection of a family medical history that is routinely updated for all pediatric cancer patients, and that families with early onset adult cancers or clusters of several cancers are referred for genetic counseling. PMID- 23661178 TI - Functional outcome of en bloc resection and osteoarticular allograft reconstruction with locking compression plate for giant cell tumor of the distal radius. AB - BACKGROUND: Giant cell tumors of the distal radius at Campanacci grade III are particularly challenging to treat. We have treated 15 cases of giant cell tumor of the distal radius by en bloc excision and osteoarticular allograft reconstruction with locking compression plate (LCP). The purpose of this study was to assess the intermediate outcomes of all patients treated with this surgery. METHODS: From July 2002 to January 2009, we followed up 15 patients with giant cell tumors of the distal radius who were treated with en bloc excision and osteoarticular allograft reconstruction with LCPs that were long enough to approach the distal end of the allograft. All of the cases were evaluated based on clinical and radiologic examinations, the passive range of motion of the wrist joint, complications, Mayo wrist score, and short form (SF)-36. RESULTS: The clinical follow-up time after reconstruction averaged 5.2 years. The mean resected length of the radius was 8.1 cm. One patient had tumor recurrence in the soft tissues after 3 years (recurrence rate 6.67 %). No patient had allograft bone fracture, nonunion, or metastases. Subchondral bone alterations and joint narrowing were present in all cases, with 1 patient suffering from the pain, but the pain could be endured without the need for analgesics. The average range of motion of the wrist was 46.7 degrees of dorsiflexion, 33.3 degrees of volar flexion, 61.3 degrees of supination, and 72.3 degrees of pronation. The mean Mayo wrist score was 70 and the mean modified SF-36 score was 71. CONCLUSIONS: En bloc excision and osteoarticular allograft reconstruction with an appropriate LCP for a Campanacci grade III giant cell tumor of the distal radius result in a reasonable functional outcome at intermediate follow-up evaluation. This method can excise the tumor integrally with a low rate of recurrence, good function, and a satisfactory range of motion. PMID- 23661177 TI - Macrophages transmit potent proangiogenic effects of oxLDL in vitro and in vivo involving HIF-1alpha activation: a novel aspect of angiogenesis in atherosclerosis. AB - Neovascularization has been linked to the progression and vulnerability of atherosclerotic lesions. Angiogenesis is increased in lipid-rich plaque. Hypoxia inducible factor alpha (HIF-1alpha) is a key transcriptional regulator responding to hypoxia and activating genes, which promote angiogenesis, among them vascular endothelial growth factor (VEGF). Oxidized low-density lipoprotein (oxLDL) is generated in lipid-rich plaque by oxidative stress. It triggers an inflammatory response and was traditionally thought to inhibit endothelial cells. New data, however, suggest that oxLDL can activate HIF-1alpha in monocytes in a hypoxia independent fashion. We hypothesized that HIF-1alpha activation in monocyte macrophages could transmit proangiogenic effects of oxLDL linking hyperlipidemia, inflammation, and angiogenesis in atherosclerosis. First, we examined the effect of oxLDL on HIF-1alpha and VEGF expression in monocyte-macrophages and on their proangiogenic effect on endothelial cells in vitro in a monocyte macrophage/endothelial co-culture model. OxLDL strongly induced HIF-1alpha and VEGF in monocyte-macrophages and significantly increased tube formation in co cultured endothelial cells. HIF-1alpha inhibition reversed this effect. Second, we demonstrated a direct proangiogenic effect of oxLDL in an in vivo angiogenesis assay. Again, HIF-1alpha inhibition abrogated the proangiogenic effect of oxLDL. Third, in a rabbit atherosclerosis model, we studied the effect of dietary lipid lowering on arterial HIF-1alpha and VEGF expression. The administration of low lipid diet significantly reduced the expression of both HIF-1alpha and VEGF, resulting in decreased plaque neovascularization. Our data point to oxLDL as a proangiogenic agent linking hyperlipidemia, inflammation, and angiogenesis in atherosclerosis. This effect is dependent on macrophages and, at least in part, on the induction of the HIF-1alpha pathway. PMID- 23661179 TI - Medium-term results after complex intra-articular fractures of the tibial plateau. AB - BACKGROUND: To present the medium-term results of intra-articular, bicondylar AO/OTA classification type C fractures of the tibial plateau in a retrospective study at a level-1 trauma center in 22 patients with 23 fractures. METHODS: Demographic data for the patients and details of current clinical and radiological follow-up findings were obtained to assess range of motion, clinical stability and alignment of the knee, and posttraumatic arthrosis (Kellgren/Lawrence score). Functional outcomes were assessed using the Lysholm score, Knee Injury and Osteoarthritis Outcome Score (KOOS), and International Knee Documentation Committee (IKDC) form. RESULTS: Patients' mean age was 46 years (range 20-67 years). Leading causes of the fractures were high-energy traffic accidents and falls. There were seven C1, seven C2, and nine C3 fractures. ORIF was performed in 20 patients; in two patients an external fixator and in one patient cannulated screws alone were used. In 13/22 patients, an angle stable locking plate (Less Invasive Stabilization System, LISS) was used for osteosynthesis. The mean follow-up period was 67 months (range 36-109 months). The overall complication rate was 39.1%, including four infections and four cases of pseudarthrosis (17.4%). The average flexion of the injured knee was significantly lower in comparison with the contralateral side (124.9 degrees vs. 135.2 degrees ). Knee stability did not differ statistically significantly. Current radiographs revealed no signs of posttraumatic arthrosis in 30.4% of cases, mild signs in 34.8%, clear signs in 26.1%, and severe signs in 13% using the Kellgren and Lawrence scale. The average Lysholm score was 66.2 points, and the average KOOS score was 67.84. One patient was in category A, and 2 were in category B in the IKDC overall categories, whereas 5 patients were in category C and 14 were even in category D. CONCLUSIONS: Complex articular tibial plateau fractures are associated with a high rate of complications, continue to have a severe impact on function in the injured knee, lead to early post-traumatic arthrosis, and result in long-lasting subjective symptoms for the patients. PMID- 23661180 TI - [Open questions - Non-muscle invasive carcinoma of the bladder - Introduction]. PMID- 23661183 TI - Are breast cancer subtypes prognostic for nodal involvement and associated with clinicopathologic features at presentation in early-stage breast cancer? AB - BACKGROUND: Breast cancer subtypes (BCS) determined from immunohistochemical staining have been correlated with molecular subtypes and associated with prognosis and outcomes, but there are limited data correlating these BCS and axillary node involvement. This study was conducted to assess whether BCS predicted for nodal metastasis or was associated with other clinicopathologic features at presentation. METHODS: Patients with stage I/II disease who underwent breast-conserving surgery and axillary surgical assessment with available tissue blocks underwent a institutional pathological review and construction of a tissue microarray. The slides were stained for estrogen receptor, progesterone receptor, and HER-2/neu (HER-2) for classification into BCS. Nodal involvement and other clinicopathologic features were analyzed to assess associations between BCS and patient and tumor characteristics. Outcomes were calculated a function of BCS. RESULTS: The study cohort consisted of 453 patients (luminal A 48.6%, luminal B 16.1%, HER-2 11.0%, triple negative 24.2%), of which 22% (n=113) were node positive. There were no significant associations with BCS and pN stage, node positivity, or absolute number of nodes involved (p>0.05 for all). However, there were significant associations with subtype and age at presentation (p<0.001), method of detection (p=0.049), tumor histology (p<0.001), race (p=0.041), and tumor size (pT stage, p<0.001) by univariate and multivariate analysis. As expected, 10-year outcomes differed by BCS, with triple negative and HER-2 subtypes having the worse overall (p=0.03), disease-free (p=0.03), and distant metastasis-free survival (p<0.01). CONCLUSIONS: There is a significant association between BCS and age, T stage, histology, method of detection, and race, but no associations to predict nodal involvement. If additionally validated, these findings suggest that BCS may not be a useful prognostic variable for influencing regional management considerations. PMID- 23661182 TI - Central stress-integrative circuits: forebrain glutamatergic and GABAergic projections to the dorsomedial hypothalamus, medial preoptic area, and bed nucleus of the stria terminalis. AB - Central regulation of hypothalamo-pituitary-adrenocortical (HPA) axis stress responses is mediated by a relatively circumscribed group of projections to the paraventricular hypothalamus (PVN). The dorsomedial hypothalamus (DMH), medial preoptic area (mPOA), and bed nucleus of the stria terminalis (BST) provide direct, predominantly inhibitory, innervation of the PVN. These PVN-projecting neurons are controlled by descending information from limbic forebrain structures, including the prefrontal cortex, amygdala, hippocampus, and septum. The neurochemical phenotype of limbic circuits targeting PVN relays has not been systematically analyzed. The current study combined retrograde tracing and immunohistochemistry/in situ hybridization to identify the specific sites of glutamatergic and GABAergic inputs to the DMH, mPOA, and BST. Following Fluoro gold (FG) injections in the DMH, retrogradely labeled cells co-localized with vesicular glutamate transporter mRNA in the prefrontal cortex, ventral hippocampus, and paraventricular thalamus. Co-localization of FG and glutamic acid decarboxylase mRNA was present throughout the central and medial amygdaloid nuclei and septal area. In addition, the mPOA received predominantly GABAergic input from the septum, amygdala, and BST. The BST received glutamatergic projections from the hippocampus and basomedial amygdala, whereas, GABAergic inputs arose from central and medial amygdaloid nuclei. Thus, discrete sets of neurons in the hypothalamus and BST are positioned to summate limbic inputs into PVN regulation and may play a role in HPA dysfunction and stress-related illness. PMID- 23661184 TI - Diagnostic ureteroscopy independently correlates with intravesical recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma. AB - BACKGROUND: Little is known about the effects of diagnostic ureteroscopy on intravesical recurrence after nephroureterectomy. METHODS: This study was designed to determine the effect of diagnostic ureteroscopy on intravesical recurrence after nephroureterectomy. From 2004 to 2010, 446 patients underwent nephroureterectomy for upper urinary tract cancer at our tertiary medical center. We included 115 patients who underwent preoperative diagnostic ureteroscopy and 281 patients who did not. This study analyzed the impact of the reported risk factors and diagnostic ureteroscopy for intravesical recurrence after nephroureterectomy by multivariate Cox regression model. RESULTS: The rates of metastasis and cancer-specific mortality did not differ significantly between the two groups. Diagnostic ureteroscopy was associated with a higher incidence of intravesical recurrence in patients with (p=0.02) and without (p=0.016) a previous history of bladder cancer. Ureter tumor biopsy (p=0.272) and ureter involvement (p=0.743) were not associated with the rate of intravesical recurrence in this study. Multivariate Cox regression analysis showed that only bladder cancer history (p<0.001), multifocal tumor (p=0.05), and diagnostic ureteroscopy (p=0.05) were independently associated with intravesical recurrence. CONCLUSIONS: Diagnostic ureteroscopy for upper urinary tract cancer was not associated with metastasis and cancer-specific mortality. However, ureteroscopy was associated with an increased incidence of intravesical tumor recurrence. Methods of prevention should be considered to decrease intravesical recurrence and avoid repeated surgical interventions or the development of advanced bladder disease in patients at risk. PMID- 23661185 TI - Low self-esteem as a risk factor for loneliness in adolescence: perceived - but not actual - social acceptance as an underlying mechanism. AB - Low self-esteem has been shown to relate to concurrent and later feelings of loneliness in adolescence. However, it remains unclear why low self-esteem puts adolescents at risk for experiencing loneliness. Further, longitudinal research on the direction of effects between loneliness and self-esteem is virtually non existent. The present study aims to fill these gaps in the literature. First, the direction of effects between loneliness and self-esteem was investigated in two independent longitudinal studies: a five-wave study sampling Dutch adolescents (M age = 15.22 years at T1; 47 % female; N = 428) and a three-wave study sampling Belgian adolescents (M age = 14.95 years at T1; 63 % female; N = 882). Second, the underlying role of social acceptance was investigated in the latter sample by applying a multi-method approach that included actual (i.e., peer-reported) and perceived (i.e., self-reported) social acceptance. Results indicated that self esteem and loneliness influenced one another in a reciprocal manner. Furthermore, the dominant path from self-esteem to loneliness was partially mediated by perceived--but not actual--social acceptance. The importance of distinguishing actual from perceived social acceptance is discussed, and suggestions for future research are outlined. PMID- 23661186 TI - Growth of large-scale vertically aligned GaN nanowires and their heterostructures with high uniformity on SiO(x) by catalyst-free molecular beam epitaxy. AB - The catalyst-free molecular beam epitaxial growth of GaN nanowires and their heterostructures on a SiOx template is studied in detail. It was found that by optimizing the growth temperature, highly uniform and vertically aligned GaN nanowires and InGaN/GaN heterostructures with excellent optical properties can be obtained on a SiOx template in a large-scale. This work provides an entirely new avenue for GaN nanowire based optoelectronic devices. PMID- 23661187 TI - Tandem cathode for proton exchange membrane fuel cells. AB - The efficiency of proton exchange membrane fuel cells is limited mainly by the oxygen reduction reaction at the cathode. The large cathodic overpotential is caused by correlations between binding energies of reaction intermediates in the reduction of oxygen to water. This work introduces a novel tandem cathode design where the full oxygen reduction, involving four electron-transfer steps, is divided into formation (equilibrium potential 0.70 V) followed by reduction (equilibrium potential 1.76 V) of hydrogen peroxide. The two part reactions contain only two electron-transfer steps and one reaction intermediate each, and they occur on different catalyst surfaces. As a result they can be optimized independently and the fundamental problem associated with the four-electron catalysis is avoided. A combination of density functional theory calculations and published experimental data is used to identify potentially active and selective materials for both catalysts. Co-porphyrin is recommended for the first step, formation of hydrogen peroxide, and three different metal oxides - SrTiO3(100), CaTiO3(100) and WO3(100) - are suggested for the subsequent reduction step. PMID- 23661188 TI - Highly efficient transformation of levulinic acid into pyrrolidinones by iridium catalysed transfer hydrogenation. AB - Levulinic acid (LA) is transformed into pyrrolidinones via iridium-catalysed reductive amination using formic acid as the hydrogen source under aqueous conditions. The catalytic system is the most active and performs under the mildest conditions ever reported for the reductive amination of LA. PMID- 23661189 TI - The effects of list composition and perceptual fluency on judgments of learning (JOLs). AB - The perceptual fluency hypothesis proposes that items that are easier to perceive at study will be given higher memorability ratings, as compared with less fluent items. However, prior research has examined this metamemorial cue primarily using mixed-list designs. Furthermore, certain memory effects are moderated by the design (mixed list vs. pure list) used to present stimuli. The present study utilized mixed as well as pure lists to assess whether judgments of learning based on perceptual fluency are relative or absolute and whether people are sensitive to differences in recall produced by variation in list composition. Using font size and generation manipulations, Experiments 1 and 2 showed that the effect of perceptual fluency on metamemory is relative in nature, occurring only in mixed lists. Experiments 2 and 3 revealed that metamemory is insensitive to the effect of list composition on recall. These findings are consistent with the assumptions of Koriat's (Journal of Experimental Psychology: General 126: 349 370, 1997) cue-utilization framework, that JOLs reflect a comparative process and are insensitive to cues pertaining to conditions of learning. PMID- 23661191 TI - Palladium-catalyzed cross-coupling of cyclopropanol-derived ketone homoenolates with aryl bromides. AB - The cross-coupling reaction of cyclopropanol-derived ketone homoenolates bearing beta-hydrogens with aryl and hetaryl bromides has been achieved for the first time. This reaction is high yielding, is broad in scope and uses a simple catalytic system. Notably, the proposed palladium homoenolates do not undergo beta-hydride elimination to the corresponding alpha,beta-unsaturated ketones. PMID- 23661190 TI - Memory as discrimination: what distraction reveals. AB - Recalling information involves the process of discriminating between relevant and irrelevant information stored in memory. Not infrequently, the relevant information needs to be selected from among a series of related possibilities. This is likely to be particularly problematic when the irrelevant possibilities not only are temporally or contextually appropriate, but also overlap semantically with the target or targets. Here, we investigate the extent to which purely perceptual features that discriminate between irrelevant and target material can be used to overcome the negative impact of contextual and semantic relatedness. Adopting a distraction paradigm, it is demonstrated that when distractors are interleaved with targets presented either visually (Experiment 1) or auditorily (Experiment 2), a within-modality semantic distraction effect occurs; semantically related distractors impact upon recall more than do unrelated distractors. In the semantically related condition, the number of intrusions in recall is reduced, while the number of correctly recalled targets is simultaneously increased by the presence of perceptual cues to relevance (color features in Experiment 1 or speaker's gender in Experiment 2). However, as is demonstrated in Experiment 3, even presenting semantically related distractors in a language and a sensory modality (spoken Welsh) distinct from that of the targets (visual English) is insufficient to eliminate false recalls completely or to restore correct recall to levels seen with unrelated distractors . Together, the study shows how semantic and nonsemantic discriminability shape patterns of both erroneous and correct recall. PMID- 23661192 TI - Fat grafting versus adipose-derived stem cell therapy: distinguishing indications, techniques, and outcomes. PMID- 23661193 TI - Inexpensive method of liposuction cannula port-site protection. PMID- 23661194 TI - Severe equinus deformity after radiofrequency-induced calf muscle reduction. AB - INTRODUCTION: Radiofrequency-induced calf muscle volume reduction is a commonly used method for cosmetic shaping of the lower leg contour. Functional disabilities associated with the use of the radiofrequency (RF) technique, with this procedure targeting the normal gastrocnemius muscle, still have not been reported. However, the authors have experienced several severe ankle equinus cases after RF-induced calf muscle volume reduction. MATERIAL AND METHOD: This study retrospectively reviewed 19 calves of 12 patients who showed more than 20 degrees of fixed equinus even though they underwent physical therapy for more than 6 months. All were women with a mean age of 32 years (range, 23-41 years). Of the 12 patients, 7 were bilateral. All the patients received surgical Achilles lengthening for deformity correction. To evaluate the clinical outcome, serial ankle dorsiflexion was measured, and the American Orthopedic Foot and Ankle Society (AOFAS) score was evaluated at the latest follow-up visit. The presence of soleus muscle involvement and an ongoing lesion that might affect the postoperative results of preoperative magnetic resonance imaging (MRI) were investigated. Statistical analysis was conducted to analyze preoperative factors strongly associated with patient clinical outcomes. RESULTS: The mean follow-up period after surgery was 18.6 months (range, 12-28 months). At the latest follow up visit, the mean ankle dorsiflexion was 9 degrees (range, 0-20 degrees ), and the mean AOFAS score was 87.7 (range, 80-98). On preoperative MRI, 13 calves showed soleus muscle involvement. Seven calves had ongoing lesions. Five of the ongoing lesions were muscle edema, and the remaining two lesions were cystic mass lesions resulting from muscle necrosis. Ankle dorsiflexion and AOFAS scores at the latest follow-up evaluation were insufficient in the ongoing lesions group. CONCLUSION: Although RF-induced calf muscle reduction is believed to be a safer method than conventional procedures, careful handling is needed because of the side effects that may occur in some instances. The slow progression of fibrosis could be observed after RF-induced calf reduction. Therefore, long-term follow-up evaluation is needed after the procedure. LEVEL OF EVIDENCE IV: Therapeutic case series. PMID- 23661195 TI - Characterization and functional analyses of the chitinase-encoding genes in the nematode-trapping fungus Arthrobotrys oligospora. AB - Nematode-trapping fungi can secrete many extracellular hydrolytic enzymes such as serine proteases and chitinases to digest and penetrate nematode/egg-cuticles. However, little is known about the structure and function of chitinases in these fungi. In this study, 16 ORFs encoding putative chitinases, which all belong to glycoside hydrolase (GH) family 18, were identified from the Arthrobotrys oligospora genome. Bioinformatics analyses showed that these 16 putative chitinases differ in their functional domains, molecular weights and pI. Phylogenetic analysis grouped these A. oligospora chitinases into four clades: clades I, II, III and IV, respectively, including an A. oligospora-specific subclade (Clade IV-B) that contained high-molecular weight chitinases (>=100 kDa). Transcriptional analysis of A. oligospora chitinases suggested that the expression of most chitinases was repressed by carbon starvation, and all chitinases were up-regulated under nitrogen starvation. However, chitinase AO-190 was up-regulated under carbon and/or nitrogen starvation. Moreover, several chitinases (such as AO-59, AO-190 and AO-801) were up-regulated in the presence of chitinous substrates or a plant pathogenic fungus, indicating that they could play a role in biocontrol applications of A. oligospora. Our results provided a basis for further understanding the functions, diversities and evolutionary relationships between chitinase genes in nematode-trapping fungi. PMID- 23661196 TI - Themoanaerobacterium calidifontis sp. nov., a novel anaerobic, thermophilic, ethanol-producing bacterium from hot springs in China. AB - A novel thermophilic Gram staining positive strain Rx1 was isolated from hot springs in Baoshan of Yunnan Province, China. The strain was characterized as a hemicellulose-decomposing obligate anaerobe bacterium that is rod-shaped (diameter: 0.5-0.7 MUm; length: 2.0-6.7 MUm), spore-forming, and motile. Its growth temperature range is 38-68 degrees C (optimum 50-55 degrees C) and pH range is 4.5-8.0 (optimum 7.0). The maximum tolerance concentration of NaCl was 3 %. Rx1 converted thiosulfate to elemental sulfur and reduced sulfite to hydrogen sulfide. The bacterium grew by utilizing xylan and starch, as well as a wide range of monosaccharide and polysaccharides, including glucose and xylose. The main products of fermentation were ethanol, lactate, acetate, CO2, and H2. The maximum xylanase activity in the culture supernatant after 30 h of incubation at 55 degrees C was 16.2 U/ml. Rx1 DNA G + C content was 36 mol %. 16S rRNA gene sequence analysis indicated that strain Rx1 belonged to the genus Thermoanaerobacterium of the family 'Thermoanaerobacteriaceae' (Firmicutes), with Thermoanaerobacterium aciditolerans 761-119 (99.2 % 16S rRNA gene sequence similarity) being its closest relative. DNA-DNA hybridization between Rx1 and T. aciditolerans 761-119 showed 36 % relatedness. Based on its physiological and biochemical tests and DNA-DNA hybridization analyses, the isolate is considered to represent a novel species in the genus Thermoanaerobacterium, for which the name Thermoanaerobacterium calidifontis sp. nov. is proposed, with the type strain is Rx1 (=JCM 18270 = CCTCC M 2011109). PMID- 23661197 TI - NMR (1H) analysis of crude extracts detects light stress in Beta vulgaris and Spinacia oleracea leaves. AB - In highlight stress conditions, the mechanism of non-photochemical quenching (NPQ) of chlorophyll fluorescence is triggered at the chloroplast level. This process allows thermal quenching of the excessive excitation energy and it is strictly related to the efficiency of the xanthophyll cycle. Nowadays, the utilization of the nuclear magnetic resonance (NMR) spectroscopy provides a powerful complementary way for the identification and quantitative analysis of plant metabolites either in vivo or in tissue extracts. Seeing that the oxidative damage caused by light stress in plants and the consequent involvement of pigments are widely studied, NMR spectroscopy can be utilized to compare crude leaf extract at different levels of light stress, allowing an analysis of these compounds. In this paper, the identification of possible relationships between light stress and 1H NMR signal variations is discussed. The analysis of the 1H NMR (1D) spectra of two agronomic species (Spinacia oleracea and Beta vulgaris) exposed to different light intensities is presented. In particular, change in carotenoids and xanthophylls signals are analyzed. PMID- 23661198 TI - Microfluidic genome-wide profiling of intrinsic electrical properties in Saccharomyces cerevisiae. AB - Methods to analyze the intrinsic physical properties of cells - for example, size, density, rigidity, or electrical properties - are an active area of interest in the microfluidics community. Although the physical properties of cells are determined at a fundamental level by gene expression, the relationship between the two remains exceptionally complex and poorly characterized, limiting the adoption of intrinsic separation technologies. To improve our current understanding of how a cell's genotype maps to a measurable physical characteristic and quantitatively investigate the potential of using these characteristics as biomarkers, we have developed a novel screen that combines microfluidic cell sorting with high-throughput sequencing and the haploid yeast deletion library to identify genes whose functions modulate one such characteristic - intrinsic electrical properties. Using this screen, we are able to establish a high-content electrical profile of the haploid yeast gene deletion strains. We find that individual genetic deletions can appreciably alter the electrical properties of cells, affecting ~10% of the 4432 gene deletion strains screened. Additionally, we find that gene deletions affecting electrical properties in specific ways (i.e. increasing or decreasing effective conductivity at higher or lower electric field frequencies) are strongly associated with an enriched subset of fundamental biological processes that can be traced to specific pathways and complexes. The screening approach demonstrated here and the attendant results are immediately applicable to the intrinsic separations community. PMID- 23661201 TI - Women's concerns and satisfaction with induced labour at term in a Nigerian population. AB - AIMS AND OBJECTIVES: To explore the concerns, experiences and satisfaction of women who had induction of labour at term MATERIALS AND METHODS: A cross sectional study conducted in Nigeria, among 252 pregnant women who had induction of labour at term using a two part pre and post induction questionnaire. RESULTS: Concerns expressed by the women prior to labour induction were the fear of caesarean delivery (16.6%), labour pains (15.1%) and an adverse foetal or maternal outcome (4.8%). Overall, 180 women (71.4%) expressed satisfaction with the induction process while 72 (28.6%) were dissatisfied. Comparatively, a higher mean age and shorter induction-delivery interval (470+/-180 vs 660+/-370, p<0.001) was significantly associated with maternal satisfaction with induced labour. It was also associated with significantly lower caesarean section rates (13.3% vs 61.1%, p=0.001) and composite maternal or foetal morbidities. The common reasons for dissatisfaction with induced labour included caesarean delivery (13.4%), painful labour (8.7%) while 2.4% felt the duration of the procedure was too long. CONCLUSION: This study suggests that a substantial number of pregnant women who had induction of labour had unsatisfactory experience. The reasons for dissatisfaction should be addressed by physicians in order to promote a positive psycho-emotional experience of pregnancy and childbirth. PMID- 23661202 TI - Changing trend in the incidence of myocardial infarction among medical admissions in Ilorin, north-central Nigeria. AB - AIMS AND OBJECTIVES: This study aimed at reviewing cases of myocardial infarction managed between January 2006 and June 2009. MATERIALS AND METHODS: Records of all patients managed for acute MI during the period were studied. Diagnosis was based on presence of ischemic type of chest discomfort, serial electrocardiographic (ECG) changes compatible with MI, a rise in troponin I level and echocardiographic abnormalities. RESULTS: Fourteen patients consisting of 13 (92.9%) males and 1 (7.1%) female had MI. They were all Nigerians, their ages ranged from 40 to 82 years with a mean of 55.6+/-12.7 years; and 85.7% of them belonged to social class 1. MI accounted for 0.21% of the total 6647 admissions during the period. Present hospital incidence (0.21%) is significantly higher (Chi2=6.8, p=0.01) than previously reported incidence of 0.075%. Twelve patients had systemic hypertension, 8 had high body mass index, 6 had dyslipidaemia, 5 smoked cigarette and 2 had diabetes mellitus. Three patients died giving a case fatality rate of 21.4% and another 3 developed chronic left ventricular systolic failure. CONCLUSION: Incidence of MI is increasing among hospital admissions in Ilorin and there is an urgent need for community interventions targeted at early detection and treatment of hypertension, diabetes mellitus, dyslipidaemia and obesity. Campaigns against cigarette smoking should be sustained. PMID- 23661203 TI - Bacterial isolates from cerebrospinal fluid of children with suspected acute meningitis in a Nigerian tertiary hospital. AB - AIMS AND OBJECTIVES: To determine the common aetiolog of acute bacterial meningitis in children and their antibiotic susceptibility pattern. MATERIALS AND METHODS: A retrospective study with a review of cerebrospinal fluid culture reports of paediatric patients aged 0-15 years, suspected of acute meningitis in the Medical Microbiology Department of Aminu Kano Teaching Hospital, Kano, Nigeria from October 2006 to October 2009 from October 2006 to October 2009. RESULTS: A positive culture bacterial isolation rate of 3.3% (n=50/1500) with prevalence of Streptococcus pneumoniae (24%), Neisseria meningitidis (22%), Escherichia coli (16%), Haemophilus influenzae (14%), Group B streptococci (8%) and Enterococci (8%) which were susceptible to ceftriaxone (96%), cefotaxime (95%) and ciprofloxacin (93%) across the bacterial isolates. Neonates were 55% (n=6.8/12.4) most at risk. CONCLUSION: Neonates are the most at risk of acute bacterial meningitis. In the absence of antibiotic susceptibility report, ceftriaxone should be considered as a first choice reliable antibiotic for empirical treatment of meningitis in children, in this environment. PMID- 23661199 TI - How are depression and type D personality associated with outcomes in chronic heart failure patients? AB - This review aims to summarize the current evidence for the association of depression and Type D personality with clinical and patient-centred outcomes and self-care in chronic heart failure (CHF) patients. Emotional distress is highly prevalent in CHF patients. In contrast to results in coronary artery disease, there is inconsistent evidence for the adverse effects of depression and Type D on prognosis. Type D and depression are important predictors of impaired health status in CHF, and patients characterised by depression or Type D report reduced self-care. Pathophysiological processes associated with depression and Type D are discussed, as they may contribute to disease progression. Future research may benefit from taking inconsistencies in and problems with assessment of depression and Type D into account, as well as focusing on the network of psychophysiological and behavioural factors to elucidate their precise role in CHF patients with depression or Type D. Furthermore, it is advised that clinicians address the observed differences in self-care behaviours to improve health in CHF patients with depression or Type D personality. PMID- 23661204 TI - Radiographic pattern of skeletal trauma in children seen in a tertiary hospital in Sagamu, South West Nigeria. AB - AIMS AND OBJECTIVES: The study was aimed at identifying the pattern of skeletal trauma in the paediatric age group as it relates to the causes. MATERIALS AND METHODS: A retrospective analysis of the records on the request cards, case notes, radiographs and reports (where available) of all children aged one day to 15 years who were referred to the radiology department of Olabisi Onabanjo University Teaching Hospital, Sagamu was carried out. Fractures were analysed with respect to sex, age, causes, type and location of fracture. RESULTS: The analysis spanned a period of twenty-eight months during which a total of three hundred and twenty eight radiographs were analysed. The mean ages of male and female patients were 5.4+/-4.6 and 5.1+/-4.6 years, respectively, with a range of 0.2-15 years. Normal radiographs were found in 124 (37.80%) patients,53.1 (16.1%) had 55 fractures, and 39 (11.9%) had soft tissue swelling. Fractures were found most commonly in male children and in the age range 4-6 years. Fractures occur three times more in the upper limbs, and the bones most frequently affected are the humerus, radius, and the ulna in descending order. Most of the fractures were due to Road Traffic Injury (RTI) seen in 18.9%, falls seen in 18.9%, and birth trauma, which was responsible for 7.5%. The most frequently involved bone in fractures is the humerus followed by the femur bone. Skull fractures occur mostly in the parietal bone. CONCLUSIONS: Fractures are still mostly investigated with plain radiographs. Fractures are more frequent in male children and in the 4-6 year age range; it is seen more in the upper limb bones especially in the humerus. Skull fractures are relatively rare. Half of the fractures occur in the distal and mid portions of long bones. This study has also high lighted the importance of road traffic injury and falls as aetiological factors in fracture occurring in children. Effort should be made to ease deliveries in order to reduce the incidence of birth trauma. PMID- 23661205 TI - Vaginal candidiasis and its risk factors among women attending a Nigerian teaching hospital. AB - AIMS AND OBJECTIVES: The study was set to detect Candida species in female genital discharge and validate the associated risk factors. MATERIALS AND METHODS: A prospective study of female genital swabs collected from women with abnormal vaginal discharge (test group) and a control group who were attending gynaecology, family planning, antenatal care or HIV/STI clinics of Aminu Kano Teaching Hospital, Kano Nigeria and analysed for microscopy and culture in microbiology laboratory from December 2008 to December 2009. Data on epidemiologic indices were collected from the patients, using structured interviewer- administered questionnaires. RESULTS: Candida species were detected in the test group in 60% (n=600/1000) cases of infective vaginal discharge while 12% (120/1000) in the control group. The isolation rate of Candida albicans was 69% more than the non- albicans. Distribution of vaginal candidiasis in the test group, was prevalent in young adults age group of 21 to 30 years with 50% (n=300/600), in patients with pregnancy 38% (n=225/600) and patients with chronically debilitating illnesses 26% (n=157/600). CONCLUSION: The result shows that vaginal candidiasis is quite common and Candida albicans is the most prevalent species. We therefore recommend early diagnosis and prompt treatment of vaginal candidiasis in all women clinics especially among the patients with chronic debilitating illness, pregnancy and young adults in order to avert the complications of vaginal candidiasis and reduce HIV transmission. PMID- 23661206 TI - Ocular features and management challenges of Marfan's Syndrome in Benin City, Nigeria. AB - AIMS AND OBJECTIVES: The objective of this study is to describe the ocular features of Marfan's Syndrome in Benin City, Nigeria and highlight problems associated with their management MATERIALS AND METHODS: A study of all consecutive patients with a diagnosis of Marfan's syndrome at the eye clinic of the University of Benin Teaching Hospital, Benin City, Nigeria was done between June 1st 2009 and December 31st 2010. RESULTS: There were 13 patients (8 males and 5 females). The age range was 10 to 50 years with a mean age of 23+10.1 years. The duration of symptoms was 1 year to 22 years with a mean of 7.9 years. The ocular features were ectopia lentis in 92.3% of the patients, cataract in 69.2%, glaucoma and myopia in 30.8% each. Others were strabismus (7.7%), unilateral corneal opacities from the use of traditional eye medication (15.4%), phthisis bulbi and retinal detachment in 7.7% each. Three (23%) patients were bilaterally blind while 7(53.8%) had unilateral blindness. The best corrected visual acuity in 4 out of 5 patients who had cataract extraction at 8 weeks post op. was 6/60 to 6/12. There was no improvement in 1 patient. CONCLUSION: Patients with Marfan's syndrome in Benin City, Nigeria have visual impairment and blindness due to delay in presentation and the use of traditional eye medications. Health education and early presentation to hospital is recommended. This will help in reducing avoidable visual impairment and blindness and thus improve survival and quality of life in these patients. PMID- 23661207 TI - Relationship between post-stroke functional recovery and quality of life among Nigerian stroke survivors. AB - AIMS AND OBJECTIVES: This study explored relationship between post-stroke functional recovery and QoL among Nigeria SSv with first-ever stroke. PATIENTS, MATERIALS AND METHODS: This Study involved 65 (33 males and 32 females) individuals diagnosed of first-ever episode of stroke in the University College Hospital, Ibadan, Nigeria. The National Stroke Severity scale was used to assess their stroke sequeles. Their functional performance and QoL was assessed using the combination of the standard values of Barthel Index and Frenchay Activities Index, and the Stroke-Specific QoL questionnaire respectively. They were assessed at 14 days and fortnightly for 12 months post-stroke. Data were analysed using the Pearson's Moment Correlation and paired t-test at p=0.05. RESULTS: Fifty-five (84.61%) out of the 65 SSv completed this study while 10 (15.39%) died. Participants' age was 58.1+/-15.7 years with majority (90.6%) of them between 40 years and 79 years. Mean QoL score increased significantly at day 14-day through 6-month and non-significantly through 12-month post-stroke. Mean functional performance significantly increased from 3.2+/-2.1 at day 14 to 66.3+/-14.2 at 6 month but non-significantly from 6-month to 76.14+/-12.1 at 12-month post-stroke. Their functional recovery had direct positive relationship with their QoL scores during the 12 months follow-up. CONCLUSION: Stroke has negative impact on both the functional performance and quality of life of stroke survivors. Quality of life of stroke survivors increases with improvement in functional recovery. PMID- 23661208 TI - Knowledge of Glasgow coma scale by physicians in a tertiary health institution in Nigeria. AB - AIMS AND OBJECTIVES: The Glasgow coma scale (GCS) form the basis for important management decisions by the attending physicians or other health personnel in the care of comatose patients. Inaccurate reporting may result in unnecessary treatment and diagnostic tests. The purpose of this study is to assess the knowledge of GCS among physicians in different specialties of training in a tertiary centre in Nigeria. MATERIALS AND METHODS: The study was a descriptive survey conducted among doctors at the University of Ilorin Teaching Hospital (UITH) Ilorin, in North Central Nigeria. Physicians from different specialties and all levels of training were surveyed. Questionnaires were administered simultaneously within a department without prior notification. Participants were instructed not to use any reference materials while completing the questionnaire. RESULTS: Majority of the physicians could indicate correctly what GCS stands for (97%) and identify each category correctly. However, only 37% could score all the categories correctly. There was a positive impact in theoretical knowledge and recall among respondents who has had training in GCS. The level of training of respondents correlated well with recall of GCS with Residents and interns faring better than fellows and medical officers. Recall of GCS scoring was least among Physicians in family medicine compared to physicians in other specialties. CONCLUSION: Improved training with retention strategies in the use of the GCS and retraining of all physicians involved in the management of the comatose patients should be the focus of future strategic plans. PMID- 23661209 TI - Influence of ageing process on body composition of antioxidant and lipid peroxidation among healthy individuals in South West Nigeria. AB - AIMS AND OBJECTIVES: To evaluate the effect of ageing on the level of antioxidants and lipid peroxidation in healthy individual of various age groups. SUBJECTS AND METHODS: A total number of 162 healthy males and females volunteer between the ages of 18-80 years were divided into three groups. These volunteers were divided into group i(18-30 yr), group ii (31-60 yrs) and group iii (60-80 yr). Plasma concentration of total bilirubin, uric acid, ascorbic acid, a tocopherol, retinol, total antioxidant status (TAS), malondialdehyde (MDA), glutathione (GSH) and ceruloplasmin measured. Erythrocyte antioxidant enzyme activities of superoxide dismutase (SOD), catalase (CAT), glutathione and peroxidase (GSHPx) were measured using standard methods. RESULTS: Erythrocyte antioxidant enzymes (GSH-Px and SOD) activities and GSH level were significantly reduced among group iii (p<0.01) and group ii (p<0.05) age group subjects compared to the younger age group i. Conversely, MDA showed a significant increase in group iii (p<0.01) and group ii (p<0.01) compared to younger age group i. CAT activity and TAS level were reduced significantly (p<0.05) in both groups iii and ii compared to younger age group i. Ascorbic acid, a-tocopherol and retinol levels were significantly reduced among group iii (p<0.05) compared to group i. CONCLUSION: Ageing was associated with increased lipid peroxidation and lower antioxidant defenses. Changes that occur during ageing cannot be avoided but may be delayed and controlled to some extent. To counter these changes, dietary supplementation of a variety of antioxidants might be beneficial. PMID- 23661210 TI - Clinico-pathologic characterisation of metastatic prostate cancer in the Radiotherapy and Oncology Department, Ahmadu Bello University Teaching Hospital, Zaria-Nigeria: 2006-2009. AB - AIMS AND OBJECTIVES: To evaluate the Clinico-pathologic Characteristics of Metastatic prostate cancer patients seen in the Radiotherapy and Oncology Department, Ahmadu Bello University Teaching Hospital, Nigeria. MATERIALS AND METHODS: Between January 2006 and December 2009, a period of 4 years, 72 new patients with prostate cancers were seen of which 43 patients had distant metastases. Only patients with histologic confirmation of prostate cancer and having metastases were included in the study irrespective of age, co-morbidity and performance status. Patients' folders were reviewed retrospectively with a structured pro forma. Information retrieved from patient's folder included age, histology, Gleason score, co-morbidities, interval between diagnosis and referral to oncology unit, interval between referral and presentation at oncology unit, PSA at diagnosis and presentation at oncology unit, sites of metastases, bones sites involved in bone metastases, types of treatment received and follow up status. Results were analysed using Epi Info soft ware Version 3.4.1; 2007 Edition. RESULTS: 43 patients had distant metastases from prostate cancer during initial evaluation at presentation in the radiotherapy and oncology centre. The mean age was 66.2 years (range, 47-82 years, median age 66 years and modal age group was 65-69 years). Co-morbidity was seen in 18 patients, with hypertension being the commonest (HT=14, DM=2 and HIV 2 patients). No morbidity seen in 25 patients. The range of duration from diagnosis to referral was 1-84 months. Only 20 patients presented at radiotherapy and oncology centre within 6 months of diagnosis and 18 patients presented after 12 months of diagnosis. 33 patients presented within 1 month of being referred for further management. 6 patients reported within 2 months and 2 patients within 3 months and another 2 patients within 4 months. Only 27 patients had PSA done at diagnosis. No PSA was done in 16 patients. The PSA range at diagnosis was 10.0-232 ng/ml, mean PSA was 67.46 ng/ml while only 40 patients did PSA on presentation for further management with a range of 1-245 ng/ml and a mean of 57.95 ng/ml. The histology report revealed adenocarcinoma and transitional carcinoma in 42 and 1 patients respectively. The Gleason score range was 6-10, with a mean score of 7.8. The Gleason score was not reported in 3 patients. Multiple organs involvement by metastases was seen in 16 patients. Bone metastases was the commonest (35), followed by lungs (8), liver (7), Virchow's lymph nodes (6), brain (5), and soft tissue (5). The lumbar vertebrae was the commonest site of bone metastases (32) followed by the sacrum (17), pelvis (11), and long bones (7). 3 patients had metastases to the ribs and 2 patients each to the skull, sternum and cervical spines. All the patients received hormonal therapy, 30 patients received palliative radiotherapy, 29 patients had surgical castration, 25 patients had radical radiotherapy to pelvis, 18 patients had systemic chemotherapy and definitive surgery was done in 16 patients. Only 6 patients received Ibandronate due to cost. 13 patients are alive and attending follow up, 11 confirmed dead and 19 lost to follow up. CONCLUSION: The patients were referred for management late after surgery. Bones, predominately the lumbosacral spines was the commonest organ involved in metastases. Skeletal survey with bone scan and plain x-rays especially lumbosacral spines should be part of the staging investigation for all patients with advanced stage. There is need for more awareness on other treatment modalities emphasizing the multidiscipline and multimodality management of prostate cancer. PMID- 23661211 TI - Benign prostate hyperplasia: average volume in southwestern Nigerians and correlation with anthropometrics. AB - OBJECTIVES: To determine the prevalent age of symptomatic benign prostate hyperplasia (BPH), the average BPH volume, and the association between BPH volumes and the age, and anthropometrics in our immediate black community. PATIENTS, MATERIALS AND METHOD: Selected patients with lower urinary tract symptoms (LUTS) due to BPH with tissue diagnosis, and adult men of similar age group with no irritative or obstructive LUTS were prospectively studied from July 2003 to June 2009. The age, height and weight were recorded, prostate volumes determined with ultrasound, body mass index (bmi) calculated, and correlations determined between the prostate volume and the age, and anthropometrics. RESULTS: 105 patients aged 43-88 yrs (mean=64.4, 8.88 SD) managed for BPH were studied with 93 asymptomatic men aged 43-80 yrs (mean=56.15, 9.89 SD). The mean (SD) prostate volume, height, weight and bmi were 83.8 (37.7) ml, 1.67 (0.07) m, 63.6 (9.32) kg and 22.8 (3.03) kg/m2, and 24.5 (9.2) ml, 1.69 (0.06) m, 68.9 (10.6) kg and 24.2 (3.44) kg/m2 respectively for symptomatic and asymptomatic groups. In the symptomatic group, BPH volume showed significant positive correlation with the age (p=0.030), but no correlation with the weight (p=0.550), height (p=0.375) and bmi (p=0.840). In the asymptomatic group, prostate volume also showed significant positive correlation with the age (p=0.041), but no correlation with the weight (p=0.434), height (p=0.394), and bmi (p=0.203). CONCLUSION: The prevalent age of symptomatic BPH in our community is 43- 88 years with 83.79 (37.66) ml mean (SD) volume in symptomatic patients and 24.45 (9.21) ml in asymptomatic men. BPH volume correlates with age but not with anthropometrics. Lack of correlation with BPH volume suggests that anthropometrics may not be risk factors for development of BPH in our community. PMID- 23661212 TI - Routine reporting of estimated glomerular filtration rate (eGFR) in African laboratories and the need for its increased utilisation in clinical practice. AB - Chronic Kidney Disease (CKD) is defined as the presence of markers of kidney damage or of estimated glomerular filtration rate (eGFR)<60 mL.min(-1).(1.73 m2) [<1 mL(-1) (1.73 m2)1 for three months or more. CKD is associated with poor outcomes and high cost, disproportionately affecting the elderly, the Black race and the middle aged in Nigeria. Thus, new public health campaigns focus on early detection of CKD. To facilitate early detection of CKD, many national and international organisations now recommend routine reporting of estimated glomerular filtration rate (eGFR) whenever serum creatinine is measured. The formulae/equations provide a quick estimate (eGFR) of the GFR without need for urine collection in clinical practice. Current guidelines advocate the use of prediction equations, such as the Cockcroft-Gault (CG) formula and the Modification of Diet in Renal Disease (MDRD) study-derived equations. Laboratories in African should commence routine reporting of eGFR for a number of reasons; 1. The sensitivity of serum creatinine (Scr) in identifying CKD is low.2. In Nigeria, a representative country; screening for Chronic Kidney Disease (CKD) is hardly considered in the routine practice of the primary and secondary care medical officers.3 Studies have shown that routine reporting of eGFR improved the documentation and identification of CKD by almost 50%.4 There is the possibility of reversing CKD if picked earlier.5. The high cost of treating CKD patients in advanced stages and the low per capital income status of the populace in Sub-Saharan Africa.6. Poor health infrastructure to manage advanced CKD patients in the continent.7. Several studies, now show lack of awareness of CKD among non-nephrologists that is related, at least in part, to difficulty in interpreting serum creatinine concentrations (the reciprocal, non-linear relationship between GFR and serum creatinine).8 Mathematical estimates of GFR [ as in eGFR] that incorporate creatinine concentration, as well as factors affecting creatinine production rates, such as size, gender, age and ethnic background, are more sensitive to changes in renal function than serum creatinine value alone.9 Recent guidelines define "action plans" for CKD according to the GFR, including referral to nephrologists at GFRs<30 mL.min(-1).(1.73 m2). PMID- 23661213 TI - Unrecognised guide wire migration during internal jugular cannulation and its retrieval--a case report. AB - AIMS AND OBJECTIVES: The objective of this article is to report a case of unrecognised missed guide wire diagnosed two months after right internal jugular cannulation and which was successfully retrieved from the right femoral vein. PATIENT AND METHODS: The case record of a patient that had retained intravenous guide wire was reviewed with relevant literature. RESULT: A 40-yr-old female had an emergency left thoracotomy on account of haemorrhagic pleural effusion. A right internal jugular central venous catheter (CVC) insertion was performed for resuscitation and haemodynamic monitoring before induction of anaesthesia. A follow-up thoraco-abdominal Computed tomography (CT) scan taken after 8 weeks showed a pigtail intravascular metallic foreign body traversing the distal superior vena cava, right atrium, inferior vena cava, and ending at the right femoral vein. The guide wire was successfully removed via a right femoral venotomy under local anaesthesia. CONCLUSION: Intravascular loss of a guide wire is a rare complication of CVC insertion. If basic precautionary measures were taken, the loss of guide wire would have been avoided. PMID- 23661214 TI - Gallbladder carcinoma with skeletal metastasis in a Nigerian woman: a case report and review of literature. AB - AIMS AND OBJECTIVES: To present a case of skeletal metastasis from a gallbladder malignancy, a rare occurrence. CASE REPORT: A 75 year old Nigerian woman presented in the surgical outpatient clinic of the University of Port Harcourt Teaching Hospital with a two month history of right hypochondrial pain and three weeks swelling on the forehead. Physical examination revealed an ill looking, emaciated elderly woman in mild painful distress. She was pale, afebrile and anicteric. Skull x-ray revealed a well circumscribed soft tissue mass over a lytic bone defect in the frontal region. Abdominal ultrasound scan showed an enlarged gallbladder with a thickened wall and intraluminal echogenic mass, surrounding lymphadenopathy and intrahepatic metastasis. Radiological diagnosis of advanced gallbladder carcinoma with both local and distant metastases was made. CONCLUSION: Carcinoma of the gallbladder with skeletal metastasis is a rare finding. However, in any patient with gallbladder malignancy distant metastasis with skeletal involvement should be sought. PMID- 23661215 TI - Bupivacaine induces short-term alterations and impairment in rat tendons. AB - BACKGROUND: Toxicity of the local anesthetic bupivacaine (BV) has been a matter of debate across medical fields. Numerous in vitro studies demonstrate considerable toxicity of BV on various cell types. PURPOSE: This study addresses the question of how tendon tissue responds to BV in vivo and in vitro. STUDY DESIGN: Controlled laboratory study. METHODS: In vitro studies on cultured rat Achilles tendon-derived cells were performed with cell viability assays and cleaved caspase 3 immunocytochemistry. Quantitative reverse transcription polymerase chain reaction, Western blotting, gelatin zymography, and a biomechanical testing routine were applied on rat Achilles tendons at 1 and 4 weeks after a single unilateral peritendinous injection of 0.5% BV. The BV mediated cell death in tendons was estimated with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and immunohistochemical detection of cleaved caspase 3. RESULTS: Treatment of rat tendon-derived cells with 0.5% bupivacaine for 10 minutes had detrimental effects on cell viability, which can be reduced by N-acetyl-L-cysteine or reduction of extracellular calcium. In vivo, single peritendinous injections of BV caused apoptosis in endotenon cells and an increase of pro-matrix metalloproteinase-9 after 6 hours. The collagen ratio shifted toward collagen type III after 6 hours and 2 days; scleraxis messenger RNA (mRNA) expression was reduced by 87%. Maximum tensile load was reduced by 17.6% after 1 week. CONCLUSION: Bupivacaine exerts a severe, reactive oxygen species-mediated effect on tendon cell viability in vitro in a time- and dose-dependent manner, depending on extracellular calcium concentration. Culture conditions need to be taken into account when in vitro data are translated into the in vivo situation. In vivo, administration of BV elicits a marked but temporary functional damage. CLINICAL RELEVANCE: Local anesthetics cause short-term alterations in rat tendons, which, if occurring in humans to a similar extent, may be relevant regarding decreased biomechanical properties and increased vulnerability to tendon overload or injury. PMID- 23661216 TI - Prediction of the in vivo force-velocity relationship of slow human skeletal muscle from measurements in myofibers. AB - Direct measurement of the in vivo contractile properties of an individual muscle cannot be made in humans. The objective of this study was to predict the force velocity (F-V) properties of slow human skeletal muscle for the in vivo temperature of 37 degrees C from F-V measurements in type I myofibers. Specifically, to quantitatively link myofiber measurements, which must be conducted at relatively low temperatures, to in vivo properties, the temperature dependence of contractile properties must be modeled. We estimated the kinetic parameters of a crossbridge model within 15-30 degrees C from F-V measurements recorded in the myofibers of one subject, extrapolated their values at 37 degrees C, and then predicted the in vivo shortening and lengthening F-V curves. The prediction for maximal shortening velocity was 2.2 +/- 0.2 fiber lengths per second and that for saturation force during lengthening was 2.3 +/- 0.2 times isometric force. These estimates agree with previously reported in vivo measurements but are substantially different than those used in muscle models for many musculoskeletal simulations. The results from this study indicate that during low levels of muscle activation when slow motor units are primarily recruited, musculoskeletal models should consider having F-V properties that reflect the contractile properties of type I myofibers. PMID- 23661221 TI - The tourism carrying capacity of underwater trails in Isabel Island National Park, Mexico. AB - The popularity of ecotourism in the marine protected areas of Mexico has increased over the last 10 years; in particular there is a large development of a SCUBA diving industry in the Mexican Pacific including Isabel Island. Given the risks associated with human activity in the marine environments around this island, we propose two ecotourism management strategies: (1) the creation and use of underwater trails, and (2) the estimation of the specific tourism carrying capacity (TCC) for each trail. Six underwater trails were selected in sites that presented elements of biological, geological, and scenic interest, using information obtained during field observations. The methodology used to estimate the TCC was based upon the physical and biological conditions of each site, the infrastructure and equipment available, and the characteristics of the service providers and the administrators of the park. Correction factors of the TCC included elements of the quality of the visit and the threat and vulnerability of the marine environment of each trail (e.g., divers' expertise, size and distance between groups of divers, accessibility, wind, coral coverage). The TCC values ranged between 1,252 and 1,642 dives/year/trail, with a total of 8,597 dives/year for all six trails. Although these numbers are higher than the actual number of recreational visitors to the island (~1,000 dives per year), there is a need for adequate preventive management if the diving sites are to maintain their esthetic appeal and biological characteristics. Such management might be initially directed toward using only the sites and the TCC proposed here. PMID- 23661220 TI - A Danish population-based twin study on autism spectrum disorders. AB - Genetic epidemiological studies of Autism Spectrum Disorders (ASDs) based on twin pairs ascertained from the population and thoroughly assessed to obtain a high degree of diagnostic validity are few. All twin pairs aged 3-14 years in the nationwide Danish Twin Registry were approached. A three-step procedure was used. Five items from the "Child Behaviour Checklist" (CBCL) were used in the first screening phase, while screening in the second phase included the "Social and Communication Questionnaire" and the "Autism Spectrum Screening Questionnaire". The final clinical assessment was based on "gold standard" diagnostic research procedures including diagnostic interview, observation and cognitive examination. Classification was based on DSM-IV-TR criteria. The initial sample included 7,296 same-sexed twin pairs and, after two phases of screening and clinical assessment, the final calculations were based on 36 pairs. The probandwise concordance rate for ASD was 95.2% in monozygotic (MZ) twins (n=13 pairs) and 4.3% in dizygotic (DZ) twins (n=23 pairs). The high MZ and low DZ concordance rate support a genetic aetiology to ASDs. PMID- 23661222 TI - Comparing the accuracy of experimental estimates to guessing: a new perspective on replication and the "Crisis of Confidence" in psychology. AB - We develop a general measure of estimation accuracy for fundamental research designs, called v. The v measure compares the estimation accuracy of the ubiquitous ordinary least squares (OLS) estimator, which includes sample means as a special case, with a benchmark estimator that randomizes the direction of treatment effects. For sample and effect sizes common to experimental psychology, v suggests that OLS produces estimates that are insufficiently accurate for the type of hypotheses being tested. We demonstrate how v can be used to determine sample sizes to obtain minimum acceptable estimation accuracy. Software for calculating v is included as online supplemental material (R Core Team, 2012). PMID- 23661223 TI - Transition-metal-free oxidative trifluoromethylation of unsymmetrical biaryls with trifluoromethanesulfinate. AB - A transition-metal-free direct oxidative trifluoromethylation of unsymmetrical biaryls has been achieved by the simple combination of trifluoromethanesulfinate and phenyliodine bis(trifluoroacetate). The trifluoromethylation is selectively observed in the electron-rich arenes. PMID- 23661224 TI - Using patient-reported measurement to pave the path towards personalized medicine. AB - OBJECTIVE: Given the potential and importance of personalized or individualized medicine for health care delivery and its effects on patients' quality of life, a plenary session was devoted to personalized medicine during the 19th Annual Conference of the International Society for Quality of Life Research held in October 2012 in Budapest, Hungary. This paper summarizes the three presentations and discusses their implications for quality-of-life research. METHODS: Reviews of the literature and presentation of empirical studies. RESULTS: Personalized screening for breast cancer. To individualize screening and only target those women with an increased risk for breast cancer, researchers at the Karolinska Institutet in Stockholm perform a large population-based study to identify high risk women based on lifestyle, genetics, mammographic morphology, and other markers as well as quality of life. Personalized support for treatment adherence. Inclusion of a simple, brief adherence measure into the clinical visit has demonstrated significant improvement in medication-taking behaviour and resultant improvement in health status. Personalized diagnosis of mental disorders. The DSM 5, the current manual for mental disorders, contains patient-based symptom and diagnosis severity measures that allow more individualized diagnosis than was hitherto possible. CONCLUSIONS: Personalized medicine will continue to be increasingly applied and holds the potential to improve health outcomes including quality of life. At the same time, it will invite a host of new ethical, practical, and psychosocial questions. Further reflection and discussion of how our field can embrace and address these emerging challenges is needed. PMID- 23661225 TI - Self-esteem and life satisfaction in adolescents-gender and age as potential moderators. AB - PURPOSE: The present paper investigated gender differences on life satisfaction and self-esteem as well as the association between self-esteem and life satisfaction in Norwegian adolescents aged 13-18 years. The potential moderating role of gender and age in the relation between self-esteem and life satisfaction was also investigated. METHODS: A total of 1,239 adolescents from public elementary and secondary schools in mid-Norway participated in the school-based survey study. Mean score differences on the variables used in the study were tested using t tests. Hierarchical multiple regression analysis was used to evaluate the association between self-esteem and life satisfaction, controlled for gender, age, stress, subjective health, and chronic health conditions. RESULTS: The results showed that boys scored higher than girls on both self esteem and life satisfaction. Self-esteem was positively associated with life satisfaction, explaining 24 % of the variance. However, no interaction effect of gender * self-esteem or age * self-esteem was found in relation to life satisfaction. CONCLUSION: The results give support for that boys report higher self-esteem and life satisfaction than girls. Self-esteem has a positive role in association with adolescents' life satisfaction, and this relationship is equally strong for both genders and across age. PMID- 23661227 TI - Synergistic induction of apoptosis by sulindac and simvastatin in A549 human lung cancer cells via reactive oxygen species-dependent mitochondrial dysfunction. AB - Prevention of lung cancer is more feasible and holds greater promise when different agents are used in combination to target multiple processes during carcinogenesis. The mechanisms by which non-steroidal anti-inflammatory drugs and statins inhibit cancer cell growth and induce apoptosis are not fully understood. This study was designed to investigate lung cancer chemoprevention through a mechanism-based approach using sulindac at low doses in combination with simvastatin. We found that sulindac-induced cytotoxicity was significantly enhanced in the presence of simvastatin. The combination of sulindac and simvastatin induced more extensive caspase-dependent apoptosis in A549 cells compared to that induced with either drug alone. The combination of sulindac and simvastatin also increased the loss of mitochondrial transmembrane potential (?Psim) and the cytosolic release of cytochrome c. In addition, ROS generation in cells treated with both sulindac and simvastatin was markedly increased compared to cells treated with either sulindac or simvastatin alone. The enhancement of ROS generation by sulindac and simvastatin was abrogated by pretreatment with NAC, which also prevented apoptosis and mitochondrial dysfunction induced by sulindac and simvastatin. These results suggest that sulindac and simvastatin induced ROS generation in A549 lung cancer cells causes their accumulation in mitochondria, triggering the release of apoptogenic molecules from the mitochondria to the cytosol, and thus leading to caspase activation and cell death. PMID- 23661229 TI - Infiltrating sulfur in hierarchical architecture MWCNT@meso C core-shell nanocomposites for lithium-sulfur batteries. AB - We present hierarchical architecture MWCNT (multi-walled carbon nanotubes)@meso C core-shell nanostructures as a carbon matrix for effective trapping of sulfur/polysulfides as a cathode material for Li-S batteries. The unique structure of MWCNT@meso C core-shell nanocomposites was achieved by using a sol gel coating method followed by nanocasting. By infiltrating sulfur into the matrix, S/MWCNT@meso C core-shell nanocomposites were achieved. This material exhibited an initial discharge capacity of 1248 mA h g(-1) although it decayed to about 640 mA h g(-1) after 50 cycles. However, this performance is much better than that of S directly deposited on MWCNT (S/MWCNT) which only retained a capacity of 120 mA h g(-1) after 50 cycles. Our composite exhibited excellent rate capability even at a discharge current density of 2 A g(-1). The improvement in electrochemical performance is attributed to the synergetic effect between MWCNT cores, which provide electronic conduction pathways, and the mesoporous carbon shells with a relatively high surface area, which can trap sulfur/polysulfides and provide Li(+) ion pathways. PMID- 23661230 TI - Chiral ruthenium(II) complexes with phenolic hydroxyl groups as dual poisons of topoisomerases I and IIalpha. AB - A series of novel chiral ruthenium(II) complexes with phenolic hydroxyl groups were synthesized and characterized. These ruthenium(II) complexes exhibited strong dual inhibition of topoisomerases I and IIalpha, with approximate IC50 values of 3-15 mM, which were more efficient than the widely clinically used single TopoI poison camptothecin (CPT) or TopoIIalpha poison etoposide (VP-16). Delta-1 and Lambda-1 with more hydroxyls were observed to be more potent inhibitors. To further evaluate the mechanism of the complexes at a cellular level, these complexes were investigated for their effect on cell proliferation, cell cycle progression and induction of apoptosis. The results indicated that ruthenium(II) complexes permeated the nuclei in cancer cells and inhibited the activities of nuclear enzymes topoisomerases I and IIalpha, then triggered DNA damage and induced apoptosis in the cancer cells. The simultaneous inhibition of TopoI and TopoIIalpha induced the death of cancer cells, which may be a promising and effective strategy for cancer therapy. PMID- 23661228 TI - Astrocyte- neuron interaction as a mechanism responsible for generation of neural synchrony: a study based on modeling and experiments. AB - Neural synchronization is considered as an important mechanism for information processing. In addition, based on recent neurophysiologic findings, it is believed that astrocytes regulate the synaptic transmission of neuronal networks. Therefore, the present study focused on determining the functional contribution of astrocytes in neuronal synchrony using both computer simulations and extracellular field potential recordings. For computer simulations, as a first step, a minimal network model is constructed by connecting two Morris-Lecar neuronal models. In this minimal model, astrocyte-neuron interactions are considered in a functional-based procedure. Next, the minimal network is extended and a biologically plausible neuronal population model is developed which considers functional outcome of astrocyte-neuron interactions too. The employed structure is based on the physiological and anatomical network properties of the hippocampal CA1 area. Utilizing these two different levels of modeling, it is demonstrated that astrocytes are able to change the threshold value of transition from synchronous to asynchronous behavior among neurons. In this way, variations in the interaction between astrocytes and neurons lead to the emergence of synchronous/asynchronous patterns in neural responses. Furthermore, population spikes are recorded from CA1 pyramidal neurons in rat hippocampal slices to validate the modeling results. It demonstrates that astrocytes play a primary role in neuronal firing synchronicity and synaptic coordination. These results may offer a new insight into understanding the mechanism by which astrocytes contribute to stabilizing neural activities. PMID- 23661231 TI - Causal inference, probability theory, and graphical insights. AB - Causal inference from observational studies is a fundamental topic in biostatistics. The causal graph literature typically views probability theory as insufficient to express causal concepts in observational studies. In contrast, the view here is that probability theory is a desirable and sufficient basis for many topics in causal inference for the following two reasons. First, probability theory is generally more flexible than causal graphs: Besides explaining such causal graph topics as M-bias (adjusting for a collider) and bias amplification and attenuation (when adjusting for instrumental variable), probability theory is also the foundation of the paired availability design for historical controls, which does not fit into a causal graph framework. Second, probability theory is the basis for insightful graphical displays including the BK-Plot for understanding Simpson's paradox with a binary confounder, the BK2-Plot for understanding bias amplification and attenuation in the presence of an unobserved binary confounder, and the PAD-Plot for understanding the principal stratification component of the paired availability design. PMID- 23661232 TI - Inhibitory effects of resveratrol on MCP-1, IL-6, and IL-8 production in human coronary artery smooth muscle cells. AB - Resveratrol, a representative polyphenol compound, is known to have antiatherogenic effects through its various actions including an anti inflammatory action. The processes of initiation and progression of atherosclerosis are mediated by proinflammatory cytokines. The aim of this study was to determine whether resveratrol affects cytokine production in human coronary artery smooth muscle cells (HCASMCs). Each cytokine concentration in the culture medium of HCASMCs was measured by flow cytometry using the cytometric bead array system, and extracellular signal-regulated kinase (ERK) activity was evaluated by Western blotting. Basal levels of monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6, and IL-8 were significantly decreased in the presence of resveratrol at 1-50 MUM in a concentration-dependent manner and were significantly decreased in the presence of U0126, an ERK inhibitor. Resveratrol significantly decreased both basal and interferon-gamma (IFN-gamma) (200 ng/ml) stimulated levels of MCP-1, IL-6, and IL-8 and significantly attenuated both basal and IFN-gamma-stimulated activity of ERK. TNF-alpha, IL-1beta, IL-10, and IL-12p70 were detected only as trace levels in the culture medium with or without IFN-gamma. Therefore, resveratrol is thought to inhibit production of MCP-1, IL 6, and IL-8 in HCASMCs through attenuating ERK activity. Inhibition of cytokine production in coronary artery smooth muscle cells may in part explain antiatherogenic action of resveratrol. PMID- 23661233 TI - Optoelectronic tweezers integrated with lensfree holographic microscopy for wide field interactive cell and particle manipulation on a chip. AB - We demonstrate an optoelectronic tweezer (OET) coupled to a lensfree holographic microscope for real-time interactive manipulation of cells and micro-particles over a large field-of-view (FOV). This integrated platform can record the holographic images of cells and particles over the entire active area of a CCD sensor array, perform digital image reconstruction to identify target cells, dynamically track the positions of cells and particles, and project light beams to trigger light-induced dielectrophoretic forces to pattern and sort cells on a chip. OET technology has been previously shown to be capable of performing parallel single cell manipulation over a large area. However, its throughput has been bottlenecked by the number of cells that can be imaged within the limited FOV of a conventional microscope objective lens. Integrating lensfree holographic imaging with OET solves this fundamental FOV barrier, while also creating a compact on-chip cell/particle manipulation platform. Using this unique platform, we have successfully demonstrated real-time interactive manipulation of thousands of single cells and micro-particles over an ultra-large area of e.g., 240 mm(2) (i.e. 17.96 mm * 13.52 mm). PMID- 23661236 TI - Pulmonary Langerhans cell histiocytosis. AB - Herein, we described 16-year-old boy with pulmonary cysts in both lung fields and diagnosed as isolated pulmonary Langerhans cell histiocytosis. PMID- 23661235 TI - Reference intervals of alpha-glycosidase, beta-glycosidase, and alpha galactosidase in dried blood spot in a Turkish newborn population. AB - Inherited lysosomal storage diseases (LSDs) are rare, and diagnosis is often delayed for 7-10 years. Since the therapies have become available for a limited number of LSDs, (Fabry, Gaucher, Pompe, and MPS-1), early diagnosis of treatable LSDs can be lifesaving or ameliorating and allows timely treatment before irreversible damage occurs. Recently, the use of dried blood spot test (DBS) for newborn screening of LSDs has been proposed for newborn screening tests. They are noninvasive, sensitive, and specific assays with the further advantage of a fast turnaround time compared to measurement in leukocyte and/or fibroblast culture. We aimed to determine the reference intervals for lysosomal enzyme activities of newborn babies in our population and to investigate the effect of gestational week on enzyme activity. One hundred thirty healthy newborn babies (70 girls, 60 boys) were included into the study. alpha-Glycosidase, beta-glycosidase, and alpha-galactosidase activities in DBS samples of newborns were determined fluorometrically. Reference intervals were calculated using Dixon's rule and percentiles of 2.5-97.5. Cutoff limits (5 %) for alpha-glycosidase, beta glycosidase, and alpha-galactosidase activities were 0.57, 0.92, and 2.18, respectively. alpha-Galactosidase activity was higher in girls compared to boys (p < 0.05). Interestingly, alpha-glycosidase and beta-glycosidase activities of newborns who were delivered before 38 weeks were significantly lower than those who were delivered at 39-40 weeks. Conclusion It is of utmost importance to define the reference intervals for lysosomal enzyme activities as well as cutoff limits for newborn babies with regard to gestational age and sex. More studies to clarify the reason for the change in enzyme activity by gestational week will be required. PMID- 23661237 TI - Parental monitoring: a way to decrease substance use among Swiss adolescents? AB - The objective of this research was to determine whether the level of parental monitoring is associated with substance use among adolescents in Switzerland, and to assess whether this effect remains when these adolescents have consuming peers. For this purpose, we used a nationally representative sample from the Swiss participation in the 2007 European School Project on Alcohol and Other Drugs survey, which included 7,611 adolescents in public schools (8th-10th grades). Four levels of parental control were created and four substances (tobacco, alcohol, cannabis, and ecstasy) were analyzed. All significant variables at the bivariate level were included in the multivariate analysis. Most adolescents had a high level of parental monitoring and that was associated with younger age, females, high socioeconomic status, intact family structure, and satisfactory relationships with mother, father, and peers. Overall, substance use decreased as parental monitoring increased and high parental monitoring decreased as having consuming peers increased. Results remained essentially the same when the variable "having consuming peers" was added to the analysis. CONCLUSION: parental monitoring is associated to positive effects on adolescent substance use with a reduction of consumption and a lower probability of having consuming peers, which seems to protect adolescents against potentially negative peer influence. Encouraging parents to monitor their adolescents' activities and friendships by establishing rules about what is allowed or not is a way to limit the negative influence of consuming peers on adolescent substance use. PMID- 23661239 TI - Mechanics of rolling of nanoribbon on tube and sphere. AB - The configuration of graphene nano-ribbon (GNR) assembly on carbon nanotube (CNT) and sphere is studied through theoretical modeling and molecular simulation. The GNR can spontaneously wind onto the CNT due to van der Waals (vdW) interaction and form two basic configurations: helix and scroll. The final configuration arises from the competition among three energy terms: the bending energy of the GNR, the vdW interaction between GNR and CNT, the vdW between the GNR itself. We derive analytical solutions by accounting for the three energy parts, with which we draw phase diagrams and predict the final configuration (helix or scroll) based on the selected parameters. The molecular simulations are conducted to verify the model with the results agree well with the model predicted. Our work can be used to actively control and transfer the tube-like nanoparticles and viruses as well as to assemble ribbon-like nanomaterials. PMID- 23661234 TI - The burden of seasonal and pandemic influenza in infants and children. AB - The burden of influenza is unevenly distributed, with more severe outcomes in children aged <5 years than older children and adults. In spite of this, immunisation policies for young children are far from universal. This article provides an overview of the published evidence on the burden of influenza in children worldwide, with a particular interest in the impact of pandemic influenza in 2009-2010 (caused by the H1N1pdm09 virus). In an average season, up to 9.8 % of 0- to 14-year olds present with influenza, but incidence rates can be markedly higher in younger children. Children aged <5 years have greater rates of hospitalisation and complications than their older counterparts, particularly if the children have co-existing illnesses; historically, this age group have had higher mortality rates from the disease than other children, although during the 2009-2010 pandemic the median age of those who died of influenza was higher than in previous seasons. Admissions to hospital and emergency departments appear to have been more frequent in children with H1N1pdm09 infections than during previous seasonal epidemics, with pneumonia continuing to be a common complication in this setting. Outcomes in children hospitalised with severe disease also seem to have been worse for those infected with H1N1pdm09 viruses compared with seasonal viruses. Studies in children confirm that vaccination reduces the incidence of seasonal influenza and the associated burden, underlining the importance of targeting this group in national immunisation policies. CONCLUSIONS: Children aged <5 years are especially vulnerable to influenza, particularly that caused by seasonal viruses, and vaccination in this group can be an effective strategy for reducing disease burden. PMID- 23661240 TI - A comparison of parathyroid hormone-related protein (1-36) and parathyroid hormone (1-34) on markers of bone turnover and bone density in postmenopausal women: the PrOP study. AB - Parathyroid hormone-related protein (PTHrP)(1-36) increases lumbar spine (LS) bone mineral density (BMD), acting as an anabolic agent when injected intermittently, but it has not been directly compared with parathyroid hormone (PTH)(1-34). We performed a 3-month randomized, prospective study in 105 postmenopausal women with low bone density or osteoporosis, comparing daily subcutaneous injections of PTHrP(1-36) to PTH(1-34). Thirty-five women were randomized to each of three groups: PTHrP(1-36) 400 ug/day; PTHrP(1-36) 600 ug/day; and PTH(1-34) 20 ug/day. The primary outcome measures were changes in amino-terminal telopeptides of procollagen 1 (PINP) and carboxy-terminal telopeptides of collagen 1 (CTX). Secondary measures included safety parameters, 1,25(OH)2 vitamin D, and BMD. The increase in bone resorption (CTX) by PTH(1-34) (92%) (p < 0.005) was greater than for PTHrP(1-36) (30%) (p < 0.05). PTH(1-34) also increased bone formation (PINP) (171%) (p < 0.0005) more than either dose of PTHrP(1-36) (46% and 87%). The increase in PINP was earlier (day 15) and greater than the increase in CTX for all three groups. LS BMD increased equivalently in each group (p < 0.05 for all). Total hip (TH) and femoral neck (FN) BMD increased equivalently in each group but were only significant for the two doses of PTHrP(1 36) (p < 0.05) at the TH and for PTHrP(1-36) 400 (p < 0.05) at the FN. PTHrP(1 36) 400 induced mild, transient (day 15) hypercalcemia. PTHrP(1-36) 600 required a dose reduction for hypercalcemia in three subjects. PTH(1-34) was not associated with hypercalcemia. Each peptide induced a marked biphasic increase in 1,25(OH)2 D. Adverse events (AE) were similar among the three groups. This study demonstrates that PTHrP(1-36) and PTH(1-34) cause similar increases in LS BMD. PTHrP(1-36) also increased hip BMD. PTH(1-34) induced greater changes in bone turnover than PTHrP(1-36). PTHrP(1-36) was associated with mild transient hypercalcemia. Longer-term studies using lower doses of PTHrP(1-36) are needed to define both the optimal dose and full clinical benefits of PTHrP. (c) 2013 American Society for Bone and Mineral Research. PMID- 23661241 TI - alphav-Integrin isoform expression in primary human tumors and brain metastases. AB - To determine whether metastasis to brain is associated with altered expression patterns of integrins, we investigated the expression of alphavbeta3, alphavbeta5, alphavbeta6 and alphavbeta8 integrins in primary malignancies and metastases to brain of breast, lung and renal carcinomas and in malignant melanoma. Inhibitors of alphav integrins are currently in clinical trials for glioblastoma. The role of integrins in the process of brain metastasis from other human tumors is unknown. Immunohistochemistry with novel integrin subtype specific rabbit monoclonal antibodies was performed on tissue microarrays of archival material of surgical biopsies taken from primary tumors and brain metastases. Integrin alphavbeta3 expression was increased in brain metastases compared to primary tumors of breast adenocarcinoma, non-small cell lung cancer, renal clear cell cancer and malignant cutaneous melanoma (all p < 0.01). Similarly, integrin alphavbeta8 expression was increased in brain metastases compared to primary tumors of breast cancer (p < 0.0001), lung cancer (p < 0.01) and renal cancer (p < 0.0001), with a similar trend in metastatic melanoma. Integrin alphavbeta5 was expressed in most primary tumors (98% breast cancer; 67% lung cancer; 90% renal cancer; 89% melanoma) and showed a stronger expression in brain metastases compared to primary tumors from lung cancer and melanoma (p < 0.05). Also integrin alphavbeta6 expression was increased in brain metastases compared to primary breast cancer (p < 0.001). CONCLUSIONS: The stronger alphav integrin expression in brain metastases, especially of alphavbeta3 and alphavbeta8 integrins, suggests that certain alphav integrin are involved in the process of brain metastasis. alphav Integrins may be therapeutic targets for patients with metastatic cancer in brain. PMID- 23661243 TI - Humor, laughter, and the cerebellum: insights from patients with acute cerebellar stroke. AB - Extent of cerebellar involvement in cognition and emotion is still a topic of ongoing research. In particular, the cerebellar role in humor processing and control of laughter is not well known. A hypermetric dysregulation of affective behavior has been assumed in cerebellar damage. Thus, we aimed at investigating humor comprehension and appreciation as well as the expression of laughter in 21 patients in the acute or subacute state after stroke restricted to the cerebellum, and in the same number of matched healthy control subjects. Patients with acute and subacute cerebellar damage showed preserved comprehension and appreciation of humor using a validated humor test evaluating comprehension, funniness and aversiveness of cartoons ("3WD Humor Test"). Additionally, there was no difference when compared to healthy controls in the number and intensity of facial reactions and laughter while observing jokes, humorous cartoons, or video sketches measured by the Facial Action Coding System. However, as depression scores were significantly increased in patients with cerebellar stroke, a concealing effect of accompanying depression cannot be excluded. Current findings add to descriptions in the literature that cognitive or affective disorders in patients with lesions restricted to the cerebellum, even in the acute state after damage, are frequently mild and might only be present in more sensitive or specific tests. PMID- 23661244 TI - The streptavidin/biotinylated DNA/protein bound complex protocol for determining the association of c-JUN protein with NANOG promoter. AB - Chromatin immunoprecipitation (ChIP) is a widely used and pre-eminent technique for detecting the association of an individual protein or a particular protein complex with its specific DNA sequence(s) in vivo. Herein we introduce a novel and simple biotinylated-oligonucleotide-mediated ChIP method for testing specific binding of the c-JUN protein to the M1-DNA-regulatory element in the NANOG promoter. We prepared a 260-bp DNA PCR amplicon containing -300 bp to -59 bp, relative to the transcriptional start site of the human NANOG gene, which was transfected into mouse embryonic fibroblasts (MEF) containing wild-type (c jun(+/+)) or knockout c-jun (c-jun(-/-)) alleles. Whole cells that were cross linked using formaldehyde and protein-DNA interactions were immunoprecipitated using streptavidin-coupled Dynabeads. Protein-DNA cross-links were reversed during incubation at 95 degrees C, and protein samples were visualized using SDS PAGE electrophoresis and western blotting. This streptavidin/biotinylated DNA/protein-bound complex protocol can be used for detecting the interactions between multiple transcription factors and their DNA binding sites. PMID- 23661245 TI - Isolation of human umbilical cord blood aldehyde dehydrogenase-expressing progenitor cells that modulate vascular regenerative functions in vitro and in vivo. AB - This unit describes the isolation and application of human umbilical cord blood progenitor cells to modulate vascular regenerative functions using in vitro co culture systems and in vivo transplantation models. Using aldehyde dehydrogenase as a marker of stem cell function, blood-derived progenitors can be efficiently purified form human umbilical cord blood using flow cytometry. We describe in vitro approaches to measure cell-mediated effects on the survival, proliferation, and tube-forming function of endothelial cells using growth-rate assays and Matrigel tube-forming assays. Additionally, we provide a detailed protocol for inducing acute unilateral hindlimb ischemia in immune-deficient mice to assess progenitor cell-modulated effects on vascular regeneration by tracking the recovery of blood flow using noninvasive laser Doppler perfusion imaging. Collectively, we present combined in vitro and in vivo transplantation strategies for the pre-clinical assessment of human progenitor cell-based therapies to treat ischemic disease. PMID- 23661246 TI - Expanding donor muscle-derived cells for transplantation. AB - Studies in mice showed tremendous promise for the eventual clinical utility of myoblast transplantation to treat human muscular dystrophies. Initial attempts to translate the murine studies to humans, however, were not successful, due in part to limited engraftability of expanded donor myoblasts. Conventionally, muscle cells have been cultured on collagen-coated tissue culture-treated polystyrene. However, this promotes lineage progression and differentiation of cells, which limits engraftment potential. This unit describes the isolation of canine muscle derived cells, ex vivo expansion of cells on plates coated with a modified Notch ligand, and the xenotransplant method used to evaluate engraftment potential. Activation of Notch signaling in freshly isolated canine muscle-derived cells with Delta-1(ext)-IgG inhibits myogenic differentiation, and maintains cells earlier in myogenic lineage progression. Delta-1(ext)-IgG-expanded cells engraft into the regenerating muscle of NOD/SCID mice more effectively than control cells expanded on human IgG, as evidenced by a significant increase in the number of muscle fibers expressing canine dystrophin in recipient murine muscle. Therefore, this protocol provides the basis for further developing culture conditions for ex vivo expansion of donor muscle cells for transplant. PMID- 23661248 TI - The compositional and institutional sources of union dissolution for married and unmarried parents in the United States. AB - Unmarried parents have less stable unions than married parents, but there is considerable debate over the sources of this instability. Unmarried parents may be more likely than married parents to end their unions because of compositional differences, such as more disadvantaged personal and relationship characteristics, or because they lack the normative and institutional supports of marriage, thus rendering their relationships more sensitive to disadvantage. In this article, we evaluate these two sources of union instability among married, cohabiting, and dating parents following the birth of a shared child, using five waves of longitudinal data from the Fragile Families and Child Wellbeing Study. Using discrete-time event history models, we find that demographic, economic, and relationship differences explain more than two-thirds of the increased risk of dissolution for unmarried parents relative to married parents. We also find that differential responses to economic or relationship disadvantage do not explain why unmarried parents are more likely to end their unions than married parents. PMID- 23661247 TI - Revealing neuronal circuitry using stem cell-derived neurons. AB - Mouse embryonic stem cell (mESC)-derived neurons are a renewable cell source for investigation of neuronal circuits. Engineering circuit-tracing components into stem cells facilitates studies on mechanisms of synaptic coupling and circuitogenesis. This unit details methods for the generation of mESC-derived neurons harboring trans-synaptic viral tracing elements, which are used for investigation of synaptic connections within circuits in vitro, ex vivo, and in vivo. The first protocol describes procedures for feeder-free passaging of mESCs, modified to carry reporter and rabies virus tracing elements. The second protocol describes in vitro generation of neurons from these ESCs. The last protocols describe the use of ESC-derived neurons as "source cells" for rabies virus circuit-tracing to identify inputs onto synaptically connected neurons. Given the broad applicability, these protocols can be applied to investigate the ability of in vitro-derived neurons to establish/maintain synaptic connections in disease models, and/or with human-induced pluripotent stem cells. PMID- 23661249 TI - College raises concern about GPs' role in government plans to restrict access to NHS. PMID- 23661250 TI - Government has lost "credibility on public health" for inaction on cigarettes and alcohol, campaigners say. PMID- 23661251 TI - Review that found PIP implants to be safe was flawed, say campaigners. PMID- 23661252 TI - A PCR based magnetic assembled sensor for ultrasensitive DNA detection. AB - An ultrasensitive method for DNA detection based on magnetic assembly induced by polymerase chain reaction (PCR) was developed. The sensor showed a low limit of detection (LOD) of 4.26 aM with a wide range of target DNA from 0.01 fM to 10,000 fM. PMID- 23661254 TI - Modulation of u-PA, MMPs and their inhibitors by a novel nutrient mixture in adult human sarcoma cell lines. AB - Adult sarcomas are highly aggressive tumors that are characterized by high levels of matrix metalloproteinase (MMP)-2 and -9 secretions that degrade the ECM and basement membrane, allowing cancer cells to spread to distal organs. Proteases play a key role in tumor cell invasion and metastasis by digesting the basement membrane and ECM components. Strong clinical and experimental evidence demonstrates association of elevated levels of u-PA and MMPs with cancer progression, metastasis and shortened patient survival. MMP activities are regulated by specific tissue inhibitors of metalloproteinases (TIMPs). Our main objective was to study the effect of a nutrient mixture (NM) on the activity of u PA, MMPs and TIMPs in various human adult sarcomas. Human fibrosarcoma (HT-1080), chondrosarcoma (SW-1353), liposarcoma (SW-872), synovial sarcoma (SW-982) and uterine leimyosarcoma (SK-UT-1) cell lines (ATCC) were cultured in their respective media and treated at confluence with NM at 0, 50, 100, 250, 500 and 1,000 ug/ml. Analysis of u-PA activity was carried out by fibrin zymography, MMPs by gelatinase zymography and TIMPs by reverse zymography. Fibrosarcoma, chondrosarcoma, liposarcoma and leiomyosarcoma cancer cell lines expressed u-PA, which was inhibited by NM in a dose-dependent manner. However, no bands corresponding to u-PA were detected for synovial sarcoma cells. On gelatinase zymography, fibrosarcoma, chondrosarcoma, liposarcoma and synovial sarcoma showed bands corresponding to MMP-2 and MMP-9 with enhancement of MMP-9 with PMA (100 ng/ml) treatment. Uterine leiomyosarcoma showed strong bands corresponding to inactive and active MMP-9 and a faint band corresponding to MMP-9 dimer induced with PMA treatment, but no MMP-2 band. NM inhibited their expression in a dose dependent manner. Activity of TIMPs was upregulated by NM in all cancer cell lines in a dose-dependent manner. Analysis revealed a positive correlation between u-PA and MMPs and a negative correlation between u-PA/MMPs and TIMPs. These findings suggest the therapeutic potential of NM in treatment of adult sarcomas. PMID- 23661255 TI - Preparation of methotrexate-loaded, large, highly-porous PLLA microspheres by a high-voltage electrostatic antisolvent process. AB - A high-voltage (10 kV) electrostatic antisolvent process was used to prepare methotrexate (MTX)-loaded, large, highly-porous poly-L-lactide (PLLA) microspheres. MTX solution in dimethyl sulfoxide (DMSO) and PLLA solution in dichloromethane (DCM) were homogeneously mixed, and then ammonium bicarbonate (AB) aqueous solution was added. The mixed solution was emulsified by ultrasonication with Pluronic F127 (PF127) as an emulsion stabilizer. The emulsion was electrosprayed by the specific high-voltage apparatus and dropped into a 100 mL of ethanol, which acted as an antisolvent for the solute and extracted DMSO and DCM, causing the co-precipitation of PLLA and MTX, thus forming microspheres with AB aqueous micro-droplets uniformly inlaid. The obtained MTX-PLLA microspheres were subsequently lyophilized to obtain large, highly-porous MTX-PLLA microspheres, which exhibited an identifiable spherical shape and a rough surface furnished with open pores, with a mean particle size of 25.0 MUm, mass median aerodynamic diameter of 3.1 +/- 0.2 MUm, fine-particle fraction of 57.1 +/- 1.6 %, and porosity of 81.8 %; furthermore, they offered a sustained release of MTX. X-ray diffraction and Fourier transform-infrared spectra revealed that no crystallinity or alteration of chemical structure occurred during the high-voltage electrostatic antisolvent process, which in this study was proved to have great potential for preparing highly-porous drug-loaded polymer microspheres for use in pulmonary drug delivery. PMID- 23661256 TI - Osteoblastic cells culture on electrospun poly(epsilon-caprolacton) scaffolds incorporating amphiphilic PEG-POSS telechelic. AB - In this work, novel poly(epsilon-caprolactone) (PCL) fibrous membranes incorporating amphiphilic polyhedral oligosilsesquioxane (POSS) telechelic (PEG POSS telechelic) were prepared via electrospinning. The unique microstructure, morphology, thermal stability of the resulting PCL/PEG-POSS telechelic electrospun nanowebs were investigated by X-ray diffraction, scanning electron microscopy, and thermogravimetric analysis, respectively. The addition of amphiphilic PEG-POSS telechelic strongly influenced the fiber diameters, microstructures of the resultant PCL/PEG-POSS telechelic nanofibers, compared to pure PCL nanofibers. The potential biomedical applications of such PEG-POSS telechelic nanowebs as a scaffolding material were also evaluated in vitro using mouse osteoblast-like MC3T3-E1 cells. The cell adhesion, spreading, and interaction behavior of pure PCL and PCL/PEG-POSS telechelic fibrous membranes were explored. It was found that electrospun PCL fibrous membranes incorporating amphiphilic PEG-POSS telechelic showed higher initial cell attachment than pure PCL due to the higher surface free energy of POSS siloxanes. Moreover, the obtained PCL/PEG-POSS telechelic fibrous scaffolds were found to be nontoxic and to maintain the good adhesion ratio between cells and surface (about ~93 %) after cell culturing for 24 h. PMID- 23661257 TI - Highly fluorescent and biocompatible iridium nanoclusters for cellular imaging. AB - Highly fluorescent iridium nanoclusters were synthesized and investigated its application as a potential intracellular marker. The iridium nanoclusters were prepared with an average size of ~2 nm. Further, these nanoclusters were refluxed with aromatic ligands, such as 2,2'-binaphthol (BINOL) in order to obtain fluorescence properties. The photophysical properties of these bluish-green emitting iridium nanoclusters were well characterized by using UV-Visible, fluorescence and lifetime decay measurements. The emission spectrum for these nanoclusters exhibit three characteristic peaks at 449, 480 and 515 nm. The fluorescence quantum yield of BINOL-Ir NCs were estimated to be 0.36 and the molar extinction co-efficients were in the order of 10(6) M(-1)cm(-1). In vitro cytotoxicity studies in HeLa cells reveal that iridium nanoclusters exhibited good biocompatibility with an IC50 value of ~100 MUg/ml and also showed excellent co-localization and distribution throughout the cytoplasm region without entering into the nucleus. This research has opened a new window in developing the iridium nanoparticle based intracellular fluorescent markers and has wide scope to act as biomedical nanocarrier to carry many biological molecules and anticancer drugs. PMID- 23661258 TI - A scoping review of important urinary catheter induced complications. AB - This study presents a scoping review of the literature on the morbidity and mortality associated with several common complications of urinary catheterization. Data gathered from the open literature were analyzed graphically to gain insights into the most important urinary catheter induced complications. The results reveal that the most significant catheter complications are severe mechanical trauma (perforation, partial urethral damage and urinary leakage), symptomatic bacterial infection, and anaphylaxis, catheter toxicity and hypersensitivity. The data analysis also revealed that the complications with the highest morbidity are all closely related to the mechanical interaction of the catheter with the urethra. This suggests that there is a strong need for urinary catheter design to be improved to minimize mechanical interaction, especially mechanical damage to the urinary tract, and to enhance patient comfort. Several urinary catheter design directions have been proposed based on tribological principles. Among the key recommendations is that catheter manufacturers develop catheter coatings which are both hydrophilic and antibacterial, and which maintain their antibacterial patency for at least 90 days. PMID- 23661259 TI - Impact of preoperative breast MRI on surgical decision making and clinical outcomes: a systematic review. AB - BACKGROUND: Preoperative magnetic resonance imaging (MRI) is increasingly used in the workup of breast cancer patients and could lead to changes in surgical management. It is unclear how the information gained from MRI studies affects surgical decision making and influences clinical outcomes. These issues are addressed in this review. METHODS: PubMed database searches were performed to retrieve and analyze respective original research and review articles on preoperative MRI in the evaluation of breast cancer patients. RESULTS: Preoperative MRI is a highly sensitive but nonspecific method that leads to changes in surgical management with increased numbers of more extended surgical interventions. It appears that a relatively large proportion of MRI-driven changes in surgical management result in overtreatment without conclusively proven beneficial effects on such clinical outcomes as decrease in reoperation rates or improved patient survival. CONCLUSIONS: Thus, routine use of supplementary preoperative breast MRI should be discouraged until compelling evidence of its effectiveness is available. PMID- 23661260 TI - Should diaphragmatic involvement preclude resection of large hepatic tumors? AB - BACKGROUND: Treatment of peripherally located liver tumors with diaphragmatic invasion is technically demanding but does not preclude resection for cure. The aim of the present study was to compare patients undergoing combined liver and diaphragmatic resection with those submitted to hepatectomy alone so as to evaluate the safety, effectiveness, and value of this complex surgical procedure. METHODS: From January 2000 to September 2011, 36 consecutive patients underwent en bloc liver-diaphragm resection (group A). These were individually matched for age, gender, tumor size, pathology, and co-morbitidies with 36 patients who underwent hepatectomy alone during the same time (group B). Operative time, warm ischemia time, blood loss, required transfusions, postoperative complications, and long-term survival were evaluated. RESULTS: Mean operative time was significantly longer in group A than in group B (165 vs 142 min; P = 0.004). The two groups were comparable regarding warm ischemia time, intraoperative blood loss, required transfusions, and postoperative laboratory value fluctuations. Some 33 % of group A patients developed complications postoperatively as opposed to 23 % of group B patients (P = 0.03). The mortality rate was 2.8 % in group A compared to 0 % in group B. Postoperative follow-up demonstrated 60 % 1-year survival for group A patients as opposed to 80 % 1-year survival for group B patients, a difference that is practically eliminated the longer the follow-up period is extended (35 vs 40 % 3-year survival and 33 vs 37 % 5-year survival for group A and group B patients, respectively). CONCLUSIONS: En bloc diaphragmatic and liver resection is a challenging but safe surgical procedure that is fully justified when diaphragmatic infiltration cannot be ruled out and the patient is considered fit enough to undergo surgery. PMID- 23661261 TI - Nematode 18S rRNA gene is a reliable tool for environmental biosafety assessment of transgenic banana in confined field trials. AB - Information on relatedness in nematodes is commonly obtained by DNA sequencing of the ribosomal internal transcribed spacer region. However, the level of diversity at this locus is often insufficient for reliable species differentiation. Recent findings suggest that the sequences of a fragment of the small subunit nuclear ribosomal DNA (18S rRNA or SSU), identify genera of soil nematodes and can also distinguish between species in some cases. A database of soil nematode genera in a Ugandan soil was developed using 18S rRNA sequences of individual nematodes from a GM banana confined field trial site at the National Agricultural Research Laboratories, Kawanda in Uganda. The trial was planted to evaluate transgenic bananas for resistance to black Sigatoka disease. Search for relatedness of the sequences gained with entries in a public genomic database identified a range of 20 different genera and sometimes distinguished species. Molecular markers were designed from the sequence information to underpin nematode faunal analysis. This approach provides bio-indicators for disturbance of the soil environment and the condition of the soil food web. It is being developed to support environmental biosafety analysis by detecting any perturbance by transgenic banana or other GM crops on the soil environment. PMID- 23661262 TI - Hydrogenolysis of ethylene glycol to methanol over modified RANEY(r) catalysts. AB - There is tremendous growing interest in utilizing biomass molecules for energy provision due to their carbon neutrality. Here, we employ ethylene glycol as a model compound for catalytic activation, which represents a basic unit for complex carbohydrate molecules (polyols). In this paper, hydrogenolysis of ethylene glycol to produce methanol in hydrogen over modified RANEY(r) Ni and Cu catalysts has been studied. This work provides essential information that may leads to the development of new catalysts for carbohydrate activation to methanol, a novel but important reaction concerning biomass conversion to transportable form of energy. Particularly, in this study, modification of electronic structure hence adsorption properties of RANEY(r) catalysts has mainly been achieved by blending with second metal(s). It is found that the activity and selectivity of this reaction can be significantly affected by this approach. In contrast, there is no subtle effect on methanol selectivity despite a great variation in the d-band centre position which shows a distinctive effect on other products. This result suggests that methanol is produced on specific surface sites independent from the other sites at an intrinsic rate and will not be converted to other products by the d-band alteration. PMID- 23661263 TI - A Bayesian approach to strengthen inference for case-control studies with multiple error-prone exposure assessments. AB - In case-control studies, exposure assessments are almost always error-prone. In the absence of a gold standard, two or more assessment approaches are often used to classify people with respect to exposure. Each imperfect assessment tool may lead to misclassification of exposure assignment; the exposure misclassification may be differential with respect to case status or not; and, the errors in exposure classification under the different approaches may be independent (conditional upon the true exposure status) or not. Although methods have been proposed to study diagnostic accuracy in the absence of a gold standard, these methods are infrequently used in case-control studies to correct exposure misclassification that is simultaneously differential and dependent. In this paper, we proposed a Bayesian method to estimate the measurement-error corrected exposure-disease association, accounting for both differential and dependent misclassification. The performance of the proposed method is investigated using simulations, which show that the proposed approach works well, as well as an application to a case-control study assessing the association between asbestos exposure and mesothelioma. PMID- 23661264 TI - Novel pathways and molecular targets for the treatment of sarcoma. AB - Sarcomas collectively represent over 100 different subtypes of bone and soft tissue tumors of mesenchymal origin. The low response rate to cytotoxic chemotherapies has necessitated the need for development of either histologically driven or pathway-specific targeted therapies. As our understanding of the molecular mechanisms driving certain subtypes is rapidly advancing, the number of targeted therapies is also increasing. Recently identified novel druggable targets include the MDM2 amplifications in well-differentiated and dedifferentiated liposarcomas, the new translocation NAB2:STAT6 of solitary fibrous tumors, the angiopoeitin-TIE2 pathway in angiosarcoma, the suppression of Mcl1 in X:18/synovial sarcomas, the mTOR pathway in malignant peripheral nerve sheath tumors, CDK4 in alveolar rhabdomyosarcoma, cMET regulation in alveolar soft parts sarcoma, the metabolic abnormalities in wild-type/SHD GIST, and the lack of argininosuccinate synthetase 1 expression seen in most sarcomas. It is through a fundamental understanding of sarcoma biology that clinical trials based on molecular targets can be developed. PMID- 23661265 TI - Cardiovascular and renal complications to postsurgical hypoparathyroidism: a Danish nationwide controlled historic follow-up study. AB - We aimed to identify all patients with postsurgical hypoparathyroidism (HypoPT) and to evaluate their risks of renal complications and cardiovascular disease in relation to their disease and its treatment. We identified possible patients through the Danish National Patient Registry and a prescription database. Case status was adjudicated by review of individual patients' hospital records. For each patient with postsurgical HypoPT due to surgery for nonmalignant diseases between 1988 and 2012, three age-matched (+/- 2 years) and gender-matched controls were selected from the general background population. The prevalence of postsurgical HypoPT was 22 per 100,000 inhabitants. We identified 688 patients who had undergone neck surgery since 1988 with subsequent hypocalcaemia and inappropriate low parathyroid hormone (PTH) levels that necessitated treatment with calcium and/or vitamin D supplementation for more than 6 months. The average age at diagnosis was 49 years (range, 17-87 years), and 88% were women. Sixteen percent of all patients had had neck surgery prior to the operation causing HypoPT. Compared with controls, patients with HypoPT had an increased risk of renal complications (hazard ratio [HR], 3.67; 95% confidence interval [CI], 2.41 5.59) and hospitalization due to seizures (HR, 3.82; 95% CI, 2.15-6.79), whereas there was no increased risk of cardiac arrhythmias (HR, 1.11; 95% CI, 0.79-1.57) or cardiovascular disease or death (HR, 0.89; 95% CI, 0.73-1.09). In conclusion, although risk of seizures and renal complications is increased, mortality and risk of cardiovascular diseases or arrhythmias is not increased in patients with HypoPT. Further study should try to determine how to reduce the risk of seizures and renal complications in HypoPT. PMID- 23661266 TI - Applicability of partial characterization of cytochrome oxidase I in identification of forensically important flies (Diptera) from China and Egypt. AB - Precise species identification of every insect sample collected from criminal scenes play an essential role in the accurate estimation of postmortem interval. The morphological similarity poses a great challenge for forensic entomologists. DNA-based method can be used as a supplemental means of morphological method. In the present study, we demonstrate the applicability of the 304-bp cytochrome oxidase I gene fragment in molecular identification of forensically important Diptera. We analyzed 75 specimens belonging to 19 species of 3 families originating from China (Calliphoridae: Chrysomya megacephala, Chrysomya albiceps, Chrysomya rufifacies, Chrysomya nigripes, Aldrichina grahami; Lucilia bazini, Lucilia caesar, Lucilia cuprina, Lucilia sericata, Lucilia porphyrina; Muscidae: Musca autumnalis, Musca domestica, Fannia canicularis, Stomoxys calcitrans; Sarcophagidae: Sarcophaga albiceps, Sarcophaga dux, Helicophagella melanura) and Egypt (Calliphoridae: C. megacephala, C. albiceps, L. sericata; Muscidae: M. domestica, F. canicularis, S. calcitrans, Synthesiomyia nudiseta; Sarcophagidae: Sarcophaga argyrostoma). This region was amplified using polymerase chain reaction followed by direct sequencing of the amplification products. Nucleotide sequence divergences were calculated using the Kimura two-parameter distance model and a neighbor-joining phylogenetic tree generated. Intraspecific variation ranged from 0-0.8 % and interspecific variation occurred between 1-19 %. Although all examined specimens were assigned to the correct species and formed distinct monophyletic clades, the data of the phylogenetic analysis were not completely in accordance with the traditional morphological classification. As both C. nigripes and A. grahami unexpectedly joined with Muscidae and Sarcophagidae groups respectively. Moreover, both Calliphorinae and Luciliinae clades failed to represent Calliphoridae as a separate group. Therefore, although molecular methods are beneficial especially if the available evidence are immature stage or degraded fragments of insect, we suggest using this fragment only in addition to other identification methods. PMID- 23661267 TI - Endothelial plasticity governs the site-specific leukocyte recruitment in hepatocellular cancer. AB - The correct programming of the endothelial cell phenotype is crucial for efficient leukocyte recruitment to tumor tissue. It has been previously described that T cells infiltrated hepatocellular cancer (HCC) tissue mainly in peritumoral, stromal and tumor border areas. In the current study, phenotype features of tumor endothelial cells and their potential impact on leukocyte recruitment were analyzed in murine tissue of HCC. In the murine model, proinflammatory stimulation with IL-1beta induced leukocyte recruitment in the blood vessels of peripheral tumor areas and in nonmalignant liver tissue, but not in deeper tumor blood vessels. Furthermore, peripheral tumor endothelium, but not deeper tumor blood vessels exhibited a "normalized" hepatic sinusoidal endothelial cell (HSEC)-like phenotype with regard to the expression of adhesion molecules and liver sinusoidal endothelial markers. When tumor endothelial cells were isolated and incubated in vitro, their phenotype rapidly changed and became almost identical to normal hepatic endothelial cells. Interestingly, cytokine production in HCC was strongly dysregulated as compared to normal liver, with IL 1RN exhibiting the most prominent elevation. Experiments with isolated hepatic endothelial cells showed that IL-1RN effectively antagonized the activating action of IL-1beta on the expression of adhesion molecules and T cell attachment. These novel insights indicate that tumor endothelium of HCC represents a plastic system that is susceptible to microenvironmental changes. The peritumoral and tumor border areas have distinct endothelial cell phenotype, which promotes leukocyte recruitment to HCC tissue. PMID- 23661269 TI - Acute vibration induces transient expression of anabolic genes in the murine intervertebral disc. AB - OBJECTIVE: Low-amplitude whole-body vibration has been adopted for the treatment of back pain and spinal disorders. However, there is limited knowledge of the impact of vibration on the intervertebral disc (IVD). This study was undertaken to examine the effects of acute vibration on anabolic and catabolic pathways in the IVD and to characterize the dependence of these changes on time and frequency. METHODS: Custom-designed platforms were developed to apply acute vibration to ex vivo and in vivo mouse models. Spinal segments (ex vivo) or mice (in vivo) were subjected to vibration (for 30 minutes at 15-90 Hz with peak acceleration at 0.3g), and IVDs were examined at specific time points after vibration. Gene expression was quantified using real-time polymerase chain reaction, and protein levels were examined by quantitative mass spectrometry and immunofluorescence. RESULTS: In the ex vivo model, acute vibration at 15 Hz induced expression of anabolic genes (aggrecan, biglycan, decorin, type I collagen, and Sox9) and suppressed expression of Mmp13, with the most pronounced changes detected 6 hours following vibration. These beneficial effects were frequency dependent and were no longer evident between 45 and 90 Hz. In vivo, the effects on anabolic gene expression were even more robust and were accompanied by decreased expression of Adamts4, Adamts5, and Mmp3. Moreover, significant increases in the protein levels of aggrecan, biglycan, decorin, and type I collagen were detected in vivo. CONCLUSION: These findings demonstrate dramatic anabolic effects of acute vibration on IVD tissue, responses that are dependent on frequency. The similarity of the in vivo and ex vivo responses indicates that at least some effects of vibration are tissue autonomous. PMID- 23661271 TI - Alternating temperatures affect life table parameters of Phytoseiulus persimilis, Neoseiulus californicus (Acari: Phytoseiidae) and their prey Tetranychus urticae (Acari: Tetranychidae). AB - Increasing energy costs force glasshouse growers to switch to energy saving strategies. In the temperature integration approach, considerable daily temperature variations are allowed, which not only have an important influence on plant growth but also on the development rate of arthropods in the crop. Therefore, we examined the influence of two constant temperature regimes (15 degrees C/15 degrees C and 20 degrees C/20 degrees C) and one alternating temperature regime (20 degrees C/5 degrees C, with an average of 15 degrees C) on life table parameters of Phytoseiulus persimilis and Neoseiulus californicus and their target pest, the two-spotted spider mite Tetranychus urticae at a 16:8 (L:D) h photoperiod and 65 +/- 5 % RH. For females of both predatory mites the alternating temperature regime resulted in a 25-30 % shorter developmental time as compared to the corresponding mean constant temperature regime of 15 degrees C/15 degrees C. The immature development of female spider mites was prolonged for 7 days at 15 degrees C/15 degrees C as compared to 20 degrees C/5 degrees C. With a daytime temperature of 20 degrees C, no differences in lifetime fecundity were observed between a nighttime temperature of 20 and 5 degrees C for P. persimilis and T. urticae. The two latter species did show a higher lifetime fecundity at 20 degrees C/5 degrees C than at 15 degrees C/15 degrees C, and their daily fecundity at the alternating regime was about 30 % higher than at the corresponding mean constant temperature. P. persimilis and T. urticae showed no differences in sex ratio between the three temperature regimes, whereas the proportion of N. californicus females at 15 degrees C/15 degrees C (54.2 %) was significantly lower than that at 20 degrees C/5 degrees C (69.4 %) and 20 degrees C/20 degrees C (67.2 %). Intrinsic rates of increase were higher at the alternating temperature than at the corresponding mean constant temperature for both pest and predators. Our results indicate that thermal responses of the studied phytoseiid predators to alternating temperature regimes used in energy saving strategies in glasshouse crops may have consequences for their efficacy in biological control programs. PMID- 23661270 TI - Effects of local protein environment on the binding of diatomic molecules to heme in myoglobins. DFT and dispersion-corrected DFT studies. AB - The heme-AB binding energies (AB = CO, O2) in a wild-type myoglobin (Mb) and two mutants (H64L, V68N) of Mb have been investigated in detail with both DFT and dispersion-corrected DFT methods, where H64L and V68N represent two different, opposite situations. Several dispersion correction approaches were tested in the calculations. The effects of the local protein environment were accounted for by including the five nearest surrounding residues in the calculated systems. The specific role of histidine-64 in the distal pocket was examined in more detail in this study than in other studies in the literature. Although the present calculated results do not change the previous conclusion that the hydrogen bonding by the distal histidine-64 residue plays a major role in the O2/CO discrimination by Mb, more details about the interaction between the protein environment and the bound ligand have been revealed in this study by comparing the binding energies of AB to a porphyrin and the various myoglobins. The changes in the experimental binding energies from one system to another are well reproduced by the calculations. Without constraints on the residues in geometry optimization, the dispersion correction is necessary, since it improves the calculated structures and energetic results significantly. PMID- 23661273 TI - Electro-assisted solid-phase microextraction based on poly(3,4 ethylenedioxythiophen) combined with GC for the quantification of tricyclic antidepressants. AB - In this study, a platinum wire coated with poly(3,4-ethylenedioxythiophen) was used as an electro-assisted solid-phase microextraction fiber for the quantification of tricyclic antidepressant drugs in biological samples by coupling to GC employing a flame ionization detector. In this study, an electric field increased the extraction rate and recovery. The fiber used as a solid phase was synthesized by the electropolymerization of 3,4-ethylenedioxythiophen monomers onto a platinum wire. The ability of this fiber to extract imipramine, desipramine, and clomipramine by using the electro-assisted solid-phase microextraction technique was evaluated. The effect of various parameters that influence the extraction efficiency, which include solution temperature, extraction time, stirring rate, ionic strength, time and temperature of desorption, and thickness of the fiber, was optimized. Under optimized conditions, the linear ranges and regression coefficients of calibration curves were in the range of 0.5-250 and 0.990-0.998 ng/mL, respectively. Detection limits were in the range of 0.15-0.45 ng/mL. Finally, this method was applied to the determination of drugs in urine and wastewater samples and recoveries were 4.8-108.9%. PMID- 23661274 TI - Staphylococcal biofilm growth on smooth and porous titanium coatings for biomedical applications. AB - Implant-related infections are a serious complication in prosthetic surgery, substantially jeopardizing implant fixation. As porous coatings for improved osseointegration typically present an increased surface roughness, their resulting large surface area (sometimes increasing with over 700% compared to an ideal plane) renders the implant extremely susceptible to bacterial colonization and subsequent biofilm formation. Therefore, there is particular interest in orthopaedic implantology to engineer surfaces that combine both the ability to improve osseointegration and at the same time reduce the infection risk. As part of this orthopaedic coating development, the interest of in vitro studies on the interaction between implant surfaces and bacteria/biofilms is growing. In this study, the in vitro staphylococcal adhesion and biofilm formation on newly developed porous pure Ti coatings with 50% porosity and pore sizes up to 50 MUm is compared to various dense and porous Ti or Ti-6Al-4V reference surfaces. Multiple linear regression analysis indicates that surface roughness and hydrophobicity are the main determinants for bacterial adherence. Accordingly, the novel coatings display a significant reduction of up to five times less bacterial surface colonization when compared to a commercial state-of-the-art vacuum plasma sprayed coating. However, the results also show that a further expansion of the porosity with over 15% and/or the pore size up to 150 MUm is correlated to a significant increase in the roughness parameters resulting in an ascent of bacterial attachment. Chemically modifying the Ti surface in order to improve its hydrophilicity, while preserving the average roughness, is found to strongly decrease bacteria quantities, indicating the importance of surface functionalization to reduce the infection risk of porous coatings. PMID- 23661275 TI - Dynamic exercise improves cognitive function in association with increased prefrontal oxygenation. AB - The Stroop test was performed before and after ergometer exercise for 15 min at 20, 40, and 60 % of maximum voluntary exercise (EXmax), in order to examine whether dynamic exercise is capable of improving cognitive function and whether the changes in regional cerebral blood flow of the prefrontal cortex are associated with the cognitive improvement. Subjects were asked to answer the displayed color of incongruent color words as quickly as possible. The total time period and the number of errors for the Stroop test were measured as an index of cognitive function. The concentrations of oxygenated-hemoglobin (Oxy-Hb) and deoxygenated-hemoglobin (Deoxy-Hb) in the cerebral prefrontal area were measured with near-infrared spectroscopy to determine the changes in regional cerebral blood flow. Ergometer exercise at 40 % of EXmax, but not 20 and 60 % of EXmax, shortened (P < 0.05) the total time period for the Stroop test by 6.6 +/- 1.5 % as compared to the time control. In contrast, the number of errors was not altered by exercise at any intensity. The Oxy-Hb in bilateral prefrontal cortices increased during the Stroop test, while the Deoxy-Hb in those areas was unchanged. Ergometer exercise at 40 % of EXmax, but not at 20 and 60 % of EXmax, significantly augmented the response in the prefrontal Oxy-Hb during the Stroop test. The magnitude of the increased prefrontal Oxy-Hb response tended to correlate with the reduction in total time period for the Stroop test. Thus, it is likely that ergometer exercise at moderate intensity for 15 min may improve cognitive function through the increased neural activity in the prefrontal cortex. PMID- 23661276 TI - Role of loops connecting secondary structure elements in the stabilization of proteins isolated from thermophilic organisms. AB - It has been recently discovered that the connection of secondary structure elements (betabeta-unit, betaalpha- and alphabeta-units) in proteins follows quite stringent principles regarding the chirality and the orientation of the structural units (Koga et al., Nature 2012;491:222-227). By exploiting these rules, a number of protein scaffolds endowed with a remarkable thermal stability have been designed (Koga et al., Nature 2012;491:222-227). By using structural databases of proteins isolated from either mesophilic or thermophilic organisms, we here investigate the influence of supersecondary associations on the thermal stability of natural proteins. Our results suggest that beta-hairpins of proteins from thermophilic organisms are very frequently characterized by shortenings of the loops. Interestingly, this shortening leads to states that display a very strong preference for the most common connectivity of the strands observed in native protein hairpins. The abundance of selective states in these proteins suggests that they may achieve a high stability by adopting a strategy aimed to reduce the possible conformations of the unfolded ensemble. In this scenario, our data indicate that the shortening is effective if it increases the adherence to these rules. We also show that this mechanism may operate in the stabilization of well-known protein folds (thioredoxin and RNase A). These findings suggest that future investigations aimed at defining mechanism of protein stabilization should also consider these effects. PMID- 23661278 TI - Highly selective gas sensor arrays based on thermally reduced graphene oxide. AB - The electrical properties of reduced graphene oxide (rGO) have been previously shown to be very sensitive to surface adsorbates, thus making rGO a very promising platform for highly sensitive gas sensors. However, poor selectivity of rGO-based gas sensors remains a major problem for their practical use. In this paper, we address the selectivity problem by employing an array of rGO-based integrated sensors instead of focusing on the performance of a single sensing element. Each rGO-based device in such an array has a unique sensor response due to the irregular structure of rGO films at different levels of organization, ranging from nanoscale to macroscale. The resulting rGO-based gas sensing system could reliably recognize analytes of nearly the same chemical nature. In our experiments rGO-based sensor arrays demonstrated a high selectivity that was sufficient to discriminate between different alcohols, such as methanol, ethanol and isopropanol, at a 100% success rate. We also discuss a possible sensing mechanism that provides the basis for analyte differentiation. PMID- 23661279 TI - Determinants of internet poker adoption. AB - In nearly all jurisdictions, adoption of a new form of gambling has been a controversial and contentious subject. Online gambling has been no different, though there are many aspects that affect online gambling that do not appear in the brick and mortar environment. This study seeks to identify whether demographic, economic, political, technological, and/or sociological determinants contribute to online poker gambling adoption. A theoretical discussion of these categories' importance to online poker is provided and exploratory empirical analysis is used to examine their potential validity. The analysis revealed support for all of the proposed categories of variables thought to be predictive of online gambling legality. PMID- 23661280 TI - Logistic-AFT location-scale mixture regression models with nonsusceptibility for left-truncated and general interval-censored data. AB - In conventional survival analysis there is an underlying assumption that all study subjects are susceptible to the event. In general, this assumption does not adequately hold when investigating the time to an event other than death. Owing to genetic and/or environmental etiology, study subjects may not be susceptible to the disease. Analyzing nonsusceptibility has become an important topic in biomedical, epidemiological, and sociological research, with recent statistical studies proposing several mixture models for right-censored data in regression analysis. In longitudinal studies, we often encounter left, interval, and right censored data because of incomplete observations of the time endpoint, as well as possibly left-truncated data arising from the dissimilar entry ages of recruited healthy subjects. To analyze these kinds of incomplete data while accounting for nonsusceptibility and possible crossing hazards in the framework of mixture regression models, we utilize a logistic regression model to specify the probability of susceptibility, and a generalized gamma distribution, or a log logistic distribution, in the accelerated failure time location-scale regression model to formulate the time to the event. Relative times of the conditional event time distribution for susceptible subjects are extended in the accelerated failure time location-scale submodel. We also construct graphical goodness-of-fit procedures on the basis of the Turnbull-Frydman estimator and newly proposed residuals. Simulation studies were conducted to demonstrate the validity of the proposed estimation procedure. The mixture regression models are illustrated with alcohol abuse data from the Taiwan Aboriginal Study Project and hypertriglyceridemia data from the Cardiovascular Disease Risk Factor Two township Study in Taiwan. PMID- 23661281 TI - Engaging all doctors in continuous quality improvement: a structured, supported programme for first-year doctors across a training deanery in England. AB - The structure of postgraduate medical training rightly puts enormous emphasis on gathering clinical experience and constantly updating knowledge of relevant medical research to use in practice. At most, this can be contrasted with the slight emphasis on clinical leadership and acquiring the skills to effect change and improve the quality of care. Doctors play central roles in orchestrating the clinical management of patients across multiple settings within the healthcare system. They also routinely encounter the many problems within the systems that they work, affecting their own practices as well as those of other healthcare professionals. They thus represent a tremendous resource for identifying solutions to these problems and playing leadership roles in implementing them. However, physician training programs focus almost entirely on the knowledge and skills to manage clinical problems, with almost no training in skills related to healthcare management or effective quality improvement. In this article, we describe one attempt to improve this situation. In four hospitals in the Severn Deanery in the Southwest of England, first-year doctors carry out a structured and supported quality improvement project of their choice throughout their first year of training. To date, 30 such projects have been or are being run. This has significant benefits for both the trusts they are working for as well as for their own professional development. We describe the successes, difficulties and future of this programme. PMID- 23661282 TI - Preparation and characterization of octadecyl acrylate monoliths for capillary electrochromatography by photochemical, thermal, and chemical initiation. AB - Monolithic stationary phases based on octadecyl acrylate for CEC using different initiating systems (UV irradiation, thermal, and chemical initiation) in the presence of lauroyl peroxide as initiator were synthesized. For each initiation mode, the influence of the porogenic solvent composition on both the morphological and electrochromatographic properties of the resulting monoliths was investigated. Under optimal conditions, excellent efficiencies for the photochemically and chemically polymerized monoliths (minimum plate heights of 6.9-10.7 and 6.5-12.6 MUm, respectively) were achieved. Thermally initiated columns gave lower efficiency values, permeabilities, and longer analysis times compared to these initiating systems. The produced monolithic stationary phases were evaluated in terms of reproducibility and gave RSD values below 9.2, 10.6, and 9.8% for UV, thermally, and chemically initiated columns, respectively. PMID- 23661283 TI - Effects of repeated dosing with mirtazapine, trazodone, or placebo on driving performance and cognitive function in healthy volunteers. AB - OBJECTIVE: This study aimed to evaluate the effects of repeated treatments with the sedative antidepressants mirtazapine and trazodone on driving performance and cognitive function. METHODS: Nineteen healthy men received continuous nocturnal doses of 15-mg mirtazapine , 25-mg trazodone, or placebo for 8 days in a double blinded, three-way crossover trial. Subjects were asked to perform three driving tasks (road tracking, car following, and harsh braking) using a driving simulator and cognitive tasks (the Wisconsin Card Sorting Test, Continuous Performance Test, and N-back Test) at baseline and on Days 2 and 9. Stanford Sleepiness Scale scores were also assessed. RESULTS: Mirtazapine significantly increased the standard deviation of lateral position in the road-tracking task as compared with trazodone on Day 2. Mirtazapine significantly increased Stanford Sleepiness Scale scores as compared with trazodone and placebo. For the remaining tasks, no significant effects of treatment were observed. CONCLUSIONS: Acute treatment of mirtazapine impaired road-tracking performance and increased sleepiness, but sedative effects disappeared under repeated administrations. Trazodone did not affect driving performance or cognitive function under acute or repeated administrations. Both initial sedative effects and pharmacological profiles should be taken into consideration when using sedative antidepressants. PMID- 23661284 TI - Individual and geographic disparities in human papillomavirus types 16/18 in high grade cervical lesions: Associations with race, ethnicity, and poverty. AB - BACKGROUND: Current vaccines protect against 2 human papillomavirus (HPV) types, HPV 16 and 18, which are associated with 70% of cervical cancers and 50% of high grade cervical lesions. HPV type distribution was examined among women with high grade lesions by individual and area-based measures of race, ethnicity, and poverty. METHODS: This analysis included 832 women aged 18 to 39 years reported to a surveillance registry in Connecticut during 2008 to 2010. Diagnostic specimens were obtained for HPV DNA testing. Individual measures were obtained from surveillance reports, medical records, and patient interviews. Cases were geocoded to census tracts and linked to area-based measures of race, ethnicity, and poverty. Statistical analysis included use of generalized estimating equations. RESULTS: Overall, 44.8% of women had HPV 16/18. In a multivariate model controlled for confounding by age and diagnosis grade, black race (adjusted prevalence ratio [aPR] = 0.54, 95% confidence interval [CI] = 0.34-0.88), Hispanic ethnicity (aPR = 0.59, 95% CI = 0.40-0.88), and higher area-based poverty (aPR = 0.59, 95% CI = 0.40-0.87) were associated with a lower likelihood of HPV 16/18 positivity. Black and Hispanic women were less likely to have HPV 16/18 than white women across all levels of area-based measures. CONCLUSIONS: Black race, Hispanic ethnicity, and higher area-based poverty are salient predictors of lower HPV 16/18 positivity among women with high-grade cervical lesions. These data suggest that HPV vaccines might have lower impact among black and Hispanic women and those living in high poverty areas. These findings have implications for vaccine impact monitoring, vaccination programs, and new vaccine development. PMID- 23661285 TI - Genetically modified T cells targeting neovasculature efficiently destroy tumor blood vessels, shrink established solid tumors and increase nanoparticle delivery. AB - Converting T cells into tumor cell killers by grafting them with a chimeric antigen receptor (CAR) has shown promise as a cancer immunotherapeutic. However, the inability of these cells to actively migrate and extravasate into tumor parenchyma has limited their effectiveness in vivo. Here we report the construction of a CAR containing an echistatin as its targeting moiety (eCAR). As echistatin has high binding affinity to alphavbeta3 integrin that is highly expressed on the surface of endothelial cells of tumor neovasculature, T cells engrafted with eCAR (T-eCAR) can efficiently lyse human umbilical vein endothelial cells and tumor cells that express alphavbeta3 integrin when tested in vitro. Systemic administration of T-eCAR led to extensive bleeding in tumor tissues with no evidence of damage to blood vessels in normal tissues. Destruction of tumor blood vessels by T-eCAR significantly inhibited the growth of established bulky tumors. Moreover, when T-eCAR was codelivered with nanoparticles in a strategically designed temporal order, it dramatically increased nanoparticle deposition in tumor tissues, pointing to the possibility that it may be used together with nanocarriers to increase their capability to selectively deliver antineoplastic drugs to tumor tissues. PMID- 23661286 TI - Primary intracranial angioleiomyomas: diagnosis, treatment, and literature review. AB - Intracranial angioleiomyomas (ALMs) are extremely rare, benign, mesenchymal soft tissue tumours. Early diagnosis is difficult without histopathology. We present 2 new cases of extra-axial ALMs involving the cavernous sinus and right temporal lobe. Moreover, present a literature review based on a search in PubMed using the words "angioleiomyomas, vascular leiomyomas, or angiomyomas". This review exclusively included studies in English of primary intracranial ALMs with detailed clinical data. The histopathology of the presented cases was similar. Both lesions consisted of thick-walled vessels blending with smooth muscle cells and bands of collagen in a disorganized pattern. Mitosis, cytological atypia, necrosis, or pleomorphism was rarely observed. The Ki-67 labelling index was less than 1 %. Smooth muscle actin, desmin, and vimentin were positive, but cytokeratin and HMB45 were negative. Multifocality of mature fat cells was observed in one case. To date, only 12 cases of intracranial ALMs have been described. The mean age of these patients is 45.7 years, and they are predominantly male (M/F ratio 4.5:1). Neuroradiologic characteristics were indistinctive and were all misdiagnosed preoperatively. Intracranial ALMs are rare independent entities and favourable outcomes can be achieved by complete resection. Though rare, the possibility of ALM is considered during preoperative assessment. PMID- 23661287 TI - Single rice growth period was prolonged by cultivars shifts, but yield was damaged by climate change during 1981-2009 in China, and late rice was just opposite. AB - Based on the crop trial data during 1981-2009 at 57 agricultural experimental stations across the North Eastern China Plain (NECP) and the middle and lower reaches of Yangtze River (MLRYR), we investigated how major climate variables had changed and how the climate change had affected crop growth and yield in a setting in which agronomic management practices were taken based on actual weather. We found a significant warming trend during rice growing season, and a general decreasing trend in solar radiation (SRD) in the MLRYR during 1981-2009. Rice transplanting, heading, and maturity dates were generally advanced, but the heading and maturity dates of single rice in the MLRYR (YZ_SR) and NECP (NE_SR) were delayed. Climate warming had a negative impact on growth period lengths at about 80% of the investigated stations. Nevertheless, the actual growth period lengths of YZ_SR and NE_SR, as well as the actual length of reproductive growth period (RGP) of early rice in the MLRYR (YZ_ER), were generally prolonged due to adoption of cultivars with longer growth period to obtain higher yield. In contrast, the actual growth period length of late rice in the MLRYR (YZ_LR) was shortened by both climate warming and adoption of early mature cultivars to prevent cold damage and obtain higher yield. During 1981-2009, climate warming and decrease in SRD changed the yield of YZ_ER by -0.59 to 2.4%; climate warming during RGP increased the yield of YZ_LR by 8.38-9.56%; climate warming and decrease in SRD jointly reduced yield of YZ_SR by 7.14-9.68%; climate warming and increase in SRD jointly increased the yield of NE_SR by 1.01-3.29%. Our study suggests that rice production in China has been affected by climate change, yet at the same time changes in varieties continue to be the major factor driving yield and growing period trends. PMID- 23661288 TI - Comparison of a novel Aspergillus lateral-flow device and the Platelia(r) galactomannan assay for the diagnosis of invasive aspergillosis following haematopoietic stem cell transplantation. AB - PURPOSE: The detection of galactomannan in serum is a cornerstone for the diagnosis of invasive fungal disease (IFD). Because a delay in treatment initiation is associated with a poor outcome, the results have to be available promptly. However, due to methodological and economic reasons, the test frequencies of the commonly used galactomannan assays vary between daily to weekly, meaning that results may be available too late to be clinically useful. The novel Aspergillus lateral-flow device (Aspergillus-LFD) is a rapid test that may overcome these limitations. METHODS: We compared the diagnostic performance of the Aspergillus-LFD and the Platelia(r) Aspergillus EIA (GM-EIA) in serum from 101 patients during and after allogeneic haematopoietic stem cell transplantation (HSCT). Clinical data and sera were collected prospectively and patients classified according to the European Organisation for Research and Treatment of Cancer (EORTC)/Mycoses Study Group (MSG) 2008 guidelines. RESULTS: By the end of hospitalisation, one proven, nine probable and 20 possible cases of IFD were identified. Depending on the number of positive serum samples required for test positivity, the sensitivities, specificities and diagnostic odds ratios in patients with proven and probable IFD were as follows. One positive serum required: Aspergillus-LFD 40.0 %, 86.8 % and 3.03; GM-EIA 40.0 %, 89.0 % and 3.64. Two positive sera required: Aspergillus-LFD 20.0 %, 97.8 % and 11.13; GM EIA 30.0 %, 98.9 % and 38.57. Although the GM-EIA was positive in a higher percentage of samples, this did not result in an earlier diagnosis. CONCLUSIONS: If used as a screening test (one positive serum required for test positivity) or to rule out IFD, the Aspergillus-LFD has shown a comparable diagnostic performance to the GM-EIA. However, if the results have to be confirmed by a second positive serum, the GM-EIA exhibited superior sensitivity. In terms of practicability, the Aspergillus-LFD has demonstrated to be a quick (15 min) and easy-to-use test for single-patient detection of Aspergillus antigens. PMID- 23661289 TI - Artemisinin induces A549 cell apoptosis dominantly via a reactive oxygen species mediated amplification activation loop among caspase-9, -8 and -3. AB - This report is designed to explore the roles of caspase-8, -9 and -3 in artemisinin (ARTE)-induced apoptosis in non-small cell lung cancer cells (A549 cells). ARTE induced reactive oxygen species (ROS)-mediated apoptosis in dose- and time-dependent fashion. Although ARTE treatment did not induce Bid cleavage and significant loss of mitochondrial membrane potential, it induced release of Smac and AIF but not cytochrome c from mitochondria, and silencing of Bak but not Bax significantly prevented ARTE-induced cytotoxicity. Moreover, ARTE treatment induced ROS-dependent activation of caspase-9, -8 and -3. Of the utmost importance, silencing or inhibiting any one of caspase-8, -9 and -3 almost completely prevented ARTE-induced activation of all the three caspases and remarkably abrogated the cytotoxicity of ARTE, suggesting that ARTE triggered an amplification activation loop among caspase-9, -8 and -3. Collectively, our data demonstrate that ARTE induces a ROS-mediated amplification activation loop among caspase-9, -8 and -3 to dominantly mediate the apoptosis of A549 cells. PMID- 23661291 TI - Using one-step nucleic acid amplification (OSNA) for intraoperative detection of lymph node metastasis in breast cancer patients avoids second surgery and accelerates initiation of adjuvant therapy. AB - BACKGROUND: Sentinel lymph node (SLN) analysis is conventionally analyzed using immunohistochemistry and in the case of SLN involvement, justifies a second surgery for axillary lymph node (ALN) resection, thus delaying the initiation of adjuvant therapies. PATIENTS AND METHODS: Three hundred and eighty-one patients with early stage breast cancer (BC) were considered in this retrospective study. SLNs were detected using combined radioisotope and dye detection. SLN involvement was analyzed using routine intraoperative One-Step Nucleic Acid Amplification (OSNA) assay, in 100 patients and compared with the conventional histopathology carried out previously in 281 patients. RESULTS: Considering positive SLNs as '++' (CK19 mRNA copy number>5000), '+' (250 < CK19 mRNA copy number <5000) and positive by inhibition in the OSNA group and macro-, micrometastases and isolated tumor cells in the histopathology group, no difference in SLN involvement rate was found between the two groups with 29.0% and 29.9% of positive SLNs, respectively. Using OSNA intraoperatively, the mean time to process the SLN was 42 min allowing immediate ALN resection, reduced significantly (P < 0.01) the re intervention rate (9% versus 39%) and significantly (P < 0.01) accelerated the initiation of adjuvant therapy (6.2 versus 8.4 weeks). CONCLUSIONS: Using OSNA for intraoperative SLN analysis avoids second surgery for ALN resection in most patients and accelerates initiation of adjuvant therapy. PMID- 23661290 TI - Efficacy of anti-staphylococcal protein P128 for the treatment of canine pyoderma: potential applications. AB - In this study, we demonstrate the antibacterial activity of P128 on Staphylococcus isolates responsible for canine pyoderma. Eighty seven swabs were collected from dogs suffering from pyoderma and subjected to antibiotic sensitivity test and 46 Staphylococcus strains were isolated and characterized. In-vitro antimicrobial susceptibility testing with P128 was done by Minimum Inhibitory Concentration (MIC) method as per CLSI guidelines. All the Staphylococci isolated from the dogs with pyoderma, although showed resistance to various antibiotics tested, were lysed by P128. Clinical efficacy of P128 was examined in 17 dogs with pyoderma by application of the P128 hydrogel twice daily for 8 days and the results indicated complete healing of all the lesions of all the dogs under treatment. Under the conditions of this study, P128 was found to be a potent convenient proteinaceous drug for the treatment of staphylococcal pyoderma in dogs. PMID- 23661292 TI - Evaluation of Mucin-1 protein and mRNA expression as prognostic and predictive markers after neoadjuvant chemotherapy for breast cancer. AB - BACKGROUND: Mucin-1 (MUC1) is a promising antigen for the development of tumor vaccines. We evaluated the frequency of MUC1 expression and its impact on therapy response and survival after neoadjuvant chemotherapy for breast cancer. PATIENTS AND METHODS: Pre-treatment core biopsies of patients from the GeparTrio neoadjuvant trial (NCT 00544765) were evaluated for MUC1 by immunohistochemistry (IHC; N = 691) and quantitative RT-PCR (qRT-PCR; N = 286) from formalin-fixed paraffin-embedded (FFPE) samples. RESULTS: MUC1 protein and mRNA was detectable in the majority of cases and was associated with hormone-receptor-positive status (P < 0.001). High MUC1 protein and mRNA expression were associated with lower probability of pathologic complete response (P = 0.017 and P < 0.001) and with longer patient survival (P = 0.03 and P < 0.001). In multivariable analysis, MUC1 protein and mRNA expression were independently predictive (P = 0.001 and P < 0.001). MUC1 protein and mRNA expression were independently prognostic for overall survival (P = 0.029 and P = 0.015). CONCLUSIONS: MUC1 is frequently expressed in breast cancer and detectable on mRNA and protein level from FFPE tissue. It provides independent predictive information for therapy response and survival after neoadjuvant chemotherapy. In clinical immunotherapy trials, MUC1 expression may serve as a predictive marker. PMID- 23661293 TI - Long-term follow-up of a phase III study comparing radiotherapy with or without weekly oxaliplatin for locoregionally advanced nasopharyngeal carcinoma. AB - BACKGROUND: Previous results from our trial showed that adding oxaliplatin to radiotherapy (RT) increased survival in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) at 2 years. Here, we present the data of long-term efficacy and late toxic effects. PATIENTS AND METHODS: Between January 2001 and January 2003, 115 Patients with nonkeratinizing/undifferentiated locoregionally advanced NPC were randomly to receive either RT alone (n = 56) or plus concurrent oxaliplatin 70 mg/m(2) weekly for six cycles (n = 59). RESULTS: After a median follow-up of 114 months (range 18-139 months), the 5-year overall survival (OS) and metastasis-free survival (MFS) rates in the concurrent chemoradiotherapy (CCRT) group were significantly higher than those observed in the RT-alone group (OS, 73.2% versus 60.2%, P = 0.028; MFS, 74.7% versus 63.0%, P = 0.027). However, CCRT did not improve locoregional failure-free survival significantly. Subgroup analyses showed that the superiorities of CCRT mainly existed in the T3-4N0-1 stage subgroup (OS: HR = 0.394, P = 0.034). The grade 3/4 late toxic effects were similar in the two groups. CONCLUSION(S): The long-term follow-up data confirms the role of CCRT as a treatment of locoregionally advanced NPC. Oxaliplatin can be considered as an alternative optional therapeutic regimen for these patients due to its high efficiency and low toxic effect. PMID- 23661294 TI - Correlation of endogenous hormonal levels, fibroglandular tissue volume and percent density measured using 3D MRI during one menstrual cycle. AB - BACKGROUND: We measured breast density (BD) on MRI and correlated with endogenous hormonal levels. PATIENTS AND METHODS: Twenty-four premenopausal women received four weekly breast MRI. A blood sample was collected on the same day of MRI. BD was measured using a computer-based algorithm. The generalized estimation equation method was applied to model mean fibroglandular tissue volume (FV) and mean percent density (PD) from predictor variables including estradiol, progesterone, and week during a cycle. RESULTS: In week 3, a borderline significant correlation between estradiol and PD (r = 0.43, P = 0.04), estradiol and FV (r = 0.40, P = 0.05) and between progesterone and FV (r = 0.42, P = 0.04) was noted. The FV and PD measured in weeks 4 and 1 were higher than in weeks 2 and 3, adjusted for variation in endogenous estradiol and progesterone, indicating that the hormone change could not account for the changes in density. No lag effect of endogenous hormone on the change of FV or PD was noted (all P values > 0.05). CONCLUSIONS: Our results showed that BD is not strongly associated with the endogenous hormone. Their association with breast cancer risk was likely coming from different mechanisms, and they should be considered as independent risk factors. PMID- 23661296 TI - Neuromuscular monitoring, residual blockade, and reversal: time for re-evaluation of our clinical practice. PMID- 23661297 TI - Cerebral oxygen desaturation during one-lung ventilation: correlation with hemodynamic variables. AB - PURPOSE: Cerebral desaturation occurs frequently in patients undergoing one-lung ventilation for thoracic surgery. The mechanism of this desaturation is unclear regarding its etiology. The objective of this study was to investigate whether or not decreases in cerebral oxygen saturation associated with one-lung ventilation were a consequence of decreased cardiac output. METHODS: A blinded observational study was conducted in 23 patients undergoing one-lung ventilation with thoracic surgery. Eighteen patients completed the study. Cerebral oxygen saturation was monitored using near-infrared spectroscopy (FORE-SIGHT((r)) monitor). Invasive blood pressure was monitored and hemodynamic variables were interrogated using the FloTrac((r)) system. Anesthesia was maintained with sevoflurane with a F(i)O(2) of 1.0. Post-hoc analysis involved a comparison between baseline and integrated changes in cerebral saturation, heart rate, stroke index, cardiac index, and stroke volume variability. RESULTS: All patients showed cerebral desaturation from a baseline of two-lung ventilation in the lateral decubitus position following institution of one-lung ventilation. The cardiac index was stable at these times, but with one-lung ventilation, the heart rate decreased and the stroke index increased to maintain a stable product. The integral of heart rate * time was inversely correlated with the integral of cerebral desaturation * time (linear regression analysis; P = 0.02; (df) = 16)). CONCLUSIONS: Cerebral oxygen desaturation was universal during one-lung ventilation in this study. There was no correlation between cerebral desaturation and cardiac output or other hemodynamic variables. PMID- 23661295 TI - Functional studies of N-terminally modified CYP2J2 epoxygenase in model lipid bilayers. AB - CYP2J2 epoxygenase is a membrane bound cytochrome P450 that converts omega-3 and omega-6 fatty acids into physiologically active epoxides. In this work, we present a comprehensive comparison of the effects of N-terminal modifications on the properties of CYP2J2 with respect to the activity of the protein in model lipid bilayers using Nanodiscs. We demonstrate that the complete truncation of the N-terminus changes the association of this protein with the E.coli membrane but does not disrupt incorporation in the lipid bilayers of Nanodiscs. Notably, the introduction of silent mutations at the N-terminus was used to express full length CYP2J2 in E. coli while maintaining wild-type functionality. We further show that lipid bilayers are essential for the productive use of NADPH for ebastine hydroxylation by CYP2J2. Taken together, it was determined that the presence of the N-terminus is not as critical as the presence of a membrane environment for efficient electron transfer from cytochrome P450 reductase to CYP2J2 for ebastine hydroxylation in Nanodiscs. This suggests that adopting the native-like conformation of CYP2J2 and cytochrome P450 reductase in lipid bilayers is essential for effective use of reducing equivalents from NADPH for ebastine hydroxylation. PMID- 23661298 TI - Towards integrated nanoplasmonic logic circuitry. AB - Surface plasmon polaritons (SPPs) may serve as ultimate data processing expedients in future nanophotonic applications. SPPs combine the high localization of electrons with the bandwidth, frequency and propagation properties of photons, thus supplying nature with the best of two worlds. However, although plasmonics have recently gained constantly growing scientific attention, logic devices that operate on SPPs on a deep nanometer scale are yet to be demonstrated. Here, we design, fabricate and experimentally verify the smallest, first ever reported all optical nanoplasmonic XOR logic gate. The introduced XOR device is based on a novel engineerable interferometry scheme with extremely compact dimensions of lambda(3)/15,500, which can be used to realize a variety of plasmonic logic functionalities. We use frequency modulated Kelvin probe microscopy to provide evidence of binary XOR functionality performed directly on SPPs with lambda(3)/80,000 mode volumes. An extinction ratio of 10 dB is achieved for a device length of 150 nm, increasing up to 30 dB for a device length of 280 nm. Our findings confirm plasmonics as the favorite data carriers in integrated all optical logic devices operating on the deep nanoscale, and pave the way to the development of future ultrafast information processing technologies based on SPPs. PMID- 23661299 TI - CORR Insights (r): The peripheral neuronal phenotype is important in the pathogenesis of painful human tendinopathy: a systematic review. PMID- 23661301 TI - Risk factors for early revision after primary TKA in Medicare patients. AB - BACKGROUND: Patient, surgeon, health system, and device factors are all known to influence outcomes in total knee arthroplasty (TKA). However, patient-related factors associated with an increased risk of early failure are not well understood, particularly in elderly patients. QUESTIONS/PURPOSES: The purpose of this study was to identify specific comorbid conditions associated with increased risk of early revision in Medicare patients undergoing TKA. METHODS: A total of 117,903 Medicare patients who underwent primary TKA between 1998 and 2010 were identified from the Medicare 5% national sample administrative database and used to determine the relative risk of revision within 12 months after primary TKA as a function of baseline medical comorbidities. Cox regression was used to evaluate the impact of 29 comorbid conditions on risk of early failure controlling for age, sex, race, census region, socioeconomic status, and all other baseline comorbidities. RESULTS: The most significant independent risk factors for revision TKA within 12 months were chronic pulmonary disease, depression, alcohol abuse, drug abuse, renal disease, hemiplegia or paraplegia, and obesity. CONCLUSIONS: This information could be valuable to patients and their surgeons when making shared medical decisions regarding elective TKA and for risk stratifying publicly reported outcomes in Medicare patients undergoing TKA. PMID- 23661300 TI - CT pulmonary angiography after total joint arthroplasty: overdiagnosis and iatrogenic harm? AB - BACKGROUND: CT pulmonary angiography (CTPA) has become widely adopted to detect pulmonary embolism (PE) after total joint arthroplasty (TJA). CTPA is a sensitive tool, which has the ability to detect emboli that may be clinically insignificant. This may lead to iatrogenic harm from overtreatment. QUESTIONS/PURPOSES: The purpose of this study was to assess changing prevalence, mortality, treatment complications, and resource consumption associated with PE after TJA before and after the introduction of CTPA. METHODS: The Nationwide Inpatient Sample was used to identify 2,335,248 patients undergoing TJA from 1993 to 1998 before the introduction of CTPA and 6,321,671 patients from 1999 to 2008 after the introduction of CTPA. Bivariate and multivariate regression analysis was performed to compare changing prevalence of PE, mortality, potential treatment complications of anticoagulation, length of stay, and total charges before and after the introduction of CTPA in patients with PE. RESULTS: In hospital diagnosis of PE after TJA increased (p < 0.001) from an average of 0.27% to 0.37% after the introduction of CTPA. All-cause mortality in patients with a diagnosis of PE decreased (p < 0.001) from 11.5% to 4.6% (odds ratio, 2.3; 95% confidence interval, 2.1-2.6) after the introduction of CTPA. Overall, PE was associated with increased (p < 0.001) risks for hematoma/seroma, postoperative infection, gastrointestinal bleed, and drug-related thrombocytopenia, although the prevalence of these complications has decreased after 1998 (p < 0.001). Length of stay doubled for patients with PE (both before and after CTPA) and total charges increased over 69% in both study periods for these patients. CONCLUSIONS: Adoption of CTPA appears to be associated with an increase in the diagnosis of PE after TJA and an associated decrease in case-fatality. Although CTPA may improve our ability to diagnose PE and possibly reduce mortality, the observed decrease in case-fatality could also be explained by the overdiagnosis of clinically unimportant emboli. The diagnosis of PE was strongly associated with potential iatrogenic harm from anticoagulation and increased length of stay and hospital charges in this study, emphasizing the importance of further investigation to define the role of CTPA in the diagnosis and treatment of PE after TJA. PMID- 23661302 TI - How useful is MRI in diagnosing isolated bundle ACL injuries? AB - BACKGROUND: Selective bundle anterior cruciate ligament (ACL) reconstruction and/or remnant ACL preservation may be reasonable options for some patients. However, the frequency of isolated anteromedial (AM) or posterolateral (PL) bundle injuries in patients undergoing ACL reconstruction is unknown, and the value of MRI for prediction of this injury pattern is likewise unknown. QUESTIONS/PURPOSES: We sought to determine (1) the proportion of knees with an intact AM or PL bundle in patients undergoing ACL reconstruction; (2) whether MRI predicted the bundle conditions seen at the time of surgery; and (3) whether the accuracy of the MRI prediction was affected by the timing of MRI after injury. METHODS: During primary ACL reconstructions of 156 knees, conditions of AM and PL bundles were separately examined and classified into three categories: (1) completely torn; (2) attenuated; and (3) intact. Then, the bundles were assessed by blinded observers on MRI and classified into the corresponding three categories for 77 patients who had an MRI at our institution using a standard protocol. Diagnostic accuracy of MRI was computed, and the early MRI group (<=6 weeks from injury to MRI acquisition) was compared with the late MRI group (>6 weeks). RESULTS: Only 11 (7%) of the 156 knees we treated had an intact AM (one knee) or PL bundle (10 knees). Another 55 knees (35%) had a structurally continuous but attenuated AM or PL bundle. The overall diagnostic accuracy of MRI was 83%; accuracy was better for the AM bundle than the PL bundle (91% versus 78%; p=0.026). MR prediction was less accurate in the early MRI group, particularly for PL bundle injury. CONCLUSIONS: An isolated bundle tear is uncommon in patients with ACL tears undergoing reconstruction. MRI can help surgeons predict bundle injury pattern with satisfactory precision, but caution should be used in predicting PL bundle injury using MRI with early acquisition time from injury. LEVEL OF EVIDENCE: Level III, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 23661303 TI - Interpreting physical performance in professional soccer match-play: should we be more pragmatic in our approach? AB - Academic and practitioner interest in the physical performance of male professional soccer players in the competition setting determined via time-motion analyses has grown substantially over the last four decades leading to a substantial body of published research and aiding development of a more systematic evidence-based framework for physical conditioning. Findings have forcibly shaped contemporary opinions in the sport with researchers and practitioners frequently emphasising the important role that physical performance plays in match outcomes. Time-motion analyses have also influenced practice as player conditioning programmes can be tailored according to the different physical demands identified across individual playing positions. Yet despite a more systematic approach to physical conditioning, data indicate that even at the very highest standards of competition, the contemporary player is still susceptible to transient and end-game fatigue. Over the course of this article, the author suggests that a more pragmatic approach to interpreting the current body of time-motion analysis data and its application in the practical setting is nevertheless required. Examples of this are addressed using findings in the literature to examine (a) the association between competitive physical performance and 'success' in professional soccer, (b) current approaches to interpreting differences in time-motion analysis data across playing positions, and (c) whether data can realistically be used to demonstrate the occurrence of fatigue in match-play. Gaps in the current literature and directions for future research are also identified. PMID- 23661304 TI - An examination of factors influencing delayed discharge of older people from hospital. AB - OBJECTIVE: This study aimed to investigate the factors associated with the delayed discharge of older people from hospital and their length of stay (LOS). METHODS: Data were collected retrospectively from inpatient records and adult social care services on older patients referred to the latter prior to hospital discharge. RESULTS: Data on two related measures--delayed discharge and LOS--were analysed separately within a four-stage sequential framework. Using bivariate analysis, we found that cognitive impairment and dependency were significantly associated with delay. Patients admitted to trauma and orthopaedics specialties were significantly more likely to be delayed on discharge. Respiratory illness was negatively associated with delay. Factors related to care received as an inpatient associated with delayed discharge from hospital were not being in the responsible consultant's bed for part of their stay, two or more moves between specialties and receipt of rehabilitation services. Admission to a care home and receipt of domiciliary care if returning to a private dwelling on discharge were associated with delay. In the multivariate analysis, dependence and cognitive impairment impacted differently on delay and LOS. Hospital variables were the most important predictors of LOS and social care variables in respect of delayed discharge. CONCLUSION: Patient characteristics and especially the organisation of care in hospital and the provision of services on discharge are related to the likelihood of delayed discharge and LOS. Improved services and structures to systematically assess and treat patient needs in hospital, together with the timely provision of services providing post-discharge services tailored to individual circumstances, are required. PMID- 23661305 TI - NanoPad: an integrated platform for bacterial production of camel nanobodies aimed at detecting environmental biomarkers. AB - The presence of given antigens in environmental samples (e.g. biodegradative enzymes) reports the quality and catalytic vigor of particular soils or aquatic ecosystems. In this context, we have developed the NanoPad system consisting of a complete platform for isolation, amplification, and extracellular production of specific antibodies against antigens that diagnose the occurrence of protein markers in crude environmental samples. The workflow starts with the inoculation of camels (Camelus dromedarius) with various proteins (e.g. catabolic enzymes) for generating a phage display library of variable heavy-chain antibody H fragment (VHH ) domains that bind the different antigens. Instead of being subjected to a conventional panning, such a library is then probed with a Western panning technique that allows direct isolation of specific binders of proteins blotted on membranes from polyacrylamide gels. Finally, VHH s are fused to the C domain of hemolysin for secretion to the culture media as virtually pure dimeric proteins that can be used as a primary antibody without further processing. The value of NanoPad is shown with the selection of nanobodies for detection of biphenyl 2,3-dioxygenase, a key enzyme for biodegradation of polychlorinated biphenyls. The thereby generated anti-biphenyl 2,3-dioxygenase VHH s revealed the presence of this enzyme in the metaproteome of an oil refinery waste treatment plant. PMID- 23661307 TI - A rare combination of vascular variations of both kidneys. AB - Bilateral variations of renal vessels were encountered during the dissection of a 54-year-old male cadaver. There were triple renal arteries bilaterally, double renal veins on the right, and an unusual formation of renal vein on the left side. A bilateral occurrence of triple renal arteries has not been encountered in the literature, so does an incidence. Additional renal vessels have the potential to cause clinical complications such as hydronephrosis. Their existence has utmost importance in surgical and radiological interventions and radiological examinations. PMID- 23661306 TI - Lack of evidence for frequent MED12 p.L1224F mutation in prostate tumours from Caucasian patients. AB - Recently mutations in the MED12 gene have been reported in 5.4% of prostate tumours from Caucasian patients analysed by exome sequencing (Barbieri CE, Baca SC, Lawrence MS, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nature Genet 2012; 44: 685-689). In more than 70% of prostate tumours with MED12 mutation, a recurrent p.L1224F mutation in exon 26 was found. In order to validate this MED12 p.L1224F mutation, an unselected cohort of prostate tumours from Caucasian patients was analysed by Sanger sequencing. Overall, 223 prostate tumours and three lymph node metastases were analysed. The MED12 p.L1224F mutation could not be detected in any of the cases. So far, the recently reported MED12 p.L1224F mutation could not be validated in our unselected cohort of prostate tumours. Contrary to the findings of Barbieri et al, our data indicate either that the p.L1224F mutation in the MED12 gene plays no role in prostate carcinogenesis or that this alteration is only relevant in a small subgroup of tumours. PMID- 23661309 TI - Congenital intrapericardial diaphragmatic hernia with omphalocele. AB - Congenital intrapericardial diaphragmatic hernia with omphalocele is very rare. Few cases have been reported in the literature. The embryologic mechanism of this is considered to be abnormal development of the ventral mesoderm at 3-4 weeks after conception. Sometimes, omphalocele is repaired, rather than intrapericardial diaphragmatic hernia, thus causing serious consequences because of the high intra-abdominal pressure. In this paper, we present a case who underwent successful open repair. PMID- 23661308 TI - Laparoscopic repair for recurrent incisional hernias: a single institute experience of 10 years. AB - PURPOSE: The treatment of recurrent incisional hernias (RIH) has been associated with unsatisfactory postoperative (PO) morbidity and high failure rates. The aim of this study is to retrospectively investigate our single-center experience of laparoscopic repair (LR) for RIH. METHODS: The case records of 69 patients with RIH who underwent LR in our institution between January 2002 and November 2011 were reviewed. The operative technique has been standardized and provides onlay placement of an ePTFE mesh fixed with titanium tacks. Patients' demographic data and comorbidities, intraoperative course, PO complications and recurrences at follow-up were systematically collected and analyzed. The influence of defect's size and obesity variables on clinical outcomes was also investigated. RESULTS: The mean operative time was 147.6 +/- 71.2 min and mean hospital stay was 5.8 +/- 1.8 days. No conversion occurred while five intraoperative complications (7.2 %) were recorded: three bowel injuries treated by laparoscopic sutures, one omentum bleeding and one epigastric vessel lesion. PO mortality was null, while overall morbidity was 13 % (9 patients) with a prevalence of seroma lasting over 8 weeks in six patients (8.7 %). Along a mean follow-up of 41 months (range 6-119), recurrence rate was 5.7 % (4 patients). Univariate analysis for width of defects and BMI showed no significant influence on patients' outcomes. CONCLUSIONS: Surgical treatment for RIH remains controversial because of lack in literature of specific studies on this topic. Morbid obesity and large defects have been often associated with technical difficulties and worse results. Our 10 years' experience with LR provided satisfactory results in terms of PO morbidity and recurrence rate, despite any kind of patient selection. PMID- 23661310 TI - Tattooing: more than skin deep. PMID- 23661311 TI - Uncertainty, mood states, and symptom distress in patients with primary brain tumors: analysis of a conceptual model using structural equation modeling. AB - BACKGROUND: Patients with primary brain tumors (PBTs) face uncertainty related to prognosis, symptoms, treatment response, and toxicity. The authors of this report examined the direct/indirect relations among patients' uncertainty, mood states, and symptoms. METHODS: In total, 186 patients with PBTs were accrued at various points in the illness trajectory. Data-collection tools included an investigator completed clinician checklist, a patient-completed demographic data sheet, the Mishel Uncertainty in Illness Scale-Brain Tumor Form (MUIS-BT), the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT), and the Profile of Mood States Short Form (POMS-SF). Structural equation modeling was used to explore correlations among variables. RESULTS: Participants were primarily white (80%) men (53%) with a variety of brain tumors. They ranged in age from 19 to 80 years (mean +/- standard deviation, 44.2 +/- 12.6 years). Lower functional status and earlier point in the illness trajectory were associated with greater uncertainty (P < .01 for both). Uncertainty (P < .05), except in the model of "confusion," and the 5 negative mood states measured by the POMS-SF were directly associated with symptom severity perceived by patients (P < .01 for all). The impact of uncertainty on perceived symptom severity also was mediated significantly by mood states. CONCLUSIONS: The results from the study clearly demonstrated distinct pathways for the relations between uncertainty-mood states-symptom severity for patients with PBTs. Uncertainty in patients with PBTs is higher for those who have a poor performance status and directly impacts negative mood states, which mediate patient-perceived symptom severity. This conceptual model suggests that interventions designed to reduce uncertainty or that target mood states may help lessen patients' perception of symptom severity, which, in turn, may result in better treatment outcomes and quality of life. PMID- 23661313 TI - Attenuation correction for the HRRT PET-scanner using transmission scatter correction and total variation regularization. AB - In the standard software for the Siemens high-resolution research tomograph (HRRT) positron emission tomography (PET) scanner the most commonly used segmentation in the MU -map reconstruction for human brain scans is maximum a posteriori for transmission (MAP-TR). Bias in the lower cerebellum and pons in HRRT brain images have been reported. The two main sources of the problem with MAP-TR are poor bone/soft tissue segmentation below the brain and overestimation of bone mass in the skull. METHOD: We developed the new transmission processing with total variation (TXTV) method that introduces scatter correction in the MU map reconstruction and total variation filtering to the transmission processing. RESULTS: Comparing MAP-TR and the new TXTV with gold standard CT-based attenuation correction, we found that TXTV has less bias as compared to MAP-TR. We also compared images acquired at the HRRT scanner using TXTV to the GE Advance scanner images and found high quantitative correspondence. TXTV has been used to reconstruct more than 4000 HRRT scans at seven different sites with no reports of biases. CONCLUSION: TXTV-based reconstruction is recommended for human brain scans on the HRRT. PMID- 23661312 TI - Inferring group-wise consistent multimodal brain networks via multi-view spectral clustering. AB - Quantitative modeling and analysis of structural and functional brain networks based on diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) data have received extensive interest recently. However, the regularity of these structural and functional brain networks across multiple neuroimaging modalities and also across different individuals is largely unknown. This paper presents a novel approach to inferring group-wise consistent brain subnetworks from multimodal DTI/resting-state fMRI datasets via multi-view spectral clustering of cortical networks, which were constructed upon our recently developed and validated large-scale cortical landmarks-DICCCOL (dense individualized and common connectivity-based cortical landmarks). We applied the algorithms on DTI data of 100 healthy young females and 50 healthy young males, obtained consistent multimodal brain networks within and across multiple groups, and further examined the functional roles of these networks. Our experimental results demonstrated that the derived brain networks have substantially improved inter-modality and inter-subject consistency. PMID- 23661314 TI - Model-based correction of velocity measurements in navigated 3-D ultrasound imaging during neurosurgical interventions. AB - In neurosurgery, information of blood flow is important to identify and avoid damage to important vessels. Three-dimensional intraoperative ultrasound color Doppler imaging has proven useful in this respect. However, due to Doppler angle dependencies and the complexity of the vascular architecture, clinical valuable 3 D information of flow direction and velocity is currently not available. In this work, we aim to correct for angle-dependencies in 3-D flow images based on a geometric model of the neurovascular tree generated on-the-fly from free-hand 2-D imaging and an accurate position sensor system. The 3-D vessel model acts as a priori information of vessel orientation used to angle-correct the Doppler measurements, as well as provide an estimate of the average flow direction. Based on the flow direction we were also able to do aliasing correction to approximately double the measurable velocity range. In vitro experiments revealed a high accuracy and robustness for estimating the mean direction of flow. Accurate angle-correction of axial velocities were possible given a sufficient beam-to-flow angle for at least parts of a vessel segment . In vitro experiments showed an absolute relative bias of 9.5% for a challenging low-flow scenario. The method also showed promising results in vivo, improving the depiction of flow in the distal branches of intracranial aneurysms and the feeding arteries of an arteriovenous malformation. Careful inspection by an experienced surgeon confirmed the correct flow direction for all in vivo examples. PMID- 23661315 TI - Natural variation and the capacity to adapt to ocean acidification in the keystone sea urchin Strongylocentrotus purpuratus. AB - A rapidly growing body of literature documents the potential negative effects of CO2 -driven ocean acidification (OA) on marine organisms. However, nearly all this work has focused on the effects of future conditions on modern populations, neglecting the role of adaptation. Rapid evolution can alter demographic responses to environmental change, ultimately affecting the likelihood of population persistence, but the capacity for adaptation will differ among populations and species. Here, we measure the capacity of the ecologically important purple sea urchin Strongylocentrotus purpuratus to adapt to OA, using a breeding experiment to estimate additive genetic variance for larval size (an important component of fitness) under future high-pCO2 /low-pH conditions. Although larvae reared under future conditions were smaller than those reared under present-day conditions, we show that there is also abundant genetic variation for body size under elevated pCO2 , indicating that this trait can evolve. The observed heritability of size was 0.40 +/- 0.32 (95% CI) under low pCO2 , and 0.50 +/- 0.30 under high-pCO2 conditions. Accounting for the observed genetic variation in models of future larval size and demographic rates substantially alters projections of performance for this species in the future ocean. Importantly, our model shows that after incorporating the effects of adaptation, the OA-driven decrease in population growth rate is up to 50% smaller, than that predicted by the 'no-adaptation' scenario. Adults used in the experiment were collected from two sites on the coast of the Northeast Pacific that are characterized by different pH regimes, as measured by autonomous sensors. Comparing results between sites, we also found subtle differences in larval size under high-pCO2 rearing conditions, consistent with local adaptation to carbonate chemistry in the field. These results suggest that spatially varying selection may help to maintain genetic variation necessary for adaptation to future OA. PMID- 23661317 TI - Joint sparse learning for 3-D facial expression generation. AB - 3-D facial expression generation, including synthesis and retargeting, has received intensive attentions in recent years, because it is important to produce realistic 3-D faces with specific expressions in modern film production and computer games. In this paper, we present joint sparse learning (JSL) to learn mapping functions and their respective inverses to model the relationship between the high-dimensional 3-D faces (of different expressions and identities) and their corresponding low-dimensional representations. Based on JSL, we can effectively and efficiently generate various expressions of a 3-D face by either synthesizing or retargeting. Furthermore, JSL is able to restore 3-D faces with holes by learning a mapping function between incomplete and intact data. Experimental results on a wide range of 3-D faces demonstrate the effectiveness of the proposed approach by comparing with representative ones in terms of quality, time cost, and robustness. PMID- 23661316 TI - Ergogenic effect of dietary L-carnitine and fat supplementation against exercise induced physical fatigue in Wistar rats. AB - L-carnitine (LC) plays a central role in fatty acid metabolism and in skeletal muscle bioenergetics. LC supplementation is known to improve physical performance and has become widespread in recent years without any unequivocal support to this practice. A scientific-based knowledge is needed, to understand the implications of LC supplementation on physical fatigue. In current study, we have explored synergistic effects of dietary LC and fat content against physical fatigue in rats. Ninety male Wistar rats were supplemented with different concentrations of LC (0.15, 0.3, and 0.5 %) and fat content (5, 10, and 15 %) through diet in different combinations. Our results elucidated that LC (0.5 %) along with 10 and 15 % fat diet supplemented rats showed significant ergogenic effect. The swimming time until exhaustion was increased by ~2- and ~1.5-fold in rats fed with 10 and 15 % fat diet containing LC (0.5 %). LC supplementation improved the energy charge by increasing the levels of ATP, tissue glycogen, reduced GSH, plasma triglyceride, plasma glucose levels, and enzymatic antioxidant status, i.e., superoxide dismutase, catalase, and glutathione peroxidase. LC supplementation also significantly reduced lipid peroxidation, lactic acid, plasma urea nitrogen, creatinine, creatinekinase, and lactate dehydrogenase levels in various tissues compared to its respective control group. Thus the present study indicates that LC ameliorates the various impairments associated with physical endurance in rats. PMID- 23661318 TI - Hierarchical super-resolution-based inpainting. AB - This paper introduces a novel framework for examplar-based inpainting. It consists in performing first the inpainting on a coarse version of the input image. A hierarchical super-resolution algorithm is then used to recover details on the missing areas. The advantage of this approach is that it is easier to inpaint low-resolution pictures than high-resolution ones. The gain is both in terms of computational complexity and visual quality. However, to be less sensitive to the parameter setting of the inpainting method, the low-resolution input picture is inpainted several times with different configurations. Results are efficiently combined with a loopy belief propagation and details are recovered by a single-image super-resolution algorithm. Experimental results in a context of image editing and texture synthesis demonstrate the effectiveness of the proposed method. Results are compared to five state-of-the-art inpainting methods. PMID- 23661319 TI - Naturalness preserved enhancement algorithm for non-uniform illumination images. AB - Image enhancement plays an important role in image processing and analysis. Among various enhancement algorithms, Retinex-based algorithms can efficiently enhance details and have been widely adopted. Since Retinex-based algorithms regard illumination removal as a default preference and fail to limit the range of reflectance, the naturalness of non-uniform illumination images cannot be effectively preserved. However, naturalness is essential for image enhancement to achieve pleasing perceptual quality. In order to preserve naturalness while enhancing details, we propose an enhancement algorithm for non-uniform illumination images. In general, this paper makes the following three major contributions. First, a lightness-order-error measure is proposed to access naturalness preservation objectively. Second, a bright-pass filter is proposed to decompose an image into reflectance and illumination, which, respectively, determine the details and the naturalness of the image. Third, we propose a bi log transformation, which is utilized to map the illumination to make a balance between details and naturalness. Experimental results demonstrate that the proposed algorithm can not only enhance the details but also preserve the naturalness for non-uniform illumination images. PMID- 23661320 TI - Inter-trial analysis of post-movement Beta activities in EEG signals using multivariate empirical mode decomposition. AB - Event-related desynchronization/synchronization (ERD/ERS) is a technique to quantify subject's nonphase-locked neural activities underlying specific frequency bands, reactive to external/internal stimulus. However, conventional ERD/ERS studies usually utilize fixed frequency band determined from one or few channels to filter whole-head EEG/MEG data, which may inevitably include task unrelated signals and result in underestimation of reactive oscillatory activities in multichannel studies. In this study, we adopted multivariate empirical mode decomposition (MEMD) to extract beta-related oscillatory activities in performing self-paced right and left index-finger lifting tasks. The MEMD extracts common modes from all channels in same-index intrinsic mode functions (IMFs) which allows the temporal-frequency features among different channels can be compared in each subband. The beta-band oscillatory activities were further bandpass filtered within trial-specific beta bands determined from sensorimotor-related channels (C3 and C4), and then rectified using amplitude modulation method to detect trial-by-trial beta rebound (BR) values in ERS time courses. The validity of the MEMD approach in BR values extraction has been demonstrated in multichannel EEG study which showed larger BR values than conventional ERS technique. The MEMD-based method enables the trial-by-trial extraction of sensorimotor oscillatory activities which might allow the exploration of subtle brain dynamics in future studies. PMID- 23661321 TI - Online Segmentation of Human Motion for Automated Rehabilitation Exercise Analysis. AB - To enable automated analysis of rehabilitation movements, an approach for accurately identifying and segmenting movement repetitions is required. This paper proposes an approach for online, automated segmentation and identification of movement segments from continuous time-series data of human movement, obtained from body-mounted inertial measurement units or from motion capture data. The proposed approach uses a two-stage identification and recognition process, based on velocity features and stochastic modeling of each motion to be identified. In the first stage, motion segment candidates are identified based on a characteristic sequence of velocity features such as velocity peaks and zero velocity crossings. In the second stage, hidden Markov models are used to accurately identify segment locations from the identified candidates. The proposed approach is capable of online segmentation and identification, enabling interactive feedback in rehabilitation applications. The approach is validated on 20 healthy subjects and four rehabilitation patients performing rehabilitation movements, achieving segmentation accuracy of 87% with user specific templates and 79%-83% accuracy with user-independent templates. PMID- 23661322 TI - Accelerometry-based gait analysis and its application to Parkinson's disease assessment--part 1: detection of stride event. AB - Gait analysis is widely recognized as a promising tool for obtaining objective information on the walking behavior of Parkinson's disease (PD) patients. It is especially useful in clinical practices if gait properties can be captured with minimal instrumentation that does not interfere with the subject's usual behavioral pattern under ambulatory conditions. In this study, we propose a new gait analysis system based on a trunk-mounted acceleration sensor and automatic gait detection algorithm. The algorithm identifies the acceleration signal with high intensity, periodicity, and biphasicity as a possible gait sequence, from which gait peaks due to stride events are extracted by utilizing the cross correlation and anisotropy properties of the signal. A total of 11 healthy subjects and 12 PD patients were tested to evaluate the performance of the algorithm. The result indicates that gait peaks can be detected with an accuracy of more than 94%. The proposed method may serve as a practical component in the accelerometry-based assessment of daily gait characteristics. PMID- 23661323 TI - The highly dynamic oligomeric structure of bradavidin II is unique among avidin proteins. AB - Bradavidin II is a biotin-binding protein from Bradyrhizobium japonicum that resembles chicken avidin and bacterial streptavidin. A biophysical characterization was carried out using dynamic light scattering, native mass spectrometry, differential scanning calorimetry, and isothermal titration calorimetry combined with structural characterization using X-ray crystallography. These observations revealed that bradavidin II differs from canonical homotetrameric avidin protein family members in its quaternary structure. In contrast with the other avidins, bradavidin II appears to have a dynamic (transient) oligomeric state in solution. It is monomeric at low protein concentrations but forms higher oligomeric assemblies at higher concentrations. The crystal structure of bradavidin II revealed an important role for Phe42 in shielding the bound ligand from surrounding water molecules, thus functionally replacing the L7,8 loop essential for tight ligand binding in avidin and streptavidin. This bradavidin II characterization opens new avenues for oligomerization-independent biotin-binding protein development. PMID- 23661325 TI - Nicotine from edible Solanaceae and risk of Parkinson disease. AB - OBJECTIVE: To test whether risk of Parkinson disease (PD) is associated with consumption of nicotine-containing edibles from the same botanical family as tobacco, Solanaceae, including peppers, tomatoes, and potatoes. METHODS: In a population-based study with 490 newly diagnosed idiopathic PD cases diagnosed during 1992-2008 at the University of Washington Neurology Clinic or Group Health Cooperative in western Washington State and 644 unrelated, neurologically normal controls, we examined whether PD was associated with self-reported typical frequency of consumption of peppers, tomatoes, tomato juice, and potatoes during adulthood, while adjusting for consumption of other vegetables, age, sex, race/ethnicity, tobacco use, and caffeine. RESULTS: PD was inversely associated with consumption of all edible Solanaceae combined (relative risk [RR] = 0.81, 95% confidence interval [CI] = 0.65-1.01 per time per day), but not consumption of all other vegetables combined (RR = 1.00, 95% CI = 0.92-1.10). The trend strengthened when we weighted edible Solanaceae by nicotine concentration (ptrend = 0.004). An inverse association was also evident for peppers specifically (ptrend = 0.005). The potentially protective effect of edible Solanaceae largely occurred in men and women who had never used tobacco or who had smoked cigarettes < 10 years. INTERPRETATION: Dietary nicotine or other constituents of tobacco and peppers may reduce PD risk. However, confirmation and extension of these findings are needed to strengthen causal inferences that could suggest possible dietary or pharmaceutical interventions for PD prevention. PMID- 23661326 TI - DNA methylation in germ cell tumour aetiology: current understanding and outstanding questions. AB - Germ cell tumours (GCTs) are a diverse group of neoplasms that can be histologically subclassified as either seminomatous or non-seminomatous. These two subtypes have distinct levels of differentiation and clinical characteristics, the non-seminomatous tumours being associated with poorer prognosis. In this article, we review how different patterns of aberrant DNA methylation relate to these subtypes. Aberrant DNA methylation is a hallmark of all human cancers, but particular subsets of cancers show unusually high frequencies of promoter region hypermethylation. Such a 'methylator phenotype' has been described in non-seminomatous tumours. We discuss the possible cause of distinct methylation profiles in GCTs and the potential of DNA methylation to provide new targets for therapy. We also consider how recent developments in our understanding of this epigenetic modification and the development of genome-wide technologies are shedding new light on the role of DNA methylation in cancer aetiology. PMID- 23661324 TI - Influences of situational factors and alcohol expectancies on sexual desire and arousal among heavy-episodic drinking women: acute alcohol intoxication and condom availability. AB - Although studies suggest that alcohol increases women's sexual desire, no studies to our knowledge have examined the effects of acute alcohol intoxication on women's sexual desire. The majority of research examining alcohol's effects on sexual arousal in women suggests that alcohol increases self-reported arousal. In an alcohol administration study in which women projected themselves into an eroticized scenario depicting a consensual sexual encounter with a new male partner, we examined the effects of alcohol and condom condition on women's sexual desire and arousal. The moderating effects of sex-related alcohol expectancies were also examined. Results revealed that alcohol intoxication was related to less desire to engage in sex with a new partner and condom presence was related to more desire. Alcohol interacted with sexual disinhibition alcohol expectancies, indicating that more expectancy endorsement was associated with greater sexual desire and self-reported arousal in the alcohol condition, but not the control condition. Condom condition had no effect on self-reported sexual arousal. The present research suggests that sexual desire merits research attention in non-clinical samples, and experimental methodology can provide valuable information about alcohol's influence on women's sexual desire, thus advancing our understanding of this relationship beyond cross-sectional correlations. The current findings also provide evidence that sex-related alcohol expectancies may play an important role in alcohol-involved sexual experiences including desire and arousal. PMID- 23661327 TI - Complementing anatomy education using three-dimensional anatomy mobile software applications on tablet computers. AB - Anatomy has traditionally been a cornerstone of medical education, which has been taught via dissection and didactic lectures. The rising prevalence of mobile tablet technology means medical software applications ("apps") play an increasingly important role in medical education. The applications highlighted in this article will aid anatomical educators to identify which are the most useful in clinical, academic, and educational environments. These have been systematically identified by downloading all applications with keywords related to anatomy and then carrying out qualitative assessment. Novel anatomy applications from developers such as Visible Body, 3D4Medical, and Pocket Anatomy allow students to visualize and manipulate complex anatomical structures using detailed 3D models. They often contain additional content including clinical correlations and a range of media from instructional videos to interactive quiz functions. The strength of tablet technology lies in its ability to consolidate and present anatomical information to the user in the most appropriate manner for their learning style. The only question mark remains over the level of detail and accuracy of these applications. Innovative medical educators who embrace tablet technology will find that anatomy applications serve as a useful learning tool when used in conjunction with existing teaching setups. PMID- 23661328 TI - Mercury (Hg) exposure in breast-fed infants and their mothers and the evidence of oxidative stress. AB - The objective of this work was to assess exposure to mercury (Hg) and its induction of oxidative stress in 155 healthy lactating Saudi mothers and their infants. Samples of breast milk and blood were collected from the mothers, while urine was taken from both infants and mothers. Both urinary 8-hydroxy-2' deoxyguanosine (8-OHdG) and malondialdehyde (MDA) were measured in mothers and infants as biomarkers of oxidative stress. The mean concentration of Hg in breast milk was 1.19 MUg/L (range 0.012-6.44 MUg/L) with only one mother having Hg >4 MUg/L, the upper limit established by the US Agency for Toxic Substance and Disease Registry. However, 57.4 % had Hg >=1 MUg/L, the background level for Hg in human milk. The mean urinary Hg corrected for creatinine (Hg-C) in mothers and infants was 1.47 and 7.90 MUg/g creatinine, respectively, with a significant correlation between the two (p < 0.001). Urinary Hg levels over 5 MUg/g creatinine (the background level in an unexposed population) were found in 3.3 % of mothers and 50.1 % of infants. None of the mothers had total blood Hg above the US Environmental Protection Agency's maximum reference dose of 5.8 MUg/L. No correlation was noted between urinary Hg in infants and Hg in breast milk (p > 0.05). Hg in breast milk, though, was associated with Hg in blood (p < 0.001), suggesting the efficient transfer of Hg from blood to milk. Hg in the breast milk of mothers and in the urine of infants affected the excretion of urinary MDA and 8-OHdG, respectively, in a dose-related manner. These findings reveal for the first time lactational exposure to Hg-induced oxidative stress in breast-fed infants, which may play a role in pathogenesis, particularly during neurodevelopment. This will also contribute to the debate over the benefits of breast milk versus the adverse effects of exposure to pollutants. Nevertheless, breastfeeding should not be discouraged, but efforts should be made to identify and eliminate the source of Hg exposure in the population. PMID- 23661331 TI - Late extrusion of a venous microvascular coupling ring. PMID- 23661330 TI - Impact of methimazole treatment on magnesium concentration and lymphocytes activation in adolescents with Graves' disease. AB - The aim of this research was to assess plasma magnesium (Mg) concentration, the frequencies of activated T CD4+ and T CD8+ lymphocytes and B lymphocytes in adolescents with hyperthyroidism due to Graves' disease (GD), and to assess changes in the above-mentioned parameters during methimazole (MMI) treatment. The frequencies of activated T and B cells were measured by flow cytometry method and plasma Mg concentration was determined by spectrophotometry method in 60 adolescents at the time of GD diagnosis and after receiving the normalisation of the thyroid hormones levels. The control group consisted of 20 healthy volunteers. We observed lower plasma Mg concentration, and higher frequencies of activated T and B lymphocytes in the study group before the treatment in comparison with healthy controls, and with study group in MMI-induced euthyreosis (p < 0.01).Statistically significant negative correlations between the percentages of activated T CD3+, T CD4+, T CD8+ and B CD19+ lymphocytes, and plasma Mg concentration before the treatment were found (r < -0.335, p < 0.002). After the treatment no vital differences in plasma Mg concentration, and in percentages of activated cells between GD patients and controls were found, except CD8+CD25+ cells (p = 0.03). The present study demonstrates that both activated T and B cells might play an important role in the pathogenesis of GD, and activation is related to Mg plasma level. The use of MMI in treatment of hyperthyroidism due to GD leads to decrease the frequencies of activated lymphocytes and normalisation of Mg levels. PMID- 23661329 TI - Influence of vanadium-organic ligands treatment on selected metal levels in kidneys of STZ rats. AB - The objective of the study was to investigate the effects of five organic vanadium complexes supplement and a small dose of insulin injection on V, Fe, Cu, Zn, Mn, Ca, and K level in the streptozotocin diabetic rat's kidney during a 5 week treatment with the tested complexes. In all groups of animals, metal level in the lyophilized kidney organs was investigated by means of the proton induced X-ray emission method. Tissue vanadium level was naturally higher in vanadium treated rats. The maximum level of vanadium was observed in the kidney (x(mean) = 16.6 MUg/g). The influence of vanadium administration on other metal level in rat's tissue was also investigated. Spectacular influence of vanadium action was observed on copper and zinc level in examined tissue. PMID- 23661332 TI - Analysis of free flap complications and utilization of intensive care unit monitoring. AB - We aimed to determine the optimal time for intensive care unit (ICU) monitoring after free flap reconstruction based on the timing of surgical complications. We reviewed retrospectively 179 free flaps in 170 subjects during an 8-year period at University Hospital. Thirty-seven flaps were reoperated due to vascular (n = 16, 8.9%) and nonvascular complications (n = 21, 11.7%). Vascular complications presented earlier relative to nonvascular complications (10.8 versus 99.3 hours). The flap survival rate was 93.2% with a mean ICU length of stay of 6.2 days. The lack of standardized monitoring protocols can lead to overutilization of ICU. Sometimes, flap monitoring is not the limiting factor, as patients with other comorbidities necessitate longer ICU stays. However, our study suggests that close monitoring of flaps seems most critical during the first 24 to 48 hours, when most thrombotic complications occur and prompt identification and re exploration is critical. Some thrombosis and most hematomas present within 72 hours, and thus close monitoring is still warranted. We suggest close monitoring of free flaps in the ICU or dedicated flap monitoring unit where nursing can check the flap on an every-1-to-2-hour basis for the first 72 hours postoperatively to assure optimal surveillance of any potential problems. PMID- 23661333 TI - The correlation between calcium intensity and histopathological changes in brachial plexus nerve injuries. AB - BACKGROUND: After nerve injury, an influx of calcium exceeds the homeostatic capacity, which damages peripheral nerves. Previous studies identified that following nerve crush, function improves as calcium levels normalize. METHODS: Electrophysiological analysis was performed to measure the compound muscle action potential of 15 patients' damaged nerves. These samples were evaluated for calcium level and also stained with a Luxol fast blue and neurofilament antibodies to evaluate the myelin sheath and neurofilaments of the nerves. Based on the Sunderland scale, we identified three exclusive types of peripheral nerve injury groups. RESULTS: There was a correlation between histopathological damage and calcium levels of 0.81 (p < 0.005). The average relative fluorescence units (RFUs) was 235.28 +/- 19, which corresponds to 5.3 * 10-7 M of calcium, five times the normal value. CONCLUSION: Our study shows promising clinical implications via faster pathology results by the RFU technique. This approach of calcium staining, though still in clinical trials, offers significant clinical application, allowing physicians to get the clinically diagnostic nerve injury degree faster and will also facilitate better strategies for further treatment or future surgeries. PMID- 23661334 TI - Identification of recurrent FGFR3 fusion genes in lung cancer through kinome centred RNA sequencing. AB - Oncogenic fusion genes that involve kinases have proven to be effective targets for therapy in a wide range of cancers. Unfortunately, the diagnostic approaches required to identify these events are struggling to keep pace with the diverse array of genetic alterations that occur in cancer. Diagnostic screening in solid tumours is particularly challenging, as many fusion genes occur with a low frequency. To overcome these limitations, we developed a capture enrichment strategy to enable high-throughput transcript sequencing of the human kinome. This approach provides a global overview of kinase fusion events, irrespective of the identity of the fusion partner. To demonstrate the utility of this system, we profiled 100 non-small cell lung cancers and identified numerous genetic alterations impacting fibroblast growth factor receptor 3 (FGFR3) in lung squamous cell carcinoma and a novel ALK fusion partner in lung adenocarcinoma. PMID- 23661335 TI - Correlations between concentrations of interleukin (IL)-17A, IL-17B and IL-17F, and endothelial cells and proangiogenic cytokines in systemic lupus erythematosus patients. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease of multifactorial pathoaetiology. Different organs and blood vessels may be affected by chronic inflammation. A direct cause of the disease has not yet been found, so research is being carried out to this effect. The role of the recently identified helper T lymphocyte CD4+, described as Th17, and its dependent cytokines have been of particular interest. The aim of the study was to evaluate IL-17A, IL-17B, IL-17F and IL-23 in 60 SLE patients and 26 age-matched, healthy volunteers and also to investigate the correlation between levels of the investigated cytokines and VEGF, PIGF, as well as number of endothelial cells. IL-17A, IL-17B, IL-17BR and IL-17F levels were found to be higher in SLE patients than in the control group. However, only IL-17F levels showed a statistically significant correlation with the number of endothelial cells (aCEC) and disease activity. Correlations between levels of IL-17F and VEGF and PIGF as well as VEGF and IL-17A and IL-23 were statistically significant. Increased levels of the selected cytokines from the IL 17 family in SLE patients suggest a role for them not only in the inflammatory process but also in angiogenesis. This also highlights the role of IL-17F in activating vascular endothelial cells and consequently blood vessel formation, and in the relationship between the inflammatory reaction and angiogenesis in the development of SLE. PMID- 23661336 TI - Lipid rescue 911: Are poison centers recommending intravenous fat emulsion therapy for severe poisoning? AB - Intravenous fat emulsion (IFE) therapy is a novel treatment that has been used to reverse the acute toxicity of some xenobiotics with varied success. We sought to determine how US Poison Control Centers (PCCs) have incorporated IFE as a treatment strategy for poisoning. A closed-format multiple-choice survey instrument was developed, piloted, revised, and then sent electronically to every medical director of an accredited US PCC in March 2011. Addresses were obtained from the American Association of Poison Control Centers listserv, and participation was voluntary and remained anonymous. Data were analyzed using descriptive statistics. The majority of PCC medical directors completed the survey (45 out of 57; 79 %). Of the 45 respondents, all felt that IFE therapy played a role in the acute overdose setting. Most PCCs (30 out of 45; 67 %) have a protocol for IFE therapy. In a scenario with "cardiac arrest" due to a single xenobiotic, directors stated that their center would "always" or "often" recommend IFE after overdose of bupivacaine (43 out of 45; 96 %), verapamil (36 out of 45; 80 %), amitriptyline (31 out of 45; 69 %), or an unknown xenobiotic (12 out of 45; 27 %). In a scenario with "shock" due to a single xenobiotic, directors stated that their PCC would "always" or "often" recommend IFE after overdose of bupivacaine (40 out of 45; 89 %), verapamil (28 out of 45; 62 %), amitriptyline (25 out of 45; 56 %), or an unknown xenobiotic (8 out of 45; 18 %). IFE therapy is being recommended by US PCCs; protocols and dosing regimens are nearly uniform. Most directors feel that IFE is safe but are more likely to recommend IFE in patients with cardiac arrest than in patients with severe hemodynamic compromise. PMID- 23661337 TI - Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: a Hellenic Oncology Research Group (HORG) randomized phase 3 study. AB - BACKGROUND: In this superiority study, pemetrexed was compared with erlotinib in pre-treated patients with metastatic non-small cell lung cancer (NSCLC). METHODS: Patients with stage IIIB/IV NSCLC who progressed after first-line or second-line treatment were randomized to receive either pemetrexed or erlotinib. In total, 21.7% of patients in the pemetrexed arm and 23.5% of patients in the erlotinib arm had squamous cell histology, and treatment was third line in 39.2% and 46.4% of patients, respectively. The primary study endpoint was time to tumor progression (TTP). Epidermal growth factor receptor/v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (EGFR/KRAS) mutation status also was investigated. RESULTS: There was no difference in terms of the TTP (P = .195), the objective response rate (P = .469), or overall survival (P = .986) between the 2 treatment arms. In patients who had squamous cell histology, erlotinib resulted in a superior TTP compared with pemetrexed (4.1 months vs 2.5 months, respectively; P = .006). The incidence of grade 3 and 4 neutropenia, thrombocytopenia, and asthenia was significantly higher in the pemetrexed arm, whereas the incidence of grade 3 and 4 skin rash was higher in the erlotinib arm. CONCLUSIONS: Both pemetrexed and erlotinib had comparable efficacy in pre-treated patients with metastatic NSCLC, and the current results indicated that genotyping of tumor cells may have an important effect on treatment efficacy. PMID- 23661338 TI - A projection of ozone-induced wheat production loss in China and India for the years 2000 and 2020 with exposure-based and flux-based approaches. AB - Using a high-resolution (40 * 40 km) chemical transport model coupled with the Regional Emission inventory in Asia (REAS), we simulated surface ozone concentrations ([O3 ]) and evaluated O3 -induced wheat production loss in China and India for the years 2000 and 2020 using dose-response functions based on AOT40 (accumulated [O3 ] above 40 ppb) and PODY (phytotoxic O3 dose, accumulated stomatal flux of O3 above a threshold of Y nmol m(-2) s(-1) ). Two O3 dose metrics (90 days AOT40 and POD6 ) were derived from European experiments, and the other two (75 days AOT40 and POD12 ) were adapted from Asian studies. Relative yield loss (RYL) of wheat in 2000 was estimated to be 6.4-14.9% for China and 8.2 22.3% for India. POD6 predicted greater RYL, especially for the warm regions of India, whereas the 90 days AOT40 gave the lowest estimates. For the future projection, all the O3 dose metrics gave comparable estimates of an increase in RYL from 2000 to 2020 in the range 8.1-9.4% and 5.4-7.7% for China and India, respectively. The lower projected increase in RYL for India may be due to conservative estimation of the emission increase in 2020. Sensitivity tests of the model showed that the PODY -based estimates of RYL are highly sensitive to perturbations in the meteorological inputs, but that the estimated increase in RYL from 2000 to 2020 is much more robust. The projected increase in wheat production loss in China and India in the near future is substantially larger than the uncertainties in the estimation and indicates an urgent need for curbing the rapid increase in surface [O3 ] in these regions. PMID- 23661340 TI - Biochemical and quantitative proteomics investigations in Arabidopsis ggt1 mutant leaves reveal a role for the gamma-glutamyl cycle in plant's adaptation to environment. AB - The existence of a gamma-glutamyl cycle consisting of intracellular GSH synthesis, extrusion to the apoplastic space and recovery by gamma-glutamyl transferase (GGT)-assisted degradation into its constituent amino acids, has been demonstrated in plants. To address the significance of this cycle in plant cells, we performed integrated biochemical, immunocytochemical, and quantitative proteomics analyses in the Arabidopsis thaliana ggt1 knockout mutant (lacking apoplastic GGT1 isoform) and its corresponding wild-type (WT). The ggt1 knockout leaves exhibited an increased ascorbate and GSH content, increased apoplastic GSH content, and enhanced protein carbonylations in the low-molecular weight range compared to WT. The combined iTRAQ and LC-MS/MS-based quantitative proteomics approach identified 70 proteins (out of 1013 identified proteins) whose abundance was significantly different in leaves of ggt1 mutant compared to WT, with a fold change >=1.5. Mining of the proteome data for GSH-associated genes showed that disruption of gamma-glutamyl cycle in ggt1 knockout-leaves was associated with the induction of genes encoding four GSTs in the phi class (GSTF2, GSTF6, GSTF9, and GSTF10), a GSH peroxidase (GPX1), and glyoxylase II. Proteins with a lower abundance compared to the WT are involved in chloroplast functions, carbohydrate/maltose metabolism, and vegetative storage protein synthesis. Present findings suggest that GGT1 plays a role in redox signaling. The disruption of the gamma-glutamyl cycle in the ggt1 mutant results in pleiotropic effects related to biotic and abiotic stress response, antioxidant metabolism, senescence, carbohydrate metabolism, and photosynthesis, with strong implications for plant adaptation to the environment. PMID- 23661341 TI - Stereoselective degradation and microbial epimerization of triadimenol in soils. AB - Triadimenol is a widely used triazole fungicide and consists of four stereoisomers with 1R,2S, 1S,2R, 1R,2R, and 1S,2S configurations. The trans enantiomeric pair (1R,2S-isomer and 1S,2R-isomer) is also called triadimenol-A and the cis-enantiomeric pair (1R,2R-isomer and 1S,2S-isomer) triadimenol-B. In this study, the stereoselective degradation and chiral stability of triadimenol in two soils were investigated in details. The dissipation of technical triadimenol, a 6:1 mixture of triadimenol-A and triadimenol-B, showed significant epimerization from triadimenol-A to triadimenol-B occurred along with the dissipation process. The degradation exhibited some stereoselectivity, resulting in a concentration order of 1S,2S > 1R,2R > 1R,2S > 1S,2R or 1S,2S > 1R,2R > 1S,2R > 1R,2S at the end of the 100 days incubation for Baoding soil or Wuhan soil, respectively. Further incubation of triadimenol-B revealed no epimerization, i.e. triadimenol-B was configurationally stable in soil, and 1R,2R triadimenol degraded slightly slower in the former part and slightly faster in the later part of the incubation than 1S,2S-triadimenol. Moreover, by incubation of enantiopure 1S,2R-triadimenol and 1R,2S-triadimenol, the results documented the epimerization for each enantiomer occurred at both C-1 and C-2 positions. Finally, the present work also documented that the enantiomerization reaction for all the four stereoisomers was nearly negligible in the soils. PMID- 23661339 TI - Effects of the Fc-III tag on activity and stability of green fluorescent protein and human muscle creatine kinase. AB - The Fc-III tag is a newly developed fusion tag that can be applied to protein purification and detection. In the present work, we use the Fc-III-tagged green fluorescent protein (GFP) and human muscle creatine kinase (CK) as model systems to investigate effects of the Fc-III tag on activities and stabilities of the expressed multicysteine-containing proteins. Our results show the Fc-III tag has no adverse effects on the fluorescence of GFP and reduces the occurrence of GFP misfolding due to incorrect Cys oxidation compared with the His-tagged protein. The activity and stability of the Fc-III-tagged CK is slightly lower than that of the tag-free CK, but is higher than that of the His-tagged CK as determined by the ratio of the oxidized versus reduced CK. A major portion of His-tagged CK is in its oxidized form, while that of the Fc-III-tagged CK is in its reduced form. A folding model of CK with different tags was proposed, which may provide insights into the effect of the Fc-III tag on the conformations of disulfide bridged proteins. PMID- 23661342 TI - Rice suspension cultured cells are evaluated as a model system to study salt responsive networks in plants using a combined proteomic and metabolomic profiling approach. AB - Salinity is one of the major abiotic stresses affecting plant productivity but surprisingly, a thorough understanding of the salt-responsive networks responsible for sustaining growth and maintaining crop yield remains a significant challenge. Rice suspension culture cells (SCCs), a single cell type, were evaluated as a model system as they provide a ready source of a homogenous cell type and avoid the complications of multicellular tissue types in planta. A combination of growth performance, and transcriptional analyses using known salt induced genes was performed on control and 100 mM NaCl cultured cells to validate the biological system. Protein profiling was conducted using both DIGE- and iTRAQ based proteomics approaches. In total, 106 proteins were identified in DIGE experiments and 521 proteins in iTRAQ experiments with 58 proteins common to both approaches. Metabolomic analysis provided insights into both developmental changes and salt-induced changes of rice SCCs at the metabolite level; 134 known metabolites were identified, including 30 amines and amides, 40 organic acids, 40 sugars, sugar acids and sugar alcohols, 21 fatty acids and sterols, and 3 miscellaneous compounds. Our results from proteomic and metabolomic studies indicate that the salt-responsive networks of rice SCCs are extremely complex and share some similarities with thee cellular responses observed in planta. For instance, carbohydrate and energy metabolism pathways, redox signaling pathways, auxin/indole-3-acetic acid pathways and biosynthesis pathways for osmoprotectants are all salt responsive in SCCs enabling cells to maintain cellular function under stress condition. These data are discussed in the context of our understanding of in planta salt-responses. PMID- 23661343 TI - Effects of dispersed oil on reproduction in the cold water copepod Calanus finmarchicus (Gunnerus). AB - Following a 120-h exposure period to 3 concentrations of oil dispersions (0.022 mg L(-1) , 1.8 mg L(-1) , and 16.5 mg L(-1) , plus controls) generated from a North Sea crude oil and a subsequent 21-d recovery, mortality, and several reproduction endpoints (egg production rates, egg hatching success, and fraction of females participating in reproduction) in Calanus finmarchicus were studied. Concentration-dependent mortality was found during exposure, averaging to 6%, 3%, 15%, and 42% for the controls and 3 exposure levels, respectively. At the start of the recovery period, mean egg production rates of surviving females from the highest concentrations were very low, but reproduction subsequently improved. In a 4-d single female reproduction test starting 13 d postexposure, no significant differences in egg production rates or hatching success were found between reproducing control and exposed copepods. However, a significantly lower portion of the surviving females from the highest exposure participated in egg production. The results indicate that although short-term exposure to oil polluted water after an oil spill can induce severe mortality and temporarily suspend reproduction, copepods may recover and produce viable offspring soon after exposure. The results might imply that for C. finmarchicus populations, the impact from short-term exposure to an oil spill might be predicted from acute mortality and that delayed effects make only a limited contribution to population decrease. PMID- 23661344 TI - Relationship between beta-catenin expression and prognostic parameters of colorectal carcinomas. AB - OBJECTIVE: Colorectal carcinomas are the most frequent tumors of the gastrointestinal tract. beta-catenin, which is related to cadherins, is a cytoplasmic protein responsible for intercellular adhesion. It is also an important component in the Wnt signal pathway. Recent studies have shown structural alterations in the APC gene and axin in patients with colorectal carcinoma, along with beta-catenin. We aimed to compare beta-catenin expression, which is a prognostic factor itself, with other prognostic parameters. MATERIAL AND METHOD: A total of 70 patients who had surgical intervention for colorectal malignancies between January 1994 and December 2003 were included in the study. Fift y-nine of the patients (84.3%) were male, 11 of the patients (15.7%) were female; their ages varied between 24 and 82 (mean 60.3 +/-15.2) years. Paraff in blocks were immunohistochemically stained for beta-catenin. The number of stained cell nuclei was assessed according to the stage of disease using the TNM classification, histological grade, lymphatic invasion, vascular invasion and tumor's local invasion. RESULTS: When groups constituted according to tumor histologic grade were compared for prognostic parameters in terms of stain density for beta-catenin and number of stained cell nuclei, stain density was mild (+) and the number of stained nuclei was smaller in well-differentiated groups while stain density was strong (+++) and the number of stained nuclei was higher in poorly differentiated groups. There was a relation between beta-catenin expression and differentiation grade, lymph node metastasis, stage and tumor size but not with vascular invasion. CONCLUSION: These data indicate that beta- catenin, with functions in cell homeostasis and relations with the APC gene, has a substantial role in colorectal carcinogenesis. PMID- 23661345 TI - Value of Glut-1 and Koc markers in the differential diagnosis of reactive mesothelial hyperplasia, malignant mesothelioma and pulmonary adenocarcinoma. AB - OBJECTIVE: Malignant mesothelioma (MM) is a primary malignant tumor developing from mesothelial cells lining the serosal surfaces and particularly the pleura, and has a very poor prognosis. It may display a variety of histological patterns and has a wide spectrum of cytomorphological characteristics, causing problems in its differential diagnosis from lung adenocarcinomas and sometimes from benign mesothelial proliferations. Immunohistochemical examination is the most useful method for this distinction. In our study, we aimed to determine the value of glucose transporter isoform-1 (GLUT-1) and K homology domain-containing protein (KOC) markers in the differential diagnosis of reactive mesothelial hyperplasia, malignant mesothelioma and lung adenocarcinoma. MATERIAL AND METHOD: Our study included 30 samples of malignant mesothelioma, 30 samples of pulmonary adenocarcinoma and 30 samples of reactive mesothelial hyperplasia selected from the archives of the Firat University Hospital's Pathology Department Laboratory. The samples were applied GLUT-1 and KOC markers by immunohistochemistry and the place of these markers in the differential diagnosis was examined. RESULTS: GLUT 1 was found positive in 80% of malignant mesothelioma cases, 83.3% of adenocarcinoma cases and 6.6% of reactive mesothelial hyperplasia cases. KOC was positive in 83.3% of malignant mesothelioma cases, 76.6% of adenocarcinoma cases and 46.6% of reactive mesothelial hyperplasia cases. There was no statistically significant difference between malignant mesothelioma and lung adenocarcinoma cases in terms of the diffuseness and intensity of staining with GLUT-1, whereas a significant difference was established when these groups were compared with reactive mesothelial hyperplasia cases. However, the KOC staining diffuseness and intensity results were similar to those obtained with GLUT-1. CONCLUSION: In conclusion, GLUT-1 and KOC markers do not differentiate malignant mesotheliomas from pulmonary adenocarcinomas but can be useful in differentiating reactive mesothelial hyperplasia from malignant mesothelioma and lung adenocarcinoma. PMID- 23661346 TI - Cyclin d1 expression in odontogenic cysts. AB - OBJECTIVE: In the present study expression of cyclin D1 in the epithelial lining of odontogenic keratocyst, radicular cyst, dentigerous cyst and glandular odontogenic cyst was investigated to compare proliferative activity in these lesions. MATERIAL AND METHOD: Immunohistochemical staining of cyclin D1 on formalin-fixed, paraffin-embedded tissue sections of odontogenic keratocysts (n=23), dentigerous cysts (n=20), radicular cysts (n=20) and glandular odontogenic cysts (n=5) was performed by standard EnVision method. Then, slides were studied to evaluate the following parameters in epithelial lining of cysts: expression, expression pattern, staining intensity and localization of expression. RESULTS: The data analysis showed statistically significant difference in cyclin D1 expression in studied groups (p < 0.001). Assessment of staining intensity and staining pattern showed more strong intensity and focally pattern in odontogenic keratocysts, but difference was not statistically significant among groups respectively (p=0.204, 0.469). Considering expression localization, cyclin D1 positive cells in odontogenic keratocysts and dentigerous cysts were frequently confined in parabasal layer, different from radicular cysts and glandular odontogenic cysts. The difference was statistically significant (p < 0.01). CONCLUSION: Findings showed higher expression of cyclin D1 in parabasal layer of odontogenic keratocyst and the entire cystic epithelium of glandular odontogenic cysts comparing to dentigerous cysts and radicular cysts, implying the possible role of G1-S cell cycle phase disturbances in the aggressiveness of odontogenic keratocyst and glandular odontogenic cyst. PMID- 23661347 TI - Follicular mucinosis and follicular mycosis fungoides: clinicopathological evaluation of seven cases. AB - OBJECTIVE: Follicular mucinosis is a disease characterized by follicular degeneration and mucin accumulation. It can be seen in mycosis fungoides, although idiopathic or forms associated with other diseases are also known. Follicular mycosis fungoides is a type of mycosis fungoides with different clinicopathological and prognostic features. MATERIAL AND METHOD: Seven cases with follicular centered lesions and multiple biopsies (2-6) were included. Cases were evaluated according to their clinical, histological and immunophenotypical features and follow-up data. RESULTS: All cases were male, and the mean age was 40.3 (range 18-61). Clinical complaints were follicular prominence, erythema and alopecia at head and neck, trunk, and lower limbs. Follicular mucinosis (6/7), and dermal lymphoid infiltration showing minimal-intensive folliculotropism accompanied by eosinophils was seen. Lymphoid infiltration was composed of small medium sized cells, with scattered hyperchromatic nuclei in six cases. In one case there was only minimal cytological atypia. Intense folliculotropism of atypical lymphocytes and dense dermal infiltration without follicular mucinosis was seen in one case. Local and/or systemic treatments were applied and partial remission was achieved histologically. In three cases new and increasing lesions were seen. Density of infiltration and atypia were increased. CONCLUSION: The findings supported the opinion that follicular mucinosis is an important finding seen in mycosis fungoides. There can be important differences concerning the amount of infiltration and degree of atypia. In cases where the density of infiltration associated with follicular mucinosis is not diagnostic for MF, there can be progression over time. Long-term follow up is necessary in such cases where the differential diagnosis is difficult. PMID- 23661348 TI - Effects of contraception on cervical cytology: data from Mardin City. AB - OBJECTIVE: Mardin is an area of low socioeconomic level with low rates of contraceptive method use. Our aim in this study was to evaluate the effects of the contraceptive methods used in the area on epithelial cell abnormalities and vaginal flora changes. MATERIAL AND METHOD: Cervical smear samples received at the Pathology Department between 2010 and 2012 of 526 patients who had used a contraceptive method and 112 who had never used one were included in the study. The cases were divided into 3 groups as those using hormonal contraception (107, 20.3%), those using an intrauterine device (343, 65.2%) and those using a barrier method (76, 14.4%). The evaluation was made using the Bethesda 2001 criteria for cervical epithelial abnormalities and specific cervicovaginal infections. RESULTS: There was no significant difference between the groups for epithelial cell abnormalities while bacterial vaginitis (12%, p=0.03) and Trichomonas vaginalis (7.6%) were more common in the IUD users. The Actinomyces rate in RIA users was 1.3%. There was only 1 case of bacterial vaginitis in the barrier group and none of the other patients had a specific infection. DISCUSSION: We did not find a significant cytopathic effect of using a IUD or hormonal contraception in our study. There was a low rate of epithelial abnormality in the barrier method group. IUD was seen to increase the incidence of bacterial vaginitis, Trichomonas vaginalis and Actinomyces. We did not find a significant effect of hormone use on the vaginal flora. PMID- 23661349 TI - Diagnostic contribution of postmortem needle biopsies in neonates. AB - OBJECTIVE: We examined the contribution of neonatal postmortem needle biopsy in circumstances of autopsy denial where magnetic resonance imaging cannot be performed. MATERIAL AND METHOD: 247 postmortem needle biopsy specimens of 76 neonatal cases who died in the neonatal intensive care ward of a tertiary hospital between 2005 and 2010 and where the family did not give permission for an autopsy were retrospectively evaluated. RESULTS: 90 needle biopsy attempts (36.4%) were unsuccessful among the 247 biopsies. Liver needle biopsies were found to yield the most valuable diagnostic contribution. A total of 53 liver biopsies provided clinical information that contributed to the diagnosis. CONCLUSION: The postmortem needle biopsy should be applied in all cases in which standard biopsy cannot be performed. Success rates and level of information gained by extrahepatic needle organ biopsies in neonates were found to be quite low whereas needle biopsies of the liver yielded valuable results. We believe it is more appropriate to perform percutaneous postmortem biopsies solely on the liver in neonates. PMID- 23661350 TI - Is there any relationship between the clinical, radiological and histopathologic findings in sinonasal polyposis? AB - OBJECTIVE: The aim of this study was to assess the relationship between clinical, radiological and histopathological findings in nasal polyposis. MATERIAL AND METHOD: This was a retrospective study of 85 patients with nasal polyposis who were treated by endoscopic sinus surgery between the years of 2005 and 2010. All patients underwent preoperative paranasal sinus Computerized Tomography scan in the coronal plane and these images was evaluated with Lund-Mackay scores. The biopsy materials diagnosed as nasal polyp were identified by archive scanning at the pathology department. The Haematoxylin-Eosin stained preparations of the biopsy materials were re-evaluated. All of the results were analyzed by using the SPSS 13.0 soft ware program. Statistical significance was determined as p-value < 0.05. RESULTS: When the patients with (16.4%) and without (83.6%) bronchial asthma were compared regarding the eosinophil, lymphocyte, neutrophil, macrophage, mast cells and goblet cells/ epithelial cell rate, no statistical significance was found (p > 0.05). There was a positive relationship between the preoperative complaint durations and the total Lund-Mackay scores (r=0.270, p=0.012). The neutrophil amount (16.53 +/- 19.87) on the preparations of the patients with metaplasia was higher than the neutrophil amount (8.71 +/- 23.98) on the preparations of the patients without metaplasia (p=0.001). Radiologically, there was a positive correlation between the infiltration of anterior-posterior sinuses by the polyp tissues and the Lund-Mackay score of the nasal cavity. CONCLUSION: There was a positive correlation between preoperative complaint duration and squamous metaplasia; and there was also a positive correlation between the preoperative complaint duration and the total Lund-Mackay score. There was no histopathological difference between the polypoid infiltration of the front and rear group sinuses. PMID- 23661351 TI - Signet ring lobular carcinoma in situ as a part of the "Rosen Triad" (tubular carcinoma, columnar cell hyperplasia, and lobular carcinoma in situ). AB - OBJECTIVE: The association of tubular carcinoma, columnar cell lesions and lobular carcinoma in situ, also known as the "Rosen Triad", may be encountered in breast biopsies performed for evaluation of mammographically detected microcalcifications. CASE REPORT: A case in which tubular carcinoma and columnar cell hyperplasia were associated with a histologically unusual form of signet ring lobular carcinoma in situ is presented. Signet ring non-invasive lobular carcinoma is classified as high-grade lobular carcinoma in situ, but herein is associated with changes that belong to the molecular pathway of low-grade mammary neoplasia. CONCLUSION: We reported the case of lobular carcinoma in situ associated with columnar cell hyperplasia and tubular carcinoma, in which the lobular carcinoma in situ was presented in a histologically unexpected form comprised predominantly of signet ring cells. PMID- 23661352 TI - Large cell neuroendocrine carcinoma of urinary bladder; case presentation. AB - Large cell neuroendocrine tumor of the urinary bladder is very rare. It is a type of neuroendocrine carcinoma that is morphologically different from small cell carcinoma. This manuscript describes a 67-year-old man who presented with hematuria. Ultrasonogrophic and computer tomography revealed a 5 cm mass in right posterolateral wall of the bladder that invaded perivesical tissue and he subsequently underwent transurethral resection. Microscopic examination showed a tumor with a sheet-like and trabecular growth pattern comprising necrotic areas which infiltrated the muscularis propria. Tumoral cells had coarse chromatin, prominent nucleoli, moderate amount of cytoplasm and immunohistochemically stained strongly positive with synaptophysin, chromogranin and CD56. There are only few case reports of large cell neuroendocrine tumor of the urinary bladder so the biological behavior and the treatment protocol of these tumors are still obscure. Appropriate management protocols and prognostic estimation could be achived by the increased number of cases being reported. Therefore in a case of a poorly differentiated tumor in bladder, although rare, it is important to consider large cell neuroendocrine carcinoma in differential diagnosis. PMID- 23661353 TI - Microfilaria in association with adrenal lymphoma diagnosed on cytology: an extremely rare case report. AB - Filariasis is a common public health problem in Asian countries. In this report, the authors have described detection of microfilaria in the cytological specimen of adrenal lymphoma. To the best of our knowledge, this is the first reported case in the literature where microfilaria was seen in an adrenal gland involved by lymphoma. The literature is briefly reviewed. PMID- 23661354 TI - [Diffuse lipid infiltration and squamous metaplasia accompanying amyloid goiter: case report]. AB - Systemic amyloidosis is one of the serious complications of Familial Mediterranean Fever (FMF). Amyloid accumulation secondary to FMF can cause pressure symptoms in thyroid gland rarely. A 17-year-old male patient with the diagnosis of FMF performed the complaints of dyspnea during his follow-up period. He has demonstrated a rapidly increasing mass localized in front of his neck within the last three months that was diagnosed as a diffuse, hyperplasic and pressuring thyroid gland. Total thyroidectomy was performed. Histopathological investigation of the material obtained aft er thyroidectomy revealed diffuse lipid infiltration in parenchyma, intense amyloid accumulation around and between the follicles that caused pressure on the follicles, and cystic areas in the tissue. Squamous metaplasia foci in cyst epithelium were detected. Upon these findings the case was diagnosed as amyloid goiter accompanied by metaplastic variations. In conclusion, it can be appropriate to take into account the possibility that metaplastic variations could accompany amyloid goiter in patients with long-term FMF. PMID- 23661355 TI - Warthin-like papillary carcinoma of the thyroid: a case series and review of the literature. AB - Warthin-like tumor of the thyroid is a recently described rare variant of thyroid papillary carcinoma. The distinguishing histological feature of this variant is papillary foldings lined by oncocytic neoplastic cells with clear nuclei and nuclear pseudoinclusions, accompanied by prominent lymphocytic infiltrate in the papillary stalks. Its prognosis has been reported to be almost similar to conventional papillary carcinoma. In this case series, we report four cases with Warthin-like papillary carcinoma of the thyroid, diagnosed at Dokuz Eylul University Faculty of Medicine Department of Pathology in 2008 and 2009. Three patients were female. The mean patient age was 39 years (range, 20-56) and the mean tumor size was 1.7 cm (range, 0.9-2.0 cm). All of the cases had lymphocytic thyroiditis in the background. None of the tumors showed lymphovascular invasion. The patients are free of any recurrence and/or distant metastasis with a mean follow-up of 25 months. This rare variant of thyroid papillary carcinoma with distinct histopathological features should be indicated in pathology reports. Further studies and long-term follow-up of patients are needed to highlight the biological behavior of this variant. PMID- 23661356 TI - [Eccrine porocarcinoma of the scalp]. AB - OBJECTIVE: Eccrine porocarcinoma is a rare malignant tumor of eccrine sweat glands. It may arise de novo, but it usually develops in pre-existing eccrine poroma. Here we report a case of eccrine porocarcinoma in the grafted area on the scalp of a male patient who had recurrent basal cell carcinoma of the scalp, with clinical, histopathological and, immunohistochemical features. CASE: We report a case of eccrine porocarcinoma in 78-year-old male patient who had recurrent basal cell carcinoma of the scalp. The tumor was polypoid, granular and heterogenous colored. Microscopic examination revealed a tumor composed of basaloid-poroid neoplastic cells in the dermis which showed solid and cystic areas. Focal clear cell change, and atypical and frequent mitoses were also observed. Neoplastic cells were diffusely positive with pankeratin. There was focal positivity with EMA and CEA. CONCLUSION: Eccrine porocarcinoma is a rare tumor. There are no large series that evaluate the diagnosis, monitoring and treatment of these tumors. In addition, this entity has to be kept in mind in the differential diagnosis of epidermal and skin appendix tumors. PMID- 23661357 TI - [Atypical teratoid rhabdoid tumor: case report]. AB - Atypical teratoid rhabdoid tumor is a rare highly malignant embryonal tumor of the central nervous system that is often seen in early childhood. It is very important to distinguish it from other brain tumors because it has a very poor prognosis and there are differences in its treatment. A case of atypical teratoid rhabdoid tumor in a six-week-old male baby is presented. The tumor was located at posterior fossa. Histopathologically, the tumor has rhabdoid tumor cells and mesenchymal components beside the undifferentiated small cells. While EMA, vimentin, synaptophysin and smooth muscle actin have been stained with immunohistochemical staining, desmin, chromogranin, CD 99 and CD 56 have not been stained. The patient died four months after surgery despite the chemotherapy given. In conclusion, morphological characteristics can vary to a large extent that it is difficult to recognize atypical teratoid rhabdoid tumor. Immunohistochemical panel and molecular genetic study will help to establish the correct diagnosis. PMID- 23661358 TI - The impact of climate change measured at relevant spatial scales: new hope for tropical lizards. AB - Much attention has been given to recent predictions that widespread extinctions of tropical ectotherms, and tropical forest lizards in particular, will result from anthropogenic climate change. Most of these predictions, however, are based on environmental temperature data measured at a maximum resolution of 1 km(2), whereas individuals of most species experience thermal variation on a much finer scale. To address this disconnect, we combined thermal performance curves for five populations of Anolis lizard from the Bay Islands of Honduras with high resolution temperature distributions generated from physical models. Previous research has suggested that open-habitat species are likely to invade forest habitat and drive forest species to extinction. We test this hypothesis, and compare the vulnerabilities of closely related, but allopatric, forest species. Our data suggest that the open-habitat populations we studied will not invade forest habitat and may actually benefit from predicted warming for many decades. Conversely, one of the forest species we studied should experience reduced activity time as a result of warming, while two others are unlikely to experience a significant decline in performance. Our results suggest that global-scale predictions generated using low-resolution temperature data may overestimate the vulnerability of many tropical ectotherms to climate change. PMID- 23661359 TI - Parameterization of annealing kinetics in pharmaceutical glasses. AB - Numerical simulations indicate that neglecting the canonical nonlinearity of glassy-state annealing kinetics in pharmaceutical (and other) glasses leads to good KWW fits to the dependence of enthalpy on annealing time, but with spurious KWW parameters that are affected by nonlinearity. A simplified treatment of nonlinearity that uses the Struik shift factor is found to be a useful approximation for these analyses, and can account for previously reported differences between linear and nonlinear KWW parameters (Kawakami K, Pikal MJ. 2005. J Pharm Sci 94:948-965). PMID- 23661362 TI - Global partnerships for international fieldwork in occupational therapy: reflection and innovation. AB - International fieldwork placements (IFPs) have become very popular among healthcare students including those in occupational therapy programmes. There are many potential benefits that can accrue to the students; however, there are critiques of international placements especially for students going to underserviced areas. The purpose of this paper is to provide a case study/model programme description that critically reflects on six partnerships in three underserviced countries that provide IFPs to students from one Canadian university. The personal opinions of each partner were collected verbally, by email and by a qualitative review of the past 10 years of partnership interaction. Some of the benefits reported by partners include the development of an increased number of sustainable long-term quality placements, orientation materials, student supports and the involvement of university faculty in research and capacity building projects in partner countries. A number of challenges were identified including the need for an expanded formal agreement, more bilateral feedback and examination of supervision models. This paper examines a limited number of partnerships with only one Canadian partner. Direct input of students is not utilized, although feedback given to co-authors by students is reflected. More research is needed on perspectives of partners in IFPs, impact of IFPs on clinical practice in student's home countries, impact of IFPS on underserviced areas and effective strategies for debriefing. PMID- 23661360 TI - LIF and the heart: just another brick in the wall? AB - Multiple studies have shown that the cytokine leukemia inhibitory factor (LIF) is protective of the myocardium in the acute stress of ischemia-reperfusion. All three major intracellular signaling pathways that are activated by LIF in cardiac myocytes have been linked to actions that protect against oxidative stress and cell death, either at the level of the mitochondrion or via nuclear transcription. In addition, LIF has been shown to contribute to post-myocardial infarction cardiac repair and regeneration, by stimulating the homing of bone marrow-derived cardiac progenitors to the injured myocardium, the differentiation of resident cardiac stem cells into endothelial cells, and neovascularization. Whether LIF offers protection to the heart under chronic stress such as hypertension-induced cardiac remodeling and heart failure is not known. However, mice with cardiac myocyte restricted knockout of STAT3, a principal transcription factor activated by LIF, develop heart failure with age, and cardiac STAT3 levels are reported to be decreased in heart failure patients. In addition, endogenously produced LIF has been implicated in the cholinergic transdiffrentiation that may serve to attenuate sympathetic overdrive in heart failure and in the peri-infarct region of the heart after myocardial infarction. Surprisingly, therapeutic strategies to exploit the beneficial actions of LIF on the injured myocardium have received scant attention. Nor is it established whether the purported so called adverse effects of LIF observed in isolated cardiac myocytes have physiological relevance in vivo. Here we present an overview of the actions of LIF in the heart with the goal of stimulating further research into the translational potential of this pleiotropic cytokine. PMID- 23661361 TI - The potential effect of gender in CYP1A1 and GSTM1 genotype-specific associations with pediatric brain tumor. AB - Brain tumors are the common site for solid tumors in childhood. Very few studies have investigated genes with low penetrance in relation to pediatric brain tumor (pBT) development. Brain tumors do occur more frequently in males compared to females regardless of age, tumor histology, or region of the world. Taken into account these facts, we have designed a study aimed to analyse the contribution of some genetic factors to pBP in males and females. Patients with glial and embryonic brain tumors (160 males, 124 females) and healthy controls (277 males, 187 females) were included in the study. All subjects were genotyped for eight polymorphic variants in the genes of xenobiotics detoxification CYP1A1 (rs2606345, rs4646903, rs1048943), GSTM1 (Ins/del), GSTT1 (Ins/del), repair ERCC2 (rs1799793, rs13181), and folate pathway MTHFR (rs1801133). Genotype-specific risks of pBT were sex-dependent. GSTM1 deletion and dual deletions in GSTM1-GSTT1 loci were associated with brain tumor in males (P = 1.2 * 10(-5); odds ratio (OR) = 2.56; 95 % confidence interval (CI), 1.45-3.85 and P = 4.9 * 10(-4); OR = 3.09; 95 % CI, 1.63-5.89, relatively). The increased risk of brain tumors was evident for CYP1A1 rs2606345 (P = 0.0028; OR = 2.06; 95 % CI, 1.27-3.34) and minor haplotypes rs2606345-rs1048943-rs4646903 in females (global haplotype association P value, 0.0011). This study provides first evidence for the different pronounced pBT associations in males and females. This phenomenon possibly reflects the sexual dimorphism as an important determinant of brain tumor biology. PMID- 23661363 TI - Utilizing micro-computed tomography to evaluate bone structure surrounding dental implants: a comparison with histomorphometry. AB - Although histology has proven to be a reliable method to evaluate the ossoeintegration of a dental implant, it is costly, time consuming, destructive, and limited to one or few sections. Microcomputed tomography (uCT) is fast and delivers three-dimensional information, but this technique has not been widely used and validated for histomorphometric parameters yet. This study compared uCT and histomorphometry by means of evaluating their accuracy in determining the bone response to two different implant materials. In total, 32 titanium (Ti) and 16 hydroxyapatite (HA) implants were installed in 16 lop-eared rabbits. After 2 and 4 weeks, the animals were scarified, and the samples retrieved. After embedding, the samples were scanned with uCT and analyzed three-dimensionally for bone area (BA) and bone-implant contact (BIC). Thereafter, all samples were sectioned and stained for histomorphometry. For the Ti implants, the mean BIC was 25.25 and 28.86% after 2 and 4 weeks, respectively, when measured by histomorphometry, while it was 24.11 and 24.53% when measured with uCT. BA was 35.4 and 31.97% after 2 and 4 weeks for histomorphometry and 29.06 and 27.65% for uCT. For the HA implants, the mean BIC was 28.49 and 42.51% after 2 and 4 weeks, respectively, when measured by histomorphometry, while it was 33.74 and 42.19% when measured with uCT. BA was 30.59 and 47.17% after 2 and 4 weeks for histomorphometry and 37.16 and 44.95% for uCT. Direct comparison showed that only the 2 weeks BA for the titanium implants was significantly different between uCT and histology (p = 0.008). Although the technique has its limitations, uCT corresponded well with histomorphometry and should be considered as a tool to evaluate bone structure around implants. PMID- 23661366 TI - Cdc25B phosphatase participates in maintaining metaphase II arrest in mouse oocytes. AB - Cdc25B is an essential regulator for meiotic resumption in mouse oocytes. However, the role of this phosphatase during the later stage of the meiotic cell cycle is not known. In this study, we investigated the role of Cdc25B during metaphase II (MII) arrest in mouse oocytes. Cdc25B was extensively phosphorylated during MII arrest with an increase in the phosphatase activity toward Cdk1. Downregulation of Cdc25B by antibody injection induced the formation of a pronucleus-like structure. Conversely, overexpression of Cdc25B inhibited Ca(2+) mediated release from MII arrest. Moreover, Cdc25B was immediately dephosphorylated and hence inactivated during MII exit, suggesting that Cdk1 phosphorylation is required to exit from MII arrest. Interestingly, this inactivation occurred prior to cyclin B degradation. Taken together, our data demonstrate that MII arrest in mouse oocytes is tightly regulated not only by the proteolytic degradation of cyclin B but also by dynamic phosphorylation of Cdk1. PMID- 23661364 TI - Do sirtuins promote mammalian longevity? A critical review on its relevance to the longevity effect induced by calorie restriction. AB - Sirtuins (SIRTs), a family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, are emerging as key molecules that regulate aging and age-related diseases including cancers, metabolic disorders, and neurodegenerative diseases. Seven isoforms of SIRT (SIRT1-7) have been identified in mammals. SIRT1 and 6, mainly localized in the nucleus, regulate transcription of genes and DNA repair. SIRT3 in the mitochondria regulates mitochondrial bioenergetics. Initial studies in yeasts, nematodes, and flies indicated a strong connection of SIRT with the life-prolonging effects of calorie restriction (CR), a robust experimental intervention for longevity in a range of organisms. However, subsequent studies reported controversial findings regarding SIRT roles in the effect of CR. This review describes the functional roles of mammalian SIRTs and discusses their relevance to mechanisms underlying the longevity effect of CR. PMID- 23661365 TI - Requirement of vesicle-associated membrane protein 721 and 722 for sustained growth during immune responses in Arabidopsis. AB - Extracellular immune responses to ascomycete and oomycete pathogens in Arabidopsis are dependent on vesicle-associated secretion mediated by the SNARE proteins PEN1 syntaxin, SNAP33 and endomembrane-resident VAMP721/722. Continuous movement of functional GFP-VAMP722 to and from the plasma membrane in non stimulated cells reflects the second proposed function of VAMP721/722 in constitutive secretion during plant growth and development. Application of the bacterium-derived elicitor flg22 stabilizes VAMP721/722 that are otherwise constitutively degraded via the 26S proteasome pathway. Depletion of VAMP721/722 levels by reducing VAMP721/722 gene dosage enhances flg22-induced seedling growth inhibition in spite of elevated VAMP721/722 abundance. We therefore propose that plants prioritize the deployment of the corresponding secretory pathway for defense over plant growth. Interstingly, VAMP721/722 specifically interact in vitro and in vivo with the plasma membrane syntaxin SYP132 that is required for plant growth and resistance to bacteria. This suggests that the plant growth/immunity-involved VAMP721/722 form SNARE complexes with multiple plasma membrane syntaxins to discharge cue-dependent cargo molecules. PMID- 23661367 TI - Intravitreal injection of ranibizumab for recovery of macular function in eyes with subfoveal polypoidal choroidal vasculopathy. AB - PURPOSE: To evaluate changes in macular function in eyes with polypoidal choroidal vasculopathy (PCV) after intravitreal ranibizumab (IVR) treatment. METHODS: Twenty-three eyes from 23 patients with treatment-naive subfoveal PCV received three monthly injections of IVR, followed by as-needed injections. Visual acuity (VA); retinal thickness (measured with optical coherence tomography); macular sensitivity (measured with microperimetry); and focal macular electroretinograms (fmERGs) were evaluated both before the initiation of therapy and after 3 and 12 months. RESULTS: Before treatment, cystoid macular edema was observed in five eyes, serous retinal detachments in 13 eyes, and serosanguinous pigment epithelial detachments in 18 eyes. IVR treatment resulted in substantial morphological improvements and consequent marked reductions in foveal thickness (P = 0.008). Although logarithm of the minimum angle of resolution (logMAR) VA did not improve significantly over the 12-month study period (P = 0.623), the amplitude of the fmERG photopic negative response and macular sensitivity within 4 degrees had increased significantly at 3 months (P = 0.004, P = 0.026, respectively). This trend persisted until the end of the 12 month monitoring period. Among the eyes with preexisting serous retinal detachments, those in which the detachments had resolved completely at 3 months also exhibited greater increases in fmERG a-wave amplitudes (P = 0.048). CONCLUSIONS: IVR therapy resulted in morphological improvements and the partial recovery of macular function in eyes with subfoveal PCV. This therapy may improve photoreceptor function by resolving serous retinal detachments. PMID- 23661368 TI - Comprehensive mutation analysis by whole-exome sequencing in 41 Chinese families with Leber congenital amaurosis. AB - PURPOSE: Leber congenital amaurosis (LCA) is a genetically heterogeneous disease with, to date, 19 identified causative genes. Our aim was to evaluate the mutations in all 19 genes in Chinese families with LCA. METHODS: LCA patients from 41 unrelated Chinese families were enrolled, including 25 previously unanalyzed families and 16 families screened previously by Sanger sequencing, but with no identified mutations. Genetic variations were screened by whole-exome sequencing and then validated using Sanger sequencing. RESULTS: A total of 41 variants predicted to affect protein coding or splicing was detected by whole exome sequencing, and 40 were confirmed by Sanger sequencing. Bioinformatic and segregation analyses revealed 22 potentially pathogenic variants (17 novel) in 15 probands, comprised of 3 of 16 previously analyzed families and 12 of 25 (48%) previously unanalyzed families. In the latter 12 families, mutations were found in CEP290 (three probands); GUCY2D (two probands); and CRB1, CRX, RPE65, IQCB1, LCA5, TULP1, and IMPDH1 (one proband each). Based on the results from 87 previously analyzed probands and 25 new cases, GUCY2D, CRB1, RPGRIP1, CEP290, and CRX were the five most frequently mutated genes, which was similar to the results from studies in Caucasian subjects. CONCLUSIONS: Whole-exome sequencing detected mutations in the 19 known LCA genes in approximately half of Chinese families with LCA. These results, together with our previous results, demonstrate the spectrum and frequency of mutations of the 19 genes responsible for LCA in Han Chinese individuals. Whole-exome sequencing is an efficient method for detecting mutations in highly heterogeneous hereditary diseases. Chinese Abstract. PMID- 23661370 TI - Current steering in retinal stimulation via a quasimonopolar stimulation paradigm. AB - PURPOSE: Research to restore some degree of vision to patients suffering from retinal degeneration is becoming increasingly more promising. Several groups have chosen electrical stimulation of the remaining network of a degenerate retina as a means to generate discrete light percepts (phosphenes). Approaches vary significantly, with the greatest difference being the location of the stimulating electrode itself. METHODS: Suprachoroidal positioning offers excellent mechanical stability and surgical simplicity; however, at the cost of activation thresholds and focused stimulation due to the distance from the electrodes to the target neurons. Past studies proposed a hexapolar electrode configuration to focus the cortical activation and minimize cross-talk between electrodes during concurrent stimulation. The high impedance nature of the choroid and pigment epithelium, however, cause current to shunt between the stimulating and return electrodes, resulting in even higher activation thresholds. In our study, we analyzed the effect of stimulating the feline retina using a quasimonopolar stimulation by simultaneously stimulating a hexapolar and distant monopolar return configurations. RESULTS: Results of in vivo studies showed that quasimonopolar stimulation can be used to maintain the activation containment properties of hexapolar stimulation, while lowering the activation threshold to values almost equivalent to those of monopolar stimulation. CONCLUSIONS: The optimal stimulus was found to be composed of a subthreshold monopolar stimulus combined with a suprathreshold hexapolar stimulation. This resulted in a decrease of activation threshold of 60% with respect to hexapolar alone, but with no discernible deleterious effect on the charge containment of a pure hexapolar stimulation. PMID- 23661371 TI - Binocular vision and eye movement disorders in older adults. AB - PURPOSE: To determine the prevalence of binocular vision (BV) and eye movement disorders in a clinic population of older adults. METHODS: Retrospective clinic data were abstracted from files of 500 older patients seen at the University of Waterloo Optometry Clinic over a 1-year period. Stratified sampling gave equal numbers of patients in the 60 to 69, 70 to 79, and 80+ age groups. Data included age, general and ocular history and symptoms, use of antidepressants, a habit of smoking, refraction, visual acuity, BV and eye movement status for the most recent full oculo-visual assessment, and an assessment 10 years prior. The prevalence of any BV or eye movement abnormal test (AT) result, defined as a test result outside the normal range, was determined. This included strabismus (any) or phoria; incomitancy; poor pursuits; and remote near point of convergence (NPC). The prevalence of significant BV disorders (diagnostic entities, i.e., a clinical condition that may need treatment and may have functional implications) was also determined. RESULTS: The prevalence of any BV or eye movement at was 41%, 44%, and 51% in the 60 to 69, 70 to 79, and 80+ age groups, respectively. These figures were lower for 10 years earlier: 31%, 36%, and 40% for ages 50 to 59, 60 to 69, and 70+, respectively. The prevalence of any BV or eye movement disorder was 27%, 30%, and 38% for the three age groups and 17%, 19%, and 24% for 10 years prior. Age and use of antidepressants most commonly predicted BV or eye movement AT or disorder. CONCLUSIONS: BV disorders are common among older adults. PMID- 23661369 TI - Next-generation sequencing-based molecular diagnosis of a Chinese patient cohort with autosomal recessive retinitis pigmentosa. AB - PURPOSE: Retinitis pigmentosa (RP) is a highly heterogeneous genetic disease; therefore, an accurate molecular diagnosis is essential for appropriate disease treatment and family planning. The prevalence of RP in China had been reported at 1 in 3800, resulting in an estimated total of 340,000 Chinese RP patients. However, genetic studies of Chinese RP patients have been very limited. To date, no comprehensive molecular diagnosis has been done for Chinese RP patients. With the emergence of next-generation sequencing (NGS), comprehensive molecular diagnosis of RP is now within reach. The purpose of this study was to perform the first NGS-based comprehensive molecular diagnosis for Chinese RP patients. METHODS: Thirty-one well-characterized autosomal recessive RP (arRP) families were recruited. For each family, the DNA sample from one affected member was sequenced using our custom capture panel, which includes 163 retinal disease genes. Variants were called, filtered, and annotated by our in-house automatic pipeline. RESULTS: Twelve arRP families were successfully molecular diagnosed, achieving a diagnostic rate of approximately 40%. Interestingly, approximately 63% of the pathogenic mutations we identified are novel, which is higher than that observed in a similar study on European descent (45%). Moreover, the clinical diagnoses of two families were refined based on the pathogenic mutations identified in the patients. CONCLUSIONS: We conclude that comprehensive molecular diagnosis can be vital for an accurate clinical diagnosis of RP. Applying this tool on patients from different ethnic groups is essential for enhancing our knowledge of the global spectrum of RP disease-causing mutations. PMID- 23661372 TI - Overexpression of SIRT1 promotes high glucose-attenuated corneal epithelial wound healing via p53 regulation of the IGFBP3/IGF-1R/AKT pathway. AB - PURPOSE: To investigate how Sirtuin (silent mating type information regulation 2 homolog) 1 (SIRT1) promotes high glucose-attenuated corneal epithelial wound healing. METHODS: The effects of high glucose on SIRT1 expression were assessed in primary human corneal epithelial cells (CECs) in treatment of 5 mM d-glucose (normal glucose [NG]) and 25 mM D-glucose (high glucose [HG]) and corneas from Ins2(Akita/+) mice by Western blotting. The osmotic pressure of the NG medium was adjusted to that of the HG medium by adding 20 mM mannitol. Pifithrin-alpha (PFT alpha) was used to inhibit the expression of p53 and an adenovirus was used for overexpression of SIRT1 in vivo and in vitro. How overexpression of SIRT1 promotes HG-attenuated corneal epithelial wound healing via p53 regulation of the IGFBP3 (insulin-like growth factor binding protein-3)/IGF-1 (insulin-like growth factor-1)/AKT pathway was investigated in CECs and Ins2(Akita/+) mice. RESULTS: HG induced the downregulation of SIRT1 and the upregulation of p53 acetylation in primary human CECs and corneas from Ins2(Akita/+) mice. The results of cell migration assay and corneal wound healing from Ins2(Akita/+) mice demonstrated that SIRT1 overexpression strongly promoted wound healing in the presence of HG levels via the downregulation of the IGFBP3 protein. The levels of total p53 expression and acetylated p53 decreased dramatically in the presence of PFT alpha, whereas the IGF-1R/AKT pathway was activated in CECs. The results of cell migration assay suggested this posttranslational modification of p53 was involved in the response to cell injury under HG conditions in CECs. CONCLUSIONS: The molecular mechanism by which SIRT1 promotes corneal epithelial wound healing was involved in an enhancement of the IGFBP3/IGF-1/AKT pathway through the deacetylation of p53. This study also suggests that SIRT1 has a protective role in the pathogenesis of diabetic keratopathy. PMID- 23661373 TI - In vitro and in vivo assessment of titanium surface modification for coloring the backplate of the Boston keratoprosthesis. AB - PURPOSE: Recent use of a titanium (Ti) backplate has improved the design and biocompatibility of the Boston Keratoprosthesis (BKpro). Titanium's shiny metallic appearance, however, makes the cosmetic outcome less favorable. The purpose of this study was to develop and test a coloring surface modification of Ti. METHODS: Ti coloring was achieved using electrochemical anodization. Color assessment included scanning electron microscopy, atomic force microscopy (AFM), x-ray diffraction crystallography (XRD), and Fourier transform infrared spectroscopy (FTIR). Biocompatibility assessment of Ti disks included in vitro proliferation and cytotoxicity in coculture with human corneal limbal epithelial (HCLE) cells, primary human corneal fibroblasts, and immortalized human corneal endothelial cells (HCEnCs), and in vivo intralamellar implantation in rabbit corneas. Histologic appearance (hematoxylin-eosin and trichrome staining) and presence of cell inflammation (CD45), apoptosis (TUNEL), and corneal neovascularization (CD31) were evaluated 27 and 53 days post implantation. RESULTS: Blue and brown coloration of Ti was achieved. Analysis showed the presence of a nanoporous oxide surface with no chemical change of the modified Ti surface. In vitro assessment showed no significant differences in cell proliferation and cytotoxicity between anodized and nonanodized Ti (P > 0.05; ANOVA for all cell types). Analysis of corneal tissues harboring the Ti disks showed normal cellular appearance, and lack of CD45, TUNEL, and CD31-positive cells. CONCLUSIONS: A biocompatible Ti backplate coloring was achieved by electrochemical anodization. In vitro and in vivo results suggest that the anodized Ti is equally biocompatible and as safe as the standard nonanodized Ti. The color modification of the BKpro may improve the cosmesis and acceptance of the BKpro by patients. PMID- 23661374 TI - Association between baseline angle width and induced angle opening following prophylactic laser peripheral iridotomy. AB - PURPOSE: To evaluate the association between baseline angle width and laser peripheral iridotomy (LPI)-induced opening of the anterior chamber angle. METHODS: Anterior segment optical coherence tomography images captured before and after LPI were analyzed to determine the angle opening distance at 250 MUm (AOD250), 500 MUm (AOD500), and 750 MUm (AOD750) from the scleral spur; trabecular-iris space area at 500 MUm (TISA500) and 750 MUm (TISA750) from the scleral spur; angle recess area at 750 MUm (ARA750) from the scleral spur; and trabecular-iris angle (TIA). Differences in preoperative and postoperative measurements for the anterior chamber angle width parameters were compared by paired Student's t-tests. Univariate and linear mixed-effects regression models were used to examine the association between baseline and LPI-induced opening of anterior chamber angle width parameters. RESULTS: Eighty-four eyes of 52 primary angle closure suspects were included in the analysis. AOD250, AOD500, AOD750, TISA500, TISA750, ARA750, and TIA significantly increased following LPI by paired Student's t-tests (all P < 0.0001). Lower baseline measurements were significantly associated with greater postoperative opening in all anterior chamber angle width parameters in both univariate and linear mixed-effects regression analyses (all P < 0.05). CONCLUSIONS: Our results showed significant opening of the anterior chamber angle width after LPI and demonstrated an inverse association between baseline and LPI-induced opening of the anterior chamber angle width, such that eyes with a more crowded anterior chamber angle undergoing LPI had a greater magnitude of increase in anterior chamber angle width after the procedure. PMID- 23661375 TI - Predicting progression in glaucoma suspects with longitudinal estimates of retinal ganglion cell counts. AB - PURPOSE: We evaluated the ability of baseline and longitudinal estimates of retinal ganglion cell (RGC) counts in predicting progression in eyes suspected of having glaucoma. METHODS: The study included 288 glaucoma suspect eyes of 288 patients followed for an average of 3.8 +/- 1.0 years. Participants had normal standard automated perimetry (SAP) at baseline. Retinal nerve fiber layer thickness assessment was performed with optical coherence tomography (OCT). Progression was defined as development of repeatable abnormal SAP or glaucomatous progressive optic disc changes. Estimates of RGC counts were obtained by combining data from SAP and OCT according to a previously described method. Joint longitudinal survival models were used to evaluate the ability of baseline and rates of change in estimated RGC counts for predicting progression over time, adjusting for confounding variables. RESULTS: A total of 48 eyes (17%) showed progression during follow-up. The mean rate of change in estimated RGC counts was -18,987 cells/y in progressors versus -8,808 cells/y for nonprogressors (P < 0.001). Baseline RGC counts and slopes of RGC loss were significantly predictive of progression, with HRs of 1.56 per 100,000 cells lower (95% confidence interval [CI], 1.18-2.08; P = 0.002) and 2.68 per 10,000 cells/y faster loss (95% CI, 1.22 5.90; P = 0.014), respectively. The longitudinal model including estimates of RGC counts performed significantly better than models including only structural or functional indexes separately. CONCLUSIONS: Baseline and longitudinal estimates of RGC counts may be helpful in predicting progression and performed significantly better than conventional approaches for risk stratification of glaucoma suspects. PMID- 23661376 TI - Equivalent intrinsic noise, sampling efficiency, and contrast sensitivity in patients with retinitis pigmentosa. AB - PURPOSE: To determine the relationships among equivalent intrinsic noise (Neq), sampling efficiency, and contrast sensitivity (CS) in patients with retinitis pigmentosa (RP), where Neq is an estimate of the amount of noise within the visual pathway and sampling efficiency represents the subject's ability to use stimulus information optimally. METHODS: Participants included 10 patients with RP aged 10 to 54 years, who had visual acuities of 20/40 or better, and 10 visually normal control subjects aged 22 to 65 years. CS was measured for 2 cycles-per-degree Gabor patch targets presented in the absence of noise (CS0) and in five levels of noise spectral density. Data were fit with a standard linear amplifier model, which provided estimates of Neq and sampling efficiency. RESULTS: CS0 for the patients ranged from normal to as much as a factor of 3 below the lower limit of normal. All 10 patients had abnormally high Neq, including two patients with normal CS0. In comparison, only two patients had lower-than-normal sampling efficiency, and these two patients also had below normal CS0. Log CS0 for the patients was correlated significantly with log Neq (r = -0.80, P < 0.05), but not with log efficiency (r = 0.54, P = 0.11). CONCLUSIONS: Low CS was associated with elevated intrinsic noise in this group of RP patients, but even patients with normal CS had elevated noise levels. The results suggest that CS measurement in both the presence and absence of luminance noise can provide important information about visual dysfunction in RP patients. PMID- 23661377 TI - Directing adult human periodontal ligament-derived stem cells to retinal fate. AB - PURPOSE: To investigate the retinal fate competence of human postnatal periodontal ligament (PDL)-derived stem cells (PDLSC) through a directed differentiation mimicking mammalian retinogenesis. METHODS: Human teeth were collected from healthy subjects younger than 35 years old. Primary PDLSC were isolated by collagenase digestion and cultivated. PDLSC at passage 3 were cultured in the induction media containing Noggin (antagonist of bone morphogenic protein) and Dkk-1 (antagonist of Wnt/beta-catenin signaling). Gene expression of neural crest cells, retinal progenitors, and retinal neurons, including photoreceptors, was revealed by RNA analyses, immunofluorescence, and flow cytometry. The neuronal-like property of differentiated cells in response to excitatory glutamate was examined by fluo-4-acetoxymethyl calcium imaging assay. RESULTS: Primary human PDLSC stably expressed marker genes for neural crest (Notch1, BMP2, Slug, Snail, nestin, and Tuj1), mesenchymal stem cell (CD44, CD90, and vimentin), and embryonic stem cell (c-Myc, Klf4, Nanog, and SSEA4). Under low attachment culture, PDLSC generated neurospheres expressing nestin, p75/NGFR, Pax6, and Tuj1 (markers of neural progenitors). When neurospheres were plated on Matrigel-coated surface, they exhibited rosette-like outgrowth. They expressed eye field transcription factors (Pax6, Rx, Lhx, Otx2). By flow cytometry, 94% of cells were Pax6(nuclear)Rx(+), indicative of retinal progenitors. At prolonged induction, they expressed photoreceptor markers (Nrl, rhodopsin and its kinase) and showed significant responsiveness to excitatory glutamate. CONCLUSIONS: Primary human PDLSC could be directed to retinal progenitors with competence for photoreceptor differentiation. Human neural crest-derived PDL is readily accessible and can be an ample autologous source of undifferentiated cells for retinal cell regeneration. PMID- 23661382 TI - Low temperatures enhance the toxicity of copper and cadmium to Enchytraeus crypticus through different mechanisms. AB - Knowledge about how toxicity changes with temperature is important for determining the extent of safety factors required when extrapolating from standard laboratory conditions to variable field scenarios. In the present study, the authors evaluated the toxicity of Cu and Cd to the potworm Enchytraeus crypticus at 6 temperatures in the range of 11 degrees C to 25 degrees C. For both metals, reproductive toxicity decreased approximately 2.5-fold with increasing temperature. This is contrary to what most other studies have found. Measurements of the bioavailable fraction of the metals in the soils and the internal metal concentrations in the worms over time showed that the major cause of change in toxicity with temperature for Cu was the worms' ability to regulate internal concentration at high temperatures. Uptake of Cd increased with time at all temperatures and with higher rates at high temperatures. Hence, the lower toxicity of Cd at high temperatures is proposed to be due to the E. crypticus being more efficient at immobilizing Cd and/or repairing damages at high compared to low temperatures. The present study concludes that no consistent relationship between metal toxicity and temperature across species can be made. The metabolic dependence of the species in terms of regulating metal uptake, excretion, immobilization, damage, and repair processes, will be crucial factors in determining species susceptibility to metals at varying temperatures. PMID- 23661383 TI - Greater phenological sensitivity to temperature on higher Scottish mountains: new insights from remote sensing. AB - Mountain plants are considered among the species most vulnerable to climate change, especially at high latitudes where there is little potential for poleward or uphill dispersal. Satellite monitoring can reveal spatiotemporal variation in vegetation activity, offering a largely unexploited potential for studying responses of montane ecosystems to temperature and predicting phenological shifts driven by climate change. Here, a novel remote-sensing phenology approach is developed that advances existing techniques by considering variation in vegetation activity across the whole year, rather than just focusing on event dates (e.g. start and end of season). Time series of two vegetation indices (VI), normalized difference VI (NDVI) and enhanced VI (EVI) were obtained from the moderate resolution imaging spectroradiometer MODIS satellite for 2786 Scottish mountain summits (600-1344 m elevation) in the years 2000-2011. NDVI and EVI time series were temporally interpolated to derive values on the first day of each month, for comparison with gridded monthly temperatures from the preceding period. These were regressed against temperature in the previous months, elevation and their interaction, showing significant variation in temperature sensitivity between months. Warm years were associated with high NDVI and EVI in spring and summer, whereas there was little effect of temperature in autumn and a negative effect in winter. Elevation was shown to mediate phenological change via a magnification of temperature responses on the highest mountains. Together, these predict that climate change will drive substantial changes in mountain summit phenology, especially by advancing spring growth at high elevations. The phenological plasticity underlying these temperature responses may allow long lived alpine plants to acclimate to warmer temperatures. Conversely, longer growing seasons may facilitate colonization and competitive exclusion by species currently restricted to lower elevations. In either case, these results show previously unreported seasonal and elevational variation in the temperature sensitivity of mountain vegetation activity. PMID- 23661384 TI - Effect of xenogenic cortical bone on fracture healing in a canine fracture model. AB - The purpose of this study was to investigate the effect of xenogenic cortical bone (XCB) on fracture repair in the canine ulna. The entire group of animals (n = 12) had a transverse resection of 5 mm length at the middle part of the right ulnar diaphysis. In Group A (eight beagles), the fracture was treated with XCB and metal bone screw. In Group B (four beagles), the fracture was treated with metal bone plate and screw. Radiological, micro-computed tomography (micro-CT), histological examination and mechanical testing were employed to evaluate bone healing and reaction of XCB in the host bone. In Group A, bone union was noticed in 6 out of 8 dogs (75%), starting from the 4th week onwards. Micro-CT and histological examinations showed that the XCB was absorbed and incorporated into the host bone. Incorporation of XCB was observed in 7 cases (88%); it started from the 10th week onwards and continued to week 32 after surgery. Biomechanical strength of the bone fracture site was higher in Group A than in Group B, and was similar to that of normal bone. XCB enhances the bone healing process and can be used as absorbable internal fixation for the management of long bone fractures in dogs. PMID- 23661385 TI - Penetrating keratoplasty and graft rejection in eight horses. AB - The aim of this study was to describe long-term follow-up and difference in immune reactions in the tear film following penetrating keratoplasty (PK) in horses when differently preserved corneas were utilised. This report describes for the first time the use of corneal grafts preserved in tissue culture media in equine PK. Eight experimental horses with normal eyes were included and freshly harvested, frozen or preserved corneal grafts were used for the PK. The graft taking technique and storage, PK surgery, postoperative treatments and complications are described. The mean postoperative follow-up time was 286 days. Tear film samples taken before and periodically after surgery were measured for IgM, IgG and IgA contents by direct ELISA. All grafts were incorporated into the donor horse but were rejected to some degree. The differently harvested corneal grafts healed in the same manner and looked similar. Preoperatively, the clear corneas meant low risk for graft failure, and the fresh or stored tissues provided intact endothelium, although there were no clear graft sites postoperatively. The presence of IgA, IgG and IgM was demonstrated in the tear film from the early postoperative period. IgG levels were lower than IgA or IgM and had a constant baseline in every case, as IgA and IgM had great variability with time and an individual pattern in each eye. PMID- 23661386 TI - Dose-related genotoxic effect of T-2 toxin measured by comet assay using peripheral blood mononuclear cells of healthy pigs. AB - T-2 toxin is the most acutely toxic trichothecene mycotoxin: it inhibits protein, DNA and RNA synthesis. The main goal of this study was to evaluate the rate of DNA damage caused by T-2 toxin in porcine mononuclear cells in increasing concentrations (0.1, 0.5 and 1.0 MUmol) and after two different incubation periods (24 and 42 h). The lowest concentration caused DNA damage and about 50% of the treated cells could be categorised as having 1 to 4 scores in comet assay. In parallel with the increase of T-2 toxin concentration, the frequency of intact lymphocytes decreased from 50.2% (0.1 MUM) to 36.3% (1.0 MUM) in the first 24 h. In case of score 3, the highest concentration of T-2 toxin resulted in a 5-fold change, as compared to the lowest dose. Cells with score 4 were found only after exposure to 1.0 MUM T-2 toxin. The exposure time did not have a significant effect on the results, while concentration did (P < 0.0001). However, a significant interaction between concentration and time as fixed factors (P < 0.0001) was found. When these were combined as a single factor, the results showed a significant toxin treatment effect on the results. It was concluded that a time- and dose-dependent DNA damaging effect of T-2 toxin could be demonstrated using peripheral blood mononuclear cells from healthy pigs by comet assay. PMID- 23661387 TI - Evaluation of mercury and lead content in the liver of the cormorant (Phalacrocorax carbo sinensis) population of Kis-Balaton, Hungary. AB - Mercury and lead concentrations were measured in the livers of cormorant (Phalacrocorax carbo sinensis), an aquatic bird species living and nesting in the special, highly protected nature conservation area of Kis-Balaton, Hungary. The measurements of metal concentrations were performed by atomic absorption spectrometry using the cold vapour method for mercury and the electrothermal method for lead. Mercury concentrations in the livers were significantly higher in the adult population (4.479 +/- 3.336 mg/kg dry matter, DM) than in the juvenile birds (2.682 +/- 2.087 mg/kg DM), indicating an increase of bioaccumulation with age. A similar pattern was not observed for lead. There were no statistical differences between males and females either in mercury or in lead concentrations. The average levels of mercury (3.580 +/- 2.906 mg/kg DM) and lead (0.746 +/- 0.499 mg/kg DM) were statistically different in the liver. No correlation was found between the concentrations of the two heavy metals. Recently, the wild birds have been chronically exposed to subtoxic amounts of metals which have a tendency to accumulate especially in the soft tissues. PMID- 23661388 TI - Effect of thyme oil on small intestine integrity and antioxidant status, phagocytic activity and gastrointestinal microbiota in rabbits. AB - The effects of 0.5 g thyme oil per kg dry matter (DM) of diet on duodenal tissue integrity, antioxidant status, phagocytic activity and selected microbiota in the caecum and faeces of rabbits were studied. Twenty-four rabbits were divided into two groups and were fed a commercial granulated diet for growing rabbits (CD) with access to water ad libitum. The first group was fed the CD, while to the CD of the second group thyme oil was added. Intestinal integrity was tested by measuring the transepithelial electrical resistance (TEER). Thyme oil significantly increased the value of total antioxidant status (TAS) in the blood plasma and glutathione peroxidase (GPx) activity in the liver, and it decreased malondialdehyde (MDA) concentration in the duodenal tissue. Thyme oil resulted in strengthened intestinal integrity, as the essential oil supplementation significantly increased TEER values in the experiment. The faecal microbiota of rabbits was almost completely balanced in both groups, and only a slight decrease was found in the microbial population at day 42 of the trial. In both groups, the bacterial counts were generally lower in the caecum than in the faecal samples. In conclusion, dietary supplementation with 0.5 g/kg DM thyme oil may improve intestinal integrity, and it may have an antioxidant effect. A tendency was also found for thyme oil to stimulate the abundance of some microbes beneficial in the rabbit gut. PMID- 23661389 TI - Value of semen parameters, with special reference to TNF-alpha, in predicting the quality of boar semen after short-term storage. AB - The aim of this study was to address the question whether changes in boar semen quality after short-term storage could be predicted on the basis of standard semen parameters and TNF-alpha level determined on the day of semen collection under commercial conditions. Progressive motility showed the highest positive correlation with morphology on day 0 of collection, and progressive motility on day 3 (P < 0.05) showed a negative correlation with acrosome abnormalities (P < 0.05). According to the area under receiver operating characteristics (ROC) curves (AUCs), progressive motility could also be used in predicting semen quality after 3 days of storage (AUC > 0.5; P < 0.05). TNF-alpha in seminal plasma is the only parameter measured on day 0 to show a significant correlation with the percentage of viable spermatozoa after 3 days of semen storage (r = 0.495, P < 0.05). ROC analysis shows that TNF-alpha level is helpful in discriminating viability outcome after semen storage (AUC = 0.94, P < 0.001). We can predict with 92.35% certainty that fresh semen samples with more than 150 pg/ml of TNF-alpha in the seminal plasma will retain more than 85% of viable spermatozoa after 3 days of storage. Thus, TNF-alpha can contribute to predicting the quality of short-term stored semen. PMID- 23661390 TI - Effect of the denervation of porcine ovaries on dexamethasone-induced cyst formation. AB - Previously, we have shown that the activity of noradrenergic nerve fibres increased and the steroid content changed in porcine ovaries with dexamethasone (DXM-) induced polycystic status. To better understand the role of the ovarian nerves in the formation of cystic status, the morphology and steroidogenic activity of the ovaries of DXM-treated gilts after denervation of the gonads were investigated in this study. Ovarian denervation was performed on day 3 of the first studied oestrous cycle and then, on days 7-21 of the cycle, DXM was administered. Following neurectomy and DXM treatment, cysts, medium-sized follicles and corpora lutea were not present, while the number of small-sized follicles increased. Denervation and DXM application led to a reduction in the number of dopamine-beta-hydroxylase- and/or neuropeptide Y-immunoreactive nerve fibres. The concentrations of progesterone, androstenedione, testosterone and oestradiol-17beta in the follicular fluid and/or in the wall of small-sized follicles of the experimental gilts were lower than in the controls. A similar result was demonstrated for P450scc, 3beta-HSD and P450arom protein contents in the small follicles. Our data showed that DXM was not able to stimulate the formation of cysts in denervated porcine ovaries, indicating that the ovarian peripheral nerves might participate in the aetiopathogenesis of polycystic status. PMID- 23661391 TI - Transmission of porcine circovirus type 2b (PCV2b) in Kunming mice. AB - To investigate porcine circovirus type 2b (PCV2b) transmission by contact and vertical infection in Kunming mice (an outbred mouse stock deriving from Swiss albino mice with a high ratio of gene heterozygosis), four mice in cage 6 were inoculated with PCV2b and 25 mice without any treatment were placed into cages 1 to 5 (five mice in each cage). Seven days after being infected, the PCV2 binoculated mice were co-mingled with non-inoculated mice from cages 1 to 5 successively at 7, 14, 21, 28 and 35 days post infection (dpi), respectively, for 3 days. In addition, eleven pregnant mice were injected with PCV2b. Samples were collected from non-inoculated mice and three newborn mice from each litter for PCV2b detection by polymerase chain reaction (PCR) and immunohistochemistry (IHC). The PCR results showed that PCV2b transmission rate among mice in cages 1, 2, 3, 4 and 5 was 0/5, 2/5, 5/5, 5/5 and 1/5, respectively. PCV2b antigen signals generally appeared in most organs of the non-inoculated mice in which viruses were detected by PCR. PCV2b DNA was also detected in newborn mice of PCV2b infected litters, and viral antigen signals were observed in their organs as well. PCV2b was transmitted in Kunming mice by contact, and it also caused vertical infection through the placenta. PMID- 23661392 TI - Genetic diversity of acute bee paralysis virus in Slovenian honeybee samples. AB - The genetic diversity of acute bee paralysis virus (ABPV) in honeybees was studied in Slovenia. A total of 248 honeybee samples obtained from 134 different apiaries in Slovenia were tested for the presence of ABPV by RT-PCR. Specific 398 base pair (bp) products were generated with primers amplifying the ORF2 region and 452-base pair (bp) products with primers amplifying the ORF1 region of the viral genome. To characterise the overall nucleotide diversity among the ABPV sequences, phylogenetic trees with 54 and 29 samples were constructed from 357 nucleotides from ORF2 and 408 nucleotides from ORF1, respectively. The nucleotide comparison of Slovenian ABPV strains revealed two distinct clusters in ORF2 and ORF1, showing 91.2-92.5% and 96.7-97.2% nucleotide identity, respectively. Comparison of data regarding the geographical location of the ABPV-positive samples with the constructed phylogenetic trees revealed the random distribution of the two clusters throughout Slovenia. PMID- 23661393 TI - Phylogeny and expression of the nucleocapsid gene of porcine epidemic diarrhoea virus. AB - Porcine epidemic diarrhoea virus (PEDV) is one of the important pathogens that may cause severe diarrhoea in piglets. In this study, the nucleocapsid (N) gene of a Chinese PEDV isolate designated HLJBY was cloned. The phylogeny of PEDV strains was investigated by constructing a phylogenetic tree based on the N protein sequences. The results indicate that there are two major groups of Chinese PEDVs, a Japanese PEDV group and a Korean PEDV group. High-level expression of the N protein was achieved in Escherichia coli. The immunoreactivity between PEDV particles or the bacterially expressed N protein and rabbit anti-PEDV serum was confirmed by immunofluorescence assays and Western blot. Both PEDV N protein and the polyclonal antibody generated in this study are valuable diagnostic reagents for PEDV surveillance. PMID- 23661394 TI - Isolation and molecular characterisation of a pestivirus from goats in Egypt. AB - Nine fetuses and neonates from sheep and goats in Egypt were screened for pestiviruses using immunohistochemistry (IHC), virus isolation, and reverse transcription-polymerase chain reaction (RT-PCR). Two goat kids with typical border disease (BD) were positive for pestivirus infection by immunohistochemistry (IHC) using polyclonal anti-BDV serum but not when four different monoclonal antibodies (MAbs) were used. On inoculation in MDBK cells, a cytopathic bovine viral diarrhoea virus (BVDV) was isolated from one of the two kids. PCR amplification followed by sequencing of the 5'-UTR region confirmed it as BVDV subtype 1b. Although the circulating virus in Egypt is considered to be BVDV 1a, this report confirms the existence of BVDV 1b in addition to BVDV 1a. To our knowledge, this is the first report of isolation of a pestivirus from goats in Egypt and is probably the second report worldwide of a goat kid showing central nervous signs associated with border disease. PMID- 23661395 TI - Effects of bovine viral diarrhoea virus on the fertility of cows. AB - The aim of the present study was to determine the possible relationship between bovine viral diarrhoea (BVD) virus infection and the appearance of cervical mucous discharge (CMD) and the reproductive performance of cows in oestrus. For this purpose, CMD from 97 Holstein cows in oestrus was evaluated visually before artificial insemination (AI). Cows in oestrus were inseminated with frozen semen free from BVD virus (BVDV). Blood samples were tested by enzyme-linked immunoassay (ELISA) for antigen (Ag) and antibodies (Ab) of BVDV. The presence of the BVDV genome in cervical mucus samples was tested by reverse transcriptase polymerase chain reaction (RT-PCR). The presence of BVDV Ab, Ag or genome was not associated with abnormal cervical mucous discharge (A-CMD). However, the presence of BVDV Ag (but not of the BVDV Ab) in blood samples was associated with a lower first service conception rate (FSCR; 27.8 vs. 70.9%; P < 0.01), indicating that BVDV viraemia at the time of AI has a negative effect on the fertility of cows. PMID- 23661396 TI - Rational development of solid dispersions via hot-melt extrusion using screening, material characterization, and numeric simulation tools. AB - Effective and predictive small-scale selection tools are inevitable during the development of a solubility enhanced drug product. For hot-melt extrusion, this selection process can start with a microscale performance evaluation on a hot stage microscope (HSM). A batch size of 400 mg can provide sufficient materials to assess the drug product attributes such as solid-state properties, solubility enhancement, and physical stability as well as process related attributes such as processing temperature in a twin-screw extruder (TSE). Prototype formulations will then be fed into a 5 mm TSE (~1-2 g) to confirm performance from the HSM under additional shear stress. Small stress stability testing might be performed with these samples or a larger batch (20-40 g) made by 9 or 12 mm TSE. Simultaneously, numeric process simulations are performed using process data as well as rheological and thermal properties of the formulations. Further scale up work to 16 and 18 mm TSE confirmed and refined the simulation model. Thus, at the end of the laboratory-scale development, not only the clinical trial supply could be manufactured, but also one can form a sound risk assessment to support further scale up even without decades of process experience. PMID- 23661398 TI - Determination of genetic variation among chickpea genotypes and their F1 crosses with RAPD markers. AB - The intensity of genetic diversity amongst chickpea genotypes and their crosses is unknown. The current study investigated the genetic diversity of chickpea genotypes and their F1 crosses by using random amplified polymorphic DNA (RAPD) markers. We assessed the variation among six chickpea genotypes and 15 F1 crosses with the RAPD markers. The six parents and their 21 hybrids were carefully studied based on the presence or absence of bands. The level of polymorphism varied with different primers. Out 28 primers used, 21 amplified the genomic DNA in all the varieties, 15 generated polymorphic bands among all the varieties, and six produced similar banding patterns. PMID- 23661397 TI - Detection of MGMT, RASSF1A, p15INK4B, and p14ARF promoter methylation in circulating tumor-derived DNA of central nervous system cancer patients. AB - Despite the growing understanding of the mechanisms of carcinogenesis, cancers of the central nervous system are usually associated with unfavorable prognosis. The use of an appropriate molecular marker may improve the treatment outcome by allowing early diagnosis and treatment susceptibility monitoring. Since methylation of tumor-derived DNA can be detected in the serum of cancer patients, this makes DNA methylation-based biomarkers one of the most promising diagnostic strategies. In this study, the methylation profiles of MGMT, RASSF1A, p15INK4B, and p14ARF genes were evaluated in serum free-circulating DNA and the corresponding tumor tissue in a group of 33 primary or metastatic central nervous system cancer patients. Gene promoter methylation was assessed using methylation specific polymerase chain reaction (PCR). All the tested genes were found to be methylated to a different extent in both serum and tumor samples. In comparison to metastatic brain tumor patients, the patients with glial tumors were characterized by a higher frequency of gene hypermethylation. The hypermethylation of RASSF1A differentiated primary from metastatic brain cancers. Moreover, the gene methylation profiles observed in serum, in most cases, matched the methylation profiles detected in paired tumor samples. PMID- 23661400 TI - Lack of association between Cyclin D1 gene G870A polymorphism and esophageal cancer: evidence from a meta-analysis. AB - The association between the Cyclin D1 gene (CCND1) G870A polymorphism and esophageal cancer has been widely evaluated, with conflicting results. As meta analysis is a reliable approach to resolving discrepancies, we aimed to evaluate this association. Data were available from 9 study populations incorporating 1898 cases and 3046 controls. Overall, the allelic/genotypic association between the G870A polymorphism and esophageal cancer was nonsignificant [for allele: odds ratio (OR) = 1.14, 95% confidence interval (95%CI) = 0.94-1.38, P = 0.184; for genotype homozygous comparison: OR = 1.36, 95%CI = 0.90-2.06, P = 0.140; for dominant model: OR = 1.24, 95%CI = 0.88-1.75, P = 0.222; for recessive model: OR = 1.13, 95%CI = 0.90-1.43, P = 0.292]. Moreover, subgroup analyses according to study designs, geographic areas, types of esophageal cancer, genotyping methods, and ethnicities failed to demonstrate a significant association between this polymorphism and esophageal cancer. In addition, there was significant publication bias as reflected by funnel plots and the Egger test (P = 0.042). Taken together, our results suggest that the CCND1 G870A polymorphism might not be a potential candidate for predicting esophageal cancer risk. PMID- 23661399 TI - Age-dependent expression of the BPI gene in Sutai piglets. AB - We compared and analyzed the expression of the BPI gene of Sutai piglets ranging from newborn to post-weaning days 8, 18, 30, and 35 by the real-time PCR method, in order to determine if it is involved in protection against disease caused by ETEC F18. There was a significant difference between 18 and 35-day expression in the jejunum. There were also significant differences between 35-day expression and expression at the other development stages in the duodenum. There were no significant differences in expression at 8, 18, and 30 days in the jejunum. We conclude that the porcine BPI gene may be the direct factor that resisted the ETEC F18 in weaning piglets, and that the resistance to ETEC F18 in weaning piglets is related to up-regulation of mRNA expression of BPI gene to a certain extent. PMID- 23661401 TI - Genetic diversity of the endangered scaly-sided merganser (Mergus squamatus) in the wintering habitat of central-southern China. AB - The scaly-sided merganser (Mergus squamatus), found in temperate East Asia, has been reduced to a very small population. Central and southern China are its main wintering habitat. However, populations have declined greatly since the 1980s due to habitat loss and degradation, and poaching. To meet the urgent need for up-to date conservation information, we examined RAPD DNA markers from 156 specimens in 6 populations in Jiangxi Province. We found that genetic diversity (based on individual similarities) is in fact low; molecular variance between populations ranged from 0.137 to 0.347. Genetic similarity ranged from 0.683 to 0.866. In conclusion, the geographical pattern of genetic diversity supports the long-term refugial status of the scaly-sided merganser in central-southern China; strong conservation measures should be taken to maintain the merganser in this region. PMID- 23661402 TI - Stereoselective accumulation of propranolol enantiomers in K562 and K562/ADR cells. AB - The stereoselective uptake of propranolol enantiomers was investigated by using the K562 and K562 adriamycin-resistant cell line (K562/ADR) as a model. An enantioselective RP-HPLC method was applied to determine the accumulation of propranolol (PPL) stereoisomers in K562 and K562/ADR cells. The concentration, time and temperature dependent studies showed that the accumulation of S-(-)-PPL was higher than R-(+)-PPL in K562 cells and uptake of R-(+)-PPL was significantly higher than that of S-(-)-PPL in K562/ADR cells. The results indicate the enantioselective accumulation of propranolol enantiomers in K562 and K562 / ADR cells. PMID- 23661403 TI - Perioperative increase in global blood flow to explicit defined goals and outcomes after surgery: a Cochrane Systematic Review. AB - This systematic review and meta-analysis summarizes the clinical effects of increasing perioperative blood flow using fluids with or without inotropes/vasoactive drugs to explicit defined goals in adults. We included randomized controlled trials of adult patients (aged 16 years or older) undergoing surgery. We included 31 studies of 5292 participants. There was no difference in mortality at the longest follow-up: 282/2615 (10.8%) died in the control group and 238/2677 (8.9%) in the treatment group, RR of 0.89 (95% CI: 0.76-1.05; P=0.18). However, the results were sensitive to analytical methods and withdrawal of studies with methodological limitations. The intervention reduced the rate of three morbidities (renal failure, respiratory failure, and wound infections) but not the rates of arrhythmia, myocardial infarction, congestive cardiac failure, venous thrombosis, and other types of infections. The number of patients with complications was also reduced by the intervention. Hospital length of stay was reduced in the treatment group by 1.16 days. There was no difference in critical care length of stay. The primary analysis of this review showed no difference between groups but this result was sensitive to the method of analysis, withdrawal of studies with methodological limitations, and was dominated by a single large study. Patients receiving this intervention stayed in hospital 1 day less with fewer complications. It is unlikely that the intervention causes harm. The balance of current evidence does not support widespread implementation of this approach to reduce mortality but does suggest that complications and duration of hospital stay are reduced. PMID- 23661404 TI - Propofol for adult procedural sedation in a UK emergency department: safety profile in 1008 cases. AB - BACKGROUND: Concerns exist regarding the safe use of propofol by Emergency Physicians for procedural sedation. The World SIVA International Sedation Task Force has recently created an adverse event tool, in an effort to standardize reporting. We present a safety analysis of our use of propofol using this tool. METHOD: Propofol was given according to a previously published guideline. We analysed our dedicated departmental sedation database between December 2006 and March 2012 and cross-examined the original sedation chart for each case recorded. We stratified the identified adverse events according to consensus agreement. RESULTS: Of the 1008 consecutive cases, we identified 11 sentinel (5 cases of hypoxia, 6 of hypotension), 34 moderate, 25 minor, and 3 minimal risk adverse events. There were no adverse outcomes. CONCLUSIONS: Our large series of propofol sedations performed by emergency physicians supports the safety of this practice. The sentinel adverse event rate of 1% that we identify prompts review: we will in future emphasize adherence to the reduced 0.5 mg kg(-1) propofol dose in the elderly, and reconsider our use of metaraminol. We believe that our application of the World SIVA adverse event tool sets a benchmark for further studies. PMID- 23661405 TI - Dynamic output and control of the hypothalamic-pituitary-adrenal axis in critical illness and major surgery. AB - The hypothalamic-pituitary-adrenal (HPA) axis is a neuro-endocrine system that regulates circulating levels of glucocorticoid hormones. These hormones are vital for normal homeostasis and play a pivotal role in the response to stress. Levels of cortisol fluctuate throughout the day in a diurnal rhythm, underlying which is an ultradian rhythm of approximately hourly pulses, and this pulsatility directly affects transcriptional outcomes. Pulsatility is not the result of a 'pulse generator', but is inherent within the system as a result of negative feedback. These patterns of secretion change in both acute and chronic illness as a result of inflammatory mediators, splanchnic nerve output, and central nervous system control. Levels of cortisol in both normal and illness states are highly dynamic and so previously used static assessment tools for diagnosing corticosteroid related critical illness insufficiency (CRCI) are not likely to be useful. Therapeutic regimens have also failed so far, to take secretory patterns into account. In this review we look at the dynamic control and effects of glucocorticoids and frame in this context the current evidence surrounding steroid use in critical care and major surgery. PMID- 23661406 TI - Antifibrinolytic agents in current anaesthetic practice. AB - Antifibrinolytic drugs have become almost ubiquitous in their use during major surgery when bleeding is expected or commonplace. Inhibition of the fibrinolytic pathway after tissue injury has been consistently shown to reduce postoperative or traumatic bleeding. There is also some evidence for a reduction of perioperative blood transfusion. However, evidence of complications associated with exaggerated thrombosis also exists, although this appears to be influenced by the choice of the individual agent and the dose administered. There is controversy over the use of the serine protease inhibitor aprotinin, whose license was recently withdrawn but may shortly become available on the market again. In the UK, tranexamic acid, a tissue plasminogen and plasmin inhibitor, is most commonly used, with evidence for benefit in cardiac, orthopaedic, urological, gynaecological, and obstetric surgery. In the USA, epsilon aminocaproic acid, which also inhibits plasmin, is commonly used. We have reviewed the current literature for this increasingly popular class of drugs to support clinical judgement in daily anaesthetic practice. PMID- 23661407 TI - An approach to neuraxial anaesthesia for the severely scoliotic spine. AB - We report on a case in which computed tomography was used to guide placement of an epidural catheter in a patient with severe scoliosis and congenital dwarfism. In addition, the computed tomograms were corroborated with ultrasound and fluoroscopic images in the patient. Three years later, the patient had a spinal anaesthetic performed with only the use of ultrasound-guidance. Ease of placement of the epidural and spinal was greatly enhanced by imaging. We present an algorithmic approach to neuraxial anaesthesia in the patient with scoliosis to help guide placement. The algorithm first directs the provider to determine the type and severity of the scoliosis from the patient's history, physical examination, and any prior radiologic studies. If the anaesthesia provider understands and is comfortable with the patient's anatomy, then the provider may cautiously proceed with placement. Depending upon the degree of lateral curvature (Cobb angle), idiopathic scoliosis is classified as mild (11-25 degrees ), moderate (25-50 degrees ), or severe (>50 degrees ). Mild idiopathic scoliosis is managed with good positioning. Moderate idiopathic scoliosis is managed with a paramedian approach on the convex-side of the curve or a midline approach with angulation towards the convex-side or with the aid of imaging such as ultrasound. Severe idiopathic scoliosis is managed with the assistance of imaging or an alternative form of pain management should be considered. A systematic approach may facilitate safe, efficient, and successful neuraxial anaesthesia procedures in the scoliotic patient. PMID- 23661408 TI - Poly(2-vinylpyridine)-block -Poly(epsilon-caprolactone) single crystals in micellar solution. AB - Self-assembly of poly(2-vinylpyridine)-block-poly(epsilon-caprolactone) (P2VP-b PCL) diblock copolymer in the presence of a selective solvent is investigated by transmission electron microscopy and atomic force microscopy. Addition of water into a P2VP-b-PCL solution in N,N-dimethylformamide at 20 degrees C produces elongated truncated lozenge shaped single crystals of uniform size and shape in large quantities. The single crystals are composed of PCL single-crystal layer sandwiched between two P2VP layers tethered on the top and bottom basal surfaces. The formation of the single crystals is found to depend on the temperature. These findings provide a facile approach to the preparation of uniform single crystals in large quantities. PMID- 23661409 TI - Influences of Sr dose on the crystal structure parameters and Sr distributions of Sr-incorporated hydroxyapatite. AB - Stoichiometric strontium-incorporated hydroxyapatite (Sr-HA) with different Sr concentrations [Sr/(Sr+Ca)] were synthesized using a wet chemical approach and characterized by X-ray diffraction, Fourier-transformed infrared absorption, X ray photoelectron spectroscopy, and Rietveld Structure Refinement. The crystal lattice parameter, Sr distribution, chemical state of Sr, and also the relationships between their variations and the Sr concentrations have been intensively studied. The results show that both the crystal lattice parameters and crystal plane space of Sr-HA remarkably increase with the Sr concentration increasing. Whether Sr preferably occupies the Ca(I) site or Ca(II) site after incorporated into apatite lattice depends on the Sr number incorporated into apatite. All the Sr ions completely occupy the Ca(II) sites when the Sr concentration is below 5%. With the exception of partial Sr ions occupying the Ca(II) sites, the other Sr ions start to occupy the Ca(I) sites when the Sr concentration doped in HA is beyond 10%. The ratio of Sr ions occupying the Ca(I) sites increases with the further raising Sr concentration up to 20%. The Sr ions inherit the chemical state and environment of the original Ca(I) or Ca(II) site after incorporated into apatite. PMID- 23661410 TI - Effects of tilted orientations and face-like configurations on visual search asymmetry in macaques. AB - Visual search asymmetry has been used as an important tool for exploring cognitive mechanisms in humans. Here, we examined visual search asymmetry in two macaques toward two types of stimulus: the orientation of line stimuli and face like stimuli. In the experiment, the monkeys were required to detect an odd target among numerous uniform distracters. The monkeys detected a tilted-lines target among horizontal- or vertical-lined distracters significantly faster than a horizontal- or vertical-lined target among tilted-lined distracters, regardless of the display size. However, unlike the situation in which inverted-face stimuli were introduced as distracters, this effect was diminished if upright-face stimuli were used as distracters. Additionally, monkeys detected an upright-face target among inverted-face distracters significantly faster than an inverted-face target among upright-face distracters, regardless of the display size. These results demonstrate that macaques can search a target efficiently to detect both tilted lines among non-tilted lines and upright faces among inverted faces. This clarifies that there are several types of visual search asymmetry in macaques. PMID- 23661412 TI - Photothermally activated hybrid films for quantitative confined release of chemical species. AB - Illuminating films of a porous chitosan matrix containing gold nanorods and thermosensitive micelles loaded with a chemical stimulates local photothermal conversion of the gold nanorods. The heat produced activates the ejection of the chemical from the micelles (see scheme), and causes the transient permeabilization of adjacent cell membranes, resulting in a selective cellular uptake of the released chemical with control over spatiotemporal parameters and dosage. PMID- 23661411 TI - Assessing bioavailability of DDT and metabolites in marine sediments using solid phase microextraction with performance reference compounds. AB - Solid-phase microextraction (SPME) has often been used to estimate the freely dissolved concentration (Cfree ) of organic contaminants in sediments. A significant limitation in the application of SPME for Cfree measurement is the requirement for attaining equilibrium partition, which is often difficult for strongly hydrophobic compounds such as DDT. A method was developed using SPME with stable isotope-labeled analogues as performance reference compounds (PRCs) to measure Cfree of DDT and metabolites (DDTs) in marine sediments. Six (13) C labeled or deuterated PRCs were impregnated into polydimethylsiloxane (PDMS) fiber before use. Desorption of PRCs from PDMS fibers and absorption of DDTs from sediment were isotropic in a range of sediments evaluated ex situ under well mixed conditions. When applied to a historically contaminated marine sediment from a Superfund site, the PRC-SPME method yielded Cfree values identical to those found by using a conventional equilibrium SPME approach (Eq-SPME), whereas the time for mixing was reduced from 9 d to only 9 h. The PRC-SPME method was further evaluated against bioaccumulation of DDTs by Neanthes arenaceodentata in the contaminated sediment with or without amendment of activated carbon or sand. Strong correlations were consistently found between the derived equilibrium concentrations on the fiber and lipid-normalized tissue residues for DDTs in the worms. Results from the present study clearly demonstrated the feasibility of coupling PRCs with SPME sampling to greatly shorten sampling time, thus affording much improved flexibility in the use of SPME for bioavailability evaluation. PMID- 23661413 TI - Array of community health education and promotion intervention. PMID- 23661414 TI - Community capacity as means to improved health practices and an end in itself: evidence from a multi-stage study. AB - This three-phase study characterized, validated, and applied community capacity domains in a health communication project evaluation in Zambia. Phase I explored community capacity domains from community members' perspectives (16 focus groups, 14 in-depth interviews, 4 sites. These were validated in Phase II with 720 randomly selected adults. The validated domains were incorporated into a program evaluation survey (2,462 adult women, 2,354 adult men; October 2009). The results indicated that the intervention had direct effects on community capacity; enhanced capacity was then associated with having taken community action for health. Finally, community capacity mediated by community action and controlling for confounders, had a significant effect on women's contraceptive use, children's bed net use, and HIV testing. The results indicate that building community capacity served as a means to an end-improved health behaviors and reported collective action for health-and an end-in-itself, both of which are essential to overall wellbeing. PMID- 23661415 TI - School-based HIV prevention in Dakar, Senegal: findings from a peer-led program. AB - This evaluation study examines the effectiveness of a peer-led technology-focused HIV prevention program targeting in-school youth in Dakar, Senegal. A quasi experimental design was used to examine differences in knowledge, attitudes, and behavioral intentions related to HIV testing among students at three intervention schools and a comparison school. Findings at the school level vary; however, results suggest that students exposed to intervention activities had a 1.5 greater odds of intending to get HIV tested compared with students not exposed to the program. As access to and use of digital technologies continue to increase throughout parts of sub-Saharan Africa, programs will continue to leverage this medium to diffuse effective health education and promotion messages for intervention. PMID- 23661416 TI - Out-of-pocket expenses for maternity care in rural Bangladesh: a public-private comparison. AB - Out-of-pocket expenses incurred by women for availing maternal healthcare services at public and private health facilities in Bangladesh were examined using a baseline household survey evaluating the impact of demand side financing vouchers on utilization and service delivery for maternal healthcare. The survey was conducted in 2010 among 3,300 women who gave birth in the previous 12 months from the start of data collection. Information on costs incurred to receive antenatal, delivery, and postnatal care services was collected. Findings reveal that the majority of women reported paying out-of-pocket expenses for availing maternal healthcare services both at public and private health facilities. Out-of pocket expenses include registration, consultation, laboratory examination, medicine, transportation, and other associated costs incurred for receiving maternal healthcare services. On average, women paid US$3.60 out-of-pocket expenses for receiving antenatal care at public health facilities and US$12.40 at private health facilities. Similarly, women paid one and half times more for normal (US$42.30) and cesarean deliveries (US$136.20) at private health facilities compared to public health facilities. On the other hand, costs for postnatal care services did not vary significantly between public and private health facilities. Utilization of maternal healthcare services can be improved if out-of-pocket expenses can be minimized. At the same time, effective demand generation strategies are necessary to encourage women to utilize health facilities. PMID- 23661417 TI - Intention to continue with ivermectin treatment for onchocerciasis control after eight years of annual distribution in Cameroon, Nigeria, and Uganda. AB - This study identified the socio-demographic correlates of intention to comply with ivermectin treatment, from a structured interview of 2,306 persons aged 10 years and above, grouped into high and low compliers, who took ivermectin 6-8 times and 0-2 times respectively. Simple descriptive statistics were employed in characterizing the respondents into high and low compliers, while some socio demographic and key perceptual factors were employed in regression models constructed to explain levels of compliance among the respondents. Demographic and perceptual factors associated with intention to comply with prolonged treatment with ivermectin were identified. Intention to comply was higher among married persons (91.8%, p < 0.001); local populations (89.8%, p < 0.001); and those with history of complying with treatment (98.2%, p < 0.001). Perception of onchocerciasis and effectiveness of ivermectin influenced intention to continue. The perceptual factors that drive the intention to comply should inform plans for health education at the project and village levels. PMID- 23661418 TI - Using the health belief model in qualitative focus groups to identify HPV vaccine acceptability in college men. AB - This study determines predictors of HPV vaccine acceptability among college-aged male students through the qualitative data collection strategy of focus groups. Over the course of 2 months, six focus groups were conducted with 50 participants, with approximately 10 participants in each focus group. Participants were predominately single, heterosexual, about 20 years old, Caucasian males attending a large Midwestern University. The Health Belief Model (HBM) was used as a guide in developing questions for the focus groups. Each question related to a construct of the HBM. A lack of perceived susceptibility, perceived severity of HPV, and barriers toward taking the HPV vaccine were major themes identified from the focus groups. Overall, the focus group proved to be effective in understanding predictors toward HPV vaccine acceptability. Results enabled the researchers to develop an understanding of content needed for effective interventions. This study indicates a need for more qualitative studies exploring attitudes, beliefs, and behaviors related to HPV vaccine acceptability among at-risk populations. PMID- 23661419 TI - Empowering clients through e-Health in healthcare services: case Brunei. AB - The adoption of Web 2.0 in many business sectors is increasing because it offers the ability for customers to have a greater control in generating contents to their personalized web. Customers are empowered in the sense of controlling the process of interaction(s) between a firm with its customers, and among customers themselves. However, providing empowerment in any state of interaction levels to customers (patients) in a healthcare organization is challenging. Many healthcare organizations have adopted empowerment in their e-health scenario; therefore, it needs a mechanism to measure at which level they have implemented empowerment within their organizations. This article proposes three layers of customers' empowerment in e-health systems based on a reference model called Personal Health Cycle (PHC). The layers of empowerment are personal, social, and medical layers respectively. The modular approach is used to simplify healthcare organizations identifying which modules to be adopted in implementing a strategy for customers' empowerment. The model is derived based on recent studies of empowerment in healthcare organizations. A survey also has been conducted in Brunei Darussalam (Brunei) to verify and improve our initial model and to understand the responses of people regarding empowerment in the e-health services. Questions for the survey are derived from the features of the PHC. The respondents reacted positively to the features of empowerment proposed. We use PHC to define and distinguish electronic health record (EHR) from electronic medical record (EMR). PMID- 23661422 TI - Autogenous peritoneo-fascial graft: a versatile and inexpensive technique for repair of inferior vena cava. PMID- 23661421 TI - Dysregulating IRES-dependent translation contributes to overexpression of oncogenic Aurora A Kinase. AB - Overexpression of the oncoprotein Aurora A kinase occurs in multiple types of cancer, often early during cell transformation. To identify the mechanism(s) contributing to enhanced Aurora A protein expression, a comparison between normal human lung fibroblast and breast epithelial cells to nontumorigenic breast (MCF10A and MCF12A) and tumorigenic breast (MCF-7) and cervical cell lines (HeLa S3) was performed. A subset of these immortalized lines (MCF10A, MCF12A, and HeLa S3) exhibited increased levels of Aurora A protein, independent of tumorigenicity. The increase in Aurora A protein in these immortalized cells was not due to increased transcription/RNA stability, protein half-life, or cap dependent translation. Assays utilizing monocistronic and dicistronic RNA constructs revealed that the 5'-leader sequence of Aurora A contains an internal ribosomal entry site (IRES), which is regulated in a cell cycle-dependent manner, peaking in G2/M phase. Moreover, IRES activity was increased in the immortalized cell lines in which Aurora A protein expression was also enhanced. Additional studies indicated that the increased internal initiation is specific to the IRES of Aurora A and may be an early event during cancer progression. These results identify a novel mechanism contributing to Aurora A kinase overexpression. IMPLICATIONS: The current study indicates that Aurora A kinase contributes to immortalization and tumorigenesis. PMID- 23661423 TI - A new matrix assisted ionization method for the analysis of volatile and nonvolatile compounds by atmospheric probe mass spectrometry. AB - Matrix assisted ionization of nonvolatile compounds is shown not to be limited to vacuum conditions and does not require a laser. Simply placing a solution of analyte dissolved with a suitable matrix such as 3-nitrobenzonitrile (3-NBN) or 2,5-dihydroxyacetophenone on a melting point tube and gently heating the dried sample near the ion entrance aperture of a mass spectrometer using a flow of gas produces abundant ions of peptides, small proteins, drugs, and polar lipids. Fundamental studies point to matrix-mediated ionization occurring prior to the entrance aperture of the mass spectrometer. The method is analytically useful, producing peptide mass fingerprints of bovine serum albumin tryptic digest consuming sub-picomoles of sample. Application of 100 fmol of angiotensin I in 3 NBN matrix produces the doubly and triply protonated molecular ions as the most abundant peaks in the mass spectrum. No carryover is observed for samples containing up to 100 pmol of this peptide. A commercial atmospheric samples analysis probe provides a simple method for sample introduction to an atmospheric pressure ion source for analysis of volatile and nonvolatile compounds without using the corona discharge but using sample preparation similar to matrix assisted laser desorption/ionization. PMID- 23661424 TI - Estimation of activation energy from the survival yields: fragmentation study of leucine enkephalin and polyethers by tandem mass spectrometry. AB - A simple collision model for multiple collisions occurring in quadrupole type mass spectrometers was derived and tested with leucine enkaphalin a common mass spectrometric standard with well-characterized properties. Implementation of the collision model and Rice-Ramsperger-Kassel-Marcus (RRKM) algorithm into a spreadsheet software allowed a good fitting of the calculated data to the experimental survival yield (SY) versus collision energy curve. In addition, fitting also ensured to estimate the efficiencies of the kinetic to internal energy conversion for Leucine enkephalin in quadrupole-time-of-flight and triple quadrupole instruments. It was observed that the experimental SY versus collision energy curves for the leucine enkephalin can be described by the Rice-Ramsperger Kassel (RRK) formalism by reducing the total degrees of freedom (DOF) to about one-fifth. Furthermore, this collision model with the RRK formalism was used to estimate the critical energy (E(o)) of lithiated polyethers, including polyethylene glycol (PEG), polypropylene glycol (PPG), and polytetrahydrofurane (PTHF) with degrees of freedom similar to that of leucine enkephalin. Applying polyethers with similar DOF provided the elimination of the effect of DOF on the unimolecular reaction rate constant. The estimated value of E(o) for PEG showed a relatively good agreement with the value calculated by high-level quantum chemical calculations reported in the literature. Interestingly, it was also found that the E(o) values for the studied polyethers were similar. PMID- 23661425 TI - Laser beam filtration for high spatial resolution MALDI imaging mass spectrometry. AB - We describe an easy and inexpensive way to provide a highly defined Gaussian shaped laser spot on target of 5 MUm diameter for imaging mass spectrometry using a commercial MALDI TOF instrument that is designed to produce a 20 MUm diameter laser beam on target at its lowest setting. A 25 MUm pinhole filter on a swivel arm was installed in the laser beam optics outside the vacuum ion source chamber so it is easily flipped into or out of the beam as desired by the operator. The resulting ion images at 5 MUm spatial resolution are sharp since the satellite secondary laser beam maxima have been removed by the filter. Ion images are shown to demonstrate the performance and are compared with the method of oversampling to achieve higher spatial resolution when only a larger laser beam spot on target is available. PMID- 23661426 TI - A case of certolizumab-induced interstitial lung disease in a patient with rheumatoid arthritis. PMID- 23661427 TI - Systemic sclerosis sine scleroderma: distinct features in a large Brazilian cohort. AB - OBJECTIVE: Systemic sclerosis sine scleroderma (ssSSc) is an infrequent SSc variant characterized by visceral and immunological manifestations of SSc in the absence of clinically detectable skin involvement. We sought to delineate the characteristics of ssSSc in a cohort of Brazilian patients and contrast them with those in the literature. METHODS: SSc patients seen at two academic medical centres in Brazil were retrospectively analysed. Patients were classified as ssSSc if they presented with RP, positive ANAs and at least one visceral involvement typical of SSc in the absence of skin thickening. Demographics, clinical and laboratory data were obtained by chart review. Literature review was performed by searching available original studies up until June 2012. RESULTS: Among the 947 consecutive patients with SSc, 79 (8.3%) were classified as ssSSc. Oesophagus was the most frequently affected organ (83.1%), followed by pulmonary involvement (63.2%). Compared with the limited cutaneous form of SSc, telangiectasia was the only variable significantly different after multivariate logistic regression analyses (odds ratio 0.46; 95% CI 0.27, 0.81). Compared with the diffuse cutaneous form of SSc, multivariate analyses revealed that ssSSc patients were less likely to be male (odds ratio 0.15; 95% CI 0.04, 0.57), have digital ulcers (odds ratio 0.26; 95% CI 0.13, 0.51) or anti-Scl70 antibodies (odds ratio 0.19; 95% CI 0.07, 0.55) and less frequently treated with CYC (odds ratio 0.23; 95% CI 0.12, 0.43). These features were comparable to those in the published literature. CONCLUSION: In this series, patients with ssSSc had a relatively mild disease with good prognosis. PMID- 23661428 TI - Necrotizing vasculitis secondary to disseminated histoplasmosis simulating pyoderma gangrenosum. PMID- 23661429 TI - Tactile acuity is disrupted in osteoarthritis but is unrelated to disruptions in motor imagery performance. AB - OBJECTIVE: To determine whether tactile acuity is disrupted in people with knee OA and to determine whether tactile acuity, a clinical signature of primary sensory cortex representation, is related to motor imagery performance (MIP; evaluates working body schema) and pain. METHODS: Experiment 1: two-point discrimination (TPD) threshold at the knee was compared between 20 participants with painful knee OA, 20 participants with arm pain and 20 healthy controls. Experiment 2: TPD threshold, MIP (left/right judgements of body parts) and usual pain were assessed in 20 people with painful knee OA, 17 people with back pain and 38 healthy controls (20 knee TPD; 18 back TPD). RESULTS: People with painful knee OA had larger TPD thresholds than those with arm pain and healthy controls (P < 0.05). TPD and MIP were not related in people with knee OA (P = 0.88) but were related in people with back pain and in healthy controls (P < 0.001). Pain did not relate to TPD threshold or to MIP (P > 0.15 for all). CONCLUSION: In painful knee OA, tactile acuity at the knee is decreased, implying disrupted representation of the knee in primary sensory cortex. That TPD and MIP were unrelated in knee OA, but related in back pain, suggests that the relationship between them may vary between chronic pain conditions. That pain was not related to TPD threshold nor MIP suggests against the idea that disrupted cortical representations contribute to the pain of either condition. PMID- 23661431 TI - Polypeptoids by living ring-opening polymerization of N-substituted N carboxyanhydrides from solid supports. AB - The nucleophilic living ring-opening polymerization of N-substituted glycine N carboxyanhydrides using solid-phase synthesis resins is reported. By variation of experimental parameters, products with near Poisson distributions are obtained. As opposed to reversible deactivation radical polymerization, the living polymerization is demonstrated to be viable to high monomer conversion and through multiple monomer addition steps. Successful preparation of a multiblock copolypeptoid is proof for a highly living and robust character of the solid phase peptoid polymerization. PMID- 23661432 TI - Isolation and analysis of alpha-expansin genes in the tree Anthocephalus chinensis (Rubiaceae). AB - Expansins are cell wall-associated proteins that induce wall extension and relax stress by disrupting noncovalent bonds between cellulose microfibrils and cross linking glycan chains, thereby promoting wall creep. Anthocephalus chinensis is a very fast-growing economically important tree found mainly in South Asia. Sixteen cDNAs, designated AcEXPA1 to AcEXPA16 (GenBank accession Nos. FJ417847, JF922686 JF922700) with corresponding genomic DNA sequences (GenBank accession Nos. GQ228823, JF922701-JF922715), were isolated by amplifying conserved domain binding with genomic walking and RACE techniques from four differential growth tissues in A. chinensis. These alpha-expansin homologues were highly conserved in size and sequence; they had the same sequence structures as an N-terminal signal peptide, three exons and two introns. Their amino acid alignment showed that A. chinensis expansin genes are divided into three subgroups: A, B and C. This study is the first report on expansin genes from A. chinensis. It will be used for a tissue-specific expression model and for studying the relationship between expansin genes, growth rate and wood quality of the xylem in this fast-growing tree. PMID- 23661430 TI - Putative tumor suppressor gene SEL1L was downregulated by aberrantly upregulated hsa-mir-155 in human pancreatic ductal adenocarcinoma. AB - Sel-1-like (SEL1L) is a putative tumor suppressor gene that is significantly downregulated in human pancreatic ductal adenocarcinoma (PDA). The mechanism of the downregulation is unclear. Here, we investigated whether aberrantly upregulated microRNAs (miRNAs) repressed the expression of SEL1L. From reported miRNA microarray studies on PDA and predicted miRNA targets, we identified seven aberrantly upregulated miRNAs that potentially target SEL1L. We assessed the expression levels of SEL1L mRNA and the seven miRNAs in human PDA tumors and normal adjacent tissues using real-time quantitative polymerase chain reaction. Then statistical methods were applied to evaluate the association between SEL1L mRNA and the miRNAs. Furthermore, the interaction was explored by functional analysis, including luciferase assay and transient miRNA overexpression. SEL1L mRNA expression levels were found to correlate inversely with the expression of hsa-mir-143, hsa-mir-155, and hsa-mir-223 (P < 0.0001, P < 0.0001, and P = 0.002, respectively). As the number of these overexpressed miRNAs increased, SEL1L mRNA expression progressively decreased (Ptrend = 0.001). Functional analysis revealed that hsa-mir-155 acted as a suppressor of SEL1L in PDA cell lines. Our study combined statistical analysis with biological approaches to determine the relationships between several miRNAs and the SEL1L gene. The finding that the expression of the putative tumor suppressor SEL1L is repressed by upregulation of hsa-mir-155 helps to elucidate the mechanism for SEL1L downregulation in some human PDA cases. Our results suggest a role for specific miRNAs in the pathogenesis of PDA and indicate that miRNAs have potential as therapeutic targets for PDA. PMID- 23661433 TI - Inheritance of resistance to Pepper yellow mosaic virus in Capsicum baccatum var. pendulum. AB - We investigated inheritance of resistance to Pepper yellow mosaic virus (PepYMV) in Capsicum baccatum var. pendulum accessions UENF 1616 (susceptible) crossed with UENF 1732 (resistant). Plants from generations P1, P2, F1, F2, BC1:1, and BC1:2 were inoculated and the symptoms were evaluated for 25 days. Subsequently, an area under the disease progress curve was calculated and subjected to generation means analysis. Only the average and epistatic effects were significant. The broad and narrow sense heritability estimates were 35.52 and 21.79%, respectively. The estimate of the minimum number of genes that control resistance was 7, indicating that resistance is polygenic and complex. Thus, methods to produce segregant populations that advocate selection in more advanced generations would be the most appropriate to produce chili pepper cultivars resistant to PepYMV. PMID- 23661434 TI - Genetic variability in Blanco Orejinegro breed cattle populations in Colombia. AB - We analyzed population structure and genetic diversity in Blanco Orejinegro Creole cattle with 12 microsatellite markers, genotyping 138 individuals belonging to 7 commercial and 3 conservation herds. These markers showed a high level of polymorphism; 171 alleles were identified. The mean number of alleles per locus was 5.63 (3.82-6.58). The total number of alleles per marker was 14.2 and ranged from 16 (TGLA126) to 22 (TGLA227). The mean expected heterozygosity (0.73) was higher than the observed heterozygosity (0.65), with a significant excess of heterozygosity in almost all populations (FIS = 0.09; P < 0.05). This may be due to crossing between different lines of this breed, affecting the inbreeding levels. Analysis of relationships among populations, assessed by principal component analysis and Nei's genetic distances, indicated a close relationship between some herds. Furthermore, analysis of population structure demonstrated a low probability of admixture with Zebu breeds, as it shows the cluster assignment and the FST values obtained. We conclude that there is high allelic diversity in this breed, even though a low effective population size has been maintained and the level of inbreeding has not been monitored. Therefore, appropriate conservation efforts should be undertaken, such as adopting strategies aimed at minimizing inbreeding, to avoid losing genetic variability. PMID- 23661435 TI - Complete mitochondrial genome sequence of the humphead wrasse, Cheilinus undulatus. AB - The humphead wrasse (Cheilinus undulatus) is a large coral fish that has become threatened due to habitat loss and fishing pressure. We sequenced the mitochondrial genome of C. undulatus, using a normal PCR method. The complete mtDNA sequence encoded 13 protein genes, 22 tRNA genes and 2 rRNA genes. It was found to be 16,613 bp in length and had an overall H-strand base compositions of 27.3 for A, 30.9 for C, 16.8 for G, and 25.0% for T. Compared with the sequences of 8 other members of the family Labridae, gene content, genome organization, and nucleotide compositions were similar. All tRNAs formed a typical clover-leaf structure, except tRNA(Ser) (AGY), and most of the size variations among tRNAs stemmed from variations of length in the arm and loop of TPsi, and loop of DHU. PMID- 23661436 TI - S-adenosylmethionine, a methyl donor, up regulates tissue inhibitor of metalloproteinase-2 in colorectal cancer. AB - DNA methylation is a fundamental epigenetic mechanism in regulating the expression of genes controlling crucial cell functions in cancer development. Gene silencing via CpG island methylation/demethylation in the promoter region is one of the mechanisms by which different genes are inactivated/activated in human cancers. Tissue inhibitor of metalloproteinase-2 (TIMP-2) is known to antagonize matrix metalloproteinase (MMP) activity and to suppress tumor growth, angiogenesis, invasion, and metastasis. TIMP-2 expression has been found to be both upregulated and downregulated in various cancers. The inconsistent TIMP-2 expression and unclear epigenetic regulation lead us to investigate its role in colorectal cancer in the presence of a methylating agent. Highly invasive human colorectal cells SW-620 were treated with the methyl donor S-adenosylmethionine (SAM) and its effect was evaluated by cell proliferation, cell cycle, invasion and migration assay. The ability of SAM to down regulate a panel of activated prometastatic, angiogenesis and growth- and cell cycle-regulatory genes was evaluated using end-point and real-time PCR. Treatment of SW-620 with SAM diminished cell proliferation and altered cell cycle kinetic G2/M phase cell cycle arrest. An in vitro matrigel invasion assay of SAM-treated cells showed a significant reduction in the invasive potential compared to untreated SW-620 cells. Treatment of SW-620 cells with SAM resulted in activation of TIMP-2 and inhibition of the expression of genes such as MMP (MMP-2, MT1-MMP), urokinase plasminogen activator, and vascular endothelial growth factors. The level of expression of tumor suppressor and apoptotic genes was not significantly higher compared to the untreated control. No changes in the levels of expression of genes (growth and cell cycle regulator), such as TGF-beta, Smad2, Smad4, and p21 were observed. Our data support the hypothesis that TIMP-2, along with other prometastatic genes, is hypomethylated and expressed differently in colorectal cancer. Further in-depth analysis is warranted to confirm the promoter region CpG methylation pattern of the TIMP-2 gene. PMID- 23661437 TI - Genetic diversity analysis of the Uruguayan Creole cattle breed using microsatellites and mtDNA markers. AB - The Uruguayan Creole cattle population (N = 600) is located in a native habitat in south-east Uruguay. We analyzed its genetic diversity and compared it to other populations of American Creole cattle. A random sample of 64 animals was genotyped for a set of 17 microsatellite loci, and the D-loop hyper-variable region of mtDNA was sequenced for 28 calves of the same generation. We identified an average of 5.59 alleles per locus, with expected heterozygosities between 0.466 and 0.850 and an expected mean heterozygosity of 0.664. The polymorphic information content ranged from 0.360 to 0.820, and the global FIS index was 0.037. The D-loop analysis revealed three haplotypes (UY1, UY2 and UY3), belonging to the European matriline group, with a haplotype diversity of 0.532. The history of the population, changes in the effective population size, bottlenecks, and genetic drift are possible causes of the genetic variability patterns that we detected. PMID- 23661438 TI - Evaluation of genotoxic and cytotoxic effects of antileishmanial extract from Julocroton triqueter (Euphorbiaceae). AB - Julocroton triqueter extracts have antileishmanial activity; however, the effect on genetic stability has not been studied. We evaluated genotoxic and cell death induction potential (in vitro and in vivo) of J. triqueter var. triqueter hydroalcoholic extracts, as well as their antigenotoxic potential in vivo. The in vitro genotoxic studies were performed using human leukocytes at four different concentrations. For the in vivo tests, Swiss mice were treated with 125, 250 or 500 mg/kg of extract injected intraperitoneally. Antigenotoxic effects of the extract were measured before and after cyclophosphamide treatment. An absence of genotoxic effects was observed both in vitro and in vivo. In the antigenotoxic studies, no significant difference was observed between the treatments and the positive control, indicating that the extracts did not protect against damage caused by cyclophosphamide. Hydroalcoholic extracts of J. triqueter did not provoke DNA damage at concentrations and doses normally used for antileishmanial treatment; however, they reduced apoptotic cell death and induced necrotic cell death. PMID- 23661439 TI - Expression of glutamine synthetase in Tegillarca granosa (Bivalvia, Arcidae) hemocytes stimulated by Vibrio parahaemolyticus and lipopolysaccharides. AB - The blood cockle, Tegillarca granosa, is a widely consumed clam in the Indo Pacific region. Glutamine synthetase (GS) is an enzyme that plays an essential role in the metabolism of nitrogen by catalyzing the condensation of glutamate and ammonia to form glutamine. We identified the GS of T. granosa (Tg-GS) from hemocytes by 3'- and 5'-rapid amplification of cDNA ends (RACE)-PCR. The full length cDNA consisted of 1762 bp, with a 1104-bp open reading frame encoding 367 amino acids. Sequence comparison showed that Tg-GS has homology to GS of other organisms, with 79.78% identity with GS from the Pacific oyster Crassostrea gigas, 71.98% identity with GS from the zebrafish Danio rerio, and 68.96% identity with human Homo sapiens GS. A C-beta-Grasp domain and an N-catalytic domain were identified in Tg-GS, indicating that Tg-GS should be classified as a new member of the GS family. A quantitative RT-PCR assay was used to detect mRNA expression of Tg-GS in five different tissues. Higher levels of mRNA expression of GS were detected in the tissues of hemocytes and the mantle. Up-regulation of GS by challenge with the bacteria Vibrio parahaemolyticus and with bacterial wall lipopolysaccharides showed that GS plays a role in anti-bacterial immunity. We conclude that pathogen infection significantly induces expression level of Tg- GS, and that activation of GS influences the immune response of T. granosa by increasing glutamine concentration. PMID- 23661440 TI - Genetic diversity analysis of Capsicum spp germplasm bank accessions based on alpha/beta-esterase polymorphism. AB - Genetic diversity and structure were analyzed in 10 accessions belonging to Banco Ativo de Germoplasma de Capsicum located at Federal University of Piaui in northwestern Brazil that receives pepper samples grown in community gardens in various regions and Brazilian states. Selections were made from seeds of C. chinense (4 accessions), C. annuum (5 accessions), and C. baccatum (1 accession). Samples consisting of leaves were collected from 4-10 plants of each accession (a total of 85 plants). Native polyacrylamide gel electrophoresis was used to identify alpha- and beta-esterase polymorphisms. Polymorphism was clearly detected in 5 loci. Sixteen alleles were found at 5 alpha/beta-esterase loci of the three Capsicum species. In the C. chinense samples, the highest HO and HE values were 0.3625 and 0.4395, respectively, whereas in C. annuum samples, HO and HE values were 0.2980 and 0.3310, respectively; the estimated HO and HE values in C. chinense samples were higher than those detected in C. annuum samples. A deficit of homozygous individuals was found in C. chinense (FIS = -0.6978) and C. annuum (FIS = 0.7750). Genetic differentiation between C. chinense and C. annuum at these loci was high (FST = 0.1867) indicating that C. chinense and C. annuum are genetically structured species for alpha/beta- esterase isozymes. The esterase analysis showed high genetic diversity among the C. chinense and C. annuum samples and very high genetic differentiation (FST = 0.6321) among the C. chinense and C. annuum samples and the C. baccatum accession. PMID- 23661441 TI - Mutational analyses of the TSC1 and TSC2 genes in cases of tuberous sclerosis complex in Chinese Han children. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant neurogenetic disorder characterized by hamartomas in multiple organs and is caused by a wide spectrum of mutations in 1 of 2 causative genes (TSC1 or TSC2). Here, we present mutational analyses of the TSC1 and TSC2 genes in 4 cases of TSC in Chinese Han children, including 2 familial and 2 sporadic cases, using PCR and DNA sequencing of the entire coding region as well as exon-intron boundaries of these genes. Three mutations were identified in the TSC2 gene. Of these mutations, 2 mutations (c.3312-3313delGA and c.45delT) were novel, and the 3rd mutation (c.5238-5255del) was previously reported in Chinese Han and other populations. These mutations were not present in healthy family members or in 100 unrelated normal controls. The identification of these mutations in this study further expands the spectrum of known TSC2 gene mutations and contributes to prenatal molecular diagnosis and preimplantation genetic testing of TSC. PMID- 23661442 TI - Comparative multiplex dosage analysis in spinocerebellar ataxia type 2 patients. AB - We developed a new application of comparative multiplex dosage analysis (CMDA) for evaluation of the ataxin 2 gene. Expansions of the triplet CAG can cause spinocerebellar ataxia type 2 (SCA2), a neurodegenerative disease with an autosomal-dominant mode of inheritance. Molecular diagnosis of SCA2 is routinely based on the use of conventional PCR to detect the CAG expansion. However, PCR does not amplify an allele with an expansion of many triplets (>80), which is typically found in infantile and juvenile forms of SCA2, thus leading to false negatives. We propose the analysis of the ATXN2 gene by CMDA to complement existing methods currently used for the detection of large expansions of the CAG repeat. Using CMDA, the presence of any longer mutated allele in a heterozygous patient or fetus would be inferred due to dosage variation of the very frequent normal allele #22. CMDA can be completed in 1 day, at very low cost, and would be a useful tool for prenatal diagnosis and for diagnosis of presymptomatic forms of early-onset SCA2. PMID- 23661444 TI - Significance of Bcl10 gene mutations in the clinical diagnosis of MALT-type ocular adnexal lymphoma in the Chinese population. AB - We investigated the expression of Bcl10 gene mutations in mucosa-associated lymphoid tissue-type ocular adnexal lymphoma (OAL), atypical lymphoid hyperplasia (ALH), and reactive lymphoid hyperplasia (RLH) in the Chinese population and its role in clinical diagnosis and pathogenesis. Forty-three samples were collected during patient surgeries. Pathological diagnosis confirmed OAL in 23 cases, ALH in 10 cases, and RLH in 10 cases. Normal peripheral lymph tissues from 12 cases were used as negative controls. Bcl10 gene expression was examined using molecular biological methods, and DNA sequences and mutations were compared with published data. The protein expression of Bcl10 and nuclear factor kappaB (NF kappaB) were detected with immunohistological and immunofluorescence colocalization. Bcl10 gene expression was detected in 15 OAL cases. Novel mutations were found in 11 cases. Notably, 1 mutation, which matched a published mutation, was detected in 1 ALH case; 1 novel mutation was found in 1 RLH case; and no Bcl10 gene mutation was found in controls. Most novel mutations were truncation mutations, resulting in a truncated protein product of 99 amino acids (compared to the full-length 233 amino acids; GenBank accession No. EF189176). Results of tests for abnormal Bcl10 gene expression in nuclei or cytoplasm were consistent with changes in NF-kappaB translocation. This report is the first of newly discovered mutations in the Bcl10 gene in the Chinese population. The distribution of the mutations is consistent with and more sensitive than that of the pathological diagnosis. These mutations can be used to identify the stage and clinical characteristics even when morphological changes are absent. PMID- 23661443 TI - Construction of a cDNA library of the Chinese wild Vitis amurensis under cold stress and analysis of potential hardiness-related expressed sequence tags. AB - A cDNA library of Chinese wild Vitis amurensis, which is the most cold-resistant species in the genus Vitis, was constructed using young leaves of seedlings of the clone Heilongjiang potted and subjected to cold stress. The leaves were harvested at various times after cold stress for total RNA extraction, which was used to generate expressed sequence tags (ESTs). The titer of the original library was 2.67 x 10(6) pfu/mL and the corresponding combination frequency was 98.5%. The test values of the amplified library were 1.53 x 10(9) pfu/mL and 98.2%, respectively. After randomly choosing, cloning and sequencing, 227 ESTs with high quality were obtained and submitted to GenBank database. Using BLASTX, 79.7% of the ESTs shared homology with known functional DNA sequences and 20.3% shared significant homology with unknown proteins. Some potential hardiness related ESTs were obtained, which were involved in signal transduction, stress inducement, defense reactions, transcription factors, etc. Some functional genes identified from the cDNA library have potential for plant defense. These sequences will be subjected to further researches on hardiness genes and their molecular mechanisms. PMID- 23661445 TI - Genetic diversity in wild Dipsacus chinensis populations from China based on ISSR markers. AB - Wild Dipsacus chinensis plants in China have become endangered owing to over harvesting and habitat fragmentation. We examined the genetic diversity and genetic structure of 90 individuals from three populations using inter-simple sequence repeat markers and found that 106 of 173 bands amplified by 22 informative and reliable primers were polymorphic. These findings correspond to a medium level of genetic diversity. At the species level, the estimates of parameters of genetic diversity were as follows: polymorphic loci (61.27%); effective number of alleles (1.3873); Nei's genetic diversity (0.2202); Shannon's information index (0.3235). At the population level, the estimates were polymorphic loci (9.53%); effective number of alleles (1.0419); Nei's genetic diversity (0.0258); Shannon's information index (0.0402). Nei's coefficient of genetic differentiation was 0.8829, which is consistent with Shannon's coefficient of genetic differentiation (0.8757). Most of the genetic variation existed among populations, and some differentiation may have resulted from habitat fragmentation and barriers to gene flow (gene flow = 0.0663). Combining our results with those of on-site field investigation, we conclude that the present genetic diversity and genetic structure of natural populations of D. chinensis have been strongly affected by harvesting and habitat fragmentation. We also propose strategies for the conservation of this plant. PMID- 23661446 TI - Cassava interspecific hybrids with increased protein content and improved amino acid profiles. AB - Cassava (Manihot esculenta) is a principal food for large populations of poor people in the tropics and subtropics. Its edible roots are poor in protein and lack several essential amino acids. Interspecific hybrids may acquire high protein characteristics from wild species. We analyzed 19 hybrids of M. esculenta with its wild relative, M. oligantha, for crude protein, amino acid profile, and total cyanide. Some hybrids produced roots with high protein content of up to 5.7%, while the common cultivar that we examined had just 2.3% crude protein. The essential amino acids alanine, phenylalanine, and valine were detected in the hybrids. The sulfur-containing amino acids cysteine and methionine were found at relatively high concentrations in the roots of 4 hybrids. The proportion of lysine in one hybrid was 20 times higher than in the common cultivar. The levels of total cyanide ranged from 19.73 to 172.56 mg/kg and most of the roots analyzed were classified as "non-toxic" and "low toxic". Furthermore, 2 progenies showed reasonable levels of cyanide, but higher protein content and amino acid profile more advantageous than the common cassava. PMID- 23661447 TI - Molecular cloning and tissue expression analyses of two novel pepper genes: heterotrimeric G protein beta 2 subunit and ArcA1. AB - We isolated two transcription factor genes, heterotrimeric G protein beta 2 subunit (Gbeta2) and ArcA1, from pepper (Capsicum annuum). The complete coding sequences were amplified using reversed transcriptase PCR based on conserved sequence information of Solanum lycopersicum and several other plant species. Nucleotide sequence analysis of these two genes revealed that the pepper Gbeta2 gene encodes a protein of 376 amino acids that belongs to the WD40 superfamily. Tissue expression analysis indicated that this gene is highly expressed in the pericarp, moderately expressed in stem, flower, placenta, and leaves, and weakly expressed in seed. There was no expression in the roots. The ArcA1 gene encodes a protein of 331 amino acids that also belongs to the WD40 superfamily. Tissue expression analysis indicated that the pepper ArcA1 gene is moderately expressed in the pericarp and weakly expressed in seed. There was no expression in root, stem, flower, placenta, or leaves. PMID- 23661448 TI - Phenotypic and genotypic variation among Capsicum annuum recombinant inbred lines resistant to bacterial spot. AB - A breeding program carried out under Brazilian growing conditions to obtain Capsicum annuum cultivars with disease resistance to bacterial spot (BS) produced 8 promising recombinant inbred lines (RILs). The present study aimed to characterize these RILs using phenotypic descriptors and molecular markers (inter simple sequence repeat) and to confirm their resistance to BS. Twenty-two phenotypic descriptors and 15 inter-simple sequence repeat primers were used to characterize the RILs. The parent, UENF 1381, which is resistant to BS, and 'Casca Dura Ikeda', a traditional cultivar, were used as standards. Variability among genotypes was observed considering either binary or multicategorical characteristics, such as fruit length, fruit diameter, and fruit longitudinal and transversal section. Such variability in fruit traits can be exploited to develop new genotypes with BS resistance for various types of market consumption. RILs numbered 1, 3, and 6 were the most homogenous, whereas those coded 2, 5, 8, and 11 had the same level of heterogeneity as that observed in 'Casca Dura Ikeda'. Molecular analysis clustered the genotypes into 5 groups, with RILs 1, 2, 3, and 5 allocated in isolated groups. RILs 1, 2, 6, and 8 confirmed resistance to BS. Considering homogeneity level and BS resistance, RILs 1 and 6 were suitable for use as pre-cultivars in final tests to register and release two new C. annuum cultivars. PMID- 23661449 TI - Genetic analysis of agronomic traits associated with plant architecture by QTL mapping in maize. AB - Maize (Zea mays L.) is one of the most important cereal crops worldwide, and increasing the grain yield and biomass has been among the most important goals of maize production. The plant architecture can determine the grain yield and biomass to some extent; however, the genetic basis of the link between the plant architecture and grain yield/biomass is unclear. In this study, an immortal F9 recombinant inbred line population, derived from the cross Mo17 x Huangzao4, was used to detect quantitative trait loci (QTLs) for 3 traits associated with plant architecture under two nitrogen regimes: plant height, ear height, and leaf number. As a result, 8 and 10 QTLs were identified under the high nitrogen regime and low nitrogen regime, respectively. These QTLs mapped to chromosomes 1 (six QTLs), 2 (one QTL), 3 (one QTL), 7 (two QTLs), and 9 (eight QTLs), and had different genetic distances to their closest markers, ranging from 0 to 22.0 cM, explaining 4.7 to 20.5% of the phenotypic variance. Because of an additive effect, 9 and 9 could make the phenotypic values of traits increase and decrease to some extent, respectively. These results are beneficial for understanding the genetic basis of agronomic traits associated with plant architecture and for performing marker-assisted selection in maize breeding programs. PMID- 23661450 TI - Impacts of single nucleotide polymorphisms and haplotypes in the bovine Dapper1 gene on body weight. AB - The Dapper1 protein plays important role in multiple developmental processes via negative modulation of the Wnt signaling pathway. We detected variations in Dapper1 in 1185 individuals from 5 Chinese cattle breeds and determined their effects on bovine body weight. Two silent mutations (g.8344C>T and g.8428C>T) in exon 6 along with two substitutions (g.10513A>G and g.10765C>G) in the 3' untranslated region were detected with DNA pool sequencing and forced polymerase chain reaction-restriction fragment length polymorphism. Haplotype variability and the extent of linkage disequilibrium of the 4 single nucleotide polymorphisms (SNPs) were analyzed, and the results revealed 16 haplotypes and 7 combined haplotypes in the 5 cattle breeds. Statistical analyses indicated that genotypes CC and AA in the g.8344C>T and g.10513A>G loci were associated with heavier body weight at 6 months in the Nanyang cattle population (P < 0.05), and the combined haplotype had consistent significant effects on body weight with a single SNP. Cattle with haplotype combinations H1H5 (CCCTAACC) displayed the heaviest body weight at 6 months compared with that of other haplotypes (P < 0.05). Our results provide evidence that 4 SNPs and haplotypes in Dapper1 may be used for marker assisted selection in beef cattle breeding programs. PMID- 23661451 TI - DNA methylation involved in proline accumulation in response to osmotic stress in rice (Oryza sativa). AB - Proline accumulation is involved in plant osmotic stress tolerance. Given that DNA methylation is related to almost all metabolic processes through regulation of gene expression, we suspected that this epigenetic modification and proline biosynthesis are probably related. To test this, we investigated whether osmotic stress-induced proline accumulation is associated with DNA methylation modifications in rice. We assessed DNA methylation and expression of 3 key genes (P5CR, P5CS, and delta-OAT) involved in proline biosynthesis, and measured proline content under both osmotic stress (15% polyethylene glycol) and control conditions. After osmotic stress, selfed progenies of osmotic-stressed plants accumulated higher concentrations of proline in leaves under both normal conditions and under osmotic stress than the unstressed control plants. Concomitantly, under osmotic stress, the selfed progeny plants showed higher expression levels of P5CS and delta-OAT than the control. This up-regulated expression was stably inherited by the subsequent generation. Methylation sensitive Southern blotting indicated that 2 of the 3 genes, P5CS and delta-OAT, had greater DNA demethylation in the selfed progenies than in the control. Apparently DNA demethylation facilitated proline accumulation by up-regulating expression of the P5CS and delta-OAT genes in response to osmotic stress. PMID- 23661452 TI - Paeonia (Paeoniaceae) expressed sequence tag-derived microsatellite markers transferred to Paeonia delavayi. AB - Paeonia Franchet contains approximately 30 species of perennial herbs and is the only member of the family Paeoniaceae. Paeonia delavayi is an endangered ornamental plant that has a compound flower color and is endemic to southwest China. Its optimal habitats have been fragmented and its population size has greatly decreased as a result of human activities. Using a modified biotin streptavidin capture method, 51 primer sets were identified in 3 wild populations of P. delavayi in this study. Ten primers displayed polymorphisms and 41 amplified no products, gave weak or indistinct bands, or gave larger sizes than expected. The number of alleles per locus ranged from 1 to 3, and the values for observed and expected heterozygosities ranged from 0.000 to 0.571 and from 0.000 to 0.509, with averages of 0.113 and 0.295, respectively. These markers will be useful for further investigations in resource conservation, selection of parental types in cross-breeding, the molecular evolution of this species, and for related research in Paeonia species. PMID- 23661453 TI - Karyotype characterization reveals active 45S rDNA sites located on chromosome termini in Smilax rufescens (Smilacaceae). AB - The genus Smilax (Smilacaceae) includes species of medicinal interest; consequently, their identification is important for the control of raw material used in the manufacture of phytotherapeutic products. We investigated the karyotype of Smilax rufescens in order to look for patterns that would be useful for comparative studies of this genus. To accomplish this, we developed procedures to grow plants and optimize root pretreatment with mitotic fuse inhibitors to obtain metaphase spreads showing clear chromosome morphology. The karyotype, analyzed in Feulgen-stained preparations, was asymmetric, with N = 16 chromosomes gradually decreasing in size; the larger ones were subtelocentric and the smaller chromosomes were submetacentric or metacentric. Nearly terminal secondary constrictions were visualized on the short arm of chromosome pairs 7, 11, and 14, but they were clearly detected only in one of the homologues of each pair. The nucleolus organizer regions (NORs) were mapped by silver staining and fluorescent in situ hybridization of 45S rDNA probes. Silver signals (Ag-NORs) colocalized with rDNA loci were detected at the termini of the short arm of 6 chromosomes. The secondary constriction heteromorphism observed in Feulgen stained metaphases suggests that differential rRNA gene expression between homologous rDNA loci can occur, resulting in different degrees of chromatin decondensation. In addition, a heteromorphic chromosome pair was identified and was interpreted as being a sex chromosome pair in this dioecious species. PMID- 23661454 TI - Smallest critical region for microcephaly in a patient with mosaic ring chromosome 13. AB - A ring chromosome 13 or r(13) exhibits breakage and reunion at breakage points on the long and short arms of chromosome 13, with deletions of the chromosomal segments distal to the breakage points. The r(13) chromosome accounts for approximately 20% of ring chromosomes compatible with life. We describe a female patient with mental retardation, growth retardation, microcephaly, craniofacial dysmorphy, hearing impairment, and prolonged prothrombin time. Chromosomal analysis via GTG banding of peripheral blood lymphocytes revealed a karyotype of 46,XX,r(13)(p13q34)[71]/45,XX,-13[12]/ 46,XX,dic r(13;13)(p13q34;p13q34)[9]/46,XX,-13,+mar[5]/47, XX,+r(13) (p13q34)x2[2]/46,XX[1] at the age of 6 years and 46,XX,r(13)(p13q34)[82]/45,XX,-13[14]/46,XX,dic r(13;13)(p13q34; p13q34)[2]/46,XX, -13,+mar[2]. Array comparative genomic hybridization analysis of the blood demonstrated a 4.37-Mb deletion on chromosome 13q [arr cgh 13q34q34(109,743,729-144,110,721)]. A cytogenetic study of peripheral blood revealed a rare chromosomal abnormality associated with different cell lines that included structural and numerical abnormalities of chromosome 13. This case, along with 14 previously reported cases, indicate that the smallest critical region for chromosome 13 microcephaly is 109,743,729 144,110,721. PMID- 23661455 TI - Enhancement of recombinant adeno-associated virus mediated transgene expression by targeted echo-contrast agent. AB - Ultrasound-targeted microbubble destruction (UTMD) has been recently developed for destroying bubbles carrying drugs or genes, thereby permitting local release of these target molecules. We investigated whether SonoVue(r), a new contrast agent that contains phospholipid-stabilized microbubbles filled with sulfur hexafluoride vapor, is effective at delivering a recombinant adeno-associated viral (rAAV) vector to the rat heart by UTMD. Serotype-2 (rAAV2) marked with green fluorescent protein (GFP) as a reporter gene was attached to the surface of sulfur hexafluoride-filled microbubbles. Microbubbles were infused into the tail vein of rats with or without simultaneous echocardiography. Additional controls included ultrasound microbubbles that did not contain virus, virus alone, and virus plus ultrasound. One group underwent echocardiographic destruction of microbubbles followed by rAAV2-GFP infusion. Rats were killed after 4 weeks and examined for GFP expression. Green fluorescence was detected in all groups that received the rAAV2-GFP vector, indicating expression of the rAAV2 transgene; however, GFP expression in the UTMD group was significantly higher than that in control groups. We conclude that ultrasound-mediated destruction mediated by SonoVue is a promising method for delivery of rAAV2 to the heart in vivo. PMID- 23661456 TI - HNF1b is involved in prostate cancer risk via modulating androgenic hormone effects and coordination with other genes. AB - Prostate cancer is one of the most commonly diagnosed male malignancies. Genome wide association studies have revealed HNF1b to be a major risk gene for prostate cancer susceptibility. We examined the mechanisms of involvement of HNF1b in prostate cancer development. We integrated data from Gene Expression Omnibus prostate cancer genes from the Dragon Database of Genes Implicated in Prostate Cancer, and used meta-analysis data to generate a panel of HNF1b-associated prostate cancer risk genes. An RT-PCR was used to assess expression levels in DU145, PC3, LNCaP, and RWEP-1 cells. Twelve genes (BAG1, DDR1, ERBB4, ESR1, HSPD1, IGFBP2, IGFBP5, NR4A1, PAWR, PIK3CG, RAP2A, and TPD52) were found to be associated with both HNF1b and prostate cancer risk. Six of them (BAG1, ERBB4, ESR1, HSPD1, NR4A1, and PIK3CG) were mapped to the KEGG pathway, and submitted to further gene expression assessment. HNF1b, NR4A1, and HSPD1 were found to be highly expressed in the LNCaP androgenic hormone-dependent cell line. Compared to expression levels in wild-type prostate cancer cells, NR4A1, HSPD1, ERBB4, and ESR1 expression levels were also found to be significantly increased in the HNF1b transfected cells. We conclude that the mechanism of action of HNF1b in prostate cancer involves modulation of the association between androgenic hormone and prostate cancer cells. Gene-gene interaction and coordination should be taken into account to determine relationships between specific loci and diseases. PMID- 23661457 TI - Evaluation of a histocompatibility antigen related to hepatitis B virus in patients with hepatocellular carcinoma in the western Brazilian Amazon. AB - Hepatocellular carcinoma is an infection of variable incidence that can be caused by hepatitis B virus (HBV), which is endemic in the Amazon region. The diagnosis of HBV can be performed through the use of serum markers such as the hepatitis B surface antigen. The chronic HBV can cause mutagenesis and carcinogenesis, being the susceptibility of infection due to allele human leukocyte antigen (HLA). Thus, we evaluated the clinical, molecular and laboratory profile (histocompatibility complex) of HBV in 22 patients with hepatocellular carcinoma in Amazonia, including 18 males and 4 females, using a blood sample for generic HLA class II. The results showed increased frequency of disease evolution in adults between 25 and 64 years old, who comprised 19 of the 22 patients studied. Most patients (16/22) presented high levels of alpha-fetoprotein and transaminases (14/22). The most common HLA alleles were DRB1 04 (8/44), DRB1 08 (9/44), DRB 03 (16/44), and DQB1 04 (9/44). When we compared specific phenotype frequencies of HLA-DRB1 between patients and controls, we found that patients had a significantly higher frequency of allele DRB1 08 and a significantly lower frequency of DRB1 07 and DRB1 12 compared to previous studies on Asian and Amazonian populations suggesting ethnic differences. We suggest that alleles HLA DRB 08, HLA-DRB 03 and HLA-DQB1 04 may be risk factors for hepatocellular carcinoma in Amazon. PMID- 23661458 TI - A proposed model for the flowering signaling pathway of sugarcane under photoperiodic control. AB - Molecular analysis of floral induction in Arabidopsis has identified several flowering time genes related to 4 response networks defined by the autonomous, gibberellin, photoperiod, and vernalization pathways. Although grass flowering processes include ancestral functions shared by both mono- and dicots, they have developed their own mechanisms to transmit floral induction signals. Despite its high production capacity and its important role in biofuel production, almost no information is available about the flowering process in sugarcane. We searched the Sugarcane Expressed Sequence Tags database to look for elements of the flowering signaling pathway under photoperiodic control. Sequences showing significant similarity to flowering time genes of other species were clustered, annotated, and analyzed for conserved domains. Multiple alignments comparing the sequences found in the sugarcane database and those from other species were performed and their phylogenetic relationship assessed using the MEGA 4.0 software. Electronic Northerns were run with Cluster and TreeView programs, allowing us to identify putative members of the photoperiod-controlled flowering pathway of sugarcane. PMID- 23661459 TI - Genetic characterization of Fusarium graminearum and F. culmorum isolates from Turkey by using random-amplified polymorphic DNA. AB - Five Fusarium graminearum and 12 F. culmorum isolates, primarily pathogenic species of Fusarium head blight, were obtained from naturally infected wheat from various agro-ecological regions of Turkey. Genotyping of the isolates was carried out using random-amplified polymorphic DNA (RAPD). Sixty-five 10-mer oligonucleotide primers were used to amplify the RAPD markers. Among them, 50 primers produced strong and reproducible DNA amplicons. The remaining primers generated either insufficient or no amplification patterns. In total, 1200 fragments were scored, 311 of which were determined to be polymorphic and unique to the isolates. The produced RAPD markers ranged from 0.2 to 5 kb. The mean genetic similarity values of the F. graminearum and F. culmorum isolates were 61.5 and 65%, respectively. The similarity coefficient was 43 to 76.1% among F. graminearum isolates and 49 to 81.1% among F. culmorum isolates. Genetically, the most similar F. graminearum isolates were F6 and F7 (76.1%), which originated from the same agro-ecological region (Sakarya). The most similar F. culmorum isolates were F20 and F21 (81.1%), which were from different geographic regions (Bilecik and UAYak, respectively). Moreover, interspecific variation between the two species was determined to be 86.3 to 93.3%. Cluster analysis generated two branched groups, each containing isolates of one species, except F13 of F. culmorum. The sequencing of stable and reproducible monomorphic and polymorphic RAPD markers indicated that the Fusarium genome shared high similarity (105-625 bit scores) with the genomes of other organisms as well as with the F. graminearum reference genome. PMID- 23661460 TI - CTLA-4 and CD86 genetic variants and haplotypes in patients with rheumatoid arthritis in southeastern China. AB - The cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and costimulatory molecule (CD80/CD86) genes are important susceptibility genes associated with autoimmune diseases. CTLA-4 polymorphisms have been found to be associated with various autoimmune diseases. However, the association data are inconsistent for rheumatoid arthritis (RA). We investigated the genetic association of CTLA-4 and CD86 polymorphisms with RA in a Chinese population. Four single nucleotide polymorphisms (SNPs) (rs5742909 and rs231775 in CTLA-4, and rs17281995 and rs1129055 in CD86) were genotyped in 213 patients with RA and 303 healthy controls using polymerase chain reaction-restriction fragment length polymorphism. The genotype and allele distributions of rs5742909 differ significantly between RA patients and controls (P < 0.05) and the dominant model was found to be the best inheritance model. Stratification studies showed that CTLA-4 gene polymorphisms were more significantly associated with rheumatoid factor-negative and anti-cyclic citrullinated peptide-negative subgroups in the southeastern Han Chinese population. We also found that the haplotype of 2 CTLA-4 SNPs showed significant association with the disease (P = 0.0025) with the T-A (OR = 1.88, 95%CI = 1.12-3.15) and T-G (OR = 3.45, 95%CI = 1.10-10.87) haplotypes being observed more frequently in cases than in controls. We failed to find any significant association of the 2 CD86 SNPs with RA. These results indicate that the polymorphisms of CTLA-4 (rs5742909) may be important genetic factors for RA risk in the southeastern Han Chinese population. PMID- 23661461 TI - Evaluation of genetic diversity in fig accessions by using microsatellite markers. AB - Fig (Ficus carica L.) is a fruit of great importance worldwide. Its propagation is carried out with stem cuttings, a procedure that favors the occurrence of synonymy among specimens. Thus, molecular markers have become an important tool for studies of DNA fingerprinting, germplasm characterization, and genetic diversity evaluation in this plant species. The aim of this study was the analysis of genetic diversity among accessions of fig and the detection of synonyms among samples using molecular markers. Five microsatellite markers previously reported as polymorphic to fig were used to characterize 11 fig cultivars maintained in the germplasm bank located in Lavras, Minas Gerais. A total of 21 polymorphic DNA fragments were amplified, with an average of 4.2 alleles per locus. The average allelic diversity and polymorphic information content were 0.6300 and 0.5644, respectively, whereas the total value for the probability of identity was 1.45 x 10(-4). The study allowed the identification of 10 genotypes and 2 synonymous individuals. The principal coordinate analysis showed no defined clusters despite the formation of groups according to geographical origin. However, neighbor-joining analysis identified the same case of synonymy detected using principal coordinate analysis. The data also indicated that the fig cultivars analyzed constitute a population of individuals with high genetic diversity and a broad range of genetic variation. PMID- 23661462 TI - The insertion/deletion polymorphism in the ACE gene and chronic obstructive pulmonary disease. AB - An insertion/deletion (I/D) polymorphism was identified in intron 16 of the gene encoding the human angiotensin I-converting enzyme (ACE), a candidate gene for chronic obstructive pulmonary disease (COPD). We investigated the relationship between this polymorphism in the ACE gene and the risk of developing COPD. Sixty six COPD in-patients and 40 non-smoking control individuals were recruited for this study. The distribution of ACE genotypes in these individuals was studied. The frequencies of ACE genotypes were found to be 47.0% for DD, 30.3% for ID, and 22.7% for II in the COPD group and 32.5% for DD, 47.5% for ID, and 20.0% for II in the control group. The allele frequencies were found to be 0.62% for the D allele and 0.38% for the I allele in the COPD group and 0.56% for the D allele and 0.44% for the I allele in the control group. A significant difference was found between I and D allele frequencies (P < 0.05) of the study and control groups. Our results suggest that this ACE polymorphism may be associated with the development of COPD. PMID- 23661463 TI - Target replacement strategy for selection of DNA aptamers against the Fc region of mouse IgG. AB - Aptamers that recognize the IgG Fc region are of great interest because of their wide application as an immunology probing tool, for diagnostics, and as affinity agents for antibody purification. We developed a target replacement strategy as a modification of conventional Systematic Evolution of Ligands by EXponential enrichment (SELEX) in order to efficiently select and identify novel DNA aptamers against the Fc region of mouse IgG. In this new approach, multiple IgG subclasses (IgG1, IgG2a, mouse IgG Fc, and anti-HBs IgG) were sequentially used to select aptamers in one continuous SELEX. After 8 rounds of selection, the aptamers were analyzed using dot blot and an electrophoretic mobility shift assay, which showed universal binding capability to different IgG subclasses. Secondary structure analysis of the aptamers indicated that the stem-loop structure of the aptamers play an important role in binding to the common site in different mouse IgG subclasses. This demonstrated the feasibility of using multiple target replacement SELEX for the selection of aptamers. This target replacement strategy is also expected to be useful for selecting aptamers that bind common regions of molecules other than antibodies. PMID- 23661464 TI - Peroxidase is involved in Pepper yellow mosaic virus resistance in Capsicum baccatum var. pendulum. AB - Pathogenesis-related proteins (PRs) are among the defense mechanisms of plants that work as an important barrier to the development of pathogens. These proteins are classified into 17 families according to their amino acid sequences, serology, and/or biological or enzyme activity. The present study aimed to identify PRs associated with the pathosystem of Capsicum baccatum var. pendulum: Pepper yellow mosaic virus (PepYMV). Forty-five-day-old plants from accession UENF 1624, previously identified as resistant to PepYMV, were inoculated with the virus. Control and infected leaves were collected for analysis after 24, 48, 72, and 96 h. The inoculated and control plants were grown in cages covered with anti aphid screens. Proteins were extracted from leaf tissue and the presence of beta 1,3-glucanase, chitinase, peroxidase, and lipid transport protein was verified. No difference was observed between the protein pattern of control and infected plants when beta-1,3-glucanase, chitinase, and lipid transport protein were compared. However, increased peroxidase expression was observed in infected plants at 48 and 72 h after inoculation, indicating that this PR is involved in the response of resistance to PepYMV in C. baccatum var. pendulum. PMID- 23661465 TI - Updated analysis of studies on the cytotoxic T-lymphocyte-associated antigen-4 gene A49G polymorphism and Hashimoto's thyroiditis risk. AB - Published data on the association between the cytotoxic T-lymphocyte-associated antigen-4 gene A49G polymorphism and the risk for Hashimoto's thyroiditis (HT) are inconclusive. A meta-analysis was performed to derive a more precise estimation. Published case-control studies in English or Chinese were identified. In total, 24 studies with 2295 cases and 4521 controls were investigated. A random-effect model was performed irrespective of between-study heterogeneity. Study quality was assessed in duplicate, and subgroup analyses were conducted by ethnicity or age. Overall, the 49G allele was associated with an increase in HT risk [odds ratio (OR) = 1.31; 95% confidence interval (95%CI) = 1.17-1.47; P < 0.00001]. In a subgroup analysis by ethnicity, comparison of allele 49G with 49A generated a 27% increased risk among East Asians (OR = 1.48; 95%CI = 1.24-1.76; P < 0.00001) and whites (OR = 1.27; 95%CI = 1.12-1.44; P = 0.0002). We also found an increased risk among adults (OR = 1.31; 95%CI = 1.17-1.47; P < 0.00001) but not among children (OR = 1.44; 95%CI = 0.75-2.79; P = 0.27), possibly owing to the small sample sizes in children. No publication biases were observed. This meta-analysis suggested that the cytotoxic T-lymphocyte-associated antigen-4 gene 49G allele was associated with an increased HT risk, especially in adults. PMID- 23661466 TI - Genes associated with disc degeneration identified using microarray gene expression profiling and bioinformatics analysis. AB - Disc degeneration is strongly associated with back or neck pain, sciatica, and disc herniation or prolapse. It places an enormous economic burden on society and can greatly affect quality of life. Alternative treatment approaches, such as genetic therapies, are urgently needed to slow or reverse the disc degeneration process. We downloaded gene expression data from Gene Expression Omnibus during various stages of disc degeneration and identified differentially expressed genes (DEGs) as well as dysfunctional pathways through comparisons with controls. We identified 2 significant DEGs between grade II and III discs and 8 significant DEGs between grade II and IV discs. By constructing an interactive network of the DEGs, we found that mitogen-activated protein family genes and Ras homologous (Rho) family genes - in particular, MAP2K6 and RHOBTB2 - may play important roles in the progression of degeneration of grade III and IV discs, respectively. MAP2K6 and RHOBTB2 may be specific therapeutic molecular targets in the treatment of disc degeneration. However, further experiments are needed to confirm this result. PMID- 23661467 TI - ATP-dependent chromatin remodeling and histone acetyltransferases in 5-FU cytotoxicity in Saccharomyces cerevisiae. AB - Chromatin is thought to modulate access of repair proteins to DNA lesions, and may be altered by chromatin remodelers to facilitate repair. We investigated the participation of chromatin remodelers and DNA repair in 5-fluorouracil (5-FU) cytotoxicity in Saccharomyces cerevisiae. 5-FU is an antineoplastic drug commonly used in clinical settings. Among the several strains tested, only those with deficiencies in ATP-dependent chromatin remodeling (CR) and some histone acetyltransferases (HAT) exhibited sensitivity to 5-FU. CR and HAT double-mutants exhibited increased resistance to 5-FU in comparison to the wild-type mutant, but were still arrested in G2/M, as were the sensitive strains. The participation of Htz1p in 5-FU toxicity was also evaluated in single- and double-mutants of CR and HAT; the most significant effect was on cell cycle distribution. 5-FU lesions are repaired by different DNA repair machineries, including homologous recombination (HR) and post-replication repair (PRR). We investigated the role of CR and HAT in these DNA repair pathways. Deficiencies in Nhp10 and CR combined with deficiencies in HR or PRR increased 5-FU sensitivity; however, combined deficiencies of HAT, HR, and PRR did not. CRs are directly recruited to DNA damage and lead to chromatin relaxation, which facilitates access of HR and PRR proteins to 5-FU lesions. Combined deficiencies in HAT with defects in HR and PRR did not potentiate 5-FU cytotoxicity, possibly because they function in a common pathway. PMID- 23661468 TI - Estimation of genetic parameters for growth traits in a breeding program for rainbow trout (Oncorhynchus mykiss) in China. AB - Genetic parameters and breeding values for growth traits were estimated in the first and, currently, the only family selective breeding program for rainbow trout (Oncorhynchus mykiss) in China. Genetic and phenotypic data were collected for growth traits from 75 full-sibling families with a 2-generation pedigree. Genetic parameters and breeding values for growth traits of rainbow trout were estimated using the derivative-free restricted maximum likelihood method. The goodness-of-fit of the models was tested using Akaike and Bayesian information criteria. Genetic parameters and breeding values were estimated using the best fit model for each trait. The values for heritability estimating body weight and length ranged from 0.20 to 0.45 and from 0.27 to 0.60, respectively, and the heritability of condition factor was 0.34. Our results showed a moderate degree of heritability for growth traits in this breeding program and suggested that the genetic and phenotypic tendency of body length, body weight, and condition factor were similar. Therefore, the selection of phenotypic values based on pedigree information was also suitable in this research population. PMID- 23661469 TI - Molecular characterization and functional analysis of the Nep1-like protein encoding gene from Phytophthora capsici. AB - Phytophthora capsici is an aggressive plant pathogen that affects solanaceous and cucurbitaceous hosts. Nep1-like proteins (NLPs) are a group of effectors found particularly in oomycetes and considered important virulence factors. We identified an NLP gene (phcnlp1) from the highly virulent P. capsici strain Phyc12 that had an encoded polypeptide of 476-amino acid residues and a predicted molecular mass of 51.75 kDa. We performed quantitative reverse transcription polymerase chain reaction to detect the expression pattern of phcnlp1 during various phases of interaction with the host plant, and the results showed that phcnlp1 was increasingly expressed during symptom development after P. capsici infection of pepper leaves. We also confirmed that phcnlp1 caused significant necrosis on tobacco plants when expressed based on potato virus agroinfection. All results indicated that phcnlp1 belongs to the NLP gene family and is important for the pathogenesis of P. capsici in its hosts. PMID- 23661470 TI - Complete Genome Sequence of a Peste des Petits Ruminants Virus Recovered from an Alpine Goat during an Outbreak in Morocco in 2008. AB - Here, we announce the first complete genome sequence of a field isolate of a peste des petits ruminants virus (PPRV) from northern Africa. This isolate is derived from an Alpine goat that suffered from severe clinical disease during the 2008 outbreak in Morocco. The full genome sequence of this isolate clusters phylogenetically with the lineage IV isolates of PPRV, sharing high levels of sequence identity with other lineage IV isolates. PMID- 23661471 TI - Genome Sequencing of Ralstonia solanacearum FQY_4, Isolated from a Bacterial Wilt Nursery Used for Breeding Crop Resistance. AB - Ralstonia solanacearum strain FQY_4 was isolated from a bacterial wilt nursery, which is used for breeding crops for Ralstonia resistance in China. Here, we report the complete genome sequence of FQY_4 and its comparison with other published R. solanacearum genomes, especially with the strains GMI1000 and Y45 in the same group. PMID- 23661472 TI - Complete genome sequences of four virulent rabies virus strains isolated from rabid animals in Russia. AB - Rabies virus (RABV) strains Rus(Lipetsk)-8052f, Rus(Lipetsk)-8053c, Rus(Lipetsk) 8054f, and Rus(Lipetsk)-8057f were isolated from foxes (Vulpes vulpes) and a cat (Felis catus) in the Lipetsk region of Russia in 2011. Close relationships between these strains and the members of the "Cosmopolitan" group from Russia (98% homology) and from Europe (95% homology) were estimated. PMID- 23661473 TI - Complete genome sequence of a newly emerging newcastle disease virus isolated in china. AB - Goose/GD/2010 is a newly emerging Newcastle disease virus (NDV) isolated from a sick goose flock in southern China. Here, we report the complete genome sequence of this isolate, which belongs to NDV subgenotype VIIb. This is the first report about the complete genome information of an isolate of subgenotype VIIb in China. PMID- 23661474 TI - Draft Genome Sequence of Kocuria sp. Strain UCD-OTCP (Phylum Actinobacteria). AB - Here, we present the draft genome of Kocuria sp. strain UCD-OTCP, a member of the phylum Actinobacteria, isolated from a restaurant chair cushion. The assembly contains 3,791,485 bp (G+C content of 73%) and is contained in 68 scaffolds. PMID- 23661475 TI - Complete genome sequence of a European genotype porcine reproductive and respiratory syndrome virus in china. AB - Here, we report a novel European genotype porcine reproductive and respiratory syndrome virus (PRRSV) strain with 15 nucleotide deletions in the nonstructural protein 2 region and 3 nucleotide deletions in the overlapping regions of the open reading frame 3 (ORF3) and ORF4 regions. This study will aid in further exploration of the genetic and antigenic diversity of the European genotype of the PRRSV in China. PMID- 23661476 TI - Genome Sequence of Klebsiella pneumoniae HSL4, a New Strain Isolated from Mangrove Sediment for Biosynthesis of 1,3-Propanediol. AB - Klebsiella pneumoniae HSL4 is a 1,3-propanediol-producing bacterium strain isolated from mangrove sediment. We present here a 5,221,448-bp assembly of its genome sequence. Genome analysis revealed that it contains 10 coding sequences (CDSs) responsible for glycerol fermentation to 1,3-propanediol, 19 CDSs encoding glycerol utilization, and 140 CDSs related to its virulence. PMID- 23661477 TI - Whole-Genome Sequence of the Microcin E492-Producing Strain Klebsiella pneumoniae RYC492. AB - Here, we report the draft genome sequence of the Gram-negative strain Klebsiella pneumoniae RYC492, which produces the amyloid-forming and antibacterial peptide microcin E492. The sequenced genome consists of a 5,095,761-bp assembled open chromosome where the gene cluster for microcin production is located in a putative 31-kb genomic island flanked by sequence repeats and containing a putative integrase-coding gene. PMID- 23661478 TI - Draft Genome Sequence of Lactobacillus pobuzihii E100301T. AB - Lactobacillus pobuzihii E100301(T) is a novel Lactobacillus species previously isolated from pobuzihi (fermented cummingcordia) in Taiwan. Phylogenetically, this strain is closest to Lactobacillus acidipiscis, but its phenotypic characteristics can be clearly distinguished from those of L. acidipiscis. We present the draft genome sequence of strain L. pobuzihii E100301(T). PMID- 23661479 TI - Complete genome sequence of a newly emerging newcastle disease virus. AB - The complete genome sequence of a newly emerging Newcastle disease virus, isolated in China, was determined. A phylogenetic analysis based on the F gene revealed that the isolate is phylogenetically related to Newcastle disease virus genotype VIId. Sequence analysis indicated that amino acid residue substitutions occur at neutralizing epitopes on the hemagglutinin-neuraminidase (HN) protein. PMID- 23661480 TI - Draft Genome Sequence of Dietzia sp. Strain UCD-THP (Phylum Actinobacteria). AB - Here, we present the draft genome sequence of an actinobacterium, Dietzia sp. strain UCD-THP, isolated from a residential toilet handle. The assembly contains 3,915,613 bp. The genome sequences of only two other Dietzia species have been published, those of Dietzia alimentaria and Dietzia cinnamea. PMID- 23661481 TI - Draft Genome Sequence of Methylophaga lonarensis MPLT, a Haloalkaliphilic (Non Methane-Utilizing) Methylotroph. AB - Methylophaga lonarensis strain MPL(T) is a haloalkaliphilic methylotroph isolated from Lonar Lake, a saline and alkaline lake in Maharashtra, India. Strain MPL(T) utilizes methanol as its sole carbon and energy source. Here, we present the draft genome sequence of M. lonarensis MPL(T) (VKM B-2684(T) = MCC 1002(T)). PMID- 23661482 TI - Draft Genome Sequence of Erwinia toletana, a Bacterium Associated with Olive Knots Caused by Pseudomonas savastanoi pv. Savastanoi. AB - Erwinia toletana was first reported in 2004 as a bacterial species isolated from olive knots caused by the plant bacterium Pseudomonas savastanoi pv. savastanoi. Recent studies have shown that the presence of this bacterium in the olive knot environment increases the virulence of the disease, indicating possible interspecies interactions with P. savastanoi pv. savastanoi. Here, we report the first draft genome sequence of an E. toletana strain. PMID- 23661483 TI - Genome Sequence of a Gamma- and UV-Ray-Resistant Strain, Deinococcus wulumuqiensis R12. AB - Deinococcus wulumuqiensis R12, isolated from radiation-polluted soil, is a red pigmented strain of the extremely radioresistant genus Deinococcus. It contains a major carotenoid, namely, deinoxanthin. Here, we present a 3.39-Mb assembly of its genome sequence, which might provide various kinds of useful information related to Deinococcus, such as about the key enzymes of its radioresistance mechanism and carotenoid biosynthetic pathways. PMID- 23661484 TI - Genome Sequences of Pseudomonas spp. Isolated from Cereal Crops. AB - Compared to those of dicot-infecting bacteria, the available genome sequences of bacteria that infect wheat and barley are limited. Herein, we report the draft genome sequences of four pseudomonads originally isolated from these cereals. These genome sequences provide a useful resource for comparative analyses within the genus and for cross-kingdom analyses of plant pathogenesis. PMID- 23661485 TI - Whole-Genome Sequences of Four Salmonella enterica Serotype Newport Strains from Humans. AB - Salmonellosis contributes significantly to the public health burden globally. Salmonella enterica serotype Newport is among Salmonella serotypes most associated with food-borne illness in the United States and China. It was thought to be polyphyletic and to contain different lineages. We report draft genomes of four S. Newport strains isolated from humans in China. PMID- 23661486 TI - Draft Genome Sequence of Myxococcus xanthus Wild-Type Strain DZ2, a Model Organism for Predation and Development. AB - Myxococcus xanthus is a member of the Myxococcales order within the Deltaproteobacteria subdivision. The myxobacteria reside in soil, have relatively large genomes, and display complex life cycles. Here, we report the whole-genome shotgun sequence of strain DZ2, which includes unique genes not found previously in strain DK1622. PMID- 23661487 TI - Complete genome sequences of two sweet potato chlorotic stunt virus isolates from china. AB - Sweet potato chlorotic stunt virus (SPCSV) was first detected in China in 2010, and several partial sequences have been determined for Chinese SPCSV isolates. This report describes the complete genome sequences of two SPCSV isolates from the Guangdong and Jiangsu provinces and will be valuable for understanding the characteristics of SPCSVs in China. PMID- 23661488 TI - Draft Genome Sequence of Strain JLT2015T, Belonging to the Family Sphingomonadaceae of the Alphaproteobacteria. AB - Strain JLT2015(T) was isolated from the southeastern Pacific, as a representative of a new genus of the family Sphingomonadaceae of the Alphaproteobacteria. Here, we present the draft genome sequence of strain JLT2015(T), which provides insight into the oligotrophic strategy of this organism. PMID- 23661489 TI - Genome Sequence of Hydrothermal Arsenic-Respiring Bacterium Marinobacter santoriniensis NKSG1T. AB - Marinobacter santoriniensis NKSG1(T) originates from metalliferous marine sediment. It can respire and redox cycle arsenic species and perform mixotrophic, nitrate-dependent Fe(II) oxidation. The genome sequence, reported here, will help further elucidate the genetic mechanisms underlying these and other potential biogeochemically relevant functions, such as arsenic and mercury resistance and hydrocarbon degradation. PMID- 23661490 TI - Subcutaneous tissue reaction and cytotoxicity of polyvinylidene fluoride and polyvinylidene fluoride-trifluoroethylene blends associated with natural polymers. AB - Cytotoxicity and subcutaneous tissue reaction of innovative blends composed by polyvinylidene fluoride and polyvinylidene fluoride-trifluoroethylene associated with natural polymers (natural rubber and native starch) forming membranes were evaluated, aiming its applications associated with bone regeneration. Cytotoxicity was evaluated in mouse fibroblasts culture cells (NIH3T3) using trypan blue staining. Tissue response was in vivo evaluated by subcutaneous implantation of materials in rats, taking into account the presence of necrosis and connective tissue capsule around implanted materials after 7, 14, 21, 28, 35, 60, and 100 days of surgery. The pattern of inflammation was evaluated by histomorphometry of the inflammatory cells. Chemical and morphological changes of implanted materials after 60 and 100 days were evaluated by Fourier transform infrared (FTIR) absorption spectroscopy and scanning electron microscopy (SEM) images. Cytotoxicity tests indicated a good tolerance of the cells to the biomaterial. The in vivo tissue response of all studied materials showed normal inflammatory pattern, characterized by a reduction of polymorphonuclear leukocytes and an increase in mononuclear leukocytes over the time (p < 0.05 Kruskal-Wallis). On day 60, microscopic analysis showed regression of the chronic inflammatory process around all materials. FTIR showed no changes in chemical composition of materials due to implantation, whereas SEM demonstrated the delivery of starch in the medium. Therefore, the results of the tests performed in vitro and in vivo show that the innovative blends can further be used as biomaterials. PMID- 23661491 TI - The cellular composition of lymph nodes in the earliest phase of inflammatory arthritis. AB - OBJECTIVES: Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease of unknown aetiology. Recent work has shown that systemic autoimmunity precedes synovial inflammation, and animal models have suggested that changes in the lymph nodes may precede those in the synovial tissue. Therefore, we investigated the cellular composition of the lymph node in the earliest phases of inflammatory arthritis. METHODS: Thirteen individuals positive for immunoglobulin M (IgM) rheumatoid factor and/or anticitrullinated protein antibodies without arthritis were included. Additionally, we studied 14 early arthritis patients (arthritis duration <=6 months, naive for disease-modifying antirheumatic drugs), and eight healthy controls. All subjects underwent ultrasound-guided inguinal lymph node biopsy. Different T- and B-lymphocyte subsets were analysed by multicolour flow cytometry. RESULTS: There was an increase in activated CD69 CD8 T cells and CD19 B cells in early arthritis patients compared with healthy controls. We also observed a trend towards increased CD19 B cells in autoantibody-positive individuals without arthritis compared with healthy controls. CONCLUSIONS: This exploratory study suggests that there is increased immune cell activation within lymph nodes of early arthritis patients as well as in autoantibody-positive individuals at risk of developing RA. This method provides a unique tool to investigate immunological changes in the lymph node compartment in the earliest phases of inflammatory arthritis. PMID- 23661492 TI - Periarticular and generalised bone loss in patients with early rheumatoid arthritis: influence of alendronate and intra-articular glucocorticoid treatment. Post hoc analyses from the CIMESTRA trial. AB - OBJECTIVES: The aims of this study were to investigate the influence of alendronate and intra-articular betamethasone treatment on bone mineral density (BMD) changes in hand, lumbar spine and femoral neck during 1 year of a treat-to target study (Cyclosporine, Methotrexate, Steroid in RA (CIMESTRA)). PATIENTS AND METHODS: A hundred and sixty patients with early, active rheumatoid arthritis (RA) received methotrexate, intra-articular betamethasone and ciclosporin /placebo-ciclosporin. Patients with Z-score <=0 also started alendronate 10 mg/day. BMD of the hand (digital x-ray radiogrammetry (DXR-BMDhand)), BMD of lumbar spine and femoral neck (dual x-ray absorptiometry (DXA-BMDlumbar spine and DXA-BMDfemoral neck)) and x-rays of hands, wrists and forefeet (modified Sharp van der Heijde score) were measured at baseline and 1 year, with complete data available in 107 patients. RESULTS: The change in BMD in hand, lumbar spine and femoral neck was negatively associated with the dose of intra-articular betamethasone (p<0.01 for all), but the bone loss in hand was modest and in the axial skeleton comparable with that of healthy individuals. Alendronate did not influence changes in DXR-BMDhand, which averaged -2.8%, whereas significant changes were observed in DXA-BMDlumbar spine and DXA-BMDfemoral neck in alendronate-treated patients (1.8% and 0.8%) compared with untreated patients ( 1.8% and -2.2%) (p<0.01 and 0.02). Alendronate did not affect the radiographic progression (alendronate-treated patients: 0 (range 0-19), non-alendronate: 0 (0 18)). CONCLUSIONS: In early active RA, intra-articular betamethasone injections added to disease-modifying antirheumatic drug (DMARD) treatment led to minimal loss of hip and lumbar BMD, and the loss could be prevented by treatment with alendronate. Alendronate treatment did not affect radiographic progression. PMID- 23661493 TI - Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-beta signalling to prevent fibrosis. AB - OBJECTIVES: Targeted therapies for systemic sclerosis (SSc) and other fibrotic diseases are not yet available. We evaluated the efficacy of heat shock protein 90 (Hsp90) inhibition as a novel approach to inhibition of aberrant transforming growth factor (TGF)-beta signalling and for the treatment of fibrosis in preclinical models of SSc. METHODS: Expression of Hsp90 was quantified by quantitative PCR, western blot and immunohistochemistry. The effects of Hsp90 inhibition were analysed in cultured fibroblasts, in bleomycin-induced dermal fibrosis, in tight-skin (Tsk-1) mice and in mice overexpressing a constitutively active TGF-beta receptor I (TbetaRI). RESULTS: Expression of Hsp90beta was increased in SSc skin and in murine models of SSc in a TGF-beta-dependent manner. Inhibition of Hsp90 by 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17 DMAG) inhibited canonical TGF-beta signalling and completely prevented the stimulatory effects of TGF-beta on collagen synthesis and myofibroblast differentiation. Treatment with 17-DMAG decreased the activation of canonical TGF beta signalling in murine models of SSc and exerted potent antifibrotic effects in bleomycin-induced dermal fibrosis, in Tsk-1 mice and in mice overexpressing a constitutively active TbetaRI. Dermal thickness, number of myofibroblasts and hydroxyproline content were all significantly reduced on treatment with 17-DMAG. No toxic effects were observed with 17-DMAG at antifibrotic doses. CONCLUSIONS: Hsp90 is upregulated in SSc and is critical for TGF-beta signalling. Pharmacological inhibition of Hsp90 effectively blocks the profibrotic effects of TGF-beta in cultured fibroblasts and in different preclinical models of SSc. These results have translational implications, as several Hsp90 inhibitors are in clinical trials for other indications. PMID- 23661494 TI - Postoperative effects of neuromuscular exercise prior to hip or knee arthroplasty: a randomised controlled trial. AB - OBJECTIVE: To investigate the postoperative efficacy of a supervised programme of neuromuscular exercise prior to hip or knee arthroplasty. METHODS: In this assessor-blinded randomised controlled trial, we included 165 patients scheduled for hip or knee arthroplasty due to severe osteoarthritis (OA). An 8-week preoperative neuromuscular supervised exercise programme was delivered twice a week for 1 h as adjunct treatment to the standard arthroplasty procedure and compared with the standard arthroplasty procedure alone. The primary outcome was self-reported physical function measured on the activities of daily living (ADL) subscale in the Hip disability and Osteoarthritis Outcome Score (HOOS) and the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaires for patients with hip and knee OA, respectively. Primary endpoint was 3 months after surgery. RESULTS: 165 patients randomised to the two groups were on average 67+/-8 years, 84 (51%) had hip OA and 92 (56%) were women. 153 patients (93%) underwent planned surgery and were evaluated postoperatively. There was no statistically significant difference in effects between hip or knee patients (p=0.7370). Three months postoperatively, no difference was found between groups for ADL (4.4, 95% CI -0.8 to 9.5) or pain (4.5, 95% CI -0.8 to 9.9). However, there was a statistically significant difference indicating an effect of exercise over the entire period (baseline to 3-months postoperatively) (p=0.0029). CONCLUSIONS: Eight weeks of supervised neuromuscular exercise prior to total joint arthroplasty (TJA) of the hip or knee did not confer additional benefits 3 months postoperatively compared with TJA alone. However, the intervention group experienced a statistically significant short-term benefit in ADL and pain, suggesting an earlier onset of postoperative recovery. TRIAL REGISTRATION: ClinicalTrials NCT01003756. PMID- 23661495 TI - Long-term outcome of rheumatoid arthritis defined according to the 2010 classification criteria. AB - OBJECTIVE: The 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria for rheumatoid arthritis (RA) have been thoroughly studied for the test characteristics but it is unclear whether '2010 RA' has a different phenotype than '1987 RA' when assessing the severity of the disease course. Therefore this study compared two long-term disease outcomes. METHODS: 1502 early arthritis patients that had no other diagnoses than RA or undifferentiated arthritis (UA) were studied on fulfilling the 1987 ACR criteria, 2010 criteria or both. The severity of joint damage was studied with yearly radiographs over 7 years. Achieving disease-modifying anti-rheumatic drug (DMARD) free sustained remission was assessed over 10-years follow-up. Multivariate normal regression and Cox-proportional hazard regression were used, adjusting for age, gender and treatment. RESULTS: 550 patients fulfilled the 1987 criteria, 788 patients the 2010 criteria and 489 both criteria sets. Patients fulfilling the 2010 criteria developed less severe radiological joint damage (p=0.023) and achieved DMARD-free sustained remission more often (HR=1.18 (0.93-1.50)) than patients fulfilling the 1987 criteria, though the latter was not statistically significant. All 1987+2010- patients were anti-citrullinated peptide antibody (ACPA)-negative. When also applying the radiologic criterion of the 2010 criteria, half of the 1987+2010- patients became 2010 criteria positive, but results on the long-term outcome remained similar. CONCLUSIONS: '2010 RA' has a milder disease course than '1987 RA'. This may have important implications for basic scientific studies and clinical trials in RA. PMID- 23661496 TI - Fast relapse upon discontinuation of tumour necrosis factor blocking therapy in patients with peripheral spondyloarthritis. PMID- 23661498 TI - Dynamics and environmental risk assessment of the herbicide glyphosate and its metabolite AMPA in a small vineyard river of the Lake Geneva catchment. AB - The use of pesticides may lead to environmental problems, such as surface water pollution, with a risk for aquatic organisms. In the present study, a typical vineyard river of western Switzerland was first monitored to measure discharged loads, identify sources, and assess the dynamic of the herbicide glyphosate and its metabolite aminomethylphosphonic acid (AMPA). Second, based on river concentrations, an associated environmental risk was calculated using laboratory tests and ecotoxicity data from the literature. Measured concentrations confirmed the mobility of these molecules with elevated peaks during flood events, up to 4970 ng/L. From April 2011 to September 2011, a total load of 7.1 kg was calculated, with 85% coming from vineyards and minor urban sources and 15% from arable crops. Compared with the existing literature, this load represents an important fraction (6-12%) of the estimated amount applied because of the steep vineyard slopes (~10%). The associated risk of these compounds toward aquatic species was found to be negligible in the present study, as well as for other rivers in Switzerland. A growth stimulation was nevertheless observed for the algae Scenedesmus vacuolatus with low concentrations of glyphosate, which could indicate a risk of perturbation in aquatic ecosystems, such as eutrophication. The combination of field and ecotoxicity data allowed the performance of a realistic risk assessment for glyphosate and AMPA, which should be applied to other pesticide molecules. PMID- 23661499 TI - Direct site-specific and highly enantioselective gamma-functionalization of linear alpha,beta-unsaturated ketones: bifunctional catalytic strategy. PMID- 23661497 TI - Invariant natural killer T (iNKT) cell exhaustion in sarcoidosis. AB - Invariant natural killer T (iNKT) cells are integral components of immune responses during many chronic diseases, yet their surface phenotypes, subset distribution, and polyfunctional capacity in this environment are largely unknown. Therefore, using flow cytometry, we determined iNKT cell phenotypic and functional characteristics in subjects with chronic inflammatory disease sarcoidosis and matched controls. We found that sarcoidosis subjects displayed lower iNKT-cell frequencies, which correlated with lung fibrosis, C-reactive protein levels, and other measures of clinical disease. The CD4(-) CD8(-) (double negative, DN) iNKT-cell population was selectively lower in diseased individuals and the remaining DN iNKT cells exhibited higher frequencies of the activation markers CD69 and CD56. Functionally, both total IFN-gamma(+) and the dual functional IFN-gamma(+) TNF-alpha(+) iNKT cells were decreased in sarcoidosis subjects and these functional defects correlated with total iNKT-cell circulating frequencies. As the loss of polyfunctionality can reflect functional exhaustion, we measured the surface antigens programmed death-1 receptor and CD57 and found that levels inversely correlated with dual-functional iNKT-cell percentages. These findings reveal that, similar to traditional T cells, iNKT cells may also undergo functional exhaustion, and that circulating iNKT-cell frequencies reflect these defects. Programmed death-1 receptor antagonists may therefore be attractive therapeutic candidates for sarcoidosis and other iNKT-cell-mediated chronic diseases. PMID- 23661500 TI - SERPINB2 down-regulation contributes to chemoresistance in head and neck cancer. AB - Resistance to cisplatin-based chemotherapy is responsible for the majority of deaths from head and neck squamous cell carcinoma (HNSCC). In this study, using genome-wide gene expression analysis to investigate potential molecular mediators of HNSCC chemoresistance, we identified SERPINB2, a known inhibitor of extracellular serine proteinase urokinase-type plasminogen activator (uPA), as an important candidate. Whereas SERPINB2 is known to function as a suppressor of uPA molecular cascades, many of which play important roles in tumor invasion and metastasis, a role for SERPINB2 in cancer drug resistance has not been examined. By using quantitative real-time PCR and Western blot analysis, we determined that SERPINB2 mRNA and protein levels correlated with chemoresistance in HNSCC cell lines, and significantly lower SERPINB2 expression levels were observed in two cisplatin resistant HNSCC subclones compared to their isogenic drug-sensitive parental lines. Immunohistochemical analysis of HNSCC tumor tissues from patients treated with neoadjuvant cisplatin-based chemotherapy (n = 67 cases) revealed a significant association between SERPINB2 protein levels, tumor differentiation and patient relapse. Moreover, SERPINB2 down-regulation was a strong predictor of reduced overall survival in patients with HNSCC who received cisplatin-based chemotherapy (P = 0.001, log rank test). Studies using either siRNA-mediated down regulation or forced over-expression of SERPINB2 in HNSCC cell lines confirmed a functional role for SERPINB2 in drug resistance. The findings were further supported using chemical inhibitors of STAT3 activity (a downstream effecter of uPAR signaling pathway), showing that STAT3 suppression altered HNSCC cell line cisplatin sensitivity. This is the first report on a role for SERPINB2 in acquired resistance to cisplatin in patients with HNSCC. PMID- 23661501 TI - Human sperm CRISP2 is released from the acrosome during the acrosome reaction and re-associates at the equatorial segment. AB - Sperm CRISP2 has been proposed to be involved in sperm-egg fusion. After the acrosome reaction, it appears at the equatorial segment (EqS) of human sperm; the mechanism underlying the appearance of CRISP2 at the EqS remains unknown, though. Here, we provide evidence showing the re-association of sperm acrosomal CRISP2 at the EqS during the acrosome reaction. Results showed that F-actin is not involved in the relocalization of CRISP2. We found that basic, but not acidic, conditions can solubilize CRISP2 from sperm cells, suggesting that CRISP2 is a component of the acrosome and that it is released from the acrosome during the acrosome reaction. Purified, biotinylated human sperm acrosomal CRISP2 binds to the EqS of acrosome-reacted sperm in a dose-dependent manner, revealing that CRISP2 detected at the EqS of acrosome-reacted sperm comes from the population stored in the acrosome. The association of CRISP2 at the EqS is very strong, and does not depend on ionic interactions or intermolecular disulfide bonds. Interestingly, the restriction of CRISP2 at the EqS was diminished when EGTA was present in the media, indicating that Ca(2+) is required for maintaining CRISP2 at the EqS. This study supports the possibility that CRISP2 may help modify the EqS membrane to make this domain fusion-competent. PMID- 23661502 TI - Metal injection molding as enabling technology for the production of metal prosthesis components: electrochemical and in vitro characterization. AB - Industrial manufacturing of prosthesis components could take significant advantage by the introduction of new, cost-effective manufacturing technologies with near net-shape capabilities, which have been developed during the last years to fulfill the needs of different technological sectors. Among them, metal injection molding (MIM) appears particularly promising for the production of orthopedic arthroplasty components with significant cost saving. These new manufacturing technologies, which have been developed, however, strongly affect the chemicophysical structure of processed materials and their resulting properties. In order to investigate this relationship, here we evaluated the effects on electrochemical properties, ion release, and in vitro response of medical grade CoCrMo alloy processed via MIM compared to conventional processes. MIM of the CoCrMo alloy resulted in coarser polygonal grains, with largely varying sizes; however, these microstructural differences between MIM and forged/cast CoCrMo alloys showed a negligible effect on electrochemical properties. Passive current densities values observed were 0.49 uA cm(-2) for MIM specimens and 0.51 uA cm(-2) for forged CoCrMo specimens, with slightly lower transpassive potential in the MIM case; open circuit potential and Rp stationary values showed no significant differences. Moreover, in vitro biocompatibility tests resulted in cell viability levels not significantly different for MIM and conventionally processed alloys. Although preliminary, these results support the potential of MIM technology for the production of CoCrMo components of implantable devices. PMID- 23661503 TI - With(out) a little help from my friends: an IL-12/CD40L-mediated feed-forward loop between CD8+ T cells and DCs. AB - CD40-CD40L interactions are important for both antigen-dependent B-cell differentiation and effector and memory T-cell formation. The prevailing view is that CD40L is expressed on activated CD4(+) T cells, which enables them to provide help to high-affinity B cells in GCs and to license DCs for efficient induction of CD8(+) T-cell responses. Interestingly, CD8(+) T cells themselves can also express CD40L and, in this issue of the European Journal of Immunology, Thiel and colleagues [Eur. J. Immunol. 2013. 43: 1511-1517] show that CD40L expression on these cells can be part of a self-sustaining feed-forward loop, in which expression of CD40L is induced by IL-12 and TCR signaling. This provides a paradigm shift in our thinking about the requirements of effector CD8(+) T-cell development and the role herein of CD4(+) T cells to provide help in this process. PMID- 23661505 TI - Recombinant human follicle-stimulating hormone and transforming growth factor alpha enhance in vitro maturation of porcine oocytes. AB - The biological functions of recombinant human follicle-stimulating hormone (FSH) and transforming growth factor-alpha (TGF-alpha) on in vitro maturation of porcine oocytes were investigated. Cumulus-oocyte complexes were matured in defined porcine oocyte medium containing 0-0.1 IU/ml FSH in the presence or absence of 10 ng/ml TGF-alpha. The percentage of oocytes reaching metaphase II was significantly higher with the addition of 0.01-0.1 IU/ml FSH compared with no addition, and was further enhanced in the presence of TGF-alpha. The rates of sperm penetration and blastocyst formation were significantly higher with the addition of 0.05-0.1 IU/ml FSH compared with no addition after in vitro fertilization and embryo culture. There was no beneficial effect of FSH and TGF alpha on nuclear maturation of denuded oocytes. The specific EGF receptor inhibitor, AG1478, completely inhibited TGF-alpha-induced meiotic resumption, but did not completely prevent the stimulatory effect of FSH. Addition of both FSH and TGF-alpha significantly enhanced cumulus expansion compared with no addition. When cumulus expansion-related genes (HAS2, HAPLN1, and VCAN) mRNA expression in COCs was measured during in vitro maturaiton, addition of both of FSH and TGF alpha upregulated the expression of HAS2 mRNA after 20 hr culture and HAPLN1 mRNA after 44 hr culture compared with no addition. Expression of VCAN mRNA was significantly higher in the presence of FSH compared with addition of TGF-alpha alone. These results suggest that FSH and TGF-alpha synergistically enhance porcine oocyte maturation via cumulus cells, and act through different signaling pathways. PMID- 23661506 TI - TPD52 represents a survival factor in ERBB2-amplified breast cancer cells. AB - TPD52 and ERBB2 co-expression has been persistently reported in human breast cancer and animal models of this disease, but the significance of this is unknown. We identified significant positive associations between relative TPD52 and ERBB2 transcript levels in human diagnostic breast cancer samples, and maximal TPD52 expression in the hormone receptor (HR)- and ERBB2-positive sub group. High-level TPD52 expression was associated with significantly reduced metastasis-free survival, within the overall cohort (log rank test, P = 8.6 * 10( 4), n = 375) where this was an independent predictor of metastasis-free survival (hazard ratio, 2.69, 95% confidence interval 1.59-4.54, P = 2.2 * 10(-4), n = 359), and the HR- and ERBB2-positive sub-group (log rank test, P = 0.035, n = 47). Transient TPD52 knock-down in the ERBB2-amplified breast cancer cell lines SK-BR-3 and BT-474 produced significant apoptosis, both singly and in combination with transient ERBB2 knock-down. Unlike ERBB2 knock-down, transient TPD52 knock down produced no reduction in pAKT levels in SK-BR-3 or BT-474 cells. We then derived multiple SK-BR-3 cell lines in which TPD52 levels were stably reduced, and measured significant inverse correlations between pERBB2 and TPD52 levels in viable TPD52-depleted and control cell lines, all of which showed similar proliferative capacities. Our results therefore identify TPD52 as a survival factor in ERBB2-amplified breast cancer cells, and suggest complementary cellular functions for TPD52 and ERBB2. PMID- 23661504 TI - Quantifying repetitive speech in autism spectrum disorders and language impairment. AB - We report on an automatic technique for quantifying two types of repetitive speech: repetitions of what the child says him/herself (self-repeats) and of what is uttered by an interlocutor (echolalia). We apply this technique to a sample of 111 children between the ages of four and eight: 42 typically developing children (TD), 19 children with specific language impairment (SLI), 25 children with autism spectrum disorders (ASD) plus language impairment (ALI), and 25 children with ASD with normal, non-impaired language (ALN). The results indicate robust differences in echolalia between the TD and ASD groups as a whole (ALN + ALI), and between TD and ALN children. There were no significant differences between ALI and SLI children for echolalia or self-repetitions. The results confirm previous findings that children with ASD repeat the language of others more than other populations of children. On the other hand, self-repetition does not appear to be significantly more frequent in ASD, nor does it matter whether the child's echolalia occurred within one (immediate) or two turns (near-immediate) of the adult's original utterance. Furthermore, non-significant differences between ALN and SLI, between TD and SLI, and between ALI and TD are suggestive that echolalia may not be specific to ALN or to ASD in general. One important innovation of this work is an objective fully automatic technique for assessing the amount of repetition in a transcript of a child's utterances. PMID- 23661507 TI - Selective catalytic hydrodefluorination as a key step for the synthesis of hitherto inaccessible aminopyridine derivatives. PMID- 23661508 TI - Chemical exchange saturation transfer effect in blood. AB - PURPOSE: In this report, the feasibility of using blood as an agent for Chemical Exchange Saturation Transfer (CEST) effect is investigated. METHODS: The CEST effect of porcine blood samples was investigated on a 3.0 T MRI scanner using various power levels and on a 14.1 T NMR spectrometer. As a proof-of-concept that CEST can be used to image blood in vivo, the technique was applied in two locations of healthy human volunteers, namely, the femoral artery and the M1 segment of the middle cerebral artery. RESULTS: The blood sample experiments showed that maximum CEST Magnetization Transfer Ratio asymmetry (MTRasym) values of ~ 12% were achieved, with likely contributions from multiple blood components. These findings were confirmed during the in vivo experiments where CEST signal of blood was clearly greater than surrounding muscular (2%) and brain tissue (3%). CONCLUSION: Ex vivo and in vivo results show that blood is a suitable CEST agent that generates sufficient CEST contrast relative to surrounding tissue. PMID- 23661509 TI - Improvement of the compressive strength of a cuttlefish bone-derived porous hydroxyapatite scaffold via polycaprolactone coating. AB - Cuttlefish bones (CBs) have emerged as attractive biomaterials because of their porous structure and components that can be converted into hydroxyapatite (HAp) via a hydrothermal reaction. However, their brittleness and low strength restrict their application in bone tissue engineering. Therefore, to improve the compressive strength of the scaffold following hydrothermal conversion to a HAp form of CB (CB-HAp), the scaffold was coated using a polycaprolactone (PCL) polymer at various concentrations. In this study, raw CB was successfully converted into HAp via a hydrothermal reaction. We then evaluated their surface properties and composition by scanning electron microscopy and X-ray diffraction analysis. The CB-HAp coated with PCL showed improved compressive performance and retained a microporous structure. The compressive strength was significantly increased upon coating with 5 and 10% PCL, by 2.09- and 3.30-fold, respectively, as compared with uncoated CB-HAp. However, coating with 10% PCL resulted in a reduction in porosity. Furthermore, an in vitro biological evaluation demonstrated that MG-63 cells adhered well, proliferated and were able to be differentiated on the PCL-coated CB-HAp scaffold, which was noncytotoxic. These results suggest that a simple coating method is useful to improve the compressive strength of CB-HAp for bone tissue engineering applications. PMID- 23661510 TI - Vitamin A notches up CD11b hi DC development. AB - Vitamin A and its metabolite retinoic acid influence various aspects of immunity. Although the capacity of vitamin A to condition intestinal CD103(+) DCs to imprint tissue-specific homing programs onto activated lymphocytes is well documented, it is unclear whether vitamin A also regulates DC populations in other tissues. A study published in this issue of the European Journal of Immunology, Beijer et al. [Eur. J. Immunol. 2013. 43: 1608-1616] now demonstrates that vitamin A exerts profound effects on the subset composition of splenic DCs. By resolving that splenic ESAM(hi) CD11b(hi) DCs are preferentially responsive to regulation by vitamin A, these novel insights not only further support the notion that ESAM expression marks two distinct lineages of splenic CD11b(hi) DCs, but also provide an important extension to our understanding of how vitamin A influences the immune system. PMID- 23661511 TI - Serum secretory phospholipase A2-IIa (sPLA2-IIA) levels in patients surviving acute myocardial infarction. AB - BACKGROUND: The increase of secretory phospholipase A2-IIa (sPLA2-IIa) in culprit coronary lesions is associated with myocardial infarction, and the increase of sPLA2-IIa in peripheral plasma levels has a significant risk and prognostic value in patients with coronary artery disease. Little is known about the prognostic significance of elevated serum sPLA2-IIa in post-acute myocardial infarction (post-AMI) patients. OBJECTIVES: The present study is designed to investigate the potential association between serum sPLA2-IIa and prognosis in post-acute myocardial infarction (post-AMI) patients. PATIENTS AND METHODS: From Oct 1998 to Sep 2008, a total of 964 post-AMI patients with serum samples collected in the convalescent stage were studied. Serum levels of sPLA2-IIa were measured by ELISA. According to the optimal cut-off value for sPLA2-IIa concentration, patients were then divided into 2 groups. Categorical variables were compared between the 2 groups using the chi2 test. All continuous variables are described as mean +/- SD and were compared using Student's t-test. Statistical associations between clinicopathological observations and sPLA2-IIa levels were determined using the Mann-Whitney U test. The clinical value of sPLA2-IIa level as a prognostic parameter was evaluated using the Cox's proportional hazards model. RESULTS: During a median follow-up period of 1,462 days, 123 patients (12.7%) had adverse events (all-cause mortality, n=52; non-fatal MI, n=31; readmission for heart failure [HF], n=40). Patients were divided into 2 groups according to a serum sPLA2-IIa level of 360 ng/dl, which was determined to be the optimal cut off for discriminating all-cause mortality based on the maximum value of the area under the receiver operating characteristic curve. Patients with elevated sPLA2 IIa (> 360 ng/dl, n=164) had a significantly higher prevalence of death (18.3% [30/164] vs. 2.75% [22/800] p < 0.001) and readmission for HF (14% [23/164/ vs. 2.1% [17/800], p < 0.0001), but not of non-fatal MI (4.88% [8/164]vs. 2.87% [23/800], p = 0.096), compared to those with sPLA2-IIa < 360 ng/dl. Multivariate Cox regression analysis indicated that elevated serum sPLA2-IIa was associated with an increased risk of mortality and readmission for HF. CONCLUSIONS: Elevated serum sPLA2-IIa during the convalescent stage of AMI predicted long-term mortality and readmission for HF after survival discharge in the post-AMI patients. PMID- 23661512 TI - Predictive value of plasma galectin-3 in patients with chronic heart failure. AB - AIM: To study the predictive value of plasma galectin-3 in patients with chronic heart failure (CHF). MATERIALS AND METHODS: Patients with CHF (New York Heart Association functional class II-IV) caused by coronary heart disease were recruited. The levels of plasma galectin-3 and NT-proBNP were measured by enzyme linked immuno sorbent assay. Echocardiography was performed to determine the diastolic left atrial diameter (LAD), left ventricular end-diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF). Receiver-operating characteristic (ROC) curve was used to analyze the prognostic value of galectin-3 or NT-proBNP for CHF. RESULTS: The level of galectin-3 was significantly higher in NYHA functional class III and IV compared with that in control (p < 0.05 and p < 0.01, respectively). The level of plasma galectin-3 was positively correlated with LAD (r = 0.271, p < 0.05) and LVEDD (r = 0.480, p < 0.01), but negatively correlated with LVEF (r = -0.683, p < 0.01). The level of plasma NT-proBNP was positively correlated with LAD (r = 0.481, p < 0.01) and LVEDD (r = 0.270, p < 0.05), but negatively correlated with LVEF (r = -0.516, p < 0.01). AUC was 0.798 when the level of plasma galectin-3 was more than 7.52 ng/ml. The sensitivity to predict CHF was 62.9%, and the specificity was 90%. AUC was 0.901 when the level of plasma NT-proBNP was more than 1143 pg/ml. The sensitivity to predict CHF was 92.8% and the specificity was 85%. CONCLUSIONS: The level of plasma galectin-3 is related to the changes of left ventricular structure and function, indicating that galectin-3 may have been involved in the process of left ventricular remodeling in CHF. The specificity of galectin-3 to predict CHF is higher than NT proBNP, but not the sensitivity. PMID- 23661513 TI - Non-valvular atrial fibrillation in the elderly; preliminary results from the National AFTER (Atrial Fibrillation in Turkey: Epidemiologic Registry) Study. AB - OBJECTIVE: This study aimed at the assessment of the clinical approach to atrial fibrillation (AF) in the older population and the consistency with the guidelines based on the records of the multicenter, prospective AFTER (Atrial Fibrillation in Turkey: Epidemiologic Registry) study. PATIENTS AND METHODS: 2242 consecutive patients admitted to the Cardiology Outpatient Clinics of 17 different tertiary Health Care Centers with at least one AF attack determined on electrocardiographic examination, were included in the study. Among the patients included in the study, 631 individuals aged 75 years and older were analyzed. RESULTS: The mean age of the patients was determined as 80.3+/-4.2 years. The most frequent type of AF in geriatric population was the persistent-permanent type with a percentage of 88%. 60% of the patients with AF were female. Hypertension was the most common co-morbidity in patients with AF (76%). While in 16% of patients a history of stroke, transient ischemic attack or systemic thromboembolism was present, a history of bleeding was present in 14% of the patients. 37% of the patients were on warfarin treatment and 60% of the patients were on aspirin treatment. In 38% of the patients who were on oral anticoagulant treatment, INR level was in the effective range. CONCLUSIONS: The rate of anticoagulant use in the elderly with AF was 37% and considering the reason of this situation was the medication not being prescribed by the physician, one should pay more attention particularly in the field of treatment. PMID- 23661514 TI - Blood pressure control and clustering of cardiovascular risk factors in Mediterranean post-menopausal hypertensive women. AB - BACKGROUND: Control of hypertension is unsatisfactory among older women. Data about Mediterranean countries are not currently reported. AIM: The aim of the present study was to describe the features of blood pressure (BP) control and the clustering of other cardiovascular (CV) risk factors in Mediterranean post menopausal hypertensive women. PATIENTS AND METHODS: We consecutively selected 516 post-menopausal female patients (mean age 69+/-11 years) with drug-treated essential hypertension (ESH/ESC grade 1 and 2) for this cross-sectional study. All patients were divided in 4 groups: < 60 years; 60-69 years; 70-79 years; >= 80 years. RESULTS: The Kruskal-Wallis analysis of variance showed a significant difference among the 4 age groups both for systolic BP (p < 0.001) and diastolic BP (p < 0.01). Mann-Whitney test for multiple comparisons of each age group vs. octogenarians demonstrated that there is a significant incremental trend of SBP through the age decades. Mean diastolic BP values were significantly higher in younger patients (age decades < 60 and 60-69 years, p < 0.01 and p < 0.05 respectively), while in patients aged 70-79 years there was no difference vs. octogenarians. Dyslipidemia was the more prevalent clustered risk factor with a peak rate of 49% in patients aged 60-69 years, statistically different (p < 0.05) from octogenarians. Global BP control (i.e. treated BP < 140/90 mmHg) was low (33.5% in the whole population) and there was no trend through age decades. CONCLUSIONS: BP control varied across age groups, but was poor. Nevertheless, the studied population appeared to be at low cardiovascular risk, due to a modest clustering of traditional risk factors. PMID- 23661515 TI - Which is a better treatment for carotid artery stenosis: stenting or endarterectomy? AB - Carotid stenosis amenable to surgical or interventional revascularization accounts for 5-12% of all new strokes. Several randomized trials have shown that carotid endarterectomy (CEA) for the treatment of symptomatic and asymptomatic carotid stenosis is superior to medical treatment. Application of a carotid artery stent (CAS) representing a good alternative for many patients. CAS application has become comparatively safe with the use of embolism-preventive systems developed in recent years. Complication rates reported in some randomized trials and case studies in the literature are similar with CEA. CAS may be recommended as the first choice or alternative treatment for patients with symptomatic stenosis carrying high risks for open surgery. However, more randomized studies are necessary to recommend CAS for patients carrying at low surgical risks or patients with asymptomatic stenosis. This is a systematic review of the literature investigating the effectiveness of the treatment methods for carotid artery stenosis. PMID- 23661516 TI - Hydrogen-rich saline reduces airway remodeling via inactivation of NF-kappaB in a murine model of asthma. AB - BACKGROUND AND OBJECTIVES: Recent studies suggest that hydrogen has great therapeutic and prophylactic potential against organ injury caused by oxidative stress and inflammation. Here we investigated the effect of hydrogen-rich saline on airway inflammation and remodeling in a murine model of asthma. MATERIALS AND METHODS: Asthma was induced by ovalbumin (OVA) sensitization and challenge. Then mice were treated with normal saline or hydrogen-rich saline at low and high doses. Cell counts and cytokine levels in bronchoalveolar lavage fluid (BALF) were determined, bronchial tissue was analyzed for pathology, and expression of MUC5AC, collagen III, VEGF, and total and phosphorylated NF-kappaB p65 was measured. Immunohistochemistry was used to identify levels and localization of VEGF expression in lung. RESULTS: The results showed that hydrogen-rich saline reduced cell counts and levels of cytokines IL-4, IL-5, IL-13 and TNF-alpha in BALF. Hydrogen-rich saline treatment also significantly decreased mucus index, collagen deposition, and expression of MUC5AC, collagen III and VEGF. The ratio of phospho-NF-kappaB p65 to total NF-kappaB p65 was much lower in mice treated with hydrogen-rich saline than in untreated mice. These effects of hydrogen-rich saline on airway inflammation and remodeling were dose-dependent. CONCLUSIONS: These findings suggest that hydrogen-rich saline reduces airway inflammation and remodeling in OVA-exposed mice by inhibiting NF-kappaB. PMID- 23661517 TI - DNA microarray-based screening of differentially expressed genes related to acute lung injury and functional analysis. AB - OBJECTIVES: The purpose of this study was to identify differentially expressed genes (DEGs) related to acute lung injury (ALI) induced by sepsis with DNA microarray. MATERIALS AND METHODS: Gene expression profile GSE10474 was downloaded from Gene Expression Omnibus (GEO) database which includes 34 samples, among which 13 patients with ALI + sepsis and 21 patients with sepsis alone. The DEGs were identified between ALI + sepsis and sepsis alone samples using R, which were further analyzed using bioinformatics methods. Firstly, HitPredict was used to search protein-protein interactions of the DEGs. Secondly, WebGestalt was adopted for functional enrichment analysis of genes in the interaction networks. Finally, DNA methylation was analyzed to explain the differential expression. RESULTS: A total of 12 genes were identified as DEGs by comparing chip data from ALI + sepsis samples and those from sepsis alone samples, among which occludin (OCLN) and major histocompatibility complex, class II, DQ beta 1 (HLA-DQB1) had 21 and 6 interactors, respectively. Functional enrichment analysis revealed several significantly over-represented terms: cellular component organization, macromolecular organization and biosynthesis, and response to stimulus. In addition, methylation was found in the promoters of OCLN and HLA-DQB1. CONCLUSIONS: We screened DEGs in septic ALI samples, and several interesting genes were obtained, especially OCLN and HLA-DQB1. They may be developed into marker genes for diagnosis or treatment of ALI. PMID- 23661518 TI - Inhibition of activin receptor-like kinase 5 induces matrix metallopeptidase 9 expression and aggravates lipopolysaccharide-induced pulmonary injury in mice. AB - BACKGROUND: TGF-beta (Transforming Growth Factor-beta) mediates its biological effects through members of activin receptor-like kinase (ALK) family and TGF beta/Smad3 signaling link inflammation to pulmonary fibrosis. AIM: The aim of this study was to evaluate the role of SB431542 as a specific inhibitor of Activin receptor-Like Kinase 5 (ALK5) in pneumonic injury. MATERIALS AND METHODS: Anesthetized and endo-tracheally intubated C57BL/6 mice were randomized to three groups: the control group with intra-tracheal instillation of 1.5 mg/kg normal saline (NS); LPS stimulation group with intra-tracheal instillation of 3 mg/kg LPS (lipopolysaccharide); and LPS+SB431542 group with intra-peritoneal (i.p.) injection of 4.2 mg/kg SB431542 1 h before intra-tracheal instillation of 3 mg/kg LPS. The lung tissue was obtained 6 h after injury, and the degree of pulmonary injury was evaluated by pathologic scoring. The lung wet/dry weight ratio was measured. TNF-alpha, IL-1beta, and MMP-9 (matrix metallopeptidase-9) mRNA expression levels were assayed by real time PCR (polymerase chain reaction). The content of MMP-9 total protein was measured by Western blotting. The content of active MMP-9 was detected by gelatin zymography. Location of MMP-9 in mouse lung tissue was monitored by immunohistochemistry. RESULTS: The results showed that (1) pathologic changes including interstitial pulmonary edema, neutrophil infiltration, alveolar edema and hemorrhage were observed 6 h after LPS instillation. The lung wet/dry weight rate and pathologic scores confirmed that SB431542 administration aggravated LPS injury to the mouse lung; (2) the amount of TNF-alpha and IL-1beta mRNA expression in LPS groups was significantly higher than that in the control group, and the highest in LPS+SB431542 group; (3) the amount of MMP-9 mRNA and MMP-9 protein expression and active MMP-9 in the lung tissue of LPS groups was significantly higher than that in the control group 6 h after injury, and the highest in LPS+SB431542 group; and (4) MMP-9 expression was mainly observed in the airway epithelial cells, vascular smooth muscle cells and cytoplasm of inflammatory cells as shown by immunohistochemistry, and brownish yellow uniformed stained areas were also seen in the exudate from part of the alveoli. CONCLUSIONS: These results indicate that blocking the activity of TGF beta/Smad pathway by specific inhibitor SB431542 of ALK5 promoted the releaser of large amounts of TNF-alpha, IL-1beta and other pro-inflammatory cytokines from the lung tissue of mice sustaining acute lung injury (ALI). At the same time, the amount and activity of MMP-9 expression in the lung were increased, and MMP-9 expression was mainly located in the airway epithelial cells, vascular smooth muscle cells and inflammatory cells, causing increased permeability of the pulmonary blood vessels, degradation of the extracellular matrix and destruction of the normal lung tissue structures, which directly or indirectly promotes the progression of pulmonary inflammatory responses and aggravates ALI. PMID- 23661519 TI - Prospective follow up of fertility after adolescent laparoscopic varicocelectomy. AB - BACKGROUND: Varicocele associated with infertility has been recognized for years. Referential literature provides few papers, even meta-analyses which did not confirm the success of surgery related to the increasing of the semen quality. AIM: The purpose of the presented paper is referred in arising the quantum of knowledge related to usefulness of surgery in varicocele treatment. PATIENTS AND METHODS: The varococele incidence was established in premature age (7-18) in population of 969 boys. In those who suffered from varicocele, we estimated their semen analysis parameters before and three months after the surgery, and followed up the pregnancy rate in surgically treated subjects many years after the treatment. RESULTS: A prevalence of 9.7% in premature age, significantly raising in the group aged 15-18 was showed. After the laparoscopic varicocelectomy, all of the semen parameters (left testicular volume, pH, sperm count, abnormal forms and viability) were improved, since the semen volume and the progressive motility not significantly. Since we observed adolescent varicocele, some of the semen parameters initialy have not been out of reference limits. Following the surgically treated subjects for next 12-17 years, the pregnancy rate is at least 75%, since not all of them have been married yet. CONCLUSIONS: We recorded improvement of two out of three parameters of fertility after the operation in a group of 23 surgically treated patients. This fact encourages those who advocate surgical treatment of varicocele in adolescents, since the early therapy would prevent fertility disorders. PMID- 23661520 TI - Effects of infectious complications on patients' survival in peritoneal dialysis. AB - AIM: To investigate the impacts of infectious complications on mortality and morbidity; and to identify the other potential factors effective in mortality in peritoneal dialysis (PD) patients. PATIENTS AND METHODS: We included patients who initiated therapy between 2001-2011. Patients were divided into two groups regarding to presence or absence of infectious complications. Socio-demographic data and clinical courses were compared and the reasons for PD withdrawal were obtained. Survival analysis of all patients was performed and the effects of infectious complications on mortality were investigated. RESULTS: 301 patients were included in this retrospective study. 214 patients (mean follow-up time 28.7+/-16.5 months) had infection history, 87 patients (mean follow-up time 48.9+/-29.6 months) had no infection history. There were no statistically significant difference in comparison of the groups in terms age, gender, education levels, hemodialysis history. In patients with infection history, 465 peritonitis and 213 catheter exit site infection attacks were diagnosed. The most frequently agent was methicillin-sensitive Staphylococcus aureus and Methicillin resistant Staphylococcus aureus in both conditions, while 25% of catheter exit site infection and 25% of peritonitis attacks were culture negative. During follow-up period, 60 patients transferred to hemodialysis, 58 patients died, 18 patients had renal transplantation in patients with infection history. In other group, 27 patients died, 23 patients had renal transplantation and 11 patients transferred to hemodialysis. Mean survival times were 56.3+/-2.8 months in patients with infection history and 86.8+/-6.1 months in other group. Mortality rate was found higher in patients with infection history (long-rank: 0.030). PD preference (OR: 5.213, p < 0.001), pretreatment low serum albumin (OR: 0.378, p = 0.001), low hemoglobin levels (OR: 0.810, p = 0.029) were found as predictors of survival in patients with infection history. CONCLUSIONS: Infectious complications have negative effects on patient survival. Nature of PD preference, initial hypoalbuminemia and anemia were found to increase the mortality rate. The major causes of deaths were peritonitis and/or sepsis in patients with infectious complications, while the major cause of death was cardiac reasons in patients without infectious complications. PMID- 23661521 TI - A comparative study of beneficial effects of Olanzapine and sodium valproate on aggressive behavior of patients who are on methadone maintenance therapy: a randomized triple blind clinical trial. AB - BACKGROUND: Previous studies have shown a high prevalence of aggressive behavior in abstinent heroin users who are on methadone maintenance therapy (MMT) compared with healthy controls. Some studies suggest that olanzapine and valproate may be effective in managing aggressive behavior and preventing a relapse of substance misuse in patients on methadone regime. AIM: The aim of the present study was to evaluate and compare the effectiveness of these medications in the management of aggressive behavior and prevention of relapse in patients maintained on methadone. PATIENTS AND METHODS: Two hundred and one patients on MMT were randomized into two treatment groups of olanzapine (2.5-15 mg) and sodium valproate (600-1000 mg). Both groups were treated for 12 weeks. Patients visited the clinic twice weekly to receive medication. Patients' urine samples were screened for trace of any illicit substances on each visit. Upon each consultation, the clinicians, using overt aggression scale-modified version (OAS M), assessed the degree and frequency of aggressiveness in each patient. RESULTS: Fifty three patients completed the trial. Both medications significantly reduced the overt aggression and subscales of irritability, aggression and suicidality. Improvement was more pronounced in the group treated with olanzapine. The mean percentages of positive urine samples for morphine, cannabis and methamphetamine abuse for the 12 weeks period of the study were not significantly different between the two groups. CONCLUSIONS: Both olanzapine and sodium valproate are useful as an adjunctive agent in reducing aggressive behavior in heroin dependent individuals who are on MMT, but the beneficial effect of olanzapine was greater than sodium valproate in this respect. PMID- 23661522 TI - Behavioral profile of Hypericum perforatum (St. John's Wort) extract. A comparison with standard antidepressants in animal models of depression. AB - BACKGROUND AND OBJECTIVES: Hypericum (H.) perforatum, popularly called St. John's Wort has been used traditionally for the treatment of anxiety, depression and as a nerve tonic. Large amount of clinical and animal experimental data demonstrate that H. perforatum acts by biochemical mechanisms similar to the tricyclic antidepressants or serotonin reuptake inhibitors. However, its efficacy in comparison to standard antidepressant drugs is not well studied. The present study evaluated H. perfortum extract in animal models of depression compared to clinically used antidepressants. MATERIALS AND METHODS: The effects of standardized extract of H. perforatum was compared with standard antidepressants using animal models of depression such as forced swim test (FST), yohimbine induced lethality test, pnetylenetetrazole (PTZ) induced convulsion and locomotor activity tests. Different doses of the plant extract and standard drugs were administered to rats or mice intraperitoneally (i.p). RESULTS: In the FST, H. perforatum extract (30-90 mg/kg i.p.) caused a dose dependent reduction in immobility time in rats with maximal effect being 53% at 90 mg/kg. This effect was reversed at higher doses (100 mg/kg) showing a U-shaped dose response curve. Fluoxetine and imipramine (30-70 mg/kg i.p.) produced similar reduction in the immobility time in rats. Venlafaxine exhibited weak antidepressant effect. H. perforatum extract (30-100 mg/kg i.p.), dothiepin (10-50 mg/kg i.p.), fluoxetine (30-60 mg/kg i.p.) and venlafaxine (20-40 mg/kg i.p.) potentiated yohimbine induced lethality. PTZ induced toxicity was also enhanced with these agents. In the locomotor activity test H. perforatum decreased the locomotor counts of mice similar to standard antidepressants. CONCLUSIONS: H. perforatum has antidepressant properties similar to standard antidepressants. The antidepressant profile of H. perforatum is closely related to the selective serotonin reuptake inhibitors class of antidepressants. PMID- 23661523 TI - A randomized clinical trial with two doses of a omega 3 fatty acids oral and arginine enhanced formula in clinical and biochemical parameters of head and neck cancer ambulatory patients. AB - INTRODUCTION: Postsurgical patients with head and neck cancer could have a high rate of ambulatory complications. The aim was to investigate whether oral ambulatory nutrition of head and neck cancer patients with recent weight loss, using two different doses of an omega 3 fatty acids and arginine enhanced diets could improve nutritional parameters. DESIGN: At Hospital discharge post surgical head and neck cancer patients (n=37) were asked to consume two or three cans per day of a designed omega 3 fatty acid and arginine enhanced supplement for a twelve week period. RESULTS: Albumin, prealbumin, transferrin and lymphocytes levels improved in both groups. Weight, fat mass and fat free mass improved during supplementation in group II (3 bricks per day). No differences were detected in anthropometric parameters in group I. Gastrointestinal tolerance with both formulas was good, no episodes were reported. There are no differences between both formulas on postsurgical complications rates. CONCLUSIONS: Omega 3 and arginine enhanced formulas improved blood protein concentrations and lymphocyte levels in ambulatory postoperative head and neck cancer patients. A high dose of arginine and omega 3 fatty acids formula improved weight, too. PMID- 23661524 TI - Significance of relaxin-2 expression in hepatocellular carcinoma: relation with clinicopathological parameters. AB - BACKGROUND: A number of putative roles, including the modulation of tumor growth, neovascularization, metastasis and oncogenic progression, have been correlated to relaxin-2 overexpression. However, the clinical significance of relaxin-2 expression in hepatocellular carcinoma (HCC) remains unclear. The aim of this study was to investigate the expression of relaxin-2 in HCC and determine its correlation with tumor progression and prognosis. PATIENTS AND METHODS: 180 HCC patients who had undergone curative liver resection were selected and immunohistochemistry was performed to analyze relaxin-2 expression in the respective tumors. RESULTS: Immunohistochemistry confirmed relaxin-2 overexpression in HCC tissues compared with their adjacent nonneoplastic tissues (p < 0.01). Additionally, immunostaining showed more relaxin-2 positive cells in the higher tumor grade (III) than in the lower tumor stage (I, II; p = 0.026). Moreover, HCC patients with high relaxin-2 expression were significantly associated with lower 5-year overall survival (p < 0.01) and lower 5-year disease free survival (p < 0.01), respectively. Furthermore, immunostaining showed more relaxin-2 positive cells in the tumor recurrence (ETR) patients than non-ETR patients (p = 0.001). The Cox proportional hazards model further showed that relaxin-2 was an independent poor prognostic factor for both 5-year disease-free survival (hazards ratio [HR] = 1.872, 95% confidence interval [CI] = 1.18-5.146, p = 0.023) and 5-year overall survival (HR = 3.637, CI = 1.443-7.15, p = 0.001) in HCC. CONCLUSIONS: Our data suggest for the first time that the overexpression of relaxin-2 protein in HCC tissues is of predictive value on tumor progression and poor prognosis. PMID- 23661526 TI - Diagnosis and treatment of 29 cases of adrenal ganglioneuroma. AB - AIM: To evaluate diagnosis and treatment experience for adrenal ganglioneuroma and provide data for clinical surgery. PATIENTS AND METHODS: Analysis clinical feature and iconography and endocrine examination and clinical data of 29-cases adrenal ganglioneuroma in our Hospital. RESULTS: Back discomfort in 10 cases and convulsivum dizziness in 6-cases (hypertension in 2 cases), central obesity in 1 case. 12-cases were found by physical examination. 9-cases were diagnosed as adrenal ganglioneuroma and others were diagnosed as adrenal tumor. After operation, all of the cases were diagnosed as adrenal ganglioneuroma by pathology. Beside one patient were still dizzy with BP (blood pressure): 150/95 mmHg, all of patients completly recovered. CONCLUSIONS: For diagnosis on adrenal ganglioneuroma, we should depend on iconography and pathology. The operation is main method and most of patients can be cured. PMID- 23661525 TI - RNAi-mediated knockdown of relaxin decreases in vitro proliferation and invasiveness of osteosarcoma MG-63 cells by inhibition of MMP-9. AB - PURPOSE: The purpose of this study is to determine the role of relaxin knowdown by siRNA transfection in cellular growth and invasion of osteosarcoma MG-63 cells, and discusses the molecular mechanisms of this action. MATERIALS AND METHODS: The expression of relaxin in MG-63 cell was examined by western blot or RT-PCR. To evaluate the biological role of relaxin, proliferation assay (MTT) and invasion assay (BD MatrigelTM), apoptosis assay (TUNEL and ELISA) and cell cycle analysis (flow cytometer) were performed after silencing relaxin using siRNA. MMP 9 expressions were analyzed using RT-PCR, western blot and zymography after silencing relaxin. RESULTS: Results showed that the downregulation of relaxin expression by siRNA in human osteosarcoma MG-63 cells significantly inhibited cell proliferation and invasion in vitro. Furthermore, relaxin knockdown led to cell arrest in the G1/G0 phase of the cell cycle, and eventual apoptosis enhancement in MG-63 cells. We provide evidence in our cell model that the relaxin siRNA down-regulated the expression of MMP-9 and the MMP-9 activity, suggesting that relaxin may promote the proliferation, invasion and metastasis of osteosarcoma cells by regulating the expression of MMP-9 and facilitating ECM degradation. CONCLUSIONS: Therefore, siRNA-directed knockdown of relaxin may represent a viable clinical therapy for osteosarcoma. PMID- 23661527 TI - Successful treatment of thalidomide for recurrent bleeding due to gastric angiodysplasia in hereditary hemorrhagic telangiectasia. AB - Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder, which is uncommon anomaly to recurrent gastrointestinal bleeding. Although there are several forms of therapy ranging from local therapy to operations or drug therapy, there is a lack of more effective treatment for the disease. In this report, we presented a Chinese patient with recurrent melena due to gastric angiodysplasia in HHT treated successfully with thalidomide. PMID- 23661528 TI - Treatment of glaucomatous patients by means of food supplement to reduce the ocular discomfort: a double blind randomized trial. AB - BACKGROUND AND AIM: Chronic use of multi-dose eye drops containing preservatives, such as it may happen in patients affected by primary open angle glaucoma, often results in a damage of the ocular surface due to the inherent toxicity of preservatives, that with time may lead to a lacrimal dysfunction syndrome and eye dryness. PATIENTS AND METHODS: This double blind, randomized, pilot study was conducted on 38 glaucomatous patients suffering from dry eye induced by long-term use of eye drops preserved with BAK. RESULTS: Treatment of these patients with a food supplement containing an association of forskolin, rutin and vitamins B1 and B2 for 30 days increased significantly their OPI values and improved the symptoms of dry eye with respect to a placebo-treated control group. CONCLUSIONS: The association of forskolin, rutin and vitamins B1 and B2 appears to be protective for the ocular surface, contributing to restore a normal equilibrium of the tear film in those subjects in which toxic agents such as BAK had determined alterations of its homeostasis. PMID- 23661529 TI - Treatment and non-treatment related ocular manifestations in patients with chronic hepatitis B or C. AB - BACKGROUND: Worldwide, 480-520 million people are chronically infected with hepatitis B or C virus. In addition to their effects in the liver, chronic hepatitis viral infections may have serious extra hepatic manifestations. These manifestations have been more widely studied in chronic HCV infection, where they are more frequently described, but they have been also reported chronic HBV infection. AIM: Among those, of great interest are the ocular manifestations caused by the HBV or HCV infection or induced by chronic hepatitis therapy. These we attempted to review. MATERIALS AND METHODS: A PubMed search was conducted using the terms hepatitis, ocular, eye. RESULTS: This article describes the ocular symptoms related to HBV and HCV hepatitis such as xerophthalmia, Mooren's ulcer and retinopathy as well as other rare manifestations caused by either the infection or the therapy. CONCLUSIONS: The ocular manifestations of HCV infections best supported by the literature include a dry eye syndrome similar to Sjogren's syndrome, and ischemic retinopathy caused by either HCV-induced vasculitis or treatment with interferon. There are no serious ocular manifestations of HBV infection other than dry eye syndrome. Special consideration should be held for possible connection between HBV vaccine and uveitis. PMID- 23661530 TI - Ductopenia and fetal liver-like architecture as unique and evocative sign of Turner syndrome. AB - BACKGROUND: Turner syndrome is the most common genetic disorder in females. In most subjects, with a normal physical appearance at birth, the diagnosis is suspected long after birth because of short stature, delayed puberty, primary or secondary amenorrhea or infertility. Abnormalities of liver function tests are reported in literature, with a prevalence ranging from 20% to 80%. In most subjects liver diseases are self-limiting, associated with obesity, hormonal therapy and autoimmune diseases. An association between Turner syndrome and cryptogenic liver disease has been reported. Abnormalities of liver function tests could be the unique sign of Turner syndrome in subjects with normal phenotypes. The histological picture of "fetal liver-like architecture" and "ductopenia" is of fundamental importance for the diagnosis of chromosomopathy. AIM: Review the causes of hypertransaminasemia by focusing on more rare as metabolic and genetic diseases. MATERIALS AND METHODS: We evaluated a 10 year old girl with a normal phenotype affected by chronic hypertransaminasemia and cholestasis, in whom a needle liver biopsy was performed after the most common causes of hypertransaminasemia were excluded. RESULTS: Liver histological evaluation revealed a smoldering colangiopathy with mild ductopenia and a fetal liver-like architecture. Turner syndrome, suspected on the basis of this histological picture, was confirmed by a pelvic ultrasound and a chromosome analysis. CONCLUSIONS: The histological features of "fetal liver-like architecture" and "ductopenia" represent an evocative sign that could indicate the diagnostic suspicion of Turner syndrome in a subject lacking in signs or symptoms of this disease. It is important to perform a pelvic ultrasound and an endocrinological evaluation in all females with chronic asymptomatic hypertransaminasemia even though they have normal phenotypes. PMID- 23661531 TI - Poststreptococcal glomerulonephritis and rheumatic fever: two faces of the same coin. PMID- 23661532 TI - Sipa1 promoter polymorphism predicts risk and metastasis of lung cancer in Chinese. AB - Signal-induced proliferation associated gene 1 (Sipa1) is a signal transducer to activate the Ras-related proteins and modulate cell progression, differentiation, adhesion and cancer metastasis. In this study, we tested the hypothesis that single nucleotide polymorphisms (SNPs) in Sipa1 are associated with lung cancer risk and metastasis. Three common SNPs (rs931127A > G, rs2448490G > A, and rs3741379G > T) were genotyped in a discovery set of southern Chinese population and then validated the promising SNPs in a validation set of an eastern Chinese population in a total of 1559 lung cancer patients and 1679 cancer-free controls. The results from the two sets were consistent, the rs931127GG variant genotype had an increased risk of lung cancer compared to the rs931127AA/GA genotypes (OR = 1.27; 95% CI = 1.09-1.49) after combination of the two populations, and the rs931127GG interacted with pack-year smoked on increasing lung cancer risk (P = 0.037); this SNP also had an effect on patients' clinical stages (P = 0.012) that those patients with the rs931127GG genotype had a significant higher metastasis rate and been advanced N, M stages at diagnosis. However, these associations were not observed for rs2448490G > A and rs3741379G > T in the discovery set. Our data suggest that the SNP rs931127A > G in the promoter of Sipa1 was significantly associated with lung cancer risk and metastasis, which may be a biomarker to predict the risk and metastasis of lung cancer. PMID- 23661533 TI - Fatty acid oxidation: systems analysis and applications. AB - Fatty acids (FAs) are essential components of cellular structure and energy generating routes in living organisms. They exist in a variety of chemical configurations and functionalities and are catabolized by different oxidative routes, according to their structure. alpha- and omega-Oxidation are minor routes that occur only in eukaryotes, while beta-oxidation is the major degradation route in eukaroytes and prokaryotes. These pathways have been characterized and engineered from different perspectives for industrial and biomedical applications. The severity of FA oxidation disorders in humans initially guided the study of FA metabolism at a molecular-level. On the other hand, recent advances in metabolic engineering and systems biology have powered the study of FA biosynthetic and catabolic routes in microorganisms at a systems-level. Several studies have proposed these pathways as platforms for the production of fuels and chemicals from biorenewable sources. The lower complexity of microbial systems has allowed a more comprehensive study of FA metabolism and has opened opportunities for a wider range of applications. Still, there is a need for techniques that facilitate the translation of high-throughput data from microorganisms to more complex eukaryotic systems in order to aid the development of diagnostic and treatment strategies for FA oxidation disorders. In addition, further systems biology analyses on human systems could also provide valuable insights on oxidation disorders. This article presents a comparison of the three main FA oxidative routes, systems biology analyses that have been used to study FA metabolism, and engineering efforts performed on microbial systems. PMID- 23661534 TI - Comparison of optical and electromagnetic tracking for navigated lateral skull base surgery. AB - BACKGROUND: Navigation with optical tracking sometimes makes it difficult to establish a line-of-sight in cluttered operating theatres. On the other hand, the accuracy of electromagnetic tracking is influenced by ferromagnetic surgical equipment. We compared electromagnetic with optical tracking under controlled conditions for the lateral skull base. METHODS: Six anatomical specimens were dissected to measure the target registration error (TRE) in and around the petrous bone in a wet laboratory to simulate an intraoperative setting. Specimens were registered with passive optical and electromagnetic tracking. RESULTS: Overall accuracy was better using optical tracking than electromagnetic tracking (0.22 mm; 0.07-0.48 vs 0.99 mm; 0.56-1.27 mm; median, lower and upper quartiles, respectively; p < 0.001). CONCLUSION: The accuracy of optical tracking was near the resolution of the camera system, whereas the accuracy of electromagnetic tracking was lower. Only optical tracking allows for an application accuracy of considerably less than 1 mm in high-resolution datasets. PMID- 23661535 TI - Measurements of orbital volume using cone-beam computed tomography in eye movement abnormalities. AB - PURPOSE: To measure the orbital volume in adult patients with unilateral eye movement abnormalities originating in childhood. METHODS: Cone-beam computed tomography was performed in 2 patients with eye movement abnormalities. A 28-year old woman was treated because of right divergent squint originating at 8 years of age after penetrating corneal trauma. A 38-year-old man was examined because of abnormal head posture caused by left superior oblique underaction originating at 6 years of age. Orbital scans were analyzed with Cranioviewer 3D craniofacial cephalometric program. We measured bony orbital area in 6 slices (in ventro dorsal direction per 4.8 mm) in every orbit on coronal scans. RESULTS: The volume was more in the orbit with unilateral divergent squint and less in the orbit with unilateral superior oblique underaction compared to the contralateral orbital volume measurements. CONCLUSION: Cranioviewer 3D craniofacial cephalometric program is suitable for volumetric analysis of the bony orbit on cone-beam computed tomography files. The development of the orbit can be influenced by extraocular muscle movements. PMID- 23661536 TI - Review on the worldwide epidemiology of uveitis. AB - PURPOSE: We describe the worldwide epidemiology of uveitis through a systematic literature review.? METHODS: Data obtained from the most relevant studies published until November 2012 were reported.? RESULTS: Results of our research were structured in sections about the epidemiology of uveitis by anatomical location of inflammation (anterior, intermediate, posterior, and panuveitis), type of inflammation (infectious and noninfectious), and by age (children and elderly). Difficulties encountered analyzing the different epidemiologic studies were discussed in a dedicated section.? CONCLUSIONS: Limited information is available regarding the epidemiology of uveitis. Worldwide epidemiologic studies may help the clinician in the management of patients with inflammatory ocular diseases, enabling the comparison of different uveitis entities. PMID- 23661537 TI - Relationship between socioeconomic deprivation ?or urban/rural residence and visual acuity before cataract surgery in Northern Scotland. AB - PURPOSE: To evaluate the influence of socioeconomic factors on visual acuity before cataract surgery. ? METHODS: The medical case notes of 240 consecutive patients listed for cataract surgery from January 1, 2010, at Grampian University Hospital, Aberdeen, were reviewed retrospectively. Patients with ocular comorbidity were excluded. Demographics, postal codes, and visual acuity were recorded. Scottish Index of Multiple Deprivation was used to determine the deprivation rank. Home location was classified as urban or rural. The effect of these parameters on preoperative visual acuity was investigated using chi-square tests or Fisher exact test as appropriate. ? RESULTS: A total of 184 patients (mean 75 years) were included. A total of 127 (69%) patients had visual acuity of 6/12 or better. An association was found between affluence and preoperative visual acuity of 6/12 or better (chi2trend = 4.97, p = 0.03), with a significant rising trend across quintile of deprivation. There was no evidence to suggest association between geographical region and preoperative visual acuity (p = 0.63). ? CONCLUSION: Affluence was associated with good visual acuity (6/12 or better) before cataract surgery. There was no difference in preoperative visual acuity between rural and urban populations. PMID- 23661538 TI - Ophthalmologic findings in Russian children with fetal alcohol syndrome. AB - PURPOSE: To study functional and anatomic characteristics of eyes of Russian children with fetal alcohol syndrome (FAS).? METHODS: One hundred children aged 10-16 years from Russian orphanages (St. Petersburg) were examined: 50 with verified diagnosis of FAS and 50 healthy children. All children were tested for distance visual acuity (VA) with subjective optimal correction (Sivtsev chart), skiascopy, visual inspection for FAS external ocular features, biomicroscopy, eye alignment using cover test, and indirect ophthalmoscopy.? RESULTS: All analyzed parameters were worse in children with FAS compared with controls. Children with FAS showed a higher incidence of amblyopia, hyperopia, astigmatism, and anisometropia. In children with FAS, the incidence of blepharophimosis was 34% (8% in controls), epicanthus 14% (2% in controls), telecanthus 32% (compared to 4% in controls), eyelid ptosis 9% (none in controls), and strabismus 26% (10% in controls). Ophthalmoscopy revealed a tilted optic disc in 5 children with FAS (7%) compared with none in controls.? CONCLUSION: Russian children with FAS have a higher incidence of vision problems and eye pathology that needs to be taken into account and requires ophthalmologist monitoring. PMID- 23661539 TI - First 100: learning curve for Descemet stripping automated endothelial keratoplasty. AB - PURPOSE: Endothelial keratoplasty is largely replacing penetrating keratoplasty for the routine treatment of corneal endothelial failure. The aim of the study was to describe the performance, complications, and outcome of the first 100 Descemet stripping automated endothelial keratoplasty (DSAEK) procedures performed at a major medical center, with an emphasis on the learning curve. ? METHODS: A retrospective, comparative case series study was conducted by a single surgeon at a tertiary, university-affiliated medical center. Data were collected on 100 consecutive DSAEK procedures performed between September 2008, when the technique was introduced in the ophthalmology department, and January 2011. Main outcome measures include best-corrected visual acuity, graft dislocation rate, primary failure rate, and endothelial cell loss. Findings were compared between the first (early group) and last (late group) 50 cases.? RESULTS: Mean (SD) logMAR best-corrected visual acuity at 1 year improved from 1.02 +/- 0.36 to ?0.38 +/- 0.35 in the early group (p<0.05) and from 0.93 +/- 0.48 to 0.25 +/- 0.21 in the late group (p<0.05) ?(n = 86). Although the late group included more complex cases (presence of anterior chamber intraocular lens, need for combination cataract surgery or secondary scleral intraocular lens fixation), graft dislocation was more common in the early group (20% versus 10%, p = 0.26). Primary and late graft failures occurred only in the early group (12% vs 0, p = 0.03). ? CONCLUSIONS: Rates of primary failure and disc dislocation for DSAEK decrease as surgeons gain experience with the procedure, and the number of functional grafts increases accordingly. Visual outcome improves regardless of surgical experience. PMID- 23661540 TI - Unilateral acute maculopathy related to hand, foot, and mouth disease: OCT and fluorescein angiography findings of a very rare disease. AB - PURPOSE: Hand, foot, and mouth disease is a contagious enteroviral infection occurring primarily in children and characterized by vesicular palmoplantar eruptions and erosive stomatitis. There are very few cases of unilateral acute idiopathic maculopathy associated with hand, foot, and mouth infection. We described a case with unilateral outer retinitis occurring a few days after the onset of disease. METHODS: A 30-year-old man with reduced vision in his right eye underwent complete ophthalmologic examination including fluorescein angiography and spectral optical coherence tomography. RESULTS: Fundus fluorescein angiography demonstrated mottled hyperfluorescence in the early phase and leakage in the late phase. Spectral domain optical coherence tomography revealed subretinal fluid suggesting a serous detachment and also showed mild intraretinal cystic changes. The fluid disappeared in 1 week with some retinal pigment epithelium changes in the center of the macula. CONCLUSIONS: Although this disease is a viral infection associated with reversible symptoms, this case suggests that it can resolve with mild visual loss, and the disease should be considered in the differential diagnosis of acute central serous chorioretinopathy. PMID- 23661541 TI - Accessibility as a conditioning factor in treatment for exudative age-related macular degeneration. AB - PURPOSE: Ranibizumab and bevacizumab coexist as the main therapeutic strategies for the treatment of neovascular age-related macular degeneration (NV-AMD). In Argentina, the access pathways to the drugs are different. Patients with different pathways and gatekeepers to access may experience different outcomes. The purpose of this work was to estimate the impact on therapeutic effects and visual outcome of the different accessibilities to NV-AMD treatment. ? METHODS: A retrospective analysis of the charts of 78 patients with previously untreated exudative AMD, who were treated with ranibizumab or bevacizumab between January 2009 and December 2011, was conducted. The main outcomes measured included time delay and change in mean best-corrected visual acuity (BCVA) between diagnosis and treatment and mean BCVA change at 1-year follow-ups.? RESULTS: The delay between diagnosis and treatment and decrease in visual acuity over this time was significantly higher for patients treated with ranibizumab. At 1 year after the initiation of treatment, BCVA had a mean increase from baseline of 0.11 letters in the bevacizumab group with a mean of 4.71 injections, compared with a decrease of 8.87 letters with a mean of 2.98 injections in the ranibizumab group.? CONCLUSIONS: Access to treatment can be a key factor for success of therapy. Waiting times and availability of doses are crucial in the treatment of NV-AMD. Solving the problems related to delayed initiation of therapy and the difficulties in the maintenance phase are more important than define whether bevacizumab or ranibizumab is used. PMID- 23661542 TI - Influence of prostaglandin analogue on outcome after combined cataract surgery and trabecular aspiration in pseudoexfoliative glaucoma. AB - PURPOSE: The aim of this study was to analyze the postoperative outcome and risk profile after combined clear cornea phacoemulsification and trabecular aspiration in the treatment of pseudoexfoliative glaucoma (PEX) associated with cataract. ? METHODS: In this retrospective study, 69 eyes of 60 patients with visually significant cataract and PEX were treated with small-incision cataract surgery combined with trabecular aspiration. The intraocular pressure (IOP), number of antiglaucoma eyedrops before and after surgery, as well as complications were measured at all postoperative visits (1 day, 7 days, 6 weeks, 6 months, 12 months). ? RESULTS: There was a statistically significant decrease in postoperative IOP during the follow-up ?period. There was no significant difference in the number of medications being used after 6 weeks follow-up. Six months and 12 months after surgery, the number of antiglaucoma eyedrops decreased significantly. Complications were fibrinotic iritis in 4 eyes (5.9%), cystoid macular edema in 3 eyes (4.4%), and hyphema in 1 eye (1.4%). Fibrinotic iritis and macular edema were present in only 37 of ?69 eyes that were treated with prostaglandin analogues.? CONCLUSIONS: Small-incision cataract surgery combined with trabecular aspiration in cases of PEX associated with cataract is effective in IOP reduction over a 1-year follow-up. Prostaglandin analogues may increase the risk of postoperative macular edema and fibrinotic iritis. Preoperative medication exchange may be considered. PMID- 23661543 TI - Dexamethasone intravitreal implant for idiopathic retinal vasculitis, aneurysms, and neuroretinitis. AB - PURPOSE: To present the short-term favorable clinical results with the dexamethasone intravitreal implant in a patient with florid idiopathic retinal vasculitis, aneurysms, and neuroretinitis syndrome (IRVAN).? METHODS: A 26-year old man presented with significant bilateral deterioration of vision due to vitreous hemorrhage and neuroretinitis with a background of vasculitis and neovascularization. The patient was initially treated with high doses of oral steroids (80 mg prednisolone), which were gradually tapered, and also received extensive argon laser photocoagulation in ischemic areas in both eyes. Despite vigorous treatment and an initial positive response to treatment, pars plana vitrectomy was eventually needed to address the recurrent vitreous hemorrhages in the left eye. Consequently, visual acuity improved from 0.1 to 0.2 (Snellen) and there was no relapse of vitreous hemorrhage. Persistent macular edema was noted, however, and it was decided to treat with a dexamethasone 0.7 mg intravitreal implant.? RESULTS: Following the dexamethasone implant OS, visual acuity improved significantly from 0.2 to 0.5 (Snellen), the patient reported much less distortion, and there was marked reduction in central retinal thickness from 467 to 234 microns. The patient remains in remission without any exudation in the macula at 4 months follow-up.? CONCLUSION: Dexamethasone 0.7 mg intravitreal implant appears to be a safe and effective solution in the treatment of macular edema in patients with IRVAN syndrome and could possibly be a treatment option for other cases of inflammatory induced macular edema. PMID- 23661544 TI - Bilateral retinal vasculopathy associated with autosomal dominant dyskeratosis congenita. AB - PURPOSE: To report a case of autosomal dominant dyskeratosis congenita (AD-DC) complicated by bilateral retinal vasculopathy and proliferative retinopathy with vitreous hemorrhage in the right eye, in the absence of pancytopenia.? METHODS: We report a 32-year-old woman who presented with floaters in her right eye. She underwent complete ophthalmic examination and fundus fluorescein angiography.? RESULTS: Funduscopic examination revealed vascular sheathing in the temporal periphery of both eyes and a vitreous hemorrhage in the right eye. Fluorescein angiography showed retinal neovascularization in the right eye and bilateral temporal peripheral capillary nonperfusion. Treatment consisted of laser photocoagulation directed to the areas of capillary nonperfusion in both eyes. A point mutation in the TERC gene confirmed the diagnosis of AD-DC.? CONCLUSIONS: Autosomal dominant dyskeratosis congenita is a rare form of inherited bone marrow failure and its presentation is milder than seen in patients with X-linked and autosomal recessive mutations. These patients may lack the classic clinical triad, so it is important to have a high index of suspicion and to be aware of retinal vasculopathy as a complication of dyskeratosis congenita as it may severely compromise vision. Appropriate treatment includes prompt laser photocoagulation to areas of retinal nonperfusion. PMID- 23661545 TI - Day-night and reproductive cycle profiles of melatonin receptor, kiss, and gnrh expression in orange-spotted grouper (Epinephelus coioides). AB - It is suggested that the MT1 melatonin receptor mediates the effects of melatonin on reproduction in rodents. Three melatonin receptor types, MT1, MT2, and Mel1c, have been identified in fish. To understand the potential roles of each type of melatonin receptor on reproduction, we explored the day-night and reproductive cycle profiles of melatonin receptor, kiss, and gnrh expression in the orange spotted grouper (Epinephelus coioides). cDNAs encoding melatonin receptors (MT1, MT2, and Mel1c) were first isolated from the brain of the orange-spotted grouper. Quantitative real-time PCR analysis demonstrated that the expression levels of MT1 and MT2 were higher in most of the brain areas and pituitary, while mel1c mRNA was mainly distributed in some peripheral tissues and the pituitary. The expression levels of MT1 were much higher than those of MT2 and mel1c in most of the brain regions, and the day-night expression variations of MT1 were counter to those of kiss2 and gnrh1. Reproductive cycle variations in MT1 daytime expression were different from those for kiss2 and gnrh1, and contrary to ovarian fecundity. Our results suggest that MT1 may modulate gnrh1 expression through kiss2, or may directly influence it. Together, these signal cascades may regulate the seasonal breeding of the orange-spotted grouper. As the day-length variations were consistent with the ovarian fecundity variation observed during the reproductive cycle, we infer that photoperiod affects ovarian development of the orange spotted grouper through MT1. PMID- 23661546 TI - Polyglycolic acid-hyaluronan scaffolds loaded with bone marrow-derived mesenchymal stem cells show chondrogenic differentiation in vitro and cartilage repair in the rabbit model. AB - In cartilage repair, scaffold-assisted one-step approaches are used to improve the microfracture (Mfx) technique. Since the number of progenitors in Mfx is low and may further decrease with age, aim of our study was to analyze the chondrogenic potential of freeze-dried polyglycolic acid-hyaluronan (PGA-HA) implants preloaded with mesenchymal stem cells (MSCs) in vitro and in a rabbit articular cartilage defect model. Human bone marrow-derived MSC from iliac crest were cultured in freeze-dried PGA-HA implants for chondrogenic differentiation. In a pilot study, implants were loaded with autologous rabbit MSC and used to cover 5 mm * 6 mm full-thickness femoral articular cartilage defects (n = 4). Untreated defects (n = 3) served as controls. Gene expression analysis and histology showed induction of typical chondrogenic marker genes like type II collagen and formation of hyaline-like cartilaginous tissue in MSC-laden PGA-HA implants. Histological evaluation of rabbit repair tissue formation after 30 and 45 days showed formation of repair tissue, rich in chondrocytic cells and of a hyaline-like appearance. Controls showed no articular resurfacing, tissue repair in the subchondral zone and fibrin formation. These results suggest that MSC laden PGA-HA scaffolds have chondrogenic potential and are a promising option for stem cell-mediated cartilage regeneration. PMID- 23661547 TI - High permittivity pads reduce specific absorption rate, improve B1 homogeneity, and increase contrast-to-noise ratio for functional cardiac MRI at 3 T. AB - PURPOSE: To improve image quality and reduce specific absorption rate in functional cardiac imaging at 3 T. METHODS: Two high permittivity dielectric pads on the anterior and posterior sides of the thorax were numerically designed and implemented using an aqueous suspension of barium titanate. The effects on the average transmit efficiency, B(1) homogeneity, reception sensitivity, and contrast-to-noise ratio were verified in vivo on a dual-transmit system with the body coil driven in conventional quadrature and radiofrequency-shimmed mode. RESULTS: Statistically significant improvements in average transmit efficiency, B(1) homogeneity, and contrast-to-noise ratio were measured in healthy volunteers (n = 11) with body mass indices between 20.3 and 34.9. Simulations show that no radiofrequency hot spots are introduced by the dielectric material. CONCLUSION: High permittivity pads are shown to reduce specific absorption rate, improve B(1) homogeneity, and increase contrast-to-noise ratio in functional cardiac magnetic resonance at 3 T. The results presented in this work show that the current approach is more effective than dual-channel radiofrequency shimming. PMID- 23661548 TI - Prohibitin-2 promotes hepatocellular carcinoma malignancy progression in hypoxia based on a label-free quantitative proteomics strategy. AB - The rapid growth of hepatocellular carcinoma (HCC) leading to tumor hypoxia is a common pathological phenomenon. Meanwhile, tumor hypoxia can promote a change in the biological properties of tumor cells. It may enhance the survival of tumor cells under stress conditions, resulting in resistance to apoptosis and angiogenesis. The moleculars that could modulate the malignant phenotypes of HCC cells remain largely unknown. Based on label-free quantitative proteomic data, we found a significant upregulation of prohibitin-2 (PHB2) in HCC tissues. Treatment of hepatoma cells with small interfering RNAs against PHB2 suppressed cell growth and colony formation, led to G1 phase arrest and sensitized HCC cells to apoptosis. Moreover, inhibition of PHB2 expression dramatically repressed the ability of HCC cells to adapt to hypoxic microenvironments and resist chemotherapy-induced apoptosis. Thus, PHB2 in HCC supports the development and progression of hepatocellular malignancy to hypoxia, and implicates the potential antagonist function of PHB2 in transarterial chemoembolization treatment. PMID- 23661550 TI - Toxicity and enantiospecific differences of two beta-blockers, propranolol and metoprolol, in the embryos and larvae of zebrafish (Danio rerio). AB - The risk presented by beta-blockers on aquatic organisms remains uncertain, particularly given the enantiospecific differences in toxicity of chiral beta blockers. In this study, the toxicity of two beta-blockers, propranolol and metoprolol, was determined. The 96-h LC50 of propranolol in the zebrafish larvae was 2.48 mg/L, whereas 50 mg/L metoprolol did not result in death. Both beta blockers decreased the heart rate and hatching rate and increased the mortality of the zebrafish embryos. Among these indicators, the heart rate was the most sensitive. However, the acute larval and embryo toxicity results displayed no enantioselectivity. Additionally, the transcriptional response of the genes encoding the beta-adrenergic receptors and those involved in other physiological processes, including the antioxidant response, detoxification, and apoptosis, in zebrafish larvae exposed to the beta-blockers was examined. Although the changes in gene transcription were fairly minor, significant enantioselectivity was observed for beta-blockers, suggesting that the transcriptional response was more sensitive for the evaluation of enantiospecific toxicity. Based on these results, the pharmaceutical drugs were not expected to pose a risk to fish; however, this conclusion should not be considered final. These results also demonstrated that the enantiospecific toxicity of chiral beta-blockers should be investigated when performing an ecological risk assessment. PMID- 23661549 TI - Detection of a TLR2 agonist by hematopoietic stem and progenitor cells impacts the function of the macrophages they produce. AB - Several groups have shown that detection of microbial components by TLRs on hematopoietic stem and progenitor cells (HSPCs) instructs myeloid cell generation, raising interest in the possibility of targeting TLRs on HSPCs to boost myelopoiesis. However, although "TLR-derived" cells exhibit myeloid cell characteristics (phagocytosis, cytokine production, antigen presentation), it is not clear whether they are functionally equivalent to macrophages derived in the absence of TLR activation. Our in vitro and in vivo studies show that macrophages derived from mouse and human HSPC subsets (including stem cells) exposed to a TLR2 agonist prior to or during macrophage differentiation produce lower levels of inflammatory cytokines (TNF-alpha, IL-6, and IL-1beta) and reactive oxygen species. This is in contrast to prior exposure of differentiated macrophages to the TLR2 agonist ("tolerance"), which suppresses inflammatory cytokine production, but elevates reactive oxygen species. Soluble factors produced following exposure of HSPCs to a TLR2 agonist can also act in a paracrine manner to influence the function of macrophages derived from unexposed HSPCs. Our data demonstrate that macrophage function can be influenced by TLR signaling in the HSPCs from which they are derived, and that this may impact the clinical utility of targeting TLRs on HSPCs to boost myelopoiesis. PMID- 23661551 TI - Characterization of physicochemical properties of nanomaterials and their immediate environments in high-throughput screening of nanomaterial biological activity. AB - Thousands of nanomaterials (NMs) are in commerce and few have toxicity data. To prioritize NMs for toxicity testing, high-throughput screening (HTS) of biological activity may be the only practical and timely approach to provide the necessary information. As in all nanotoxicologic studies, characterization of physicochemical properties of NMs and their immediate environments in HTS is critical to understanding how these properties affect NM bioactivity and to allow extrapolation to NMs not screened. The purpose of the study, the expert-groups recommended minimal characterization, and NM physicochemical properties likely to affect measured bioactivity all help determine the scope of characterization. A major obstacle in reaping the full benefits of HTS for NMs is the low throughput of NM physicochemical characterization, which may require more sample quantity than HTS assays. Increasing the throughput and speed, and decreasing the amount of NMs needed for characterization are crucial. Finding characterization techniques and biological activity assays compatible with diverse classes of NMs is a challenge and multiple approaches for the same endpoints may be necessary. Use of computational tools and nanoinformatics for organizing and analyzing data are important to fully utilize the power of HTS. Other desired advances include the ability to more fully characterize: pristine NM without prior knowledge of NM physicochemical properties; non-pristine NMs (e.g., after use); NM in not perfectly-dispersed suspension; and NM in biological samples at exposure-relevant conditions. Through combining HTS and physicochemical characterization results, we will better understand NM bioactivities, prioritize NMs for further testing, and build computational models to predict NM toxicity. PMID- 23661552 TI - Identifying the Ubiquitin Ligase complex that regulates the NF1 tumor suppressor and Ras. AB - The NF1 tumor suppressor protein neurofibromin is a negative regulator of Ras. Neurofibromin is dynamically regulated by the proteasome, and its degradation and reexpression are essential for maintaining appropriate levels of Ras-GTP. Like p53, NF1/neurofibromin can be inactivated in cancer by both mutations and excessive proteasomal destruction; however, little is known about the mechanisms that underlie this latter process. Here, we show that a Cullin 3 (Cul3)/kelch repeat and BTB domain-containing 7 complex controls both the regulated proteasomal degradation of neurofibromin and the pathogenic destabilization of neurofibromin in glioblastomas. Importantly, RNAi-mediated Cul3 ablation and a dominant-negative Cul3 directly stabilize neurofibromin, suppress Ras and extracellular signal-regulated kinase, and inhibit proliferation in an NF1 dependent manner. Moreover, in glioblastomas where neurofibromin is chronically destabilized, Cul3 inhibition restabilizes the protein and suppresses tumor development. Collectively, these studies show a previously unrecognized role for Cul3 in regulating Ras and provide a molecular framework that can be exploited to develop potential cancer therapies. PMID- 23661554 TI - Extracorporeal membrane oxygenation cannula malposition in the azygos vein in an infant. AB - INTRODUCTION: Misplacement of extracorporeal membrane oxygenation (ECMO) venous cannula in the azygos vein has previously been described only in newborns. CASE: For the first time, we report an aberrant ECMO cannula placement in the azygos vein in a child outside neonatal period. History of chronic lung disease and ligation of persistent ductus arteriosus leading to elevated right ventricular pressure was the potential risk factor. CONCLUSIONS: This rare complication should be considered whenever the patient has inadequate venous return on ECMO and it can be easily ruled out with a lateral chest radiograph. PMID- 23661553 TI - TGF-beta signaling in myeloid cells is required for tumor metastasis. AB - TGF-beta is overexpressed in advanced human cancers. It correlates with metastasis and poor prognosis. However, TGF-beta functions as both a tumor suppressor and a tumor promoter. Here, we report for the first time that genetic deletion of Tgfbr2 specifically in myeloid cells (Tgfbr2(MyeKO)) significantly inhibited tumor metastasis. Reconstitution of tumor-bearing mice with Tgfbr2(MyeKO) bone marrow recapitulated the inhibited metastasis phenotype. This effect is mediated through decreased production of type II cytokines, TGF-beta1, arginase 1, and inducible nitric oxide synthase, which promoted IFN-gamma production and improved systemic immunity. Depletion of CD8 T cells diminished the metastasis defect in the Tgfbr2(MyeKO) mice. Consistent with animal studies, myeloid cells from patients with advanced-stage cancer showed increased TGF-beta receptor II expression. Our studies show that myeloid-specific TGF-beta signaling is an essential component of the metastasis-promoting puzzle of TGF-beta. This is in contrast to the previously reported tumor-suppressing phenotypes in fibroblasts, epithelial cells, and T cells. PMID- 23661556 TI - Suppression of titanium particle-induced TNF-alpha expression and apoptosis in human U937 macrophages by siRNA silencing. AB - Aseptic loosening of joint prosthetics is one of the most frequent reasons for the failure of total joint replacement surgeries. A major cause of the aseptic loosening is osteolysis caused by a periprosthetic inflammatory response to wear particles released from implanted prosthetics. Tumor necrosis factor (TNF)-alpha is thought to play a dominant role in wear-induced inflammation. It was shown previously by our group, as well as by other researchers, that macrophages produce abundant TNF-alpha when exposed to particulate titanium (Ti), which is widely used as a biomaterial in arthroplastic surgery. In the present study, we have tested the feasibility of using siRNA as a therapeutic intervention against wear-induced TNF-alpha production. Our data show that transfection of U937 macrophage cells with TNF-alpha siRNA inhibits Ti particle-induced expression of TNF-alpha mRNA and protein by >65%. Moreover, U937 cells transfected with TNF alpha siRNA were significantly more resistant to Ti particle-induced apoptosis (>60%, p<0.05) and caspase-3 activation (>50%, p<0.05) compared with normal U937 cells. Collectively, our data show that siRNA can be an effective way to inhibit Ti particle-induced TNF-alpha expression and the activation of downstream pathways such as apoptosis in macrophages. These data provide a foundation for future studies to investigate the use of siRNA targeting inflammatory cytokines as a therapeutic modality for the treatment of aseptic loosening of prosthetic materials used in arthroplastic surgery. PMID- 23661555 TI - Immobilization of BMP-2 on a nano-hydroxyapatite-coated titanium surface using a chitosan calcium chelating agent. AB - We conducted experiments to determine the most effective calcium chelating agents for use in enhancing adhesion of human bone marrow mesenchymal stem cells (BM MSCs) on nano-hydroxyapatite (nHAp)-coated titanium substrates by covalently immobilizing bone morphogenetic protein-2 (BMP-2). The quantity of amine groups on the chitosan chelated surface was 7 ug/surface area, and it was 1.4 ug/surface area on the alendronate chelated surface. The quantity of BMP-2 on the BMP-2 immobilized surface chelated with chitosan (4 ng/surface area) was higher than that on BMP-2 immobilized surface chelated with alendronate (2.2 ng/surface area). Contact angles of the nHAp-coated titanium, alendronate chelated, chitosan chelated, and BMP-2 immobilized surfaces chelated with alendronate were 68.8 +/- 3.6 degrees , 78.2 +/- 1.9 degrees , 74.8 +/- 5.2 degrees , and 76.0 +/- 2.5 degrees , respectively. The contact angle of the BMP-2 immobilized surface chelated with chitosan was significantly lower (56.2 +/- 2.0 degrees ) than that of any of the other groups. BM-MSCs on the chitosan surface and BMP-2 immobilized on the surface chelated with chitosan appeared to be healthy and showed a spindle like fibroblastic morphology. In addition, BM-MSCs on these surfaces appeared to have the ability to differentiate into bone-forming cells. We suggest that chitosan can be used as an effective calcium chelating agent for implants. PMID- 23661557 TI - Effects of hemoperfusion in the treatment of childhood Henoch-Schonlein purpura nephritis. AB - PURPOSE: Immune mediators play a role in the pathogenesis of Henoch-Schonlein purpura (HSP) nephritis. Since hemoperfusion (HP) is able to eliminate the immune mediators in many diseases, we investigated the effects of HP in the treatment of HSP nephritis. METHODS: 90 children with HSP nephritis were enrolled and followed up for 12 months. They were assigned to the HP group or the control group, respectively. Both groups were treated with corticosteroids and other supportive therapy. Patients in the HP group received HP for 3 consecutive days. The major outcomes included the percentage of patients with HSP nephritis, extrarenal symptoms, and recurrences and changes in serum levels of immune mediators. RESULTS: The percentage of patients with nephritis in the HP group was less than that in the control group at each visit; the differences for prortions at 1, 3, 6, 12 months were 16.7% (p = 0.133), 31.3% (p = 0.004), 10.8% (p = 0.283), and 20.6% (p = 0.003), respectively. The severity and duration of abdominal and joint pains in the acute phase were significantly improved in the HP group compared to those in the control group. Hemoperfusion also significantly reduced patients' serum levels of immune mediators including IgA, TNF-alpha, IL-6, and LTB4. However, recurrences between the two groups were not significantly different. CONCLUSIONS: Hemoperfusion in combination with corticosteroid was more effective than corticosteroid alone in treating HSP nephritis. The effects may be achieved by eliminating immune mediators. PMID- 23661558 TI - Extended characterization of a new class of membranes for blood purification: the high cut-off membranes. AB - High cut-off membranes are a new class of blood purification membranes whose particular characteristics present challenges for commonly-used characterization methods. Dextran sieving curves for representative blood purification membranes of the high-flux and high cut-off types were measured and compared to curves for the glomerular filtration barrier (GFB). The performance was also determined after blood exposure for the most permeable synthetic membranes. High cut-off membranes were observed to be more open than the GFB before blood exposure, but become tighter and more selective after the exposure, keeping the permeation for low and middle molecules while restraining the filtration of large species. Based on dextran sieving experiments for a variety of commercially available blood purification membranes, we present a novel method for classifying blood purification membranes. By using a well-established technique and introducing a new characteristic parameter for the sieving curve--the molecular weight retention onset (MWRO)--a graph of molecular weight cut-off versus molecular weight retention onset provides the landscape of dialysis membrane types. This meaningful representation is based on only one in vitro method, and allows the membrane classification by indirectly considering two structural parameters: pore size and pore size distribution. In this way, the families of low-flux, high flux, protein leaking, and high cut-off membranes are clearly differentiated. The differentiation allows for the definition of MWCO/MWRO regions for the different types, so that further classification of newly developed membranes can be easily achieved. PMID- 23661559 TI - Long-term peritoneal dialysis experience: quality control supports the use of fluconazole to prevent fungal peritonitis. AB - BACKGROUND: Fungal peritonitis (FP) is rare, but it is associated with high morbidity and mortality. PATIENTS AND METHODS: A prospective study was conducted based on the peritonitis episodes registry to evaluate FP rate, possible risk factors, and outcomes. The impact of prophylactic intervention with oral fluconazole was evaluated. RESULTS: Over 24 years of experience, 417 patients underwent peritoneal dialysis (PD), followed for 956 patient-years. By the end of the study, the peritonitis rate reached 0.47 episodes per patient-year of treatment (ep/pt-y). FP was detected in 24 patients. The global rate of FP was 0.03 ep/pt-y (4.8%). Candida species accounted for 92% of the FP. Risk factors identified: recent use of antibiotics in 63% (13 episodes of bacterial peritonitis and 2 exit-site infections (ESI)) and immunosuppressive therapy in 8%. While rare, the FP proportion was still observed to increase from the beginning of the program, reaching 7.8% (0.05 ep/pt-y). A strategy of antifungal prophylaxis with oral fluconazole during peritonitis or ESI antibiotic therapy was adopted, which allowed thereafter a 4.0% falling FP proportion (by study end, rate of 0.01 ep/pt-y). Catheter removal occurred in all patients. The mortality rate was 12.5%. Reinsertion of dialysis catheter was attempted in 4 patients and PD was successfully resumed in 3 patients. CONCLUSIONS: FP was associated with high mortality and required early removal of the catheter in all patients. Recent use of antibiotics was a predisposing factor to PF. The quality control process determined a prophylactic strategy and reduction of PF after introduction of oral fluconazole was implemented. PMID- 23661561 TI - Commentary on "The effectiveness of varenicline medication guide for conveying safety information to patients: a REMS assessment survey" by Enger et al. PMID- 23661560 TI - Implant-abutment gap versus microbial colonization: Clinical significance based on a literature review. AB - Microorganisms from the oral cavity may settle at the implant-abutment interface (IAI). As a result, tissue inflammation could occur around these structures. The databases MEDLINE/PubMed and PubMed Central were used to identify articles published from 1981 through 2012 related to the microbial colonization in the implant-abutment gap and its consequence in terms of crest bone loss and osseointegration. The following considerations could be put forward, with respect to the clinical importance of IAI: (a) the space present at the IAI seems to allow bacterial leakage to occur, in spite of the size of this space; (b) bacterial leakage seems to occur at the IAI, irrespective of the type of connection. More studies are necessary to clarify the relationship between leakage at IAI and abutment connection designs; (c) losses at the peri-implant bone crests cannot be related to the IAI size, since few studies have shown no relationship. Also, the microbial leakage at the IAI cannot be related to the bone crest loss, since there are no articles reporting this relationship; remains controversial the influence of the IAI position on the bone crest losses. PMID- 23661562 TI - Multiple sclerosis lymphocytes upregulate A2A adenosine receptors that are antiinflammatory when stimulated. AB - Multiple sclerosis (MS) is an autoimmune-mediated inflammatory disease characterized by multifocal areas of demyelination. Experimental evidence indicates that A2A adenosine receptors (ARs) play a pivotal role in the inhibition of inflammatory processes. The aim of this study was to investigate the contribution of A2A ARs in the inhibition of key pro-inflammatory mediators for the pathogenesis of MS. In lymphocytes from MS patients, A1, A2A, A2B, and A3 ARs were analyzed by using RT-PCR, Western blotting, immunofluorescence, and binding assays. Moreover the effect of A2A AR stimulation on proinflammatory cytokine release such as TNF-alpha, IFN-gamma, IL-6, IL-1beta, IL-17, and on lymphocyte proliferation was evaluated. The capability of an A2A AR agonist on the modulation of very late antigen (VLA)-4 expression and NF-kappaB was also explored. A2A AR upregulation was observed in lymphocytes from MS patients in comparison with healthy subjects. The stimulation of these receptors mediated a significant inhibition of TNF-alpha, IFN-gamma, IL-6, IL-1beta, IL-17, and cell proliferation as well as VLA-4 expression and NF-kappaB activation. This new evidence highlights that A2A AR agonists could represent a novel therapeutic tool for MS treatment as suggested by the antiinflammatory role of A2A ARs in lymphocytes from MS patients. PMID- 23661563 TI - All or nothing: protein complexes flip essentiality between distantly related eukaryotes. AB - In the budding yeast Saccharomyces cerevisiae, the subunits of any given protein complex are either mostly essential or mostly nonessential, suggesting that essentiality is a property of molecular machines rather than individual components. There are exceptions to this rule, however, that is, nonessential genes in largely essential complexes and essential genes in largely nonessential complexes. Here, we provide explanations for these exceptions, showing that redundancy within complexes, as revealed by genetic interactions, can explain many of the former cases, whereas "moonlighting," as revealed by membership of multiple complexes, can explain the latter. Surprisingly, we find that redundancy within complexes cannot usually be explained by gene duplication, suggesting alternate buffering mechanisms. In the distantly related Schizosaccharomyces pombe, we observe the same phenomenon of modular essentiality, suggesting that it may be a general feature of eukaryotes. Furthermore, we show that complexes flip essentiality in a cohesive fashion between the two species, that is, they tend to change from mostly essential to mostly nonessential, or vice versa, but not to mixed patterns. We show that these flips in essentiality can be explained by differing lifestyles of the two yeasts. Collectively, our results support a previously proposed model where proteins are essential because of their involvement in essential functional modules rather than because of specific topological features such as degree or centrality. PMID- 23661564 TI - Cytoplasmic organelle DNA preferentially inserts into open chromatin. AB - DNA transfer from chloroplasts and mitochondria to the nucleus is ongoing in eukaryotes but the mechanisms involved are poorly understood. Mitochondrial DNA was observed to integrate into the nuclear genome through DNA double-strand break repair in Nicotiana tabacum. Here, 14 nuclear insertions of chloroplast DNA (nupts) that are unique to Oryza sativa subsp. indica were identified. Comparisons with the preinsertion nuclear loci identified in the related subspecies, O. sativa subsp. japonica, which lacked these nupts, indicated that chloroplast DNA had integrated by nonhomologous end joining. Analyzing public DNase-seq data revealed that nupts were significantly more frequent in open chromatin regions of the nucleus. This preference was tested further in the chimpanzee genome by comparing nuclear loci containing integrants of mitochondrial DNA (numts) with their corresponding numt-lacking preinsertion sites in the human genome. Mitochondrial DNAs also tended to insert more frequently into regions of open chromatin revealed by human DNase-seq and Formaldehyde-Assisted Isolation of Regulatory Elements-seq databases. PMID- 23661566 TI - Use of nitric oxide nanoparticulate platform for the treatment of skin and soft tissue infections. AB - The incidence of skin and soft tissue infections (SSTI) due to multi-drug resistant pathogens is increasing. The concomitant increase in antibiotic use along with the ease with which organisms develop mechanisms of resistance have together become a medical crisis, underscoring the importance of developing innovative and effective antimicrobial strategies. Nitric oxide (NO) is an endogenously produced molecule with many physiologic functions, including broad spectrum antimicrobial activity and immunomodulatory properties. The risk of resistance to NO is minimized because NO has multiple mechanisms of antimicrobial action. NO's clinical utility has been limited largely because it is highly reactive and lacks appropriate vehicles for storage and delivery. To harness NO's antimicrobial potential, a variety exogenous NO delivery platforms have been developed and evaluated, yet limitations preclude their use in the clinical setting. Nanotechnology represents a paradigm through which these limitations can be overcome, allowing for the encapsulation, controlled release, and focused delivery of NO for the treatment of SSTI. PMID- 23661567 TI - Different transcriptional responses of heat shock protein 20 in the marine diatom Ditylum brightwellii exposed to metals and endocrine-disrupting chemicals. AB - Diatoms are sensitive indicators of water quality, and hence used for environmental hazard assessments; however, their toxicogenomic studies have been insufficiently attempted. In the present study, we determined the cDNA sequence of heat shock protein 20 (Hsp20) gene from the diatom Ditylum brightwellii, and examined the transcriptional responses of the gene after exposing it to environmental stressors such as thermal shock, metals, and endocrine-disrupting chemicals (EDCs). The open reading frame (ORF) of DbHsp20 was 531 bp long, encoding 177 amino acid residues (19.49 kDa) with a conserved C-terminal and alpha-crystallin domain. The genomic region of DbHsp20 did not contain introns. Phylogeny of eukaryotic Hsp20s showed D. brightwellii was closely related to other diatoms. With regard to the gene expressional profile, real-time PCR results showed that the gene was significantly upregulated (P < 0.001) under thermal stress, with the highest change of 3.2-fold. Metals' (copper and nickel) treatments showed that it was induced after a certain point of treated concentration. On the contrary, EDCs did not display noticeable change on the expression of DbHsp20. These results suggest that the diatom Hsp20 basically responds to thermal stress, but may differentially respond to toxic substances such as metals and organic compounds such as EDCs. PMID- 23661569 TI - Zebularine inhibits the growth of A549 lung cancer cells via cell cycle arrest and apoptosis. AB - Zebularine (Zeb) is a DNA methyltransferase (DNMT) inhibitor to that has an anti tumor effect. Here, we evaluated the anti-growth effect of Zeb on A549 lung cancer cells in relation to reactive oxygen species (ROS) levels. Zeb inhibited the growth of A549 cells with an IC50 of approximately 70 uM at 72 h. Cell cycle analysis indicated that Zeb induced an S phase arrest in A549 cells. Zeb also induced A549 cell death, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsim ), Bcl-2 decrease, Bax increase, p53 increase and activation of caspase-3 and -8. In contrast, Zeb mildly inhibited the growth of human pulmonary fibroblast (HPF) normal cells and lead to a G1 phase arrest. Zeb did not induce apoptosis in HPF cells. In relation to ROS level, Zeb increased ROS level in A549 cells and induced glutathione (GSH) depletion. The well-known antioxidant, N-acetyl cysteine (NAC) prevented the death of Zeb treated A549 cells. Moreover, Zeb increased the level of thioredoxin reductase 1 (TrxR1) in A549 cells. While the overexpression of TrxR1 attenuated death and ROS level in Zeb-treated A549 cells, the downregulation of TrxR1 intensified death and ROS level in these cells. In conclusion, Zeb inhibited the growth of A549 lung cancer cells via cell cycle arrest and apoptosis. The inhibition was influenced by ROS and TrxR1 levels. PMID- 23661568 TI - Preparation of poly(L-lactic acid)-modified polypropylene mesh and its antiadhesion in experimental abdominal wall defect repair. AB - A new type of polypropylene (PP) hernia mesh, modified with poly(L-lactic acid) (PLLA), was developed and used to repair rat abdominal wall defect. The PP mesh was first treated with oxygen plasma and then grafted with PLLA in phosphorus pentachloride (PCl5 ) solution in dichloride methane. The water contact angle changed during the procedure, and the coverage percentage of PLLA on the PP was about 80%. ATR-FTIR spectroscopy measurements showed the existence of carbonyl group absorption peak (1756.9 cm(-1) ), and atomic force microscope and scanning electron microscope morphological observation indicated that the surface of the PP mesh was covered with PLLA graft. X-ray photoelectron spectroscopy spectra was used to probe chemical group changes and confirmed that the PLLA was grafted onto the PP. A total of 36 Sprague-Dawley rats were randomly divided into six groups, and they received either modified meshes (experimental groups) or PP meshes (control groups) to repair abdominal wall defects. All animals survived until the end of the experiment. Rats in each group were dissected after the operation (after 1 week, 2 weeks, and 1 month, respectively), and the adhesion effects were evaluated. Sections of the mesh parietal peritoneum overlap were examined histologically and graded for inflammation reaction. Compared with the control groups, the experimental groups showed a better ability to resist peritoneal cavity adhesions (P < 0.05), and there was no increase in inflammation formation (P > 0.05). This new type of PLLA-modified PP mesh displayed an additional property of antiadhesion in animal abdominal wall defect repair. PMID- 23661571 TI - Q-ing for health--a new approach to eliciting the public's views on health care resource allocation. AB - The elicitation of societal views about healthcare priority setting is an important, contemporary research area, and there are a number of studies that apply either qualitative techniques or quantitative preference elicitation methods. However, there are methodological challenges in connecting qualitative information (what perspectives exist about a subject) with quantitative questions (to what extent are those perspectives 'supported' in a wider population). In this paper, we present an integrated, mixed-methods approach to the elicitation of public perspectives in two linked studies applying Q methodology. In the first study, we identify three broad viewpoints on the subject of health priorities. In the second study, using Q-survey methods, we describe and illustrate methods to investigate the distribution of those views in the wider population. The findings of the second study suggest that no single viewpoint dominates and none of the three views represents a 'minority perspective'. We demonstrate the potential of Q methodology as a methodological framework that can be used to link qualitative and quantitative questions and suggest some advantages of this over other approaches. However, as this represents the first applied study of this kind, there are methodological questions that require further exploration and development. PMID- 23661570 TI - (3)He pO2 mapping is limited by delayed-ventilation and diffusion in chronic obstructive pulmonary disease. AB - PURPOSE: Lung pO2 mapping with (3)He MRI assumes that the sources of signal decay with time during a breath-hold are radiofrequency depolarization and oxygen dependent T1 relaxation, but the method is sensitive to other sources of spatio temporal signal change such as diffusion. The purpose of this work was to assess the use of (3)He pO2 mapping in patients with chronic obstructive pulmonary disease. METHODS: Ten patients with moderate to severe chronic obstructive pulmonary disease were scanned with a 3D single breath-hold pO2 mapping sequence. RESULTS: Images showed signal increasing over time in some lung regions due to delayed ventilation during breath-hold. Regions of physically unrealistic negative pO2 values were seen in all patients, and regional mean pO2 values of 0.3 bar were measured in the two patients most affected by delayed ventilation (where mean time to signal onset was 3-4 s). CONCLUSIONS: Movement of gas within the lungs during breath-hold causes regional changes in signal over time that are not related to oxygen concentration, leading to erroneous pO2 measurements using the linear oxygen-dependent signal decay model. These spatio-temporal sources of signal change cannot be reliably separated at present, making pO2 mapping using this methodology unreliable in chronic obstructive pulmonary disease patients with significant bullous emphysema or delayed ventilation. PMID- 23661565 TI - CRISPR regulation of intraspecies diversification by limiting IS transposition and intercellular recombination. AB - Mobile genetic elements (MGEs) and genetic rearrangement are considered as major driving forces of bacterial diversification. Previous comparative genome analysis of Porphyromonas gingivalis, a pathogen related to periodontitis, implied such an important relationship. As a counterpart system to MGEs, clustered regularly interspaced short palindromic repeats (CRISPRs) in bacteria may be useful for genetic typing. We found that CRISPR typing could be a reasonable alternative to conventional methods for characterizing phylogenetic relationships among 60 highly diverse P. gingivalis isolates. Examination of genetic recombination along with multilocus sequence typing suggests the importance of such events between different isolates. MGEs appear to be strategically located at the breakpoint gaps of complicated genome rearrangements. Of these MGEs, insertion sequences (ISs) were found most frequently. CRISPR analysis identified 2,150 spacers that were clustered into 1,187 unique ones. Most of these spacers exhibited no significant nucleotide similarity to known sequences (97.6%: 1,158/1,187). Surprisingly, CRISPR spacers exhibiting high nucleotide similarity to regions of P. gingivalis genomes including ISs were predominant. The proportion of such spacers to all the unique spacers (1.6%: 19/1,187) was the highest among previous studies, suggesting novel functions for these CRISPRs. These results indicate that P. gingivalis is a bacterium with high intraspecies diversity caused by frequent insertion sequence (IS) transposition, whereas both the introduction of foreign DNA, primarily from other P. gingivalis cells, and IS transposition are limited by CRISPR interference. It is suggested that P. gingivalis CRISPRs could be an important source for understanding the role of CRISPRs in the development of bacterial diversity. PMID- 23661572 TI - Rational prescribing in paediatrics in a resource-limited setting. AB - INTRODUCTION: There is evidence of inappropriate medication use, causing unnecessary costs for health systems, particularly those with limited resources. Overprescription is commonly reported and can lead to antibiotic resistance. Prescribing patterns differ between countries; little is known about paediatric prescribing practices in Africa. OBJECTIVES: To investigate prescribing practices in children in The Gambia, West Africa. METHOD: A retrospective survey of prescribing practices in children under 5 years of age based on WHO protocol DAP/93.1 was conducted. Twenty government-run health centres across all six regions in The Gambia were assessed. The first 10 encounters each month in 2010 were recorded. For each encounter, patient demographics, diagnoses and medications were recorded as per protocol. RESULTS: Two thousand and four hundred patient encounters were included. The mean number of medications per encounter was 2.2 (median 2.0, IQR 2.0-3.0). Across different geographical regions within The Gambia antibiotics were prescribed in 63.4% (IQR 62.8-65.8%) and micronutrients in 21.7% (IQR 15.3-27.1%) of patient encounters. There was evidence of high antibiotic prescription in children with cough and coryzal symptoms (54.5%; IQR 35.8-59.0%) and simple diarrhoea without dehydration (44.8%; IQR 36.7-61.3%). 74.8% (IQR 71.8-76.1%) of medications were prescribed generically. CONCLUSIONS: The study showed an overprescription of antibiotics and substantial usage of micronutrients despite a lack of international evidence based guidelines. Cost-effective interventions to improve prescribing practices are called for and more studies with a focus on rational prescribing in paediatrics in low-income settings are urgently required to fill the gap in current knowledge. PMID- 23661573 TI - Ethical and regulatory considerations in the use of individual participant data for studies of disease prediction. PMID- 23661574 TI - Morbidity among child travellers with sickle-cell disease visiting tropical areas: an observational study in a French tertiary care centre. AB - OBJECTIVE: To examine morbidity among children with sickle-cell disease (SCD) during and after travel to a tropical area. DESIGN: Observational study. SETTING: Tertiary care children; Robert Debre Hospital, Paris, France. POPULATION: Children with SCD younger than 18 years old and managed in the SCD referral centre at the Robert Debre Hospital who travelled to a tropical or subtropical area between 1 June 2009 and 31 December 2009. MAIN OUTCOME: To assess morbidity, we used the number of clinical events requiring medical consultation during the trip as the primary outcome and the number of hospitalisations required after returning as the secondary outcome. RESULTS: Thirty-nine children were included. The median age was 7.8 years (4.3-11.7 years). All of the children and their parents attended a pretravel visit focusing on the prevention of travel-related diseases. Twelve children (30%) consulted a physician while they were abroad. Thirteen children (33%) were hospitalised, and 23 children (59%) consulted a physician while they were abroad or within 3 months after returning to France. Considering the 3 months before and after travel, the number of children hospitalised after travel (n=12, 30.7%) was significantly higher than the number hospitalised before (n=4, 10.2%; p=0.01). One child was hospitalised for multifocal osteoarthritis as a complication of Salmonella enterica septicaemia of gastrointestinal origin. CONCLUSIONS: Travels to tropical areas are associated with high morbidity in children with SCD. Salmonella infection is a particularly significant threat, and empirical antibiotic therapy should be prescribed routinely for traveller's diarrhoea in this population. PMID- 23661575 TI - School-based physical activity programme in preadolescent girls (9-11 years): a feasibility trial in Karachi, Pakistan. AB - BACKGROUND: Effective strategies to combat childhood obesity are challenging, especially among South Asian girls. We conducted a pilot cluster trial of a school-based physical activity programme among preadolescent girls to determine the feasibility (recruitment, retention and implementation) of the programme and influence on blood pressure (BP) and body mass index (BMI). METHODS: This two-arm parallel cluster intervention trial was conducted in four similar all-girls public sector schools in Karachi over a 20-week period. All girls aged 9-11 years were included. Intervention was a physical activity programme of 30 min duration four times a week. Primary outcome was to assess the feasibility of the physical activity programme defined as recruitment and retention >70% and treatment fidelity of >80% of physical activity programme. Secondary outcomes were changes in systolic BP (SBP), diastolic BP (DBP) and BMI from baseline to follow-up. RESULTS: A total of 360 participants were invited to participate, 280 girls met eligibility criteria, and were recruited; 131 (77%) in the intervention group and 146 (87%) in control group. At follow-up, the overall retention of participants was 222 (79.2%); 105 (80.1%) in the intervention group and 117 (78.5%) in the control group. The difference in mean change from baseline to follow-up in SBP, DBP and BMI score was 1.9 mm Hg, 0.7 mm Hg and 0.55 kg/m2 between intervention and control arms, respectively. CONCLUSIONS: A school-based physical activity programme in a public sector girls school of urban Pakistan is feasible. There was a favourable trend in BP and BMI at follow-up. (Clinical trial ID NCT 00533819). PMID- 23661577 TI - Bone markers for monitoring efficacy in patients ?with bone metastases receiving zoledronic acid: ?a review of published data. AB - Bone metastases occur frequently in patients with advanced solid tumors and can create serious clinical problems that are commonly referred to as skeletal related events. Although bisphosphonates, especially zoledronic acid, have emerged as an integral determinant of managing metastatic bone disease, their application remains a challenge because of the lack of standardized measures and their side effects. Since factors derived from bone metabolism are potentially useful to measure the efficacy of zoledronic acid, several clinical trials have investigated these bone markers with respect to their monitoring values. The results suggest that a greater decline in bone marker levels is associated with a more reduced incidence of skeletal-related events and a better improvement of symptoms. This review summarizes the available evidence on the clinical use of bone markers in monitoring zoledronic acid in various cancers with bone metastases including breast, prostate and lung cancer. PMID- 23661576 TI - CD133 expression in circulating tumor cells from breast cancer patients: potential role in resistance to chemotherapy. AB - CD133 has been associated with cell properties such as self renewal, migration and vasculogenic mimicry, potentially involved in generation of circulating tumor cells (CTCs). We characterized CD133 expression in CTCs of 98 nometastatic breast cancer (BC) patients. CTCs were isolated by immunomagnetic techniques using magnetic beads labeled with a multicytokeratin(CK)-specific antibody (CK3-11D5) and CTCs and CD133 detection through immunocytochemical methods. CK(+) /CD133(+) CTCs were identified in 65% of patients at baseline and 47.8% after systemic therapy (p = 0.53). Correlation of CD133 status in CTCs with classical clinicopathological characteristics and response to therapy was performed. Her2 not amplified and low Ki-67 index were positively correlated with presence of CK(+) /CD133(+) CTCs. Before any treatment, CK(+) /CD133(+) CTCs were more frequently isolated in patients with luminal BC subtype. No statistically significant differences were found between proportion of CK(+) /CD133(+) CTCs and BC subtypes after systemic therapy, implying a relative enrichment of CK(+) /CD133(+) CTCs in triple negative and HER2-amplified tumors. While CK(+) /CTCs decreases after chemotherapy when analyzing the whole population, CK(+) /CD133(+) CTCs were enriched in post-treatment samples in nonluminal BC subtypes. These findings suggest the potential role of CD133 as a promising marker of chemoresistance in nonluminal BC patients. Further prospective studies and extensive preclinical modeling will be needed to confirm whether CD133 is a marker of resistance to chemotherapy, and its role as a target for novel anticancer therapies targeting cancer stem cells and tumor vasculature. PMID- 23661578 TI - Chlorpyrifos-based insecticides induced genotoxic and cytotoxic effects in the ten spotted live-bearer fish, Cnesterodon decemmaculatus (Jenyns, 1842). AB - Mortality, genotoxicity, and cytotoxicity of the 48% chlorpyrifos (CPF)-based formulations Lorsban* 48E((r)) and CPF Zamba((r)) were evaluated on Cnesterodon decemmaculatus (Jenyns, 1842) (Pisces, Poeciliidae) under laboratory conditions. Induction of micronucleus (MN) and alterations in the erythrocyte/erythroblast frequencies were employed as end points for genotoxicity and cytotoxicity, respectively. For Lorsban* 48E((r)) , mean values of 0.13 and 0.03 mg/L were determined for LC50 at 24 and 96 h, respectively, and these concentrations reached mean values of 0.40 and 0.21 mg/L for CPF Zamba((r)) . Mortality values increased as a positive linear function of the CPF Zamba((r)) concentrations, but not for Lorsban* 48E((r)) concentrations. There was no significant relationship between mortality and exposure time within the 0-96 h period for both formulations. LC50 values indicated that the fish were seven fold more sensitive to Lorsban* 48E((r)) than to CPF Zamba((r)) . Lorsban* 48E((r)) within the concentration range of 0.008-0.025 mg/L increased MN frequency at both 48 and 96 h of treatment. Similar results were also observed when fish were exposed to 0.052-0.155 mg/L of CPF Zamba((r)) , regardless of the exposure time. Cellular cytotoxicity was found after Lorsban* 48E((r)) and CPF Zamba((r)) treatments for all concentrations and time exposures, estimated by a decrease in the frequency of mature erythrocytes and a concomitant enhanced frequency of erythroblasts in circulating blood. Furthermore, our results demonstrated that Lorsban* 48E((r)) and CPF Zamba((r)) should be considered as CPF-based commercial formulations with marked genotoxic and cytotoxic properties. PMID- 23661579 TI - A fatal case involving a caffeine-containing fat burner. PMID- 23661580 TI - Do they know what is at risk? Health risk perception among the obese. AB - The perception of health risks and risky health behaviors are closely associated. In this paper, we investigate the accuracy of health risk perceptions among obese individuals, aged 50-62 years. We compare subjective risk perceptions for various diseases elicited in the American Life Panel to individual's objective risks of the same diseases. We find that obese individuals significantly underestimate their 5-year risks of arthritis or rheumatism and hypertension, whereas they systematically overestimate their 5-year risks of a heart attack and a stroke. Obese individuals are thus aware of some but not all obesity-related health risks. For given diseases, we document substantial heterogeneities in the accuracy of expectations across individuals. PMID- 23661581 TI - Effect of bleaching agents and soft drink on titanium surface topography. AB - The effects of carbamide peroxide, hydrogen peroxide and cola soft drink on the topographic modifications of commercially-pure titanium (CP-Ti) and Ti-6Al-4V were investigated. Ti discs were divided into 18 groups (n = 4) based on the solution treatment and Ti type. Specimens were immersed in 3 mL of each solution for 4 h per day (for the remaining 20 h, discs were left dry or immersed in artificial saliva) for 15 days. For control, specimens were immersed in only artificial saliva. Ti surfaces were examined using scanning electron (SEM) and atomic force (AFM) microscopes and their surface roughness (in um) and surface chemical modifications were investigated. Data were analyzed by ANOVA and Tukey's test (alpha = 0.05). Groups immersed in 35% hydrogen peroxide showed the highest roughness (Ra) (171.65 +/- 4.04 for CP-Ti and 145.91 +/- 14.71 for Ti-6Al-4V) (p < 0.05), followed by groups treated with carbamide peroxide 16% (110.91 +/- 0.8 for CP-Ti and 49.28 +/- 0.36 for Ti-6Al-4V) and 35% (65.67 +/- 1.6 for CP-Ti and 53.87 +/- 1.98 for Ti-6Al-4V); treatment with artificial saliva did not affect the results. These values were statistically superior to those observed prior to the treatment and to those of the control group (31.0 +/- 0.99 for CP-Ti and 29.95 +/- 0.58 for Ti-6Al-4V). Cola soft drink did not alter the surface roughness of either Ti type (p > 0.05). SEM and AFM revealed dramatic changes in the specimens surfaces immersed in the 35% hydrogen peroxide, mainly for CP-Ti. No detectable chemical modifications on the Ti surface were observed. Bleaching agents promoted significant changes in Ti topography, which could affect the longevity of implants treatments. PMID- 23661582 TI - Structured metal film as a perfect absorber. AB - A new type of absorber, a four-tined fish-spear-like resonator (FFR), constructed by the two-photon polymerization process, is reported. An absorbance of more than 90% is experimentally realized and the resonance occurs in the space between the tines. Since a continuous layer of metallic thin film covers the structure, it is perfectly thermo- and electroconductive, which is the mostly desired feature for many applications. PMID- 23661584 TI - Tumor necrosis factor alpha induces Warburg-like metabolism and is reversed by anti-inflammatory curcumin in breast epithelial cells. AB - The reprogramming of cellular metabolism in cancer cells is a well-documented effect. It has previously been shown that common oncogene expression can induce aerobic glycolysis in cancer cells. However, the direct effect of an inflammatory microenvironment on cancer cell metabolism is not known. Here, we illustrate that treatment of nonmalignant (MCF-10a) and malignant (MCF-7) breast epithelial cells with low-level (10 ng/ml) tumor necrosis factor alpha (TNF-alpha) significantly increased glycolytic reliance, lactate export and expression of the glucose transporter 1 (GLUT1). TNF-alpha decreased total mitochondrial content; however, oxygen consumption rate was not significantly altered, suggesting that overall mitochondrial function was increased. Upon glucose starvation, MCF7 cells treated with TNF-alpha demonstrated significantly lower viability than nontreated cells. Interestingly, these properties can be partially reversed by coincubation with the anti-inflammatory agent curcumin in a dose-dependent manner. This work demonstrates that aerobic glycolysis can be directly induced by an inflammatory microenvironment independent of additional genetic mutations and signals from adjacent cells. Furthermore, we have identified that a natural dietary compound can reverse this effect. PMID- 23661587 TI - Expression of fibrosis-related genes in human renal allografts with interstitial fibrosis and tubular atrophy. AB - BACKGROUND: Gene expression analysis of fibrosis-related genes may became useful for the early identification of fibrosis processes. We quantitatively assessed messenger RNA transcripts of the CTGF, TGF-beta and KIM-1 genes, in biopsy samples from renal transplant recipients with graft dysfunction, to test the hypothesis that in patients with chronic disease of the renal transplant, these molecules could be markers of the development and severity of graft fibrosis. METHODS: Ninety-six kidney transplant recipients who undertook 121 indication graft biopsies between January 2008 and December 2009 were included. Patients and biopsies were classified into 4 major diagnostic groups according to the Banff 2007 classification: acute tubular necrosis (ATN; n = 20), acute rejection (AR; n = 58), acute calcineurin inhibitor nephrotoxicity (CIN; n = 13) and interstitial fibrosis and tubular atrophy (IF/TA; n = 30). RESULTS: Messenger RNA transcripts of the CTGF and TGF-beta genes were significantly higher in IF/TA compared with all other conditions. Messenger RNA transcripts of the KIM-1 gene in the IF/TA group were higher than in the CIN group. In addition, it was observed that gene expression of CTGF, TGF-beta and KIM-1 increased with severity of fibrosis observed in the pathological examinations. CONCLUSIONS: Gene expression evaluation of the kidney graft tissue may be used to improve pathological diagnosis and perhaps for the future development of noninvasive biomarkers. PMID- 23661583 TI - DCE-MRI analysis methods for predicting the response of breast cancer to neoadjuvant chemotherapy: pilot study findings. AB - PURPOSE: The purpose of this pilot study is to determine (1) if early changes in both semiquantitative and quantitative DCE-MRI parameters, observed after the first cycle of neoadjuvant chemotherapy in breast cancer patients, show significant difference between responders and nonresponders and (2) if these parameters can be used as a prognostic indicator of the eventual response. METHODS: Twenty-eight patients were examined using DCE-MRI pre-, post-one cycle, and just prior to surgery. The semiquantitative parameters included longest dimension, tumor volume, initial area under the curve, and signal enhancement ratio related parameters, while quantitative parameters included K(trans), v(e), k(ep), v(p), and tau(i) estimated using the standard Tofts-Kety, extended Tofts Kety, and fast exchange regime models. RESULTS: Our preliminary results indicated that the signal enhancement ratio washout volume and k(ep) were significantly different between pathologic complete responders from nonresponders (P < 0.05) after a single cycle of chemotherapy. Receiver operator characteristic analysis showed that the AUC of the signal enhancement ratio washout volume was 0.75, and the AUCs of k(ep) estimated by three models were 0.78, 0.76, and 0.73, respectively. CONCLUSION: In summary, the signal enhancement ratio washout volume and k(ep) appear to predict breast cancer response after one cycle of neoadjuvant chemotherapy. This observation should be confirmed with additional prospective studies. PMID- 23661588 TI - Fluctuation of serum C3 levels reflects disease activity and metabolic background in patients with IgA nephropathy. AB - BACKGROUND: We focused on the fluctuations of serum C3 levels throughout the clinical course of patients and investigated the relationship between these fluctuations and clinical findings. METHODS: IgA nephropathy patients (n = 122) were enrolled in the present study. Serum C3 and other clinical markers were compared at the time of renal biopsy and at last follow-up (6.67 +/- 2.07 years). Patients were divided into 3 groups based on serum C3 levels: Group I with first C3 levels below the mean -1 SD, which turned into an increase at last observation; group II with first C3 levels more than the mean +1 SD, which turned into a decrease at last observation; and group III, with first C3 levels more than the mean +1 SD, which turned into an increase at last observation. First and last levels of clinical markers were compared among the 3 groups. RESULTS: Serum C3 levels of the patients whose renal symptoms, including hematuria, proteinuria and estimated glomerular filtration rate (eGFR), were improved, were significantly increased at last observation (p<0.05, p<0.01, p<0.01, respectively). Age, total cholesterol and triglyceride levels in group III were significantly higher than those in group I. Group II showed a significant reduction of urinary protein. Groups I and II maintained renal function, but group III showed a significant deterioration of renal function. CONCLUSIONS: The levels and fluctuations of serum C3 might reflect the disease activity and metabolic alteration in patients with IgA nephropathy. PMID- 23661589 TI - Ultrafiltration in acute decompensated heart failure: friend or foe for the kidney? AB - BACKGROUND: Congestion represents the common pathogenetic mechanism of both the acute decompensation episodes of heart failure and progression of the syndrome; it also increases the risk of rehospitalization, and is associated with renal function worsening. Diuretic therapy still represent the mainstay of therapy of congestion; however, ultrafiltration (i.e., fluid removal from blood by hemoconcentration obtained with dedicated machines) has been recently suggested as a more rapid and effective alternative to the conventional therapeutic approach. METHODS: On the basis of the proposed mechanisms of action and rationale of ultrafiltration in heart failure, this review is aimed at discussing efficacy and safety issues of this mechanical modality of fluid removal, with special regard to renal function.? RESULTS: The available evidence, also including recent data from a randomized clinical trial comparing ultrafiltration with adequately managed diuretic therapy (the CARRESS study), does not support its extensive employment as an alternative to well protocolized conventional diuretic therapy, especially in patients with acute decompensated heart failure. As a matter of fact, in this latter case highly negative effects on renal function are also to be expected.? CONCLUSION: Ultrafiltration should be reserved to very selected patients with advanced heart failure and true diuretic resistance, as part of a more complex strategy aiming at an adequate control of fluid retention. PMID- 23661590 TI - Treatment of membranous nephropathy in patients with renal insufficiency: what regimen to choose? PMID- 23661591 TI - Twenty-three-year review of disease patterns from renal biopsies: an experience from a pediatric renal center. AB - BACKGROUND: The aim of this study was to investigate the clinical and pathological characteristics as well as their associations with trends for diseases in 1,579 pediatric renal biopsies from 1989 to 2012. METHODS: The clinical and pathological data were retrospectively analyzed for children undergoing renal biopsy from 1989 to 2012 in our hospital. RESULTS: Primary glomerulonephritis (PGN) accounted for 60.1% of total cases, followed by secondary glomerulonephritis (SGN) (31.2%) and hereditary nephropathy (8.3%). The major clinical patterns of PGN and SGN were nephritic syndrome (NS) and Henoch Schonlein purpura nephritis (HSPN), respectively. Minimal change disease/mild disease (MCD/ML), IgAN and mesangial proliferative glomerulonephritis (MsPGN) were the most common pathological patterns of PGN. Male patients were most likely to suffer from NS, HBV-associated glomerulonephritis (HBVGN) or Alport syndrome, while females were most likely to suffer from isolated hematuria, rapidly progressive glomerulonephritis (RPGN), lupus nephritis (LN), ANCA-associated glomerulonephritis or thin basement membrane disease. The proportions of NS, isolated hematuria, acute nephritic syndrome, chronic nephritic syndrome, HBVGN, LN and hemolytic uremic syndrome changed significantly with aging. The clinical patterns of PGN were significantly correlated with the distribution of pathological types: MCD/ML and IgMN presented most often as NS; MCD/ML and IgAN presented most often as isolated hematuria; IgAN and MsPGN presented most often as hematuria with proteinuria. The spectrum of NS, HSPN, HBVGN and IgAN changed during the 23 years, and the percentage of repeated renal biopsies was low (1.2%) in pediatric cases with kidney disease. CONCLUSIONS: Glomerular diseases in children are closely related to age and sex of patient. The spectrum of kidney diseases from our center has changed significantly over the last 23 years. PMID- 23661592 TI - Urodilatin regulates renal dopamine metabolism. AB - BACKGROUND: Sodium and water transport across renal proximal tubules is regulated by diverse hormones such as dopamine and urodilatin. We have previously reported that urodilatin stimulates extraneuronal dopamine uptake in external renal cortex by activation of the type A natriuretic peptide receptor, coupled to cyclic guanylate monophosphate signaling and protein kinase G. Moreover, urodilatin enhances dopamine-induced inhibition of Na+, K+-ATPase activity in renal tubules. The aim of the present study was to evaluate whether urodilatin could also alter renal dopamine synthesis, release, catabolism and turnover. METHODS: The effects of urodilatin on dopamine synthesis, release, catabolism and turnover were measured in samples of renal cortex from Sprague Dawley rats. RESULTS: The results indicate that urodilatin increases L-DOPA decarboxylase activity and decreases catechol-o-methyl transferase and monoamine oxidase activity. Moreover, urodilatin does not affect either dopamine basal secretion or potassium chloride induced dopamine release in external renal cortex, and reduces amine turnover. CONCLUSIONS: Both the present results and previous findings show that urodilatin modifies dopamine metabolism in external renal cortex of rats by enhancing dopamine uptake and synthesis and by decreasing catechol-o-methyl transferase and monoamine oxidase activity and dopamine turnover. Those effects taken together may favor dopamine accumulation in renal cells and increase its endogenous content and availability. This would permit D1 receptor recruitment and stimulation and, in turn, overinhibition of Na+, K+-ATPase activity, which results in decreased sodium reabsorption. Therefore, urodilatin and dopamine enhance natriuresis and diuresis through a common pathway. PMID- 23661593 TI - Structural equation modeling for implementation intentions, cancer worry, and stages of mammography adoption. AB - OBJECTIVES: This study aimed to develop a structural model for mammography adoption in Japanese middle-aged women by using constructs from the transtheoretical model (TTM), the theory of planned behavior (TPB), implementation intentions, and cancer worry. METHODS: Questionnaires based on items including TTM, TPB, implementation intentions, cancer worry-related variables, and demographic variables were distributed to 1000 adult women aged 40 to 59 years, with 641 subjects being used in the final analysis (response rate = 64.1%). RESULTS: Regarding the stage of adoption, 79 participants (12.3%) were at the precontemplation stage, 30 (4.7%) were at the relapse stage, 142 (22.2%) were at the contemplation stage, 88 (13.7%) were at the action stage, and 302 (47.1%) were at the maintenance stage. Our model, derived from structural equation modeling, revealed that the stage of mammography adoption was significantly affected by goal intentions, implementation intentions, perceived barriers, history of breast cancer screening, and relative risk. A logistic regression analysis revealed that goal intentions and implementation intentions significantly predicted mammography uptake within 1 year. CONCLUSION: This study developed an integrated model constructed from TTM, TPB, implementation intentions, and cancer worry to account for mammography adoption in Japan, and also confirmed the predictive validity of the model. PMID- 23661594 TI - A breach in patients' safety in randomized controlled trials of antibiotic drugs. AB - In a number of randomized controlled trials of antibiotic drugs the pathogens cultured from patients and their in vitro susceptibilities to the study drugs were not disclosed to the physicians during the whole course of the disease. These trials included patients with sepsis and bacteraemia. In clinical practice the information on the pathogen and its susceptibilities serves to re-evaluate the antibiotic treatment on the second or third day. As there is strong evidence that antibiotic treatment (empirical and definitive) matching the in vitro susceptibility of the pathogen reduces fatality rates in severe infections, withholding these data is a breach in patient safety. Sponsors and investigators of clinical trials of antibiotic drugs should ensure that the susceptibility of pathogens to the trial drugs are made available to clinicians in real time and taken into account when considering change in patient management, as would be the case in routine clinical practice. Members of research ethics committees should make sure that the protocols provide for this, while journals considering publication of clinical trial results should ask that details on the availability of susceptibilities to the trial antibiotics are disclosed in the methods section. PMID- 23661596 TI - Mechanically tunable, self-adjuvanting nanoengineered polypeptide particles. AB - DNA-loaded polypeptide particles are prepared via templated assembly of mesoporous silica for the delivery of adjuvants. The elasticity and cargo-loading capacity of the obtained particles can be tuned by the amount of cross-linker used to stabilize the polypeptide particles. The use of polypeptide particles as biocarriers provides a promising method for vaccine delivery. PMID- 23661597 TI - Frequent detection of human cytomegalovirus in neuroblastoma: a novel therapeutic target? AB - Neuroblastoma is the most common and deadly tumor of childhood, where new therapy options for patients with high-risk disease are highly warranted. Human cytomegalovirus (HCMV) is prevalent in the human population and has recently been implicated in different cancer forms where it may provide mechanisms for oncogenic transformation, oncomodulation and tumor cell immune evasion. Here we show that the majority of primary neuroblastomas and neuroblastoma cell lines are infected with HCMV. Our analysis show that HCMV immediate-early protein was expressed in 100% of 36 primary neuroblastoma samples, and HCMV late protein was expressed in 92%. However, no infectious virus was detected in primary neuroblastoma tissue extracts. Remarkably, all six human neuroblastoma cell lines investigated contained CMV DNA and expressed HCMV proteins. HCMV proteins were expressed in neuroblastoma cells expressing the proposed stem cell markers CD133 and CD44. When engrafted into NMRI nu/nu mice, human neuroblastoma cells expressed HCMV DNA, RNA and proteins but did not produce infectious virus. The HCMV-specific antiviral drug valganciclovir significantly reduced viral protein expression and cell growth both in vitro and in vivo. These findings indicate that HCMV is important for the pathogenesis of neuroblastoma and that anti-viral therapy may be a novel adjuvant treatment option for children with neuroblastoma. PMID- 23661599 TI - Methyl nutrients, DNA methylation, and cardiovascular disease. AB - Diet plays an important role in the development and prevention of cardiovascular disease (CVD), but the molecular mechanisms are not fully understood. DNA methylation has been implicated as an underlying molecular mechanism that may account for the effect of dietary factors on the development and prevention of CVD. DNA methylation is an epigenetic process that provides "marks" in the genome by which genes are set to be transcriptionally activated or silenced. Epigenomic marks are heritable but are also responsive to environmental shifts, such as changes in nutritional status, and are especially vulnerable during development. S-adenosylmethionine is the methyl group donor for DNA methylation and several nutrients are required for the production of S-adenosylmethionine. These methyl nutrients include vitamins (folate, riboflavin, vitamin B12, vitamin B6, choline) and amino acids (methionine, cysteine, serine, glycine). As such, imbalances in the metabolism of these nutrients have the potential to affect DNA methylation. The focus of this review is to provide an overview on the current understanding of the relationship between methyl nutrient status and DNA methylation patterns and the potential role of this interaction in CVD pathology. PMID- 23661598 TI - APT-weighted and NOE-weighted image contrasts in glioma with different RF saturation powers based on magnetization transfer ratio asymmetry analyses. AB - PURPOSE: To investigate the saturation-power dependence of amide proton transfer (APT)-weighted and nuclear Overhauser enhancement-weighted image contrasts in a rat glioma model at 4.7 T. METHODS: The 9L tumor-bearing rats (n = 8) and fresh chicken eggs (n = 4) were scanned on a 4.7-T animal magnetic resonance imaging scanner. Z-spectra over an offset range of +/-6 ppm were acquired with different saturation powers, followed by the magnetization transfer-ratio asymmetry analyses around the water resonance. RESULTS: The nuclear Overhauser enhancement signal upfield from the water resonance (-2.5 to -5 ppm) was clearly visible at lower saturation powers (e.g., 0.6 uT) and was larger in the contralateral normal brain tissue than in the tumor. Conversely, the APT effect downfield from the water resonance was maximized at relatively higher saturation powers (e.g., 2.1 uT) and was larger in the tumor than in the contralateral normal brain tissue. The nuclear Overhauser enhancement decreased the APT-weighted image signal, based on the magnetization transfer-ratio asymmetry analysis, but increased the APT weighted image contrast between the tumor and contralateral normal brain tissue. CONCLUSION: The APT and nuclear Overhauser enhancement image signals in tumor are maximized at different saturation powers. The saturation power of roughly 2 MUT is ideal for APT-weighted imaging at clinical B0 field strengths. PMID- 23661595 TI - Genome sequences of 65 Helicobacter pylori strains isolated from asymptomatic individuals and patients with gastric cancer, peptic ulcer disease, or gastritis. AB - Helicobacter pylori, inhabitant of the gastric mucosa of over half of the world population, with decreasing prevalence in the U.S., has been associated with a variety of gastric pathologies. However, the majority of H. pylori-infected individuals remain asymptomatic, and negative correlations between H. pylori and allergic diseases have been reported. Comprehensive genome characterization of H. pylori populations from different human host backgrounds including healthy individuals provides the exciting potential to generate new insights into the open question whether human health outcome is associated with specific H. pylori genotypes or dependent on other environmental factors. We report the genome sequences of 65 H. pylori isolates from individuals with gastric cancer, preneoplastic lesions, peptic ulcer disease, gastritis, and from asymptomatic adults. Isolates were collected from multiple locations in North America (USA and Canada) as well as from Columbia and Japan. The availability of these H. pylori genome sequences from individuals with distinct clinical presentations provides the research community with a resource for detailed investigations into genetic elements that correlate either positively or negatively with the epidemiology, human host adaptation, and gastric pathogenesis and will aid in the characterization of strains that may favor the development of specific pathology, including gastric cancer. PMID- 23661600 TI - Ferulic acid in the treatment of post-diabetes testicular damage: relevance to the down regulation of apoptosis correlates with antioxidant status via modulation of TGF-beta1, IL-1beta and Akt signalling. AB - The aim of this study was to investigate the protective effect of ferulic acid at different doses (50 mg kg(-1) alternative day and 50 mg kg(-1) daily) on the streptozotocin (STZ)-induced post-diabetes rat testicular damage. Diabetes was induced by a single intraperitoneal injection of STZ (50 mg/kg). Rats treated with ferulic acid were given once a day orally for 10 weeks, starting 3 days after STZ injection. Testis tissue and blood samples were collected for investigating biochemical analysis, antioxidant status, sperm parameters, and histopathological, immunohistochemical and apoptotic studies. Treatment with ferulic acid to diabetic rats significantly improved the body weight, testis weight, serum insulin level, serum testosterone level and sperm parameters (viability, motility and count). Histopathological study also revealed that ferulic acid-treated diabetic rats showed an improved histological appearance. Our data indicated that significant reduction in the activity of apoptosis by using terminal deoxyuridine triphosphate nick end-labelling and reduced expression of transforming growth factor-beta1 and interleukin-1beta in the testis tissue of ferulic acid-treated diabetic rats. Conversely, it was also revealed that ferulic acid-treated diabetic rats markedly enhanced the serine/threonine protein kinase protein expression in the testis tissue. Our result suggests that ferulic acid inhibits testicular damage in diabetic rats by declining oxidative stress. PMID- 23661602 TI - Mechanism of action of ribavirin in anti-HCV regimens: new insights for an age old question? PMID- 23661603 TI - Resveratrol role in Staphylococcus aureus-induced corneal inflammation. AB - The aim of this study was to evaluate the role of trans-resveratrol on Staphylococcus aureus-induced keratitis. Rabbit corneas (intact corneas, abraded corneas and abraded corneas exposed to inactivated S. aureus strains) were placed in an ex vivo culture model. The abraded corneas exposed to S. aureus were divided into two 1-h-treatment sub-groups: corneas treated with trans-resveratrol and corneas treated with vehicle. The tissues were examined by immunohistochemical analyses and quantitative real-time RT-PCR to determine whether resveratrol could reduce TLR2-mediated recognition of S. aureus on epithelial cells and, if so, whether this reduction repressed the expression of inflammatory cytokines. The results demonstrated that resveratrol treatment effectively downregulated cell surface TLR2 on cells stimulated by S. aureus and reduced the expression of interleukin-8 gene. In addition, the corneal culture model tested, which is simple and reproducible, could be an alternative to in vivo animal testing for the development of novel specific therapies. PMID- 23661601 TI - Chimeric negative regulation of p14ARF and TBX1 by a t(9;22) translocation associated with melanoma, deafness, and DNA repair deficiency. AB - Melanoma is the most deadly form of skin cancer and DiGeorge syndrome (DGS) is the most frequent interstitial deletion syndrome. We characterized a novel balanced t(9;22)(p21;q11.2) translocation in a patient with melanoma, DNA repair deficiency, and features of DGS including deafness and malformed inner ears. Using chromosome sorting, we located the 9p21 breakpoint in CDKN2A intron 1. This resulted in underexpression of the tumor suppressor p14 alternate reading frame (p14ARF); the reduced DNA repair was corrected by transfection with p14ARF. Ultraviolet radiation-type p14ARF mutations in his melanoma implicated p14ARF in its pathogenesis. The 22q11.2 breakpoint was located in a palindromic AT-rich repeat (PATRR22). We identified a new gene, FAM230A, that contains PATRR22 within an intron. The 22q11.2 breakpoint was located 800 kb centromeric to TBX1, which is required for inner ear development. TBX1 expression was greatly reduced. The translocation resulted in a chimeric transcript encoding portions of p14ARF and FAM230A. Inhibition of chimeric p14ARF-FAM230A expression increased p14ARF and TBX1 expression and improved DNA repair. Expression of the chimera in normal cells produced dominant negative inhibition of p14ARF. Similar chimeric mRNAs may mediate haploinsufficiency in DGS or dominant negative inhibition of other genes such as those involved in melanoma. PMID- 23661604 TI - Accumulation of micron sized iron oxide particles in endothelin-1 induced focal cortical ischemia in rats is independent of cell migration. AB - PURPOSE: Endogenous labeling of stem/ progenitor cells via intracerebroventricular injection of micron-sized particles of iron oxide (MPIOs) has become standard methodology for MRI of adult neurogenesis. While this method is well characterized in the naive rodent brain, it has not been fully investigated in disease models. Here, we describe methodological challenges that can confound data analysis when this technique is applied to a rat model of stroke, the endothelin-1 model of focal cortical ischemia. METHODS: We intended to track endogenous neuroblast migration from the subventricular zone to the stroke area using previously described methods for in vivo labeling of endogenous neuroblasts with MPIOs and following migration with high resolution MRI. RESULTS: MPIOs accumulation in stroke regions of endothelin-1-treated brains involves two dynamic steps: an initial rapid cell independent mechanism, followed by slower MPIOs accumulation. While the latter may in part be attributable to cell dependent delivery of the particles, the cell independent mechanism complicates the interpretation of the data. Strategies aimed at prelabeling the stem cell niche reduced cell independent MPIOs accumulation, but failed to abolish it. CONCLUSION: We conclude that MRI-based neural stem/progenitor cell tracking via direct injection of MPIOs into the lateral and third ventricles, requires significant validation in models of brain disease/trauma. PMID- 23661605 TI - Phenethyl isothiocyanate inhibits androgen receptor-regulated transcriptional activity in prostate cancer cells through suppressing PCAF. AB - SCOPE: Androgen receptor (AR) signaling is critical for all aspects of prostate growth and tumorigenesis. The glucosinolate-derived phenethyl isothiocyanate (PEITC) has recently been demonstrated to reduce the risk of prostate cancer (PCa) and inhibit PCa cell growth. We previously reported that p300/CBP associated factor (PCAF), a co-regulator for AR, is upregulated in PCa cells through suppression of the mir-17 gene. Here, we assessed the effects of PEITC on PCAF expression and AR-regulated transcriptional activity in PCa cells. METHODS AND RESULTS: Using AR-responsive LNCaP cells, we observed the inhibitory effects of PEITC on the dihydrotestosterone-stimulated AR transcriptional activity and cell growth of PCa cells. Interestingly, overexpression of PCAF attenuated the inhibitory effects of PEITC on dihydrotestosterone-stimulated AR transcriptional activity. Expression of PCAF was upregulated in PCa cells through suppression of miR-17. PEITC treatment significantly decreased PCAF expression and promoted transcription of miR-17 in LNCaP cells. Functional inhibition of miR-17 attenuated the suppression of PCAF in cells treated by PEITC. CONCLUSION: Our results indicate that PEITC inhibits AR-regulated transcriptional activity and cell growth of PCa cells through miR-17-mediated suppression of PCAF, suggesting a new mechanism by which PEITC modulates PCa cell growth. PMID- 23661606 TI - Dietary chemopreventative benzyl isothiocyanate inhibits breast cancer stem cells in vitro and in vivo. AB - A small subset of mammary tumor-initiating cells (also known as breast cancer stem cells; bCSC), characterized by expression of different markers [CD44(high)/CD24(low)/epithelial-specific antigen (ESA)+], aldehyde dehydrogenase 1 (ALDH1) activity, and ability to form mammospheres under ultra-low attachment culture conditions, are suspected to evade conventional therapies leading to disease recurrence. Elimination of both therapy-sensitive epithelial tumor cells and therapy-resistant bCSC is therefore necessary for prevention of breast cancer. We have shown previously that a nontoxic small-molecule constituent of edible cruciferous vegetables (benzyl isothiocyanate; BITC) inhibits mammary cancer development in mouse mammary tumor virus-neu (MMTV-neu) transgenic mice by causing epithelial tumor cell apoptosis. The present study shows efficacy of BITC against bCSC in vitro and in vivo. Mammosphere formation frequency and CD44(high)/CD24(low)/ESA+ and/or ALDH1+ populations in cultured MCF-7 (estrogen receptor-positive) and SUM159 (triple-negative) human breast cancer cells were decreased significantly in the presence of plasma achievable concentrations of BITC. BITC administration in the diet (3 MUmol BITC/g diet for 29 weeks) resulted in a marked decrease in bCSCs in the MMTV-neu mice tumors in vivo. Overexpression of full-length Ron as well as its truncated form (sfRon), but not urokinase-type plasminogen activator receptor, conferred near complete protection against BITC mediated inhibition of bCSCs in MCF-7 cells. The BITC treatment downregulated protein levels of Ron and sfRon in cultured breast cancer cells and in tumor xenografts. Ron overexpression resulted in upregulation of bCSC-associated genes Oct-4, SOX-2, and Nanog. In conclusion, the present study indicates that BITC treatment eliminates bCSCs in vitro and in vivo. PMID- 23661607 TI - Plk1-dependent microtubule dynamics promotes androgen receptor signaling in prostate cancer. AB - BACKGROUND: The androgen receptor (AR) signaling continues to be essential in castrate-resistant prostate cancer (CRPC). Taxel-based chemotherapy is the current standard treatment for CRPC patients. Unfortunately, almost all patients eventually develop resistance toward this chemotherapy. Significantly, it was recently found that the anti-tumor effect of paclitaxel in CRPC is due to its inhibition of AR activity via its inhibition of microtubule dynamics. Polo-like kinase 1 (Plk1), a critical regulator in many cell cycle events, is elevated in prostate cancer (PCa) and linked to tumor grades. Of note, we have previously shown that Plk1 phosphorylates CLIP-170 and p150(Glued) , two important regulators of microtubule dynamics. METHODS: We compared paclitaxel-mediated phenotypes (inhibition of the AR signaling, decrease of microtubule dynamics and cell death) of PCa cells expressing different forms of CLIP-170 and p150(Glued) with different Plk1 phosphorylation states. RESULTS: We show that Plk1 phosphorylation of CLIP-170 and p150(Glued) affects cellular responses to paclitaxel. Expression of Plk1-unphosphorylatable mutants of CLIP-170 and p150(Glued) results in increased paclitaxel-induced apoptosis, increased protein degradation of the AR, and decreased nuclear accumulation of the AR in response to androgen in prostate cancer cells. Finally, we show that cells expressing unphosphorylatable mutants of CLIP-170 have defective microtubule dynamics, thus providing a new mechanism to understand how Plk1-associated kinase activity promotes constitutive activation of AR signaling in CRPC. CONCLUSIONS: Our data suggest that a combination of inhibition of Plk1 and paclitaxel might be a novel avenue for treatment of CRPC. PMID- 23661609 TI - A novel function for CUGBP2 in controlling the pro-inflammatory stimulus in H9c2 cells: subcellular trafficking of messenger molecules. AB - Accumulating evidence demonstrates that chronic inflammation plays an important role in heart hypertrophy and cardiac diseases. However, the fine-tuning of cellular and molecular mechanisms that connect inflammatory process and cardiac diseases is still under investigation. Many reports have demonstrated that the overexpression of the cyclooxygenase-2 (COX-2), a key enzyme in the conversion of arachidonic acid to prostaglandins and other prostanoids, is correlated with inflammatory processes. Increased level of prostaglandin E2 was also found in animal model of left ventricle of hypertrophy. Based on previous observations that demonstrated a regulatory loop between COX-2 and the RNA-binding protein CUGBP2, we studied cellular and molecular mechanisms of a pro-inflammatory stimulus in a cardiac cell to verify if the above two molecules could be correlated with the inflammatory process in the heart. A cellular model of investigation was established and H9c2 was used. We also demonstrated a regulatory connection between COX-2 and CUGBP2 in the cardiac cells. Based on a set of different assays including gene silencing and fluorescence microscopy, we describe a novel function for the RNA-binding protein CUGBP2 in controlling the pro-inflammatory stimulus: subcellular trafficking of messenger molecules to specific cytoplasmic stress granules to maintain homeostasis. PMID- 23661608 TI - Synthesis of tetrodotoxin, a classic but still fascinating natural product. AB - Tetrodotoxin, a toxic principle of puffer fish intoxication, is one of the most famous marine natural products due to its densely functionalized structure and potent toxicity. Despite its small molecular size (MW 319 g mol-1), tetrodotoxin has long been well known as a formidable molecule in natural product synthesis. We have devoted more than twenty years to developing synthetic strategies for this molecule, resulting in the preparation of a variety of analogues of tetrodotoxin for biological experiments. This account describes a brief history of tetrodotoxin research and an overview of our synthetic efforts toward tetrodotoxin with the underlying logic and strategy. PMID- 23661610 TI - Cellular imaging and texture analysis distinguish differences in cellular dynamics in mouse brain tumors. AB - PURPOSE: The heterogeneous tumor cell population and dynamic microenvironment within a tumor lead to regional variations in cell proliferation, migration, and differentiation. In this work, MRI and optical projection tomography were used to examine and compare the redistribution of a cellular label in two mouse glioma models. METHODS: GL261 and 4C8 glioma cells labeled with iron oxide particles or with a fluorescent probe were injected into the brains of syngeneic mice and allowed to develop into ~10-mm(3) tumors. Texture analysis was used to quantitatively describe and compare the label distribution patterns in the two tumor types. RESULTS: The label was seen to remain predominantly in the tumor core in GL261 tumors, but become more randomly distributed throughout the tumor volume in 4C8 tumors. Histologically, GL261 tumors displayed a more invasive, aggressive phenotype, although the distribution of mitotic cells in the two tumors was similar. CONCLUSION: The redistribution of a cellular label during tumor growth is characteristic of a tumor model. The label distribution map reflects more than simple differences in cell proliferation and is likely influenced by differences in the tumor microenvironment. PMID- 23661611 TI - Maximal respiratory pressure reference values for Navajo children ages 6-14. AB - BACKGROUND: Since anthropometric variables are critical to the creation of pulmonary nomograms for FVC, FEV1, and other volumes and capacities, it is logical that anthropometric variables also influence the values of the maximal respiratory pressures (MRPs). Since nomograms are race-specific, it is important that tribe-specific tables of normal maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) be developed. To date normal tables for MRPs do not exist for Navajo children. OBJECTIVE: Therefore the purpose of this study was to derive MRP normative reference values for Navajo children in the age range of 6-14 years. METHODS-PARTICIPANTS AND MEASUREMENTS: A cross-sectional study was undertaken with a representative sample of 534 healthy children, ages 6-14 years, attending Navajo Nation elementary schools in Arizona. MIP and MEP were measured. RESULTS: Test results from 275 girls and 259 boys met American Thoracic Society quality control standards and showed that MRPs all increased with height. Mean MIP in cm H2 O was 77 for boys and 67 for girls with lower limits of 44 and 40, respectively. Mean MEP in cm H2 O was 75 for boys and 66 for girls with the lower limits of 42 and 38, respectively. CONCLUSION: Since the data were collected from the population of interest, the resulting MIP and MEP reference equations should be used when testing Navajo children ages 6-14 years. PMID- 23661612 TI - Photosensitizer-gold nanorod composite for targeted multimodal therapy. AB - In this work, a DNA inter-strand replacement strategy for therapeutic activity is successfully designed for multimodal therapy. In this multimodal therapy, chlorin e6 (Ce6) photosensitizer molecules are used for photodynamic therapy (PDT), while aptamer-AuNRs, are used for selective binding to target cancer cells and for photothermal therapy (PTT) with near infrared laser irradiation. Aptamer Sgc8, which specifically targets leukemia T cells, is conjugated to an AuNR by a thiol Au covalent bond and then hybridized with a Ce6-labeled photosensitizer/reporter to form a DNA double helix. When target cancer cells are absent, Ce6 is quenched and shows no PDT effect. However, when target cancer cells are present, the aptamer changes structure to release Ce6 to produce singlet oxygen for PDT upon light irradiation. Importantly, by combining photosensitizer and photothermal agents, PTT/PDT dual therapy supplies a more effective therapeutic outcome than either therapeutic modality alone. PMID- 23661613 TI - Immunohistochemical expression of ERG in the molecular epidemiology of fatal prostate cancer study. AB - BACKGROUND: Gene fusions between the ERG transcription factor and the androgen regulated gene TMPRSS2 occur in a subset of prostate cancers and contribute to transformation of prostatic epithelial cells. Prior reports have used fluorescence in situ hybridization (FISH) or quantitative PCR (QPCR) to determine the presence of TMPRSS2-ERG fusions or ERG expression, respectively. Recently, several groups have reported on immunohistochemistry (IHC) to measure ERG expression, which is much more readily performed in clinical practice. However, the prior studies examining ERG expression by IHC had small sample sizes or they failed to clarify the association of ERG protein expression with important clinico-pathological features or prostate cancer-specific mortality. METHODS: To address these deficits, we evaluated ERG expression by IHC in 208 radical prostatectomy samples from the Kaiser Permanente Molecular Epidemiology of Fatal Prostate Cancer (MEFPC) study, a case-control study of prostate cancer-specific mortality. RESULTS: Nuclear ERG expression was seen in neoplastic prostate epithelia in 49 of the samples (23.7%). ERG expression in tumor cells was associated with higher tumor stage (OR = 2.0, 95% confidence interval 1.0-4.0, P value = 0.04). ERG immunoreactivity was positively associated with prostate cancer-specific mortality, although the confidence interval was wide (OR = 1.9, 95% confidence interval 0.88-4.0, P value = 0.10). CONCLUSIONS: Our results demonstrate that ERG protein expression is readily quantifiable with an existing commercial antibody. Evaluating ERG protein expression may improve our ability to identify the subset of more aggressive, invasive prostate cancers. PMID- 23661614 TI - A multilevel analysis of the effect of Malawi's Social Cash Transfer Pilot Scheme on school-age children's health. AB - OBJECTIVE: The primary goal was to examine whether Malawi Social Cash Transfer Pilot Scheme, initially implemented in a rural district in central Malawi, improved health outcomes for children aged 6-17. Secondary goals were to examine the effects of individual child- (orphan status and gender) and household-level factors (number of working-age adults and sick adults) on health outcomes. Another secondary goal was to examine whether orphan status modified the cash transfer effect on health outcomes. METHODS: This multilevel study used panel data collected in 2007-08 from a randomized controlled evaluation study of phase one of the programme. The analyses included 1197 children aged 6-17 in 486 households. The four outcomes of interest were: illness in the past month, illness that stopped normal activities in the past month, missing school due to illness or injury in the past month and health care use for worst illness in the past year. FINDINGS: Approximately two-thirds of children in cash transfer eligible households were orphans. Compared with children in non-beneficiary households, those in beneficiary households had a 37% lower odds of child illness (P<0.05), 42% lower odds of illness that stopped normal activities (P<0.01) and substantially higher odds of utilizing health services for a serious illness (odds ratio=10.98; P<0.01). An increase in the household number of working-age adults was associated with 34% lower odds of child illness (P<0.01). An increase in the household number of sick adults increased the odds of child illness by 97% (P<0.01) and serious illness by 49% (P<0.01). No statistically significant differences were observed by orphan status and child's gender. Consistent differential programme effects by orphan status were not observed. CONCLUSION: Unconditional cash transfer programmes to poor households have the potential to improve health outcomes for all vulnerable children aged 6-17. PMID- 23661615 TI - Evaluation of the capacity of mosaic-like porous ceramics with designed pores to support osteoconduction. AB - Under osteoconductive conditions, porous calcium phosphate ceramics are known to induce new bone formation within their pores. A critical aspect of the design of porous ceramics is the geometrical features of their pores, with regard to promoting bone formation and mass transfer management in pore networks. However, the pore geometries of common porous ceramics lack clear details. Further, the connections between pores are hard to characterize and thus have not been thoroughly researched. To address these issues, we have developed an original method for fabricating porous ceramics, which we have termed "mosaic-like ceramics fabrication (MLCF)." Using MLCF, pore geometries can be designed and fabricated by each unit, and a network covering all the pores can be fabricated. Furthermore, MLCF can be used to build porous ceramics with custom-made shapes. In this study, we assessed the osteogenic influences of MLCF products (MLPC) composed of hydroxyapatite units on the differentiation of rat bone-marrow derived mesenchymal stem cells (MSCs) in vitro and in vivo. Two types of commercial porous artificial bone were used as positive controls. MLPC was superior in osteogenic potential, and proved to be a reliable scaffold for bone tissue engineering. Furthermore, this study succeeded in defining the important geometries for osteoconduction. PMID- 23661616 TI - Cost effectiveness of enhanced recovery after surgery programme for vaginal hysterectomy: a comparison of pre and post-implementation expenditures. AB - Enhanced Recovery After Surgery programmes were first conceived to optimise perioperative patient care and have been delivered by surgical specialities in the UK for over a decade. Although their safety and acceptability have been ratified in many surgical fields including gynaecology and colorectal surgery, the cost effectiveness of its implementation in benign vaginal surgery remains unclear. In this case-control study, the perioperative expenditure for 45 women undergoing vaginal hysterectomy at a North London teaching hospital after implementation of an enhanced recovery pathway was compared with 45 matched controls prior to implementation. Frequency of catheter use (84.4% vs. 95.6%) and median length of stay (23.5 vs. 42.9 h) were significantly lower following implementation of pathway (both p < 0.05). Although enhanced recovery patients were more likely to attend the accident and emergency department for minor symptoms following discharge (15.6% vs. 0%, p < 0.05), the inpatient readmission rate (6.7% vs. 0.0%, p > 0.05) was similar in both groups. Establishing the programme incurred additional expenditures including delivering a patient orientated gynaecology 'school' and employing a specialist enhanced recovery nurse, but despite these, we demonstrated a saving of 15.2% (or L164.86) per patient. The cost efficiency savings, coupled with increased satisfaction and no rise in morbidity, offers a very attractive means of managing women undergoing vaginal hysterectomy. We believe that our data can be reproduced in other centres and recommend that the pathway be used routinely in women undergoing these procedures. PMID- 23661618 TI - Hydrolytic cationic ester microparticles for highly efficient DNA vaccine delivery. AB - DNA vaccination holds great potential to be a safer and more efficient alternative to traditional vaccination strategies, but the current lack of nontoxic and effective delivery systems is the greatest impediment to its clinical implementation. In this work, a convenient one-step method is used to prepare a degradable "microgel" delivery platform, featuring hydrolytic esters. Prior to hydrolysis, these micrometer-sized gel particles can effectively condense DNA due to their positive surface charge. Upon entering antigen presenting cells (APCs), the microgels can be hydrolyzed to nontoxic zwitterionic polymers, consequently releasing the DNA and inducing phagosomal escape. Surface charge, DNA loading, cytotoxicity, and gene transfection efficiency of the hydrolysable microparticles with different tertiary to quaternary amine ratios are systematically studied. Nonhydrolysable counterparts and commercially developed PLGA-CTAB particles are used as the control. The passive targeting effect is further evaluated by blocking the phagocytosis pathway of the cells. The hydrolytic microgels prepared in this study possess great potential to become a platform for DNA vaccine delivery. PMID- 23661617 TI - Comparison of lung clearance index measured during helium washin and washout in children with cystic fibrosis. AB - AIM: Lung clearance index (LCI) is a sensitive marker of early lung disease in cystic fibrosis (CF). This preliminary study compares results obtained from the washin and the washout phase of the multiple breath washout in CF children and healthy controls using an early commercially available device. METHODS: LCI was measured using a device measuring flow and mainstream molar mass with helium as the inert gas. Sixty-five healthy controls and 65 CF children (age range 4.6-17.9 years) were included. RESULTS: LCI measured on the washout (LCIWO ) and on the washin (LCIWI ) were correlated in CF children (R = 0.440, P < 0.001, n = 185). LCIWO was higher than LCIWI with a mean difference of 1.08 (95% limits of agreement -2.11 to 4.27, n = 185) in CF children and 0.26 (95% LA -3.2 to 3.72, n = 185) in controls. Within-test repeatability criteria were met in 107/130 WO and 93/130 WI (P = 0.034), In 81 children, LCIWI and LCIWO were obtained. LCIWI was higher in CF patients than in controls (7.72 vs. 6.55, P < 0.001), as was LCIWO (8.49 vs. 7.13, P < 0.001). In 34 CF patients with normal FEV1 , LCIWI only was abnormal in five, LCIWO only in five and both were abnormal in three. One of seven CF patients with abnormal FEV1 had normal LCIWI and LCIWO . CONCLUSION: In CF patients, discordances between abnormal LCIWI and LCIWO were observed. LCIWI and LCIWO were only weakly correlated. This likely resulted from technical factors as the use of mainstream molar mass signal, a temperature model validated for infants only and absence of CO2 correction. PMID- 23661619 TI - Murine pulmonary acinar mechanics during quasi-static inflation using synchrotron refraction-enhanced computed tomography. AB - We visualized pulmonary acini in the core regions of the mouse lung in situ using synchrotron refraction-enhanced computed tomography (CT) and evaluated their kinematics during quasi-static inflation. This CT system (with a cube voxel of 2.8 MUm) allows excellent visualization of not just the conducting airways, but also the alveolar ducts and sacs, and tracking of the acinar shape and its deformation during inflation. The kinematics of individual alveoli and alveolar clusters with a group of terminal alveoli is influenced not only by the connecting alveolar duct and alveoli, but also by the neighboring structures. Acinar volume was not a linear function of lung volume. The alveolar duct diameter changed dramatically during inflation at low pressures and remained relatively constant above an airway pressure of ~8 cmH2O during inflation. The ratio of acinar surface area to acinar volume indicates that acinar distension during low-pressure inflation differed from that during inflation over a higher pressure range; in particular, acinar deformation was accordion-like during low pressure inflation. These results indicated that the alveoli and duct expand differently as total acinar volume increases and that the alveolar duct may expand predominantly during low-pressure inflation. Our findings suggest that acinar deformation in the core regions of the lung is complex and heterogeneous. PMID- 23661620 TI - Contribution of central vs. peripheral factors to the force loss induced by passive stretch of the human plantar flexors. AB - The purpose of the present research was to identify the contribution of central vs. peripheral factors to the force loss after passive muscle stretching. Thirteen men randomly performed both a 5-min constant-torque stretch of the plantar flexors on an isokinetic dynamometer and a resting condition on 2 separate days. The triceps surae electromyogram (EMG) was recorded simultaneously with plantar flexor isometric torque. Measures of central drive, including the EMG amplitude normalized to the muscle compound action potential amplitude (EMG/M), percent voluntary activation and first volitional wave amplitude, and measures of peripheral function, including the twitch peak torque, 20-to-80-Hz tetanic torque ratio and torque during 20-Hz stimulation preceded by a doublet, were taken before and immediately and 15 min after each condition. Peak torque ( 15.7%), EMG/M (-8.2%), and both twitch (-9.4%) and 20-Hz peak torques (-11.5%) were reduced immediately after stretch but recovered by 15 min. There were strong correlations between the torque loss and the reductions in central drive parameters (r = 0.65-0.93). Torque recovery was also strongly correlated with the recovery in EMG/M and percent voluntary activation (r = 0.77-0.81). The moderate decreases in measures of peripheral function were not related to the torque loss or recovery. These results suggest that 1) central factors were strongly related to the torque reduction immediately after stretch and during torque recovery; and 2) the muscle's contractile capacity was moderately reduced, although these changes were not associated with the torque reduction, and changes in excitation contraction coupling efficiency were not observed. PMID- 23661622 TI - Arm movements can increase leg muscle activity during submaximal recumbent stepping in neurologically intact individuals. AB - Facilitation of leg muscle activity by active arm movements during locomotor tasks could be beneficial during gait rehabilitation after spinal cord injury. The present study explored the effects of arm movements on leg muscle activity during submaximal recumbent stepping. Healthy subjects exercised on a recumbent stepping machine both with and without arm movements. Activity of five leg muscles was recorded and compared for stepping with and without arm movements. To determine which arm movements are optimal for leg muscle facilitation, subjects were instructed to step with 1) mechanically coupled vs. decoupled arm and leg movements, 2) synchronous vs. asynchronous arm movements, and 3) at 50 vs. 70 RPM. Leg muscle activity was increased by active arm movements in all muscles, except the vastus lateralis muscle. Activity of other extensors (soleus, medial gastrocnemius, and biceps femoris) was primarily increased during the extension phase, whereas activity of flexors (tibialis anterior) was also increased during the flexion phase. Facilitation was more or less consistent for both frequencies and for synchronous and asynchronous movements. For coupled arm movements, facilitation tended to be diminished or absent. The observed facilitation in the present study is probably of neuromuscular rather than biomechanical origin, since the arms are probably hardly involved in postural control or weight-bearing during recumbent stepping. Further studies in patients should explore the possibility to integrate neuromuscular facilitation in rehabilitation programs. PMID- 23661621 TI - Acute right ventricular pressure overload compromises left ventricular function by altering septal strain and rotation. AB - While right ventricular (RV) dysfunction has long been known to affect the performance of left ventricle (LV), the mechanisms remain poorly defined. Recently, speckle-tracking echocardiography has demonstrated that preservation of strain and rotational dynamics is crucial to both LV systolic and diastolic function. We hypothesized that alteration in septal strain and rotational dynamics of the LV occurs during acute RV pressure overload (RVPO) and leads to decreased cardiac performance. Seven anesthetized pigs underwent median sternotomy and placement of intraventricular pressure-volume conductance catheters. Two-dimensional echocardiographic images and LV pressure-volume loops were acquired for offline analysis at baseline and after banding of the pulmonary artery to achieve RVPO (>50 mmHg) induced RV dysfunction. RVPO resulted in a significant decrease (P < 0.05) in LV end-systolic elastance (50%), systolic change in pressure over change in time (19%), end-diastolic volume (22%), and cardiac output (37%) that correlated with decrease in LV global circumferential strain (58%), LV apical rotation (28%), peak untwisting (reverse rotation) rate (27%), and prolonged time to peak rotation (17%), while basal rotation was not significantly altered. RVPO reduced septal radial and circumferential strain, while no other segment of the LV midpapillary wall was affected. RVPO decreased septal radial strain on LV side by 27% and induced a negative radial strain from 28 +/- 5 to -16 +/- 2% on the RV side of the septum. The septal circumferential strain on both LV and RV side decreased by 46 and 50%, respectively, following RVPO (P < 0.05). Our results suggest that acute RVPO impairs LV performance by primarily altering septal strain and apical rotation. PMID- 23661623 TI - Design and development of reactive injectable and settable polymeric biomaterials. AB - Injectable and settable biomaterials are a growing class of therapeutic technologies within the field of regenerative medicine. These materials offer advantages compared to prefabricated implants because of their ability to be utilized as part of noninvasive surgical procedures, fill complex defect shapes, cure in situ, and incorporate cells and other active biologics. However, there are significant technical barriers to clinical translation of injectable and settable biomaterials, such as achieving clinically relevant handling properties and benign reaction conditions. This review focuses on the engineering challenges associated with the design and development of injectable and chemically settable polymeric biomaterials. Additionally, specific examples of the diverse chemistries utilized to overcome these challenges are covered. The future translation of injectable and settable biomaterials is anticipated to improve patient outcomes for a number of clinical conditions. PMID- 23661624 TI - An ecological public health approach to understanding the relationships between sustainable urban environments, public health and social equity. AB - The environmental determinants of public health and social equity present many challenges to a sustainable urbanism-climate change, water shortages and oil dependency to name a few. There are many pathways from urban environments to human health. Numerous links have been described but some underlying mechanisms behind these relationships are less understood. Combining theory and methods is a way of understanding and explaining how the underlying structures of urban environments relate to public health and social equity. This paper proposes a model for an ecological public health, which can be used to explore these relationships. Four principles of an ecological public health-conviviality, equity, sustainability and global responsibility-are used to derive theoretical concepts that can inform ecological public health thinking, which, among other things, provides a way of exploring the underlying mechanisms that link urban environments to public health and social equity. Theories of more-than-human agency inform ways of living together (conviviality) in urban areas. Political ecology links the equity concerns about environmental and social justice. Resilience thinking offers a better way of coming to grips with sustainability. Integrating ecological ethics into public health considers the global consequences of local urban living and thus attends to global responsibility. This way of looking at the relationships between urban environments, public health and social equity answers the call to craft an ecological public health for the twenty-first century by re-imagining public health in a way that acknowledges humans as part of the ecosystem, not separate from it, though not central to it. PMID- 23661625 TI - The use of doripenem in pediatric cystic fibrosis patients in case of meropenem shortages. AB - Ceftazidime is the only anti-pseudomonal beta-lactam that has been reported to be administered by extended infusion in pediatric cystic fibrosis (CF) patients. A small pediatric pharmacokinetic/pharmacodynamic study has been published regarding the use of intermittent extended infusion doripenem in the treatment of an acute pulmonary exacerbation (APE) in pediatric CF patients; however, clinical use of intermittent extended infusion doripenem in pediatric CF patients has not been previously reported. We present three cases administering intermittent extended infusion doripenem in pediatric CF patients for the treatment of an APE in the case of replacing meropenem due to shortage. The delivery of beta-lactam antibiotics via intermittent extended infusion should be considered in order to optimize the pharmacodynamics of beta-lactams in the treatment of an APE. PMID- 23661626 TI - An E3-14.7K peptide that promotes microtubules-mediated transport of plasmid DNA increases polyplexes transfection efficiency. AB - Chemical vectors as cationic polymers and cationic lipids are promising alternatives to viral vectors for gene therapy. Beside endosome escape and nuclear import, plasmid DNA (pDNA) migration in the cytosol toward the nuclear envelope is also regarded as a limiting step for efficient DNA transfection with non-viral vectors. Here, the interaction between E3-14.7K and FIP-1 to favor migration of pDNA along microtubules is exploited. E3-14.7K is an early protein of human adenoviruses that interacts via FIP-1 (Fourteen.7K Interacting Protein 1) protein with the light-chain components of the human microtubule motor protein dynein (TCTEL1). This peptide is conjugated with pDNA and mediates interaction of pDNA in vitro with isolated microtubules as well as with microtubules in cellulo. Videomicroscopy and tracking treatment of images clearly demonstrate that P79 98/pDNA conjugate exhibits a linear transport with large amplitude along microtubules upon 2 h transfection with polyplexes whereas control pDNA conjugate exhibits small non-directional movements in the cytoplasm. Remarkably, P79 98/peGFP polyplexes enhance by a factor 2.5 (up to 76%) the number of transfected cells. The results demonstrate, for the first time, that the transfection efficiency of polyplexes can be drastically increased when the microtubules migration of pDNA is facilitated by a peptide allowing pDNA docking to TCTEL1. This is a real breakthrough in the non viral gene delivery field that opens hope to build artificial viruses. PMID- 23661627 TI - Improved hMSC functions on titanium coatings by type I collagen immobilization. AB - In this study, type I collagen was fixed onto plasma-sprayed porous titanium coatings by either adsorptive immobilization or covalent immobilization. Surface characterization by scanning electron microscopy (SEM), diffuse reflectance Fourier transform infrared spectroscopy (DR-FTIR) and X-ray photoelectron spectroscopy (XPS) confirmed the biochemical modification of the titanium coatings. The immobilizing effects of type I collagen, including variations in the amount and stability of collagen, were investigated using Sirius red staining. A greater amount of collagen was found on the covalently immobilized titanium coating, and higher stability was achieved relative to the absorptive immobilization surface. Human mesenchymal stem cells (hMSCs) were used to evaluate the cytocompatibility of the modified titanium coatings. Type I collagen immobilized on titanium coating led to enhance cell-material interactions and improved hMSC functions, such as attachment, proliferation, and differentiation. Interestingly, covalently immobilized collagen on titanium coating showed a greater capability to regulate the osteogenic activity of hMSCs than did absorbed collagen, which was explained in terms of the increased amount and higher stability of the covalently linked collagen. The type I collagen covalently immobilized titanium coatings with improved biological function may exhibit better osteointegration in clinical application. PMID- 23661628 TI - Metabolic regulation of osteoclast differentiation and function. AB - The osteoclast is a giant cell that resorbs calcified matrix by secreting acids and collagenolytic enzymes. The molecular mechanisms underlying metabolic adaptation to the increased biomass and energetic demands of osteoclastic bone resorption remain elusive. Here we show that during osteoclastogenesis the expression of both glucose transporter 1 (Glut1) and glycolytic genes is increased, whereas the knockdown of hypoxia-inducible factor 1-alpha (Hif1alpha), as well as glucose deprivation, inhibits the bone-resorbing function of osteoclasts, along with a suppression of Glut1 and glycolytic gene expression. Furthermore, the expression of the glutamine transporter solute carrier family 1 (neutral amino acid transporter), member 5 (Slc1a5) and glutaminase 1 was increased early in differentiation, and a depletion of L-glutamine or pharmacological inhibition of the Slc1a5 transporter suppressed osteoclast differentiation and function. Inhibition of c-Myc function abrogated osteoclast differentiation and function, along with a suppression of Slc1a5 and glutaminase 1 gene expression. Genetic and pharmacological inhibition of mammalian target of rapamycin (mTOR), as well as the activation of adenosine monophosphate (AMP) activated protein kinase (AMPK), inhibited osteoclastogenesis. Thus, the uptake of glucose and glutamine and utilization of the carbon sources derived from them, coordinated by HIF1alpha and c-Myc, are essential for osteoclast development and bone-resorbing activity through a balanced regulation of the nutrient and energy sensors, mTOR and AMPK. PMID- 23661631 TI - Prevalence, determinants, and inappropriateness of calcium supplementation among men and women in a Spanish Mediterranean area: cross-sectional data from the ESOSVAL cohort. AB - Recently, safety concerns about calcium supplementation have arisen. In this situation, ensuring appropriateness of use is highly important. We aimed to describe the use of calcium and vitamin D supplements, the factors related to it, and to assess the appropriateness of calcium prescription among men and women aged 50 years or older. We performed a cross-sectional study in 2009-2010 including 11,035 adults who belong to the ESOSVAL cohort and attend 272 primary healthcare centers in the Valencia region of Spain. Criteria for the inappropriateness of calcium prescription, based on guidelines and recent evidence, were: excessive or insufficient daily total intake (diet plus supplements), excessive single doses of supplements, excessive or insufficient association with vitamin D, and overall inappropriateness. Calcium and/or vitamin D were prescribed to about 17% of the population. Older age, antiosteoporotic treatment, use of glucocorticoids, and a diagnosis of osteoporosis were related to prescription. The presence of other secondary causes of osteoporosis determined supplementation only in men. Calcium dietary intake was not related to the prescription of supplements. Among calcium users, 85.8% met at least one criterion of inappropriate prescription; 29% had an inappropriate daily total intake mainly resulting from excessive consumption (>2000 mg/day); 53.8% of patients were given calcium supplements in quantities higher than 500 mg per dose; and 38.9% of individuals receiving calcium supplements had inappropriate (absent or below 800 UI/day) vitamin D supplementation (all of them at high risk). In conclusion, we found high inappropriateness of calcium supplementation, mainly because of calcium overdosing, and also to undertreatment and underdosing of vitamin D in high-risk patients. Physicians should be encouraged to assess calcium dietary intakes before supplementation, recommending intake from food whenever possible, and to prescribe low calcium doses and high vitamin D doses when given in fixed-dose combinations, or vitamin D alone when calcium is not necessary. PMID- 23661632 TI - Association between symptom dimensions and categorical diagnoses of psychosis: a cross-sectional and longitudinal investigation. AB - CONTEXT: Cross-sectional studies of the signs and symptoms of psychosis yield dimensional phenotypes. However, the validity and clinical utility of such dimensions remain debated. This study investigated the structure of psychotic symptomatology, the stability of the structure over time, and the concordance between symptom dimensions and categorical diagnoses. METHODS: Sample consisted of 500 first-episode psychotic patients. A cross-sectional study (N = 500) investigated the organizational structure of symptom dimensions at the onset of psychosis and its concordance with categorical diagnoses; next, a nested longitudinal study (N = 100) examined the stability of the symptom dimensions structure after 5-10 years of follow-up. RESULTS: Factor analyses identified 6 first-order factors (mania, negative, disorganization, depression, hallucinations, and delusions) and 2 high-order factors (affective and nonaffective psychoses). Cumulative variance accounted for by the first and high order factors was 63%: 31% by the first-order factors and 32% by the high-order factors. The factorial structure of psychotic symptoms during first episode remained stable after 5-10 years of follow-up. The overall concordance between 4 categorical diagnostic groups (schizophrenia, mania with psychosis, psychotic depression and schizoaffective disorder) and dimensional symptom ranged from 62.2% to 73.1% (when the schizoaffective group was excluded). CONCLUSIONS: Symptoms of psychosis assume a multidimensional hierarchical structure. This hierarchical model was stable over time and showed good concordance with categorical diagnoses. The combined use of dimensional and categorical approach to psychotic disorders would be of clinical and research utility. PMID- 23661633 TI - Associations of white matter integrity and cortical thickness in patients with schizophrenia and healthy controls. AB - Typical brain development includes coordinated changes in both white matter (WM) integrity and cortical thickness (CT). These processes have been shown to be disrupted in schizophrenia, which is characterized by abnormalities in WM microstructure and by reduced CT. The aim of this study was to identify patterns of association between WM markers and cortex-wide CT in healthy controls (HCs) and patients with schizophrenia (SCZ). Using diffusion tensor imaging and structural magnetic resonance imaging data of the Mind Clinical Imaging Consortium study (130 HC and 111 SCZ), we tested for associations between (a) fractional anisotropy in selected manually labeled WM pathways (corpus callosum, anterior thalamic radiation, and superior longitudinal fasciculus) and CT, and (b) the number of lesion-like WM regions ("potholes") and CT. In HC, but not SCZ, we found highly significant negative associations between WM integrity and CT in several pathways, including frontal, temporal, and occipital brain regions. Conversely, in SCZ the number of WM potholes correlated with reduced CT in the left lateral temporal gyrus, left fusiform, and left lateral occipital brain area. Taken together, we found differential patterns of association between WM integrity and CT in HC and SCZ. Although the pattern in HC can be explained from a developmental perspective, the reduced gray matter CT in SCZ patients might be the result of focal but spatially heterogeneous disruptions of WM integrity. PMID- 23661635 TI - SGEF enhances EGFR stability through delayed EGFR trafficking from early to late endosomes. AB - Previously, we demonstrated an elevated SH3-containing guanine nucleotide exchange factor (SGEF) expression in clinical specimens with prostate cancer and implicated the role of SGEF in prostate tumorigenesis. However, the molecular mechanism behind the SGEF regulation of prostate cancer development is not known. In this study, we show that SGEF expression delays epidermal growth factor receptor (EGFR) degradation in prostate cancer cells and is independent from its guanine nucleotide exchange factor (GEF) function. We further show that the delayed degradation is due to a delay in EGFR trafficking from early to late endosomes and not to a decrease in EGFR ubiquitination. Finally, we show that depletion of SGEF significantly inhibits epidermal growth factor-induced EGFR signaling cascade and cell migration in the prostate cancer cells. We report for the first time an SGEF function for RhoG that excludes GEF and the ability of SGEF to enhance EGFR stability and signaling by delaying its lysosomal sorting and degradation. This could be one mechanism by which SGEF contributes to prostate cancer progression. PMID- 23661634 TI - Dopaminergic modulation of probabilistic reasoning and overconfidence in errors: a double-blind study. AB - INTRODUCTION: Reasoning biases such as jumping to conclusions (JTC) and overconfidence in errors have been well replicated in patients with delusions. However, their relation to dopaminergic activity, central to pathophysiologic models of psychosis, has not yet been investigated. This study aimed to examine the effects of a dopaminergic agonist (L-dopa) and a dopaminergic antagonist (haloperidol) on the JTC bias and overconfidence in errors after single-dose administration in healthy individuals. METHODS: The study used a randomized, double-blind, placebo-controlled, 3-way crossover design. Participants were 36 healthy individuals aged 18-36 years. The variables of interest were draws to decision and probability threshold to decision on a computerized variant of the beads task and the number of high-confident incorrect responses on a visual memory task. RESULTS: There were no significant effects of substance on draws to decision and probability threshold to decision. A significant effect emerged for high-confident incorrect responses in the memory task; pairwise comparisons indicated a significant reduction of the number of high-confident incorrect responses after administration of haloperidol vs l-dopa and placebo. CONCLUSIONS: This is the first study to investigate the direct effects of dopaminergic drugs on reasoning biases. The JTC bias and overconfidence in errors showed a differential pattern of dopaminergic modulation, suggesting that they represent different facets of reasoning abnormalities that interact with each other to produce delusions in susceptible individuals. PMID- 23661636 TI - Left ventricular twist dynamics: principles and applications. PMID- 23661637 TI - Impaired endothelial function in persons with obstructive sleep apnoea: impact of obesity-the response. PMID- 23661638 TI - Pure arterial CABG using bilateral internal mammary artery. PMID- 23661639 TI - Polyarteritis nodosa presenting as acute myocardial infarction in a young man: importance of invasive angiography. PMID- 23661640 TI - The authors' reply. PMID- 23661641 TI - Hydrogen isotopes in lunar volcanic glasses and melt inclusions reveal a carbonaceous chondrite heritage. AB - Water is perhaps the most important molecule in the solar system, and determining its origin and distribution in planetary interiors has important implications for understanding the evolution of planetary bodies. Here we report in situ measurements of the isotopic composition of hydrogen dissolved in primitive volcanic glass and olivine-hosted melt inclusions recovered from the Moon by the Apollo 15 and 17 missions. After consideration of cosmic-ray spallation and degassing processes, our results demonstrate that lunar magmatic water has an isotopic composition that is indistinguishable from that of the bulk water in carbonaceous chondrites and similar to that of terrestrial water, implying a common origin for the water contained in the interiors of Earth and the Moon. PMID- 23661642 TI - Structure of parkin reveals mechanisms for ubiquitin ligase activation. AB - Mutations in the PARK2 (parkin) gene are responsible for an autosomal recessive form of Parkinson's disease. The parkin protein is a RING-in-between-RING E3 ubiquitin ligase that exhibits low basal activity. We describe the crystal structure of full-length rat parkin. The structure shows parkin in an autoinhibited state and provides insight into how it is activated. RING0 occludes the ubiquitin acceptor site Cys(431) in RING2, whereas a repressor element of parkin binds RING1 and blocks its E2-binding site. Mutations that disrupted these inhibitory interactions activated parkin both in vitro and in cells. Parkin is neuroprotective, and these findings may provide a structural and mechanistic framework for enhancing parkin activity. PMID- 23661643 TI - Pliocene warmth, polar amplification, and stepped Pleistocene cooling recorded in NE Arctic Russia. AB - Understanding the evolution of Arctic polar climate from the protracted warmth of the middle Pliocene into the earliest glacial cycles in the Northern Hemisphere has been hindered by the lack of continuous, highly resolved Arctic time series. Evidence from Lake El'gygytgyn, in northeast (NE) Arctic Russia, shows that 3.6 to 3.4 million years ago, summer temperatures were ~8 degrees C warmer than today, when the partial pressure of CO2 was ~400 parts per million. Multiproxy evidence suggests extreme warmth and polar amplification during the middle Pliocene, sudden stepped cooling events during the Pliocene-Pleistocene transition, and warmer than present Arctic summers until ~2.2 million years ago, after the onset of Northern Hemispheric glaciation. Our data are consistent with sea-level records and other proxies indicating that Arctic cooling was insufficient to support large-scale ice sheets until the early Pleistocene. PMID- 23661645 TI - Clarifying the dominant sources and mechanisms of cirrus cloud formation. AB - Formation of cirrus clouds depends on the availability of ice nuclei to begin condensation of atmospheric water vapor. Although it is known that only a small fraction of atmospheric aerosols are efficient ice nuclei, the critical ingredients that make those aerosols so effective have not been established. We have determined in situ the composition of the residual particles within cirrus crystals after the ice was sublimated. Our results demonstrate that mineral dust and metallic particles are the dominant source of residual particles, whereas sulfate and organic particles are underrepresented, and elemental carbon and biological materials are essentially absent. Further, composition analysis combined with relative humidity measurements suggests that heterogeneous freezing was the dominant formation mechanism of these clouds. PMID- 23661644 TI - GPR15-mediated homing controls immune homeostasis in the large intestine mucosa. AB - Lymphocyte homing, which contributes to inflammation, has been studied extensively in the small intestine, but there is little known about homing to the large intestine, the site most commonly affected in inflammatory bowel disease. GPR15, an orphan heterotrimeric guanine nucleotide-binding protein (G protein) coupled receptor, controlled the specific homing of T cells, particularly FOXP3(+) regulatory T cells (Tregs), to the large intestine lamina propria (LILP). GPR15 expression was modulated by gut microbiota and transforming growth factor-beta1, but not by retinoic acid. GPR15-deficient mice were prone to develop more severe large intestine inflammation, which was rescued by the transfer of GPR15-sufficient Tregs. Our findings thus describe a T cell-homing receptor for LILP and indicate that GPR15 plays a role in mucosal immune tolerance largely by regulating the influx of Tregs. PMID- 23661646 TI - The human malaria parasite Pfs47 gene mediates evasion of the mosquito immune system. AB - Plasmodium falciparum transmission by Anopheles gambiae mosquitoes is remarkably efficient, resulting in a very high prevalence of human malaria infection in sub Saharan Africa. A combination of genetic mapping, linkage group selection, and functional genomics was used to identify Pfs47 as a P. falciparum gene that allows the parasite to infect A. gambiae without activating the mosquito immune system. Disruption of Pfs47 greatly reduced parasite survival in the mosquito, and this phenotype could be reverted by genetic complementation of the parasite or by disruption of the mosquito complement-like system. Pfs47 suppresses midgut nitration responses that are critical to activate the complement-like system. We provide direct experimental evidence that immune evasion mediated by Pfs47 is critical for efficient human malaria transmission by A. gambiae. PMID- 23661649 TI - Nocardia cyriacigeorgica intracavitary lung colonization: first report of an actinomycetic rather than fungal ball in bronchiectasis. AB - We report the first case of an isolated endobronchial mass caused by Nocardia cyriacigeorgica in an immunocompetent patient with a history of lung surgery; this is a rare presentation of an emerging opportunistic pathogen. The infection was successfully eradicated by surgery. Microbiologists and clinicians should pay more attention to this group of filamentous bacteria, which in the past have often been neglected by medical personnel. PMID- 23661650 TI - Unusual solid mass in the popliteal fossa. AB - We present a clinical case image of a 20-year-old man with a lump behind his knee. A radiograph taken in the emergency department demonstrated the classical appearance of an osteochondroma. Osteochondroma is the commonest skeletal neoplasm. Surgical excision results in symptom resolution in over 90% of patients. PMID- 23661648 TI - Histone deacetylase inhibitors interact with melanoma differentiation associated 7/interleukin-24 to kill primary human glioblastoma cells. AB - We presently demonstrate that histone deacetylase inhibitors (HDACIs) enhance toxicity of melanoma differentiation-associated gene-7/interleukin 24 (mda-7/IL 24) in invasive primary human glioblastoma multiforme (GBM) cells. Additionally, a method is described to augment the efficacy of adenoviral delivery of mda-7/IL 24 in these cells. HDACIs synergized with melanoma differentiation-associated (MDA)-7/IL-24 killing GBM cells. Enhanced lethality correlated with increased autophagy that was dependent on the expression of ceramide synthase 6. HDACIs interacted with MDA-7/IL-24 prolonging generation of reactive oxygen species and Ca(2+). Quenching of reactive oxygen species and Ca(2+) blocked HDACI and MDA 7/IL-24 killing. In vivo MDA-7/IL-24 prolonged the survival of animals carrying orthotopic tumors, and HDACIs enhanced survival further. A serotype 5/3 adenovirus more effectively delivers mda-7/IL-24 to GBM tumors than a serotype 5 virus. Hence, we constructed a serotype 5/3 adenovirus that conditionally replicates in tumor cells expressing MDA-7/IL-24, in which the adenoviral early region 1A (E1A) gene was driven by the cancer-specific promoter progression elevated gene-3 [Ad.5/3 (INGN 241)-PEG-E1A-mda-7; also called Ad.5/3-CTV (cancer terminator virus)]. Ad.5/3-CTV increased the survival of mice carrying GBM tumors to a significantly greater extent than did a nonreplicative virus Ad.5/3-mda-7. Ad.5/3-CTV exhibited no toxicity in the brains of Syrian hamsters. Collectively our data demonstrate that HDACIs enhance MDA-7/IL-24 lethality, and adenoviral delivery of mda-7/IL-24 combined with tumor-specific viral replication is an effective preclinical GBM therapeutic. PMID- 23661651 TI - Symptomatic lobar intracerebral haemorrhage preceded by transient focal neurological episodes. AB - We report the case of a symptomatic intracerebral haemorrhage (ICH) in an elderly woman, secondary to cerebral amyloid angiopathy (CAA), and present the relevant imaging. A few months before, our patient experienced multiple, stereotyped, brief episodes of spreading paraesthesias, which were considered to be transient ischaemic attacks (TIAs) and treated with antithrombotic agents. In this case report, we explore CAA, a highly prevalent but under-recognised form of small vessel cerebrovascular disease and common cause of ICH. We then briefly discuss the clinical significance of transient focal neurological episodes in the context of CAA, as potential warning signs of future ICH. An important clinical message is that misdiagnosis of CAA-related focal neurological symptoms as TIAs (and prescribing antithrombotic drugs) could lead to potentially avoidable ICH. We also provide the current evidence base for the acute and secondary prevention treatment of patients with lobar ICH attributed to CAA, and discuss the prognosis. PMID- 23661652 TI - Malignant neuroendocrine tumour of the gallbladder with elevated carcinoembryonic antigen: case report and literature review. AB - A 58-year-old woman presented to a tertiary care centre with signs and symptoms of acute cholecystitis, cholelithiasis and diagnoses of a high-grade neuroendocrine tumour of the gallbladder primarily with peritoneal and liver metastases. She had a liver abscess secondary to Salmonella and Enterococcus fecalis that was drained and treated with appropriate antibiotics. Interestingly, the serum chromogranin A levels were within normal limits, but carcinoembryonic antigen was elevated, which helped evaluate responses and pick progression. She was treated with 10 cycles of palliative chemotherapy when malignancy associated complications started to recur, that is, cholangitis, worsening pain, cachexia, intestinal obstruction, etc leading to chemotherapy delays. Her disease progressed during these times with rapid deterioration of performance status. She died of septic complications postlaparotomy for intestinal obstruction. Her progression-free survival remained for 8 months with subjective and objective improvements, and her overall survival remained at 13 months. We describe the course of her illness and give a brief review of the literature. PMID- 23661653 TI - Giant aneurysm in a left coronary artery fistula: diagnostic cardiovascular imaging and treatment considerations. AB - Congenital coronary artery fistula complicated with giant coronary artery aneurysm is a very rare condition. In this case report, we present a 65-year-old woman, referred to us with a continuous heart murmur, occasional atypical chest pain and few episodes of fainting. A giant aneurysm and a coronary-pulmonary fistula were diagnosed using multiple cardiovascular imaging modalities to provide a sufficient anatomical picture. The patient was considered at high risk of sudden death from aneurysm rupture and received surgical treatment. Subsequent histopathological examination revealed a true aneurysm with severe wall calcifications, ulcerations and large areas with marked thinning of the wall. The postoperative course was uneventful. PMID- 23661654 TI - Nitrofurantoin: cause of DRESS syndrome. AB - Urinary tract infections (UTIs) are a common pathological entity among elderly patients. The widespread use of antibiotics for uncomplicated UTIs has gained many opponents mainly due to the increasing drug resistance observed. Nitrofurantoin is a commonly used antibacterial drug because it has low side effects and a good antiurinary bacterial profile. However, in this paper, we present a case of a nitrofurantoin-induced DRESS (drug reaction/rash with eosinophilia and systemic symptoms) syndrome in a 77-year-old woman. During UTI treatment, the patient developed an acute skin rash which spread all over the body and a considerable decrease in urine volume. At the emergency department, we found her developing eosinophilic pneumonia, anaemia and renal impairment that we relate to nitrofurantoin administration. To our knowledge, this is the second published case report which evokes nitrofurantoin as a possible cause of DRESS syndrome. PMID- 23661655 TI - Acute and chronic spectral domain optical coherence tomography features of branch retinal artery occlusion. AB - Branch retinal artery occlusion (BRAO) is a common vascular occlusive disorder. BRAO involving the posterior pole is usually symptomatic, but occasionally has very limited clinical features. We describe 2 cases where the underlying pathology was initially unclear and the diagnosis therefore not reached at presentation. Use of the latest retinal imaging, spectral domain optical coherence tomography (SD-OCT) enabled correct diagnosis of BRAO. The images demonstrate and contrast the fine changes that can be seen in the acute and chronic phases of this condition and illustrate how the pathogenesis of BRAO is confined to the outer retinal layers. We believe the subtle presentations of this common condition that we discuss highlight how diagnosis of BRAO can often be challenging, but may be facilitated by the use of SD-OCT retinal imaging. PMID- 23661656 TI - Nodular secondary syphilis in a woman. AB - We report the case of a 21-year-old woman with symmetrically distributed, ulcerated nodules and plaques on the face, neck and arms. Initial differential diagnoses included pyoderma or sarcoidosis based on the clinical presentation and histopathology with non-caseating granulomas. After inefficient treatment with topical and systemic fusidic acid and steroids, we diagnosed nodular secondary syphilis owing to positive serology and immunohistochemical staining of Treponema pallidum in lesional skin. After treatment with benzathine penicillin, skin lesions improved and antibody titres declined significantly within 3 months. Nodular skin lesions in secondary syphilis are rare with 15 reported cases within the last 20 years. Furthermore, the granulomatous histology is often misleading. Our patient's case suggests that the physicians should be aware of syphilis as a possible differential diagnosis also in patients outside a high-risk population for sexually transmitted diseases and with an unusual clinical presentation. PMID- 23661657 TI - Unwanted baggage. AB - An elderly woman with a rapidly progressing lower leg ulcer presented with features of systemic inflammatory response syndrome (SIRS). The ulcer had occurred after hitting her leg against a piece of luggage. The causative pathogen in our case was by Corynebacterium ulcerans, demonstrated in bacterial cultures and by PCR. Disease progression was stopped only by Linezolid intravenous. after several other antibiotics failed to help. Diphtheria is known to most physicians as a respiratory disease caused by Corynebacterium diphtheria which is occurring in the developed world infrequently because of widespread use of immunisation programmes. However, cutaneous infection with diphtheria is increasingly being diagnosed. PMID- 23661658 TI - Concurrent caecal and transverse colonic tuberculosis masquerating synchronous colonic carcinoma. AB - We present a 46-year-old Somalian woman, who attended our hospital, with 1 week history of worsening epigastric pain and vomiting, worse after eating on a background of 3 months history of four stones loss of weight, malaise and decreased appetite. CT scan of the abdomen revealed an annular 10 cm long mass of the right transverse colon with a second mass of the caecum raising concerns of a synchronous colonic cancer. She underwent an extended right hemi-colectomy due to the development of obstruction from the transverse colon lesion. The histology revealed caseating, transmural granulomatous inflammation consistent with tuberculosis. She had an uneventful recovery and was discharged on the tenth postoperative day on antituberculosis (anti-TB) medications. She reports complete resolution of her symptoms 4 months after discharge. PMID- 23661659 TI - Large spontaneous pneumothorax with relatively minor symptoms. PMID- 23661660 TI - Mucopolysaccharidosis type IIIB (MPS IIIB) masquerading as a behavioural disorder. AB - Inborn errors of metabolism (IEMs) that manifest primarily as psychiatric and behavioural symptoms in childhood are often mistaken for idiopathic primary psychiatric disorders. The pathophysiological basis of these symptoms may be overlooked until later in the disease course when neurological deficits become dominant; this results in a significant delay in establishing a proper diagnosis. To illustrate this, we describe two siblings who presented with behavioural issues and mild learning disabilities in childhood, and were consequently given multiple psychiatric diagnoses. In early adulthood, however, they manifested a rapid cognitive decline. Subsequent cranial MRI imaging revealed progressive brain iron accumulation in deep brain nuclei. Whole exome sequencing and biochemical investigation confirmed the diagnosis of mucopolysaccharidosis type IIIB. Their long diagnostic odyssey illustrates the importance of considering IEMs when assessing individuals with behavioural abnormalities and cognitive impairment. PMID- 23661661 TI - Critical upper airway obstruction in sporadic angioedema responding to C1 esterase inhibitor. AB - We describe a case of recurrent oropharyngeal angioedema in a 16-year-old boy with a history of sickle cell disease and thrombocytopenia and with no family history of angioedema. Emergency treatment of angioedema with C1-esterase inhibitor (C1-INH) provided immediate relief, avoiding the placement of a surgical airway. Further evaluation has shown C1-INH to be normal in quantity and function, with normal complement studies during acute attacks. Genetic testing revealed no abnormality in the factor XII gene. Our case exemplifies that even in cases of sporadic angioedema, treatment with C1-INH may be an effective and life saving management strategy. PMID- 23661662 TI - An efficient method for correction of anterior crossbite without using bite plates. AB - In cases of anterior crossbite we need to disocclude the bite so as to initiate unrestricted pathway for the teeth to come into the arch. Various techniques have been advocated for this purpose but most of them are either costly, time consuming or not very effective. So, by the use of simple bondable Begg bracket and elastics we devised a method to disocclude the bite and help in correction of anterior crossbite. It is easy, economical, efficient and less time consuming. PMID- 23661663 TI - Polymorphous low-grade adenocarcinoma of maxillary alveolus metastasising to the abdomen: the role of immunomarkers in diagnosis. AB - Polymorphous low-grade adenocarcinoma (PLGA) originating mostly in the minor salivary glands of the posterior hard and soft palate is characterised by its indolent growth and a slower rate of metastasis. Seldom does the PLGA present an aggressive behaviour and demonstrate distant metastasis, as in the present case where a 73-year-old female patient with a swelling in the maxillary alveolus was diagnosed as PLGA exhibiting high-grade transformation, subsequently metastasizing to the abdomen and lungs. The importance of immunomarkers, c-kit and ki-67 in deciphering the clinical behaviour of this PLGA is highlighted. Distant metastasis to the abdomen has not yet been reported; hence, this case of PLGA emphasises the importance of immunohistochemistry in assessing its aggressiveness and understanding a novel aspect of its pathogenesis. PMID- 23661664 TI - Oral lichenoid reaction due to nickel alloy contact hypersensitivity. PMID- 23661665 TI - Simultaneous Moyamoya disease and cervical spinal cord low-grade astrocytoma in a child with neurofibromatosis type 1. PMID- 23661666 TI - A digital picture is worth a thousand words in a different dialect: improving adherence to antiretroviral medication. PMID- 23661667 TI - Question 1: what are the options for treating latent TB infection in children? PMID- 23661668 TI - Towards evidence based medicine for paediatricians. PMID- 23661669 TI - Question 2: can a conservative approach to the treatment of hypertrophic pyloric stenosis with atropine be considered a real alternative to surgical pyloromyotomy? PMID- 23661670 TI - Identification of volatile organic compounds produced by bacteria using HS-SPME GC-MS. AB - The analysis of volatile organic compounds (VOCs) as a tool for bacterial identification is reported. Headspace solid-phase microextraction (HS-SPME) coupled to gas chromatography-mass spectrometry (GC-MS) was applied to the analysis of bacterial VOCs with the aim of determining the impact of experimental parameters on the generated VOC profiles. The effect of culture medium, SPME fiber type and GC column were fully evaluated with the Gram-negative bacteria Escherichia coli and Klebsiella pneumoniae and the Gram-positive species Staphylococcus aureus. Multivariate analysis, including cluster analysis and principal component analysis, was applied to VOC data to determine whether the parameters under investigation significantly affected bacterial VOC profiles. Culture medium, and to a lesser extent, SPME fiber type, were found to significantly alter detected bacterial VOC profiles. The detected VOCs varied little with the polarity of the GC column. The results indicate that the generated bacterial VOC profiles need careful evaluation if they are to be used for clinical diagnostics. The whole process is limited by the need to grow the bacteria in broth (18 h) before extraction and analysis (63 min). PMID- 23661671 TI - Determination of phthalates released from paper packaging materials by solid phase extraction-high-performance liquid chromatography. AB - A solid phase extraction (SPE) high-performance liquid chromatography (HPLC) method was developed for the simultaneous determination of 10 phthalic acid esters (dimethyl phthalate, diethyl phthalate, dipropyl phthalate, benzylbutyl phthalate, diisobutyl phthalate, dicyclohexyl phthalate, diamyl phthalate, di-n hexyl phthalate, di-n-octyl phthalate and di-2-ethylhexyl phthalate) released from food paper packaging materials. The use of distilled water, 3% acetic acid (w/v), 10% ethanol (v/v) and 95% ethanol (v/v) instead of the different types of food simulated the migration of 10 phthalic acid esters from food paper packaging materials; the phthalic acid esters in four food simulants were enriched and purified by a C18 SPE column and nitrogen blowing, and quantified by HPLC with a diode array detector. The chromatographic conditions and extraction conditions were optimized and all 10 of the phthalate acid esters had a maximum absorbance at 224 nm. The method showed limitations of detection in the range of 6.0-23.8 ng/mL the correlation coefficients were greater than 0.9999 in all cases, recovery values ranged between 71.27 and 106.97% at spiking levels of 30, 60 and 90 ng/mL and relative standard deviation values ranged from 0.86 to 8.00%. The method was considered to be simple, fast and reliable for a study on the migration of these 10 phthalic acid esters from food paper packaging materials into food. PMID- 23661672 TI - Coronary heart disease in systemic lupus erythematosus is associated with interferon regulatory factor-8 gene variants. AB - BACKGROUND: Patients with systemic lupus erythematosus have increased morbidity and mortality in coronary heart disease (CHD). We asked whether there was a genetic influence on CHD in systemic lupus erythematosus. METHODS AND RESULTS: The association between single-nucleotide polymorphisms (SNPs) and CHD in 2 populations of patients with systemic lupus erythematosus was assessed. Patients were genotyped on a custom 12k Illumina Array. The allele frequencies were compared between patients with (n=66) and without (n=509) CHD. We found 61 SNPs with an association (P<0.01) to CHD, with the strongest association for 3 SNPs located in the interferon regulatory factor-8 (IRF8) gene. Comparison of the allele frequencies of these 61 SNPs in patients with (n=27) and without (n=212) CHD in the second study population revealed that 2 SNPs, rs925994 and rs10514610 in IRF8 (linkage disequilibrium, r2=0.84), were associated with CHD in both study populations. Meta-analysis of the SNP rs925994 gave an odds ratio of 3.6 (2.1 6.3), P value 1.9*10-6. The identified IRF8 allele remained as a risk factor for CHD after adjustment for traditional CHD risk factors. The IRF8 risk allele was associated with the presence of carotid plaques (P<0.001) and increased intima media thickness (P=0.01). By electrophoretic mobility shift assays, we show weaker binding of protein to the risk allele of the highly linked SNP rs11117415, and by flow cytometry, a reduced frequency of circulating B cells was detected in patients with the IRF8 risk allele. CONCLUSIONS: There is a considerable genetic component for CHD in systemic lupus erythematosus, with IRF8 as a strong susceptibility locus. PMID- 23661673 TI - Functional characterization of a novel mutation in NKX2-5 associated with congenital heart disease and adult-onset cardiomyopathy. AB - BACKGROUND: The transcription factor NKX2-5 is crucial for heart development, and mutations in this gene have been implicated in diverse congenital heart diseases and conduction defects in mouse models and humans. Whether NKX2-5 mutations have a role in adult-onset heart disease is unknown. METHODS AND RESULTS: Mutation screening was performed in 220 probands with adult-onset dilated cardiomyopathy. Six NKX2-5 coding sequence variants were identified, including 3 nonsynonymous variants. A novel heterozygous mutation, I184M, located within the NKX2-5 homeodomain, was identified in 1 family. A subset of family members had congenital heart disease, but there was an unexpectedly high prevalence of dilated cardiomyopathy. Functional analysis of I184M in vitro demonstrated a striking increase in protein expression when transfected into COS-7 cells or HL-1 cardiomyocytes because of reduced degradation by the Ubiquitin-proteasome system. In functional assays, DNA-binding activity of I184M was reduced, resulting in impaired activation of target genes despite increased expression levels of mutant protein. CONCLUSIONS: Certain NKX2-5 homeodomain mutations show abnormal protein degradation via the Ubiquitin-proteasome system and partially impaired transcriptional activity. We propose that this class of mutation can impair heart development and mature heart function and contribute to NKX2-5-related cardiomyopathies with graded severity. PMID- 23661674 TI - Endothelial protease nexin-1 is a novel regulator of A disintegrin and metalloproteinase 17 maturation and endothelial protein C receptor shedding via furin inhibition. AB - OBJECTIVE: Human protein C is a plasma serine protease that plays a key role in hemostasis, and activated protein C (aPC) is known to elicit protective responses in vascular endothelial cells. This cytoprotective activity requires the interaction of the protease with its cell membrane receptor, endothelial protein C receptor. However, the mechanisms regulating the beneficial cellular effects of aPC are not well known. We aimed to determine whether a serine protease inhibitor called protease nexin-1 (PN-1) or serpinE2, expressed by vascular cells, can modulate the effect of aPC on endothelial cells. APPROACH AND RESULTS: We found that vascular barrier protective and antiapoptotic activities of aPC were reduced both in endothelial cells underexpressing PN-1 and in endothelial cells whose PN 1 function was blocked by a neutralizing antibody. Our in vitro data were further confirmed in vivo. Indeed, we found that vascular endothelial growth factor mediated hyperpermeability in the skin of mice was markedly reduced by local intradermal injection of aPC in wild-type mice but not in PN-1-deficient mice. Furthermore, we demonstrated a previously unknown protective role of endothelial PN-1 on endothelial protein C receptor shedding. We provided evidence that PN-1 inhibits furin, a serine protease that activates a disintegrin and metalloproteinase 17 involved in the shedding of endothelial protein C receptor. We indeed evidenced a direct interaction between PN-1 and furin in endothelial cells. CONCLUSIONS: Our results thus demonstrate an original role of PN-1 as a furin convertase inhibitor, providing new insights for understanding the regulation of endothelial protein C receptor-dependent aPC endothelial protective effects. PMID- 23661675 TI - Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. AB - OBJECTIVE: Angiopoietin-like 3 (Angptl3) is a regulator of lipoprotein metabolism at least by inhibiting lipoprotein lipase activity. Loss-of-function mutations in ANGPTL3 cause familial combined hypolipidemia through an unknown mechanism. APPROACH AND RESULTS: We compared lipolytic activities, lipoprotein composition, and other lipid-related enzyme/lipid transfer proteins in carriers of the S17X loss-of-function mutation in ANGPTL3 and in age- and sex-matched noncarrier controls. Gel filtration analysis revealed a severely disturbed lipoprotein profile and a reduction in size and triglyceride content of very low density lipoprotein in homozygotes as compared with heterozygotes and noncarriers. S17X homozygotes had significantly higher lipoprotein lipase activity and mass in postheparin plasma, whereas heterozygotes showed no difference in these parameters when compared with noncarriers. No changes in hepatic lipase, endothelial lipase, paraoxonase 1, phospholipid transfer protein, and cholesterol ester transfer protein activities were associated with the S17X mutation. Plasma free fatty acid, insulin, glucose, and homeostatic model assessment of insulin resistance were significantly lower in homozygous subjects compared with heterozygotes and noncarriers subjects. CONCLUSIONS: These results indicate that, although partial Angptl3 deficiency did not affect the activities of lipolytic enzymes, the complete absence of Angptl3 results in an increased lipoprotein lipase activity and mass and low circulating free fatty acid levels. This latter effect is probably because of decreased mobilization of free fatty acid from fat stores in human adipose tissue and may result in reduced hepatic very low density lipoprotein synthesis and secretion via attenuated hepatic free fatty acid supply. Altogether, Angptl3 may affect insulin sensitivity and play a role in modulating both lipid and glucose metabolism. PMID- 23661676 TI - Basilar artery diameter is an independent predictor of incident cardiovascular events. AB - OBJECTIVE: Basilar arterial (BA) dolichoectasia is associated with cerebral small vessel disease and stroke. However, the association between moderate dilation of the BA and cerebral small-vessel disease or subsequent cardiovascular events remains unclear. This study aims to clarify the factors related to BA diameter and to clarify whether the BA diameter is an independent predictor of cardiovascular events. APPROACH AND RESULTS: The study subjects comprised 493 outpatients with atherosclerotic risk factors. BA diameter, lacunar infarct, severity of deep white matter hyperintensities, and intracranial steno-occlusive lesions were assessed with MRI and magnetic resonance angiography. Then, we prospectively evaluated the association between BA diameter and cardiovascular events. The BA diameter ranged from 1.1 to 5.2 mm, and only 0.8% of the patients had dolichoectasia. Male sex, the presence of lacunar infarcts, the severity of deep white matter hyperintensities, the fetal-type variation of the circle of Willis, and intracranial steno-occlusive lesions were independently associated with BA diameter. In the mean follow-up of 6.0 years, 91 patients developed cardiovascular events. BA diameter was independently associated with total cardiovascular events after adjusting for age, sex, and conventional risk factors (hazard ratio, 1.55 per 1 mm increase in BA diameter; P=0.009). CONCLUSIONS: Increased BA diameter within the normal range is related to both large-vessel disease and cerebral small-vessel disease, and it could be a new predictor of cardiovascular events. PMID- 23661678 TI - Impact of inherited genetic variants associated with lipid profile, hypertension, and coronary artery disease on the risk of intracranial and abdominal aortic aneurysms. AB - BACKGROUND: Epidemiological studies show that an unfavorable lipid profile and coronary artery disease (CAD) are risk traits for abdominal aortic aneurysms (AAAs) but not for intracranial aneurysms (IAs), and that hypertension is a main risk trait for IAs but not for AAAs. To evaluate these observations, we investigated single-nucleotide polymorphisms associated with serum lipid levels, hypertension, and CAD and tested their contribution to AAA and IA risk. METHODS AND RESULTS: We defined sets of single-nucleotide polymorphisms previously reported to be associated with serum lipid levels, CAD, and blood pressure. From previously collected genome-wide data, we extracted genotypes for these single nucleotide polymorphism sets in 709 IA cases and 2692 controls and 807 AAA cases and 1905 controls (all of Dutch origin). We computed genetic scores for each individual by summing the observed number of risk alleles weighted by their previously published effect size. Using logistic regression, we tested the genetic scores for association with IAs and AAAs and found significant associations for genetic scores of total cholesterol (P=3.6*10-6), low-density lipoprotein-cholesterol (P=5.7*10-7), and CAD (P=0.0014) with AAAs and for the blood pressure score with IAs (P=0.0030). CONCLUSIONS: We demonstrate that genetic risk profiles of lipid factors and CAD are associated with AAAs but not with IAs, and the genetic risk profile of blood pressure is associated with IAs but not with AAAs. These findings are consistent with epidemiological observations. PMID- 23661677 TI - Mineralocorticoid receptor agonists induce mouse aortic aneurysm formation and rupture in the presence of high salt. AB - OBJECTIVE: Elevated plasma aldosterone concentrations in patients have been linked to a spectrum of cardiovascular diseases. Mineralocorticoid receptor antagonists provide additional benefits in patients with heart failure. However, whether aldosterone and the mineralocorticoid receptor are involved in aortic aneurysm is unknown. APPROACH AND RESULTS: We report that administration of deoxycorticosterone acetate (DOCA) and salt or aldosterone and salt, but not DOCA or salt alone, to C57BL/6 male mice induced abdominal and thoracic aortic aneurysm formation and rupture in an age-dependent manner. DOCA and salt- or aldosterone and salt-induced aortic aneurysm mimicked human aortic aneurysm with respect to elastin degradation, inflammatory cell infiltration, smooth muscle cell degeneration and apoptosis, and oxidative stress. Aortic aneurysm formation did not correlate with the increase in blood pressure induced by DOCA and salt. Systemic administration of the angiotensin-converting enzyme inhibitor, enalapril, or angiotensin type 1 receptor antagonist, losartan, did not affect DOCA and salt-induced aortic aneurysm. In contrast, the mineralocorticoid receptor antagonists, spironolactone or eplerenone, significantly attenuated DOCA and salt- or aldosterone and salt-induced aortic aneurysm. CONCLUSIONS: The current study describes a novel aortic aneurysm animal model induced by mineralocorticoid receptor agonist and high salt, and reveals a previously unrecognized but potentially significant role of aldosterone in the pathogenesis of aortic aneurysm. These findings imply that mineralocorticoid receptor antagonists may be effective in the treatment of some aortic aneurysms. PMID- 23661679 TI - The Fanconi anemia associated protein FAAP24 uses two substrate specific binding surfaces for DNA recognition. AB - To maintain the integrity of the genome, multiple DNA repair systems exist to repair damaged DNA. Recognition of altered DNA, including bulky adducts, pyrimidine dimers and interstrand crosslinks (ICL), partially depends on proteins containing helix-hairpin-helix (HhH) domains. To understand how ICL is specifically recognized by the Fanconi anemia proteins FANCM and FAAP24, we determined the structure of the HhH domain of FAAP24. Although it resembles other HhH domains, the FAAP24 domain contains a canonical hairpin motif followed by distorted motif. The HhH domain can bind various DNA substrates; using nuclear magnetic resonance titration experiments, we demonstrate that the canonical HhH motif is required for double-stranded DNA (dsDNA) binding, whereas the unstructured N-terminus can interact with single-stranded DNA. Both DNA binding surfaces are used for binding to ICL-like single/double-strand junction containing DNA substrates. A structural model for FAAP24 bound to dsDNA has been made based on homology with the translesion polymerase iota. Site-directed mutagenesis, sequence conservation and charge distribution support the dsDNA binding model. Analogous to other HhH domain-containing proteins, we suggest that multiple FAAP24 regions together contribute to binding to single/double-strand junction, which could contribute to specificity in ICL DNA recognition. PMID- 23661680 TI - Single-molecule study of the CUG repeat-MBNL1 interaction and its inhibition by small molecules. AB - Effective drug discovery and optimization can be accelerated by techniques capable of deconvoluting the complexities often present in targeted biological systems. We report a single-molecule approach to study the binding of an alternative splicing regulator, muscleblind-like 1 protein (MBNL1), to (CUG)n = 4,6 and the effect of small molecules on this interaction. Expanded CUG repeats (CUG(exp)) are the causative agent of myotonic dystrophy type 1 by sequestering MBNL1. MBNL1 is able to bind to the (CUG)n-inhibitor complex, indicating that the inhibition is not a straightforward competitive process. A simple ligand, highly selective for CUG(exp), was used to design a new dimeric ligand that binds to (CUG)n almost 50-fold more tightly and is more effective in destabilizing MBNL1 (CUG)4. The single-molecule method and the analysis framework might be extended to the study of other biomolecular interactions. PMID- 23661681 TI - STRAW: Species TRee Analysis Web server. AB - The coalescent methods for species tree reconstruction are increasingly popular because they can accommodate coalescence and multilocus data sets. Herein, we present STRAW, a web server that offers workflows for reconstruction of phylogenies of species using three species tree methods-MP-EST, STAR and NJst. The input data are a collection of rooted gene trees (for STAR and MP-EST methods) or unrooted gene trees (for NJst). The output includes the estimated species tree, modified Robinson-Foulds distances between gene trees and the estimated species tree and visualization of trees to compare gene trees with the estimated species tree. The web sever is available at http://bioinformatics.publichealth.uga.edu/SpeciesTreeAnalysis/. PMID- 23661682 TI - Cell type specificity and structural determinants of IRES activity from the 5' leaders of different HIV-1 transcripts. AB - Internal ribosome entry site (IRES) RNAs are important regulators of gene expression, but their diverse molecular mechanisms remain partially understood. The HIV-1 gag transcript leader contains an IRES that may be a good model for understanding the function of many other IRESs. We investigated the possibility that this IRES' function is linked to both the structure of the RNA and its cellular environment. We find that in the context of a bicistronic reporter construct, HIV-1 gag IRES' activity is cell type-specific, with higher activity in T-cell culture systems that model the natural target cells for HIV-1 infection. This finding underscores how an IRES may be fine tuned to function in certain cells, perhaps owing to cell type-specific protein factors. Using RNA probing and mutagenesis, we demonstrate that the HIV-1 gag IRES does not use pre folded RNA structure to drive function, a finding that gives insight into how conformationally dynamic IRESs operate. Furthermore, we find that a common exon drives IRES activity in a diverse set of alternatively spliced transcripts. We propose a mechanism in which a structurally plastic RNA element confers the ability to initiate translation internally, and activity from this common element is modulated by 3' nucleotides added by alternative splicing. PMID- 23661683 TI - Control of DNA minor groove width and Fis protein binding by the purine 2-amino group. AB - The width of the DNA minor groove varies with sequence and can be a major determinant of DNA shape recognition by proteins. For example, the minor groove within the center of the Fis-DNA complex narrows to about half the mean minor groove width of canonical B-form DNA to fit onto the protein surface. G/C base pairs within this segment, which is not contacted by the Fis protein, reduce binding affinities up to 2000-fold over A/T-rich sequences. We show here through multiple X-ray structures and binding properties of Fis-DNA complexes containing base analogs that the 2-amino group on guanine is the primary molecular determinant controlling minor groove widths. Molecular dynamics simulations of free-DNA targets with canonical and modified bases further demonstrate that sequence-dependent narrowing of minor groove widths is modulated almost entirely by the presence of purine 2-amino groups. We also provide evidence that protein mediated phosphate neutralization facilitates minor groove compression and is particularly important for binding to non-optimally shaped DNA duplexes. PMID- 23661684 TI - Differential roles of human Dicer-binding proteins TRBP and PACT in small RNA processing. AB - During RNA interference and related gene regulatory pathways, the endonuclease Dicer cleaves precursor RNA molecules to produce microRNAs (miRNAs) and short interfering RNAs (siRNAs). Human cells encode a single Dicer enzyme that can associate with two different double-stranded RNA (dsRNA)-binding proteins, protein activator of PKR (PACT) and trans-activation response RNA-binding protein (TRBP). However, the functional redundancy or differentiation of PACT and TRBP in miRNA and siRNA biogenesis is not well understood. Using a reconstituted system, we show here that PACT and TRBP have distinct effects on Dicer-mediated dsRNA processing. In particular, we found that PACT in complex with Dicer inhibits the processing of pre-siRNA substrates when compared with Dicer and a Dicer-TRBP complex. In addition, PACT and TRBP show non-redundant effects on the production of different-sized miRNAs (isomiRs), which in turn alter target-binding specificities. Experiments using chimeric versions of PACT and TRBP suggest that the two N-terminal RNA-binding domains of each protein confer the observed differences in dsRNA substrate recognition and processing behavior of Dicer-dsRNA binding protein complexes. These results support the conclusion that in humans, Dicer-associated dsRNA-binding proteins are important regulatory factors that contribute both substrate and cleavage specificity during miRNA and siRNA production. PMID- 23661686 TI - Transcriptional analysis of the groES-groEL1, groEL2, and dnaK genes in Corynebacterium glutamicum: characterization of heat shock-induced promoters. PMID- 23661685 TI - Reconstructing mitochondrial genomes directly from genomic next-generation sequencing reads--a baiting and iterative mapping approach. AB - We present an in silico approach for the reconstruction of complete mitochondrial genomes of non-model organisms directly from next-generation sequencing (NGS) data-mitochondrial baiting and iterative mapping (MITObim). The method is straightforward even if only (i) distantly related mitochondrial genomes or (ii) mitochondrial barcode sequences are available as starting-reference sequences or seeds, respectively. We demonstrate the efficiency of the approach in case studies using real NGS data sets of the two monogenean ectoparasites species Gyrodactylus thymalli and Gyrodactylus derjavinoides including their respective teleost hosts European grayling (Thymallus thymallus) and Rainbow trout (Oncorhynchus mykiss). MITObim appeared superior to existing tools in terms of accuracy, runtime and memory requirements and fully automatically recovered mitochondrial genomes exceeding 99.5% accuracy from total genomic DNA derived NGS data sets in <24 h using a standard desktop computer. The approach overcomes the limitations of traditional strategies for obtaining mitochondrial genomes for species with little or no mitochondrial sequence information at hand and represents a fast and highly efficient in silico alternative to laborious conventional strategies relying on initial long-range PCR. We furthermore demonstrate the applicability of MITObim for metagenomic/pooled data sets using simulated data. MITObim is an easy to use tool even for biologists with modest bioinformatics experience. The software is made available as open source pipeline under the MIT license at https://github.com/chrishah/MITObim. PMID- 23661687 TI - Heat shock proteome analysis of wild-type Corynebacterium glutamicum ATCC 13032 and a spontaneous mutant lacking GroEL1, a dispensable chaperone. PMID- 23661689 TI - Echocardiographic assessment of cardiac valvular regurgitation with lorcaserin from analysis of 3 phase 3 clinical trials. AB - BACKGROUND: Lorcaserin is a selective 5-HT2C agonist evaluated for weight management in clinical trials. Echocardiographic monitoring was conducted to test the hypothesis that selective 5-HT2C agonism would avoid valvular heart disease. METHODS AND RESULTS: Echocardiographic and weight change data from 5249 obese and overweight patients in 3 phase 3 trials were integrated. Treatment duration with 10 mg lorcaserin twice daily or placebo was 52 weeks. The proportions of patients who developed Food and Drug Administration-defined valvulopathy (>= mild aortic or >= moderate mitral regurgitation) and changes in regurgitant grade at each heart valve were evaluated. Possible associations between weight or body mass index change and valvulopathy were explored. New valvulopathy was present in 2.04% of placebo and 2.37% of lorcaserin recipients at 52 weeks (risk difference, 0.33%; 95% confidence interval, -0.46 to 1.13; risk ratio, 1.16 [all patients with sufficient echocardiographic data, last-observation-carried-forward imputation] or 1.03 [patients who completed 52 weeks]). Changes in weight and body mass index were negatively associated with presence of valvulopathy at week 52 (P=0.02 and P=0.04, respectively); a 5% decrease in weight was associated with an odds ratio of 1.15 for Food and Drug Administration-defined valvulopathy. Most changes in regurgitation were +/-1 grade in both treatment groups at all heart valves. CONCLUSIONS: In 3 prospective placebo-controlled trials with integrated data for 5249 patients, the rate of echocardiographic valvulopathy was similar with lorcaserin and placebo. Point estimates for risk ratios ranged from 1.03 to 1.16 and may be at least partially influenced by greater weight loss in the lorcaserin group than in the placebo group. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00395135, NCT00603291, NCT00603902. PMID- 23661690 TI - What has balANZ taught us about balancing ultrafiltration with membrane preservation? PMID- 23661691 TI - Double embolic protection during carotid artery stenting with persistent hypoglossal artery. AB - A woman presented with 75% stenosis of the right internal carotid artery (ICA) with extension to the origin of a persistent hypoglossal artery (PHA). The PHA is a rare fetal variant of carotid-basilar anastomosis that elevates the risk of ischemia and embolic infarction within the posterior cerebral circulation in patients with carotid disease proximal to the anastomosis. Our case is highly unique because of the extremely rare nature of the PHA with associated ICA stenosis that extended to the PHA. Additionally, a novel treatment approach was employed by stenting and angioplasty while protecting both the anterior and posterior cerebral circulations. PMID- 23661692 TI - 'What really stands behind the numbers?': occupational diseases and their social construction. PMID- 23661693 TI - CMAP: Complement Map Database. AB - SUMMARY: The human complement system is increasingly perceived as an intricate protein network of effectors, inhibitors and regulators that drives critical processes in health and disease and extensively communicates with associated physiological pathways ranging from immunity and inflammation to homeostasis and development. A steady stream of experimental data reveals new fascinating connections at a rapid pace; although opening unique opportunities for research discoveries, the comprehensiveness and large diversity of experimental methods, nomenclatures and publication sources renders it highly challenging to keep up with the essential findings. With the Complement Map Database (CMAP), we have created a novel and easily accessible research tool to assist the complement community and scientists from related disciplines in exploring the complement network and discovering new connections. AVAILABILITY: http://www.complement.us/cmap. CONTACT: lambris@upenn.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23661694 TI - Adaptive reference-free compression of sequence quality scores. AB - MOTIVATION: Rapid technological progress in DNA sequencing has stimulated interest in compressing the vast datasets that are now routinely produced. Relatively little attention has been paid to compressing the quality scores that are assigned to each sequence, even though these scores may be harder to compress than the sequences themselves. By aggregating a set of reads into a compressed index, we find that the majority of bases can be predicted from the sequence of bases that are adjacent to them and, hence, are likely to be less informative for variant calling or other applications. The quality scores for such bases are aggressively compressed, leaving a relatively small number at full resolution. As our approach relies directly on redundancy present in the reads, it does not need a reference sequence and is, therefore, applicable to data from metagenomics and de novo experiments as well as to re-sequencing data. RESULTS: We show that a conservative smoothing strategy affecting 75% of the quality scores above Q2 leads to an overall quality score compression of 1 bit per value with a negligible effect on variant calling. A compression of 0.68 bit per quality value is achieved using a more aggressive smoothing strategy, again with a very small effect on variant calling. AVAILABILITY: Code to construct the BWT and LCP-array on large genomic data sets is part of the BEETL library, available as a github repository at git@github.com:BEETL/BEETL.git. PMID- 23661695 TI - iFUSE: integrated fusion gene explorer. AB - We present iFUSE (integrated fusion gene explorer), an online visualization tool that provides a fast and informative view of structural variation data and prioritizes those breaks likely representing fusion genes. This application uses calculated break points to determine fusion genes based on the latest annotation for genomic sequence information, and where relevant the structural variation (SV) events are annotated with predicted RNA and protein sequences. iFUSE takes as input a Complete Genomics (CG) junction file, a FusionMap fusion detection report file or a file already analysed and annotated by the iFUSE application on a previous occasion. RESULTS: We demonstrate the use of iFUSE with case studies from tumour-normal SV detection derived from Complete Genomics whole-genome sequencing results. AVAILABILITY: iFUSE is available as a web service at http://ifuse.erasmusmc.nl. PMID- 23661696 TI - pyDockWEB: a web server for rigid-body protein-protein docking using electrostatics and desolvation scoring. AB - pyDockWEB is a web server for the rigid-body docking prediction of protein protein complex structures using a new version of the pyDock scoring algorithm. We use here a new custom parallel FTDock implementation, with adjusted grid size for optimal FFT calculations, and a new version of pyDock, which dramatically speeds up calculations while keeping the same predictive accuracy. Given the 3D coordinates of two interacting proteins, pyDockWEB returns the best docking orientations as scored mainly by electrostatics and desolvation energy. AVAILABILITY AND IMPLEMENTATION: The server does not require registration by the user and is freely accessible for academics at http://life.bsc.es/servlet/pydock. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23661697 TI - International Society for Computational Biology honors Goncalo Abecasis with top bioinformatics/computational biology award for 2013. PMID- 23661698 TI - Biological and structural characterization of glycosylation on ephrin-A1, a preferred ligand for EphA2 receptor tyrosine kinase. AB - The EphA2 receptor tyrosine kinase is overexpressed in a number of malignancies and is activated by ephrin ligands, most commonly by ephrin-A1. The crystal structure of the ligand-receptor complex revealed a glycosylation on the Asn-26 of ephrin-A1. Here we report for the first time the significance of the glycosylation in the biology of EphA2 and ephrin-A1. Ephrin-A1 was enzymatically deglycosylated, and its activity was evaluated in several assays using glioblastoma (GBM) cells and recombinant EphA2. We found that deglycosylated ephrin-A1 does not efficiently induce EphA2 receptor internalization and degradation, and does not activate the downstream signaling pathways involved in cell migration and proliferation. Data obtained by surface plasmon resonance confirms that deglycosylated ephrin-A1 does not bind EphA2 with high affinity. Mutations in the glycosylation site on ephrin-A1 result in protein aggregation and mislocalization. Analysis of Eph/ephrin crystal structures reveals an interaction between the ligand's carbohydrates and two residues of EphA2: Asp-78 and Lys-136. These findings suggest that the glycosylation on ephrin-A1 plays a critical role in the binding and activation of the EphA2 receptor. PMID- 23661699 TI - Structural and biochemical characterization of compounds inhibiting Mycobacterium tuberculosis pantothenate kinase. AB - Mycobacterium tuberculosis, the bacterial causative agent of tuberculosis, currently affects millions of people. The emergence of drug-resistant strains makes development of new antibiotics targeting the bacterium a global health priority. Pantothenate kinase, a key enzyme in the universal biosynthesis of the essential cofactor CoA, was targeted in this study to find new tuberculosis drugs. The biochemical characterizations of two new classes of compounds that inhibit pantothenate kinase from M. tuberculosis are described, along with crystal structures of their enzyme-inhibitor complexes. These represent the first crystal structures of this enzyme with engineered inhibitors. Both classes of compounds bind in the active site of the enzyme, overlapping with the binding sites of the natural substrate and product, pantothenate and phosphopantothenate, respectively. One class of compounds also interferes with binding of the cofactor ATP. The complexes were crystallized in two crystal forms, one of which is in a new space group for this enzyme and diffracts to the highest resolution reported for any pantothenate kinase structure. These two crystal forms allowed, for the first time, modeling of the cofactor-binding loop in both open and closed conformations. The structures also show a binding mode of ATP different from that previously reported for the M. tuberculosis enzyme but similar to that in the pantothenate kinases of other organisms. PMID- 23661700 TI - Exosomes derived from HIV-1-infected cells contain trans-activation response element RNA. AB - Exosomes are nano-sized vesicles produced by healthy and virus-infected cells. Exosomes derived from infected cells have been shown to contain viral microRNAs (miRNAs). HIV-1 encodes its own miRNAs that regulate viral and host gene expression. The most abundant HIV-1-derived miRNA, first reported by us and later by others using deep sequencing, is the trans-activation response element (TAR) miRNA. In this study, we demonstrate the presence of TAR RNA in exosomes from cell culture supernatants of HIV-1-infected cells and patient sera. TAR miRNA was not in Ago2 complexes outside the exosomes but enclosed within the exosomes. We detected the host miRNA machinery proteins Dicer and Drosha in exosomes from infected cells. We report that transport of TAR RNA from the nucleus into exosomes is a CRM1 (chromosome region maintenance 1)-dependent active process. Prior exposure of naive cells to exosomes from infected cells increased susceptibility of the recipient cells to HIV-1 infection. Exosomal TAR RNA down regulated apoptosis by lowering Bim and Cdk9 proteins in recipient cells. We found 10(4)-10(6) copies/ml TAR RNA in exosomes derived from infected culture supernatants and 10(3) copies/ml TAR RNA in the serum exosomes of highly active antiretroviral therapy-treated patients or long term nonprogressors. Taken together, our experiments demonstrated that HIV-1-infected cells produced exosomes that are uniquely characterized by their proteomic and RNA profiles that may contribute to disease pathology in AIDS. PMID- 23661702 TI - A heme-based redox sensor in the methanogenic archaeon Methanosarcina acetivorans. AB - Based on a bioinformatics study, the protein MA4561 from the methanogenic archaeon Methanosarcina acetivorans was originally predicted to be a multidomain phytochrome-like photosensory kinase possibly binding open-chain tetrapyrroles. Although we were able to show that recombinantly produced and purified protein does not bind any known phytochrome chromophores, UV-visible spectroscopy revealed the presence of a heme tetrapyrrole cofactor. In contrast to many other known cytoplasmic heme-containing proteins, the heme was covalently attached via one vinyl side chain to cysteine 656 in the second GAF domain. This GAF domain by itself is sufficient for covalent attachment. Resonance Raman and magnetic circular dichroism data support a model of a six-coordinate heme species with additional features of a five-coordination structure. The heme cofactor is redox active and able to coordinate various ligands like imidazole, dimethyl sulfide, and carbon monoxide depending on the redox state. Interestingly, the redox state of the heme cofactor has a substantial influence on autophosphorylation activity. Although reduced protein does not autophosphorylate, oxidized protein gives a strong autophosphorylation signal independent from bound external ligands. Based on its genomic localization, MA4561 is most likely a sensor kinase of a two component system effecting regulation of the Mts system, a set of three homologous corrinoid/methyltransferase fusion protein isoforms involved in methyl sulfide metabolism. Consistent with this prediction, an M. acetivorans mutant devoid of MA4561 constitutively synthesized MtsF. On the basis of our results, we postulate a heme-based redox/dimethyl sulfide sensory function of MA4561 and propose to designate it MsmS (methyl sulfide methyltransferase-associated sensor). PMID- 23661701 TI - Zinc-induced self-association of complement C3b and Factor H: implications for inflammation and age-related macular degeneration. AB - The sub-retinal pigment epithelial deposits that are a hallmark of age-related macular degeneration contain both C3b and millimolar levels of zinc. C3 is the central protein of complement, whereas C3u is formed by the spontaneous hydrolysis of the thioester bridge in C3. During activation, C3 is cleaved to form active C3b, then C3b is inactivated by Factor I and Factor H to form the C3c and C3d fragments. The interaction of zinc with C3 was quantified using analytical ultracentrifugation and x-ray scattering. C3, C3u, and C3b associated strongly in >100 MUM zinc, whereas C3c and C3d showed weak association. With zinc, C3 forms soluble oligomers, whereas C3u and C3b precipitate. We conclude that the C3, C3u, and C3b association with zinc depended on the relative positions of C3d and C3c in each protein. Computational predictions showed that putative weak zinc binding sites with different capacities exist in all five proteins, in agreement with experiments. Factor H forms large oligomers in >10 MUM zinc. In contrast to C3b or Factor H alone, the solubility of the central C3b Factor H complex was much reduced at 60 MUM zinc and even more so at >100 MUM zinc. The removal of the C3b-Factor H complex by zinc explains the reduced C3u/C3b inactivation rates by zinc. Zinc-induced precipitation may contribute to the initial development of sub-retinal pigment epithelial deposits in the retina as well as reducing the progression to advanced age-related macular degeneration in higher risk patients. PMID- 23661703 TI - Plasticity and epigenetic inheritance of centromere-specific histone H3 (CENP-A) containing nucleosome positioning in the fission yeast. AB - Nucleosomes containing the specific histone H3 variant CENP-A mark the centromere locus on each chromatin and initiate kinetochore assembly. For the common type of regional centromeres, little is known in molecular detail of centromeric chromatin organization, its propagation through cell division, and how distinct organization patterns may facilitate kinetochore assembly. Here, we show that in the fission yeast S. pombe, a relatively small number of CENP-A/Cnp1 nucleosomes are found within the centromeric core and that their positioning relative to underlying DNA varies among genetically homogenous cells. Consistent with the flexible positioning of Cnp1 nucleosomes, a large portion of the endogenous centromere is dispensable for its essential activity in mediating chromosome segregation. We present biochemical evidence that Cnp1 occupancy directly correlates with silencing of the underlying reporter genes. Furthermore, using a newly developed pedigree analysis assay, we demonstrated the epigenetic inheritance of Cnp1 positioning and quantified the rate of occasional repositioning of Cnp1 nucleosomes throughout cell generations. Together, our results reveal the plasticity and the epigenetically inheritable nature of centromeric chromatin organization. PMID- 23661705 TI - Characterization of a novel beta-glucosidase from a compost microbial metagenome with strong transglycosylation activity. AB - The beta-glucosidase encoded by the td2f2 gene was isolated from a compost microbial metagenomic library by functional screening. The protein was identified to be a member of the glycoside hydrolase family 1 and was overexpressed in Escherichia coli, purified, and biochemically characterized. The recombinant beta glucosidase, Td2F2, exhibited enzymatic activity with beta-glycosidic substrates, with preferences for glucose, fucose, and galactose. Hydrolysis occurred at the nonreducing end and in an exo manner. The order of catalytic efficiency for glucodisaccharides and cellooligosaccharides was sophorose > cellotetraose > cellotriose > laminaribiose > cellobiose > cellopentaose > gentiobiose, respectively. Intriguingly, the p-nitrophenyl-beta-D-glucopyranoside hydrolysis activity of Td2F2 was activated by various monosaccharides and sugar alcohols. At a D-glucose concentration of 1000 mM, enzyme activity was 6.7-fold higher than that observed in the absence of D-glucose. With 31.3 mM D-glucose, Td2F2 catalyzed transglycosylation to generate sophorose, laminaribiose, cellobiose, and gentiobiose. Transglycosylation products were detected under all activated conditions, suggesting that the activity enhancement induced by monosaccharides and sugar alcohols may be due to the transglycosylation activity of the enzyme. These results show that Td2F2 obtained from a compost microbial metagenome may be a potent candidate for industrial applications. PMID- 23661704 TI - Transcriptional regulation by the Wilms tumor protein, Wt1, suggests a role of the metalloproteinase Adamts16 in murine genitourinary development. AB - ADAMTS16 (a disintegrin and metalloproteinase with thrombospondin motifs) is a secreted mammalian metalloproteinase with unknown function. We report here that murine Adamts16 is co-expressed with the Wilms tumor protein, Wt1, in the developing glomeruli of embryonic kidneys. Adamts16 mRNA levels were significantly reduced upon transfection of embryonic murine kidney explants with Wt1 antisense vivo-morpholinos. Antisense knockdown of Adamts16 inhibited branching morphogenesis in kidney organ cultures. Adamts16 was detected by in situ mRNA hybridization and/or immunohistochemistry also in embryonic gonads and in spermatids and granulosa cells of adult testes and ovaries, respectively. Silencing of Wt1 by transfection with antisense vivo-morpholinos significantly increased Adamts16 mRNA in cultured embryonic XY gonads (11.5 and 12.5 days postconception), and reduced Adamts16 transcripts in XX gonads (12.5 and 13.5 days postconception). Three predicted Wt1 consensus motifs could be identified in the promoter and the 5'-untranslated region of the murine Adamts16 gene. Binding of Wt1 protein to these elements was verified by EMSA and ChIP. A firefly luciferase reporter gene under control of the Adamts16 promoter was activated ~8 fold by transient co-transfection of human granulosa cells with a Wt1 expression construct. Gradual shortening of the 5'-flanking sequence successively reduced and eventually abrogated Adamts16 promoter activation by Wt1. These findings demonstrate that Wt1 differentially regulates the Adamts16 gene in XX and XY embryonic gonads. It is suggested that Adamts16 acts immediately downstream of Wt1 during murine urogenital development. We propose that Adamts16 is involved in branching morphogenesis of the kidneys in mice. PMID- 23661706 TI - Transmembrane Protein 214 (TMEM214) mediates endoplasmic reticulum stress-induced caspase 4 enzyme activation and apoptosis. AB - Endoplasmic reticulum (ER) stress caused by excessive aggregation of misfolded proteins induces apoptosis. Although ER stress-induced apoptosis has been implicated in many diseases, the detailed mechanisms are not well understood. Here, we identified human transmembrane protein 214 (TMEM214) as a critical mediator of ER stress-induced apoptosis. Overexpression of TMEM214 induced apoptosis, whereas knockdown of TMEM214 inhibited ER stress-induced apoptosis. TMEM214 was localized on the outer membrane of the ER and constitutively associated with procaspase 4, which was also critical for ER stress-induced apoptosis. TMEM214-induced apoptosis was abolished by a dominant negative mutant of procaspase 4, whereas caspase 4-induced apoptosis was inhibited by knockdown of TMEM214. Furthermore, knockdown of TMEM214 inhibited the activation and cleavage of procaspase 4 by impairing its recruitment to the ER. Our findings suggest that TMEM214 is essential for ER stress-induced apoptosis by acting as an anchor for recruitment of procaspase 4 to the ER and its subsequent activation. PMID- 23661708 TI - (-)-Epigallocatechin-3-gallate, a potential inhibitor to human dicarbonyl/L xylulose reductase. AB - Dicarbonyl/l-xylulose reductase (DCXR), mainly catalysing the reduction of alpha dicarbonyl compounds and l-xylulose, belongs to the short-chain dehydrogenase/reductase superfamily. Its enzyme activity can be inhibited by short-chain fatty acids. In this study, a novel DCXR inhibitor named (-) epigallocatechin-3-gallate (EGCG) was reported. First, we overexpressed recombinant human DCXR in Escherichia coli, purified the enzyme by affinity chromatography and measured its activity. The inhibition effects of EGCG and its analogues on DCXR were determined subsequently, and EGCG showed the strongest inhibition with 50% inhibition concentration value of 78.8 MUM. The surface plasmon resonance analysis also indicated that the equilibrium dissociation constant (KD) reached to 7.11 * 10(-8) M, which implied a high affinity between EGCG and DCXR. From enzyme kinetic analysis, EGCG acted as a mixed inhibitor against its forward and reverse substrates and the coenzyme, reduced nicotinamide adenine dinucleotide phosphate (NADPH). However, the inhibition is pH dependent. The molecular docking finally showed that EGCG formed several hydrogen bonds with the Thr190 residue of DCXR, and the model was further verified by site-directed mutagenesis. Therefore, EGCG is a potential inhibitor to human DCXR. PMID- 23661707 TI - The arrestin-selective angiotensin AT1 receptor agonist [Sar1,Ile4,Ile8]-AngII negatively regulates bradykinin B2 receptor signaling via AT1-B2 receptor heterodimers. AB - The renin-angiotensin and kallikrein-kinin systems are key regulators of vascular tone and inflammation. Angiotensin II, the principal effector of the renin angiotensin system, promotes vasoconstriction by activating angiotensin AT1 receptors. The opposing effects of the kallikrein-kinin system are mediated by bradykinin acting on B1 and B2 bradykinin receptors. The renin-angiotensin and kallikrein-kinin systems engage in cross-talk at multiple levels, including the formation of AT1-B2 receptor heterodimers. In primary vascular smooth muscle cells, we find that the arrestin pathway-selective AT1 agonist, [Sar(1),Ile(4),Ile(8)]-AngII, but not the neutral AT1 antagonist, losartan, inhibits endogenous B2 receptor signaling. In a transfected HEK293 cell model that recapitulates this effect, we find that the actions of [Sar(1),Ile(4), Ile(8)]-AngII require the AT1 receptor and result from arrestin-dependent co internalization of AT1-B2 heterodimers. BRET50 measurements indicate that AT1 and B2 receptors efficiently heterodimerize. In cells expressing both receptors, pretreatment with [Sar(1),Ile(4),Ile(8)]-AngII blunts B2 receptor activation of Gq/11-dependent intracellular calcium influx and Gi/o-dependent inhibition of adenylyl cyclase. In contrast, [Sar(1),Ile(4),Ile(8)]-AngII has no effect on B2 receptor ligand affinity or bradykinin-induced arrestin3 recruitment. Both radioligand binding assays and quantitative microscopy-based analysis demonstrate that [Sar(1),Ile(4),Ile(8)]-AngII promotes internalization of AT1-B2 heterodimers. Thus, [Sar(1),Ile(4),Ile(8)]-AngII exerts lateral allosteric modulation of B2 receptor signaling by binding to the orthosteric ligand binding site of the AT1 receptor and promoting co-sequestration of AT1-B2 heterodimers. Given the opposing roles of the renin-angiotensin and kallikrein-kinin systems in vivo, the distinct properties of arrestin pathway-selective and neutral AT1 receptor ligands may translate into different pharmacologic actions. PMID- 23661709 TI - High-density lipoprotein extinguishes fire in fat. PMID- 23661710 TI - The discovery of the ACE2 gene. PMID- 23661711 TI - Advances in blood pressure genomics. AB - The elucidation of genes implicated in Mendelian forms of hypertension demonstrates rare variants with substantial effects are responsible, and often these genes lie within pathways managing sodium homeostasis. More recently with advances in affordable high-throughput genotyping strategies, multiple common genetic variants with modest effects on blood pressure (<1 mmHg systolic) have been discovered in the population. In aggregate, these common variants explain <3% of the variance of blood pressure. Although these findings may offer new mechanistic insights into the biology of blood pressure, a key question is can these findings translate into patient benefit? It is timely to reflect on recent advances in genomics, and the use of new resources, such as the 1000 Genomes Project and the Encyclopedia of DNA Elements, to annotate likely causal variants, and their relevance to cardiovascular disease. In this review, we discuss the advances in relation to our knowledge of the genetic architecture of blood pressure, and whether gene discoveries might influence cardiovascular risk assessment, help to stratify patient response to medicine, or identify new biological pathways for novel therapeutic targets. PMID- 23661713 TI - Questing for circadian dependence in ST-segment-elevation acute myocardial infarction: a multicentric and multiethnic study. AB - RATIONALE: Four monocentric studies reported that circadian rhythms can affect left ventricular infarct size after ST-segment-elevation acute myocardial infarction (STEMI). OBJECTIVE: To further validate the circadian dependence of infarct size after STEMI in a multicentric and multiethnic population. METHODS AND RESULTS: We analyzed a prospective cohort of subjects with first STEMI from the First Acute Myocardial Infarction study that enrolled 1099 patients (ischemic time <6 hours) in Italy, Scotland, and China. We confirmed a circadian variation of STEMI incidence with an increased morning incidence (from 6:00 am till noon). We investigated the presence of circadian dependence of infarct size plotting the peak creatine kinase against time onset of ischemia. In addition, we studied the patients from the 3 countries separately, including 624 Italians; all patients were treated with percutaneous coronary intervention. We adopted several levels of analysis with different inclusion criteria consistent with previous studies. In all the analyses, we did not find a clear-cut circadian dependence of infarct size after STEMI. CONCLUSIONS: Although the circadian dependence of infarct size supported by previous studies poses an intriguing hypothesis, we were unable to converge toward their conclusions in a multicentric and multiethnic setting. Parameters that vary as a function of latitude could potentially obscure the circadian variations observed in monocentric studies. We believe that, to assess whether circadian rhythms can affect the infarct size, future study design should not only include larger samples but also aim to untangle the molecular time dynamic mechanisms underlying such a relation. PMID- 23661714 TI - Of mice and men: the quest to determine a circadian basis for myocardial protection in ischemia/reperfusion injury. PMID- 23661716 TI - Lung cancer in never-smokers. Does smoking history matter in the era of molecular diagnostics and targeted therapy? AB - Lung cancer in never-smokers was recognised as a distinct clinical entity around the mid-2000s because these patients tended to be Asian women and diagnosed at a younger age with a preponderance of adenocarcinoma and better survival outcome despite a more advanced stage of presentation. It was soon discovered that lung cancer in never-smokers had a higher prevalence of activating EGFR mutations and we tend to classify lung cancer by smoking status for screening purpose. With the discoveries of many actionable driver mutations such as activating EGFR mutations and ALK rearrangement in adenocarcinoma of the lung we have switched to classifying non-small cell lung cancer into different individual molecular subgroups based on the presence of a dominant driver mutation. Although many actionable driver mutations are found in never-smokers with adenocarcinoma, this review will summarise that a substantial proportion of patients with these actionable driver mutations had a previous smoking history. Alternatively among the driver mutations that are associated with smoking history, a fair amount of these patients were never-smokers. Thus smoking status should not be used as a screen strategy for identifying driver mutations in clinical practice. Finally smoking history may have predictive and/or prognostic significance within individual molecular subgroups and identifying the difference according to smoking history may help optimise future targeted therapy. PMID- 23661717 TI - Reduced sodium channel function unmasks residual embryonic slow conduction in the adult right ventricular outflow tract. AB - RATIONALE: In patients with Brugada syndrome, arrhythmias typically originate in the right ventricular outflow tract (RVOT). The RVOT develops from the slowly conducting embryonic outflow tract. OBJECTIVE: We hypothesize that this embryonic phenotype is maintained in the fetal and adult RVOT and leads to conduction slowing, especially after sodium current reduction. METHODS AND RESULTS: We determined expression patterns in the embryonic myocardium and performed activation mapping in fetal and adult hearts, including hearts from adult mice heterozygous for a mutation associated with Brugada syndrome (Scn5a1798insD/+). The embryonic RVOT was characterized by expression of Tbx2, a repressor of differentiation, and absence of expression of both Hey2, a ventricular transcription factor, and Gja1, encoding the principal gap-junction subunit for ventricular fast conduction. Also, conduction velocity was lower in the RVOT than in the right ventricular free wall. Later in the development, Gja1 and Scn5a expression remained lower in the subepicardial myocardium of the RVOT than in RV myocardium. Nevertheless, conduction velocity in the adult RVOT was similar to that of the right ventricular free wall. However, in hearts of Scn5a1798insD/+ mice and in normal hearts treated with ajmaline, conduction was slower in the RVOT than in the right ventricular wall. CONCLUSIONS: The slowly conducting embryonic phenotype is maintained in the fetal and adult RVOT and is unmasked when cardiac sodium channel function is reduced. PMID- 23661712 TI - Transcriptional regulation of endothelial cell and vascular development. AB - The establishment and maintenance of the vascular system is critical for embryonic development and postnatal life. Defects in endothelial cell development and vessel formation and function lead to embryonic lethality and are important in the pathogenesis of vascular diseases. Here, we review the underlying molecular mechanisms of endothelial cell differentiation, plasticity, and the development of the vasculature. This review focuses on the interplay among transcription factors and signaling molecules that specify the differentiation of vascular endothelial cells. We also discuss recent progress on reprogramming of somatic cells toward distinct endothelial cell lineages and its promise in regenerative vascular medicine. PMID- 23661718 TI - Endothelial Shc regulates arteriogenesis through dual control of arterial specification and inflammation via the notch and nuclear factor-kappa-light-chain enhancer of activated B-cell pathways. AB - RATIONALE: Arteriogenesis, the shear stress-driven remodeling of collateral arteries, is critical in restoring blood flow to ischemic tissue after a vascular occlusion. Our previous work has shown that the adaptor protein Shc mediates endothelial responses to shear stress in vitro. OBJECTIVE: To examine the role of the adaptor protein Shc in arteriogenesis and endothelial-dependent responses to shear stress in vivo. METHODS AND RESULTS: Conditional knockout mice in which Shc is deleted from endothelial cells were subjected to femoral artery ligation. Hindlimb perfusion recovery was attenuated in Shc conditional knockout mice compared with littermate controls. Reduced perfusion was associated with blunted collateral remodeling and reduced capillary density. Bone marrow transplantation experiments revealed that endothelial Shc is required for perfusion recovery because loss of Shc in bone marrow-derived hematopoietic cells had no effect on recovery. Mechanistically, Shc deficiency resulted in impaired activation of the nuclear factor kappa-light-chain-enhancer of activated B-cell-dependent inflammatory pathway and reduced CD45+ cell infiltration. Unexpectedly, Shc was required for arterial specification of the remodeling arteriole by mediating upregulation of the arterial endothelial cell marker ephrinB2 and activation of the Notch pathway. In vitro experiments confirmed that Shc was required for shear stress-induced activation of the Notch pathway and downstream arterial specification through a mechanism that involves upregulation of Notch ligands delta-like 1 and delta-like 4. CONCLUSIONS: Shc mediates activation of 2 key signaling pathways that are critical for inflammation and arterial specification; collectively, these pathways contribute to arteriogenesis and the recovery of blood perfusion. PMID- 23661719 TI - Tracking of cardiovascular risk factors across generations: family linkage within the population-based HUNT study, Norway. AB - BACKGROUND: Parent-offspring studies have shown that cardiovascular risk factors cluster within families. However, most studies have assessed the offspring cardiovascular risk factor level at a young age, and whether an association persists into the offspring's adult life is less clear. This study linked information between parents and their adult offspring to investigate the intergenerational association of anthropometric measures, blood pressure, blood lipid levels and physical activity. METHODS: The study population consisted of parent and adult offspring pairs (11,931 fathers-sons, 12,563 fathers-daughters, 15,626 mothers-sons and 16,449 mothers-daughters) who participated in the second and third cross-sectional waves of the Nord-Trondelag Health Study (HUNT 2, 1995 1997 and HUNT 3, 2006-2008). A general linear model and logistic regression were used to estimate the association between the parent and offspring risk factor levels. RESULTS: All continuously measured cardiovascular risk factors under study showed a statistically significant positive association between parents and offspring, except the waist-hip ratio. Adjusted coefficients from linear regression ranged from 0.09 (95% CI 0.07 to 0.11) for waist circumference to 0.29 (95% CI 0.27 to 0.32) for body weight. Moreover, offspring were two to three times more likely to be obese, have a high cholesterol level, or hypertension when comparing extreme categories of the corresponding parental risk factor level. Physically active parents had a lower risk of having physically inactive offspring. CONCLUSIONS: The results suggested that cardiovascular risk factors track across generations and persist into the offspring's adult life. PMID- 23661720 TI - Epidemiological evidence on association between ambient air pollution and stroke mortality. AB - BACKGROUND: Inconsistent results have been found on the association between air pollution and stroke mortality. Additionally, evidence on people who are potentially sensitive to air pollution-associated stroke mortality is limited. METHODS: Daily stroke mortality of adults aged over 65 between 2003 and 2008 in Shanghai, China were collected. The time-stratified case-crossover approach was used to assess the association between daily concentrations of air pollutants including particles with size <10 um, sulfur dioxide (SO2) and nitrogen dioxide (NO2) and stroke mortality. RESULTS: Both total-stroke and ischaemic-stroke mortalities were found to be significantly associated with all three air pollutants. Haemorrhagic stroke was significantly associated with SO2 and NO2 only. Substantial differences were observed for effect estimates of ischaemic stroke mortality in relation to NO2 among people with cardiac diseases compared with those without; for an increase of 10 MUg/m(3) in NO2, the increase in ischaemic-stroke mortality was 7.05% (95% CI 1.92% to 12.17%) for people with comorbid cardiac diseases versus 0.60% (95% CI -0.49% to 1.68%) for those without. We did not find evidence of effect modification by hypertension and diabetes. CONCLUSIONS: This study provides new evidence for the association between exposure to ambient air pollution and stroke mortality. Our results also suggest that underlying cardiac disorder may increase the risk for ischaemic stroke mortality in relation to air pollution exposure, especially NO2. . PMID- 23661721 TI - Pet ownership and cardiovascular risk: a scientific statement from the American Heart Association. PMID- 23661722 TI - Predictors of mortality and outcomes of therapy in low-flow severe aortic stenosis: a Placement of Aortic Transcatheter Valves (PARTNER) trial analysis. AB - BACKGROUND: The prognosis and treatment of patients with low-flow (LF) severe aortic stenosis are controversial. METHODS AND RESULTS: The Placement of Aortic Transcatheter Valves (PARTNER) trial randomized patients with severe aortic stenosis to medical management versus transcatheter aortic valve replacement (TAVR; inoperable cohort) and surgical aortic valve replacement versus TAVR (high risk cohort). Among 971 patients with evaluable echocardiograms (92%), LF (stroke volume index <=35 mL/m(2)) was observed in 530 (55%); LF and low ejection fraction (<50%) in 225 (23%); and LF, low ejection fraction, and low mean gradient (<40 mm Hg) in 147 (15%). Two-year mortality was significantly higher in patients with LF compared with those with normal stroke volume index (47% versus 34%; hazard ratio, 1.5; 95% confidence interval, 1.25-1.89; P=0.006). In the inoperable cohort, patients with LF had higher mortality than those with normal flow, but both groups improved with TAVR (46% versus 76% with LF and 38% versus 53% with normal flow; P<0.001). In the high-risk cohort, there was no difference between TAVR and surgical aortic valve replacement. In patients with paradoxical LF and low gradient (preserved ejection fraction), TAVR reduced 1-year mortality from 66% to 35% (hazard ratio, 0.38; P=0.02). LF was an independent predictor of mortality in all patient cohorts (hazard ratio, ~1.5), whereas ejection fraction and gradient were not. CONCLUSIONS: LF is common in severe aortic stenosis and independently predicts mortality. Survival is improved with TAVR compared with medical management and similar with TAVR and surgical aortic valve replacement. A measure of flow (stroke volume index) should be included in the evaluation and therapeutic decision making of patients with severe aortic stenosis. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrial.gov. Unique identifier: NCT0053089.4. PMID- 23661724 TI - On effective leadership. PMID- 23661723 TI - Quantifying options for reducing coronary heart disease mortality by 2020. AB - BACKGROUND: The American Heart Association (AHA) 2020 Strategic Impact Goal proposes a 20% improvement in cardiovascular health of all Americans. We aimed to estimate the potential reduction in coronary heart disease (CHD) deaths. METHODS AND RESULTS: We used data on 40 373 adults free of cardiovascular disease from the National Health and Nutrition Examination Survey (NHANES; 1988-2010). We quantified recent trends for 6 metrics (total cholesterol, systolic blood pressure, physical inactivity, smoking, diabetes mellitus, and obesity) and generated linear projections to 2020. We projected the expected number of CHD deaths in 2020 if 2006 age- and sex-specific CHD death rates remained constant, which would result in ~480 000 CHD deaths in 2020 (12% increase). We used the previously validated IMPACT CHD model to project numbers of CHD deaths in 2020 under 2 different scenarios: (1) Assuming a 20% improvement in each cardiovascular health metric, we project 365 000 CHD deaths in 2020 (range 327 000-403 000) a 24% decrease reflecting modest reductions in total cholesterol ( 41 000), systolic blood pressure (-36 000), physical inactivity (-12 000), smoking (-10 000), diabetes mellitus (-10 000), and obesity (-5000); (2) Assuming that recent risk factor trends continue to 2020, we project 335 000 CHD deaths (range 274 000-386 000), a 30% decrease reflecting improvements in total cholesterol, systolic blood pressure, smoking, and physical activity (~167 000 fewer deaths), offset by increases in diabetes mellitus and body mass index (~24 000 more deaths). CONCLUSIONS: Two contrasting scenarios of change in cardiovascular health metrics could prevent 24% to 30% of the CHD deaths expected in 2020, though with differing effects by age. Unfavorable continuing trends in obesity and diabetes mellitus would have substantial adverse effects. This analysis demonstrates the utility of modelling to inform health policy. PMID- 23661729 TI - AIDS research. More woes for struggling HIV vaccine field. PMID- 23661730 TI - NASA. Planetary scientists casting doubt on feasibility of plan to corral asteroid. PMID- 23661731 TI - U.S. science policy. Proposed change in awarding grants at NSF spurs partisan sniping. PMID- 23661732 TI - Newsmaker interview: Michael Yaffe. Boston bombing victims aided by biologist surgeon. Interview with Trisha Gura. PMID- 23661733 TI - Infectious diseases. Amid heightened concerns, new name for novel coronavirus emerges. PMID- 23661734 TI - Pesticides under fire for risks to pollinators. PMID- 23661735 TI - How big a role should neonicotinoids play in food security? PMID- 23661736 TI - Genetic disease. China heads off deadly blood disorder. PMID- 23661737 TI - Tohoku disaster. Insistence on gathering real data confirms low radiation exposures. PMID- 23661738 TI - No excuse for habitat destruction. PMID- 23661739 TI - Unpalatable politics. PMID- 23661740 TI - Don't cull wild birds yet. PMID- 23661742 TI - Comment on "Evidence of abundant purifying selection in humans for recently acquired regulatory functions". AB - Ward and Kellis (Reports, 28 September 2012, p. 1675; published online 5 September 2012) found altered patterns of human polymorphism in biochemically active but non-mammalian-conserved genomic regions relative to control regions and interpreted this as due to lineage-specific purifying selection. We find on closer inspection of their data that the polymorphism trends are primarily attributable to mutational variation and technical artifacts rather than selection. PMID- 23661744 TI - Research priorities. The NIH BRAIN Initiative. PMID- 23661743 TI - Response to comment on "Evidence of abundant purifying selection in humans for recently acquired regulatory functions". AB - Green and Ewing propose corrections to our methodology, which we incorporate and extend here. The improved methodology supports our initial conclusion of extensive lineage-specific constraint concentrated in ENCODE elements. We clarify that our estimate is dependent on the constrained and neutral references used, which can further increase the number of nucleotides involved, because a particularly stringent definition was initially used. PMID- 23661745 TI - Genetics. Simple genetics for a complex disease. PMID- 23661746 TI - Paleontology. Feathers before flight. PMID- 23661748 TI - Applied physics. A fresh start for foam physics. PMID- 23661747 TI - Immunology. Crowdsourcing immunity. PMID- 23661749 TI - Physics. Controlling atomic line shapes. PMID- 23661750 TI - Neuroscience. Why adults need new brain cells. PMID- 23661751 TI - Bacterial subversion of host innate immune pathways. AB - The pathogenesis of infection is a continuously evolving battle between the human host and the infecting microbe. The past decade has brought a burst of insights into the molecular mechanisms of innate immune responses to bacterial pathogens. In parallel, multiple specific mechanisms by which microorganisms subvert these host responses have been uncovered. This Review highlights recently characterized mechanisms by which bacterial pathogens avoid killing by innate host responses, including autophagy pathways and a proinflammatory cytokine transcriptional response, and by the manipulation of vesicular trafficking to avoid the toxicity of lysosomal enzymes. PMID- 23661753 TI - Morals and markets. AB - The possibility that market interaction may erode moral values is a long standing, but controversial, hypothesis in the social sciences, ethics, and philosophy. To date, empirical evidence on decay of moral values through market interaction has been scarce. We present controlled experimental evidence on how market interaction changes how human subjects value harm and damage done to third parties. In the experiment, subjects decide between either saving the life of a mouse or receiving money. We compare individual decisions to those made in a bilateral and a multilateral market. In both markets, the willingness to kill the mouse is substantially higher than in individual decisions. Furthermore, in the multilateral market, prices for life deteriorate tremendously. In contrast, for morally neutral consumption choices, differences between institutions are small. PMID- 23661752 TI - Cellular self-defense: how cell-autonomous immunity protects against pathogens. AB - Our prevailing view of vertebrate host defense is strongly shaped by the notion of a specialized set of immune cells as sole guardians of antimicrobial resistance. Yet this view greatly underestimates a capacity for most cell lineages-the majority of which fall outside the traditional province of the immune system-to defend themselves against infection. This ancient and ubiquitous form of host protection is termed cell-autonomous immunity and operates across all three domains of life. Here, we discuss the organizing principles that govern cellular self-defense and how intracellular compartmentalization has shaped its activities to provide effective protection against a wide variety of microbial pathogens. PMID- 23661754 TI - Lorentz meets Fano in spectral line shapes: a universal phase and its laser control. AB - Symmetric Lorentzian and asymmetric Fano line shapes are fundamental spectroscopic signatures that quantify the structural and dynamical properties of nuclei, atoms, molecules, and solids. This study introduces a universal temporal phase formalism, mapping the Fano asymmetry parameter q to a phase phi of the time-dependent dipole response function. The formalism is confirmed experimentally by laser-transforming Fano absorption lines of autoionizing helium into Lorentzian lines after attosecond-pulsed excitation. We also demonstrate the inverse, the transformation of a naturally Lorentzian line into a Fano profile. A further application of this formalism uses quantum-phase control to amplify extreme-ultraviolet light resonantly interacting with He atoms. The quantum phase of excited states and its response to interactions can thus be extracted from line-shape analysis, with applications in many branches of spectroscopy. PMID- 23661755 TI - Multiscale modeling of membrane rearrangement, drainage, and rupture in evolving foams. AB - Modeling the physics of foams and foamlike materials, such as soapy froths, fire retardants, and lightweight crash-absorbent structures, presents challenges, because of the vastly different time and space scales involved. By separating and coupling these disparate scales, we have designed a multiscale framework to model dry foam dynamics. This leads to a predictive and flexible computational methodology linking, with a few simplifying assumptions, foam drainage, rupture, and topological rearrangement, to coupled interface-fluid motion under surface tension, gravity, and incompressible fluid dynamics. Our computed results match theoretical analyses and experimentally observed physical effects, including thin film drainage and interference, and are used to study bubble rupture cascades and macroscopic rearrangement. The developed multiscale model allows quantitative computation of complex foam evolution phenomena. PMID- 23661756 TI - Spin-optical metamaterial route to spin-controlled photonics. AB - Spin optics provides a route to control light, whereby the photon helicity (spin angular momentum) degeneracy is removed due to a geometric gradient onto a metasurface. The alliance of spin optics and metamaterials offers the dispersion engineering of a structured matter in a polarization helicity-dependent manner. We show that polarization-controlled optical modes of metamaterials arise where the spatial inversion symmetry is violated. The emerged spin-split dispersion of spontaneous emission originates from the spin-orbit interaction of light, generating a selection rule based on symmetry restrictions in a spin-optical metamaterial. The inversion asymmetric metasurface is obtained via anisotropic optical antenna patterns. This type of metamaterial provides a route for spin controlled nanophotonic applications based on the design of the metasurface symmetry properties. PMID- 23661757 TI - Enhanced role of transition metal ion catalysis during in-cloud oxidation of SO2. AB - Global sulfate production plays a key role in aerosol radiative forcing; more than half of this production occurs in clouds. We found that sulfur dioxide oxidation catalyzed by natural transition metal ions is the dominant in-cloud oxidation pathway. The pathway was observed to occur primarily on coarse mineral dust, so the sulfate produced will have a short lifetime and little direct or indirect climatic effect. Taking this into account will lead to large changes in estimates of the magnitude and spatial distribution of aerosol forcing. Therefore, this oxidation pathway-which is currently included in only one of the 12 major global climate models-will have a significant impact on assessments of current and future climate. PMID- 23661758 TI - Networks of bZIP protein-protein interactions diversified over a billion years of evolution. AB - Differences in biomolecular sequence and function underlie dramatic ranges of appearance and behavior among species. We studied the basic region-leucine zipper (bZIP) transcription factors and quantified bZIP dimerization networks for five metazoan and two single-cell species, measuring interactions in vitro for 2891 protein pairs. Metazoans have a higher proportion of heteromeric bZIP interactions and more network complexity than the single-cell species. The metazoan bZIP interactomes have broadly similar structures, but there has been extensive rewiring of connections compared to the last common ancestor, and each species network is highly distinct. Many metazoan bZIP orthologs and paralogs have strikingly different interaction specificities, and some differences arise from minor sequence changes. Our data show that a shifting landscape of biochemical functions related to signaling and gene expression contributes to species diversity. PMID- 23661759 TI - Robust circadian oscillations in growing cyanobacteria require transcriptional feedback. AB - The remarkably stable circadian oscillations of single cyanobacteria enable a population of growing cells to maintain synchrony for weeks. The cyanobacterial pacemaker is a posttranslational regulation (PTR) circuit that generates circadian oscillations in the phosphorylation state of the clock protein KaiC. Layered on top of the PTR is transcriptional-translational feedback regulation (TTR), common to all circadian systems, consisting of a negative feedback loop in which KaiC regulates its own production. We found that the PTR circuit is sufficient to generate oscillations in growing cyanobacteria. However, in the absence of TTR, individual oscillators were less stable and synchrony was not maintained in a population of cells. Experimentally constrained mathematical modeling reproduced sustained oscillations in the PTR circuit alone and demonstrated the importance of TTR for oscillator synchrony. PMID- 23661760 TI - Wolbachia invades Anopheles stephensi populations and induces refractoriness to Plasmodium infection. AB - Wolbachia is a maternally transmitted symbiotic bacterium of insects that has been proposed as a potential agent for the control of insect-transmitted diseases. One of the major limitations preventing the development of Wolbachia for malaria control has been the inability to establish inherited infections of Wolbachia in anopheline mosquitoes. Here, we report the establishment of a stable Wolbachia infection in an important malaria vector, Anopheles stephensi. In A. stephensi, Wolbachia strain wAlbB displays both perfect maternal transmission and the ability to induce high levels of cytoplasmic incompatibility. Seeding of naturally uninfected A. stephensi populations with infected females repeatedly resulted in Wolbachia invasion of laboratory mosquito populations. Furthermore, wAlbB conferred resistance in the mosquito to the human malaria parasite Plasmodium falciparum. PMID- 23661761 TI - Delineating antibody recognition in polyclonal sera from patterns of HIV-1 isolate neutralization. AB - Serum characterization and antibody isolation are transforming our understanding of the humoral immune response to viral infection. Here, we show that epitope specificities of HIV-1-neutralizing antibodies in serum can be elucidated from the serum pattern of neutralization against a diverse panel of HIV-1 isolates. We determined "neutralization fingerprints" for 30 neutralizing antibodies on a panel of 34 diverse HIV-1 strains and showed that similarity in neutralization fingerprint correlated with similarity in epitope. We used these fingerprints to delineate specificities of polyclonal sera from 24 HIV-1-infected donors and a chimeric siman-human immunodeficiency virus-infected macaque. Delineated specificities matched published specificities and were further confirmed by antibody isolation for two sera. Patterns of virus-isolate neutralization can thus afford a detailed epitope-specific understanding of neutralizing-antibody responses to viral infection. PMID- 23661762 TI - Emergence of individuality in genetically identical mice. AB - Brain plasticity as a neurobiological reflection of individuality is difficult to capture in animal models. Inspired by behavioral-genetic investigations of human monozygotic twins reared together, we obtained dense longitudinal activity data on 40 inbred mice living in one large enriched environment. The exploratory activity of the mice diverged over time, resulting in increasing individual differences with advancing age. Individual differences in cumulative roaming entropy, indicating the active coverage of territory, correlated positively with individual differences in adult hippocampal neurogenesis. Our results show that factors unfolding or emerging during development contribute to individual differences in structural brain plasticity and behavior. The paradigm introduced here serves as an animal model for identifying mechanisms of plasticity underlying nonshared environmental contributions to individual differences in behavior. PMID- 23661763 TI - Compartmentalization of GABAergic inhibition by dendritic spines. AB - gamma-aminobutyric acid-mediated (GABAergic) inhibition plays a critical role in shaping neuronal activity in the neocortex. Numerous experimental investigations have examined perisomatic inhibitory synapses, which control action potential output from pyramidal neurons. However, most inhibitory synapses in the neocortex are formed onto pyramidal cell dendrites, where theoretical studies suggest they may focally regulate cellular activity. The precision of GABAergic control over dendritic electrical and biochemical signaling is unknown. By using cell type specific optical stimulation in combination with two-photon calcium (Ca(2+)) imaging, we show that somatostatin-expressing interneurons exert compartmentalized control over postsynaptic Ca(2+) signals within individual dendritic spines. This highly focal inhibitory action is mediated by a subset of GABAergic synapses that directly target spine heads. GABAergic inhibition thus participates in localized control of dendritic electrical and biochemical signaling. PMID- 23661764 TI - Day-to-day associations between subjective sleep and affect in regard to future depression in a female population-based sample. AB - BACKGROUND: Poor sleep is a risk factor for depression, but little is known about the underlying mechanisms. AIMS: Disentangling potential mechanisms by which sleep may be related to depression by zooming down to the 'micro-level' of within person daily life patterns of subjective sleep and affect using the experience sampling method (ESM). METHOD: A population-based twin sample consisting of 553 women underwent a 5-day baseline ESM protocol assessing subjective sleep and affect together with four follow-up assessments of depression. RESULTS: Sleep was associated with affect during the next day, especially positive affect. Daytime negative affect was not associated with subsequent night-time sleep. Baseline sleep predicted depressive symptoms across the follow-up period. CONCLUSIONS: The subtle, repetitive impact of sleep on affect on a daily basis, rather than the subtle repetitive impact of affect on sleep, may be one of the factors on the pathway to depression in women. PMID- 23661765 TI - Adult attention-deficit hyperactivity disorder and obesity: epidemiological study. AB - BACKGROUND: A significant association between attention-deficit hyperactivity disorder (ADHD) and obesity has been reported. This study addresses unexplored aspects of this relationship. AIMS: To evaluate the association between adult obesity and: (a) persistent, remitted or lifetime ADHD; (b) number of childhood ADHD symptoms, controlling for socioeconomic status and mood, anxiety and substance use disorders. METHOD: Face-to-face psychiatric interviews in 34 653 US adults from the National Epidemiologic Study on Alcohol and Related Conditions. Obesity was defined as a body mass index >=30. RESULTS: Persistent, lifetime or remitted ADHD were not associated with obesity after controlling for confounders. The number of childhood ADHD symptoms was significantly associated with adult obesity, even after adjustment, in women. CONCLUSIONS: Childhood ADHD symptoms are associated with obesity in women even after comorbid psychiatric disorders are accounted for. This provides a rationale for longitudinal studies assessing the impact of the treatment of childhood ADHD symptoms on obesity in women. PMID- 23661766 TI - Changes in capacity to consent over time in patients involved in psychiatric research. AB - BACKGROUND: Informed consent is a key element of ethical clinical research. Patients with serious mental illness may be at risk for impaired consent capacity. Corrective feedback improves within-session comprehension of consent relevant information, but little is known about the trajectory of patients' comprehension after the initial enrolment session. AIMS: To examine whether within-session gains in understanding after feedback were maintained between study visits and to examine stability of decisional capacity over time. METHOD: This was a longitudinal, within-participants comparison of decisional capacity assessed at baseline, 1 week, 3 months, 12 months and 24 months in 161 people with schizophrenia or bipolar disorder. RESULTS: Within-session gains from corrective feedback generally dissipated over each follow-up interval. Decisional capacity showed a general pattern of stability, but there was significant between participant heterogeneity. Better neuropsychological performance was associated with better decisional capacity across time points. Positive symptoms of schizophrenia did not predict any aspects of decisional capacity, but general psychopathology, negative symptoms and depression evidenced some modest associations with certain subdomains of decisional capacity. CONCLUSIONS: Informed consent may be most effectively construed as an ongoing dialogue with participants at each study visit. PMID- 23661767 TI - The structure of paranoia in the general population. AB - BACKGROUND: Psychotic phenomena appear to form a continuum with normal experience and beliefs, and may build on common emotional interpersonal concerns. AIMS: We tested predictions that paranoid ideation is exponentially distributed and hierarchically arranged in the general population, and that persecutory ideas build on more common cognitions of mistrust, interpersonal sensitivity and ideas of reference. METHOD: Items were chosen from the Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II) questionnaire and the Psychosis Screening Questionnaire in the second British National Survey of Psychiatric Morbidity (n = 8580), to test a putative hierarchy of paranoid development using confirmatory factor analysis, latent class analysis and factor mixture modelling analysis. RESULTS: Different types of paranoid ideation ranged in frequency from less than 2% to nearly 30%. Total scores on these items followed an almost perfect exponential distribution (r = 0.99). Our four a priori first-order factors were corroborated (interpersonal sensitivity; mistrust; ideas of reference; ideas of persecution). These mapped onto four classes of individual respondents: a rare, severe, persecutory class with high endorsement of all item factors, including persecutory ideation; a quasi-normal class with infrequent endorsement of interpersonal sensitivity, mistrust and ideas of reference, and no ideas of persecution; and two intermediate classes, characterised respectively by relatively high endorsement of items relating to mistrust and to ideas of reference. CONCLUSIONS: The paranoia continuum has implications for the aetiology, mechanisms and treatment of psychotic disorders, while confirming the lack of a clear distinction from normal experiences and processes. PMID- 23661768 TI - Evaluating the impact of a quality of life assessment with feedback to clinicians in patients with schizophrenia: randomised controlled trial. AB - BACKGROUND: Quality of life (QoL) measurements are increasingly considered to be an important evaluation of the treatment and care provided to patients with schizophrenia. However, there is little evidence that assessing QoL improves patient outcomes in clinical practice. AIMS: To investigate the impact of a QoL assessment with feedback for clinicians regarding satisfaction and other health outcomes in patients with schizophrenia. METHOD: We conducted a 6-month, prospective, randomised and controlled open-label study. Patients with schizophrenia were assigned to one of three groups: standard psychiatric assessment; QoL assessment with standard psychiatric assessment; and QoL feedback with standard psychiatric assessment. The primary outcome was patient satisfaction at 6 months. The local ethics committee (Comite de Protection des Personnes Sud-Mediterraneee V, France, trial number 07 067) and the French drug and device regulation agency (Agence Francaise de Securite Sanitaire des Produits de Sante, France, trial number A01033-50) approved this study. RESULTS: We randomly assigned 124 patients into groups. Quality of life feedback significantly affected patient satisfaction. Global satisfaction was significantly higher in the QoL feedback group (72.5% of patients had a high level of satisfaction) compared with the standard psychiatric assessment (67.5%) and QoL assessment groups (45.2%). Despite trends towards decreased severity for all clinical outcomes and increased changes to medication in the QoL feedback group at 6-month follow-up, these effects were not significant. CONCLUSIONS: Quality of life feedback positively influences patient satisfaction, which confirms the relevance of measuring QoL in clinical practice. The absence of a significant effect of QoL feedback on clinical outcomes also suggests that clinicians did not use these data optimally. Our findings suggest a nocebo effect of QoL assessment without feedback that should be considered by researchers and clinicians. PMID- 23661769 TI - Therapeutic values clarification and values development for end-of-life patients: a conceptual model. AB - The social, emotional, cognitive, and spiritual challenges that may be a major concern for a certain category of end-of-life patients are the focus of a conceptual counseling model. The intervention that was developed as a result of several years of practice is referred to as therapeutic values clarification and values development. This article outlines 4 phases of this intervention. This therapeutic process is illustrated by a case vignette with explanation of the key concepts. This model is suggested for use with end-of-life patients that are self aware, emotionally and cognitively competent, and have adequate verbal skills. It may be useful as an optional tool for hospice workers, social workers, and clergy who render services to terminally ill patients and their families. PMID- 23661770 TI - Factors affecting the place of death among hospice home care cancer patients in Taiwan. AB - BACKGROUND: Some patients who receive hospice home care still end up dying in hospital. The significance of the variables possibly affecting the place of death in patients with terminal cancer who received hospice home care was examined. METHODS: Retrospective study. RESULTS: Four hundred and thirty-nine patients were enrolled in this study. In all, 60.8% of the patients died at home and 39.2% of the patients died in hospital. Multiple logistic regression analysis revealed that preferred place of death was the prior factor associated with home death, followed by average days of rehospitalization, education level, distance between home and hospital, and age. CONCLUSIONS: For a better hospice care service, it is essential to inquire patients or their relatives on preferred place of death while concerning the influences of other factors. PMID- 23661771 TI - LDL oxidation and its association with carotid artery intima-media thickness and other cardiovascular risk factors in a sample of Spanish general population. AB - We studied the association between oxidized low-density lipoproteins (OxLDLs) and early atherosclerosis, assessed by carotid artery intima-media thickness (cIMT), as well as with other known atherosclerosis risk factors in a sample of the general middle- and old-age population of Burgos (Spain). Circulating OxLDL showed a significant and independent association with the average cIMT of both carotid arteries but not with the absence or presence of >=1 carotid atheroma plaques. Plasma OxLDL concentrations were associated with age, smoking, low density lipoprotein-cholesterol, and triglycerides, independently of other variables. Our findings in an asymptomatic sample representative of the Spanish middle- and old-age population underscore the role of OxLDL in early atherosclerosis represented by the cIMT especially in older asymptomatic individuals, but this cannot be extended to more advanced atherosclerosis, represented by carotid plaques. PMID- 23661772 TI - Heart rate and estimated energy expenditure of flapping and gliding in black browed albatrosses. AB - Albatrosses are known to expend only a small amount of energy during flight. The low energy cost of albatross flight has been attributed to energy-efficient gliding (soaring) with sporadic flapping, although little is known about how much time and energy albatrosses expend in flapping versus gliding during cruising flight. Here, we examined the heart rates (used as an instantaneous index of energy expenditure) and flapping activities of free-ranging black-browed albatrosses (Thalassarche melanophrys) to estimate the energy cost of flapping as well as time spent in flapping activities. The heart rate of albatrosses during flight (144 beats min(-1)) was similar to that while sitting on the water (150 beats min(-1)). In contrast, heart rate was much higher during takeoff and landing (ca. 200 beats min(-1)). Heart rate during cruising flight was linearly correlated with the number of wing flaps per minute, suggesting an extra energy burden of flapping. Albatrosses spend only 4.6+/-1.4% of their time flapping during cruising flight, which was significantly lower than during and shortly after takeoff (9.8+/-3.5%). Flapping activity, which amounted to just 4.6% of the time in flight, accounted for 13.3% of the total energy expenditure during cruising flight. These results support the idea that albatrosses achieve energy efficient flight by reducing the time spent in flapping activity, which is associated with high energy expenditure. PMID- 23661773 TI - Ontogenetic development of magnetic compass orientation in domestic chickens (Gallus gallus). AB - Domestic chickens (Gallus gallus) can be trained to search for a social stimulus in a specific magnetic direction, and cryptochrome 1a, found in the retina, has been proposed as a receptor molecule mediating magnetic directions. The present study combines immuno-histochemical and behavioural data to analyse the ontogenetic development of this ability. Newly hatched chicks already have a small amount of cryptochrome 1a in their violet cones; on day 5, the amount of cryptochrome 1a reached the same level as in adult chickens, suggesting that the physical basis for magnetoreception is present. In behavioural tests, however, young chicks 5 to 7 days old failed to show a preference of the training direction; on days 8, 9 and 12, they could be successfully trained to search along a specific magnetic axis. Trained and tested again 1 week later, the chicks that had not shown a directional preference on days 5 to 7 continued to search randomly, while the chicks tested from day 8 onward preferred the correct magnetic axis when tested 1 week later. The observation that the magnetic compass is not functional before day 8 suggests that certain maturation processes in the magnetosensitive system in the brain are not yet complete before that day. The reasons why chicks that have been trained before that day fail to learn the task later remain unclear. PMID- 23661774 TI - Intra- and inter-individual variation in flight direction in a migratory butterfly co-vary with individual mobility. AB - Flight direction is a major component of an animal's migratory success. However, few studies have focused on variation in flight direction both between and within individuals, which is likely to be correlated with other traits implied in migration processes. We report patterns of intra- and inter-individual variation in flight direction in the large white butterfly Pieris brassicae. The presence of inter-individual variation in flight direction for individuals tested in the same conditions suggests that this trait is inherited in P. brassicae and we propose that a rapid loss of migratory skills may exist in the absence of selection for migration. The magnitude of intra-individual variation was negatively correlated to two surrogates of the potential for migration: mobility and wing length. Highly mobile and longed-winged individuals within the same family were found to fly in similar directions, whereas less mobile and short winged individuals displayed divergent flight direction compared with the average direction of their kin. There was also a negative correlation between the variance to the mean flight direction of a family and its average mobility, but no correlation with wing length. We discuss these issues in terms of the evolution of traits potentially implied in both migration and dispersal in P. brassicae. PMID- 23661775 TI - Aluminum exposure impacts brain plasticity and behavior in Atlantic salmon (Salmo salar). AB - Aluminum (Al) toxicity occurs frequently in natural aquatic ecosystems as a result of acid deposition and natural weathering processes. Detrimental effects of Al toxicity on aquatic organisms are well known and can have consequences for survival. Fish exposed to Al in low pH waters will experience physiological and neuroendocrine changes that disrupt homeostasis and alter behavior. To investigate the effects of Al exposure on both the brain and behavior, Atlantic salmon (Salmo salar) kept in water treated with Al (pH 5.7, 0.37+/-0.04 MUmol 1( 1) Al) for 2 weeks were compared with fish kept in under control conditions (pH 6.7, <0.04 MUmol 1(-1) Al). Fish exposed to Al and acidic conditions had increased Al accumulation in the gills and decreased gill Na(+), K(+)-ATPase activity, which impaired osmoregulatory capacity and caused physiological stress, indicated by elevated plasma cortisol and glucose levels. Here we show for the first time that exposure to Al in acidic conditions also impaired learning performance in a maze task. Al toxicity also reduced the expression of NeuroD1 transcript levels in the forebrain of exposed fish. As in mammals, these data show that exposure to chronic stress, such as acidified Al, can reduce neural plasticity during behavioral challenges in salmon, and may impair the ability to cope with new environments. PMID- 23661776 TI - The effects of caudal fin loss and regeneration on the swimming performance of three cyprinid fish species with different swimming capacities. AB - In nature, the caudal fins of fish species are frequently lost to some extent by aggressive behaviour, predation and diseases. To test whether the swimming performance of fish with different swimming capacities would be differentially affected due to caudal fin loss and regeneration, we investigated the critical swimming speed (Ucrit), swimming metabolic rate (M(O2)), tail beat frequency (f(TB)) and tail beat amplitude (A(TB)) after caudal fin loss and regeneration (20 days) in juveniles of three cyprinid fish species: the qingbo (Spinibarbus sinensis; strong swimmer), the common carp (Cyprinus carpio; intermediate swimmer) and the goldfish (Carassius auratus; poor swimmer). The Ucrit values of the caudal-fin-lost qingbo, common carp and goldfish were 49, 32 and 35% significantly lower than those of the control groups, respectively. The maximum tail beat amplitude (A(TBmax)) (all three fishes), the maximum tail beat frequency (f(TBmax)) (only the common carp and the goldfish) and/or the active metabolic rate (M(O2active)) (only the common carp) of the caudal-fin-lost fish were significantly higher than those of the control groups. After 20 days of recovery, the caudal fins recovered to 41, 47 and 24% of those of the control groups for the qingbo, the common carp and the goldfish, respectively. However, the Ucrit values of the fin-regenerated qingbo, common carp and goldfish recovered to 86, 91 and 95% of those of the control group, respectively. The caudal-fin-regenerated qingbo and common carp showed a significantly higher A(TBmax) and f(TBmax), respectively, compared with those of the control groups. The qingbo had a higher f(TBmax) but a lower A(TBmax) than the common carp and the goldfish, which suggested that a strong swimmer may maintain swimming speed primarily by maintaining a greater f(TBmax), for which the caudal fin plays a more important role during swimming, than a poor swimmer. The M(O2active) of fish (common carp) with a redundant respiratory capacity could increase due to caudal fin loss to meet the increase in energy expenditure required by an increase in f(TBmax). In addition, the sustained swimming performance may not be the only selective pressure acting on caudal fin size in these three species, and the present caudal fin size may be a trade-off between sustain swimming performance and other factors (e.g. sexual selection, escape responses). PMID- 23661777 TI - Heart rate responses to temperature in free-swimming Pacific bluefin tuna (Thunnus orientalis). AB - The bluefin tuna heart remains at ambient water temperature (Ta) but must supply blood to warm regions of the body served by countercurrent vascular heat exchangers. Despite this unusual physiology, inherent difficulties have precluded an understanding of the cardiovascular responses to Ta in free-swimming bluefin tunas. We measured the heart rate (f(H)) responses of two captive Pacific bluefin tunas (Thunnus orientalis; 9.7 and 13.3 kg) over a cumulative period of 40 days. Routine f(H) during fasting in the holding tank at a Ta of 20 degrees C was 45.1+/-8.0 and 40.7+/-6.5 beats min(-1) for Tuna 1 and Tuna 2, respectively. f(H) decreased in each fish with a Q10 temperature coefficient of 2.6 (Tuna 1) and 3.1 (Tuna 2) as Ta in the tank was slowly decreased to 15 degrees C (~0.4 degrees C h(-1)), despite a gradual increase in swimming speed. The same thermal challenge during digestion revealed similar thermal dependence of f(H) and indicated that the rate of visceral cooling is not buffered by the heat increment of feeding. Acutely decreasing Ta from 20 to 10 degrees C while Tuna 1 swam in a tunnel respirometer caused a progressive increase in tail-beat frequency and oxygen consumption rate (M(O2)). f(H) of this fish decreased with a Q10 of 2.7 as Ta decreased between 20 and 15 degrees C, while further cooling to 10 degrees C saw a general plateau in f(H) around 35 beats min(-1) with a Q10 of 1.3. A discussion of the relationships between f(H), and haemoglobin-oxygen binding sheds further light on how bluefin cardiorespiratory systems function in a changing thermal environment. PMID- 23661778 TI - Selective prey avoidance learning in the predatory sea slug Pleurobranchaea californica. AB - Predator-prey interactions involving aposematic signaling, where predators learn the warning cues of well-defended prey, are clear examples of cost-benefit decisions in foraging animals. However, knowledge of the selectivity of predator learning and the natural conditions where it occurs is lacking for those foragers simpler in brain and body plan. We pursued the question in the sea slug Pleurobranchaea californica, a generalist forager of marked simplicity of body form, nervous system and behavior. This predator exploits many different types of prey, some of which are costly to attack. When offered Flabellina iodinea, an aeolid nudibranch with a stinging defense, biting attack was followed by rapid rejection and aversive turns. The predatory sea slug rapidly learned avoidance. Notable exceptions were animals with extremely high or low feeding thresholds that either ignored F. iodinea or completely consumed it, respectively. Experienced slugs showed strong avoidance of F. iodinea for days after exposure. Aposematic odor learning was selective: avoidance was not linked to change in feeding thresholds, and trained animals readily attacked and consumed a related aeolid, Hermissenda crassicornis. For P. californica, aposematic learning is a cognitive adaptation in which sensation, motivation and memory are integrated to direct cost-benefit choice, and thereby lend flexibility to the generalist's foraging strategy. PMID- 23661779 TI - Oxidative stress, photodamage and the role of screening pigments in insect eyes. AB - Using red-eyed mutant triatomine bugs (Hemiptera: Reduvidae), we tested the hypothesis of an alternative function of insect screening pigments against oxidative stress. To test our hypothesis, we studied the morphological and physiological changes associated with the mutation. We found that wild-type eyes possess a great amount of brown and red screening pigment inside the primary and secondary pigment cells as well as in the retinular cells. Red-eyed mutants, however, have only scarce red granules inside the pigmentary cells. We then compared the visual sensitivity of red-eyed mutants and wild types by measuring the photonegative responses of insects reared in light:dark cycles [12 h:12 h light:dark (LD)] or constant darkness (DD). Finally, we analyzed both the impact of oxidative stress associated with blood ingestion and photodamage of UV light on the eye retina. We found that red-eyed mutants reared in DD conditions were the most sensitive to the light intensities tested. Retinae of LD-reared mutants were gradually damaged over the life cycle, while for DD-reared insects retinae were conserved intact. No retinal damage was observed in non-fed mutants exposed to UV light for 2 weeks, whereas insects fed on blood prior to UV exposure showed clear signs of retinal damage. Wild-type insects exposed to UV light showed a marked increase in the amount and density of screening pigments. PMID- 23661780 TI - Fertilisation is not a new beginning: sperm environment affects offspring developmental success. AB - For organisms with complex life histories, the direction and magnitude of phenotypic links among life-history stages can have important ecological and evolutionary effects. While the phenotypic links between mothers and offspring, as well as between larvae and adults, are well recognised, the links between sperm phenotype and offspring phenotype have been less well explored. Here, we used a split-clutch/split-ejaculate design to examine whether the environment that sperm experience affects the subsequent performance of larvae in the broadcast spawning marine invertebrate Galeolaria gemineoa. The environment that sperm experienced affected the developmental success of larvae sired by these sperm; larvae sired by sperm that experienced low salinities had poorer developmental success than larvae sired by sperm that experienced a normal salinity. When we explored the interactive effects of the sperm environment and the larval environment with an orthogonal design, we found an interaction; when sperm and larvae experienced the same environment, performance was generally higher than when the sperm and larval environments differed. These effects could be due to selection on specific sperm phenotypes, phenotypic modification of the sperm or both. Together, our results challenge the traditional notion that sperm are merely transporters of genetic material; instead, significant covariance between sperm and offspring phenotypes exists. Our study adds to a growing list that demonstrates that fertilisation does have a homogenising effect on the phenotype of the zygote, and that events before fertilisation during the gamete phase can carry through to affect performance in later life-history stages. PMID- 23661781 TI - Modulation of Rh glycoproteins, ammonia excretion and Na+ fluxes in three freshwater teleosts when exposed chronically to high environmental ammonia. AB - We investigated relationships among branchial unidirectional Na(+) fluxes, ammonia excretion, urea excretion, plasma ammonia, plasma cortisol, and gill transporter expression and function in three freshwater fish differing in their sensitivity to high environmental ammonia (HEA). The highly ammonia-sensitive salmonid Oncorhynchus mykiss (rainbow trout), the less ammonia-sensitive cyprinid Cyprinus carpio (common carp) and the highly ammonia-resistant cyprinid Carassius auratus (goldfish) were exposed chronically (12-168 h) to 1 mmol l(-1) ammonia (as NH4HCO3; pH 7.9). During HEA exposure, carp and goldfish elevated ammonia excretion (JAmm) and Na(+) influx rates ( ) while trout experienced higher plasma ammonia (TAmm) and were only able to restore control rates of JAmm and . All three species exhibited increases in Na(+) efflux rate ( ). At the molecular level, there was evidence for activation of a 'Na(+)/NH4(+) exchange metabolon' probably in response to elevated plasma cortisol and TAmm, though surprisingly, some compensatory responses preceded molecular responses in all three species. Expression of Rhbg, Rhcg (Rhcg-a and Rhcg-b), H(+)-ATPase (V-type, B-subunit) and Na(+)/K(+)-ATPase (NKA) mRNA was upregulated in goldfish, Rhcg-a and NKA in carp, and Rhcg2, NHE-2 (Na(+)/H(+) exchanger) and H(+)-ATPase in trout. Branchial H(+) ATPase activity was elevated in goldfish and trout, and NKA activity in goldfish and carp, but NKA did not appear to function preferentially as a Na(+)/NH4(+) ATPase in any species. Goldfish alone increased urea excretion rate during HEA, in concert with elevated urea transporter mRNA expression in gills. Overall, goldfish showed more effective compensatory responses towards HEA than carp, while trout were least effective. PMID- 23661782 TI - Idiosyncratic intermittent nocturnal priapism occurring after quetiapine dose reduction. PMID- 23661783 TI - Risk assessment for violence and self-harm in first episode psychosis and the need for early psychosis intervention services. PMID- 23661784 TI - The relationship between psychosocial functioning and resilience and negative symptoms in individuals at ultra-high risk for psychosis. AB - OBJECTIVE: Decline in psychosocial functioning seems to be a core feature in schizophrenia across various phases of the disorder. Little is known about the relationship between psychosocial functioning and protective factors or psychopathologies in individuals in the prodrome phase of psychosis. We aimed to investigate whether psychosocial functioning is impaired in individuals in the putative prodromal phase of schizophrenia, and, if so, to identify factors associated with compromised psychosocial functioning. METHOD: Sixty participants at ultra-high risk (UHR) for psychosis and 47 healthy controls were recruited. All subjects were assessed in terms of psychosocial functioning using the Quality of Life Scale. A clinical assessment of psychopathology and protective factors, including resilience and coping style, was also conducted. RESULTS: Psychosocial functioning in UHR participants was found to be compromised; this dysfunction was associated with negative symptoms, adaptive coping, and resilience. In addition, baseline resilience was lower among those in the UHR group who converted to frank psychosis than among those who did not. CONCLUSIONS: These findings imply that treatment strategies for individuals at UHR for psychosis should be comprehensive, promoting resilience as well as targeting the reduction of positive and negative symptoms to foster social reintegration and recovery. PMID- 23661786 TI - Brevity takes time. PMID- 23661785 TI - Ketamine as a new treatment for depression: a review of its efficacy and adverse effects. AB - OBJECTIVE: Narrative review of the literature on the efficacy and safety of subanaesthetic doses of ketamine for the treatment of depression. METHOD: Medline and PubMed databases were searched up to October 2012 using appropriate keywords. RESULTS: The studies consistently report substantial efficacy with high response and remission rates from 4 to 72 hours (averages 77% and 43%, respectively) from single doses, though not all patients respond to ketamine. Early relapse is common. While the usual procedure involves the administration of intravenous ketamine at a dose of 0.5 mg/kg over 40 minutes, some preliminary evidence suggests other dosing regimens and routes of administration may be useful or even better. Repeated doses and maintenance pharmacological treatments have been investigated in order to prolong the antidepressant effects, with only modest success. CONCLUSIONS: Current research on the antidepressant effects of ketamine has consistently shown rapid and substantial improvement in mood in the majority of patients. However, these effects have often been found to be short-lived. Future research should focus on identifying predictors of response (e.g. clinical, genetic, pharmacokinetic, environmental), examining different dosing regimens and routes of administration, and strategies to maintain the antidepressant response. PMID- 23661787 TI - Neurocognitive considerations in the treatment of attachment and complex trauma in children. AB - Accumulating evidence suggests that children suffering deprivation and maltreatment at critical times in their development often pay a cognitive toll. While children vary to the extent that neurocognitive domains are affected, those factors influence how children process, manage and understand traumatic and attachment experiences as well as how they respond to treatment. Current research on trauma and attachment favor some aspects of cognition over others. The literature discusses attention, memory, cognitive biases, internal working models, beliefs and attributions as ways that impact an individual's understanding of experience. Other categories such as working memory, processing speed, verbal, auditory or perceptual processing, metacognitive skills, and cognitive rigidity or flexibility rarely surface. This paper examines what is and is not known about the interface of cognition with attachment and complex trauma and how that knowledge can inform treatment. It explores existing research and offers a case vignette as an example of how that knowledge can be integrated into treatment strategies. PMID- 23661788 TI - Implementing an aim-based outcome measure in a psychoanalytic child psychotherapy service: insights, experiences and evidence. AB - In this paper, we describe the use of an aim-based outcome measure used in routine outcome monitoring of child and adolescent psychotherapy within a child and adolescent mental health service. We aim to explore the clinical feasibility and implications of the routine use of this measure. We argue that use of the measure provides a simple and useful way of clarifying the focus of the clinical work and reflecting its progress, while also having the potential to illuminate the clinical picture by contributing an additional source of clinical information from a collaborative process with the patient, parents or both. We argue that while there are some cases where use of the measure may be impossible, or even perverse, in general it enhances rather than detracts from clinical work. PMID- 23661789 TI - An adolescent female with chronic musculoskeletal pain. PMID- 23661791 TI - An 11-year-old male with a swollen lip. PMID- 23661790 TI - Incidence of serious bacterial infections in febrile children with sickle cell disease. AB - OBJECTIVE: To determine the incidence of serious bacterial infections in febrile children with sickle cell disease and to describe the outcomes of children discharged from the pediatric emergency department. METHODS: We conducted a retrospective chart review of 188 febrile patients with sickle cell disease presenting to our pediatric emergency department over a 10-year period. Serious bacterial infection was defined as bacteremia, meningitis, urinary tract infection, osteomyelitis, or pneumonia. RESULTS: Our overall incidence rate for serious bacterial infections was 16.0% (95% confidence interval [CI] = 10.8% to 21.2%). Pneumonia had the highest incidence rate of 13.8% (95% CI = 8.8% to 18.8%). This was followed by bacteremia and urinary tract infections, both with incidence rates of 1.1% (95% CI = 0.0% to 2.5%). We had no cases of meningitis or osteomyelitis in our study group. CONCLUSION: We had an incidence of 16.0% for serious bacterial infections in febrile children with sickle cell disease, with the majority of patients diagnosed with pneumonia. PMID- 23661792 TI - Vaccine poliovirus shedding and immune response to oral polio vaccine in HIV infected and -uninfected Zimbabwean infants. AB - BACKGROUND: With prolonged replication, attenuated polioviruses used in oral polio vaccine (OPV) can mutate into vaccine-derived poliovirus (VDPV) and cause poliomyelitis outbreaks. Individuals with primary humoral immunodeficiencies can become chronically infected with vaccine poliovirus, allowing it to mutate into immunodeficiency-associated VDPV (iVDPV). It is unclear if children perinatally infected with the human immunodeficiency virus (HIV), who have humoral as well as cellular immunodeficiencies, might be sources of iVDPV. METHODS: We conducted a prospective study collecting stool and blood samples at multiple time points from Zimbabwean infants receiving OPV according to the national schedule. Nucleic acid extracted from stool was analyzed by real-time polymerase chain reaction for OPV serotypes. RESULTS: We analyzed 825 stool samples: 285 samples from 92 HIV infected children and 540 from 251 HIV-uninfected children. Poliovirus shedding was similar after 0-2 OPV doses but significantly higher in the HIV-infected versus uninfected children after >= 3 OPV doses, particularly within 42 days of an OPV dose, independent of seroconversion status. HIV infection was not associated with prolonged or persistent poliovirus shedding. HIV infection was associated with significantly lower polio seroconversion rates. CONCLUSIONS: HIV infection is associated with decreased mucosal and humoral immune responses to OPV but not the prolonged viral shedding required to form iVDPV. PMID- 23661793 TI - Inhibiting the programmed death 1 pathway rescues Mycobacterium tuberculosis specific interferon gamma-producing T cells from apoptosis in patients with pulmonary tuberculosis. AB - BACKGROUND: Overexpression of programmed death 1 (PD-1) receptor is thought to inhibit the effector T-cell response in human tuberculosis. However, the precise mechanism of such inhibition remains unclear. The present study addresses the role of PD-1 in dampening host T-cell function among patients with pulmonary tuberculosis. METHODS: Expression of PD-1 and its ligands (PD-L1/L2) on T cells, B cells, and monocytes was evaluated by flow cytometry (FACS). In vitro stimulation of peripheral blood mononuclear cells in the presence of Mycobacterium tuberculosis antigens was performed with and without blocking PD-1, and intracellular cytokine production was measured by FACS. RESULTS: We showed higher frequencies of T cells, monocytes, and B cells expressing PD-1 and its ligand(s) among patients with pulmonary tuberculosis. Infections with live M. tuberculosis upregulated PD-L1 expression on monocytes. In vitro PD-1 blocking rescued M. tuberculosis-specific interferon gamma (IFN-gamma)-producing T cells from undergoing apoptosis. The number of PD-1-expressing T cells decreased significantly during therapy and inversely correlated with IFN-gamma-dominant T cell response against M. tuberculosis. CONCLUSIONS: Manipulation of PD-1 signaling may restore the host T-cell response and thus may have therapeutic potential. PD-1 also may serve as a biomarker to monitor host immunity among patients with tuberculosis during therapy and vaccine studies. PMID- 23661794 TI - Antiretrovirals during pregnancy: a note of caution. PMID- 23661795 TI - Reply to Shao et al. PMID- 23661796 TI - Programmed death 1 lives up to its reputation in active tuberculosis. PMID- 23661797 TI - Bacterial complications of respiratory tract viral illness: a comprehensive evaluation. AB - BACKGROUND: Respiratory tract infection is one of the most common reasons for hospitalization among adults, and recent evidence suggests that many of these illnesses are associated with viruses. Although bacterial infection is known to complicate viral infections, the frequency and impact of mixed viral-bacterial infections has not been well studied. METHODS: Adults hospitalized with respiratory illness during 3 winters underwent comprehensive viral and bacterial testing. This assessment was augmented by measuring the serum level of procalcitonin (PCT) as a marker of bacterial infection. Mixed viral-bacterial infection was defined as a positive viral test result plus a positive bacterial assay result or a serum PCT level of >= 0.25 ng/mL on admission or day 2 of hospitalization. RESULTS: Of 842 hospitalizations (771 patients) evaluated, 348 (41%) had evidence of viral infection. A total of 212 hospitalizations (61%) involved patients with viral infection alone. Of the remaining 136 hospitalizations (39%) involving viral infection, results of bacterial tests were positive in 64 (18%), and PCT analysis identified bacterial infection in an additional 72 (21%). Subjects hospitalized with mixed viral-bacterial infections were older and more commonly received a diagnosis of pneumonia. Over 90% of hospitalizations in both groups involved subjects who received antibiotics. Notably, 4 of 10 deaths among subjects hospitalized with viral infection alone were secondary to complications of Clostridium difficile colitis. CONCLUSIONS: Bacterial coinfection is associated with approximately 40% of viral respiratory tract infections requiring hospitalization. Patients with positive results of viral tests should be carefully evaluated for concomitant bacterial infection. Early empirical antibiotic therapy for patients with an unstable condition is appropriate but is not without risk. PMID- 23661798 TI - Candida albicans and Candida parapsilosis induce different T-cell responses in human peripheral blood mononuclear cells. AB - Candida parapsilosis is the third most frequent cause of candidemia. Despite its clinical importance, little is known about the human immunological response to C. parapsilosis. In this study, we compared the cytokine responses evoked by Candida albicans and C. parapsilosis. C. parapsilosis-stimulated human peripheral blood mononuclear cells (PBMCs) produced similar quantities of tumor necrosis factor alpha and interleukin 6 and slightly lower amounts of interleukin 1beta, compared with C. albicans-stimulated cells. PBMCs stimulated with C. parapsilosis displayed a skewed T-helper cell response, producing more interleukin 10 and less interferon gamma than cells stimulated with C. albicans. Notably, C. parapsilosis induced much less interleukin 17 and interleukin 22 production as compared to C. albicans. Inhibition of the 3 classical mitogen-activated protein kinases (p38 kinase, ERK, and JNK) revealed kinase-dependent differences in reductions in cytokine production by the 2 Candida species. Decreased cytokine production after inhibition of dectin 1 revealed that this receptor plays a major role in the recognition of both C. albicans and C. parapsilosis. These data improve understanding of the immune response triggered by C. parapsilosis, a first step for the future design of immunotherapeutic strategies for these infections. PMID- 23661799 TI - Toward understanding Chlamydia infection-induced infertility caused by dysfunctional oviducts. PMID- 23661800 TI - Virological and immunological characteristics of human cytomegalovirus infection associated with Alzheimer disease. AB - Serum, cerebrospinal fluid (CSF), and cryopreserved lymphocytes from subjects in the Rush Alzheimer's Disease Center Religious Orders Study were analyzed for associations between cytomegalovirus (CMV) infection and clinical and pathological markers of Alzheimer disease. CMV antibody levels were associated with neurofibrillary tangles (NFTs). CSF interferon gamma was only detected in seropositive subjects and was significantly associated with NFTs. The percentage of senescent T cells (CD4+ or CD8+CD28-CD57+) was significantly higher for CMV seropositive as compared to CMV-seronegative subjects and was marginally associated with the pathologic diagnosis of Alzheimer disease (CD4+) or amyloid beta (CD8+). Immunocytochemical analysis showed induction of amyloid-beta in human foreskin fibroblasts (HFFs) infected with each of 3 clinical CMV strains. In the same subjects, there was no association of herpes simplex virus type 1 (HSV-1) antibody levels with CMV antibody levels or clinical or pathological markers of Alzheimer disease. HSV-1 infection of HFFs did not induce amyloid beta. These data support an association between CMV and the development of Alzheimer disease. PMID- 23661801 TI - Loss of passively acquired maternal antibodies in highly vaccinated populations: an emerging need to define the ontogeny of infant immune responses. PMID- 23661802 TI - Waning of maternal antibodies against measles, mumps, rubella, and varicella in communities with contrasting vaccination coverage. AB - BACKGROUND: The combined measles, mumps, and rubella (MMR) vaccine has been successfully administered for >20 years. Because of this, protection by maternal antibodies in infants born to vaccinated mothers might be negatively affected. METHODS: A large cross-sectional serologic survey was conducted in the Netherlands during 2006-2007. We compared the kinetics of antibody concentrations in children and women of childbearing age in the highly vaccinated general population with those in orthodox Protestant communities that were exposed to outbreaks. RESULTS: The estimated duration of protection by maternal antibodies among infants in the general population, most of whom were born to vaccinated mothers, was short: 3.3 months for measles, 2.7 months for mumps, 3.9 months for rubella, and 3.4 months for varicella. The duration of protection against measles was 2 months longer for infants born in the orthodox communities, most of whom had unvaccinated mothers. For rubella, mothers in the orthodox communities had higher concentrations of antibodies as compared to the general population. CONCLUSION: Children of mothers vaccinated against measles and, possibly, rubella have lower concentrations of maternal antibodies and lose protection by maternal antibodies at an earlier age than children of mothers in communities that oppose vaccination. This increases the risk of disease transmission in highly vaccinated populations. PMID- 23661803 TI - FGF21 mediates the lipid metabolism response to amino acid starvation. AB - Lipogenic gene expression in liver is repressed in mice upon leucine deprivation. The hormone fibroblast growth factor 21 (FGF21), which is critical to the adaptive metabolic response to starvation, is also induced under amino acid deprivation. Upon leucine deprivation, we found that FGF21 is needed to repress expression of lipogenic genes in liver and white adipose tissue, and stimulate phosphorylation of hormone-sensitive lipase in white adipose tissue. The increased expression of Ucp1 in brown adipose tissue under these circumstances is also impaired in FGF21-deficient mice. Our results demonstrate the important role of FGF21 in the regulation of lipid metabolism during amino acid starvation. PMID- 23661804 TI - Comparative effectiveness research in cancer genomics and precision medicine: current landscape and future prospects. AB - A major promise of genomic research is information that can transform health care and public health through earlier diagnosis, more effective prevention and treatment of disease, and avoidance of drug side effects. Although there is interest in the early adoption of emerging genomic applications in cancer prevention and treatment, there are substantial evidence gaps that are further compounded by the difficulties of designing adequately powered studies to generate this evidence, thus limiting the uptake of these tools into clinical practice. Comparative effectiveness research (CER) is intended to generate evidence on the "real-world" effectiveness compared with existing standards of care so informed decisions can be made to improve health care. Capitalizing on funding opportunities from the American Recovery and Reinvestment Act of 2009, the National Cancer Institute funded seven research teams to conduct CER in genomic and precision medicine and sponsored a workshop on CER on May 30, 2012, in Bethesda, Maryland. This report highlights research findings from those research teams, challenges to conducting CER, the barriers to implementation in clinical practice, and research priorities and opportunities in CER in genomic and precision medicine. Workshop participants strongly emphasized the need for conducting CER for promising molecularly targeted therapies, developing and supporting an integrated clinical network for open-access resources, supporting bioinformatics and computer science research, providing training and education programs in CER, and conducting research in economic and decision modeling. PMID- 23661806 TI - Renal CD133(+)/CD73(+) progenitors produce erythropoietin under hypoxia and prolyl hydroxylase inhibition. AB - The identity of the peritubular population of cells with mesenchymal phenotype thought responsible for producing erythropoietin in humans remains unclear. Here, renal CD133(+)/CD73(+) progenitor cells, isolated from the human renal inner medulla and described as a population of mesenchymal progenitors, released erythropoietin under hypoxic conditions. CD133(-) cells did not synthesize erythropoietin, and CD133(+) progenitor cells stopped producing erythropoietin when they differentiated and acquired an epithelial phenotype. Inhibition of prolyl hydroxylases, using either dimethyloxalylglycine or a small hairpin RNA against prolyl hydroxylase-2, increased both hypoxia-inducible factor-2alpha (HIF 2alpha) expression and erythropoietin transcription. Moreover, under hypoxic conditions, inhibition of prolyl hydroxylase significantly increased erythropoietin release by CD133(+) progenitors. Finally, blockade of HIF-2alpha impaired erythropoietin synthesis by CD133(+) progenitors. Taken together, these results suggest that it is the renal CD133(+) progenitor cells that synthesize and release erythropoietin under hypoxia, via the prolyl hydroxylase-HIF-2alpha axis, in the human kidney. In addition, this study provides rationale for the therapeutic use of prolyl hydroxylase inhibitors in the setting of acute or chronic renal injury. PMID- 23661805 TI - Mutation of the Mg2+ transporter SLC41A1 results in a nephronophthisis-like phenotype. AB - Nephronophthisis (NPHP)-related ciliopathies are recessive, single-gene disorders that collectively make up the most common genetic cause of CKD in the first three decades of life. Mutations in 1 of the 15 known NPHP genes explain less than half of all cases with this phenotype, however, and the recently identified genetic causes are exceedingly rare. As a result, a strategy to identify single-gene causes of NPHP-related ciliopathies in single affected families is needed. Although whole-exome resequencing facilitates the identification of disease genes, the large number of detected genetic variants hampers its use. Here, we overcome this limitation by combining homozygosity mapping with whole-exome resequencing in a sibling pair with an NPHP-related ciliopathy. Whole-exome capture revealed a homozygous splice acceptor site mutation (c.698G>T) in the renal Mg(2+) transporter SLC41A1. This mutation resulted in skipping of exon 6 of SLC41A1, resulting in an in-frame deletion of a transmembrane helix. Transfection of cells with wild-type or mutant SLC41A1 revealed that deletion of exon 6 completely blocks the Mg(2+) transport function of SLC41A1. Furthermore, in normal human kidney tissue, endogenous SLC41A1 specifically localized to renal tubules situated at the corticomedullary boundary, consistent with the region of cystogenesis observed in NPHP and related ciliopathies. Last, morpholino-mediated knockdown of slc41a1 expression in zebrafish resulted in ventral body curvature, hydrocephalus, and cystic kidneys, similar to the effects of knocking down other NPHP genes. Taken together, these data suggest that defects in the maintenance of renal Mg(2+) homeostasis may lead to tubular defects that result in a phenotype similar to NPHP. PMID- 23661809 TI - Cultural Anchors and the Organization of Differences: A Multi-method Analysis of LGBT Marches on Washington. AB - Social scientists describe culture as either coherent or incoherent and political dissent as either unifying or divisive. This article moves beyond such dichotomies. Content, historical, and network analyses of public debates on how to organize four lesbian, gay, bisexual, and transgender (LGBT) Washington marches provide evidence for an integrative position. Rather than just describe consistencies or contradictions, we contend that the key analytic challenge is to explain the organization of differences. We propose one way of doing this using the mechanism of a cultural anchor. Within and across marches, a small collection of ideas remains fixed in the national conversation, yet in a way that allows activists to address their internal diversity and respond to unfolding historical events. These results suggest that activists do not simply organize around their similarities but, through cultural anchors, they use their commonalities to build a thinly coherent foundation that can also support their differences. Situated at the nexus of culture, social movements, sexualities, and networks, this article demonstrates how the anchoring mechanism works in the context of LGBT political organizing. PMID- 23661807 TI - Rheb/mTORC1 signaling promotes kidney fibroblast activation and fibrosis. AB - Ras homolog enriched in brain (Rheb) is a small GTPase that regulates cell growth, differentiation, and survival by upregulating mammalian target of rapamycin complex 1 (mTORC1) signaling. The role of Rheb/mTORC1 signaling in the activation of kidney fibroblasts and the development of kidney fibrosis remains largely unknown. In this study, we found that Rheb/mTORC1 signaling was activated in interstitial myofibroblasts from fibrotic kidneys. Treatment of rat kidney interstitial fibroblasts (NRK-49F cell line) with TGFbeta1 also activated Rheb/mTORC1 signaling. Blocking Rheb/mTORC1 signaling with rapamycin or Rheb small interfering RNA abolished TGFbeta1-induced fibroblast activation. In a transgenic mouse, ectopic expression of Rheb activated kidney fibroblasts. These Rheb transgenic mice exhibited increased activation of mTORC1 signaling in both kidney tubular and interstitial cells as well as progressive interstitial renal fibrosis; rapamycin inhibited these effects. Similarly, mice with fibroblast specific deletion of Tsc1, a negative regulator of Rheb, exhibited activated mTORC1 signaling in kidney interstitial fibroblasts and increased renal fibrosis, both of which rapamycin abolished. Taken together, these results suggest that Rheb/mTORC1 signaling promotes the activation of kidney fibroblasts and contributes to the development of interstitial fibrosis, possibly providing a therapeutic target for progressive renal disease. PMID- 23661810 TI - Ghana's burden of chronic non-communicable diseases: future directions in research, practice and policy. AB - The prevalence of major chronic non-communicable diseases and their risk factors has increased over time and contributes significantly to the Ghana's disease burden. Conditions like hypertension, stroke and diabetes affect young and old, urban and rural, and wealthy and poor communities. The high cost of care drives the poor further into poverty. Lay awareness and knowledge are limited, health systems (biomedical, ethnomedical and complementary) are weak, and there are no chronic disease policies. These factors contribute to increasing risk, morbidity and mortality. As a result chronic diseases constitute a public health and a developmental problem that should be of urgent concern not only for the Ministry of Health, but also for the Government of Ghana. New directions in research, practice and policy are urgently needed. They should be supported by active partnerships between researchers, policymakers, industry, patient groups, civil society, government and development partners. PMID- 23661808 TI - Scaffolding proteins DLG1 and CASK cooperate to maintain the nephron progenitor population during kidney development. AB - DLG1 (discs-large homolog 1) and CASK (calcium/calmodulin-dependent serine protein kinase) interact at membrane-cytoskeleton interfaces and function as scaffolding proteins that link signaling molecules, receptors, and other scaffolding proteins at intercellular and synaptic junctions. Dlg1-null mice exhibit hydronephrosis, hydroureter, and occasionally hypoplastic kidneys, whereas Cask-null mice do not. To investigate whether DLG1 and CASK cooperate in the developing urogenital system, we generated mice deficient in both DLG1 and CASK either 1) globally, 2) in metanephric mesenchyme, or 3) in nephron progenitors. With each approach, Dlg1;Cask double-knockout (DKO) kidneys were severely hypoplastic and dysplastic and demonstrated rapid, premature depletion of nephron progenitors/stem cells. Several cellular and molecular defects were observed in the DKO kidneys, including reduced proliferation and increased apoptosis of cells in the nephrogenic zone and a progressive decrease in the number of cells expressing SIX2, a transcription factor essential for maintaining nephron progenitors. Fgf8 expression was reduced in early-stage DKO metanephric mesenchyme, accompanied by reduced levels of components of the Ras pathway, which is activated by fibroblast growth factor (FGF) signaling. Moreover, Dlg1(+/ );Cask(-/-) (het/null) kidneys were moderately hypoplastic and demonstrated impaired aggregation of SIX2-positive cells around the ureteric bud tips. Nephron progenitor-specific het/null mice survived with small kidneys but developed glomerulocystic kidney disease and renal failure. Taken together, these results suggest that DLG1 and CASK play critical cooperative roles in maintaining the nephron progenitor population, potentially via a mechanism involving effects on FGF signaling. PMID- 23661811 TI - A review of population-based studies on hypertension in Ghana. AB - BACKGROUND: Hypertension is becoming a common health problem worldwide with increasing life expectancy and increasing prevalence of risk factors. Epidemiological data on hypertension in Ghana is necessary to guide policy and develop effective interventions. METHODS: A review of population-based studies on hypertension in Ghana was conducted by a search of the PUBMED database, supplemented by a manual search of bibliographies of the identified articles and through the Ghana Medical Journal. A single reviewer extracted data using standard data collection forms. RESULTS: Eleven studies published on hypertension with surveys conducted between 1973 and 2009 were identified. The prevalence of hypertension was higher in urban than rural areas in studies that covered both types of area and increased with increasing age (prevalence ranging from 19.3% in rural to 54.6% in urban areas). Factors associated with high blood pressure included increasing body mass index, increased salt consumption, family history of hypertension and excessive alcohol intake. The levels of hypertension detection, treatment and control were generally low (control rates ranged from 1.7% to 12.7%). CONCLUSION: An increased burden of hypertension should be expected in Ghana as life expectancy increases and with rapid urbanisation. Without adequate detection and control, this will translate into a higher incidence of stroke and other adverse health outcomes for which hypertension is an established risk factor. Prevention and control of hypertension in Ghana is thus imperative and any delays in instituting preventive measures would most likely pose a greater challenge on the already overburdened health system. PMID- 23661812 TI - Stroke in Ashanti region of Ghana. AB - OBJECTIVE: To determine the morbidity and mortality in adult in-patients with stroke admitted to the Komfo Anokye Teaching Hospital (KATH). METHODS: A retrospective study of in-patients with stroke admitted to the KATH, from January 2006 to december 2007 was undertaken. Data from admission and discharge registers were analysed to determine stroke morbidity and mortality. RESULTS: Stroke constituted 9.1% of total medical adult admissions and 13.2% of all medical adult deaths within the period under review. The mean age of stroke patients was 63.7 (95% ci=62.8, 64.57) years. Males were younger than females. The overall male to female ratio was 1:0.96, and the age-adjusted risk of death from stroke was slightly lower for females than males (relative risk= 0.88; 95% ci=0.79, 1.02, p=0.08). The stroke case fatality rate was 5.7% at 24 hours, 32.7% at 7 days, and 43.2% at 28 days. CONCLUSION: Stroke constitutes a significant cause of morbidity and mortality in Ghana. Major efforts are needed in the prevention and treatment of stroke. Population-based health education programs and appropriate public health policy need to be developed. This will require a multidisciplinary approach of key players with a strong political commitment. There is also a clear need for further studies on this topic including, for example, an assessment of care and quality of life after discharge from hospital. The outcomes of these studies will provide important information for the prevention efforts. PMID- 23661813 TI - Diseases of ageing in Ghana. AB - OBJECTIVE: The objective of the paper was to outline the chronic non-communicable disease burden of older adults and predict the odds of living with a chronic non communicable disease in Ghana. DESIGN: The paper utilized descriptive and analytical statistical methods to assess the level of chronic noncommunicable diseases among older adults. SETTING: Data from the Study on Global Ageing and Adult Health (SAGE) conducted in 2005 in Ghana were used. It comprises 507 individuals aged 50 years and over across the country. RESULTS: The result shows that 45% had oral health problems, 33% were hypertensive, 14% reported having arthritis; 7% had been diagnosed with diabetes, 6% had a cardiovascular condition (Angina) and 4.9% were receiving treatment for stroke or had been diagnosed with stroke. The odds ratio of having a chronic non-communicable condition for those who lived in a rural area was twice as likely as those who reside in an urban area. CONCLUSIONS: Chronic non-communicable disease will have significant health and economic implications for the individual, family and the country. The paper posits that the prevalence of chronic non-communicable diseases among the elderly in the country will increase. PMID- 23661814 TI - A review of epidemiological studies of asthma in Ghana. AB - CONTEXT/BACKGROUND: The last few decades have witnessed a rise in the global prevalence of asthma with a number of risk factors being linked to this increase. Although there is insufficient data on the prevalence of asthma in Ghana, a few studies conducted in this country have shed light on the disease aetiology and associated risk factors. EVIDENCE ACQUISITION: The purpose of this review is to explore the literature on epidemiological studies on asthma carried out in Ghana and how these findings fit into the wider context of observations from other countries. RESULTS: Asthma research in Ghana has focused mainly on children between the ages of 5-16 years with one published study that included adults. Different markers for the disease have been used such as clinician-diagnosed asthma, exercise-induced bronchospasm (EIB) as well as questionnaire-derived symptoms of asthma. Factors found to be associated with asthma in Ghana include atopic sensitisation to environmental allergens, inner-city residence and socioeconomic differences. Other implicated factors are family history of asthma, sib-ship position, breast-feeding duration and helminth infections. CONCLUSIONS: Future research in Ghana must establish the burden of disease among all age groups as well as clearly differentiate between allergic and non-allergic asthma. Studies are also needed to examine the role of environmental air pollutants on the disease's pathogenesis. PMID- 23661816 TI - Structural barriers to coping with type 1 diabetes mellitus in Ghana: experiences of diabetic youth and their families. AB - OBJECTIVE: To explore the structural barriers faced by families coping with type 1 diabetes mellitus (T1DM) in Ghana, and to provide insight for policy development. METHODS: Qualitative study conducted with families with a child with T1DM, receiving care in the greater Accra area. Total of 17 individuals were interviewed using individual and dyadic approaches: 7 youth with T1DM, 9 parents of children with T1DM, and one medical doctor. FINDINGS: 5 key barriers emerged from the data: primary care, schools, financial burden, lack of formal support, and access to information. Participants expressed concern over the misdiagnosis of T1DM at primary care facilities, resulting in some of the children going into a diabetic coma before receiving proper care. Children and parents noted discrimination and poor care at school. Financial burden was due to the high costs of medications and appliances needed for proper diabetes management. A lack of formal support was credited by participants to be the result of the lethargy of advocacy groups or resource centers. Finally, there was a lack of readily available and accessible information for children and parents on T1DM. CONCLUSION: Awareness of T1DM needs to be increased, by incorporating lessons on recognition into already existing campaigns for type 2 diabetes mellitus (T2DM). Schools need to be more engaged with their responsibility for children with diabetes. Pressuring policy makers and pharmaceutical companies to make diabetes supplies more affordable and accessible could ease the financial burden. Social support networks need to be explored and strengthened. Study into the experiences of youth with T1DM in rural settings and other parts of Ghana, as well as, youth from low socioeconomic backgrounds is necessary. PMID- 23661815 TI - Mental health research in Ghana: a literature review. AB - CONTEXT/BACKGROUND: Mental health is a neglected area in health care in Ghana. With few clinicians and trained researchers in the field, research has been limited both in quantity and quality. METHOD: A search of the available literature revealed 98 articles published between 1955 and 2009. Sixty-six are reviewed in this paper. RESULTS: Topics covered included hospital and community based prevalence studies, psychosis, depression, substance misuse, self-harm, and help-seeking. Much of the research was small in scale and thus largely speculative in its conclusions. Epidemiological data is scarce and unreliable and no large-scale studies have been published. There are very few studies of clinical practice in mental health. CONCLUSIONS: The existing literature suggests several important areas for future research to inform the development of targeted and effective interventions in mental health care in Ghana. PMID- 23661817 TI - When darkness falls at mid-day: young patients' perceptions and meanings of chronic illness and their implications for medical care. AB - BACKGROUND: This study illustrates the perceptions and meanings that patients who have had the onset of certain chronic diseases at young adulthood ascribe to their condition of chronic illness. The paper further examines the implications of such perceptions and construction for medical care. DESIGN: Qualitative and ethnography. SETTING: Outpatient chronically ill patients were recruited from the Korle Bu Teaching Hospital, Accra Ghana. Patients were followed up and studied in depth in their homes. PARTICIPANTS: Purposive sample of 24 consenting patients diagnosed of cancer, renal disease and stroke. METHODS: Anthropological data collection techniques mainly in-depth interviews, narratives, conversation and observations were used. Issues explored included patients' perceptions, causal explanations, meanings ascribed to diagnosis, and search for treatment and cure. RESULTS: Young adults had very low knowledge of chronic illnesses and did not consider themselves at risk to chronic diseases. The search for diagnosis, upon the presentation of symptoms, was long and winding. Families of young patients were more likely to make future search for "spiritual diagnoses" than elderly patients and their families. Keeping silent and maintaining secrecy about diagnosis are important ways by which young adult patients cope with their condition. Irrespective of the prognosis, young patients nurture a strong hope of cure. CONCLUSION: Young adults diagnosed of certain chronic illnesses ascribe supernatural interpretations to their disease condition. These determine their attitude to their condition as well as health seeking behaviours adopted by them and their families. Responses interfered with their biomedical care and thus have implications for health promotion and healthcare planning and policy. PMID- 23661818 TI - Household burden of chronic diseases in Ghana. AB - BACKGROUND: This paper assesses the burden of non-fatal chronic non-communicable diseases on households in the midst of a paradigm change in Ghana's health policy that shifts healthcare costs to persons and households. METHOD: Using data on 4,121 households from the World Health Survey for Ghana 2003, measures of direct and indirect burden of chronic diseases at the household level are constructed and assessed using bivariate and multivariate analyses. RESULT: About 18% of the respondents indicated they had been diagnosed with one or more NCDs with 45% of them currently receiving treatment. About 11% of the respondents currently receiving treatment are living with more than one NCD condition, 7 in 10 of whom belong to households in the middle and higher income quintiles. Female respondents are more likely to report having NCDs, and the odds that a respondent would currently have NCDs increases with age and household income quintile. Mean healthcare expenditure for households with respondent currently living with NCDs is 49% higher than households with healthier respondents. CONCLUSION: The relatively high direct cost of illness among households with person(s) living with NCDs and the associated high indirect burden of illness places undue stress on households. Research requires better measurement of the indirect burden with focus on the household. These findings suggest the necessity of interventions at the national and community levels that focus on households providing care and support to persons living with NCDs. PMID- 23661819 TI - Lay representations of chronic diseases in Ghana: implications for primary prevention. AB - BACKGROUND: Ghana's health system is ill-equipped to tackle the country's double burden of infectious and chronic diseases. The current focus is on empowering lay communities to adopt healthy practices to prevent chronic diseases. Understanding how individuals make sense of health, illness and chronic illnesses is an important first step to developing practical interventions. METHODS: Six focus group discussions with lay people (N= 51) in Accra, Nkoranza and Kintampo to explore: (1) knowledge of prevalent chronic diseases in Ghana; (2) chronic disease causal theories; and (3) chronic disease treatment. RESULTS: Nineteen conditions were listed cumulatively. Diabetes and hypertension were listed by all groups. Rural groups included HIV/AIDS on their list as well as diseases with alleged spiritual roots, in particular epilepsy and sickle cell disease. Multiple causal theories were presented for diabetes and hypertension; cancers were attributed to toxic foods; asthma attributed to environmental pollution. Biomedical care was preferred by the majority. Lay representations were drawn from multiple sources: medical professionals and chronically ill individuals were the most legitimate knowledge sources. CONCLUSION: This study provides insights on how lay representations of common chronic diseases and their major risk factors provide public health specialists with the conceptual tools to develop primary prevention strategies. The first challenge will be to train health experts to provide accurate information in practical language that lay people can understand and apply to their daily lives. A second challenge will be to develop sustainable behaviour-change interventions. Best practices from other African countries can inform interventions in Ghana. PMID- 23661820 TI - A comprehensive review of the policy and programmatic response to chronic non communicable disease in Ghana. AB - INTRODUCTION: Chronic non-communicable diseases (NCDs) in Ghana have caused significant illness and death in Ghana for many years. Yet, until recently, they have been neglected and not considered a health priority. This paper reviews the national policy and programme response to chronic NCDs over the period 1992 to 2009. METHODS: Unpublished reports, documents, relevant files of the Ghana Health Service (GHS) were examined to assess programmatic response to chronic NCDs. Literature was searched to locate published articles on the epidemiology of chronic NCDs in Ghana. The websites of various local and international health institutions were also searched for relevant articles. RESULTS: Several policy and programme initiatives have been pursued with limited success. A national control programme has been established, NCDs are currently a national policy priority, draft tobacco control legislation prepared, public education campaigns on healthy lifestyles, instituted cervical cancer screening and a national health insurance system to reducing medical costs of chronic NCD care. Major challenges include inefficient programme management, low funding, little political interest, low community awareness, high cost of drugs and absence of structured screening programmes. Emerging opportunities include improving political will, government's funding of a national cancer screening programme; basic and operational research; and using funds from well-resourced health programmes for overall health system strengthening. CONCLUSIONS: Although Ghana has recently determined to emphasise healthy lifestyles and environment as a major health policy for the prevention and control of chronic NCDs, low funding and weak governance have hindered the effective and speedy implementation of proposed interventions. PMID- 23661821 TI - Golden jubilee of the Ghana Medical Journal. PMID- 23661822 TI - Comment: a historical survey of psychiatric practice in Ghana (1962). PMID- 23661823 TI - Outbreak of cholera in the East Akim Municipality of Ghana following unhygienic practices by small-scale gold miners, November 2010. AB - BACKGROUND: In October 2010 an outbreak of cholera began among a group of small scale gold miners in the East-Akim Municipality (EAM), Eastern Region. We investigated to verify the diagnosis, identify risk factors and recommend control measures. METHODS: We conducted a descriptive investigation, active case-search and an unmatched case-control study. A cholera case-patient was a person with acute watery diarrhoea, with or without vomiting in EAM from 1st October to 20(th) November, 2010. Stool from case-patients and water samples were taken for laboratory diagnosis. We performed univariate and bivariate analysis using epi info version 3.3. RESULTS: Of 136 case-patients, 77 (56.6%) were males, of which 40% were miners or from miners households. Index case, a 20 yr-old male miner from Apapam village reported on October 13(th), and case-patients peaked (18.4%) 20 days later. Attack rate was 2/1000 population with no fatality. Ages ranged from 1-84 years; mean of 34+/-18 yrs. Age-group 20-29 yrs was mostly affected (30.1%) with Apapam village having most case-patients (19.9%). Vibrio cholera serotype ogawa was isolated from stool samples. The main water source, Birim river was polluted by small-scale miners through defecation, post-defecation baths and sand-washings. Compared to controls, case-patients were more likely to have drunk from Birim-River [OR= 6.99, 95% CI: 2.75-18]. CONCLUSION: Vibrio cholera serotype ogawa caused the EAM cholera-outbreak affecting many young adult males. Drinking water from contaminated community-wide -River was the major risk factors. Boiling or chlorination of water was initiated based on our recommendations and this controlled the outbreak. PMID- 23661824 TI - Prevalence of childhood overweight/obesity in basic school in Accra. AB - BACKGROUND: This study intends to determine the prevalence of obesity among children in the University Primary School, Legon. It also intends to determine relationship between the prevalence of obesity in children and socio-economic status of their parents and the most endemic age group. METHOD: The study was conducted using 270 students sampled at random in the basic school. Children's height, weight and skin fold measurement were taken. Children's parent's socio economic status was assessed using close and open-ended questionnaires administered to parents. Data obtained was then analyzed using SPSS software. RESULTS: Prevalence of obesity in the university primary school was found to be 10.9% with higher prevalence in girls (15.0%) than in boys (7.2%) (P value=0.001). There was higher prevalence among children from high socioeconomic background (21 - 23%) with least prevalence in those from low socio-economic homes (10 - 20%) though this was not significant (p-value=0.23). Girls showed a higher body fat composition between 10 - 12years, whiles boys showed higher body fat stores between 8 - 10 years old. Increasing mother educational level reduced prevalence of child obesity (p-value=0.043) but this was not seen in increasing fathers' educational level (p-value=0.261). CONCLUSIONS: The prevalence of obesity in children in University primary school was very high and worrying. The prevalence increased with socio-economic status and it is more common in females than males. It was recommended that similar study should be expanded nationwide. PMID- 23661825 TI - Patterns of health service utilization at a medical school clinic in Ghana. AB - BACKGROUND: The University of Ghana Medical School (UGMS) Clinic provides healthcare service which is free at point of service to students, staff, retired staff and dependents of staff of the College of Health Sciences. However, since 1983, no in-depth review of health service provision or utilization has been undertaken. This study reviewed client characteristics, utilization and disease patterns at the clinic and also compared the disease patterns to that of other primary health facilities nationwide. METHODS: This was an analytical cross sectional study undertaken at the UGMS clinic in Korle-Bu. It was a retrospective review of records of all clients attending the facility from January 2002 to December, 2004. RESULTS: More males than females attended the clinic and majority (63.9%) of clients were between 15-44 years (median age was 26 years). Dependents of staff constituted the highest attendants (41%) to the clinic. Among staff, junior staffs were in the majority. Malaria, respiratory tract infection and musculoskeletal pain were the most common conditions seen. Overall, 83% of clients were treated and discharged per visit without the need for review visits. CONCLUSION: Dependents of staff used the facility the most and they live in many different part of the city of Accra, and to ask them to attend the clinic for care is not efficient. It will be better to provide or supplement their securing of insurance so that they could access health care close to their homes and save time and attention to students and staff. PMID- 23661826 TI - Improving medical records filing in a municipal hospital in Ghana. AB - BACKGROUND: Medical records are kept in the interest of both the patient and clinician. Proper filing of patient's medical records ensures easy retrieval and contributes to decreased patient waiting time at the hospital and continuity of care. This paper reports on an intervention study to address the issue of misfiling and multiple patient folders in a health facility. DESIGN: Intervention study. SETTING: Municipal Hospital, Goaso, Asunafo North District, Brong Ahafo Region, Ghana. METHODS: Methods employed for data collection were records review, direct observation and tracking of folders. Interventions instituted were staff durbars, advocacy and communication, consultations, in-service trainings, procurement and monitoring. Factors contributing to issuance of multiple folders and misfiling were determined. Proportion of multiple folders was estimated. RESULTS: Results revealed direct and indirect factors contributing to issuance of multiple patient folders and misfiling. Interventions and monitoring reduce acquisition of numerous medical folders per patient and misfiling. After the intervention, there was significant reduction in the use of multiple folders (i.e., overall 97% reduction) and a high usage of single patient medical folders (i.e., 99%). CONCLUSION: In conclusion, a defined medical records filing system with adequate training, logistics and regular monitoring and supervision minimises issuance of multiple folders and misfiling. PMID- 23661827 TI - Malignant tumours of the genital tract among Batswana women. AB - BACKGROUND: To determine the frequency and pattern of malignant tumours of the female genital tract among Batswana women. DESIGN: A four-year retrospective histological study of the pattern of female genital tract malignancy in Botswana. SETTING: University of Botswana and the National Health Laboratory Gaborone, Botswana. The National Health Laboratory is the only public tertiary referral laboratory that provides diagnostic pathology services in the South-Eastern part of Botswana. It is located just adjacent to Princess Marina Hospital, the major tertiary referral hospital in the country. METHODS: All histologically confirmed diagnoses of female genital tract malignancies from January 1(st) 2006 to December 31(st) 2009 were reviewed by two pathologists and diagnoses re-confirmed by taking fresh tissue sections from paraffin embedded archival tissue blocks. RESULTS: The age of patients ranged from 13-96 years with a mean age of 54.5 +/- 6.4 years. Cancer of the cervix constituted 80.6%, followed by uterine cancer (10.0%), carcinomas of the vulva (4.5%) and ovary (3.4%) in that order. Ovarian cancers predominated in the younger age group. There was a steady increase in the frequencies of cervical, uterine and ovarian cancers over the 4-year study period with a decline in uterine cancer in the 4(th) year. CONCLUSION: Cervical cancer incidence is high among Batswana women and all female genital tract cancers occurred at a relatively early mean age. Therefore the importance of established and accessible screening programs and awareness campaigns need more emphasis than it is being given currently. PMID- 23661828 TI - Knowledge and beliefs about cervical cancer screening among men in Kumasi, Ghana. AB - INTRODUCTION: The age-standardized mortality rate for cervical cancer in Ghana, West Africa is more than three times the global cervical cancer mortality rate (27.6/100,000 vs. 7.8/100,000 respectively). The Pap test and visual inspection with acetic acid are available at public and private hospitals in Ghana. Approximately, 2.7% of Ghanaian women obtain cervical cancer screenings regularly. Men in middle-income countries play a key role in cervical cancer prevention. Increasing spousal support for cervical cancer screening may increase screening rates in Ghana. METHODS: Five focus groups were conducted with Ghanaian men (N = 29) to assess their cervical cancer and cervical cancer screening knowledge and beliefs. The qualitative data was analyzed via indexed coding. RESULTS: Targets for education interventions were identified including inaccurate knowledge about cervical cancer and stigmatizing beliefs about cervical cancer risk factors. Cultural taboos regarding women's health care behaviours were also identified. Several participants indicated that they would be willing to provide spousal support for cervical cancer screening if they knew more about the disease and the screening methods. CONCLUSIONS: Men play a significant role in the health behaviours of some Ghanaian women. Cervical cancer education interventions targeting Ghanaian men are needed to correct misconceptions and increase spousal support for cervical cancer screening. PMID- 23661830 TI - A historical survey of psychiatric practice in Ghana. 1962. PMID- 23661829 TI - The role of plasma melatonin and vitamins C and B12 in the development of idiopathic tinnitus in the elderly. AB - BACKGROUND: To determine the correlation between plasma levels of melatonin, vitamin C and vitamin B12 and the presence of tinnitus among elderly subjects with unexplained subjective tinnitus. METHOD: Prospective involving apparently healthy elderly with subjective tinnitus and those without. Plasma levels of melatonin, vitamin C and vitamin B12 were determined using high performance liquid chromatography and correlation determined by comparing subjects with and without tinnitus. RESULT: There were 139 elderly subjects (78 females and 61males), the mean(SD) range of the age was 66.9years (0.77) 60-98 years. Of these 58.3% had tinnitus. The mean (SD) range of the plasma levels of melatoninn was 11.2 pg/mL(4.2) 5.1 pg/mL - 30.2 pg/mL while that of Vitamin C was 0.7 umol/L (0.1) 0.3 umol/L - 1.2 umol/L, and vitamin B12 was 43.0pmol/L (3.1) 25.4 pmol/L - 71.6pmol/L. Comparing the plasma levels of the markers between elderly with and those without tinnitus, the plasma levels of melatonin (p=0.01) and vitamin B12 (p=0.03) were significantly lower among the elderly with tinnitus compared to those without, while the difference in the plasma level of vitamin C (p=0.6) was not. CONCLUSION: Low plasma melatonin and vitamin B12 have significant correlation with the development of subjective idiopathic tinnitus among the elderly. This finding suggests the need for the trial of correction of these markers in the reversal or control of tinnitus. PMID- 23661831 TI - Congenital malaria in newborn twins. AB - A 28-year-old woman (G2P1A), with 36 weeks gestation, reported to a health facility in Sunyani on 22(nd) February 2009 with history of labour pains, without fever. She was reported to have taken sulphadoxine-pyrimethamine for malaria prophylaxis during the pregnancy but did not use insecticide-treated net. She delivered twins on the same day. The mother and the twins developed fever on the same day. A laboratory investigation on the three of them was positive for malaria parasites. The three were successfully treated with quinine. Congenital malaria is real and it is therefore recommended that babies born to mothers with malaria should be screened for congenital malaria. PMID- 23661832 TI - The first cases of Lassa fever in Ghana. AB - Lassa fever is a zoonotic disease endemic in West Africa but with no previous case reported in Ghana. We describe the first two laboratory confirmed cases of Lassa fever from the Ashanti Region of Ghana detected in October and December, 2011. PMID- 23661833 TI - Reversible binocular visual loss in temporal association with artesunate amodiaquine treatment in a child on mefloquine chemoprophylaxis. AB - A case of an acute reversible visual loss in a 10-year-old child who was on mefloquine prophylaxis, and was treated with artesunate-amodiaquine for an acute febrile illness diagnosed clinically as uncomplicated malaria, is reported. On admission the patient could not perceive light and had bilateral papilloedema. She was treated with dexamethasone and recovered her sight gradually over a 21 day period. There has been no previous report to our knowledge, of an association between acute visual loss and mefloquine, amodiaquine, or artesunate in the published literature, even though mefloquine is associated with blurring of vision, and antimalarials of the quinoline class have been associated with retinopathy (during long term use). While causality is difficult to ascribe in this case, it may be prudent to avoid the use of quinoline-based antimalarials for treating acute malaria in travelers taking mefloquine prophylaxis, because information on the safety of concurrent use of artemisinin combination therapies and mefloquine, or other recommended prophylactic regimens, is limited. PMID- 23661834 TI - Complete spontaneous bone regeneration following partial mandibulectomy. AB - Bone formation in small deposits following the loss of part of the mandible has often been reported in the literature, but reports of complete bone regeneration extending over the entire anterior mandible from angle to angle is rare. Even rarer, are reports on the behaviour of such new bone in terms of facial development, over a long term and the effect of load carrying on it. Presented here is an unusual case of bone regeneration after resection of a large portion of the mandible in a 12 year-old female patient with ameloblastoma in the anterior mandible. Inter-maxillary fixation, bone grafting, or insertion of any kind of implant was not employed. Spontaneous bone regeneration was noted six weeks after surgery, and the entire resected portion of the mandible completely regenerated when the patient was seen again six years later. Mandibular growth was not significantly affected and thirteen years after her treatment, including five years of partial denture usage over the new bone, the shape of the mandible is satisfactory without any evidence of bone resorption. The periosteum was totally preserved, perhaps accounting for the complete bone regeneration and normal mandibular growth and form. PMID- 23661835 TI - Aflatoxin exposure in pregnant women in Ghana. PMID- 23661836 TI - Socio-demographic determinants of aflatoxin B1-lysine adduct levels among pregnant women in Kumasi, Ghana. AB - OBJECTIVES: Aflatoxins are fungal metabolites that contaminate staple food crops in many developing countries. Although studies have linked these toxins to adverse birth outcomes and poor infant development, no study has investigated the socio-demographic and economic determinants of aflatoxin levels among pregnant women living in sub-Saharan Africa. DESIGN: A cross-sectional study was conducted among 785 pregnant women in Kumasi. Aflatoxin B1 lysine adduct levels (AF-ALB) were determined by High Performance Liquid Chromatography. Analysis of variance was used to determine mean log AF-ALB levels and significance of differences in these levels according to socio-demographic variables. Logistic regression was used to identify independent associations of socio-demographics with having AF ALB levels (>= 11.34 pg/mg; upper quartile). RESULTS: AF-ALB levels ranged from 0.44 pg/mg to 268.73 pg/mg albumin with a median level of 5.0 pg/mg. Bivariate analyses indicates that mean ln AF-ALB as well as the percent of women having high AF-ALB levels (>= 11.34 pg/mg; upper quartile) were inversely associated with indices of higher socioeconomic status: higher education and income, being employed and having a flush toilet. Higher income, being employed, having one child (verses no children) and having a flush toilet (verses no toilet facilities) were each independently associated with a 30-40% reduced odds of high AF-ALB levels. CONCLUSIONS: Additional research is needed to investigate how socio-demographic and economic factors interact to influence aflatoxin ingestion by individuals in regions with high aflatoxin crop contamination. This knowledge can be used to formulate and implement policies that will reduce exposure of women and their unborn children to these toxins. PMID- 23661837 TI - Challenges in provider payment under the Ghana National Health Insurance Scheme: a case study of claims management in two districts. AB - In 2004, Ghana started implementing a National Health Insurance Scheme (NHIS) to remove cost as a barrier to quality healthcare. Providers were initially paid by fee - for - service. In May 2008, this changed to paying providers by a combination of Ghana - Diagnostic Related Groupings (G-DRGs) for services and fee - for - service for medicines through the claims process. OBJECTIVE: The study evaluated the claims management processes for two District MHIS in the Upper East Region of Ghana. METHODS: Retrospective review of secondary claims data (2008) and a prospective observation of claims management (2009) were undertaken. Qualitative and quantitative approaches were used for primary data collection using interview guides and checklists. The reimbursements rates and value of rejected claims were calculated and compared for both districts using the z test. The null hypothesis was that no differences existed in parameters measured. FINDINGS: Claims processes in both districts were similar and predominantly manual. There were administrative capacity, technical, human resource and working environment challenges contributing to delays in claims submission by providers and vetting and payment by schemes. Both Schemes rejected less than 1% of all claims submitted. Significant differences were observed between the Total Reimbursement Rates (TRR) and the Total Timely Reimbursement Rates (TTRR) for both schemes. For TRR, 89% and 86% were recorded for Kassena Nankana and Builsa Schemes respectively while for TTRR, 45% and 28% were recorded respectively. CONCLUSION: Ghana's NHIS needs to reform its provider payment and claims submission and processing systems to ensure simpler and faster processes. Computerization and investment to improve the capacity to administer for both purchasers and providers will be key in any reform. PMID- 23661838 TI - Effects of consumer and provider moral hazard at a municipal hospital out-patient department on Ghana's National Health Insurance Scheme. AB - BACKGROUND: In 2003, Ghana introduced the national health insurance scheme (NHIS) to promote access to healthcare. This study determines consumer and provider factors which most influence the NHIS at a municipal health facility in Ghana. METHOD: This is an analytical cross-sectional study at the Winneba Municipal Hospital (WHM) in Ghana between January-March 2010. A total of 170 insured and 175 uninsured out-patients were interviewed and information extracted from their folders using a questionnaire. Consumers were from both the urban and rural areas of the municipality. RESULTS: The mean number of visits by insured consumers to a health facility in previous six months was 2.48 +/- 1.007 and that for uninsured consumers was 1.18 +/- 0.387(p-value<0.001). Insured consumers visited the health facility at significantly more frequent intervals than uninsured consumers (chi(2) = 55.413, p-value< 0.001). Overall, insured consumers received more different types of medications for similar disease conditions and more laboratory tests per visit than the uninsured. In treating malaria (commonest condition seen), providers added multivitamins, haematinics, vitamin C and intramuscular injections as additional medications more for insured consumers than for uninsured consumers. CONCLUSION: Findings suggest consumer and provider moral hazard may be two critical factors affecting the NHIS in the Effutu Municipality. These have implications for the optimal functioning of the NHIS and may affect long-term sustainability of NHIS in the municipality. Further studies to quantify financial/ economic cost to NHIS arising from moral hazard, will be of immense benefit to the optimal functioning of the NHIS. PMID- 23661839 TI - The feelings and experiences of patients with tuberculosis in the Sekondi Takoradi Metropolitan district: implications for TB control efforts. AB - OBJECTIVES: To explore the feelings and experiences of TB patients, and to highlight how TB stigma may affect case finding and compliance with treatment. DESIGN: Qualitative research approach using focus groups and individual interviews. SETTING: Sekondi-Takoradi Metropolitan district, Ghana. PARTICIPANTS: Purposeful selection of TB patients receiving TB at four government hospitals in the district. INTERVENTION: None. RESULTS: Because of TB stigma, majority of the patients failed to recognise their symptoms as due to TB, and attributed it to malaria and ordinary cough. They reported to the hospital only after prolonged period of self-medication in the community, with some indicating multiple visits before a diagnosis was made. When diagnosed, some were worried and cried, questioned how they got the disease, contemplated committing suicide, and others doubted it was TB. Most of them hid the diagnosis from others, and were isolated within the family and community. CONCLUSIONS: Most TB patients failed to recognize their symptoms as due to TB, because of the stigma attached to the disease in society. The way people treat those with TB, especially close contacts is also a source of worry to the patients. This may lead to delay in reporting to the hospital and consequently increase mortality from the disease. It may also make it difficult for the patients to comply with the long duration of TB treatment. PMID- 23661840 TI - Mass oseltamivir prophylaxis halts pandemic influenza A H1N1 2009 outbreak in a secondary school in Ashanti Region, Ghana. AB - OBJECTIVES: To describe the epidemiology and public health response to H1N1 outbreak and make recommendations to prevent future outbreaks. DESIGN: A descriptive study of an outbreak investigation. SETTING: A secondary school in Asante Akim South District. METHODS: Influenza A H1N1 2009 infection was laboratory-confirmed by Polymerase Chain Reaction (PCR) in clinically ill students after collecting throat swabs. Sixty students of the school had presented with fever, cough, headache and sore throat. The students' dormitories were also inspected to assess degree of ventilation and general level of cleanliness in the rooms. RESULTS: The outbreak followed a propagated transmission lasting 10 days with two peaks on 22(nd) and 24(th) June, 2010.The clinical attack rate was 9.9%. Secondary attack rates at the highly congested female dormitory were 28%, 31.3% and 17.8% for Rooms 1, 2 and 3 respectively. The generation time for the Influenza H1N1 a 2009 outbreak in the school was about two days. CONCLUSION: A mild form of Influenza A H1N1 2009 was confirmed in a secondary school affecting mainly those in the boarding house. Cases identified were treated, but post-exposure prophylaxis with oseltamivir administered to the remaining school population actually halted the outbreak, after social distancing interventions had not succeeded. PMID- 23661841 TI - Combined iron and zinc supplementation improves haematologic status of pregnant women in Upper West Region of Ghana. AB - BACKGROUND: Though pregnant women in Ghana routinely receive iron and folic acid supplements, the prevalence of anaemia continues to be as high as 70%. OBJECTIVE: To determine the impact of zinc deficiency on iron status indicators in pregnant women. DESIGN: A double-blind, randomized controlled trial (RCT) of joint iron and zinc supplementation. SETTING: The study was conducted in the Upper West Region of Ghana, where the prevalence of anaemia is high. PARTICIPANTS: The study population comprised pregnant women who presented themselves for antenatal care (ANC) in the Wa Regional Hospital of the Upper West Region in Ghana. INTERVENTIONS: The intervention group received a combined supplement of 40 mg zinc as zinc gluconate and 40 mg iron as ferrous sulphate. The control group received 40 mg elemental iron as ferrous sulphate. MAIN OUTCOME MEASURES: The primary outcome measures were mean and percentage changes in Hb. Serum ferritin and zinc concentrations serve as secondary outcomes. RESULTS: Adjusted mean Hb increase was 0.6g/dl higher among women who were not iron replete (SF ferritin <= 20 ug/L) and received the iron-zinc supplement, compared to women who received iron-only supplement, F (1, 99) = 4.356, p = 0.039. Women who had low plasma zinc levels were 3-fold increased odds of developing iron deficiency at recruitment, (OR 3.41, 95% CI: 1.19-9.76). CONCLUSIONS: Iron-zinc supplementation was effective in raising Hb and serum ferritin values among women who were iron deficient in early pregnancy but not among iron sufficient women. PMID- 23661843 TI - Implementing the Mental Health Act in Ghana: any challenges ahead? AB - Ghana successfully passed a Mental Health Act law in March 2012. The passing of the Act was a culmination of a lot of work by various individuals and institutions spanning several decades. Finally there is a raised prospect of the delivery of a better quality mental healthcare and also the protection of human rights of people with mental disorders in Ghana. This paper identifies and describes clusters of related potential problems referred to as 'challenges' involving different aspects of service delivery, which are anticipated to be encountered during the implementation of the law. Finally, it cautions against the risk of allowing the new mental health law to add a new 'legal' burden to a list of perennial 'burdens' including underfunding, serious levels of understaffing and plummeting staff morale, which bisected earlier attempts at implementing a similar law that laid fallow for forty years. PMID- 23661844 TI - Surgical reconstruction of penile stump in a patient with Klingsor syndrome. AB - Self-mutilation of genitalia is an extremely rare entity, usually found in psychotic patients. Klingsor syndrome is a condition in which such an act is based upon religious delusions. The extent of genital mutilation can vary from superficial cuts to partial or total amputation of penis to total emasculation. The management of these patients is challenging. The aim of the treatment is restoration of the genital functionality. Microvascular reanastomosis of the phallus is ideal but it is often not possible due to the delay in seeking medical attention, non viability of the excised phallus or lack of surgical expertise. Hence, it is not unusual for these patients to end up with complete loss of the phallus and a perineal urethrostomy. We describe a patient with Klingsor syndrome who presented to us with near total penile amputation. The excised phallus was not viable and could not be used. The patient was managed with surgical reconstruction of the penile stump which was covered with loco-regional flaps. The case highlights that a functional penile reconstruction is possible in such patients even when microvascular reanastomosis is not feasible. This technique should be attempted before embarking upon perineal urethrostomy. PMID- 23661842 TI - Epidemiology and prevention of nosocomial pneumonia associated with Panton Valentine Leukocidin (PVL) producing Staphylococcus aureus in Departmental Hospital Centre of Zou Collines in Benin. AB - BACKGROUND: An eight (8) months prospective study was carried out to control an outbreak of nosocomial pneumonia due to a Panton-Valentine Leukocidin (PVL) producing Staphylococcus aureus, in the paediatrics' unit at the Zou/Collines Departmental Hospital (CHDZ/C), (Benin). METHODS: Between 1(st) September 2004 and 30(th) May 2005 an investigation was conducted that involved the screening of all patients suspected to have nosocomial pneumonia, hospital environment sampling and the follow-up of cases until the end of hospital admission period. Isolates were identified, tested for antimicrobial susceptibility and analysed for PVL production. The study period was divided into Period I, corresponding to the outbreak period and Period II, after the complete renovation of the Unit along with hand washing promotion. RESULTS: A total of 453 patients were admitted during the period of the study; (235 during Period I and 218 during Period II) in the malnourished children sector. Twenty eight (28) cases of pneumonia due to S. aureus were discovered and PVL-producing S. aureus constituted 61% (17/28) of identified cases. The mortality rate among the PVL- producing strains was 15/17 (88%) while it was 1/11 (9%) among non PVL-producing strains. Enhanced hygiene measures helped to terminate the outbreak. CONCLUSIONS: This study showed that PVL was strongly linked to nosocomial pneumonia. PVL-producing S aureus can be controlled in the hospital by a combination of the promotion of preventive measures, decontamination of the environment and the early use of the correct antibiotic at the appropriate dose and for an adequate duration. PMID- 23661845 TI - Haemophagocytic lymphohistiocytosis in a Ghanaian child. AB - We report a case of a previously well nine-month-old infant who presented with prolonged fever, hepatosplenomegaly and pancytopenia. A diagnosis of haemophagocytic lymphohistiocytosis (HLH) was made during the course of hospital admission. There was good initial response to dexamethasone but the patient died less than two months after diagnosis. This is the first report of HLH from Ghana. The disease has a significant mortality rate if untreated and a high index of suspicion is required in all severely ill children. PMID- 23661846 TI - Idiopathic spontaneous haemoperitoneum in the third trimester of pregnancy. AB - Spontaneous haemoperitoneum in pregnancy, more especially idiopathic ones are rare and can be life threatening. We present a case of a 30 year old pregnant woman who at 29 weeks gestation developed spontaneous haemoperitoneum. An exploratory laparotomy was done which did not reveal the source of the bleeding. She subsequently had conservative management as an inpatient until term when she had elective caesarean section. A review of the literature was undertaken. PMID- 23661847 TI - Haemodialysis treatment for end stage chronic kidney disease and acute kidney injury in Africa. PMID- 23661849 TI - Haemodialysis practice in a resource-limited setting in the tropics. AB - BACKGROUND: OBJECTIVE: To provide information on the challenges of haemodialysis in a resource limited setting in South-Western Nigeria. METHODS: This is a 5 year audit of all haemodialysis sessions carried out at the renal unit of the Ladoke Akintola University Teaching Hospital (LAUTECH), Osogbo, Nigeria. RESULTS: A total of 225 patients were offered haemodialysis (HD) during this period with age range of 10 to 85 years (mean age of 49 years+/-16.25). There were 155 males and 70 females (male to female ratio of 2.2:1). Chronic kidney failure accounted for 180 (80%) of the cases while acute kidney injury (AKI) constituted 45 (20%) of the cases offered haemodialysis. The sessions of HD in both cases ranged from 1 to 27 with an average of 3 sessions. Hypotension is still the commonest intradialytic complication at our setting while diabetic nephropathy is rapidly emerging as a major cause of end stage renal disease at our setting requiring HD. As seen in other parts of the tropics sepsis, nephrotoxins and pregnancy related cases still accounted for a large percentage of AKI cases requiring haemodialysis. Only three patients were able to afford haemodialysis support for more than three months. CONCLUSION: Haemodialysis still remains a veritable option in renal replacement therapy. Problems encountered were similar to many other settings in the tropics. Intensive efforts should still be geared at preventing the risk factors for both acute kidney injury and chronic kidney disease in our environment. PMID- 23661850 TI - Factors contributing to poor management outcome of sinonasal malignancies in South-west Nigeria. AB - OBJECTIVE: To describe the clinico-pathologic manifestations of sinonasal malignancies, identify the contributing factors to delay in presentation and recommend ways of preventing them in a resource challenged environment. DESIGN: A questionnaire based cross sectional descriptive study of patients with sinonasal malignancies between 2006 and 2011. SETTING: Hospital based study at the Otorhinolaryngology Department, University College Hospital, Ibadan. PARTICIPANTS: 61 patients diagnosed with sinonasal malignancies. MAIN OUTCOME MEASURES: Patients demographic and essential medical data were collected with a structured, interviewer assisted questionnaire and results analysed using descriptive statistics. RESULTS: There were 28(45.9%) males and 33(54.I %) females; mean age 37years. The common presentations were epistaxis, nasal obstruction and facial asymmetry and 96.7% patients with squamous cell carcinoma presented in advanced disease stage (Stage 3 & 4). Over 47% patients presented a year after onset of symptoms. Factors which included self-medication, wrong advice from relations/friends to consult traditional herbalist or quacks for treatment and traditional & religious beliefs contributed to delay in presentation to hospitals. High cost of medical treatment, unwelcoming attitudes of some hospital staff, lack of confidence in orthodox medicine and proximity to health facilities were reasons given for not considering hospital as the first place to seek medical treatment. CONCLUSION: Health education to create awareness of sinonasal malignancies and provision of affordable and accessible health facilities especially in rural areas are recommended ways to encourage patients to present early in hospitals. This will improve the management outcome and quality of life of patients with sinonasal malignancies. PMID- 23661851 TI - Soluble fluoride levels in drinking water-a major risk factor of dental fluorosis among children in Bongo community of Ghana. AB - BACKGROUND: The purpose of the study was to investigate the relationship between fluoride ions in drinking water and the incidence of dental fluorosis in some endemic areas of Bongo District, Ghana. METHOD: Two hundred children were randomly selected from various homes and taken through a questionnaire. Their teeth were examined for the detection of dental fluorosis using the Dean's specific index. Samples of their permanent sources of water were taken for the determination of soluble fluoride levels by SPADNS spectrophotometric method. RESULTS: The study revealed that the incidence of dental fluorosis among the children in the main Bongo township was 63.0%, whereas villages outside the township recorded less than 10.0%. The respondents from the various communities had similar age group, educational background, sources of drinking water, oral hygiene habits and usage of oral health products, p-value > 0.05. However, there were statistically significant differences in the cases of dental fluorosis and fluoride ions among the communities, p-value < 0.05. The fluoride ion concentration in the Bongo township was above the WHO requirement of 1.50 ppm, whereas the nearby villages showed acceptable fluoride levels. Statistically, there was no significant relationship between the presence of dental fluorosis and the other characteristics, except the age group and fluoride ion concentration of the area. CONCLUSION: These findings strongly support the association between the dental fluorosis and the high fluoride levels in the underground water of Bongo community. Therefore, policy makers need to consider an alternative source of drinking water for the area. PMID- 23661852 TI - Duration of exclusive breastfeeding and subsequent child feeding adequacy. AB - OBJECTIVE: Mothers of young children in Ghana believe that breastfeeding exclusively for six months impairs subsequent introduction of other foods. The current study was designed to determine whether feeding adequacy among 9-23 months old children is influenced by duration of exclusive breastfeeding. DESIGN: We surveyed 300 mother-infant pairs attending child-welfare-clinic at the University of Ghana Hospital, Accra. Data collected included sociodemographic characteristics, morbidity, breastfeeding history, and maternal practices and perception on child feeding and temperament. Current child feeding was assessed using 24-hour dietary recall. Adequately fed children were defined as 9-23 month old children meeting three basic feeding adequacy thresholds: 1) was fed complementary foods, at least three times in the last 24 hours, 2) was fed from at least three food groups, and 3) received breast milk in the last 24 hours. Multiple logistic regressions were used to identify independent predictors of child feeding adequacy. RESULTS: About 66% of children were exclusively breastfed for six months and only 56% were adequately fed in the in the 24 hours preceding the survey. Child feeding adequacy was unrelated to duration of exclusive breastfeeding (OR=0.73; p=0.30). After controlling for child sex, age, and maternal education, the independent determinants of feeding adequacy included recent child morbidity (OR=0.41; p=0.03), number of caregivers who feed child (OR=1.33; p=0.03), and maternal perception that child does not like food (OR=0.25; p<0.01). Child temperament was unrelated to feeding adequacy. CONCLUSION: Child feeding adequacy is not affected by duration of exclusive breastfeeding. The study provides evidence to address misperceptions about exclusively breastfeeding for six months. PMID- 23661853 TI - Awareness and attitudes towards face and organ transplant in Kumasi, Ghana. AB - OBJECTIVES: This study aimed to determine the level of awareness and attitudes towards face and organ transplant among the people of Kumasi, Ghana. DESIGN: An observational study was employed, where participants were randomly selected for the study. PARTICIPANTS: The respondents were commuters waiting to board public vehicles at the Kejetia lorry station, Bantama/Komfo Anokye Teaching Hospital taxi station, Buokrom Estate F-line lorry station, traders, and residents of Adum and Bantama, all in Kumasi. METHODS: The descriptive study was conducted from 1(st) February to 30(th) April 2009. An interview-based questionnaire was used for the convenient sample of respondents. Data obtained included: demographic profile and items covering awareness, attitudes and beliefs towards face and organ transplant. RESULTS: Out of the 1020 respondents, females (53.2%) outnumbered males. The age of respondents ranged from 10 to 89 years; mean was 27.50+/- 2.98 years; majority (72.3%) was Christians, whilst 61.8% had gone through tertiary education. Few (33.5%) of the respondents were aware of face transplant; 70.0% and 62.1% were willing to receive a face if their face was disfigured or donate their face when dead respectively. Also, 50.6% were aware of organ transplant, whiles 59.1% would receive/donate an organ when required. Multiple regression analysis shows statistical significant association between attitudes, awareness and demographic variables listed. CONCLUSION: Face and organ transplant were found to have a relatively low and high awareness level respectively. However, an affirmative attitude was recorded for face and organ transplant. More education on face and organ donations is needed. PMID- 23661854 TI - Where, when and what type of alcohol do pregnant women drink? AB - BACKGROUND: Drinking alcohol in pregnancy is of a serious public health concern worldwide. Previous study in the Bosomtwe district put the prevalence of women drinking alcohol in pregnancy as 20.4%. OBJECTIVES: To describe the alcohol drinking behaviour of pregnant women in the Bosomtwe district of Ghana. DESIGN: The study was a descriptive cross-sectional, conducted among 397 pregnant women who attended ANC in 2010. METHOD: The study was conducted in all the 10 health facilities providing reproductive health care in the Bosomtwe district using administered questionnaires. RESULTS: The main findings of the study were that 20.4% of pregnant women drank alcoholic beverage of which the most preferred drink was Akpeteshie (36.4%), a locally brewed or distilled alcoholic beverage followed by the liqueurs (Ginseng, Kasapreko or-Pusher -27.3%. Study participants drank an average of 'half-tot' (15 mls) of akpeteshie and 'one-tot'-30mls-of liqueurs per a drinking session respectively. They usually drank at home and before meals. The 25-29 year group 26(32.1%), married 50(61.7%) and Junior High School educated 37(45.7%) as well as christians 69(85.0%) and traders 28(34.6%) drank most. CONCLUSIONS: The findings identified akpeteshie as the most preferred alcoholic beverage among pregnant women in the district. It is recommended that the health authority creates awareness of the existence of the problem of alcohol drinking in pregnancy and its potential effects on the foetus. PMID- 23661855 TI - Towards an improved pathology service in Ghana. PMID- 23661856 TI - Chronic daily headache in a patient with cavum septum pellucidum and cavum verge. AB - Cavum septum pellucidum (CSP) and cavum Vergae (CV) are unusual variants and usually asymptomatic, but their expansion or inside lesions can produce symptoms by mass effect. A 46-year-old female Taiwanese worker presented with chronic daily headaches for eight years. Magnetic resonance imaging revealed coexistent CSP and CV. She declined surgical drainage recommended by a neurosurgeon and thus visited our clinic for a second opinion. Physical examination did not show any abnormality. With the help of the patient's one-month headache diary, she was diagnosed with chronic migraine according to the International Classification of Headache Disorders, 2(nd) edition, with further modification in 2006. In addition, hypertension was also identified. Over the following week, taking a daily selective beta1-antagonist relieved the headache and hypertension. The medication was continued and the following year was uneventful. Therefore, the chronic daily headache was ascribed to chronic migraine, rather than symptomatic CSP and CV. PMID- 23661857 TI - Foreign body in scrotum following a boat engine blast accident. AB - Male genital injuries, demand prompt management to prevent long-term sexual and psychological damage. Injuries to the scrotum and contents may produce impaired fertility.We report our experience in diagnosing and managing a case of a foreign body in the scrotum following a boat engine blast accident. This case report highlights the need for a good history and thorough general examination to establish the mechanism of injury in order to distinguish between an embedded penetrating projectile injury and an injury with an exit wound. Prompt surgical exploration with hematoma evacuation limits complications. PMID- 23661858 TI - Boerhaave's syndrome: diagnosis and successful primary repair one month after the oesophageal perforation. AB - Boerhaave's syndrome (Spontaneous oesophageal perforation following forceful vomiting) is uncommon. However, when it occurs and the appropriate treatment is not given on time, it is fraught with early complications, leading to a very high mortality rate. This is a characteristic feature of this syndrome. Patient survival is in days. We present the case of an uncommon scenario of this syndrome in which the actual diagnosis was made one month after the oesophageal perforation, which was followed by primary repair, with a very good outcome. PMID- 23661859 TI - Comparison of Aqueous and 1-Octanol Solubility as well as Liquid-Liquid Distribution of Acyclovir Derivatives and Their Complexes with Hydroxypropyl-beta Cyclodextrin. AB - The aim of the presented work is the comparison of aqueous and 1-octanol solubilities of different acyclovir derivatives and their hydroxypropyl-beta cyclodextrin inclusion complexes. The solubility measurements were carried out at different temperatures over the range 25-45 degrees C using water, 1-octanol, water saturated with 1-octanol, 1-octanol saturated with water, buffered aqueous solutions (pH = 5.5 and 7.0) and buffered aqueous solutions containing cyclodextrin as solvents. The aqueous solubilities of the compounds are very low but may be enhanced by complexation with hydroxypropyl-beta-cyclodextrin, especially if the acyclovir derivatives have aromatic groups which may be included in the cyclodextrin cavity. The values of 1-octanol-water partition coefficients of acyclovir derivatives, obtained using extraction experiments, showed a similar sequence as the solubility results in 1-octanol. Additionally, some molecular mechanics and molecular dynamic calculations were performed to determine optimized structures of acyclovir derivative complexes with beta cyclodextrin treated as a model. PMID- 23661860 TI - Clinical diagnosis in Ayurveda: Challenges and solutions. PMID- 23661862 TI - Rhazes' concepts and manuscripts on nutrition in treatment and health care. AB - The use of nutrition in medical practice has a long history dating back to 6000 years. The great Persian chemist, physician, and philosopher, Rhazes (865-925 AD), wrote over 200 books in different branches of science. Some of his work drew attention to the notion that nutrition is an important part of treating diseases and health care procedures. Rhazes formulated highly developed concepts of nutrition and wrote several special books about food and diet such as manfe' al aghzie va mazareha (Benefits of Food and its Harmfulness), teb al moluki (Medicine for Kings), and Ata'me al marza (Food for Patients). His writing included detailed guidance about eating fruit ma iaghdam men al favakeh va al aghzieh va ma yoakhar (Fruit Before or After Meal), and other food types keifiat al eghteza (Temperament and Quality of Foods) and al aghziat al mokhtasareh (Brief Facts about Food). Considering the time that these books were written, they have had a great influence on approaches to nutrition in the history of medicine, so Rhazes can be considered as a pioneer in the scientific field of nutrition. PMID- 23661861 TI - Tinospora cordifolia: One plant, many roles. AB - Natural products with medicinal value are gradually gaining importance in clinical research due to their well-known property of no side effects as compared to drugs. Tinospora cordifolia commonly named as "Guduchi" is known for its immense application in the treatment of various diseases in the traditional ayurvedic literature. Recently the discovery of active components from the plant and their biological function in disease control has led to active interest in the plant across the globe. Our present study in this review encompasses (i) the genetic diversity of the plant and (ii) active components isolated from the plant and their biological role in disease targeting. The future scope of the review remains in exploiting the biochemical and signaling pathways affected by the compounds isolated from Tinospora so as to enable new and effective formulation in disease eradication. PMID- 23661863 TI - Quality control parameters for Tamra (copper) Bhasma. AB - BACKGROUND: Metallic Bhasmas are highly valued and have their own importance in Ayurvedic formulations. To testify the Bhasmas various parameters have been told in Rasashastra classics. Tamra Bhasma (TB) with its different properties is used in the treatment of various diseases is quiet famous among the Ayurvedic physicians (Vaidyas). OBJECTIVES: The present study was carried out to set up the quality control parameters for the TB by making the use of classical tests along with advanced analytical tools. SETTINGS AND DESIGN: Copper wire taken for the preparation of Bhasma was first analyzed for its copper content and then subjected to Shodhana, Marana and Amrutikarana procedures as per the classical references. Final product complied with all the classical parameters like Rekhapurnatwa, Varitaratwa etc. MATERIALS AND METHODS: After complying with these tests TB was analyzed by advanced analytical techniques like particle size distribution (PSD) analysis, scanning electron microscopy (SEM), and inductive coupled plasma spectrometry (ICP). RESULTS: PSD analysis of TB showed volumetric mean diameter of 28.70 MUm, 50% of the material was below 18.40 MUm size. Particle size less than 2MUm were seen in SEM. 56.24 wt % of copper and 23.06 wt % of sulphur was found in ICP-AES. Heavy metals like cadmium, selenium were not detected while others like arsenic, lead and mercury were present in traces. CONCLUSIONS: These observations could be specified as the quality control parameters conforming to all the classical tests under the Bhasma Pariksha. PMID- 23661864 TI - Abhraka Bhasma treatment ameliorates proliferation of germinal epithelium after heat exposure in rats. AB - This study was conducted to evaluate the protective effect of Abhraka Bhasma on spermatogenesis in heat-damaged testis. A histological analysis over the sukravaha srotomula (testes) of male albino Wistar rat was carried out in order to examine the potency of the test drug in preventing the organ from heat damage. The current experiment was carried out on 32 healthy adult male albino Wistar rats divided into four groups. Sahastraputi Abhraka Bhasma, subjected to 1000 putas, was used as the test drug. On sacrificing the animals after 30 days, it was observed that control animals (G1) had normal spermatogenesis and drug induced animals (G2) showed hyperactive tubules. Testicular hyperthermia occurred in few (G3) animals, who were subjected to 43 degrees C for 1 h daily for four consecutive weeks, resulting in degeneration of tubules with inspissated spermatozoa (25%) leading to atrophy of the organ. 3% tubules showed disintegration, 23% were in the recovery stage while 71% tubules exhibited enhanced proliferation of germinal epithelium leading to hypertrophy and hyperplasia. The present study reveals that the test drug can correct heat induced male infertility and provides us with the possibility of treatment of human heat-induced oligozoospermia and azoospermia. Hence, this ayurvedic maharasa (primary mineral) can be a promising formulation as an anti-impotency fecundity drug. PMID- 23661865 TI - Phytochemical investigation and pharmacognostic standardization of Cissampelos pareira root. AB - BACKGROUND: In ethno-medicinal practices, the roots of Cissampelos pareira(Patha) are used in the treatment of various ailments related to urinary problems and skin infections, and in tumorinhibitor activity, antibacterial, antimalarial, diuretic activity,anticonvulsant activity etc., The main problem encountered in standardization of Ayurvedic drugs is proper identification of the source plant. MATERIALS AND METHODS: The macroscopic features of each anatomical component have been observed by a high-resolution camera. The moisture content, total ash, acid insoluble ash, and water-alcohol and ether extractive values of the powdered sampleswere determined by the method as per WHO guidelines. The phytochemical investigation of the methanolic extract of Cissampelos pareira root was performed by the standard chemical ltests and by TLC on silica gel G using solvent systems proposed by Harborne. RESULT: The microscopic characteristics showed the wavy epidermis with unicellular trichomes. Lignified xylem vessels, radial medullary rays, and prismatic calcium oxalate crystals had also been found. Phytochemical screening revealed that the Cissampelos pareira root extract contains terpenoids, alkaloids, tannins, amino acid proteins, and carbohydrates. Alkaloids and essential oil were detected in TLC of the Cissampelos pareira root extract developed using blends of methanol:concentrated ammonia (200:3) and n butanol:acetone:water (3:1:1) and benzene:ethyl acetate:formic acid(9:7:4) as solvent systems for alkaloid whereas chloroform(100%), benzene (100%), chloroform:benzene(1:1),and ether:benzene(1:1) as solvent systems for essential oil. CONCLUSION: These findings will be useful toward establishing pharmacognostic standards on identification, purity,quality, and classification of the plant, which is gaining relevance in plant drug research. PMID- 23661866 TI - The effects of green Ocimum basilicum hydroalcoholic extract on retention and retrieval of memory in mice. AB - The purpose of this study was evaluation of green Ocimum basilicum (sweet basil) hydroalcoholic extract on memory retention and retrieval of mice by using passive avoidance apparatus. For this purpose, after weighting, coding and classifying the mice, they were grouped (n = 8) as follow as: test groups (electric shock plus sweet basil extract by doses: 100, 200, 400 and 800 mg/kg, i.p.), control group (Only electric shock) and blank group (electric shock plus normal saline). In all mentioned groups delay time of leaving the platform for both retention and retrieval test of memory was measured. In retention test, sweet basil extract was administered immediately after receiving electric shock and in retrieval test it was administered 24 hours after receiving electric shock. The results indicated that hydroalcoholic extract of green Ocimum basilicum significantly (P < 0.05) increased memory retention. The best response was achieved with 400 mg/Kg of the extract. Also, results showed that sweet basil extract significantly (P < 0.05) increased memory retrieval and the best result was achieved with 400 mg/Kg too. It can be concluded that memory enhancing effects of green Ocimum basilicum is because of antioxidant activity of flavonoids, tannins and terpenoids. PMID- 23661867 TI - Botanical pharmacognosy of stem of Gmelina asiatica Linn. AB - Gmelina asiatica Linn (G. parvifolia Roxb.) is a large shrub or a small tree. Roots and aerial parts are used in Ayurvedic medicine and also have ethno-medical uses. Root is reported as adulterant to G. arborea roxb roots. Pharmacognostical characters of root were reported. Owing to the shortage of genuine drug and ever increasing demands in market, it becomes necessary to search an alternative with equal efficacy without compromising the therapeutic value. Nowadays, it becomes a common practice of using stem. In case of roots phytochemical and pharmacological analysis of stem was reported. However, there is no report on the pharmacognostical characters of stem and to differentiate it from roots. The present report describes the botanical pharmacognostical characters of stem and a note to differentiate it from root. Hollow pith, faint annual rings in cut ends, alternatively arranged macrosclereids and bundle cap fibers, and presence of abundant starch grains and calcium oxalates in pith and in ray cells are the diagnostic microscopic characters of stem. Stem pieces can be differentiated from roots by absence of tylosis. PMID- 23661868 TI - Pharmacognostical evaluation of leaf of Bada Rasna [Nelsonia canescens (Lam.) Spreng.; Acanthaceae]. AB - Nelsonia canescens (Lam.) Spreng. (Acanthaceae), a well-known plant in traditional systems of medicine, known as "Bada Rasna" by the traditional practitioners of Odisha, is being used as Rasna for managing pain and inflammation. The detailed macroscopic and microscopic characters of the plant, except its root, are lacking. Hence, it was thought worth to study the leaves of the plant for its detailed morphological and microscopical characters, by following the standard pharmacognostical procedures. The study shows the presence of diacytic stomata in the lower epidermis of lamina, microsphenoidal and prismatic crystals of calcium oxalate in the mesophyll cells, simple and glandular trichomes. The observed major diagnostic characters of the leaf may find useful for its standardization. PMID- 23661869 TI - Estimation of total alkaloid in Chitrakadivati by UV-Spectrophotometer. AB - BACKGROUND: Herbal formulation standardization by adopting newer technique is need of the hour in the field of Ayurvedic pharmaceutical industry. As very few reports exist. These kind of studies would certainly widen the herbal research area. Chitrakadivati is one such popular herbal formulation used in Ayurveda. Many of its ingredients are known for presence of alkaloids. METHODOLOGY: Presence of alkaloid was tested qualitatively by Dragondroff's method then subjected to quantitative estimation by UV-Spectrophotometer. This method is based on the reaction between alkaloid and bromocresol green (BCG). RESULTS AND CONCLUSION: Study discloses that out of 16 ingredients, 9 contain alkaloid. Chitrakadivati has shown 0.16% of concentration of alkaloid and which is significantly higher than it's individual ingredients. PMID- 23661870 TI - Effect of aqueous extracts of Achyranthes aspera Linn. on experimental animal model for inflammation. AB - BACKGROUND: Achyranthes aspera is known as Chirchita (Hindi), Apamarga (Sanskrit), Aghedi (Gujarati), Apang (Bengali), Nayurivi (Tamil), Kalalat (Malyalam) and Agadha (Marathi) in our country. It possesses valuable medicinal properties and used in treatment of cough, bronchitis and rheumatism, malarial fever, dysentery, asthma, hypertension and diabetes in Indian folklore. Present study was designed to evaluate anti-inflammatory activity of an aqueous extracts of Achyranthes aspera (AEAA). MATERIALS AND METHODS: AEAA leaves and whole plant (i.e. Aqueous extracts of Achyranthes aspera leaves (AEAAL)/Aqueous extracts of A. aspera whole plant (AEAAW) were studied in albino mice using carrageenan induced left hind paw edema. Both extracts were subjected to preliminary phytochemical analysis and acute toxicity of the extracts was also studied using Organization for Economic Co-operation and Development OECD guidelines 423. RESULTS: Acute toxicity study confirmed toxic dose of AEAA to be more than 2,000 mg/kg. Flavonoids, alkaloids, saponins and triterpenoids were the major constituents found in extracts. AEAA reduced the edema induced by carrageenan by 35.71-54.76% on intraperitoneally administration of 400 mg/kg and 800 mg/kg as compared to the untreated control group. Diclofenac sodium at 10 mg/kg inhibited the edema volume by 42.85%. The results indicated that the AEAA 800 mg/kg body weight shows more significant (P < 0.01, P < 0.001) anti-inflammatory activity when compared with the standard and untreated control respectively. CONCLUSION: Both AEAA exhibit promising anti-inflammatory activity attributed to flavonoids, alkaloids, saponins and triterpenoids phytoconstituents. PMID- 23661871 TI - Randomised controlled trials and alternative therapy. PMID- 23661872 TI - Pomegranate juice on dental plaque microorganisms. PMID- 23661873 TI - Traditional Indian medicine: Ayurveda, natural medicine and integrative medicine [corrected]. PMID- 23661874 TI - Hormones in pregnancy. AB - The endocrinology of human pregnancy involves endocrine and metabolic changes that result from physiological alterations at the boundary between mother and fetus. Progesterone and oestrogen have a great role along with other hormones. The controversies of use of progestogen and others are discussed in this chapter. Progesterone has been shown to stimulate the secretion of Th2 and reduces the secretion of Th1 cytokines which maintains pregnancy. Supportive care in early pregnancy is associated with a significant beneficial effect on pregnancy outcome. Prophylactic hormonal supplementation can be recommended for all assisted reproduction techniques cycles. Preterm labor can be prevented by the use of progestogen. The route of administration plays an important role in the drug's safety and efficacy profile in different trimesters of pregnancy. Thyroid disorders have a great impact on pregnancy outcome and needs to be monitored and treated accordingly. Method of locating review: Pubmed, scopus. PMID- 23661875 TI - A review of tip apex distance in dynamic hip screw fixation of osteoporotic hip fractures. AB - Fractured neck of femur is a common problem seen in elderly osteoporotic females, mostly in Western countries, among which are the extra-capsular fractures such as intertrochanteric and pertrochanteric fractures also known as peritrochanteric fractures, and commonly treated with dynamic hip screw (DHS) or compression hip screw (CHS). The DHS is based on tension band principle and allows the screw to slide within the barrel to enable compression of the fracture when the patient begins to bear weight. This principle only works in the presence of intact medial wall and so cannot be successful in a reverse oblique fracture of the proximal femur. However, it is important that the technique of screw placement is precise and should ideally be central in the femoral neck, on both AP and lateral radiographs. This is why the concept of tip apex distance (TAD) is critical to the outcome of fixation and can accurately predict failure or survival of the screw. A systematic review of articles published in PubMed/Medline, from 1991 to 2011 (twenty years), was carried out to critically analyse common practice with regards to DHS fixation of extra-capsular femoral neck fractures, and review the recommendations of previous authors, with regard to the effect of TAD in DHS fixation. Search words used include TAD, DHS, sliding hip screw, femoral neck fractures, peritrochanteric fractures, tension band principle, fracture collapse, screw cut-out, DHS failure, and failure of fixation. At the end of the review, recommendations and suggestions regarding the ideal techniques of placement of DHS screw into the femoral neck will be made in line with current published literature, in order to establish an evidence base for best practice. A total of forty eight (48) published articles were found relevant to the review topic. Most papers suggested that Tip Apex Distance (TAD) is the most important predictive factor for DHS failure, followed by lag screw position, fracture pattern and reduction, patient's age and presence of osteoporosis. Therefore, we recommend proper training of surgeons, as well as attention to detail while performing DHS for intertrochanteric neck of femur fractures. PMID- 23661876 TI - Intra-operative grading of coronary artery atherosclerosis associated with homocysteine levels in postmenopausal women undergoing elective off-pump CABG surgery. AB - BACKGROUND: Atherosclerosis is one of the common causes of morbidity and mortality, in postmenopausal women. Homocysteine, a sulfur-containing amino acid product of methionine metabolism, may play an important role in the development of cardiovascular diseases. This study was designed to evaluate the relationship between intra-operative grading of coronary artery atherosclerosis and homocysteine level in postmenopausal women who were candidates for off-pump coronary bypass graft surgery (CABG). MATERIALS AND METHODS: In this cross sectional study, 136 postmenopausal women (with the mean age of 54.9+/-4 years) were enrolled as candidates for elective off-pump CABG. For each patient the extent and severity of atherosclerosis was assessed by intra-operative grading (IOG) and Gensini score system. Total homocysteine was determined with ELISA method after 12 hours of fasting. The patients were classified into two groups (diffuse vs. discrete) based on intra-operative findings. Finally the relation between age, IOG, and Gensini score with homocysteine level was assessed by ANOVA, T-test, and Tukey HSD test. RESULTS: There was a positive correlation between intra-operative grading and homocysteine level in both groups (P=0.005). The association between Gensini score and homocysteine was significant in higher levels of hyperhomocysteinemia (P<0.05). The homocysteine level also increased with age; therefore, patients were classified into two categories (<54 years and >=54 years) by Levene test. Statistical analysis indicated no relationship between IOG, Gensini score, and homocysteine level in the patients who were younger than 54 years (P=0.3, P=0.2), but significant relation was detected between IOG, Gensini score, and homocysteine in the patients who were older than 54 years with diffuse or discrete lesions in coronary arteries (P=0.001, P=0.001). CONCLUSION: According to our findings, homocysteine level increases in post-menopausal women that can be an important risk factor for atherosclerosis and cardiovascular diseases. PMID- 23661878 TI - Maternal characteristics influencing birth weight and infant weight gain in the first 6 weeks post-partum: A cross-sectional study of a post-natal clinic population. AB - BACKGROUND: To investigate the relationship between certain maternal characteristic and infant birth weight and weight gain in puerperal women seen at a tertiary health centre. MATERIALS AND METHODS: We measured the weight of 318, randomly selected infants after a complete physical examination at birth and at 6 weeks postnatal using standard procedures and related them to certain maternal characteristics. RESULTS: There were 318 women and baby pairs. Maternal ages ranged from 16 to 42 years, with a mean of 25.6+/-1.3 years. Mean birth weight of babies was 3.10+/-1.89 kg; mean gestational age was 36+/-4.6 weeks, with 9.4% and 3.0% of babies born having low birth weight or Macrosomia respectively. Mothers from the North of the country, multiparity and systolic and/or diastolic hypertensions were factors associated with low birth weight. At 6 weeks, 27.1% of infants failed to gain weight as expected for their age. Similarly, 37.0% of infants born to mothers with some tertiary education showed slowed weight gain compared with those who had secondary (19.2%) or primary (14.7%) education, P=0.03. Maternal weight at delivery positively correlated with birth weight of the infant (r=0.357, P<0.001). However, maternal weight and blood pressure negatively correlated with infant weight gain at 6 weeks post-delivery. CONCLUSION: Our study demonstrates that certain maternal characteristics could play a role in the birth weight and early infant weight gain, and are preventable through simple public health approaches. PMID- 23661877 TI - The sensitivity and specificity of Lassa virus IgM by ELISA as screening tool at early phase of Lassa fever infection. AB - BACKGROUND: Early diagnosis, prompt treatment, and disease containment are vital measures in the management of Lassa fever (LF), a lethal and contagious arenaviral hemorrhagic disease prevalent in West Africa. Lassa Virus (LAV) specific Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) test, the gold standard for diagnosis, is unavailable in most centers. Serologic detection of LAV IgM is a more accessible tool and this work was to investigate its adequacy as an early marker for LF. PATIENTS AND METHODS: A prospective case-control study conducted July 2007-March 2011 in a tertiary referral health center in Nigeria. Blood samples for test and control were evaluated for Lassa specific antigens and IgM using RT-PCR (primers S36+ and LVS 339) and indirect ELISA (Lassa Nucleo protein (NP)-Antigen) respectively. RT-PCR outcome was used as standard to test for the sensitivity and specificity of IgM. RESULTS: Of the 37 confirmed cases of LF infection by RT-PCR, 21 (57%) were IgM positive. Amongst the 35 confirmed negative cases (control group), eight were IgM positive. The diagnostic sensitivity and specificity of the IgM assay were 57% and 77% respectively. The negative and positive predictive values of the IgM serological assay were 63% and 72%, respectively, while the efficiency of the test was 67%. CONCLUSION: The specificity and sensitivity of IgM as a screening tool for early detection of LF appear weak and, hence, the need for a reliable LF "rapid screening kit" since RT PCR is unavailable in most centers. In the interim, "high clinical index of suspicion," irrespective of IgM status, requires urgent referral to confirmatory centers. PMID- 23661879 TI - Morphology of root canals in lower human premolars. AB - BACKGROUND: The knowledge of the root canal morphology and the possible anatomical variations of mandibular premolars are important for the successful endodontic treatment of such cases. The aim of this study was to investigate the presence of two or three root canals in extracted first and second mandibular premolars which were collected from health centers in Syria. MATERIALS AND METHODS: One hundred and ten human mandibular premolars (70 first premolars and 40 second premolars) with fully developed roots were investigated. After access the cavity of the teeth, the root canals were explored and radiographs were taken. RESULTS: Premolars with one canal were found in 87% of cases (53% first premolar and 34% second premolar) and premolars with two canals were found in 12% of cases (10% first premolar and 2% second premolar). There was just one case (1%) where a first premolar had three canals. These differences were statistically significant with P<0.05. CONCLUSION: Clinicians should be aware of the anatomical variation in the mandibular premolars and be able to apply this knowledge in radiographical and clinical interpretation. PMID- 23661880 TI - Nonconsensual sexual relationship and prevalence of HIV infection in adolescent in Jos, Nigeria. AB - BACKGROUND: HIV infection in adolescents is promoted by sexual risky behaviours and nonconsensual sex. Nonconsensual sex ranges from forced sex/rape, unwanted touch and inducement by gifts. This study was designed to determine the prevalence of nonconsensual sex (NCS) and HIV infection in adolescents. MATERIALS AND METHODS: Eight hundred and eighty three adolescents from 10 secondary schools were randomly selected and given a questionnaire to fill. All had group pre-test counseling had HIV screening. HIV positive subjects had a confirmatory test done after individual post-test counseling. Ethical clearance was received from the relevant authorities and persons. RESULTS: Of the 883 students, 169 (19.2%) were sexually experienced. Of which 101/169 (59.8%) were males and 40.2% females. Mean age at first sexual debut was 14.4+/-2.6 years; males 13.3+/-2.7 years and females 14.6+/-3.2 years, P=0.006. Seventy three of 127 respondents (57.5%) indicated consensual sex and 42.5% (54/127) indicated NCS. Of the 54 subjects, 74% were females and 22% males. Mean age at first sex in NCS was 13.5 + 3.4 yrs; males, 12.5+/-2.9 yr in NCS and 14+/-2.6 in consensual, P=0.045; females 14+/-3.5 in NCS and 16.5+/-1.2 in consensual P=0.02. Circumstances of sex showed 59.3% were forced sex or rape, 7.4% was following gifts. Over 70% of NCS group use no form of protection. In the population studied 9/883 (1.02%) were HIV positive. Among the sexually experienced HIV prevalence was 2.4% (4/169), and 3.7% (2/54) among NCS. CONCLUSION: Prevalence of NCS is high, occurring at an earlier age and associated with lack of condom use as well as a higher HIV prevalence. PMID- 23661881 TI - Knowledge, attitude, and practice of primary health care physicians in the management of osteoarthritis in Al-Jouf province, Saudi Arabia. AB - BACKGROUND: Primary health care (PHC) physicians manage most patients with osteoarthritis (OA). In Saudi Arabia, very little is known about the management of OA by PHC physicians. This study aims to assess knowledge, attitude, and practice of PHC physicians in the management of OA. MATERIALS AND METHODS: During October 2011, a cross-sectional survey was conducted on physicians who were practicing at the primary care centers in AlJouf province of Saudi Arabia. The physicians were asked to fill a valid questionnaire comprised of 35 closed ended questions, 6 items about their socio-demographic characters, and a very well modified 29 questions about their knowledge, attitude, and practice in the management of OA. Data was processed and analysed using SPSS (version 16) program, the level of significance was set as Chi-square test was applied for analysis of categorical data. RESULTS: Response rate (77/90=85.6% yielded 77 questionnaires for analysis. The mean +/- SD age of respondents was 38 (12.3) years. Majority of the physicians surveyed, 58 (75.3%) considered OA as a common health problem in Saudi Arabia. Only 28 (36.4%) physicians surveyed will achieve continuity of care for OA, whereas more than half (n=44; 57.1%) will refer OA immediately or later to the specialists. The proportion of continuity of care for OA among physicians with diplomas was more than that found among general practitioner (57.1% vs 34.1%; <.05). Only 30 (39%) of physicians appeared to know the radiographic changes associated with OA. 21 (27.3%) of physicians manage an average of 5-10 patients with OA per week. Almost 3/4 (th) of the physicians (n=57; 74%) prescribe NSAIDs, and only (n=14; 18.2%) prescribe acetaminophen for OA. Less than 1/5 (th) of the physicians surveyed (n=12; 15.6%) prescribe herbal medicine for OA. Almost all physicians subscribe to regular training programs about OA. CONCLUSIONS: Appropriate attitude with lack of knowledge was found, and practice of our physicians with regards to this disorder appeared inappropriate. More education focusing on the disorder is recommended. PMID- 23661882 TI - Awareness and knowledge of disease surveillance and notification by health-care workers and availability of facility records in Anambra state, Nigeria. AB - BACKGROUND: Disease surveillance and notification (DSN) is part of the Health Management Information System (HMIS) which comprises databases, personnel, and materials that are organized to collect data which are utilized for informed decision making. The knowledge about DSN is very important for the reporting of notifiable diseases. OBJECTIVE: The aim of this study is to examine the awareness and knowledge of health-care workers about DSN, and availability of facility records in Anambra State, Nigeria. MATERIALS AND METHODS: The study was a descriptive cross-sectional one in which relevant data were collected from health care workers selected by a multistage sampling technique. Qualitative information was also elicited by key informant interviews, whereas an observational checklist, preceded by a desk review was used to examine the availability of facility records. RESULTS: Although 89.8% of the health-care workers were aware of the DSN system, only 33.3, 31.1, and 33.7% of them knew the specific uses of forms IDSR 001, IDSR 002, and IDSR 003 (IDSR: Integrated Diseases Surveillance and Response), respectively. Knowledge of use of the various forms at the facility and local government area (LGA) levels were generally low, although the observational checklist revealed that IDSR 001 and IDSR 002 forms were predominantly found in primary health-care facilities. HMIS forms were less likely to be available in secondary health-care facilities (chi(2)=7.67, P=0.005). CONCLUSIONS: Regular training and retraining of concerned health-care workers on DSN at the LGA level is recommended. This should run concurrently with adequate and regular provision of IDSR forms, copies of the standard case definitions, and other necessary logistics to the health-care facilities by the local and state governments. PMID- 23661883 TI - Knowledge of medical ethics among Nigerian medical doctors. AB - BACKGROUND: The knowledge of medical ethics is essential for health care practitioners worldwide. The main objective of this study was to evaluate the knowledge of medical doctors in a tertiary care hospital in Nigeria in the area of medical ethics. MATERIALS AND METHODS: A cross-sectional questionnaire-based study involving 250 medical doctors of different levels was carried out. The questionnaire, apart from the bio-data, also sought information on undergraduate and postgraduate training in medical ethics, knowledge about the principles of biomedical ethics and the ethical dilemmas encountered in daily medical practice. RESULTS: One hundred and ninety (190) respondents returned the filled questionnaire representing a response rate of 76%. One hundred and fifty-two respondents (80%) have had some sort of medical ethics education during their undergraduate level in the medical education. The median duration of formal training or exposure to medical ethics education was 3.00 hours (range: 0-15). One hundred and twenty-nine respondents have read at least once the code of medical ethics of the Medical and Dental Council of Nigeria while 127 (66.8%) have some general knowledge of the principles of biomedical ethics. The breakdown of the identified ethical dilemmas shows that discharge against medical advice was the most identified by the respondents (69.3%) followed by religious/cultural issues (56.6%) while confidentiality was recognized by 53.4%. CONCLUSION: The knowledge of medical ethics by Nigerian medical doctors is grossly inadequate. There is an urgent need for enhancement of the teaching of the discipline at both undergraduate and postgraduate levels in Nigeria. PMID- 23661884 TI - Brain computed tomography of patients with HIV/AIDS before the advent of subsidized treatment program in Nigeria. AB - BACKGROUND: The objective is to study intracranial complications of HIV/AIDS using brain-computed tomography in patients who presented with neurological features before the advent of subsidized HIV/AIDS treatment program with highly active antiretroviral therapy (HAART) in Nigeria. MATERIALS AND METHODS: Retrospective study of patients' records retrieved from radiology and medical records departments of the hospital. The studied patients had HIV/AIDS and presented with neurological features and underwent CT scan. RESULTS: A total of 36 patients who tested positive for HIV and who presented with neurological features suspected to be complications of AIDS were examined with CT scan. They consisted of 24 male and 12 females. The male to female ratio was 2:1. The age of the patients ranged from 27 to 45 years. Seventeen patients (47.2%) were aged 30 34 years. Twenty-four patients (60%) were single while 12 (40%) were married. Twenty-seven patients (75%) were infected with HIV 1 and 2, five patients (13.9%) were infected only with HIV-1 while four were infected with only HIV-2. Presenting neurological complaints include left hemiplegia 13 (36.1%), right hemiplegia 6 (16.7%), coma 7 (19.4%), memory loss/dementia complex 5 (13.9%), convulsion with coma 2 (5.6%), left hemi-pariesis with memory loss 2 (5.6%), and staggering gait 1 (2.8%). The findings in CT scan include infarcts-like lesions 14 (38.9%), multiple ring-enhancing lesions 7 (19.4%), cerebral atrophy 5 (13.9%), multiple nodular lesions 4 (11.1%), acute intracerebral hemorrhage 3 (8.3%), cerebral hemiatrophy 2 (5.6%), and solitary ring-enhancing lesions 1 (2.8%). Eight patients with single or multiple ring enhancing lesions were treated with empirical treatment for toxoplasmosis but only three (37.5%) made full recovery. CONCLUSION: Brain CT scan showed extensive structural damages in patients with HIV/AIDS who were not treated with HAART. Out-of-pocket payment for investigations and treatment and absence of HAART could be partly responsible for high rate of advanced disease. PMID- 23661885 TI - Gestational age at booking for antenatal care in a tertiary health facility in north-central, Nigeria. AB - BACKGROUND: Early initiation of antenatal care is widely believed to improve maternal and fetal outcome. This study was designed to ascertain the gestational age at booking using World Health Organization recommendations for developing countries. MATERIALS AND METHODS: This cross-sectional study was carried out using interviewer-administered questionnaire to 345 willing participants at a booking clinic in a tertiary health facility in North-Central, Nigeria. RESULTS: A total of 345 women were interviewed. The average age of the clients was 27.1+/ 5.1 years. Almost (45.8%) had at least secondary level of education. One-third of the women were not working women. The average gestational age at booking was 19.1+/-7.8. Late booking (>=17 weeks) was significantly influenced by the client's level of education (P=0.017). Reasons for booking late were given as follows: Not being sick (26.1%), Lack of knowledge of booking time (22.8%), having booked elsewhere (14.1%), financial constraints (9.2%), fear of too many follow-up visits (4.9%), spouse's un co-operative attitude (3.9%), lack of transport to the health care facility (2.2%), and other minor reasons (16.8%). CONCLUSION: Most women booked for antenatal care (ANC) late. Efforts toward maternal education, public health enlightenment campaigns, poverty reduction, and use of focused antenatal care model should be sustained as measures to encourage early initiation of ANC. PMID- 23661886 TI - Photometric facial analysis of the Igbo Nigerian adult male. AB - BACKGROUND: A carefully performed facial analysis can serve as a strong foundation for successful facial reconstructive and plastic surgeries, rhinoplasty or orthodontics. AIM: The purpose of this study is to determine the facial features and qualities of the Igbo Nigerian adult male using photometry. MATERIALS AND METHODS: One hundred and twenty subjects aged between 18 and 28 years were studied at the Anambra State University, Uli, Nigeria. The frontal and right lateral view photographs of their faces were taken and traced out on tracing papers. On these, two vertical distances, nasion to subnasal and subnasale to menton, and four angles, nasofrontal (NF), nasofacial, nasomental (NM) and mentocervical, were measured. RESULTS: The result showed that the Igbo Nigerian adult male had a middle face that was shorter than the lower one (41.76% vs.58.24%), a moderate glabella (NF=133.97 degrees ), a projected nose (NM=38.68 degrees ) and a less prominent chin (NM=125.87 degrees ). CONCLUSION: This study is very important in medical practice as it can be used to compare the pre- and post-operative results of plastic surgery and other related surgeries of the face. PMID- 23661887 TI - Paediatric head and neck cancers in Nigeria: Implications for treatment planning in resource limited settings. AB - BACKGROUND: The head and neck (H/N) is a common site for childhood cancers. This study examined all cases of H/N childhood cancers diagnosed in a major teaching hospital in Nigeria over 18 years to determine patterns of broad lineage cancer groups. MATERIALS AND METHODS: Primary pediatric childhood malignancies diagnosed between 1990 and 2008 were analysed. Logistic regression models were fitted to determine significant clinical correlates of childhood cancer. RESULTS: Lymphomas were the commonest cancers (49.5%). After controlling for site and age, there was no significant difference in the incidence of Burkitt's lymphoma (BL) by sex (P=0.423). The jaw bones (mandible and maxilla) were the commonest sites in the H/N for involvement of BL, with over 20 times the odds of occurrence when compared to other non-jaw sites of the H/N region (Adjusted Odds Ratio [AOR]=21.41, P<0.001). Among the jaw bones, there was no significant difference in the occurrence of BL (P=0.860). CONCLUSION: Lymphomas are the commonest cancer group among children in Nigeria. In resource limited settings where diagnoses depend majorly on clinical intuition, an awareness of predictors of a disease can shorten the time spent on arriving at a working diagnosis and guide the immediate choice of investigations and treatment. PMID- 23661888 TI - Prevalence of hepatitis B surface antigen seropositivity among HIV-infected and non-infected individuals in Nnewi, Nigeria. AB - BACKGROUND: Co-infection of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) is common as both viruses share common routes of transmission. HIV significantly affects the natural history of HBV, hence the need to determine the prevalence of co-infection. MATERIALS AND METHODS: This was a retrospective study between 2005 and 2009, in which is a total of 2018 subjects who reported at our University Teaching Hospital blood bank and human immunodeficiency virus clinic were studied. Hepatitis B surface antigen (HBsAg) was tested for using a one step lateral flow rapid chromatographic immunoassay (Acumen labs and diagnostic centre, Bangalore, India) and HIV 1/2 was tested using two kits, Determine (made by Abbot, Japan for Inverness Medical, Japan). RESULTS: A total of 2018 subjects were studied out of which 1176 were HIV positive (964 males and 212 females) and 842 (334 males and 508 females) were negative. The prevalence of HBsAg positivity in the study population was 5.9%. It was 6.3% and 5.6% in the HIV-infected and un infected population, respectively. Although the prevalence was higher in those who are HIV infected, the difference was not statistically significant (P=0.52). Males who were HIV positive were found to be more likely to have co-infection than females (8.7% vs. 4.2%, P=0.02, OR=1.917). CONCLUSION: This study showed that in south-eastern Nigeria, infection with HBV is relatively common in both HIV-infected and un-infected individuals. Routine screening for HBV should be done for all HIV positive individuals. PMID- 23661889 TI - Total laparoscopic hysterectomy: A case report from ILE-IFE, Nigeria. AB - Total laparoscopic hysterectomy (TLH) is an advanced gynecological laparoscopic procedure that is widely performed in the developed world. However, its feasibility in resource-poor settings is hampered by obvious lack of equipments and/or skilled personnel. Indeed, TLH has never been reported from any Nigerian hospital. We present a 50-year-old multipara scheduled for hysterectomy on account of pre-malignant disease of the cervix, who had TLH with bilateral salpingo-oophorectomy in the Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, southwestern Nigeria and was discharged home on the first post operative day. She was seen in the gynecology clinic a week later in stable condition and she was highly pleased with the outcome of her surgery. This case is presented to highlight the attainability of operative gynecological laparoscopy, including advanced procedures like TLH in a resource-constrained setting, through the employment of adequate local adaptation and clever improvisation. PMID- 23661890 TI - Incisional endometriosis: A rare cause for a painful scar - A report and commentary. AB - Endometriosis is the presence of endometrial tissue outside the Uterus. The true incidence of endometriosis is not really known, but it is believed that 10-15% of all women in their reproductive age will develop endometriosis and 25-35% of all women who are infertile have endometriosis. Incisional endometriosis (IE) is a rare entity reported in 0.03-1.08% of women following obstetric or gynaecologic surgeries. Most cases reported in literature have appeared after caesarean sections and were often clinically mistaken for hernia, abscess, suture granuloma or lipoma. The diagnosis is frequently made only after excision of the diseased tissue. A case report of a patient with a painful troublesome scar after a caesarean section is presented. PMID- 23661891 TI - Helicobacter pylori eradication therapy: A review of current trends. AB - Helicobacter pylori has been implicated in the formation of chronic gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue lymphoma and gastric cancer. Eradication of H. Pylori has been recommended as treatment and prevention for these complications. This review is based on a search of Medline, the Cochrane Database of Systemic Reviews, and citation lists of relevant publications. Subject heading and key words used include H. Pylori, current treatment and emerging therapy. Only articles in English were included. There has been a substantial decline in the H. pylori eradication rates over the years, despite the use of proton pump inhibitor and bismuth salts for triple and quadruple therapies respectively. The reasons for eradication failure are diverse, among them, antibiotic resistance is an important factor in the treatment failure. Primary resistance to clarithromycin or metronidazole significantly affects the efficacy of eradication therapy. This has led to the introduction of second line, third line "rescue," and sequential therapies for resistant cases. Subsequently, new antibiotic combinations with proton-pump inhibitors and bismuth salts are being studied in the last decade, to find out the antibiotics that are capable of increasing the eradication rates. Some of these antibiotics include Levofloxacin, Doxycycline, Rifaximin, Rifampicin, Furazolidone based therapies. Studies are ongoing to determine the efficacy of Lactoferrin based therapy. PMID- 23661892 TI - Serum lipid profile in alcoholic cirrhosis: A study in a teaching hospital of north-eastern India. AB - BACKGROUND: Alcoholic cirrhosis is often associated with impaired lipid metabolism. However, there are only a few studies regarding lipid profile in alcoholic cirrhosis that have been undertaken in India. The aim of the study is to assess the degree of alteration of serum lipid profile in alcoholic cirrhotic patients and also to detect its relationship with the age of the patients and the alcohol consumption pattern. PATIENTS AND METHODS: This cross-sectional study was conducted in a teaching hospital of north-eastern India for 1 year with 100 patients with alcoholic cirrhosis (cases) and 50 healthy individuals (controls) without history of alcohol consumption. A questionnaire of personal characteristics including history of alcoholism was completed for each patient. Serum lipid profile (total, low-density lipoprotein (LDL), high-density lipoprotein (HDL) cholesterol and triglyceride) was recorded for each case and control. t test of significance was applied for statistical analysis. RESULTS: Majority of the cases were in the 41-50 years age group. There was no relationship of cirrhosis with the type of alcoholic beverage, but a definite relationship was observed with the quantity and the duration of alcohol consumption. In patients with cirrhosis, the total serum cholesterol level was decreased. There was a significant decrease in serum HDL and LDL cholesterol compared with the control group ( P < 0.001). However, the serum triglyceride levels were significantly increased in alcoholic cirrhotic patients compared with the control group ( P < 0.001). CONCLUSION: In this study, we found that there was marked alteration of serum lipid profile values in patients with alcoholic cirrhosis compared with normal, non-cirrhotic individuals. Therefore, a search for lipid profile abnormality should be performed in every cirrhotic patient. PMID- 23661893 TI - The human health implications of crude oil spills in the Niger delta, Nigeria: An interpretation of published studies. AB - BACKGROUND: The health hazards created by oil exploration and exploitation are covert and slow in action. They are not given the deserved attention in official documents in Nigeria, even as they can be major contributors to the disease burden in oil-bearing communities. This study is an interpretation of the data reported in several published studies on crude oil spills in the Niger delta region, Nigeria. MATERIALS AND METHODS: A manual and Internet search was conducted to extract quantitative data on the quantity of crude oil spilled; the concentrations of the pollutants in surface water, ground water, ambient air and plant and animal tissue; and the direct impact on human health and household food security. RESULTS: An average of 240,000 barrels of crude oil are spilled in the Niger delta every year, mainly due to unknown causes (31.85%), third party activity (20.74%), and mechanical failure (17.04%). The spills contaminated the surface water, ground water, ambient air, and crops with hydrocarbons, including known carcinogens like polycyclic aromatic hydrocarbon and benxo (a) pyrene, naturally occurring radioactive materials, and trace metals that were further bioaccumulated in some food crops. The oil spills could lead to a 60% reduction in household food security and were capable of reducing the ascorbic acid content of vegetables by as much as 36% and the crude protein content of cassava by 40%. These could result in a 24% increase in the prevalence of childhood malnutrition. Animal studies indicate that contact with Nigerian crude oil could be hemotoxic and hepatotoxic, and could cause infertility and cancer. CONCLUSIONS: The oil spills in the Niger delta region have acute and long-term effects on human health. Material relief and immediate and long-term medical care are recommended, irrespective of the cause of the spill, to ensure that the potential health effects of exposures to the spills are properly addressed. PMID- 23661894 TI - The impact of seat-belts in limiting the severity of injuries in patients presenting to a university hospital in the developing world. AB - BACKGROUND: Road traffic injuries are major public health problems and a leading cause of death and injury around the world. Approximately 1.2 million people are killed each year in road crashes worldwide, with up to 50 million more injured. Over 95% of these deaths and injuries occur in the low- and middle-income countries of the world. The aim of this study is to evaluate the impact of the use of seat-belts in reducing the severity of injuries from road traffic crashes and to determine the compliance and awareness of the importance of the use of seat-belts among Nigerian motorists. PATIENTS AND METHODS: The injury patterns and outcome of care in 140 patients who were seen at the emergency department of our tertiary hospital were evaluated. Initial care and resuscitation was carried out on all patients using the advanced trauma life support protocol. RESULTS: A total of 81 (57%) patients used seat-belts, while 59 (42.1%) did not. Nineteen (13.6%) patients died as a result of their injuries; 4 (21.1%) of these had used seat-belts, while 15 (79%) had not (P = 0.001). The mortality rate of 79% for patients who did not use seat-belt was statistically significant. CONCLUSIONS: The seat-belt is an effective safety tool that not only saves lives, but also significantly reduces the severity of the injury that a vehicle occupant may have sustained if they were not wearing the device. More public enlightenment is needed to increase the awareness and compliance of use of seat-belts among Nigerian motorists. PMID- 23661895 TI - Cord blood haemoglobin and ferritin concentrations in newborns of anaemic and non anaemic mothers in Lagos, Nigeria. AB - BACKGROUND: Pre-delivery haemoglobin and serum ferritin concentrations of anaemic and non-anaemic mothers were determined, and cord blood haemoglobin and serum ferritin concentrations of their newborns were compared. This is to establish the mean values for pre-delivery haemoglobin and serum ferritin concentrations of anaemic and non-anaemic mothers and the cord blood haemoglobin and serum ferritin concentrations of their newborns at term. MATERIALS AND METHODS: A case-control study was done involving 142 pregnant women and their newborns. They were divided into two groups - the anaemic group (n = 65) and the non-anaemic (n = 77) group. Five millilitres of blood was collected from each woman and 2 ml was collected from the cord of their newborns into ethylenediaminetetraacetic acid (EDTA) bottle and plain bottle for full blood count analysis and ferritin assay, respectively. RESULTS: The mean pre-delivery haemoglobin concentrations of the women in anaemic group and non-anaemic group were 9.5 +/- 1.01 g/dl and 12.15 +/- 1.07 g/dl, respectively, and their mean serum ferritin concentrations were 64.45 +/- 138.76 MUg/l and 32.83 +/- 35.36 MUg/l, respectively. The mean cord blood haemoglobin concentrations for anaemic and for non-anaemic groups were 12.54 +/- 2.54 g/dl and 13.44 +/- 2.23 g/dl (P = 0.02), respectively, and the mean cord blood serum ferritin concentrations (non-anaemic, 69.38 +/- 78.88 MUg/l; anaemic, 7.26 +/- 115.60 MUg/l) (P = 0.00) were higher in the newborns of non-anaemic than of anaemic mothers. Significant association was found between maternal anaemia and cord blood ferritin concentrations (P = 0.025). CONCLUSION: Maternal anaemia has significant effects on cord blood haemoglobin and serum ferritin concentrations. PMID- 23661896 TI - Barriers to utilisation of maternal health services in a semi-urban community in northern Nigeria: The clients' perspective. AB - BACKGROUND: Low level of utilisation of maternal health services is a major factor responsible for high maternal mortality in northwestern region of Nigeria. This study was aimed at determining the barriers to utilisation of maternal health services from the perspective of mothers in northwestern Nigeria. MATERIALS AND METHODS: A cross-sectional study of 150 mothers, selected through multistage technique, was conducted. Data were collected using a structured interviewer-administered questionnaire, and analysed using SPSS statistics 17.0. RESULTS: Only 2.7% utilised preconception service, 98.7% antenatal care service (ANC), 24.0% delivery, 35.3% postnatal care and 14.0% utilised family planning service. Major reasons for non-utilisation of delivery service were not having a delivery complication in the past (57% (CI = 47.4-66.1)) and negative provider attitude (23.7% (CI = 16.4-32.7)). For non-utilisation of postnatal care, the major reasons were also not having a postnatal complication in the past (60.8% (CI = 50.4-70.4)) and negative provider attitude (27.8% (CI = 19.4-38.0)). As for non-utilisation of family planning service, the major reason was desire to have more children (32.6% (CI = 24.7-41.4)). Reasons for non-use of preconception care and ANC were not computed because respondents to these questions were not enough; only 6 (4.0%) were aware of preconception care in the first place and only 2 (1.3%) were not using ANC. CONCLUSION: Despite living near a health facility, most of the mothers were not using maternal health services. It is recommended that while there is the need to raise awareness on the utilisation of maternal health services, bring it closer to the mothers and make it more affordable, there is a more pressing need to improve its quality, especially through the alleviation of negative attitude of health care providers. PMID- 23661897 TI - Attitude, perception and feedback of second year medical students on teaching learning methodology and evaluation methods in pharmacology: A questionnaire based study. AB - BACKGROUND: To assess the student's attitude, perception and feedback on teaching learning methodology and evaluation methods in pharmacology. MATERIALS AND METHODS: One hundred and forty second year medical students studying at Smt. Kashibai Navale Medical College, Pune, were selected. They were administered a pre-validated questionnaire containing 22 questions. Suggestions were also asked regarding the qualities of good pharmacology teachers and modification in pharmacology teaching methods. Descriptive statistics were used and results were expressed as percentage. RESULTS: Majority of the students found cardiovascular system (49.25%) as the most interesting topic in pharmacology, whereas most of the students opined that cardiovascular system (60.10%), chemotherapy (54.06%) and central nervous system (44.15%) are going to be the most useful topics in internship. 48.53% students preferred clinical/patient-related pharmacology and 39.13% suggested use of audiovisual-aided lectures. Prescription writing and criticism of prescription were amongst the most useful and interesting in practical pharmacology. Students expressed interest in microteaching and problem based learning, whereas seminars, demonstrations on manikin and museum studies were mentioned as good adjuvants to routine teaching. Multiple Choice Question (MCQ) practice tests and theory viva at the end of a particular system and periodical written tests were mentioned as effective evaluation methods. Students were found to have lot of interest in gathering information on recent advances in pharmacology and suggested to include new drug information along with prototype drugs in a comparative manner. CONCLUSION: There is a need of conducting few microteaching sessions and more of clinical-oriented problem-based learning with MCQ-based revisions at the end of each class in the pharmacology teaching at undergraduate level. PMID- 23661898 TI - Is there any relationship between Chlamydophila pneumoniae and coronary atherosclerosis among Iranians? AB - BACKGROUND: Atherosclerosis is a coronary heart disease, andis the most common cause of death in the industrialized world. Some studies suggested that atherosclerosis may be triggered by infectious agents, mostly Chlamydophila pneumoniae. However, the role of C. pneumoniae in the pathogenesis of coronary atherosclerosis is still controversial. OBJECTIVES: This study was performed to evaluate whether there is a significant association between coronary artery atherosclerosis and C. pneumoniae by the polymerase chain reaction (PCR) method. MATERIALS AND METHODS: This case-control study was carried out on formalin-fixed paraffin-embedded tissue biopsies of the coronary arteries obtained from 30 patients with coronary atherosclerosis and 30 subjects without atherosclerosis living in Northeast of Iran. All subjects' weight and height were determined, and the body mass index was calculated. We also reviewed the medical history and previous laboratory reports of patients. Deoxyribonucleic acid (DNA) was extracted, and C. pneumonia DNA was amplified and detected using PCR assay. RESULTS: The age of the patients in the study group was from 18 to 50 years, and the male to female ratio was 5:1. Only oneout of the 30 coronary tissue samples had positive PCR for C. pneumoniae (3.3%), while it was negative for patients in the control group. CONCLUSIONS: This study showed that C. pneumoniae infection is not strongly associated with coronary artery atherosclerosis in Northeast of Iran. PMID- 23661899 TI - Barriers to postnatal care and exclusive breastfeeding among urbanwomen in southeastern Nigeria. AB - BACKGROUND: Available evidence shows that only a small proportion of Nigerian women access postnatal care and practice exclusive breastfeeding. Given that both interventions are critical to the survival of both the mother and the new born, it is important to identify factors that militate against an effective postnatal care and exclusive breastfeeding in the country, in order to scale up services. The aim was to determine the major barriers to postnatal care and exclusive breastfeeding among urban women in southeastern Nigeria. MATERIALS AND METHODS: A cross-sectional survey of 400 urban market women using semistructured questionnaires and focus group discussions. RESULTS: Out of 400 women interviewed, 365 (91.7%) attended postnatal clinic. Lack of knowledge about postnatal care services (42.2%; n = 14), distant location of the hospitals (36.4%; n = 12) and feeling that postnatal visits was not necessary (21.1%; n = 7) were the main reasons for non-attendance to postnatal clinic. With respect to exclusive breastfeeding, 143 (35.9%) of the women practiced EBF. The main reasons for nonpractice of EBF were that EBF was very stressful (26.2%; n = 67), mother's refusal (23.5%; n = 60), and the feeling that EBF was not necessary (18.1%; n = 46). Thirty five (13.7%) of the women were constrained by time while the husband's refusal accounted for 1.5% (n = 3) of the reasons for nonpractice of exclusive breastfeeding. CONCLUSION: Poor knowledge and inaccessibility to health facilities were the main obstacles to postnatal care while the practice of exclusive breastfeeding was limited by the stress and mothers refusal. PMID- 23661900 TI - Childhood acquired heart diseases in Jos, north central Nigeria. AB - BACKGROUND: The patterns of childhood acquired heart diseases (AHD) vary in different parts of the world and may evolve over time. We aimed to compare the pattern of childhood AHD in our institution to the historical and contemporary patterns in other parts of the country, and to highlight possible regional differences and changes in trend. MATERIALS AND METHODS: Pediatric echocardiography records spanning a period of 10 years were reviewed. Echocardiography records of children with echocardiographic or irrefutable clinical diagnoses of AHD were identified and relevant data extracted from their records. RESULTS: One hundred and seventy five children were diagnosed with AHD during the period, including seven that had coexisting congenital heart disease (CHD). They were aged 4 weeks to 18 years (mean 9.84?4.5 years) and comprised 80 (45.7%) males and 95 (54.3%) females. Rheumatic heart disease (RHD) was the cause of the AHD in 101 (58.0%) children, followed by dilated cardiomyopathy (33 cases, 18.9%) which was the most frequent AHD in younger (under 5 years) children. Other AHD encountered were cor pulmonale in 16 (9.1%), pericardial disease in 15 (8.6%), infective endocarditis in 8 (4.6%) and aortic aneurysms in 2 (1.1%) children. Only one case each of endomyocardial fibrosis (EMF) and Kawasaki Disease were seen during the period. CONCLUSIONS: The majority of childhood acquired heart diseases in our environment are still of infectious aeitology, with RHD remaining the most frequent, particularly in older children. Community based screening and multicenter collaborative studies will help to better describe the pattern of AHD in our country. More vigorous pursuit of the Millennium development goals will contribute to reducing the burden of childhood acquired heart diseases in the country. PMID- 23661901 TI - Risk factors, ulcer grade and management outcome of diabetic foot ulcers in a Tropical Tertiary Care Hospital. AB - BACKGROUND: The objective was to determine the risk factors, ulcer grade, and management outcome of patients with diabetic foot ulcers (DFU) managed in a tropical tertiary hospital. MATERIALS AND METHODS: This is a prospective observational study of all consecutive diabetes mellitus (DM) patients with DFU admitted in the University of Benin Teaching Hospital, Benin City, Nigeria over a 26-month period. Data documented included age, gender, type of DM, duration of DM, risk factors of DFU, duration of DFU, Wagner's ulcer grade, and the blood glucose at presentation and management outcome. RESULTS: Thirty-four (55.7%) of the 61 study subjects were females. Their mean age was 56.29+/-12.71 years. 85.2% had type 2 DM. 13.1% of the patients were newly diagnosed diabetic at presentation. The mean duration of DM was 7.8+/-6.98 years. The mean duration of DFU was 46.09+/-47.82 days and the casual blood glucose level at presentation was 18.41+/-9.31mmol/l. Risk factors of DFU included spontaneous blisters (52.46%), peripheral vascular disease (44.3%), peripheral neuropathy (42.6%), and visual impairment (21.3%). The common ulcer grades were IV (44.3%) and III (36.1%).The amputation rate was 52.2% while the mortality rate was 14.3%.The baseline ulcer grade was significantly associated with the risk of lower extremity amputation, and the odds ratio was 2.36 (95% 1.06-5.21). CONCLUSIONS: Spontaneous blisters, peripheral vascular disease, peripheral neuropathy,and visual impairment are common risk factors of DFUs. Many of our patients with DFUs presented with grade IV and V ulcers with the resultant high rate of lower extremity amputations (LEAs). Early presentation and treatment of DFUs will reduce LEAs. PMID- 23661902 TI - Application of queuing theory to patient satisfaction at a tertiary hospital in Nigeria. AB - BACKGROUND: Queuing theory is the mathematical approach to the analysis of waiting lines in any setting where arrival rate of subjects is faster than the system can handle. It is applicable to healthcare settings where the systems have excess capacity to accommodate random variations. MATERIALS AND METHODS: A cross sectional descriptive survey was done. Questionnaires were administered to patients who attended the general outpatient department. Observations were also made on the queuing model and the service discipline at the clinic. Questions were meant to obtain demographic characteristics and the time spent on the queue by patients before being seen by a doctor, time spent with the doctor, their views about the time spent on the queue and useful suggestions on how to reduce the time spent on the queue. A total of 210 patients were surveyed. RESULTS: Majority of the patients (164, 78.1%) spent 2 h or less on the queue before being seen by a doctor and less than 1 h to see the doctor. Majority of the patients (144, 68.5%) were satisfied with the time they spent on the queue before being seen by a doctor. Useful suggestions proffered by the patients to decrease the time spent on the queue before seeing a doctor at the clinic included: that more doctors be employed (46, 21.9%), that doctors should come to work on time (25, 11.9%), that first-come-first served be observed strictly (32, 15.2%) and others suggested that the records staff should desist from collecting bribes from patients in order to place their cards before others. The queuing method employed at the clinic is the multiple single channel type and the service discipline is priority service. The patients who spent less time on the queue (<1 h) before seeing the doctor were more satisfied than those who spent more time (P < 0.05). CONCLUSION: The study has revealed that majority of the patients were satisfied with the practice at the general outpatient department. However, there is a need to employ measures to respond to the suggestions given by the patients who are the beneficiaries of the hospital services. PMID- 23661903 TI - Primary neuroendocrine carcinoma of the thymus. AB - Primary neuroendocrine tumors of the thymus, previously known as carcinoid tumors of the thymus, are unusual and rare tumors, and prognosis for these patients has been difficult to predict. We hereby report a case of primary neuroendocrine tumor of the thymus that had an aggressive and fatal course in spite of surgical resection and adjuvant chemotherapy. These tumors must be regarded as a malignant neoplasm that is prone to metastasize to distant sites, even after total excision. PMID- 23661904 TI - Analysis of the BOLD Characteristics in Pass-Band bSSFP fMRI. AB - Balanced steady-state free precession (bSSFP) has been proposed as an alternative method to acquire the blood oxygenation level dependent contrast. Particularly, pass-band bSSFP functional magnetic resonance imaging (fMRI) is believed to utilize the T2 sensitivity of bSSFP in a relatively wide and flat off-resonance frequency band of the bSSFP profile. The method has a potential to provide higher signal to noise ratio (SNR) efficiency with reduced imaging artifacts compared to conventional approaches. Previous experimental results suggested that the level of the functional contrast and its characteristics are significantly influenced by the sequence parameters. However, few of these contrast characteristics have been investigated systematically. In this study, a computer simulation was performed to investigate the sources of functional contrast and the influence of scan parameters on the functional contrast to elucidate the contrast characteristics of pass-band bSSFP fMRI. Experiments were performed to validate the simulation results. PMID- 23661905 TI - Background and Mathematical Analysis of Diffusion MRI Methods. AB - The addition of a pair of magnetic field gradient pulses had initially provided the measurement of spin motion with nuclear magnetic resonance (NMR) techniques. In the adaptation of DW-NMR techniques to magnetic resonance imaging (MRI), the taxonomy of mathematical models is divided in two categories: model matching and spectral methods. In this review, the methods are summarized starting from early diffusion weighted (DW) NMR models followed up with their adaptation to DW MRI. Finally, a newly introduced Fourier analysis based unifying theory, so-called Complete Fourier Direct MRI, is included to explain the mechanisms of existing methods. PMID- 23661907 TI - Publication process at Lung India: Some FAQs and the editorial perspective. PMID- 23661906 TI - Expression of inflammation-related genes is altered in gastric tissue of patients with advanced stages of NAFLD. AB - Obesity is associated with chronic low-grade inflammation perpetuated by visceral adipose. Other organs, particularly stomach and intestine, may also overproduce proinflammatory molecules. We examined the gene expression patterns in gastric tissue of morbidly obese patients with nonalcoholic fatty liver disease (NAFLD) and compared the changes in gene expression in different histological forms of NAFLD. Stomach tissue samples from 20 morbidly obese NAFLD patients who were undergoing sleeve gastrectomy were profiled using qPCR for 84 genes encoding inflammatory cytokines, chemokines, their receptors, and other components of inflammatory cascades. Interleukin 8 receptor-beta (IL8RB) gene overexpression in gastric tissue was correlated with the presence of hepatic steatosis, hepatic fibrosis, and histologic diagnosis of nonalcoholic steatohepatitis (NASH). Expression levels of soluble interleukin 1 receptor antagonist (IL1RN) were correlated with the presence of NASH and hepatic fibrosis. mRNA levels of interleukin 8 (IL8), chemokine (C-C motif) ligand 4 (CCL4), and its receptor chemokine (C-C motif) receptor type 5 (CCR5) showed a significant increase in patients with advanced hepatic inflammation and were correlated with the severity of the hepatic inflammation. The results of our study suggest that changes in expression patterns for inflammatory molecule encoding genes within gastric tissue may contribute to the pathogenesis of obesity-related NAFLD. PMID- 23661908 TI - Test of reversibility of airway obstruction: Time for a review? PMID- 23661909 TI - A comparison of cognitive functions in non-hypoxemic chronic obstructive pulmonary disease (COPD) patients and age-matched healthy volunteers using mini mental state examination questionnaire and event-related potential, P300 analysis. AB - OBJECTIVE: To assess sub-clinical cognitive dysfunctions in stable chronic obstructive pulmonary disease (COPD) patients having no hypoxemia vs. age-matched healthy volunteers using (i) an electrophysiological test: Auditory event related potential, P300 test and (ii) a questionnaire tool: Mini-mental state examination (MMSE) questionnaire. MATERIALS AND METHODS: EIGHTY MALE SUBJECTS WERE INCLUDED: 40 stable COPD patients (smoking history >20 pack years) and 40 healthy volunteers (HVs). Age, duration of illness, smoking pack years, and spirometric indices were assessed. MMSE scores were evaluated in these groups. Latency of P300 wave and amplitude of P300 wave were studied in both groups to detect P300 abnormalities in COPD group. Correlations of P300 abnormalities with patient characteristic parameters and MMSE scores were assessed. In addition, individual COPD patients having significant cognitive dysfunctions beyond cut-off value of 99(th) percentile of HVs were analyzed. RESULTS: We observed significantly prolonged P300 latency (P < 0.001) and decreased P300 amplitude (P < 0.001) in COPD group. MMSE scores were significantly reduced in COPD group (P < 0.001). 10/40 COPD patients had prolongation of P300 latency, and 27/40 COPD patients had reduced MMSE scores beyond 99(th) percentile of HV. However, we did not observe any statistically significant correlation between P300 abnormalities and patients' characteristics or MMSE scores (P > 0.05 for all). CONCLUSIONS: Our study explores cognitive dysfunctions in stable COPD patients with no hypoxemia. This study highlights the relative importance of using MMSE and P300. Cognitive dysfunctions were detected both by MMSE and P300; however, MMSE abnormalities were more frequent compared to P300 abnormalities (27/40 vs. 10/40) in COPD patients. PMID- 23661910 TI - The role of VATS in the staging of non small cell lung cancer. AB - INTRODUCTION: Since determining of prognosis and treatment method is related to accurate evaluation of TNM staging of non small cell lung cancer (NSCLC), we aimed to evaluate the role of Video-assisted thoracic surgery (VATS) in staging of NSCLC. MATERIALS AND METHODS: This study was performed on 40 patients with NSCLC who had undergone preoperative staging and were candidate for curative surgery between 2008-2010. They underwent VATS immediately before the surgery. After performing VATS, the patients underwent thoracotomy by posterolateral incision unless any criteria of inoperability were present. Diagnostic accuracy of VATS for confirmation or modification of preoperative staging was evaluated. RESULTS: M/F ratio was 21/19. Mean age of the patients was 57.2 +/- 16.64 yrs. The most common symptom was coughing in 90% of patients. 72.5% of the patients had endobronchial mass and only for 27.5% tissue sample was obtained by transthoracic needle biopsy (TTNB) method. After performing VATS, 6 patients were excluded from surgery (3 cases (7.5%) due to seeding plural metastasis, 2 cases (5%) due to N2 involvement and one case (2.5%) due to satellite lesion in other lobes). Other 34 patients underwent surgery. Surgical resection was performed successfully in 31 cases (77.5%), but in 3 cases (7.5%) due to adhesion to hillum of the lung tumor was not resectable. According to the above results, VATS diagnosing accuracy was 92.5%. CONCLUSION: VATS can help to determine TNM staging and prevent unnecessary thoracotomy in some patients and we recommend this method for accurate staging of NSCLC. PMID- 23661911 TI - Does 'weight reduction' help all adult snorers? AB - BACKGROUND: Obesity is now a global epidemic. Obese people are at higher risk of snoring. Weight reduction could influence the prevalence of snoring. Present study tried to find out, whether weight reduction is of benefit in all adult snorers. MATERIALS AND METHODS: It is a cross sectional study, on 349 subjects (196 males and 153 females). They and their spouses were asked for snoring habits. Their neck circumference, height and weight was measured and Body mass index (BMI) was calculated, and they were classified into low normal, high normal, pre-obese and obese BMI groups. Prevalence rates of snoring in different groups were compared, to find out any statistically significant difference, between them. RESULTS: Statistically significant difference, in prevalence rates of snoring was found, when obese and pre-obese group were compared with normal BMI group, separately. No significant difference was found in prevalence rates, when comparison was made between obese and pre-obese group. Difference in prevalence of snoring, was also not significant, when comparison was made between low normal and high normal BMI groups. Neck circumference of snorers was significantly more than the neck circumference of non-snorers in all BMI groups. Gender wise difference, in prevalence of snoring was also not significant. CONCLUSION: Body mass index target needs to be set at 25 kg/m(2), in weight reduction programmes, to achieve clinically relevant response in a snorer. There is no need to put extra emphasis, on further reduction of BMI. Weight reduction, is not helpful in all adult snorers, especially those with normal BMI, where other causes of snoring, like fat around upper airways, need to be considered. PMID- 23661912 TI - Mortality following bone metastasis and skeletal-related events among patients 65 years and above with lung cancer: A population-based analysis of U.S. Medicare beneficiaries, 1999-2006. AB - BACKGROUND: To quantify the impact of bone metastasis and skeletal-related events (SREs) on mortality among older patients with lung cancer. MATERIALS AND METHODS: Using the linked Surveillance, Epidemiology and End Results-Medicare database, we identified patients aged 65 years or older diagnosed with lung cancer between July 1, 1999 and December 31, 2005 and followed them to determine deaths through December 31, 2006. We classified patients as having possible bone metastasis and SREs using discharge diagnoses from inpatient claims and diagnoses paired with procedure codes from outpatient claims. We used Cox regression to estimate mortality hazards ratios (HR) among patients with bone metastasis with or without SRE, compared to patients without bone metastasis. RESULTS: Among 126,123 patients with lung cancer having a median follow-up of 0.6 years, 24,820 (19.8%) had bone metastasis either at lung cancer diagnosis (9,523, 7.6%) or during follow-up (15,297, 12.1%). SREs occurred in 12,665 (51%) patients with bone metastasis. The HR for death was 2.4 (95% CI = 2.4-2.5) both for patients with bone metastasis but no SRE and for patients with bone metastasis plus SRE, compared to patients without bone metastasis. CONCLUSIONS: Having a bone metastasis, as indicated by Medicare claims, was associated with mortality among patients with lung cancer. We found no difference in mortality between patients with bone metastasis complicated by SRE and patients with bone metastasis but without SRE. PMID- 23661913 TI - A study on non-resolving pneumonia with special reference to role of fiberoptic bronchoscopy. AB - CONTEXT: Non-resolving pneumonia is often an area of concern for pulmonologists. Fiber optic bronchoscopy (FOB) may have a special role in etiologic evaluation of non-resolving pneumonias. There is paucity of recent studies in this field. AIMS: This study aimed to assess the patients of non-resolving or slowly resolving pneumonia with special emphasis on efficacy of FOB and computed tomography (CT) guided fine needle aspiration cytology (FNAC) in diagnosis. SETTINGS AND DESIGN: Prospective, observational study conducted in a tertiary care institute over a period of one year. MATERIALS AND METHODS: After fulfilling the definition of non resolving pneumonia by clinical and radiological parameters, patients were evaluated by FOB with relevant microbiological, cytological, histopathological investigations and CT scan of thorax. CT-guided FNAC was done in selected cases where FOB was inconclusive. RESULTS: Sixty patients were enrolled in the study. Mean age was 51.33 +/- 1.71 years with male to female ratio 2:1. Right lung was more commonly involved (65%), and right upper lobe was the commonest site (25%). Pyogenic infection was the commonest etiology (53.3%), bronchogenic carcinoma and tuberculosis accounted for 26.7% and 16.7% cases, respectively. Both, FOB (85.7%) and CT-guided FNAC (91.67%) were very useful for etiological diagnosis of non resolving pneumonia. Both the procedures were safe, and no major complication was observed. CONCLUSIONS: Because of the high yield of FOB, it is very useful and safe diagnostic tool for evaluation of non-resolving pneumonia. CT-guided FNAC also gives good yield when cases are properly selected. PMID- 23661914 TI - Assessment of the lung function status of the goldsmiths working in an unorganized sector of India. AB - CONTEXT: Exposure to various types of fumes and gases are very common in Jewelery industries. No Report is available regarding the effects of those fumes and gases on the respiratory functions of the goldsmiths. Due to lack of proper monitoring of the workplace environments in these unorganized sectors, workers get very much affected by the occupational exposures to those irritants. AIMS: The present study aimed to investigate whether the occupational exposures to fumes and gases might alter the lung functions of the goldsmiths. MATERIALS AND METHODS: A total of 118 goldsmiths and 66 unexposed control subjects were taken randomly for the study. The goldsmiths were further classified in 3 groups according to duration (year) of exposures in the work environment, ETA1 (less than 5 years), ETA2 (more than 5 years but less than 10 years), and ETA3 (more than 10 years). Peak expiratory flow rates (PEFR), forced vital capacity (FVC), and forced expiratory flow rates of different intervals (FEF25%, FEF50%, FEF75%, FEF25-75%) were measured using computerized Spirometer (Maestros Mediline, India). The statistical analyses were carried out using Minitab software version 3. RESULTS: Lung functions of the goldsmiths significantly (P < 0.01) decreased from that of the control group. Inter-group comparison also showed the deteriorations of lung functions was associated with exposure time, and more exposed workers had significantly less (P < 0.01) efficiencies of lung functions. CONCLUSIONS: Workplace fumes and gases were responsible for deterioration of the lung function status of the goldsmiths. PMID- 23661915 TI - Obesity and asthma. AB - Asthma is a chronic disorder affecting millions of people worldwide. The prevalence of asthma is around 300 million and is expected to increase another 100 million by 2025. Obesity, on the other hand, also affects a large number of individuals. Overweight in adults is defined when body mass index (BMI) is between 25 to 30 kg/m(2) and obesity when the BMI >30 kg/m(2). It has been a matter of interest for researchers to find a relation between these two conditions. This knowledge will provide a new insight into the management of both conditions. At present, obese asthma patients may be considered a special category and it is important to assess the impact of management of obesity on asthma symptoms. PMID- 23661917 TI - Pleural tuberculosis presented as multiple pleural masses: An atypical presentation. AB - Tuberculous involvement of the pleura usually presents as pleural effusion, empyema or pleural thickening. Pleural tuberculosis presenting with multiple masses without parenchymal involvement or lymphadenopathy has been reported rarely in the English literature. We report a case of a 68-year-old male with unilateral pleural tuberculosis presenting as multiple different sized nodular masses evident on computed tomography (CT) of the chest with a large hemorrhagic pleural effusion, which initially raised a possibility of mesothelioma. Pleuroscopy also revealed multiple pleural masses. Pathological examination of the biopsy specimen showed multiple epitheloid cell granulomas confirming the diagnosis. PMID- 23661918 TI - Endobronchial leiomyoma: A rare and innocent tumour of the bronchial tree. AB - An endobronchial leiomyoma is a rare tumor of the bronchial tree. Very few cases have been reported in literature. Leiomyomas account for less than 2% of all benign lung tumors. Only one third is endobronchial in location, usually presenting as primary solitary lesions and airway obstruction findings. Literature on primary endobronchial leiomyomas is therefore scarce, with a few more than 100 cases being reported. These tumors arise from the smooth muscle of the bronchial tree. Symptomatology is based on the degree of endoluminal bronchial obstruction and surgical resection has generally been the mainstay of treatment. We describe a case of endobronchial leiomyoma in a 42 year old female. A diagnosis of Primary endobronchial leiomyoma was made on the basis of histopathology and immunohistochemistry. Rarity of this tumor in the bronchial tree with coexisting interstitial peumonitis urges us to report this case. PMID- 23661916 TI - Fat embolism syndrome. AB - Fat embolism syndrome is an often overlooked cause of breathlessness in trauma wards. Presenting in a wide range of clinical signs of varying severity, fat embolism is usually diagnosed by a physician who keeps a high degree of suspicion. The clinical background, chronology of symptoms and corroborative laboratory findings are instrumental in a diagnosis of fat embolism syndrome. There are a few diagnostic criteria which are helpful in making a diagnosis of fat embolism syndrome. Management is mainly prevention of fat embolism syndrome, and organ supportive care. Except in fulminant fat embolism syndrome, the prognosis is usually good. PMID- 23661919 TI - Isoniazid-induced flu-like syndrome: A rare side effect. AB - Drug-induced flu-like syndrome is very rare. It is mainly produced by rifampicin. We report a case of pulmonary tuberculosis (PTB) that developed isoniazid-induced flu-like syndrome, but could be cured with a modified regimen replacing isoniazid with levofloxacin. A 10-year-old girl with PTB was treated with isoniazid (H), rifampicin (R), ethambutol (E), and pyrazinamide (Z). She developed features of flu from the sixth day. Symptoms recurred everyday within 1 h of drug ingestion and subsided automatically by next 12 h. After admission, HREZ were continued. She developed symptoms of flu after 1 h of drug ingestion. Antitubercular therapy (ATT) was stopped and symptoms subsided automatically. Individual drug was started one by one after three days. Severe symptoms of flu developed after taking isoniazid, while other drugs were tolerated well. Levofloxacin was used as an alternative to isoniazid. She was cured after 6 months of chemotherapy. Isoniazid can possibly cause flu-like syndrome and the treating physician should be aware of this possible side effect when using ATT. PMID- 23661920 TI - Removal of self expandable metallic airway stent: A rare case report. AB - Covered self expandable metallic airway stents (SEMS) have been used for benign tracheal stenosis, post intubation tracheal stenosis, tracheal burn or trauma, tracheo-broncho-malacia, and extrinsic compression of trachea. Their placement is considered to be permanent, with open surgery the only way to remove the stent, though there are few cases reports of their removal with the bronchoscope, but the complications after their removal are very high. In our patient, one and a half years after placement of SEMS, she developed cough with dyspnoea, video bronchoscopy showed stenosis above the level of stent with granulation tissue inside the stent, stent fracture in lower part and stent migration to right main bronchus, thus she had all conceivable complications of stent placement. The stent was removed with the help of rigid bronchoscope under general anaesthesia. She was discharged the following day. The case is being reported because it was unique in having all the possible complications of stent placement, and rare as we could take out the stent in Toto. Thirdly, the stent could be removed without any complication. PMID- 23661921 TI - Intense focal Fluoro-deoxyglucose uptake in the lungs with no corresponding computed tomography abnormality. AB - Scenario such as uptake of Fluoro-deoxyglucose (FDG) with no corresponding abnormality on computed tomography (CT) is encountered in case of brown fat uptake. However, it is rarely encountered in the lung parenchyma. We report one such case of a focal FDG uptake in the lung parenchyma with no corresponding CT abnormality, in a treated case of hypopharyngeal cancer. PMID- 23661922 TI - Eosinophilic pleural effusion and giardiasis: A causal or a casual relationship? AB - A case of bilateral eosinophilic pleural effusion with coincidental intestinal infestation of giardia lamblia is being reported. After reviewing the possible causes of this type of pleural effusion, no clinical or laboratory data were obtained which could explain this condition except giardiasis. Moreover the clearance of pleural effusion with the treatment of giardia with metronidazole suggests giardia as the probable cause of bilateral eosinophilic pleural effusion. PMID- 23661923 TI - Reverse halo sign. PMID- 23661924 TI - Multiple bilateral lung nodules. PMID- 23661925 TI - Multiple pulmonary arterial aneurysms in a young male patient with incomplete Behcet's syndrome. PMID- 23661926 TI - Socioeconomic impact of tuberculosis on patients: Further study needed. PMID- 23661927 TI - Comments: Prevalence of obstructive airway diseases by spirometric indices in non smoker subjects with IHD and HTN. PMID- 23661928 TI - Tell-tale signs of a chronic smoker. PMID- 23661929 TI - Pulmonary sequelae of swine flu. PMID- 23661930 TI - Role of computed tomography in the preoperative diagnosis of giant benign solitary fibrous tumor pleura. PMID- 23661931 TI - High relapse rate in RNTCP: An increasing concern and time to intervene. PMID- 23661932 TI - The integration of HR-HPV increases the expression of cyclins A and E in cytologies with and without low-grade lesions. AB - BACKGROUND: Cyclin-A and cyclin-E are regulators of G1-S phase of normal cell cycle. Integration of human papilloma virus high-risk (HR-HPV) could alter this mechanism, and its overexpression has been associated with poor prognosis in cervical cancer. AIM: To determine the expression of cyclin-A and cyclin-E, types of HR-HPV and physical state of DNA in cytologies with the diagnosis of low-grade squamous intraepithelial lesion (LSIL). MATERIALS AND METHODS: 115 cytological specimens in liquid base (liquid-PREP(TM)) were analyzed. 25 specimens were with no signs of SIL (NSIL) and without HPV; 30 with NSIL with low-risk HPV (LR-HPV); 30 with NSIL with HR-HPV; and 30 with both LSIL and HR-HPV. The expression of cyclins was evaluated by immunocytochemistry; and the detection of viral DNA was done by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLPs) for genotyping or sequencing of HPV. The physical state of HPV was evaluated by in situ hybridization with amplification with tyramide. RESULTS: In the cytologies NSIL with LR-HPV, the expression of cyclin-A and cyclin-E was found respectively in 23.3% and 33.3% of the specimens. Among the specimens of NSIL with HR-HPV, 33.3% expressed cyclin-A and 40% cyclin-E, while 100% of the LSILs expressed the 2 cyclins. On the other hand, 100% of the samples NSIL with LR-HPV presented an episomal pattern. Of the specimens of NSIL with HR HPV, 56.6% exhibited an episomal pattern, 23.3% integrated and 20%, mixed. Among the LSILs, 90% were mixed and 10% integrated. CONCLUSIONS: The cyclins A and E are present in the LSILs that occur predominantly in mixed state in the presence of HR-HPV. PMID- 23661933 TI - Cytomorphology of gastrointestinal stromal tumors and extra-gastrointestinal stromal tumors: A comprehensive morphologic study. AB - BACKGROUND: The term gastrointestinal stromal tumors (GIST) is used to refer to those mesenchymal neoplasms of the gastrointestinal tract (GIT) which express CD117, a c-kit proto-oncogene protein. AIMS: To study the cytological features of GIST and extra-gastrointestinal stromal tumors (EGIST), to correlate them with histology and to determine cytological indicators of malignancy. MATERIALS AND METHODS: Cytological smears from patients diagnosed as GIST/EGIST on histology were retrieved. From Jan 2000 to July 2010, 26 GIST (13 primary, 12 metastatic, one recurrent) and seven EGIST (5 primary, one metastatic, one recurrent) cytologic samples from 27 patients were identified. RESULTS: The patients included 20 males and 7 females with a mean age of 50.6 years. Tumor sites included stomach (5), duodenum (5), ileum (2), ileocecal (1), rectum (1), liver (9), retroperitoneum (5), mesentery (1), subcutaneous nodule (1), supra-penile lump (1), ascitic (1) and pleural fluids (1). The smears were cellular with cohesive to loosely cohesive thinly spread irregularly outlined cell clusters held together by thin calibre vessels. The tumor cells were mild to moderately pleomorphic, spindle to epithelioid with variable chromatin pattern and variable cytoplasm. Cellular dyscohesion, nuclear pleomorphism, intranuclear pseudoinclusions, prominent nucleoli, mitosis and necrosis were more prominent in malignant, metastatic and recurrent tumors. CONCLUSIONS: GISTs show a wide spectrum of cytological features and the presence of mitosis, necrosis and nuclear pleomorphism can help in prediction of malignant behavior. Further, cytology is a very useful screening modality in patients of GIST and EGIST to detect early recurrence and metastasis at follow-up. PMID- 23661934 TI - Comparative study of intra-operative cytology, frozen sections, and histology of tumor and tumor-like lesions of nose and paranasal sinuses. AB - BACKGROUND: The nasal cavity and paranasal sinuses - including the maxillary, ethmoid, sphenoid, and frontal sinuses are collectively referred to as the sinonasal tract. Fine needle aspiration (FNA) of paranasal sinus lesions for early diagnosis of neoplastic lesions is difficult due to closed architecture, and only one study has been documented in the literature. AIMS: To find the efficacy of intra-operative cytology and frozen section for frequently encountered tumor and tumor-like lesions of the nose and paranasal sinuses. MATERIALS AND METHODS: Thirty cases were included in this study. The material for cytologic examination and frozen sections were taken per-operatively. Cytological smears were prepared by imprint/squash methods from the representative tissue pieces and stained with Leishman-Giemsa and Papanicolaou. Frozen section and paraffin-embedded section were stained with hematoxylin and eosin stain. A rapid opinion regarding the benign or malignant nature of the lesion and the type of tumor was given. RESULTS: The sensitivity, specificity, and positive predictive value of imprint cytology, squash cytology, and frozen section were 100%, 100%, and 100%; 100%, 96.15%, and 80.0%; and 100%, 96.15%, and 80.0%, respectively. Overall diagnostic accuracy of imprint smears, squash smears, and frozen section was100%, 96.7%, and 96.7%, respectively. Imprint smears had better specificity as cells morphology could be more accurately appreciated. CONCLUSIONS: Intra operative cytology and frozen section examinations of lesions of nose and paranasal sinuses are useful, quick, and reliable diagnostic technique for rapid diagnosis in the operation theatre and can be used as an adjunct to histopathology for better management of patients. PMID- 23661935 TI - Leishman Giemsa cocktail as a new, potentially useful cytological technique comparable to Papanicolaou staining for oral cancer diagnosis. AB - BACKGROUND: Papanicolaou staining is commonly used for staining exfoliative cytology smears with Romanowsky stains being used sparingly. Leishman Giemsa (LG) cocktail, being a relatively new staining technique, has not been used in exfoliative cytology. This easy, cost-effective and one-step technique warrants further study because of its potential application in screening of oral cancer. AIM: To study and evaluate the diagnostic efficiency and reliability of Leishman Giemsa (LG) cocktail in comparison with Papanicolaou (Pap) and May-Grunwald Giemsa (MGG) stains in exfoliated cells for the detection of oral squamous cell carcinoma. MATERIALS AND METHODS: Three smears were prepared from each 100 controls (buccal mucosa) and 100 patients, clinically diagnosed with oral squamous cell carcinoma and stained with Pap, MGG and LG cocktail stains. The slides were evaluated for the staining characteristics of nucleus and cytoplasm. The diagnostic efficiency of each stain was evaluated by comparing the cytologic diagnosis of each stain with the histopathological diagnosis. Finally, the diagnostic reliability was evaluated by comparing the three stains with each other and the histologic diagnosis. STATISTICAL ANALYSIS: The data were statistically evaluated with Friedman test, Wilcoxon sign rank test and McNemar chi square test using SPSS15 software. RESULTS: The results from the histologically confirmed cases of squamous cell carcinoma and the number of cases diagnosed by Pap and LG cocktail were almost identical and both were superior to MGG. The P value obtained for the confirmed cases of squamous cell carcinoma in comparison for Pap vs MGG was 0.001, MGG vs LG cocktail was 0.001 and LG cocktail vs Pap was 0.157. Hence, no statistical significant difference was observed between the diagnostic ability of Pap and LG cocktail stains. CONCLUSION: LG cocktail is an easy, cost-effective and one-step technique comparable to Pap staining; however, it warrants further study in its potential application in screening of oral cancer. PMID- 23661936 TI - Insight to neoplastic thyroid lesions by fine needle aspiration cytology. AB - BACKGROUND: Fine needle aspiration cytology (FNAC) is a valuable adjunct to pre operative screening in the diagnosis of thyroid nodules, and in most cases, it can distinguish between benign and malignant lesions. AIM: To study the cytology of neoplastic thyroid lesions to minimize surgical intervention and for confirmation of the diagnosis by histopathological study. MATERIALS AND METHODS: 100 cases of thyroid FNAC smears were analyzed and cyto-histopathological correlation was done in 47 cases. Galen and Gambino's method was used to calculate the sensitivity and positive predictive value. RESULTS: Of the 100 cases, 90 were diagnosed as neoplastic lesions by FNAC and ten cases as non neoplastic lesions, which turned out to be neoplasms on histopathological study. Among 100 cases, 47 were biopsied and subjected to histopathological study. The sensitivity of FNAC was 75.60%, and positive predictive value was 83.78% for malignant lesions. CONCLUSIONS: FNAC is a rapid, efficient, cost-effective, relatively painless procedure with a high diagnostic accuracy. It has high rate of sensitivity and positive predictive value in diagnosing thyroid neoplastic lesions. Hence, it is a valuable tool in the diagnosis and management of patients. PMID- 23661937 TI - Clinico-radiological and pathological evaluation of extra testicular scrotal lesions. AB - BACKGROUND: Scrotal ultrasound, though reliable in distinguishing between intratesticular and extratesticular lesions and characterizing them as cystic and solid, cannot distinguish benign from malignant pathology. Although fine needle aspiration cytology (FNAC) has proved to be of great diagnostic importance in testicular lesions, its scope in extratesticular lesions is largely unexplored. AIM: To evaluate extratesticular scrotal lesions cytologically and compare it with their clinical, radiological, and histological findings. MATERIALS AND METHODS: Sixty five patients with extratesticular scrotal lesions were assessed clinically, radiologically, and cytologically. Histopathology was done in 45 cases where surgical exploration was undertaken. All the data were then analyzed and correlated. RESULTS: Extratesticular lesions accounted for 72.2% of the scrotal swellings. Of these, the epididymis is most commonly involved (61.5% cases) with the commonest type of lesion being cystic (49.3% cases). Ultrasonography preferably with color doppler is highly useful for the evaluation of the scrotum. Apart from distinguishing extratesticular from testicular and cystic from solid lesions, it has an important role in identifying individual lesions, thus reducing the list of differential diagnosis. Fine needle aspiration cytology contributed to a definitive diagnosis in 47.7% cases. It helps classify cystic masses on the basis of their contents and defines the etiology of chronic inflammatory lesions, apart from corroborating with the clinico-radiological diagnosis. Histological evaluation was possible only in cases where surgery was performed and helps further define the diagnosis. CONCLUSION: Fine needle aspiration cytology is essentially non-traumatic and easy to carry out and should be a technique of choice for the study of scrotal pathology, main advantage being avoidance of delays in diagnosis. PMID- 23661938 TI - Evaluation of the category high-grade squamous intraepithelial lesion in The Bethesda System for reporting cervical cytology. AB - BACKGROUND: High grade squamous intraepithelial lesion (HSIL) is a category of The Bethesda System (TBS) for reporting cervical cytology that is in vogue since the introduction of the said system in 1988 and it was not modified in 2001 modification of TBS. The term includes moderate dysplasia (CIN II), severe dysplasia (CIN III) and squamous cell carcinoma in situ. Terms like ASC-US used in TBS are being considered to be not very useful in the prediction about the possible behavior of the pathological status of the cervix. After more than 10 years of use the term HSIL also needs fresh evaluation as in this category two entities of potentially different outcome are clubbed. AIMS: The aim was to find out whether it is justified to have a term like HSIL which includes different points of the spectrum of intraepithelial pathology of cervix from moderate hyperplasia through carcinoma in situ, all having different significance. MATERIALS AND METHODS: In this study 619 cases of cervical cytology reported by TBS were evaluated by comparing them with biopsy reports of the same lesion for the assessment of the sensitivity, specificity and positive predictive value of HSIL as a category of diagnosis in TBS. RESULTS: As a category, HSIL had the diagnostic sensitivity of 96.4%, specificity of 87.5%. The positive predictive value was 96.4%. CONCLUSION: HSIL as a diagnostic category shows a very good predictive accuracy, which implies that it provides a very high probability of the accurate diagnosis collectively of all the conditions in the disease spectrum from moderate dysplasia through in situ carcinoma. Hence, HSIL was found to be a very useful diagnostic category in TBS that conveys proper message to the clinician. PMID- 23661939 TI - Image-guided fine-needle aspiration of retroperitoneal masses: The role of the cytopathologist. AB - BACKGROUND: Retroperitoneal tumors constitute a difficult diagnostic category as they are not easily accessible. The advent of image-guided fine-needle aspiration (FNA) has resolved this problem significantly. AIMS: We present a short study based on guided aspiration of retroperitoneal tumors, in which we have tried to assess the role of image-guided fine-needle aspiration cytology as a tool for pre operative diagnosis. MATERIALS AND METHODS: The study was conducted on patients diagnosed with retroperitoneal masses. FNA was performed under image guidance with the help of ultrasonography and/or computed tomography; smears were prepared and meticulously screened according to a fixed protocol. The results were analyzed to determine sensitivity, specificity, and diagnostic efficacy of cytopathological diagnosis using image-guided FNA techniques. RESULTS: We assessed 38 patients with retroperitoneal masses. In all cases, adequate cellular material was obtained. No major complications were encountered. Statistical analysis was carried out in 35 cases; sensitivity, specificity, and diagnostic accuracy were 100% in these cases. CONCLUSION: FNA under image guidance should be considered a first-line diagnostic approach for retroperitoneal and other abdominal tumors, although caution should be exercised in case selection. In areas where advanced tests are not available, the cytotechnologist and cytopathologist have a very important role to play in ensuring accurate diagnoses. PMID- 23661940 TI - Intravascular papillary endothelial hyperplasia diagnosed by fine needle aspiration: Report of a case and cytology literature review. AB - Intravascular papillary endothelial hyperplasia (IVPEH) is an unusual form of intravascular endothelial proliferation. Fine needle aspiration (FNA) diagnosis of IVPEH is quite challenging and only rare reports of the cytopathological features of this entity have been published. We report a case of a 55-year-old female patient who presented with a mass on her left jaw. FNA of the mass revealed pleomorphic polygonal and spindle cells. A preliminary (onsite) cytological diagnosis of suspicious for malignancy was rendered. Subsequent cell block showed delicate papillae composed of attenuated endothelial cells overlying collagenized cores. The endothelial cells were positive for CD34 and factor VIII, supporting the cytological diagnosis of IVPEH. Surgical excision confirmed the diagnosis. To the best of our knowledge, this is the first reported case of IVPEH diagnosed by preoperative FNA. PMID- 23661941 TI - A case of pancreatic ductal adenocarcinoma with marked infiltration with IgG4 positive cells. AB - A 75-year-old man was diagnosed as having pancreatic ductal carcinoma containing remarkable lymphocytic and plasma cell infiltration, as revealed by the cytological examination of endoscopic ultrasound guided fine-needle aspiration (EUS-FNA) specimen. The EUS-FNA specimen showed small amounts of atypical epithelium with noticeable lymphocytes and plasma cells. A pancreatic resection was performed, and the histopathological features showed an invasive pancreatic ductal carcinoma with autoimmune pancreatitis (AIP) lymphoplasmacytic sclerosing pancreatitis (LPSP)-like lesions. Most of the plasma cells were immunoreactive to anti-IgG4 antibody. EUS-FNA may be necessary for the differential diagnosis of AIP and pancreatic cancer, and close attention should be given to the presence of marked lymphoplasmacytic cells in EUS-FNA specimens while making the diagnosis. PMID- 23661942 TI - Nodular sclerosing adenosis of breast: A diagnostic pitfall in fine needle aspiration cytology. AB - Fine needle aspiration cytology was performed in a 46-year-old female presenting with a breast lump and mammography suggesting a malignancy. The smears were cellular with cohesive clusters and scattered epithelial cells showing moderate nuclear pleomorphism and focal acinar formation. Stromal fragments, benign epithelial cell clusters and a few naked nuclei were noted in the background. Considering the clinical features, mammography findings as well as cytological features, a diagnosis of ductal carcinoma was suggested. Subsequent histopathological examination revealed it to be nodular sclerosing adenosis. The cytohistological correlation of this uncommon lesion, a potential pitfall in breast fine needle aspiration diagnosis which may lead to a false-positive diagnosis is discussed. PMID- 23661943 TI - Anorectal smear in the diagnosis of anorectal adenocarcinoma. AB - The purpose of this case report is to point out the diagnostic value of cytologic smears in patients presenting with anorectal complaints, such as bleeding, pain or discomfort, which may suggest a neoplastic lesion. We present a case of a 64 year-old man with a 3 months' history of anal bleeding and pain during defecation. He was diagnosed as having hemorrhoids and a hemorrhoidectomy was performed. The patient developed an anal stricture postoperatively that required operative dilation. He continued to complain about anorectal pain for 2 months and a subsequent rectoscopy revealed the presence of tumor 5 to 7 cm above the dentate line. The tumor was resected laparoscopically and was reported as an adenocarcinoma. Rectal bleeding recurred 18 months postoperatively and a smear was procured from the anorectal mucosal surface for cytologic evaluation. A definitive diagnosis of adenocarcinoma was rendered based on cytologic and histologic examination of the material. To the best of our knowledge, this is the first case report of anorectal adenocarcinoma diagnosed by cytologic smear in the English literature. PMID- 23661944 TI - Spindle cell lipoma masquerading as lipomatous pleomorphic adenoma: A diagnostic dilemma on fine needle aspiration cytology. AB - Spindle cell lipoma is a relatively uncommon benign adipocytic tumor that usually presents in subcutaneous fat of adult men. These are a rare form of lipoma, accounting for 1.5% of all lipomatous tumors, with a low rate of local recurrence and no risk of malignant behavior/dedifferentiation. Although few studies addressing the histological findings of spindle cell lipoma have been described, only a few descriptions of fine needle aspiration cytology (FNAC) findings have been documented in literature. We present a case of a 55-year-old male with a nodular swelling over left cheek (in the parotid region), which due to its location as well as prominent myxoid background prompted us to include the lipomatous salivary gland lesions in differential diagnosis. Our objective is to document and delineate the characteristic cytological features of spindle cell lipoma, which may permit a confident diagnosis on FNAC smears. PMID- 23661945 TI - Cytodiagnosis of alveolar soft part sarcoma: Report of two cases with special emphasis on the first orbital lesion diagnosed by aspiration cytology. AB - Alveolar soft part sarcoma (ASPS) is a rare neoplasm of uncertain cell of origin. Known to occur in adolescents and young adults, this tumor usually involves the muscles and deep soft tissues of the extremities and trunk. Orbital localization is rare and not yet subjected to cytological assessment, as per our literature search. We present here two cases of ASPS diagnosed by aspiration cytology, one in the orbit and the other in the lower extremity. The cells displayed abundant clear to finely vacuolated cytoplasm, often with disrupted margins and flowing of the cytoplasmic material; prominent nucleoli and scattered bare nuclei were also seen in the background. Two close cytological differential diagnoses include metastatic renal cell carcinoma and paraganglioma. Intracytoplasmic periodic acid schiff (PAS) positive, diastase-resistant, needle-shaped crystals and corresponding rhomboid crystals with regular lattice pattern on ultrastructure are the hallmarks of this neoplasm. Due to its slowly progressive clinical course and poor outcome, preoperative diagnosis of ASPS through fine-needle aspiration cytology may be essential for deciding therapy, especially in rare and difficult locations like orbit, where adjuvant radiation may not be possible. PMID- 23661946 TI - Benign breast myoepithelioma. AB - Myoepithelioma of the breast is very rare. Breast myoepithelioma can develop in women from their early 20s right up to their 80s, but it is most common in women over 50. We report a case of 20-year-old female, who presented with a well defined breast lump of 3 * 3 cm in size. Fine needle aspiration was performed. The cytological findings revealed good cellularity comprising monomorphic loosely cohesive sheets of plasmacytoid, round to polygonal cells with round to ovoid eccentrically placed nuclei, finely dispersed chromatin, and moderate amount of cytoplasm. On the basis of cytological findings, a diagnosis of benign myoepithelioma (plasmacytoid type) was made which was confirmed on histopathologic examination. The breast is a very rare localization for this type of tumor. The benign character of the disease in conjunction with its slow progression could delay its detection and diagnosis. A detailed pathology examination is a prerequisite for avoidance of misleading diagnosis. PMID- 23661947 TI - Adenomatoid tumor of testis: A rare cytological diagnosis. AB - Adenomatoid tumor is a benign neoplasm of the male and female genital tracts arising from mesothelial cells. Fine needle aspiration cytology (FNAC) plays a pivotal role in its preoperative diagnosis. Therefore, it is imperative that pathologists should be well aware of its cytological features so as to avoid erroneous diagnosis and hence prevent unnecessary surgical interventions. We hereby, present a case of adenomatoid tumor of testis in a 41 year male diagnosed by FNAC and later confirmed by histopathological examination. PMID- 23661948 TI - Pigmented Paget's disease of nipple: A diagnostic challenge on cytology. AB - Paget's disease is a rare form of breast cancer often associated with an underlying ductal carcinoma in situ or invasive cancer. A 47-year-old female patient presented with bleeding from the left nipple since 4 months. Imprint smears from the lesion showed pleomorphic malignant epithelial cells in singles and in small clusters, many of them containing dark brown cytoplasmic pigment granules. There was no palpable breast lump or axillary lymph node enlargement. Based on the physical examination and cytological features, a diagnosis of malignant melanoma with a differential of Paget's disease of the nipple was made. Biopsy showed features of Paget's disease and immunohistochemistry was positive for HER-2/neu, negative for HMB-45 and S-100, thus confirming the diagnosis. This case has been reported to emphasize the fact that Paget's cells can contain imbibed brown cytoplasmic pigment and should not be mistaken for melanoma cells on cytology smears. PMID- 23661949 TI - Cytomorphology of pleomorphic fibroma of skin: A diagnostic enigma. AB - Pleomorphic fibroma (PF) is a benign, polypoid, or dome-shaped cutaneous neoplasm with cytologically atypical fibrohistiocytic cells. We describe the cytomorphological features of PF retrospectively with histopathological diagnosis in a 38-year-old male who presented with 3 * 1.5 cm swelling in the soft tissues of the thigh for 6 months. This lesion is benign despite the presence of pleomorphic or bizarre cells. We review the differential diagnosis of PF with other mesenchymal tumors. To the best of our knowledge, cytomorphological features on fine needle aspiration cytology of this tumor are not yet documented in literature. PMID- 23661950 TI - Peritoneal washing cytology in an adult granulosa cell tumor: A case report and review of literature. AB - Adult-type granulosa cell tumors (AGCT) account for 1-2% of all ovarian tumors and 95% of granulosa cell tumors. In AGCT, at the time of peritoneal washing, tumor cells are rarely seen to exfoliate and FIGO stage is raised from IA/IB or IIA/IIB to stage IC or IIC despite the absence of a gross intraepithelial tumor. Patients with positive peritoneal washing cytology must be followed up for pelvic recurrence and metastasis. A more sensitive cytologic evaluation, histopathologic correlation and immunohistochemical staining can advance our practice. Here, we describe a case of AGCT with the emphasis on cytologic features observed in specimens obtained from peritoneal washing fluid. PMID- 23661951 TI - Role of cytology in fibroadenoma with clinging carcinoma. AB - Fibroadenoma is the most common benign breast tumor in adolescent girls and young women with a peak incidence in the second and third decades of life. Carcinoma arising within a fibroadenoma is rare and is usually discovered incidentally. We describe a case of clinging type of ductal carcinoma in situ (DCIS) arising within a fibroadenoma. Clinging carcinoma, a variant of DCIS is an under recognized entity. Diagnosis of DCIS is made based on architecture and cytology. This case report highlights the role of fine needle aspiration cytology in the diagnosis of this entity coexisting in a fibroadenoma. PMID- 23661952 TI - Cytological diagnosis of Langerhans cell histiocytosis with cutaneous involvement. AB - Langerhans cell histiocytosis (LCH) is a rare disease affecting predominantly children. The course of the disease varies, from spontaneous resolution to a progressive multisystem disorder with organ dysfunction and potential life threatening complications. Diagnosis of LCH is often difficult and may be delayed because of its rarity and especially so if it occurs with unusual presentation. Fine needle aspiration cytology of a 4 year old male child, a case of LCH is presented with a purpose of highlighting the characteristic cytological features. A high index of suspicion, awareness of characteristic cytological features of LCH and its differential diagnoses is necessary. This can obviate the need of biopsy and electron microscopy. Immunohistochemistry if available can be performed on cytology smear and cell block. PMID- 23661953 TI - Cytological diagnosis of primary cardiac diffuse large B cell lymphoma. PMID- 23661954 TI - A simple working type classification proposed for the spindle cell neoplasms of the oral cavity. PMID- 23661955 TI - An uncommonly common: Glossopharyngeal neuralgia. AB - Glossopharyngeal neuralgia is a relatively rare condition characterized by severe, paroxysmal episodes of pain localized to the external ear canal, the base of the tongue, the tonsil or the area beneath the angle of the jaw. This pain is many a times confused with Trigeminal Neuralgia and mistreated. There are various diagnostic and management dilemmas which are herein addressed in this review. PMID- 23661956 TI - The alien hand sign. AB - We report a case of alien hand sign in a male with stroke and briefly discuss the pathogenesis of this rare condition symptom. PMID- 23661957 TI - Brachial plexopathy. AB - Brachial plexus injury can occur as a result of trauma, inflammation or malignancies, and associated complications. The current topic is concerned with various forms of brachial plexopathy, its clinical features, pathophysiology, imaging findings, and management. Idiopathic brachial neuritis (IBN), often preceded with antecedent events such as infection, commonly present with abruptonset painful asymmetric upper limb weakness with associated wasting around the shoulder girdle and arm muscles. Idiopathic hypertrophic brachial neuritis, a rare condition, is usually painless to begin with, unlike IBN. Hereditary neuralgic amyotrophy is an autosomal-dominant disorder characterized by repeated episodes of paralysis and sensory disturbances in an affected limb, which is preceded by severe pain. While the frequency of the episodes tends to decrease with age, affected individuals suffer from residual deficits. Neurogenic thoracic outlet syndrome affects the lower trunk of the brachial plexus. It is diagnosed on the basis of electrophysiology and is amenable to surgical intervention. Cancer-related brachial plexopathy may occur secondary to metastatic infiltration or radiation therapy. Traumatic brachial plexus injury is commonly encountered in neurology, orthopedic, and plastic surgery set-ups. Trauma may be a direct blow or traction or stretch injury. The prognosis depends on the extent and site of injury as well as the surgical expertise. PMID- 23661958 TI - Electrodiagnosis in traumatic brachial plexus injury. AB - Electrodiagnosis (EDX) is a useful test to accurately localize the site, determine the extent, identify the predominant pathophysiology, and objectively quantify the severity of brachial plexopathies. It can also be used to examine muscles not easily assessed clinically and recognize minimal defects. Post operatively and on follow up studies, it is important for early detection of re innervation. It can be used intra-operatively to assess conduction across a neuroma, which would help the surgeon to decide further course of action. Localization of the site of the lesion can be very challenging as there may be multiple sites of involvement and hence the electroneuromyographic evaluation must be adequate. The unaffected limb also needs to be examined for comparison. The final impression must be co-related with the type and severity of injury. PMID- 23661959 TI - Brachial plexus injury in adults: Diagnosis and surgical treatment strategies. AB - Adult post traumatic Brachial plexus injury is unfortunately a rather common injury in young adults. In India the most common scenario is of a young man injured in a motorcycle accident. Exact incidence figures are not available but of the injuries presenting to us about 90% invole the above combination This article reviews peer-reviewed publications including clinical papers, review articles and Meta analysis of the subject. In addition, the authors' experience of several hundred cases over the last 15 years has been added and has influenced the ultimate text. Results have been discussed and analysed to get an idea of factors influencing final recovery. It appears that time from injury and number of roots involved are most crucial. PMID- 23661960 TI - Electrophysiological study in neuromuscular junction disorders. AB - This review is on ultrastructure and subcellular physiology at normal and abnormal neuromuscular junctions. The clinical and electrophysiological findings in myasthenia gravis, Lambert-Eaton myasthenic syndrome (LEMS), congenital myasthenic syndromes, and botulinum intoxication are discussed. Single fiber electromyography (SFEMG) helps to explain the basis of testing neuromuscular junction function by repetitive nerve stimulation (RNS). SFEMG requires skill and patience and its availability is limited to a few centers. For RNS supramaximal stimulation is essential and so is display of the whole waveform of each muscle response at maximum amplitude. The amplitudes of the negative phase of the first and fourth responses are measured from baseline to negative peak, and the percent change of the fourth response compared with the first represents the decrement or increment. A decrement greater than 10% is accepted as abnormal and smooth progression of response amplitude train and reproducibility form the crux. In suspected LEMS the effect of fast rates of stimulation should be determined after RNS response to slow rates of stimulation. Caution is required to avoid misinterpretation of potentiation and pseudofacilitation. PMID- 23661961 TI - Urodynamic profile of patients with neurogenic bladder following non-traumatic myelopathies. AB - OBJECTIVE: To observe the urodynamic profile of the patients following non traumatic myelopathies (NTMs) with neurogenic bladder. SETTING: Neurological rehabilitation department of university tertiary research hospital. MATERIALS AND METHODS: Seventy-nine patients (44 men) with monophasic NTM, with the age range 8 65 years (31.0 +/- 16.0 years), were admitted for inpatients' rehabilitation. Length of stay in rehabilitation ranged from 6 to 120 days (32.0 +/- 24.8 days). Fifty-six patients (70.9%) had spinal lesion above D10, 17 had lesion between D10 and L2 (21.5%), and 6 (7.6%) had cauda equina syndrome. All patients had neurogenic bladder with urinary complaints. Urodynamic study (UDS) was performed in all patients. RESULTS: UDS showed 71.4% patients (40/56) had neurogenic detrusor overactivity (NDO) with or without sphincter dyssynergy (DSD) with lesion above D10; only 52.9% patients (9/17) had NDO with or without DSD detrusor with lesion between D10 and L2; and majority (5/6 patients) had underactive detrusor in the cauda equina group. Bladder management was based on the UDS findings. No significant correlation was found (P > 0.05) between detrusor behavior and the level, severity (ASIA Impairment Scale) of spinal injury, or gender using chi-square test. CONCLUSIONS: Neurogenic bladder following NTM was observed in all patients. UDS suggested predominantly NDO in lesions above D10 and mixed pattern in between D10 and L2 lesions. No significant correlation was found between detrusor behavior and the level or severity of NTM in the study. PMID- 23661962 TI - Efficacy and safety of short-term use of COX-2 inhibitors in patients after an acute stroke with musculoskeletal pain. AB - OBJECTIVE: Musculoskeletal pain commonly occurs in the elderly, many of whom are also prone to suffer from strokes. We studied whether short-term use (<= 4 weeks) of cyclooxygenase-2 (COX-2) inhibitors for musculoskeletal pain in stroke patients helped them to participate in their therapies and was safe and efficacious. MATERIALS AND METHODS: Three hundred and three patients admitted consecutively with first ischemic stroke were studied. Two cohorts were defined, based on whether patients with acute stroke had sufficient musculoskeletal pain that warranted oral COX-2 inhibitors (COX-2 group) or not (case-matched controls). Primary efficacy measures were change in Fugl-Meyer (F-M) pain score and change in total functional independence measure (TFIM) scores on discharge from hospital. Safety was judged by the incidence of vascular episodes during the study period. RESULTS: From the original 303 patients, 64 patients in the COX-2 group were matched with 64 patients in the non-COX-2 group. The groups were matched for age (+/-5 years), gender, and admission TFIM score (+/- 5 points). Baseline characteristics between the 2 groups were similar. The primary and secondary outcome measures were similar between the 2 groups, except for ambulation endurance, which favored the non-COX-2 group (P < 0.03). Greater change in the pain score (less pain) was found in the COX-2 group; this effect was strongest in patients who were independent prior to their stroke (on post hoc analysis). There were too few adverse events in either group of any significance. CONCLUSIONS: The short-term use of COX-2 inhibitors reduced musculoskeletal pain in acute stroke patients, improved functional motor outcome, and were found to be safe. PMID- 23661964 TI - Deletion analysis of SMN and NAIP genes in Tunisian patients with spinal muscular atrophy. AB - BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder involving degeneration of anterior horn cells of spinal cord, resulting in progressive muscle weakness and atrophy. AIMS: The purpose of our study was to determine the frequency of SMN and NAIP deletions in Tunisian SMA patients. MATERIALS AND METHODS: Polymerase chain reaction (PCR) combined with restriction fragment length polymorphism (RFLP) was used to detect the deletion of exon 7 and exon 8 of SMN1 gene, as well as multiplex PCR for exon 5 and 13 of NAIP gene. RESULTS: Fifteen (45.4%) out of 33 SMA patients were homozygously deleted for exons 7 and/or 8 of SMN1. Homozygous deletion of NAIP gene was observed in 20% (3 / 15) of patients. CONCLUSIONS: The molecular diagnosis system based on PCR-RFLP analysis can conveniently be applied in the clinical testing, genetic counseling, prenatal diagnosis, and pre-implantation genetic diagnosis of SMA. PMID- 23661963 TI - Globus pallidus high-signal lesions: A predominant MRI finding in children with neurofibromatosis type 1. AB - INTRODUCTION: Lesions of the brain, recognized as unidentified bright objects (UBOs), are commonly observed as areas of increased T2-weighted signal intensity on magnetic resonance imaging (MRI) in children with neurofibromatosis type 1 (NF1). Identification of these lesions is not currently encompassed in the National Institute of Health (NIH) diagnostic criteria for NF1. OBJECTIVE: We aimed to determine the prevalence of UBOs in children with NF1 and identify areas of the brain that are commonly affected by these lesions, allowing us to evaluate whether UBOs should be included in the diagnostic criteria for the diagnosis of NF1. MATERIALS AND METHODS: We reviewed the cranial MRI scans of 22 children who had been diagnosed with sporadic or familial NF1 in accordance with the criteria established by NIH. UBOs were present in 81% of the children with NF1. RESULTS: These lesions have a predilection for specific areas of the brain, including the globus pallidus (72%), cerebellum (66%), brainstem (27%) and cerebral hemispheres (16%). The prevalence of UBOs identified varied significantly with age and sex; they were infrequent in children less than 4 years of age but were common in those aged between 4 and 12 years of age. UBOs were more commonly seen in males (66.6%) compared with females (33.3%). Repeat MRI scan on a subset of these patients with UBOs did not show any significant changes despite a worsening in clinical symptoms. CONCLUSION AND DISCUSSION: We have shown that UBOs are a common finding in children with NF1, and are most prevalent between the ages of 4 and 12 years. Many sites of the brain are affected by these lesions, most notably the globus pallidus and the cerebellum. Further research must be conducted to elucidate the significance of UBOs in patients with NF1 and whether these lesions have any utility in the clinical detection of NF1. PMID- 23661965 TI - Sleep assessment of children with cerebral palsy: Using validated sleep questionnaire. AB - BACKGROUND: On the basis of clinical experience, it seems that sleep disturbances are common in children with cerebral palsy (CP); however, there is a lack of research and objective data to support this observation. AIM OF WORK: Our aim was to assess sleep of children with cerebral palsy, using validated sleep questionnaire. SUBJECTS AND METHODS: one hundred children with diagnosis of CP were investigated via sleep questionnaires, with their ages from 2-12 years. The 100 children with CP were divided into two groups, pre-school group (52 children had a mean age 2.35 +/- 1.04 years) and school ages group (48 children had a mean age 10.21 +/- 3.75 years). RESULTS: We found high incidence of sleep problem in both pre-school and school age groups. We found that pre-school children have more prevalence of early insomnia (46.2%, P value 0.028) and sleep bruxism (50%, P value 0.000), while school group suffer more sleep disordered breathing (SDB) (50%, P value 0.001), more nightmares (50%, P value 0.001), more sleep talking (12.5% P value 0.049), and more excessive daytime sleepiness (EDS) (62.5%, P value 0.001). CONCLUSION: Results of our study indicate that CP children have high incidence of sleep problem in both pre-school and school age groups. PMID- 23661966 TI - Electrocardiographic abnormalities in acute cerebrovascular events in patients with/without cardiovascular disease. AB - OBJECTIVES: Electrocardiographic (ECG) changes are reported frequently after acute strokes. It seems that cardiovascular effects of strokes are modulated by concomitant or pre-existent cardiac diseases, and are also related to the type of cerebrovascular disease and its localization. We aimed to determine the pattern of ECG changes associated with pathophysiologic categories of acute stroke among patients with/without cardiovascular disease and to determine if specific ECG changes are related to the location of the lesion. MATERIALS AND METHODS: The electrocardiographic records of 361 patients with acute stroke were studied to assess the relative frequencies of ECG abnormalities among the pathophysiologic categories of stroke. RESULTS: In the present study, the most common ECG abnormalities associated with stroke were T-wave abnormalities, prolonged QTc interval and arrhythmias, which were respectively found in 39.9%, 32.4%, and 27.1% of the stroke patients and 28.9%, 30.7%, and 16.2 of the patients with no primary cardiac disease. We observed that other ECG changes comprising pathologic Q- wave, ST-segment depression, ST-segment elevation, and prominent U wave may also occur in selected or non-selected stroke patients; thereby simulate an acute myocardial injury. We observed an increased number of patients with abnormal T wave and posterior fossa bleedings and more rhythm disturbances for ischemic lesions, localized in the anterior fossa. CONCLUSION: Ischemia-like ECG changes and arrhythmias are frequently seen in stroke patients, even in those with no history or signs of primary heart disease, which support a central nervous system origin of these ECG abnormalities. Further study is necessary to better define the brain-heart interaction. PMID- 23661967 TI - Physiological genomics analysis for Alzheimer's disease. AB - Alzheimer's disease is a common kind of dementia. This disorder can be detected in all countries around the world. This neurological disorder affects millions of population and becomes an important concern in modern neurology. There are many researches on the pathogenesis of Alzheimer's disease. Although it has been determined for a long time, there is no clear-cut that this is a case with genetic disorder or not. A physiological genomics is a new application that is useful for track function to genes within the human genome and can be applied for answering the problem of underlying pathobiology of complex diseases. The physiogenomics can be helpful for study of systemic approach on the pathophysiology, and genomics might provide useful information to better understand the pathogenesis of Alzheimer's disease. The present advent in genomics technique makes it possible to trace for the underlying genomics of disease. In this work, physiological genomics analysis for Alzheimer's disease was performed. The standard published technique is used for assessment. According to this work, there are 20 identified physiogenomics relationship on several chromosomes. Considering the results, the HADH2 gene on chromosome X, APBA1 gene on chromosome 9, AGER gene on chromosome 6, GSK3B gene on chromosome 3, CDKHR1 gene on chromosome 17, APPBP1 gene on chromosome 16, APBA2 gene on chromosome 15, GAL gene on chromosome 11, and APLP2 gene on chromosome 11 have the highest physiogenomics score (9.26) while the CASP3 gene on chromosome 4 and the SNCA gene on chromosome 4 have the lowest physiogenomics score (7.44). The results from this study confirm that Alzheimer's disease has a polygenomic origin. PMID- 23661968 TI - Infrequent near death experiences in severe brain injury survivors - A quantitative and qualitative study. AB - BACKGROUND: Near death experiences (NDE) are receiving increasing attention by the scientific community because not only do they provide a glimpse of the complexity of the mind-brain interactions in 'near-death' circumstances but also because they have significant and long lasting effects on various psychological aspects of the survivors. The over-all incidence-reports of NDEs in literature have varied widely from a modest Figure of 10% to around 35%, even up to an incredible Figure of 72% in persons who have faced close brush with death. Somewhat similar to this range of difference in incidences are the differences prevalent in the opinions that theorists and researchers harbor around the world for explaining this phenomena. None the less, objective evidences have supported physiological theories the most. A wide range of physiological processes have been targeted for explaining NDEs. These include cerebral anoxia, chemical alterations like hypercapnia, presence of endorphins, ketamine, and serotonin, or abnormal activity of the temporal lobe or the limbic system. In spite of the fact that the physiological theories of NDEs have revolved around the derangements in brain, no study till date has taken up the task of evaluating the experiences of near-death in patients where specific injury has been to brain. Most of them have evaluated NDEs in cardiac-arrest patients. Post-traumatic coma is one such state regarding which the literature seriously lacks any information related to NDEs. Patients recollecting any memory of their post-traumatic coma are valuable assets for NDE researchers and needs special attention. MATERIALS AND METHODS: Our present study was aimed at collecting this valuable information from survivors of severe head injury after a prolonged coma. The study was conducted in the head injury department of Guangdong 999 Brain hospital, Guangzhou, China. Patients included in the study were the ones Recovered from the posttraumatic coma following a severe head injury. A total of 86 patients were chosen. Near death experience scale (NDES) score of 7 or more was used as the criteria of screening NDE experiences. After identifying such individuals, the Prakash-modification of the Interpretative Phenomenological Analysis (IPA) was used to interview and record the data for qualitative analysis. RESULTS: We found that contrary to earlier incidence reports, NDEs in post head injury patients were markedly low. Only 3 out of 86 of the patients recruited had a clear and confident experience of NDE. We conducted a qualitative study to explore further into these experiences. IPA of these 3 patients revealed four master themes: 1. Unique light visions 2. Intense feelings of astonishment, pleasure, and fear 3. The sense of helplessness 4. Supernatural but rationality of experience. CONCLUSION: NDE is uncommon in head-injury cases as compared to other near-death conditions. But the persons experiencing it have immense impacts on their belief systems and emotions. This experience should be further explored by studies of larger samples. PMID- 23661969 TI - Directly observed treatment, short course in tuberculous meningitis: Indian perspective. AB - BACKGROUND: Effectiveness of intermittent short course chemotherapy for tuberculous meningitis (TBM) has not been well studied. There are scarce reported studies on this issue in the world literature. Neurologists all over India are reluctant to accept Directly Observed Treatment Short course (DOTS) for TBM since its introduction in India. AIM: We did a prospective study to assess effectiveness of Revised National TB Control Program (RNTCP-DOTS) regimes among TBM patients. MATERIALS AND METHODS: In this study we include the TBM patients admitted from September 2008 to March 2011. All were referred to RNTCP for treatment. Diagnostic Algorithm as per RNTCP guidelines was strictly followed and treatment outcome and follow-up status were recorded. We exclude HIV and pediatric age group. RESULTS: A total of 42 cases registered for DOTS regimen were included in the study, of which 35 completed the treatment (83%). All the patients were started with DOTS but finally 78% received actual DOTS. All patients were given 9 months intermitted regimen as per RNTCP guidelines. Seven patients died during the treatment (16%). CONCLUSION: We found intermitted short course chemotherapy was effective in TBM. PMID- 23661970 TI - Paradoxical presentation of orthostatic headache associated with increased intracranial pressure in patients with cerebral venous thrombosis. AB - Headache is the most common symptom of cerebral venous thrombosis (CVT); however, the detailed underlying mechanisms and characteristics of headache in CVT have not been well described. Here, we report two cases of CVT whose primary and lasting presentation was orthostatic headache, suggestive of decreased intracranial pressure. Contrary to our expectations, the headaches were associated with elevated cerebrospinal fluid (CSF) pressure. Magnetic resonance imaging and magnetic resonance venography showed characteristic voiding defects consistent with CVT. We suggest that orthostatic headache can be developed in a condition of decreased intracranial CSF volume in both intracranial hypotensive and intracranial hypertensive states. In these cases, orthostatic headache in CVT might be caused by decreased intracranial CSF volume that leads to the inferior displacement of the brain and traction on pain-sensitive intracranial vessels, despite increased CSF pressure on measurement. CVT should be considered in the differential diagnosis when a patient complains of orthostatic headache. PMID- 23661971 TI - Reversible dementia as a presenting manifestation of racemose neurocysticercosis. AB - Racemose cysticercosis is a less frequent presentation of neurocysticercosis (NCC). It's presentation and management is quite different from cerebral parenchymal NCC. Diagnosis of racemose cysticercosis is based on the combination of clinical, epidemiologic, radiographic, and immunologic information. Compared with cysticercus cellulose, which most commonly presents as seizures, racemose NCC due to its extraaxial location presents with raised intracranial pressure and meningitis, and frequently requires neurosurgical intervention. Dementia as a sole presenting feature of NCC is rare. We report a case of racemose NCC with dementia as the presenting manifestation. The outcome of dementia patients with NCC seems favorable in most cases therefore a high index of suspicion for NCC should be kept especially in endemic areas. PMID- 23661972 TI - Seizure, deafness and renal agenesis: A rare case of barakat syndrome. AB - Etiologic diagnosis of seizure requires proper consideration of apparently unrelated clinical features of the patient. Here, we report the case of a patient of status epilepticus with moderate-to-severe bilateral sensorineural deafness. Investigations showed extensive intracranial calcification, hypoparathyroidism and unilateral renal agenesis. The features were consistent with Barakat syndrome, a rare developmental disorder associated with mutations in the GATA3 gene. To the best of our knowledge, this is the first reported case of Barakat syndrome from India. PMID- 23661973 TI - Spontaneous intracranial hypotension with bilateral subdural hemorrhage: Is conservative management adequate? AB - The aim of this study is to report a case of spontaneous intracranial hypotension complicated by bilateral subdural hemorrhage that resolved with conservative management. A young male presented with severe orthostatic headache associated with dizziness, neck pain and diplopia. Brain imaging revealed characteristic pachymeningeal enhancement and bilateral subdural hemorrhage. Radionuclide cisternography confirmed the Cerebrospinal fluid leak at the cervical 5 and cervical 6 vertebral level. He had clinical and radiological resolution with bed rest, hydration and analgesics and has remained symptom free since then. Spontaneous intracranial hypotension may be complicated by bilateral subdural hemorrhage. A conservative treatment approach is a viable option, as it may help improve the clinical and radiological outcome, especially when interventional facilities are not available. PMID- 23661974 TI - Recurrent craniospinal subarachnoid hemorrhage in cerebral amyloid angiopathy. AB - Cerebral amyloid angiopathy (CAA) usually manifests as cerebral hemorrhage, especially as nontraumatic hemorrhages in normotensive elderly patients. Other manifestations are subarachnoid (SAH), subdural, intraventricular hemorrhage (IVH) and superficial hemosiderosis. A 52-year-old hypertensive woman presented with recurrent neurological deficits over a period of 2 years. Her serial brain magnetic resonance imaging and computed tomography scans showed recurrent SAH hemorrhage, and also intracerebral, IVH and spinal hemorrhage, with superficial siderosis. Cerebral angiograms were normal. Right frontal lobe biopsy showed features of CAA. CAA can present with unexplained recurrent SAH hemorrhage, and may be the initial and prominent finding in the course of disease in addition to superficial cortical siderosis and intracerebal and spinal hemorrhages. PMID- 23661975 TI - Acute posterior circulation infarct due to bicuspid aortic valve vegetation: An uncommon stroke mechanism. AB - Acute ischemic stroke may be the first clinical manifestation of the underlying cardioembolic source. We are reporting a 28-year-old man presenting with acute posterior circulation infarct due to underlying bicuspid aortic valve disease with vegetation detected by transesophageal echocardiography in the absence of clinical features of heart disease and infective endocarditis. The case report highlights the importance of routine evaluation of cardioembolic sources in all cases of ischemic stroke. PMID- 23661976 TI - A rare cause of perioperative stroke. AB - Perioperative stroke can occur following 0.2-0.3% of general surgical and orthopedic procedures. We are reporting a patient who developed multiple strokes in the immediate postoperative period following total knee replacement, where etiological workup revealed multiple pulmonary arteriovenous fistulae (PAVF). The significance of PAVF with paradoxical embolism in perioperative settings has rarely been reported in the literature. PMID- 23661977 TI - 'Wine Glass' sign in recurrent postpartum hypernatremic osmotic cerebral demyelination. AB - Osmotic demyelination syndrome resulting from postpartum hypernatremia is a recently described entity wherein young women present with hypernatremic encephalopathy and white matter hyperintensities along with quadriparesis from rhabdomyolysis. It is an acute monophasic condition with acute hypernatremia occurring during puerperium with good recovery in majority of the patients with treatment. To the best of our knowledge, recurrent postpartum hypernatremia with encephalopathy, osmotic demyelination, and rhabdomyolysis has not been described. We present a young lady who had two episodes of reversible postpartum hypernatremic encephalopathy with rhabdomyolysis. Cerebral magnetic resonance imaging (MRI) before treatment revealed osmotic demyelination on both occasions. During first admission MRI revealed hyperintensities in internal capsule and corpus callosum, and at second admission revealed more extensive white matter hyperintensity, which simulated the 'wine glass' appearance. PMID- 23661978 TI - Uncommon presentation of a common disorder. AB - We report about a young male who presented with generalized muscle stiffness, involving the limb, facial, and paraspinal muscles. The stiffness was severe enough to restrict all his daily activities, progressively increased with movements and also produced recurrent falls. This clinical picture resembled one of stiff person syndrome. As he had hypertrophy of calf muscles and generalized muscle tautness he was evaluated for other disorders which can resemble stiff person syndrome. Investigations revealed severe hypothyroidism with thyroid antibodies being elevated. This case is reported to highlight the fact that myopathy as a presenting manifestation of hypothyroidism can simulate stiff person syndrome. It is essential to identify the condition early as it recovers fully with treatment. Our patient responded well to thyroid replacement therapy and was able to lead a normal life. PMID- 23661979 TI - Radiological evolution and delayed resolution of an optic nerve tuberculoma: Challenges in diagnosis and treatment. AB - Optic nerve tuberculomas are rarely reported and their natural history, prognosis, and duration of required treatment remain unclear. A 40-year-old immunocompetent male presented with complete loss of vision in his right eye, which had evolved over 6 weeks. He had optic atrophy on examination. Initial imaging showed right optic nerve swelling and thickening suggesting an infiltrative inflammatory optic neuropathy (infectious or noninfectious). Serial imaging revealed appearance of ring enhancement with a necrotic centre. Biopsy and culture of the coexistent parietal lobe lesion revealed Mycobacterium tuberculosis. Persistent optic nerve granuloma with evidence of radiological improvement was noted at 18 months follow-up with antituberculous therapy (ATT). Visual recovery could not be achieved. The salient features in this case include the clinical presentation initially mimicking an infiltrative or compressive optic neuropathy, rapidradiological evolution into a tuberculoma, subtle paradoxical radiological worsening after initiation of ATT and persistence of granuloma on follow up scan. The challenges involved in early diagnosis and during the treatment course will be discussed. PMID- 23661980 TI - A clinician's dilemma: Sturge-Weber syndrome 'without facial nevus'!! AB - Sturge-Weber syndrome (SWS) is a rare, sporadic neurocutaneous syndrome characterized by a classical triad of facial port wine nevus, ipsilateral leptomeningeal angiomatosis (LAM) and glaucoma. The incidence of SWS is 1/50,000 live births, although it is more often underreported. The incidence of SWS without facial nevus is not known, although very few patients without facial nevus have been reported. In these patients, the diagnosis of SWS is made by the findings of computed tomography, magnetic resonance imaging, and histopathology. Here, we report three patients with SWS from our cohort of 28 patients with SWS without facial nevus and discuss their clinical profile and outcome. PMID- 23661981 TI - Cerebrovascular ultrasonography: Technique and common pitfalls. AB - Although the clinical features in some patients with cerebrovascular ischemia may be ill defined, majority of the patients present with focal neurological deficits caused by an arterial occlusion, and the clinical presentations are usually referable to the involved arterial territory. Therefore, vascular imaging constitutes an important component of the diagnostic workup. Cervical duplex ultrasonography of carotid and vertebral arteries is employed to evaluate the extracranial vasculature while transcranial Doppler provides important information about intracranial hemodynamic changes in cerebrovascular ischemia. These two components of cerebrovascular ultrasonography are fast and reproducible, and can be performed at the bedside. They provide real-time information about the status of cervico-cranial arterial patency and various hemodynamic alterations, including collateral flow. The information obtained from cerebrovascular ultrasonography is useful for diagnostic as well as prognostic purposes. Furthermore, it can be used to monitor cerebral blood flow for extended periods and aid in decision making for various interventions. The hemodynamic information obtained from cerebrovascular ultrasonography helps in determining the underlying mechanisms of brain ischemia, and is complementary to the clinical examination and other imaging modalities.We describe the technique of performing cervical duplex sonography, diagnostic criteria for arterial stenosis, characterizing plaque morphology, measuring intima-media thickness and various pitfalls while performing the test. PMID- 23661982 TI - More wide-spread approach needed to explore visual creativity. PMID- 23661983 TI - Turkish perspective of Jervell and Lange-Nielsen syndrome. PMID- 23661984 TI - Neurological manifestations of scrub typhus. PMID- 23661985 TI - Top cited articles from Pharmacogn. Mag in 2012. PMID- 23661986 TI - A validated high performance thin layer chromatography method for determination of yohimbine hydrochloride in pharmaceutical preparations. AB - BACKGROUND: Yohimbine is an indole alkaloid used as a promising therapy for erectile dysfunction. A number of methods were reported for the analysis of yohimbine in the bark or in pharmaceutical preparations. MATERIALS AND METHOD: In the present work, a simple and sensitive high performance thin layer chromatographic method is developed for determination of yohimbine (occurring as yohimbine hydrochloride) in pharmaceutical preparations and validated according to International Conference of Harmonization (ICH) guidelines. The method employed thin layer chromatography aluminum sheets precoated with silica gel as the stationary phase and the mobile phase consisted of chloroform:methanol:ammonia (97:3:0.2), which gave compact bands of yohimbine hydrochloride. RESULTS: Linear regression data for the calibration curves of standard yohimbine hydrochloride showed a good linear relationship over a concentration range of 80-1000 ng/spot with respect to the area and correlation coefficient (R(2)) was 0.9965. The method was evaluated regarding accuracy, precision, selectivity, and robustness. Limits of detection and quantitation were recorded as 5 and 40 ng/spot, respectively. The proposed method efficiently separated yohimbine hydrochloride from other components even in complex mixture containing powdered plants. The amount of yohimbine hydrochloride ranged from 2.3 to 5.2 mg/tablet or capsule in preparations containing the pure alkaloid, while it varied from zero (0) to 1.5-1.8 mg/capsule in dietary supplements containing powdered yohimbe bark. CONCLUSION: We concluded that this method employing high performance thin layer chromatography (HPTLC) in quantitative determination of yohimbine hydrochloride in pharmaceutical preparations is efficient, simple, accurate, and validated. PMID- 23661987 TI - Topical royal jelly alleviates symptoms of pruritus in a murine model of allergic contact dermatitis. AB - BACKGROUND: Royal jelly is widely used as a health tonic, especially in Asia. Royal jelly is commonly used in cosmetics as well as in dietary supplements and beverages. Little is known, however, about the pharmacologic efficacy of topical royal jelly. Therefore, we investigated the antipruritic activity of topical royal jelly on chronic pruritus in experimental allergic contact dermatitis in mice. MATERIALS AND METHODS: HAIRLESS MICE (HOS: HR-1), with chronic allergic contact dermatitis induced by 5 weeks of repeated application of 2,4,6-trinitro-1 chlorobenzene (TNCB) to the entire back skin were treated topically with royal jelly (0.01% or 1%) for 5 weeks after sensitization with TNCB. The effects of royal jelly on pruritus and inflammation were evaluated by measurement of scratching behavior and skin inflammation score, respectively. RESULTS: Repeated application of TNCB to the back skin of mice elicited frequent scratching behavior immediately and 24h after challenge. Topical royal jelly (0.01% or 1%) and betamethasone (0.01%) significantly ameliorated this chronic pruritus throughout the experimental period. The level of nerve growth factor mRNA in back skin was increased in the mice with dermatitis and reduced by betamethasone, but not by royal jelly. CONCLUSION: The inhibitory effect of royal jelly on chronic pruritus may occur through different mechanisms from those of betamethasone. Topical application of royal jelly, as used in cosmetics, might be beneficial for the alleviation of chronic pruritus. PMID- 23661988 TI - Potential antianxiety activity of Fumaria indica: A preclinical study. AB - BACKGROUND: In the view of diverse CNS modulating properties of Fumaria indica, present study was planned to evaluate its putative anxiolytic activity in behavioural models of rats, followed by elucidation of mechanism of observed activity through biochemical estimations. MATERIALS AND METHODS: Effects of seven daily 100, 200 and 400 mg/kg oral doses of a Fumaria indica extract (FI) was compared with those of an acute oral dose (5 mg/kg) of lorazepam in a battery of rat models consisting of open-field, elevated plus and zero maze, social interaction, and novelty induced feeding tests. RESULTS: Dose dependant antianxiety effects of FI observed in all tests were qualitatively similar to those of the reference anxiolytic drug. Although FI treatments did not alter the concentrations of noradrenaline and serotonin in hippocampus and hypothalamus, concentrations of both these monoamines were dose dependently elevated in prefrontal cortex of FI treated animals. Flunitrazepam binding in brain frontal cortex was also elevated by the extract. Moreover, higher levels of brain expressions of the cytokines TNF-alpha, IL-1beta, and IL-10 observed in animals with prior experience on elevated plus maze were almost completely reversed by the lowest dose of FI tested in the behavioral models. CONCLUSION: Taken together, these observations strongly suggest that FI is a functionally novel type of antianxiety agent, and that inhibition of cytokine expressions in the brain could be involved in its mode of action. PMID- 23661989 TI - Anti-glycated and antiradical activities in vitro of polysaccharides from Ganoderma capense. AB - BACKGROUND: Ganoderma capense is a Ganoderma species and is widely used, especially in Asia, as a well-known medicinal mushroom for health-promoting effect and for treatment of chronic diseases, such as diabetes, aging, etc. G. capense is rich of polysaccharide. OBJECTIVE: To isolate the polysaccharides from G. capense and evaluate their anti-glycated and antiradical activities in vitro. MATERIALS AND METHODS: The dried powder of submerged fermentation culturing mycelium of G. capense was defatted, extracted with water/alkaline water followed by ethanol precipitation and deproteinated. And four crude polysaccharides, named as GC50, GC70, GC90 and GCB, were obtained. For the first time, the in vitro anti glycated activities of the four samples were studied by non-enzymatic glycation reaction. Then, the DPPH radical and hydroxyl radical assays were established to estimate the antiradical capacity of the four samples. Meanwhile the contents of polysaccharides were determined by phenol-sulphuric acid colorimetry. RESULTS AND CONCLUSION: Preliminary antiradical in vitro studies indicated that the four crude polysaccharides showed concentration-dependent scavenging abilities on DPPH and hydroxyl radicals. The evaluation of anti-glycation activity suggested that GC70 had good potential for inhibiting the formation of advanced glycation end products. Time- and dose-dependent effects were also observed for all GC70 samples. PMID- 23661990 TI - Chemical composition and biological evaluation of essential oils of Pulicaria jaubertii. AB - BACKGROUND: The present study reports and compares the results of Gas Chromatographic-Mass analyses of Pulicaria jaubertii leaf (P-1) and root (P-2) essential oils, as well as their in vitro antimicrobial and cytotoxic activities. MATERIALS AND METHODS: The chemical composition of P-1 and P-2 essential oils of P. jaubertii, was investigated by GC-MS. Moreover, the essential oils were evaluated for their antimicrobial activity using the broth micro-dilution assay for minimum inhibitory concentrations (MIC). The crystal violet staining method (CVS) was used for evaluation of their cytotoxic activity on HEPG-2 and MCF-7 human cell lines. RESULTS: This investigation led to the identification of 16 constituents in P-1, and 23 constituents in P-2, representing 99.92% and 94.74% of the oils respectively. Oxygenated monoterpenes were found to be the major group in both P-1 (99.47%) and P-2 (89.88%). P-1 consists almost entirely of p Menth-6-en-2-one (Carvotanacetone, 98.59%). P-2 is characterized by high contents of each of Dimethoxydurene (38.48%), Durenol (26.89%) and 2',4'-Dimethoxy-3' methylacetophenone (20.52%). Both oils showed moderate antimicrobial activity against the Gram-positive strains and C. albicans. However, no activity was shown against Gram-negative bacteria. P-1 showed a significant cytotoxic activity against both MCF-7 and HEPG-2 (IC50 = 3.8 and 5.1 MUg/ml, respectively), while P 2 showed selective cytotoxic activity against MCF-7 cell line (IC50 = 9.3 MUg/ml). CONCLUSION: The potent cytotoxic and moderate antimicrobial activities of P-1 may be attributed to its high content of Carvotanacetone. PMID- 23661991 TI - Simultaneous determination of 10 components in traditional Chinese medicine Dachaihu Granule by reversed-phase-high-performance liquid chromatographic-diode array detector. AB - BACKGROUND: Dachaihu Granule, commonly used for treating cholecystitis, is derived from a famous traditional Chinese formula named Dachaihu Decoction. No analytical method has been reported for simultaneous determination of 10 bioactive compounds for quality control in Dachaihu Granule so far. OBJECTIVE: To develop a high-performance liquid chromatographic (HPLC) method with diode array detector (DAD) for simultaneous determination of 10 bioactive compounds (paeoniflorin, aloe-emodin, rhein, emodin, chrysophanol, physcion, naringin, hesperidin, neohesperidin, and baicalin) in traditional Chinese medicine Dachaihu Granule. MATERIALS AND METHODS: The samples were separated on a Kromasil C18 (250 * 4.6 mm,i.d. with 5.0 MUm particle size)column with multi-wavelength detection method by a gradient elution using acetonitrile (A) and 0.2% acetic acid (B) as the mobile phase. The column temperature was maintained at 30 degrees C and the detection wavelength was set at 230 nm for paeoniflorin, 254 nm for aloe-emodin, rhein, emodin, chrysophanol, and physcion, 280 nm for naringin, hesperidin, neohesperidin, and baicalin. RESULTS: The developed method provided satisfactory precision and the accuracy of this method was in the range from 94.0% to 103.1%, all of the 10 compounds showed good linearity (r > 0.999) in a detected concentration range. CONCLUSION: The validated method was successfully applied to the simultaneously of these active components in Dachaihu Granule from different production batches. PMID- 23661992 TI - Linum narbonense: A new valuable tool for biotechnological production of a potent anticancer lignan Justicidine B. AB - BACKGROUND: Arylnaphthalene lignan Justicidin B is a lead compound in the management of bone cancer and osteoclastogenesis. The compound is the main cytotoxic principle of rare medicinal plant Linum narbonense L. (Linaceae). However, there have been no reports on the bioreactor production of justicidin B. OBJECTIVE: to develop cost-effective biotechnology for production of this anticancer metabolite. MATERIALS AND METHODS: The genetic transformation in hairy roots induced by Agrobacterium rhizogenes strain ATCC 15834, was proven by PCR analysis. The control of bioreactor was synthesized by gradient method. The optimal values of the controlling parameters were estimated with presence of technological limitation. The general structure of control system was based on "Hardware in the Loop" (HIL). RESULTS: Hairy roots produced five-fold higher yields of justicidin B (7.78mg/g DW) compared to callus. A rapidly growing root line was selected for cultivation in 2-L stirred tank bioreactor. After optimization, maximum biomass of 22.5 g.l(-1) dry wt was harvested from the bioreactor culture vessel (recording about 8 times increase over initial inoculum), with 1.42 % +/- 0.12 Justicidine B, greater than contents from flasks were obtained. The extracts were tested in a panel of human tumor cell lines, using the MTT-dye reduction assay, exert inhibitory effects against malignant cells. CONCLUSION: Our findings are the first work on large cultivation of L. narbonense hairy roots and bioreactor production of plant anticancer agent Justicidin B. To extend the research to human clinical studies, we have found a reliable biotechnological supply of plant material, produced this target compound. PMID- 23661993 TI - Phytochemical analysis and antibacterial evaluation of the ethyl acetate extract of the stem bark of Bridelia micrantha. AB - BACKGROUND: Plant cells fundamentally are chemical factories containing a rich supply of therapeutically useful phytocompounds that have the potential of being developed into potent antimicrobial agents. AIM OF THE STUDY: To investigate the antibacterial activity of fractionated extracts of the ethyl acetate extract of the stem bark of Bridelia micrantha (Hochst., Baill., Euphorbiaceae). MATERIALS AND METHODS: Thin-layer chromatography and column chromatography were used to purify the extracts and antimicrobial activity performed on reference and clinical strains of Staphylococcus aureus, Shigella sonnei, Salmonella Typhimurium, and Helicobacter pylori using direct and indirect bioautographic methods respectively. Furthermore, the eluted compound fractions were then assayed for minimum inhibitory concentration (MIC50) using the 96-well micro dilution technique. RESULTS: Better separation of phytocompounds was obtained from the non-polar Benzene/Ethanol/Ammonia (BEA) and intermediate-polar Chloroform/Ethyl acetate/Formic acid (CEF) eluents compared to the polar Ethanol/Methanol/Water (EMW). Bioautography revealed the presence of three bioactive compounds (Rf values; 0.12, 0.20, and 0.42) on the BEA plates, designated fractions 3, 7, and 8 with MIC50 values; 0.0048mg/mL to 1.25mg/mL (fraction 3), 0.0024mg/mL to 5 mg/mL (fraction 7), and 0.0024mg/mL to 2.5mg/mL (fraction 8). CONCLUSION: Our findings demonstrate that ethyl acetate extract of the stem-bark of B. micrantha possess potent bioactive phytocompounds that may be developed into new antimicrobials. PMID- 23661995 TI - Characterization and chemical composition of fatty acids content of watermelon and muskmelon cultivars in Saudi Arabia using gas chromatography/mass spectroscopy. AB - BACKGROUND: The growth in the production of biodiesel, which is principally fatty acid methyl esters (FAME), has been phenomenal in the last ten years because of the general desire to cut down on the release of greenhouse gases into the atmosphere, and also as a result of the increasing cost of fossil fuels. OBJECTIVE: Establish whether there is any relationship between two different species (watermelon and muskmelon) within the same family (Cucurbitaceae) on fatty acid compositions and enumerate the different fatty acids in the two species. MATERIALS AND METHODS: Extraction of fatty acids from the two species and preparation the extract to gas chromatography/mass spectroscopy analysis to determine the fatty acids compositions qualitatively and quantitatively. RESULTS: The analyzed plants (watermelon and muskmelon) contain five saturated fatty acids; tetrdecanoic acid, pentadecanoic acid, hexadecanoic acid, heptadecanoic acid and octadecanoic acid with different concentrations, while muskmelon contains an extra saturated fatty acid named eicosanoic acid. The watermelon plant contains five unsaturated fatty acids while muskmelon contains three only, the two plants share in two unsaturated fatty acids named 9-hexadecenoic acid and 9-octadecenoic acid, the muskmelon plant contains higher amounts of these two acids (2.04% and 10.12%, respectively) over watermelon plant (0.88% and 0.25%, respectively). CONCLUSION: The chemical analysis of watermelon and muskmelon revealed that they are similar in saturated fatty acids but differ in unsaturated fatty acids which may be a criterion of differentiation between the two plants. PMID- 23661994 TI - Dietary phytochemicals as potent chemotherapeutic agents against breast cancer: Inhibition of NF-kappaB pathway via molecular interactions in rel homology domain of its precursor protein p105. AB - BACKGROUND: Dietary phytochemicals consist of a wide variety of biologically active compounds that are ubiquitous in plants, many of which have been reported to have anti-tumor as well as anti-inflammatory properties. OBJECTIVE: In the present study, we aimed to validate these findings by using docking protocols and explicate the possible mechanism of action for a dataset of nine phytochemicals namely boswellic acid, 1-caffeoylquinic acid, ellagic acid, emodin, genistein, guggulsterone, quercetin, resveratrol, and sylibinin from different plants against the nuclear factor- kappaB (NF-kappaB) precursor protein p105, an important transcription factor reported to be overexpressed in breast cancer. MATERIALS AND METHODS: 2-D structures of all phytochemicals were retrieved from PubChem Compound database and their subsequent conversion into 3-D structures was performed by using online software system CORINA. The X-ray crystallographic structure of the NF-kappaB precursor p105 was extracted from Brookhaven Protein Data Bank. Molecular docking simulation study was carried out by using AutoDock Tools 4.0. RESULTS: Our results showed significant binding affinity of different phytochemicals with the Rel homology domain of the NF-kappaB precursor protein p105. Quercetin and 1-caffeoylquinic acid were found to be very effective inhibitors against target molecule as they showed binding energy of -12.11 and 11.50 Kcal/mol, respectively. The order of affinity of other ligands with p105 was found as follows: guggulsterone > sylibinin > emodin > resveratrol > genistein > boswellic acid > ellagic acid. CONCLUSION: Our in silico study has explored the possible chemopreventive mechanism of these phytochemicals against the NF-kappaB precursor protein p105 and deciphered that quercetin, 1 caffeoylquinic acid and guggulsterone were the potent inhibitors against target molecule. In addition, large scale preclinical and clinical trials are needed to explore the role of these chemotherapeutic molecules against the NF-kappaB precursor protein p105 in cure and prevention of breast cancer. PMID- 23661996 TI - The high-performance liquid chromatographic fingerprints study of Awei capsules. AB - BACKGROUND: Awei Capusules are Hospital preparation for Hyperlipidemia. It was composed by Awei, Magnoliae Officinalis and Polygonum Bistoral etc. Manufacture and quality standard of Awei Capusules had been studied. Results of animal pharmacodynamic and clinical study all displayed that Awei Capusules can reduce serum levels of TC, TG, LDL-C, increases HDL-C/TC. It was safe. It could improve hemorrheology and vessel function of blood stasis animal. On the basis of these, we studied on fingerprint of Awei capsule. MATERIALS AND METHODS: The gradient elution method was used for analyzing samples on HPLC. Fingerprint similarity calculation software was used for data analysis. RESULTS: We got a good separation of Awei Capusules peaks. There were 15 peaks in fingerprint of Awei capusles. Gallic acid, magnolol and honokiol were identified. CONCLUSION: HPLC fingerprinting of Awei Capusules can provide to reference. It can control preparations quality of Awei Capusules. PMID- 23661997 TI - Effect of Mangiferin and Mahanimbine on Glucose Utilization in 3T3-L1 cells. AB - BACKGROUND: Stem barks of Mangifera indica contain a rich content of mangiferin (xanthone glucoside), whereas Murraya koenigii leaves contain rich sources of mahanimbine (carbazole alkaloid) and used traditionally for the treatment of diabetes. OBJECTIVE: To investigate the effects of mangiferin (xanthone glucoside) and mahanimbine (carbazole alkaloid) on glucose utilization in 3T3-L1 cells. MATERIALS AND METHODS: Mangiferin was isolated from stem barks of Mangifera indica and mahanimbine was isolated from Murraya koenigii leaves. These isolated compounds were subjected to MTT assay and glucose utilization test with 3T3-L1 cells. RESULTS: Treatment of the 3T3-L1 cells with mangiferin and mahanimbine increased the glucose utilization in a dose-dependent manner. At a concentration of 1 mM, mangniferin showed 2-fold increase in glucose utilization compared with untreated control. In case of mahanimbine, the observed effect at 1 mM was almost equivalent to positive control (insulin at 1 MUM). Moreover, MTT assay showed that both of these compounds were less toxic at a concentration of 1 mM (nearly 75% cells are viable). CONCLUSION: The present results indicated that these natural products (mangiferin and mahanimbine) exhibited potential ethnomedical uses in management of diabetes. PMID- 23661998 TI - Secondary metabolites from the stem of Ravenia spectabilis Lindl. AB - BACKGROUND: Ravenia spectabilis is a medium tall shrub found widespread in South America. It also found in India, Pakistan, Bangladesh etc. Few alkaloid and steroid compounds were reported from the plant previously. MATERIALS AND METHODS: Methanol extract from the stems of Ravenia spectabilis were partitioned into n hexane, carbon tetrachloride, chloroform and aqueous soluble fractions, respectively. The crude methanol extract, carbon tetrachloride fraction and chloroform fraction were fractionated by column chromatography of Silica gel and Sephadex LH-20 for isolation and purification of compounds. The structures of the isolated compounds were determined by extensive NMR spectral analysis, including 2D NMR, mass spectroscopy etc. RESULTS: Ten compounds, gamma-fagarine (1), ravenoline (2), N-methyl atanine (3),2,3,3,5-tetramethyl-2,3,4,5- tetrahydrofurano [3,2-c] quinolin-4-one (4), arborinine (5), 3-geranyl indole (6), atanine (7), steroids sitosta-4-en- 3-one (8), stigmasterol (9) and 3 methoxy-4-hydroxy cinnamic acid (10) were isolated from the stems of Ravenia spectabilis. CONCLUSION: Compounds N-methyl atanine (3), 2,3,3,5-tetramethyl 2,3,4,5-tetrahydrofurano [3,2-c] quinolin-4-one (4), 3-geranyl indole (6), sitosta-4-en-3-one (8) and 3-methoxy-4-hydroxy cinnamic acid (10) were isolated from this plant for the first time. 3-geranyl indole (6) was also isolated second time from natural sources. PMID- 23662000 TI - Flexible ureterorenoscopy: Tips and tricks. AB - With advancement in technology, improvement in endoscope and ancillary equipment, more complex procedures can be performed using flexible ureterorenoscopy. In this review article we provide a summary of flexible ureterorenoscopic procedures with "tips and tricks" for success for each type of procedure. It looks at the disposables used with flexible ureterorenoscopic procedures, set up and patient positioning for gaining access, insertion and handling of scope and the use of urethral access sheath. We also provide techniques for various flexible ureterorenoscopic procedures including management of renal stones, calyceal diverticula and upper tract urothelial tumours. PMID- 23662001 TI - Comparable effect with minimal morbidity of low-dose Tokyo 172 strain compared with regular dose Connaught strain as an intravesical bacillus Calmette-Guerin prophylaxis in nonmuscle invasive bladder cancer: Results of a randomized prospective comparison. AB - AIM: The aim was to compare patients' morbidity and response of bacillus Calmette Guerin (BCG) prophylaxis after the intravesical instillation of low-dose Tokyo 172 strain and regular dose Connaught strain in patients with nonmuscle invasive bladder cancer (NMIBC). PATIENTS AND METHODS: This was a randomized, active controlled, open-label, monocenter study. Thirty-eight, NMIBC patients were treated sequentially, in a random order, with low-dose Tokyo 172 strain and regular dose Connaught strain, receiving each therapy for 6 weeks. A total of 18 and 20 patients were randomly assigned to a Tokyo 172 strain arm and a Connaught strain arm, respectively. Complication, morbidity, and recurrence-free survival (RFS) after each treatment were compared. RESULTS: There was no significant difference in the 1-year RFS rate in patients treated with Tokyo 172 strain and Connaught strain (72.2% vs. 83.5%, respectively; P = 0.698). There were no significant differences in adverse events between the arms. Severe adverse events (>Grade 3) were seen in 15% of the Connaught strain group while no severe adverse events were observed as a result of Tokyo 172 strain. CONCLUSION: Our results indicated that low-dose Tokyo 172 strain decreased adverse events although it was not significant, and the RFS difference was not statistically significant between the two arms. Further investigation is warranted. PMID- 23662002 TI - Adult multilocular cystic nephroma: Report of six cases with clinical, radio pathologic correlation and review of literature. AB - BACKGROUND: Cystic renal neoplasms of the kidney can be benign or malignant. Multicystic nephroma (MCN) represents a rare benign cystic lesion of the kidney, which usually presents as a unilateral multicystic renal mass without solid elements. According to the World Health Organization (WHO) classification of the renal neoplasms, it is grouped along with mixed epithelial-stromal tumor of the kidney. MATERIALS AND METHODS: We report a retrospective review of six cases of MCN of kidney. Patient demographics, imaging findings, operative details and final histology were recorded. RESULTS: All patients had suspicious/malignant features on radiological examination, leading to a radical nephrectomy. However, microscopically these lesions were lined by cuboidal epithelium, and in a few places hobnail epithelium. No cells with clear cytoplasm, blastemal or immature elements were seen. In one case, foci of inflammatory cells and histiocytes were present. CONCLUSIONS: MCN is a benign cystic lesion and clinical presentations are nonspecific with symptoms such as abdominal pain, hematuria and urinary tract infection. These nonspecific clinical presentations and confusing radiological features create difficult preoperative differentiation from malignant cystic renal neoplasms. PMID- 23662003 TI - Assessment of Clavien-Dindo classification in patients >75 years undergoing nephrectomy/nephroureterectomy. AB - INTRODUCTION: There is a paucity of a standardized post-operative complications grading system in urology especially in the elderly population. Studies show satisfactory survival and oncological outcomes albeit with a slight increase in post-operative morbidity compared to younger patients. The Clavien-Dindo classification for post-operative complications is established as a valid system worldwide and applicable in many fields of surgery. PURPOSE: Retrospective assessment of post-operative complications in patients >75 years who underwent open/laparoscopic nephrectomy/nephroureterectomy for renal diseases and grading the post-operative complications according to the Clavien-Dindo classification. MATERIALS AND METHODS: Retrospective review of case notes was performed in patients >75 years who underwent a laparoscopic/open nephrectomy/nephroureterectomy between 2000 and 2008. Post-operative complications were graded according to the Clavien-Dindo classification. RESULTS: A total of 54 patients >75 years underwent nephrectomy/nephroureterectomy. 29 patients had laparoscopy and 25 had open surgery. Fifty one patients had a malignancy and 3 had benign diseases. Grade I, II, IIIa, IIIb and IVa were 25.6%, 41.1%, 7.7%, 7.7% and 17.9% respectively. No significant difference was noted in the 2 groups. CONCLUSIONS: We believe that in elderly patients, laparoscopic surgery can be offered safely without significantly increasing the surgical risks. The Clavien-Dindo classification is easy to use and effectively applied to categorize post-operative complications associated with nephrectomy/nephroureterectomy in elderly population. However, this system needs slight modification to incorporate intra-operative complications and large studies are needed to validate and standardize this classification for all urological procedures. PMID- 23662004 TI - Commentary. PMID- 23662005 TI - ERRATUM. AB - [This corrects the article on p. 133 in vol. 3, PMID: 21976925.]. PMID- 23662006 TI - Do we really know the prevalence of multi-drug resistant Escherichia coli in the territorial and nosocomial population? AB - INTRODUCTION: The purpose of this work was to evaluate the prevalence of the Quinolones resistant Escherichia coli and/or ESBL producers in the population of our catchment area and hospital component. MATERIALS AND METHODS: From January 2008 to December 2010, all data concerning urine cultures in patients with suspected urinary tract infection and/or asymptomatic bacteriuria referring at our center located in the south of Milan were prospectively evaluated. RESULTS: In 2008, 2136 outpatient and 1232 hospital urine cultures were analyzed. The presence of quinolone-resistant strains was 21% at a local level and 53% in hospitals. ESBL-producing strains were isolated in 3.5% of cases at a local level and 20.5% in hospitals. In 2009, 2396 outpatient and 1320 hospital urine cultures were analyzed. The presence of quinolone-resistant strains was 21% at a local level and 46% in hospitals. ESBL-producing strains were isolated in 5.4% of cases at a local level and 20% in hospitals. In 2010, 2601 outpatient and 1717 hospital urine cultures were analyzed. The presence of quinolone-resistant strains was 34% at a local level and 26% in hospitals. ESBL-producing strains were isolated in 6.7% of cases at a local level and 20.6% in hospitals. The multidrug resistance was significantly (P < 0.01) higher in ESBL-positive strains. CONCLUSION: Due to rising antibiotic resistance among uropathogens, it is important to have knowledge of the organisms causing urinary tract infections and their antibiotic sensitivity patterns. In areas with high prevalence of E. Coli resistance, performing urine culture before every surgical procedure became mandatory, in order to prevent fatal sepsis. PMID- 23662007 TI - Hemosepermia after transrectal ultrasound-guided prostatic biopsy: A prospective study. AB - OBJECTIVES: Trans-rectal ultrasound (TRUS) is a safe, cost-effective, radiation free imaging modality for evaluation of prostate. But unfortunately, hemospermia is known to be associated with TRUS-guided prostate biopsy. The aim of this study is to measure the incidence and risk factors of hemospermia in patients undergoing TRUS. PATIENTS AND METHODS: A prospective observational study involving patients undergoing TRUS for suspected prostate cancer has been conducted at Al-Hussein and Sayed Galal Hospitals. Forty patients were included in the study. RESULTS: Most men (90% = 36 patient) undergoing TRUS-guided prostatic biopsy, who were able to ejaculate, experienced hemospermia, which was associated with some degree of anxiety. The mean duration of hemospermia was 4 (+/-1.4) weeks. The number of ejaculations before the complete resolution of hemospermia was 6 (+/-5.6). None of the clinical and pathological factors was a significant predictor of the duration of hemospermia. CONCLUSION: Patients should be adequately counseled before TRUS-guided prostatic biopsy to avoid anxiety and alterations in sexual activity. PMID- 23662008 TI - Reliability of Arabic ICIQ-UI short form in Saudi Arabia. AB - CONTEXT: The International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) provides a brief measure of symptoms and impact of urinary incontinence on quality of life. It is suitable for use in clinical practice and research. An Arabic version of the ICIQ-UI SF was translated and validated in Egypt and Syria. AIMS: The objective was to assess the reliability of the Arabic version of the ICIQ-UI SF in women from Saudi Arabia. SETTINGS AND DESIGN: A study at the Urogynecology Clinic was conducted from November 2010 until August 2011. MATERIALS AND METHODS: Thirty-seven consecutive Saudi women attending urogynecologic clinic were recruited. Questionnaires were distributed for self-completion and then redistributed to the same set of respondents two to four weeks later as part of a test-retest analysis for assessing questionnaire's stability. STATISTICAL ANALYSIS USED: Agreement between two measurements was determined by weighted Kappa. Internal consistency was assessed using Cronbach's alpha coefficient. RESULTS: Participants had a mean (SD) age of 39 (9.9), median parity of 4, and mean BMI (SD) of 30.9 kg/m(2) (4.6). There were no differences in the frequency and amount of urine leaks or the impact of UI on quality of life observed between the two visits. Assessment of internal consistency was excellent with the Cronbach's alpha coefficient of 0.97 (95% CI: 0.88-0.98). Participants agreed that the questionnaire was clear, appropriate, and easy to understand. CONCLUSIONS: The Arabic ICIQ-UI SF is a stable and clear questionnaire that can be used for UI assessment in clinical practice and research among Saudi women. PMID- 23662009 TI - Primary testicular plasmocytoma: A five year follow-up. AB - The testicular plasmocytoma represents only 5% of the non-germinative cell testicular tumors, and accounts for only 2% of all plasma cell neoplasms. Approximately, 50 cases of testicular plasmocytoma have been reported in medical literature; however, only 9 of these are isolated tumors without previous history or progression to multiple myeloma. A 47-year-old patient, presenting progressive and painless growth of the right testicle in the last four years, underwent surgical treatment in another hospital two years ago, to correct a hydrocele in the same testicle with no improvement at all. Sonography showed a tumor with the following measurements for the right testicle: 84 * 59 * 80 mm. The tumor marker values were all normal. An abdominal computed tomography found no evidence of retroperitoneal lymph nodes invasion. The patient underwent a right radical orchiectomy. Pathologic analysis revealed a malignant neoplasia described as a plasmocytoma (solitary myeloma) that produces immunoglobulin's kappa light chain. After five years of follow-up, there were no signs of metastasis or local recurrence in the exams. Case report and review of literature have been presented here. PMID- 23662010 TI - Radio-frequency ablation helps preserve nephrons in salvage of failed microwave ablation for a renal cancer in a solitary kidney. AB - Recurrent tumors after renal ablative therapy present a challenge for clinicians. New ablative modalities, including microwave ablation (MWA), have very limited experience in methods of retreating ablation failures. Additionally, in MWA, no long-term outcomes have been reported. In patients having local tumor recurrence, options for surveillance or surgical salvage must be assessed. We present a case to help assess radio-frequency ablation (RFA) for salvage of failed MWA. We report a 63-year-old male with a 4.33-cm renal mass in a solitary kidney undergoing laparoscopic MWA with simultaneous peripheral fiber-optic thermometry (Lumasense, Santa Clara, CA, USA) as primary treatment. Follow-up contrast enhanced computed tomography (CT) scan was performed at 1 and 4.3 months post-op with failure occurring at 4.3 months as evidenced by persistent enhancement. Subsequently, a laparoscopic RFA (LRFA) with simultaneous peripheral fiber-optic thermometry was performed as salvage therapy. Clinical and radiological follow-up with a contrast-enhanced CT scan at 1 and 11 months post-RFA showed no evidence of disease or enhancement. Creatinine values pre-MWA, post-MWA, and post-RFA were 1.01, 1.14, and 1.17 mg/ml, respectively. This represents a 15% decrease in estimated glomerular filtration rate (eGFR) (79 to 67 ml/min) post-MWA and no change in eGFR post-RFA. Local kidney tumor recurrence often requires additional therapy and a careful decisionmaking process. It is desirable not only to preserve kidney function in patients with a solitary kidney or chronic renal insufficiency, but also to achieve cancer control. We show the feasibility of RFA for salvage treatment of local recurrence of a T1b tumor in a solitary kidney post-MWA. PMID- 23662011 TI - Chylous ascites after laparoscopic hand-assisted donor nephrectomy: Is it specific for the left-side? AB - We describe a case-report of a chylous ascites after laparoscopic donor nephrectomy, summarize the current literature, and hypothesize on the etiology of this complication. PMID- 23662012 TI - The type of lymphocyte infiltration near urothelial carcinoma is diagnostic for chronic lymphocytic leukemia. AB - T-lymphocytic infiltration near the tumor site is an expected immune response in bladder cancers. However, reports of patients with bladder cancer exhibiting small lymphocytic infiltration of the bladder tissue are very rare in the literature. Here, the patient was presented to our group with hematuria, but subsequently diagnosed as exhibiting invasive bladder cancer and chronic lymphocytic leukemia with suspicious lymphocytic infiltration in a transurethral resection specimen. This case emphasizes the importance of lymphocytic infiltration's nature near urothelial carcinoma. PMID- 23662013 TI - Eosinophilic cystitis mimicking tuberculosis: An analysis of five cases with review of literature. AB - Eosinophilic cystitis (EC) is a rare disease. It is a transmural inflammation of the bladder, predominantly with eosinophils. High index of suspicion is needed for timely intervention. EC should be kept as a differential diagnosis in patients presenting with lower urinary tract symptoms due to small capacity bladder with a negative workup for urinary tuberculosis and in patients having hematuria and negative cytology, or incidentally found bladder lesions with known risk factors. Initial treatment is conservative with removal of risk factor, anti histaminics and steroids. Augmentation cystoplasty should be considered in patients with a small capacity bladder. These patients need a strict and long term follow-up. PMID- 23662014 TI - Spermatic cord metastasis as early manifestation of small bowel adenocarcinoma. AB - Malignant tumors of the spermatic cord are rare. There are a few case reports on spermatic cord metastasis from colonic, gastric, pancreas, and prostatic cancer. Here, we report a 36-year-old man with brucellosis presenting with spermatic cord metastasis as early manifestation of small bowel adenocarcinoma. PMID- 23662015 TI - Robot-assisted laparoscopic radical prostatectomy after heart transplantation. AB - Prostate cancer (CaP) is the leading visceral malignancy in males. Patients who undergo cardiac transplantation are immune compromised, thus presenting a therapeutic challenge. Immunosuppresion could accelerate tumor growth, while medical intervention may be associated with increased treatment mortality or morbidity. Due to paucity of such cases, there are no randomized trials that address the treatment algorithm for cardiac transplant patients with CaP, with only a few scattered reports in the literature. Treatment options range from hormonal manipulation to radiation therapy to radical prostatectomy. To our knowledge, we report the first successful robot-assisted laparoscopic radical prostatectomy in a heart transplant patient with CaP. PMID- 23662016 TI - When angels fall...are we lowering the standards of medical education in India? PMID- 23662017 TI - The dawn of hedgehog inhibitors: Vismodegib. AB - Cancer, one of the leading causes of death worldwide is estimated to increase to approximately 13.1 million by 2030. This has amplified the research in oncology towards the exploration of novel targets. Recently there has been lots of interest regarding the hedgehog (Hh) pathway, which plays a significant role in the development of organs and tissues during embryonic and postnatal periods. In a normal person, the Hh signaling pathway is under inhibition and gets activated upon the binding of Hh ligand to a transmembrane receptor called Patched (PTCH1) thus allowing the transmembrane protein, smoothened (SMO) to transfer signals through various proteins. One of the newer drugs namely vismodegib involves the inhibition of Hh pathway and has shown promising results in the treatment of advanced basal-cell carcinoma as well as medulloblastoma. It has been granted approval by US Food and Drug Administration's (US FDA) priority review program on January 30, 2012 for the treatment of advanced basal-cell carcinoma. The drug is also being evaluated in malignancies like medulloblastoma, pancreatic cancer, multiple myeloma, chondrosarcoma and prostate cancer. Moreover various Hh inhibitors namely LDE 225, saridegib, BMS 833923, LEQ 506, PF- 04449913 and TAK 441 are also undergoing phase I and II trials for different neoplasms. Hence this review will describe briefly the Hh pathway and the novel drug vismodegib. PMID- 23662018 TI - Strategies and challenges for safe injection practice in developing countries. AB - Injection is one of the important health care procedures used globally to administer drugs. Its unsafe use can transmit various blood borne pathogens. This article aims to review the history and status of injection practices, its importance, interventions and the challenges for safe injection practice in developing countries. The history of injections started with the discovery of syringe in the early nineteenth century. Safe injection practice in developed countries was initiated in the early twentieth century but has not received adequate attention in developing countries. The establishment of "Safe Injection Global Network (SIGN)" was an milestone towards safe injection practice globally. In developing countries, people perceive injection as a powerful healing tool and do not hesitate to pay more for injections. Unsafe disposal and reuse of contaminated syringe is common. Ensuring safe injection practice is one of the greatest challenges for healthcare system in developing countries. To address the problem, interventions with active involvement of a number of stakeholders is essential. A combination of educational, managerial and regulatory strategies is found to be effective and economically viable. Rational and safe use of injections can save many lives but unsafe practice threatens life. Safe injection practice is crucial in developing countries. Evidence based interventions, with honest commitment and participation from the service provider, recipient and community with aid of policy makers are required to ensure safe injection practice. PMID- 23662019 TI - Accessibility and use of essential medicines in health care: Current progress and challenges in India. AB - Essential Medicine Concept, a major breakthrough in health care, started in 1977 when World Health Organization (WHO) published its first list. Appropriate use of essential medicines is one of the most cost-effective components of modern health care. The selection process has evolved from expert evaluation to evidence-based selection. The first Indian list was published in 1996 and the recent revision with 348 medicines was published in 2011 after 8 years. Health expenditure is less in India as compared to developed countries. India faces a major challenge in providing access to medicines for its 1.2 billion people by focusing on providing essential medicines. In the future, countries will face challenges in selecting high-cost medicines for oncology, orphan diseases and other conditions. There is a need to develop strategies to improve affordable access to essential medicines under the current health care reform. PMID- 23662020 TI - Effect of Casilan((r)) on (13)C-caffeine metabolism in overnight-fasted healthy Nigerian children. AB - OBJECTIVE: To determine the effect of Casilan((r)) on (13)C-caffeine metabolism in healthy Nigerian children. MATERIALS AND METHODS: TWELVE HEALTHY NIGERIAN CHILDREN (MALE: six, female: six) aged 3-8 years were studied on three occasions. After an overnight fast, the children were studied after ingesting Casilan((r)) only (Week 1). They were restudied after ingesting 3 mg/kg of labeled caffeine only (Week 2), and further re-studied after ingesting both Casilan((r)) and labeled caffeine (Week 3). Breath samples were collected by blowing via a straw into an exentainer bottle. The cumulative percentage of (13)C-caffeine exhaled as (13)CO2 was measured over 2 h. RESULTS: The time courses of (13)C-enrichments in exhaled CO2 for all the children, after they had ingested labeled caffeine only and after they had ingested both Casilan((r)) and labeled caffeine, were identical. There was a gradual rise and peak of the enrichments at about 60-75 min, followed by a gradual fall (II) or a plateau (III). Contrarily, the time course of (13)C-enrichments for all the children was consistently low and stable after they had ingested Casilan((r)) only (I). The mean values of cumulative percent (13)C-doses recovered in the CO2 exhaled over a 2-h period, after ingesting labeled caffeine only (8.59 +/- 1.10 delta%/mg) and after ingesting both Casilan((r)) and labeled caffeine (8.58 +/- 1.33 delta%/mg), were identical, with no statistically significant difference (P = 0.972). This suggests that Casilan((r)) did not affect the CYP1A2 metabolic pathway. CONCLUSIONS: Casilan((r)) is a safe, reliable and quantitative food supplement for overnight fasted children undergoing caffeine breath test. PMID- 23662021 TI - Effect of addition of either sitagliptin or pioglitazone in patients with uncontrolled type 2 diabetes mellitus on metformin: A randomized controlled trial. AB - OBJECTIVE: To compare and study the dipeptidy1 peptidase-4 (DPP-4) inhibitors in combination with metformin against established combination therapies. MATERIALS AND METHODS: This 16-week study was designed to compare sitagliptin versus pioglitazone as add-on therapy in patients of type 2 diabetes mellitus inadequately controlled with metformin alone. Fifty-two patients were randomized into two groups to receive either sitagliptin 100 mg (group 1) or pioglitazone 30 mg (group 2) in addition to metformin. The primary efficacy end point was change in HbA1c. Secondary end points included change in fasting plasma glucose (FPG), body weight and lipid profile. Treatment satisfaction was assessed using the Diabetes Treatment Satisfaction Questionnaire. Both the groups had a significant decrease in HbA1c. RESULTS: There was no significant difference between mean reductions in FPG in both the groups. There was a significant decrease in the mean body weight and body mass index in group 1 in contrast to the significant increase in the same in group 2. Both the treatment groups reported a significant decrease in High-density lipoprotein (HDL-C) and Triglyceride. CONCLUSION: Sitagliptin was well tolerated without any incidence of hypoglycemia. It was concluded that sitagliptin as an add-on to metformin is as effective and well tolerated as pioglitazone. PMID- 23662022 TI - Comparison of the efficacy and tolerability of ivabradine and ranolazine in patients of chronic stable angina pectoris. AB - INTRODUCTION: To compare the efficacy and tolerability of Ivabradine (IVA) and Ranolazine (RAN) in chronic angina patients. MATERIALS AND METHODS: This was a follow-on, open-label trial conducted in a tertiary care hospital of Uttarakhand. Thirty patients each taking IVA 5 mg twice daily or RAN 500 mg twice daily were distributed to the respective groups. Patients were asked to fill a pretested questionnaire on frequency of anginal attacks and adverse reactions before and 2, 4 and 8 weeks after taking the respective medicines. Their blood pressure, heart rate and routine hematological and biochemical estimations were performed at baseline and after intervention. Results were statistically analyzed using different statistical tests, with P < 0.05 considered as significant. RESULTS: There was no significant difference in the frequency of anginal attacks per week between the groups. The adverse drug reactions (ADRs) reported in the IVA group were dizziness (30%), headache (16.6%), backache (16.6%), vertigo (13.3%), blurred vision (13.3%), muscle cramps (10%), arthralgia (10%), cough and dyspnea (6.6%), hypersensitivity rash (6.6%), fever (3.3%) and nausea (3.3%). The ADRs in the RAN group were nausea (26.6%), dizziness (23.3%), vomiting (3.3%), constipation (3.3%) and vertigo (3.3%). The blood pressure, heart rate and routine hematological and biochemical evaluations did not show any significant difference in the pre-post values. IVA significantly decreased the resting heart rate after eight weeks of intervention. CONCLUSIONS: Both antianginal agents appeared equiactive. However, RAN had a better safety and tolerability profile than IVA. Serum sickness-like reaction was an adverse event noticed with IVA, which needs causality establishment. PMID- 23662023 TI - Efficacy and safety of Tinospora cordifolia lotion in Sarcoptes scabiei var hominis-infected pediatric patients: A single blind, randomized controlled trial. AB - OBJECTIVE: To evaluate the clinical efficacy and safety of Tinospora cordifolia lotion including its cure rate and clearance time compared with permethrin lotion. MATERIALS AND METHODS: A single blind, randomized, controlled, pilot clinical study was performed in three government institutions to investigate clinical efficacy of T. cordifolia lotion in sixty-six clinically-diagnosed scabies-infected patients. The patients were treated with T. cordifolia or permethrin lotions for three consecutive days for two weeks and clinical assessment of each patient was performed for five weeks. RESULTS: T. cordifolia lotion and permethrin significantly reduced the mean global evaluation score after four weeks of treatment. The two lotions showed comparable effects as anti scabies agent. Moreover, the clearance time (days) and cure rate using the two lotions did not differ. Clinical improvement, mean clearance time and cure rate of T. cordifolia lotion are comparable with permethrin. CONCLUSIONS: Tinospora cordifolia lotion exhibits anti-scabies activity comparable with permethrin. Its incorporation as therapeutic reagent in Sarcoptes scabiei infections is highly recommended. PMID- 23662024 TI - Oleanolic acid prevents progression of streptozotocin induced diabetic nephropathy and protects renal microstructures in Sprague Dawley rats. AB - OBJECTIVE: To study the effect of oleanolic acid (OA) on streptozotocin induced diabetic nephropathy in Sprague Dawley rats. MATERIALS AND METHODS: Four weeks after intra-peritoneal injection of streptozotocin (STZ; 55 mg/kg), the rats with proteinuria were grouped as: Control (non-diabetic, treated orally with vehicle), diabetic control (treated orally with vehicle) and three diabetic groups receiving 20, 40 and 60 mg/kg/day oral doses of OA. At the end of 8 weeks, urine and serum samples from the rats were processed for determination of creatinine, BUN and GFR. The kidney samples were processed for determination of weight changes, oxidative stress related parameters like catalase, superoxide dismutase and reduced glutathione levels. A part of one kidney from each rat was used for transmission electron microscopy (TEM). RESULT: As evident in TEM, OA inhibited the nephropathy induced alterations in podocyte integrity, basement membrane thickness and spacing between the podocytes at 60 mg/kg dose. It increased GFR and reduced oxidative stress in the kidneys in a dose dependent manner. These findings conclusively demonstrate the efficacy of OA in diabetic nephropathy. Significant decrease in the oxidative stress in kidneys indicates the role of anti-oxidant mechanisms in the effects of OA. However, OA is known to act through multiple mechanisms like inhibition of the generation of advanced glycation end products and improving the insulin secretion. These mechanisms might have contributed to its efficacy. CONCLUSION: These results conclusively demonstrate the efficacy of OA in diabetic nephropathy through its possible antioxidant activity. PMID- 23662026 TI - Prescribing pattern of gastroprotective agents with non-steroidal anti inflammatory drugs. PMID- 23662025 TI - Genetic variation and haplotype structure of the gene Vitamin K epoxide reductase complex, subunit 1 in the Tamilian population. AB - OBJECTIVE: To study the genetic variation and haplotype structure of Vitamin K epoxide reductase complex, subunit 1 (VKORC1) gene in the Tamilian population. MATERIALS AND METHODS: The study was performed on 210 unrelated, healthy volunteers of the Tamilian population, of either sex between the age group of 18 60 years. Five ml of venous blood sample was collected using sodium ethylene diamine tetra acetic acid (EDTA) as anticoagulant. DNA was extracted using phenol chloroform extraction method. Eight single nucleotide polymorphisms (SNPs) VKORC1 rs9923231 (G), rs7196161 (T), rs2884737 (T), rs17708472 (C), rs9934438 (C), rs8050894 (G), rs23596121 (C), and rs7294 (A) were studied using real-time quantitative Polymerase Chain Reaction (qPCR) method and they were included for constructing five-major haplotype blocks of VKORC1 gene. RESULTS: The major alleles of VKORC1 rs9923231 (G), rs7196161 (T), rs2884737 (T), rs17708472 (C), rs9934438 (C), rs8050894 (G), and rs23596121 (C), were found to be at frequencies of 90.0%, 89.2%, 90.9%, 94.1%, 90.7%, 89.5% and 91.2%, respectively. The variant allele of VKORC1 rs7294 (A) was more frequent (83.6%) in the Tamilian population. The frequencies of haplotypes HAP1 (GTTCCGCA), HAP2 (ACGCTCTG), HAP3 (GTTTCGCG), HAP4 (GTTCCGCG) and HAP5 (GCTCCCCG) were found to be 80.0%, 7.4%, 4.7%, 1.5% and 1.1%, respectively. CONCLUSION: In the present study the allele- frequency distributions, genotype and haplotype frequencies of the VKORC1 gene was considered. The findings of this study provide the genetic information required for learning the association of VKORC1 genetic variation and oral anticoagulant dose variability among patients receiving oral anticoagulants in the Tamilian population. PMID- 23662027 TI - Effectiveness of ellagic acid on isoniazid-rifampicin induced liver damage in rats. PMID- 23662028 TI - A study of non-prescription usage of antibiotics in the upper respiratory tract infections in the urban population. PMID- 23662029 TI - Calcium channel blocking activity of a dihydropyrimidine derivative (BKVIII) on rabbit's aortic strip. PMID- 23662030 TI - A structured course in laboratory animal science for postgraduates: Is it a necessity? PMID- 23662031 TI - Aceclofenac induced Stevens-Johnson/toxic epidermal necrolysis overlap syndrome. AB - The purpose of this paper is to report a rare occurrence of Stevens-Johnson/Toxic epidermal necrolysis (SJS/TEN) overlap syndrome after the use of aceclofenac. A 38 year old healthy adult male presented with rapidly evolving rash over face and upper body with ulceration of buccal mucosa and breathlessness after taking aceclofenac tablet. Naranjo score for this adverse drug event was six, thereby making it a probable adverse drug reaction. Despite aggressive fluid resuscitation and use of antihistamines and systemic steroids, patient's health rapidly worsened and died within six hours of presentation. Aceclofenac induced SJS/TEN overlap is an extremely rare clinical association previously reported only once in medical literature. To the best of our knowledge, this is the first case report of such an association in the Indian population. We are presenting this case to highlight the serious adverse reactions possible from a routinely prescribed drug. PMID- 23662032 TI - An unusual cause of cardiac arrest in a hospitalized patient. AB - We present an unusual case of 24 year old male who was hospitalized for dental procedure and developed cardiac arrest 2 days after the procedure. The patient presented with swelling of buccal cavity for which a biopsy was taken. Two days after the procedure, apparently normal patient suddenly presented at mid night with VT and VF, which were intractable requiring multiple DC shocks. During this period arterial blood gas analysis revealed severe acidosis. The circumstances led us to suspect poisoning as one of the cause for his medical condition. We looked for commonly available toxins. One of the commonly available toxins is hand sanitizer which contains Isopropyl alcohol, glycerin and perfume. Due to prolonged cardiac arrest and intractable arrhythmia patient had sustained hypoxic brain injury. Patient remained hemodynamically stable for next 9 days although his CNS status did not improve. Patient succumbed to sepsis on 9(th) day. Healthcare professionals should be aware of such possibilities and treat the patients at the earliest and put a check on the easy availability of IPA based hand sanitizers. PMID- 23662033 TI - Ticagrelor: An emerging oral antiplatelet agent. PMID- 23662034 TI - Neurobiological bases of reading comprehension: Insights from neuroimaging studies of word level and text level processing in skilled and impaired readers. AB - For accurate reading comprehension, readers must first learn to map letters to their corresponding speech sounds and meaning and then they must string the meanings of many words together to form a representation of the text. Furthermore, readers must master the complexities involved in parsing the relevant syntactic and pragmatic information necessary for accurate interpretation. Failure in this process can occur at multiple levels and cognitive neuroscience has been helpful in identifying the underlying causes of success and failure in reading single words and in reading comprehension. In general, neurobiological studies of skilled reading comprehension indicate a highly overlapping language circuit for single word reading, reading comprehension and listening comprehension with largely quantitative differences in a number of reading and language related areas. This paper reviews relevant research from studies employing neuroimaging techniques to study reading with a focus on the relationship between reading skill, single word reading, and text comprehension. PMID- 23662035 TI - Messenger RNA Detection in Leukemia Cell lines by Novel Metal-Tagged in situ Hybridization using Inductively Coupled Plasma Mass Spectrometry. AB - Conventional gene expression profiling relies on using fluorescent detection of hybridized probes. Physical characteristics of fluorophores impose limitations on achieving a highly multiplex gene analysis of single cells. Our work demonstrates the feasibility of using metal-tagged in situ hybridization for mRNA detection by inductively coupled plasma mass spectrometry (ICP-MS). ICP-MS as an analytical detector has a number of unique and relevant properties: 1) metals and their stable isotopes generate non-overlapping distinct signals that can be detected simultaneously; 2) these signals can be measured over a wide dynamic range; 3) ICP-MS is quantitative and very sensitive. We used commercial antibodies conjugated to europium (Eu) and gold together with biotinylated oligonucleotide probes reacted with terbium-labeled streptavidin to demonstrate simultaneous mRNA and protein detection by ICP-MS in leukemia cells. PMID- 23662036 TI - c-Met Mutational Analysis in the Sema and Juxtamembrane Domains in Small-Cell Lung-Cancer. AB - BACKGROUND: c-Met mutations play a critical role in the development and progression of primary tumors and metastases. Activation of the HGF/SF-c-Met pathway determines a poor prognosis in non-small-cell and small-cell lung cancer (SCLC) patients. Missense mutations of c-Met have been identified in SCLC patients located in the juxtamembrane (JM) and in the Sema domain. To determine the role of the c-Met pathway in SCLC, we have investigated the presence of c-Met mutations in SCLC patients. PATIENTS AND METHODS: Forty-four tumor tissue samples from SCLC patients were obtained with bronchoscopy before beginning treatment. Analysis of c-Met mutations was performed in exon 2 and exon 14. RESULTS: Of the 44 patients included in this study, 23 were classified as limited disease and were treated with sequential or concurrent chemotherapy and thoracic radiotherapy. Twenty-one patients with extensive disease received chemotherapy alone, the majority with cisplatin or carboplatin plus etoposide. The median survival was 14 months (95% CI: 9.4 to 18.5 months) and the 2- and 5-year survival rates were 24% and 15%, respectively. Previously identified missense mutations E168D, R988C and T1010I in c-Met were not found in our study. However, novel mutations were identified, including T995I in the juxtamembrane domain (T995I) and a mutation which does not change amino acid in codon 178 in the Sema domain. CONCLUSION: In SCLC patients, the presence of mutations in c-Met gene is a rare event. Other genetic alterations involved in the HGF/SF-c-Met pathway should be assessed to define the role of this signaling pathway in SCLC. PMID- 23662037 TI - Mithramycin targets sp1 and the androgen receptor transcription level-potential therapeutic role in advanced prostate cancer. AB - Multiple lines of evidence implicate over-expression and activation of the androgen receptor (AR) in the progression of prostate cancer (PC) to androgen independence (AI) and resistance to therapy. The mechanisms leading to AR over expression are not fully understood but binding of Sp1 to specific Sp1-binding sites in the AR promoter and 5'-untranslated region (5'-UTR) was shown to up regulate AR transcription. In this work, we further characterized the role of Sp1 in the control of AR transcription and explored its potential as a therapeutic target in androgen-dependent (AD) and independent (AI) LNCaP cells. We identified a pair of new Sp1-binding site in the 5'-UTR of AR which we named ARSp1-3. ARSp1 3 binds Sp1 with higher affinity than other known Sp1-binding sites in the promoter/5'-UTR and in transfection experiments, the ARSp1-3 reporter showed higher transcriptional activity in AI than in AD cells. Treatment of these cells with nanomolar concentrations of Mithramycin inhibited binding of Sp1 to its binding sites in the promoter/5'-UTR of the AR gene but more specifically the binding of ARSp1-3 while other regulatory elements of the AR promoter were not affected. Inhibition of Sp1 binding by Mithramycin decreased the AR transcription and transactivation of PSA reporter constructs. At the lowest concentrations, Mithramycin decreased endogenous AR protein and proliferation of AD and AI LNCaP cells. The combinations of Mithramycin with either paclitaxel or bicalutamide were highly synergistic. CONCLUSION: Sp1 binding induces AR transcription in LNCaP cells. The higher affinity of ARSp1-3 for Sp1 may support higher AR mRNA levels in AI than AD LNCaP cells. Mithramycin is a potent and specific inhibitor of Sp1 and AR transcription with potential, at very low concentrations, to enhance the efficacy of hormones or taxane based therapy in patients with recurrent or androgen-independent progression that sustain AR expression. PMID- 23662038 TI - Kidney toxicogenomics of chronic potassium bromate exposure in f344 male rats. AB - BACKGROUND: Potassium bromate (KBrO3), used in both the food and cosmetics industry, and a drinking water disinfection by-product, is a nephrotoxic compound and rodent carcinogen. To gain insight into the carcinogenic mechanism of action and provide possible biomarkers of KBrO3 exposure, the gene expression in kidneys from chronically exposed male F344 rats was investigated. METHODS: Male F344 rats were exposed to KBrO3 in drinking water for 52 and 100 wk. Kidneys were removed, frozen, and stored at -80 degrees C, then used for Affymetrix microarray analysis. Gene expression patterns were examined using a non-carcinogenic (20 ppm) and carcinogenic dose (400 ppm) at 52 wk, and compared to 100 wk high dose (400 ppm) and adenoma gene expression. RESULTS: Statistical analysis revealed 144, 224, 43, and 994 genes out of 15866 from the 52 wk low, 52 wk high, 100 wk high, and adenomas respectively, were differentially expressed when compared to control kidneys. Gene ontology classification of the 52 wk high dose showed alterations of gene transcripts involved in oxidative stress, lipid metabolism, kidney function/ion transport, and cellular function. In a comparison of kidney development gene expression, alterations were seen in the adenomas but not in the 52 wk bromate-treated kidneys. However, the normal kidney from the high dose group resembled the adenoma expression pattern with early kidney development genes being up-regulated and adult phase genes being down-regulated. Moreover, eight genes were identified which could serve as biomarkers of carcinogenic exposure to bromate. The most promising of these was Pendrin, or Slc26a4, a solute carrier of chloride and iodide active in the kidney, thyroid, and inner ear. All these tissues are targets of KBrO3 toxicity. Expression array results were verified with quantitative real-time rtPCR. CONCLUSIONS: These data demonstrate that the 400 ppm carcinogenic dose of KBrO3 showed marked gene expression differences from the 20 ppm non-carcinogenic dose. Comparison of kidney development gene expression showed that the adenoma patterns were more characteristic of embryonic than adult kidneys, and that the normal kidney from the high dose group resembled the adenoma-like gene expression pattern. Taken together, the analysis from this study identifies potential biomarkers of exposure and illuminates a possible carcinogenic mode of action for KBrO3. PMID- 23662039 TI - Current concepts on the pathogenesis of the hypereosinophilic syndrome/chronic eosinophilic leukemia. AB - Chronic eosinophilic leukemia is a clonal disease characterized by hypereosinophilia and eosinophilia-related pathologic manifestations. Recently, the fusion gene FIP1L1/PDGFRA was found in the long arm of chromosome 4 and its expression has been shown to be associated with development of a clinical hypereosinophilic syndrome (HES) in a significant proportion of patients. FIP1L1/PDGFRalpha, the product of the gene FIP1L1/PDGFRA, is a constitutively activated tyrosine kinase and can be inhibited by imatinib mesylate. Several investigations have tried to dissect the mechanism of leukemogenesis and signaling induced by FIP1L1/PDGFRalpha in cell lines, primary human eosinophils and in murine myeloproliferative models. In this review, we analyzed the current knowledge on the relationship between FIP1L1/PDGFRalpha-induced signaling and eosinophil proliferation, survival and activation, specially focusing on its possible role in the modulation of cytokine and chemoattractant signaling pathways. PMID- 23662040 TI - Optic disc size and progression of visual field damage in patients with normal tension glaucoma. AB - PURPOSE: Our goal was to evaluate the influence of optic disc size on the progression of visual field damage in patients with normal-tension glaucoma (NTG). SUBJECTS AND METHODS: Eighty-two eyes of 82 NTG patients who had been receiving topical antiglaucoma medications and followed-up for more than 4 years were enrolled in this study. The patients were allocated to two groups, according to the mean size of their optic discs. The data were analyzed using regression analysis, based on the Cox proportional hazard model. RESULTS: The probability of visual field stability was significantly lower in eyes with large discs than in those with small discs (log rank test, P = 0.007). Progression of visual field damage was significantly associated with the optic disc area (hazard ratio [HR]: 1.812, P = 0.018), occurrence of disc hemorrhage (HR: 2.116, P = 0.028), and intraocular pressure reduction ratio (HR: 0.957, P = 0.014). CONCLUSION: The optic disc area correlates with progression of visual field damage in patients with NTG. PMID- 23662041 TI - Tonometry in corneal edema after cataract surgery: dynamic contour tonometry versus Goldmann applanation tonometry. AB - INTRODUCTION: Intraocular pressure (IOP) determination using dynamic contour tonometry (DCT) has been considered to be independent of central corneal thickness (CCT), while Goldmann applanation tonometry (GAT) is known to be influenced by various corneal properties. In this study, IOP was measured before and 1 day after cataract surgery using GAT and DCT to investigate the possible effects of corneal edema on IOP measurements. METHODS: Thirty patients with advanced cataracts were included in a pilot study. IOP was measured using GAT and DCT before and 1 day after phacoemulsification. CCT was determined before and after surgery to quantify postsurgical corneal edema. RESULTS: CCT increased significantly (by 89.7 +/- 107.4 MUm, P < 0.0001) 1 day after surgery. No significant difference was found for IOP measurements using GAT and DCT before surgery (mean IOP GAT: 17.5 +/- 5.7 mmHg; mean IOP DCT: 17.9 +/- 6.4 mmHg; P = 0.67) and 1 day after surgery (mean IOP GAT: 16.1 +/- 6.6 mmHg; mean IOP DCT: 16.8 +/- 8.3 mmHg; P = 0.69). IOP values using GAT and DCT were significantly correlated before as well as 1 day after surgery (before surgery: r = 0.82, P < 0.0001; after surgery r = 0.83, P < 0.0001). Bland-Altman plots showed a high variability in the difference in IOP measurements between methods before and 1 day after surgery. CONCLUSION: GAT and DCT seem to be equally valuable in IOP determination in postsurgical central corneal edema, although large differences between both methods are present in individual patients. IOP evaluation in corneal edema remains a difficult clinical challenge. PMID- 23662042 TI - Contribution of the R8 substituent to the in vitro antibacterial potency of besifloxacin and comparator ophthalmic fluoroquinolones. AB - INTRODUCTION: Previous work has shown that besifloxacin, an 8-chloro fluoroquinolone, has more potent activity against gram-positive pathogens than moxifloxacin and gatifloxacin, which carry an 8-methoxy group. This study was conducted to determine the contribution of the R7 and R8 substituent to fluoroquinolone antibacterial activity. MATERIALS AND METHODS: Besifloxacin, moxifloxacin, gatifloxacin, their R8 structural analogs, and ciprofloxacin were tested against representative isolates of various gram-positive and gram-negative species and previously characterized fluoroquinolone-resistant mutants of Staphylococcus aureus. Minimum inhibitory and minimum bactericidal concentrations were determined according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Reserpine was used to determine the effect of efflux pumps on antibacterial activity. RESULTS: In general, exchanging the R8 residue in besifloxacin slightly reduced the molecule's potency, while introducing an 8 chloro group in moxifloxacin increased its potency. A similar change in gatifloxacin had little to no effect. Substituting the R8 residues did not increase the susceptibility to the efflux pump inhibitor reserpine or result in a loss of bactericidal activity. In contrast, the positive control, ciprofloxacin, was shown to be a substrate for reserpine and lost bactericidal activity against some fluoroquinolone-resistant isolates of S. aureus. CONCLUSION: The data presented here show that, depending on the R7 substituent, replacing an 8-methoxy group with an 8-chloro substituent can improve potency or can have little-to-no effect. These findings highlight the importance of the interplay between the R7 and R8 substituents in determining antibacterial potency. PMID- 23662043 TI - Hereditary angioedema: epidemiology, management, and role of icatibant. AB - Hereditary angioedema (HAE) is an autosomal dominant, potentially life threatening condition, manifesting as recurrent and self-limiting episodes of facial, laryngeal, genital, or peripheral swelling with abdominal pain secondary to intra-abdominal edema. The estimated prevalence of HAE in the general population is one individual per 50,000, with reported ranges from 1:10,000 to 1:150,000, without major sex or ethnic differences. Various treatment options for acute attacks and prophylaxis of HAE are authorized and available in the market, including plasma-derived (Berinert(r), Cinryze(r), and Cetor(r)) and recombinant (Rhucin(r) and RuconestTM) C1 inhibitors, kallikrein inhibitor-ecallantide (Kalbitor(r)), and bradykinin B2 receptor antagonist-icatibant (Firazyr(r)). Some of these drugs are used only to treat HAE attacks, whereas others are only approved for prophylactic therapies and all of them have improved disease outcomes due to their different mechanisms of action. Bradykinin and its binding to B2 receptor have been demonstrated to be responsible for most of the symptoms of HAE. Thus icatibant (Firazyr(r)), a bradykinin B2 receptor antagonist, has proven to be an effective and more targeted treatment option and has been approved for the treatment of acute attacks of HAE. Rapid and stable relief from symptoms of cutaneous, abdominal, or laryngeal HAE attacks has been demonstrated by 30 mg of icatibant in Phase III clinical trials. Self-resolving mild to moderate local site reactions after subcutaneous injection of icatibant were observed. Icatibant is a new, safe, and effective treatment for acute attacks of HAE. HAE has been reported to result in enormous humanistic burden to patients, affecting both physical and mental health, with a negative impact on education, career, and work productivity, and with substantial economic burdens. The timely and proper use of disease-specific treatments could improve patients' quality of life, reduce the disease-specific morbidity and mortality, and, last but not least, reduce costs associated with hospitalizations and emergency room visits. Therefore, the paradigm of HAE treatment has the potential to evolve significantly, thereby exponentially improving a patient's quality of life. PMID- 23662045 TI - Successful management of an inadvertent excessive treprostinil overdose. AB - Pulmonary hypertension is defined by 25 mmHg pressure at rest, and 35 mmHg pressure at exercise, in the pulmonary arteries. Hypertension either primary or secondary. The exact prevalence of all types of pulmonary hypertension is not yet known. We present a case of a 58-year-old female patient suffering from CREST syndrome, Raynaud's syndrome, esophageal motility impairment, and severe pulmonary hypertension who had previously obtained a specially developed implantable pump, named Lenus Pro((r)), to facilitate continuous parenteral treatment of pulmonary arterial hypertension with treprostinil. Treprostinil is a prostanoid derivative with very stable physiochemical properties which allows subcutaneous treatment of pulmonary arterial hypertension in the outpatient. Treprostinil is normally dosed individually in a range of 0.6 to 50 ng/kg/minute. In the underlying case, a dose of more than 100 mg given over 1 minute is equivalent to a 1000 fold overdose. The patient's critical condition required installment of a central venous access, full monitoring, sedation, oxygen nasal tube, fluid balance, and parenteral nutrition. The patient could be hemodynamically stabilized within 24 hours after the overdose. After 6 days of recovery, the patient left the hospital with no remaining health impairment. PMID- 23662044 TI - Targeted inhibition of mammalian target of rapamycin (mTOR) enhances radiosensitivity in pancreatic carcinoma cells. AB - The mammalian target of rapamycin (mTOR) is a protein kinase that regulates protein translation, cell growth, and apoptosis. Rapamycin (RPM), a specific inhibitor of mTOR, exhibits potent and broad in vitro and in vivo antitumor activity against leukemia, breast cancer, and melanoma. Recent studies showing that RPM sensitizes cancers to chemotherapy and radiation therapy have attracted considerable attention. This study aimed to examine the radiosensitizing effect of RPM in vitro, as well as its mechanism of action. 3-(4,5-Dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay and colony formation assay showed that 10 nmol/L to 15 nmol/L of RPM had a radiosensitizing effects on pancreatic carcinoma cells in vitro. Furthermore, a low dose of RPM induced autophagy and reduced the number of S-phase cells. When radiation treatment was combined with RPM, the PC-2 cell cycle arrested in the G2/M phase of the cell cycle. Complementary DNA (cDNA) microarray and reverse transcription polymerase chain reaction (RT-PCR) revealed that the expression of DDB1, RAD51, and XRCC5 were downregulated, whereas the expression of PCNA and ABCC4 were upregulated in PC-2 cells. The results demonstrated that RPM effectively enhanced the radiosensitivity of pancreatic carcinoma cells. PMID- 23662046 TI - A review of tasquinimod in the treatment of advanced prostate cancer. AB - Castration resistant prostate cancer remains a major clinical burden and novel therapeutic options are urgently required to improve survival. Tasquinimod is an orally administered quinoline-3-carboxamide with potent antiangiogenic and antitumorigenic action that has shown promise in the treatment of advanced prostate cancers. This review explores both preclinical and clinical findings to date. In summary, tasquinimod has been shown to demonstrate a potent in vitro and in vivo anticancer action and completed early phase clinical trials have demonstrated good drug tolerance and prolonged progression-free survival. Although Phase III clinical trials are on-going, the findings to date highlight the promise of this drug in the treatment of advanced prostate cancer. PMID- 23662047 TI - Azelnidipine plus olmesartan versus amlodipine plus olmesartan on arterial stiffness and cardiac function in hypertensive patients: a randomized trial. AB - PURPOSE: To compare the long-term effects of olmesartan combined with either azelnidipine or amlodipine on central blood pressure (CBP), left ventricular (LV) mass index (LVMI), LV diastolic function (e' velocity, E/e' ratio, E/A ratio) and arterial stiffness (brachial-ankle pulse wave velocity [baPWV] and augmentation index normalized for a heart rate of 75 bpm [AIx]). PATIENTS AND METHODS: Patients with systolic BP >= 140 mmHg and/or diastolic BP >= 90 mmHg received olmesartan monotherapy (20 mg/day) for 12 weeks. They were then randomly assigned to fixed-dose add-on therapy with azelnidipine (16 mg/day; n = 26) or amlodipine (5 mg/day; n = 26) for a further 2 years. CBP, LVMI, e' velocity, E/e' ratio, E/A ratio, baPWV, and AIx were measured at baseline, 6 months, and 2 years. RESULTS: Baseline characteristics of both groups were similar. The decrease in brachial BP over 2 years was similar in both groups. CBP, LVMI, E/e' ratio, baPWV, and AIx decreased significantly, and the E/A ratio and e' velocity increased significantly in both groups. The decreases in CBP (P < 0.001), AIx (P < 0.001), baPWV (P < 0.001), LVMI (P < 0.001), and E/e' (P = 0.002) as well as the increase in E/A ratio (P = 0.03) over 2 years were significantly greater in the olmesartan/azelnidipine group than in the olmesartan/amlodipine group. Multivariate linear regression analyses showed that the changes in baPWV (beta = 0.41, P < 0.001) and CBP (beta = 0.47, P = 0.01) were independently associated with the change in LVMI, the change in baPWV (beta = 0.25, P < 0.001) was independently associated with the change in E/e' ratio, and the changes in baPWV (beta = 0.21, P = 0.001) and AIx (beta = 0.25, P = 0.03) were independently associated with the change in E/A ratio. CONCLUSION: Treatment with olmesartan/azelnidipine for 2 years resulted in greater improvements in CBP, LVMI, and LV diastolic function, and arterial stiffness compared with olmesartan/amlodipine. Improvements in LV diastolic function were associated with improvements in arterial stiffness. PMID- 23662048 TI - Novel 4-substituted phenyl-2,2'-bichalcophenes and aza-analogs as antibacterial agents: a structural activity relationship. AB - Antibiotic resistance is a major health problem; therefore, new antibacterial agents will need to be continuously developed. A series of novel bichalcophenes has been tested and found to have antimicrobial activity against selected bacteria. Due to the promising antimicrobial effects of these 4-substituted phenyl bichalcophene derivatives, the study reported here was launched to examine the interaction between novel bichalcophenes and tetracycline. The minimum inhibitory concentration values for all bichalcophenes were between 8 and 64 MUM. Many of the bichalcophenes had synergistic activity that increased the inhibitory effect of tetracycline against bacterial growth, as indicated by the fractional inhibitory concentration index. The post-antibiotic effects of the novel bichalcophenes were determined. Many bichalcophenes were able to elongate the period required for bacteria to recover and grow after a brief exposure to tetracycline. Escherichia coli did not develop resistance to many bichalcophenes over a period of 7 days. A structural activity relationship could be characterized, as monocationic derivatives were more active than the corresponding mononitriles. The presence of a pyridyl group and/or furan ring reduced the activity, while the presence of a phenyl or thiophene ring enhanced the antibacterial activity. Our results suggest that bichalcophenes could be useful to elevate the shelf life of many antibiotics. PMID- 23662049 TI - Patient satisfaction with the laborist model of care in a large urban hospital. AB - BACKGROUND: The obstetric practice environment is evolving to include more laborists staffing obstetric units, with the hope of improving quality of care and provider satisfaction, yet there are scant data on the impact of a laborist care model on patient satisfaction or delivery outcomes. We sought to assess patient satisfaction after implementation of the laborist model of obstetric care in a large urban teaching hospital. METHODS: Postpartum patients were asked to complete an anonymous survey assessing their satisfaction with care, particularly with regard to the laborist model. Survey questions included rating the overall experience of labor and delivery. All responses were based on a five-point Likert scale. Press-Ganey results were compared from before and after initiation of the model. Descriptive statistics were used to analyze the results. RESULTS: Post laborist implementation obstetric and delivery experience surveys were collected from 4166 patients, representing a 54% response rate. Ninety percent of patients reported that they were highly satisfied with the overall experience in the labor and delivery unit. A subgroup was asked to rate their experience with the practitioner for their current delivery. Of the 687 respondents, 75% answered excellent, 18% answered good/very good, and 3.4% answered neutral. Eighty-five percent of this subgroup stated that they were informed during prenatal care that they may be delivered by someone other than the practitioner or group that they saw during the pregnancy. Thirty-seven percent (n = 1553) of the total respondents reported that they had had a previous delivery at this institution, 97% (n = 1506) of whom stated "yes" to having their next delivery at this institution. Press-Ganey results were similarly favorable in both time periods (91.3 [n = 811] versus 93.4 [n = 747], P = 0.08). CONCLUSION: Patient satisfaction does not appear to be adversely affected by initiation of the laborist model. Additional research is needed to understand further the implications of this model for provider satisfaction, and maternal and neonatal outcomes. PMID- 23662050 TI - The safety and efficacy of aspirin intake in photoselective vaporization laser treatment of benign prostate hyperplasia. AB - Endoscopic surgical treatment has become an option to treat benign prostate hyperplasia. We evaluated the safety and effectiveness of photoselective vaporization of the prostate (PVP) in patients. We evaluated preoperative and perioperative parameters, functional outcomes, and adverse events up to 12 months postoperatively of patients on oral anticoagulation therapy undergoing PVP, and compared the results with patients who did not take anticoagulation therapy. A total of 89 patients who received photoselective vaporization laser for benign prostate hyperplasia from May 2006 to February 2011 in our hospital were enrolled in our study. The patients were divided into two groups based on whether or not they were taking oral aspirin; 23 (25.8%) patients were taking aspirin derivatives (aspirin group), and 66 (74.2%) were not taking aspirin derivatives (control group). The mean prostate volume (58.8 mL vs 51 mL; P = 0.16) and mean energy consumption (235,268 J vs 289,793 J; P = 0.097) were comparable between the aspirin group and control group. The average postoperative results of hemoglobin were 13.4 mg/ dL for the aspirin group versus 13.9 mg/dL for the control group (P = 0.327). A significantly higher maximum flow rates and 80% improved post-void residual urine were noted during the followup. Postoperatively all variable showed significant improvement starting at month 1 of followup and remained improved for the 12 month followup. Postoperative complications were low and comparable between groups. PVP was characterized by excellent hemostatic properties and a very low intraoperative complication rate, even in the patients who were taking aspirin. On the basis of our perioperative results, we recommend PVP as a safe and effective procedure for patients with symptomatic benign prostate hyperplasia when taking an aspirin derivative. PMID- 23662051 TI - Influence of aging and chronic heart failure on temporal dispersion of myocardial repolarization. AB - BACKGROUND AND PURPOSE: QT and T(peak)-T(end) (Te) intervals are associated with sudden cardiac death in patients with chronic heart failure (CHF). We studied age dependent influence on short-term temporal dispersion of these two variables in patients with postischemic CHF. METHOD: We grouped 75 CHF and 53 healthy control subjects into three age subsets: <= 50 years, >50 years and <= 65 years, and >65 years. We then calculated the following indices: QT and Te variability index (QTVI and TeVI), the ratio between the short-term variability (STV) of QT or Te, and the STV of resting rate (RR) (QT/RR STV and Te/RR STV). RESULTS: In all different age subgroups, patients with CHF showed a higher level of QTVI than age matched control subjects (<= 50 years: P < 0.0001; >50 years and <= 65 years: P < 0.05; >65 years: P < 0.05). Patients with CHF < 50 years old also had all repolarization variability indices higher than normal age-matched controls (TeVI, P < 0.05; QT/RR STV, P < 0.05; Te/RR STV, P < 0.05), whereas we did not find any difference between the two older classes of subjects. Both QTVI (r2: 0.178, P < 0.05) and TeVI (r2: 0.433, P < 0.001) were positively related to age in normal subjects, even if the first correlation was weaker than the second one. CONCLUSION: Our data showed that QTVI could be used in all ages to evaluate repolarization temporal liability, whereas the other indices are deeply influenced by age. Probably, the age-dependent increase in QTVI was more influenced by a reduction of RR variability reported in older normal subjects. PMID- 23662052 TI - Tools that assess functional decline: systematic literature review update. AB - BACKGROUND: Screening for risk of functional decline in the elderly is increasingly important in ambulatory health care settings, to ensure that appropriate services are provided to reduce the risk of downstream decline. These screening tools should have sound psychometric properties and clinical utility. DESIGN: An updated systematic literature review for (1) new screening tools published since the last review, conducted in 2007 and published in 2008, and (2) recent research into psychometric properties of the five tools identified in the previous review. METHODS: A comprehensive review of multiple databases using the search terms from the Sutton et al review was conducted. The reference lists of included articles were hand-searched for additional articles, and the literature was evaluated with the appropriate critical appraisal tool. Included screening tools should be designed for, or applicable to, hospital emergency departments. RESULTS: Two relevant new tools were identified (the Simplified PROFUNCTION index and Brief Risk Identification for Geriatric Health Tool). Six additional papers testing psychometric properties of four of the five previously reported screening tools were also found. CONCLUSION: Seven relevant screening tools are available with similar validity and reliability estimates. They consider similar constructs and have convincing evidence of applicability to a range of older populations, or different cultures. Identification of Seniors at Risk, is the most frequently reported screening tool. The wider unanswered question is how, why, and where these functional decline screening tools are used; how valid the findings are on ill, stressed, older people in emergency departments; and how the findings are acted upon in terms of community intervention to slow functional decline. PMID- 23662053 TI - Pilot study: can older inactive adults learn how to reach the required intensity of physical activity guideline? AB - Most individuals do not reach the recommended physical activity level of at least 150 minutes of aerobic exercise (AE) at moderate-to-vigorous intensity per week. For example, only 13% of older Canadian adults reach World Health Organization physical activity guideline (PAG). One of the reasons might be a difficulty identifying the required intensity. Twenty-five inactive older adults received one session about the AE-PAG and how to use a tool or strategy to help them identify AE intensity: heart-rate (HR) monitor (% of maximal HR; N = 9); manual pulse (% of maximal HR; N = 8); or pedometer (walking cadence; N = 8). Participants had 8 weeks to implement their specific tool with the aim of reaching the PAG by walking at home. At pre- and post-intervention, the capacity to identify AE intensity and AE time spent at moderate-to-vigorous intensity were evaluated. Only the two groups using a tool increased total AE time (both P < 0.01), but no group improved the time spent at moderate-to-vigorous intensity. No significant improvement was observed in the ability to correctly identify AE intensity in any of the groups, but a tendency was observed in the pedometer group (P = 0.07). Using walking cadence with a pedometer should be explored as a tool to reach the PAG as it is inexpensive, easy to use, and seemed the best tool to improve both AE time and perception of intensity. PMID- 23662054 TI - Induction of osteogenic differentiation of stem cells via a lyophilized microRNA reverse transfection formulation on a tissue culture plate. AB - MicroRNA (miRNA) regulation is a novel approach to manipulating the fate of mesenchymal stem cells, but an easy, safe, and highly efficient method of transfection is required. In this study, we developed an miRNA reverse transfection formulation by lyophilizing Lipofectamine 2000-miRNA lipoplexes on a tissue culture plate. The lipoplexes can be immobilized on a tissue culture plate with an intact pseudospherical structure and lyophilization without any lyoprotectant. In this study, reverse transfection resulted in highly efficient cellular uptake of miRNA and enabled significant manipulation of the intracellular target miRNA level. Reverse transfection formulations containing Lipofectamine 2000 1 MUL per well generated much higher transfection efficiency without obvious cytotoxicity compared with conventional and other transfection methods. Further, the transfection efficiency of the reverse transfection formulations did not deteriorate during 90 days of storage at 4 degrees C and -20 degrees C. We then assessed the efficiency of the miRNA reverse transfection formulation in promoting osteogenic differentiation of mesenchymal stem cells. We found that transfection with anti-miR-138 and miR-148b was efficient for enhancing osteogenic differentiation, as indicated by enhanced osteogenesis related gene expression, amount of alkaline phosphatase present, production of collagen, and matrix mineralization. Overall, the miRNA reverse transfection formulation developed in this study is a promising approach for miRNA transfection which can control stem cell fate and is suitable for loading miRNAs onto various biomaterials. PMID- 23662056 TI - Dalfampridine extended release tablets: 1 year of postmarketing safety experience in the US. AB - BACKGROUND: Dalfampridine extended release tablets (dalfampridine-ER; prolonged-, modified, or sustained-release fampridine in some countries) were approved in the US to improve walking in patients with multiple sclerosis, as demonstrated by improvement in walking speed. Postmarketing safety experience is available from exposure of approximately 46,000 patients in the US from product approval through March 2011. OBJECTIVE: To provide a descriptive analysis of all spontaneously reported postmarketing adverse events (AEs) for dalfampridine-ER since product launch. METHODS: AE data were extracted from the safety database from product launch through March 31, 2011; AEs were classified using the Medical Dictionary for Regulatory Activities. Seizure cases were reviewed for patient demographics, time to event from treatment onset, and presence of additional risk factors. RESULTS: THE MOST FREQUENTLY REPORTED POSTMARKETING AES WERE SIMILAR TO THOSE REPORTED DURING CLINICAL DEVELOPMENT: dizziness, insomnia, balance disorder, headache, nausea, urinary tract infection, asthenia, and back pain (all included in US product labeling). New clinically significant findings are related to lack of efficacy and inappropriate dosing. Of the approximately 46,000 patients exposed, 85 seizures were reported (~5.4/1000 patient-years), of which 82 were reported or confirmed by a health care practitioner (~5.2/1000 patient-years). Beyond the intrinsic multiple sclerosis-related seizure risk, more than half of the 85 cases (62%) had an additional potential risk factor for seizure including a previous history of convulsions, renal impairment, incorrect dosing, or use of concurrent medications with a labeled seizure risk. Duration of treatment prior to the seizure ranged from one dose to 365 days; 26/85 (31%) patients suffered a seizure within a week of starting treatment. CONCLUSION: Spontaneous safety data from the US postmarketing experience were consistent with the safety profile seen during clinical development. Although first-year seizure incidence was not substantially different from that observed in dalfampridine-ER clinical trials, patients should be monitored for concomitant use of drugs that lower seizure threshold. PMID- 23662055 TI - Intravenously delivered graphene nanosheets and multiwalled carbon nanotubes induce site-specific Th2 inflammatory responses via the IL-33/ST2 axis. AB - Carbon-based nanomaterials (CBN), such as graphene nanosheets (GNS) and multiwalled carbon nanotubes (MWCNT), have been proposed for potential nanomedicine applications such as biomedical devices and carriers for drug delivery. However, our current understanding regarding the systemic toxicity of these CBN through intravenous (iv) injection is limited. In this study, we compare the immune response resulting from GNS and MWCNT exposure. We hypothesize that iv administration of GNS and MWCNT would result in divergent systemic inflammatory responses due to physicochemical differences between these two CBN. In the lungs of C57BL/6 mice, GNS actuate a Th2 immune response 1 day following iv administration, which consists of neutrophilic influx and a significant increase in interleukin (IL)-5, IL-13, IL-33, and its soluble receptor (sST2) in the bronchoalveolar lavage fluid. MWCNT elicited a significant increase in the messenger ribonucleic acid expression of cytokines in the spleen including IL-4 and IL-33, which are associated with an increase in splenic cell differentiation (CD)4(+) and CD8(+) T-cells in C57BL/6 mice following iv injection. The observed Th2 responses in both the lung and spleen are absent in ST2(-/-) mice administrated GNS or MWCNT, suggesting a critical role for IL-33. In conclusion, the use of GNS or MWCNT as nanocarriers for drug delivery may result in Th2 immune responses that are mediated through the IL-33/ST2 axis and therefore may promote adverse allergic reactions. PMID- 23662057 TI - Diagnostic performance of a combination of Mini-Mental State Examination and Clock Drawing Test in detecting Alzheimer's disease. AB - OBJECTIVE: Because of the growing need for quick cognitive screening tests to distinguish Alzheimer's disease (AD) from mild cognitive impairment (MCI), we compare the diagnostic performance of a combination of the Mini-Mental State Examination (MMSE) and a Clock Drawing Test (CDT) to the Japanese version of the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-J cog) in differentiating between patients with AD, patients with MCI, and healthy controls (HC). METHODS: Data from 146 subjects with AD and 60 subjects with MCI, as well as 49 HC, was retrospectively analyzed. We used logistic regression analysis with diagnosis as dependent variables and scores of the MMSE, the CDT-command, and the CDT-copy as independent variables, and receiver operating characteristic analysis to distinguish patients with AD from patients with MCI or HC. RESULTS: When patients with AD were compared to HC, the independent predictors of AD were scores on the MMSE and the CDT-command. This combination was more sensitive than the MMSE alone and has nearly the same sensitivity and specificity as the ADAS-J cog. When patients with AD were compared to patients with MCI, the independent predictors were the MMSE and the CDT-copy. This combination was more sensitive and specific than the MMSE alone and was almost as sensitive and specific as the ADAS-J cog. CONCLUSION: The combination of the MMSE and the CDT could be a powerful screening tool for differentiating between patients with AD, patients with MCI, and HC. Its sensitivity and specificity are comparable to ADAS-J cog, which takes more time. PMID- 23662058 TI - Soccer practice as an add-on treatment in the management of individuals with a diagnosis of schizophrenia. AB - Physical activity is an important aspect of good health for everyone; it is even more important for psychiatric patients who usually live an unhealthy lifestyle. In recent years, there has been growing focus on the use of soccer as a vehicle to improve the health of subjects with severe mental illness. The aim of this study was to investigate the effects of soccer practice on the self-reported health quality of life (SRHQL) and sports performance (SP) in psychotic subjects. Eighteen male patients with diagnosis of schizophrenia were randomized into either a trained (TG) or a control group (CG). The TG was trained for 12 weeks using two soccer training sessions per week. The CG did not perform any regular sports activity during the experimental period. Anthropometric measurements, SRHQL, personal time records in a 30 meter sprint test and slalom test running with a ball were evaluated before and after the experimental period. SRHQL was assessed using Short Form-12 questionnaire measuring physical and mental component summary scores. After the training period, the TG showed a relevant decrease by 4.6% in bodyweight (BW) and body mass index compared to baseline. Conversely, the CG showed an increased BW and body mass index by 1.8% from baseline to posttest. Moreover, after 12 weeks we found that control patients increased their BW significantly when compared to trained patients (Delta = 5.4%; P < 0.05). After the training period, comparing the baseline TG's Short Form-12 scores to posttest results, we found an improvement of 10.5% and 10.8% in physical component summary and mental component summary, respectively. In addition, performances on the 30 meter sprint test and slalom test running with a ball in the TG improved significantly (P < 0.01) from baseline to posttest when compared to CG. Soccer practice appears able to improve psychophysical health in individuals with diagnosis of schizophrenia. Indeed, our study demonstrated that programmed soccer physical activity could reduce antipsychotic medication-related weight gain and improve SRHQL and sports performance in psychotic subjects. PMID- 23662059 TI - Effectively managing intractable central hyperthermia in a stroke patient by bromocriptine: a case report. AB - Central hyperthermia is characterized by a rapid onset, high temperature, marked temperature fluctuation, and poor response to antipyretics and antibiotics. Although poststroke central hyperthermia is common, prolonged instances are rare. We report a case of prolonged central fever after an intracranial hemorrhage. Before the accurate diagnosis and management of central fever, the patient underwent long-term antibiotic use that led to pseudomembranous colitis. Bromocriptine was used to treat the prolonged central hyperthermia, after which the fever did not exceed 39 degrees C. A week later, the body temperature baseline was reduced to 37 degrees C and a low-grade fever with minor temperature fluctuation occurred only a few times. No fever occurred in the month following the treatment. After the fever subsided, the patient could undergo an aggressive rehabilitation program. PMID- 23662060 TI - Assessing public speaking fear with the short form of the Personal Report of Confidence as a Speaker scale: confirmatory factor analyses among a French speaking community sample. AB - BACKGROUND: The main aim of this study was to assess the reliability and structural validity of the French version of the 12-item version of the Personal Report of Confidence as Speaker (PRCS), one of the most promising measurements of public speaking fear. METHODS: A total of 611 French-speaking volunteers were administered the French versions of the short PRCS, the Liebowitz Social Anxiety Scale, the Fear of Negative Evaluation scale, as well as the Trait version of the Spielberger State-Trait Anxiety Inventory and the Beck Depression Inventory-II, which assess the level of anxious and depressive symptoms, respectively. RESULTS: Regarding its structural validity, confirmatory factor analyses indicated a single-factor solution, as implied by the original version. Good scale reliability (Cronbach's alpha = 0.86) was observed. The item discrimination analysis suggested that all the items contribute to the overall scale score reliability. The French version of the short PRCS showed significant correlations with the Liebowitz Social Anxiety Scale (r = 0.522), the Fear of Negative Evaluation scale (r = 0.414), the Spielberger State-Trait Anxiety Inventory (r = 0.516), and the Beck Depression Inventory-II (r = 0.361). CONCLUSION: The French version of the short PRCS is a reliable and valid measure for the evaluation of the fear of public speaking among a French-speaking sample. These findings have critical consequences for the measurement of psychological and pharmacological treatment effectiveness in public speaking fear among a French-speaking sample. PMID- 23662061 TI - Case of femoral diaphyseal stress fracture after long-term risedronate administration diagnosed by iliac bone biopsy. AB - Bisphosphonate excessively inhibits bone resorption and results in pathological fracture of the femur or ilium. The subject of this study was administered risedronate for 7 years; we suspected an easy fracture of the femoral diaphysis. In this study, we report the results of this patient's bone biopsy and bone morphometric analysis. A 76-year-old female patient presented with right femoral pain. Bone mineral density of the anteroposterior surface of the 2nd to 4th lumbar vertebrae (L2-L4) was decreased and levels of bone turnover markers were high. Therefore, we initiated treatment with risedronate. As she continued the medication, urinary levels of cross-linked N-terminal telopeptides of type I collagen and alkaline phosphatase (bone-type isozyme) were found to be within the normal ranges. After 7 years of administration, the patient experienced pain when she put weight on the right femur and right femoral pain while walking. Plain radiographic examination revealed polypoid stress fracture-like lesions on the right femoral diaphysis and on the slightly distal-lateral cortical bone. Similar lesions were observed on magnetic resonance imaging and bone scintigraphy. We suspected severely suppressed bone turnover. Bone biopsy was obtained after labeling with tetracycline, and bone morphometric analysis was performed. On microscopic examination, slight double tetracycline labeling was observed. The trabeculae were narrow, and the numbers of osteoblasts and osteoclasts were decreased. Further, rates of bone calcification and bone formation were slow. Hence, we diagnosed fracture as a result of low turnover osteopathy. Risedronate was withdrawn, and Vitamin D3 was administered to improve the bone turnover. At 6 months, abnormal signals on magnetic resonance imaging had decreased and her pain while walking or undergoing the stress test disappeared as well. Thus, long-term administration of bisphosphonates may lead to easy fracture, although bone turnover markers were observed to be within the normal range. During bisphosphonate administration, physicians need to monitor closely and treat their patients for any pain experienced in the femoral region while walking or undergoing a stress test. PMID- 23662062 TI - Long-term safety and efficacy of telmisartan/amlodipine single pill combination in the treatment of hypertension. AB - The use of multiple drug regimens is increasingly recognized as a tacit requirement for the management of hypertension, a necessity fueled in part by rising rates of metabolic syndrome and diabetes. By targeting complementary pathways, combinations of antihypertensive drugs can be applied to provide effective blood pressure control while minimizing side effects and reducing exposure to high doses of individual medications. In addition, combination therapies, including angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs), have the added benefit of reducing cardiovascular mortality and morbidity over other dual therapies while providing equivalent blood pressure control. It is possible that angiotensin receptor blockers (ARBs), which unlike ACE inhibitors are minimally affected by upregulation of alternative pathways for angiotensin II accumulation following long-term treatment, would also provide such outcome benefits. At issue, however, is maintaining patient compliance, as adding medications is known to reduce adherence to treatment regimens. The purpose of this review is to summarize existing trial data for the long-term safety and efficacy of a recent addition to the armamentarium of dual antihypertensive therapeutic options, the telmisartan/amlodipine single pill combination. The areas where long-term data are lacking, notably clinical information regarding minorities and women, will also be discussed. PMID- 23662063 TI - Awareness, treatment, and control of major cardiovascular risk factors in a small scale Italian community: results of a screening campaign. AB - INTRODUCTION: Hypertension, hypercholesterolemia, and diabetes are the main causes of cardiovascular diseases in developed countries. However, these conditions are still poorly recognized and treated. OBJECTIVE: This study aimed at estimating the prevalence, awareness, treatment, and control rates of major cardiovascular risk factors in an unselected sample of individuals of a small community located in northern Italy. METHODS: We screened 344 sequential subjects in this study. Data collection included family and clinical history, anthropometric data, blood pressure, blood glucose, and serum cholesterol values. Individual cardiovascular risk profiles were assessed by risk charts of the Progetto Cuore. RESULTS: Based on personal history and/or measured values, 78.2% of subjects had hypercholesterolemia (total cholesterol levels > 190 mg/dL), 61.0% had central obesity (waist circumference >= 94 cm for men and >=80 cm for women), 51.2% had arterial hypertension (blood pressure >= 140/90 mmHg), 8.1% had diabetes (blood glucose >= 126 mg/dL), 22.7% had impaired fasting glucose (blood glucose 100-125 mg/dL), and 35.5% were overweight (body mass index 25-29 kg/m(2)). Alcohol drinkers and smokers accounted for 46.2% and 22.4% of subjects, respectively. Awareness of hypertension, hypercholesterolemia, and diabetes was poor, and control of these risk factors, except for diabetes, was even worse. Prevalence of high blood pressure, high serum cholesterol, overweight, and obesity significantly increased with aging. Hypercholesterolemia and obesity were significantly more common in women, while overweight and diabetes in men. In 15.4% of participants, the risk of a major cardiovascular event in the next 10 years was either high or very high. CONCLUSION: In a small community in a wealthy region of Italy, the prevalence of major cardiovascular risk factors is high, while awareness, treatment, and control are poor. Such a result highlights the importance of screening campaigns as a strategy to improve early diagnosis and access to treatment, and thus effective prevention of cardiovascular diseases in the general population. PMID- 23662064 TI - Platelet function testing to predict hyporesponsiveness to clopidogrel in patients with chest pain seen in the emergency department. AB - BACKGROUND: A dual antiplatelet regimen has been shown to reduce the risk of major adverse cardiovascular events after percutaneous coronary intervention. However, there is little information available on inhibition of platelet aggregation in patients with a prior coronary stent presenting with chest pain. This study evaluated the prevalence of hyporesponsiveness to clopidogrel and factors associated with this in patients presenting to our emergency department with chest pain who had previously undergone coronary stent placement and were prescribed dual antiplatelet therapy. METHODS: Responsiveness to clopidogrel was evaluated in a cohort of 533 consecutive stented patients presenting to the emergency department with chest pain. P2Y12 reaction units (PRU) and percent P2Y12 inhibition with clopidogrel were measured in all patients. Of 533 patients, 221 (41.6%) had PRU >= 230. A multivariate logistic regression model was used to determine the relationship between hyporesponsiveness to clopidogrel (defined as PRU >= 230) and several potential risk factors, ie, gender, age, race, type 1 or type 2 diabetes, hypertension, smoking, chronic renal failure, and obesity. RESULTS: There was a greater risk of hyporesponsiveness in African Americans than in non-African American patients (adjusted odds ratio [OR] = 2.165), in patients with type 2 diabetes than in those without (adjusted OR = 2.109), and in women than in men (adjusted OR = 1.813), as well as a greater risk of hyporesponsiveness with increasing age (adjusted OR = 1.167 per decade). CONCLUSION: There was a high prevalence of hyporesponsiveness to clopidogrel in patients presenting with chest pain and a prior coronary stent. Non-insulin dependent diabetes mellitus and African American race were the strongest predictors of hyporesponsiveness to clopidogrel, followed by gender and age. PMID- 23662066 TI - Building shared situational awareness in surgery through distributed dialog. AB - BACKGROUND: Failure to convey time-critical information to team members during surgery diminishes members' perception of the dynamic information relevant to their task, and compromises shared situational awareness. This research reports the dialog around clinical decisions made by team members in the time-pressured and high-risk context of surgery, and the impact of these communications on shared situational awareness. METHODS: Fieldwork methods were used to capture the dynamic integration of individual and situational elements in surgery that provided the backdrop for clinical decisions. Nineteen semistructured interviews were performed with 24 participants from anesthesia, surgery, and nursing in the operating rooms of a large metropolitan hospital in Queensland, Australia. Thematic analysis was used. RESULTS: The domain "coordinating decisions in surgery" was generated from textual data. Within this domain, three themes illustrated the dialog of clinical decisions, ie, synchronizing and strategizing actions, sharing local knowledge, and planning contingency decisions based on priority. CONCLUSION: Strategies used to convey decisions that enhanced shared situational awareness included the use of "self-talk", closed-loop communications, and "overhearing" conversations that occurred at the operating table. Behaviors that compromised a team's shared situational awareness included tunneling and fixating on one aspect of the situation. PMID- 23662067 TI - 3' untranslated region 1630 C>T polymorphism of prohibitin increases risk of breast cancer. AB - BACKGROUND: Prohibitin 3' untranslated region 1630 C>T (rs6917) polymorphism creates a variant T allele that lacks the antiproliferative activity of the more common functional C allele. Previous studies indicate that women carrying the prohibitin T allele have an increased susceptibility to breast cancer. However, the role of 1630 C>T polymorphism in mRNA expression of prohibitin and its contribution to carcinogenesis in the breast remains controversial. METHODS: Using mRNA expression data from the HapMap online database, we sought an association between prohibitin 1630 C>T polymorphism and its mRNA expression, then conducted a meta-analysis of prohibitin 1630 C>T polymorphism and risk of breast cancer. RESULTS: Although no significant association was found between prohibitin 1630 C>T polymorphism and mRNA expression in lymphoblastoid cell lines from the HapMap database (P trend = 0.543), the present meta-analysis involving 5072 cases and 4796 controls demonstrated that prohibitin 1630 C>T polymorphism was significantly correlated with breast cancer risk in allele contrast model T versus C (odds ratio [OR] 1.09, 95% confidence interval [CI] 1.01-1.18), the homozygote codominant model TT versus CC (OR 1.47, 95% CI 1.12-1.92), and the recessive model TT versus CC/CT (OR 1.45, 95% CI 1.10-1.89). CONCLUSION: Our study indicates that minor allele T of prohibitin 1630 C>T polymorphism is associated with increased susceptibility to breast cancer. PMID- 23662068 TI - Clinical and economic outcomes among hospitalized patients with acute coronary syndrome: an analysis of a national representative Medicare population. AB - OBJECTIVE: To evaluate the clinical and economic burden of acute coronary syndrome (ACS), a common cardiovascular illness, in the Medicare population. METHODS: Data from the Medicare Current Beneficiary Survey were analyzed. Patients with incident hospitalization for ACS without similar events during the 6 months prior were included. Outcomes evaluated included inpatient mortality, 30 day mortality and readmission, subsequent hospitalization events, and total direct health care costs. Sample population weights were applied, accounting for multistage sampling design to obtain nationally representative estimates for the US Medicare population. RESULTS: Between March 1, 2002 and December 31, 2006, we identified 795 incident ACS patients (mean age 76 years; 49% male) representing 2,542,211 Medicare beneficiaries. The inpatient mortality rate was 9.71% and the 30-day mortality ranged from 10.96% to 13.93%. The 30-day readmission rate for surviving patients was 18.56% for all causes and 17.90% for cardiovascular disease (CVD)-related diagnoses. The incidence of death since admission was 309 cases per 1000 person-years. Among patients discharged alive, the incidence was 197 for death, 847 for CVD-related admission, and 906 for all-cause admission. During the year when the ACS event occurred, mean annual total direct health care costs per person were US$50,458, with more than half attributable to inpatient hospitalization ($27,609). CONCLUSION: In this national representative Medicare population, we found a substantial clinical and economic burden for ACS. These findings suggest a continuing unmet medical need for more effective management of patients with ACS. The continuous burden underscores the importance of development of new interventions and/or strategies to improve long-term outcomes. PMID- 23662065 TI - Endoglin: a critical mediator of cardiovascular health. AB - Endoglin (CD105) is a type III auxiliary receptor for the transforming growth factor beta (TGFbeta) superfamily. Several lines of evidence suggest that endoglin plays a critical role in maintaining cardiovascular homeostasis. Seemingly disparate disease conditions, including hereditary hemorrhagic telangiectasia, pre-eclampsia, and cardiac fibrosis, have now been associated with endoglin. Given the central role of the TGFbeta superfamily in multiple disease conditions, this review provides a detailed update on endoglin as an evolving therapeutic target in the management of cardiovascular disease. PMID- 23662069 TI - Homozygous familial hypercholesterolemia (HoFH) in Germany: an epidemiological survey. AB - INTRODUCTION: In Europe a disease is recognized as rare if less than 1 in 2000 people suffer from the specific disease. In patients with familial homozygous hypercholesterolemia (HoFH) the accumulation of low-density lipoprotein cholesterol (LDL-C) leads to generalized atherosclerosis due to an insufficient functioning of the LDL-C receptors. Patients die early sometimes even in the mid 30s, from myocardial infarction or stroke. For the German population, insufficient epidemiological evidence exists. METHODS: A systematic literature search in EMBASE and Medline was performed in conjunction with a targeted manual search for epidemiological HoFH studies. Additionally a nationwide survey was conducted in Germany in all identified apheresis- and lipid centers. The purpose of the survey was the validation of the systematic literature search results based on empirical (practice) data. RESULTS: In total 961 publications were found, 874 were excluded based on pre-defined exclusion criteria leaving only 87 for further review. After review of the identified abstracts (n = 87) 23 publications were identified as epidemiological studies. Only one publication was found which reported a prevalence of 1:1,000,000. The qualitative survey among 187 physicians in Germany also revealed a low prevalence: 95 HoFH patients were identified in 35 centers. CONCLUSION: The estimated frequency of homozygous familial hypercholesterolemia patients in Germany is around 95 (1:860,000) and the disease should be recognized as rare according to the definition of the European Medical Agency. PMID- 23662070 TI - Occupational risk and chronic kidney disease: a population-based study in the United States adult population. AB - OBJECTIVE: Previous studies on occupational risk for chronic kidney disease (CKD) have analyzed a limited range of occupations and focused on nephrotoxins. The primary purpose of this study was to examine the relative risk for the occurrence of CKD between different occupations in the US adult population. MATERIALS AND METHODS: This was a population-based survey study of 91,340 participants in the US, who completed the National Health Interview Survey, 2004 through 2008. The outcome variable, CKD, was defined as having weakening/failing kidneys in the past 12 months, as diagnosed by a physician. The predictor variable, occupation, was obtained using the census occupational codes, regrouped according to North American Industrial Classification System. RESULTS: After controlling for age, gender, hypertension, and education, and with the category Life, Physical, and Social Science Occupations as a reference group, the likelihood of developing CKD was 4.3 times higher in respondents working in Building, Grounds Cleaning and Maintenance Occupations, 4.4 times higher in Healthcare Practitioners and Technical Occupations, 4.7 times higher in Transportation and Material Moving Occupations and in Computer and Mathematical Occupations, 4.8 times higher in Production Occupations, 5.3 times higher in Food Preparation and Serving Related Occupations, and 6.1 times higher in Healthcare Support Occupations and in Legal Occupations. CONCLUSION: This study identified occupation groups in US adult population with increased risk for CKD. Alleviation of workplace stress is suggested as a goal for behavioral intervention in high-risk occupations. PMID- 23662071 TI - Phosphate induced crystal acute kidney injury - an under-recognized cause of acute kidney injury potentially leading to chronic kidney disease: case report and review of the literature. AB - Acute phosphate nephropathy or nephrocalcinosis is a tubulointerstitial nephropathy characterized by tubular calcium phosphate deposition - crystal nephropathy - and slowly progressive renal insufficiency during or following treatment with preparations containing sodium phosphate. We report a patient who developed nephrocalcinosis (crystal induced acute kidney injury) following the administration of a combination of oral and rectal sodium phosphate for treatment of postoperative constipation. A timely renal replacement therapy procedure may reverse the process of crystallization and the irreversible slope towards chronic dialysis. PMID- 23662072 TI - Is there a link between hyperuricemia, morning blood pressure surge, and non dipping blood pressure pattern in metabolic syndrome patients? AB - BACKGROUND: Hypertensive patients usually have a blunted nocturnal decrease, or even increase, in blood pressure during sleep. There is also a tendency for increased occurrence of cardiovascular events between 6 and 12 am due to increased morning blood pressure surge (MBPS). Co-occurrence of metabolic syndrome (MetS) and hypertension is also a common problem. Hyperuricemia might trigger the development of hypertension, chronic renal failure, and insulin resistance. In this study, we aimed to determine whether there is a relationship between hyperuricemia, MetS, nocturnal blood pressure changes, and MBPS. METHOD: A total of 81 newly diagnosed hypertensive MetS patients were included in this study. Ambulatory blood pressure monitoring of patients was done and patients' height, weight, and waist and hip circumferences were recorded. Fasting blood glucose (FBG), lipid profile, creatinine, potassium, uric acid, hematocrit levels were studied. RESULTS: Non-dipper (ie, those whose blood pressure did not drop overnight) patients had higher waist-hip ratios (WHR) (P = 0.003), uric acid (P = 0.0001), FBG (P = 0.001), total and low-density lipoprotein cholesterol levels (P = 0.0001). Risk analysis revealed that hyperuricemia was a risk factor for non dipping pattern (P < 0.0001, odds ratio = 8.1, 95% confidence interval = 1.9 33.7). Patients in the highest quadrant for uric acid levels had higher FBG (P = 0.001), low-density lipoprotein cholesterol (P = 0.017), WHR (P = 0.01), MBPS (P = 0.003), and night diastolic blood pressure compared with lowest quadrant patients (P = 0.013). Uric acid levels were also positively correlated with night ambulatory blood pressure (ABP) (r = 0.268, P =0.05), night diastolic blood pressure (r =0.3, P =0.05), and MBPS (r =0.3, P =0.05). CONCLUSION: Evaluation of hypertensive patients should also include an assessment of uric acid level and anthropometric measurements such as abdominal obesity. Hyperuricemia seems to be closely related to undesired blood pressure patterns and this may signal to the clinician that an appropriate therapeutic approach is required. PMID- 23662073 TI - Reduced use of erythropoiesis-stimulating agents and intravenous iron with ferric citrate: a managed care cost-offset model. AB - BACKGROUND: Ferric citrate (FC) is a phosphate binder in development for the treatment of hyperphosphatemia in patients with end-stage renal disease (ESRD). In clinical trials, FC improved patient serum phosphorus levels and increased serum ferritin and percent transferrin saturation. Because nephrologists respond to increases in these iron measures by reducing intravenous (IV) iron and erythropoiesis-stimulating agent (ESA) doses, the decreased use of iron and ESA associated with FC may reduce costs. OBJECTIVES: To develop a cost-offset model from a managed care perspective estimating the cost savings associated with FC use. METHODS: We created a cost-offset model from the managed care payer perspective that compared the treatment costs of ESRD for patients given FC. The model considered the number of dialysis sessions per month; number of ESRD patients enrolled in the health plan; cost of ESAs, iron, and dialysis sessions; and the proportion of patients on phosphate binder therapy. The model assumed equivalent efficacy and cost neutrality between FC and other phosphate binders. Monte Carlo simulations were conducted by varying model inputs. RESULTS: When FC was compared to other phosphate binders, the monthly cost of ESA and IV iron per 500 patients with ESRD (85% treated with phosphate binders) was reduced by 8.15% and 33.2%, respectively. When incorporated into the total cost of dialysis for patients with ESRD (dialysis, ESA, and IV iron), the decrease in the monthly cost of dialysis care was US$80,214 per 500 ESRD patients. Monte Carlo simulations suggest that a plan serving 500 dialysis patients could save between US$626,000 and US$1,106,000 annually with the use of FC. CONCLUSION: The use of FC in ESRD patients with hyperphosphatemia may help reduce treatment costs. PMID- 23662074 TI - Getting it right: the impact of a continuing medical education program on hepatitis B knowledge of Australian primary care providers. AB - INTRODUCTION: In Australia, chronic hepatitis B (CHB) disproportionately affects migrants born in hepatitis B endemic countries, but its detection and management in high risk populations remains suboptimal. We piloted a primary care based program for CHB detection and management in an area of high disease prevalence in Sydney, Australia. Prior to its launch, all local general practitioners were invited to take part in a continuing medical education (CME) program on hepatitis B diagnosis and management. MATERIAL AND METHODS: Preceding each CME activity, participants completed an anonymous survey recording demographic data and hepatitis B knowledge, confidence in CHB management, and preferred CME modalities. We compared knowledge scores of first-time and repeat attendees. RESULTS: Most participants (75%) were males, spoke more than one language with their patients (91%), self-identified as Asian-Australians (91%), and had graduated over 20 years previously (69%). The majority (97%) knew what patient groups require CHB and hepatocellular cancer screening, but fewer (42%-75%) answered hepatitis B management and vaccination questions correctly. Knowledge scores were not significantly improved by seminar attendance and the provision of hepatitis B resources. At baseline, participants were fairly confident about their ability to screen for CHB, provide vaccinations, and manage CHB. This did not change with repeat attendances, and did not correlate with survey outcomes. Large group CMEs were the preferred learning modality. DISCUSSION: Knowledge gaps in hepatitis B diagnosis and management translate into missed opportunities to screen for CHB, to vaccinate those susceptible, and to prevent disease complications. The results suggest that a range of innovative CME programs are required to update general practitioners on the modern management of CHB infection. PMID- 23662075 TI - Comparative diagnostic study of biomarkers using FibroMaxTM and pathology for prediction of liver steatosis in patients with chronic hepatitis C virus infection: an Egyptian study. AB - BACKGROUND: Steatosis is common in patients with hepatitis C virus (HCV) infection and may be a major determinant of progression of liver injury. This study evaluated FibroMaxTM for noninvasive diagnosis of steatosis in patients with chronic HCV. METHODS: This cross-sectional study included 44 patients naive to treatment who were referred to our hepatology clinic for assessment of fitness for antiviral therapy. Chronic HCV infection was diagnosed by viral markers. Investigations included assessment of abdominal ultrasonography, liver biopsy, calculation of body mass index, and biomarker parameters in serum using FibroMax. RESULTS: Histopathology of liver biopsies showed steatosis in 30 of 44 (68%) patients. FibroMax results were positively correlated with viral load by quantitative polymerase chain reaction and histopathological findings. Body mass index was significantly higher in steatotic patients (P = 0.003) and was significantly associated with the results on FibroMax (P = 0.005). CONCLUSION: FibroMax was correlated with histopathology and body mass index in patients with HCV. Abdominal ultrasonography could not be used as a single tool to diagnose steatosis with HCV. Steatosis is correlated with viral load, which suggests a direct viral effect. We recommend FibroMax assessment in a larger number of patients to assess its applicability in patients with HCV and steatosis. PMID- 23662076 TI - Serum calcium levels, TRPM7, TRPC1, microcalcifications, and breast cancer using breast imaging reporting and data system scores. AB - BACKGROUND: An association between higher serum calcium (Ca2+) levels and breast cancer has been previously reported. However, little is known regarding the relationship between serum Ca2+ levels and the expression of Ca2+ channels in the presence of breast microcalcifications. METHODS: A retrospective analysis of women newly diagnosed with breast microcalcifications was performed based on the Breast Imaging Reporting and Data System (BI-RADS). The expression of TRPC1, TRPC3, and TRPM7 using normal biopsy without microcalcifications (controls) and infiltrating ductal carcinoma with microcalcifications was evaluated. RESULTS: Data on 138 women were analyzed. Seventy percent of women had a BI-RADS score (1 3) corresponding to benign disease. Seventy-six percent of women with a BI-RADS score (4 or 5) were diagnosed with breast cancer, 56% were cancers in situ, and 93% were infiltrating ductal carcinomas. No difference in the distribution of corrected serum Ca2+ levels between BI-RADS scores (1-3) and BI-RADS scores (4-5) (P = 0.82) was observed. Serum Ca2+ levels were similar in women without cancer and women diagnosed with breast cancer (P = 0.94). However, the expression of TRPM7 and TRPC1, but not TRPC3, Ca2+ channels were increased in infiltrating ductal carcinoma samples with microcalcifications when compared with age-matched controls without calcification or cancer. CONCLUSION: We observed an increase in the expression of TRPM7 and TRPC1 Ca2+ channels in infiltrating ductal carcinoma samples with microcalcifications, whereas no change in serum Ca2+ levels was observed. Together these data suggest that increased expression of these channels might lead to an increase in intracellular Ca2+ levels thereby restoring serum Ca2+ levels, but these can contribute to the breast microcalcifications. However, future studies exploring the intracellular Ca2+ levels as well as the role of TRPM7 and TRPC1 function according to BI-RADS scores are needed. PMID- 23662078 TI - Influence of handpiece maintenance sprays on resin bonding to dentin. AB - OBJECTIVE: To investigate the influence of maintenance spray on resin bonding to dentin. MATERIALS AND METHODS: The crown of extracted, caries-free human molars was transversally sectioned with a model trimmer to prepare the dentin surfaces from mid-coronal sound dentin, and then uniformly abraded with #600 silicon carbide paper. The dentin surfaces were randomly divided into three groups: oil free spray group where maintenance cleaner for air bearing handpieces was sprayed onto the dentin surface for 1 s and rinsed with water spray for 30 s; oil containing spray group where maintenance cleaner for micro motor handpieces was sprayed onto the dentin surface for 1 s and rinsed with water spray for 30 s; and control group where the surface was rinsed with water spray for 30 s and then air dried. These surfaces were then bonded with Clearfil SE Bond (Kuraray Medical), and resin composite (Clearfil AP-X, Kuraray Medical) build-up crowns were incrementally constructed on the bonded surfaces. After storage for 24 h in 37 degrees C water, the bonded teeth were sectioned into hour-glass shaped slices (0.7-mm thick) perpendicular to the bonded surfaces. The specimens were then subjected to microtensile bond strength (MUTBS) testing at a crosshead speed of 1.0 mm/min. Data were analyzed with one-way ANOVA and the Tukey-Kramer test. RESULTS: Maintenance spray-contaminated specimens (oil-free and oil-containing spray groups) showed significantly lower MUTBS than control specimens (P < 0.05). However, there was no significant difference between the spray-contaminated groups (P > 0.05). CONCLUSION: Maintenance spray significantly reduces the bond strength of Clearfil SE Bond to dentin. PMID- 23662077 TI - Marginal and internal fit of zirconia based fixed dental prostheses fabricated with different concepts. AB - The purpose of this in vitro study was to compare the precision of fit of substructures milled from semi-sintered zirconia blocks, fabricated with two different fabrication concepts. Three-unit, posterior fixed dental prostheses (FDP) were fabricated for standardized dies (n = 10) with the laboratory Computer Aided Design (CAD)/Computer Aided Manufacturing (CAM) system Cercon(r) Brain (Brain) and the centralized CAD/CAM system Compartis Integrated Systems (Compartis). After cementation to the dies, the FDP were embedded and sectioned. Four cross-sections were made of each abutment tooth, and marginal and internal fit were evaluated under an optical microscope. A one-way analysis of variance (ANOVA) was used to compare data (alpha = 0.05). Mean gap dimensions at the marginal opening for Brain and Compartis were 56.0 (+/-34.5) MUm and 51.7 (+/ 45.2) MUm, respectively. Mean internal gap dimensions of 62.8 (+/-37.5) MUm to 164.6 (+/-33.4) MUm were measured depending on the measurement location and the fabrication concept. Mean marginal openings and internal adaptations were not significantly different for both systems. Three out of four measurement locations showed significantly different cement gaps. Within the limitations of this study, the results suggest that the accuracy of both investigated systems is satisfactory for clinical use. The laboratory fabrication exhibited similar accuracy as the centralized manufacturing. PMID- 23662079 TI - Primary tuberculous lymphadenitis: A case report. AB - Tuberculosis (TB) is a prevalent systemic bacterial infectious disease usually caused by Mycobacterium tuberculosis. It is estimated that approximately 8 million people develop TB each year, and 3 million people die of complications associated with the disease. In this article we report a case of a 17-year-old female patient with a painful swelling in her right submandibular region. She was diagnosed with right submandibular tuberculous lymphadenitis. Tuberculous lymphadenitis, when occurring in the cervical region, continues to be a common cause of extrapulmonary TB. TB is a recognized occupational risk for dentists, as they work in close proximity to the nasal and oral cavities of patients, with the possible generation of potentially infectious sprays during routine operative procedures. PMID- 23662080 TI - A multimethod investigation including direct observation of 3751 patient visits to 120 dental offices. AB - This report defines verbal interactions between practitioners and patients as core activities of dental practice. Trained teams spent four days in 120 Ohio dental practices observing 3751 patient encounters with dentists and hygienists. Direct observation of practice characteristics, procedures performed, and how procedure and nonprocedure time was utilized during patient visits was recorded using a modified Davis Observation Code that classified patient contact time into 24 behavioral categories. Dentist, hygienist, and patient characteristics were gathered by questionnaire. The most common nonprocedure behaviors observed for dentists were chatting, evaluation feedback, history taking, and answering patient questions. Hygienists added preventive counseling. We distinguish between preventive procedures and counseling in actual dental offices that are members of a practice-based research network. Almost a third of the dentist's and half of the hygienist's patient contact time is utilized for nonprocedure behaviors during patient encounters. These interactions may be linked to patient and practitioner satisfaction and effectiveness of self-care instruction. PMID- 23662081 TI - Shear bond strength of precoated orthodontic brackets: an in vivo study. AB - OBJECTIVE: To evaluate the shear bond strength of precoated orthodontic brackets bonded with self-etching primer relative to that of noncoated conventionally bonded brackets at two different time intervals. METHODS: Twenty-one subjects were selected for randomized split-mouth bonding of two types of brackets to the maxillary arch. Half of the teeth had precoated brackets bonded using self etching adhesive, and the other half had regular brackets bonded using Transbond XT adhesive. Nitinol wires were tied to the upper arch and were left until the time of debonding. The patients were randomly divided into two groups: one debonded after one hour and the other debonded two weeks after the initial wire placement. The shear bond strength was directly recorded from the patients' mouths using an in vivo debonding device. RESULTS: There were no significant differences in shear bond strength between the precoated and conventional groups or within each group at different time intervals. There were significant differences between anterior and posterior teeth in both the precoated and conventional groups. CONCLUSION: Pre-coated brackets bonded with self-etching adhesive have the same bonding strength as the conventionally bonded brackets. PMID- 23662083 TI - Cutaneous sinus tracts (or emerging sinus tracts) of odontogenic origin: a report of 3 cases. AB - Three cases are presented in which patients presented with either cutaneous swelling or cutaneous sinus tracts of odontogenic origin. A cutaneous sinus tract of odontogenic origin is a pathway through the alveolar bone that typically begins at the apex of an infected tooth or of an infected portion of the dental alveolus and empties infected material (pus) through the skin. Where as the more common finding of an oral fistula is a pathway from the apical periodontal area of a tooth to the surface of the oral mucous membrane, permitting the discharge of suppurative material. Diagnosis, etiology and treatment are discussed with reference to patient history, clinical examinations, imaging, and treatment perspectives. PMID- 23662082 TI - Advances in bone surgery: the Er:YAG laser in oral surgery and implant dentistry. AB - The erbium-doped yttrium aluminium garnet (Er:YAG) laser has emerged as a possible alternative to conventional methods of bone ablation because of its wavelength of 2.94 MUm, which coincides with the absorption peak of water. Over the last decades in several experimental and clinical studies, the widespread initial assumption that light amplification for stimulated emission of radiation (laser) osteotomy inevitably provokes profound tissue damage and delayed wound healing has been refuted. In addition, the supposed disadvantage of prolonged osteotomy times could be overcome by modern short-pulsed Er:YAG laser systems. Currently, the limiting factors for a routine application of lasers for bone ablation are mainly technical drawbacks such as missing depth control and a difficult and safe guidance of the laser beam. This article gives a short overview of the development process and current possibilities of noncontact Er:YAG laser osteotomy in oral and implant surgery. PMID- 23662084 TI - Candida albicans susceptibility to lactoperoxidase-generated hypoiodite. AB - In vivo, lactoperoxidase produces hypothiocyanite (OSCN(-)) from thiocyanate (SCN(-)) in the presence of hydrogen peroxide (H2O2); in vitro, iodide (I(-)) can be oxidized into hypoiodite (OI(-)) by this enzyme. The aim of this study was to compare in vitro the anti-Candida effect of iodide versus thiocyanate used as lactoperoxidase substrate to prevent Candida biofilms development. Candida albicans ATCC 10231 susceptibility upon both peroxidase systems was tested in three different experimental designs: (i) in a liquid culture medium, (ii) in an interface model between solid culture medium and gel containing the enzymic systems, (iii) in a biofilm model onto titanium and acrylic resin. Yeast growth in liquid medium was monitored by turbidimetry at 600 nm. Material-adherent yeast biomass was evaluated by the tetrazolium salt MTT method. The iodide-peroxidase system has been shown to inhibit Candida biofilm formation at lower substrate concentrations (~200 fold less H2O2 donor) and for longer incubation periods than the thiocyanate-peroxidase system. In conclusion, efficiency of lactoperoxidase generated OI(-) to prevent C. albicans biofilm development allows refining iodine antifungal use in ex vivo conditions. PMID- 23662086 TI - Remineralization of eroded enamel by a NaF rinse containing a novel calcium phosphate agent in an in situ model: a pilot study. AB - PURPOSE: An in situ study evaluated the remineralization potential of 225 ppm fluoride (F) rinses with and without a calcium phosphate agent (TCP-Si-Ur) on eroded enamel. METHODS: 20 human patients participated in this IRB approved study. Enamel blocks extracted from 20 human molars were assigned to each of the three study phases (G1, G2, G3). Each block was eroded using 1% citric acid (pH = 2.5), with a slice cut from each block to establish baseline lesion parameters (ie, integrated mineral loss DeltaZ, and lesion depth LD) using transverse microradiography (TMR). Participants and assigned blocks were randomly divided into three 28-day phases. The blocks were mounted into modified orthodontic brackets and bonded to the buccal surface of one of the subject's mandibular molars. The appliance remained in the subject's mouth for 28 days. Prior to each study phase, participants observed a one-week-washout period using a fluoride free dentifrice. In each phase, participants brushed with the fluoride-free dentifrice for 1 min, followed by one of the following coded treatments: G1: 225 ppm F + 40 ppm TCP-Si-Ur rinse (1 min); G2: 225 ppm F rinse (1 min); G3: no rinse (saliva-only). After each phase, appliances were removed and specimens were analyzed using TMR. RESULTS: TMR data (ie, DeltaZ and LD) revealed all three groups significantly remineralized eroded enamel (paired t-tests, P < 0.001). Net mineralization (% change in DeltaZ, LD) were as follows (mean (std.dev): G1: 44.1 (22.6), 30.5 (27.0); G2: 30.0 (7.4), 29.4 (10.5); G3: 23.8 (16.4), 25.7 (15.5). Furthermore, G1 was found to cause significantly more remineralization than G2 (P = 0.039) and G3, (P = 0.002). CONCLUSION: Mouthrinse containing 225 ppm F plus TCP-Si-Ur provided significantly greater remineralization relative to 225 ppm F only or saliva alone. PMID- 23662087 TI - Soft tissue grafting to improve implant esthetics. AB - Dental implants are becoming the treatment of choice to replace missing teeth, especially if the adjacent teeth are free of restorations. When minimal bone width is present, implant placement becomes a challenge and often resulting in recession and dehiscence around the implant that leads to subsequent gingival recession. To correct such defect, the author turned to soft tissue autografting and allografting to correct a buccal dehiscence around tooth #24 after a malpositioned implant placed by a different surgeon. A 25-year-old woman presented with the chief complaint of gingival recession and exposure of implant threads around tooth #24. The patient received three soft tissue grafting procedures to augment the gingival tissue. The first surgery included a connective tissue graft to increase the width of the keratinized gingival tissue. The second surgery included the use of autografting (connective tissue graft) to coronally position the soft tissue and achieve implant coverage. The third and final surgery included the use of allografting material Alloderm to increase and mask the implant from showing through the gingiva. Healing period was uneventful for the patient. After three surgical procedures, it appears that soft tissue grafting has increased the width and height of the gingiva surrounding the implant. The accomplished thickness of gingival tissue appeared to mask the showing of implant threads through the gingival tissue and allowed for achieving the desired esthetic that the patient desired. The aim of the study is to present a clinical case with soft tissue grafting procedures. PMID- 23662085 TI - Treating chronic periodontitis: current status, challenges, and future directions. AB - Periodontitis affects roughly one-third of the US population. A timely diagnosis of chronic periodontitis at its earliest stage is essential to avoid more challenging severe stages of the disease. Most cases of slight and moderate chronic periodontitis can be successfully managed by mechanical removal and/or reduction of subgingival bacterial biofilms and calculus. However, any factor that affects either the local environment or the host response may contribute to progression of the disease and a poor treatment response. Thus, it is essential that clinicians are aware of etiologic and risk factors associated with disease development and progression in order to plan and execute a successful treatment. This paper reviews a variety of risk factors, both local and systemic, that can impact the successful treatment of chronic periodontitis. PMID- 23662088 TI - Pattern of third molar impaction in a Saudi population. AB - OBJECTIVE: To evaluate the current pattern of third molar impaction in a sample of Saudi patients. METHODS: One thousand thirty-nine orthopantomograms (OPG) of patients ranging in age from 19 to 46 years (536 males and 503 females) were evaluated to determine the frequency of impacted third molars, their levels of eruption, and their angulations. RESULTS: Four hundred twenty-two (40.5%) of the 1039 OPG showed at least one impacted third molar, with no significant difference between males (222; 52.6%) and females (200; 47.4%) (P = 0.284). The most common number of impacted third molars per OPG was one (72.5%). Impacted third molars were 1.64 times more likely to occur in the mandible than in the maxilla. The most common angulation of impaction in the mandible was the mesial (33.4%), while the most common angulation in the maxilla, was the vertical (49.6%). Level B impaction was the most common in both maxilla (48.2%) and mandible (67.7%). There was no significant difference in the frequency of impaction between the right and left sides in both jaws. CONCLUSION: The pattern of third molar impaction in the western region of Saudi Arabia is characterized by a high prevalence of impaction that is greater in the mandibles and with no sex predilection. PMID- 23662089 TI - Hematological profile of normal pregnant women in Lagos, Nigeria. AB - BACKGROUND: Hematological profile is considered one of the factors affecting pregnancy and its outcome. Anemia is the most common hematological problem in pregnancy, followed by thrombocytopenia. Leukocytosis is almost always associated with pregnancy. The study reported here was designed to evaluate the overall mean values of seven major hematological parameters and their mean values at different trimesters of pregnancy. SUBJECTS AND METHODS: This examination was a cross sectional study of 274 pregnant women who registered to attend the Lagos University Teaching Hospital or Lagos State University Teaching Hospital antenatal clinics between their first and third trimester. Blood (4.5 mL) was collected from each participant into a tube containing the anticoagulant ethylenediaminetetraacetic acid (EDTA). A full blood count was performed on each sample and the results were analyzed. RESULTS: Overall, the values obtained were (mean +/- standard deviation [SD]): hematocrit level, 30.16% +/- 5.55%; hemoglobin concentration, 10.94 +/- 1.86 g/dL; white blood cells, 7.81 +/- 2.34 * 10(9); platelets, 228.29 +/- 65.6 * 10(9); cell volume 78.30 +/- 5.70 fL, corpuscular hemoglobin, 28.57 +/- 2.48 pg; and corpuscular hemoglobin concentration, 36.45 +/- 1.10 g/dL. When grouped by trimester, the mean +/- SD value of packed cell volume at first trimester was 32.07% +/- 6.80%; of second trimester, 29.76% +/- 5.21%; and of third, 33.04% +/- 3.88%. The mean +/- SD hemoglobin concentration values were 11.59 +/- 2.35 g/dL, 10.81 +/- 1.72 g/dL, and 10.38 +/- 1.27 g/dL for women in their first, second, and third trimester, respectively. Mean +/- SD white blood cell concentration for first, second, and third trimesters were 7.31 +/- 2.38 * 10(9), 7.88 +/- 2.33 * 10(9), and 8.37 +/- 2.15 * 10(9), respectively, while the mean +/- SD platelet values for first, second, and third trimesters were 231.50 +/- 79.10 * 10(9), 227.57 +/- 63 * 10(9), and 200.82 +/- 94.42 * 10(9), respectively. A statistically significant relationship was found to exist between packed cell volume and white blood cell count with increase in gestational age (P = 0.010 and 0.001, respectively). However, there was no statistically significant association between platelet count and increase in gestational age (P = 0.296). CONCLUSION: These findings reinforce the need for supplementation and provide additional information on hematological reference values in pregnancy in Nigeria. PMID- 23662090 TI - Prevention and treatment of venous thromboembolism in pregnancy in patients with hereditary antithrombin deficiency. AB - OBJECTIVE: The aims of the study reported here were to provide data from six pregnant subjects who were enrolled in a clinical trial of antithrombin (AT) concentrate, discuss other published case series and case reports, and provide general guidance for the use of AT concentrate for inherited AT deficiency in pregnancy. METHODS: In the late 1980s, 31 AT-deficient subjects were enrolled in a prospective treatment trial of the plasma-derived AT concentrate Thrombate III(r). Herein, newly available treatment data about the six pregnant subjects in the trial is tabulated and summarized. RESULTS: All six experienced venous thromboembolism (VTE) during pregnancy, were dosed according to a weight-based protocol, and were treated concomitantly with anticoagulation. Loading doses of AT concentrate of 54-62 units/kg were followed by maintenance doses of 50%-100% of the loading dose for 3-10 days. At the time of labor, loading doses of 46-50 units/kg were followed by maintenance doses of 50%-75% of the loading dose for 5 7 days. None of the six experienced recurrent thrombosis while receiving treatment with AT concentrate. CONCLUSION: Currently we suggest that women with AT deficiency who are pregnant or postpartum and have a personal history of VTE or current VTE receive AT concentrates. PMID- 23662091 TI - Bioresorbable scaffolds in the treatment of coronary artery disease. AB - Drug-eluting stents have reduced the risk of in-stent restenosis and have broadened the application in percutaneous coronary intervention in coronary artery disease. However, the concept of using a permanent metallic endovascular device to restore the patency of a stenotic artery has inherited pitfalls, namely the presence of a foreign body within the artery causing vascular inflammation, late complications such as restenosis and stent thrombosis, and impeding the restoration of the physiologic function of the stented segment. Bioresorbable scaffolds (BRS) were introduced to potentially overcome these limitations, as they provide temporary scaffolding and then disappear, liberating the treated vessel from its cage. Currently, several BRSs are available, undergoing evaluation either in clinical trials or in preclinical settings. The aim of this review is to present the new developments in BRS technology, describe the mechanisms involved in the resorption process, and discuss the potential future prospects of this innovative therapy. PMID- 23662092 TI - Approved Beta interferons in relapsing-remitting multiple sclerosis: is there an odd one out? AB - Three interferons are marketed for the treatment of relapsing-remitting multiple sclerosis. In its pivotal trial, one of them demonstrated impressive efficacy as a once-weekly regimen, but later head-to-head studies and reviews questioned its superiority. Analysis of this pivotal trial in publications and health authority reviews has shown that its early termination might have caused attrition bias. Censored patients were different from those completing the study on magnetic resonance imaging parameters and benefited from placebo in terms of relapse rate. Early progression of disability and differences in follow-up duration could have favored the benefit observed for the progression of disability outcome. Only the raw data could be of help to confirm or refute doubts about this trial. Raw data should be made available to the scientific community. PMID- 23662093 TI - Teachers' attitudes towards adolescent sexuality and life skills education in rural South Africa. AB - This study investigated the attitudes of 43 teachers and school administrators towards sex education, young people's sexuality and their communities in 19 secondary schools in rural KwaZulu-Natal, South Africa, and how these attitudes affect school-based HIV prevention and sex education. In interviews, teachers expressed judgemental attitudes towards young people's sexuality and pregnant students, and focused on girls' perceived irresponsible behaviour instead of strategies to minimise HIV risk. Despite general awareness of the HIV epidemic, few teachers perceived it as an immediate threat, and teachers' own HIV risk was infrequently acknowledged. Teachers perceived themselves to have higher personal standards and moral authority than members of the communities and schools they served. Male administrators' authority to determine school policies and teachers' attitudes towards sexuality fundamentally affect the content and delivery of school-based sexuality education and HIV prevention activities. Opportunities to create a supportive educational environment for students and for female teachers are frequently missed. Improving teachers' efficacy to deliver impartial, non judgemental and accurate information about sex and HIV is essential, as are efforts to acknowledge and address their own HIV risks. PMID- 23662095 TI - Modification of Emission Properties of ZnO Layers due to Plasmonic Near-Field Coupling to Ag Nanoislands. AB - A simple fabrication method of silver (Ag) nanoislands on ZnO films is presented. Continuous wave and time-resolved photoluminescence and transmission are employed to investigate modifications of visible and UV emissions of ZnO brought about by coupling to localized surface plasmons residing on Ag nanoislands. The size of the nanoislands, determining their absorption and scattering efficiencies, is found to be an important factor governing plasmonic modification of optical response of ZnO films. The presence of the Ag nanoislands of appropriate dimensions causes a strong (threefold) increase in emission intensity and up to 1.5 times faster recombination. The experimental results are successfully described by model calculations within the Mie theory. PMID- 23662094 TI - The Use of Exposure-Based Treatment Among Individuals With PTSD and Co-occurring Substance Use Disorders: Clinical Considerations. AB - Integrative treatments for co-occurring posttraumatic stress (PTSD) and substance use disorders have been shown to be safe and effective. Improvement in PTSD symptoms can positively impact substance use outcomes. Interventions that include exposure-based techniques, which are considered the treatment of choice for PTSD, have not been well studied in substance abusing populations. Concurrent Treatment of PTSD and Substance Use Disorders with Prolonged Exposure (COPE) is a manualized psychotherapy that combines both imaginal and in vivo exposure techniques for PTSD with cognitive behavioral techniques for substance use disorders. Preliminary studies using COPE demonstrate promise and feasibility. This article explores the clinical considerations when implementing exposure based therapy for PTSD in substance abusing individuals. PMID- 23662096 TI - Why Do Some Irish Drink So Much? Family, Historical and Regional Effects on Students' Alcohol Consumption and Subjective Normative Thresholds. AB - This paper studies determinants of drinking behavior and formation of subjective thresholds of acceptable drinking behavior using a sample of students in a major Irish University. We find evidence of strong associations between amounts of alcohol students consume and drinking of their fathers and older siblings. In contrast, we find little evidence of impacts of other non-drinking aspects of family background on students' drinking. Parental and older sibling drinking appears to affect subjective attitudes of students towards what constitutes problem drinking behavior. We investigated historical origins of drinking behavior including the role of the Church, English cultural influences, the importance of the brewery and distilling industry, and the influence of weather. We find relatively strong influences of the Catholic Church and English colonial settlement patterns on Irish drinking patterns but little influence of Irish weather. Historical licensing restrictions on the number of pubs and off-license establishments also appear to matter. PMID- 23662097 TI - Perceived Risks and Benefits of Quitting Smoking in Non-Treatment Seekers. AB - Little is known about beliefs about quitting and treatment motivation in non treatment seeking smokers. One hundred eight-eight daily cigarette smokers not currently motivated to quit smoking completed measures of perceived risks and benefits of quitting and motivation to quit. Self esteem related to quitting was positively related to desire to quit, expected success at quitting, confidence in quitting, and motivation to quit. Greater perceived risks of cravings were related to greater expected difficulty of remaining abstinent, and greater perceived risk of increased negative affect was related to decreased expectation of success at quitting, confidence for quitting, and increased expectation for difficulty remaining abstinent. Greater perceived risk of weight gain was related to being less likely to have a goal of complete abstinence. There were no gender, ethnicity, age, or education differences in the relationship of perceived risks and benefits of quitting and motivation. Knowing the risks and benefits that relate to motivation to quit for non-treatment seeking smokers provides the foundation for targeting this group in campaigns to increase quit motivation. PMID- 23662098 TI - Efficacy and Tolerability of Peginterferon alpha -2a and Peginterferon alpha -2b, Both plus Ribavirin, for Chronic Hepatitis C: A Meta-Analysis of Randomized Controlled Trials. AB - Background. The efficacy and tolerability of peginterferon alpha -2a and peginterferon alpha -2b in chronic hepatitis C (CHC) patients remain controversial. Methods. PubMed, Ovid, and Cochrane libraries were electronically searched until August 30, 2012. Studies that met the inclusion criteria were systematically evaluated by two reviewers independently. Results. The overall sustained virologic response (SVR) rate of the peginterferon alpha -2a group was significantly higher than that of the peginterferon alpha -2b group (46.7% versus 42.4%, P value = 0.01). The same tendency was observed for naive, genotype 1/4, and genotype 2/3 patients. The early virologic response (EVR) and end-of treatment response (ETR) rates were significantly higher in the peginterferon alpha -2a group than in the peginterferon alpha -2b group (56.1% versus 49.8%, P < 0.0001; 67.9% versus 56.6%, P < 0.00001, resp.). Peginterferon alpha -2a had a significantly lower discontinuation rate than peginterferon alpha -2b (27.9% versus 33.9%, P < 0.0001) in naive patients. In both naive CHC and hepatitis C virus genotype 1 patients, peginterferon alpha -2a had a higher relapse rate than peginterferon alpha -2b. Conclusions. Peginterferon alpha -2a has superior efficacy with higher EVR, ETR, and SVR than peginterferon alpha -2b for CHC patients, both plus ribavirin. Peginterferon alpha -2a might obtain a similar or even lower discontinuation rate than peginterferon alpha -2b. However, peginterferon alpha -2a had a higher relapse rate than peginterferon alpha -2b. PMID- 23662099 TI - Antimicrobial, Antioxidant, and Wound Healing Properties of Kigelia africana (Lam.) Beneth. and Strophanthus hispidus DC. AB - Microbial infections of various types of wounds are a challenge to the treatment of wounds and wound healing. The study was to investigate antimicrobial and antioxidant properties of methanol leaf and stem bark extracts of Kigelia africana and methanol leaf and root extracts of Strophanthus hispidus and also to determine wound healing properties of the extracts. The antimicrobial activities of the methanol extracts were determined against two Gram-positive and two Gram negative bacteria and a fungus using agar diffusion and micro-dilution methods. The antioxidant activity was determined using 1,1-diphenyl-2-picryl-hydrazyl (DPPH) method. The influence of the extracts on rate of wound closure was investigated using the excision wound model and histopathological investigation of treated and untreated wound tissues performed. The MICs of leaf extract of K. africana against test organisms were 2.5-7.5 mg/mL and stem bark extract were 2.25-7.5 mg/mL. The leaf extract of S. hispidus had MIC range of 2.5-7.5 mg/mL and 2.5-10 mg/mL for root extract. The IC50 of leaf and stem bark extracts of K. africana were 56.9 and 13.7 MU g/mL, respectively and leaf and root of S. hispidus were 49.8 and 45.1 MU g/mL, respectively. K. africana extracts (7.5% w/w) showed significant (P < 0.05) wound contraction at day 7 with 72% of wound closure whiles significant (P < 0.05) wound contractions were observed on day 11 for stem bark of K. africana, leaf and root extracts of S. hispidus. Wound tissues treated with the extracts showed improved collagenation, re epitheliazition and rapid granulation formation compared with untreated wound tissues. The extracts were found to contain alkaloids, saponins, tannins, flavonoids, carbohydrates, and sapogenetic glycosides. The HPLC finger-printing of the extracts were developed. The leaf, stem bark and root extracts of K. africana and S. hispidus exhibited antimicrobial, antioxidant, and enhanced wound healing properties and these may justify the medicinal uses of the plants for treatment of microbial infections and wounds. PMID- 23662100 TI - Clinical significance of amyloid precursor protein in patients with testicular germ cell tumor. AB - Introduction. The biological role of amyloid precursor protein (APP) is not well understood, especially in testicular germ cell tumors (TGCTs). Therefore, we aimed to investigate the immunoreactivity (IR) and expression of APP in TGCTs and evaluated its clinical relevance. Materials and Methods. We performed an analysis of immunohistochemistry and mRNA expression of APP in 64 testicular specimens and 21 snap-frozen samples obtained from 1985 to 2004. We then evaluated the association between APP expression and clinicopathological status in TGCTs. Results. Positive APP IR was observed in 9.8% (4/41) of seminomatous germ cell tumors (SGCTs) and 39.1% (9/23) of nonseminomatous germ cell tumors (NGCTs). NGCTs showed significantly more cases of positive IR (P = 0.00870) and a higher mRNA expression level compared with those of SGCTs (P = 0.0140). Positive APP IR was also significantly associated with alpha -fetoprotein ( alpha FP) elevation (P = 0.00870) and venous invasion (P = 0.0414). Conclusion. We observed an elevated APP expression in TGCTs, especially in NGCTs. APP may be associated with a more aggressive cancer in TGCTs. PMID- 23662101 TI - How to estimate fat mass in overweight and obese subjects. AB - Background. The prevalence of overweight and obesity is increasing and represents a primary health concern. Body composition evaluation is rarely performed in overweight/obese subjects, and the diagnosis is almost always achieved just considering body mass index (BMI). In fact, whereas BMI can be considered an important tool in epidemiological surveys, different papers stated the limitations of the use of BMI in single individuals. Aim. To assess the determinants of body composition in overweight and obese subjects. Methods. In 103 overweight or obese subjects (74 women, aged 41.5 +/- 10 years, and 29 men, aged 43.8 +/- 8 years), a multidimensional evaluation was performed including the assessment of body composition using Dual Energy X-Ray Absorptiometry (DXA), anthropometry, bioimpedance analysis (BIA), and biochemical parameters (total cholesterol, triacylglycerol, HDL- and LDL-cholesterol, free fatty acids and glycerol, glucose, insulin, C-reactive protein, plasma acylated and unacylated ghrelin, adiponectin, and leptin serum levels). Results. BMI does not represent the main predictor of FM estimated by DXA; FM from BIA and hip circumference showed a better association with FM from DXA. Moreover, models omitting BMI explained a greater part of variance. These data are confirmed by the predictive value analysis where BMI showed a performance similar to a "coin flip." PMID- 23662102 TI - Self-repair of rat cortical bone microdamage after fatigue loading in vivo. AB - Bone microdamage can be repaired through bone remodeling induced by loading. In this study, a loading device was developed for improved efficiency and the self repair process of bone microdamage was studied in ovariectomized rats. First, four-point bending fixtures capable of holding two live rats simultaneously were designed. Rats were loaded and subjected to a sinusoidal wave for 10,000 cycles. They were then divided into four groups to evaluate time points from 1 to 4 weeks in the microdamage repair process. The loaded right ulna was used for microdamage parameter analysis, and the loaded right radius was tested for mechanical properties. In all groups, microdamage consisted primarily of microcracks, which were observed in bone surrounding the force-bearing point. The values of the microdamage parameters were significantly lower at 3 weeks than at 2 weeks. However, none of the differences in mechanical properties between any four groups were statistically significant. This study shows that the improved application of loading in the form of bending for double-rat simultaneous administration was practical and efficient. These results suggest that microdamage was repaired between 2 weeks to 3 weeks after fatigue damage and microdamage is a more sensitive index of bone quality than mechanical properties. PMID- 23662103 TI - Calcium activity of upper thoracic dorsal root ganglion neurons in zucker diabetic Fatty rats. AB - The aim of the present study was to examine the calcium activity of C8-T5 dorsal root ganglion (DRG) neurons from Zucker diabetic fatty rats. In total, 8 diabetic ZDF fatty animals and 8 age-matched control ZDF lean rats were employed in the study. C8-T5 dorsal root ganglia were isolated bilaterally from 14 to 18 weeks old rats, and a primary culture was prepared. Calcium activity was measured ratiometrically using the fluorescent Ca(2+)-indicator Fura-2 acetoxymethyl ester. All neurons were stimulated twice with 20 mM K(+), followed by stimulation with either 0.3 or 0.5 MU M Capsaicin, alone or in combination with algogenic chemicals (bradykinin, serotonin, prostaglandin E2 (all 10(-5) M), and adenosine (10(-3) M)) at pH 7.4 and 6.0. Neurons from diabetic animals exhibited an overall increased response to stimulation with 20 mM K(+) compared to neurons from control. Stimulation with Capsaicin alone caused an augmented response in neurons from diabetic animals compared to control animals. When stimulated with a combination of Capsaicin and algogenic chemicals, no differences between the two groups of neurons were measured, neither at pH 7.4 nor 6.0. In conclusion, diabetes-induced alterations in calcium activity of the DRG neurons were found, potentially indicating altered neuronal responses during myocardial ischemia. PMID- 23662104 TI - Bone mineral density and osteoporosis after preterm birth: the role of early life factors and nutrition. AB - The effects of preterm birth and perinatal events on bone health in later life remain largely unknown. Bone mineral density (BMD) and osteoporosis risk may be programmed by early life factors. We summarise the existing literature relating to the effects of prematurity on adult BMD and the Developmental Origins of Health and Disease hypothesis and programming of bone growth. Metabolic bone disease of prematurity and the influence of epigenetics on bone metabolism are discussed and current evidence regarding the effects of breastfeeding and aluminium exposure on bone metabolism is summarised. This review highlights the need for further research into modifiable early life factors and their effect on long-term bone health after preterm birth. PMID- 23662105 TI - Emergent laparoscopic repair of a spigelian hernia: case report and review of the literature. AB - A spigelian hernia is a protrusion through an anterior abdominal wall defect along the linea semilunaris. The traditional method of repair consists of an open surgical technique requiring a lengthy abdominal incision to allow visualization of the defect. However, with the emergence and availability of laparoscopic techniques, a minimally invasive approach is feasible. Only eight prior case reports have documented emergent laparoscopic repair of a spigelian hernia. We describe the first successful laparoscopic repair of a spigelian hernia in an emergent setting at our institution. PMID- 23662106 TI - Adrenal incidentalomas in cancer patients are not always "innocent": a case report and review of the literature. AB - Herein, we report an unusual case of a 78-year-old woman with synchronous presentation of sigmoid cancer and a nonfunctioning primary adrenal cortex carcinoma, who developed superior vena cava syndrome due to metastatic lymphadenopathy from the latter malignancy. Our case suggests that adrenal incidentalomas during initial staging evaluation after cancer diagnosis are not always "innocent" and should not be "a priori" considered incidental findings attributed to hyperplasia, adenoma or even a non life-threatening metastasis from the primary tumor. It also emphasizes the importance of a continuous assessment of patients with synchronous primary malignancies, in order to timely evaluate changes in clinical or biological behavior and administrate the appropriate treatment. PMID- 23662107 TI - Genetic-based biomarkers and next-generation sequencing: the future of personalized care in colorectal cancer. AB - The past 5 years have witnessed extraordinary advances in the field of DNA sequencing technology. What once took years to accomplish with Sanger sequencing can now be accomplished in a matter of days with next-generation sequencing (NGS) technology. This has allowed researchers to sequence individual genomes and match combinations of mutations with specific diseases. As cancer is inherently a disease of the genome, it is not surprising to see NGS technology already being applied to cancer research with promises of greater understanding of carcinogenesis. While the task of deciphering the cancer genomic code remains ongoing, we are already beginning to see the application of genetic-based testing in the area of colorectal cancer. In this article we will provide an overview of current colorectal cancer genetic-based biomarkers, namely mutations and other genetic alterations in cancer genome DNA, discuss recent advances in NGS technology and speculate on future directions for the application of NGS technology to colorectal cancer diagnosis and treatment. PMID- 23662108 TI - After the revolution? Ethical and social challenges in 'personalized genomic medicine' AB - Personalized genomic medicine (PGM) is a goal that currently unites a wide array of biomedical initiatives, and is promoted as a 'new paradigm for healthcare' by its champions. Its promissory virtues include individualized diagnosis and risk prediction, more effective prevention and health promotion, and patient empowerment. Beyond overcoming scientific and technological hurdles to realizing PGM, proponents may interpret and rank these promises differently, which carries ethical and social implications for the realization of PGM as an approach to healthcare. We examine competing visions of PGM's virtues and the directions in which they could take the field, in order to anticipate policy choices that may lie ahead for researchers, healthcare providers and the public. PMID- 23662109 TI - Development and validation of acupuncture fear scale. AB - Objectives. Strong aversions to acupuncture have been an obstacle to understanding its intrinsic action of acupuncture. Thus, it is necessary to evaluate the nature and extent of fear of acupuncture treatment. Our study aims to develop and validate an instrument that evaluates a patient's fear of acupuncture treatment. Methods. We have developed an acupuncture fear scale, a 16 item instrument which assesses the acupuncture fear score and uses it to survey 275 participants in South Korea, thus testing the reliability and validity of the instrument. Results. Internal consistency was high (Cronbach's alpha = 0.935). Test-retest reliability (Spearman's rank correlation coefficient) among 33 participants out of 275 ranged from 0.565 to 0.797 (P < 0.001). Principal component analysis revealed two factors accounting for 68% of the variance, which are painful sensation and possible adverse events, respectively. The acupuncture fear scale was positively correlated with the total of fear of pain questionnaire III (r = 0.423, P < 0.001). Conclusions. The acupuncture fear scale can be a valid and reliable instrument that can measure fear of acupuncture treatment. These results strongly suggest that it would be a clinically useful tool to assess fear of acupuncture in the acupuncture clinic setting and an important instrument to understand the complex social-behavioral component of acupuncture modality. PMID- 23662111 TI - Control group design: enhancing rigor in research of mind-body therapies for depression. AB - Although a growing body of research suggests that mind-body therapies may be appropriate to integrate into the treatment of depression, studies consistently lack methodological sophistication particularly in the area of control groups. In order to better understand the relationship between control group selection and methodological rigor, we provide a brief review of the literature on control group design in yoga and tai chi studies for depression, and we discuss challenges we have faced in the design of control groups for our recent clinical trials of these mind-body complementary therapies for women with depression. To address the multiple challenges of research about mind-body therapies, we suggest that researchers should consider 4 key questions: whether the study design matches the research question; whether the control group addresses performance, expectation, and detection bias; whether the control group is ethical, feasible, and attractive; and whether the control group is designed to adequately control for nonspecific intervention effects. Based on these questions, we provide specific recommendations about control group design with the goal of minimizing bias and maximizing validity in future research. PMID- 23662110 TI - Sulforaphane attenuates gentamicin-induced nephrotoxicity: role of mitochondrial protection. AB - Sulforaphane (SFN), an isothiocyanate naturally occurring in Cruciferae, induces cytoprotection in several tissues. Its protective effect has been associated with its ability to induce cytoprotective enzymes through an Nrf2-dependent pathway. Gentamicin (GM) is a widely used antibiotic; nephrotoxicity is the main side effect of this compound. In this study, it was investigated if SFN is able to induce protection against GM-induced nephropathy both in renal epithelial LLC-PK1 cells in culture and in rats. SFN prevented GM-induced death and loss of mitochondrial membrane potential in LLC-PK1 cells. In addition, it attenuated GM induced renal injury (proteinuria, increases in serum creatinine, in blood urea nitrogen, and in urinary excretion on N-acetyl- beta -D-glucosaminidase, and decrease in creatinine clearance and in plasma glutathione peroxidase activity) and necrosis and apoptosis in rats. The apoptotic death was associated with enhanced active caspase-9. Caspase-8 was unchanged in all the studied groups. In addition, SFN was able to prevent GM-induced protein nitration and decrease in the activity of antioxidant enzymes catalase and glutathione peroxidase in renal cortex. In conclusion, the protective effect of SFN against GM-induced acute kidney injury could be associated with the preservation in mitochondrial function that would prevent the intrinsic apoptosis and nitrosative stress. PMID- 23662112 TI - Honokiol Eliminates Human Oral Cancer Stem-Like Cells Accompanied with Suppression of Wnt/ beta -Catenin Signaling and Apoptosis Induction. AB - Honokiol, an active compound of Magnolia officinalis, exerted many anticancer effects on various types of cancer cells. We explored its effects on the elimination of cancer stem-like side population (SP) cells in human oral squamous cell carcinoma SAS cells. The sorted SP cells possessed much higher expression of stemness genes, such as ABCG2, ABCC5, EpCAM, OCT-4, CD133, CD44, and beta catenin, and more clonogenicity as compared with the Non-SP cells. After 48 h of treatment, honokiol dose dependently reduced the proportion of SP from 2.53% to 0.09%. Apoptosis of honokiol-treated SP cells was evidenced by increased annexin V staining and cleaved caspase-3 as well as decreased Survivin and Bcl-2. Mechanistically, honokiol inhibited the CD44 and Wnt/ beta -catenin signaling of SP cells. The Wnt signaling transducers such as beta -catenin and TCF-4 were decreased in honokiol-treated SP cells, while the beta -catenin degradation promoting kinase GSK-3 alpha / beta was increased. Consistently, the protein levels of beta -catenin downstream targets such as c-Myc and Cyclin D1 were also downregulated. Furthermore, the beta -catenin-related EMT markers such as Slug and Snail were markedly suppressed by honokiol. Our findings indicate honokiol may be able to eliminate oral cancer stem cells through apoptosis induction, suppression of Wnt/ beta -catenin signaling, and inhibition of EMT. PMID- 23662113 TI - Kaurenoic Acid from Aralia continentalis Inhibits Biofilm Formation of Streptococcus mutans. AB - We isolated a single chemical compound from A. continentalis and identified it to be kaurenoic acid (KA) and investigated the influence of anticariogenic properties. Inhibitory effects of KA on cariogenic properties such as growth, acid production, biofilm formation, and the adherence of S. mutans were evaluated. Furthermore, real-time PCR analysis was performed to evaluate the influence of KA on the genetic expression of virulence factors. KA significantly inhibited the growth and acid production of S. mutans at 2-4 MU g/mL and 4 MU g/mL of KA, respectively. Furthermore, the adherence onto S-HAs was inhibited at 3-4 MU g/mL of KA and biofilm formation was significantly inhibited when treated with 3 MU g/mL KA and completely inhibited at 4 MU g/mL. Also, the inhibitory effect of KA on biofilm formation was confirmed by SEM. In confocal laser scanning microscopy, bacterial viability gradually decreased by KA in a dose dependent manner. Real-time PCR analysis showed that the expressions of gtfB, gtfC, gbpB, spaP, brpA, relA, and vicR were significantly decreased in S. mutans when it was treated with KA. These results suggest that KA from A. continentalis may be a useful agent for inhibiting the cariogenic properties of S. mutans. PMID- 23662114 TI - Cyclohexylmethyl Flavonoids Suppress Propagation of Breast Cancer Stem Cells via Downregulation of NANOG. AB - Breast cancer stem cells (CSCs) are highly tumorigenic and possess the capacity to self-renew. Recent studies indicated that pluripotent gene NANOG involves in regulating self-renewal of breast CSCs, and expression of NANOG is correlated with aggressiveness of poorly differentiated breast cancer. We initially confirmed that breast cancer MCF-7 cells expressed NANOG, and overexpression of NANOG enhanced the tumorigenicity of MCF-7 cells and promoted the self-renewal expansion of CD24(-/low)CD44(+) CSC subpopulation. In contrast, knockdown of NANOG significantly affected the growth of breast CSCs. Utilizing flow cytometry, we identified five cyclohexylmethyl flavonoids that can inhibit propagation of NANOG-positive cells in both breast cancer MCF-7 and MDA-MB231 cells. Among these flavonoids, ugonins J and K were found to be able to induce apoptosis in non-CSC populations and to reduce self-renewal growth of CD24(-/low)CD44(+) CSC population. Treatment with ugonin J significantly reduced the tumorigenicity of MCF-7 cells and efficiently suppressed formation of mammospheres. This suppression was possibly due to p53 activation and NANOG reduction as either addition of p53 inhibitor or overexpression of NANOG can counteract the suppressive effect of ugonin J. We therefore conclude that cyclohexylmethyl flavonoids can possibly be utilized to suppress the propagation of breast CSCs via reduction of NANOG. PMID- 23662115 TI - Emerging roles of propolis: antioxidant, cardioprotective, and antiangiogenic actions. AB - Propolis has attracted attention in recent years due to its beneficial effects, which make it a potential preventive and therapeutic agent as well as a useful additive in food and cosmetics. The aim of this review is to discuss the growing evidence that propolis may, via a diverse array of biological actions, assist in the prevention of some inflammation-mediated pathologies including cardiovascular disease. The active components of propolis that have been identified so far include polyphenols and flavonoids. These compounds have cardioprotective, vasoprotective, antioxidant, antiatherosclerotic, anti-inflammatory and antiangiogenic actions. Many studies have been undertaken to elucidate the mechanism(s) by which propolis acts, which involve cellular signaling targets and interactions at the genomic level. This review will highlight the effects of propolis that may assist in the prevention of chronic degenerative diseases, such as cardiovascular disease. PMID- 23662116 TI - Discovery of endothelium and mesenchymal properties of primo vessels in the mesentery. AB - Recent evidences demonstrated that endothelial-to-mesenchymal transition (EndMT) has a crucial role in cancer and is recognized as a unique source of cancer associated fibroblasts (CAFs). Primo vascular system (PVS) is a new circulatory system which may play an important role in cancer metastasis and regeneration. In the current study, we applied previously established time-saving method to identify primo vessels and further investigated the immunocytochemical properties of primo vessels. Both primo vessels and primary primo vessel cells in the mesentery expressed endothelial markers and fibroblast markers. Double-labeling experiments demonstrated that endothelial and fibroblast markers are coexpressed in primo vessels. In addition, under the stimulation of TGF-beta1 in vitro, primary primo vessel cells differentiated into fibroblasts. Therefore, we found that primo vessels in the mesentery had a transitional structure between endothelium and mesenchymal. This is a new finding of EndMT in normal postnatal animals. PMID- 23662117 TI - Tibetan medicine: a systematic review of the clinical research available in the west. AB - Background. Little is known about Tibetan medicine (TM), in Western industrialized countries. Objectives. To provide a systematic review of the clinical studies on TM available in the West. Data Sources. Seven literature databases, published literature lists, citation tracking, and contacts to experts and institutions. Study Eligibility Criteria. Studies in English, German, French, or Spanish presenting clinical trial results. Participants. All patients of the included studies. Interventions. Tibetan medicine treatment. Study Appraisal and Synthesis Methods. Included studies were described quantitatively; their quality was assessed with the DIMDI HTA checklist; for RCTs the Jadad score was used. Results. 40 studies from 39 publications were included. They were very heterogeneous regarding study type and size, treated conditions, treatments, measured outcomes, and quality. Limitations. No Russian, Tibetan, or Chinese publications were included. Possible publication bias. Conclusions. The number of clinical trials on TM available in the West is small; methods and results are heterogeneous. Implications of Key Findings. Higher quality larger trials are needed, as is a general overview of traditional usage to inform future clinical trials. Systematic Review Registration Number. None. PMID- 23662119 TI - Ganoderma tsugae Extract Inhibits Growth of HER2-Overexpressing Cancer Cells via Modulation of HER2/PI3K/Akt Signaling Pathway. AB - Ganoderma, also known as Lingzhi or Reishi, has been used for medicinal purposes in Asian countries for centuries. It is a medicinal fungus with a variety of biological properties including immunomodulatory and antitumor activities. In this study, we investigated the molecular mechanisms by which Ganoderma tsugae (GT), one of the most common species of Ganoderma, inhibits the proliferation of HER2-overexpressing cancer cells. Here, we show that a quality assured extract of GT (GTE) inhibited the growth of HER2-overexpressing cancer cells in vitro and in vivo and enhanced the growth-inhibitory effect of antitumor drugs (e.g., taxol and cisplatin) in these cells. We also demonstrate that GTE induced cell cycle arrest by interfering with the HER2/PI3K/Akt signaling pathway. Furthermore, GTE curtailed the expression of the HER2 protein by modulating the transcriptional activity of the HER2 gene and the stability/degradation of the HER2 protein. In conclusion, this study suggests that GTE may be a useful adjuvant therapeutic agent in the treatment of cancer cells that highly express HER2. PMID- 23662120 TI - ZHENG-Omics Application in ZHENG Classification and Treatment: Chinese Personalized Medicine. AB - With the hope to provide an effective approach for personalized diagnosis and treatment clinically, traditional chinese medicine (TCM) is being paid increasing attention as a complementary and alternative medicine. It performs treatment based on ZHENG (TCM syndrome) classification, which could be identified clinical special phenotypes by symptoms and signs of patients even if they have a different disease. However, it caused controversy because ZHENG classification only depends on observation, knowledge, and clinical experience of TCM practitioners, which lacks objectivity and repeatability. Although researchers and scientists of TCM have done some work with a lot of beneficial methods, the results could not reach satisfactory with the shortcomings of generalizing the entire state of the body or ignoring the patients' feelings. By total summary, mining, and integration of existing researches, the present paper attempts to introduce a novel macro-microconcept of ZHENG-omics, with the prospect of bright future in providing an objective and repeatable approach for Chinese personalized medicine in an effective way. In this paper, we give the brief introduction and preliminary validation, and discuss strategies and system-oriented technologies for achieving this goal. PMID- 23662118 TI - From Acupuncture to Interaction between delta-Opioid Receptors and Na (+) Channels: A Potential Pathway to Inhibit Epileptic Hyperexcitability. AB - Epilepsy is one of the most common neurological disorders affecting about 1% of population. Although the precise mechanism of its pathophysiological changes in the brain is unknown, epilepsy has been recognized as a disorder of brain excitability characterized by recurrent unprovoked seizures that result from the abnormal, excessive, and synchronous activity of clusters of nerve cells in the brain. Currently available therapies, including medical, surgical, and other strategies, such as ketogenic diet and vagus nerve stimulation, are symptomatic with their own limitations and complications. Seeking new strategies to cure this serious disorder still poses a big challenge to the field of medicine. Our recent studies suggest that acupuncture may exert its antiepileptic effects by normalizing the disrupted neuronal and network excitability through several mechanisms, including lowering the overexcited neuronal activity, enhancing the inhibitory system, and attenuating the excitatory system in the brain via regulation of the interaction between delta -opioid receptors (DOR) and Na(+) channels. This paper reviews the progress in this field and summarizes new knowledge based on our work and those of others. PMID- 23662121 TI - Topical treatment of nonhealing venous leg ulcer with propolis ointment. AB - An investigation of effectiveness of topical treatment of nonhealing chronic venous leg ulcers with propolis ointment was conducted. 56 patients were included in the study and randomized into two groups. In group 1, there were 28 patients (ulceration area: 6.9-9.78 cm(2)) treated by means of topical propolis ointment application and short stretch bandage compression. In group 2, there were 29 patients (ulceration area: 7.2-9.4 cm(2)) treated by means of Unna boot leg compression without topical propolis treatment. In the study, the efficacy of both treatment methods in patients with resistive venous leg ulcers was compared. The ulceration of patients from group 1 healed completely after 6 weeks of therapy in all cases. In all patients from group 2, the process of healing was longer but successfully completed after 16 weeks of the therapy. We found that an adjunctive propolis ointment treatment increases the efficacy of the short stretch bandage compression stocking, and this combined treatment is more effective than Unna's boot compression alone. PMID- 23662122 TI - Neuromuscular damage and repair after dry needling in mice. AB - Objective. Some dry needling treatments involve repetitive and rapid needle insertions into myofascial trigger points. This type of treatment causes muscle injury and can also damage nerve fibers. The aim of this study is to determine the injury caused by 15 repetitive punctures in the muscle and the intramuscular nerves in healthy mouse muscle and its ulterior regeneration. Methods. We repeatedly needled the levator auris longus muscle of mice, and then the muscles were processed with immunohistochemistry, methylene blue, and electron microscopy techniques. Results. Three hours after the dry needling procedure, the muscle fibers showed some signs of an inflammatory response, which progressed to greater intensity 24 hours after the procedure. Some inflammatory cells could still be seen when the muscle regeneration was almost complete seven days after the treatment. One day after the treatment, some changes in the distribution of receptors could be observed in the denervated postsynaptic component. Reinnervation was complete by the third day after the dry needling procedure. We also saw very fine axonal branches reinnervating all the postsynaptic components and some residual sprouts the same day. Conclusion. Repeated dry needling punctures in muscle do not perturb the different stages of muscle regeneration and reinnervation. PMID- 23662123 TI - In Vitro Antibacterial Activity of Essential Oils against Streptococcus pyogenes. AB - Streptococcus pyogenes plays an important role in the pathogenesis of tonsillitis. The present study was conducted to evaluate the in vitro antibacterial activities of 18 essential oils chemotypes from aromatic medicinal plants against S. pyogenes. Antibacterial activity of essential oils was investigated using disc diffusion method. Minimum Inhibitory Concentration of essential oils showing an important antibacterial activity was measured using broth dilution method. Out of 18 essential oils tested, 14 showed antibacterial activity against S. pyogenes. Among them Cinnamomum verum, Cymbopogon citratus, Thymus vulgaris CT thymol, Origanum compactum, and Satureja montana essential oils exhibited significant antibacterial activity. The in vitro results reported here suggest that, for patients suffering from bacterial throat infections, if aromatherapy is used, these essential oils, considered as potential antimicrobial agents, should be preferred. PMID- 23662124 TI - Caffeic Acid phenethyl ester inhibits epithelial-mesenchymal transition of human pancreatic cancer cells. AB - Background. This study aimed to investigate the effect of propolis component caffeic acid phenethyl ester (CAPE) on epithelial-mesenchymal transition (EMT) of human pancreatic cancer cells and the molecular mechanisms underlying these effects. Methods. The transforming growth factor beta (TGF-beta-) induced EMT in human pancreatic PANC-1 cancer cells was characterized by observation of morphology and the expression of E-cadherin and vimentin by western blotting. The migration potential was estimated with wound closure assay. The expression of transcriptional factors was measured by quantitative RT-PCR and immunocytochemistry staining. The orthotopic pancreatic cancer xenograft model was used for in vivo assessment. Results. The overexpression of vimentin was attenuated by CAPE, and the alteration in morphology from polygonal to spindle shape was partially reversed by CAPE. Furthermore, CAPE delayed the TGF-beta stimulated migration potential. CAPE treatment did not reduce the expression levels of Smad 2/3, Snail 1, and Zeb 1 but inhibited the expression of transcriptional factor Twist 2. By using an orthotopic pancreatic cancer model, CAPE suppressed the expression of Twist 2 and growth of PANC-1 xenografts without significant toxicity. Conclusion. CAPE could inhibit the orthotopic growth and EMT of pancreatic cancer PANC-1 cells accompanied by downregulation of vimentin and Twist 2 expression. PMID- 23662125 TI - A Small Molecule Swertisin from Enicostemma littorale Differentiates NIH3T3 Cells into Islet-Like Clusters and Restores Normoglycemia upon Transplantation in Diabetic Balb/c Mice. AB - Aim. Stem cell therapy is one of the upcoming therapies for the treatment of diabetes. Discovery of potent differentiating agents is a prerequisite for increasing islet mass. The present study is an attempt to screen the potential of novel small biomolecules for their differentiating property into pancreatic islet cells using NIH3T3, as representative of extra pancreatic stem cells/progenitors. Methods. To identify new agents that stimulate islet differentiation, we screened various compounds isolated from Enicostemma littorale using NIH3T3 cells and morphological changes were observed. Characterization was performed by semiquantitative RT-PCR, Q-PCR, immunocytochemistry, immunoblotting, and insulin secretion assay for functional response in newly generated islet-like cell clusters (ILCC). Reversal of hyperglycemia was monitored after transplanting ILCC in STZ-induced diabetic mice. Results. Among various compounds tested, swertisin, an isolated flavonoid, was the most effective in differentiating NIH3T3 into endocrine cells. Swertisin efficiently changed the morphology of NIH3T3 cells from fibroblastic to round aggregate cell cluster in huge numbers. Dithizone (DTZ) stain primarily confirmed differentiation and gene expression studies signified rapid onset of differentiation signaling cascade in swertisin-induced ILCC. Molecular imaging and immunoblotting further confirmed presence of islet specific proteins. Moreover, glucose induced insulin release (in vitro) and decreased fasting blood glucose (FBG) (in vivo) in transplanted diabetic BALB/c mice depicted functional maturity of ILCC. Insulin and glucagon expression in excised islet grafts illustrated survival and functional integrity. Conclusions. Rapid induction for islet differentiation by swertisin, a novel herbal biomolecule, provides low cost and readily available differentiating agent that can be translated as a therapeutic tool for effective treatment in diabetes. PMID- 23662126 TI - A two-level model for the analysis of syndrome of acute ischemic stroke: from diagnostic model to molecular mechanism. AB - Prompt and accurate diagnosis of acute ischemic stroke is critical to seek acute therapy. In traditional Chinese medicine (TCM) science, there is a comprehensive system of diagnosis and medical care of acute ischemic stroke. Here we introduce a two-level model for the analysis of TCM syndrome of acute ischemic stroke. Owing to the limitation of sample size and imbalance, we focused on the analysis of wind-phlegm collateral obstruction syndrome (Feng Tan Yu Zu Zheng). Firstly, a Support-Vector-Machine- (SVM-) based diagnostic model was set up through selection of core symptoms. After pairwise undersampling, we improved the performance of prediction and generated the core symptoms-based diagnostic model of wind-phlegm collateral obstruction syndrome. Next, Pathway Pattern-based method and MetaDrug platform were used to shed light on the molecular basis of the significance of core symptoms in three complementary aspects: symptom-gene pathway multilayer correlation network, enriched pathways, and most relevant interaction network. The integration of diagnostic model and molecular mechanism analysis creates an interesting perspective for better understanding the syndrome. The two-level model would provide a new opportunity for the study of TCM syndromes. PMID- 23662127 TI - Pharmacological Effects of Lactuca serriola L. in Experimental Model of Gastrointestinal, Respiratory, and Vascular Ailments. AB - Lactuca serriola L. has traditionally been used in folkloric medicine to manage respiratory, gastrointestinal, and multiple other ailments. The present study was undertaken to explore the effect of methanol extract of L. serriola on isolated rabbit tissue preparations, that is, jejunum, trachea, and aorta in an attempt to validate its folkloric use in traditional medicine for gastrointestinal, respiratory, and vascular ailments. The application of the methanol extract to isolated rabbit jejunum preparations exhibited concentration-dependent spasmogenic effect (0.03 to 3.0 mg/mL), but interestingly further increase in concentration (5.0 mg/mL) resulted in complete spasmolytic effect. The pretreatment of the tissue preparations with atropine (0.1 MU M) caused the suppression of the contractile response. Moreover, the same extract also caused relaxation of K(+)-(80 mM) induced spastic contractions of isolated rabbit jejunum preparations (5.0 mg/mL) and shifted the Ca(++) dose response curves towards right at concentration range of 0.3-1.0 mg/mL. Similarly, the extract application to isolated rabbit tracheal preparations relaxed the carbachol-(1 MU M) induced (0.3-1.0 mg/mL) as well as K(+)-(80 mM) induced contractions (3.0 mg/mL). Furthermore, it relaxed the phenylephrine (1 MU M)-induced contractions in isolated rabbit aorta preparations (3.0 mg/mL) and K(+) (80 mM)-induced contractions (1.0 mg/mL). These effects were found comparable to that of dicyclomine, as an antagonist of muscarinic receptors as well as a possible Ca(++) channel blocker. The previously mentioned findings may partially justify the folkloric use of Lactuca serriola in the management of conditions pertaining to spasm of intestine, bronchioles, and vasculature. PMID- 23662128 TI - Active Component of Danshen (Salvia miltiorrhiza Bunge), Tanshinone I, Attenuates Lung Tumorigenesis via Inhibitions of VEGF, Cyclin A, and Cyclin B Expressions. AB - Tanshinone I (T1) and tanshinone II (T2) are the major diterpenes isolated from Danshen (Salvia miltiorrhiza Bunge). Three human lung adenocarcinoma cell lines, A549, CL1-0, and CL1-5, were treated with T1 and T2 for the in vitro antitumor test. Results showed that T1 was more effective than T2 in inhibiting the growth of lung cancer cells via suppressing the expression of VEGF, Cyclin A, and Cyclin B proteins in a dose-dependent manner. Moreover, a transgenic mice model of the human vascular endothelial growth factor-A165 (hVEGF-A 165) gene-induced pulmonary tumor was further treated with T1 for the in vivo lung cancer therapy test. T1 significantly attenuated hVEGF-A165 overexpression to normal levels of the transgenic mice (Tg) that were pretreated with human monocytic leukemia THP-1 cell-derived conditioned medium (CM). It also suppressed the formation of lung adenocarcinoma tumors (16.7%) compared with two placebo groups (50% for Tg/Placebo and 83.3% for Tg/CM/Placebo; P < 0.01). This antitumor effect is likely to slow the progression of cells through the S and G2/M phases of the cell cycle. Blocking of the tumor-activated cell cycle pathway may be a critical mechanism for the observed antitumorigenic effects of T1 treatment on vasculogenesis and angiogenesis. PMID- 23662129 TI - Molecular mechanisms of large-conductance ca (2+) -activated potassium channel activation by ginseng gintonin. AB - Gintonin is a unique lysophosphatidic acid (LPA) receptor ligand found in Panax ginseng. Gintonin induces transient [Ca(2+)]i through G protein-coupled LPA receptors. Large-conductance Ca(2+)-activated K(+) (BKCa) channels are expressed in blood vessels and neurons and play important roles in blood vessel relaxation and attenuation of neuronal excitability. BKCa channels are activated by transient [Ca(2+)]i and are regulated by various Ca(2+)-dependent kinases. We investigated the molecular mechanisms of BKCa channel activation by gintonin. BKCa channels are heterologously expressed in Xenopus oocytes. Gintonin treatment induced BKCa channel activation in oocytes expressing the BKCa channel alpha subunit in a concentration-dependent manner (EC50 = 0.71 +/- 0.08 ug/mL). Gintonin-mediated BKCa channel activation was blocked by a PKC inhibitor, calphostin, and by the calmodulin inhibitor, calmidazolium. Site-directed mutations in BKCa channels targeting CaM kinase II or PKC phosphorylation sites but not PKA phosphorylation sites attenuated gintonin action. Mutations in the Ca(2+) bowl and the regulator of K(+) conductance (RCK) site also blocked gintonin action. These results indicate that gintonin-mediated BKCa channel activations are achieved through LPA1 receptor-phospholipase C-IP3-Ca(2+)-PKC calmodulin-CaM kinase II pathways and calcium binding to the Ca(2+) bowl and RCK domain. Gintonin could be a novel contributor against blood vessel constriction and over-excitation of neurons. PMID- 23662130 TI - Modified dachengqi decoction combined with conventional treatment for treating acute exacerbation of chronic obstructive pulmonary disease: a systematic review based on randomized controlled trials. AB - Objective. This study intended to systematically evaluate the effectiveness and safety of modified Dachengqi Decoction (MDD) combined with conventional treatment for treating acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Method. An extensive search was performed within 6 English and Chinese electronic databases from inception to April 2012. Methodological quality was assessed according to Cochrane risk of bias assessment. Data were analyzed using Review Manager 5.1. Results. A total of 16 studies (involving 1112 patients) were included. The result showed that MDD and its modification combined with routine treatment were more effective in improving FEV1%pred, enhancing the significant effectiveness, reducing PCO2, and shortening duration of mechanical ventilation. Adverse events were reported in two trials with symptom of diarrhea, while no serious adverse effect was reported. Conclusion. Modified Dachengqi Decoction appears to be effective for treating AECOPD. However, more regular designed RCTs are needed because of insufficient methodological problems. PMID- 23662131 TI - Astragalus in the prevention of upper respiratory tract infection in children with nephrotic syndrome: evidence-based clinical practice. AB - Aims. To explore whether Astragalus or its formulations could prevent upper respiratory infection in children with nephrotic syndrome and how best to use it. Methods. We transformed a common clinical question in practice to an answerable question according to the PICO principle. Databases, including the Cochrane Library (Issue 5, 2012), PUBMED (1966-2012.8), CBM (1978-2012.8), VIP (1989 2012.8), and CNKI (1979-2012.8), were searched to identify Cochrane systematic reviews and clinical trials. Then, the quality of and recommendations from the clinical evidence were evaluated using the GRADEpro software. Results. The search yielded 537 papers. Only two studies with high validity were included for synthesis calculations. The results showed that Astragalus granules could effectively reduce URTI in children with nephrotic syndrome compared with prednisone treatment alone (23.9% versus 42.9%; RR = 0.56 and 95% CI = 0.33 0.93). The dose of Astragalus granules was 2.25 gram (equivalent to 15 gram crude Astragalus) twice per day, at least for 3-6 months. The level of evidence quality was low, but we still recommended the evidence to the patient according to GRADEpro with the opinion of the expert. Followup showed the incidence of URTI in this child decreased significantly. Conclusions. Astragalus granules may reduce the incidence of URTI in children with nephrotic syndrome. PMID- 23662133 TI - A Special Ingredient (VtR) Containing Oligostilbenes Isolated from Vitis thunbergii Prevents Bone Loss in Ovariectomized Mice: In Vitro and In Vivo Study. AB - Vitis thunbergii is used in Taiwan as a botanical supplement for inflammatory bone diseases. This study aims to examine its direct effect on bone metabolism. Three-month-old female mice were randomly divided into ovariectomized control (OVX), sham operated (SHAM), and ovariectomy treated with either 17 beta estradiol or a special ingredient (VtR) fractionated from an ethanol extract of V. thunbergii started two weeks after ovariectomy. VtR treatment for 8 weeks significantly ameliorated the deterioration of bone mineral density and reversed all the ovariectomy-induced changes in MU -CT parameters. The antiosteoporotic effect of VtR accompanied decrease in serum levels of C-terminal telopeptides of type I collagen (CTx), interleukin-7, and ration of RANKL/osteoprotegerin (OPG) but rise in osteocalcin concentration. Sparse calcified microarchitecture and less alkaline-phosphatase- (ALP-) positive cells were observed at the femur and vertebral sites in OVX mice while VtR remarkably restored such variation. HPLC analysis showed (+)-vitisin-A, (-)-vitisin-B, and ampelopsin C predominated in VtR. Both (-)-vitisin B and ampelopsin C increased ALP activity and bone nodule formation in cultured osteoblasts. Instead of stimulating osteoblastogenesis, (+) vitisin A dramatically repressed osteoclasts differentiation and bone resorption. The results suggested VtR composed of diverse components to reciprocally drive osteoblastogenesis and interdict osteoclastogenesis may serve as a potential botanic drug for osteoporosis therapy. PMID- 23662134 TI - Platelet aggregation pathway network-based approach for evaluating compounds efficacy. AB - Traditional Chinese medicines (TCMs) contain a large quantity of compounds with multiple biological activities. By using multitargets docking and network analysis in the context of pathway network of platelet aggregation, we proposed network efficiency and network flux model to screen molecules which can be used as drugs for antiplatelet aggregation. Compared with traditional single-target screening methods, network efficiency and network flux take into account the influences which compounds exert on the whole pathway network. The activities of antiplatelet aggregation of 19 active ingredients separated from TCM and 14 nonglycoside compounds predicated from network efficiency and network flux model show good agreement with experimental results (correlation coefficient = 0.73 and 0.90, resp.). This model can be used to evaluate the potential bioactive compounds and thus bridges the gap between computation and clinical indicator. PMID- 23662135 TI - Compounds from the Fruits of the Popular European Medicinal Plant Vitex agnus castus in Chemoprevention via NADP(H):Quinone Oxidoreductase Type 1 Induction. AB - As part of our continuing efforts in the search for potential biologically active compounds from medicinal plants, we have isolated 18 compounds including two novel nitrogen containing diterpenes from extracts of the fruits of Vitex agnus castus. These isolates, along with our previously obtained novel compound vitexlactam A (1), were evaluated for potential biological effects, including cancer chemoprevention. Chemically, the nitrogenous isolates were found to be two labdane diterpene alkaloids, each containing an alpha , beta -unsaturated gamma lactam moiety. Structurally, they were elucidated to be 9 alpha -hydroxy-13(14) labden-16,15-amide (2) and 6 beta -acetoxy-9 alpha -hydroxy-13(14)-labden-15,16 amide (3), which were named vitexlactams B and C, respectively. The 15 known isolates were identified as vitexilactone (4), rotundifuran (5), 8-epi-manoyl oxide (6), vitetrifolin D (7), spathulenol (8), cis-dihydro-dehydro diconiferylalcohol-9-O- beta -D-glucoside (9), luteolin-7-O-glucoside (10), 5 hydroxy-3,6,7,4'-tetramethoxyflavone (11), casticin (12), artemetin (13), aucubin (14), agnuside (15), beta -sitosterol (16), p-hydroxybenzoic acid (17), and p hydroxybenzoic acid glucose ester (18). All compound structures were determined/identified on the basis of 1D and/or 2D NMR and mass spectrometry techniques. Compounds 6, 8, 9, and 18 were reported from a Vitex spieces for the first time. The cancer chemopreventive potentials of these isolates were evaluated for NADP(H):quinone oxidoreductase type 1 (QR1) induction activity. Compound 7 demonstrated promising QR1 induction effect, while the new compound vitexlactam (3) was only slightly active. PMID- 23662132 TI - Herbal therapies for type 2 diabetes mellitus: chemistry, biology, and potential application of selected plants and compounds. AB - Diabetes mellitus has been recognized since antiquity. It currently affects as many as 285 million people worldwide and results in heavy personal and national economic burdens. Considerable progress has been made in orthodox antidiabetic drugs. However, new remedies are still in great demand because of the limited efficacy and undesirable side effects of current orthodox drugs. Nature is an extraordinary source of antidiabetic medicines. To date, more than 1200 flowering plants have been claimed to have antidiabetic properties. Among them, one-third have been scientifically studied and documented in around 460 publications. In this review, we select and discuss blood glucose-lowering medicinal herbs that have the ability to modulate one or more of the pathways that regulate insulin resistance, beta-cell function, GLP-1 homeostasis, and glucose (re)absorption. Emphasis is placed on phytochemistry, anti-diabetic bioactivities, and likely mechanism(s). Recent progress in the understanding of the biological actions, mechanisms, and therapeutic potential of compounds and extracts of plant origin in type 2 diabetes is summarized. This review provides a source of up-to-date information for further basic and clinical research into herbal therapy for type 2 diabetes. Emerging views on therapeutic strategies for type 2 diabetes are also discussed. PMID- 23662136 TI - Effects of Flower and Fruit Extracts of Melastoma malabathricum Linn. on Growth of Pathogenic Bacteria: Listeria monocytogenes, Staphylococcus aureus, Escherichia coli, and Salmonella typhimurium. AB - Melastoma malabathricum Linn. is a shrub that comes with beautiful pink or purple flowers and has berries-like fruits rich in anthocyanins. This study was carried out with the aim to evaluate the inhibitory activities of different concentrations of the M. malabathricum Linn. flower and fruit crude extracts against Listeria monocytogenes IMR L55, Staphylococcus aureus IMR S244, Escherichia coli IMR E30, and Salmonella typhimurium IMR S100 using the disc diffusion method. The lowest concentrations of the extracts producing inhibition zones against the test microorganisms were used to determine their minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs). In addition, the growth of Listeria monocytogenes IMR L55 and Staphylococcus aureus IMR S244 grown in medium supplemented with the respective extracts at different temperatures (4 degrees C, 25 degrees C, and 37 degrees C) and pHs (4, 6, 7, and 8) was determined. PMID- 23662137 TI - Long-Term Stimulation with Electroacupuncture at DU20 and ST36 Rescues Hippocampal Neuron through Attenuating Cerebral Blood Flow in Spontaneously Hypertensive Rats. AB - This study was designed to investigate the effect of long-term electroacupuncture at Baihui (DU20) and Zusanli (ST36) on cerebral microvessels and neurons in CA1 region of hippocampus in spontaneously hypertensive rats (SHR). A total of 45 male Wistar rats and 45 SHR were randomly grouped, with or without electroacupuncture (EA) at DU20 and ST36, once every other day for a period of 8 weeks. The mean arterial pressure (MAP) was measured once every 2 weeks. Cerebral blood flow (CBF) and the number of open microvessels in hippocampal CA1 region were detected by Laser Doppler and immunohistochemistry, respectively. Nissl staining and Western blotting were performed, respectively, to determine hippocampus morphology and proteins that were implicated in the concerning signaling pathways. The results showed that the MAP in SHR increased linearly over the observation period and was significantly reduced following electroacupuncture as compared with sham control SHR rats, while no difference was observed in Wistar rats between EA and sham control. The CBF, learning and memory capacity, and capillary rarefaction of SHR were improved by EA. The upregulation of angiotensin II type I receptor (AT1R), endothelin receptor (ETAR), and endothelin-1 (ET-1) in SHR rats was attenuated by electroacupuncture, suggesting an implication of AT1R, ETAR, and ET-1 pathway in the effect of EA. PMID- 23662138 TI - Rhinacanthus nasutus Ameliorates Cytosolic and Mitochondrial Enzyme Levels in Streptozotocin-Induced Diabetic Rats. AB - The present study was conducted to evaluate the therapeutic efficacy of Rhinacanthus nasutus (R. nasutus) on mitochondrial and cytosolic enzymes in streptozotocin-induced diabetic rats. The rats were divided into five groups with 6 rats in each group. The methanolic extract of R. nasutus was orally administered at a dose of 200 mg/kg/day, and glibenclamide was administered at a dose of 50 mg/kg/day. All animals were treated for 30 days and were sacrificed. The activities of both intra- and extramitochondrial enzymes including glucose-6 phosphate dehydrogenase (G6PDH), succinate dehydrogenase (SDH), glutamate dehydrogenase (GDH), and lactate dehydrogenase (LDH) were measured in the livers of the animals. The levels of G6PDH, SDH, and GDH were significantly reduced in the diabetic rats but were significantly increased after 30 days of R. nasutus treatment. The increased LDH level in diabetic rats exhibited a significant reduction after treatment with R. nasutus. These results indicate that the administration of R. nasutus altered the activities of oxidative enzymes in a positive manner, indicating that R. nasutus improves mitochondrial energy production. Our data suggest that R. nasutus should be further explored for its role in the treatment of diabetes mellitus. PMID- 23662139 TI - Metabonomics Combined with UPLC-MS Chemical Profile for Discovery of Antidepressant Ingredients of a Traditional Chinese Medicines Formula, Chaihu-Shu Gan-San. AB - This study proposed a new strategy for uncovering the active chemical constituents of a traditional Chinese medicines (TCMs) formula, Chaihu-Shu-Gan San (CSGS). Metabonomics and chemical profile were integrated in combination with the multivariate statistical analysis (MVA) to discover the chemical constituents which contribute to the antidepressant effect of CSGS. Based upon the difference between CSGS and QZ (CSGS without Zhi-Qiao) extracts in the chemical profiles and the regulations of metabolic disturbances induced by CUMS, synephrine, naringin, hesperidin, and neohesperidin were recognized as the active constituents of CSGS from Zhi-qiao responsible for those missing regulations of CSGS when Zhi-Qiao was subtracted from the whole formula. They participated in the regulations of the deviated metabolites 2-4, 10-14, and 22-25, involved in metabolic pathways of ketone bodies synthesis, phenylalanine, tyrosine and tryptophan biosynthesis, valine, aspartate, glutamate metabolism, and glycolysis/gluconeogenesis. Furthermore, the assay of MAO-A activity confirmed the potential antidepressant effect of naringin and its active sites on the MAO-A was inferred by molecular docking study. The integration of metabonomics and chemical profile was proved to be a useful strategy for uncovering what the active chemical constituents in TCM formula are and how they make contributions for the efficacy of the formula. PMID- 23662140 TI - A Study of Tongue and Pulse Diagnosis in Traditional Korean Medicine for Stroke Patients Based on Quantification Theory Type II. AB - In traditional Korean medicine (TKM), pattern identification (PI) diagnosis is important for treating diseases. The aim of this study was to comprehensively investigate the relationship between the PI type and tongue diagnosis or pulse diagnosis variables. The study included 1,879 stroke patients who were admitted to 12 oriental medical university hospitals from June 2006 through March 2009. The status of the pulse and tongue was examined in each patient. Additionally, to investigate relatively important indicators related to specialist PI, the quantification theory type II analysis was performed regarding the PI type. In the first axis quantification of the external criteria, the Qi-deficiency and the Yin-deficiency patterns were located in the negative direction, while the dampness-phlegm (DP) and fire-heat patterns were located in the positive direction. The explanatory variable with the greatest impact on the assessment was a fine pulse. In the second axis quantification, the external criteria were divided into either the DP or non-DP patterns. The slippery pulse exhibited the greatest effect on the division. This study attempted to build a model using a statistical method to objectively quantify PI and various indicators that constitute the unique diagnosis system of TKM. These results should assist the development of future diagnostic standards in stroke PI. PMID- 23662141 TI - Expert consensus on the treatment of hypertension with chinese patent medicines. AB - Objectives. This study was aimed to determine the therapeutic principle and identify Chinese Patent Medicine (CPM) with corresponding indications for hypertension treatment. Methods. Three rounds of Delphi survey were mailed among 40 cardiovascular integrative medicine specialists. Items with agreement of more than 80% respondents were included in the consensus. Results. According to majority of the panelists, CPM is suitable for most hypertensive patients and should be used according to traditional Chinese medicine pattern classification. CPM could be used alone for grade 1 hypertension and could be used in combination with Western biomedicine (WM) for both grade 2 and grade 3 hypertension. It is recommended that less than two CPMs are used simultaneously. For the treatment of grade 2 and 3 hypertension, CPM and WM should be taken separately. Recommended CPMs included Tianma Gouteng granule, Qiju Dihuang capsule, Jinkui Shenqi pill, Yinxingye tablet, Niuhuang Jiangya pill and Banxia Tianma pill. The indications of 4 CPMs were specified with symptoms related to TCM pattern classification by the experts. Conclusions. An expert consensus on CMP application was formed for the treatment of hypertension in the form of integrative medicine. A flow of IM hypertension management was proposed based on the results of the survey. PMID- 23662142 TI - An Aqueous Extract of Radix Astragali, Angelica sinensis, and Panax notoginseng Is Effective in Preventing Diabetic Retinopathy. AB - Diabetic retinopathy (DR), in which inflammation has been implicated playing important roles, is one of the most common diabetes complications. Dang Gui Bu Xue Tang (DBT), an aqueous extract of Radix Astragali and Radix Angelica sinensis, is a classical prescription in Traditional Chinese Medicine for treating inflammation and ischemic diseases. Here, we investigated the effects of a modified recipe of DBT, with addition of Panax notoginseng, in treating diabetic retinopathy. An aqueous extract of Radix Astragali, Radix Angelica sinensis, and Panax notoginseng (RRP) was given to Goto-Kakizaki (GK) rats and streptozotocin-induced Sprague-Dawley (SD) rats. Leukostasis, vascular leakage, and acellular capillaries in retinal vasculature of animals were determined. Expression of retinal inflammatory biomarkers was assessed. We found that RRP reduced leukostasis, acellular capillaries, and vascular leakage compared to diabetic control rats. We also found that RRP decreased the expression of inflammatory factors including IL-1 beta , IL-6, TNF- alpha , NF- kappa B, MCP-1, ICAM-1, or VCAM-1 in the retinas of GK rats and reversed high glucose-induced inhibition of endothelial cell migration and proliferation in vitro. We conclude that RRP has a potent effect in preventing the pathogenesis and/or progression of DR and thus may serve as a promising nontoxic therapeutic approach of DR. PMID- 23662143 TI - In Vitro Antimicrobial Activity of Ethanolic Extract of Polish Propolis against Biofilm Forming Staphylococcus epidermidis Strains. AB - The aim of the presented study was to examine the antimicrobial activity of ethanol extract of Polish propolis (EEPP) against biofilm-forming CoNS strains in vitro. Our results revealed that EEPP displayed varying degrees of activity against CoNS with MIC values ranging from 1.56 to 0.78 mg/mL. The average MIC was 1.13 +/- 0.39 mg/mL while calculated MIC50 and MIC90 values were 0.78 mg/mL and 1.56 mg/mL, respectively. The biofilm formation ability by all tested S. epidermidis strains was inhibited at EEPP concentrations ranging from 0.39 to 1.56 mg/mL. The degree of reduction of AlamarBlue was directly associated with the proliferation of S. epidermidis strains. The increased proliferation of S. epidermidis strains was observed after 12 and 24 hours of incubation in the presence of EEPP concentrations ranging from 0.025 to 0.39 mg/mL. These results suggest that antimicrobial activities of EEPP against S. epidermidis expressed as the reduction of bacterial growth, reduction of biofilm formation ability, and the intensity of proliferation were significantly affected by incubation time and EEPP concentration used as well as the interactions between these factors. PMID- 23662144 TI - Electroacupuncture at Zusanli (ST36) Prevents Intestinal Barrier and Remote Organ Dysfunction following Gut Ischemia through Activating the Cholinergic Anti Inflammatory-Dependent Mechanism. AB - This study investigated the protective effect and mechanism of electroacupuncture at ST36 points on the intestinal barrier dysfunction and remote organ injury after intestinal ischemia and reperfusion injury in rats. Rats were subjected to gut ischemia for 30 min, and then received electroacupuncture for 30 min with or without abdominal vagotomy or intraperitoneal administration of cholinergic alpha 7 nicotinic acetylcholine receptor ( alpha 7nAChR) inhibitor. Then we compared its effects with electroacupuncture at nonchannel points, vagal nerve stimulation, or intraperitoneal administration of cholinergic agonist. Cytokine levels in plasma and tissue of intestine, lung, and liver were assessed 60 min after reperfusion. Intestinal barrier injury was detected by histology, gut injury score, the permeability to 4 kDa FITC-dextran, and changes in tight junction protein ZO-1 using immunofluorescence and Western blot. Electroacupuncture significantly lowered the levels of tumor necrosis factor- alpha and interleukin-8 in plasma and organ tissues, decreased intestinal permeability to FITC-dextran, and prevented changes in ZO-1 protein expression and localization. However, abdominal vagotomy or intraperitoneal administration of cholinergic alpha 7nAChR inhibitor reversed these effects of electroacupuncture. These findings suggest that electroacupuncture attenuates the systemic inflammatory response through protection of intestinal barrier integrity after intestinal ischemia injury in the presence of an intact vagus nerve. PMID- 23662145 TI - Carica papaya Leaves Juice Significantly Accelerates the Rate of Increase in Platelet Count among Patients with Dengue Fever and Dengue Haemorrhagic Fever. AB - The study was conducted to investigate the platelet increasing property of Carica papaya leaves juice (CPLJ) in patients with dengue fever (DF). An open labeled randomized controlled trial was carried out on 228 patients with DF and dengue haemorrhagic fever (DHF). Approximately half the patients received the juice, for 3 consecutive days while the others remained as controls and received the standard management. Their full blood count was monitored 8 hours for 48 hours. Gene expression studies were conducted on the ALOX 12 and PTAFR genes. The mean increase in platelet counts were compared in both groups using repeated measure ANCOVA. There was a significant increase in mean platelet count observed in the intervention group (P < 0.001) but not in the control group 40 hours since the first dose of CPLJ. Comparison of mean platelet count between intervention and control group showed that mean platelet count in intervention group was significantly higher than control group after 40 and 48 hours of admission (P < 0.01). The ALOX 12 (FC = 15.00) and PTAFR (FC = 13.42) genes were highly expressed among those on the juice. It was concluded that CPLJ does significantly increase the platelet count in patients with DF and DHF. PMID- 23662146 TI - Cytotoxic Activity of Six Samples of Brazilian Propolis on Sea Urchin (Lytechinus variegatus) Eggs. AB - The cytotoxic activities of extracts of four samples of propolis from the state of Minas Gerais (Southeast Brazil) and two from the state of Parana (South Brazil) were evaluated using sea urchin (Lytechinus variegatus) eggs. Cytotoxic activity was observed, characterized mainly by the inhibition of the first cleavage of newly fertilized eggs. Methanol extracts at 32 ug mL(-1) of all samples were highly active (97-100%). Extracts were also prepared by successive treatments of the samples with hexane, chloroform, ethyl acetate, and methanol. High activity was observed using the ethyl acetate fractions of all samples, but hexane and chloroform fractions of some samples also had high activity. Based on the chemical composition of the extracts and fractions (published previously), it is hypothesized that the cytotoxic activities observed are due mainly to artepillin C, p-coumaric acid, and kaempferide. The results suggest that caffeoylquinic acids have no cytotoxic activity in sea urchin eggs. PMID- 23662147 TI - Differentiating blood, lymph, and primo vessels by residual time characteristic of fluorescent nanoparticles in a tumor model. AB - Fluorescent nanoparticles (FNPs) which were injected into a tumor tissue flowed out through the blood and lymph vessels. The FNPs in blood vessels remained only in the order for few minutes while those in lymph vessels remained for a long time disappearing completely in 25 hours. We found a primo vessel inside a lymph vessel near a blood vessel, and FNPs remained in the primo vessel for longer than 25 hours. In addition, we examined in detail the residual time characteristics of lymph vessels because it could be useful in a future study of fluid dynamical comparison of the three conduits. These residual time characteristics of FNPs in the three kinds of vessels may have implications for the dynamics of nanoparticle drugs for cancer chemotherapy. PMID- 23662148 TI - Establishment and comparison of combining disease and syndrome model of asthma with "kidney yang deficiency" and "abnormal savda". AB - THE STUDY WAS THE FIRST TIME TO ESTABLISH AND COMPARE TWO RAT MODELS OF TWO COMMON SYNDROMES: Kidney Yang Deficiency syndrome (KYDS) in traditional Chinese medicine (TCM) and abnormal savda syndrome (ASS) in traditional Uighur medicine (TUM). Then, we also established and evaluated rat models of combining disease and syndrome models of asthma with KYDS or ASS. Results showed that usage of the high dose of corticosterone (CORT) injection or external factors could successfully establish the KYDS or ASS rat models, and the two models had similar changes in biological characterization, abnormal behaviors, dysfunction of hypothalamic-pituitary-target organ axes (HPTOA), and sympathetic/parasympathetic (S/P) nerve system but varied in different degrees. The rat models of combining disease and syndrome of asthma with KYDS or ASS had either pathological characteristics of asthma such as airway hyperresponsiveness (AHR), airway inflammation, airway remodeling, which were more serious than allergy exposure alone, or the syndrome performance of Kidney Yang Deficiency in TCM and abnormal savda in TUM. These findings provide a biological rationale for further investigation of combining disease and syndrome model of asthma as an effective animal model for exploring asthma based on the theory of traditional medicine. PMID- 23662149 TI - Hyperthermia versus Oncothermia: Cellular Effects in Complementary Cancer Therapy. AB - Hyperthermia means overheating of the living object completely or partly. Hyperthermia, the procedure of raising the temperature of a part of or the whole body above normal for a defined period of time, is applied alone or as an adjunctive with various established cancer treatment modalities such as radiotherapy and chemotherapy. However, hyperthermia is not generally accepted as conventional therapy. The problem is its controversial performance. The controversy is originated from the complications of the deep heating and the focusing of the heat effect. The idea of oncothermia solves the selective deep action on nearly cellular resolution. We would like to demonstrate the force and perspectives of oncothermia, as a highly specialized hyperthermia in clinical oncology. Our aim is to prove the ability of oncothermia to be a candidate to become a widely accepted modality of the standard cancer care. We would like to show the proofs and the challenges of the hyperthermia and oncothermia applications to provide the presently available data and summarize the knowledge in the topic. Like many early stage therapies, oncothermia lacks adequate treatment experience and long-range, comprehensive statistics that can help us optimize its use for all indications. PMID- 23662150 TI - Study of the Interference between Plectranthus Species Essential Oils from Brazil and Aminoglycosides. AB - Plectranthus is one of the most representative genera of Lamiaceae family. In this study, the essential oils from Plectranthus amboinicus, Plectranthus ornatus, and Plectranthus barbatus were investigated for their chemical composition and antimicrobial and modulatory activities. The major components found were carvacrol (54.4%-P. amboinicus) and eugenol (22.9%-P. ornatus e 25.1% P. barbatus). In vitro antimicrobial activity was conducted against Escherichia coli, Proteus vulgaris, Bacillus cereus, Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus aureus (multiresistant) using microdilution method. The results of bioassay showed that all strains were sensitive to the oils, except P. aeruginosa that was resistant to P. amboinicus and P. ornatus. A synergistic effect of all essential oils combined with the aminoglycosides was demonstrated. These results show that P. amboinicus, P. ornatus, and P. barbatus inhibit the growth of pathogenic microorganism, and besides this they present antibiotic modifying activity, providing a new perspective against the problem of bacterial resistance to antibiotics. PMID- 23662151 TI - The effect of aromatherapy abdominal massage on alleviating menstrual pain in nursing students: a prospective randomized cross-over study. AB - Dysmenorrhea is a common cause of sickness absenteeism from both classes and work. This study investigated the effect of aromatherapy massage on a group of nursing students who are suffering of primary dysmenorrhea. A randomized blind clinical trial of crossover design was used. In the first treatment phase, group 1 (n = 48) received aromatherapy abdominal massage once daily for seven days prior to menstruation using the essential oils (cinnamon, clove, rose, and lavender in a base of almond oil). Group 2 (n = 47) received the same intervention but with placebo oil (almond oil). In the second treatment phase, the two groups switched to alternate regimen. Level and duration of pain and the amount of menstrual bleeding were evaluated at the baseline and after each treatment phase. During both treatment phases, the level and duration of menstrual pain and the amount of menstrual bleeding were significantly lower in the aromatherapy group than in the placebo group. These results suggests that aromatherapy is effective in alleviating menstrual pain, its duration and excessive menstrual bleeding. Aromatherapy can be provided as a nonpharmacological pain relief measure and as a part of nursing care given to girls suffering of dysmenorrhea, or excessive menstrual bleeding. PMID- 23662152 TI - Salvianolic Acid B prevents arsenic trioxide-induced cardiotoxicity in vivo and enhances its anticancer activity in vitro. AB - Clinical attempts to reduce the cardiotoxicity of arsenic trioxide (ATO) without compromising its anticancer activities remain to be an unresolved issue. In this study, we determined whether Sal B can protect against ATO-induced cardiac toxicity in vivo and increase the toxicity of ATO toward cancer cells. Combination treatment of Sal B and ATO was investigated using BALB/c mice and human hepatoma (HepG2) cells and human cervical cancer (HeLa) cells. The results showed that the combination treatment significantly improved the ATO-induced loss of cardiac function, attenuated damage of cardiomyocytic structure, and suppressed the ATO-induced release of cardiac enzymes into serum in BALB/c mouse models. The expression levels of Bcl-2 and p-Akt in the mice treated with ATO alone were reduced, whereas those in the mice given the combination treatment were similar to those in the control mice. Moreover, the combination treatment significantly enhanced the ATO-induced cytotoxicity and apoptosis of HepG2 cells and HeLa cells. Increases in apoptotic marker cleaved poly (ADP-ribose) polymerase and decreases in procaspase-3 expressions were observed through western blot. Taken together, these observations indicate that the combination treatment of Sal B and ATO is potentially applicable for treating cancer with reduced cardiotoxic side effects. PMID- 23662153 TI - A new type of biphasic calcium phosphate cement as a gentamicin carrier for osteomyelitis. AB - Osteomyelitis therapy is a long-term and inconvenient procedure for a patient. Antibiotic-loaded bone cements are both a complementary and alternative treatment option to intravenous antibiotic therapy for the treatment of osteomyelitis. In the current study, the biphasic calcium phosphate cement (CPC), called alpha TCP/HAP ( alpha -tricalcium phosphate/hydroxyapatite) biphasic cement, was prepared as an antibiotics carrier for osteomyelitis. The developed biphasic cement with a microstructure of alpha -TCP surrounding the HAP has a fast setting time which will fulfill the clinical demand. The X-ray diffraction and Fourier transform infrared spectrometry analyses showed the final phase to be HAP, the basic bone mineral, after setting for a period of time. Scanning electron microscopy revealed a porous structure with particle sizes of a few micrometers. The addition of gentamicin in alpha -TCP/HAP would delay the transition of alpha TCP but would not change the final-phase HAP. The gentamicin-loaded alpha TCP/HAP supplies high doses of the antibiotic during the initial 24 hours when they are soaked in phosphate buffer solution (PBS). Thereafter, a slower drug release is produced, supplying minimum inhibitory concentration until the end of the experiment (30 days). Studies of growth inhibition of Staphylococcus aureus and Pseudomonas aeruginosa in culture indicated that gentamicin released after 30 days from alpha -TCP/HAP biphasic cement retained antibacterial activity. PMID- 23662154 TI - Pomegranate supplementation improves affective and motor behavior in mice after radiation exposure. AB - Currently, NASA has plans for extended space travel, and previous research indicates that space radiation can have negative effects on cognitive skills as well as physical and mental health. With long-term space travel, astronauts will be exposed to greater radiation levels. Research shows that an antioxidant enriched diet may offer some protection against the cellular effects of radiation and may provide significant neuroprotection from the effects of radiation-induced cognitive and behavioral skill deficits. Ninety-six C57BL/6 mice (48 pomegranate fed and 48 control) were irradiated with proton radiation (2 Gy), and two-month postradiation behaviors were assessed using a battery of behavioral tests to measure cognitive and motor functions. Proton irradiation was associated with depression-like behaviors in the tail suspension test, but this effect was ameliorated by the pomegranate diet. Males, in general, displayed worse coordination and balance than females on the rotarod task, and the pomegranate diet ameliorated this effect. Overall, it appears that proton irradiation, which may be encountered in space, may induce a different pattern of behavioral deficits in males than females and that a pomegranate diet may confer protection against some of those effects. PMID- 23662155 TI - Significance of Kampo, Japanese traditional medicine, in the treatment of obesity: basic and clinical evidence. AB - The cause of obesity includes genetic and environmental factors, including cytokines derived from adipocytes (adipo-cytokines). Although drug therapy is available for obesity, it is highly risky. Our main focus in this review is on the traditional form of Japanese medicine, Kampo, in the treated of obesity. Two Kampo formulas, that is, bofutsushosan () and boiogito (), are covered by the national health insurance in Japan for the treatment of obesity. Various issues related to their action mechanisms remain unsolved. Considering these, we described the results of basic experiments and presented clinical evidence and case reports on osteoarthritis as examples of clinical application of their two Kampo medicine. Traditional medicine is used not only for treatment but also for prevention. In clinical practice, it is of great importance to prove the efficacy of combinations of traditional medicine and Western medicine and the utility of traditional medicine in the attenuation of adverse effects of Western medicine. PMID- 23662156 TI - Noninvasive characterisation of foot reflexology areas by swept source-optical coherence tomography in patients with low back pain. AB - Objective. When exploring the scientific basis of reflexology techniques, elucidation of the surface and subsurface features of reflexology areas (RAs) is crucial. In this study, the subcutaneous features of RAs related to the lumbar vertebrae were evaluated by swept source-optical coherence tomography (SS-OCT) in subjects with and without low back pain (LBP). Methods. Volunteers without LBP (n = 6 (male : female = 1 : 1)) and subjects with LBP (n = 15 (male : female = 2 : 3)) were clinically examined in terms of skin colour (visual perception), localised tenderness (visual analogue scale) and structural as well as optical attributes as per SS-OCT. From each subject, 6 optical tomograms were recorded from equidistant transverse planes along the longitudinal axis of the RAs, and from each tomogram, 25 different spatial locations were considered for recording SS-OCT image attributes. The images were analysed with respect to the optical intensity distributions and thicknesses of different skin layers by using AxioVision Rel. 4.8.2 software. The SS-OCT images could be categorised into 4 pathological grades (i.e., 0, 1, 2, and 3) according to distinctness in the visible skin layers. Results. Three specific grades for abnormalities in SS-OCT images were identified considering gradual loss of distinctness and increase in luminosity of skin layers. Almost 90.05% subjects were of mixed type having predominance in certain grades. Conclusion. The skin SS-OCT system demonstrated a definite association of the surface features of healthy/unhealthy RAs with cutaneous features and the clinical status of the lumbar vertebrae. PMID- 23662157 TI - Viral hepatitis in resource-limited countries and access to antiviral therapies: current and future challenges. AB - Chronic viral hepatitis is a major public health issue worldwide and mostly affects resource-limited countries. These regions combine a considerable set of barriers to containing the epidemic, including shortage of healthcare workers, poor medical infrastructures, insufficient screening and poor access to care and treatment. At a time when morbidity and mortality of chronic liver disease has been widely improved in wealthy countries by new innovative strategies and potent antiviral drugs, it is now urgent to face the challenges of better management of chronic hepatitis in resource-poor countries from the perspectives of global health and social justice. PMID- 23662158 TI - Simulation of intra-aneurysmal blood flow by different numerical methods. AB - The occlusional performance of sole endoluminal stenting of intracranial aneurysms is controversially discussed in the literature. Simulation of blood flow has been studied to shed light on possible causal attributions. The outcome, however, largely depends on the numerical method and various free parameters. The present study is therefore conducted to find ways to define parameters and efficiently explore the huge parameter space with finite element methods (FEMs) and lattice Boltzmann methods (LBMs). The goal is to identify both the impact of different parameters on the results of computational fluid dynamics (CFD) and their advantages and disadvantages. CFD is applied to assess flow and aneurysmal vorticity in 2D and 3D models. To assess and compare initial simulation results, simplified 2D and 3D models based on key features of real geometries and medical expert knowledge were used. A result obtained from this analysis indicates that a combined use of the different numerical methods, LBM for fast exploration and FEM for a more in-depth look, may result in a better understanding of blood flow and may also lead to more accurate information about factors that influence conditions for stenting of intracranial aneurysms. PMID- 23662160 TI - Encoding scratch and scrape features for wear modeling of total joint replacements. AB - Damage to hard bearing surfaces of total joint replacement components typically includes both thin discrete scratches and broader areas of more diffuse scraping. Traditional surface metrology parameters such as average roughness (R a) or peak asperity height (R p) are not well suited to quantifying those counterface damage features in a manner allowing their incorporation into models predictive of polyethylene wear. A diffused lighting technique, which had been previously developed to visualize these microscopic damage features on a global implant level, also allows damaged regions to be automatically segmented. These global level segmentations in turn provide a basis for performing high-resolution optical profilometry (OP) areal scans, to quantify the microscopic-level damage features. Algorithms are here reported by means of which those imaged damage features can be encoded for input into finite element (FE) wear simulations. A series of retrieved clinically failed implant femoral heads analyzed in this manner exhibited a wide range of numbers and severity of damage features. Illustrative results from corresponding polyethylene wear computations are also presented. PMID- 23662159 TI - Exploratory bioinformatics study of lncRNAs in Alzheimer's disease mRNA sequences with application to drug development. AB - Long noncoding RNA (lncRNA) within mRNA sequences of Alzheimer's disease genes, namely, APP, APOE, PSEN1, and PSEN2, has been analyzed using fractal dimension (FD) computation and correlation analysis. We examined lncRNA by comparing mRNA FD to corresponding coding DNA sequences (CDSs) FD. APP, APOE, and PSEN1 CDSs select slightly higher FDs compared to the mRNA, while PSEN2 CDSs FDs are lower. The correlation coefficient for these sequences is 0.969. A comparative study of differentially expressed MAPK signaling pathway lncRNAs in pancreatic cancer cells shows a correlation of 0.771. Selection of higher FD CDSs could indicate interaction of Alzheimer's gene products APP, APOE, and PSEN1. Including hypocretin sequences (where all CDSs have higher fractal dimensions than mRNA) in the APP, APOE, and PSEN1 sequence analyses improves correlation, but the inclusion of erythropoietin (where all CDSs have higher FD than mRNA) would suppress correlation, suggesting that HCRT, a hypothalamus neurotransmitter related to the wake/sleep cycle, might be better when compared to EPO, a glycoprotein hormone, for targeting Alzheimer's disease drug development. Fractal dimension and entropy correlation have provided supporting evidence, consistent with evolutionary studies, for using a zebrafish model together with a mouse model, in HCRT drug development. PMID- 23662161 TI - Structural complexity of DNA sequence. AB - In modern bioinformatics, finding an efficient way to allocate sequence fragments with biological functions is an important issue. This paper presents a structural approach based on context-free grammars extracted from original DNA or protein sequences. This approach is radically different from all those statistical methods. Furthermore, this approach is compared with a topological entropy-based method for consistency and difference of the complexity results. PMID- 23662162 TI - Examining similarity structure: multidimensional scaling and related approaches in neuroimaging. AB - This paper covers similarity analyses, a subset of multivariate pattern analysis techniques that are based on similarity spaces defined by multivariate patterns. These techniques offer several advantages and complement other methods for brain data analyses, as they allow for comparison of representational structure across individuals, brain regions, and data acquisition methods. Particular attention is paid to multidimensional scaling and related approaches that yield spatial representations or provide methods for characterizing individual differences. We highlight unique contributions of these methods by reviewing recent applications to functional magnetic resonance imaging data and emphasize areas of caution in applying and interpreting similarity analysis methods. PMID- 23662163 TI - Multiple suboptimal solutions for prediction rules in gene expression data. AB - This paper discusses mathematical and statistical aspects in analysis methods applied to microarray gene expressions. We focus on pattern recognition to extract informative features embedded in the data for prediction of phenotypes. It has been pointed out that there are severely difficult problems due to the unbalance in the number of observed genes compared with the number of observed subjects. We make a reanalysis of microarray gene expression published data to detect many other gene sets with almost the same performance. We conclude in the current stage that it is not possible to extract only informative genes with high performance in the all observed genes. We investigate the reason why this difficulty still exists even though there are actively proposed analysis methods and learning algorithms in statistical machine learning approaches. We focus on the mutual coherence or the absolute value of the Pearson correlations between two genes and describe the distributions of the correlation for the selected set of genes and the total set. We show that the problem of finding informative genes in high dimensional data is ill-posed and that the difficulty is closely related with the mutual coherence. PMID- 23662164 TI - Retinal image graph-cut segmentation algorithm using multiscale Hessian enhancement-based nonlocal mean filter. AB - We propose a new method to enhance and extract the retinal vessels. First, we employ a multiscale Hessian-based filter to compute the maximum response of vessel likeness function for each pixel. By this step, blood vessels of different widths are significantly enhanced. Then, we adopt a nonlocal mean filter to suppress the noise of enhanced image and maintain the vessel information at the same time. After that, a radial gradient symmetry transformation is adopted to suppress the nonvessel structures. Finally, an accurate graph-cut segmentation step is performed using the result of previous symmetry transformation as an initial. We test the proposed approach on the publicly available databases: DRIVE. The experimental results show that our method is quite effective. PMID- 23662166 TI - Nudging best practice: the HITECH act and behavioral medicine. AB - In February 2009, the US Congress passed the Health Information Technology for Economic and Consumer Health (HITECH) Act in order to stimulate the "meaningful use" of health information technology within medical practice. Economists have noted that other sectors in the economy have demonstrated substantive productivity improvements from investments in information technology but that the health sector lags behind. The "meaningful use" stipulation of the HITECH Act focuses systems redesign within the health sector on user's behavior, a provision that opens a window of contribution from specialists in behavioral medicine. There are several ways for behavioral medicine to become involved in the redesign. One is to help craft a health services environment that optimizes communication between providers and patients, between primary care and specialist care providers, and between patients and their caregivers. Another is to help practitioners and policy-makers create new "decisional architectures" for "nudging" behavior in positive ways through better incentives, understandable instructions, healthy defaults, instructive feedback, back-ups for error, and structured decision-making. New funding opportunities in research, implementation, and training may facilitate the involvement of behavioral medicine-an involvement that is crucial for ensuring the success of reform efforts in the long run. PMID- 23662167 TI - Molecular Electronic Coupling Controls Charge Recombination Kinetics in Organic Solar Cells of Low Bandgap Diketopyrrolopyrrole, Carbazole, and Thiophene Polymers. AB - Low-bandgap diketopyrrolopyrrole- and carbazole-based polymer bulk-heterojunction solar cells exhibit much faster charge carrier recombination kinetics than that encountered for less-recombining poly(3-hexylthiophene). Solar cells comprising these polymers exhibit energy losses caused by carrier recombination of approximately 100 mV, expressed as reduction in open-circuit voltage, and consequently photovoltaic conversion efficiency lowers in more than 20%. The analysis presented here unravels the origin of that energy loss by connecting the limiting mechanism governing recombination dynamics to the electronic coupling occurring at the donor polymer and acceptor fullerene interfaces. Previous approaches correlate carrier transport properties and recombination kinetics by means of Langevin-like mechanisms. However, neither carrier mobility nor polymer ionization energy helps understanding the variation of the recombination coefficient among the studied polymers. In the framework of the charge transfer Marcus theory, it is proposed that recombination time scale is linked with charge transfer molecular mechanisms at the polymer/fullerene interfaces. As expected for efficient organic solar cells, small electronic coupling existing between donor polymers and acceptor fullerene (Vif < 1 meV) and large reorganization energy (lambda ~ 0.7 eV) are encountered. Differences in the electronic coupling among polymer/fullerene blends suffice to explain the slowest recombination exhibited by poly(3-hexylthiophene)-based solar cells. Our approach reveals how to directly connect photovoltaic parameters as open-circuit voltage to molecular properties of blended materials. PMID- 23662165 TI - Breast cancer brain metastases: new directions in systemic therapy. AB - The management of patients with brain metastases from breast cancer continues to be a major clinical challenge. The standard initial therapeutic approach depends upon the size, location, and number of metastatic lesions and includes consideration of surgical resection, whole-brain radiotherapy, and stereotactic radiosurgery. As systemic therapies for control of extracranial disease improve, patients are surviving long enough to experience subsequent progression events in the brain. Therefore, there is an increasing need to identify both more effective initial treatments as well as to develop multiple lines of salvage treatments for patients with breast cancer brain metastases. This review summarises the clinical experience to date with respect to cytotoxic and targeted systemic therapies for the treatment of brain metastases, highlights ongoing and planned trials of novel approaches and identifies potential targets for future investigation. PMID- 23662168 TI - Mononuclear nickel(II)-superoxo and nickel(III)-peroxo complexes bearing a common macrocyclic TMC ligand. AB - Mononuclear metal-dioxygen adducts, such as metal-superoxo and -peroxo species, are generated as key intermediates in the catalytic cycles of dioxygen activation by heme and non-heme metalloenzymes. We have shown recently that the geometric and electronic structure of the Ni-O2 core in [Ni(n-TMC)(O2)]+ (n = 12 and 14) varies depending on the ring size of the supporting TMC ligand. In this study, mononuclear Ni(II)-superoxo and Ni(III)-peroxo complexes bearing a common macrocylic 13-TMC ligand, such as [NiII(13-TMC)(O2)]+ and [NiIII(13-TMC)(O2)]+, were synthesized in the reaction of [NiII(13-TMC)(CH3CN)]2+ and H2O2 in the presence of tetramethylammonium hydroxide (TMAH) and triethylamine (TEA), respectively. The Ni(II)-superoxo and Ni(III)-peroxo complexes bearing the common 13-TMC ligand were successfully characterized by various spectroscopic methods, X ray crystallography, and DFT calculations. Based on the combined experimental and theoretical studies, we conclude that the superoxo ligand in [NiII(13-TMC)(O2)]+ is bound in an end-on fashion to the nickel(II) center, whereas the peroxo ligand in [NiIII(13-TMC)(O2)]+ is bound in a side-on fashion to the nickel(III) center. Reactivity studies performed with the Ni(II)-superoxo and Ni(III)-peroxo complexes toward organic substrates reveal that the former possesses an electrophilic character, whereas the latter is an active oxidant in nucleophilic reaction. PMID- 23662169 TI - Readership: The heart of Pulmonary Circulation. PMID- 23662170 TI - Spread the word, children are still not "small adults". PMID- 23662171 TI - Pulmonary heart disease: The heart-lung interaction and its impact on patient phenotypes. AB - Pulmonary heart disease (PHD) refers to altered structure or function of the right ventricle occurring in association with abnormal respiratory function. Although nearly always associated with some degree of PH, the degree, nature, severity, and causality of PH in relation to the PHD is not necessarily linear and direct. Abnormal gas exchange is a fundamental underpinning of PHD, affecting pulmonary vascular, cardiac, renal, and neurohormonal systems. Direct and indirect effects of chronic respiratory disease can disrupt the right ventricular pulmonary arterial (RV-PA) interaction and, likewise, factors such as sympathetic nervous system activation, altered blood viscosity, and salt and water retention can function in a feedback loop to further influence RV-PA function. Left heart function may also be affected, especially in those with pre-existing left heart disease. Thus, the physiologic interactions between abnormal respiratory and cardiovascular function are complex, with PHD representing a heterogeneous end organ effect of an integrated multisystem process. In this review, we propose to separate PHD into two distinct entities, "Type I" and "Type II" PHD. Type I PHD is most common, and refers to subjects with chronic respiratory disease (CRD) where the perturbations in respiratory function dominate over more mild cardiac and circulatory disruptions. In contrast, Type II PHD refers to the smaller subset of patients with more severe pulmonary vascular and right heart dysfunction, whom often present in a fashion similar to patients with PAH. Phenotypic differences are not made by PA pressure alone, but instead by differences in the overall physiology and clinical syndrome. Thus, key differences can be seen in symptomatology, physical signs, cardiac imaging, hemodynamics, and the cardiovascular and gas exchange responses to exercise. Such key baseline differences in the overall physiologic phenotype are likely critical to predicting response to PH specific therapy. Recognizing PHD as distinct phenotypes assists in the necessary distinction of these patients, and may also provide a key clinical and pathophysiologic framework for improved patient selection for future studies investigating the role of pulmonary hypertension specific therapies in PHD. PMID- 23662172 TI - Nitric oxide deficiency in pulmonary hypertension: Pathobiology and implications for therapy. AB - Nitric oxide (NO) is a diffusible gas with diverse roles in human physiology and disease. Significant progress in the understanding of its biological effects has taken place in recent years. This has led to a better understanding of the pathobiology of pulmonary hypertension (PH) and the development of new therapies. This article provides an overview of the NO physiology and its role in the pathobiology of lung diseases, particularly PH. We also discuss current and emerging specific treatments that target NO signaling pathways in PH. PMID- 23662174 TI - Vascular histomolecular analysis by sequential endoarterial biopsy in a shunt model of pulmonary hypertension. AB - The molecular mechanisms of pulmonary arterial hypertension (PAH) remain ill defined. The aims of this study were to obtain sequential endoarterial biopsy samples in a surgical porcine model of PAH and assess changes in histology and mRNA expression during the disease progression. Differentially expressed genes were then analyzed as potential pharmacological targets. Four Yucatan micro-pigs underwent surgical anastomosis of the left pulmonary artery to the descending aorta. Endovascular samples were obtained with a biopsy catheter at baseline (before surgery) and from the left lung 7, 60, and 180 days after surgery. RNA was isolated from biopsy samples, amplified and analyzed. Dysregulated genes were linked to drugs with potential to treat or prevent PAH. With the development of PAH in our model, we identified changes in histology and in the expression of several genes with known or investigational inhibitors and several novel genes for PAH. Gene dysregulation displayed time-related variations during disease progression. Endoarterial biopsy provides a new method of assessing pulmonary vascular histology and gene expression in PAH. This analysis could identify novel applications for existing and new PAH drugs. The detection of stage- and disease specific variation in gene expression could lead to individualized therapies. PMID- 23662173 TI - Dysfunctional resident lung mesenchymal stem cells contribute to pulmonary microvascular remodeling. AB - Pulmonary vascular remodeling and oxidative stress are common to many adult lung diseases. However, little is known about the relevance of lung mesenchymal stem cells (MSCs) in these processes. We tested the hypothesis that dysfunctional lung MSCs directly participate in remodeling of the microcirculation. We employed a genetic model to deplete extracellular superoxide dismutase (EC-SOD) in lung MSCs coupled with lineage tracing analysis. We crossed (floxp)sod3 and mT/mG reporter mice to a strain expressing Cre recombinase under the control of the ABCG2 promoter. We demonstrated In vivo that depletion of EC-SOD in lung MSCs resulted in their contribution to microvascular remodeling in the smooth muscle actin positive layer. We further characterized lung MSCs to be multipotent vascular precursors, capable of myofibroblast, endothelial and pericyte differentiation in vitro. EC-SOD deficiency in cultured lung MSCs accelerated proliferation and apoptosis, restricted colony-forming ability, multilineage differentiation potential and promoted the transition to a contractile phenotype. Further studies correlated cell dysfunction to alterations in canonical Wnt/beta-catenin signaling, which were more evident under conditions of oxidative stress. Our data establish that lung MSCs are a multipotent vascular precursor population, a population which has the capacity to participate in vascular remodeling and their function is likely regulated in part by the Wnt/beta-catenin signaling pathway. These studies highlight an important role for microenviromental regulation of multipotent MSC function as well as their potential to contribute to tissue remodeling. PMID- 23662175 TI - Human immunodeficiency virus-1 transgene expression increases pulmonary vascular resistance and exacerbates hypoxia-induced pulmonary hypertension development. AB - Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary arterial resistance and vessel remodeling. Patients living with human immunodeficiency virus-1 (HIV-1) have an increased susceptibility to develop severe pulmonary hypertension (PH) irrespective of their CD4+ lymphocyte counts. While the underlying cause of HIV-PAH remains unknown, the interaction of HIV-1 proteins with the vascular endothelium may play a critical role in HIV-PAH development. Hypoxia promotes PH in experimental models and in humans, but the impact of HIV-1 proteins on hypoxia-induced pulmonary vascular dysfunction and PAH has not been examined. Therefore, we hypothesize that the presence of HIV-1 proteins and hypoxia synergistically augment the development of pulmonary vascular dysfunction and PH. We examined the effect of HIV-1 proteins on pulmonary vascular resistance by measuring pressure-volume relationships in isolated lungs from wild-type (WT) and HIV-1 Transgenic (Tg) rats. WT and HIV-1 Tg rats were exposed to 10% O2 for four weeks to induce experimental pulmonary hypertension to assess whether HIV-1 protein expression would impact the development of hypoxia-induced PH. Our results demonstrate that HIV-1 protein expression significantly increased pulmonary vascular resistance (PVR). HIV-1 Tg mice demonstrated exaggerated pulmonary vascular responses to hypoxia as evidenced by greater increases in right ventricular systolic pressures, right ventricular hypertrophy and vessel muscularization when compared to wild-type controls. This enhanced PH was associated with enhanced expression of HIF-1alpha and PCNA. In addition, in vitro studies reveal that medium from HIV-infected monocyte derived macrophages (MDM) potentiates hypoxia-induced pulmonary artery endothelial proliferation. These results indicate that the presence of HIV-1 proteins likely impact pulmonary vascular resistance and exacerbate hypoxia induced PH. PMID- 23662176 TI - Comparison of acute hemodynamic effects of inhaled nitric oxide and inhaled epoprostenol in patients with pulmonary hypertension. AB - Inhaled nitric oxide (iNO) is used for acute vasoreactivity testing in pulmonary arterial hypertension (PAH) patients. Inhaled epoprostenol (iPGI2) has pulmonary selectivity and is less costly. We sought to compare acute hemodynamic effects of iNO (20 ppm) and iPGI2 (50 ng/kg/min) and determine whether their combination has additive effects. We conducted a prospective, single center, randomized, cross over study in 12 patients with PAH and seven with heart failure with preserved ejection fraction (HFpEF). In PAH patients, iNO lowered mean pulmonary artery pressure (mPAP) by 9 +/- 12% and pulmonary vascular resistance (PVR) by 14 +/- 32% (mean +/- SD). iPGI2 decreased mPAP by 10 +/- 12% and PVR by 12 +/- 36%. Responses to iNO and iPGI2 in mPAP and PVR were directly correlated (r(2) = 0.68, 0.70, respectively, P < 0.001). In HFpEF patients, mPAP dropped by 4 +/- 7% with each agent, and PVR dropped by 33 +/- 23% with iNO, and by 25 +/- 29% with iPGI2 (P = NS). Pulmonary artery wedge pressure (PAWP) increased significantly with iPGI2 versus baseline (20 +/- 3 vs. 17 +/- 2 mmHg, P = 0.02) and trended toward an increase with iNO and the combination (20 +/- 2, 19 +/- 4 mmHg, respectively). There were no additive effects in either group. In PAH patients, the vasodilator effects of iNO and iPGI2 correlated at the doses used, making iPGI2 a possible alternative for testing acute vasoreactivity, but their combination lacks additive effect. Exposure of HFpEF patients to inhaled vasodilators worsens the PAWP without hemodynamic benefit. PMID- 23662177 TI - Pim-1: A new biomarker in pulmonary arterial hypertension. AB - Provirus integration site for Moloney murine leukemia virus (Pim-1) is an oncoprotein overexpressed in lungs from pulmonary arterial hypertension (PAH) patients and involved in cell proliferation via the activation of the NFAT/STAT3 signaling pathway. We hypothesized that Pim-1 plasma levels would predict the presence of PAH and correlate with disease severity. Pim-1 plasma levels were measured at the time of catheterization in 49 PAH patients, including nonvasoreactive ( n = 19) and vasoreactive idiopathic PAH (n = 5), and PAH related to connective tissue disease (n = 16) and congenital heart disease (n = 9). Fifty controls were also recruited. The capacity of Pim-1 to discriminate PAH from controls and its association with disease severity were assessed. Pim-1 plasma levels were higher in PAH than in controls (9.6 +/- 4.0 vs. 7.2 +/- 2.4 ng/mL, P < 0.01). Pim-1 appropriately discriminated proliferative PAH from controls (AUC = 0.78 to 0.94 using ROC curves). Among PAH patients, Pim-1 correlated with traditional markers of PAH severity. The 1-year survival was 97% and 47% for PAH patients with baseline Pim-1 levels lower and higher than 11.1 ng/mL, respectively (HR 11.4 (3.3-39.7); P < 0.01). After adjustment for hemodynamic and biochemical variables, Pim-1 levels remained an independent predictor of mortality (P < 0.01). Pim-1 is a promising new biomarker in PAH. PMID- 23662179 TI - Time from symptoms to definitive diagnosis of idiopathic pulmonary arterial hypertension: The delay study. AB - Survival rates for patients with idiopathic pulmonary arterial hypertension (IPAH) have improved with the introduction of PAH-specific therapies. However, the time between patient-reported onset of symptoms and a definitive diagnosis of IPAH is consistently delayed. We conducted a retrospective, multi-center, descriptive investigation in order to (a) understand what factors contribute to persistent diagnostic delays, and (b) examine the time from initial symptom onset to a definitive diagnosis of IPAH. Between January 2007 and December 2008, we enrolled consecutively diagnosed adults with IPAH from four tertiary referral centers in Australia. Screening of patient records and "one-on-one" interviews were used to determine the time from patient-described initial symptoms to a diagnosis of IPAH, confirmed by right heart catheterization (RHC). Thirty-two participants (69% female) were studied. Mean age at symptom onset was 56 +/- 16.4 years and 96% reported exertional dyspnea. Mean time from symptom onset to diagnosis was 47 +/- 34 months with patients subsequently aged 60 +/- 17.3 years. Patients reported 5.3 +/- 3.8 GP visits and 3.0 +/- 2.1 specialist reviews before being seen at a pulmonary hypertension (PH) center. Advanced age, number of general practitioner (GP) visits, heart rate, and systolic blood pressure at the time of diagnosis were significantly associated with the observed delay. We found a significant delay of 3.9 years from symptom onset to a diagnosis of IPAH in Australia. Exertional dyspnea is the most common presenting symptom. Current practice within Australia does not appear to have the specific capacity for timely, multi-factorial evaluation of breathlessness and potential IPAH. PMID- 23662178 TI - Differences between basal lung levels of select eicosanoids in rat and mouse. AB - Metabolites of arachidonic acid play an important role in mediating inflammation, cell proliferation, and oxidative stress that contribute to many pulmonary diseases. We hypothesized that the substantial differences between rats and mice in their responses to experimental pulmonary hypertensive stimuli would be associated with parallel differences in their basal eicosanoid profile. Rat and mouse lung extracts were subjected to liquid chromatography tandem mass spectrometry that was optimized for simultaneous separation and rapid quantification of the major hydroxyeicosatetraenoic acids (HETEs) and prostaglandins (PGs). Basal levels (pg/MUg protein) of arachidonic acid metabolites differed significantly between rat and mouse lungs. Median values of the following major eicosanoids were significantly higher in mouse than in rat lungs: 5-HETE, 8-HETE, 12-HETE, 15-HETE, PGE2, and PGI2, as well as isoprostane E2 and -F2alpha. In addition, the PGI2/TXB2 ratio was increased in mouse relative to rat lungs. On the basis of the important roles that these compounds play in determining pulmonary vascular tone, the differences in select eicosanoid profiles, especially the PGI2/TXB2 ratio, between rat and mouse lungs may underlie the interspecies differences in susceptibility to the development of pulmonary hypertension. PMID- 23662180 TI - Mechanical forces stimulate endothelial microparticle generation via caspase dependent apoptosis-independent mechanism. AB - Microparticle release by vascular endothelium has been implicated in various cardiovascular pathologies. Ventilator-induced lung injury (VILI) is a life threatening complication of mechanical ventilation at high tidal volumes associated with excessive mechanical stretch of pulmonary vascular endothelial cells. However, a role of VILI-relevant levels of cyclic stretch in microparticle generation by vascular endothelium remains unknown. We report microparticle formation by human pulmonary endothelial cells exposed to pathologic, but not physiologic, levels of mechanical stress. Stretch-induced microparticle generation was not affected by cell co-treatment with inflammatory agents thrombin or bacterial wall lipopolysacharide. Neither the basal nor the pathologic cyclic stretch-induced microparticle production was affected by Rho kinase and calpain inhibitors, but were instead abolished by caspase inhibitor. In contrast to lipopolysacharide, pathologic mechanical strain did not significantly induce apoptosis in pulmonary endothelial cells. These results show for the first time that mechanical strain of pulmonary endothelial cells at levels relevant to high tidal volume mechanical ventilation is a potent activator of microparticle formation, which requires caspase activity; however, this mechanism is independent of apoptosis. These results suggest a novel mechanism that may contribute to VILI-associated vascular dysfunction. PMID- 23662181 TI - Supplementation of iron in pulmonary hypertension: Rationale and design of a phase II clinical trial in idiopathic pulmonary arterial hypertension. AB - Our aim is to assess the safety and potential clinical benefit of intravenous iron (Ferinject) infusion in iron deficient patients with idiopathic pulmonary arterial hypertension (IPAH). Iron deficiency in the absence of anemia (1) is common in patients with IPAH; (2) is associated with inappropriately raised levels of hepcidin, the key regulator of iron homeostasis; and (3) correlates with disease severity and worse clinical outcomes. Oral iron absorption may be impeded by reduced absorption due to elevated hepcidin levels. The safety and benefits of parenteral iron replacement in IPAH are unknown. Supplementation of Iron in Pulmonary Hypertension (SIPHON) is a Phase II, multicenter, double-blind, randomized, placebo-controlled, crossover clinical trial of iron in IPAH. At least 60 patients will be randomized to intravenous ferric carboxymaltose (Ferinject) or saline placebo with a crossover point after 12 weeks of treatment. The primary outcome will be the change in resting pulmonary vascular resistance from baseline at 12 weeks, measured by cardiac catheterization. Secondary measures include resting and exercise hemodynamics and exercise performance from serial bicycle incremental and endurance cardiopulmonary exercise tests. Other secondary measurements include serum iron indices, 6-Minute Walk Distance, WHO functional class, quality of life score, N-terminal pro-brain natriuretic peptide (NT-proBNP), and cardiac anatomy and function from cardiac magnetic resonance. We propose that intravenous iron replacement will improve hemodynamics and clinical outcomes in IPAH. If the data supports a potentially useful therapeutic effect and suggest this drug is safe, the study will be used to power a Phase III study to address efficacy. PMID- 23662183 TI - Transitioning from parenteral treprostinil to inhaled treprostinil in patients with pulmonary arterial hypertension. AB - Treprostinil is a potent prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH, World Health Organization Group I). Previously, treprostinil was available only in subcutaneous (SC) or intravenous (IV) formulations. Availability of an inhaled formulation of treprostinil has provided clinicians with an alternative to continuous SC or IV treprostinil in appropriate patients. Stable PAH patients whose quality of life has been dramatically impacted by side effects of parenteral therapy or those who have had recurrent, life-threatening bloodstream infections but are otherwise responding well to treatment may be the candidates for continuing prostacyclin therapy with inhaled treprostinil. However, there is little clinical experience with transitioning patients from parenteral to inhaled treprostinil. We present the results of two cases that highlight important considerations in transitioning patients from parenteral to inhaled therapy, including the pharmacologic and clinical equivalence of formulations, dose titration of formulations and suggested criteria for patient selection. PMID- 23662182 TI - Phospholipase D signaling mediates reactive oxygen species-induced lung endothelial barrier dysfunction. AB - Reactive oxygen species (ROS) have emerged as critical players in the pathophysiology of pulmonary disorders and diseases. Earlier, we have demonstrated that ROS stimulate lung endothelial cell (EC) phospholipase D (PLD) that generates phosphatidic acid (PA), a second messenger involved in signal transduction. In the current study, we investigated the role of PLD signaling in the ROS-induced lung vascular EC barrier dysfunction. Our results demonstrated that hydrogen peroxide (H2O2), a typical physiological ROS, induced PLD activation and altered the barrier function in bovine pulmonary artery ECs (BPAECs). 1-Butanol, the quencher of PLD, generated PA leading to the formation of physiologically inactive phosphatidyl butanol but not its biologically inactive analog, 2-butanol, blocked the H2O2-mediated barrier dysfunction. Furthermore, cell permeable C2 ceramide, an inhibitor of PLD but not the C2 dihydroceramide, attenuated the H2O2-induced PLD activation and enhancement of paracellular permeability of Evans blue conjugated albumin across the BPAEC monolayers. In addition, transfection of BPAECs with adenoviral constructs of hPLD1 and mPLD2 mutants attenuated the H2O2-induced barrier dysfunction, cytoskeletal reorganization and distribution of focal adhesion proteins. For the first time, this study demonstrated that the PLD-generated intracellular bioactive lipid signal mediator, PA, played a critical role in the ROS-induced barrier dysfunction in lung vascular ECs. This study also underscores the importance of PLD signaling in vascular leak and associated tissue injury in the etiology of lung diseases among critically ill patients encountering oxygen toxicity and excess ROS production during ventilator-assisted breathing. PMID- 23662184 TI - Should cardiopulmonary exercise testing become a part of regular evaluation for patients with a family history of pulmonary hypertension? Regarding "Cardiopulmonary exercise testing reveals onset of disease and response to treatment in a case of heritable pulmonary arterial hypertension". PMID- 23662185 TI - Author's reply. PMID- 23662186 TI - Rare etiological causes of Takotsubo cardiomyopathy Regarding "Takotsubo cardiomyopathy after treatment of pulmonary arterial hypertension". PMID- 23662187 TI - Author's reply. PMID- 23662188 TI - Mechanics and mechanisms of pulmonary hypertension: An introduction to the 55(th) annual Thomas L. Petty Aspen Lung Conference. PMID- 23662189 TI - Mechanics and mechanisms of pulmonary hypertension-Conference summary and translational perspectives. PMID- 23662190 TI - Mechanisms of right heart failure-A work in progress and a plea for failure prevention. PMID- 23662191 TI - Metabolism and bioenergetics in the right ventricle and pulmonary vasculature in pulmonary hypertension. AB - Pulmonary arterial hypertension (PAH) is a syndrome in which pulmonary vascular cross sectional area and compliance are reduced by vasoconstriction, vascular remodeling, and inflammation. Vascular remodeling results in part from increased proliferation and impaired apoptosis of vascular cells. The resulting increase in afterload promotes right ventricular hypertrophy (RVH) and RV failure. Recently identified mitochondrial-metabolic abnormalities in PAH, notably pyruvate dehydrogenase kinase-mediated inhibition of pyruvate dehydrogenase (PDH), result in aerobic glycolysis in both the lung vasculature and RV. This glycolytic shift has diagnostic importance since it is detectable early in experimental PAH by increased lung and RV uptake of (18)F-fluorodeoxyglucose on positron emission tomography. The metabolic shift also has pathophysiologic and therapeutic relevance. In RV myocytes, the glycolytic switch reduces contractility while in the vasculature it renders cells hyperproliferative and apoptosis-resistant. Reactivation of PDH can be achieved directly by PDK inhibition (using dichloroacetate), or indirectly via activating the Randle cycle, using inhibitors of fatty acid oxidation (FAO), trimetazidine and ranolazine. In experimental PAH and RVH, PDK inhibition increases glucose oxidation, enhances RV function, regresses pulmonary vascular disease by reducing proliferation and enhancing apoptosis, and restores cardiac repolarization. FAO inhibition increases RV glucose oxidation and RV function in experimental RVH. The trigger for metabolic remodeling in the RV and lung differ. In the RV, metabolic remodeling is likely triggered by ischemia (due to microvascular rarefaction and/or reduced coronary perfusion pressure). In the vasculature, metabolic changes result from redox mediated activation of transcription factors, including hypoxia-inducible factor 1alpha, as a consequence of epigenetic silencing of SOD2 and/or changes in mitochondrial fission/fusion. Randomized controlled trials are required to assess whether the benefits of enhancing glucose oxidation are realized in patients with PAH. PMID- 23662192 TI - Combining induced pluripotent stem cell with next generation sequencing technology to gain new insights into pathobiology and treatment of pulmonary arterial hypertension. PMID- 23662193 TI - Developing treatments for pulmonary arterial hypertension. AB - Developing new treatments for pulmonary arterial hypertension (PAH) is a challenge. We have enjoyed success with regulatory approvals for three drug classes-prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors. But we have also seen some disappointing results, for example, from studies with vasoactive intestinal polypeptide, statins and tergolide. Animal models are an unreliable predictor of efficacy in humans. The best model for the disease is the patient. This review discusses three major issues facing the evaluation of drugs in PAH patients-target validation, choosing the right dose, and early trial design. PMID- 23662194 TI - Mechanisms of development of chronic obstructive pulmonary disease-associated pulmonary hypertension. AB - Pulmonary hypertension is a prevalent complication of chronic obstructive pulmonary disease (COPD) that is associated with poor prognosis. Although pulmonary hypertension is usually diagnosed in patients with advanced disease, changes in pulmonary vessels are already apparent at early disease stages, and in smokers without airflow obstruction. Changes in pulmonary vessels include intimal hyperplasia, resulting from proliferating mesenchymal cells, and elastic and collagen deposition as well as endothelial dysfunction. Dysregulation of endothelium-derived mediators and growth factors and inflammatory mechanisms underlie the endothelial dysfunction and vessel remodeling. Circumstantial and experimental evidence suggests that cigarette smoke products can initiate pulmonary vascular changes in COPD and that, at advanced disease stages, hypoxia may amplify the effects of cigarette smoke on pulmonary arteries. Bone marrow derived progenitor cells may contribute to vessel repair and to vessel remodeling, a process that appears to be facilitated by transforming growth factor-beta. PMID- 23662195 TI - Human immunodeficiency virus, herpes virus infections, and pulmonary vascular disease. AB - The following state-of-the-art seminar was delivered as part of the Aspen Lung Conference on Pulmonary Hypertension and Vascular Diseases held in Aspen, Colorado in June 2012. This paper will summarize the lecture and present results from a nonhuman primate model of infection with Simian (Human) Immunodeficiency Virus - nef chimeric virions as well as the idea that polymorphisms in the HIV-1 nef gene may be driving the immune response that results in exuberant inflammation and aberrant endothelial cell (EC) function. We will present data gathered from primary HIV nef isolates where we tested the biological consequences of these polymorphisms and how their presence in human populations may predict patients at risk for developing this disease. In this article, we also discuss how a dysregulated immune system, in conjunction with a viral infection, could contribute to pulmonary arterial hypertension (PAH). Both autoimmune diseases and some viruses are associated with defects in the immune system, primarily in the function of regulatory T cells. These T-cell defects may be a common pathway in the formation of plexiform lesions. Regardless of the route by which viruses may lead to PAH, it is important to recognize their role in this rare disease. PMID- 23662196 TI - Integrating molecular genetics and systems approaches to pulmonary vascular diseases. AB - There is incredible potential to advance our understanding of disease pathogenesis, enhance our diagnostic capability, and revolutionize our treatment modalities with the advent of advanced systems approaches to genetic, genomic, and epigenetic discoveries. Investigation using these technologies is beginning to impact our understanding of pulmonary arterial hypertension (PAH). The following review details work to date on single gene mutations in PAH, and expression array analysis in the disease. The wider use of DNA-based arrays for genome wide association studies (GWAS) and copy number alterations is examined. The impact of epigenomic modulation in the pathobiology of PAH and its therapeutic implications is investigated. Finally, a summary of the capabilities and promises for next-generation sequencing is discussed. A framework for studies of the future is proposed. PMID- 23662197 TI - Development of the pulmonary vasculature: Current understanding and concepts for the future. AB - The pulmonary circulation is a highly specialized vascular bed that physically and functionally connects the heart and the lungs. The interdependence of these two organs is illustrated in embryonic development, when the lung endoderm protrudes into the surrounding mesoderm as the heart tube elongates and folds into structurally distinct chambers. The pulmonary vascular precursors then undergo highly stereotyped cellular maturation and patterning to form a multilayered vascular network that parallels the airways and links the arterial and venous poles of the heart. Upon the first breath, the mature pulmonary circulation is poised to receive the entire cardiac output for efficient gas exchange, and deliver oxygenated blood to the systemic circulation. Disruption of this developmental process can result in congenital defects such as the syndrome tetralogy of Fallot, or differentiation defects leading to persistent pulmonary hypertension of the newborn. Prior studies into the role of angiogenesis and vasculogenesis in pulmonary vascular development have not clearly yielded the identity of pulmonary vascular precursors, or the signals coordinating vascular maturation. We outline key questions on pulmonary vascular development that consider the role of heart-lung interaction in promoting the differentiation and patterning of the pulmonary vasculature. PMID- 23662198 TI - The pulmonary hypertension academic research consortium. PMID- 23662199 TI - Updating clinical endpoint definitions. AB - The 6-Minute Walk Distance (6-MWD) has been the most utilized endpoint for judging the efficacy of pulmonary arterial hypertension (PAH) therapy in clinical trials conducted over the past two decades. Despite its simplicity, widespread use in recent trials and overall prognostic value, the 6-MWD has often been criticized over the past several years and pleas from several PAH experts have emerged from the literature to find alternative endpoints that would be more reliable in reflecting the pulmonary vascular resistance as well as cardiac status in PAH and their response to therapy. A meeting of PAH experts and representatives from regulatory agencies and pharmaceutical companies was convened in early 2012 to discuss the validity of current as well as emerging valuable endpoints. The current work represents the proceedings of the conference. PMID- 23662200 TI - Advancing clinical trial design in pulmonary hypertension. AB - In pulmonary hypertension, as in many other diseases, there is a need for a smarter approach to evaluating new treatments. The traditional randomized controlled trial has served medical science well, but constrains the development of treatments for rare diseases. A workshop was established to consider alternative clinical trial designs in pulmonary hypertension and here discusses their merits, limitations and challenges to implementation of novel approaches. PMID- 23662202 TI - Clinical trials in pulmonary hypertension: Time for a consortium. AB - Current and past clinical trials in pulmonary hypertension, while valuable, are limited by the absence of mechanistic aims, by dissatisfaction with endpoints and the inability to share data. Clinical studies in pulmonary hypertension might be enhanced by a consortium approach that utilizes the expertise of academic medicine, the treatment initiatives of the pharmaceutical industry and study design from funding agencies interested in biological mechanisms. A meeting of interested parties, the Pulmonary Hypertension Academic Research Consortium (PHARC), was held from 30 April to 1 May 2012 in Bethesda, Maryland. Members at the conference were from the USA Federal Drug Administration (FDA); pharmaceutical industry (Pfizer, Novartis, Bayer and Gilead); USA National Institutes of Health (NHLBI); the Pulmonary Vascular Research Institute (PVRI), a non-governmental organization (NGO); and research and clinical members of pulmonary hypertension programs of international scope. A recommendation to develop a clinical trials consortium was the product of the working group on academic standards in clinical trials. The working group concluded that clinical trials hold immense promise to move the field of pulmonary hypertension forward if the trials are designed by a consortium with input from multiple groups. This would result in study design, conduct and analysis determined by consortium members with a high degree of independent function. The components of a well balanced consortium that give it scientific effectiveness are: (1) the consortium can work with multiple companies simultaneously; (2) sponsors with special interests, such as testing biological mechanisms, can add investigations to a study at lower cost than with present granting strategies; (3) data handling including archiving, analysis and future sharing would be improved; (4) ancillary studies supported by the collection and dissemination of tissues and fluids would generate a broader approach to discovery than is now possible; and (5) development of improved endpoints in consultation with regulatory agencies, industry and academia would be possible. PMID- 23662205 TI - Cloning, Expression, and Purification of Nucleoside Diphosphate Kinase from Acinetobacter baumannii. AB - Acinetobacter baumannii is a multidrug resistant pathogenic bacteria associated with hospital acquired infections. This bacterium possesses a variety of resistance mechanisms which makes it more difficult to control the bacterium with conventional drugs, and, so far no effective drug treatment is available against it. Nucleoside diphosphate kinase is an important enzyme, which maintains the total nucleotide triphosphate pool inside the cell by the transfer of gamma phosphate from NTPs to NDPs. The role of nucleoside diphosphate kinase (Ndk) has also been observed in pathogenesis in other organisms. However, intensive studies are needed to decipher its other putative roles in Acinetobacter baumannii. In the present study, we have successfully cloned the gene encoding Ndk and achieved overexpression in bacterial host BL-21 (DE3). The overexpressed protein is further purified by nickel-nitrilotriacetic acid (Ni-NTA) chromatography. PMID- 23662203 TI - Clinical trials in neonates and children: Report of the pulmonary hypertension academic research consortium pediatric advisory committee. AB - Drug trials in neonates and children with pulmonary hypertensive vascular disease pose unique but not insurmountable challenges. Childhood is defined by growth and development. Both may influence disease and outcomes of drug trials. The developing pulmonary vascular bed and airways may be subjected to maldevelopment, maladaptation, growth arrest, or dysregulation that influence the disease phenotype. Drug therapy is influenced by developmental changes in renal and hepatic blood flow, as well as in metabolic systems such as cytochrome P450. Drugs may affect children differently from adults, with different clearance, therapeutic levels and toxicities. Toxicity may not be manifested until the child reaches physical, endocrine and neurodevelopmental maturity. Adverse effects may be revealed in the next generation, should the development of ova or spermatozoa be affected. Consideration of safe, age-appropriate tablets and liquid formulations is an obvious but often neglected prerequisite to any pediatric drug trial. In designing a clinical trial, precise phenotyping and genotyping of disease is required to ensure appropriate and accurate inclusion and exclusion criteria. We need to explore physiologically based pharmacokinetic modeling and simulations together with statistical techniques to reduce sample size requirements. Clinical endpoints such as exercise capacity, using traditional classifications and testing cannot be applied routinely to children. Many lack the necessary neurodevelopmental skills and equipment may not be appropriate for use in children. Selection of endpoints appropriate to encompass the developmental spectrum from neonate to adolescent is particularly challenging. One possible solution is the development of composite outcome scores that include age and a developmentally specific functional classification, growth and development scores, exercise data, biomarkers and hemodynamics with repeated evaluation throughout the period of growth and development. In addition, although potentially costly, we recommend long-term continuation of blinded dose ranging after completion of the short-term, double-blind, placebo-controlled trial for side-effect surveillance, which should include neurodevelopmental and peripubertal monitoring. The search for robust evidence to guide safe therapy of children and neonates with pulmonary hypertensive vascular disease is a crucial and necessary goal. PMID- 23662201 TI - Anticipated classes of new medications and molecular targets for pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) remains a life-limiting condition with a major impact on the ability to lead a normal life. Although existing therapies may improve the outlook in some patients there remains a major unmet need to develop more effective therapies in this condition. There have been significant advances in our understanding of the genetic, cell and molecular basis of PAH over the last few years. This research has identified important new targets that could be explored as potential therapies for PAH. In this review we discuss whether further exploitation of vasoactive agents could bring additional benefits over existing approaches. Approaches to enhance smooth muscle cell apotosis and the potential of receptor tyrosine kinase inhibition are summarised. We evaluate the role of inflammation, epigenetic changes and altered glycolytic metabolism as potential targets for therapy, and whether inherited genetic mutations in PAH have revealed druggable targets. The potential of cell based therapies and gene therapy are also discussed. Potential candidate pathways that could be explored in the context of experimental medicine are identified. PMID- 23662206 TI - Sources of Information on HIV and Sexual and Reproductive Health for Couples Living with HIV in Rural Southern Malawi. AB - WITH WIDER ACCESS TO ANTIRETROVIRAL THERAPY, PEOPLE LIVING WITH HIV ARE RECONSIDERING THEIR REPRODUCTIVE DECISIONS: remarrying and having children. The purpose of the paper is to explore sources of information for reproductive decision used by couples living with HIV in patrilineal and matrilineal districts of Malawi. Data were collected from forty couples from July to December 2010. Our results illuminate five specific issues: some of the informants (1) remarry after divorce/death of a spouse, (2) establish new marriage relationship with spouses living with HIV, and (3) have children hence the need for information to base their decisions. There are (4) shared and interactive couple decisions, and (5) informal networks of people living with HIV are the main sources of information. In addition, in matrilineal community, cultural practices about remarriage set up structures that constrained information availability unlike in patrilineal community where information on sexual and reproductive health, HIV, and AIDS was disseminated during remarriage counselling. However, both sources are not able to provide comprehensive information due to complexity and lack of up to date information. Therefore, health workers should, offer people living with HIV comprehensive information that takes into consideration the cultural specificity of groups, and empower already existing and accepted local structures with sexual and reproductive health, HIV, and AIDS knowledge. PMID- 23662207 TI - Improved outcome of severe acute pancreatitis in the intensive care unit. AB - Background. Severe acute pancreatitis (SAP) is associated with serious morbidity and mortality. Our objective was to describe the case mix, management, and outcome of patients with SAP receiving modern critical care in the Intensive Care Unit (ICU). Methods. Retrospective analysis of patients with SAP admitted to the ICU in a single tertiary care centre in the UK between January 2005 and December 2010. Results. Fifty SAP patients were admitted to ICU (62% male, mean age 51.7 (SD 14.8)). The most common aetiologies were alcohol (40%) and gallstones (30%). On admission to ICU, the median Acute Physiology and Chronic Health Evaluation (APACHE) II score was 17, the pancreatitis outcome prediction score was 8, and the median Computed Tomography Severity Index (CTSI) was 4. Forty patients (80%) tolerated enteral nutrition, and 46% received antibiotics for non-SAP reasons. Acute kidney injury was significantly more common among hospital nonsurvivors compared to survivors (100% versus 42%, P = 0.0001). ICU mortality and hospital mortality were 16% and 20%, respectively, and median lengths of stay in ICU and hospital were 13.5 and 30 days, respectively. Among hospital survivors, 27.5% developed diabetes mellitus and 5% needed long-term renal replacement therapy. Conclusions. The outcome of patients with SAP in ICU was better than previously reported but associated with a resource demanding hospital stay and long-term morbidity. PMID- 23662209 TI - The interspinous spacer: a new posterior dynamic stabilization concept for prevention of adjacent segment disease. AB - Introduction. Posterior Dynamic stabilization using the interspinous spacer device is a known to be used as an alternative to rigid fusion in neurogenic claudication patients in the absence of macro instability. Actually, it plays an important in the management of adjacent segment disease in previously fused lumbar spine. Materials and Method. We report our experience with posterior dynamic stabilization using an interspinous spacer. 134 cases performed in our institution between September 2008 and August 2012 with different lumbar spine pathologies. The ages of our patients were between 40 and 72 years, with a mean age of 57 years. After almost 4 years of follow up in our patient and comparing their outcome to our previous serious we found that in some case the interspinous distracter has an important role not only in the treatment of adjacent segment disease but also in its prevention. Results and Discussion. Clinical improvement was noted in ISD-treated patients, with high satisfaction rate. At first, radicular pain improves with more than 3/10 reduction of the mean score on visual analog scale (VAS). In addition, disability score as well as disc height and lordotic angle showed major improvement at 3 to 6 months post operatively. And, no adjacent segment disease was reported in the patient operated with interspinous spacer. Conclusion. The interspinous spacer is safe and efficient modality to be used not only as a treatment of adjacent segment disease but also as a preventive measure in patients necessitating rigid fusion. PMID- 23662210 TI - Comparison of conventional polyethylene wear and signs of cup failure in two similar total hip designs. AB - Multiple factors have been identified as contributing to polyethylene wear and debris generation of the acetabular lining. Polyethylene wear is the primary limiting factor in the functional behavior and consequent longevity of a total hip arthroplasty (THA). This retrospective study reviewed the clinical and radiographic data of 77 consecutive THAs comparing in vivo polyethylene wear of two similar acetabular cup liners. Minimum follow-up was 7 years (range 7-15). The incidence of measurable wear in a group of machined liners sterilized with ethylene oxide and composed of GUR 1050 stock resin was significantly higher (61%) than the compression-molded, GUR 1020, O2-free gamma irradiation sterilized group (24%) (P = 0.0004). Clinically, at a 9-year average followup, both groups had comparable HHS scores and incidence of thigh or groin pain, though the machined group had an increased incidence of osteolysis and annual linear wear rate. PMID- 23662212 TI - Application of dual mask for postoperative respiratory support in obstructive sleep apnea patient. AB - In some conditions continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BIPAP) therapy alone fails to provide satisfactory oxygenation. In these situations oxygen (O2) is often being added to CPAP/BIPAP mask or hose. Central sleep apnea and obstructive sleep apnea (OSA) are often present along with other chronic conditions, such as chronic obstructive pulmonary disease (COPD), congestive heart failure, pulmonary fibrosis, neuromuscular disorders, chronic narcotic use, or central hypoventilation syndrome. Any of these conditions may lead to the need for supplemental O2 administration during the titration process. Maximization of comfort, by delivering O2 directly via a nasal cannula through the mask, will provide better oxygenation and ultimately treat the patient with lower CPAP/BIPAP pressure. PMID- 23662211 TI - Dynamic stabilization for challenging lumbar degenerative diseases of the spine: a review of the literature. AB - Fusion and rigid instrumentation have been currently the mainstay for the surgical treatment of degenerative diseases of the spine over the last 4 decades. In all over the world the common experience was formed about fusion surgery. Satisfactory results of lumbar spinal fusion appeared completely incompatible and unfavorable within years. Rigid spinal implants along with fusion cause increased stresses of the adjacent segments and have some important disadvantages such as donor site morbidity including pain, wound problems, infections because of longer operating time, pseudarthrosis, and fatigue failure of implants. Alternative spinal implants were developed with time on unsatisfactory outcomes of rigid internal fixation along with fusion. Motion preservation devices which include both anterior and posterior dynamic stabilization are designed and used especially in the last two decades. This paper evaluates the dynamic stabilization of the lumbar spine and talks about chronologically some novel dynamic stabilization devices and thier efficacies. PMID- 23662213 TI - Multifactorial Model and Treatment Approaches of Refractory Hypotension in a Patient Who Took an ACE Inhibitor the Day of Surgery. AB - In the field of anesthesiology, there is wide debate on discontinuing angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) therapy the day of noncardiac surgery. Although there have been many studies attributing perioperative hypotension to same-day ACEI and ARB use, there are many additional variables that play a role in perioperative hypotension. Additionally, restoring blood pressure in these patients presents a unique challenge to anesthesiologists. A case report is presented in which a patient took her ACEI the day of surgery and developed refractory hypotension during surgery. The evidence of ACEI use on the day of surgery and development of hypotension is reviewed, and additional variables that contributed to this hypotensive episode are discussed. Lastly, current challenges in restoring blood pressure are presented, and a basic model on treatment approaches for refractory hypotension in the setting of perioperative ACEI use is proposed. PMID- 23662214 TI - Mobitz Type II Atrioventricular Block Followed by Remifentanil in a Patient with Severe Aortic Stenosis. AB - Opioids have been considered for their hemodynamic stability. Remifentanil is an opioid analgesic with rapid metabolism and fast primary effect and recovery. In this paper, a very rare effect of using remifentanil along with propofol was presented. An 84-year-old male patient with severe aortic stenosis underwent general anesthesia. In order to induce anesthesia and maintain it, fentanyl, pancuronium, and propofol, along with a combination of propofol and remifentanil, were used, respectively. At beginning of remifentanil infusion, bradycardia and then Mobitz type II conduction block with a hemodynamic disorder occurred for the patient. The decreased blood pressure responded to injection of atropine and ephedrine; however, dysrhythmia only improved after cessation of remifentanil. Therefore remifentanil should be used with caution in aortic stenosis. PMID- 23662215 TI - Three independent mesial canals in a mandibular molar: four-year followup of a case using cone beam computed tomography. AB - Endodontic treatment of mandibular molars is challenging because of variable root canal morphology. The nonsurgical endodontic management of a mandibular first molar presenting an independent middle mesial canal is reported. After coronal access, additional clinical inspection of the mesial canals' orifices and their interconnecting groove using an endodontic explorer and 4.5* loupes enabled the identification of the middle mesial canal orifice. All root canals were chemomechanically prepared and filled. The tooth was asymptomatic and functional after 4 years of followup. Cone beam computed tomography (CBCT) images revealed normal periapical status and three-dimensional (3D) anatomical aspects of the root canal system. PMID- 23662216 TI - Pseudoporphyria associated with nonhemodialyzed renal insufficiency, successfully treated with oral N-acetylcysteine. AB - Pseudoporphyria (PP) is a relatively rare, photodistributed bullous dermatosis that resembles porphyria cutanea tarda (PCT), but it is not accompanied by porphyrin abnormalities in the serum, urine, or stool. It was initially described in renal failure patients on dialysis. Thereafter, it has been associated with several aetiological factors. We report a case of PP in a 67-year-old woman with mild renal failure, successfully treated with N-acetylcysteine. This is the second reported case of PP developing in nondialyzed chronic renal failure. Such cases support the view that renal impairment itself may play a more important aetiological role in developing PP than it was originally considered. PMID- 23662217 TI - Gunshot wound of the thoracic aorta with right popliteal artery embolization: a case report of bullet embolism with review of relevant literature. AB - Bullet embolism is a well-known but relatively uncommon complication of gunshot injuries. Their rarity and the potential lack of early symptoms lead to delays in diagnosis and often in inadequate early management that can potentially result in the loss of a limb or life. We present an interesting case in which a small caliber bullet to the upper anterior abdomen penetrated the thoracic aorta and traveled to the right popliteal artery embolizing the vessel. The exploratory laparotomy failed to locate neither the bullet nor the trajectory resulting in sudden deterioration and eventual death 5 hours into the postoperative period. PMID- 23662218 TI - Late complication of laparoscopic sleeve gastrectomy. AB - Laparoscopic sleeve gastrectomy (LSG) is gaining popularity for the treatment of morbid obesity. It is a simple, low-cost procedure resulting in significant weight loss within a short period of time. LSG is a safe procedure with a low complication rate. The complications encountered nevertheless can result in morbidity and even mortality. The most significant complications are staple-line bleeding, stricture, and staple-line leak. The purpose of this paper is to present a patient who suffered from a staple-line leak presenting 16 months after LSG. Review of the current literature regarding this complication as well as outline of a strategy for the management of post-LSG gastric leaks is suggested. PMID- 23662219 TI - Targeted next-generation resequencing of f5 gene identifies novel multiple variants pattern in severe hereditary factor v deficiency. AB - The present study investigated the genetic defects underlying severe Factor V deficiency in a 26-year-old Columbian (South America) female and her immediate family (both parents and newborn child) by next generation sequencing (NGS) of the entire F5 gene locus. Five mutations in the coding sequence of F5, including three missense single-nucleotide variants (R2102H, R513K, D107H) and two synonymous variants (A135A , S184S), were identified and confirmed by the Sanger sequencing in the investigated proband (homozygote for all detected mutations), her parents, and her newborn child (all heterozygotic carriers for identified mutations). Each of the three missense variants was previously associated with separate phenotypes, including Factor V deficiency (R2102H), thrombosis (R513K) and frequent miscarriages (D107H). In addition, at least 75 additional single nucleotide variants (including six novels) were identified in untranslated region of F5. PMID- 23662220 TI - Detection of Rare Beta Globin Gene Mutation [+22 5UTR(G>A)] in an Infant, Despite Prenatal Screening. AB - Background. Beta thalassemia is one of the most common hereditary disorders worldwide. In Iran, it is frequently reported from northern and southern provinces. In order to prevent child birth to be affected by this complication, prenatal screening and diagnosis are carried out nationwide. However, in some instances, this program is unable to identify rare mutations leading to thalassemia. Case Presentation. A married couple, who took part in prenatal screening and diagnosis, gave birth to a child who is affected by thalassemia major. After several molecular examinations, a rare mutation [+22 5UTR (G>A)] in compound heterozygote state along with a common mutation [codon 8 (-AA)] was found. Conclusion. This case study suggests that more advanced molecular evaluations must be integrated in prenatal screening programs to identify rare mutations and antenatal diagnosis of thalassemia cases. PMID- 23662221 TI - Isolated laryngeal leishmaniasis in immunocompetent patients: an underdiagnosed disease. AB - We describe a case of isolated primary laryngeal leishmaniasis in an immunocompetent Italian patient with a previous medical history negative for visceral or cutaneous leishmaniasis, presenting with hoarseness. We also summarize the epidemiological, clinical, and diagnostic features and the therapeutic management of other cases of laryngeal leishmaniasis in immunocompetent subjects, described in the literature. Considering the insidious and nonspecific clinical presentation, the increasing number of different forms of mild or underestimated immunosuppressive conditions, and the number of people travelling in endemic zones, along with the ability of Leishmania amastigotes to survive for a long period in the body, we believe it is important for pathologists and clinicians to be aware of this unusual form of leishmaniasis in order to avoid delayed recognition and treatment. The rarity of the presentation and the lack of guidelines on mucosal leishmaniasis may contribute to the potential undiagnosed cases or delayed diagnosis, the possible relapses, as well as the correct pharmacological and/or surgical therapeutic approach. PMID- 23662222 TI - Septicemia and Aortic Valve Endocarditis due to Erysipelothrix rhusiopathiae in a Homeless Man. AB - We report a case of bacterial endocarditis due to Erysipelothrix rhusiopathiae in a homeless man with no animal exposure. His course was complicated by an allergic reaction to ampicillin, urinary bladder infection, respiratory failure, and acute kidney injury. He recovered completely after aortic valve replacement and a 6 week course of intravenous ceftriaxone. PMID- 23662223 TI - A 29-year-old female with progressive myoclonus and cognitive decline. AB - Myoclonic epilepsy with red ragged fibres (MERRF) is a rare mitochondrial disorder presenting with progressive myoclonus, epilepsy, and cognitive decline. Here, the authors present a case of a 29-year-old lady presenting with myoclonus and describe the subsequent investigations that led to a diagnosis of MERRF. In addition, we examine her cognitive decline over a 9-year period, demonstrating a feature commonly seen in mitochondrial cytopathies. PMID- 23662224 TI - Borderline Ovarian Tumor during Pregnancy: A Case Report. AB - We report a case of a 33 year-old pregnant woman who was diagnosed at the time of the first trimester ultrasound with a multilocular solid arising form the right ovary. An abdominal MRI was performed afterwards and it revealed a pelvic mass, developing from the right ovary, with a liquid component but with a major solid area. CA 125 was within the normal range values. A laparotomy followed by right salpingo-oophorectomy was performed at 14 weeks of gestation and both the frozen section and the definitive histology revealed a borderline mucinous ovarian tumor. Ovarian tumors of low malignant potential comprise 10%-20% of all ovarian malignancies. They carry an excellent prognosis with 95%-99% long-term survival. Whereas in the past, radical surgery (hysterectomy and bilateral salpingo oophorectomy with peritoneal staging) was standard regardless of the age of the patient, unilateral salpingo-oophorectomy with or without staging has become the recommended management for women who desire childbearing. In the absence of large prospective randomized trials it is difficult to know which are the best management practices and especially to determine the right moment during pregnancy to perform surgery in these patients. PMID- 23662225 TI - Vaginal myomectomy for a thirteen-centimeter anterior myoma. AB - Vaginal myomectomy is an uncommon but advantageous approach for large interstitial uterine fibroids. Myomectomy is performed via laparotomy and laparoscopy; however, in selected cases, vaginal myomectomy has been proven to be a safe and an effective surgical procedure. We report the case of a 38-year-old para one woman with complaints of chronic lower abdominal pain. Preoperative workup revealed a thirteen-centimeter interstitial uterine myoma in the anterior wall. Successful myomectomy was performed via the vaginal route. We will share the preoperative images, operative technique, and postoperative images. PMID- 23662226 TI - A Case Presentation: Decidualized Endometrioma Mimicking Ovarian Cancer during Pregnancy. AB - During pregnancy, masses that are larger than 5 cm and appearing in the Doppler ultrasonography as having increased blood flow, echoes of heterogeneous density, and containing solid components are suspicious for malignancy; however, differential diagnosis of decidualized endometriomas should also be considered. The patient was an 8 weeks pregnant primigravida. The ultrasonographic evaluation showed a cystic mass of size 65 * 57 mm in the left ovary that was well circumscribed, heterogeneous, with highly dense internal echo, and containing a solid component of size 8 * 14 mm. In the 12th week, the ultrasonographic examination revealed an increase in the size of the mass and increased arterial blood flow in the mass. The patient underwent surgery. It was observed that both ovaries were adherent in the Douglas pouch and that the left ovary contained an endometrioma of size 8cm. While the capsule was being peeled, lesions of soft density, with irregular surfaces, and with adhesion in the Douglas pouch were observed. The results of the frozen section revealed decidualized endometrioma and decidual structures. Even in pregnant women when adnexal masses are encountered and the ultrasonography, Doppler, MRI, and CA 125 level analysis still do not favor endometriosis, decidualized endometrioma should be considered in the differential diagnosis. PMID- 23662227 TI - Juvenile dermatomyositis in pregnancy. AB - Juvenile dermatomyositis has variable clinical presentations both in and outside of pregnancy. A literature review indicated that optimal maternal and fetal outcomes can be anticipated when the pregnancy is undertaken while the disease is in remission. Poorer outcomes are associated with flare-up of the disease in early pregnancy compared with exacerbation in the second or third trimester, when fetal prognosis is usually good. We present a case of JDM in pregnancy with disease exacerbation late in pregnancy and review of the relevant literature. PMID- 23662228 TI - Gastric small-cell carcinoma found on esophagogastroduodenoscopy: a case report and literature review. AB - Introduction. Characterized as an undifferentiated, neuroendocrine tumor arising from totipotent stem cells, small-cell carcinoma (SCC) most commonly arises from the lung. Extrapulmonary small-cell carcinomas (ESCC) are rare and account for only four percent of SCC. Gastric ESCC, more commonly seen in Japanese male patients in their seventh decade of life, accounts for approximately 0.1 percent of ESCC. Case Presentation. A 75-year-old Hispanic male presented with a several week history of worsening epigastric pain with nausea and vomiting. Computer tomography (CT) of the abdomen and pelvis showed a large heterogeneous mass involving the posterior gastric wall with diffuse extension into the gastric cardia. Esophagogastroduodenoscopy (EGD) revealed a large fungating mass in the lesser curvature of the stomach. Biopsy of the mass revealed small-cell carcinoma of the stomach. The patient was diagnosed with extensive/stage 4 disease and started on chemoradiation. Discussion. Our case, of a very rare condition highlights, the importance of recognizing atypical pathologic diagnoses. More research will need to be conducted with GSCC patients in order to better characterize disease pathogenesis, genetic mutations, and optimal disease management. The hope is to identify biomarkers that will identify patients earlier in their disease course when cure is possible. PMID- 23662229 TI - Cystoid macular edema induced by low doses of nicotinic Acid. AB - Cystoid macular edema (CME) is a condition that involves the macula, causing painless vision loss. In this paper, we report a case of niacin-induced bilateral cystoid macular edema (CME) in a middle-age woman taking low dose of niacin (18 mg of nicotinic acid). Optical coherence tomography (OCT) showed retinal thickening and cystoid spaces in both eyes, whereas fluorescein angiography (FA; HRA 2, Heidelberg Engineering) revealed the absence of fluorescein leakage also in later phases. Four weeks after discontinuation of therapy there were a complete disappearance of macular edema at funduscopic examination and an improvement of visual acuity in both eyes. Furthermore OCT showed a normal retinal profile in both eyes. In our opinion considering the wide availability of niacin, medical monitoring and periodical examination should be considered during niacin administration. To our knowledge, this is the first report in the literature that described the very low-dose niacin-induced bilateral niacin maculopathy. PMID- 23662230 TI - Iliopsoas tendon reformation after psoas tendon release. AB - Internal snapping hip syndrome, or psoas tendonitis, is a recognised cause of nonarthritic hip pain. The majority of patients are treated conservatively; however, occasionally patients require surgical intervention. The two surgical options for iliopsoas tendinopathy are step lengthening of the iliopsoas tendon or releasing the tendon at the lesser trochanter. Although unusual, refractory snapping usually occurs soon after tenotomy. We report a case of a 47-year-old active female with internal snapping and pain following an open psoas tenotomy. Postoperatively she was symptom free for 13 years. An MRI arthrogram revealed reformation of a pseudo iliopsoas tendon reinserting into the lesser trochanter. The pain and snapping resolved after repeat iliopsoas tendon release. Reformation of tendons is an uncommon sequela of tenotomies. However the lack of long-term studies makes it difficult to calculate prevalence rates. Tendon reformation should be included in the differential diagnosis of failed tenotomy procedures after a period of symptom relief. PMID- 23662231 TI - Distal humeral fixation of an intramedullary nail periprosthetic fracture. AB - Distal humeral periprosthetic fractures below intramedullary nail devices are complex and challenging to treat, in particular due to the osteopenic/porotic nature of bone found in these patients. Fixation is often difficult to satisfactorily achieve around the intramedullary device, whilst minimising soft tissue disruption. Descriptions of such cases in the current literature are very rare. We present the case of a midshaft humeral fracture treated with a locking compression plate that developed a nonunion, in a 60-year old female. This went on to successful union after exchange for an intramedullary humeral nail. Unfortunately, the patient developed a distal 1/5th humeral periprosthetic fracture, which was then successfully addressed with a single-contoured, extra articular, distal humeral locking compression plate (Synthes) with unicortical locking screws and cerclage cables proximally around the distal nail tip region. An excellent postoperative range of motion was achieved. PMID- 23662232 TI - The dentato-rubro-olivary tract: clinical dimension of this anatomical pathway. AB - Symptomatic palatal tremor is potentially the result of a lesion in the triangle of Guillain-Mollaret (1931) and is associated with hypertrophic olivary degeneration (HOD) which has characteristic MR findings. The triangle is defined by dentate efferents ascending through the superior cerebellar peduncle and crossing in the decussation of the brachium conjunctivum inferior to the red nucleus, to finaliy reach the inferior olivary nucleus (ION) via the central tegmental tract. The triangle is completed by ION decussating efferents terminating on the original dentate nucleus via the inferior cerebellar peduncle. We can demonstrate the anatomy of this anatomical triangle using a clinical case of palatal tremor presenting with bilateral subjective pulsatile tinnitus along with the pathognomonic MR findings previously described. The hyperintense T2 signal in these patients may be permanent, but the hypertrophied olive normally regresses after 4 years. The temporal relationship between the evolution of the histopathology and the development of the palatal tremor remains unknown as does the natural history of the tremor. Botox injection at the level of tensor and levator veli palatini insertion have been used to treat patients with disabling tremor synchronous tinnitus. A lesion involving the triangle can have a quite varied clinical expression. PMID- 23662233 TI - Size of metastatic lymph nodes. AB - We present a case and review of the literature of well-differentiated sigmoid adenocarcinoma with numerous metastases into pericolic lymph nodes. All positive lymph nodes were small. The authors concluded that there is no clear correlation between nodal size and the likelihood of metastasis in the lymph node, and the status of small lymph nodes must receive special attention by clinicians and pathologists. PMID- 23662234 TI - Metastatic pulmonary calcification in multiple myeloma in a 45-year-old man. AB - Metastatic calcification has been associated with multiple-myeloma-induced hypercalcemia. Despite of a relatively high prevalence of metastatic pulmonary calcification in patients with multiple myeloma, only a few cases have been clinically and radiologically detected. A 45-year-old Hispanic male presented to the Emergency Department with complaint of worsening weakness and myalgia. Laboratory findings revealed renal insufficiency and hypercalcemia. CT scan of chest revealed calcified pleural and pulmonary nodule. Technetium (Tc) 99 bone scan revealed diffuse activity in the pulmonary parenchyma consistent with metastatic pulmonary calcification. Metastatic pulmonary calcification, despite its high prevalence, remains undetected. This is, in part, due to its radiographic characteristic properties that evade detection by routine imaging studies. We present a case of a metastatic pulmonary calcification in a patient diagnosed with multiple myeloma and chronic kidney disease, as well as a brief literature review including clinical findings and treatment options. PMID- 23662235 TI - Pediatric plastic bronchitis: case report and retrospective comparative analysis of epidemiology and pathology. AB - Plastic bronchitis (PB) is a pathologic condition in which airway casts develop in the tracheobronchial tree causing airway obstruction. There is no standard treatment strategy for this uncommon condition. We report an index patient treated using an emerging multimodal strategy of directly instilled and inhaled tissue plasminogen activator (t-PA) as well as 13 other cases of PB at our institution between 2000 and 2012. The majority of cases (n = 8) occurred in patients with congenital heart disease. Clinical presentations, treatments used, histopathology of the casts, and patient outcomes are reviewed. Further discussion is focused on the epidemiology of plastic bronchitis and a systematic approach to the histologic classification of casts. Comorbid conditions identified in this study included congenital heart disease (8), pneumonia (3), and asthma (2). Our institutional prevalence rate was 6.8 per 100,000 patients, and our case fatality rate was 7%. PMID- 23662236 TI - The Amyand's Hernia: A Rare Clinical Entity Diagnosed by Computed Tomography. AB - Amyand's hernia, named for the first person to describe an inguinal hernia containing the vermiform appendix, is an uncommon variant of an inguinal hernia. Amyand's hernia is an extremely rare condition and is often misdiagnosed. Traditionally, these hernias have been diagnosed at surgery but are increasingly diagnosed by abdominal computed tomography (CT) scans. CT of the abdomen may help in guiding the diagnosis. PMID- 23662237 TI - Unilateral RS3PE in a Patient of Seronegative Rheumatoid Arthritis. AB - Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare but well-reported clinical entity. It is classically described as symmetrical involvement of both upper extremities. Asymmetrical involvement had also been reported, but unilateral presentation is very rare. We hereby report a case of unilateral RS3PE in a patient of seronegative rheumatoid arthritis which was initially misdiagnosed as cellulitis and was given high dose antibiotics without any significant improvement. Later a rheumatologic consultation leads to a prompt diagnosis, and treatment with steroids leads to dramatic reversal of symptoms. This case demonstrates the rare presentation of this rare clinical entity and highlights the necessity of awareness regarding unilateral disease to clinicians. PMID- 23662238 TI - Congenital diverticular disease of the entire colon. AB - Congenital or true colonic diverticulosis is a rare condition typified by the preservation of the colonic wall architecture within the diverticular outpouching. Cases of multiple jejunal diverticula have been reported as well as cases of solitary giant diverticula of the colon. There have been no reports in the literature of pancolonic congenital diverticulosis. PMID- 23662239 TI - Idiopathic unilateral adrenal haemorrhage and adrenal mass: a case report and review of the literature. AB - We report an unusual case of idiopathic unilateral adrenal haemorrhage (AH) in a 55-year-old patient. This rare case had two characteristics that made it worth of report. First, idiopathic adrenal haemorrhage is very uncommon, and second it was presented as a huge, 23 cm diameter and 2,123 gr weight, "silent" adrenal mass. It is important to distinguish a benign lesion like this from a neoplasm, although we were not able to identify it preoperatively and the diagnosis was only made after the excised specimen was examined by a group of experienced histopathologists. Only a few similar published cases, to our knowledge, are described in the worldwide literature and even fewer of this size. PMID- 23662240 TI - Rescue surgery 19 years after composite root and hemiarch replacement. AB - A 59-year-old male patient with Marfan's syndrome was referred to our clinic due to acute chest pain. His medical history contains complex surgery for type A aortic dissection 19 years ago including composite root replacement using a mechanical aortic valve. Immediate computed tomography indicated perforation at the distal ascending aortic anastomosis plus complete avulsion of both coronary ostia. The patient underwent successful rescue surgery with ascending aortic and arch replacement using a modified Cabrol technique. PMID- 23662241 TI - Artificially Positive Crossmatches Not Leading to the Refusal of Kidney Donations due to the Usage of Adequate Diagnostic Tools. AB - Allografting patients with human leukocyte antigens (HLA) which are recognized by preformed antibodies constitutes the main cause for hyper-acute or acute rejections. In order to select recipients without these donor-specific antibodies, the complement-dependent cytotoxicity crossmatch (CDC-CM) assay was developed as a standard procedure about forty years ago. The negative outcome of pretransplant crossmatching represents the most important requirement for a successful kidney graft survival. The artificially positive outcomes of CDC-based crossmatches due to the underlying disease Systemic Lupus Erythematosus (SLE), however, may lead to the unjustified refusal of adequate kidney grafts. Two prospective female recipients destined for a living as well as for a cadaver kidney donation, respectively, exhibited positive CDC-based crossmatch outcomes although for both patients no historical immunizing events were known. Furthermore, solid phase-based screening or antibody differentiation analyses never led to positive results. Immediate reruns of the CDC-based crossmatch assays using the alternative antibody monitoring system (AMS-)crossmatch ELISA resulted in unequivocally negative outcomes. Consequently both transplantations were performed without any immunological complications for the hitherto follow-up time of 25 and 28 months, respectively. We here show two case reports demonstrating an alternative methodical approach to circumvent CDC-based artefacts and point to the urgent need to substitute the CDC-based crossmatch procedure at least for special groups of patients. PMID- 23662242 TI - Solitary fibrous tumor of the kidney: a case report. AB - Solitary fibrous tumor is a spindle cell neoplasm mostly originating from pleura; however, it has also recently been reported to be extrapleural. A 57-year-old man presented with left lumbal pain. Ultrasonography and computed tomography showed a cystic lesion of 14 * 11 cm with solid areas and septations in middle and lower poles of the left kidney. Radical nephrectomy was performed. Immunohistochemical studies showed strong reactions with CD34 and CD99. A nuclear positivity with Ki 67 was observed in less than 1% of cells. Despite repeated stainings with vimentin, no clear tumor evaluation could be made due to artifacts. The tumor was negative with Bcl-2, desmin, HMB-45, S100, FVIII, and CD31. Histopathological and molecular studies made the diagnosis of a solitary fibrous tumor. The patient is now currently free of disease at the 26th month of followup. PMID- 23662243 TI - Renal cell carcinoma metastatic to thyroid gland, presenting like anaplastic carcinoma of thyroid. AB - Background. Renal cell carcinoma (RCC) has unpredictable and diverse behavior. The classic triad of hematuria, loin pain, and abdominal mass is uncommon. At time of diagnosis, 25%-30% of patients are found to have metastases. Bones, lungs, liver, and brain are the frequent sites of metastases. RCC with metastasis to the head and neck region and thyroid gland is the rarest manifestation and anaplastic carcinoma behaving metastatic thyroid mass is an extremely rare presentation of RCC. Case Presentation. A 56-year-old Saudi man with past history of right radical nephrectomy 5 years back presented with 3 months history of rapid increasing neck mass with dysphagia, presenting like anaplastic thyroid carcinoma. Tru-cut biopsy turned out to be metastatic renal cell carcinoma. Patient was treated with radiation therapy 30 Gy in 10 fractions to mass. Patient died 4 months after the discovery of anaplastic thyroid looking metastasis. Conclusion. Rapidly progressing thyroid metastases secondary to RCC are rare and found often unresectable which are not amenable to surgery. Palliative radiotherapy can be considered for such patients. PMID- 23662244 TI - Spontaneous bladder perforation in an infant neurogenic bladder: laparoscopic management. AB - Spontaneous bladder perforation is an uncommon event in childhood. It is usually associated with bladder augmentation. We are presenting a case of bladder rupture in an infant with neurogenic bladder without prior bladder surgery. Three days after lipomyelomeningocele excision the patient showed signs and symptoms of acute abdomen. The ultrasound exploration revealed significant amount of intraperitoneal free fluid and therefore a laparoscopic exploration was performed. A posterior bladder rupture was diagnosed and repaired laparoscopically. Currently, being 3 years old, she keeps successfully dry with clean intermittent catheterization. Neurogenic bladder voiding function can change at any time of its evolution and lead to complications. Early diagnosis of spontaneous bladder rupture is of paramount importance, so it is essential to think about it in the differential diagnosis of acute abdomen. PMID- 23662245 TI - Advanced hepatocellular carcinoma with subtotal occlusion of the inferior vena cava and a right atrial mass. AB - Hepatocellular carcinoma usually metastasizes to regional lymph nodes, lung, and bones but can rarely invade the inferior vena cava with intravascular extension to the right atrium. We present the case of a 75-year-old man who was admitted for generalized oedema and was found to have advanced HCC with invasion of the inferior vena cava and endovascular extension to the right atrium. In contrast to the great majority of hepatocellular carcinoma, which usually develops on the basis of liver cirrhosis due to identifiable risk factors, none of those factors were present in our patient. PMID- 23662246 TI - Detection of paroxysmal atrial fibrillation in stroke/tia patients. AB - One-third of stroke and transient ischemic attack (TIA) are cryptogenic, and paroxysmal atrial fibrillation (PAF) has been suggested as a possible cause for these cryptogenic strokes. Multiple studies have recently evaluated long-term cardiac rhythm monitoring with good yield for PAF. The duration of monitoring varies between studies as well as the qualifying event definition. Moreover, the clinical significance of very brief atrial fibrillation events is unclear in the literature. This paper provides an overview of current advances in the detection of paroxysmal atrial fibrillation, the clinical and genetic factors predictive of arrhythmia detection, and the therapeutic dilemma concerning this approach. PMID- 23662247 TI - Generation of Lung Epithelium from Pluripotent Stem Cells. AB - The understanding of key processes and signaling mechanisms in lung development has been mainly demonstrated through gain and loss of function studies in mice, while human lung development remains largely unexplored due to inaccessibility. Several recent reports have exploited the identification of key signaling mechanisms that regulate lineage commitment and restriction in mouse lung development, to direct differentiation of both mouse and human pluripotent stem cells towards lung epithelial cells. In this review, we discuss the recent advances in the generation of respiratory epithelia from pluripotent stem cells and the potential of these engineered cells for novel scientific discoveries in lung diseases and future translation into regenerative therapies. PMID- 23662250 TI - Tissue engineering: Propagating the wave of change. PMID- 23662249 TI - Natural Polyphenols Inhibit Lysine-Specific Demethylase-1 in vitro. AB - Natural polyphenols, such as resveratrol, have beneficial functions on major human diseases such as cancer, diabetes, and cardiovascular disease. Besides acting as antioxidants, some of these polyphenols can also target proteins to modulate specific biological pathways. The lysine-specific histone demethylase LSD1 plays important roles in cell growth, differentiation and nutrient metabolism. Here, we studied the effect of natural polyphenols resveratrol, curcumin, quercetin and analogs on LSD1. Using in vitro LSD1 enzymatic assays, we show that resveratrol, curcumin and quercetin displayed a potent inhibitory effect on the LSD1 activity and were more potent than the known LSD1 inhibitor trans-2-phenylcyclopropylamine (TCP). The new function of resveratrol, curcumin and quercetin is independent of their antioxidant properties, as other antioxidants had no effect on LSD1 under the similar conditions. In C2C12 fibroblasts, resveratrol and curcumin can efficiently inhibit myogenic expression and differentiation, for which LSD1 is required. Thus, our study has identified LSD1 as a novel target of bioactive natural compounds, such as resveratrol, curcumin and quercetin, and such finding suggests that LSD1 inhibition can at least partially contribute to some of the previously observed beneficial effects of these compounds. PMID- 23662251 TI - Research in maxillofacial surgery. PMID- 23662252 TI - The role of distraction osteogenesis in the management of craniofacial syndromes. AB - Distraction osteogenesis (DO) has been established as a useful technique in the correction of skeletal anomalies of the long bones for several decades. However, the use of DO in the management of craniofacial deformities has been evolving over the past 20 years, with initial experience in the mandible, followed by the mid-face and subsequently, the cranium. This review aims to provide an overview of the current role of DO in the treatment of patients with craniofacial anomalies. PMID- 23662254 TI - Costal cartilage nasal augmentation rhinoplasty: Study on warping. AB - BACKGROUND: To retrospectively study the costochondral graft (CCG) based nasal dorsum augmentation failures due to warping. MATERIALS AND METHODS: All patients fulfilling inclusion and exclusion criteria between January 2008 and December 2011 were included in the study. The details of the dorsal nasal length (DNL) immediate postoperative and 1 week postoperative period as well as the degree of divergence from midline by warping noted down in mm along with age, gender, and nature of graft. STATISTICS: Data analyzed using Statistical Package for the Social Sciences version 17. Descriptive statistics, Chi-square test and one-way analysis of variance are presented. P value <=0.05 was considered significant. RESULT: One hundred and fifty seven cases fulfilled the criteria. Of these, 44 (28%) were males and rest were females. The mean age of the patients was 24.41 +/ 4.9 years with a range of 17-37 years. In 102 cases (65%) had soft CCG while 55 (35%) were identified to be gritty type of CCG. Of the 157 cases, warping was identified in 41 cases (26.1%) and required revision of the surgery. Age group was significantly associated with presence of warping (P = 0.000). DISCUSSION: With increase in age, the number of patients with gritty CCG was higher. Older patients had lesser incidence of warping while younger patients had more incidence of warping. The incidence was not significantly related to gender or the DNL. The grafts that were relatively straight had less incidence of warping. PMID- 23662253 TI - Premaxillary characteristics in complete bilateral cleft lip and palate: A predictor for treatment outcome. AB - OBJECTIVES: The aim of the current study was to investigate how bilateral cleft lip and palate (BCLP) cases responded differently to presurgical orthopedics (PSO) and primary lip repair (LR) based on premaxillary characteristics. We suggest a clinically oriented descriptive classification for BCLP based on premaxillary characteristics. DESIGN AND SETTING: A retrospective longitudinal comparative study where available records of all non-syndromic patients with complete BCLP attending the Cleft Clinic, affiliated to the Oral and Maxillofacial Surgery department, Ain-Shams University, Cairo, Egypt were assessed. SAMPLE POPULATION AND METHODOLOGY: Twenty-two cases were collected over a 4-years period from 2008 to 2011 (15 boys and 7 girls). Model assessment was performed for serial models representing four stages of treatment; M1: Prior to start of PSO, M2: At the end of PSO, M3: One month after LR, M4: Three months after LR. The premaxillary and vomerine widths were measured on M1. Models (M1 M4) were assessed for changes in anteroposterior projection, anterior arch width, intercanine width and posterior arch width and results were statistically analyzed. Intra-and postoperative surgical findings during and after primary LR were recorded. The sample was divided into two groups based on the premaxillary size and characteristics; Group R: Rudimentary premaxilla and Group P: Prominent premaxilla. RESULTS: There was a highly significant difference in premaxillary width between the two groups (P = 0.00), changes in anteroposterior projection of the premaxilla were significant one and three months after LR. Changes in maxillary anterior arch width, intercanine and posterior arch widths were non significant between groups. Mean age difference between the two groups was only statistically significant at the stage of LR. Surgical differences were noted between the two groups. Postoperatively as compared to group R; group P showed more premaxillary bulge and show at rest, as well as more prolabial stretching. In addition, facial profile was more convex in group P. CONCLUSION: The two types of BCLP outlined in this study are different from several aspects, and hence management should be modified according to each case. This descriptive classification provides a useful tool for evaluation and planning of patients with BCLP. PMID- 23662248 TI - Protein Oxidative Modifications: Beneficial Roles in Disease and Health. AB - Protein oxidative modifications, also known as protein oxidation, are a major class of protein posttranslational modifications. They are caused by reactions between protein amino acid residues and reactive oxygen species (ROS) or reactive nitrogen species (RNS) and can be classified into two categories: irreversible modifications and reversible modifications. Protein oxidation has been often associated with functional decline of the target proteins, which are thought to contribute to normal aging and age-related pathogenesis. However, it has now been recognized that protein oxidative modifications can also play beneficial roles in disease and health. This review summarizes and highlights certain positive roles of protein oxidative modifications that have been documented in the literature. Covered oxidatively modified protein adducts include carbonylation, 3 nitrotyrosine, s-sulfenation, s-nitrosylation, s-glutathionylation, and disulfide formation. All of which have been widely analyzed in numerous experimental systems associated with redox stress conditions. The authors believe that selected protein targets, when modified in a reversible manner in prophylactic approaches such as preconditioning or ischemic tolerance, may provide potential promise in maintaining health and fighting disease. PMID- 23662255 TI - Fixation of zygomatic and mandibular fractures with biodegradable plates. AB - CONTEXT: In this prospective study, 13 randomly selected patients underwent treatment for zygomatic-complex fractures (2 site fractures) and mandibular fractures using 1.5 / 2 / 2.5-mm INION CPS biodegradable plates and screws. AIMS: To assess the fixation of zygomatic-complex and mandibular fractures with biodegradable copolymer osteosynthesis system. MATERIALS AND METHODS: In randomly selected 13 patients, zygomatic-complex and mandibular fractures were plated using resorbable plates and screws using Champy's principle. All the cases were evaluated clinically and radiologically for the type of fracture, need for the intermaxillary fixation (IMF) and its duration, duration of surgery, fixation at operation, state of reduction at operation, state of bone union after operation, anatomic reduction, paresthesia, occlusal discrepancies, soft tissue infection, immediate and late inflammatory reactions related to biodegradation process, and any need for the removal of the plates. STATISTICAL ANALYSIS USED: Descriptives, Frequencies, and Chi-square test were used. RESULTS: In our study, the age group range was 5 to 55 years. Road traffic accidents accounted for the majority of patients six, (46.2%). Postoperative occlusal discrepancies were found in seven patients as mild to moderate, which resolved with IMF for 1-8 weeks. There were minimal complications seen and only as soft tissue infection. CONCLUSIONS: Use of biodegradable osteosynthesis system is a reliable alternative method for the fixation of zygomatic-complex and mandibular fractures. The biodegradable system still needs to be refined in material quality and handling to match the stability achieved with metal system. Biodegradable plates and screws is an ideal system for pediatric fractures with favorable outcome. PMID- 23662256 TI - Ultrasound guided drainage of submasseteric space abscesses. AB - BACKGROUND AND OBJECTIVES: The objective of this study was to evaluate the usefulness of ultrasound guided surgical drainage in submasseteric space abscess of odontogenic origin without incision. MATERIALS AND METHODS: Eleven patients (4 males and 7 females) aged 18 to 36 years were included in this study. Each patient had clinically and radiologically diagnosed submasseteric space abscesses of odontogenic origin. All the patients underwent ultrasound guided drainage by using 5.7 MHz B-mode, gray scale, ultrasound scanner. The aspirated pus was sent for microbiological culture and sensitivity tests. All the patients were given a prescription of antibiotics like Amoxicillin with Clavulanate in a dose of 625 mg 8 hourly daily, Metronidazole 400 mg 8 h daily and analgesic Diclofenac potassium in a dose of 50 mg 8 h daily. Infection was considered resolving when the following criteria were met like ceased or minimal drainage. RESULTS: There was successful resolution of abscess in 10 cases, 1 case underwent incision and drainage because of spread of infection to other spaces. CONCLUSION: This study on 11 cases supported ultrasonography as an intraoperative aid in the assessment of the abscess cavity and its real-time imaging facility will help in the location and drainage of the abscess cavity effectively. It avoids large, unsightly, postoperative facial scars and often eliminates the need of general anesthesia and hospitalization. PMID- 23662257 TI - Enlarged lymph nodes in head and neck cancer: Analysis with triplex ultrasonography. AB - BACKGROUND: Presence of cervical metastasis is one of the factors influencing the outcome of patients with carcinoma of the head and neck, its early detection is potentially very important. Triplex ultrasonography technology have definitive role in detecting clinically undetectable involvement of lymph nodes (LNs). The purpose of this study was to evaluate, whether triplex ultrasonography characterization of cervical LNs could, with an acceptable degree of certainty, differentiate malignant from benign/reactive LNs, in order to prevent invasive diagnostic procedures. MATERIALS AND METHODS: A total of 50 patients with oral cancer, were subjected to ultrasonographic investigation of the neck for grayscale, color flow imaging, and pulsed Doppler. All the parameters were compared with histopathologic examination. Correlation was then made between ultrasound and Doppler investigation and histopathology results to evaluate the sensitivity specificity, positive predictive value (PPV) and negative predictive value (NPV) of color Doppler ultrasonography in detecting metastatic neck nodes. RESULTS: Study results showed that malignant LNs, especially metastatic nodes, are accompanied with significantly high resistive index (RI) and pulsatility index (PI) values, rounded shape, size, loss of central hilar echogenicity and peripheral vascularity. Among these sonographic findings, nodal shape (longitudinal nodal diameter to transverse diameter ratio or L/T ratio), RI and PI values were more accurate for differentiating benign from malignant LNs. CONCLUSION: In this study, triplex sonographic findings had relatively high accuracy in differentiating benign from malignant cervical LNs. Ultrasound hence can be recommended for initial non-invasive evaluation of the neck in patients with oral cancers with or without palpable cervical lymph nodes. PMID- 23662258 TI - Residual diplopia in treated orbital bone fractures. AB - BACKGROUND: Residual diplopia (RD) is the main post-treatment complication of orbital bone fracture (OBF) reduction. The cause of RD is varied and often related to the degree of inflammation, surgical timing, graft requirement, and trauma to orbital musculature, fat, as well as nerves. The exact prevalence of these and the influence of these factors on RD is not widely reported in literature. MATERIALS AND METHODS: This retrospective study was conducted from January 1, 2000 through December 31, 2011. Sixty nine patients fulfilling inclusion and exclusion criteria were enrolled in this study. The nature of the defect causing RD was identified. Demographics, nature of initial OBF, extent and type of treatment, and grafts were noted. Corrective surgeries were performed. Data entry and analysis were performed using SPSS. Descriptive statistics and Chi square tests were employed. P value <= 0.05 was taken as significant. RESULTS: Inferior rectus muscle (71%) and other periorbital musculature (56.5%) was entrapped, leading to RD. Globe position abnormalities was observed in 52.1% of cases. Degree of inflammation, types of grafts (P = 0.000) were significantly related. DISCUSSION: Preoperative swelling, musculature inflammation, and graft placement significantly influenced the surgical outcome of OBF. RD is related to these factors. Adequate control with OBF healing and remodeling needs to be considered while timing OBF. Author's modification with mesh and cartilage in secondary corrective surgery for RD provided an effective solution for immediate intervention. PMID- 23662259 TI - Review of secondary alveolar cleft repair. AB - INTRODUCTION: The alveolar cleft is a bony defect that is present in 75% of the patients with cleft lip and palate. Although secondary alveolar cleft repair is commonly accepted for these patients, nowadays, controversy still remains regarding the surgical technique, the timing of the surgery, the donor site, and whether the use of allogenic materials improve the outcomes. The purpose of the present review was to evaluate the protocol, the surgical technique and the outcomes in a large population of patients with alveolar clefts that underwent secondary alveolar cleft repair. MATERIALS AND METHODS: A total of 109 procedures in 90 patients with alveolar cleft were identified retrospectively after institutional review board approval was obtained. The patients were treated at a single institution during a period of 10 years (2001-2011). Data were collected regarding demographics, type of cleft, success parameters of the procedure (oronasal fistulae closure, unification of the maxillary segments, eruption and support of anterior teeth, support to the base of the nose, normal ridge form for prosthetic rehabilitation), donor site morbidity, and complications. Pre- and postoperative radiological examination was performed by means of orthopantomogram and computed tomography (CT) scan. RESULTS: The average patient age was 14.2 years (range 4-21.3 years). There were 4 right alveolar-lip clefts, 9 left alveolar-lip clefts, 3 bilateral alveolar-lip clefts, 18 right palate-lip clefts, 40 left palate-lip clefts and 16 bilateral palate-lip clefts. All the success parameters were favorable in 87 patients. Iliac crest bone grafts were employed in all cases. There were three bone graft losses. In three cases, allogenic materials used in a first surgery performed in other centers, underwent infection and lacked consolidation. They were removed and substituted by autogenous iliac crest bone graft. CONCLUSIONS: THE USE OF AUTOGENOUS ILIAC CREST FOR SECONDARY ALVEOLAR BONE GRAFTING ACHIEVES ALL THESE SEVERAL OBJECTIVES: (1) to obtain maxillary arch continuity, (2) to maximize bone support for the dentition, (3) to stabilize the maxillary segments after orthodontic treatment, (4) to eliminate oronasal fistulae, (5) to provide nasal alar cartilage support, (6) to establish ideal alveolar morphology, and (7) to provide available bone with attached soft tissue for future endosteal implant placement in cases where there is a residual dental space. We advocate for the use of a minimal incision to obtain the iliac crest bone graft and for the use of a corticocancellous block of bone in combination with bone chips. PMID- 23662260 TI - Immunohistochemical profiling of Ameloblastomas using cytokeratin, vimentin, smooth muscle actin, CD34 and S100. AB - BACKGROUND: Ameloblastoma is characterized as a slow growing, non-metastatic and a locally invasive tumor with a high risk of recurrence. Immunohistochemical evaluation of ameloblastomas using epithelial and connective tissue specific markers help in studying the histogenesis and assessing the biological behavior. The aim of the study was to study the expression patterns of cytokeratin, vimentin, smooth muscle actin (SMA), S100 and CD34 in ameloblastomas. MATERIALS AND METHODS: The material for the study consisted of 24 cases of ameloblastomas. The excised specimens were grossed and bits were taken from different areas of the specimen. Based on the histopathology, the cases were classified into different types and stained for immunohistochemistry. RESULTS: The cases showed strong positivity to cytokeratin, vimentin, moderate positivity for SMA and S100. Five cases were also moderately positive for CD34 in blood vessels. CONCLUSION: The results and hypothesis achieved from the study, proved to be consistent, not only augmenting the already existing hypothesis but also imparting new concepts of hypothesis. PMID- 23662261 TI - Gene p63: In ectrodactyly-ectodermal dysplasia clefting, ankyloblepharon ectodermal dysplasia, Rapp-Hodgkin syndrome. AB - INTRODUCTION: An analysis was made of three different syndromes associated with p63 gene mutations, known as ectrodactyly-ectodermal dysplasia-clefting syndrome (EEC), ankyloblepharon-ectodermal dysplasia clefting syndrome (AEC or Hay-Wells) and Rapp-Hodgkin syndrome (RHS). The postoperative complications associated with their cleft reconstructions were also evaluated. MATERIALS AND METHODS: Extensive demographic information, in particular of the clinical appearances, associated malformations, and the types and complications of the reconstructive surgical procedures, were recorded of these syndromic cases occurring in a database of 3621 facial cleft deformity patients. The data was analyzed using the Microsoft Excel program. RESULTS: A total of 10 (0.28%) cases of p63 associated syndromes were recorded: EEC (6), RHS (3), and AEC (1). The following clinical cleft appearances were noted - EEC = 6: CLA 1 -right side unilateral (female); CLAP 4 - right side (1) + left side (1) unilateral (male + female); bilateral (2) (males); hPsP 1 (female) (divided in 3 Black, 2 White, 1 Indian); RHS = 3: CLAP 2 (White males); hPsP 1 (White female); AEC = 1: CLAP bilateral (White male). Other features of the syndromes were: skin, hand, foot, tooth, hair and nail involvement, and light sensitivity. Postoperative complications included: (i) stenosis of nasal opening, especially after reconstruction of the bilateral cleft lip and the columella lengthening (2 cases), (ii) premaxilla-prolabium fusion (2 cases), (iii) repeated occurrence of oro-nasal fistula in the hard palate (4 cases), and (iv) dysgnathial development of midfacial structures (3 cases). DISCUSSION: Three different p63 associated syndromes (EEC, AEC, and RHS) were diagnosed (0.27% of the total facial cleft deformities database). The majority of the cases presented with a bilateral CLAP in males only. A number of females and males had unilateral CLA. The hPsP-cleft was recorded in females only. The associated ectodermal component most probably had a profoundly negative influence on postoperatively wound healing, which was observed in particular at the nasal openings, the premaxilla sulcus and in the hard palate mucosa. The reconstruction of p63 associated syndromes is a greater challenge than the usual cleft reconstruction to the surgeon. PMID- 23662262 TI - Craniosynostosis: Esthetic protocol in open technique. AB - INTRODUCTION: The past two decades have seen advances relative to the treatment of patients with craniosynostosis in the areas of resorbable fixation, imaging, and both intraoperative and perioperative management. The purpose of this study is to present open cranial vault reshaping techniques and anesthetic protocol used at Louisiana State University Health - Shreveport, USA. MATERIALS AND METHODS: The surgical procedure of choice was single-stage open cranial vault reshaping with barrel-staving and orbital bandeau advancement as needed for supra orbital rim deficiencies. RESULTS: The outcomes of single-stage cranial vault reshaping with selective postoperative dynamic orthotics yielded symmetrical and consistent clinical results with only three children out of over 100 cases requiring later surgical correction. DISCUSSION: Our review of techniques provides a safe protocol for management of craniosynostosis with symmetrical clinical head shape. The techniques presented here are aimed at improving the multidisciplinary management of these patients. PMID- 23662263 TI - Craniofacial fibrous dysplasia: Surgery and literature review. AB - OBJECTIVE: To highlight the clinical and radiologic features and management of craniofacial fibrous dysplasia with review of literature. MATERIALS AND METHODS: A retrospective review of 6 patients who underwent surgical treatment in a tertiary healthcare centre was done using the parameters of patients' details, clinical features, radiological findings, management and postoperative review. RESULTS: Of the six patients, 3 females and 2 males were in the 2(nd) decade of life and 1 male in the 1(st) decade of life. The disease was restricted to maxilla in 3 patients, involved the temporal and frontal bones in addition to maxilla in one, involved the frontal bone in one patient and involved frontal and parietal bones in one patient. The primary reason for seeking treatment in all the 6 cases was facial deformity. There was absence of pain in all 6 cases. For surgical treatment in all three cases involving the maxilla, the approach was intraoral while bicoronal approach was used for the other three cases. Treatment consisted of surgical contouring and reshaping the area. All cases were followed up over a period of 2 years with no signs of recurrence. CONCLUSION: Treatment of craniofacial fibro-osseous lesions is highly individualized. Most cases of craniofacial fibrous dysplasia manifest as swellings that cause facial deformity and surgical recontouring after cessation of growth seems to provide the best results. PMID- 23662264 TI - Microsurgical free flaps: Controversies in maxillofacial reconstruction. AB - Reconstructive microsurgery for oral and maxillofacial (OMF) defects is considered as a niche specialty and is performed regularly only in a handful of centers. Till recently the pectoralis major myocutaneous flap (PMMC) was considered to be the benchmark for OMF reconstruction. This philosophy is changing fast with rapid advancement in reconstructive microsurgery. Due to improvement in instrumentation and the development of finer techniques of flap harvesting we can positively state that microsurgery has come of age. Better techniques, microscopes and micro instruments enable us to do things previously unimaginable. Supramicrosurgery and ultrathin flaps are a testimony to this. Years of innovation in reconstructive microsurgery have given us a reasonably good number of very excellent flaps. Tremendous work has been put into producing some exceptionally brilliant research articles, sometimes contradicting each other. This has led to the need for clarity in some areas in this field. This article will review some controversies in reconstructive microsurgery and analyze some of the most common microvascular free flaps (MFF) used in OMF reconstruction. It aims to buttress the fact that three flaps-the radial forearm free flap (RFFF), anterolateral thigh flap (ALT) and fibula are the ones most expedient in the surgeon's arsenal, since they can cater to almost all sizeable defects we come across after ablative surgery in the OMF region. They can thus aptly be titled as the workhorses of OMF reconstruction with regard to free flaps. PMID- 23662265 TI - TMJ imaging by CBCT: Current scenario. AB - Radiographic examination forms an integral component of the clinical assessment routine in patients with temporomandibular joint disorders (TMJ). There are several imaging modalities to visualize the TMJ. Cone beam computed tomography (CBCT) is a developing technique that is being increasingly used in dentomaxillofacial imaging due to its relatively low-dose high-spatial-resolution characteristics. Research in TMJ imaging has been greatly inspired by the advent of CBCT. In this paper we aim to discuss the present scenario of the role of CBCT in TMJ imaging. PMID- 23662266 TI - Cleft palate in Williams syndrome. AB - Williams-Beuren syndrome (WBS) is a genomic neurodevelopmental disorder, estimated to occur in approximately 1 in 10,000 persons. It is caused by a deletion of the "elastin" gene on chromosome 7q11.23 and was described officially in 1961 by Williams, Barrat-Boyes, and Lowe. Cleft palate is not considered in the medical literature as a part of the multisystem disorders of the Williams syndrome but it was yet described. We present our experience of a patient who presents cleft palate among other congenital malformations. PMID- 23662267 TI - Degloving facial injury treated with hydroconductive dressing. AB - COMPLEX, OPEN MAXILLOFACIAL FRACTURES ARE OFTEN ACCOMPANIED BY EXTENSIVE CONTAMINATION, CRUSH, OR AVULSION OF THE OVERLYING SOFT TISSUE, THERE HAVE BEEN TWO ALTERNATIVES TO TREATMENT: either radical debridement of all contaminated tissue, fixation of the underlying fractures, and soft tissue closure by pedicle flap or graft is done; or more conservative debridement is repeated multiple times until the contaminated tissue is removed and fracture fixation is deemed safe. Debridement is usually accomplished by sharp debridement or with high pressure intermittent irrigation or some combination of both modalities. The problems with this standard treatment in the face are that facial features may be distorted, superficial branches of the facial and/or trigeminal nerve can be inadvertently sacrificed (even with the use of nerve stimulators), and scarring can distort contours and radically change facial appearance. A serious facial degloving injury with necrotic malodorous tissue and no clear anatomical delineations demanded special attention. The purpose of this report is to demonstrate the management of a soft tissue avulsive contaminated injury of the face with underlying maxillofacial fractures. PMID- 23662268 TI - Ectopic tooth in maxillary sinus: Case series. AB - Ectopic eruption of a tooth within the dentate region of the jaws is often noticed in clinical practice and is well documented in the literature. But the ectopic eruption into the non dentate region is rare and scantly documented. The maxillary sinus is one such a non dentate region, apart from nasal septum, mandibular condyle, coronoid process and the palate, to accommodate such ectopic eruptions of teeth. Due to its rarity and lack of consensus over its management, the incidence deserves to be added to the literature and discussed. Early surgical intervention for removal of ectopic tooth along with enucleation of the associated cyst, if any, is the treatment of choice. PMID- 23662269 TI - Burried broken extraction instrument fragment. AB - Despite adequate effort to perform tooth removal carefully, some accidents may happen when defective instruments are unknowingly used. This article reports of a non-symptomatic case of a retained fractured dental elevator tip during an uneventful extraction a decade earlier. Patient was not aware till routine radiographic examination revealed its presence. Use of three dimensional imaging techniques in this case is highlighted. Rarely, instruments breakage may occur during surgical procedures. It is duty of the dentists to check the surgical instrument for signs of breakage and be prepared to solve a possible emergency. Retained fragments should be carefully studied prior to attempt of removal. PMID- 23662270 TI - Non-Hodgkin's lymphoma of maxillary sinus: An unusual presentation. AB - Non-Hodgkin's Lymphoma (NHL) are a group of neoplasms that originate from the cells of the lymphoreticular system. Forty percent of Non-Hodgkin's lymphoma arises from extranodal sites. The nasal cavities and paranasal sinuses are rarely affected by primary NHL. Common primary extranodal sites of lymphomas include stomach, liver, soft tissue, dura, bone, intestine and bone marrow. Most patients present with rapidly enlarging masses, often with symptoms both locally and systemically (fever, recurrent night sweats, or weight loss). The vast majority of patients with localized disease are curable with combined modality therapy or combination chemotherapy alone. About 50% patients are cured with doxorubicin based combination chemotherapy and rituximab. An atypical case of extranodal Non Hodgkin's lymphoma of maxillary sinus is discussed. PMID- 23662271 TI - Swelling on lower lip...not always a mucocele !!! AB - Schwannomas are well characterized uncommon neural neoplasms which may rarely present with variation in clinical manifestation. Oral Schwannomas clinically simulate other lesions like traumatic fibroma, pyogenic granuloma, mucocele and salivary gland lesions. The diagnosis of schwannoma is typically made at the time of surgery following biopsy and surgical resection is the mainstay of treatment with no chances of recurrence as they are well encapsulated. We present a case of schwannoma of lower lip occurring in a 21-year-old female patient. PMID- 23662272 TI - Psammomatoid type juvenile ossifying fibroma of mandible. AB - Juvenile ossifying fibroma (JOF) is a rare fibro-osseous neoplasm that arises within the craniofacial bones in individuals under 15 years of age, and these lesions are usually benign and tend to grow slowly. The psammomatous type of juvenile ossifying fibroma (PsJOF) mainly involves the bones of the orbit and paranasal sinuses, whereas the trabecular type commonly involves the jaws. We are presenting a case of PsJOF of ramus of mandible in a 7-years-old boy, which is an uncommon condition, and histologically showed predominantly a cellular connective tissue stroma, composed of numerous spindle-shaped cells arranged in fascicular storiform pattern. In between these irregular strands of trabeculae with plump osteoblast, spheroidal ossicles with basophilic in center and eosinophilic in periphery resembling psammoma-like bodies are noticed. PMID- 23662273 TI - Are we under-estimating basic first line drug regimes of beta-lactam antibiotics clindamycin and metronidazole in dental oral and maxillofacial infections? PMID- 23662274 TI - SPER 2(nd) Annual Conference: 09(th) March 2013 at Jamia Hamdard, New Delhi, India. PMID- 23662275 TI - New drug discovery: Where are we heading to? PMID- 23662276 TI - Current concepts and prospects of herbal nutraceutical: A review. AB - Nutraceuticals are food or part of food that provides medical or health benefits including the prevention and/or treatment of a disease. Nutraceutical has advantage over the medicine because they avoid side effect, have naturally dietary supplement, etc. Nutraceutical; on the basis of their natural source, chemical grouping, categories into three key terms -nutrients, herbals, dietary supplements, dietary fiber, etc. The most rapidly growing segments of the industry were dietary supplements (19.5 percent per year) and natural/herbal products (11.6 percent per year). Global nutraceutical market is estimated as USD 117 billion. FDA regulated dietary supplements as foods to ensure that they were safe. In 2006, the Indian government passed Food Safety and Standard Act to regulate the nutraceutical industry. Herbal nutraceutical is used as a powerful instrument in maintaining health and to act against nutritionally induced acute and chronic diseases, thereby promoting optimal health, longevity, and quality of life. PMID- 23662277 TI - Nanoparticles laden in situ gelling system for ocular drug targeting. AB - Designing an ophthalmic drug delivery system is one of the most difficult challenges for the researchers. The anatomy and physiology of eye create barriers like blinking which leads to the poor retention time and penetration of drug moiety. Some conventional ocular drug delivery systems show shortcomings such as enhanced pre-corneal elimination, high variability in efficiency, and blurred vision. To overcome these problems, several novel drug delivery systems such as liposomes, nanoparticles, hydrogels, and in situ gels have been developed. In situ-forming hydrogels are liquid upon instillation and undergo phase transition in the ocular cul-de-sac to form viscoelastic gel and this provides a response to environmental changes. In the past few years, an impressive number of novel temperature, pH, and ion-induced in situ-forming systems have been reported for sustain ophthalmic drug delivery. Each system has its own advantages and drawbacks. Thus, a combination of two drug delivery systems, i.e., nanoparticles and in situ gel, has been developed which is known as nanoparticle laden in situ gel. This review describes every aspects of this novel formulation, which present the readers an exhaustive detail and might contribute to research and development. PMID- 23662278 TI - In vitro dissolution study of atorvastatin binary solid dispersion. AB - The aim of the present study was to improve the solubility and dissolution rate of atorvastatin (ATV), a slight water-soluble drug, by solid dispersion (SD) technique using a hydrophilic carrier Poloxamer 188 (POL188). Physical mixing (PM) and solvent evaporation (SE) method were used to prepare ATV-SD where different drug-carrier ratios were used. Prepared formulations were characterized in their solid state by solubility study; differential scanning calorimetry, scanning electron microscopy, and Fourier transform infrared spectroscopy which demonstrated changes in the formulations supporting the improved solubility. Percent content of POL188 in the SD matrix was found to play the pivotal role in the improvement of dissolution property of ATV. In case of PM, highest enhancement in drug release was found for 1:3 ratio (P < 0.05, ANOVA Single factor) whereas in case of SE, 3:0.5 ratio of ATV-POL188 resulted the maximum enhancement in ATV release (P < 0.05, ANOVA Single factor). Analysis of dissolution data of optimized formula indicated the best fitting with Peppas Korsmeyer model and the drug release kinetics was fickian diffusion. In conclusion, binary SD prepared by both PM and SE technique using POL188 could be considered as a simple, efficient method to prepare ATV solid dispersions with significant improvement in the dissolution rate. PMID- 23662279 TI - Antioxidant markers based TLC-DPPH differentiation on four commercialized botanical sources of Shankhpushpi (A Medhya Rasayana): A preliminary assessment. AB - Shankhpushpi is a cognition boosting traditional ayurvedic brain supplement. Convolvulus pluricaulis (Convolvulaceae), Evolvulus alsinoides (Convolvulaceae), Clitoria ternatea (Papilionaceae), and Canscora decussata (Gentianaceae) are botanical claimants of Shankhpushpi. This investigation is to focus the identification of the compound based on biological marker differentiation of four botanical claimants of Shankhpushpi for their antioxidant evaluation on thin layer chromatography (TLC) by 2,2-diphenyl-1-picrylhydrazyl (DPPH) method. A rapid TLC-DPPH method was developed to identify and differentiate four botanical claimants of Shankhpushpi in terms of presence of beta-carotene, rutin, scopoletin, chlorogenic acid, and mangiferin. C. pluricaulis shows presence of scopoletin; E. alsinoides shows presence of beta-carotene, scopoletin, and chlorogenic acid; C. ternatea shows presence of beta-carotene, scopoletin, and rutin; and C. decussata shows presence of beta-carotene, scopoletin, and mangiferin. The order, they followed, based on their antioxidant potential is beta-carotene < mangiferin < rutin < scopoletin < chlorogenic acid. Antioxidants are attributed for their beneficial role in age-related cognition decline. The proposed method provides an edge in terms of identification and quantification of antioxidant constituents in a multi-component system. This method may also provide application for identification of correct plant sources used in the name of Shankhpushpi in marketed ayurvedic formulation, food supplement, and extracts. PMID- 23662280 TI - Formulation and in vitro evaluation of Eudragit S-100 coated naproxen matrix tablets for colon-targeted drug delivery system. AB - The purpose of the present investigation was to prepare matrix tablets of naproxen using a hydrophobic polymer, i.e., Eudragit RLPO, RSPO, and combination of both, by wet granulation method. The tablets were further coated with different concentrations of Eudragit S-100, a pH-sensitive polymer, by dip immerse method. In vitro drug release studies of tablets were carried out in different dissolution media, i.e., 0.1 N HCl (pH 1.2), phosphate buffers pH 6.8 and 7.4, with or without rat cecal content. The swelling studies of the optimized formulation were carried out. The physicochemical parameters of all the formulations were found to be in compliance with the pharmacopoeial standards. The effect of dissolution medium on the surface of matrix tablet was determined by using Scanning Electron Microscopy technique. The stability studies of all formulations were performed as per ICH guidelines. The results demonstrated that the tablets coated with Eudragit S-100 (2% w/v) showed a sustained release of 94.67% for 24 h, but drug release increased to about 98.60% for 24 h in the presence of rat cecal content while the uncoated tablets released the drug within 5 h. With regard to release kinetics, the data were best fitted with the Higuchi model with non-Fickian drug release kinetics mechanism. The stability studies of tablets showed less degradation during accelerated and room temperature storage conditions for 6 months. The enteric-coated Eudragit S-100 coated matrix tablets of naproxen showed promising site-specific drug delivery in the colon region. PMID- 23662281 TI - Semisolid matrix-filled hard gelatin capsules for rapid dissolution of amlodipine besilate: Development and assessment. AB - The objective of the study was to prepare semisolid capsules (SSCs) of poorly water-soluble drug amlodipine besilate (AB) using a combination of technologies involving solid dispersion (SD) preparation and converting it into semisolid matrix filled in hard gelatin capsules (termed as SSCs) with the aim of reducing lag time in drug release and to improve the dissolution rate. AB is used for its anti-arrhythmic, anti-anginal, and anti-hypertensive activity. These are the emergency activities which should be treated as fast as possible like in the case of angina attack (heart attack). Any lag time that is generated due to its poor dissolution can add on in this emergency and that can be avoided by developing a readily dissolvable formulation: SDs of AB. SD of AB was prepared by fusion method using varying combinations of Poloxamer 407 and Plasdone S630. A total of nine batches (SD1-SD9) were characterized for the in vitro dissolution behavior in phosphate buffer pH7.4. SD8 with 95.8% cumulative drug release in 60 min, t 50% = 4.1 min and DE30 Min = 84.2% were selected for the development of the semisolid matrix. Differential scanning calorimetry of SD8 revealed molecular dispersion of AB and Plasdone S630 in Poloxamer 407. SD8 was then formulated as SSCs using gelucire 44/14 and PEG 400 as semisolid components and PEG 6000 as a suspending agent to achieve the reduction in lag time for drug release. A total of seven SSC formulations were prepared and evaluated for drug release. Formulation of SSC4 showed maximum cumulative drug release (CDR) of 98.9% within 20 min that was almost a threefold reduction in the time required to achieve similar CDR by SD of AB. Thus, SSCs present an excellent approach to enhance the dissolution as well as to reduce the lag time of dissolution for poor water soluble drugs especially to those therapeutic classes that are intended for faster onset of action. PMID- 23662282 TI - Pharmacophore modeling and 3D quantitative structure-activity relationship analysis of febrifugine analogues as potent antimalarial agent. AB - Febrifugine and its derivatives are effective against Plasmodium falciparum. Using PHASE algorithm, a five-point pharmacophore model with two hydrogen bond acceptor (A), one positively ionizable (P) and two aromatic rings (R), was developed to derive a predictive ligand-based statistically significant 3D quantitative structure-activity relationship (QSAR) model (r(2) = 0.972, SD = 0.3, F = 173.4, Q(2) = 0.712, RMSE = 0.3, Person-R = 0.94, and r(2) pred = 0.8) to explicate the structural attributes crucial for antimalarial activity. The developed pharmacophore model and 3D QSAR model can be a substantial tool for virtual screening and related antimalarial drug discovery research. PMID- 23662283 TI - Antitussive, expectorant activity of Marsilea minuta L., an Indian vegetable. AB - Marsilea minuta L., an aquatic or sub-aquatic fern used as a vegetable, has wide applications in traditional/folk medicine in India and Bangladesh. In our study, we evaluated the antitussive, expectorant activity of M. minuta crude extracts. The antitussive activity of M. minuta methanol, ethyl acetate, and petroleum ether extracts was evaluated using ammonia and sulfur dioxide induced mice coughing. The expectorant activity was evaluated by the volume of phenol red in mice's tracheas. Extracts significantly increased mice's cough latent period and inhibited the frequency of cough induced by ammonia and sulfur dioxide, and improved tracheal phenol red output in expectorant evaluation. Methanol extract produced the highest activity in all tested models. Methanol extract at 500 mg/kg showed 59.5% and 55.8% inhibition in the number of coughing induced by ammonium liquor and SO2, respectively, while it showed 89.3% increase in phenol red secretion at the same dose, which showed superior activity compared to other extracts. The present study provided evidence for M. minuta to be used as an antitussive and expectorant in Indian folk medicine. PMID- 23662284 TI - Development and validation of an high-performance liquid chromatographic, and a ultraviolet spectrophotometric method for determination of Ambroxol hydrochloride in pharmaceutical preparations. AB - A high-performance liquid chromatographic (HPLC) and ultraviolet (UV) methods were developed and validated for the quantitative determination of Ambroxol hydrochloride (AMH) in pharmaceutical dosage form. HPLC was carried out by reversed phase (RP) technique on an RP-18 column with a mobile phase composed of acetonitrile and water (pH 3.5 adjusted with orthophosphoric acid [60:40, v/v]). UV method was performed with the lambdamax at 250 nm. Both the methods showed good linearity, reproducibility, and precision. No spectral or chromatographic interferences from the tablet excipients were found in UV and HPLC. The method was successfully applied to commercial tablets. Validation parameters such as linearity, precision, accuracy, and specificity were determined. The HPLC Limit of detection (LOD) and Limit of quantification (LOQ) for Ambroxol were found to be 1 and 5 ng/ml, respectively. The UV LOD and LOQ for Ambroxol were found to be 1 and 4 MUg/ml, respectively. The results were statistically compared using one way analysis of variance. The proposed economical method could be applicable for routine analysis of AMH and monitoring of the quality of marketed drugs. PMID- 23662287 TI - Nonmedical use of prescription opioids: what is the real problem? PMID- 23662286 TI - Cursing the darkness: reactions to fibromyalgia. PMID- 23662285 TI - From notochord formation to hereditary chordoma: the many roles of Brachyury. AB - Chordoma is a rare, but often malignant, bone cancer that preferentially affects the axial skeleton and the skull base. These tumors are both sporadic and hereditary and appear to occur more frequently after the fourth decade of life; however, modern technologies have increased the detection of pediatric chordomas. Chordomas originate from remnants of the notochord, the main embryonic axial structure that precedes the backbone, and share with notochord cells both histological features and the expression of characteristic genes. One such gene is Brachyury, which encodes for a sequence-specific transcription factor. Known for decades as a main regulator of notochord formation, Brachyury has recently gained interest as a biomarker and causative agent of chordoma, and therefore as a promising therapeutic target. Here, we review the main characteristics of chordoma, the molecular markers, and the clinical approaches currently available for the early detection and possible treatment of this cancer. In particular, we report on the current knowledge of the role of Brachyury and of its possible mechanisms of action in both notochord formation and chordoma etiogenesis. PMID- 23662288 TI - Use and nonmedical use of prescription opioid analgesics in the general population of Canada and correlations with dispensing levels in 2009. AB - BACKGROUND: In Canada, harm from nonmedical prescription opioid analgesic (POA) use (NMPOU) has increased in recent years; however, there are limitations to the current estimates of NMPOU. The 2009 Canadian Alcohol and Drug Use Monitoring Survey presents an opportunity to produce more accurate estimates of NMPOU. OBJECTIVES: To determine the prevalence of POA use, NMPOU and use of pain relievers to 'get high', and to assess correlations of these indicators with age, sex and provincial levels of dispensed POAs in Canada in 2009. METHODS: Data regarding POA use were obtained from the 2009 Canadian Alcohol and Drug Use Monitoring Survey (n=13,032). The amount of POAs dispensed in standardized daily doses was obtained from a representative sample of 2700 retail pharmacies across Canada. Associations among POA use, age, sex and the amount of POAs dispensed were evaluated using regression models. Differences in POA use across provinces were assessed using the Wald test. RESULTS: In Canada in 2009, the prevalence of POA use was 19.2% (95% CI 18.0% to 20.5%), NMPOU was 4.8% (95% CI 4.1% to 5.5%) and the use of pain relievers to get high was 0.4% (95% CI 0.1% to 0.8%). NMPOU was significantly associated with age. The use of pain relievers to get high varied significantly across provinces, while POA use and NMPOU did not show significant variations. The amount of POAs dispensed per province was not significantly correlated with any type of POA use. CONCLUSIONS: These findings confirm high POA use and NMPOU across Canada. Research is required to identify determinants of NMPOU. PMID- 23662289 TI - Controlled-release oxycodone and naloxone in the treatment of chronic low back pain: a placebo-controlled, randomized study. AB - BACKGROUND: For Canadian regulatory purposes, an analgesic study was required to complement previously completed, pivotal studies on bowel effects and analgesia associated with controlled-release (CR) oxycodone/CR naloxone. OBJECTIVES: To compare the analgesic efficacy and safety of CR oxycodone/CR naloxone versus placebo in patients with chronic low back pain. METHODS: Patients requiring opioid therapy underwent a two- to seven-day opioid washout before being randomly assigned to receive either 10 mg/5 mg CR oxycodone/CR naloxone or placebo every 12 h, titrated weekly according to efficacy and tolerability to 20 mg/10 mg, 30 mg/15 mg or 40 mg/20 mg every 12 h. After four weeks, patients crossed over to the alternative treatment for an additional four weeks. Acetaminophen/codeine (300 mg/30 mg every 4 h to 6 h as needed) was provided as rescue medication. RESULTS: Of the 83 randomized patients, 54 (65%) comprised the per-protocol population. According to per-protocol analysis, CR oxycodone/CR naloxone resulted in significantly lower mean (+/- SD)pain scores measured on a visual analogue scale (48.6 +/- 23.1 mm versus 55.9 +/- 25.4 mm; P=0.0296) and five-point ordinal pain intensity scores (2.1 +/- 0.8 versus 2.4 +/- 0.9; P=0.0415) compared with placebo. After the double-blinded phase, patients and investigators both preferred CR oxycodone/CR naloxone over placebo. These outcomes continued in the 79% of patients who chose to continue receiving CR oxycodone/CR naloxone in a six month, open-label evaluation. CONCLUSIONS: In patients complying with treatment as per protocol, CR oxycodone/CR naloxone was effective for the management of chronic low back pain of moderate or severe intensity. PMID- 23662290 TI - Continuing methadone for pain in palliative care. AB - BACKGROUND: Methadone is one of the most important medications used for the treatment of refractory pain in the palliative care setting, and is usually initially prescribed by one of a limited number of physicians who have acquired authorization for its use. A lack of authorized physicians able to take over prescribing when the patient is stable is a barrier to accessing methadone for analgesia. OBJECTIVE: To determine the barriers to family physicians becoming authorized to prescribe methadone for pain in palliative care. METHODS: A survey exploring the perceived barriers to continuing methadone for pain in palliative care following initial prescription by a specialist was mailed to a randomly selected group of 870 family physicians in British Columbia. RESULTS: The response rate was 30.9%. Of the 204 responding physicians, 76.1% described themselves as positioned to provide ongoing palliative care to their patients. Within this group, 38 (18.6%) were already authorized to prescribe methadone for pain. The remaining 166 (81.4%) had significant knowledge deficits regarding methadone use in palliative care, but were largely aware of their deficits, and more than one-half were willing to learn more and to obtain an authorization if requested. CONCLUSIONS: Responding family physicians had mostly received little education regarding methadone for pain, but were aware of their need for education and were willing to learn. Physicians who had already become authorized were generally satisfied with the process of authorization, and believed the process of education through authorization was appropriate and not onerous. PMID- 23662291 TI - Children and adolescents with complex regional pain syndrome: more psychologically distressed than other children in pain? AB - BACKGROUND: Historically, in both adult and pediatric populations, a lack of knowledge regarding complex regional pain syndrome (CRPS) and absence of clear diagnostic criteria have contributed to the view that this is a primarily psychiatric condition. OBJECTIVE: To test the hypothesis that children with CRPS are more functionally disabled, have more pain and are more psychologically distressed than children with other pain conditions. METHODS: A total of 101 children evaluated in a tertiary care pediatric pain clinic who met the International Association for the Study of Pain consensus diagnostic criteria for CRPS participated in the present retrospective study. Comparison groups included 103 children with abdominal pain, 291 with headache and 119 with back pain. Children and parents completed self-report questionnaires assessing disability, somatization, pain coping, depression, anxiety and school attendance. RESULTS: Children with CRPS reported higher pain intensity and more recent onset of pain at the initial tertiary pain clinic evaluation compared with children with other chronic pain conditions. They reported greater functional disability and more somatic symptoms than children with headaches or back pain. Scores on measures of depression and anxiety were within normal limits and similar to those of children in other pain diagnostic groups. CONCLUSIONS: As a group, clinic-referred children with CRPS may be more functionally impaired and experience more somatic symptoms compared with children with other pain conditions. However, overall psychological functioning as assessed by self-report appears to be similar to that of children with other chronic pain diagnoses. Comprehensive assessment using a biopsychosocial framework is essential to understanding and appropriately treating children with symptoms of CRPS. PMID- 23662297 TI - Label-free electrochemiluminescent detection of DNA by hybridization with a molecular beacon to form hemin/G-quadruplex architecture for signal inhibition. AB - A facile label-free electrochemiluminescent (ECL) DNA sensor was designed using a molecular beacon with a guanine-rich stem as a recognition probe. The ECL emission was produced from surface unpassivated CdTe quantum dots (QDs) co immobilized with colloidal gold nanoparticles (AuNPs) on a chitosan-modified electrode surface. The molecular beacon was adsorbed onto the AuNPs by the thiolated stem. Upon the hybridization of the molecular beacon with target DNA to open the cycle in the presence of hemin, the dissociated guanine-rich sequence could conjugate hemin to form a G-quadruplex architecture. The formed DNAzyme then catalyzed the reduction of dissolved oxygen, the endogenous coreactant for ECL emission of QDs, leading to a decrease in ECL signal. The variations in surface morphology during the fabrication and recognition processes of the ECL sensor were characterized by atomic force microscopy and electrochemical impedance spectroscopy. The ECL signal inhibition depended linearly on the logarithmic value of DNA concentration ranging from 5.0 fM to 0.1 nM, with a detection limit of 0.9 fM. This proposed label-free method is a promising application of QDs-based ECL emission for ultrasensitive DNA assay. PMID- 23662292 TI - Effects of gabapentin on pain and opioid consumption after abdominal hysterectomy. AB - BACKGROUND: Postoperative pain is an important factor affecting anesthesia and surgery. OBJECTIVES: The present study assessed the effects of 1200 mg gabapentin, an anticonvulsant drug that acts through voltage-dependent calcium channels, for the control of postoperative pain in patients undergoing abdominal hysterectomy. METHODS: Fifty patients undergoing hysterectomy were enrolled in the present study. Subjects received either 1200 mg gabapentin or placebo 2 h before surgery. The amount of morphine consumption and level of postoperative pain at 2 h, 6 h, 12 h and 24 h after surgery were measured. RESULTS: There were no significant differences in age, duration of surgery and anesthesia, or body mass index between the two groups. The mean intensity of pain in the gabapentin group was significantly lower than in the placebo group. The mean amount of morphine used in the placebo group (5.2 +/- 2.8 mg) was significantly higher than in gabapentin group (1.2 +/- 0.29 mg; P=0.001). Nausea and vomiting in the placebo group was more common than in the gabapentin group (P=0.001). The time interval for initial ambulation after surgery was significantly shorter in the gabapentin group (12.24 +/- 2.18 h) compared with the placebo group (15 +/- 3.61 h; P=0.002). CONCLUSION: 1200 mg gabapentin reduced postoperative pain and the need for opioids, and enabled earlier ambulation of the patient. Significant side effects were not observed. PMID- 23662298 TI - Solid-state voltammetry-based electrochemical immunosensor for Escherichia coli using graphene oxide-Ag nanoparticle composites as labels. AB - A new electrochemical immunosensor based on solid-state voltammetry was fabricated for the detection of Escherichia coli (E. coli) by using graphene oxide-Ag nanoparticle composites (P-GO-Ag) as labels. To construct the platform, Au nanoparticles (AuNPs) were first self-assembled on an Au electrode surface through cysteamine and served as an effective matrix for antibody (Ab) attachment. Under a sandwich-type immunoassay format, the analyte and the probe (P-GO-Ag-Ab) were successively captured onto the immunosensor. Finally, the bonded AgNPs were detected through a solid-state redox process in 0.2 M of KCl solution. Combining the advantages of the high-loading capability of graphene oxide with promoted electron-transfer rate of AuNPs, this immunosensor produced a 26.92-fold signal enhancement compared with the unamplified protocol. Under the optimal conditions, the immunosensor exhibited a wide linear dependence on the logarithm of the concentration of E. coli ranging from 50 to 1.0 * 10(6) cfu mL( 1) with a detection limit of 10 cfu mL(-1). Moreover, as a practical application, the proposed immunosensor was used to monitor E. coli in lake water with satisfactory results. PMID- 23662299 TI - A disposable electrochemical immunosensor for the determination of leptin in serum and breast milk. AB - The preparation of a disposable electrochemical immunosensor for the quantification of the hormone leptin is described in this work. The preparation approach involved immobilization of a specific biotinylated anti-leptin antibody on the surface of streptavidin-functionalized magnetic beads (Strept-MBs) and a sandwich-type immunoassay involving the target analyte, monoclonal anti-leptin, and IgG labeled with alkaline phosphatase (AP-IgG). The electrochemical transduction step was accomplished by trapping the MBs bearing the immunoconjugates onto screen-printed carbon electrodes (SPCEs) by means of an Nd magnet and measuring the electrochemical oxidation of the 1-naphthol generated in the AP enzyme reaction upon 1-naphthyl phosphate (1-NPP) additions by differential pulse voltammetry (DPV). A calibration plot with a linear range between 5 and 100 pg mL(-1) as well as a detection limit of 0.5 pg mL(-1) (3sb/m) were achieved. This value is more than 27 times lower than that reported in the only voltammetric immunosensor for leptin described in the literature until now. The usefulness of the immunosensor was demonstrated by analyzing different types of real samples: human serum, infant powdered milk, and breast milk from a nursing mother with two months of breastfeeding. PMID- 23662300 TI - Change in the microenvironment of breast cancer studied by FTIR imaging. AB - Fourier transform infrared (FTIR) imaging was applied on histopathological specimens of breast cancer of different tumor histological grades. Focus was given to the extracellular matrix. FTIR spectral changes were observed when examining the extracellular matrix close to and far from carcinoma. Major changes were observed, in particular in the relative intensities of the collagen bands at 1640 and 1630 cm(-1). PCA analysis and global fitting indicate a continuous progression in collagen spectral features when moving away from the tumor. These preliminary results suggest FTIR spectral features present in the 1700-1600 cm( 1) spectral range could be used as spectral markers to identify cancer-induced modifications in collagen. This chemical imaging approach to analyze the breast cancer microenvironment could be used in the future for improving diagnostics of breast cancer. PMID- 23662301 TI - A new fluorescence "switch on" assay for heparin detection by using a functional ruthenium polypyridyl complex. AB - In the present study, a new strategy for heparin detection and quantification in biological media, such as fetal bovine serum (FBS), is developed by monitoring the emission change of a functional ruthenium polypyridyl complex ([Ru(phen)(2)dppz-idzo](2+), complex 1) in buffer solution. Polyanionic heparin is found to interact with a positively charged Ru-complex through electrostatic effects and/or hydrogen bonding interactions, which leads to a significant fluorescence enhancement of the Ru-complex. To get insight into this fluorescence "switch on" behavior, the binding model of the Ru-complex to heparin is established by employing molecular docking simulations based on the fluorescence and UV absorption results. The selectivity results of the fluorescence assay reveal that our complex displayed good fluorescence selectivity towards heparin over its analogues, such as chondroitin 4-sulfate (Chs) or hyaluronic acid (Hya), which have lower charge density and/or structural compatibility as compared to that of heparin. Quantification of heparin is also performed and a linear calibration curve is observed in the range of 0.01-4.87 U mL(-1) (the limit of detection is 0.01 U mL(-1)) for heparin detection in diluted FBS solution. This "one-step" fluorescence "switch on" assay for heparin detection is label-free, convenient, sensitive and selective, and has a long emission wavelength and large Stokes shift. PMID- 23662302 TI - Fluorescent optical fiber sensors for cell viability monitoring. AB - A new simple method for non-invasive cell culture viability monitoring based on vital fluorescent stains is introduced, and its efficiency for long-term experiments on cells is demonstrated. In contrast to common methods for cell viability control, which are usually either destructive (like flow-type counters or dead cells coloring and counting), or hardly quantitative like fluorescent microscopy, the method described is automated, does not require the removal of cells from their growth area and is sensitive enough to deal with as low as tens of cells. PMID- 23662303 TI - Determination of cell cycle phases in live B16 melanoma cells using IRMS. AB - The knowledge of cell cycle phase distribution is of paramount importance for understanding cellular behaviour under normal and stressed growth conditions. This task is usually assessed using Flow Cytometry (FC) or immunohistochemistry. Here we report on the use of FTIR microspectroscopy in Microfluidic Devices (MD IRMS) as an alternative technique for studying cell cycle distribution in live cells. Asynchronous, S- and G0-synchronized B16 mouse melanoma cells were studied by running parallel experiments based on MD-IRMS and FC using Propidium Iodide (PI) staining. MD-IRMS experiments have been done using silicon-modified BaF2 devices, where the thin silicon layer prevents BaF2 dissolution without affecting the transparency of the material and therefore enabling a better assessment of the Phosphate I (PhI) and II (PhII) bands. Hierarchical Cluster Analysis (HCA) of cellular microspectra in the 1300-1000 cm(-1) region pointed out a distribution of cells among clusters, which is in good agreement with FC results among G0/G1, S and G2/M phases. The differentiation is mostly driven by the intensity of PhI and PhII bands. In particular, PhI almost doubles from the G0/G1 to G2/M phase, in agreement with the trend followed by nucleic acids during cellular progression. MD-IRMS is then proposed as a powerful method for the in situ determination of the cell cycle stage of an individual cell, without any labelling or staining, which gives the advantage of possibly monitoring specific cellular responses to several types of stimuli by clearly separating the spectral signatures related to the cellular response from those of cells that are normally progressing. PMID- 23662304 TI - A novel Ag3AsO4 visible-light-responsive photocatalyst: facile synthesis and exceptional photocatalytic performance. AB - A novel Ag3AsO4 photocatalyst has been prepared via a facile precipitation method. It exhibited higher activity than Ag3PO4 or AgI in degradation of rhodamine B or methyl orange. The excellent activity of Ag3AsO4 is attributed to its more separated photogenerated carriers and high absorption capacity of visible light. PMID- 23662305 TI - Reply to K. Jackson et al and W. Leppert. PMID- 23662306 TI - Reply to L. Celio et al and H. Ishiguro et al. PMID- 23662308 TI - Abstracts of the 47th Annual Meeting of the Association for European Paediatric and Congenital Cardiology (AEPC) with joint sessions with the Japanese Society of Pediatric Cardiology and Cardiac Surgery. London, United Kingdom. May 22-25, 2013. PMID- 23662307 TI - Reply to R. Steiner et al. PMID- 23662309 TI - Three authors reply. PMID- 23662310 TI - Abstracts of the 54th Congress of the German Society for Pneumology and Ventilatory Support. March 20-23, 2013. Hannover, Germany. PMID- 23662311 TI - Editor's note. PMID- 23662312 TI - A cardiovascular study that includes a million subjects. PMID- 23662313 TI - Response to letter regarding article, "Ischemic preconditioning for prevention of contrast medium-induced nephropathy: randomized Pilot RenPro-Trial (Renal Protection Trial)". PMID- 23662314 TI - ADR: a new global phenomenon, thanks to the ICH. PMID- 23662316 TI - A brief history of bismuth encephalopathy. PMID- 23662317 TI - Ruxolitinib. Bone marrow fibrosis: theory versus practice. AB - Currently, the only curative treatment for bone marrow fibrosis is haematopoietic stem cell transplantation, but it is only feasible in a minority of patients. Ruxolitinib (Jakavi, Novartis) inhibits Janus kinases, enzymes necessary for haematopoiesis. Many cases of bone marrow fibrosis appear to be due to mutations that interfere with the expression of these kinases. Clinical assessment of ruxolitinib is based on a randomised placebo-controlled trial in 309 patients in whom conventional treatments had failed, and on a randomised, unblinded trial versus standard management in 219 patients. The patients enrolled in the placebo controlled trial had a poor prognosis. Mortality appeared to be lower in the ruxolitinib arm after 24 and 51 weeks, but not in the trial versus standard management. Ruxolitinib had a short-lived symptomatic effect, but almost all patients enrolled in a non-comparative study discontinued ruxolitinib because of inadequate efficacy or adverse effects. Discontinuation often led to symptom rebound. The primary endpoint in these trials was the reduction in spleen volume, a surrogate outcome measure. Ruxolitinib was effective on this endpoint, but it is unclear whether reduction in spleen volume correlates with symptoms. Ruxolitinib aggravates haematological disorders associated with bone marrow fibrosis (anaemia, thrombocytopenia) and also causes neurological disorders (headache, dizziness, confusion). In practice, ruxolitinib appears to have an unfavourable harm-benefit balance in most patients. It is therefore better to avoid using this drug. Additional clinical trials are needed in patients for whom haematopoietic stem cell transplantation is not feasible, especially those with a large, expanding spleen. PMID- 23662315 TI - Bismuth + metronidazole + tetracycline. Why risk adding bismuth? AB - The standard treatment for peptic ulcer associated with Helicobacter pylori is a combination of omeprazole, amoxicillin and clarithromycin, which renders the bacterium undetectable in about 70% of cases. A fixed-dose combination of bismuth subcitrate potassium + metronidazole + tetracycline has been authorised in some European countries for use in this setting, combined with high-dose omeprazole. In a European trial with 440 patients, the 4-drug combination of omeprazole + bismuth subcitrate + metronidazole + tetracycline was significantly more active than the standard 3-drug regimen in terms of H. pylori eradication, as measured with the urea breath test (79.8% with bismuth, 55.4% without bismuth). In a North American trial with 275 patients the success rate was similar with the two treatments, again based on the urea breath test. There are no comparative trials of the 4-drug regimen in patients in whom standard treatment has failed. The main adverse effects of the 4-drug regimen observed in clinical trials were black stools, nausea, headache and dizziness. However, the trials were too small to detect infrequent but serious adverse effects such as bismuth encephalopathy. Safety during pregnancy is not known. Some patients included in clinical trials had detectable plasma bismuth concentrations. Omeprazole increases the absorption of bismuth subcitrate potassium. In practice, the 4-drug regimen combining omeprazole + bismuth subcitrate potassium + metronidazole + tetracycline is probably more effective than standard 3-drug therapy against H. pylori, at least in Europe, but this combination should be avoided due to uncertainties on the possible neurotoxicity of bismuth. Other antibiotic combinations are preferable, and there are too many questions surrounding the adverse effects of this combination for it to replace the standard 3-drug regimen in France. PMID- 23662318 TI - Drugs that delay wound healing. AB - Healing of surgical and traumatic wounds mainly involves the clotting process, inflammation, cell proliferation and tissue remodelling. Healing time depends on the depth of the wound. In order to identify drugs that can slow the healing process, we reviewed comparative clinical trials, epidemiological studies and detailed case reports, using the standard Prescrire methodology. Delayed healing of surgical or traumatic wounds is associated with persistent bleeding, increased wound seepage and, in some cases, failed wound closure. Delayed wound healing can have severe and sometimes life-threatening consequences, including deep-seated infection, prolonged hospitalisation, repeat surgery to join or rejoin the wound edges, and delayed functional recovery of a transplanted organ. Delayed healing may be due to failure of one or several steps in the healing process, caused by metabolic, cardiovascular, infectious, immunological or drug-related disorders. The principal drugs that can slow wound healing are cytotoxic antineoplastic and immunosuppressive agents, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and anticoagulants. In practice, when wound healing is delayed, it is best to keep in mind that a drug may be the cause, and to consider withdrawing any drug or drugs known to have this effect, in order to allow the wounds to heal. PMID- 23662319 TI - The natural healing process of skin wounds. AB - The time required for a skin wound to heal depends on its depth and on the distance between the wound edges. Very superficial wounds do not bleed and heal completely within about a week. When the dermis is damaged, repair begins at the wound edges. When these edges are close together, healing can take up to 3 weeks. The scar then continues to evolve for 12 to 18 months. PMID- 23662320 TI - Digoxin and breast cancer. AB - Several epidemiological studies, some of which included several thousand women, have shown a link between digoxin exposure and the risk of breast cancer. A cohort study of women with angina, identified in the Danish Prescription Registry, showed a statistically significant increase in the risk of breast cancer among women taking digoxin compared with those not taking digoxin. An increase in the risk of breast cancer of similar magnitude was observed in a case control study based on Danish hospital registries. In both studies, the risk of breast cancer was increased by about one-third with digoxin (relative risk around 1.3). A causal link is plausible, given the oestrogen-like properties of digoxin. In practice, this risk must be taken into account, especially in patients at risk of breast cancer. Women should be informed of the increased risk of breast cancer before deciding whether the impact of digoxin on cardiac symptoms warrants taking this risk. PMID- 23662321 TI - Deep venous thrombosis and pulmonary embolism. Part 1. Initial treatment: usually a low-molecular-weight heparin. AB - Patients with deep venous thrombosis are at a short-term risk of symptomatic or even life-threatening pulmonary embolism, and a long-term risk of post-thrombotic syndrome, characterised by lower-limb pain, varicose veins, oedema, and sometimes skin ulcers. What is the best choice of initial antithrombotic therapy following deep venous thrombosis or pulmonary embolism, in terms of mortality and short term and long-term complications? How do the harm-benefit balances of the different options compare? To answer these questions, we reviewed the available literature using the standard Prescrire methodology. Unfractionated heparin has documented efficacy in reducing mortality and recurrent thromboembolic events in patients with pulmonary embolism or symptomatic proximal (above-knee) deep venous thrombosis. The authors of a systematic review selected 23 trials of low molecular-weight heparin (LMWH) versus adjusted-dose unfractionated heparin in a total of 9587 patients. Deaths, recurrences and major bleeds were less frequent with LMWH than with unfractionated heparin. The results of other meta-analyses are similar, but all are undermined by a probable publication bias and methodological flaws. Compared to unfractionated heparin, LMWHs have the advantage of fixed-dose administration, once or twice daily, by subcutaneous injection. All available LMWHs seem to have similar efficacy. Those with the longest experience of use are enoxaparin, dalteparin and nadroparin. The harm benefit balances of fondaparinux and rivaroxaban do not appear more favourable than that of an LMWH followed by an adjusted-dose vitamin K antagonist. A meta analysis included 12 trials comparing thrombolysis with anticoagulation alone in 700 patients with deep venous thrombosis. Adding a thrombolytic drug did not reduce mortality or the incidence of pulmonary embolism, whereas it increased the incidence of bleeding. A meta-analysis of 13 trials failed to show that adding a thrombolytic drug to initial anticoagulant therapy reduced mortality or recurrences after pulmonary embolism. In the 5 trials that included patients with massive pulmonary embolism, thrombolytic therapy appeared to reduce mortality by about one-half (6% versus 13%). This difference is noteworthy, even if it did not reach the usual threshold of statistical significance. The results of the 6 trials involving patients with deep venous thrombosis, and those of 2 trials and 8 cohort studies in patients with pulmonary embolism at low risk of complications, suggest that outpatient management is acceptable in some cases. Clinical practice guidelines largely agree on the use of LMWH or fondaparinux as initial therapy for most patients with deep venous thrombosis or pulmonary embolism. Unfractionated heparin is generally recommended for patients with renal failure. Thrombolysis is recommended for massive pulmonary embolism and, in some guidelines, for iliofemoral venous thrombosis. In practice, initial treatment of deep venous thrombosis and pulmonary embolism should be based on LMWH in patients without renal failure. Thrombolytic agents may be useful in case of massive pulmonary embolism, but more evaluation is needed. Bleeding and heparin thrombocytopenia are the main adverse effects of these treatments. PMID- 23662322 TI - Anticoagulants and their adverse effects. PMID- 23662323 TI - New drugs and indications in 2012. Sluggish progress, timid measures to protect patients. AB - The therapeutic advances identified in 2012 were minimal, and 15 new drugs or indications are dangerous. The dearth of improvement in patient care contrasts with the sometimes disproportionately high prices agreed upon for drugs, especially in oncology. The few steps taken by health authorities that benefited patients, mainly by withdrawing or revoking reimbursement for drugs with an unfavourable harm-benefit balance, were insufficient in view of the constant pressure from the pharmaceutical industry to sell ever more drugs. PMID- 23662324 TI - Drug policy: let's maintain pressure on regulatory authorities. PMID- 23662325 TI - Towards better patient care: drugs to avoid. AB - Common sense dictates that one should choose tried and tested drugs with proven, concrete benefits that outweigh their adverse effects. Many new drugs are approved each year, often despite a lack of solid evidence that they are any better than existing treatments. Worse, some are approved despite being less effective or more harmful than current options. Massive promotion is used to ensure that such drugs achieve a positive image in the eyes of healthcare professionals and patients. Renowned "opinion leaders" intervene in their favour at conferences and in specialist media, and their opinions are further propagated by specialists in the field. Finally, campaigns in the lay media are used to highlight the target illness, encouraging patients to request a prescription. New data sometimes show that older, initially promising drugs are less effective or more harmful than first thought. For all these reasons, many drugs that are now present on the market are more harmful than beneficial and should be avoided. Unfortunately, negative assessment data and warnings are often drowned in the flood of promotion and advertising. Front-line healthcare professionals who are determined to act in their patients' best interests can find themselves swimming against a tide of specialist opinion, marketing authorisation, and reimbursement decisions. By leaving drugs that are more harmful than beneficial on the market and contenting themselves with simple half-measures, healthcare authorities are failing in their duty to protect patients. Prescrire, a journal funded solely by its subscribers, does not seek to do the work of health authorities, and does not have the means to do so. Prescrire's goal is simply to help healthcare professionals provide better care. The following text lists the principal drugs that we consider more harmful than beneficial, based on our reviews published between 2010 and 2012 in our French edition. These drugs should not be used. Patients and healthcare professionals should reassess ongoing treatments and, if necessary, replace these drugs with proven treatments. Without waiting for the authorities to remove them from the market in a timely manner, as the accumulation of data showing that they are more harmful than beneficial would require. PMID- 23662326 TI - Twice stigmatized: provider's perspectives on drug-using women in the Republic of Georgia. AB - This study examined attitudes and perspectives of 34 health service providers through in-depth interviews in the Republic of Georgia who encountered an injection drug-using woman at least once in the past two months. Most participants' concept of drug dependence treatment was detoxification, as medication-assisted therapy was considered part of harm reduction, although it was thought to have relatively better treatment outcomes compared to detoxification. Respondents reported that drug dependence in women is much more severe than in men. They also expresSed less tolerance towards drug-using women, as most providers view such women as failuresas a good mother, wife, or child. Georgian women are twice stigmatized, once by a society that views them as fulfilling only a limited purposeful role and again by their male drug-using counterparts. Further, the vast majority of respondents were unaware of the availability of specific types of drug-treatment services in their city, and even more did not seek connections with other service providers, indicating a lack of linkages between drug-related and other services. The need for women-specific services and a comprehensive network of service linkages for all patients in drug treatment is critical. These public health issues require immediate consideration by policy makers, and swift action to address them. PMID- 23662327 TI - Seeking safety therapy for pathological gambling and PTSD: a pilot outcome study. AB - This pilot study evaluated Seeking Safety (SS) therapy for seven outpatients with current comorbid pathological gambling (PG) and posttraumatic stress disorder (PTSD). This represents the first treatment outcome study of this population, and included both genders and 29% minorities. We found significant improvements in: PTSD/trauma (the PTSD Checklist criterion B symptoms; the Trauma Symptom Inventory overall mean and subscales anxiety, dissociation, sexual abuse trauma index, sex problems; and the World Assumptions Scale benevolence subscale); gambling (the Gamblers Beliefs Questionnaire overall mean and subscales illusion of control); functioning (the Basis-32 overall mean and depression/anxiety subscale); psychopathology (the Brief Symptom Inventory overall mean and subscales anxiety and depression; and the Addiction Severity Index, ASI, psychiatric composite score); self-compassion (the Self-Compassion Scale overall mean and subscales isolation, overidentified, and self-judgment); and helping alliance (the Helping Alliance Questionnaire overall mean). One variable indicated worsening (employment composite subscale on the ASI), possibly reflecting measurement issues. SS attendance was excellent. PTSD onset occurred prior to PG onset for most of the sample, and most believed the two disorders were related. Overall, we found that SS can be effectively conducted for comorbid PTSD and PG, with improvements in numerous domains and high acceptability. Limitations are discussed. PMID- 23662329 TI - Substance abuse treatment for adolescents: how are family factors related to substance use change? AB - Parental involvement in adolescents' substance abuse treatment is highly recommended, even though the mechanisms explaining how this favors youths' recovery are not well understood. The present study examines the association between (1) changes in adolescents' substance use and parenting practices, as measured by adolescent self-disclosure and parental warmth; (2) changes in mothers' mental health and their parenting practices, and (3) parental use of services offered by substance abuse treatment centres, parenting practices and adolescent substance use. In total, 147 adolescents and 69 mothers participated in this study. Participants were assessed upon adolescent admission into treatment, as well as at three- and six-month follow-up. Results show an association between improved maternal mental health and greater parental warmth, as perceived by adolescents. In addition, greater parental use of treatment services was found to be associated with greater adolescent self-disclosure and greater reduction of adolescent substance use. Finally, greater adolescent self disclosure and parental warmth were both associated with lower adolescent substance use. These findings underscore the need to facilitate parents' access to and involvement in treatment of adolescents. The parent-adolescent relationship and the mental health of parents are essential aspects to consider for interventions. PMID- 23662328 TI - Causes, consequences, and prevention of burnout among substance abuse treatment counselors: a rural versus urban comparison. AB - Substance abuse counselors are vulnerable to burnout, which has negative repercussions for the counselor, employing organization, and clients. However, little is known about differences in counselor burnout from the counselors' perspective in rural versus urban treatment centers. In 2008, focus group data from 28 rural and urban counselors in a southern state were analyzed, revealing three burnout themes across all counselors: causes, consequences, and prevention. However, there were various differences between rural and urban counselors in subthemes, with only rural counselors citing office politics and low occupational prestige as causes of burnout. Only urban counselors reported responses endorsing the subthemes of role reversal, clients trying to choose their counselors, and changing jobs as consequences of burnout. All counselors cited coworker support, clinical supervision, and self-care as important strategies for managing burnout. In sum, context clearly matters as rural counselors cited more causes of burnout; yet, the implications of burnout are universal in that they often lead to poor quality clinical care. There is a continued need for greater understanding of addiction as a disease, which would reduce stigma, especially in rural areas, as well as increase the prestige and earning potential of the substance abuse counseling occupation. PMID- 23662330 TI - The role of mental illness in alcohol abuse and prescription drug misuse: gender specific analysis of college students. AB - The present study examined whether and how collegians' misuse of prescription drugs and alcohol abuse are associated with mental illness and with a lack of mental health care. Nationally representative data were derived from 5,241 full time American college students who completed the 2010 National Survey on Drug Use and Health. We observed the presence of alcohol abuse/dependence and the nonmedical use of prescription drugs to be associated with relatively serious mental illness and with lack of health care. In pursuing gender-specific results, we found that the association between alcohol abuse and mental illness was stronger among females than males. PMID- 23662332 TI - Deleuze and the theory of addiction. AB - This theoretical article presents and applies the theories of the French philosopher Gilles Deleuze. The article takes as its starting point the observation that current biomedical, social and psychological research does not provide a coherent view of the nature of addiction and there is a great deal of controversy in the field. The material philosophy of Deleuze provides the opportunity to introduce new ideas and bridge the gaps between different theories and approaches. Deleuze's philosophy is especially useful since neurological research on addiction has developed rapidly. Deleuzian concepts have implications not only for the general theory of addiction, but also for different theories on treatment and recovery. A Deleuzian theory, developed in this article, analyzes addictions as situational and interactional processes. Alcohol and drugs are used because they are connected with situations and interactions that enable the production of desire. They change and alter the body. Addiction alters the production of desire and life itself begins to be reduced to alcohol, drugs or a specific mode of behavior. Recovery from addictions is connected with the changes in life that offer subjects an open future. A recovering body must increase its capacity to be affected and be capable of creating new biopsychosocial connections of desire. PMID- 23662331 TI - Diversion of benzodiazepines through healthcare sources. AB - Benzodiazepines (BZ) are often diverted from legal sources to illicit markets at various points in the distribution process beginning with a pharmaceutical manufacturer, followed by healthcare providers, and finally, to the intended users. Little is known about the extent of BZ diversion involving distribution points directly related to healthcare sources versus points further down the distribution chain. The present study examines the scope of BZ diversion, and the association between BZ dependence and the direct utilization of particular healthcare-related diversion sources among a diverse sample of prescription drug abusers in South Florida. Cross-sectional data were collected from five different groups of drug users: methadone-maintenance clients (n = 247), street drug users (n = 238), public-pay treatment clients (n = 245), private-pay treatment clients (n = 228), and stimulant-using men who have sex with men (MSM; n = 249). Findings suggest that those who are ages 26 to 35 years old, non-Hispanic White participants, private-pay treatment clients, those who are insured, and those with higher incomes had higher odds of utilizing healthcare diversion sources. Those who reported BZ dependence had 2.5 times greater odds of using a healthcare source to obtain BZs than those who did not meet criteria for dependence. PMID- 23662333 TI - Safety and side effects of ayahuasca in humans--an overview focusing on developmental toxicology. AB - Despite being relatively well studied from a botanical, chemical, and (acute) pharmacological perspective, little is known about the possible toxic effects of ayahuasca (an hallucinogenic brew used for magico-ritual purposes) in pregnant women and in their children, and the potential toxicity of long-term ayahuasca consumption. It is the main objective of the present text to do an overview of the risks and possible toxic effects of ayahuasca in humans, reviewing studies on the acute ayahuasca administration to humans, on the possible risks associated with long-term consumption by adults and adolescents, and on the possible toxic effects on pregnant animals and in their offspring. Acute ayahuasca administration, as well as long-term consumption of this beverage, does not seem to be seriously toxic to humans. Although some nonhuman developmental studies suggested possible toxic effects of ayahuasca or of some of its alkaloids, the limited human literature on adolescents exposed to ayahuasca as early as in the uterus reports no serious toxic effects of the ritual consumption of the brew. Researchers must take caution when extrapolating nonhuman data to humans and more data are needed in basic and human research before a definite opinion can be made regarding the possible toxic effects of ayahuasca in pregnant women and in their children. PMID- 23662334 TI - Recreational use of D-lysergamide from the seeds of Argyreia nervosa, Ipomoea tricolor, Ipomoea violacea, and Ipomoea purpurea in Poland. AB - Recently, there are important changes in recreational drug use. The aim of the present study was to analyse reports published on a recreational web site by drug users who ingested seeds of plants belonging to the Convolvulaceae family and to compare them with available medical case reports. We have also included reports describing the effects induced by "druids fantasy," which is a new drug allegedly containing the same alkaloid as the seeds of A. nervosa. Our search reveals the reoccurrence of recreational use of I. tricolor and violacea (morning glory), which had not been reported in medical literature since 1968. We have also found that drug users are experimenting with other species, such as I. purpurea, whose psychoactive properties are unknown. Symptoms and doses reported by drug users were comparable with the few available medical case reports. The most worrying symptom was suicidal ideation reported by two subjects who ingested A. nervosa and Ipomoea seeds. Effects induced by druids fantasy were comparable with the effects induced by A. nervosa and various Ipomoea species. The ingestion of seeds was frequently associated with taking drugs such as cannabis and hashish, although other combinations, for example with dextromethorphan, were also reported. PMID- 23662335 TI - A case of drug-facilitated sexual assault involving 3,4-methylenedioxy methylamphetamine. AB - Typical scenarios of drug-facilitated sexual assaults usually involve victims having ingested a drink after which they had little, partial or no recollection of events for a period of time. We were surprised by the case of a woman who was sexually assaulted and described a state of amazement, leading to an incapacity to resist physically or verbally to her aggressor, and who remembered everything. Alcohol was first suspected but toxicological analysis revealed the presence of 3,4-methylene-dioxy-methylamphetamine (MDMA, Ecstasy). In the literature review, a few cases of sexual assault involving involuntarily MDMA intake are described. PMID- 23662336 TI - A new interface element with progressive damage and osseointegration for modeling of interfaces in hip resurfacing. AB - Finite element models of orthopedic implants such as hip resurfacing femoral components usually rely on contact elements to model the load-bearing interfaces that connect bone, cement and implant. However, contact elements cannot simulate progressive degradation of bone-cement interfaces or osseointegration. A new interface element is developed to alleviate these shortcomings. This element is capable of simulating the nonlinear progression of bone-cement interface debonding or bone-implant interface osseointegration, based on mechanical stimuli in normal and tangential directions. The new element is applied to a hip resurfacing femoral component with a stem made of a novel biomimetic composite material. Three load cases are applied sequentially to simulate the 6-month period required for osseointegration of the stem. The effect of interdigitation depth of the bone-cement interface is found to be negligible, with only minor variations of micromotions. Numerical results show that the biomimetic stem progressively osseointegrates (alpha averages 0.7 on the stem surface, with spot welds) and that bone-stem micromotions decrease below 10 microm. Osseointegration also changes the load path within the femoral bone: a decrease of 300 microepsilon was observed in the femoral head, and the inferomedial part of the femoral neck showed a slight increase of 165 microepsilon. There was also increased stress in the implant stem (from 7 to 11 MPa after osseointegration), indicating that part of the load is supported through the stem. The use of the new osseointegratable interface element has shown the osseointegration potential of the biomimetic stem. Its ability to model partially osseointegrated interfaces based on the mechanical conditions at the interface means that the new element could be used to study load transfer and osseointegration patterns on other models of uncemented hip resurfacing femoral components. PMID- 23662337 TI - A novel cross-linked human amniotic membrane for corneal implantations. AB - The aim of this study was to evaluate the efficacy of Al2(SO4)3 cross-linked human amniotic membrane for ocular surface reconstruction using tissue culture techniques. The human amniotic membrane was cross-linked with Al2(SO4)3, and the cross-linked human amniotic membrane was characterized for its mechanical properties, percentage of swelling in water, sterility, infrared spectroscopy and scanning electron microscopy. The potential of cross-linked human amniotic membrane to support the attachment and proliferation of corneal limbal epithelial cells was assessed in vitro, using static culture system. About 125% increase in the tensile strength was observed in the cross-linked human amniotic membrane compared to human amniotic membrane. Infrared spectroscopy studies have confirmed the cross-linking of human amniotic membrane with Al2(SO4)3. The cross-linked human amniotic membrane was found to be sterile up to 1 year. In culture studies, confluent sheets of epithelial cells were seen at the end of 14th day resembling the morphological features of limbal epithelia. The cross-linked human amniotic membrane has exhibited improved mechanical properties, and the tissue culture studies have shown its feasibility to be used as a limbal transplant. It was concluded that the crosslinked human amniotic membrane with its improved mechanical properties could be used on par with human amniotic membrane. PMID- 23662338 TI - Pilot validation study on a quasi-static weight-bearing knee rig. AB - This article presents a pilot study on a quasi-static knee rig designed to investigate the influence of pathologies and surgical interventions on the patellofemoral kinetics of cadaveric knees. The knee rig allows cadaveric knees to flex and extend under a simulated body weight by transmitting a force to the quadriceps tendon. During the squat simulation, the ground reaction force stays within physiological values. Before using this device to answer clinical questions, two knee specimens were tested to assess the repeatability of the rig. Four repeated flexion-extension cycles were performed under a simulated body weight of 700 N, with an isolated force on the quadriceps tendon up to 2700 N and with a ground reaction force close to 350 N. The resulting patellofemoral contact area shifted from distal to proximal during knee flexion. From 20 degrees to 60 degrees of knee flexion, the mean contact area and pressure increased from 80.2 +/- 3.3 to 349.5 +/- 10.1 mm2 and from 0.9 +/- 0.2 to 5.9 +/- 0.7 MPa, respectively. The transmitted force on the quadriceps tendon, the ground reaction force and the patellofemoral contact area and pressure were continuously measured and showed a relative variability of 1.6%, 2.4%, 2.8% and 3.2%, respectively. The presented knee rig shows a good repeatability that allows us to use this knee rig to quantify the influence of anatomical changes on the patellofemoral contact area and pressures during a squat simulation. PMID- 23662339 TI - Automated diagnosis of epileptic electroencephalogram using independent component analysis and discrete wavelet transform for different electroencephalogram durations. AB - Epilepsy is a disorder of the brain depicted by recurrent seizures. Electroencephalogram signals can be used to study the characteristics of epileptic seizures. In this study, we propose a method for the automated classification of electroencephalogram into normal, interictal and ictal classes using 6, 12, 18 and 23.6 s of data. We employed discrete wavelet transform to decompose electroencephalogram signals into frequency sub-bands. These discrete wavelet transform coefficients were then subjected to independent component analysis for reducing the data dimension. The independent component analysis features were then fed to six classifiers, namely, decision tree, K-nearest neighbor, probabilistic neural network, fuzzy, Gaussian mixture model and support vector machine to select the best classifier. We observed that the support vector machine classifier with radial basis function kernel function gave the best results with an average accuracy of 96%, sensitivity of 96% and specificity of 97% for 23.6 s of electroencephalogram data. Our results show that as the duration of the data increases, the classification accuracy increases. This proposed technique can be used as an automatic seizure monitoring software to aid the doctors in providing timely quality care for the patients suffering from epilepsy. PMID- 23662340 TI - Biomechanical comparison of supplemental posterior fixations for two-level anterior lumbar interbody fusion. AB - Posterior instrumentations have been used to supplement anterior lumbar interbody fusion with cages. Biomechanical studies on single-level anterior lumbar interbody fusion show that stand-alone cages supplemented with posterior translaminar facet or transfacet screw fixation exhibit comparable stability to those supplemented with pedicle screw/rod fixation, while stability of multilevel anterior lumbar interbody fusion remains mostly unknown. The objectives of this study are to compare the stabilization of three supplemental posterior fixations to two-level anterior lumbar interbody fusion, including translaminar facet fixation, transfacet screw fixation, and pedicle screw/rod fixation. Flexibility tests were conducted on fresh-frozen calf spines with moment up to 8.5 N m in flexion, extension, lateral bending, and axial rotation. Each specimen was tested at three stages: intact, anterior lumbar interbody fusion using Polyetheretherketone (PEEK) interbody cage at L3-L4 and L4-L5, and the same anterior lumbar interbody fusion plus one of the three supplemental posterior fixations. The addition of the supplemental posterior fixation increased stiffness at the fusion levels significantly in flexion (9.9 times), extension (5.4 times), and lateral bending (4.1 times). The pedicle screw/rod and translaminar screw fixations provide approximately 40% higher stiffness than the transfacet screw in lateral bending. The pedicle screw/rod fixation also displayed a trend of superior fixation in extension. Supplemental posterior fixation significantly improved stability of two-level anterior lumbar interbody fusion when compared to the stand-alone cages. Pedicle screw/rod system is still the "gold standard" in providing supplemental stability. However, both translaminar facet screws and transfacet screws are good alternatives to provide adequate fixation. PMID- 23662341 TI - Decision support system for diabetic retinopathy using discrete wavelet transform. AB - Prolonged duration of the diabetes may affect the tiny blood vessels of the retina causing diabetic retinopathy. Routine eye screening of patients with diabetes helps to detect diabetic retinopathy at the early stage. It is very laborious and time-consuming for the doctors to go through many fundus images continuously. Therefore, decision support system for diabetic retinopathy detection can reduce the burden of the ophthalmologists. In this work, we have used discrete wavelet transform and support vector machine classifier for automated detection of normal and diabetic retinopathy classes. The wavelet-based decomposition was performed up to the second level, and eight energy features were extracted. Two energy features from the approximation coefficients of two levels and six energy values from the details in three orientations (horizontal, vertical and diagonal) were evaluated. These features were fed to the support vector machine classifier with various kernel functions (linear, radial basis function, polynomial of orders 2 and 3) to evaluate the highest classification accuracy. We obtained the highest average classification accuracy, sensitivity and specificity of more than 99% with support vector machine classifier (polynomial kernel of order 3) using three discrete wavelet transform features. We have also proposed an integrated index called Diabetic Retinopathy Risk Index using clinically significant wavelet energy features to identify normal and diabetic retinopathy classes using just one number. We believe that this (Diabetic Retinopathy Risk Index) can be used as an adjunct tool by the doctors during the eye screening to cross-check their diagnosis. PMID- 23662342 TI - Design and development of an automated, portable and handheld tablet personal computer-based data acquisition system for monitoring electromyography signals during rehabilitation. AB - This article describes the design of a robust, inexpensive, easy-to-use, small, and portable online electromyography acquisition system for monitoring electromyography signals during rehabilitation. This single-channel (one-muscle) system was connected via the universal serial bus port to a programmable Windows operating system handheld tablet personal computer for storage and analysis of the data by the end user. The raw electromyography signals were amplified in order to convert them to an observable scale. The inherent noise of 50 Hz (Malaysia) from power lines electromagnetic interference was then eliminated using a single-hybrid IC notch filter. These signals were sampled by a signal processing module and converted into 24-bit digital data. An algorithm was developed and programmed to transmit the digital data to the computer, where it was reassembled and displayed in the computer using software. Finally, the following device was furnished with the graphical user interface to display the online muscle strength streaming signal in a handheld tablet personal computer. This battery-operated system was tested on the biceps brachii muscles of 20 healthy subjects, and the results were compared to those obtained with a commercial single-channel (one-muscle) electromyography acquisition system. The results obtained using the developed device when compared to those obtained from a commercially available physiological signal monitoring system for activities involving muscle contractions were found to be comparable (the comparison of various statistical parameters) between male and female subjects. In addition, the key advantage of this developed system over the conventional desktop personal computer-based acquisition systems is its portability due to the use of a tablet personal computer in which the results are accessible graphically as well as stored in text (comma-separated value) form. PMID- 23662343 TI - Developments in stem cells: implications for future joint replacements. AB - Will stem cell research reverse the projected sevenfold increase in primary and revision knee replacements expected in the United States between 2005 and 2030? A focus on prevention and treatment of osteoarthritis may end the need for primary joint replacements. A more likely scenario can be described as slow and incremental changes in the prevention and treatment of osteoarthritis, accompanied by the continuing development of implant technology. Since the discovery of stem cells in the 1950s, research has increased exponentially. Expanded autologous chondrocytes, and more recently ex vivo expanded skeletal stem cells, are currently injected into osteochondral defects in the hope of regenerating cartilage and halting progression towards osteoarthritis. In addition, mesenchymal stem cells are being injected into human joints as a treatment for osteoarthritis despite a lack of quantitative research. Concurrently, stem cell research continues to contribute to chemical and topographical advancements in implant design. Advances in co-culture techniques mean it is possible that biologic articular replacements will develop prior to the cessation of the need for arthroplasty and radically change the nature of joint replacements. Whether it is through implant design or a potential cure for the pain attributable to osteoarthritis, as we hope to show in this 'forward look article', it is our opinion that stem cells will certainly impact future joint replacement. PMID- 23662344 TI - Effect of complex wavelet transform filter on thyroid tumor classification in three-dimensional ultrasound. AB - Ultrasonography has great potential in differentiating malignant thyroid nodules from the benign ones. However, visual interpretation is limited by interobserver variability, and further, the speckle distribution poses a challenge during the classification process. This article thus presents an automated system for tumor classification in three-dimensional contrast-enhanced ultrasonography data sets. The system first processes the contrast-enhanced ultrasonography images using complex wavelet transform-based filter to mitigate the effect of speckle noise. The higher order spectra features are then extracted and used as input for training and testing a fuzzy classifier. In the off-line training system, higher order spectra features are extracted from a set of images known as the training images. These higher order spectra features along with the clinically assigned ground truth are used to train the classifier and obtain an estimate of the classifier or training parameters. The ground truth tells the class label of the image (i.e. whether the image belongs to a benign or malignant nodule). During the online testing phase, the estimated classifier parameters are applied on the higher order spectra features that are extracted from the testing images to predict their class labels. The predicted class labels are compared with their corresponding original ground truth to evaluate the performance of the classifier. Without utilizing the complex wavelet transform filter, the fuzzy classifier demonstrated an accuracy of 91.6%, while utilizing the complex wavelet transform filter, the accuracy significantly boosted to 99.1%. PMID- 23662345 TI - Effect of storage methods on indentation-based material properties of abdominal organs. AB - To investigate the possible changes in material properties of cadaveric abdominal organs due to the preservation methods, the indentation data obtained from porcine abdominal organs (kidney, liver, and spleen) preserved by cooling and freezing are analyzed statistically in this study. Indentation tests were first conducted on fresh specimens. One half of the specimens of each organ were then frozen (preserved at - 12 degrees C), and the other half of the specimens were cooled (preserved at 4 degrees C). All preserved specimens were retested after 20 days. Force and displacement data recorded during indentation were analyzed using a quasi-linear viscoelastic model. The results show that both cooling and freezing storage increased the kidney stiffness. In contrast, both storage methods decreased the stiffness of the spleen specimens. While cooling increased the liver stiffness, no significant changes of the instantaneous elastic response were observed in the liver specimens preserved by freezing. The liver and spleen's reduced relaxation responses and the liver's instantaneous elastic response were significantly different when comparing between cooling and freezing effects after 20 days of preservation. This study showed that both cooling and freezing storage methods significantly changed the material properties of abdominal organs, especially the instantaneous elastic response. More research is needed in investigating the effect of preservation on failure properties and mechanical properties under large deformation. PMID- 23662346 TI - Haptically guided robotic technology in total hip arthroplasty: a cadaveric investigation. AB - The longevity of total hip arthroplasty (THA) continues to improve with advancements in design and bearing materials. However, the incidence of dislocation and impingement-related failures continue to rise, with the inability of the surgeon to achieve optimal component orientation cited as a cause. Computer-assistance has been shown to increase the accuracy of component orientation and robotic-assistance has been developed to translate this advantage into precise surgical execution. We sought to validate a haptically-guided robotic arm system in performing THA with the aim of comparing the accuracy of robotic-assisted acetabular cup placement to manual placement. We implanted 12 acetabular components in 6 cadaveric pelvises comparing robotic-assistance on one side with manual implantation on the other. We measured planned and actual center of rotation (COR), cup position, leg-length equalization and offset for each THA using computed tomography and the robotic platform. The root-mean-square (RMS) error for the robotic-assisted system was within 3 degrees for cup placement and within 1 mm for leg-length equalization and offset when compared to computed tomography. The robotic-assisted system was significantly more accurate than manual implantation in reproducing the COR and cup orientation, as determined by a preoperative plan. The RMS error for manual implantation compared to robotic assistance was 5 times higher for cup inclination and 3.4 times higher for cup anteversion (p < 0.01). Robotic-assistance is more accurate than manual implantation in achieving optimal cup orientation. It has the ability to eliminate human error from THA and should be considered in light of THA failures due to component malposition. PMID- 23662347 TI - Hydromechanical stimulator for chondrocyte-seeded constructs in articular cartilage tissue engineering applications. AB - Mechanical stimulation is a key technique used for controlling the mechanical properties of tissue engineered articular cartilage constructs proposed for defect repair. The present study introduces a new technical method and device for 'hydromechanical' stimulation of tissue engineered articular cartilage constructs. The stimulation consists of simultaneous cyclic compression, frictional shear from a sliding indenter contact and direct pressurized fluid perfusion. Each of these modes of mechanical loading has been shown by other research groups to effectively stimulate tissue engineered constructs. A device for applying these conditions was designed, developed and tested. Two sets (high and low perfusion flow rates) of three experiments were performed, each with two samples subjected to hydromechanical stimulation conditions (compression and friction forces along with perfusion). Two other samples from each set were subjected to just compression and dynamic frictional shear forces, and two more were used as controls (not stimulated). The average amount of glycosaminoglycan retained in the constructs after 3 weeks ranked from low to high as follows: controls, hydromechanical conditions with the low-flow rate, hydromechanical conditions with the high-flow rate and just compression plus dynamic frictional shear. Statistically significant differences were not detected. However, future studies would focus on glycosaminoglycan production in the superficial zone, measuring the glycosaminoglycan released to the nutrient media, and address altering the hydromechanical stimulation parameters using the results of the present study as guidance, in attempts to achieve statistically significant increases in glycosaminoglycan production compared with the controls. PMID- 23662348 TI - Influence of the grain size on the in vivo degradation behaviour of the magnesium alloy LAE442. AB - The aim of this study was to investigate the differences in the in vivo degradation behaviour of magnesium implants with various grain sizes and damaged surfaces. For this purpose, three different LAE442 magnesium implants were produced: cast, single and double extruded implants, in order to obtain different grain sizes. Furthermore, defects were positioned on the surfaces of some of the single extruded implants. The initial stability was determined. Four pins of each implant material were implanted into rabbits' tibiae and regularly clinically, radiologically and micro-computed tomographically investigated over a period of 27 weeks. Following explantation, investigations were carried out using stereo and scanning electron microscopy including energy-dispersive X-ray analyses. Weight and strength changes were measured. The double extruded implants possessing the finest grains exhibited the highest initial stability (179.18 N). These implants demonstrated the lowest in vivo corrosion rates (0.0134 mm/year) and the least radiologically visible changes. The highest corrosion rate was computed for the implants possessing damaged surfaces. Radiologically discernible bone changes occurred at almost the same time as implant changes for all groups. Based on these results, the aim should be to produce fine-grained magnesium-based alloys for resorbable implants and to avoid any surface damage. PMID- 23662349 TI - Interlimb relation during the double support phase of gait: an electromyographic, mechanical and energy-based analysis. AB - The purpose of this study is to analyse the interlimb relation and the influence of mechanical energy on metabolic energy expenditure during gait. In total, 22 subjects were monitored as to electromyographic activity, ground reaction forces and VO2 consumption (metabolic power) during gait. The results demonstrate a moderate negative correlation between the activity of tibialis anterior, biceps femoris and vastus medialis of the trailing limb during the transition between mid-stance and double support and that of the leading limb during double support for the same muscles, and between these and gastrocnemius medialis and soleus of the trailing limb during double support. Trailing limb soleus during the transition between mid-stance and double support was positively correlated to leading limb tibialis anterior, vastus medialis and biceps femoris during double support. Also, the trailing limb centre of mass mechanical work was strongly influenced by the leading limbs, although only the mechanical power related to forward progression of both limbs was correlated to metabolic power. These findings demonstrate a consistent interlimb relation in terms of electromyographic activity and centre of mass mechanical work, being the relations occurred in the plane of forward progression the more important to gait energy expenditure. PMID- 23662350 TI - Investigations on the viscoelastic behaviour of a human healthy heel pad: in vivo compression tests and numerical analysis. AB - The aim of this study was to investigate the viscoelastic behaviour of the human heel pad by comparing the stress-relaxation curves obtained from a compression device used on an in vivo heel pad with those obtained from a three-dimensional computer-based subject-specific heel pad model subjected to external compression. The three-dimensional model was based on the anatomy revealed by magnetic resonance imaging of a 31-year-old healthy female. The calcaneal fat pad tissue was described with a viscohyperelastic model, while a fibre-reinforced hyperelastic model was formulated for the skin. All numerical analyses were performed to interpret the mechanical response of heel tissues, with loading conditions and displacement rate in agreement with experimental tests. The heel tissues showed a non-linear, viscoelastic behaviour described by characteristic hysteretic curves, stress-relaxation and viscous recovery phenomena. The reliability of the investigations was validated by the interpretation of the mechanical response of heel tissues under the application of three pistons with diameter of 15, 20 and 40 mm, at the same displacement rate of about 1.7 mm/s. The maximum and minimum relative errors were found to be less than 0.95 and 0.064, respectively. PMID- 23662351 TI - Multiple oral yellow papules. Oral Sebaceous hyperplasia. PMID- 23662352 TI - Invited commentary. PMID- 23662353 TI - Invited commentary. PMID- 23662354 TI - "Action is the foundational key to all success" (Pablo Picasso). PMID- 23662355 TI - Is caudal dexmedetomidine in pediatric cardiac surgery a novel idea? PMID- 23662356 TI - [Study on the pollution and health condition of handworked painters for interior decoration]. PMID- 23662357 TI - [The study of self-rated health status of medical female staff in Beijing and research into the influence factors]. PMID- 23662358 TI - [The intervention effect of health care of female workers in enterprises in Beijing]. PMID- 23662359 TI - [Influence of ethylbenzene on oxidative damage and apoptosis in rat renal epithelial cells NRK-52e]. AB - OBJECTIVE: To study the oxidative damage and apoptosis of renal tubular epithelial cells (NRK-52e cell line) induced by ethylbenzene. METHODS: NRK-52e cells were exposed to 30, 60, 90, 120 MUmol/L ethylbenzene for 24 hours. Cell viability were measured using MTT, the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), the contents of malondialdehyde (MDA) and glutathione (GSH) were detected respectively. PI fluorescent staining assay was applied to detect percentage of apoptosis in ethylbenzene-treated groups. RESULTS: Compared with control group, cell outline became clear, cell diopter increased, cell became smaller and shrinkage, some cells broke in 60 MUmol/L ethylbenzene-treated group. Plenty of cells died, suspension cells increased significantly in 90 MUmol/L ethylbenzene-treated group. Compared with control group, cell viability the activities of SOD and CAT and the content of GSH were significantly decreased in 60 and 90 MUmol/L ethylbenzene-treated groups (P<0.05). The MDA content were remarkably elevated in 90 MUmol/L ethylbenzene-treated groups (P<0.05). CONCLUSION: Ethylbenzene can induce oxidative stress and apoptosis in NRK-52e cells (P<0.05). PMID- 23662360 TI - [Determination of methylal in the air of workplace with solvent desorption by gas chromatography]. PMID- 23662361 TI - The health of professionals involved with public security. PMID- 23662362 TI - Case management insider. Managing length of stay using patient flow--Part 3. AB - As lengths of stay shorten across the country, opportunities to continue to reduce length of stay become more difficult to identify. Monitoring care progression processes is the foundation of patient flow and requires daily point of care monitoring as well as data analysis retrospectively. Each case management department should create a patient flow infrastructure that includes daily monitoring and correction as well as a database that allows for collection of information that can be used later for analysis and performance improvement. In next month's issue of Case Management Insider, we will review a couple of different patient flow report cards that can be used to monitor delays and bottlenecks across the continuum of care. PMID- 23662363 TI - Clinton delivers transformative healthcare message at HIMSS13. PMID- 23662364 TI - HIEs facilitate more than just data exchange. PMID- 23662365 TI - Preventable readmissions: the care-transition crisis. PMID- 23662366 TI - The key to making telemedicine work. PMID- 23662367 TI - Enhancing patient care across borders. PMID- 23662368 TI - Consolidating healthcare. PMID- 23662369 TI - Compliance training enhances N.C. health system. PMID- 23662370 TI - Great patient care begins at registration. PMID- 23662371 TI - New Orleans' HIMSS13 breaks attendance records. PMID- 23662372 TI - Achieve compliance with SNOMED CT. PMID- 23662373 TI - Abandoning ICD-10. PMID- 23662374 TI - Health ramifications of the Gush Katif evacuation. AB - BACKGROUND: Following the 2005 evacuation of Gush Katif, a community of Jewish settlements located in the greater Gaza Strip, many evacuees reported a deterioration in their health status. OBJECTIVES: To determine if and to what degree the evacuation of Gush Katif caused a worsening in the health status of the evacuees. METHODS: In this retrospective cohort study we assessed the medical records of 2962 evacuees for changes in prevalence of diabetes, hypertension and ischemic heart disease in the period beginning 1 year before and ending 5 years after the evacuation. The findings were compared to those for the general israeli population. A questionnaire was distributed to 64 individuals to assess lifestyle and social change. RESULTS: An increase in diabetes and hypertension was found in men aged 45-64. The prevalence of diabetes mellitus in the 45-54 male group rose from 8.7% in 2004 to 12.6% in 2007 to 18.7% in 2010; in the 55-64 age group it rose from 24.6% in 2004 to 29.9% in 2007 to 32.9% in 2010. Hypertension in 45-64 year old men rose from 27.1% in 2004 to 35.12% in 2010. The increases in diabetes were significant and higher than those in the general population. The increases in hypertension were of similar magnitude. The prevalence of heart disease did not change and is similar to that in the general population. The questionnaire sample showed an increase in depression and overweight. CONCLUSIONS: The Gush Katif evacuation appears to be associated with increased morbidity of chronic disease. This may be attributed to any of several mechanisms, with unemployment, depression, inactivity and overweight playing significant roles. Preventive medical interventions and measures should be employed to screen and treat this population which underwent a major stressful event and as a result seem at greater risk than their peers. PMID- 23662375 TI - Foreign students' experience during a time of war. AB - BACKGROUND: Due to the war in Gaza in 2009, Ben-Gurion University's Medical School for International Health with a student body of 165 international multicultural students canceled a week of classes. Third-year students continued clerkships voluntarily and fourth-year students returned to Israel before departing for electives in a developing country. A debriefing session was held for the entire school. OBJECTIVES: To assess the academic and psychological effects of political conflict on students. METHODS: We asked all students to fill out an anonymous Google electronic survey describing their experience during the war and evaluating the debriefing. A team of students and administrators reviewed the responses. RESULTS: Sixty-six students (40% of the school) responded (first year 26%, second year 39%, third year 24%, fourth year 8%, taking time off 3%, age 23-40 years old). Eighty-three percent were in Israel for some portion of the war and 34% attended the debriefing. Factors that influenced individuals' decision to return/stay in the war zone were primarily of an academic and financial nature. Other factors included family pressure, information from peers and information from the administration. Many reported psychological difficulties during the war rather than physical danger, describing it as "draining" and that it was difficult to concentrate while studying. As foreigners, many felt their role was undefined. Although there is wide variation in the war's effect on daily activities and emotional well-being during that time, the majority (73%) reported minimal residual effects. CONCLUSIONS: This study lends insight to the way students cope during conflict and highlights academic issues during a war. Open and frequent communication and emphasis on the school as a community were most important to students. PMID- 23662376 TI - Comparative outcome of bomb explosion injuries versus high-powered gunshot injuries of the upper extremity in a civilian setting. AB - BACKGROUND: Explosion injuries to the upper extremity have specific clinical characteristics that differ from injuries due to other mechanisms. OBJECTIVES: To evaluate the upper extremity injury pattern of attacks on civilian targets, comparing bomb explosion injuries to gunshot injuries and their functional recovery using standard outcome measures. METHODS: Of 157 patients admitted to the hospital between 2000 and 2004, 72 (46%) sustained explosion injuries and 85 (54%) gunshot injuries. The trauma registry files were reviewed and the patients completed the DASH Questionnaire (Disabilities of Arm, Shoulder and Hand) and SF 12 (Short Form-12) after a minimum period of 1 year. RESULTS: Of the 157 patients, 72 (46%) had blast injuries and 85 (54%) had shooting injuries. The blast casualties had higher Injury Severity Scores (47% vs. 22% with a score of > 16, P = 0.02) and higher percent of patients treated in intensive care units (47% vs. 28%, P = 0.02). Although the Abbreviated Injury Scale score of the upper extremity injury was similar in the two groups, the blast casualties were found to have more bilateral and complex soft tissue injuries and were treated surgically more often. No difference was found in the SF-12 or DASH scores between the groups at follow up. CONCLUSIONS: The casualties with upper extremity blast injuries were more severely injured and sustained more bilateral and complex soft tissue injuries to the upper extremity. However, the rating of the local injury to the isolated limb is similar, as was the subjective functional recovery. PMID- 23662377 TI - Patients' perceptions of radical prostatectomy for localized prostate cancer: a qualitative study. AB - BACKGROUND: Radical prostatectomy is one option for treating localized prostate cancer, but it can cause functional impairment of the urogenital system. OBJECTIVES: To describe the outcomes of radical prostatectomy as perceived by the patients, and their ways of coping with them. METHODS: We conducted a qualitative study of 22 men with localized prostatic cancer 1 year after surgery. The key questions related to the effect of the disease and the surgery on their lives and their view on the value of the surgery. RESULTS: The surgery was perceived as a necessary solution for the diagnosed cancer. All the participants suffered from varying degrees of urinary incontinence and erectile dysfunction. Urinary incontinence caused severe suffering. The impaired sexual ability affected relations with partners and led to feelings of shame and guilt and a decreased sense of self-esteem. In retrospect, the participants still viewed the surgery as a life-saving procedure. Faith in the surgeon contributed to their affirmation of the decision to undergo surgery despite the difficulties. CONCLUSIONS: Patients were prepared to suffer the inevitable physical and psychological sequelae of radical prostatectomy because they believed the surgery to be a definitive solution for cancer. Surgeons advising patients with localized prostatic cancer on treatment options should address these difficult issues and provide psychological support, either themselves or in collaboration with professionals. PMID- 23662378 TI - Open globe eye injury characteristics and prognostic factors in southern Israel: a retrospective epidemiologic review of 10 years experience. AB - BACKGROUND: Open globe injury (OGI) is a common cause of unilateral visual loss in all age groups. OBJECTIVES: To describe and identify clinical characteristics, prognostic factors and visual outcome in a group of patients with OGI in southern Israel. METHODS: We conducted a retrospective review of all cases of OGI examined in the ophthalmology department at Soroka University Medical Center, Beer Sheva, Israel, from 1996 to 2005. A total of 118 eyes with OGI were detected and analyzed statistically. We recorded demographic data, cause of injury, initial visual acuity (VA), associated globe morbidity and injuries, Ocular Trauma Score (OTS), surgical procedures, postoperative complications, and final VA. RESULTS: The mean age of the study group was 36.1 years and included 84% males. The median follow-up was 13.3 months (range 6-66 months). The annual incidence of open globe injuries was 3.1 cases/100,000. In 84 cases (71%) the mechanism of open eye injury was laceration. Most of the injuries were work related (45%). Bilateral injury was observed in two patients. An intraocular foreign body was observed in 45 eyes (38%). Primary surgical repair was performed in 114 eyes. Six patients (5.1%) had complications with posttraumatic endophthalmitis and 12 patients (10.1%) underwent evisceration or enucleation. Clinical signs associated with poor visual outcomes included reduced initial VA, eyelid injury, and retinal detachment at presentation. CONCLUSIONS: In our study population the most important prognostic factors in open globe injury were initial VA, eyelid injury and retinal detachment. PMID- 23662379 TI - Failure to insert a levonorgestrel-releasing intrauterine system: a survey based on self-reports by Israeli gynecologists. AB - BACKGROUND: The insertion of a levonorgestrel-releasing intrauterine system (LNG IUS) requires experience and is associated with a low failure rate. OBJECTIVES: To assess the reasons given by gynecologists why they failed to insert a LNG-IUS. METHODS: We obtained data from the sole distributor in Israel that prospectively recorded these cases when contacted by gynecologists following an insertion failure. RESULTS: The mean rate of failed insertions was 0.95% (range 0.77-1.03%) for the 5 year study period 2006-2010. The most common reasons reported by gynecologists for LNG-IUS insertion failure were loss of sterility of the device, inability to insert the device due to a stenotic cervical canal, accidental removal of the device following a successful insertion due to hasty removal of the inserter or the use of blunt scissors, and removal of the newly inserted LNG IUS following ultrasound evidence that it was misplaced. CONCLUSIONS: Gynecologists should be aware of the common pitfalls associated with insertion of an LNG-IUS. Several techniques that may aid in avoiding these mishaps are described. PMID- 23662380 TI - Septicemia following rotavirus gastroenteritis. AB - BACKGROUND: Rotavirus gastroenteritis is a prevalent childhood illness rarely complicated by secondary bacterial sepsis. Although there are case reports of septicemia after rotavirus infection, there are no recent reviews on this topic. OBJECTIVES: To add new cases of septicemia after rotavirus to the literature, review the few cases of septicemia after rotavirus that have been reported, calculate the incidence of septicemia in children hospitalized for rotavirus gastroenteritis, and discuss the characteristics of septicemia after rotavirus infection and implications for current pediatric practice. METHODS: We identified children whose illness was complicated by septicemia from among all hospitalizations at our facility for rotavirus gastroenteritis from May 1999 through May 2010. We also review the few cases reported in the English literature. RESULTS: We identified two cases of septicemia from among 632 hospitalizations for rotavirus gastroenteritis in this time period, for an incidence rate of 0.32%, which is comparable to other estimates in the English literature. The typical course for cases of bacterial superinfection involves a second peak of high fever; other clinical signs are variable. CONCLUSIONS: Septicemia after rotavirus gastroenteritis is a rare but dangerous entity. Early identification of a child developing bacterial superinfection after rotavirus, as in any case of sepsis, is of the utmost importance, as is obtaining blood cultures in a child with a rotavirus infection and a second fever spike. PMID- 23662382 TI - Making war a part of medical education. PMID- 23662381 TI - Effects of allicin on cardiovascular risk factors in spontaneously hypertensive rats. AB - BACKGROUND: Allium sativum, the active ingredient in garlic, is known to have a beneficial effect on major cardiovascular risk factors, including dyslipidemia, blood pressure, blood glucose and insulin levels. However, the data on the significance of these effects are inconsistent due to methodological limitations, especially the use of whole garlic cloves which does not allow controlled dosing of the active compound. OBJECTIVES: To study the effects of purified allicin on the cardiovascular system. METHODS: Spontaneously hypertensive rats treated for 6 weeks with a daily dose of 80 mg/kg/day of purified allicin added to their chow were compared to control rats that were fed regular chow. Weight, systolic blood pressure (SBP), triglycerides, cholesterol, insulin and adiponectin were measured at baseline and at the end of the study. RESULTS: Allicin had no effect on body weight whereas it reduced SBP significantly from 190 +/- 7.5 mmHg to 168 +/- 5.7 (P < 0.0001) and triglyceride levels from 96 +/- 25 mg/dl to 71 +/- 19 (P = 0.009). Allicin had no effect on plasma cholesterol, insulin and adiponectin levels. CONCLUSIONS: Allicin lowered blood pressure and triglyceride levels in spontaneously hypertensive rats. This effect was not mediated through weight loss. PMID- 23662383 TI - Prostate cancer: do patients understand what they choose? PMID- 23662384 TI - Wegener's granulomatosis and the salivary glands. PMID- 23662385 TI - Acute viral myocarditis: current concepts in diagnosis and treatment. AB - Acute myocarditis is one of the most challenging diseases to diagnose and treat in cardiology. The true incidence of the disease is unknown. Viral infection is the most common etiology. Modern techniques have improved the ability to diagnose specific viral pathogens in the myocardium. Currently, parvovirus B19 and adenoviruses are most frequently identified in endomyocardial biopsies. Most patients will recover without sequelae, but a subset of patients will progress to chronic inflammatory and dilated cardiomyopathy. The pathogenesis includes direct viral myocardial damage as well as autoimmune reaction against cardiac epitopes. The clinical manifestations of acute myocarditis vary widely--from asymptomatic changes on electrocardiogram to fulminant heart failure, arrhythmias and sudden cardiac death. Magnetic resonance imaging is emerging as an important tool for the diagnosis and follow-up of patients, and for guidance of endomyocardial biopsy. In the setting of acute myocarditis endomyocardial biopsy is required for the evaluation of patients with a clinical scenario suggestive of giant cell myocarditis and of those who deteriorate despite supportive treatment. Treatment of acute myocarditis is still mainly supportive, except for giant cell myocarditis where immunotherapy has been shown to improve survival. Immunotherapy and specific antiviral treatment have yet to demonstrate definitive clinical efficacy in ongoing clinical trials. This review will focus on the clinical manifestations, the diagnostic approach to the patient with clinically suspected acute myocarditis, and an evidence-based treatment strategy for the acute and chronic form of the disease. PMID- 23662386 TI - Parotid gland involvement as initial presentation of Wegener's granulomatosis: a diagnostic pitfall. PMID- 23662388 TI - Granulomatosis and polyangiitis: the rituximab option. PMID- 23662387 TI - Parotitis as the presenting symptom of Wegener's granulomatosis: case report and meta-analysis. PMID- 23662389 TI - BCG: Luebeck, not Hamburg. PMID- 23662390 TI - Reproducibility of microvolt T-wave alternans in patients with ischemic heart disease. PMID- 23662391 TI - Author's reply. PMID- 23662392 TI - Generic atorvastatin-induced thrombocytopenic purpura: a raised red flag. PMID- 23662393 TI - [Effects of pioglitazone on TGFbeta1 expression in ischemia/reperfusion injury myocardium of rats]. AB - OBJECTIVE: To investigate the effects of pioglitazone on transforming growth factor beta1 (TGFbeta1) expression in ischemia/reperfusion injury myocardium of rats. METHODS: Thirty SD rats were randomly divided into five groups (n = 6): ischemia/reperfusion group, pioglitazone 5 mg/(kg x d) group, pioglitazone 10 mg/(kg x d) group, pioglitazone 20 mg/(kg x d) group and pioglitazone 20 mg/(kg x d) + peroxisome proliferator-activated receptor gamma (PPARgamma) specific antagonist GW9662 group. Left anterior descending coronary artery of rats were ligated for 30 min and reperfused for 120 min to establish the model of ischemia/reperfusion in vivo. RT-PCR was performed to detect the expression of TGFbeta1 mRNA. Western blot was performed to detect the expression of TGFbeta1 protein. RESULTS: Myocardial apoptosis was significantly suppressed by pioglitazone. Pioglitazone upregulated TGFPbeta1 expression both in mRNA and protein level. GW9662 reversed the inhibition of myocardial apoptosis and the upregulation of TGFbeta1 expression by pioglitazone. CONCLUSION: Pioglitazone can inhibit the myocardial apoptosis induced by ischemia/reperfusion. Pioglitazone may protect the myocardium from ischemia/reperfusion via upregulation of TGFbeta1. This protection may be mediated by PPARgamma. PMID- 23662394 TI - [The expression of AMPK alpha and phosphorylated-AMPK alpha in different types of skeletal muscles during exercise]. PMID- 23662395 TI - [HMGB1/SREBP-1 mediated IFN-gamma-induced lipid deposition in mouse mesangial cells]. AB - OBJECTIVE: To explore the possible mechanism of lipid deposition induced by interferon-gamma (IFN-gamma). METHODS: The mouse mesangial cells (MMC) were randomly divided into control group, stimulation group, stimulation + control vector group (sh-HMGB1) and stimulation+ specific sh-vector group (sh-SREBP-1). RT-PCR was used to detect the expression of HMGB1, SREBP-1 and fatty acid synthetase (FAS) mRNA; the protein expression was determined by Western blot. RESULTS: The Oil Red O staining revealed that the mouse mesangial cells showed significant lipid droplet in IFN-gamma group. IFN-gamma up-regulated the expression of HMGB1, SREBP-1, FAS mRNA and protein time-dependently; Transfection of MMC with HMGB1 siRNA resulted in the suppression of SREBP-1, FAS protein levels induced by IFN-gamma, following with decrease of lipid deposition. Stimulation with HMGB1 markedly induced expression of SREBP-1, FAS expression and peaked at 8 h, decreased at 12 h compared with that at 8 h. Sh-SREBP-1 decreased the lipid deposition induced by HMGB1 in MMC. CONCLUSION: IFN-gamma might induce lipid deposition in mouse mesangial cells partly by up-regulating the expression of HMGB1/SREBP-1/FAS. PMID- 23662396 TI - [Improved methods for researching isolated carotid sinus baroreceptors automatically controlling for sinus pressure]. AB - OBJECTIVE: To develop a system for automatically controlling carotid sinus pressure in the study on baroreceptors. METHODS: The preparation containing carotid sinus with parts of the connected vessels and carotid sinus nerve (CS CSN) were isolated and perfused. A critical pressure controlling component (PRE U, Hoerbiger, Deutschland) dictated by a computer was integrated into the system to clamp the intrasinus pressure. The pressure command and the relevant intrasinus pressure were compared to evaluate the validity of the pressure controlling system. RESULTS: A variety of sinus pressure-controlling patterns, including pulsation, ramp and step pressures, could be achieved accurately by using the system, and the pressure-dependent discharge activities of sinus nerve were confirmed. CONCLUSION: This system for clamping carotid sinus pressure could realize multiple pressure-controlling patterns and is a useful and flexible pressure controlling method that could applied in the study on mechano-electric transduction of baroreceptors. PMID- 23662397 TI - [Effect of puerarin on hemorheology and pulmonary pressure in rat pneumo-cardiac disease]. PMID- 23662398 TI - [Construction of gene vaccine of myostatin fusion with T-helper epitope and its effects on forelimb grip in immunized mice]. AB - OBJECTIVE: To further study the therapy of wasting muscle by myostatin as a new targets, the eucaryotic expression vector coupled the foreign T-helper epitope of tetanus toxin (TT) to the N terminus of myostatin was constructed, and the effects of the gene vaccine on forelimb grip were tested in immunized mice. METHODS: A DNA fragment encoding the TT epitope followed by the N terminus of mature myostatin (330bp) was synthesized. The eucaryotic expression vector of myostatin was constructed and the chinese hamster ovary (CHO) cells were infected with the recombinant plasmids pVAC-TT-Ms by liposome transfection according to routine laboratory procedure. The myostatin expression was tested by cell immunofluorescence technique in transfected CHO. The forelimbs grip were tested in immunized mice with myostatin gene vaccine. RESULTS: The eucaryotic expression vector of myostatin coupled TT epitope was constructed successfully through the restriction analysis and sequencing. The recombinant plasmids pVAC-TT-Ms met quality criterion as gene vaccine by analysis OD260/280 and electrophoresis. The myostatin expression was detected obviously in transfected CHO. The forelimb grip in immunized mice had an obvious increase. The average value of forelimb grip of the mice immunized with pVAC-TT-Ms was about 29.88% greater than that of control mice. CONCLUSION: The construction of eucaryotic expression vector of myostatin coupled TT epitope is successful in expression for recombinant human mature peptide of myostatin. The gene vaccine of myostatin meet quality criterion. The immunized mice has an obvious increase in forelimb grip. PMID- 23662399 TI - [Effects of TOLL-like receptor 4 on passively sensitized human airway smooth muscle cells proliferation and synthesis and secretion function of TGF-beta1]. AB - OBJECTIVE: To investigate the activation of Toll like receptor 4 (TLR4) on passively sensitized human airway smooth muscle cells (HASMCs) proliferation and the synthesis and secretion function. METHODS: Through the cultivation of primary HASMCs, we studied TLR4 expression on cell surface, cell proliferation and transformation of parturient factor-beta1 (TGF-beta1) in asthma under the condition of synthesis and secretion level by passively sensitized HASMCs with asthma serum. RESULTS: Compared with the control group, in passive sensitized group and TNF-alpha group TLR4 expression were significantly increased (P < 0.01), significantly enhanced proliferation (P < 0.01), total protein concentration, IgE secretion and TGF-beta1 were significantly higher (P < 0.01); and all the above parameters were increased more significantly in TNF group compared with those in the target effect of passively group; and those parameters were significantly reduced in anti-TLR4 antibody group compared with those in the target effect both of passively sensitized group and TNF-alpha group. CONCLUSION: TLR4 on passively sensitized HASMCs activated can induce the excessive proliferation of HASMCs and a large number of synthesis and secretion of TGF beta1, resulting in changing airway micro-environment, which involved in airway remodeling in asthma. PMID- 23662400 TI - [Comparison of membrane current of vascular smooth muscle cells in brain artery of spontaneously hypertensive rats and Wistar rats]. AB - OBJECTIVE: To investigate the difference in membrane current of vascular smooth muscle cells (VSMCs) in brain artery (BA) of spontaneously hypertensive rats (SHR) and Wistar rats. METHODS: We compared the properties of spontaneous transient outward K+ currents (STOCs), the density and composition of current of VSMCs in BA of SHR and Wistar rats by whole-cell patch clamp technique. RESULTS: (1) When the command voltage was 0, + 20, + 40 and + 60 mV respectively, the current densities of VSMCs in BA of SHR and Wistar rats were significant different (P < 0.01). (2) The whole-cell current of VSMCs was partly inhibited by 1 mmol/L4-AP (voltage-gated K+ channel blocker) or 1 mmol/L TEA (big conductance Ca(2+)-activated K+ channel blocker) respectively. (3) The frequency and amplitude of STOCs in SHR were faster and bigger than those in Wistar rats. 1 mmol/L TEA almostly inhibited the STOCs, but not by 4-AP. CONCLUSION: These results suggest that the current densities of VSMCs in BA of SHR and Wistar rats are significant different, the outward current of VSMCs in BA of SHR and Wistar rats are composed by Kv and BK(Ca). SHR express more STOCs mediated by BK(Ca), than Wistar rats. PMID- 23662401 TI - [Effects of cadmium on action potential and L-type Ca2+ current in rat ventricular myocytes]. PMID- 23662402 TI - [Effect of limb ischemic preconditioning on the expression of p38 MAPK and HSP 70 in CA3 and DG regions of the hippocampus of rats]. AB - OBJECTIVE: To observe the expression of p38 MAPK and HSP 70 in CA3 and dentate gyrus (DG) regions of the hippocampus of rats induced by limb ischemic preconditioning (LIP). METHODS: Ninety-six rats were randomly divided into sham and LIP groups. And the animals in the LIP group were further divided into LIP 6 h, LIP 12 h, LIP 1 d, LIP 2 d, LIP 3 d, LIP 4 d and LIP 5 d subgroups according to the time of reperfusion after LIP. Immunohistochemical staining and Western blot were used to observe the expression of p38 MAPK and HSP 70 in CA3 and DG regions of the hippocampus. RESULTS: The results of the immunohistochemical staining and Western blot were consistent, which indicated that there were fluctuation in the p-p38 MAPK and HSP 70 expression in CA3 and DG regions after LIP compared with those of the sham group. The expression of p-p38 MAPK began to be up-regulated 1d after LIP and reached its peak at 3 d and lasted for 4 d after LIP. However, the expression of HSP 70 was significantly up-regulated 2 d after LIP compared to the sham group, reached its peak at 3 d and lasted until the 4 d after LIP. CONCLUSION: LIP up-regulates the expression of p38 MAPK and HSP 70 in the CA3 and DG regions of the hippocampus of rats. PMID- 23662403 TI - [Experimental research on the effects of seabuckthorn oil on the oxidative damage in training rats myocardium and liver]. PMID- 23662404 TI - [Calreticulin-mediated thermal treatment on the adaptation change of calmodulin mechanism in rat skeletal muscle]. AB - OBJECTIVE: To study the protection of stress protein calreticulin (CRT) in rat skeletal muscle during the adaptation mechanism of calmodulin in the course of heat treatment. METHODS: Increased heat treatment program would be applied, 40 SD rats were randomly divided into the quiet control group C (n = 8) and heat treated group H (n = 32), then the heat treatment group would be divided into immediately group (H1), 24-hour post-heat treatment group (H2), 48 -hour post heat treatment group (H3) and six days post-heat treatment group (H4) (n = 8). RESULTS: After heat treatment, the Ca(2+)-ATP activity in rat skeletal muscle sarcoplasmic reticulum in H2 group reached the highest value compared with that in the quiet control group C (P < 0.01), and the value in H1 group showed significant differences compared with control group C (P < 0.05); The Ca(2+)-ATP activity in mitochondrial had the highest value in H1 group, compared with the quiet control group C (P < 0.05), while the Ca2+ concentration in rat skeletal muscle sarcoplasmic reticulum had the highest in group H2, followed by H1 group, both showing significant difference compared with the quiet control group (P < 0.05); The Ca2+ concentration in mitochondrial was high in H1 and H2 group than that of the quiet control group C, and the value in H3 and H4 group was lower than that of the quiet control group C, which had no difference; After heat treatment, the expression of stress proteins of CRT from H1, H2 and H3 group in rat skeletal muscle increased significantly compared with quiet group C. CONCLUSION: In the process of increased heat treatment, calreticulin played the regulatory role on the imbalance of calcium homeostasis in skeletal muscle cells, and the adaptation protection from the thermal stimulation could have the very good effect on muscle. PMID- 23662405 TI - [The role of TLR4-mediated MyD88-dependent pathway in neuroinflammation in hippocampal neurons of rats]. AB - OBJECTIVE: To investigate weather there is a toll-like receptor 4 (TLR4)-mediated myeloid differentiation factor 88 (MyD88)-dependent pathway in hippocampal neurons of rats and the probable role of the pathway in neuroinflammation. METHODS: To establish the proper model, primarily cultured hippocampal neurons were treated with lipopolysaccharides (LPS), or pretreated with TLR4 antibody then co-treated with LPS. The expression of mRNA of MyD88 and TNF-alpha receptor associated factor 6 (TRAF6) were tested by RT-qPCR. The content of MyD88 and TRAF6 were tested by Western blot. The nuclear translocation of nuclear factor kappaB/P65 (NF-kappaB/p65) was tested by immunofluorescence. The content of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and nitric oxide (NO) were tested by ELISA. RESULTS: LPS could increase MyD88 and TRAF6 mRNA, upregulate protein level of MyD88 and TRAF6 and increase the level of TNF-alpha, IL-1beta and NO in cell culture supernatant. LPS also could promote NF-kappa B/p65 translation to the nucleus. The pretreatment with TLR4 antibody reduced the translocation to nucleus for NF-kappaB/P65 and the contents of TNF-alpha, IL 1beta and NO in the culture supernatant. CONCLUSION: There is a TLR4-mediated MyD88-dependent pathway in hippocampal neurons. The activation of this pathway can increase the level of TNF-alpha, IL-1beta and NO in cell culture supernatant. TLR4-mediated MyD88-dependent pathway in hippocampal neurons participate in neuroinflammation, that means neurons are not passive in inflammation. PMID- 23662406 TI - [Amelioration of icariin for the epididymis impairment induced by streptozocin (STZ) in rats]. AB - OBJECTIVE: To investigate the effects of icariin on the streptozocin (STZ) induced epididymis impair in rats. METHODS: The epididymis impair was induced by injection of streptozocin at dosage of 60 mg/kg ip in SD rats. Animals were randomly divided into six groups (n = 14): normal control, model group, three icariin treated group with different dosages (P.O, 20 mg/kg, 40 mg/kg, 80 mg/kg especially) and rosiglitazone group (P.O, 3 mg/kg), 12 weeks later, animals were sacrificed. The level of serum glucose, the activity of lactate dehydrogenase (LDH), acid phosphatase (ACP), gamma-glutamyltranspeptidase (gamma-GT), alpha glucosidase activity as well as sialic acid (SA), fructose level in the epididymis were determined. The pathological examination was performed under microscope after the epididymis was fixed by 4% poly-formalin and stained by HE. RESULTS: Compared with the normal control, the activity of LDH, ACP, gamma-GT and alpha-glucosidase in the epididymis revealed a decline, with lower level of SA and fructose. Histological examination showed that mature spermatocytes in the epididymis markedly decreased. These alterations were ameliorated in the groups with the treatment of icariin at 40 mg/kg and 80 mg/kg, but not at 20 mg/kg. CONCLUSION: Icariin ameliorated the signs of epididymis in diabetic rats induced by streptozocin, this effect might carry out by promoting the elevation of special enzyme and energy metabolism in the epididymis. PMID- 23662407 TI - [The analysis of women boxing athletes EEG monitoring for high-intensity training before games]. PMID- 23662408 TI - [Role of GDNF in the behavior and cognitive impairment of mice induced by chronic stress and aging]. AB - OBJECTIVE: To investigate the effects of chronic stress on the spatial learning memory and the role of glial cell line-derived neurotrophic factor (GDNF) of prefrontal cortex (PFC) and hippocampus (HP) in different age mice. METHODS: The chronic stress model mice in 21 days with multiple chronic unpredictable stressors were applied. The spontaneous behavior and spatial learning-memory ability of mice were tested, using Open field and Morris water maze task, and the expression of GDNF in HP and PFC were detected by immunohistochemical method. RESULTS: Compared with young mice, the spontaneous behaviors were significantly decreased and the spatial learning-memory function were significantly decreased (P < 0.05, P < 0.01) in aged mice. The GDNF expression in the CA3, DG of HP and PFC were significantly reduced in aged mice (P < 0.05, P < 0.01). After chronic stress, the spontaneous behaviors were remarkably decreased and the ability of spatial learning-memory of the stress group mice were significantly decreased (P < 0.05, P < 0.01) compared with those of the control group mice. The expression of GDNF in HP and PFC were remarkably reduced (P < 0.05, P < 0.01) in stress group mice. The aged stress mice had more serious changes after chronic stress. CONCLUSION: The brain aging and chronic stress in mice causes behavioral changes and the damage of spatial learning-memory function, and which may be nearly related to the expression of GDNF in HP and PFC. PMID- 23662409 TI - [Protective effects of propofol combined with ulinastatin on acute lung injury induced by endotoxin in rats]. PMID- 23662410 TI - [The role of HO/CO in the spinal nociception transmission and hyperalgesia of rats induced by formalin]. AB - OBJECTIVE: To investigate the role of heme oxygenase and carbon monoxide (HO/CO) in the development of spontaneous pain and hyperalgesia of rats induced by formalin injection. METHODS: Zinc protoporphyrin Znpp (the inhibitor of HO) was intrathecally injected to the rats with formalin inflammatory pain. Hemin (the agonist of HO) was intrathecally injected to the normal rats. The weighted pain scores were used to evaluate the degree of pain response. Thermal withdrawal latency and mechanical withdrawal threshold were observed to assess the degree of thermal hyperalgesia and mechanical allodynia. RESULTS: After the intrathecal injection of Znpp, the weighted pain score obviously reduced in a dose-dependent manner compared with the rats with formalin inflammatory pain. Intrathecal injection of Znpp had no obvious effect on thermal withdrawal latency and mechanical withdrawal threshold in injected feet compared with formalin group. But there was a prolongation in a dose-dependent manner in non injected feet. Intrathecal injection of Hemin to normal rats could shorten the thermal withdrawal latency and reduce the mechanical withdrawal threshold on both sides of hindpaws. CONCLUSION: Intrathecal injection of the HO inhibitor produced prominent inhibition to pain related behavior and thermal and mechanical hyperalgesia induced by formalin injection. Intrathecal injection of HO inductor could induce thermal and mechanical hyperalgesia in normal rats. The results indicated that HO/CO took part in the processes of spinal cord nociceptive information transmission and the development of thermal and mechanical hyperalgesia. PMID- 23662411 TI - [The expression of bFGF, GAP-43 and neurogenesis after cerebral ischemia/reperfusion in rats]. AB - OBJECTIVE: To observe time points of the expressions of basic fibroblast growth factor (bFGF), growth associated protein-43 (GAP-43) and neurogenesis after cerebral ischemia/reperfusion in rats and explore its possible mechanism of neurogenesis. METHODS: Models of middle cerebral artery occlusion (MCAO) were established in SD rats which were divided into 3 d, 7 d, 14 d and 28 d groups (n = 6). The neurological severity was evaluated by neurological severity scores (NSS) and scores of motor test (SMT). Neuronal injury in the boundary zone of the infarction area was evaluated by TUNEL and Nissl staining; The expressions of bFGF and GAP-43 and neurogenesis were evaluated by Western blot and 5 bromodeoxyuridine (Brdu) fluorescence staining, respectively. RESULTS: It showed up neurologic impairment and motor dysfunction after cerebral ischemia/reperfusion in rats at 3 d, the numbers of neuron apoptosis also peaked at 3d, the protein levels of bFGF and GAP-43 were significantly increased in time dependent manner, peaked at 7 d and then decreased gradually, meanwhile, Brdu and NeuN double fluorescence staining displayed scattered Brdu-and NeuN-positive cells in the boundary zone of the infarction area. CONCLUSION: These results suggest that the upregulation of bFGF and GAP-43 may contribute to the neurogenesis after cerebral ischemia/reperfusion. PMID- 23662412 TI - [The effect of niflumic acid on gamma aminobutyric acid activated current in DRG neurons]. AB - OBJECTIVE: To explore the modulatory effect of niflumic acid (NFA) on gamma aminobutyric acid (GABA)-activated currents of dorsal root ganglion (DRG) neurons in rat. METHODS: The whole-cell patch-clamp technique was used to record the NFA- and GABA-activated currents in neurons freshly dissociated from rat DRG neurons. RESULTS: Application of NFA(0.1 - 100 micromol/L) could induce concentration dependent outward currents in some cells (21/48,43.75%), and GABA (0.1 - 100 micromol/L) could induce concentration-dependent inward currents in some cells(150/159,94.32%). NFA-(100 micromol/L) and GABA-(100 micromol/L) activated currents were (0.27 +/- 0.06) nA (n = 12) and (1.29 +/- 0.72) nA (n = 53) respectively. However, pre-application of NFA (0.1 - 100 micromol/L) could inhibit the GABA-activated inward current which was identified to be GABAA receptor-mediated current. The inhibitory effects of NFA were concentration dependent. NFA could not alter the EC50 (about 30 micromol/L) and inverse potential (about -10 mV) of GABA-activated current (P > 0.05). CONCLUSION: Pre application of NFA exerts a more strong inhibitory effect on the peak value of GABA-activated current. PMID- 23662413 TI - [The genetic screening of a dominant zebrafish mutant in long-term memory]. AB - OBJECTIVE: To screen the learning and memory mutant from N-ethyl-N-nitrosourea (ENU) mutagenic zebrafish F1, and to get the new model animal to study the mechanism of learning and memory. METHODS: Zebrafish mutant was screened by inhibitory avoidance behavioral test and identified by the expression of gene c fos with qRT-PCR. RESULTS: We isolated a zebrafish mutant related to learning and memory, fgt. In this fgt zebrafish mutant long-term memory was much lower than that in wild-type when tested at 24 h after training. The 24 h long-term memory in about half of fgt mutant F2 (13/30) were significantly lower than those in wild-type, and the others relatively normal. Compared with the expression in wild type fishes, the expression of immediate-early genes (IEGs) c-fos in half of fgt mutant F2 (13/30) after exploring in a novel environment increased distinctly from the basal control levels statistically, and the others relatively normal, which were in accordance with the behavioral results. CONCLUSION: The zebrafish mutant fgt is a dominant mutant with defect in long-term memory. PMID- 23662414 TI - [Effects of Enshi green tea tea polysaccharide on serum glucose in experimental diabetic rats]. AB - OBJECTIVE: To study the effects of Enshi green tea tea polysaccharide on serum glucose in experimental diabetic rats. METHODS: Diabetic rats model were established by alloxan, Enshi green tea tea polysaccharide was poured into rats' stomach for four weeks, then the changes of the level about fasting blood glucose (FBG), glucokinase (GK), insulin (INS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), spleen index and thymus index were observed. RESULTS: Enshi green tea tea polysaccharide could reduce the level of FBG in diabetic rats, and increase the activity of KG, SOD and GSH-Px, moreover, it could reduce the level of MDA and increase the spleen index and thymus index. CONCLUSION: Enshi green tea tea polysaccharide has remarkable effect on playing down the blood sugar, and can increase the antioxygenic activity and immunity. PMID- 23662415 TI - [Effects of sodium selenite on the cell growth inhibition and intracellular reactive oxygen species of human brain glioma stem cells]. PMID- 23662416 TI - [Study on the levels of DA and metabolite in striatum in rats with Parkinson's disease treated by BDNF gene modified bone mesenchymal stem cells]. AB - OBJECTIVE: To investigate the effects of dopamine (DA) and metabolite in striatum of Parkinson's disease (PD) rats treated by bone mesenchymal stem cells (MSCs) modified by plasmid pIRESneo-EGFP-BDNF. METHOD: pIRESneo-EGFP-BDNF was transfected to MSCs with electroporation. The rat models of PD were set up by 6 OHDA and then divided into four groups randomly, which were Sham group, PD group, BDNF group. The rotating behavior of rat models induced by apomorphine (APO) intraperitoneally which transplanting bone MSCs or MSCs modified by plasmid pIRESneo-EGFP-BDNF through cerebral lateral ventricle after 2, 4 and 8 weeks. The levels of DA, homovanillic acid (HVA), dihydroxy-phenylacetic acid (DOPAC) were measured by high performance liquid chromatography (HPLC) in striatum of each group. RESULTS: The rotation numbers (r/min) of MSCs group or BDNF group in the 2nd, 4th and 8th week after transplanting were significantly decreased compared with that of PD group (P < 0.05). Those of BDNF group were specially significant compared with those of MSCs group (P < 0.05). The levels of DA, HVA, DOPAC and the ratios of DA/HVA, DA/DOPAC in stratum after PD rats intervened by transplanting cells through cerebral lateral ventricle after eight weeks were increased significantly in BDNF group or MSCs group while compared with PD group, especially in BDNF group. CONCLUSION: The behavior of rat with PD was improved significantly by increasing the levels of DA and decreasing metabolic rate of DA in striatum while transplanting BDNF modified bone MSCs through cerebral lateral ventricle. PMID- 23662417 TI - [The effects of eccentric exercise on the skeletal muscle apoptosis and proliferation in rats]. AB - OBJECTIVE: To reveal the effects of three days' repeated exhausted eccentric exercise on the skeletal muscle apoptosis and proliferation in rats. METHODS: Fifty male SD rats aged at 8 week old were randomly divided into control group (C) and training groups (B1, B2, B3, B4) (n = 10), the training groups ran on a treadmill every day till exhausted. After they had been trained repeatedly for three days, their medial head of triceps brachii muscle cell apoptosis was detected in paraffin section by the TUNEL, expression of proliferating cell nuclear antigen (PCNA) protein was examined by immunohistochemistry. RESULTS: (1) The apoptosis appeared sequential change, and it was consistent with the exercise induced skeletal muscle micro-injury (EIMmI). The apoptosis index in the training group after exercise was much greater than that in the control group (P < 0.05), and it reached the peak at 24 h after exercise, then it reduced at 48 h after exercise. (2) The express of PCNA exhibited a sequential change after exercise, the proliferation index in the training group after exercise was greater than that in the control group (P < 0.05), it increased after exercise immediately, but it reduced at 3 h after exercise, then was reached the peak at 24 h after exercise, the proliferation index was moderately correlated with the apoptosis index (P < 0.05). CONCLUSION: (1) Cell apoptosis can induce the delayed skeletal muscle damage. (2) Apoptosis may be a start factor of skeletal muscle regeneration. PMID- 23662418 TI - [The functional changes in L-type Ca2+ channel of hypertrophied cardiomyocytes in neonatal rats induced by angiotensin II]. AB - OBJECTIVE: To investigate the molecular and functional changes in L-type Ca2+ channel of hypertrophied cardiomyocytes in neonatal rats induced by angiotensin II (Ang II). METHODS: The in vitro model of cardiomyocyte hypertrophy was established in cultured cardiomyocytes from neonatal rats. Whole cell patch clamp was used to measure the L-type Ca2+ currents. Semi-quantitative RT-PCR was used to determine the mRNA expression of L-type Ca2+ channel alpha1C subunits. RESULTS: In the hypertrophied cardiomyocytes induced by Ang II, I(Ca, L) densities were increased, whereas the features of I(Ca,L) activation, inactivation or recovery from inactivation were not affected. Meanwhile, Ang II increased the mRNA expression of L-type Ca2+ channel alpha1C subunits in cardiomyocytes. All these actions of Ang II could be blocked by the angiotensin II 1 type receptor blocker losartan. CONCLUSION: During cardiomyocyte hypertrophy induced by Ang II, there are significant changes in the molecule and function of L-type Ca2+ channels, which are mediated by the angiotensin II 1 type receptor. PMID- 23662419 TI - [Nikolai Konstantinovich Kol'tsov: the father of the Russian school of experimental biology]. PMID- 23662420 TI - [The template principle: paradigm of modern genetics]. AB - The idea of continuity in living systems, which was initially developed in mid 19th century, reached its peak in 1928 thanks to N.K. Koltsov, who proposed the template principle in chromosome reproduction. The determination of genetic functions of nucleic acids and the advent of molecular genetics led to F. Crick's statement of the central dogma of molecular biology in 1958. This dogma became a contemporary version of the template principle (templates of the first order). The discovery of "protein inheritance" underlay the notion of steric or conformational templates (second order) for reproducing conformation in a number of proteins. The template principle supplemented by this notion claims to be the main paradigm of modern genetics. PMID- 23662421 TI - [Organization of eukaryotic chromosomes: from Kol'tsov's studies up to present day]. AB - N. K. Kol'tsov ideas and views on the organization of eukaryotic chromosomes, including the notion of a giant hereditary molecule (genoneme) and its structural functional organization, are considered. Different approaches to chromosome studies are discussed, ranging from the examination of a chromosome as a stained cell organelle and the visualization of individual chromosomes in a living cell to the identification of topological domains of human and murine chromosomes using 3C and 5C technologies. The prospects of studies of chromosome organization using up-to-date methods of cytology, molecular biology, and bioinformatics are discussed. PMID- 23662422 TI - [Barrier elements of chromatin domains and nuclear envelope]. AB - The results of investigating the functions of different barrier elements, including insulators and MARs/SARs and the models of their effect, are described. The functions of neDNA (DNA from the nuclear envelopes) as a barrier element that protects the transgene from position-effect variegation and its interaction with insulators are discussed. The possible mechanisms of the functioning of structural and functional units of eukaryotic chromosomes of different species are suggested. PMID- 23662423 TI - [Regulatory transcription codes in eukaryotic genomes]. AB - Key aspects of gene transcription regulation in multicellular organisms, including the characteristics of their promoters, transcription-factor binding sites, and composition elements are reviewed. The functional role of transcription regulatory proteins (basal factors and regulatory transcription factors), and the mechanisms responsible for regulation of their activity are also discussed. Furthermore, we describe the importance of DNA-encoded nucleosome organization and chromatin modifications in the course of transcription regulation, as well as some mechanisms that regulate the activity of transcription factors associated with genetic networks. The current outlook on regulatory gene expression codes in eukaryotes is presented. PMID- 23662424 TI - [Study of regeneration in amphibians in age of molecular-genetic approaches and methods]. AB - The results of molecular-genetic mechanisms of regeneration in amphibians are reviewed. Based on the examples of traditional and well-studied models of the restoration of the retinas and lenses of eyes, as well as limbs and tails in amphibians, we analyze the current state of regeneration problems and questions linked to cell reprogramming, growth, and generate morphogenesis. The development of the Kol'tsov school of thought in the age of molecular-genetic approaches and methods are monitored. The contemporary interpretation of organ regeneration in terms of molecular-genetic regulation and a new look at the definition of regeneration as repeated development is proposed. We also emphasize the current problems that exist in that field of developmental biology and are caused by the many difficulties of genome sequencing and the introduction oftransgenesis in Urodela, the animal species with the highest regeneration abilities. PMID- 23662425 TI - [Large-scale genome duplications and paralog divergence in fish]. AB - Based on fish genomic studies, we review mechanisms of divergence in duplicated genes (paralogs), resulted in small ("subfunctionalization") or large ("neofunctionalization") changes in paralogs. Gene divergence occurs due to several processes, such as non-synonymous substitutions, exon-intron structure rearrangement, and alterations in regulatory regions, which cause differential temporal or spatial expression of paralogous gene copies during ontogenesis. PMID- 23662426 TI - [Genetic toxicology: findings and challenges]. AB - The review highlights the history of genetic toxicology as a distinct research area, as well as the issues of genetic toxicology and development of its methodology. The strategies and testing patterns of genotoxic compounds are discussed with the purpose of identifying potential human carcinogens, as well as compounds capable of inducing heritable mutations in humans. The main achievements of genetic toxicology in the 20th century are summarized and the challenges of the 21st century are discussed. PMID- 23662427 TI - [Molecular genetic bases of adaptation processes and approaches to their analysis]. AB - Great interest in studying the molecular genetic bases of the adaptation processes is explained by their importance in understanding evolutionary changes, in the development ofintraspecific and interspecific genetic diversity, and in the creation of approaches and programs for maintaining and restoring the population. The article examines the sources and conditions for generating adaptive genetic variability and contribution of neutral and adaptive genetic variability to the population structure of the species; methods for identifying the adaptive genetic variability on the genome level are also described. Considerable attention is paid to the potential of new technologies of genome analysis, including next-generation sequencing and some accompanying methods. In conclusion, the important role of the joint use of genomics and proteomics approaches in understanding the molecular genetic bases of adaptation is emphasized. PMID- 23662428 TI - [Development and study of spring bread wheat variety Pamyati Maystrenko with introgression of genetic material from synthetic hexaploid Triticum timopheevii zhuk. x Aegilops tauschii Coss]. AB - Synthetic hexaploids are bridges for transferring new genes that determine resistance to stress factors from wild-type species to bread wheat. In the present work, the method of developing the spring bread wheat variety Pamyati Maystrenko and the results of its study are described. This variety was obtained using one of the immune lines produced earlier via the hybridization of the spring bread wheat variety Saratovskaya 29 with the synthetic hexaploid T. timopheevii Zhuk. x Ae. tauschii Coss. The C-staining of chromosomes in the Pamyati Maystrenko variety revealed substitutions of 2B and 6B chromosomes by the homeologous chromosomes of the G genome of T. timopheevii and the substitution of chromosome 1D by an orthologous chromosome ofAe. tauschii. It was found that this variety is characterized by resistance to leaf and stem rust, powdery mildew, and loose smut as well as by high grain and bread-making qualities. The role of the alien genetic material introgressed into the bread-wheat genome in the expression of adaptive and economically valuable traits in the Pamyati Maystrenko variety is discussed. PMID- 23662429 TI - [Allele frequency distributions of -174G/C polymorphism in regulatory region of interleukin 6 gene (IL6) in Russian and worldwide populations]. AB - Allele and genotype frequencies of the -174G/C polymorphism (rs1800795) in the regulatory region of the IL6 gene, which encode anti-inflammatory cytokine interleukin 6, were determined in seven populations representing five ethnic groups from the European part of Russia (440 individuals), as well as in small cohorts that represent populations from 24 countries of Africa and Eurasia (365 individuals). The maps of the geographic distribution of the -174G/C allele frequencies were constructed based on personal (22 populations) and the literature data (66 populations), and the data from dbSNP database obtained by the HapMap project (10 populations). The frequency of the -174G allele varied from 45 to 100% and was characterized by nonrandom geographic distribution. These data could reflect the adaptive load of the alleles examined, which was different in different regions of the world. It is suggested that the level of pathogen prevalence is one of the environmental factors that determine different adaptive values of the IL6*--174G/C alleles. This suggestion is supported by a positive correlation between the -174G allele frequency and level of pathogen prevalence calculated based on historical data (R = 0.768; p < 0.0001). PMID- 23662430 TI - [Systems of genes and proteins affecting mycobacteria virulence and their homologs participation in conjugation of mycobacterium smegmatis]. AB - This review describes and summarizes the data of ESX secretory system peculiarities characteristic of mainly mycobacteria. This system is involved in the secretion of small proteins of the WXG100 family. Some of these proteins represent virulence factors of Mycobacterium tuberculosis and other pathogenic mycobacteria. The role of these proteins in pathogenesis apparently consists of protecting mycobacteria from lysis in the macrophages that absorb them; the cytolysis of macrophages; and, hence, mycobacterium output into the surrounding tissue. A number of proteins that make up this secretory system are homologs of proteins involved in the conjugation process in saprophytic Mycobacterium smegmatis. PMID- 23662431 TI - [Chloroplast prenylated lipids in response to stress in plants]. PMID- 23662432 TI - [Calcium homeostasis in the animal cell--an outline]. AB - Calcium ions are universal and versatile intracellular signalling molecule which is involved in regulation of many cellular functions in all living cells throughout all animal species. It results from unique properties of Ca2+ in comparison to other two- and monovalent cations commonly present inside and outside cells. On the other hand an excessive increase of intracellular Ca2+ accumulation may exert toxic effect leading to cell death. Therefore calcium content in particular cellular compartment must be precisely regulated. All cells have a complex set of proteins which allow them to remove, store or take up Ca2+ in very controlled manner. This article gives a concise survey of mechanisms involved cellular calcium homeostasis and signalling. PMID- 23662433 TI - [The role of calmodulin in calcium-dependent signalling in excitable cells]. AB - Calmodulin (CaM) is a sensor protein, which takes part in calcium-dependent signaling, regulating processes like growth, differentiation, proliferation and motility. Calmodulin binds calcium ions during induction of intracellular signaling. It is also involved in silencing of calcium signal through activation of plasma membrane Ca(2+)-ATPase (directly) or SERCA pump (indirectly). Calmodulin may affect various channels, e.g. voltage gated calcium channels (VGCCs), transient receptor potential channels (TRPCs), NMDA receptors, calcium channels dependent on cyclic nucleotides or these located in endoplasmic reticulum (ryanodine receptors and all isoforms of IP3-dependent receptors). PMID- 23662434 TI - [Role of calcium in physiology and pathology of neurons]. AB - In this article we present evolutionary aspects of the dual role of Ca2+ as signaling molecules and cytotoxic cations. We discuss the mechanisms of calcium homeostasis in neurons, taking into account the specific features of excitable cells and the mechanisms of generation and transduction of calcium signals. Based on this information we outline the role of Ca2+ ions in specific functions of the nerve cell, such as excitability, propagation of the action potential, synaptic transmission, neuronal plasticity and various forms of mobility. Then we discuss the role of disturbances of calcium homeostasis and signaling function in the mechanisms of injury and death of neurons in acute diseases with special regard to cerebral ischemia, and in chronic neurodegenerative disorders. PMID- 23662435 TI - [The role of calcium for functioning of the vascular endothelium]. AB - The vascular endothelium plays many important functions and its mechanical failure or abnormal operation may have serious consequences to health and even life of the organism. It controls the contraction and relaxation of blood vessels, affects the inflammatory processes, immune response and blood clotting and regulation of the permeability and integrity of the vessel wall. Impaired secretion of nitric oxide and prostacyclin 2, whose secretion is calcium concentration dependent, indicates endothelial dysfunction. Calcium is very important in many processes typical for vascular endothelium and is essential for proper functioning. Oxidative stress, induction of pro-inflammatory response and, consequently, a significant increase in the production of reactive oxygen species are a cause of damage in the vascular endothelium. In this paper we will discuss selected issues concerning the functioning of the vascular endothelium in normal and pathological conditions, as well as their connection point at the regulation of calcium signaling in these cells. PMID- 23662436 TI - S100A proteins in propagation of a calcium signal in norm and pathology. AB - Calcium ions are essential factors controlling the balance between cell survival, growth, differentiation and metabolism. Ca2+ acts as a global second messenger involved in the regulation of all aspects of cell function. Fluctuations in the intra- and extracellular Ca2+ concentration [Ca2+] in response to different environmental stimuli drive most cellular functions. Therefore, sustenance of calcium homeostasis requires perfect organization in time and space that is achieved by calcium binding proteins (CaBPs). These proteins are involved in sensing and transforming calcium signals to downstream cellular responses. Growing number of evidence suggests than many human disorders, including cancer progression, are related to deregulation of cellular calcium homeostasis and defects in CaBPs functions. In this review we will focus on the roles of S100A proteins in intracellular and extracellular calcium signalling and homeostasis. The S100A subfamily is among the most distinctive of EF-hand CaBPs and are found exclusively in vertebrates. They are believed to have evolved to enable activation of specific biochemical pathways in parallel to the activity of Ca2+ sensors such as calmodulin and/or annexins. The importance of S100 proteins is underscored by their deregulated expression in neurodegenerative and inflammatory disorders, myopathies and cancer. In addition, S100 proteins serve as diagnostic markers in the clinic and are under constant investigation. Their roles and the roles of the S100A protein partners in normal and pathology will be also discussed. PMID- 23662437 TI - [Calcium ions in the regulation of acto-myosin interactions]. AB - Muscle contraction and different forms of motility of nonmuscle cells depend on cyclic interactions between actin filaments and myosin motors. Calcium ions are the main intracellular signal, which induces activation of actin-myosin interactions. Depending on the cell type and the class of myosin, the molecular mechanisms of regulation are different and take place on two levels - actin filament and myosin. In striated muscle, the actin thin filament is regulated by the troponin-tropomyosin complex. In smooth muscle and nonmuscle cells, actin filaments are predominantly regulated by caldesmon. The control of myosin activity in these cells also depends on the myosin light chain phosphorylation and the phosphorylation of the heavy chain. Direct binding of calcium ions to the myosin light chains (which could be calmodulin molecules) was observed in myosin from molluscan muscle and in some unconventional myosins. Intensive world-wide studies allow us to understand details of the mechanisms of actin-myosin interactions. In this article, we present the contemporary view on these mechanisms. PMID- 23662438 TI - [Store-operated calcium entry--are all elements of the system already identified?]. AB - Store-operated Ca2+ entry (SOCE) is an ubiquitous mechanism leading to a transient increase of Ca2+ concentration in the cytoplasm ([Ca2+]c) of a leaving cell followed by refill of the internal stores with calcium. Discovery of STIM1 and STIM2 proteins located in the endoplasmic reticulum (ER) and playing a role of sensors of calcium, led to our understanding how the calcium signal from ER is propagated to calcium release-activated calcium channels (CRAC) located in the plasma membrane, resulting in their activation, flow of calcium into a cytoplasm and activation of calcium-dependent signaling. In light of controversies existing in identification of CRAC channels (such as Oral, TRPC and others), as well as identification of mechanisms of calcium entry that are independent of the presence of calcium in the internal calcium stores, in this review we discuss the newest theories about SOCE, proteins that are engaged in this mechanism as well as pathologies related to impaired SOCE. PMID- 23662439 TI - [See the signal--methods for calcium imaging in the cell]. AB - Calcium ions are among the most universal secondary messengers existing in the living world. In the past thirty years the set of methods allowing the calcium signal visualization have been developed. Those in vivo methods allow us to observe the level of the free calcium ions in cells, tissues and organisms. The following text presents calcium imaging research tools available today as well as the calcium imaging methods and image calibration procedures. PMID- 23662440 TI - [Pathologies of calcium-phosphate homeostasis]. AB - The colossal progress in understanding of vitamin D and phosphate metabolism introduces new perspectives in chronic kidney disease (CKD) therapy. Increasing demand for phosphate excretion per nephron triggers the vicious cycle that leads to increase in FGF-23 and PTH and decrease in vitamin D and Klotho. Restriction of dietary phosphate intake (low phosphate diet) and administration of phosphate binder can be regarded as the most important interventions in this case. Because the vicious cycle is likely activated long before hyperphosphatemia occurs during CKD progression, phosphate restriction would have been more effective if started before serum phosphate levels increased, perhaps as soon as serum FGF-23 levels rose. Phosphate restriction alleviates phosphate overload per nephron and can disrupt the vicious cycle: phosphate restriction can reduce serum FGF-23 levels and increase vitamin D, which in turn increase Klotho expression in kidney and parathyroid glands. Inhibitors of rennin-angiotensin system (rosiglitazone, angiotensin-converting enzyme inhibitors) and proper vitamin D supplementation may also up-regulate Klotho expression. Increased Klotho in the kidney may improve FGF-23 sensitivity, which further reduce the amount of FGF-23 required for excreting a given amount of phosphate. Increased Klotho in parathyroid may improve the ability of FGF-23 to suppress PTH. Proper supplementation with vitamin D increase the concentration of substrate for local 1,25(OH)2D synthesis 25(OH)D, which directly suppress PTH, increase Klotho, and decrease FGF-23 by proanabolic action on bone. Improving vitamin D status by inhibition of CYP24A is also under evaluation, as well as antibodies against FGF-23, as modern therapies in CKD. PMID- 23662441 TI - [Angiotensins as neuromodulators]. AB - The primary function of angiotensin II, the main peptide of central renin angiotensin system (RAS), is regulation of blood pressure. Recently, new functions of so-called local (or tissue) RAS have been discovered in brain. AT1 and AT2 angiotensin receptors, found in many parts of central nervous system (CNS), stimulate various signalling pathways. Gamma-amniobutyric acid (GABA), which acts by three types of receptors, is the crucial inhibitory neurotransmitter. GABA and angiotensins are found in brain regions like paraventricular nucleus of hypothalamus, nucleus tractus solitari and rostral ventrolateral medulla, all involved in blood pressure regulation. The influence of angiotensin II on GABA action is different in various CNS regions, but mainly it is associated with cardiovascular neurons activity. There are other neurotransmitters which may interact with angiotensins action. Adenosine has inhibitory effect and play important role in epilepsy. Its beneficial influence may be stronger in presence of angiotensin. Angiotensins also interact with dopamine (DA) activity by stimulation of DA-synthesizing nerves. PMID- 23662442 TI - [Salvinorin A and related diterpenes--biological activity and potential therapeutic uses]. AB - Salvinorin A (SA) is the main active ingredient of Salvia divinorum, a naturally occurring hallucinogen plant from Mexico. Traditionally, herbal preparations obtained from Salvia were used by the Mazatec Indians for their divination rites and the treatment of gastrointestinal disorders. SA is a selective K-opioid receptor agonist, producing antinociception in animals and humans and displaying regulatory effect on colonic function. Studies in humans demonstrated potent hallucinogenic effect of SA. The extensive research on SA and related neoclerodane diterpenes over the past few years resulted in a number of reports on their isolation, synthesis, and pharmacological characterization. In this review we try to summarize, from the pharmacological and synthetic point of view, the structure-activity relationship studies of SA and discuss the possible use of SA and its derivatives as therapeutics. PMID- 23662443 TI - Simplified evaluation of apoptosis using the Muse cell analyzer. AB - The degree of apoptosis in a cell population is an important parameter of cell health and is characterized by distinct morphological changes. Current methods of accurate detection and measurement of cellular apoptosis require expensive and complicated instrument platforms and expertise. The Muse Cell Analyzer is a unique instrument that enables multidimensional cell health analysis on a single platform. In this study, we used the Muse Cell Analyzer for apoptosis studies using the Muse Annexin V & Dead Cell Assay. The assay is based on the detection of phosphatidylserine (PS) on the surface of apoptotic cells. The results obtained from Muse Cell Analyzer were compared with traditional methods for apoptosis analysis. Our results indicate that Muse Annexin V & Dead Cell Assay and software module enabled the acquisition of accurate and highly precise measurements of cellular apoptosis. The assay is versatile and works with both suspension and adherent cell lines and multiple treatment conditions. PMID- 23662444 TI - [Fungi of the genus Penicillium as producers of physiologically active compounds (review)]. AB - Fungi of the genus Penicillium isolated from little studied habitats are able to synthesize both previously known and new physiologically active compounds with diverse structures. They include secondary metabolites of alkaloid nature, i.e., ergot alkaloids, diketopiperazines, quinolines, quinazolines, benzodiazepines, and polyketides. We discuss the use of profiles of secondary metabolites for taxonomy purposes. Studying the physicochemical characteristics of producers of biologically active compounds showed that the biosynthesis of alkaloids is initiated on the first days of cultivation and proceeds simultaneously with growth. The cyclic character of alkaloid accumulation was recorded related to the processes of alkaloid biosynthesis, excretion from cells, degradation in culture fluid, and consumption by cells. Synchronic variations in the concentrations of intracellular tryptophan and alkaloids are necessary for the regulation of the optimal quantity of tryptophan necessary for the culture. PMID- 23662445 TI - Refolding of recombinant human interferon alpha-2a from Escherichia coli by urea gradient size exclusion chromatography. AB - Protein refolding is still a puzzle in the production of recombinant proteins expressed as inclusion bodies (IBs) in Escherichia coli. Gradient size exclusion chromatography (SEC) is a recently developed method for refolding of recombinant proteins in IBs. In this study, we used a decreasing urea gradient SEC for the refolding of recombinant human interferon alpha-2a (rhLFNalpha-2a) which was overexpressed as IBs in E. coli. In chromatographic process, the denatured rhLFNalpha-2a would pass along the 8.0-3.0 M urea gradient and refold gradually. Several operating conditions, such as final concentration of urea along the column, gradient length, the ratio of reduced to oxidized glutathione and flow rate were investigated, respectively. Under the optimum conditions, 1.2 x 10(8) IU/mg of specific activity and 82% mass recovery were obtained from the loaded 10 ml of 1.75 mg/ml denatured protein, and rhLFNalpha-2a was also purified during this process with the purity of higher than 92%. Compared with dilution method, urea gradient SEC was more efficient for the rhl FNalpha-2a refolding in terms of specific activity and mass recovery. PMID- 23662446 TI - [Physicochemical properties and antiproliferative activity of recombinant Yersinia pseudotuberculosis L-asparaginase]. AB - The physicochemical, catalytic, and antiproliferative activity of a recombinant L asparaginase from Yersinia pseudotuberculosis (YpA) have been studied. The following results were obtained: the K(M) value for L-asparagine is 17 +/- 0.9 microM, the optimal temperature is 60 degrees C, pH is 8.0, pI is 5.4 +/- 0.3, the L-glutaminase activity is no more than 5-6% of the L-asparaginase activity, and the antiproliferative activity on the Fisher L5178y lymphadenosis cell line comprised T/C = 136% (p < 0.001) at a 15% recovery rate. The described characteristic allows one to regard YpA as an antitumor enzyme with biological features similar to the L-asparaginase of E. coli. PMID- 23662447 TI - [An amylase from fresh fruiting bodies of the monkey head mushroom Hericium erinaceum]. AB - An amylase with a molecular mass of 55 kDa and an N-terminal sequence exhibiting similarity to enzyme from Bacteroides thetaitaomicron was isolated from fruiting bodies of the monkey head mushroom Hericium erinaceum. The purification scheme included extraction with distilled water, ion exchange chromatography on DEAE cellulose and SP-sepharose, and gel filtration by FPLC on Superdex 75. The amylase of H. erinaceum was adsorbed on DEAE-cellulose in 10 mM Tris-HCl buffer (pH 7.4) and eluted with 0.2 M NaCl in the same buffer. The enzyme was subsequently adsorbed on SP-Sepharose in 10 mM ammonium acetate buffer (pH 4.5) and eluted with 0.3 M NaCl in the same buffer. This fraction was subsequently subjected to gel filtration on Superdex 75. The first peak eluted had a molecular mass of 55 kDa in SDS-PAGE. The amylase of H. erinaceum exhibited a pH optimum of 4.6 and a temperature optimum of 40 degrees C. The enzyme activity was enhanced by Mn2+ and Fe3+ ions, but inhibited by Hg2+ ions. PMID- 23662448 TI - [Heterologous expression, purification, and properties of a chymotrypsin inhibitor isolated from potatoes]. AB - The PKPIJ-B gene encoding a chymotrypsin inhibitor from a subfamily of potato Kunitz-type proteinase inhibitors (PKPI) in potatoes (Solanum tuberosum L. cv. Yubilei Zhukova) was cloned into a pET23a vector and then expressed in Escherichia coli. The recombinant PKPIJ-B protein obtained in the inclusion bodies was denatured, purified by high-performance liquid chromatography (HPLC) on Mono Q under denaturing conditions, and renaturated. The renaturated protein was additionally purified using HPLC on DEAE-ToyoPearl. The PKPIJ-B protein efficiently suppressed chymotrypsin activity, had a weaker effect on trypsin, and inhibited the growth and development of phytopathogenic microorganisms affecting potato plants. PMID- 23662449 TI - [Crystal formation peculiarities in pigmented cultures of Bacillus thuringiensis]. AB - A direct correlation has been established between pink-colored pigmentation and the production of insecticide crystals (toxins) for some Bacillus thuringiensis (BT) pigmented cultures. This regularity was for the first time determined by us for BT strains ofthe H3, H10, and H16 serotype. Pigment-free clones of these serotypes do not produce crystals. A correlation was not observed in the case of H14 serotype strains with oval inclusions. The revealed correlation makes it possible to distinguish crystal-yielding colonies in cultures of the above mentioned serotypes by the availability of pigmentation. This method can serve as an effective express method for the detection of virulent clones, which is especially important if these strains are used for obtaining insecticide preparations. PMID- 23662450 TI - [Beta-glucan content and hydration properties of filamentous fungi]. AB - The aim of this work was to isolate and identify filamentous fungi from several sources to study the dietary fiber and beta-glucan content. The fungal hydration properties such as water absorption and water holding capacities were also evaluated. Total dietary fiber of isolates exhibited a noticeable variability from 16 to 53% and the highest values were obtained for the genera Paecilomyces and Penicillium, a fact consistent with a higher content of beta-glucans (24 and 17%, respectively), higher than previously reported for Basidiomycetes and yeast. We observed a large decrease (75%) in the water holding capacity when the mycelia were dried. Isolates of filamentous fungi with greater water holding capacity also exhibited greater absorption capacity. Paecilomyces variotii and Penicillium nalgiovense had the best hydration properties. Our results contribute to the search for new unconventional ingredients providing a high protein and beta glucans content. The addition of these dried mycelia could change the hydration properties in the food system. PMID- 23662451 TI - [Biodiesel fuel production from lipids of filamentous fungi]. AB - The main stages in the production of biodiesel fuel from lipids of filamentous fungi belonging to the order Mucorales are described. Fungi of the family Cunninghamellaceae have been screened; the lipogenic activity of the examined strains has been assessed; and a producer generating up to 50% of lipids, represented by triacylglycerols, has been found. The substitution effect of a source of carbon and nitrogen with less expensive components (in particular, various industrial wastes) has been studied, as well as their influence on the quantity and major characteristics of the final product. An ecologically friendly method for extracting lipids from fungal mycelia, utilizing supercritical technologies, has been used. A correlation between the lipid content in the spore inoculum and the maximal lipid content in biomass has been discovered; this correlation is proposed for optimizing the biotechnology and increasing the yield of final products. PMID- 23662452 TI - [Effect of plant stilbene precursors on the biosynthesis of resveratrol in Vitis amurensis Rupr. cell cultures]. AB - The biosynthesis of resveratrol after the application of a precursor for biosynthesis, i.e., phenylalanine (Phe), has been studied. The application of Phe has been shown to increase significantly the expression of the phenylalanine ammonia-lyase (PAL) and stilbene synthase (STS) genes and enhance the production of resveratrol by 8.5 times. Data on resveratrol production after the addition of Phe and coumaric acid (CA) were compared with known analogs. PMID- 23662453 TI - [Effect of cyclopentene beta,beta'-triketone disodium salt on the activity of hydrolases and the state of tobacco mosaic virus particles in tobacco leaves]. AB - The activity of hydrolases (protease, RNase) in uninfected and tobacco mosaic virus-infected tobacco leaves of the Samsun variety, untreated and treated with disodium salt of 2-acetyl-4-hydroxycarbonyl-methylthio-5-chlorocyclopent-4-en-1,3 dione (DS), was determined. It was shown that treatment of leaves with this compound significantly increased the activity of hydrolases in them compared to untreated leaves. In infected leaves treated with DS one day before infection, along with an increased level of hydrolases, one revealed more viral particles exposed to destructive changes in infected, rather than untreated, leaves. It is assumed that the DS-caused activation of hydrolases promotes the destruction of viral particles and is therefore one of the cell defense mechanisms induced by this compound that prevents the intracellular accumulation of virus. PMID- 23662454 TI - [Biochemical markers of virus cytopathogenicity in macrophages]. AB - The results of macrophage metabolism studies at their infection by viruses differing in the level of virulence are presented. With the purpose of optimizing the estimation of viral cytopathogenic effects on macrophages, an index of cell reactions, which allows one to reveal the degree of virus influence in standard units, is offered. Generally, the application of high-sensitivity methods for functional activity determination and identification of the correlative communication between its changes and morphological features of cells can be prescribed to objective identification methods of not only viral reproduction, but also differentiation of types and the degree of their cytopathogenic effects. PMID- 23662455 TI - [Antiradical properties of oregano, thyme, and savory essential oils]. AB - In model reactions with the stable free 2,2-diphenyl-1-picrylhydrazyl radical, the antiradical properties of essential oils of thyme (Thymus vulgare), oregano (Origanum vulgare), and savory (Satureja hortensis) that are similar in the qualitative composition, but differ in the quantitative content of the main components, were studied and compared with the properties of synthetic antioxidant ionol. The reaction rates of components of essential oils with the radical were almost identical for all essential oils and were twice the reaction rate of ionol. The antiradical efficiency values were close to each other for all essential oils and by an order of magnitude smaller than for ionol. PMID- 23662456 TI - [Development of multiplex PCR for fast detection of Paenibacillus larvae in putrid masses and in isolated bacterial colonies]. AB - The present study was performed to develop a fast and sensitive multiplex polymerase chain reaction protocol for routine diagnostics of American foulbrood. A new approach for detection of Paenibacillus larvae in putrid masses was described. Forty five samples of putrid masses obtained from bee combs suspicious for American foulbrood, a reference strain Paenibacillus larvae (NBIMCC 8478), clinical isolates and 4 strains of closely related bacterial species were included in experiments. Bacterial colonies' DNA was isolated by heat and centrifugation method (standard procedure) and with prepGem commercial kit. DNA from putrid masses was isolated by standard and modified procedure. Three pairs of primers specific for 16S rRNA and one pair specific for 35 kDa metalloproteinase genes of Paenibacillus larvae were tested as single pair and in different combinations as multiplex PCR. The sensitivity of the multiplex PCR protocol for putrid masses, developed in study was 100%, versus 45.2% for the standard protocol. The developed multiplex PCR protocol could be successfully used for rapid and specific detection of Paenibacillus larvae in both putrid masses and isolated bacterial colonies. PMID- 23662457 TI - [Endogenous biorhythms of the specific growth rate in individual development of Lymnaea stagnalis (Lymnaeidae, Gastropoda)]. AB - On the basis of data on the growth of freshwater gastropods Lymnaea stagnalis, the dependence of the specific growth rate on age in the late postlarval ontogeny is calculated. The presence of two endogenous biorhythms of the specific growth rate with periods of 10.3 weeks and 6.5 weeks was revealed using singular spectrum analysis. Local maxima of both biorhythms in different individuals fall on the same age, and their periods are approximately the same in all animals studied and remain unchanged during individual postlarval development. The biorhythm with a period of 10.3 weeks is decaying, its amplitude is reduced from 3.2 year(-1) (at the age of 10 weeks) to 0.8 year(-1) (at the time of death of the shellfish). The biorhythm with a period of 6.5 weeks is non-decaying and has an average amplitude of 0.8 year(-1). PMID- 23662458 TI - [Variability of cytochrome b gene of mitochondrial DNA of pink salmon Oncorhynchus gorbuscha(Walbaum) from the rivers of the continental coast of the Sea of Okhotsk and Zavyalov Island]. AB - Data on the structure and variability of the nucleotide sequence of the cytochrome b (cytb) gene fragment of mitochondrial DNA (mtDNA) in pink salmon of adjacent generations from the rivers of the continental coast of the Sea of Okhotsk and Zavyalov Island were obtained. The differences between adjacent generations were discovered. By the marker studied, pink salmon of the even-year line are characterized by a high level of genetic variability. It is shown that reproductive isolation has led to accumulation of specific mutations of the mtDNA cytb gene in each line and, consequently, to their divergence. Analysis of the data showed that the share of intrapopulation genetic variability of northern Sea of Okhotsk pink salmon accounts for about 91%. The intergroup component that was calculated for adjacent generations of the species is relatively small and is 9%, which seems to be indicative of a relatively recent divergence of adjacent generations of salmon. PMID- 23662459 TI - [Description of the phylogenetic structure of hydrolytic prokaryotic complex in the soils]. AB - With the help of the molecular-biological method of cell hybridization in situ (FISH), the abundance of a physiologically active hydrolytic prokaryotic complex in chernozem and gley-podzolic soils is determined. The total proportion of metabolically active cells, which were detected by hybridization with universal probes as representatives of the domains Bacteria and Archaea, in samples of the studied soil, was from 38% for chernozem up to 78% for gley-podzolic soil of the total number of cells. The differences in the structure of chitinolytic and pectinolytic prokaryotic soil complexes are detected. Along with the high abundance of Actinobacteria and Firmicutes in the soils with chitin, an increase in phylogenetic groups such as Alphaproteobacteria and Bacteroidetes is observed. PMID- 23662460 TI - [Development of Scotch pine seedlings and functioning of antioxidant systems under the chronic action of lead ions]. AB - This study has shown that the effect of Pb2+ ions (10-150 microM) on Scotch pine seedlings is manifested by a biomass decrease and a delay in development of the root system, including shortening of the main root, reduction of the lateral root formation zone, and reduction of the number of lateral roots. The ability of the root system to deposit Pb2+ ions and to perform a barrier function, preventing Pb2+ uptake into assimilating organs, has been revealed. This ability is blocked if the Pb2+ concentration in the nutrient medium exceeds 80 microM. In the case of heightened Pb2+ concentrations, the content of photosynthetic pigments in pine needles decreases, whereas that in cotyledons increases. Analysis of the proline content and the functioning of the antioxidant enzyme system (superoxide dismutase, catalase, ascorbate peroxidase, and peroxidase) shows that the presence of Pb2+ ions in a wide concentration range does not induce intensive oxidative stress in pine seedlings. PMID- 23662461 TI - [Diversity of the rDNA ITS haplotypes of the nematodes Haemonchus contortus (Trichostrongyloidea, Rhabditida) of the same host]. AB - Specimens sampled in Central Mongolia have been examined for the intraspecific polymorphism of the nucleotide sequences of ribosomal DNA internal transcribed spacers (ITS-1 + 5.8S + ITS-2) of the parasitic nematode Haemonchus contortus. A considerable diversity of haplotypes differing in the nucleotide composition of this DNA region has been observed. The phylogenetic relationships between the haplotypes detected in Central Mongolia and the corresponding sequences from other parts of the nematode distribution area (deposited with the NCBI GenBank) have been analyzed. Significantly different sequences have been found along with the haplotypes already observed in H. contortus or differing from them by one-two nucleotides. PMID- 23662462 TI - [Brent goose colonies near snowy owls: internest distances in relation to breeding Arctic fox densities]. AB - This study was conducted in 2005 near Medusa Bay (73 degrees 21' N, 80 degrees 32' E) and the delta of the Pyasina River (74 degrees 10' N, 86 degrees 45' E), northwest of the Taimyr Peninsula. It was shown that in the years when the numbers of the Arctic foxes are high, even though the lemming numbers are high as well, Brent geese nest considerably closer to owls' nests than in the years with low Arctic fox numbers. At values of the Arctic fox densities greater than one breeding pair per 20 km2, the factor of lemming numbers ceases to affect the distance between owl and geese nests. This distance becomes dependent on the Arctic fox density (numbers). When the Arctic fox density is greater than the pronounced threshold, the owl-Brent internest distance is inversely and linearly related to the Arctic fox density. PMID- 23662463 TI - [The mountain weasel Mustela kathiah (Carnivora: Mustelidae): molecular and karyological data]. AB - The karyotype of Mustela kathiah was first described. Its structure is most similar to the karyotype of M. altaica, differing inthe morphological peculiarites of five pairs of large chromosomes. A comparative analysis of mitochondrial genes in the species Mustela allowed us to clarify understanding of the place of M. kathiah in the system of the genus. The earlier hypothesized proximity of the species to a group of small weasels (altaica, nivalis) or to a group of South Asian species (strigidorsa, nudipes) was not confirmed. A high level of differences between M. kathiah of Vietnam and specimens from southern China in nucleotide sequences of the cytochrome b (7.7%) and ND2 (6-6.2%) genes was found. Perhaps these differences, manifested in populations of M. kathiah from different regions, are adaptive. PMID- 23662464 TI - [Population aspects of sexual dimorphism in guild of the Mustelidae: Mustela lutreola, Neovison vison, Mustela putorius, Martes martes as an example]. AB - Size sexual dimorphism was investigated on 695 skulls of four Mustelidae species. By extent of increasing of differences between sexes the species are placed in following order: European pine marten (Martes martes), European mink (Mustela lutreola), American mink (Neovison vison), and European polecat (Mustela putorius). Extent of the dimorphism characterizes ecological plasticity of the species and is population characteristic. It is shown that M. martes takes specific and relatively narrow ecological niche of forest ecosystems, entering into weak competitive relationships with smaller Mustelidae species. The level of sexual dimorphism of M. lutreola, N. vison and M. putorius reflects intensity of its interspecific relationships within study area. High level of sexual dimorphism of M. putorius is determined by further divergence of ecological niches of males and females, and also appears to be compensatory mechanism reducing consequences of hardened environmental requirements. PMID- 23662465 TI - [Intraspecies variation of reproductive strategies in river perch (Perca fluviatilis)]. AB - The variation of reproductive strategies in different populations of river perch and intrapopulation groups differing in the rate of growth have been analyzed. Using a bioenergetic approach, the origin and differences between these groups have been studied. It was shown that bioenergetic mechanisms of regulation of the sizes and weight of the eggs lead to formation of the strategy of forced reproduction in the slow-growing group of perch, unlike the reproductive strategy of the fast-growing group of perch characterized by a later reaching of sexual maturity at a greater relative weight of gonads and spawning of larger eggs, which provides for a longer lifespan of larvae. The great number of age groups in the spawning part of this group compensates for a decrease in reproduction in years with unfavorable conditions. PMID- 23662466 TI - [The current flow of migrants and its contribution to Rhopalocera lepidopteran (Lepidoptera, Rhopalocera) fauna on marine islands with young allochthonous biotas]. AB - The concept that the mechanisms limiting immigration of new Lepidoptera species are analogous for islands with different ages and degrees of endemism of their biotas is discussed. Specific features of individual species play a key role in establishment of the fauna and population on small islands rather than competitive interactions between these species. It is most likely that the species stably coexisting on an island will display similar ecological characteristics and life cycles, which complies with the concepts of the neutral theory of biodiversity and biogeography. PMID- 23662467 TI - [Expression of the RT1A molecule of the class I major histocompatibility complex in a Walker 256 tumor after transplantation into Brattleboro rats with a genetic defect of arginine-vasopressin synthesis]. AB - The dynamics of expression of the RT1A antigen of the class I major histocompatibility complex (MHC) in a Walker 256 tumor after its transplantation into Brattleboro rats with a genetic defect of Arginine-Vasopressin synthesis in the hypothalamus was studied. Expression of the RT1A antigen was detected by means of Western-blotting and flow cytometry in the tumor cells on the 14th-17th days after transplantation. In addition, a simultaneous increase in the portion of cells that express the RT1A antigen and in the level of its expression per cell was observed. It is presupposed that at a deficiency of Arginine Vasopressin, a renewal of expression of the class I MHC antigens, which results in an increase of immunogenicity of this tumor and regression, occurs in the Walker 256 tumor in the Brattleboro rats. PMID- 23662468 TI - [New records of bacteria-spirochetes in crystalline style of fresh water gastropods]. AB - Freshwater mollusks belonging to 17 species, in 7 families are examined purposely to search for spirochete bacteria in their crystalline style of the digestive system. As result of this study spirochetes are recorded in gastropod families Amnicolidae, Bithyniidae, Baicaliidae and Benedictiidae, represented by 12 species, occupying different habitats. Gastropods belonging to Valvatidae, Lymnaeidae and Planorbidae, characterized by lack of crystalline style did not include spirochetes in their stomachs. Studied gastropods having spirochetes or free of them are grazers or filter-feeders and mainly phyto-detrito bacteriaphagous. PMID- 23662469 TI - [Possibilities for identification of cryptic species of Chiroptera using host specific ectoparasites]. AB - The possibility of identification of the sibling species of Chiroptera by the example of Myotis daubentonii Kuhl, 1817 and Myotis petax Hollister, 1912 by their host-specific ectoparasitic fauna is discussed. Their habitat limits are defined. PMID- 23662470 TI - [Parental care and testosterone in males of the bank vole (Myodes glareolus): sensitization and androgenic stimulation of parental behavior]. AB - The relationship between parental responsiveness of bank vole males and their body weight, testes mass, and plasma and gonadal testosterone levels were examined. Two groups of voles were studied: Group I consisted of 14 breeding pairs where females gave birth to young within a month after formation of pairs, and Group II represented 13 pairs without offspring and signs of pregnancy in females. Males in Group I, unlike those in Group II, had contact with pups before the tests on parental responsiveness. In Group I, males were found to have larger testes and to exhibit a higher level of care-giving activity (pup retrieval) as compared to males in Group II. Both the plasma and gonadal testosterone levels in males exhibiting pup retrieval were revealed to be significantly higher than those for males exhibiting infanticide. Thus, promiscuity, competition for receptive females, and a higher level of testosterone secretion, which are characteristic of bank vole males during the breeding season, are not out of the realm of possibility of the males that care for young. Our findings suggest that factors promoting parental responsiveness in bank vole males are sensitization due to contact with pups and an increase in testosterone secretion. Obviously, there is a need to reexamine the role that testosterone plays in regulating rodent parental behavior. PMID- 23662471 TI - [Single-cell study: from physiology to transcriptome analysis]. AB - Gene expression analysis facilitates the study of physiological processes operating at the single-cell level. It allows for the identification of key molecules that are involved in distinct intracellular processes in individual cells. The review focuses on the modern techniques and strategies that are used to establish gene expression profile of a single cell. Particularly, it describes how analysis of gene expression patterns at the single-cell level had provided significant insight into understanding of molecular and cellular mechanisms of odor and taste transduction in mammals. PMID- 23662472 TI - [Cholesterol and lipid rafts in the biological membranes. Role in the release, reception and ion channel functions]. AB - Traditionally, membrane protein molecules that form ion channels, transporters, pumps, signaling complexes, machine of exo- and endocytosis is assigned as the main players of the cellular processes. Recently, the findings that indicate the importance of lipids in regulating of cell physiology are accumulated. Attention is attracting to cholesterol molecule because it can directly interact with different proteins and together with sphingolipids to form membrane microdomains (lipid rafts). Many receptors (for neurotransmitters, hormones, growth factors), signaling proteins and proteins involved in vesicular and ion transport are concentrated in the lipid rafts. Changes in stability and structure of rafts cause dramatic cellular dysfunction. In the review the current views on lipid variants that make up the biological membrane, the distribution of cholesterol, the organization and the formation of lipid rafts and caveolae are described. Accent is made on researches that focus on the significance of lipid rafts in the extra- and intracellular signaling, neurotransmitters release, receptor and ion channels function at the excitable cells. PMID- 23662473 TI - [Effect of peptide bioregulators and cytokines on life span and age-related changes of hemostasis]. AB - The review considers literature data and own results of research of cytokines functions and their effects on hemostatic system and life span. The data of age related changes in the hemostatic system is presented in this article. A big part of the review is devoted to the action of regulatory peptides (RP) on various body systems. It is established that the RP can normalize the expression of cytokine genes in humans and animals with stress and pathological conditions. Effect of RP on the cytokines has geroprotective action, which is based on anti oxidant, anti-inflammatory action, stimulation of cell proliferation and differentiation, as well as a normalizing effect on the immune system and hemostasis. PMID- 23662474 TI - [The influence of beta-amyloid peptide on the functions of excitable tissues: physiological and pathological aspects]. AB - Beta-amyloid peptide (betaAP) is a product of proteolytic cleavage of wide-spread transmembrane amyloid precursor protein. Betaap is physiological oligopeptide, which is present in biological fluids and tissues of healthy human organism at picomolar concentrations. However, excessive production, polymerization and accumulation of betaAP in tissues (first in neural tissue) underlie the pathogenesis of a number of neurodegenerative diseases (Alzheimer's disease and others). Although the presence of insoluble deposits of fibrillar betaAP (senile plaques) is a characteristic histopathological sign of Alzheimer's disease, soluble betaAP oligomers (dimers, trimers, etc.) possess most neurotoxicity. Soluble betaAP induces mitochondrial dysfunction, increased production of reactive oxygen species in neurons, disorganization of cell plasma membranes, disturbances of ion transport across cell membranes, impairment of synaptic transmission and long-term synaptic plasticity, etc. Recently a lot of attention is paid to possible peripheral effects of betaAP, related to its toxic influence on excitable structures of neuromuscular apparatus and cardiovascular system. At current review we represented state-of-art views on the processes of production and aggregation of betaAP in organism, cellular and molecular mechanisms of betaAP influence on physiological functions of excitable cells, the role of betaAP in pathogenesis of neurodegenerative diseases (Alzheimer's disease and others), as well as the results of our own studies in this field. PMID- 23662475 TI - [Nitric oxide and autonomic nervous system]. AB - The review of the literature on the role of nitric oxide in the regulation of cardiovascular, gastrointestinal and bronchopulmonary systems is presented. Mechanisms of interaction of nitric oxide with cholinergic and adrenergic divisions of the vegetative nervous system are described. The results of studies on the role of NO in the regulation of contractile function of the esophagus are presented. PMID- 23662476 TI - [Evolution of mechanisms of Ca(2+)-signalization. Role of Ca2+ in regulation of specialized cell functions]. AB - The review considers peculiarities of Ca(2+)-signalization in electroexcitable cells of the higher eukaryotes. The light has been thrown upon the problems of Ca(2+)-dependent mechanisms of regulation of muscle contractility and of neuronal synaptic plasticity in the higher vertebrate animals. A particular attention has been paid to analysis of contribution of such poorly studied components of Ca(2+) signalization as non-selective TRPC-channels, Orai channels, sensory STIMI proteins, Ca(2+)-controlled K(+)-channels of high and low conductivity, and neuronal Ca(2+)-sensors (NCS). PMID- 23662477 TI - [Metabolic effects of ganglioside GM1 on PC12 cells at oxidative stress depend on modulation of activity of tyrosine kinase of trk receptor]. AB - Evidence has been obtained that only GM1, but also other main brain gangliosides (GD1a, GD1b, and GT1b) increase viability of ells of the PC12 neuronal line submitted to action of H2O2. By the example of GM1 and GD1a, gangliosides have been shown to induce a protective effect when acting on PC12 cells under conditions of oxidative stress both at micro- and nanomolar concentrations that are physiological concentrations of gangliosides in cerebrospinal fluid. It has been shown for the first time that GM1 at nanomolar concentrations decrease the H2O2-induced formation of reactive oxygen species (ROS). It was found that in the presence of K-252a, an inhibitor of tyrosine kinase of Trk receptors, GM1 at concentrations of 10 microM and 10 nM lost the ability to increase viability of these cells under conditions of oxidative stress. The dependence of protective and metabolic effects of ganglioside GM 1 in PC 12 cells at action on them of H2O2 on modulation of activity of tyrosine kinase of Trk receptors (i. e., on the same signal system) agrees with concept of the essential role of the GM1 antioxidant effect in its increase of cell viability. PMID- 23662478 TI - [Effect of population density on enzymatic activity of antioxidative and phenol oxidase systems of imagoes and nymphs of the marble cockroach Nauphoeta cinerea]. AB - The work deals with effect of density of population on functional activity of components pf protective system of adult individuals and nymphs of the marble cockroach. The resistance of individuals has been noted to decrease both at individual maintenance and under conditions of overpopulation. Changes in activities of enzymes of antioxidative and phenoloxidase systems are studied ion the insect hemolymph and intestine. Possible consequences of isolation and overpopulation are discussed both for stability and for individual development. PMID- 23662479 TI - [Regulatory properties of adenylyl and guanylyl cyclases in human spermatozoa]. AB - Completion of the process of maturation of spermatozoa (capacitation) occurs in the female genital tract. As a result, spermatozoa acquire hypermobility and the capability for the acrosomal reaction, which determine their fertility. There exist data that participating in these processes are the adenylyl cyclase and guanylyl cyclase signaling systems that are present in human and mammalian spermatozoa. The goal of the present work to characterize these systems in the human ejaculate spermatozoa (ES) and in the human fertile spermatozoa (FS) isolated by the density gradient centrifugation. In the FS homogenate the basal activity of adenylyl cyclase (AC) activity was significantly higher that in ES: 47 +/- 5 vs 28 +/- 3 pmol cAMP/min per mg of protein, respectively. At the same time, the AC-stimulating effects of non-hormonal activators of AC forms (NaHCO3, Mn2+, forskolin, and non-hydrolysable GTP analogue - GppNHp) were lower as compared with ES. The AC activity in ES were stimulated by isoproterenol, serotonin, PACAP-38, and, to the letter degree, by noradrenalin and adenosine. Among the AC-inhibiting hormones, adenosine alone decreased the enzyme activity. In FS, on the contrary, the AC-inhibiting effects of adenosine, noradrenaline, and serotonin were clearly expressed, whereas the stimulatory effects of these hormones were attenuated or absent. The basal activity of guanylyl cyclase (GC) in the ES and FS homogenates amounted to 27 +/- 3 and to 21 +/- 2 pmol cGMP for 1 min per 1 mg protein, respectively, and was significantly increased in the presence of 10 mM Mn2+. The GC-stimulating effects of natriuretic peptides - atrial natriuretic peptide (ANP) and the C-type natriuretic peptide (CNP)- activators of the GC receptor forms, were in ES significantly higher than in FS, the ANP effect being more pronounced as compared with CNP. The obtained data indicate multiplicity of the cAMP- and cGMP-dependent signal cascades regulating fertility of human spermatozoa. It has been established that sensitivity of AC and GC to hormones in the total ES pool and in the supermobile FS fraction isolated by centrifugation differs essentially, which is to be taken into account when using FS for auxiliary reproductive technologies. PMID- 23662480 TI - [Liver monoamine oxidase activity of the lamprey Lampetra fluviatilis. the substrate-inhibitory specificity]. AB - Based on data of substrate-inhibitory analysis with use of specific inhibitors- deprenyl, chlorgi-lin--and specific substrates--serotonin, noradrenalin, benzylamine, beta-phenylethylamine, and N-methylhistamine--a suggestion is put forward about the possible existence of one molecular form of monoamine oxidase (MAO) in liver of mature individuals of the European lamprey Lampetra fluviatilis. There are determined kinetic parameters of monoamine oxidase deamination of eight substrates, which indicates the large spectrum of substrate specificity of the lamprey liver MAO. The studied enzyme does not deaminate histamine and putrescine and is not sensitive to 10(-2) M semicarbaside. Results of study of the substrate-inhibitor specificity allow us to suggest some resemblance of catalytic properties of the lamprey liver MAO and the mammalian form A MAO. The revealed low activity of the enzyme at deamination of all used substrates seems to be connected with low detoxational functional of the lamprey liver. PMID- 23662481 TI - [Adaptation of differential sensitivity of auditory neurons to amplitude modulation after a sharp change of signal intensity]. AB - In the common frog Rana temporaria, the neuronal firing evoked by long amplitude modulated tones was recorded in auditory regions of medulla (dorsal nucleus) and of midbrain (torus semicircularis). We recorded firing rate, synchronization with modulation, and phase of response every 2 or 4 s. After adaptation of neuronal response to the acting stimulus (30-60 s after its onset) the mean level of signal sharply changed (by 20-40 dB), whereas frequency and modulation depth remained constant. Changes of firing density and of degree of its synchronization with modulation period were recorded, as well as the phase of maximum of reaction at the period of modulation. At low modulation depths at the initial site, we observed an adaptation decrease of impulsation density accompanied by an improvement of the response synchronization. A sharp increase (by 20-40 dB) in the mean level led to a rise in the implication density, which could be accompanied either by a continued increase of synchronicity (the more typical effect for the dorsal nucleus) or by a sharp fall of synchronicity with its subsequent slow recovery (the more typical effect for the torus semicircularis). The character of changes in reaction after replacement of intensity could also depend on the signal parameters (the initial level, the jump value, the frequency and depth of modulation). The connection of the revealed physiological effects with psychophysics of perception of small amplitude modulations is discussed. PMID- 23662482 TI - [Function of alveoles as a result of evolutionary development of respiratory system in mammals]. AB - Reaction of hemoglobin oxygenation is known to occur for 40 femtoseconds (40 x 10(-15) s). However, the process of oxygen diffusion to hemoglobin under physiologic conditions decelerated this reaction approximately billion times. In mammalian lungs, blood is moving at a high rate and in a relatively high amount. The human lung mass is as low as 600 g, but the complete cardiac output approaches 6 1/min. In rat, from 20 to 40 ml of blood is passed for q min through the lung whose mass is about 1.5 g. Such blood flow rate is possible, as in lungs of high animals there exists a dense network of relatively large microvessels with diameter from 20 to 40 microm and more. In spite of a large volume and a high blood flow rate hampering oxygen diffusion, the complete blood oxygenation occurs in lung alveoli. This is due to peculiar mechanisms that facilitate markedly the oxygen diffusion and that developed in alveoli of mammals in the course of many million years of evolution of their respiratory system. Thus, alveolus is not a bubble with air, but a complex tool of fight with inertness of diffusion. It is interesting that in lungs of the low vertebrates, neither such system of blood vessels nor alveoli exist, and their blood flow rate is much lower than in mammals. PMID- 23662483 TI - [Blood supply as a factor regulating pacemaker activity of the rat uterine horn]. AB - Effect of ischemia of the uterine artery supplying with blood the main rhythmogenic zone (the ovarian region) of the uterine horn on parameters of activity both of this locus and of all subsequent pacemaker areas up to the uterine cervix was studied in non-pregnant rats. The most pronounced changes in characteristics of the activity (amplitude, frequency, and burst genesis duration) were revealed in the ovarian horn end. The uterine corpus and the horn cervical end were less affected by ischemia. Meanwhile, under these conditions, amplitude of the slow-wave oscillations rose more than 1.5 times. The obtained data allow us to conclude about the presence of a certain connection between the horn ovarian end and the uterine cervix. Morphological studies have revealed strong vascularization of the upper part of uterine horn. PMID- 23662484 TI - [Production and characteristics of the growth and marker properties of mesenchymal stem cells of urinary bladder]. AB - Mesenchymal stem cells (MSC) are capable for transdifferentiation into cells of another functional phenotype and are a perspective resourse of recovery therapy. MSC of different tissues differ by differentiation potential and in some cases express tissue-specific markers, which indicates close mesenchymal and parenchymal phenotypes of the same tissue. The homoorgan MSC might possibly be induced more effectively for tissue-specific differentiation and the preferred for cell therapy of diseases of the same organ as compared with widely used cells of the bone marrow origin. By using explants of the urinary bladder tissue, we obtained primary urinary bladder cell cultures of MSC of fetal and mature Balb/c mice (MSC-UBF and MSC-UBM) and characterized their properties in the course of long-term passing in culture. Unlike cells of mature animals, MSC-UBF have the steady capability for growth in vitro, clonogenic activity, and differentiation into adipose and bone cells. MSC-UBF express mesenchymal markers CD29, XD44, CD49f, CD90, and CD105, but not panleukocytic marker CD45, and do not differ by these parameters from the bone marrow MSC. Under normal conditions, MSC-UBF produce such urothelial markers as Ck14 and FOXA1, although their expression level is significantly lower than in the urinary bladder tissue. The hypomethylating reagent 5-azacytidin produces in MSC-UBF the expression of activator of urothelial differentiation PPARgamma and of markers of functional urothelium--UP1a, UP1b, UP3a, and UP3b. The obtained data indicate a possibility of epigenetic reprogramming of the urinary bladder MSC into urothelium at their treatment with 5-azacytidin, which can serve a basis for a novel model of cell therapy of urinary bladder diseases. PMID- 23662485 TI - [Morphfunctional interaction of cart-peptide and dopaminergic brain neurons]. AB - In Wistar rats, after 6 h of sleep deprivation and subsequent 2 h postdeprivation sleep, we found significant changes in optical density of CART-peptide in neurons of hypothalamic nucleus accumbens and nucleus arcuatus as well as in processes coming into substantia nigra from nucleus accumbens. The obtained data revealed unidirectional changes of optical density of tyrosine hydroxylase: a decrease after sleep deprivation (p < 0.05) and, on the contrary, an increase on the background of postdeprivation sleep (p < 0.05). Confocal laser microscopy showed morphological connections of CART and dopaminergic neurons and possible colocalization of these both substances in the same neuron at the postdeprivation sleep. In experiments in vitro, after 1 h of incubation of survived brain slices from the substantia nigra area in the medium with CART-peptide there was revealed a rise of optical density of tyrosine hydroxylase in the substantia nigra compact part by 55 % (p < 0.05). The obtained data indicate an activating effect of CART peptide on brain dopaminergic neurons and its as a modulator of their functional activity. PMID- 23662486 TI - [A method of automatized determination of parameters of intracranial liquorodynamics by data of rheoencephalogram and transcranial dopplerogram]. PMID- 23662487 TI - [Imperative and obstructive urination disorders in patients with chronic inflammatory diseases of the urinary tract]. AB - The estimation of functional parameters of the lower urinary tract in 116 patients with chronic cystitis and 51 patients with chronic nonobstructive pyelonephritis was performed. Urethral instability was revealed in 53 (45.68%) patients with chronic cystitis (mean age, 40.72 +/- 14.45 years), detrusor overactivity--in 10 (8.62%, mean age, 45.55 +/- 13.45 years) patients. Variations in detrusor pressure were 22.16 +/- 15.8 cm H20. Combination of urethral instability and detrusor overactivity was diagnosed in 26 (22.4%) patients of the study group (mean age, 65.16 +/- 10.49 years). The maximum urethral pressure was 75.5 +/- 21.44 cm H2O, variations in urethral pressure--37.45 +/- 17.44 cm H2O. Reduction in the maximum urinary flow rate less than 15 ml/s was detected in 47 (40.5%) patients. Signs ofdetrusor-sphincter dyssynergia were observed in 29 (25%) patients. After processing the urodynamic studies of patients with non obstructive pyelonephritis, 20 (39.21%) patients with severe detrusor hypotension, 18 (35.29%)--with detrusor overactivity, 26 (50.98%)--with urethral instability were identified. Based on the results of the study, it was concluded that women's chronic inflammation in the bladder and kidneys may not be the cause but the consequence of functional disorders of the lower urinary tract infections associated with the disorders of the nervous regulation of these organs. Inflammation in the bladder wall against the background of dysfunction of the lower urinary tract, in turn, can support a dysfunction of the bladder and/or urethra. Drugs affecting the function of the sympathetic and parasympathetic elements of the autonomic nervous system can be used for the elimination of functional disorders of the lower urinary tract and improvement the functioning of these organs. Thus, the pathogenetic treatment of chronic cystitis should be based on the disruption of "vicious circle" dysfunction--inflammation. In view of these data, and due to the frequent detection of imperative and functional obstructive urination disorders, in addition, based on the neurophysiological concept of their occurrence, the use of alpha-adrenoblockers and M anticholinergics agents is important in the treatment strategy with regard to patients with chronic recurrent cystitis and non-obstructive pyelonephritis. PMID- 23662489 TI - [Colovesical fistula as a complication of diverticular disease]. AB - The results of research on the clinical picture, features of manifestation, diagnosis, and treatment of patients with diverticular disease complicated by sigmovesical fistula are presented. The study included 31 patients (19 [61.3%] men, 12 [38.7%] women), aged 32-83 (55.6 +/- 7.1) years. Diagnostic program included physical examination, laboratory blood and urine tests, endoscopic, radiological, ultrasound examinations. All patients underwent different interventions according to the severity and extent of the inflammatory process, the involvement of other organs of the abdominal cavity and the extent of diverticular lesions of the colon. Long-term results were assessed in all patients in a period of 5 months to 12 years, with a median follow-up 4.7 years. It is shown that the clinical manifestations of intestinovesical fistula did not match the severity of complications, and were subclinical. Timing for referral the patient to coloproctologist was 5 months after the occurrence of first clinical signs. In any case, conservative treatment has not led to spontaneous colovesical fistula closure. Average size of parafistulous infiltration on the wall of the bladder and perivesical tissue was 6.5 +/- 2.4 cm. All the patients underwent different types of colon resection. Postoperative complications did not requiring recurrent surgery were detected in 5 (16.1%) patients. None of these has experienced recurrence complications of diverticular disease. For the optimization the treatment strategy, physicians should follow multidisciplinary approach immediately after revealing the patient with persistent bacteriuria, pneumaturia and fecaluria. The surgery is the method of choice in the treatment of colovesical fistula as a complication of diverticular disease. PMID- 23662488 TI - [Urogenital tuberculosis today]. AB - In order to analyze the structure of urogenital tuberculosis, retrospective analysis of medical records of 131 patients with newly diagnosed urogenital tuberculosis observed in the Novosibirsk Regional TB Dispensary from 2009 to 2011 was performed. The renal tuberculosis is main form in the structure is urotuberculosis, detected in 75% of patients, and widespread destructive forms of the disease were diagnosed in more than half of cases. Isolated nephrotuberculosis was more often diagnosed in women--56.8%. 15.9% of patients had asymptomatic nephrotuberculosis; one-third of patients complained of pain in the lumbar region and frequent painful urination (35.2 and 39.8%, respectively); symptoms of intoxication were present in 17% of patients, renal colic--in 9.1%, and gross hematuria--in 7.9% of patients. Mycobacteriuria in isolated nephrotuberculosis was detected in 31.8% of cases. Acute tuberculous orchiepididymitis developed in 35.7% of patients, hemospermia was observed in 7.1% of patients, dysuria was in 35.7% of patients. The pain in the perineum, frequent painful urination (both by 31.6%), hemospermia (26.3%) were main complaints in prostate tuberculosis. Mycobacteria was detected in 10.5% of cases. It was found that urogenital tuberculosis has no pathognomonic symptoms; the most alarming manifestations include long-term dysuria, hematuria, hemospermia. PMID- 23662490 TI - [Comparative clinical and morphofunctional evaluation of the intestinal and colonic gastric orthotopic urinary reservoirs at different times of functioning]. AB - The complex clinical and morphological evaluation of different variants of orthopic urinary reservoir (OUR) at different times of functioning was performed. During 1996-2012, orthotopic cystoplasty was performed in 265 patients (ileocystoplasty--in 204, gastrocystoplasty--in 24, and sigmocystoplasty--in 29 patients). There were 207 (77%) men and 61 (23%) women aged 22-75 years (mean age, 57.5 +/- 1,3 years). Cold biopsy over time (1 to 6) was performed in 105 patients. The total number of biopsies was 150. Duration of morphological study was 2-12 years. Clinical examination included assessment of acid-base balance and electrolyte balance of within 3-24 months, evaluation of urodynamic parameters (OUR volume, daytime and nighttime continence, micturition volume), assessment of the frequency and the nature of infection, resistance of microorganisms to antibiotics and the symptoms of inflammatory reaction in period 1-90 months after surgery. Morphological study included histological, histochemical, immunohistochemical, and morphometric methods. Application of a set of clinical, morphological, immunohistochemical examinations is a premise for individual choice of cystoplasty, and creates the preconditions for the correction of the process of adaptation to the OUR, regardless of its form in the early and later stages of its functioning. Due to the good adaptation to the new conditions in all three types of OUR and absence of trends to malignant transformation of its mucosa, the ileocystoplasty is method of choice for creation of OUR, and gastrocystoplasty and sigmocystoplasty are alternatives. PMID- 23662492 TI - [Dynamic magnetic resonance imaging of the pelvis in the differential diagnosis of types of urinary incontinence in women]. AB - The technique was developed, and the results of static and dynamic magnetic resonance imaging of the pelvis in 52 women with clinically diagnosed descent or prolapse of internal genital organs are presented. Episodes ofinvoluntary urination during physical exertion were recorded in 42 women. The developed MRI method allows to fix not only the degree of prolapse of pelvic organs with an increase in intra-abdominal pressure (Valsalva maneuver, cough), but an involuntary opening of the urethra and its filling by contents of the bladder at the height of increased intra-abdominal pressure and the immediate closure of the urethra at the decrease of intra-abdominal pressure--leading features of stress urinary incontinence. PMID- 23662491 TI - [The effectiveness of certain magnesium salts in nephrolithiasis caused by the use of sodium oxalate and celecoxib]. AB - The study was aimed to evaluation the effect of different magnesium salts and their combinations with pyridoxine on a course of calcium-oxalate nephrolithiasis, which was modeled by adding the sodium oxalate (3% of weight of the diet) and selective cyclooxygenase-2 inhibitor celecoxib at a dose 100 mg/kg body weight to a diet for 4 weeks. Starting from the 2nd week of the experiment, the animals had received one of the following compounds: magnesium L-aspartate, magnesium chloride, and their combination with vitamin B6; magnesium sulfate and Magne B6 (magnesium lactate and vitamin B6) as comparators. 28 days after the start of the experiment, disorders progressed in the group receiving only celecoxib and oxalate-rich diet: the urine level of oxalate increased by 171% (p < 0,0001), crystalluria had increased (up to 105 crystals in 10 microml of urinary sediment, p < 0,0001), creatinine clearance decreased by 29%, compared to control (p = 0,087). Increasing calcium/magnesium and oxalate/creatinine ratios in urine by 16 and 189%, respectively, was observed. In the renal parenchyma of animals treated with sodium oxalate and celebrex, calcifications with a volume fraction of 4% were identified, whereas these changes were absent in intact animals. According to the degree of correction ofhyperoxaluria and elimination of calcium oxalate crystals, investigated salts showed similar efficacy, with the exception of magnesium sulfate, which less contributed the compensation of abnormalities in kidney and urinary. According to the data of morphological study, the volume fraction of calcifications was lowest in the groups receiving magnesium L-aspartate and Magne B6. PMID- 23662493 TI - [Ozone therapy and tamsulosin in the treatment of cystitis]. AB - Treatment of cystitis remains an urgent problem in urology due to its prevalence, physical and social disadaptation of patients, and not always satisfactory treatment results. The article presents the results of treatment of 40 women aged 41.5 +/- 12.4 years with chronic cystitis. 20 patients received ozone therapy, 20 patients--ozone therapy in combination with alpha-adrenoblocker tamsulosin. Effectiveness of the treatment was evaluated using clinical data, data of bladder diaries, IPSS score, and uroflowmetry data. Dynamics of all the parameters in patients treated with ozone therapy in combination with tamsulosin was significantly higher in comparison with that in patients treated with ozone therapy only. As a result of the treatment, increased urine flow rate was accompanied by an increase in urination. Combination therapy with the use of ozone therapy and tamsulosin can be successfully and safely used in the treatment of patients with cystitis. PMID- 23662494 TI - [Features of the incidence of cystitis depending on the type of contraception]. AB - For the purpose of evaluation the effect of contraceptive methods on the incidence of recurrent bacterial cystitis in women, 215 clinical records of patients with cystitis were analyzed. In addition, incidence of recurrent cystitis in three groups of sexually active women of reproductive age was compared: 26 patients (Group 1) received conventional therapy and used condom as a method of contraception; 31 patients (Group 2) received combined oral contraceptives (COC), and 32 patients (Group 3) received COC and two courses of treatment with canephrone. A negative correlation between COC use and the risk of cystitis was detected. After conventional therapy, recurrences were observed in 43.3% of patients in Group 1, in 25.8% of patients in Group 2, and only in 15.6% of women in Group 3. Thus, the choice of COCs for contraception lead to 2-fold reduction of risk of recurrence of bacterial cystitis, and additional use of canephrone--to 3-fold reduction. PMID- 23662495 TI - [Modern approaches to the treatment of patients with overactive bladder and urge urinary incontinence]. AB - Overactive bladder (OAB) is found in 20% of patients with various disorders of urination, and the imperative urinary incontinence diagnosed in one third of these patients. The study was aimed to improvement the treatment outcomes in OAB women with imperative incontinence and obstructive urination disorders by using a combination of alpha1-adrenoblockers and PDE-5 inhibitors, and to evaluation of relationship between clinical and urodynamic manifestations of the disease. The state of the microcirculation of the bladder mucosa before and after treatment was also evaluated. We have examined and treated 40 women aged 17 to 69 years with disease duration ranged from 1 to 20 years. Patients received combination of al-adrenoblocker alfuzosin (dalfaz) 5 mg at night and reversible selective PDE5 inhibitor tadalafil (Cialis) 5 mg daily in the morning for a month. After treatment, according to the uroflowmetry and cystometry data, the time of urination was reduced, urinary volume and maximum urinary flow rate, as well as cystometric capacity have increased; involuntary detrusor contractions in the bladder filling phase (spontaneous or provoked) became less, or absent. According to the results of ultrasound examination, residual urine volume has decreased. Laser Doppler flowmetry showed an increase of neurogenic tone in precapillary, bypass coefficient and microcirculation effectiveness index, increase in microcirculation index and the coefficient of variation, indicating an improvement of microcirculation in the bladder mucosa. As a result of treatment, the clinical effect was seen in 29 (73%) patients, urinary incontinence was noted only in 6 (15%) patients. PMID- 23662496 TI - [An experimental study of the effectiveness of the drug afalaza in chronic aseptic prostatitis]. AB - A pilot study evaluated the efficacy of the drug afalaza (mixture of affinity purified antibodies to PSA and endothelial NO-synthase) compared with the Serenoa repens extract in a model of chronic abacterial prostatitis in Wistar rats caused by suturing of prostate tissue by silk thread. Except for the animals of intact group, rats (n = 13 in each group) underwent intraperitoneal injection of distilled water (10 ml/kg), afalaza (at a doses of 5, 7.5 and 10 ml/kg) or an Serenoa repens extract (50 mg/kg) 1 month after surgery for 45 days. After infusion, the mass, volume, and prostate weighting factor were evaluated, and prostate tissue was examined histologically. 2.5 months after surgery, development of chronic abacterial prostatitis was observed in the control group. Compared with intact group, significant increase in weight, weighting factor, and volume of prostate were detected in control group. Against the background of administration of Serenoa repens extract and afalaza, these parameters were not significantly different from control values. The use of Serenoa repens extract prevented the development of atrophic processes and slowed the development of sclerotic processes. Administration of afalaza at all studied doses prevented the development of sclerotic changes, and a dose of 7.5 ml/kg prevented the development of atrophic processes with the effectiveness matching to Serenoa repens extract. Taking into account the high safety of afalaza, this drug is a promising treatment for chronic prostatitis. PMID- 23662497 TI - [The use of drug vitaprost forte in patients with benign prostate hyperplasia]. AB - The efficacy and safety of vitaprost forte rectal suppositories 100 mg in 30 patients with benign prostate hyperplasia (BPH) were evaluated. It is proven, that the use of this drug positively affects both the subjective and the objective symptoms of BPH. Vitaprost forte significantly reduces the clinical signs of the disease and improves quality of life, that is, reduces the severity of bladder outlet obstruction (according to the data of uroflowmetry, it increases maximum urinary flow rate), decreases the amount of residual urine. In addition, moderate reduction in mean prostate volume was revealed in BPH patients receiving vitaprost forte. PMID- 23662498 TI - [Experience of use of allokin-alfa in the treatment of genitourinary infections complicated by excretory-toxic infertility]. AB - The results of the examination and treatment of 67 patients aged 18 to 45 years are presented. Patients suffered from chronic prostatitis, chronic prostatovesiculitis, chronic uretroprostatitis complicated by excretory-toxic infertility. Pathogens, including sexually transmitted infections (STIs), were identified in all patients. The control group received conventional therapy (causative agents, a-adrenoblockers, enzyme therapy). In the study group, patients received allokin alpha in addition to conventional therapy. The use of allokin-alfa promoted more rapid and complete eradication of STI pathogens, and normalization of the spermogram. The results of this study allow to recommend allokin-alfa for the combined treatment of patients with infectious and inflammatory diseases of the genitourinary system, complicated by excretory-toxic infertility. PMID- 23662499 TI - [Surgical treatment of lung metastases of kidney cancer]. AB - The medical records of 60 patients who underwent surgery to remove the lung metastases of T1-4N0-2 kidney cancer were retrospectively analyzed. The age of patients ranged from 31 to 70 years. Synchronous lung metastases were diagnosed in 20 (33.3%) cases, metachronous - in 40 (66.7%). 53 (88.3%) patients had lesions in one lung, and 7 (11.7%) patients--in both lungs. Solitary metastases were present in 41 (68.3%) patients, multiple--in 19 (31.7%). In 69.4% of cases, the size of lung metastases was more than 2 cm. Metastasis at other sites at the time of surgery on the lungs were present in 1 patient (supraclavicular lymph nodes). The primary tumor was removed in 56 (93.3%) of 60 patients. All 60 patients underwent removal of lung metastases (radical--53 [88.3%]). One patient underwent a radical supraclavicular lymph node dissection. All tumor lesions were removed in 50 (83.3%) patients. Median followup period was 20 (3-155) months. Perioperative complication rate was 6.6%; no deaths caused by complications of treatment were registered. Histologically, metastases of renal cell carcinoma were verified in all removed lesions from the lungs; 3 (5%) patients had mediastinal lymph node metastases. Five- and 10-year overall, specific and recurrence free survival rates were 36.3 and 19.1%, 38.9% and 27.2, 20.4 and 11.7%, respectively. Univariate analysis demonstrated an adverse effect of pN + category, bilateral pulmonary lesions, the presence of mediastinal lymph nodes metastases and non-radical removal of malignant lesions of the lung on the specific survival. Multivariate analysis confirmed a significant effect of radical surgery on the survival. PMID- 23662500 TI - [High-intensity focused ultrasound (HIFU) for the prostate cancer treatment: 5 year resuts]. AB - During 2007-2012 748 patients with prostate cancer (PCa) underwent ultrasound ablation (HIFU). Patients were divided into 3 groups according to the prevalence and risk of disease progression: low risk (localized prostate cancer, 465 (62%) of patients) stage T1-2N0M0, total Gleason score < or = 6, the level of prostate specific antigen (PSA) less than 20 ng/ml), high risk (locally advanced prostate cancer, 251 (34%) of patients)--stage T2-3N0M0, total Gleason score < or = 9, the PSA level from 20 to 60 ng/ml, the presence of local recurrence after radical prostatectomy (RPE) and external beam radiation (EBRT)--32 (4%) patients. Median follow-up after HIFU-therapy was 36 (3-54) months. At 12 and 48 months after treatment in patients with a low risk of progression median PSA was 0.2 and 0.5 ng/ml, in the group with a high risk 0.8 and 1.2 ng/ml, in patients with local recurrence after RPE and EBRT--0.5 and 1.7 ng/ml respectively. Generally HIFU treatment was successful in 90.9% of patients. It is shown that HIFU is safe minimally invasive treatment for localizes and locally advanced prostate cancer. It can be successfully performed in patients with local recurrence after RPE and EBRT. PMID- 23662501 TI - [First experience of monoport laparoscopic surgery in the treatment of kidney diseases]. AB - The results of research on the effectiveness of monoport laparoscopic surgery for kidney disease are presented. Operations using LESS method (Laparo-Endoscopic Single-Site Surgery) were performed in 21 patients, including 14 nephrectomies and 7 cyst resections. In five cases, nephrectomy was performed due to terminal hydronephrosis, in two cases--due to presence of arteriolosclerotic kidney, in seven cases--due to renal cell carcinoma (T1a-bN0M0). "Pain DETECT" questionnaire was used for assessment of pain symptom. Maximum longitudinal size of a removed organ was 14 cm, the average volume of intraoperative blood loss--80 ml. Duration of monoport laparoscopic radical nephrectomies ranged from 125 to 230 min (mean duration, 164 min). The time for renal cyst resection ranged from 40 to 120 minutes. Moderate intensity pain was observed in all patients but only at the first day after surgery. The average hospital stay was 4 days. The length of postoperative skin scar varied from 2.5 to 6.0 cm. Early and late postoperative complications were not observed. During follow-up period 6 to 8 months, tumor or cyst recurrence were not registered. PMID- 23662502 TI - [Retrograde nephrolithotripsy in treatment of staghorn nephrolithiasis]. AB - The article presents the results of 42 retrograde nephrolithotripsy (RNLT) performed on 38 patients with staghorn nephrolithiasis. The staghorn cacculi SN-2 were most frequently indication for the intervention. 3 months after surgery, full exemption of the kidney from the fragments was observed in 85,6% of patients. RNLT is an effective and safe treatment for patients with staghorn stones with relatively low need for additional procedures. RNLT allows to reduce postoperative hospital stay and recovery period of patients. PMID- 23662503 TI - [Comparative analysis of the efficacy and safety of percutaneous nephrolithotomy for staghorn calculi]. AB - The widespread introduction of percutaneous nephrolithotomy has led to a significant narrowing of the traditional indications for surgery for staghorn calculi. We analyzed the efficacy and safety of percutaneous nephrolithotomy, depending on the stage ofstaghorn nephrolithiasis. In a period of 2008-2011, 120 patients with staghorn calculus underwent percutaneous nephrolithotomy. Data from spiral computed tomography were used in planning the surgical approach. In the preoperative period, staghorn calculi SN1-SN2 were diagnosed in 31.7% of patients (Group 1), and complex forms of stones corresponding SH3-SN4--in 68,3% (Group 2). The between-group analysis showed that the average time of surgery was significantly (p < 0,01) higher in patients in Group 2, the same group reported more frequent blood loss requiring to stop operation, as well as hyperthermia, hypotension during surgery, but the difference was not significant compared to Group 1 (p > 0,05). Conversion to open surgery was required in 2,6 and 2,7% of patients in Group 1 and Group 2, respectively. Application of PNL allowed to completely remove SN1-SN2 calculi in 94,7% of cases in Group 1, but similar result was achieved only in 63.4% of cases in most difficult group of patients with SN3-SN4. PMID- 23662504 TI - [Postoperative infectious-inflammatory complications of endoscopic surgery for urolithiasis]. AB - Retrospective analysis of 1027 percutaneous radioendoscopic surgeries for upper urinary tract stones was performed. Postoperative acute pyelonephritis was the most common complication (11.2%), the frequency of which was significantly dependent on the presence of source of infection in the urinary tract, and the frequency of intra- and postoperative complications. When performing PPN, patients with urolithiasis and with the presence of the initial infection in the urinary tract, intra- and postoperative complications should be referred to the group of patients with a high risk of postoperative infectious and inflammatory complications. The analysis showed that the development of acute pyelonephritis after PPN increases the cost of treatment by 25%. PMID- 23662505 TI - [The choice of method of urethroplasty in patients with distal and middle hypospadias]. AB - Retrospective analysis of results of the most frequently used methods of urethroplasty: urethroplasty using tubularized dissected urethral area (TIP), urethroplasty using tubularized dissected urethral area with inset the free flap of the foreskin (GTIP) and Mathieu surgery in patients with coronary, distal and middle hypospadias (in primary and recurrent surgery), was performed. From 2005 to 2010, 300 patients aged 7 months to 19 years underwent the surgery. There were no early postoperative complications in any patient, with the exception of early accidental removal of the catheter in 4 patients. Long-term results of one-stage correction of hypospadias were followed-up during period of 6 months to 4 years. Late complications included urethral fistula and stenosis. Analysis of the results of operations led to the conclusion that the TIP urethroplasty with Snodgrass modification can be performed as either primary or recurrent surgery in case of normal size of balanus and urethral area. However, in case of changes in the urethral area, scarring and small sizes of balanus, appropriate surgery is Mathieu operation. PMID- 23662506 TI - [Staghorn nephrolithiasis complicated by renal abscess, purulent paranephritis with subsequent delayed sequelas]. PMID- 23662507 TI - [The use of the vermiform appendix in reconstructive urology]. PMID- 23662508 TI - [Surgical treatment of unilateral and bilateral staghorn nephrolithiasis]. PMID- 23662509 TI - [The use of plant uroseptic Uroprofit in urological practice]. PMID- 23662510 TI - [Heart function changes during pregnancy]. AB - The aim of the study was to assess the left ventricle (LV) systolic and diastolic functions during normal pregnancy. Patients were divided in 2 groups: women with normal pregnancy (30-40 weeks) and a control group--healthy non-pregnant women. Echocardiography and tissue Doppler imaging (TDI) were registered in both groups. Women age, height and weight were additionally registered. Static handling included correlation analysis with calculation of Pearson and Spirmen pair factors correlation. Obtained data showed that stroke volume during pregnancy plays a key role not only in minute volume increase, but also in its regulation in general. Preload and stroke volume increase during constant heart rate is in need of systolic and diastolic LV walls movement speed and myocardium contractility function increase. Results of our research explain imperfection of pregnant women adaptable mechanisms to hypertransfusions and heavy hypovolemia. PMID- 23662511 TI - [Relationship between uteroplacental blood flow and of intra-abdominal hypertension in pregnant women]. AB - RESEARCH AND OBJECTIVE: Identification of relationship between intra-abdominal pressure and uteroplacental blood flow MATERIALS AND METHODS: 90 second trimester women (20-24 weeks) were examined. An assessment of intra-abdominal pressure (IAP) was carried out by "Unometerabdopressure" system through a bladder. Doppler imaging with resistance index in uterine arteries (RIUA) and umbilical cord arteries (UCA) assessment was carried out to evaluate uteroplacental blood flow. We calculated indicator (1) that characterize extent uteroplacental blood flow compensation degree. Pregnancy course and birth results were studied. RESULTS: It is established that uteroplacental blood flow disturbances during 2nd trimester of pregnancy are closely connected with IAP level. RIUA and I data are assessment criteria of chronic intra-abdominal hypertension compensation degree in pregnant women. Obstetric and perinatal complications frequency is closely connected with IAP value. IAP and uteroplacental blood flow data are important parameters which can be received with use of noninvasive techniques. PMID- 23662512 TI - [Haemostasis disorders and ways of its correction in HIV-positive pregnant women receiving chemopreventive antiretroviral therapy]. AB - The analysis of 162 surgical deliveries cases in HIV-positive patients with antiretroviral therapy--induced haemostasis disturbances and thrombocytopenia was carried out. The article gives the perioperative management during surgical delivery. PMID- 23662513 TI - [Correction of anaemia in HIV-positive pregnant women receiving antiretroviral therapy]. AB - The analysis of 162 surgical deliveries cases in HIV-infected pregnant women was carried out. Anaemia type identification was based on blood analysis data and erythrocytes morphology. Ways of disease correction were defined. Recommendations for anemia prevention and treatment in HIV-infected patients receiving anti retroviral drugs are presented. PMID- 23662514 TI - [Emergency obstetrics: the resuscitation mobile center experience]. AB - This article is devoted to topical problem in obstetrics critical states therapy and reflects long-term experience of resuscitation mobile center of S.P. Botkin hospital. Epidemiology of critical state in obstetrics and modern approaches to treatment of these conditions are considered on a voluminous clinical data. Mobile telemedical complexes and multidisciplinary consultations are used for decision-making optimization in difficult clinical situations. The modern concept of anaesthesiology safety level increase is presented. This organizational approach, mobile forms of anaesthesiology and resuscitation care are utterly effective and economically reasonable in Moscow obstetric care system. PMID- 23662515 TI - [Acid-base status dynamics in patients after cesarean section with different types of infusion therapy]. AB - The objective of the research was to estimate Cesarean section results during different types of infusion therapy. The article represents results of the simple blind perspective cohort randomized research which has been carried out in 54 women after planned Cesarean section. It is revealed that use of unbalanced solutions in infusion therapy causes statistically significant changes in acid base balance status in comparison with control group receiving balanced ones. PMID- 23662516 TI - [Diagnostics and correction of coagulopathy in pregnant women and puerperas with gestosis]. AB - INTRODUCTION. Gestosis is a complication of normal pregnancy which for long years takes the 2-3rd place in maternal and perinatal mortality and women morbidity structure. 396 patients with moderate and heavy gestosis from 2007 to 2011 were studied. In 53 women (13.4%) it was accompanied by complex haemostasis disturbances and part of women had sepsis. Therefore the retrospective differential analysis of haemostasis disturbances with algorithm presented in this article was carried out. Haemostasis status, complete blood count, biochemical blood analysis data were analyzed. Correction of haemostasis disturbances in the postnatal period was performed according to legacy recommendations. As a result of retrospective differential diagnostics of haemostasis disturbances, the chronic disseminate intravascular clotting (DIC) syndrome, a HELLP-syndrome, thrombotic thrombocytopenic purpura (TTP) and a haemolytic uremic syndrome (HUS) were revealed. The received results indicate that in obstetrics there are essential difficulties with coagulopathy timely diagnostics, especially, TTP and HUS. The most difficult problem is differential diagnostics between a HELLP-syndrome, TTP and HUS. Clear algorithm of differential diagnostics appeared only in 2010. We analyzed all coagulopathy cases since 2007. TTP and HUS were diagnosed by 3rd days of the postnatal period, also specific therapy of these syndromes was late that was reflected in ICU length-of-stay, frequency of sepsis and need of uterectomy respectively. PMID- 23662517 TI - [Abdominal cross section space blockade as a component of the multimodal postoperative analgesia in patients after cesarean section: blockade efficiency analysis]. AB - RESEARCH PURPOSE: To compare postoperative analgesia after Cesarean section with abdominal cross section space (ACSB) blockade in a combination with non-opioid analgesics versus conventional system anaesthesia. MATERIALS AND METHODS: 62 patients (2 groups of 31), after planned Cesarean section were included in this randomized research. In main group ACSB was used for postoperative analgesia, in control--a system anaesthesia. Research included pain assessment with visual analogue scale (VAS) during rest and cough after spinal block regression and 12 and 24 hrs postoperatively. Additionally vital capacity of lungs changes was measured. RESULTS: In the main group VAS data in rest and at cough at stages 12 and 24 of h. after operation were significantly lower, than in control group. Vital capacity of lungs in this group was reliably higher at a stage of 24 h. CONCLUSION: ACSB in a combination with non-opioid analgesics provides high analgesia level without narcotic analgesics application, increases postoperative patients comfort after Cesarean section. PMID- 23662518 TI - [Noninvasive total hemoglobin monitoring based on multiwave spectrophotometry in obstetrics and gynecology]. AB - Results of prospective randomized comparative research of 2 total hemoglobin estimation methods are presented. There were laboratory tests and continuous noninvasive technique with multiwave spectrophotometry on the Masimo Rainbow SET. Research was carried out in two stages. At the 1st stage (gynecology)--67 patients were included and in second stage (obstetrics)--44 patients during and after Cesarean section. The standard deviation of noninvasive total hemoglobin estimation from absolute values (invasive) was 7.2 and 4.1%, an standard deviation in a sample--5.2 and 2.7 % in gynecologic operations and surgical delivery respectively, that confirms lack of reliable indicators differences. The method of continuous noninvasive total hemoglobin estimation with multiwave spectrophotometry on the Masimo Rainbow SET technology can be recommended for use in obstetrics and gynecology. PMID- 23662519 TI - [Angiogenic growth factors in the ceresbropinal liquid of pregnant women during planned cesarean section under combined spinal - epidural anaesthesia]. AB - The content of soluble angiogenic growth factors in cerebrospinal liquid and blood serum in 33 pregnant women aged from 21 to 37 years (30.9 +/- 6.2 years) before spinal - epidural anaesthesia during Cesarean section was studied in observative, prospective, stratificative research. All patients without somatic pathology were divided into 2 groups -control and main. 12 pregnant women with high degree myopia as a main indication for Cesarean section were included in the 1st control group. 21 pregnant women were included in the 2nd main group. This group was divided into 2 subgroups: group 2a--with eukinetic haemodynamics type (12 patients), group 2b--with hyperkinetic haemodynamics type and moderate hypoxemia (9 patients). The indications for planned Cesarean section in patients of the 2nd group were uterine scar and/or pelvis bones pathology. The analysis of angiogenic growth factors content in cerebrospinal liquid revealed differences between group 2b and group 2a. Results of angiogenic growth factors content in cerebrospinal liquid testify hidden intracerebral hypoxemia and can be used for its assessment before anaesthesia and for the testifying of the haemodynamics status and system hypoxemia relationship. PMID- 23662520 TI - [Perinatal anaesthesia risk scale and prognosis of perinatal results during cesarean section]. AB - The article presents analysis of informative importance of the scales estimating the somatic status and surgical and anaesthesiology risk: American Society of Anesthesiologists (ASA), Moscow Scientific Society of Anaesthesiology and Resuscitation (MSSAR) and Anaesthesiology Perinatal Risk (APR). Reliably high correlation between APR scale and blood loss, pregnancy term, Apgar score assessment, newborn body weight is shown in the article. Information importance of APR scale, its sensitivity, specificity and efficiency concerning perinatal results reliably authentically exceeded ASA and MSSAR scales. CONCLUSION: Use of the APR scale in maternity clinics and perinatal centers will allow to optimize preoperative assessment before Cesarean section, and reliably predict perinatal outcomes. PMID- 23662521 TI - [Neuro-autonomic inhibition and haemodynamics management optimization during cesarean section under spinal anaesthesia in pregnant women with gestosis]. AB - Results showed that autonomic nervous system (ANS) and blood circulation system (BCS) dysfunction in 3rd trimester pregnant women with gestosis are more pronounced, than in healthy pregnant women, despite the prescribed treatment. The most significant disturbances were vagotonia and hypokinetic haemodynamics type (often iatrogenic). Spinal anaesthesia (SA) during Cesarean section in pregnant women is accompanied by blood pressure decrease to the level demanding on vasopressors use. Considering normal indicators of SI, CI, oxygen transportation and electrocardiogram vasopressor was not introduced Apgar score assessment of newborns was within normal. However, vagotonia and hypokinetic haemodynamics type during anaesthesia that certifies autoregulation reserves insufficiency. Atropine introduction in pregnant women with vagotonia and hypokinetic haemodynamics type (often iatrogenic, owing to irrational therapy) before SA beginning of promoted neurovegetative inhibition optimization and haemodynamics stabilization in eukinetic range. Vagus blockade (elimination of ANS dysfunction) was accompanied by more physiologic sympathicotonia development with smaller decrease of blood pressure (without stroke index reduction!), absence of bradycardia and vomiting. Research showed that the blood pressure cannot be the only objective criterion of vasopressors use. PMID- 23662522 TI - [Central haemodynamics parameters during different anaesthesia methods of surgical delivery in preeclampsia women]. AB - RESEARCH OBJECTIVE: To study influence of various anaesthesia methods on key central haemodynamics parameters in patients with heavy preeclampsia during surgical delivery. MATERIALS AND METHODS: Prospective randomized comparative research was carried out. 60 pregnant women were included in research with a heavy preeclampsia after Cesarean section. Patients were randomized (a method of envelopes) in 2 groups (30 patients each): group with spinal anesthesia and general anaesthesia. RESULTS: In spinal anaesthesia group there was more favorable haemodynamic profile at all investigation phases: moderate decrease in blood pressure, stroke volume increase and peripheral vascular resistance decrease were observed. General sevoflurane anaesthesia was accompanied by tachycardia, arterial hypertension, stroke volume decrease at a prenatal stage and stabilization of indicators only at the following investigation phases. pinal anaesthesia during surgery delivery in heavy preeclampsia patients is more preferable from the point of view of haemodynamic stability. PMID- 23662523 TI - [Validity of APACHE II, APACHE III, SAPS 2, SAPS 3 and SOFA scales in obstetric patients with sepsis]. AB - RESEARCH OBJECTIVE: to estimate efficiency of APACHE II, APACHE III, SAPS II, SAPS III, SOFA scales for obstetric patients with heavy sepsis. MATERIALS AND METHODS: 186 medical cards retrospective analysis of pregnant women with pulmonary sepsis, 40 women with urosepsis and puerperas with abdominal sepsis--66 was performed. Middle age of women was 26.7 (22.4-34.5). RESULTS: In population of puerperas with abdominal sepsis APACHE II, APACHE III, SAPS 2, SAPS 3, SOFA scales showed to good calibration, however, high resolution was observed only in APACHE III, SAPS 3 and SOFA (AUROC 0.95; 0.93; 0.92 respectively). APACHE III and SOFA scales provided qualitative prognosis in pregnant women with urosepsis; resolution ratio of these scales considerably exceeds APACHE II, SAPS 2 and SAPS 3 (AUROC 0.73; 0.74; 0.79 respectively). APACHE II scale is inapplicable because of a lack of calibration (X2 = 13.1; p < 0.01), and at other scales (APACHE III, SAPS 2, SAPS 3, SOFA) was observed the insufficient resolution (AUROC < 0.9) in pregnant women with pulmonary sepsis. CONCLUSION: Prognostic possibilities assessment of score scales showed that APACHE III, SAPS 3 and SOFA scales can be used for a lethality prognosis for puerperas with abdominal sepsis, in population of pregnant women with urosepsis--only APACHE III and SOFA, and with pulmonary sepsis--SAPS 3 and APACHE III only in case of additional clinical information. PMID- 23662524 TI - [Characteristics of septic shock in obstetrics]. AB - Peculiarities of septic shock in obstetrics are considered in this article. Traits of pregnant woman organism concerning infectious process, etiology and risk factors, modern criteria of heavy sepsis diagnosis and septic shock are discussed. It is pointed out that septic process system manifestations considerably outstrips local manifestations of purulent process in a uterus and it is necessary to take into account modern markers and criteria when making decision on initial infection center sanitization. The modern protocol of septic shock initial intensive therapy where are defined not only modern methods of treatment, but also time of their implementation, and the basic principles of pyosepsis caused maternity mortality decrease. PMID- 23662525 TI - [Hypovolemic shock during pregnancy]. PMID- 23662526 TI - [Anaesthesia peculiarities during delivery in morbid obese women]. AB - This review presents principals of complications prevention, anaesthesia methods choose, preoperative preparation, anaesthesia management and postoperative care in morbid obese patients. PMID- 23662527 TI - [Too much regard for childless peoples wishes]. PMID- 23662528 TI - [A warning for "patients" that tricks physicians]. PMID- 23662529 TI - [Surgery must be responsive and driving--and aim for the future. Minimally invasive technique part of the radical change within surgery]. PMID- 23662530 TI - [More children can be helped to better movement]. PMID- 23662531 TI - [Congenital instability and dislocation of the hip--management today]. PMID- 23662532 TI - [The Ponseti method--established standard treatment of clubfoot]. PMID- 23662533 TI - [Leg length inequality and crooked legs are best corrected during growth]. PMID- 23662534 TI - [Neuromuscular diseases are many but rare]. PMID- 23662535 TI - [Good help from modern treatment of juvenile idiopathic arthritis]. PMID- 23662536 TI - [Knee injuries common among children practicing sports]. PMID- 23662537 TI - [Treatment of spasticity can improve everyday life]. PMID- 23662538 TI - [Positive development with follow up program for children with cerebral palsy]. PMID- 23662539 TI - [Writing a scientific paper--a few steps on the road]. PMID- 23662540 TI - [Doing research is and should be fun]. PMID- 23662541 TI - [Vaginal estradiol and venous thrombosis]. PMID- 23662542 TI - [Reorganization and subspecialization needed for emergency and trauma surgery]. PMID- 23662543 TI - [The ethical review committees should become a single authority]. PMID- 23662544 TI - [Unworthy behavior of the Swedish Medical Association]. PMID- 23662545 TI - [Do a total remake]. PMID- 23662547 TI - [Key points in anterior esthetic restorations with all ceramic]. AB - This paper introduced the key points in fabricating anterior esthetic restorations with all ceramic materials, including pre-operative smile design, standard tooth preparation, provisional restoration fabrication, all ceramic materials selection, all ceramic restoration bonding, ceramic crack and fracture prevention. And then, the authors summarized and reviewed the clinical common problems in anterior esthetic restorations. PMID- 23662546 TI - [A physician's life in pictures]. PMID- 23662548 TI - [The effects of tissue inhibitor of metalloproteinases on beta-dystroglycan in salivary adenoid cystic carcinoma]. AB - OBJECTIVE: To investigate the expression of beta-dystroglycan (beta-DG) and the roles of tissue inhibitor of metalloproteinases (TIMPs) on beta-DG in salivary adenoid cystic carcinoma (SACC). METHODS: beta-DG in highly lung metastatic cell line ACC-M and lowly lung metastatic one ACC-2 was tested by immunocytochemistry with different concentrations (10, 15, 20, 25 micromol x L(-1)) of TIMPs, and that without the regulation of TIMPs was served as controls. beta-DG was detected in seven specimens of SACC and ten cases of normal salivary gland tissues which were considered as a comparison group by immunohistochemistry. RESULTS: There was no positive beta-DG immune-staining at the ACC-2 and ACC-M cell lines without TIMPs in the cell culture. beta-DG expressed after the regulation of TIMPs. beta DG expression was localized predominantly in basement membrane of the acinus, while the negative results were distributed in the carcinoma cells and around the cancer cell nests. CONCLUSION: Beta-DG is widely expressed by transmembrane protein that plays important roles in connecting the extracellular matrix to the cytoskeleton, the fracture of this structure means that it is easy to invade and transfer, so restoration of beta-DG expression by TIMPs is considered to be critical for successful treatment of SACC. PMID- 23662549 TI - [Effects of experimentally created unilateral anterior crossbite prosthesis on the expression of parathyroid hormone-related peptide and parathyroid hormone receptor-1 in mandibular condylar cartilage of rat]. AB - OBJECTIVE: To study the effects of experimentally created unilateral anterior crossbite prosthesis on the expression of parathyroid hormone-related peptide (PTHrP) and parathyroid hormone receptor-1 (PTH1R) in mandibular condylar cartilage of SD rat. METHODS: In experimental groups, the unilateral anterior crossbite metal prosthesis was cemented to the left incisors of the maxilla and mandible of 6-week-old SD rats, respectively. Animals were sacrificed at 2, 4, 8 weeks. Hematoxylin-eosin (HE) staining were carried out for studying the morphological changes of the condylar cartilage. Immunohistochemical staining and real-time polymerase chain reaction (PCR) analysis were performed to detect the levels of expression of PTHrP and PTH1R in the condylar cartilages. RESULTS: The obvious degenerative changes were found in the condylar cartilages in experimental group at 8 weeks. Comparing to the control group, the expression of PTHrP mRNA (P < 0.01) and protein(P < 0.01) in the experimental group were increased, whereas PTH1R mRNA (P < 0.01) and protein (P < 0.01) levels were decreased. CONCLUSION: The expression of PTHrP was increased in the condylar cartilage of rat with unilateral anterior crossbite metal prosthesis but its effects might be limited because of decreased expression of PTH1R in the condylar cartilage. The low level expression of PTH1R should be a part of the constitution of the molecular pathomechanism of temporomandibular joint osteoarthritis (TMJOA) like lesion. PMID- 23662550 TI - [Research on the microstructure of antibacterial nanocomposite membrane and it's biocompatibility as a guided bone regeneration membrane]. AB - OBJECTIVE: To study the microstructure of the Ag-nHA-nTiO2/PA66 membrane and investigate its biocompatibility. METHODS: The microstructure of Ag-nHA-nTiO2PA66 membrane and e-polytetra fluoroethylene (e-PTFE) membrane were observed by light microscope and scanning electron microscope(SEM). MG63 osteoblast-like cells were cultured on the two kinds of membrane and blank group. The cell proliferation was checked by methyl thiazolyl tetrazolium (MTT) method and alkaline phosphatase (ALP) activity was detected by enzyme linked immunosorbent assay (ELISA). The adhesion and proliferation of the cells on the two kinds of membrane was observed by SEM. RESULTS: The Ag-nHA-nTiO2/PA66 membrane was composed of the obverse face and the opposite face. The obverse face was porous and the opposite face was smooth. Microstructures of the obverse and the opposite face of the e-PTFE membrane were same. The e-PTFE membrane showed many tiny lined cracks in elliptic structure. MTT assay and ALP measurement showed that there were no significant difference between each of the two membrane groups and the blank (P > 0.05). The adhesion and proliferation of cells on the Ag-nHA-nTiO2/PA66 membrane were better than the e-PTFE membrane. CONCLUSION: Ag-nHA-nTiO2/PA66 membrane has no negative effects on the growth of osteoblast-like cells. Ag-nHA-nTiO/PA66 membrane is biocompatible and its microstructure is appropriate as a guided bone regeneration materials. PMID- 23662551 TI - [Chronchemotherapy of oxaliplatin to oral squamous cell carcinoma]. AB - OBJECTIVE: To compare the differences of the efficacy and adverse reaction of Oxaliplatin (L-OHP) treatment to oral squamous cell carcinoma (OSCC) at four different daily time points, and to analyze the characteristics of circadian rhythms. METHODS: Seventy-five nude mice were placed under 12h light and 12h dark cycles. Human OSCC cell line BcaCD885 was inoculated on the cheek of nude mice to establish a nude mice model of OSCC. After 3 weeks, mice were divided into 5 groups (4 experimental groups and 1 control group), with 15 in each group. L-OHP (17 mg x kg(-1)) was injected intravenously at 4 different time points during a period of 24 h, including 4 hours after lights on JHALO), 10 HALO, 16 HALO and 22 HALO for 4 experimental groups. The control group received normal saline of the same volume as that of L-OHP. The efficacy (tumor inhibition rate and survival time) and adverse reaction (body weight, white blood cell and perianal swelling) were observed after administration. The circadian rhythms of the efficacy and adverse reaction were examined by cosine analysis. RESULTS: L-OHP injected at 4, 16 and 22 HALO had great tumor inhibition rates, however, only 16 and 22 HALO groups significantly prolonged survival time of mice. The adverse reactions at 4 and 10 HALO were significantly severer than that of 16 and 22 HALO. Cosine analysis showed survival time, body weight and white blood cell counts had significant circadian rhythms. Mice received L-OHP at 14.88 HALO had the longest survival time. CONCLUSION: The time factor should be considered in L-OHP chronchemotherapy of patients with OSCC in order to increase the efficacy, decrease the adverse reaction of the drug and to improve the life quality of patients with OSCC. PMID- 23662552 TI - [Preliminary screen of high cariogenicity Streptococcus mutans strains isolated from clinical specimens]. AB - OBJECTIVE: To screen of high cariogenicity Streptococcus mutans (S. mutans) strains isolated from clinical specimens preliminary. METHODS: Acidogenicity, aciduricity, extracellular polysaccharide production and adhesion of 41 strains of S. mutans isolated from clinical specimens were investigated to screen high cariogenicity S. mutans strains. RESULTS: There were different cariogenicity among 41 strains of S. mutans, in which 3 strains of S. mutans had all high ability to produce extracellular polysaccharide, adhere to the saliva-coated hydroxyapatite, produce acid and tolerate acid, indicated there were 3 strains with high cariogenicity S. mutans strains isolated from clinical specimens. Another 3 strains of S. mutans with all low ability to produce extracellular polysaccharide, adhere to the saliva-coated hydroxyapatite, produce acid and tolerate acid indicated they were low cariogenicity S. mutans strains isolated from clinical specimens. CONCLUSION: We may have obtained high cariogenicity S. mutans strains isolated from clinical specimens. PMID- 23662553 TI - [Effect of OHOLV on the remineralization of early enamel caries]. AB - OBJECTIVE: To observe the effect of OHOLV on the remineralization of early enamel caries. METHODS: Fifty bovine teeth with artificial early caries were divided into five groups randomly and treated with OHOLV, casein phosphopeptide amorphous calcium phosphate (CPP-ACP), NaF, OHOLV+NaF and distilled and deionized water (DDW) respectively. Then the teeth were subjected to the pH-cycling. The surface microhardness (SMH) of enamel before demineralization and after remineralization were measured by microhardness detector and the histomorphologic changes of the enamel surface were compared by scanning election microscope (SEM). RESULTS: The SMH of all the experimental groups increased significantly after remineralization (P < 0.001). The SMH of the OHOLV group was lower than that of NaF group (P < 0.001), while there was no significant difference between the OHOLV group and the CPP-ACP group (P > 0.05). After remineralization, a large amount of comparatively large mineral particles deposited on the surface of the enamel treated with OHOLV. CONCLUSION: OHOLV can promote the remineralization of the early enamel caries. PMID- 23662554 TI - [The study of serine/threonine kinase signaling pathway-mediated inhibition of proliferation and invasion of oral squamous cell carcinoma transfected with p53 gene]. AB - OBJECTIVE: To evaluate the molecular mechanism of proliferation and invasion inhibition in oral squamous cell carcinoma transfected with recombinant adenovirus-p53 (Ad-p53). METHODS: Tca8113 cell lines were transfected with Ad p53. Then the effect of p53 overexpression on cancer cells proliferation and invasion was observed. The expression of mitogen-activated protein kinase (MAPK), serine/threonine kinase (AKT) signaling pathway related proteins, cell cycle and apoptosis related proteins Cyclin D1, P21 and Bcl-2 were detected by Western blotting analysis. RESULTS: After transfected with Ad-p53, the proliferation and invasion of Tca8113 cells were significantly inhibited (P < 0.01) and the apoptosis of Tca8113 cells significantly increased (P < 0.001). The results of Western blotting demonstrated that the protein expression of P53 and P21 significantly increased, Cyclin D1 and Bcl-2 protein expression and phosphorylation of AKT protein significantly decreased (P < 0.01). CONCLUSION: The AKT signaling pathway may be a key molecular mechanism for proliferation and invasion inhibition of oral squamous cell carcinoma caused by p53. The protein of Cyclin D1, P21 and Bcl-2 may be the downstream targets of AKT signaling pathway. This may provide a new evidence for AKT pathway and downstream targets as a promising therapeutic target for malignant tumors. PMID- 23662555 TI - [Three-dimensional finite element study on the change of glossopharyngeum in patient with obstructive sleep apnea hypopnea syndrome during titrated mandible advancement]. AB - OBJECTIVE: To construct a three-dimensional finite element model of the upper airway and adjacent structure of an obstructive sleep apnea hypopnea syndrome (OSAHS) patient for biomechanical analysis. And to study the influence of glossopharyngeum of an OSAHS patient with three-dimensional finite element model during titrated mandible advancement. METHODS: DICOM format image information of an OSAHS patient's upper airway was obtained by thin-section CT scanning and digital image processing were utilized to construct a three-dimensional finite element model by Mimics 10.0, Imageware 10.0 and Ansys software. The changes and the law of glossopharyngeum were observed by biomechanics and morphology after loading with titrated mandible advancement. RESULTS: A three-dimensional finite element model of the adjacent upper airway structure of OSAHS was established successfully. After loading, the transverse diameter of epiglottis tip of glossopharyngeum increased significantly, although the sagittal diameter decreased correspondingly. The principal stress was mainly distributed in anterior wall of the upper airway. The location of principal stress concentration did not change significantly with the increasing of distance. The stress of glossopharyngeum increased during titrated mandible advancement. CONCLUSION: A more precise three-dimensional finite model of upper airway and adjacent structure of an OSAHS patient is established and improved efficiency by Mimics, Imageware and Ansys software. The glossopharyngeum of finite element model of OSAHS is analyzed by titrated mandible advancement and can effectively show the relationship between mandible advancement and the glossopharyngeum. PMID- 23662556 TI - [The effect of modified bone morphogenetic protein-2 polylactic acid nanospheres sustained-release system on promoting mandibular defect repair]. AB - OBJECTIVE: To investigate the effect of modified bone morphogenetic protein-2 polylactic acid nanospheres (BMP-2-PLA-Ns) sustained-release system on rabbit mandibular defect repair. METHODS: The polylactic acid s nanospheres (PLA-Ns) and BMP-2-PLA-Ns were prepared by ultrasonic emulsification after graft polymerization. Forty-five rabbits were randomly divided into 3 groups: Blank group, PLA-Ns gel group(control group), and BMP-2-PLA-Ns gel group (experimental group). The rabbit mandibular defect models were established. The defect area of control group was implanted with PLA-Ns gel, meanwhile, the experimental group was implanted with BMP-2-PLA-Ns gel, the blank group experienced no special handling. Rabbits were killed in 1, 2, 4 weeks after operation and the iconography, hematine eosin(HE) staining and PCNA immunohistochemistry were used to detect the reparative effect on rabbit mandible defects. RESULTS: Image observation showed that bone defect repair in the experimental group was well and the shadow was not obvious. Better repair effect was seen compared with the control group and blank group. HE staining showed that the experimental group and the control group had a large number of neovascularization and secondary callus formation, callus in experimental group was obviously higher than that of control group and blank group. Immunohistochemical observation showed that the experimental group's PCNA positive chondrocytes were more than those in the control group and the blank group in the first 2 weeks; all groups of PCNA positive cells were rare in the fourth week, PCNA positive expression rate of the fourth week was lower than that of the first 2 weeks. CONCLUSION: The modified BMP-2-PLA-Ns sustained-release system promotes mandibular defect repair obviously. PMID- 23662557 TI - [Effects of different major connectors on pronunciation and comfort in Kennedy I dentition defect]. AB - OBJECTIVE: To analyze the effect on pronunciation and comfort level when 4 different major connectors (type 1: Palatal plate; type 2: Single palatal strap; type 3: Anterior-posterior joint palatal strap; type 4: Anterior-posterior joint palatal bar) were used in patients with Kennedy I deletion. METHODS: Tirty young volunteers were chosen to wear 4 different major connectors. The pronunciation of consonants /s/, /t/, /j/, /sh/ were detected and the different formant parameters(F1 and F2) were analyzed by the computer speech analytical system. The comfort levels of 4 major connectors were compared by questionnaire survey. RESULTS: 1)There was no significant difference(P5).05) in pronunciation of consonants /s/, /sh/, /t/(F1 and F2) among the 4 types of connectors whatever wearing or not, but there was significant difference (P < 0.05) in pronunciation of consonant /j/ among wearing type 3, type 4 and no wearing. 2)There was no significant difference in comfort level (P > 0.05) among the four connectors. CONCLUSION: The effect on pronunciation of patients with Kennedy I deletion was less when wearing the first and the second types of connectors than that of wearing the third and the fourth types of connectors. There was no significant difference in comfort level among the four connectors. PMID- 23662558 TI - [Comparative study on the penetration abilities of resin infiltration into proximal initial caries lesions in primary molars and permanent posterior teeth]. AB - OBJECTIVE: To compare the penetration abilities of resin infiltration into proximal lesions in primary molars and permanent posterior teeth in vitro. METHODS: Extracted or exfoliated primary molars (n = 32) and permanent posterior teeth (n = 36) with proximal white spot lesions were selected. Roots of the teeth were removed, and the crowns were cut across the caries lesions perpendicular to the surface. Cut surfaces were examined with stereo microscopy and classified with respect to histological lesion extension (C1-C4): Lesions confined to the outer half on enamel (C1), lesions confined to the inner half on enamel(C2), lesions confined to the outer half on dentin(C3), lesions extending into the inner half of dentin (C4). C4 were excluded. Caries lesions were etched for 2 min with 15% hydrochloric acid gel and were subsequently treated for 5 min with resin infiltration. Thin sections from each lesion were prepared and specimens were observed with confocal laser scanning microscopy (CLSM) through a dual fluorescence staining technique. Lesion depth (LD) and penetration depth (PD) of resin infiltration were measured in primary molars and permanent posterior teeth in confocal microscopic images, and percentage penetration (PP) were calculated respectively. The date were collected and analyzed. RESULTS: There were no significant differences for overall PP in primary molars and permanent posterior teeth groups (P > 0.05). However, the penetration abilities in primary molars were slight higher than those in permanent posterior teeth in C1 group (P < 0.05). The penetration abilities had no significant difference in primary molars and permanent posterior teeth in both C2 and C3 groups (P > 0.05). CONCLUSION: Resin infiltration have satisfied penetration abilities in primary molars and permanent posterior teeth with proximal initial lesions. The better penetration abilities of resin infiltration in primary molars are shown in Cl lesions than those in permanent posterior teeth. PMID- 23662559 TI - [New finding of the expression of human beta defensin-4 in healthy gingiva]. AB - OBJECTIVE: To investigate the expression and the distribution of human beta defensin (hBD)-4 in healthy gingiva. METHODS: Healthy gingival specimens were collected. The expression of hBD-4 peptides in 18 gingival specimens were detected by immunohistochemistry. The hBD-4 mRNA were determined in freshly isolated gingival tissue by real time reverse transcription-polymerase chain reaction (real time RT-PCR) in 30 gingival specimens. RESULTS: In 18 gingival specimens, hBD-4 peptides were expressed in 13 gingival specimens. In 30 gingival specimens, hBD-4 were detected in 4 gingival specimens by real time RT-PCR. CONCLUSION: The distribution and the expression levels of hBD-4 are different in healthy gingiva. This result may suggest that the hBD-4 play a role in maintaining the periodontal health. PMID- 23662560 TI - [Clinical application of transconjunctival approach to treat orbitozygomatic complex fractures]. AB - OBJECTIVE: To evaluate the effective of transconjunctival approach in treating orbitozygomatic complex fractures. METHODS: Fifty-four transconjunctival incisions were applied to correct enophthalmos and face collapse in 46 patients who suffered by orbitozygomatic complex fractures. All operative procedures were performed with an additional lateral canthotomy (5-10 mm) and 43 of them with gingivobuccal sulcus incisions simultaneously. The infraorbital rim and lateral orbital wall were stabilized with titanium plates. Titanium nets were used to reconstruct the comminuted orbit floor fractures. RESULTS: The bilateral zygomaticas of 46 cases with orbitozygomatic complex fractures were basically symmetric, and the eyeball positions were reset anatomically. The treatment effectiveness were satisfactory. There were no obvious postoperative complications, except one corneal epithelium stripped on the right side and one overtime swelling of conjunctiva which cured after relevant treatments. CONCLUSION: The transconjunctival approach has good exposure to the orbital floor without visible scar and injury to facial nerve branches, it is a preferable procedure to reconstruct orbitozygomatic fractures. PMID- 23662561 TI - [The influences upon the passive tensile of the masticatory muscles and ligaments by twin-block appliance under various bite reconstruction]. AB - OBJECTIVE: To study the regularity of the passive tensile of the masticatory muscles and ligaments by Twin-Block appliance under various bite reconstruction, and to provide some biomechanical references for the clinical use and improvement of Twin-Block appliance. METHODS: "Temporomandibular joint, mandible and Twin Block appliance" model was set up by the three dimensional finite element method, and the related masticatory muscles and ligaments were added on it. Seven experimental groups were designed according to the clinical and research, the occlusal inclined plate's angles of Twin-Block appliance were 40 degrees, 45 degrees, 50 degrees, 55 degrees, 60 degrees, 65 degrees and 70 degrees. The passive tensile in the masticatory muscles and ligaments were analyzed by the computer. RESULTS: Under various experimental groups, the passive tensile in the anterior deep masseter (AM), the posterior deep masseter (PM), the anterior temporalis (AT), the posterior temporalis (PT), the stylomandibular ligament and sphenomandibular ligament improved with the increased slant angles of occlusal guide. The maximum value of the passive tensile was 82.57 N, the minimum value was 0.07 N. CONCLUSION: 1) In various experimental groups, AT, AM, PM, PT, stylomandibular ligament and sphenomandibular ligament are subject to passive tension force in the process of Twin-Block appliance guiding the mandibular forward and play the important role on the remodeling of the mandible. 2)All groups of occlusal inclined plate's angle are in physiologically tolerable range and can be used in clinic. PMID- 23662562 TI - [Investigation and analysis on status quo of oral professional and technical personnel of Guyuan city, Ningxia]. AB - OBJECTIVE: To study the status quo of oral professional and technical personnel of Guyuan city, Ningxia. METHODS: In consultation with Administrative Department of Public Health, all oral health institutions by age, gender, education, professional, and department in four counties (Longde, Jingyuan, Pengyang and Xiji) and Yuanzhou district in Guyuan City were investigated. The distribution, basic information, professional branch, ratio with the amount of health system medical staff and population were analyzed. RESULTS: All comprehensive hospital at the county level and above set up department of stomatology. Center for Disease Control and Prevention, health inspection bureau, maternity and child health care bureau and 78.46% town health center didn't set up department of stomatology. Oral professional and technical personnel of Guyuan city in number was 115 and mainly young doctors, men were more than women. On education, the tertiary education was mostly received. On professional title, number of middle and senior professional title was relatively small. On profession, multi disciplinary was common. The ratio of oral professional to general medical staff were 1:30, to local population was 1:13 thousands. CONCLUSION: The education and professional title of oral professional and technical personnel should be improved. It is recommended that comprehensive hospitals above the county level should branch in Stomatology, Center for Disease Control and Prevention, health inspection bureau, maternity and child health care bureau and town health center should offer services of stomatology, at least provide one dental professional and technical personnel in each place. PMID- 23662564 TI - [Effects of non-saccharomyces albicans metabolic products on the proliferation of human umbilical vein endothelial cell ECV304]. AB - OBJECTIVE: To evaluate the effects of non-Saccharomyces albicans metabolic products on the cell cycle distribution and proliferation of human umbilical vein endothelial cell ECV304 cells in vitro. METHODS: The parallel dilution supernatant of Saccharomyces tropicalis, Saccharomyces krusei and Saccharomyces glabrata were prepared, and 1, 4, 16-fold(s) diluted concentration and control group were set up. The line of human umbilical vein endothelial cell ECV304 was cultured in vitro and treated by non-Saccharomyces albicans supernatant. The proliferous effect of ECV304 induced by non-Saccharomyces albicans supernatant after 24, 48, 72 h was detected by the methods of MTT, and the changes of cell density and cycle after 48 h were investigated by inverted microscope and flow cytometry. RESULTS: At the 24th hour, all of the higher concentration (1-fold) of non-Saccharomyces albicans supernatant and the 4-folds diluted Saccharomyces krusei could promote ECV304 proliferation(P < 0.05). After adding various non Saccharomyces albicans supernatant at 48h and 72th hour, Saccharomyces krusei supernatant and Saccharomyces glabrata supernatant significantly increased proliferation rate of ECV304, while Saccharomyces tropicalis supernatant group showed no significant change no matter which concentration was tested. At 48th hour after adding the non-Saccharomyces albicans supernatant, the ECV304 cells density treated by Saccharomyces krusei supernatant and Saccharomyces glabrata supernatant were significantly higher under the inverted microscope. The G0/G1 population of ECV304 cells decreased while cell proliferation index (PI) increased after incubated with Saccharomyces krusei supernatant and Saccharomyces glabrata supernatant for 48 hours (P < 0.05). Saccharomyces tropicalis group showed no significant change (P > 0.05). CONCLUSION: The metabolic products of Sacharoymces krusei and Saccharomyces glabrata could induce proliferation of ECV304 cell, which suggests non-Saccharomyces albicans should be undergone more attention clinically in detection and treatment. PMID- 23662563 TI - [A preliminary study on the consonant articulation of older patients with cleft palate]. AB - OBJECTIVE: To investigate the consonant pronunciation characteristics of older unoperated cleft palate patients. METHODS: One hundred unoperated cleft palate patients (more than 8 years old) were included. Subjective speech assessment was delivered to each patient. The incidence and distribution of varies consonant misarticulation errors consisting of manners and places of articulation were summarized. RESULTS: Consonant misarticulation existed among 86% of all cases. Compensatory misarticulation was observed in 66% patients, while 14% patients demonstrated completely normal articulation. The articulation manners of the highest correction rate, in succession, were nasals, lateral, fricatives, stops, and affricates. The error type of stops and affricates mainly consisted of compensation and omission. The articulation places of the highest correction rate, in succession, were bilabial, alveolar, linguadental, and velar. CONCLUSION: Compensatory, omission, and substitution, which happen in all the stops, fricatives and affricates, are the top three misarticulation. The misarticulation incidence of unaspirated sound is higher than that of aspirated. Compensatory errors a the most common ones in aspirated sounds, while omission and weak pressure are more frequent in unaspirated sounds. Weak pressure is mainly observed in unaspirated consonants. As the articulation spot move backward, the compensation of fricatives and stops deteriorate, the omission of affricates increase. PMID- 23662565 TI - [Expression of high mobility group box 1 in gingival tissues of chronic periodontitis]. AB - OBJECTIVE: To investigate the expression of high mobility group box 1 (HMGB1) in gingival tissues of chronic periodontitis. METHODS: Human peripheral blood mononuclear cells(PBMC) were stimulated with 1 microg x mL(-1) lipopolysaccharide (LPS) for 24 h or 48 h. Expression and release of HMGB1 were checked by immunofluorescence and enzyme-linked immunosorbent assay (ELISA), respectively. PBMC were stimulated with 100 ng x mL(-1) HMGB1 or 50 ng x mL(-1) tumor necrosis factor-alpha (TNF-alpha), the expressions of TNF-alpha and HMGB1 in the supernatant were studied by ELISA. Gingival tissues and gingival crevicular fluids (GCF) were collected from patients and healthy people. Expression of HMGB1 in gingival tissues and GCF was studied using immunofluorescence and ELISA, respectively. RESULTS: HMGB1 was translocated from nucleus to cytosol in PBMC after LPS stimulation for 24 h. The content of HMGB1 in the supernatant from stimulated cells was significantly higher than that from unstimulated cells after 48 h (P < 0.01). HMGB1 was released by PBMC in response to TNF-alpha stimulation, it also stimulated PBMC to release TNF-alpha (P < 0.01). Translocation of HMGB1 from nucleus to cytosol was also found in infiltrated cells in gingival tissues from patients, and HMGB1 in GCF from patients was significantly higher than that from healthy people P < 0.01). CONCLUSION: The results suggest that HMGB1 may play an important role in the pathological progress of chronic periodontitis. PMID- 23662566 TI - [Evaluation of two different cold plasma treatments on root canal infected with enterococcus faecalis biofilms]. AB - OBJECTIVE: To compare the bactericidal efficacy of two different cold plasma (glow discharge and dielectric barrier discharge) treatments on root canal infected with Enterococcus faecalis biofilms in vitro. METHODS: One hundred and twenty teeth infected with Enterococcus faecalis biofilm in the roots for seven days were divided into twelve groups randomly. Two served as negative control group (gas only, no discharge). Five were teeth treated by dielectric barrier discharge cold plasma and the other five were treated by glow discharge cold plasma. The treatment time in each five groups was 2, 4, 6, 8 and 10 min, respectively. The disinfection of Enterococcus faeccalis biofilm was evaluated by colony forming unit (CFU) counting. The plasma component produced by different devices was analyzed by optical emission spectroscopy (OES). RESULTS: Comparing the two plasma treatments, the plasma produced by dielectric barrier discharge had better bactericidal effect than that produced by glow discharge at different treatment time (P < 0.05). The advantage was obvious with the time getting longer. The OES indicated that active components of the two type plasmas were similar. But the peak of excited Ar atom of dielectric barrier discharge was twice as that of glow discharge. CONCLUSION: The cold plasma produced by dielectric barrier discharge has more bactericidal efficiency in the treatment of root canal infected with Enterococcus faecalis biofilms. PMID- 23662567 TI - [Effect of Osterix overexpression on osteogenic differentiation of human periodontal ligament cells]. AB - OBJECTIVE: To investigate the effects of Osterix (Osx) overexpression on the osteogenic differentiation of human periodontal ligament cells in response to mechanical force. METHODS: Human periodontal ligament cells were isolated and cultured in vitro with explant method. Cells were transfected with either an Osx expression vector pcDNA3.1 flag-Osx or the mock control vector pcDNA3.1 flag. Then, cells were centrifuged for 6 h. After transfection and centrification, the expression of Osx mRNA and protein in untransfected cells, mock-transfected cells and Osx-transfected cells were measured by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot respectively. Furthermore, the changes of mRNA expressions of core-binding factor cal (Cbfal), alkaline phosphatase (ALP), osteopontin (OPN), osteocalcin (OC), bone sialoprotein(BSP) and collagen protein al (Col I ) genes were measured to assess the differentiation of human periodontal ligament cells. RESULTS: At 24 h after transfection, Osx mRNA and protein level increased significantly in Osx-transfected cells (P < 0.01), while there were no significant difference in Osx mRNA and protein levels between mock transfected cells and untransfected cells(P > 0.05). Simultaneously, the upregulated mRNA expressions of all the five osteogenic genes were observed (P < 0.05, P < 0.01). After 6 h of mechanical stimulation, a significant increase in Osx expression was shown in all three groups. However, compared to mock transfected and untransfected cells, Osx-transfected cells further showed the highest Osx mRNA and protein expression level. Furthermore, the mRNA expressions of all five osteogenic markers in Osx-transfected cells also exhibited the greater increase and showed the highest levels. CONCLUSION: The overexpression of Osx promotes the mechanical stress-induced osteogenic differentiation of human periodontal ligament cells. Osx may be essential for mechanical stress-induced differentiation of human periodontal ligament cells to osteoblas tic-like cells and be involved in orthodontic osteogenic remodeling. PMID- 23662569 TI - [Mucinous adenocarcinoma of salivary gland: a case report]. AB - Mucinous adenocarcinoma is a rare epithelial malignant tumor which usually arises in appendix, pancreas, breast and other sites, rarely occurs in salivary gland. In this article, a mucinous adenocarcinoma of salivary gland was reported and relevant literatures were reviewed. PMID- 23662568 TI - [Histological study of dual factor inducing axial vascularization in double layered scaffold]. AB - OBJECTIVE: To construct an double-layered tube-shaped poly (lactic-co-glycolic acid) (PLGA) scaffold composited with vascular endothelial growth factor (VEGF)/ platelet-derived growth factor (PDGF), and to evaluate in vivo the axial vascularization from femoral arteriovenous bundle encapsulated. METHODS: Eighteen male adult New Zealand rabbits were assigned randomly into 3 groups: Experimental group (n = 8), experimental control group (n = 8), empty control group (n=2). The femoral arteriovenous bundle were separated and encapsulated in double-layered tubeshaped PLGA scaffold prepared by solution casting and particle leaching. According to the way of cell factors being composited to the prepared double layered scaffold: 1) experimental group: VEGF in inner layer and PDGF in outer layer; 2) experimental control group: VEGF in inner layer with blank outer layer; 3) empty control group: Pure blank. Specimens were retrieved at 7, 10, 14, 21 days postoperatively (7, 10 days in empty control group). The histological evaluation was performed. RESULTS: At 7 days postoperatively, blood vessel sprouts were observed in experimental group and experimental control group, radially from the central femoral arteriovenous bundle. At 10 days postoperatively, completely penetrations of the double-layered scaffold by abundant new generated blood vessel sprouts were observed, and density descended gradiently from inside to outside. At 14 days postoperatively, new blood vessels in experimental group showed more thickness and layered structure of the wall, while monolayer endothelial cells in experimental control group. At 21 days postoperatively, new blood vessels in experimental group showed more mature characteristics, while less density of blood vessels in experimental control group. There was no obvious blood vessel structure in empty control group. CONCLUSION: The double-layered tube-shaped PLGA scaffold composited with VEGF/PDGF could induce early angiogenesis. PMID- 23662570 TI - [Chronic periapical periodontitis of left maxillary first premolar with localized mineralized structure at periapical region: a case report]. AB - Chronic periapical periodontitis is characterized by destruction of periapical tissue and demonstrates translucent feature under X-ray examination. In this article, a localized mineralized structure, which showed high density under X-ray examination, was reported in a patient with chronic periapical periodontitis of left maxillary first premolar. Possible causes of the structure were analyzed and relevant literatures were reviewed. PMID- 23662571 TI - [Gingival health and esthetics--another aspect of objectives of orthodontic treatment]. AB - Contemporary orthodontic care should be a team approach to achieve health and esthetics of soft and hard tissue. It should be given enough attention that periodontal health provides the foundation for tooth movement, and that distinct esthetic results can be achieved by subtle changes in tooth alignment and gingival contours. Orthodontic treatment planning should include evaluation of gingival health and esthetics to anticipate the need for interdisciplinary approaches. Studies on the effect of orthodontic treatment on gingiva can provides basis for maintaining gingival health and esthetic. This article will focus primarily on the gingival health and esthetic care in orthodontic treatment. PMID- 23662572 TI - [The novel species and genus discovered and nominated from the human oral cavity in 2009--2012]. AB - Bacterium is dominant microflora population in human oral cavity, and the novel species and novel genus were discovered and named one after another. This article reviewed the major biological characteristics of 5 novel genus and 16 novel species isolated from the human oral cavity from 2009 to 2012. PMID- 23662573 TI - [Menstrual blood stem cells as a potential substrate of cell therapy]. AB - Cell replacement and restorative therapies have great perspectives in the treatment of various diseases and traumas. Various types of stem cells, most different in the biological properties, are evaluated as the potential substrates of cell therapy for such diseases. Mesenchymal stem cells (MSC) posses relatively high proliferative activity and high level of plasticity, and can be differentiated not only to the cells of the mesenchymal lineage, but also to the neurons. Among the MSC populations, a population of endometrial stem cells, including that present in the menstrual blood, is available most readily. In the current study, we analyze biological properties of the menstrual blood stem cells and evaluate those cells as a potential substrate of cell therapy. PMID- 23662574 TI - [Optional protocols of hematopoietic stem cell expansion in vitro]. AB - Hematopoietic stem cells (HSC) effectively and continuously renew a full spectrum of blood cell populations. Bone marrow and umbilical cord blood stem cells transplantation (SCT) restore hematopoietsis, when used in various hematological and oncohematological disorders in adults and children. However, wider clinical application of effective SCT-based approaches is limited by the low number of the primitive HSC in the available biospecimens. Development of effective protocols for HSC expansion in vitro is therefore necessary. In this review, a concept of bone marrow hematopoiesis niche being a complex cellular system is discussed; a comparative analysis of various methods for HSC expansion in vitro is provided. The review is illustrated by the authors own data supporting application of various feeder cell types for human HSC expansion in vitro. PMID- 23662575 TI - [C-peptide structure, functions and molecular mechanisms of action]. AB - C-peptide, which is formed during the biosynthesis of insulin, has long been considered as a biologically inactive substance. However in the recent years there is convincing evidence that the deficit of C-peptide in type 1 diabetes mellitus (DM) or its excess in DM2 lead to the development of disorders in the cardiovascular, nervous, excretory, and other systems of organism. It is shown than C-peptide in the physiological concentrations has anti-inflammatory, immunomodulatory and neuroprotective effects, so that it and its synthetic analogs can be widely used to treat diabetic patients and to prevent DM complications diabetes. To effectively use C-peptide in medicine it is necessary to study its structural-functional organization and the molecular mechanisms of regulatory action of C-peptide on the fundamental cellular processes. It is established that C-peptide coupled with Gi/o protein-coupled receptors of the serpentine type regulates the functional activity of many intracellular signaling pathways, which include phospholipase Cbeta, different forms of protein kinase C, phosphatidylinositol 3-kinases and mitogen-activated protein kinases, endothelial NO-synthase, Na+/K+-ATPase, a wide range of transcription factors and nuclear receptors. C-peptide controls the stability of the insulin hexamer complexes, and, thus,affects on the activity of insulin and insulin-regulated signaling pathways. The present review analyse the current state of the problem of structural-functional organization of C-peptide and its mechanism of action on the intracellular signaling pathways, as well as the prospects for the use of C peptide in the fundamental biology and clinical medicine. PMID- 23662576 TI - [Actin cytoskeleton rearrangements during the gravitropic response of Arabidopsis roots]. AB - Gravitropic response is a plant growth response against changing its position relative to the gravity vector. In the present work we studied actin cytoskeleton rearrangements during Arabidopsis root gravitropic response. Two alternative approaches were used to visualize actin microfilaments: histochemical staining of fixed roots with rhodamine-phalloidin and live imaging of microfilaments in GFP fABD2 transgenic plants. The curvature of actin microfilaments was shown to be increased within 30-60 min of gravistimulation, the fraction of auxially oriented microfilaments decreased with a concomitant increase in the fraction of oblique and transversally oriented microfilaments. Methodological issues of actin cytoskeleton visualization in the study of Arabidopsis root gravitropic response, as well as the role of microfilaments at the stages of gravity perception, signal transduction and gravitropic bending formation are discussed. It is concluded that the actin cytoskeleton rearrangements observed are associated with the regulation of basic mechanisms of cell extension growth by which the gravitropic bending is formed. PMID- 23662578 TI - [Influence of mesenchymal stromal cells on B-cell line growth and immunoglobulin synthesis]. AB - A number of publications contain contradictory data about influence of mesenchymal stromal cells (MSC) on B-lymphocyte growth, differentiation and production of immunoglobulins (Ig). The aim of the study was to investigate the influence of MSC derived from adipose tissue of healthy donors and cancer patients on the proliferation and Ig synthesis of lymphoblastoid cell line Namalva and myeloma cell line U266. Co-cultivation of Namalva cells with MSC stimulated their proliferation, decreased the doubling time and the minimal effective seeding dose and therefore made cloning of these lymphoblastoid cells possible. The presence of MSC supported the survival and proliferation of Namalva cells cultivated in growth factor deficient medium. MSC also stimulated proliferation of U266 myeloma cells. Both MSC derived from adipose tissue from the healthy donors and from patients with breast cancer effectively stimulated B cell lines proliferation. Presence of MSC in mixed cultures had no influence on the production of IgM or IgE by Namalva or U266 cells respectively. Co cultivation of Namalva or U266 with MSC resulted in the formation of close intercellular contacts between cells of both types. PMID- 23662577 TI - [Zajdela hepatoma cells cultured in vitro]. AB - Two continuous cell lines, monolayer (ZH-ad) and suspension (ZH-fl), which doffer in the level of cell differentiation and tumorigenicity, were obtained from explants of ascitic Zajdela hepatoma. Using tumor-specific rabbit immune serum tumor-associated antigens were detected in the fraction of plasma membrane of ZH fl cells, synthesis of that was reduced or suppressed in ZH-ad cells. Intraperitoneal injection of ZH-fl cells as few as 0.5 - 10(6) cells/rat was enough for development of ascites tumor, while minimal dose for ZH-ad cells increase to 20 - 10(6) cells. Three types of generated clones were revealed by means of clonogenic analysis of ZH-fl cells: nonadhesive sphere colonies and two types of monolayer clones ranging in proliferative potential, shape of colonies and cell composition. When the spherical colonies had reached a critical size they disintegrated with dissociation of single cells or islets of various sizes, part of which attached to the plate to form a monolayer. Three clonal cell lines were obtained: IC - as a result of expansion of sphere clone cells, 4G and 10E - from monolayer clones. Our results demonstrate a clonogenic origin of multicellular islets of ascetic hepatoma Zajdela. PMID- 23662579 TI - [Cytophotometric determination of genome size in two species of Cyclops Lake Baikal (Crustacea: Copepoda: Cyclopoina) in ontogenetic development]. AB - Genome size of Cyclops in cells at early stages of cleavage (up to the 5th division) and in somatic cells were estimated by a static digital Feulgen cytophotometry in order to study the quantitative changes in DNA content during chromatin diminution. Our realization of the cytophotometric method was approbeted on five different digital-imaging systems in blood cells of four vertebrate species. In all cases, we observed a direct correlation of the obtained and known from the literature data on the genome size and a high reproducibility, which allows to use these systems in future work. We also optimized the conditions for DNA hydrolysis of both blood smears, and for two species of Cyclops from the Moscow population, as 30 min in 5 N HCl at 24 degrees C. Here we first revealed chromatin diminution in two endemic Baikal species of Cyclopoida: Acanthocyclops incolotaenia and Diacyclops galbinus estimated the extent ofchromatin diminution in Diacyclops galbinus as 95.5-96.2 %. Cytometric analysis of the third species, Mesocyclops leuckarti, did not reveal obvious chromatin diminution. We also optimized the conditions for DNA hydrolysis of both blood smear preparations, and for two species of copepods from the Moscow population, as 30 min in 5N HCl at 24 degrees C. PMID- 23662580 TI - [Influence of antibodies to DNA on MDCK cells and their intracellular localization]. AB - Objects of the study were highly purified by liquid chromatography antibodies to DNA (IgG class) from the blood serums of healthy donors, patients with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), and clinically healthy relatives of RA patients. It has been shown that, depending on the pathology, these antibodies differ in the DNA-hydrolyzing activity and differently affect the number of viable cells, morphology and chromatin of MDCK cells after co culture. The antibodies to DNA were located in the area of nuclei. Biological role of the antibodies to DNA is discussed. PMID- 23662581 TI - [Mesenchymal stem cells of human endometrium do not undergo spontaneous transformation during long-term cultivation]. AB - Mesenchymal stem cells isolated from human endometrium (eMSC) are perspective source of stem cells for regenerative medicine. Large amount of these cells accumulated by in vitro cultivation is usually required for transplantation into patients. We established several cell eMSC lines and cultivated them during long period of time to examine the possibility of their spontaneous transformation. All cell lines demonstrate limited lifespan, undergo replicative senescence and die. Karyotypic analysis on different passages reveals that most cells display karyotypic stability. Thus, extended in vitro cultivation of eMSCs does not lead to spontaneous transformation that makes therapeutic application of these cells safety for patients. During long-term cultivation eMSCs sustain the expression of surface markers. PMID- 23662582 TI - [The use of mathematical models to describe the kinetics of human neutrophils attachment to the substrate in vitro]. AB - The kinetics of morphometric parameters (perimeter, square, compactness) of human blood neutrophils, which attached to a glass slide, was described by the equations similar to the kinetic equations of the first order irreversible reactions. The calculated values of morphometric parameters of neutrophils in suspension, and attached ones are consistent to literature data. It was found that the compactness of neutrophils does not change in the process of the attachment. Time of termination in the process of attachment was found using the kinetic equations and amount to about 3 h. PMID- 23662583 TI - Advance in novel boron nitride nanosheets to nanoelectronic device applications. AB - We report low-temperature synthesis of large-scale boron nitride nanosheets (BNNSs) and their applications for high-performance Schottky diode and gas sensor. Ten minutes of synthesis with a short-pulse-laser-produced plasma deposition technique yields a large amount of highly flat, transparent BNNSs. A basic reason for using short-pulse plasma beams is to avoid nanosheet thermal ablation or have low heat generated. Consequently, it greatly reduces the stress and yield large, flat BNNSs. The average size of obtained BNNS is around 10 MUm and thickness is around 1.7 nm. Carbon element has been used for doping BNNSs and achieving BNNSs-based Schottky diode and gas sensing device. Typical current versus voltage characteristics of diode are examined. The breakdown reverse voltage is around -70 V. This probably indicates that the breakdown electric field of BNNSs-based diode is up to 1 * 10(8) V/cm. Sensing behavior of BNNSs based gas sensor toward methane diluted with dry air is also characterized. The response time and recovery time are around 3 and 5 s at the operating temperature of 150 degrees C. Relatively, the sensor has poor sensitivity to oxygen gas. PMID- 23662584 TI - Oxygen isotope indicators of selenate reaction with Fe(II) and Fe(III) hydroxides. AB - Selenate (SeO(4)(2-)) reduction to elemental selenium is an important Se immobilization process in subsurface environments that could be mediated by Fe(II)-rich minerals or selenate-respiring microorganisms. We report the kinetic isotope effects for (18)O within selenate during abiotic reactions with iron bearing hydroxides within laboratory experiments. Selenate was reduced to Se(0) by a green rust (chloride interlayer type) and ferrous hydroxide, the two known environmentally relevant mineral reductants for selenate. Reaction kinetics are described by a rapid, low-fractionating uptake step caused by diffusive exchange between selenate and chloride followed by a slower, high-fractionating reduction step caused by electron transfer from structural Fe(II). The dual-phase kinetics cannot be described with the traditional Rayleigh fractionation model; however, well after the initial uptake step, the extent of selenate reaction is well correlated with delta(18)O values in accordance with the Rayleigh model. Selenate (18)O enrichment (epsilonO) was nearly identical for reaction with chloride green rust (22.7 +/- 2.20/00) and ferrous hydroxide (22.1 +/- 1.10/00) which suggests a common reduction mechanism by structural Fe(II). The minor enrichment due to anion exchange alone (1.4 +/- 0.20/00) was confirmed using iowaite, a nonredox active Mg(II)-Fe(III) layered double hydroxide. Our epsilonO results may contribute to Se isotope forensics to identify selenate reduction within field sites and to possibly distinguish between abiotic and biotic reduction processes. PMID- 23662585 TI - Capillary electrophoresis-systematic evolution of ligands by exponential enrichment selection of base- and sugar-modified DNA aptamers: target binding dominated by 2'-O,4'-C-methylene-bridged/locked nucleic acid primer. AB - Chemically modified DNA aptamers specific to human alpha-thrombin were obtained from oligodeoxyribonucleotide (ODN) libraries by using a capillary electrophoresis-systematic evolution of ligands by exponential enrichment (CE SELEX) method. These libraries contained 2'-O,4'-C-methylene-bridged/linked bicyclic ribonucleotides (B/L nucleotides) in the primer region and/or C5 modified thymidine bearing N(6)-ethyladenine (t) in the nonprimer region. Modified DNA aptamers showed high binding affinities to the target, with dissociation constants (Kd) values in the range of subnanomolar to several ten nanomolar levels. The introduction of base modification significantly suppressed the frequency of G-quadruplex motifs, which are often seen in thrombin-binding DNA aptamers. The resulting alternatives contained the 10-mer consensus sequence t5Gt2G2, which is frequently found in modified DNA aptamers with subnanomolar protein binding affinities. Furthermore, some base- and sugar-modified DNA aptamers with the 12-mer consensus sequence t2G2tC(A/G)A2G2t displayed binding activities that were dependent on the presence of B/L nucleotides in the primer region. Such aptamers were interestingly not recovered from a natural DNA library or from DNA libraries modified with either B/L nucleotides or t's. This emerging characteristic binding property will enable the creation of a direct selection methodology for DNA-based molecular switches that are triggered by chemical conversion of B/L nucleotides introduced to constant sequence regions in ODN libraries. PMID- 23662586 TI - Isomer-selective detection of hydrogen-bond vibrations in the protonated water hexamer. AB - The properties of hydrogen ions in aqueous solution are governed by the ability of water to incorporate ions in a dynamical hydrogen bond network, characterized by a structural variability that has complicated the development of a consistent molecular level description of H(+)(aq). Isolated protonated water clusters, H(+)(H2O)n, serve as finite model systems for H(+)(aq), which are amenable to highly sensitive and selective gas phase spectroscopic techniques. Here, we isolate and assign the infrared (IR) signatures of the Zundel-type and Eigen-type isomers of H(+)(H2O)6, the smallest protonated water cluster for which both of these characteristic binding motifs coexist, down into the terahertz spectral region. We use isomer-selective double-resonance population labeling spectroscopy on messenger-tagged H(+)(H2O)6.H2 complexes from 260 to 3900 cm(-1). Ab initio molecular dynamics calculations qualitatively recover the IR spectra of the two isomers and allow attributing the increased width of IR bands associated with H bonded moieties to anharmonicities rather than excited state lifetime broadening. Characteristic hydrogen-bond stretching bands are observed below 400 cm(-1). PMID- 23662587 TI - Paracrine cytokine mechanisms underlying the hyperpigmentation of seborrheic keratosis in covered skin areas. AB - We previously reported that increased expression of the endothelin (EDN)1/EDNB receptor (EDNBR) as well as the stem cell factor (SCF)/SCF receptor (c-KIT) linkages is mainly responsible for the activation of melanocytes in the epidermal hyperpigmentation of ultraviolet (UV)-B melanosis and lentigo senilis (LS). In this study, we characterized seborrheic keratosis (SK) to examine the paracrine cytokine mechanism(s) involved in its epidermal hyperpigmentation by reverse transcription polymerase chain reaction, immunohistochemistry and western blotting analyses. In contrast to our previous study which showed the upregulated expression of EDN1 and EDNBR at the transcriptional and translational levels in the epidermis of SK, we observed unexpectedly that the cytokine SCF and its receptor c-KIT are not upregulated, but are downregulated at both the gene and protein levels. We established SK cell lines to examine whether SK basaloid cells are less sensitive to SCF-inducible stimulation than are normal human keratinocytes (NHK). Comparison of the stimulatory effects of interleukin (IL) 1alpha or tumor necrosis factor (TNF)-alpha on SCF production between SK cells and NHK demonstrated that SK cells do not respond to IL-1alpha or TNF-alpha to stimulate production of SCF, whereas a significant stimulation of SCF is elicited by those same cytokines in NHK. These finding underscore a role of phenotypic changes in melanogenic cytokine production in the epidermis between SK and LS/UV B melanosis. PMID- 23662588 TI - Molecular dynamics simulations of membrane-sugar interactions. AB - It is well documented that disaccharides in general and trehalose (TRH) in particular strongly affect physical properties and functionality of lipid bilayers. We investigate interactions between lipid membranes formed by 1,2 dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and TRH by means of molecular dynamics (MD) computer simulations. Ten different TRH concentrations were studied in the range wTRH = 0-0.20 (w/w). The potential of mean force (PMF) for DMPC bilayer-TRH interactions was determined using two different force fields, and was subsequently used in a simple analytical model for description of sugar binding at the membrane interface. The MD results were in good agreement with the predictions of the model. The net affinities of TRH for the DMPC bilayer derived from the model and MD simulations were compared with experimental results. The area per lipid increases and the membrane becomes thinner with increased TRH concentration, which is interpreted as an intercalation effect of the TRH molecules into the polar part of the lipids, resulting in conformational changes in the chains. These results are consistent with recent experimental observations. The compressibility modulus related to the fluctuations of the membrane increases dramatically with increased TRH concentration, which indicates higher order and rigidity of the bilayer. This is also reflected in a decrease (by a factor of 15) of the lateral diffusion of the lipids. We interpret these observations as a formation of a glassy state at the interface of the membrane, which has been suggested in the literature as a hypothesis for the membrane-sugar interactions. PMID- 23662589 TI - Tumors masquerading in patients with thyroid eye disease. AB - Thyroid eye disease (TED) is the most common cause of proptosis in adults. The external manifestations of TED are characteristic and the diagnosis is typically made without imaging. Although there are multiple descriptions of primary and secondary orbital tumors initially mistaken for TED in the literature, there are limited reports detailing the findings of patients with long-standing TED whom developed an orbital tumor at a later date. Herein, we present a 6-year retrospective multi-center report of three patients with long-standing TED who developed an initially unsuspected orbital or cavernous sinus tumor. PMID- 23662590 TI - Bradyarrhythmias and pacemaker therapy in dogs with Chagas disease. AB - BACKGROUND: Chagas disease (Trypanosomiasis) is a cause of myocarditis in the southern United States causing cardiac conduction abnormalities, arrhythmias, and heart failure. OBJECTIVES: To report clinical findings and outcome in Chagas positive (CP) dogs requiring pacemaker implantation for bradyarrhythmias. ANIMALS: One hundred and forty-four client-owned dogs requiring pacemaker implantation. METHODS: Retrospective case series. Information regarding history, physical exam, laboratory and diagnostic imaging findings, treatment, and survival were obtained from medical records, with additional follow-up information obtained by contacting referring veterinarians and owners. RESULTS: Of the 144 dogs requiring pacemaker implantation from January 2001 to May 2010, 83 (57.6%) had a Chagas titer performed and 9 (10%) were CP. Concurrent ventricular arrhythmias (odds ratio 1.61, P = .005) or atrioventricular (AV) block (odds ratio 4.18, P < .001) increased the likelihood that a Chagas titer was submitted. Median age for CP dogs was 6.2 years (range, 0.3-10); 7 were male. Bradyarrhythmias included high-grade 2nd or 3rd degree AV block (n = 8) and sinus bradycardia with 1st degree AV block (n = 1); 5 had concurrent ventricular arrhythmias. A positive Chagas titer had a negative impact on survival (hazard ratio 4.04; 95% CI 1.36-12.1, P = .012) with a reported median survival time of 365 days (interquartile range, 84-973 days). CONCLUSIONS AND CLINICAL IMPORTANCE: Bradyarrhythmias can result in clinical signs requiring pacemaker implantation in CP dogs, and although the diagnosis negatively impacts survival, pacemaker therapy is a viable treatment option. PMID- 23662591 TI - A focus on Trotula de Ruggiero: a pioneer in women's and children's health in history of medicine. AB - Trotula de Ruggiero was the first female physician in history of medicine and her role at Medical School of Salerno. Her reputation in the Middle Ages was so important that her theoretical manuscripts were diffused in all European universities and laid the foundations for modern medicine. Of note, Trotula deepened medicine as an eternal dichotomy between art and science, narrative and evidence. In particular, she spent all her life in treating children's diseases, exhibiting a kind of emotional, cultural and spiritual maternity of inestimable value. PMID- 23662593 TI - Students entering internship show readiness in the nutrition care process. AB - BACKGROUND: The British Dietetic Association and the International Confederation of Dietetic Associations are developing an international model for dietetics practice as an aid in providing evidence-based practice. In the USA, undergraduate programmes are mandated by the Academy of Nutrition and Dietetics (formerly the American Dietetic Association) to incorporate the nutrition care process (NCP) into the curriculum so that students can use the process during their dietetic internship and later practice. The present study aimed to assess interns' readiness in the NCP prior to beginning a dietetic internship. METHODS: Before starting the internship, the 40 interns in the 2009-2010 class of a university-based internship were sent an e-mail requesting they complete an online survey. Questions inquired about their NCP background with respect to: academic preparation, work or volunteer experiences, knowledge and confidence in ability to apply the NCP. Survey results were analysed with SPSS statistical software (SPSS Inc., Chicago, IL, USA). RESULTS: The 39 interns completing the survey indicated they had prior exposure to the NCP. All but one reported that their academic coursework covered the NCP. Approximately half of the interns worked or volunteered in settings that used the NCP. Overall, students correctly answered most of the questions assessing their basic knowledge in the NCP. Thirty seven of the 39 interns had some confidence or felt confident in their ability to apply the NCP during internship rotations. CONCLUSIONS: This distance internship attracts students from all over the USA, and so the findings of the present study shed light on current undergraduate preparation in the NCP. PMID- 23662592 TI - Arabidopsis FRS4/CPD25 and FHY3/CPD45 work cooperatively to promote the expression of the chloroplast division gene ARC5 and chloroplast division. AB - ARC5 is a dynamin-related GTPase essential for the division of chloroplasts in plants. The arc5 mutant frequently exhibits enlarged, dumbbell-shaped chloroplasts, indicating a role for ARC5 in the constriction of the chloroplast division site. In a screen for chloroplast division mutants with a phenotype similar to arc5, two mutants, cpd25 and cpd45, were obtained. CPD45 was identified as being the same gene as FHY3, a key regulator of far-red light signaling recently shown to be involved in the regulation of ARC5. CPD25 was previously named FRS4 and is homologous to FHY3. We found that CPD25 is also required for the expression of ARC5, suggesting that its function is not redundant to that of FHY3. Moreover, cpd25 does not have the far-red light sensing defect present in fhy3 and far1. Both FRS4/CPD25 and FHY3/CPD45 could bind to the FBS-like 'ACGCGC' motifs in the promoter region of ARC5, and the binding efficiency of FRS4/CPD25 was much higher than that of FHY3/CPD45. Unlike FHY3/CPD45, FRS4/CPD25 has no ARC5 activation activity. Our data suggest that FRS4/CPD25 and FHY3/CPD45 function as a heterodimer that cooperatively activates ARC5, that FRS4/CPD25 plays the major role in promoter binding, and that FHY3/CPD45 is largely responsible for the gene activation. This study not only provides insight into the mechanisms underlying the regulation of chloroplast division in higher plants, but also suggests a model that shows how members of a transcription factor family can evolve to have different DNA-binding and gene activation features. PMID- 23662594 TI - Getting a grip on the evolution of grasping in musteloid carnivorans: a three dimensional analysis of forelimb shape. AB - The ability to grasp and manipulate is often considered a hallmark of hominins and associated with the evolution of their bipedal locomotion and tool use. Yet, many other mammals use their forelimbs to grasp and manipulate objects. Previous investigations have suggested that grasping may be derived from digging behaviour, arboreal locomotion or hunting behaviour. Here, we test the arboreal origin of grasping and investigate whether an arboreal lifestyle could confer a greater grasping ability in musteloid carnivorans. Moreover, we investigate the morphological adaptations related to grasping and the differences between arboreal species with different grasping abilities. We predict that if grasping is derived from an arboreal lifestyle, then the anatomical specializations of the forelimb for arboreality must be similar to those involved in grasping. We further predict that arboreal species with a well-developed manipulation ability will have articulations that facilitate radio-ulnar rotation. We use ancestral character state reconstructions of lifestyle and grasping ability to understand the evolution of both traits. Finally, we use a surface sliding semi-landmark approach capable of quantifying the articulations in their full complexity. Our results largely confirm our predictions, demonstrating that musteloids with greater grasping skills differ markedly from others in the shape of their forelimb bones. These analyses further suggest that the evolution of an arboreal lifestyle likely preceded the development of enhanced grasping ability. PMID- 23662595 TI - Developing web-based Triple P 'Positive Parenting Programme' for families of children with asthma. AB - BACKGROUND: We examined the feasibility of self-directed Triple P 'Positive Parenting Programme' for optimizing parents' management of childhood asthma and behaviour. METHODS: Eligible families were invited to access asthma-specific web based Triple P as part of a preliminary randomized controlled study. RESULTS: Initial study information and introductory website pages received considerable interest but intervention uptake was poor with high rates of attrition. CONCLUSIONS: Although parents of children with asthma show willingness to access web-based parenting support, further work is necessary to develop engaging websites and determine barriers to uptake, and adherence to online parenting interventions with this population. PMID- 23662597 TI - Theory of mind performance in women with posttraumatic stress disorder related to childhood abuse. AB - OBJECTIVE: Key questions remain unaddressed concerning the nature of interpersonal functioning in trauma survivors, including the ability to understand and interpret other people's thoughts and feelings. Here, we investigate theory of mind (ToM) performance of women with PTSD related to childhood abuse in comparison to healthy controls. METHOD: Participants completed two ToM tasks, the Interpersonal Perception Task-15 (IPT-15) and the Reading the Mind in the Eyes Task - Revised (RMET). RESULTS: Relative to controls, women with a history of childhood trauma had difficulty recognizing familial relationships depicted in the IPT-15 (P = 0.005). No other category of the IPT-15 showed significant group differences. In addition, while healthy women displayed faster RMET reaction times to emotionally valenced mental states (positive: P = 0.003; negative: P = 0.016) compared with neutral mental states, the PTSD group showed similar reaction times across all valences. The presence of dissociative symptoms (e.g., disengagement, amnesia, identity dissociation) was strongly associated with hindered accuracy of complex mental state identification and altered perception of kinship interactions. CONCLUSION: Women with PTSD stemming from childhood trauma show changes in ToM abilities particularly those often involved in the interpretation of family interactions. In addition, individuals with PTSD showed slower reaction times during the recognition of complex mental states from emotionally salient facial/eye expressions in comparison with healthy subjects. PMID- 23662596 TI - Two new compounds from Khaya senegalensis. AB - Two new compounds, khayseneganin I (1) and 2alpha,3alpha,16beta-trihydroxy-20 acetoxy-20(R)-pregnane (2), along with six known compounds, 2alpha,3alpha,20 trihydroxy-16beta-acetoxy-20(R)-pregnane (3), 2alpha,3beta-dihydroxypregnan-16 one-2beta,19-hemiketal (4), (+)-catechin (5), ivorenolide A (6), luteolin-7-O alpha-l-rhamnoside (7), and ( - )-5'-methoxy-isolariciresinol-2a-O-beta-d xylopyranoside (8), were isolated from the leaves and twigs of Khaya senegalensis. The structures of new compounds were elucidated by 2D NMR spectroscopy and MS. Selected compounds (2-8) were evaluated for their antimicrobial activities and compounds 5 and 7 showed weak antimicrobial activities against MRSA 92(#) and MRSA 98(#). PMID- 23662598 TI - TAM receptors in apoptotic cell clearance, autoimmunity, and cancer. AB - Receptor tyrosine kinases, Tyro-3, Axl and Mer, collectively designated as TAM, are involved in the clearance of apoptotic cells. TAM ligands, Gas6 and Protein S, bind to the surfaces of apoptotic cells, and at the same time, interact directly with TAM expressed on phagocytes, impacting the engulfment and clearance of apoptotic cells and debris. The well-tuned and balanced actions of TAM may affect a variety of human pathologies including autoimmunity, retinal degeneration, and cancer. This article emphasizes some of the emerging findings and mechanistic insights into TAM functions that are clinically relevant and possibly therapeutically targeted. PMID- 23662599 TI - Efficacy of cyclo-oxygenase inhibition by two commercially available firocoxib products in horses. AB - REASONS FOR PERFORMING STUDY: Two firocoxib preparations for oral use are approved for use in animals in many countries: a chewable canine tablet and an equine paste. In order to reduce costs, many veterinarians use the canine product in horses even though this is an off-label use of the preparation. OBJECTIVE: To determine the relative efficacy of 2 commercially available firocoxib products to inhibit prostaglandin E2 (PGE2) synthesis after oral dosing in horses. STUDY DESIGN: A crossover design using 8 adult horses (n = 4 for each preparation during each treatment period). Body weight range 532-614 kg. METHODS: Horses received 57 mg of the assigned firocoxib preparation orally once daily for 7 days, with a 14 day washout period between drug crossover. Ten healthy adult light breed horses were used as no-treatment controls. During each treatment period, blood was taken before dosing on Days 0 and 7 and on Day 7 1 h after dosing for ex vivo lipopolysaccharide (LPS) stimulation to induce (PGE2 ) synthesis. Heparinised plasma was also collected on Day 7 immediately prior to and 1 h after dosing to determine plasma firocoxib concentrations. RESULTS: In the control group, there was no significant change in LPS-induced PGE2 over time. In contrast, immediately prior to and 1 h after treatment on Day 7, the mean LPS induced PGE2 concentration decreased significantly compared to Day 0 values in all treated horses. There was no difference in PGE2 or plasma firocoxib concentrations between firocoxib treatment groups. CONCLUSION: In this model, the canine chewable preparation of firocoxib was as effective as the equine paste formulation at reducing LPS-induced PGE2 synthesis. POTENTIAL RELEVANCE: The canine chewable preparation of firocoxib may be a suitable alternative to the paste formulation in horses for situations where extra-label drug use can be legally justified. The Summary is available in Chinese - see Supporting information. PMID- 23662600 TI - Sensitivity of assays for the detection of HPA-1a antibodies: results of an international workshop demonstrating the impact of cation chelation from integrin alphaIIbbeta3 on three widely used assays. AB - BACKGROUND AND OBJECTIVES: HPA-1a antibodies account for 70-80% of cases of fetal neonatal alloimmune thrombocytopenia (FNAIT) in Caucasians. However, numerous workshops have demonstrated variability in their detection. We recently showed that exposure of alphaIIbbeta3 to ethylene diamine tetraacetic acid (EDTA) affected binding of many anti-alphaIIbbeta3 monoclonal, and HPA-1a allo-, antibodies; this adversely affected sensitivity of the monoclonal antibody specific immobilization of platelet antigens (MAIPA) assay and indirect platelet immunofluorescence test (PIFT). This study presents results from an international workshop studying the impact of cation chelation on HPA-1a antibody detection in routine diagnostic laboratories. MATERIALS AND METHODS: Serum and EDTA anticoagulated plasma samples containing anti-HPA-1a were distributed to 39 laboratories. Participants were asked to detect and identify any HPA antibodies present. RESULTS: 2/39 (5.1%) participants were able to detect and identify anti HPA-1a in the serum, but not in the plasma sample. EDTA plasma reduced MAIPA assay sensitivity by >= 20% in 17/24 (70.8%) laboratories and by >= 50% in 9/24 (37.5%) when using HPA-1a1a platelets (mean: 27.7%, range 0-85.1%); when using HPA-1a1b platelets 3/4 (75%), participants reported >= 50% loss of sensitivity (mean 65.6%, range 0-96.6%). A small but significant increase in optical densities was observed in antigen capture ELISA assays when using plasma (mean difference: 0.081, P < 0.01). Insufficient PIFT data were returned to draw firm conclusions. CONCLUSION: Use of EDTA plasma significantly affects the sensitivity of the MAIPA assay and can affect detection of even potent, FNAIT-causing examples of anti-HPA-1a. These data highlight the importance of use of alphaIIbbeta3 in an appropriate conformation for the sensitive detection of anti HPA-1a. PMID- 23662601 TI - Long-term performance of beat-to-beat automatic ventricular threshold adjustment in infants with congenital atrioventricular block. AB - BACKGROUND: AutoCaptureTM (AC) of St. Jude Medical (SJM; St. Paul, MN, USA) pacemakers provides beat-to-beat ventricular capture verification and allows low amplitude pacing. There has been concern about evoked response signal (ERS) amplitude decreasing over time, leading to discontinuation of AC. The purpose of this study was to evaluate the long-term performance of AC in infants with epicardial pacing leads. METHODS: Data on 16 newborns with congenital complete atrioventricular block (CCAVB) implanted with a SJM Microny pacemaker between January 1998 and December 2004 were collected. The ERS at discharge, at 12 +/- 2 months, and long-term AC performance were analyzed retrospectively. The median follow-up time was 5.3 years (range 0.4-8.6 years), the end point of follow-up being either lead or generator exchange. RESULTS: AC could be activated in all patients at discharge; the median ERS was 9.3 mV (3.7-19.0 mV). At 12 +/- 2 months, the median ERS measured 4.6 +/- 3.6 mV (n = 13), showing a significant decrease (P = 0.002) and leading to discontinuation of AC in three (23%) of 13 patients. AC use was possible in eight patients and long-term use in six patients. CONCLUSIONS: In epicardially paced CCAVB newborns, the ERS amplitude decreased significantly during the first year. ERS decrease was the most common reason for AC failure. At 1-year follow-up, AC was functional in only 53% of patients, although it could originally be activated in all patients. During the first year of follow-up, special attention to AC parameters is recommended in this subgroup of pediatric pacemaker patients. PMID- 23662603 TI - Particulate pulmonary delivery systems containing anti-tuberculosis agents. AB - There is renewed interest in delivering anti-tuberculosis (TB) drugs to the lungs by inhalation. Several groups have investigated particulate pulmonary drug delivery formulations containing anti-TB agents, prepared using a variety of design approaches and processes. This review summarizes trends that indicate feasibility and translation of research efforts aimed at developing inhaled therapies for TB. Whereas formulations intended for reconstitution as solutions prior to nebulization can be produced with relative ease, particle engineering for powder formulations is more specialized. Spray drying and emulsion methods used to prepare particulate pulmonary delivery systems of anti-TB agents are compared. Pharmaceutical characterization is outlined. Administration of repeated inhalations to laboratory animals, especially under Animal Biosafety Level-3 (ABSL-3) containment as required for TB research, is another major challenge. Techniques employed by different groups are reviewed in the context of suitability for drug delivery and amenability towards use in ABSL-3 settings. It is concluded that spray drying is suitable for production of inhalable particles, rigorous physicochemical characterization is necessary for developing inhaled therapies as drug products, and pulmonary delivery of formulations containing anti-TB drugs to animals infected with Mycobacterium tuberculosis can best be carried out using handheld devices. PMID- 23662602 TI - Trends in racial disparities for injured patients admitted to trauma centers. AB - OBJECTIVE: To determine whether outcome disparities between black and white trauma patients have decreased over the last 10 years. DATA SOURCE: Pennsylvania Trauma Outcome Study. STUDY DESIGN: We performed an observational cohort study on 191,887 patients admitted to 28 Level 1 and Level II trauma centers. The main outcomes of interest were (1) death, (2) death or major complication, and (3) failure-to-rescue. Hospitals were categorized according to the proportion of black patients. Multivariate regression models were used to estimate trends in racial disparities and to assess whether the source of racial disparities was within or between hospitals. PRINCIPAL FINDINGS: Trauma patients admitted to hospitals with high concentrations of blacks (>20 percent) had a 45 percent higher odds of death (adj OR: 1.45, 95 percent CI: 1.09-1.92) and a 73 percent higher odds of death or major complication (adj OR: 1.73, 95 percent CI: 1.42 2.11) compared with patients admitted to hospitals treating low proportions of blacks. Blacks and whites admitted to the same hospitals had no difference in mortality (adj OR: 1.05, 95 percent CI: 0.87, 1.27) or death or major complications (adj OR: 1.01; 95 percent CI: 0.90, 1.13). The odds of overall mortality, and death or major complications have been reduced by 32 percent (adj OR: 0.68; 95 percent CI: 0.54-0.86) and 28 percent (adj OR: 0.72; 95 percent CI: 0.60-0.85) between 2000 and 2009, respectively. Racial disparities did not change over 10 years. CONCLUSION: Despite the overall improvement in outcomes, the gap in quality of care between black and white trauma patients in Pennsylvania has not narrowed over the last 10 years. Racial disparities in trauma are due to the fact that black patients are more likely to be treated in lower quality hospitals compared with whites. PMID- 23662604 TI - Peptide and protein delivery using new drug delivery systems. AB - Pharmaceutical and biotechnological research sorts protein drug delivery systems by importance based on their various therapeutic applications. The effective and potent action of the proteins/peptides makes them the drugs of choice for the treatment of numerous diseases. Major research issues in protein delivery include the stabilization of proteins in delivery devices and the design of appropriate target-specific protein carriers. Many efforts have been made for effective delivery of proteins/peptidal drugs through various routes of administrations for successful therapeutic effects. Nanoparticles made of biodegradable polymers such as poly lactic acid, polycaprolactone, poly(lactic-co-glycolic acid), the poly(fumaric-co-sebacic) anhydride chitosan, and modified chitosan, as well as solid lipids, have shown great potential in the delivery of proteins/peptidal drugs. Moreover, scientists also have used liposomes, PEGylated liposomes, niosomes, and aquasomes, among others, for peptidal drug delivery. They also have developed hydrogels and transdermal drug delivery systems for peptidal drug delivery. A receptor-mediated delivery system is another attractive strategy to overcome the limitation in drug absorption that enables the transcytosis of the protein across the epithelial barrier. Modification such as PEGnology is applied to various proteins and peptides of the desired protein and peptides also increases the circulating life, solubility and stability, pharmacokinetic properties, and antigenicity of protein. This review focuses on various approaches for effective protein/peptidal drug delivery, with special emphasis on insulin delivery. PMID- 23662605 TI - Nanocurcumin: a promising therapeutic advancement over native curcumin. AB - Curcumin, a naturally occurring polyphenolic compound, is known to have a wide range of therapeutic and pharmacological properties. Although it is a considerably promising compound, its poor water solubility and fast degradation profile make it compromise over its bioavailability way below the threshold level on administration. Over a period of time, a lot of emphasis has been given to improve the biodistribution of native curcumin, but it is only recently that the application of the field of nanotherapeutics has significantly improved its therapeutic efficacy. This is through the development of nanorange formulations of curcumin, popularly known as the "nanocurcumin." These attempts have given a strong platform to reap all the biological benefits from this phytodrug, which was not significantly plausible earlier. This review gives an insight into the reasons that make nanocurcumin a more therapeutically advanced drug than its native counterpart. It also discusses various nanometric formulations of curcumin that have been reported for its controlled and targeted delivery along with a critical comparison of its therapeutic efficacy with free curcumin. We also summarize the biological applications, patented technologies, and current status of the ongoing clinical trials related to nanocurcumin. PMID- 23662606 TI - Hydration properties of ligands and drugs in protein binding sites: tightly bound, bridging water molecules and their effects and consequences on molecular design strategies. AB - Some water molecules in binding sites are important for intermolecular interactions and stability. The way binding site explicit water molecules are dealt with affects the diversity and nature of designed ligand chemical structures and properties. The strategies commonly employed frequently assume that a gain in binding affinity will be achieved by their targeting or neglect. However, in the present work, 2332 high-resolution X-ray crystal structures of hydrated and nonhydrated, drug and nondrug compounds in biomolecular complexes with reported Ki or Kd show that compounds that use tightly bound, bridging water molecules are as potent as those that do not. The distribution of their energies, physicochemical properties, and ligand efficiency indices were compared for statistical significance, and the results were confirmed using 2000 permutation runs. Ligand cases were also split into agonists and antagonists, and crystal structure pairs with differing tightly bound water molecules were also compared. In addition, agonists and antagonists that use tightly bound water bridges are smaller, less lipophilic, and less planar; have deeper ligand efficiency indices; and in general, possess better physicochemical properties for further development. Therefore, tightly bound, bridging water molecules may in some cases be replaced and targeted as a strategy, though sometimes keeping them as bridges may be better from a pharmacodynamic perspective. The results suggest general indications on tightly hydrated and nontightly hydrated compounds in binding sites and practical considerations to adopt a strategy in drug and molecular design when faced with this special type of water molecules. There are also benefits of lower log P and better developability for tightly hydrated compounds, while stronger potency is not always required or beneficial. The hydrated binding site may be one of the many structure conformations available to the receptor, and different ligands will have a different ability to select either hydrated or nonhydrated receptor binding site conformations. Compounds may thus be designed, and if a tightly bound, bridging water molecule is observed in the binding site, attempts to replace it should only be made if the subsequent ligand modification would improve also its ligand efficiency, enthalpy, specificity, and pharmacokinetic properties. If the modification does succeed in replacing the tightly bound, bridging water molecule, it will have at least achieved benefits for ligand optimization and development independently of either positive or negative change in binding affinity outcome. PMID- 23662607 TI - Aerobic dehydrogenation of cyclohexanone to phenol catalyzed by Pd(TFA)2/2 dimethylaminopyridine: evidence for the role of Pd nanoparticles. AB - We have carried out a mechanistic investigation of aerobic dehydrogenation of cyclohexanones and cyclohexenones to phenols with a Pd(TFA)2/2 dimethylaminopyridine catalyst system. Numerous experimental methods, including kinetic studies, filtration tests, Hg poisoning experiments, transmission electron microscopy, and dynamic light scattering, provide compelling evidence that the initial Pd(II) catalyst mediates the first dehydrogenation of cyclohexanone to cyclohexenone, after which it evolves into soluble Pd nanoparticles that retain catalytic activity. This nanoparticle formation and stabilization is facilitated by each of the components in the catalytic reaction, including the ligand, TsOH, DMSO, substrate, and cyclohexenone intermediate. PMID- 23662608 TI - Insights on the binding of Thioflavin derivative markers to amyloid-like fibril models from quantum chemical calculations. AB - Thioflavin-T (ThT) is one of the most widely used dyes for staining and identifying amyloid fibrils, which share a common parallel in register beta-sheet structure. Unfortunately, ThT is a charged molecule, which limits its ability to cross the blood brain barrier and its use as an efficient dye for in vivo detection of amyloid fibrils. For this reason, several uncharged ThT derivatives have been designed and their binding properties to Abeta fibrils studied by fluorescence assays. However, there are still many unknowns on the binding mechanism and the role of noncovalent interactions on the affinity of these ligands toward beta-sheet structures. The present contribution analyzes the binding of ThT (1) and neutral ThT derivatives (2-7) to a beta-sheet model by means of quantum chemical B3LYP-D calculations and including solvent effects with the continuum CPCM method. Results show that, in all cases, ligand binding is mainly driven by dispersion interactions. In addition, ligands with -NH groups display hydrogen bond interactions with CO groups of the peptide strand, increasing the intrinsic affinity toward the beta-sheet surface. Solvent effects notably reduce the affinity of charged ThT, as compared to neutral systems, due to its larger solvation energy. As a result, neutral derivatives display significantly higher affinities than ThT in solution, in agreement with experimental observations. Analysis of the hydrogen bonding network of the beta sheet structure indicates that stacking interactions upon ligand binding induce a shortening of interstrand hydrogen bonding, suggesting a strengthening of the beta-sheet. PMID- 23662609 TI - Detection of brain amyloid beta deposition in patients with neuropsychological impairment after traumatic brain injury: PET evaluation using Pittsburgh Compound B. AB - OBJECTIVE: Traumatic brain injury (TBI) is an epigenetic risk factor for Alzheimer's disease (AD) and amyloid beta (Abeta) deposition is observed histopathologically in the traumatized brain. This study was conducted to detect cerebral Abeta deposition using amyloid positron emission tomography (PET) in patients with neuropsychological impairment after TBI. METHODS: Twelve patients with post-traumatic neuropsychological impairment (11 men and one woman, age range = 21-78 years) were examined using Pittsburgh Compound B ((11)C-PIB) PET at the chronic stage after TBI (range = 5-129 months). RESULTS: (11)C-PIB was positive in three patients and negative in the other nine patients. There was no correlation between (11)C-PIB deposition and the severity of injury; initial CT findings; elapsed time from the injury; and neuropsychological test scores. CONCLUSIONS: The absence of Abeta deposition in many patients with chronic neuropsychological impairment after TBI does not support the premise that Abeta pathology progresses over time in the traumatized brain. Early and sequential (11)C-PIB PET examination may clarify the time course of Abeta deposition in the traumatized brain and the relationship between traumatic brain insult and subsequent neuropsychological impairment. PMID- 23662610 TI - Hepcidin, iron status, and inflammation variables among healthy pregnant women in the Turkish population. AB - PURPOSE: To investigate hepcidin levels in each trimester and their association with other haematological variables and inflammation markers during normal pregnancy among low-risk pregnant women in rural Turkey. METHOD: The series comprised 103 healthy Turkish primigravida women with a normal pregnancy. Blood samples were obtained at 11-14, 24-28 and 30-34 weeks of gestation. Haemoglobin, hematocrit, red cell indices, white blood cell count, platelet count, iron status indicators (plasma iron, transferrin, ferritin levels and iron binding capacity), serum hepcidin, interleukin-6 and C-reactive protein levels were analysed. The proportions were compared using Pearson's chi2 test or Friedman's test. RESULTS: The mean serum hepcidin concentrations at 11-14, 24-28 and 30-34 weeks of gestation were as follows: 7.8 +/- 3.4 ng/mL, 8.6 +/- 3.1 ng/mL and 7.3 +/- 3.0 ng/mL, respectively. The mean serum ferritin concentrations with median values at each trimester were 14.2 (11.5), 9.5 (8.8) and 11.2 (9.3), respectively. The mean serum CRP values at each trimester were 5.1 (4.0), 5.5 (4.6) and 6.0 (5.5), respectively. The serum hepcidin levels were not related to iron status or the haemoglobin, IL-6 or C-reactive protein levels. CONCLUSIONS: There was no association between serum hepcidin and serum ferritin, IL-6 or CRP concentrations in each trimester among low-risk pregnant women. PMID- 23662611 TI - The cloning, characterization, and functional analysis of a gene encoding an isopentenyl diphosphate isomerase involved in triterpene biosynthesis in the Lingzhi or reishi medicinal mushroom Ganoderma lucidum (higher Basidiomycetes). AB - An isopentenyl diphosphate isomerase (IDI) gene, GlIDI, was isolated from Ganoderma lucidum, which produces triterpenes through the mevalonate pathway. The open reading frame of GlIDI encodes a 252 amino acid polypeptide with a theoretical molecular mass of 28.71 kDa and a theoretical isoelectric point of 5.36. GlIDI is highly homologous to other fungal IDIs and contains conserved active residues and nudix motifs shared by the IDI protein family. The color complementation assay indicated that GlIDI can accelerate the accumulation of beta-carotene and confirmed that the cloned complementary DNA encoded a functional GlIDI protein. Gene expression analysis showed that the GlIDI transcription level was relatively low in the mycelia and reached a relatively high level in the mushroom primordia. In addition, its expression level could be up-regulated by 254 uM methyl jasmonate. Our results suggest that this enzyme may play an important role in triterpene biosynthesis. PMID- 23662612 TI - Heat-stable components of wood ear mushroom, Auricularia polytricha (higher Basidiomycetes), inhibit in vitro activity of beta secretase (BACE1). AB - The consumption of mushrooms has been linked with protection against dementia, including Alzheimer's disease (AD), by several biological pathways including inhibiting beta-site APP-cleaving enzyme (BACE1), which is responsible for releasing toxic beta-amyloid peptide in the brain. We have investigated the capacity of several medicinal mushroom species-Auricularia polytricha (wood ear mushroom), Agaricus bisporus (button mushroom), Flammulina velutipes (winter or enoki mushroom), and Lentinus edodes (shiitake mushroom)-in the regulation of BACE1. Mushrooms were subjected to a generic food-compatible processing method to detect process-stable or process-modified products; the effects of processing were interpreted to infer the chemical classes associated with bioactivity. We have shown previously that in addition to enzyme inhibition, in the presence of the BACE1 proenzyme, heteropolymeric species such as heparin can activate BACE1 by modulating access to the catalytic site. We observed both inhibitory and activating components of the various mushrooms. Only BACE1 inhibitory species were detected in unprocessed and processed forms of A. polytricha, whereas the dominant extracted species from A. bisporus, F. velutipes, and L. edodese were activators of BACE1. It is not known whether activating species were masking the presence of inhibitory species in A. bisporus, F. velutipes, and L. edodes. Inhibitory species were attributed to hispidin-derived polyphenols, whereas activating species were attributed to soluble polysaccharides and possibly low mass Maillard products produced during processing. Larger molecular BACE1 activating species are unlikely to be bioavailable to brain in contrast with possible brain bioavailability of smaller, lipophilic hispidins. PMID- 23662613 TI - Antioxidant and immunomodulating activities of exo-and endopolysaccharide fractions from submerged mycelia cultures of culinary-medicinal mushrooms. AB - A number of mushrooms are known to possess pharmacological activities. In this study, the phenolic and flavonoid contents of extracts of exo- and endopolysaccharide fractions obtained from submerged mycelia cultures of 7 edible or medicinal mushroom species, as well as their antioxidant and immunomodulatory properties, were evaluated. The exo- and endopolysaccharide yields were 0.576 1.950 and 0.438-0.933 g/L, respectively. The sugar and protein contents of these fractions were analyzed and contained predominantly sugars (52.3-87.6%). The exo- and endopolysaccharide fractions contained appreciable amounts of phenolics and flavonoids. The highest flavonoid contents were found in Cryptosporus volvatus (349.6 mg/g), followed by Cordyceps militaris (312.6 mg/g). The antioxidant activities were evaluated by 4 assays: biological assay using Saccharomyces cerevisiae, DPPH radical scavenging activity, chelating ability for ferrous ions and ferric reducing antioxidant power. The mycelia polysaccharide fractions had more ferric reducing antioxidant power than other antioxidant activities. Both exo- and endo polysaccharides of C. volvatus inhibited production of the T lymphocyte Th1 cytokines interferon (IFN)-gamma and interleukin (IL)-2, the Th2 cytokines IL-4 and IL-5, and macrophage enzyme activity. Although those from C. militaris had similar inhibitory effects on cytokine production, the exopolysaccharides stimulated macrophage enzyme activity. The other exopolysaccharides (Pleurotus citrinopileatus, P. australis, and P. pulmonarius) inhibited IFN-gamma and IL-5 production, but they had varying effects on IL-2 and IL-4 production. Only 3 exopolysaccharides (P. pulmonarius, Tremella mesenterica, and Cordyceps sinensis) also stimulated macrophage enzyme activity to the same extent as lipopolysaccharides. All of them reduced IL-5 production, but those from T. mesenterica also inhibited IFN-gamma, IL-2, and IL-4 production. Thus the polysaccharide fractions from the mushrooms studied have antioxidant activities and general immunomodulating effects in vitro. PMID- 23662614 TI - Antioxidant properties of fruiting bodies, mycelia, and fermented products of the culinary-medicinal king oyster mushroom, Pleurotus eryngii (higher Basidiomycetes), with high ergothioneine content. AB - The culinary-medicinal king oyster mushroom Pleurotus eryngii is known to contain ergothioneine, and its products, including fruiting bodies, mycelia, and solid state fermented products (adlay and buckwheat), were prepared to study their antioxidant properties. Fruiting bodies, regular and Hi-Ergo mycelia, and fermented products contained 2.05, 1.68, 5.76, 0.79-0.80 mg/g of ergothioneine, respectively. On the basis of the results obtained, P. eryngii products had effective antioxidant activity, reducing power, and scavenging ability on 1,1 diphenyl-2-picrylhydrazyl radicals and chelating ability on ferrous ions. Hi-Ergo mycelia was the most effective in the first 3 antioxidant properties in addition to its ergothioneine content. In addition, fruiting bodies were more effective in all antioxidant properties than regular mycelia. For ethanolic and hot water extracts from mycelia and fruiting bodies, the correlation coefficients between total phenol contents and each antioxidant attribute were 0.483-0.921. Overall, P. eryngii products with high amounts of ergothioneine could be used beneficially as a functional food. PMID- 23662615 TI - Aqueous extracts of Cordyceps militaris (Ascomycetes) lower the levels of plasma glucose by activating the cholinergic nerve in streptozotocin-induced diabetic rats. AB - In our previous research, Cordyceps militaris (CM) had a hypoglycemic effect in normal rats. In this study we wanted to elucidate whether CM also had an effect on diabetic rats. Twelve rats with streptozotocin-induced diabetes were separated randomly into 2 groups. First, aqueous extracts of CM 10 mg/kg (CM group) or saline (control group) was fed to the rats; then the plasma glucose levels were assayed. Second, the signaling proteins IRS-1 and GLUT-4 collected from the muscle were detected. Finally, another 2 groups of rats were injected with atropine 0.1 mg/kg intraperitoneally just before the CM/saline feeding, and the assays mentioned above were repeated. Blood glucose decreased 7.2% in the CM group but only 1.5% in the control group (P < 0.05). The IRS-1 signal was 2.9 fold higher than actin in the CM group but only 0.8-fold higher in the control group (P < 0.005). In GLUT-4 signal, the difference was 1.7- vs. 0.6-fold, respectively, compared with actin (P < 0.05). However, atropine injection made CM induced hypoglycemia or elevation of IRS-1 and GLUT-4 not significant. In conclusion, CM had a hypoglycemic effect in diabetic rats and atropine blocked it. Therefore, the cholinergic activation also was considered to be involved in the hypoglycemic effect of CM in rats with streptozotocin-induced diabetes. PMID- 23662616 TI - The medicinal cracked-cap polypore mushroom Phellinus rimosus (higher Basidiomycetes) attenuates alloxan-induced hyperglycemia and oxidative stress in rats. AB - Diabetes is usually associated with increased production of reactive oxygen species (ROS), impaired antioxidant defense systems, or both, which result in oxidative damage and lead to ROS-mediated diabetic pathogenesis. This investigation was undertaken to evaluate the role of extract from the wood inhabiting polypore medicinal mushroom Phellinus rimosus in an alloxan-induced diabetic model and the oral glucose tolerance test in rats. Oral administration of extract at doses of 50 and 250 mg/kg body weight/day for 10 days to rats with alloxan-induced diabetes was found to possess significant dose-dependent hypoglycemic activity. In the oral glucose tolerance test, hypoglycemic effect of P. rimosus (250 mg/kg) was significant (P < 0.01) and maximum at 90 minutes after the glucose challenge when compared with that of control group. The effect of extract on antioxidant status in the pancreas, liver, and kidney was estimated. The diabetic control rats exhibited elevated levels of lipid peroxidation and lower activities of copper/zinc superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and reduced glutathione (GSH) content in pancreatic, hepatic, and renal tissues compared with normal tissues. The activities of SOD, CAT, GPx, and GSH were found to be increased in diabetic rats treated with the extract. The increased level of lipid peroxidation in diabetic rats also was found to revert to near-normal status in groups treated with the extract. The findings thus suggest the therapeutic efficiency of Ph. Rimosus against declined antioxidant status as well as hyperglycemia associated with diabetes. PMID- 23662617 TI - Enhanced antiproliferative effects of aqueous extracts of some medicinal mushrooms on colon cancer cells. AB - Cancer is one of the most prevalent chronic diseases of the world. Certain edible mushroom species are rich in antioxidants, which perform a vital role in preventing this risk in manifesting itself. Initial screening was followed by qualitative phytochemical analysis; estimation of total phenolic content, DPPH radical scavenging activity, and the ferric-reducing ability of plasma (FRAP) of the ethanolic and the aqueous extracts of 3 edible medicinal mushroom species, namely, Auricularia polytricha, Macrolepiota procera, and Pleurotus ostreatus. Furthermore, based on promising results from studies of antioxidant activities, these extracts were carried forward to study cytotoxic, antiproliferative, and antiapoptotic effects on breast (MCF-7), colon (COLO-205), and kidney (ACHN) cancer cell lines. Among all the extracts, the aqueous extract of P. ostreatus and the ethanolic extract of M. procera showed the highest cytotoxic effect on all 3 cancer cell lines, especially COLO-205. The scientific data obtained so far show that the aqueous extracts of all 3 species of mushrooms have a remarkable irreversible antiproliferative effect on COLO-205 compared with other cancer cell lines. This decrease in cell viability, morphological changes, and apoptotic hallmarks observed upon treatment with the extracts validated the anticancerous property of these mushroom species. PMID- 23662618 TI - Comparative study of contents of several bioactive components in fruiting bodies and mycelia of culinary-medicinal mushrooms. AB - Mushrooms (including fruiting bodies and mycelia) contain several bioactive components such as lovastatin, gamma-aminobutyric acid (GABA), and ergothioneine. This article reports the results of 49 samples, including 9 fruiting bodies, 39 mycelia, and 1 vegetative cell, of 35 species of culinary-medicinal mushrooms from 18 genera: Agaricus, Agrocybe, Coprinus, Cordyceps, Cyathus, Daedalia, Flammulina, Fomes, Ganoderma, Grifola, Laetiporus, Lentinus, Morchella, Ophiocordyceps, Pleurotus, Trametes, Tremella, and Verpa. The results show that Cyathus striatus strain 978 contained the highest amount of lovastatin (995.66 mg/kg) in mycelia. Among fruiting bodies, 6 samples contained a high amount of GABA (274.86-822.45 mg/kg), whereas among mycelia, contents of GABA in 27 samples ranged from 215.36 to 2811.85 mg/kg. Among mycelia, Pleurotus cornucopiae strain 1101 contained the highest amount of ergothioneine (3482.09 mg/kg). Overall, these 3 bioactive components were commonly found in most mushrooms, and the results obtained might be related to their beneficial effects. PMID- 23662619 TI - Antigenotoxic potential of aqueous extracts from the chanterelle mushroom, Cantharellus cibarius (higher Basidiomycetes), on human mononuclear cell cultures. AB - Cantharellus cibarius is one of the most important wild, edible, and ectomycorrhizal mushrooms growing at La Malinche National Park, Tlaxcala, Mexico; therefore, the assessment of its biological properties is of great interest to know its potential as an alternative treatment to chemopreventive strategies when it is consumed as part of a diet. Comet assay was used to evaluate the antigenotoxic properties of several concentrations of aqueous extracts (0.0125, 0.025, 0.05, 0.1, and 0.2% w/v) prepared at room temperature (22 +/- 2 degrees C). As a test system we used human mononuclear cells exposed to methyl methanesulphonate (MMS) in vitro according to 3 different protocols: previous, simultaneous, and posterior. Previous (0.0125%) and simultaneous (0.1%) treatments resulted in the highest inhibitory efficiency. In the former, the cells assessed showed a tail length of 94.9 +/- 64 um; in the latter, the tails measured 106.2 +/- 40 um. Resulting percentages of reduction in damage were 236% and 196.1%, respectively. We did not obtain a dose-dependent response. The mean tail length for each protocol (previous, 133.1 +/- 80 um; simultaneous, 127.8 +/- 57 um; posterior, 146.3 +/- 74 um) was statistically significant with regard to the positive control (MMS). PMID- 23662620 TI - Studies of mild traumatic brain injury. PMID- 23662621 TI - Endonasal dacryocystorhinostomy for nasolacrimal duct obstruction in patients with sarcoidosis. AB - PURPOSE: To evaluate the outcomes of endonasal dacryocystorhinostomy (EN-DCR) surgery in patients with sarcoidosis. METHODS: Retrospective chart review of all patients with sarcoidosis undergoing EN-DCR in 6 practices from 1999-2011. RESULTS: We included 18 procedures in 14 patients (8 female, 6 male) who underwent EN-DCR for acquired NLDO secondary to sarcoidosis. The mean age was 53.7 (range 38-82). The presenting symptom in all cases was epiphora. Eight patients (57%) complained of having additional nasal congestion. Surgery was performed using endoscopic powered-type DCR with flaps in 12/18 (67%) and non endoscopic mechanical EN-DCR in 6/18 (33%). In 15 (83%) cases the lacrimal sac and nasal mucosa appeared abnormally yellowish, crusty, oedematous and friable. Five patients were treated with pre-operative oral steroid and overall 8 patients had oral prednisolone post operatively, 30-60 mg tapered within 10 days-8 weeks. One patient had difficulties in tapering down the oral steroids at 6 months of follow-up. All patients were free of epiphora and patent to syringing, with nasal endoscopy revealing free flow of fluorescein through the ostium at a mean follow up of 11.3 months (median follow-up 9 months). CONCLUSIONS: All 18 cases of acquired nasolacrimal duct obstruction secondary to sarcoidosis were treated successfully with EN-DCR. An abnormal appearance of the nasal mucosa is an important sign. Nasal congestion is a frequent sign. A successful outcome may not depend on intensive long-term therapy with local or systemic steroids. Mechanical or powered EN-DCR for nasolacrimal duct obstruction secondary to sarcoidosis achieves encouraging medium-term outcomes. PMID- 23662622 TI - Double-bundle ACL reconstruction: novice surgeons utilizing computer-assisted navigation versus experienced surgeons. AB - PURPOSE: Anatomic double-bundle ACL reconstruction presents a unique technical challenge for surgeons, requiring precise placement of multiple tunnels in a relatively small area. As the necessity of anatomic reconstruction has been stressed throughout the literature, developing a method to consistently improve the accuracy and precision of tunnel placement is essential. We aimed to investigate whether computer-assisted navigation allows novice surgeons to place double-bundle ACL tunnels with a similar degree of accuracy to experienced surgeons operating without computer assistance. METHODS: A novice surgeon group comprising three medical students performed double-bundle ACL reconstruction using passive computer-assisted navigation in 11 cadaver knees. Their individual results were compared to those of three experienced orthopaedic surgeons, each performing the identical procedure without the use of computer-assisted navigation in 9 cadaver knees. RESULTS AND CONCLUSION: There were no significant differences in placement of either the AM or PL tunnels on the tibial plateau between the novice surgeons using computer-assisted navigation and the experienced surgeons. However, on the lateral femoral condyle, the novice surgeons placed the AM and PL tunnels significantly more anterior along Blumensaat's line, on average, compared to the experienced surgeons. PMID- 23662623 TI - Nitrite reactivity with magnetite. AB - Under Fe(3+)-reducing conditions, soil Fe(2+) oxidation has been shown to be coupled with nitrate (NO3(-)) reduction. One possible secondary reaction is the involvement of NO3(-) and nitrite (NO2(-)) with magnetite, a mixed valence Fe(2+)/Fe(3+) mineral found in many natural environments. Currently, little information exists on NO3(-) and NO2(-) reactivity with magnetite. This study investigates NO3(-) and NO2(-) reactivity with magnetite under anoxic conditions using batch kinetic experiments across a range of pH values (5.5-7.5) and in the presence of added dissolved Fe(2+). Solid phase products were characterized using X-ray diffraction (XRD), Mossbauer spectroscopy, and scanning electron microscopy (SEM). Nitrate removal by magnetite was much slower when compared with NO2(-). There was a pH-dependence in the reduction of NO2(-) by magnetite; the initial rate of NO2(-) removal was two times faster at pH 5.5 than at pH 7.5. The influence of pH was explained by the binding of NO2(-) to positively charged sites on magnetite (= S-OH2(+)) and to neutral sites (= S-OH(0)). As NO2(-) was removed from solution, nitric oxide (NO) and nitrous oxide (N2O) were identified as products confirming that nitrite was reduced. Structural Fe(2+) in magnetite was determined to be the reductant of NO2(-) based on the lack of measurable dissolved Fe(2+) release to solution coupled with Mossbauer spectra and XRD analysis of solid phase products. Addition of dissolved Fe(2+) to magnetite slurries resulted in adsorption and an acceleration in the rate of nitrite reduction at a given pH value. In summary, findings reported in this study demonstrate that if magnetite is present in Fe(3+)-reducing soil and NO2(-) is available, it can remove NO2(-) from solution and reduce a portion of it abiotically to NO and subsequently to N2O by a heterogeneous electron transfer process. PMID- 23662624 TI - pH-Triggered charge-reversal polypeptide nanoparticles for cisplatin delivery: preparation and in vitro evaluation. AB - A series of pH-responsive random copolymer poly(l-glutamic acid-co-l-lysine) [P(Glu-co-Lys)] were synthesized through the ring-opening polymerization (ROP) of gamma-benzyl-l-glutamate N-carboxyanhydride (BLG-NCA) and 3-benzyloxycarbonyl-l lysine N-carboxyanhydride (ZLys-NCA) and the subsequent deprotection. The chemical structure of the P(Glu-co-Lys)s was confirmed by NMR. Critical aggregation concentration and transmission electron microscopy measurements indicated that the P(Glu-co-Lys)s could self-assemble into aggregates in phosphate buffer. The surface charge of P(Glu-co-Lys) aggregates was greatly affected by the solution's pH and l-glutamic acid/l-lysine ratio because the carboxyl and amino groups present on the P(Glu-co-Lys) aggregates could be protonated or deprotonated to become charged. The pH value of the solution at which the surface charge of the P(Glu-co-Lys) aggregates reversed could be manipulated by the feed ratio of BLG-NCA and ZLys-NCA. In vitro methyl thiazolyl tetrazolium assays demonstrated that negatively charged P(Glu-co-Lys)s were nontoxic and biocompatible. Positive charged P(Glu-co-Lys)s showed some cytotoxicity to Hela cells. Cisplatin (CDDP) was used as a model anticancer drug to evaluate the charge-reversal drug delivery system. By the manipulation of CDDP loading content, the surface charge of the CDDP/P(Glu-co-Lys) nanoparticles could be reversed to positive from negative at tumor extracellular pH (pHe 6.5-7.2). An enhanced drug uptake and inhibition of cancer cell proliferation were observed for the tumoral pHe triggered charge-reversal CDDP/P(Glu-co-Lys) drug delivery system. These indicated that the CDDP/P(Glu-co-Lys) nanoparticles could be used as intelligent drug delivery systems for cancer therapy. PMID- 23662625 TI - NiCo2S4@graphene as a bifunctional electrocatalyst for oxygen reduction and evolution reactions. AB - Here, the hybrid of NiCo2S4 nanoparticles grown on graphene in situ is first described as an effective bifunctional nonprecious electrocatalyst for oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) in the alkaline medium. NiCo2S4@N/S-rGO was synthesized by a one-pot solvothermal strategy using Co(OAc)2, Ni(OAc)2, thiourea, and graphene oxide as precursors and ethylene glycol as the dispersing agent; simultaneously, traces of nitrogen and sulfur were double-doped into the reduced graphene oxide (rGO) in the forms of pyrrolic N, pyridinic-N, and thiophenic-S, which are often desirable for metal-free ORR catalysts. In comparison with commercial Pt/C catalyst, NiCo2S4@N/S-rGO shows less reduction activity, much better durability, and superior methanol tolerance toward ORR in 0.1 M KOH; it reveals higher activity toward OER in both KOH electrolyte and phosphate buffer at pH 7.0. NiCo2S4@graphene demonstrated excellent overall bicatalytic performance, and importantly, it suggests a novel kind of promising nonprecious bifunctional catalyst in the related renewable energy devices. PMID- 23662626 TI - Phase I clinical trial of vinorelbine in tumor-bearing cats. AB - BACKGROUND: Vinorelbine (VRL) has been investigated in dogs, but its use in cats has not been studied. HYPOTHESIS/OBJECTIVES: To determine the maximal tolerated dose (MTD) and dose-limiting toxicity (DLT) of VRL in tumor-bearing cats. ANIMALS: Cats were included in this prospective phase I trial if they had confirmed malignancy, received >=1 VRL treatment, and had adequate follow-up. Previous treatment was acceptable, but concurrent chemotherapy or radiotherapy was not permitted. METHODS: Using a modified phase I design, cats were enrolled in cohorts of 3 at a starting dosage of 9 mg/m(2) . Cats tolerating the first treatment well were eligible to receive additional VRL treatments at escalating dosages; escalations beyond the perceived MTD were permitted based on individual tolerance. Intended treatment interval was 7 days. Patient histories, physical examinations, and complete blood counts were performed weekly. RESULTS: Nineteen cats were included. Sixty-one VRL treatments were administered. Median number of treatments was 2 (range, 1-9). Starting dosages were 9-12 mg/m(2) . Maximal dosage administered was 15.5 mg/m(2) . The MTD was 11.5 mg/m(2) . Acute DLTs were neutropenia, vomiting, and nephrotoxicity. Other notable toxicities were weight loss and anemia. CONCLUSIONS AND CLINICAL IMPORTANCE: Vinorelbine is tolerated in cats at a weekly interval. Recommended starting dosage is 11.5 mg/m(2) . Neutropenia was transient, lasting <7 days; vomiting was self-limiting in most cases. Although VRL-associated nephrotoxicity has not been reported, potential attribution of this toxicity to VRL must not be discounted. Further investigation of the efficacy of VRL in feline malignancies is warranted. PMID- 23662627 TI - Reducing the cost of dietary assessment: self-completed recall and analysis of nutrition for use with children (SCRAN24). AB - BACKGROUND: Self-Completed Recall and Analysis of Nutrition (scran24) is a prototype computerised 24-h recall system for use with 11-16 year olds. It is based on the Multiple Pass 24-h Recall method and includes prompts and checks throughout the system for forgotten food items. METHODS AND RESULTS: The development of scran24 was informed by an extensive literature review, a series of focus groups and usability testing. The first stage of the recall is a quick list where the user is asked to input all the foods and drinks they remember consuming the previous day. The quick list is structured into meals and snacks. Once the quick list is complete, additional information is collected on each food to determine food type and to obtain an estimate of portion size using digital images of food. Foods are located within the system using a free text search, which is linked to the information entered into the quick list. A time is assigned to each eating occasion using drag and drop onto a timeline. The system prompts the user if no foods or drinks have been consumed within a 3-h time frame, or if fewer than three drinks have been consumed throughout the day. The food composition code and weight (g) of all items selected are automatically allocated and stored. Nutritional information can be generated automatically via the scran24 companion Access database. CONCLUSIONS: scran24 was very well received by young people and was relatively quick to complete. The accuracy and precision was close to that of similar computer-based systems currently used in dietary studies. PMID- 23662628 TI - Goal setting with mothers in child development services. AB - AIM: The aim of this grounded theory study was to explore mothers' perspectives of the processes of collaborative goal setting in multidisciplinary child development services involving follow-up home therapy. METHODS: Semi-structured interviews were conducted in South East Queensland, Australia with 14 mothers of children aged 3-6 years who were accessing multidisciplinary child development services. Interviews were focussed around the process of goal setting. RESULTS: A grounded theory of Maternal Roles in Goal Setting (The M-RIGS Model) was developed from analysis of data. Mothers assumed Dependent, Active Participator and Collaborator roles when engaging with the therapist in goal-setting processes. These roles were characterized by the mother's level of dependence on the therapist and insight into their child's needs and therapy processes. Goal Factors, Parent Factors and Therapist Factors influenced and added complexity to the goal-setting process. CONCLUSION: The M-RIGS Model highlights that mothers take on a range of roles in the goal-setting process. Although family-centred practice encourages negotiation and collaborative goal setting, parents may not always be ready to take on highly collaborative roles. Better understanding of parent roles, goal-setting processes and influencing factors will inform better engagement with families accessing multidisciplinary child development services. PMID- 23662629 TI - A tandem Kunitz protease inhibitor (KPI106)-serine carboxypeptidase (SCP1) controls mycorrhiza establishment and arbuscule development in Medicago truncatula. AB - Plant proteases and protease inhibitors are involved in plant developmental processes including those involving interactions with microbes. Here we show that a tandem between a Kunitz protease inhibitor (KPI106) and a serine carboxypeptidase (SCP1) controls arbuscular mycorrhiza development in the root cortex of Medicago truncatula. Both proteins are only induced during mycorrhiza formation and belong to large families whose members are also mycorrhiza specific. Furthermore, the interaction between KPI106 and SCP1 analysed using the yeast two-hybrid system is specific, indicating that each family member might have a defined counterpart. In silico docking analysis predicted a putative P1 residue in KPI106 (Lys173) that fits into the catalytic pocket of SCP1, suggesting that KPI106 might inhibit the enzyme activity by mimicking the protease substrate. In vitro mutagenesis of the Lys173 showed that this residue is important in determining the strength and specificity of the interaction. The RNA interference (RNAi) inactivation of the serine carboxypeptidase SCP1 produces aberrant mycorrhizal development with an increased number of septated hyphae and degenerate arbuscules, a phenotype also observed when overexpressing KPI106. Protease and inhibitor are both secreted as observed when expressed in Nicotiana benthamiana epidermal cells. Taken together we envisage a model in which the protease SCP1 is secreted in the apoplast where it produces a peptide signal critical for proper fungal development within the root. KPI106 also at the apoplast would modulate the spatial and/or temporal activity of SCP1 by competing with the protease substrate. PMID- 23662630 TI - The evolution of queen pheromones in the ant genus Lasius. AB - Queen pheromones are among the most important chemical messages regulating insect societies yet they remain largely undiscovered, hindering research into interesting proximate and ultimate questions. Identifying queen pheromones in multiple species would give new insight into the selective pressures and evolutionary constraints acting on these ubiquitous signals. Here, we present experimental and comparative evidence that 3-methylalkanes, hydrocarbons present on the queen's cuticle, are a queen pheromone throughout the ant genus Lasius. Interspecific variation in the chemical profile is consistent with 3 methylalkanes evolving more slowly than other types of hydrocarbons, perhaps due to differential selection or evolutionary constraints. We argue that the sensory ecology of the worker response imposes strong stabilizing selection on queen pheromones relative to other hydrocarbons. 3-Methylalkanes are also strongly physiologically and genetically coupled with fecundity in at least one Lasius species, which may translate into evolutionary constraints. Our results highlight how honest signalling could minimize evolutionary conflict over reproduction, promoting the evolution and maintenance of eusociality. PMID- 23662631 TI - Bronchial collapse during bronchoalveolar lavage in horses is an indicator of lung inflammation. AB - REASONS FOR PERFORMING STUDY: The bronchoalveolar lavage (BAL) procedure can return variable volumes of fluid, possibly depending on the presence of bronchial collapse during fluid aspiration and on the severity of lung inflammation. OBJECTIVES: We tested the hypothesis that horses with bronchial collapse during BAL are at higher risk of having severe lung inflammation. STUDY DESIGN: Prospective field study. METHODS: Bronchial collapse was graded using a new simple scoring method (0, 1 or 2) during a standardised BAL procedure in the field on 131 horses with normal, mild/moderate or severe lower airway inflammation on cytology of BAL fluid. RESULTS: Of the 131 horses, 37 (28%), 55 (42%) and 39 (30%) horses had bronchial collapse scores of 0, 1 and 2, respectively. There was a difference in collapse scores between all the BAL inflammation categories (P<0.001). Severe collapse had a positive predictive value of 0.95 for both mild/moderate and severe BAL inflammation, with a prevalence of 63% and 20%, respectively. The BAL fluid return volume in the horses with severe collapse scores was lower than volumes in the partial (score 1/2) and no collapse (score 0/2) groups (P<0.001). The BAL fluid volume was negatively correlated with BAL neutrophil percentage (P<0.001). CONCLUSIONS: Airway collapse during BAL is associated with airway inflammation and neutrophilia. POTENTIAL RELEVANCE: During a standardised BAL procedure, clinicians can expect lung inflammation in horses that have bronchial collapse and bronchial collapse in horses with lung inflammation. Lung inflammation may be a contributing factor in the mechanism of bronchial collapse during BAL in horses. PMID- 23662632 TI - Barriers and motivators to blood donation among university students in Japan: development of a measurement tool. AB - BACKGROUND AND OBJECTIVES: Despite growing demand for transfusion, the number of voluntary young blood donors has steadily decreased over recent years in Japan. This study aimed to develop an easy-to-use survey tool to assess barriers and motivators to blood donation among Japanese university students. MATERIALS AND METHODS: We conducted cross-sectional studies at two universities in Fukushima Prefecture, Japan, in December 2011 (Stage 1) and February 2012 (Stage 2) using self-administered questionnaires. A short list of motivators and barriers to blood donation was developed from the open-ended questions asked of 50 students in Stage 1. In the Stage 2, we asked 105 students how important these items were when they decided whether or not to donate blood. Items showing a significant difference between donors and non-donors were kept in the final list. RESULTS: Overall, 56% of the 100 participants analysed in Stage 2 were men, and ages ranged from 19 to 24 with a median of 20 years. Comparison of motivators and barriers between donors and non-donors revealed that only barrier item 8 ('Frightened by blood donation') showed a significant difference (P = 0.0006) in an expected direction and with a consistency between two universities. CONCLUSIONS: This study identified fear as being the most significant barrier to blood donation among Japanese university students, which could be used as a single convenient indicator to assess their readiness to donate. More academic and clinical efforts are needed to understand and address students' fear towards blood donation in order to increase the donor pool in Japan. PMID- 23662633 TI - Social anxiety and interpretation of ambiguous smiles. AB - This study investigated whether social anxiety facilitates the discrimination between genuine and ambiguous smiles. Socially anxious (N=20) and nonanxious (N=20) participants categorized as "happy" or "not happy" faces with either (1) a truly happy expression (i.e., happy eyes and a smile), (2) truly nonhappy expressions (e.g., angry eyes and an angry mouth), or (3) blended expressions with a smiling mouth and nonhappy (e.g., angry, sad, etc.) eyes. Results indicated that, relative to nonanxious participants, those high in social anxiety were more likely to judge as "not happy" any blended expression with nonhappy eyes, and they were faster in judging as "not happy" the blended expressions with angry, fearful, or disgusted eyes (but not those with sad, surprised, or neutral eyes). These results suggest, respectively, that social anxiety inhibits a benign interpretation of all the ambiguous expressions with a smile, and speeds up the detection of threatening eyes in such expressions. Importantly, no differences appeared as a function of social anxiety for truly happy or nonhappy faces. This rules out a response-bias explanation, and also reveals that social anxiety does not affect sensitivity in the recognition of prototypical expressions. PMID- 23662636 TI - Collapse of the keratin filament network through the expression of mutant keratin 6c observed in a case of focal plantar keratoderma. AB - Focal palmoplantar keratoderma (PPK) with severe pain is a hallmark of pachyonychia congenita, a rare autosomal dominant disorder involving PPK and hypertrophic nail dystrophy. Some families present focal PPK with either minimal or no nail changes. Dominant-negative mutations in any of the four identified keratin genes, KRT6A, KRT6B, KRT16 or KRT17, lead to pachyonychia congenita. However, the majority of families with focal PPK showing minimal or no nail changes do not harbor mutations in these genes. Recently, mutations of KRT6C were identified in families with focal PPK alone. Here, we report a 26-year-old Japanese man with focal plantar hyperkeratosis that developed at approximately 10 years of age with no palmar involvement and no nail alterations. We identified a missense KRT6C mutation c.1414G>A resulting in an p.Glu472Lys substitution, as reported in other Japanese patients. When the mutant keratin 6c protein is exogenously expressed in human HaCaT cells, a collapse of the keratin filament network is observed in a dose-dependent manner, suggesting the mutation has a dominant-negative effect on keratin filament network formation. The mutated residue is located at the helix termination motif of keratin 6c. The peptide sequence around this residue is highly conserved among type II, III and IV intermediate filament proteins. Glu to Lys mutations of the equivalent residue have been reported in a variety of inherited diseases, including neurodegenerative diseases, corneal dystrophy and skin disorders, suggesting that this residue is vital to keratin function. PMID- 23662635 TI - Postoperative junctional ectopic tachycardia: risk factors for occurrence in the modern surgical era. AB - BACKGROUND: Postoperative (PO) junctional ectopic tachycardia (JET) can be a life threatening arrhythmia that follows surgical repair of congenital heart disease (CHD) and results in PO morbidity. METHODS: We reviewed 750 open heart surgeries (OHS) for CHD performed between January 2005 and February 2009. Kaplan-Meier and Cox proportional hazards model analyses were used to estimate the frequency and evaluate risk factors that might predict JET occurrence. RESULTS: The patients ranged in age from 1 day to 36.6 years; half were less than 4.8 months at the time of OHS. JET occurred in 115 of 750 (15.3%) OHS. JET was bimodally distributed by age with a peak incidence between 1-2 weeks and 1-3 years. JET occurred more commonly: (1) in specific types of OHS (single ventricle [19.5%] and cono-truncal defects [19.3%]) (P = 0.03); (2) with increased total surgical time (P = 0.001), aortic cross-clamp time (P < 0.001), cardiopulmonary bypass time (P < 0.001); and (3) followed use of inotropic agents (dopamine or milrinone, P < 0.001). JET lengthened intensive care stay by 3 days (P = 0.0001) and increased mortality (+JET [9.6%] vs -JET [4.6%], P = 0.03). In a multiple variable Cox regression model, total surgical time and PO use of milrinone were the best predictors for JET risk. PO administration of nitroprusside decreased risk of JET. CONCLUSIONS: JET occurred more commonly following OHS associated with prolonged surgical times and PO use of inotropic medications. In contrast to previous reports, our results suggest that mechanical injury to the atrioventricular node area is not strongly associated with JET. PMID- 23662637 TI - End-group cleavage in MALDI of ATRP-made polystyrene: a silver-catalyzed reaction during sample preparation. AB - Cleavage of the labile halide termination upon matrix-assisted laser desorption/ionization (MALDI) has always been reported as a major concern in mass analysis of polystyrene prepared by atom transfer radical polymerization (ATRP). By studying this issue using nuclear magnetic resonance (NMR) and electrospray ionization-mass spectrometry, we evidence here that the ionization step is not involved in this deleterious process. Instead, removal of the halogen was shown to readily occur upon interaction of the silver salt (AgTFA) used as the cationizing agent in mass spectrometry, either in solution or in the solid-state when performing solvent-free sample preparation. In solution, this silver-induced reaction mostly consists of a nucleophilic substitution, leading to polystyrene molecules holding different terminations, depending on relative nucleophilicity of species present in the liquid-phase solution composition. In chloroform supplemented with AgTFA, trifluoroacetate-terminated PS were evidenced in ESI-MS spectra but experienced end-group cleavage in MALDI. In contrast, the major methoxy-terminated PS macromolecules formed when the silver-catalyzed nucleophilic substitution was performed in methanol were generated as intact gas phase ions using both ionization techniques. This controlled and fast modification could hence be advantageously used as a rapid sample pretreatment for safe MALDI mass analysis of ATRP-made polystyrene. PMID- 23662634 TI - The neurobiological correlates of childhood adversity and implications for treatment. AB - OBJECTIVE: This article provides an overview of research on the neurobiological correlates of childhood adversity and a selective review of treatment implications. METHOD: Findings from a broad array of human and animal studies of early adversity were reviewed. RESULTS: Topics reviewed include neuroendocrine, neurotrophic, neuroimaging, and cognitive effects of adversity, as well as genetic and epigenetic influences. Effects of early-life stress on treatment outcome are considered, and development of treatments designed to address the neurobiological abnormalities is discussed. CONCLUSION: Early adversity is associated with abnormalities of several neurobiological systems that are implicated in the development of psychopathology and other medical conditions. Early-life stress negatively impacts treatment outcome, and individuals may require treatments that are specific to this condition. PMID- 23662638 TI - Thermally active hybridization drives the crystallization of DNA-functionalized nanoparticles. AB - The selectivity of DNA recognition inspires an elegant protocol for designing versatile nanoparticle (NP) assemblies. We use molecular dynamics simulations to analyze dynamic aspects of the assembly process and identify ingredients that are key to a successful assembly of NP superlattices through DNA hybridization. A scale-accurate coarse-grained model faithfully captures the relevant contributions to the kinetics of the DNA hybridization process and is able to recover all experimentally reported to date binary superlattices (BCC, CsCl, AlB2, Cr3Si, and Cs6C60). We study the assembly mechanism in systems with up to 10(6) degrees of freedom and find that the crystallization process is accompanied with a slight decrease of enthalpy. Furthermore, we find that the optimal range of the DNA linker interaction strengths for a successful assembly is 12-16kBT, and the optimal mean lifetime of a DNA hybridization event is 10(-4)-10(-3) of the total time it takes to form a crystal. We also obtain the optimal percentage of hybridized DNA pairs for different binary systems. On the basis of these results, we propose suitable linker sequences for future nanomaterials design. PMID- 23662639 TI - The effectiveness of artificial intelligent 3-D virtual reality vocational problem-solving training in enhancing employment opportunities for people with traumatic brain injury. AB - BACKGROUND: People with traumatic brain injury (TBI) often experience cognitive deficits in attention, memory, executive functioning and problem-solving. The purpose of the present research study was to examine the effectiveness of an artificial intelligent virtual reality (VR)-based vocational problem-solving skill training programme designed to enhance employment opportunities for people with TBI. METHOD: This was a prospective randomized controlled trial (RCT) comparing the effectiveness of the above programme with that of the conventional psycho-educational approach. Forty participants with mild (n = 20) or moderate (n = 20) brain injury were randomly assigned to each training programme. Comparisons of problem-solving skills were performed with the Wisconsin Card Sorting Test, the Tower of London Test and the Vocational Cognitive Rating Scale. RESULTS: Improvement in selective memory processes and perception of memory function were found. Across-group comparison showed that the VR group performed more favourably than the therapist-led one in terms of objective and subjective outcome measures and better vocational outcomes. CONCLUSIONS: These results support the potential use of a VR-based approach in memory training in people with MCI. Further VR applications, limitations and future research are described. PMID- 23662640 TI - Is induction of labor risky for twins compare to singleton pregnancies? AB - OBJECTIVE: The aim of this study was to investigate whether induction of labor in twin pregnancies is associated with higher rates of maternal complications as compared to singletons. METHOD: A retrospective population-based study was conducted to compare maternal complications following induction of labor in twin pregnancies and singletons at Soroka University Medical Center, Be'er-Sheva, Israel, between 1988 and 2010. Stratified analysis using a multiple logistic regression model was performed to control for confounders. RESULTS: The study population included 25 913 patients following induction of labor, of these 191 (0.73%) were in twin pregnancies. Induction of labor in twin pregnancies was not associated with adverse maternal outcomes such as cervical tears, third degree perineal tears, uterine rupture, peripartum hysterectomy, post-partum hemorrhage or retained placenta. However, labor induction in twins was significantly associated with cesarean deliveries (31.2% versus 17.1%; p < 0.001). Using a multivariable analysis controlling for confounders, induction at twins was an independent risk factor for cesarean delivery (CD; adjusted OR = 2.2, 95% CI 1.7 2.7, p < 0.001). CONCLUSION: Induction of labor in twin pregnancies does not increase the risk for maternal complications. However, it is an independent risk factor for CD. PMID- 23662641 TI - Orbital metastasis secondary to merkel cell carcinoma: case report and literature review. AB - INTRODUCTION: Merkel cell carcinoma is an aggressive malignancy often associated with metastatic spread, but has never been reported to metastasize to the orbit. CASE: An 80 year old male with metastatic Merkel cell carcinoma presented with ptosis and extraocular movement abnormalities, and was found to have a lesion of the orbit consistent with metastatic spread. The lesion responded favorably to radiation therapy. COMMENT: Although the orbit is a frequent site of metastatic disease, this is the first reported case of presumed Merkel cell carcinoma metastasizing to the orbit. PMID- 23662642 TI - Estimating inpatient hospital prices from state administrative data and hospital financial reports. AB - OBJECTIVE: To develop a tool for estimating hospital-specific inpatient prices for major payers. DATA SOURCES: AHRQ Healthcare Cost and Utilization Project State Inpatient Databases and complete hospital financial reporting of revenues mandated in 10 states for 2006. STUDY DESIGN: Hospital discharge records and hospital financial information were merged to estimate revenue per stay by payer. Estimated prices were validated against other data sources. PRINCIPAL FINDINGS: Hospital prices can be reasonably estimated for 10 geographically diverse states. All-payer price-to-charge ratios, an intermediate step in estimating prices, compare favorably to cost-to-charge ratios. Estimated prices also compare well with Medicare, MarketScan private insurance, and the Medical Expenditure Panel Survey prices for major payers, given limitations of each dataset. CONCLUSIONS: Public reporting of prices is a consumer resource in making decisions about health care treatment; for self-pay patients, they can provide leverage in negotiating discounts off of charges. Researchers can also use prices to increase understanding of the level and causes of price differentials among geographic areas. Prices by payer expand investigational tools available to study the interaction of inpatient hospital price setting among public and private payers- an important asset as the payer mix changes with the implementation of the Affordable Care Act. PMID- 23662646 TI - Layer-by-layer film growth using polysaccharides and recombinant polypeptides: a combinatorial approach. AB - Nanostructured films consisting of polysaccharides and elastin-like recombinamers (ELRs) are fabricated in a layer-by-layer manner. A quartz-crystal microbalance with dissipation monitoring (QCM-D) is used to follow the buildup of hybrid films containing one polysaccharide (chitosan or alginate) and one of several ELRs that differ in terms of amino acid content, length, and biofunctionality in situ at pH 4.0 and pH 5.5. The charge density of the ingredients at each pH is determined by measuring their zeta-potential, and the thickness of a total of 36 different films containing five bilayers is estimated using the Voigt-based viscoelastic model. A comparison of the values obtained reveals that thicker films can be obtained when working at a pH close to the acidity constant of the polysaccharide used (near-pKa conditions), suggesting that the construction of such films is more favorable when based on the presence of hydrophobic interactions between ELRs and partially neutralized polysaccharides. Further analysis shows that the molecular weight of the ELRs plays only a minor role in defining the growth tendency. When taken together, these results point to the most favorable conditions for constructing nanostructured films from natural and distinct recombinant polypeptides that can be tuned to exhibit specialized biofunctionality for tissue-engineering, drug-delivery, and biotechnological applications. PMID- 23662647 TI - CE the effect of varying diagnostic terminology within patient discharge information on expected mild traumatic brain injury outcome. AB - This study aimed to determine if systematic variation of the diagnostic terminology embedded within written discharge information (i.e., concussion or mild traumatic brain injury, mTBI) would produce different expected symptoms and illness perceptions. We hypothesized that compared to concussion advice, mTBI advice would be associated with worse outcomes. Sixty-two volunteers with no history of brain injury or neurological disease were randomly allocated to one of two conditions in which they read a mTBI vignette followed by information that varied only by use of the embedded terms concussion (n = 28) or mTBI (n = 34). Both groups reported illness perceptions (timeline and consequences subscale of the Illness Perception Questionnaire-Revised) and expected Postconcussion Syndrome (PCS) symptoms 6 months post injury (Neurobehavioral Symptom Inventory, NSI). Statistically significant group differences due to terminology were found on selected NSI scores (i.e., total, cognitive and sensory symptom cluster scores (concussion > mTBI)), but there was no effect of terminology on illness perception. When embedded in discharge advice, diagnostic terminology affects some but not all expected outcomes. Given that such expectations are a known contributor to poor mTBI outcome, clinicians should consider the potential impact of varied terminology on their patients. PMID- 23662648 TI - Cotransport of titanium dioxide and fullerene nanoparticles in saturated porous media. AB - This study investigated the cotransport of titanium dioxide nanoparticles (nTiO2) and fullerene nanoparticles (nC60), two of the most widely utilized nanoparticles, in saturated quartz sand under a series of ionic strengths in NaCl solutions (0.1-10 mM) at both pH 5 and 7. Under all examined ionic strengths at pH 5, both breakthrough curves and retained profiles of nTiO2 in the copresence of nC60 were similar to those without nC60, indicating that nC60 nanoparticles copresent in suspensions did not significantly affect the transport and retention of nTiO2 in quartz sand at pH 5. In contrast, under all examined ionic strengths at pH 7, the breakthrough curves of nTiO2 in the copresence of nC60 in suspensions were higher and the retained profiles were lower than those without nC60, which demonstrated that the presence of nC60 in suspensions increased the rate of transport (decreased retention) of nTiO2 in quartz sand at pH 7. Competition of deposition sites on quartz sand surfaces by the copresence of nC60 was found to contribute to the increased nTiO2 transport at pH 7. Under all examined ionic strength conditions at both pH 5 and 7, the breakthrough curves of nC60 were reduced in the copresence of nTiO2, and the corresponding retained profiles were higher than those without nTiO2, indicating that the presence of nTiO2 decreased the transport of nC60 in quartz sand. Co-deposition of nC60 with nTiO2 in the form of nTiO2-nC60 clusters as well as the deposition of nC60 onto previously deposited nTiO2 were responsible for the increased nC60 deposition in the presence of nTiO2 at pH 5, whereas deposition of nC60 onto surfaces of predeposited nTiO2 was found to be responsible for the increased nC60 deposition at pH 7. PMID- 23662649 TI - In situ expression of heat-shock proteins and 3-nitrotyrosine in brains of young rats exposed to a WiFi signal in utero and in early life. AB - The bioeffects of exposure to Wireless High-Fidelity (WiFi) signals on the developing nervous systems of young rodents was investigated by assessing the in vivo and in situ expression levels of three stress markers: 3-Nitrotyrosine (3 NT), an oxidative stress marker and two heat-shock proteins (Hsp25 and Hsp70). These biomarkers were measured in the brains of young rats exposed to a 2450 MHz WiFi signal by immunohistochemistry. Pregnant rats were first exposed or sham exposed to WiFi from day 6 to day 21 of gestation. In addition three newborns per litter were further exposed up to 5 weeks old. Daily 2-h exposures were performed blind in a reverberation chamber and whole-body specific absorption rate levels were 0, 0.08, 0.4 and 4 W/kg. 3-NT and stress protein expression was assayed in different areas of the hippocampus and cortex. No significant difference was observed among exposed and sham-exposed groups. These results suggest that repeated exposure to WiFi during gestation and early life has no deleterious effects on the brains of young rats. PMID- 23662650 TI - Prolongation of life span in the accelerated aging klotho mouse model, by low dose-rate continuous gamma irradiation. AB - While lifespan studies provide basic information for estimating the risk of ionizing radiation, findings on the effect of low-dose/low-dose-rate irradiation on the lifespan of mammals are controversial. Here we evaluate the effect of continuous exposure to low-dose-rate gamma radiation on the lifespan of mice with accelerated aging caused by mutation of the klotho gene. While control mice died within 80 days after birth, more than 10% of mice exposed continuously to 0.35 or 0.7 or mGy/h gamma radiation from 40 days after birth survived for more than 80 days. Two of 50 mice survived for more than 100 days. Low-dose-rate irradiation significantly increased plasma calcium concentration in mutant mice, and concomitantly increased hepatic catalase activity. Although hepatic activity of superoxide dismutase in mutant mice decreased significantly compared to wild-type mice, continuous gamma irradiation decreased the activity in mutant mice significantly. These results suggest that low-dose-rate ionizing radiation can prolong the lifespan of mice in certain settings. PMID- 23662651 TI - Multiple tubulins: evolutionary aspects and biological implications. AB - Plant tubulin is a dimeric protein that contributes to formation of microtubules, major intracellular structures that are involved in the control of fundamental processes such as cell division, polarity of growth, cell-wall deposition, intracellular trafficking and communications. Because it is a structural protein whose function is confined to the role of microtubule formation, tubulin may be perceived as an uninteresting gene product, but such a perception is incorrect. In fact, tubulin represents a key molecule for studying fundamental biological issues such as (i) microtubule evolution (also with reference to prokaryotic precursors and the formation of cytomotive filaments), (ii) protein structure with reference to the various biochemical features of members of the FstZ/tubulin superfamily, (iii) isoform variations contributed by the existence of multi-gene families and various kinds of post-translational modifications, (iv) anti-mitotic drug interactions and mode of action, (v) plant and cell symmetry, as determined using a series of tubulin mutants, (vi) multiple and sophisticated mechanisms of gene regulation, and (vii) intron molecular evolution. In this review, we present and discuss many of these issues, and offer an updated interpretation of the multi-tubulin hypothesis. PMID- 23662652 TI - Evaluation of methods to improve the diagnosis of systemic inflammation in alpacas. AB - BACKGROUND: The stoic nature of alpacas and limitations of current diagnostic tests make early recognition of inflammatory diseases in this species challenging. OBJECTIVES: In a model of mild systemic inflammation, this study evaluated the utility of different clinical and clinicopathologic variables as accurate predictors of inflammation in alpacas. ANIMALS: Twelve clinically healthy alpacas were randomly assigned to equal-sized treatment (TG) and control (CG) groups. After collection of initial blood samples (0 hour), lipopolysaccharide (LPS; 20 MUg/kg/24 h) or saline was administered by SC osmotic mini-pumps (OMP) for 96 hours. Additional blood samples were collected at 12, 18, 24, 36, 48, 72, 96, 120, 144, and 240 hours and differential leukocyte counts and concentrations of globulin, albumin, iron, haptoglobin, and serum amyloid A were measured. RESULTS: Mild swelling was observed at OMP implantation sites in both groups. Other clinical signs of systemic inflammation were not observed. Total leukocytes, neutrophils, albumin, and globulin concentrations were not significantly different between groups. Compared with CG-alpacas, TG-alpacas had fewer lymphocytes (P = .0322), more band neutrophils (P = .0087), and higher neutrophil/lymphocyte ratios (P = .0295) during the first 96 hours of the study. During LPS administration, serum iron concentrations were significantly decreased in TG-alpacas (P < .0001). Haptoglobin concentrations of TG-animals exceeded those of CG-animals after removal of OMP (P = .0056). Serum amyloid A was not detectable in alpacas in this study. CONCLUSION AND CLINICAL IMPORTANCE: These results indicated that neutrophil/lymphocyte ratios and serum iron concentrations are early indicators of inflammation in alpacas. Additional research is needed to evaluate the acute phase protein responses of alpacas. PMID- 23662654 TI - Dietary practices and influences on diet intake among women in a Woodland Cree community. AB - BACKGROUND: Overweight and obesity are increasing concerns among Aboriginal women, and lifestyle behaviours (i.e. dietary patterns and physical activity) are considered to be contributing factors. The present study aimed to explore the social, cultural, behavioural and environmental factors influencing diet intake from a trans-generational perspective and to characterise the dietary practices among Woodland Cree women. METHODS: A mixed methods design using a concurrent triangulation approach explored the factors influencing diet intake and healthy eating among First Nations women on a reserve community in northern Saskatchewan, Canada. Dietary practices were assessed using 24-h recalls. RESULTS: Dietary analysis revealed low intake of fruits and vegetables and milk and alternatives in the sample, with high intake of 'other' foods. Limited amounts of traditional food (TF) were reported. Taste primarily influenced food choice, with a preference for TF highlighted among older participants. Healthy eating was considered to be a health-promoting behaviour, yet a lack of availability, high costs and difficulties accessing various foods were the most noted barriers to healthy eating. CONCLUSIONS: The dietary practices in this sample indicate the limited consumption and variety of TF and fruits and vegetables, and a high consumption of 'other' foods, which suggests inadequate intakes of various vitamins and nutrients. The findings from a trans-generational perspective highlight various barriers across the age groups that can substantially impact food choices, and reinforces the need for community and age-specific strategies to address issues of exposure, accessibility and affordability to nutritious foods that improve the diet and preserve cultural identity among residents living in reserve communities. PMID- 23662653 TI - Performance of a clinical prediction score for thrombotic thrombocytopenic purpura in an independent cohort. AB - BACKGROUND AND OBJECTIVES: Idiopathic thrombotic thrombocytopenic purpura (TTP) is a rare, clinically diagnosed disorder characterized by widespread intravascular platelet thrombosis. The pathophysiology involves acquired deficiency of ADAMTS13 (A disintegrin and metalloprotease with thrombospondin type 1 repeats), the enzyme responsible for cleavage of high molecular weight vonWillebrand factor multimers. Disease mortality is high, although prompt treatment with plasma exchange is generally effective. A readily available and highly reliable method of identifying ADAMTS13-deficient patients for appropriate plasma exchange is therefore of interest. MATERIALS AND METHODS: Our initial study involved the assessment of multiple clinical and laboratory variables in patients with clinically suspected TTP for whom ADAMTS13 assay was performed. Five variables were found to be of significant predictive power. This enabled the development of a point-based scoring system to efficiently determine the likelihood of TTP and response to plasma exchange in a given patient. This current study involved a separate validation cohort of patients with clinically suspected TTP who underwent ADAMTS13 testing within two large healthcare systems in Utah between 2009 and 2011. The previously derived score was applied to this cohort and its performance was analysed. Additionally, the original and validation cohorts were combined to revisit the predictive power of individual variables and the five-variable prediction score. RESULTS: A total of 84 (11 paediatric cases excluded) patients comprised the validation population. The percentage of TTP diagnoses in this group (10%) was identical to that in the initial cohort. Using an ADAMTS13 activity of <10% of normal, our original score correctly predicted or excluded severe ADAMTS13 deficiency in all patients in the second cohort when data for all variables was available. Individual variables retained predictive power and the performance of a three-variable parsimonious model, as well as the ultimate diagnoses for patients in the second cohort are described. CONCLUSION: This work confirms the predictive power of a simple point based score to exclude TTP as evidenced by severe ADAMTS13 deficiency in appropriately selected patients. It may enable clinicians to rapidly begin plasma exchange or to pursue an alternative cause of thrombotic microangiopathy. PMID- 23662655 TI - Craniomaxillofacial surgery planning based on 3D models derived from Cone-Beam CT data. AB - INTRODUCTION: Individual planning of complex maxillofacial corrections may require 3D models which can be manufactured based on DICOM datasets. The gold standard for image acquisition is still high-resolution multi-slice computed tomography (MSCT). However, appropriate datasets for model fabrication can be acquired by modern Cone-Beam CT (CBCT) devices that have been developed specifically for maxillofacial imaging. The clinical utility of individual models fabricated on the basis of CBCT datasets was assessed. METHODS: In five patients affected by different deficiencies of the maxillofacial skeleton, preoperative imaging was performed with ILUMA CBCT. Segmentation of hard tissues was performed manually by thresholding. Corresponding STL datasets were created and exported to an industrial service provider (Alphaform, Munich, Germany) specializing in rapid prototyping, and 3D models were fabricated by the selective laser sintering (SLS) technique. For variance analysis, landmark measurements were performed on both virtual and 3D models. Subsequently, maxillofacial surgery was performed according to the model-based planning. RESULTS: All CBCT-based DICOM datasets could be used for individual model fabrication. Detailed reproduction of individual anatomy was achieved and a topographic survey showed no relevant aberrance between the virtual and real models. The CBCT-based 3D models were therefore used for planning and transfer of different maxillofacial procedures. CONCLUSIONS: CBCT-based datasets can be used for the fabrication of surgical 3D models if the correct threshold is set. Preoperative workflow and patient comfort is improved in terms of the fast-track concept by using this "in-house" imaging technique. PMID- 23662656 TI - Unusual manifestations of a common gastrointestinal disorder. AB - We present an instructive case of a 13-year old male who presented with bilateral scrotal redness, swelling and tenderness, but with a normal testicular exam. His scrotal swelling persisted despite treatment with intravenous antibiotics, and on further history he reported 2 years of intermittent upper lip swelling. After a referral to a dermatologist, a lip biopsy showed granulomatous changes and he was referred to the gastroenterology department. A gastroscopy and colonoscopy was performed and histology confirmed non-caseating granulomas consistent with Crohn's disease (CD). Eighteen months after the diagnosis of CD he developed perianal disease with a fistula and distal anal stricture. He was successfully treated with insertion of a seton and escalation of therapy to azathioprine and infliximab. CD is a phenotypically diverse chronic inflammatory condition with an increasing incidence in Australia and other Western countries. Non-typical presentations, such as perianal manifestations or orofacial granulomatosis, can be the only presenting symptom in CD, and this highlights the importance for a high degree of clinical suspicion. Genital involvement is rare, but reported. PMID- 23662657 TI - Instrumentation related complications in spine surgery. AB - Spinal instrumentation constructs are frequently necessary for the surgical management of patients with variable spinal pathology. However, surgical complications may appear. These should be detected early and managed to achieve recovery and good functional outcome for the patient. This article provides an in depth analysis of the most common instrumentation-related complications of spine surgery as well as a diagnostic plan and treatment options for the management of these challenging entities once they occur. PMID- 23662658 TI - Hip pain and pseudo-lengthening of the leg due to iliopsoas haematoma following implantation of an uncemented component in acetabular cotyloplasty technique. AB - We report early symptomatic (groin pain and apparent limb lengthening) findings in our 12 consecutive patients who underwent total hip replacements using a cementless acetabular cotyloplasty technique. This report is the first in the literature to mention such an early complication in a large number of patients and also to describe early detection and treatment in these cases. During the period of January 2007 to December 2010, 12 patients (seven female, five male) with dysplastic hip underwent total hip arthroplasty. The mean age of the patients was 57 years (range 52-61 years) and the mean follow-up time was 18 months (12-36 months). A cotyloplasty technique was performed and uncemented acetabular and femoral components were implanted in all these 12 patients. All patients were reviewed postoperatively for clinical and radiographic assessment at six weeks, three months, six months, and one year, and then annually thereafter. During the first one to two months (mean time 22 +/- 16 days), all patients complained of a constant pain in the groin that started in the early postoperative period. A pseudo lengthening of the operated hip and pelvic tilt was found on clinical examination at the three-month follow-up. The True length did not reveal a significant leg length discrepancy. Hip pain, pseudo lengthening, and pelvic tilt resolved within 123 +/- 17 days post-op. A cotyloplasty technique using an uncemented acetabular implant can cause an intrapelvic hematoma of the iliopsoas muscle giving rise to temporary groin pain, pseudo lengthening on the operated side, and gait disturbances to the patient in the early postoperative period. Symptoms resolved completely in all of our cases. Iliopsoas physiotherapy could be useful and should be encouraged during the symptomatic period. Patients have to be informed during consenting and reassured about this symptomatology. Awareness of this likely complication would help surgeons to detect the problem and initiate treatment early. PMID- 23662659 TI - Treatment of adhesive capsulitis of the shoulder with a static progressive stretch device: a prospective, randomized study. AB - Stress relaxation and static progressive stretch (SPS) are techniques that may be used to nonoperatively restore joint range of motion in the setting of adhesive capsulitis. The purpose of this study was to prospectively compare standard physical therapy alone to a combination of physical therapy with a static progressive stretch orthosis in the treatment of shoulder adhesive capsulitis. A prospective, randomized, blinded, controlled study was conducted with a total of 60 patients diagnosed with shoulder adhesive capsulitis (30 patients in the control group, 30 patients in the treatment group). The control group received physical therapy for 4 weeks, while the experimental group received physical therapy and were treated with a static progressive stretch shoulder device for 4 weeks. Active and passive abduction, passive external rotation, DASH scores, and VAS pain scores were recorded for all patients at 4, 12, and 24 weeks follow-up. Use of a static progressive stretch orthosis compared to physical therapy alone demonstrated a significantly greater mean improvement in all range-of-motion categories. Mean passive abduction was 162 degrees with the orthosis versus 136 degrees with physical therapy alone. Mean active abduction was 141 degrees and 114 degrees , respectively. Mean external rotation was 73 degrees and 52 degrees , respectively. DASH scores were significantly better when a static progression stretch orthosis was used (5 vs.15 points). Use of a static progressive stretch orthosis for patients with shoulder adhesive capsulities resulted in significantly better range of motion and DASH scores within 1 month of beginning treatment than physical therapy alone. PMID- 23662660 TI - Assessment of static progressive stretch for the treatment of shoulder stiffness: a prospective case series. AB - INTRODUCTION: The purpose of this study was to evaluate the use of a patient directed static progressive stretch orthosis for the treatment of shoulder stiffness. METHODS: Twenty-three patients who had limitations in range of motion of the shoulder and who had failed conventional physical therapy methods were studied. This cohort included 15 women and 8 men with a mean age of 53 years. Treatment comprised one to three 30- to 60-minute sessions per day with a patient controlled orthosis utilizing static progressive stretch. The patients adjusted the degree of stretch at 5-minute intervals as tolerated. Compliance, range of motion, patient satisfaction, and complications were assessed, and a two-way repeated measure ANOVA was performed to assess the effects of age or gender. RESULTS: After a mean treatment duration of 10 weeks (range, 4 to 19 weeks), the patients gained a mean of 22 degrees (range, -47 to 57 degrees ) of external rotation, 18 degrees (range, -19 to 55 degrees ) of internal rotation, 46 degrees (range, 3 to 97 degrees ) of abduction, and 23 degrees (range, 3 to 40 degrees ) of forward flexion. In total, 22 of 23 patients (96%) experienced increases in range of motion that were maintained at 1 year following treatment. Statistically significant increases in range of motion and clinical function scores were noted; age and gender did not appear to influence the outcomes. DISCUSSION: This device compared favorably to other treatment methods for shoulder stiffness. An orthosis utilizing static progressive stretch was a useful adjunct for the treatment of shoulder stiffness refractory to conventional therapy. PMID- 23662661 TI - Long-term survival of a flat-on-flat total condylar knee arthroplasty fixed with a hybrid cementing technique for tibial components. AB - PURPOSE: Total knee arthroplasty is one of the most successful procedures of modern orthopedics. Several implants have been proposed over the years with different designs, kinematics, and cementing techniques, with good results. The aim of the study was to assess the clinical and radiographic long-term follow-up of a series of patients undergoing total knee replacement that used a specific design of knee implant with cemented femoral and patellar components, and a hybrid fixation technique for tibial trays that used a cemented base plate and press-fit keels. METHODS: A total of 145 implants in 135 patients were studied with clinical and radiologic evaluations. The mean follow-up was 17.1 years. RESULTS: Seven failures for aseptic loosening and four failures for infection were registered. Twenty-nine implants showed nonprogressive radiolucencies, mostly at a single component, which did not need revision. The overall survivorship at the mean follow-up of 15 years considering aseptic loosening as the endpoint was 92.1%. CONCLUSIONS: The authors confirm the good rates of success and the long-term survival of this specific implant and the effectiveness of the tibial hybrid cementing technique, which is still debated among researchers. PMID- 23662662 TI - Computer-assisted navigation in knee surgery. AB - Although computer-assisted navigation has been used in clinical practice for more than 15 years, it has only recently started to gain acceptance in a variety of orthopedic procedures. Different types of computer-assisted navigation are available, which allow the surgeon to obtain real-time feedback and offer him the potential to decrease intraoperative errors. However, its increased cost and lacking evidence of long-term superiority have made many surgeons skeptical about its clinical usefulness. The scope of this article is to review the clinical applications of computer-assisted navigation in orthopedic surgery of the knee joint. PMID- 23662663 TI - Dental implantation: an opportunity to stop smoking. AB - Cigarette smoking and tobacco consumption are serious hazards threatening the health of human beings. Several strategies have been proposed for smoking cessation in patients presenting to medical centers to seek treatment. Some believe that the dental profession plays a key role in quit smoking programs due to its extensive and long-term relationship with patients. Use of known strategies to create motivation for quitting smoking among patients has yielded relatively optimal results. However, it seems that patients' attitudes toward smoking can be changed if we enhance their knowledge about the hazards of tobacco consumption and its adverse effects on dental and oral health and especially the health of dental implants' surrounding structures. This study reports smoking cessation in two patients requiring dental implant treatment. Twenty-eight months after loading of implants, treatment success was confirmed by use of clinical and radiographic indices. No sign of peri-implant disease was detected and the patients were eagerly following the smoking cessation program. It seems that contemporary dental treatments, especially dental implant therapy, can provide a good opportunity to create the motivation required for lifestyle changes in patients. PMID- 23662664 TI - A real-world comparative assessment of complications following various mid urethral sling procedures for the treatment of stress urinary incontinence. AB - Stress urinary incontinence affects a significant proportion of the adult female population in the United States with prevalence increasing with growing age. Mid urethral slings are among surgical options offering important improvement in the condition. The aim of this study was to evaluate clinical outcomes of different mid-urethral sling products with respect to postsurgery complications. This retrospective study utilized data from the Premier Perspective Database for mid urethral sling procedures between 2005 and 2009. Patients were grouped into retropubic or transobturator cohorts, and these cohorts were further divided by the sling utilized during the procedure. Surgical outcomes and 12-month complication rates were assessed. In general, there were fewer complications noted for transobturator procedures than for retropubic procedures. In the retropubic category, Gynecare TVT had significantly lower rates of urinary obstruction/retention than other retropubic procedures. In the transobturator category, lower rates of overall pelvic complications as well as urologic complications, including urgency incontinence and urinary tract infections, were observed in the Gynecare TVTO subgroup than other transobturator procedures. Results of this study confirm the low overall rate of complications for midurethral sling procedures while at the same time suggesting that product choice may also have an impact on complication rates. PMID- 23662665 TI - X chromosome inactivation and epigenetic responses to cellular reprogramming. AB - Reprogramming somatic cells to derive induced pluripotent stem cells (iPSCs) has provided a new method to model disease and holds great promise for regenerative medicine. Although genetically identical to their donor somatic cells, iPSCs undergo substantial changes in the epigenetic landscape during reprogramming. One such epigenetic process, X chromosome inactivation (XCI), has recently been shown to vary widely in human female iPSCs and embryonic stem cells (ESCs). XCI is a form of dosage compensation whose chief regulator is the noncoding RNA Xist. In mouse iPSCs and ESCs, Xist expression and XCI strictly correlate with the pluripotent state, but no such correlation exists in humans. Lack of XIST expression in human cells is linked to reduced developmental potential and an altered transcriptional profile, including upregulation of genes associated with cancer, which has therefore led to concerns about the safety of pluripotent stem cells for use in regenerative medicine. In this review, we describe how different states of XIST expression define three classes of female human pluripotent stem cells and explore progress in discovering the reasons for these variations and how they might be countered. PMID- 23662666 TI - Cellular assays for drug discovery in genetic disorders of intracellular trafficking. AB - Intracellular membrane trafficking is essential for organelle biogenesis, structure, and function; the exchange of material between organelles; and communication between the cell and its external environment. Genetic disorders affecting intracellular trafficking can lead to a variety of human diseases, but specific therapies for these diseases are notably lacking. In this article, we focus on how current knowledge about genetic disorders that affect intracellular trafficking can be used to develop strategies for cell-based assays in order to identify drugs using high-content screening approaches. PMID- 23662667 TI - Modified ventral stabilization using positively threaded profile pins and polymethylmethacrylate for atlantoaxial instability in 49 dogs. AB - OBJECTIVE: To describe diagnostic findings, complications, and long-term outcome of dogs with atlantoaxial instability (AAI) that had modified ventral stabilization with positively threaded profile pins and polymethylmethacrylate by 1 surgeon and to evaluate the potential prognostic indicators. STUDY DESIGN: Retrospective case series. ANIMALS: Dogs (n = 49) with AAI. METHODS: Medical records (2000-2010) of dogs with AAI that had modified ventral stabilization were reviewed. Data on pre- and postoperative neurologic status, diagnostic findings, and outcomes were retrieved. Age, neurologic grade, duration of clinical abnormalities, dens abnormalities, and MRI findings were evaluated as the potential predictors for recovery. Age and cancellous bone grafting were evaluated as the potential predictors of postoperative pin breakage. RESULTS: Two dogs died during the perioperative period. In 47 dogs with follow up (median: 29 months; range, 4-110 months), 46 dogs (94%) improved neurologically after surgery, but 1 dog did not become ambulatory. There were no long term complications that resulted in serious neurologic deterioration or that required additional surgery. Partial pin breakage (1-5 pins) occurred in 16 dogs at 1-27.5 months (median, 5 months) without neurologic deterioration. Only the nonambulatory preoperative grade was significantly (P = .002) associated with non/incomplete recovery compared with ambulatory dogs. CONCLUSIONS: Adequate stabilization of the vertebrae and improved neurologic status were achieved in most dogs with AAI using a modified ventral stabilization technique with positively threaded profile pins and polymethylmethacrylate. PMID- 23662668 TI - Computed tomographic features of lesions detected in horses with tarsal lameness. AB - REASONS FOR PERFORMING STUDY: Tarsal pain is a common cause of hindlimb lameness in horses. Diagnosis can usually be made with radiography and ultrasonography; however, in some cases, these techniques are inconclusive and additional imaging is necessary. No studies describing computed tomography (CT) features of different tarsal lesions in horses with tarsal lameness are reported. OBJECTIVES: Our aims were as follows: 1) to characterise CT abnormalities in horses with tarsal lameness; 2) to compare CT findings with those from other imaging techniques; and 3) to assess whether CT can help to diagnose tarsal pathology. STUDY DESIGN: Retrospective case series. METHODS: Computed tomography of the tarsus was performed on 15 horses (n = 17 joints) with tarsal lameness. The horses were divided into 3 groups depending on the reason for CT examination, as follows: 1) other imaging techniques were inconclusive; 2) evaluation of a fracture; or 3) other imaging techniques showed tarsal lesions, and CT was performed to assess whether additional lesions were present. RESULTS: Group 1 included 7 horses. Lesions detected with CT included subchondral cyst-like lesions (2 horses); an osteolytic lesion in the cochlea tibiae (one horse); degenerative changes of the distal tarsal joints (2 horses); osteolytic lesions tarsometatarsal joint (one horse); and sclerosis of the third tarsal bone with a lesion of the tarsometatarsal interosseous ligament (one horse). In this group, CT provided information on the character and extent of the lesion that was not available with other imaging techniques. Computed tomography revealed more information about the extent and complexity of the fracture than radiography in Group 2, whereas CT did not provide extra information in Group 3. CONCLUSIONS: Focal lesions located between the tarsal bone surfaces are difficult or even impossible to detect with radiography and ultrasonography, but they can be detected and characterised with CT. POTENTIAL RELEVANCE: Computed tomography of the tarsus should be considered when radiography and ultrasonography are inconclusive, or for further evaluation of tarsal fractures. PMID- 23662669 TI - GdN nanoisland-based GaN tunnel junctions. AB - Tunnel junctions could have a great impact on gallium nitride and aluminum nitride-based devices such as light-emitting diodes and lasers by overcoming critical challenges related to hole injection and p-contacts. This paper demonstrates the use of GdN nanoislands to enhance interband tunneling and hole injection into GaN p-n junctions by several orders of magnitude, resulting in low tunnel junction specific resistivity (1.3 * 10(-3) Omega-cm(2)) compared to the previous results in wide band gap semiconductors. Tunnel injection of holes was confirmed by low-temperature operation of GaN p-n junction with a tunneling contact layer, and strong electroluminescence down to 20 K. The low tunnel junction resistance combined with low optical absorption loss in GdN is very promising for incorporation in GaN-based light emitters. PMID- 23662670 TI - Involuntary treatment of schizophrenia patients 2004-2010 in Denmark. AB - OBJECTIVE: Treatment of schizophrenia is frequently complicated by patients' ambivalence and lack of insight into the disease, occasionally warranting involuntary treatment. This study aims to describe involuntary treatment in Danish schizophrenia patients. METHOD: Patients diagnosed with a lifetime ICD-10 F20 schizophrenia diagnosis and alive in the period 2004-2010 were identified in the Danish Psychiatric Central Research Register, and data were linked to The Registry of Coercive Measures in Psychiatric Treatment. RESULTS: Within the study period, a total of 18,599 admitted patients were identified, 3078 of which underwent involuntary treatment. The incidence rate for any involuntary treatment was 2.1 per in-patient year and 1.7 and 0.3 per in-patient year for rapid tranquilization and involuntary treatments, respectively. Somatic diseases comprised 34.5% of all involuntary treatments. Psychotropics comprised 56.9% with antipsychotics as the most common drug class (99.5%). Olanzapine was the most commonly used antipsychotic drug (33.2%). Treatment with depot injection and clozapine comprised only 13% and 4.8% of the antipsychotics used, respectively. Electroconvulsive therapy comprised 4.8% of all involuntary treatment. CONCLUSION: Involuntary treatment involved a wide range of somatic treatment. Antipsychotic medicine was the most common psychotropic used. Involuntary treatment with depot antipsychotics and clozapine were rare. PMID- 23662671 TI - Pyrrole-fused azacoronene family: the influence of replacement with dialkoxybenzenes on the optical and electronic properties in neutral and oxidized states. AB - A novel pyrrole-fused azacoronene family was synthesized via oxidative cyclodehydrogenation of the corresponding hexaarylbenzenes as the key step, and the crystal structures of tetraazacoronene 3b and triazacoronene 4a were elucidated. The photophysical properties for neutral compounds 1-4 were investigated using steady-state UV-vis absorption/emission spectroscopy and time resolved spectroscopy (emission spectra and lifetime measurements) at both room temperature and 77 K. The observation of both fluorescence and phosphorescence allowed us to estimate the small S1-T1 energy gap (DeltaES-T) to be 0.35 eV (1a), 0.26 eV (2a), and 0.36 eV (4a). Similar to the case of previously reported hexapyrrolohexaazacoronene 1 (HPHAC), electrochemical oxidation revealed up to four reversible oxidation processes for all of the new compounds. The charge and spin delocalization properties of the series of azacoronene pi-systems were examined using UV-vis-NIR absorption, ESR, and NMR spectroscopies for the chemically generated radical cations and dications. Combined with the theoretical calculations, the experimental results clearly demonstrated that the replacement of pyrrole rings with dialkoxybenzene plays a critical role in the electronic communication, where resonance structures significantly contribute to the thermodynamic stability of the cationic charges/spins and determine the spin multiplicities. For HPHAC 1 and pentaazacoronene 2, the overall aromaticity predicted for closed-shell dications 1(2+) and 2(2+) was primarily based on the theoretical calculations, and the open-shell singlet biradical or triplet character was anticipated for tetraazacoronene 3(2+) and triazacoronene 4(2+) with the aid of theoretical calculations. These polycyclic aromatic hydrocarbons (PAHs) represent the first series of nitrogen-containing PAHs that can be multiply oxidized. PMID- 23662672 TI - Early cranioplasty may improve outcome in neurological patients with decompressive craniectomy. AB - PRIMARY OBJECTIVE: Decompressive craniectomy is an effective therapy to relieve intractable intracranial hypertension following acute brain injury. However, little is known about the optimal timing for cranioplasties in the sub-acute phase. The objective of the present study was to analyse the effect of cranioplasty timing on neurological outcomes. RESEARCH DESIGN: Single-centre observational study. METHODS AND PROCEDURES: One hundred and forty-seven consecutive patients with decompressive craniectomy and cranioplasty during the course of inpatient neurorehabilitation were identified by means of a retrospective hospital database search. This database contains the following prospectively-entered weekly scores: Barthel-Index (BI), Functional Independence Measure (FIM) and Coma Remission Scale (CRS). Additional clinical data were taken retrospectively from patient charts. Regression analysis was used to identify factors that influenced the end-of-rehabilitation outcome. MAIN OUTCOMES AND RESULTS: Patients with shorter delays to cranioplasty (<86 days) had a better functional outcome than patients with longer delays of >85 days (60 +/- 29.5 versus 25 +/- 24.1 BI points; p < 0.01, respectively). Age, pre-operative BI and CRS scores were additional independent outcome factors. Complication rates were not different between early and late cranioplasty groups. CONCLUSIONS: Patients with decompressive craniectomy for management of intracranial hypertension may benefit from early cranioplasty. PMID- 23662673 TI - Pachydermoperiostosis: a rare cause of marked blepharoptosis and floppy eyelid syndrome. AB - A 34-year-old African-American man was referred for eyelid swelling and ocular discomfort. He was found to have floppy hypertrophic eyelids and marked bilateral mechanical ptosis that was present since childhood. Systemic examination was significant for furrows on his forehead and scalp, coarse facial features, and enlarged hands and feet with clubbing of the fingers and toes. Radiographic imaging of the long bones demonstrated periostosis, and MRI of the head revealed a pituitary macroadenoma. Pituitary and thyroid hormone levels were normal. The patient was diagnosed with pachydermoperiostosis and a non-secreting pituitary macroadenoma. Bilateral upper lid tightening via wedge resection was followed by bilateral external levator advancement ptosis repair in a staged manner. The patient achieved symptom relief and improved lid position postoperatively. PMID- 23662674 TI - Female fetuses are more reactive when mother eats chocolate. AB - OBJECTIVE: The aim of our study was to analyze whether there is a gender difference in the effects of maternal chocolate ingestion (80% cocoa) on the fetus, as expressed by the fetal heart rate (FHR). STUDY DESIGN: One hundred pregnant women with uncomplicated term gestation, matched for age and parity, underwent computerized FHR recording before and after eating 30 g of 80% cocoa chocolate; 46 carried a male fetus, and 54 carried a female. Computerized cardiotocography parameters (baseline FHR in beats per minute, number of contractions/hour, fetal movements/hour, accelerations of at least 15 bpm for 15 s, episodes of high variation/min and short-term variation in ms) were expressed as the mean and SD. We calculated the difference before and after maternal chocolate eating both in male and female fetuses and then compared the gender differences in the FHR variation. Statistical significance was set at p < 0.05. RESULTS: While baseline FHR and number of contractions did not change, the number of: fetal movements/hour, accelerations, episodes of high variation/min, and the short-term variation significantly increased after chocolate ingestion. The percent variation of the movements (101.7 +/- 89.23 males versus 252.0 +/- 297.6 females; p = 0.002), accelerations (70.90 +/- 46.98 males versus 153.3 +/- 178.5 females; p = 0.004) and short-term FHR variation (21.47 +/- 18.73 males versus 37.35 +/- 27.46 females; p = 0.002) increased to a greater degree in the female fetuses than in the males. CONCLUSIONS: The maternal ingestion of dark chocolate induces much more reactivity in female fetuses than in males. This finding supports the existence of an innate gender difference for the effects of chocolate, present even since the fetal period. PMID- 23662676 TI - Simultaneous analysis of the equilibrium hygroscopicity and water transport kinetics of liquid aerosol. AB - We demonstrate that the equilibrium hygroscopic response of an aerosol droplet and the kinetics of water condensation and evaporation can be retrieved with high accuracy, even close to saturation, through comparative measurements of probe and sample aerosol droplets. The experimental methodology is described and is based on an electrodynamic balance with a newly designed trapping chamber. Through use of a probe aerosol, composed of either pure water or a sodium chloride solution of known concentration, the gas-phase relative humidity (RH) can be accurately measured with an uncertainty of typically <0.005. By fast manipulation of the airflows into the chamber, a step-change in RH over a time scale of <0.5 s can be achieved. Using this approach, the kinetics of mass transfer are studied using the comparative procedure, and results are compared to theoretical mass flux predictions. The time-dependent measured mass fluxes for sodium chloride, ammonium sulfate, sorbitol, and galactose are used to calculate droplet water activities as a function of the droplet growth factor, allowing retrieval of a hygroscopic growth curve in a matter of seconds. Comparisons with both new and established thermodynamic predictions of hygroscopicity, as well as to optical tweezers measurements, are presented, demonstrating good agreement within the experimental uncertainties. PMID- 23662675 TI - Results of upper airway radiography and ultrasonography predict dynamic laryngeal collapse in affected horses. AB - REASONS FOR PERFORMING STUDY: The pathogenesis of dynamic bilateral laryngeal collapse (DLC) associated with poll flexion is unknown. Diagnosis is dependent upon exercise endoscopy while replicating the flexed head position harness racehorses experience during racing. OBJECTIVES: To describe the effects of poll flexion on rostrocaudal laryngeal positioning and laryngeal lumen width in resting horses diagnosed with DLC compared to controls, and to establish diagnostic criteria for DLC by use of diagnostic imaging. STUDY DESIGN: Case control study. METHODS: Fifty harness racehorses were prospectively included in the study: 25 cases diagnosed with DLC by treadmill endoscopy and 25 controls in which treadmill endoscopy revealed no abnormal findings. Laryngeal radiography and ultrasonography were obtained in neutral and flexed head positions. Laryngeal positioning and laryngohyoid conformation were compared between the groups and head positions. RESULTS: Poll flexion induced a greater rostral advancement of the larynx in relation to the hyoid apparatus in resting harness racehorses affected with DLC compared to controls (P = 0.007). At the level of the vocal folds, poll flexion resulted in a smaller laryngeal lumen width in horses affected with DLC compared to controls (P = 0.04). Horses were significantly more likely to be affected with DLC when the thyrohyoid bone to thyroid cartilage distance was >=12 mm in poll flexion (odds ratio 21.3, 95% confidence interval 3.65-124.8, P = 0.004) and when laryngeal lumen width at the level of the vocal folds was less in poll flexion than in the neutral head position (odds ratio 8.4; 95% confidence interval 1.6-44.1, P = 0.012). CONCLUSIONS AND POTENTIAL RELEVANCE: In DLC horses, poll flexion advanced the larynx more rostrally and resulted in a decreased airway lumen width compared to control horses. Laryngeal ultrasound and radiography may facilitate the diagnosis of DLC at rest. PMID- 23662677 TI - Probing the electronic structure and chemical bonding in tricoordinate uranyl complexes UO2X3- (X = F, Cl, Br, I): competition between Coulomb repulsion and U X bonding. AB - While uranyl halide complexes [UO2(halogen)n](2-n) (n = 1, 2, 4) are ubiquitous, the tricoordinate species have been relatively unknown until very recently. Here photoelectron spectroscopy and relativistic quantum chemistry are used to investigate the bonding and stability of a series of gaseous tricoordinate uranyl complexes, UO2X3(-) (X = F, Cl, Br, I). Isolated UO2X3(-) ions are produced by electrospray ionization and observed to be highly stable with very large adiabatic electron detachment energies: 6.25, 6.64, 6.27, and 5.60 eV for X = F, Cl, Br, and I, respectively. Theoretical calculations reveal that the frontier molecular orbitals are mainly of uranyl U-O bonding character in UO2F3(-), but they are from the ligand valence np lone pairs in the heavier halogen complexes. Extensive bonding analyses are carried out for UO2X3(-) as well as for the doubly charged tetracoordinate complexes (UO2X4(2-)), showing that the U-X bonds are dominated by ionic interactions with weak covalency. The U-X bond strength decreases down the periodic table from F to I. Coulomb barriers and dissociation energies of UO2X4(2-) -> UO2X3(-) + X(-) are calculated, revealing that all gaseous dianions are in fact metastable. The dielectric constant of the environment is shown to be the key in controlling the thermodynamic and kinetic stabilities of the tetracoordinate uranyl complexes via modulation of the ligand ligand Coulomb repulsions. PMID- 23662678 TI - Extrarenal roles of the with-no-lysine[K] kinases (WNKs). AB - Identified over a decade ago, the with-no-lysine[K] kinases (WNKs) have been the subsequent focus of intense research into the renal handling of Na(+) , Cl(-) and K(+) and several rare monogenetic diseases. However, the potential extrarenal roles for WNKs have been less well explored. Thiazides and Gordon syndrome are known to have effects on bone mineral density, Ca(2+) and PO4 (3-) homeostasis, which were originally assumed to be an indirect effect through the kidney. However, current data suggest a complex and direct role for WNKs in the physiology of bone. The WNKs also modulate systemic blood pressure at several levels, including the vascular resistance vessels, where they cause vasoconstriction by altering the abundance of the transient receptor potential canonical channel 3 and/or phosphorylation of the Na(+) -K(+) -2Cl(-) cotransporter 1 in vascular smooth muscle cells. The WNKs and many of the cation coupled Cl(-) cotransporters they regulate are highly expressed in the central nervous system and recent work suggests that WNK dysfunction may have a role in the development of autism, schizophrenia and hereditary sensory and autonomic neuropathy Type 2. Finally, the WNK-sterile 20 kinase signalling axis represents an evolutionarily ancient mechanism for maintaining osmotic homeostasis, but a rapidly expanding body of evidence also shows a role in immunity and cellular regulation. PMID- 23662679 TI - Timely expression of the Arabidopsis stoma-fate master regulator MUTE is required for specification of other epidermal cell types. AB - Epidermal differentiation in Arabidopsis thaliana aerial organs involves stomatal lineage development. Lineages derive from meristemoids, which arise from asymmetric divisions of protodermal cells. Each meristemoid divides repeatedly in an inward spiral before it transits to a guard mother cell (GMC) that produces the stoma, leaving a trail of surrounding stomatal lineage ground cells (SLGCs) that eventually differentiate into endoreplicated pavement cells. MUTE is a bHLH transcription factor that is expressed in late meristemoids and drives their transition to GMCs. Loss-of-function mute mutants are stomata-less dwarf plants with arrested lineages, in which stunted putative SLGCs surround a halted meristemoid. We analysed MUTE functions using a chemically inducible system for mute-3 complementation based on conditional MUTE expression in its normal domain. Continuous induction from germination produced stomata-bearing, normal-sized plants with viable mute-3 seeds. In 2-week-old mute-3 cotyledons, meristemoids appeared to retain their identity and synchronously formed stomata in response to induced MUTE expression. However, arrested SLGCs were not complemented: many produced stomata, leading to stomatal clusters, and others remained unexpanded and diploid. In contrast, non-lineage pavement cells, which are under endoreplicated in mute-3, expanded and increased their ploidy level upon induction, showing that the lack of response of SLGCs is specific to this arrested cell type. Leaf phenotypic mosaics include wild-type lineages and adjacent mute-3 lineages, whose meristemoids and putative SLGCs remained arrested, indicating that the role of MUTE in SLGC fate is strictly lineage autonomous. These results show that timely MUTE expression is essential to prevent stomatal fate in SLGCs and to promote their differentiation as pavement cells. PMID- 23662680 TI - Separating annihilation and excitation energy transfer dynamics in light harvesting systems. AB - The dependence of excitation energy transfer kinetics on the electronic state of the acceptor (ground vs excited) has been resolved with a novel multipulse prePump-Pump-Probe spectroscopy. The primary energy transfer and annihilation dynamics in two model light-harvesting systems were explored: an artificially synthesized carotenoid-zinc-phthalocyanine dyad and a naturally occurring light harvesting peridinin-chlorophyll protein complex from Amphidinium carterae. Both systems use carotenoid as the primary excitation energy donor with porphyrin chromophores as the acceptor molecules. The prePump-Pump-Probe transient signals were analyzed with Monte Carlo modeling to explicitly address the underlying step by-step kinetics involved in both excitation migration and annihilation processes. Both energy transfer and annihilation dynamics were demonstrated to occur with approximately the same rate in both systems, regardless of the excitation status of the acceptor pigments. The possible reasons for these observations are discussed in the framework of the Forster energy transfer model. PMID- 23662681 TI - Cryopyrin-associated periodic syndromes and the eye. AB - AIM: To describe the ophthalmologic findings in two patients with Muckle-Wells Syndrome, a phenotype of the Cryopyrin Associated Periodic Syndromes (CAPS) spectrum. There is currently sparse ophthalmic literature regarding the ocular manifestations of CAPS. We hope to increase awareness of this spectrum of diseases and the importance of proper treatment amongst eye care professionals. METHODS: Interventional Case Series. RESULTS: Patient 1 experienced resolution of aseptic meningitis, papilledema, and anterior uveitis following treatment with anikinra. Patient 2 experienced resolution of panuveitis following treatment with anikinra. CONCLUSIONS: The severe ocular manifestations of the most severe CAPS phenotype, Chronic Infantile Neurological Cutaneous and Articular Syndrome/Neonatal Onset Multisystem Inflammatory Disease Syndrome (CINCA/NOMID) have been previously described. There is increasing evidence that patients may experience similar ocular disease with the milder phenotype of Muckle-Wells Sydnrome. There is also increasing evidence that appropriate therapy can have a profound effect on patient prognosis. PMID- 23662683 TI - Year 7 dietary intake: a comparison of two schools with middle-high socio economic status. AB - BACKGROUND: With an established, yet avoidable, link between dietary intake and poor health, the nutritional habits of adolescents remains a public health concern. Previous studies report an inverse relationship between dietary intake and socio-economic status (SES), although few studies have considered the influence of the SES gradient. The present study compared the nutritional profiles of neighbouring schools with pupils from middle to high economic backgrounds. METHODS: One hundred and ninety pupils from a high SES school (HSESS) and 159 pupils from a middle SES school (MSESS) (aged 11-12 years) completed a 63-item validated food frequency questionnaire. Pupils rated their diet quality and this was compared with a composite Healthy Eating Index (HEI). RESULTS: Children attending MSESS consumed significantly higher intakes of energy (P < 0.001), carbohydrate (P = 0.001), fat (P < 0.001) and protein (P = 0.001). As a percentage of energy contribution, pupils in both schools consumed excess saturated fat (HSESS, +5% boys, +4% girls; MSESS, +4% both boys and girls) and sugar (HSESS, +9% boys, +11% girls; MSESS, +10% boys, +11% girls). When HEI was compared with self-report diet quality, 96% HSESS pupils and 94% MSESS pupils over-rated the quality of their diet. CONCLUSIONS: The present study identified that, although pupils from MSESS consume a significantly higher intake of energy and macronutrient compared to a nearby HSESS, the percentage of energy contribution of saturated fat and sugar is above government recommendations for pupils from both schools. Additionally, the majority of pupils from both schools substantially over-rated their diet quality compared to a HEI. PMID- 23662684 TI - Outcomes and complications associated with epicardial pacemakers in 28 dogs and 5 cats. AB - OBJECTIVE: To report signalment, history, indications, complications and outcome for 28 dogs and 5 cats in which 34 permanent epicardial pacing leads were surgically placed by transdiaphragmatic approach (32) or intercostal thoracotomy (2). METHODS: Medical records (2005-2010) were reviewed. Signalment, age, species, gender, clinical signs, presence of structural heart disease and/or congestive heart failure, ECG diagnosis, body weight (<10 or >10 kg), and overall survival rate were recorded. Statistical correlations were made between these variables and major and minor complications rates. RESULTS: Except for body weight, no statistical differences were identified in prevalence of major (life threatening or requiring replacement of the pacemaker system) or minor (self limiting) complications; dogs weighing >10 kg had significantly more major complications (P = .03). There was a trend (P = .051) for lower survival in animals that had major complications. CONCLUSIONS: Larger dogs (>10 kg) may be predisposed to more major complications with epicardial pacemaker (EP) implantation. Major complication rate and survival time are similar to those reported for transvenous pacing and therefore implantation of EPs remains a suitable alternative. PMID- 23662682 TI - The proportion of work-related emergency department visits not expected to be paid by workers' compensation: implications for occupational health surveillance, research, policy, and health equity. AB - OBJECTIVE: To examine trends in the proportion of work-related emergency department visits not expected to be paid by workers' compensation during 2003 2006, and to identify demographic and clinical correlates of such visits. DATA SOURCE: A total of 3,881 work-related emergency department visit records drawn from the 2003-2006 National Hospital Ambulatory Medical Care Surveys. STUDY DESIGN: Secondary, cross-sectional analyses of work-related emergency department visit data were performed. Odds ratios and 95 percent confidence intervals were modeled using logistic regression. PRINCIPAL FINDINGS: A substantial and increasing proportion of work-related emergency department visits in the United States were not expected to be paid by workers' compensation. Private insurance, Medicaid, Medicare, and workers themselves were expected to pay for 40 percent of the work-related emergency department visits with this percentage increasing annually. Work-related visits by blacks, in the South, to for-profit hospitals and for work-related illnesses were all more likely not to be paid by workers' compensation. CONCLUSIONS: Emergency department-based surveillance and research that determine work-relatedness on the basis of expected payment by workers' compensation systematically underestimate the occurrence of occupational illness and injury. This has important methodological and policy implications. PMID- 23662685 TI - The ex utero intrapartum treatment (EXIT) procedure: application of a new therapeutic paradigm. AB - The ex utero intrapartum treatment (EXIT) procedure is a term given to a technique that can transform a potentially fatal neonatal emergency to a controlled intervention with an improved outcome. It has revolutionised the care of prenatally diagnosed congenital malformations in which severe upper airway obstruction is anticipated. An extended period of utero-placental circulation can be utilised to avoid profound cardiopulmonary compromise. Its therapeutic applications have been broadened to include fetuses with congenital diaphragmatic hernia after tracheal plugging, high-risk intrathoracic masses, severe cardiac malformations and conjoined twins. It requires the co-ordination of a highly skilled and experienced multidisciplinary team. The recent enthusiasm for the EXIT procedure needs to be balanced against maternal morbidity. Specific indications and guidelines are likely to be refined as a consequence of ongoing advances in fetal intervention and antenatal imaging. PMID- 23662686 TI - Feasibility of aqueous shunts for reduction of intraocular pressure in horses. AB - REASONS FOR PERFORMING STUDY: Based on the current literature, neither medical, surgical nor combination therapy adequately controls equine glaucoma for many horses. Aqueous shunts have been useful in other species to control glaucoma. OBJECTIVES: To determine whether aqueous shunts in normal equine eyes significantly reduce intraocular pressure (IOP) without causing vision threatening complications. STUDY DESIGN: Prospective experimental trial. METHODS: Aqueous shunts were placed in 7 normal eyes of 4 horses. The shunts were placed dorsotemporally. Examinations were initially performed daily for 7 days and after that every 3 days through 4 weeks after implantation. Horses were then subjected to euthanasia and globes enucleated for routine histological examination. The IOPs for each day post operatively were compared to the preoperative value (Day 1) using a Wilcoxon signed ranks test. Significance was set at P<0.05. RESULTS: The mean IOP preoperatively (20.7 +/- 3.0 mmHg) was significantly higher than on any post operative day (P values ranged from 0.018 to 0.048). The aqueous shunts remained in situ for the entire study. Two eyes developed corneal ulcers that resolved. Shallow anterior chambers were noted in 2 eyes after shunt placement, which normalised after placement of full eye cup masks. Histologically, 7/7 eyes had fibrosis surrounding the implant. Minimal peripheral neovascularisation and neutrophilic keratitis were noted in 5/7 eyes. Corneal damage was scored as none in 3/7, mild in 2/7, moderate in 1/7 and marked in 1/7 eyes. CONCLUSIONS: After placement of aqueous shunts, a significant decrease in IOP was noted from preoperatively (Day -1) to Day 28 despite fibrosis surrounding the implants. No vision threatening complications were noted. POTENTIAL RELEVANCE: Aqueous shunts may represent a feasible therapeutic option for equine glaucoma. The results of this study suggest that further studies in glaucomatous horses would be warranted. PMID- 23662687 TI - New isoflavones with cytotoxic activity from the rhizomes of Iris germanica L. AB - Two new compounds, 5-methoxy-3',4'-dihydroxy-6,7-methylenedioxy-4H-1-benzo-pyran 4-one(iriskashmirianin A) (1) and 5,3'-dihydroxy-3-(4'-beta-D-glucopyranosyl)-6,7 methylenedioxy-4H-1-benzo-pyran-4-one (germanaism H) (2), along with eight known compounds (3-10), were isolated from the rhizomes of Iris germanica L. The cytotoxicities of these compounds were tested using Ehrlich's ascites carcinoma (EAC) cancer cell line by 3-(4, 5-dimethylthiazole-2-yl)-2, 5-diphenyltetrazoli umbromide (MTT) and ATP assays. The results showed that these compounds possessed antiproliferative effects on EAC cell line. Among them, compound 1 possessed the best cytotoxic activity with IC50 +/- SD of 20.9 +/- 2.7 and 4.3 +/- 0.9 MUM for MTT and ATP assay methods, respectively. PMID- 23662688 TI - Relative incidence of blepharoptosis subtypes in an oculoplastics practice at a tertiary care center. AB - PURPOSE: In patients referred with blepharoptosis, the possibility of an underlying systemic cause for their ptosis can warrant a more detailed evaluation. The purpose of this study is to determine both the incidence and demographic characteristics associated with different types of ptosis in patients referred to the oculoplastics division at a tertiary care center. METHODS: A retrospective chart review was performed on all patients referred to the oculoplastics division between 2007 and 2010. Final etiology for each patient's ptosis was determined based on history, standard eyelid measurements, and ancillary testing. Based on etiology, ptosis was categorized as aponeurotic, neurogenic, myogenic, traumatic, congenital, or mechanical. Demographics, including median age and sex were analyzed for patients in each category of ptosis. RESULTS: Of the 251 patients, aponeurotic ptosis was the most common type of ptosis (60.2%), followed by traumatic (11.2%), congenital (10.4%), mechanical (8.8%), neurogenic (5.6%), and myogenic (4.0%). Of the neurogenic group, 35.7% of patients had cranial nerve 3 (CN 3) palsy, 28.6% had myasthenia gravis, 14.3% had aberrant regeneration, and 7.1% had Horner's syndrome. Thirty percent of the myogenic group had chronic progressive external ophthalmoplegia (CPEO). The congenital group had the youngest median age (10.5 years), yet the aponeurotic group had the oldest (62 years). CONCLUSIONS: A significant proportion of patients referred with ptosis had more serious conditions such as neurogenic or myogenic ptosis. Thus, clinicians should maintain a high degree of suspicion and thoroughly evaluate all patients with ptosis in order to properly assess for underlying systemic associations. PMID- 23662689 TI - Crosstalk between Fas and JNK determines lymphocyte apoptosis after ionizing radiation. AB - Radiation simultaneously activate Fas and JNK pathway in lymphocytes but their precise interaction is not clearly understood. Activation of Fas pathway is required for radiation induced apoptosis, however induction of JNK pathway may or may not contribute in apoptosis. Here we report that Fas, Fas associated death domain and total JNK are activated in a dose- and time-dependent radiation exposure. A biphasic pattern of phospho-JNK was found at lower doses (1 and 2 Gy), however at higher doses of radiation phospho-JNK was continuously activated. Interestingly, Fas ligand expression remained biphasic at all the doses of radiation. Our results suggest that the Fas pathway is the major player in radiation-induced apoptosis, with JNK playing a contributory role. We also observed that Fas ligand expression by radiation is dependent on JNK activation. We also propose that radiation activates JNK pathway, but sustained activation is required for maximal induction of apoptosis at later times. Our findings define a mechanism for crosstalk between JNK and Fas pathway in radiation-induced apoptosis, which may lead to the development of new therapeutic strategies. PMID- 23662690 TI - Prediction of low birth weight using modified Indian council of medical research antenatal scoring method. AB - OBJECTIVE: To study the prediction of low birth weight (LBW) using modified Indian Council of Medical Research (ICMR) antenatal scoring method. METHOD: The present longitudinal study was carried out amongst 1138 pregnant women residing in area covered by Kinaye primary health centre (PHC) in rural Karnataka, India. RESULTS: Modified ICMR risk scoring revealed that 597 (52.5%) women had a risk score 6-10 (mild risk), 142 (12.5%) women had risk score 11-15 (moderate risk) and 29 (2.5%) had risk score >=16 (severe risk), whereas, remaining 370 (32.5%) had a score of 0-5 considered as "no risk group". The incidence of LBW had direct relationship with the risk score. The sensitivity was high (80.6%), whereas, specificity was slightly low (70.4%), positive predictive value was low (43.8%) and negative predictive value high (92.7%) for LBW when the risk score cut-off point was >7. CONCLUSION: The modified ICMR antenatal scoring method can be used at all levels of health care and is an ideal instrument for prediction of LBW at the community level. It can be easily applied by even a health worker, not time consuming and at the same time does not lose its predictability. PMID- 23662691 TI - Barriers and facilitators of sports in Dutch Paralympic athletes: An explorative study. AB - The purpose of this study was to gain insight in barriers and facilitators of sports in paralympic athletes. An online questionnaire was distributed through the Netherlands Olympic Committee and National Sports Confederation to determine personal and environmental barriers and facilitators of sports participation. The International Classification of Functioning, Disability and Health model and theory of planned behavior were used to respectively categorize the results in environmental and personal factors, and attitude, subjective norm and perceived behavioral control. Seventy-six Dutch Paralympic athletes completed the questionnaire (51% response rate). Barriers and facilitators experienced by ambulant and wheelchair athletes were compared. Most frequently mentioned personal barrier was dependency of others (22%), while most frequently mentioned environmental barrier was lack of sports facilities (30%). Wheelchair athletes mentioned more barriers (median = 3, interquartile range: 0.5-6), than ambulant athletes (median = 1.0,interquartile range:0.0-3.0, P = 0.023). One-third of the athletes did not experience any barriers. Most frequently mentioned personal facilitators to initiate sports participation were fun (78%), health (61%), and competition (53%). Most frequently mentioned environmental facilitator was social support (40%). This study indicated that barriers of sport were mostly environmental, while facilitators were usually personal factors. Attitude and subjective norm were considered the most important components for intention to participation in sports. The facilitators outweighed the barriers and kept the athletes being active in sports. PMID- 23662692 TI - skNAC depletion stimulates myoblast migration and perturbs sarcomerogenesis by enhancing calpain 1 and 3 activity. AB - skNAC (skeletal and heart muscle specific variant of nascent polypeptide associated complex alpha) is a skeletal and heart muscle-specific protein known to be involved in the regulation of sarcomerogenesis. The respective mechanism, however, is largely unknown. In the present paper, we demonstrate that skNAC regulates calpain activity. Specifically, we show that inhibition of skNAC gene expression leads to enhanced, and overexpression of the skNAC gene to repressed, activity of calpain 1 and, to a lesser extent, calpain 3 in myoblasts. In skNAC siRNA-treated cells, enhanced calpain activity is associated with increased migration rates, as well as with perturbed sarcomere architecture. Treatment of skNAC-knockdown cells with the calpain inhibitor ALLN (N-acetyl-leucyl-leucyl norleucinal) reverts both the positive effect on myoblast migration and the negative effect on sarcomere architecture. Taken together, our data suggest that skNAC controls myoblast migration and sarcomere architecture in a calpain dependent manner. PMID- 23662693 TI - Doping and quantum confinement effects in single Si nanocrystals observed by scanning tunneling spectroscopy. AB - We have applied scanning tunneling spectroscopy in studies of the electronic level structure of surface-functionalized colloidal Si nanocrystals (Si-NCs) as a function of their size for various capping ligands. The energy gaps extracted from the tunneling spectra increase with decreasing NC size, manifesting the effect of quantum confinement. This is consistent with the blueshift revealed by photoluminescence (PL) from dodecene functionalized Si-NCs. The tunneling spectra measured on NCs functionalized with NH4Br or allylamine show band-edge shifts toward higher energies, akin to p-type doping. This behavior can be accounted for by the combined contributions of the ligands' dipole moments and charge transfer between a Si-NC and its surface groups. Concomitantly, size-independent PL spectra, which cannot be associated with NC band gap variations, were observed for the latter Si-NCs. PMID- 23662695 TI - Lung lavage in meconium aspiration syndrome. PMID- 23662694 TI - Estimation of Te-132 distribution in Fukushima Prefecture at the early stage of the Fukushima Daiichi Nuclear Power Plant reactor failures. AB - Tellurium-132 ((132)Te, half-life: 3.2 d) has been assessed as the radionuclide with the third largest release from the Fukushima Daiichi Nuclear Power Plant (FDNPP) in March 2011; thus it would have made some dose contribution during the early stage of the reactor failures. The available data for (132)Te are, however, limited. In this study, available reported values of other isotopes of Te were compiled to estimate (132)Te concentration (in MBq m(-2)). It was found that (132)Te and (129m)Te (half-life: 33.6 d) concentrations were well correlated (R = 0.99, p < 0.001) by t test. Thus, (132)Te concentrations on March 11, 2011 were estimated from (129m)Te using the concentration conversion factor ((132)Te /(129m)Te) of 14.5. It was also found that since deposited (129m)Te was well retained in the soil, the data collected in March-May of 2011 were applicable to (132)Te estimation. It was possible to obtain the first (132)Te concentration contour map for the eastern part of Fukushima Prefecture, including data from within the 20-km exclusion zone around the FDNPP, using these newly available estimated (132)Te data sets. PMID- 23662696 TI - Preparation and evaluation of charged solid lipid nanoparticles of tetrandrine for ocular drug delivery system: pharmacokinetics, cytotoxicity and cellular uptake studies. AB - In this study, tetrandrine-loaded cationic solid lipid nanoparticles (TET-CNP) and solid lipid nanoparticles (TET-NP) were prepared by the emulsion evaporation solidification at low temperature method. The particle size, zeta potential, and entrapment efficiency of TET-CNP and TET-NP were characterized. The results showed that the TET-CNP and TET-NP had average diameters of (15.29 +/- 1.34) nm and (18.77 +/- 1.23) nm with zeta potentials of (5.11 +/- 1.03) mV and (-8.71 +/- -1.23) mV and entrapment efficiencies of (94.1 +/- 2.37)% and (95.6 +/- 2.43)%, respectively. In vitro release studies indicated that the TET-CNP and TET-NP retained the drug entity better than tetrandrine ophthalmic solutions (TET-SOL). In the pharmacokinetics studies, the AUC values of TET-CNP and TET-NP were 1.96 fold and 2.00-fold higher than that of TET-SOL ( p < 0.05); the Cmax values of TET-CNP and TET-NP were 2.45-fold and 2.53-fold higher than that of the TET-SOL (p < 0.05), respectively. Cytotoxicity study showed that TET-CNP and TET-NP had no significant toxicity at low concentrations. Flow cytometry studies and confocal microscopy analysis demonstrated that calcein labeled NP (CA-NP) uptake by SRA 01/04 cells was much higher than those of calcein labeled CNP (CA-CNP) and calcein solution (CA-SOL). PMID- 23662697 TI - A literature review and meta-analysis of drug company-funded mental health websites. AB - OBJECTIVE: The pharmaceutical industry exercises pervasive influence in the mental health field. The internet has become a primary source of mental health information for the public and practitioners. This study therefore compared mental health websites funded and not funded by drug companies. METHOD: A systematic literature review of studies examining the role of drug companies in the funding of mental health websites was conducted, followed by a meta-analysis of studies comparing drug company-funded (DCF) sites with sites not funded by the industry. RESULTS: Mental health websites, in general, overemphasize biogenetic causal explanations and medication. Many mental health websites (42%) are either drug company owned (6%) or receive funding from drug companies (36%). A meta analysis found that DCF sites are significantly more biased toward biogenetic causes (P < 0.01) and toward medication (P < 0.0001) than sites that are financially independent of the industry. CONCLUSION: Practitioners are encouraged to inform patients about the bias inherent in industry-sponsored websites and to recommend, instead, more balanced websites that present a range of evidence-based information about causes and treatments. PMID- 23662699 TI - Endothelin receptors in augmented vasoconstrictor responses to endothelin-1 in chronic intermittent hypoxia. AB - Chronic intermittent hypoxia (CIH) contributes to the development of cardiovascular diseases in patients with obstructive sleep apnoea. Many studies have shown an association between increased circulating endothelin (ET)-1 levels and CIH. The aim of the present study was to determine the role of ET receptors in altered aortic function in an animal model of CIH. Rats were subjected to CIH (Fi o2 9% for 1 min, repeated every 2 min for 8 h/day, 7 days/week) for 3 weeks. After 3 weeks, the rats were killed and their aortas retrieved for use in in vitro experiments (isometric force measurement), histological analysis, immunohistochemistry and western blotting. Aortas from rats subjected to CIH exhibited marked endothelial dysfunction and increased responsiveness to ET-1. Furthermore, CIH induced increased ET-1 and ETA receptor expression, whereas ETB receptor expression was decreased. Aortic contractile responses to ET-1 were inhibited by the ETA and ETB receptor antagonists BQ-123 and BQ-788, respectively. Acetylcholine-induced relaxation responses were significantly attenuated in aortas from rats subjected to CIH, whereas CIH had no significant effect on aortic responses to sodium nitroprusside. The results of the present study suggest that increased expression of ETA receptors, which mediate a potent vasoconstrictor response, plays an important role in the pathogenesis of CIH. In addition, decreased endothelial ETB receptor expression, which is associated with the functional decline of endothelium-dependent vasodilation, also contributes to the pathogenesis of CIH. It appears that the ETB receptor-induced buffering of ET 1 responsiveness is mediated via a nitric oxide-dependent mechanism. PMID- 23662698 TI - Cotton GhCKI disrupts normal male reproduction by delaying tapetum programmed cell death via inactivating starch synthase. AB - Anther infertility under high temperature (HT) conditions is a critical factor contributing to yield loss in cotton (Gossypium hirsutum). Using large-scale expression profile sequencing, we studied the effect of HT on cotton anther development. Our analysis revealed that altered carbohydrate metabolism or disrupted tapetal programmed cell death (PCD) underlie anther sterility. Expression of the Gossypium hirsutum casein kinase I (GhCKI) gene, which encodes a homolog of casein kinase I (CKI), was induced in an HT-sensitive cotton line after exposure to HT. As mammalian homologs of GhCKI are involved in inactivation of glycogen synthase and the regulation of apoptosis, GhCKI may be considered a target gene for improving anther fertility under HT conditions. Our studies suggest that GhCKI exhibits starch synthase kinase activity, increases glucose content in early-stage buds and activates the accumulation of abscisic acid, thereby disturbing the balance of reactive oxygen species and eventually disrupting tapetal PCD, leading to anther abortion or indehiscence. These results indicate that GhCKI may be a key regulator of tapetal PCD and anther dehiscence, with the potential to facilitate regulation of HT tolerance in crops. PMID- 23662700 TI - Aerobic dehydrogenation of cyclohexanone to cyclohexenone catalyzed by Pd(DMSO)2(TFA)2: evidence for ligand-controlled chemoselectivity. AB - The dehydrogenation of cyclohexanones affords cyclohexenones or phenols via removal of 1 or 2 equiv of H2, respectively. We recently reported several Pd(II) catalyst systems that effect aerobic dehydrogenation of cyclohexanones with different product selectivities. Pd(DMSO)2(TFA)2 is unique in its high chemoselectivity for the conversion of cyclohexanones to cyclohexenones, without promoting subsequent dehydrogenation of cyclohexenones to phenols. Kinetic and mechanistic studies of these reactions reveal the key role of the dimethylsulfoxide (DMSO) ligand in controlling this chemoselectivity. DMSO has minimal kinetic influence on the rate of Pd(TFA)2-catalyzed dehydrogenation of cyclohexanone to cyclohexenone, while it strongly inhibits the second dehydrogenation step, conversion of cyclohexenone to phenol. These contrasting kinetic effects of DMSO provide the basis for chemoselective formation of cyclohexenones. PMID- 23662701 TI - Interaction of G-quadruplex with RecA protein studied in bulk phase and at the single-molecule level. AB - As in the human genome there are numerous repeat DNA sequences to adopt into non B DNA structures such as hairpin, triplex, Z-DNA, G-quadruplex, and so on, an understanding of the interaction between DNA repair proteins and a non-B DNA forming sequence is very important. In this regard, the interaction between RecA protein and human telomeric 5'-TAGGG-(TTAGGG)3-TT-3' sequence and the G quadruplex formed from this sequence has been investigated in bulk phase and at the single-molecule level. The RecA@ssDNA filament, which is formed by the interaction between RecA protein and a G-rich sequence, was dissociated by the addition of K(+) ions, and the dissociated G-rich sequence was quickly folded to a G-quadruplex structure, indicating that the G-quadruplex structure is more favorable than the RecA@ssDNA filament in the presence of K(+) ions. In addition, we demonstrate that the conformation of the G-quadruplex, which is heterogeneous in the absence of RecA, converged to the specific G-quadruplex with one double chain-reversal loop upon association of RecA protein. PMID- 23662702 TI - High-sensitivity Raman spectrometer to study pristine and irradiated interstellar ice analogs. AB - We discuss the novel design of a sensitive, normal-Raman spectrometer interfaced to an ultra-high vacuum chamber (5 * 10(-11) Torr) utilized to investigate the interaction of ionizing radiation with low temperature ices relevant to the solar system and interstellar medium. The design is based on a pulsed Nd:YAG laser which takes advantage of gating techniques to isolate the scattered Raman signal from the competing fluorescence signal. The setup incorporates innovations to achieve maximum sensitivity without detectable heating of the sample. Thin films of carbon dioxide (CO2) ices of 10 to 396 nm thickness were prepared and characterized using both Fourier transform infrared (FT-IR) spectroscopy and HeNe interference techniques. The nu+ and nu- Fermi resonance bands of CO2 ices were observed by Raman spectroscopy at 1385 and 1278 cm(-1), respectively, and the band areas showed a linear dependence on ice thickness. Preliminary irradiation experiments are conducted on a 450 nm thick sample of CO2 ice using energetic electrons. Both carbon monoxide (CO) and the infrared inactive molecular oxygen (O2) products are readily detected from their characteristic Raman bands at 2145 and 1545 cm(-1), respectively. Detection limits of 4 +/- 3 and 6 +/- 4 monolayers of CO and O2 were derived, demonstrating the unique power to detect newly formed molecules in irradiated ices in situ. The setup is universally applicable to the detection of low-abundance species, since no Raman signal enhancement is required, demonstrating Raman spectroscopy as a reliable alternative, or complement, to FT-IR spectroscopy in space science applications. PMID- 23662703 TI - Two cases of food bolus obstruction in children. PMID- 23662704 TI - Bilateral subconjunctival masses as a rare presentation of Churg-Strauss syndrome. PMID- 23662705 TI - Equine proliferative enteropathy--a review of recent developments. AB - Equine proliferative enteropathy (EPE) is a disease of foals caused by the obligate intracellular organism Lawsonia intracellularis. This emerging disease affects mainly weanling foals and causes fever, lethargy, peripheral oedema, diarrhoea, colic and weight loss. The diagnosis of EPE may be challenging and relies on the presence of hypoproteinaemia, thickening of segments of the small intestinal wall observed upon abdominal ultrasonography, positive serology and molecular detection of L. intracellularis in faeces. Although the clinical entity, diagnostic approach and treatment of EPE are well established and described, the epidemiology for this disease has remained largely unaddressed. This article focuses on new developments in the field of EPE, including epidemiology, pathophysiology, clinical signs, diagnosis, treatment and prevention. PMID- 23662706 TI - The current role of decompressive craniectomy in the management of neurological emergencies. AB - Decompressive craniectomy has been used as a lifesaving procedure for many neurological emergencies, including traumatic brain injury, ischaemic stroke, subarachnoid haemorrhage, cerebrovenous thrombosis, severe intracranial infection, inflammatory demyelination and encephalopathy. The evidence to support using decompressive craniectomy in these situations is, however, limited. Decompressive craniectomy has only been evaluated by randomized controlled trials in traumatic brain injury and ischaemic stroke and, even so, its benefits and risks in these situations remain elusive. If one considers a modified Rankin Scale of 4 or 5 or dependency in daily activity as an unfavourable outcome, decompressive craniectomy is associated with an increased risk of survivors with unfavourable outcome (relative risk [RR] = 2.9, 95% confidence interval [CI] = 1.5-5.8, p = 0.002, I(2 )= 0%; number needed to operate to increase an unfavourable outcome = 3.5, 95% CI = 2.4-7.4), but not the number of survivors with a favourable outcome (RR = 1.5, 95% CI = 0.9-2.6, p = 0.13, I(2 )= 0%). PMID- 23662707 TI - Use of plain radiography in the diagnosis, surgical management, and postoperative treatment of obstructive urolithiasis in 25 goats and 2 sheep. AB - OBJECTIVE: To describe use of plain radiography for diagnosis, surgical management, and postoperative treatment of obstructive urolithiasis in small ruminants. STUDY DESIGN: Retrospective case series. ANIMALS: Small ruminants (n = 27; 25 goats, 2 sheep). METHODS: Medical records (January 2002-November 2011) and radiographs for all small ruminants diagnosed with obstructive urolithiasis and having plain abdominal radiographs were reviewed. Signalment, surgical procedures, radiographic findings, ultrasonographic findings, position of calculi, and how plain radiography influenced surgical management and postoperative treatment were recorded. RESULTS: Radiopaque urinary calculi were detected in 23 (85%) plain radiographic studies. Location of uroliths determined by plain radiography included: cystic only (n = 5), distal to the sigmoid flexure and cystic (5), subischial (5), distal to the sigmoid flexure only (3), sigmoid flexure (3), and subischial and cystic (2). In 8 of these animals, postoperative radiographs revealed residual calculi in the urethra and were essential for their targeted removal by urethrotomy in 7 animals. CONCLUSIONS: In regions where radiopaque calculi (calcium carbonate, calcium oxalate, silica) are commonly encountered in small ruminants, plain radiographs are recommended to determine the appropriate surgical approach(es) and to confirm resolution of the obstruction. PMID- 23662708 TI - The disparate impact of the ACA-dependent expansion across population subgroups. AB - OBJECTIVE: This study presents evidence on how the dependent provision in the Affordable Care Act (ACA) differentially affected coverage for young adults across states and population subgroups. STUDY DESIGN/METHODS/DATA: The data derive from the American Community Survey. Using a difference-in-difference design, we compare the target population (ages 19-25) with a control group (ages 26-29). PRINCIPAL FINDINGS: Net private health insurance coverage increased by 4.6 percentage points and overall coverage increased by 4.2 percentage points for people aged 19-25; more for Whites than non-White subgroups. CONCLUSIONS AND IMPLICATIONS: Changes in coverage for states appear driven by demographics rather than the existence of prior dependent expansions by the state. Disparities in health care coverage remain, but the absolute level of coverage is improving. PMID- 23662709 TI - Funding considerations for the disclosure of genetic incidental findings in biobank research. AB - The use of biobanks in biomedical research has grown considerably in recent years. As a result of the increasing analysis of tissue samples stored in biobanks, there has also been an increase in the probability of discovering-in addition to the research target-incidental findings (IF). We identified 23 laws, policies and guidelines from international, regional and national organizations that provide guidance or identify the need for the disclosure of IF to research participants. We analyzed these instruments to determine their contemplation of the funding considerations for the disclosure of IF, examining their guidance for who discloses and the extent of researcher responsibilities. We found that the available normative documents provide little guidance to researchers and biobanks for how they should address cost and funding concerns associated with IF disclosure. It is therefore essential that the research and policy communities think through the financial implications of imposing an ethical responsibility to disclose IF. Concerted efforts should be made by policymakers, ethicists, researchers, clinicians and research institutions to develop detailed funding recommendations, potentially universal in application, to aid in the disclosure of IF, and we provide recommendations on steps that can be taken to ensure full consideration of these issues. PMID- 23662710 TI - Psychophysiological and stress responses to competition in team sport coaches: an exploratory study. AB - Examinations of stress in coaches have mainly been qualitative and focused on chronic stressors. This exploratory study examined stress responses in coaches during competition, including psychological and physiological indices. Using reversal theory, we examined metamotivational state profiles during competition. Ten male team sport coaches (mean age 39.8 +/- 13.12 years) reported levels of subjective stress, pleasant and unpleasant emotions, metamotivational state, and provided saliva samples, on a competition day: 15 min prior to the pre-match team talk; start of the match; end of the first half; start of the second half, and end of the match, then at equivalent times on a noncompetition day. Saliva samples were assayed for alpha-amylase activity. On competition day, alpha amylase activity was significantly higher, as were subjective stress, arousal, and unpleasant emotions. Prior to and during active play, participants were mainly in the conformist, alloic (other-oriented), and mastery states, and at the end of the match, in the telic and sympathy states. Only 22 metamotivational state reversals were observed, mostly at the start and end of the match. The elevated levels of subjective stress, alpha-amylase activity, and unpleasant emotions suggest that educational programs may be useful for some coaches to manage psychological states during competition. PMID- 23662711 TI - Targeted drug delivery in cancer cells with red-light photoactivated mesoporous silica nanoparticles. AB - Mesoporous nanoparticles for drug delivery would benefit significantly from further improvements in targeting efficiency and endosomal release. We present a system based on colloidal mesoporous silica nanoparticles with targeting-ligands and a red-light photosensitizer. This nanoparticle system provides spatial and temporal control of the release of drugs into the cytosol of cancer cells. Furthermore, the system presents a general platform since it can be loaded with different cargos and adapted for targeting of multiple cell types. PMID- 23662713 TI - Interaction of S-nitrosoglutathione with methemoglobin under conditions of modeling carbonyl stress. AB - The Maillard reaction is the key process in protein modification during pathologies connected with carbonyl stress. It was shown in system modeling that Maillard reaction interaction of L-lysine (L-lys) with methylglyoxal (MG) led to the formation of compounds reducing methemoglobin (metHb). Under the above conditions and in the presence of S-nitrosoglutathione (GSNO), metHb nitrosylation took place. Processes of metHb reduction and nitrosylation had the lag phase that was dependent on the presence of oxygen (O2) in the reaction mixture. Oxygen interacting with organic free radicals of the Maillard reaction inhibited hemoglobin (Hb) reduction and hence Hb nitrosylation during the first minutes of the reaction. It was also shown that the yield of organic free-radical intermediates of the L-lys with MG was increased in the presence of GSNO and metHb. All effects described could be a result of the formation of active red-ox GSNO derivates in the Maillard reaction. These derivates are probably mediators of one-electron oxidation of dialkylimine by MG. Anion radicals of S nitrosothiols can function as such mediators. PMID- 23662714 TI - Growth in prepubertal Nigerian children is highly dependent on socio-economic status. AB - AIM: To relate height, weight and body mass index (BMI) of prepubertal children in Sagamu, Nigeria, to parental socio-economic class (SEC). METHODS: Cross sectional study of 1606 children aged 5-11 years from eight public and eight private primary schools. Height, weight and BMI from 1557 prepubertal children were standardized using two references: US-CDC birth cohorts 1929-1974 and Swedish birth cohort 1974. RESULTS: Children in private schools were taller and heavier than those in public schools (p < 0.0001). Most children (73.2%) belonged to lower SEC, 17.6% to middle and 9.2% to upper. HeightSDS , weightSDS and BMISDS increased with increasing parental SEC. Upper SEC children were taller and heavier with higher BMIs than those from lower SEC (p < 0.0001). HeightSDS , weightSDS and BMISDS were below '0' in all SEC and gender groups (all p < 0.002). Younger children were taller and heavier than the older (p < 0.0001). CONCLUSION: Fathers/mothers with higher education/occupation had taller and heavier children with higher BMI than other groups. Children in private schools were taller and heavier than children in public schools. Disparities in parental SEC still constrain optimal child growth in Nigeria: whereas height and weight of children of upper SEC were close to the US-CDC29-74 reference mean, they were still below Swedish74 reference mean representing more optimal growth. PMID- 23662715 TI - Development of a Raman method to follow the evolution of coating thickness of pellets. AB - CONTEXT: Although several methods have been investigated to measure the film thickness of tablets and its correlation with the dissolution behavior, much fewer such investigations exist for pharmaceutical pellets. OBJECTIVE: To study the possibility of measuring the film thickness and predicting the dissolution behavior of pellets produced in different fluid bed equipments with Raman spectroscopy. MATERIALS AND METHODS: Pyridoxine hydrochloride-layered pellets were produced and coated in two different Strea-1 equipments. Raman spectra were collected and analysed to set up a calibration model based on the film thickness data calculated from Camsizer analysis results. Dissolution tests were done according to Ph. Eur. standards. RESULTS: Raman spectroscopy proved to be a good tool in the measurement of film thickness. Polymer weight gain showed a linear correlation with film thickness but was a poor predictor of dissolution results below a threshold value. CONCLUSION: The Raman spectroscopic measurement of a small sample can provide accurate data of the film thickness. The investigation suggests that a threshold value might exist for the film thickness above which it can be used to judge future dissolution results. PMID- 23662716 TI - Study of granule growth kinetics during in situ fluid bed melt granulation using in-line FBRM and SFT probes. AB - OBJECTIVE: The aim of this work was to study the granule growth kinetics during in situ fluid bed melt granulation process using real-time particle size measurement techniques. In addition, the usefulness of these techniques during scale-up of melt granulation was evaluated. MATERIALS AND METHODS: Focused beam reflectance measurement (FBRM) and spatial filtering technique (SFT) probes were used within the process chamber of fluid bed granulator for real-time in-line granule size analysis. RESULTS: The results demonstrated that the use of in-line particle size probes in fluid bed granulator during the process offers an insightful view of granule growth and allows in-process monitoring of granule chord length changes. The effect of selected critical parameters (binder content, inlet air temperature and product endpoint temperature) on the granule growth was clearly presented by in-line measurements in a laboratory scale. A comparison of granule size measurements from both FBRM and SFT probes showed similar particle growth trends, which were in close correlation to the product temperature. Comparable trends in end granule particle size were observed when comparing different in-line, at-line and off-line particle size measurements. CONCLUSION: The in-line FBRM and SFT probes were successfully employed in in situ fluid bed melt granulation process to study the influence of critical formulation/process parameters on the granule growth kinetics. The scale-up experiment confirmed the potential of these in-line granule size measurement techniques as a viable tool for process monitoring during the transfer of granulation to the larger scale or another manufacturing site/equipment. PMID- 23662717 TI - An introduction to the Irish Longitudinal Study on Ageing. PMID- 23662718 TI - Design and methodology of the Irish Longitudinal Study on Ageing. AB - OBJECTIVES: To provide comprehensive data on older people in Ireland and new insights into the causal processes underlying the aging transformation. DESIGN: The Irish Longitudinal Study on Ageing (TILDA) is a population-representative prospective cohort study with baseline assessment conducted between October 2009 and February 2011 and follow-up waves planned every 2 years. Participants were sampled in geographic clusters, with each member of the Irish population aged 50 and older having an equal probability of being invited to participate in the study. SETTING: Community-living population of the Republic of Ireland aged 50 and older. PARTICIPANTS: Eight thousand one hundred seventy-five participants aged 50 and older at time of interview participated in the study, along with 329 spouses or partners younger than 50. MEASUREMENTS: The Irish Longitudinal Study on Ageing includes detailed assessments of the mental and physical health and social and financial circumstances of participants, which are assessed in a home interview, a self-completion questionnaire, and a detailed health assessment that takes place at a dedicated health center or in the respondent's home. RESULTS: The response rate was 62.0%, with response rate varying according to educational attainment. Data from the first wave of data collection are available for researchers at the Irish Social Sciences Data Archive. CONCLUSION: The Irish Longitudinal Study on Ageing provides an opportunity to study the interactions between the health and social and economic circumstances of the older population in a nationally representative sample. PMID- 23662719 TI - Health and aging: development of the Irish Longitudinal Study on Ageing health assessment. AB - OBJECTIVES: To assist researchers planning studies similar to The Irish Longitudinal Study on Ageing (TILDA), concerning the development of the health assessment component, to promote use of the archived data set, to inform researchers of the methods employed, and to complement the accompanying article on normative values. DESIGN: Prospective, longitudinal study of older adults. SETTING: Republic of Ireland. PARTICIPANTS: Eight thousand five hundred four community-dwelling adults who participated in wave 1 of the TILDA study. MEASUREMENTS: The main areas of focus for the TILDA health assessments are neurocardiovascular instability, locomotion, and vision. RESULTS: The article describes the scientific rationale for the choice of assessments and seeks to determine the potential advantages of incorporating novel biomeasures and technologies in population-based studies to advance understanding of aging related disorders. CONCLUSION: The detailed description of the physical measures will facilitate cross-national comparative research and put into context the normative values outlined in the subsequent article. PMID- 23662720 TI - Normative values of cognitive and physical function in older adults: findings from the Irish Longitudinal Study on Ageing. AB - OBJECTIVES: To provide normative values of tests of cognitive and physical function based on a large sample representative of the population of Ireland aged 50 and older. DESIGN: Data were used from the first wave of The Irish Longitudinal Study on Ageing (TILDA), a prospective cohort study that includes a comprehensive health assessment. SETTING: Health assessment was undertaken at one of two dedicated health assessment centers or in the study participant's home if travel was not practicable. PARTICIPANTS: Five thousand eight hundred ninety seven members of a nationally representative sample of the community-living population of Ireland aged 50 and older. Those with severe cognitive impairment, dementia, or Parkinson's disease were excluded. MEASUREMENTS: Measurements included height and weight, normal walking speed, Timed Up-and-Go, handgrip strength, Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Color Trails Test, and bone mineral density. Normative values were estimated using generalized additive models for location shape and scale (GAMLSS) and are presented as percentiles, means, and standard deviations. RESULTS: Generalized additive models for location shape and scale fit the observed data well for each measure, leading to reliable estimates of normative values. Performance on all tasks decreased with age. Educational attainment was a strong determinant of performance on all cognitive tests. Tests of walking speed were dependent on height. Distribution of body mass index did not change with age, owing to simultaneous declines in weight and height. CONCLUSION: Normative values were found for tests of many aspects of cognitive and physical function based on a representative sample of the general older Irish population. PMID- 23662721 TI - Cognitive and physical health of the older populations of England, the United States, and Ireland: international comparability of the Irish Longitudinal Study on Ageing. AB - This article discusses the contribution that international comparisons of the health and well-being of older people make. The comparability of the "HRS family" of studies that have been modeled on the U.S. Health and Retirement Study (HRS) is discussed. The Irish Longitudinal Study of Ageing (TILDA) is introduced, and the comparability of TILDA data with respect to the HRS family and other studies is described, along with what TILDA will add to international aging research. Data from the 2010 waves of TILDA, HRS and the English Longitudinal Study of Ageing are used to compare the physical and cognitive health of older Irish adults with that of the U.S. and English populations. The study shows that the physical and cognitive health of older people in Ireland is closer to that of their English counterparts than of those in the United States and that similar health inequalities exist in all three countries. PMID- 23662722 TI - Quality of life in older age: evidence from an Irish cohort study. AB - OBJECTIVES: To compare the role of different life domains in determining quality of life (QoL) in Ireland with international results. DESIGN: Cross-sectional study of responses to The Irish Longitudinal Study of Ageing. SETTING: Individuals aged 50 and older living in private residential addresses in the Republic of Ireland. PARTICIPANTS: Eight thousand five hundred four individuals living in 6,279 households in the Republic of Ireland (response rate 62%) were interviewed and completed a self-completion questionnaire. MEASUREMENTS: Quality of life was measured using the Control, Autonomy, Self-realization and Pleasure measure (CASP-19). The domains of physical and mental health, social participation, economic resources, and sociodemographic status were measured using a large number of indicators. Ordinary least squares regression models were used to estimate the effect of factors on CASP-19, with the relative contribution of different domains to total explanation measured using a measure of statistical fit. RESULTS: The mean CASP-19 score for the sample was 43.8 (95% confidence interval = 43.6-44.1), significantly higher than the mean score for the English Longitudinal Study of Ageing (mean 42.5: 42.3-42.7). In unadjusted analyses, CASP 19 was curvilinear with age, peaking at 67 and falling thereafter. Controlling for predictors of QoL, CASP-19 continued to rise, at a decreasing rate, with age. Mental health independently explained the largest proportion of variance in CASP 19 (7.6%), but no single domain of life dominated in terms of explanation. CONCLUSION: Increasing longevity can be associated with increasing QoL as long as it is accompanied by reasonable levels of mental and physical health, high quality relationships, and social participation. Even if physical health becomes poor, evidence suggests that QoL can often remain high as individuals find value and enjoyment in other dimensions of life. PMID- 23662723 TI - Tuning of the properties of transition-metal bispidine complexes by variation of the basicity of the aromatic donor groups. AB - Bispidines (3,7-diazabicyclo[3.3.1]nonanes) as very rigid and highly preorganized ligands find broad application in the field of coordination chemistry, and the redox potentials of their transition-metal complexes are of importance in oxidation reactions by high-valent iron complexes, aziridination catalyzed by copper complexes, and imaging by (64)Cu positron emission tomography tracers. Here, we show that the redox potentials and stability constants of the copper(II) complexes of 15 tetradentate bispidines can be varied by substitution of the pyridine rings (variation of the redox potential over ca. 450 mV and of the complex stability over approximately 10 log units). It is also shown that these variations are predictable by the pKa values of the pyridine groups as well as by the Hammett parameters of the substituents, and the density functional theory based energy decomposition analysis also allows one to accurately predict the redox potentials and concomitant complex stability. It is shown that the main contribution emerges from the electrostatic interaction energy, and the partial charges of the pyridine donor groups therefore also correlate with the redox potentials. PMID- 23662724 TI - Sensitive to sleep loss or not: neurons, working memory, insomnia and the heart. PMID- 23662725 TI - Surveillance of equine influenza viruses through the RESPE network in France from November 2005 to October 2010. AB - REASONS FOR PERFORMING THE STUDY: The Reseau d'Epidemio-Surveillance en Pathologie Equine (RESPE, the French epidemiological network for equine diseases) is a network for epidemio-surveillance of major equine diseases based around sentry veterinarians in France. OBJECTIVE: The aim of this study was to evaluate the contribution of RESPE to efficient surveillance of equine influenza virus (EIV) in France. STUDY DESIGN: Retrospective cross-sectional study. METHODS: From November 2005 to October 2010, epidemiological and phylogenetic studies were performed on 1426 nasopharyngeal swabs received at the Frank Duncombe Laboratory. Detection was performed by real-time reverse transcription polymerase chain reaction using original primers and probes designed in the matrix protein gene. Phylogenetic analysis was carried out on the HA1 part of haemagglutinin gene amplified from 47 positive-testing samples. Epidemiological information was provided with the majority of samples submitted through RESPE. RESULTS: Of the 920 samples submitted by RESPE-associated veterinarians, 121 (13.1%) from 42 premises were positive for EIV, compared to 26 (5.1%) of the 607 samples received from non-RESPE associated veterinarians. The most extensive outbreak was observed between February and May 2009, affecting 70 horses on 23 premises, 15 of which were managed by RESPE-associated veterinarians. All strains belonged to the American lineage, Florida sublineage, Clade 1 and Clade 2. Clade 1 was identified only during the Grosbois episode. CONCLUSION: RESPE improved detection of EIV in France, enabled characterisation of the virus strains, yielded valuable information relating to the epidemiology of the disease and identified vaccine breakdown. POTENTIAL RELEVANCE: Implementation of a similar surveillance network in other countries may reduce the economic losses associated with outbreaks of EIV. PMID- 23662726 TI - The surgical outcome of intracapsular cesarean myomectomy. A match control study. AB - Authors evaluated the outcome of intracapsular cesarean myomectomy by a prospective case-control study on 68 patients who underwent intracapsular cesarean myomectomy, compared with a control group of 72 patients with myomatosic pregnant uterus who underwent cesarean section (CS) without myomectomy. Mostly of removed myomas were subserous or intramural, fundal in 37 women (54.4%), corporal in 22 (32.3%) and peri-low uterine segment in 9 women (18.7%). The average myoma' size was 8 cm (1.5-20), in 40 women, with 8 myomas measuring 4-6 cm, 14 myomas between 10 and 12 cm and >13 cm in 6 patients. Difference in blood tests and surgical outcome in intracapsular cesarean myomectomy was non significant (p > 0.05). The average duration of hospitalization of intracapsular cesarean myomectomies was 5 days. There was no correlation between complications or duration of hospital stay and patient age, gravidity, parity or indication for CS. The intracapsular cesarean myomectomy could be a reliable, feasible and safe obstetric procedure. Meticulous attention to gentle hemostasis, sharp pseudocapsule dissection, adequate approximation of the myometrium edges and all dead spaces to prevent hematoma formation, can further increase the safety of the procedure, without significant complications by experienced obstetricians. PMID- 23662727 TI - Formation of colloidal molecules induced by alternating-current electric fields. AB - We report a versatile method for building colloidal molecules from particles that are isotropic in geometry and interfacial properties. When an external alternating-current electric field is applied, the particles experience anisotropic interactions that lead to the formation of colloidal oligomers via different assembly pathways that strikingly resemble chemical reactions of real molecules. We propose a mechanism for the formation of colloidal molecules that agrees well with the experiments. Our method can be used to build colloidal analogues of molecules using spherical particles with isotropic properties, which offers considerable advantages over existing methods. Moreover, our approach does not rely on material-specific properties and thus could have potential applications to a broad range of particles with different chemical properties. PMID- 23662728 TI - Methicillin-resistant staphylococcal contamination of clothing worn by personnel in a veterinary teaching hospital. AB - OBJECTIVE: To determine the methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus pseudintermedius (MRSP) contamination rate of white coats (WC) and surgical scrubs (SS) worn by personnel at the Ontario Veterinary College Health Sciences Centre (OVCHSC) and to identify risk factors associated with clothing contamination. STUDY DESIGN: Cross-sectional study. SAMPLE POPULATION: Personnel including clinical faculty, house officers, technicians, and veterinary students working at the OVCHSC. METHODS: Electrostatic cloths were used to sample WC and SS of hospital personnel. Samples were tested for MRSA and MRSP and isolates were typed. Participants completed a self-administered questionnaire and data was evaluated for risk factors. RESULTS: Of 114 specimens, MRS were isolated from 20 (17.5%), MRSA from 4 (3.5%), and MRSP from 16 (14.0%). Technicians were 9.5* (OR = 0.95, 95% CI: 1.2-infinity, P = .03) more likely than students to have clothing contaminated with MRSA. No risk factors were identified for MRSP or for overall MRS contamination. CONCLUSIONS: Standard hospital clothing was found to have a high prevalence of MRS contamination in a veterinary teaching hospital and could be a source of hospital acquired infections. PMID- 23662729 TI - Results of combined multispecialty endoscopic dacryocystorhinostomy. AB - OBJECTIVE: To characterize the pre- and post-operative findings in patients undergoing endoscopic dacryocystorhinostomy (eDCR) performed jointly by ophthalmologists and otolaryngologists. METHODS: Retrospective case series consisting of all the patients who underwent eDCR for nasolacrimal duct obstruction at New York Presbyterian Hospital/Weill Cornell Medical College between the 2009-2012 academic years. Patients were followed post-operatively for at least six months. The primary endpoint assessed in this study was symptom recurrence (epiphora). RESULTS: A total of 20 patients (25 total cases) underwent eDCR within the study interval. Of the 25 cases, 7 (28.0%) represented reoperations due to recurrent symptoms. All 20 patients in the study exhibited sinus pathology, as determined during a pre-operative otolaryngology assessment. As a result, 16 of these patients (80.0%) underwent concurrent sinonasal surgery at the time of eDCR. The success rate in cases without prior DCR was 83.3% (15/18). Only 57.1% of revision cases (4/7) reported resolution of epiphora following surgery. CONCLUSION: While a joint approach to eDCR did not appear to significantly improve efficacy, it offered the advantage of having an otolaryngologist assess and treat concurrent sinonasal pathology, which was seen in every patient in our series. Given our findings, as well as the technical difficulty often associated with the procedure, there may be great utility in performing eDCR in conjunction with an otolaryngologist. PMID- 23662730 TI - Single point mutation alters the microstate dynamics of amyloid beta-protein Abeta42 as revealed by dihedral dynamics analyses. AB - The aggregation of amyloid beta-protein (Abeta) has been associated with the pathogenesis of Alzheimer's disease. A number of single point mutations at residues A21, E22, D23, and M35 have been identified to show increased or decreased aggregation tendency. Although the effects of point mutations on the structural properties of Abeta peptides have been intensively studied, how single point mutation affects the kinetics of Abeta remains unknown. In this work, dihedral dynamics analyses, which combine dihedral principle component analysis (dPCA), potential of mean force (PMF) calculations, and Markov state models (MSMs), were proposed to elucidate the different global free energy landscapes (FELs), the PMF of individual dihedral angle, and microstates/macrostates for a number of Abeta42 mutants (Flemish A21G, Arctic E22G, Italian E22K, Dutch E22Q, Iowa D23N, Japanese E22Delta, and M35 oxidation Met35(OX)). Our simulation results show that one point mutation is sufficient to change the rugged FEL of Abeta42 by altering the energy barriers around basins. This alteration was also observed in the potential of each dihedral angle to varying degrees, although most minima of PMF do not shift. MSMs further reveal that E22 mutants (E22Delta, E22G, E22K, and E22Q) and D23N generate more hub-like microstates than wild type Abeta42, thus creating diverse alternative pathways for conformational transitions and increasing subsequent aggregation. In contrast, transitions are more preferred within the same microstate of A21G and Met35(OX). Mapping MSM to FEL suggests that transitions between different sets of microstates are kinetically feasible but thermodynamically difficult. PMID- 23662731 TI - An expanded genetic code in mammalian cells with a functional quadruplet codon. AB - We have utilized in vitro evolution to identify tRNA variants with significantly enhanced activity for the incorporation of unnatural amino acids into proteins in response to a quadruplet codon in both bacterial and mammalian cells. This approach will facilitate the creation of an optimized and standardized system for the genetic incorporation of unnatural amino acids using quadruplet codons, which will allow the biosynthesis of biopolymers that contain multiple unnatural building blocks. PMID- 23662733 TI - Divergent manifestations of irritability in patients with mild and moderate-to severe traumatic brain injury: perspectives of awareness and neurocognitive correlates. AB - PRIMARY OBJECTIVES: To evaluate irritability in patients with mild traumatic brain injury (mTBI) and moderate-to-severe traumatic brain injury (msTBI), respectively. RESEARCH DESIGN: A prospective study was conducted at a level I trauma centre. METHODS AND PROCEDURES: A total of 160 participants, which included 80 healthy subjects and 80 patients with TBI, were recruited. Irritability was assessed by the National Taiwan University Irritability Scale and other cognitive functions, which included memory, executive function and information processing, were also evaluated. MAIN OUTCOMES AND RESULTS: The results showed post-injury self-reported irritability in patients with mTBI and family-reported irritability in patients with msTBI were significantly higher than irritability reported by healthy participants. Irritability was significantly associated with information processing ability in patients with mTBI, but it was not associated with any cognitive functions in patients with msTBI. CONCLUSIONS: Irritability was found to be prominent after TBI. Divergent causes of irritability seemed apparent in patients with mTBI and msTBI. Irritability after mTBI appeared might be related to the cognitive functions disrupted after the injury, whereas irritability after msTBI appeared to result directly from the brain lesions involved. PMID- 23662732 TI - Automated assignments of N- and O-site specific glycosylation with extensive glycan heterogeneity of glycoprotein mixtures. AB - Site-specific glycosylation (SSG) of glycoproteins remains a considerable challenge and limits further progress in the areas of proteomics and glycomics. Effective methods require new approaches in sample preparation, detection, and data analysis. While the field has advanced in sample preparation and detection, automated data analysis remains an important goal. A new bioinformatics approach implemented in software called GP Finder automatically distinguishes correct assignments from random matches and complements experimental techniques that are optimal for glycopeptides, including nonspecific proteolysis and high mass resolution liquid chromatography/tandem mass spectrometry (LC/MS/MS). SSG for multiple N- and O-glycosylation sites, including extensive glycan heterogeneity, was annotated for single proteins and protein mixtures with a 5% false-discovery rate, generating hundreds of nonrandom glycopeptide matches and demonstrating the proof-of-concept for a self-consistency scoring algorithm shown to be compliant with the target-decoy approach (TDA). The approach was further applied to a mixture of N-glycoproteins from unprocessed human milk and O-glycoproteins from very-low-density-lipoprotein (vLDL) particles. PMID- 23662734 TI - Metal-free synthesis of 2-aminobenzothiazoles via aerobic oxidative cyclization/dehydrogenation of cyclohexanones and thioureas. AB - A metal-free process for the synthesis of 2-aminobenzothiazoles from cyclohexanones and thioureas has been developed using catalytic iodine and molecular oxygen as the oxidant under mild conditions. Various 2 aminobenzothiazoles, 2-aminonaphtho[2,1-d]thiazoles, and 2-aminonaphtho[1,2 d]thiazoles were prepared via this method in satisfactory yields. PMID- 23662736 TI - Phenotypic clines, energy balances and ecological responses to climate change. AB - The Metabolic Theory of Ecology has renewed interest in using energetics to scale across levels of ecological organization. Can scaling from individual phenotypes to population dynamics provides insight into why species have shifted their phenologies, abundances and distributions idiosyncratically in response to recent climate change? We consider how the energetic implications of phenotypes may scale to understand population and species level responses to climate change using four focal grasshopper species along an elevation gradient in Colorado. We use a biophysical model to translate phenotypes and environmental conditions into estimates of body temperatures. We measure thermal tolerances and preferences and metabolic rates to assess rates of energy use and acquisition. Body mass declines along the elevation gradient for all species, but mass-specific metabolic rates increases only modestly. We find interspecific differences in both overall thermal tolerances and preferences and in the variation of these metrics along the elevation gradient. The more dispersive species exhibit significantly higher thermal tolerance and preference consistent with much of their range spanning hot, low elevation areas. When integrating these metrics to consider metabolic constraints, we find that energetic costs decrease along the elevation gradient due to decreasing body size and temperature. Opportunities for energy acquisition, as reflected by the proportion of time that falls within a grasshopper's thermal tolerance range, peak at mid elevations. We discuss methods for translating these energetic metrics into population dynamics. Quantifying energy balances and allocation offers a viable approach for predicting how populations will respond to climate change and the consequences for species composed of populations that may be locally adapted. PMID- 23662735 TI - The origin recognition complex in human diseases. AB - ORC (origin recognition complex) serves as the initiator for the assembly of the pre-RC (pre-replication complex) and the subsequent DNA replication. Together with many of its non-replication functions, ORC is a pivotal regulator of various cellular processes. Notably, a number of reports connect ORC to numerous human diseases, including MGS (Meier-Gorlin syndrome), EBV (Epstein-Barr virus) infected diseases, American trypanosomiasis and African trypanosomiasis. However, much of the underlying molecular mechanism remains unclear. In those genetic diseases, mutations in ORC alter its function and lead to the dysregulated phenotypes; whereas in some pathogen-induced symptoms, host ORC and archaeal-like ORC are exploited by these organisms to maintain their own genomes. In this review, I provide detailed examples of ORC-related human diseases, and summarize the current findings on how ORC is involved and/or dysregulated. I further discuss how these discoveries can be generalized as model systems, which can then be applied to elucidating other related diseases and revealing potential targets for developing effective therapies. PMID- 23662737 TI - Temporal development of baroreceptor dysfunction in a rodent model of chronic kidney disease. AB - Altered autonomic control of the cardiovascular system in chronic kidney disease (CKD) contributes to an increased risk of cardiovascular events. The aim of the present study was to determine whether and when autonomic dysfunction occurs in a conscious, telemetered, rodent model of CKD. In Lewis polycystic kidney (LPK; n = 8) and Lewis (n = 8) rats, blood pressure (BP), heart rate (HR), HR variability (HRV), systolic BP variability (SBPV) and baroreflex sensitivity (BRS) were determined from 10 to 16 weeks of age. The LPK rats had higher systolic BP (average across all ages: 230 +/- 10 vs 122.6 +/- 0.3 mmHg; P < 0.001), increased SBPV (average across all ages: 13.9 +/- 1.9 vs 5.2 +/- 0.2 mmHg(2) ; P < 0.01) and reduced low-frequency HRV power (average across all ages: 1.5 +/- 0.3 vs 2.6 +/- 0.2 msec(2) ; P < 0.05). Between 10 and 12 weeks of age, SBPV increased twofold in the LPK rat (8.13 +/- 1.05 vs 16.10 +/- 1.31 mmHg(2) for 10 vs 12 weeks of age, respectively; P < 0.001), coinciding with an approximate 40% reduction in BRS (1.32 +/- 0.14 vs 0.79 +/- 0.11 ms/mmHg for 10 vs 12 weeks of age, respectively; P < 0.05). There was no difference in BRS between LPK and Lewis rats at 10 weeks of age; however, from 12 weeks onwards, BRS was reduced in LPK rats (0.75 +/- 0.01 vs 1.17 +/- 0.04 ms/mmHg; P < 0.01). Baroreceptor regulation of HR becomes impaired between 10 and 12 weeks of age in the LPK rat, coinciding with an increase in SBPV. Preventing baroreflex dysfunction in CKD may reduce SBPV and the associated mortality risks. PMID- 23662739 TI - Neonatal stomach volume and physiology suggest feeding at 1-h intervals. AB - There is insufficient evidence on optimal neonatal feeding intervals, with a wide range of practices. The stomach capacity could determine feeding frequency. A literature search was conducted for studies reporting volumes or dimensions of stomach capacity before or after birth. Six articles were found, suggesting a stomach capacity of 20 mL at birth. CONCLUSION: A stomach capacity of 20 mL translates to a feeding interval of approximately 1 h for a term neonate. This corresponds to the gastric emptying time for human milk, as well as the normal neonatal sleep cycle. Larger feeding volumes at longer intervals may therefore be stressful and the cause of spitting up, reflux and hypoglycaemia. Outcomes for low birthweight infants could possibly be improved if stress from overfeeding was avoided while supporting the development of normal gastrointestinal physiology. Cycles between feeding and sleeping at 1-h intervals likely meet the evolutionary expectations of human neonates. PMID- 23662740 TI - Cytomegalovirus retinitis in immunocompetent patients: case reports and literature review. AB - PURPOSE: The purpose of this study was to examine 2 cases of cytomegalovirus (CMV) retinitis, occuring in 2 immunocompentent adult patients. METHODS: Case selection and literature review. RESULTS: Both patients cited significantly decreased vision despite systemic, topical, and/or local corticosteroid use. Neither patient was using high-dose immunosuppressant therapy at the time of diagnostic testing. Both patients exhibited confirmed CMV infection via polymerase chain reaction DNA testing. Oral antivirals were employed and have stabilized both patients. CONCLUSION: The cases described herein serve to inform ophthalmologists of the urgent need to include CMV in their differential when encountering an immunocompetent adult with significant comorbidities or with a history of previous exposure. Proper treatment is heavily reliant on proper diagnosis. PMID- 23662738 TI - Genetics of the corneal endothelial dystrophies: an evidence-based review. AB - The aim of this review was to provide an evidenced-based review of the genetic basis of the corneal endothelial dystrophies. A review of the English language peer-reviewed literature describing the molecular genetic basis of posterior polymorphous corneal dystrophy (PPCD), congenital hereditary endothelial dystrophy (CHED), Fuchs endothelial corneal dystrophy (FECD) and X-linked endothelial corneal dystrophy (XECD) was performed. Mutations in several genes have been implicated as playing a pathogenic role in the corneal endothelial dystrophies: VSX1 mutations in PPCD1; COL8A2 mutations in PPCD2 and FECD; ZEB1 mutations in PPCD3 and FECD; and SLC4A11 mutations in CHED2 and FECD. However, linkage, association and familial segregation analyses support a role of only one gene in each corneal endothelial dystrophy: ZEB1 in PPCD3, SLC4A11 in CHED2 and COL8A2 in FECD (early onset). In addition, insufficient evidence exists to consider the autosomal dominant form of CHED (CHED1) as distinct from PPCD. An accurate classification of the corneal endothelial dystrophies requires a critical review of the evidence to support the role of each suggested chromosomal locus, gene and genetic mutation associated with a corneal endothelial dystrophy. Only after the separation of evidence from opinion is performed can a critical examination of the molecular pathways that lead to endothelial dysfunction in each of these disorders be accurately performed. PMID- 23662741 TI - Synthesis of novel polyazacryptands for recognition of tetrahedral oxoanions and their X-ray structures. AB - The Mannich reaction of tris(pyrrolyl-alpha-methyl)amine (H3tpa) with a mixture of formaldehyde and primary amine hydrochloride (methyl or ethyl) gave two novel macrobicyclic molecules: a hexapyrrolic pentaazacryptand and an unusual pentapyrrolic tetraazacryptand, which were separated by column chromatography and their structures were determined by X-ray diffraction method. The analogous reaction using benzylamine hydrochloride yielded the encapsulated chloride anion complex in 16% yield even after neutralization with aqueous K2CO3, which was also characterized by X-ray diffraction. In addition, the anion binding properties of these macrobicycles were investigated by NMR titration methods, and the binding constants for halides and oxoanions were determined with the EQNMR program. The cavity of the hexapyrrolic pentaazacryptand is flexible and large enough enabling it to form inclusion complexes with the smaller size fluoride ion as well as with the bulkier oxoanions. This was demonstrated by (19)F NMR spectroscopy and by the X-ray structures of the encapsulated sulfate, phosphate, and arsenate ion complexes. Upon complexation the distance between the bridgehead nitrogen atoms changes. Further, anion induced conformational changes were observed in the structures of the oxoanion complexes, particularly in the arsenate structure which represents the first azacryptand encapsulated structure of an arsenate ion. Furthermore, the competition crystallization experiment showed that the phosphate ion complex of the hexapyrrolic pentaazacryptand is the sole crystallization product from an aqueous-organic medium, as confirmed by IR and powder X-ray diffraction studies. PMID- 23662742 TI - Global child health. PMID- 23662743 TI - Potential for genotoxic and reprotoxic effects of vanadium compounds due to occupational and environmental exposures: an article based on a presentation at the 8th International Symposium on Vanadium Chemistry, Biological Chemistry, and Toxicology, Washington DC, August 15-18, 2012. AB - Research on the biological effects of vanadium in humans has shown that acute poisoning in workers can manifest itself in a number of symptoms. There are no reports in humans about reproductive and developmental effects induced by vanadium compounds in humans; however, some studies with rats and mice indicate that vanadium can cross the placental barrier and accumulate in fetal membranes rather than the fetus itself. In this case, probably most consequences of administration of vanadium to pregnant females like reabsorptions, fetal death and reduction in size can be the result of maternal toxicity. Concerning genetic and related effects in humans exposed to different vanadium compounds, data are controversial. Data on genotoxic effects in workers exposed to vanadium indicate that they can have an increased risk to develop cancer, and DNA instability can give rise to an onset of genetic syndromes, fetal malformations, and cancer. This paper presents materials presented at the 8th International Symposium on Vanadium Chemistry, Biological Chemistry, and Toxicology in a session titled 'Relationship between occupational and environmental exposure to vanadium compounds and the reprotoxic and genotoxic effects'. PMID- 23662744 TI - Toxicity of essential oil of Satureja khuzistanica: in vitro cytotoxicity and anti-microbial activity. AB - In nature, essential oils play an important role in the protection of the plants by exerting anti-bacterial, -viral, -fungal, -oxidative, -genotoxic, and free radical scavenging properties, as well as in some cases acting as insecticides. Several Satureja species are used in traditional medicine due to recognized therapeutic properties, namely anti-microbial and cytotoxic activities. The purpose of the present work was to determine the biologic activity of the essential oil of S. khuzistanica Jamzad (Lamiaceae) against four human cancer cell lines, as well as its inhibitory effects against a wide array (i.e. n = 11) of pathogenic bacteria and fungi. The essential oil was isolated by hydro distillation and analyzed by GC-FID and GC-MS. Carvacrol (92.87%) and limonene (1.2%) were found to be the main components of the isolated oil. Anti-microbial activity of the essential oil was assessed using a disc diffusion method; an MTT cytotoxicity assay was employed to test effects of the oil on each cancer cell line. The oil exhibited considerable anti-microbial activity against the majority of the tested bacteria and fungi. The test oil also significantly reduced cell viability of Vero, SW480, MCF7, and JET 3 cells in a dose-dependent manner, with the IC50 values calculated for each cell type being, respectively, 31.2, 62.5, 125, and 125 MUg/ml. Based on the findings, it is concluded that the essential oil of S. khuzistanica and its major constituents have a potential for further use in anti-bacterial and anti-cancer applications, pending far more extensive testing of toxicities in normal (i.e. primary) cells. PMID- 23662745 TI - Equine grass sickness in Scotland: a case-control study of signalment- and meteorology-related risk factors. AB - REASONS FOR PERFORMING STUDY: Equine grass sickness (EGS) remains a frequently fatal disease of equids in Britain. Since previous investigations of signalment- and meteorology-related risk factors for EGS have yielded some conflicting data, further investigation is warranted. OBJECTIVES: To identify signalment- and meteorology-related risk factors for EGS in Scotland. STUDY DESIGN: Retrospective time-matched case-control study. METHODS: This study was undertaken using data for 455 EGS cases and 910 time-matched controls that were referred to the Royal (Dick) School of Veterinary Studies, and average UK Meteorological Office weather station meteorological values from the month of admission of the animal, from the 3, 6 and 12 months prior to admission, and for the entire 1990-2006 period. RESULTS AND CONCLUSION: Signalment-related risk factors associated with an increased risk of EGS were native Scottish pure breeds compared with crossbreeds (odds ratio [OR] = 3.56, 95% confidence interval [CI] 2.43-5.43) and animals living on premises located further north within the study region (OR = 1.08, 95% CI 1.06-1.10). There was a decreased risk of EGS in animals aged 11-20 years compared with animals 2-10 years (OR = 0.32, 95% CI 0.22-0.45), non-native Scottish pure breeds compared with crossbreeds (OR = 0.71, 95% CI 0.54-0.94), and stallions compared with mares (OR = 0.43, 95% CI 0.22-0.86). Meteorology-related risk factors associated with an increased risk of EGS were (if Ordnance Survey northing is excluded) more sun hours (OR>1.43) and more frost days (OR>1.13), while there was a decreased risk of EGS with higher average maximum temperature (OR<0.83). POTENTIAL RELEVANCE: The signalment-related risk factors will help owners identify high-risk animals, thereby allowing them to prioritise management strategies. The identification of meteorological risk factors may assist studies on the aetiology of EGS. PMID- 23662746 TI - Improving knowledge about prenatal screening options: can group education make a difference? AB - OBJECTIVE: To determine if the addition of group education regarding maternal serum screening and diagnostic testing for aneuploidy and neural tube defects improves patient knowledge and affects the uptake of testing compared to individual education alone. METHOD: We conducted a prospective study of 443 obstetric patients to assess knowledge of prenatal testing options based on individual provider counseling (n = 331) or provider counseling with supplemental group education (n = 112). We used a chi-square test to compare the number of correct survey answers between the two groups. RESULTS: There was no difference in baseline knowledge. Patients receiving group education showed a statistically significant improvement in knowledge. After initiation of group education, the uptake of maternal serum screening declined while the uptake of amniocentesis remained unchanged. CONCLUSION: Group education in addition to individual counseling to discuss prenatal testing options appears to be effective in improving knowledge compared to individual provider counseling alone. Improved knowledge may affect uptake of prenatal screening tests due to more informed decision making. PMID- 23662747 TI - Expression of human endogenous retrovirus HERV-K18 is associated with clinical severity in osteoarthritis patients. AB - OBJECTIVES: The aim of this study was to evaluate the involvement of human endogenous retrovirus K18 (HERV-K18) in osteoarthritis (OA), by genotyping the HERV-K18 env locus in OA patients and controls, and analysing HERV-K18 RNA expression and its association with OA risk and clinical variables. METHOD: We recruited 558 patients with symptomatic OA and 600 controls. We performed the genotyping by TaqMan assays and the analysis of expression by quantitative real time polymerase chain reaction (qRT-PCR). Scores on the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC), the Lequesne index, and the Stanford Health Assessment Questionnaire (HAQ) were analysed with regard to the expression levels of HERV-K18. RESULTS: The 18.3 haplotype tended towards an association with OA risk and concordantly this haplotype was associated with a higher HERV-K18 expression (p = 0.05). We found statistically significant differences when we compared the scores on the WOMAC, the Lequesne index for knee and hip, and the HAQ between OA patients with higher expression [normalization ratio (NR) > 10] and OA patients without HERV-K18 expression (p = 0.0003, 0.0005, 0.002, and 0.05, respectively), and also when the comparison was made between OA patients with higher expression (NR > 10) and OA patients with low expression of HERV-K18 (NR = 1) for the WOMAC and the Lequesne index for knee and hip (p = 0.002, 0.013, and 0.006, respectively). CONCLUSIONS: We found an association between health status measurement systems and severity index for OA and the levels of expression of HERV-K18. These results suggest the possible involvement of HERV-K18 in the aetiopathogenesis of the disease. PMID- 23662748 TI - Residual anaesthesia drugs in intravenous lines--a silent threat? PMID- 23662749 TI - Pressure changes during tracheal suctioning--a laboratory study. AB - Suctioning is essential in managing tracheal tubes, but also has drawbacks. Using a bench model, we demonstrated the extent and time course of pressure changes during suctioning, examined their relationship with tracheal tube and catheter diameters and assessed the effects of artificial 'sputum' and of compensatory gas flow in the system. We suctioned at -20 kPa (-150 mmHg) and -80 kPa (-600 mmHg) using three different sized catheters and a 5.9-mm diameter bronchoscope through tracheal tubes ranging from 6.5 mm to 9.0 mm in diameter. Pressure changes ranged from -0.1 kPa (-0.8 mmHg) to -20.4 kPa (-153.0 mmHg). We demonstrated more negative pressures with decreasing tracheal tube diameter (p = 0.024) and increasing catheter diameter (p = 0.038). Addition of artificial 'sputum' led to more negative, but unpredictable, pressures than those seen with clean tubes (p = 0.012). Bronchoscopic suctioning produced pressure changes even greater than the largest suction catheter (p = 0.0039). Using a closed system with continuous positive airway pressure and 155 l.min(-1) compensatory gas flow attenuated the pressure changes generated both with a 4.0-mm catheter (p = 0.0005) and on bronchoscopic suctioning (p = 0.0078). The time taken to reach 50% of minimum pressure was always less than 1 s. The use of high compensatory flows during suctioning merits clinical evaluation. PMID- 23662750 TI - Epidural anaesthesia and analgesia for liver resection. AB - Although epidural analgesia is routinely used in many institutions for patients undergoing hepatic resection, there are unresolved issues regarding its safety and efficacy in this setting. We performed a review of papers published in the area of anaesthesia and analgesia for liver resection surgery and selected four areas of current controversy for the focus of this review: the safety of epidural catheters with respect to postoperative coagulopathy, a common feature of this type of surgery; analgesic efficacy; associated peri-operative fluid administration; and the role of epidural analgesia in enhanced recovery protocols. In all four areas, issues are raised that question whether epidural anaesthesia is always the best choice for these patients. Unfortunately, the evidence available is insufficient to provide definitive answers, and it is clear that there are a number of areas of controversy that would benefit from high quality clinical trials. PMID- 23662751 TI - A bolt from the blue. PMID- 23662752 TI - Cardiac arrest and remifentanil PCA. PMID- 23662753 TI - Remifentanil PCA and midwife training. PMID- 23662754 TI - Unknowns in the use of remifentanil PCA for labour analgesia. PMID- 23662755 TI - Chlorhexidine arachnoiditis. PMID- 23662756 TI - Nottingham hip fracture score, hypovolaemia and broken hips. PMID- 23662757 TI - Differences between hip fracture guidelines. PMID- 23662758 TI - Central venous catheter failure. PMID- 23662759 TI - A reply. PMID- 23662760 TI - Entrapment of a central venous catheter guidewire. PMID- 23662761 TI - A reply. PMID- 23662763 TI - Drug errors--the ten commandments. PMID- 23662762 TI - Improving noradrenaline infusion technique. PMID- 23662764 TI - Colour-coding of drug packaging. PMID- 23662765 TI - Ultrasound-guided retrolaminar paravertebral block. PMID- 23662766 TI - Inaccuracy of fluid container volume markings. PMID- 23662767 TI - Litigation and the older anaesthetist. PMID- 23662768 TI - Incorrect quoting of ASA grade 5. PMID- 23662769 TI - A reply. PMID- 23662771 TI - Knotting of a nasal temperature probe. PMID- 23662770 TI - Difficulties using the C-MAC paediatric videolaryngoscope. PMID- 23662772 TI - "The margin for error": Ritual coping with cultural pressures. AB - Meritocratic sport cultures, media attention, coaches' ambitions, and "enthused" parents create stress and make coping pivotal for athletes' performance. A transdisciplinary dialogue between a sports-sociologist and a sport-psychologist manifests ritual practices in athletes' lived sport experiences as coping strategies. Based on two empirical strands, field observations of boy's handball and interviews with elite male wrestlers', analysis of pregame routines scrutinize psychosocial dimensions of athletes' ritual practice. The implications of ritual meaning making are investigated as a means to cope with sport specific sociocultural anxieties. Rituals are interpreted as psychosocial processes applied to construct perceived order and comfort in stressful sport milieus. We contend that it is reasonable to believe that successful coping is not solely because of athletes' psychological competencies and experiences, but also their ability to ritually use culture in meaningful ways. To manifest important contextual aspects of athletes' lived sport experiences, to nurture task-oriented sport milieus, and to create change in sport and physical cultural contexts, we consequently suggest that the cultural meanings applied in ritual should be an important aspect to address. PMID- 23662773 TI - Capillary malformation--arteriovenous malformation syndrome: review of the literature, proposed diagnostic criteria, and recommendations for management. AB - Capillary malformation-arteriovenous malformation syndrome is an autosomal dominant disorder caused by mutations in the RASA1 gene and characterized by multiple small, round to oval capillary malformations with or without arteriovenous malformations. Ateriovenous malformations occur in up to one-third of patients and may involve the brain and spine. Although making the diagnosis is straightforward in some patients, there are other patients for whom diagnostic criteria may be helpful in their evaluation. Here we review the literature regarding capillary malformation-arteriovenous malformation syndrome, propose diagnostic criteria, and discuss the care of patients with this condition. PMID- 23662775 TI - Colonization resistance and microbial ecophysiology: using gnotobiotic mouse models and single-cell technology to explore the intestinal jungle. AB - The highly diverse intestinal microbiota forms a structured community engaged in constant communication with itself and its host and is characterized by extensive ecological interactions. A key benefit that the microbiota affords its host is its ability to protect against infections in a process termed colonization resistance (CR), which remains insufficiently understood. In this review, we connect basic concepts of CR with new insights from recent years and highlight key technological advances in the field of microbial ecology. We present a selection of statistical and bioinformatics tools used to generate hypotheses about synergistic and antagonistic interactions in microbial ecosystems from metagenomic datasets. We emphasize the importance of experimentally testing these hypotheses and discuss the value of gnotobiotic mouse models for investigating specific aspects related to microbiota-host-pathogen interactions in a well defined experimental system. We further introduce new developments in the area of single-cell analysis using fluorescence in situ hybridization in combination with metabolic stable isotope labeling technologies for studying the in vivo activities of complex community members. These approaches promise to yield novel insights into the mechanisms of CR and intestinal ecophysiology in general, and give researchers the means to experimentally test hypotheses in vivo at varying levels of biological and ecological complexity. PMID- 23662774 TI - Parathyroid hormone-related protein is induced by hypoxia and promotes expression of the differentiated phenotype of human articular chondrocytes. AB - PTHrP (parathyroid hormone-related protein) is crucial for normal cartilage development and long bone growth and acts to delay chondrocyte hypertrophy and terminal differentiation in the growth plate. After growth plate closure adult HACs (human articular chondrocytes) still produce PTHrP, suggesting a possible role for this factor in the permanent articular cartilage. However, the expression regulation and function of PTHrP in the permanent articular cartilage is unknown. Human articular cartilage is an avascular tissue and functions in a hypoxic environment. The resident chondrocytes have adapted to hypoxia and use it to drive their tissue-specific functions. In the present study, we explored directly in normal articular chondrocytes isolated from a range of human donors the effect of hypoxia on PTHrP expression and whether PTHrP can regulate the expression of the permanent articular chondrocyte phenotype. We show that in HACs PTHrP is up-regulated by hypoxia in a HIF (hypoxia-inducible factor)-1alpha and HIF-2alpha-dependent manner. Using recombinant PTHrP, siRNA-mediated depletion of endogenous PTHrP and by blocking signalling through its receptor [PTHR1 (PTHrP receptor 1)], we show that hypoxia-induced PTHrP is a positive regulator of the key cartilage transcription factor SOX9 [SRY (sex determining region on the Y chromosome)-box 9], leading to increased COL2A1 (collagen type II, alpha1) expression. Our findings thus identify PTHrP as a potential factor for cartilage repair therapies through its ability to promote the differentiated HAC phenotype. PMID- 23662776 TI - Structural and functional characterization of CalS11, a TDP-rhamnose 3'-O methyltransferase involved in calicheamicin biosynthesis. AB - Sugar methyltransferases (MTs) are an important class of tailoring enzymes that catalyze the transfer of a methyl group from S-adenosyl-l-methionine to sugar based N-, C- and O-nucleophiles. While sugar N- and C-MTs involved in natural product biosynthesis have been found to act on sugar nucleotide substrates prior to a subsequent glycosyltransferase reaction, corresponding sugar O-methylation reactions studied thus far occur after the glycosyltransfer reaction. Herein we report the first in vitro characterization using (1)H-(13)C-gHSQC with isotopically labeled substrates and the X-ray structure determination at 1.55 A resolution of the TDP-3'-O-rhamnose-methyltransferase CalS11 from Micromonospora echinospora. This study highlights a unique NMR-based methyltransferase assay, implicates CalS11 to be a metal- and general acid/base-dependent O methyltransferase, and as a first crystal structure for a TDP-hexose-O methyltransferase, presents a new template for mechanistic studies and/or engineering. PMID- 23662777 TI - Exploring neural cell dynamics with digital holographic microscopy. AB - In this review, we summarize how the new concept of digital optics applied to the field of holographic microscopy has allowed the development of a reliable and flexible digital holographic quantitative phase microscopy (DH-QPM) technique at the nanoscale particularly suitable for cell imaging. Particular emphasis is placed on the original biological information provided by the quantitative phase signal. We present the most relevant DH-QPM applications in the field of cell biology, including automated cell counts, recognition, classification, three dimensional tracking, discrimination between physiological and pathophysiological states, and the study of cell membrane fluctuations at the nanoscale. In the last part, original results show how DH-QPM can address two important issues in the field of neurobiology, namely, multiple-site optical recording of neuronal activity and noninvasive visualization of dendritic spine dynamics resulting from a full digital holographic microscopy tomographic approach. PMID- 23662778 TI - Cardiovascular magnetic resonance: deeper insights through bioengineering. AB - Heart disease is the main cause of morbidity and mortality worldwide, with coronary artery disease, diabetes, and obesity being major contributing factors. Cardiovascular magnetic resonance (CMR) can provide a wealth of quantitative information on the performance of the heart, without risk to the patient. Quantitative analyses of these data can substantially augment the diagnostic quality of CMR examinations and can lead to more effective characterization of disease and quantification of treatment benefit. This review provides an overview of the current state of the art in CMR with particular regard to the quantification of motion, both microscopic and macroscopic, and the application of bioengineering analysis for the evaluation of cardiac mechanics. We discuss the current clinical practice and the likely advances in the next 5-10 years, as well as the ways in which clinical examinations can be augmented by bioengineering analysis of strain, compliance, and stress. PMID- 23662779 TI - Profiling the careers of Thoroughbred horses racing in Hong Kong between 2000 and 2010. AB - REASONS FOR PERFORMING STUDY: Research in Thoroughbred racehorses is often specific to horses from a given racing population or region. In order to investigate trends in racehorse careers across populations accurately, population specific benchmarks for performance outcomes must be established. OBJECTIVES: To provide summary statistics for performance outcomes for Thoroughbreds racing in Hong Kong between 2000 and 2010 and to document and provide evidence on the current differences in racing careers across sexes and regions of origin for horses racing in Hong Kong. STUDY DESIGN: Performance data on the population of Thoroughbreds racing in Hong Kong between 3 September 2000 and 12 March 2011 (n = 4950) were acquired and used to describe and compare the careers of Thoroughbred racehorses in Hong Kong. METHODS: Career length, number of career starts and number of spells from racing per year were evaluated. Kaplan-Meier survival curves, stratified by sex, age group, country of origin and region of origin were produced for career length. A Cox's proportional hazards model was fitted to assess factors influencing the risk of retirement from racing in Hong Kong. RESULTS: Log-rank tests for equality of career length survivor functions showed significant differences (P<0.001) across sexes, age groups, countries of origin and regions of origin. An increased age at first start in Hong Kong tended to increase the hazard rate for retirement from racing in Hong Kong, whereas greater earnings per race and originating from Europe tended to reduce the hazard rate for racing retirement. CONCLUSIONS AND POTENTIAL RELEVANCE: Differences in career outcomes within a racing population appear to be influenced partly by the region from which a horse originates, with specific effects on each performance outcome also varying between regions. Future research should take into account these potential differences when comparing results across populations. PMID- 23662781 TI - Response to the letter by prof. Dal Moro: the dark side of the Swoon- antihypertensive treatment in the elderly. PMID- 23662782 TI - Rituximab therapy for refractory idiopathic scleritis. AB - PURPOSE: To report 2 cases of refractory idiopathic scleritis treated with rituximab. DESIGN: Interventional case series. METHODS AND RESULTS: Case 1: A 54 year-old woman, presented with anterior idiopathic scleritis in her right eye. Treatment with systemic steroids was not effective. Intravenous cyclophosphamide was discontinued after an adverse event. Case 2: A 43-year-old woman presented with idiopathic posterior scleritis in her left eye. Initial treatment with steroids was ineffective. In both cases, long-lasting remission without further relapses was achieved after 4 weekly doses (375 mg/m(2)) of rituximab. CONCLUSION: Rituximab was found to be an effective treatment for refractory idiopathic anterior and posterior scleritis. PMID- 23662783 TI - A novel Lewis acid catalyzed [3 + 3]-annulation strategy for the syntheses of tetrahydro-beta-carbolines and tetrahydroisoquinolines. AB - A novel Lewis acid catalyzed [3 + 3]-annulation process for the efficient syntheses of both tetrahydro-beta-carbolines and tetrahydroisoquinolines from readily available benzylic alcohols and aziridines was developed, which would be a highly valuable complement to the widely used Pictet-Spengler reaction. A probable mechanism was proposed based on the isolation and characterization of two key intermediates. This strategy enables facile access to important alkaloid frameworks not easily available with other known methods. PMID- 23662784 TI - Uncertainty analysis in the use of chemical thermometry: a case study with cyclohexene. AB - A general method to evaluate the absolute uncertainties in temperatures derived using chemical thermometry is developed and applied to the retro Diels-Alder reaction of cyclohexene. Experiments from previous studies of this reaction are reanalyzed to establish the minimum absolute uncertainty limit. Chemical thermometry results are compared with thermocouple measurements in experiments performed in a flow reactor at 6.1 atm pressure and at temperatures from 957 to 978 K . Using conservative uncertainty estimates, our analysis yields absolute (1sigma) uncertainties of temperature through chemical thermometry using this reaction greater than +/-20 at 1000 K. Neither more refined experimental techniques nor computational theory is likely to refine rate correlation parameters sufficiently to reach the absolute temperature uncertainties often reported in the literature for chemical thermometry using the retro Diels-Alder reaction of cyclohexene. Published chemical thermometry uncertainty estimates typically have not quantitatively considered the absolute uncertainties of the original data from which the reference rate correlations were based. PMID- 23662786 TI - Editorial: The new DSM is coming--it needs tough love.... PMID- 23662787 TI - Automatic chemical structure annotation of an LC-MS(n) based metabolic profile from green tea. AB - Liquid chromatography coupled with multistage accurate mass spectrometry (LC MS(n)) can generate comprehensive spectral information of metabolites in crude extracts. To support structural characterization of the many metabolites present in such complex samples, we present a novel method ( http://www.emetabolomics.org/magma ) to automatically process and annotate the LC MS(n) data sets on the basis of candidate molecules from chemical databases, such as PubChem or the Human Metabolite Database. Multistage MS(n) spectral data is automatically annotated with hierarchical trees of in silico generated substructures of candidate molecules to explain the observed fragment ions and alternative candidates are ranked on the basis of the calculated matching score. We tested this method on an untargeted LC-MS(n) (n <= 3) data set of a green tea extract, generated on an LC-LTQ/Orbitrap hybrid MS system. For the 623 spectral trees obtained in a single LC-MS(n) run, a total of 116,240 candidate molecules with monoisotopic masses matching within 5 ppm mass accuracy were retrieved from the PubChem database, ranging from 4 to 1327 candidates per molecular ion. The matching scores were used to rank the candidate molecules for each LC-MS(n) component. The median and third quartile fractional ranks for 85 previously identified tea compounds were 3.5 and 7.5, respectively. The substructure annotations and rankings provided detailed structural information of the detected components, beyond annotation with elemental formula only. Twenty-four additional components were putatively identified by expert interpretation of the automatically annotated data set, illustrating the potential to support systematic and untargeted metabolite identification. PMID- 23662785 TI - Venous and arterial disease in inflammatory bowel disease. AB - Awareness is increasing that risk of venous thromboembolism and development of atherosclerosis is elevated in patients with some chronic inflammatory diseases. This review aimed to examine the risk of vascular disease in patients with inflammatory bowel disease (IBD) and to identify potential pathogenic mechanisms and therapeutic approaches. An extensive literature search was conducted using MEDLINE database, Cochrane Library and international conference abstracts for studies pertaining to venous and arterial thromboembolism in adult IBD patients. There is a 1.1-3.6 fold risk of venothromboembolism in IBD, affecting 0.55-6.15% of patients. Risks are increased during a flare or with chronically active inflammation. Evidence is building that there may be a modestly increased risk of arterial disease overall, despite evidence that traditional risk factors may be reduced. Multiple pathogenic factors have been identified including endothelial dysfunction, inflammation-mediated calcium deposition in the media of arteries, hyperhomocysteinemia, platelet activation, and altered coagulation and fibrinolysis. The key to active and preventive therapy is to effectively treat inflammation. Recommendations for prophylaxis of venothromboembolism have followed guidelines where they exist and have been extrapolated from studies of other at-risk conditions, as have those for arterial disease, where screening for risk factors and actively treating abnormalities is encouraged. In conclusion, patients with IBD are at considerably increased risk of venothromboembolism and probably of arterial disease, in particular mesenteric ischemia and ischemic heart disease. Increased penetration of gaps between this knowledge and clinical therapeutic action to prevent thromboembolic events into IBD clinical practice is needed. PMID- 23662788 TI - The relationship between tumour necrosis factor (TNF)-alpha promoter and IL12B/IL 23R genes polymorphisms and the efficacy of anti-TNF-alpha therapy in psoriasis: a case-control study. AB - BACKGROUND: Antitumour necrosis factor (anti-TNF)-alpha agents can be used successfully to treat patients with psoriasis and other inflammatory diseases. However, very few studies have examined the relationship between TNF-alpha polymorphisms and the response to anti-TNF-alpha agents. OBJECTIVES: To study the association of single nucleotide polymorphisms (SNPs) of the TNF-alpha promoter and IL12B/IL23R genes with the response to anti-TNF-alpha in patients with psoriasis. METHODS: SNPs for the TNF-alpha promoter and IL12B/IL23R genes, and the presence of the HLA-Cw6 haplotype were genotyped for 109 patients. We studied the association between these SNPs and the efficacy of treatment at 3 and 6 months [Psoriasis Area and Severity Index (PASI) and body surface area (BSA)]. RESULTS: Patients with the TNF-alpha-238GG genotype more frequently achieved a PASI75 at 6 months (82.5% vs. 58.8%, P = 0.049). At 6 months, patients with the TNF-alpha-857CT/TT genotypes showed greater improvements in PASI score and BSA (83.1% vs. 92.7%, P = 0.004; 82.7% vs. 92.6%, P = 0.009) and more frequently achieved PASI75 (71.4% vs. 96.3%, P = 0.006). More patients with the TNF-alpha 1031TT genotype achieved PASI75 at 3 months (90.8 vs. 75.7, P = 0.047) and 6 months (85.5% vs. 65.7%, P = 0.038) and demonstrated superior improvements in PASI at 6 months (89.9% vs. 78.7%, P = 0.041). Patients with the IL23R-GG genotype (rs11209026) achieved PASI90 at 6 months more frequently (66.3% vs. 0, P = 0.006) and the improvement of the PASI score was also greater (86.8% vs. 67.8%, P = 0.013). Patients with the HLA-Cw6 haplotype showed poorer response than those without this haplotype. CONCLUSION: This study identified a relationship between certain TNF-alpha and IL12B/IL23R polymorphisms and the short-term response to anti-TNF-alpha drugs. If these results are confirmed, this information will allow for stratified consent with more accurate prediction of response/personalized choice of treatment hierarchy for the patient. PMID- 23662789 TI - Family members' of persons living with a serious mental illness: experiences and efforts to cope with stigma. AB - BACKGROUND: Studies have indicated that family members of persons with mental illness often experience stigma in relation to their relatives' illness. Less is known about the type of experiences they face and how they cope with these experiences. AIMS: To explore family members' experiences and efforts to cope with mental illness stigma in social encounters. METHOD: A qualitative immersion/crystallization analysis of focus group data was used to examine family members' experiences and responses to perceived stigma. RESULTS: Family members reported experiencing rejection, blame and avoidance by others, engendering hurt, disappointment and shame. They employed flexible coping strategies depending on their personal resources, motivation and their relatives' willingness to disclose. CONCLUSION: Findings suggest that families learn from their own experience the "art of selective disclosure": what, when, how much and who to share information with. Coping strategies are developed based on the situation and family members' needs and personal resources which differ between families and over time. PMID- 23662790 TI - Optical response of lorentzian nanoshells in the quasistatic limit. AB - Recently, plexcitonic systems consisting of a plasmonic nanoshell or a core covered by an excitonic shell are engineered. Such systems hold promise for tunable nanophotonic devices for imaging, chemical sensing, and resonance energy transfer. Their plasmonic response is grasped well, while understanding of their excitonic response remains to be improved. To this end, we have developed a methodology in which the functionalities of the dispersive properties of the spherical shell and the nanoenvironment in tuning the optical response are clearly separated. Using this methodology, we have studied the response of the Lorentzian/excitonic nanoshells with optically inactive core and embedding medium and compared it with the well-known properties of the Drude/plasmonics nanoshells. Contrary to Drude nanoshells exhibiting a resonance pair red-shifted with respect to the bulk, Lorentzian nanoshells are identified by a resonance pair blue-shifted with respect to the in-solution excitonic resonance. While the Drude red-shifting is more effective at increasing dielectric constants (core, shell, and embedding medium), the Lorentzian blue-shifting is governed by the excitonic strength and is suppressed at increasing dielectric constants. The implications of the results for manipulating the optical response of plexcitonic systems are briefly discussed. PMID- 23662791 TI - Providing comprehensive genetic-based ophthalmic care. AB - The diagnosis of an inherited retinal dystrophy can have a significant impact on both the physical and emotional lives of patients and their families. In order to optimize the health and quality of life for these individuals, a comprehensive approach to clinical care starting at the time of diagnosis and continuing throughout their lifespan is critical. A multidisciplinary team approach integrating ophthalmic and genetic counseling services can optimize the diagnostic process and long-term management of these patients. When vision loss is first appreciated, the diagnostic specificity of an ophthalmic evaluation can be enhanced by a detailed genetic work-up. This evaluation can help confirm the diagnosis and allow for accurate risk counseling of the patient and their family. Genetic counseling is critical at the time of diagnosis and is an opportunity to provide education about the diagnosis, discuss low-vision rehabilitation, and explore impacts on academics and employment. In addition, counseling can help patients deal with the current psychological aspects of their vision loss, prepare for the lifelong impact of their diagnosis and over time adjust to the impact of progressive vision loss. PMID- 23662792 TI - Discontinuous gas exchange exhibition is a heritable trait in speckled cockroaches Nauphoeta cinerea. AB - The regulation of insect respiratory gas exchange has long been an area of interest. In particular, the reason why insects from at least five orders exhibit patterns of gas exchange that include regular periods of spiracular closure has been the source of much controversy. Three adaptive hypotheses propose that these discontinuous gas-exchange cycles (DGCs) evolved to either limit water loss across respiratory surfaces, facilitate gas exchange in underground environments or to limit oxidative damage. It is possible that DGCs evolved independently multiple times and for different reasons, but for DGCs to be a plausible target for natural selection, they must be heritable and confer a fitness benefit. In a previous study of cockroaches Nauphoeta cinerea, we demonstrated that DGCs are repeatable and extend survival under food and water restriction. Here, we show for the first time that DGCs are heritable, suggesting that they are a plausible target for natural selection. PMID- 23662793 TI - Development of a home international normalized ratio monitoring program: strategic approach and evaluation. PMID- 23662794 TI - Impact of non-cardiovascular surgery on reactive hyperaemia and arterial endothelial function. AB - Vascular reactivity is a surrogate marker for atherosclerosis and is predictive of cardiovascular outcome. Non-cardiovascular surgery is associated with perioperative cardiovascular complications in high-risk patients. To evaluate the impact of non-cardiovascular surgery on reactive hyperaemia and arterial endothelial function and to investigate the relationships between endothelial dysfunction and invasive (laparotomy) or minimally invasive (laparoscopic) surgery, we prospectively evaluated 106 patients undergoing abdominal surgery under general anaesthesia (71 laparotomy, 35 laparoscopy). Measurements of blood pressure, heart rate and pain (on a visual analogue scale (VAS)) were undertaken. Brachial endothelium-dependent flow-mediated dilation (FMD), endothelium independent dilation, nitroglycerin (NTG)-induced dilation and reactive hyperaemia were measured with high-resolution B-mode ultrasound on preoperative Day 1 (baseline), as well as 2 h and 1 and 7 days postoperatively. Blood pressure and heart rate were significantly higher 2 h postoperatively. Pain, as measured on the VAS, was higher (P < 0.01) and reactive hyperaemia and FMD were significantly lower (P < 0.001) at 2 h and 1 day postoperatively compared with values at baseline and on postoperative Day 7. By postoperative Day 7, FMD had recovered to baseline levels. Patients undergoing laparoscopic surgery had less FMD reduction on Days 1 and 7 (7.5 +/- 1.5% and 7.9 +/- 1.5%, respectively) compared with those undergoing laparotomy (6.4 +/- 1.6% (P = 0.001) and 7.0 +/- 1.6% (P = 0.006), respectively), consistent with potential cardiovascular benefit. Responses to NTG were stable throughout. Backward multivariate linear regression analysis indicated that FMD was independently related to age and VAS (model R = 0.486; F = 6.4; P < 0.001). Reactive hyperaemia and arterial endothelial function are significantly reduced in the early postoperative period, particularly after laparotomy compared with laparoscopy, which may be related to postoperative cardiovascular events. PMID- 23662795 TI - Characterization of Aronia melanocarpa volatiles by headspace-solid-phase microextraction (HS-SPME), simultaneous distillation/extraction (SDE), and gas chromatography-olfactometry (GC-O) methods. AB - The profiles of volatile constituents of berry fruit of two Aronia melanocarpa genotypes were evaluated by headspace-solid-phase microextraction (HS-SPME), simultaneous distillation and extraction (SDE), and gas chromatography olfactometry (GC-O). In total, 74 volatile compounds were identified in chokeberry juice, 3-penten-2-one, 3,9-epoxy-p-menth-1-ene, and benzaldehyde being the most abundant constituents; however, their percentage concentrations were remarkably different in the HS-SPME and SDE profiles. Twenty two aroma-active compounds were detected and characterized by the trained panelists in HS-SPME using GC-O detection frequency analysis. Olfactometry revealed that ethyl-2 methyl butanoate, ethyl-3-methyl butanoate, ethyl decanoate ("fruity" aroma notes), nonanal ("green" notes), unidentified compound possessing "moldy" odor, and some other volatiles may be very important constituents in formation of chokeberry aroma of both analyzed plant cultivars. PMID- 23662796 TI - Functionalized N-heterocyclic carbene nonspectator ligands upon internal alkyne activation reactions. AB - When studying the activation of 3-arylpropiolates by [TpRu(picolyl (R)I)Cl]/NaBAr(F)4 (picolyl-(Me)I = 3-methyl-1-(2-picolyl)imidazol-2-ylidene (1); picolyl-(Me)BI = 3-methyl-1-(2-picolyl)benzoimidazol-2-ylidene (2)) a migratory insertion of the NHC into a ruthenium-carbon bond and an unprecedented C-N bond activation of the chelating picolyl-NHC ligand take place to give the new ruthenium metallacycles [TpRu(kappa(3)-C,N,N'-?C(Ph) C(CH2Py)(CO2Me)((Me)I)][BAr(F)4] 3a and 4a and [TpRu(kappa(3)-C,N,N'-?C(4-CF3Ph) C(CH2Py)(CO2Me)((Me)I)][BAr(F)4] 3b and 4b. X-ray crystal structures of 3a and 3b are reported, and a mechanistic pathway is proposed. In contrast, activation of internal alkynones by a mixture of [TpRu(picolyl-(Me)I)Cl] complex (1) and NaBAr(F)4 led to isolation and characterization of the corresponding disubstituted vinylidene complexes. Also, structures of [TpRu(picolyl (Me)I)(?CC(COR)(Ph)][BAr(F)4] (R = Me (6a); Ph (6b)) are reported. PMID- 23662797 TI - Transporter associated with antigen processing deficiency syndrome: case report of an adolescent with chronic perforated granulomatous skin lesions due to TAP2 mutation. AB - A previously unreported case of transporter associated with antigen processing (TAP) deficiency syndrome (with no parental consanguinity) due to a homozygous TAP2 mutation is presented. Characteristic nonhealing, chronic, ulcerative granulomatous leg lesions combined with recurrent otitis media and sinopulmonary infections led to this boy being diagnosed at 15 years old. The role of the dermatologist was crucial in making the correct diagnosis and thereby positively influencing the quality of life and life expectancy of this boy. PMID- 23662798 TI - First experimental evidence of dopamine interactions with negatively charged model biomembranes. AB - Dopamine is essential for receptor-related signal transduction in mammalian central and peripheral nervous systems. Weak interactions between the neurotransmitter and neuronal membranes have been suggested to modulate synaptic transmission; however, binding forces between dopamine and neuronal membranes have not yet been quantitatively described. Herein, for the first time, we have explained the nature of dopamine interactions with model lipid membranes assembled from neutral 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), negatively charged 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG), and the mixture of these two lipids using isothermal titration calorimetry and differential scanning calorimetry. Dopamine binding to anionic membranes is a thermodynamically favored process with negative enthalpy and positive entropy, quantitatively described by the mole ratio partition coefficient, K. K increases with membrane charge to reach its maximal value, 705.4 +/- 60.4 M(-1), for membrane composed from pure DMPG. The contribution of hydrophobic effects to the binding process is expressed by the intrinsic partition coefficient, K(0). The value of K(0) = 74.7 +/- 6.4 M(-1) for dopamine/DMPG interactions clearly indicates that hydrophobic effects are 10 times weaker than electrostatic forces in this system. The presence of dopamine decreases the main transition temperature of DMPG, but no similar effect has been observed for DMPC. Basing on these results, we propose a simple electrostatic model of dopamine interactions with anionic membranes with the hydrophobic contribution expressed by K(0). We suggest that dopamine interacts superficially with phospholipid membranes without penetrating into the bilayer hydrocarbon core. The model is physiologically important, since neuronal membranes contain a large (even 20%) fraction of anionic lipids. PMID- 23662799 TI - The prevalence of and risk factors associated with pterygium in a rural adult Chinese population: the Handan Eye Study. AB - PURPOSE: To describe the prevalence and risk factors for pterygium in a rural adult Chinese population. METHODS: A total of 7557 people aged 30 years and over were randomly selected from 13 villages in a rural county, Yongnian, within Handan district, Hebei Province of China. All eligible subjects were invited to undergo a comprehensive eye examination. A slit-lamp was used to examine the anterior segment for evidence of pterygium. Pterygium was graded for severity (G1 to G3) by visibility of episcleral vessels. RESULTS: Of 6685 participants (88.5% of 7557) included in this study, pterygium was present in 401 (6.0%). Using direct standardization to the 2000 China population census for rural residents, the prevalence of pterygium was 7.1% (95% confidence interval [CI], 6.5-7.8%) among subjects aged 40+ years, and 4.8% (95% CI 4.3-5.3%) when including those aged 30-39 years. Pterygium was more common in men than in women (age-adjusted odds ratio [OR] 2.0, 95% CI 1.4-2.8). Prevalence increased with age (OR 1.8, 95% CI 1.6-2.1 per decade increase in age). Current smoking appeared to be protective (OR 0.5, 95% CI 0.4-0.7). Of eyes with any pterygium, 4.6% (95% CI 1.9-7.3%) had low vision. CONCLUSION: Approximately one in ten adults had pterygium in this rural Chinese population. Age and male sex were positively, and current smoking negatively associated with the prevalence of pterygium. PMID- 23662800 TI - Reply to Letter to the Editor: does severity of psoriasis increase coronary artery calcification? PMID- 23662801 TI - MGMT promoter methylation status and prognosis of patients with primary or recurrent glioblastoma treated with carmustine wafers. AB - The prognostic role of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastoma patients treated with carmustine (BCNU) wafer implantation is unclear. Here, we report on a retrospective study of 47 patients with either newly diagnosed (30 patients) or recurrent (17 patients) glioblastoma (WHO grade IV) treated with BCNU (bis-chloroethylnitrosourea) wafers. Thirteen of the newly diagnosed patients received local BCNU and irradiation only (first-line BCNU), while 17 patients additionally received concomitant and adjuvant temozolomide (TMZ) radiochemotherapy (first-line BCNU + TMZ). Of the 17 patients treated for recurrent glioblastoma (second-line BCNU), 16 had received radiotherapy with concomitant and adjuvant TMZ as an initial treatment. Median overall survival (OS) did not significantly differ between 19 patients with MGMT promoter methylated tumors when compared to 28 patients with unmethylated tumors (18.9 vs 15.0 months; p = 0.1054). In the first-line BCNU + TMZ group, MGMT promoter methylation was associated with longer OS (21.0 vs 11.1 months, p = 0.0127), while no significant survival differences were detected in the other two subgroups. Progression-free survival did not significantly differ between patients with and without MGMT promoter methylated tumors in the entire patient cohort or any of the three subgroups. The first-line BCNU + TMZ group showed no significant difference in OS when compared to the first-line BCNU group (18.9 vs 14.7 months), but tended to have more therapy-related adverse effects (53% vs 24%, p = 0.105). In summary, MGMT promoter methylation showed a non-significant trend toward longer survival in our patient cohort. The combination of TMZ radiochemotherapy with local delivery of BCNU did not provide a significant survival benefit compared to local BCNU alone, but was associated with a higher rate of adverse effects. Owing to the small number of patients investigated, however, these findings would need to be corroborated in larger patient cohorts. PMID- 23662802 TI - Self-transcendent positive emotions increase spirituality through basic world assumptions. AB - Spirituality has mostly been studied in psychology as implied in the process of overcoming adversity, being triggered by negative experiences, and providing positive outcomes. By reversing this pathway, we investigated whether spirituality may also be triggered by self-transcendent positive emotions, which are elicited by stimuli appraised as demonstrating higher good and beauty. In two studies, elevation and/or admiration were induced using different methods. These emotions were compared to two control groups, a neutral state and a positive emotion (mirth). Self-transcendent positive emotions increased participants' spirituality (Studies 1 and 2), especially for the non-religious participants (Study 1). Two basic world assumptions, i.e., belief in life as meaningful (Study 1) and in the benevolence of others and the world (Study 2) mediated the effect of these emotions on spirituality. Spirituality should be understood not only as a coping strategy, but also as an upward spiralling pathway to and from self transcendent positive emotions. PMID- 23662803 TI - An investigation of anthelmintic efficacy against strongyles on equine yards in Scotland. AB - REASONS FOR PERFORMING STUDY: Cyathostomins comprise 50 helminth species, considered the most problematic equine endoparasites. Three classes of anthelmintic are currently licensed for their control, namely the benzimidazoles (fenbendazole), tetrahydropyrimidines (pyrantel) and macrocyclic lactones (ivermectin and moxidectin). Anthelmintic resistance in cyathostomins is common. With no new classes expected in the near future, it is essential to determine the efficacy of the available anthelmintics to inform future control programmes. OBJECTIVES: To determine the efficacy of all 3 anthelmintic classes against strongyles in equids on livery yards in east and central Scotland. STUDY DESIGN: Anthelmintic efficacy testing using the faecal egg count reduction test (FECRT). METHODS: FECRTs were performed on equids with initial strongyle faecal egg counts (FECs) of >=50 eggs per gram. Efficacy was determined by comparing pretreatment (Day 0) and 14 days post treatment (Day 14) FECs. The following chemicals were tested: fenbendazole, pyrantel, ivermectin and moxidectin. Group arithmetic mean FECR of >90% for fenbendazole and pyrantel, and >95% for ivermectin and moxidectin, represented efficacy, whereas lower mean FECR indicated potential resistance. RESULTS: A total of 447 FECRTs were performed on 15 yards, as follows (the numbers in parentheses represent the number of yards each anthelmintic was tested on): 55 equids (7 yards) fenbendazole, 111 (8 yards) pyrantel, 163 (13 yards) ivermectin and 118 (10 yards) moxidectin. Fenbendazole resistance was documented on all yards (range of mean FECR, 15.8-83.4%), whereas pyrantel (90.4 99.6%), ivermectin (99.5-100%) and moxidectin (99.4-100%) treatment had acceptable efficacy. CONCLUSIONS: Reduced efficacy of fenbendazole was widespread, whereas >90% efficacy was found after pyrantel, and >95% efficacy after ivermectin and moxidectin. Overall, efficacies were higher than reported previously in Europe and the USA, potentially reflecting differences in management and anthelmintic use on the yards surveyed. POTENTIAL RELEVANCE: The use of fenbendazole for strongyle control in Scotland should be questioned. Targeted use of pyrantel should be encouraged to reduce reliance on macrocyclic lactones. Further work to correlate management practices with the presence of anthelmintic resistance is warranted. PMID- 23662804 TI - Phosphocreatine resynthesis during recovery in different muscles of the exercising leg by 31P-MRS. AB - To investigate the high-energy phosphate metabolism by (31) P-nuclear magnetic resonance spectroscopy during off-transition of exercise in different muscle groups, such as calf muscles and biceps femoris muscles, seven male long-distance runners (LDR) and nine untrained males (UT) performed both submaximal constant and incremental exercises. The relative exercise intensity was set at 60% of the maximal work rate (60%W max) during both knee flexion and plantar flexion submaximal constant load exercises. The relative areas under the inorganic phosphate (Pi ) and phosphocreatine (PCr) peaks were determined. During the 5-min recovery following the 60%W max, the time constant for the PCr off-kinetics was significantly faster in the plantar flexion (LDR: 17.3 +/- 3.6 s, UT: 26.7 +/- 6.7 s) than in the knee flexion (LDR: 29.7 +/- 4.7 s, UT: 42.7 +/- 2.8 s, P < 0.05). In addition, a significantly faster PCr off-kinetics was observed in LDR than in UT for both exercises. The ratio of Pi to PCr (Pi /PCr) during exercise was significantly lower during the plantar flexion than during the knee flexion (P < 0.01). These findings indicated that the calf muscles had relatively higher potential for oxidative capacity than that of biceps femoris muscles with an association of training status. PMID- 23662805 TI - The paradox of elongation factor 4: highly conserved, yet of no physiological significance? AB - LepA [EF4 (elongation factor 4)] is a highly conserved protein found in nearly all known genomes. EF4 triggers back-translocation of the elongating ribosome, causing the translation machinery to move one codon backwards along the mRNA. Knockout of the corresponding gene in various bacteria results in different phenotypes; however, the physiological function of the factor in vivo is unclear. Although functional research on Guf1 (GTPase of unknown function 1), the eukaryotic homologue of EF4, showed that it plays a critical role under suboptimal translation conditions in vivo, its detailed mechanism has yet to be identified. In the present review we briefly cover recent advances in our understanding of EF4, including in vitro structural and biochemical studies, and research on its physiological role in vivo. Lastly, we present a hypothesis for back-translocation and discuss the directions future EF4 research should focus on. PMID- 23662806 TI - The expanding family of FERM proteins. AB - Our understanding of the FERM (4.1/ezrin/radixin/moesin) protein family has been rapidly expanding in the last few years, with the result that many new physiological functions have been ascribed to these biochemically unique proteins. In the present review, we will discuss a number of new FRMD (FERM domain)-containing proteins that were initially discovered from genome sequencing but are now being established through biochemical and genetic studies to be involved both in normal cellular processes, but are also associated with a variety of human diseases. PMID- 23662810 TI - Hepcidin, show some self-control! How the hormone of iron metabolism regulates its own expression. AB - Does the hormone of iron metabolism, hepcidin, exhibit 'self-control'? Hepcidin is a small, disulfide-rich peptide synthesized by the liver, which plays a keystone role in regulating systemic iron metabolism in mammals. Hepcidin acts by binding and triggering the lysosomal degradation of the cellular iron exporter ferroportin. Ultimately, decreased ferroportin leads to decreased plasma iron levels. Although various modulators of HAMP (the hepcidin antimicrobial peptide gene) expression are known, no auto-regulatory pathway has been described. In their paper published in the Biochemical Journal in April 2013, Pandur et al. identify an auto-regulatory pathway in which prohepcidin regulates HAMP expression. The authors observe that prohepcidin can bind to the inflammation regulated STAT3 (signal transducer and activator of transcription 3)-binding site in the HAMP promoter to negatively regulate HAMP expression. Furthermore, the authors find that the prohepcidin-binding partner, alpha-1 antitrypsin, inhibits prohepcidin's ability to decrease HAMP activity. This is significant as alpha-1 antitrypsin, similar to hepcidin, is an acute-phase reactant that is up-regulated by inflammation. In conclusion, the discovery of a hepcidin auto-regulatory pathway, first, supports the emerging notion that hepcidin regulation is exquisitely fine-tuned through a process of combinatorial control; and secondly, suggests that hepcidin may play a hand in its own deregulation in diseases of iron metabolism that involve aberrant cytokine signalling (e.g. the anaemia of inflammation). PMID- 23662809 TI - Evidence for novel aspects of Nox4 oxidase regulation of mitochondrial function and peroxide generation in an endothelial cell model of senescence. AB - Observations by Koziel et al. reported in this issue of the Biochemical Journal suggest the existence of novel regulatory processes associated with new evidence for increased Nox4 (NAPDH oxidase 4) regulation of mitochondrial function in a cultured endothelial cell aging-induced senescence model. Cellular aging appears to promote a Nox4 interaction with mitochondria that disrupts complex I in the electron transport chain and increases the detection of mitochondrial H(2)O(2). Nox4 appears to maintain a highly interconnected mitochondrial network, which may influence mitochondrial fission and/or fusion mechanisms in a manner that could be a contributing factor in the loss of replicative lifespan seen in senescence. PMID- 23662811 TI - Growth hormone therapy with norditropin ( somatropin ) in growth hormone deficiency. AB - INTRODUCTION: Growth hormone (GH) is indicated for therapy of growth hormone deficiency (GHD) in pediatric and adult patients. Introduction of recombinant human GH (rhGH) improved access to GH therapy. Norditropin [ somatropin (rDNA origin) injection] is rhGH, used for the replacement of endogenous GH in children and adults with GHD. AREAS COVERED: The article reviews rhGH therapy in GHD indication with focus on Norditropin Nordiflex delivery system. The goals of therapy in children are to promote linear growth and restore normal body composition. In adults with GHD rhGH restores normal body composition, improves cardiac function and normalizes cardiovascular risk factors such as low-density lipoprotein cholesterol and C-reactive protein. EXPERT OPINION: Adverse reactions of rhGH therapy include intracranial hypertension, fluid retention, glucose intolerance, and children may experience worsening of scoliosis and slipped capital femoral epiphysis. Increased risk for intracranial tumors has also been reported in teenagers and young adults treated with radiation to the head as children for a first neoplasm. RhGH therapy requires daily injections, therefore improved ease of use of delivery devices may improve treatment outcomes. Several rhGH devices have been developed, and the Norditropin FlexPro prefilled pen is the newest delivery system which has small dose increments, does not require reconstitution and has flexible storage features. PMID- 23662813 TI - E- to N-cadherin switch in melanoma is associated with decreased expression of phosphatase and tensin homolog and cancer progression. AB - BACKGROUND: Cadherin switch in melanoma, with loss of E-cadherin and upregulation of N-cadherin, is believed to underlie melanoma cell detachment from the epidermis and promotion of dermal and vascular melanoma invasion. The tumour suppressor phosphatase and tensin homolog (PTEN) has been suggested as a potential regulator of this cadherin switch. OBJECTIVES: To study the biological and clinical implications of cadherin switch and PTEN expression in melanoma progression. METHODS: We constructed tissue microarrays from primary tumour samples from 394 formalin-fixed paraffin-embedded melanomas diagnosed between 2001 and 2006. Median follow-up was 10 years. Tissue microarray sections were stained by immunohistochemistry for E-cadherin, N-cadherin and PTEN, and expression was analysed semiquantitatively. RESULTS: Breslow thickness correlated strongly with reduced/absent PTEN expression (P < 0.0001), low E-cadherin expression (P < 0.0001), high N-cadherin expression (P < 0.0001) and the combination of low E-cadherin and high N-cadherin expression (cadherin switch profile; P = 0.001). There was a significant association between reduced/absent PTEN and the presence of the cadherin switch profile (P = 0.03). In univariate analyses, low E-cadherin expression significantly predicted an adverse overall relapse-free (P = 0.04), melanoma-specific (P = 0.03) and distant-metastasis-free (P = 0.01) survival; reduced/absent PTEN predicted an adverse overall relapse free survival (P = 0.006), and the cadherin switch profile predicted adverse melanoma-specific (P = 0.005) and distant-metastasis-free (P = 0.01) survival. In multivariate analysis, the cadherin switch profile was an independent prognostic marker of melanoma-specific (P = 0.04) and distant-metastasis-free survival (P = 0.02). CONCLUSIONS: Cadherin switch and reduced/absent PTEN expression are associated in melanoma, and both factors may play important roles in the progression of melanoma. PMID- 23662807 TI - Protein kinase C pharmacology: refining the toolbox. AB - PKC (protein kinase C) has been in the limelight since the discovery three decades ago that it acts as a major receptor for the tumour-promoting phorbol esters. Phorbol esters, with their potent ability to activate two of the three classes of PKC isoenzymes, have remained the best pharmacological tool for directly modulating PKC activity. However, with the discovery of other phorbol ester-responsive proteins, the advent of various small-molecule and peptide modulators, and the need to distinguish isoenzyme-specific activity, the pharmacology of PKC has become increasingly complex. Not surprisingly, many of the compounds originally touted as direct modulators of PKC have subsequently been shown to hit many other cellular targets and, in some cases, not even directly modulate PKC. The complexities and reversals in PKC pharmacology have led to widespread confusion about the current status of the pharmacological tools available to control PKC activity. In the present review, we aim to clarify the cacophony in the literature regarding the current state of bona fide and discredited cellular PKC modulators, including activators, small-molecule inhibitors and peptides, and also address the use of genetically encoded reporters and of PKC mutants to measure the effects of these drugs on the spatiotemporal dynamics of signalling by specific isoenzymes. PMID- 23662814 TI - Scope and limitations of 1,3,5-hexatriene derivatives in regioselective cobalt catalyzed reactions. AB - Applications of 1,3,5-hexatriene derivatives in atom-economic cobalt-catalyzed transformations, such as the Diels-Alder reaction with alkynes, the 1,4 hydrovinylation reaction with terminal alkenes, and the 1,4-hydrohexatrienylation reaction, are investigated. In all cases, regioselective transformations were found to generate cyclic derivatives such as stilbenes or acyclic products with a high control of the double bond geometry in the skipped trienes derived from the 1,4-hydrovinylation process or the tetraenes generated in the so far unprecedented 1,4-hydrohexatrienylation reaction. PMID- 23662815 TI - Motivational incentives and methylphenidate enhance electrophysiological correlates of error monitoring in children with attention deficit/hyperactivity disorder. AB - BACKGROUND: Children with attention deficit hyperactivity disorder (ADHD) are characterised by developmentally inappropriate levels of hyperactivity, impulsivity and/or inattention and are particularly impaired when performing tasks that require a high level of cognitive control. Methylphenidate (MPH) and motivational incentives may help improve cognitive control by enhancing the ability to monitor response accuracy and regulate performance accordingly. METHODS: Twenty-eight children with DSM-IV ADHD (combined type) aged 9-15 years and pairwise-matched typically developing children (CTRL) performed a go/no-go task in which the incentives attached to performance on no-go trials were manipulated. The ADHD group performed the task off and on their usual dose of MPH. CTRL children performed the task twice but were never medicated. EEG data were recorded simultaneously and two electrophysiological indices of error monitoring, the error-related negativity (ERN) and error positivity (Pe) were measured. Amplitudes of each ERP were compared between diagnostic groups (CTRL, ADHD), medication days (Off MPH, On MPH) and motivational conditions (baseline - low incentive, reward, response cost). RESULTS: Error rates were lower in the reward and response cost conditions compared with baseline across diagnostic groups and medication days. ERN and Pe amplitudes were significantly reduced in ADHD compared with CTRL, and were significantly enhanced by MPH. Incentives significantly increased ERN and Pe amplitudes in the ADHD group but had no effect in CTRL. The effects of incentives did not interact with the effects of MPH on either ERP. Effect sizes were computed and revealed larger effects of MPH than incentives on ERN and Pe amplitudes. CONCLUSIONS: The findings reveal independent effects of motivational incentives and MPH on two electrophysiological markers of error monitoring in children with ADHD, suggesting that each may be important tools for enhancing or restoring cognitive control in these children. PMID- 23662816 TI - eyeGENE(r): a vision community resource facilitating patient care and paving the path for research through molecular diagnostic testing. AB - Molecular genetics and genomics are revolutionizing the study and treatment of inherited eye diseases. In recognition of the impact of molecular genetics on vision and ophthalmology, the National Eye Institute established the National Ophthalmic Disease Genotyping and Phenotyping Network (eyeGENE(r)) as a multidirectional research initiative whereby a clinical component for patients diagnosed with inherited eye disease fosters research into the causes and mechanisms of these ophthalmic diseases. This is accomplished by broadening access to genetic diagnostic testing and maintaining a repository of DNA samples from clinically characterized individuals and their families to allow investigations of the causes, interventions, and management of genetic eye disorders. The eyeGENE(r) Network currently includes Clinical Laboratory Improvement Amendments (CLIA)-certified diagnostic laboratory partners, over 270 registered clinical organizations with 500 registered users from around the United States and Canada, and is now testing approximately 100 genes representing 35 inherited eye diseases. To date, the Network has received 4400 samples from individuals with rare inherited eye diseases, which are available for access by the vision research community. eyeGENE(r) is a model partnership between the U.S. federal government, eye health care providers, CLIA-approved molecular diagnostic laboratories, private industry, and scientists who represent a broad research constituency. PMID- 23662817 TI - Development of oleanane-type triterpenes as a new class of HCV entry inhibitors. AB - Development of hepatitis C virus (HCV) entry inhibitors represents an emerging approach that satisfies a tandem mechanism for use with other inhibitors in a multifaceted cocktail. By screening Chinese herbal extracts, oleanolic acid (OA) was found to display weak potency to inhibit HCV entry with an IC50 of 10 MUM. Chemical exploration of this triterpene compound revealed its pharmacophore requirement for blocking HCV entry, rings A, B, and E, are conserved while ring D is tolerant of some modifications. Hydroxylation at C-16 significantly enhanced its potency for inhibiting HCV entry with IC50 at 1.4 MUM. Further modification by conjugation of this new lead with a disaccharide at 28-COOH removed the undesired hemolytic effect and, more importantly, increased its potency by ~5 fold (54a, IC50 0.3 MUM). Formation of a triterpene dimer via a linker bearing triazole (70) dramatically increased its potency with IC50 at ~10 nM. Mechanistically, such functional triterpenes interrupt the interaction between HCV envelope protein E2 and its receptor CD81 via binding to E2, thus blocking virus and host cell recognition. This study establishes the importance of triterpene natural products as new leads for the development of potential HCV entry inhibitors. PMID- 23662818 TI - Treatment of a carotid cavernous fistula via direct transovale cavernous sinus puncture. AB - Endovascular treatment is the treatment of choice for indirect carotid cavernous fistulas (CCFs). Direct surgical obliteration of CCFs is recommended in highly symptomatic patients or in those with an aggressive pattern of venous drainage. However, this is a technically challenging approach associated with significant procedural morbidity. The authors present a case in which they decided to attempt a novel access to the cavernous sinus through the foramen ovale before recommending surgery for an otherwise untreatable dural CCF. This 52-year-old man with an indirect CCF and neurological deficit had undergone several attempts to embolize the shunt by means of the standard approaches. Ultimately direct cavernous sinus access was obtained through the foramen ovale, resulting in complete obliteration of the shunt. The occlusion was radiographically stable at the 6-month follow-up evaluation, and the patient has remained asymptomatic. Percutaneous transovale puncture of a CCF is a feasible alternative to accessing the cavernous sinus when traditional transvenous catheterization or direct superior ophthalmic vein approach is not possible. PMID- 23662820 TI - Intraoperative neurophysiological monitoring of extracranial-intracranial bypass procedures. AB - OBJECT: Intraoperative neurophysiological monitoring (IONM) represents an established tool in neurosurgery to increase patient safety. Its application, however, is controversial. Its use has been described as helpful in avoiding neurological deterioration during intracranial aneurysm surgery. Its impact on extracranial-intracranial (EC-IC) bypass surgery involving parent artery occlusion for the treatment of complex aneurysms has not yet been studied. The authors therefore sought to evaluate the effects of IONM on patient safety, the surgeon's intraoperative strategies, and functional outcome of patients after cerebral bypass surgery. Intraoperative neurophysiological monitoring results were compared with those of intraoperative blood flow monitoring to assess bypass graft perfusion. METHODS: Compound motor action potentials (CMAPs) were generated using transcranial electrical stimulation in patients undergoing EC-IC bypass surgery. Preoperative and postoperative motor function was analyzed. To assess graft function, intraoperative flowmetry and indocyanine green fluorescence angiography were performed. Special care was taken to compare the relevance of electrophysiological and blood flow monitoring in the detection of critical intraoperative ischemic episodes. RESULTS: The study included 31 patients with 31 aneurysms and 1 bilateral occlusion of the internal carotid arteries, undergoing 32 EC-IC bypass surgeries in which radial artery or saphenous vein grafts were used. In 11 cases, 15 CMAP events were observed, helping the surgeon to determine the source of deterioration and to react to it: 14 were reversible and only 1 showed no recovery. In all cases, blood flow monitoring showed good perfusion of the bypass grafts. There were no false-negative results in this series. New postoperative motor deficits were transient in 1 case, permanent in 1 case, and not present in all other cases. CONCLUSIONS: Intraoperative neurophysiological monitoring is a helpful tool for continuous functional monitoring of patients undergoing large-caliber vessel EC-IC bypass surgery. The authors' results suggest that continuous neurophysiological monitoring during EC-IC bypass surgery has relevant advantages over flow-oriented monitoring techniques such as intraoperative flowmetry or indocyanine green-based angiography. PMID- 23662819 TI - Complement polymorphisms and cognitive dysfunction after carotid endarterectomy. AB - OBJECT: The role of genetic polymorphisms in the neurological outcome of patients after carotid endarterectomy (CEA) remains unclear. There are single nucleotide polymorphisms (SNPs) that predispose patients to postoperative cognitive dysfunction (CD). We aim to assess the predictability of three complement cascade related SNPs for CD in patients having CEAs. METHODS: In 252 patients undergoing CEA, genotyping was performed for the following polymorphisms: complement component 5 (C5) rs17611, mannose-binding lectin 2 (MBL2) rs7096206, and complement factor H (CFH) rs1061170. Differences among genotypes were analyzed via the chi-square test. Patients were evaluated with a neuropsychometric battery for CD 1 day and 1 month after CEA. A multiple logistic regression model was created. All variables with univariate p < 0.20 were included in the final model. RESULTS: The C5 genotypes A/G (OR 0.26, 95% CI 0.11-0.60, p = 0.002) and G/G (OR 0.22, 95% CI 0.09-0.52, p < 0.001) were significantly associated with lower odds of exhibiting CD at 1 day after CEA compared with A/A. The CFH genotypes C/T (OR 3.37, 95% CI 1.69-6.92, p < 0.001) and C/C (OR 3.67, 95% CI 1.30-10.06, p = 0.012) were significantly associated with higher odds of exhibiting CD at 1 day after CEA compared with T/T. Statin use was also significantly associated with lower odds of exhibiting CD at 1 day after CEA (OR 0.43, 95% CI 0.22-0.84, p = 0.01). No SNPs were significantly associated with CD at 1 month after CEA. CONCLUSIONS: The presence of a deleterious allele in the C5 and CFH SNPs may predispose patients to exhibit CD after CEA. This finding supports previous data demonstrating that the complement cascade system may play an important role in the development of CD. These findings warrant further investigation. PMID- 23662821 TI - Low-grade astrocytomas: the prognostic value of fibrillary, gemistocytic, and protoplasmic tumor histology. AB - OBJECT: Low-grade astrocytomas are slow-growing, infiltrative gliomas that over time may progress into more malignant tumors. Various factors have been shown to affect the time to progression and overall survival including age, performance status, tumor size, and the extent of resection. However, more recently it has been suggested that histological subtypes (fibrillary, protoplasmic, and gemistocytic) may impact patient outcome. In this study the authors have performed a large comparative population-based analysis to examine the characteristics and survival of patients with the various subtypes of WHO Grade II astrocytomas. METHODS: Patients diagnosed with fibrillary, protoplasmic, and gemistocytic astrocytomas were identified through the Surveillance, Epidemiology, and End Results (SEER) database. The chi-square test and Student t-test were used to evaluate differences in patient and treatment characteristics between astrocytoma subtypes. Kaplan-Meier analysis was used to assess overall survival, and the log-rank test was used to evaluate the differences between survival curves. Univariate and multivariate analyses were also performed to determine the effect of various patient, tumor, and treatment variables on overall survival. RESULTS: A total of 500 cases were included in the analysis, consisting of 326 fibrillary (65.2%), 29 protoplasmic (5.8%), and 145 gemistocytic (29%) variants. Gemistocytic astrocytomas presented at a significantly older age than the fibrillary variant (46.8 vs 37.7 years, p < 0.0001), with protoplasmic and fibrillary subtypes having a similar age. Although protoplasmic and fibrillary variants underwent radiotherapy at similar rates, gemistocytic tumors more frequently received radiotherapy (p = 0.0001). Univariate analysis revealed older age, larger tumor size, and the use of radiotherapy to be poor prognostic factors, with resection being associated with improved survival. The gemistocytic subtype (hazard ratio [HR] 1.62 [95% CI 1.27-2.07], p = 0.0001) also resulted in significantly worse survival than fibrillary tumors. Bivariate analyses demonstrated that older age, the use of radiotherapy, and resection significantly influenced median survival. Tumor subtype also affected median survival; patients who harbored gemistocytic tumors experienced less than half the median survival of fibrillary and protoplasmic tumors (38 vs 82 months, p = 0.0003). Multivariate analysis revealed increasing age (HR 1.05 [95% CI 1.04-1.05], p < 0.0001), larger tumor size (HR 1.02 [95% CI 1.01-1.03], p = 0.0002), and the use of resection (HR 0.70 [95% CI 0.52-0.94], p = 0.018) to be independent predictors of survival. Examination of tumor subtype revealed that the gemistocytic variant (HR 1.30 [95% CI 0.98-1.74], p = 0.074) was associated with worse patient survival than fibrillary tumors, although this only approached significance. The protoplasmic subtype did not affect overall survival (p = 0.33). CONCLUSIONS: Gemistocytic tumor histology was associated with worse survival than fibrillary and protoplasmic astrocytomas. As protoplasmic astrocytomas have a survival similar to fibrillary tumors, there may be limited utility to the identification of this rare variant. However, increased attention should be paid to the presence of gemistocytes in low-grade gliomas as this is associated with shorter time to progression, increased malignant transformation, and reduced overall survival. PMID- 23662822 TI - Impact of global cerebral atrophy on clinical outcome after subarachnoid hemorrhage. AB - OBJECT: Atrophy in specific brain areas correlates with poor neuropsychological outcome after subarachnoid hemorrhage (SAH). Few studies have compared global atrophy in SAH with outcome. The authors examined the relationship between global brain atrophy, clinical factors, and outcome after SAH. METHODS: This study was a post hoc exploratory analysis of the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) trial, a randomized, double-blind, placebo-controlled trial of 413 patients with aneurysmal SAH. Patients with infarctions or areas of encephalomalacia on CT, and those with large clip/coil artifacts, were excluded. The 97 remaining patients underwent CT at baseline and 6 weeks, which was analyzed using voxel-based volumetric measurements. The percentage difference in volume between time points was compared against clinical variables. The relationship with clinical outcome was modeled using univariate and multivariate analysis. RESULTS: Older age, male sex, and systemic inflammatory response syndrome (SIRS) during intensive care stay were significantly associated with brain atrophy. Greater brain atrophy was significantly associated with poor outcome on the modified Rankin scale (mRS), severity of deficits on the National Institutes of Health Stroke Scale (NIHSS), worse executive functioning, and lower EuroQol Group-5D (EQ-5D) score. Adjusted for confounders, brain atrophy was not significantly associated with Mini-Mental State Examination and Functional Status Examination scores. Brain atrophy was not associated with angiographic vasospasm or delayed ischemic neurological deficit. CONCLUSIONS: Worse mRS score, NIHSS score, executive functioning, and EQ-5D scores were associated with greater brain atrophy and older age, male sex, and SIRS burden. These data suggest outcome is associated with factors that cause global brain injury independent of focal brain injury. PMID- 23662823 TI - Microarteriovenous malformations. PMID- 23662824 TI - William P. Van Wagenen (1897-1961): pupil, mentor, and neurosurgical pioneer. AB - William Perrine ("Van") Van Wagenen (1897-1961) was the first Chief of Neurosurgery at the University of Rochester Medical Center (URMC), serving from 1928 to 1954, and was a leading figure in 20th-century neurosurgery. He was a devoted pupil of Dr. Harvey Cushing and helped to found the Harvey Cushing Society (now the AANS) in honor of his mentor and was elected as its first President in 1932. He served as the 27th President of the Society of Neurological Surgeons in 1952. Upon his death in 1961 he bequeathed an endowment for the Van Wagenen Fellowship, which has advanced the education of many leaders in American neurosurgery. His legacy of operative skill, his commitment to resident education and research in neurological disease, his inspiration for the foundation of the Cushing Brain Tumor registry, and his contributions to organized neurosurgery form the foundation of the legacy of neurosurgery at URMC. PMID- 23662825 TI - Antonius Balthazar Raymundus Hirsch and the peregrination of "gasserian ganglion". AB - The anatomical description of the fifth cranial nerve ganglion lacked detail before the work of Antonius Balthazar Raymundus Hirsch (1744-1778). Hirsch used new dissection techniques that resulted in the most meticulous report of the trigeminal ganglion (the gasserian ganglion) to have been reported. In 1765, the 21-year-old published these findings in a thesis, Paris Quinti Nervorum Encephali Disquisitio Anatomica In Quantum Ad Ganglion Sibi Proprium, Semilunare, Et Ad Originem Nervi Intercostalis Pertinet [An anatomical inquiry of the fifth pair of the nerves of the brain, so far as it relates to the ganglion unto itself, the semilunar, and to the source of the intercostal nerve]. Hirsch wrote his thesis as a paean to his ailing teacher, Johann Lorenz Gasser, but Gasser died before Hirsch was able to defend his thesis. Thereafter, Hirsch applied to teach anatomy at his alma mater, the University of Vienna, but the university did not consider his application, deeming him too young for the position. Oddly, Hirsch died at the young age of 35. For the present paper, the library at the University of Vienna (Universitat Wien), Austria, was contacted, and Anton Hirsch's thesis was digitized and subsequently translated from Latin into English. The authors here attempt to place the recognition of the fifth cranial nerve ganglion within a historical perspective and trace the trajectory of its anatomical descriptions. PMID- 23662826 TI - Association of increased body mass index with Chiari malformation Type I and syrinx formation in adults. AB - OBJECT: In this paper the authors describe an association between increased body mass index (BMI) and Chiari malformation Type I (CM-I) in adults, as well as its relationship to the development of syringomyelia. METHODS: In the period between January 2004 and December 2011, the senior author reviewed the data for all CM-I patients with or without syringomyelia and neurological deficit. Analyzed factors included clinical status (headaches and neurological signs), radiological characteristics of syringomyelia (diameter and vertical extent of syrinx), BMI, and relationship of age to BMI, syrinx diameter, and vertical extent of syrinx. RESULTS: Sixty consecutive adults had CM-I, 26 of whom also had syringomyelia. The mean BMI among all patients was 30.35 +/- 7.65, which is Class I obesity (WHO), and was similar among patients with or without syringomyelia. Extension of the vertical syrinx was greater in overweight patients (p = 0.027) than in those with a normal body weight. Evidence of de novo syrinx formation was found in 2 patients who gained an average BMI of 10.8 points. After repeated decompression and no change in holocord syrinx width or vertical extent, a reduction in the syrinx was seen after BMI decreased 11.7 points in one individual. No correlation was found between patient age and BMI, age and vertical extension of the syrinx, and age and diameter of the syrinx. CONCLUSIONS: An association between increased BMI and CM-I in adults was recognized. Gaining weight may influence the de novo creation of a syrinx in adults who previously had minimally symptomatic or asymptomatic CM-I, and reducing weight can improve a syrinx after unsuccessful surgical decompression. Therefore, a reduction in body weight should be recommended for all overweight and obese patients with CM-I. PMID- 23662827 TI - Cerebral microarteriovenous malformations: a series of 28 cases. AB - OBJECT: Microarteriovenous malformations (micro-AVMs) are a rare subgroup of brain AVMs characterized by a nidus smaller than 1 cm. The authors' purpose in this study was to assess the clinical presentation, radiological features, therapeutic management, and outcome of these lesions. METHODS: All angiography studies performed at the authors' institution since 2000 for the diagnosis of AVM were retrospectively reviewed. Clinicoradiological findings, therapeutic management, and outcome were evaluated. RESULTS: Twenty-eight patients had presented with AVMs having a nidus diameter smaller than 1 cm or no clearly identifiable nidus but an early draining vein. All patients, except 2, presented with intracranial hemorrhage, and 12 patients had a focal deficit. Supratentorial hematomas were large (mean volume 25 ml), and in 8 patients hematomas were evacuated urgently. In 6 patients cerebral digital subtraction angiography studies were normal. Magnetic resonance imaging and dynamic MR angiography revealed an AVM in 4 of these 6 patients. Treatment of the AVM consisted of surgery in 16 cases, radiosurgery in 6, and endovascular embolization in 2, and there were no posttreatment deficits. Four patients received no treatment because of their poor condition. The AVM was occluded at the follow-up in all patients treated with surgery or embolization and in 4 of the 6 patients treated with radiosurgery. The Glasgow Outcome Scale (GOS) score was good (GOS 4-5) in 23 patients (82%) and poor (GOS 3-2) in 5 (18%). CONCLUSIONS: Patients with micro AVMs generally present with large intracranial hemorrhages and neurological deficits. If the initial angiography is negative, then delayed or superselective angiography is recommended. Magnetic resonance imaging may reveal the existence of these lesions. Surgery is the treatment of choice for superficial micro-AVMs, and radiosurgery or embolization can be considered for deep lesions. PMID- 23662828 TI - Survival among patients with 10 or more brain metastases treated with stereotactic radiosurgery. AB - OBJECT: The goal of this study was to evaluate outcomes in patients with >= 10 CNS metastases treated with Gamma Knife stereotactic radiosurgery (GK-SRS). METHODS: Patients with >= 10 brain metastases treated using GK-SRS during the period between 2004 and 2010 were identified. Overall survival and local and regional control as well as necrosis rates were determined. The influence of age, sex, histological type, extracranial metastases, whole-brain radiation therapy, and number of brain metastases was analyzed using the Kaplan-Meier method. Univariate (log-rank) analyses were performed, with a p value of < 0.05 considered significant. RESULTS: Fifty-three patients with >= 10 brain metastases were treated between 2004 and 2010. All had a Karnofsky Performance Status score of >= 70. Seventy-two percent had either non-small cell lung cancer (38%) or breast cancer (34%); melanoma, small cell lung cancer, renal cell carcinoma, and testicular, colon, and ovarian cancer contributed the remaining 28%. On average, 10.9 lesions were treated in a single session. Sixty-four percent of patients received prior whole-brain radiation therapy. The median survival was 6.5 months. One-year overall survival was 42% versus 14% when comparing breast cancer and other histological types, respectively (p = 0.074). Age, extracranial metastases, number of brain metastases, and previous CNS radiation therapy were not significant prognostic factors. Although the median time to local failure was not reached, the median time to regional failure was 3 months. Female sex was associated with longer time to regional failure (p = 0.004), as was breast cancer histological type (p = 0.089). No patient experienced symptomatic necrosis. CONCLUSIONS: Patients with >= 10 brain metastases who received prior CNS radiation can safely undergo repeat treatment with GK-SRS. With median survival exceeding 6 months, aggressive local treatment remains an option; however, rapid CNS failure is to be expected. Although numbers are limited, patients with breast cancer represent one group of individuals who would benefit most, with prolonged survival and extended time to CNS recurrence. PMID- 23662829 TI - Prospective validation of a patient-reported nasal quality-of-life tool for endonasal skull base surgery: The Anterior Skull Base Nasal Inventory-12. AB - OBJECT: Patient-reported quality-of-life (QOL) end points are becoming increasingly important health care metrics. To date, no nasal morbidity instrument specifically designed for patients undergoing endonasal skull base surgery has been developed. In this study, the authors describe the development and validation of a site-specific nasal morbidity instrument to assess patient reported rhinological outcomes following endonasal skull base surgery. METHODS: Eligible patients included those with planned endonasal transsphenoidal surgery for sellar pathology identified in outpatient neurosurgical clinics of 3 skull base centers from October 2011 to July 2012. An initial 23-question pool was developed by subject matter experts, review of the literature, and from the results of a previous validation study to assess for common rhinological complaints. Symptoms were ranked by patients from "No Problem" to "Severe Problem" on a 6-point Likert scale. Exploratory factor analysis, change scores, and importance rank were calculated to define the final instrument consisting of 12 items (The Anterior Skull Base Nasal Inventory-12, or ASK Nasal-12). Psychometric validation of the final instrument was performed using standard statistical techniques. RESULTS: One hundred four patients enrolled in the study. All patients completed the preoperative survey and 100 patients (96%) completed the survey 2-4 weeks after surgery. Internal consistency of the final instrument was 0.88. Concurrent validity measures demonstrated a strong correlation between overall nasal functioning and total scores (p < 0.001). Test-retest reliability measures demonstrated a significant intraclass correlation between responses (p < 0.001). Effect size as calculated by standardized response mean suggested a large effect (0.84). Discriminant validity calculations demonstrated that the instrument was able to discriminate between preoperative and postoperative patients (p < 0.001). CONCLUSIONS: This prospective study demonstrates that the ASK Nasal-12 is a validated, site-specific, unidimensional rhinological outcomes tool sensitive to clinical change. It can be used in conjunction with multidimensional QOL instruments to assess patient-reported nasal perceptions in endonasal skull base surgery. This instrument is being used as a primary outcome measure in an ongoing multicenter nasal morbidity study. Clinical trial registration no.: NCT01504399 (ClinicalTrials.gov). PMID- 23662830 TI - Ophthalmological outcome after resection of tumors based on the pineal gland. AB - OBJECT: Descriptions of visual dysfunction in pineal gland tumors tend to focus on upward gaze palsy alone. The authors aimed to characterize the nature, incidence, and functional significance of ophthalmological dysfunction after resection of tumors based on the pineal gland. METHODS: Review of a retrospective case series was performed and included consecutive patients who underwent surgery performed by a consultant neurosurgeon between 2002 and 2011. Only tumors specifically based on the pineal gland were included; tumors encroaching on the pineal gland from other regions were excluded. All patients with visual signs and/or symptoms were reviewed by a specialist consultant neuroophthalmologist to accurately characterize the nature of their deficits. Visual disturbance was defined as visual symptoms caused by a disturbance of ocular motility. RESULTS: A total of 20 patients underwent resection of pineal gland tumors. Complete resection was obtained in 85%, and there were no perioperative deaths. Visual disturbance was present in 35% at presentation; of those who had normal ocular motility preoperatively 82% had normal motility postoperatively. In total, 55% of patients had residual visual disturbance postoperatively. Although upward gaze tended to improve, significant functional deficits remained, particularly with regard to complex convergence and accommodation dysfunction. Prisms were used in 25% but were only ever partially effective. Visual outcome was only related to preoperative visual status and tumor volume (multivariate analysis). CONCLUSIONS: Long-term visual morbidity after pineal gland tumor resection is common and leads to significant functional impairment. Improvement in deficits rarely occurs spontaneously, and prisms only have limited effectiveness, probably due to the dynamic nature of supranuclear ocular movement coordination. PMID- 23662831 TI - Expression of metallothionein-1 and metallothionein-2 as a prognostic marker in hepatocellular carcinoma. AB - BACKGROUND AND AIMS: Metallothionein (MT)-1 and -2 are low-molecular weight, cysteine-rich, intracellular metal-binding proteins involved in diverse functions, such as metal homeostasis, cell cycle progression, cell differentiation, and carcinogenesis. This study investigated the expression of MT 1 and MT-2 as a prognostic marker in hepatocellular carcinoma (HCC). METHODS: Expression of MT-1 and MT-2 were evaluated immunohistochemically in tissue microarrays containing samples from 370 HCCs, 336 adjacent noncancerous livers, and 12 normal livers. The relationships between MT-1 and MT-2 expression and the clinicopathological parameters of HCC were assessed. RESULTS: The expression of MT-1 and MT-2 was uniformly strong in the nucleus and cytoplasm of normal liver, but varied in noncancerous livers and HCCs. Loss of nuclear and cytoplasmic expression was significantly more in HCCs than in adjacent noncancerous livers (P < 0.001). The loss of nuclear expression of MT-1 and MT-2 was significantly correlated with high Edmondson-Steiner grade and the presence of microvascular invasion (P < 0.05 each). Multivariate analysis showed that the loss of nuclear expression of MT-1 and MT-2 was an independent poor prognostic factor for both recurrence-free survival and overall survival. CONCLUSIONS: The expression of MT 1 and MT-2 may play a role in HCC differentiation and carcinogenesis, and may predict prognosis in patients with HCC. PMID- 23662834 TI - Is there any relation between pseudoexfoliation syndrome and Alzheimer's type dementia? AB - PURPOSE: To investigate the frequency of Alzheimer-related dementia in patients with pseudoexfoliation syndrome (PEX). METHODS: Sixty-seven patients with PEX and 67 age-, gender-, and educational-background-matched control subjects were compared for the presence of Alzheimer-related dementia according to DSM- IV-TR. The effects of cataract, glaucoma, additional ocular and systemic disease on the dementia incidence were also evaluated in patients with PEX and the control group. RESULTS: The frequency of Alzheimer-related dementia was higher in patients with PEX (p = 0.0001). The frequency of dementia in patients who had cataract was higher than in patients without cataract (p = 0.003). There was also an association between additional ocular disease and dementia (p < 0.05). However, there was no association between systemic disease and dementia (p > 0.05). Furthermore, there was no difference for the frequency of dementia between patients who had glaucoma or not among patients with PEX (p = 0.953). CONCLUSION: The increased frequency of Alzheimer-related dementia in patients with PEX is important and a possible association between PEX and Alzheimer's disease could be present. PMID- 23662835 TI - Modeling of optical spectra of the light-harvesting CP29 antenna complex of photosystem II--part II. AB - Until recently, it was believed that the CP29 protein from higher plant photosystem II (PSII) contains 8 chlorophylls (Chl's) per complex (Ahn et al. Science 2008, 320, 794-797; Bassi et al. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 10056-10061) in contrast to the 13 Chl's revealed by the recent X-ray structure (Pan et al. Nat. Struct. Mol. Biol. 2011, 18, 309-315). This disagreement presents a constraint on the interpretation of the underlying electronic structure of this complex. To shed more light on the interpretation of various experimental optical spectra discussed in the accompanying paper (part I, DOI 10.1021/jp4004328 ), we report here calculated low-temperature (5 K) absorption, fluorescence, hole-burned (HB), and 300 K circular dichroism (CD) spectra for CP29 complexes with a different number of pigments. We focus on excitonic structure and the nature of the low-energy state using modeling based on the X ray structure of CP29 and Redfield theory. We show that the lowest energy state is mostly contributed to by a612, a611, and a615 Chl's. We suggest that in the previously studied CP29 complexes from spinach (Pieper et al. Photochem. Photobiol.2000, 71, 574-589) two Chl's could have been lost during the preparation/purification procedure, but it is unlikely that the spinach CP29 protein contains only eight Chl's, as suggested by the sequence homology-based study (Bassi et al. Proc. Natl. Acad. Sci. U.S.A.1999, 96, 10056-10061). The likely Chl's missing in wild-type (WT) CP29 complexes studied previously (Pieper et al. Photochem. Photobiol. 2000, 71, 574-589) include a615 and b607. This is why the nonresonant HB spectra shown in that reference were ~1 nm blue-shifted with the low-energy state mostly localized on about one Chl a (i.e., a612) molecule. Pigment composition of CP29 is discussed in the context of light harvesting and excitation energy transfer. PMID- 23662836 TI - Organic synthesis in the interstellar medium by low-energy carbon irradiation. AB - We present a first principles molecular dynamics (FPMD) study of the interaction of low-energy neutral carbon projectiles with amorphous solid water clusters at 30 K. Reactions involving the carbon atom at an initial energy of 11 and 1.7 eV with 30-molecule clusters have been investigated. Simulations indicate that the formation of hydroxymethylene, an intermediate in formaldehyde production, dominates at the higher energy. The reaction proceeds by fragmenting a water molecule, binding the carbon to the OH radical, and saturating the C valence with a hydrogen atom that can arise from the originally dissociated water molecule, or through a chain of proton transfer events. We identified several possible pathways for the formation of HCOH. When the initial collision occurs at the periphery of the cluster, we observe the formation of CO and the evaporation of water molecules. At the lower energy water fragmentation is not favorable, thus leading to the formation of weakly bound carbon-water complexes. PMID- 23662837 TI - Pollen feeding, resource allocation and the evolution of chemical defence in passion vine butterflies. AB - Evolution of pollen feeding in Heliconius has allowed exploitation of rich amino acid sources and dramatically reorganized life-history traits. In Heliconius, eggs are produced mainly from adult-acquired resources, leaving somatic development and maintenance to larva effort. This innovation may also have spurred evolution of chemical defence via amino acid-derived cyanogenic glycosides. In contrast, nonpollen-feeding heliconiines must rely almost exclusively on larval-acquired resources for both reproduction and defence. We tested whether adult amino acid intake has an immediate influence on cyanogenesis in Heliconius. Because Heliconius are more distasteful to bird predators than close relatives that do not utilize pollen, we also compared cyanogenesis due to larval input across Heliconius species and nonpollen-feeding relatives. Except for one species, we found that varying the amino acid diet of an adult Heliconius has negligible effect on its cyanide concentration. Adults denied amino acids showed no decrease in cyanide and no adults showed cyanide increase when fed amino acids. Yet, pollen-feeding butterflies were capable of producing more defence than nonpollen-feeding relatives and differences were detectable in freshly emerged adults, before input of adult resources. Our data points to a larger role of larval input in adult chemical defence. This coupled with the compartmentalization of adult nutrition to reproduction and longevity suggests that one evolutionary consequence of pollen feeding, shifting the burden of reproduction to adults, is to allow the evolution of greater allocation of host plant amino acids to defensive compounds by larvae. PMID- 23662838 TI - Prevalence and diagnostic spectrum of generalized retinal dystrophy in Danish children. AB - PURPOSE: The aim of the present population-based cross-sectional study was to examine the prevalence and diagnostic spectrum of generalized retinal dystrophy in Danish children. METHODS: The Danish Registry for the Blind and Partially Sighted Children comprises all visually impaired children residing in Denmark aged 0-17 years. Among registered children, the primary diagnosis of generalized retinal dystrophy was assessed by chart review, including fundus photographs and electroretinograms. Age-specific data for live children in Denmark were retrieved from Statistics Denmark. RESULTS: Of the 1,204,235 Danish children aged 0-17 years on 1 October 2011, 2017 children were registered as visually impaired. Of these, 153 cases were attributed to generalized retinal dystrophy, corresponding to a prevalence of 13 per 100,000 children. The age-specific prevalence increased prominently with increasing age. In 43% of the children the eye condition was part of a syndrome, while the remaining 57% had eye disease only. The most common hereditary pattern was autosomal recessive (99 children, 66%). CONCLUSIONS: This epidemiological survey demonstrates that the prevalence of generalized retinal dystrophy in Danish children is 13 per 100,000, which is a considerable increase compared to the 9.8 per 100,000 reported by Rosenberg in 1988. The prevalence of Leber congenital amaurosis, Usher syndrome, and Bardet-Biedl syndrome doubled, which may be explained by a documented history of consanguinity in more than one third of the children. Many of the dystrophies are the subject of clinical intervention trials, and nation-wide epidemiological data can help assess the future need for treatment. PMID- 23662839 TI - The Mohs histotechnician: a review of training and practice within 29 centres in the UK. AB - BACKGROUND: Although various assessments pertaining to the surgical aspect of Mohs micrographic surgery (MMS) have been performed, the pivotal role played by the MMS histotechnician (MH) has not previously been addressed in the UK. AIM: To undertake a review of the training and practice of MHs in all centres performing MMS within the National Health Service (NHS) in the UK. METHODS: NHS dermatology departments performing MMS in the UK were identified and contacted by telephone between November 2011 and January 2012. MMS practice data pertaining to the role of the MH in tissue processing was collected by speaking directly to a histotechnician in each department. RESULTS: In total, 29 centres were identified. The number of MHs at each centre varied from 1 to 13 (median 3). All MHs had undergraduate degrees in biomedical science. Most (85%) MHs worked full time under the directorate of their local pathology department. In 19 centres (66%), the Mohs surgeon reviewed the slides, and in the remaining 10 centres (34%), a consultant histopathologist reviewed the slides, either alone or in partnership with the Mohs surgeon. There was significant variation in tissue handling and processing techniques across the centres. All centres used MMS to treat primarily high-risk basal cell carcinomas, with over half (55%) also treating squamous cell carcinomas. MHs from all centres had learned about the specifics of MMS tissue processing 'on the job', with a minority having received formal training by attending a larger MMS centre or an MMS course. CONCLUSIONS: Significant variation in MMS tissue-processing techniques exists across the UK. A standard of practice should perhaps be considered, as this has risk-management, quality-control and possible medicolegal implications. PMID- 23662840 TI - Facile assembly of an unusual lead borate with different cluster building units via a hydrothermal process. AB - Pb(BO2)2.H2O as sources of B and Pb via a simple hydrothermal process provided the first binodal 5,9-connected lead borate, Pb6B4O11(OH)2 (1). Compound 1 crystallizes in the orthorhombic space group Pnma. The crystal structure is composed of different cluster building units of B4O9 and Pb6O4. Compound 1 has an optical band gap of 3.24 eV. PMID- 23662842 TI - Increasing throughput in targeted proteomics assays: 54-plex quantitation in a single mass spectrometry run. AB - Targeted proteomics assays such as those measuring end points in activity assays are sensitive and specific but often lack in throughput. In an effort to significantly increase throughput, a comparison was made between the traditional approach which utilizes an internal standard and the multiplexing approach which relies on isobaric tagging. A kinase activity assay was used for proof of concept, and experiments included three biological replicates for every condition. Results from the two approaches were highly similar with the multiplexing showing greater throughput. Two novel 6-plex isobaric tags were added for a total of three 6-plex experiments (18-plex) in a single run. Next, three mass variants of the target peptide were labeled with the three isobaric tags giving nine 6-plex reactions for 54-plex quantitation in a single run. Since the multiplexing approach allows all samples to be combined prior to purification and acquisition, the 54-plex approach resulted in a significant reduction in purification resources (time, reagents, etc.) and a ~50-fold improvement in acquisition throughput. We demonstrate the 54-plex assay in several ways including measuring inhibition of PKA activity in MCF7 cell lysates for a panel of nine compounds. PMID- 23662843 TI - Fabry disease: is there a role for enzyme replacement therapy? PMID- 23662841 TI - Role of plasmacytoid dendritic cell subsets in allergic asthma. AB - Plasmacytoid dendritic cells (pDCs) are major type-I interferon-producing cells that play important roles in antiviral immunity and tolerance induction. These cells share a common DC progenitor with conventional DCs, and Fms-like tyrosine kinase-3 ligand is essential for their development. Several subsets of pDCs have been identified to date including CCR9(+) , CD9(+) , and CD2(+) pDCs. Recently, three subsets of pDCs were described, namely CD8alpha(-) beta(-) , CD8alpha(+) beta(-) , and CD8alpha(+) beta(+) subsets. Interestingly, CD8alpha(+) beta(-) and CD8alpha(+) beta(+) but not CD8alpha(-) beta(-) pDCs were shown to have tolerogenic effects in experimentally induced allergic asthma. These tolerogenic effects were shown to be mediated by the generation of FOXP3(+) regulatory T cells through retinoic acid and the induction of retinaldehyde dehydrogenase enzymes. These newly described subsets of pDCs show high potentials for novel therapeutic approaches for the treatment of allergic diseases. In this review, we will address the new progress in our understanding of pDC biology with respect to allergic disease, in particular allergic asthma. PMID- 23662845 TI - Hysteroscopic hydrotubation of the equine oviduct. AB - REASON FOR PERFORMING STUDY: Diagnostic techniques for oviductal obstruction in the mare are limited and development of a more reliable and direct method to assess oviductal patency is needed. OBJECTIVE: To evaluate the feasibility of hysteroscopic selective hydrotubation of the equine oviduct via videoendoscopy in standing mares. METHODS: Using a catheter inserted under endoscopic guidance into the uterotubal junctions of 10 mares, 5 ml of indigo carmine solution (4 mg/ml) was flushed into the oviduct. After introduction of the dye, peritoneal fluid was obtained via abdominocentesis. A colpotomy was also performed to allow introduction of a videoendoscope into the abdominal cavity to assess the presence of dye visually at the ovarian end of the oviduct. RESULTS AND CONCLUSIONS: In 15 of 20 (75.0%) attempts, the catheter was successfully inserted into the uterotubal junction, and dye was observed at the ampulla, fimbria, overlying the ovary or surrounding tissue. In 2 mares, the videoendoscope could not be manipulated to identify the uterotubal junction. Only one of 2 oviducts was flushed in an additional mare because insufflation of the uterus could not be maintained. The colour of the dye was evident macroscopically and spectrophotometrically in 4 of 8 mares from which peritoneal fluid was successfully collected. POTENTIAL RELEVANCE: The equine oviduct can be evaluated by hysteroscopic selective hydrotubation. PMID- 23662846 TI - CUTE-CV: a prospective study of enhanced left atrial appendage visualization with microbubble contrast agent use during transesophageal echocardiography guided cardioversion. AB - OBJECTIVES: The aim of our study was to demonstrate that the use of contrast microbubbles during transesophageal echocardiography (TEE) guided cardioversion will improve interpretation of the TEE images. BACKGROUND: TEE-guided cardioversion of atrial flutter or fibrillation (AF) is a safe and proven method to restore sinus rhythm. However, artifacts and dense spontaneous echo contrast in the left atrial appendage (LAA) can sometimes decrease the level of confidence in excluding the presence of thrombus. METHODS: One hundred patients referred for TEE-guided cardioversion were prospectively enrolled and microbubble contrast agent (DEFINITY) was administered after the clinical decision had been made regarding suitability for cardioversion. Noncontrast and contrast images were compared during subsequent offline analysis. RESULTS: LAA dimensions and contractility indices were higher, artifacts were significantly differentiated, previously unsuspected LAA filling defects were identified, and the level of confidence in excluding thrombus was enhanced in the contrast images when compared to the noncontrast images. After 4 months follow-up, 1 stroke-associated death occurred in a patient who had LAA thrombus recognized only by contrast. Left atrial appendage visualization is enhanced with microbubble contrast agent use during transesophageal echocardiography guided cardioversion and is useful in identification of intracardiac thrombus. PMID- 23662847 TI - 1,4-Benzothiazine ATP-sensitive potassium channel openers: modifications at the C 2 and C-6 positions. AB - ATP-sensitive potassium (KATP) channels play a prominent role in controlling cardiovascular function. In this paper, a novel series of 4-(1-oxo-2 cyclopentenyl)-1,4-benzothiazine derivatives modified at the C-2, and C-6 positions were synthesized as openers of vascular KATP channels. Most of the tested compounds evoked vasorelaxing effects on rat aortic rings and membrane hyperpolarization in human vascular smooth muscle cells, with potency similar or superior to that of the reference levcromakalim (LCRK). The selective KATP blocker glibenclamide antagonized the above vascular effects, confirming that KATP channels are closely involved in the mechanism of action. The experimental results confirmed the 1,4-benzothiazine nucleus as an optimal scaffold for activators of vascular KATP channels; moreover, the high level of potency exhibited by the 6-acetyl substituted benzothiazine 8, along with the lack of any significant interference with insulin secretion from pancreatic beta-cells, paves the way to further develop a new series of potent activators of vascular KATP channels. PMID- 23662848 TI - Pd-catalyzed C-H lactonization for expedient synthesis of biaryl lactones and total synthesis of cannabinol. AB - A practical Pd(II)/Pd(IV)-catalyzed carboxyl-directed C-H activation/C-O cyclization to construct biaryl lactones has been developed. The synthetic utility of this new reaction was demonstrated in an atom-economical and operationally convenient total synthesis of the natural product cannabinol from commercially available starting materials, with the newly developed method used for two key steps. PMID- 23662849 TI - On the photodetachment from the green fluorescent protein chromophore. AB - Motivated by the discrepancies in recent experimental and theoretical studies of photodetachment from isolated model chromophores of the green fluorescent protein (GFP), this study reports calculations of the electron detachment energies and photoelectron spectra of the phenolate and deprotonated p-hydroxybenzylidene-2,3 dimethylimidazolinone (HBDI) anions. The spectra were computed using double harmonic parallel normal mode approximation. High-level coupled-cluster methods as well as density functional theory were used to compute vertical and adiabatic detachment energies of the phenolate anion serving as a model system representing anionic GFP-like chromophores (HBDI). The benchmark calculations reveal that the basis set has significant effect on the computed detachment energies, whereas the results are less sensitive to the level of electron correlation treatment. At least aug-cc-pVTZ basis set is required. The best omegaB97X-D and CCSD(T) estimates of phenolate's adiabatic detachment energy are 2.12 and 2.19 eV; these values are very close to the experimental value, 2.253 eV [Gunion et al. Int. J. Mass Spectrom. Ion Proc. 1992, 117, 601]. The best estimate of the vertical detachment energy of deprotonated HBDI is 2.76 eV, which supports bound character of the bright excited state in the Franck-Condon region. The most intense transition in the computed photoelectron spectra of both phenolate and deprotonated HBDI is the 0-0 S0-D0 transition, which is 0.11 eV below vertical detachment energy. Therefore, the position of the maximum of the photoelectron spectrum does not represent vertical detachment energy, and the direct comparison between theory and experiment must involve spectrum modeling. PMID- 23662850 TI - Intelligence assessments for children with cerebral palsy: a systematic review. AB - AIM: Cerebral palsy (CP) is defined as a primary disorder of posture and movement; however, approximately 45% of children with CP also have an intellectual impairment. Prevalence estimates are limited by a lack of guidelines for intelligence testing. This systematic review aims to identify and examine intelligence assessments for children with CP. METHOD: Electronic databases (PubMed, PsycINFO, Web of Science, CINAHL, EMBASE, and ERIC) were searched to identify assessments that (1) measured intellectual function, (2) in children aged 4 to 18 years, (3) with CP, and (4) with psychometrics available. RESULTS: Searches yielded 48 assessments, of which nine provided psychometric data for children with CP. The included tests were the Columbia Mental Maturity Scale, the Leiter International Performance Scale, the Peabody Picture Vocabulary Test, the Pictorial Test of Intelligence, the Raven's Coloured Progressive Matrices, the Stanford-Binet Intelligence Scales, the Wechsler Adult Intelligence Scale, the Wechsler Intelligence Scale for Children, and the Wechsler Preschool and Primary Scale of Intelligence. INTERPRETATION: Intelligence assessments in children with CP lack reliability data, consensus regarding validity data, and population specific norms. Research is required to establish psychometrics for children with CP. For children with higher motor involvement and/or communication and/or visual impairments, multiple options are required to assess intelligence appropriately. PMID- 23662851 TI - CD133+ cell content correlates with tumour growth in melanomas from skin with chronic sun-induced damage. AB - BACKGROUND: Melanoma is responsible for almost 80% of the deaths attributed to skin cancer. Stem cells, defined by CD133 expression, have been implicated in melanoma tumour growth, but their specific role is still uncertain. OBJECTIVES: We hypothesized that the phenotypic heterogeneity of human cutaneous melanomas is related to their content of CD133+ cells. METHODS: We compared the percentages of CD133+ cells in 29 tumours from four classic types of melanoma: lentigo maligna melanoma (LMM), superficial spreading melanoma, nodular melanoma and acral lentiginous melanoma (ALM). Also, we compared the percentages of CD133+ cells in melanomas with different degrees of exposure to ultraviolet radiation: 16 melanomas from skin with chronic sun-induced damage and 13 melanomas from skin without such damage. RESULTS: We found a statistically significant increase of CD133+ cells in three different contexts: in melanomas arising on skin with signs of chronic sun-induced damage vs. nonexposed skin, in melanomas in situ vs. invasive melanomas, and in LMM vs. ALM. The proportions of CD133+ cells did not differ among samples of normal skin with different degrees of sun exposure. A distinct subpopulation of CD133+CXCR4+ cancer stem cells (CSCs) was identified and shown to be related to the invasive phenotype of the tumours. CONCLUSIONS: Here, we provide evidence showing, for the first time, that an increase in the CD133+ cell content is associated both with melanomas arising on skin with signs of chronic sun-induced damage and in melanomas in situ with better prognosis. Moreover, our study further confirms the existence of a subpopulation of CD133+CXCR4+ CSCs in cutaneous melanomas with invasive phenotype and poor prognosis. PMID- 23662852 TI - A one-locus model of androdioecy with two homomorphic self-incompatibility groups: expected vs. observed male frequencies. AB - Androdioecy, the occurrence of males and hermaphrodites in a single population, is a rare breeding system because the conditions for maintenance of males are restrictive. In the androdioecious shrub Phillyrea angustifolia, high male frequencies are observed in some populations. The species has a sporophytic self incompatibility (SI) system with two self-incompatibility groups, which ensures that two groups of hermaphrodites can each mate only with the other group, whereas males can fertilize hermaphrodites of both groups. Here, we analyse a population genetic model to investigate the dynamics of such an androdioecious species, assuming that self-incompatibility and sex phenotypes are determined by a single locus. Our model confirms a previous prediction that a slight reproductive advantage of males relative to hermaphrodites allows the maintenance of males at high equilibrium frequencies. The model predicts different equilibria between hermaphrodites of the two SI groups and males, depending on the male advantage, the initial composition of the population and the population size, whose effect is studied through stochastic simulations. Although the model can generate high male frequencies, observed frequencies are considerably higher than the model predicts. We finally discuss how this model may help explain the large male frequency variation observed in other androdioecious species of Oleaceae: some species show only androdioecious populations, as P. angustifolia, whereas others show populations either completely hermaphrodite or androdioecious. PMID- 23662854 TI - Visualization and process understanding of material behavior in the extrusion barrel during a hot-melt extrusion process using Raman spectroscopy. AB - The aim of this research was to improve understanding of material behavior in pharmaceutical hot-melt extrusion by implementing a Raman probe in each section of the barrel. Fourier-transform infrared spectroscopy measurements were performed to confirm the Raman observations. Metoprolol tartrate (MPT) concentration (10 and 40% in Eudragit RSPO), extrusion temperature (100, 120, and 140 degrees C), and screw speed (80 and 160 rpm) were varied to examine their influence on polymer-drug solid state throughout the barrel. When extruding a formulation with a 40% MPT concentration, the broadening of MPT peaks indicates melting of MPT between sections 2 and 3, caused by the first kneading zone. Decreasing the concentration to 10% shows an additional spectral difference (i.e., peak shifts indicating interactions between MPT and the carrier) between sections 5 and 6, due to formation of a solid solution. At a 10% MPT load, increasing the extrusion temperature does not influence the solid state or the barrel section where the final solid state is obtained. At a drug load of 40%, the solid state of the end product is reached further down the barrel when the temperature decreases. Doubling the screw speed when processing a 10% MPT formulation does not affect the solid state of the product or the location where it is obtained. In contrast, at a 40% drug load, the section where the final product is produced, is situated earlier in the barrel, when applying a higher speed. The Raman spectra provide real-time information about polymer-drug behavior throughout the barrel, facilitating process understanding and optimization. PMID- 23662853 TI - Relationship between aerobic endurance training and dynamic cerebral blood flow regulation in humans. AB - The incidence of orthostatic intolerance is elevated in endurance-trained individuals. We sought to test the hypothesis that aerobic endurance training is associated with an attenuated control of the cerebral vasculature. Endurance trained (ET, n = 13) and age-matched untrained (UT, n = 11) individuals (peak O2 consumption, mean +/- SEM; 63 +/- 1 vs 42 +/- 1 mL/min/kg, P < 0.05) were examined while supine and seated upright. Dynamic cerebral autoregulation (CA) was assessed by calculation of the rate of regulation (RoR) from the arterial blood pressure (ABP) and middle cerebral artery (MCA) mean blood velocity (V mean ) responses to a bilateral thigh cuff release, which evoked a transient hypotension. Cerebral oxygenation (oxyhemoglobin; HbO2 ) was determined with near infrared spectroscopy. When seated upright, cuff release evoked a greater decrease in ABP (P < 0.001), MCA V mean (P = 0.096) and HbO2 (P < 0.001) in ET compared with UT. However, RoR was similar in ET and UT individuals while seated upright (to 0.193 +/- 0.039 vs 0.129 +/- 0.029/s, P > 0.05), and there was no significant difference in the relative change in RoR from the supine to upright positions (DeltaRoR: -65 +/- 7 and -69 +/- 7%, for ET and UT, respectively). These findings suggest that aerobic endurance training is not associated with an attenuation in dynamic CA. PMID- 23662856 TI - The pavagada pediatric eye disease study: objectives, methodology and participant characteristics. AB - PURPOSE: To explain the objectives and methodology of a population-based survey of children <=15 years in rural South India. METHODS: A population-based cross sectional survey was performed by trained field workers (1st phase). Children with eye disease were referred to the peripheral rural hospital (2nd phase) to be examined by a general ophthalmologist. If major eye disease (cataract, strabismus) was identified they were referred to a pediatric ophthalmologist (3rd phase). RESULTS: The sample size was 29,850. In the 1st phase, 23,100 children were screened (response rate 77.39%). There were about 33% of children in each of the three stratified age groups (0-5, 6-10 and 11-15 years), with a nearly equal sex distribution in each group (range 47% to 52%). Of the 23,100 screened, 1538 were referred to the peripheral rural hospital. The general ophthalmologist evaluated 647 patients (42%) who came to the peripheral rural hospital (2nd phase) and referred 59 children to the pediatric ophthalmologist (3rd phase). The pediatric ophthalmologist, in addition to evaluating the 59 children referred from the 2nd phase, also evaluated those who did not report (891/1538) to the peripheral rural hospital. This evaluation was done in the field itself. All the 1538 children referred by the field workers were thus seen by an ophthalmologist (647 by the general ophthalmologist, 891 by the pediatric ophthalmologist and 59 by both). CONCLUSION: The study is expected to provide information about the prevalence of pediatric ocular morbidity that could help plan intervention strategies in this area. PMID- 23662857 TI - Effect of cerium oxide nanoparticles on rice: a study involving the antioxidant defense system and in vivo fluorescence imaging. AB - Previous studies have reported the uptake of cerium oxide nanoparticles (nCeO2) by plants, but their physiological impacts are not yet well understood. This research was aimed to study the impact of nCeO2 on the oxidative stress and antioxidant defense system in germinating rice seeds. The seeds were germinated for 10 days in nCeO2 suspension at 62.5, 125, 250, and 500 mg L(-1) concentrations. The Ce uptake, growth performance, stress levels, membrane damage, and antioxidant responses in seedlings were analyzed. Ce in tissues increased with increased nCeO2 concentrations, but the seedlings showed no visible signs of toxicity. Biochemical assays and in vivo imaging of H2O2 revealed that, relative to the control, the 62.5 and 125 mg nCeO2 L(-1) treatments significantly reduced the H2O2 generation in both shoots and roots. Enhanced electrolyte leakage and lipid peroxidation were found in the shoots of seedlings grown at 500 mg nCeO2 L(-1). Altered enzyme activities and levels of ascorbate and free thiols resulting in enhanced membrane damage and photosynthetic stress in the shoots were observed at 500 mg nCeO2 L(-1). These findings demonstrate a nCeO2 concentration-dependent modification of oxidative stress and antioxidant defense system in rice seedlings. PMID- 23662855 TI - Sensitivity of X-ray core spectroscopy to changes in metal ligation: a systematic study of low-coordinate, high-spin ferrous complexes. AB - In order to assess the sensitivity and complementarity of X-ray absorption and emission spectroscopies for determining changes in the metal ligation sphere, a systematic experimental and theoretical study of iron model complexes has been carried out. A series of high-spin ferrous complexes, in which the ligation sphere has been varied from a three-coordinate complex, [L(tBu)Fe(SPh)] (1) (where L(tBu) = bulky beta-diketiminate ligand; SPh = phenyl thiolate) to four coordinate complexes [L(tBu)Fe(SPh)(X)] (where X = CN(t)Bu (2); 1-methylimidazole (3); or N,N-dimethylformamide (DMF) (4)), has been investigated using a combination of Fe K-edge X-ray absorption (XAS) and Kbeta X-ray emission (XES) spectroscopies. The Fe K XAS pre-edge and edge of all four complexes are consistent with a high-spin ferrous assignment, with the largest differences in the pre-edge intensities attributed to changes in covalency of the fourth coordination site. The X-ray emission spectra show pronounced changes in the valence to core region (V2C) as the identity of the coordinated ligand is varied. The experimental results have been correlated to density functional theory (DFT) calculations, to understand key molecular orbital contributions to the observed absorption and emission features. The calculations also have been extended to a series of hypothetical high-spin iron complexes to understand the sensitivity of XAS and XES techniques to different ligand protonation states ([L(tBu)Fe(II)(SPh)(NHn)](3-n) (n = 3, 2, 1, 0)), metal oxidation states [L(tBu)Fe(SPh)(N)](n-) (n = 3, 2, 1), and changes in the ligand identity [L(tBu)Fe(IV)(SPh)(X)](n-) (X = C(4-), N(3-), O(2-); n = 2, 1, 0). This study demonstrates that XAS pre-edge data have greater sensitivity to changes in oxidation state, while valence to core (V2C) XES data provide a more sensitive probe of ligand identity and protonation state. The combination of multiple X-ray spectroscopic methods with DFT results thus has the potential to provide for detailed characterization of complex inorganic systems in both chemical and biological catalysis. PMID- 23662858 TI - Neural correlates of gesture processing across human development. AB - Co-speech gesture facilitates learning to a greater degree in children than in adults, suggesting that the mechanisms underlying the processing of co-speech gesture differ as a function of development. We suggest that this may be partially due to children's lack of experience producing gesture, leading to differences in the recruitment of sensorimotor networks when comparing adults to children. Here, we investigated the neural substrates of gesture processing in a cross-sectional sample of 5-, 7.5-, and 10-year-old children and adults and focused on relative recruitment of a sensorimotor system that included the precentral gyrus (PCG) and the posterior middle temporal gyrus (pMTG). Children and adults were presented with videos in which communication occurred through different combinations of speech and gesture during a functional magnetic resonance imaging (fMRI) session. Results demonstrated that the PCG and pMTG were recruited to different extents in the two populations. We interpret these novel findings as supporting the idea that gesture perception (pMTG) is affected by a history of gesture production (PCG), revealing the importance of considering gesture processing as a sensorimotor process. PMID- 23662859 TI - Advances in the design and discovery of drugs for the treatment of prostatic hyperplasia. AB - INTRODUCTION: Benign prostatic hyperplasia (BPH) is a common medical problem in nearly 80% of geriatric male population severely affecting the quality of life. Several strategies has been suggested in the past for the management of BPH, but only alpha-blockers and 5alpha-reductase inhibitors are in clinical use. This review aims to give deep insight into advances in the design and discovery of newer chemical entities as 'druggable' molecule for the management of BPH. AREAS COVERED: In this review, the authors cover various classes of drugs that have shown their potential for management of BPH. These drugs include alpha-adrenergic antagonists, 5alpha-reductase inhibitors, phytochemical agents, phosphodiesterase inhibitor, luteinizing hormone releasing hormone antagonists and muscarinic receptor antagonists. Literature searches were carried out using Google Scholar, SciFinder and PubMed. EXPERT OPINION: The exact etiology of BPH is unknown; however, several mechanisms may be involved in the progression of the disease. Beside surgery and watchful waiting, medical therapies to treat BPH include alpha adrenergic antagonist and 5alpha-reductase inhibitors. Phytotherapeutic agents are also used in some countries. Various other chemical classes of drugs are proposed for the treatment of the disease, but none of them have reached the clinic. Many classes of drugs are currently undergoing clinical trials such as phosphodiesterase inhibitors, luteinizing hormone releasing hormone antagonists and muscarinic receptor antagonists. The current need is to develop a potent, efficacious and highly selective drug for the treatment of BPH. PMID- 23662860 TI - Unconscious priming requires early visual cortex at specific temporal phases of processing. AB - Although examples of unconscious shape priming have been well documented, whether such priming requires early visual cortex (V1/V2) has not been established. In the current study, we used TMS of V1/V2 at varying temporal intervals to suppress the visibility of preceding shape primes while the interval between primes and targets was kept constant. Our results show that, although conscious perception requires V1/V2, unconscious priming can occur without V1/V2 at an intermediate temporal interval but not at early (5-25 msec) or later (65-125 msec) stages of processing. Because the later time window of unconscious priming suppression has been proposed to interfere with feedback processing, our results further suggest that feedback processing is also essential for unconscious priming and may not be a sufficient condition for conscious vision. PMID- 23662861 TI - Objects and categories: feature statistics and object processing in the ventral stream. AB - Recognizing an object involves more than just visual analyses; its meaning must also be decoded. Extensive research has shown that processing the visual properties of objects relies on a hierarchically organized stream in ventral occipitotemporal cortex, with increasingly more complex visual features being coded from posterior to anterior sites culminating in the perirhinal cortex (PRC) in the anteromedial temporal lobe (aMTL). The neurobiological principles of the conceptual analysis of objects remain more controversial. Much research has focused on two neural regions-the fusiform gyrus and aMTL, both of which show semantic category differences, but of different types. fMRI studies show category differentiation in the fusiform gyrus, based on clusters of semantically similar objects, whereas category-specific deficits, specifically for living things, are associated with damage to the aMTL. These category-specific deficits for living things have been attributed to problems in differentiating between highly similar objects, a process that involves the PRC. To determine whether the PRC and the fusiform gyri contribute to different aspects of an object's meaning, with differentiation between confusable objects in the PRC and categorization based on object similarity in the fusiform, we carried out an fMRI study of object processing based on a feature-based model that characterizes the degree of semantic similarity and difference between objects and object categories. Participants saw 388 objects for which feature statistic information was available and named the objects at the basic level while undergoing fMRI scanning. After controlling for the effects of visual information, we found that feature statistics that capture similarity between objects formed category clusters in fusiform gyri, such that objects with many shared features (typical of living things) were associated with activity in the lateral fusiform gyri whereas objects with fewer shared features (typical of nonliving things) were associated with activity in the medial fusiform gyri. Significantly, a feature statistic reflecting differentiation between highly similar objects, enabling object-specific representations, was associated with bilateral PRC activity. These results confirm that the statistical characteristics of conceptual object features are coded in the ventral stream, supporting a conceptual feature-based hierarchy, and integrating disparate findings of category responses in fusiform gyri and category deficits in aMTL into a unifying neurocognitive framework. PMID- 23662862 TI - Top-down inhibitory control exerted by the medial frontal cortex during action selection under conflict. AB - Top-down control is critical to select goal-directed actions in changeable environments, particularly when several conflicting options compete for selection. In humans, this control system is thought to involve an inhibitory mechanism that suppresses the motor representation of unwanted responses to favor selection of the most appropriate action. Here, we aimed to evaluate the role of a region of the medial frontal cortex, the pre-SMA, in this form of inhibition by using a double coil TMS protocol combining repetitive TMS (rTMS) over the pre-SMA and a single-pulse TMS over the primary motor cortex (M1) during a visuomotor task that required participants to choose between a left or right button press according to an imperative cue. M1 stimulation allowed us to assess changes in motor excitability related to selected and nonselected (unwanted) actions, and rTMS was used to produce transient disruption of pre-SMA functioning. We found that when rTMS was applied over pre-SMA, inhibition of the nonselected movement representation was reduced. Importantly, this effect was only observed when the imperative cue produced a substantial amount of competition between the response alternatives. These results are consistent with previous studies pointing to a role of pre-SMA in competition resolution. In addition, our findings indicate that this function of pre-SMA involves the control of inhibitory influences directed at unwanted action representations. PMID- 23662864 TI - Neurobiological systems for lexical representation and analysis in English. AB - Current research suggests that language comprehension engages two joint but functionally distinguishable neurobiological processes: a distributed bilateral system, which supports general perceptual and interpretative processes underpinning speech comprehension, and a left hemisphere (LH) frontotemporal system, selectively tuned to the processing of combinatorial grammatical sequences, such as regularly inflected verbs in English [Marslen-Wilson, W. D., & Tyler, L. K. Morphology, language and the brain: The decompositional substrate for language comprehension. Philosophical Transactions of the Royal Society: Biological Sciences, 362, 823-836, 2007]. Here we investigated how English derivationally complex words engage these systems, asking whether they selectively activate the LH system in the same way as inflections or whether they primarily engage the bilateral system that support nondecompositional access. In an fMRI study, we saw no evidence for selective activation of the LH frontotemporal system, even for highly transparent forms like bravely. Instead, a combination of univariate and multivariate analyses revealed the engagement of a distributed bilateral system, modulated by factors of perceptual complexity and semantic transparency. We discuss the implications for theories of the processing and representation of English derivational morphology and highlight the importance of neurobiological constraints in understanding these processes. PMID- 23662867 TI - It's all about gender, or is it? PMID- 23662863 TI - The role of transverse occipital sulcus in scene perception and its relationship to object individuation in inferior intraparietal sulcus. AB - The parietal cortex has been functionally divided into various subregions; however, very little is known about how these areas relate to each other. Two such regions are the transverse occipital sulcus (TOS) scene area and inferior intraparietal sulcus (IPS). TOS exhibits similar activation patterns to the scene selective parahippocampal place area, suggesting its role in scene perception. Inferior IPS, in contrast, has been shown to participate in object individuation and selection via location. Interestingly, both regions have been localized to the same general area of the brain. If these two were actually the same brain region, it would have important implications regarding these regions' role in cognition. To explore this, we first localized TOS and inferior IPS in individual participants and examined the degree of overlap between these regions in each participant. We found that TOS showed only a minor degree of overlap with inferior IPS (~10%). We then directly explored the role of TOS and inferior IPS in object individuation and scene perception by examining their responses to furnished rooms, empty rooms, isolated furniture, and multiple isolated objects. If TOS and inferior IPS were the same region, we would expect to see similar response patterns in both. Instead, the response of TOS was predominantly scene selective, whereas activity in inferior IPS was primarily driven by the number of objects present in the display, regardless of scene context. These results show that TOS and inferior IPS are nearby but distinct regions, with different functional roles in visual cognition. PMID- 23662868 TI - Metacognition, OSCE performance anxiety and OSCE performance. PMID- 23662869 TI - The elusive grail of social inclusion in medical selection. PMID- 23662870 TI - Research into the use of virtual patients is moving forward by zooming out. PMID- 23662871 TI - The only girl in the room: how paradigmatic trajectories deter female students from surgical careers. AB - OBJECTIVES: Over 60% of UK medical students are female, yet only 33% of applicants to surgical training are women. Role modelling, differing educational experiences and disidentification in female medical students have been implicated in this disparity. We are yet to fully understand the mechanisms that link students' experiences with national trends in career choices. We employ a hitherto unused concept from the theory of communities of practice: paradigmatic trajectories. These are visible career paths provided by a community and are cited by Wenger as potentially the most influential factors shaping the learning of newcomers. We pioneer the use of this theoretical tool in answering the research question: How do paradigmatic trajectories shape female medical students' experiences of surgery and subsequent career intentions? METHODS: This qualitative study comprised a secondary analysis of data sourced from 19 clinical medical students. During individual, in-depth, semi-structured interviews, we explored these students' experiences at medical school. We carried out thematic analysis using sensitising concepts from communities of practice theory, notably that of 'paradigmatic trajectories'. RESULTS: Female students' experiences of surgery were strongly gendered; they were positioned as 'other' in the surgical domain. Four key processes--seeing, hearing, doing and imagining--facilitated the formation of paradigmatic trajectories, on which students could draw when making career decisions. Female students were unable to see or identify with other women in surgery. They heard about challenges to being a female surgeon, lacked experiences of participation, and struggled to imagine a future in which they would be successful surgeons. Thus, based on paradigmatic trajectories constructed from exposure to surgery, they self-selected out of surgical careers. By contrast, male students had experiences of 'hands-in' participation and were not marginalised by paradigmatic trajectories. CONCLUSIONS: The concept of the paradigmatic trajectory is a useful theoretical tool with which to understand how students' experiences shape career decisions. Paradigmatic trajectories within surgery deter female students from embarking on careers in surgery. PMID- 23662872 TI - Admission criteria and diversity in medical school. AB - CONTEXT: The under-representation in medical education of students from lower socio-economic backgrounds is an important social issue. There is currently little evidence about whether changes in admission strategies might increase the diversity of the medical student population. Denmark introduced an 'attribute based' admission track to make it easier for students who may not be eligible for admission on the 'grade-based' track to be admitted on the basis of attributes other than academic performance. The aim of this research was to examine whether there were significant differences in the social composition of student cohorts admitted via each of the two tracks during the years 2002-2007. METHODS: This prospective cohort study included 1074 medical students admitted during 2002-2007 to the University of Southern Denmark medical school. Of these, 454 were admitted by grade-based selection and 620 were selected on attributes other than grades. To explore the social mix of candidates admitted on each of the two tracks, respectively, we obtained information on social indices associated with educational attainment in Denmark (ethnic origin, father's education, mother's education, parenthood, parents living together, parent in receipt of social benefits). RESULTS: Selection strategy (grade-based or attribute-based) had no statistically significant effect on the social diversity of the medical student population. CONCLUSIONS: The choice of admission criteria may not be very important to widening access and increasing social diversity in medical schools. Attracting a sufficiently diverse applicant pool may represent a better strategy for increasing diversity in the student population. PMID- 23662873 TI - Metacognitions, worry and attentional control in predicting OSCE performance test anxiety. AB - OBJECTIVES: This study investigated the applicability of the self-regulatory executive functioning (S-REF) model to performance test anxiety (PTA) in objective structured clinical examinations (OSCEs). Specifically, it examined the relative contributions of metacognitive beliefs, trait worry and attentional control to PTA. METHODS: A cross-sectional design was used. Immediately prior to their formative Communication for Clinical Practice OSCE, 240 Year 1 medical students completed the following self-report questionnaires: the Metacognitions Questionnaire-30 (MCQ-30); the Penn State Worry Questionnaire (PSWQ); the Attentional Control Scale (ACS), and the Performance Test Anxiety questionnaire (PTA). RESULTS: Univariate analysis indicated that female students scored significantly more highly than male students on the MCQ-30 subscale for negative beliefs about the uncontrollability and danger of worry, the MCQ-30 subscale for cognitive confidence and the PSWQ subscale for trait worry. Partial correlations (controlling for gender) showed that metacognitions, worry and attentional control were significantly correlated with PTA. Multiple regression analyses showed that worry and negative beliefs about the uncontrollability and danger of worry were independent predictors of PTA in both male and female students, whereas attention focus was an independent predictor only in male students. CONCLUSIONS: The findings support predictions derived from the S-REF model that metacognitive beliefs, trait worry and attentional control processes underlie the onset and maintenance of PTA. PMID- 23662874 TI - Advancing the objective structured clinical examination: sequential testing in theory and practice. AB - CONTEXT: Models of short-term remediation for failing students are typically associated with improvements in candidate performance at retest. However, the process is costly to deliver, particularly for performance retests with objective structured clinical examinations (OSCEs), and there is increasing evidence that these traditional models are associated with the longitudinal underperformance of candidates. METHODS: Rather than a traditional OSCE model, sequential testing involves a shorter 'screening' format, with an additional 'sequential' test for candidates who fail to meet the screening standard. For those tested twice, overall pass/fail decisions are then based on results on the full sequence of tests. In this study, the impacts of sequential assessment on student performance, cost of assessment delivery and overall reliability were modelled using data sourced from a final graduating OSCE in an undergraduate medical degree programme. RESULTS: Initial modelling using pre-existing OSCE data predicted significant improvements in reliability in the critical area, reflected in pilot results: 13.5% of students (n = 228) were required to sit the sequential OSCE. One student (0.4%) was identified as representing a false positive result (i.e. under the previous system this student would have passed the OSCE but failed on extended testing). Nine students (3.9%) who would have required OSCE retests under the prior system passed the full sequence and were therefore able to graduate at the normal time without loss of earnings. Overall reliability was estimated as 0.79 for the full test sequence. Significant cost savings were realised. CONCLUSIONS: Sequential testing in OSCEs increases reliability for borderline students because the increased number of observations implies that 'observed' student marks are closer to 'true' marks. However, the station-level quality of the assessment needs to be sufficiently high for the full benefits in terms of reliability to be achieved. The introduction of such a system has financial benefits, good validity inferences and has proved acceptable to students and other stakeholders. PMID- 23662875 TI - Does student confidence on multiple-choice question assessments provide useful information? AB - CONTEXT: Feedback from multiple-choice question (MCQ) assessments is typically limited to a percentage correct score, from which estimates of student competence are inferred. The students' confidence in their answers and the potential impact of incorrect answers on clinical care are seldom recorded. Our purpose was to evaluate student confidence in incorrect responses and to establish how confidence was influenced by the potential clinical impact of answers, question type and gender. METHODS: This was an exploratory, cross-sectional study conducted using a convenience sample of 104 Year 3 dental students completing 20 MCQs on implant dentistry. Students were asked to select the most correct response and to indicate their confidence in it for each question. Identifying both correctness and confidence allowed the designation of uninformed (incorrect and not confident) or misinformed (incorrect but confident) responses. In addition to recording correct/incorrect responses and student confidence, faculty staff designated incorrect responses as benign, inappropriate or potentially harmful if applied to clinical care. Question type was identified as factual or complex. Logistic regression was used to evaluate relationships between student confidence, and question type and gender. RESULTS: Students were misinformed more often than uninformed (22% versus 8%), and misinformed responses were more common with complex than factual questions (p < 0.05). Students were significantly more likely to be confident of correct than incorrect benign, incorrect inappropriate or incorrect harmful answers (p < 0.001), but, contrary to expectations, confidence did not decrease as answers became more harmful. CONCLUSIONS: Recording student confidence was helpful in identifying uninformed versus misinformed responses, which may allow for targeted remediation strategies. Making errors of calibration (confidence and accuracy) more visible may be relevant in feedback for professional development. PMID- 23662876 TI - Beyond individualism: professional culture and its influence on feedback. AB - CONTEXT: Although feedback is widely considered essential to learning, its actual influence on learners is variable. Research on responsivity to feedback has tended to focus on individual rather than social or cultural influences on learning. In this study, we explored how feedback is handled within different professional cultures, and how the characteristics and values of a profession shape learners' responses to feedback. METHODS: Using a constructivist grounded theory approach, we conducted 12 focus groups and nine individual interviews (with a total of 50 participants) across three cultures of professional training in, respectively, music, teacher training and medicine. Constant comparative analysis for recurring themes was conducted iteratively. RESULTS: Each of the three professional cultures created a distinct context for learning that influenced how feedback was handled. Despite these contextual differences, credibility and constructiveness emerged as critical constants, identified by learners across cultures as essential for feedback to be perceived as meaningful. However, the definitions of credibility and constructiveness were distinct to each professional culture and the cultures varied considerably in how effectively they supported the occurrence of feedback with these critical characteristics. CONCLUSIONS: Professions define credibility and constructiveness in culturally specific ways and create contexts for learning that may either facilitate or constrain the provision of meaningful feedback. Comparison with other professional cultures may offer strategies for creating a productive feedback culture within medical education. PMID- 23662877 TI - Virtual patient design: exploring what works and why. A grounded theory study. AB - OBJECTIVES: Virtual patients (VPs) are online representations of clinical cases used in medical education. Widely adopted, they are well placed to teach clinical reasoning skills. International technology standards mean VPs can be created, shared and repurposed between institutions. A systematic review has highlighted the lack of evidence to support which of the numerous VP designs may be effective, and why. We set out to research the influence of VP design on medical undergraduates. METHODS: This is a grounded theory study into the influence of VP design on undergraduate medical students. Following a review of the literature and publicly available VP cases, we identified important design properties. We integrated them into two substantial VPs produced for this research. Using purposeful iterative sampling, 46 medical undergraduates were recruited to participate in six focus groups. Participants completed both VPs, an evaluation and a 1-hour focus group discussion. These were digitally recorded, transcribed and analysed using grounded theory, supported by computer-assisted analysis. Following open, axial and selective coding, we produced a theoretical model describing how students learn from VPs. RESULTS: We identified a central core phenomenon designated 'learning from the VP'. This had four categories: VP Construction; External Preconditions; Student-VP Interaction, and Consequences. From these, we constructed a three-layer model describing the interactions of students with VPs. The inner layer consists of the student's cognitive and behavioural preconditions prior to sitting a case. The middle layer considers the VP as an 'encoded object', an e-learning artefact and as a 'constructed activity', with associated pedagogic and organisational elements. The outer layer describes cognitive and behavioural change. CONCLUSIONS: This is the first grounded theory study to explore VP design. This original research has produced a model which enhances understanding of how and why the delivery and design of VPs influence learning. The model may be of practical use to authors, institutions and researchers. PMID- 23662878 TI - Medical students' tobacco use and attitudes towards tobacco control. AB - CONTEXT: Despite their important roles as future doctors in tobacco cessation counselling, the high prevalence of tobacco use among medical students may hinder them from advocating tobacco control policies and providing cessation counselling. Promoting this role among medical students is especially important in low- and middle-income countries with high burdens of tobacco use but limited resources for cessation programmes. This study examined the associations between medical students' tobacco use and their attitudes towards tobacco control policies and the roles of health professionals in the provision of tobacco cessation advice. METHODS: This cross-sectional study included data from the large multi-country dataset generated by the Global Health Professions Student Survey, 2005-2008 (n = 36,533 medical students). Thirteen binary dependent variables related to medical students' attitudes towards tobacco control policies and the health professional's role in cessation counselling were examined using random-effects logistic regression, with tobacco use status as the key explanatory variable. Covariates included gender, receipt of cessation training, country-level and gender-specific smoking prevalence, region, and country income group. RESULTS: Current tobacco use was consistently associated with less favourable attitudes towards tobacco control policy and cessation advice. Compared with never users, daily users were less likely to agree that the sale of tobacco products to adolescents should be banned (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.39-0.58) and that health professionals should routinely advise patients to quit smoking (OR = 0.48, 95% CI 0.41-0.52) or other forms of tobacco use (OR = 0.84, 95% CI 0.72-0.97). Daily users were less likely to agree that health professionals who smoke are less likely to advise patients to stop smoking (OR = 0.44, 95% CI 0.39-0.41). CONCLUSIONS: Medical schools may benefit from a thorough re-evaluation of the scope of tobacco cessation training in their curricula in order to support students in smoking cessation and to shape their attitudes towards tobacco control. Targeting medical students who are current tobacco users in tobacco control efforts may be beneficial, given the cost-effectiveness of providing cessation advice. PMID- 23662879 TI - Curricular transformations in medical school: an exploration of the promotion of change in Brazil. AB - CONTEXT: Curricular transformation is complex and involves many interrelated and influential factors. The idiosyncratic nature of the time-frame in which curricular change takes place makes it difficult to study these factors systematically. In 2002, the Brazilian government established the Programme of Incentives for Curricular Changes in Medical Schools (PROMED). Nineteen schools participated in the programme and were given resources to finance curricular reforms in an effort to align their course structures with the tenets of the government proposal. This study analyses reforms in coursework among the schools in this cohort in an effort to better understand the impact of such incentive programmes and factors that might influence the degree of impact across institutions. METHODS: We compared data on the schools before and after their participation in PROMED. To facilitate comparison, we used a scheme of axes and vectors to classify the schools according to the profundity of the curricular changes, ranging from the most conservative to the most innovative. The data used for the classification were obtained through document analysis, interviews and focus group discussions. RESULTS: Different trends were observed for each axis. Important changes were noticed in the pedagogic approach axis, particularly in terms of pedagogic changes, which called for the adoption of active teaching and learning methods. The practice scenarios axis also underwent considerable changes, specifically in terms of primary health care. The vector related to production of knowledge pertaining to health system needs showed fewer changes; none of the schools reached stage 3 (effective fulfilment of an educational innovation). CONCLUSIONS: The PROMED initiative provided considerable support for implementing and consolidating curricular reforms that placed greater emphasis on the needs of society and the health care system. The different trends observed revealed the complexity behind curricular transformation and highlighted the need for the collective construction of curricula with the participation of all groups involved. PMID- 23662880 TI - Standardised versus individualised assessment: related problems divided by a common language. PMID- 23662881 TI - Separating the wheat from the chaff: the role of systematic review in medical education. PMID- 23662882 TI - Towards a better medical curriculum. PMID- 23662883 TI - HSP90 antibodies: a detrimental factor responsible for ovarian dysfunction. AB - PROBLEM: Earlier studies from our group have established that about 47% cases of autoimmune ovarian failure are due to presence of autoantibodies to Heat Shock Protein 90 (HSP90). However, there are no reports correlating pathological effects of HSP90 autoantibodies leading to ovarian failure. METHOD OF STUDY: Antibodies to HSP90 in female mouse model were generated by active immunization with an immunodominant peptide of HSP90, followed by detailed analysis of several reproductive parameters. RESULT: Estrous cyclicity remains unchanged; however, there was a significant drop in the fertility index due to an increase in pre- and post-implantation loss, associated with an increased incidence of degenerated eggs and embryos. The ovaries showed an increase in the number of empty and degenerated follicles and extensive granulosa cell deaths, which was reflected by the decrease in the levels of Nobox and Gja1 gene expression. CONCLUSION: This study underlines a critical role played by HSP90 in ovarian folliculogenesis and highlights the implications of the presence of anti-HSP90 antibodies in infertile women. PMID- 23662884 TI - Outcomes in treatment for primary spinal anaplastic ependymomas: a retrospective series of 20 patients. AB - OBJECT: Little is known regarding the anaplastic variant of primary ependymomas that involve the spinal cord. The aim of this study was to evaluate the clinical characteristics and treatment outcomes of primary spinal anaplastic ependymomas (PSAEs). METHODS: Medical records were reviewed in 20 patients with pathologically proven PSAEs who underwent surgical treatment at the Department of Neurosurgery in Huashan Hospital between 1999 and 2008. RESULTS: This series included 7 women and 13 men between the ages of 2 and 67 years (mean 31.9 years). The mean preoperative course was 9.3 months (range 20 days to 48 months). The most common PSAE locations were the cervical and thoracic spinal cords. The most common presenting symptom was weakness, followed by numbness, bowel or bladder dysfunction, and pain. Gross-total resection (GTR) was achieved in 17 patients, and a subtotal removal was performed in 3 patients. Nine patients received radiation therapy and/or chemotherapy. The mean follow-up duration was 83.5 months. Functional assessment of the 10 patients available at the latest follow up evaluation showed that 2 had worsened and 8 remained unchanged from their preoperative status. There were 2 local recurrences and 1 lung metastasis. CONCLUSIONS: Patients with PSAEs presented with a much shorter preoperative course than patients with Grade II ependymomas in previous studies. Patients with tumors that involved the cervical spinal cord experienced a worse outcome. Surgical removal of PSAEs, with the goal of GTR, is beneficial to patients. The role of radiation therapy and chemotherapy in PSAEs remains to be determined in further studies. PMID- 23662885 TI - Placement of unilateral lag screw through the lateral mass of C-1: description of a novel technique. AB - Over the past several decades, many advancements and new techniques have emerged regarding the instrumentation and stabilization of the upper cervical spine. In this article, the authors describe a novel technique in which a unilateral lag screw was placed to reduce and stabilize a progressively widening fracture and nonunion of the right C-1 lateral mass approximately 8 weeks after the initial injury, which was sustained when a large tree branch fell onto the patient's posterior head and neck. PMID- 23662886 TI - Extradural cyst causing spinal cord compression in osteoporotic compression fracture. AB - Intraspinal cystic lesions with different pathogeneses have been reported to cause neurological deficits; however, no one has focused on the intraspinal extradural cysts that develop after osteoporotic compression fracture. The reported case features a 66-year-old woman presenting with progressive neurological deficit, back pain, and no history of additional trauma after undergoing conservative treatment for an osteoporotic fracture of L-1. The authors present serial radiographs and MR images demonstrating an epidural cyst successfully treated via a single posterior approach. This appears to be the first such case reported in the literature. PMID- 23662887 TI - Outcomes of 2-level posterior lumbar interbody fusion for 2-level degenerative lumbar spondylolisthesis. AB - OBJECT: A systematic review concerning surgical management of lumbar degenerative spondylolisthesis (DS) showed that a satisfactory clinical outcome was significantly more likely with adjunctive spinal fusion than with decompression alone. However, the role of adjunctive fusion and the optimal type of fusion remain controversial. Therefore, operative management for multilevel DS raises more complicated issues. The purpose of this retrospective study was to elucidate clinical and radiological outcomes after 2-level PLIF for 2-level DS with the least bias in determination of operative procedure. METHODS: Since 2005, all patients surgically treated for lumbar DS at the authors' hospital have been treated using posterior lumbar interbody fusion (PLIF) with pedicle screws, irrespective of severity of slippage, patient age, or bone quality. The authors conducted a retrospective review of 20 consecutive cases involving patients who underwent 2-level PLIF for 2-level DS and had been followed up for 2 years or longer (2-level PLIF group). They also analyzed data from 92 consecutive cases involving patients who underwent single-level PLIF for single-level DS during the same time period and had been followed for at least 2 years (1-level PLIF group). This second group served as a control. Clinical status was assessed using the Japanese Orthopaedic Association (JOA) score. Fusion status and sagittal alignment of the lumbar spine were assessed by comparing serial plain radiographs. Surgery-related complications and the need for additional surgery were evaluated. RESULTS: The mean JOA score improved significantly from 12.8 points before surgery to 20.4 points at the latest follow-up in the 2-level PLIF group (mean recovery rate 51.8%), and from 14.2 points preoperatively to 22.5 points at the latest follow-up in the single-level PLIF group (mean recovery rate 55.3%). At the final follow-up, 95.0% of patients in the 2-level PLIF group and 96.7% of those in the 1-level PLIF group had achieved solid spinal fusion, and the mean sagittal alignment of the lumbar spine was more lordotic than before surgery in both groups. Early surgery-related complications, including transient neurological complications, occurred in 6 patients in the 2-level PLIF group (30.0%) and 11 patients in the 1-level PLIF group (12.0%). Symptomatic adjacent segment disease was found in 4 patients in the 2-level PLIF group (20.0%) and 10 patients in the 1-level PLIF group (10.9%). CONCLUSIONS: The clinical outcome of 2-level PLIF for 2-level lumbar DS was satisfactory, although surgery-related complications including symptomatic adjacent-segment disease were not negligible. PMID- 23662888 TI - Comparison of operative and nonoperative management of spinal epidural abscess: a retrospective review of clinical and laboratory predictors of neurological outcome. AB - OBJECT: Spinal epidural abscess (SEA), once considered a rare occurrence, has showed a rapid increase in incidence over the past 20-30 years. Recent reports have advocated for conservative, nonoperative management of this devastating disorder with appropriate risk stratification. Crucial to a successful management strategy are decisive diagnosis, prompt intervention, and consistent follow-up care. The authors present a review of their institutional experience with operative and nonoperative management of SEA to assess morbidity and mortality and the accuracy of microbiological diagnosis. METHODS: A retrospective analysis of patient charts, microbiology reports, operative records, and radiology reports was performed on all cases involving patients admitted with the diagnosis of SEA between July 1998 and May 2009. RESULTS: Seventy-seven cases were reviewed (median patient age 51.4 years, range 17-78 years). Axial pain was the most common presenting symptom (67.5% of cases). Presenting signs included focal weakness (55.8%), radiculopathy (28.6%), and myelopathy (5.2%). Abscesses were localized to the lumbar, thoracic, and cervical spine, respectively, in 39 (50.6%), 20 (26.0%), and 18 (23.4%) of the patients. Peripheral blood cultures were negative in 32 (45.1%) of 71 patients. Surgical site or interventional biopsy cultures were diagnostic in 52 cases (78.8%), with concordant blood culture results in 36 (60.0%). Methicillin-resistant Staphylococcus aureus (MRSA) was the most frequent isolate in 24 cases (31.2%). The mean time from admission to surgery was 5.5 days (range 0-42 days; within 72 hours in 66.7% of cases). Outcome data were available in 72 cases. At discharge, patient condition had improved or resolved in 57 cases (79.2%), improved minimally in 6 (8.3%), and showed no improvement or worsening in 9 (12.5%). Patient age and premorbid weakness were the only factors found to be significantly associated with outcome (p = 0.04 and 0.012, respectively). CONCLUSIONS: These results strongly support immediate surgical decompression combined with appropriately tailored antibiotic therapy for the treatment of symptomatic SEA presenting with focal neurological deficit. The nonsuperiority discovered in other patient subsets may be due to allocation biases between surgically treated and nonsurgically treated cohorts. The present data demonstrate the accuracy of peripheral blood culture for the prediction of causative organisms and confirm patient age as a predictor of outcomes. PMID- 23662889 TI - Ependymomas. PMID- 23662890 TI - Radiographic and clinical evaluation of cage subsidence after stand-alone lateral interbody fusion. AB - OBJECT: Indirect decompression of the neural structures through interbody distraction and fusion in the lumbar spine is feasible, but cage subsidence may limit maintenance of the initial decompression. The influence of interbody cage size on subsidence and symptoms in minimally invasive lateral interbody fusion is heretofore unreported. The authors report the rate of cage subsidence after lateral interbody fusion, examine the clinical effects, and present a subsidence classification scale. METHODS: The study was performed as an institutional review board-approved prospective, nonrandomized, comparative, single-center radiographic and clinical evaluation. Stand-alone short-segment (1- or 2-level) lateral lumbar interbody fusion was investigated with 12 months of postoperative follow-up. Two groups were compared. Forty-six patients underwent treatment at 61 lumbar levels with standard interbody cages (18 mm anterior/posterior dimension), and 28 patients underwent treatment at 37 lumbar levels with wide cages (22 mm). Standing lateral radiographs were used to measure segmental lumbar lordosis, disc height, and rate of subsidence. Subsidence was classified using the following scale: Grade 0, 0%-24% loss of postoperative disc height; Grade I, 25%-49%; Grade II, 50%-74%; and Grade III, 75%-100%. Fusion status was assessed on CT scanning, and pain and disability were assessed using the visual analog scale and Oswestry Disability Index. Complications and reoperations were recorded. RESULTS: Pain and disability improved similarly in both groups. While significant gains in segmental lumbar lordosis and disc height were observed overall, the standard group experienced less improvement due to the higher rate of interbody graft subsidence. A difference in the rate of subsidence between the groups was evident at 6 weeks (p = 0.027), 3 months (p = 0.042), and 12 months (p = 0.047). At 12 months, 70% in the standard group and 89% in the wide group had Grade 0 or I subsidence, and 30% in the standard group and 11% in wide group had Grade II or III subsidence. Subsidence was detected early (6 weeks), at which point it was correlated with transient clinical worsening, although progression of subsidence was not observed after the 6-week time point. Moreover, subsidence occurred predominantly (68%) in the inferior endplate. Fusion rate was not affected by cage dimension (p > 0.999) or by incidence of subsidence (p = 0.383). CONCLUSIONS: Wider cages avoid subsidence and better restore segmental lordosis in stand-alone lateral interbody fusion. Cage subsidence is identified early in follow-up and can be accessed using the proposed classification scale. PMID- 23662891 TI - Outcome of endoscopic therapy for cancer bleeding in patients with unresectable gastric cancer. AB - BACKGROUND AND AIM: Gastric cancer bleeding is not rare complication in patients with advanced gastric cancer (AGC). The aim of this study was to evaluate the efficacy and clinical outcomes of endoscopic therapy (ET) for upper gastrointestinal bleeding (UGIB) from unresectable AGC. METHODS: Data from 113 patients with UGIB from unresectable AGC who underwent ET at the National Cancer Center, Korea were analyzed retrospectively. Success rates of endoscopic hemostasis, rebleeding rates, mortality at 30 days, and overall survival (OS) rate after initial hemostasis were investigated. RESULTS: The initial hemostasis rate was 92.9% (105/113). Electrocoagulation was the most common method used (92.0%, 104/113), and combination ET was required in 34 patients (30.1%). Rebleeding occurred in 43 patients (41.0%); 3-day and 30-day rebleeding rates were 18.1% and 29.5%, respectively. Multivariate logistic regression analysis showed that transfusion of packed red blood cells (> 5 units) was associated with early rebleeding (<= 3 days after initial hemostasis) (odd ratio, 4.75; 95% confidential interval, 1.45-15.57; P = 0.010). ET was attempted in 18 patients with rebleeding; hemostasis was achieved in 88.9%. The 30-day mortality rate after initial bleeding event was 15.9%. Median OS after initial hemostasis was 3.2 months. OS was lower for patients with early rebleeding than for those with late rebleeding (> 3 days after initial hemostasis) or without rebleeding (1.0, 3.1, and 4.3 months, respectively; P = 0.004). CONCLUSIONS: ET, primarily endoscopic electrocoagulation, achieved a high initial hemostasis rate for UGIB in patients with unresectable AGC. However, rebleeding frequently occurred, and early rebleeding was associated with poor survival. PMID- 23662892 TI - Characterisation of palatal dysfunction after laryngoplasty. AB - REASONS FOR PERFORMING STUDY: Dorsal displacement of the soft palate (DDSP) in the horse has been previously described as intermittent, typically occurring at fast exercise; or persistent, seen at rest. Dorsal displacement of the soft palate has recently been reported following laryngoplasty (LP) and can be associated with continued poor performance and respiratory noise. OBJECTIVES: The current study aimed to characterise the DDSP diagnosed post LP. STUDY DESIGN: Cross-sectional study. METHODS: Owners/trainers of horses undergoing LP at one institution over 6 years were contacted to determine the horse's progress and willingness for re-examination. The horses were examined at the rest, walk, trot and canter with an overground exercising endoscope. A GPS-equipped watch was carried to obtain maximal exercising speeds. Videos of horses with DDSP were reviewed to determine frequency and duration of DDSP and swallowing events at the various gaits. RESULTS: Exercising endoscopy was performed in 41 of the 89 horses that had undergone LP. Nineteen of the 41 horses were diagnosed with DDSP at exercise, of which 7/41 also had DDSP at rest. No difference was detected in the percentage of total time spent displaced at each gait (P = 0.67), or in the frequency of new DDSP events per minute between each gait (P = 0.10), or in the frequency of swallowing events per minute between each gait (P = 0.52). The majority of horses displaced at various times throughout each gait. Dorsal displacement of the soft palate was most commonly solely induced spontaneously and always corrected with a swallow. The maximum speed achieved was 8.3 m/s. CONCLUSIONS: Dorsal displacement of the soft palate was common following LP and it appears to be induced at slower gaits than DDSP that has previously been described. It also occurred at various times throughout each gait and did not always occur persistently at rest. POTENTIAL RELEVANCE: These findings suggest horses undergoing LP may be more prone to DDSP and further investigations into the aetiology of post LP palatal dysfunction are warranted. PMID- 23662893 TI - Assessment of coronary flow with transthoracic color Doppler echocardiography in patients with hypertrophic cardiomyopathy. AB - BACKGROUND: Recent advances in echocardiography have allowed assessment of flow velocity in the epicardial coronary arteries of patients with ischemic heart disease, using transthoracic color Doppler echocardiography (TTDE). However, few data are available regarding coronary blood flow in patients with hypertrophic cardiomyopathy (HCM). OBJECTIVE: To assess the epicardial coronary arteries of patients with HCM. MATERIAL AND METHODS: A group of 25 patients with HCM was assessed prospectively (mean age 57 +/- 21 years, 11 male) using TTDE; flow velocities in the epicardial coronary arteries were measured and compared with those obtained in 10 age- and gender-matched controls. Analysis of the diastolic spectral waveform included flow velocity integral (VTI), peak velocity, deceleration time, and deceleration slope measurements, while systolic waveform analysis included peak flow measurement and morphology assessment (positive, absent or negative). An analysis of variance (ANOVA) test was used for multiple comparisons for variables with a normal distribution, and a Kruskal-Wallis test was used for variables with non-Gaussian distribution. RESULTS: Patients with HCM exhibited an increase in diastolic flow velocity with a rapid deceleration slope and a systolic slope which was decreased, absent or reversed, compared to normal subjects. On linear regression analysis there was no correlation with the type of hypertrophy or magnitude of the intraventricular pressure gradient in patients with obstructive HCM. CONCLUSION: In patients with HCM, noninvasive assessment with TTDE revealed abnormal findings in the distal flow of the epicardial coronary arteries, very similar to those seen in the no-reflow phenomenon. These findings were independent of the type of hypertrophy and magnitude of the intraventricular pressure gradient in patients with obstructive HCM. PMID- 23662894 TI - The chemist in the kitchen. PMID- 23662895 TI - MetaboQuant: a tool combining individual peak calibration and outlier detection for accurate metabolite quantification in 1D (1)H and (1)H-(13)C HSQC NMR spectra. AB - Solution nuclear magnetic resonance (NMR) spectroscopy is widely used to analyze complex mixtures of organic compounds such as biological fluids and tissue extracts. Targeted profiling approaches with reliable compound quantitifcation are hampered, however, by signal overlap and other interferences. Here, we present a tool named MetaboQuant for automated compound quantification from pre processed 1D and 2D heteronuclear single quantum coherence (HSQC) NMR spectral data and concomitant validation of results. Performance of MetaboQuant was tested on a urinary spike-in data set and compared with other quantification strategies. The use of individual calibration factors in combination with the validation algorithms of MetaboQuant raises the reliability of the quantification results. MetaboQuant can be downloaded at http://genomics.uni regensburg.de/site/institute/software/metaboquant/ as stand-alone software for Windows or run on other operating systems from within Matlab. Separate software for peak fitting and integration is necessary in order to use MetaboQuant. PMID- 23662897 TI - Lane-by-lane sequencing using Illumina's Genome Analyzer II. AB - Next-generation sequencing has become an essential tool in molecular biology that has been successfully applied to a broad variety of experimental approaches. While several platforms for next-generation sequencing exist, the most commonly used approach is sequencing-by-synthesis, implemented on Illumina's Genome Analyzer II (GAII) and HiSeq2000 systems. A key constraint of these sequencers is the need to run multiple lanes of samples with identical parameters as part of a single flowcell. Here, we present a series of modifications to the Illumina Genome Analyzer II, along with a script generating tool, that allow users to run the GAII in a lane-by-lane manner. Any number of lanes can be run at one time. Repeated use of the same flowcell on multiple sequencing runs does not appreciably reduce the intensity, cluster density, or accuracy of the run. These modifications will enable smaller-scale experiments with unusual design parameters to be run routinely on the GAII. PMID- 23662896 TI - Quantifying antibody binding on protein microarrays using microarray nonlinear calibration. AB - We present a microarray nonlinear calibration (MiNC) method for quantifying antibody binding to the surface of protein microarrays that significantly increases the linear dynamic range and reduces assay variation compared with traditional approaches. A serological analysis of guinea pig Mycobacterium tuberculosis models showed that a larger number of putative antigen targets were identified with MiNC, which is consistent with the improved assay performance of protein microarrays. MiNC has the potential to be employed in biomedical research using multiplex antibody assays that need quantitation, including the discovery of antibody biomarkers, clinical diagnostics with multi-antibody signatures, and construction of immune mathematical models. PMID- 23662898 TI - Pairwise agonist scanning-flow cytometry (PAS-FC) measures inside-out signaling and patient-specific response to combinatorial platelet agonists. AB - Understanding the response of cells to multiple stimuli is vital for predicting donor specific responses and better understanding the signaling pathways involved. This is of particular importance in platelets because exposure of phosphatidylserine (PS) occurs upon costimulation but not with a single agonist. Here, we describe a multiplexed pairwise agonist scanning-flow cytometry (PAS-FC) method of measuring platelet inside-out responses to all pairs of six platelet agonists (convulxin, SFLLRN, AYPGKF, ADP, U46619, and PGE(2)) used at their EC(50) concentrations. These agonists allowed exploration of platelet signaling downstream of GPVI, PAR-1, PAR-4, P2Y(1), P2Y(12), TP, and IP receptors. The three-color flow cytometry method simultaneously measured integrin alpha(IIb)beta(3) activation with PAC-1 antibody, P-selectin exposure (via alpha granule release) with anti-P-selectin, and PS exposure with annexin V. These responses were consistent across a healthy male donor pool. In duplicate measurements with each donor, 4 of the 10 donors had a sufficiently unique 45 parameter (15 pairs * 3 colors) phenotype to self-cluster (P < 0.001). This method has the potential for efficiently scanning for patient specific responses across a broad agonist-receptor space. PMID- 23662899 TI - A convenient and efficient purification method for chemically labeled oligonucleotides. AB - We developed an efficient, cost-effective, and rapid purification method for chemically-labeled oligonucleotides that requires less time than conventional procedures such as ethanol precipitation or size-exclusion chromatography. Based on the hydrophilic and hydrophobic properties of DNA and amine-reactive fluorophores, we show that n-butanol saturated with distilled water may be used to remove unreacted fluorophores by sequestering them in the organic phase, while labeled DNA remains in the aqueous phase. This phase extraction method is simple, fast, and allows for processing multiple samples simultaneously, a necessity for high-throughput labeling strategies. PMID- 23662900 TI - Evaluation and validation of the core lower urinary tract symptom score as an outcome assessment tool for the treatment of benign prostatic hyperplasia: effects of the alpha1-adrenoreceptor antagonist silodosin. AB - We investigated the Core Lower Urinary Tract Symptom Score as an outcome assessment tool for the treatment of lower urinary tract symptoms using silodosin. In addition, the ability of the Core Lower Urinary Tract Symptom Score to detect overactive bladder in male patients with lower urinary tract symptoms was examined. The present study included 241 males with benign prostatic hyperplasia treated at 31 medical facilities between June 2009 and December 2010. All patients were given silodosin, and the effects of silodosin intake were measured using four questionnaires: the Core Lower Urinary Tract Symptom Score, International Prostate Symptom Score, Overactive Bladder Symptom Score and Quality-of-Life index. The efficacy of silodosin for treating lower urinary tract symptoms was validated according to the total scores of all four questionnaires weighted equally (P < 0.05). Spearman's rho among the Core Lower Urinary Tract Symptom Score, International Prostate Symptom Score and Overactive Bladder Symptom Score showed a mild-high correlation. However, the correlation between the baseline values of the Core Lower Urinary Tract Symptom Score and Quality-of Life index was low in the groups with benign prostatic hyperplasia (rho = 0.314) and benign prostatic hyperplasia/overactive bladder (rho = 0.244). Our findings showed the Core Lower Urinary Tract Symptom Score, both its total score and each subscore, is able to show the efficacy of silodosin, similar to other questionnaires. The Core Lower Urinary Tract Symptom Score is also useful for identifying overactive bladder symptoms in patients with benign prostatic hyperplasia. As the Core Lower Urinary Tract Symptom Score does not correlate well with the Quality-of-Life index, these two questionnaires might be better used in combination to assess treatment outcomes. PMID- 23662901 TI - Carbonate-mediated Fe(II) oxidation in the air-cathode fuel cell: a kinetic model in terms of Fe(II) speciation. AB - Due to the high redox activity of Fe(II) and its abundance in natural waters, the electro-oxidation of Fe(II) can be found in many air-cathode fuel cell systems, such as acid mine drainage fuel cells and sediment microbial fuel cells. To deeply understand these iron-related systems, it is essential to elucidate the kinetics and mechanisms involved in the electro-oxidation of Fe(II). This work aims to develop a kinetic model that adequately describes the electro-oxidation process of Fe(II) in air-cathode fuel cells. The speciation of Fe(II) is incorporated into the model, and contributions of individual Fe(II) species to the overall Fe(II) oxidation rate are quantitatively evaluated. The results show that the kinetic model can accurately predict the electro-oxidation rate of Fe(II) in air-cathode fuel cells. FeCO3, Fe(OH)2, and Fe(CO3)2(2-) are the most important species determining the electro-oxidation kinetics of Fe(II). The Fe(II) oxidation rate is primarily controlled by the oxidation of FeCO3 species at low pH, whereas at high pH Fe(OH)2 and Fe(CO3)2(2-) are the dominant species. Solution pH, carbonate concentration, and solution salinity are able to influence the electro-oxidation kinetics of Fe(II) through changing both distribution and kinetic activity of Fe(II) species. PMID- 23662902 TI - A redox economical synthesis of bioactive 6,12-guaianolides. AB - Syntheses of two 6,12-guaianolide analogs are reported within. The scope of the tandem allylboration/lactonization chemistry is expanded to provide a functionalized allene-yne-containing alpha-methylene butyrolactone that undergoes a Rh(I)-catalyzed cyclocarbonylation reaction to afford a 5-7-5 ring system. The resulting cycloadducts bear a structural resemblance to other NF-kappaB inhibitors such as cumambrin A and indeed were shown to inhibit NF-kappaB signaling and cancer cell growth. PMID- 23662903 TI - Discovery of 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6 dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2 methylpropanamide (GDC-0032): a beta-sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity. AB - Dysfunctional signaling through the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway leads to uncontrolled tumor proliferation. In the course of the discovery of novel benzoxepin PI3K inhibitors, we observed a strong dependency of in vivo antitumor activity on the free-drug exposure. By lowering the intrinsic clearance, we derived a set of imidazobenzoxazepin compounds that showed improved unbound drug exposure and effectively suppressed growth of tumors in a mouse xenograft model at low drug dose levels. One of these compounds, GDC-0032 (11l), was progressed to clinical trials and is currently under phase I evaluation as a potential treatment for human malignancies. PMID- 23662904 TI - Dynamic social behaviour in a bacterium: pseudomonas aeruginosa partially compensates for siderophore loss to cheats. AB - Cooperation underlies diverse phenomena including the origins of multicellular life, human behaviour in economic markets and the mechanisms by which pathogenic bacteria cause disease. Experiments with microorganisms have advanced our understanding of how, when and why cooperation evolves, but the extent to which microbial cooperation can recapitulate aspects of animal behaviour is debated. For instance, understanding the evolution of behavioural response rules (how should one individual respond to another's decision to cooperate or defect?) is a key part of social evolution theory, but the possible existence of such rules in social microbes has not been explored. In one specific context (biparental care in animals), cooperation is maintained if individuals respond to a partner's defection by increasing their own investment into cooperation, but not so much that this fully compensates for the defector's lack of investment. This is termed 'partial compensation'. Here, I show that partial compensation for the presence of noncooperating 'cheats' is also observed in a microbial social behaviour: the cooperative production of iron-scavenging siderophores by the bacterium Pseudomonas aeruginosa. A period of evolution in the presence of cheats maintains this response, whereas evolution in the absence of cheats leads to a loss of compensatory behaviour. These results demonstrate (i) the remarkable flexibility of bacterial social behaviour, (ii) the potential generality of partial compensation as a social response rule and (iii) the need for mathematical models to explore the evolution of response rules in multi-player social interactions. PMID- 23662905 TI - Discovering vanished paints and naturally formed gold nanoparticles on 2800 years old phoenician ivories using SR-FF-microXRF with the color X-ray camera. AB - Phoenician ivory objects (8(th) century B.C., Syria) from the collections of the Badisches Landesmuseum, Karlsruhe, Germany, have been studied with full field X ray fluorescence microimaging, using synchrotron radiation (SR-FF-microXRF). The innovative Color X-ray Camera (CXC), a full-field detection device (SLcam), was used at the X-ray fluorescence beamline of the ANKA synchrotron facility (ANKA FLUO, KIT, Karlsruhe, Germany) to noninvasively study trace metal distributions at the surface of the archeological ivory objects. The outstanding strength of the imaging technique with the CXC is the capability to record the full XRF spectrum with a spatial resolution of 48 MUm on a zone of a size of 11.9 * 12.3 mm(2) (264 * 264 pixels). For each analyzed region, 69696 spectra were simultaneously recorded. The principal elements detected are P, Ca, and Sr, coming from the ivory material itself; Cu, characteristic of pigments; Fe and Pb, representing sediments or pigments; Mn, revealing deposited soil minerals; Ti, indicating restoration processes or correlated with Fe sediment traces; and Au, linked to a former gilding. This provides essential information for the assessment of the original appearance of the ivory carvings. The determined elemental maps specific of possible pigments are superimposed on one another to visualize their respective distributions and reconstruct the original polychromy and gilding. Reliable hypotheses for the reconstruction of the original polychromy of the carved ivories are postulated on this basis. PMID- 23662906 TI - Sleep disorders in children with traumatic brain injury: a case of serious neglect. AB - AIM: The aim of this study was to review the basic aspects of sleep disturbance in children with traumatic brain injury (TBI). METHOD: A search was performed on reports of sleep disturbances in children who had suffered TBI. Adults with TBI were also considered to anticipate the nature and significance of such disturbances in younger patients. Types of reported sleep disturbance were noted and their possible aetiology and management considered. RESULTS: Sleep disturbance has consistently been associated with TBI but the literature suggests that this aspect of patient care is often inadequately considered and there has been little research on the subject, especially in relation to children. Excessive daytime sleepiness is often mentioned, less so insomnia and parasomnias, but there is little information about the specific sleep disorders underlying these problems. INTERPRETATION: Sleep disorders with potentially important developmental consequences have been neglected in the care of children with TBI. Screening for sleep problems should be routine and followed, if indicated, by a detailed diagnosis of the child's underlying specific sleep disorder, the possible aetiology of which includes neuropathology and potential medical, psychological, or psychiatric comorbidities. Appropriate assessments and modern treatment options are now well defined although generally underutilized. Further well-designed research is needed for which guidelines are available. PMID- 23662907 TI - Attachment patterns in medically serious suicide attempts: the mediating role of self-disclosure and loneliness. AB - Although the study of medically serious suicide behavior is an important strategy for understanding the nature of suicide, little is known about its underlying psychological mechanisms. This gap is addressed here by applying insights from attachment theory to severe suicidal behavior. The results show that both anxious and avoidant attachment patterns predict medical lethality. Path analysis indicated that interpersonal difficulties mediated the paths between insecure attachment patterns and lethality of suicide attempts. These results suggest that the psychological mechanisms of medically serious suicide behavior involve high levels of mental pain amplified by insecure attachment patterns and interpersonal difficulties. Implications for prevention and therapeutic intervention strategies are discussed. PMID- 23662908 TI - The novel CTSC homozygous nonsense mutation p.Lys106X in a patient with Papillon Lefevre syndrome with all permanent teeth remaining at over 40 years of age. PMID- 23662909 TI - Influence of socio-demographic characteristics on eye care expenditure: data from the Medical Expenditure Panel Survey 2007. AB - OBJECTIVE: To evaluate the association between sociodemographic factors and eye care expenditure and to assess the burden of ocular expenditure compared to total health care expenditure. METHODS: A retrospective analysis of ocular expenditure in participants of the 2007 Medical Expenditure Panel Survey. Data from 20,620 unique participants aged >=18 years were evaluated for eye care expenditure by demographic characteristics. RESULTS: A total of 22% of the studied population had eye care expenditures in 2007. Demographic factors significantly associated with higher probability of having eye care expenditures included older age (65+ years 35%, 45-64 years 23%, <45 years 17%), female sex (female 26%, male 19%), higher educational attainment (greater than high school education 25%, less than high school education 17%), having insurance (private 24%, uninsured 13%), and visual impairment (mild 31%, none 22%). Older age, female sex, higher educational attainment, having insurance, and presence of visual impairment were also significantly associated with higher mean eye care expenditure. In those with eye care expenditure, the mean ratio between eye care and total medical expenditure was 24%, with uninsured patients spending 42% of their medical care expenditure on eye care. CONCLUSIONS: Demographic factors are associated with both the probability of having ocular expenditure and the amount of expenditure. Of all factors examined, insurance status has the most potential for modification. Policy makers should consider these numbers when devising the terms by which eye care coverage will be provided under the Patient Protection and Affordable Care Act. PMID- 23662911 TI - Heterogeneous oxidation of terbuthylazine by "dark" OH radicals under simulated atmospheric conditions in a flow tube. AB - In order to investigate the heterogeneous oxidation kinetics of the herbicide terbuthylazine (TERB), a stable and reproducible generation system of "dark" hydroxyl radical in the gas phase was developed and optimized using a PTR-MS. TERB was adsorbed on silica particles, which were coated on the walls of a flow tube. The hydroxyl radical was produced in the dark through the ozonolysis of 2,3 dimethyl-2-butene (DMB). The radical concentration was determined applying two different methods of calculation based on the monitoring of (i) a gaseous compound used as a tracer, m-xylene; (ii) one of the OH radical precursors, DMB. The obtained gaseous OH radical concentration in the reactor was (9.0 +/- 4.0) * 10(7) radical cm(-3). Exposing TERB to the oxidant for 1-14 h, a heterogeneous kinetic constant of kOH = (1.5 +/- 0.8) * 10(-13) cm(3) molecule(-1) s(-1) was found at 26 degrees C and RH < 1%. As a result, the heterogeneous oxidation of TERB by OH radicals seems to be much slower (by a factor of 63) when the organic compound is present in the particulate phase than when it reacts in homogeneous gas phase. PMID- 23662912 TI - High-field MRS in clinical drug development. AB - INTRODUCTION: Magnetic resonance spectroscopy (MRS) will continue to play an ever increasing role in drug discovery because MRS does readily define biomarkers for several hundreds of clinically distinct diseases. Published evidence based medicine (EBM) surveys, which generally conclude the opposite, are seriously flawed and do a disservice to the field of drug discovery. AREAS COVERED: This article presents MRS and how it has guided several hundreds of practical human 'drug discovery' endeavors since its development. Specifically, the author looks at the process of 'reverse-translation' and its influence in the expansion of the number of preclinical drug discoveries from in vivo MRS. The author also provides a structured approach of eight criteria, including EBM acceptance, which could potentially re-open the field of MRS for productive exploration of existing and repurposed drugs and cost-effective drug-discovery. EXPERT OPINION: MRS-guided drug discovery is poised for future expansion. The cost of clinical trials has escalated and the use of biomarkers has become increasingly useful in improving patient selection for drug trials. Clinical MRS has uncovered a treasure-trove of novel biomarkers and clinical MRS itself has become better standardized and more widely available on 'routine' clinical MRI scanners. When combined with available new MRI sequences, MRS can provide a 'one stop shop' with multiple potential outcome measures for the disease and the drug in question. PMID- 23662913 TI - Developing long-acting growth hormone formulations. AB - Daily recombinant growth hormone (GH) restores normal growth and body composition in GH-deficient children and adults; however, daily injections are inconvenient and can be distressing for some children. On top of this compliance is a problem in up to 75% of children. Developing long-acting GH formulations has proved challenging, and questions remain regarding safety and efficacy. In this review, we focus on the rationale for generating long-acting GH agonists and the technologies being developed to deliver prolonged exposure to GH. PMID- 23662914 TI - Experience-dependent effects of context and restraint stress on corticolimbic c Fos expression. AB - Stressors are typically multidimensional, comprised of multiple physical and sensory components that rarely occur as single isolated events. This study used a 2-day stress exposure paradigm to assess functional activation patterns (by Fos expression) in key corticolimbic structures following repeated context, repeated restraint, context followed by restraint or restraint followed by context. On day 1, rats were transported to a novel context and either restrained for 6 h or left undisturbed. On day 2, these two groups were either restrained or not in the same context, then processed for Fos immunohistochemistry. Regardless of prior stress experience, rats exposed to context only on day 2 expressed more Fos-like immunoreactive (IR) labeling in CA1 and CA3 of dorsal hippocampus, basolateral amygdala and central amygdala than those that were not. This pattern was reversed in the dentate gyrus infrapyramidal blade. In contrast, in the infralimbic region of the medial prefrontal cortex (mPFC), the experience of a single restraint on either day 1 or day 2 rats elevated Fos-like IR relative to rats that had been exposed to context alone. These data show that exposure to context produces robust Fos induction in the hippocampus and amygdala, regardless of prior experience with restraint and compared to the immediate experience of restraint, with prior experience modulating Fos expression within the mPFC. PMID- 23662915 TI - Rebamipide suppresses PolyI:C-stimulated cytokine production in human conjunctival epithelial cells. AB - PURPOSE: We previously documented that ocular surface epithelial cells could regulate ocular surface inflammation and suggested that, while Toll-like receptor 3 upregulates, EP3, one of the prostaglandin E2 receptors, downregulates ocular surface inflammation. Others reported that rebamipide, a gastroprotective drug, could not only increase the gastric mucus production, but also suppressed gastric mucosal inflammation and that it was dominantly distributed in mucosal tissues. The eyedrop form of rebamipide, approved in Japan for use in the treatment of dry eye diseases, upregulates mucin secretion and production, thereby suppressing superficial punctate keratopathy on the ocular surface of patients with this disease. In the current study, we investigated whether rebamipide has anti- inflammatory effects on the ocular surface. METHODS: To examine the effects of rebamipide on polyI:C-induced cytokine expression by primary human conjunctival epithelial cells, we used enzyme-linked immunosorbent assay and quantitative reverse transcription-polymerase chain reaction assay. We studied the effects of rebamipide on ocular surface inflammation in our murine experimental allergic conjunctivitis (EAC) model. RESULTS: Rebamipide could suppress polyI:C-induced cytokine production and the expression of mRNAs for CXCL10, CXCL11, RANTES, MCP 1, and IL-6 in human conjunctival epithelial cells. In our EAC model, the topical administration of rebamipide suppressed conjunctival allergic eosinophil infiltration. CONCLUSIONS: The topical application of rebamipide on the ocular surface might suppress ocular surface inflammation by suppressing the production of cytokines by ocular surface epithelial cells. PMID- 23662916 TI - Matching structural, effective, and functional connectivity: a comparison between structural equation modeling and ancestral graphs. AB - In this study, we examined the accuracy of ancestral graphs (AGs) to study effective connectivity in the brain. Unlike most other methods that estimate effective connectivity, an AG is able to explicitly model missing brain regions in a network model. We compared AGs with the conventional structural equation models (SEM). We used both methods to estimate connection strengths between six regions of interest of the visual cortex based on functional magnetic resonance imaging data of a motion perception task. In order to examine which method is more accurate to estimate effective connectivity, we compared the connection strengths of the AG and SEM models with connection probabilities resulting from probabilistic tractography obtained from diffusion tensor images. This was done by correlating the connection strengths of the best fitting AG and SEM models with the connection probabilities of the probabilistic tractography models. We show that, in general, AGs result in more accurate models to estimate effective connectivity than SEM. The reason for this is that missing regions are taken into account when modeling with AG but not when modeling with SEM: AG can be used to explicitly test the assumption of missing regions. If the set of regions is complete, SEM and AG perform about equally well. PMID- 23662918 TI - Intramodality and intermodality agreement in radiography and computed tomography of equine distal limb fractures. AB - REASONS FOR PERFORMING STUDY: Computed tomography (CT) is increasingly accessible in equine referral hospitals. OBJECTIVES: To document the level of agreement within and between radiography and CT in characterising equine distal limb fractures. STUDY DESIGN: Retrospective descriptive study. METHODS: Images from horses that underwent radiographic and CT evaluation for suspected distal limb fractures were reviewed, including 27 horses and 3 negative controls. Using Cohen's kappa and weighted kappa analysis, the level of agreement among 4 observers for a predefined set of diagnostic characteristics for radiography and CT separately and for the level of agreement between the 2 imaging modalities were documented. RESULTS AND CONCLUSIONS: Both CT and radiography had very good intramodality agreement in identifying fractures, but intermodality agreement was lower. There was good intermodality and intramodality agreement for anatomical localisation and the identification of fracture displacement. Agreement for articular involvement, fracture comminution and fracture fragment number was towards the lower limit of good agreement. There was poor to fair intermodality agreement regarding fracture orientation, fracture width and coalescing cracks; intramodality agreement was higher for CT than for radiography for these features. POTENTIAL RELEVANCE: Further studies, including comparisons with surgical and/or post mortem findings, are required to determine the sensitivity and specificity of CT and radiography in the diagnosis and characterisation of equine distal limb fractures. PMID- 23662917 TI - Differentiation of human dental stem cells reveals a role for microRNA-218. AB - BACKGROUND: Regeneration of lost periodontium is the ultimate goal of periodontal therapy. Advances in tissue engineering have demonstrated the multilineage potential and plasticity of adult stem cells located in periodontal apparatus. However, it remains unclear how epigenetic mechanisms controlling signals determine tissue specification and cell lineage decisions. To date, no data are available on micro-RNA (miRNA) activity behind human-derived dental stem cells (DSCs). MATERIAL AND METHODS: In this study, we isolated periodontal ligament stem cells, dental pulp stem cells and gingival stem cells from extracted third molars; human bone marrow stem cells were used as a positive control. The expression of OCT4A and NANOG was confirmed in these undifferentiated cells. All cells were cultured under osteogenic inductive conditions and RUNX2 expression was analyzed as a marker of mineralized tissue differentiation. The miRNA expression profile was obtained at baseline and after osteogenic induction in all cell types. RESULTS: The expression of RUNX2 demonstrated successful osteogenic induction of all cell types, which was confirmed by alizarin red stain. The analysis of 765 miRNAs demonstrated a shift in miRNA expression that occurred in all four stem cell types, including a decrease in hsa-mir-218 across all differentiated cell populations. Hsa-mir-218 targets RUNX2 and decreases RUNX2 expression in undifferentiated human DSCs. DSC mineralized tissue type differentiation is associated with a decrease in hsa-mir-218 expression. CONCLUSION: These data reveal a miRNA-regulated pathway for the differentiation of human DSCs and a select network of human miRNAs that control DSC osteogenic differentiation. PMID- 23662919 TI - Cardiac device-related invasive aspergilloma assessed by live/real time three dimensional transthoracic echocardiography. AB - Cardiac device-related infection caused by Aspergillus species is a rare finding associated with high mortality. Prompt recognition and treatment is imperative, but difficult as blood cultures are often negative and diagnosis requires a high index of suspicion. Live/real time three-dimensional transthoracic echocardiography (3DTTE) provides incremental knowledge in the characterization of valvular vegetations. Here, we provide a detailed description of an invasive cardiac device-related infection caused by Aspergillus fumigatus using 3DTTE. Findings described here highlight the role for 3DTTE in the prompt diagnosis of invasive cardiac Aspergillus infections as well as surgical planning in such cases. PMID- 23662920 TI - Ultrasonographic characteristics of the cisterna chyli in eight dogs and four cats. AB - Ultrasonography of the cisterna chyli has been used in humans to diagnose increased lymphatic flow or lymph flow obstruction and to guide percutaneous embolization of the thoracic duct via the cisterna chyli. The aim of this study was to describe the ultrasonographic characteristics of the dorsal portion of cisterna chyli in dogs and cats with chylous ascites or chylothorax and in a group of healthy dogs and cats. The aorta and the cranial mesenteric artery were used as anatomic landmarks. Ultrasonography was performed before and 2 h after a fatty meal in healthy dogs and cats. The visualized structure was confirmed to be a dilated cisterna chyli at necropsy in a dog with chylous ascites. The confirmed or presumed cisterna chyli was consistently detected using ultrasonography in nonfasted healthy animals and clinically affected animals and appeared as an anechoic tubular structure, without detectable flow, at the right dorsolateral aspect of the aorta. It had a similar ultrasonographic appearance in patients with chyloabdomen and in nonfasted healthy dogs and cats. There was considerable overlap in diameters of the cisterna chyli for affected and healthy animals. The shape and size of the cisterna chyli in an individual animal were variable during the same ultrasound examination and between different examinations. This study demonstrated the appearance of the presumed dorsal portion of the cisterna chyli by ultrasonography and might provide useful preliminary data for further studies into the feasibility of ultrasound-guided injections or aspirations of the cisterna chyli in dogs and cats. PMID- 23662921 TI - Comparative pathogenicity study of ten different betanodavirus strains in experimentally infected European sea bass, Dicentrarchus labrax (L.). AB - Viral encephalopathy and retinopathy (VER), otherwise known as viral nervous necrosis (VNN), is a severe pathological condition caused by RNA viruses belonging to the Nodaviridae family, genus Betanodavirus. The disease, described in more than 50 fish species worldwide, is considered as the most serious viral threat affecting marine farmed species in the Mediterranean region, thus representing one of the bottlenecks for further development of the aquaculture industry. To date, four different genotypes have been identified, namely red spotted grouper nervous necrosis virus (RGNNV), striped jack nervous necrosis virus (SJNNV), tiger puffer nervous necrosis virus and barfin flounder nervous necrosis virus, with the RGNNV genotype appearing as the most widespread in the Mediterranean region, although SJNNV-type strains and reassortant viruses have also been reported. The existence of these genetically different strains could be the reason for the differences in mortality observed in the field. However, very little experimental data are available on the pathogenicity of these viruses in farmed fish. Therefore, in this study, the pathogenicity of 10 isolates has been assessed with an in vivo trial. The investigation was conducted using the European sea bass, the first target fish species for the disease in the Mediterranean basin. Naive fish were challenged by immersion and clinical signs and mortality were recorded for 68 days; furthermore, samples collected at selected time points were analysed to evaluate the development of the infection. Finally, survivors were weighed to estimate the growth reduction. The statistically supported results obtained in this study demonstrated different pathogenicity patterns, underlined the potential risk represented by different strains in the transmission of the infection to highly susceptible species and highlighted the indirect damage caused by a clinical outbreak of VER/VNN. PMID- 23662922 TI - A quantitative approach to histopathological dissection of elastin-related disorders using multiphoton microscopy. AB - BACKGROUND: Multiphoton microscopy (MPM) is a novel imaging technology that has recently become applicable for diagnostic purposes. The use of (near) infrared light in MPM allows for deep tissue imaging. In addition, this modality exploits the autofluorescent nature of extracellular matrix fibres within the skin. OBJECTIVES: To quantitate the structure and abundance of elastic fibres in human dermis in three dimensions utilizing autofluorescent signals generated by MPM for the objective examination of elastin-related skin disorders. METHODS: Cross sections of skin samples from elastin-related disorders were analysed by MPM and correlated to histopathology. In situ visualization of elastic fibres by MPM was conducted by en face imaging of ex vivo skin samples through the intact epidermis. Image analysis software was used to quantify elastic fibres in three dimensions. RESULTS: Based on the MPM-detected elastin-specific autofluorescence, we developed the Dermal Elastin Morphology Index (DEMI), calculated as the ratio of elastic fibre surface area and volume. This enabled objective three dimensional quantification of elastic fibres. Quantitative scoring of sun-damaged skin using DEMI correlated with qualitative histopathological grading of the severity of solar elastosis. Furthermore, this approach was applied to changes in elastic fibre architecture in other disorders, such as pseudoxanthoma elasticum (PXE), PXE-like syndrome, elastofibroma, focal dermal elastosis, anetoderma, mid dermal elastolysis and striae distensae. We imaged elastic fibres in intact ex vivo skin imaged en face through the epidermis, indicating that this approach could be used in vivo. CONCLUSIONS: MPM has the potential for noninvasive in vivo visualization of elastic fibres in the dermis with near histological resolution. DEMI allows objective assessment of elastic fibres to support diagnosis and monitoring of disease progress or therapy of elastin-related skin disorders. PMID- 23662923 TI - Natural selection. VII. History and interpretation of kin selection theory. AB - Kin selection theory is a kind of causal analysis. The initial form of kin selection ascribed cause to costs, benefits and genetic relatedness. The theory then slowly developed a deeper and more sophisticated approach to partitioning the causes of social evolution. Controversy followed because causal analysis inevitably attracts opposing views. It is always possible to separate total effects into different component causes. Alternative causal schemes emphasize different aspects of a problem, reflecting the distinct goals, interests and biases of different perspectives. For example, group selection is a particular causal scheme with certain advantages and significant limitations. Ultimately, to use kin selection theory to analyse natural patterns and to understand the history of debates over different approaches, one must follow the underlying history of causal analysis. This article describes the history of kin selection theory, with emphasis on how the causal perspective improved through the study of key patterns of natural history, such as dispersal and sex ratio, and through a unified approach to demographic and social processes. Independent historical developments in the multivariate analysis of quantitative traits merged with the causal analysis of social evolution by kin selection. PMID- 23662925 TI - Editorial comment to "Evaluation and validation of the core lower urinary tract symptom score as an outcome assessment tool for the treatment of benign prostatic hyperplasia: effects of the alpha1-adrenoreceptor antagonist silodosin". PMID- 23662924 TI - Evidence for the specific species of benzyltriethoxysilane derivatives with a high-coordination silicon atom. AB - Evidence for the specific species of benzyltriethoxysilane derivatives with a high-coordination silicon atom is presented. Nanosecond laser flash photolyses of benzyltriethoxysilane and triethoxysilyldiphenylmethane have been studied in polar and nonpolar solvents. For the transient absorption spectra of benzyltriethoxysilane and triethoxysilyldiphenylmethane in methanol, a characteristic band attributed to the benzyl radical or diphenylmethyl radical was observed at around 317 and 330 nm, with a second-order decay rate constant of 5.7 * 10(9) and 4.2 * 10(9) M(-1) s(-1), respectively. While in cyclohexane, an absorption band attributable to the specific species with a high-coordination silicon atom was observed at around 330 nm with a first-order decay rate constant of 5.7 * 10(4) and 1.2 * 10(4) s(-1) for benzyltriethoxysilane and triethoxysilyldiphenylmethane, respectively. A two-step laser-induced fluorescence study of triethoxysilyldiphenylmethane supports the assignment that the transient absorption bands observed at around 330 nm in methanol and in cyclohexane are ascribed to the diphenylmethyl radical and the specific species of triethoxysilyldiphenylmethane with a high-coordination silicon atom, respectively. The candidates for this specific species with a high-coordination silicon atom have been calculated by means of the TD-DFT method and SAC-CI method, and their molecular structures were discussed. PMID- 23662926 TI - Population structure of the mosquito Aedes aegypti (Stegomyia aegypti) in Pakistan. AB - Eleven microsatellite markers were used to determine the genetic population structure and spread of Aedes aegypti (Stegomyia aegypti) (Diptera: Culicidae) in Pakistan using mosquitoes collected from 13 different cities. There is a single genetic cluster of Ae. aegypti in Pakistan with a pattern of isolation by distance within the population. The low level of isolation by distance suggests the long-range passive dispersal of this mosquito, which may be facilitated by the tyre trade in Pakistan. A decrease in genetic diversity from south to north suggests a recent spread of this mosquito from Karachi. A strong negative correlation between genetic distance and the quality of road connections shows that populations in cities connected by better road networks are less differentiated, which suggests the human-aided passive dispersal of Ae. aegypti in Pakistan. Dispersal on a large spatial scale may facilitate the strategy of introducing transgenic Ae. aegypti or intracellular bacteria such as Wolbachia to control the spread of dengue disease in Pakistan, but it also emphasizes the need for simple measures to control container breeding sites. PMID- 23662927 TI - Simultaneous biosensing with quartz crystal microbalance with a dissipation coupled-gate semiconductor device. AB - In this study, we proposed and demonstrated a novel simultaneous analysis system of biosensing by combining a semiconductor-based field effect transistor (FET) with quartz crystal microbalance with a dissipation (QCM-D) monitoring system. Using the combined system, the changes of not only mass and viscoelasticity but also electrical charge for interaction of charged dextran molecules with substrate, recognition of glucose with low molecular weight, and programmed cell death, apoptosis, were simultaneously and quantitatively monitored in a label free and real-time manner. The combined system will give more detailed information of biomolecule/substrate interface for development of new biomaterial. PMID- 23662928 TI - Addition of thiopurines can recapture response in patients with Crohn's disease who have lost response to anti-tumor necrosis factor monotherapy. AB - BACKGROUND AND AIM: Anti-tumor necrosis factor (TNF) antibodies are effective in maintaining remission in Crohn's disease. However, a significant proportion of patients lose response to these agents with time. This study aimed to determine whether the introduction of a thiopurine in patients who have lost response to anti-TNF monotherapy results in regained response. METHODS: Five patients (four males; aged 22-38 years) with active Crohn's disease, who had an initial response to anti-TNF therapy but had lost response, were commenced on azathioprine or mercaptopurine at standard doses while continuing anti-TNF therapy. All had previously failed thiopurine therapy prior to starting anti-TNF treatment. RESULTS: All patients experienced improved clinical symptoms within 2-6 months, with benefit sustained over a mean follow-up of 19 months. Two patients with an elevated C-reactive protein at the time of thiopurine addition demonstrated a fall in C-reactive protein. Colonoscopy before and after thiopurine addition in four patients showed improvement in all, with mucosal healing achieved in two. No adverse effects of treatment were noted. CONCLUSIONS: Addition of a thiopurine in patients who have lost response to anti-TNF monotherapy is an effective strategy to recapture response even if the patient has previously failed thiopurine therapy. Thiopurines may reduce immunogenicity or act synergistically with anti TNF therapy. PMID- 23662929 TI - Intracerebral schwannomas: a rare disease with varying natural history. AB - Although intracerebral schwannomas are typically regarded as benign intracranial tumors, malignancy and recurrence have been reported among patients harboring such neoplasms. The available literature consists of case reports and small series that present variable characteristics distinguishing these unusual lesions. Little advancement has been made to further the understanding and management of these tumors. The authors present 3 cases from their institution that highlight the difference between typical benign intracerebral schwannomas and histopathological variants that may portend more aggressive behavior. Also provided is a review of the literature in the hope of gaining a better understanding of these rare tumors. PMID- 23662930 TI - Longitudinal quantitative analysis of the tuber-to-brain proportion in patients with tuberous sclerosis. AB - OBJECT: In patients with tuberous sclerosis complex (TSC), the tuber-to-brain proportion (TBP) is a marker of seizure severity and cognitive function. However, few studies have quantified the TBP. Furthermore, authors of these studies have measured the TBP at only a single time point, despite the fact that tuber cells were found to express proliferation markers, suggesting that they may be dynamic lesions. Authors of the present study used a semi-automated tuber segmentation program to determine whether the TBP changes over time. METHODS: Axial FLAIR MR images were retrospectively identified for patients with TSC who had undergone imaging at the authors' institution between February 1998 and June 2009. Using FireVoxel software, the TBP was measured for each patient at a minimum interval of 2 years. RESULTS: Twelve patients meeting the study inclusion criteria were identified. The mean TBP was 1.88% (range 0.38%-3.70%). Eight patients demonstrated minimal changes and 3 patients demonstrated small increases in TBP. The remaining patient exhibited a decrease of 1.00%, which correlated with a visible decrease in the size of 2 cerebellar lesions. CONCLUSIONS: Semi-automated brain segmentation is a valuable tool in the longitudinal study of tubers. A subset of patients with TSC, particularly those with cerebellar lesions, may exhibit changes in the TBP over time. PMID- 23662931 TI - Attempted bladder reinnervation and creation of a scratch reflex for bladder emptying through a somatic-to-autonomic intradural anastomosis. AB - An intradural somatic-to-autonomic anastomosis, or Xiao procedure, has been described to create a "skin-CNS-bladder" reflex that improves bladder and bowel function in patients with neurogenic bladder and bowel dysfunction. The authors present their experience with a 10-year-old boy with chronic neurogenic bladder and bowel dysfunction related to spinal cord injury who underwent the Xiao procedure. After undergoing a left L-5 ventral root to left S2-3 intradural anastomosis, the patient reported that his bladder and bowel dysfunction improved between 6 and 12 months. Two years after the procedure, however, he reported that there was no change in his bladder or bowel dysfunction as compared with his condition prior to the procedure. Frequent, systematic multidisciplinary evaluations produced conflicting data. Electrophysiological and histological evaluation of the previously performed anastomosis during surgical reexploration 3 years after the Xiao procedure revealed that the anastomosis was in anatomical continuity but neuroma formation had prevented reinnervation. Nerve action potentials were not demonstrable across the anastomosis, and stimulation of the nerve above and below the anastomosis created no bladder or perineal contractions. This is the first clinical report on the outcome of the Xiao procedure in a child with spinal cord injury outside of China. It is impossible to draw broad conclusions about the efficacy of the procedure based on a single patient with no demonstrable benefit. However, future studies should carefully interpret transient improvements in bladder function, urodynamic findings, and the patient's ability to void in response to scratching after the Xiao procedure. The authors' experience with the featured patient, in whom reinnervation could not be demonstrated, suggests that such changes could be related to factors other than the establishment of a skin-CNS-bladder reflex as a result of a somatic-to autonomic anastomosis. PMID- 23662932 TI - Complex dural arteriovenous fistula in Bannayan-Riley-Ruvalcaba syndrome. AB - In this paper the authors report the case of a complex dural arteriovenous fistula (dAVF) with high-risk features in a 14-year-old girl with Bannayan-Riley Ruvalcaba syndrome (BRRS), a phosphatase and tensin homolog-associated syndrome, presenting with signs and symptoms of increased intracranial pressure (ICP) that had previously been attributed to pseudotumor cerebri. This fistula was obliterated following 2 stages of embolization, and the patient experienced immediate symptomatic improvement. At the 2-month follow-up evaluation, the fistula remained angiographically occluded, and her symptoms continue to improve. This is the third reported case of an intracranial dAVF in a patient with BRRS. Because high-risk dAVFs can result in devastating morbidity, early detection with vascular imaging is crucial for patients with BRRS presenting with signs of increased ICP. Goals of treatment should include complete fistula obliteration whenever possible. PMID- 23662933 TI - Nonoperative management of solitary eosinophilic granulomas of the calvaria. AB - OBJECT: Solitary eosinophilic granuloma (EG) of the calvaria is most commonly treated with surgical excision. The authors hypothesize that many solitary EGs will resolve without intervention, and observation may be a reasonable option. This study was undertaken to investigate that hypothesis. METHODS: The authors reviewed their institutional records and identified 14 cases of solitary calvarial EG. In 6 cases the patients underwent resection based on family and/or neurosurgeon preferences. A strategy of nonoperative management (purposeful observation) was chosen for the other 8 cases. The authors report the clinical course and imaging results in these 8 cases. RESULTS: One of the 8 patients underwent surgery 2 months after presentation because of slight enlargement of the lesion and increasing pain. After a median follow-up period of 1 year (range 6-19 months), none of the other patients had required surgery. Five of these 7 patients had pain at presentation. Pain resolved completely in all 5. The remaining 2 remained asymptomatic. Complete resolution of pain was reported in the 5 patients who had pain at presentation. There was complete clinical resolution of the palpable soft-tissue lesion in all 7 cases. Complete radiographic resolution of the lesion was observed in 5 cases and near-complete resolution in the remaining 2. CONCLUSIONS: Observation is a safe and reasonable approach in the management of solitary calvarial EG and may prevent unnecessary surgical interventions. PMID- 23662934 TI - Pancraniosynostosis following endoscope-assisted strip craniectomy and helmet orthosis for sagittal suture craniosynostosis in a nonsyndromic patient. AB - A variety of surgical strategies are used to correct sagittal craniosynostosis. There is increasing experience with the use of endoscope-assisted techniques, although there is no consensus regarding the optimal technique. Pancraniosynostosis occurring after the surgical repair of single-suture craniosynostosis is an unusual complication. The authors describe the case of a nonsyndromic patient who underwent an endoscope-assisted strip craniectomy with the subsequent use of a helmet orthosis for correction of an isolated sagittal suture craniosynostosis. The patient's early postoperative course was uneventful. Pancraniosynostosis subsequently developed, requiring much more extensive surgical correction. Awareness of this potential complication is necessary to ensure its recognition and appropriate management. PMID- 23662935 TI - Arachnoid cyst slit valves: the mechanism for arachnoid cyst enlargement. AB - Arachnoid cysts are common, accounting for approximately 1% of intracranial mass lesions. Most are congenital, clinically silent, and remain static in size. Occasionally, they increase in size and produce symptoms due to mass effect or obstruction. The mechanism of enlargement of arachnoid cysts is controversial. One-way slit valves are often hypothesized as the mechanism for enlargement. The authors present 4 cases of suprasellar prepontine arachnoid cysts in which a slit valve was identified. The patients presented with hydrocephalus due to enlargement of the cyst. The valve was located in the arachnoid wall of the cyst directly over the basilar artery. The authors believe this slit valve was responsible for the net influx of CSF into the cyst and for its enlargement. They also present 1 case of an arachnoid cyst in the middle cranial fossa that had a small circular opening but lacked a slit valve. This cyst did not enlarge but surgery was required because of rupture and the development of a subdural hygroma. One-way slit valves exist and are a possible mechanism of enlargement of suprasellar prepontine arachnoid cysts. The valve was located directly over the basilar artery in each of these cases. Caudad-to-cephalad CSF flow during the cardiac cycle increased the opening of the valve, whereas cephalad-to-caudad CSF flow during the remainder of the cardiac cycle pushed the slit opening against the basilar artery and decreased the size of the opening. Arachnoid cysts that communicate CSF via circular, nonslit valves are probably more likely to remain stable. PMID- 23662936 TI - Perspectives on communicating risks of chemicals. AB - The Agrochemicals Division symposium "Perfecting Communication of Chemical Risk", held at the 244th National Meeting and Exposition of the American Chemical Society in Philadelphia, PA, August 19-23, 2012, is summarized. The symposium, organized by James Seiber, Kevin Armbrust, John Johnston, Ivan Kennedy, Thomas Potter, and Keith Solomon, included discussion of better techniques for communicating risks, lessons from past experiences, and case studies, together with proposals to improve these techniques and their communication to the public as effective information. The case studies included risks of agricultural biotechnology, an organoarsenical (Roxarsone) in animal feed, petroleum spill derived contamination of seafood, role of biomonitoring and other exposure assessment techniques, soil fumigants, implications of listing endosulfan as a persistant organic pollutant (POP), and diuron herbicide in runoff, including use of catchment basins to limit runoff to coastal ecozones and the Great Barrier Reef. The symposium attracted chemical risk managers including ecotoxicologists, environmental chemists, agrochemists, ecosystem managers, and regulators needing better techniques that could feed into better communication of chemical risks. Policy issues related to regulation of chemical safety as well as the role of international conventions were also presented. The symposium was broadcast via webinar to an audience outside the ACS Meeting venue. PMID- 23662937 TI - Sungsanpin, a lasso peptide from a deep-sea streptomycete. AB - Sungsanpin (1), a new 15-amino-acid peptide, was discovered from a Streptomyces species isolated from deep-sea sediment collected off Jeju Island, Korea. The planar structure of 1 was determined by 1D and 2D NMR spectroscopy, mass spectrometry, and UV spectroscopy. The absolute configurations of the stereocenters in this compound were assigned by derivatizations of the hydrolysate of 1 with Marfey's reagents and 2,3,4,6-tetra-O-acetyl-beta-d glucopyranosyl isothiocyanate, followed by LC-MS analysis. Careful analysis of the ROESY NMR spectrum and three-dimensional structure calculations revealed that sungsanpin possesses the features of a lasso peptide: eight amino acids (-Gly(1) Phe-Gly-Ser-Lys-Pro-Ile-Asp(8)-) that form a cyclic peptide and seven amino acids (-Ser(9)-Phe-Gly-Leu-Ser-Trp-Leu(15)) that form a tail that loops through the ring. Sungsanpin is thus the first example of a lasso peptide isolated from a marine-derived microorganism. Sungsanpin displayed inhibitory activity in a cell invasion assay with the human lung cancer cell line A549. PMID- 23662939 TI - Relation of insulin-like growth factor-I and IGF binding protein 3 with markers of inflammation: results of a population-based study. AB - OBJECTIVE: Previous studies in acromegaly and growth hormone deficiency observed inverse associations between insulin-like growth factor-I (IGF-I) levels and inflammatory biomarkers including high-sensitive C-reactive protein (hsCRP), interleukin-6 or fibrinogen. We aimed to assess the relations between IGF-I or IGF binding protein 3 (IGFBP-3) levels and hsCRP, interleukin-6, fibrinogen and white blood cell count (WBC) in a population-based sample. DESIGN AND PATIENTS: Data from 3480 subjects from the population-based Study of Health in Pomerania (SHIP) were used. IGF-I, IGFBP-3 and inflammatory biomarkers were measured. Analysis of variance (anova), quantile regression models and logistic regression models, adjusted for age, smoking, diabetes mellitus and waist circumference, were performed. MEASUREMENTS AND RESULTS: anova and/or quantile regression showed inverse associations between IGF-I and hsCRP as well as positive associations between IGF-I and fibrinogen among both sexes. Furthermore, the odds of elevated fibrinogen levels increased with increasing IGF-I levels (per SD IGF-I increase: men: odds ratio (OR) 1.35 [95% confidence interval (CI) 1.04, 1.55]; women: OR 1.44 [95% CI 1.21, 1.71]) in both sexes, whereas the odds of increased hsCRP (women: OR 0.46 [95% CI 0.36, 0.58]) and interleukin-6 (men: odds ratio (OR) 0.77 [95% CI 0.61, 0.96]; women: OR 0.69 [95% CI 0.55, 0.86]) decreased. CONCLUSION: Serum IGF-I levels are associated with inflammatory biomarkers including hsCRP, interleukin-6 and fibrinogen. Further experimental studies are needed to elucidate the mechanisms underlying the relation between the GH/IGF axis and the inflammatory system. PMID- 23662938 TI - Targeted capture and sequencing for detection of mutations causing early onset epileptic encephalopathy. AB - PURPOSE: Early onset epileptic encephalopathies (EOEEs) are heterogeneous epileptic disorders caused by various abnormalities in causative genes including point mutations and copy number variations (CNVs). In this study, we performed targeted capture and sequencing of a subset of genes to detect point mutations and CNVs simultaneously. METHODS: We designed complementary RNA oligonucleotide probes against the coding exons of 35 known and potential candidate genes. We tested 68 unrelated patients, including 15 patients with previously detected mutations as positive controls. In addition to mutation detection by the Genome Analysis Toolkit, CNVs were detected by the relative depth of coverage ratio. All detected events were confirmed by Sanger sequencing or genomic microarray analysis. KEY FINDINGS: We detected all positive control mutations. In addition, in 53 patients with EOEEs, we detected 12 pathogenic mutations, including 9 point mutations (2 nonsense, 3 splice-site, and 4 missense mutations), 2 frameshift mutations, and one 3.7-Mb microdeletion. Ten of the 12 mutations occurred de novo; the other two had been previously reported as pathogenic. The entire process of targeted capture, sequencing, and analysis required 1 week for the testing of up to 24 patients. SIGNIFICANCE: Targeted capture and sequencing enables the identification of mutations of all classes causing EOEEs, highlighting its usefulness for rapid and comprehensive genetic testing. PMID- 23662940 TI - Microarrays and microneedle arrays for delivery of peptides, proteins, vaccines and other applications. AB - INTRODUCTION: Peptide and protein microarray and microneedle array technology provides direct information on protein function and potential drug targets in drug discovery and delivery. Because of this unique ability, these arrays are well suited for protein profiling, drug target identification/validation and studies of protein interaction, biochemical activity, immune responses, clinical prognosis and diagnosis and for gene, protein and drug delivery. AREAS COVERED: The aim of this review is to describe and summarize past and recent developments of microarrays in their construction, characterization and production and applications of microneedles in drug delivery. The scope and limitations of various technologies in this respect are discussed. EXPERT OPINION: This article offers a review of microarray/microneedle technologies and possible future directions in targeting and in the delivery of pharmacologically active compounds for unmet needs in biopharmaceutical research. A better understanding of the production and use of microarrays and microneedles for delivery of peptides, proteins and vaccines is needed. PMID- 23662941 TI - Mercury isotope signatures as tracers for Hg cycling at the New Idria Hg mine. AB - Mass-dependent fractionation (MDF) and mass-independent fractionation (MIF) of Hg isotopes provides a new tool for tracing Hg in contaminated environments such as mining sites, which represent major point sources of Hg pollution into surrounding ecosystems. Here, we present Hg isotope ratios of unroasted ore waste, calcine (roasted ore), and poplar leaves collected at a closed Hg mine (New Idria, CA, U.S.A.). Unroasted ore waste was isotopically uniform with delta(202)Hg values from -0.09 to 0.160/00 (+/- 0.100/00, 2 SD), close to the estimated initial composition of the HgS ore (-0.260/00). In contrast, calcine samples exhibited variable delta(202)Hg values ranging from -1.910/00 to +2.100/00. Small MIF signatures in the calcine were consistent with nuclear volume fractionation of Hg isotopes during or after the roasting process. The poplar leaves exhibited negative MDF (-3.18 to -1.220/00) and small positive MIF values (Delta(199)Hg of 0.02 to 0.210/00). Sequential extractions combined with Hg isotope analysis revealed higher delta(202)Hg values for the more soluble Hg pools in calcines compared with residual HgS phases. Our data provide novel insights into possible in situ transformations of Hg phases and suggest that isotopically heavy secondary Hg phases were formed in the calcine, which will influence the isotope composition of Hg leached from the site. PMID- 23662942 TI - Processes and outcomes for a successful engagement between a medical school and a remote Indigenous community in North Queensland, Australia. AB - INTRODUCTION: Medical students should be equipped with the necessary knowledge, skills and attitudes to engage with local communities on placement, and later act as agents of change in addressing health system priorities and inequities. Determining what are the necessary knowledge, skills and attitudes requires the medical school to collect input from the local communities they serve. This study describes the steps taken by the James Cook University (JCU) School of Medicine & Dentistry (SMD) to develop a systematic process for collecting input from a local Indigenous community. METHODS: This 2011 study utilised a participatory action research design. An Indigenous Reference Group (IRG) consisting of 13 local Indigenous people including health professionals, Elders and community members was established by the JCU SMD in the North Queensland town of Mount Isa. 'Yarning Circle' discussions between SMD representatives and the IRG developed a Terms of Reference (ToR) to guide the engagement process, and negotiated reciprocal benefits to compensate participants for time involved in consultations and to promote sustainability. RESULTS: A framework for engaging with the Mount Isa Indigenous community was developed. Benefits for the SMD included a list of the good and bad engagement strategies with the local Indigenous community. Benefits for the IRG members included assistance with grant applications, media skills and organizing a community-wide health event. CONCLUSIONS: Successful and sustainable community partnerships between a medical school and an Indigenous community can be achieved, with Indigenous researchers and community members guiding the engagement process, and for stakeholders to follow through in providing the negotiated reciprocal benefits. Having an established IRG should increase Indigenous input and participation into the medical curriculum, and into future research and community activities to improve the health of the Indigenous people. PMID- 23662943 TI - Lung abscess. PMID- 23662945 TI - Factors contributing to diabetes patients not receiving annual dilated eye examinations. AB - PURPOSE: Early detection of diabetic eye disease by dilated eye exam can limit potential vision loss from diabetic retinopathy. The purpose of this study was to examine what variables contribute to diabetes patients not receiving annual dilated eye examinations. METHODS: This study used national 2009 Behavioral Risk Factor Surveillance System survey data. Variables used in the analysis included sociodemographics, insurance status, mentally unhealthy days, receipt of annual dilated eye exams, insulin dependence, a history of diabetes education classes, timely annual diabetic foot exams, and history of cardiovascular disease. Survey proportions were calculated, and survey logistic regression was performed with the consideration of survey strata and weight to correct for biases. RESULTS: The likelihood of receiving annual dilated eye exams was correlated with eight statistically significant variables. These variables included age category, income level, education level, health insurance status, mentally unhealthy days within the past month, insulin dependence, a history of diabetic education classes, and timeliness of annual diabetic foot examinations. CONCLUSIONS: This study provides a snapshot of variables that may have a bearing on diabetes patients seeking annual dilated retinal examinations. Eight variables were statistically significant in affecting the timeliness of diabetic eye examinations. Thus, resolutions for these factors could be implemented for future improvement of comprehensive health care provided to those with diabetes. PMID- 23662946 TI - An in vivo experimental model to determine antigenic variations among infectious bursal disease viruses. AB - Infectious bursal disease virus (IBDV) is a double-stranded RNA virus causing infectious bursal disease in chickens. IBDV undergoes antigenic drift, so characterizing the antigenicity of IBDV plays an important role for identification and selection of vaccine candidates. In this study, an in vivo experimental model was developed to differentiate a new antigenic variant of IBDV. To this end, a hyper-immune serum to IBDV E/Del-type virus was generated in specific pathogen-free chickens and a standard volume of the hyper-immune serum was serially diluted and injected in specific pathogen-free birds via intravenous, subcutaneous, or intramuscular routes. The chickens were bled at different time points in order to evaluate the dynamics of virus neutralization titres. Based on the results, chickens were injected with different serum dilutions by the subcutaneous route. Twenty-four hours later, chickens were bled and then challenged with 100 median chicken infectious doses of the E/Del virus and a new IBDV variant. Chickens were euthanized at 7 days post infection and the bursa of Fabricius was removed for microscopic evaluation to determine the bursal lesion score. The determined virus neutralization titre along with the bursal lesion score was used to determine the breakthrough titre in the in vivo chicken model. Based on the data obtained, an antigenic subtype of IBDV was identified and determined to be different from E/Del. This model is a sensitive model for determination of IBDV antigenicity of non-tissue culture adapted IBDV. PMID- 23662944 TI - Prevalence, association with stifle conditions, and histopathologic characteristics of tibial tuberosity radiolucencies in dogs. AB - A tibial tuberosity radiolucency is sometimes identified on lateral radiographs of canine stifle joints, however little is known about the cause or significance. The purpose of this study was to describe the prevalence, association with other stifle conditions, and histopathologic characteristics of tibial tuberosity radiolucencies in a group of dogs. Radiographs of all canine stifle joints over 5 years were evaluated. Presence or absence of a tibial tuberosity radiolucency was recorded by an observer who was unaware of clinical status. Patient signalment and presence of other stifle joint conditions were recorded from medical records. A tibial tuberosity radiolucency was found in 145/675 dogs (prevalence = 21.5%). Statistically significant associations were identified between tibial tuberosity radiolucency and stifle condition (P < 0.0001), breed size (P = 0.011), and younger age of presentation (P = 0.001), but not with gender (P = 0.513). Dogs with a tibial tuberosity radiolucency had higher odds of having a medial patellar luxation than dogs without (OR = 9.854, P < 0.0001, 95% CI 6.422-15.120). Dogs with a tibial tuberosity radiolucency had lower odds of having a cranial cruciate ligament rupture than dogs without (OR = 0.418, P < 0.0001, 95% CI 0.287-0.609). Four canine cadavers, two with normal stifles and two with tibial tuberosity radiolucencies, underwent radiographic, computed tomographic, and histologic examination of the stifles. Computed tomography revealed a hypoattenuating cortical defect in the lateral aspect of the proximal tibial tuberosity that corresponded histopathologically to a hyaline cartilage core. Findings indicated that the tibial tuberosity radiolucency may be due to a retained cartilage core and associated with medial patellar luxation in dogs. PMID- 23662947 TI - Editorial comment to "Nocturia and sleep quality after transurethral resection of the prostate". PMID- 23662948 TI - The photochemistry of 4,5-carbomethoxy-1,2,3-thiadiazole: direct observation of thiirene formation and its decay in solution. AB - The photochemistry of 4,5-carbomethoxy-1,2,3-thiadiazole in solution was studied at room temperature with use of UV-vis and IR transient absorption spectroscopies (lambda(ex) = 266 nm). Ultrafast time-resolved techniques demonstrate that there is a very fast rise (<0.4 ps) of bis(carbomethoxy)thiirene in acetonitrile, and that it is the only intermediate formed. The lifetime of the thiirene is limited by dimerization to eventually form tetra(carbomethoxy)thiophene. PMID- 23662949 TI - Bioluminescent yeast assay for detection of organotin compounds. AB - Organotin compounds are toxic and endocrine disrupting compounds, which have been intensively used as antifouling paints for ship hulls and thus are widely spread in the environment. They are suspected to cause imposex, the formation of male characteristics in female gastropods, because of the activation of retinoid X receptor (RXR) at very low environmental concentrations. Here we report the development and optimization of a bioluminescent yeast assay for the detection of organotin compounds based on the interaction with a hybrid RXR and subsequent expression of a reporter luciferase gene. This assay is highly specific toward organotin compounds and natural ligands of the RXR. It detects tributyltin and triphenyltin in nanomolar concentrations (detection limits were found to be 30 nM and 110 nM, respectively) and allows small-scale high-throughput analyses. Furthermore it was possible to measure tributyltin directly in untreated spiked sediments. Thus, the results provided within one working day can be used for the assessment of bioavailability and mixture effect of organotin compounds in environmental samples. PMID- 23662950 TI - Familial pyoderma gangrenosum in association with common variable immunodeficiency. PMID- 23662951 TI - Relationships between heart rate and age, bodyweight and breed in 10,849 dogs. AB - OBJECTIVES: To evaluate relationships between heart rate and clinical variables in healthy dogs and dogs examined at a referral hospital. METHODS: Clinical data were extracted from the electronic patient records of a first opinion group (5000 healthy dogs) and a referral hospital (5849 dogs). Univariable and multi-variable general linear models were used to assess associations between heart rate and clinical characteristics. Separate multi-variable models were constructed for first opinion and referral populations. RESULTS: In healthy dogs, heart rate was negatively associated with bodyweight (P<0.001) but was higher in Chihuahuas. The mean difference in heart rate between a 5 and 55 kg dog was 10.5 beats per minute. In dogs presenting to a referral hospital, heart rate was negatively associated with bodyweight (P<0.001) and the following breeds; border collie, golden retriever, Labrador retriever, springer spaniel and West Highland white terrier and positively associated with age, admitting service (emergency and critical care, emergency first opinion and cardiology) and the following breeds; Cavalier King Charles spaniel, Staffordshire bull terrier and Yorkshire terrier. CLINICAL SIGNIFICANCE: Bodyweight, age, breed and disease status all influence heart rate in dogs, although these factors account for a relatively small proportion of the overall variability in heart rate. PMID- 23662952 TI - Dose ratios between high dose oral morphine or equivalents and oral methadone. AB - BACKGROUND: Methadone is a commonly used opioid in hospice and palliative care for patients with refractory pain. Various methadone dose conversion methods utilize progressively higher morphine equivalent dose (MED) to methadone dose ratios to compensate for increased methadone potency with escalating opioid doses. OBJECTIVE: The purpose of this study was to determine the dose ratio between equianalgesic doses of high dose oral morphine (daily doses >1200 mg morphine or MED) and oral methadone. METHODS: This study was a retrospective chart review of 324 patients who received methadone at Strong Memorial Hospital or the associated outpatient clinic during a nine-month period in 2011. Ten patients met the study inclusion and exclusion criteria. A Wilcoxon signed-rank test was used to compare the pain scale scores. The Spearman correlation coefficient was used to assess level of correlation between morphine dose and methadone dose. RESULTS: Patients rotated to methadone from high opioid doses had a two-point improvement in median pain scale scores after conversion (p=0.039). However, there was no correlation identified for patients taking daily doses >1200 mg oral morphine or MED prior to methadone rotation (p=0.19). There were no reported methadone adverse effects during the study. CONCLUSIONS: No correlation was identified between high MED doses and methadone at dose stabilization after opioid rotation. A fixed maximum methadone dose of 30 mg/day produced clinically meaningful improvements in pain scores without adverse drug effects. Caution should be exercised before considering rotation to methadone doses higher than 30 mg/day in a patient receiving >1200 mg oral MED/day. PMID- 23662953 TI - The diverse landscape of palliative care clinics. AB - BACKGROUND: Many health care organizations are interested in instituting a palliative care clinic. However, there are insufficient published data regarding existing practices to inform the development of new programs. OBJECTIVE: Our objective was to obtain in-depth information about palliative care clinics. METHODS: We conducted a cross-sectional survey of 20 outpatient palliative care practices in diverse care settings. The survey included both closed- and open ended questions regarding practice size, utilization of services, staffing, referrals, services offered, funding, impetus for starting, and challenges. RESULTS: Twenty of 21 (95%) practices responded. Practices self-identified as: hospital-based (n=7), within an oncology division/cancer center (n=5), part of an integrated health system (n=6), and hospice-based (n=2). The majority of referred patients had a cancer diagnosis. Additional common diagnoses included chronic obstructive pulmonary disease, neurologic disorders, and congestive heart failure. All practices ranked "pain management" and "determining goals of care" as the most common reasons for referrals. Twelve practices staffed fewer than 5 half-days of clinic per week, with 7 operating only one half-day per week. Practices were staffed by a mixture of physicians, advanced practice nurses or nurse practitioners, nurses, or social workers. Eighteen practices expected their practice to grow within the next year. Eleven practices noted a staffing shortage and 8 had a wait time of a week or more for a new patient appointment. Only 12 practices provide 24/7 coverage. Billing and institutional support were the most common funding sources. Most practices described starting because inpatient palliative providers perceived poor quality outpatient care in the outpatient setting. The most common challenges included: funding for staffing (11) and being overwhelmed with referrals (8). CONCLUSIONS: Once established, outpatient palliative care practices anticipate rapid growth. In this context, outpatient practices must plan for increased staffing and develop a sustainable financial model. PMID- 23662954 TI - On the shoulders of a giant: his legacy will live on. PMID- 23662955 TI - The role of luminance and chromatic cues in emmetropisation. AB - PURPOSE: At birth most, but not all eyes, are hyperopic. Over the course of the first few years of life the refraction gradually becomes close to zero through a process called emmetropisation. This process is not thought to require accommodation, though a lag of accommodation has been implicated in myopia development, suggesting that the accuracy of accommodation is an important factor. This review will cover research on accommodation and emmetropisation that relates to the ability of the eye to use colour and luminance cues to guide the responses. RECENT FINDINGS: There are three ways in which changes in luminance and colour contrast could provide cues: (1) The eye could maximize luminance contrast. Monochromatic light experiments have shown that the human eye can accommodate and animal eyes can emmetropise using changes in luminance contrast alone. However, by reducing the effectiveness of luminance cues in monochromatic and white light by introducing astigmatism, or by reducing light intensity, investigators have revealed that the eye also uses colour cues in emmetropisation. (2) The eye could compare relative cone contrast to derive the sign of defocus information from colour cues. Experiments involving simulations of the retinal image with defocus have shown that relative cone contrast can provide colour cues for defocus in accommodation and emmetropisation. In the myopic simulation the contrast of the red component of a sinusoidal grating was higher than that of the green and blue component and this caused relaxation of accommodation and reduced eye growth. In the hyperopic simulation the contrast of the blue component was higher than that of the green and red components and this caused increased accommodation and increased eye growth. (3) The eye could compare the change in luminance and colour contrast as the eye changes focus. An experiment has shown that changes in colour or luminance contrast can provide cues for defocus in emmetropisation. When the eye is exposed to colour flicker the eye grows almost twice as much, and becomes more myopic, compared to when the eye is exposed to luminance flicker. SUMMARY: Neural responses of the luminance and colour mechanisms direct accommodation and emmetropisation mechanisms to different focal planes. Therefore, it is likely that the set point of refraction and accommodation is dependent on the sensitivity of the eye to changes in spatial and temporal, colour and luminance contrast. PMID- 23662956 TI - Dynamics of active emmetropisation in young chicks--influence of sign and magnitude of imposed defocus. AB - PURPOSE: Young eyes compensate for the defocus imposed by spectacle lenses by changing their rate of elongation and their choroidal thickness, bringing their refractive status back to the pre-lens condition. We asked whether the initial rate of change either in the ocular components or in refraction is a function of the power of the lenses worn, a result that would be consistent with the existence of a proportional controller mechanism. METHODS: Two separate studies were conducted; both tracked changes in refractive errors and ocular dimensions. Study A: To study the effects of lens power and sign, young chicks were tracked for 4 days after they were fitted with positive (+5, +10 or +15 D) or negative ( 5, -10, -15 D) lenses over one eye. In another experiment, biometric changes to plano, +1, +2 and +3 D lenses were tracked over a 24 h treatment period. Study B: Normal emmetropisation was tracked from hatching to 6 days of age and then a defocusing lens, either +6 D or -7 D, was fitted over one eye and additional biometric data collected after 48 h. RESULTS: In study A, animals treated with positive lenses (+5, +10 or +15 D) showed statistical similar initial choroid responses, with a mean thickening 24 MUm h(-1) over the first 5 h. Likewise, with the low power positive lenses, a statistically similar magnitude of choroidal thickening was observed across groups (+1 D: 46.0 +/- 7.8 MUm h(-1); +2 D: 53.5 +/- 9.9 MUm h(-1); +3 D 53.3 +/- 24.1 MUm h(-1)) in the first hour of lens wear compared to that of a plano control group. These similar rates of change in choroidal thickness indicate that the signalling response is binary in nature and not influenced by the magnitude of the myopic defocus. Treatments with -5, -10 and -15 D lenses induced statistically similar amounts of choroidal thinning, averaging -70 +/- 15 MUm after 5 h and -96 +/- 45 MUm after 24 h. Similar rates in inner axial length changes were also seen with these lens treatments until compensation was reached, once again indicating that the signalling response is not influenced by the magnitude of hyperopic defocus. In study B, after 48 h of +6 D lens treatment, the average refractive error and choroidal changes were found to be larger in magnitude than expected if perfect compensation had taken place, with a + 2.4 D overshoot in refractive compensation. CONCLUSION: Taken together, our results with both weak and higher power positive lenses suggest that eye growth is guided more by the sign than by the magnitude of the defocus, and our results for higher power negative lenses support a similar conclusion. These behaviour patterns and the overshoot seen in Study B are more consistent with the behaviour of a bang-bang controller than a proportional controller. PMID- 23662957 TI - Temporal properties of the myopic response to defocus in the guinea pig. AB - PURPOSE: Hyperopic defocus induces myopia in all species tested and is believed to underlie the progression of human myopia. We determined the temporal properties of the effects of hyperopic defocus in a mammalian eye. METHODS: In Experiment 1, the rise and decay time of the responses elicited by hyperopic defocus were calculated in 111 guinea pigs by giving repeated episodes of monocular -4 D lens wear (from 5 to 6 days of age for 12 days) interspersed with various dark intervals. In Experiment 2, the decay time constant was calculated in 152 guinea pigs when repeated periods of monocular -5 D lens-wear (from 4 days of age for 7 days) were interrupted with free viewing periods of different lengths. At the end of the lens-wear period, ocular parameters were measured and time constants were calculated relative to the maximum response induced by continuous lens wear. RESULTS: When hyperopic defocus was experienced with dark intervals between episodes, the time required to induce 50% of the maximum achievable myopia and ocular elongation was at most 30 min. Saturated 1 h episodes took at least 22 h for refractive error and 31 h for ocular length, to decay to 50% of the maximum response. However, the decay was an order of magnitude faster when hyperopic defocus episodes were interrupted with a daily free viewing period, with only 36 min required to reduce relative myopia and ocular elongation by 50%. CONCLUSIONS: Hyperopic defocus causes myopia with brief exposures and is very long lasting in the absence of competing signals. However, this myopic response rapidly decays if interrupted by periods of 'normal viewing' at least 30 min in length, wherein ocular growth appears to be guided preferentially by the least amount of hyperopic defocus experienced. PMID- 23662959 TI - Hemi-field and full-field form-deprivation induce timing changes in multifocal ERG responses in chick. AB - PURPOSE: In animal models hemi-field deprivation results in localised, graded vitreous chamber elongation and presumably deprivation induced localised changes in retinal processing. The aim of this research was to determine if there are variations in ERG responses across the retina in normal chick eyes and to examine the effect of hemi-field and full-field deprivation on ERG responses across the retina and at earlier times than have previously been examined electrophysiologically. METHODS: Chicks were either untreated, wore monocular full-diffusers or half-diffusers (depriving nasal retina) (n = 6-8 each group) from day 8. mfERG responses were measured using the VERIS mfERG system across the central 18.2o* 16.7o (H * V) field. The stimulus consisted of 61 unscaled hexagons with each hexagon modulated between black and white according to a pseudorandom binary m-sequence. The mfERG was measured on day 12 in untreated chicks, following 4 days of hemi-field diffuser wear, and 2, 48 and 96 h after application of full-field diffusers. RESULTS: The ERG response of untreated chick eyes did not vary across the measured field; there was no effect of retinal location on the N1-P1 amplitude (p = 0.108) or on P1 implicit time (p > 0.05). This finding is consistent with retinal ganglion cell density of the chick varying by only a factor of two across the entire retina. Half-diffusers produced a ramped retina and a graded effect of negative lens correction (p < 0.0001); changes in retinal processing were localized. The untreated retina showed increasing complexity of the ERG waveform with development; form-deprivation prevented the increasing complexity of the response at the 2, 48 and 96 h measurement times and produced alterations in response timing. CONCLUSIONS: Form deprivation and its concomitant loss of image contrast and high spatial frequency images prevented development of the ERG responses, consistent with a disruption of development of retinal feedback systems. The characterisation of ERG responses in normal and deprived chick eyes across the retina allows the assessment of concurrent visual and retinal manipulations in this model. PMID- 23662958 TI - Effects of muscarinic agents on chick choroids in intact eyes and eyecups: evidence for a muscarinic mechanism in choroidal thinning. AB - PURPOSE: In chicks, ocular growth inhibition is associated with choroidal thickening and growth stimulation with choroidal thinning, suggesting a mechanistic link between the two responses. Because muscarinic antagonists inhibit the development of myopia in animal models by a non-accommodative mechanism, we tested the hypothesis that agonists would stimulate eye growth and thin the choroid. We also hypothesized that the effective growth-inhibiting antagonists would thicken the choroid. METHODS: Chicks, age 12-16 days, were used. In vivo: Agonists: Single intravitreal injections (20 MUL) of oxotremorine (oxo), pilocarpine (pilo), carbachol (carb), or arecaidine (arec) were given to otherwise untreated eyes. A-scan ultrasonography was done prior to injections, and at 3, 24, 48 and 72 h. Antagonists: -10D lenses were worn on one eye for 4 days. Atropine (atro), pirenzepine (pirz), oxyphenonium (oxy) or dicyclomine (dicy) were injected (20 MUL) daily into lens-wearing eyes; saline injections were done as controls. Ultrasonography was done on d1 and on d4; on d4 measurements were done before and 3 h after injections. In vitro: Paired eyecups of retinal pigment epithelium (RPE), choroid and sclera were made from 1-week old chicks. All drugs except atropine were tested on one eyecup, its pair in plain medium. Choroidal thickness was measured at various times over 48 h. RESULTS: Agonists: In vivo, oxotremorine caused an increase in the rate of axial elongation (drug vs saline: 24-72 h: 338 MUm vs 250 MUm; p < 0.001). All except pilocarpine caused choroidal thinning by 24 h (oxo, carb and arec vs saline: -25, -35 and -46 MUm vs 3 MUm). In vitro, all agonists thinned choroids by 24 h (oxo: 6 vs 111 MUm; pilo: 45 vs 212 MUm; carb: -58 vs 65 MUm; arec: 47 vs 139 MUm; p < 0.05). Antagonists: Atropine, pirenzepine and oxyphenonium inhibited the development of myopia in negative lens-wearing eyes, and also caused choroidal thickening (drug vs saline: 42, 80, 88 vs 10 MUm per 3 h). In vitro, pirenzepine thickened choroids by 3 h (77 vs 2 MUm, p < 0.01). CONCLUSIONS: Muscarinic agonists caused choroidal thinning in intact eyes and eyecups, supporting a role for acetylcholine in the choroidal response to hyperopic defocus or form deprivation. Only oxotremorine stimulated eye growth, which is inconsistent with a muscarinic receptor mechanism for antagonist-induced eye growth inhibition. The dissociation between choroidal thinning and ocular growth stimulation for the other agonists in vivo suggest separate pathways for the two. PMID- 23662960 TI - A randomised clinical trial to assess the effect of a dual treatment on myopia progression: the Cambridge Anti-Myopia Study. AB - PURPOSE: To evaluate the effect of a dual treatment modality for myopia, by improving accommodative functions, on myopia progression. METHODS: A double blind randomised control trial was conducted on 96 subjects. The treatment modality for the trial employed custom designed contact lenses which control spherical aberration in an attempt to optimise static accommodation responses during near work, and a vision-training programme to improve accommodation dynamics. Myopia progression was assessed over a 2 year period using cycloplegic autorefraction and biometry. RESULTS: The mean progression was found to be -0.33 Dioptres (D) over the 2 years of the study. There was no interaction between contact lens treatment and vision training treatment at 24 months (p = 0.72). There was no significant treatment effect of either Vision Training or Contact Lens Spherical Aberration control on myopia progression. CONCLUSIONS: This study is unable to demonstrate that the progression of myopia can be reduced over a 2 year period by either of the two treatments aimed at improving accommodative function. Neither treatment group (contact lens or vision training) progressed at a slower rate over the 2 years of the study than did the appropriate control group. PMID- 23662961 TI - Relative peripheral refraction in children: twelve-month changes in eyes with different ametropias. AB - PURPOSE: To determine the peripheral refraction of children with different types of ametropias and to evaluate the relationship between central refractive changes, baseline relative peripheral refraction (RPR) and changes in RPR over a 12-month monitoring period. METHODS: Cycloplegic central and peripheral refraction were performed biannually on the right eyes of children aged 6-9 for 12 months, using an open-view autorefractor. Peripheral refraction were measured along 10 degrees , 20 degrees and 30 degrees from central fixation in both nasal and temporal fields. Refractive data were transposed into M, J0 and J45 vectors for analyses. RPR was determined by subtracting the central measurement from each peripheral measurement. RESULTS: Hyperopic eyes showed relative peripheral myopia while myopic eyes had relative hyperopia across the central 60 degrees horizontal field at baseline. Emmetropic eyes had relative myopia within but showed relative hyperopia beyond the central 30 degrees field. However, there was no significant correlation between central refractive changes and baseline RPR or between changes in central refraction and RPR over twelve months in any refractive groups. Correlations between changes in PR and central myopic shift were found mainly in the nasal field in different groups. In the subgroup analysis on the initially emmetropic and the initially myopic groups, the subgroups with faster myopic progression did not have significantly different RPR from the subgroups with slower progression. The RPR pattern of the initially emmetropic and the initially myopic groups became more asymmetric at the end of the study period with a larger increase in relative hyperopia in the temporal field. CONCLUSIONS: RPR patterns were different among hyperopic, emmetropic and myopic eyes. However, baseline RPR and changes in RPR cannot predict changes in central refraction over time. Our results did not provide evidence to support the hypothesis of RPR as a causative factor for myopic central refractive changes in children. PMID- 23662962 TI - The time course of blur adaptation in emmetropes and myopes. AB - PURPOSE/BACKGROUND: This study examined the effect of myopic defocus on visual acuity (VA) over time, with attention being paid to the first point at which blur adaptation had a significant and measurable effect on defocused VA. Visual acuity was sampled at a higher rate than previous studies in order to assess the time course of blur adaptation processes in myopic and emmetropic observers. METHODS: Participants were 24 normally-sighted observers (12 emmetropes and 12 myopes, median age: 22.5 years). All ametropic participants wore their full refractive correction throughout the experiment. 1 D and 3 D of myopic defocus were introduced in two separate, randomised sessions. Visual acuity was measured using Test Chart 2000 at 2 min intervals over a 30 min session whilst looking through defocus lenses. Recovery clear VA was also measured every 2 min for a further 20 min. RESULTS: Defocused VA was found to improve significantly within 4 min after the introduction of defocus for both 1 D (P < 0.0001) and 3 D conditions (P < 0.0001). The improvements reached a plateau shortly after, with no significant further improvements in defocused VA after 6 min. There were no significant differences found in the temporal blur adaptation profiles between emmetropes and myopes (P = 0.267). Data were fitted with an exponential decay function; the lowest R(2) value for this fit was 0.95. CONCLUSIONS: Blur adaptation has a clinically significant and measurable effect on VA within 4 min of exposure to defocus. This finding indicates that the visual system instigates the neural compensatory mechanisms shortly after the appearance of defocus. Our results relate particularly to real-life vision of uncorrected myopes or myopes who remove their correction for part of the day. PMID- 23662963 TI - Nearwork-induced transient myopia (NITM) in anisometropia. AB - OBJECTIVE: To assess the magnitude of nearwork-induced transient myopia (NITM) under binocular viewing conditions separately in each eye of individuals with mild to moderate anisometropia to determine the relationship between NITM and their interocular refractive error. METHODS: Forty-three children and young adults with anisometropia [cycloplegic spherical equivalent (SE) difference >1.00 D] were tested (ages 9-28 years). NITM was measured with binocular viewing separately in each eye after binocularly performing a sustained near task (5 D) for 5 min incorporating a cognitive demand using an open-field, infrared autorefractor (Grand-Seiko, WAM-5500). Data were averaged over 10 s bins for 3 min in each eye. Initial NITM, its decay time (DT), and its decay area (DA) were determined. A-scan ultrasound ocular biometry was also performed to determine the axial length of each eye. RESULTS: The more myopic eye exhibited increased initial NITM, DT, and DA as compared to the less myopic eye (0.21 +/- 0.16 D vs 0.15 +/- 0.13 D, p = 0.026; 108.4 +/- 64.3 secs vs 87.0 +/- 65.2 secs, p = 0.04; and 17.6 +/- 18.7 D*secs vs 12.3 +/- 15.7 D*secs, p = 0.064), respectively. The difference in DA and the difference in SE between the more versus less myopic eye were significantly correlated (r = 0.31, p = 0.044). Furthermore, 63% (27/43), 56% (24/43), and 70% (30/43) of the more myopic eyes exhibited increased initial NITM, longer DT, and larger DA, respectively, than found in the less myopic eye. CONCLUSIONS: In approximately two-thirds of the anisometropic individuals, the initial NITM and its decay area were significantly increased in the more myopic eye as compared to the less myopic eye. NITM may play an important role in the development of interocular differences in myopia, although a causal relationship is yet to be established. Furthermore, the findings have potentially important implications regarding accommodative control and interocular accommodative responsitivity in anisometropia, in particular for anisomyopia. PMID- 23662964 TI - Myopia and international educational performance. AB - PURPOSE: To analyse the relationship between myopia, educational performance and engagement in after-school tutorial classes. METHODS: Educational performance data and data on engagement in after-school tutorial classes were taken from the results of the Organisation for Economic Cooperation and Development (OECD) Program in Secondary Assessment (PISA) reports for 2009, which tested educational outcomes in representative samples of 15 year-old school children from 65 jurisdictions. High prevalence of myopia (>70%) and low prevalence of myopia (<40%) locations were identified by systematic literature search. RESULTS: Six locations with a high prevalence of myopia were identified from among the participants in PISA 2009 - Shanghai-China, Hong Kong-China, Taiwan, Singapore, Japan and South Korea. All were ranked in the top quartile on educational performance. Other participants in the top educational performance quartile were identified as locations with a low prevalence of myopia, including Australia and Finland. The locations with a high prevalence of myopia combined high educational performance and high engagement in after-school tutorials, whereas the locations with a low prevalence of myopia combined high educational performance with little engagement in tutorials. DISCUSSION: These results show that it is possible to achieve high educational outcomes without extensive engagement in after-school tutorials, and that the combination of high educational outcomes with extensive use of tutorials is associated with high prevalence rates of myopia. We suggest that extensive use of after-school tutorials may be a marker of educational environments which impose high educational loads. Further quantification of educational loads to include after- school educational activities, such as homework, tutorials and other after-school classes, as well as formal school classes, is desirable. Policy initiatives to decrease these loads may contribute to the prevention of myopia, perhaps, at least in part, by enabling children to spend more time outdoors. PMID- 23662965 TI - An introduction to Point-Counterpoint articles. PMID- 23662967 TI - Can the retina alone detect the sign of defocus? AB - In the following point-counterpoint article, internationally-acclaimed myopia researchers were challenged to defend the two opposing sides of the topic defined by the title; their contributions, which appear in the order, Point followed by Counterpoint, were peer-reviewed by both the editorial team and an external reviewer. Independently of the invited authors, the named member of the editorial team provided an Introduction and Summary, both of which were reviewed by the other members of the editorial team. By their nature, views expressed in each section of the Point-Counterpoint article are those of the author concerned and may not reflect the views of all of the authors. PMID- 23662966 TI - Form deprivation and lens-induced myopia: are they different? AB - In the following point-counterpoint article, internationally-acclaimed myopia researchers were challenged to defend the two opposing sides of the topic defined by the title; their contributions, which appear in the order Point followed by Counterpoint, were peer-reviewed by both the editorial team and an external reviewer. Independently of the invited authors, the named member of the editorial team provided an Introduction and Summary, both of which were reviewed by the other members of the editorial team. By their nature, views expressed in each section of the Point-Counterpoint article are those of the author concerned and may not reflect the views of all of the authors. PMID- 23662968 TI - Does sunlight (bright lights) explain the protective effects of outdoor activity against myopia? AB - In the following point-counterpoint article, internationally-acclaimed myopia researchers were challenged to defend the two opposing sides of the topic defined by the title; their contributions, which appear in the order, Point followed by Counterpoint, were peer-reviewed by both the editorial team and an external reviewer. Independently of the invited authors, the named member of the editorial team provided an Introduction and Summary, both of which were reviewed by the other members of the editorial team. By their nature, views expressed in each section of the Point-Counterpoint article are those of the author concerned and may not reflect the views of all of the authors. PMID- 23662969 TI - How does atropine exert its anti-myopia effects? AB - In the following point-counterpoint article, internationally-acclaimed myopia researchers were challenged to defend the two opposing sides of the topic defined by the title; their contributions, which appear in the order, Point followed by Counterpoint, were peer-reviewed by both the editorial team and an external reviewer. Independently of the invited authors, the named member of the editorial team provided an Introduction and Summary, both of which were reviewed by the other members of the editorial team. By their nature, views expressed in each section of the Point-Counterpoint article are those of the author concerned and may not reflect the views of all of the authors. PMID- 23662970 TI - Does peripheral retinal input explain the promising myopia control effects of corneal reshaping therapy (CRT or ortho-K) & multifocal soft contact lenses? AB - In the following point-counterpoint article, internationally-acclaimed myopia researchers were challenged to defend the two opposing sides of the topic defined by the title; their contributions, which appear in the order Point followed by Counterpoint, were peer-reviewed by both the editorial team and an external reviewer. Independently of the invited authors, the named member of the editorial team provided an Introduction and Summary, both of which were reviewed by the other members of the editorial team. By their nature, views expressed in each section of the Point-Counterpoint article are those of the author concerned and may not reflect the views of all of the authors. PMID- 23662971 TI - Is scleral cross-linking a feasible treatment for myopia control? PMID- 23662972 TI - Incidence, causes and outcomes of lameness cases in a working military horse population: a field study. AB - REASONS FOR PERFORMING STUDY: Lameness is a common problem in the horse. Despite this, information on the incidence of lameness in horses in the UK is restricted to studies of lameness in performance horses, racehorses or referral hospital populations. OBJECTIVES: To determine the overall incidence and common causes of lameness in a working horse population and incidence, duration and outcome of conditions observed. STUDY DESIGN: Prospective questionnaire study. METHODS: Questionnaires were used to record lameness episodes in 294 horses in an equine military establishment. Information recorded included age, years of service, type of work, causal lesion, time taken to return to work and outcome. Lameness problems could be reported by any staff involved in the horses' care and were diagnosed by a veterinary surgeon or qualified farrier. Trends between lame and nonlame populations were compared using Chi-square analysis. Lameness diagnoses were grouped and analysed by disease category. RESULTS: Completed questionnaires for 273 horses were analysed. The mean monthly incidence of lameness was 2.1%, equivalent to an annual rate of 25.4 cases per 100 horses per annum, with a mean of 1.2 lameness episodes per horse in the lame population. Horse age and duration of service were not significantly different between lame and nonlame populations. The most common diagnoses were cellulitis (18.6%), skin wounds (16.3%) and foot/shoeing problems (11.6%) and 88% of cases had returned to previous levels of work by the conclusion of the study. CONCLUSIONS: This initial field study showed that lameness is a common occurrence in this working military horse population and the majority of cases make a full return to work. The most common causes of lameness identified in this study and outcomes of these conditions differ from existing literature. POTENTIAL RELEVANCE: This study highlights the need for further studies of lameness in the wider horse population. PMID- 23662973 TI - Diagnosis of double-chambered left ventricle using advanced cardiovascular imaging. AB - Double-chambered ventricle is a rare congenital cardiac abnormality, most commonly affecting the right ventricle. Here, we report a case of an incidental diagnosis of this condition affecting the left ventricle (LV), which is found much less frequently, and the use of contrast echocardiography in its evaluation. The addition of computed tomography (CT), highlighting the blood supply of both chambers by the left anterior descending (LAD) artery allowed us to confirm the diagnosis. PMID- 23662974 TI - The safety and efficacy of apixaban : where do we stand in 2013? AB - INTRODUCTION: Traditional oral anticoagulants, such as warfarin, are effective but require frequent laboratory monitoring for dose adjustment and have several known interactions with food and other drugs. Oral direct factor Xa inhibitors are an emerging class of anticoagulants that do not require routine laboratory monitoring. We reviewed the pharmacokinetics and pharmacology as well as the clinical safety and efficacy of apixaban , an oral direct factor Xa inhibitor. AREAS COVERED: Data from Phase II and III clinical trials and secondary analysis involving apixaban were included. Studies using apixaban for stroke prevention in patients with atrial fibrillation, for the prevention and treatment of venous thromboembolism, and for secondary prevention of ischemic events in patients with acute coronary syndromes are discussed. EXPERT OPINION: Apixaban is a safe, effective, and attractive alternative to warfarin for stroke prevention in patients with nonvalvular atrial fibrillation. It is also a good option for the prevention of venous thromboembolic events after major orthopedic surgery and for the extended treatment of deep vein thrombosis and pulmonary embolism. Apixaban at a dose of 5 mg twice daily did not have a favorable risk/benefit profile for secondary prevention in high-risk patients with acute coronary syndromes. PMID- 23662975 TI - Giant prolactinomas: the therapeutic approach. AB - BACKGROUND: Giant prolactinomas are an unusual subset of macroprolactinomas and are more commonly found in men. The goal of this review is to propose a giant prolactinoma definition and discuss the available therapeutic options for biochemical and tumour volume control. METHODS: A comprehensive search of all published studies was performed between April and November 2012 in electronic databases (PubMed and Ovid). RESULTS: A giant prolactinoma should be defined as an adenoma with a maximum diameter of more than 4 cm that is associated with serum prolactin above 5300 mIU/l. Regarding treatment, cabergoline is the preferred dopamine agonist for medical management of giant prolactinomas because of its excellent efficacy and tolerability. Normalization of prolactin level and significant tumour reduction may be achieved in the majority of patients. Combined therapy, particularly cabergoline and surgery, may be necessary due to the large tumour load. Radiotherapy and temozolomide may be used for patients with aggressive giant prolactinomas in whom tumour volume control is not achieved with cabergoline and surgery. CONCLUSION: There is a scarcity of large studies about the management of giant prolactinoma. Cabergoline is the first-line treatment. However, caution should be exercised when comparing efficacy rates among the different treatment modalities due to the variability in study design and data quality. In this scenario, a 'standard' definition for giant prolactinomas and larger series may be helpful to assess the real efficacy and safety of each therapeutic modality. PMID- 23662976 TI - Comparison of clinical effectiveness of the emergent colonoscopy in patients with hematochezia according to the type of bowel preparation. AB - BACKGROUND AND AIMS: Colonoscopy (CFS) is a valuable diagnostic tool in patients with hematochezia. However, the optimal preparation method of emergent CFS for hematochezia has not been defined. We investigated the clinical effectiveness of bowel preparation of patients with hematochezia using polyethylene glycol (PEG) solution and glycerin or water enemas. METHODS: The medical records of the past 7 years were reviewed. Patients presenting with hematochezia that occurred within 24 h before admission were eligible for the study. All patients underwent CFS within 24 h after visiting the emergency room for hematochezia. Patients were classified into two groups according to the preparation method used (enema vs. PEG). RESULTS: Overall, 194 patients (125 enema vs. 69 PEG) were enrolled. The diagnostic rate of bleeding focus was lower in the enema group than in the PEG group (84% vs. 97.1%, P = 0.008). Performance of endoscopic hemostasis at the initial CFS was more frequent in the enema group than in the PEG group (40.8% vs. 10.1%, P < 0.001). The rate of repeated CFS was higher in the enema group than in the PEG group (44.0% vs. 18.8%, P < 0.001). Post-polypectomy bleeding (n = 33) was diagnosed during the initial study and was treated endoscopically. In cases of post-polypectomy bleeding, CFS (93.9%) was performed after an enema in all but two cases. CONCLUSIONS: In hematochezia patients, the PEG group showed a higher diagnostic rate and lower rate of repeated CFS. However, emergent CFS after an enema only seems to be useful in patients with severe hematochezia or if the bleeding focus can be presumed. PMID- 23662977 TI - Outcomes of cardiopulmonary resuscitation efforts in a Greek tertiary hospital. AB - INTRODUCTION: In-hospital cardiac arrest is a leading cause of death and despite recent advances in cardiopulmonary resuscitation, the survival to hospital discharge is poor. The aim of our study was to evaluate the success of resuscitation efforts in a tertiary hospital. PATIENTS AND METHODS: We retrospectively collected and analysed data on all patients in whom cardiopulmonary resuscitation was attempted after in-hospital cardiac arrest in one-year period. RESULTS: 96 cardiac arrest victims were studied. Sustained return of spontaneous circulation was achieved in 15 (15.6%) patients, while all of them survived for 24 h. Training in cardiopulmonary resuscitation, initiation of resuscitation efforts in less than 5 min, and intubation time < 1 min after team arrival were predictive factors associated with restoration of spontaneous circulation. Non-certified residents resuscitated 87 (90.6%) patients with 6 (6.8%) of them achieving return of spontaneous circulation and surviving for 24 h. On the contrary, certified ward residents resuscitated nine (9.3%) patients with 100% immediate and 24-h survival. CONCLUSION: In our hospital, certified providers had remarkably higher successful resuscitation rates for in-hospital cardiac arrest than non-certified providers. This finding suggests that training in cardiopulmonary resuscitation, continuing medical education, and implementation of the existing legislation will result in increased survival. PMID- 23662978 TI - Recovering speciation and extinction dynamics based on phylogenies. AB - Phylogenetic trees of only extant species contain information about the underlying speciation and extinction pattern. In this review, I provide an overview over the different methodologies that recover the speciation and extinction dynamics from phylogenetic trees. Broadly, the methods can be divided into two classes: (i) methods using the phylogenetic tree shapes (i.e. trees without branch length information) allowing us to test for speciation rate variation and (ii) methods using the phylogenetic trees with branch length information allowing us to quantify speciation and extinction rates. I end the article with an overview on limitations, open questions and challenges of the reviewed methodology. PMID- 23662979 TI - Quenching and sensitizing fullerene photoreactions by natural organic matter. AB - Effects of natural organic matter (NOM) on the photoreaction kinetics of fullerenes (i.e., C60 and fullerenol) were investigated using simulated sunlight and monochromatic radiation (365 nm). NOM from several sources quenched (slowed) the photoreaction of C60 aggregates in water (aqu/nC60), but sensitized (accelerated) photoreaction of fullerenol. Kinetic studies indicated that the quenching occurred through a static mechanism involving NOM molecules adsorbed on the aqu/nC60 surface. Quenching constants for the photoreaction of aqu/nC60 correlated approximately with optical parameters related to the aromaticity and molecular size of the NOM. Association of aqu/nC60 particles with NOM was investigated indirectly via the study of the aggregation kinetics of colloidal C60 in the presence and absence of NOM as a function of NaCl strength at pH 7. In contrast to aqu/nC60, the photoreaction efficiencies of the hydrophilic fullerene, fullerenol, increased linearly with increasing NOM concentrations and kinetic parameters for the sensitized photoreactions increased as the spectral slope coefficients and ratio of absorption coefficients at 254 to 365 nm (E2:E3) of the NOM increased. The results indicate that triplet excited states of the NOM are key intermediates in the photosensitized reactions. PMID- 23662980 TI - Evolution of ordered metal chalcogenide architectures through chemical transformations. AB - Metal chalcogenides are important materials for a myriad of devices, but the ability to control their porosity is lacking. We report a method of inducing hierarchically ordered porosity using surface-treated nanocrystals and complementary architecture-directing agents. The resulting mesoporous materials are robust to thermal annealing and chemical transformations. PMID- 23662981 TI - Dimerization of a flocculent protein from Moringa oleifera: experimental evidence and in silico interpretation. AB - Many proteins exist in dimeric and other oligomeric forms to gain stability and functional advantages. In this study, the dimerization property of a coagulant protein (MO2.1) from Moringa oleifera seeds was addressed through laboratory experiments, protein-protein docking studies and binding free energy calculations. The structure of MO2.1 was predicted by homology modelling, while binding free energy and residues-distance profile analyses provided insight into the energetics and structural factors for dimer formation. Since the coagulation activities of the monomeric and dimeric forms of MO2.1 were comparable, it was concluded that oligomerization does not affect the biological activity of the protein. PMID- 23662982 TI - Imaging diagnosis-pulmonary-tracheobronchial prolapse in a new Caledonian giant gecko (Rhacodactylus leachianus). AB - A 3-year-old male New Caledonian giant gecko, or Leach's gecko (Rhacodactylus leachianus) presented with acute lethargy and coelomic distention. Findings from survey radiographs and an upper gastrointestinal tract contrast study were consistent with severe aerophagia, a collapsed left lung, and hyperinflation of the right lung due to suspected bronchial obstruction. The gecko was treated with conservative medical management, but was found dead 5 days after presentation. Necropsy findings showed intussusception of the proximal left lung into the left mainstem bronchus and trachea. PMID- 23662983 TI - Rising trends in the prevalence of asthma and allergic diseases among school children in the north-west coastal part of Croatia. AB - OBJECTIVE: To estimate time trends in prevalence of symptoms and reported diagnosis related to asthma, allergic rhinitis/conjunctivitis and eczema among school children in the north-west coastal part of Croatia. METHODS: Results of two identical cross-sectional surveys conducted on the same area 8 years apart (school years 2001/02 versus 2009/10) in complete adherence to the protocol of the International Study of Asthma and Allergies in Childhood were compared. Surveyed population comprised two age groups: 6-7 years (n = 1634 versus n = 1052) and 13-14 years (n = 2194 versus 1181). RESULTS: Significant (p < 0.001) increases in prevalence (%) of symptoms related to asthma (8.4 versus 14.0), allergic rhinitis (17.5 versus 25.6), allergic rhinoconjunctivitis (6.7 versus 15.3) and eczema (3.4 versus 5.9) were observed in the 13-14-year-olds. In the 6 7-year-olds there were observed significant (p < 0.001) increases in prevalence of symptoms of eczema (5.4 versus 8.7) and allergic rhinitis (16.9 versus 22.1) whereas prevalence of symptoms related to asthma (9.7 versus 9.4; p = 0.398) and allergic rhinoconjunctivitis (5.6 versus 6.8; p = 0.102) showed to be stable. Significant increases in prevalence of reported diagnosis were observed for asthma (5.2 versus 6.9; p = 0.02) and hay fever (10.5 versus 14.6; p < 0.001) in the older, and for eczema (10.6 versus 14.1; p < 0.001) in the younger age group. CONCLUSION: Prevalence of asthma and allergic diseases among the school children living on the surveyed area showed a rising trend. PMID- 23662984 TI - Psychiatric symptoms in children prior to epilepsy surgery differ according to suspected seizure focus. AB - PURPOSE: Children and adolescents with epilepsy have an overrepresentation of psychiatric illness. However, few studies in pediatrics have characterized specific psychiatric conditions associated with seizure localization. In addition, degree to which psychiatric illness may be more prominent in children refractory to standard medical treatment for epilepsy is not known. The aim of this study was to assess psychiatric symptoms in children with medically refractory epilepsy and ascertain whether symptoms were associated with specific localization. METHODS: Case records were reviewed for 40 children with medically refractory epilepsy at the time of their referral for presurgical evaluation. Patients received a clinical psychiatric evaluation and parents completed the Child Behavioral Checklist (CBCL). Seizure localization was verified by pediatric epileptologists, and suitability for surgical procedures was verified by neurosurgical specialists. Groups were compared based on localization of seizure foci, either in the temporal lobe or predominantly extratemporal. KEY FINDINGS: The majority of the sample had psychiatric diagnoses and behavior problems, well beyond the level reported in chronic epilepsy populations. In addition, children with temporal lobe seizure foci had more CBCL behavioral problem categories rated in the clinically significant range, and also were more likely to have clinical diagnoses of depression. SIGNIFICANCE: Routine psychiatric evaluation prior to epilepsy surgery may be important for pediatric patients with medically refractory epilepsy. Psychiatric illness, particularly depression, may be especially prominent for those with temporal lobe seizure foci. PMID- 23662985 TI - Effect of two microbial phytases on mineral availability and retention and bone mineral density in low-phosphorus diets for broilers. AB - 1. The efficacy of supplementation of a low-phosphorus (low-P) maize-soyabean meal diet for broiler chickens with two different microbial (fungal and bacterial) phytases was examined. 2. Broiler chickens received a low-P maize soyabean meal diet containing either no phytase or one of the two phytases included at one and two times the manufacturer's recommended inclusion level for 21 d. 3. Titanium dioxide was included in the diets as an indigestible marker. Excreta were collected quantitatively from d 18 to 21, and at the end of the study the birds were killed and ileal digesta and leg bone samples collected. 4. No differences were observed for body weight gain and feed intake or apparent metabolisable energy (AME) among all dietary treatment groups. 5. Dietary phytase supplementation improved the apparent retention of Ca, Na and Cu and ileal phytate P absorption from 32% to 44% across inclusion levels. 6. Bone mineral density (BMD) was improved for both phytases across inclusion levels by, on average, 9% for the tibia and 13% for the femur. 7. Dietary phytase supplementation of the low-P diet improved apparent ileal digestibility of serine, glycine, valine, isoleucine, tyrosine, histidine, lysine and arginine. 8. When the results from the present study were combined with the results from other similar published studies and analysed statistically, factors such as dietary P and Ca concentration, as well as bird breed and age, rather than the type or activity of microbial phytase, had the greatest impact on the extent to which dietary supplementation improved P and Ca retention. 9. More work is required to explain the interrelationships between the multiple factors influencing the efficacy of phytase on the availability of dietary minerals. PMID- 23662987 TI - XRCC1 Arg194Trp and Arg399Gln polymorphisms are significantly associated with shorter survival in acute myeloid leukemia. AB - In the base excision repair pathway, the predominant DNA damage repair mechanism, X-ray repair cross-complementing group 1 (XRCC1) gene, has a crucial role. Defects in repair pathways are involved in cancer pathogenesis. Therefore, DNA repair genes might be involved in acute myeloid leukemia (AML) susceptibility. Our study aimed to evaluate the relationship between XRCC1 Arg194Trp, Arg280His and Arg399Gln polymorphisms and AML. Sixty-nine patients with AML and 147 healthy controls were included. We noted a significant association between the polymorphisms Arg194Trp (p-value = 0.0002 for Trp allele) and Arg399Gln (p-value = 0.003 for Gln allele) and AML risk. There was a significantly better overall survival among patients with AML with wild-type homozygous compared to those with at least one variant allele in the case of Arg194Trp (p-value = 0.0019) and Arg399Gln polymorphisms (p-value = 0.049). Our study suggests the involvement of XRCC1 Arg194Trp and Arg399Gln polymorphisms in the genetic predisposition to AML. These two XRCC1 polymorphisms could also be prognostic markers in AML as they were significantly associated with overall survival. PMID- 23662986 TI - Emerging moxifloxacin resistance in Pseudomonas aeruginosa keratitis isolates in South India. AB - PURPOSE: To describe temporal trends in Pseudomonas aeruginosa resistance to moxifloxacin in keratitis isolates from South India. METHODS: The Steroids for Corneal Ulcers Trial (SCUT) was a randomized, double-masked, placebo-controlled trial assessing outcomes in patients with culture positive bacterial corneal ulcers randomized to receive prednisolone phosphate or placebo. All patients received moxifloxacin, and susceptibility to moxifloxacin was measured at baseline using Etest. We investigated trends in moxifloxacin susceptibility of P. aeruginosa during 2007, 2008, and 2009 isolated in SCUT in South India. RESULTS: There were 89 P. aeruginosa isolates during 2007, 2008, and 2009 in SCUT that were eligible for this study. There was an increase in the proportion of resistant isolates from 19% in 2007 to 52% in 2009 (p = 0.02, chi(2) test for trend). Logistic regression showed that there was a 2-fold increase in odds of resistance per 1 year increase during the study period (odds ratio 2.16, 95% confidence interval 1.09-4.26, p = 0.027). CONCLUSIONS: We found a sharp increase in the proportion of isolates that were resistant to moxifloxacin from 2007 to 2009. Further work needs to be done to characterize the nature of this increase. PMID- 23662988 TI - Plasma cell CD20 expression: primary aberrant expression or receptor up regulation. PMID- 23662989 TI - Searching the central nervous system for relapsed acute promyelocytic leukemia. PMID- 23662991 TI - Analysis of activation-induced cytidine deaminase mRNA levels in patients with chronic lymphocytic leukemia with different cytogenetic status. AB - Activation induced cytidine deaminase (AID) enzyme, which converts cytosine into uracil and is expressed only by activated B lymphocytes, plays a role in B cells in both the mechanisms of somatic hypermutation (SHM) and class switch recombination (CSR). There are studies showing that AID can cause numerous translocations in different lymphoproliferative diseases. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of monoclonal B cells in bone marrow and peripheral blood. The predictability and clinical status of B-CLL are difficult to determine. About 30-50% of patients have chromosomal abnormalities. AID, which is thought to create fraction segments for translocations, might also cause deletions in DNA regions of 17p13, 11q22.3, 13q14 and 13q34 that are associated with prognostic implications in patients with CLL. In this study, the AID gene expression in patients with CLL with and without deletions was investigated. When compared to healthy subjects and patients without deletions, increased levels of AID expression in patients with deletions of 17p13, 11q22.3 or 13q14 were found, but not for the 13q34 region. Our results show that AID expression may be associated with deletions in patients with CLL. PMID- 23662990 TI - The characteristics and outcomes of patients with multiple myeloma dual refractory or intolerant to bortezomib and lenalidomide in the era of carfilzomib and pomalidomide. AB - Patients with multiple myeloma who are refractory or intolerant to both bortezomib and lenalidomide have a poor prognosis. Next-generation therapies carfilzomib and pomalidomide have shown promising activity in this dual refractory population. Here we describe the clinical characteristics and ascertain the effects of carfilzomib and pomalidomide on survival in this patient cohort. We retrospectively reviewed the records of 65 patients with dual refractory/intolerant myeloma diagnosed between January 2007 and May 2012 at a single institution. The median overall survival (OS) from the time patients became dual refractory/intolerant was 10.2 months. Patients who received carfilzomib or pomalidomide after they became dual refractory/intolerant had a better OS compared to those who did not (12.6 vs. 6.8 months, p = 0.03 by Wilcoxon test). Prospective randomized control trials are needed for confirmation. PMID- 23662992 TI - Higher World Health Organization grades of follicular lymphoma correlate with better outcome in two Nordic Lymphoma Group trials of rituximab without chemotherapy. AB - Abstract A common treatment for follicular lymphoma is rituximab monotherapy. To identify patients for whom this regimen is adequate as first-line therapy, we applied the World Health Organization (WHO) classification for grading follicular lymphoma in a prospective central pathology review of the biopsies of previously untreated patients in two randomized trials of rituximab without chemotherapy. In the first trial (n1 = 53), higher WHO grades correlated with longer time to next treatment, independently of clinical prognostic factors (p = 0.030); the finding was replicated in the second trial (n2 = 221; p = 0.019). Higher grades were associated with better treatment responses (p = 0.018). Furthermore, also grades externally confirmed by independent local pathologists correlated with time to next treatment (p = 0.048). Flow cytometry in a separate patient series showed that the intensity of CD20 increased with the malignant cell size (p < 0.00005). In conclusion, WHO grade 1 follicular lymphoma correlates with inferior outcome after rituximab monotherapy. WHO grading might provide a clinically useful tool for personalized therapy. PMID- 23662993 TI - L-asparaginase: an effective agent in the treatment of acute lymphoblastic leukemia. AB - L-asparaginase (L-ASNase) is an enzyme used most effectively in the treatment of acute lymphoblastic leukemia (ALL) for more than 30 years. It catalyzes the hydrolysis of amino acid l-asparagine to aspartic acid and ammonia, which leads to cell death. Clinical trials have been conducted using L-ASNase in combination with other drugs and radiotherapy, which have led to great success in the treatment of ALL. Treatments consist of induction therapy and central nervous system therapy. The achievement of complete remission in patients is associated with a few side-effects of using L-asparaginase, including pancreatitis, coagulation abnormalities and allergic reactions. Sometimes tumor cells may develop resistance to L-ASNase. To overcome these difficulties, the drug is modified by pegylation or immobilization, and also treatment protocols can be modified to increase the efficiency of the drug. PMID- 23662994 TI - Tensor decomposition and vibrational coupled cluster theory. AB - The use of tensor decomposition in the calculation of anharmonic vibrational wave functions is discussed. The correlation amplitudes of vibrational coupled cluster (VCC) and vibrational configuration interaction (VCI) theories are considered as tensors and decomposed. A pilot code is implemented allowing a numerical study of the performance of the canonical decomposition/parallel factors (CP) for three and higher mode couplings in computations on water, formaldehyde, and 1,2,5 thiadiazole. The results show that there is a significant perspective in applying tensor decomposition in the context of anharmonic vibrational wave functions, with the CP tensor decomposition providing compression of data and a computational convenient representation. The calculations also illustrate how the multiplicative separability of the VCC ansatz with respect to noninteracting degrees of freedom goes well together with a tensor decomposition approach. Tensor decomposition opens for adjusting the computational effort spent on a particular mode-coupling according to the significance of that particular coupling, which is guaranteed to decrease to zero in the case of VCC in the limit of noninteracting subsystems. PMID- 23662995 TI - Factors associated with the relapse of infantile haemangiomas in children treated with oral propranolol. AB - BACKGROUND: Although propranolol has become the first-line therapy for infantile haemangiomas (IHs), no study has yet investigated factors associated with the risk of relapse in children with IH treated with propranolol after cessation of treatment. OBJECTIVES: To compare factors associated with the risk of relapse in children with IH treated with oral propranolol. METHODS: We conducted a single centre retrospective observational study. All files and photographs of patients with IH aged 5 months or less at the time of treatment initiation, and who were seen between 1 June 2008 and 31 December 2011 at the National Reference Center for rare skin diseases of Bordeaux, were retrospectively reviewed. RESULTS: In total 158 children were included, of whom 118 had not relapsed and 40 had relapsed. Fifty-two patients were boys and 106 were girls (male : female ratio 1 : 2), and 19 had a segmental IH (12%). When conducting multivariate analysis, only IHs with a deep component and those with segmental distribution were independently associated with relapse. CONCLUSIONS: Our study shows that segmental IHs, as well as haemangiomas with a deeper component, are more at risk of relapse and should thus indicate closer follow-up after treatment interruption, and/or longer treatment. PMID- 23662996 TI - A long-term study on the clinical effects of mechanical widening of cheek teeth diastemata for treatment of periodontitis in 202 horses (2008-2011). AB - REASON FOR PERFORMING STUDY: Cheek teeth diastemata are a common cause of painful periodontal disease in horses, but there is limited objective information on their treatment. OBJECTIVE: To assess the long-term response to diastema widening in clinically affected horses. STUDY DESIGN: Retrospective study. METHOD: Medical records from cases of cheek teeth diastemata treated by diastema widening referred to the University of Edinburgh Equine Hospital from 2008 to 2011 were analysed. RESULTS: During this period, 302 horses were diagnosed with clinically significant cheek teeth diastemata, of which 202, median age 11 years, with severe associated periodontitis were treated by widening of 674 problematic diastemata; 89.8% between mandibular cheek teeth and 10.2% between maxillary cheek teeth, with a mean of 1.5 treatments performed per case. These 202 cases showed quidding in 76.2%; weight loss in 33.2%; bitting problems in 20.1% and halitosis in 10.9%, with 5.4% being asymptomatic. Follow-up of 92% of treated cases, a mean of 20.8 months after their initial treatment, showed that 72.6% had complete remission of clinical signs that was permanent (for the duration of this study) in 50.5% and temporary in 22%. A partial response was obtained in 17.2%, no response was obtained in 4.3%, and owners were unsure of response in 5.9%. Clinical improvement was sometimes delayed, with 19% taking >4 weeks following treatment for improvement. Inappropriate sites were burred in individual teeth of 6 horses, causing iatrogenic pulpar exposure in 2 cases, but following treatment none developed clinical signs of apical infection. CONCLUSIONS: Diastema widening is an effective but potentially invasive treatment for horses with cheek teeth diastemata with severe periodontitis. POTENTIAL RELEVANCE: Diastema widening by trained personnel is suitable for advanced cases of cheek teeth diastema, but many cases require repeated treatments. PMID- 23662997 TI - Editorial comment to "Differential diagnosis between bacterial infection and neoplastic fever in patients with advanced urological cancer: the role of procalcitonin". PMID- 23662998 TI - Doppler markers of elevated left atrial and ventricular filling pressure in a critically ill patient. AB - Accurate assessment of intracardiac flows by Doppler echocardiography may add important hemodynamic information in the critically ill patient. Detailed analysis of flow gradients through different sites and their correlation with timing of cardiac events may help us in better understanding the pathophysiology of the underlying disease. We report the clinical case of a 78-year-old patient with septic shock, in whom an A-dip of aortic regurgitation, shortening of diastolic filling, and diastolic mitral regurgitation were detected by Doppler analysis. Pathophysiologic explanation of these phenomena and their evolution after inotropic drug infusion are reported. PMID- 23662999 TI - In-season root-zone N management for mitigating greenhouse gas emission and reactive N losses in intensive wheat production. AB - Although both the grain yields and environmental costs of nitrogen (N) fertilization are gaining more public and scientific debate, the complex linkages among crop productivity, N application rate, environmental footprints, and the consequences of improved N management are not well understood. We considered the concept of linking greenhouse gas (GHG) emission, reactive N losses, and N fertilizer application rates with crop productivity to determine the response of the GHG emission and reactive N losses to N surplus and further evaluated the potential to reduce these N environmental footprints by in-season root-zone N management. A meta-analysis suggested an exponential increase in the response of direct N2O emissions and nitrate leaching to an increasing N surplus, while NH3 volatilization increased linearly with an increasing N application rate for intensive wheat production in north China. The GHG emission and reactive N losses during N fertilizer application increased exponentially with an increasing N surplus. By pooling all 121 on-farm experimental sites, an in-season root-zone N management strategy was shown to reduce the N application rate by 61% from 325 kg N ha(-1) to 128 kg N ha(-1) compared to the farmers' N practice, with no loss in wheat grain yield. As a result, the intensity of GHG emission and reactive N losses were reduced by 77% and 80%, respectively. The intensity of GHG emission and reactive N losses can be further reduced due to the improved N recovery and increased grain yield achieved by best crop management. In conclusion, N recovery efficiency and yield improvements should be used to reduce future agricultural N environmental footprints, rather than reducing the N application rate. PMID- 23663000 TI - Perceived vision-related quality of life and risk of falling among community living elderly people. AB - Falls and fall injuries among the elderly population are common, since ageing is a risk factor of falling. Today, this is a major problem because the ageing population is increasing. There are predictive factors of falling and visual impairment is one of them. Usually, only visual acuity is considered when measuring visual impairment, and nothing regarding a person's functional visual ability is taken into account. Therefore, the aim of this study was to assess the perceived vision-related quality of life among the community living elderly using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) and to investigate whether there was any association among vision-related quality of life and falls. There were 212 randomly selected elderly people participating in the study. Our study indicated that the participants had an impaired perceived vision-related health status. General health was the only NEI VFQ-25 variable significantly associated with falls in both men and women. However, among men, near and distance activities, vision-specific social functioning, role difficulties and dependency, color and peripheral vision were related to falls. PMID- 23663001 TI - Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies. AB - PURPOSE: Three phase III studies (304 [ClinicalTrials.gov identifier: NCT00699972], 305 [NCT00699582], 306 [NCT00700310]) evaluated perampanel, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, as adjunctive therapy for refractory partial seizures. We report post hoc analyses of pooled study data by randomized dose. METHODS: Patients with partial seizures despite receiving 1-3 antiepileptic drugs were randomized to once-daily placebo, perampanel 8 or 12 mg (studies 304, 305), or placebo, perampanel 2, 4, or 8 mg (study 306). Studies included a 6-week baseline period and double-blind treatment phase (6-week titration; 13-week maintenance). Primary end points were median change in partial seizure frequency (baseline vs. double blind phase) and percentage of patients achieving >= 50% reduction in seizure frequency (baseline vs. maintenance). Here, these end points, together with secondary, exploratory, and safety end points, were assessed using pooled study data. KEY FINDINGS: The pooled intent-to-treat analysis set (randomized, treated patients with any seizure data) included 1,478 patients. Median changes in partial seizure frequency were greater with perampanel than placebo (perampanel 4 mg, -23.3%; 8 mg, -28.8%; 12 mg, -27.2%; placebo, -12.8%; p < 0.01, each dose vs. placebo), as were 50% responder rates (perampanel 4 mg, 28.5%; 8 mg, 35.3%; 12 mg, 35.0%; placebo, 19.3%; p < 0.05, each dose vs. placebo). In addition, median changes in complex partial plus secondary generalized seizure frequency were also greater with perampanel than placebo (perampanel 4 mg, -31.2%; 8 mg, -35.6%; 12 mg, -28.6%; placebo, -13.9%). Perampanel was generally well tolerated. The most frequent treatment-emergent adverse events (TEAEs) were dizziness, somnolence, and headache. Most TEAEs were mild/moderate; relatively few patients experienced severe TEAEs (placebo, 5.4%; perampanel, 8.9%) or serious TEAEs (placebo, 5.0%; perampanel, 5.5%). There were no deaths and no clinically important mean changes in laboratory values, electrocardiography (ECG) findings, or vital signs. SIGNIFICANCE: Perampanel reduced partial seizure frequency and improved responder rates compared with placebo, with an acceptable tolerability profile. PMID- 23663002 TI - MAPK cascades in plant disease resistance signaling. AB - Mitogen-activated protein kinase (MAPK) cascades are highly conserved signaling modules downstream of receptors/sensors that transduce extracellular stimuli into intracellular responses in eukaryotes. Plant MAPK cascades play pivotal roles in signaling plant defense against pathogen attack. In this review, we summarize recent advances in the identification of upstream receptors/sensors and downstream MAPK substrates. These findings revealed the molecular mechanisms underlying MAPK functions in plant disease resistance. MAPK cascades have also emerged as battlegrounds of plant-pathogen interactions. Activation of MAPKs is one of the earliest signaling events after plant sensing of pathogen/microbe associated molecular patterns (PAMPs/MAMPs) and pathogen effectors. MAPK cascades are involved in signaling multiple defense responses, including the biosynthesis/signaling of plant stress/defense hormones, reactive oxygen species (ROS) generation, stomatal closure, defense gene activation, phytoalexin biosynthesis, cell wall strengthening, and hypersensitive response (HR) cell death. Pathogens, however, employ effectors to suppress plant MAPK activation and downstream defense responses to promote pathogenesis. PMID- 23663003 TI - Status and prospects of plant virus control through interference with vector transmission. AB - Most plant viruses rely on vector organisms for their plant-to-plant spread. Although there are many different natural vectors, few plant virus-vector systems have been well studied. This review describes our current understanding of virus transmission by aphids, thrips, whiteflies, leafhoppers, planthoppers, treehoppers, mites, nematodes, and zoosporic endoparasites. Strategies for control of vectors by host resistance, chemicals, and integrated pest management are reviewed. Many gaps in the knowledge of the transmission mechanisms and a lack of available host resistance to vectors are evident. Advances in genome sequencing and molecular technologies will help to address these problems and will allow innovative control methods through interference with vector transmission. Improved knowledge of factors affecting pest and disease spread in different ecosystems for predictive modeling is also needed. Innovative control measures are urgently required because of the increased risks from vector-borne infections that arise from environmental change. PMID- 23663004 TI - Pine wood nematode, Bursaphelenchus xylophilus. AB - After devastating vast areas of pine forests in Asian countries, the pine wilt disease spread into European forests in 1999 and is causing worldwide concern. This disease involves very complicated interactions between a pathogenic nematode, its vector beetle, host pine species, and fungi in dead hosts. Pathogenicity of the pine wood nematode is determined not only by its physical and chemical traits but also by its behavioral traits. Most life history traits of the pine wood nematode, such as its phoretic relationship with vector beetles, seem to be more effective in virulent than in avirulent isolates or species. As the pathogenicity determinants, secreted enzymes, and surface coat proteins are very important, they have therefore been studied intensively. The mechanism of quick death of a large pine tree as a result of infection by a tiny nematode could be ascribed to the dysfunction of the water-conducting system caused by the death of parenchyma cells, which must have originally evolved as an inherent resistant system. PMID- 23663005 TI - The life history of Pseudomonas syringae: linking agriculture to earth system processes. AB - The description of the ecology of Pseudomonas syringae is moving away from that of a ubiquitous epiphytic plant pathogen to one of a multifaceted bacterium sans frontieres in fresh water and other ecosystems linked to the water cycle. Discovery of the aquatic facet of its ecology has led to a vision of its life history that integrates spatial and temporal scales spanning billions of years and traversing catchment basins, continents, and the planet and that confronts the implication of roles that are potentially conflicting for agriculture (as a plant pathogen and as an actor in processes leading to rain and snowfall). This new ecological perspective has also yielded insight into epidemiological phenomena linked to disease emergence. Overall, it sets the stage for the integration of more comprehensive contexts of ecology and evolutionary history into comparative genomic analyses to elucidate how P. syringae subverts the attack and defense responses of the cohabitants of the diverse environments it occupies. PMID- 23663006 TI - The potential role of valsartan + AHU377 ( LCZ696 ) in the treatment of heart failure. AB - INTRODUCTION: Heart failure remains a syndrome with a very high mortality rate and a poor quality of life. For patients with heart failure and a preserved ejection fraction (HFpEF), no drugs have shown to improve mortality and morbidity, and therefore novel drugs are highly needed. LCZ696 , a first in class angiotensin receptor neprilysin inhibitor (ARNi), might be an interesting novel drug for the treatment of heart failure. AREAS COVERED: Previous studies have shown promising effects of a combination drug with a neutral endopeptidase and an angiotensin-converting enzyme inhibitor (omapatrilat) for the treatment of patients with heart failure. However, the occurrence of angioedema prevented the drug from further development. The majority of this paper will discuss the metabolism, pharmacokinetics, pharmacodynamics, clinical effects, and safety of LCZ696, with a particular focus on heart failure. EXPERT OPINION: LCZ696 is superior to valsartan alone in reducing blood pressure. Preliminary results from a Phase II trial showed that LCZ696 reduced NT-proBNP to a greater extent than valsartan alone, and in addition LCZ696 had beneficial effects on symptoms. With these promising first results, the results of ongoing further studies in heart failure are eagerly awaited. PMID- 23663007 TI - Repeated and controlled growth of monolayer, bilayer and few-layer hexagonal boron nitride on Pt foils. AB - Atomically thin hexagonal boron nitride (h-BN), as a graphene analogue, has attracted increasing interest because of many fascinating properties and a wide range of potential applications. However, it still remains a great challenge to synthesize high-quality h-BN with predetermined number of layers at a low cost. Here we reported the controlled growth of h-BN on polycrystalline Pt foils by low cost ambient pressure chemical vapor deposition with ammonia borane as the precursor. Monolayer, bilayer and few-layer h-BN domains and large-area films were selectively obtained on Pt by simply changing the concentration of ammonia borane. Moreover, using a bubbling method, we have achieved the nondestructive transfer of h-BN from Pt to arbitrary substrates and the repeated use of the Pt for h-BN growth, which not only reduces environmental pollution but also decreases the production cost of h-BN. The monolayer and bilayer h-BN obtained are very uniform with high quality and smooth surfaces. In addition, we found that the optical band gap of h-BN increases with decreasing number of layers. The repeated growth of large-area, high-quality monolayer and bilayer h-BN films, together with the successful growth of graphene, opens up the possibility for creating various functional heterostructures for large-scale fabrication and integration of novel electronics. PMID- 23663008 TI - An evaluation of asthma medication utilization for risk evaluation and mitigation strategies (REMS) in the United States: 2005-2011. AB - PURPOSE: The purpose of this study was to assess drug utilization patterns of fluticasone propionate (FP)/salmeterol (SAL) combination (FSC) and SAL over the 7 year period of 2005-2011 in patients with asthma as part of the Risk Evaluation and Mitigation Strategies (REMS). METHODS: A descriptive, retrospective observational study utilizing national pharmacy data and employer-based claims data to characterize drug utilization patterns. RESULTS: For patients with asthma, the total number of FSC and SAL dispensings and users of FSC and SAL has declined between 2005 and 2011. During this period, FSC and SAL dispensing for asthma decreased 24% and 76%, respectively, with a more pronounced decline between 2010 and 2011 relative to other years. The total number of patients with asthma who were dispensed FSC has decreased by 10% among adults and by 40% in children and adolescents. While SAL-containing medications decreased, dispensing of FP monotherapy increased 39% during the same 7-year period. The number of patients dispensed FP for asthma has increased 47% in children 4-11 years of age, 72% in adolescents 12-17 years of age, and 6% in adults. SAL use without a controller was infrequent and decreasing, reported by 1.7% and 0.5% of patients with asthma in 2005 and 2011, respectively. CONCLUSIONS: In patients with asthma, use of FSC and SAL decreased between 2005 and 2011, while the use of FP increased. Use of SAL monotherapy was infrequent and declined during the study period. The data suggest that the substantial communication activities have encouraged appropriate prescribing of long-acting beta2-adrenergic agonist (LABA). PMID- 23663009 TI - Clinical implications of menstrual cycle length in oligomenorrhoeic young women. AB - OBJECTIVE: Although menstrual irregularity is associated with insulin resistance and hyperandrogenism, the relationship between the severity of menstrual infrequency and clinical phenotypes in young women with oligomenorrhoea (OM) is unclear. We evaluated whether a longer menstrual cycle length is associated with less favourable metabolic features. DESIGN/PATIENTS/MEASUREMENTS: A total of 1174 young women (aged 19-39 years) with a menstrual cycle length over 40 days and 1430 women with regular menstrual cycles participated voluntarily. Metabolic parameters, insulin sensitivity index (ISI) and testosterone were measured. Oligomenorrhoeic women were divided into three groups: (i) polycystic ovary syndrome (PCOS) by National Institute of Health criteria, (ii) severe OM (menstrual cycle length >60 days), and (iii) mild OM (menstrual cycle length 40 60 days). RESULTS: In normal-weight women (BMI < 23 kg/m(2)), the degrees of insulin resistance and hyperandrogenaemia are the highest in PCOS and higher in severe OM compared with mild OM. In overweight or obese women, PCOS was more insulin resistant and hyperandrogenaemic, but there was no difference between severe and mild OM. After excluding PCOS, women with severe OM showed a twofold increased risk of metabolic syndrome compared with regular cycling women (odds ratio 2.4, 95% confidence interval 1.1-5.6). By linear regression analysis, a longer menstrual cycle length was associated with ISI after adjustment for age, BMI, metabolic risk factors and testosterone. CONCLUSIONS: Women with a menstrual cycle length over 60 days should be more closely monitored for the metabolic syndrome than women with a menstrual cycle length of 40-60 days, even if they have no PCOS. PMID- 23663010 TI - Exploring the structural features of Aspartate Trans Carbamoylase (TtATCase) from Thermus thermophilus HB8 through in silico approaches: a potential drug target for inborn error of pyrimidine metabolism. AB - Enzymes involved in the pyrimidine biosynthesis pathway have become an important target for the pharmacological intervention. One among those enzymes, Aspartate Trans Carbamoylase (ATCase), catalyses the condensation of aspartate and carbamoyl phosphate to form N-carbamoyl-l-aspartate and inorganic phosphate. The present study provides the molecular insights into the enzyme ATCase. The three dimensional structure of ATCase from Thermus thermophilus HB8 was modeled based on the crystal structure of ATCase in Pyrococcus abyssi (PDB ID:1ML4). Molecular dynamics simulation was performed to identify the conformational stability of TtATCase with and without its ligand complexes. Based on the pharmacokinetic properties and the glide-docking scores of ligands from four databases (Maybridge, Binding, Asinex and Technology for Organic Synthesis (TOS laboratory) for the screening of ligands, we identified four potential ligand molecules for TtATCase. From the molecular docking results, we proposed that the residues Thr53, Arg104, and Gln219 are consistently involved in strong hydrogen-bonding interactions and play a vital role in the TtATCase activity. From the results of molecular dynamics simulation, the ligand molecules are found to bind appropriately to the target enzyme. However, the structure of TtATCase needs to be determined experimentally to confirm this. PMID- 23663012 TI - Use of cardiac magnetic resonance imaging for alcohol septal ablation in hypertrophic obstructive cardiomyopathy. AB - This is a report of a 58-year-old man with severe hypertrophic obstructive cardiomyopathy who underwent alcohol septal ablation to relieve symptoms due to severe left ventricular outflow obstruction. Cardiac magnetic resonance was performed before and after the procedure. This case highlights the potential use of cardiac magnetic resonance imaging in the surgical planning of alcohol septal ablation as well as following the procedure to assess for complications and morphological changes. PMID- 23663011 TI - Human induced pluripotent stem cells as a tool to model a form of Leber congenital amaurosis. AB - Our purpose was to investigate genes and molecular mechanisms involved in patients with Leber congenital amaurosis (LCA) and to model this type of LCA for drug screening. Fibroblasts from two unrelated clinically identified patients with a yet undetermined gene mutation were reprogrammed to pluripotency by retroviral transduction. These human induced pluripotent stem cells (hiPSCs) were differentiated into neural stem cells (NSCs) that mimicked the neural tube stage and retinal pigmented epithelial (RPE) cells that could be targeted by the disease. A genome-wide transcriptome analysis was performed with Affymetrix Exon Array GeneChip((r)), comparing LCA-hiPSCs derivatives to controls. A genomic search for alteration in all genes known to be involved in LCA revealed a common polymorphism on the GUCY2D gene, referenced as the LCA type I (OMIM *600179 and #204000), but the causative gene remained unknown. The hiPSCs expressed the key pluripotency factors and formed embryoid bodies in vitro containing cells originating from all three germ layers. They were successfully differentiated into NSC and RPE cells. One gene, NNAT, was upregulated in LCA cell populations, and three genes were downregulated, GSTT1, TRIM61 and ZNF558, with potential correlates for molecular mechanisms of this type of LCA, in particular for protein degradation and oxidative stress. The two LCA patient-specific iPSC lines will contribute to modeling LCA phenotypes and screening candidate drugs. PMID- 23663014 TI - Citric acid-assisted two-step enrichment with TiO2 enhances the separation of multi- and monophosphorylated peptides and increases phosphoprotein profiling. AB - Phosphopeptide enrichment is essential for large-scale phosphoprotein profiling. Titanium dioxide (TiO2) is widely used in phosphopeptide enrichment, but it is limited in the isolation of multiphosphorylated peptides due to their strong binding. In this study, we found that citric acid greatly affects the binding of mono- and multiphosphopeptides with TiO2, which can be used for stepwise phosphopeptide separation coupled with mass spectrum (MS) identification. We first loaded approximately 1 mg of peptide mixture of HeLa cell digests onto TiO2 beads in highly concentrated citric acid (1 M). Then the flow-through fraction was diluted to ensure low concentration of citric acid (50 mM) and followed by loading onto another aliquot of TiO2 beads. The two eluted fractions were subjected to nanoLC-MS/MS analysis. We identified 1,500 phosphorylated peptides, of which 69% were multiphosphorylated after the first enrichment. After the second enrichment, 2,167 phosphopeptides, of which 92% were monophosphorylated, were identified. In total, we successfully identified 3,136 unique phosphopeptides containing 3,973 phosphosites utilizing this strategy. Finally, more than 37% of the total phosphopeptides and 2.6-fold more of the multiphosphorylated peptides were identified as compared to the frequently used DHB/TiO2 enrichment strategy. Combining SCX with CATSET, we identified 14,783 phosphopeptides and 15,713 phosphosites, of which 3,678 were unrecorded in PhosphoSitePlus database. This two-step separation procedure for sequentially enriching multi- and monophosphorylated peptides by using citric acid is advantageous in multiphosphorylated peptide separation, as well as for more comprehensive phosphoprotein profiling. PMID- 23663013 TI - Ependymal and periventricular magnetic resonance imaging changes in four dogs with central nervous system blastomycosis. AB - Rapid detection of central nervous system (CNS) involvement is important for dogs with blastomycosis, as this can affect antifungal drug selection and has been associated with an increased risk of death. Previous reports describing magnetic resonance imaging (MRI) characteristics of canine CNS blastomycosis primarily identified mass lesions. The purpose of this retrospective study was to determine whether other MRI characteristics of CNS blastomycosis may also occur. Medical records of the Purdue University Veterinary Teaching Hospital were searched and four dogs met inclusion criteria. Magnetic resonance imaging characteristics included periventricular edema, periventricular and meningeal contrast enhancement, and ventriculomegaly. Periventricular lesions most commonly involved the rostral horn of the lateral ventricles and the third ventricle. Increased meningeal contrast enhancement involved the cerebrum, thalamus, sella turcica, and brainstem. Findings indicated that, in addition to mass lesions, MRI characteristics of periventricular hyperintensity, contrast enhancement, and ventriculomegaly may also occur in dogs with CNS blastomycosis. PMID- 23663015 TI - An answer to the lack of psychiatric services in developing countries. PMID- 23663016 TI - Clients' perspectives of the relationship of vulnerability and resilience in the context of HIV infection. AB - Clients with HIV infection have been described as both vulnerable and resilient. In addition, the conceptualization of clients with HIV infection has evolved. The purpose of this study is to examine this relationship among a sample of people with HIV infection. Qualitative description was the design used in this study. Interviews of 15 participants with HIV infection were conducted and analyzed using content analysis. All participants provided descriptions of the relationship of vulnerability and resilience in the context of HIV infection. Three different themes emerged from the data: Simultaneity, Dichotomy, and Vacillation. These themes were used to describe the relationship of vulnerability and resilience from the participants' perspectives. Among people with HIV infection vulnerability and resilience are related concepts. In the context of HIV infection, the relationship of these concepts needs further study in order to relate these concepts to the physical and mental health of people living with HIV infection, which may then assist in making these concepts less abstract and more clinically useful. PMID- 23663017 TI - Events prior to completed suicide: perspectives of family survivors. AB - Relatively little is known about the experiences of those bereaved by suicide, particularly in the weeks leading to the death of a loved one. This study used a qualitative methodology to explore the perspectives of close survivors of a completed suicide. Ten people who were bereaved by suicide participated in face to-face interviews that were digitally recorded, transcribed verbatim, and thematically analysed. Analysis revealed the following three themes: He Tried to Hang Himself: Purposeful indications of the intent to end life; They Still Ignored It: Disappointment with health services; and Nobody Talked to Me: Exclusion of family members from treatment information. Prior to the suicide of their loved one, participants had identified that the loved one was at risk and perceived they were unable to acquire appropriate assistance from services. Rather, services were perceived by participants as unsupportive and inadequate. Health and social service professionals could benefit from further specialised education concerning suicide and its sequelae to ensure more effective and sensitive care delivery to suicide survivors. PMID- 23663018 TI - The experience of seclusion and restraint in psychiatric settings: perspectives of patients. AB - Many studies report that the use of seclusion and restraint (SR) is experienced negatively by patients who experience feelings of shame, helplessness, and humiliation, and may relive previous trauma events. Since 2000, in Quebec, exceptional measures like SR have been framed by a protocol. This protocol provides health care teams with guidelines for relieving, containing, and reducing the suffering caused by SR. We have no knowledge, however, about the views of patients regarding application of the protocol. This study aims to understand the perception of patients regarding application of the SR protocol. For this purpose, a questionnaire was presented to patients (n = 50) who experienced an episode of SR in a psychiatric hospital in Canada. Results show that patients had a nuanced perception of SR: Some felt that SR was a helpful measure, while others felt that SR was not a helpful measure. Patients tended to agree with statements related to the comfort and safety of seclusion rooms and the meeting of their physical needs. Regarding support, they suggested relational, drug, and environmental interventions to prevent seclusion. Finally, nearly all patients perceived that the health care team did not follow-up with the patients after the experience; such follow-up is essential for reconstructing a sometimes confusing event. PMID- 23663019 TI - Minority caregivers' emotional responses and perceptions of the emotional responses of their children to asthma: comparing boys and girls. AB - Approximately 7.1 million children in the US suffer from asthma. An exploratory qualitative study using a stratified purposive sampling method was conducted. The sample included four Latina and four African American female caregivers of children (ages 6-12) who had asthma. Caregivers were asked open-ended questions about perceptions of their children's emotional responses to asthma. Major themes and subthemes were identified with content analysis. Sons were reported as quiet when experiencing asthma. Daughters were described as being verbal, worried, excited. A question from the study was whether the children's responses were related to caregivers' (a) actions, (b) responses to asthma, and/or(c) race/ethnicity. PMID- 23663020 TI - Active coping, personal satisfaction, and attachment to land in older African American farmers. AB - Elevated suicide mortality rates have been reported for farmers and for the elderly. Very little literature exists that looks at the health of older minority farmers. This mixed-method study describes older African-American farmers (N = 156) in the contexts of active coping, personal satisfaction from farm work, and attachment to their farmland to provide insight into the psychosocial dimensions of their mental health. Findings show that the farmers have positive perspectives on work and farm future, and strong attachment to the land. Differences were noted by gender. Nurses can use these findings to frame culturally appropriate strategies for aging farmers to maximize positive outcomes. PMID- 23663021 TI - Developing a manual for strengthening mental health nurses' clinical supervision. AB - In this article, we report findings from a study aimed at developing the content and implementation of a manual for a research-based intervention on clinical supervision of mental health nursing staff. The intervention was designed to strengthen already existing supervision practices through educational preparation for supervision and systematic reflection on supervision. The intervention consists of three sessions and was implemented on two groups of mental health hospital staff. We present an outline of the manual and explain how the trial sessions made us adjust the preliminary manual. The effects of implementing the manual will subsequently be analysed in an independent randomised controlled trial. PMID- 23663022 TI - Preventing the development of metabolic syndrome in people with psychotic disorders--difficult, but possible: experiences of staff working in psychosis outpatient care in Sweden. AB - The aim of this study was to explore mental health staffs' experiences of assisting people with psychotic disorders to implement lifestyle changes in an effort to prevent metabolic syndrome. Qualitative interviews were conducted with 12 health care professionals working in psychosis outpatient care in Sweden. Data were analysed using a qualitative content analysis. The results illustrate that implementation of lifestyle changes among people with psychotic disorders was experienced as difficult, but possible. The greatest obstacles experienced in this work were difficulties due to the reduction of cognitive functions associated with the disease. Guidelines available to staff in order to help them identify and prevent physical health problems in the group were not always followed and the content was not always relevant. Staff further described feelings of uncertainty about having to motivate people to take anti-psychotic medication while simultaneously being aware of the risks of metabolic deviations. Nursing interventions focusing on organising daily routines before conducting a more active prevention of metabolic syndrome, including information and practical support, were experienced as necessary. The importance of healthy eating and physical activity needs to be communicated in such a way that it is adjusted to the person's cognitive ability, and should be repeated over time, both verbally and in writing. Such efforts, in combination with empathic and seriously committed community-based social support, were experienced as having the best effect over time. Permanent lifestyle changes were experienced as having to be carried out on the patient's terms and in his or her home environment. PMID- 23663023 TI - Hearing the silent voices: narratives of health care and homelessness. AB - Most homeless individuals lack adequate health care. With existing literature as a backdrop, this study sought to understand the experience of homeless persons in the health care system. Using a phenomenological approach, 11 homeless participants were interviewed and the transcripts from these interviews were analyzed for meaning. The health care experiences of the participants could be understood only when viewed within the context of homelessness. The four polar themes that emerged from the analysis--same/different, fair/unfair, freedom/barriers, and choice/no choice--highlighted the great divide between the health care experiences of those with a home and those without. Such understanding can help mental health nurses provide more appropriate care to this population. PMID- 23663024 TI - Life goes on: the experiences of wives of multiply-deployed National Guard soldiers. AB - Whether a service member is active duty or part of the National Guard, deployment of these service members is a major issue for most families. There is limited knowledge of the experience of multiple deployments on the family. The purpose of this study was to describe experiences of wives of National Guard soldiers that were deployed more than once. Nine wives were interviewed. An analysis of the interviews revealed four themes: (1) "Life Goes On" (i.e., despite the repeated deployments, life continues at home); (2) the "Guard is a Different Animal" (i.e., life as a National Guard spouse is different from that of an active duty spouse); (3) "It's a Mind-Set" (i.e., how wives cope their husband's deployment); and (4) "Going Back Again" (i.e., wives' experiences of multiple deployments). Exploring how multiple deployments affects wives of National Guard soldiers is helpful in understanding their experiences and the adjustments that must be made in family life. Knowledge of the experiences of these wives may help in formulating more effective interventions with families who have experienced multiple deployments. PMID- 23663025 TI - Caring as a scripted discourse versus caring as an expression of an authentic relationship between self and other. AB - As health care has become increasingly complex, the human caring associated with nursing has become eclipsed by financial bottom lines and managed care initiatives. Because patients and others expect a caring health care system, hospitals have responded in varying ways to re-infuse caring into the patient's experience. This article examines two approaches (the Jean Watson Caring Science Approach and the Studer Group Approach) and considers the effect of each on the authenticity of the nurse patient relationship. PMID- 23663026 TI - AIDS 2012: Goals and accomplishments, the XIX international conference. PMID- 23663029 TI - Use of high-definition optical coherent tomography (HD-OCT) for imaging of melanoma. PMID- 23663028 TI - Speciation in ninespine stickleback: reproductive isolation and phenotypic divergence among cryptic species of Japanese ninespine stickleback. AB - Although similar patterns of phenotypic diversification are often observed in phylogenetically independent lineages, differences in the magnitude and direction of phenotypic divergence have been also observed among independent lineages, even when exposed to the same ecological gradients. The stickleback family is a good model with which to explore the ecological and genetic basis of parallel and nonparallel patterns of phenotypic evolution, because there are a variety of populations and species that are locally adapted to divergent environments. Although the patterns of phenotypic divergence as well as the genetic and ecological mechanisms have been well characterized in threespine sticklebacks, Gasterosteus aculeatus, we know little about the patterns of phenotypic diversification in other stickleback lineages. In eastern Hokkaido, Japan, there are three species of ninespine sticklebacks, Pungitius tymensis and the freshwater type and the brackish-water type of the P. pungitius-P. sinensis species complex. They utilize divergent habitats along coast-stream gradients of rivers. Here, we investigated genetic, ecological and phenotypic divergence among three species of Japanese ninespine sticklebacks. Divergence in trophic morphology and salinity tolerance occurred in the direction predicted by the patterns observed in threespine sticklebacks. However, the patterns of divergence in armour plate were different from those previously found in threespine sticklebacks. Furthermore, the genetic basis of plate variation may differ from that in threespine sticklebacks. Because threespine sticklebacks are well established model for evolutionary research, the sympatric trio of ninespine sticklebacks will be an invaluable resource for ecological and genetic studies on both common and lineage-specific patterns of phenotypic diversification. PMID- 23663031 TI - Somatotropic axis resistance and ghrelin in critically ill foals. AB - REASONS FOR PERFORMING STUDY: Resistance to the somatotropic axis and increases in ghrelin concentrations have been documented in critically ill human patients, but limited information exists in healthy or sick foals. OBJECTIVES: To investigate components of the somatotropic axis (ghrelin, growth hormone and insulin-like growth factor-1 [IGF-1]) with regard to energy metabolism (glucose and triglycerides), severity of disease and survival in critically ill equine neonates. It was hypothesised that ghrelin and growth hormone would increase and IGF-1 would decrease in proportion to severity of disease, supporting somatotropic axis resistance, which would be associated with severity of disease and mortality in sick foals. STUDY DESIGN: Prospective multicentre cross sectional study. METHODS: Blood samples were collected at admission from 44 septic, 62 sick nonseptic (SNS) and 19 healthy foals, all aged <7 days. Foals with positive blood cultures or sepsis scores >=12 were considered septic, foals with sepsis scores of 5-11 were classified as SNS. Data were analysed by nonparametric methods and multivariate logistic regression. RESULTS: Septic foals had higher ghrelin, growth hormone and triglyceride and lower IGF-1 and glucose concentrations than healthy foals (P<0.01). Sick nonseptic foals had higher growth hormone and triglycerides and lower IGF-1 concentrations than healthy foals (P<0.05). Growth hormone:IGF-1 ratio was higher in septic and SNS foals than healthy foals (P<0.05). Hormone concentrations were not different between septic nonsurvivors (n = 14) and survivors (n = 30), but the growth hormone:IGF-1 ratio was lower in nonsurvivors (P = 0.043). CONCLUSIONS: Somatotropic axis resistance, characterised by a high growth hormone:IGF-1 ratio, was frequent in sick foals, associated with the energy status (hypoglycaemia, hypertriglyceridaemia) and with mortality in septic foals. POTENTIAL RELEVANCE: A functional somatotropic axis appears to be important for foal survival during sepsis. Somatotropic resistance is likely to contribute to severity of disease, a catabolic state and likelihood of recovery. PMID- 23663032 TI - Minimally Invasive Surgery: Endoscopic Removal of a Bullet from the Orbital Apex. AB - Abstract I present an endoscopic approach to removal of a bullet from the orbital apex in an attempted suicide, emphasising the importance of fast, minimally invasive surgery, performing endoscopy through the bullet entrance hole, to prevent major complications and to ensure a speedy recovery. PMID- 23663033 TI - Salty glycerol versus salty water surface organization: bromide and iodide surface propensities. AB - Salty NaBr and NaI glycerol solution interfaces are examined in the OH stretching region using broadband vibrational sum frequency generation (VSFG) spectroscopy. Raman and infrared (IR) spectroscopy are used to further understand the VSFG spectroscopic signature. The VSFG spectra of salty glycerol solutions reveal that bromide and iodide anions perturb the interfacial glycerol organization in a manner similar as that found in aqueous halide salt solutions, thus confirming the presence of bromide and iodide anions at the glycerol surface. Surface tension measurements are consistent with the surface propensity suggested by the VSFG data and also show that the surface excess increases with increasing salt concentration, similar to that of water. In addition, iodide is shown to have more surface prevalence than bromide, as has also been determined from aqueous solutions. These results suggest that glycerol behaves similarly to water with respect to surface activity and solvation of halide anions at its air/liquid interface. PMID- 23663030 TI - Maintenance of Th1 hepatitis C virus (HCV)-specific responses in individuals with acute HCV who achieve sustained virological clearance after treatment. AB - BACKGROUND AND AIM: T-cell responses against hepatitis C are believed to be critical in achieving both natural and treatment-induced clearance. However, rapid clearance of antigen with early treatment of primary infection may result in reduced or poorly sustained cellular immunity. This study longitudinally examined Th1 and Th2 hepatitis C virus (HCV)-specific cytokine production and T cell effector function from subjects enrolled in the Australian Trial in Acute Hepatitis C comparing three groups: treatment-induced clearance (sustained virological response [SVR]), treatment non-response, and untreated spontaneous clearance. METHODS: HCV-specific T-cell responses were characterized by HCV peptide ELISpot, in vitro cytokine production, and T-cell flow cytometry assays. RESULTS: Treated subjects with a sustained virological response (SVR) displayed a better maintenance of HCV-specific Th1 responses compared to treatment non responders (higher interferon [IFN]-gamma and interleukin (IL)-2 magnitude at week 24, broader IFN-gamma responses at weeks 24 and 48, P < 0.05) and significantly increased IFN-gamma responses between screening and week 48 (magnitude P = 0.026, breadth P = 0.009). Treatment-induced viral clearance was also associated with a trend toward decreased IL-10 responses (screening to week 48, P = 0.070), higher expression of CD45RO (P = 0.042) and CD38 (P = 0.088) on CD4+ T cells, and higher IFN-gammaR expression (CD56+ IFN-gammaR+ P = 0.033) compared to treatment non-responders. Untreated subjects with viral clearance also displayed high magnitude and broad HCV-specific IFN-gamma and IL-2 responses early in infection; however, IFN-gamma responses were not as well maintained compared to treated subjects with a SVR (week 48 magnitude, breadth P = 0.064). CONCLUSION: Treatment-induced viral clearance of recent HCV infection is associated with maintenance of HCV-specific Th1 responses. PMID- 23663035 TI - A new-generation asymmetric multi-bore hollow fiber membrane for sustainable water production via vacuum membrane distillation. AB - Due to the growing demand for potable water, the capacities for wastewater reclamation and saline water desalination have been increasing. More concerns are raised on the poor efficiency of removing certain contaminants by the current water purification technologies. Recent studies demonstrated superior separation performance of the vacuum membrane distillation (VMD) technology for the rejection of trace contaminants such as boron, dye, endocrine-disruptive chemical, and chloro-compound. However, the absence of suitable membranes with excellent wetting resistance and high permeation flux has severely hindered the VMD application as an effective water production process. This work presents a new generation multibore hollow fiber (MBF) membrane with excellent mechanical durability developed for VMD. Its micromorphology was uniquely designed with a tight surface and a fully porous matrix to maximize both high wetting resistance and permeation flux. Credit to the multibore configuration, a 65% improvement was obtained on the antiwetting property. Using a synthetic seawater feed, the new membrane with optimized fabrication condition exhibits a high flux and the salt rejection is consistently greater than 99.99%. In addition, a comparison of 7 bore and 6-bore MBF membranes was performed to investigate the optimum geometry design. The newly designed MBF membrane not only demonstrates its suitability for VMD but also makes VMD come true as an efficient process for water production. PMID- 23663036 TI - NSP1 is a component of the Myc signaling pathway. AB - Nodulation and arbuscular mycorrhization require the activation of plant host symbiotic programs by Nod factors, and Myc-LCOs and COs, respectively. The pathways involved in the perception and downstream signaling of these signals include common and distinct components. Among the distinct components, NSP1, a GRAS transcription factor, has been considered for years to be specifically involved in nodulation. Here, we analyzed the degree of conservation of the NSP1 sequence in arbuscular mycorrhizal (AM) host and non-AM host plants and carefully examined the ability of Medicago truncatula nsp1 mutants to respond to Myc-LCOs and to be colonized by an arbuscular mycorrhizal fungus. In AM-host plants, the selection pressure on NSP1 is stronger than in non-AM host ones. The response to Myc-LCOs and the frequency of mycorrhizal colonization are significantly reduced in the nsp1 mutants. Our results reveal that NSP1, previously described for its involvement in the Nod factor signaling pathway, is also involved in the Myc-LCO signaling pathway. They bring additional evidence on the evolutionary relatedness between nodulation and mycorrhization. PMID- 23663037 TI - Emerging drugs for prevention of graft failure after allogeneic hematopoietic stem cell transplantation. AB - INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the treatment of choice for many patients suffering from hematological malignancies, severe hemoglobinopathies, bone marrow failures or severe primary immunodeficiencies. Graft rejection/failure (GF) is a life-threatening complication following allo-HSCT that is most commonly caused by the reactivity of recipient T cells, natural killer (NK) cells or antibodies against donor grafted hematopoietic cells. The increasing use of allo-HSCT following reduced intensity conditioning (RIC) and the increasing use of alternative donors (unrelated cord blood and human leukocyte antigen (HLA)-mismatched donor) have resulted in higher frequency of GF. AREAS COVERED: This review describes the pathogenesis and current prevention and treatment of GF as well as agents in development for GF prevention or treatment. EXPERT OPINION: The risk of GF may be reduced in the future by optimizing the conditioning regimens and post-grafting immunosuppression, increasing the number of hematopoietic stem cells (HSCs) and/or immune cells transplanted, optimizing HSC homing and better detecting patients at high risk of GF by searching for pre-transplant donor-specific anti HLA antibodies in patients given grafts from HLA-mismatched donors, or by closely monitoring donor T- and/or NK-cell chimerism after allo-HSCT following RIC. PMID- 23663038 TI - Hippocampal hyperexcitability and specific epileptiform activity in a mouse model of Dravet syndrome. AB - PURPOSE: Dravet syndrome (DS) is caused by dominant mutations of the SCN1A gene, encoding the NaV 1.1 sodium channel alpha subunit. Gene targeted mouse models of DS mutations replicate patients' phenotype and show reduced gamma-aminobutyric acid (GABA)ergic inhibition. However, little is known on the properties of network hyperexcitability and on properties of seizure generation in these models. In fact, seizures have been studied thus far with surface electroencephalography (EEG), which did not show if specific brain regions are particularly involved. We have investigated hyperexcitability and epileptiform activities generated in neuronal networks of a mouse model of DS. METHODS: We have studied heterozygous NaV 1.1 knock-out mice performing field potential recordings in combined hippocampal/cortical slices in vitro and video/depth electrode intracerebral recordings in vivo during hyperthermia-induced seizures. KEY FINDINGS: In slices, we have disclosed specific signs of hyperexcitability of hippocampal circuits in both the pre-epileptic and epileptic periods, and a specific epileptiform activity was generated in the hippocampus upon application of the convulsant 4-aminopyridine in the epileptic period. During in vivo hyperthermia-induced seizures, we have observed selective hippocampal activity in early preictal phases and pronounced hippocampal activity in the ictal phase. SIGNIFICANCE: We have identified specific epileptiform activities and signs of network hyperexcitability, and disclosed the important role of the hippocampus in seizure generation in this model. These activities may be potentially used as targets for screenings of antiepileptic approaches. PMID- 23663039 TI - The incremental value of RT three-dimensional TEE in the evaluation of prosthetic mitral valve ring thrombosis complicated with thromboembolism. AB - PURPOSE: Although nonobstructive prosthetic valve thrombosis (PVT) does not develop hemodynamic compromise, it carries potential risk for thromboembolism. Real time three-dimensional transesophageal echocardiography (RT-3DTEE), has emerged as a complementary tool in depicting "en face" views of prosthesis compared with two-dimensional transesophageal echocardiography (2DTEE). We aimed to evaluate the utility of RT-3DTEE in assessment of mitral ring-located thrombosis. METHOD: We present 3 cases of mechanical mitral valve thrombosis complicated by thromboembolism, who were all examined and followed-up by 2D transthoracic echocardiography (TTE), 2DTEE, and RT-3DTEE. RESULT: The consequencies of thromboembolism in the patients were coronary embolism, transient ischemic attack, and ischemic stroke, respectively. They were all inadequately anticoagulated at the time of admission. 2DTTE and TEE examination was unsatisfactory; RT-3DTEE depicted nonobstructive mitral ring thrombosis in each of the patients. The patients were followed up under effective anticoagulation and antiplatelet therapy. RT-3DTEE was able to demonstrate the evolution of thrombus size in each of the patients. CONCLUSION: Nonobstructive ring-located PVT which poses risk for thromboembolism, may be diagnosed with certainty and imaged with clarity utilizing RT-3DTEE. PMID- 23663040 TI - No evidence for feature overwriting in visual working memory. AB - The effect of repeating features in a short-term memory task was tested in three experiments. Experiments 1 and 2 used a recognition paradigm. Participants encoded four serially presented objects and then decided whether a probe matched one of them with regard to all three features. In the control condition no feature was repeated; in the experimental condition features were repeated in two memory objects. Experiment 3 used a cued recall paradigm with the same list design. After list presentation one feature was used as a cue uniquely indicating one of the memory objects. Participants recalled the remaining two features of the probed object. Feature overwriting as one component of the interference model of Oberauer and Kliegl (2006) predicts worse performance in the experimental compared to the control condition. Results of all three experiments did not support this hypothesis. Recognition performances in Experiments 1 and 2 were not impaired by repeating features. Recall performance in Experiment 3 was better for repeated features, contrary to the predictions of feature overwriting. Predictions from feature overwriting for the shape of serial position curves were also not confirmed. PMID- 23663041 TI - Ethnic group differences in cardiovascular risk assessment scores: national cross sectional study. AB - OBJECTIVES: There are marked inequalities in cardiovascular disease (CVD) incidence and outcomes between ethnic groups. CVD risk scores are increasingly used in preventive medicine and should aim to accurately reflect differences between ethnic groups. Ethnicity, as an independent risk factor for CVD, can be accounted for in CVD risk scores primarily using two methods, either directly incorporating it as a risk factor in the algorithm or through a post hoc adjustment of risk. We aim to compare these two methods in terms of their prediction of CVD across ethnic groups using representative national data from England. DESIGN: A cross-sectional study using data from the Health Survey for England. We measured ethnic group differences in risk estimation between the QRISK2, which includes ethnicity and Joint British Societies 2 (JBS2) algorithm, which uses post hoc risk adjustment factor for South Asian men. RESULTS: The QRISK2 score produces lower median estimates of CVD risk than JBS2 overall (6.6% [lower quartile-upper quartile (LQ-UQ)=4.0-18.6] compared with 9.3% [LQ-UQ=2.3 16.9]). Differences in median risk scores are significantly greater in South Asian men (7.5% [LQ-UQ=3.6-12.5]) compared with White men (3.0% [LQ-UQ=0.7-5.9]). Using QRISK2, 19.1% [95% confidence interval (CI)=16.2-22.0] fewer South Asian men are designated at high risk compared with 8.8% (95% CI=5.9-7.8) fewer in White men. Across all ethnic groups, women had a lower median QRISK2 score (0.72 [LQ-UQ=- 0.6 to 2.13]), although relatively more (2.0% [95% CI=1.4-2.6]) were at high risk than with JBS2. CONCLUSIONS: Ethnicity is an important CVD risk factor. Current scoring tools used in the UK produce significantly different estimates of CVD risk within ethnic groups, particularly in South Asian men. Work to accurately estimate CVD risk in ethnic minority groups is important if CVD prevention programmes are to address health inequalities. PMID- 23663042 TI - Editorial comment from Dr. Nair to "Laparoscopic simultaneous bilateral adrenalectomy for testosterone-secreting bilateral adrenal tumors". PMID- 23663043 TI - Case of intravascular natural killer cell lymphoma. PMID- 23663044 TI - The authors' reply: oestradiol concentrations are not elevated in obesity associated hypogonadotrophic hypogonadism. PMID- 23663045 TI - Chemical nano-gardens: growth of salt nanowires from supramolecular self-assembly gels. AB - In this article, we examine the phenomenon of single-crystal halide salt wire growth at the surface of porous materials. We report the use of a single-step casting technique with a supramolecular self-assembly gel matrix that upon drying leads to the growth of single-crystal halide (e.g., NaCl, KCl, and KI) nanowires with diameters ~130-200 nm. We demonstrate their formation using electron microscopy and electron-dispersive X-ray spectroscopy, showing that the supramolecular gel stabilizes the growth of these wires by facilitating a diffusion-driven base growth mechanism. Critically, we show that standard non supramolecular gels are unable to facilitate nanowire growth. We further show that these nanowires can be grown by seeding, forming nanocrystal gardens. This study helps understand the possible prefunctionalization of membranes to stimulate ion-specific filters or salt efflorescence suppressors, while also providing a novel route to nanomaterial growth. PMID- 23663047 TI - Mycobacterium tuberculosis PE_PGRS17 promotes the death of host cell and cytokines secretion via Erk kinase accompanying with enhanced survival of recombinant Mycobacterium smegmatis. AB - Tuberculosis (TB) remains a serious threat to global public health, largely due to the successful manipulation of the host immunity by its etiological agent Mycobacterium tuberculosis. The PE_PGRS protein family of M. tuberculosis might be a contributing factor. To investigate the roles of PE_PGRS17, the gene of PE_PGRS 17 was expressed in nonpathogenic fast growing Mycobacterium smegmatis. We found that the recombinant strain survives better than the control in macrophage cultures, accompanied by more host cell death and a marked higher secretion of tumor necrosis factor-alpha by a recombinant strain compared with control. Blocking the action of Erk kinase by an inhibitor can abolish the above effects. In brief, our data showed that PE_PGRS 17 might facilitate pathogen survival and disserve the host cell via remodeling the macrophages immune niche largely consisting of inflammatory cytokines. This furnishes a novel insight into the immune role of this mycobacterium unique gene family. PMID- 23663048 TI - Influence of IQ in interpreting MMSE scores in patients with multiple sclerosis. AB - The Mini-Mental State Examination (MMSE) and Wechsler Adult Intelligence Scale Fourth Edition (WAIS-IV) were administered to 46 outpatients diagnosed with multiple sclerosis (MS). MMSE total raw score was significantly and positively correlated with all WAIS-IV indexes, even when controlling for the effects of participant educational level, with the strongest relationship being with Full Scale IQ. These results suggest that clinicians consider patient intellectual functioning, in particular Full Scale IQ, when diagnosing neurocognitive impairment based on screening with the MMSE in individuals with MS. PMID- 23663046 TI - Peripheral type I interferon receptor correlated with oxidative stress in chronic hepatitis B virus infection. AB - Type I interferon receptor (IFNAR) has been involved in the progression of chronic hepatitis B (CHB). Oxidative stress is also associated with hepatitis B virus (HBV) infection and might contribute to the structure and function of protein synthesis including the IFNAR family. This study was aimed to determine the possible associations between oxidative stress and peripheral IFNAR expression in chronic HBV infection. Fifty-four CHB patients and 31 liver cirrhosis (LC) patients were consecutively collected, as well as 11 healthy subjects as controls. Expression levels of IFNAR1 and IFNAR2 in peripheral blood lymphocytes and monocytes were measured by flow cytometry. IFNAR1 and IFNAR2c mRNA were detected by real-time reverse transcription-polymerase chain reaction. Levels of plasma-soluble IFNAR and oxidative stress parameters, including xanthine oxidase (XOD), malondialdehyde (MDA), glutathione (GSH), glutathione S transferase (GST), and glutathione peroxidase (GSH-Px) were detected by enzyme linked immunosorbent assay (ELISA). The frequencies of IFNAR1 and IFNAR2 in lymphocytes and monocytes were significantly increased in CHB and LC patients than in healthy controls. Expression levels of IFNAR1 and IFNAR2c mRNA and plasma soluble IFNAR level in CHB and LC patients were upregulated compared with healthy controls. Mean fluorescence intensity (MFI) of IFNAR2 in monocytes of CHB patients was higher than that in LC patients. Levels of plasma XOD, MDA, and GST were significantly increased in CHB and LC patients compared with healthy controls. Meanwhile, GSH and GSH-Px in CHB and LC patients were decreased than that in healthy controls. Furthermore, plasma MDA, GSH, and GST levels in CHB patients were higher than that in LC patients. In CHB patients, plasma GST level was negatively correlated with MFI of IFNAR2 in lymphocytes. Our results suggested that oxidative stress play an important role in the regulation of IFNAR in chronic HBV infection. PMID- 23663049 TI - Photosynthetic and anatomical responses of Eucalyptus grandis leaves to potassium and sodium supply in a field experiment. AB - Although vast areas in tropical regions have weathered soils with low potassium (K) levels, little is known about the effects of K supply on the photosynthetic physiology of trees. This study assessed the effects of K and sodium (Na) supply on the diffusional and biochemical limitations to photosynthesis in Eucalyptus grandis leaves. A field experiment comparing treatments receiving K (+K) or Na (+Na) with a control treatment (C) was set up in a K-deficient soil. The net CO2 assimilation rates were twice as high in +K and 1.6 times higher in +Na than in the C as a result of lower stomatal and mesophyll resistance to CO2 diffusion and higher photosynthetic capacity. The starch content was higher and soluble sugar was lower in +K than in C and +Na, suggesting that K starvation disturbed carbon storage and transport. The specific leaf area, leaf thickness, parenchyma thickness, stomatal size and intercellular air spaces increased in +K and +Na compared to C. Nitrogen and chlorophyll concentrations were also higher in +K and +Na than in C. These results suggest a strong relationship between the K and Na supply to E. grandis trees and the functional and structural limitations to CO2 assimilation rates. PMID- 23663050 TI - Organosulfur garlic compounds induce neovasculogenesis in human endothelial progenitor cells through a modulation of MicroRNA 221 and the PI3-K/Akt signaling pathways. AB - Human endothelial progenitor cells (EPCs) play crucial roles in the prevention of ischemic injury via neovasculogenesis. Frequent garlic consumption is reportedly associated with a low incidence of cardiovascular diseases (CVD). However, the molecular mechanisms by which garlic extracts, including diallyl disulfide (DADS) and diallyl trisulfide (DATS), exert an effect on neovasculogenesis have not been elucidated yet. The current study investigated the effects of these organosulfur compounds on neovasculogenesis by using vascular tube formation assay, Western blotting assay, real-time polymerase chain reaction (RT-PCR), and immunohistochemical (IHC) staining assays in both in vitro and in vivo models. The current study demonstrates that DADS and DATS dose-dependently enhance the neovasculogenesis of human EPCs in vitro. The mechanism of actions included the up-regulation of the c-kit protein, as well as the phosphorylation (i.e., activation) of the Akt and ERK 1/2 signaling molecules in human EPCs. Furthermore, DATS suppressed the expression of microRNA (miR) 221 in vitro. In a mouse xenograft model of neovasculogenesis, DATS consumption induced the formation of new blood vessels at a dosage of 10 mg/kg of body weight/day. It is suggested that garlic consumption enhances neovasculogenesis in human EPCs and thereby probably exerts a preventive effect against ischemic injuries. PMID- 23663051 TI - Imaging diagnosis--Conventional and functional magnetic resonance imaging of a brain abscess in a goat. AB - A 2-month-old female goat was presented for depressed mental status and multifocal central neurologic signs 3 weeks after hot-iron disbudding. Conventional magnetic resonance imaging (MRI) findings included a large intra axial mass in the left frontal lobe that was T2 hyperintense and T1 hypointense centrally with a contrast-enhancing peripheral capsule and perilesional T2 hyperintensity. A restrictive pattern was present in diffusion-weighted imaging. Magnetic resonance spectroscopy demonstrated an increased amount of succinate, acetate, amino acids, lipids; minimal amounts of lactate; and decreased amounts of N-acetyl aspartate and choline. A cerebral abscess due to Trueperella pyogenes was confirmed from necropsy and tissue culture. PMID- 23663052 TI - Testing hypotheses involving Cronbach's alpha using marginal models. AB - We discuss the statistical testing of three relevant hypotheses involving Cronbach's alpha: one where alpha equals a particular criterion; a second testing the equality of two alpha coefficients for independent samples; and a third testing the equality of two alpha coefficients for dependent samples. For each of these hypotheses, various statistical tests have been proposed. Over the years, these tests have depended on progressively fewer assumptions. We propose a new approach to testing the three hypotheses that relies on even fewer assumptions, is especially suited for discrete item scores, and can be applied easily to tests containing large numbers of items. The new approach uses marginal modelling. We compared the Type I error rate and the power of the marginal modelling approach to several of the available tests in a simulation study using realistic conditions. We found that the marginal modelling approach had the most accurate Type I error rates, whereas the power was similar across the statistical tests. PMID- 23663053 TI - Photoisomerization quantum yield of azobenzene-modified DNA depends on local sequence. AB - Photoswitch-modified DNA is being studied for applications including light harvesting molecular motors, photocontrolled drug delivery, gene regulation, and optically mediated assembly of plasmonic metal nanoparticles in DNA-hybridization assays. We study the sequence and hybridization dependence of the photoisomerization quantum yield of azobenzene attached to DNA via the popular d threoninol linkage. Compared to free azobenzene we find that the quantum yield for photoisomerization from trans to cis form is decreased 3-fold (from 0.094 +/- 0.004 to 0.036 +/- 0.002) when the azobenzene is incorporated into ssDNA, and is further reduced 15-fold (to 0.0056 +/- 0.0008) for azobenzene incorporated into dsDNA. In addition, we find that the quantum yield is sensitive to the local sequence including both specific mismatches and the overall sequence-dependent melting temperature (Tm). These results serve as design rules for efficient photoswitchable DNA sequences tailored for sensing, drug delivery, and energy harvesting applications, while also providing a foundation for understanding phenomena such as photonically controlled hybridization stringency. PMID- 23663054 TI - Bimolecular catalysis and turnover from a macromolecular host system. AB - The synthesis of a globular macromolecule and its application as a bimolecular catalyst are reported. The macromolecular structure supports (at least) two zinc metalated porphyrin units, each capable of binding a single reactant. The proximity of the two bound reactants results in an increased local concentration, leading to a maximum 300-fold increase in the reaction rate. In contrast to other synthetic catalysts, where bidentate products inhibit further reactions, this macromolecular system allows the product to be displaced by the reactants leading to turnover and catalysis. We believe that this is due to the dynamics of the macromolecular host system, which maintains enough flexibility to adopt a favorable/reactive geometry, which allows the reactants to get close and react while possessing sufficient rigidity/poor geometry to reduce and disrupt any cooperative/inhibitive bidentate binding. PMID- 23663055 TI - N-(3', 4'-dimethoxycinnamonyl) anthranilic acid alleviated experimental colitis by inhibiting autoimmune response and inducing CD4+ CD25+ regulatory T cells production. AB - BACKGROUND AND AIM: Crohn's disease treatments available today are not quite satisfactory. N-(3', 4'-dimethoxycinnamonyl) anthranilic acid (3, 4-DAA) has been proved to be effective in many autoimmune diseases. Therefore, we investigated the immunologic function of 3, 4-DAA on trinitrobenzene sulfonic acid (TNBS) colitis and human Crohn's disease. METHODS: Mice with TNBS-induced colitis were treated with 3, 4-DAA or 1-methyl-tryptophan (1-MT). Colitis severity was assessed with clinical and histological scores. Cell proliferation, cytokine expression, and the percentage of CD4(+) CD25(+) T cells were measured in both mice and human samples. RESULTS: In mice treated with 3, 4-DAA, the clinical and histological scores were decreased (P < 0.05); the proliferation of mesenteric lymph nodes (MLNs) cells and lamina propria mononuclear cells (LPMCs) were inhibited (P < 0.05); Th1 cytokine expressions were decreased (P < 0.05), and Th2 cytokine levels were increased (P < 0.05). 3, 4-DAA also induced CD4(+) CD25(+) T cells expression (5.88 +/- 2.1 vs 11.03 +/- 2.93, P < 0.05) in mice MLNs. Transfer of these cells into TNBS colitis mice resulted in the reduction of the disease activity index (DAI) and histological scores. In LPMCs isolated from human Crohn's disease, 3, 4-DAA had the same effect. It can inhibit the cell proliferation, decrease Th1 cytokine expressions (P < 0.05), and increase Th2 cytokine levels (P < 0.05). The percentage of CD4(+) CD25(+) T cells were also increased (1.60 +/- 0.14 vs 2.45 +/- 0.50, P < 0.05). 1-MT treatment led to opposite outcomes. CONCLUSION: 3, 4-DAA can alleviate the severity of colitis through inhibiting Th1 cells response, promoting Th2 cytokines expression and inducing CD4(+) CD25(+) T cells expression. PMID- 23663056 TI - A giant right-sided heart due to idiopathic pulmonary hypertension. PMID- 23663057 TI - Why care? Inferring the evolution of complex social behaviour. AB - Phylogenetic comparative analyses of complex traits often reduce the traits of interests into a single (or a few) component variables. Here, we show that this may be an over-simplification, because components of a complex trait may evolve independently from each other. Using eight components of parental care in 400 bird species from 89 avian families that represent the relative contribution of male vs. female to a particular type of care, we show that some components evolve in a highly correlated manner, whereas others exhibit low (or no) phylogenetic correlation. Correlations were stronger within types of parental activity (brooding, feeding, guarding) than within stages of the breeding cycle (incubation, prefledging care, post-fledging care). A phylogenetically corrected cluster analysis identified two groups of parental care components that evolved in a correlated fashion: one group included incubation and brooding, whereas the other group comprised of the remaining components. The two groups of components provide working hypotheses for follow-up studies to test the underlying genetic, developmental and ecological co-evolutionary mechanism between male and female care. Furthermore, the components within each group are expected to respond consistently to different ambient and social environments. PMID- 23663058 TI - Mechanism of persulfate activation by phenols. AB - The activation of persulfate by phenols was investigated to further the understanding of persulfate chemistry for in situ chemical oxidation (ISCO). Phenol (pKa = 10.0) activated persulfate at pH 12 but not at pH 8, suggesting activation occurred only via the phenoxide form. Evaluation of the phenoxide activation mechanism was complicated by the concurrent activation of persulfate by hydroperoxide anion, which is generated by the base catalyzed hydrolysis of persulfate. Therefore, phenoxide activation was investigated using pentachlorophenoxide at pH 8.3, midway between the pKa of pentachlorophenol (pKa = 4.8) and that of hydrogen peroxide (pKa = 11.8). Of the two possible mechanisms for phenoxide activation of persulfate (reduction or nucleophilic attack) the results were consistent with reduction of persulfate by phenoxide with oxidation of the phenoxide. The concentration of phenoxide required for maximum persulfate activation was low (1 mM). The results of this research document that phenoxides activate persulfate via reduction; phenolic moieties ubiquitous to soil organic matter in the subsurface may have a significant role in the activation of persulfate during its injection into the subsurface for ISCO. Furthermore, the results provide the foundation for activation of persulfate by other organic anions without the toxicity of phenols, such as keto acids. PMID- 23663059 TI - Peptide-based vector of VEGF plasmid for efficient gene delivery in vitro and vessel formation in vivo. AB - Critical limb ischemia is regarded as a potentially lethal disease, and the treatment effects of existing therapies are limited. Here, in order to develop a potential approach to improve the therapy effects, we designed a peptide of TAT PKKKRKV as the vector for VEGF165 plasmid to facilitate in vivo angiogenesis. In in vitro studies, TAT-PKKKRKV with low cytotoxicity exhibited efficient transfection ability either with or without serum. Additionally, application of TAT-PKKKRKV/VEGF165 complexes in hindlimb ischemia rats obviously promoted the expression of VEGF protein, which further enhanced effective angiogenesis. The results indicated that TAT-PKKKRKV is an efficient gene vector with low toxicity both in vitro and in vivo, which has great potential for clinical gene therapy. PMID- 23663060 TI - Inferential false memories of events: negative consequences protect from distortions when the events are free from further elaboration. AB - The present experiment was conducted to investigate whether negative emotionally charged and arousing content of to-be-remembered scripted material would affect propensity towards memory distortions. We further investigated whether elaboration of the studied material through free recall would affect the magnitude of memory errors. In this study participants saw eight scripts. Each of the scripts included an effect of an action, the cause of which was not presented. Effects were either negatively emotional or neutral. Participants were assigned to either a yes/no recognition test group (recognition), or to a recall and yes/no recognition test group (elaboration + recognition). Results showed that participants in the recognition group produced fewer memory errors in the emotional condition. Conversely, elaboration + recognition participants had lower accuracy and produced more emotional memory errors than the other group, suggesting a mediating role of semantic elaboration on the generation of false memories. The role of emotions and semantic elaboration on the generation of false memories is discussed. PMID- 23663061 TI - Sodium thiosulfate in the treatment of non-uremic calciphylaxis. AB - Calciphylaxis is a metastatic calcification-induced vasculopathy that results in the occlusion of small blood vessels. Although calciphylaxis is normally associated with end-stage renal disease, calciphylaxis from non-uremic origin occurs as well. While the number of reports continues to increase, a standard treatment for non-uremic calciphylaxis has yet to be established. Sodium thiosulfate (STS), which has been proven to be effective in the treatment of uremic calciphylaxis, shows promise; however, reports of its use in non-uremic cases are limited. We describe a case of non-uremic calciphylaxis in a patient with normal renal and parathyroid function who had complete resolution of disease after treatment with STS, and we review similar cases in the published work. Based on the successful outcomes detailed in this case series, STS appears to be an effective therapy for non-uremic calciphylaxis. PMID- 23663062 TI - Anomalous mitral arcade variant with accessory mitral leaflet and chordae presenting for the first time with acute decompensated heart failure in an adult. AB - The anomalous mitral arcade is a rare congenital malformation of the mitral valve and its tensor apparatus. It is characterized by enlarged papillary muscles connected to each other and to the free edge of the anterior mitral leaflet by a bridge of fibrous tissue. We report a rare variant of anomalous mitral arcade that was associated with accessory mitral leaflet in subaortic area and accessory chordae. Our patient was asymptomatic till the age of 18 years, when he presented for the first time in acute decompensated heart failure secondary to severe mitral regurgitation and left ventricular dysfunction. The patient had rapid deterioration with fatal outcome. PMID- 23663063 TI - Visual field defects after radiosurgery for mesial temporal lobe epilepsy. AB - PURPOSE: Gamma knife radiosurgery (RS) may be an alternative to open surgery for mesial temporal lobe epilepsy (MTLE), but morbidities and the anticonvulsant mechanisms of RS are unclear. Examination of visual field defects (VFDs) after RS may provide evidence of the extent of a postoperative fixed lesion. VFDs occur in 52-100% of patients following open surgery for MTLE. METHODS: This multicenter prospective trial of RS enrolled patients with unilateral hippocampal sclerosis and concordant video-electroencephalography (EEG) findings. Patients were randomized to low (20 Gy) or high (24 Gy) doses delivered to the amygdala, hippocampal head, and parahippocampal gyrus. Postoperative perimetry were obtained at 24 months after RS. Visual field defect ratios (VFDRs) were calculated to quantify the degree of VFDs. Results were contrasted with age, RS dose and 50% isodose volume, peak volume of radiation-induced change at the surgical target, quality of life measurements, and seizure remission. KEY FINDINGS: No patients reported visual changes and no patients had abnormal bedside visual field examinations. Fifteen (62.5%) of 24 patients had postoperative VFDs, all homonymous superior quadrantanopsias. None of the VFDs were consistent with injury to the optic nerve or chiasm. Clinical diagnosis of VFDs correlated significantly with VFDRs (p = 0.0005). Patients with seizure remission had smaller (more severe) VFDRs (p = 0.04). No other variables had significant correlations. SIGNIFICANCE: VFDs appeared after RS in proportions similar to historical comparisons from open surgery for MTLE. The nature of VFDs was consistent with lesions of the optic radiations. The findings support the hypothesis that the mechanism of RS involves some degree of tissue damage and is not confined entirely to functional changes in neuromodulation. PMID- 23663065 TI - High circulating levels of CCL2 in patients with Klinefelter's syndrome. PMID- 23663066 TI - Development of a real-time PCR to detect Streptococcus equi subspecies equi. AB - REASONS FOR PERFORMING STUDY: Infection with Streptococcus equi subspecies equi (S. equi) is endemic in the UK. A proportion of horses serve as long-term carriers and act as a reservoir of infection. Detection of these persistently infected horses is difficult using standard culture techniques owing to a lack of sensitivity and overgrowth by contaminating bacteria. In addition, differentiation of this causative bacterium from the closely related S. equi zooepidemicus has made the development of reliable and accurate diagnostic tests difficult. OBJECTIVE: To develop and validate a sensitive and specific real-time PCR assay to detect S. equi and to compare the results with traditional culture techniques. STUDY DESIGN: Retrospective cross-sectional study. METHODS: The assay was validated using a panel of 92 samples from suspected clinical cases of strangles. These were cultured using microbial techniques and tested using the S. equi real-time PCR. The results of the 2 methods were compared, and the diagnostic sensitivity and specificity of the real-time PCR were calculated. The real-time PCR was tested for cross-reactivity with horse commensal bacteria, and the efficiencies and limits of detection were established. RESULTS: The assay had a diagnostic sensitivity of 95% and specificity of 86%. No cross-reactivity was observed with any of the bacterial species tested, including S. equi zooepidemicus. The assay detected as few as 3 gene copies. CONCLUSION: The assay is fast, sensitive and specific and will detect S. equi DNA directly from a crude extract of clinical material on a swab. POTENTIAL RELEVANCE: This assay could aid in the rapid detection of subclinical shedders of S. equi, enabling quicker treatment and helping to limit the spread of strangles in equine populations. PMID- 23663067 TI - Clinico-Radiological Spectrum and Management of Orbital Schwannomas: A Tertiary Care Institute Study. AB - Abstract Purpose: The aim is to study clinical presentations, radiological features and outcome in histopathologically proven orbital schwannomas. Methods: A retrospective and longitudinal study of 16 patients between January 1999 and July 2011 was undertaken by reviewing the appropriate charts. Clinical and radiological data of all orbital schwannomas patients were analyzed. Results: Mean age was 28.18 years (range 8-40 years). Of 16 patients, 10 were males and 6 females. Duration of symptoms was chronic in 15(93%). Chief complaints were proptosis in 10(62.5%), eyelid swelling in 5(31%) and eyelid mass lesion in 2(12.5%). This included a rare case of cystic schwannoma with microphthalmos. Mass was extraconal in 11(69%). Radiological findings varied from solid to cystic, intraconal to extraconal, no enhancement to intense enhancement and presence of calcification. Thirteen (81%) were excised via anterior orbitotomy route while fronto-orbital craniotomy was done in 3(19%). Postoperatively, vision improved or remained stable in 15(94%) and worsened in one (6%). Final visual acuity of 6/6 was achieved in 11(69%), 6/9 in 2, 6/36 in one. Conclusions: Schwannomas may mimic a variety of mass lesions in the orbit because of variable clinical or imaging features and should be considered in the differential diagnosis of all well circumscribed orbital lesions. PMID- 23663068 TI - Antenatal corticosteroid exposure at term increases adult adiposity: an experimental study in sheep. AB - Clinical practice guidelines for elective cesarean section at early-term gestation (37-38 weeks) recommend antenatal corticosteroids to reduce neonatal respiratory morbidity. However, the long-term health implications for offspring exposed to corticosteroids at term are unknown and may differ from the effects of preterm corticosteroid exposure. We therefore randomized singleton-bearing ewes (n = 64) to receive a clinically relevant dose of corticosteroids at term or no treatment. Body composition was assessed in adult offspring using dual-energy X ray absorptiometry. Relative to skeletal size female, but not male, offspring of steroid-treated ewes had increased weight and a greater fat mass than controls (relative weight: 49.1 +/- 1.1 vs. 52.9 +/- 1.2 kg/m2, p = 0.02; relative fat mass: 5.4 +/- 0.7 vs. 3.4 +/- 0.7 kg/m2, p = 0.04). Whether corticosteroid exposure at early-term gestation increases adult adiposity in humans is unknown and needs further investigation. PMID- 23663070 TI - Si microwire solar cells: improved efficiency with a conformal SiO2 layer. AB - Silicon microwire arrays have attracted considerable attention recently due to the opportunity they present as highly efficient and cost-effective solar cells. In this study, we report on efficient Si microwire array solar cells with areas of 1 cm(2) and Air Mass 1.5 Global conversion efficiencies of up to 10.6%. These solar cells show an open-circuit voltage of 0.56 V, a short-circuit current density of 25.2 mA/cm(2), and a fill factor of 75.2%, with a silicon absorption region that is only 25 MUm thick. In particular, the maximum overall efficiency of the champion device is improved from 8.71% to 10.6% by conformally coating the wires with a 200 nm thick SiO2 layer. Optical measurements reveal that the layer reduces reflection significantly over the entire visible range. PMID- 23663069 TI - Identifying individual psychosocial and adherence support needs in patients with psoriasis: a multinational two-stage qualitative and quantitative study. AB - BACKGROUND: Psoriasis has a serious impact on patients' lives. However, adherence to medications is often poor, potentially compounding the burden of disease. Identifying patients who need support with psychosocial problems, or issues with adherence, can be complex. OBJECTIVES: We aimed to develop statements that could assist the consultation process, identifying the relative importance of factors related to effective management of psoriasis for patients. METHODS: A two-stage study design was used to comprehensively identify, and assess validity of, statements describing psoriasis impact and management issues. Both components were conducted in Canada, France, Germany, Italy, Spain, the United Kingdom and the United States. Findings from patient observation and interviews were analysed for pattern strength, and were then used to inform the development of statements that were quantitatively assessed using a survey. The association of drivers towards agreement with 'my psoriasis dictates how I lead my life' was assessed using anova. RESULTS: Fifty-six patients participated in the qualitative component, and 1,884 patients using prescription medications completed the survey. Two thematic categories were identified; disappointment with treatments, and confusion regarding psoriasis associated with a lack of direction. When assessed quantitatively, key statements associated with a strong burden of psoriasis on patients' lives were related to isolation, social stigma, visible symptoms, impact on activities and feelings of hopelessness. A mixture of patient , doctor- and treatment-related factors were among the most common reasons for non-adherence. CONCLUSION: Questioning using the statements most associated with psychosocial impact and non-adherence could help identify patients with additional support needs, and assist in overcoming adherence issues. PMID- 23663071 TI - Effect of laser thermal injury on Langerhans cells in mouse and hairless guinea pig epidermis. AB - To examine the effect of laser thermal injury on Langerhans cells (LC) within the epidermis, the dorsal skin of mice and hairless guinea pigs was exposed to varying levels of laser irradiation using a thulium laser at a wavelength of 2.0 MUm. At 6, 24 and 48 h post irradiation, animals were euthanized, skin samples prepared for histology and the epidermis obtained and stained by major histocompatibility complex-II staining (mice) or ATPase assay (hairless guinea pigs) for the enumeration of LC. Mouse skin exhibited histological evidence of thermal damage at 24 h post irradiation at even the lowest dose (0.14 W) and decreases in the numbers of epidermal LC were observed at all doses and decreases were proportional to dose. In contrast, hairless guinea pig skin only showed consistent histological evidence of thermal damage at the highest dose of irradiation (0.70 W) at 24 and 48 h post irradiation and exhibited a statistically significant decrease in numbers of epidermal LC only at this dose. Thus, epidermal LC depletion occurred in the skin of both mice and hairless guinea pigs in response to laser treatment and the magnitude of depletion directly correlated with the extent of thermal damage both within and between species. PMID- 23663073 TI - Interfacial structure of a DOPA-inspired adhesive polymer studied by sum frequency generation vibrational spectroscopy. AB - Marine mussels deposit adhesive proteins containing 3,4-dihydroxyphenylalanine (DOPA) to attach themselves to different surfaces. Isolating such proteins from biological sources for adhesion purposes tends to be challenging. Recently, a simplified synthetic adhesive polymer, poly[(3,4-dihydroxystyrene)-co-styrene] (PDHSS), was developed to mimic DOPA-containing proteins. The pendant catechol group in this polymer provides cross-linking and adhesion much like mussel proteins do. In this work, sum frequency generation (SFG) vibrational spectroscopy was applied to reveal the structures of this DOPA-inspired polymer at air, water, and polymer interfaces. SFG spectroscopy results showed that when underwater, the catechol rings and the quinone rings were ordered, ready to adhere to surfaces. At the hydrophobic polystyrene interface, benzene pi-pi stacking is likely the adhesive force, whereas at the hydrophilic poly(allylamine) interface, primary amines may form hydrogen bonds with catechol or react with quinones for adhesion. PMID- 23663074 TI - Dual-stimulus luminescent lanthanide molecular switch based on an unsymmetrical diarylperfluorocyclopentene. AB - A [2]pseudorotaxane formed from an unsymmetrical diarylperfluorocyclopentene (1) and a Eu(3+) complex of terpyridinyldibenzo-24-crown-8 (2) revealed excellent reversible lanthanide luminescence switching behavior dual-modulated by host guest and optical stimuli. PMID- 23663072 TI - Feasibility and repeatability for in vivo measurements of stiffness gradients in the canine gastrocnemius tendon using an acoustoelastic strain gauge. AB - B-mode ultrasound is an established imaging modality for evaluating canine tendon injury. However, full extent of tendon injury often remains difficult to estimate, as small changes in sonographic appearance are associated with large changes in biomechanical strength. The acoustoelastic strain gauge (ASG) is an ultrasound-based tissue evaluation technique that relates the change in echo intensity observed during relaxation or stretching of tendons to the tissue's mechanical properties. This technique deduces stiffness gradient (the rate of change of normalized stiffness as a function of tissue strain) by analyzing the ultrasound dynamic images captured from gradually deforming tissue. ASG has been proven to accurately model strain and stiffness within tendons in vitro. To determine the feasibility and repeatability for in vivo ASG measurements of canine tendon function, stiffness gradients for the gastrocnemius tendons of 10 clinically normal dogs were recorded by two nonindependent observers at three sites (musculotendinous junction, mid tendon, and insertion). Average stiffness gradient indices (0.0132, 0.0141, 0.0136) and dispersion values (0.0053, 0.0054, 0.0057) for each site, respectively, were consistent with published mechanical properties for normal canine tendon. Mean differences of the average stiffness gradient index and dispersion value between observers and between limbs for each site were less than 16%. Using interclass coefficients (ICC), intra-observer (ICC 0.79-0.98) and interobserver (ICC 0.77-0.95) reproducibility was good to excellent. Right and left limb values were symmetric (ICC 0.74-0.92). Findings from this study indicated that ASG is a feasible and repeatable technique for measuring stiffness gradients in canine tendons. PMID- 23663075 TI - Genetic deletion of granzyme B does not confer resistance to the development of spontaneous diabetes in non-obese diabetic mice. AB - Granzyme B (GzmB) and perforin are proteins, secreted mainly by natural killer cells and cytotoxic T lymphocytes that are largely responsible for the induction of apoptosis in target cells. Because type 1 diabetes results from the selective destruction of beta cells and perforin deficiency effectively reduces diabetes in non-obese diabetic (NOD) mice, it can be deduced that beta cell apoptosis involves the GzmB/perforin pathway. However, the relevance of GzmB remains totally unknown in non-obese diabetic (NOD) mice. In this study we have focused on GzmB and examined the consequence of GzmB deficiency in NOD mice. We found that NOD.GzmB(-/-) mice developed diabetes spontaneously with kinetics similar to those of wild-type NOD (wt-NOD) mice. Adoptive transfer study with regulatory T cell (Treg )-depleted splenocytes (SPCs) into NOD-SCID mice or in-vivo Treg depletion by anti-CD25 antibody at 4 weeks of age comparably induced the rapid progression of diabetes in the NOD.GzmB(-/-) mice and wt-NOD mice. Expression of GzmA and Fas was enhanced in the islets from pre-diabetic NOD.GzmB(-/-) mice. In contrast to spontaneous diabetes, GzmB deficiency suppressed the development of cyclophosphamide-promoted diabetes in male NOD mice. Cyclophosphamide treatment led to a significantly lower percentage of apoptotic CD4(+) , CD8(+) and CD4(+) CD25(+) T cells in SPCs from NOD.GzmB(-/-) mice than those from wt-NOD mice. In conclusion, GzmB, in contrast to perforin, is not essentially involved in the effector mechanisms for beta cell destruction in NOD mice. PMID- 23663076 TI - Delayed mammalian meat-induced anaphylaxis confirmed by skin test to cetuximab. PMID- 23663077 TI - Tensions in naturopathic education. PMID- 23663078 TI - Predictors of adherence to a 26-week viniyoga intervention among post-treatment breast cancer survivors. AB - OBJECTIVES: This study aimed to identify demographic, psychological, health related, and geographic predictors of adherence to home-based and supervised components of a yoga intervention in breast cancer survivors. METHODS: Participants were the 32 post-treatment breast cancer survivors who were randomized to the Viniyoga intervention arm of a controlled trial. Participants were asked to practice yoga 5 times per week for 6 months, including at least one weekly facility-based session. Adherence was monitored using sign-in sheets and logs. Height and weight were measured; other potential predictors of adherence were obtained from baseline questionnaires. RESULTS: Participants attended 19.6+/ 13.0 yoga classes and performed 55.8+/-32.8 home-based yoga sessions. Participants adhered to 58% of the overall yoga practice goal (75% of the goal for yoga classes and 54% of the goal for home based-sessions). Higher class attendance and home practice were predicted by greater self-efficacy for yoga (p=0.004 and 0.06, respectively). Additionally, employment outside the home was associated with greater class attendance (p=0.004), while higher waist circumference was marginally associated with lower adherence to home-based yoga (p=0.05). CONCLUSIONS: High levels of facility- and home-based yoga practice were achieved. Breast cancer survivors who have lower self-efficacy for yoga or who have a higher waist circumference may benefit from additional support or intervention tailoring. Adherence may also be improved by ensuring that class times are convenient to both working and nonworking women. PMID- 23663079 TI - Sedative music facilitates deep sleep in young adults. AB - OBJECTIVES: To investigate the effect of sedative music on the different stages of the sleep cycle in young adults with various sleep latencies by using polysomnography (PSG). DESIGN: Prospective, randomized, controlled, crossover study. SETTING: Sleep center of a teaching hospital. PARTICIPANTS: Young adults with different sleep latencies. Poor sleepers (Pittsburgh Sleep Quality Index score >=5) were excluded. INTERVENTIONS: Each participant stayed one night in the sleep center for adaptation and on each of the following two nights was assigned to (1) music and (2) control (without music) conditions in random order. In the music condition, sedative music composed by certified music therapists was played on a compact disc player for the first hour the participant was in bed. OUTCOME MEASURES: Sleep measures recorded with PSG, including sleep latency and durations of sleep stages. RESULTS: Twenty-four young adults (mean+/-standard deviation, 24.5+/-2.6 years) participated. They were classified into the short sleep latency (SL) group if the baseline SL of the adaptation night was shorter than 10 minutes or into the long SL group if the baseline SL was 10 minutes or longer. Sedative music did not alter the SL in either group. Sedative music reduced stage II sleep in both SL groups (main effect of music, p=0.03; interaction effect, p=0.87) but increased the duration of deep sleep (stages III and IV) only in the long SL group (main effect of music, p=0.15; interaction effect, p=0.02). CONCLUSIONS: In participants with long SL, sedative music improved the quality of sleep by prolonging the duration of deep sleep. This effect provides an alternative and noninvasive way to improve sleep in selected persons experiencing sleep problems. PMID- 23663080 TI - Design, synthesis and antistaphylococcal activity of marine pyrrole alkaloid derivatives. AB - A novel set of 16 hybrids of bromopyrrole alkaloids with aroyl hydrazone were designed, synthesized and evaluated for antibacterial and antibiofilm activities against methicillin-resistant Staphylococcus aureus (MRSA; ATCC 43866), methicillin-susceptible Staphylococcus aureus (MSSA; ATCC 35556) and Staphylococcus epidermidis (SE, S. epidermidis ATCC 35984). Of the 16 tested hybrids, 14 exhibited equal or superior antibiofilm activity against MSSA and MRSA relative to standard vancomycin. Compound 4m showed highest potency with antibiofilm activity of 0.39 ug/mL and 0.78 ug/mL against MSSA and MRSA, respectively. Thus, this compound could act as a potential lead for further development of new antistaphylococcal drugs. PMID- 23663081 TI - Design, synthesis and biological evaluation of novel inosine 5'-monophosphate dehydrogenase (IMPDH) inhibitors. AB - This study is based on our attempts to further explore the structure-activity relationship (SAR) of VX-148 (3) in an attempt to identify inosine 5'-mono phosphate dehydrogenase (IMPDH) inhibitors superior to mycophenolic acid. A five point pharmacophore developed using structurally diverse, known IMPDH inhibitors guided further design of novel analogs of 3. Several conventional as well as novel medicinal chemistry strategies were tried. The combined structure- and ligand-based approaches culminated in a few analogs with either retained or slightly higher potency. The compounds which retained the potency were also checked for their ability to inhibit human peripheral blood mononuclear cells proliferation. This study illuminates the stringent structural requirements and strict SAR for IMPDH II inhibition. PMID- 23663082 TI - Continuous imaging of esophagogastric junction in patients with reflux esophagitis using 320-row area detector CT: a feasibility study. AB - BACKGROUND AND AIM: The function of the lower esophageal sphincter (LES) is evaluated using an esophageal manometric study. However, information regarding the surrounding organs is difficult to obtain with use of a sensor catheter. We investigated the utility of 320-row area detector computed tomography (CT) to evaluate morphological changes of the esophagogastric junction and surrounding organs. METHODS: The study subjects were 18 healthy volunteers and 29 patients with reflux esophagitis (RE). Immediately after swallowing a diluted contrast agent, continuous imaging of the esophagogastric junctional area was performed for 15 s. Using CT images, the presence or absence of esophageal hiatal hernia, His angle before and after swallowing, size of the diaphragmatic hiatus, morphologically identified-LES (MI-LES) length, intraluminal horizontal area of MI-LES during relaxation phase, MI-LES thickness, abdominal esophagus length, subcutaneous fat area, visceral fat area, and esophagogastric junction fat area were evaluated. RESULTS: Analysis of CT images showed more frequent occurrence of hiatal hernia, greater His angle, and a larger diaphragmatic hiatus in patients with severe RE, while the lengths of MI-LES and abdominal esophagus were shorter in those patients. Visceral and esophagogastric junction fat areas tended to be greater in patients with RE. In all subjects, the posterior wall of the MI-LES was thicker than the anterior wall. CONCLUSION: Continuous imaging with 320-row area detector CT is useful to evaluate morphological changes in the esophagogastric junction area in both normal individuals and patients with reflux esophagitis. PMID- 23663083 TI - Characterization of the LTR retrotransposon repertoire of a plant clade of six diploid and one tetraploid species. AB - Comparisons of closely related species are needed to understand the fine-scale dynamics of retrotransposon evolution in flowering plants. Towards this goal, we classified the long terminal repeat (LTR) retrotransposons from six diploid and one tetraploid species of Orobanchaceae. The study species are the autotrophic, non-parasitic Lindenbergia philippensis (as an out-group) and six closely related holoparasitic species of Orobanche [O. crenata, O. cumana, O. gracilis (tetraploid) and O. pancicii] and Phelipanche (P. lavandulacea and P. ramosa). All major plant LTR retrotransposon clades could be identified, and appear to be inherited from a common ancestor. Species of Orobanche, but not Phelipanche, are enriched in Ty3/Gypsy retrotransposons due to a diversification of elements, especially chromoviruses. This is particularly striking in O. gracilis, where tetraploidization seems to have contributed to the Ty3/Gypsy enrichment and led to the emergence of seven large species-specific families of chromoviruses. The preferential insertion of chromoviruses in heterochromatin via their chromodomains might have favored their diversification and enrichment. Our phylogenetic analyses of LTR retrotransposons from Orobanchaceae also revealed that the Bianca clade of Ty1/Copia and the SMART-related elements are much more widely distributed among angiosperms than previously known. PMID- 23663084 TI - The cultural life script of Qatar and across cultures: effects of gender and religion. AB - Cultural life scripts (CLS) are culturally shared cognitive representations of the expected order and timing of important life events in a prototypical life. Through three studies data from Qatar were analysed and compared to previously collected data from Denmark, Turkey, and the US. In Study 1 we examined the CLS of Qatar in order to determine whether the clear segregation of men and women as well as the centrality of religion in this society would influence the CLS. A total of 55 Qatari undergraduates completed the standard CLS task, imaging a Qatari infant of their own as well as the opposite gender. In Study 2 important personal life story events were collected from 83 Qatari undergraduates in order to explore the overlap between remembered life events and CLS events. Study 3 was a reanalysis of CLS data from Denmark, Turkey, and the US. There was a considerable overlap of events across cultures, but we also found that the Qatari CLS showed more gender differences and contained more religious and positive events compared to the other three countries. PMID- 23663085 TI - Severe hypertriglyceridaemia in horses and ponies with endocrine disorders. AB - REASONS FOR PERFORMING THE STUDY: Severe hypertriglyceridaemia in horses and ponies with endocrine disorders has been reported anecdotally but has not been documented in the literature. OBJECTIVES: To describe historical and clinicopathological findings as well as progression and outcome in horses and ponies with severe hypertriglyceridaemia (serum triglyceride concentration >5.65 mmol/l) secondary to an endocrine disorder that were otherwise apparently healthy. METHODS: Cases from 6 participating institutions were identified and case details extracted from the medical records. RESULTS: Case details of 3 horses and 4 ponies were available. Presenting complaints included weight loss despite good appetite in 4 animals, while in 3 hypertriglyceridaemia was identified incidentally. All animals were bright and alert and showed a normal or increased appetite. Serum triglyceride concentrations ranged from 10.5 to 60.3 mmol/l. Other abnormalities included hyperglycaemia in 6 animals, suspected insulin resistance and mild to severe increases in hepatic enzyme activities. In 2 animals, moderate hepatic lipidosis was confirmed histologically. Three horses and 3 ponies were diagnosed with pituitary pars intermedia dysfunction based on clinical signs and basal adrenocorticotropic hormone (ACTH) concentrations or dexamethasone suppression test results. In 5 of these, type 2 diabetes mellitus was also confirmed, while one pony suffered from type 2 diabetes mellitus without concurrent pituitary pars intermedia dysfunction. Laboratory abnormalities improved in 4 animals with treatment (pergolide and/or insulin), in one horse specific treatment was not attempted, and in 2 ponies treatment was impaired by the owner or only partly effective. In one of the latter cases, biochemical abnormalities persisted for 7 years without apparent ill effects. CONCLUSIONS AND POTENTIAL RELEVANCE: Horses and ponies may develop severe hypertriglyceridaemia secondary to endocrine disorders that are associated with insulin resistance. Hypertriglyceridaemia can resolve with treatment of the endocrinopathy. Although biochemical evidence of hepatic compromise was present, clinical abnormalities were not noted in these animals. PMID- 23663086 TI - The "super mutant" of yeast FMN adenylyltransferase enhances the enzyme turnover rate by attenuating product inhibition. AB - FMN adenylyltransferase (FMNAT) is an essential enzyme catalyzing the last step of a two-step pathway converting riboflavin (vitamin B2) to FAD, the ubiquitous flavocoenzyme. A structure-based mutagenesis and steady-state kinetic analysis of yeast FMNAT unexpectedly revealed that mutant D181A had a much faster turnover rate than the wild-type enzyme. Product inhibition analysis showed that wild-type FMNAT is strongly inhibited by FAD, whereas the D181A mutant has an attenuated product inhibition. These results provide a structural basis for the product inhibition of the enzyme and suggest that product release may be the rate limiting step of the reaction. PMID- 23663087 TI - A novel pedigree with familial cortical myoclonic tremor and epilepsy (FCMTE): clinical characterization, refinement of the FCMTE2 locus, and confirmation of a founder haplotype. AB - PURPOSE: We describe the clinical, neurophysiologic, and genetic features of a new, large family with familial cortical myoclonic tremor and epilepsy (FCMTE). METHODS: Reliable clinical information was obtained on the 127 members. Thirty one collaborative individuals were assessed by a detailed clinical interview and a complete neurologic examination. A polygraphic study was conducted in 15 patients, back-averaging analysis and somatosensory evoked potentials with C reflex study in four. The genetic study investigated 30 subjects with microsatellite markers at three loci on chromosomes 8q (FCMTE1), 2p (FCMTE2), and 5p (FCMTE3). KEY FINDINGS: The pedigree included 25 affected members (M/F: 9/16). We studied 16 of the 19 living affected members (M/F: 5/11; mean age 47.8 years). Cortical myoclonic tremor (CMT) was associated with generalized seizures in 10 patients (62.5%). The mean age at onset of CMT and seizures was 28.1 and 33.8 years, respectively. Four patients (25%) reported a slow progression of CMT, with severe gait impairment in one. Psychiatric disorders of variable severity recurred in 37.5% of cases. Rhythmic bursts at 7-15 Hz were recorded in all 11 affected members tested. Additional neurophysiologic investigations disclosed a cortical origin of myoclonus in all patients tested. Generalized epileptiform discharges were recorded in 25% of cases, and a photoparoxysmal response in 31%. Genetic analysis established linkage to the FCMTE2 locus on chromosome 2p11.1 2q12.2 (OMIM 607876) and narrowed the critical interval to a 10.4 Mb segment. Haplotype analysis in the present family identified a founder haplotype identical to that previously observed in families from the same geographic area. SIGNIFICANCE: This study confirms evidence of a founder effect in Italian families and reduces the number of positional candidate genes in the FCMTE2 locus to 59, thereby contributing to future gene identification by Next Generation Sequencing approaches. PMID- 23663088 TI - Success rates of prosthetic restorations on endodontically treated teeth; a systematic review after 6 years. AB - The aims of this systematic review were to investigate the success rates of prosthetic restorations on endodontically treated teeth and their manner of failure. PubMed and hand literature searches were conducted on studies published until June 2012. Only clinical studies on human subjects referring to the success rates of prosthetic restorations on endodontically treated teeth with a follow-up period of at least 6 years were reviewed. A total of four studies were identified. Meta-analysis showed the success rate to be 92% (CI 82-98%) for single crowns on endodontically treated teeth and 79% (72-86%) for fixed dental prostheses. Only one study reported on removable dental prostheses with a success rate of 66%. Single crowns on teeth restored without posts demonstrated a success rate of 94% (CI 84-99%), whereas where posts were placed, the success rate was lower (92% CI 82-98%). Single crowns over cast post-and-cores and prefabricated posts showed success rates of 93% (CI 82-99%) and 94% (CI 90-97%), respectively; both differences were not statistically significant (significance level of 5%). The most common reason for failure was post-debonding. Single crowns seem to be the best treatment modality for endodontically treated teeth. However, due to the low number of studies included and their design, the results of this systematic review should be interpreted with caution. Further clinical studies are needed to provide high-quality evidence on the topic. PMID- 23663089 TI - Experimental evidence for diel delta15N-patterns in different tissues, xylem and phloem saps of castor bean (Ricinus communis L.). AB - Nitrogen isotope signatures in plants might give insights in the metabolism and allocation of nitrogen. To obtain a deeper understanding of the modifications of the nitrogen isotope signatures, we determined delta(15)N in transport saps and in different fractions of leaves, axes and roots during a diel course along the plant axis. The most significant diel variations were observed in xylem and phloem saps where delta(15)N was significantly higher during the day compared with during the night. However in xylem saps, this was observed only in the canopy, but not at the hypocotyl positions. In the canopy, delta(15)N was correlated fairly well between phloem and xylem saps. These variations in delta(15)N in transport saps can be attributed to nitrate reduction in leaves during the photoperiod as well as to (15)N-enriched glutamine acting as transport form of N. delta(15)N of the water soluble fraction of roots and leaves partially affected delta(15)N of phloem and xylems saps. delta(15)N patterns are likely the result of a complex set of interactions and N-fluxes between plant organs. Furthermore, the natural nitrogen isotope abundance in plant tissue is not constant during the diel course - a fact that needs to be taken into account when sampling for isotopic studies. PMID- 23663090 TI - Genetic drift or natural selection? Hybridization and asymmetric mitochondrial introgression in two Caribbean lizards (Anolis pulchellus and Anolis krugi). AB - Hybridization and gene introgression can occur frequently between closely related taxa, but appear to be rare phenomena among members of the species-rich West Indian radiation of Anolis lizards. We investigated the pattern and possible mechanism of introgression between two sister species from Puerto Rico, Anolis pulchellus and Anolis krugi, using mitochondrial (ND2) and nuclear (DNAH3, NKTR) DNA sequences. Our findings demonstrated extensive introgression of A. krugi mtDNA (k-mtDNA) into the genome of A. pulchellus in western Puerto Rico, to the extent that k-mtDNA has mostly or completely replaced the native mtDNA of A. pulchellus on this part of the island. We proposed two not mutually exclusive scenarios to account for the interspecific matings between A. pulchellus and A. krugi. We inferred that hybridization events occurred independently in several populations, and determined that k-mtDNA haplotypes harboured in individuals of A. pulchellus can be assigned to four of the five major mtDNA clades of A. krugi. Further, the spatial distribution of k-mtDNA clades in the two species is largely congruent. Based on this evidence, we concluded that natural selection was the probable driving mechanism for the extensive k-mtDNA introgression into A. pulchellus. Our two nuclear data sets yielded different results. DNAH3 showed reciprocal monophyly of A. pulchellus and A. krugi, indicating no effect of hybridization on this marker. In contrast, the two species shared nine NKTR alleles, probably due to incomplete lineage sorting. Our study system will provide an excellent opportunity to experimentally assess the behavioural and ecological mechanisms that can lead to hybridization in closely related taxa. PMID- 23663092 TI - Complete hydrodehalogenation of polyfluorinated and other polyhalogenated benzenes under mild catalytic conditions. AB - Polyfluorinated arenes are increasingly used in industry and can be considered emerging contaminants. Environmentally applicable degradation methods leading to full defluorination are not reported in the literature. In this study, it is demonstrated that the heterogeneous catalyst Rh/Al2O3 is capable of fully defluorinating and hydrogenating polyfluorinated benzenes in water under mild conditions (1 atm H2, ambient temperature) with degradation half-lives between 11 and 42 min. Analysis of the degradation rates of the 12 fluorobenzene congeners showed two trends: slower degradation with increasing number of fluorine substituents and increasing degradation rates with increasing number of adjacent fluorine substituents. The observed fluorinated intermediates indicated that adjacent fluorine substituents are preferably removed. Besides defluorination and hydrogenation, the scope of the catalyst includes dehalogenation of polychlorinated benzenes, bromobenzene, iodobenzene, and selected mixed dihalobenzenes. Polychlorobenzene degradation rates, like their fluorinated counterparts, decreased with increasing halogen substitution. In contrast to the polyfluorobenzenes though, removal of chlorine substituents was sterically driven. All monohalobenzenes were degraded at similar rates; however, when two carbon-halogen bonds were in direct intramolecular competition, the weaker bond was broken first. Differences in sorption affinities of the substrates are suggested to play a major role in determining the relative rates of transformation of halobenzenes by Rh/Al2O3 and H2. PMID- 23663091 TI - Hospitalisation rates in patients switched from oral anti-psychotics to aripiprazole once-monthly for the management of schizophrenia. AB - OBJECTIVE: To report the design and preliminary results of a mirror-image study comparing total psychiatric hospitalisation rates pre- and post-switch to aripiprazole once-monthly, an extended release injectable solution. METHODS: A multi-center, open-label mirror-image study of patients (18-65 years) with schizophrenia to compare total psychiatric hospitalisation rates between retrospective treatment with oral standard-of-care (SOC) anti-psychotics and prospective treatment with aripiprazole once-monthly in a naturalistic community setting in North America. Total psychiatric hospitalisation rates were assessed between retrospective (Months -4 to -1) and prospective treatment periods (Months 4-6) for patients who completed >=3 months aripiprazole once-monthly. RESULTS: One hundred and eighty-three patients entered the prospective phase. After switching to aripiprazole once-monthly, total psychiatric hospitalisation rates for the 3-month prospective period were significantly lower (p < 0.0001, Exact McNemar's test) compared with the retrospective 3-month period when the same patients received SOC anti-psychotics (6.6% [n = 8/121] vs 28.1% [n = 34/121], respectively; rate ratio = 0.24). Similarly, total psychiatric hospitalisation rates for all patients who entered the prospective treatment phase were significantly lower (p < 0.0001, Exact McNemar's test) for the prospective 6 months following switch to aripiprazole once-monthly, compared with the retrospective 6-month SOC period (14.2% [n = 26/183] vs 41.5% [n = 76/183], respectively; rate ratio = 0.34). Common treatment-emergent adverse events (occurring in >=5% of patients) were psychotic disorder (7.7%), akathisia (7.2%), and insomnia (7.2%). Discontinuation (all causes) during the prospective phase was 44.8% (n = 82/183). LIMITATIONS: Mirror-image studies do not include a parallel active control; as each patient serves as their own control, it cannot be determined whether other treatments may have similar effects. Treatment and trial effects may be difficult to separate. Independent factors such as admission patterns, insurance coverage, availability of hospital beds, and community support may influence rates of hospitalisation. CONCLUSIONS: Switching to aripiprazole once-monthly substantially reduced total psychiatric hospitalisation rates compared with retrospective rates in the same patients taking oral SOC. PMID- 23663093 TI - Openness to experience is related to better memory ability in older adults with questionable dementia. AB - The personality traits Openness to experience and Neuroticism of the five-factor model have previously been associated with memory performance in nondemented older adults, but this relationship has not been investigated in samples with memory impairment. Our examination of 50 community-dwelling older adults (29 cognitively intact; 21 with questionable dementia as determined by the Clinical Dementia Rating Scale) showed that demographic variables (age, years of education, gender, and estimated premorbid IQ) and current depressive symptoms explained a significant amount of variance of Repeatable Battery of Neuropsychological Status Delayed Memory (adjusted R (2) = 0.23). After controlling for these variables, a measure of global cognitive status further explained a significant portion of variance in memory performance (DeltaR(2) = 0.13; adjusted R(2) = 0.36; p < .01). Finally, adding Openness to this hierarchical linear regression model explained a significant additional portion of variance (DeltaR(2) = 0.08; adjusted R(2) = 0.44; p < .01) but adding Neuroticism did not explain any additional variance. This significant relationship between Openness and better memory performance above and beyond one's cognitive status and demographic variables may suggest that a lifelong pattern of involvement in new cognitive activities could be preserved in old age or protect from memory decline. This study suggests that personality may be a powerful predictor of memory ability and clinically useful in this heterogeneous population. PMID- 23663094 TI - Evaluation of contextual and demographic factors on licorice effects on reducing hot flashes in postmenopause women. AB - Menopause is an important stage in the life of every woman. Hot flashes are the most common climacteric symptom and a major cause of suffering in postmenopausal women. Licorice is one of the plants that is used to relieve menopausal symptoms. The present study was undertaken to evaluate the effects of licorice on hot flash symptoms in menopausal women. The participants of this randomized, double blind, clinical trial study were 60 menopausal women randomly allocated to licorice or hormone replacement therapy (HRT) groups. The participants in this trial received licorice (1140 mg/day) or HRT (a conjugated estrogen 0.312 mg/day and Medroxyprogesterone 2.5 mg/day) for 90 days. In this study we observed that licorice is not very different from hormones in terms of reducing the number and duration of hot flashes, but that HRT can reduce the severity of hot flashes significantly better than licorice can. In addition, there was no significant difference between age, education level, marital status, occupation, income, number of pregnancies, time from cessation of menstruation, and severity of hot flashes in the two groups. We observed that licorice seems more effective than HRT in improving hot flash duration, but that HRT can reduce the duration and severity of hot flashes more than licorice. PMID- 23663095 TI - Effect of radiation therapy on intraocular pressure in patients with Graves' orbitopathy. AB - PURPOSE: To describe the effect of radiation therapy on intraocular pressure in patients who have had orbital radiation for Graves' orbitopathy, and to provide a descriptive analysis of these patients. DESIGN: Retrospective case series. PARTICIPANTS: 24 consecutive patients referred for orbital radiation therapy for Graves' orbitopathy from December 1st, 2001 through July 31st, 2009. INTERVENTION: Patients received a total of 2000 cGy fractionated over 10 days. MAIN OUTCOME MEASURES: Medical records were reviewed for: demographics, tobacco history, ocular history, history related to Graves' disease, medications, visual field tests, retinopathy, and physical exam findings. The two-tailed Student's t test was used to determine statistically significant differences in intraocular pressure before radiation therapy and 0-3 (T1), 4-6 (T2), 7-12 (T3), and 13-18 (T4) months following radiation therapy. RESULTS: 34 eyes were available for analysis. There was no correlation between intraocular pressure and SPECS scores. Mean intraocular pressure prior to radiation therapy was 18.15 +/- 3.83 mm Hg. Patients who had orbital decompression, eye muscle surgery, or glaucoma were excluded from the final analysis. There were 7, 11, 14, and 11 eyes with data at times T1, T2, T3, and T4 following radiation therapy, respectively. There was a significant decrease in mean intraocular pressure at T2, T3 and T4 of 26.00% +/- 9.25%, 11.75% +/- 27.58%, and 16.72% +/- 13.94%, respectively. CONCLUSIONS: There was a significant drop in mean intraocular pressure between 4 and 18 months after radiation therapy in our patient population. The mechanism by which this decrease in intraocular pressure occurs is not understood. PMID- 23663096 TI - The role of three-dimensional echocardiography in diagnosis and management of ruptured sinus of valsalva aneurysm. PMID- 23663097 TI - Encapsulation of flaxseed oil using a benchtop spray dryer for legume protein maltodextrin microcapsule preparation. AB - Flaxseed oil was microencapsulated employing a wall material matrix of either chickpea (CPI) or lentil protein isolate (LPI) and maltodextrin using a benchtop spray dryer. Effects of emulsion formulation (oil, protein and maltodextrin levels) and protein source (CPI vs LPI) on the physicochemical characteristics, oxidative stability, and release properties of the resulting capsules were investigated. Microcapsule formulations containing higher oil levels (20% oil, 20% protein, 60% maltodextrin) were found to have higher surface oil and lower encapsulation efficiencies. Overall, LPI-maltodextrin capsules gave higher flaxseed oil encapsulation efficiencies (~88.0%) relative to CPI-maltodextrin matrices (~86.3%). However, both designs were found to provide encapsulated flaxseed oil protection against oxidation over a 25 d room temperature storage study relative to free oil. Overall, ~37.6% of encapsulated flaxseed oil was released after 2 h under simulated gastric fluid, followed by the release of an additional ~46.6% over a 3 h period under simulated intestinal fluid conditions. PMID- 23663098 TI - Radiation therapy for lymph node metastasis from extramammary Paget's disease. AB - BACKGROUND: Inoperable patients with lymph node metastasis from extramammary Paget's disease (EMPD) have limited curative treatment options. OBJECTIVE: The aim of this study was to review the efficacy and toxicity of radiation therapy for lymph node metastasis from EMPD. METHODS: Eight EMPD patients with pelvic and inguinal lymph node metastasis, representing a total of 43 metastatic lymph nodes, underwent radiation therapy. Of these eight patients, two received radiation therapy as an initial treatment for EMPD and six for recurrence only in the lymph nodes after they had undergone surgery. Total doses of 45-61.2 Gy (median, 59.4 Gy) were delivered to metastatic lymph nodes in 25-34 fractions (median, 33 fractions). RESULTS: Of the 43 metastatic lymph nodes in the eight patients, all but one had no progression at the median follow-up time of 22 months. The 2-year local control rates were 86% in all patients and 98% in all metastatic lymph nodes, respectively. No therapy-related toxicities of grade 3 or greater were observed. CONCLUSION: Radiation therapy is effective and safe, and appears to offer a curative treatment option for lymph node metastasis from EMPD. PMID- 23663099 TI - Gold(I)-catalyzed formation of bicyclo[4.2.0]oct-1-enes. AB - Gold(I) catalysts effectively promote the Cope rearrangement of acyclic 1,5 dienes bearing a terminal cyclopropylidene. When this methodology is applied to cyclic substrates an unexpected transformation occurs, resulting in the formation of a tricyclic compound incorporating a bicyclo[4.2.0]oct-1-ene core, a portion of which is found in a number of natural products. Density functional theory calculations (M06 and M06-2X) reveal insight into the mechanism and thermodynamics of this unique transformation. PMID- 23663101 TI - Management of idiopathic granulomatous mastitis diagnosed by core biopsy: a retrospective multicenter study. AB - Idiopathic granulomatous mastitis (IGM) is a rare, benign, chronic inflammatory condition of the breast, which usually mimics breast carcinoma. The aim of this study was to analyze the clinical features of IGM by identifying a more reliable diagnostic protocol, and evaluating the treatment methods and patient outcomes on follow-up. We performed a retrospective analysis of 46 patients diagnosed with IGM and managed by the same surgical team between 1999 and 2011, at three high volume hospitals. The median age of the patients was 33 years. The most common symptom was painful breast mass (n = 39), followed by abscess (n = 11). All patients underwent ultrasonography (USG). Mammography (MG) and magnetic resonance imaging (MRI) were also performed in 20 patients (43%) and 17 patients (37%), respectively. The mean size of the lesions was 32.8 +/- 8.8 mm and ranged from 15 to 50 mm. Preoperative diagnosis of IGM was established by core needle biopsy (CNB) under USG guidance. Eighteen patients (39%) underwent complete excision of the lesion and 25 (54%) were treated with steroids. Three patients treated with steroids subsequently underwent local excision. The mean follow-up period was 35.4 +/- 30.9 months. Eight patients (17%) developed disease recurrence; three of these were successfully treated with steroids, one with surgery, and four with both steroids and surgery. CNB in conjunction with high diagnostic accuracy has a significant role in distinctive diagnosis of IGM and hence, is useful for treatment planning. Treatment can be designated according to the extent and the severity of the disease, and the patient's general health and treatment preferences. Patients with IGM must be closely followed up due to the frequency of disease recurrence. PMID- 23663100 TI - n->pi* interactions of amides and thioamides: implications for protein stability. AB - Carbonyl-carbonyl interactions between adjacent backbone amides have been implicated in the conformational stability of proteins. By combining experimental and computational approaches, we show that relevant amidic carbonyl groups associate through an n->pi* donor-acceptor interaction with an energy of at least 0.27 kcal/mol. The n->pi* interaction between two thioamides is 3-fold stronger than between two oxoamides due to increased overlap and reduced energy difference between the donor and acceptor orbitals. This result suggests that backbone thioamide incorporation could stabilize protein structures. Finally, we demonstrate that intimate carbonyl interactions are described more completely as donor-acceptor orbital interactions rather than dipole-dipole interactions. PMID- 23663102 TI - Case report of anti-transcription intermediary factor-1-gamma/alpha antibody positive dermatomyositis associated with gastric cancer and immunoglobulin G4 positive pulmonary inflammatory pseudotumor. AB - Dermatomyositis is a rare connective tissue disease often associated with internal malignancy and interstitial pneumonitis. Serologically, various auto antibodies (Ab) are associated with dermatomyositis. Anti-transcription intermediary factor-1-gamma/alpha (TIF-1-gamma/alpha) Ab was recently identified as an auto-Ab and was observed mostly in cancer-associated dermatomyositis. IgG4 related disease is a newly described entity characterized by increased serum IgG4 levels and IgG4-positive plasma cell infiltration with fibrosis in organs such as the pancreas and parotid gland. IgG4-related disease also includes inflammatory pseudotumors in various organs. We report herein a 59-year-old Japanese man who had dermatomyositis complicated with a gastric cancer and an IgG4-related pulmonary inflammatory pseudotumor. He manifested typical classical Gottron's papules on the fingers, V-sign erythema on the chest, flagellate erythema on the back, nail fold bleeding and facial erythema. Serum levels of anti-TIF-1 gamma/alpha Ab were positive as assessed by immunoprecipitation assay. He also had bilateral swelling of the parotid gland, and an excised specimen of the lung showed inflammatory pseudotumor with IgG4-positive plasma cells. As far as we know, this case is the first to report the association of IgG4-related disease and TIF-1-gamma/alpha-positive dermatomyositis. Further accumulation of such cases is required to elucidate the mechanism of this association. PMID- 23663104 TI - Current treatment of community-acquired pneumonia. AB - INTRODUCTION: Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. Management decisions regarding site of care, extent of assessment and level of treatment are based primarily on disease severity (outpatient, inpatient and ICU admission). Despite the developments in antibiotic therapy, CAP is still the most common infectious cause of death. AREAS COVERED: There are several challenges with the management of CAP, from the accurate diagnosis, decisions about place of therapy and the choice of appropriate antibiotics. An extensive literature review of manuscripts, in PubMed, published in the past 10 years has been performed, using combinations of words and terms appropriate to the concepts of CAP, treatment, guidelines and corticoids. Some empirical antimicrobial regimens, such as macrolides, are still being debated; some new antibiotics and adjunctive therapies (corticoids) have recently been tested. This is a review of current recommended antimicrobials regimens, novel approaches and adjunctive drugs for the treatment of CAP. EXPERT OPINION: Effective management of CAP requires risk stratification of patients by severity and proper place of therapy. Additional therapeutic interventions along with antibiotics may help to improve outcome in patients with CAP, especially in severe CAP. PMID- 23663103 TI - Streptococcal-vimentin cross-reactive antibodies induce microvascular cardiac endothelial proinflammatory phenotype in rheumatic heart disease. AB - Rheumatic heart disease (RHD) is characterized by the presence of anti streptococcal group A antibodies and anti-endothelial cell antibodies (AECA). Molecular mimicry between streptococcal antigens and self proteins is a hallmark of the pathogenesis of rheumatic fever. We aimed to identify, in RHD patients, autoantibodies specific to endothelial autoantigens cross-reactive with streptococcal proteins and to evaluate their role in inducing endothelial damage. We used an immunoproteomic approach with endothelial cell-surface membrane proteins in order to identify autoantigens recognized by AECA of 140 RHD patients. Cross-reactivity of purified antibodies with streptococcal proteins was analysed. Homologous peptides recognized by serum cross-reactive antibodies were found through comparing the amino acid sequence of streptococcal antigens with human antigens. To investigate interleukin (IL)-1R-associated kinase (IRAK1) and nuclear factor-kappaB (NF-kappaB) activation, we performed a Western blot analysis of whole extracts proteins from unstimulated or stimulated human microvascular cardiac endothelial cells (HMVEC-C). Adhesion molecule expression and release of proinflammatory cytokines and growth factors were studied by multiplex bead based immunoassay kits. We observed anti-vimentin antibodies in sera from 49% RHD AECA-positive patients. Cross-reactivity of purified anti vimentin antibodies with heat shock protein (HSP)70 and streptopain streptococcal proteins was shown. Comparing the amino acid sequence of streptococcal HSP70 and streptopain with human vimentin, we found two homologous peptides recognized by serum cross-reactive antibodies. These antibodies were able to stimulate HMVEC-C inducing IRAK and NF-kappaB activation, adhesion molecule expression and release of proinflammatory cytokines and growth factors. In conclusion, streptococcal vimentin cross-reactive antibodies were able to activate microvascular cardiac endothelium by amplifying the inflammatory response in RHD. PMID- 23663105 TI - Plasma fructosamine concentrations in horses with pituitary pars intermedia dysfunction with and without laminitis. AB - REASONS FOR PERFORMING STUDY: Plasma fructosamine concentration ([fructosamine]) is believed to reflect medium term, average blood glucose concentration and in a previous study was higher in horses with active laminitis than in normal horses. Pituitary pars intermedia dysfunction (PPID) is associated with hyperglycaemia and laminitis. OBJECTIVES: To test the hypotheses that: [fructosamine] is higher in PPID cases than normal animals; furthermore, that within cases of PPID [fructosamine] is higher in those with active laminitis than nonlaminitic cases and in cases that have been affected by active laminitis in the preceding year than those that have not. STUDY DESIGN: Observational, case-control/cross sectional study. METHODS: [Fructosamine] was measured in cases of PPID (n = 46) and normal animals (n = 139). A normal range was calculated; values were compared between the 2 groups and within the PPID group, between cases with and without active laminitis and between cases that had and had not been affected by active laminitis in the preceding year. RESULTS: In normal animals mean [fructosamine] was 248.7 MUmol/l; the normal range (mean +/- 2 s.d.) was 195.5-301.9 MUmol/l. Plasma [fructosamine] was not higher in PPID cases than in normal animals. In PPID cases, [fructosamine] was significantly (P = 0.006) higher in cases with active laminitis (mean +/- s.d. 261.2 +/- 39.2 MUmol/l) compared with those without active laminitis (234.5 +/- 32.9 MUmol/), but [fructosamine] was not higher in cases that had been affected by active laminitis in the preceding year than those that had not. CONCLUSIONS: In horses affected by PPID, [fructosamine] is higher in cases with active laminitis than in cases without active laminitis. POTENTIAL RELEVANCE: Clinical use of [fructosamine] is limited due to overlap with the normal range. Further studies into glucose and protein metabolism in cases of PPID are warranted. PMID- 23663106 TI - PpeTAC1 promotes the horizontal growth of branches in peach trees and is a member of a functionally conserved gene family found in diverse plants species. AB - Trees are capable of tremendous architectural plasticity, allowing them to maximize their light exposure under highly competitive environments. One key component of tree architecture is the branch angle, yet little is known about the molecular basis for the spatial patterning of branches in trees. Here, we report the identification of a candidate gene for the br mutation in Prunus persica (peach) associated with vertically oriented growth of branches, referred to as 'pillar' or 'broomy'. Ppa010082, annotated as hypothetical protein in the peach genome sequence, was identified as a candidate gene for br using a next generation sequence-based mapping approach. Sequence similarity searches identified rice TAC1 (tiller angle control 1) as a putative ortholog, and we thus named it PpeTAC1. In monocots, TAC1 is known to lead to less compact growth by increasing the tiller angle. In Arabidopsis, an attac1 mutant showed more vertical branch growth angles, suggesting that the gene functions universally to promote the horizontal growth of branches. TAC1 genes belong to a gene family (here named IGT for a shared conserved motif) found in all plant genomes, consisting of two clades: one containing TAC1-like genes; the other containing LAZY1, which contains an EAR motif, and promotes vertical shoot growth in Oryza sativa (rice) and Arabidopsis through influencing polar auxin transport. The data suggest that IGT genes are ancient, and play conserved roles in determining shoot growth angles in plants. Understanding how IGT genes modulate branch angles will provide insights into how different architectural growth habits evolved in terrestrial plants. PMID- 23663107 TI - Ubiquilin-1 modulates gamma-secretase-mediated epsilon-site cleavage in neuronal cells. AB - Ubiquilin-1 is an Alzheimer's disease-associated protein, which is known to modulate amyloid precursor protein (APP) processing, amyloid-beta (Abeta) secretion, and presenilin-1 (PS1) accumulation. Here, we aim to elucidate the molecular mechanisms by which full-length transcript variant 1 of ubiquilin-1 (TV1) affects APP processing and gamma-secretase function in human neuroblastoma cells stably overexpressing APP (SH-SY5Y-APP751). We found that TV1 overexpression significantly increased the level of APP intracellular domain (AICD) generation. However, there was no increase in the levels of secreted Abeta40, Abeta42, or total Abeta, suggesting that ubiquilin-1 in particular enhances gamma-secretase-mediated epsilon-site cleavage. This is supported by the finding that TV1 also significantly increased the level of intracellular domain generation of another gamma-secretase substrate, leukocyte common antigen-related (LAR) phosphatase. However, in these cells, the increase in AICD levels was abolished, suggesting a preference of the gamma-secretase for LAR over APP. TV2, another ubiquilin-1 variant that lacks the protein fragment encoded by exon 8, did not increase the level of AICD generation like TV1 did. The subcellular and plasma membrane localization of APP or gamma-secretase complex components PS1 and nicastrin was not altered in TV1-overexpressing cells. Moreover, the effects of TV1 were not mediated by altered expression or APP binding of FE65, an adaptor protein thought to regulate AICD generation and stability. These data suggest that ubiquilin-1 modulates gamma-secretase-mediated epsilon-site cleavage and thus may play a role in regulating gamma-secretase cleavage of various substrates. PMID- 23663108 TI - Nanomechanical actuation of a silicon cantilever using an azo dye, self-assembled monolayer. AB - The emerging fields of nanomotors and optomechanics are based on the harnessing of light to generate force. However, our ability to detect small surface stresses is limited by temperature drift, environmental noise, and low-frequency flicker electronic noise. To address these limitations, we functionalized microfabricated silicon cantilevers with an azo dye, silane-based self-assembled monolayer and modulated the surface stress by exciting the optical switch with a 405-nm laser. Atomic force microscopy, contact angle analysis, ellipsometry, and X-ray photoelectron spectroscopy verified successful assembly of molecules on the cantilever. Ultraviolet and visible spectra demonstrate optical switching of the synthesized molecule in solution. By turning the laser on and off at a specific rate (e.g., 1 Hz), the cantilever deflection can be measured via Fourier techniques, thus separating the signal of interest from the noise. This technique empowers the design of highly sensitive surface stress measurements. PMID- 23663109 TI - Comprehensive evaluation of the psychosocial parameters of epilepsy: a representative population-based study in Prey Veng (Cambodia). AB - PURPOSE: We conducted a population-based study of epilepsy in Prey Veng (Cambodia) to explore self-esteem, fear, discrimination, knowledge-attitude practice (KAP), social-support, stigma, coping strategies, seizure-provoking factors, and patient-derived factors associated with quality of life (QOL). METHODS: The results are based on a cohort of 96 cases and matched controls (n = 192), randomly selected from the same source population. Various questionnaires were developed and validated for internal consistency (by split-half, Spearman Brown prophecy, Kuder-Richardson 20), content clarity and soundness. Summary, descriptive statistics, classical tests of hypothesis were conducted. Uncorrected chi-square was used. Group comparison was done to determine statistically significant factors, for each domain, by conducting logistic regression; 95% confidence interval (CI) with 5% (two-sided) statistical significance was used. KEY FINDINGS: All questionnaires had high internal consistency. Stress was relevant in 14.0% cases, concealment in 6.2%, denial in 8.3%, negative feelings in public in 3.0%. Mean self-esteem was 7.5, range 0-8, related to seizure frequency. Mean discrimination was least during social interactions. Coping strategies were positive (e.g. look for treatment). Postictal headache, anger, no nearby health facility, etc. were associated with QOL. SIGNIFICANCE: The reliability of our questionnaires was high. A positive social environment was noted with many infrequent social and personal prejudices. Not all populations should (by default) be considered as stigmatized or equipped with poor KAP. We addressed themes that have been incompletely evaluated, and our approach could therefore become a model for other projects. PMID- 23663110 TI - Expression of genes for microRNA-processing enzymes is altered in advanced non alcoholic fatty liver disease. AB - BACKGROUND AND AIM: Recently, microRNAs (miRNA) have been linked to the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and its progression to non-alcoholic steatohepatitis (NASH). First transcribed as pri-miRNA, these molecules are further processed by a complex of endonuclear and cytosolic RNA binding molecules to form mature miRNAs. The aim of this study is to investigate mechanisms of miRNA regulation in the visceral adipose of obese NAFLD patients via measuring expression of miRNA processing enzymes and pri-miRNA. METHODS: Total RNAs were extracted from visceral adipose tissue (VAT) samples collected from patients undergoing bariatric surgery. All patients had biopsy-proven NAFLD (NASH patients [n = 12] and non-NASH NAFLD [n = 12]). For each patient, we profiled mRNA levels for three miRNA processing elements (Drosha, DGCR8, and Dicer1) and seven pri-miRNAs (pri-miR-125b-2, pri-miR-16-2, pri-miR-26a-1, pri miR-26a-2, pri-miR-7-1, pri-miR-7-2, and pri-miR-7-3). RESULTS: Expression of Dicer1, Drosha and DGCR8 was significantly increased within the NASH cohort along with expression of pri-miR-7-1. The presence of focal necrosis on the liver biopsy correlated significantly with levels of Dicer1 and DGRC8. Both NASH and ballooning degeneration of hepatocytes correlated negatively with the expression levels of hsa-miR-125b. Histologic NASH correlated positively with the expression levels of pri-miR-16-2 and pri-miR-7-1. The presence of the hepatocyte's ballooning degeneration in the liver biopsy correlated positively with pri-miR 26a-1 and pri-miR-7-1. The expression profile of pri-miR-125b-2 also correlated positively with body mass index. CONCLUSIONS: Our findings support the hypothesis that VAT-derived miRNA may contribute to the pathogenesis of NASH in obese patients. PMID- 23663111 TI - Life cycle assessment of a power tower concentrating solar plant and the impacts of key design alternatives. AB - A hybrid life cycle assessment (LCA) is used to evaluate four sustainability metrics over the life cycle of a power tower concentrating solar power (CSP) facility: greenhouse gas (GHG) emissions, water consumption, cumulative energy demand (CED), and energy payback time (EPBT). The reference design is for a dry cooled, 106 MW(net) power tower facility located near Tucson, AZ that uses a mixture of mined nitrate salts as the heat transfer fluid and storage medium, a two-tank thermal energy storage system designed for six hours of full load equivalent storage, and receives auxiliary power from the local electric grid. A thermocline-based storage system, synthetically derived salts, and natural gas auxiliary power are evaluated as design alternatives. Over its life cycle, the reference plant is estimated to have GHG emissions of 37 g CO2eq/kWh, consume 1.4 L/kWh of water and 0.49 MJ/kWh of energy, and have an EPBT of 15 months. Using synthetic salts is estimated to increase GHG emissions by 12%, CED by 7%, and water consumption by 4% compared to mined salts. Natural gas auxiliary power results in greater than 10% decreases in GHG emissions, water consumption, and CED. The thermocline design is most advantageous when coupled with the use of synthetic salts. PMID- 23663112 TI - A comparison of the sensory profile and sensory processing measure home form for children with fetal alcohol spectrum disorders. AB - This exploratory study compared the performance of children with fetal alcohol spectrum disorders (FASD; n = 11) and children with typical development (TD) without alcohol exposure (n = 12) on the Short Sensory Profile (SSP) and Sensory Processing Measure (SPM) Home Form. The child's primary caregiver completed both measures. For children with FASD, 90.9% had probable or definite differences on the SSP and 81.8% had some problems or definite dysfunction on the SPM Home Form. All children with TD (100%) scored in the typical range on total scores for both measures. For the children with FASD, the percent agreement between the two measures was 36.6% for the three classification categories (typical, probable/some, and definite) and 81.8% when classification was collapsed into two categories (typical and probable/definite difference). Both measures detected sensory processing differences for children with FASD, however, categorization of clinical severity varied based on the cutoffs used. PMID- 23663113 TI - Use of a porous polyethylene lid spacer for management of eyelid retraction in patients with Boston type II keratoprosthesis. AB - PURPOSE: To report a novel application of a porous polyethylene implant for lid stabilization and management of eyelid retraction in a patient with an exposed Boston Keratoprosthesis Type II. METHODS: A 54-year-old woman with a history of mucous membrane pemphigoid and failed penetrating keratoplasty of the left eye underwent implantation of a Boston Keratoprosthesis (KPro) Type II along with permanent surgical fusion of the upper and lower lids of the left eye in January 2010. At one month follow-up, significant retraction of the lower lid around the inferior margin of the optic was noted, resulting in partial exposure of the keratoprosthesis. The patient subsequently underwent left lower eyelid reconstruction with a porous polyethylene implant to ensure coverage and stability of the KPro. RESULTS: Eyelid reconstruction using a porous polyethylene implant resulted in stable retention of the KPro Type II for over 2 years. CONCLUSION: In patients with Boston KPro Type II in the setting of severe cicatrizing ocular surface disease, the use of a porous polyethylene implant during eyelid reconstruction around the KPro optic may aid in maintaining eyelid integrity and improving KPro stability and longevity. PMID- 23663114 TI - Constraining 3-PG with a new delta13C submodel: a test using the delta13C of tree rings. AB - A semi-mechanistic forest growth model, 3-PG (Physiological Principles Predicting Growth), was extended to calculate delta(13)C in tree rings. The delta(13)C estimates were based on the model's existing description of carbon assimilation and canopy conductance. The model was tested in two ~80-year-old natural stands of Abies grandis (grand fir) in northern Idaho. We used as many independent measurements as possible to parameterize the model. Measured parameters included quantum yield, specific leaf area, soil water content and litterfall rate. Predictions were compared with measurements of transpiration by sap flux, stem biomass, tree diameter growth, leaf area index and delta(13)C. Sensitivity analysis showed that the model's predictions of delta(13)C were sensitive to key parameters controlling carbon assimilation and canopy conductance, which would have allowed it to fail had the model been parameterized or programmed incorrectly. Instead, the simulated delta(13)C of tree rings was no different from measurements (P > 0.05). The delta(13)C submodel provides a convenient means of constraining parameter space and avoiding model artefacts. This delta(13)C test may be applied to any forest growth model that includes realistic simulations of carbon assimilation and transpiration. PMID- 23663115 TI - The role of local ecology during hybridization at the initial stages of ecological speciation in a marine snail. AB - Hybrid zones of ecologically divergent populations are ideal systems to study the interaction between natural selection and gene flow during the initial stages of speciation. Here, we perform an amplified fragment length polymorphism (AFLP) genome scan in parallel hybrid zones between divergent ecotypes of the marine snail Littorina saxatilis, which is considered a model case for the study of ecological speciation. Ridged-Banded (RB) and Smooth-Unbanded (SU) ecotypes are adapted to different shore levels and microhabitats, although they present a sympatric distribution at the mid-shore where they meet and mate (partially assortatively). We used shell morphology, outlier and nonoutlier AFLP loci from RB, SU and hybrid specimens captured in sympatry to determine the level of phenotypic and genetic introgression. We found different levels of introgression at parallel hybrid zones and nonoutlier loci showed more gene flow with greater phenotypic introgression. These results were independent from the phylogeography of the studied populations, but not from the local ecological conditions. Genetic variation at outlier loci was highly correlated with phenotypic variation. In addition, we used the relationship between genetic and phenotypic variation to estimate the heritability of morphological traits and to identify potential Quantitative Trait Loci to be confirmed in future crosses. These results suggest that ecology (exogenous selection) plays an important role in this hybrid zone. Thus, ecologically based divergent natural selection is responsible, simultaneously, for both ecotype divergence and hybridization. On the other hand, genetic introgression occurs only at neutral loci (nonoutliers). In the future, genome-wide studies and controlled crosses would give more valuable information about this process of speciation in the face of gene flow. PMID- 23663116 TI - The contribution of trail making to the prediction of performance-based instrumental activities of daily living in Parkinson's disease without dementia. AB - Performance on Part B of the Trail Making Test (TMT) contributes to the prediction of ability to complete instrumental activities of daily living (IADLs) in Parkinson's disease (PD). Although this suggests that cognitive flexibility is important in the everyday functioning of individuals with PD, this may not be the case as the TMT is multifactorial, involving motor speed, visual scanning, sequencing, and cognitive flexibility. The purpose of the current study was to determine which elements of the task contribute to the prediction of IADLs in a sample of 30 nondemented individuals with PD. Correlational analyses indicated strong relationships between a performance-based measure of IADLs and measures involving scanning, sequencing, and cognitive flexibility from the Delis-Kaplan Executive Function System (D-KEFS) TMT. Results from standard regressions indicated that measures of sequencing and level of depression but not scanning, cognitive flexibility, or demographic variables made a significant, independent contribution to the prediction of IADLs. These results suggest that the sequencing element of the TMT is paramount in the prediction of IADLs in PD. PMID- 23663117 TI - Biosorption of multifold toxic heavy metal ions from aqueous water onto food residue eggshell membrane functionalized with ammonium thioglycolate. AB - A new biosorbent material from eggshell membrane was synthesized through thiol functionalization, which is based on the reduction of disulfide bonds in eggshell membrane by ammonium thioglycolate. The thiol-functionalized eggshell membrane was characterized, and its application as an adsorbent for removal of Cr(VI), Hg(II), Cu(II), Pb(II), Cd(II), and Ag(I) from aqueous water has been investigated. The experimental results revealed that the adsorption abilities of the thiol-functionalized eggshell membrane toward Cr(VI), Hg(II), Cu(II), Pb(II), Cd(II), and Ag(I) improved 1.6-, 5.5-, 7.7-, 12.4-, 12.7-, and 21.1-fold, respectively, compared with that of the eggshell membrane control. The adsorption mechanism and adsorption performance, including the adsorption capacity and the kinetics of the thiol-functionalized eggshell membrane for the target heavy metals, were investigated. The effects of solution pH, coexisting substances, and natural water matrices were studied. The thiol-functionalized eggshell membrane can be used as column packing to fabricate a column for real wastewater purification. PMID- 23663118 TI - In vitro chipping behaviour of all-ceramic crowns with a zirconia framework and feldspathic veneering: comparison of CAD/CAM-produced veneer with manually layered veneer. AB - The purpose of this in vitro study was to assess the breaking load of zirconia based crowns veneered with either CAD/CAM-produced or manually layered feldspathic ceramic. Thirty-two identical zirconia frameworks (Sirona inCoris ZI, mono L F1), 0.6 mm thick with an anatomically shaped occlusal area, were constructed (Sirona inLab 3.80). Sixteen of the crowns were then veneered by the use of CAD/CAM-fabricated feldspathic ceramic (CEREC Bloc, Sirona) and 16 by the use of hand-layered ceramic. The CAD/CAM-manufactured veneer was attached to the frameworks by the use of Panavia 2.0 (Kuraray). Half of the specimens were loaded until failure without artificial ageing; the other half of the specimens underwent thermal cycling and cyclic loading (1.2 million chewing cycles, force magnitude F(max) = 108 N) before the assessment of the ultimate load. To investigate the new technique further, finite element (FE) computations were conducted on the basis of the original geometry. Statistical assessment was made by the use of non-parametric tests. Initial breaking load was significantly higher in the hand-layered group than in the CAD/CAM group (mean: 1165.86 N versus 395.45 N). During chewing simulation, however, 87.5% (7/8) of the crowns in the hand-layered group failed, whereas no crown in the CAD/CAM group failed. The CAD/CAM-produced veneer was significantly less sensitive to ageing than the hand-layered veneer. PMID- 23663120 TI - Dis-assembly of a benzylic CF3 group mediated by a niobium(III) imido complex. AB - All three C-F bonds in CF3-substituted arenes are activated by a niobium imido complex, driven by the formation of strong Nb-F bonds. The mechanism of this transformation was studied by NMR spectroscopy, which revealed the involvement of Nb(III). Attempts to extend this chemistry to nonaromatic CF3 groups led to intramolecular reactivity. PMID- 23663119 TI - Thirty days of resveratrol supplementation does not affect postprandial incretin hormone responses, but suppresses postprandial glucagon in obese subjects. AB - AIMS: Resveratrol, a natural polyphenolic compound produced by various plants (e.g. red grapes) and found in red wine, has glucose-lowering effects in humans and rodent models of obesity and/or diabetes. The mechanisms behind these effects have been suggested to include resveratrol-induced secretion of the gut incretin hormone glucagon-like peptide-1. We investigated postprandial incretin hormone and glucagon responses in obese human subjects before and after 30 days of resveratrol supplementation. METHODS: Postprandial plasma responses of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide and glucagon were evaluated in 10 obese men [subjects characteristics (mean +/- standard error of the mean): age 52 +/- 2 years; BMI 32 +/- 1 kg/m(2), fasting plasma glucose 5.5 +/- 0.1 mmol/l] who had been given a dietary supplement of resveratrol (Resvida((r)) 150 mg/day) or placebo for 30 days in a randomized, double-blind, crossover design with a 4-week washout period. At the end of each intervention period a standardized meal test (without co administration of resveratrol) was performed. RESULTS: Resveratrol supplementation had no impact on fasting plasma concentrations or postprandial plasma responses (area under curve values) of glucose-dependent insulinotropic polypeptide (11.2 +/- 2.1 vs. 11.8 +/- 2.2 pmol/l, P = 0.87; 17.0 +/- 2.2 vs. 14.8 +/- 1.6 min * nmol/l, P = 0.20) or glucagon-like peptide-1 (15.4 +/- 1.0 vs. 15.2 +/- 0.9 pmol/l, P = 0.84; 5.6 +/- 0.4 vs. 5.7 +/- 0.3 min * nmol/l, P = 0.73). Resveratrol supplementation significantly suppressed postprandial glucagon responses (4.4 +/- 0.4 vs. 3.9 +/- 0.4 min * nmol/l, P = 0.01) without affecting fasting glucagon levels (15.2 +/- 2.2 vs. 14.5 +/- 1.5 pmol/l, P = 0.56). CONCLUSIONS: Our data suggest that 30 days of resveratrol supplementation does not affect fasting or postprandial incretin hormone plasma levels in obese humans, but suppresses postprandial glucagon responses. PMID- 23663121 TI - Recurrence of Hirschsprung disease due to maternal mosaicism of a novel RET gene mutation. PMID- 23663122 TI - A comparison of lesbian, bisexual, and heterosexual college undergraduate women on selected mental health issues. AB - OBJECTIVE: To investigate selected mental health characteristics of lesbians and bisexual undergraduate college women as compared with heterosexual college women. PARTICIPANTS: Self-identified lesbians and bisexual and heterosexual female college students who took part in the American College Health Association National College Health Assessment II (ACHA-NCHA-II) in Fall 2008, Spring 2009, and Fall 2009. METHODS: A secondary analysis of the ACHA-NCHA-II data set for 3 semesters was conducted. Comparisons of lesbians and bisexual and heterosexual female college students were made. RESULTS: Bisexual women reported the worst mental health status in all areas studied including anxiety, anger, depressive symptoms, self-injury, and suicidal ideation and attempts. Both bisexual women and lesbians had a far greater likelihood of having these mental health issues when compared with heterosexual women. Lesbians and bisexual women utilized significantly more mental health services (with the exception of clergy) than heterosexual women. CONCLUSIONS: College health professionals should recognize and address the mental health needs of bisexual and lesbian undergraduate college women. PMID- 23663123 TI - Human immunodeficiency virus and chlamydia/gonorrhea testing among heterosexual college students: who is getting tested and why do some not? AB - OBJECTIVE: This study explored college students' reported history of human immunodeficiency virus (HIV) and chlamydia/gonorrhea and characteristics of students reporting testing. Additionally, it assessed their motivation regarding future testing and reasons for lack of motivation. PARTICIPANTS: The sample consisted of 292 sexually experienced college students self-identifying as heterosexual at a midwestern university. METHODS: Participants completed a 26 item survey during the 2010-2011 academic year. RESULTS: Demographics (sex, age, race/ethnicity), behaviors (higher numbers of sex partners, currently not using condoms), and motivation for future testing distinguished those who had been tested ever and those who had not. Half of participants were not motivated to seek testing in the next 3 months; the most common reason for no motivation being perceived lack of risk. CONCLUSIONS: Interventions promoting testing can use these findings to target those likely to never have been tested. These results also highlight the need to find ways to motivate students to get tested. PMID- 23663124 TI - Social context of smoking hookah among college students: scale development and validation. AB - OBJECTIVE: To develop an instrument that measures the social context of hookah use among college students. PARTICIPANTS: A pool of 50 potential items, based on 44 in-depth interviews with regular college hookah smokers, was administered to a sample of 274 hookah users between October and December 2011. METHODS: Participants were approached in hookah bars and asked to complete the survey. RESULTS: A principle components analysis revealed 3 reliable factors: social facilitation, family/cultural influence, and alternative to smoking cigarettes and drinking. These were examined across different categories of hookah use: Weekly hookah users were more likely to smoke in a context of social facilitation than the other 2 groups. Similar effects were observed for family/cultural influence. Asians were more likely to smoke in a context of family and cultural influence than non-Asians. CONCLUSIONS: This scale has potential for identifying situation-specific contexts of hookah use that may help in designing effective interventions for college students. PMID- 23663125 TI - Fraternity membership and sexual aggression: an examination of mediators of the association. AB - OBJECTIVE: This prospective study examined attitudes (ie, hostility toward women, acceptance of rape myths), peer influences (ie, peer pressure to have sex, peer approval of forced sex), and risky behaviors (ie, high-risk alcohol use, number of sexual partners) as possible mediators of the association between fraternity membership and sexual aggression. PARTICIPANTS: The sample included 424 males recruited as freshmen from a large state university in the southeastern United States. METHODS: Respondents completed survey measures in their first, second, and third years of enrollment at the university. RESULTS: Path analyses revealed that the prospective effect of fraternity membership on sexual aggression was mediated by high-risk alcohol use. CONCLUSIONS: The findings indicate that high risk alcohol use accounts for much of the association between fraternity membership and sexual aggression. PMID- 23663126 TI - Ethnicity, family socioeconomic inequalities, and prevalence of vaginal douching among college students: the implication for health. AB - OBJECTIVE: This study assessed the association between ethnicity and family socioeconomic status (SES) as it relates to the prevalence of vaginal douching among female undergraduates in a university community. PARTICIPANTS AND METHODS: This was a cross-sectional survey conducted between September 2011 and February 2012 among 1,535 female undergraduates using a semistructured behavioral questionnaire adapted by the authors from previous research related to vaginal douching practice. RESULTS: The overall prevalence of vaginal douching was 79.35% and the practice was significantly associated with the mother's age, ethnicity, low SES (educational level, occupation, and monthly income), and area of residence. The father's age and SES were statistically nonsignificant. CONCLUSION: Ethnicity and low SES of mothers were significantly associated with a higher prevalence of douching in daughters. These factors should be considered among others in any intervention to discourage vaginal douching among college women. PMID- 23663127 TI - Knowledge of acute human immunodeficiency virus infection among gay and bisexual male college students. AB - OBJECTIVE: To examine human immunodeficiency virus (HIV)-related knowledge, attitudes, and behaviors in at-risk college men who have sex with men (MSM), focusing on knowledge about acute HIV infection (AHI). PARTICIPANTS AND METHODS: A one-time anonymous survey was administered to college students attending a lesbian, gay, bisexual, transgender, and queer conference in February 2012. This article reports on a study subsample of MSM. RESULTS: A total of 100 MSM completed the survey. Participants had an average age of 20.4 years. Sixty-six percent reported condom use the last time they had sex. Only 46% had ever heard of symptoms related to AHI. Forty-two percent would likely seek medical care when showing acute symptoms in a setting consistent with AHI. CONCLUSION: Despite having multiple risk factors for HIV infection, many MSM college students are unaware of AHI. HIV prevention programs should target this population and include information about signs, symptoms, and diagnosis of AHI. PMID- 23663128 TI - Major changes in chemotherapy regimens administered to breast cancer patients during 2000-2008 in the Netherlands. AB - There is little information available on the patterns of chemotherapy regimens administered in daily practice to patients with early stage and metastatic or recurrent breast cancer. To determine the trends in type of chemotherapy regimens used in breast cancer patients, newly diagnosed breast cancer patients in the period 2000-2008 who received chemotherapy were identified from the Eindhoven Cancer Registry (ECR) and linked to the PHARMO RLS, including data on, e.g., in- and outpatient drug use. Chemotherapy regimens were classified based on the received combinations and sequences. Trends in the distribution of adjuvant chemotherapy regimens (for early-stage breast cancer) and palliative chemotherapy regimens (for metastatic or recurrent breast cancer) were determined and stratified by Her2/neu status when possible. In this study, 422 patients diagnosed with early-stage breast cancer received adjuvant chemotherapy. The use of CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) decreased from 90% in 2000 to almost none since 2005. Administration of regimens that included anthracyclines increased from 4% in 2000 to 96% in 2005, but decreased to 68% in 2008. The use of trastuzumab- and taxane-containing regimens (with or without anthracyclines) increased from 2005 onwards to 24% and 34%, respectively, in 2008. Among the 82 breast cancer patients who received palliative chemotherapy at diagnosis or after breast cancer recurrence, the use of CMF and anthracyclines (without taxanes) decreased, while the use of taxanes (with or without anthracyclines) increased (26% in 2008). Trastuzumab was used as palliative chemotherapy from 2003 onwards, with 22% of the metastatic breast cancer patients receiving trastuzumab-containing regimens in 2008, and bevacizumab was administered since 2007 with 19% of the patients receiving bevacizumab-containing regimens in 2008. In conclusion, major changes have taken place in the chemotherapeutic treatment of patients with early and recurrent breast cancer. These changes reflect the key findings from large clinical trials, as incorporated in the Dutch guidelines. PMID- 23663129 TI - Appropriateness of empiric therapy in patients with suspected Clostridium difficile infection. AB - OBJECTIVE: The objective of this study was to test the hypothesis that many patients with suspected Clostridium difficile infection (CDI) receive inappropriate empiric therapy and/or receive continued therapy despite negative test results. METHODS: We performed a 3 month prospective cohort study at the Cleveland Veteran Affairs Medical Center to assess the appropriateness of empiric CDI therapy for all patients with stool samples submitted for CDI testing. Empiric therapy for CDI was considered appropriate if patients with suspected CDI had findings suggestive of severe or complicated illness. RESULTS: Of 251 patients tested for CDI, 53 (21%) received empiric treatment, including 45 (85%) treated with metronidazole and 8 (15%) treated with vancomycin. Of the 53 empirical therapy regimens, only 20 (38%) were deemed appropriate based on criteria for severe or severe, complicated CDI and 39 (74%) had negative laboratory testing for CDI. Twenty-one of 39 (54%) patients with negative testing were continued on therapy for three or more days despite the negative results. The key limitations of the study are the fact that it was conducted in a single institution and had a small sample size. CONCLUSION: In our facility, empiric treatment for CDI was common and more than half of empirical treatment was deemed inappropriate because patients did not meet criteria for severe CDI. Because CDI therapy may be associated with adverse effects, there is a need for interventions to improve the appropriateness of empiric CDI treatment. PMID- 23663130 TI - Results of the CAPPS: COPD--assessment of practice in primary care study. AB - OBJECTIVE: Since many patients with COPD in the US are managed by primary care physicians, we evaluated adherence to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines in a primary care setting. METHODS: A cross-sectional study was conducted using a random sample of patients (n=50-150 per site) aged 40-89 years with diagnosed COPD. Patients were identified for study inclusion (N=1517) from 11 US primary care sites. Demographic and clinical information was extracted from primary care medical records via retrospective chart review. The main outcome measures were adherence to GOLD primary care guidelines, assessed via three components as follows: 1. Is there a current diagnostic spirometry test measurement available within the patient's medical record during the prior calendar year? 2. Are comorbid conditions, if present, being treated appropriately? 3. Are adequate risk reduction measures being taken? RESULTS: Mean patient age was 67.2 (SD+/-11.3) years, 54% were female, and 34% were current smokers. Overall, 19% of patients had comorbid asthma, 66% hypertension, 61% dyslipidemia, 30% cardiovascular disease, and 28% diabetes. Mean duration of COPD was approximately 4.8 years. Only 27% of patients had a spirometry test result documented within the past year. More than half (52%) of patients did not have a documented COPD stage; 20% were classified as stage I, 13% stage II, 12% stage III, 3% stage IV. About 63% of patients met at least one guideline component, while only 3% of patients met all components; 27% met diagnostic, 25% comorbid conditions management, and 32% met risk reduction criteria. LIMITATIONS: The retrospective design of our study did not allow evaluation of some possible covariates or causal assessment, and spirometry measurements were unavailable for many patients. CONCLUSIONS: Results suggest that treatment per COPD primary care guidelines was not consistently applied among participating practices (range 0.0%-8.7% for meeting all three components). Educational initiatives may increase primary care providers' knowledge of and adherence to COPD treatment guidelines and recommended patient management strategies. PMID- 23663131 TI - The catalytic domain CysPc of the DEK1 calpain is functionally conserved in land plants. AB - DEK1, the single calpain of land plants, is a member of the ancient membrane bound TML-CysPc-C2L calpain family that dates back 1.5 billion years. Here we show that the CysPc-C2L domains of land plant calpains form a separate sub-clade in the DEK1 clade of the phylogenetic tree of plants. The charophycean alga Mesostigma viride DEK1-like gene is clearly divergent from those in land plants, suggesting that a major evolutionary shift in DEK1 occurred during the transition to land plants. Based on genetic complementation of the Arabidopsis thaliana dek1 3 mutant using CysPc-C2L domains of various origins, we show that these two domains have been functionally conserved within land plants for at least 450 million years. This conclusion is based on the observation that the CysPc-C2L domains of DEK1 from the moss Physcomitrella patens complements the A. thaliana dek1-3 mutant phenotype. In contrast, neither the CysPc-C2L domains from M. viride nor chimeric animal-plant calpains complement this mutant. Co-evolution analysis identified differences in the interactions between the CysPc-C2L residues of DEK1 and classical calpains, supporting the view that the two enzymes are regulated by fundamentally different mechanisms. Using the A. thaliana dek1-3 complementation assay, we show that four conserved amino acid residues of two Ca2+-binding sites in the CysPc domain of classical calpains are conserved in land plants and functionally essential in A. thaliana DEK1. PMID- 23663132 TI - The influence of suture pattern on the incidence of incisional drainage following exploratory laparotomy. AB - REASONS FOR PERFORMING STUDY: Incisional complications following exploratory celiotomy increase morbidity, extend hospitalisation and increase cost. Retrospective studies seek to identify risk factors and measures for prevention of surgical site infection. The relatively high incidence of incisional complications following exploratory laparotomy necessitates identification of ideal surgical closure methods. OBJECTIVES: The study sought to identify the incidence of incisional drainage within our hospital population, and to identify risk factors for incisional complications while determining surgical practices that reduce the incidence of incisional drainage. STUDY DESIGN: Retrospective cohort study. METHODS: A retrospective study, with telephone follow-up, was performed on 199 horses that underwent exploratory laparotomy at the University of Georgia from 2 January 2008 to 31 December 2010, examining associations between case background, lesion type, access to the lumen of the bowel, and closure methods and incisional draining. The linea alba incisions were closed by the primary surgeon and junior house officers closed the subcutaneous tissues and skin. RESULTS: The incidence of purulent or persistent serosanguinous incisional drainage in 142 horses with complete follow-up information was 21.8%. Background, lesion type, and enterotomy or enterectomy were not associated with a significantly increased likelihood of incisional drainage. However, closure of the subcutaneous tissues and skin in a 2-layer, modified subcuticular pattern was associated with a significantly lower incidence of post operative incisional drainage. Follow-up information identified subsequent episodes of colic in 28.9% of horses. However, 80.3% of horses had returned to their previous level of work. CONCLUSIONS AND POTENTIAL RELEVANCE: Incisional drainage is common following ventral midline laparotomy. The use of a 2-layer, modified subcuticular closure was associated with a significant reduction in the incidence of incisional drainage compared with closure performed with skin sutures, but not closure performed with staples. PMID- 23663133 TI - Pathophysiology and pharmacotherapy of gastroparesis: current and future perspectives. AB - INTRODUCTION: Gastroparesis is an important clinical disorder characterised by delayed gastric emptying in the absence of mechanical outlet obstruction. Idiopathic, diabetes and postsurgical causes represent the most common aetiologies. The condition commonly manifests as upper gastrointestinal symptoms, including nausea, vomiting, postprandial fullness, early satiety, abdominal pain and bloating. AREAS COVERED: This paper provides a review of the prevalence, pathophysiology and clinical features associated with gastroparesis, with a particular focus on current pharmacological management options and novel and emerging therapies. A literature search was undertaken using the search terms: gastroparesis, diabetic gastroparesis, idiopathic gastroparesis, gastric emptying, prokinetic, metoclopramide, domperidone, erythromycin, motilin, alemcinal, KC11458, mitemcinal, ghrelin, TZP-101, TZP-102, RM-131, tegaserod, prucalopride, naronapride, velusetrag, levosulpiride, itopride, botulinum toxin, gastric electrical stimulation, Enterra. EXPERT OPINION: Strategies for the management of gastroparesis include correction of malnutrition, dehydration and electrolyte imbalance, relief of symptoms by appropriate use of prokinetic and antiemetic agents and, in patients with gastroparesis associated with diabetes or critical illness-induced hyperglycaemia, optimisation of glycaemic control. Conventional prokinetic agents form the mainstay of treatment. While novel pharmacotherapies are in development, compelling evidence for their efficacy, particularly in symptom relief, remains to be established. PMID- 23663134 TI - Case of diffuse cutaneous systemic sclerosis with anti-Ku and anti-centromere antibodies. AB - We report the case of a 58-year-old man who had an ulcer on the right middle finger that was cured by surgery 4 years before consultation with our department. A few years after the surgery, he noticed recurrence of the ulcer and sclerosis of the skin. At the initial examination, skin sclerosis was observed from the fingers to the upper arms and from the feet to the thighs. Pitting scars on the fingertips and punctured hemorrhages of the nail-fold capillaries were also present. Gastroscopy showed slight reflex esophagitis. Laboratory findings were positive for antinuclear antibody (ANA; 1:640) with a speckled and discrete speckled pattern. Anti-topoisomerase I (anti-topo I) antibody and anti-RNA polymerase III were negative, but anti-centromere antibody was positive in an enzyme-linked immunosorbent assay. Anti-Ku antibody was positive in an immunoprecipitation assay using extracts of the leukemia cell line K562. Therefore, the patient was diagnosed with diffuse cutaneous systemic sclerosis with anti-Ku and anti-centromere antibodies. Treatment with an oral antiplatelet agent, vitamin E, a proton pump inhibitor, and i.v. lipoprostaglandin E1 were started. Subsequently, there has been repeated recurrence of finger ulcers, but no muscle involvement has been detected since his first visit. This is the first reported case of systemic sclerosis with anti-Ku and anti-centromere antibodies. PMID- 23663135 TI - Controlled arrays of self-assembled peptide nanostructures in solution and at interface. AB - Controlling the formation of large and homogeneous arrays of bionanostructures through the self-assembly approach is still a great challenge. Here, we report the spontaneous formation of highly ordered arrays based on aligned peptide nanostructures in a solution as well as at an interface by self-assembly. By controlling the time and temperature of self-assembly in the solution, parallel fibrous alignments and more sophisticated two-dimensional "knitted" fibrous arrays could be formed from aligned rod-like fibers. During the formation of such arrays, the "disorder-to-order" transitions are controlled by the temperature responsible motile short hydrophobic tails of the gemini-like amphiphilic peptides (GAPs) with asymmetric molecular conformation. In addition, the resulting long-range-ordered "knitted" fibrous arrays are able to direct mineralization of calcium phosphate to form organic-inorganic composite materials. In this study, the self-assembly behavior of these peptide building blocks at an interface was also studied. Highly ordered spatial arrays with vertically or horizontally aligned nanostructures such as nanofibers, microfibers, and microtubes could be formed through interfacial assembly. The regular structures and their alignments on the interface are controlled by the alkyl chain length of building blocks and the hydrophilicity/hydrophobicity property of the interface. PMID- 23663136 TI - Feasibility of sentinel node navigation surgery after noncurative endoscopic resection for early gastric cancer. AB - BACKGROUND AND AIM: Recently, the use of additional surgery after noncurative endoscopic resection has gradually increased due to the rapid spread of endoscopic treatments in selected patients with early gastric cancer. Sentinel node navigation surgery (SNNS) has also been recognized as a minimally invasive surgery with personalized lymphadenectomy in early gastric cancer. Here, we assessed the feasibility of SNNS after noncurative endoscopic resection for early gastric cancer. METHODS: Sixteen patients with early gastric cancer, in whom additional surgery had been indicated due to noncurative endoscopic resection, were enrolled. They underwent a gastrectomy with standard lymphadenectomy. One day before surgery, (99m) technetium-tin colloid was endoscopically injected into the submucosa around the tumor. After surgery, the uptake of radioisotope in dissected lymph nodes was measured using Navigator GPS. Then, all dissected lymph nodes were investigated by hematoxylin-eosin staining and immunohistochemistry using an antihuman cytokeratin monoclonal antibody. RESULTS: Hematoxylin-eosin staining demonstrated lymph node metastasis in two (12.5%) of 16 patients and in three (0.8%) of 382 nodes. However, immunohistochemistry showed that none of the patients had lymph node micrometastasis. Sentinel nodes (SNs) were identified in all patients. The mean number of SNs was 3.1 (range, 1-6). Among two patients with lymph node metastasis, the SNs, at least, contained positive nodes. Accordingly, the false-negative and accuracy rates were 0% and 100%, respectively. CONCLUSION: Our results indicate that SNNS may have potential as a further minimally invasive surgery in early gastric cancer patients after noncurative endoscopic resection. PMID- 23663137 TI - "It's the participation that motivates him": physical activity experiences of youth with cerebral palsy and their parents. AB - Youth with cerebral palsy (CP) face significant barriers to participation in physical activity (PA). There is little information available about the nature of these barriers. Seventeen (17) youth and/or their parents participated in focus groups and individual interviews to identify factors that make it easy or hard to be physically active. Four themes emerged across functional levels: environmental and personal factors, limitations related to impairment in body structure and function, the perception that health benefits alone do not motivate youth to be physically active, and variable preferences for activity delivery. Dialogue with participants revealed that interventions to promote PA in youth should mitigate the interactions between personal and environmental factors that act as barriers to PA, and enhance the interactions that facilitate PA. Partnerships between researchers, policy makers, service providers, and families must be developed to address system barriers and build capacity in youth with CP and their communities. PMID- 23663138 TI - NK/T-cell lymphoma of the nasal cavity causing contralateral dacryoadenitis. AB - PURPOSE: To report a case of NK/T-cell lymphoma of the nasal cavity with contralateral lacrimal gland involvement. METHODS: Observational case report. RESULTS: A 39-year-old woman with a 5-month history of right fungal rhinosinusitis was referred to our hospital. A nasal mucosal biopsy performed before referral was consistent with Aspergillus sp. Despite surgical and parenteral antifungal treatment, the symptoms continued to deteriorate. On admission, the ophthalmic evaluation showed inflammation over the left lacrimal gland area. The fundus examination revealed bilateral subretinal infiltration. Computed tomography scans of the orbits and sinuses showed mucosal thickening of the right nasal mucosa and sinuses. There was heterogeneous enhancement and infiltration of the left lacrimal gland. Lacrimal gland biopsy and repeated biopsies of the nasal cavity and sinus tissue were performed. Immunohistopathology of the lacrimal glands and nasal mucosa showed extranodal nasal-type NK/T-cell lymphoma. The patient was treated with cyclophosphamide, vincristine, adriamycin, prednisolone (3 cycles), and intrathecal methotrexate. The patient developed sepsis and died 2 months after initiation of chemotherapy. CONCLUSION: Dacryoadenitis can be a clinical manifestation of NK/T-cell lymphoma. To our knowledge, this is the first reported case of nasal NK/T-cell lymphoma with contralateral dacryoadenitis. PMID- 23663139 TI - A comprehensive behavioral evaluation in the lithium-pilocarpine model in rats: effects of carisbamate administration during status epilepticus. AB - PURPOSE: Administration of carisbamate during status epilepticus (SE) prevents the occurrence of motor seizures in the lithium-pilocarpine model and leads in a subpopulation of rats to spike-and-wave discharges characteristic of absence epilepsy. Widespread neuroprotection accompanied this change in seizure expression. To assess whether these carisbamate-induced changes affected comorbidity, we used a large battery of behavioral tests in rats that had developed temporal lobe or absence-like seizures. METHODS: Lithium-pilocarpine or saline was administered to 60 adult rats. Carisbamate (90 mg/kg) or diazepam and saline was given 1 h after SE onset, and repeated 8 h later and twice daily over 6 more days. Rats were video-monitored for 2 months. Subsequently, locomotor activity, anxiety, and various types of memory were assessed. KEY FINDINGS: In rats with motor seizures, treated or not with carisbamate, all features of behavior were impaired compared to controls. Rats exhibiting absence-like seizures after carisbamate treatment behaved as controls in all paradigms tested along with widespread neuroprotection. SIGNIFICANCE: Carisbamate treatment leading to absence-like instead of temporal lobe seizures impressively prevented behavioral comorbidities reported by patients with epilepsy as the most disabling. PMID- 23663140 TI - Genotype-by-genotype specificity remains robust to average temperature variation in an aphid/endosymbiont/parasitoid system. AB - Genotype-by-genotype interactions demonstrate the existence of variation upon which selection acts in host-parasite systems at respective resistance and infection loci. These interactions can potentially be modified by environmental factors, which would entail that different genotypes are selected under different environmental conditions. In the current study, we checked for a G * G * E interaction in the context of average temperature and the genotypes of asexual lines of the endoparasitoid wasp Lysiphlebus fabarum and isolates of Hamiltonella defensa, a protective secondary endosymbiont of the wasp's host, the black bean aphid Aphis fabae. We exposed genetically identical aphids harbouring different isolates of H. defensa to three asexual lines of the parasitoid and measured parasitism success under three different temperatures (15, 22 and 29 degrees C). Although there was clear evidence for increased susceptibility to parasitoids at the highest average temperature and a strong G * G interaction between the host's symbionts and the parasitoids, no modifying effect of temperature, that is, no significant G * G * E interaction, was detected. This robustness of the observed specificity suggests that the relative fitness of different parasitoid genotypes on hosts protected by particular symbionts remains uncomplicated by spatial or temporal variation in temperature, which should facilitate biological control strategies. PMID- 23663141 TI - Glucose-oxidase label-based redox cycling for an incubation period-free electrochemical immunosensor. AB - Catalytic reactions of enzyme labels in enzyme-linked immunosorbent assays require a long incubation period to obtain high signal amplification. We present herein a simple immunosensing scheme in which the incubation period is minimized without a large increase in the detection limit. This scheme is based on electrochemical-enzymatic (EN) redox cycling using glucose oxidase (GOx) as an enzyme label, Ru(NH3)6(3+) as a redox mediator, and glucose as an enzyme substrate. Fast electron mediation of Ru(NH3)6(3+) between the electrode and the GOx label attached to the electrode allows high signal amplification. The acquisition of chronocoulometric charges at a potential in the mass transfer controlled region excludes the influence of the kinetics of Ru(NH3)6(2+) electrooxidation and also facilitates high signal-to-background ratios. The reaction between reduced GOx and Ru(NH3)6(3+) is rapid even in air-saturated Tris buffer, where the faster competitive reaction between reduced GOx and dissolved oxygen also occurs. The direct electrooxidation of glucose at the electrode and the direct electron transfer between glucose and Ru(NH3)6(3+) that undesirably increase background levels occur relatively slowly. The detection limit for the EN redox cycling-based detection of cancer antigen 125 (CA-125) in human serum is slightly higher than 0.1 U/mL for the incubation period of 0 min, and the detection limits for the incubation periods of 5 and 10 min are slightly lower than 0.1 U/mL, indicating that the detection limits are almost similar irrespective of the incubation period and that the immunosensor is highly sensitive. PMID- 23663142 TI - Solvent-free enantioselective Friedlander condensation with wet 1,1' binaphthalene-2,2'-diamine-derived prolinamides as organocatalysts. AB - Wet unsupported and supported 1,1'-binaphthalene-2,2'-diamine (BINAM) derived prolinamides are efficient organocatalysts under solvent-free conditions at room temperature to perform the synthesis of chiral tacrine analogues in good yields (up to 93%) and excellent enantioselectivies (up to 96%). The Friedlander reaction involved in this process takes place with several cyclohexanone derivatives and 2-aminoaromatic aldehydes, and it is compatible with the presence of either electron-withdrawing or electron-donating groups at the aromatic ring of the 2-aminoaryl aldehyde derivatives used as electrophiles. The reaction can be extended to cyclopentanone derivatives, affording a regioisomeric but separable mixture of products. The use of the wet silica gel supported organocatalyst, under solvent-free conditions, for this process led to the expected product (up to 87% enantiomeric excess), with its reuse being possible at least up to five times. PMID- 23663143 TI - Exploitation of pairwise class distances for ordinal classification. AB - Ordinal classification refers to classification problems in which the classes have a natural order imposed on them because of the nature of the concept studied. Some ordinal classification approaches perform a projection from the input space to one-dimensional (latent) space that is partitioned into a sequence of intervals (one for each class). Class identity of a novel input pattern is then decided based on the interval its projection falls into. This projection is trained only indirectly as part of the overall model fitting. As with any other latent model fitting, direct construction hints one may have about the desired form of the latent model can prove very useful for obtaining high-quality models. The key idea of this letter is to construct such a projection model directly, using insights about the class distribution obtained from pairwise distance calculations. The proposed approach is extensively evaluated with 8 nominal and ordinal classifiers methods, 10 real-world ordinal classification data sets, and 4 different performance measures. The new methodology obtained the best results in average ranking when considering three of the performance metrics, although significant differences are found for only some of the methods. Also, after observing other methods of internal behavior in the latent space, we conclude that the internal projections do not fully reflect the intraclass behavior of the patterns. Our method is intrinsically simple, intuitive, and easily understandable, yet highly competitive with state-of-the-art approaches to ordinal classification. PMID- 23663144 TI - Spike-based probabilistic inference in analog graphical models using interspike interval coding. AB - Temporal spike codes play a crucial role in neural information processing. In particular, there is strong experimental evidence that interspike intervals (ISIs) are used for stimulus representation in neural systems. However, very few algorithmic principles exploit the benefits of such temporal codes for probabilistic inference of stimuli or decisions. Here, we describe and rigorously prove the functional properties of a spike-based processor that uses ISI distributions to perform probabilistic inference. The abstract processor architecture serves as a building block for more concrete, neural implementations of the belief-propagation (BP) algorithm in arbitrary graphical models (e.g., Bayesian networks and factor graphs). The distributed nature of graphical models matches well with the architectural and functional constraints imposed by biology. In our model, ISI distributions represent the BP messages exchanged between factor nodes, leading to the interpretation of a single spike as a random sample that follows such a distribution. We verify the abstract processor model by numerical simulation in full graphs, and demonstrate that it can be applied even in the presence of analog variables. As a particular example, we also show results of a concrete, neural implementation of the processor, although in principle our approach is more flexible and allows different neurobiological interpretations. Furthermore, electrophysiological data from area LIP during behavioral experiments are assessed in light of ISI coding, leading to concrete testable, quantitative predictions and a more accurate description of these data compared to hitherto existing models. PMID- 23663145 TI - Information transfer through stochastic transmission of a linear combination of rates. AB - In this work, the Shannon information transfer rate due to the transmission of a linear combination of the firing rates of a number of afferent neurons is examined. The transmission of this linear combination (transfer statistic) takes place through a stochastic firing process, while a rate code is assumed. Constraints are imposed on the transmission process by the requirement that the coefficient of variation for the transfer statistic is small and by the relative variance of the individual terms in the calculation of the statistic. In the regime of no noise or signal correlations among the input neurons, simulations suggest that information transfer for fixed overall input is favored when there are few high-firing neurons, as opposed to more lower-firing neurons. Signal correlations among low-firing neurons can result in aggregates of high firing rates, improving in this way information transfer and calculational robustness. Under reasonable rate code assumptions, information transfer rates obtained are of the order 3 to 10 bit/sec. PMID- 23663146 TI - The evolution of representation in simple cognitive networks. AB - Representations are internal models of the environment that can provide guidance to a behaving agent, even in the absence of sensory information. It is not clear how representations are developed and whether they are necessary or even essential for intelligent behavior. We argue here that the ability to represent relevant features of the environment is the expected consequence of an adaptive process, give a formal definition of representation based on information theory, and quantify it with a measure R. To measure how R changes over time, we evolve two types of networks--an artificial neural network and a network of hidden Markov gates--to solve a categorization task using a genetic algorithm. We find that the capacity to represent increases during evolutionary adaptation and that agents form representations of their environment during their lifetime. This ability allows the agents to act on sensorial inputs in the context of their acquired representations and enables complex and context-dependent behavior. We examine which concepts (features of the environment) our networks are representing, how the representations are logically encoded in the networks, and how they form as an agent behaves to solve a task. We conclude that R should be able to quantify the representations within any cognitive system and should be predictive of an agent's long-term adaptive success. PMID- 23663147 TI - EEG data space adaptation to reduce intersession nonstationarity in brain computer interface. AB - A major challenge in EEG-based brain-computer interfaces (BCIs) is the intersession nonstationarity in the EEG data that often leads to deteriorated BCI performances. To address this issue, this letter proposes a novel data space adaptation technique, EEG data space adaptation (EEG-DSA), to linearly transform the EEG data from the target space (evaluation session), such that the distribution difference to the source space (training session) is minimized. Using the Kullback-Leibler (KL) divergence criterion, we propose two versions of the EEG-DSA algorithm: the supervised version, when labeled data are available in the evaluation session, and the unsupervised version, when labeled data are not available. The performance of the proposed EEG-DSA algorithm is evaluated on the publicly available BCI Competition IV data set IIa and a data set recorded from 16 subjects performing motor imagery tasks on different days. The results show that the proposed EEG-DSA algorithm in both the supervised and unsupervised versions significantly outperforms the results without adaptation in terms of classification accuracy. The results also show that for subjects with poor BCI performances when no adaptation is applied, the proposed EEG-DSA algorithm in both the supervised and unsupervised versions significantly outperforms the unsupervised bias adaptation algorithm (PMean). PMID- 23663148 TI - Dynamics of multiple-choice decision making. AB - Neuroscientists have carried out comprehensive experiments to reveal the neural mechanisms underlying the perceptual decision making that pervades daily life. These experiments have illuminated salient features of decision making, including probabilistic choice behavior, the ramping activity of decision-related neurons, and the dependence of decision time and accuracy on the difficulty of the task. Spiking network models have reproduced these features, and a two-dimensional mean field model has demonstrated that the saddle node structure underlies two alternative decision making. Here, we reduced a spiking network model to an analytically tractable, partial integro-differential system and characterized not only multiple-choice decision behaviors but also the time course of neural activities underlying decisions, providing a mechanistic explanation for the observations noted in the experiments. First, we observed that a two-bump unstable steady state of the system is responsible for two-choice decision making, similar to the saddle node structure in the two-dimensional mean field model. However, for four-choice decision making, three types of unstable steady states collectively predominate the time course of the evolution from the initial state to the stable states. Second, the time constant of the unstable steady state can explain the fact that four-choice decision making requires a longer time than two-choice decision making. However, the quicker decision, given a stronger motion strength, cannot be explained by the time constant of the unstable steady state. Rather, the decision time can be attributed to the projection coefficient of the difference between the initial state and the unstable steady state on the eigenvector corresponding to the largest positive eigenvalue. PMID- 23663150 TI - A bio-inspired, computational model suggests velocity gradients of optic flow locally encode ordinal depth at surface borders and globally they encode self motion. AB - Visual navigation requires the estimation of self-motion as well as the segmentation of objects from the background. We suggest a definition of local velocity gradients to compute types of self-motion, segment objects, and compute local properties of optical flow fields, such as divergence, curl, and shear. Such velocity gradients are computed as velocity differences measured locally tangent and normal to the direction of flow. Then these differences are rotated according to the local direction of flow to achieve independence of that direction. We propose a bio-inspired model for the computation of these velocity gradients for video sequences. Simulation results show that local gradients encode ordinal surface depth, assuming self-motion in a rigid scene or object motions in a nonrigid scene. For translational self-motion velocity, gradients can be used to distinguish between static and moving objects. The information about ordinal surface depth and self-motion can help steering control for visual navigation. PMID- 23663151 TI - Excitation-emission spectra and fluorescence quantum yields for fresh and aged biogenic secondary organic aerosols. AB - Certain biogenic secondary organic aerosols (SOA) become absorbent and fluorescent when exposed to reduced nitrogen compounds such as ammonia, amines, and their salts. Fluorescent SOA may potentially be mistaken for biological particles by detection methods relying on fluorescence. This work quantifies the spectral distribution and effective quantum yields of fluorescence of water soluble SOA generated from two monoterpenes, limonene and alpha-pinene, and two different oxidants, ozone (O3) and hydroxyl radical (OH). The SOA was generated in a smog chamber, collected on substrates, and aged by exposure to ~100 ppb ammonia in air saturated with water vapor. Absorption and excitation-emission matrix (EEM) spectra of aqueous extracts of aged and control SOA samples were measured, and the effective absorption coefficients and fluorescence quantum yields (~0.005 for 349 nm excitation) were determined from the data. The strongest fluorescence for the limonene-derived SOA was observed for lambdaexcitation = 420 +/- 50 nm and lambdaemission = 475 +/- 38 nm. The window of the strongest fluorescence shifted to lambdaexcitation = 320 +/- 25 nm and lambdaemission = 425 +/- 38 nm for the alpha-pinene-derived SOA. Both regions overlap with the EEM spectra of some of the fluorophores found in primary biological aerosols. Despite the low quantum yield, the aged SOA particles may have sufficient fluorescence intensities to interfere with the fluorescence detection of common bioaerosols. PMID- 23663152 TI - A randomised trial of a simplified method for complete denture fabrication: patient perception and quality. AB - Complete denture fabrication involves a series of complex technical procedures. Nevertheless, simplified methods may be as effective as conventional ones albeit the lesser use of time and resources, without disadvantage for the patient. This study compared a simplified method for complete denture fabrication to a conventional protocol in terms of oral health-related quality of life (OHRQoL), patient satisfaction and denture quality. Forty-two edentulous patients requesting treatment with complete dentures were randomly allocated into two study groups. Group S received dentures fabricated by a simplified method and Group C received conventionally fabricated dentures. Before interventions and after three and 6 months following insertion, OHRQoL and patient satisfaction were analysed by specific instruments. A prosthodontist assessed denture quality 3 months after delivery. Groups presented no difference for OHRQoL, denture quality and general satisfaction. Differences regarding patient satisfaction with some aspects of the dentures were found after 3 months (S > C), but were insignificant at 6 months. It was concluded that the simplified method is able to produce dentures of a quality comparable to those produced by the conventional method, influencing OHRQoL and patient satisfaction similarly. PMID- 23663149 TI - Analysis of the stabilized supralinear network. AB - We study a rate-model neural network composed of excitatory and inhibitory neurons in which neuronal input-output functions are power laws with a power greater than 1, as observed in primary visual cortex. This supralinear input output function leads to supralinear summation of network responses to multiple inputs for weak inputs. We show that for stronger inputs, which would drive the excitatory subnetwork to instability, the network will dynamically stabilize provided feedback inhibition is sufficiently strong. For a wide range of network and stimulus parameters, this dynamic stabilization yields a transition from supralinear to sublinear summation of network responses to multiple inputs. We compare this to the dynamic stabilization in the balanced network, which yields only linear behavior. We more exhaustively analyze the two-dimensional case of one excitatory and one inhibitory population. We show that in this case, dynamic stabilization will occur whenever the determinant of the weight matrix is positive and the inhibitory time constant is sufficiently small, and analyze the conditions for supersaturation, or decrease of firing rates with increasing stimulus contrast (which represents increasing input firing rates). In work to be presented elsewhere, we have found that this transition from supralinear to sublinear summation can explain a wide variety of nonlinearities in cerebral cortical processing. PMID- 23663153 TI - The hemorrhagic risk: how to evaluate it. AB - This issue addresses the evaluation of hemorrhagic risk during antithrombotic treatment in atrial fibrillation patients. It illustrates the relevance of bleeding complications in the management of anticoagulation therapy and demonstrates the size of the problem among patients taking old and novel oral anticoagulant drugs. A survey of the main factors affecting the bleeding risk with pertinent supporting evidence is performed. Finally the paper discusses how to estimate the individual bleeding risk focusing on the HAS-BLED score, whose use is recommended by international guidelines. PMID- 23663154 TI - Evaluation of process parameters governing the aroma generation in three hazelnut cultivars (Corylus avellana L.) by correlating quantitative key odorant profiling with sensory evaluation. AB - The majority of the world hazelnut crop is roasted, thus developing a unique aroma that depends on the cultivar used and on the roasting conditions applied. Although several studies have investigated the volatile fraction of different cultivars and have correlated the data with overall sensory profiles, studies establishing a correlation between key odorants among the bulk of odorless volatiles and the respective aroma profiles are not yet available. On the basis of recently published stable isotope dilution assays (SIDAs) using comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (GC*GC-TOF MS), differences in concentrations of key odorants in different hazelnut cultivars roasted under defined conditions were monitored and compared with sensory data obtained by projective mapping, aroma profile analysis, and triangle tests. The results showed that the aroma-active compounds 2-acetyl-1-pyrroline, 2 propionyl-1-pyrroline, 5-methyl-(E)-2-hepten-4-one, 2,3-diethyl-5-methylpyrazine, 3,5-dimethyl-2-ethylpyrazine, and 2-furfurylthiol are appropriate marker odorants to differentiate the various nut aromas. In particular, the appreciated roasty, nutty aroma of optimally roasted hazelnuts was developed if both 5-methyl-(E)-2 hepten-4-one and 3-methyl-4-heptanone were >450 MUg/kg, whereas the sum of the two 2-acyl-1-pyrrolines and two pyrazines should not exceed 400 MUg/kg to avoid an over-roasted smell. Such a desired aroma can be obtained for each cultivar, but obviously specific roasting times, temperatures, and roasting techniques had to be applied. PMID- 23663155 TI - Evolution of photoprotection mechanisms upon land colonization: evidence of PSBS dependent NPQ in late Streptophyte algae. AB - Light is the energy source for photosynthetic organisms but, if absorbed in excess, it can drive to the formation of reactive oxygen species and photoinhibition. One major mechanism to avoid oxidative damage in plants and algae is the dissipation of excess excitation energy as heat, called non photochemical quenching (NPQ). Eukaryotic algae and plants, however, rely on two different proteins for NPQ activation, the former mainly depending on LHCSR (Lhc like protein Stress Related; previously called Li818, Light Induced protein 818), whereas in the latter the major role is played by a distinct protein, PSBS (photosystem II subunit S). In the moss Physcomitrella patens, which diverged from vascular plants early after land colonization, both these proteins were found to be present and active in inducing NPQ, suggesting that during plants evolution both mechanisms co-existed. In order to investigate in more detail NPQ adaptation toward land colonization, we analyzed Streptophyte algae, the latest organisms to diverge from the land plants ancestors. Among them we found evidence of a PSBS-dependent NPQ in species belonging to Charales, Coleochaetales and Zygnematales, the latest groups to diverge from land plants ancestors. On the contrary earlier diverging algae, as Mesostigmatales and Klebsormidiales, likely rely on LHCSR for their NPQ activation. Presented evidence thus suggests that PSBS-dependent NPQ, although possibly present in some Chlorophyta, was stably acquired in the Cambrian period about 500 million years ago, before late Streptophyte algae diverged from plants ancestors. PMID- 23663156 TI - Sulphonylureas and risk of cardiovascular disease: systematic review and meta analysis. AB - AIMS: Sulphonylurea use has been linked with increased cardiovascular disease risk; however, previous studies have been inconsistent. Type 2 diabetes independently increases risk for cardiovascular disease, so understanding the link between longer-term use of anti-diabetic medications and cardiovascular disease has important clinical implications. METHODS: Literature search in MEDLINE and CENTRAL was conducted throughout December 2011 for clinical and observational studies that reported the association between sulphonylurea and cardiovascular disease events. Ratios (relative risk, odds ratios or hazard ratios) adjusted for potential confounders (concomitant medications, baseline cardiovascular risk, diabetes severity) were pooled using a random-effects model to yield relative risks and associated 95% confidence intervals. RESULTS: This meta-analysis included 33 studies (n = 1,325,446 patients), followed for a range of 0.46-10.4 years. In all studies, compared with other oral diabetes drugs, sulphonylurea use was associated with a significantly increased risk of cardiovascular death (relative risk 1.27, 95% confidence interval 1.18-1.34, n = 27 comparisons) and composite cardiovascular event (including myocardial infarction, stroke, cardiovascular-related hospitalization or cardiovascular death) (relative risk 1.10, 95% confidence interval 1.04-1.16, n = 43 comparisons). In studies comparing sulphonylurea vs. metformin, these relative risks were 1.26 (95% confidence interval 1.17-1.35, n = 17 comparisons) and 1.18 (95%confidence interval 1.13-1.24, n = 16 comparisons), respectively. CONCLUSIONS: Results suggest that sulphonylurea use may elevate the risk of cardiovascular disease among patients with diabetes. This meta-analysis expands the pool of studies evaluating cardiovascular mortality compared with prior observations while using adjusted estimates, and assessing an additional outcome of a composite cardiovascular event. This finding warrants consideration in clinical practice when other treatment options may be available. PMID- 23663157 TI - What is the impact of first pregnancy outcome for future pregnancy planning in Japan? PMID- 23663158 TI - Redox activity and two-step valence tautomerism in a family of dinuclear cobalt complexes with a spiroconjugated bis(dioxolene) ligand. AB - A family of dinuclear cobalt complexes with bridging bis(dioxolene) ligands derived from 3,3,3',3'-tetramethyl-1,1'-spirobis(indane-5,5',6,6'-tetrol) (spiroH4) and ancillary ligands based on tris(2-pyridylmethyl)amine (tpa) has been synthesized and characterized. The bis(dioxolene) bridging ligand is redox active and accessible in the (spiro(cat-cat))(4-), (spiro(SQ-cat))(3-), and (spiro(SQ-SQ))(2-) forms, (cat = catecholate, SQ = semiquinonate). Variation of the ancillary ligand (Mentpa; n = 0-3) by successive methylation of the 6 position of the pyridine rings influences the redox state of the complex, governing the distribution of electrons between the cobalt centers and the bridging ligands. Pure samples of salts of the complexes [Co2(spiro)(tpa)2](2+) (1), [Co2(spiro)(Metpa)2](2+) (2), [Co2(spiro)(Me2tpa)2](2+) (3), [Co2(spiro)(Me3tpa)2](2+) (4), [Co2(spiro)(tpa)2](3+) (5), and [Co2(spiro)(tpa)2](4+) (6) have been isolated, and 1, 4, and 6 have been characterized by single crystal X-ray diffraction. Studies in the solid and solution states using multiple techniques reveal temperature invariant redox states for 1, 2, and 4-6 and provide clear evidence for four different charge distributions: 1 and 2 are Co(III)-(spiro(cat-cat))-Co(III), 4 is Co(II) (spiro(SQ-SQ))-Co(II), 5 is Co(III)-(spiro(SQ-cat))-Co(III), and 6 is Co(III) (spiro(SQ-SQ))-Co(III). Of the six complexes, only 3 shows evidence of temperature dependence of the charge distribution, displaying a rare thermally induced two-step valence tautomeric transition from the Co(III)-(spiro(cat-cat)) Co(III) form to Co(II)-(spiro(SQ-cat))-Co(III) and then to Co(II)-(spiro(SQ-SQ)) Co(II) in both solid and solution states. This is the first time a two-step valence tautomeric (VT) transition has been observed in solution. Partial photoinduction of the VT transition is also possible in the solid. Magnetic and spectroscopic studies of 5 and 6 reveal that spiroconjugation of the bis(dioxolene) ligand allows electronic interaction across the spiro bridge, suggesting that thermally activated vibronic coupling between the two cobalt dioxolene moieties plays a key role in the two-step transition evident for 3. PMID- 23663159 TI - Regulation of hypoxia-inducible factor-1alpha and related genes in equine digital lamellae and in cultured keratinocytes. AB - REASONS FOR PERFORMING STUDY: Hypoxia-inducible factor-1alpha (HIF-1A) is an important protein in the regulation/induction of many genes in the cellular and tissue response to hypoxia and a central mediator in inflammatory signalling. As both hypoxia and inflammatory events are purported to occur in the lamellar epidermis in sepsis-related laminitis in the equid, HIF-1A may play a central role in this disease process. OBJECTIVESS: To assess the regulation of HIF-1A and HIF-1A-related genes in the equine keratinocyte in vitro and in the lamellar tissue of horses with sepsis-related laminitis. STUDY DESIGN: In vivo and in vitro experiments. METHODS: Real-time quantitative PCR (RT-qPCR) and immunoblotting were performed to assess the mRNA and protein concentrations of HIF-1A and the mRNA concentrations of HIF-1A-related genes in cultured equine keratinocytes and in lamellar samples from black walnut extract (BWE)- and carbohydrate overload (CHO)-induced laminitis. Hypoxia-inducible factor-1alpha was further localised via indirect immunofluorescence in frozen lamellar tissue sections. RESULTS: Hypoxia-inducible factor-1alpha appears to be regulated primarily at the post transcriptional level in the cultured equine keratinocyte, resulting in increased HIF-1A in response to hypoxia but not to lipopolysaccharide exposure. Hypoxia-inducible factor-1alpha is present at high concentrations in the normal equine lamina, and is increased in Obel grade 1 (OG1) stage laminitis in the CHO model of laminitis. Equine lamellar mRNA concentrations of cyclo-oxygenase-2 and inducible nitric oxide synthase, but not glucose transporter 1, are increased in the BWE and CHO models of laminitis. CONCLUSIONS AND POTENTIAL RELEVANCE: These data indicate that the normal equine lamellae are profoundly hypoxic in comparison with other tissues. The increased mRNA concentrations of cyclo-oxygenase-2 and inducible nitric oxide synthase 2 in equine keratinocytes exposed to hypoxia and lipopolysaccharide, and in lamellar tissue from BWE and CHO models of sepsis-related laminitis, suggest that the marked lamellar inflammatory gene expression in sepsis-related laminitis may be due to an interaction of constitutively high lamellar keratinocyte HIF-1A signalling with inflammatory signalling, possibly induced by circulating inflammatory mediators. PMID- 23663160 TI - Substituted oxadiazoles: a patent review (2010 - 2012). AB - INTRODUCTION: The oxadiazoles represent a class of five-membered heterocyclic compounds which are of considerable interest in different areas of medicinal chemistry and drug discovery. Oxadiazoles can exist in different regioisomeric forms and employ in various agents with a broad range of biological activities. This review covers the work reported on various biological activities of oxadiazole derivatives from 2010 to 2012. AREAS COVERED: Oxadiazole derivatives attract great attention due to their different kinds of pharmaceutical activities including antiviral, antimicrobial, anticancer, anticonvulsant, antidiabetic and anti-inflammatory activity. This paper provides a general review of oxadiazole derivatives published in international journals and patented between 2010 and 2012. EXPERT OPINION: Oxadiazoles have been used frequently in drug-like molecules as bioisosteres for ester and amide functionalities and displayed numerous prominent pharmacological effects. The broad pharmacological profile of oxadiazole derivatives has attracted the attention of many researchers to explore this scaffold to its multiple potential against several activities. Therefore, oxadiazole motif is likely to be present in other therapeutic molecules in the future. PMID- 23663161 TI - Umbilical artery Doppler assessment: a clear disparity in ultrasound practice in a national survey. PMID- 23663162 TI - Colour-variable birds have broader ranges, wider niches and are less likely to be threatened. AB - Coloration fulfils a variety of adaptive functions in animals. Colour variability, both between and within species, can be caused by different colours being favoured for different functions and in different environments. Thus, species with highly variable coloration may have greater potential to persist in new and changing environments. As a consequence, such colour-variable species may be more able to adapt, colonize new areas and niches, occupy larger ranges, speciate more readily and in general be less vulnerable to environmental change and extinction. These predictions have been supported by comparative analyses on amphibians and reptiles. However, as coloration in ectotherms plays a key role in thermoregulation, it is unclear whether these results can be generalized to endotherms, such as birds and mammals. Here, we test the hypothesis that more colour-variable endotherms occupy larger ranges/niches and are less vulnerable to the threat of extinction by focussing on colour variation in Australian parrots and passerine birds. As predicted, colour variability was correlated with range size (parrots and passerines) and niche breadth (dietary heterogeneity, parrots only). These relationships support the predicted link between colour variability and adaptability, whereby range size and niche breadth may be a cause of colour variability or vice versa. Irrespective, and as predicted, colour variability was lower in threatened species, even after statistically controlling for other confounding variables. Hence, our study supports the hypothesis that colour variable species in general are more resilient to environmental change. PMID- 23663163 TI - Successful treatment of the pain associated with melorheostosis with spinal cord stimulation: a case study. PMID- 23663164 TI - Pathogenesis of Crimean-Congo hemorrhagic fever. AB - Although Crimean-Congo hemorrhagic fever (CCHF) is a widespread tick-borne disease, little is known about its pathogenesis. The interaction of the virus with host cells is most likely responsible for the pathogenesis of CCHF. The main contributors are endothelial cells (ECs) and immune cells. There are 2 theories underlying the CCHF pathogenesis: One is that the virus interacts with the ECs directly and the other that it interacts indirectly via immune cells with subsequent release of soluble mediators. ECs are activated upon infection by the upregulation of soluble molecules and proinflammatory cytokines. Probably, in severe cases, deregulation and excessive release of the cytokines accompanied by endothelial activation have toxic effects, leading to increased vascular permeability, vasodilatation, and subsequently hypotension, multiple organ failure, shock, and death. Studies indicate that CCHF virus (CCHFV) also can impair the innate immune system and cause a delay in adaptive immune response, which is critical for the clearance of CCHFV. The virus has many different ways to block the immune response, leading to uncontrolled viral replication followed by systemic spread of the virus throughout the body. Partial activation of dendritic cells and macrophages, delayed induction of interferons, weak antibody response, apoptosis of lymphocytes, and hemophagocytosis are some of these tactics. However, there are many points waiting for clarification about the pathogenesis of CCHF. Although the high risk of contagiousness limits research, we need more studies to understand the CCHF pathogenesis better. Here we review the main characteristics of the pathogenesis of CCHF. PMID- 23663166 TI - Medical management of periorbital necrotising fasciitis. AB - Necrotising fasciitis (NF) is a rapidly progressing necrotizing infection of the subcutaneous tissue and superficial fascia with secondary necrosis of overlying skin. Periorbital NF, albeit uncommon, has a reported mortality of 8-15% and rate of vision loss of 13.8%. Early surgical debridement has been advocated as a critical factor in the management of these patients however, emerging reports describe successful outcomes with intravenous antibiotic therapy alone. We describe a patient who was treated conservatively with good results. PMID- 23663165 TI - Leptospirosis and human immunodeficiency virus co-infection among febrile inpatients in northern Tanzania. AB - BACKGROUND: Leptospirosis and human immunodeficiency virus (HIV) infection are prevalent in many areas, including northern Tanzania, yet little is known about their interaction. METHODS: We enrolled febrile inpatients at two hospitals in Moshi, Tanzania, over 1 year and performed HIV antibody testing and the microscopic agglutination test (MAT) for leptospirosis. Confirmed leptospirosis was defined as >= four-fold rise in MAT titer between acute and convalescent serum samples, and probable leptospirosis was defined as any reciprocal MAT titer >= 800. RESULTS: Confirmed or probable leptospirosis was found in 70 (8.4%) of 831 participants with at least one serum sample tested. At total of 823 (99.0%) of 831 participants had HIV testing performed, and 203 (24.7%) were HIV infected. Among HIV-infected participants, 9 (4.4%) of 203 had confirmed or probable leptospirosis, whereas among HIV-uninfected participants 61 (9.8%) of 620 had leptospirosis. Leptospirosis was less prevalent among HIV-infected as compared to HIV-uninfected participants [odds ratio (OR) 0.43, p=0.019]. Among those with leptospirosis, HIV-infected patients more commonly presented with features of severe sepsis syndrome than HIV-uninfected patients, but differences were not statistically significant. Among HIV-infected patients, severe immunosuppression was not significantly different between those with and without leptospirosis (p=0.476). Among HIV-infected adolescents and adults, median CD4 percent and median CD4 count were higher among those with leptospirosis as compared to those with other etiologies of febrile illness, but differences in CD4 count did not reach statistical significance (p=0.015 and p=0.089, respectively). CONCLUSIONS: Among febrile inpatients in northern Tanzania, leptospirosis was not more prevalent among HIV-infected patients. Although some indicators of leptospirosis severity were more common among HIV-infected patients, a statistically significant difference was not demonstrated. Among HIV-infected patients, those with leptospirosis were not more immunosuppressed relative to those with other etiologies of febrile illness. PMID- 23663167 TI - Functional dissection and evidence for intercellular transfer of the heterocyst differentiation PatS morphogen. AB - The formation of a diazotrophic cyanobacterial filament represents a simple example of biological development. In Anabaena, a non-random pattern of one nitrogen-fixing heterocyst separated by about 10 photosynthetic vegetative cells results from lateral inhibition elicited by the cells differentiating into heterocysts. Key to this process is the patS gene, which has been shown to produce an inhibitor of heterocyst differentiation that involves the C-terminal RGSGR pentapeptide. Complementation of a DeltapatS Anabaena mutant with different versions of PatS, including point mutations or tag fusions, showed that patS is translated into a 17-amino acid polypeptide. Alterations in the N-terminal part of PatS produced inhibition of heterocyst differentiation, thus this part of the peptide appears necessary for proper processing and self-immunity in the producing cells. Alterations in the C-terminal part of PatS led to over differentiation, thus supporting its role in inhibition of heterocyst differentiation. A polypeptide, produced in proheterocysts, consisting of a methionine followed by the eight, but not the five, terminal amino acids of PatS recreated the full activity of the native peptide. Immunofluorescence detection showed that an RGSGR-containing peptide accumulated in the cells adjacent to the producing proheterocysts, illustrating intercellular transfer of a morphogen in the cyanobacterial filaments. PMID- 23663168 TI - Effects of wobbling angle on the stability measures of orthodontic mini-implants during insertion and removal procedures. AB - OBJECTIVE: To investigate the effects of wobbling angle on the stability measures of orthodontic mini-implants (OMIs) during insertion and removal procedures in artificial bone blocks. MATERIALS AND METHODS: A total of 36 OMIs (self-drilling type, cylindrical shape, 7 mm in length, 1.45 mm in diameter) were allocated into three groups according to the amount of wobbling angle (W-0 degrees , W-2 degrees , and W-4 degrees groups; N = 12 per group). The OMIs were installed and subsequently removed from artificial bone blocks (Sawbone) using a driving torque tester with a uniform speed of 28 rpm. Insertion peak time (IPT), maximum insertion torque (MIT), total insertion energy (TIE), near-peak insertion energy (NPIE), maximum removal torque (MRT), and near-peak removal energy (NPRE) were measured. RESULTS: The W-4 degrees group showed the longest IPT and highest TIE and NPIE, followed by the W-2 degrees and W-0 degrees groups (W-0 degrees < W 2 degrees < W-4 degrees , all P < .001). The W-2 degrees and W-4 degrees groups showed significant increase in MIT compared with the W-0 degrees group (W 0 degrees < [W-4 degrees ,W-2 degrees ]; P < .001). Although there was no significant difference in NPRE among the three groups, the W-4 degrees group showed a decrease in MRT compared with the W-0 degrees and W-2 degrees groups (W-4 degrees < {W-2 degrees ,W-0 degrees ]; P < .05). Although the W-4 degrees group showed a 14.5% (2.9 Ncm) increase in MIT compared with the W-0 degrees group, there was only a 6% (1.3 Ncm) decrease in MRT from the W-0 degrees group to the W-4 degrees group. CONCLUSION: Slight wobbling during the OMI insertion procedure may be acceptable in terms of the stability measures of OMIs during insertion and removal procedures. PMID- 23663169 TI - Segregation analysis of mandibular prognathism in Korean orthognathic surgery patients and their families. AB - OBJECTIVE: To investigate the existence of genetic influences on the incidence of mandibular prognathism (MP) in Korean Class III patients. MATERIALS AND METHODS: The probands consisted of 100 Class III patients with MP (51 men and 49 women; mean age, 22.1 +/- 5.2 years; SNA, 81.2 degrees +/- 3.2 degrees ; SNB, 84.1 degrees +/- 3.9 degrees ) who underwent orthognathic surgery. Using three generation pedigree charts, questionnaires, and clinical examinations, general information and information regarding MP for a total of 3777 relatives of the probands (1911 men and 1866 women) was ascertained. Familial correlations of MP between possible pairs in the pedigree were estimated. Heritability (h(2)) of MP under various models was estimated. Segregation analysis was conducted under the assumption of the nonpolygenic multivariate logistic model and finite polygenic mixed model. One-, two-, and three-susceptibility-type models were evaluated. RESULTS: Among 3777 relatives, 199 (97 men and 102 women) were affected with MP (5.3%). Correlation coefficients of MP incidence in full siblings and in parent offspring were .2003 and .2036, respectively (all P < .001). The h(2) of MP was estimated as 21.5% after adjusting for sex and founder effects. Two- and three susceptibility-type models showed that the general model fit better than the other models. MP incidence did not have a major gene transmission model and was influenced by numerous minor effect genes and their additive effects. CONCLUSION: These results suggest that the inherited susceptibility to MP in Korean Class III patients might be due to the summation of minor effects from a variety of different genes and/or influence of environmental factors, rather than Mendelian transmission of major genes. PMID- 23663170 TI - Sensomics analysis of key hazelnut odorants (Corylus avellana L. 'Tonda Gentile') using comprehensive two-dimensional gas chromatography in combination with time of-flight mass spectrometry (GC*GC-TOF-MS). AB - Comprehensive two-dimensional gas chromatography-mass spectrometry (GC*GC-MS) has been used a few times to identify and quantitate single aroma-active compounds, but the capability of this technique to monitor a complete set of key odorants evoking the aroma of a given food in one run has not been exploited so far. A fast, multiodorant analysis using GC*GC-TOF-MS in combination with stable isotope dilution assays (SIDA) was developed to quantitate the entire set of aroma compounds, the sensometabolome, of raw and roasted hazelnuts ( Corylus avellana L. 'Tonda Gentile') previously established by GC-olfactometry. The capability of the method to evaluate the aroma contribution of each sensometabolite was evaluated by introducing a new term, the limit of odor activity value (LOAV), indicating whether a given aroma compound can be determined down to an odor activity value (OAV) of 1 (odor activity value = ratio of concentration to odor threshold). The advantage of the new method was proven by comparing the performance parameters with a traditional one-dimensional approach using GC-ion trap mass-spectrometry (GC-IT-MS). The results showed that the detector linearity and sensitivity of GC*GC-TOF-MS was on average higher by a factor of 10 compared to GC-IT-MS, thus enabling the quantitation of the aroma relevant amounts of 22 key odorants of hazelnuts in one run of the 30 aroma-active compounds. Seven novel isotopically labeled internal standards were synthesized to meet the analytical requirements defined by electron impact ionization in TOF-MS, that is, to keep the label. On the basis of the quantitative results obtained, it was possible to closely mimic the aroma of raw and roasted 'Tonda Gentile' hazelnuts by preparing an aroma recombinate containing the key odorants at their natural concentrations occurring in the nuts. PMID- 23663171 TI - Rhodium(III)-catalyzed azacycle-directed intermolecular insertion of arene C-H bonds into alpha-diazocarbonyl compounds. AB - Cp*Rh(III)-catalyzed intermolecular C-C couplings between activated alpha diazocarbonyl compounds and arenes bearing a range of azacyclic directing groups have been achieved. This catalytic alkylation reaction operates under mild conditions with good functional group tolerance. PMID- 23663172 TI - Polypeptoid brushes by surface-initiated polymerization of N-substituted glycine N-carboxyanhydrides. AB - Polypeptoid brushes were synthesized by surface-initiated polymerization of N substituted glycine N-carboxyanhydrides on self-assembled amine monolayers. Using the presented grafting-from approach, polypeptoid brush thicknesses of approximately 40 nm could be obtained as compared to previously reported brush thicknesses of 4 nm. Moreover, hydrophilic, hydrophobic and amphiphilic polymer brushes were realized which are expected to have valuable applications as nonfouling surfaces and as model or references systems for surface grafted polypeptides. PMID- 23663173 TI - Simultaneous all-optical determination of molecular concentration and extinction coefficient. AB - Absolute molecular number concentration and extinction coefficient are simultaneously determined from linear and nonlinear spectroscopic measurements. This method is based on measurements of absolute femtosecond pump-probe signals. Accounting for pulse propagation, we present a closed form expression for molecular number concentration in terms of absorbance, fluorescence, absolute pump-probe signal, and laser pulse parameters (pulse energy, spectrum, and spatial intensity profile); all quantities are measured optically. As in gravimetric and coulometric determinations of concentration, no standard samples are needed for calibration. The extinction coefficient can then be determined from the absorbance spectrum and the concentration. For fluorescein in basic methanol, the optically determined molar concentrations and extinction coefficients match gravimetric determinations to within 10% for concentrations from 0.032 to 0.540 mM, corresponding to absorbance from 0.06 to 1. In principle, this photonumeric method is extensible to transient chemical species for which other methods are not available. PMID- 23663174 TI - Transvenous retrieval of foreign objects lost during cardiac device implantation or revision: a 10-year experience. AB - BACKGROUND: Many techniques for the endovascular retrieval of lost or misplaced foreign objects have been developed, and the removal of almost every foreign object has become possible. In this paper, we report our experience in retrieving foreign objects lost during cardiac device implantations or previous extraction procedures. METHODS: This study was a retrospective analysis of the case records of all patients referred to our institution for transvenous retrieval of intravascular foreign objects. RESULTS: Over 10 years, 45 consecutive patients underwent procedures for the retrieval of intravascular foreign objects. These objects were: 25 distal portions of introducer sheaths, 18 pacing lead fragments, one guidewire, and one anchoring sleeve. The majority of fragments were located in the right ventricle and subclavian and caval veins. Some had migrated to the pulmonary artery or more distally. The median dwell time of the fragments was 3 months. Retrieval was most frequently achieved through the femoral veins, and was successful in 42 (93%) procedures. No procedure-related complications occurred in this series. CONCLUSIONS: In the present single-center experience, the endovascular approach to retrieving intravascular objects lost during cardiac device implantation or previous extraction procedures seemed effective with currently available tools and was associated with no complications. PMID- 23663175 TI - Spatial transposition gradients in visual working memory. AB - In list memory, access to individual items reflects limits of temporal distinctiveness. This is reflected in the finding that neighbouring list items tend to be confused most often. This article investigates the analogous effect of spatial proximity in a visual working-memory task. Items were presented in different locations varying in spatial distance. A retro-cue indicated the location of the item relevant for the subsequent memory test. In two recognition experiments, probes matching spatially close neighbours of the relevant item led to more false alarms than probes matching distant neighbours or non-neighbouring memory items. In two probed-recall experiments, one with simultaneous, the other with sequential memory item presentation, items closer to the cued location were more frequently chosen for recall than more distant items. These results reflect a spatial transposition gradient analogous to the temporal transposition gradient in serial recall and challenge fixed-capacity models of visual working memory (WM). PMID- 23663176 TI - Association between MEFV gene mutations and recurrent aphthous stomatitis in a cohort of Turkish patients. AB - Recurrent aphthous stomatitis (RAS) has a multifactorial etiopathogenesis, an interaction between predisposing factors and/or systemic conditions and immunological components in genetically predisposed subjects. The Mediterranean fever (MEFV) gene has already been identified as being responsible for familial Mediterranean fever. Because the association between MEFV gene mutations and Behcet's disease has been reported before in several studies, we considered that the role of MEFV gene mutations should be studied in patients with RAS, because of the clinical similarities of both diseases. The aim of this study was to explore the frequency and clinical significance of MEFV gene mutations in a cohort of Turkish patients with RAS. The study population comprised 100 unrelated patients with a clinical diagnosis of RAS and 156 healthy controls. Genomic DNA was isolated and genotyped using polymerase chain reaction and restriction fragment length polymorphism for the four MEFV gene mutations (M694V, M680I, V726A and E148Q). There were statistically significant differences of the MEFV gene mutation carrier rates and allele frequencies between RAS patients and healthy controls (P = 0.042, odds ratio [OR] = 1.9, 95% confidence interval [CI] = 1.01-3.41; and P = 0.039, OR = 1.8, 95% CI = 1.02-3.14, respectively). Even if it is not statistically significant, the E148Q allele frequency was higher in patients with RAS than the control group. A statistically significant increased prevalence of MEFV variants in RAS patients was found. This is the first study to report that missense mutations of MEFV is associated with RAS in the Turkish population. PMID- 23663177 TI - Insulin allergy. PMID- 23663178 TI - BLH1 and KNAT3 modulate ABA responses during germination and early seedling development in Arabidopsis. AB - The signal transduction pathway governed by the phytohormone abscisic acid (ABA) regulates not only abiotic stress responses but also early developmental programs such as seed dormancy, germination and seedling growth in response to environmental signals. Optimal plant growth and development depend on the integration of environmental stimuli and intrinsic developmental programs. Here, we show that the homeodomain transcription factors BLH1 and KNAT3, previously implicated in embryo sac development, have additional functions in ABA-mediated seed dormancy and early seedling development. The ABA-dependent induction of BLH1 and KNAT3 expression required the presence of functional PYR/PYL/RCAR receptors. The blh1 and knat3 mutants were less sensitive than the wild-type to ABA or salinity exposure during seed germination and early seedling development. In contrast, BLH1 over-expressing lines were hypersensitive to ABA and salinity, and exhibited increased expression of ABA-responsive genes, such as ABI3 and ABI5. BLH1 interacted with KNAT3 and enhanced the retention of KNAT3 in the nucleus. BLH1 and KNAT3 synergistically increased the ABA responses by binding to and subsequently activating the ABI3 promoter. Taken together, we propose that BLH1 and KNAT3 together modulate seed germination and early seedling development by directly regulating ABI3 expression. PMID- 23663179 TI - Correlation of previous experience, patient expectation and the number of post delivery adjustments of complete dentures with patient satisfaction in a Brazilian population. AB - A number of variables may influence the outcome of complete denture therapy. The objective of this study was to verify possible correlations between previous experience with dentures, patient expectation and the number of post-delivery adjustments with patient satisfaction after treatment. One hundred patients (mean age 61.9 +/- 10.3) rated their previous experiences with complete dentures and their expectations before and satisfaction after treatment on a visual analogue scale (VAS) using scores from 0 (worst results) to 10 (best results). The number of post-delivery adjustments and other patient-related clinical variables was also noted. Patient expectation scores were higher than previous experience scores and satisfaction after treatment scores. Positive and weak correlations were found between previous chewing experiences with complete dentures, with regard to chewing expectations and comfort of use. Phonetics and comfort of use in previous experiences presented a positive correlation with expectations for chewing, aesthetics, phonetics and comfort of use. Groups of patients with different levels of education presented significant differences in expectation scores regarding comfort of use as well. A negative and weak correlation was found between phonetics satisfaction and the number of post-delivery adjustments. Patients' expectations for the therapy were higher than their satisfaction after treatment. Previous experiences with complete dentures could slightly influence patients' expectations and satisfaction, whereas lower scores for previous experience with complete dentures caused lower scores for both expectation and satisfaction. Patients' educational levels and the number of post-delivery adjustments influenced negatively the expectations about comfort of use and patient satisfaction, respectively. PMID- 23663180 TI - Fast deswelling of nanocomposite polymer hydrogels via magnetic field-induced heating for emerging FO desalination. AB - Freshwater shortage is one of the most pressing global issues. Forward osmosis (FO) desalination technology is emerging for freshwater production from saline water, which is potentially more energy-efficient than the current reverse osmosis process. However, the lack of a suitable draw solute is the major hurdle for commercial implementation of the FO desalination technology. We have previously reported that thermoresponsive hydrogels can be used as the draw agent for a FO process, and this new hydrogel-driven FO process holds promise for further development for practical application. In the present work, magnetic field-induced heating is explored for the purpose of developing a more effective way to recover water from swollen hydrogel draw agents. The composite hydrogel particles are prepared by copolymerization of sodium acrylate and N isopropylacrylamide in the presence of magnetic nanoparticles (gamma-Fe2O3, <50 nm). The results indicate that the magnetic heating is an effective and rapid method for dewatering of hydrogels by generating the heat more uniformly throughout the draw agent particles, and thus, a dense skin layer commonly formed via conventional heating from the outside of the particle is minimized. The FO dewatering performance is affected by the loading of magnetic nanoparticles and magnetic field intensity. Significantly enhanced liquid water recovery (53%) is achieved under magnetic heating, as opposed to only around 7% liquid water recovery obtained via convection heating. Our study shows that the magnetic heating is an attractive alternative stimulus for the extraction of highly desirable liquid water from the draw agent in the polymer hydrogel-driven forward osmosis process. PMID- 23663181 TI - Caesarean section and risk for endometriosis: a prospective cohort study of Swedish registries. AB - OBJECTIVE: To investigate the association between caesarean section and later endometriosis. DESIGN: A prospective cohort study. SETTING: The Swedish Patient Register (PAR) and the Swedish Medical Birth Registry (MBR). SAMPLE: Women who were delivered in Sweden between 1986 and 2004. METHODS: Women with the diagnosis of endometriosis, defined as codes 617 (International Classification of Diseases, ninth revision, ICD-9) or N80 (ICD-10), were retrieved from the PAR. Obstetric outcome was assessed through linkage with the MBR. Out of 709,090 women, 3110 were treated as inpatients with a first diagnosis of endometriosis after their first delivery. Women with a diagnosis of endometriosis before their first delivery were excluded. Cox analyses were performed to obtain hazard ratios for endometriosis and adjusted for maternal age at first delivery, body mass index, maternal smoking, and years of involuntary childlessness at study entry. Kaplan Meier estimates were performed to calculate the risk according to time elapsed. MAIN OUTCOME: In-hospital diagnosis of endometriosis. RESULTS: The Cox analyses yielded a hazard ratio of 1.8 (95% CI 1.7-1.9) for endometriosis in women who had had a previous caesarean section compared with women with vaginal deliveries only. The risk of endometriosis increased over time: one additional case of endometriosis was found for every 325 women undergoing caesarean section within 10 years. No increase in risk could be seen after two caesarean deliveries. The risk of caesarean scar endometrioma was 0.1%. CONCLUSION: In addition to the recognised risk of scar endometrioma, we found an association between caesarean section and general pelvic endometriosis. Further studies are needed to confirm our findings. PMID- 23663182 TI - Acute and subchronic dermal toxicity of Vitex negundo essential oil. AB - Vitex negundo is a common herb in different herbal formulation. The potential acute and sub-chronic dermal toxicities were evaluated as per OECD (Organization for Economic Cooperation and Development) guidelines 402 and 411, respectively. Both sexes of Wistar rats were exposed to Vitex negundo oil of 2000 mg/kg body weight for acute dermal toxicity, whereas in the dermal sub-chronic toxicity study, rats were exposed to Vitex negundo oil 250, 500 and 1000 mg/kg body weight, respectively, for five times a week for 90 d. In acute and sub-chronic toxicity studies, all animals were normal without any behavioral, serum biochemistry, hematology, necroscopical and histopathological changes. The no observed effect level (NOEL) and no observed adverse effect level (NOAEL) of Vitex negundo oil were 250 and 1000 mg/kg/day, respectively. Vitex negundo oil is under the category 5 (Unclassified) according to the Globally Harmonized System, with an LD50 value of over 2000 mg/kg. PMID- 23663183 TI - Worldwide policies on haemochromatosis and blood donation: a survey among blood services. AB - BACKGROUND AND OBJECTIVES: Haemochromatosis (HC) is a disorder of iron metabolism, requiring frequent phlebotomy to normalize high serum iron levels. There is currently no consensus relating to the eligibility of these patients to donate blood for transfusion. To gain a better understanding of the policies worldwide, a survey amongst blood services was performed. MATERIALS AND METHODS: A web-based questionnaire was developed and distributed among 44 blood services in 41 countries to identify the different policies relating to patients with HC and blood donation. RESULTS: Respondents from 35 blood services (80%) of 33 countries completed the questionnaire. In 24 blood services among them (69%), individuals with genetic susceptibility for HC and/or patients with HC are accepted as blood donors. In approximately one-third of these blood centres (33%), genetic carriers/patients are allowed to donate blood more frequently than regular donors. Prescription from/approval by the patient's treating physician and/or a donor physician is required in the majority of the blood services (87%). Similar policies were identified in a few countries; however, in general, the policies regarding blood donation from patients with HC remain widely variable. CONCLUSION: The results of our survey demonstrate large differences in the blood donation policies regarding carriers/patients with HC illustrating the need for uniform evidence-based and cost-effective policies which could benefit both HC patients and the blood supply around the world. PMID- 23663184 TI - Current management of patients hospitalized with complicated skin and soft tissue infections across Europe (2010-2011): assessment of clinical practice patterns and real-life effectiveness of antibiotics from the REACH study. AB - Complicated skin and soft tissue infections (cSSTI) are common and frequently require treatment in hospital. Comprehensive current data on management practices in patients hospitalized with cSSTI are limited. REACH was a retrospective, observational cohort study designed to provide data on current clinical management of moderate to severe cSSTI in European hospitals. Data were collected via an electronic case report form from 129 sites in ten European countries. The study population comprised patients >=18 years, hospitalized between March 2010 and February 2011 with cSSTI who received intravenous antibiotic treatment. Presented here is an analysis of the disease characteristics, treatment patterns during hospitalization and clinical outcomes identified by the study. The total population included 1995 patients (mean age 60.6 years; 57.7% male). Initial antibiotic treatment modification was reported in 39.6% (n = 791) of patients; it was more common in patients with co-morbidities (42.6%), those requiring surgical intervention (43.4%), those with more severe infections such as bacteraemia (51.6%) or with fascia affected (49.0%), those admitted to the intensive care unit (56.2%) and those with lesions > 50 cm(2) (44.3%). A switch to narrower spectrum antibiotic treatment (streamlining) occurred in 5.6% of patients. Mean length of hospital stay was 18.5 days (+/-19.9; median 12.0) and the total mortality rate was 3.4%. The data collected in REACH give a comprehensive and current view of real-life clinical management of cSSTI in European hospitals and provide evidence of a high rate of initial antibiotic treatment modification. PMID- 23663185 TI - Are there radiologically identifiable prodromal changes in Thoroughbred racehorses with parasagittal fractures of the proximal phalanx? AB - REASONS FOR PERFORMING STUDY: Fractures of the proximal phalanx are generally considered to result from monotonic supraphysiological loads, but radiological observations from clinical cases suggest there may be a stress-related aetiology. OBJECTIVES: To determine whether there are radiologically identifiable prodromal changes in Thoroughbred racehorses with confirmed parasagittal fractures of the proximal phalanx. STUDY DESIGN: Retrospective cross-sectional study. METHODS: Case records and radiographs of Thoroughbred racehorses with parasagittal fractures of the proximal phalanx were analysed. Thickness of the subchondral bone plate was measured in fractured and contralateral limbs, and additional radiological features consistent with prodromal fracture pathology documented. RESULTS: The subchondral bone plate was significantly thicker in affected than in contralateral limbs. Evidence of additional prodromal fracture pathology was observed in 15/110 (14%) limbs with parasagittal fractures, and in 4% of contralateral limbs. CONCLUSIONS: The results of this study are not consistent with monotonic loading as a cause of fracture in at least a proportion of cases, but suggest a stress-related aetiology. Increased thickness of the subchondral bone plate may reflect (failed) adaptive changes that precede fracture. POTENTIAL RELEVANCE: Better understanding of the aetiology of fractures of the proximal phalanx may help develop strategies to reduce the risk of fracture. PMID- 23663186 TI - Colloidal synthesis of Cu2SnSe3 tetrapod nanocrystals. AB - The formation of Cu2SnSe3 tetrapod nanocrystals is reported using a hot injection colloidal synthesis. The ternary copper chalcogenide nanocrystals nucleate with a cubic core with four short wurzite arms. PMID- 23663187 TI - Correlation analysis of Shiga toxin-producing Escherichia coli shedding and faecal bacterial composition in beef cattle. AB - AIMS: The objectives of this study were to investigate the correlations between Shiga toxin-producing Escherichia coli (STEC) shedding and faecal microflora in beef cattle and to identify functional species that might be used for STEC control. METHODS AND RESULTS: Faecal samples were collected from 110 calves and 92 dams. The number and prevalence of STEC were determined using CHROMagarTM STEC; denaturing gradient gel electrophoresis (DGGE) was employed to analyse faecal bacterial composition. Six-month-old calves had the highest STEC shedding levels (3.03 +/- 1.41 Log CFU g(-1)) and prevalence (95.5%). Both the number and prevalence decreased significantly as the calf age increased (P < 0.05). The DGGE analysis showed that faecal bacterial diversity increased, while cattle ages increased and STEC shedding levels decreased. Significant correlations between STEC shedding, cattle age and bacterial compositions were observed by redundancy analysis (P < 0.05). T-value biplots and sequencing results indicated that butyrate-producing bacteria (BPB) negatively correlated with STEC shedding. CONCLUSIONS: Higher STEC shedding levels and prevalence were associated with younger cattle age, lower faecal bacterial diversity and lower BPB levels. SIGNIFICANCE AND IMPACT OF THE STUDY: Butyrate-producing bacteria in GI tract might serve as an option for the future development of STEC shedding control strategy. PMID- 23663188 TI - Flexible kinesthetic distance perception: when do your arms tell you how far you have walked? AB - Given the flexible organization of locomotion evidenced in the many ways the limbs can be coordinated, the authors explored the potentially correspondingly flexible organization of nonvisual (kinesthetic) distance perception. As kinesthetic distance perception is known to be affected by how the limbs are coordinated, the authors probed the potential perceptual contribution of the arms during locomotion by manipulating arm-leg coordination patterns in blind-walked distance-matching tasks. Whereas manipulation of arm-leg coordination for walking with free-swinging arms had no observable perceptual consequences, comparable manipulation for walking with hiking poles did affect distance matching. These results suggest that under conditions in which the arms act to propel the body (e.g., crawling or stair-climbing) a person's nonvisual sense of movement is conveyed in the coordinated actions of all four limbs. PMID- 23663189 TI - The influence of robotic guidance on different types of motor timing. AB - Robotic guidance as a means to facilitate motor learning and rehabilitation has received considerable attention during the last few years. However, mixed outcomes suggest that the benefits might be restricted to certain movement characteristics. The authors investigate the effects of robotic guidance on different kinds of motor timing. Two groups of participants performed 2 variants of a circle drawing task in a synchronization-continuation paradigm. One variant was continuous circle drawing (emergent timing), the other variant was intermittent circle drawing (event-based timing). The total duration of movement cycles (absolute timing) and the relative duration of submovements (relative timing) were measured. Half of the participants in each group were guided by a robot device during synchronization (robot-guided group), the other half of the participants received no guidance (control group). Guided participants had superior performance during the synchronization phase with both timing tasks. During continuation there were no benefits of haptic guidance anymore with the continuous circle drawing task. In contrast, with the intermittent circle drawing task guided participants were more accurate in their relative timing than control participants already in the first few trials, and this advantage did not increase in the course of practice. The benefit is thus rather immediate and not cumulative. This finding is consistent with the notion that movement characteristics such as relative timing, which are hard to demonstrate visually or verbally, profit from robotic guidance because of the more accurate demonstrations of the correct movements. PMID- 23663190 TI - Does implicit motor imagery ability predict reaching correction efficiency? A test of recent models of human motor control. AB - Neurocomputational models of reaching indicate that efficient purposive correction of movement midflight (e.g., online control) depends on one's ability to generate and monitor an accurate internal (neural) movement representation. In the first study to test this empirically, the authors investigated the relationship between healthy young adults' implicit motor imagery performance and their capacity to correct their reaching trajectory. As expected, after controlling for general reaching speed, hierarchical regression demonstrated that imagery ability was a significant predictor of hand correction speed; that is, faster and more accurate imagery performance associated with faster corrections to reaching following target displacement at movement onset. They argue that these findings provide preliminary support for the view that a link exists between an individual's ability to represent movement mentally and correct movement online efficiently. PMID- 23663191 TI - The effect of balance training on cervical sensorimotor function and neck pain. AB - The authors' aim was to evaluate the effect of balance training on cervical joint position sense in people with subclinical neck pain. Thirty-four participants were randomly assigned to balance training or to stay active. Sensorimotor function was determined before and after 5 weeks of training by assessing the ability to reproduce the neutral head position and a predefined rotated head position. After balance training, the intervention group showed improved joint repositioning accuracy and decreased pain whereas no effects were observed in the control group. A weak correlation was identified between reduced neck pain intensity and improved joint repositioning. The present data demonstrate that balance training can effectively improve cervical sensorimotor function and decrease neck pain intensity. PMID- 23663192 TI - Two new cases of metastatic basal cell carcinoma from the eyelids. AB - BACKGROUND: Basal cell carcinoma (BCC) is an extremely common malignancy. Unlike other skin cancers, it very rarely metastasises. METHODS: We present two cases of advanced BCC on the eyelids that metastasized to the parotid region after local excision. DISCUSSION: We include a review of patients with metastatic BCC originating from the eyelids. CONCLUSION: Metastatic BCC from the eyelids is rare, but appears to occur in an older age group with a shorter time before metastasis when compared to metastatic BCC as a whole. PMID- 23663193 TI - Intrahepatic cholestasis of pregnancy is common among patients' first-degree relatives. AB - Intrahepatic cholestasis of pregnancy has been shown to have a genetic predisposition. We studied whether Finnish women who had suffered from the disorder reported their first-degree relatives to have had liver dysfunction during their pregnancies. Questionnaires were sent in autumn 2010 to a total of 544 former intrahepatic cholestasis of pregnancy patients and 1235 controls, all having delivered during 1969-1988. The response rate was 66.2%. The incidence of intrahepatic cholestasis is 0.5-1.5% of pregnancies in Finland. In our survey, altogether 12.8% of mothers (odds ratio 9.2), 15.9% of sisters (odds ratio 5.3) and 10.3% of daughters (odds ratio 4.8) of women who had suffered from intrahepatic cholestasis of pregnancy had had liver dysfunction during pregnancy. Our findings strengthen the earlier knowledge of the genetic component in intrahepatic cholestasis of pregnancy. We suggest that all pregnant women are asked about their family history regarding liver dysfunction during pregnancy. PMID- 23663194 TI - No evidence for behavioural adaptations to nematode parasitism by the fly Drosophila putrida. AB - Behavioural adaptations of hosts to their parasites form an important component of the evolutionary dynamics of host-parasite interactions. As mushroom-feeding Drosophila can tolerate deadly mycotoxins, but their Howardula nematode parasites cannot, we asked how consuming the potent mycotoxin alpha-amanitin has affected this host-parasite interaction. We used the fly D. putrida and its parasite H. aoronymphium, which is both highly virulent and at high prevalence in some populations, and investigated whether adult flies utilize food with toxin to prevent infection in the next generation or consume the toxin to reduce the virulence of an already established infection. First, we found that uninfected females did not prefer to eat or lay their eggs on toxic food, indicating that selection has not acted on the flies to alter their behaviour towards alpha amanitin to prevent their offspring from becoming infected by Howardula. However, we cannot rule out that flies use an alternate cue that is associated with toxin presence in the wild. Second, we found that infected females did not prefer to eat food with alpha-amanitin and that consuming alpha-amanitin did not cure or reduce the virulence of the parasite in adults that were already infected. In sum, our results indicate there are no direct effects of eating alpha-amanitin on this host-parasite interaction, and we suggest that toxin tolerance is more likely maintained by selection due to competition for resources than as a mechanism to avoid parasite infection or to reduce the virulence of infection. PMID- 23663195 TI - Hydrogen-bonding-induced chain folding and vesicular assembly of an amphiphilic polyurethane. AB - We have reported synthesis and vesicular assembly of a novel amphiphilic polyurethane with hydrophobic backbone and hydrophilic pendant carboxylic acid groups which were periodically grafted to the backbone via a tertiary amine group. In aqueous medium the polymer chain adopted a folded conformation which was stabilized by intrachain H-bonding among the urethane groups. Such a model was supported by concentration and solvent-dependent FT-IR, powder XRD, and urea mediated "denaturation" experiments. Folded polymer chains further formed vesicular assembly which was probed by dynamic light scattering, TEM, AFM, SEM, and fluorescence microscopic studies, and dye encapsulation experiments. pH dependent DLS and fluorescence microscopic studies revealed stable polymersome in entire tested pH window of 3.5-11.0. Zeta potential measurements showed a negatively charged surface in basic pH while a charge-neutral surface in neutral and acidic pH. MTT assay with CHO cell line indicated good cell viability. PMID- 23663196 TI - Deep brain stimulation of the subthalamic nucleus for peripherally induced parkinsonism. PMID- 23663197 TI - Responses to Medicare drug costs among near-poor versus subsidized beneficiaries. AB - OBJECTIVE: There is limited information on the protective value of Medicare Part D low-income subsidies (LIS). We compared responses to drug costs for LIS recipients with near-poor (<=200 percent of the Federal Poverty Level) and higher income beneficiaries without the LIS. DATA SOURCES/STUDY SETTING: Medicare Advantage beneficiaries in 2008. STUDY DESIGN: We examined three drug cost responses using multivariate logistic regression: cost-reducing behaviors (e.g., switching to generics), nonadherence (e.g., not refilling prescriptions), and financial stress (e.g., going without necessities). DATA COLLECTION: Telephone interviews in a stratified random sample (N = 1,201, 70 percent response rate). PRINCIPAL FINDINGS: After adjustment, a comparable percentage of unsubsidized near-poor (26 percent) and higher income beneficiaries reported cost-reducing behaviors (23 percent, p = .63); fewer LIS beneficiaries reported cost-reducing behaviors (15 percent, p = .019 vs near-poor). Unsubsidized near-poor beneficiaries were more likely to reduce adherence (8.2 percent) than higher income (3.5 percent, p = .049) and LIS beneficiaries (3.1 percent, p = .027). Near-poor beneficiaries also more frequently experienced financial stress due to drug costs (20 percent) than higher income beneficiaries (11 percent, p = .050) and LIS beneficiaries (11 percent, p = .015). CONCLUSIONS: Low-income subsidies provide protection from drug cost-related nonadherence and financial stress. Beneficiaries just above the LIS income threshold are most at risk for these potentially adverse behaviors. PMID- 23663198 TI - Effects of diagnostic test accuracy and treatment efficacy on the occurrence of suspected failure of heartworm prophylaxis in dogs. AB - BACKGROUND: Food and Drug Administration Center for Veterinary Medicine (FDA/CVM) cited concern regarding failure of heartworm prophylaxis. The positive and negative predictive value of the heartworm antigen test is an estimate of the probability of adult heartworm infection. HYPOTHESIS/OBJECTIVES: Assess the sensitivity, specificity, and predictive value of heartworm antigen tests. Explore the role of heartworm test accuracy and treatment with immiticide to generate reports of suspected failure of heartworm prophylaxis. METHODS: Literature searches for published information on the accuracy of heartworm antigen tests and efficacy of immiticide for treatment of the adult heartworm. RESULTS: Weighted averages for heartworm antigen test sensitivity and specificity were 78.2 and 97.3%, respectively. Efficacy of immiticide by 2-injection or alternate dose protocols were 88.3 and 89.1%, respectively. Depending on prevalence, the positive predictive value of the heartworm antigen test ranged from 15 to 54% and negative predictive value from 99 to 99.9%. For a hospital testing 1,000 dogs per year, false-positive test results may vary from 24 to 27 dogs. If these dogs were on heartworm preventive, they may undergo treatment and be classified as prophylaxis failures. Ten percent of dogs who were treated and continued or placed on prophylaxis at the time of treatment may have adult heartworms when tested 1 year later and be presumed to represent failure of prophylaxis. CONCLUSIONS: When interpreting heartworm antigen test results, clinical signs, history, and regional prevalence of heartworm disease should be considered in estimating the predictive value of the test result. Limitations of test and treatment should be discussed with clients as part of the decision making process. PMID- 23663199 TI - Direct experimental evidence of non-first order degradation kinetics and sorption induced isotopic fractionation in a mesoscale aquifer: 13C/12C analysis of a transient toluene pulse. AB - The injection of a mixed toluene and D2O (conservative tracer) pulse into a pristine mesoscale aquifer enabled a first direct experimental comparison of contaminant-specific isotopic fractionation from sorption versus biodegradation and transverse dispersion on a relevant scale. Water samples were taken from two vertically resolved sampling ports at 4.2 m distance. Analysis of deuterium and toluene concentrations allowed quantifying the extent of sorption (R = 1.25) and biodegradation (37% and 44% of initial toluene at the two sampling ports). Sorption and biodegradation were found to directly affect toluene (13)C/(12)C breakthrough curves. In particular, isotope trends demonstrated that biodegradation underwent Michaelis-Menten kinetics rather than first-order kinetics. Carbon isotope enrichment factors obtained from an optimized reactive transport model (Eckert et al., this issue) including a possible isotope fractionation of transverse dispersion were epsilon(equ)(sorption) = -0.31 0/00, epsilon(kin)(transverse-dispersion) = -0.82 0/00, and epsilon(kin)(biodegradation) = -2.15 0/00. Extrapolation of our results to the scenario of a continuous injection predicted that (i) the bias in isotope fractionation from sorption, but not transverse dispersion, may be avoided when the plume reaches steady-state; and (ii) the relevance from both processes is expected to decrease at longer flow distances when isotope fractionation of degradation increasingly dominates. PMID- 23663200 TI - The hallmarks of Parkinson's disease. AB - Since the discovery of dopamine as a neurotransmitter in the 1950s, Parkinson's disease (PD) research has generated a rich and complex body of knowledge, revealing PD to be an age-related multifactorial disease, influenced by both genetic and environmental factors. The tremendous complexity of the disease is increased by a nonlinear progression of the pathogenesis between molecular, cellular and organic systems. In this minireview, we explore the complexity of PD and propose a systems-based approach, organizing the available information around cellular disease hallmarks. We encourage our peers to adopt this cell-based view with the aim of improving communication in interdisciplinary research endeavors targeting the molecular events, modulatory cell-to-cell signaling pathways and emerging clinical phenotypes related to PD. PMID- 23663201 TI - Nuclear mitochondrial pseudogenes in Austinograea alayseae hydrothermal vent crabs (Crustacea: Bythograeidae): effects on DNA barcoding. AB - Members of the brachyuran crab family, Bythograeidae, are among the most abundant and common crabs in vent fields. However, their identification based on morphological characteristics often leads to incorrect species recognition due to a lack of taxonomic factors and the existence of sibling (or cryptic) species. For these reasons, we used DNA barcoding for vent crabs using mitochondrial cytochrome c oxidase subunit 1 (CO1). However, several nuclear mitochondrial pseudogenes (Numts) were amplified from Austinograea alayseae Guinot, 1990, using universal primers (Folmer primers). The Numts were characterized in six haplotypes, with 13.58-14.11% sequence divergence from A. alayseae, a higher nonsynonymous substitution ratio than true CO1, and the formation of an independent clade in bythograeids. In a neighbour-joining tree, the origin of the Numts would be expected to incorporate into the nucleus at an ancestral node of Austinograea, and they mutated more slowly in the nucleus than CO1 in the mitochondria. This evolutionary process may have resulted in the higher binding affinity of Numts for the Folmer primers than CO1. In the present study, we performed long PCR for the amplification of CO1 in A. alayseae. We also present evidence that Numts can introduce serious ambiguity into DNA barcoding, including overestimating the number of species in bythograeids. These results may help in conducting taxonomic studies using mitochondrial genes from organisms living in hydrothermal vent fields. PMID- 23663202 TI - Reversible intercalation of hexagonal boron nitride with Bronsted acids. AB - Hexagonal boron nitride (h-BN) is an insulating compound that is structurally similar to graphite. Like graphene, single sheets of BN are atomically flat, and they are of current interest in few-layer hybrid devices, such as transistors and capacitors, that contain insulating components. While graphite and other layered compounds can be intercalated by redox reactions and then converted chemically to suspensions of single sheets, insulating BN is not susceptible to oxidative intercalation except by extremely strong oxidizing agents. We report that stage-1 intercalation compounds can be formed by simple thermal drying of h-BN in Bronsted acids H2SO4, H3PO4, and HClO4. X-ray photoelectron and vibrational spectra, as well as electronic structure and molecular dynamics calculations, demonstrate that noncovalent interactions of these oxyacids with the basic N atoms of the sheets drive the intercalation process. PMID- 23663203 TI - Social communicative variation in 1-3-year-olds with severe visual impairment. AB - BACKGROUND: Although the social communicative domain is recognized as being at risk in young children with visual impairment (VI), few tools are available for identifying those most at risk or the aspects that are most vulnerable. METHODS: A standard parent interview - Social Communication Interview for young children with visual impairment (SOCI-VI), was developed and tested with 55 parents of 17 profoundly, 15 severely VI and 23 normally sighted children; mean age 22 months (range 10-40 months). The 35-item SOCI-VI 35 showed adequate inter-rater and test retest reliability (P < 0.001). RESULTS: Thirteen of 35 items discriminated within and between the vision groups (anova P 0.008). The group with profound VI scored significantly lower than the Sighted group on the reduced 13 item SOCI-VI 13 (t-test P 0.002), the disparity being greatest for items exploring joint attention. The reduced SOCI-VI 13 showed adequate internal consistency (Cronbach alpha > 0.75) and concurrent validity with the Vineland adaptation questionnaire within a randomized VI subgroup (r 0.8, P < 0.01). CONCLUSIONS: The study reveals trends in early social communicative development in the young VI population and provides preliminary reliability and validity testing for future research within a clinical context. PMID- 23663204 TI - Spectroscopy of protonated tetraphenylporphyrins with amino/carbomethoxy substituents: hyperporphyrin effects and evidence for a monoprotonated porphyrin. AB - Spectrophotometric titrations for a full series of para-amino/carbomethoxy substituted tetraphenylporphyrins were carried out using methanesulfonic acid in DMSO to study the hyperporphyrin effect across different substitution patterns. The series included zero, one, two (cis and trans), three, and four amino groups, with the remaining para substituents carbomethoxy groups. With increasing numbers of aminophenyl groups, the relative basicity increased and the hyperporphyrin effect increased, marked by a strong red band and a split Soret band. The cis diamino derivative showed a stronger hyperporphyrin effect compared to the trans isomer, which can be explained based on simple resonance forms. For the monoamino derivative, an initial increase in the Soret band upon acid titration along with well-defined isosbestic points provided evidence for a monoprotonated porphyrin, distinct from the diprotonated and triprotonated states. The relative stability of this unusual intermediate is proposed to be due to charge delocalization of the first cation to the single amino group and destabilization of the second protonation by the electron-withdrawing carbomethoxy substituents. PMID- 23663206 TI - Topical anaesthesia does not affect cutaneous vasomotor or sudomotor responses in human skin. AB - (1) The effects of local sensory blockade (topical anaesthesia) on eccrine sweat glands and cutaneous circulation are not well understood. This study aimed to determine whether topical lidocaine/prilocaine alters eccrine sweat gland and cutaneous blood vessel responses. (2) Sweating (capacitance hygrometry) was induced via forearm intradermal microdialysis of five acetylcholine (ACh) doses (1 * 10(-4) to 1 * 10(0) m, 10-fold increments) in control and treated forearm sites in six healthy subjects. Nitric oxide-mediated vasodilatory (sodium nitroprusside) and adrenergic vasoconstrictor (noradrenaline) agonists were iontophoresed in lidocaine/prilocaine-treated and control forearm skin in nine healthy subjects during blood flow assessment (laser Doppler flowmetry, expressed as% from baseline cutaneous vascular conductance; CVC; flux/mean arterial pressure). (3) Non-linear regression curve fitting identified no change in the ED50 of ACh-induced sweating after sensory blockade (-1.42 +/- 0.23 logM) compared to control (-1.27 +/- 0.23 logM; P > .05) or in Emax (0.43 +/- 0.08 with, 0.53 +/- 0.16 mg cm(-2) min(-1) without lidocaine/prilocaine; P > .05). Sensory blockade did not alter the vasodilator response to sodium nitroprusside (1280 +/- 548% change from baseline CVC with, 1204 +/- 247% without lidocaine/prilocaine) or vasoconstrictor response to noradrenaline (-14 +/- 4% change from baseline CVC with, -22 +/- 14% without lidocaine/prilocaine; P > 0.05). (4) Cutaneous sensory blockade does not appear to alter nitric oxide mediated vasodilation, adrenergic vasoconstriction, or cholinergic eccrine sweating dose-response sensitivity or responsiveness to maximal dose. Thus, lidocaine/prilocaine treatment should not affect sweat gland function or have blood flow implications for subsequent research protocols or clinical procedures. PMID- 23663205 TI - The availability of purine nucleotides regulates natural competence by controlling translation of the competence activator Sxy. AB - Many bacteria are naturally competent, able to bind and take up DNA from their extracellular environment. This DNA can serve as a significant source of nutrients, in addition to providing genetic material for recombination. The regulation of competence in several model organisms highlights the importance of this nutritional function, although it has often been overlooked. Natural competence is induced by starvation in Haemophilus influenzae, the model for competence regulation in the gamma-proteobacteria. This induction depends on the activation of the global metabolic regulator CRP, which occurs upon depletion of phosphotransferase sugars. In this work, we show that the depletion of purine nucleotides under competence-inducing conditions activates the CRP-dependent competence-specific regulator Sxy. Depletion of extra- or intra-cellular purine nucleotides activates Sxy translation, while high levels inhibit it. This is modulated by the stem structure formed by sxy mRNA. The exact mechanism by which the nucleotide depletion signal is transduced is unclear, but it does not involve direct binding of purine intermediates to the sxy stem, and does not require Hfq or competence proteins. Similar regulation occurs in the relatives of H. influenzae, Actinobacillus pneumoniae and A. suis, confirming the importance of processes enabling competent bacteria to exploit the abundant DNA in their environments. PMID- 23663207 TI - The effect of increased centrifugation temperature on the quality of red-blood cell concentrates of automated whole blood processing. AB - BACKGROUND AND OBJECTIVES: There are manual and automated methods to separate whole blood (WB) available. The Atreus whole blood processing system is an automated method, which combines centrifugation and expression of components into a single device. A major difference to conventional methods is that centrifugation temperature is not controlled at 22 degrees C. The aim of this study was to examine the influence of increased centrifugation temperatures on the quality of red-blood-cell concentrates (RCC) after active cooling of WB prior to processing. MATERIALS AND METHODS: A total of 28 WB were processed: 16 at centrifugation temperatures of up to 28 degrees C (1st protocol) and 12 at 34 degrees C (2nd protocol). RCC quality parameters were tested weekly for 42 days. RESULTS: Red-blood-cell concentrates (RCC) quality complied with the European and German guidelines. Haemolysis was not significantly different throughout storage. Significant statistical differences were detected between both protocols in potassium concentration at the end of storage and in ATP levels at the day of processing. CONCLUSION: Centrifugation temperatures of up to 34 degrees C are well tolerated by the red blood cells with minimal interference with the RCC quality parameters. PMID- 23663208 TI - Re: a rare cause of sensing integrity count in a patient with ICD and dedicated true bipolar lead. PMID- 23663209 TI - Meta-analyses of QTL for grain yield and anthesis silking interval in 18 maize populations evaluated under water-stressed and well-watered environments. AB - BACKGROUND: Identification of QTL with large phenotypic effects conserved across genetic backgrounds and environments is one of the prerequisites for crop improvement using marker assisted selection (MAS). The objectives of this study were to identify meta-QTL (mQTL) for grain yield (GY) and anthesis silking interval (ASI) across 18 bi-parental maize populations evaluated in the same conditions across 2-4 managed water stressed and 3-4 well watered environments. RESULTS: The meta-analyses identified 68 mQTL (9 QTL specific to ASI, 15 specific to GY, and 44 for both GY and ASI). Mean phenotypic variance explained by each mQTL varied from 1.2 to 13.1% and the overall average was 6.5%. Few QTL were detected under both environmental treatments and/or multiple (>4 populations) genetic backgrounds. The number and 95% genetic and physical confidence intervals of the mQTL were highly reduced compared to the QTL identified in the original studies. Each physical interval of the mQTL consisted of 5 to 926 candidate genes. CONCLUSIONS: Meta-analyses reduced the number of QTL by 68% and narrowed the confidence intervals up to 12-fold. At least the 4 mQTL (mQTL2.2, mQTL6.1, mQTL7.5 and mQTL9.2) associated with GY under both water-stressed and well watered environments and detected up to 6 populations may be considered for fine mapping and validation to confirm effects in different genetic backgrounds and pyramid them into new drought resistant breeding lines. This is the first extensive report on meta-analysis of data from over 3100 individuals genotyped using the same SNP platform and evaluated in the same conditions across a wide range of managed water-stressed and well-watered environments. PMID- 23663210 TI - Association between dietary quality and mortality in older adults: a review of the epidemiological evidence. AB - The population is aging worldwide. Delayed mortality is associated with an increased burden of chronic health conditions, many of which have a dietary component. A literature search was conducted to retrieve and review relevant articles considering quality of diets in association with mortality in older adults aged 60 years and older. In the studies we reviewed, diet quality defined using either a priori methods, which characterize dietary patterns based on existing dietary guidelines, or a posteriori methods, which define dietary patterns through statistical methods met review criteria. Sixteen articles met criteria for review. Generally, dietary patterns that demonstrated greater adherence to diets that emphasized whole fruits and vegetables, whole grains, low fat dairy, lean meats, and legumes and nuts were inversely associated with mortality. However, a priori methods have not yet demonstrated associations between diet and mortality in older adults in the United States. Development of new methods based on regional variations in dietary intake may offer the best approach to assess associations with mortality. PMID- 23663212 TI - Exploration of functional food consumption in older adults in relation to food matrices, bioactive ingredients, and health. AB - The functional food industry is expanding, yet research into consumer perceptions of functional foods is limited. Older adults could benefit from functional foods due to age-related food and health issues. This research gathered information about functional foods from community-dwelling older adults (n = 200) who completed a researcher-administered questionnaire about consumption, food matrices, bioactive ingredients, and health areas addressed through functional foods. Overall prevalence of functional food consumption was found to be 93.0%. Commonly consumed foods included yogurt with probiotics (56.0%), eggs with omega 3 fatty acids (37.0%), and bread with fiber (35.5%). Functional food matrices primarily consumed were yogurt (51.5%), bread (44.0%), and cereal (40.0%). The primary functional food bioactive consumed was dietary fiber (79.5%). Most participants (86.2%) indicated that they consume functional foods to improve health, and the major areas specified were osteoporosis/bone health (67.5%), heart disease (61.0%), and arthritis (55.0%). These results inform health professionals regarding the potential of functional foods to support health among older adults. PMID- 23663211 TI - Dietary habits moderate the association between heart failure and cognitive impairment. AB - Cognitive impairment is common in heart failure patients. Poor dietary habits are associated with reduced neurocognitive function in other medical populations, including diabetes and Alzheimer's disease. This study examined whether dietary habits help moderate the relationship between heart failure severity and cognitive function. A total of 152 persons with heart failure completed neuropsychological testing and a fitness assessment. Dietary habits were assessed using the Starting the Conversation-Diet questionnaire, a nutrition measure suggested for use in primary care settings. Moderation analyses showed that better dietary habits attenuated the adverse impact of heart failure severity on frontal functioning (b = 1.28, p < 0.05). Follow-up analyses revealed consumption of foods high in sodium was associated with reduced cognitive function (p < 0.05). This study suggests dietary habits can moderate the association between heart failure and performance on tests of attention and executive function. Longitudinal studies are needed to confirm and clarify the mechanisms for our findings. PMID- 23663213 TI - Effectiveness of community intervention in improving bone health behaviors in older adults. AB - An 8-week, bone-health community program addressed risks/lifestyle changes within the Health Belief Model and Theory of Reasoned Action frameworks in a randomized format (treatment group n = 35; control group n = 34). Median week 1 values for calcium (control, 963 mg; treatment, 1023 mg) and vitamin D (81 IU both groups) were below recommendations, increasing throughout the program for both control (1023 mg calcium, 128 IU vitamin D) and treatment (1005 mg calcium, 122 IU vitamin D) groups. There was limited response to the exercise outcome variables, with many not participating in that section of the program. Psychosocial variables were positive for both control and treatment groups at week 1, with no significant difference at postintervention. Regression analysis indicated that those with a positive attitude about calcium intake and belief that they could choose calcium-fortified foods were more likely to have higher calcium intake. Intention to exercise was modified by peer and family support. Community-based programs can translate and use clinical trial key topics and outcomes, but participation bias makes impact results difficult to interpret the effectiveness of the program. PMID- 23663214 TI - Identification of environmental supports for healthy eating in older adults. AB - Many environmental settings and influences can affect food choices and eating behaviors in the growing population of community-dwelling older adults. Using the Social Ecological model, an expert panel participated in online discussions and an Analytic Hierarchy Process survey to identify the most important and changeable environmental settings and enabling factors that promote healthy eating in older adults. Food stores were rated most important when considering accessibility and affordability. Congregate nutrition sites were important for social support along with supporting access and affordability of healthful foods and living accommodations. Senior housing, health care, and religious settings also contributed to the goal of promoting healthful eating in aging adults. Restaurants were rated of lower importance. Based on these results, it is recommended that community food policies include the nutritional needs of older adults by addressing food accessibility and affordability, social support, and living accommodations, with a focus on congregate nutrition sites, food stores, senior housing, health care, and religious organizations. PMID- 23663215 TI - Light quality influences the virulence and physiological responses of Colletotrichum acutatum causing anthracnose in pepper plants. AB - AIMS: To explore the effects of light quality on the physiology and pathogenicity of Colletotrichum acutatum, we analysed the morphological traits, melanin production and virulence of the pathogen under different light wavelengths. METHODS AND RESULTS: The influence of light wavelength on the mycelial growth and conidial germination of C. acutatum was investigated using red, green, blue and white light sources. Red and green light reduced the mycelial growth in comparison with blue and white light, and dark conditions. The least percentage of conidial germination was observed under blue light, while the germination rate among white, red and green light, as well as in the dark, was insignificant. In comparison with its influence on mycelial growth and conidial germination, light wavelength significantly affected the pathogen's virulence towards hot pepper fruits. The highest disease severity was observed under blue light, which was at least a twofold increase compared with the disease severity under other light conditions. To elucidate the effect of light on the disparity in virulence, scytalone was assayed by HPLC, and scd1 gene expression was examined with real time PCR. The highest and lowest scytalone production was observed in the cultures incubated under blue (10.9 mAU) and green light (1.5 mAU), respectively. Higher scd1 gene expression (~ 40-fold increase) was observed in cultures incubated under blue and white light in comparison with those incubated in the dark. CONCLUSIONS: This study revealed that light affects the growth, colonial morphology and virulence of C. acutatum. The pathogen needs light for its active melanin production and also to attain higher virulence. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report on the effect of light quality on the virulence of C. acutatum. The findings of this study will broaden our knowledge of the influence of light on physiological responses of fungal pathogens. PMID- 23663217 TI - A novel structural effector from rust fungi is capable of fibril formation. AB - It has been reported that filament-forming surface proteins such as hydrophobins are important virulence determinants in fungi and are secreted during pathogenesis. Such proteins have not yet been identified in obligate biotrophic pathogens such as rust fungi. Rust transferred protein 1 (RTP1p), a rust protein that is transferred into the host cytoplasm, accumulates around the haustorial complex. To investigate RTP1p structure and function, we used immunocytological, biochemical and computational approaches. We found that RTP1p accumulates in protuberances of the extra-haustorial matrix, a compartment that surrounds the haustorium and is separated from the plant cytoplasm by a modified host plasma membrane. Our analyses show that RTP1p is capable of forming filamentous structures in vitro and in vivo. We present evidence that filament formation is due to beta-aggregation similar to what has been observed for amyloid-like proteins. Our findings reveal that RTP1p is a member of a new class of structural effectors. We hypothesize that RTP1p is transferred into the host to stabilize the host cell and protect the haustorium from degradation in later stages of the interaction. Thus, we provide evidence for transfer of an amyloid-like protein into the host cell, which has potential for the development of new resistance mechanisms against rust fungi. PMID- 23663216 TI - Barrett's esophagus and the risk of obstructive sleep apnea: a case-control study. AB - BACKGROUND: Prior studies suggest that obstructive sleep apnea may be associated with gastroesophageal reflux disease, a strong risk factor for Barrett's esophagus. The goals of this pilot case-control study were to determine whether Barrett's esophagus patients have an increased likelihood of obstructive sleep apnea and to determine whether nocturnal gastroesophageal reflux symptoms affect the relationship between Barrett's esophagus and obstructive sleep apnea risk. METHODS: Patients with Barrett's esophagus completed the Berlin Questionnaire, a validated survey instrument identifying subjects at high risk for obstructive sleep apnea. Two outpatient control groups were recruited: 1) EGD Group, subjects matched to Barrett's esophagus cases by age, race, and gender with esophagogastroduodenoscopy negative for Barrett's esophagus; and 2) Colonoscopy Group, patients getting colonoscopy. Rates of scoring at high risk for obstructive sleep apnea were compared. Respondents were also questioned regarding severity of their typical gastroesophageal reflux symptoms and presence of nocturnal gastroesophageal reflux symptoms. RESULTS: The study included 287 patients (54 Barrett's esophagus, 62 EGD, and 171 colonoscopy subjects). Barrett's esophagus patients were slightly older than colonoscopy patients and more obese. 56% (n = 30) of Barrett's esophagus subjects scored at high risk for obstructive sleep apnea, compared with 42% (n = 26) of EGD subjects (OR 1.73, 95% CI [0.83, 3.62]) and 37% (n = 64) of colonoscopy patients (OR 2.08, 95% CI [1.12, 3.88]). The association between Barrett's esophagus and scoring at high risk for obstructive sleep apnea compared with colonoscopy patients disappeared after adjusting for age. Barrett's esophagus patients reported more severe typical heartburn and regurgitation symptoms than either control group. Among all subjects, patients with nocturnal reflux symptoms were more likely to score at high risk for obstructive sleep apnea than patients without nocturnal reflux. CONCLUSIONS: In this pilot study, a high proportion of Barrett's esophagus subjects scored at high risk for obstructive sleep apnea. Having Barrett's esophagus was associated with more severe gastroesophageal reflux symptoms, and nocturnal reflux symptoms were associated with scoring at high risk for obstructive sleep apnea. The need for obstructive sleep apnea screening in Barrett's esophagus patients with nocturnal gastroesophageal reflux symptoms should be further evaluated. PMID- 23663218 TI - Problems experienced by gynecologists/obstetricians in sickness certification consultations. AB - OBJECTIVE: To explore frequencies and experiences with problems in sickness certification consultations among gynecologists and obstetricians in two different years. DESIGN: Cross-sectional surveys on two occasions; in 2004 and 2008. SETTING: Gynecological, obstetric and maternal health care. SAMPLE: Physicians working in gynecology, obstetrics or maternal health care in two Swedish counties from two samples: in 2004 (n = 315), and in 2008 (n = 327). METHODS: Data regarding sickness certification consultations were obtained from comprehensive questionnaires that had been mailed to the physicians in two Swedish counties in 2004 and in 2008, respectively. OUTCOME MEASURES: Frequencies and types of problems in sickness certification consultations, organizational support, and need to acquire more competence. RESULTS: The majority experienced that patients requested to be on sick leave for a reason other than work incapacity due to disease or injury, at least a few times per year (85% in 2004 and 88% in 2008). The most problematic situation to handle was when the physician and the patient had different opinions about the need for sick leave (2004: 66% and 2008: 58%). The physicians expressed a need for more competence about the options and responsibilities of employers, social insurance officers and physicians in sickness certification cases. CONCLUSIONS: Most gynecologists/obstetricians find sickness certification consultations problematic and especially when encountering patients requesting to be on sick leave for reasons other than disease. The physicians expressed a need for more competence in insurance medicine, especially about their own and other stakeholders' options and responsibilities. PMID- 23663219 TI - Epidermolysis bullosa pruriginosa triggered by scabies infestation. AB - Epidermolysis bullosa pruriginosa (EB-Pr) is an unusual variant of dystrophic EB. Potential genetic disease modifiers and metabolic factors have been investigated, but thus far no specific insight into this phenotype has emerged. We report an in depth description of three patients diagnosed as having EB-Pr in whom this particular phenotype developed after scabies infestation and dramatically improved after full treatment. This short communication suggests that scabies infestation could be one of the important triggering factors for the development of the EB-Pr phenotype. PMID- 23663220 TI - The development of Japanese passive syntax as indexed by structural priming in comprehension. AB - A number of previous studies reported a phenomenon of syntactic priming with young children as evidence for cognitive representations required for processing syntactic structures. However, it remains unclear how syntactic priming reflects children's grammatical competence. The current study investigated structural priming of the Japanese passive structure with 5- and 6-year-old children in a visual-world setting. Our results showed a priming effect as anticipatory eye movements to an upcoming referent in these children but the effect was significantly stronger in magnitude in 6-year-olds than in 5-year-olds. Consistently, the responses to comprehension questions revealed that 6-year-olds produced a greater number of correct answers and more answers using the passive structure than 5-year-olds. We also tested adult participants who showed even stronger priming than the children. The results together revealed that language users with the greater linguistic competence with the passives exhibited stronger priming, demonstrating a tight relationship between the effect of priming and the development of grammatical competence. Furthermore, we found that the magnitude of the priming effect decreased over time. We interpret these results in the light of an error-based learning account. Our results also provided evidence for prehead as well as head-independent priming. PMID- 23663221 TI - Radiographic configuration and healing of 121 fractures of the proximal phalanx in 120 Thoroughbred racehorses (2007-2011). AB - REASONS FOR PERFORMING STUDY: Although fractures of the proximal phalanx are one of the most common long bone fractures of Thoroughbred horses in training, limited details on variations in morphology and radiological progression have been published. OBJECTIVES: To describe in detail the configuration of parasagittal fractures of the proximal phalanx in a group of Thoroughbred racehorses, to report fracture distribution within this group of horses and to document radiological progression of fracture healing in cases treated by internal fixation. STUDY DESIGN: Restrospective case series. METHODS: Case records and radiographs of Thoroughbred racehorses with parasagittal fractures of the proximal phalanx admitted to Newmarket Equine Hospital between 2007 and 2011 were analysed. RESULTS: One hundred and twenty-one fractures were identified in 120 Thoroughbred racehorses. Fractures were frequently more complex than was appreciated immediately following injury; a feature that has not been reported previously. There was seasonality of fractures in 2- and 3-year-old horses, but not in older horses. CONCLUSIONS AND POTENTIAL RELEVANCE: Fractures of the proximal phalanx may be more complex than recognised previously, although often their complexity cannot be identified radiographically immediately following injury. The seasonality observed in 2- and 3-year-old horses is most likely to be a consequence of the timing of the turf-racing season in the UK. The Summary is available in Chinese - see Supporting information. PMID- 23663222 TI - Functional analysis of novel variants in the organic cation/ergothioneine transporter 1 identified in Singapore populations. AB - The human organic cation/ergothioneine transporter 1 (hOCTN1, gene symbol SLC22A4) is responsible for the cellular uptake of substances, such as L ergothioneine, which is an important antioxidant in mammalian cells. The common function-altered variant L503F-hOCTN1 has been associated with susceptibility to Crohn's disease in certain populations. Previously, we identified eight novel nonsynonymous single-nucleotide polymorphisms (SNPs) in the SLC22A4 gene in the Chinese and Indian populations of Singapore. The present study evaluated the impact of these novel SNPs on hOCTN1 transport function in HEK-293 cells. Transport uptake assays with L-ergothioneine were used to assess the function of the variant transporters. Cell surface biotinylation and Western blot analysis were used to characterize cellular transporter expression. Comparative modeling was used to locate amino acid substitutions in the topology of hOCTN1 in order to account for altered transport function. Transporter activity was markedly impaired in four of the naturally occurring hOCTN1 variants (R63H, R83P, G482D, and I500N). Multiple glycosylated isoforms of hOCTN1 proteins were identified in the plasma membrane and in the whole cell. Either the total cellular or membrane expression of the functionally deficient transporter variants was lower than that of the wild-type hOCTN1. The underlying mechanism involves both impaired transporter-substrate binding affinity and turnover rate. Considered together, several naturally occurring SNPs in the SLC22A4 gene encode variant hOCTN1 transporters that may impact the cellular uptake of L-ergothioneine and other substrates, with the potential to influence the antioxidant capacity of human cells. PMID- 23663223 TI - A retrospective cross-sectional study: fresh cycle endometrial thickness is a sensitive predictor of inadequate endometrial thickness in frozen embryo transfer cycles. AB - BACKGROUND: The purpose of this study is to assess predictors of inadequate endometrial cavity thickness (ECT), defined as < 8 mm, in frozen embryo transfer (FET) cycles. METHODS: This is a retrospective cross-sectional study at an academic fertility center including 274 women who underwent their first endometrial preparation with estradiol for autologous FET in our center from 2001 2009. Multivariable logistic regression was performed to determine predictors of inadequate endometrial development in FET cycles. RESULTS: Neither age nor duration of estrogen supplementation were associated with FET endometrial thickness. Lower body mass index, nulliparity, previous operative hysteroscopy and thinner fresh cycle endometrial lining were associated with inadequate endometrial thickness in FET cycles. A maximum thickness of 11.5 mm in a fresh cycle was 80% sensitive and 70% specific for inadequate frozen cycle thickness. CONCLUSIONS: Previous fresh cycle endometrial cavity thickness is associated with subsequent FET cycle endometrial cavity thickness. Women with a fresh cycle thickness of 11.5 mm or less may require additional intervention to achieve adequate endometrial thickness in preparation for a frozen cycle. PMID- 23663225 TI - Detection of specific antibodies against West Nile and Usutu viruses in healthy blood donors in northern Italy, 2010-2011. AB - Neutralizing antibodies against West Nile (WNV) and Usutu (USUV) viruses were measured in 6000 samples collected, between 1 September 2010 and 30 June 2011, from blood donors living in different districts of Emilia-Romagna, northeastern Italy. On the basis of the microneutralization assay (MNTA), 47 (0.78%) subjects were positive for WNV and 14 (0.23%) for USUV. These results were compared with those obtained 2 years ago and suggest an increased circulation of USUV among humans in Emilia-Romagna. PMID- 23663224 TI - An investigation of factors identified at birth in relation to anxiety and depression in old age: the Hordaland Health Study (HUSK). AB - BACKGROUND: Although life course influences have long been recognised in affective disorder, little is known about the influence of early life factors on late life anxiety and depression. The aim was to investigate the extent to which birth measures, maternal health and family circumstances were associated with symptoms of anxiety and depression in late life. METHODS: A retrospective cohort study was constructed from a cross-sectional survey sample of community residents aged 72-74 years, 406 of whom had traceable birth records. Cases and controls for late life anxiety and depression were defined applying standard cut-offs to the Hospital Anxiety and Depression Scale. A range of measures and circumstances were extracted from birth records blind to survey data and compared in age- and gender adjusted models. RESULTS: There were no differences in any anthropometric measure in either case control comparison. Case-level anxiety and depression were both associated with significantly lower maternal age. Late-life anxiety was additionally associated with smaller maternal pelvic size and the mother's condition being rated as poor at birth/discharge. Late-life depression was associated with a lower status paternal occupation. CONCLUSIONS: There was no evidence for a substantial influence of early life size on late life affective disorder. However, there was some evidence in secondary analyses for an enduring influence of the family's socioeconomic environment and maternal health. PMID- 23663226 TI - Role of the N-terminal signal peptide in the membrane insertion of Aquifex aeolicus F1F0 ATP synthase c-subunit. AB - Rotary ATPases are membrane protein complexes that couple ATP hydrolysis to ion translocation across the membrane. Overall, they are evolutionarily well conserved, but the N-terminal segments of their rotary subunits (c-subunits) possess different lengths and levels of hydrophobicity across species. By analyzing the N-terminal variability, we distinguish four phylogenetic groups of c-subunits (groups 1-4). We characterize a member of group 2, the c-subunit from Aquifex aeolicus F1F0 ATP synthase, both in native cells and in a heterologous expression system. We demonstrate that its N-terminal segment forms a signal peptide with signal recognition particle (SRP) recognition features and is obligatorily required for membrane insertion. Based on our study and on previous characterizations of c-subunits from other organisms, we propose that c-subunits follow different membrane insertion pathways. PMID- 23663227 TI - Protective effects of stem bark of Harungana madgascariensis on the red blood cell membrane. AB - BACKGROUND: Anemia is a condition that has multiple origins. One such origin is the destruction of red blood cells' (RBCs) membrane induced by free radicals. Treatment of anemia could therefore be enhanced by the use of free radicals' scavengers potentially found in some medicinal plants. In this study, the protective effect of Harungana madagascariensis on the RBCs' membrane physiology was investigated in vitro and in vivo. METHODS: In vitro hemolytic anemia was induced by incubation of fresh human RBCs with carbontetrachloride (CCl4) in Olive oil (Oo). Relaxation times of protons excited at 20 MHz (Carr-Purcell Meiboom-Gill pulse sequence) in the absence or presence of paramagnetic Mn2+ ions (T2i for "extracellular" water and T2a for "intracellular" water, respectively) were determined at several temperatures (25-37 degrees C) via Nuclear Magnetic Resonance (NMR) on a Bruker Minispec spectrometer. Water exchange times (Te) were consequently calculated using the Conlon-Outhred equation: 1/Te = (1/T2a) - (1/T2i). Morphological characteristics (mean cell volume, V, and cell surface area, A) were determined by photonic microscopy and the RBCs' diffusional water permeability (Pd) was calculated as Pd = (1/Te)*(Va/A), where Va is the aqueous volume in the RBC and is about 0.7 of the cell volume (V). The activation energy of the diffusional process (Ea) for the respective temperature range was estimated using the Arrhenius modified equation k = A(T/T0)n*e-Ea/RT. Inhibition of the water diffusion induced by incubation with para-chloro-mercuribenzoic acid (PCMB) at 25, 30 and 37 degrees C was calculated as I(%) = [(Pd control - Pd sample)/Pd control]*100.To investigate the protective influence of the extract on the RBC membrane, inhibition of the water permeability was evaluated on membranes pre-incubated with the Harungana madagascariensis extract. Male rats were used in in vivo investigations. Malondialdehyde (MDA) and cholesterol in the RBC membrane were estimated by induction of lipid peroxidation while the antioxidant properties of catalase (CAT) and superoxide dismutase (SOD) on the membrane were evaluated in regard to their antioxidant properties on the membrane. RESULTS: T2a significantly decreased at each temperature. Te results were higher in both RBCs and RBCs + extract groups incubated with PCMB compared to non-incubated controls, but differences were not statistically significant. A high percentage (73.81 +/- 7.22) of RBCs pre-incubated with the extract presented the regular biconcave shape. Inhibition by PCMB of the RBCs' membrane water permeability was increased at 30 degrees C and decreased in the presence of extract (25 degrees C and 37 degrees C), while Ea decreased from 30.52 +/- 1.3 KJ/mol to 25.49 +/- 1.84 KJ/mol. Presence of the Harungana madagascariensis extract normalized the SOD and CAT activities as well as the MDA and membrane cholesterol concentrations altered by the CCl4-induced oxidative stress. CONCLUSION: Harungana madagascariensis could protect the RBCs' membrane through its antioxidative properties. PMID- 23663228 TI - Low-intensity focused ultrasound pulsation device used during magnetic resonance imaging: evaluation of magnetic resonance imaging-related heating at 3 Tesla/128 MHz. AB - OBJECTIVE: The objective of this study was to determine magnetic resonance imaging (MRI)-related heating for a low-intensity focused ultrasound pulsation (LIFUP) device used during MRI performed at 3 T/128 MHz. MATERIALS AND METHODS: A special phantom was constructed to mimic the thermal properties of the human brain, and a piece of human temporal bone (skull) was embedded on top. Four fluoroptic thermometry probes, placed above and below the skull, were used to measure temperature changes during MRI (3 T/128 MHz; scanner-reported head average specific absorption rate 1.1-2 W/kg) with and without concurrent LIFUP sonication. LIFUP sonication was applied using a focused ultrasound device (BXPulsar 1001, Brainsonix, Inc., Los Angeles, CA, USA) at a derated spatial-peak temporal-average intensity of 3870 mW/cm(2) . RESULTS: MRI performed at relatively high specific absorption rate (SAR) caused a slight elevation in temperature (<=0.6 degrees C). Concurrent use of MRI at a medium-strength SAR and LIFUP sonication resulted in maximum temperature rise of 3.1 degrees C after 8 min of continuous use. CONCLUSIONS: Under the specific conditions utilized for this investigation, LIFUP sonication does not appear to present significant heating risks when used concurrently with MRI. This information has important implications for the use of the LIFUP sonication in human subjects undergoing MRI at 3 T/128 MHz. PMID- 23663229 TI - Racial/Ethnic differences in receipt of timely adjuvant therapy for older women with breast cancer: are delays influenced by the hospitals where patients obtain surgical care? AB - OBJECTIVE: To examine whether hospitals where patients obtain care explain racial/ethnic differences in treatment delay. DATA SOURCE: Surveillance, Epidemiology, and End Results data linked with Medicare claims. STUDY DESIGN: We examined delays in adjuvant chemotherapy or radiation for women diagnosed with stage I-III breast cancer during 1992-2007. We used multivariable logistic regression to assess the probability of delay by race/ethnicity and included hospital fixed effects to assess whether hospitals explained disparities. PRINCIPAL FINDINGS: Among 54,592 women, black (11.9 percent) and Hispanic (9.9 percent) women had more delays than whites (7.8 percent, p < .0001). After adjustment, black (vs. white) women had higher odds of delay (odds ratio = 1.25, 95 percent confidence interval = 1.10-1.42), attenuated somewhat by including hospital fixed effects (OR = 1.17, 95 percent CI = 1.02-1.33). CONCLUSIONS: Hospitals are the important contributors to racial disparities in treatment delay. PMID- 23663230 TI - External quality assessment of human neutrophil antigen (HNA)-specific antibody detection and HNA genotyping from 2000 to 2012. AB - Since 2000, Quality Assurance (QA) exercises for the detection and identification of granulocyte antibodies and DNA typing for human neutrophil antigens (HNA) have been distributed within the International Granulocyte Immunobiology Workshops, which are linked to International Society of Blood Transfusion. The exercises were standardised at the outset to enable laboratory performance to be monitored. Between 2000 and 2012, nine exercises were distributed to 20 laboratories. Overall, 45 examples of 42 unique samples containing defined granulocyte reactive antibodies were distributed for serological analysis together with 20 samples for HNA genotyping. The level of satisfactory serological performance was initially set at 50% and later increased to 70%, while the 'cut-off' for HNA genotyping was set at 100% after 2008. Failure to achieve the minimum score in the QA exercises in consecutive years resulted in temporary exclusion. In 2000, the 15 participating laboratories had a mean score of 56.1% for serological analysis and 13 laboratories attempted HNA-1a and -1b genotyping, while 11 attempted HNA-1c typing. Steady improvements in proficiency for serological testing and HNA typing occurred in subsequent exercises. In 2012, the mean score for serology was 88.5% and 12/13 laboratories scored 100% for HNA-1a, -1b, -1c, -3a, -3b, -4a, -4bw, -5a and -5bw genotyping. These QA exercises have provided an invaluable tool to monitor and improve the standard of granulocyte immunology investigations for participating laboratories, thereby enhancing performance for both clinical investigations and donor screening programmes to reduce the incidence of TRALI. PMID- 23663231 TI - A comprehensive pathological survey of duodenal biopsies from dogs with diet responsive chronic enteropathy. AB - BACKGROUND: The detailed pathological phenotype of diet-responsive chronic enteropathy (CE) and its modulation with dietary therapy remain poorly characterized. HYPOTHESIS/OBJECTIVES: Key mucosal lesions of diet-responsive CE resolve with dietary therapy. METHODS: This was a prospective observational study of 20 dogs with diet-responsive CE. Endoscopic duodenal biopsies collected before and 6 weeks after the start of a dietary trial were assessed by means of qualitative and quantitative histopathological, immunohistochemical, and ultrastructural criteria. Control duodenal biopsies were obtained from 10 healthy Beagle dogs on 1 occasion. RESULTS: Compared with control dogs, the CE dogs had higher villus stunting scores and higher overall WSAVA scores, a lower villus height-to-width ratio, and higher lamina propria density of eosinophils. The CE dogs also had ultrastructural lesions of the mitochondria and brush border. In common with other studies in which the disease and control populations are not matched for breed, age, sex, and environment, these comparisons should be interpreted with caution. Comparing biopsies collected at presentation and 6 weeks after starting the dietary trial, mean lamina propria mononuclear cell score and lamina propria densities of eosinophils and mononuclear cells decreased. Dietary therapy also improved ultrastructural lesions of the mitochondria and brush border, eliciting a decrease in intermicrovillar space and an increase in microvillus height. CONCLUSIONS AND CLINICAL IMPORTANCE: In dogs with diet-responsive CE, the remission of clinical signs with dietary therapy is associated with subtle decreases in lamina propria density of eosinophils and mononuclear cells, and resolution of ultrastructural lesions of the enterocyte. PMID- 23663232 TI - Why go online when you have pain? A qualitative analysis of teenagers' use of the Internet for pain management advice. AB - BACKGROUND: Adolescents are routinely recognized as native to online technologies. However, we know from previous research that this familiarity does not often translate into its use for help-seeking around health. We designed this study to examine the experience of adolescents in using the Internet to access pain management information, specifically why some adolescents may be reluctant to use these resources. METHODS: Twenty-six healthy, school attending, adolescents aged between 14 and 17 years old were recruited to a qualitative study of focus groups. Seventeen participants were female and nine were male. Participation was limited to those who self-selected as frequent users of the Internet, but who were loath to use it as a resource for health information as we wished to explore reasons for non-use. All data were thematically analysed. RESULTS: Most participants reported using the Internet to seek health information at least once. Experiences with online content were typically negative and drawn on only when all other sources of information and pain coping were exhausted. Three themes emerged, Drivers of Internet use, Barriers, and Anxiety around use. Adolescent health websites were reported to be confusing, anxiety provoking and hard to negotiate. The Internet was judged to be less accessible than other forms of pain and health coping information. Secondary themes related to topic embarrassment, the strive for independence and reassurance, preferred information source failure, curiosity, website design, availability of OTC analgesics, effort, fear-provoking narratives, mistrust of quality of online content and pain related anxiety. CONCLUSIONS: Counter to many positive reports of the health benefits of Internet use during information seeking, its value is questionable to some adolescents. Typical experience was anxiety provoking, unlikely to yield helpful results, and wasteful comparative to off-line resources for pain. PMID- 23663233 TI - Interaction of small RNA-8105 and the intron of IbMYB1 RNA regulates IbMYB1 family genes through secondary siRNAs and DNA methylation after wounding. AB - Small RNAs (sRNAs) play important roles in plants under stress conditions. However, limited research has been performed on the sRNAs involved in plant wound responses. In the present study, a novel wounding-induced sRNA, sRNA8105, was identified in sweet potato (Ipomoea batatas cv. Tainung 57) using microarray analysis. It was found that expression of sRNA8105 increased after mechanical wounding. Furthermore, Dicer-like 1 (DCL1) is required for the sRNA8105 precursor (pre-sRNA8105) to generate 22 and 24 nt mature sRNA8105. sRNA8105 targeted the first intron of IbMYB1 (MYB domain protein 1) before RNA splicing, and mediated RNA cleavage and DNA methylation of IbMYB1. The interaction between sRNA8105 and IbMYB1 was confirmed by cleavage site mapping, agro-infiltration analyses, and use of a transgenic sweet potato over-expressing pre-sRNA8105 gene. Induction of IbMYB1-siRNA was observed in the wild-type upon wounding and in transgenic sweet potato over-expressing pre-sRNA8105 gene without wounding, resulting in decreased expression of the whole IbMYB1 gene family, i.e. IbMYB1 and the IbMYB2 genes, and thus directing metabolic flux toward biosynthesis of lignin in the phenylpropanoid pathway. In conclusion, sRNA8105 induced by wounding binds to the first intron of IbMYB1 RNA to methylate IbMYB1, cleave IbMYB1 RNA, and trigger production of secondary siRNAs, further repressing the expression of the IbMYB1 family genes and regulating the phenylpropanoid pathway. PMID- 23663234 TI - Adjuvant therapy with carboplatin and pamidronate for canine appendicular osteosarcoma. AB - Amputation and chemotherapy are the mainstay of treatment for canine appendicular osteosarcoma (OSA). In vitro studies have demonstrated anti-tumour activity of pamidronate against canine OSA. The purpose of this study was to assess the safety of adding pamidronate to standard post-operative carboplatin chemotherapy in 17 dogs with appendicular OSA treated with limb amputation. Median disease free interval (DFI) and median survival time (MST) were evaluated as secondary endpoints. Incidence of side effects and treatment outcomes were compared to 14 contemporary control patients treated with carboplatin alone. There were no identified side effects to the pamidronate treatment. The median DFI for the study group was 185 days compared to 172 days for the control group (P = 0.90). The MST of the study group was 311 days compared to 294 days for the control group (P = 0.89). Addition of pamidronate to carboplatin chemotherapy for the treatment of canine appendicular OSA is safe and does not impair efficacy of standard carboplatin treatment. PMID- 23663235 TI - Lean red meat consumption and lipid profiles in adolescent girls. AB - BACKGROUND: Epidemiological studies of red meat consumption often fail to distinguish between leaner and fattier or processed cuts of meat. Red meat has also been frequently linked with less healthy diet patterns. Data exploring the health effects of lean red meat in younger individuals are scarce, particularly in the context of a healthy diet. The present study examined the effects of lean red meat in combination with higher intakes of fruit/nonstarchy vegetables on lipid profiles in older adolescent girls. METHODS: Data from 1461 girls who were followed for 10 years, starting at 9-10 years of age, in the National Heart Lung and Blood Institute Growth and Health Study were used. Diet was assessed using multiple sets of 3-day records collected over eight examination cycles. Outcome measures included fasting levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C and triglycerides at age 18-20 years. RESULTS: After adjusting for age, race, socioeconomic status, height, activity level, hours of television per day, and intakes of whole grains and dairy foods using multivariable modelling, girls consuming >=6 oz lean red meat per week combined with two or more servings of fruit/nonstarchy vegetables per day had LDL-C levels approximately 6-7 mg dL(-1) lower (P < 0.05) than girls with lower intakes of lean red meat and fruit/nonstarchy vegetables. In addition, girls with higher intakes of both were 33% less likely (odds ratio = 0.67, 95% confidence interval = 0.48-0.94) to have an LDL-C >=110 mg dL(-1) and 41% less likely (odds ratio = 0.59, 95% confidence interval = 0.42-0.83) to have an elevated LDL : HDL ratio (>=2.2) at the end of adolescence. CONCLUSIONS: These analyses suggest that lean red meat may be included in a healthy adolescent diet without unfavourable effects on lipid values. PMID- 23663236 TI - Delayed brain ischemia tolerance induced by electroacupuncture pretreatment is mediated via MCP-induced protein 1. AB - BACKGROUND: Emerging studies have demonstrated that pretreatment with electroacupuncture (EA) induces significant tolerance to focal cerebral ischemia. The present study seeks to determine the involvement of monocyte chemotactic protein-induced protein 1 (MCPIP1), a recently identified novel modulator of inflammatory reactions, in the cerebral neuroprotection conferred by EA pretreatment in the animal model of focal cerebral ischemia and to elucidate the mechanisms of EA pretreatment-induced ischemic brain tolerance. METHODS: Twenty four hours after the end of the last EA pretreatment, focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 90 minutes in male C57BL/6 mice and MCPIP1 knockout mice. Transcription and expression of MCPIP1 gene was monitored by qRT-PCR, Western blot and immunohistochemistry. The neurobehavioral scores, infarction volumes, proinflammatory cytokines and leukocyte infiltration in brain and NF-kappaB signaling were evaluated after ischemia/reperfusion. RESULTS: MCPIP1 protein and mRNA levels significantly increased specifically in mouse brain undergoing EA pretreatment. EA pretreatment significantly attenuated the infarct volume, neurological deficits, upregulation of proinflammatory cytokines and leukocyte infiltration in the brain of wild-type mice after MCAO compared with that of the non-EA group. MCPIP1-deficient mice failed to evoke EA pretreatment-induced tolerance compared with that of the control MCPIP1 knockout group without EA treatment. Furthermore, the activation of NF-kappaB signaling was significantly reduced in EA-pretreated wild-type mice after MCAO compared to that of the non-EA control group and MCPIP1-deficient mice failed to confer the EA pretreatment-induced inhibition of NF-kappaB signaling after MCAO. CONCLUSIONS: Our data demonstrated that MCPIP1 deficiency caused significant lack of EA pretreatment-induced cerebral protective effects after MCAO compared with the control group and that MCPIP1 is involved in EA pretreatment-induced delayed brain ischemia tolerance. PMID- 23663237 TI - Dexamethasone uptake in the murine organ of Corti with transtympanic versus systemic administration. AB - OBJECTIVE: To investigate glucocorticoid uptake in auditory hair cells following transtympanic versus systemic administration of dexamethasone. STUDY DESIGN: Controlled experimental study. SETTING: Translational science experimental laboratory. METHODS: Swiss-Webster mice were injected with dexamethasone via transtympanic or systemic administration. At 1, 6, or 12 hours post-injection the temporal bones were harvested. After cryosectioning, immunohistochemical staining was performed using an antibody for dexamethasone. RESULTS: Dexamethasone labelling was greatest at 1 hour. Inner hair cells demonstrated much higher steroid uptake than outer hair cells. Both transtympanic injection and high-dose systemic administration resulted in strong dexamethasone labelling of hair cells, and a decreasing basal-to-apical gradient of hair cell fluorescence intensity was observed. Systemically delivered dexamethasone was rapidly eliminated from the inner ear, demonstrating mild labelling after 6 hours and none after 12 hours. In contrast, the mice receiving transtympanic injection had persistent moderate intensity fluorescence at 6 and 12 hours post-injection. CONCLUSION: There is similar uptake of dexamethasone by auditory hair cells after transtympanic and high-dose systemic delivery. Novel findings include the presence of a decreasing basal-apical gradient of steroid uptake, and demonstration of greater affinity of inner hair cells for dexamethasone compared to outer hair cells. In this animal model transtympanic injection resulted in prolonged steroid uptake. These findings help further our understanding of the pharmacokinetics of steroids in the cochlea, with a focus on auditory hair cells. PMID- 23663238 TI - Open-irrigated laser catheter ablation produces flow-dependent sizes of lesions. AB - BACKGROUND: Growth and sizes of lesions produced during catheter ablation is difficult to control. Laser lesion formation was evaluated during various flow rates and energy settings by using an open-irrigated laser catheter on a thigh muscle dog model. METHODS: Laser radiation at 15 W or 20 W was applied in blood for 10 seconds, 20 seconds, 30 seconds, 40 seconds, and 50 seconds during an irrigation flow of 16 mL/min or 35 mL/min, in direct contact, and in a noncontact mode of laser application. Lesions were evaluated morphometrically. RESULTS: There was a linear increase of lesions with the increase of the level of energy applied. Maximal depth of lesions achieved during a flow rate of 16 mL/min at 15 W/50 seconds increased significantly from 9.9 +/- 0.3 mm to 12.1 +/- 0.5 mm, and at 20 W/50 seconds from 11.1 +/- 0.55 mm to 12.4 +/- 0.26 mm, when irrigation flow was 35 mL/min (P < 0.5). However, difference of lesion increase between 15 W and 20 W was not significant (P = 0.30). Lesions were achieved also in a noncontact mode of radiation at a distance of 1-2 mm, but not at 5 mm away. Radiation at 20 W > 40 seconds and a flow rate of 35 mL/min may cause steam pop with intramural cavitation. CONCLUSIONS: By using an open-irrigated laser catheter augmentation of catheter flow increases lesion sizes. Lesions can be achieved also in a noncontact mode of radiation. In order to avoid unwanted effects the level of energy applied must be limited. PMID- 23663239 TI - Protocol for systematic reviews of determinants/correlates of obesity-related dietary and physical activity behaviors in young children (preschool 0 to 6 years): evidence mapping and syntheses. AB - BACKGROUND: The aim of these reviews is to inform the design and content of interventions to reduce obesity in young children. The behaviors that are associated with obesity/overweight have been studied extensively; however, the factors associated with these behaviors in young children (0 to 6 years) have not been systematically reviewed. Over the past few years the focus of obesity prevention has shifted to preschool children because of the high prevalence of obesity at school entry and recognition that habits formed in early life could track into adulthood. In order to develop effective interventions and change behavior, it is important to understand the factors that are associated with those behaviors. For example, we need to understand whether it would be more important to target the family, childcare settings or the wider environment and identify the most effective way of changing these energy balance related behaviors. METHODS/DESIGN: Quantitative (intervention and observational) and qualitative literature on determinants/correlates of fruit and vegetable intake, sugar sweetened beverage and other unhealthy diet intake, and physical activity and sedentary behaviors in young children will be systematically identified, mapped and reviewed. A common search strategy (no language or period restrictions) will be used to identify papers from eight electronic databases and this will be supplemented by hand-searching. Next, studies in developed countries that examine the factors associated with these behaviors in children aged 0 to 6 years (at baseline) will be screened and mapped descriptively followed by in depth data extraction, quality assessment and synthesis. Data from quantitative studies will be summarized using either forest plots or harvest plots and narrative synthesis, and qualitative studies using thematic analysis. Qualitative evidence will be integrated with the quantitative evidence, using a parallel synthesis approach, to provide a deeper understanding of effective strategies to influence these energy balance related behaviors. DISCUSSION: In addition to updating and mapping current research, these reviews will be the first to comprehensively synthesize and integrate both the quantitative and qualitative evidence pertaining to determinants/correlates/barriers/facilitators of obesity related behaviors in this young age group (0 to 6 years) with the aim of informing future interventions. TRIAL REGISTRATION: International Prospective Register for Systematic Reviews (PROSPERO) Registration number: CRD42012002881. PMID- 23663241 TI - Percutaneous cartilage injection: a prospective animal study on a rabbit model. AB - BACKGROUND: Cartilage grafting is a useful technique in nasal reconstruction. Implantation of a whole graft is usually done through an incision. Crushed cartilage can also be used. Injection of cartilage could be an alternative to implantation. The objective of this study is to compare the long-term viability of percutaneously injected crushed auricular cartilage to surgically implanted cartilage in the rabbit. METHODS: Auricular cartilage was harvested bilaterally in 10 New Zealand white rabbits. A 1 cm2 cartilage graft was implanted surgically on the upper nasal dorsum. The remaining cartilage was crushed and percutaneously injected on the lower nasal dorsum. Volume and mass of each graft were compared between pre-implantation and after 3 months of observation. A histological study was conducted to evaluate chondrocyte viability and degree of fibrosis on pre and post-implantation cartilage. RESULTS: Mass and volume remained similar for surgically implanted cartilage grafts. Mass and volume diminished by an average of 47% and 40% respectively after 3 months for the injected crushed cartilage grafts. Chondrocyte viability was an average of 25% lower in the injected grafts. CONCLUSIONS: Cartilage injection is a promising technique that must be refined to increase chondrocyte viability. Developing an appropriate injection apparatus would improve this technique. PMID- 23663240 TI - How oncologists communicate information to women with recurrent ovarian cancer in the context of treatment decision making in the medical encounter. AB - BACKGROUND: Women with recurrent ovarian cancer depend on their physicians to provide them with information about their diagnosis and available treatment options if they wish to participate in the process of choosing the treatment. There is no information on how oncologists give information to women during the physician-patient encounter at the time the disease recurs. OBJECTIVES: To explore from the oncologists' perspective (i) the extent to which oncologists provide their own patients who are experiencing their first recurrence of ovarian cancer with the same information about management options, and (ii) any explicit or implicit criteria they use to decide whether and how to tailor the information to individual patients. METHODS: We adopted a qualitative, exploratory descriptive approach to begin to understand oncologists' perspectives on how they gave information to patients within the context of their clinical practice. Individual interviews were used to identify themes related to the study objectives. RESULTS: Fifteen gynaecologic and five medical oncologists participated. Theme 1 describes the extent to which oncologists give information to their patients in the same way or in different ways. This section describes how the same oncologist may modify the depth of information transfer based on several factors. Theme 2 focuses on the factors that influence what information is given. For example, the amount and type of information given is based on the oncologist's on-going assessment of how the patient is assimilating the information shared during the medical encounter, the oncologists' perception of their relationship with the patient and the oncologist's assessment of what role they should take in decision making. Theme 3 involves the factors that influenced how information is given. For example, the information shared may vary based on the oncologist's perception of the patient's vitality, the patient's comprehension of the information, the patient's emotional well-being. In addition, the oncologist may make the information relevant for the patient by using analogies. Different types of information may be shared based on the oncologist's perception of patient- or family-initiated question. The information relay may be curtailed based on competing demands for the oncologist. DISCUSSION AND CONCLUSIONS: Oncologists provide women with information on their disease status, their treatment options and the side effects of treatment. The oncologists use perceptions to determine what information and how to provide information. The question this paper raises is whether the oncologist's perceptions reflect the individual patient's information and decision-making needs. PMID- 23663242 TI - Case of epidermal cyst on the glans penis. PMID- 23663243 TI - Expression of pAkt affects p53 codon 72 polymorphism-based prediction of response to radiotherapy in nasopharyngeal carcinoma. AB - BACKGROUND: Codon 72 (Arg/Pro), the most frequently studied single nucleotide polymorphism (SNP) of p53 to date, is associated with the ability of the gene to induce cell apoptosis. The PI3K/Akt pathway plays an essential role in the transcriptional activation function of p53, and is an important factor in radiotherapy resistance. The present study was designed to evaluate the prediction of response to radiotherapy based on p53 codon 72 SNP and pAkt expression in biopsy specimens of locoregional nasopharyngeal carcinoma (NPC) before treatment. MATERIALS AND METHODS: In total, 75 consecutive patients with locoregional NPC were enrolled. The p53 codon 72 SNP was identified from retrospectively collected paraffin-embedded biopsy specimens using Sanger sequencing. Expression patterns of p53, p21, 14-3-3sigma, and pAkt proteins were investigated using immunohistochemical analyses. The effects of genetic polymorphisms and protein expression on progression-free survival (PFS) were evaluated using the Cox proportional hazards model, Kaplan-Meier method, and log rank test. RESULTS: The p53 codon 72 Pro/Pro carriers showed lower risk of disease progression (local recurrence and distant metastases) (HR: 0.300; 95% CI: 0.092-0.983; p=0.047). However, this association between the p53 codon 72 polymorphism and PFS was not significant in the pAkt-positive subgroup. No association was observed between protein expression of p53, p21 or 14-3-3sigma and p53 codon72 polymorphisms. Notably, positive expression of p53 protein appeared to be correlated with poorer PFS among patients diagnosed as local regional lymph node metastasis (N+) before treatment (p=0.032). CONCLUSIONS: The p53 codon 72 Pro/Pro genotype may be an effective independent prognostic marker for better outcome in patients with locoregional NPC. Based on the current findings, we hypothesize that pAkt weakens the predictive value of p53 codon 72 SNP in NPC. A combination of positive p53 protein expression and local regional lymph node metastasis may additionally be predictive of high risk of disease progression. PMID- 23663244 TI - The significance of rhinovirus detection in hospitalized children: clinical, epidemiological and virological features. AB - Recent developments in molecular diagnostic tools have led to the easy and rapid detection of a large number of rhinovirus (HRV) strains. However, the lack of clinical and epidemiological data hampers the interpretation of these diagnostic findings. From October 2009 to January 2011, we conducted a prospective study in hospitalized children from whom samples were taken for the detection of respiratory viruses. Clinical, epidemiological and microbiological data from 644 patients with 904 disease episodes were collected. When HRV tested positive, strains were further characterized by sequencing the VP4/VP2 region of the HRV genome. HRV was the single respiratory virus detected in 254 disease episodes (28%). Overall, 99 different serotypes were detected (47% HRV-A, 12% HRV-B, 39% HRV-C). Patients with HRV had more underlying pulmonary illness compared with patients with no virus (p 0.01), or patients with another respiratory virus besides HRV (p 0.007). Furthermore, cough, shortness of breath and a need for oxygen were significantly more present in patients with HRV infection. Particularly, patients with HRV-B required extra oxygen. No respiratory symptom, except for oxygen need, was predictive of the presence of HRV. In 22% of HRV positive disease episodes, HRV infection was hospital acquired. Phylogenetic analysis revealed several clusters of HRV; in more than 25% of these clusters epidemiological information was suggestive of transmission within specific wards. In conclusion, the detection of HRV may help in explaining respiratory illness, particular in patients with pulmonary co-morbidities. Identifying HRV provides opportunities for timely implementation of infection control measures to prevent intra-hospital transmission. PMID- 23663245 TI - Lung cancer diagnosis on ovary mass: a case report. AB - Metastatic neoplasms to the ovary often cause diagnostic problems, in particular those large ovarian masses mimicking primary tumors. Most of these tumors arise from digestive system or breast, while 37-year-old woman diagnosed as right adnexal complex mass, with a subpleural nodule in the apical part of the left lower lobe, at preoperative chest computed tomography scan. The patient underwent total abdominal hysterectomy with right salpingo-oophorectomy (ovarian mass 220 * 200 mm), total omentectomy, left ovarian biopsy, peritoneal random biopsies, and peritoneal washings for cytology. Pathologic and immunohistochemical examination of ovarian specimen suggested morphology and expression of metastatic lung adenocarcinoma with an intense positivity for Thyroid Transcriptional Factor-1 (TTF-1) and Cytokeratin 7 (CK7) staining. Fine needle biopsy of the lung nodule found epithelioid like malignant cells, confirming the diagnosis of an ovarian metastasis from a primary lung cancer.This report focused on the clinical and pathologic diagnostic challenge of distinguishing secondary from primary ovarian neoplasms. Issues on useful immunohistochemical stains are also discussed. PMID- 23663247 TI - Evaluation of hemostatic activity of canine frozen plasma for transfusion by thromboelastography. AB - BACKGROUND: In humans, fresh frozen plasma (FFP) loses factor V and VIII activities after 1 year. It then becomes frozen plasma (FP), and theoretically is unsuitable for use in patients with coagulopathies. These findings have not been reported for dogs. HYPOTHESIS: Canine FP is hemostatically active after 5 years of storage. ANIMALS: Fresh plasma (Group FsP; n = 15) and 5-year-old FP (Group FzP; n = 10) from blood bank donors. METHODS: Group FsP and Group FzP samples were evaluated by thromboelastography (TEG), one-stage prothrombin time (OSPT), activated partial thromboplastin time (APTT), fibrinogen, and antithrombin. Fresh plasma (n = 6) and a subset of Group FzP (n = 8) were evaluated for clotting factor activities (V, VIII, IX, X). A 2nd experiment using short-term storage of thawed FP under suboptimal conditions (refrigerated [4 degrees C] or refrozen [ 20 degrees C]) by TEG was performed to simulate general practice storage capabilities. RESULTS: Group FzP had shorter reaction time (P = .0007) and larger angle (P = .0004) compared with Group FsP by TEG, suggesting hypercoaguability. Factor VIII and X activities were lower in Group FzP (P = .02 and .005, respectively). Fibrinogen, OSPT, and APTT were significantly lower or longer for Group FzP than Group FsP (P < .05), but most values remained within reference intervals for dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: Five-year-old canine FP stored at -30 degrees C is hemostatically active and should be clinically evaluated in patients with coagulopathies. If active, the monetary savings of using older plasma will be substantial. PMID- 23663248 TI - Detectability of hypervascularity in early dynamic PET depends on tracer kinetics: 18 F-FDG versus 68 Ga-DOTATOC in hepatic NET metastasis. PMID- 23663246 TI - Genome of the long-living sacred lotus (Nelumbo nucifera Gaertn.). AB - BACKGROUND: Sacred lotus is a basal eudicot with agricultural, medicinal, cultural and religious importance. It was domesticated in Asia about 7,000 years ago, and cultivated for its rhizomes and seeds as a food crop. It is particularly noted for its 1,300-year seed longevity and exceptional water repellency, known as the lotus effect. The latter property is due to the nanoscopic closely packed protuberances of its self-cleaning leaf surface, which have been adapted for the manufacture of a self-cleaning industrial paint, Lotusan. RESULTS: The genome of the China Antique variety of the sacred lotus was sequenced with Illumina and 454 technologies, at respective depths of 101* and 5.2*. The final assembly has a contig N50 of 38.8 kbp and a scaffold N50 of 3.4 Mbp, and covers 86.5% of the estimated 929 Mbp total genome size. The genome notably lacks the paleo triplication observed in other eudicots, but reveals a lineage-specific duplication. The genome has evidence of slow evolution, with a 30% slower nucleotide mutation rate than observed in grape. Comparisons of the available sequenced genomes suggest a minimum gene set for vascular plants of 4,223 genes. Strikingly, the sacred lotus has 16 COG2132 multi-copper oxidase family proteins with root-specific expression; these are involved in root meristem phosphate starvation, reflecting adaptation to limited nutrient availability in an aquatic environment. CONCLUSIONS: The slow nucleotide substitution rate makes the sacred lotus a better resource than the current standard, grape, for reconstructing the pan-eudicot genome, and should therefore accelerate comparative analysis between eudicots and monocots. PMID- 23663249 TI - Calmodulin in a heartbeat. AB - Calmodulin is the primary sensor of intracellular calcium (Ca(2+)) levels in eukaryotic cells playing a key role in the proper deciphering of Ca(2+) signalling. Given the versatility of Ca(2+) as a secondary messenger, it is not surprising that calmodulin interacts with a vast number of proteins. Calmodulin is an extraordinarily conserved protein, which has not evolved since the genesis of the vertebrate lineage, and further is encoded by three different non-allelic genes in the human genome. The protein displays a high degree of conformational plasticity, allowing for target proteins to evolve specific modes of calmodulin interaction and regulation during Ca(2+) sensing. The recent identification of two calmodulin mutations giving rise to a heart arrhythmia with catecholaminergic polymorphic ventricular tachycardia-like symptoms and sudden cardiac death in young individuals, and the following identification of another three calmodulin mutations linked to recurrent cardiac arrest in infants, is in many ways intriguing. How can mutations result in cardiac-specific phenotypes when calmodulin is fundamental for correct Ca(2+) signal interpretation in virtually all cells in vertebrate organisms? Are there specific cardiac target protein interactions that are affected by these mutations? Another challenge is to elucidate how one mutated allele out of six encoding an identical calmodulin protein results in a dominant phenotype. Here we aim to give an overview of components in the cardiac contraction cycle whose function is modulated by calmodulin. In principle, these may all be implicated in the pathogenic molecular mechanism linking calmodulin mutations to cardiac arrhythmia and sudden cardiac death. PMID- 23663253 TI - Antioxidant activity and components of a traditional Chinese medicine formula consisting of Crataegus pinnatifida and Salvia miltiorrhiza. AB - BACKGROUND: The aims of this study were to evaluate the antioxidant activity and to identify the antioxidant components of a traditional Chinese medicine formula consisting of a combination of Shanzha (the fruit of Crataegus pinnatifida Bge. var. major N.E.Br., SZ) and Danshen (the root of Salvia miltiorrhiza Bge., DS). This medicine is extensively used to treat cardiovascular disease. METHODS: Twelve samples extracted and fractionated from SZ, DS and the formula (SZ+DS) were analyzed. The concentrations of eight phenolic compounds were determined by high performance liquid chromatography. Oxygen radical absorbance capacity (ORAC) assay and 1,1-diphenyl-2-picrylhydrazyl assay were conducted to explore the antioxidant activities of the samples and of the 15 phenolic compounds detected. Correlation analysis of the antioxidant activity of herb samples and their phenolic components was performed. RESULTS: The main phenolic component in all SZ+DS samples was salvianolic acid B, which exhibited strong antioxidant activity (ORAC value: 16.73 +/- 2.53, IC50 value: 8.80 +/- 0.06 MUM) compared with the other phenolic compounds. For all samples, there was a positive relationship between their total phenolic components and their antioxidant activities. CONCLUSIONS: Phenolic compounds were the bioactive components of the herb samples, and salvianolic acid B was identified as the main bioactive compound in the SZ+DS formula. PMID- 23663250 TI - Haplotype analysis of sucrose synthase gene family in three Saccharum species. AB - BACKGROUND: Sugarcane is an economically important crop contributing about 80% and 40% to the world sugar and ethanol production, respectively. The complicated genetics consequential to its complex polyploid genome, however, have impeded efforts to improve sugar yield and related important agronomic traits. Modern sugarcane cultivars are complex hybrids derived mainly from crosses among its progenitor species, S. officinarum and S. spontanuem, and to a lesser degree, S. robustom. Atypical of higher plants, sugarcane stores its photoassimilates as sucrose rather than as starch in its parenchymous stalk cells. In the sugar biosynthesis pathway, sucrose synthase (SuSy, UDP-glucose: D-fructose 2-a-D glucosyltransferase, EC 2.4.1.13) is a key enzyme in the regulation of sucrose accumulation and partitioning by catalyzing the reversible conversion of sucrose and UDP into UDP-glucose and fructose. However, little is known about the sugarcane SuSy gene family members and hence no definitive studies have been reported regarding allelic diversity of SuSy gene families in Saccharum species. RESULTS: We identified and characterized a total of five sucrose synthase genes in the three sugarcane progenitor species through gene annotation and PCR haplotype analysis by analyzing 70 to 119 PCR fragments amplified from intron containing target regions. We detected all but one (i.e. ScSuSy5) of ScSuSy transcripts in five tissue types of three Saccharum species. The average SNP frequency was one SNP per 108 bp, 81 bp, and 72 bp in S. officinarum, S. robustom, and S. spontanuem respectively. The average shared SNP is 15 between S. officinarum and S. robustom, 7 between S. officinarum and S. spontanuem , and 11 between S. robustom and S. spontanuem. We identified 27, 35, and 32 haplotypes from the five ScSuSy genes in S. officinarum, S. robustom, and S. spontanuem respectively. Also, 12, 11, and 9 protein sequences were translated from the haplotypes in S. officinarum, S. robustom, S. spontanuem, respectively. Phylogenetic analysis showed three separate clusters composed of SbSuSy1 and SbSuSy2, SbSuSy3 and SbSuSy5, and SbSuSy4. CONCLUSIONS: The five members of the SuSy gene family evolved before the divergence of the genera in the tribe Andropogoneae at least 12 MYA. Each ScSuSy gene showed at least one non synonymous substitution in SNP haplotypes. The SNP frequency is the lowest in S. officinarum, intermediate in S. robustum, and the highest in S. spontaneum, which may reflect the timing of the two rounds of whole genome duplication in these octoploids. The higher rate of shared SNP frequency between S. officinarum and S. robustum than between S. officinarum and in S. spontaneum confirmed that the speciation event separating S. officinarum and S. robustum occurred after their common ancestor diverged from S. spontaneum. The SNP and haplotype frequencies in three Saccharum species provide fundamental information for designing strategies to sequence these autopolyploid genomes. PMID- 23663254 TI - Pregnant women's perception on signs and symptoms during pregnancy and maternal health care in a rural low-resource setting. AB - OBJECTIVE: Women's understanding of pregnancy and antenatal care is influenced by their cultural context. In low-income settings women may have limited influence over their reproductive health, including when to seek health care. Awareness of signs of pregnancy complications is essential for timely care. The use of antenatal care services in Vietnam has been studied with quantitative methods but there are few qualitative studies on the perceptions of pregnancy and maternal health care among Vietnamese women. DESIGN: Four focus group discussions with pregnant women were performed. SETTING: The study was conducted in a rural district in northern Vietnam. POPULATION: Pregnant women in the last trimester. METHOD: Manifest and latent content analysis. RESULT: The latent theme that emerged was a need for "securing pregnancy during its normal course and at deviation", consisting of the main categories "ensuring a healthy pregnancy" and "separating the normal from the abnormal". CONCLUSION: This qualitative study of pregnant women in rural Vietnam indicates how women create a strategy to promote a healthy pregnancy through lifestyle adjustments, gathering of information, and seeking timely medical care. Insight into pregnancy-related conditions was sought from various sources and influenced both by local traditions and modern medical knowledge. Public knowledge about different symptoms during pregnancy and a high confidence in maternal health care are the most likely contributing factors to the relatively good maternal health status in Vietnam. PMID- 23663255 TI - Typology of persons with severe mental disorders. AB - BACKGROUND: Persons with severe mental disorders (PSMD) form a highly heterogeneous group. Identifying subgroups sharing similar PSMD profiles may help to develop treatment plans and appropriate services for their needs. This study seeks to establish a PSMD typology by looking at individual characteristics and the amount and adequacy of help received. METHODS: The study recruited a sample of 352 persons located in south-western Montreal (Quebec, Canada). Cluster analysis was used to create a PSMD typology. RESULTS: Analysis yielded five clusters: 1. highly functional older women with mood disorders, receiving little help from services; 2. middle-aged men with diverse mental disorders and alcohol abuse, receiving insufficient and inadequate help; 3. middle-aged women with serious needs, mood and personality disorders and suicidal tendencies, living in autonomous apartments, and receiving ample but inadequate help; 4. highly educated younger men with schizophrenia, living in autonomous apartments, and receiving adequate help; and 5. older poorly educated men with schizophrenia, living in supervised apartments, with ample help perceived as adequate. Marked differences were found between men and women, between users diagnosed with schizophrenia and others, and between persons living in supervised or autonomous apartments. CONCLUSION: Our study highlights the existence of parallel subgroups among PSMD related to their socio-demographic status, clinical needs and service use profiles, which could be used to focus more appropriate interventions. For mental health service planning, it demonstrates the relevance of focusing on individuals showing critical needs who are affected by multiple mental disorders (especially when associated with alcohol abuse), and often find help received as less adequate. PMID- 23663256 TI - Incidence, distribution, seasonality, and demographic risk factors of Salmonella Enteritidis human infections in Ontario, Canada, 2007-2009. AB - BACKGROUND: In Canada, surveillance systems have highlighted the increasing trend of Salmonella enterica serovar Enteritidis (S. Enteritidis) human infections. Our study objectives were to evaluate the epidemiology of S. Enteritidis infections in Ontario using surveillance data from January 1, 2007 through December 31, 2009. METHODS: Annual age-and-sex-adjusted incidence rates (IRs), annual and mean age-adjusted sex-specific IRs, and mean age-and-sex-adjusted IRs by public health unit (PHU), were calculated for laboratory-confirmed S. Enteritidis cases across Ontario using direct standardization. Multivariable Poisson regression with PHU as a random effect was used to estimate incidence rate ratios (IRRs) of S. Enteritidis infections among years, seasons, age groups, and sexes. RESULTS: The annual age-and-sex-adjusted IR per 100,000 person-years was 4.4 [95% CI 4.0-4.7] in 2007, and 5.2 [95% CI 4.8-5.6] in both 2008 and 2009. The annual age-adjusted sex-specific IRs per 100,000 person-years ranged from 4.5 to 5.5 for females and 4.2 to 5.2 for males. The mean age-adjusted sex-specific IR was 5.1 [95% CI 4.8 5.4] for females and 4.8 [95% CI 4.5-5.1] for males. High mean age-and-sex adjusted IRs (6.001-8.10) were identified in three western PHUs, one northern PHU, and in the City of Toronto. Regression results showed a higher IRR of S. Enteritidis infections in 2009 [IRR = 1.18, 95% CI 1.06-1.32; P = 0.003] and 2008 [IRR = 1.17, 95% CI 1.05-1.31; P = 0.005] compared to 2007. Compared to the fall season, a higher IRR of S. Enteritidis infections was observed in the spring [IRR = 1.14, 95% CI 1.01-1.29; P = 0.040]. Children 0-4 years of age (reference category), followed by children 5-9 years of age [IRR = 0.64, 95% CI 0.52-0.78; P < 0.001] had the highest IRRs. Adults >= 60 years of age and 40-49 years of age [IRR = 0.31, 95% CI 0.26-0.37; P < 0.001] had the lowest IRRs. CONCLUSIONS: The study findings suggest that there was an increase in the incidence of S. Enteritidis infections in Ontario from 2007 to 2008-2009, and indicate seasonal, demographic, and regional differences, which warrant further public health attention. PMID- 23663257 TI - Growth hormone response to submaximal doses of ghrelin remains unchanged during the follicular phase of the cycle. AB - BACKGROUND: Previous data have shown that ghrelin-induced growth hormone (GH) secretion is augmented in women by exogenous but not by endogenous estrogens. The purpose of this study was to examine the response of GH to low-dose scheme of ghrelin administration in relation to physiological changes in estradiol levels during the normal menstrual cycle. METHODS: Ten normally cycling women were studied in two menstrual cycles. Two consecutive dosages of ghrelin (0.15 MUg/kg and 0.30 MUg/kg) were injected intravenously at 0 and 90 min in the early and late follicular phases of one cycle. Saline was injected in the preceding cycle. Blood samples were taken at -15, 0, 30, 60, 90, 120, 150 and 180 min. The GH response was assessed. RESULTS: Serum estradiol concentrations were significantly higher in the late than in the early follicular phase. After ghrelin, but not after saline administration, plasma ghrelin and serum GH levels increased significantly in both phases, peaking at 30 min and 120 min. The peak value at 120 min was significantly higher than at 30 min (P<0.001). There were no significant differences in ghrelin and GH levels between the two phases at all time points. CONCLUSIONS: The present results show no difference in GH response to two consecutive submaximal doses of ghrelin between the early and the late follicular phase of the cycle. It is suggested that estradiol is not possibly involved in the physiological process that regulates ghrelin-induced GH secretion in women during the normal menstrual cycle. PMID- 23663258 TI - Proteomic analysis of the supernatant of red blood cell units: the effects of storage and leucoreduction. AB - BACKGROUND: Red blood cell (RBC) transfusion is a life-saving intervention for critically ill patients; however, it has been linked to increased morbidity and mortality. We hypothesize that a number of important proteins accumulate during routine storage of RBCs, which may explain some of the adverse effects seen in transfused patients. STUDY DESIGN: Five RBC units were drawn and divided (half prestorage leucoreduced (LR-RBC) and half left as an unmodified control (RBC). The supernatant was separated on days 1 and 42 of storage and proteomic analyses completed with in-gel tryptic digestion and nano-liquid chromatography tandem mass spectrometry. RESULTS: In RBC supernatants, 401 proteins were identified: 203 increased with storage, 114 decreased, and 84 were unchanged. In LR-RBC supernatant, 231 proteins were identified: 84 increased with storage, 30 decreased, and 117 were unchanged. Prestorage leucoreduction removed many platelet- and leucocyte-derived structural proteins; however, a number of intracellular proteins accumulated including peroxiredoxins (Prdx) 6 and latexin. The increases were confirmed by immunoblotting, including the T-phosphorylation of Prdx-6, indicating that it may be functioning as an active phospholipase. Active matrix metalloproteinase-9 also increased with a coinciding decrease in the metalloproteinase inhibitor 1 and cystatin C. CONCLUSION: We conclude that a number of proteins increase with RBC storage, which is partially ameliorated with leucoreduction, and transfusion of stored RBCs may introduce mediators that result in adverse events in the transfused host. PMID- 23663259 TI - Examining health promotion interventions for patients with chronic conditions using a novel patient-centered complexity model: protocol for a systematic review and meta-analysis. AB - BACKGROUND: Successful chronic care self-management requires adherence to healthy lifestyle behaviors, but many healthcare-based health promotion interventions have resulted in small and unsustainable changes in patient behavior. Patients with chronic conditions may already be overwhelmed by burdensome illnesses and treatments, and not have the capacity to respond well to the additional work required of behavior modifications. To explore this phenomenon, we will apply the cumulative complexity model (CCM), a patient-centered model of patient complexity, to a systematic review and meta-analysis of healthcare-based health behavior interventions. METHODS/DESIGN: This systematic review will include randomized trials published between 2002 and 2012 that compared healthcare-based interventions aimed at improving healthy diet and physical activity in community dwelling adult patients with chronic conditions. After extracting study and risk of bias features from each trial, we will classify the interventions according to the conceptual model. We will then use meta-analysis and subgroup analysis to test hypotheses based on the conceptual model. DISCUSSION: Healthcare providers need evidence of successful health promoting interventions for patients with chronic conditions who display common behavioral risk factors. To better understand how patients respond to interventions, we will apply the CCM, which accounts for both the capacity of patients with chronic conditions and their treatment-related workload, and posits that a balance between capacity and workload predicts successful enactment of self-care. Analysis will also include whether patients with multiple chronic conditions respond differently to interventions compared to those with single chronic conditions. The results of this review will provide insights as to how patients with chronic conditions respond to health-promoting interventions. REVIEW REGISTRATION: PROSPERO registration number: CRD42012003428. PMID- 23663260 TI - Computational simulation of the bone remodeling using the finite element method: an elastic-damage theory for small displacements. AB - BACKGROUND: The resistance of the bone against damage by repairing itself and adapting to environmental conditions is its most important property. These adaptive changes are regulated by physiological process commonly called the bone remodeling. Better understanding this process requires that we apply the theory of elastic-damage under the hypothesis of small displacements to a bone structure and see its mechanical behavior. RESULTS: The purpose of the present study is to simulate a two dimensional model of a proximal femur by taking into consideration elastic-damage and mechanical stimulus. Here, we present a mathematical model based on a system of nonlinear ordinary differential equations and we develop the variational formulation for the mechanical problem. Then, we implement our mathematical model into the finite element method algorithm to investigate the effect of the damage. CONCLUSION: The results are consistent with the existing literature which shows that the bone stiffness drops in damaged bone structure under mechanical loading. PMID- 23663261 TI - mHCN4 genetically modified canine mesenchymal stem cells provide biological pacemaking function in complete dogs with atrioventricular block. AB - BACKGROUND: The study was undertaken to assess the properties of mouse HCN4 (mHCN4)-modified canine mesenchymal stem cells (cMSCs) in dogs with experimentally induced complete atrioventricular (AV) block and electronic pacing. METHODS: Complete AV block was induced in adult dogs who had undergone implantation of backup electronic pacemakers. cMSCs were transfected with mHCN4 genes. Evidence of successful IHCN4 expression was provided by patch-clamp detection. mHCN4-cMSCs or normal cMSCs were injected subepicardially into the left ventricular anterior wall of the dogs. Cardiac parameters were monitored for 6 weeks. Heart rate variability (HRV) was evaluated using quantitative Poincare plots of R-RN against R-RN+1 intervals. cMSCs survival and expression of HCN4 in vivo were examined by histological studies and Western blot. RESULTS: In 2 weeks, the maximum heart rate and the number of impulses generated from the injection sites were much higher in dogs injected with HCN4-modified MSCs than in control dogs. Basal heart rate increased in the HCN4 group and became fully stabilized by Week 4, evidenced by markedly reduced numbers of electronic pacemaker beats. At Week 2, HRV during exercise was significantly higher in HCN4 dogs than in controls as shown by descriptors of both instantaneous (SD1) and longer term (SD2) beat-to-beat deviations (P < 0.05). Hematoxylin-eosin staining and Western blot proved that cMSCs survive and express HCN4 protein in situ in heart of HCN4 dog. CONCLUSION: Transplantation of mHCN4-modified cMSCs provided a stable biological pacemaking function that allowed an appropriate chronotropic response to physical exercise for up to 6 weeks. PMID- 23663262 TI - The Caenorhabditis elegans voltage-gated calcium channel subunits UNC-2 and UNC 36 and the calcium-dependent kinase UNC-43/CaMKII regulate neuromuscular junction morphology. AB - BACKGROUND: The conserved Caenorhabditis elegans proteins NID-1/nidogen and PTP 3A/LAR-RPTP function to efficiently localize the presynaptic scaffold protein SYD 2/alpha-liprin at active zones. Loss of function in these molecules results in defects in the size, morphology and spacing of neuromuscular junctions. RESULTS: Here we show that the Cav2-like voltage-gated calcium channel (VGCC) proteins, UNC-2 and UNC-36, and the calmodulin kinase II (CaMKII), UNC-43, function to regulate the size and morphology of presynaptic domains in C. elegans. Loss of function in unc-2, unc-36 or unc-43 resulted in slightly larger GABAergic neuromuscular junctions (NMJs), but could suppress the synaptic morphology defects found in nid-1/nidogen or ptp-3/LAR mutants. A gain-of-function mutation in unc-43 caused defects similar to those found in nid-1 mutants. Mutations in egl-19, Cav1-like, or cca-1, Cav3-like, alpha1 subunits, or the second alpha2/delta subunit, tag-180, did not suppress nid-1, suggesting a specific interaction between unc-2 and the synaptic extracellular matrix (ECM) component nidogen. Using a synaptic vesicle marker in time-lapse microscopy studies, we observed GABAergic motor neurons adding NMJ-like structures during late larval development. The synaptic bouton addition appeared to form in at least two ways: (1) de novo formation, where a cluster of vesicles appeared to coalesce, or (2) when a single punctum became enlarged and then divided to form two discrete fluorescent puncta. In comparison to wild type animals, we found unc-2 mutants exhibited reduced NMJ dynamics, with fewer observed divisions during a similar stage of development. CONCLUSIONS: We identified UNC-2/UNC-36 VGCCs and UNC 43/CaMKII as regulators of C. elegans synaptogenesis. UNC-2 has a modest role in synapse formation, but a broader role in regulating dynamic changes in the size and morphology of synapses that occur during organismal development. During the late 4th larval stage (L4), wild type animals exhibit synaptic morphologies that are similar to those found in animals lacking NID-1/PTP-3 adhesion, as well as those with constitutive activation of UNC-43. Genetic evidence indicates that the VGCCs and the NID-1/PTP-3 adhesion complex provide opposing functions in synaptic development, suggesting that modulation of synaptic adhesion may underlie synapse development in C. elegans. PMID- 23663263 TI - Exploring the larval transcriptome of the common sole (Solea solea L.). AB - BACKGROUND: The common sole (Solea solea) is a promising candidate for European aquaculture; however, the limited knowledge of the physiological mechanisms underlying larval development in this species has hampered the establishment of successful flatfish aquaculture. Although the fact that genomic tools and resources are available for some flatfish species, common sole genomics remains a mostly unexplored field. Here, we report, for the first time, the sequencing and characterisation of the transcriptome of S. solea and its application for the study of molecular mechanisms underlying physiological and morphological changes during larval-to-juvenile transition. RESULTS: The S. solea transcriptome was generated from whole larvae and adult tissues using the Roche 454 platform. The assembly process produced a set of 22,223 Isotigs with an average size of 726 nt, 29 contigs and a total of 203,692 singletons. Of the assembled sequences, 75.2% were annotated with at least one known transcript/protein; these transcripts were then used to develop a custom oligo-DNA microarray. A total of 14,674 oligonucleotide probes (60 nt), representing 12,836 transcripts, were in situ synthesised onto the array using Agilent non-contact ink-jet technology. The microarray platform was used to investigate the gene expression profiles of sole larvae from hatching to the juvenile form. Genes involved in the ontogenesis of the visual system are up-regulated during the early stages of larval development, while muscle development and anaerobic energy pathways increase in expression over time. The gene expression profiles of key transcripts of the thyroid hormones (TH) cascade and the temporal regulation of the GH/IGF1 (growth hormone/insulin-like growth factor I) system suggest a pivotal role of these pathways in fish growth and initiation of metamorphosis. Pre-metamorphic larvae display a distinctive transcriptomic landscape compared to previous and later stages. Our findings highlighted the up-regulation of gene pathways involved in the development of the gastrointestinal system as well as biological processes related to folic acid and retinol metabolism. Additional evidence led to the formation of the hypothesis that molecular mechanisms of cell motility and ECM adhesion may play a role in tissue rearrangement during common sole metamorphosis. CONCLUSIONS: Next-generation sequencing provided a good representation of the sole transcriptome, and the combination of different approaches led to the annotation of a high number of transcripts. The construction of a microarray platform for the characterisation of the larval sole transcriptome permitted the definition of the main processes involved in organogenesis and larval growth. PMID- 23663264 TI - Sinonasal undifferentiated carcinoma (SNUC): the Alberta experience and literature review. AB - BACKGROUND: Sinonasal undifferentiated carcinoma (SNUC) is a rare malignancy with often dismal outcomes. This study set to determine provincial and literature-wide survival outcomes based on treatment modality. METHODS: Retrospective chart review of all SNUC patients in the province of Alberta from 1986-2010 was conducted. A review of the literature of SNUC patients was also performed. Patient/tumor characteristics, treatment, and follow-up/survival data were collected. Kaplan-Meier and Cox regression survival analyses were performed. RESULTS: 20 patients were treated for SNUC in Alberta and 140 patients were identified in the literature. Pooled median disease-free survival was 12. 7 months and 5-year survival estimate was 6.25%. Cox-Regression analysis demonstrated an overall survival advantage with multimodality treatments (Log Rank test: p = 0.015). However, no statistically significant differences in disease-free and overall survival were identified between patients treated with chemoradiation or surgery followed by adjuvant therapy. CONCLUSIONS: Treatment of SNUC remains challenging with poor survival outcomes. There appears to be no statistically significant difference in overall, or disease-free survival between treatment modalities. PMID- 23663265 TI - Successful implantation after reducing matrix metalloproteinase activity in the uterine cavity. AB - BACKGROUND: Recently, the concept of recurrent implantation failure (RIF) in assisted reproductive technology has been enlarged. Chronic uterine inflammation is a known cause of implantation failure and is associated with high matrix metalloproteinase (MMP) activity in uterine cavity flushing. MMP activity of women with RIF has been reported to be higher than that of fertile women. In the present retrospective study we evaluated the efficacy of treatment for high MMP activity in the uterine cavity of patients with RIF. METHODS: Of the 597 patients recruited to the study, 360 patients underwent MMP measurements and 237 patients did not (control group). All patients had failed to become pregnant, despite at least two transfers of good-quality embryos. Gelatinase MMP-2 and MMP-9 activity in uterine flushing fluid was detected by enzymology (MMP test). All samples were classified into two groups (positive or negative) based on the intensity of the bands on the enzyme zymogram, which represents the degree of MMP activity. Patients who tested positive on the initial test were treated for 2 weeks with a quinolone antibiotic and a corticosteroid, and subsequently underwent a second MMP test. Negative results on the second MMP tests after treatment and subsequent rates of pregnancy and miscarriage were used to evaluate the efficacy of treatment. Data were analyzed by the Mann-Whitney U-test and the chi-square test. RESULTS: Of the patients who underwent the MMP test, 15.6% had positive results (high MMP activity). After treatment, 89.3% of patients had negative results on the second MMP test. These patients had a significantly better pregnancy rate (42.0%) than the control group (26.6%), as well as a lower miscarriage rate (28.5% vs 36.5%, respectively). CONCLUSIONS: A 2-week course of antibiotics and corticosteroids effectively improves the uterine environment underlying RIF by reducing MMP activity. PMID- 23663266 TI - To what extent does the Health Professions Admission Test-Ireland predict performance in early undergraduate tests of communication and clinical skills? An observational cohort study. AB - BACKGROUND: Internationally, tests of general mental ability are used in the selection of medical students. Examples include the Medical College Admission Test, Undergraduate Medicine and Health Sciences Admission Test and the UK Clinical Aptitude Test. The most widely used measure of their efficacy is predictive validity.A new tool, the Health Professions Admission Test- Ireland (HPAT-Ireland), was introduced in 2009. Traditionally, selection to Irish undergraduate medical schools relied on academic achievement. Since 2009, Irish and EU applicants are selected on a combination of their secondary school academic record (measured predominately by the Leaving Certificate Examination) and HPAT-Ireland score. This is the first study to report on the predictive validity of the HPAT-Ireland for early undergraduate assessments of communication and clinical skills. METHOD: Students enrolled at two Irish medical schools in 2009 were followed up for two years. Data collected were gender, HPAT-Ireland total and subsection scores; Leaving Certificate Examination plus HPAT-Ireland combined score, Year 1 Objective Structured Clinical Examination (OSCE) scores (Total score, communication and clinical subtest scores), Year 1 Multiple Choice Questions and Year 2 OSCE and subset scores. We report descriptive statistics, Pearson correlation coefficients and Multiple linear regression models. RESULTS: Data were available for 312 students. In Year 1 none of the selection criteria were significantly related to student OSCE performance. The Leaving Certificate Examination and Leaving Certificate plus HPAT-Ireland combined scores correlated with MCQ marks.In Year 2 a series of significant correlations emerged between the HPAT-Ireland and subsections thereof with OSCE Communication Z-scores; OSCE Clinical Z-scores; and Total OSCE Z-scores. However on multiple regression only the relationship between Total OSCE Score and the Total HPAT-Ireland score remained significant; albeit the predictive power was modest. CONCLUSION: We found that none of our selection criteria strongly predict clinical and communication skills. The HPAT- Ireland appears to measures ability in domains different to those assessed by the Leaving Certificate Examination. While some significant associations did emerge in Year 2 between HPAT Ireland and total OSCE scores further evaluation is required to establish if this pattern continues during the senior years of the medical course. PMID- 23663267 TI - Patient characteristics but not virulence factors discriminate between asymptomatic and symptomatic E. coli bacteriuria in the hospital. AB - BACKGROUND: Escherichia coli is a common cause of asymptomatic and symptomatic bacteriuria in hospitalized patients. Asymptomatic bacteriuria (ASB) is frequently treated with antibiotics without a clear indication. Our goal was to determine patient and pathogen factors suggestive of ASB. METHODS: We conducted a 12-month prospective cohort study of adult inpatients with E. coli bacteriuria seen at a tertiary care hospital in St. Louis, Missouri, USA. Urine cultures were taken at the discretion of treating physicians. Bacterial isolates were tested for 14 putative virulence genes using high-throughput dot-blot hybridization. RESULTS: The median age of the 287 study patients was 65 (19-101) years; 78% were female. Seventy percent had community-acquired bacteriuria. One-hundred ten (38.3%) patients had ASB and 177 (61.7%) had symptomatic urinary tract infection (sUTI). Asymptomatic patients were more likely than symptomatic patients to have congestive heart failure (p = 0.03), a history of myocardial infarction (p = 0.01), chronic pulmonary disease (p = 0.045), peripheral vascular disease (p = 0.04), and dementia (p = 0.03). Patients with sUTI were more likely to be neutropenic at the time of bacteriuria (p = 0.046). Chronic pulmonary disease [OR 2.1 (95% CI 1.04, 4.1)] and dementia [OR 2.4 (95% CI 1.02, 5.8)] were independent predictors for asymptomatic bacteriuria. Absence of pyuria was not predictive of ASB. None of the individual virulence genes tested were associated with ASB nor was the total number of genes. CONCLUSIONS: Asymptomatic E. coli bacteriuria in hospitalized patients was frequent and more common in patients with dementia and chronic pulmonary disease. Bacterial virulence factors could not discriminate symptomatic from asymptomatic bacteriurias. Asymptomatic E. coli bacteriuria cannot be predicted by virulence screening. PMID- 23663268 TI - Multifocal periostitis as a complication of chronic use of voriconazole in a lung transplant recipient. AB - Fungal infections are common in solid organ transplantation. An increasing number of transplant recipients receive antifungal therapy for prolonged duration owing to invasive fungal infections. Herein, we describe a diagnosis of periostitis as a complication of chronic use of voriconazole in a lung transplant recipient. The patient was diagnosed with probable pulmonary aspergillosis and was treated with oral voriconazole for a total of 9 months. Evidence of multifocal periostitis was observed in the axial and appendicular skeleton. Early recognition of this phenomenon is important to prevent unnecessary tests and procedures. Prompt discontinuation of voriconazole should result in improvement of symptoms. PMID- 23663269 TI - From the catastrophe to a humane mental-health care and successful research in German psychiatry (1951-2012) -- as I remember it. PMID- 23663271 TI - A haunting that never stops: psychiatry's problem of description. PMID- 23663270 TI - As I remember it. PMID- 23663272 TI - Psychopathology: re-humanizing psychiatry. PMID- 23663273 TI - Karl Jaspers (1883-1969) and the centenary of 'allgemeine psychopathologie'. PMID- 23663274 TI - Trauma, post-traumatic stress disorder, and schizophrenia. PMID- 23663278 TI - Abstracts of the American Society of Hypertension, Inc. 28th Annual Scientific Meeting and Exposition. May 15-18, 2013. San Francisco, California, USA. PMID- 23663276 TI - Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword? AB - Interleukin (IL)-6 is a cytokine with pleiotropic functions in different tissues and organs. Skeletal muscle produces and releases significant levels of IL-6 after prolonged exercise and is therefore considered as a myokine. Muscle is also an important target of the cytokine. IL-6 signaling has been associated with stimulation of hypertrophic muscle growth and myogenesis through regulation of the proliferative capacity of muscle stem cells. Additional beneficial effects of IL-6 include regulation of energy metabolism, which is related to the capacity of actively contracting muscle to synthesize and release IL-6. Paradoxically, deleterious actions for IL-6 have also been proposed, such as promotion of atrophy and muscle wasting. We review the current evidence for these apparently contradictory effects, the mechanisms involved and discuss their possible biological implications. PMID- 23663277 TI - Safe and targeted anticancer therapy for ovarian cancer using a novel class of curcumin analogs. AB - A diagnosis of advanced ovarian cancer is the beginning of a long and arduous journey for a patient. Worldwide, approximately half of the individuals undergoing therapy for advanced cancer will succumb to the disease, or consequences of treatment. Well-known and widely-used chemotherapeutic agents such as cisplatin, paclitaxel, 5-fluorouracil, and doxorubicin are toxic to both cancer and non-cancerous cells, and have debilitating side effects Therefore, development of new targeted anticancer therapies that can selectively kill cancer cells while sparing the surrounding healthy tissues is essential to develop more effective therapies. We have developed a new class of synthetic curcumin analogs, diarylidenyl-piperidones (DAPs), which have higher anticancer activity and enhanced bio-absorption than curcumin. The DAP backbone structure exhibits cytotoxic (anticancer) activity, whereas the N-hydroxypyrroline (-NOH) moiety found on some variants functions as a cellular- or tissue-specific modulator (antioxidant) of cytotoxicity. The anticancer activity of the DAPs has been evaluated using a number of ovarian cancer cell lines, and the safety has been evaluated in a number of non-cancerous cell lines. Both variations of the DAP compounds showed similar levels of cell death in ovarian cancer cells, however the compounds with the -NOH modification were less toxic to non-cancerous cells. The selective cytotoxicity of the DAP-NOH compounds suggests that they will be useful as safe and effective anticancer agents. This article reviews some of the key findings of our work with the DAP compounds, and compares this to some of the targeted therapies currently used in ovarian cancer therapy. PMID- 23663279 TI - Acculturation and obesity among migrant populations in high income countries--a systematic review. AB - BACKGROUND: There is evidence to suggest that immigrant populations from low or medium-income countries to high income countries show a significant change in obesogenic behaviors in the host society, and that these changes are associated with acculturation. However, the results of studies vary depending on how acculturation is measured. The objective of this study is to systematically review the evidence on the relationship between acculturation--as measured with a standardized acculturation scale--and overweight/obesity among adult migrants from low/middle countries to high income countries. METHODS: A systematic review of relevant studies was undertaken using six EBSCOhost databases and following the Centre for Reviews and Dissemination's Guidance for Undertaking Reviews in Health Care. RESULTS: The initial search identified 1135 potentially relevant publications, of which only nine studies met the selection criteria. All of the studies were from the US with migrant populations from eight different countries. Six studies employed bi-directional acculturation scales and three used uni directional scales. Six studies indicated positive general associations between higher acculturation and body mass index (BMI), and three studies reported that higher acculturation was associated with lower BMI, as mainly among women. CONCLUSION: Despite the small number of studies, a number of potential explanatory hypotheses were developed for these emerging patterns. The 'Healthy Migrant Effect' may diminish with greater acculturation as the host culture potentially promotes more unhealthy weight gain than heritage cultures. This appears particularly so for men and a rapid form of nutrition transition represents a likely contributor. The inconsistent results observed for women may be due to the interplay of cultural influences on body image, food choices and physical activity. That is, the Western ideal of a slim female body and higher values placed on physical activity and fitness may counteract the obesogenic food environment for female migrants. PMID- 23663280 TI - Development of a transoral robotic surgery program in Canada. AB - Due to significant differences in healthcare structure between the United States and Canada, there are unique barriers to adopting new medical technology in Canada. In this article, we describe our experience developing a transoral robotic surgery (TORS) program at Western University. Specifically, we outline the steps that were necessary to obtain institutional and multidisciplinary team approval, financial support, as well as surgeon and allied healthcare personnel training. This experience can potentially be used as a roadmap for other Canadian institutions pursuing a TORS program. PMID- 23663282 TI - Pseudo-pseudo confusion. PMID- 23663281 TI - Economic evaluation of agomelatine relative to other antidepressants for treatment of major depressive disorders in Greece. AB - BACKGROUND: Major depressive disorder (MDD) constitutes an important public health problem, as it is highly prevalent in the industrialized world and it is associated with substantial economic consequences for patients, health care providers, insurance and social security organizations and employers. To conduct an economic evaluation comparing agomelatine with other commonly used alternatives for treating patients with major depressive disorder (MDD) in Greece. METHODS: An existing international Markov model designed to evaluate the cost-effectiveness of agomelatine was adapted to the Greek setting. It reflects six different health states, in which patients may move on a monthly basis. The analysis was undertaken from a societal perspective. Transition probabilities, utilities and costs assigned to each health state were extracted from the published literature, government sources and expert opinion. Data reflects the year 2012 and was discounted using a rate of 3.5%. Probabilistic analysis was undertaken to deal with uncertainty. RESULTS: Base case analyses revealed that agomelatine is a dominant therapy for MDD relative to escitalopram, fluoxetine and sertraline, and it appeared to be cost-effective compared to venlafaxine (ICER: ?547/QALY). Agomelatine remained a dominant treatment against generic sertraline and fluoxetine, and it appeared to be a cost-effective alternative compared to generic venlafaxine and escitalopram (ICER: ?1,446/QALY and ?3,303/QALY, respectively). Excluding the indirect cost from the analysis, agomelatine remained a cost-effective alternative over all comparators. In the probabilistic sensitivity analysis agomelatine was dominant in 44.5%, 89.6%, 70.6% and 84.6% of simulated samples against branded venlafaxine, escitalopram, fluoxetine and sertraline, respectively. CONCLUSION: The present evaluation indicates that agomelatine is either a dominant or a cost-effective alternative relative to branded or generic alternatives, in Greece. PMID- 23663283 TI - Reimbursement by current German diagnosis-related groups system penalises complex congenital heart surgery. AB - A total of 458 hospital stays during the year 2011 were analysed to determine whether reimbursement by the current German Diagnosis-Related Groups system covers the costs incurred during hospital stay for congenital heart surgery. The costs of every hospital stay were estimated according to the guidelines of the Institute for the Hospital Remuneration System, an institute responsible for encoding hospital reimbursement in Germany. Cost-weight values of the year 2012 were applied for reimbursement. Related additional compensations were also included. Hospital costs ranged from 8896.26 to 193,671.94 euros per case, with a mean of 30,597 and standard deviation of 25,032 euros. Reimbursement varied from 8630.35 to 173,710.65 euros, with a mean of 25,514 and standard deviation of 18,497 euros: an underfunding of 17%. Fifty-nine per cent (271/458) of cases were classified, according to Aristotle complexity score, in higher comprehensive complexity: Levels 4-6. Costs highly correlated with complexity levels (Spearman's r coefficient = 0.89) and the regression was linear. Underfunding increased, linearly, from 6% for procedures with Level 1, lowest comprehensive complexity, to 23% for those with Level 6, highest complexity. In conclusion, this study demonstrates that reimbursement by the current German Diagnosis Related Groups system increasingly penalises complex congenital heart surgery. Aristotle complexity score could help to correct this prejudicial situation. PMID- 23663284 TI - Extending predictive processing to the body: emotion as interoceptive inference. AB - The Bayesian brain hypothesis provides an attractive unifying framework for perception, cognition, and action. We argue that the framework can also usefully integrate interoception, the sense of the internal physiological condition of the body. Our model of "interoceptive predictive coding" entails a new view of emotion as interoceptive inference and may account for a range of psychiatric disorders of selfhood. PMID- 23663285 TI - Environmental interventions to reduce fear of crime: systematic review of effectiveness. AB - BACKGROUND: Fear of crime is associated with negative health and wellbeing outcomes, and may mediate some impacts of the built environment on public health. A range of environmental interventions have been hypothesized to reduce the fear of crime. METHODS: This review aimed to synthesize the literature on the effectiveness of interventions in the built environment to reduce the fear of crime. Systematic review methodology, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance, was used. Studies of environmental interventions which reported a fear of crime outcome and used any prospective evaluation design (randomized controlled trial (RCT), trial or uncontrolled before-and-after study) were included. Eighteen databases were searched. The Hamilton tool was used to assess quality. A narrative synthesis of findings was undertaken. RESULTS: A total of 47 studies were included, 22 controlled and 25 uncontrolled, with total sample sizes ranging from n = 52 to approximately n = 23,000. Thirty-six studies were conducted in the UK, ten studies in the USA and one study in the Netherlands. The quality of the evidence overall is low. There are some indications that home security improvements and non-crime-related environmental improvements may be effective for some fear of crime outcomes. There is little evidence that the following reduce fear of crime: street lighting improvements, closed-circuit television (CCTV), multi-component environmental crime prevention programs or regeneration programs. CONCLUSIONS: There is some evidence for the effectiveness of specific environmental interventions in reducing some indicators of fear of crime, but more attention to the context and possible confounders is needed in future evaluations of complex social interventions such as these. PMID- 23663286 TI - Passive anti-amyloid immunotherapy in Alzheimer's disease: What are the most promising targets? AB - Alzheimer's disease (AD) is the most common dementia in the industrialized world, with prevalence rates well over 30% in the over 80-years-old population. The dementia causes enormous costs to the social healthcare systems, as well as personal tragedies for the patients, families and caregivers. AD is strongly associated with Amyloid-beta (Abeta) protein aggregation, which results in extracellular plaques in the brain, and according to the amyloid cascade hypothesis appeared to be a promising target for the development of AD therapeutics. Within the past decade convincing data has arisen positioning the soluble prefibrillar Abeta-aggregates as the prime toxic agents in AD. However, different Abeta aggregate species are described but their remarkable metastability hampers the identification of a target species for immunization. Passive immunotherapy with monoclonal antibodies (mAbs) against Abeta is in late clinical development but recently the two most advanced mAbs, Bapineuzumab and Solanezumab, targeting an N-terminal or central epitope, respectively, failed to meet their target of improving or stabilizing cognition and function. Preliminary data from off-label treatment of a small cohort for 3 years with intravenous polyclonal immunoglobulins (IVIG) that appear to target different conformational epitopes indicate a cognitive stabilization. Thus, it might be the more promising strategy reducing the whole spectrum of Abeta-aggregates than to focus on a single aggregate species for immunization. PMID- 23663287 TI - Validation of SAPS3 admission score and its customization for use in Korean intensive care unit patients: a prospective multicentre study. AB - BACKGROUND AND OBJECTIVE: To externally validate the simplified acute physiology score 3 (SAPS3) and to customize it for use in Korean intensive care unit (ICU) patients. METHODS: This is a prospective multicentre cohort study involving 22 ICUs from 15 centres throughout Korea. The study population comprised patients who were consecutively admitted to participating ICUs from 1 July 2010 to 31 January 2011. RESULTS: A total of 4617 patients were enrolled. ICU mortality was 14.3%, and hospital mortality was 20.6%. The patients were randomly assigned into one of two cohorts: a development (n = 2309) or validation (n = 2308) cohort. In the development cohort, the general SAPS3 had good discrimination (area under the receiver operating characteristics curve = 0.829), but poor calibration (Hosmer Lemeshow goodness-of-fit test H = 123.06, P < 0.001, C = 118.45, P < 0.001). The Australasia SAPS3 did not improve calibration (H = 73.53, P < 0.001, C = 70.52, P < 0.001). Customization was achieved by altering the logit of the original SAPS3 equation. The new equation for Korean ICU patients was validated in the validation cohort, and demonstrated both good discrimination (area under the receiver operating characteristics curve = 0.835) and good calibration (H = 4.61, P = 0.799, C = 5.67, P = 0.684). CONCLUSIONS: General and regional Australasia SAPS3 admission scores showed poor calibration for use in Korean ICU patients, but the prognostic power of the SAPS3 was significantly improved by customization. Prediction models should be customized before being used to predict mortality in different regions of the world. PMID- 23663288 TI - A randomized trial of video self-instruction in cardiopulmonary resuscitation for lay persons. AB - BACKGROUND: Cardiopulmonary resuscitation (CPR) improves outcomes after cardiac arrest. Much of the lay public is untrained in CPR skills. We evaluated the effectiveness of a compression-only CPR video self-instruction (VSI) with a personal manikin in the lay public. METHODS: Adults without prior CPR training in the past year or responsibility to provide medical care were randomized into one of three groups: 1) Untrained before testing, 2) 10-minute VSI in compressions only CPR (CPR Anytime, American Heart Association, Dallas, TX), or 3) 22-minute VSI in compressions and ventilations (CPR Anytime). CPR proficiency was assessed using a sensored manikin. The primary outcome was composite skill competence of 90% during five minutes of skill demonstration. Evaluated were alternative cut points for skill competence and individual components of CPR. 488 subjects (143 in untrained group, 202 in compressions-only group and 143 in compressions and ventilation group) were required to detect 21% competency with compressions-only versus 7% with untrained and 34% with compressions and ventilations. RESULTS: Analyzable data were available for the untrained group (n = 135), compressions only group (n = 185) and the compressions and ventilation group (n = 119). Four (3%) achieved competency in the untrained group (p-value = 0.57 versus compressions-only), nine (4.9%) in the compressions-only group, and 12 (10.1%) in the compressions and ventilations group (p-value 0.13 vs. compressions-only). The compressions-only group had a greater proportion of correct compressions (p-value = 0.028) and compressions with correct hand placement (p-value = 0.0004) compared to the untrained group. CONCLUSIONS: VSI in compressions-only CPR did not achieve greater overall competency but did achieve some CPR skills better than without training. PMID- 23663290 TI - Quality and cost-effectiveness of interventional pain procedures: minimally invasive lumbar decompression (MILD) as a paradigm? PMID- 23663291 TI - Role of P-glycoprotein in the uptake/efflux transport of oral vitamin K antagonists and rivaroxaban through the Caco-2 cell model. AB - Vitamin K antagonists (VKAs) are prescribed worldwide and remain the oral anticoagulant of choice. These drugs are characterized by a narrow therapeutic index and a large inter- and intra-individual variability. P-glycoprotein could contribute to this variability. The aim of this study was to investigate the involvement of P-gp in the transport of acenocoumarol, phenprocoumon and warfarin using an in vitro Caco-2 cell monolayer model. These results were compared with those obtained with rivaroxaban, a new oral anticoagulant known to be a P-gp substrate. The transport of these four drugs was assessed at pH conditions 6.8/7.4 in the presence or absence of the P-gp inhibitor cyclosporine A (10 MUM) and the more potent and specific P-gp inhibitor valspodar (5 MUM). Analytical quantification was performed by LC/MS. With an efflux ratio of 1.7 and a significant decrease in the efflux (Papp B-A), in the presence of P-gp inhibitors at a concentration of 50 MUM, acenocoumarol can be considered as a weak P-gp substrate. Concerning phenprocoumon, the results suggest that this molecule is a poor P-gp substrate. The P-gp inhibitors did not affect significantly the transport of warfarin. The efflux of rivaroxaban was strongly inhibited by the two P-gp inhibitors. In conclusion, none of the three VKAs tested are strong P-gp substrates. However, acenocoumarol can be considered as a weak P-gp substrate and phenprocoumon as a poor P-gp substrate. PMID- 23663289 TI - Discovering putative prion sequences in complete proteomes using probabilistic representations of Q/N-rich domains. AB - BACKGROUND: Prion proteins conform a special class among amyloids due to their ability to transmit aggregative folds. Prions are known to act as infectious agents in neurodegenerative diseases in animals, or as key elements in transcription and translation processes in yeast. It has been suggested that prions contain specific sequential domains with distinctive amino acid composition and physicochemical properties that allow them to control the switch between soluble and beta-sheet aggregated states. Those prion-forming domains are low complexity segments enriched in glutamine/asparagine and depleted in charged residues and prolines. Different predictive methods have been developed to discover novel prions by either assessing the compositional bias of these stretches or estimating the propensity of protein sequences to form amyloid aggregates. However, the available algorithms hitherto lack a thorough statistical calibration against large sequence databases, which makes them unable to accurately predict prions without retrieving a large number of false positives. RESULTS: Here we present a computational strategy to predict putative prion-forming proteins in complete proteomes using probabilistic representations of prionogenic glutamine/asparagine rich regions. After benchmarking our predictive model against large sets of non-prionic sequences, we were able to filter out known prions with high precision and accuracy, generating prediction sets with few false positives. The algorithm was used to scan all the proteomes annotated in public databases for the presence of putative prion proteins. We analyzed the presence of putative prion proteins in all taxa, from viruses and archaea to plants and higher eukaryotes, and found that most organisms encode evolutionarily unrelated proteins with susceptibility to behave as prions. CONCLUSIONS: To our knowledge, this is the first wide-ranging study aiming to predict prion domains in complete proteomes. Approaches of this kind could be of great importance to identify potential targets for further experimental testing and to try to reach a deeper understanding of prions' functional and regulatory mechanisms. PMID- 23663292 TI - American rural women's exercise self-efficacy and awareness of exercise benefits and safety during pregnancy. AB - Though the positive link between physical activity and maternal health is well documented, physical activity declines during pregnancy and, internationally, rural mothers are less likely than urban mothers to engage in physical activity. Some evidence suggests that self-efficacy is related to sustained engagement in physical activity. The purpose of this study was to examine self-efficacy, perceived benefits, and knowledge of safe exercise among 88 rural pregnant women in a southeastern region of the United States. Exercise self-efficacy was significantly related to maternal age and gestation. Women over age 26 years, and those in the second and third trimesters, scored significantly higher than younger women or those in the first trimester. Fifty-two percent (n = 46) of participants perceived that activity would decrease energy levels, 37.5% (n = 33) did not know that exercise can decrease the risk of gestational diabetes, and 47.6% (n = 41) were unaware that a mother who is overweight is more likely to have an overweight child. Results confirm a need for education to improve women's knowledge about health benefits and safety information related to physical activity during pregnancy. PMID- 23663293 TI - Does HPV type affect outcome in oropharyngeal cancer? AB - BACKGROUND: An epidemic of human papillomavirus (HPV)-related oropharyngeal squamous cell cancer (OPSCC) has been reported worldwide largely due to oral infection with HPV type-16, which is responsible for approximately 90% of HPV positive cases. The purpose of this study was to determine the rate of HPV positive oropharyngeal cancer in Southwestern Ontario, Canada. METHODS: A retrospective search identified ninety-five patients diagnosed with OPSCC. Pre treatment biopsy specimens were tested for p16 expression using immunohistochemistry and for HPV-16, HPV-18 and other high-risk subtypes, including 31,33,35,39,45,51,52,56,58,59,67,68, by real-time qPCR. RESULTS: Fifty nine tumours (62%) were positive for p16 expression and fifty (53%) were positive for known high-risk HPV types. Of the latter, 45 tumors (90%) were identified as HPV-16 positive, and five tumors (10%) were positive for other high-risk HPV types (HPV-18 (2), HPV-67 (2), HPV-33 (1)). HPV status by qPCR and p16 expression were extremely tightly correlated (p < 0.001, Fishers exact test). Patients with HPV-positive tumors had improved 3-year overall (OS) and disease-free survival (DFS) compared to patients with HPV-negative tumors (90% vs 65%, p = 0.001; and 85% vs 49%, p = 0.005; respectively). HPV-16 related OPSCC presented with cervical metastases more frequently than other high-risk HPV types (p = 0.005) and poorer disease-free survival was observed, although this was not statistically significant. CONCLUSION: HPV-16 infection is responsible for a significant proportion of OPSCC in Southwestern Ontario. Other high-risk subtypes are responsible for a smaller subset of OPSCC that present less frequently with cervical metastases and may have a different prognosis. PMID- 23663294 TI - Functional proteomic analysis of seminal plasma proteins in men with various semen parameters. AB - BACKGROUND: Alterations at the molecular level in spermatozoa and seminal plasma can affect male fertility. The objective of this study was to determine if analysis of differential expression of proteins in varying semen parameters can serve as potential biomarkers for male infertility. METHODS: The differential expression of proteins in the seminal plasma of men based on sperm count and morphology were examined utilizing proteomic tools. Subjects were categorized based on sperm concentration and morphology into 4 groups: 1) normal sperm count and normal morphology (NN); 2) normal sperm count and abnormal morphology (NA); 3) oligozoospermia and normal morphology (ON); and 4) oligozoospermia and abnormal morphology (OA). Proteomic analysis was performed by LC-MS/MS followed by functional bioinformatics analysis. Protein distribution in the NA, ON and OA groups was compared with that of the NN group. RESULTS: Twenty proteins were differentially expressed among the 4 groups. Among the unique proteins identified, 3 were downregulated in the NA group, 1 in the ON group and 1 in the OA group while 2 were upregulated in the ON and OA groups. The functional analysis 1) identified biological regulation as the major processes affected and 2) determined that most of the identified proteins were of extracellular origin. CONCLUSIONS: We have identified proteins that are over-or underexpressed in the seminal plasma of men with poor sperm quality. The distinct presence of some of the proteins may serve as potential biomarkers and provide insight into the mechanistic role played by these proteins in male infertility. Further studies using Western Blot analysis are required to validate these findings. PMID- 23663295 TI - ST9 MRSA strains carrying a variant of type IX SCCmec identified in the Thai community. AB - BACKGROUND: Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in Thailand occur most frequently in healthcare facilities. However, reports of community-associated MRSA are limited. METHODS: We characterized 14 MRSA isolates from outpatients (O-1 to O-14) by phenotypic and genotypic methods and compared them with 5 isolates from inpatients (I-1 to I-5). Thai MRSA isolates from a healthcare worker (N-1) and a pig (P-1) were also included as ST9 MRSA strains from other sources. RESULTS: All MRSA isolates from the outpatients and inpatients were multidrug-resistant (resistant to >=3 classes of antimicrobials). All of them except strains O-2 and I-3 carried type III SCCmec and belonged to agrI, coagulase IV, spa type t037 or t233, which related to ST239. The strain O-2 (JCSC6690) carried type IX SCCmec and belonged to agrII, coagulaseXIc, spa type t337 and ST9, whereas the strain I-3 carried a type III SCCmec and belonged to ST1429. Nucleotide sequence determination revealed that the type IX SCCmec element in strain O-2 was distinct from that in a Thai ST398 strain (JCSC6943) previously identified in 2011; nucleotide identities of ccrA and ccrB were 93 and 91%, respectively and several open reading frames (ORFs) at the joining regions were different. PCR experiments suggested that strain O-2 and N-1 carried similar SCCmec element, whereas that of strain P-1 was different, suggesting that distinct ST9-MRSA-IX clones might be spreading in this province. CONCLUSIONS: The SCCmecIX-ST9 MRSA clones of distinct SCCmec subtypes might have emerged in the Thai community and might also have disseminated into the hospital. PMID- 23663296 TI - Developing a diagnostic checklist of traditional Chinese medicine symptoms and signs for psoriasis: a Delphi study. AB - BACKGROUND: Psoriasis is a chronic inflammatory skin disease with a genetic basis. Its ill-defined causes make it difficult to diagnose. This study aims to develop a diagnostic checklist for psoriasis classification in the context of traditional Chinese medicine. METHODS: A Delphi study was conducted with three rounds by a panel of 16 dermatology experts to develop a checklist for traditional Chinese medicine symptoms and signs of psoriasis. Dermatology experts in psoriasis research, nine in Yunnan and seven in Beijing, were selected as the expert panel. The initial list of symptoms and signs in psoriasis was developed by reviewing the literature retrieved from Chinese and English journals. Experts rated each item of the list on a 5-point Likert scale. The list was revised and re-evaluated in the same manner for a total of 3 rounds before it was finalized. RESULTS: One hundred and thirty items were extracted from the literature review. After three rounds of expert ratings, 96 items were retained with eight domains: color, type and shape of skin lesion, physical expression, tongue and coating, pulse, associated factors, and living environment. Intraclass correlation coefficient and Kappa statistics indicated an inter-rater agreement in the final checklist. CONCLUSION: A checklist containing 96 items in 8 domains was developed for psoriasis diagnosis using traditional Chinese medicine symptoms and signs. PMID- 23663297 TI - Equivalency of risk for a modified health endpoint: a case from recreational water epidemiology studies. AB - BACKGROUND: The United States Environmental Protection Agency (USEPA) and its predecessors have conducted three distinct series of epidemiological studies beginning in 1948 on the relationship between bathing water quality and swimmers' illnesses. Keeping pace with advances in microbial technologies, these studies differed in their respective microbial indicators of water quality. Another difference, however, has been their specific health endpoints. The latest round of studies, the National Epidemiological Assessment of Recreational (NEEAR) Water studies initiated in 2002, used a case definition, termed "NEEAR GI illness" (NGI), for gastrointestinal illness corresponding closely to classifications employed by contemporary researchers, and to that proposed by the World Health Organization. NGI differed from the previous definition of "highly credible gastrointestinal illness" (HCGI) upon which the USEPA's 1986 bathing water criteria had been based, primarily by excluding fever as a prerequisite. METHODS: Incidence of NGI from the NEEAR studies was compared to that of HCGI from earlier studies. Markov chain Monte Carlo method was used to estimate the respective beta binomial probability densities for NGI and HCGI establish credible intervals for the risk ratio of NGI to HCGI. RESULTS: The ratio of NGI risk to that of HCGI is estimated to be 4.5 with a credible interval 3.2 to 7.7. CONCLUSIONS: A risk level of 8 HCGI illnesses per 1000 swimmers, as in the 1986 freshwater criteria, would correspond to 36 NGI illnesses per 1000 swimmers. Given a microbial DNA based (qPCR) water quality vs. risk relationship developed from the NEEAR studies, 36 NGI per 1000 corresponds to a geometric mean of 475 qPCR cell equivalents per 100 ml. PMID- 23663298 TI - A comparison of steep and shallow needle trajectories in blind axillary vein puncture. AB - BACKGROUND: Previously developed techniques for pacemaker lead introduction usually require some form of image guidance to facilitate the axillary vein puncture process. The existing blind vein puncture methods have not gained widespread acceptance. We aimed to investigate whether our blind vein puncture approach is effective and safe. METHODS: We compared the patient characteristics and clinical outcomes of 600 consecutive patients who underwent different blind axillary vein puncture procedures. In group I, a steep needle puncture method was used, whereas in group II a shallow needle puncture technique was used. RESULTS: The shallow needle puncture method was associated with a higher success rate than the steep needle puncture method (94% vs 54%, P < 0.00001). The shallow needle puncture method was also associated with a much shorter puncture and lead insertion time (7 +/- 2 minutes vs 10 +/- 3 minutes, P = 0.02). CONCLUSION: Our shallow needle puncture technique does not require any extra equipment. In addition, this method is effective and safe and may be used as the initial attempt for venous access during pacemaker implantation. PMID- 23663299 TI - Why give birth in health facility? Users' and providers' accounts of poor quality of birth care in Tanzania. AB - BACKGROUND: In Tanzania, half of all pregnant women access a health facility for delivery. The proportion receiving skilled care at birth is even lower. In order to reduce maternal mortality and morbidity, the government has set out to increase health facility deliveries by skilled care. The aim of this study was to describe the weaknesses in the provision of acceptable and adequate quality care through the accounts of women who have suffered obstetric fistula, nurse-midwives at both BEmOC and CEmOC health facilities and local community members. METHODS: Semi-structured interviews involving 16 women affected by obstetric fistula and five nurse-midwives at maternity wards at both BEmOC and CEmOC health facilities, and Focus Group Discussions with husbands and community members were conducted between October 2008 and February 2010 at Comprehensive Community Based Rehabilitation in Tanzania and Temeke hospitals in Dar es Salaam, and Mpwapwa district in Dodoma region. RESULTS: Health care users and health providers experienced poor quality caring and working environments in the health facilities. Women in labour lacked support, experienced neglect, as well as physical and verbal abuse. Nurse-midwives lacked supportive supervision, supplies and also seemed to lack motivation. CONCLUSIONS: There was a consensus among women who have suffered serious birth injuries and nurse midwives staffing both BEmOC and CEmOC maternity wards that the quality of care offered to women in birth was inadequate. While the birth accounts of women pointed to failure of care, the nurses described a situation of disempowerment. The bad birth care experiences of women undermine the reputation of the health care system, lower community expectations of facility birth, and sustain high rates of home deliveries. The only way to increase the rate of skilled attendance at birth in the current Tanzanian context is to make facility birth a safer alternative than home birth. The findings from this study indicate that there is a long way to go. PMID- 23663300 TI - Effect of high pressure on the structure and antibacterial activity of bovine lactoferrin treated in different media. AB - The effect of high-pressure treatment (400, 500 and 650 MPa) on the structure and activity of bovine lactoferrin in different iron-saturation forms has been studied by several techniques. The structural changes produced in lactoferrin by high-pressure were analysed by differential scanning calorimetry and fluorescence spectroscopy, and the immunoreactivity by ELISA. The effect of high-pressure was also studied on some biological properties of lactoferrin, such as iron binding capacity, retention of the bound iron, and antibacterial activity against Escherichia coli O157:H7. Results obtained indicate that treatment at 400 MPa does not substantially modify the conformation of lactoferrin, meanwhile treatments at 500 and 650 MPa greatly affect some of its properties. With respect to the antibacterial activity, the apo and native forms of lactoferrin maintain that activity against Esch. coli only after 400 MPa treatment. PMID- 23663301 TI - Clinical use of lactate monitoring in critically ill patients. AB - Increased blood lactate levels (hyperlactataemia) are common in critically ill patients. Although frequently used to diagnose inadequate tissue oxygenation, other processes not related to tissue oxygenation may increase lactate levels. Especially in critically ill patients, increased glycolysis may be an important cause of hyperlactataemia. Nevertheless, the presence of increased lactate levels has important implications for the morbidity and mortality of the hyperlactataemic patients. Although the term lactic acidosis is frequently used, a significant relationship between lactate and pH only exists at higher lactate levels. The term lactate associated acidosis is therefore more appropriate. Two recent studies have underscored the importance of monitoring lactate levels and adjust treatment to the change in lactate levels in early resuscitation. As lactate levels can be measured rapidly at the bedside from various sources, structured lactate measurements should be incorporated in resuscitation protocols. PMID- 23663302 TI - Assessment of bone mineral density by dual energy x-ray absorptiometry in patients with mucopolysaccharidoses. AB - BACKGROUND: Patients with mucopolysaccharidoses (MPS) are associated with poor bone growth and mineralization, however, information regarding the assessment of bone mineral density (BMD) in relation to age and treatment in this disorder is limited. METHODS: Dual energy x-ray absorptiometry (DXA) was performed in 30 patients with MPS (21 males and 9 females; 2 with MPS I, 12 with MPS II, 2 with MPS IIIB, 9 with MPS IVA, and 5 with MPS VI; median age, 10.8 years; age range, 5.0 years to 23.7 years; 26 patients were under 19 and 4 were above 19 years of age) to assess BMD of the lumbar spine (L1-L4), using the Hologic QDR 4500 system (Bedford, MA, USA). RESULTS: For 26 patients under 19 years of age, standard deviation scores (z scores) for height, weight, body mass index (BMI), and BMD were -4.53 +/- 2.66, -1.15 +/- 1.55, 0.74 +/- 1.23, and -3.03 +/- 1.62, respectively, and they were all negatively correlated with age (p < 0.05). However, after correction for height-for-age z score (HAZ), HAZ adjusted BMD z score was -0.7 +/- 1.24. Eight patients (31%) had osteopenia (HAZ adjusted BMD z score < -1 and >= -2), and 4 patients (15%) had osteoporosis (HAZ adjusted BMD z score < -2). Of 8 patients with MPS I, II or VI who underwent follow-up DXA after receiving enzyme replacement therapy for 1.0 to 7.4 years, all showed increase in absolute BMD values. CONCLUSIONS: These findings and the follow-up data can be used to develop quality of care strategies for patients with MPS. PMID- 23663303 TI - Spontaneous regression of a large rhabdomyoma of the interventricular septum. AB - We report the case of a large congenital rhabdomyoma of the interventricular septum diagnosed prenatally. The foetus was strictly monitored with ultrasound throughout the gestation period showing that the mass had increased in size until delivery. Despite the size of the mass, which appeared to occupy the right ventricle, the baby presented no symptoms both in utero and after birth. Serial echocardiography was used to document the regression of the mass in childhood. PMID- 23663304 TI - The potential for multi-disciplinary primary health care services to take action on the social determinants of health: actions and constraints. AB - BACKGROUND: The Commission on the Social Determinants of Health and the World Health Organization have called for action to address the social determinants of health. This paper considers the extent to which primary health care services in Australia are able to respond to this call. We report on interview data from an empirical study of primary health care centres in Adelaide and Alice Springs, Australia. METHODS: Sixty-eight interviews were held with staff and managers at six case study primary health care services, regional health executives, and departmental funders to explore how their work responded to the social determinants of health and the dilemmas in doing so. The six case study sites included an Aboriginal Community Controlled Organisation, a sexual health non government organisation, and four services funded and managed by the South Australian government. RESULTS: While respondents varied in the extent to which they exhibited an understanding of social determinants most were reflexive about the constraints on their ability to take action. Services' responses to social determinants included delivering services in a way that takes account of the limitations individuals face from their life circumstances, and physical spaces in the primary health care services being designed to do more than simply deliver services to individuals. The services also undertake advocacy for policies that create healthier communities but note barriers to them doing this work. Our findings suggest that primary health care workers are required to transverse "dilemmatic space" in their work. CONCLUSIONS: The absence of systematic supportive policy, frameworks and structure means that it is hard for PHC services to act on the Commission on the Social Determinants of Health's recommendations. Our study does, however, provide evidence of the potential for PHC services to be more responsive to social determinants given more support and by building alliances with communities and social movements. Further research on the value of community control of PHC services and the types of policy, resource and managerial environments that support action on social determinants is warranted by this study's findings. PMID- 23663306 TI - Molecular differentiation of Trichinella spiralis, T. pseudospiralis, T. papuae and T. zimbabwensis by pyrosequencing. AB - Nematodes of the genus Trichinella which infect wildlife and domestic animals show a cosmopolitan distribution. These zoonotic parasites are the aetiological agents of a severe human disease, trichinellosis. Twelve taxa are recognized in the Trichinella genus, but they cannot be identified by morphology since they are sibling species/genotypes. For epidemiological studies, it is extremely important to identify each taxon since they have different distribution areas and host ranges. In the present study, polymerase chain reaction (PCR) amplification of the mitochondrial large subunit ribosomal RNA (lsu-RNA) gene coupled with a pyrosequencing technique was developed to distinguish among four Trichinella species: Trichinella spiralis, T. pseudospiralis, T. papuae and T. zimbabwensis. A PCR method was used to amplify the lsu-RNA of Trichinella sp. larvae in mouse muscles and single larvae collected from infected muscles by digestion. The results show that the four Trichinella species can be distinguished by using 26 nucleotides in the target region and the method is sensitive enough to identify individual larvae. The pyrosequencing provides a simple, rapid and high throughput tool for the differentiation of Trichinella species. PMID- 23663305 TI - Nurses' workarounds in acute healthcare settings: a scoping review. AB - BACKGROUND: Workarounds circumvent or temporarily 'fix' perceived workflow hindrances to meet a goal or to achieve it more readily. Behaviours fitting the definition of workarounds often include violations, deviations, problem solving, improvisations, procedural failures and shortcuts. Clinicians implement workarounds in response to the complexity of delivering patient care. One imperative to understand workarounds lies in their influence on patient safety. This paper assesses the peer reviewed empirical evidence available on the use, proliferation, conceptualisation, rationalisation and perceived impact of nurses' use of workarounds in acute care settings. METHODS: A literature assessment was undertaken in 2011-2012. Snowballing technique, reference tracking, and a systematic search of twelve academic databases were conducted to identify peer reviewed published studies in acute care settings examining nurses' workarounds. Selection criteria were applied across three phases. 58 studies were included in the final analysis and synthesis. Using an analytic frame, these studies were interrogated for: workarounds implemented in acute care settings by nurses; factors contributing to the development and proliferation of workarounds; the perceived impact of workarounds; and empirical evidence of nurses' conceptualisation and rationalisation of workarounds. RESULTS: The majority of studies examining nurses' workarounds have been published since 2008, predominantly in the United States. Studies conducted across a variety of acute care settings use diverse data collection methods. Nurses' workarounds, primarily perceived negatively, are both individually and collectively enacted. Organisational, work process, patient-related, individual, social and professional factors contribute to the proliferation of workarounds. Group norms, local and organisational culture, 'being competent', and collegiality influence the implementation of workarounds. CONCLUSION: Workarounds enable, yet potentially compromise, the execution of patient care. In some contexts such improvisations may be deemed necessary to the successful implementation of quality care, in others they are counterproductive. Workarounds have individual and cooperative characteristics. Few studies examine nurses' individual and collective conceptualisation and rationalisation of workarounds or measure their impact. The importance of displaying competency (image management), collegiality and organisational and cultural norms play a role in nurses' use of workarounds. PMID- 23663307 TI - A responsible way to treat patients and pain. PMID- 23663309 TI - 2:1 pacemaker block below the upper tracking rate. PMID- 23663308 TI - A burst of ABC genes in the genome of the polyphagous spider mite Tetranychus urticae. AB - BACKGROUND: The ABC (ATP-binding cassette) gene superfamily is widespread across all living species. The majority of ABC genes encode ABC transporters, which are membrane-spanning proteins capable of transferring substrates across biological membranes by hydrolyzing ATP. Although ABC transporters have often been associated with resistance to drugs and toxic compounds, within the Arthropoda ABC gene families have only been characterized in detail in several insects and a crustacean. In this study, we report a genome-wide survey and expression analysis of the ABC gene superfamily in the spider mite, Tetranychus urticae, a chelicerate ~ 450 million years diverged from other Arthropod lineages. T. urticae is a major agricultural pest, and is among of the most polyphagous arthropod herbivores known. The species resists a staggering array of toxic plant secondary metabolites, and has developed resistance to all major classes of pesticides in use for its control. RESULTS: We identified 103 ABC genes in the T. urticae genome, the highest number discovered in a metazoan species to date. Within the T. urticae ABC gene set, all members of the eight currently described subfamilies (A to H) were detected. A phylogenetic analysis revealed that the high number of ABC genes in T. urticae is due primarily to lineage-specific expansions of ABC genes within the ABCC, ABCG and ABCH subfamilies. In particular, the ABCC subfamily harbors the highest number of T. urticae ABC genes (39). In a comparative genomic analysis, we found clear orthologous relationships between a subset of T. urticae ABC proteins and ABC proteins in both vertebrates and invertebrates known to be involved in fundamental cellular processes. These included members of the ABCB-half transporters, and the ABCD, ABCE and ABCF families. Furthermore, one-to-one orthologues could be distinguished between T. urticae proteins and human ABCC10, ABCG5 and ABCG8, the Drosophila melanogaster sulfonylurea receptor and ecdysone-regulated transporter E23. Finally, expression profiling revealed that ABC genes in the ABCC, ABCG ABCH subfamilies were differentially expressed in multi-pesticide resistant mite strains and/or in mites transferred to challenging (toxic) host plants. CONCLUSIONS: In this study we present the first comprehensive analysis of ABC genes in a polyphagous arthropod herbivore. We demonstrate that the broad plant host range and high levels of pesticide resistance in T. urticae are associated with lineage-specific expansions of ABC genes, many of which respond transcriptionally to xenobiotic exposure. This ABC catalogue will serve as a basis for future biochemical and toxicological studies. Obtaining functional evidence that these ABC subfamilies contribute to xenobiotic tolerance should be the priority of future research. PMID- 23663310 TI - Investigating highly replicated asthma genes as candidate genes for allergic rhinitis. AB - BACKGROUND: Asthma genetics has been extensively studied and many genes have been associated with the development or severity of this disease. In contrast, the genetic basis of allergic rhinitis (AR) has not been evaluated as extensively. It is well known that asthma is closely related with AR since a large proportion of individuals with asthma also present symptoms of AR, and patients with AR have a 5-6 fold increased risk of developing asthma. Thus, the relevance of asthma candidate genes as predisposing factors for AR is worth investigating. The present study was designed to investigate if SNPs in highly replicated asthma genes are associated with the occurrence of AR. METHODS: A total of 192 SNPs from 21 asthma candidate genes reported to be associated with asthma in 6 or more unrelated studies were genotyped in a Swedish population with 246 AR patients and 431 controls. Genotypes for 429 SNPs from the same set of genes were also extracted from a Singapore Chinese genome-wide dataset which consisted of 456 AR cases and 486 controls. All SNPs were subsequently analyzed for association with AR and their influence on allergic sensitization to common allergens. RESULTS: A limited number of potential associations were observed and the overall pattern of P-values corresponds well to the expectations in the absence of an effect. However, in the tests of allele effects in the Chinese population the number of significant P-values exceeds the expectations. The strongest signals were found for SNPs in NPSR1 and CTLA4. In these genes, a total of nine SNPs showed P-values <0.001 with corresponding Q-values <0.05. In the NPSR1 gene some P-values were lower than the Bonferroni correction level. Reanalysis after elimination of all patients with asthmatic symptoms excluded asthma as a confounding factor in our results. Weaker indications were found for IL13 and GSTP1 with respect to sensitization to birch pollen in the Swedish population. CONCLUSIONS: Genetic variation in the majority of the highly replicated asthma genes were not associated to AR in our populations which suggest that asthma and AR could have less in common than previously anticipated. However, NPSR1 and CTLA4 can be genetic links between AR and asthma and associations of polymorphisms in NPSR1 with AR have not been reported previously. PMID- 23663311 TI - Color plumage polymorphism and predator mimicry in brood parasites. AB - BACKGROUND: Plumage polymorphism may evolve during coevolution between brood parasites and their hosts if rare morph(s), by contravening host search image, evade host recognition systems better than common variant(s). Females of the parasitic common cuckoo (Cuculus canorus) are a classic example of discrete color polymorphism: gray females supposedly mimic the sparrowhawk (Accipiter nisus), while rufous females are believed to mimic the kestrel (Falco tinnunculus). Despite many studies on host responses to adult cuckoos comprehensive tests of the "hawk mimicry" and "kestrel mimicry" hypotheses are lacking so far. RESULTS: We tested these hypotheses by examining host responses to stuffed dummies of the sparrowhawk, kestrel, cuckoo and the innocuous turtle dove (Streptopelia turtur) as a control at the nest. Our experimental data from an aggressive cuckoo host, the great reed warbler (Acrocephalus arundinaceus), showed low effectiveness of cuckoo-predator mimicry against more aggressive hosts regardless of the type of model and the degree of perfection of the mimic. Specifically, warblers discriminated gray cuckoos from sparrowhawks but did not discriminate rufous cuckoos from kestrels. However, both gray and rufous cuckoos were attacked vigorously and much more than control doves. The ratio of aggression to gray vs. rufous cuckoo was very similar to the ratio between frequencies of gray vs. rufous cuckoo morphs in our study population. CONCLUSIONS: Overall, our data combined with previous results from other localities suggest polymorphism dynamics are not strongly affected by local predator model frequencies. Instead, hosts responses and discrimination abilities are proportional, other things being equal, to the frequency with which hosts encounter various cuckoo morphs near their nests. This suggests that female cuckoo polymorphism is a counter adaptation to thwart a specific host adaptation, namely an ability to not be fooled by predator mimicry. We hypothesize the dangerousness of a particular model predator (sparrowhawks are more dangerous to adult birds than kestrels) may be another important factor responsible for better discrimination between the gray cuckoo and its model rather than between the rufous cuckoo and its model. We also provide a review of relevant existing literature, detailed discussion of plumage polymorphism in cuckoos, methodological recommendations and new ideas for future work. PMID- 23663312 TI - Applications of predictive control in neuroscience. AB - The sensory cortex has been interpreted as coding information rather than stimulus properties since Sokolov in 1960 showed increased response to an unexpected stimulus decrement. The motor cortex is also organized around expectation, coding the goal of an act rather than a set of muscle movements. Expectation drives not only immediate responses but also the very structure of the cortex, as demonstrated by development of receptive fields that mirror the structure of the visual world. PMID- 23663314 TI - Ketamine in pain management. AB - For ketamine's fiftieth birthday, a narrative review of this unique drug in pain management is presented. Its history is traced from its conception, and its heritage, as a phencyclidine offspring, delineated. The earliest roots of the conceptions concerning the mechanisms of action are sought, and then followed in preclinical as well as clinical research. The major proposed mechanisms in the literature are commented on and evaluated. The growth of the clinical evidence for perioperative pain, acute pain, and chronic pain is followed from early attempts to systematic reviews. Finally, an attempt is made to foresee what the next 50 years might hold in store for our 50 years old. PMID- 23663313 TI - How to feed small for gestational age newborns. AB - Feeding small for gestational age (SGA) newborns is extremely challenging and the neonatologist should be brave and cautious at the same time. Although these babies have a high risk of milk intolerance and necrotising enterocolitis, enteral feeding guidelines are not well established and practice varies widely among different neonatal units. Currently available studies on this topic include extremely and very low birth weight neonates, but are not focused specifically on small for gestational age infants. This review analyzes papers focused on feeding interventions in order to provide the best available evidences about the optimum timing for introduction of enteral feeding, how fast feed volume can be advanced, which milk and which feeding method is more appropriate in SGA infants. PMID- 23663315 TI - Capacity of middle management in health-care organizations for working with people-the case of Slovenian hospitals. AB - BACKGROUND: Effective human resources management plays a vital role in the success of health-care sector reform. Leaders are selected for their clinical expertise and not their management skills, which is often the case at the middle management level. The purpose of this study was to examine the situation in some fields that involve working with people in health-care organizations at middle management level. METHODS: The study included eight state-owned hospitals in Slovenia. A cross-sectional study included 119 middle managers and 778 employees. Quota sampling was used for the subgroups. Structured survey questionnaires were administered to leaders and employees, each consisting of 24 statements in four content sets evaluated on a 5-point Likert-type scale. Respondents were also asked about the type and number of training or education programmes they had participated in over the last three years. Descriptive statistics, two-way analysis of variance, Pearson's correlation coefficient and multiple linear regression were used. The study was conducted from March to December 2008. RESULTS: Statistically significant differences were established between leaders and employees in all content sets; no significant differences were found when comparing health-care providers and health-administration workers. Employment position was found to be a significant predictor for employee development (beta = 0.273, P < 0.001), the leader-employee relationship (beta = 0.291, P < 0.001) and organizational motivation (beta = 0.258, P < 0.001). Area of work (beta = 0.113, P = 0.010) and employment position (beta = 0.389, P < 0.001) were significant predictors for personal involvement. Level of education correlated negatively with total scores for organizational motivation: respondents with a higher level of education were rated with a lower score (beta = -0.117, P = 0.024). Health care providers participate in management programmes less frequently than do health-administration workers. CONCLUSION: Employee participation in change implementation processes was low, as was awareness of the importance of employee development. Education of employees in Slovenian hospitals for leadership roles is still not perceived as a necessary investment for improving work processes. Hospitals are state owned and a national strategy should be developed on how to improve leadership and management in Slovenian hospitals. PMID- 23663316 TI - In vitro study of isoflavones and isoflavans as potent inhibitors of human 12- and 15-lipoxygenases. AB - In this study, we have investigated 16 isoflavone and isoflavan derivatives as potential inhibitors of human lipoxygenase (platelet 12-lipoxygenase, reticulocyte 15-lipoxygenase-1, and epithelial 15-lipoxygenase-2). The flavonoid baicalein, a known lipoxygenase inhibitor, was used as positive control. Four compounds, 6,7-dihydroxy-3'-chloroisoflavone (1c), 7-hydroxy-8-methyl-4' chloroisoflavan (5a), 7,8-dihydroxy-4'-methylisoflavan (5b), and 7,8-dihydroxy-3' methylisoflavan (5c), were effective inhibitors of 12-lipoxygenases and 15 lipoxygenase-1 with IC50 's <10 MUm, while 6,7-dihydroxy-4'-nitroisoflavone (1b) was a selective inhibitor of 12-lipoxygenases. Docking studies, antioxidant assays, and kinetic measurements were carried out for the three best inhibitors (1b, 5b, 5c). The results showed that a catechol group in ring A is critical for the antioxidant properties of these compounds, and probably essential for their inhibitory activity. Kinetic assays showed that compounds 1b, 5b, and 5c are competitive inhibitors with Ki values in the range of 0.3-3 MUm. PMID- 23663317 TI - The new age of play audiometry: prospective validation testing of an iPad-based play audiometer. AB - OBJECTIVE: The timely diagnosis of hearing loss in the pediatric population has significant implications for a child's development. However, audiological evaluation in this population poses unique challenges due to difficulties with patient cooperation. Though specialized adaptations exist (such as conditioned play audiometry), these methods can be time consuming and costly. The objective of this study was to validate an iPad-based play audiometer that addresses the shortcomings of existing audiometry. METHODS: We designed a novel, interactive game for the Apple(r) iPad(r) that tests pure tone thresholds. In a prospective, randomized study, the efficacy of this tool was compared to standard play audiometry. 85 consecutive patients presenting to the Audiology Clinic at the Children's Hospital of Eastern Ontario (ages 3 and older) were recruited into this study. Their hearing was evaluated using both tablet and traditional play audiometry. OUTCOME MEASURE: Warble-tone thresholds obtained by both tablet and traditional audiometry. RESULTS: The majority of children in this age group were capable of completing an audiologic assessment using the tablet computer. The data demonstrate no statistically significant difference between warble-tone thresholds obtained by tablet and traditional audiometry (p=0.29). Moreover, the tablet audiometer demonstrates strong sensitivity (93.3%), specificity (94.5%) and negative predictive value (98.1%). CONCLUSION: The tablet audiometer is a valid and sensitive instrument for screening and assessment of warble-tone thresholds in children. PMID- 23663319 TI - Donor Vdelta1+ gammadelta T cells expand after allogeneic hematopoietic stem cell transplantation and show reactivity against CMV-infected cells but not against progressing B-CLL. AB - gammadelta T lymphocytes play an important role in immune reactions towards infections and malignancies. In particular, Vgamma9-Vdelta1+ T lymphocytes are thought to play protective antiviral roles in human CMV infection. Recently, Vdelta1+ T lymphocytes were proposed to also have anti- B-CLL reactivity. Here we report a case of 48-year-old man who received allogeneic stem cell transplantation for progressive B-CLL. Within one year after transplantation, lymphoma relapsed despite a dramatic increase of Vdelta1+ T cells in the patient's blood. In vitro killing assays revealed activity of patient's gammadelta cells against CMV target cells, but not against the relapsing lymphoma cells. This argues for a contribution of Vdelta1+ cells in the immune reaction against CMV reactivation, but does not support a strong correlation of expanded Vdelta1+ T cells and favorable disease outcome in B-CLL patients. PMID- 23663318 TI - Compassion fatigue and satisfaction: a cross-sectional survey among US healthcare workers. AB - Professional quality of life among healthcare providers can impact the quality and safety of patient care. The purpose of this research was to investigate compassion satisfaction and compassion fatigue levels as measured by the Professional Quality of Life Scale self-report instrument in a community hospital in the United States. A cross-sectional survey study examined differences among 139 RNs, physicians, and nursing assistants. Relationships among individual and organizational variables were explored. Caregivers for critical patients scored significantly lower on the Professional Quality of Life subscale of burnout when compared with those working in a noncritical care unit. Linear regression results indicate that high sleep levels and employment in critical care areas are associated with less burnout. Identification of predictors can be used to design interventions that address modifiable risks. PMID- 23663321 TI - Propranolol for infantile haemangiomas: initiating treatment on an outpatient basis. PMID- 23663320 TI - Normal cognition in transgenic BRI2-Abeta mice. AB - BACKGROUND: Recent research in Alzheimer's disease (AD) field has been focused on the potential role of the amyloid-beta protein that is derived from the transmembrane amyloid precursor protein (APP) in directly mediating cognitive impairment in AD. Transgenic mouse models overexpressing APP develop robust AD like amyloid pathology in the brain and show various levels of cognitive decline. In the present study, we examined the cognition of the BRI2-Abeta transgenic mouse model in which secreted extracellular Abeta1-40, Abeta1-42 or both Abeta1 40/Abeta1-42 peptides are generated from the BRI-Abeta fusion proteins encoded by the transgenes. BRI2-Abeta mice produce high levels of Abeta peptides and BRI2 Abeta1-42 mice develop amyloid pathology that is similar to the pathology observed in mutant human APP transgenic models. RESULTS: Using established behavioral tests that reveal deficits in APP transgenic models, BRI2-Abeta1-42 mice showed completely intact cognitive performance at ages both pre and post amyloid plaque formation. BRI2-Abeta mice producing Abeta1-40 or both peptides were also cognitively intact. CONCLUSIONS: These data indicate that high levels of Abeta1-40 or Abeta1-42, or both produced in the absence of APP overexpression do not reproduce memory deficits observed in APP transgenic mouse models. This outcome is supportive of recent data suggesting that APP processing derivatives or the overexpression of full length APP may contribute to cognitive decline in APP transgenic mouse models. Alternatively, Abeta aggregates may impact cognition by a mechanism that is not fully recapitulated in these BRI2-Abeta mouse models. PMID- 23663322 TI - Lipids for intravenous nutrition in hospitalised adult patients: a multiple choice of options. AB - Lipids used in parenteral nutrition provide energy, building blocks and essential fatty acids. Traditionally, these lipids have been based on n-6 PUFA-rich vegetable oils particularly soyabean oil. This may not be optimal because soyabean oil may present an excessive supply of linoleic acid. Alternatives to use of soyabean oil include its partial replacement by medium-chain TAG, olive oil or fish oil, either alone or in combination. Lipid emulsions containing these alternatives are well tolerated without adverse effects in a wide range of hospitalised adult patients. Lipid emulsions that include fish oil have been used in parenteral nutrition in adult patients' post-surgery (mainly gastrointestinal). This has been associated with alterations in patterns of inflammatory mediators and in immune function and, in some studies, a reduction in length of intensive care unit and hospital stay. These benefits are emphasised through recent meta-analyses. Perioperative administration of fish oil may be superior to post-operative administration. Parenteral fish oil has been used in critically ill adults. Here, the influence on inflammatory processes, immune function and clinical endpoints is not clear, since there are too few studies and those that are available report contradictory findings. However, some studies found reduced inflammation, improved gas exchange and shorter length of hospital stay in critically ill patients if they receive fish oil. More and better trials are needed in patient groups in which parenteral nutrition is used and where fish oil may offer benefits. PMID- 23663323 TI - Development and pilot outcome data of a midlife women's health assessment clinic: a comprehensive and multidisciplinary approach to health care. AB - INTRODUCTION: As women enter midlife, health issues and chronic health problems can emerge. The University of Utah Health Science Center's Midlife Women's Health Assessment Clinic was developed to provide a personalized approach to healthy aging by individual assessment, group education, motivational interviewing, and wellness coaching to women. This article describes the model of care and an initial evaluation of this model. METHODS: Four pilot clinics were conducted to determine if the model would be successful. Data analyzed included patient history questionnaires, laboratory and diagnostic test results, new diagnoses, and follow-up recommendations; telephone surveys of patients 2 to 4 weeks after clinic visits; and verbal queries of clinicians about their experiences and recommendations for improving the clinics. RESULTS: Among the 62 women attending the clinics, the most frequent concern was healthy aging. Two-thirds of the women had new diagnoses during the clinics. Both the women and clinicians participating positively evaluated the pilot clinics. DISCUSSION: This model of care could be replicated to provide comprehensive and efficient health care to aging women in a variety of settings. PMID- 23663324 TI - Predictions in the light of your own action repertoire as a general computational principle. AB - We argue that brains generate predictions only within the constraints of the action repertoire. This makes the computational complexity tractable and fosters a step-by-step parallel development of sensory and motor systems. Hence, it is more of a benefit than a literal constraint and may serve as a universal normative principle to understand sensorimotor coupling and interactions with the world. PMID- 23663325 TI - Modulation of airway epithelial cell functions by Pidotimod: NF-kB cytoplasmatic expression and its nuclear translocation are associated with an increased TLR-2 expression. AB - BACKGROUND: Recurrent respiratory infections are one of the most important causes of morbidity in childhood. When immune functions are still largely immature, the airway epithelium plays a primary defensive role since, besides providing a physical barrier, it is also involved in the innate and the adaptive immune responses. A study was therefore designed to evaluate in vitro whether pidotimod, a synthetic dipeptide able to stimulate the inflammatory and immune effector cells, could activate bronchial epithelial cell functions involved in response to infections. METHODS: BEAS-2B cell line (human bronchial epithelial cells infected with a replication-defective Adenovirus 12-SV40 virus hybrid) were cultured in the presence of pidotimod, with or without tumor necrosis factor (TNF)-alpha or zymosan to assess: a) intercellular adhesion molecule (ICAM)-1 expression, by flow cytometry; b) toll-like receptor (TLR)-2 expression and production, by immunofluorescence flow cytometry and western blotting; d) interleukin (IL)-8 release, by enzyme-linked immunosorbent assay (ELISA); e) activated extracellular signal-regulated kinase (ERK1/2) phosphorylation and nuclear factor-kappa B (NF kB) activation, by western blotting. RESULTS: The constitutive expression of ICAM 1 and IL-8 release were significant up-regulated by TNF-alpha (ICAM-1) and by TNF alpha and zymosan (IL-8), but not by pidotimod. In contrast, an increased TLR-2 expression was found after exposure to pidotimod 10 and 100 MUg/ml (p < 0.05) and to the association pidotimod 100 MUg/ml + TNF-alpha (p < 0.05). Western blot analysis substantiated that the constitutive TLR-2 expression was significantly increased after exposure to all the stimuli. Finally, while a remarkable inhibition of TNF-alpha -induced ERK1/2 phosphorylation was observed in the presence of pidotimod, both TNF-alpha and pidotimod were effective in inducing NF kB protein expression in the cytoplasm and its nuclear translocation. CONCLUSION: Through different effects on ERK1/2 and NF-kB, pidotimod was able to increase the expression of TLR-2 proteins, surface molecules involved in the initiation of the innate response to infectious stimuli. The lack of effect on ICAM-1 expression, the receptor for rhinovirus, and on IL-8 release, the potent chemotactic factor for neutrophils (that are already present in sites of infection), may represent protective functions. If confirmed in vivo, these activities may, at least in part, clarify the mechanism of action of this molecule at airway level. PMID- 23663326 TI - Genome-wide identification, characterization and expression analysis of populus leucine-rich repeat receptor-like protein kinase genes. AB - BACKGROUND: Leucine-rich repeat receptor-like kinases (LRR-RLKs) comprise the largest group within the receptor-like kinase (RLK) superfamily in plants. This gene family plays critical and diverse roles in plant growth, development and stress response. Although the LRR-RLK families in Arabidopsis and rice have been previously analyzed, no comprehensive studies have been performed on this gene family in tree species. RESULTS: In this work, 379 LRR-RLK genes were retrieved from the Populus trichocarpa genome and further grouped into 14 subfamilies based on their structural and sequence similarities. Approximately 82% (312 out of 379) of the PtLRR-RLK genes are located in segmental duplication blocks indicating the role of duplication process in the expansion of this gene family. The conservation and variation in motif composition and intron/exon arrangement among PtLRR-RLK subfamilies were analyzed to provide additional support for their phylogenetic relationship and more importantly to indicate the potential divergence in their functions. Expression profiling of PtLRR-RLKs showed that they were differentially expressed in different organs and tissues and some PtLRR RLKs were specifically expressed in meristem tissues, which indicated their potential involvement in tissue development and differentiation. For most AtLRR RLKs with defined functions, Populus homologues exhibiting similar expression patterns could be identified, which might indicate the functional conservation during evolution. Among 12 types of environmental cues analyzed by the genome wide microarray data, PtLRR-RLKs showed specific responses to shoot organogenesis, wounding, low ammonium feeding, hypoxia and seasonal dormancy, but not to drought, re-watering after drought, flooding, AlCl3 treatment and bacteria or fungi treatments. CONCLUSIONS: This study provides the first comprehensive genomic analysis of the Populus LRR-RLK gene family. Segmental duplication contributes significantly to the expansion of this gene family. Populus and Arabidopsis LRR-RLK homologues not only share similar genetic structures but also exhibit comparable expression patterns which point to the possible functional conservation of these LRR-RLKs in two model systems. Transcriptome profiling provides the first insight into the functional divergence among PtLRR-RLK gene subfamilies and suggests that they might take important roles in growth and adaptation of tree species. PMID- 23663327 TI - "Communicate to vaccinate": the development of a taxonomy of communication interventions to improve routine childhood vaccination. AB - BACKGROUND: Vaccination is a cost-effective public health measure and is central to the Millennium Development Goal of reducing child mortality. However, childhood vaccination coverage remains sub-optimal in many settings. While communication is a key feature of vaccination programmes, we are not aware of any comprehensive approach to organising the broad range of communication interventions that can be delivered to parents and communities to improve vaccination coverage. Developing a classification system (taxonomy) organised into conceptually similar categories will aid in: understanding the relationships between different types of communication interventions; facilitating conceptual mapping of these interventions; clarifying the key purposes and features of interventions to aid implementation and evaluation; and identifying areas where evidence is strong and where there are gaps. This paper reports on the development of the 'Communicate to vaccinate' taxonomy. METHODS: The taxonomy was developed in two stages. Stage 1 included: 1) forming an advisory group; 2) searching for descriptions of interventions in trials (CENTRAL database) and general health literature (Medline); 3) developing a sampling strategy; 4) screening the search results; 5) developing a data extraction form; and 6) extracting intervention data. Stage 2 included: 1) grouping the interventions according to purpose; 2) holding deliberative forums in English and French with key vaccination stakeholders to gather feedback; 3) conducting a targeted search of grey literature to supplement the taxonomy; 4) finalising the taxonomy based on the input provided. RESULTS: The taxonomy includes seven main categories of communication interventions: inform or educate, remind or recall, teach skills, provide support, facilitate decision making, enable communication and enhance community ownership. These categories are broken down into 43 intervention types across three target groups: parents or soon-to-be-parents; communities, community members or volunteers; and health care providers. CONCLUSIONS: Our taxonomy illuminates and organises this field and identifies the range of available communication interventions to increase routine childhood vaccination uptake. We have utilised a variety of data sources, capturing information from rigorous evaluations such as randomised trials as well as experiences and knowledge of practitioners and vaccination stakeholders. The taxonomy reflects current public health practice and can guide the future development of vaccination programmes. PMID- 23663328 TI - Systematic review on measurement properties of questionnaires assessing the neighbourhood environment in the context of youth physical activity behaviour. AB - BACKGROUND: High-quality measurement instruments for assessing the neighbourhood environment are a prerequisite for identifying associations between the neighbourhood environment and a person's physical activity. The aim of this systematic review was to identify reliable and valid questionnaires assessing neighbourhood environmental attributes in the context of physical activity behaviours in children and adolescents. In addition, current gaps and best practice models in instrumentation and their evaluation are discussed. METHODS: We conducted a systematic literature search using six databases (Web of Science, Medline, TRID, SportDISCUS, PsycARTICLES and PsycINFO). Two independent reviewers screened the identified English-language peer-reviewed journal articles. Only studies examining the measurement properties of self- or proxy-report questionnaires on any aspects of the neighbourhood environment in children and adolescents aged 3 to 18 years were included. The methodological quality of the included studies was assessed using the COSMIN checklists. RESULTS: We identified 13 questionnaires on attributes of the neighbourhood environment. Most of these studies were conducted in the United States (n = 7). Eight studies evaluated self report measures, two studies evaluated parent-report measures and three studies included both administration types. While eight studies had poor methodological quality, we identified three questionnaires with substantial test-retest reliability and two questionnaires with acceptable convergent validity based on sufficient evidential basis. CONCLUSIONS: Based on the results of this review, we recommend that cross-culturally adapted questionnaires should be used and that existing questionnaires should be evaluated especially in diverse samples and in countries other than the United States. Further, high-quality studies on measurement properties should be promoted and measurement models (formative vs. reflexive) should be specified to ensure that appropriate methods for psychometric testing are applied in future studies. PMID- 23663329 TI - Ten principles of good interdisciplinary team work. AB - BACKGROUND: Interdisciplinary team work is increasingly prevalent, supported by policies and practices that bring care closer to the patient and challenge traditional professional boundaries. To date, there has been a great deal of emphasis on the processes of team work, and in some cases, outcomes. METHOD: This study draws on two sources of knowledge to identify the attributes of a good interdisciplinary team; a published systematic review of the literature on interdisciplinary team work, and the perceptions of over 253 staff from 11 community rehabilitation and intermediate care teams in the UK. These data sources were merged using qualitative content analysis to arrive at a framework that identifies characteristics and proposes ten competencies that support effective interdisciplinary team work. RESULTS: Ten characteristics underpinning effective interdisciplinary team work were identified: positive leadership and management attributes; communication strategies and structures; personal rewards, training and development; appropriate resources and procedures; appropriate skill mix; supportive team climate; individual characteristics that support interdisciplinary team work; clarity of vision; quality and outcomes of care; and respecting and understanding roles. CONCLUSIONS: We propose competency statements that an effective interdisciplinary team functioning at a high level should demonstrate. PMID- 23663330 TI - Kir6.1 knockdown aggravates cerebral ischemia/reperfusion-induced neural injury in mice. AB - BACKGROUND AND PURPOSE: ATP-sensitive potassium (K-ATP) channels couple energy metabolism with electric activity, which play important roles in brain diseases including stroke. However, the impacts of Kir6.1-containing K-ATP channels that mainly expressed on glia in stroke remain unclear. METHODS AND RESULTS: In this study, we found that expression of Kir6.1 was significantly decreased in the ischemic brain area of C57BL/6J mice after 1-h middle cerebral artery occlusion (MCAO) and 24-h reperfusion. Then, we subjected Kir6.1 heterozygote knockout (Kir6.1(+/-) ) mice to cerebral ischemia/reperfusion (I/R) injury and found that Kir6.1(+/-) mice exhibited exacerbated neurological disorder and enlarged infarct size, companied by glial over-activation and blood-brain barrier (BBB) damages. Furthermore, we showed that Kir6.1 knockdown aggravated endoplasmic reticulum (ER) stress and thereby increased the levels of proinflammatory factors tumor necrosis factor-alpha and interleukin-1beta (TNF-alpha and IL-1beta) in mouse brain. CONCLUSIONS: Our findings reveal that Kir6.1 knockdown exacerbates cerebral I/R-induced brain damages via increasing ER stress and inflammatory response, indicating that Kir6.1-containing K-ATP channels may be a potential therapeutic target for stroke. PMID- 23663331 TI - [Analysis of propionylcarnitine in blood and methylmalonic acid in urine of 162 patients with methylmalonic acidemia]. AB - OBJECTIVE: To analyze the levels of methylmalonic acid and methylcitrate in urine, propionylcarnitine (C3) in plasma and C3/acetylcarnitine (C2) of patients with methylmalonic acidemia (MMA) and explore their applications in the diagnosis of MMA. METHODS: From December 2003 to March 2012, a total of 162 patients with MMA (MMA group) and 200 healthy children (control group) of Xinhua Hospital, Shanghai Jiaotong University School of Medicine were recruited. MMA patients with a definite classification were divided into 2 groups: isolate MMA group (n = 51) and MMA complicated with homocysteinemia group (n = 65). Gas chromatography-mass spectrometry was used to measure the urine levels of methylmalonic acid and methylcitrate and tandem mass spectrometry to measure the blood levels of free carnitine (C0), acylcarnitines and methionine (Met). RESULTS: In the MMA group, the median levels of methylmalonic acid (259.10 (6.73 - 6429.28)), methylcitrate (4.39 (0 - 248.96)), C3 (8.52 (1.50 - 52.11) umol/L) and C3/C2 (0.73(0.28 - 2.89)) were all higher than the upper limit values (0.2 - 3.6, 0 - 1.1, 0.50 - 4.00 umol/L and 0.04 - 0.25 respectively). And they were all higher than those in the control group (0 (0 - 1.87), 0.10 (0 - 1.84), 1.40 (0.53 - 3.90) umol/L, 0.10 (0.04 - 0.23), all P < 0.01). C3/C2 increased significantly in 15 patients while the C3 level remained normal. The median level of Met was normal in the isolate MMA group. But in patients with homocysteinemia, the level of 8.71 (0.68 - 31.95) umol/L was below the reference value (10.00 - 35.00 umol/L) and lower than that in the isolate MMA group (15.35 (4.18 - 59.50) umol/L) and the control group (15.59 (10.20 - 34.68) umol/L, all P < 0.05). CONCLUSIONS: Significant increases in the urine level of methylmalonic acid and C3/C2 may be specific to MMA. Organic acid analyses of gas chromatography-mass spectrometry and acylcarnitines with tandem mass spectrometry are required for a definite diagnosis of this disorder. And repeated tests and genomic mutation analysis are necessary for patients with mildly abnormal biochemical indices. PMID- 23663332 TI - [Brachial ankle pulse wave velocity in the patients of metabolic syndrome]. AB - OBJECTIVE: To investigate the association between metabolic syndrome (MS) and brachial ankle pulse wave velocity (baPWV). METHODS: A total of 5476 subjects were enrolled from annual health checkups. Blood pressure, fasting plasma glucose, waist circumference, triglyceride, cholesterol, high-density and low density lipoprotein cholesterols were measured routinely. And baPWV was determined by VP-1000 (BP-203RPE III). RESULTS: The values of baPWV and its change rates in MS patients were both higher than those in non-MS subjects respectively (1419.0 (1284.0 - 1586.5) cm/s vs 1275.0 (1160.5 - 1419.6) cm/s, 16.3% (6.6% - 27.3%) vs 7.1% (1.0% - 17.2%), both P < 0.01). Systolic blood pressure, fasting blood glucose, low-density lipoprotein cholesterol and triglyceride were the important influencing components of baPWV. CONCLUSION: MS patients have early alterations of arterial wall elasticity and function. And examination of pulse wave velocity helps to screen early arteriosclerosis. PMID- 23663333 TI - [Clinical characteristics of 22 cases of fungal infective endocarditis]. AB - OBJECTIVE: To explore the clinical characteristics, treatment regimens and outcomes of the patients with fungal infective endocarditis. METHODS: An observational study was conducted at our hospital and recruited 22 consecutive patients with a definite diagnosis of fungal infective endocarditis. Their overall characteristics, treatments, complications and outcomes were analyzed. RESULTS: The mean age at presentation was 45 years with a slight male preponderance. Among them, 13 cases had healthcare-associated infective endocarditis and 1 patient was an intravenous drug user. Aortic valve (40.9%) was most commonly affected and it was followed by mitral valve (13.6%). The most common etiological agent was Candida (68.2%), followed by Aspergillus (22.7%). Risk factors include the prosthetic valve replacement surgery, impaired immune function, and so on. Major complications during the acute infective phase were also recorded, including heart failure, embolic events, uncontrolled infections and renal dysfunction. The overall hospital mortality rate was 40.9%. There were 15 patients with antifungal treatment, which including fluconazole, itraconazole, caspofungin acetate and voriconazole itraconazole. The remaining 7 patients (31.8%) underwent valve replacement surgery, including 3 cases of cardiac valve re-replacement. A better outcome was observed in patients on a combined regimen of medical and surgical therapies. CONCLUSIONS: Fungal endocarditis is associated with more invasive interventions and immunocompromised patients. The incidence of embolic events and in-hospital mortality is still high in patients with fungal endocarditis, and the larger vegetation is more common. Heart failure, sepsis and repeated arterial embolization are the most common cause of death. PMID- 23663334 TI - [Epidemiological survey of children asthma prevalence in Beijing urban area]. AB - OBJECTIVE: To explore the prevalence, diagnosis and management of childhood asthma in Beijing urban area. METHODS: Multi-stage, stratified and random cluster sampling was used to recruit children born during November 1, 1995 to October 31, 2010 from Beijing or other provinces but residing in Beijing for over half a year. The same screening questionnaires for the third national epidemiological survey of children's asthma were distributed to parents of children at schools, kindergartens and communities during October 2010 to March 2011. Asthmatic children were picked among the screening-positive children based on on-the-spot inquiries, physical examinations, medical records and supporting test results. Further survey of asthmatics was carried out to investigate the diagnosis and treatment status of childhood asthma and other associated allergic diseases. All data required double entry by Epi-Info 3.5.3 software and were processed by SPSS 19.0. RESULTS: Among a total of 14 085 questionnaires, 13 513 were completed with a response rate of 95.94%. And 497 (3.68%) children were diagnosed with typical (n = 451, 3.34%) and cough variant (n = 46, 0.34%) asthma. Among them, 40.64% (202/497) were newly diagnosed and 59.36% (295/497) had been previously diagnosed with asthma. The prevalence of asthma was higher in boys than in girls (4.80% (345/1790) vs 2.40% (152/6323), chi(2) = 54.446, P < 0.01). The asthma prevalence of preschoolers (3 - < 7 years old) was the highest (5.05% (180/3563)). In the past two years, the symptoms of 69.42% (345/497) children persisted and the current two-year prevalence of asthma was 2.55% (345/13513). Among the 295 children with previous asthma, only 46.44% (137/295) received inhaled corticosteroids according to the Global Initiative for Asthma (GINA) and 82.37% (243/295) of them used antibiotics. CONCLUSIONS: The prevalence of asthma is 3.68% in children under 14 years old in Beijing urban area and it varies in children with different genders and ages. A considerable number of children are not diagnosed or treated properly. And the management of asthma requires further improvement. PMID- 23663335 TI - [Value of adrenal venous sampling in the subtype diagnosis of primary aldosteronism]. AB - OBJECTIVE: To assess the diagnostic value of adrenal venous sampling (AVS) in the subtype diagnosis of primary aldosteronism (PA). METHODS: The diagnosis of PA was made in 36 patients based on an elevated ratio of plasma aldosterone (ALD) to plasma rennin activity (PRA) (ARR) and confirmed tests (saline infusion or captopril challenge) in recent 3 years. All PA patients underwent adrenal computed tomographic scan (CT) and AVS. The diagnostic accuracy of CT and AVS in the subtype differentiation of PA were evaluated by comparing the differences of CT findings, AVS results and clinical outcomes. RESULTS: Fifteen of 36 patients (42%) had a final diagnosis of aldosterone-producing adenoma (APA) and another 21 patients (58%) with bilateral adrenal hyperplasia (BAH). The level of ALD was significantly higher in APA group than that in BAH group (298.9 +/- 91.0 vs 226.3 +/- 59 ng/L, P < 0.05). PRA (ng*ml(-1)*h(-1)) in APA patients were markedly lower than that in BAH counterparts (0.18 +/- 0.14 vs 0.28 +/- 0.29 ng*ml(-1)*h(-1), P < 0.01). Consequently, ARR in APA group was evidently higher than that in BAH group (2444.7 +/- 1405.2 vs 1550.0 +/- 1059.8, P < 0.05). Plasma potassium in APA patients was lower than that in those with BAH (2.71 +/- 0.57 vs 3.17 +/- 0.40 mmol/L). But there was no statistic significance (P > 0.05). The CT findings were discordant with the AVS results in 27.8% of patients (10/36). The accuracy of adrenal CT scan was only 72.2% in the subtype diagnosis of PA, provided AVS was the gold standard for distinguishing between APA and BAH. Reliance on CT findings could lead to inappropriate management in 25% of PA patients. Conversely, the AVS results were concordant with the clinical outcomes in 94.4% of all patients. CONCLUSION: CT scan is not a reliable method of differentiating primary aldosteronism. Compared with CT, AVS is more accurate in establishing a correct diagnosis of primary aldosteronism. AVS should be performed routinely before operation in PA patients opting for adrenalectomy. PMID- 23663336 TI - [Efficacies of hematopoietic stem cell transplantation plus imatinib in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia: a comparative study]. AB - OBJECTIVE: To compare the efficacies of hematopoietic stem cell transplantation with and without imatinib in the treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia by evaluating the post transplantation survival and quality-of-life. METHODS: A total of 35 acute lymphoblastic leukemia patients with Philadelphia chromosome-positive underwent hematopoietic stem cell transplantation from 2003 to 2011. They were divided into the imatinib (n = 23) and control (n = 12) groups. The incidence of graft-versus host disease (GVHD), overall survival (OS), disease-free survival (DFS) and non relapse mortality (NRM) of two groups were compared to identify the superiority of combined treatment. RESULTS: Age, gender, cytogenetic classification, donor type, proposed regimen and counts of infused stem cells were comparable between two groups. The proportion of patients in the first remission (CR1) in the imatinib group was higher than that in control group (20/23 vs 6/12, P = 0.038). However, single factor analysis showed that it did not affect the survival significantly (P = 0.884, 0.924). The estimated incidence of acute GVHD was 45.5% in the imatinib group versus 66.7% in the control group (P = 0.386). And the incidence of acute GVHD of Grades II-IV were 26.1% and 41.7% (P = 0.349) respectively. The estimated 5-year OS of two groups showed statistical difference (62.6% vs 41.7%, P = 0.028) and estimated 5-year DFS were 53.7% and 33.3% respectively (P = 0.054). The 5-year NRM was 41.7% in the control group and the main causes were infection and severe GVHD versus 22.7% in the imatinib group (P = 0.084) and the main cause was infection. The engraftment of white blood cell (median time: 13 vs 11 days, P = 0.008) and platelet (median time: 14 vs 11 days, P = 0.002) was delayed in imatinib group compared with control group. CONCLUSIONS: The patients of Philadelphia chromosome-positive acute lymphoblastic leukemia may acquire a better survival from the combined regimen of hematopoietic stem cell transplantation and imatinib, without increasing the hazard of acute GVHD and NRM. PMID- 23663337 TI - [Surgical treatment for endoscopically unresectable polyps of colon and rectum]. AB - OBJECTIVE: To explore the characteristics and risks of cancer in endoscopically unresectable polyps and compare the surgical outcomes of different operations. METHODS: A retrospective review of 40 patients undergoing surgical operations for polyps unresectable at colonoscopy between August 2006 and July 2012 from Department of Gastrointestinal Surgery was performed. The follow-up period was 3 to 72 months (median: 24.5 months). RESULTS: The rate of endoscopically unresectable polyps with invasive cancer was 67.5% (27/40). And it was significantly influenced by patient age and number of polyps (both P < 0.01). Perioperative volume of blood loss ((86 +/- 58) ml vs (44 +/- 32) ml, P = 0.0066), time to first flatus ((2.7 +/- 1.3) d vs (1.7 +/- 0.6) d, P = 0.0018), incidence of complication (2 cases vs 0, P = 0.0365) and hospital stay ((11.2 +/- 1.0) d vs (15.0 +/- 5.0) d, P = 0.0164) were significantly different between open colectomy and laparoscopic group. And the long-term survival outcomes were similar in both groups (90.9% (10/11) vs 100.0% (27/27), 90.9% (10/11) vs 96.3% (26/27), both P > 0.05). CONCLUSIONS: Endoscopically unresectable polyps of colon and rectum have high malignancy rate. Polyps in elderly patients and multiple polyps are more likely to develop invasive cancer. Long-term outcomes are similar between open colectomy and laparoscopic colectomy groups, but laparoscopic group has better short-term outcomes. For endoscopically unresectable polyps, laparoscopic colectomy may be the first choice. PMID- 23663338 TI - [Clinical and serological analyses of 70 erythrocyte allo-antibodies to MNS blood group system]. AB - OBJECTIVE: To explore the occurrence and clinical significance of erythrocyte allo-antibodies to MNS blood group system among hospitalized patients in China. METHODS: The specificity and clinical features of erythrocyte allo-antibodies detected from August 2009 to July 2012 were retrospectively analyzed. RESULTS: A total of 187 erythrocyte allo-antibodies were detected from 66 042 hospitalized patients (0.28%) among which 70 (37.4%) were specific to MNS blood group system. Antibody frequencies were as follows: anti-M, 18.2%; anti-Mi(a), 18.2%; anti-S, 1.1%. Anti-Mi(a) was more frequent among transfused patients (16/34 vs 5/34, P = 0.004), and tended to be accompanied by other allo-antibodies. CONCLUSIONS: Antibodies to MNS blood group system are second only to Rh system as the most common erythrocyte allo-antibodies in China. And anti-Mi(a) is an important transfusion-related allo-antibody among the patients of southern ancestry. PMID- 23663339 TI - [Case constitution and medication intention of bipolar disordered outpatients at two grade IIIa hospitals in Beijing]. AB - OBJECTIVE: To acquire the case constitution of bipolar disordered (BPD) in mood disordered (MD) outpatients at two local Beijing hospitals to understand the case constitution and medication intention of clinical psychiatrists in terms of differentiation and treatment of BPD. METHODS: All psychiatrists at Anding Hospital and neurological physicians at Xuanwu Hospital were surveyed by self rated questionnaires and the analysis focused on the composition of proportions of BPD cases out of MD patients. The items included estimated ratio of BPD cases, doctors' intention of drug prescription and clinical therapeutic regimen for treatment of BPD. RESULTS: (1) BPD ratio in MD outpatients of two hospitals were 41.79% and 12.24% respectively; (2) Doctor's ratio who estimated BPD ratio in MD cases < 40% were 60% and 100% respectively; (3) 100% psychiatrists at Beijing Anding Hospital and 72.22% neurological physicians at Beijing Xuanwu Hospital prescribed antidepressant to BPD cases; (4) Doctor's ratio who adopted therapeutic schedule of 'antidepressant + mood stabilizer' or 'antidepressant + mood stabilizer + antipsychotic' agents for BPD were 100% and 66.67% respectively. CONCLUSION: Regardless of mental specialized hospital or general hospital, the physicians should pay great attention to the differentiation of BPD and the rationality of drug prescription. PMID- 23663340 TI - [Transurethral plasmakinetic enucleation of prostate and suprapubic small cut in the treatment of high risk and senior patient with benign prostatic hyperplasia and bladder stones]. AB - OBJECTIVE: To explore the safety and efficiency of transurethral plasmakinetic enucleation of prostate (TUPKEP) and suprapubic small cut in the treatment of high-risk and senior patients with benign prostatic hyperplasia and bladder stones. METHODS: A retrospective review was conducted for 68 high-risk and senior patients with benign prostatic hyperplasia and bladder stones. All of them were treated by TUPKEP and suprapubic small cut. RESULTS: Operation was successfully performed in all 68 cases. And there was no instance of transurethral resection syndrome, shock, myocardial infarct, cerebral infarction, cerebral hemorrhage, permanent urinary incontinence or surgical site infection. Seven patients with temporal urinary incontinence recovered at a mean time of (9.48 +/- 1.52) days post-operation. The mean operative duration was (48.63 +/- 4.14) min and the mean volume of blood loss (50.97 +/- 5.33) ml. The changes of maximum flow rate (Qmax), international prostatic symptom score (I-PSS) and quality-of-life (QOL) were statistically significant before and after operation. Qmax increased from (4.56 +/- 0.35) to (18.82 +/- 1.65) ml/s (P < 0.001), I-PSS decreased form (21.96 +/- 1.89) to (11.23 +/- 0.86) (P = 0.018) and QOL decreased from (4.94 +/- 0.35) to (1.95 +/- 0.32) (P = 0.011). CONCLUSION: The approach of TUPKEP and suprapubic small cut is both safe and effective in the treatment of high-risk and senior patient with benign prostatic hyperplasia and bladder stones and should be widely applied. PMID- 23663341 TI - [Clinical study of combined treatment of remifemin and paroxetine for perimenopausal depression]. AB - OBJECTIVE: To explore the efficacies and safety of combined treatment of remifemin and paroxetine for perimenopausal depression. METHODS: A total of 120 patients with perimenopausal depression were digital randomly divided into the treatment and control groups (n = 60 each). The treatment group received oral remifemin one tablet twice daily and paroxetine 20 mg once daily for 2 months while the control group oral paroxetine 20 mg once daily for 2 months. The Hamilton depression scale (HAMD) and Kupperman scale were used to assess the therapeutic efficacies. Blood and urine routine, electrocardiography, liver function, kidney function and blood pressure before and after treatment were examined to assess the side effects. RESULTS: For the improvement of perimenopausal depression on HAMD, the total effective rates of the treatment and control groups were 88.3% and 78.3% respectively. The therapeutic efficacy of the treatment group was significantly higher than that of the control group (P < 0.05). After 8-week treatment, Kupperman menopausal indices of the treatment and control groups were 9.89 +/- 3.76 and 15.75 +/- 5.84 respectively. There was also significant difference (P < 0.01). No significant changes existed in blood routine, urine routine, liver function, kidney function, blood pressure, ECG or blood pressure before and after treatment (P > 0.05). CONCLUSION: The combined treatment of remifemin and paroxetine for perimenopausal depression can improve the efficacies. It is easily accepted by patients for its higher safety and fewer side-effects. It is worthy of a wider application and further researches. PMID- 23663342 TI - [Pathogenic analysis of solid organ transplant recipients with pulmonary opportunistic infections via bronchoscopy]. AB - OBJECTIVE: To evaluate the diagnostic utility of bronchoscopy in solid organ transplant recipients with pulmonary opportunistic infections. METHODS: From December 2006 to September 2011, 117 cases of bronchoscopy with protected specimen brush and bronchoalveolar lavage were performed in 114 solid organ transplant recipients at Tianjin First Central Hospital. The indication for bronchoscopy was suspected pulmonary infections. The bronchoscopic manifestations were described and the specimens analyzed with regards to bacteriology, cytomegalovirus, P carinii, mycobacterium tuberculosis and other fungal cultures. RESULTS: A definite infectious etiology was confirmed in 63 patients (53.8%). And opportunistic infections were the most frequent etiology (56/63, 88.9% including 7 cases with two mixed opportunistic infections). Among 63 pathogens, P carinii was demonstrated in 36 episodes, cytomegalovirus in 24 episodes and mycobacterium tuberculosis in 3 episodes. Bacterial infections (mainly Gram-negative) accounted for 16 of 63 episodes (25.9% including 9 cases with mixed opportunistic/bacterial infection). In accordance with the diagnostic results, antibiotic treatment was changed in 45 cases. CONCLUSIONS: As an extremely useful tool, bronchoscopy is of great value for pathogenic detection in transplant recipients with suspected pulmonary infections, especially for opportunistic infections. And the bronchoscopic findings may guide targeted antimicrobial therapy. PMID- 23663343 TI - [Role of MEK1/ERK1, 2 pathways in the calcium-sensing receptor mediation of hypoxia-induced proliferation of rat pulmonary artery smooth muscle cells]. AB - OBJECTIVE: To explore the cell signal transduction pathway of calcium-sensing receptor (CaSR) mediated hypoxia-induced proliferation of rat pulmonary artery smooth muscle cells (PASMCs). METHODS: The expressions of proliferating cell nuclear antigen (PCNA) and extracellular signal-regulated protein kinase 1, 2 (ERK1, 2) were analyzed by Western blot. Cell proliferation was tested by a 5 bromo-2-deoxyuridine (BrdU) incorporation assay. Cell cycle and proliferation index (PI) were analyzed by flow cytometry. RESULTS: Hypoxia significantly increased the expression of PCNA (0.528 +/- 0.028), p-ERK1, 2 (1.12 +/- 0.05, 0.91 +/- 0.06), BrdU incorporation (143.3 +/- 4.2) and cell proliferation index (12.5 +/- 0.9) (all P < 0.05, versus control group, 0.243 +/- 0.025, 0.47 +/- 0.03, 0.40 +/- 0.03, 100.0 +/- 5.4, 7.5 +/- 1.2). Gadolinium chloride (GdCl3, a CaSR agonist) amplified the effect of hypoxia (0.770 +/- 0.039, 1.50 +/- 0.06, 1.61 +/- 0.05, 187.4 +/- 3.9, 19.8 +/- 0.6, all P < 0.05). PD98059 (a MEK1 inhibitor) decreased the up-regulation of PCNA expression, BrdU incorporation and the increase of cell proliferation index induced by hypoxia and GdCl3 in PASMCs (0.441 +/- 0.020, 0.71 +/- 0.07, 0.72 +/- 0.06, 115.5 +/- 4.0, 9.3 +/- 1.1, all P < 0.05). CONCLUSION: Calcium-sensing receptor mediates hypoxia-induced proliferation of rat pulmonary artery smooth muscle cells through ERK1, 2 pathways. PMID- 23663344 TI - [Impacts of atovastatin and tinidazole on cardiac muscle inflammation factors of tumor necrosis factor-alpha, interleukin-1 and metalloproteinase-2 of experimental rabbits with atherosclerosis and periodontitis]. AB - OBJECTIVE: To explore the effects of atovastatin and tinidazole on atherosclerosis and the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) and matrix metalloproteinase-2 (MMP-2) in periodontitis. METHODS: A total of 48 male New Zealand white rabbits were randomly divided into 4 groups (n = 12 each): control group (A), atovastatin group (B), tinidazole group (C) and combination group (D, atovastatin + tinidazole). All groups received interventions according to the experiment design. During Week 1-4, mandibular first premolars were used to establish periodontitis model. For Week 1, adaptive feeding was provided with 50% normal diet + 50% high-fat diet. Then a full high fat-diet was used to establish atherosclerosis model. During Week 16 20, experimental drug intervention was administered twice weekly: group A received the same volume of saline, group B atorvastatin tablets 1.5 mg/kg, group C tinidazole tablets 150 mg/kg and group D atorvastatin tablets 1.5 mg/kg + tinidazole tablets 150 mg/kg. At the end of 20-week intervention, the animals were sacrificed to take vascular and heart tissue samples. Immunohistochemistry and fluorescent polymerase chain reaction (PCR) were employed for quantitative determinations. RESULTS: The positive areas of MMP-2 expression in groups B, C and D were smaller than that of group A respectively (35% +/- 17%, 69% +/- 5%, 30% +/- 7% vs 86% +/- 9%, all P < 0.05). And the PCR results showed the levels of TNF-alpha and IL-1 in group D was the lowest of four groups (all P < 0.05). CONCLUSION: Atovastatin and tinidazole can reduce the expression levels of TNF alpha, IL-1 and MMP-2 in the rabbits with atherosclerosis and periodontitis respectively. And the combination of both drugs may achieve a better efficacy. PMID- 23663345 TI - [Effects of autophagy modulator on autophagy and uridine 5'-diphospho glucuronosyltransferase 1A1 induced by sulforaphane]. AB - OBJECTIVE: To explore the effects of 3-methyladenine (3-MA) and rapamycin (Rapa) on autophagy and uridine 5'-diphospho-glucuronosyltransferase 1A1 (UGT1A1) induced by sulforaphane (SFN) in human colon cancer Caco-2 cells. METHODS: Western blot was used to detect the expression of microtubule-associated protein 1 light chain 3 (LC3) and UGT1A1 proteins. And immunocytochemistry was employed to observe the intracellular distribution of LC3 and nuclear localization of NF E2-related factor 2 (Nrf2). Quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) was employed to examine the mRNA expression of UGT1A1 and human pregnane X receptor (hPXR). RESULTS: After the treatment of SFN, the LC3-II protein was induced in a dose and time-dependent manner. SFN-induced LC3-II protein could be attenuated and enhanced by 3-MA and Rapa respectively. In comparison with the control group, UGT1A1 mRNA levels increased significantly after the treatment of Rapa, SFN or their combination (2.4, 4.12 and 2.41 folds respectively, all P < 0.01). And the combination of SFN and Rapa possessed the highest level. UGT1A1 protein band intensity was also enhanced in three groups. There was no obvious nuclear staining of Nrf2 in control group while intense nuclear fluorescent labeling of Nrf2 could be observed in the SFN-treated groups, especially the combination group of SFN and Rapa. The hPXR mRNA levels increased significantly in the Rapa and combination groups (1.82 and 1.4 folds respectively, both P < 0.01). CONCLUSION: The treatment of 3-MA or Rapa may attenuate or enhance SFN-induced autophagy respectively. And Rapa also potentiates SFN-induced UGT1A1 expression. The mechanism for the synergic effect of Rapa and SFN on UGT1A1 induction may be a simultaneous activation of Nrf2 and hPXR signaling pathway. PMID- 23663346 TI - [Effects of selective phosphodiesterase 4 inhibitor on expression of aquaporin 5 in airway mucus hypersecretion model of rats]. AB - OBJECTIVE: To explore the mechanism of selective phosphodiesterase 4 (PDE4) inhibitor and observe its effects on the in vitro expression of aquaporin 5 (AQP5) in a rat model of airway mucus hypersecretion. METHODS: Forty healthy male rats were randomized into 4 groups (n = 10 each). The normal control and drug control groups underwent normal saline aerosol inhalation or YM976 lavage respectively for 12 days while the model and treatment groups acrolein atomization inhalation or acrolein atomization inhalation plus YM976 lavage respectively for 12 days. The middle lobe of right lung were fixed, embedded and stained by hematoxylin and eosin to observe the histological changes of small airway. The mucin secretion by goblet cells in lung tissue was tested by alcian blue staining. And the effects of selective PDE4 inhibitor on the expression of AQP5 were detected by immunohistochemical stain. Reverse transcription-polymerase chain reaction and Western blot were used to determine the levels of AQP5 mRNA and protein. RESULTS: In the treatment group, mucus gland hyperplasia and airway mucus hypersecretion and positive staining area ratio of alcian blue staining decreased significantly compared with the model group (10.23% +/- 0.94% vs 14.74% +/- 1.06%, P < 0.05). And the expression of AQP5 mRNA (1.26 +/- 0.19) and protein (0.56 +/- 0.13) also declined significantly versus the model group ((0.96 +/- 0.17), (0.43 +/- 0.15), P < 0.05). CONCLUSION: Selective PDE4 inhibitors alleviate the pathological damage of lung tissue and enhance the expression of AQP-5 in airway mucus hypersecretion. PMID- 23663347 TI - [Effects and mechanisms of phosphatidylinositol 3 kinase B signal pathway on colon cancer cell SW480]. AB - OBJECTIVE: To explore the effects of phosphatidylinositol 3 kinase-protein kinase B (PI3K-AKT) signal pathway on the proliferation, apoptosis and invasiveness of colon cancer cell line SW480 and explore its possible mechanisms. METHODS: SW480 cells were cultured with various concentrations (0, 5, 10, 20 and 40 umol/L) of LY294002 and methyl thiazolyl tetrazolium (MTT) assay was conducted after 24, 48 and 72 hours. SW480 cells were cultured for 24 hours with various concentrations (0, 10, 20 and 40 umol/L) of LY294002. The apoptotic rate was measured by flow cytometry (FCM). The difference of invasiveness was examined by Transwell invasion test. Western blotting was used to examine the expressions of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9). One-way ANOVA was used for statistical analysis. RESULTS: MTT assay showed that the proliferation rate of all SW480 cells except for the lowest concentration group (5 umol/L) was lower than the control group (0 umol/L) and a time-dosage dependence existed (all P < 0.05). The results of FCM demonstrated that the apoptotic rates of 10, 20 and 40 umol/L groups were 13.3% +/- 0.9%, 30.9% +/- 2.5% and 41.2% +/- 4.1% respectively, and were all significantly higher than control group (5.2% +/- 1.8%, all P < 0.05). The number of cells penetrating through the membrane of 10, 20 and 40 umol/L groups were 87 +/- 6, 65 +/- 7 and 46 +/- 11 respectively. All invasiveness groups were all lower than control group (100 +/- 10, all P < 0.05) except the 10 umol/L concentration group (P = 0.096). Western blotting showed that the expressions of VEGF and MMP-9 were all lower than control group (all P < 0.05). CONCLUSIONS: PI3K-AKT signal pathway plays an important role in the proliferation, apoptosis and inhibition of colonic cancer cells. Its mechanism is probably related with the inhibitions of VEGF and MMP-9. PI3K-AKT signal pathway may become a potential target for the treatment of colon cancer. PMID- 23663348 TI - [Influencing of hep-2 cell function by RNAi silencing E-cadherin expression]. AB - OBJECTIVE: To explore the function of human laryngeal carcinoma Hep-2 cell after down-regulating the expression of E-cadherin gene to provide theoretical rationales for gene therapy of laryngeal cancer. METHODS: According to the GenBank database, 3 pairs of shRNA sequences of E-cadherin gene were designed and synthesized. shRNAs were transfected into the cell line Hep-2 by liposome. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the silencing effect of E-cadherin expression. The changed capacity of cell proliferation were detected in vitro by methyl thiazolyl tetrazolium (MTT) assay in the transfected Hep-2 cells and the cell proliferation rate (survival rate) was calculated. And Transwell was used to detect the migratory capacity of Hep-2 cells after siRNA transfection. RESULTS: The E-cadherin gene expression of RNAi transfected Hep-2 cells significantly decreased in interference group. And the proliferation of interference group became markedly enhanced. In Transwell test, the migrated cell numbers in interference group were significant higher than those in negative control group (262 +/- 15, 288 +/- 12, 292 +/- 6 vs 74 +/- 8, all P < 0.01). CONCLUSIONS: RNA interference silencing of E-cadherin gene expression can significantly enhance the proliferation and migratory capacity of Hep-2 cells. And E-cadherin may be considered as one of gene therapy targets for laryngeal cancer. PMID- 23663349 TI - Design, synthesis, and evaluation of indolebutylamines as a novel class of selective dopamine D3 receptor ligands. AB - A series of indolebutylamine derivatives were designed, synthesized, and evaluated as a novel class of selective ligands for the dopamine 3 receptor. The most potent compound 11q binds to dopamine 3 receptor with a Ki value of 124 nm and displays excellent selectivity over the dopamine 1 receptor and dopamine 2 receptor. Investigation based on structural information indicates that site S182 located in extracellular loop 2 may account for high selectivity of compounds. Interaction models of the dopamine 3 receptor-11q complex and structure-activity relationships were discussed by integrating all available experimental and computational data with the eventual aim to discover potent and selective ligands to dopamine 3 receptor. PMID- 23663350 TI - Ovarian cancer G protein coupled receptor 1 suppresses cell migration of MCF7 breast cancer cells via a Galpha12/13-Rho-Rac1 pathway. AB - BACKGROUND: Ovarian cancer G protein coupled receptor 1 (OGR1) mediates inhibitory effects on cell migration in human prostate and ovarian cancer cells. However, the mechanisms and signaling pathways that mediate these inhibitory effects are essentially unknown. METHODS: MCF7 cell line was chosen as a model system to study the mechanisms by which OGR1 regulates cell migration, since it expresses very low levels of endogenous OGR1. Cell migratory activities were assessed using both wound healing and transwell migration assays. The signaling pathways involved were studied using pharmacological inhibitors and genetic forms of the relevant genes, as well as small G protein pull-down activity assays. The expression levels of various signaling molecules were analyzed by Western blot and quantitative PCR analysis. RESULTS: Over-expression of OGR1 in MCF7 cells substantially enhanced activation of Rho and inhibition of Rac1, resulting in inhibition of cell migration. In addition, expression of the Galpha12/13 specific regulator of G protein signaling (RGS) domain of p115RhoGEF, but not treatment with pertussis toxin (PTX, a Galphai specific inhibitor), could abrogate OGR1 dependent Rho activation, Rac1 inactivation, and inhibition of migration in MCF7 cells. The bioactive lipids tested had no effect on OGR1 function in cell migration. CONCLUSION: Our data suggest, for the first time, that OGR1 inhibits cell migration through a Galpha12/13 -Rho-Rac1 signaling pathway in MCF7 cells. This pathway was not significantly affected by bioactive lipids and all the assays were conducted at constant pH, suggesting a constitutive activity of OGR1. This is the first clear delineation of an OGR1-mediated cell signaling pathway involved in migration. PMID- 23663352 TI - Interactions between specific phytoplankton and bacteria affect lake bacterial community succession. AB - Time-series observations and a phytoplankton manipulation experiment were combined to test the hypothesis that phytoplankton succession effects changes in bacterial community composition. Three humic lakes were sampled weekly May-August and correlations between relative abundances of specific phytoplankton and bacterial operational taxonomic units (OTUs) in each time series were determined. To experimentally characterize the influence of phytoplankton, bacteria from each lake were incubated with phytoplankton from one of the three lakes or no phytoplankton. Following incubation, variation in bacterial community composition explained by phytoplankton treatment increased 65%, while the variation explained by bacterial source decreased 64%. Free-living bacteria explained, on average, over 60% of the difference between phytoplankton and corresponding no phytoplankton control treatments. Fourteen out of the 101 bacterial OTUs that exhibited positively correlated patterns of abundance with specific algal populations in time-series observations were enriched in mesocosms following incubation with phytoplankton, and one out of 59 negatively correlated bacterial OTUs was depleted in phytoplankton treatments. Bacterial genera enriched in mesocosms containing specific phytoplankton assemblages included Limnohabitans (clade betI-A), Bdellovibrio and Mitsuaria. These results suggest that effects of phytoplankton on certain bacterial populations, including bacteria tracking seasonal changes in algal-derived organic matter, result in correlations between algal and bacterial community dynamics. PMID- 23663351 TI - A novel TRPC6 mutation in a family with podocytopathy and clinical variability. AB - BACKGROUND: Mutation in several podocyte-specific genes have been noted to result in phenotypic heterogeneity. Herein, we report a novel, autosomal dominant TRPC6 mutation in a family with disease ranging from asymptomatic minimal change disease to end-stage kidney disease. CASE PRESENTATION: A 35 year old woman developed asymptomatic, nephrotic range proteinuria during pregnancy that did not resolve after delivery. Her mother had end-stage kidney disease of unknown etiology and her brother had asymptomatic proteinuria. Kidney biopsy revealed minimal change disease in both the proband and her brother. Genetic testing was performed in the proband and mother, revealing a novel frameshift mutation in TRPC6, D873fsX878. The proband continues to have subnephrotic range proteinuria and normal creatinine but her brother has since developed progressive chronic kidney disease. CONCLUSIONS: The current case report underscores the heterogeneity of disease in podocytopathies and related genes. Genetic testing of podocyte genes is useful in order to understand the pathophysiologic processes underlying these overlapping diseases. PMID- 23663353 TI - Organization and characterization of a biosynthetic gene cluster for bafilomycin from Streptomyces griseus DSM 2608. AB - Streptomyces griseus DSM 2608 produces bafilomycin, an antifungal plecomacrolide antibiotic. We cloned and sequenced an 87.4-kb region, including a polyketide synthase (PKS) region, methoxymalonate genes, flavensomycinate genes, and other putative regulatory genes. The 58.5kb of PKS region consisting 12 PKS modules arranged in five different PKS genes, was assumed to be responsible for the biosynthesis of plecomacrolide backbone including 16-membered macrocyclic lactone. All the modules showed high similarities with typical type I PKS genes. However, the starting module of PKS gene was confirmed to be specific for isobutyrate by sequence comparison of an acyltransferase domain. In downstream of PKS region, the genes for methoxymalonate biosynthesis were located, among which a gene for FkbH-like protein was assumed to play an important role in the production of methoxymalonyl-CoA from glyceryl-CoA. Further the genes encoding flavensomycinyl-ACP biosynthesis for the post-PKS tailoring were also found in the upstream of PKS region. By gene disruption experiments of a dehydratase domain of module 12 and an FkbH-like protein, this gene cluster was confirmed to be involved in the biosynthesis of bafilomycin. PMID- 23663356 TI - INR reduction after prothrombin complex concentrate (Co-fact(c)) administration: comparison of INR outcomes in different patient categories at the emergency department. AB - BACKGROUND: Co-fact(c), prothrombin complex concentrate, is used for restoring the international normalized ratio (INR) in patients on vitamin K antagonists (VKA) presenting with acute bleeding. In this prospective cohort study, we evaluated whether adequate INR values were reached in ED patients using the Sanquin (Federation of Dutch Thrombosis Services) treatment protocol. METHODS: We evaluated this protocol for two target INR groups: group 1, target INR <= 1.5 (for life-threatening bleeding/immediate intervention); group 2, target INR 1.6 2.1 (in cases of a minor urgent surgery or serious overdosing of anticoagulant). We specifically wanted to identify both under- and over-treated patients. Reversing VKA anticoagulation therapy to unnecessarily low INR values may involve thrombotic risks. Apart from this risk, the patient is also administered an excess amount of the drug. This means unnecessary costs and may present problems with restoring an anticoagulated state at a later time. RESULTS: In our cohort, the Sanquin dosing protocol was followed for 45/60 patients. It appeared that out of the 41 patients in group 1 (target INR <= 1.5), 35 (85%) achieved the goal INR. This occurred more often than for the 19 patients in group 2 (target INR 1.6 2.1), where only 6 (32%) achieved the goal INR. Using the protocol resulted in a positive trend toward better INR reversal in group 1. In group 2, no relation between using the protocol and achieving the desired INR value was detected. Physicians ignoring the proposed dose of Co-fact(c) prescribed significantly less Co-fact(c) (even when correcting for patient weight). It appeared that patients in group 1 had a significantly lower baseline INR than patients in group 2. Group 2 patients, on the other hand, had a baseline INR > 7.5 in 53% of the cases. CONCLUSION: In our cohort, for most patients in INR group 2 treated with Co fact(c), the achieved INR value was outside the desired range of 1.6-2.1. The supra-therapeutic range of baseline INR in group 2 may have contributed to the different kind of bleeding witnessed in this patient group. Our results support the idea that treatment of patients on vitamin K antagonists with Co-fact(c) could benefit from a slightly different approach, taking into account the INR value to which the patient needs to be reversed. PMID- 23663355 TI - Transdiagnostic and disorder-specific models of intergenerational transmission of internalizing pathology. AB - BACKGROUND: Numerous studies have supported an association between maternal depression and child psychiatric outcomes, but few have controlled for the confounding effects of both maternal and offspring co-morbidity. Thus, it remains unclear whether the correspondence between maternal and offspring depressive and anxiety disorders is better explained by associations between shared features of maternal and offspring internalizing disorders or by specific effects exerted by unique aspects of individual disorders. METHOD: Pairs of mothers and offspring overselected for maternal depression (n = 815) were assessed at offspring age 15 years for anxiety and depressive disorders; 705 completed a follow-up at offspring age 20 years. For both mothers and offspring, structural equation modeling was used to distinguish transdiagnostic internalizing pathology- representing the overlap among all depressive and anxiety disorders--from diagnosis-specific forms of pathology. To discriminate between general versus specific pathways of intergenerational transmission of psychopathology, we examined (a) the general association between the maternal and offspring internalizing factors and (b) the correlations between maternal and offspring diagnosis-specific pathology for each disorder. RESULTS: For mothers and offspring, a unidimensional latent variable model provided the best fit to the correlations among depressive and anxiety disorders. The maternal transdiagnostic internalizing factor strongly predicted the corresponding factor among offspring. In addition, the unique component of post-traumatic stress disorder among offspring was significantly related to the analogous unique component among mothers, but specific components of other maternal disorders, including depression, did not predict corresponding offspring pathology. CONCLUSIONS: Results suggest that intergenerational transmission of internalizing disorders is largely non-specific. PMID- 23663357 TI - The incidence and magnitude of fibrinolytic activation in trauma patients: a reply to a rebuttal. PMID- 23663358 TI - Stopover optimization in a long-distance migrant: the role of fuel load and nocturnal take-off time in Alaskan northern wheatears (Oenanthe oenanthe). AB - INTRODUCTION: In long-distance migrants, a considerably higher proportion of time and energy is allocated to stopovers rather than to flights. Stopover duration and departure decisions affect consequently subsequent flight stages and overall speed of migration. In Arctic nocturnal songbird migrants the trade-off between a relatively long migration distance and short nights available for travelling may impose a significant time pressure on migrants. Therefore, we hypothesize that Alaskan northern wheatears (Oenanthe oenanthe) use a time-minimizing migration strategy to reach their African wintering area 15,000 km away. RESULTS: We estimated the factors influencing the birds' daily departure probability from an Arctic stopover before crossing the Bering Strait by using a Cormack-Jolly-Seber model. To identify in which direction and when migration was resumed departing birds were radio-tracked. Here we show that Alaskan northern wheatears did not behave as strict time minimizers, because their departure fuel load was unrelated to fuel deposition rate. All birds departed with more fuel load than necessary for the sea crossing. Departure probability increased with stopover duration, evening fuel load and decreasing temperature. Birds took-off towards southwest and hence, followed in general the constant magnetic and geographic course but not the alternative great circle route. Nocturnal departure times were concentrated immediately after sunset. CONCLUSION: Although birds did not behave like time-minimizers in respect of the optimal migration strategies their surplus of fuel load clearly contradicted an energy saving strategy in terms of the minimization of overall energy cost of transport. The observed low variation in nocturnal take-off time in relation to local night length compared to similar studies in the temperate zone revealed that migrants have an innate ability to respond to changes in the external cue of night length. Likely, birds maximized their potential nightly flight range by taking off early in the night which in turn maximizes their overall migration speed. Hence, nocturnal departure time may be a crucial parameter shaping the speed of migration indicating the significance of its integration in future migration models. PMID- 23663359 TI - A versatile, efficient strategy for assembly of multi-fragment expression vectors in Saccharomyces cerevisiae using 60 bp synthetic recombination sequences. AB - BACKGROUND: In vivo recombination of overlapping DNA fragments for assembly of large DNA constructs in the yeast Saccharomyces cerevisiae holds great potential for pathway engineering on a small laboratory scale as well as for automated high throughput strain construction. However, the current in vivo assembly methods are not consistent with respect to yields of correctly assembled constructs and standardization of parts required for routine laboratory implementation has not been explored. Here, we present and evaluate an optimized and robust method for in vivo assembly of plasmids from overlapping DNA fragments in S. cerevisiae. RESULTS: To minimize occurrence of misassembled plasmids and increase the versatility of the assembly platform, two main improvements were introduced; i) the essential elements of the vector backbone (yeast episome and selection marker) were disconnected and ii) standardized 60 bp synthetic recombination sequences non-homologous with the yeast genome were introduced at each flank of the assembly fragments. These modifications led to a 100 fold decrease in false positive transformants originating from the backbone as compared to previous methods. Implementation of the 60 bp synthetic recombination sequences enabled high flexibility in the design of complex expression constructs and allowed for fast and easy construction of all assembly fragments by PCR. The functionality of the method was demonstrated by the assembly of a 21 kb plasmid out of nine overlapping fragments carrying six glycolytic genes with a correct assembly yield of 95%. The assembled plasmid was shown to be a high fidelity replica of the in silico design and all glycolytic genes carried by the plasmid were proven to be functional. CONCLUSION: The presented method delivers a substantial improvement for assembly of multi-fragment expression vectors in S. cerevisiae. Not only does it improve the efficiency of in vivo assembly, but it also offers a versatile platform for easy and rapid design and assembly of synthetic constructs. The presented method is therefore ideally suited for the construction of complex pathways and for high throughput strain construction programs for metabolic engineering purposes. In addition its robustness and ease of use facilitate the construction of any plasmid carrying two or more genes. PMID- 23663361 TI - Whole-genome mRNA expression profiling identifies functional and prognostic signatures in patients with mesenchymal glioblastoma multiforme. AB - BACKGROUND: The Cancer Genome Atlas (TCGA) has divided patients with glioblastoma multiforme (GBM) into four subtypes based on mRNA expression microarray. The mesenchymal subtype, with a larger proportion, is considered a more lethal one. Clinical outcome prediction is required to better guide more personalized treatment for these patients. AIMS: The objective of this study was to identify a mRNA expression signature to improve outcome prediction for patients with mesenchymal GBM. RESULTS: For signature identification and validation, we downloaded mRNA expression microarray data from TCGA as training set and data from Rembrandt and GSE16011 as validation set. Cox regression and risk-score analysis were used to develop the 4 signatures, which were function and prognosis associated as revealed by Gene Ontology (GO) analysis and Gene Set Variation Analysis (GSVA). Patients who had high-risk scores according to the signatures had poor overall survival compared with patients who had low-risk scores. CONCLUSIONS: The signatures were identified as risk predictors that patients who had a high-risk score tended to have unfavorable outcome, demonstrating their potential for personalizing cancer management. PMID- 23663360 TI - Characterization of human plasma-derived exosomal RNAs by deep sequencing. AB - BACKGROUND: Exosomes, endosome-derived membrane microvesicles, contain specific RNA transcripts that are thought to be involved in cell-cell communication. These RNA transcripts have great potential as disease biomarkers. To characterize exosomal RNA profiles systemically, we performed RNA sequencing analysis using three human plasma samples and evaluated the efficacies of small RNA library preparation protocols from three manufacturers. In all we evaluated 14 libraries (7 replicates). RESULTS: From the 14 size-selected sequencing libraries, we obtained a total of 101.8 million raw single-end reads, an average of about 7.27 million reads per library. Sequence analysis showed that there was a diverse collection of the exosomal RNA species among which microRNAs (miRNAs) were the most abundant, making up over 42.32% of all raw reads and 76.20% of all mappable reads. At the current read depth, 593 miRNAs were detectable. The five most common miRNAs (miR-99a-5p, miR-128, miR-124-3p, miR-22-3p, and miR-99b-5p) collectively accounted for 48.99% of all mappable miRNA sequences. MiRNA target gene enrichment analysis suggested that the highly abundant miRNAs may play an important role in biological functions such as protein phosphorylation, RNA splicing, chromosomal abnormality, and angiogenesis. From the unknown RNA sequences, we predicted 185 potential miRNA candidates. Furthermore, we detected significant fractions of other RNA species including ribosomal RNA (9.16% of all mappable counts), long non-coding RNA (3.36%), piwi-interacting RNA (1.31%), transfer RNA (1.24%), small nuclear RNA (0.18%), and small nucleolar RNA (0.01%); fragments of coding sequence (1.36%), 5' untranslated region (0.21%), and 3' untranslated region (0.54%) were also present. In addition to the RNA composition of the libraries, we found that the three tested commercial kits generated a sufficient number of DNA fragments for sequencing but each had significant bias toward capturing specific RNAs. CONCLUSIONS: This study demonstrated that a wide variety of RNA species are embedded in the circulating vesicles. To our knowledge, this is the first report that applied deep sequencing to discover and characterize profiles of plasma-derived exosomal RNAs. Further characterization of these extracellular RNAs in diverse human populations will provide reference profiles and open new doors for the development of blood-based biomarkers for human diseases. PMID- 23663363 TI - Sparse coding and challenges for Bayesian models of the brain. AB - While the target article provides a glowing account for the excitement in the field, we stress that hierarchical predictive learning in the brain requires sparseness of the representation. We also question the relation between Bayesian cognitive processes and hierarchical generative models as discussed by the target article. PMID- 23663362 TI - Smoking, mental illness and socioeconomic disadvantage: analysis of the Australian National Survey of Mental Health and Wellbeing. AB - BACKGROUND: High rates of smoking and lower rates of smoking cessation are known to be associated with common mental disorders such as anxiety and depression, and with individual and community measures of socioeconomic status. It is not known to what extent mental illness and socioeconomic status might be jointly associated with smoking behaviour. We set out to examine the relationship between mental illness, measures of socioeconomic disadvantage and both current smoking and smoking cessation rates. METHODS: We used data from the 2007 Australian National Survey of Mental Health and Wellbeing to examine the relationship between mental illness, socioeconomic status and both current smoking and smoking cessation. We used cross-classified tables and logistic regression to examine the relationship between psychosocial and sociodemographic predictors and current smoking. We also used proportional hazards regression to examine the relationship between the factors and smoking cessation. RESULTS: Both mental illness and socioeconomic status were independently associated with current smoking and with lower likelihood of smoking cessation, with gradients in smoking by mental health status being observed within levels of socioeconomic indicators and vice versa. Having a mental illness in the past 12 months was the most prevalent factor strongly associated with smoking, affecting 20.0% of the population, associated with increased current smoking (OR 2.43; 95% CI: 1.97-3.01) and reduced likelihood of smoking cessation (HR: 0.77; 95% CI: 0.65-0.91). CONCLUSIONS: The association between mental illness and smoking is not explained by the association between mental illness and socioeconomic status. There are strong socioeconomic and psychosocial gradients in both current smoking and smoking cessation. Incorporating knowledge of the other adverse factors in smokers' lives may increase the penetration of tobacco control interventions in population groups that have historically benefitted less from these activities. PMID- 23663364 TI - Impact of clinical and health services research projects on decision-making: a qualitative study. AB - BACKGROUND: This article reports on the impact assessment experience of a funding program of non-commercial clinical and health services research. The aim was to assess the level of implementation of results from a subgroup of research projects (on respiratory diseases), and to detect barriers (or facilitators) in the translation of new knowledge to informed decision-making. METHODS: A qualitative study was performed. The sample consisted of six projects on respiratory diseases funded by the Agency for Health Quality and Assessment of Catalonia between 1996 and 2004. Semi-structured interviews to key informants including researchers and healthcare decision-makers were carried out. Interviews were recorded, transcribed verbatim and analysed on an individual (key informant) and group (project) basis. In addition, the differences between achieved and expected impacts were described. RESULTS: Twenty-three semi-structured interviews were conducted. Most participants indicated changes in health services or clinical practice had resulted from research. The channels used to transfer new knowledge were mainly conventional ones, but also in less explicit ways, such as with the involvement of local scientific societies, or via debates and discussions with colleagues and local leaders. The barriers and facilitators identified were mostly organizational (in research management, and clinical and healthcare practice), although there were also some related to the nature of the research as well as personal factors. Both the expected and achieved impacts enabled the identification of the gaps between what is expected and what is truly achieved. CONCLUSIONS: In this study and according to key informants, the impact of these research projects on decision-making can be direct (the application of a finding or innovation) or indirect, contributing to a more complex change in clinical practice and healthcare organization, both having other contextual factors. The channels used to transfer this new knowledge to clinical practice are complex. Local scientific societies and the relationships between researchers and decision-makers can play a very important role. Specifically, the relationships between managers and research teams and the mutual knowledge of their activity have shown to be effective in applying research funding to practice and decision-making. Finally the facilitating factors and barriers identified by the respondents are closely related to the idiosyncrasy of the human relations between the different stakeholders involved. PMID- 23663365 TI - Synthesis, anti-MRSA, and anti-VRE activity of hemin conjugates with amino acids and branched peptides. AB - The increasing prevalence of antibiotic-resistant bacterial strains has necessitated the synthesis of novel antibacterial agents. It was previously shown that naturally occurring metalloporphyrin hemin possesses dark antibacterial activity against Gram-positive bacteria. To improve hemin antibacterial activity, we synthesized a number of hemin conjugates with amino acids and branched peptides. Arginine-containing hemin conjugates demonstrated high antibacterial activity against Gram-positive bacteria including methicillin- and vancomycin resistant strains in vitro. Most of the synthesized conjugates showed low toxicity against human erythrocytes and leukocytes. PMID- 23663366 TI - [Proper medication of patients is a medical core service]. PMID- 23663367 TI - [Need for new thinking in surgical education]. PMID- 23663368 TI - [Increase in working hours is an option for improving surgical education in Denmark]. AB - Danish surgeons in training have a 37-hour workweek. These are relatively few hours compared with the hours in England and USA where surgeons have a workweek of respectively 48 and 80 hours. The optimal length of a workweek during surgical education is unknown, but studies have shown that surgeons working more hours have improved abilities in clinical judgment. Learning outcome may improve if Danish surgeons in training were allowed to work more hours. We suggest a 37 + 11 hour workweek, where 11 hours are reserved for educational purposes. PMID- 23663369 TI - [Neuromyelitis optica is a frequently seen inflammatory demyelinating disease]. AB - Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system with autoimmune characteristics. Serum immunoglobulin G autoantibodies have been identified in the majority of NMO patients with the water channel aquaporin-4 (AQP4) as their main target autoantigen. Clinical criteria have defined NMO and NMO-spectrum disease. The clinical features include inflammation of the optic nerve. PMID- 23663370 TI - [Familial adenomatous polyposis]. AB - Familial adenomatous polyposis (FAP) is an autosomally dominant disease characterized by early development of up to thousands of colorectal adenomas and colorectal carcinoma in untreated patients. Extra-colonic manifestations include duodenal adenomatosis and desmoid development. Due to identification of gene carriers by DNA analysis or endoscopy the prognosis is good after early colectomy, but life-long surveillance of the rectum and the duodenum is necessary. The Danish Polyposis Register coordinates prophylactic examination and treatment in the families, and serves as basis for research. PMID- 23663371 TI - [Checklist for training and evaluation of consultants can work in a clinical setting]. AB - Formalised educational programmes for consultants are uncommon in Denmark. Our objective was to introduce a checklist for training and formative evaluation for consultants to see if this was a feasible method. Sixteen anaesthesiologists participated. A checklist for the use of a difficult airway device was developed. The consultants observed an experienced colleague use the device and then did the procedure themselves supervised in the clinical setting, and finally taught a fellow consultant how to do the procedure. Afterwards they were interviewed about the training method. Checklists seem a promising method for consultants and may be applied in the future. PMID- 23663372 TI - [Limited effect of interferon-beta for the treatment of secondary progressive multiple sclerosis]. AB - Interferon (IFN)-beta 1b is approved for the treatment of secondary progressive multiple sclerosis (SPMS) with relapses in the EU. This Cochrane review analysed all double- or single-blinded randomised placebo controlled studies that had evaluated the efficacy of IFN-beta versus placebo in SPMS. The meta-analysis included five studies with 3,122 patients in all; 1,829 of these received IFN beta. The study concluded that IFN-beta did not prevent the development of permanent physical disability in patients with SPMS, but significantly reduced the risk of relapse and of short-term relapse-related disability. In accordance with these findings, the Danish national guidelines recommend IFN-beta 1b treatment only for relapsing or rapidly progressing SPMS. Evaluation of the beneficial effect must be done every 6-12 months and the treatment should be discontinued if progression continues. PMID- 23663373 TI - [Herpes simplex can cause acute abdomen]. AB - In rare cases herpes simplex virus (HSV) can cause disseminated and severe disease, especially in immunoincompetent patients. An apparently immunocompetent 27-year-old woman presented to a gynaecological ward with one week of unexplained abdominal pain. After some days of observation and tests, she underwent a diagnostic laparoscopy. Vesicular elements were seen on the bladder wall, and biopsies showed HSV type 2. PMID- 23663374 TI - [A case of severe exercise-associated hyponatremia]. AB - The woman presented to the emergency department with lethargy after a spinning marathon. Severe electrolyte disturbances were measured (Na(+) 109 mmol/l, K(+) 3,2 mmol/l, Cl(-) 86, Ca(++) 0,95 mmol/l). A computed tomography showed signs of brain swelling. During her stay in the intensive care unit the patient had a negative fluid balance of 8,000 ml. She was discharged with habitual weight. We present a brief discussion of the genesis and treatment of EAH. PMID- 23663375 TI - [Eagle's syndrome]. PMID- 23663376 TI - In situ activity of a dominant Prochlorococcus ecotype (eHL-II) from rRNA content and cell size. AB - In the open ocean genetically diverse clades of the unicellular cyanobacteria Prochlorococcus are biogeographically structured along environmental gradients, yet little is known about their in situ activity. To address this gap, here we use the numerically dominant Prochlorococcus clade eHL-II (eMIT9312) as a model organism to develop and apply a method to examine their in situ activity using rRNA content and cell size as metrics of cellular physiology. For two representative isolates (MIT9312 and MIT9215) rRNA cell(-1) increases linearly with specific growth rate but is anticorrelated with cell size indicated by flow cytometrically measured (SSC). Although each strain has a unique relationship between cellular rRNA (or cell size) and growth rate, both strains have the same strong positive correlation between rRNA cell(-1) SSC(-1) and growth rate. We field test this approach and observe distinct patterns of eHL-II clade specific activity (rRNA cell(-1) SSC(-1)) with depth that are consistent with patterns of photosynthetic rates. This molecular technique provides unique insight into the ecology of Prochlorococcus and could potentially be expanded to include other microbes to unravel the ecological and biogeochemical contributions of genetically distinct marine side scatter microbes. PMID- 23663377 TI - Online Victim Tracking and Tracing System (ViTTS) for major incident casualties. AB - INTRODUCTION: Dealing with major incidents requires an immediate and coordinated response by multiple organizations. Communicating and coordinating over multiple geographical locations and organizations is a complex process. One of the greatest challenges is patient tracking and tracing. Often, data about the number of victims, their condition, location and transport is lacking. This hinders an effective response and causes public distress. To address this problem, a Victim Tracing and Tracking system (ViTTS) was developed. METHODS: An online ViTTS was developed based on a wireless network with routers on ambulances, and direct online registration of victims and their triage data through barcode injury cards. The system was tested for feasibility and usability during disaster drills. RESULTS: The formation of a local radio network of hotspots with mobile routers and connection over General Packet Radio Service (GPRS) to the central database worked well. ViTTS produced accurately stored data, real-time availability, and a real-time overview of the patients (number, seriousness of injury, and location). CONCLUSION: The ViTTS provides a system for early, unique registration of victims close to the impact site. Online application and connection of the various systems used by the different chains in disaster relief promotes interoperability and enables patient tracking and tracing. It offers a real-time overview of victims to all involved disaster relief partners, which is necessary to generate an adequate disaster response. PMID- 23663378 TI - Paradoxical worsening of seizure activity with pregabalin in an adult with isodicentric 15 (IDIC-15) syndrome involving duplications of the GABRB3, GABRA5 and GABRG3 genes. AB - BACKGROUND: Isodicentric 15 syndrome (IDIC-15) is due to partial duplications of chromosome 15 that may includes the q11-13 region that includes genes encoding the alpha5 (GABRA5) and beta3 - gamma3 (GABRB3) receptor subunits. The disease causes intellectual and physical developmental delay, seizures, intellectual disability and behavioral disorders that may be related to abnormal GABA receptor function and morphology. Seizures are often severe and may be refractory to treatment. There are however no specific guidelines for the treatment of the seizures and it is unknown whether drugs that affect the GABAergic system have a different effect in IDIC-15 seizures. CASE PRESENTATION: We report the case of an adult individual with IDIC-15 whose complex-partial seizures worsened dramatically after the introduction of pregabalin, with increased seizure frequency, frequent generalization, and appearance of new seizure pattern. Her cognitive function and verbal skills also worsened during treatment with pregabalin. Her seizures and cognitive skills quickly improved after pregabalin was discontinued and treatment with lacosamide started. DISCUSSION: As her genetic testing confirmed that her region of duplication included GABA receptor encoding genes, it is plausible that the worsening of seizures were due to induction of an abnormal GABAergic response to pregabalin. CONCLUSION: As her genetic testing confirmed that her region of duplication included GABA receptor encoding genes, it is plausible that the worsening of seizures were due to induction of an abnormal GABAergic response to pregabalin.This case may help define proper therapeutic strategies for the treatment of IDIC-15 associated seizures. PMID- 23663379 TI - Cross-linked enzyme aggregates (CLEAs) of selected lipases: a procedure for the proper calculation of their recovered activity. AB - In the last few years, synthesis of carrier-free immobilized biocatalysts by cross-linking of enzyme aggregates has appeared as a promising technique. Cross linked enzyme aggregates (CLEAs) present several interesting advantages over carrier-bound immobilized enzymes, such as highly concentrated enzymatic activity, high stability of the produced superstructure, important production costs savings by the absence of a support, and the fact that no previous purification of the enzyme is needed. However, the published literature evidences that a) much specific non-systematic exploratory work is being done and, b) recovered activity calculations in CLEAs still need to be optimized. In this context, this contribution presents results of an optimized procedure for the calculation of the activity retained by CLEAs, based on the comparison of their specific activity relative to their free enzyme counterparts. The protocol implies determination of precipitable protein content in commercial enzyme preparations through precipitation with ammonium sulphate and a protein co feeder. The identification of linear ranges of activity versus concentration/amount of protein in the test reaction is also required for proper specific activity determinations. By use of mass balances that involve the protein initially added to the synthesis medium, and the protein remaining in the supernatant and washing solutions (these last derived from activity measurements), the precipitable protein present in CLEAs is obtained, and their specific activity can be calculated. In the current contribution the described protocol was applied to CLEAs of Thermomyces lanuginosa lipase, which showed a recovered specific activity of 11.1% relative to native lipase. The approach described is simple and can easily be extended to other CLEAs and also to carrier bound immobilized enzymes for accurate determination of their retained activity. PMID- 23663380 TI - Treatment of canine generalized demodicosis associated with hyperadrenocorticism with spot-on moxidectin and imidacloprid. AB - BACKGROUND: Canine generalized demodicosis associated with hyperadrenocorticism is often problematic and might be intractable. The aim of this study was to report the efficacy of a weekly application of spot-on moxidectin/imidacloprid in dogs with hyperadrenocorticism and secondary generalized demodicosis. METHODS: Dogs with hyperadrenocorticism and secondary generalized demodicosis were included. The condition of hyperadrenocorticism was treated and stabilized with trilostane before and throughout the study period in all dogs. RESULTS: Average total live adult mite counts before treatment and after four, eight and 12 weeks of spot-on moxidectin/imidacloprid (2.5/10 mg/kg) applications were 20.1+/-6.3 (range, 13-33), 0.5+/-0.7 (range, 0-2; 6/11 were negative), 0.2+/-0.4 (range, 0 1; 9/11 were negative), 0.2+/-0.4 (range, 0-1; 9/11 were negative) and 0.1+/-0.3 (range, 0-1; 10/11 were negative) respectively; this difference was significant (P<0.001). Ten of 11 dogs (90.1%) achieved clinical remission, as demonstrated by the absence of demodectic mites at any life stage at monthly scrapings for eight consecutive weeks, and maintained remission throughout the 12-month follow-up period. CONCLUSION: The weekly application of spot-on moxidectin/imidacloprid appeared to be effective and safe against generalized adult onset canine demodicosis associated with hyperadrenocorticism. PMID- 23663382 TI - Identifying a consistent pattern of neural function in attention deficit hyperactivity disorder: a meta-analysis. AB - BACKGROUND: The neurobiological underpinnings of attention deficit hyperactivity disorder (ADHD) are inconclusive. Activation abnormalities across brain regions in ADHD compared with healthy controls highlighted in task-based functional magnetic resonance imaging (fMRI) studies are heterogeneous. To identify a consistent pattern of neural dysfunction in ADHD, a meta-analysis of fMRI studies using Go/no-go, Stop and N-back tasks was undertaken. METHOD: Several databases were searched using the key words: 'ADHD and fMRI' and 'ADHD and fMRI task'. In all, 20 studies met inclusion criteria comprising 334 patients with ADHD and 372 healthy controls and were split into N-back, Stop task and Go/no-go case-control groups. Using Signed Differential Mapping each batch was meta-analysed individually and meta-regression analyses were used to examine the effects of exposure to methylphenidate (MPH), length of MPH wash-out period, ADHD subtype, age and intelligence quotient (IQ) differences upon neural dysfunction in ADHD. RESULTS: Across all tasks less activity in frontal lobe regions compared with controls was detected. Less exposure to treatment and lengthier wash-out times resulted in less left medial frontal cortex activation in N-back and Go/no-go studies. Higher percentage of combined-type ADHD resulted in less superior and inferior frontal gyrus activation. Different IQ scores between groups were linked to reduced right caudate activity in ADHD. CONCLUSIONS: Consistent frontal deficits imply homogeneous cognitive strategies involved in ADHD behavioural control. Our findings suggest a link between fMRI results and the potentially normalizing effect of treatment and signify a need for segregated examination and contrast of differences in sample characteristics in future studies. PMID- 23663381 TI - Mosquito-borne arbovirus surveillance at selected sites in diverse ecological zones of Kenya; 2007 - 2012. AB - BACKGROUND: Increased frequency of arbovirus outbreaks in East Africa necessitated the determination of distribution of risk by entomologic arbovirus surveillance. A systematic vector surveillance programme spanning 5 years and covering 11 sites representing seven of the eight provinces in Kenya and located in diverse ecological zones was carried out. METHODS: Mosquitoes were sampled bi annually during the wet seasons and screened for arboviruses. Mosquitoes were identified to species, pooled by species, collection date and site and screened for arboviruses by isolation in cell culture and/or RT-PCR screening and sequencing. RESULTS: Over 450,000 mosquitoes in 15,890 pools were screened with 83 viruses being detected/isolated that include members of the alphavirus, flavivirus and orthobunyavirus genera many of which are known to be of significant public health importance in the East African region. These include West Nile, Ndumu, Sindbis, Bunyamwera, Pongola and Usutu viruses detected from diverse sites. Ngari virus, which was associated with hemorrhagic fever in northern Kenya in 1997/98 was isolated from a pool of Anopheles funestus sampled from Tana-delta and from Aedes mcintoshi from Garissa. Insect only flaviviruses previously undescribed in Kenya were also isolated in the coastal site of Rabai. A flavivirus most closely related to the Chaoyang virus, a new virus recently identified in China and two isolates closely related to Quang Binh virus previously unreported in Kenya were also detected. CONCLUSION: Active transmission of arboviruses of public health significance continues in various parts of the country with possible undetermined human impact. Arbovirus activity was highest in the pastoralist dominated semi-arid to arid zones sites of the country where 49% of the viruses were isolated suggesting a role of animals as amplifiers and indicating the need for improved arbovirus disease diagnosis among pastoral communities. PMID- 23663383 TI - Retinal vein and artery occlusions: a risk factor for stroke in atrial fibrillation. AB - BACKGROUND: Retinal vascular occlusions may constitute an independent risk factor for stroke in patients with atrial fibrillation. METHODS: We performed a retrospective study on a nationwide cohort with atrial fibrillation from 1997 to 2008. The rate of stroke/systemic thromboembolism (TE)/transitory ischemic attack (TIA) was determined for atrial fibrillation patients with and without a history of retinal vascular occlusion. A Cox regression analysis, adjusted for risk factors and medications, was performed to determine the independent predictive value of retinal arterial or venous occlusion for the risk of ischemic stroke, TE or TIA in atrial fibrillation patients. RESULTS: We included 87 202 patients with non-valvular atrial fibrillation. At baseline, a history of retinal arterial occlusion was diagnosed in 224 patients (0.26%) and a history of retinal venous occlusion in 361 (0.41%). Patients without retinal occlusion had a rate of stroke/TE/TIA of 4.52 (95% confidence interval [CI] 4.44-4.60). For patients with retinal arterial occlusion, the rate of stroke/TE/TIA was 8.16 (95% CI 6.35 10.49) per 100 person-years, and for patients with retinal venous occlusion it was 7.28 (95% CI 5.93-8.94) per 100 person-years. In multivariate analysis, both retinal arterial occlusions (hazard ratio [HR] 1.39, 95% CI 1.08-1.79) and retinal venous occlusions (HR 1.26, 95% CI 1.02-1.54) were associated with an increased risk of future stroke/TE/TIA. CONCLUSIONS: A history of retinal arterial or retinal venous occlusion is associated with an increased risk of stroke/TE/TIA in patients with atrial fibrillation. Thus, prior retinal vascular occlusion may be considered as a previous thromboembolic event when evaluating stroke risk in patients with atrial fibrillation. PMID- 23663384 TI - Sequencing platform and library preparation choices impact viral metagenomes. AB - BACKGROUND: Microbes drive the biogeochemistry that fuels the planet. Microbial viruses modulate their hosts directly through mortality and horizontal gene transfer, and indirectly by re-programming host metabolisms during infection. However, our ability to study these virus-host interactions is limited by methods that are low-throughput and heavily reliant upon the subset of organisms that are in culture. One way forward are culture-independent metagenomic approaches, but these novel methods are rarely rigorously tested, especially for studies of environmental viruses, air microbiomes, extreme environment microbiology and other areas with constrained sample amounts. Here we perform replicated experiments to evaluate Roche 454, Illumina HiSeq, and Ion Torrent PGM sequencing and library preparation protocols on virus metagenomes generated from as little as 10 pg of DNA. RESULTS: Using %G+C content to compare metagenomes, we find that (i) metagenomes are highly replicable, (ii) some treatment effects are minimal, e.g., sequencing technology choice has 6-fold less impact than varying input DNA amount, and (iii) when restricted to a limited DNA concentration (<1 MUg), changing the amount of amplification produces little variation. These trends were also observed when examining the metagenomes for gene function and assembly performance, although the latter more closely aligned to sequencing effort and read length than preparation steps tested. Among Illumina library preparation options, transposon-based libraries diverged from all others and adaptor ligation was a critical step for optimizing sequencing yields. CONCLUSIONS: These data guide researchers in generating systematic, comparative datasets to understand complex ecosystems, and suggest that neither varied amplification nor sequencing platforms will deter such efforts. PMID- 23663385 TI - Association between EXOC3L2 rs597668 polymorphism and Alzheimer's disease. AB - BACKGROUND: EXOC3L2 gene rs597668 polymorphism was identified to be significantly associated with Alzheimer's disease (AD) in Caucasian population. However, recent studies reported consistent and inconsistent results in Caucasian and Asian populations. AIMS: In order to assess this association, we performed a meta analysis of rs597668 polymorphism using RevMan (v.5.1) software. METHODS: We searched PubMed and Google scholar databases and selected 4 independent publications, which included 16 independent studies. We conducted sensitivity analysis and evaluated the publication bias. In the end, we calculated the odds ratio (OR) using fixed effect model (Mantel-Haenszel). RESULTS: We observed significant association between rs597668 polymorphism and AD using allele model (P = 0.006, OR = 1.09, 95% CI 1.03-1.16) and the dominant model (P = 0.008, OR = 1.11, 95% CI 1.03-1.21). DISCUSSION AND CONCLUSIONS: To our knowledge, this is the first study that assesses the association between rs597668 polymorphism and AD by meta-analysis. We believe that our findings will be very useful for future genetic studies in AD. PMID- 23663386 TI - The clinical relevance of attentional bias in substance use disorders. AB - Individuals with substance use disorders typically show an "attentional bias" for substance-related cues: Those cues are able to grab and hold the attention, in preference to other cues in the environment. We discuss the theoretical context for this work before reviewing the measurement of attentional bias, and its relationship to motivational state and relapse to substance use after a period of abstinence. Finally, we discuss the implications of this research for the treatment of substance use disorders. We conclude that attentional bias is associated with subjective craving, and that moment-by-moment fluctuations in attentional bias may precede relapse to substance use. The evidence regarding the predictive relationship between attentional bias assessed in treatment contexts and subsequent relapse is inconsistent. Furthermore, there is currently insufficient evidence to endorse attentional bias modification as a treatment for substance use disorders. Clinical implications and suggestions for future research are highlighted. PMID- 23663387 TI - Evaluation of ambulance offload delay at a university hospital emergency department. AB - BACKGROUND: Ambulance offload delay (AOD) has been recognized by the National Association of EMS Physicians (NAEMSP) as an important quality marker. AOD is the time between arrival of a patient by EMS and the time that the EMS crew has given report and moved the patient off of the EMS stretcher, allowing the EMS crew to begin the process of returning to service. The AOD represents a potential delay in patient care and a delay in the availability of an EMS crew and their ambulance for response to emergencies. This pilot study was designed to assess the AOD at a university hospital utilizing direct observation by trained research assistants. FINDINGS: A convenience sample of 483 patients was observed during a 12-month period. Data were analyzed to determine the AOD overall and for four groups of National Emergency Department Overcrowding Scale (NEDOCS) score ranges. The AOD ranged from 0 min to 157 min with a median of 11 min. When data were grouped by NEDOCS score, there was a statistically significant difference in median AOD between the groups (p < 0.001), indicating the relationship between ED crowding and AOD. CONCLUSION: The median AOD was considered significant and raised concerns related to patient care and EMS system resource availability. The NEDOCS score had a positive correlation with AOD and should be further investigated as a potential marker for determining diversion status or for destination decision-making by EMS personnel. PMID- 23663390 TI - Patient preferences for HIV/AIDS therapy - a discrete choice experiment. AB - OBJECTIVES: An increasing emphasis on patient-centred health care and shared decision making requires an intensive consideration of patient preferences. In the present study, patient preferences regarding treatment of HIV/AIDS were explored using direct assessment and discrete choice experiment (DCE). METHODS: Based on literature research about preferences of HIV/AIDS patients we conducted a qualitative pre-study. The results were used to compose a questionnaire on relevant aspects of HIV/AIDS treatment which underwent a pre-test. In the subsequent quantitative study phase presented here, the following data were collected online or on paper including socio-demographic data, SF12v2, data on HIV/AIDS, antiretroviral treatment and patient preferences for therapy characteristics using direct measurement, as well as a discrete choice experiment. RESULTS: 218 patients completed the quantitative main study, 82% of these on paper. 86% were male and the most frequent age group was between 45 and 54 years (37.6%). The SF12v2 showed a mean value of 43 points for the "mental health" component sum score. In the direct measurement the most relevant therapy characteristics were "Self-application of the drug (at home or on-the-go) possible", "Drug has very high efficacy (reduction of viral load)" and "Long term (hidden) damage (e.g. organ damage) is unlikely". Based on a factor analysis, six treatment characteristics were selected and used to generate eight virtual therapies. To evaluate the patient assessments a random effect logit model was employed. All of the characteristics were statistically significant predictors of the model of patient preference. The most important therapy characteristic was that the disease is not obvious for others. CONCLUSIONS: The main result is the high impact of quality of life, in particular the emotional quality of life on patient preferences on the selection of treatments. Thus, the selection of particular treatment options should be accompanied by a deliberate consideration of treatment features, which need to be considered in order to maximize patient adherence and compliance. PMID- 23663391 TI - Strains in the genus Thauera exhibit remarkably different denitrification regulatory phenotypes. AB - Denitrifiers differ in how they handle the transition from oxic to anoxic respiration, with consequences for NO and N2O emissions. To enable stringent comparisons we defined parameters to describe denitrification regulatory phenotype (DRP) based on accumulation of NO2(-) , NO and N2O, oxic/anoxic growth and transcription of functional genes. Eight Thauera strains were divided into two distinct DRP types. Four strains were characterized by a rapid, complete onset (RCO) of all denitrification genes and no detectable nitrite accumulation. The others showed progressive onset (PO) of the different denitrification genes. The PO group accumulated nitrite, and no transcription of nirS (encoding nitrite reductase) was detected until all available nitrate (2 mM) was consumed. Addition of a new portion of nitrate to an actively denitrifying culture of a PO strain (T. terpenica) resulted in a transient halt in nitrite reduction, indicating that the electron flow was redirected to nitrate reductase. All eight strains controlled NO at nano-molar concentrations, possibly reflecting the importance of strict control for survival. Transient N2O accumulation differed by two orders of magnitude between strains, indicating that control of N2O is less essential. No correlation was seen between phylogeny (based on 16S rRNA and functional genes) and DRP. PMID- 23663392 TI - [Validity of diagnoses in the Danish Psychiatric Central Research Register]. PMID- 23663393 TI - [Hormonal contraception and venous thrombosis]. PMID- 23663394 TI - [Fourth generation oral contraceptives are associated with a higher risk of venous thromboembolism compared to second generation]. AB - It has been widely discussed whether fourth generation oral contraceptives (OC) are associated with a higher risk of venous thromboembolism (VTE) compared to second generation. Lack of randomized controlled trials, methodological problems and inconsistent criteria for the VTE event has led to conflicting results. Three newly published studies utilising improved methodology show that fourth generation OC are associated with an increased risk of VTE compared to second generation OC. This knowledge has led to a change in recommendation of the first drug of choice, which is now second generation OC. PMID- 23663395 TI - [Organ transplant recipients need intensive control and treatment of skin cancer]. AB - The risk of non-melanoma skin cancer (NMSC) and in particular squamous cell carcinoma is significantly increased in organ transplant recipients due to long term treatment with immunosuppressives. Dermatologic management in the form of a multidisciplinary approach, including patient education, skin surveillance and early treatment of premalignant and malignant lesions is recommended. Field directed rather than lesional therapy is preferred for actinic keratosis in field cancerized skin; and high-efficacy therapies are recommended in NMSC due to an increased risk of recurrences and metastases. PMID- 23663396 TI - [Ulcerative colitis]. AB - Ulcerative colitis (UC) is a prevalent inflammatory bowel disease of the colonic mucosa affecting approximately 20,000-25,000 Danes. Apart from subgroups with early onset, extensive and long-standing inflammation, or primary sclerosing cholangitis the risk of developing colorectal cancer is of the same magnitude as in the background population. The symptoms are usually diarrhoea including bloody stools, rectal tenesmi, anaemia, and fatigue. This review is an update on diagnostics and treatment strategies of relevance for clinicians, and as UC often affects patients during their peak reproductive years, emphasis is additionally put on the management of pregnant patients with UC. PMID- 23663397 TI - [Electromagnetic navigated bronchoscopy can be applied for diagnosing peripherally located lung cancer in patients with severely reduced lung function]. AB - Electromagnetic navigated (EMN) bronchoscopy is a new diagnostic method, which has been used in Denmark since 2008. It is a safe method for diagnosing lung cancer in patients with severely reduced lung function. The method allows diagnosis of peripherally located tumours. From September 2009 to January 2012, the procedure has been performed in 56 patients. In total, 67 tumour evaluations have been conducted. In 15 patients a cancer diagnosis was made. In two patients, pneumothorax occurred. The risk of pneumothorax as a consequence of the EMN procedure was 3%. This is in line with results and experiences from other studies. PMID- 23663398 TI - [Kirner's deformity of the little finger can be misdiagnosed as an overlooked fracture]. AB - Kirner's deformity of the little finger is a very rare condition affecting one in 40,000 persons. The deformity is characterized by palmar and radial deviation of the distal phalanx of the little finger. It is usually bilateral and is twice as common in women. The condition starts at puberty and does not resolve in time. Treatment is seldom required as it is mostly a cosmetic condition. This case report illustrates the need for a correct diagnosis as the condition otherwise could be mistaken as an overlooked fracture. PMID- 23663399 TI - [Abdominal cocoon is a rare cause of ileus]. AB - Partial or total encapsulation of bowel in a membrane-like sac is a rare cause of mechanical bowel obstruction. Three different types of encapsulation have been described: a congenital, a secondary and an idiopathic or "abdominal cocoon". The present case describes a 34-year-old male, who was admitted with small bowel obstruction caused by an "abdominal cocoon", which was successfully treated by surgery. Precise preoperative diagnosis is often missed, but a computed tomography visualizing bowel loops enclosed in a membrane is a characteristic finding. PMID- 23663400 TI - [Cardiac arrest caused by massive pulmonary embolism during treatment with tranexamic acid]. AB - Pulmonary embolism (PE) as the direct cause of cardiac arrest is well known but probably under-diagnosed. Treatment of menorrhagia with antifibrinolytics is a well documented treatment modality and it is considered safe although thromboembolic complications have been reported. We describe a case of a 30-year old otherwise healthy woman, who had been treated with antifibrinolytics for up to six months prior to the event, presenting with fatal acute, massive PE and cardiac arrest, which was treated with prompt resuscitation including thrombolysis with recombinant tissue plasminogen activator and subsequent return of spontaneous circulation. PMID- 23663401 TI - Persistent thebesian vessels involving the right and left ventricles leading to coronary steal phenomena and ischemia. AB - We report an extremely rare case of thebesian vein microfistulae to both ventricles. A 65-year-old woman, with no major cardiovascular risk factors, presented with multiple episodes of chest pain. The resting electrocardiogram showed T-wave inversion in leads V(1) -V(4). A Dipyridamole myocardial perfusion imaging revealed large and severe inferior defect with complete reversibility. Coronary angiography showed no coronary artery disease. On contrast injection, an exaggerated capillary blush from the distal portions of the right and left coronary artery systems was seen in both ventricles, mimicking the image of ventriculography. This appearance suggests prominent thebesian vessels, a congenital communication between the coronaries and the two ventricles. The clinical relevance of these myocardial sinusoids is still not well established. Although the majority of these fistulas are small in size and with no clinical significance, they can rarely present with chest pain, cardiac arrhythmia, syncope, myocardial infarction, and/or pulmonary hypertension. These fistulae when excessive can cause significant shunting of blood to the ventricles, leading to coronary steal phenomena and ischemia. This phenomenon is facilitated by the low resistance in these microfistulae as opposed to the higher resistance in the normal coronary circulation. Due to the diffuse nature of these microfistulae, neither surgery nor transcatheter therapy is feasible. This condition can only be managed medically; however, it should be noted that vasodilator agents, such as nitrates, can worsen the coronary steal phenomenon. Our patient was treated with ranolazine with significant improvement in her symptoms, which was not reported previously. Multiple coronary artery microfistulae could be an underestimated condition of angina in patient with normal coronaries. PMID- 23663402 TI - World Allergy Organization Journal (WAO Journal) at five years: updates and changes. PMID- 23663403 TI - Depleting NFAT1 expression inhibits the ability of invasion and migration of human lung cancer cells. AB - BACKGROUND: Nuclear factor of activated T-cells (NFAT) is a general name applied to a family of transcription factors shown to be important in immune response. One or more members of the NFAT family are expressed in most cells of the immune system. NFAT1 is considered to involve in the development of cardiac, skeletal muscle, nervous systems, and tumorigenesis. METHODS: In the current study, we analyzed MEKK1 expression in 159 surgically resection non-small cell lung cancer patient's samples by immunohistochemistry and determined its role in SK-EMS-1 cells via RNAi experiment. RESULTS: The abilities of invasion, motility, and adhesion of SK-EMS-1 cells were detected by transwell assay, wound healing assay and adhesion assay, respectively. The result showed NFAT1 was highly expressed in lung tumor tissues instead of adjacent lung tissues (54.1% vs 8.8%, p < 0.05); its overexpression was positively correlated with lymph node metastasis (p < 0.05). Depleting its expression in SK-EMS-1 cells can inhibit its invasion and migration abilities significantly (p < 0.05); and also can reduce proliferation of lung cancer cells (p < 0.05). CONCLUSION: Our study showed NFAT1 plays an important role in origination, invasion and metastasis of non-small lung cancer cells; its underlying action mechanism needs further study. PMID- 23663404 TI - The influence of Apolipoprotein E genotype on regional pathology in Alzheimer's disease. AB - BACKGROUND: Carriers of the ApoE epsilon4 allele are at a greater risk for developing Alzheimer's disease (AD) and those who do develop AD tend to have a much greater neuropathological disease burden. Although several studies have shown significant differences in AD pathology among epsilon4 carriers and non carriers, few have characterized these differences in terms of brain region and neuropathological score frequency. METHODS: 566 pathologically-confirmed AD cases who were followed prospectively with antemortem dementia diagnoses (312 ApoE epsilon4 carriers and 254 ApoE epsilon4 non-carriers) were compared on the frequencies of neuropathological frequency scores (none, sparse, moderate, frequent) among several different brain regions (frontal, temporal, parietal, hippocampal, and entorhinal) using the CERAD scoring system. Pathology score frequencies were analyzed by carrier status (epsilon4 carrier vs. epsilon4 non carrier) and by genotype (2/3, 3/3, 2/4, 3/4, 4/4). Both analyses investigated pathology score frequencies among different brain regions (frontal, temporal, parietal, hippocampal, and entorhinal). RESULTS: epsilon4 carriers had a significantly lower age at death (p <0.001) and significantly higher Braak scores (p <0.001) than epsilon4 non-carriers. Genotype comparison revealed that plaque and tangle pathologies increased in the following pattern, 2/3<3/3<2/4<3/4<4/4, for several brain regions. When stratified by age and ApoE epsilon4 carrier status, epsilon4 carriers tended to have significantly more frequent scores across most cortical areas. However, non-carriers age 90 and older tended to have greater plaque pathology than carriers. For tangle pathology, epsilon4 carriers tended to have significantly more "frequent" scores than non-carriers, except for the hippocampal and entorhinal areas in individuals age 90 and older. CONCLUSIONS: ApoE epsilon4 carriers had a significantly higher percentage of "frequent" scores for plaques and tangles when compared to ApoE epsilon4 non carriers for several brain regions. However, epsilon4 non-carriers age 90 and older tended to have less plaque and tangle pathology in certain brain regions. These results demonstrate that AD pathology may manifest itself differently based on ApoE genotype and suggest that ApoE carriers and non-carriers may have different patterns of AD neuropathology location and density. PMID- 23663405 TI - Spontaneous and cued gaze-following in autism and Williams syndrome. AB - BACKGROUND: From a young age the typical development of social functioning relies upon the allocation of attention to socially relevant information, which in turn allows experience at processing such information and thus enhances social cognition. As such, research has attempted to identify the developmental processes that are derailed in some neuro-developmental disorders that impact upon social functioning. Williams syndrome (WS) and autism are disorders of development that are characterized by atypical yet divergent social phenotypes and atypicalities of attention to people. METHODS: We used eye tracking to explore how individuals with WS and autism attended to, and subsequently interpreted, an actor's eye gaze cue within a social scene. Images were presented for 3 seconds, initially with an instruction simply to look at the picture. The images were then shown again, with the participant asked to identify the object being looked at. Allocation of eye gaze in each condition was analyzed by analysis of variance and accuracy of identification was compared with t tests. RESULTS: Participants with WS allocated more gaze time to face and eyes than their matched controls, both with and without being asked to identify the item being looked at; while participants with autism spent less time on face and eyes in both conditions. When cued to follow gaze, participants with WS increased gaze to the correct targets; those with autism looked more at the face and eyes but did not increase gaze to the correct targets, while continuing to look much more than their controls at implausible targets. Both groups identified fewer objects than their controls. CONCLUSIONS: The atypicalities found are likely to be entwined with the deficits shown in interpreting social cognitive cues from the images. WS and autism are characterized by atypicalities of social attention that impact upon socio-cognitive expertise, but, importantly, the type of atypicality is syndrome specific. PMID- 23663406 TI - Nuclear war between Israel and Iran: lethality beyond the pale. AB - BACKGROUND: The proliferation of nuclear technology in the politically volatile Middle East greatly increases the likelihood of a catastrophic nuclear war. It is widely accepted, while not openly declared, that Israel has nuclear weapons, and that Iran has enriched enough nuclear material to build them. The medical consequences of a nuclear exchange between Iran and Israel in the near future are envisioned, with a focus on the distribution of casualties in urban environments. METHODS: Model estimates of nuclear war casualties employed ESRI's ArcGIS 9.3, blast and prompt radiation were calculated using the Defense Nuclear Agency's WE program, and fallout radiation was calculated using the Defense Threat Reduction Agency's (DTRA's) Hazard Prediction and Assessment Capability (HPAC) V404SP4, as well as custom GIS and database software applications. Further development for thermal burn casualties was based on Brode, as modified by Binninger, to calculate thermal fluence. ESRI ArcGISTM programs were used to calculate affected populations from the Oak Ridge National Laboratory's LandScanTM 2007 Global Population Dataset for areas affected by thermal, blast and radiation data. RESULTS: Trauma, thermal burn, and radiation casualties were thus estimated on a geographic basis for three Israeli and eighteen Iranian cities. Nuclear weapon detonations in the densely populated cities of Iran and Israel will result in an unprecedented millions of numbers of dead, with millions of injured suffering without adequate medical care, a broad base of lingering mental health issues, a devastating loss of municipal infrastructure, long-term disruption of economic, educational, and other essential social activity, and a breakdown in law and order. CONCLUSIONS: This will cause a very limited medical response initially for survivors in Iran and Israel. Strategic use of surviving medical response and collaboration with international relief could be expedited by the predicted casualty distributions and locations. The consequences for health management of thermal burn and radiation patients is the worst, as burn patients require enormous resources to treat, and there will be little to no familiarity with the treatment of radiation victims. Any rational analysis of a nuclear war between Iran and Israel reveals the utterly unacceptable outcomes for either nation. PMID- 23663407 TI - Potential animal and environmental sources of Q fever infection for humans in Queensland. AB - Q fever is a vaccine-preventable disease; despite this, high annual notification numbers are still recorded in Australia. We have previously shown seroprevalence in Queensland metropolitan regions is approaching that of rural areas. This study investigated the presence of nucleic acid from Coxiella burnetii, the agent responsible for Q fever, in a number of animal and environmental samples collected throughout Queensland, to identify potential sources of human infection. Samples were collected from 129 geographical locations and included urine, faeces and whole blood from 22 different animal species; 45 ticks were removed from two species, canines and possums; 151 soil samples; 72 atmospheric dust samples collected from two locations and 50 dust swabs collected from domestic vacuum cleaners. PCR testing was performed targeting the IS1111 and COM1 genes for the specific detection of C. burnetii DNA. There were 85 detections from 1318 animal samples, giving a detection rate for each sample type ranging from 2.1 to 6.8%. Equine samples produced a detection rate of 11.9%, whilst feline and canine samples showed detection rates of 7.8% and 5.2%, respectively. Native animals had varying detection rates: pooled urines from flying foxes had 7.8%, whilst koalas had 5.1%, and 6.7% of ticks screened were positive. The soil and dust samples showed the presence of C. burnetii DNA ranging from 2.0 to 6.9%, respectively. These data show that specimens from a variety of animal species and the general environment provide a number of potential sources for C. burnetii infections of humans living in Queensland. These previously unrecognized sources may account for the high seroprevalence rates seen in putative low-risk communities, including Q fever patients with no direct animal contact and those subjects living in a low-risk urban environment. PMID- 23663408 TI - Whatever next? Predictive brains, situated agents, and the future of cognitive science. AB - Brains, it has recently been argued, are essentially prediction machines. They are bundles of cells that support perception and action by constantly attempting to match incoming sensory inputs with top-down expectations or predictions. This is achieved using a hierarchical generative model that aims to minimize prediction error within a bidirectional cascade of cortical processing. Such accounts offer a unifying model of perception and action, illuminate the functional role of attention, and may neatly capture the special contribution of cortical processing to adaptive success. This target article critically examines this "hierarchical prediction machine" approach, concluding that it offers the best clue yet to the shape of a unified science of mind and action. Sections 1 and 2 lay out the key elements and implications of the approach. Section 3 explores a variety of pitfalls and challenges, spanning the evidential, the methodological, and the more properly conceptual. The paper ends (sections 4 and 5) by asking how such approaches might impact our more general vision of mind, experience, and agency. PMID- 23663410 TI - Prediction, explanation, and the role of generative models in language processing. AB - We propose, following Clark, that generative models also play a central role in the perception and interpretation of linguistic signals. The data explanation approach provides a rationale for the role of prediction in language processing and unifies a number of phenomena, including multiple-cue integration, adaptation effects, and cortical responses to violations of linguistic expectations. PMID- 23663409 TI - The differential effects of written and spoken presentation for the modification of interpretation and judgmental bias in children. AB - BACKGROUND: Interpretation training programs, in which individuals are trained to interpret ambiguous scenarios in either a negative or benign way, have proven effective in altering anxiety-related cognitive biases in both children and adults. AIMS: The current study investigated whether the effects of the interpretation training procedure in children are differentiated according to the mode of presentation of the training. METHOD: Ninety-four primary school children (aged 10-12 years) scoring above the mean on a social anxiety scale were randomly allocated to four groups, in which they were trained using written or spoken presentation of training materials in either the negative or benign direction. RESULTS: For the negative training, children who heard the training material spoken aloud (spoken presentation) made more negative interpretations of ambiguous social events, compared to children who read the training material (written presentation). However, for the benign training, there was less clear evidence for a differentiation of the effects between the two modes of presentation, although children in the spoken presentation group performed better in a stressful task and showed a trend to rate their mood as more positive after the task than children in the written presentation group. CONCLUSIONS: These results not only forward our understanding of the mechanism of the genesis of cognitive bias in children, but also highlight the need for further investigation of how to optimize the effectiveness of interpretation training in children. PMID- 23663411 TI - Adaptation of Saccharomyces cerevisiae to toxic manganese concentration triggers changes in inorganic polyphosphates. AB - The ability of Saccharomyces cerevisiae to adapt to toxic Mn(2+) concentration (4 mM) after an unusually long lag phase has been demonstrated for the first time. The mutants lacking exopolyphosphatase PPX1 did not change the adaptation time, whereas the mutants lacking exopolyphosphatase PPN1 reduced the lag period compared with the wild-type strains. The cell populations of WT and DeltaPPN1 in the stationary phase at cultivation with Mn(2+) contained a substantial number of enlarged cells with a giant vacuole. The adaptation correlated with the triggering of polyphosphate metabolism: the drastic increase in the rate and chain length of acid-soluble polyphosphate. The share of this fraction, which is believed to be localized in the cytoplasm, increased to 76%. Its average chain length increased to 200 phosphate residues compared with 15 at the cultivation in the absence of manganese. DAPI-stained inclusions in the cytoplasm were accumulated in the lag phase during the cultivation with Mn(2+). PMID- 23663412 TI - Imaging receptor for advanced glycation end product expression in mouse model of hind limb ischemia. AB - BACKGROUND: The purpose of this study is to image the effect of diabetes on expression of receptor for advanced glycation endproducts (RAGE) in limb ischemia in live animals. METHODS: Male wild-type C57BL/6 mice were either made diabetic or left as control. Two months later, diabetic and non-diabetic mice underwent left femoral artery ligation. The right leg served as lesion control. Five days later, mice were injected with 15.1 +/- 4.4 MBq 99mTc-anti-RAGE F(ab')2 and 4 to 5 h later (blood pool clearance) underwent SPECT/CT imaging. At the completion of imaging, mice were euthanized, hind limbs counted and sectioned, and scans reconstructed. Regions of interest were drawn on serial transverse sections comprising the hind limbs and activity in millicuries summed and divided by the injected dose (ID). Quantitative histology was performed for RAGE staining and angiogenesis. RESULTS: Uptake of 99mTc-anti-RAGE F(ab')2 as %ID * 10-3 was higher in the left (ischemic) limbs for the diabetic mice (n = 8) compared to non diabetic mice (n = 8) (1.20 +/- 0.44% vs. 0.49 +/- 0.40%; P = 0.0007) and corresponded to less angiogenesis in the diabetic mice. Uptake was also higher in the right limbs of diabetic compared to non-diabetic animals (0.82 +/- 0.33% vs. 0.40 +/- 0.14%; P = 0.0004). CONCLUSIONS: These data show the feasibility of imaging and quantifying the effect of diabetes on RAGE expression in limb ischemia. PMID- 23663414 TI - MRI findings of radiation-induced changes of masticatory muscles: a systematic review. AB - BACKGROUND: Radiotherapy to the head and neck regions can result in serious consequences to the temporomandibular joint (TMJ) and chewing muscles. Magnetic resonance imaging (MRI) demonstrates soft-tissue alterations after radiotherapy, such as morphology and signal intensity. OBJECTIVE: The purpose of this review is to critically and systematically analyse the available evidence regarding the masticatory muscles alterations, as demonstrated on MRI, after radiotherapy for head and neck cancer. DATA SOURCES: Electronic search of MEDLINE, EMBASE, EBM reviews and Scopus. INCLUSION CRITERIA: Reports of any study design investigating radiation-induced changes in masticatory muscles after radiotherapy in patients with head and neck cancer were included. RESULTS AND SYNTHESIS METHODS: An electronic database search resulted in 162 papers. Sixteen papers were initially selected as potentially relevant studies; however, only four papers satisfied all inclusion criteria. The included papers focused on the MRI appearance of masticatory muscles following radiotherapy protocol. Two papers reported outcome based on retrospective clinical and imaging records, whereas the remaining two papers were case reports. Irradiated muscles frequently show diffuse increase in T2 signal and post-gadolinium enhancement post-irradiation. Also, muscle size changes were reported based on subjective comparison with the contralateral side. The quality of all included papers was considered poor with high risk of bias. CONCLUSION: There is no evidence that MRI interpretations indicate specific radiation-induced changes in masticatory muscles. There is a clear need for a cohort study comparing patients with pre- and post-radiotherapy MRI. PMID- 23663413 TI - Alterations in expression of endometrial genes coding for proteins secreted into the uterine lumen during conceptus elongation in cattle. AB - BACKGROUND: We hypothesized that genes that are up-regulated in the uterine endometrium at the initiation of conceptus elongation in cattle, and that encode for secreted proteins, contribute to the composition of the uterine luminal fluid (ULF) and ultimately, drive conceptus elongation. The aims of this study were to: 1) screen endometrial transcriptomic data for genes that encode secreted proteins on Day 13; 2) determine temporal changes in the expression of these genes during the estrous cycle/early pregnancy; 3) determine if expression of these genes is affected by altered concentrations of progesterone (P4) in vivo and 4) determine if the protein products of these genes are detectable in ULF. RESULTS: Of the fourteen candidate genes examined, quantitative real-time PCR analysis revealed the expression of APOA1, ARSA, DCN, LCAT, MUC13, NCDN, NMN, NPNT, NXPH3, PENK, PLIN2 and TINAGL1 was modulated in the endometrium (P<0.05) as the estrous cycle/early pregnancy progressed. APOA1, DCN and NPNT expression was higher in cyclic compared to pregnant heifers, and pregnancy increased (P<0.05) the expression of LCAT, NCDN, NMN, PLIN2 and TINAGL1. The magnitude of the increase in expression of APOA1, PENK and TINAGL1 on Day 13 was reduced (P<0.05) in heifers with low P4. Furthermore, low P4 decreased (P<0.05) the expression of LCAT and NPNT on Day 7, while an early increase (P<0.05) in the expression of NXPH3 and PLIN2 was observed in heifers with high P4. The protein products of 5 of the candidate genes (APOA1, ARSA, LCAT, NCDN and PLIN) were detected in the ULF on either Days 13, 16 or 19 of pregnancy. CONCLUSION: Using a candidate gene approach, we determined that both P4 concentration and the presence of the conceptus alter endometrial expression of PLIN2, TINAGL1, NPNT, LCAT, NMN and APOA1. Comparison of the expression profiles of these genes to proteins detected in ULF during conceptus elongation (i.e., Days 13 through 19) revealed the presence of APOA1, ARSA, LCAT, NCDN as well as members of the PLIN family of proteins that may play roles in driving conceptus elongation in cattle. PMID- 23663415 TI - TH1 cytokine response to HCV peptides in Egyptian health care workers: a pilot study. AB - Our objective was to elucidate the effects of different HCV peptides on TH1 cytokine synthesis (interleukin 2(IL2), gamma interferon (INFgamma) and tumor necrosis factor alpha (TNF alpha)), in a proliferative response in a high risk population of HCV seronegative aviremic Egyptian healthcare workers (HCW). We studied the TH1 cytokine response to different HCV peptides among 47 HCW with and without evidence of HCV infection. Participants were classified according to the proliferation index (PI) in a CFSE proliferation assay as an indicator of previous exposure to HCV. Cytokines were analyzed using Luminex xMAP technology. Results showed that positive PI HCW produced a higher IL2 in response to all HCV peptides except NS4, a higher IFNgamma response to NS3 and NS4 and no difference in TNFalpha response when compared to the negative PI HCWs. When compared to chronic HCV HCW, positive PI HCW showed no difference in the IL2 response, a higher IFNgamma response to NS4 and NS5 HCV peptides and a higher TNFalpha response to all peptides. In conclusion the magnitude and type of cytokines produced in HCV infection is critical in determining the outcome of infection. NS4 & NS5 HCV peptides induce a protective TH1 response in positive PI HCW. PMID- 23663416 TI - Correlates of physical activity in adolescence: a study from a developing country. AB - BACKGROUND: Physical activity is important for adolescent health. The current study aimed to explore factors that predict physical activity among adolescents. METHODS: This was a cross-sectional study of physical activity among a sample of adolescents in Tabriz, Iran. Information on physical activity was collected using a modified version of the Adolescent Physical Activity and Recall Questionnaire (APARQ). In addition, a self-administrated questionnaire was used to collect data on demographic characteristics, perceived family support, and self-efficacy. Both univariate and multivariate logistic regression analyses were performed to examine the association between physical activity and independent variables including gender and psychosocial predictors. RESULTS: In all, 402 students were studied. The mean age of adolescents was 12.93 (SD=0.49) years; 51.5% were female. The mean time of moderate and vigorous physical activity for all adolescents was 44.64 (SD=23.24) Metabolic Equivalent (MET) min per day. This figure for female adolescents was 38.77 (SD=19.94) MET min per day and for males it was 50.87 (SD=24.88) (P<0.001). The results obtained from multiple logistic regression analysis indicated that female gender (OR=2.59, 95% CI=1.46-4.57, P=0.001) and poor family support (OR=1.10, 95% CI=1.03-1.20, P=0.038) were the most significant contributing factors to low level physical activity in adolescents. Other variables studied did not show any significant results. CONCLUSION: The findings from the current study indicated that female adolescents were at risk of lower level of physical activity. In addition, it was found that the lack of family support represented an increased risk for low-level physical activity. It seems that family support should be an integrated part of any health education/promotion programs for improving physical activity among young adolescents in general and for female adolescents in particular. PMID- 23663417 TI - Aquagenic urticaria in twins. AB - We describe the case of 18 year old twin brothers who presented to our unit with a 3 year history of aquagenic urticaria. This rare form of urticaria usually presents within an hour of contact with water. The aetiology is unknown. Most cases are sporadic but there are a small number of familial cases in the medical literature. A specific genetic mutation has not yet been found. To our knowledge, this is the first report of aquagenic urticaria in monozygotic twins, further supporting a genetic component to this disease. PMID- 23663418 TI - Pediatric giant right atrial aneurysm: a case series and review of the literature. AB - Giant right atrial aneurysm is a rare form of congenital heart disease with a wide spectrum of clinical presentation varying from asymptomatic patients to those with refractory atrial arrhythmias or severe airway obstruction. Diagnosis is often confused with other causes of right atrial dilation such as Ebstein disease. Because of its rare occurrence and variable clinical presentation, inconsistencies in medical and surgical management strategies exist between centers. We present five cases of giant right atrial aneurysm managed at our institution and discuss the clinical presentation, diagnostic challenges, and medical and surgical management. PMID- 23663419 TI - Soil metatranscriptomics for mining eukaryotic heavy metal resistance genes. AB - Heavy metals are pollutants which affect all organisms. Since a small number of eukaryotes have been investigated with respect to metal resistance, we hypothesize that many genes that control this phenomenon remain to be identified. This was tested by screening soil eukaryotic metatranscriptomes which encompass RNA from organisms belonging to the main eukaryotic phyla. Soil-extracted polyadenylated mRNAs were converted into cDNAs and 35 of them were selected for their ability to rescue the metal (Cd or Zn) sensitive phenotype of yeast mutants. Few of the genes belonged to families known to confer metal resistance when overexpressed in yeast. Several of them were homologous to genes that had not been studied in the context of metal resistance. For instance, the BOLA ones, which conferred cross metal (Zn, Co, Cd, Mn) resistance may act by interfering with Fe homeostasis. Other genes, such as those encoding 110- to 130-amino-acid long, cysteine-rich polypeptides, had no homologues in databases. This study confirms that functional metatranscriptomics represents a powerful approach to address basic biological processes in eukaryotes. The selected genes can be used to probe new pathways involved in metal homeostasis and to manipulate the resistance level of selected organisms. PMID- 23663422 TI - Position paper of the EPMA and EFLM: a global vision of the consolidated promotion of an integrative medical approach to advance health care. AB - The authors consider acute problems in the quality and management of medical services challenging health care systems worldwide. This actuality has motivated the representatives of the European Association for Predictive, Preventive and Personalised Medicine and European Federation of Clinical Chemistry and Laboratory Medicine to consider the efforts in promoting an integrative approach based on multidisciplinary expertise to advance health care. The current paper provides a global overview of the problems related to medical services: pandemic scenario in the progression of common chronic diseases, delayed interventional approaches of reactive medicine, poor economy of health care systems, lack of specialised educational programmes, problematic ethical aspects of treatments as well as inadequate communication among professional groups and policymakers. Further, in the form of individual paragraphs, the article presents a consolidated position of the represented European organisations. This position is focused on the patients' needs, expert recommendations for the relevant medical fields and plausible solutions which have a potential to advance health care services if the long-term strategies were to be effectively implemented as proposed here. PMID- 23663420 TI - Vasoactive agents for the prediction of early- and late-onset preeclampsia in a high-risk cohort. AB - BACKGROUND: To evaluate the soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and sFlt-1/PlGF ratio for the prediction of early and late-onset preeclampsia in a high-risk cohort. METHODS: We studied serial serum samples collected prospectively at 12+0-14+0, 18+0-20+0, and 26+0-28+0 weeks+days of gestation in 6 women who developed early-onset preeclampsia (before 34 weeks of gestation) and in 21 women who developed late-onset preeclampsia (after 34 weeks of gestation) with automated ElecSys 2010 immunoanalyzer (Roche Diagnostics, Germany). Twenty-six high-risk women and 53 women without risk factors with normal pregnancies served as controls. RESULTS: Serum PlGF concentrations were lower at 18+0 to 20+0, and 26+0 to 28+0 weeks of gestation in women who developed early-onset preeclampsia compared to women who developed late onset preeclampsia and to controls (p<0.05 for all comparisons). At 18+0 to 20+0 weeks of gestation area under the receiver-operating characteristic curve (AUC) for serum PlGF was 99.8% (p=0.0007, 95% CI 99.0-100.0). At 26+0 to 28+0 weeks of gestation serum sFlt-1/PlGF ratio explicitly detects those women who developed early-onset preeclampsia (AUC 100.0%, p=0.0007, 95% CI 100-100). Amongst women with late-onset preeclampsia, those who developed severe form of the disease (N=8) had significantly higher serum sFlt-1 concentrations at all three timepoints (p=0.004, p=0.006, and p=0.003, respectively) compared to women with non-severe form (N=13). CONCLUSIONS: Low serum PlGF concentration predicts early onset preeclampsia from the second trimester and elevated serum sFlt-1/PlGF ratio from 26 to 28 weeks of gestation. Elevated serum sFlt-1 concentration in the first trimester in women who later develop late-onset, severe preeclampsia may suggest different etiology compared to the late-onset non-severe form of the disease. PMID- 23663421 TI - Physical condition of Olyset(r) nets after five years of utilization in rural western Kenya. AB - BACKGROUND: Long-lasting insecticidal nets (LLINs) are a cornerstone of malaria control at present, and millions are used each day across the globe. However, there is limited information about the durability of LLINs under different conditions of utilization and there is no consensus about when a LLIN ceases to be protective due to physical deterioration. This knowledge is important for malaria control programmes to plan for procurement and replacement. METHODS: A cross-sectional survey of 208 households where Olyset(r) nets distributed five years ago were still present was conducted in the village of Sauri, western Kenya, in the context of the Millennium Villages Project. Information on bed net utilization and maintenance was collected in each household through a structured questionnaire, and one five-year-old Olyset(r) net from each sampled household was randomly selected and collected for physical examination. All holes larger than 0.5 cm were measured in each net, registering their position, and a hole index was calculated following WHO guidelines. Nets were classified as in good condition, moderately damaged or badly torn based on the hole index. The analysis explored the associations between demographic and socioeconomic characteristics of households, patterns of bed net utilization and maintenance and physical condition of the nets. Additional analysis was conducted using malaria prevalence data collected in a separate survey to explore if there was any association between the condition of the net collected in a household and the presence of malaria parasites in members of that household. RESULTS: 81.4% of Olyset(r) nets distributed five years ago were still present in the surveyed households, and 98.97% of the nets were reportedly used the previous night. Nets had an average of 34.2 holes (95% CI 30.12-38.22), and the mean hole index was 849 (95% CI 711 986), IQR 174-1,135. 15.2% of nets were still in good condition, 46.1% were moderately damaged and 38.7% were badly torn after five years of utilization. There was no association between household characteristics or patterns of bed net utilization or maintenance and physical condition of the nets. The only predictor of the physical condition of the net was the cleanliness at the time of examination. There was a difference of 17.6 percentage points in the proportion of households with at least one blood smear positive for Plasmodium falciparum between households with a net in good condition (5.3%) and those with a moderately damaged or badly torn net (22.9%), 95% CI (0.04-0.305), t=2.77 with unequal variance, p=0.009. CONCLUSIONS: Olyset(r) nets were used extensively in Sauri, western Kenya after five years of distribution, regardless of their physical condition. However, only 15% were found in good condition. Nets in good condition seem to be still protective after five years of utilization, while nets with more than 100 cm2 of holed surface may be associated with higher malaria parasitaemia at household level. Continued replacement of damaged nets and promotion of net maintenance and repair may be necessary to maintain the protective effectiveness of LLINs. PMID- 23663423 TI - Framing education on headache disorders into the Global Burden of Disease Study 2010. The European Headache Federation stands ready. AB - Framing education on headache disorders into the Global Burden of Disease Study 2010. The European Headache Federation stands ready. PMID- 23663424 TI - Active inference and free energy. AB - Why do brains have so many connections? The principles exposed by Andy Clark provide answers to questions like this by appealing to the notion that brains distil causal regularities in the sensorium and embody them in models of their world. For example, connections embody the fact that causes have particular consequences. This commentary considers the imperatives for this form of embodiment. PMID- 23663425 TI - A standard vector for the chromosomal integration and characterization of BioBrickTM parts in Escherichia coli. AB - BACKGROUND: The chromosomal integration of biological parts in the host genome enables the engineering of plasmid-free stable strains with single-copy insertions of the desired gene networks. Although different integrative vectors were proposed, no standard pre-assembled genetic tool is available to carry out this task. Synthetic biology concepts can contribute to the development of standardized and user friendly solutions to easily produce engineered strains and to rapidly characterize the desired genetic parts in single-copy context. RESULTS: In this work we report the design of a novel integrative vector that allows the genomic integration of biological parts compatible with the RFC10, RFC23 and RFC12 BioBrickTM standards in Escherichia coli. It can also be specialized by using BioBrickTM parts to target the desired integration site in the host genome. The usefulness of this vector has been demonstrated by integrating a set of BioBrickTM devices in two different loci of the E. coli chromosome and by characterizing their activity in single-copy. Construct stability has also been evaluated and compared with plasmid-borne solutions. CONCLUSIONS: Physical modularity of biological parts has been successfully applied to construct a ready-to-engineer BioBrickTM vector, suitable for a stable chromosomal insertion of standard parts via the desired recombination method, i.e. the bacteriophage integration mechanism or homologous recombination. In contrast with previously proposed solutions, it is a pre-assembled vector containing properly-placed restriction sites for the direct transfer of various formats of BioBrickTM parts. This vector can facilitate the characterization of parts avoiding copy number artefacts and the construction of antibiotic resistance-free engineered microbes, suitable for industrial use. PMID- 23663426 TI - Comparison of cyclic RGD peptides for alphavbeta3 integrin detection in a rat model of myocardial infarction. AB - BACKGROUND: Expression of alphavbeta3 integrin is increased after myocardial infarction as part of the repair process. Increased expression of alphavbeta3 has been shown by molecular imaging with 18F-galacto-RGD in a rat model. The 68Ga labelled RGD compounds 68Ga-NODAGA-RGD and 68Ga-TRAP(RGD)3 have high specificity and affinity, and may therefore serve as alternatives of 18F-galacto-RGD for integrin imaging. METHODS: Left coronary artery ligation was performed in rats. After 1 week, rats were imaged with [13N]NH3, followed by 18F-galacto-RGD, 68Ga NODAGA-RGD or 68Ga-TRAP(RGD)3 using a dedicated animal PET/CT device. Rats were killed, and the activity in tissues was measured by gamma counting. The heart was sectioned for autoradiography and histology. Immunohistochemistry was performed on consecutive sections using CD31 for the endothelial cells and CD61 for beta3 expression (as part of the alphavbeta3 receptor). RESULTS: In vivo imaging showed focal RGD uptake in the hypoperfused area of infarcted myocardium as defined with [13N]NH3 scan. In autoradiography images, augmented uptake of all RGD tracers was observed within the infarct area as verified by the HE staining. The tracer uptake ratios (infarct vs. remote) were 4.7 +/- 0.8 for 18F-galacto-RGD, 5.2 +/- 0.8 for 68Ga-NODAGA-RGD, and 4.1 +/- 0.7 for 68Ga-TRAP(RGD)3. The 68Ga-NODAGA-RGD ratio was higher compared to 68Ga-TRAP(RGD)3 (p = 0.04), but neither of the 68Ga tracers differed from 18F-galacto-RGD (p > 0.05). The area of augmented 68Ga-RGD uptake was associated with beta3 integrin expression (CD61). CONCLUSION: 68Ga NODAGA-RGD and 68Ga-TRAP(RGD)3 uptake was equally increased in the infarct area at 1 week post infarction as 18F-galacto-RGD. These results show the potential of 68Ga-labelled RGD peptides to monitor integrin expression as a part of myocardial repair and angiogenesis after ischaemic injury in vivo. PMID- 23663428 TI - Effects of southern rice black-streaked dwarf virus on the development and fecundity of its vector, Sogatella furcifera. AB - BACKGROUND: Southern rice black-streaked dwarf virus (SRBSDV) threatens rice production in China and Vietnam. The virus is vectored by the migrating white backed planthopper (WBPH, Sogatella furcifera) in a circulative, propagative, and persistent manner. A persistently-transmitted plant virus might affect its vector's development and fecundity directly by infecting the vector itself and/or indirectly altering the host plant. This study evaluated the direct and indirect effects of SRBSDV on WBPH performance to better understand the virus-vector-host plant relationship in terms of its effects on the biological parameters of the vector. METHODS: Three experimental WBPH populations were established. Viruliferous and non-viruliferous populations were fed on SRBSDV-infected rice seedlings for 48 h as first-instar nymphs; infection status was confirmed by RT PCR after they died. The control population was fed on healthy rice. Each insect was individually transferred to a healthy rice plant grown in a glass tube at 20 degrees C, 25 degrees C, or 28 degrees C. Life parameters, including nymphal duration, survival rate, adult sex ratio, macropterous proportion, longevity, and oviposition amounts, of each population were measured at each temperature. RESULTS: The life parameter data indicated that SRBSDV and infected rice plants adversely influenced WBPH; the effects were temperature dependent. Compared with the control population, viruliferous populations showed significant changes, including prolonged nymphal stages and reduced survival rates at 20 degrees C, while the non-viruliferous population had higher survival rates at 20 degrees C and lower rates at 28 degrees C compared with the control. Both populations had significantly shorter adult life spans at 25 degrees C and lower oviposition amounts at 28 degrees C relative to the control. CONCLUSIONS: Both SRBSDV infection and feeding on infected rice plants affected vector performance. Although a longer nymphal period benefits viral acquisition and transmission by nymphs and might increase rice infection rate, in general, SRBSDV infection of the vectors and host plants was unfavorable to WBPH population expansion. PMID- 23663430 TI - The impact of the food-based and nutrient-based standards on lunchtime food and drink provision and consumption in secondary schools in England. AB - OBJECTIVES: To assess lunchtime provision of food and drink in English secondary schools and the choices and consumption of food and drink by pupils having school lunches, and to compare provision in 2011 with that in 2004. DESIGN: Cross sectional data collected between October 2010 and April 2011. In each school, food and drink provision, including portion weights and number of portions of each item served at lunchtime, were recorded over five consecutive days. Caterers provided recipe information. SETTING: England. SUBJECTS: A random selection of 5969 pupils having school lunches in a nationally representative sample of eighty secondary schools in England. RESULTS: Compared with 2004, significantly more schools in 2011 provided main dishes, vegetables and salads, water, fruit juice and other drinks on 4 or 5 d/week (P < 0.005). The number of schools offering items not permitted under the food-based standards for school food on 4 or 5 d/week fell significantly over time (P < 0.005), while the number not offering these items on any day increased significantly (P < 0.005). Meals eaten by pupils were well-balanced in relation to macronutrients. CONCLUSIONS: Lunchtime food provision and consumption in secondary schools have improved considerably since 2004, following the introduction of new compulsory standards for school food in 2009. To maximise their energy and nutrient intake at lunchtime, pupils should be encouraged to select a full meal, and to take and eat more fruit and vegetables. Schools also need continued support to increase the micronutrient content of menus and recipes. PMID- 23663427 TI - Directional protein secretion by the retinal pigment epithelium: roles in retinal health and the development of age-related macular degeneration. AB - The structural and functional integrity of the retinal pigment epithelium (RPE) is fundamental for maintaining the function of the neuroretina. These specialized cells form a polarized monolayer that acts as the retinal-blood barrier, separating two distinct environments with highly specialized functions: photoreceptors of the neuroretina at the apical side and Bruch's membrane/highly vascularized choriocapillaris at the basal side. The polarized nature of the RPE is essential for the health of these two regions, not only in nutrient and waste transport but also in the synthesis and directional secretion of proteins required in maintaining retinal homoeostasis and function. Although multiple malfunctions within the RPE cells have been associated with development of age related macular degeneration (AMD), the leading cause of legal blindness, clear causative processes have not yet been conclusively characterized at the molecular and cellular level. This article focuses on the involvement of directionally secreted RPE proteins in normal functioning of the retina and on the potential association of incorrect RPE protein secretion with development of AMD. Understanding the importance of RPE polarity and the correct secretion of essential structural and regulatory components emerge as critical factors for the development of novel therapeutic strategies targeting AMD. PMID- 23663431 TI - Convergence of two major pathophysiologic mechanisms in nasal polyposis: immune response to Staphylococcus aureus and airway remodeling. AB - This review is addressed two pathophysiologic mechanisms implicated in the pathogenesis of nasal polyposis: the unique remodeling process found in nasal polyp tissue and the immune response of patients with nasal polyposis to Staphylococcus aureus. These two theories converge to the same direction in different aspects, including decreased extracellular matrix production, impaired T regulation and favoring of a Th2 immune response.In patients with nasal polyposis, an exaggerated immune response to Staphylococcus aureus may aggravate the airway remodeling process. PMID- 23663432 TI - Cisplatin-induced caspase activation mediates PTEN cleavage in ovarian cancer cells: a potential mechanism of chemoresistance. AB - BACKGROUND: The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor protein is a central negative regulator of the PI3K/AKT signaling cascade and suppresses cell survival as well as cell proliferation. PTEN is found to be either inactivated or mutated in various human malignancies. In the present study, we have investigated the regulation of PTEN during cisplatin induced apoptosis in A2780, A270-CP (cisplatin resistant), OVCAR-3 and SKOV3 ovarian cancer cell lines. METHODS: Cells were treated with 10MUM of cisplatin for 24h. Transcript and protein levels were analysed by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and western blotting, respectively. Immunofluorescence microscopy was used to assess the intracellular localization of PTEN. Proteasome inhibitor and various caspases inhibitors were used to find the mechanism of PTEN degradation. RESULTS: PTEN protein levels were found to be decreased significantly in A2780 cells; however, there was no change in PTEN protein levels in A2780-CP, OVCAR-3 and SKOV3 cells with cisplatin treatment. The decrease in PTEN protein was accompanied with an increase in the levels of AKT phosphorylation (pAKT) in A2780 cells and a decrease of BCL-2. Cisplatin treatment induced the activation/cleavage of caspase-3, -6, -7, -8, -9 in all cell lines tested in this study except the resistant variant A2780-CP cells. In A2780 cells, restoration of PTEN levels was achieved upon pre-treatment with Z-DEVD-FMK (broad range caspases inhibitor) and not with MG132 (proteasome inhibitor) and by overexpression of BCL-2, suggesting that caspases and BCL-2 are involved in the decrease of PTEN protein levels in A2780 cells. CONCLUSION: The decrease in pro-apoptotic PTEN protein levels and increase in survival factor pAKT in A2780 ovarian cancer cells suggest that cisplatin treatment could further exacerbate drug resistance in A2780 ovarian cancer cells. PMID- 23663433 TI - RubisCO-based CO2 fixation and C1 metabolism in the actinobacterium Pseudonocardia dioxanivorans CB1190. AB - Pseudonocardia is an actinobacterial genus of interest due to its potential biotechnological, medical and environmental remediation applications, as well as for the ecologically relevant symbiotic relationships it forms with attine ants. Some Pseudonocardia spp. can grow autotrophically, but the genetic basis of this capability has not previously been reported. In this study, we examined autotrophy in Pseudonocardia dioxanivorans CB1190, which can grow using H2 and CO2, as well as heterotrophically. Genomic and transcriptomic analysis of CB1190 cells grown with H2/bicarbonate implicated the Calvin-Benson-Bassham (CBB) cycle in growth-supporting CO2 fixation, as well as a [NiFe] hydrogenase-encoding gene cluster in H2 oxidation. The CBB cycle genes are evolutionarily most related to actinobacterial homologues, although synteny has not been maintained. Ribulose 1,5-bisphosphate carboxylase activity was confirmed in H2/bicarbonate-grown CB1190 cells and was detected in cells grown with the C1 compounds formate, methanol and carbon monoxide. We also demonstrated the upregulation of CBB cycle genes upon exposure of CB1190 to these C1 substrates, and identified genes putatively involved in generating CO2 from the C1 substrates by using RT-qPCR. Finally, the potential for autotrophic growth of other Pseudonocardia spp. was explored, and the ecological implications of autotrophy in attine ant- and plant root-associated Pseudonocardia discussed. PMID- 23663434 TI - Extracardiac complications in adults with congenital heart disease. AB - With the increasing number of adults living with repaired, or unrepaired, congenital heart disease, there is a growing incidence of extracardiac comorbidities. These comorbidities can affect various organ systems in complex ways, and may have a significant impact on a patient's quality of life and survival. Many of these potential complications may go undiagnosed until there is already a significant bearing on the patient's life. Therefore, it is important for physicians who care for the adult congenital patient to be mindful of these potential extracardiac complications, and actively assess for these complications in their adult congenital practice. Continued research to identify modifiable risk factors is needed so that both preventative and therapeutic management options for these extracardiac complications may be developed. PMID- 23663435 TI - Attention is more than prediction precision. AB - A cornerstone of the target article is that, in a predictive coding framework, attention can be modelled by weighting prediction error with a measure of precision. We argue that this is not a complete explanation, especially in the light of ERP (event-related potentials) data showing large evoked responses for frequently presented target stimuli, which thus are predicted. PMID- 23663436 TI - Transcription profile of soybean-root-knot nematode interaction reveals a key role of phythormones in the resistance reaction. AB - BACKGROUND: Root-knot nematodes (RKN- Meloidogyne genus) present extensive challenges to soybean crop. The soybean line (PI 595099) is known to be resistant against specific strains and races of nematode species, thus its differential gene expression analysis can lead to a comprehensive gene expression profiling in the incompatible soybean-RKN interaction. Even though many disease resistance genes have been studied, little has been reported about phytohormone crosstalk on modulation of ROS signaling during soybean-RKN interaction. RESULTS: Using 454 technology to explore the common aspects of resistance reaction during both parasitism and resistance phases it was verified that hormone, carbohydrate metabolism and stress related genes were consistently expressed at high levels in infected roots as compared to mock control. Most noteworthy genes include those encoding glycosyltransferases, peroxidases, auxin-responsive proteins and gibberellin-regulated genes. Our data analysis suggests the key role of glycosyltransferases, auxins and components of gibberellin signal transduction, biosynthesis and deactivation pathways in the resistance reaction and their participation in jasmonate signaling and redox homeostasis in mediating aspects of plant growth and responses to biotic stress. CONCLUSIONS: Based on this study we suggest a reasonable model regarding to the complex mechanisms of crosstalk between plant hormones, mainly gibberellins and auxins, which can be crucial to modulate the levels of ROS in the resistance reaction to nematode invasion. The model also includes recent findings concerning to the participation of DELLA-like proteins and ROS signaling controlling plant immune or stress responses. Furthermore, this study provides a dataset of potential candidate genes involved in both nematode parasitism and resistance, which can be tested further for their role in this biological process using functional genomics approaches. PMID- 23663437 TI - Over-diagnosis of malaria by microscopy in the Kilombero Valley, Southern Tanzania: an evaluation of the utility and cost-effectiveness of rapid diagnostic tests. AB - BACKGROUND: Early and accurate diagnosis of febrile patients is essential to treat uncomplicated malaria cases properly, prevent severe malaria, and avert unnecessary anti-malarial treatments. Improper use of anti-malarials increases the risk of adverse drug reaction and the evolution of drug/parasite resistance. While microscopy is the most common form of malaria diagnosis, concerns over its accuracy have prompted the incorporation of malaria rapid diagnostic tests (RDTs) into many national malaria control programmes. METHODS: Over a three-month period, a direct comparison between microscopy and RDTs was made in a rural, private dispensary in the Kilombero Valley, Morogoro District, southern Tanzania, with the aim of estimating the extent of malaria over-diagnosis and over treatment with anti-malarials. The study cohort was made up of patients referred by the dispensary's clinician for malaria testing. One hundred percent of patients approached agreed to participate in this study and were then tested using both microscopy and RDTs. Using the results from the comparison of the two tests at this dispensary, the potential cost effectiveness of introducing RDTs to a neighbouring public health centre was estimated on the basis of this centre's past malaria records spanning December 2007 to August 2011. RESULTS: At the private dispensary, the apparent prevalence of malaria was 78% based on microscopy whereas the true prevalence, calculated using RDTs as the gold standard, was estimated at 14%. This discrepancy indicates that when using microscopy as the sole diagnostic test, malaria is being over-diagnosed by approximately a factor of five in this setting. At the public clinic, apparent malaria prevalence based on microscopy was 74%. If similar rates of over diagnosis are assumed, 5,285 patients of the 6,769 patients positively diagnosed with malaria using microscopy were likely given unnecessary anti-malarials, and their true cause of illness was not addressed. The introduction of RDTs to the public clinic would be highly cost-efficient, with an estimated net saving of over 96 USD/month. CONCLUSIONS: Compared with RDTs, microscopy led to almost four out of five patients being over-diagnosed with malaria in this rural part of Tanzania. A policy that encompasses both the private and public sectors of health care is needed to ensure quality diagnostic testing for febrile patients. With estimated prevalence at 14%, RDT introduction is recommended given WHO findings that RDTs are predicted to be cost-effective in prevalence areas of less than 20%. The use of RDTs in malaria diagnosis would not only reduce government spending but would prove beneficial to ensuring appropriate care and treatment of febrile illness. PMID- 23663438 TI - Complications associated with endobronchial ultrasound-guided transbronchial needle aspiration: a nationwide survey by the Japan Society for Respiratory Endoscopy. AB - BACKGROUND: With the recent widespread use of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), there have been occasional reports on complications associated with its use. Previous reviews on EBUS-TBNA have been limited to studies by skilled operators, thus the results may not always be applicable to recent clinical practice. To assess the safety of EBUS-TBNA for the staging and diagnosis of lung cancer in Japan, a nationwide survey on its current usage status and complications associated with its use was conducted by the Japan Society for Respiratory Endoscopy (JSRE). METHODS: A questionnaire about EBUS TBNA performed between January 2011 and June 2012 was mailed to 520 JSRE accredited facilities. RESULTS: Responses were obtained from 455 facilities (87.5%). During the study period, EBUS-TBNA was performed in 7,345 cases in 210 facilities (46.2%) using a convex probe ultrasound bronchoscope, for 6,836 mediastinal and hilar lesions and 275 lung parenchymal lesions. Ninety complications occurred in 32 facilities. The complication rate was 1.23% (95% confidence interval, 0.97%-1.48%), with hemorrhage being the most frequent complication (50 cases, 0.68%). Infectious complications developed in 14 cases (0.19%) (Mediastinitis, 7; pneumonia, 4; pericarditis, 1; cyst infection, 1; and sepsis, 1). Pneumothorax developed in 2 cases (0.03%), one of which required tube drainage. Regarding the outcome of the cases with complications, prolonged hospitalization was observed in 14 cases, life-threatening conditions in 4, and death in 1 (severe cerebral infarction) (mortality rate, 0.01%). Breakage of the ultrasound bronchoscope occurred in 98 cases (1.33%) in 67 facilities (31.9%), and that of the puncture needle in 15 cases (0.20%) in 8 facilities (3.8%). CONCLUSIONS: Although the complication rate associated with EBUS-TBNA was found to be low, severe complications, including infectious complications, were observed, and the incidence of device breakage was high. Since the use of EBUS TBNA is rapidly expanding in Japan, an educational program for its safe performance should be immediately established. PMID- 23663439 TI - Personalized medicine: myth or reality? The position of Russian clinical pharmacologists. AB - A personalized medicine, a recent trend of clinical pharmacology, makes possible the individual approach to the choice of the drugs and their dosage. According to the results of a study of the activity of different biomarkers, particularly the isoenzymes of the cytochrome P-450, they provide the efficiency and safety of the pharmacotherapy. The activity of the isoenzymes of the cytochrome P-450 determines an individual pharmacological response and depends on many factors, including genetic ones. The biomarkers of the activity of the isoenzymes of the cytochrome P-450 should be tested in the clinical practice settings using the simple and cheap methods, one of the most available is an immunofluorescent assay. The skilled staff and the centers of personalized medicine are necessary for this approach. PMID- 23663445 TI - Patient centred care in diabetology: an Islamic perspective from Iran. AB - Patient-centred system of care is essential in managing many disorders such as diabetes mellitus. The cultural and religious context can influence the involvement of patients and their families in such a care. We intend to discuss patient-centred care in diabetology in view of Islam. For more clarification, we will take into consideration a few illustrative lines of argument in detail about situation in Iran. In conclusion, dynamic spirit of Islamic jurisprudence is reflected in its adaptability to change in medical practice. In recent decades, Iranian religious scholars have provided scientists in new fields of science and research with appropriate directions and guidelines. Decree issued by Iranian religious leaders permitting research on stem cells for therapeutic purposes in many disorders including diabetes mellitus is one example. Understanding of the nature of Islam is importance for communication with patients in Islamic countries. PMID- 23663441 TI - Never tested for HIV in Latin-American migrants and Spaniards: prevalence and perceived barriers. AB - INTRODUCTION: Increasing the uptake of HIV testing and decreasing the number of undiagnosed people is a priority for HIV prevention. Understanding the barriers that hinder people from testing is vital, particularly when working with especially vulnerable populations like migrants. Most data available on migrants are based on African migrants in the UK, while barriers to HIV testing in Latin American migrants living in Europe remain unexplored. Still, they account for a quarter of new diagnosis in Spain and suffer higher rates of delayed diagnosis. METHODS: Between May 2008 and March 2011, a mobile unit offered free rapid HIV tests in different Spanish cities. We compared the prevalence of no previous testing, adjusting for potential confounders by two multivariate logistic models, and described differences in perceived barriers to testing in Latin-American migrants living in Spain versus Spaniards. Participants included men who have sex with men (MSM), men who have sex exclusively with women (MSW), and women. RESULTS: Of the 5920 individuals who got tested and answered a self-administered questionnaire, 36.5% were MSM (20.4% previously untested), 28.9% were MSW (49% previously untested) and 34.6% were women (53% previously untested). Almost one quarter were Latin-American, of whom 30% had never been tested versus 45% of untested Spaniards. After adjusting for potential confounders, Spaniards were more likely to report no previous testing than Latin-Americans among women and MSW all together (Odds Ratio (OR)=2.0; 95% Confidence Interval (CI): 1.7-2.4) and among MSM (OR=1.6; 95% CI: 1.2-2.0). Among the 2455 who had never undergone an HIV test before, main barriers to testing were low perceived risk (54% Spaniards vs. 47% Latin-American) and concerns arising from the loss of anonymity (19.5% vs. 16.9%). Fear of rejection or discrimination and fear of legal problems were a barrier for <2%. CONCLUSIONS: Latin-American migrants living in Spain were more likely to get tested than Spaniards. Regardless of nationality, low perceived risk was the main barrier to testing whereas fear of stigma or discrimination and fear of legal problems were merely incidental. However, new Spanish austerity policies regarding healthcare for migrants in response to the economic crisis may reverse this situation. PMID- 23663440 TI - The biodiversity hypothesis and allergic disease: world allergy organization position statement. AB - Biodiversity loss and climate change secondary to human activities are now being associated with various adverse health effects. However, less attention is being paid to the effects of biodiversity loss on environmental and commensal (indigenous) microbiotas. Metagenomic and other studies of healthy and diseased individuals reveal that reduced biodiversity and alterations in the composition of the gut and skin microbiota are associated with various inflammatory conditions, including asthma, allergic and inflammatory bowel diseases (IBD), type1 diabetes, and obesity. Altered indigenous microbiota and the general microbial deprivation characterizing the lifestyle of urban people in affluent countries appear to be risk factors for immune dysregulation and impaired tolerance. The risk is further enhanced by physical inactivity and a western diet poor in fresh fruit and vegetables, which may act in synergy with dysbiosis of the gut flora. Studies of immigrants moving from non-affluent to affluent regions indicate that tolerance mechanisms can rapidly become impaired in microbe-poor environments. The data on microbial deprivation and immune dysfunction as they relate to biodiversity loss are evaluated in this Statement of World Allergy Organization (WAO). We propose that biodiversity, the variability among living organisms from all sources are closely related, at both the macro- and micro levels. Loss of the macrodiversity is associated with shrinking of the microdiversity, which is associated with alterations of the indigenous microbiota. Data on behavioural means to induce tolerance are outlined and a proposal made for a Global Allergy Plan to prevent and reduce the global allergy burden for affected individuals and the societies in which they live. PMID- 23663446 TI - God, the devil, and the details: Fleshing out the predictive processing framework. AB - The predictive processing framework lacks many of the architectural and implementational details needed to fully investigate or evaluate the ideas it presents. One way to begin to fill in these details is by turning to standard control-theoretic descriptions of these types of systems (e.g., Kalman filters), and by building complex, unified computational models in biologically realistic neural simulations. PMID- 23663448 TI - Electron backscatter diffraction in conservation science: phase identification of pigments in paint layers. AB - Electron backscatter diffraction (EBSD) was used in Conservation Science for characterization of ancient materials collected from works of art. The results demonstrate the feasibility of EBSD analysis on heterogeneous matrices as very small samples of paint layers collected from paintings. Two reference pigments were selected from those used by artists to investigate the relationship existing between EBSD pattern quality and properties of the investigated material (i.e., average atomic number, density, and Mohs hardness). The technique was also tested to investigate the pigment phases on two real samples collected from Romanino's Santa Giustina altarpiece, an oil on wood painting dated 1514 (Civic Museum, Padova, Italy). Results show for the first time the acquisition of EBSD patterns from painting samples mounted in resin, i.e., painting cross sections, opening a new powerful tool to elucidate the pigment phases avoiding large sampling on works of arts and to further study the complex mechanisms of pigment deterioration. PMID- 23663447 TI - A survey of enabling technologies in synthetic biology. AB - BACKGROUND: Realizing constructive applications of synthetic biology requires continued development of enabling technologies as well as policies and practices to ensure these technologies remain accessible for research. Broadly defined, enabling technologies for synthetic biology include any reagent or method that, alone or in combination with associated technologies, provides the means to generate any new research tool or application. Because applications of synthetic biology likely will embody multiple patented inventions, it will be important to create structures for managing intellectual property rights that best promote continued innovation. Monitoring the enabling technologies of synthetic biology will facilitate the systematic investigation of property rights coupled to these technologies and help shape policies and practices that impact the use, regulation, patenting, and licensing of these technologies. RESULTS: We conducted a survey among a self-identifying community of practitioners engaged in synthetic biology research to obtain their opinions and experiences with technologies that support the engineering of biological systems. Technologies widely used and considered enabling by survey participants included public and private registries of biological parts, standard methods for physical assembly of DNA constructs, genomic databases, software tools for search, alignment, analysis, and editing of DNA sequences, and commercial services for DNA synthesis and sequencing. Standards and methods supporting measurement, functional composition, and data exchange were less widely used though still considered enabling by a subset of survey participants. CONCLUSIONS: The set of enabling technologies compiled from this survey provide insight into the many and varied technologies that support innovation in synthetic biology. Many of these technologies are widely accessible for use, either by virtue of being in the public domain or through legal tools such as non-exclusive licensing. Access to some patent protected technologies is less clear and use of these technologies may be subject to restrictions imposed by material transfer agreements or other contract terms. We expect the technologies considered enabling for synthetic biology to change as the field advances. By monitoring the enabling technologies of synthetic biology and addressing the policies and practices that impact their development and use, our hope is that the field will be better able to realize its full potential. PMID- 23663449 TI - The impact of clinical versus pathological staging in oral cavity carcinoma--a multi-institutional analysis of survival. AB - OBJECTIVES: To evaluate any disparity in clinical versus pathological TNM staging in oral cavity squamous cell carcinoma (OCSCC) patients and any impact of this on survival. DESIGN: Demographic, survival, staging, and pathologic data on all patients undergoing surgical treatment for OCSCC in Alberta between 1998 and 2006 was collected. Clinical and pathological TNM staging data were compared. Patients were stratified as pathologically downstaged, upstaged or unchanged. SETTING: Tertiary care centers in Alberta, Canada. MAIN OUTCOME MEASURES: Survival differences between groups were analyzed using Kaplan-Meier and Cox regression models. RESULTS: Patients with clinically early stage tumors were pathologically upstaged in 21.9% of cases and unchanged in 78.1% of cases. Patients with clinically advanced stage tumors were pathologically downstaged in 7.9% of cases and unchanged in 92.1% of cases. Univariate and multivariate estimates of disease specific survival showed no statistically significant differences in survival when patients were either upstaged or downstaged. CONCLUSIONS: Some disparity exists in clinical versus pathological staging in OCSCC, however, this does not have any significant impact on disease specific survival. PMID- 23663451 TI - Abdominal coarctation and associated comorbidities in children. AB - OBJECTIVE: The purpose of this study is to report a single institution's experience with abdominal coarctation in children and report associated comorbidities. BACKGROUND: Abdominal coarctation is a rare condition, accounting for less than 2% of aortic coarctations. Single patients with abdominal coarctation have been reported with additional vascular disease in pediatric patients. METHODS: Our echocardiography database between January 2001 and January 2012 was searched to identify all patients with abdominal coarctation. Relevant clinical data were reviewed. RESULTS: Nine patients were identified with abdominal coarctation. Median age at diagnosis was 4.7 years (IQR 1.1-14.3 years). Additional cardiac diagnoses were found in three patients: one had moderate aortic regurgitation and aortic root dilatation; one had mild aortic regurgitation, severe mitral regurgitation, and atrial flutter; and one had a thoracic coarctation previously repaired. Eight patients (89%) had an associated noncardiac comorbidity. Comorbidities included: Takayasu arteritis (n = 3), systemic lupus erythematosus (n = 1), epidermal nevus syndrome (n = 1), abdominal hemangioma (n = 1), Williams syndrome (n = 1), and renal artery stenosis (n = 2). Intervention was performed in four patients (57%): two underwent surgical grafting and two had angioplasty with stent placement. Patients with surgical grafting required no further intervention, whereas both patients who underwent angioplasty and stenting required further stent placement. CONCLUSION: Abdominal coarctation is a rare anomaly. It is frequently associated with other vascular abnormalities. Vasculitis should be suspected in children with abdominal coarctation. All patients, even if treated, require continued close observation. PMID- 23663450 TI - Genetic polymorphisms of DNA double-strand break repair pathway genes and glioma susceptibility. AB - BACKGROUND: Genetic variations in DNA double-strand break repair genes can influence the ability of a cell to repair damaged DNA and alter an individual's susceptibility to cancer. We studied whether polymorphisms in DNA double-strand break repair genes are associated with an increased risk of glioma development. METHODS: We genotyped 10 potentially functional single nucleotide polymorphisms (SNPs) in 7 DNA double-strand break repair pathway genes (XRCC3, BRCA2, RAG1, XRCC5, LIG4, XRCC4 and ATM) in a case-control study including 384 glioma patients and 384 cancer-free controls in a Chinese Han population. Genotypes were determined using the OpenArray platform. RESULTS: In the single-locus analysis there was a significant association between gliomas and the LIG4 rs1805388 (Ex2 +54C>T, Thr9Ile) TT genotype (adjusted OR, 3.27; 95% CI, 1.87-5.71), as well as the TC genotype (adjusted OR, 1.62; 95% CI, 1.20-2.18). We also found that the homozygous variant genotype (GG) of XRCC4 rs1805377 (IVS7-1A>G, splice-site) was associated with a significantly increased risk of gliomas (OR, 1.77; 95% CI, 1.12 2.80). Interestingly, we detected a significant additive and multiplicative interaction effect between the LIG4 rs1805388 and XRCC4 rs1805377 polymorphisms with an increasing risk of gliomas. When we stratified our analysis by smoking status, LIG4 rs1805388 was associated with an increased glioma risk among smokers. CONCLUSIONS: These results indicate for the first time that LIG4 rs1805388 and XRCC4 rs1805377, alone or in combination, are associated with a risk of gliomas. PMID- 23663452 TI - Major depressive disorder in a Kenyan youth sample: relationship with parenting behavior and parental psychiatric disorders. AB - BACKGROUND: Studies on mental health problems during childhood and youth development phases have reported that families of children diagnosed with a depressive disorder tend to be dysfunctional. These dysfunctions have been shown to be mediating factors for children to develop psychiatric disorders in the future. OBJECTIVE: This study was designed to investigate whether perceived parenting behavior and parental psychiatric disorders have any relationship with youth presenting with major depressive disorder. METHODOLOGY: The study sample had a total number of 250 purposely selected youth attending the Youth Clinic at Kenyatta National Hospital in Nairobi. RESULTS: This study found associations between major depressive disorders (MDD) in the youth and co-morbid psychiatric disorders among the youth: conduct disorder (OR = 2.93, 95% CI 1.04 to 8.26, p = 0.035), any anxiety disorder (OR = 2.41, 95% CI 1.20 to 4.87, p = 0.012), drug abuse (OR = 3.40, 95% CI 2.01 to 5.76, p < 0.001), alcohol use (OR = 3.29, 95% CI 1.94 to 5.57, p < 0.001), and suicidal behavior (OR = 5.27, 95% CI 2.39 to 11.66, p < 0.001). The results also indicate that a higher proportion of youth between 16 and 18 years had major depressive disorder than the youth below 16 years or above 18 years of age (OR = 2.66, 95% CI 1.40 to 5.05, p = 0.003). Multivariate analysis shows that both rejecting maternal behavior (AOR = 2.165, 95% CI 1.060 to 4.422, p = 0.003) and maternal MDD (AOR = 5.27, 95% CI 1.10 to 14.76, p < 0.001) are associated with MDD in youth. CONCLUSION: Negative maternal parenting behavior and maternal depressive disorder are associated with major depressive disorder in children. PMID- 23663453 TI - Cell of origin in radiation-induced premalignant thymocytes with differentiation capability in mice conditionally losing one Bcl11b allele. AB - Bcl11b is a haploinsufficient tumor suppressor, mutations or deletion of which has been found in 10-16% of T-cell acute lymphoblastic leukemias. Bcl11b(KO) (/+) heterozygous mice are susceptible to thymic lymphomas, a model of T-cell acute lymphoblastic leukemia, when gamma-irradiated, and irradiated Bcl11b(KO) (/+) mice generate clonally expanding or premalignant thymocytes before thymic lymphoma development. Cells with radiation-induced DNA damages are assumed to be the cells of origin in tumors; however, which thymocyte is the tumor cell origin remains obscure. In this study we generated Bcl11b(flox/+) ;Lck-Cre and Bcl11b(flox/+) ;CD4-Cre mice; in the former, loss of one Bcl11b allele occurs in thymocytes at the immature CD4(-) CD8(-) stage, whereas in the latter the loss occurs in the more differentiated CD4(+) CD8(+) double-positive stage. We examined clonal expansion and differentiation of thymocytes in mice 60 days after 3 Gy gamma-irradiation. Half (9/18) of the thymuses in the Bcl11b(flox/+) ;Lck Cre group showed limited rearrangement sites at the T-cell receptor-beta (TCRbeta) locus, indicating clonal cell expansion, but none in the Bcl11b(flox/+) ;CD4-Cre group did. This indicates that the origin of the premalignant thymocytes is not in double-positive cells but immature thymocytes. Interestingly, those premalignant thymocytes underwent rearrangement at various different sites of the TCRalpha locus and the majority showed a higher expression of TCRbeta and CD8, and more differentiated phenotypes. This suggests the existence of a subpopulation of immature cells within the premalignant cells that is capable of proliferating and continuously producing differentiated thymocytes. PMID- 23663454 TI - Fate of the human Y chromosome linked genes and loci in prostate cancer cell lines DU145 and LNCaP. AB - BACKGROUND: Prostate cancer is a known cause of mortality in men worldwide although the risk factor varies among different ethnic groups. Loss of the Y chromosome is a common chromosomal abnormality observed in the human prostate cancer. RESULTS: We screened 51 standard sequence tagged sites (STSs) corresponding to a male-specific region of the Y chromosome (MSY), sequenced the coding region of the SRY gene and assessed the status of the DYZ1 arrays in the human prostate cancer cell lines DU145 and LNCaP. The MSY was found to be intact and coding region of SRY showed no sequence variation in both the cell lines. However, DYZ1 arrays showed sequence and copy number variations. DU145 and LNCaP cells were found to carry 742 and 1945 copies of the DYZ1, respectively per 3.3 pg of genomic DNA. The DYZ1 copies detected in these cell lines are much below the average of that reported in normal human males. Similarly, the number of "TTCCA" repeat and its derivatives within the DYZ1 arrays showed variation compared to those of the normal males. CONCLUSIONS: Clearly, the DYZ1 is maximally affected in both the cell lines. Work on additional cell lines and biopsied samples would augment our understanding about the susceptibility of this region. Based on the present work, we construe that copy number status of the DYZ1 may be exploited as a supplementary prognostic tool to monitor the occurrence of prostate cancer using biopsied samples. PMID- 23663455 TI - Elemental composition of natural populations of key microbial groups in Atlantic waters. AB - Intracellular carbon (C), nitrogen (N) and phosphorus (P) content of marine phytoplankton and bacterioplankton can vary according to cell requirements or physiological acclimation to growth under nutrient limited conditions. Although such variation in macronutrient content is well known for cultured organisms, there is a dearth of data from natural populations that reside under a range of environmental conditions. Here, we compare C, N and P content of Synechococcus, Prochlorococcus, low nucleic acid (LNA) content bacterioplankton and small plastidic protists inhabiting surface waters of the North and South subtropical gyres and the Equatorial Region of the Atlantic Ocean. While intracellular C:N ratios ranged between 3.5 and 6, i.e. below the Redfield ratio of 6.6, all the C:P and N:P ratios were up to 10 times higher than the corresponding Redfield ratio of 106 and 16, respectively, reaching and in some cases exceeding maximum values reported in the literature. Similar C:P or N:P ratios in areas with different concentrations of inorganic phosphorus suggests that this is not just a response to the prevailing environmental conditions but an indication of the extremely low P content of these oceanic microbes. PMID- 23663456 TI - Whenever next: hierarchical timing of perception and action. AB - The target article focuses on the predictive coding of "what" and "where" something happened and the "where" and "what" response to make. We extend that scope by addressing the "when" aspect of perception and action. Successful interaction with the environment requires predictions of everything from millisecond-accurate motor timing to far future events. The hierarchical framework seems appropriate for timing. PMID- 23663458 TI - Mandatory HIV screening for emergency physicians in Ontario: protecting the public or alarming them? PMID- 23663460 TI - Who should fund CME? PMID- 23663457 TI - Maresin-1 reduces the pro-inflammatory response of bronchial epithelial cells to organic dust. AB - BACKGROUND: Exposure to organic dust causes detrimental airway inflammation. Current preventative and therapeutic measures do not adequately treat resulting disease, necessitating novel therapeutic interventions. Recently identified mediators derived from polyunsaturated fatty acids exhibit anti-inflammatory and pro-resolving actions. We tested the potential of one of these mediators, maresin 1 (MaR1), in reducing organic dust-associated airway inflammation. METHODS: As bronchial epithelial cells (BECs) are pivotal in initiating organic dust-induced inflammation, we investigated the in vitro effects of MaR1 on a human BEC cell line (BEAS-2B). Cells were pretreated for 1 hour with 0-200 nM MaR1, followed by 1-24 hour treatment with 5% hog confinement facility-derived organic dust extract (HDE). Alternatively, a mouse lung slice model was utilized in supportive cytokine studies. Supernatants were harvested and cytokine levels determined via enzyme-linked immunosorbent assays. Epithelial cell protein kinase C (PKC) isoforms alpha and epsilon, and PKA activities were assessed via radioactivity assays, and NFkappaB and MAPK-related signaling mechanisms were investigated using luciferase vector reporters. RESULTS: MaR1 dose-dependently reduced IL-6 and IL-8 production following HDE treatment of BECs. MaR1 also reduced HDE stimulated cytokine release including TNF-alpha in a mouse lung slice model when given before or following HDE treatment. Previous studies have established that HDE sequentially activates epithelial PKCalpha and PKCepsilon at 1 and 6 hours, respectively that regulated TNF-alpha, IL-6, and IL-8 release. MaR1 pretreatment abrogated these HDE-induced PKC activities. Furthermore, HDE treatment over a 24 hour period revealed temporal increases in NFkappaB, AP-1, SP-1, and SRE DNA binding activities, using luciferase reporter assays. MaR1 pretreatment did not alter the activation of NFkappaB, AP-1, or SP-1, but did reduce the activation of DNA binding at SRE. CONCLUSIONS: These observations indicate a role for MaR1 in attenuating the pro-inflammatory responses of BECs to organic dust extract, through a mechanism that does not appear to rely on reduced NFkappaB, AP-1, or SP 1-related signaling, but may be mediated partly through SRE-related signaling. These data offer insights for a novel mechanistic action of MaR1 in bronchial epithelial cells, and support future in vivo studies to test MaR1's utility in reducing the deleterious inflammatory effects of environmental dust exposures. PMID- 23663461 TI - Innovative staffing in emergency departments: the role of midlevel providers. AB - NPs and PAs are increasingly common in US and Canadian EDs. Emergency medicine is a unique specialty with a vast knowledge base performed in a high-risk environment; therefore, supervisory models and regulatory requirements developed for lower-risk settings (e.g., primary care) and more circumscribed practices (e.g., diabetes clinic) are unlikely to be sufficient for EDs. As innovative ED staffing models evolve, specific roles and scopes of practice for midlevel providers should be based on an objective analysis of existing care gaps and system needs, local provider availability, operational efficiency, cost effectiveness, regulatory compliance, risk management, and quality of care. Although it is tempting to reduce cost by using PAs or NPs, de-emphasis of emergency physician involvement should proceed cautiously to avoid negatively impacting patient care. Variability in midlevel provider use and the relative paucity of evidence describing optimal provider roles, scopes of practice, and care outcomes in different patient populations highlight the need for a measured approach, appropriate supervisory models, effective quality assurance programs, and cost-effectiveness analyses looking at both clinical and economic outcomes of this important health system evolution. PMID- 23663463 TI - Effect of a preauthorization policy on the utilization rate of after-hours emergency department neuroradiology computed tomography. AB - OBJECTIVE: To evaluate the impact of an emergency department (ED) automatic preauthorization policy on after-hours utilization of neuroradiology computed tomography (CT). METHODS: All CT studies of the head with contrast facial bones, orbits, spine, and neck requested through the ED and performed between January 1, 2004, and December 31, 2010, were reviewed. The preauthorization policy was instituted on February 25, 2008. A control group of noncontrast CT head studies was used for comparison. Pre- and postpolicy implementation utilization rates were compared between the control group of noncontrast CT head studies and the study group neuroradiology CT studies. RESULTS: During the study period, 408,501 ED patient visits occurred and 20,703 neuroradiology CT studies were carried out. The pre- and postimplementation groups of noncontrast CT head scans totalled 7,474 and 6,094, respectively, whereas the pre- and postimplementation groups of all other neuroradiology CT studies totalled 3,833 and 3,302, respectively. The CT utilization between the two groups did not differ significantly: the noncontrast head group pre- and postpolicy implementation increased by 0.31 to 3.41%, whereas the utilization of all other neuroradiology CT studies increased by 0.22 to 1.84% (p value = 0.061 for a difference between groups). CONCLUSION: Implementation of an automatic preauthorization policy for after-hours neuroradiology CT studies did not result in a statistically significant increase in CT utilization. This suggests that concerns regarding the negative effects of such policies may be unfounded, and further research in this area is warranted. PMID- 23663462 TI - Prevalence of methicillin-resistant Staphylococcus aureus in skin and soft tissue infections in patients presenting to Canadian emergency departments. AB - BACKGROUND: Community-associated methicillin-resistant Staphylococcus aureus (MRSA) is an increasingly common cause of skin and soft tissue infection (SSTI) worldwide. The prevalence of MRSA in SSTIs across Canada has not been well described. Studies in the United States have shown significant geographic variability in the prevalence of MRSA. This study characterizes the geographic prevalence and microbiology of MRSA in patients presenting to Canadian emergency departments with SSTIs. METHODS: Using a prospective, observational design, we enrolled patients with acute purulent SSTIs presenting to 17 hospital emergency departments and 2 community health centres (spanning 6 Canadian provinces) between July 1, 2008, and April 30, 2009. Eligible patients were those whose wound cultures grew S. aureus. MRSA isolates were characterized by antimicrobial susceptibility testing and pulsed-field gel electrophoresis. All patients were subjected to a structured chart audit, and patients whose wound swabs grew MRSA were contacted by telephone to gather detailed information regarding risk factors for MRSA infection, history of illness, and outcomes. RESULTS: Of the 1,353 S. aureus-positive encounters recorded, 431 (32%) grew MRSA and 922 (68%) wounds grew methicillin-susceptible S. aureus. We observed significant variation in both the prevalence of MRSA (11-100%) and the proportion of community-associated strains of MRSA (0-100%) across our study sites, with a significantly higher prevalence of MRSA in western Canada. INTERPRETATION: MRSA continues to emerge across Canada, and the prevalence of MRSA in SSTIs across Canada is variable and higher than previously expected. PMID- 23663464 TI - Adverse events are rare among adults 50 years of age and younger with flank pain when abdominal computed tomography is not clinically indicated according to the emergency physician. AB - OBJECTIVE: Many emergency physicians (EPs) order "confirmatory" abdominal computed tomography (CT) in young flank pain patients, despite a high clinical suspicion of renal colic and the risk of radiation exposure. We measured the adverse outcome rate among flank pain patients identified as not requiring abdominal CT by the EP on a data form, regardless of whether CT was eventually ordered. Our secondary objective was to describe diagnoses other than renal colic identified by CT in this population. METHODS: We conducted a prospective observational study at two community EDs. We asked staff EPs to complete a data sheet on patients ages 18 to 50 years with a first episode of flank pain, recording 1) if the flank pain was consistent with renal colic and 2) if the EP felt abdominal CT was indicated. Adverse outcomes (defined a priori as urgent surgical procedures, disability, or death) were assessed by research assistants at 4 weeks using telephone follow-up and a hospital records search. RESULTS: We enrolled 389 patients; 353 completed follow-up (91%). The average age was 38.8 years, and 72.0% were male. Of 212 patients identified in the "CT not indicated" group, 2 had another diagnosis identified (unruptured diverticulitis and a ruptured ovarian cyst), but none had adverse outcomes (95% CI 0-1.4). CONCLUSIONS: Adverse events were rare (< 1.5%) among patients < 50 years old with flank pain when CT was not required according to the clinical assessment of the EP. Future research should assess the adverse outcomes of withholding CT in low risk patients using a larger patient sample. PMID- 23663465 TI - Implementation of small-group reflection rounds at an emergency medicine residency program. AB - Few residency curricular interventions have focused on improving well-being and promoting humanism. We describe the implementation of a novel curriculum based on small-group reflection rounds--the Emergency Medicine Reflection Rounds (EMRR)- at a 4-year US emergency medicine (EM) residency. During the inaugural year (2010 2011), nine residents volunteered to take part in 1-hour monthly sessions with faculty facilitators. Residents were provided with a confidential environment to discuss difficult ethical and interpersonal encounters from their clinical experiences. Ongoing feedback from participants was solicited, culminating with a four-question survey in which all respondents remarked that the EMRR contributed to improving their own well-being and agreed that it provided an important forum for residents to discuss difficult issues in a safe environment. In this article, we describe our innovation as an example of a wellness initiative that has promoted reflective practice and fostered cooperative learning around the communication, professional, and ethical challenges inherent in EM practice. Our EMRR model may be useful to other EM residences looking to supplement their wellness curriculum. PMID- 23663466 TI - The reverse classroom: lectures on your own and homework with faculty. AB - With the arrival of a technologically proficient generation of learners (often described with the moniker "digital natives") into Canadian medical schools and residency programs, there is an increasing trend toward harnessing technology to enhance education and increase teaching efficiency. We present an instructional method that allows medical educators to "reverse" the traditional classroom paradigm. Imagine that prior to an academic half-day session, learners watch an e lecture on their own time; then during class, they do "homework" with tailored consultations from a content expert. The reverse classroom uses simple, readily accessible technology to allow faculty members to engage learners in high-order learning such as information analysis and synthesis. With this instructional method, the inefficient, repetitious delivery of recurring core lectures is no longer required. The reverse classroom is an effective instructional method. Using this technique, learners engage in high-order learning and interaction with teachers, and teachers are able to optimally share their expertise. PMID- 23663467 TI - Wilderness medicine opportunities in Canada do exist. PMID- 23663468 TI - Acute epiglottitis complicating an emphysematous abscess. PMID- 23663469 TI - Delayed pericardial effusion and cardiac tamponade following penetrating chest trauma. AB - We present the case of a 20-year-old man who was stabbed in the left chest and was diagnosed with a large pericardial effusion by focused emergency department (ED) ultrasonography. After placement of a left chest tube for presumed tension pneumothorax, the pericardial effusion had resolved. The patient's postinjury course was complicated by pericarditis and recurrent tamponade, which required repeated pericardiocentesis for management. This case illustrates the role of focused ED ultrasonography for diagnosis of pericardial effusion in penetrating trauma and the potential for delayed pericardial effusion and tamponade in such patients. Although the pathophysiology of delayed pericardial effusion is unclear, autoimmune postpericardiotomy syndrome has been proposed as the cause of this rare condition. Our case underscores the importance of close monitoring of patients with known or suspected pericardial injuries due to their potential for the development of life-threatening complications. PMID- 23663470 TI - 20:21. PMID- 23663471 TI - Wind down noir. PMID- 23663472 TI - [Intergenerational sensitivity]. PMID- 23663473 TI - Recognition of allergic conjunctivitis in patients with allergic rhinitis. AB - AIMS: To identify the incidence of allergic conjunctivitis in patients with allergic rhinitis. METHODS: One hundred and eighty seven consecutive patients with allergic rhinitis (AR) were directly questioned if they have allergic conjunctivitis (AC) and this was clarified using standard screening questions relating to red, itchy and watery eyes recorded through a total ocular symptom score (TOSS). Patients were also asked about further symptoms that may be attributable to AC: eyelid dermatitis, frequent blinking; eye sensitivity and frontal headache from squinting or. blinking. All patients were given a drop of olopatadine hydrochloride 0.1% in each eye to help identify "silent" disease. 20 healthy non-atopic controls were also treated with olopatadine drops and questioned on ocular symptoms. RESULTS: Fifty five percent of patients with AR were identified as having AC by direct questioning and the use of the TOSS questionaire. A further 41% were identifiable by asking additional questions and performing therapeutic challenge with olopadatine. CONCLUSIONS: AC is a frequent comorbid condition occurring in 95% of our patients with AR. Only 55% of patients were able to identify that they had AC based on standard screening questions. Additional specific questioning and a therapeutic challenge in suspected patients can help identify patients who may benefit from treatment of AC. PMID- 23663475 TI - A member of the Plasmodium falciparum PHIST family binds to the erythrocyte cytoskeleton component band 4.1. AB - BACKGROUND: Plasmodium falciparum parasites export more than 400 proteins into the cytosol of their host erythrocytes. These exported proteins catalyse the formation of knobs on the erythrocyte plasma membrane and an overall increase in erythrocyte rigidity, presumably by modulating the endogenous erythrocyte cytoskeleton. In uninfected erythrocytes, Band 4.1 (4.1R) plays a key role in regulating erythrocyte shape by interacting with multiple proteins through the three lobes of its cloverleaf-shaped N-terminal domain. In P. falciparum-infected erythrocytes, the C-lobe of 4.1R interacts with the P. falciparum protein mature parasite-infected erythrocyte surface antigen (MESA), but it is not currently known whether other P. falciparum proteins bind to other lobes of the 4.1R N terminal domain. METHODS: In order to identify novel 4.1R interacting proteins, a yeast two-hybrid screen was performed with a fragment of 4.1R containing both the N- and alpha-lobes. Positive interactions were confirmed and investigated using site-directed mutagenesis, and antibodies were raised against the interacting partner to characterise it's expression and distribution in P. falciparum infected erythrocytes. RESULTS: Yeast two-hybrid screening identified a positive interaction between the 4.1R N- and alpha-lobes and PF3D7_0402000. PF3D7_0402000 is a member of a large family of exported proteins that share a domain of unknown function, the PHIST domain. Domain mapping and site-directed mutagenesis established that it is the PHIST domain of PF3D7_0402000 that interacts with 4.1R. Native PF3D7_0402000 is localized at the parasitophorous vacuole membrane (PVM), and colocalizes with a subpopulation of 4.1R. DISCUSSION: The function of the majority of P. falciparum exported proteins, including most members of the PHIST family, is unknown, and in only a handful of cases has a direct interaction between P. falciparum-exported proteins and components of the erythrocyte cytoskeleton been established. The interaction between 4.1R and PF3D7_0402000, and localization of PF3D7_0402000 with a sub-population of 4.1R at the PVM could indicate a role in modulating PVM structure. Further investigation into the mechanisms for 4.1R recruitment is needed. CONCLUSION: PF3D7_0402000 was identified as a new binding partner for the major erythrocyte cytoskeletal protein, 4.1R. This interaction is consistent with a growing body of literature that suggests the PHIST family members function by interacting directly with erythrocyte proteins. PMID- 23663476 TI - Pretreatment on Miscanthus lutarioriparious by liquid hot water for efficient ethanol production. AB - BACKGROUND: The C4 perennial grass Miscanthus giganteus has proved to be a promising bio-energy crop. However, the biomass recalcitrance is a major challenge in biofuel production. Effective pretreatment is necessary for achieving a high efficiency in converting the crop to fermentable sugars, and subsequently biofuels and other valued products. RESULTS: Miscanthus lutarioriparious was pretreated with a liquid hot water (LHW) reactor. Between the pretreatment severity (PS) of 2.56-4.71, the solid recovery was reduced; cellulose recovery remained nearly unchanged; and the Klason lignin content was slightly increased which was mainly due to the dissolving of hemicellulose and the production of a small amount of pseudo-lignin. The result shows that a LHW PS of 4.71 could completely degrade the hemicellulose in Miscanthus. Hemicellulose removal dislodged the enzymatic barrier of cellulose, and the ethanol conversion of 98.27% was obtained. CONCLUSIONS: Our study demonstrated that LHW served as an effective pretreatment in case that Miscanthus lutarioriparious was used for ethanol production by simultaneous saccharification and fermentation. The combination and the pretreatment method of Miscanthus feedstock holds a great potential for biofuel production. PMID- 23663477 TI - Inherited fabric in an omphacite symplectite: reconstruction of plastic deformation under ultra-high pressure conditions. AB - We investigated an eclogitic gneiss from the Western Gneiss Region in Norway, which underwent subduction as part of Baltica lithosphere beneath Laurentia during the Scandian orogeny. Petrologic data indicate that the eclogite was deformed plastically at about 4 GPa and 800 degrees C producing a strong macroscopic foliation and lineation. Whereas garnet remained largely stable during the retrograde uplift, omphacite was transformed statically into a symplectite consisting of lamellar diopside and plagioclase with more equant grains of hornblende and orthopyroxene. Measurements of the crystallographic preferred orientation with electron backscatter diffraction show that diopside and hornblende, as well as orthopyroxene, have a systematic orientation relationship with the macroscopic fabric, as well as the (presumed) orientation of the host omphacite. The orientation relationship between the chain silicates is very sharp with the crystallographic forms {100}, {010}, and <001> being parallel. Their bulk texture shows a maximum of <001> parallel to the lineation and girdles of {010} and {110} perpendicular to the lineation with maxima subparallel to the foliation corresponding to an L-type texture of the original omphacite and indicating constrictional strain with an additional component of pure shear/simple shear component. PMID- 23663478 TI - The effect of cigarette smoke exposure on vitamin D level and biochemical parameters of mothers and neonates. AB - BACKGROUND: Exposure to cigarette smoke during pregnancy leads to several adverse effects on mother and child. The purpose of this study was to evaluate the effect of being a passive smoker during pregnancy on vitamin D level and related biochemical indices including parathyroid hormone, calcium, phosphorus and alkaline phosphatase in mothers and newborns. METHODS: One hundred eight pregnant women and their newborns participated in a historical cohort study in two equal groups (n = 54) with and without cigarette smoke exposure. Maternal blood and urine samples and blood samples of umbilical cord were obtained in the delivery room. Concentration of 25-hydroxy vitamin D and related biochemical indices in samples of maternal and cord blood were investigated. Exposure to cigarette smoke was evaluated through questionnaire and maternal urine and umbilical cord serum cotinine levels. RESULTS: The mean level of 25-hydroxyvitamin D in maternal serum was 9.28 +/- 5.19 ng/mlin exposed and 10.75 +/- 5.26 ng/ml in non-exposed group(p > 0.05). The mean concentration of 25-hydroxy vitamin D in cord serum was 10.83 +/- 6.68 ng/ml in the exposed and 11.05 +/- 4.99 ng/ml in the non-exposed group(p > 0.05). The exposed mothers had significantly higher parathyroid hormone level (p = 0.013), lower serum calcium (p = 0.024) and higher serum alkaline phosphatase (p = 0.024). There was a significant correlation between maternal and umbilical cord serum 25-hydroxyvitamin D within both exposed and non-exposed groups (p < 0.001). CONCLUSION: Maternal exposure to cigarette smoking during pregnancy negatively influences serum calcium level and increase parathyroid hormone and alkaline phosphatase in mothers. PMID- 23663479 TI - Action-oriented predictive processing and the neuroeconomics of sub-cognitive reward. AB - Clark expresses reservations about Friston's reductive interpretation of action oriented predictive processing (AOPP) models of cognition, but he doesn't link these reservations to specific alternatives. Neuroeconomic models of sub cognitive reward valuation, which, like AOPP, integrate attention with action based on prediction error, are such an alternative. They interpret reward valuation as an input to neocortical processing instead of reducing it. PMID- 23663480 TI - A review of sensitivity, specificity, and likelihood ratios: evaluating the utility of the electrocardiogram as a screening tool in hypertrophic cardiomyopathy. AB - Appropriate interpretation of a screening test's validity poses a challenge to the clinician. The purpose of this review is to revisit the terms sensitivity, specificity, likelihood ratio, and pre- and posttest probability and their application to the clinical setting. For illustration, we use a recently published article in the American Journal of Cardiology that investigates the false negative rate of electrocardiograms in athletic preparticipation screening for hypertrophic cardiomyopathy. PMID- 23663482 TI - Oncogenic role of protein tyrosine kinase 7 in esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is a common subtype of esophageal cancer that is particularly prevalent in East Asian countries. Our previous expression profile analysis showed that the gene encoding protein tyrosine kinase 7 (PTK7) is upregulated in ESCC tissues. Here, we aimed to validate PTK7 as a prognostic factor and a candidate target for molecular treatment of ESCC. Both RT PCR and Western blot analysis of tissues from ESCC patients revealed that PTK7 was significantly upregulated in tumor tissue samples of ESCC. Immunohistochemical staining of PTK7 showed that increased expression of PTK7 was inversely correlated with overall survival (P = 0.021). In vitro knockdown of PTK7 inhibited proliferation, survival, wound healing, and invasion of ESCC cells. In addition, PTK7 knockdown decreased phosphorylation of Akt, Erk, and focal adhesion kinase (FAK), important determinants of cell proliferation, survival, and migration. Therefore, our findings suggest that PTK7 has potential as a prognostic marker for ESCC and might also be a candidate for targeted therapy in the treatment of ESCC. PMID- 23663483 TI - Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells. AB - BACKGROUND: Epidemiological studies have shown direct associations between type 2 diabetes and obesity, both conditions associated with hyperglycaemia and hyperinsulinemia, and the risk of pancreatic cancer. Up to 80% of pancreatic cancer patients present with either new-onset type 2 diabetes or impaired glucose tolerance at the time of diagnosis. Recent population studies indicate that the incidence of pancreatic cancer is reduced among diabetics taking metformin. In this study, the effects of exposure of pancreatic cancer cells to high glucose levels on their growth and response to metformin were investigated. METHODS: The human pancreatic cancer cell lines AsPC-1, BxPC-3, PANC-1 and MIAPaCa-2 were grown in normal (5 mM) or high (25 mM) glucose conditions, with or without metformin. The influence by metformin on proliferation, apoptosis and the AMPK and IGF-IR signalling pathways were evaluated in vitro. RESULTS: Metformin significantly reduced the proliferation of pancreatic cancer cells under normal glucose conditions. Hyperglycaemia however, protected against the metformin induced growth inhibition. The anti-proliferative actions of metformin were associated with an activation of AMP-activated protein kinase AMPKThr172 together with an inhibition of the insulin/insulin-like growth factor-I (IGF-I) receptor activation and downstream signalling mediators IRS-1 and phosphorylated Akt. Furthermore, exposure to metformin during normal glucose conditions led to increased apoptosis as measured by poly(ADP-ribose) polymerase (PARP) cleavage. In contrast, exposure to high glucose levels promoted a more robust IGF-I response and Akt activation which correlated to stimulated AMPKSer485 phosphorylation and impaired AMPKThr172 phosphorylation, resulting in reduced anti-proliferative and apoptotic effects by metformin. CONCLUSION: Our results indicate that metformin has direct anti-tumour activities in pancreatic cancer cells involving AMPKThr172 activation and suppression of the insulin/IGF signalling pathways. However, hyperglycaemic conditions enhance the insulin/IGF-I responses resulting in an altered AMPK activation profile and prevent metformin from fully switching off the growth promoting signals in pancreatic cancer cells. PMID- 23663485 TI - Emergence of multilateral proto-institutions in global health and new approaches to governance: analysis using path dependency and institutional theory. AB - The role of multilateral donor agencies in global health is a new area of research, with limited research on how these agencies differ in terms of their governance arrangements, especially in relation to transparency, inclusiveness, accountability, and responsiveness to civil society. We argue that historical analysis of the origins of these agencies and their coalition formation processes can help to explain these differences. We propose an analytical approach that links the theoretical literature discussing institutional origins to path dependency and institutional theory relating to proto institutions in order to illustrate the differences in coalition formation processes that shape governance within four multilateral agencies involved in global health. We find that two new multilateral donor agencies that were created by a diverse coalition of state and non-state actors, such as the Global Fund to Fight AIDS, Tuberculosis and Malaria and GAVI, what we call proto-institutions, were more adaptive in strengthening their governance processes. This contrasts with two well-established multilateral donor agencies, such as the World Bank and the Asian Development Bank, what we call Bretton Woods (BW) institutions, which were created by nation states alone; and hence, have different origins and consequently different path dependent processes. PMID- 23663484 TI - Interfacing cellular networks of S. cerevisiae and E. coli: connecting dynamic and genetic information. AB - BACKGROUND: In recent years, various types of cellular networks have penetrated biology and are nowadays used omnipresently for studying eukaryote and prokaryote organisms. Still, the relation and the biological overlap among phenomenological and inferential gene networks, e.g., between the protein interaction network and the gene regulatory network inferred from large-scale transcriptomic data, is largely unexplored. RESULTS: We provide in this study an in-depth analysis of the structural, functional and chromosomal relationship between a protein-protein network, a transcriptional regulatory network and an inferred gene regulatory network, for S. cerevisiae and E. coli. Further, we study global and local aspects of these networks and their biological information overlap by comparing, e.g., the functional co-occurrence of Gene Ontology terms by exploiting the available interaction structure among the genes. CONCLUSIONS: Although the individual networks represent different levels of cellular interactions with global structural and functional dissimilarities, we observe crucial functions of their network interfaces for the assembly of protein complexes, proteolysis, transcription, translation, metabolic and regulatory interactions. Overall, our results shed light on the integrability of these networks and their interfacing biological processes. PMID- 23663486 TI - Epithelium and stroma from nasal polyp mucosa exhibits inverse expression of TGF beta1 as compared with healthy nasal mucosa. AB - OBJECTIVE: To evaluate TGF-beta1 expression in polypoid mucosa (epithelium and stroma) of patients with chronic rhinosinusitis with nasal polyposis (CRSwNP). METHODS: Cross-sectional study with two groups: 17 patients with nasal polyposis and 11 controls. Polyps and normal nasal mucosa were processed by immunohistochemical methods for TGF-beta1 visualization. Then, the percentage of TGF-beta1 expression in stroma and epithelium was objectively quantified using UT Morph software. RESULTS: A lower percentage of positive expression was found in the epithelium of CRSwNP patients (32.44%) versus normal controls (55.91%) (p < 0.05), and a higher percentage of positive expression in the stroma of CRSwNP patients (23.24%) versus controls (5.88%) (p < 0.05). CONCLUSION: The lower percentage of TGF-beta1 expression in the nasal epithelium of CRSwNP patients may have an impact on epithelium-directed topical treatments employed in this patient population. PMID- 23663487 TI - Can otoplasty impact hearing? A prospective randomized controlled study examining the effects of pinna position on speech reception and intelligibility. AB - OBJECTIVES: Otoplasty is a commonly performed surgical procedure that restores the ideal position of the pinna. Although the pinna is a well-recognized component of the auditory apparatus, no studies have assessed the audiological effects of this procedure. We sought to quantify the impact of pinna repositioning on speech intelligibility and reception. METHODS: Eighteen adults with normal hearing and pinnae were recruited and the pinna positions were randomized in each participant. Intracanal acoustical analysis was performed to calculate the Speech Intelligibility Index (SII). Hearing In Noise Test (HINT) with two azimuth speaker arrangement was also performed. The outcome measures were compared using paired t-tests for both pinna positions. RESULTS: The SII significantly improved with the pinna in forward position (49.3 vs. 45.8, p<0.001). HINT thresholds also improved with the pinna forward (-6.43 dB vs. 5.08 dB, p=0.0003). CONCLUSIONS: Pinna position affects audiological performance, in both speech intelligibility and speech reception in noise. These are novel findings that may impact the informed consent process and decision to treat for patients undergoing otoplasty. PMID- 23663488 TI - Relieving nasal congestion in children with seasonal and perennial allergic rhinitis: efficacy and safety studies of mometasone furoate nasal spray. AB - BACKGROUND: In surveys of children with allergic rhinitis (AR), nasal congestion has been identified as the most frequently experienced and bothersome symptom. This analysis was conducted to investigate the effect of mometasone furoate nasal spray (MFNS) on congestion in children with AR. METHODS: Two multicenter, double blind, placebo-controlled studies randomly assigned children to MFNS 100 MUg or placebo, 1 spray/nostril QD for 4 weeks (Study 1: ages 6-11 years with seasonal AR [SAR] >=1 year; Study 2: ages 3-11 years with perennial AR [PAR] >=1 year). Least square (LS) means were obtained from an ANCOVA model with treatment and study center effects, with baseline score as a covariate. We conducted post hoc evaluation of changes from baseline in AM/PM PRIOR (average of reflective AM and PM scores) nasal congestion (0=none to 3=severe). RESULTS: Study 1: MFNS (n=134) reduced congestion significantly more than placebo (n=135) on day 2 (P=.004) and on 23/29 days (P<=.037). Change from baseline was -0.53 and -0.28 for MFNS and placebo (P<.001) over days 1-15 and -0.64 and -0.38 for MFNS and placebo (P<.001) over days 1-29. Study 2: MFNS (n=185) reduced congestion significantly more than placebo (n=189) on day 3 (P=.015) and on 22/29 days (P<=.047). Change from baseline was -0.56 and -0.36 for MFNS and placebo (P<.001) over days 1-15 and 0.64 and -0.45 for MFNS and placebo (P<.001) over days 1-29. MFNS was well tolerated, with no unusual or unexpected adverse events. CONCLUSION: MFNS effectively relieved nasal congestion and was well tolerated in children with SAR or PAR. PMID- 23663489 TI - Anti-inflammatory effects of clarithromycin in ventilator-induced lung injury. AB - BACKGROUND: Mechanical ventilation can promote lung injury by triggering a pro inflammatory response. Macrolides may exert some immunomodulatory effects and have shown significant benefits over other antibiotics in ventilated patients. We hypothesized that macrolides could decrease ventilator-induced lung injury. METHODS: Adult mice were treated with vehicle, clarithromycin or levofloxacin, and randomized to receive mechanical ventilation with low (12 cmH2O, PEEP 2 cmH2O) or high (20 cmH2O, ZEEP) inspiratory pressures for 150 minutes. Histological lung injury, neutrophil infiltration, inflammatory mediators (NFkappaB activation, Cxcl2, IL-10) and levels of adhesion molecules (E-selectin, ICAM) and proteases (MMP-9 and MMP-2) were analyzed. RESULTS: There were no differences among groups after low-pressure ventilation. Clarithromycin significantly decreased lung injury score and neutrophil count, compared to vehicle or levofloxacin, after high-pressure ventilation. Cxcl2 expression and MMP-2 and MMP-9 levels increased and IL-10 decreased after injurious ventilation, with no significant differences among treatment groups. Both clarithromycin and levofloxacin dampened the increase in NFkappaB activation observed in non-treated animals submitted to injurious ventilation. E-selectin levels increased after high pressure ventilation in vehicle- and levofloxacin-treated mice, but not in those receiving clarithromycin. CONCLUSIONS: Clarithromycin ameliorates ventilator-induced lung injury and decreases neutrophil recruitment into the alveolar spaces. This could explain the advantages of macrolides in patients with acute lung injury and mechanical ventilation. PMID- 23663490 TI - Clinical management and burden of bipolar disorder: results from a multinational longitudinal study (WAVE-bd). AB - Bipolar disorder is a mood disorder which requires complex treatment. Current treatment guidelines are based on the results of published randomized clinical trials and meta-analyses which may not accurately reflect everyday clinical practice. This multi-national, multi-centre, observational cohort study describes clinical management and clinical outcomes related to bipolar disorder in real life settings, assesses between-country variability and identifies factors associated with clinical outcomes. Adults from 10 countries in Europe and South America who experienced at least one mood episode in the preceding 12 months were included. Overall, 2896 patients were included in the analyses and followed for at least 9 months across a retrospective and prospective study phase. Main outcome measures were the number and incidence rate of mood episodes (relapses and recurrences) and healthcare resource use including pharmacological treatments. Relapses and recurrences were reported in 18.2 and 40.5% of patients, respectively; however, the reported incidence rate of relapses was higher than that of recurrences [1.562 per person-year (95% CI 1.465-1.664) vs. 0.691 per person-year (95% CI 0.657-0.726)]. Medication use was high during all episode types and euthymia; the percentage of patients receiving no medication ranged from 11.0% in mania to 6.1% in euthymia. Antipsychotics were the most commonly prescribed drug class in all disease phases except for patients with depression, where antidepressants were more frequently prescribed. Visits to the psychiatrist were the most frequently used healthcare resource. These results provide a description of treatment patterns for bipolar disorder across different countries and indicate factors related to relapse and recurrence. PMID- 23663491 TI - Advances in biotechnology and genomics of switchgrass. AB - Switchgrass (Panicum virgatum L.) is a C4 perennial warm season grass indigenous to the North American tallgrass prairie. A number of its natural and agronomic traits, including adaptation to a wide geographical distribution, low nutrient requirements and production costs, high water use efficiency, high biomass potential, ease of harvesting, and potential for carbon storage, make it an attractive dedicated biomass crop for biofuel production. We believe that genetic improvements using biotechnology will be important to realize the potential of the biomass and biofuel-related uses of switchgrass. Tissue culture techniques aimed at rapid propagation of switchgrass and genetic transformation protocols have been developed. Rapid progress in genome sequencing and bioinformatics has provided efficient strategies to identify, tag, clone and manipulate many economically-important genes, including those related to higher biomass, saccharification efficiency, and lignin biosynthesis. Application of the best genetic tools should render improved switchgrass that will be more economically and environmentally sustainable as a lignocellulosic bioenergy feedstock. PMID- 23663492 TI - The Multicenter Pediatric and Adult Congenital EP Quality (MAP-IT) Initiative rationale and design: report from the pediatric and congenital electrophysiology society's MAP-IT taskforce. AB - Multicenter clinical registries are increasingly recognized as valuable tools for establishing benchmarks, facilitating patient-centered quality improvement and research. In 2010, the Pediatric and Congenital Electrophysiology Society convened a taskforce of its members to design, construct, and implement a clinical registry known as the Multicenter Pediatric and Adult Congenital EP Quality (MAP-IT) Initiative. The present aim of the MAP-IT Initiative is to create an infrastructure by which we can measurably improve patient-centered outcomes and reduce complications associated with electrophysiology studies and catheter ablation in pediatric and congenital heart disease patients. The purpose of this writing is to report the progress to date from three of the four subcommittees of the MAP-IT taskforce. Specifically, we present our initial set of key data elements and definitions, recommended database table structure, and considerations regarding wide-scale implementation of the registry. Development of a risk/complexity score for use in the MAP-IT registry is presented in a separate companion manuscript. It is our intent that these manuscripts will serve to introduce the electrophysiology and pediatric cardiology community to the MAP IT initiative and provide a rationale for its design and recommended implementation strategy. PMID- 23663493 TI - A systematic review of suicide prevention interventions targeting indigenous peoples in Australia, United States, Canada and New Zealand. AB - BACKGROUND: Indigenous peoples of Australia, Canada, United States and New Zealand experience disproportionately high rates of suicide. As such, the methodological quality of evaluations of suicide prevention interventions targeting these Indigenous populations should be rigorously examined, in order to determine the extent to which they are effective for reducing rates of Indigenous suicide and suicidal behaviours. This systematic review aims to: 1) identify published evaluations of suicide prevention interventions targeting Indigenous peoples in Australia, Canada, United States and New Zealand; 2) critique their methodological quality; and 3) describe their main characteristics. METHODS: A systematic search of 17 electronic databases and 13 websites for the period 1981 2012 (inclusive) was undertaken. The reference lists of reviews of suicide prevention interventions were hand-searched for additional relevant studies not identified by the electronic and web search. The methodological quality of evaluations of suicide prevention interventions was assessed using a standardised assessment tool. RESULTS: Nine evaluations of suicide prevention interventions were identified: five targeting Native Americans; three targeting Aboriginal Australians; and one First Nation Canadians. The main intervention strategies employed included: Community Prevention, Gatekeeper Training, and Education. Only three of the nine evaluations measured changes in rates of suicide or suicidal behaviour, all of which reported significant improvements. The methodological quality of evaluations was variable. Particular problems included weak study designs, reliance on self-report measures, highly variable consent and follow-up rates, and the absence of economic or cost analyses. CONCLUSIONS: There is an urgent need for an increase in the number of evaluations of preventive interventions targeting reductions in Indigenous suicide using methodologically rigorous study designs across geographically and culturally diverse Indigenous populations. Combining and tailoring best evidence and culturally-specific individual strategies into one coherent suicide prevention program for delivery to whole Indigenous communities and/or population groups at high risk of suicide offers considerable promise. PMID- 23663494 TI - Bifidobacterium longum NCC3001 inhibits AH neuron excitability. AB - BACKGROUND: Bifidobacterium longum (B. longum) NCC3001 can affect behavior and brain biochemistry, but identification of the cellular targets needs further investigation. Our hypothesis was that the communication with the brain might start with action on enteric sensory neurons. METHODS: Ileal segments from adult mice were used to create a longitudinal muscle-myenteric-plexus preparation to expose sensory after-hyperpolarizing (AH) neurons in the myenteric plexus to allow access with microelectrodes. The intrinsic excitability of AH neurons was tested in response to the perfusion of conditioned media (B. longum culture supernatant) or unconditioned media (growth medium, MRS). KEY RESULTS: B. longum conditioned medium significantly reduced the excitability of AH neurons compared to perfusion with the unconditioned medium. Specifically, a reduction was seen in the number of action potentials fired per depolarizing test pulse, the instantaneous and time-dependent input resistances and the magnitude of the hyperpolarization-activated cationic current (Ih ). CONCLUSIONS & INFERENCES: The probiotic B. longum reduces excitability of AH sensory neurons likely via opening of potassium channels and closing of hyperpolarization-activated cation channels. PMID- 23663495 TI - Adenosine A(2A) receptors promote collagen production by a Fli1- and CTGF mediated mechanism. AB - INTRODUCTION: Adenosine, acting through the A(2A) receptor, promotes tissue matrix production in the skin and the liver and induces the development of dermal fibrosis and cirrhosis in murine models. Since expression of A(2A) receptors is increased in scleroderma fibroblasts, we examined the mechanisms by which the A(2A) receptor produces its fibrogenic effects. METHODS: The effects of A(2A) receptor ligation on the expression of the transcription factor, Fli1, a constitutive repressor for the synthesis of matrix proteins, such as collagen, is studied in dermal fibroblasts. Fli1 is also known to repress the transcription of CTGF/CCN2, and the effects of A(2A) receptor stimulation on CTGF and TGF-beta1 expression are also examined. RESULTS: A(2A) receptor occupancy suppresses the expression of Fli1 by dermal fibroblasts. A(2A) receptor activation induces the secretion of CTGF by dermal fibroblasts, and neutralization of CTGF abrogates the A(2A) receptor-mediated enhancement of collagen type I production. A(2A)R activation, however, resulted in a decrease in TGF-beta1 protein release. CONCLUSIONS: Our results suggest that Fli1 and CTGF are important mediators of the fibrogenic actions of adenosine and the use of small molecules such as adenosine A(2A) receptor antagonists may be useful in the therapy of dermal fibrosis in diseases such as scleroderma. PMID- 23663496 TI - A cost function analysis of child health services in four districts in Malawi. AB - BACKGROUND: Recent analyses show that donor funding for child health is increasing, but little information is available on actual costs to deliver child health care services. Understanding how unit costs scale with service volume in Malawi can help planners allocate budgets as health services expand. METHODS: Data on facility level inputs and outputs were collected at 24 health centres in four districts of Malawi visiting a random sample of government and a convenience sample of Christian Health Association of Malawi (CHAM) health centres. In the cost function, total outputs, quality, facility ownership, average salaries and case mix are used to predict total cost. Regression analysis identifies marginal cost as the coefficient relating cost to service volume intensity. RESULTS: The marginal cost per patient seen for all health centres surveyed was US$ 0.82 per additional patient visit. Average cost was US$ 7.16 (95% CI: 5.24 to 9.08) at government facilities and US$ 10.36 (95% CI: 4.92 to 15.80) at CHAM facilities per child seen for any service. The first-line anti-malarial drug accounted for over 30% of costs, on average, at government health centres. Donors directly financed 40% and 21% of costs at government and CHAM health centres, respectively. The regression models indicate higher total costs are associated with a greater number of outpatient visits but that many health centres are not providing services at optimal volume given their inputs. They also indicate that CHAM facilities have higher costs than government facilities for similar levels of utilization. CONCLUSIONS: We conclude by discussing ways in which efficiency may be improved at health centres. The first option, increasing the total number of patients seen, appears difficult given existing high levels of child utilization; increasing the volume of adult patients may help spread fixed and semi-fixed costs. A second option, improving the quality of services, also presents difficulties but could also usefully improve performance. PMID- 23663497 TI - Distinguishing theory from implementation in predictive coding accounts of brain function. AB - It is often helpful to distinguish between a theory (Marr's computational level) and a specific implementation of that theory (Marr's physical level). However, in the target article, a single implementation of predictive coding is presented as if this were the theory of predictive coding itself. Other implementations of predictive coding have been formulated which can explain additional neurobiological phenomena. PMID- 23663498 TI - The brain is not an isolated "black box," nor is its goal to become one. AB - In important ways, Clark's "hierarchical prediction machine" (HPM) approach parallels the research agenda we have been pursuing. Nevertheless, we remain unconvinced that the HPM offers the best clue yet to the shape of a unified science of mind and action. The apparent convergence of research interests is offset by a profound divergence of theoretical starting points and ideal goals. PMID- 23663499 TI - A gene expression restriction network mediated by sense and antisense Alu sequences located on protein-coding messenger RNAs. AB - BACKGROUND: Alus are primate-specific retrotransposons which account for 10.6% of the human genome. A large number of protein-coding mRNAs are encoded with sense or antisense Alus in the un-translated regions. RESULTS: We postulated that mRNAs carrying Alus in the two opposite directions can generate double stranded RNAs, capable of regulating the levels of other Alu-carrying mRNAs post transcriptionally. A gene expression profiling assay showed that the levels of antisense and sense Alus-carrying mRNAs were suppressed in a reversible manner by over-expression of exogenous sense and antisense Alus derived from mRNAs (Family wise error rate P=0.0483 and P<0.0001 respectively). Screening through human mRNAs on the NCBI-RefSeq database, it was found that sense and antisense Alu carrying transcripts were enriched in distinct cellular functions. Antisense Alu carrying genes were particularly enriched in neurological and developmental processes, while sense Alu-carrying genes were enriched in immunological functions. CONCLUSIONS: Taken together, we proposed a novel Alu-mediated regulation network capable of stabilizing Alu-carrying mRNA levels in different cell types and restricting the activated expression levels of protein-coding, Alu carrying mRNAs. PMID- 23663500 TI - Genetic association between selected cytokine genes and glioblastoma in the Han Chinese population. AB - BACKGROUND: Glioblastoma (GBM) is the most malignant brain tumor. Many abnormal secretion and expression of cytokines have been found in GBM, initially speculated that the occurrence of GBM may be involved in these abnormal secretion of cytokines. This study aims to detect the association of cytokine genes with GBM. METHODS: We selected seven tag single nucleotide polymorphisms (tSNPs) in six cytokine genes, which previously reported to be associated with brain tumors, and analyzed their association with GBM in a Han Chinese population using chi(2) test and genetic model analysis. RESULTS: We found two risk tSNPs and one protective tSNP. By chi(2) test, the rs1801275 in IL-4R showed an increased risk of GBM. In the genetic model analysis, the genotype "TC" of rs20541 in IL-13 gene showed an increased risk of GBM in over-dominant model (OR = 2.00; 95% CI, 1.13 3.54, p = 0.015); the genotype "CT" of rs1800871 in the IL-10 gene showed a decrease risk in the over-dominant model (OR = 0.57; 95% CI, 0.33 - 0.97; p = 0.037). The genotype "AG" of rs1801275 in the IL-4R gene showed an increase risk in over-dominant model (OR = 2.29; 95% CI, 1.20 - 4.35; p = 0.0081) We further analyzed whether the six cytokine genes have a different effect on the disease in gender specific population, and found that the allele "G" of rs2243248 in the IL 4 gene showed a decrease risk of GBM in female (OR = 0.35, 95% CI, 0.13 - 0.94, p = 0.0032), but the allele "T" showed a decrease risk in male (OR = 0.30, 95% CI, 0.17 - 0.53, p = 0.0032). CONCLUSIONS: Our findings, combined with previously reported results, suggest that cytokine genes have potential role in GBM development, which may be useful to early prognostics for GBM in the Han Chinese population. PMID- 23663501 TI - Global health experiences of U.S. Physicians: a mixed methods survey of clinician researchers and health policy leaders. AB - BACKGROUND: Interest and participation in global health activities among U.S. medical trainees has increased sharply in recent decades, yet the global health activities of physicians who have completed residency training remain understudied. Our objectives were to assess associations between individual characteristics and patterns of post-residency global health activities across the domains of health policy, education, and research. METHODS: Cross-sectional, mixed methods national survey of 521 physicians with formal training in clinical and health services research and policy leadership. Main measures were post residency global health activity and characteristics of this activity (location, funding, products, and perceived synergy with domestic activities). RESULTS: Most respondents (73%) hold faculty appointments across 84 U.S. medical schools and a strong plurality (46%) are trained in internal medicine. Nearly half of all respondents (44%) reported some global health activity after residency; however, the majority of this group (73%) reported spending <=10% of professional time on global health in the past year. Among those active in global health, the majority (78%) reported receiving some funding for their global health activities, and most (83%) reported at least one scholarly, educational, or other product resulting from this work. Many respondents perceived synergies between domestic and global health activities, with 85% agreeing with the statement that their global health activities had enhanced the quality of their domestic work and increased their level of involvement with vulnerable populations, health policy advocacy, or research on the social determinants of health. Despite these perceived synergies, qualitative data from in-depth interviews revealed personal and institutional barriers to sustained global health involvement, including work family balance and a lack of specific avenues for career development in global health. CONCLUSIONS: Post-residency global health activity is common in this diverse, multi-specialty group of physicians. Although those with global health experience describe synergies with their domestic work, the lack of established career development pathways may limit the benefits of this synergy for individuals and their institutions. PMID- 23663502 TI - Methods of measuring the iridocorneal angle in tomographic images of the anterior segment of the eye. AB - INTRODUCTION: This paper presents the problem of automatic measurement of the iridocorneal angle in tomographic images of the anterior segment of the eye. It includes the results of the comparison of well-known methods for measuring the iridocorneal angle with new methods, proposed in this paper. All these methods concern tomographic image analysis and processing. MATERIAL AND METHOD: In total, approximately 100'000 tomographic images (from about 6'000 patients) were analysed. They were obtained using two devices: SOCT Copernicus (Optopol Tech. SA, Zawiercie, Poland) and Visante OCT (Carl Zeiss Meditec, Inc, Dublin, California, USA). The patients, aged 12 to 78 years with varying degrees of the iridocorneal angle pathology, were from the region of Silesia, Poland. The images were in DICOM or RAW formats and analysed in the software developed by the authors for the purposes of this study. RESULTS: The results indicate that the measurement method proposed by the authors, which is based on the calculation of the minimum distance between the iris and the cornea in the adopted area, is the most accurate. For this method sensitivity was 0.88, specificity 0.89 and the area under the Receiver Operating Characteristic curve (AUC) was 0.88. The other known methods for measuring the iridocorneal angle gave worse results, that is, for example, for the measurement of the distance between the iris and the cornea AUC = 0.87, sensitivity = 0.86 and specificity = 0.71. For another well-known method of measuring the iridocorneal angle AUC = 0.77, sensitivity = 0.82 and specificity = 0.61. CONCLUSIONS: The study proved that the proposed method of measuring the minimum distance between the iris and the cornea within the adopted area is the most effective in the classification of the iridocorneal angle in patients with a high degree of pathology of all the compared measurement methods based on tomographic images. However, it requires fully automated measurement. PMID- 23663503 TI - Fibrolipoma of the nasal septum; report of the first case. AB - BACKGROUND/OBJECTIVE: Fibrolipomas are a rare subtype of lipomas and very rare in the oral and maxillofacial region. Lipomas affecting the central nervous system are even more infrequent occurring with a frequency of 0.1%. STUDY DESIGN, METHODS: Case report. CASE PRESENTATION: This report includes a patient who had a nasal septal fibrolipoma and an accompanying corpus callosum lipoma. CONCLUSIONS: To our knowledge, this is the first reported nasal septal fibrolipoma case in the literature. The diagnostic and surgical features of this case and the unity of septal fibrolipoma and intracranial lipomas are discussed. PMID- 23663504 TI - Difficult to control atopic dermatitis. AB - Difficult to control atopic dermatitis (AD) presents a therapeutic challenge and often requires combinations of topical and systemic treatment. Anti-inflammatory treatment of severe AD most commonly includes topical glucocorticosteroids and topical calcineurin antagonists used for exacerbation management and more recently for proactive therapy in selected cases. Topical corticosteroids remain the mainstay of therapy, the topical calcineurin inhibitors tacrolimus and pimecrolimus are preferred in certain locations. Systemic anti-inflammatory treatment is an option for severe refractory cases. Microbial colonization and superinfection contribute to disease exacerbation and thus justify additional antimicrobial / antiseptic treatment. Systemic antihistamines (H1) may relieve pruritus but do not have sufficient effect on eczema. Adjuvant therapy includes UV irradiation preferably of UVA1 wavelength. "Eczema school" educational programs have been proven to be helpful. PMID- 23663505 TI - Platelet-derived growth factor alpha and beta receptors have overlapping functional activities towards fibroblasts. AB - BACKGROUND: Platelet-derived growth factor (PDGF) signalling is essential for many key cellular processes in mesenchymal cells. As there is redundancy in signalling between the five PDGF ligand isoforms and three PDGF receptor isoforms, and deletion of either of the receptors in vivo produces an embryonic lethal phenotype, it is not know which ligand and receptor combinations mediate specific cellular functions. Fibroblasts are key mediators in wound healing and tissues repair. Recent clinical trials using broad spectrum tyrosine kinase inhibitors in fibrotic diseases have highlighted the need to further examine the specific cellular roles each of the tyrosine kinases plays in fibrotic processes. In this study, we used PDGFR-specific neutralising antibodies to dissect out receptor-specific signalling events in fibroblasts in vitro, to further understand key cellular processes involved in wound healing and tissue repair. RESULTS: Neutralising antibodies against PDGFRs were shown to block signalling through PDGFRalpha and PDGFRbeta receptors, reduce human PDGF-AA and PDGF-BB induced collagen gel remodelling in dermal fibroblasts, and reduce migration stimulated by all PDGF ligands in human dermal and lung fibroblasts. CONCLUSIONS: PDGFRalpha and PDGFRbeta neutralising antibodies can be a useful tool in studying PDGFR isoform-specific cellular events. PMID- 23663507 TI - Babes in the wood--a unique window into sea scorpion ontogeny. AB - BACKGROUND: Few studies on eurypterids have taken into account morphological changes that occur throughout postembryonic development. Here two species of eurypterid are described from the Pragian Beartooth Butte Formation of Cottonwood Canyon in Wyoming and included in a phylogenetic analysis. Both species comprise individuals from a number of instars, and this allows for changes that occur throughout their ontogeny to be documented, and how ontogenetically variable characters can influence phylogenetic analysis to be tested. RESULTS: The two species of eurypterid are described as Jaekelopterus howelli (Kjellesvig-Waering and Stormer, 1952) and Strobilopterus proteus sp. nov. Phylogenetic analysis places them within the Pterygotidae and Strobilopteridae respectively, both families within the Eurypterina. Jaekelopterus howelli shows positive allometry of the cheliceral denticles throughout ontogeny, while a number of characteristics including prosomal appendage length, carapace shape, lateral eye position, and relative breadth all vary during the growth of Strobilopterus proteus. CONCLUSIONS: The ontogeny of Strobilopterus proteus shares much in common with that of modern xiphosurans, however certain characteristics including apparent true direct development suggest a closer affinity to arachnids. The ontogenetic development of the genital appendage also supports the hypothesis that the structure is homologous to the endopods of the trunk limbs of other arthropods. Including earlier instars in the phylogenetic analysis is shown to destabilise the retrieved topology. Therefore, coding juveniles as individual taxa in an analysis is shown to be actively detrimental and alternative ways of coding ontogenetic data into phylogenetic analyses should be explored. PMID- 23663506 TI - Comparative analysis of cancer vaccine settings for the selection of an effective protocol in mice. AB - BACKGROUND: Cancer vaccines are considered a promising therapeutic approach. However, their clinical results are not yet satisfactory. This may be due to the the difficulty of selection of an efficient tumor associated antigen (TAA) and immunization protocol. Indeed, the weak antigenicity of many TAA impairs the design of robust procedures, therefore a systematic analysis to identify the most efficient TAA is mandatory. Here, we performed a study to compare different gp100 vaccination strategies to identify the best strategy to provide a 100% protection against experimental melanoma in a reproducible manner. METHODS: C57BL/6J mice were challenged subcutaneously with B16F10 melanoma cells, after vaccination with: a) mouse or human gp10025-33 peptide plus CpG adjuvant; b) mouse or human gp100 gene; c) mouse or human gp10025-33 peptide-pulsed dendritic cells (DC). Alternatively, a neutralizing anti-IL-10 monoclonal antibody (mAb) was subcutaneously administered at the site of tumor challenge to counteract regulatory cells. Finally, combinatorial treatment was performed associating human gp10025-33 peptide-pulsed DC vaccination with administration of the anti-IL 10 mAb. RESULTS: Vaccination with human gp10025-33 peptide-pulsed DC was the most effective immunization protocol, although not achieving a full protection. Administration of the anti-IL-10 mAb showed also a remarkable protective effect, replicated in mice challenged with a different tumor, Anaplastic Large Cell Lymphoma. When immunization with gp10025-33 peptide-pulsed DC was associated with IL-10 counteraction, a 100% protective effect was consistently achieved. The analysis on the T-cell tumor infiltrates showed an increase of CD4+granzyme+ T cells and a decreased number of CD4+CD25+Foxp3+ Treg elements from mice treated with either gp10025-33 peptide-pulsed DC vaccination or anti-IL-10 mAb administration. These data suggest that processes of intratumoral re-balance between effector and regulatory T cell subpopulations may play a critical protective role in immunotherapy protocols. CONCLUSIONS: Here we demonstrate that, in the setting of a cancer vaccine strategy, a comparative analysis of different personalized approaches may favour the unveiling of the most effective protocol. Moreover, our findings suggest that counteraction of IL-10 activity may be critical to revert the intratumoral environment promoting Treg polarization, thus increasing the effects of a vaccination against selected TAA. PMID- 23663508 TI - Glucose-induced incretin hormone release and insulin sensitivity are impaired in patients with idiopathic gastroparesis: results from a pilot descriptive study. AB - BACKGROUND: Incretin hormones [glucagon-like peptide-1 (GLP-1) and glucose dependent insulinotropic peptide (GIP)] released by the gut modulate gastrointestinal motility and influence gastric emptying (GE). Abnormal secretion or sensitivity to these hormones could contribute to the pathogenesis of gastroparesis. The aim of this study was to investigate incretin hormone secretion during a prolonged oral glucose load in non-diabetic patients with documented idiopathic gastroparesis. METHODS: Fifteen patients referred for digestive postprandial discomfort with delayed GE demonstrated by a (13) C labeled octanoate breath test were included and compared with 10 healthy controls. A 75 g oral glucose load was performed, with blood samplings every 30 min for 5 h, to determine glucose, insulin, GIP, and GLP-1 blood levels. KEY RESULTS: Fasting GIP concentration was significantly higher in the patient group (56.1 +/- 5.8 pg mL(-1) vs 29.9 +/- 7.7 pg mL(-1), P =0.012). Postglucose load GIP concentrations were also significantly elevated in patients with gastroparesis, whereas GLP-1 concentrations during fasting and postglucose load conditions were not different to those of healthy controls. Moreover, glucose tolerance during glucose load was abnormal in patients, combining hyperglycemic insulin resistance and hyperinsulinism patterns, while fasting values for glycemia, insulin sensitivity, and insulin concentrations were normal. CONCLUSIONS & INFERENCES: Patients with idiopathic gastroparesis exhibit abnormal GIP levels associated with impaired insulin sensitivity during oral glucose load. Further studies are needed to establish the involvement of these defects in the pathophysiology of gastroparesis. PMID- 23663509 TI - Grounding predictive coding models in empirical neuroscience research. AB - Clark makes a convincing case for the merits of conceptualizing brains as hierarchical prediction machines. This perspective has the potential to provide an elegant and powerful general theory of brain function, but it will ultimately stand or fall with evidence from basic neuroscience research. Here, we characterize the status quo of that evidence and highlight important avenues for future investigations. PMID- 23663510 TI - Equivalent beneficial effects of unilateral and bilateral prefrontal cortex transcranial magnetic stimulation in a large randomized trial in treatment resistant major depression. AB - Repetitive transcranial magnetic stimulation treatment (rTMS) is an effective treatment for depression but the optimal methods of administration have yet to be determined. Recent studies have produced conflicting results as to whether unilateral rTMS is more or less effective than sequentially applied bilateral rTMS. To address this we conducted a trial comparing sequential bilateral rTMS to right-sided unilateral rTMS using a priming protocol. Patients with treatment resistant depression (n = 179) were enrolled in a two-arm randomized controlled trial across a 4-wk time period. The primary outcome assessment was the Hamilton Depression Rating Scale. Overall, there was a substantial response rate of >50% (and a 40% remission rate); however, there were no significant differences in clinical response between the two treatment groups. rTMS was well tolerated with a very low discontinuation rate. There was no relationship between response in the current trial and previous response, or non-response, to electroconvulsive therapy. We found no significant differences in clinical response between sequential bilateral rTMS and right-sided unilateral rTMS applied with a priming protocol. The results of this study do not support superior efficacy of bilateral rTMS and instead suggest that other approaches should be explored to increase treatment efficacy. PMID- 23663512 TI - An endonasal approach to the resection of a papillary seromucinous adenocarcinoma of the eustacian tube. AB - OBJECTIVES: Papillary seromucinous adenocarcinoma of the sinonasal tract is exceedingly rare. The objectives of this case report are to describe a case of papillary seromucinous adenocarcinoma presenting in the nasopharynx and to review the literature pertaining to other similar cases. METHODS: A review of the patient's chart and a review of the English literature were conducted. RESULTS: We describe the case of a 64 year-old woman who presented with a 3-year history of epistaxis and right-sided otitis media with effusion. The patient had been followed for a known nasopharyngeal mass that had twice been biopsied and in both cases was considered a benign mass pathologically. A third biopsy was diagnosed as a low-grade papillary seromucinous adenocarcinoma. The patient was otherwise asymptomatic. The patient was referred to a multidisciplinary cancer clinic at which endoscopic resection was determined to be the preferred treatment modality. A literature review and approach to patients with nasopharyngeal masses will be presented. CONCLUSIONS: Papillary seromucinous adenocarcinoma is a rare tumor that can present in the nasopharynx. We describe the endoscopic surgical management of one such patient that presented to our care. PMID- 23663511 TI - Methods to increase participation in organised screening programs: a systematic review. AB - BACKGROUND: The European Community recommends the implementation of population based screening programmes for cervical, breast, and colorectal cancers. This recommendation is supported by many observational studies showing that organised programmes effectively reduce mortality and control the inappropriate use of screening tests. We conducted a systematic review of studies assessing the efficacy of interventions to increase participation in organised population-based screening programs. METHODS: We included all studies on interventions aimed at increasing screening participation published between 1/1999 and 7/2012. For those published before 1999, we considered the Jepson et al. (2000) review (Health Technol Assess 4:1-133, 2000). RESULTS: Including studies from the Jepson review, we found 69 with quantitative information on interventions in organised screening: 19 for cervical, 26 for breast, 20 colorectal cancers, and 4 for cervical and breast cancer together.Effective interventions were: postal (breast RR = 1,37 95% Confidence Interval (95% CI): 1.25-1.51; cervical RR = 1.71 95% CI: 1.60-1.83; colorectal RR = 1.33 95% CI: 1.17-1.51) and telephone reminders (with heterogeneous methods for implementation); GP's signature on invitation letter (breast RR = 1.13 95% CI: 1.11-1.16; cervical RR = 1.20 95% CI: 1.10-1.30; colorectal RR = 1.15 95% CI: 1.07-1.24); scheduled appointment instead of open appointment (breast RR = 1.26 95% CI: 1.02-1.55; cervical RR = 1.49 95% CI: 1.27 1.75; colorectal RR = 1.79 95% CI: 1.65-1.93). Mailing a kit for self-sampling cervical specimens increased participation in non-responders (RR = 2.37 95% CI: 1.44-3.90). CONCLUSION: Although some interventions did prove to be effective, some specific variables may influence their effectiveness in and applicability to organised population-based screening programs. PMID- 23663513 TI - ECG phenomena: pseudopreexcitation and repolarization disturbances resembling ST elevation myocardial infarction caused by an intraatrial rhabdomyoma in a newborn. AB - As is known from other reports, a rhabdomyoma or tumor metastasis may alter intracardiac electrical conduction, producing electrical phenomena like pseudopreexcitation or repolarization disturbances resembling ST-elevation myocardial infarction or Brugada's syndrome. We present a newborn with a giant atrial rhabdomyoma and additionally multiple ventricular rhabdomyomas. He presented with several electrocardiogram (ECG) phenomena due to tumor-caused atrial depolarization and repolarization disturbances. Except from the cardiac tumors, the physical status was within normal range. Initial ECG showed a rapid atrial tachycardia with a ventricular rate of 230 bpm, which was terminated by electrical cardioversion. Afterwards, the ECG showed atrial rhythm with frequent atrial premature contractions and deformation of the PR interval with large, broad P waves and loss of discret PR segment, imposing as pseudopreexcitation. The following QRS complex was normal, with seemingly abnormal ventricular repolarization resembeling ST-elevation myocardial infarction. The atrial tumor was resected with consequent vast atrial reconstruction using patch plastic. The ventricular tumors were left without manipulation. After surgery, pseudopreexcitation and repolarization abnormalities vanished entirely and an alternans between sinus rhythm and ectopic atrial rhythm was present. These phenomena were supposably caused by isolated atrial depolarization disturbances due to tumor-caused heterogenous endocardial activation. The seemingly abnormal ventricular repolarization is probably due to repolarization of the atrial mass, superimposed on the ventricular repolarization. Recognizably, the QRS complex before and after surgical resection of the rhabdomyoma is identical, underlining the atrial origin of the repolarization abnormalities before surgery. PMID- 23663514 TI - Race/ethnicity, insurance, income and access to care: the influence of health status. AB - OBJECTIVES: To examine health care access disparities with regard to health status and presence of functional limitations, a common measure of disability and multimorbidity, after controlling for individual's race/ethnicity, insurance status and income in the U.S. using the latest survey data. METHODS: Using data from the 2009 Family Core component of the National Health Interview Survey (NHIS), we examined six measures of access to care in the twelve months prior to the interview. Covariates included self-perceived health status and the presence of functional limitations, race/ethnicity, insurance status, income, and other socioeconomic characteristics. Multiple logistic regressions were used to examine the associations. RESULTS: People with functional limitations or worse health status experience greater barriers to access. Insurance status was the single factor that was associated with all six measures of access. Disparities among racial/ethnic groups in most access indicators as well as income levels were insignificant after taking into account individuals' health status measures. CONCLUSIONS: Interventions to expand insurance coverage and the Patient Protection and Affordable Care Act are expected to contribute to reducing disparities in access to care. However, to further improve access to care, emphasis must be placed on those with poorer health status and functional limitations. PMID- 23663515 TI - Prenatal ultrasound exposure and association with postnatal hearing outcomes. AB - OBJECTIVE: Prenatal ultrasound exams have become increasingly frequent. Although no serious adverse effects are known, the public health implications would be enormous should adverse effects on auditory development be shown. This study looks to establish a possible correlation between hearing loss and increased prenatal ultrasound exposure. DESIGN: Retrospective cohort analysis. SETTING: Tertiary academic referral center. METHODS: A retrospective review of 100 children undergoing newborn hearing screening was conducted. Extensive data collection was performed, and this data was analyzed for a potential correlation between failure of newborn hearing screening and increased prenatal ultrasound exposure, as well as for a potential correlation of other variables with hearing loss. MAIN OUTCOME MEASURES: Postnatal hearing outcomes. RESULTS: A higher number of both total and 3rd trimester ultrasound exams as well as a younger gestational age at birth were all found to be significantly associated with a higher likelihood of passing the newborn hearing screen (p<0.001 for each). No other factors were found to reach statistical significance. CONCLUSIONS: Our results show that there is no correlation between a higher level of prenatal ultrasound exposure and hearing loss. Indeed, infants who had more prenatal ultrasounds in the third trimester were more likely to pass their screening hearing exams. The finding that children receiving more prenatal ultrasounds have a higher likelihood of passing newborn hearing screens serves as an excellent reminder of the classic statistics rule that correlation does not imply causation. PMID- 23663516 TI - The results of surgery for colorectal hepatic metastases following expansion of the indications in 2005. AB - AIM: Safety and survival were investigated in patients treated according to expanded surgical indications for colorectal hepatic metastases. METHOD: A retrospective analysis of all consecutive patients who underwent resection of colorectal hepatic metastases at Zhongshan Hospital from 2000 to 2010 was conducted. The patients were divided into two groups based on a change in the surgical indications introduced in 2005. Patients in Group I underwent hepatic surgery between 2000 and 2004 and those in Group II between 2005 and 2010. The clinicopathological data and survival rates of both groups were analysed. RESULTS: There were 530 patients who underwent hepatic surgery between 2000 and 2010. After the expansion of surgical indications, the rate of surgical resection rose from 25.1 to 35.1% (P < 0.05). There was no significant difference in perioperative mortality (2.2% vs 0.9%) or morbidity (20.9% vs 29.8%). Recurrence occurred in 27.5% and 36.7% in Groups I and II, respectively, and 5-year overall survival was 43% and 49%, respectively (not significant). CONCLUSION: Expanding the indications for surgical resection of hepatic metastases increased the resection rate but had no significant effect on survival. PMID- 23663517 TI - The most common aeroallergens in a tropical region in Southwestern Iran. AB - BACKGROUND: Respiratory allergies are the most important public health issues in the world. They are caused by aeroallergens which play great role in pathogenesis of respiratory allergic diseases. METHODS: The current study was conducted to evaluate the prevalence of positive skin test for various aeroallergens among allergic patients in Ahvaz, southwest Iran. 299 participants with allergic rhinitis (seasonal or perennial) were selected. Skin prick test using twenty three common allergen extracts was performed on all patients. RESULTS: The overall frequency of sensitization to any allergen was 85.6%. In outdoor allergens the most prevalent aeroallergen category was weeds (89%) followed by tree and grasses, and in indoor allergens, mites (43%) were the most prevalent aeroallergen. The mean and median numbers of positive test reactions among those with positive test responses were 11.5 and 13.0, respectively. 84% of patients were poly-sensitised and about 50% of them were sensitised to more than twelve different allergens. CONCLUSION: The results of the study revealed that prevalence of the skin prick reactivity to weed pollens is significant in southwest Iran and multiple sensitizations were common. PMID- 23663518 TI - Effects of light-emitting diodes on muscle fatigue and exercise tolerance in patients with COPD: study protocol for a randomized controlled trial. AB - BACKGROUND: Light-emitting diodes (LED) have been used to minimize muscle fatigue in athletes and healthy subjects. Patients with chronic obstructive pulmonary disease (COPD) are susceptible to early muscle fatigue. OBJECTIVE: The objective of this study is to investigate the acute effects of LED on muscle function, exercise capacity and cardiorespiratory responses during isometric and dynamic exercise in patients with COPD. METHODS: This study will assess 30 patients with moderate to severe obstruction (forced expiratory volume-one second,FEV1 <=70% predicted). Isometric and dynamic protocols will be conducted in two visits each, for a total of four visits a week apart. First, venous blood will be taken from the patients. The isometric protocol will start with the determination of the maximum voluntary isometric contraction (MIVC) to determine the workload (60% of MIVC) for the isometric endurance test (IET). Patients will be randomized to receive either the placebo or LED application (each point will be irradiated for 30 s and the energy received at each point will be 41.7 J). Immediately after finishing this procedure, the patients will carry out the IET until the limit of tolerance or until a 20% fall of strength is observed. After the test, another blood draw will be taken. In another visit (one week later), the same order of procedures will be performed, except with the opposite (LED or placebo). For the dynamic endurance test (DET), the same procedures described above will be followed, except with 75% of the maximal workload obtained from the incremental cycle ergometer test used instead of the IET. The electromyography will be recorded during the isometric and dynamic protocols. Differences in muscle function, exercise capacity and cardiorespiratory responses between the LED and placebo applications will be analyzed. The therapeutic effects of LED could minimize muscle fatigue in patients with COPD by increasing exercise tolerance. TRIAL REGISTRATION: TRIAL REGISTRATION NUMBER: NCT01448564. PMID- 23663519 TI - Arthroaspis n. gen., a common element of the Sirius Passet Lagerstatte (Cambrian, North Greenland), sheds light on trilobite ancestry. AB - BACKGROUND: Exceptionally preserved Palaeozoic faunas have yielded a plethora of trilobite-like arthropods, often referred to as lamellipedians. Among these, Artiopoda is supposed to contain taxa united by a distinctive appendage structure. This includes several well supported groups, Helmetiida, Nektaspida, and Trilobita, as well as a number of problematic taxa. Interrelationships remain unclear, and the position of the lamellipedian arthropods as a whole also remains the subject of debate. RESULTS: Arthroaspis bergstroemi n. gen. n. sp., a new arthropod from the early Cambrian Sirius Passet Lagerstatte of North Greenland shows a striking combination of both dorsal and ventral characters of Helmetiida, Nektaspida, and Trilobita. Cladistic analysis with a broad taxon sampling of predominantly early Palaeozoic arthropods yields a monophyletic Lamellipedia as sister taxon to the Crustacea or Tetraconata. Artiopoda is resolved as paraphyletic, giving rise to the Marrellomorpha. Within Lamellipedia, a clade of pygidium bearing taxa is resolved that can be shown to have a broadly helmetiid like tergite morphology in its ground pattern. This morphology is plesiomorphically retained in Helmetiida and in Arthroaspis, which falls basally into a clade containing Trilobita. The trilobite appendages, though similar to those of other lamellipedians in gross morphology, have a unique outward rotation of the anterior trunk appendages, resulting in a 'hard wired' lateral splay, different to that observed in other Lamellipedia. CONCLUSIONS: The combination of helmetiid, trilobite, and nektaspid characters in Arthroaspis gives important hints concerning character polarisation within the trilobite-like arthropods. The distinctive tergite morphology of trilobites, with its sophisticated articulating devices, is derived from flanged edge-to-edge articulating tergites forming a shield similar to the helmetiids, previously considered autapomorphic for that group. The stereotypical lateral splay of the appendages of lamellipedians is a homoplastic character shown to be achieved by several groups independently. PMID- 23663520 TI - Molecular apocrine breast cancers are aggressive estrogen receptor negative tumors overexpressing either HER2 or GCDFP15. AB - INTRODUCTION: Molecular apocrine (MA) tumors are estrogen receptor (ER) negative breast cancers characterized by androgen receptor (AR) expression. We analyzed a group of 58 transcriptionally defined MA tumors and proposed a new tool to identify these tumors. METHODS: We performed quantitative reverse transcription PCR (qRT-PCR) for ESR1, AR, FOXA1 and AR-related genes, and immunohistochemistry (IHC) for ER, PR, Human Epidermal Growth Factor Receptor 2 (HER2), CK5/6, CK17, EGFR, Ki67, AR, FOXA1 and GCDFP15 and we analyzed clinical features. RESULTS: MA tumors were all characterized by ESR1(-) AR(+) FOXA1(+) and AR-related genes positive mRNA profile. IHC staining on these tumors showed 93% ER(-), only 58% AR(+) and 90% FOXA1(+). 67% and 57% MA tumors were HER2(3+) and GCDFP15(+), respectively. Almost all MA tumors (94%) had the IHC signature HER2(3+) or GCDFP15(+) but none of the 13 control basal-like (BL) tumors did. Clinically, MA tumors were rather aggressive, with poor prognostic factors. CONCLUSION: MA tumors could be better defined by their qRT-PCR-AR profile than by AR IHC. In addition, we found that HER2 or GCDFP15 protein overexpression is a sensitive and specific tool to differentiate MA from BL in the context of ER negative tumors. A composite molecular and IHC signature could, therefore, help to identify MA tumors in daily practice. PMID- 23663521 TI - The effectiveness of proactive telephone support provided to breastfeeding mothers of preterm infants: study protocol for a randomized controlled trial. AB - BACKGROUND: Although breast milk has numerous benefits for infants' development, with greater effects in those born preterm (at < 37 gestational weeks), mothers of preterm infants have shorter breastfeeding duration than mothers of term infants. One of the explanations proposed is the difficulties in the transition from a Neonatal Intensive Care Unit (NICU) to the home environment. A person centred proactive telephone support intervention after discharge from NICU is expected to promote mothers' sense of trust in their own capacity and thereby facilitate breastfeeding. METHODS/DESIGN: A multicentre randomized controlled trial has been designed to evaluate the effectiveness and cost-effectiveness of person-centred proactive telephone support on breastfeeding outcomes for mothers of preterm infants. Participating mothers will be randomized to either an intervention group or control group. In the intervention group person-centred proactive telephone support will be provided, in which the support team phones the mother daily for up to 14 days after hospital discharge. In the control group, mothers are offered a person-centred reactive support where mothers can phone the breastfeeding support team up to day 14 after hospital discharge. The intervention group will also be offered the same reactive telephone support as the control group. A stratified block randomization will be used; group allocation will be by high or low socioeconomic status and by NICU. Recruitment will be performed continuously until 1116 mothers (I: 558 C: 558) have been included. PRIMARY OUTCOME: proportion of mothers exclusively breastfeeding at eight weeks after discharge. SECONDARY OUTCOMES: proportion of breastfeeding (exclusive, partial, none and method of feeding), mothers satisfaction with breastfeeding, attachment, stress and quality of life in mothers/partners at eight weeks after hospital discharge and at six months postnatal age. Data will be collected by researchers blind to group allocation for the primary outcome. A qualitative evaluation of experiences of receiving/providing the intervention will also be undertaken with mothers and staff. DISCUSSION: This paper presents the rationale, study design and protocol for a RCT providing person-centred proactive telephone support to mothers of preterm infants. Furthermore, with a health economic evaluation, the cost-effectiveness of the intervention will be assessed. PMID- 23663522 TI - Quantification of left ventricular trabeculae using fractal analysis. AB - BACKGROUND: Left ventricular noncompaction (LVNC) is a myocardial disorder characterized by excessive left ventricular (LV) trabeculae. Current methods for quantification of LV trabeculae have limitations. The aim of this study is to describe a novel technique for quantifying LV trabeculation using cardiovascular magnetic resonance (CMR) and fractal geometry. Observing that trabeculae appear complex and irregular, we hypothesize that measuring the fractal dimension (FD) of the endocardial border provides a quantitative parameter that can be used to distinguish normal from abnormal trabecular patterns. METHODS: Fractal analysis is a method of quantifying complex geometric patterns in biological structures. The resulting FD is a unitless measure index of how completely the object fills space. FD increases with increased structural complexity. LV FD was measured using a box-counting method on CMR short-axis cine stacks. Three groups were studied: LVNC (defined by Jenni criteria), n=30(age 41+/-13; men, 16); healthy whites, n=75(age, 46+/-16; men, 36); healthy blacks, n=30(age, 40+/-11; men, 15). RESULTS: In healthy volunteers FD varied in a characteristic pattern from base to apex along the LV. This pattern was altered in LVNC where apical FD were abnormally elevated. In healthy volunteers, blacks had higher FD than whites in the apical third of the LV (maximal apical FD: 1.253+/-0.005 vs. 1.235+/-0.004, p<0.01) (mean+/-s.e.m.). Comparing LVNC with healthy volunteers, maximal apical FD was higher in LVNC (1.392+/-0.010, p<0.00001). The fractal method was more accurate and reproducible (ICC, 0.97 and 0.96 for intra and inter-observer readings) than two other CMR criteria for LVNC (Petersen and Jacquier). CONCLUSIONS: FD is higher in LVNC patients compared to healthy volunteers and is higher in healthy blacks than in whites. Fractal analysis provides a quantitative measure of trabeculation and has high reproducibility and accuracy for LVNC diagnosis when compared to current CMR criteria. PMID- 23663524 TI - Skull-bound perception and precision optimization through culture. AB - Clark acknowledges but resists the indirect mind-world relation inherent in prediction error minimization (PEM). But directness should also be resisted. This creates a puzzle, which calls for reconceptualization of the relation. We suggest that a causal conception captures both aspects. With this conception, aspects of situated cognition, social interaction and culture can be understood as emerging through precision optimization. PMID- 23663523 TI - Physiological stressors and invasive plant infections alter the small RNA transcriptome of the rice blast fungus, Magnaporthe oryzae. AB - BACKGROUND: The rice blast fungus, Magnaporthe oryzae is a destructive pathogen of rice and other related crops, causing significant yield losses worldwide. Endogenous small RNAs (sRNAs), including small interfering RNAs (siRNAs) and microRNAs (miRNAs) are critical components of gene regulation in many eukaryotic organisms. Recently several new species of sRNAs have been identified in fungi. This fact along with the availability of genome sequence makes M. oryzae a compelling target for sRNA profiling. We have examined sRNA species and their biosynthetic genes in M. oryzae, and the degree to which these elements regulate fungal stress responses. To this end, we have characterized sRNAs under different physiological stress conditions, which had not yet been examined in this fungus. RESULTS: The resulting libraries are composed of more than 37 million total genome matched reads mapping to intergenic regions, coding sequences, retrotransposons, inverted, tandem, and other repeated regions of the genome with more than half of the small RNAs arising from intergenic regions. The 24 nucleotide (nt) size class of sRNAs was predominant. A comparison to transcriptional data of M. oryzae undergoing the same physiological stresses indicates that sRNAs play a role in transcriptional regulation for a small subset of genes. Support for this idea comes from generation and characterization of mutants putatively involved in sRNAs biogenesis; our results indicate that the deletion of Dicer-like genes and an RNA-Dependent RNA Polymerase gene increases the transcriptional regulation of this subset of genes, including one involved in virulence. CONCLUSIONS: Various physiological stressors and in planta conditions alter the small RNA profile of the rice blast fungus. Characterization of sRNA biosynthetic mutants helps to clarify the role of sRNAs in transcriptional control. PMID- 23663525 TI - Unraveling the mind. AB - A radical interpretation of the predictive coding approach suggests that the mind is "seamless" - that is, that cancellation of error signals can propagate smoothly from highest to lowest levels of the control hierarchy, dissolving a distinction between belief and perception. Delusions of alien control provide a test case. Close examination suggests that while they are evidence of predictive coding within the cortex, they are not evidence for the seamless interpretation. PMID- 23663526 TI - Impact of intestinal electrical stimulation on nutrient-induced GLP-1 secretion in vivo. AB - BACKGROUND: Increases in L-cell release of GLP-1 are proposed to serve as a negative feedback signal for postprandial changes in gastric emptying and/or motility. Previous ex vivo data suggests that direct electrical stimulation (E stim) of ileal segments stimulates secretion of GLP-1. This suggests potential feed-forward increases in GLP-1 driven by intestinal neuronal and/or motor activity. METHODS: To determine if E-stim could increase GLP-1 levels in an in vivo setting, we administered E-stim and nutrients to male Long- Evans rats (300 350 g) under general anesthesia. KEY RESULTS: Nutrient infusion into the duodenum or ileum significantly increased plasma GLP-1 levels, but E-stim applied to these locations did not (P < 0.05). However, the combination of E-stim and nutrient infusion, in either the ileum or duodenum, significantly increased plasma GLP-1 when compared to nutrient infusion alone (P < 0.05), and this effect was not blocked by either norepinephrine or atropine. To test the impact of intestinal motor activity, the effect of extra-luminal mechanical stimulation (M-stim) on GLP-1 levels was assessed. In the duodenum, but not the ileum, M-stim plus nutrient infusion significantly increased GLP-1 over nutrient infusion or M-stim alone (P < 0.05). CONCLUSIONS & INFERENCES: Thus, both E- and M-stim of the duodenum, but only E-stim of the ileum augmented nutrient-stimulated GLP-1 release. These data demonstrate that factors beyond enteral nutrients could contribute to the regulation of GLP-1 secretion. PMID- 23663528 TI - Patellar tendon ossification after anterior cruciate ligament reconstruction using bone--patellar tendon--bone autograft. AB - BACKGROUND: Among the various complications described in literature, the patellar tendon ossification is an uncommon occurrence in anterior cruciate ligament (ACL) reconstruction using bone - patellar tendon - bone graft (BPTB). The heterotopic ossification is linked to knee traumatism, intramedullary nailing of the tibia and after partial patellectomy, but only two cases of this event linked to ACL surgery have been reported in literature. CASE PRESENTATION: We present a case of a 42-year-old Caucasian man affected by symptomatic extended heterotopic ossification of patellar tendon after 20 months from ACL reconstruction using BPTB. The clinical diagnosis was confirmed by Ultrasound, X-Ray and Computed Tomography studies, blood tests were performed to exclude metabolic diseases then the surgical removal of the lesion was performed. After three years from surgery, the patient did not report femoro-patellar pain, there was not range of motion limitation and the clinical-radiological examinations resulted negative. CONCLUSION: The surgical removal of the ossifications followed by anti inflammatory therapy, seems to be useful in order to relieve pain and to prevent relapses. Moreover, a thorough cleaning of the patellar tendon may reveal useful, in order to prevent bone fragments remain inside it and to reduce patellar tendon heterotopic ossification risk. PMID- 23663527 TI - A specific immune transcriptomic profile discriminates chronic kidney disease patients in predialysis from hemodialyzed patients. AB - BACKGROUND: Chronic kidney disease (CKD) patients present a complex interaction between the innate and adaptive immune systems, in which immune activation (hypercytokinemia and acute-phase response) and immune suppression (impairment of response to infections and poor development of adaptive immunity) coexist. In this setting, circulating uremic toxins and microinflammation play a critical role. This condition, already present in the last stages of renal damage, seems to be enhanced by the contact of blood with bioincompatible extracorporeal hemodialysis (HD) devices. However, although largely described, the cellular machinery associated to the CKD- and HD-related immune-dysfunction is still poorly defined. Understanding the mechanisms behind this important complication may generate a perspective for improving patients outcome. METHODS: To better recognize the biological bases of the CKD-related immune dysfunction and to identify differences between CKD patients in conservative (CKD) from those in HD treatment, we used an high-throughput strategy (microarray) combined with classical bio-molecular approaches. RESULTS: Immune transcriptomic screening of peripheral blood mononuclear cells (1030 gene probe sets selected by Gene Ontology) showed that 275 gene probe sets (corresponding to 213 genes) discriminated 9 CKD patients stage III-IV (mean+/-SD of eGFR: 32.27+/-14.7 ml/min) from 17 HD patients (p<0.0001, FDR=5%). Seventy-one genes were up- and 142 down-regulated in HD patients. Functional analysis revealed, then, close biological links among the selected genes with a pivotal role of PTX3, IL-15 (up regulated in HD) and HLA-G (down-regulated in HD). ELISA, performed on an independent testing-group [11 CKD stage III-IV (mean+/-SD of eGFR: 30.26+/-14.89 ml/min) and 13 HD] confirmed that HLA-G, a protein with inhibition effects on several immunological cell lines including natural killers (NK), was down expressed in HD (p=0.04). Additionally, in the testing-group, protein levels of CX3CR1, an highly selective chemokine receptor and surface marker for cytotoxic effector lymphocytes, resulted higher expressed in HD compared to CKD (p<0.01). CONCLUSION: Taken together our results show, for the first time, that HD patients present a different immune-pattern compared to the un-dialyzed CKD patients. Among the selected genes, some of them encode for important biological elements involved in proliferation/activation of cytotoxic effector lymphocytes and in the immune-inflammatory cellular machinery. Additionally, this study reveals new potential diagnostic bio-markers and therapeutic targets. PMID- 23663529 TI - Substance use, dental hygiene, and physical activity in adult patients with single ventricle physiology. AB - OBJECTIVES: The study aims to describe substance use, dental hygiene, and physical activity in adult survivors with single ventricle physiology (SVP) and to compare the behaviors with matched controls, while the patients are particularly at risk for general health problems. DESIGN: The present study is part of a larger research project on long-term outcomes in adult patients with SVP. A cross-sectional, case-control study including 59 patients out of 83 eligible patients participated in the study (response rate 71%). The patients were matched to 172 healthy controls. A questionnaire was mailed to the patients. Nonresponders did not differ significantly from the included participants on age, gender, or physical function. SETTING: The study was conducted at the Heart Center of Copenhagen University Hospital or the Department of Cardiology, Aarhus University Hospital. RESULTS: In these patients, 85% report alcohol consumption (92% in controls; odds ratio [OR] = 0.91; P = 0.575); 26% admit "binge drinking" (41% in controls; OR = 0.56; P = 0.041); 20% are cigarette smokers (36% in controls; OR = 0.59; P = 0.100); 12% have used cannabis over the past year (15% in controls; OR = 0.80; P = 0.596); 20% have had no dental visits during the last year (25% in controls; OR = 1.07; P = 0.684); 46% are not flossing their teeth (32% in controls; OR = 1.32; P = 0.239); and 39% are not physically active (24% in controls; OR = 1.63; P = 0.069). CONCLUSIONS: While in general there was no significant differences in overall health behaviors between SVP patients and controls, SVP patients are less physically active and are less likely to binge drink. PMID- 23663530 TI - Geographical variation of unmet medical needs in Italy: a multivariate logistic regression analysis. AB - BACKGROUND: Unmet health needs should be, in theory, a minor issue in Italy where a publicly funded and universally accessible health system exists. This, however, does not seem to be the case. Moreover, in the last two decades responsibilities for health care have been progressively decentralized to regional governments, which have differently organized health service delivery within their territories. Regional decision-making has affected the use of health care services, further increasing the existing geographical disparities in the access to care across the country. This study aims at comparing self-perceived unmet needs across Italian regions and assessing how the reported reasons - grouped into the categories of availability, accessibility and acceptability - vary geographically. METHODS: Data from the 2006 Italian component of the European Union Statistics on Income and Living Conditions are employed to explore reasons and predictors of self-reported unmet medical needs among 45,175 Italian respondents aged 18 and over. Multivariate logistic regression models are used to determine adjusted rates for overall unmet medical needs and for each of the three categories of reasons. RESULTS: Results show that, overall, 6.9% of the Italian population stated having experienced at least one unmet medical need during the last 12 months. The unadjusted rates vary markedly across regions, thus resulting in a clear-cut north-south divide (4.6% in the North-East vs. 10.6% in the South). Among those reporting unmet medical needs, the leading reason was problems of accessibility related to cost or transportation (45.5%), followed by acceptability (26.4%) and availability due to the presence of too long waiting lists (21.4%). In the South, more than one out of two individuals with an unmet need refrained from seeing a physician due to economic reasons. In the northern regions, working and family responsibilities contribute relatively more to the underutilization of medical services. Logistic regression results suggest that some population groups are more vulnerable than others to experiencing unmet health needs and to reporting some categories of reasons. Adjusting for the predictors resulted in very few changes in the rank order of macro-area rates. CONCLUSIONS: Policies to address unmet health care needs should adopt a multidimensional approach and be tailored so as to consider such geographical heterogeneities. PMID- 23663531 TI - Backwards is the way forward: feedback in the cortical hierarchy predicts the expected future. AB - Clark offers a powerful description of the brain as a prediction machine, which offers progress on two distinct levels. First, on an abstract conceptual level, it provides a unifying framework for perception, action, and cognition (including subdivisions such as attention, expectation, and imagination). Second, hierarchical prediction offers progress on a concrete descriptive level for testing and constraining conceptual elements and mechanisms of predictive coding models (estimation of predictions, prediction errors, and internal models). PMID- 23663532 TI - Colorectal neoplasia in long-standing ulcerative colitis - a prospective study from a low-prevalence area. AB - AIM: Despite increasing recognition of ulcerative colitis (UC) in Asia in recent decades, reports on the occurrence of colorectal neoplasia (CRN) in UC are scarce and surveillance for this complication is not routinely practised in this region. We aimed to assess the outcome of a newly initiated pilot screening programme for screening CRN among UC patients in India. METHOD: In this prospective study from an academic hospital setting, patients with UC at high risk of CRN were offered screening by magnifying chromocolonoscopy and the frequency of neoplastic lesions was assessed. RESULTS: Twenty-nine (70.7%) of 41 eligible patients [a median age of 46 (interquartile range 36-54.5) years; 17 (58.6%) men] enrolled for surveillance; 41 colonoscopies were undertaken over 42 months. The median disease duration was 10 (interquartile range 7.5-14.5) years. Sixteen (55.1%) had extensive colitis. On initial screening, low-grade dysplasia (LGD) was seen in five (17.2%) and high-grade dysplasia (HGD) in three (10.3%). Of these three, one accepted proctocolectomy immediately, one underwent surgery for adenocarcinoma and one refused surgery. Twelve follow-up colonoscopies in nine patients revealed three new LGD. CONCLUSIONS: High-grade dysplasia and subsequent adenocarcinoma can be detected with careful follow-up in Indian patients with long-standing UC but acceptance of surveillance and subsequent therapy are suboptimal. We found evidence that screening and surveillance programmes are useful for detecting neoplasias in UC, and need to be customized for this region. PMID- 23663533 TI - Medical orders for life-sustaining treatment: is it time yet? AB - OBJECTIVE: As the aging population faces complex end-of-life issues, we studied the intervals between long-term care admission and advance directive completion, and between completion and death. We also sought to determine the interdisciplinary team's compliance with documented wishes. METHOD: A cross sectional study of 182 long-term care residents in two facilities with and without completed medical orders for life-sustaining treatment (MOLST) in the New York Metropolitan area was conducted. Demographic variables included: gender, age, ethnicity, and diagnosis. Measures included: admission date, MOLST execution date, and date of death. Resident advance directive documentation was compared with clinical intervention at time of death, including intubation and mechanical ventilation. RESULTS: Of the residents studied, 68.7% were female, 91% were Caucasian and 91.8% were >= 65 years of age (mean age: 83). The median time from admission to MOLST signing was 48 days. Median time from admission to MOLST signing for Caucasians was 21 days; for non-Caucasians was 229 days. Fifty-two percent of MOLST were signed by children, and 24% by residents. Of those with signed forms, 25% signed on day of admission, 37% signed within 7 days, and 47% signed within 21 days. Only 3% of residents died the day their MOLST was signed, whereas 12% died within a week, and 22% died within 30 days. Finally, among the 68 subjects who signed a MOLST and died, 87% had their wishes met. SIGNIFICANCE OF RESULTS: In this era of growing time constraints and increased regulations, medical directors of long-term care facilities and those team members caring for residents urgently need a clear and simple approach to the goals of care for their residents. The MOLST is an ideal tool in caring for older adults at the end of life, providing concrete guidance, not only with regard to do not resuscitate (DNR) and do not intubate (DNI) orders, but also for practical approaches to daily care for the interdisciplinary team. PMID- 23663534 TI - Mindfulness-based intervention for teenagers with cancer: study protocol for a randomized controlled trial. AB - BACKGROUND: Individuals living with cancer must learn to face not only the physical symptoms of their condition, but also the anxiety and uncertainty related to the progression of the disease, the anticipation of physical and emotional pain related to illness and treatment, the significant changes implied in living with cancer, as well as the fear of recurrence after remission. Mindfulness-based meditation constitutes a promising option to alleviate these manifestations. METHODS/DESIGN: This article presents the rationale and protocol development for a research project aimed at evaluating the effects of a mindfulness-based meditation intervention on quality of life, sleep, and mood in adolescents with cancer compared to a control group. A prospective, longitudinal, experimental design involving three time points (baseline, post-intervention, and follow-up) and two groups (experimental and control) was developed for this project. Participants will be assigned randomly to either group. Eligible participants are adolescents aged 11 to 18 years with a diagnosis of cancer, with no specific selection/exclusion based on type, stage, or trajectory of cancer. A final sample size of 28 participants is targeted. Adolescents in the experimental group will be completing the mindfulness meditation intervention, taught by two trained therapists. The intervention will comprise of eight weekly sessions, lasting 90 min each. Once the follow-up assessment is completed by the experimental group, wait-list controls will be offered to complete the mindfulness-based program. Intra-group analyses will serve to evaluate the impact of the mindfulness-based meditation intervention on quality of life, sleep, and mood pre-post intervention, as well as follow-up. Analyses will also be used to carry out inter-group comparisons between the experimental group and the wait list controls. Voluntary participation, risk of attrition, and the small sample size are potential limitations of this project. In spite of possible limitations, this project will be one among very few aimed at improving quality of life, sleep, and mood in adolescents living with cancer, will evaluate the potential benefits of such a practice on both psychological and physical health of youth with cancer, and help in creating mindfulness-based intervention programs, in order to provide the necessary psychological help to adolescents living with cancer. TRIAL REGISTRATION: TRIAL REGISTRATION NUMBER: NCT01783418. PMID- 23663535 TI - Inter-study reproducibility of cardiovascular magnetic resonance tagging. AB - BACKGROUND: The aim of this study is to determine the test-retest reliability of the measurement of regional myocardial function by cardiovascular magnetic resonance (CMR) tagging using spatial modulation of magnetization. METHODS: Twenty-five participants underwent CMR tagging twice over 12 +/- 7 days. To assess the role of slice orientation on strain measurement, two healthy volunteers had a first exam, followed by image acquisition repeated with slices rotated +/-15 degrees out of true short axis, followed by a second exam in the true short axis plane. To assess the role of slice location, two healthy volunteers had whole heart tagging. The harmonic phase (HARP) method was used to analyze the tagged images. Peak midwall circumferential strain (Ecc), radial strain (Err), Lambda 1, Lambda 2, and Angle alpha were determined in basal, mid and apical slices. LV torsion, systolic and early diastolic circumferential strain and torsion rates were also determined. RESULTS: LV Ecc and torsion had excellent intra-, interobserver, and inter-study intra-class correlation coefficients (ICC range, 0.7 to 0.9). Err, Lambda 1, Lambda 2 and angle had excellent intra- and interobserver ICC than inter-study ICC. Angle had least inter-study reproducibility. Torsion rates had superior intra-, interobserver, and inter-study reproducibility to strain rates. The measurements of LV Ecc were comparable in all three slices with different short axis orientations (standard deviation of mean Ecc was 0.09, 0.18 and 0.16 at basal, mid and apical slices, respectively). The mean difference in LV Ecc between slices was more pronounced in most of the basal slices compared to the rest of the heart. CONCLUSIONS: Intraobserver and interobserver reproducibility of all strain and torsion parameters was excellent. Inter-study reproducibility of CMR tagging by SPAMM varied between different parameters as described in the results above and was superior for Ecc and LV torsion. The variation in LV Ecc measurement due to altered slice orientation is negligible compared to the variation due to slice location. TRIAL REGISTRATION: This trial is registered as NCT00005487 at National Heart, Lung and Blood institute. PMID- 23663536 TI - The ototoxic effect of intratympanic terbinafine applied in the middle ear of rats. AB - BACKGROUND: Otomycosis is defined as an infection of the external ear canal with fungal agents. The treatment of the disease is cleansing and drying of the external ear canal, identification and treatment of any predisposing factors and application of topical antifungal agents. Terbinafine is used as an antifungal agent to treat otomycosis. We proposed to investigate the probable ototoxic effect of terbinafine solution on auditory brain stem response (ABR) and distortion product otoacoustic emission (DPOAE) when applied intratympanically in the middle ear of rats. METHODS: The experiment was performed on 30 female Wistar albino rats. Thirty animals were divided into three groups of 10 animals each. 1% terbinafine solution was administered to the first group (group T). The second group (group G) was administered 40 mg/ml gentamicin solution (ototoxic control). The third group (group S) was administered saline solution (negative control). Baseline DPOAE measurements and ABR testing from the left ears were obtained from the animals in all groups under general anesthesia. Ear solutions were applied in the middle ear intratympanically with a dental needle. Treatment was initiated after baseline measurements and repeated once every two days for fifteen days. RESULTS: Pre and post-treatment DPOAE responses for all tested frequencies of group T and Group S showed no statistically significant difference. However, the group G demonstrated a significant change in ABR thresholds and DPOAE responses. CONCLUSIONS: Terbinafine solution is a broad spectrum antifungal agent effective in the treatment of otomycosis. The present study demonstrated that its direct administration in the middle ear of rats does not affect inner ear function as measured by ABR and DPOAE responses. PMID- 23663539 TI - Dental implants-induced task-specific oromandibular dystonia. PMID- 23663537 TI - Variants in the 3' UTR of general Transcription factor IIF, polypeptide 2 affect female calving efficiency in Japanese Black cattle. AB - BACKGROUND: Calving efficiency can be described as the measure of a cow's ability to produce viable offspring within a specific period of time. This trait is crucial in beef cattle because calves are necessary both for the production of beef and for heifer replacements. Recently, the number of calves produced at 4 years of age (NCP4) has been used to evaluate the calving efficiency of Japanese Black cattle. To identify variants associated with calving efficiency in Japanese Black cattle, we conducted a genome-wide association study (GWAS) using 688 animals with extreme NCP4 values selected from 15,225 animals. RESULTS: We identified genetic variants on bovine chromosome 12 (BTA12) that were associated with NCP4. The General Transcription Factor IIF, polypeptide 2 (GTF2F2), located in the 132 kbp-associated region, proved to be in strong linkage disequilibrium. We found 15 associated variants in the promoter and the 3' UTR regions. Consistent with this finding, transcripts of GTF2F2 derived from the haplotype (Q) with the increased number of calves were 1.33-fold more abundant than q derived transcripts. Furthermore, luciferase assays revealed that the activity of the 3' UTR, a region that includes nine SNPs, was higher in constructs with the Q haplotype than in those with the q haplotype by approximately 1.35-fold. In contrast, the activity of the promoter region did not differ between haplotypes. The association was replicated in an independent sample of 827 animals that were randomly selected from the remainder of the cohort from the same farms used in the GWAS. In the replicated population, the frequency of the Q haplotype is 0.313, and this haplotype accounts for 2.69% of the total phenotypic variance. The effect of the Q to q haplotype substitution on NCP4 was 0.054 calves. These findings suggest that variants in the 3' UTR of GTF2F2 affect the level of GTF2F2 mRNA, which is associated with calving efficiency. CONCLUSIONS: This GWAS has identified variants in the 3' UTR of GTF2F2 that were associated with the NCP4 of Japanese Black cattle, and this association was validated in an independent sample. The Q haplotype will be immediately useful in improving the calving efficiency of Japanese Black cattle. PMID- 23663538 TI - Postictal psychosis in temporal lobe epilepsy: a case-control study. AB - BACKGROUND AND PURPOSE: To investigate the prevalence of postictal psychosis (PP) in patients with temporal lobe epilepsy (TLE) and to estimate the predictive value of various variables for the development of PP. METHODS: By retrospectively reviewing the charts of all patients evaluated with video-electroencephalogram (EEG)-monitoring at our unit between January 1995 and February 2012, we identified 684 patients with TLE, of which 48 patients had a history of PP. Patients with TLE and PP were compared with 200 controls (patients with TLE without a psychotic history) on demographic, clinical, EEG and magnetic resonance imaging (MRI) variables. RESULTS: The prevalence of PP in our TLE sample was 7.0%. Aggressive behaviour during PP was present in 22.9% of the sample. Univariate analysis revealed that PP was significantly associated with early age at epilepsy onset (P = 0.007), longer duration of epilepsy (P = 0.002), presence of ictal fear (P = 0.005), impaired intellectual function (P = 0.045), and bilateral ictal and interictal epileptiform activity (both P < 0.0001). Using logistic regression analysis, ictal fear [odds ratio (OR) 2.88; P = 0.015] and bilateral interictal EEG activity (OR 6.40; P < 0.0001) were predictive of PP development. No association of PP with MRI pathology or epilepsy-relevant aetiological factors was found. CONCLUSIONS: PP is a frequent and potentially dangerous complication within the course of TLE. Bilateral or widespread functional central nervous system disturbances rather than distinct structural brain alterations or certain predisposing aetiologies of epilepsy appear to be a risk factor for the development of PP. Ictal fear may be a predictive clinical variable of PP in TLE. PMID- 23663540 TI - Severe microcephaly with polynodular heterotopia: a high-field MRI and neuropathological case study. PMID- 23663541 TI - Exacerbation of restless legs syndrome presenting as a psychiatric emergency. PMID- 23663542 TI - The prevalence of left atrial appendage thrombus and spontaneous echocardiographic contrast is positively correlated with the CHADS2 and CHA2 DS2 VASc scores. PMID- 23663543 TI - Response to the letter: 'The prevalence of left atrial appendage thrombus and spontaneous echocardiographic contrast is positively correlated with the CHADS2 and CHA2 DS2 -VASc scores'. PMID- 23663545 TI - Effect of avian influenza A H5N1 infection on the expression of microRNA-141 in human respiratory epithelial cells. AB - BACKGROUND: Avian influenza remains a serious threat to human health. The consequence of human infection varies markedly among different subtypes of avian influenza viruses. In addition to viral factors, the difference in host cellular response is likely to play a critical role. This study aims at elucidating how avian influenza infection perturbs the host's miRNA regulatory pathways that may lead to adverse pathological events, such as cytokine storm, using the miRNA microarray approach. RESULTS: The results showed that dysregulation of miRNA expression was mainly observed in highly pathogenic avian influenza A H5N1 infection. We found that miR-21*, miR-100*, miR-141, miR-574-3p, miR-1274a and miR1274b were differentially expressed in response to influenza A virus infection. Interestingly, we demonstrated that miR-141, which was more highly induced by H5N1 than by H1N1 (p < 0.05), had an ability to suppress the expression of a cytokine - transforming growth factor (TGF)-beta2. This was supported by the observation that the inhibitory effect could be reversed by antagomiR-141. CONCLUSIONS: Since TGF-beta2 is an important cytokine that can act as both an immunosuppressive agent and a potent proinflammatory molecule through its ability to attract and regulate inflammatory molecules, and previous report showed that only seasonal influenza H1N1 (but not the other avian influenza subtypes) could induce a persistent expression of TGF-beta2, we speculate that the modulation of TGF-beta2 expression by different influenza subtypes via miR 141 might be a critical step for determining the outcome of either normal or excessive inflammation progression. PMID- 23663546 TI - Hospital outcomes for paediatric pneumonia and diarrhoea patients admitted in a tertiary hospital on weekdays versus weekends: a retrospective study. AB - BACKGROUND: Quality of patient care in hospitals has been shown to be inconsistent during weekends and night-time hours, and is often associated with reduced patient monitoring, poor antibiotic prescription practices and poor patient outcomes. Poorer care and outcomes are commonly attributed to decreased levels of staffing, supervision and expertise and poorer access to diagnostics. However, there are few studies examining this issue in low resource settings where mortality from common childhood illnesses is high and health care systems are weak. METHODS: This study uses data from a retrospective cross-sectional study aimed at "evaluating the uptake of best practice clinical guidelines in a tertiary hospital" with a pre and post intervention approach that spanned the period 2005 to 2009. We evaluated a primary hypothesis that mortality for children with pneumonia and/or dehydration aged 2-59 months admitted on weekends differed from those admitted on weekdays. A secondary hypothesis that poor quality of care could be a mechanism for higher mortality was also explored. Logistic regression was used to examine the association between mortality and the independent predictors of mortality. RESULTS: Our analysis indicates that there is no difference in mortality on weekends compared to weekdays even after adjusting for the significant predictors of mortality (OR = 1.15; 95% CI 0.90 1.45; p = 0.27). There were similarly no significant differences between weekends and weekdays for the quality of care indicators, however, there was an overall improvement in mortality and quality of care through the period of study. CONCLUSION: Mortality and the quality of care does not differ by the day of admission in a Kenyan tertiary hospital, however mortality remains high suggesting that continued efforts to improve care are warranted. PMID- 23663547 TI - Association between autoimmune reactions and severity of atopic dermatitis in children with herpes virus infection. AB - BACKGROUND: Patients with atopic dermatitis (AD) can develop autoantibodies against intracellular proteins. AD patients often suffer from herpes viruses (HV) infection which complicates the inflammatory process in the skin. The aim of the study was to reveal IgE and IgG antibodies (abs) specific to some skin antigens and to compare their levels with the severity of AD with HV infection in children. METHODS: IgE and IgG abs specific to tissue antigens, total IgE, IgE abs to environmental common allergens as well as IgG abs specific to HV were detected in serum samples by ELISA in 157 AD children. RESULTS: IgE and IgG antibody production to keratin and elastin was observed in children with AD and elevated proportionally to the severity of AD. IgG - abs to herpes simplex virus was increased in children and associated with the severity of clinical course of AD. CONCLUSION: Our data shown that clinical course of severe AD is accompanied with autoimmune response to epidermal antigens (keratin and elastin). Elevated levels of the autoantibodies, especially against the background of HV infection may be useful serological parameter for monitoring of the disease activity. PMID- 23663548 TI - Patient experiences, attitudes and expectations towards receiving information about anti-TNF medication--"It could give me two heads and I'd still try it!". AB - BACKGROUND: Anti-tumour necrosis factor (anti-TNF) therapies are an important recent development in the treatment of autoimmune disease. Despite important side effects relating to immune suppression, there is lack of research into patient experiences, attitudes and expectations about the information they receive prior to starting anti-TNF therapy. METHODS: In May 2011 participants were purposively sampled to form two focus groups varying in age, anti-TNF agent and pre-therapy disease activity. A semi-structured topic guide was used to explore patients' experiences regarding the information they received prior to commencing anti-TNF therapy. The focus groups were audio-taped and transcribed verbatim. Data were analysed using content analysis. RESULTS: Four key themes were identified.Firstly, weighing the risks and benefits of anti-TNF therapy. However, most participants attached limited importance to side effects, saying their strong desire for RA symptom control was overriding. Two reported deliberately concealing illness in order to continue their medication. Secondly, the desire for information. They suggested that counselling should occur at an early stage and not during a severe RA flare-up. Thirdly, the process of starting anti-TNF. Many identified that their biggest worry was whether they would be eligible for the new medication. They remembered little about the investigations they underwent, and none said they would have objected to being tested for blood borne viruses. Finally, the experience of being on anti-TNF. Most were positive, describing effects on quality of life as well as symptoms. CONCLUSIONS: The use of qualitative methodology in this study has enabled an understanding of patients' attitudes towards receiving information about anti-TNF therapy. The results may be useful to health professionals in terms of the timing and content of the information given to patients prior to commencing anti-TNF therapy. PMID- 23663550 TI - Expecting ourselves to expect: the Bayesian brain as a projector. AB - Clark's essay lays the foundation for a Bayesian account of the "projection" of consciously perceived properties: The expectations that our brains test against inputs concern the particular affordances that evolution has designed us to care about, including especially expectations of our own expectations. PMID- 23663551 TI - The limits of p-values for biological data mining. PMID- 23663552 TI - Affect and non-uniform characteristics of predictive processing in musical behaviour. AB - The important roles of prediction and prior experience are well established in music research and fit well with Clark's concept of unified perception, cognition, and action arising from hierarchical, bidirectional predictive processing. However, in order to fully account for human musical intelligence, Clark needs to further consider the powerful and variable role of affect in relation to prediction error. PMID- 23663553 TI - Renal abnormalities among HIV-infected, antiretroviral naive children, Harare, Zimbabwe: a cross-sectional study. AB - BACKGROUND: Data on the prevalence of renal and urine abnormalities among HIV infected children in Sub-Saharan Africa are limited. We set out to determine the prevalence of proteinuria; low estimated glomerular filtration rate (eGFR), urinary tract infection and associated factors among HIV-infected antiretroviral therapy (ART) naive children, aged 2-12 years, attending the paediatric HIV clinic at a tertiary hospital in Harare. METHODS: Consecutive ART naive children attending the clinic between June and October 2009 were recruited. Detailed medical history was obtained and a complete physical examination was performed. Children were screened for urinary tract infection and for significant persistent proteinuria. Serum creatinine was used to estimate GFR using the modified Counahan-Barratt formula. The Student's t-test was used to analyse continuous variables and the chi-square or Fisher's exact test was used to analyse categorical data. Logistic regression was performed to assess the relationship between study factors and urine abnormalities, persistent proteinuria and the eGFR. RESULTS: Two hundred and twenty children were enrolled into the study. The median age was 90 months (Q1=65.5; Q3=116.5). The prevalence of urinary tract infection was 9.5%. Escherichia coli was the predominant organism. There was uniform resistance to cotrimoxazole. Persistent proteinuria (urine protein to creatinine ratio greater than 0.2, a week apart) was found in 5% of the children. Seventy-five children (34.6%) had mild to moderate renal impairment shown by a low eGFR (30 to <90 ml/min/1.73 m2). Persistent proteinuria was more likely to be found in children who were wasted, weight-for-height (WHZ) z-score <-2 (p=0.0005). Children with WHO clinical stage 4 were more likely to have a low eGFR than children with less advanced stages (OR 2.68; CI 1.24-5.80). Urine abnormalities were more likely to be observed in children with WHO clinical stages 3 and 4 (OR 2.20; CI 1.06-4.60). CONCLUSION: There is significant renal impairment among HIV-infected, ART naive children aged 2-12 years attending the outpatient paediatric HIV clinic at Harare Central Hospital. The abnormalities are more likely to occur in children with advanced HIV/AIDS. Screening for renal impairment and urinary tract infections in HIV-infected children before initiation of ART and regularly thereafter would be helpful in their management. KEYWORDS: HIV, renal disease, persistent proteinuria, glomerular filtration rate, urinary tract infection. PMID- 23663554 TI - Zn3N2 nanowires: growth, properties and oxidation. AB - Zinc nitride (Zn3N2) nanowires (NWs) with diameters of 50 to 100 nm and a cubic crystal structure have been grown on 1 nm Au/Al2O3 via the reaction of Zn with NH3 including H2 between 500 degrees C and 600 degrees C. These exhibited an optical band gap of ~ 3.2 eV, estimated from steady state absorption-transmission spectroscopy. We compared this with the case of ZnO NWs and discussed the surface oxidation of Zn3N2 NWs which is important and is expected to lead to the formation of a Zn3N2/ZnO core-shell NW, the energy band diagram of which was calculated via the self-consistent solution of the Poisson-Schrodinger equations within the effective mass approximation by taking into account a fundamental energy band gap of 1.2 eV. In contrast, only highly oriented Zn3N2 layers with a cubic crystal structure and an optical band gap of ~ 2.9 eV were obtained on Au/Si(001) using the same growth conditions. PMID- 23663555 TI - Net transfer of nutrients to the duodenum and disappearance of n-alkanes in the reticulo-rumen and the hindgut of sheep fed grass/legume combinations. AB - An experiment was carried out to examine the effect of increasing the proportion of Wimmera ryegrass hay in a lucerne hay-based diet on net transfer of nutrients to the intestine, and on the disappearance of n-alkanes in the reticulo-rumen and the hindgut of sheep. Following a latin square design, four adult ewes were fed 1:0, 0.33:0.67, 0.67:0.33 and 0:1 proportions of legume and grass. Increasing the proportion of ryegrass in the diet linearly decreased the intake of DM (P= 0.017), organic matter (P= 0.021) and N (P= 0.001). However, neutral-detergent fibre intake was not affected (P= 0.148), nor was its digestibility coefficient (P>0.10). Diet had no effect on duodenal flows of nutrients (P>0.10), although the proportion of N intake (NI) recovered at the duodenum as non-NH3 N (NAN) increased linearly with Lolium rigidum in the diet (P= 0.002). Full recovery of NI as NAN was achieved at NH3 concentrations in the rumen below 110 g/l. Microbial N contribution to NAN varied in a quadratic manner (P< 0.05) with the proportion of grass in the diet, although efficiency of microbial synthesis was not affected (P>0.10). Duodenal recovery of consumed n-alkanes was not affected by diet and was complete for those present in higher concentrations in the forages. Isolated rumen bacteria contained significant amounts of n-alkanes, contributing to the duodenal flow of these hydrocarbons in variable proportions depending on the diet consumed. PMID- 23663556 TI - Update on the collaborative interventions for circulation and depression (COINCIDE) trial: changes to planned methodology of a cluster randomized controlled trial of collaborative care for depression in people with diabetes and/or coronary heart disease. AB - BACKGROUND: The COINCIDE trial aims to evaluate the effectiveness and cost effectiveness of a collaborative care intervention for depression in people with diabetes and/or coronary heart disease attending English general practices. DESIGN: This update details changes to the cluster and patient recruitment strategy for the COINCIDE study. The original protocol was published in Trials (http://www.trialsjournal.com/content/pdf/1745-6215-13-139.pdf). Modifications were made to the recruitment targets in response to lower-than-expected patient recruitment at the first ten general practices recruited into the study. In order to boost patient numbers and retain statistical power, the number of general practices recruited was increased from 30 to 36. Follow-up period was shortened from 6 months to 4 months to ensure that patients recruited to the trial could be followed up by the end of the study. RESULTS: Patient recruitment began on the 01/05/2012 and is planned to be completed by the 30/04/2013. Recruitment for general practices was completed on 31/10/2012, by which time the target of 36 practices had been recruited. The main trial results will be published in a peer reviewed journal. CONCLUSION: The data from the trial will provide evidence on the effectiveness and cost-effectiveness of collaborative care for depression in people with diabetes and/or coronary heart disease. TRIAL REGISTRATION: TRIAL REGISTRATION NUMBER: ISRCTN80309252. PMID- 23663557 TI - The problem with brain GUTs: conflation of different senses of "prediction" threatens metaphysical disaster. AB - Clark appears to be moving toward epistemic internalism, which he once rightly rejected. This results from a double over-interpretation of predictive coding's significance. First, Clark argues that predictive coding offers a Grand Unified Theory (GUT) of brain function. Second, he over-reads its epistemic import, perhaps even conflating causal and epistemic mediators. We argue instead for a plurality of neurofunctional principles. PMID- 23663558 TI - Predicting multiple sclerosis following isolated optic neuritis in children. AB - BACKGROUND AND PURPOSE: Isolated optic neuritis (ON) is frequently the initial symptom of multiple sclerosis (MS). The aim of our study was to investigate the risk of conversion to MS in children following isolated ON and to evaluate the performance of current diagnostic methods such as cranial magnetic resonance imaging (cMRI), visual evoked potentials (VEPs) and oligoclonal bands in spinal fluid (OCB) as predictive factors for MS development. METHODS: Medical records of 159 patients presenting with acute ON between 2000 and 2010 at the Department of Pediatrics, University of Erlangen, were screened; 34 patients with isolated ON were identified. Progression to MS was defined according to the revised McDonald criteria 2005. Age, sex, VEPs, ON type, cMRI, OCB and visual recovery were assessed as predictors of progression to MS using simple logistic regressions. A multiple logistic regression model included variables found to be significant in univariate analyses. RESULTS: Abnormal cMRI was associated with an increase in the odds of MS development (odds ratio 20.57; 95% CI 2.16-196.10, P < 0.001), as was positive OCB (odds ratio 12.0; 95% CI 1.29-111.32, P = 0.001). However, only cMRI remained statistically significant in multiple regressions. CONCLUSIONS: Multiple sclerosis-like cMRI lesions and OCB are suitable for assessing the risk of progression to MS following isolated ON, as children with both cMRI abnormalities and positive OCB at onset of ON are at high risk of developing MS. PMID- 23663559 TI - Outcome of 12-month surveillance colonoscopy in high-risk patients in the National Health Service Bowel Cancer Screening Programme. AB - AIM: Current British guidelines recommend surveillance colonoscopy at 12 months for individuals found to have five or more adenomas, or three or more adenomas of which at least one is >= 1 cm in size. This study describes the yield of surveillance colonoscopy in this group and explores patient and clinical factors that may be associated with the presence of advanced adenomas or cancer at surveillance. METHOD: Data were retrieved from the national database of the National Health Service Bowel Cancer Screening Programme. The detection of advanced colonic neoplasia (ACN, cancer or advanced adenoma) was used as the main outcome variable. Multivariable analysis was used to analyse relationships between patient factors (age, gender, body mass index, smoking and alcohol use) and clinical findings (number, size and nature of adenomas detected during index colonoscopy) with the outcome variable. RESULTS: One-thousand, seven-hundred and sixty individuals were included in the study. The yield of ACN at 12-month surveillance was 6.6% (116/1760), of which 14/1760 (0.8%) had colorectal cancer. Nine (64.3%) of these 14 cancers were Dukes A at diagnosis. The presence of a villous adenoma or a right-sided adenoma at screening colonoscopy was associated with ORs of 1.98 (95% CI: 1.11-3.53, P = 0.012) and 1.76 (95% CI: 1.13-2.74, P = 0.020), respectively, for detection of ACN at surveillance. CONCLUSION: Twelve month surveillance colonoscopy is necessary in this group of patients. The presence of villous or proximal lesions at baseline is associated with increased risk of ACN at surveillance. Site and histological type of baseline lesions may be relevant for determining the surveillance interval. PMID- 23663561 TI - Test-retest reliability and sensitivity of the 20-meter walk test among patients with knee osteoarthritis. AB - BACKGROUND: The 20-meter walk test is a physical function measure commonly used in clinical research studies and rehabilitation clinics to measure gait speed and monitor changes in patients' physical function over time. Unfortunately, the reliability and sensitivity of this walk test are not well defined and, therefore, limit our ability to evaluate real changes in gait speed not attributable to normal variability. The aim of this study was to assess the test restest reliability and sensitivity of the 20-meter walk test, at a self-selected pace, among patients with mild to moderate knee osteoarthritis (OA) and to suggest a standardized protocol for future test administration. METHODS: This was a measurement reliability study. Fifteen consecutive people enrolled in a randomized-controlled trial of intra-articular corticosteroid injections for knee OA participated in this study. All participants completed 4 trials on 2 separate days, 7 to 21 days apart (8 trials total). Each day was divided into 2 sessions, which each involved 2 walking trials. We compared walk times between trials with Wilcoxon signed-rank tests. Similar analyses compared average walk times between sessions. To confirm these analyses, we also calculated Spearman correlation coefficients to assess the relationship between sessions. Finally, smallest detectable differences (SDD) were calculated to estimate the sensitivity of the 20-meter walk test. RESULTS: Wilcoxon signed-rank tests between trials within the same session demonstrated that trials in session 1 were significantly different and in the subsequent 3 sessions, the median differences between trials were not significantly different. Therefore, the first session of each day was considered a practice session, and the SDD between the second session of each day were calculated. SDD was -1.59 seconds (walking slower) and 0.15 seconds (walking faster). CONCLUSIONS: Practice trials and a standardized protocol should be used in administration of the 20-meter walk test. Changes in walk time between -1.59 seconds (walking slower) and 0.15 seconds (walking faster) should be considered within the range of normal variability of 20-meter walking speed. The primary limitation of our study was a small sample size, which may influence the generalizability of our findings. PMID- 23663560 TI - Expression and sub-cellular localization of an epigenetic regulator, co-activator arginine methyltransferase 1 (CARM1), is associated with specific breast cancer subtypes and ethnicity. AB - BACKGROUND: Co-Activator Arginine Methyltransferase 1(CARM1) is an Estrogen Receptor (ER) cofactor that remodels chromatin for gene regulation via methylation of Histone3. We investigated CARM1 levels and localization across breast cancer tumors in a cohort of patients of either European or African ancestry. METHODS: We analyzed CARM1 levels using tissue microarrays with over 800 histological samples from 549 female cancer patients from the US and Nigeria, Africa. We assessed associations between CARM1 expression localized to the nucleus and cytoplasm for 11 distinct variables, including; ER status, Progesterone Receptor status, molecular subtypes, ethnicity, HER2+ status, other clinical variables and survival. RESULTS: We found that levels of cytoplasmic CARM1 are distinct among tumor sub-types and increased levels are associated with ER-negative (ER-) status. Higher nuclear CARM1 levels are associated with HER2 receptor status. EGFR expression also correlates with localization of CARM1 into the cytoplasm. This suggests there are distinct functions of CARM1 among molecular tumor types. Our data reveals a basal-like subtype association with CARM1, possibly due to expression of Epidermal Growth Factor Receptor (EGFR). Lastly, increased cytoplasmic CARM1, relative to nuclear levels, appear to be associated with self-identified African ethnicity and this result is being further investigated using quantified genetic ancestry measures. CONCLUSIONS: Although it is known to be an ER cofactor in breast cancer, CARM1 expression levels are independent of ER. CARM1 has distinct functions among molecular subtypes, as is indicative of its sub-cellular localization and it may function in subtype etiology. These sub-cellular localization patterns, indicate a novel role beyond its ER cofactor function in breast cancer. Differential localization among ethnic groups may be due to ancestry-specific polymorphisms which alter the gene product. PMID- 23663562 TI - Prognostic factors for metastatic cutaneous squamous cell carcinoma of the parotid. AB - OBJECTIVE: To explore the prognostic significance of patient and disease characteristics on the survival of patients with metastatic cutaneous squamous cell carcinoma of the parotid gland at a tertiary care center in Halifax, Nova Scotia, Canada. METHODS: A retrospective chart review for all patients diagnosed with metastatic cutaneous squamous cell carcinoma to the parotid gland from January 2000 to December 2010. Multiple variables were examined related to: patient demographics, surgical details, non-surgical procedure details, and tumor pathologic description. RESULTS: A total of 54 patients [48 men (88%) and 6 women (12%)], with a median age at surgery of 78 years (range 47-93 years) were included in the study. All patients had a minimum follow up of 12 months or until deceased, with a median duration of follow up of 24 months. Predictors that were significant for cancer recurrence were pretreatment N-stage, pathologic neck node status, total number of positive neck nodes, and perineural invasion. Predictors that were significant for cancer death were the total number of positive neck nodes and perineural invasion. The remainder of the predictors including margin status were non-significant. Only age and nodal status were significant for both cancer death and recurrence on multivariate analysis. CONCLUSION: Our results showed only two variables that remained significant on multivariate analysis were age and number of involved neck nodes, this finding suggests that re-resection of positive margins may not be necessary and that radiation therapy is the mainstay of treatment for positive margins. PMID- 23663563 TI - Genome-wide association study of antibody response to Newcastle disease virus in chicken. AB - BACKGROUND: Since the first outbreak in Indonesia in 1926, Newcastle disease has become one of the most common and contagious bird diseases throughout the world. To date, enhancing host antibody response by vaccination remains the most efficient strategy to control outbreaks of Newcastle disease. Antibody response plays an important role in host resistance to Newcastle disease, and selection for antibody response can effectively improve disease resistance in chickens. However, the molecular basis of the variation in antibody response to Newcastle disease virus (NDV) is not clear. The aim of this study was to detect genes modulating antibody response to NDV by a genome-wide association study (GWAS) in chickens. RESULTS: To identify genes or chromosomal regions associated with antibody response to NDV after immunization, a GWAS was performed using 39,833 SNP markers in a chicken F(2) resource population derived from a cross between two broiler lines that differed in their resistance. Two SNP effects reached 5% Bonferroni genome-wide significance (P<1.26*10(-6)). These two SNPs, rs15354805 and rs15355555, were both on chicken (Gallus gallus) chromosome 1 and spanned approximately 600 Kb, from 100.4 Mb to 101.0 Mb. Rs15354805 is in intron 7 of the chicken Roundabout, axon guidance receptor, homolog 2 (ROBO2) gene, and rs15355555 is located about 243 Kb upstream of ROBO2. Rs15354805 explained 5% of the phenotypic variation in antibody response to NDV, post immunization, in chickens. Rs15355555 had a similar effect as rs15354805 because of its linkage disequilibrium with rs15354805 (r(2)=0.98). CONCLUSION: The region at about 100 Mb from the proximal end of chicken chromosome 1, including the ROBO1 and ROBO2 genes, has a strong effect on the antibody response to the NDV in chickens. This study paves the way for further research on the host immune response to NDV. PMID- 23663564 TI - The expression and significance of insulin-like growth factor-1 receptor and its pathway on breast cancer stem/progenitors. AB - INTRODUCTION: Dysregulation of the insulin-like growth factor-1 receptor (IGF 1R)/phosphatidylinositol-3-kinase (PI3K)/Akt pathway was shown to correlate with breast cancer disease progression. Cancer stem cells are a subpopulation within cancer cells that participate in tumor initiation, radio/chemoresistance and metastasis. In breast cancer, breast cancer stem cells (BCSCs) were identified as CD24-CD44+ cells or cells with high intracellular aldehyde dehydrogenase activity (ALDH+). Elucidation of the role of IGF-1R in BCSCs is crucial to the design of breast cancer therapies targeting BCSCs. METHODS: IGF-1R expression in BCSCs and noncancer stem cells sorted from xenografts of human primary breast cancers was examined by fluorescence-activated cell sorting (FACS), western blot analysis and immunoprecipitation. The role of IGF-1R in BCSCs was assessed by IGF-1R blockade with chemical inhibitor and gene silencing. Involvement of PI3K/Akt/mammalian target of rapamycin (mTOR) as the downstream pathway was studied by their phosphorylation status upon IGF-1R inhibition and the effects of chemical inhibitors of these signaling molecules on BCSCs. We also studied 16 clinical specimens of breast cancer for the expression of phosphor-Akt in the BCSCs by FACS. RESULTS: Expression of phosphorylated IGF-1R was greater in BCSCs than in non-BCSCs from xenografts of human breast cancer, which were supported by western blot and immunoprecipitation experiments. The sorted IGF-1R-expressing cells displayed features of cancer stem/progenitors such as mammosphere formation in vitro and tumorigenicity in vivo, both of which were suppressed by knockdown of IGF-1R. A specific inhibitor of the IGF-1R, picropodophyllin suppressed phospho AktSer473 and preferentially decreased ALDH+ BCSC populations of human breast cancer cells. Furthermore, picropodophyllin inhibited the capacity of CD24-CD44+ BCSCs to undergo the epithelial-mesenchymal transition process with downregulation of mesenchymal markers. Inhibitors of signal molecules downstream of IGF-1R including PI3K/Akt/mTOR also reduced the ALDH+ population of breast cancer cells. Furthermore, the mTOR inhibitor, rapamycin, suppressed BCSCs in vitro and in vivo. CONCLUSION: Our data support the notion that IGF-1R is a marker of stemness, and IGF-1R and its downstream PI3K/Akt/mTOR pathway are attractive targets for therapy directed against breast cancer stem/progenitors. PMID- 23663565 TI - Allergic manifestations and cutaneous histamine responses in patients with McCune Albright syndrome. AB - BACKGROUND: McCune Albright syndrome (MAS) is a rare disorder characterized by precocious puberty, cafe-au-lait spots, and fibrous dysplasia. Its cause is an activating mutation in the GNAS gene, encoding a subunit of the stimulatory G protein, Gsalpha (Gsalpha). The action of any mediator that signals via Gsalpha and cyclic AMP can be up regulated in MAS. We had observed gastritis, gastroesophageal reflux, and anaphylaxis in McCune Albright patients. OBJECTIVE: As histamine is known to signal via histamine 1 (H1) and histamine 2 (H2) receptors, which couple with stimulatory G proteins, we attempted to mechanistically link histamine responsiveness to the activating GNAS mutation. We hypothesized that responsiveness to histamine skin testing would differ between MAS patients and healthy controls. PATIENTS AND METHODS: After obtaining informed consent, we performed a systematic review of histamine responsiveness and allergic manifestations in 11 MAS patients and 11 sex-matched, Tanner-stage matched controls. We performed skin prick testing, quantifying the orthogonal diameters of wheals and erythema. We also quantitated G protein mRNA expression. RESULTS: The peak wheal and flare responses to histamine were significantly higher in MAS patients compared to controls. CONCLUSIONS: This study suggests that MAS patients may be at risk for exaggerated histamine responsiveness compared to unaffected controls. PMID- 23663566 TI - Comparing the effects of isoflurane and pentobarbital on the responses of cutaneous mechanoreceptive afferents. AB - BACKGROUND: While pentobarbital has been used extensively in neurophysiological experiments investigating activity in peripheral nerves, it has fallen out of favor as an anesthetic because of safety concerns and is often replaced with isoflurane. However, the effects of isoflurane on the excitability of mechanoreceptive afferents have yet to be conclusively elucidated. METHODS: To fill this gap, we collected extracellular single-unit recordings of cutaneous mechanoreceptive afferents from the sciatic nerve of 21 rats during vibratory stimulation of the hindpaw. We then compared the strength and temporal structure of the afferent response measured under pentobarbital and isoflurane anesthesia. RESULTS: We found that the strength and temporal structure of afferent responses were statistically equivalent whether these were evoked under isoflurane or pentobarbital. CONCLUSIONS: We conclude that, if these two anesthetics have any effect on the responses of mechanoreceptive afferents, their effects are indistinguishable. PMID- 23663567 TI - In vitro evaluation of beta-carboline alkaloids as potential anti-Toxoplasma agents. AB - BACKGROUND: Toxoplasmosis is a worldwide infection caused by the protozoan parasite Toxoplasma gondii, which causes chorioretinitis and neurological defects in congenitally infected newborns or immunodeficient patients. The efficacy of the current treatment is limited, primarily by serious host toxicity. In recent years, research has focused on the development of new drugs against T. gondii. beta-Carbolines (betaCs), such as harmane, norharmane and harmine, are a group of naturally occurring alkaloids that show microbicidal activity. In this work, harmane, norharmane and harmine were tested against T. gondii. FINDINGS: The treatment of extracellular tachyzoites with harmane, norharmane and harmine showed a 2.5 to 3.5-fold decrease in the invasion rates at doses of 40 MUM (harmane and harmine) and 2.5 MUM (norharmane) compared with the untreated parasites. Furthermore, an effect on the replication rate could also be observed with a decrease of 1 (harmane) and 2 (norharmane and harmine) division rounds at doses of 5 to 12.5 MUM. In addition, the treated parasites presented either delayed or no monolayer lysis compared with the untreated parasites. CONCLUSIONS: The three betaC alkaloids studied (norharmane, harmane and harmine) exhibit anti T. gondii effects as evidenced by the partial inhibition of parasite invasion and replication. A dose-response effect was observed at a relatively low drug concentration (< 40 MUM), at which no cytotoxic effect was observed on the host cell line (Vero). PMID- 23663569 TI - [Centralization, dynamic triage and multidisciplinary teamwork on the platform of critical care medicine: the key of success during the rescue of 4/20 Lushan earthquake victims]. AB - OBJECTIVE: To summarize the rescue experiences of the 4/20 Lushan earthquake victims by the 2nd "National medical experts team" and analyze the current emergent therapies for earthquake victims in China. METHODS AND RESULTS: Principles of "four centralization" (centralized the victims, the medical experts, the equipment and treatment) during the rescue of Lushan earthquake were clarified to transport the critical victims to the central hospitals as soon as possible,and cover the several aspects at the same time; and to set up a multi series connection among the mobile ambulance hospital in epicentral area, the triage/transfer hub in surrounding area as well as the central hospitals in rear. A multidisciplinary and multi-level experts team according to the different characteristic of each wave of earthquake, cooperation between the national multidisciplinary experts team and the local health care workers, and dynamic multi-time triage were built to detect the critical or potential critical victim in time. Clinical therapy was performed with rehabilitation medicine in early stage. All of above were our successful experiences leading to the minimization of mortality and disability of the earthquake victims. CONCLUSIONS: The rescue of the 4/20 Lushan earthquake victims is an example in recent years, characterized by timely, powerful, rapid, scientific and highly efficient. The principle of "four centralization" (centralized the victims, the medical experts, the equipment and the treatment) is a fundamental guarantee for successful rescue. PMID- 23663568 TI - Primary surgery versus chemoradiotherapy for advanced oropharyngeal cancers: a longitudinal population study. AB - BACKGROUND: Treatment for advanced stage oropharyngeal squamous cell carcinoma (OPSCC) includes combined chemoradiation therapy or surgery followed by radiation therapy alone or in combination with chemotherapy. The goal of this study was to utilize available evidence to examine survival outcome differences in patients with advanced stage OPSCC treated with these different modalities. METHODS: Patients with advanced stage OPSCC were identified. Primary outcome measurements were disease specific and overall survival rates with differences examined via Kaplan-Meier and logistic regression analysis. RESULTS: 344 patients were enrolled. 94 patients underwent triple modality therapy inclusive of surgery followed by adjuvant combined chemotherapy and radiation therapy (S-CRT). 131 had surgery and radiation therapy (S-RT), while 56 had chemoradiation (CRT) therapy as their primary treatment. A total of 63 patients had single modality radiation therapy and were excluded from analysis due to the large number of palliative patients. Kaplan-Meier overall survival analysis showed that therapy with S-CRT had the highest disease specific survival at five years (71.1%). This is contrasted against S-RT and CRT, with five year survival rates at 53.9%, and 48.6%, respectively. Cox regression showed that the comparison of S-CRT vs. S-RT, and CRT is associated with statistically significant increased hazard ratios of 1.974, and 2.785, indicating that both S-RT and CRT are associated with a reduced likelihood of survival at 5 years when compared to S-CRT. CONCLUSIONS: In this population based cohort study S-CRT is associated with a 17-22% 5 year disease specific survival benefit compared to CRT or S-RT. PMID- 23663570 TI - The ponderance in research of medical rescue in disasters. PMID- 23663571 TI - [Implementation of telemedicine services in the earthquake disaster relief: the best medical experts provide direct medical service to the affected people]. AB - OBJECTIVE AND METHOD: To sum up the experience and significance of the remote medical consultation system used by the PLA General Hospital in 4/20 Sichuan Lushan earthquake medical rescue in 2013. RESULTS AND CONCLUSIONS: After the Lushan earthquake in April 20, 2013, the expert medical rescue team of the PLA General Hospital immediately took the wireless portable telemedicine system to the converge hospital which had received many wounds in earthquake and had been connected with other hospitals, medical rescue teams and rescue ambulances to open the remote medical consultation system for disaster services including intensive care, emergency treatment, orthopedics, cerebral surgery, hepatobiliary surgery, obstetrics, gynecology and other related professional remote assistance services. The experts put forward the diagnosis and treatment for victims and had a benign interaction between the experts in disaster site and rear experts, as a result improved the ability of treatment of the disaster expert medical team. The PLA General Hospital treated more than 110 patients by remote medical consultation system in the Lushan earthquake and achieved real-time HD consultation and on-site operation guide. The using of remote medical consultation system achieved the connection between multimedia communication system and medical information system of the hospital and the interconnection of video, audio, data and medical services among each united hospitals, which can provide the significant experience of using remote medical consultation system in our disaster medical rescue activities. PMID- 23663572 TI - [Medical rescue of China National Earthquake Disaster Emergency Search and Rescue Team in Lushan earthquake]. AB - OBJECTIVE: To summarize and analyze the medical mission of China National Earthquake Disaster Emergency Search and Rescue Team (CNESAR) in Lushan earthquake, to promote the medical rescue effectiveness incorporated with search and rescue. METHODS: Retrospective analysis of medical work data by CNESAR from April 21th, 2013 to April 27th during Lushan earthquake rescue, including the medical staff dispatch and the wounded case been treated. RESULTS: The reasonable medical corps was composed by 22 members, including 2 administrators, 11 doctors [covering emergency medicine, orthopedics (joints and limbs, spinal), obstetrics and gynecology, gastroenterology, cardiology, ophthalmology, anesthesiology, medical rescue, health epidemic prevention, clinical laboratory of 11 specialties], 1 ultrasound technician, 5 nurses, 1 pharmacist, 1 medical instrument engineer and 1 office worker for propaganda. There were two members having psychological consultants qualifications. The medical work were carried out in seven aspects, including medical care assurance for the CNESAR members, first aid cooperation with search and rescue on site, clinical work in refugees' camp, medical round service for scattered village people, evacuation for the wounded, mental intervention, and the sanitary and anti-epidemic work. The medical work covered 24 small towns, and medical staff established 3 medical clinics at Taiping Town, Shuangshi Town of Lushan County and Baoxing County. Medical rescue, mental intervention for the old and kids, and sanitary and anti epidemic were performed at the above sites. The medical corps had successful evacuated 2 severe wounded patients and treated the wounded over thousands. Most of the wounded were soft tissue injuries, external injury, respiratory tract infections, diarrhea, and heat stroke. CONCLUSIONS: Compared with the rescue action in 2008 Wenchuan earthquake, the aggregation and departure of rescue team in Lushan earthquake, the traffic control order in disaster area, the self-aid and buddy aid are better, which give rise to the casualties to the lowest. The medical mission incorporated with search and rescue work showed that the medical performance manner altered with stages, the medical staff match changed with the mission, and the focus related with rescue time. PMID- 23663573 TI - [Professional technology being reached to the field, so that traumatic treatment level is elevated in earthquake]. PMID- 23663574 TI - [Discussion about health assessment and epidemic prevention mode for China National Earthquake Disaster Emergency Search and Rescue Team in Lushan earthquake]. AB - OBJECTIVE: To discuss health assessment and epidemic prevention in earthquake rescue, to establish emergency health and epidemic prevention mode for the national earthquake emergency medical rescue team scientifically, and to provide references and consultations for emergency hygiene and epidemic prevention measures in disaster medicine. METHODS AND RESULTS: China National Earthquake Disaster Emergency Search and Rescue Team gathered and evaluated environment, food, drinking water and other health related information around more than 2000 earthquake victims in Baoxing County, Shuangshi Town and Qingren Township from 20th April 2013 to 27th by using methods such as field epidemiological investigations. The national earthquake emergency medical rescue team spread comprehensive evaluation focusing on the local epidemics, find out the starting point of epidemic prevention, and then built reporting system in disaster area. The team also formulated the emergency detection system of food and drinking water and carried out health education. CONCLUSION: After the golden 72 hours, by comprehensive evaluation the establishment of early response in disaster area and spreading epidemic prevention, this team achieved the full coverage of three in the earthquake area, the resettlement of residents and families in that area and gradually formed a disaster medical rescue hygiene and epidemic prevention mode. PMID- 23663575 TI - [The particularity of rescue technology and equipment in earthquake confined space]. PMID- 23663576 TI - [The development and the future of information technology in critical care medicine]. PMID- 23663577 TI - [Relevance of erythrocyte parameters on fluid management in critical care]. AB - OBJECTIVE: To manage fluid therapy in severely ill patients through investigating the relationship between erythrocyte parameters and central venous pressure (CVP) and its denoted blood volume. METHODS: The research project was divided into two parts. Part I: CVP and concurrent erythrocyte parameters [red blood count (RBC), hemoglobin (Hb), haematocrit (HCT)] were serially recorded in a severely ill patient every morning for 38 days. The obtained values of CVP were divided into three groups (<8 cm H2O group, 8-10 cm H2O group, >10 cm H2O group), then erythrocyte parameters of each period were compared to obtain the relationship among them. At the same time, "the best" CVP (blood volume was in suitable state) and "the best" erythrocyte parameters (accordingly the blood was not be diluted or concentrated) were obtained. Part II: "the best" CVP and corresponding "the best" erythrocyte parameters were determined in another patient. When the patient's blood volume was in doubt, detected her erythrocyte parameters right away. If the variance between the "practical" and "the best" values was notable, blood volume replenishment or diureses were performed. Then the resulting CVP of fluid expansion or diuresis before and after the treatment were compared, or else other influencing factors should be seeked. RESULTS: Part I: the values of RBC, Hb and HCT in group CVP>10 cm H2O were lower than those of group CVP<8 cm H2O and CVP 8-10 cm H2O (RBC: 3.05+/-0.32*10(9)/L vs. 3.59+/-0.25*10(9)/L, 3.42+/ 0.24*10(9)/L; Hb: 85.3+/-6.8 g/L vs. 104.2+/-3.6 g/L, 97.5+/-4.9 g/L; HCT: 0.271+/-0.023 vs. 0.321+/-0.015, 0.309+/-0.019, all P<0.01), and Hb in group CVP 8-10 cm H2O was lower than group CVP<8 cm H2O (97.5+/-4.9 g/L vs. 104.2+/-3.6 g/L, P<0.01). CVP was negatively correlated with RBC, Hb and HCT, and coefficients of correlation (r value) were -0.735, -0.903 and -0.822, respectively (all P<0.01), and positive correlations were found among RBC, Hb and HCT, with r value 0.804, 0.931 and 0.863, respectively (all P<0.01). The patient's vital signs were stable when CVP was 8 to 10 cm H2O, therefore it was assigned as "the best" CVP, and the corresponding "the best" erythrocyte parameters were determined (RBC was 3.43*10(9)/L, Hb was 97.4 g/L, HCT was 0.310). Part II: "the best" CVP of the this patient was 8 to 10 cm H2O too, accordingly "the best" erythrocyte parameter in term of Hb was 105 g/L. The CVP was obviously elevated in the group in which Hb was higher than "the best" Hb subsequent to fluid expansion (8.29+/-1.80 cm H2O vs. 5.86+/-1.57 cm H2O, P<0.05), and the CVP was obvious lowered in the group which Hb was lower than "the best" Hb through diuresis (8.80+/-2.39 cm H2O vs. 12.20+/-1.92 cm H2O, P<0.05). CONCLUSION: CVP was negatively correlated with erythrocyte parameters, "the best" erythrocyte parameters accompanying "the best" CVP would probably guide fluid therapy best in severely ill patients. PMID- 23663578 TI - [Effects of early supplemental parenteral nutrition on nutrition intakes and clinical outcomes in trauma patients]. AB - OBJECTIVE: To evaluate energy and protein intake changes in early supplemental parenteral nutrition (PN) in trauma patients, and to assess its impact on clinical outcomes. METHODS: Clinical results of patients receiving or not receiving additional PN during the first 7 days after injury were retrospectively analyzed, with a total of 195 patients classified into two groups: control group (n=105) and mixed nutrition group (n=90). The time of nutrition support, intakes of protein and energy within 14 days after trauma, and clinical outcomes were compared between two groups. RESULTS: The degree of injury was comparable between two groups with no significant differences in acute physiology and chronic health evaluation II score, injury severity score (ISS) and Glasgow coma score (GCS). Compared with the control group, the mixed nutrition group received parenteral nutritional support earlier (40.0+/-21.0 hours vs. 55.1+/-23.5 hours, P<0.01), with later beginning of enteral nutrition (EN, 75.2+/-54.5 hours vs. 55.1+/-23.5 hours, P<0.01) and lower rate of EN in 48 hours after admission [14.4% (13/90) vs. 43.8% (46/105), P<0.01]. The time of restoring oral diet was not different between the mixed nutrition group and control group (10.8+/-3.7 days vs. 11.4+/ 3.6 days, P>0.05). The energy intake was significantly higher in the mixed nutrition group than in the control group in 3, 7, 14 days (3 days: 3981.6+/ 2209.3 kJ vs. 2683.2+/-1414.9 kJ, 7 days: 5477.5+/-2008.4 kJ vs. 3619.1+/-1429.9 kJ, 14 days: 6250.2+/-2533.2 kJ vs. 5199.9+/-1972.7 kJ, P<0.05 or P<0.01). In both groups the protein intake was insufficient, and it was significantly lower in the mixed nutrition group than in the control group on day 3 (20.6+/-18.4 g vs. 26.5+/-13.8 g, P<0.05). The patients in the mixed nutrition group had longer hospital stay time (73.9+/-62.5 days vs. 50.9+/-33.3 days, P<0.01). The mortality rate of mixed nutrition group and control group was 4.4% (4/90) and 3.8% (4/105) respectively, the rate of infection and acute respiratory distress syndrome (ARDS) were 8.9% (8/90) and 3.8% (4/105), 5.6% (5/90) and 7.6% (8/105) respectively, duration of mechanical ventilation (days) was 8.3+/-4.6 and 7.3+/ 4.7, duration of stay in ICU was 17.6+/-13.2 days and 14.2+/-11.3 days respectively, and no significant difference was found between two groups (all P>0.05). CONCLUSION: Although early supplemental PN within 7 days after injury increases energy intake, PN without a standard protocol does not improve clinical outcomes and may prolong hospital stay time. PMID- 23663579 TI - [Prevention of non-acute stent thrombosis after drug-eluting stent implantation]. AB - OBJECTIVE: To decrease acute myocardial infarction (AMI) and incidence of other cardiovascular event after drug-eluting stent (DES) implantation, so as to prevent non-acute stent thrombosis. METHODS: Patients who had undergone percutaneous coronary intervention with DES from January 2005 to September 2008 were enrolled. All patients were randomly assigned into two groups with different treatment protocols for anti-thrombosis. The patients in control group were treated with aspirin and clopidogrel for anti-thrombosis (double anti-treatment), while those in observation group were treated with tirofiban and warfarin on top of basic treatment with double anti-thromotic drugs. The latter group of patients received warfarin in addition for 6 months, with the international normalized ratio (INR) maintained at 1.5-2.0. The patients in both groups were followed up at 1-3 months after the treatment, and the deadline was October 2012. Stent thrombosis was assessed by the definition of Dublin for Academic Research Consortium. The main ending point indexes were main adverse cardiac and cerebral events (MACCE), and the secondary ending point indexes were incidence of bleeding and other adverse events. RESULTS: A total of 505 consecutive patients treated with DES implantation were enrolled, 245 in the observation group while 260 in the control. The rates of MACCE at 1- 48 months after operation in observational group were significantly lower than those in control group (1 month: 0.41% vs. 3.08%, 2-6 months: 0 vs. 2.31%, 7-12 months: 0.82% vs. 4.23%, 13-24 months: 1.22% vs. 8.85%, 25- 48 months: 2.04% vs. 12.31%, all P<0.05). Cardiac death (13-24 months: 0.41% vs. 3.08%, 25-48 months: 0.82% vs. 4.23%), non-lethal acute myocardial infarction unrelated with target vessels (25-48 months: 0.41% vs. 3.08%), and rates of revascularization of target vessels (13-24 months: 0.41% vs. 3.08%, 25-48 months: 0.82% vs. 4.23%) in observation group were significantly lower than those in the control group (all P<0.05). The rates of sub-acute stent thrombosis, late stent thrombosis, and very late stent thrombosis in observation group were significantly lower than those in control group (0 vs. 2.31%, 0.82% vs. 4.23%, 1.63% vs. 8.46%, all P<0.05). The rate of bleeding in observational group was a litter higher than control group (3.27% vs. 1.54%, P=0.167) and no severe bleeding occurred. Other severe adverse events were not found in both groups. CONCLUSION: The results indicate that tirofiban and warfarin combined with aspirin and clopidogrel could reduce the rates of MACCE and bleeding, and it could prevent non-acute stent thrombosis safely and effectively after percutaneous coronary intervention with DES. PMID- 23663580 TI - [Protection of anisodamine on the mitochondrial injury induced by oxidative stress in swine with cardiac arrest]. AB - OBJECTIVE: To investigate the protection of anisodamine on cardiac ischemia/reperfusion (I/R) injury by oxidative stress by observing the changes in oxidation and antioxidant markers in plasma and myocardium, and the damage of cardiac mitochondria structure in pigs with cardiac arrest (CA). METHODS: Twenty three healthy male swine were divided into three groups using random digits table: sham group (n=5), epinephrine group (n=9), and anisodamine group (n=9). The CA model was reproduced by alternating current. Blood samples were collected before CA, 8 minutes after CA, and 0 minute, 30 minutes, 24 hours after recovery of spontaneous circulation (ROSC), and hearts were harvested at 24 hours after ROSC. The content of malondialdehyde (MDA) and the enzyme activity of superoxide dismutase (SOD) were analyzed by spectrophotography, the cardiac ATP content was assayed by high performance liquid chromatography, the generation of reactive oxygen species (ROS) was detected by laser confocal microscope, and the myocardial ultrastructures were observed with transmission electron microscope to assess mitochondrial damage score. RESULTS: At 30 minutes and 24 hours after ROSC, plasma MDA level of anisodamine group was lower than that of epinephrine group (30 minutes: 43.38+/-8.12 MUmol/L vs. 55.47+/-10.97 MUmol/L, 24 hours: 29.96+/-6.04 MUmol/L vs. 37.87+/-7.85 MUmol/L, both P<0.05). Compared with epinephrine group, the cardiac SOD activity and ATP content of anisodamine group were elevated (SOD: 1.35+/-0.50 U/mg vs. 0.54+/-0.19 U/mg, ATP: 4.17+/-1.06 MUmol/g vs. 2.95+/-0.94 MUmol/g, P<0.01 and P<0.05), and the mitochondrial ROS level (RFU) was lowered (88.00+/-17.67 vs. 107.00+/-21.35, P<0.05). Although the cardiac MDA content was also reduced, but the difference between two resuscitation groups showed no statistical significance (16.66+/-2.89 MUmol/mg vs. 19.28+/-3.90 MUmol/mg, P>0.05). Using electron microscope, in epinephrine group disordered arrangement of cardiac myocyte arrangement was observed, and the mitochondrial alignment and morphology were significantly different from the sham group (mitochondrial damage score: 0.41+/-0.08 vs. 0.12+/-0.01, P<0.01). The level of mitochondrial injury in anisodamine group was milder than that of epinephrine group (mitochondrial damage score: 0.21+/-0.05 vs. 0.41+/-0.08, P<0.05). CONCLUSION: Through regulating oxygen radical metabolism, anisodamine alleviates the injury to myocardial mitochondria structure and function injury as induced by oxidative stress. PMID- 23663581 TI - [Analysis of the risk factors for early death in acute severe traumatic cervical spinal cord injury]. AB - OBJECTIVE: To survey the risk factors for early death of patients with acute severe traumatic cervical spinal cord injury. METHODS: A retrospective analysis of data of consecutive patients with acute severe traumatic cervical spinal cord injury admitted from January 1st 1994 to October 1st 2012 were made. The patients died within 30 days or not were allocated for death group or survival group. The risk factors for early death were analyzed through univariate analysis and logistic analysis. RESULTS: Among 1093 patients with acute traumatic cervical spinal cord injury, 352 patients with severe injury were included, and the early death rate was 14.49% (51/352). The leading causes of spinal cord injury were vehicle accidents (153 cases) and falls (117 cases). The main causes of early death were respiratory failure (16 cases), multiple organ failure (MOF, 14 cases) and gastrointestinal bleeding (11 cases). Combining the results of univariate and logistic analysis, it was found that high acute physiology and chronic health evaluation II(APACHEII) score [>15, odds ratio (OR)=11.595, P=0.000], high damage level (OR=3.519, P=0.032), hyponatremia (OR=6.316, P=0.000), neurogenic shock (OR=6.209, P=0.000), pulmonary infection (OR=14.627, P=0.000) and tracheostomy (OR=8.983, P=0.000) were risk factors for early death of patients with acute severe traumatic cervical spinal cord injury, however, the impact of gender, age, surgery, fracture and dislocation, high central fever, and administration of steroids on early death of patients with acute severe traumatic cervical spinal cord injury were uncertain. CONCLUSION: The factors reflecting disease severity and occurrence of related complications were more important in predicting the early death among patients with acute severe traumatic cervical spinal cord injury, while the influence of age, surgical manipulation etc. were minor factors. PMID- 23663582 TI - [Design of obstetrical "potential severe disease" score and its application in 3269 pregnant women]. AB - OBJECTIVE: To study the applicability and practicability of "potential severe disease" score in prognosticating severity of potential disease in late pregnancy and puerperal mother and newborn. METHODS: "Potential severe disease" score was designed based on the characters of obstetrical patients, and 3269 puerperal women were surveyed and the condition of mother and child were investigated after delivery. RESULTS: The mean rank of "potential severe disease" score in the group with severe illness (n=137) was extremely higher than that of smooth pregnancy group (n=3132, 2969.390 vs. 1576.630, Z=-18.052, P<0.01). The result indicated the score could evaluate the degree of illness. The area under the receiver operating characteristic curve (AUC) of the "potential severe disease" score was 0.926, the optimal cut-off point of score was 3, with sensibility 73.72%, specificity 92.21%. There was no significant difference in the mean rank of "potential severe disease" score between fetal distress group (n=507) and normal fetus group (n=2726, 1572.920 vs. 1646.400, Z=-1.498, P>0.05), therefore it indicated that the "potential severe disease" score had not the identification ability on fetal distress. CONCLUSION: Obstetrical "potential severe disease" score may be applied for obstetrics because of speediness, simplicity and better identification in evaluating the disease in late pregnancy. PMID- 23663583 TI - [Effect of albumin and hemoglobin level on prognosis of patients with uncomplicated severe traumatic brain injury: a retrospective cohort study]. AB - OBJECTIVE: To evaluate the best level of albumin and hemoglobin for the patients with uncomplicated severe traumatic brain injury (TBI). METHODS: A retrospective cohort study was conducted. One hundred and sixty-eight patients with uncomplicated severe TBI admitted to intensive care unit (ICU) of Anhui Provincial Hospital were enrolled. The relationship between albumin and hemoglobin level within 3 days after admission and prognosis was analyzed. Mean 3 day albumin level was obtained, and then the patients were divided into <25, 25 28, 29-31 and >=32 g/L groups according to quartiles based on mean albumin, and also were divided into <90, 90-99, 100-109 and>=110 g/L groups according to the mean hemoglobin concentration. Multivariable log-binomial regression was used to model the association between mean albumin and hemoglobin concentration and prognosis. RESULTS: One hundred and nine patients were enrolled based on inclusion/exclusion criteria. Among them, 32 patients (29.4%) received a red blood cell (RBC) transfusion, and 24 patients (22.0%) were given albumin treatment. According to the average level of albumin, there were significant differences in mortality among <25, 25-28, 29-31 and >=32 g/L groups [85.2%(23/27), 59.3%(16/27), 32.1%(9/28), 44.4%(12/27), respectively, P=0.001]. According to the hemoglobin level, there was no significant difference in mortality rate among <90, 90-99, 100-109 and >=110 g/L groups[61.8%(34/55), 43.8%(7/16), 53.3%(8/15), 47.8%(11/23), respectively, P>0.05]. When using the albumin level, Glasgow coma score (GCS), age and time of onset for logistic analysis, albumin level and age had influence on the mortality of patients, and mortality rate was generally decreased with an increase in albumin. But when the levels of albumin was >=32 g/L, the risk of death was higher than in the 29-31 g/L group[relative risk (RR) of albumin 29-31 g/L=0.070, 95% confidence interval (95%CI) 0.015-0.331, P=0.001; RR of albumin>=32 g/L=0.153, 95%CI 0.035-0.663, P=0.012; RR of age=0.691, 95%CI 0.526-0.907, P=0.008]. When the hemoglobin level, GCS, age and time of onset were used for logistic regression analysis, only GCS entered the regression model (RR=0.696,95%CI 0.550-0.880, P=0.002), illustrating that the hemoglobin level had no significant influence on mortality, and mortality rate declined with an increase in GCS. CONCLUSIONS: The most favorable level of albumin for uncomplicated severe traumatic brain injury is 29-31 g/L. There is no difference in mortality rate when hemoglobin >90 g/L. PMID- 23663586 TI - [The potential clinical value of sodium pyruvate]. PMID- 23663585 TI - [Treatment of hemorrhage of patients with coagulopathy after severe trauma with 20AA compound amino acid injection and high-dose vitamin B6]. PMID- 23663587 TI - [A review of plethysmographic variability index as a novel fluid responsiveness indicator]. PMID- 23663584 TI - [The effect of continuous hemofiltration in the treatment of traumatic patients with refractory acute cephalocele after craniotomy]. AB - OBJECTIVE: To investigate the effect and the possible mechanism of continuous hemofiltration in the treatment of traumatic patients with refractory acute cephalocele. METHODS: Continuous venous-venous hemofiltration (CVVH) was applied to 9 traumatic patients with refractory acute cephalocele after craniotomy. The changes in patients' physical signs, electrolytes, blood gas analysis, biochemical and blood clotting indexes as well as the outcome were observed. RESULTS: (1) The later the CVVH started, the worse the disorders became such as unstable body temperature, respiratory rate, heart rate, blood pressure and abnormal blood gas analysis. The most significant abnormality emerged with a delay of 12 hours. The above abnormalities returned to normal and kept stable within 12 hours of CVVH. CVVH maintained body temperature in hypothermic state, and serum lactic acid was kept at a low level without disturbance of blood coagulation function. (2) The duration between occurrence of cephalocele and beginning of CVVH was 2-16 hours, with a mean of (5.4+/-5.1) hours, the duration of CVVH was 23-129 hours, with a mean of (75.7+/-34.3) hours, and the net volume of liquid balance (NVLB) was -1.2-3.1 L, with a mean of (0.76+/-1.46) L. Height of encephalocele over skull window (HEOSW) was 51.8+/-10.0 mm and 51.0+/-10.0 mm before and 72 hours after CVVH. NVLB and HEOSW did not show obvious correlation with the prognosis of the patients. (3) Four patients survived, and 2 patients showed satisfactory outcome with Glasgow outcome scale (GOS) over 12 after follow up for 3 months, and 2 patients showed improvement with GOS of 8 but in vegetative state 3 months later. Five patients died of respiratory failure and multiple organ dysfunction syndrome (MODS) 9-35 days after the termination of CVVH. CONCLUSIONS: CVVH was safe and effective in certain extent in the treatment of refractory acute cephalocele. The direct causes of death of the patients were complications instead of the cephalocele itself. The outcomes of the patients were related to the time of beginning of CVVH and the duration of CVVH, and there was nothing to do with the NVLB and the HEOSW. The study implicated that the effect of CVVH on these patients was not brain-dehydration solely. It also exerted certain effect on regulating water-electrolyte balance, acid-base balance and body temperature. PMID- 23663588 TI - Treatment of traumatized refugees with sertraline versus venlafaxine in combination with psychotherapy - study protocol for a randomized clinical trial. AB - BACKGROUND: Sufficient evidence is lacking to draw final conclusions on the efficiency of medical and psychological treatments of traumatized refugees with PTSD. The pharmacological treatments of choice today for post-traumatic stress disorder are antidepressants from the subgroup selective serotonin reuptake inhibitors, especially sertraline. The evidence for the use of selective serotonin reuptake inhibitors in the treatment of complex post-traumatic stress disorder in traumatized refugees is very limited. Venlafaxine is a dual-action antidepressant that works on several pathways in the brain. It influences areas in the brain which are responsible for the enhanced anxiety and hyper-arousal experienced by traumatized refugees and which some studies have found to be enlarged among patients suffering from post-traumatic stress disorder. DESIGN: This study will include approximately 150 patients, randomized into two different groups treated with either sertraline or venlafaxine. Patients in both groups will receive the same manual-based cognitive behavioral therapy, which has been especially adapted to this group of patients. The treatment period will be 6 to 7 months. The trial endpoints will be post-traumatic stress disorder and depressive symptoms and social functioning, all measured on validated ratings scales. Furthermore the study will examine the relation between a psycho-social resources and treatment outcome based on 15 different possible outcome predictors. DISCUSSION: This study is expected to bring forward new knowledge on treatment and clinical evaluation of traumatized refugees and the results are expected to be used in reference programs and clinical guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT01569685. PMID- 23663589 TI - ANO5-muscular dystrophy: clinical, pathological and molecular findings. AB - BACKGROUND AND PURPOSE: Anoctamin 5 (ANO5) is a putative intracellular calcium activated chloride channel. Recessive mutations in ANO5 cause primary skeletal muscle disorders (limb-girdle muscular dystrophy 2L and distal muscular dystrophy), which are phenotypically similar to dysferlinopathy, a muscular dystrophy due to dysferlin-encoding gene (DYSF) mutations. METHODS: This study reports the phenotype and genotype of seven unrelated patients with ANO5-muscular dystrophy. RESULTS: Three patients had amyloid deposition in muscle and two had cardiac involvement. An additional patient without skeletal muscle amyloidosis had cardiac involvement with septal hypokinesis and supraventricular tachycardia requiring ablation. Amyloid subtyping using laser capture microdissection and mass spectrometry-based proteomic analysis did not identify ANO5 or any fragment of ANO5 in the amyloid deposits, but detected other known amyloidogenic proteins. Three patients had myotonic discharges without clinical myotonia. Four ANO5 mutations are novel, including a heterozygous 0.4 Mb deletion involving the entire ANO5 gene. CONCLUSIONS: The results of the present study suggest that ANO5 mutations can be associated with amyloid deposition in muscle, but the nature of the amyloid deposits remains indeterminate, as does their relationship with cardiac involvement. ANO5 analysis should be considered in cases of muscle amyloid deposition of indeterminate etiology. Electrical myotonia can accompany ANO5-muscular dystrophy. PMID- 23663590 TI - Synthesis and photoelectrochemical response of CdS quantum dot-sensitized TiO2 nanorod array photoelectrodes. AB - A continuous and compact CdS quantum dot-sensitive layer was synthesized on TiO2 nanorods by successive ionic layer adsorption and reaction (SILAR) and subsequent thermal annealing. The thickness of the CdS quantum dot layer was tuned by SILAR cycles, which was found to be closely related to light absorption and carrier transformation. The CdS quantum dot-sensitized TiO2 nanorod array photoelectrodes were characterized by scanning electron microscopy, X-ray diffraction, ultraviolet-visible absorption spectroscopy, and photoelectrochemical property measurement. The optimum sample was fabricated by SILAR in 70 cycles and then annealed at 400 degrees C for 1 h in air atmosphere. A TiO2/CdS core-shell structure was formed with a diameter of 35 nm, which presented an improvement in light harvesting. Finally, a saturated photocurrent of 3.6 mA/cm2 was produced under the irradiation of AM1.5G simulated sunlight at 100 mW/cm2. In particular, the saturated current density maintained a fixed value of approximately 3 mA/cm2 without decadence as time passed under the light conditions, indicating the steady photoelectronic property of the photoanode. PMID- 23663591 TI - Bayesian animals sense ecological constraints to predict fitness and organize individually flexible reproductive decisions. AB - A quantitative theory of reproductive decisions (Gowaty & Hubbell 2009) says that individuals use updated priors from constantly changing demographic circumstances to predict their futures to adjust actions flexibly and adaptively. Our ecological/evolutionary models of ultimate causes seem consistent with Clark's ideas and thus suggest an opportunity for a unified proximate and ultimate theory of Bayesian animal brains, senses, and actions. PMID- 23663592 TI - Re: Comparison of oncological outcomes after segmental ureterectomy or radical nephroureterectomy in urothelial carcinomas of the upper urinary tract: results from a large French multicentre study. PMID- 23663593 TI - Re: Ureteroscopic and extirpative treatment of upper urinary tract urothelial carcinoma: a 15-year comprehensive review of 160 consecutive patients. PMID- 23663594 TI - Re: Renal cortical tumors: use of multiphasic contrast-enhanced MR imaging to differentiate benign and malignant histologic subtypes. PMID- 23663595 TI - Re: Targeted delayed scanning at CT urography: a worthwhile use of radiation? PMID- 23663596 TI - Re: Association of polymorphisms in oxidative stress genes with clinical outcomes for bladder cancer treated with Bacillus Calmette-Guerin. PMID- 23663597 TI - Re: 11C-choline PET/CT in patients with hormone-resistant prostate cancer showing biochemical relapse after radical prostatectomy. PMID- 23663598 TI - Re: Analysis of urological procedures in men who died from prostate cancer using a population-based approach. PMID- 23663599 TI - Re: 20-year survival after radical prostatectomy as initial treatment for cT3 prostate cancer. PMID- 23663600 TI - Re: Early salvage radiation therapy combined with short-term hormonal therapy in recurrent prostate cancer after radical prostatectomy: single-institution 4-year data on outcome, toxicity, health-related quality of life and co-morbidities from 184 consecutive patients treated with 70 Gy. PMID- 23663601 TI - Re: Socioeconomic status, healthcare density, and risk of prostate cancer among African American and Caucasian men in a large prospective study. PMID- 23663602 TI - Re: Explaining racial differences in prostate cancer mortality. PMID- 23663603 TI - Re: Active surveillance for prostate cancer compared with immediate treatment: an economic analysis. PMID- 23663604 TI - Re: Barriers to the implementation of surveillance for stage I testicular seminoma. PMID- 23663605 TI - Re: alpha-Blockers, antibiotics and anti-inflammatories have a role in the management of chronic prostatitis/chronic pelvic pain syndrome. PMID- 23663606 TI - Re: Continuous intravesical lidocaine treatment for interstitial cystitis/bladder pain syndrome: safety and efficacy of a new drug delivery device. PMID- 23663607 TI - Re: Determinants of urolithiasis in patients with intestinal fat malabsorption. PMID- 23663608 TI - Re: The relation between bone and stone formation. PMID- 23663609 TI - Re: Review of penile prosthetic reservoir: complications and presentation of a modified reservoir placement technique. PMID- 23663610 TI - Re: Laparascopic capsulotomy to treat autoinflation of inflatable penile prostheses. PMID- 23663615 TI - Re: The efficacy of posterior tibial nerve stimulation for the treatment of overactive bladder in women: a systematic review. PMID- 23663616 TI - Re: Association of overactive bladder and C-reactive protein levels. Results from the Boston Area Community Health (BACH) Survey. PMID- 23663617 TI - Re: Efficacy and tolerability of mirabegron, a beta3-adrenoceptor agonist, in patients with overactive bladder: results from a randomised European-Australian phase 3 trial. PMID- 23663611 TI - Re: Dorsal penile nerve block prior to inflatable penile prosthesis placement: a randomized, placebo-controlled trial. PMID- 23663618 TI - Re: OnabotulinumtoxinA improves health-related quality of life in patients with urinary incontinence due to idiopathic overactive bladder: a 36-week, double blind, placebo-controlled, randomized, dose-ranging trial. PMID- 23663620 TI - Re: Influence of oxidative stress on inducing micturition dysfunction following chronic infravesical obstruction and the protective role of an antioxidant diet association of in vivo and in vitro studies in rats. PMID- 23663622 TI - Re: Systematic review of care intervention studies for the management of incontinence and promotion of continence in older people in care homes with urinary incontinence as the primary focus (1966-2010). PMID- 23663621 TI - Re: Prevalence and correlates of nocturia in community-dwelling older men: results from the Korean longitudinal study on health and aging. PMID- 23663623 TI - Re: Risk factors for fecal incontinence in older women. PMID- 23663624 TI - Re: Involvement of estrogen receptors in prostatic diseases. PMID- 23663625 TI - Re: Sleep analysis of patients with nocturia and benign prostatic obstruction. PMID- 23663627 TI - Re: Independent of nephrectomy, weaning immunosuppression leads to late sensitization after kidney transplant failure. PMID- 23663628 TI - Re: Value of routine voiding cystourethrography after renal transplantation. PMID- 23663629 TI - Re: A multivariate twin study of female sexual dysfunction. PMID- 23663630 TI - Re: Is female sexual function related to the male partners' erectile function? PMID- 23663631 TI - Re: Cognitive performance in healthy women during induced hypogonadism and ovarian steroid addback. PMID- 23663634 TI - Re: Relationship of sex hormones and nocturia in lower urinary tract symptoms induced by benign prostatic hyperplasia. PMID- 23663633 TI - Re: A case-control study on the association between chronic prostatitis/chronic pelvic pain syndrome and erectile dysfunction. PMID- 23663635 TI - Re: Association between lower urinary tract symptoms and sexual dysfunction assessed using the core lower urinary tract symptom score and International Index of Erectile Function-5 questionnaires. PMID- 23663636 TI - Re: Dietary patterns and semen quality in young men. PMID- 23663637 TI - Re: Micronutrients intake is associated with improved sperm DNA quality in older men. PMID- 23663638 TI - Re: South African plants and male reproductive healthcare: conception and contraception. PMID- 23663639 TI - Re: Clinical characteristics and reproductive outcomes in infertile men with testicular early and late maturation arrest. PMID- 23663640 TI - Re: Epigenetic disruption of the PIWI pathway in human spermatogenic disorders. PMID- 23663641 TI - Re: Unilateral multicystic dysplastic kidney: does initial size matter? PMID- 23663642 TI - Re: Desmopressin and oxybutynin in monosymptomatic nocturnal enuresis: a randomized, double-blind, placebo-controlled trial and an assessment of predictive factors. PMID- 23663643 TI - Re: Ileal bladder augmentation and vitamin B12: levels decrease with time after surgery. PMID- 23663645 TI - Re: Ureteroscopy in pediatric patients with spinal abnormalities. PMID- 23663646 TI - Re: Protease nexin 1 inhibits hedgehog signaling in prostate adenocarcinoma. PMID- 23663647 TI - Re: Both osteopontin-c and osteopontin-b splicing isoforms exert pro-tumorigenic roles in prostate cancer cells. PMID- 23663648 TI - Re: Inhibition of Ca2+ -activated Cl- channel ANO1/TMEM16A expression suppresses tumor growth and invasiveness in human prostate carcinoma. PMID- 23663649 TI - Characterizing rapid, activity-linked conformational transitions in proteins via sub-second hydrogen deuterium exchange mass spectrometry. AB - This review outlines the application of time-resolved electrospray ionization mass spectrometry (TRESI-MS) and hydrogen-deuterium exchange (HDX) to study rapid, activity-linked conformational transitions in proteins. The method is implemented on a microfluidic chip which incorporates all sample-handling steps required for a 'bottom-up' HDX workflow: a capillary mixer for sub-second HDX labeling, a static mixer for HDX quenching, a microreactor for rapid protein digestion, and on-chip electrospray. By combining short HDX labeling pulses with rapid digestion, this approach provides a detailed characterization of the structural transitions that occur during protein folding, ligand binding, post translational modification and catalytic turnover in enzymes. This broad spectrum of applications in areas largely inaccessible to conventional techniques means that microfluidics-enabled TRESI-MS/HDX is a unique and powerful approach for investigating the dynamic basis of protein function. PMID- 23663650 TI - Differential effects of PCSK9 loss of function variants on serum lipid and PCSK9 levels in Caucasian and African Canadian populations. AB - OBJECTIVES: Variants of the secreted glycoprotein, proprotein convertase subtilisin/kexin 9 (PCSK9), associate with both hypo- and hyper-cholesterolemic phenotypes. Herein, we carried out full exonic sequencing of PCSK9 documenting the frequency of single and multiple PCSK9 variations and their effects on serum lipoprotein and PCSK9 levels in Caucasian Canadians. METHODS: The 12 exons of PCSK9 were sequenced in 207 unrelated Caucasian Canadians. Minor allele frequencies of PCSK9 variants were compared amongst LDL cholesterol (LDLC) quintiles. Serum PCSK9 levels were measured by ELISA and lipoproteins by enzymatic methods. Comparisons were made with a Caucasian family cohort (n=51) and first generation African Canadians (n=31). RESULTS: In Caucasians, but not African Canadians, the c.61_63insCTG (denoted L10Ins) and A53V PCSK9 variations were linked and their frequency was significantly higher among Caucasian Canadians with LDLC levels in the <25th percentile. In both the unrelated and family Caucasian cohorts those carrying the L10A53V PCSK9 variant had significantly lower LDLC without reduction in plasma PCSK9. The I474V PCSK9 variant associated with significantly lower serum PCSK9 and LDLC. A novel PCSK9 variant was identified; E206K. We found that the frequency of multiple PCSK9 variations was higher in first generation African Canadians. CONCLUSIONS: We showed that the L10A53V and I474V PCSK9 variants were significantly associated with lower LDLC levels in Caucasian Canadians but differed in their effect on serum PCSK9 concentrations, illuminating differences in their mechanism of inaction and indicating that that PCSK9 measurement alone may not always be a good indicator of PCSK9 function.Full exonic sequencing of PCSK9 pointed to factors that may contribute to L10Ins PCSK9 variant loss of function in Canadians of Caucasian but not those of African descent. These included; (1) its tight linkage with the A53V variant in Caucasians and/or (2) for both the L10 and I474V, the combined (and negating) effect of multiple, differing phenotypic PCSK9 variants within individuals of African ancestry for which combinations of PCSK9 variations and their overall frequency was higher. No population studies, to our knowledge, have addressed or accessed the effect of multiple PCSK9 variants on cholesterol profiles. Our results indicate that this should be considered. PMID- 23663651 TI - Investigating the efficacy of integrated cognitive behavioral therapy for adult treatment seeking substance use disorder patients with comorbid ADHD: study protocol of a randomized controlled trial. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) frequently co-occurs with substance use disorders (SUD). The combination of ADHD and SUD is associated with a negative prognosis of both SUD and ADHD. Pharmacological treatments of comorbid ADHD in adult patients with SUD have not been very successful. Recent studies show positive effects of cognitive behavioral therapy (CBT) in ADHD patients without SUD, but CBT has not been studied in ADHD patients with comorbid SUD. METHODS/DESIGN: This paper presents the protocol of a randomized controlled trial to test the efficacy of an integrated CBT protocol aimed at reducing SUD as well as ADHD symptoms in SUD patients with a comorbid diagnosis of ADHD. The experimental group receives 15 CBT sessions directed at symptom reduction of SUD as well as ADHD. The control group receives treatment as usual, i.e. 10 CBT sessions directed at symptom reduction of SUD only. The primary outcome is the level of self-reported ADHD symptoms. Secondary outcomes include measures of substance use, depression and anxiety, quality of life, health care consumption and neuropsychological functions. DISCUSSION: This is the first randomized controlled trial to test the efficacy of an integrated CBT protocol for adult SUD patients with a comorbid diagnosis of ADHD. The rationale for the trial, the design, and the strengths and limitations of the study are discussed. PMID- 23663652 TI - Schizophrenia-related phenomena that challenge prediction error as the basis of cognitive functioning. AB - There are aspects of schizophrenia that pose challenges for Clark's model. These include: (1) evidence for excitatory activity underlying self-organizing neural ensembles that support coordinating functions, and their impairment in schizophrenia; (2) evidence regarding hallucinations that suggest they are not due to excessive prediction error; and (3) the critical role of emotional factors as setting conditions for delusion formation. PMID- 23663653 TI - Validation of the minimal citrate tube fill volume for routine coagulation tests on ACL TOP 500 CTS(r). AB - INTRODUCTION: CLSI recommends a minimal citrate tube fill volume of 90%. A validation protocol with clinical and analytical components was set up to determine the tube fill threshold for international normalized ratio of prothrombin time (PT-INR), activated partial thromboplastin time (aPTT) and fibrinogen. METHODS: Citrated coagulation samples from 16 healthy donors and eight patients receiving vitamin K antagonists (VKA) were evaluated. Eighty-nine tubes were filled to varying volumes of >50%. Coagulation tests were performed on ACL TOP 500 CTS((r)) . Receiver Operating Characteristic (ROC) plot, with Total error (TE) and critical difference (CD) as possible acceptance criteria, was used to determine the fill threshold. RESULTS: Receiving Operating Characteristic was the most accurate with CD for PT-INR and TE for aPTT resulting in thresholds of 63% for PT and 80% for aPTT. By adapted ROC, based on threshold setting at a point of 100% sensitivity at a maximum specificity, CD was best for PT and TE for aPTT resulting in thresholds of 73% for PT and 90% for aPTT. For fibrinogen, the method was only valid with the TE criterion at a 63% fill volume. CONCLUSION: In our study, we validated the minimal citrate tube fill volumes of 73%, 90% and 63% for PT-INR, aPTT and fibrinogen, respectively. PMID- 23663654 TI - Novel genomic resources for a climate change sensitive mammal: characterization of the American pika transcriptome. AB - BACKGROUND: When faced with climate change, species must either shift their home range or adapt in situ in order to maintain optimal physiological balance with their environment. The American pika (Ochotona princeps) is a small alpine mammal with limited dispersal capacity and low tolerance for thermal stress. As a result, pikas have become an important system for examining biotic responses to changing climatic conditions. Previous research using amplified fragment length polymorphisms (AFLPs) has revealed evidence for environmental-mediated selection in O. princeps populations distributed along elevation gradients, yet the anonymity of AFLP loci and lack of available genomic resources precluded the identification of associated gene regions. Here, we harnessed next-generation sequencing technology in order to characterize the American pika transcriptome and identify a large suite of single nucleotide polymorphisms (SNPs), which can be used to elucidate elevation- and site-specific patterns of sequence variation. RESULTS: We constructed pooled cDNA libraries of O. princeps from high (1400 m) and low (300 m) elevation sites along a previously established transect in British Columbia. Transcriptome sequencing using the Roche 454 GS FLX titanium platform generated 780 million base pairs of data, which were assembled into 7,325 high coverage contigs. These contigs were used to identify 24,261 novel SNP loci. Using high resolution melt analysis, we developed 17 of these SNPs into genotyping assays, which were validated with independent DNA samples from British Columbia Canada and Oregon State USA. In addition, we detected haplotypes in the NADH dehydrogenase subunit 5 of the mitochondrial genome that were fixed and different among elevations, suggesting that this may be an informative target gene for studying the role of cellular respiration in local adaptation. We also identified contigs that were unique to each elevation, including a high elevation specific contig that was a positive match with the hemoglobin alpha chain from the plateau pika, a species restricted to high elevation steppes in Asia. Elevation-specific contigs may represent candidate regions subject to differential levels of gene expression along this elevation gradient. CONCLUSIONS: To our knowledge, this is the first broad-scale, transcriptome-level study conducted within the Ochotonidae, providing novel genomic resources for studying pika ecology, behaviour and population history. PMID- 23663655 TI - Comment on Luo et al.: diabetes mellitus and the incidence and mortality of colorectal cancer: a meta-analysis of 24 cohort studies. PMID- 23663656 TI - Protein body formation in stable transgenic tobacco expressing elastin-like polypeptide and hydrophobin fusion proteins. AB - BACKGROUND: Plants are recognized as an efficient and inexpensive system to produce valuable recombinant proteins. Two different strategies have been commonly used for the expression of recombinant proteins in plants: transient expression mediated by Agrobacterium; or stable transformation of the plant genome. However, the use of plants as bioreactors still faces two main limitations: low accumulation levels of some recombinant proteins and lack of efficient purification methods. Elastin-like polypeptide (ELP), hydrophobin I (HFBI) and Zera(r) are three fusion partners found to increase the accumulation levels of recombinant proteins and induce the formation of protein bodies (PBs) in leaves when targeted to the endoplasmic reticulum (ER) in transient expression assays. In this study the effects of ELP and HFBI fusion tags on recombinant protein accumulation levels and PB formation was examined in stable transgenic Nicotiana tabacum. RESULTS: The accumulation of recombinant protein and PB formation was evaluated in two cultivars of Nicotiana tabacum transformed with green fluorescent protein (GFP) fused to ELP or HFBI, both targeted and retrieved to the ER. The ELP and HFBI tags increased the accumulation of the recombinant protein and induced the formation of PBs in leaves of stable transgenic plants from both cultivars. Furthermore, these tags induced the formation of PBs in a concentration-dependent manner, where a specific level of recombinant protein accumulation was required for PBs to appear. Moreover, agro-infiltration of plants accumulating low levels of recombinant protein with p19, a suppressor of post-transcriptional gene silencing (PTGS), increased accumulation levels in four independent transgenic lines, suggesting that PTGS might have caused the low accumulation levels in these plants. CONCLUSION: The use of ELP and HFBI tags as fusion partners in stable transgenic plants of tobacco is feasible and promising. In a constitutive environment, these tags increase the accumulation levels of the recombinant protein and induce the formation of PBs regardless of the cultivar used. However, a specific level of recombinant protein accumulation needs to be reached for PBs to form. PMID- 23663657 TI - Blockade of the negative co-stimulatory molecules PD-1 and CTLA-4 improves survival in primary and secondary fungal sepsis. AB - INTRODUCTION: Fungal sepsis is an increasingly common problem in intensive care unit patients.Mortality from fungal sepsis remains high despite antimicrobial therapy that is highly active against most fungal pathogens, a finding consistent with defective host immunity that is present in many patients with disseminated fungemia.One recently recognized immunologic defect that occurs in patients with sepsis is T cell "exhaustion" due to increased expression of programmed cell death -1 (PD-1).This study tested the ability of anti-PD-1 and anti-programmed cell death ligand -1 (anti-PD-L1) antagonistic antibodies to improve survival and reverse sepsis-induced immunosuppression in two mouse models of fungal sepsis. METHODS: Fungal sepsis was induced in mice using two different models of infection, that is, primary fungal sepsis and secondary fungal sepsis occurring after sub-lethal cecal ligation and puncture (CLP).Anti-PD-1 and anti-PD-L1 were administered 24 to 48 h after fungal infection and effects on survival, interferon gamma production, and MHC II expression were examined. RESULTS: Anti PD-1 and anti-PD-L1 antibodies were highly effective at improving survival in primary and secondary fungal sepsis.Both antibodies reversed sepsis-induced suppression of interferon gamma and increased expression of MHC II on antigen presenting cells.Blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4), a second negative co-stimulatory molecule that is up-regulated in sepsis and acts like PD 1 to suppress T cell function, also improved survival in fungal sepsis. CONCLUSIONS: Immuno-adjuvant therapy with anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies reverse sepsis-induced immunosuppression and improve survival in fungal sepsis.The present results are consistent with previous studies showing that blockade of PD-1 and CTLA-4 improves survival in bacterial sepsis.Thus, immuno-adjuvant therapy represents a novel approach to sepsis and may have broad applicability in the disorder.Given the relative safety of anti-PD-1 antibody in cancer clinical trials to date, therapy with anti-PD-1 in patients with life threatening sepsis who have demonstrable immunosuppression should be strongly considered. PMID- 23663658 TI - The effect of bosentan on exercise capacity in Fontan patients; rationale and design for the TEMPO study. AB - BACKGROUND: Palliative treatment with the Fontan procedure has greatly improved survival for children with functionally univentricular heart. Since Fontan performed the first successful operation, the procedure has evolved and is now performed as Total Cavo-Pulmonary Connection (TCPC).An increasing prevalence and longer life expectancy of TCPC patients have raised new challenges. The survivors are often suffering complications such as arrhythmias, myocardial dysfunction, thromboembolic events, neuropsychological deficit, protein-losing enteropathy and reduced exercise capacity. Several causes for the reduced exercise capacity may be present e.g. impaired function of the single ventricle, valve dysfunction and chronotropic impairment, and perhaps also increased pulmonary vascular resistance. Thus, plasma endothelin-1 has been shown to correlate with increased pulmonary vascular resistance and the risk of failing Fontan circulation. This has raised the question of the role for pulmonary vasodilation therapy, especially endothelin receptor antagonist in the management of TCPC patients. METHODS/DESIGN: The TEMPO trial aims to investigate whether Bosentan, an endothelin receptor antagonist, can be administered safely and improve exercise capacity in TCPC patients. The trial design is randomized, double-blind and placebo-controlled. Bosentan/placebo is administered for 14 weeks with control visits every four weeks. The primary endpoint is change in maximal oxygen consumption as assessed on bicycle ergometer test. Secondary endpoints include changes in pulmonary blood flow during exercise test, pro brain natriuretic peptide and quality of life. DISCUSSION: We hypothesize that treatment with Bosentan, an endothelin receptor antagonist, can be administered safely and improve exercise capacity in TCPC patients. PMID- 23663659 TI - Accuracy of tympanic temperature measurement using an infrared tympanic membrane thermometer. AB - BACKGROUND: During investigation and diagnosis of patients, accurate temperature measurement is of great importance. The advantages of tympanic membrane thermometry are speed (temperature reading available within seconds), safety, and ease of use. The aim of this study was to compare the accuracy of infrared tympanic thermometers in comparison to mercury thermometers in measurement of body temperature. METHODS: Axillary and tympanic temperature was measured simultaneously in consecutive patients using mercury glass and infrared tympanic thermometers at Omdurman Hospital, Sudan during October 2012. RESULTS: In total, temperature was measured in 174 patients, 95 of whom (54.6%) were male. The mean (SD) patient age and weight was 33.18 (25.07) years and 52.13 (69.85) kg. There was no significant difference in mean (SD) temperature measurement between mercury and infrared tympanic membrane thermometers, 37.29 degrees C (0.91) versus 37.38 degrees C (0.95), P = 0.373, respectively. There was a significant positive correlation between axillary and tympanic body temperature measurements (r = 0.697, P < 0.001). The mean difference between the two readings (with limits of agreements) was - 0.093 (-0.20; 0.02) degrees C. CONCLUSION: In this study, tympanic membrane thermometry is as reliable and accurate as axillary mercury glass thermometry. Thus, tympanic thermometry can be used in clinical practice, especially in the emergency setting, where ease of use and speed of obtaining the temperature reading are important. PMID- 23663660 TI - Rapid, responsive, relevant (R3) research: a call for a rapid learning health research enterprise. AB - Our current health research enterprise is painstakingly slow and cumbersome, and its results seldom translate into practice. The slow pace of health research contributes to findings that are less relevant and potentially even obsolete. To produce more rapid, responsive, and relevant research, we propose approaches that increase relevance via greater stakeholder involvement, speed research via innovative designs, streamline review processes, and create and/or better leverage research infrastructure. Broad stakeholder input integrated throughout the research process can both increase relevance and facilitate study procedures. More flexible and rapid research designs should be considered before defaulting to the traditional two-arm randomized controlled trial (RCT), but even traditional RCTs can be designed for more rapid findings. Review processes for grant applications, IRB protocols, and manuscript submissions can be better streamlined to minimize delays. Research infrastructures such as rapid learning systems and other health information technologies can be leveraged to rapidly evaluate new and existing treatments, and alleviate the extensive recruitment delays common in traditional research. These and other approaches are feasible but require a culture shift among the research community to value not only methodological rigor, but also the pace and relevance of research. PMID- 23663661 TI - Medial mandibulotomies: is there sufficient space in the midline to allow a mandibulotomy without compromising the dentition? AB - OBJECTIVES: The objective of this study was to determine the frequency of complications in median and paramedian mandibulotomies. In addition, the interdental space in the median and paramedian region was calculated. STUDY DESIGN: Retrospective study. SETTING: Tertiary care center. METHODS: A retrospective chart review was performed for all cases where a mandibulotomy was performed from 2002 to 2010. 117 charts (61 paramedian and 56 median) were identified. We included data on complications, which fell in the following 2 categories: plate and dental complications. For our second objective, we evaluated 40 different patients with base of tongue or tonsillar cancer treated with intensity modulated radiation therapy (IMRT). The interdental space between the lateral incisors and the canines was electronically calculated on the digital Panorex images. MAIN OUTCOME MEASURES: Dental and plate complications were evaluated. We also assessed interdental space. RESULTS: Patient characteristics were not significantly different. The median group had significantly more dental complications (p=0.0375, RD=0.19 and 95% CI (0.0139-0.3661)). The paramedian group had significantly more plate complications (p=0.0375, RD=0.082 and 95% CI (0.0131-0.1508). The distance between the central incisors was significantly less than the distance between the lateral incisors and canines both at the crestal and apical levels (p=0.0086 and p<0.001). CONCLUSIONS: There are significantly more dental complications in the median approach. There were significantly more plate complications in the paramedian group. In addition, there is significantly less space in the between the median region as compared to the paramedian region. This is the first study that documents the advantage of the paramedian approach for dental complications. PMID- 23663662 TI - Conservation of two distinct types of 100S ribosome in bacteria. AB - In bacteria, 70S ribosomes (consisting of 30S and 50S subunits) dimerize to form 100S ribosomes, which were first discovered in Escherichia coli. Ribosome modulation factor (RMF) and hibernation promoting factor (HPF) mediate this dimerization in stationary phase. The 100S ribosome is translationally inactive, but it dissociates into two translationally active 70S ribosomes after transfer from starvation to fresh medium. Therefore, the 100S ribosome is called the 'hibernating ribosome'. The gene encoding RMF is found widely throughout the Gammaproteobacteria class, but is not present in any other bacteria. In this study, 100S ribosome formation in six species of Gammaproteobacteria and eight species belonging to other bacterial classes was compared. There were several marked differences between the two groups: (i) Formation of 100S ribosomes was mediated by RMF and short HPF in Gammaproteobacteria species, similar to E. coli, whereas it was mediated only by long HPF in the other bacterial species; (ii) RMF/short HPF-mediated 100S ribosome formation occurred specifically in stationary phase, whereas long HPF-mediated 100S ribosome formation occurred in all growth phases; and (iii) 100S ribosomes formed by long HPF were much more stable than those formed by RMF and short HPF. PMID- 23663663 TI - Multimeric and differential binding of CIN85/CD2AP with two atypical proline-rich sequences from CD2 and Cbl-b*. AB - The CD2AP (CD2-associated protein) and CIN85 (Cbl-interacting protein of 85 kDa) adaptor proteins each employ three Src homology 3 (SH3) domains to cluster protein partners and ensure efficient signal transduction and down-regulation of tyrosine kinase receptors. Using NMR, isothermal titration calorimetry and small angle X-ray scattering methods, we have characterized several binding modes of the N-terminal SH3 domain (SH3A) of CD2AP and CIN85 with two natural atypical proline-rich regions in CD2 (cluster of differentiation 2) and Cbl-b (Casitas B lineage lymphoma), and compared these data with previous studies and published crystal structures. Our experiments show that the CD2AP-SH3A domain forms a type II dimer with CD2 and both type I and type II dimeric complexes with Cbl-b. Like CD2AP, the CIN85-SH3A domain forms a type II complex with CD2, but a trimeric complex with Cbl-b, whereby the type I and II interactions take place at the same time. Together, these results explain how multiple interactions among similar SH3 domains and ligands produce a high degree of diversity in tyrosine kinase, cell adhesion or T-cell signaling pathways. PMID- 23663665 TI - Highly reproducible surface-enhanced Raman scattering-active Au nanostructures prepared by simple electrodeposition: origin of surface-enhanced Raman scattering activity and applications as electrochemical substrates. AB - The fabrication of effective surface-enhanced Raman scattering (SERS) substrates has been the subject of intensive research because of their useful applications. In this paper, dendritic gold (Au) rod (DAR) structures prepared by simple one step electrodeposition in a short time were examined as an effective SERS-active substrate. The SERS activity of the DAR surfaces was compared to that of other nanostructured Au surfaces with different morphologies, and its dependence on the structural variation of DAR structures was examined. These comparisonal investigations revealed that highly faceted sharp edge sites present on the DAR surfaces play a critical role in inducing a high SERS activity. The SERS enhancement factor was estimated to be greater than 10(5), and the detection limit of rhodamine 6G at DAR surfaces was 10(-8)M. The DAR surfaces exhibit excellent spot-to-spot and substrate-to-substrate SERS enhancement reproducibility, and their long-term stability is very good. It was also demonstrated that the DAR surfaces can be effectively utilized in electrochemical SERS systems, wherein a reversible SERS behavior was obtained during the cycling to cathodic potential regions. Considering the straightforward preparation of DAR substrates and the clean nature of SERS-active Au surfaces prepared in the absence of additives, we expect that DAR surfaces can be used as cost-effective SERS substrates in analytical and electrochemical applications. PMID- 23663666 TI - Accurate determination of trace amounts of phosphorus in geological samples by inductively coupled plasma atomic emission spectrometry with ion-exchange separation. AB - In order to determine trace amounts of phosphorus in geological and cosmochemical rock samples, simple as well as reliable analytical schemes using an ICP-AES instrument were investigated. A (conventional) ICP-AES procedure could determine phosphorus contents at the level of several 100 MUg g(-1) with a reasonable reproducibility (<10% for 200 MUg g(-1); 1sigma). An ICP-AES procedure coupled with matrix-separation using cation and anion exchange resins could lower the quantification level down to 1 MUg g(-1) or even lower under the present experimental conditions. The matrix-separation ICP-AES procedure developed in this study was applied to twenty-one geological reference samples issued by Geological Survey of Japan. Obtained values vary from 1250 MUg g(-1) for JB-3 (basalt) to 2.07 MUg g(-1) for JCt-1 (carbonate). Matrix-separation ICP-AES yielded reasonable reproducibility (less than 8.3%; 1sigma) of three replicate analyses for all the samples analyzed. In comparison of our data with certificate values as well as literature or reported values, there appear to be an apparent (and large) discrepancy between our values and certificate/reported values regardless of phosphorus contents. Based on the reproducibility of our data and the analytical capability of the matrix-separation ICP-AES procedure developed in this study (in terms of quantification limit, recovery, selectivity of an analyte through pre-concentration process, etc.), it is concluded that certified values for several reference standard rocks should be reevaluated and revised accordingly. It may be further pointed that some phosphorus data reported in literatures should be critically evaluated when they are to be referred in later publications. PMID- 23663667 TI - Thorough tuning of the aspect ratio of gold nanorods using response surface methodology. AB - In the present work a central composite design based on response surface methodology (RSM) is employed for fine tuning of the aspect ratios of seed mediated synthesized gold nanorods (GNRs). The relations between the affecting parameters, including ratio of l-ascorbic acid to Au(3+) ions, concentrations of silver nitrate, CTAB, and CTAB-capped gold seeds, were explored using a RSM model. It is observed that the effect of each parameter on the aspect ratio of developing nanorods highly depends on the value of the other parameters. The concentrations of silver ions, ascorbic acid and seeds are found to have a high contribution in controlling the aspect ratios of NRs. The optimized parameters led to a high yield synthesis of gold nanorods with an ideal aspect ratio ranging from 1 (spherical particle) to 4.9. In addition, corresponding tunable surface Plasmon absorption band has been extended to 880 nm. The resulted nanorods were characterized by UV-visible spectrometry and transmission electron microscopy. PMID- 23663669 TI - Improved potentiometric response of solid-contact lanthanum (III) selective electrode. AB - For the first time, the analytical application of integrate ionophore-transducer material based on magnetic graphene hybrids and 2,2-dithiodipyridine (DTDP) in solid-contact lanthanum (III) selective electrode is reported. The attachment of Fe3O4 nanoparticles (NPs) to graphene oxide (GO) for magnetic graphene hybrid is achieved by covalent bonding, and the universal problem, Fe3O4 NPs may easily leach out from the graphene during application, is successfully solved by the method above. The proposed electrode exhibits an excellent near-Nernstian response to lanthanum (III) ranging from 1.0*10(-9) to 1.0*10(-3)M with a slope of 17.81 mV/dec. Moreover, the excellent performance on fairly good selectivity, wide applicable pH range (3.0(_)8.0), fast response time (10s) and long life time (2 months) reveal the superiority of the electrode. Most importantly, we have made a great improvement in the detection limit (2.75*10(-10)M), which brings new dawn to the real-time detection of lanthanum (III) using ion selective electrode. PMID- 23663668 TI - Fabrication of beta-cyclodextrin-coated poly (diallyldimethylammonium chloride) functionalized graphene composite film modified glassy carbon-rotating disk electrode and its application for simultaneous electrochemical determination colorants of sunset yellow and tartrazine. AB - We proposed a green and facile approach for the synthesis of beta-cyclodextrin coated poly(diallyldimethylammonium chloride)-functionalized graphene composite film (beta-CD-PDDA-Gr) by using L-ascorbic acid (L-AA) as the reducing agent at room temperature. The beta-CD-PDDA-Gr composite film modified glassy carbon rotating disk electrode (GC-RDE) was then developed for the sensitive simultaneous determination of two synthetic food colorants: sunset yellow (SY) and tartrazine (TT). By cyclic voltammetry (CV), the peak currents of SY and TT increased obviously on the developed electrochemical sensor. The kinetic parameters, such as diffusion coefficient D and standard heterogeneous rate constant kb, were estimated by linear sweep voltammetry (LSV). Under the optimal conditions, the differential pulse voltammetry (DPV) signals of SY and TT on the beta-CD-PDDA-Gr modified GC-RDE were significantly enhanced. The enhanced anodic peak currents represented the excellent analytical performance of simultaneous detection of SY and TT in the range of 5.0*10(-8) to 2.0*10(-5) mol L(-1), with a low limit of detection (LOD) of 1.25*10(-8) mol L(-1) for SY and 1.43*10(-8) mol L(-1) for TT (SN(-1)=3). This proposed method displayed outstanding selectivity, good stability and acceptable repeatability and reproducibility, and also has been used to simultaneously determine SY and TT in some commercial soft drinks with satisfactory results. The obtained results were compared to HPLC of analysis for those two colorants and no significant differences were found. By the treatment of the experimental data, the electrochemical reaction mechanisms of SY and TT both involved a one-electron-one-proton-transfer process. PMID- 23663670 TI - Differences in infrared spectroscopic data of connective tissues in transflectance and transmittance modes. AB - Fourier transform infrared imaging spectroscopy (FT-IRIS) has been used extensively to characterize the composition and orientation of macromolecules in thin tissue sections. Earlier and current studies of normal and polarized FT-IRIS data have primarily used tissues sectioned onto infrared transmissive substrates, such as salt windows. Recently, the use of low-emissivity ("low-e") substrates has become of great interest because of their low cost and favorable infrared optical properties. However, data are collected in transflectance mode when using low-e slides and in transmittance mode using salt windows. In the current study we investigated the comparability of these two modes for assessment of the composition of connective tissues. FT-IRIS data were obtained in transflectance and transmittance modes from serial sections of cartilage, bone and tendon, and from a standard polymer, polymethylmethacrylate. Both non-polarized and polarized FTIR data differed in absorbance, and in some cases peak position, between transflectance and transmittance modes. However, the FT-IRIS analysis of the collagen fibril orientation in cartilage resulted in the expected zonal arrangement of fibrils in both transmittance and transflectance. We conclude that numerical comparison of FT-IRIS-derived parameters of tissue composition should account for substrate type and data collection mode, while analysis of overall tissue architecture may be more invariant between modes. PMID- 23663671 TI - Investigating the feasibility of mid infrared spectroscopy for monitoring an industrial de-racemization biotransformation process. AB - Biotransformation processes have become industrially important in recent years as routes to the manufacture of high value chemical intermediates. However, measurements of key process features and analyte concentrations during these processes are still typically carried out using off-line analysis methods. Vibrational spectroscopic techniques have been extensively utilised for the monitoring and control of a variety of industrial processes. Despite the techniques success with a range of challenging biological matrices, including fermentation and cell culture systems, application of this approach to biotransformation systems has been limited. In the present study the potential of mid infrared spectroscopy to monitor an industrially relevant de-racemization biotransformation process has been investigated. This process presents a number of difficulties due to the optically challenging sample media, close structural similarities and stoichiometric relationship between the key analytes of interest. A PLS model based on the mid infrared spectra obtained during three replicates of the biotransformation process was constructed. In order to ensure that co-linearity within the system had been adequately addressed the spectral contributors to the model were examined. External validation of the constructed model was achieved by challenging the model with two previously unseen replicates of the process. The constructed model was able to predict the concentrations of two key analytes in various samples from these unseen replicates without the requirement for any time consuming sample pre-treatment stages, thus demonstrating the feasibility of near real-time mid infrared monitoring of such an industrial de-racemization biotransformation process. PMID- 23663672 TI - Direct measurement of ammonia in simulated human breath using an inkjet-printed polyaniline nanoparticle sensor. AB - A sensor fabricated from the inkjet-printed deposition of polyaniline nanoparticles onto a screen-printed silver interdigitated electrode was developed for the detection of ammonia in simulated human breath samples. Impedance analysis showed that exposure to ammonia gas could be measured at 962 Hz at which changes in resistance dominate due to the deprotonation of the polymer film. Sensors required minimal calibration and demonstrated excellent intra-electrode baseline drift (<=1.67%). Gases typically present in breath did not interfere with the sensor. Temperature and humidity were shown to have characteristic impedimetric and temporal effects on the sensor that could be distinguished from the response to ammonia. While impedance responses to ammonia could be detected from a single simulated breath, quantification was improved after the cumulative measurement of multiple breaths. The measurement of ammonia after 16 simulated breaths was linear in the range of 40-2175 ppbv (27-1514 MUg m(-3)) (r(2)=0.9963) with a theoretical limit of detection of 6.2 ppbv (4.1 MUg m(-3)) (SN(-1)=3). PMID- 23663673 TI - Microfluidic bead-based multienzyme-nanoparticle amplification for detection of circulating tumor cells in the blood using quantum dots labels. AB - This study reports the development of a microfluidic bead-based nucleic acid sensor for sensitive detection of circulating tumor cells in blood samples using multienzyme-nanoparticle amplification and quantum dot labels. In this method, the microbeads functionalized with the capture probes and modified electron rich proteins were arrayed within a microfluidic channel as sensing elements, and the gold nanoparticles (AuNPs) functionalized with the horseradish peroxidases (HRP) and DNA probes were used as labels. Hence, two signal amplification approaches are integrated for enhancing the detection sensitivity of circulating tumor cells. First, the large surface area of Au nanoparticle carrier allows several binding events of HRP on each nanosphere. Second, enhanced mass transport capability inherent from microfluidics leads to higher capture efficiency of targets because continuous flow within micro-channel delivers fresh analyte solution to the reaction site which maintains a high concentration gradient differential to enhance mass transport. Based on the dual signal amplification strategy, the developed microfluidic bead-based nucleic acid sensor could discriminate as low as 5 fM (signal-to-noise (S/N)3) of synthesized carcinoembryonic antigen (CEA) gene fragments and showed a 1000-fold increase in detection limit compared to the off-chip test. In addition, using spiked colorectal cancer cell lines (HT29) in the blood as a model system, the detection limit of this chip-based approach was found to be as low as 1 HT29 in 1 mL blood sample. This microfluidic bead-based nucleic acid sensor is a promising platform for disease-related nucleic acid molecules at the lowest level at their earliest incidence. PMID- 23663675 TI - Silica nanoparticle supported molecularly imprinted polymer layers with varied degrees of crosslinking for lysozyme recognition. AB - Surface imprinting over nanosized support materials is particularly suitable for protein templates, considering the problems with mass transfer limitation and low binding capacity. Previously we have demonstrated a strategy for surface protein imprinting over vinyl-modified silica nanopartiles with lysozyme as a model template by polymerization in high-dilution monomer solution to prevent macrogelation. Herein, the synthesis process was further studied toward enhancement of the imprinting performance by examining the effect of several synthesis conditions. Interestingly, the feed crosslinking degree was found to have a great impact on the thickness of the formed imprinting polymer layers and the recognition properties of the resulting imprinted materials. The imprinted particles with a crosslinking degree up to 50% showed the best imprinting effect. The imprinting factor achieved 2.89 and the specific binding reached 23.3 mg g( 1), which are greatly increased compared to those of the lowly crosslinked imprinted materials reported previously. Moreover, the relatively high crosslinking degree led to no significant retarding of the binding kinetics to the imprinted particles, and the saturated adsorption was reached within 10 min. Therefore, this may be a promising method for protein imprinting. PMID- 23663674 TI - Self-assembly and imprinting of macrocyclic molecules in layer-by-layered TiO2 ultrathin films. AB - Alternate TiO2 gel ultrathin films assembled with a macrocyclic carboxylic acids of tetrakis-4-carboxyphenyl porphine (TCPP) or tetra-4-carboxylphthalocyanine cobalt (II) (Co-TCPc) were prepared by the surface sol-gel process. To confirm the film growth and imprinting effect, quartz crystal microbalance (QCM) and UV vis spectroscopy measurements were employed. The binding of TCPP was 1.2-14.3 times more selective compared to structurally related macrocyclic guest molecules. Among other findings, tetrakis-4-carboxymethyloxyphenyl porphine (TCMOPP) that has a spacer (-O-CH2-) between the phenyl rings and carboxylic acid moieties of TCPP showed a significantly lower binding efficiency equal to 0.07, regardless of its similar molecular structure to the template molecule. Structural difference of porphyrin and phthalocyanine analogs could be also selectively discriminated: the TCPP imprinted film showed ca. 13 times higher selectivity for recognition of TCPP itself from the mixture of TCPP and Co-TCPc. Characterization by AFM demonstrated that the TiO2/TCPP film has highly uniform surface and ultrathin thickness, while both TEM and SEM studies confirmed the immobilized structures of TCPP inside the film. PMID- 23663676 TI - Thickness and morphology of polyelectrolyte coatings on silica surfaces before and after protein exposure studied by atomic force microscopy. AB - Analyte-wall interaction is a significant problem in capillary electrophoresis (CE) as it may compromise separation efficiencies and migration time repeatability. In CE, self-assembled polyelectrolyte multilayer films of Polybrene (PB) and dextran sulfate (DS) or poly(vinylsulfonic acid) (PVS) have been used to coat the capillary inner wall and thereby prevent analyte adsorption. In this study, atomic force microscopy (AFM) was employed to investigate the layer thickness and surface morphology of monolayer (PB), bilayer, (PB-DS and PB-PVS), and trilayer (PB-DS-PB and PB-PVS-PB) coatings on glass surfaces. AFM nanoshaving experiments providing height distributions demonstrated that the coating procedures led to average layer thicknesses between 1 nm (PB) and 5 nm (PB-DS-PB), suggesting the individual polyelectrolytes adhere flat on the silica surface. Investigation of the surface morphology of the different coatings by AFM revealed that the PB coating does not completely cover the silica surface, whereas full coverage was observed for the trilayer coatings. The DS-containing coatings appeared on average 1 nm thicker than the corresponding PVS-containing coatings, which could be attributed to the molecular structure of the anionic polymers applied. Upon exposure to the basic protein cytochrome c, AFM measurements showed an increase of the layer thickness for bare (3.1 nm) and PB-DS-coated (4.6 nm) silica, indicating substantial protein adsorption. In contrast, a very small or no increase of the layer thickness was observed for the PB and PB-DS-PB coatings, demonstrating their effectiveness against protein adsorption. The AFM results are consistent with earlier obtained CE data obtained for proteins using the same polyelectrolyte coatings. PMID- 23663677 TI - Metal organic framework-organic polymer monolith stationary phases for capillary electrochromatography and nano-liquid chromatography. AB - In this study, metal organic framework (MOF)-organic polymer monoliths prepared via a 5-min microwave-assisted polymerization of ethylene dimethacrylate (EDMA), butyl methacrylate (BMA), and 2-acrylamido-2-methylpropane sulfonic acid (AMPS) with the addition of various weight percentages (30-60%) of porous MOF (MIL 101(Cr)) were developed as stationary phases for capillary electrochromatography (CEC) and nano-liquid chromatography (nano-LC). Powder X-ray diffraction (PXRD) patterns and nitrogen adsorption/desorption isotherms of these MOF-organic polymer monoliths showed the presence of the inherent characteristic peaks and the nano-sized pores of MIL-101(Cr), which confirmed an unaltered crystalline MIL 101(Cr) skeleton after synthesis; while energy dispersive spectrometer (EDS) and micro-FT-IR spectra suggested homogenous distribution of MIL-101(Cr) in the MIL 101(Cr)-poly(BMA-EDMA) monoliths. This hybrid MOF-polymer column demonstrated high permeability, with almost 800-fold increase compared to MOF packed column, and efficient separation of various analytes (xylene, chlorotoluene, cymene, aromatic acids, polycyclic aromatic hydrocarbons and trypsin digested BSA peptides) either in CEC or nano-LC. This work demonstrated high potentials for MOF-organic polymer monolith as stationary phase in miniaturized chromatography for the first time. PMID- 23663678 TI - Perception versus action: the computations may be the same but the direction of fit differs. AB - Although predictive coding may offer a computational principle that unifies perception and action, states with different directions of fit are involved (with indicative and imperative contents, respectively). Predictive states are adjusted to fit the world in the course of perception, but in the case of action, the corresponding states act as a fixed target towards which the agent adjusts the world. This well-recognised distinction helps side-step some problems discussed in the target article. PMID- 23663679 TI - Obesity effect on a multimodal physiotherapy program for low back pain suffers: patient reported outcome. AB - BACKGROUND: Several studies have linked obesity to the increased likelihood of lower back pain, but there are no studies focussing on the effectiveness of a multimodal physiotherapy programme (MPP) in obese subjects who suffer from chronic non-specific lower back pain (CNLBP). The aim of this study was to compare the effectiveness of an MPP in obese (G1) (body mass index (BMI):>=30) and non-obese (G2) (BMI:<30) patients with CNLBP. METHODS: A quasi-experimental study with pre- and post-intervention evaluations of an MPP (lasting 8 weeks) was conducted on obese and non-obese patients with CNLBP. A total of 53 people were included in the study: G1, composed of 19 patients (10 men and 9 women) with a BMI of 33.75 and a mean age of 52.94 years, and G2, composed of 34 patients (18 men and 16 women) with a mean age of 49.19 years and an average BMI of 25.56. All patients were measured to calculate pre-intervention (baseline) and post intervention (8 weeks) changes in disability (RMQ) and health related quality of life in physical and mental health component state of SF12 and quality of life (EQ-5D and EQ-VAS). RESULTS: Post-intervention, non-obese group shown significant high improve than obese group in disability (RMQ: 4.00), physical component state of SF-12: (-7.26) and quality of life (EQ-VAS.: -10.49). CONCLUSIONS: In patients with CNLBP, a BMI more than or equal to 30 minimises the effects of an MPP lasting 8 weeks. PMID- 23663680 TI - Temperature dependence of time-resolved photoluminescence in closely packed alignment of Si nanodisks with SiC barriers. AB - We study the temperature dependence of time-resolved photoluminescence (PL) in closely packed alignment of Si nanodisks (NDs) with SiC barriers, fabricated by neutral beam etching using bio-nano-templates. The PL time profile indicates three decaying components with different decay times. The PL intensities in the two slower decaying components depend strongly on temperature. These temperature dependences of the PL intensity can be quantitatively explained by a three-level model with thermal activation energies of 410 and 490 meV, depending on the PL components. The activation energies explain PL quenching due to thermal escape of electrons from individual NDs. This thermal escape affects the PL decay times above 250 K. Dark states of photo-excited carriers originating from the separate localization of electron and hole into different NDs are elucidated with the localization energies of 70 and 90 meV. In contrast, the dynamics of the fastest PL decaying component is dominated by electron tunneling among NDs, where the PL intensity and decay time are constant for temperature. PMID- 23663681 TI - Henoch-Schonlein purpura nephritis and IgA nephropathy: a comparative clinical study. AB - OBJECTIVES: Henoch-Schonlein purpura nephritis (HSPN) and IgA nephropathy (IgAN) are related syndromes. In the present study we aimed to compare the clinical characteristics and outcome of a large and unselected series of patients diagnosed as having HSPN and IgAN. METHODS: Comparative study of a wide and unselected population of HSPN (142 patient) and IgAN (61 patients) from a teaching hospital of Northern Spain. RESULTS: All of the following comparisons were expressed between HSPN vs. IgAN, respectively. HSPN patients were younger (30.6+/-26.4 vs. 37.1+/-16.5 years, p<0.001). Precipitating events, usually an upper respiratory tract infection and/or drug intake, were more frequently observed in HSPN (38% vs. 23%, p=0.03). Extra-renal manifestations were also more common in HSPN than in IgAN; skin lesions (100% vs. 1.8%; p<0.001), gastrointestinal (62% vs. 7.4%; p<0.001), and joint involvement (61.3% vs. 3.6%; p<0.001). However, nephritis was less severe in HSPN, renal insufficiency (25% in HSPN vs. 63.4% in IgAN; p<0.001), nephrotic syndrome (12.5%, vs. 43.7%; p<0.001), and nephritic syndrome (6.8% vs. 10.7%; NS). Leukocytosis was more frequent in HSPN (22.5% vs. 8.2%; p=0.015) and anaemia in IgAN (12.7% in HSPN vs. 36% in IgAN, p<0.001). The frequency of corticosteroid (79.6% vs. 69%; NS) and cytotoxic drug (19% vs. 16.5%, NS) use was similar. The frequency of relapses was similar (38.6% in HSPN vs. 36.3% in IgAN). After a median follow-up of 120.8 (IQR; 110 132) months in HSPN and 138.6 (IQR; 117-156) in IgAN, requirement for dialysis (2.9% vs. 43.5%; p<0.001), renal transplant (0% vs. 36%, p<0.001) and residual chronic renal insufficiency (4.9% vs. 63.8%; p<0.001) was more frequently observed in patients with in IgAN. CONCLUSIONS: HSPN and IgAN represent different syndromes. IgAN has more severe renal involvement while HSPN is associated with more extra-renal manifestations. PMID- 23663682 TI - Incidence of granulomatosis with polyangiitis (Wegener's) in Greenland and the Faroe Islands: epidemiology of an ANCA-associated vasculitic syndrome in two ethnically distinct populations in the North Atlantic area. AB - OBJECTIVES: Previous studies suggest that the incidence of granulomatosis with polyangiitis (Wegener's; GPA) increases along a south-north gradient in the Northern Hemisphere with an incidence of 8.0/million/year reported for the population of Northern Norway. In the present study, we assessed the incidence of GPA in the predominantly Inuit population of Greenland and in the Caucasian population of the Faroe Islands. METHODS: Greenlandic and Faroese patients affected by severe rheumatic diseases are routinely referred to the National University Hospital in Denmark for treatment. By means of the Danish National Hospital register, we identified all Greenlandic and Faroese patients treated at the hospital under a diagnosis of GPA during 1992-2011. For each patient, the GPA diagnosis was validated by medical files review. RESULTS: One patient born and living in Greenland and 6 from the Faroe Islands were identified. The incidence of GPA was 1.0/million/year (95% CI 0.02-5.6) in Greenland and 6.4/million/year (95% 2.4-14.0) in the Faroe Islands. During the period of study, no cases of GPA occurred among Greenlanders aged 0-44 years, while an incidence of 4.1/million/year (95% CI: 0.1-22.9) was calculated for those aged >=45 years. In the Faroese population, incidences of 1.7/million/year (95% CI 0.4-9.4) and 14.8/million/year (95% CI 4.8-34.6) were calculated for the age-groups 0-44 and >=45 years, respectively. CONCLUSIONS: The occurrence of GPA is lower among Inuit in Greenland than among Caucasians living in the Faroe Islands. This observation demonstrates that the risk of GPA varies across ethnic groups populating the northernmost regions of the world. PMID- 23663683 TI - Progressive multifocal encephalopathy after cyclophosphamide in granulomatosis with polyangiitis (Wegener) patients: case report and review of literature. AB - Progressive multifocal encephalopathy (PML) is a rare demyelinating disorder targeting the central nervous system and resulting from JC virus reactivation. PML occurs in patients immunocompromised because of haematological malignancies, HIV infection or treatment with cytotoxic drugs. Herein, we describe PML occurring in 2 granulomatosis with polyangiitis (Wegener) patients treated with steroids and cyclophosphamide. The outcome was progressively favourable after immunosuppressant discontinuation for 1 patient and fatal for the other. Four previously reported GPA patients developed PML in the course of their disease. One of them improved gradually after immunosuppressant withdrawal. PML should be strongly suspected whenever unusual central neurological manifestations appear in this context. No effective treatment is available, but immunosuppressants should be discontinued if possible. PMID- 23663684 TI - Pathogenesis of giant cell arteritis: new insight into the implication of CD161+ T cells. AB - Giant cell arteritis (GCA) is a granulomatous large-vessel vasculitis that usually affects the aorta and/or its major branches, especially the branches of the carotid arteries. Histo-pathological lesions are observed in all layers of the artery leading to segmental and focal panarteritis with a polymorphic cell infiltrate that includes T cells, macrophages and multinucleated giant cells, a fragmented internal elastic lamina and intimal hyperplasia. The pathophysiology of GCA is complex and not fully understood. In this review, we discuss the immunological aspects of GCA pathogenesis with a particular emphasis on T cell responses. Upon dendritic cell activation in the adventitia, CD4 T cells co expressing CD161 are recruited in the arterial wall and polarised into Th1 and Th17 cells that produce IFN-gamma and IL-17, respectively. These cytokines activate macrophages, giant cells and vascular smooth muscle cells, thus inducing vascular remodelling which leads to the ischaemic manifestations of GCA. Macrophages infiltrating the adventitia produce IL-1beta and IL-6, which are responsible for the general symptoms encountered in GCA. PMID- 23663685 TI - Seven clinical conundrums in the treatment of ANCA-associated vasculitis. AB - Granulomatosis with polyangiitis and microscopic polyangiitis are two autoimmune diseases characterised by necrotising small-vessel vasculitis and presence of antineutrophil cytoplasm autoantibodies (ANCA). Current immunosuppressive regimes that combine cyclophosphamide and glucocorticoids have dramatically improved the outcome for these patients. However, these treatments are associated with toxic effects and do not lead to permanent remission in the majority of cases. Newer approaches have been sought during the last 15 years, with improvement in medication protocols and inclusion of novel therapies. This review develops on seven clinical conundrums of evidence-based therapeutic strategies for ANCA vasculitis, posed as questions on aspects such as the role of established drugs in both remission induction and maintenance: glucocorticoids (and its duration), oral cyclophosphamide, methotrexate, TNF-alpha blockers, plasma exchange, mycophenolate mofetil, plus one related to newer developments in treatment with agents blocking the complement system and the possible role of sequential or combined therapies, mainly directed against B cells. PMID- 23663686 TI - Systemic vasculitis: a critical digest of the recent literature. AB - Herewith we provide a critical digest of the recent literature on systemic vasculitis. In this manuscript, we reviewed all the articles published during the last 12 months on large-, medium- and small-vessel vasculitis and selected the most relevant studies regarding the epidemiology, pathogenesis and management of systemic vasculitis. In particular we focused the attention on giant cell arteritis, ANCA-associated vasculitis and cryoglobulinemia. PMID- 23663687 TI - Ocular involvement in giant cell arteritis. PMID- 23663688 TI - Effects of polyunsaturated fatty acids on the growth of gastric cancer cells in vitro. AB - Polyunsaturated fatty acids (PUFAs) have tumoricidal action, though the exact mechanism of their action is not clear. The results of the present study showed that of all the fatty acids tested, linoleic acid (LA) and alpha-linolenic acid (ALA) were the most effective in suppressing the growth of normal gastric cells (GES1) at 180 and 200 MUM, while gastric carcinoma cells (MGC and SGC) were inhibited at 200 MUM. Arachidonic acid (AA) suppressed the growth of GES1, MGC and SGC cells and lower concentrations (120 and 160 MUM) of AA were more effective against gastric carcinoma (MGC and SGC) cells compared to normal gastric cells (GES1). Paradoxically, both eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids though are more unsaturated than AA, were less effective compared with LA, ALA and AA in suppressing the growth of both normal and cancer cells. At the concentration used, methotrexate showed much less growth suppressive action compared to all the fatty acids tested. PUFAs-treated cells showed accumulation of lipid droplets. A close association was noted between apoptosis and lipid peroxides formed compared to the ability of normal and tumor cells to generate ROS (reactive oxygen species) and induce SOD (superoxide dismutase activity) in response to fatty acids tested and methotrexate. Both normal and tumor cells generated lipoxin A4 (LXA4) in response to supplementation of fatty acids and methotrexate though no significant correlation was noted between their ability to induce apoptosis and LXA4 formed. These results suggest that PUFAs induced apoptosis of normal gastric and gastric carcinoma cells could, partly, be attributed to lipid peroxidation process. PMID- 23663689 TI - Leukocyte cell population data (volume conductivity scatter) in postprandial leukocyte activation. AB - INTRODUCTION: Changes in leukocyte cell population data have been reported in various infectious diseases, but little is known in other inflammatory conditions such as the postprandial state. We investigated whether leukocyte cell population data change during postprandial leukocyte activation. METHODS: Healthy volunteers underwent a standardized oral fat loading test (OFLT). Flowcytometric quantitation of leukocyte activation markers CD11b, CD66b, CD35, and CD36, together with leukocyte cell population data from LH750 hematology analyzers were measured fasting and at 4 and 8 h postprandially. RESULTS: Twelve volunteers were included. Postprandial leukocyte activation was confirmed by increased expression of CD11b by monocytes (+11.7%) and neutrophils (+15.0%) and by increased expression of CD66b (+14.7%) and CD35 (+16.6%) by neutrophils at T = 4 h. The mean scatter from neutrophils, reflecting granularity, significantly decreased at T = 4 h (P < 0.05) and returned to baseline at T = 8 h (P-anova 0.048). The mean volume of monocytes increased significantly at T = 4 h (P < 0.001) and returned to baseline at T = 8 h (P-anova 0.0008). At T = 4 h, CD11b expression on neutrophils was associated with a reduction in mean scatter of neutrophils (Pearson's r: -0.677, P = 0.016). CONCLUSION: Postprandial leukocyte activation is accompanied by temporary changes in leukocyte cell population data, similar to changes observed during various infections, but to a lesser extent. PMID- 23663690 TI - Prevalence of obesity and overweight among Chinese children with attention deficit hyperactivity disorder: a survey in Zhejiang Province, China. AB - BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is often comorbid with psychiatric and developmental disorders. This study aimed to investigate the prevalence of obesity and overweight among Chinese children with ADHD, and to explore which subtypes of the disorder may specifically be associated with obesity/overweight. METHODS: Children meeting the DSM-IV criteria for ADHD were enrolled in the study. Weight, weight z-score, height, height z-score, BMI, and BMI z-score were used to evaluate growth status. Obesity and overweight were determined using the National Growth Reference for Chinese Children and Adolescents. Relations between the prevalence of obesity/overweight and different ADHD subtypes and pubertal development were analyzed. RESULTS: A total of 158 children with ADHD (mean age: 9.2 years) were recruited for the study. The prevalences of obesity, overweight, and combined obesity/overweight were 12.0%, 17.1%, and 29.1%, respectively, which were significantly higher than in the general Chinese population (2.1%, 4.5%, and 6.6%, respectively). Multivariable analysis showed that the children with the combined subtype of ADHD and the onset of puberty were at a higher risk of becoming obese or overweight. CONCLUSIONS: The prevalence of obesity in Chinese children with ADHD is higher than that of the general population. Children with the ADHD combined subtype who were at the onset of puberty were more likely to be overweight or obese. PMID- 23663691 TI - Transcriptional analysis of oligosaccharide utilization by Bifidobacterium lactis Bl-04. AB - BACKGROUND: Probiotic bifidobacteria in combination with prebiotic carbohydrates have documented positive effects on human health regarding gastrointestinal disorders and improved immunity, however the selective routes of uptake remain unknown for most candidate prebiotics. The differential transcriptomes of Bifidobacterium animalis subsp. lactis Bl-04, induced by 11 potential prebiotic oligosaccharides were analyzed to identify the genetic loci involved in the uptake and catabolism of alpha- and beta-linked hexoses, and beta-xylosides. RESULTS: The overall transcriptome was modulated dependent on the type of glycoside (galactosides, glucosides or xylosides) utilized. Carbohydrate transporters of the major facilitator superfamily (induced by gentiobiose and beta-galacto-oligosaccharides (GOS)) and ATP-binding cassette (ABC) transporters (upregulated by cellobiose, GOS, isomaltose, maltotriose, melibiose, panose, raffinose, stachyose, xylobiose and beta-xylo-oligosaccharides) were differentially upregulated, together with glycoside hydrolases from families 1, 2, 13, 36, 42, 43 and 77. Sequence analysis of the identified solute-binding proteins that determine the specificity of ABC transporters revealed similarities in the breadth and selectivity of prebiotic utilization by bifidobacteria. CONCLUSION: This study identified the differential gene expression for utilization of potential prebiotics highlighting the extensive capabilities of Bifidobacterium lactis Bl-04 to utilize oligosaccharides. Results provide insights into the ability of this probiotic microbe to utilize indigestible carbohydrates in the human gastrointestinal tract. PMID- 23663693 TI - When the predictive brain gets it really wrong. AB - Clark examines the notion of the "predictive brain" as a unifying model for cognitive neuroscience, from the level of basic neural processes to sensorimotor control. Although we are in general agreement with this notion, we feel that there are many details that still need to be fleshed out from the standpoint of perception and action. PMID- 23663692 TI - A detergent-free strategy for the reconstitution of active enzyme complexes from native biological membranes into nanoscale discs. AB - BACKGROUND: The reconstitution of membrane proteins and complexes into nanoscale lipid bilayer structures has contributed significantly to biochemical and biophysical analyses. Current methods for performing such reconstitutions entail an initial detergent-mediated step to solubilize and isolate membrane proteins. Exposure to detergents, however, can destabilize many membrane proteins and result in a loss of function. Amphipathic copolymers have recently been used to stabilize membrane proteins and complexes following suitable detergent extraction. However, the ability of these copolymers to extract proteins directly from native lipid bilayers for subsequent reconstitution and characterization has not been explored. RESULTS: The styrene-maleic acid (SMA) copolymer effectively solubilized membranes of isolated mitochondria and extracted protein complexes. Membrane complexes were reconstituted into polymer-bound nanoscale discs along with endogenous lipids. Using respiratory Complex IV as a model, these particles were shown to maintain the enzymatic activity of multicomponent electron transporting complexes. CONCLUSIONS: We report a novel process for reconstituting fully operational protein complexes directly from cellular membranes into nanoscale lipid bilayers using the SMA copolymer. This facile, single-step strategy obviates the requirement for detergents and yields membrane complexes suitable for structural and functional studies. PMID- 23663699 TI - Abstracts of the Annual Scientific Meeting of the British Association of Urological Surgeons 2013. Manchester, United Kingdom. June 17-20, 2013. PMID- 23663694 TI - Serum biomarkers of papillary thyroid cancer. AB - OBJECTIVE: To identify serum biomarkers of papillary thyroid cancer. METHODS: Prospective analysis was performed of banked tumor and serum specimens from 99 patients with thyroid masses. Enzyme-linked immunosorbent assay (ELISA) was employed to measure levels of five serum proteins previously demonstrated to be up-regulated in papillary thyroid cancer (PTC): angiopoietin-1 (Ang-1), cytokeratin 19 (CK-19), tissue inhibitor of metalloproteinase-1 (TIMP-1), chitinase 3 like-1 (YKL-40), and galectin-3 (GAL-3). Serum levels were compared between patients with PTC and those with benign tumors. RESULTS: A total of 99 patients were enrolled in the study (27 men, 72 women), with a median age of 54 years. Forty-three patients had PTC and 58 cases were benign tumors. There were no statistically significant differences when comparing all five different biomarkers between PTC and other benign thyroid tumors. The p-values were 0.94, 0.48, 0.72, 0.48, and 0.90 for YKL-40, Gal-3, CK19, TIMP-1, and Ang-1, respectively. CONCLUSION: Serum levels of four of the five proteins were elevated in patients with thyroid masses relative to normal values. However, the difference between benign and PTC was not significant. Two of the markers (Gal-3 & TIMP-1) displayed a greater potential difference, which may warrant further investigation. This study suggests that other serum markers should be sought. This is the first study to investigate potential serum biomarkers based on over expressed proteins in thyroid cancer versus benign pathology. PMID- 23663695 TI - Antithrombin attenuates myocardial dysfunction and reverses systemic fluid accumulation following burn and smoke inhalation injury: a randomized, controlled, experimental study. AB - INTRODUCTION: We hypothesized that maintaining physiological plasma levels of antithrombin attenuates myocardial dysfunction and inflammation as well as vascular leakage associated with burn and smoke inhalation injury. Therefore, the present prospective, randomized experiment was conducted using an established ovine model. METHODS: Following 40% of total body surface area, third degree flame burn and 4 * 12 breaths of cold cotton smoke, chronically instrumented sheep were randomly assigned to receive an intravenous infusion of 6 IU/kg/h recombinant human antithrombin (rhAT) or normal saline (control group; n = 6 each). In addition, six sheep were designated as sham animals (not injured, continuous infusion of vehicle). During the 48 h study period the animals were awake, mechanically ventilated and fluid resuscitated according to standard formulas. RESULTS: Compared to the sham group, myocardial contractility was severely impaired in control animals, as suggested by lower stroke volume and left ventricular stroke work indexes. As a compensatory mechanism, heart rate increased, thereby increasing myocardial oxygen consumption. In parallel, myocardial inflammation was induced via nitric oxide production, neutrophil accumulation (myeloperoxidase activity) and activation of the p38-mitogen activated protein kinase pathway resulting in cytokine release (tumor necrosis factor-alpha, interleukin-6) in control vs. sham animals. rhAT-treatment significantly attenuated these inflammatory changes leading to a myocardial contractility and myocardial oxygen consumption comparable to sham animals. In control animals, systemic fluid accumulation progressively increased over time resulting in a cumulative positive fluid balance of about 4,000 ml at the end of the study period. Contrarily, in rhAT-treated animals there was only an initial fluid accumulation until 24 h that was reversed back to the level of sham animals during the second day. CONCLUSIONS: Based on these findings, the supplementation of rhAT may represent a valuable therapeutic approach for cardiovascular dysfunction and inflammation after burn and smoke inhalation injury. PMID- 23663700 TI - Novel study design to assess the utility of the copd assessment test in a primary care setting. AB - The quality of a consultation provided by a physician can have a profound impact on the quality of care and patient engagement in treatment decisions. When the COPD Assessment Test (CAT) was developed, one of its aims was to aid the communication between physician and patient about the impact of COPD. We developed a novel study design to assess this in a primary care consultation. Primary care physicians across five countries in Europe conducted videoed consultations with six standardised COPD patients (played by trained actors) which had patient-specific issues that the physician needed to identify through questioning. Half the physicians saw the patients with the completed CAT, and half without. Independent assessors scored the physicians on their ability to identify and address the patient-specific issues, review standard COPD aspects, their understanding of the case and their overall performance. This novel study design presented many challenges which needed to be addressed to achieve an acceptable level of robustness to assess the utility of the CAT. This paper discusses these challenges and the measures adopted to eliminate or minimise their impact on the study results. PMID- 23663701 TI - Trip12, a HECT domain E3 ubiquitin ligase, targets Sox6 for proteasomal degradation and affects fiber type-specific gene expression in muscle cells. AB - BACKGROUND: A sophisticated level of coordinated gene expression is necessary for skeletal muscle fibers to obtain their unique functional identities. We have previously shown that the transcription factor Sox6 plays an essential role in coordinating muscle fiber type differentiation by acting as a transcriptional suppressor of slow fiber-specific genes. Currently, mechanisms regulating the activity of Sox6 in skeletal muscle and how these mechanisms affect the fiber phenotype remain unknown. METHODS: Yeast two-hybrid screening was used to identify binding partners of Sox6 in muscle. Small interfering RNA (siRNA) mediated knockdown of one of the Sox6 binding proteins, Trip12, was used to determine its effect on Sox6 activity in C2C12 myotubes using quantitative analysis of fiber type-specific gene expression. RESULTS: We found that the E3 ligase Trip12, a HECT domain E3 ubiquitin ligase, recognizes and polyubiquitinates Sox6. Inhibiting Trip12 or the 26S proteasome activity resulted in an increase in Sox6 protein levels in C2C12 myotubes. This control of Sox6 activity in muscle cells via Trip12 ubiquitination has significant phenotypic outcomes. Knockdown of Trip12 in C2C12 myotubes led to upregulation of Sox6 protein levels and concurrently to a decrease in slow fiber-specific Myh7 expression coupled with an increased expression in fast fiber-specific Myh4. Therefore, regulation of Sox6 cellular levels by the ubiquitin-proteasome system can induce identity-changing alterations in the expression of fiber type-specific genes in muscle cells. CONCLUSIONS: Based on our data, we propose that in skeletal muscle, E3 ligases have a significant role in regulating fiber type specific gene expression, expanding their importance in muscle beyond their well established role in atrophy. PMID- 23663702 TI - Gastric outlet obstruction in a patient with Bouveret's syndrome: a case report. AB - BACKGROUND: Gallstone ileus accounts for 1% to 4% of cases of mechanical bowel obstruction, but may be responsible for up to 25% of cases in older age groups. In non-iatrogenic cases, gallstone migration occurs after formation of a biliary enteric fistula. In fewer than 10% of patients with gallstone ileus, the impacted gallstones are located in the pylorus or duodenum, resulting in gastric outlet obstruction, known as Bouveret's syndrome. CASE PRESENTATION: We report an 86 year-old female who was admitted to hospital with a 10-day history of persistent vomiting and prostration. She was in hypovolemic shock at the time of arrival in the emergency department. Investigations revealed a gallstone in the duodenal bulb and a cholecystoduodenal fistula. She underwent surgical gastrolithotomy. Unfortunately, she died of aspiration pneumonia on the fourth postoperative day. CONCLUSION: This case shows the importance of considering Bouveret's syndrome in the differential diagnosis of gastric outlet obstruction, especially in the elderly, even in patients with no previous history of gallbladder disease. PMID- 23663703 TI - Canadian Otolaryngology - Head and Neck Surgery clerkship curricula: evolving toward tomorrow's learners. AB - BACKGROUND: Increasing focus is being placed on Clerkship curriculum design and implementation in light of new undergraduate medical education research and accreditation standards. Canadian Otolaryngology-Head and Neck Surgery (OTOHNS) Clerkship programs are continually but independently evolving towards a common goal of improving Clerkship curriculum. METHODS: An electronic survey was sent to undergraduate OTOHNS directors at all Canadian medical schools (n = 17) examining their Clerkship curricula. Themes included Clerkship format, teaching methods, faculty support and development, program strengths, and barriers. RESULTS: Survey response rate was 76%. All responding schools had OTOHNS Clerkship programs ranging in type (mandatory, selective or elective) and length (<1 to 4 weeks). Learning modalities varied. Electronic learning tools were identified as increasingly important to curriculum delivery. Common strengths included wide clinical exposure and one-on-one mentoring. Multiple challenges were identified in curriculum implementation and evaluation. All schools expressed interest in developing national standards, objectives and e-learning resources. CONCLUSIONS: Significant variation exists in OTOHNS Clerkship experiences between Canadian medical schools. Many schools perceive barriers of insufficient time, space and curriculum standardization. Interested Canadian OTOHNS educators are eager to collaborate to improve the collective OTOHNS Clerkship experience. PMID- 23663704 TI - [Classification of vascular anomalies]. PMID- 23663705 TI - [Fegelers syndrome, acquired port-wine stain or acquired capillary malformation: three cases and a literature review]. AB - BACKGROUND: Port-wine stains or capillary malformations are generally congenital. Very few cases of acquired port-wine stains in adults have been described, and these occur particularly after trauma. PATIENTS AND METHOD: We report three cases of acquired port-wine stains and we performed a review of the literature using the keywords "port-wine stain", "capillary malformation", "angioma" and "acquired" in the Medline database PubMed. All relevant articles were included. RESULTS: Two male patients and one female patient consulted for one or more angiomatous lesions, located respectively on the upper rear part of the right thigh (case 1), the left leg (case 2) and the right side of the face, skull and chest (case 3). Each patient's skin biopsy was consistent with port-wine stain. The three patients asserted the acquired nature of the lesions: the male patients were respectively 17 and 38 years old, and the female patient was 11 years old. No causative factors were evident preceding the lesion, and there was no family history of port-wine stain. The topography was systematic in patients 2 and 3. The lesions were light red in patient 1, dark red in patient 2 and pale pink in patient 3. The remainder of the physical examination was unremarkable, except for benign angiokeratoma of the scrotum in case 1 and pigmented leucoderma-type macules in case 3. LITERATURE RESULTS: Sixty-six cases of acquired port-wine stains were reported in the literature. The average age was 25 years (3-69) with a sex-ratio of 0.88. Generally, no causative factor was given. However, trauma (30.5%), estrogenic impregnation (16.5%), and more rarely, medication, solar damage, frostbite, cluster headache, herpes zoster and acoustic neuroma were reported as causatives factors. DISCUSSION: Acquired port-wine stain is rare. Although often idiopathic, it can result from spinal trauma, which must be explored if suggested by the history. In our series, the clinical presentation suggested a latent congenital vascular malformation of late onset, in particular in patients 2 and 3, because of the segmental distribution. PMID- 23663706 TI - [Epidemiological survey of leprosy conducted in metropolitan France between 2009 and 2010]. AB - BACKGROUND: There is no official leprosy register in France. The last epidemiological survey on leprosy in metropolitan France was done between 1995 and 1998. We performed a new epidemiological study of leprosy in metropolitan France in 2009 and 2010. PATIENTS AND METHODS: We contacted 85 dermatology and infectious disease units by e-mail or by telephone in order to determine the number of leprosy patients either being followed up or newly diagnosed in 2009 and 2010. RESULTS: The response rate was 87%. In 2010, 127 patients were being followed up in metropolitan France, mostly at dermatology units (78%). Seventy five patients were on anti-bacillary treatment and the prevalence was 0.011/10,000. There were 39 new cases diagnosed in 2009 and 2010 (mean 19 cases/year) (low case-detection rate: 0.003 per 10,000 inhabitants). Among the new cases, seven patients (18%) were of French origin, with two from metropolitan France and five from French overseas territories. DISCUSSION: Our study confirms the persistence of imported leprosy in France and shows no significant decrease in the number of new cases since 1998 (19 vs. 18 new cases/year) or in disease prevalence (0.013 vs. 0.011 per 10,000 inhabitants). This prevalence is very far removed from the one per 10,000 inhabitants proposed by the World Health Organization as the criteria for endemic disease. Most patients in our survey were immigrants (82%). Lepromatous forms (46%) were more frequent than the tuberculoid forms (33%). All patients had either travelled to or lived in areas of high leprosy prevalence, including metropolitan subjects. CONCLUSION: Leprosy remains present in metropolitan France, and it is still important to continue teaching about it at medical faculties in order to ensure diagnosis of new patients as early as possible. PMID- 23663707 TI - [Adverse cutaneous effects and quality of life in patients treated with mTOR inhibitors for renal carcinoma]. AB - BACKGROUND: Mammalian target of rapamycine (mTOR) inhibitors are being increasingly prescribed as antitumoural drugs, and associated adverse cutaneous effects are frequent but poorly described. The aim of this study was to describe such adverse effects and to assess the quality of life of patients experiencing them. PATIENTS AND METHODS: Over a period of 18 months, 18 patients treated with mTOR inhibitors for renal carcinoma were included and 77 dermatological examinations performed. Wherever a cutaneous adverse event was present, quality of life was evaluated using the Skindex 30 questionnaire. RESULTS: Fifteen of the 18 patients included presented adverse cutaneous events, consisting of buccal ulcers (61.1%), xerosis (55.5%), distal onycholysis (50%), acneiform eruption (38.8%), paronychia (22.2%) and pruritus (22.2%). Buccal ulcerations and perionyxis had an especially marked impact on quality of life, which was greatest in terms of physical score (19%), followed by emotional (9%) and functional (6%) scores. CONCLUSION: Cutaneous adverse effects of mTOR inhibitors are frequent and have a considerable impact on quality of life, particularly as regards physical scores. Dermatological examination appears useful to allow early management of cutaneous adverse effects and improve the quality of life of these patients. PMID- 23663708 TI - [Pyoderma gangrenosum with lung involvement treated with infliximab]. AB - BACKGROUND: Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis often associated with systemic diseases, particularly chronic inflammatory bowel diseases. Extracutaneous manifestations (articular, ocular, renal, pulmonary, hepatosplenic, muscular) exist, with lung involvement being the most common. PATIENT AND METHODS: We report a case of PG with skin and lung involvements in a patient treated with high-dose corticosteroids in a setting of severe ulcerative colitis (UC). Lung involvement was diagnosed during the pretreatment assessment performed prior to initiation of anti-TNFalpha therapy. Infliximab resulted in rapid improvement of the lung and skin lesions. DISCUSSION: In the event of simultaneous cutaneous PG lesions and lung lesions suggestive of abscess, visceral involvement should be suspected. First-line treatment consists of oral corticosteroids. In our patient, the occurrence of lesions under corticosteroids in UC militated in favour of anti-TNFalpha therapy, which proved effective. PMID- 23663709 TI - [Leg ulcer associated with type I cryoglobulinaemia due to incipient B-cell lymphoma]. AB - BACKGROUND: Skin lesions are frequent in monoclonal cryoglobulinaemia and may be the first sign of B-cell lymphoma, especially multiple myeloma, Waldenstrom's macroglobulinaemia and B-cell chronic lymphocytic leukaemia. PATIENTS AND METHODS: A 74-year-old woman with no prior medical history presented with necrotic leg ulcer. Skin biopsy showed dermal angiomatosis with numerous PAS+ thromboses, associated with monoclonal intravascular deposits of IgM kappa, indicating monoclonal cryoglobulin, which was confirmed by laboratory tests. Subsequent blood immunophenotyping revealed an inconspicuous circulating monoclonal CD5(+) B-cell population and small B-cell clusters in the bone marrow, while the B-cell count was normal and no lymphadenopathy or splenomegaly were present. Overall, these findings indicated a small B-cell lymphoma, classed as non-MALT marginal zone lymphoma on the WHO classification, at a very early stage of development. The patient was first treated by cyclophosphamide and oral steroids without success. Subsequent administration of six cycles of rituximab, cyclophosphamide, vincristine and prednisone (RCVP) led to remission of her leg ulcer, cryoglobulinaemia and lymphoma. CONCLUSION: Skin biopsies of necrotic ulcers should undergo routine screening for intravascular deposits of type 1 cryoglobulin. Leg ulcers due to monoclonal cryoglobulinaemia may reveal incipient marginal zone B-cell lymphoma at the stage of circulating monoclonal lymphocytosis. PMID- 23663710 TI - [A case of primary cutaneous PEComa]. AB - BACKGROUND: PEComas (PEC: Perivascular epithelioid cell) are tumours expressing both melanocytic and myogenic markers. The clinical features are non-specific. PATIENTS AND METHODS: A 55-year-old woman presented with a non-specific tumour on her right arm. Histological examination revealed an intradermal tumour composed of clear epithelial cells. The tumour was positive for HMB45 and protein S100, and was negative for Melan-A and actin. A diagnosis of PEComa was retained despite negative myogenic markers. DISCUSSION: PEComas are neoplasms composed of nests and fascicles of clear to granular epithelioid cells that express both melanocytic markers (HMB45, Melan-A, NK1C3, tyrosinase) and myogenic markers (actin, caldesmin, desmin, calponin), whereas S100 protein and cytokeratins are usually absent. Included in this broad category are angiomyolipoma, clear-cell "sugar" tumours and lymphangioleiomyoma. Some deep PEComas may have a malignant course. Cutaneous primitive forms are exceptional and often benign. Histological differential diagnoses to consider are those of clear-cell tumours: paraganglioma like dermal melanocytic tumour, melanoma, metastatic clear-cell renal carcinoma and epithelioid sarcoma. In our patient, a diagnosis of cutaneous primitive PEComa was retained despite the absence of myogenic markers and the positivity of the protein S100, based on the cytological and immunohistochemical features, which were not evocative of any other diagnosis. CONCLUSION: Cutaneous PEComa are non-specific tumours. Histological analysis confirms the diagnosis and allows other more aggressive tumours to be ruled out. PMID- 23663711 TI - [Nodular cutaneous amyloidosis associated with Sjogren's syndrome]. AB - BACKGROUND: Cutaneous nodular amyloidosis is rare, and association with Sjogren's syndrome has been reported. We discuss the possible link between these two diseases based on a case we saw. PATIENTS AND METHODS: A 78-year-old woman with Sjogren's syndrome ongoing for 17 years presented for evaluation of a waxy infiltrated lesion on her left leg that had appeared 6 months earlier. Histopathological examination revealed a deposit of homogenous eosinophilic material throughout the dermis consistent with amyloidosis. Immunohistochemical study showed these deposits to be AL immunoglobin light chains. DISCUSSION: The association of cutaneous nodular amyloidosis and Sjogren's syndrome appears to be a distinct disease entity reflecting the polymorphic clinical spectrum of lymphoproliferative diseases related to Sjogren's syndrome. PMID- 23663712 TI - [Graves' dermopathy on the big toe]. AB - BACKGROUND: Localized myxoedema is a rare dermopathy in patients with Graves' disease. The pretibial area is the most commonly affected region but herein we present a case of myxoedema of the big toe. PATIENTS AND METHODS: A 44-year-old male with Graves' disease ongoing for seven years presented bilateral ophthalmopathy and myxoedema of the big toes. The myxoedema was treated successfully with intralesional steroids. DISCUSSION: The physiopathology of myxoedema involves fibroblast activation and glycosaminoglycan production. This activation could result from stimulation of TSH receptors at their surface by TSH receptor antibodies (TRAK) or from an inflammatory process. The pretibial topography may be related to the high frequency in this area of microtrauma, with modulation of the cytokine microenvironment. CONCLUSION: The atypical localization seems to correlate with a Koebner phenomenon. Treatment of Graves' disease is generally insufficient to resolve the cutaneous problems. Topical corticosteroid therapy generally results in rapid improvement of recent lesions. PMID- 23663713 TI - [Pustular psoriasis localized to the genital region]. PMID- 23663714 TI - [Acne in Algeria: a survey]. PMID- 23663715 TI - [Pigmented keratosis on the face]. PMID- 23663716 TI - [Medical compression in chronic venous conditions. Haute Autorite de Sante]. PMID- 23663717 TI - [Comments on the recommandation on compression in chronic venous disease published by the French Health Authorities (HAS)]. PMID- 23663718 TI - [Granular cell tumour or Abrikissoff's tumour]. PMID- 23663719 TI - [Hypopigmented melanoma]. PMID- 23663720 TI - [COX7B mutations in MIDAS syndrome or microphthalmia with linear skin defects (MLS)]. PMID- 23663721 TI - [Cushing's syndrome revealed by a chronic sore]. PMID- 23663722 TI - [Adult multi-organ Langerhans cell histiocytosis with fatal outcome]. PMID- 23663723 TI - [Telaprevir-induced pityriasis rubra pilaris]. PMID- 23663724 TI - Wool-waste valorization: production of protein hydrolysate with high antioxidative potential by fermentation with a new keratinolytic bacterium, Bacillus pumilus A1. AB - AIMS: Wool, a recalcitrant waste mainly composed of keratin, constituted a serious problem for the environment and was not effectively valorized. This study reported the optimization of wool-waste biodegradation by a new keratinolytic bacterium Bacillus pumilus A1. The in vitro digestibility and the antioxidant potential of wool protein hydrolysate (WPH) were also investigated. METHODS AND RESULTS: The antioxidant potential of WPH was evaluated using in vitro antioxidant assays, such as 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity, reducing power and metal (Fe(2+)) chelating activity. Cultivation on 50 g l(-1) of wool for 2 days, at 45 degrees C and at initial pH of 10, resulted in maximum production of amino acids and peptides (39.7 g l(-1)). WPH presented a very high in vitro digestibility (97%) as compared with that of the untreated wool (3%). CONCLUSIONS: The keratin present into the wool-waste was completely solubilized. Interestingly, WPH presented an important DPPH radical scavenging activity with an IC50 value of 0.14 +/- 0.01 mg ml(-1). SIGNIFICANCE AND IMPACT OF STUDY: WPH would be a very useful source of protein and antioxidants in animals' diets. PMID- 23663725 TI - Two kinds of theory-laden cognitive processes: distinguishing intransigence from dogmatism. AB - The brain is involved in theory-laden cognitive processes. But there are two different theory-laden processes. In cases where the theory is based on facts, more facts can either falsify or confirm a theory. In cases where the theory is about the choice of a benchmark or a standard, more facts can only make a theory either more or less warranted. PMID- 23663726 TI - Fabrication of Ni-silicide/Si heterostructured nanowire arrays by glancing angle deposition and solid state reaction. AB - This work develops a method for growing Ni-silicide/Si heterostructured nanowire arrays by glancing angle Ni deposition and solid state reaction on ordered Si nanowire arrays. Samples of ordered Si nanowire arrays were fabricated by nanosphere lithography and metal-induced catalytic etching. Glancing angle Ni deposition deposited Ni only on the top of Si nanowires. When the annealing temperature was 500 degrees C, a Ni3Si2 phase was formed at the apex of the nanowires. The phase of silicide at the Ni-silicide/Si interface depended on the diameter of the Si nanowires, such that epitaxial NiSi2 with a {111} facet was formed at the Ni-silicide/Si interface in Si nanowires with large diameter, and NiSi was formed in Si nanowires with small diameter. A mechanism that is based on flux divergence and a nucleation-limited reaction is proposed to explain this phenomenon of size-dependent phase formation. PMID- 23663727 TI - Oxidative stress in cancer-bearing dogs assessed by measuring serum malondialdehyde. AB - BACKGROUND: Oxidative stress, an excess of reactive oxygen species (ROS), causes lipid peroxidation resulting in cell and tissue damages. It may be associated with the development and progression of cancers in dogs. Malondialdehyde (MDA), the end product of lipid peroxidation, is commonly used as a marker of oxidative stress. The objective of this study was to assess oxidative stress in cancer bearing dogs by measuring serum MDA levels. All client-owned dogs underwent physical examination at the Veterinary Teaching Hospital, Faculty of Veterinary Medicine, Khon Kaen University to determine the health status with the owner's consent. Blood samples of cancer-bearing dogs (N = 80) and clinically normal dogs (N = 101) were obtained and subjected for determination of MDA levels. In addition, complete blood count, creatinine, and alanine aminotransferase were measured. RESULTS: Serum MDA was significantly higher in cancer-bearing dogs than in clinically normal dogs (mean +/- SD, 4.68 +/- 1.32 MUmol/L vs 2.95 +/- 0.61 MUmol/L, respectively; p < 0.001). Packed cell volume (mean +/- SD, 36.18 +/- 7.65% vs 44.84 +/- 5.54%), hemoglobin (mean +/- SD, 11.93 +/- 2.88 g% vs 15.17 +/ 2.00 g%) and red blood cells (median (IQA), 6.05 (2.15) vs 8.09 (1.34)) were all significantly lower in cancer-bearing dogs than in clinically normal dogs. However, the reverse was true for white blood cells (median (IQA), 18.20 (11.95) vs 14.90 (5.10)). Neither creatinine nor alanine aminotransferase levels were significantly different between groups. CONCLUSIONS: This study supports the conclusion that oxidative stress is associated with many types of cancers in dogs, as serum MDA levels were significantly higher in cancer-bearing dogs compared to clinically normal dogs. PMID- 23663728 TI - Interactions by 2D Gel Electrophoresis Overlap (iGEO): a novel high fidelity approach to identify constituents of protein complexes. AB - BACKGROUND: Here we describe a novel approach used to identify the constituents of protein complexes with high fidelity, using the integrin-associated scaffolding protein PINCH as a test case. PINCH is comprised of five LIM domains, zinc-finger protein interaction modules. In Drosophila melanogaster, PINCH has two known high-affinity binding partners-Integrin-linked kinase (ILK) that binds to LIM1 and Ras Suppressor 1 (RSU1) that binds to LIM5-but has been postulated to bind additional proteins as well. RESULTS: To purify PINCH complexes, in parallel we fused different affinity tags (Protein A and Flag) to different locations within the PINCH sequence (N- and C-terminus). We expressed these tagged versions of PINCH both in cell culture (overexpressed in Drosophila S2 cell culture in the presence of endogenous PINCH) and in vivo (at native levels in Drosophila lacking endogenous PINCH). After affinity purification, we analyzed PINCH complexes by a novel 2D-gel electrophoresis analysis, iGEO (interactions by 2D Gel Electrophoresis Overlap), with mass spectrometric identification of individual spots of interest. iGEO allowed the identification of protein partners that associate with PINCH under two independent purification strategies, providing confidence in the significance of the interaction. Proteins identified by iGEO were validated against a highly inclusive list of candidate PINCH interacting proteins identified in previous analyses by MuDPIT mass spectrometry. CONCLUSIONS: The iGEO strategy confirmed a core complex comprised of PINCH, RSU1, ILK, and ILK binding partner Parvin. Our iGEO method also identified five novel protein partners that specifically interacted with PINCH in Drosophila S2 cell culture. Because of the improved reproducibility of 2D-GE methodology and the increasing affordability of the required labeling reagents, iGEO is a method that is accessible to most moderately well-equipped biological laboratories. The biochemical co-purifications inherent in iGEO allow for rapid and unambiguous identification of the constituents of protein complexes, without the need for extensive follow-up experiments. PMID- 23663729 TI - No interaction between serotonin transporter gene (5-HTTLPR) polymorphism and adversity on depression among Japanese children and adolescents. AB - BACKGROUND: Identification of gene * environment interactions (G * E) for depression is a crucial step in ascertaining the mechanisms underpinning the disorder. Earlier studies have indicated strong genetic influences and numerous environmental risk factors. In relation to childhood and adolescent depression, evidence is accumulating that the quality of the parental environment is associated with serotonin biology in children. We hypothesized that maternal depression is a crucial environmental risk factor associated with serotonin regulating genes. METHODS: This study was designed to ascertain the G * E interaction for diagnosis of depression in a Japanese pediatric sample. DNA samples from 55 pediatric patients with depression and 58 healthy schoolchildren were genotyped for the 5-HTT (2 short (S) alleles at the 5-HTT locus) promoter serotonin-transporter-linked polymorphic region (5-HTTLPR) polymorphism. We examined whether an adverse parental environment, operationalized as the mother's history of recurrent major depressive disorder, interacts with 5-HTTLPR polymorphism to predict patients' depression symptoms. RESULTS: Binary logistic regression analyses revealed that maternal depression (adversity), gender, and FSIQ significantly affect the diagnosis of depression among children and adolescents. However, no main effect was found for adversity or genotype. Results of multivariable logistic regression analyses using stepwise procedure have elicited some models with a good fit index, which also suggests no interaction between 5-HTTLPR and adversity on depression. CONCLUSIONS: To assess G * E interaction, data obtained from children and adolescents who had been carefully diagnosed categorically and data from age-matched controls were analyzed using logistic regression. Despite an equivocal interaction effect, adversity and gender showed significant main effects. PMID- 23663731 TI - Lymphatics as a new active player in reverse cholesterol transport. AB - Reverse cholesterol transport (RCT), a key function of high-density lipoproteins (HDL), prevents excess cholesterol in tissues. A study in this issue (Lim et al., 2013) suggests that lymphatic vessels are critical for normal RCT and mediate the active trans-endothelial transport of HDL via the HDL receptor SR-BI. PMID- 23663730 TI - Significance of K(ATP) channels, L-type Ca2+ channels and CYP450-4A enzymes in oxygen sensing in mouse cremaster muscle arterioles in vivo. AB - BACKGROUND: ATP-sensitive K+ channels (KATP channels), NO, prostaglandins, 20 HETE and L-type Ca2+ channels have all been suggested to be involved in oxygen sensing in skeletal muscle arterioles, but the role of the individual mechanisms remain controversial. We aimed to establish the importance of these mechanisms for oxygen sensing in arterioles in an in vivo model of metabolically active skeletal muscle. For this purpose we utilized the exteriorized cremaster muscle of anesthetized mice, in which the cremaster muscle was exposed to controlled perturbation of tissue PO2. RESULTS: Change from "high" oxygen tension (PO2 = 153.4 +/- 3.4 mmHg) to "low" oxygen tension (PO2 = 13.8 +/- 1.3 mmHg) dilated cremaster muscle arterioles from 11.0 +/- 0.4 MUm to 32.9 +/- 0.9 MUm (n = 28, P < 0.05). Glibenclamide (KATP channel blocker) caused maximal vasoconstriction, and abolished the dilation to low oxygen, whereas the KATP channel opener cromakalim caused maximal dilation and prevented the constriction to high oxygen. When adding cromakalim on top of glibenclamide or vice versa, the reactivity to oxygen was gradually restored. Inhibition of L-type Ca2+ channels using 3 MUM nifedipine did not fully block basal tone in the arterioles, but rendered them unresponsive to changes in PO2. Inhibition of the CYP450-4A enzyme using DDMS blocked vasoconstriction to an increase in PO2, but had no effect on dilation to low PO2. CONCLUSIONS: We conclude that: 1) L-type Ca2+ channels are central to oxygen sensing, 2) KATP channels are permissive for the arteriolar response to oxygen, but are not directly involved in the oxygen sensing mechanism and 3) CYP450-4A mediated 20-HETE production is involved in vasoconstriction to high PO2. PMID- 23663732 TI - miR-34a and the cardiomyopathy of senescence: SALT PNUTS, SALT PNUTS! AB - The search for eternal youth is age old. In a recent Nature paper, Boon et al. (2013) describe DNA damage mechanisms and cardiac senescence provoked by miR-34a and its target, PNUTS. Interrupting this pathway may prevent age- and stress induced cardiac degeneration. PMID- 23663733 TI - Hyperglycemia-stimulated myelopoiesis causes impaired regression of atherosclerosis in type 1 diabetes. AB - People with type 1 diabetes (T1D) have a high risk of early morbidity and mortality from coronary artery disease. A study in this issue of Cell Metabolism (Nagareddy et al., 2013) now identifies a mechanism causing impaired regression of atherosclerosis in T1D. PMID- 23663734 TI - mTORC1 signaling aids in CADalyzing pyrimidine biosynthesis. AB - Mechanistic target of rapamycin complex 1 (mTORC1) regulates growth and metabolism by integrating signals from the cellular environment. Ben-Sahra et al. (2013) and Robitaille et al. (2013) demonstrate a role for mTORC1 in nucleotide production via S6K1 phosphorylation of CAD, which catalyzes the initial steps of de novo pyrimidine biosynthesis. PMID- 23663735 TI - Rejuvenating SIRT1 activators. AB - Whether the red wine component resveratrol directly activates the NAD(+) dependent protein deacetylase SIRT1 has been debated. A recent study by Hubbard et al. (2013) strengthens the case that SIRT1-activating compounds (STACs) function as positive allosteric regulators of SIRT1 and thereby regulate mitochondrial function. PMID- 23663736 TI - Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL. AB - Removal of cholesterol from peripheral tissues to the bloodstream via reverse cholesterol transport (RCT) is a process of major biological importance. Here we demonstrate that lymphatic drainage is required for RCT. We have previously shown that hypercholesterolemia in mice is associated with impaired lymphatic drainage and increased lipid accumulation in peripheral tissues. We now show that restoration of lymphatic drainage in these mice significantly improves cholesterol clearance. Conversely, obstruction of lymphatic vessels in wild-type mice significantly impairs RCT. Finally, we demonstrate using silencing RNA interference, neutralizing antibody, and transgenic mice that removal of cholesterol by lymphatic vessels is dependent on the uptake and transcytosis of HDL by scavenger receptor class B type I expressed on lymphatic endothelium. Collectively, this study challenges the current view that lymphatic endothelium is a passive exchange barrier for cholesterol transport and provides further evidence for its interplay with lipid biology in health and disease. PMID- 23663737 TI - Metabolic stress modulates Alzheimer's beta-secretase gene transcription via SIRT1-PPARgamma-PGC-1 in neurons. AB - Classic cardio-metabolic risk factors such as hypertension, stroke, diabetes, and hypercholesterolemia all increase the risk of Alzheimer's disease. We found increased transcription of beta-secretase/BACE1, the rate-limiting enzyme for Abeta generation, in eNOS-deficient mouse brains and after feeding mice a high fat, high-cholesterol diet. Up- or downregulation of PGC-1alpha reciprocally regulated BACE1 in vitro and in vivo. Modest fasting in mice reduced BACE1 transcription in the brains, which was accompanied by elevated PGC-1 expression and activity. Moreover, the suppressive effect of PGC-1 was dependent on activated PPARgamma, likely via SIRT1-mediated deacetylation in a ligand independent manner. The BACE1 promoter contains multiple PPAR-RXR sites, and direct interactions among SIRT1-PPARgamma-PGC-1 at these sites were enhanced with fasting. The interference on the BACE1 gene identified here represents a unique noncanonical mechanism of PPARgamma-PGC-1 in transcriptional repression in neurons in response to metabolic signals that may involve recruitment of corepressor NCoR. PMID- 23663739 TI - Hyperphosphorylation of glucosyl C6 carbons and altered structure of glycogen in the neurodegenerative epilepsy Lafora disease. AB - Laforin or malin deficiency causes Lafora disease, characterized by altered glycogen metabolism and teenage-onset neurodegeneration with intractable and invariably fatal epilepsy. Plant starches possess small amounts of metabolically essential monophosphate esters. Glycogen contains similar phosphate amounts, which are thought to originate from a glycogen synthase error side reaction and therefore lack any specific function. Glycogen is also believed to lack monophosphates at glucosyl carbon C6, an essential phosphorylation site in plant starch metabolism. We now show that glycogen phosphorylation is not due to a glycogen synthase side reaction, that C6 is a major glycogen phosphorylation site, and that C6 monophosphates predominate near centers of glycogen molecules and positively correlate with glycogen chain lengths. Laforin or malin deficiency causes C6 hyperphosphorylation, which results in malformed long-chained glycogen that accumulates in many tissues, causing neurodegeneration in brain. Our work advances the understanding of Lafora disease pathogenesis and suggests that glycogen phosphorylation has important metabolic function. PMID- 23663738 TI - Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. AB - Diabetes is a major risk factor for atherosclerosis. Although atherosclerosis is initiated by deposition of cholesterol-rich lipoproteins in the artery wall, the entry of inflammatory leukocytes into lesions fuels disease progression and impairs resolution. We show that diabetic mice have increased numbers of circulating neutrophils and Ly6-C(hi) monocytes, reflecting hyperglycemia-induced proliferation and expansion of bone marrow myeloid progenitors and release of monocytes into the circulation. Increased neutrophil production of S100A8/S100A9, and its subsequent interaction with the receptor for advanced glycation end products on common myeloid progenitor cells, leads to enhanced myelopoiesis. Treatment of hyperglycemia reduces monocytosis, entry of monocytes into atherosclerotic lesions, and promotes regression. In patients with type 1 diabetes, plasma S100A8/S100A9 levels correlate with leukocyte counts and coronary artery disease. Thus, hyperglycemia drives myelopoiesis and promotes atherogenesis in diabetes. PMID- 23663740 TI - Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. AB - Proper control of hepatic glucose production is central to whole-body glucose homeostasis, and its disruption plays a major role in diabetes. Here, we demonstrate that although established as an intracellular lipid chaperone, aP2 is in fact actively secreted from adipocytes to control liver glucose metabolism. Secretion of aP2 from adipocytes is regulated by fasting- and lipolysis-related signals, and circulating aP2 levels are markedly elevated in mouse and human obesity. Recombinant aP2 stimulates glucose production and gluconeogenic activity in primary hepatocytes in vitro and in lean mice in vivo. In contrast, neutralization of secreted aP2 reduces glucose production and corrects the diabetic phenotype of obese mice. Hyperinsulinemic-euglycemic and pancreatic clamp studies upon aP2 administration or neutralization demonstrated actions of aP2 in liver. We conclude that aP2 is an adipokine linking adipocytes to hepatic glucose production and that neutralizing secreted aP2 may represent an effective therapeutic strategy against diabetes. PMID- 23663741 TI - Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. AB - Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on regulating glucose and lipid homeostasis and insulin sensitivity. However, the mechanisms underlying the metabolic actions of FGF21 remain unknown. Here we show that the insulin-sensitizing adipokine adiponectin is a downstream effector of FGF21. Treatments with FGF21 enhanced both expression and secretion of adiponectin in adipocytes, thereby increasing serum levels of adiponectin in mice. Adiponectin knockout mice were refractory to several therapeutic benefits of FGF21, including alleviation of obesity-associated hyperglycemia, hypertriglyceridemia, insulin resistance, and hepatic steatosis. Furthermore, the effects of FGF21 on attenuation of obesity-induced impairment in insulin signaling in liver and skeletal muscle were abrogated in adiponectin knockout mice, whereas FGF21-mediated activation of ERK1/ERK2 in adipose tissues remained unaffected. Therefore, adiponectin couples FGF21 actions in local adipocytes to liver and skeletal muscle, thereby mediating the systemic effects of FGF21 on energy metabolism and insulin sensitivity. PMID- 23663743 TI - A classical brown adipose tissue mRNA signature partly overlaps with brite in the supraclavicular region of adult humans. AB - Human brown adipose tissue (BAT) has been detected in adults but was recently suggested to be of brite/beige origin. We collected BAT from the supraclavicular region in 21 patients undergoing surgery for suspected cancer in the neck area and assessed the gene expression of established murine markers for brown, brite/beige, and white adipocytes. We demonstrate that a classical brown expression signature, including upregulation of miR-206, miR-133b, LHX8, and ZIC1 and downregulation of HOXC8 and HOXC9, coexists with an upregulation of two newly established brite/beige markers, TBX1 and TMEM26. A similar mRNA expression profile was observed when comparing isolated human adipocytes from BAT and white adipose tissue (WAT) depots, differentiated in vitro. In conclusion, our data suggest that human BAT might consist of both classical brown and recruitable brite adipocytes, an observation important for future considerations on how to induce human BAT. PMID- 23663742 TI - An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice. AB - FGF21, a member of the fibroblast growth factor (FGF) superfamily, has recently emerged as a regulator of metabolism and energy utilization. However, the exact mechanism(s) whereby FGF21 mediates its actions have not been elucidated. There is considerable evidence that insulin resistance may arise from aberrant accumulation of intracellular lipids in insulin-responsive tissues due to lipotoxicity. In particular, the sphingolipid ceramide has been implicated in this process. Here, we show that FGF21 rapidly and robustly stimulates adiponectin secretion in rodents while diminishing accumulation of ceramides in obese animals. Importantly, adiponectin-knockout mice are refractory to changes in energy expenditure and ceramide-lowering effects evoked by FGF21 administration. Moreover, FGF21 lowers blood glucose levels and enhances insulin sensitivity in diabetic Lep(ob/ob) mice and diet-induced obese (DIO) mice only when adiponectin is functionally present. Collectively, these data suggest that FGF21 is a potent regulator of adiponectin secretion and that FGF21 critically depends on adiponectin to exert its glycemic and insulin sensitizing effects. PMID- 23663744 TI - Ultrasound imaging for the rheumatologist XLV. Ultrasound of the shoulder in psoriatic arthritis. AB - OBJECTIVES: The aims of this study were to investigate the prevalence of ultrasound (US) pathologic abnormalities in the shoulders of psoriatic arthritis (PsA) patients and to compare them with the main clinical findings. METHODS: Ninety-seven PsA patients were enrolled in the study. The subacromial/subdeltoid bursa, the sheath of the long biceps tendon, the glenohumeral joint and the acromion-clavicular joint were examined for the presence of synovial effusions and synovial hypertrophy. Rotator cuff tendons (supraspinatus, subscapularis, infraspinatus) were imaged for tendinosis, calcifications and total or partial tears, while deltoid enthesis were evaluated for local enthesitis and the lesser and greater tuberosity of the humerus for the presence of enthesophytes. RESULTS: Tendinosis represented the most frequent abnormal finding. Supraspinatus tendinosis was detected more often than subscapularis and infraspinatus tendinosis. When considering tendon tear, supraspinatus was also the most frequently involved anatomical structure. Clinical examination frequently failed to detect abnormalities in patients in whom US examination showed pathological findings. This is particularly true for tendon involvement, i.e. effusion within the sheath of the biceps tendon was imaged in 43 shoulders but clinical assessment reported abnormalities only in 22 shoulders (p<0.0001). CONCLUSIONS: US examination appears to be a useful and sensitive imaging technique, specifically in identifying joint and tendon involvement of the shoulder. PMID- 23663745 TI - Attention and perceptual adaptation. AB - Clark advertises the predictive coding (PC) framework as applying to a wide range of phenomena, including attention. We argue that for many attentional phenomena, the predictive coding picture either makes false predictions, or else it offers no distinctive explanation of those phenomena, thereby reducing its explanatory power. PMID- 23663746 TI - Harnessing the beneficial properties of adipogenic microbes for improving human health. AB - Obesity is associated with numerous metabolic comorbidities. Weight loss is an effective measure for alleviating many of these metabolic abnormalities. However, considering the limited success of most medical weight-management approaches in producing a sustained weight loss, approaches that improve obesity-related metabolic abnormalities independent of weight loss would be extremely attractive and of practical benefit. Metabolically healthy obesity supports the notion that a better metabolic profile is possible despite obesity. Moreover, adequate expansion of adipose tissue appears to confer protection from obesity-induced metabolic comorbidities. To this end, the 10th Stock conference examined new approaches to improve metabolic comorbidities independent of weight loss. In particular, human adenovirus 36 (Ad36) and specific gut microbes were examined for their potential to influence lipid and glucose homeostasis in animals and humans. While these microbes possess some undesirable properties, research has identified attributes of adenovirus Ad36 and gut microbes that may be selectively harnessed to improve metabolic profile without the obligatory weight loss. Furthermore, identifying the host signalling pathways that these microbes recruit to improve the metabolic profile may offer new templates and targets, which may facilitate the development of novel treatment strategies for obesity-related metabolic conditions. PMID- 23663747 TI - Continuous on-line glucose measurement by microdialysis in a central vein. A pilot study. AB - INTRODUCTION: Tight glucose control in the ICU has been proven difficult with an increased risk for hypoglycaemic episodes. Also the variability of glucose may have an impact on morbidity. An accurate and feasible on-line/continuous measurement is therefore desired. In this study a central vein catheter with a microdialysis membrane in combination with an on-line analyzer for continuous monitoring of circulating glucose and lactate by the central route was tested. METHODS: A total of 10 patients scheduled for major upper abdominal surgery were included in this observational prospective study at a university hospital. The patients received an extra central venous catheter with a microdialysis membrane placed in the right jugular vein. Continuous microdialysis measurement proceeded for 20 hours and on-line values were recorded every minute. Reference arterial plasma glucose and blood lactate samples were collected every hour. RESULTS: Mean microdialysis-glucose during measurements was 9.8 +/- 2.4 mmol/l.No statistical difference in the readings was seen using a single calibration compared to eighth hour calibration (P =0.09; t-test). There was a close agreement between the continuous reading and the reference plasma glucose values with an absolute difference of 0.6+0.8 mmol, or 6.8+9.3% and measurements showed high correlation to plasma readings (r = 0.92). The limit of agreement was 23.0%(1.94 mmol/l) compared to arterial plasma values with a line of equality close to zero.However, in a Clarke-Error Grid 93.3% of the values are in the A-area,and the remaining part in the B-area.Mean microdialysis-lactate was 1.3 +/- 1.1 mmol/l. The measurements showed high correlation to the blood readings (r = 0.93). CONCLUSION: Continuous on-line microdialysis glucose measurement in a central vein is a potential useful technique for continuous glucose monitoring in critically ill patients, but more improvements and testing are needed. PMID- 23663748 TI - Laser Doppler vibrometry measurements of human cadaveric tympanic membrane vibration. AB - OBJECTIVE: To determine the feasibility of measuring tympanic membrane (TM) vibrations at multiple locations on the TM to differentiate normal eardrums from those with associated ossicular pathologies. DESIGN: Cadaveric human temporal bone study. SETTING: Basic science laboratory. METHODS: A mastoidectomy and facial recess approach was performed on four cadaveric temporal bones to obtain access to the ossicles without disrupting the TM. Ossicles were palpated to ensure normal mobility and an intact ossicular chain. Laser Doppler Vibrometry (LDV) measurements were then taken on all four TMs. LDV measurements were repeated on each TM following stapes footplate fixation, incudo-stapedial joint dislocation, and malleus head fixation. MAIN OUTCOME MEASURES: LDV measurements of TM vibration at the umbo, the lateral process of the malleus, and in each of the four quadrants of the TM. RESULTS: The best signal-to-noise ratios were found between 2 and 4 kHz, at the umbo, the anterior superior quadrant, the anterior inferior quadrant, and the posterior inferior quadrant. Since our goal was to assess the ossicular chain, we selected the TM locations closest to the ossicular chain (the umbo and lateral process of the malleus) for further analysis. Differences could be seen between normals and the simulated ossicular pathologies, but values were not statistically significant. CONCLUSIONS: LDV measurements are technically challenging and require optimization to obtain consistent measurements. This study demonstrates the potential of LDV to differentiate ossicular pathologies behind an intact tympanic membrane. Future studies will further characterize the clinical role of this diagnostic modality. PMID- 23663749 TI - Testing use of payers to facilitate evidence-based practice adoption: protocol for a cluster-randomized trial. AB - BACKGROUND: More effective methods are needed to implement evidence-based findings into practice. The Advancing Recovery Framework offers a multi-level approach to evidence-based practice implementation by aligning purchasing and regulatory policies at the payer level with organizational change strategies at the organizational level. METHODS: The Advancing Recovery Buprenorphine Implementation Study is a cluster-randomized controlled trial designed to increase use of the evidence-based practice buprenorphine medication to treat opiate addiction. Ohio Alcohol, Drug Addiction, and Mental Health Services Boards (ADAMHS), who are payers, and their addiction treatment organizations were recruited for a trial to assess the effects of payer and treatment organization changes (using the Advancing Recovery Framework) versus treatment organization changes alone on the use of buprenorphine. A matched-pair randomization, based on county characteristics, was applied, resulting in seven county ADAMHS boards and twenty-five treatment organizations in each arm. Opioid dependent patients are nested within cluster (treatment organization), and treatment organization clusters are nested within ADAMHS county board. The primary outcome is the percentage of individuals with an opioid dependence diagnosis who use buprenorphine during the 24-month intervention period and the 12-month sustainability period. The trial is currently in the baseline data collection stage. DISCUSSION: Although addiction treatment providers are under increasing pressure to implement evidence-based practices that have been proven to improve patient outcomes, adoption of these practices lags, compared to other areas of healthcare. Reasons frequently cited for the slow adoption of EBPs in addiction treatment include, regulatory issues, staff, or client resistance and lack of resources. Yet the way addiction treatment is funded, the payer's role-has not received a lot of attention in research on EBP adoption.This research is unique because it investigates the role of payers in evidence-based practice implementation using a randomized controlled design instead of case examples. The testing of the Advancing Recovery Framework is designed to broaden the understanding of the impact payers have on evidence-based practice (EBP) adoption. TRIAL REGISTRATION: http://NCT01702142 (ClinicalTrials.gov registry, USA). PMID- 23663750 TI - Recruitment strategies and yields for the Pathobiology of Prediabetes in a Biracial Cohort: a prospective natural history study of incident dysglycemia. AB - BACKGROUND: The Pathobiology of Prediabetes in A Biracial Cohort study is a prospective evaluation of the transition from normal to impaired glucose regulation among African American and Caucasian adults with parental type 2 diabetes. This report describes recruitment strategies and relative yields for the 376 enrolled subjects. METHODS: Recruitment occurred over 3.4 years, with clinical and metabolic assessments during 2.1-5.5 years of quarterly follow-up. The major recruitment sources were advertisements, community outreach, and clinical facilities. Advertisements included newspaper, television, radio, Internet, distributed brochures, utility bill inserts, and direct mailing. Community outreach included screening events during religious gatherings and health fairs, and referral by friends and families. The category of clinical facilities covered all subjects referred by health workers or recruited through area clinics and hospitals. RESULTS: 57.7% of participants were African American and 42.3% were Caucasian; the mean age (+/- SD) was 44.2 +/- 10.6 years, and ~70% were female. Advertisements yielded 52.4% of all participants, compared to 34.8% from community outreach and 12.8% from clinical facilities (P for trend < 0.0001). More Caucasians than African Americans cited advertising as the source of study information, whereas more African Americans than Caucasians cited community outreach. The accrual from clinical facilities was similar in both groups. CONCLUSIONS: Advertisements and community outreach were robust recruitment sources for assembling a diverse longitudinal diabetes offspring cohort, but each had differential yields in African Americans and Caucasians. Thus, a multifaceted approach comprising passive and active components is needed to recruit a multiracial clinical research population. PMID- 23663751 TI - THREAT helps to identify epistaxis patients requiring blood transfusions. AB - OBJECTIVE: To analyze the characteristics of patients who needed a blood transfusion due to epistaxis-caused anemia and to define potential risk factors. DESIGN: Retrospective cohort study. SETTING: A total cohort of 591 epistaxis patients, prospectively included between March 2007 and April 2008 at the ENT department of the University Hospital of Zurich, was evaluated concerning the need for blood transfusions. METHODS: The clinical charts and medical histories of these patients were evaluated. MAIN OUTCOME MEASURES: Common parameters that increase the risk for severe anemia due to epistaxis. RESULTS: Twenty-two patients required blood transfusions due to their medical condition. 22.7% suffered from traumatic nosebleeds. Another 27.3% had a known medical condition with an increased bleeding tendency. These proportions were significantly higher than in the group of patients without need of blood transfusion. The odds ratio for receiving a blood transfusion was 14.0 in patients with hematologic disorders, 4.3 in traumatic epistaxis and 7.7 in posterior bleeders. The transfusion-dependent epistaxis patients suffered significantly more often from severe posterior nosebleeds with the need for a surgical therapeutic approach. CONCLUSIONS: Patients with severe nosebleeds either from the posterior part of the nose or with known hematologic disorders or traumatic epistaxis should be closely monitored by blood parameter analyses to evaluate the indication for hemotransfusion. The acronym THREAT (Trauma, Hematologic disorder, and REAr origin of bleeding -> Transfusion) helps to remember and identify the factors associated with an increased risk of receiving blood transfusion. PMID- 23663752 TI - Improvements in patient-reported outcomes with apremilast, an oral phosphodiesterase 4 inhibitor, in the treatment of moderate to severe psoriasis: results from a phase IIb randomized, controlled study. AB - BACKGROUND: Apremilast, a specific inhibitor of phosphodiesterase 4, modulates pro-inflammatory and anti-inflammatory cytokine production. OBJECTIVES: Apremilast's effect on patient-reported outcomes (PROs) in patients with moderate to severe psoriasis was evaluated in a phase IIb randomized, controlled trial (NCT00773734). METHODS: In this 16-week, placebo-controlled study, 352 patients with moderate to severe plaque psoriasis received placebo or apremilast (10, 20, or 30 mg BID). PROs included Dermatology Life Quality Index (DLQI), pruritus visual analog scale (VAS), and Short-Form Health Survey (SF-36) to assess health related quality of life (HRQOL). Changes from baseline and patients reporting improvements >=minimum clinically important differences (MCID) were analyzed. Correlations between changes across various PRO instruments were explored. RESULTS: Baseline DLQI (>10 points) and SF-36 MCS and domain scores indicated impairments in HRQOL. At 16 weeks, greater improvements from baseline in DLQI scores were reported with apremilast 20 (-5.9) and 30 mg BID (-4.4) compared with placebo (1.9; P<=0.005 for both), and a greater proportion of patients reported improvements >=MCID (20 mg BID, 49.4%, 30 mg BID, 44.3%) versus placebo (25.0%; P<0.04). Greater improvements from baseline in pruritus VAS scores were reported with apremilast 20 (-35.5%) and 30 mg BID (-43.7%) versus placebo (-6.1%; P<=0.005). Significant and clinically meaningful improvements in SF-36 mental component summary scores (P<=0.008) and Bodily Pain, Mental Health, and Role Emotional domains were reported with all apremilast doses (P<0.05), and Social Functioning with 20 and 30 mg BID (P<0.05) and Physical Functioning with 20 mg BID (P<0.03). Correlations between SF-36 scores and DLQI were moderate (r>0.30 and <=0.60) and low between SF-36 and pruritus VAS (r<=0.30), indicating they measure different aspects of the disease. CONCLUSIONS: Apremilast treatment resulted in improved HRQOL, including DLQI and pruritus VAS over 16 weeks of treatment, in patients with moderate to severe psoriasis. PMID- 23663754 TI - The expression of adhesin EF-Tu in response to mucin and its role in Lactobacillus adhesion and competitive inhibition of enteropathogens to mucin. AB - AIMS: To analyse the expression of EF-Tu in Lactobacillus strains with response to mucin exposure and its role in interfering with adhesion of enteropathogens to mucin. METHODS AND RESULTS: The Lactobacillus strains were analysed for their ability to adhere to immobilized mucin in microtiter plates. Lactobacillus delbrueckii M and Lactobacillus plantarum CS24.2 showed statistically significant adhesion to mucin, which was similar to Lactobacillus rhamnosus GG, the best binding probiotic strain. Lactobacillus rhamnosus GG, Lact. delbrueckii M, Lact. plantarum CS23 and Lact. plantarum CS24.2 were able to effectively antagonize the adhesion of Escherichia coli and Salmonella enterica serovar Typhi to mucin. In the presence of Lactobacillus adhesin - EF-Tu, the adhesion of Lact. delbrueckii M and the strains of Lact. plantarum to mucin was significantly inhibited. Similarly, EF-Tu also reduced the adhesion of enteropathogens to mucin. Furthermore, the relative fold change in gene expression analysis showed significant up-regulation of EF-Tu gene in the strains of Lact. plantarum and Lact. delbrueckii M when exposed to mucin for 3 h. CONCLUSIONS: The study shows the significant role of EF-Tu in lactobacilli adhesion and enteropathogens inhibition. SIGNIFICANCE AND IMPACT OF THE STUDY: The study suggests EF-Tu as an important factor linked to the Lactobacillus adhesion as well as enteropathogen inhibition. Lactobacillus plantarum CS23 and Lact. plantarum CS24.2 can be used as potential probiotic strains. PMID- 23663753 TI - An unexpected role of neuroligin-2 in regulating KCC2 and GABA functional switch. AB - BACKGROUND: GABAA receptors are ligand-gated Cl- channels, and the intracellular Cl- concentration governs whether GABA function is excitatory or inhibitory. During early brain development, GABA undergoes functional switch from excitation to inhibition: GABA depolarizes immature neurons but hyperpolarizes mature neurons due to a developmental decrease of intracellular Cl- concentration. This GABA functional switch is mainly mediated by the up-regulation of KCC2, a potassium-chloride cotransporter that pumps Cl- outside neurons. However, the upstream factor that regulates KCC2 expression is unclear. RESULTS: We report here that KCC2 is unexpectedly regulated by neuroligin-2 (NL2), a cell adhesion molecule specifically localized at GABAergic synapses. The expression of NL2 precedes that of KCC2 in early postnatal development. Upon knockdown of NL2, the expression level of KCC2 is significantly decreased, and GABA functional switch is significantly delayed during early development. Overexpression of shRNA-proof NL2 rescues both KCC2 reduction and delayed GABA functional switch induced by NL2 shRNAs. Moreover, NL2 appears to be required to maintain GABA inhibitory function even in mature neurons, because knockdown NL2 reverses GABA action to excitatory. Gramicidin-perforated patch clamp recordings confirm that NL2 directly regulates the GABA equilibrium potential. We further demonstrate that knockdown of NL2 decreases dendritic spines through down-regulating KCC2. CONCLUSIONS: Our data suggest that in addition to its conventional role as a cell adhesion molecule to regulate GABAergic synaptogenesis, NL2 also regulates KCC2 to modulate GABA functional switch and even glutamatergic synapses. Therefore, NL2 may serve as a master regulator in balancing excitation and inhibition in the brain. PMID- 23663755 TI - Enhanced solar energy conversion in Au-doped, single-wall carbon nanotube-Si heterojunction cells. AB - The power conversion efficiency (PCE) of single-wall carbon nanotube (SCNT)/n type crystalline silicon heterojunction photovoltaic devices is significantly improved by Au doping. It is found that the overall PCE was significantly increased to threefold. The efficiency enhancement of photovoltaic devices is mainly the improved electrical conductivity of SCNT by increasing the carrier concentration and the enhancing the absorbance of active layers by Au nanoparticles. The Au doping can lead to an increase of the open circuit voltage through adjusting the Fermi level of SCNT and then enhancing the built-in potential in the SCNT/n-Si junction. This fabrication is easy, cost-effective, and easily scaled up, which demonstrates that such Au-doped SCNT/Si cells possess promising potential in energy harvesting application. PMID- 23663756 TI - Maximal mutual information, not minimal entropy, for escaping the "Dark Room". AB - A behavioral drive directed solely at minimizing prediction error would cause an agent to seek out states of unchanging, and thus easily predictable, sensory inputs (such as a dark room). The default to an evolutionarily encoded prior to avoid such untenable behaviors is unsatisfying. We suggest an alternate information theoretic interpretation to address this dilemma. PMID- 23663757 TI - Dysphagia as a predictor of outcome and transition to palliative care among middle cerebral artery ischemic stroke patients. AB - BACKGROUND: Middle Cerebral Artery (MCA) territory strokes can be disabling and may leave patients unable to swallow safely. Decisions regarding artificial nutrition and goals of care often arise in patients with severe strokes leading to dysphagia. This study determined some predictors of early transition to palliative level of care among patients with acute ischemic MCA stroke with dysphagia. METHODS: This is a retrospective cohort study. Demographic and clinical data of patients presenting to Hartford Hospital with an acute ischemic stroke between January 2005-December 2010 were gathered utilizing the Stroke Center at Hartford Hospital Database. The 236 patients included were divided into "early transition" and "not transitioned" to palliative care cohorts. Primary outcome was transition to palliative care. Factors that were significantly associated with an early transition to palliative level of care in univariate analysis were then entered into a multivariate logistic regression analysis to identify potential independent predictors of early transition to palliative level of care. The significance level was set at p < 0.05. RESULTS: 79 patients (34%) were transitioned to palliative level of care after failing the first swallow evaluation within a median of 3 days. Factors predictive of an early transition to palliative level of care after multivariate logistic regression analysis included advancing age (p < 0.001; OR: 1.10; 95% CI :1.056-1.155) , left MCA infarct (p = 0.039; OR: 0.417; 95% CI:0.182-0.956), a high NIHSS score on admission (p = 0.017; OR: 3.038; 95% CI: 1.22-7.555), administration of intra arterial tPA (p < 0.001; OR: 7.106; 955 CI 2.541-19.873) and the inability to be assessed on the 1(st) swallow evaluation (p < 0.001; OR 0.053; 95% CI 0.022 0.131). CONCLUSIONS: The severity of dysphagia influences early transition to palliative level of care in acute stroke patients. Independent predictors of an early transition to palliative level of care among patients with an acute MCA territory stroke and dysphagia included advancing age, a left MCA infarct, a high NIHSS score on admission, administration of intra-arterial tPA and the inability to be assessed on the 1(st) swallow evaluation. This information may guide discussions with families of patients with MCA territory strokes regarding artificial nutrition and goals of care. PMID- 23663758 TI - [Study of using an individualized treatment strategy to treat patients with chronic hepatitis C]. AB - OBJECTIVE: To investigate the outcomes of chronic hepatitis C (CHC) patients treated with antiviral regimens of interferon (IFN) plus ribavirin (RBV) using individualized doses and durations. METHODS: This study was designed as an open label, prospective clinical trial to analyze the virological responses of 169 CHC patients who received individualized dosages of IFNa-2b or pegylated (Peg)IFNa-2a combined with RBV based on their weight ( less than 60 kg or more than or equal to 60 kg), age (less than 65 years or 65-75 years), morbid state (liver cirrhosis or not), and complications (such as heart disease, diabetes, thyroid disorder). Treatment duration was calculated using the time required to induce HCV RNA negativity. The rates of virological response and adverse effects among the different groups were compared. RESULTS: The IFNa-2b treatment was given to 116 patients, and PegIFNa-2a was given to 53 patients. Compared to the IFNa-2b group, the PegIFNa-2a group showed significantly higher rates of complete early virological response (cEVR; 76.7% vs. 92.5%, P less than 0.05) and sustained virological response (SVR; 53.6% vs. 92.3%, P less than 0.05) among the patients who had completed their course of treatment; the rapid virological response (RVR) rate was also higher for the PegIFNa-2a group but the difference did not reach statistical significance (48.7% vs. 60.4%, P more than 0.05). Seventy-eight patients received the routine dose, and 91 patients received the low dose; there were no significant differences between these two groups for RVR (53.8% vs. 58.9%, P more than 0.05), cEVR (78.0% vs. 80.8%, P more than 0.05), or SVR (65.5% vs. 58.3%, P more than 0.05). CONCLUSION: Use of an individualized antiviral treatment strategy designed according to the patient's baseline condition, early viral kinetics, and tolerability to adverse reactions can achieve a high rate of SVR, as well as improve the safety, prognosis, and cost-effectiveness associated with treating CHC patients. PMID- 23663759 TI - [PD-1 expression in HBcAg-specific CD8+ T cells of adolescents with chronic HBV infection]. AB - OBJECTIVE: To investigate the differential expression of programmed death-1 (PD 1) in the hepatitis B core antigen (HBcAg)17-28-specific CD8+ T cell subsets of adolescent patients with chronic hepatitis B virus (HBV) infection during the immune tolerant phase and the immune clearance phase. METHODS: A total of 105 patients between the ages of 12-28 years old (mean age 17.20+/-6.35) with chronic HBV infection and 15 healthy age-matched individuals were enrolled in the study. The patients were divided into two groups according to their current status in immune clearance phase (n = 55) or immune tolerant phase (n = 50), as determined by hepatic biopsy pathology. Flow cytometry was used to detect HLA-A2 type and PD 1 expression on peripheral blood mononuclear cells (PBMC) and HBcAg17-28-specific CD8+ T cells. PD-1 mRNA levels in PBMCs were measured by reverse transcription polymerase chain reaction (RT-PCR). Independent samples t-test was used to compare means between the two groups, and one-way ANOVA was used to compare means among multiple groups. Pearson's correlation coefficient was used to assess the significance of correlation. RESULTS: The frequency of HBcAg18-27-specific CD8+ T cells was significantly higher in the immune clearance phase group than in the immune tolerant phase group (t = 18.08, P less than 0.01), but the expression of PD-1 on the HBcAg18-27 specific CD8+ T cells was significantly lower in the immune clearance phase group than in the immune tolerant phase group (t = 4.72, P less than 0.01). A negative correlation existed between the frequency of HBcAg18 27-specific CD8+ T cells and PD-1 expression (r = -0.463, P less than 0.01). A positive correlation existed between HBV viral load and PD-1 expression on the HBcAg18-27-specific CD8+ T cells in chronic HBV infection patients (r = 0.882, P less than 0.01), and there was a negative correlation between PD-1 expression levels on HBcAg18-27-specific CD8+ T cells and hepatic tissue inflammation score (r = -0.76, P less than 0.01). PD-1 mRNA in PBMCs was significantly higher in the immune tolerant phase group than in the immune clearance phase group (t = 30.89, P less than 0.01). CONCLUSION: Up-regulated expression of PD-1 is associated with HBV-specific CD8+ T cells and may play a crucial role in inhibiting their function during the immune tolerance phase of chronic HBV infection in adolescents. PMID- 23663760 TI - [Antiviral activities of ISG20 against hepatitis C virus]. AB - OBJECTIVE: To investigate the impact of interferon-stimulated exonuclease 20 kDa (ISG20) on replication of genotype 2a hepatitis C virus (HCV) subgenomic replicon RNA and infectivity of the cell culture-derived HCV strain JFH1 to determine the potential of exogenously expressed ISG20 as an anti-viral therapy of chronic hepatitis C. METHODS: Plasma vectors containing wild-type (WT) ISG20 or a catalytically-inactive mutant ISG20m were transiently transfected into Huh7, Huh7.5 and HEK293 cells, and the replication of a monocistronic subgenomic JFH1 RNA replicon, SGRm-JFH1BlaRL, was measured. Huh7.5 cells stably expressing ISG20, ISG20m, or the control vector were established by transducing replication incompetent pCX4-Bsr-myc retroviruses encoding WT ISG20, D94G mutant ISG20, or the empty vector, respectively, and selecting with 5 mug/mL of blasticidin for approximately three weeks. The stable Huh7.5 cells were then transfected with HCV replicon RNA and infected with cell culture-derived HCV to investigate inhibition capacity of ISG20 against HCV. RESULTS: Huh7.5-ISG20, Huh7.5-ISG20m, and Huh7.5 Bsr controls cells stably expressing ISG20, ISG20m, or the control vector, respectively, were constructed successfully; the ectopically expressed ISG20 and ISG20m were distributed in both nucleus and cytoplasm, as detected by immuno uorescence. SGRm-JFH1BlaRL replicated efficiently and with similar kinetics in the Huh7.5-Bsr and Huh7.5-ISG20m cells, with expression levels plateauing at 48 96 h post-transfection. In contrast, at all time points examined, SGRm-JFH1BlaRL replication was 9.1% to 16.7% in the Huh7.5-ISG20 cells. The Huh7, Huh7.5 and HEK293 cells transiently expressing ISG20 also showed 16.7% to 25.0% of HCV replication that the respective controls. In addition, the amount of infectious progeny JFH1 virus released in culture supernatants was 9.1% to 12.5% from the Huh7.5-ISG20 cells than from the Huh7.5-Bsr and Huh7.5-ISG20m cells at 48-72 h post-infection, and the latter two cultures produced similar JFH1 virus yields. Finally, the expression of HCV core protein was also lower in the Huh7.5-ISG20 cells, as detected by immunoblot analysis. CONCLUSION: Exogenous expression of ISG20, either in a transient or stable manner, suppresses not only replication of genotype 2a HCV RNA replicons but also JFH1 virus propagation in cultured hepatocytes. The exonuclease activity of ISG20 is required for its antiviral activities against HCV. PMID- 23663761 TI - [Screening and identification of HLA-A0201 restricted cytotoxic T lymphocyte epitopes from hepatitis B virus E antigen in vitro]. AB - OBJECTIVE: To identify HLA-A0201 restricted cytotoxic T lymphocyte (CTL) epitopes derived from the hepatitis B virus e (HBe) antigen, for future use in a specific immunotherapy based on the identified epitope(s). METHODS: HBe gene sequences from the hepatitis B virus serotypes with the highest frequencies in China were analyzed by bioinformatic web-based interfaces for quantitative motif prediction, extended motif prediction, and peptide super-motif prediction. Four candidate peptides were identified: HBe1, HBe2, HBe3, and HBe4. The affinities of each were tested in vitro with T2 cells, which lack the transporter-associated with antigen transport (TAP) protein but express low levels of the MHC class I surface molecule, and measured by the T2 binding assay and DC50 assay. Flow cytometry was used to detect the fluorescence index of control and experimental groups. RESULTS: The peptides HBe1 (LLWFHISCL), HBe2 (YLVSFGVWI), HBe3 (CLTFGRETV), and HBe4 (DLLDTASAL) were identified and tested as candidate targets. HBe2 and HBe3 showed higher HLA-A0201 affinity. HBe1, HBe2, and HBe3 showed better binding stability. CONCLUSION: Two peptides based on HBe antigen, YLVSFGVWI and CLTFGRETV, possess both sufficient binding affinity and stability and may represent useful HLA-A0201-restricted CTL epitopes. Further study is needed to determine the immunogenic properties of these two peptides in vivo. PMID- 23663762 TI - [Effects of anandamide on proliferation of and pErk expression in primary hepatic stellate cells of schistosome-induced liver fibrosis mice]. AB - OBJECTIVE: To investigate the potential therapeutic properties of the endogenous cannabinoid N-arachidonic acid aminoethanols (anandamide, AEA) in liver fibrosis by observing its affects on proliferation of and expression of phosphorylated-Erk (pErk) in primary hepatic stellate cells (HSCs) from a mouse model of schistosome induced liver fibrosis. METHODS: The schistosome-induced liver fibrosis model was established by attaching cercaria to the skin on the ventral side of the mouse and allowing infection to occur via direct penetration. Six weeks later, the model was confirmed by pathological analysis of liver, with Masson trichrome staining showing collagen fiber deposition around the blood vessels and hematoxylin-eosin staining showing eosinophilic granuloma formation. Primary HSCs were isolated by discontinuous density gradient centrifugation, confirmed by immunofluorescence detection of double-staining for a-smooth muscle actin and desmin (95% purity), and cultured in the presence of absence of various concentrations of AEA. Proliferative ability was evaluated by MTT assay and the expression of pErk was observed by Western blotting. RESULTS: AEA treatment inhibited the proliferation of the primary HSCs in a concentration-dependent manner (AEA: 5 mumol/L, inhibition: 7.68%; 10 mumol/L, 11.65%; 20 mumol/L, 14.70%; 40 mumol/L, 15.07%; 60 mumol/L, 18.18%; 80 mumol/L, 20.26%; 100 mumol/L, 20.17%; 120 mumol/L, 29.24%). AEA treatment increased pERK expression in both a concentration-dependent manner (AEA: 20 mumol/L, average gray value: 39.90+/ 4.61; 60 mumol/L, 43.45+/-0.91; 120 mumol/L, 52.91+/-1.97; vs. negative control, all P less than 0.05) and a time-dependent manner (time: 15 min, average gray value: 85.05+/-15.80; 30 min, 103.41+/-11.89; 1 h, 118.02+/-12.24; 3 h, 109.17+/ 15.69; 6 h, 100.86+/-10.55; 12 h, 71.70+/-12.87; 24 h, 34.62+/-14.85; 48 h, 22.84+/-11.73; vs. negative control, all except 48 h had P less than 0.05). CONCLUSION: AEA can suppress the proliferative capacity of primary HSCs from schistosome-induced fibrotic livers through activation of the Erk signaling pathway. PMID- 23663763 TI - [Expression and correlation of angiotensin-converting enzyme 2 in CCl4-induced rat liver fibrosis]. AB - OBJECTIVE: To investigate the expression and pathogenic relevance of angiotensin converting enzyme 2 (ACE2) in liver fibrosis by using the rat model of CCl4 induced liver fibrosis. METHODS: The liver fibrosis model was generated by delivering subcutaneous injections of CCl4 (dissolved in olive oil at a 2:3 ratio; injection dose: 3 ml/kg) every three days for six weeks into male Sprague Dawley rats. Another group of rats that received simultaneous injections of olive oil alone (3 ml/kg) were used as controls. At week 0, 2, 4, or 6 after the first injection, a subset of rats from each group was sacrificed to obtain liver tissues and serum samples. Pathological analyses were carried out to detect the presence and extent of liver cell degeneration, necrosis, inflammatory cell infiltration, and collagen deposition. ACE2 and ACE gene and protein expressions were measured by real-time PCR and Western blotting, respectively. The significance of differential expression between groups and time points was assessed by t-test and one-way ANOVA or Kruskal-Wallis tests, and correlation with fibrosis was assessed by Spearman's rank correlation coefficient. RESULTS: CCl4 administration led to significantly up-regulated ACE2 mRNA levels at week 2 (3.055+/-1.034), 4 (3.545+/-1.947), and 6 (6.448+/-1.836) (vs. controls; H = 23.224, P less than 0.001). Similarly, hepatic ACE mRNA was significantly increased after the CCl4 injections (week 2: 3.055+/-1.034, week 4: 3.545+/ 1.947, week 6: 6.448+/-1.836; vs. controls: F = 12.982, P less than 0.001). There was a significant correlation between the ACE and ACE2 gene expression levels (r = 0.750, P less than 0.001). Protein levels of ACE2 also showed an increasing trend following CCl4 administration (week 0: 0.034, week 2: 0.097, week 4: 0.356, week 6: 0.512). The hepatic ACE2 gene expression strongly correlated with levels of alanine aminotransferase (r = 0.669, P less than 0.0001) and aspartate aminotransferase (r = 0.815, P less than 0.0001), and with the Ishak fibrosis score (r = 0.850, P less than 0.001). Finally, there was a significant correlation between circulating ACE2 and the Ishak fibrosis score (r = 0.730, P less than 0.001). CONCLUSION: A significant relationship exists between ACE2 gene expression and extent of liver fibrosis. ACE2 may play a crucial role in liver fibrogenesis. PMID- 23663764 TI - [Preparation and in vitro study of a high molecular weight contrast agent targeting hepatoma cells]. AB - OBJECTIVE: To prepare a specific high molecular weight polymer contrast agent capable of specifically targeting hepatocarcinoma cells (HCC) and to investigate its affinity in vitro using HepG2 cells. METHODS: The high molecular weight polymer polylactic-co-glycolic acid (PLAG)-COOH was prepared by the double emulsion technique. PLAG-COOH microbubbles were combined with glypican-3 (GPC3) antibody to generate HCC targeting high molecular polymer ultrasound contrast agents by the carbodiimide method. The affinity for HCC cells was confirmed by measuring attachment to cultured HepG2 cells by flow cytometry and comparing the results with the properties observed for non-targeted high molecular weight polymer ultrasound contrast agents. RESULTS: The average diameter of the targeted high molecular weight polymer ultrasound contrast agents was (800+/-10) nm. In vitro targeting of HepG2 cells showed that many of the targeted high molecular weight polymer ultrasound contrast agents attached tightly to the cell surface and that the GPC3-PLGA has a particularly strong targeting ability. CONCLUSION: A HCC-specific high molecular contrast agent, GPC3-PLGA, was synthesized and evidenced a strong targeting ability towards HepG2 cells in vitro. This new agent may be exploited to improve diagnosis of liver cancer at the molecular level. PMID- 23663765 TI - [Significance of high sensitivity C-reactive protein level for predicting risk of nonalcoholic fatty liver in type 2 diabetes mellitus patients]. AB - OBJECTIVE: To investigate the significance of high sensitivity C-reactive protein (hsCRP) levels in serum for detecting type 2 diabetes mellitus (T2DM) patients at risk of developing nonalcoholic fatty liver (NAFLD). METHODS: Individuals with T2DM (n = 9489) were recruited from the Kailuan Company between 2006 and 2007 for the first phase of this community-based prospective cohort study. For the second phase of the study, the original cohort was recruited for follow-up (at two years from each subject's original enrollment date (baseline)). The total followed-up subjects (n = 2802; 2344 males, 458 females, 22-88 years old) were categorized into quartiles according to baseline measurements of serum hsCRP levels (less than or equal to 0.30, > 0.30-0.60, > 0.60-1.92 and > 1.92 mg/L) and used to determine the relationship between change in incidence rates of NAFLD and predictive value of baseline serum hsCRP levels by logistic regression analysis. RESULTS: Twenty-nine percent (n = 813) of the followed-up subjects developed NAFLD. The incidence (%) of NAFLD at the two-year follow-up had increased in conjunction with the level of serum hsCRP detected at baseline (quartile 1: 22.5%, 2: 27.3%, 3: 32.1%, and 4: 34.3%; all, P less than 0.01). It was found that the subjects in the highest quartile had an increased risk of NAFLD (odds ratio (OR) = 1.80, 95% confidence interval (CI): 1.42-2.28, P less than 0.01), as compared with those in the lowest quartile. Moreover, when the regression model was adjusted for baseline factors of age, sex, triglycerides, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, fasting serum glucose, and body mass index, the risk of NAFLD remained significantly higher for the highest quartile (vs. the lowest quartile; OR = 1.49, 95% CI: 1.16-1.91, P less than 0.01). CONCLUSION: Serum hsCRP levels may be predictive of development of NAFLD in individuals with type 2 diabetes mellitus. The risk of NAFLD increases in parallel with increasing levels of serum hsCRP. PMID- 23663766 TI - [Risk factors analysis of nonalcoholic fatty liver disease in Chinese men]. AB - OBJECTIVE: To explore risk factors of nonalcoholic fatty liver disease (NAFLD) in men in order to provide a theoretical basis for developing more effective NAFLD prevention and control strategies. METHODS: One-hundred-and-two male patients (37.3+/-11.4 years old) hospitalized with NAFLD at the Dongnan Affiliated Hospital of Xiamen University between January 2009 and December 2010 were enrolled in the study, along with 23 age-matched healthy men (34.4+/-16.7 years old) to serve as the control group. The correlation(s) of body mass index (BMI; overweight defined as more than or equal to 22.717 kg/m2), waist circumference (WC), waist-to-hip ratio (WHR; central obesity defined as more than or equal to 0.866), fasting plasma glucose (FPG), triglyceride (TG), and total cholesterol (TC) with NAFLD was analyzed by univariate and multivariate logistic regression analyses. Receiver operating characteristic (ROC) curves were used to select proper thresholds for classification. RESULTS: BMI, WC, WHR, FPG, TG, and TC were significantly different between the cases and controls (P less than 0.01). BMI, WC, WHR, TG and TC were identified as risk factors of NAFLD in these male cases (P less than 0.01). Relative to WC, TG and TC, both BMI and WHR had significant predictive value for NAFLD (odds ratio (OR) = 10.819 and 10.588, respectively). In addition, BMI had the highest diagnostic value for the prediction of NAFLD (area under the curve (AUC) = 0.931) followed by WHR (AUC = 0.879). CONCLUSION: BMI, WC, WHR, TG, and TC are risk factors of NAFLD in Chinese men. BMI and WHR are effective anthroposomatology indices of NAFLD and may be useful factors on which to base future prevention and early diagnosis strategies for NAFLD in males. PMID- 23663767 TI - [Effects of quercetin on serum levels of resistin and IL-18 and on insulin resistance in nonalcoholic fatty liver disease rats]. AB - OBJECTIVE: To investigate the effects of quercetin on serum levels of resistin and interleukin (IL)-18 and incidence of insulin resistance (IR) in nonalcoholic fatty liver disease (NAFLD) using a rat model. METHODS: NAFLD was induced in Sprague-Dawley rats by administering a high-fat diet for four weeks. The model rats were then treated with quercetin (oral gavage administration; low dose group: 75 mg/kg/day, high dose group: 300 mg/kg/day) for eight weeks. Untreated model rats served as controls. Serum levels of resistin, triglyceride (TG), IL 18, fasting plasma glucose (FPG), fasting insulin (FINS), and malondialdehyde (MDA) were measured by standard biochemical assays before and after the quercetin administration. In addition, the insulin resistance index (HOMA-IR) was calculated and pathological changes in liver were observed by histological analysis. RESULTS: Compared to the untreated model rats, the quercetin treated model rats showed significantly lower serum resistin (5.98 vs. 2.70), serum IL-18 (10.93 vs. 8.21), FPG (7.45 vs. 4.99), FINS (12.69 vs. 8.59), and HOMA-IR (4.22 vs. 1.87) (all P less than 0.01). Compared to the untreated model group, the high dose group showed significantly lower TG (t = 4.70) and MDA (t = 5.14) (both P less than 0.01). Serum levels of resistin and IL-18, and levels of TG, FPG and FINS were found to be positively correlated with HOMA-IR and the degree of liver disease (r more than 0, all P less than 0.05). The degree of degeneration was decreased in accordance with the dosages of quercetin, as compared to the untreated model group (U = 4.41 and 2.19, both P less than 0.05), and the pathological degree was less extensive in the high dose group than in the low dose group (U = 2.44, P less than 0.01). CONCLUSION: Quercetin treatment reduces levels of inflammatory cytokines and improves lipid peroxidation and IR in NAFLD rats, and its beneficial effects appear to increase with higher dosage. PMID- 23663768 TI - Neuronal inference must be local, selective, and coordinated. AB - Life is preserved and enhanced by coordinated selectivity in local neural circuits. Narrow receptive-field selectivity is necessary to avoid the curse-of dimensionality, but local activities can be made coherent and relevant by guiding learning and processing using broad coordinating contextual gain-controlling interactions. Better understanding of the functions and mechanisms of those interactions is therefore crucial to the issues Clark examines. PMID- 23663769 TI - Safety of antidepressants in adults aged under 65: protocol for a cohort study using a large primary care database. AB - BACKGROUND: Antidepressants are among the most commonly prescribed drugs in primary care in England and their use is increasing. This is largely due to longer durations of treatment of depression. Observational studies have shown some differences in adverse outcomes associated with different antidepressant drugs but relatively little is known about their relative safety particularly with long term use. The primary aim of this study is to determine the relative and absolute risks of pre-defined adverse events comparing different classes of antidepressant drugs in adults aged under 65 years and diagnosed with depression. METHODS/DESIGN: The study will identify a cohort of patients with a first recorded diagnosis of depression between 1/1/2000 and 31/07/2011, and made between the ages of 20 to 64 years using a large primary care database (QResearch). Patients will be followed up until 1/08/2012. Details of all prescriptions for antidepressants in patients in the cohort will be extracted, including the date of each prescription, the type of antidepressant drug, the dose and total quantity prescribed. Prospectively recorded data will be used to ascertain information on adverse outcomes that occurred during follow-up and after entry into the cohort. These are: all-cause mortality, suicide, attempted suicide/self-harm, sudden death, antidepressant overdose/poisoning, myocardial infarction, stroke/transient ischaemic attack, cardiac arrhythmia, epilepsy/seizures, upper gastrointestinal bleeding, falls, fractures, adverse drug reactions and motor vehicle crashes. Cox proportional hazard models will be used to estimate the association of the outcomes with class of antidepressant drug adjusting for potential confounding variables. The analyses will also examine associations by duration and dose and with the most frequently prescribed individual antidepressant drugs. Self-controlled case series analyses will be used to estimate the relative incidence of the outcomes of interest for defined time periods of antidepressant use. DISCUSSION: The results of this study will help to establish the relative safety and balance of risks for different antidepressant drugs in people aged under 65. PMID- 23663771 TI - Catalyzing curriculum evolution in graduate science education. AB - Strategies in life science graduate education must evolve in order to train a modern workforce capable of integrative solutions to challenging problems. Our institution has catalyzed such evolution through building a postdoctoral Curriculum Fellows Program that provides a collaborative and scholarly education laboratory for innovation in graduate training. PMID- 23663770 TI - Parenteral diclofenac infusion significantly decreases brain-tissue oxygen tension in patients with poor-grade aneurysmal subarachnoid hemorrhage. AB - INTRODUCTION: Diclofenac, a nonsteroidal antiinflammatory drug, is commonly used as antipyretic therapy in intensive care. The purpose of this study was to investigate the effects of parenteral diclofenac infusion on brain homeostasis, including brain-tissue oxygen tension (PbtO2) and brain metabolism after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: We conducted a prospective, observational study with retrospective analysis of 21 consecutive aSAH patients with multimodal neuromonitoring. Cerebral perfusion pressure (CPP), mean arterial pressure (MAP), intracranial pressure (ICP), body temperature, and PbtO2 were analyzed after parenteral diclofenac infusion administered over a 34-minute period (20 to 45 IQR). Data are given as mean +/- standard error of mean and median with interquartile range (IQR), as appropriate. Time-series data were analyzed by using a general linear model extended by generalized estimation equations (GEEs). RESULTS: One-hundred twenty-three interventions were analyzed. Body temperature decreased from 38.3 degrees C +/- 0.05 degrees C by 0.8 degrees C +/- 0.06 degrees C (P < 0.001). A 10% decrease in MAP and CPP (P < 0.001) necessitated an increase of vasopressors in 26% (n = 32), colloids in 33% (n = 41), and crystalloids in 5% (n = 7) of interventions. PbtO2 decreased by 13% from a baseline value of 28.1 +/- 2.2 mm Hg, resulting in brain-tissue hypoxia (PbtO2 <20 mm Hg) in 38% (n = 8) of patients and 35% (n = 43) of interventions. PbtO2 <30 mm Hg before intervention was associated with brain-tissue hypoxia after parenteral diclofenac infusion (likelihood ratio, 40; AUC, 93%; 95% confidence interval (CI), 87% to 99%; P < 0.001). Cerebral metabolism showed no significant changes after parenteral diclofenac infusion. CONCLUSIONS: Parenteral diclofenac infusion after aSAH effectively reduces body temperature, but may lead to CPP decrease and brain-tissue hypoxia, which were both associated with poor outcome after aSAH. PMID- 23663772 TI - Beyond DNA: programming and inheritance of parental methylomes. AB - Epigenetic reprogramming of parental genomes following fertilization is important to ensure compatibility for totipotency and development thereafter. New studies by Jiang et al. and Potok et al. now demonstrate how the parental DNA methylomes are reset in zebrafish and reveal striking differences from events in mammals. PMID- 23663773 TI - Dwelling on T cell fate decisions. AB - Defining determinants of T cell fate is central to understanding adaptive immunity and the design of effective vaccines. Tubo et al. demonstrate that intrinsic properties of T cell receptor signaling dictate whether CD4 T cells adopt predominantly type 1 helper or follicular helper T cell phenotypes in response to bacterial or viral infection. PMID- 23663774 TI - Microbiota keep the intestinal clock ticking. AB - Daily metabolic patterns are regulated in a circadian manner often via the hypothalamic axis. Mukherji et al. now report a surprising role for commensal bacteria in the circadian regulation of glucocorticoid production by intestinal epithelial cells. PMID- 23663775 TI - Young at heart. AB - In this issue of Cell, Loffredo et al. demonstrate that exposing an old mouse to the circulatory system of a young mouse reverses age-related cardiac hypertrophy. The authors demonstrate that this effect can be recapitulated by treating old mice with growth and differentiation factor 11 (GDF11). These data suggest that GDF11 therapy may be a useful tool in combating age-related cardiac hypertrophy. PMID- 23663776 TI - Reprogramming the maternal zebrafish genome after fertilization to match the paternal methylation pattern. AB - Early vertebrate embryos must achieve totipotency and prepare for zygotic genome activation (ZGA). To understand this process, we determined the DNA methylation (DNAme) profiles of zebrafish gametes, embryos at different stages, and somatic muscle and compared them to gene activity and histone modifications. Sperm chromatin patterns are virtually identical to those at ZGA. Unexpectedly, the DNA of many oocyte genes important for germline functions (i.e., piwil1) or early development (i.e., hox genes) is methylated, but the loci are demethylated during zygotic cleavage stages to precisely the state observed in sperm, even in parthenogenetic embryos lacking a replicating paternal genome. Furthermore, this cohort constitutes the genes and loci that acquire DNAme during development (i.e., ZGA to muscle). Finally, DNA methyltransferase inhibition experiments suggest that DNAme silences particular gene and chromatin cohorts at ZGA, preventing their precocious expression. Thus, zebrafish achieve a totipotent chromatin state at ZGA through paternal genome competency and maternal genome DNAme reprogramming. PMID- 23663777 TI - Sperm, but not oocyte, DNA methylome is inherited by zebrafish early embryos. AB - 5-methylcytosine is a major epigenetic modification that is sometimes called "the fifth nucleotide." However, our knowledge of how offspring inherit the DNA methylome from parents is limited. We generated nine single-base resolution DNA methylomes, including zebrafish gametes and early embryos. The oocyte methylome is significantly hypomethylated compared to sperm. Strikingly, the paternal DNA methylation pattern is maintained throughout early embryogenesis. The maternal DNA methylation pattern is maintained until the 16-cell stage. Then, the oocyte methylome is gradually discarded through cell division and is progressively reprogrammed to a pattern similar to that of the sperm methylome. The passive demethylation rate and the de novo methylation rate are similar in the maternal DNA. By the midblastula stage, the embryo's methylome is virtually identical to the sperm methylome. Moreover, inheritance of the sperm methylome facilitates the epigenetic regulation of embryogenesis. Therefore, besides DNA sequences, sperm DNA methylome is also inherited in zebrafish early embryos. PMID- 23663778 TI - Single naive CD4+ T cells from a diverse repertoire produce different effector cell types during infection. AB - A naive CD4(+) T cell population specific for a microbial peptide:major histocompatibility complex II ligand (p:MHCII) typically consists of about 100 cells, each with a different T cell receptor (TCR). Following infection, this population produces a consistent ratio of effector cells that activate microbicidal functions of macrophages or help B cells make antibodies. We studied the mechanism that underlies this division of labor by tracking the progeny of single naive T cells. Different naive cells produced distinct ratios of macrophage and B cell helpers but yielded the characteristic ratio when averaged together. The effector cell pattern produced by a given naive cell correlated with the TCR-p:MHCII dwell time or the amount of p:MHCII. Thus, the consistent production of effector cell subsets by a polyclonal population of naive cells results from averaging the diverse behaviors of individual clones, which are instructed in part by the strength of TCR signaling. PMID- 23663779 TI - Bacterial-derived uracil as a modulator of mucosal immunity and gut-microbe homeostasis in Drosophila. AB - All metazoan guts are subjected to immunologically unique conditions in which an efficient antimicrobial system operates to eliminate pathogens while tolerating symbiotic commensal microbiota. However, the molecular mechanisms controlling this process are only partially understood. Here, we show that bacterial-derived uracil acts as a ligand for dual oxidase (DUOX)-dependent reactive oxygen species generation in Drosophila gut and that the uracil production in bacteria causes inflammation in the gut. The acute and controlled uracil-induced immune response is required for efficient elimination of bacteria, intestinal cell repair, and host survival during infection of nonresident species. Among resident gut microbiota, uracil production is absent in symbionts, allowing harmonious colonization without DUOX activation, whereas uracil release from opportunistic pathobionts provokes chronic inflammation. These results reveal that bacteria with distinct abilities to activate uracil-induced gut inflammation, in terms of intensity and duration, act as critical factors that determine homeostasis or pathogenesis in gut-microbe interactions. PMID- 23663780 TI - Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs. AB - Alterations of symbiosis between microbiota and intestinal epithelial cells (IEC) are associated with intestinal and systemic pathologies. Interactions between bacterial products (MAMPs) and Toll-like receptors (TLRs) are known to be mandatory for IEC homeostasis, but how TLRs may time homeostatic functions with circadian changes is unknown. Our functional and molecular dissections of the IEC circadian clock demonstrate that its integrity is required for microbiota-IEC dialog. In IEC, the antiphasic expression of the RORalpha activator and RevErbalpha repressor clock output regulators generates a circadian rhythmic TLR expression that converts the temporally arrhythmic microbiota signaling into circadian rhythmic JNK and IKKbeta activities, which prevents RevErbalpha activation by PPARalpha that would disrupt the circadian clock. Moreover, through activation of AP1 and NF-kappaB, these activities, together with RORalpha and RevErbalpha, enable timing homeostatic functions of numerous genes with IEC circadian events. Interestingly, microbiota signaling deficiencies induce a prediabetic syndrome due to ileal corticosterone overproduction consequent to clock disruption. PMID- 23663781 TI - Growth differentiation factor 11 is a circulating factor that reverses age related cardiac hypertrophy. AB - The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify the biological mechanisms that drive cardiac hypertrophy in aging, we tested the influence of circulating factors using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation. After 4 weeks of exposure to the circulation of young mice, cardiac hypertrophy in old mice dramatically regressed, accompanied by reduced cardiomyocyte size and molecular remodeling. Reversal of age-related hypertrophy was not attributable to hemodynamic or behavioral effects of parabiosis, implicating a blood-borne factor. Using modified aptamer-based proteomics, we identified the TGF-beta superfamily member GDF11 as a circulating factor in young mice that declines with age. Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging. PMID- 23663783 TI - SR proteins collaborate with 7SK and promoter-associated nascent RNA to release paused polymerase. AB - RNAP II is frequently paused near gene promoters in mammals, and its transition to productive elongation requires active recruitment of P-TEFb, a cyclin dependent kinase for RNAP II and other key transcription elongation factors. A fraction of P-TEFb is sequestered in an inhibitory complex containing the 7SK noncoding RNA, but it has been unclear how P-TEFb is switched from the 7SK complex to RNAP II during transcription activation. We report that SRSF2 (also known as SC35, an SR-splicing factor) is part of the 7SK complex assembled at gene promoters and plays a direct role in transcription pause release. We demonstrate RNA-dependent, coordinated release of SRSF2 and P-TEFb from the 7SK complex and transcription activation via SRSF2 binding to promoter-associated nascent RNA. These findings reveal an unanticipated SR protein function, a role for promoter-proximal nascent RNA in gene activation, and an analogous mechanism to HIV Tat/TAR for activating cellular genes. PMID- 23663784 TI - Roquin promotes constitutive mRNA decay via a conserved class of stem-loop recognition motifs. AB - Tumor necrosis factor-alpha (TNF-alpha) is the most potent proinflammatory cytokine in mammals. The degradation of TNF-alpha mRNA is critical for restricting TNF-alpha synthesis and involves a constitutive decay element (CDE) in the 3' UTR of the mRNA. Here, we demonstrate that the CDE folds into an RNA stem-loop motif that is specifically recognized by Roquin and Roquin2. Binding of Roquin initiates degradation of TNF-alpha mRNA and limits TNF-alpha production in macrophages. Roquin proteins promote mRNA degradation by recruiting the Ccr4-Caf1 Not deadenylase complex. CDE sequences are highly conserved and are found in more than 50 vertebrate mRNAs, many of which encode regulators of development and inflammation. In macrophages, CDE-containing mRNAs were identified as the primary targets of Roquin on a transcriptome-wide scale. Thus, Roquin proteins act broadly as mediators of mRNA deadenylation by recognizing a conserved class of stem-loop RNA degradation motifs. PMID- 23663782 TI - The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. AB - Proliferating mammalian cells use glutamine as a source of nitrogen and as a key anaplerotic source to provide metabolites to the tricarboxylic acid cycle (TCA) for biosynthesis. Recently, mammalian target of rapamycin complex 1 (mTORC1) activation has been correlated with increased nutrient uptake and metabolism, but no molecular connection to glutaminolysis has been reported. Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP responsive element binding 2 (CREB2). Thus, a relationship between mTORC1, SIRT4, and cancer is suggested by our findings. Indeed, SIRT4 expression is reduced in human cancer, and its overexpression reduces cell proliferation, transformation, and tumor development. Finally, our data indicate that targeting nutrient metabolism in energy-addicted cancers with high mTORC1 signaling may be an effective therapeutic approach. PMID- 23663787 TI - SnapShot: Transcription regulation: pausing. PMID- 23663786 TI - Diverse mechanisms of somatic structural variations in human cancer genomes. AB - Identification of somatic rearrangements in cancer genomes has accelerated through analysis of high-throughput sequencing data. However, characterization of complex structural alterations and their underlying mechanisms remains inadequate. Here, applying an algorithm to predict structural variations from short reads, we report a comprehensive catalog of somatic structural variations and the mechanisms generating them, using high-coverage whole-genome sequencing data from 140 patients across ten tumor types. We characterize the relative contributions of different types of rearrangements and their mutational mechanisms, find that ~20% of the somatic deletions are complex deletions formed by replication errors, and describe the differences between the mutational mechanisms in somatic and germline alterations. Importantly, we provide detailed reconstructions of the events responsible for loss of CDKN2A/B and gain of EGFR in glioblastoma, revealing that these alterations can result from multiple mechanisms even in a single genome and that both DNA double-strand breaks and replication errors drive somatic rearrangements. PMID- 23663785 TI - Sexually dimorphic neurons in the ventromedial hypothalamus govern mating in both sexes and aggression in males. AB - Sexual dimorphisms in the brain underlie behavioral sex differences, but the function of individual sexually dimorphic neuronal populations is poorly understood. Neuronal sexual dimorphisms typically represent quantitative differences in cell number, gene expression, or other features, and it is unknown whether these dimorphisms control sex-typical behavior exclusively in one sex or in both sexes. The progesterone receptor (PR) controls female sexual behavior, and we find many sex differences in number, distribution, or projections of PR expressing neurons in the adult mouse brain. Using a genetic strategy we developed, we have ablated one such dimorphic PR-expressing neuronal population located in the ventromedial hypothalamus (VMH). Ablation of these neurons in females greatly diminishes sexual receptivity. Strikingly, the corresponding ablation in males reduces mating and aggression. Our findings reveal the functions of a molecularly defined, sexually dimorphic neuronal population in the brain. Moreover, we show that sexually dimorphic neurons can control distinct sex typical behaviors in both sexes. PMID- 23663788 TI - The role of chemotherapy in advanced solitary fibrous tumors: a retrospective analysis. AB - BACKGROUND: Patients with advanced solitary fibrous tumors (SFTs) have a poor prognosis; treatment options for recurrent disease are particularly limited. Several novel targeted agents have recently shown promise against advanced SFTs, but the relative efficacy of new agents is difficult to assess because data on the efficacy of conventional chemotherapy for SFTs are limited. We thus sought to estimate the efficacy of conventional chemotherapy for SFTs by reviewing data on tumor response to therapy and progression-free survival from SFT patients who received this therapy. METHODS: We retrospectively analyzed the clinical outcomes of 21 patients with grossly measurable, advanced SFTs (unresectable metastatic disease or potentially resectable primary tumors) who received conventional chemotherapy and follow-up at The University of Texas MD Anderson Cancer Center between January 1994 and June 2007. Best tumor response to therapy was assessed using the Response Evaluation Criteria In Solid Tumors 1.1. The Kaplan-Meier method was used to estimate median progression-free survival (PFS) duration. RESULTS: Of 21 patients, 4 received more than 1 regimen of chemotherapy, for a total of 25 treatments. Doxorubicin-based chemotherapy was given in 15 cases (60%), gemcitabine-based therapy in 5 cases (20%), and paclitaxel in 5 cases (20%). First-line chemotherapy was delivered in 18 cases (72%). No patients had a complete or partial response, 16 (89%) had stable disease, and 2 (11%) had disease progression. Five patients (28%) maintained stable disease for at least 6 months after first-line treatment. The median PFS duration was 4.6 months. The median overall survival from diagnosis was 10.3 years. CONCLUSION: Conventional chemotherapy is effective in controlling or stabilizing locally advanced and metastatic SFTs. Our findings can serve as a reference for tumor response and clinical outcomes in the assessment of novel treatments for SFTs. PMID- 23663789 TI - Live well: a practical and effective low-intensity dietary counseling intervention for use in primary care patients with dyslipidemia--a randomized controlled pilot trial. AB - BACKGROUND: Diet is the first line of treatment for elevated cholesterol. High intensity dietary counseling (>=360 minutes/year of contact with providers) improves blood lipids, but is expensive and unsustainable in the current healthcare settings. Low-intensity counseling trials (<=30 minutes/year) have demonstrated modest diet changes, but no improvement in lipids. This pilot study evaluated the feasibility and the effects on lipids and diet of a low-intensity dietary counseling intervention provided by the primary care physician (PCP), in patients at risk for cardiovascular diseases. METHODS: Six month study with a three month randomized-controlled phase (group A received the intervention, group B served as controls) followed by three months of intervention in both groups.Sixty-one adults age 21 to 75 years, with LDL-cholesterol>=3.37 mmol/L, possessing Internet access and active email accounts were enrolled. Diet was evaluated using the Rate-Your-Plate questionnaire. Dietary counseling was provided by the PCP during routine office visits, three months apart, using printed educational materials and a minimally interactive counseling website. Weekly emails were sent reminding participants to use the dietary counseling resources. The outcomes were changes in LDL-cholesterol, other lipid subclasses, and diet quality. RESULTS: At month 3, group A (counseling started at month 1) decreased their LDL-cholesterol by -0.23 mmol/L, (-0.04 to -0.42 mmol/L, P=0.007) and total cholesterol by -0.26 mmol/L, (-0.05 to -0.47 mmol/L, P=0.001). At month 6, total and LDL-cholesterol in group A remained better than in group B (counseling started at month 3). Diet score in group A improved by 50.3 points (38.4 to 62.2, P<0.001) at month 3; and increased further by 11.8 (3.5 to 20.0, P=0.007) at month 6. Group B made the largest improvement in diet at month 6, 55 points (40.0 to 70.1, P<0.001), after having a small but significant improvement at month 3, 22.3 points (12.9 to 31.7, P<0.001). No significant changes occurred in HDL-cholesterol in either group. CONCLUSIONS: A low-intensity dietary counseling provided by the PCP in patients at risk for cardiovascular diseases produced clinically meaningful improvements in both diet and lipids of magnitude similar to changes reported with high intensity interventions. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01695837. PMID- 23663790 TI - Does a stubborn commitment to 'evidence' stifle innovative thinking? PMID- 23663792 TI - Treadmill training is effective for ambulatory adults with stroke: a systematic review. AB - QUESTION: Does mechanically assisted walking increase walking speed or distance in ambulatory people with stroke compared with no intervention/non-walking intervention, or with overground walking? DESIGN: Systematic review with meta analysis of randomised trials. PARTICIPANTS: Ambulatory adults with stroke. INTERVENTION: Mechanically assisted walking (treadmill or gait trainer) without body weight support. OUTCOME MEASURES: Walking speed measured in m/s during the 10-m Walk Test and walking distance measured in m during the 6-min Walk Test. RESULTS: Nine studies of treadmill training comprising 977 participants were included. Treadmill training resulted in faster walking than no intervention/non walking intervention immediately after the intervention period (MD 0.14m/s, 95% CI 0.09 to 0.19) and this was maintained beyond the intervention period (MD 0.12m/s, 95% CI 0.08 to 0.17). It also resulted in greater walking distance immediately after the intervention period (MD 40m, 95% CI 27 to 53) and this was also maintained beyond the intervention period (MD 40m, 95% CI 24 to 55). There was no immediate, statistically significant difference between treadmill training and overground training in terms of walking speed (MD 0.05m/s, 95% CI 0.12 to 0.21) or distance (MD -6m, 95% CI -45 to 33). CONCLUSION: This systematic review provides evidence that, for people with stroke who can walk, treadmill training without body weight support results in faster walking speed and greater distance than no intervention/ non-walking intervention and the benefit is maintained beyond the training period. PMID- 23663793 TI - Program-related factors are associated with adherence to group exercise interventions for the prevention of falls: a systematic review. AB - QUESTIONS: What factors are associated with adherence of older adults to group exercise interventions for the prevention of falls? What is the relationship between adherence and the falls prevention efficacy of the intervention? DESIGN: Systematic review with meta-analysis of randomised trials. PARTICIPANTS: Older adults (60 years and older) undertaking a group exercise intervention for falls prevention. INTERVENTION: Group exercise not in combination with a home program and intended at least in part for falls prevention. OUTCOME MEASURES: Adherence was measured as the mean proportion of sessions attended, including participants who discontinued the intervention. Falls prevention efficacy was measured as the proportion of fallers in the intervention versus the control group at follow-up. Various program-related factors, including intervention duration, session frequency, and components of the exercise regimen were examined for each of the studies. RESULTS: Of the 210 articles identified, 18 studies met the inclusion criteria and were analysed. The pooled estimate of adherence across the studies was 0.74 (95% CI 0.67 to 0.80). Lower levels of adherence were associated with group exercise interventions that had a duration of 20 weeks or more, two or fewer sessions per week, or a flexibility component. No significant relationship was found between adherence and falls prevention efficacy. CONCLUSION: Program related factors may influence adherence to group exercise interventions for the prevention of falls. Further research is encouraged to more precisely determine the effect of intervention level factors on adherence, and the effect of adherence on intervention efficacy. PMID- 23663794 TI - The Berg Balance Scale has high intra- and inter-rater reliability but absolute reliability varies across the scale: a systematic review. AB - QUESTIONS: What is the intra-rater and inter-rater relative reliability of the Berg Balance Scale? What is the absolute reliability of the Berg Balance Scale? Does the absolute reliability of the Berg Balance Scale vary across the scale? DESIGN: Systematic review with meta-analysis of reliability studies. PARTICIPANTS: Any clinical population that has undergone assessment with the Berg Balance Scale. OUTCOME MEASURES: Relative intra-rater reliability, relative inter rater reliability, and absolute reliability. RESULTS: Eleven studies involving 668 participants were included in the review. The relative intrarater reliability of the Berg Balance Scale was high, with a pooled estimate of 0.98 (95% CI 0.97 to 0.99). Relative inter-rater reliability was also high, with a pooled estimate of 0.97 (95% CI 0.96 to 0.98). A ceiling effect of the Berg Balance Scale was evident for some participants. In the analysis of absolute reliability, all of the relevant studies had an average score of 20 or above on the 0 to 56 point Berg Balance Scale. The absolute reliability across this part of the scale, as measured by the minimal detectable change with 95% confidence, varied between 2.8 points and 6.6 points. The Berg Balance Scale has a higher absolute reliability when close to 56 points due to the ceiling effect. We identified no data that estimated the absolute reliability of the Berg Balance Scale among participants with a mean score below 20 out of 56. CONCLUSION: The Berg Balance Scale has acceptable reliability, although it might not detect modest, clinically important changes in balance in individual subjects. The review was only able to comment on the absolute reliability of the Berg Balance Scale among people with moderately poor to normal balance. PMID- 23663795 TI - Inspiratory muscle training did not accelerate weaning from mechanical ventilation but did improve tidal volume and maximal respiratory pressures: a randomised trial. AB - QUESTION: Does inspiratory muscle training accelerate weaning from mechanical ventilation? Does it improve respiratory muscle strength, tidal volume, and the rapid shallow breathing index? DESIGN: Randomised trial with concealed allocation and intention-to-treat analysis. PARTICIPANTS: 92 patients receiving pressure support ventilation were included in the study and followed up until extubation, tracheostomy, or death. INTERVENTION: The experimental group received usual care and inspiratory muscle training using a threshold device, with a load of 40% of their maximal inspiratory pressure with a regimen of 5 sets of 10 breaths, twice a day, 7 days a week. The control group received usual care only. OUTCOME MEASURES: The primary outcome was the duration of the weaning period. The secondary outcomes were the changes in respiratory muscle strength, tidal volume, and the rapid shallow breathing index. RESULTS: Although the weaning period was a mean of 8 hours shorter in the experimental group, this difference was not statistically significant (95% CI -16 to 32). Maximal inspiratory and expiratory pressures increased in the experimental group and decreased in the control group, with significant mean differences of 10cmH2O (95% CI 5 to 15) and 8cmH2O (95% CI 2 to 13), respectively. The tidal volume also increased in the experimental group and decreased in the control group (mean difference 72 ml, 95% CI 17 to 128). The rapid shallow breathing index did not differ significantly between the groups. CONCLUSION: Inspiratory muscle training did not shorten the weaning period significantly but it increased respiratory muscle strength and tidal volume. PMID- 23663796 TI - Massage reduced severity of pain during labour: a randomised trial. AB - QUESTION: Does massage relieve pain in the active phase of labour? DESIGN: Randomised trial with concealed allocation, assessor blinding for some outcomes, and intention-to-treat analysis. PARTICIPANTS: 46 women pregnant at >= 37 weeks gestation with a single fetus, with spontaneous onset of labour, 4-5cm of cervical dilation, intact ovular membranes, and no use of medication after admission to hospital. INTERVENTION: Experimental group participants received a 30-min lumbar massage by a physiotherapist during the active phase of labour. A physiotherapist attended control group participants for the same period but only answered questions. Both groups received routine perinatal care. OUTCOME MEASURES: The primary outcome was pain severity measured on a 100mm visual analogue scale. Secondary outcomes included the Short Form McGill Pain Questionnaire, pain location, and time to analgesic medication use. After labour, a blinded researcher also recorded duration of labour, route of delivery, neonatal outcomes, and the participant's satisfaction with the physiotherapist during labour. RESULTS: At the end of the intervention, pain severity was 52mm (SD 20) in the experimental group and 72mm (SD 15) in control group, which was significantly different with a mean difference of 20mm (95% CI 10 to 31). The groups did not differ significantly on the other pain-related outcome measures. Obstetric outcomes were also similar between the groups except the duration of labour, which was 6.8hr (SD 1.6) in the experimental group and 5.7hr (SD 1.5) in the control group, mean difference 1.1hr (95% CI 0.2 to 2.0). Patients in both groups were satisfied with the care provided by the physiotherapist. CONCLUSION: Massage reduced the severity of pain in labour, despite not changing its characteristics and location. PMID- 23663797 TI - Self-efficacy for physical activity and insight into its benefits are modifiable factors associated with physical activity in people with COPD: a mixed-methods study. AB - QUESTIONS: What are the perceived reasons for people with chronic obstructive pulmonary disease (COPD) to be physically active or sedentary? Are those reasons related to the actual measured level of physical activity? DESIGN: A mixed methods study combining qualitative and quantitative approaches. PARTICIPANTS: People with mild to very severe COPD. OUTCOME MEASURES: Participants underwent a semi-structured interview and physical activity was measured by a triaxial accelerometer worn for one week. RESULTS: Of 118 enrolled, 115 participants (68% male, mean age 65 years, mean FEV1 57% predicted, mean modified Medical Research Council dyspnoea score 1.4) completed the study. The most frequently reported reason to be physically active was health benefits, followed by enjoyment, continuation of an active lifestyle from the past, and functional reasons. The most frequently reported reason to be sedentary was the weather, followed by health problems, and lack of intrinsic motivation. Mean steps per day ranged between 236 and 18 433 steps. A high physical activity level was related to enjoyment and self-efficacy for physical activity. A low physical activity level was related to the weather influencing health, financial constraints, health and shame. CONCLUSION: We identified important facilitators to being physically active and barriers that could be amenable to change. Furthermore, we distinguished three important potential strategies for increasing physical activity in sedentary people with COPD, namely reducing barriers and increasing insight into health benefits, tailoring type of activity, and improvement of self efficacy. PMID- 23663798 TI - Improving mood through physical activity for carers and care recipients (IMPACCT): protocol for a randomised trial. AB - INTRODUCTION: Family carers play an important role in providing care for frail older Australians. Carers have increased rates of depression, burden and poor physical health compared with non-carers. Physical activity has been shown to improve outcomes; however there is limited research investigating outcomes in older carers and less on physical activity for both the carer and care recipient. RESEARCH QUESTION: Does a home-based individualised physical activity intervention designed for both the carer and care recipient improve depression severity in older carers? PARTICIPANTS AND SETTING: 273 community-dwelling carers with depressive symptoms and their care recipients will be recruited for a randomised controlled trial. Baseline assessment will consist of functional, psychological, and physical measures and information about service use. INTERVENTION AND CONTROL: Participants will be randomised to receive either a physical activity program (intervention), a social support program (social control), or usual care (control). The intervention and social control groups will have five home visits over six months. MEASUREMENTS: All participants will be re-assessed after completion of the program and then six months later to evaluate sustainability of outcomes. The primary outcome measure is the 15-item Geriatric Depression Scale for carers. Secondary outcomes include physical measures for carers and care recipients, carer burden, carer satisfaction, care recipient depression, and cost-effectiveness. All assessors will be blind to group allocation. DISCUSSION: This study has the potential to demonstrate that physical activity interventions can be delivered simultaneously to older carers and care recipients to improve mental and physical outcomes. PMID- 23663799 TI - Acute low back usually resolves quickly but persistent low back pain often persists. AB - OBJECTIVE: To review the evidence of clinical course of pain and disability in patients with acute and persistent low-back pain, and to investigate whether pain and disability had similar courses. DATA SOURCES: MEDLINE, CINAHL and Embase databases were searched from 1950 to November, 2011. This search was supplemented by searching of reference lists from eligible studies. STUDY SELECTION: Inception cohort studies involving patients with acute (< 6 weeks) and persistent (>= 6 weeks) low-back pain in which pain or disability outcomes were reported. DATA EXTRACTION: Two reviewers extracted data and discrepancies were resolved by consulting a third reviewer. Methodological quality was assessed using 5 criteria suggested by Altman (2001). A meta-analysis of pain and disability outcome data was conducted, in which pain and disability were modelled as a function of time. DATA SYNTHESIS: Of 28 613 studies initially identified by the search, 43 studies (33 cohorts) with a total of 11 166 patients met the selection criteria. Data quality was insufficient in many of the studies; only 52% of the studies explicitly reported methods for assembling a representative sample, 73% had a follow-up of at least 80%, and 88% had a follow-up for at least one prognosis outcome at three months or longer. Based on the quantitative pooling of 24 cohorts and 4994 patients the variance-weighted mean pain score (0-100) was 52 (95% CI 48 to 57) at baseline, 23 (95% CI 21 to 25) at 6 weeks, 12 (95% CI 9 to 15) at 26 weeks, and 6 (95% CI 3 to 10) at 52 weeks after the onset of pain for cohorts with acute pain. Among cohorts with persistent pain, the variance weighted mean pain score (out of 100) was 51 (95% CI 44 to 59) at baseline, 33 (95% CI 29 to 38) at 6 weeks, 26 (95% CI 20 to 33) at 26 weeks, and 23 (95% CI 16 to 30) at 52 weeks after the onset of pain. The course of disability outcomes was similar to the time course of pain outcomes in the acute pain cohorts, but for persistent pain cohorts disability only improved slowly, despite substantial initial improvement in pain. There were large within-study and between-study variation in outcomes. CONCLUSION: Most people who seek care for acute or persistent low-back pain improved markedly within the first six weeks, but afterwards improvement slowed. Low to moderate levels of pain and disability were still present at one year, especially in people with persistent pain. PMID- 23663800 TI - Repetitive transcranial magnetic stimulation combined with treadmill training can modulate corticomotor inhibition and improve walking performance in people with Parkinson's disease. AB - QUESTION: Does adding repetitive transcranial magnetic stimulation (rTMS) to treadmill training modulate cortical excitability and improve walking in people with Parkinson's disease (PD)? DESIGN: Randomised controlled trial with blinded outcome assessment. SETTING: A medical centre in Taiwan. PARTICIPANTS: Individuals with Parkinson's disease (Hoehn and Yahr Stage 2-3), and ability to walk independently were key inclusion criteria. Absence of motor evoked potential in response to rTMS, history of seizure, and use of cardiac pacemaker were key exclusion criteria. Randomisation of 22 participants allocated 11 to each of the experimental and control groups. INTERVENTIONS: Both groups underwent 12 treatment sessions over 4 weeks. In each session, the experimental group received rTMS (5 Hz) applied over the leg area of the motor cortex in the hemisphere contralateral to the more affected leg for 6 minutes, immediately followed by 30 minutes of treadmill training. The control group received sham rTMS in addition to the 12 sessions of treadmill training. OUTCOME MEASURES: The primary outcomes were indicators of corticomotor excitability - motor threshold, silent period, short-latency and long-latency intracortical inhibition - measured in both cerebral hemispheres. The secondary outcomes were comfortable and fast walking speeds, and the timed-up-and go test. The outcomes were measured at baseline and after the 4-week intervention period. RESULTS: 20 participants completed the study. At the end of the 4-week intervention period, the increase in motor threshold of 3.5% and silent period of 14.0% of the contralateral hemisphere relative to the more affected leg was significantly more in the experimental group than the control group. Significantly more reduction of short-latency intracortical inhibition in the same hemisphere was also found in the experimental group relative to the control group 10.9%. The experimental group also had significantly more improvement than the control group in fast walking speed (by 10.1cm/s) and in the timed up- and-go test (by 2.0 s). No significant differences between the groups were reported in other outcomes. CONCLUSION: Repetitive transcranial magnetic stimulation can enhance the effects on corticomotor inhibition and improvement of walking function induced by treadmill training in patients with Parkinson's disease. PMID- 23663801 TI - Telehealth reduces hospital admission rates in patients with COPD. AB - QUESTION: Does telehealth reduce the hospital admission rate and cost for people with chronic obstructive pulmonary disease (COPD)? DESIGN: Randomised controlled trial with concealed allocation. SETTING: The participants' homes in Aalborg, Denmark. Participants were linked with healthcare professionals at primary and secondary healthcare facilities using telehealth technology. PARTICIPANTS: Adults were included if they had severe or very severe COPD, lived in Aalborg, and were free from other diseases that limited function (eg, heart disease). Randomisation allocated 60 to the intervention group and 51 to the control group. INTERVENTIONS: Participants in the intervention group had a telehealth monitoring device installed in their home for four months and were taught how to monitor their symptoms, measure clinical data (eg, spirometry), use a step counter, and given instructions about home exercise. Healthcare professionals accessed the data to monitor their disease and provide advice. Once a month, the telehealth team met via video to co-ordinate and discuss each participant's rehabilitation program. Those in the control group were instructed regarding home exercises but had no planned contact with healthcare professionals. OUTCOME MEASURES: Hospital admission rate and cost of hospitalisation over a 10-month period. RESULTS: A total of 105 participants completed the study. Over the follow-up period, the admission rate per patient was lower in the intervention group compared with the control group (0.49 vs 1.17, p = 0.041). The cost of hospitalisations appeared to be lower in the intervention group. CONCLUSION: Telehealth strategies that promote rehabilitation and early detection of an acute exacerbation reduced hospital admission rates in people with severe and very severe COPD. PMID- 23663802 TI - A physiotherapy telephone assessment and advice service for patients with musculoskeletal problems can improve the process of care while maintaining clinical effectiveness. AB - QUESTION: Does a physiotherapy telephone assessment and advice service (PhysioDirect) affect physical health and improve the process of care in patients with musculoskeletal problems? DESIGN: Randomised controlled trial with concealed allocation and blinded outcome assessment. SETTING: Four community physiotherapy services drawing patients from 94 general practices in England. PARTICIPANTS: Adults referred by a general practitioner or self-referred to physiotherapy for a musculoskeletal problem were eligible for inclusion. Referral from a consultant and an inability to communicate in English were key exclusion criteria. Randomisation of 2256 participants at a ratio of 2:1 allocated 1513 to PhysioDirect and 743 to the usual care physiotherapy. INTERVENTIONS: PhysioDirect participants were invited to telephone a physiotherapist for initial assessment and advice followed by further telephone advice and face-to-face physiotherapy if necessary. After the initial call most participants were sent written advice about self management and exercises. The usual-care comparison group joined a waiting list for face-to-face physiotherapy management. OUTCOME MEASURES: The primary outcome was change in physical health, measured with the physical component summary (PCS) measure from the SF-36 questionnaire at 6 weeks and 6 months. Secondary clinical outcome measures included the Measure Yourself Medical Outcomes Profile, global improvement in the main problem, and questions about satisfaction from the General Practice Assessment Questionnaire; and measures of process of care, including number of appointments, and waiting time. RESULTS: Primary outcome data were obtained from 85% of participants at 6 months. There was no difference in the SF-36 PCS measure between the PhysioDirect and comparison groups at 6 months (Mean difference (MD) = -0.01, 95% CI -0.80 to 0.79) and 6 weeks (MD 0.42, 95% CI -0.28 to 1.12). There were no differences between the groups in other clinical outcomes at 6 months, but there were small improvements in the PhysioDirect group at 6 weeks in the global improvement score (MD 0.15 units, 95% CI 0.02 to 0.28) and in the Measure Yourself Medical Outcomes Profile score (MD -0.19 units, 95%CI -0.30 to -0.07). 47% of PhysioDirect participants were managed entirely by telephone, and they had fewer face-to- face appointments (mean 1.9 vs 3.1), and a shorter wait for physiotherapy treatment (median 7 vs 34 days) than the comparison group. PhysioDirect participants were less satisfied with the service than the comparison group (MD -3.8%, 95% CI -7.3 to -0.3). CONCLUSION: Providing an initial telephone physiotherapy service for patients with musculoskeletal problems that reduced waiting time and required fewer appointments was as effective as providing face-to-face physiotherapy, but was associated with slightly lower patient satisfaction. PMID- 23663803 TI - STarT Back Screening Tool. PMID- 23663804 TI - The ten test for sensation. PMID- 23663807 TI - Concealed allocation in randomised trials. PMID- 23663809 TI - A revised stretch for preventing nocturnal cramps and a plausible mechanism for its benefit. PMID- 23663811 TI - Return of digoxin and recovery of renal function. PMID- 23663810 TI - Potential effects of digoxin on long-term renal and clinical outcomes in chronic heart failure. AB - BACKGROUND: Digitalis glycosides are known to improve the hemodynamic and neurohormonal perturbations that contribute to heart failure (HF)-induced renal dysfunction (RD). The objective of this study was to determine if randomization to digoxin is associated with improvement in renal function (IRF) and to evaluate if patients with digoxin-induced IRF have improved clinical outcomes. METHODS AND RESULTS: Patients in the Digitalis Investigation Group (DIG) dataset with protocol-driven 1-year serum creatinine levels (performed in a central laboratory; n = 980) were studied. IRF was defined as a postrandomization >=20% increase in estimated glomerular filtration rate (eGFR). IRF occurred in 15.5% of the population (mean improvement in eGFR 34.5 +/- 15.4%) and was more common in patients randomized to digoxin (adjusted odds ratio 1.6; P = .02). In patients without IRF, digoxin was not associated with reduced death or hospitalization (adjusted hazard ratio [HR] 0.96, 95% CI 0.8-1.2; P = .67). However, in the group with IRF, digoxin was associated with substantially improved hospitalization-free survival (adjusted HR 0.49, 95% CI 0.3-0.8; P = .006; P interaction = .026). CONCLUSIONS: In this subset of the DIG trial, digoxin was associated with long term improvement in kidney function and, in patients demonstrating this favorable renal response, reduction in death or hospitalization. Additional research is necessary to confirm these hypothesis-generating findings. PMID- 23663812 TI - Distinctive clinical characteristics according to age and gender in apical ballooning syndrome (takotsubo/stress cardiomyopathy): an analysis focusing on men and young women. AB - BACKGROUND: Apical ballooning syndrome (ABS) predominantly affects postmenopausal women. There is a paucity of data regarding ABS in men and young women. The aim of this study was to compare the clinical characteristics and outcomes of men and young women (<50 y) to older women (>=50 y). METHODS & RESULTS: We retrospectively reviewed the records of 224 patients and divided them into men (n = 12), young women (n = 12), and older women (n = 200). Older women were further subdivided into those who were and were not on hormone replacement therapy (HRT) at the time of presentation. Men were more likely to present after a physical trigger (100% vs 46%; P = .009), have lower ejection fractions (30.1 +/- 8.0% vs 40 +/- 13.9%; P = .04), and have greater need for mechanical ventilation (67% vs 17%; P < .0001) compared with older women. Younger women were more likely to have a history of psychiatric disorders (75% vs 24%; P = .0001) at presentation and a higher rate of recurrence (16% vs 3%; P = .017) compared with older women. Of the older women, 15 developed ABS while on chronic HRT. Those without HRT were more likely to require mechanical hemodynamic (7.7% and 0%; P = .002) and ventilatory (18.1% and 0%; P = .017) support compared with older women who were on HRT. CONCLUSIONS: Men appeared to develop ABS as a consequence of a physical trigger, whereas young women had a higher rate of psychiatric comorbidities and a greater propensity for recurrence. Treatment with HRT in older women does not preclude the development of ABS. PMID- 23663813 TI - Associations between Seattle Heart Failure Model scores and health utilities: findings from HF-ACTION. AB - BACKGROUND: The Seattle Heart Failure Model (SHFM) is a well validated prediction model of all-cause mortality in patients with heart failure, but its relationship with generic health status measures has not been evaluated. We sought to investigate relationships between SHFM scores and health utility weights, which are necessary to estimate quality-adjusted life-years in cost-effectiveness analyses. METHODS AND RESULTS: We applied mixed linear regression to examine relationships between baseline SHFM scores and EQ-5D-derived health utilities collected longitudinally in a large clinical trial. A 1-unit increase in SHFM score (higher predicted mortality) was associated with a 0.030 decrease in utility (P < .001) and an additional 0.006 decrease per year (P < .001). With SHFM score modeled as a categorical variable, EQ-5D utilities for patients with rounded SHFM scores of 1 or 2 were significantly lower (-0.041 and -0.053, respectively; both P < .001) and declined more rapidly over time (-0.011 and 0.020, respectively; both P <= .004) than for patients with scores of -1. CONCLUSIONS: Patients with higher SHFM-predicted mortality had significantly lower health utilities at baseline and greater rates of decline over time, compared with patients with lower SHFM-predicted mortality. These relationships can be applied when examining the cost-effectiveness of heart failure interventions. PMID- 23663815 TI - Gender differences in the relationship between age-related carotid intima-media thickness and cardiac diastolic function in a healthy Chinese population. AB - BACKGROUND: Ventricular-arterial coupling is a key determinant of cardiovascular performance. However, little is known about the gender differences in ventricular arterial interactions in the healthy Chinese population. OBJECTIVE: To identify gender differences in the association between carotid intima-media thickness (CIMT) and cardiac diastolic function in healthy Chinese individuals. METHODS AND RESULTS: We examined 852 healthy participants (aged 30-98 years, 46% men) in 3 northern China cities with the use of M-mode ultrasonography to analyze CIMT and cardiac structure and function. Cardiac function was measured by determining the ratio of early-diastolic peak flow velocity (E) and late-diastolic peak flow velocity (A), as well as the deceleration time of the early mitral velocity (MV DT). Cardiac dysfunction was defined as E/A values <25th percentile (E/A <0.78 for men and <0.79 for women), left atrial volume (LAV) values >75th percentile (LAV >34.9 mL for men and >32.2 mL for women), and MV-DT values >75th percentile (MV-DT >210 ms for men and >195 ms for women). CIMT, E/A, LAV, and MV-DT were significantly correlated with age in both men (CIMT: r = 0.418, P < .01; E/A: r = -0.325, P < .01, LAV: r = 0.123, P < .05; MV-DT: r = 0.175, P < .01) and women (CIMT: r = 0.429, P < .01; E/A: r = -0.423, P < .01; LAV: r = 0.180, P < .01; MV DT: r = 0.174, P < .01). Interestingly, left ventricular ejection fraction (LVEF) was not significantly correlated with age in either gender. CIMT was significantly associated with a lower E/A in an unadjusted model in tertiles II and III. The odds ratios (95% confidence interval [CI]) for men were 2.428 (1.36 4.335) and 3.017 (1.674-5.437), respectively. However, this association disappeared with age adjustment. The odds ratios (95% CI) for women were 3.298 (1.742-6.246) and 6.002 (3.202-11.251), respectively, and these were still significant after adjustments for all other variables, including age, blood pressure, blood lipid, and inflammatory markers (tertile II: 3.031, 95% CI 1.228 7.48; tertile III: 3.224, 95% CI 1.308-7.946). A higher MV-DT was significantly correlated with higher CIMT only in an unadjusted model for women, and this association was lost with age adjustment. There was no significant association between CIMT and higher LAV values. CONCLUSIONS: Age-related increases in CIMT were correlated with a decline in cardiac diastolic function only in women, which may contribute to the higher incidence of heart failure with preserved ejection fraction. PMID- 23663814 TI - Medication adherence, depressive symptoms, and cardiac event-free survival in patients with heart failure. AB - BACKGROUND: Medication nonadherence and depressive symptoms predict hospitalization and death in patients with heart failure (HF). Depressed patients have lower medication adherence than nondepressed patients. However, the predictive power of the combination of medication adherence and depressive symptoms for hospitalization and death has not been investigated in patients with HF. OBJECTIVE: The aim of this study was to explore the combined influence of medication adherence and depressive symptoms for prediction of cardiac event-free survival in patients with HF. METHODS AND RESULTS: We monitored medication adherence in 216 HF patients who completed the Patient Health Questionnaire-9 (PHQ-9) at baseline. Medication adherence was measured objectively with the use of the Medication Event Monitoring System (MEMS). Patients were followed for up to 3.5 years to collect data on cardiac events. Survival analyses were used to compare cardiac event-free survival among groups. The risk of experiencing a cardiac event for patients with medication nonadherence and depressive symptoms was 5 times higher than those who were medication adherent without depressive symptoms. The risk of experiencing a cardiac event for patients with only 1 risk factor was 1.2-1.3 times that of those with neither risk factor. CONCLUSIONS: Medication nonadherence and depressive symptoms had a negative synergistic effect on cardiac event-free survival in patients with HF. PMID- 23663816 TI - Left ventricular systolic function in sickle cell anemia: a meta-analysis. AB - BACKGROUND: We sought to evaluate whether patients with sickle cell anemia (SCA) have left ventricular (LV) systolic dysfunction. METHODS AND RESULTS: We conducted a Medline, Embase, Ebscohost, and Google scholar literature search articles published before April 2010. All studies that compared any measure of LV function (eg, ejection fraction [EF], fractional shortening [FS], or cardiac index [CI]) between normal control subjects and SCA (hemoglobin SS) patients were included. Among 57 studies that qualified for review, 19 studies including 841 SCA patients and 554 control subjects met the inclusion criteria. There were no significant differences in either LVEF (Hedge g = 0.15; 95% confidence interval 0.84 to 1.14; P = .76) or FS (P = .28) between SCA patients and control subjects. CI was significantly higher (P < .001) and LV end-systolic stress-volume index (load independent) was significantly lower (P < .001) in SCA patients. All LV systolic measures inversely correlated with age (all P < .001). LV end-systolic and -diastolic dimensions were significantly higher in SCA patients and increased with age. CONCLUSIONS: SCA patients have similar load-dependent but lower load independent measures of LV systolic function than control subjects. SCA is associated with LV dilation. LV structural and functional abnormalities appear to be age dependent with progressive LV dilation and impairment over time. PMID- 23663817 TI - Impact of timing and dose of mesenchymal stromal cell therapy in a preclinical model of acute myocardial infarction. AB - BACKGROUND: Although mesenchymal stem/stromal cells (MSC) have shown therapeutic promise after myocardial infarction (MI), the impact of cell dose and timing of intervention remains uncertain. We compared immediate and deferred administration of 2 doses of MSC in a rat model of MI. METHODS AND RESULTS: Sprague-Dawley rats were used. Allogeneic prospectively isolated MSC ("low" dose 1 * 10(6) or "high" dose 2 * 10(6) cells) were delivered by transepicardial injection immediately after MI ("early-low," "early-high"), or 1 week later ("late-low," "late-high"). Control subjects received cryopreservant solution alone. Left ventricular dimensions and ejection fraction (EF) were assessed by cardiac magnetic resonance. All 4 MSC-treatment cohorts demonstrated higher EF than control animals 4 weeks after MI (P values <.01 to <.0001), with function most preserved in the early-high group (absolute reduction in EF from baseline: control 39.1 +/- 1.7%, early-low 26.5 +/- 3.2%, early-high 7.9 +/- 2.6%, late-low 19.6 +/- 3.5%, late-high 17.9 +/- 4.0%). Cell treatment also attenuated left ventricular dilatation and fibrosis and augmented left ventricular mass, systolic wall thickening (SWT), and microvascular density. Although early intervention selectively increased SWT and vascular density in the infarct territory, delayed treatment caused greater benefit in remote (noninfarct) myocardium. All outcomes demonstrated dose dependence for early MSC treatment, but not for later cell administration. CONCLUSIONS: The nature and magnitude of benefit from MSC after acute MI is strongly influenced by timing of cell delivery, with dose dependence most evident for early intervention. These novel insights have potential implications for cell therapy after MI in human patients. PMID- 23663818 TI - Clinical pharmacy services in heart failure: an opinion paper from the Heart Failure Society of America and American College of Clinical Pharmacy Cardiology Practice and Research Network. AB - BACKGROUND: Heart failure (HF) care takes place in multiple settings, with a variety of providers, and generally involves patients who have multiple comorbidities. This situation is a "perfect storm" of factors that predispose patients to medication errors. METHODS AND RESULTS: The goals of this paper are to outline potential roles for clinical pharmacists in a multidisciplinary HF team, to document outcomes associated with interventions by clinical pharmacists, to recommend minimum training for clinical pharmacists engaged in HF care, and to suggest financial strategies to support clinical pharmacy services within a multidisciplinary team. As patients transition from inpatient to outpatient settings and between multiple caregivers, pharmacists can positively affect medication reconciliation and education, assure consistency in management that results in improvements in patient satisfaction and medication adherence, and reduce medication errors. For mechanical circulatory support and heart transplant teams, the Centers for Medicare and Medicaid Services considers the participation of a transplant pharmacology expert (e.g., clinical pharmacist) to be a requirement for accreditation, given the highly specialized and complex drug regimens used. Although reports of outcomes from pharmacist interventions have been mixed owing to differences in study design, benefits such as increased use of evidence-based therapies, decreases in HF hospitalizations and emergency department visits, and decreases in all-cause readmissions have been demonstrated. Clinical pharmacists participating in HF or heart transplant teams should have completed specialized postdoctoral training in the form of residencies and/or fellowships in cardiovascular and/or transplant pharmacotherapy, and board certification is recommended. Financial mechanisms to support pharmacist participation in the HF teams are variable. CONCLUSIONS: Positive outcomes associated with clinical pharmacist activities support the value of making this resource available to HF teams. PMID- 23663819 TI - Evaluation of a large-scale weight management program using the consolidated framework for implementation research (CFIR). AB - BACKGROUND: In the United States, as in many other parts of the world, the prevalence of overweight/obesity is at epidemic proportions in the adult population and even higher among Veterans. To address the high prevalence of overweight/obesity among Veterans, the MOVE!((r)) weight management program was disseminated nationally to Veteran Affairs (VA) medical centers. The objective of this paper is two-fold: to describe factors that explain the wide variation in implementation of MOVE!; and to illustrate, step-by-step, how to apply a theory based framework using qualitative data. METHODS: Five VA facilities were selected to maximize variation in implementation effectiveness and geographic location. Twenty-four key stakeholders were interviewed about their experiences in implementing MOVE!. The Consolidated Framework for Implementation Research (CFIR) was used to guide collection and analysis of qualitative data. Constructs that most strongly influence implementation effectiveness were identified through a cross-case comparison of ratings. RESULTS: Of the 31 CFIR constructs assessed, ten constructs strongly distinguished between facilities with low versus high program implementation effectiveness. The majority (six) were related to the inner setting: networks and communications; tension for change; relative priority; goals and feedback; learning climate; and leadership engagement. One construct each, from intervention characteristics (relative advantage) and outer setting (patient needs and resources), plus two from process (executing and reflecting) also strongly distinguished between high and low implementation. Two additional constructs weakly distinguished, 16 were mixed, three constructs had insufficient data to assess, and one was not applicable. Detailed descriptions of how each distinguishing construct manifested in study facilities and a table of recommendations is provided. CONCLUSIONS: This paper presents an approach for using the CFIR to code and rate qualitative data in a way that will facilitate comparisons across studies. An online Wiki resource (http://www.wiki.cfirwiki.net) is available, in addition to the information presented here, that contains much of the published information about the CFIR and its constructs and sub-constructs. We hope that the described approach and open access to the CFIR will generate wide use and encourage dialogue and continued refinement of both the framework and approaches for applying it. PMID- 23663820 TI - The epidemiology, antibiotic resistance and post-discharge course of peritonsillar abscesses in London, Ontario. AB - BACKGROUND: Peritonsillar abscesses (PTA) are a common complication of tonsillitis. Recent global epidemiological data regarding PTAs have demonstrated increasing antimicrobial resistance patterns. No similar studies have been conducted in Canada and no Canadian study has examined the post-discharge course of treated patients. METHODS: A prospective observational study of the epidemiology, antibiotic resistance and post-discharge course of patients presenting with a peritonsillar abscess to the Emergency Department in London, Ontario over one year. A follow-up telephone survey was conducted 2-3 weeks after abscess drainage. RESULTS: 60 patients were diagnosed with an abscess, giving an incidence of 12/100,000. 46 patients were enrolled in the study; the average duration of symptoms prior to presentation was 6 days, with 51% treated with antibiotics prior to presentation. Streptococcus pyogenes and Streptococcus anginosus were present in 56% of isolates and of those, 7/23 (32%) of specimens demonstrated resistance to clindamycin. Eight patients were treated with clindamycin and had a culture that was resistant, yet only one had recurrence. Telephone follow-up was possible for 38 patients: 51% of patients reported a return to solid food within 2 days, and 75% reported no pain by 5 days. Resolution of trismus took a week or longer for 51%. INTERPRETATION: Clindamycin resistance was identified in a third of Streptococcus isolates, which should be taken into account when prescribing antibiotics. Routine culture appears unnecessary as patients recover quickly from outpatient drainage and empiric therapy, with less pain than expected, but trismus takes time to resolve. PMID- 23663821 TI - Quantitative assessment and determinants of suture-holding capacity of human pancreas. AB - BACKGROUND: Hard pancreas is welcome by surgeons performing resective pancreatic surgery, because it is believed to offer better suture holding capacity (SHC), thus decreasing the risk for a postoperative leak. However, neither the actual SHC of pancreatic tissue in humans nor its determinants have been studied. METHODS: We directly measured SHC for polydioxanone 5-0 suture and tissue hardness at the pancreatic isthmus in 53 human pancreata using a dynamometer and a durometer. A histologic score based on fibrosis grade, fat content, pancreatic duct size, and signs of chronic pancreatitis was calculated for every sample. We tested the hypothesis that SHC of the pancreas was proportional to tissue hardness, and evaluated the role of different possible histomorphologic determinants of SHC. RESULTS: Suture-holding capacity correlated perfectly with tissue hardness (r = 0.98; P < 0.001; 95% confidence interval, 0.96-0.99). The histologic score showed a stronger correlation with both parameters than any single histologic parameter. The SHC of transductal sutures was significantly higher than that of pure transparenchymal sutures. The SHC and hardness were significantly lower in patients who developed a clinically relevant pancreatic fistula postoperatively. CONCLUSIONS: A mixture of histomorphologic features of human pancreas determines its tissue hardness and SHC. Involvement of the main pancreatic duct in the suture line appears to increase the mechanical strength of the pancreatic anastomosis. PMID- 23663823 TI - On the simultaneous motions of many blood cells. PMID- 23663822 TI - Activated N-Ras signaling regulates arterial-venous specification in zebrafish. AB - BACKGROUND: The aberrant activation of Ras signaling is associated with human diseases including hematological malignancies and vascular disorders. So far the pathological roles of activated Ras signaling in hematopoiesis and vasculogenesis are largely unknown. METHODS: A conditional Cre/loxP transgenic strategy was used to mediate the specific expression of a constitutively active form of human N-Ras in zebrafish endothelial and hematopoietic cells driven by the zebrafish lmo2 promoter. The expression of hematopoietic and endothelial marker genes was analyzed both via whole mount in situ hybridization (WISH) assay and real-time quantitative PCR (qPCR). The embryonic vascular morphogenesis was characterized both by living imaging and immunofluorescence on the sections with a confocal microscopy, and the number of endothelial cells in the embryos was quantified by flow cytometry. The functional analyses of the blood circulation were carried out by fluorescence microangiography assay and morpholino injection. RESULTS: In the activated N-Ras transgenic embryos, the primitive hematopoiesis appeared normal, however, the definitive hematopoiesis of these embryos was completely absent. Further analysis of endothelial cell markers confirmed that transcription of arterial marker ephrinB2 was significantly decreased and expression of venous marker flt4 excessively increased, indicating the activated N-Ras signaling promotes the venous development at the expense of arteriogenesis during zebrafish embryogenesis. The activated N-Ras-expressing embryos showed atrophic axial arteries and expansive axial veins, leading to no definitive hematopoietic stem cell formation, the blood circulation failure and subsequently embryonic lethality. CONCLUSIONS: Our studies revealed for the first time that activated N Ras signaling during the endothelial differentiation in vertebrates can disrupt the balance of arterial-venous specification, thus providing new insights into the pathogenesis of the congenital human vascular disease and tumorigenic angiogenesis. PMID- 23663824 TI - Sophisticated modeling uncovers atomic DNA structure in bacteriophage phi29 cavity. PMID- 23663825 TI - Please, get in my way so that I can be more efficient! PMID- 23663826 TI - A toolbox of fluorescence microscopic approaches reveals dynamics and assembly of a membrane-associated protein. PMID- 23663827 TI - Kinesin-5 seems to step to its own unique tune, but really it's a cover. PMID- 23663829 TI - Pattern formation exhibited by biofilm formation within microfluidic chambers. AB - This article investigates the dynamics of an important bacterial pathogen, Xylella fastidiosa, within artificial plant xylem. The bacterium is the causative agent of a variety of diseases that strike fruit-bearing plants including Pierce's disease of grapevine. Biofilm colonization within microfluidic chambers was visualized in a laboratory setting, showing robust, regular spatial patterning. We also develop a mathematical model, based on a multiphase approach that is able to capture the spacing of the pattern and points to the role of the exopolymeric substance as the main source of control of the pattern dynamics. We concentrate on estimating the attachment/detachment processes within the chamber because these are two mechanisms that have the potential to be engineered by applying various chemicals to prevent or treat the disease. PMID- 23663828 TI - Interacting ions in biophysics: real is not ideal. AB - Ions in water are important throughout biology, from molecules to organs. Classically, ions in water were treated as ideal noninteracting particles in a perfect gas. Excess free energy of each ion was zero. Mathematics was not available to deal consistently with flows, or interactions with other ions or boundaries. Nonclassical approaches are needed because ions in biological conditions flow and interact. The concentration gradient of one ion can drive the flow of another, even in a bulk solution. A variational multiscale approach is needed to deal with interactions and flow. The recently developed energetic variational approach to dissipative systems allows mathematically consistent treatment of the bio-ions Na(+), K(+), Ca(2+), and Cl(-) as they interact and flow. Interactions produce large excess free energy that dominate the properties of the high concentration of ions in and near protein active sites, ion channels, and nucleic acids: the number density of ions is often >10 M. Ions in such crowded quarters interact strongly with each other as well as with the surrounding protein. Nonideal behavior found in many experiments has classically been ascribed to allosteric interactions mediated by the protein and its conformation changes. The ion-ion interactions present in crowded solutions independent of conformation changes of the protein-are likely to change the interpretation of many allosteric phenomena. Computation of all atoms is a popular alternative to the multiscale approach. Such computations involve formidable challenges. Biological systems exist on very different scales from atomic motion. Biological systems exist in ionic mixtures (like extracellular and intracellular solutions), and usually involve flow and trace concentrations of messenger ions (e.g., 10(-7) M Ca(2+)). Energetic variational methods can deal with these characteristic properties of biological systems as we await the maturation and calibration of all-atom simulations of ionic mixtures and divalents. PMID- 23663830 TI - Quantitative analysis of self-association and mobility of annexin A4 at the plasma membrane. AB - Annexins, found in most eukaryotic species, are cytosolic proteins that are able to bind negatively-charged phospholipids in a calcium-dependent manner. Annexin A4 (AnxA4) has been implicated in diverse cellular processes, including the regulation of exocytosis and ion-transport; however, its precise mechanistic role is not fully understood. AnxA4 has been shown to aggregate on lipid layers upon Ca(2+) binding in vitro, a characteristic that may be critical for its function. We have utilized advanced fluorescence microscopy to discern details on the mobility and self-assembly of AnxA4 after Ca(2+) influx at the plasma membrane in living cells. Total internal reflection microscopy in combination with Forster resonance energy transfer reveals that there is a delay between initial plasma membrane binding and the beginning of self-assembly and this process continues after the cytoplasmic pool has completely relocated. Number-and-brightness analysis suggests that the predominant membrane bound mobile form of the protein is trimeric. There also exists a pool of AnxA4 that forms highly immobile aggregates at the membrane. Fluorescence recovery after photobleaching suggests that the relative proportion of these two forms varies and is correlated with membrane morphology. PMID- 23663831 TI - Single-cell force spectroscopy of probiotic bacteria. AB - Single-cell force spectroscopy is a powerful atomic force microscopy modality in which a single living cell is attached to the atomic force microscopy cantilever to quantify the forces that drive cell-cell and cell-substrate interactions. Although various single-cell force spectroscopy protocols are well established for animal cells, application of the method to individual bacterial cells remains challenging, mainly owing to the lack of appropriate methods for the controlled attachment of single live cells on cantilevers. We present a nondestructive protocol for single-bacterial cell force spectroscopy, which combines the use of colloidal probe cantilevers and of a bioinspired polydopamine wet adhesive. Living cells from the probiotic species Lactobacillus plantarum are picked up with a polydopamine-coated colloidal probe, enabling us to quantify the adhesion forces between single bacteria and biotic (lectin monolayer) or abiotic (hydrophobic monolayer) surfaces. These minimally invasive single-cell experiments provide novel, to our knowledge, insight into the specific and nonspecific forces driving the adhesion of L. plantarum, and represent a generic platform for studying the molecular mechanisms of cell adhesion in probiotic and pathogenic bacteria. PMID- 23663832 TI - Regulatory phosphorylation induces extracellular conformational changes in a CLC anion channel. AB - CLH-3b is a CLC-1/2/Ka/Kb channel homolog activated by meiotic cell cycle progression and cell swelling. Channel inhibition occurs by GCK-3 kinase-mediated phosphorylation of serine residues on the cytoplasmic C-terminus linker connecting CBS1 and CBS2. Two conserved aromatic amino acid residues located on the intracellular loop connecting membrane helices H and I and alpha1 of CBS2 are required for transducing phosphorylation changes into changes in channel activity. Helices H and I form part of the interface between the two subunits that comprise functional CLC channels. Using a cysteine-less CLH-3b mutant, we demonstrate that the sulfhydryl reagent reactivity of substituted cysteines at the subunit interface changes dramatically during GCK-3-mediated channel inhibition and that these changes are prevented by mutation of the H-I loop/CBS2 alpha1 signal transduction domain. We also show that GCK-3 modifies Zn(2+) inhibition, which is thought to be mediated by the common gating process. These and other results suggest that phosphorylation of the cytoplasmic C-terminus inhibits CLH-3b by inducing subunit interface conformation changes that activate the common gate. Our findings have important implications for understanding CLC regulation by diverse signaling mechanisms and for understanding the structure/function relationships that mediate intraprotein communication in this important family of Cl(-) transport proteins. PMID- 23663833 TI - Fractional Ca(2+) currents through TRP and TRPL channels in Drosophila photoreceptors. AB - Light responses in Drosophila photoreceptors are mediated by two Ca(2+) permeable cation channels, transient receptor potential (TRP) and TRP-like (TRPL). Although Ca(2+) influx via these channels is critical for amplification, inactivation, and light adaptation, the fractional contribution of Ca(2+) to the currents (Pf) has not been measured. We describe a slow (tau ~ 350 ms) tail current in voltage clamped light responses and show that it is mediated by electrogenic Na(+)/Ca(2+) exchange. Assuming a 3Na:1Ca stoichiometry, we derive empirical estimates of Pf by comparing the charge integrals of the exchanger and light-induced currents. For TRPL channels, Pf was ~17% as predicted by Goldman-Hodgkin-Katz (GHK) theory. Pf for TRP (29%) and wild-type flies (26%) was higher, but lower than the GHK prediction (45% and 42%). As predicted by GHK theory, Pf for both channels increased with extracellular [Ca(2+)], and was largely independent of voltage between -100 and -30 mV. A model incorporating intra- and extracellular geometry, ion permeation, diffusion, extrusion, and buffering suggested that the deviation from GHK predictions was largely accounted for by extracellular ionic depletion during the light-induced currents, and the time course of the Na(+)/Ca(2+) exchange current could be used to obtain estimates of cellular Ca(2+) buffering capacities. PMID- 23663834 TI - Impaired gating of an L-Type Ca(2+) channel carrying a mutation linked to malignant hyperthermia. AB - Recently, we characterized the functional properties of a mutant skeletal muscle L-type Ca(2+) channel (CaV1.1 R174W) linked to the pharmacogenetic disorder malignant hyperthermia. Although the R174W mutation neutralizes the innermost basic amino acid in the voltage-sensing S4 helix of the first conserved membrane repeat of CaV1.1, the ability of the mutant channel to engage excitation contraction coupling was largely unaffected by the introduction of the bulky tryptophan residue. In stark contrast, the mutation ablated the ability of CaV1.1 to produce L-type current under our standard recording conditions. In this study, we have investigated the mechanism of channel dysfunction more extensively. We found that CaV1.1 R174W will open and conduct Ca(2+) in response to strong or prolonged depolarizations in the presence of the 1,4-dihydropyridine receptor agonist +/-Bay K 8644. From these results, we have concluded that the R174W mutation impedes entry into both mode 1(low Po) and mode 2 (high Po) gating states and that these gating impairments can be partially overcome by maneuvers that promote entry into mode 2. PMID- 23663835 TI - Membrane permeability of hydrocarbon-cross-linked peptides. AB - Schafmeister, Po, and Verdine (another study) introduced a method using a hydrocarbon linker (staple) to stabilize a peptide in a helical configuration. One intended goal of this scheme is to facilitate the delivery of peptide drugs into target cells. Here, we investigate whether stapled peptides are intrinsically membrane permeable, by performing a case study on a stapled 12-mer peptide named NYAD-1. We found that the native peptide CAI (an HIV-1 inhibitor) does not bind to lipid bilayers, however NYAD-1 indeed permeates through lipid bilayers even at low solution concentrations. To understand the reason for the membrane permeability, we investigated the physical properties of NYAD-1 as a function of bound peptide/lipid molar ratio P/L. We found that NYAD-1 spontaneously binds to a lipid bilayer. At low P/L, the peptide primarily binds on the polar-apolar interface with its helical axis parallel to the bilayer, which has the effect of stretching the membrane area and thinning the membrane. The membrane thinning reaches its maximum at P/L ~1/15-1/12 in DOPC bilayers. Additional bound peptides have little thinning effect and their helical axes are normal to the plane of bilayers. Thus, the stapled peptide has a membrane interaction behavior similar to helical antimicrobial peptides, such as magainin and melittin. We emphasize that not all peptides that bind to lipid bilayers in the alpha-helical form behave this way. PMID- 23663836 TI - Cationic cell-penetrating peptide binds to planar lipid bilayers containing negatively charged lipids but does not induce conductive pores. AB - Using a cation-selective gramicidin A channel as a sensor of the membrane surface charge, we studied interactions of oligoarginine peptide R9C, a prototype cationic cell-penetrating peptide (CPP), with planar lipid membranes. We have found that R9C sorption to the membrane depends strongly on its lipid composition from virtually nonexistent for membranes made of uncharged lipids to very pronounced for membranes containing negatively charged lipids, with charge overcompensation at R9C concentrations exceeding 1 MUM. The sorption was reversible as it was removed by addition of polyanionic dextran sulfate to the membrane bathing solution. No membrane poration activity of R9C (as would be manifested by increased bilayer conductance) was detected in the charged or neutral membranes, including those with asymmetric negative/neutral and negative/positive lipid leaflets. We conclude that interaction of R9C with planar lipid bilayers does not involve pore formation in all studied lipid combinations up to 20 MUM peptide concentration. However, R9C induces leakage of negatively charged but not neutral liposomes in a process that involves lipid mixing between liposomes. Our findings suggest that direct traversing of CPPs through the uncharged outer leaflet of the plasma membrane bilayer is unlikely and that permeabilization necessarily involves both anionic lipids and CPP-dependent fusion between opposing membranes. PMID- 23663837 TI - The Ebola virus matrix protein deeply penetrates the plasma membrane: an important step in viral egress. AB - Ebola virus, from the Filoviridae family has a high fatality rate in humans and nonhuman primates and to date, to the best of our knowledge, has no FDA approved vaccines or therapeutics. Viral protein 40 (VP40) is the major Ebola virus matrix protein that regulates assembly and egress of infectious Ebola virus particles. It is well established that VP40 assembles on the inner leaflet of the plasma membrane; however, the mechanistic details of VP40 membrane binding that are important for viral release remain to be elucidated. In this study, we used fluorescence quenching of a tryptophan on the membrane-binding interface with brominated lipids along with mutagenesis of VP40 to understand the depth of membrane penetration into lipid bilayers. Experimental results indicate that VP40 penetrates 8.1 A into the hydrocarbon core of the plasma membrane bilayer. VP40 also induces substantial changes to membrane curvature as it tubulates liposomes and induces vesiculation into giant unilamellar vesicles, effects that are abrogated by hydrophobic mutations. This is a critical step in viral egress as cellular assays demonstrate that hydrophobic residues that penetrate deeply into the plasma membrane are essential for plasma membrane localization and virus-like particle formation and release from cells. PMID- 23663838 TI - Rapid fusion of synaptic vesicles with reconstituted target SNARE membranes. AB - Neurotransmitter release at neuronal synapses occurs on a timescale of 1 ms or less. Reconstitution of vesicle fusion from purified synaptic proteins and lipids has played a major role in elucidating the synaptic exocytotic fusion machinery with ever increasing detail. However, one limitation of most reconstitution approaches has been the relatively slow rate of fusion that can be produced in these systems. In a related study, a notable exception is an approach measuring fusion of single reconstituted vesicles bearing the vesicle fusion protein synaptobrevin with supported planar membranes harboring the presynaptic plasma membrane proteins syntaxin and SNAP-25. Fusion times of ~20 ms were achieved in this system. Despite this advance, an important question with reconstituted systems is how well they mimic physiological systems they are supposed to reproduce. In this work, we demonstrate that purified synaptic vesicles from rat brain fuse with acceptor-SNARE containing planar bilayers equally fast as equivalent reconstituted vesicles and that their fusion efficiency is increased by divalent cations. Calcium boosts fusion through a combined general electrostatic and synaptotagmin-specific mechanism. PMID- 23663839 TI - Theoretical and experimental SHG angular intensity patterns from healthy and proteolysed muscles. AB - SHG angular intensity pattern (SHG-AIP) of healthy and proteolysed muscle tissues are simulated and imaged here for the first time to our knowledge. The role of the spatial distribution of second-order nonlinear emitters on SHG-AIP is highlighted. SHG-AIP with two symmetrical spots is found to be a signature of healthy muscle whereas SHG-AIP with one centered spot in pathological mdx muscle is found to be a signature of myofibrillar disorder. We also show that SHG-AIP provides information on the three-dimensional structural organization of myofibrils in physiological and proteolysed muscle. Our results open an avenue for future studies aimed at unraveling more complex physiological and pathological fibrillar tissues organization. PMID- 23663840 TI - Modular aspects of kinesin force generation machinery. AB - The motor head of kinesin carries out microtubule binding, ATP hydrolysis, and force generation. Despite a high level of sequence and structural conservation, subtle variations in subdomains of the motor head determine family-specific properties. In particular, both Kinesin-1 (Kin-1) and Kinesin-5 (Kin-5) walk processively to the microtubule plus-end, yet show distinct motility characteristics suitable for their functions. We studied chimeric Kin-1/Kin-5 constructs with a combination of single molecule motility assays and molecular dynamics simulations to demonstrate that Kin-5 possesses a force-generating element similar to Kin-1, i.e., the cover-neck bundle. Furthermore, the Kin-5 neck linker makes additional contacts with the core of the motor head via loop L13, which putatively compensates for the shorter cover-neck bundle of Kin-5. Our results indicate that Kin-1 is mechanically optimized for individual cargo transport, whereas Kin-5 does not necessarily maximize its mechanical performance. Its biochemical rates and enhanced force sensitivity may instead be beneficial for operation in a group of motors. Such variations in subdomains would be a strategy for achieving diversity in motility with the conserved motor head. PMID- 23663841 TI - Analysis of the molecular pathogenesis of cardiomyopathy-causing cTnT mutants I79N, DeltaE96, and DeltaK210. AB - Three troponin T (TnT) mutants that cause hypertrophic, restrictive, and dilated cardiomyopathy (I79N, DeltaE96, and DeltaK210, respectively), were examined using the thin-filament extraction/reconstitution technique. Effects of Ca(2+), ATP, phosphate, and ADP concentrations on force and its transients were studied at 25 degrees C. Maximal Ca(2+) tension (THC) and Ca(2+)-activatable tension (Tact), respectively, were similar among I79N, DeltaE96, and WT, whereas DeltaK210 led to a significantly lower THC (~20% less) and Tact (~25% less) than did WT. In pCa solution containing 8 mM Pi and ionic strength adjusted to 200 mM, the Ca(2+) sensitivity (pCa50) of I79N (5.63 +/- 0.02) and DeltaE96 (5.60 +/- 0.03) was significantly greater than that of WT (5.45 +/- 0.04), but the pCa50 of DeltaK210 (5.54 +/- 0.04) remained similar to that of WT. Five equilibrium constants were deduced using sinusoidal analysis. All three mutants showed significantly lower K0 (ADP association constant) and larger K4 (equilibrium constant of force generation step) relative to the corresponding values for WT. I79N and DeltaK210 were associated with a K2 (equilibrium constant of cross-bridge detachment step) significantly lower than that of DeltaE96 and WT. These results demonstrated that at pCa 4.66, the force/cross-bridge is ~18% less in I79N and ~41% less in DeltaK210 than that in WT. These results indicate that the molecular pathogenesis of the cardiac TnT mutation-related cardiomyopathies is different for each mutation. PMID- 23663842 TI - Displacement-weighted velocity analysis of gliding assays reveals that Chlamydomonas axonemal dynein preferentially moves conspecific microtubules. AB - In vitro gliding assays, in which microtubules are observed to glide over surfaces coated with motor proteins, are important tools for studying the biophysics of motility. Gliding assays with axonemal dyneins have the unusual feature that the microtubules exhibit large variations in gliding speed despite measures taken to eliminate unsteadiness. Because axonemal dynein gliding assays are usually done using heterologous proteins, i.e., dynein and tubulin from different organisms, we asked whether the source of tubulin could underlie the unsteadiness. By comparing gliding assays with microtubules polymerized from Chlamydomonas axonemal tubulin with those from porcine brain tubulin, we found that the unsteadiness is present despite matching the source of tubulin to the source of dynein. We developed a novel, to our knowledge, displacement-weighted velocity analysis to quantify both the velocity and the unsteadiness of gliding assays systematically and without introducing bias toward low motility. We found that the quantified unsteadiness is independent of tubulin source. In addition, we found that the short Chlamydomonas microtubules translocate significantly faster than their porcine counterparts. By modeling the effect of length on velocity, we propose that the observed effect may be due to a higher rate of binding of Chlamydomonas axonemal dynein to Chlamydomonas microtubules than to porcine microtubules. PMID- 23663843 TI - Mapping conformational dynamics of proteins using torsional dynamics simulations. AB - All-atom molecular dynamics simulations are widely used to study the flexibility of protein conformations. However, enhanced sampling techniques are required for simulating protein dynamics that occur on the millisecond timescale. In this work, we show that torsional molecular dynamics simulations enhance protein conformational sampling by performing conformational search in the low-frequency torsional degrees of freedom. In this article, we use our recently developed torsional-dynamics method called Generalized Newton-Euler Inverse Mass Operator (GNEIMO) to study the conformational dynamics of four proteins. We investigate the use of the GNEIMO method in simulations of the conformationally flexible proteins fasciculin and calmodulin, as well as the less flexible crambin and bovine pancreatic trypsin inhibitor. For the latter two proteins, the GNEIMO simulations with an implicit-solvent model reproduced the average protein structural fluctuations and sample conformations similar to those from Cartesian simulations with explicit solvent. The application of GNEIMO with replica exchange to the study of fasciculin conformational dynamics produced sampling of two of this protein's experimentally established conformational substates. Conformational transition of calmodulin from the Ca(2+)-bound to the Ca(2+)-free conformation occurred readily with GNEIMO simulations. Moreover, the GNEIMO method generated an ensemble of conformations that satisfy about half of both short- and long-range interresidue distances obtained from NMR structures of holo to apo transitions in calmodulin. Although unconstrained all-atom Cartesian simulations have failed to sample transitions between the substates of fasciculin and calmodulin, GNEIMO simulations show the transitions in both systems. The relatively short simulation times required to capture these long-timescale conformational dynamics indicate that GNEIMO is a promising molecular-dynamics technique for studying domain motion in proteins. PMID- 23663844 TI - Structural and hydrodynamic analysis of a novel drug delivery vector: ELP[V5G3A2 150]. AB - The therapeutic potential of elastin-like polypeptide (ELP) conjugated to therapeutic compounds is currently being investigated as an approach to target drugs to solid tumors. ELPs are hydrophobic polymers that are soluble at low temperatures and cooperatively aggregate above a transition temperature (TT), allowing for thermal targeting of covalently attached drugs. They have been shown to cooperatively transition from a disordered structure to a repeating type II beta-turn structure, forming a beta-spiral above the TT. Here we present biophysical measurements of the structural, thermodynamic, and hydrodynamic properties of a specific ELP being investigated for drug delivery, ELP[V5G3A2 150]. We examine the biophysical properties below and above the TT to understand and predict the therapeutic potential of ELP-drug conjugates. We observed that below the TT, ELP[V5G3A2-150] is soluble, with an extended conformation consisting of both random coil and heterogeneous beta structures. Sedimentation velocity experiments indicate that ELP[V5G3A2-150] undergoes weak self association with increasing temperature, and above the TT the hydrophobic effect drives aggregation entropically. These experiments also reveal a previously unreported temperature-dependent critical concentration (Cc) that resembles a solubility constant. Labeling ELP[V5G3A2-150] with fluorescein lowers the TT by 3.5 degrees C at 20 MUM, whereas ELP[V5G3A2-150] dissolution in physiological media (fetal bovine serum) increases the TT by ~2.2 degrees C. PMID- 23663845 TI - Domain-domain interactions in filamin A (16-23) impose a hierarchy of unfolding forces. AB - The quaternary structure of Filamin A (FLNa) 16-23 was recently shown to exhibit multiple domain-domain interactions that lead to a propeller-like construction. Here we present single-molecule force spectroscopy experiments to show a wide variety of mechanical responses of this molecule and compare it with its linear counterpart FLNa 1-8. The compact structure of FLNa 16-23 leads to a broad distribution of rupture forces and end-to-end lengths in the force-extension mode and multiple unraveling timescales in the force-clamp mode. Moreover, a subset of force-extension trajectories reveals a mechanical hierarchy in which the rupture of domain-domain interactions at high forces (>200 pN) liberates the unfolding of individual domains at low forces (~100 pN). This mechanism may also explain the order-of-magnitude difference in the rates of the biexponential fits to the distribution of unfolding dwell times under force-clamp. Overall, FLNa 16-23 under a force of 100 pN is more compliant than the linear FLNa 1-8. Because a physiological role of FLNa is to crosslink actin filaments, this range of responses allows it to accommodate a broad spectrum of forces exerted by the cell and its environment. PMID- 23663846 TI - Helical structure determines different susceptibilities of dsDNA, dsRNA, and tsDNA to counterion-induced condensation. AB - Recent studies of counterion-induced condensation of nucleic acid helices into aggregates produced several puzzling observations. For instance, trivalent cobalt hexamine ions condensed double-stranded (ds) DNA oligomers but not their more highly charged dsRNA counterparts. Divalent alkaline earth metal ions condensed triple-stranded (ts) DNA oligomers but not dsDNA. Here we show that these counterintuitive experimental results can be rationalized within the electrostatic zipper model of interactions between molecules with helical charge motifs. We report statistical mechanical calculations that reveal dramatic and nontrivial interplay between the effects of helical structure and thermal fluctuations on electrostatic interaction between oligomeric nucleic acids. Combining predictions for oligomeric and much longer helices, we also interpret recent experimental studies of the role of counterion charge, structure, and chemistry. We argue that an electrostatic zipper attraction might be a major or even dominant force in nucleic acid condensation. PMID- 23663847 TI - Obstacles may facilitate and direct DNA search by proteins. AB - DNA recognition by DNA-binding proteins (DBPs), which is a pivotal event in most gene regulatory processes, is often preceded by an extensive search for the correct site. A facilitated diffusion process in which a DBP combines three dimensional diffusion in solution with one-dimensional sliding along DNA has been suggested to explain how proteins can locate their target sites on DNA much faster than predicted by three-dimensional diffusion alone. Although experimental and theoretical studies have recently advanced understanding of the biophysical principles underlying the search mechanism, the process under in vivo cellular conditions is poorly understood. In this study, we used various computational approaches to explore how the presence of obstacle proteins on the DNA influences search efficiency. At a low obstacle occupancy (i.e., when few obstacles occupy sites on the DNA), sliding by the searching DBP may be confined, which may impair search efficiency. The obstacles, however, can be bypassed during hopping events, and the number of bypasses is larger for higher obstacle occupancies. Dynamism on the part of the obstacles may even further facilitate search kinetics. Our study shows that the nature and efficiency of the search process may be governed not only by the intrinsic properties of the DBP and the salt concentration of the medium, but also by the in vivo association of DNA with other macromolecular obstacles, their location, and occupancy. PMID- 23663848 TI - Isopeptide bonds mechanically stabilize spy0128 in bacterial pili. AB - Pili on the surface of Streptococcus pyogenes play a crucial role in adhesion to and colonization in human cells. The major pilin subunit, Spy0128, features intramolecular covalent isopeptide bonds that autocatalytically form between the side chains of lysine and asparagine residues and are regarded as important factors in conveying structural stability. In support of this notion, single molecule force spectroscopy experiments with Spy0128 recently demonstrated the inextensibility of these bonds under mechanical load. However, the molecular determinants of their apparent absolute durability remain unknown. Here, we studied the impact of the isopeptide bond in the Spy0128 C-terminal domain on the mechanical properties of this subunit using force-probe molecular dynamics simulations and force distribution analysis. Even in the presence of the covalent cross-link, the pili beta-sandwich domain undergoes partial unfolding, albeit at ~50% higher rupture forces and with the ability to rapidly refold on the nanosecond timescale. We find that the isopeptide bond is located right at the point of stress concentration in the protein, leading to relative, yet not absolute, mechanical stabilization by the additional cross-link. Our findings indicate how the isopeptide bond enhances the mechanical stability and refolding capability at the molecular level, ensuring that the domain remains predominantly in a potentially adhesive conformation. PMID- 23663849 TI - Structural ensemble and dynamics of toroidal-like DNA shapes in bacteriophage phi29 exit cavity. AB - In the bacteriophage phi29, DNA is packed into a preassembled capsid from which it ejects under high pressure. A recent cryo-EM reconstruction of phi29 revealed a compact toroidal DNA structure (30-40 basepairs) lodged within the exit cavity formed by the connector-lower collar protein complex. Using multiscale models, we compute a detailed structural ensemble of intriguing DNA toroids of various lengths, all highly compatible with experimental observations. In particular, coarse-grained (elastic rod) and atomistic (molecular dynamics) models predict the formation of DNA toroids under significant compression, a largely unexplored state of DNA. Model predictions confirm that a biologically attainable compressive force of 25 pN sustains the toroid and yields DNA electron density maps highly consistent with the experimental reconstruction. The subsequent simulation of dynamic toroid ejection reveals large reactions on the connector that may signal genome release. PMID- 23663850 TI - Measuring shape-dependent looping probability of DNA. AB - Recently, several studies have shown that short doubled-stranded DNA (dsDNA) loops more readily than the wormlike chain model predicts. In most of these experiments, the intrinsic bendedness of dsDNA, which in theory can dramatically influence looping dynamics, was either avoided or unaccounted for. To investigate the effect of the shape of dsDNA on looping dynamics, we characterized the shapes of several synthetic dsDNA molecules of equal length but different sequences using gel electrophoresis. We then measured their looping rates using a FRET (Forster resonance energy transfer)-based assay and extracted the looping probability density known as the J factor (jM). We also used, for comparison, several dinucleotide angular parameter sets derived from the observed electrophoretic mobility to compute the jM predicted by the wormlike chain model. Although we found a strong correlation between curvature and jM, the measured jM was higher than most dinucleotide model predictions. This result suggests that it is difficult to reconcile the looping probability with the observed gel mobility within the wormlike chain model and underscores the importance of determining the intrinsic shape of dsDNA for proper theoretical analysis. PMID- 23663851 TI - Mitochondrial localization and the persistent migration of epithelial cancer cells. AB - During cancer cell invasion, faster moving cancer cells play a dominant role by invading further and metastasizing earlier. Despite the importance of these outlier cells, the source of heterogeneity in their migratory behavior remains poorly understood. Here, we show that anterior localization of mitochondria, in between the nucleus and the leading edge of migrating epithelial cancer cells, correlates with faster migration velocities and increased directional persistence. The asymmetry of mitochondrial localization along the axis of migration is absent during spontaneous cell migration on two-dimensional surfaces and only occurs in the presence of chemical attractant cues or in conditions of mechanical confinement. Moreover, perturbing the asymmetric distribution of mitochondria within migrating cells by interfering with mitochondrial fusion (opa 1) or fission (drp-1) proteins, significantly reduces the number of cells with anterior localization of mitochondria and significantly decreases the velocity and directional persistence of the fastest moving cells. We also observed similar changes after perturbing the linkage between mitochondria and microtubules by the knockdown of mitochondrial rhoGTPase-1 (miro-1). Taken together, the changes in migration velocity and directional persistence in cells with anterior-localized mitochondria could account for an order of magnitude differences in invasive abilities between cells from otherwise homogenous cell populations. PMID- 23663852 TI - Parameter importance in FRAP acquisition and analysis: a simulation approach. AB - Fluorescence recovery after photobleaching (FRAP) is a widespread technique used to determine intracellular reaction and diffusion parameters. In recent years, due to technical advances and an increasing number of mathematical models for analysis, there was a resurging interest in FRAP applications. However, care has to be taken when inverting parameters from such data. We study potential influences on FRAP acquisition and analysis like initial fluorescence distribution, membrane passage, and geometrical aspects. Monte Carlo simulations are employed for the investigation of reaction-diffusion processes to additionally include cases in which no analytical description is available. To assess the importance of influencing factors we apply a sensitivity method based on elementary effects providing an estimate for the global parameter space. The combination of simulations and sensitivity measure helps us to predict ranges of parameters used in acquisition and analysis for which a reliably inversion of reaction-diffusion parameters is possible. Using this approach, we show that FRAP data are highly susceptible to misinterpretation. However, by identifying the parameters of susceptibility, our analysis provides the means for taking measures to significantly improve FRAP data interpretation and analysis. PMID- 23663854 TI - Obituary: professor paul dan cristea. AB - Paul Dan Cristea, professor of Electrical Engineering and Computer Science at 'Politehnica' University of Bucharest died on 17 April 2013, following several years of bravely battling a perfidious illness. PMID- 23663853 TI - Mechanistically consistent reduced models of synthetic gene networks. AB - Designing genetic networks with desired functionalities requires an accurate mathematical framework that accounts for the essential mechanistic details of the system. Here, we formulate a time-delay model of protein translation and mRNA degradation by systematically reducing a detailed mechanistic model that explicitly accounts for the ribosomal dynamics and the cleaving of mRNA by endonucleases. We exploit various technical and conceptual advantages that our time-delay model offers over the mechanistic model to probe the behavior of a self-repressing gene over wide regions of parameter space. We show that a heuristic time-delay model of protein synthesis of a commonly used form yields a notably different prediction for the parameter region where sustained oscillations occur. This suggests that such heuristics can lead to erroneous results. The functional forms that arise from our systematic reduction can be used for every system that involves transcription and translation and they could replace the commonly used heuristic time-delay models for these processes. The results from our analysis have important implications for the design of synthetic gene networks and stress that such design must be guided by a combination of heuristic models and mechanistic models that include all relevant details of the process. PMID- 23663855 TI - Epidemiology of norovirus gastroenteritis outbreaks in two primary schools in a city in eastern China. AB - We describe the epidemiology of 2 outbreaks of norovirus (GII) gastroenteritis in elementary schools in a city in eastern China using data from field investigations, pathogen testing, and face-to-face interviews. The transmission shows a point source type. In a case-control study, we identified airborne and person-to-person transmission as the source of the outbreaks. PMID- 23663856 TI - Risk factors for and impact of methicillin-resistant Staphylococcus aureus nasal colonization in patients in a medical intensive care unit. AB - This retrospective cohort study investigated the impact and predictive factors of methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization in 180 patients admitted to a medical intensive care unit between July 2009 and June 2010. No significant associations between MRSA nasal colonization and the incidence of health care-associated multidrug-resistant-related infections, intensive care unit length of stay, or inpatient mortality were found. Significant risk factors for MRSA colonization included previous medical history of diabetes mellitus and congestive heart failure. PMID- 23663857 TI - Comparison of control strategies for methicillin-resistant Staphylococcus aureus. AB - BACKGROUND: Screening patients for methicillin-resistant Staphylococcus aureus (MRSA) colonization and contact precautions for colonized patients has been recommended when other control measures have been ineffective. METHODS: We compared MRSA transmission rates following implementation of a bundle of control measures that included institutional culture change, surveillance for MRSA infection and transmission, and active screening for colonization in 2 similar Veterans Health Administration hospitals. One hospital employed contact precautions as defined by the Centers for Disease Control and Prevention, and the other hospital modified contact precautions, requiring only the use of gloves. RESULTS: During the 4-year study period, there were 1.58 MRSA transmissions per 1,000 patient-days at hospital A and 1.56 MRSA transmissions per 1,000 patient days at hospital B (P = .98). Both hospitals experienced significant reductions in MRSA health care-associated infections (HAI). There was no difference between hospital A and hospital B in incidence of MRSA HAIs or MRSA surgical site infections. Annual acquisition costs for cover gowns were $183,609 at hospital A and $25,812 at hospital B. CONCLUSION: Significant reductions in MRSA HAI were associated with implementation of the MRSA control bundle. The bundle that included full contact precautions for colonized patients was no more effective in prevention of MRSA transmissions than a similar bundle that omitted the use of cover gowns. PMID- 23663859 TI - Just clean your hands: measuring the effect of a patient safety initiative on driving transformational change in a health care system. AB - In 2007, the Ontario government introduced the Just Clean Your Hands program across all provincial hospitals. The goal of this patient safety initiative was to improve hand hygiene practices among health care providers through workplace culture change. A survey questionnaire was distributed to 729 nurses employed at a single large community-based hospital from April to July 2011. Of the 223 nurses who responded to the questionnaire, 153 had completed the program (exposed group). By using the other 70 nurses as a contemporaneous control group (nonexposed), this study demonstrates that the Just Clean Your Hands program contributed to improved hand hygiene practices, but we were unable to demonstrate positive changes in patient safety culture. PMID- 23663858 TI - Withdrawal of Staphylococcus aureus from intensive care units in Turkey. AB - BACKGROUND: In the past, Staphylococcus aureus infections have displayed various patterns of epidemiologic curves in hospitals, particularly in intensive care units (ICUs). This study aimed to characterize the current trend in a nationwide survey of ICUs in Turkey. METHODS: A total of 88 ICUs from 36 Turkish tertiary hospitals were included in this retrospective study, which was performed during the first 3 months of both 2008 (period [P] 1) and 2011 (P2). A P value <=.01 was considered significant. RESULTS: Although overall rates of hospital-acquired infection (HAI) and device-associated infection densities were similar in P1 and P2, the densities of HAIs due to S aureus and methicillin-resistant S aureus (MRSA) were significantly lower in P2 (P < .0001). However, the proportion of HAIs due to Acinetobacter was significantly higher in P2 (P < .0001). CONCLUSIONS: The incidence of S aureus infections is declining rapidly in Turkish ICUs, with potential impacts on empirical treatment strategies in these ICUs. PMID- 23663860 TI - Early identification and control of carbapenemase-producing Klebsiella pneumoniae, originating from contaminated endoscopic equipment. PMID- 23663861 TI - Evaluation of detergents and contact time on biofilm removal from flexible endoscopes. AB - BACKGROUND: The formation of endoscopic biofilm reduces the results of cleaning and disinfection and may increase nosocomial infection. This study aims to evaluate the effects of various detergents and different contact time on the removal of biofilm on flexible endoscopes based on an artificial biofilm model. METHOD: Endoscopic biofilm model was established and treated with various detergents (detergent 1, Rapid Multi-Enzyme; detergent 2, Scopezime; and detergent 3, Intercept) for 3, 5, and 7 minutes. Escherichia coli viable counts and biofilm changes were measured by colony counting and electron microscopy scanning, respectively. RESULTS: Statistical differences were observed between various detergents and the control group (P < .001) but not among the different contact time groups (3, 5, and 7 minutes, P > .05). Multiple comparisons showed that statistical differences in residual biofilm bacteria were observed between the detergents and the control (P < .001). Significant differences (P < .001) in residual biofilm bacteria existed between the 2 enzymatic detergents and the nonenzymatic detergent group, whereas no significant difference was observed between the 2 enzymatic detergents (P > .05). No crossover effect was observed between various detergent groups, contact time, and the control group (P > .05). Electron microscopy scanning revealed that, after various detergents and contact time of 3, 5, and 7 minutes, the residual biofilm in the enzymatic detergent group was significantly more than that of the nonenzymatic detergent group. No significant difference was observed among the groups with the same detergent and different contact time. CONCLUSION: Significantly more biofilm bacteria and biofilms were found in the enzymatic detergent groups compared with the nonenzymatic detergent group, whereas no significant difference was observed among 3, 5, and 7 minutes groups. PMID- 23663862 TI - An exploration of the psychologic impact of contact isolation on patients in Singapore. AB - The purpose of this study was to explore the psychologic impact of contact isolation on patients in Singapore who were infected or colonized with multidrug resistant organisms. Twenty cases were compared with 20 controls for their anxiety and depressive symptoms. Cases reported significantly higher levels of depression (t = 3.731, P < .01) and anxiety (t = 4.841, P < .001) compared with the controls. Hospitals need to develop policies and interventions to address the psychologic impact of contact isolation. PMID- 23663863 TI - Multi-institutional outbreak of Burkholderia cepacia complex associated with contaminated mannitol solution prepared in compounding pharmacy. AB - BACKGROUND: Burkholderia cepacia complex (BCC) has been described as a cause of nosocomial outbreaks. We describe an outbreak of and identify risk factors for nosocomial BCC infections associated with intrinsically contaminated mannitol 3% solution. METHODS: Urinary and bloodstream infection caused by BCC were identified in hospitalized patients who underwent urologic surgery and received intraoperative irrigation of 3% mannitol solution in February 2009. The investigation included retrospective chart review, case control study, procedural review, and culture of mannitol solution. RESULTS: Seven BCC infections were identified. BCC isolates were recovered from blood and/or urine from patients and lots of mannitol in use during the outbreak period. Mannitol solution was produced by a compounding pharmacy. Receipt of larger volumes of contaminated solution was identified as a significant risk factor for infection (odds ratio, 1.5; P value < .05). BCC was also cultured in lots of mannitol in use in other hospitals. CONCLUSION: Manipulated mannitol solution is a potential source of infection. Contamination with paraben-degrading organisms can occur at the time of manufacture. Our findings suggest that contamination of mannitol at a compounding pharmacy occurred. Prompt communication to other hospitals and implementation of infection control measures were effective in avoiding further cases of infection. PMID- 23663864 TI - Carbapenem-resistant Klebsiella pneumoniae transmission associated to endoscopy. PMID- 23663865 TI - Interactively human: Sharing time, constructing materiality. AB - Predictive processing models of cognition are promising an elegant way to unite action, perception, and learning. However, in the current formulations, they are species-unspecific and have very little particularly human about them. I propose to examine how, in this framework, humans can be able to massively interact and to build shared worlds that are both material and symbolic. PMID- 23663866 TI - Personal narratives as the highest level of cognitive integration. AB - We suggest that the hierarchical predictive processing account detailed by Clark can be usefully integrated with narrative psychology by situating personal narratives at the top of an individual's knowledge hierarchy. Narrative representations function as high-level generative models that direct our attention and structure our expectations about unfolding events. Implications for integrating scientific and humanistic views of human experience are discussed. PMID- 23663867 TI - How did I miss that? The safety challenges of inattentional blindness. PMID- 23663868 TI - Home-based functional walking program for advanced cancer patients receiving palliative care: a case series. AB - BACKGROUND: Although meta-analyses have demonstrated that physical activity can positively impact quality of life outcomes in early stage cancer patients, it is not yet known whether these benefits can be extended to patients with advanced cancer. In a previous pilot survey of patients with advanced cancer with a median survival of 104 days, participants felt willing and able to participate in a physical activity intervention, and reported a strong preference for walking and home-based programming. Here, we report on the initial development and feasibility of a home-based functional walking program in patients with advanced cancer receiving palliative care. METHODS: Nine adult patients were recruited from outpatient palliative care clinics and palliative home care. A pilot intervention trial was conducted over a 6-week period. The McGill Quality of Life Questionnaire (MQOL), Late Life Function and Disability Instrument (LLFDI), Edmonton Symptom Assessment System (ESAS), Seniors Fitness Test, four-test balance scale, and grip strength, were performed pre- and post-intervention. Participants wore activPALTM accelerometers to monitor ambulatory activity levels. RESULTS: Of the nine recruited participants, three participants dropped out prior to baseline testing due to hospital admission and feeling overwhelmed, and three participants dropped out during the intervention due to severe symptoms. Only three participants completed the intervention program, pre- and post-intervention assessments: two reported improvements in total MQOL scores, yet all three shared an overall trend towards worsening symptom and total fatigue scores post-intervention. Two participants passed away within 90 days of completing the intervention. CONCLUSIONS: This case series demonstrates the challenges of a physical activity intervention in patients with advanced cancer receiving palliative care. Further feasibility research is required in this patient population. TRIAL REGISTRATION: This study is registered under ClinicalTrials.gov as NCT00438620. PMID- 23663869 TI - The essential role of endothelial nitric oxide synthase activation in insulin mediated neuroprotection against ischemic stroke in diabetes. AB - BACKGROUND: Stroke patients with diabetes have a higher mortality rate, worse neurologic outcome, and more severe disability than those without diabetes. Results from clinical trials comparing the outcomes of stroke seen with intensive glycemic control in diabetic individuals are conflicting. Therefore, the present study was aimed to identify the key factor involved in the neuroprotective action of insulin beyond its hypoglycemic effects in streptozotocin-diabetic rats with ischemic stroke. METHODS: Long-Evans male rats were divided into three groups (control, diabetes, and diabetes treated with insulin) and subjected to focal cerebral ischemia-reperfusion (FC I/R) injury. RESULTS: Hyperglycemia aggravated FC I/R injuries with an increase in cerebral infarction and neurologic deficits, inhibition of glucose uptake and membrane-trafficking activity of glucose transporter 1, and reduction of Akt and endothelial nitric oxide synthase (eNOS) phosphorylation in the cerebrum. Insulin treatment alleviated hyperglycemia and the symptoms of diabetes in streptozotocin-diabetic rats. Insulin administration also significantly decreased cerebral infarction and neurologic deficits and increased phosphorylation of Akt and eNOS protein in the cerebrum of FC I/R injured diabetic rats. However, the glucose uptake and membrane trafficking activity of glucose transporter 1 in the cerebrum were not restored by insulin treatment. Coadministration of the eNOS inhibitor, N-iminoethyl-L-ornithine, with insulin abrogated beneficial effects of insulin on cerebral infarct volume and neurologic deficits in FC I/R-injured diabetic rats without affecting the hypoglycemic action of insulin. CONCLUSIONS: These results suggest that eNOS activation is required for the neuroprotection of insulin against ischemic stroke in patients with diabetes. PMID- 23663870 TI - Development and evaluation of the Walking Estimated-Limitation Calculated by History questionnaire in patients with claudication. AB - BACKGROUND: The Walking Impairment Questionnaire (WIQ) is used to estimate walking impairment in patients with peripheral artery disease; however, it faces frequent errors when self-completed and is complex to score. We aimed to validate an alternative, easily scored four-item tool, the Walking Estimated-Limitation Calculated by History (WELCH) questionnaire. METHODS: The WIQ and WELCH were prospectively tested in five centers. We studied 434 patients, among which 298 had a treadmill test (3.2 km/h; 10% slope) to determine their maximum walking time (MWT), and 30 were seen twice during the study period. RESULTS: After self completion, we found at least one error in 177 WIQ (40.8%; 95% confidence interval [CI], 36.3%-45.5%) vs 56 WELCH (12.9%; 95% CI, 10.1%-16.4%) questionnaires (P < .0001). When scoring only questionnaires without missing or duplicate answers, 267 WIQ (61.5%; 95% CI, 56.9%-66.0%) vs 393 WELCH (90.6%; 95% CI, 87.4%-93.0%) questionnaires could be scored (P < .001). The median MWT was 233 seconds (interquartile range, 133-654 seconds) for the 298 patients who had a treadmill test. When the 296 patients who had both questionnaire scores available were studied, no difference was found between the Pearson r coefficient of correlation of the WIQ (r = 0.615) and the WELCH (r = 0.653) with MWT (P = .211). In the 30 patients who completed the WELCH twice, correlation was r = 0.839 (P < .001) between the two scores in 22 nonrevascularized patients, and the area under the receiver-operating characteristic curve was 0.830 +/- 0.105 (P < .01) to discriminate the eight revascularized from the 22 nonrevascularized patients. CONCLUSIONS: The WELCH questionnaire is a simple tool to estimate walking limitation in patients with suspected peripheral artery disease. It is easily scored by mental calculation. It may help to standardize the estimation of walking limitation in routine clinical practice. PMID- 23663871 TI - Management of endovenous heat-induced thrombus using a classification system and treatment algorithm following segmental thermal ablation of the small saphenous vein. AB - OBJECTIVE: We evaluated our experience with segmental radiofrequency ablation (RFA) of the small saphenous vein (SSV), a less common procedure than great saphenous vein ablation, and developed a classification system and algorithm for endovenous heat-induced thrombus (EHIT), based on modifications of our prior algorithm of EHIT following great saphenous ablation. METHODS: Endovenous ablation was performed on symptomatic patients with incompetent SSVs following a minimum of 3 months of compression therapy. Demographic data, risk factors, CEAP classification, procedure details, and follow-up data were recorded. A four-tier classification system and treatment algorithm was developed, based on EHIT proximity to the popliteal vein. RESULTS: Eighty limbs (in 76 patients) were treated with RFA of the SSV between January 2008 and August 2012. Duplex ultrasound was performed between 24 and 72 hours postprocedure in all patients. Ablation was successful in 98.7% (79/80) of procedures. Sixty-eight (85%) patients had level A closures (>= 1 mm caudal to popliteal vein) and 10 patients (13%) had level B closures (flush with popliteal vein) and were observed. Two limbs (3%) had EHIT extending into the popliteal vein (level C) and were treated with outpatient low-molecular-weight heparin anticoagulation. Thrombus retracted to the level of the saphenopopliteal junction in both patients following a short course of anticoagulation. No patient developed an occlusive deep vein thrombosis (DVT) (level D). Mean follow-up period was 6.2 months; no patient had small saphenous recanalization, occlusive DVT, or pulmonary embolus. The presence or absence of the Giacomini vein was not predictive of level B and C closure. CONCLUSIONS: RFA of the SSV in symptomatic patients has a high success rate with a low risk of DVT. A classification system and treatment protocol based on the level of EHIT in relation to the saphenopopliteal junction is useful in managing patients. The approach to patients with thrombus flush with the popliteal vein or bulging has not been previously defined; our outcomes were excellent, using our treatment algorithm. PMID- 23663872 TI - Defining the radiation "scatter cloud" in the interventional suite. AB - OBJECTIVE: We hypothesized that fluoroscopic imaging creates radiation fields that are unevenly scattered throughout the endovascular suite. We sought to quantify the radiation dose spectrum at various locations during imaging procedures and to represent this in a clinically useful manner. METHODS: Digital subtraction imaging (Innova 4100; GE Healthcare, Waukesha, Wisc) of the abdomen and pelvis was performed on a cadaver in anteroposterior, left lateral, and right anterior oblique 45 degrees projections. Radiation exposure was monitored in real time with DoseAware dosimeters (Phillips, Houston, Tex) in eight radial projections at distances of 2, 4, and 6 ft from the center of the imaged field, each at 5-ft heights from the floor. Three to five consecutive data points were collected for each location. RESULTS: At most positions around the angiographic table, radiation exposure decreased as the distance from the source emitter increased; however, the intensity of the exposure varied dramatically around the axis of imaging. With anteroposterior imaging, the radiation fields have symmetric dumbbell shapes, with maximal exposure perpendicular to the table at the level of the gantry. Peak levels at 4 and 6 ft from the source emitter were 2.4 times and 3.4 times higher, respectively, than predicted based on the inverse square law. Maximal radiation exposure was measured in the typical operator position 2 ft away and perpendicular to the table (4.99 mSv/h). When the gantry was rotated 45 degrees and 90 degrees , the radiation fields shifted, becoming more asymmetric, with increasing radiation doses to 10.9 and 69 mSv/h, respectively, on the side of the emitter. Minimal exposure is experienced along the axis of the table, decreasing with distance from the source (<0.77 mSv/h). CONCLUSIONS: Quantifiable and reproducible radiation scatter is created during interventional procedures. Radiation doses vary widely around the perimeter of the angiography table and change according to imaging angles. These data are easily visualized using contour plots and scatter three-dimensional mesh plots. Rather than the concentric circles predicted by the inverse square law, these data more closely resemble a "scatter cloud." Knowledge of the actual exposure levels within the endovascular environment may help in mitigating these risks to health care providers. PMID- 23663873 TI - Discussion. PMID- 23663874 TI - Natural history of cerebral dot-like cavernomas. AB - AIM: To elucidate the natural history of dot-like or "black spot" cavernomas. MATERIALS AND METHODS: Data of 18 children with black spot cavernomas were analysed retrospectively. RESULTS: Eleven boys and seven girls presented 187 black spot cavernomas during a mean observation period of 5.5 years. Mean and median age at diagnosis of the 187 cavernomas was 9.6 years. There were 70 de novo black spot cavernomas. Boys presented significantly more cavernomas than girls. There were three KRIT1 mutation carriers and four PDCD 10 mutation carriers. Children with a PDCD 10 mutation presented significantly more lesions than those children with a KRIT1 mutation (mean number of lesions per patient: 23.3 versus 3.3, respectively). There were 10 radiological haemorrhagic events caused by 10 black spot lesions. Two of these events were symptomatic. The haemorrhage rate of black spot cavernomas was 0.7% per lesion-year. CONCLUSIONS: A mean bleeding rate of 0.7% per lesion-year is lower than the overall haemorrhage rates provided in the literature. Nonetheless, black spot cavernomas are not purely benign lesions. Furthermore, genetic mutations may play a role in the natural history of black spot cavernomas. PMID- 23663875 TI - Patterns of recurrence of gastrointestinal stromal tumour (GIST) following complete resection: implications for follow-up. AB - AIM: To determine the frequency, time course and sites of recurrence following surgical resection of gastrointestinal stromal tumours (GIST) and to evaluate the performance of a risk-based surveillance protocol in detection of recurrence. METHODS: Eighty-one patients on surveillance following complete resection of GIST were included. Patients were stratified into risk groups according to accepted histopathological criteria. Computed tomography (CT) examinations were retrospectively reviewed to determine rates, sites and imaging characteristics of recurrence and to assess compliance with the local follow-up protocol. RESULTS: The median time of follow-up was 41 months. Nineteen patients suffered recurrence, all of whom were in the high-risk group. Fifty-eight percent of relapses occurred within 1 year and 84% within 3 years. Even within the high-risk group, patients with relapse had significantly larger (mean 15 versus 10.4 cm, p < 0.05) and more mitotically active primary tumours (mean 33.7 versus 5.6 mitoses per 50 high-power fields; p < 0.05) than those with no relapse. Relapse was to the liver in 12 cases (63%) and to the omentum and mesentery in nine cases (47%), and was asymptomatic in three-quarters of patients. CONCLUSIONS: The high incidence of GIST recurrence in the high-risk group in the first 3 years after surgery supports the use of intensive imaging surveillance in this period. Relapse is often asymptomatic and commonly occurs to the liver, omentum and mesentery. Stratification by tumour factors may enable improved tailoring of surveillance protocols within the high-risk group in the future. PMID- 23663876 TI - Long-term outcomes of 1,730 calcaneal fractures: systematic review of the literature. AB - The objective of the present study was to review the current data on the long term outcomes of calcaneal fractures, with special emphasis on the role of the type of treatment, surgical approach, and reduction and internal fixation. The search was limited to skeletally mature patients. Major databases were searched from 1978 to 2011 to identify studies relating to functional outcome, subjective outcome, and radiographic evaluation at least 2 years after either surgical or conservative treatment of calcaneal fractures. Of 59 initially relevant studies, 25 met our inclusion criteria. A total of 1,730 fractures were identified in 1,557 patients. The mean sample size-weighted follow-up period was 4.6 years. The findings from the present review support current clinical practice that displaced calcaneal fractures are treated surgically from 1 level I evidence study, 1 level II, and multiple studies with less than level II evidence, with open reduction and internal fixation as the method of choice. If the fracture is less complex, percutaneous treatment can be a good alternative according to current level 3 and 4 retrospective data. PMID- 23663877 TI - Short-term clinical and radiologic results of the scarf osteotomy: what factors contribute to recurrence? AB - The present retrospective investigation aimed to determine the factors associated with recurrence of hallux valgus deformity after scarf osteotomy in 50 feet in 43 consecutive patients. We hypothesized that hallux abductovalgus after scarf osteotomy recurs because of the presence of preoperative joint incongruity. The clinical and radiographic findings, including the weightbearing radiographic hallux valgus angle, first intermetatarsal angle, distal metatarsal articular angle, first metatarsophalangeal joint congruence, American Orthopaedic Foot and Ankle Society scores, and pain measured on a visual analog scale, and logistic regression analysis were used to analyze the association of the independent variables with the recurrence of deformity. The mean age of the patients was 47.7 (range 21 to 65) years, and the mean follow-up duration was 26.2 (range 18 to 36) months. The mean American Orthopaedic Foot and Ankle Society scores improved from 50.7 +/- 4.9 to 88.7 +/- 7.9, and the visual analog scale pain scores improved from 7.5 +/- 1.1 to 2.4 +/- 1.0 (p < .05). The changes in the radiographic measurements were also statistically significant. Of the 50 feet, 5 (10%) developed recurrent hallux abductovalgus, each of which occurred in feet that had displayed a first metatarsophalangeal joint incongruity on preoperative radiographs. The incongruity was observed to be a statistically significant risk factor for recurrence according to the regression models. From our experience with the patients analyzed in the present report, we believe that first metatarsophalangeal joint congruity should be given particular attention when surgical correction of hallux abductovalgus is undertaken. PMID- 23663878 TI - Letter to the editor. PMID- 23663879 TI - Scoliogeny of adolescent idiopathic scoliosis: inviting contributions for a discussion based on evidence and theoretical interpretations aiming ultimately to prevention or aetiological treatment. PMID- 23663880 TI - [Clinical observation of Hashimoto thyroiditis in patients with chronic hepatitis C undergoing pegylated-interferon alpha-2a and ribavirin combination therapy]. AB - OBJECTIVE: To investigate the relation of thyroid function with hashimoto thyroiditis (HT, an autoimmune disease of unknown etiology also known as chronic lymphocytic thyroiditis) in patients with chronic hepatitis C (CHC) receiving treatment with pegylated-interferon-alpha (Peg-IFNa) based on the observation that HT is common among individuals undergoing IFN-based therapy. METHODS: One hundred-and-seven patients with chronic hepatitis C were enrolled for study between January 2008 and December 2010. Thyroid function was assessed by electrochemiluminescence assays to detect serum levels of anti-thyroid peroxidase (A-TPO) antibodies, thyroid stimulating hormone (TSH), and free thyroxine (FT4) prior to initiation of the IFN-based therapy. The treatment strategies (drugs, doses, schedules) were designed according to HT status (CHC with HT, or CHC without HT). Patients were monitored during the 24 weeks of treatment (including measuring serum alanine aminotransferase (ALT), TSH, and FT4 every two to four weeks, and HCV RNA every four weeks) so that the IFNa dose could be adjusted and thyroid medications (levothyroxine sodium or methimazole) added as necessary. The response rate at end of treatment (week 24) was assessed. RESULTS: Twenty-one of the CHC patients were diagnosed with HT, and the incidence of thyroid dysfunction among the CHC patients with HT was 71.4% (15/21); among the CHC patients with no HT, the incidence of thyroid dysfunction was significantly lower (30.2% (26/86), X2 = 12.1995, P less than 0.01). In the CHC patients with HT, 90.5% (19/21) had serum levels of A-TPO antibodies that were more than or equal to 2-times higher than the normal value at the end of treatment. Of the 15 CHC patients with HT and thyroid dysfunction, 73.3% (11/15) continued to show thyroid dysfunction at the end of treatment. Hypothyroidism was the most common form of thyroid dysfunction observed (4/11), and all of those patients responded to levothyroxine sodium treatment. The virological response rates of the two groups (CHC with HT and CHC without HT) were not significantly different at any time point examined (treatment week 4, 12, and 24, P more than 0.05). CONCLUSION: The incidence of thyroid dysfunction is significantly higher among CHC patients with HT than among CHC patients without HT. If suspected, these patients should be carefully monitored because the clinical symptoms of thyroid dysfunction are not obvious and the drug therapy should be carefully adjusted to minimize the thyroid dysfunction while maximizing the antiviral effect. PMID- 23663881 TI - [Identification of risk factors related to the failure of immunization to interrupt hepatitis B virus perinatal transmission]. AB - OBJECTIVE: To explore the factors influencing failure of an immunization to interrupt perinatal (mother-to-child) transmission of hepatitis B virus (HBV). METHODS: Between June 2006 and March 2010, a total of 1355 pregnant women testing positive for the hepatitis B surface antigen (HBsAg), at gestational weeks 20 to 42, and without use of antiviral or immunomodulatory drugs during the pregnancy were prospectively recruited to the study. The mothers were given a choice of receiving hepatitis B immunoglobulin (HBIG; three 200 IU intramuscular injections give at four-week intervals starting from gestation week 28) or not. All neonates (1360, including five sets of twins) received hepatitis B vaccine (10 mug) plus HBIG (200 IU) combined immunization within 24 h of birth, as early as possible. Peripheral venous blood samples were collected from the neonates within 24 h of birth and at 7 and 12 months of age for detection of HBV markers, including hepatitis B e antigen (HBeAg) and HBV DNA. The infants were classified according to HBV perinatal transmission status (infection group and non-infection group) and various factors (maternal-related: age, gravidity, parity; pregnancy/birth related: threatened premature labor, complications; neonate-related: sex, birth weight, apgar score) were compared between the two groups by using non conditional logistic regression analysis to determine their potential influence on failure of immunization to inhibit transmission. RESULTS: After 12 months of follow-up, 1.54% (21/1360) of the neonates had presented with HBV infection. Analysis of the HBV-infected neonates revealed differences in infection rates between neonates born to mothers with HBIG injection (2.22% vs. without HBIG injection: 1.11%, P less than 0.05) and caesarean section (1.35% vs. vaginal delivery: 1.73%) but neither reached statistical significance (P less than 0.05); only the practice of breastfeeding showed a significant difference for infection rate, with neonates fed artificial formula having higher infection rate (3.13%) than the breastfed neonates (0.27%, P less than 0.05). The neonate HBV infection rate was also significantly higher for neonates born to HBeAg-positive mothers (4.44% vs. HBeAg-negative mothers: 0%, P less than 0.05) and HBV DNA-positive mothers (3.13% vs. HBV DNA-negative mothers: 0%, P less than 0.05). When the mothers were stratified by serum level of HBV DNA, there was a significant difference in HBV-infected neonates born to mothers with more than or equal to 1*10(7) IU/ml(6.01% vs. 10(3)-10(6) IU/ml: 0.56% and less than 1*10(3) IU/ml: 0%, both P less than 0.05). Logistic regression analysis indicated that the independent risk factors for HBV perinatal transmission despite immunization were maternal serum HBeAg-positive status (relative risk (RR)=31.74, 95% confidence interval (CI): 3.88-259.38) and maternal HBV DNA of >= 107 copies/mL (RR=22.58, 95% CI: 4.75-107.40). CONCLUSION: Failure of vaccine plus HBIG to interrupt mother-to-child transmission of HBV is influenced by maternal serum HBeAg positive status and maternal HBV DNA of >=107 copies/mL. PMID- 23663882 TI - [Effects of Wnt3a on proliferation, activation and the expression of TGFb/Smad in rat hepatic stellate cells]. AB - OBJECTIVE: To observe the effects of Wnt3a on proliferation and, activation of hepatic stellate cells (HSCs) and their the expression of the transforming growth factor beta (TGFb) and /Smad signaling factors of rat hepatic stellate cells line in vitro using a rat HSC line. METHODS: Synchronized HSC-T6 cells were stimulated with various concentrations of recombinant Wnt3a (50, 100, 200, 250 and 300 ng/mL). Unstimulated cells served as controls. Edu Effects on proliferation were determined by EdU (5-ethynyl-2'-deoxyuridine) incorporation assay and fluorescence microscopy.analysis was used to observe the proliferation of the hepatic stellate cells stimulated by different concentration of recombinant Wnt3a, and the Effects on the protein expression of TGFb/Smad signaling factors was assessed by western blot detection (gray-value analysis) of alpha-smooth muscle actin (a-SMA), a-SMA, TGFb1, Smad3, and and Smad7; glyceraldehyde 3 phosphate dehydrogenase (GAPDH) was detected as the normalization control in the hepatic stellate cells was observed by Western blot analysis .The correlation was also observed. The significance of inter-group differences was assessed by one way ANOVA, and correlations were determined using bivariate statistical modeling. RESULTS: In general, HSC The proliferation of hepatic stellate cells increased after the addition of in response to Wnt3a stimulation for 24 h, reaching its peak at the maximum proliferation rate was observed with the 200 ng/mL Wnt3a concentration (63.00+/-2.30%), and it increased dramatically compared with those in which was significantly higher than the proliferation rates of the unstimulated control cells, and the cells stimulated with 50, 100 and 150 ng/mLl group (P less than 0.05), but the increase was not significantly different from that in the compared cells stimulated with 250 and 300 ng/mLl group,it had no obvious increase(P more than 0.05).; The Wnt3a stimulation also led to time dependent increases in the protein expressions of a-SMA, TGFb1, and Smad3 increased with the addition of Wnt3a and the extension of time . For all three, The maximal amount of increased protein expression all reached to the was maximal produced by stimulation when hepatic stellate cells were treated by with 300 ng/mLl Wnt3a for 48 h hours,and the rations of(normalized gray- values:s of a SMA, 1.0860+/-0.0101; TGFb1, 1.0346+/-0.0118; Smad3, to GAPDH were 1.0860+/ 0.0101, 1.0346+/-0.0118, 1.0306+/-0.0122)respectively. However in contrast, the Wnt3a stimulation led to concentration- and time-dependent decreases in Smad7 expression varied inversely, with to them with the minimal ration of it to GAPDH the maximal decrease occurring with 300 ng/mL Wnt3a for 48 h (0.7736+/-0.0139) after being treated by 300 ng/ml Wnt3a for 48h. The comparison was remarkably discrepant, (P less than 0.05).There were positive correlations between a-SMA expression and was found to be positively correlated to TGFb1, Smad3 (r=0.968, P less than 0.05) and; Smad3 (r=0.997, P less than 0.01), but a-SMA and Smad7 had negatively correlated to Smad7 ion(r=0.960, P less than 0.05). CONCLUSION: Wnt3a can increase the stimulates proliferation as well as and activation of rat the hepatic stellate cells HSCs , and upregulate modifies the expression of TGFb/Smad signaling factors, of the hepatic stellate cells, and which may promote the hepatic fibrosis. PMID- 23663883 TI - [Effect of inflammatory stress on hepatic cholesterol accumulation and hepatic fibrosis in C57BL/6J mice]. AB - OBJECTIVE: To investigate whether inflammatory stress exacerbates hepatic cholesterol accumulation and liver fibrosis using a C57BL/6J mouse model of chronic inflammation. METHODS: Twelve male C57BL/6J mice were given a high-fat diet (15.0% fat, 1.25% cholesterol, 0.5% cholic acid) and randomly assigned to the normal control group (n=6; subcutaneously injected with 0.5 mL of isotonic saline, every other day for 14 weeks) or the chronic inflammation model group (n=6; subcutaneously injected with of 0.5 mL of 10% casein, every other day for 14 weeks). At the end of week 14, the animals were sacrificed and blood was collected from the left ventricle for serological analysis of inflammatory markers and lipid profile, including serum amyloid A (SAA), interleukin-6 (IL-6), total cholesterol (TC) and free cholesterol (FC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL)). Extracted liver tissues were divided for use in histological analysis (lipid accumulation and fibrosis evaluated by Oil Red O, Sirius red and Masson's trichrome staining) and quantitative fluorescence real time PCR (to measure b-actin normalized expression of TNF-a MCP1, SREBP-2, LDLr, HMGCoA-r, ATF-6, GRP78, BMP-7, TGF-b, and collagens type I and type IV). Comparisons between groups were made by the two-samples t-test or Satterthwaite t approximation test, collagen type I and type IV. RESULTS: Compared to the normal control group, the inflammation model group showed elevated serum IL-6 (12.55+/ 4.75 vs. 32.41+/-7.42 pg/mL, P less than 0.01), reduced serum TC (14.82+/-1.56 vs. 10.62+/-0.48 mmol/L, P less than 0.01), up-regulated hepatic TNF-a mRNA expression (1.05+/-0.35 vs. 2.12+/-0.72, P less than 0.01), and elevated hepatic TC (12.10+/-2.57 vs. 23.21+/-8.75 mmol/L, P less than 0.05). In addition, the inflammation group showed abnormal lipid deposition, and increased and thickened reticular fibers. The livers of the inflammation group also showed up-regulated mRNA expression of SREBP-2 (normal control: 1.01+/-0.19 vs. 2.63+/-0.13, P less than 0.05), GRP78 (1.07+/-0.47 vs. 2.21+/-0.99, P less than 0.05), TGF-b (1.01+/ 0.14 vs. 1.38+/-0.28, P less than 0.05), and collagen type I (1.02+/-0.27 vs. 1.71+/-0.51, P less than 0.05) and down-regulation of BMP-7 (1.01+/-0.15 vs. 0.55+/-0.25, P less than 0.01). CONCLUSION: Activation of the inflammatory system exacerbates hepatic cholesterol accumulation and hepatic fibrosis in C57BL/6J mice. PMID- 23663884 TI - [Expression and clinical significance of nerve growth factor in primary liver cancer]. AB - OBJECTIVE: To determine the expression of nerve growth factor (NGF) in hepatic tissues and serum of patients with primary liver cancer (PLC), and to investigate the relationship of serum NGF levels with clinicopathological features of PLC. METHODS: Hepatocellular carcinoma (HCC) samples and patient-matched tumor adjacent liver samples were collected from 26 PLC patients to assess the mRNA and protein expressions of NGF by reverse transcription-PCR, western blotting (b actin normalized), and immunohistochemistry. In addition, serum samples were collected from 40 PLC patients, 40 liver cirrhosis patients, 40 chronic hepatitis patients (including hepatitis B or C virus infections), and 30 healthy (normal) controls. The serum levels of NGF were measured by enzyme-linked immunosorbent assay. Intergroup differences were assessed by the t-test, and correlation with sex, age, presence of cirrhosis, tumor size, and TNM classification were assessed by the Kruskal-Wallis H test followed the Mann-Whitney U test. RESULTS: HCC tissues showed higher mRNA and protein expressions of NGF than the corresponding tumor-adjacent non-HCC tissues. Hepatic NGF expression was mainly localized to the tumor cell cytoplasm. Serum NGF expression was significantly higher in PLC patients (33.86+/-16.11 pg/ml) and cirrhosis patients (20.57+/-9.73 pg/ml) than in normal controls (11.13+/-6.12 pg/ml) and chronic hepatitis patients (13.20+/ 6.23 pg/ml) (P less than 0.01). Furthermore, when the PLC patients were stratified according to tumor size and TNM stage, the serum NGF level was found to be significantly higher in patients with tumors more than 5 cm (vs. less than 5 cm; U=83.000, P=0.002) or of TNM stage III/IV (vs. stage I/II; U=103.500, P=0.009). CONCLUSION: Elevated expression of NGF in liver cancer tissues and serum of PLC patients is related with tumor size and TNM staging. These findings suggest that NGF may play a role in HCC tumorigenesis and/or that serum NGF may represent a prognostic marker of PLC. PMID- 23663885 TI - [A clinical and pathological analysis of 22 cases of primary sclerosing cholangitis]. AB - OBJECTIVE: To characterize the clinical, laboratory, imaging and pathological features of primary sclerosing cholangitis (PSC) and investigate the impact of ursodeoxycholic acid (UDCA) therapy on patient prognosis. METHODS: The medical records of 22 patients diagnosed with PSC between 2002 and 2011 were retrospectively reviewed. The PSC diagnosis had been made in patients with suspect biochemical abnormalities following evaluation by magnetic resonance cholangiopancreatography (MRCP) and/or endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC). Fibrosis and inflammation were assessed by immunohistochemical analyses of tissue biopsies. Outcome of patients treated with UDCA (13-15 mg/kg/day, oral) were compared to that of patients without UDCA treatment by the X2 or corrected X2 tests. RESULTS: Among the 22 PSC patients, the majority was male (n=15) and presented with fatigue, dark urine, and body weight loss (n=15). Four cases had ulcerative colitis. At admission, all 22 cases showed elevated levels of alkaline phosphatase[ALP: (348+/-184) U/L], 19 cases showed elevated alanine aminotransferase [ALT: (94.0+/-67.0) U/L] and aspartate aminotransferase [AST: (98.0+/-67.0) U/L], and 15 cases showed elevated levels of total bilirubin (99.0+/-115.0) mumol/L and direct bilirubin (74.4+/-92.4 mumol/L. ERCP examination showed segmental intrahepatic bile duct stenosis with expansion, and stiff and enlarged gallbladder bile ducts, but unclear findings for the common bile ducts and pancreatic ducts. MRCP showed beading of the intrahepatic bile duct, stiffness of the bile duct wall, and dilation of the common bile duct. Fibrosis and inflammation were observed in the bile ducts, along with hyperplasia and the typical features of "onion skin" fibrosis and fibrous obliterative cholangitis. Five of the 10 patients treated with UDCA improved, and seven of the 12 patients in the non-UDCA treatment group improved. There was no statistically significant difference in outcome between the groups (paired X2=0.333, corrected X2=0.083, P more than 0.05). CONCLUSION: PSC patients were predominantly male and the common clinical manifestations were fatigue, dark urine, and body weight loss. At admission, serum biochemical indicators of cholangitis were increased significantly and subsequent imaging studies confirmed the suspected diagnosis by showing obvious characteristic changes. UDCA treatment did not significantly improve patient prognosis. PMID- 23663886 TI - [Activation of Fas/FasL and its downstream signaling pathway promotes development of alcoholic steatohepatitis and liver fibrosis in mice]. AB - OBJECTIVE: To explore the role and mechanism of the Fas/Fas ligand (FasL) system and its downstream signaling pathway related to the progression of alcoholic steatohepatitis and liver fibrosis. METHODS: Eighteen C57BL/6J mice were randomly divided into three groups: controls; alcoholic steatohepatitis model, given four weeks of a 4% ethanol-containing Lieber-DeCarli liquid diet; alcoholic steatohepatitis and liver fibrosis model, given the four-week alcohol diet followed by twice weekly intraperitoneal injections of carbon tetrachloride (5% olive oil solution; 2 mL/kg dose) during the fifth to eighth weeks. Mice in the model groups were sacrificed at the end of week 4 and 8, respectively, along with control mice for comparative analyses. Liver tissue sections were evaluated for hepatocellular apoptosis by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. The mRNA expression of Fas, FasL, cysteine aspartate specific proteases 3 (caspase 3), and cytochrome P450 2E1 (CYP 2E1) in liver tissues was detected by reverse transcription (RT)-PCR, visualized by ethidium bromide staining, and normalized to the gray-value of GAPDH expression. The protein expression of Fas and caspase 3 were detected by western blotting (b actin normalized), and of FasL and CYP 2E1 by immunohistochemistry staining. Intergroup differences and statistical significance were evaluated by single factor analysis of variance and the least squares difference-t test or the Kruskal-Wallis H test and the Mann-Whitney U test. RESULTS: The number of apoptotic cells in the liver sections was significantly higher in both model groups with alcoholic steatohepatitis (vs. controls) and the amount in the alcoholic steatohepatitis plus liver fibrosis model was significantly higher than that in the model with only alcoholic steatohepatitis. In addition, activation of Fas, FasL and its downstream signaling pathway showed an increasing trend with extent of liver injury. The hepatic mRNA (by RT-PCR) and protein (by western blotting) normalized expression levels in the controls, alcoholic steatohepatitis models, and alcoholic steatohepatitis plus liver fibrosis models were, respectively: Fas mRNA: 0.50+/-0.05, 0.61+/-0.10, 0.76+/-0.03 (H=12.137, P less than 0.05), protein: 0.52+/-0.14, 0.86+/-0.10, 0.99+/-0.09 (F=12.758, P less than 0.01); FasL mRNA: 0.31+/-0.03, 0.53+/-0.02, 1.02+/-0.04 (F=153.260, P less than 0.01); caspase 3 mRNA: 0.86+/-0.11, 0.85+/-0.05, 1.33+/-0.16 (F=8.740, P less than 0.01), protein: 0.40+/-0.03, 0.69+/-0.06, 1.02+/-0.10 (F=90.785, P less than 0.01); CYP 2E1 mRNA: 0.72+/-0.14, 1.00+/-0.15, 1.30+/-0.20 (H=4.713, P less than 0.01). The changes in hepatic FasL and CYP 2E1 expression detected by immunohistochemistry were consistent with the mRNA expression. CONCLUSION: Activation of Fas/FasL and its downstream signaling pathway, which induces hepatocellular apoptosis, contributes to the development of alcoholic steatohepatitis and liver fibrosis. PMID- 23663887 TI - [Therapeutic efficacy and mechanisms of quercetin in a rat model of nonalcoholic fatty liver disease]. AB - OBJECTIVE: To determine the efficacy of the plant-derived bioflavonoid, quercetin, for treating nonalcoholic fatty liver disease (NAFLD) by using a rat model, and to investigate the molecular mechanism underlying its therapeutic effects. METHODS: One-hundred Sprague-Dawley rats were randomly assigned into the normal control group (normal group), untreated NAFLD model control group (model group), 75 mg/kg/day quercetin treatment group (low-dose group), and 300 mg/kg/day quercetin treatment group (high-dose group). The NAFLD rat model was established by providing four weeks of a high-fat diet; the normal group received normal rat chow diet. The quercetin treatments were administered for eight weeks after model establishment and control groups received simultaneous gavages of isotonic saline, with continuation of the respective diets. At the end of the eight weeks (experimental week 12), the rats were sacrificed for liver and serum collection. Intergroup differences in liver index, fasting blood glucose (FBG), triglycerides (TG), interleukin (IL)-18, IL-10, malondialdehyde (MDA), and histopathological features were assessed by independent samples t-test (normal vs. model), one-way ANOVA (model vs. treatments), and least significant difference t-test (pairwise comparisons); correlations were assessed by Pearson's correlation coefficient. RESULTS: Compared with the normal group, the model group showed significantly higher liver index (t=-2.327), FBG (t=-3.482), TG (t= 0.302), and serum IL-18 (t=-2.704) (all P less than 0.05), but significantly lower IL-10 (t=2.622, P less than 0.05); the MDA level was also higher in the model group, but the difference was not significant (t=-1.083, P less than 0.05). Livers from the model group showed obvious histological features of inflammation (lymphocyte and neutrophil infiltration) and steatosis (cytoplasmic lipid droplets). Inflammation was positively correlated with IL-18 (P less than 0.05), but negatively correlated with IL-10 (P less than 0.05), while steatosis was negatively correlated with IL-10 (P less than 0.05). Compared to the model group, quercetin treatment (both low- and high-dose) led to significant decreases in the liver index, FBG and IL-18 (all, P less than 0.01), and significant increase in IL-10 (P less than 0.05); however, the changes in liver index, FBG and IL-10 were not significantly different between the low- and high-dose treatment groups, but the high-dose of quercetin did induce a significantly greater decrease in IL-18 than the low-dose (P less than 0.05). CONCLUSION: NAFLD rats have higher serum levels of IL-18 but lower levels of IL-10 than their healthy counterparts, and these differential cytokine expressions may be related to liver inflammation and steatosis. Quercetin treatment may help to delay the progression of NAFLD, possibly by adjusting the balance of inflammatory cytokines. PMID- 23663888 TI - [A new strategy to establish a hepatopulmonary syndrome model in rats by inducing abdominal compartment syndrome in the presence of cirrhosis]. AB - OBJECTIVE: To find a practical method to establish hepatopulmonary syndrome (HPS) in rats for use as an experimental model system. METHODS: Forty male Sprague Dawley rats were equally divided into a normal group (injected subcutaneously with 3 mL/kg of olive oil for 12 weeks), abdominal compartment syndrome (ACS) group (injected subcutaneously with 3 mL/kg olive oil for 12 weeks, followed by an intraperitoneal injection of 4% succinylated gelatin and maintenance of 20 mmHg abdominal pressure for 3 h), cirrhosis group (injected subcutaneously with 40% carbon tetrachloride (CCl4) in olive oil twice weekly for 12 weeks, with first dose doubled), and an ACS+ cirrhosis (HPS model) group (CCl4-induced, followed by the intraperitoneal injection with succinylated gelatin and 3 h of 20 mmHg abdominal pressure). The mice were sacrificed to perform blood gas analysis and to assess lung pathology. Comparisons between two groups were carried out by non-parametric analysis, and multiple comparisons were carried out by the Kruskal Wallis H test. RESULTS: Blood gas analyses showed significant differences in the values of pH for the normal group (7.41+/-0.04), the ACS group (7.22+/-0.06), the cirrhosis group (7.53+/-0.04), and the HPS model group (7.47+/-0.02) (P less than 0.05). The ACS group and the HPS model group showed significantly different values of partial pressure of oxygen (PaO2; 58.57+/-5.41 and 58.20+/-3.19 mm Hg) and of alveolar-arterial oxygen difference (AaDO2; 83.86+/-28.49 and 84.80+/ 11.82 mm Hg) than the normal group and the cirrhosis group (PaO2: 86.67+/-1.37 and 85.00+/-2.53 mm Hg; AaDO2: 38.17+/-9.20 and 37.00+/-6.23 mm Hg) (P less than 0.05). Pathological analysis of the lungs from the ACS group revealed widened alveolar septa, different-sized alveolar spaces, reduced lung capacity, edema and hemorrhage in some of the alveolar cavities, and telangiectasia in the alveolar walls. The lungs from the cirrhosis group also showed widened alveolar septa, different-sized alveolar spaces, and reduced lung capacity, but were distinct in the features of inflammatory cell infiltration, and hyperemia in the pulmonary vessels. The lungs from the HPS model group showed all of the features of both the lungs from the ACS and cirrhosis groups, but also showed macrophage accumulation and microthrombi in the pulmonary vessels. CONCLUSION: Inducing ACS in the setting of CCL4-induced cirrhosis in a rat generates pathological features that adequately mirror those of HPS and may represent a useful experimental model for in vivo studies of HPS. PMID- 23663889 TI - Generation of gene disruptions by transcription activator-like effector nucleases (TALENs) in Xenopus tropicalis embryos. AB - Transcription activator-like effector nucleases (TALENs) are novel engineered DNA nucleases, and have been proven to be effective for gene specific targeting in various species. Recently we reported gene disruptions in Xenopus embryos by using TALENs. Here we summarize the protocol that is used in our studies for gene disruption. This protocol covers selection of TALEN targeting sites, TALEN assembly with a modified Golden Gate method, and injection of TALEN mRNAs into Xenopus tropicalis embryos. We also provide details for detection of somatic and germ line transmitted mutations. And finally, we briefly describe establishment of knockout Xenopus lines. This protocol will facilitate broader applications of TALENs in studies of Xenopus biology. PMID- 23663890 TI - Orexin deficiency and narcolepsy. AB - Orexin deficiency results in the sleep disorder narcolepsy in many mammalian species, including mice, dogs, and humans, suggesting that the orexin system is particularly important for normal regulation of sleep/wakefulness states, and especially for maintenance of wakefulness. This review discusses animal models of narcolepsy; the contribution of each orexin receptor subtype to the narcoleptic phenotypes; and the etiology of orexin neuronal death. It also raises the possibility of novel therapies targeting the orexin system for sleep disorders including insomia and narcolepsy-cataplexy. PMID- 23663891 TI - [Orthostatic response of blood pressure in patients with early Parkinson's disease]. AB - OBJECTIVE: To evaluate orthostatic blood pressure response in patients with early Parkinson's disease and mild to moderate disease treated at the National Institute of Neurology and Neurosurgery. METHOD: A cross-sectional study with control group was carried out. Patients with Parkinson's disease with a disease duration of less than 5 years and mild to moderate severity along with healthy controls of the same age group were included. Those subjects with diabetes mellitus, hypertension or diagnosis of dysautonomia were excluded. Blood pressure was measured in supine position as well as after 3 and 5 min of standing. RESULTS: Seventy subjects with Parkinson's disease and 145 controls were included. There were no statistically significant differences in gender and age between both groups. There was no difference in systolic blood pressure change between groups at 3 minutes but at 5 minutes a statistically significant difference was found (P=.03). For diastolic blood pressure a difference between both groups was present at three and five minutes (P=.02 and P=.007). CONCLUSION: Patients with early Parkinson's disease have differences in orthostatic responses compared to healthy controls, these differences are more relevant at 5 minutes of standing. PMID- 23663892 TI - [A review of Kawasaki disease, a perspective from the articles published in Mexico since January 1977 to May 2012]. AB - Kawasaki disease was described in 1967 by Tomisu Kawasaki. It affects children aged between one and 5 years, and it evolves with fever and small vessel vasculitis, which leads to cardiovascular complications, including coronary aneurisms, myocarditis, valve injuries, pericardial effusion and myocardial infarction; eventually involving many others organs. The etiology actually is not well known, as the exactly pathogenic mechanisms; however, now there are important advances. If the clinical signs and symptoms are identify early and the children received treatment with aspirin and intravenous immunoglobulin, the patients evolves without sequels. The Kawasaki disease is an infrequent disease in Mexico. PMID- 23663893 TI - [Histopathological and immunohistochemical features of cardiac myxomas]. AB - Mixomas are the most common primary cardiac tumors with an estimate incidence of 0,5-1 per 10(6) individuals per year. These tumors have generated interest due to their unique location (left side of the atrial septum near the fossa ovalis), variable clinical presentation and undefined histogenesis. Most cardiac myxomas occur sporadically while approximately 10% of diagnosed cases develop as part of Carney complex. This neoplasm is of uncertain histogenesis, however, endothelial, neurogenic, fibroblastic, and cardiac and smooth muscle cells differentiation has been proposed, and rarely glandular differentiation has been observed. Recently, due to the expression of certain cardiomyocyte-specific factors, an origin of mesenchymal cardiomyocytes progenitor cells has been suggested. Histologically cardiac myxomas are mainly composed of stellated, fusiform and polygonal cells, immersed in an amorphous myxoid matrix. Immunohistochemically some endothelial markers, such as CD31, CD34, FVIIIAg, are present. Positive staining has also been reported for S-100 protein, calretinin, vimentin, desmin, smooth muscle myosin, CD56, alpha1 antitrypsin and alpha 1antichymotrypsin. Surgical resection is currently the only treatment of choice. We present in this article a histopathological and immunohistochemical review of cardiac myxomas. PMID- 23663894 TI - [Isolated left ventricular non-compaction associated with Ebstein's anomaly. Multimodality non-invasive imaging for the assessment of congenital heart disease]. AB - To establish the etiology of heart failure in patients with congenital heart disease can be challenging. Multiple concomitant anomalies that can be missed after an initial diagnosis could be seen in these patients. In patients with congenital heart disease, a more accurate evaluation of cardiac morphology and left ventricular systolic function could be evaluated by recent non-invasive cardiac imaging techniques. We present a rare case where multimodal cardiac imaging was useful to establish the final diagnosis of left ventricular non compaction associated with Ebstein's anomaly. PMID- 23663895 TI - NR4A1 enhances neural survival following oxygen and glucose deprivation: an in vitro study. AB - A worldwide epidemic of stroke is exacting a huge level of patient suffering and social cost. The ischemia damage to neural cells and the associated permanent neural function loss are central to the pathophysiology of stroke. In the current study, we were endeavored to identify NR4A1, an orphan nuclear receptor as a novel protector for neural cells in an in vitro neural ischemia model. Our results showed that oxygen and glucose deprivation (OGD) dramatically induced primary culture neural cell apoptosis and NR4A1 expression at both protein and mRNA level. Furthermore, hyperexpression or knock-down of NR4A1 significantly ameliorated or exacerbated OGD induced neural damage as manifested by decreased or increased apoptotic rates and key apoptotic protein expression respectively. As part of effort to identify the underlying mechanism, we also found that survivin is highly inducible following OGD and is required for NR4A1 action in this scenario. Our data seemed to be logical extensions of previous observations showing that NR4As are highly inducible following focal cerebral ischemia. Of note, our results also demonstrated that NR4A1 induction in this scenario may be functionally important as well and targeting NR4A1 protein can be intriguing as part of the effort to develop novel therapeutic strategies for neural protection after stroke. PMID- 23663896 TI - Observations on chronic inflammatory demyelinating polyneuropathy: A plea for a rigorous approach to diagnosis and treatment. PMID- 23663897 TI - The inferior turbinate flap in skull base reconstruction. AB - BACKGROUND: As the indications for expanded endonasal approaches continue to evolve, alternative reconstructive techniques are needed to address increasingly complex surgical skull base defects. In the absence of the nasoseptal flap, we describe our experience with the posterior pedicle inferior turbinate flap (PPITF) in skull base reconstruction. DESIGN: Case series. SETTING: Academic tertiary care centre. METHODS: Patients who underwent reconstruction of the skull base with the PPITF were identified. Medical records were reviewed for demographic, presentation, treatment, follow-up, surgical and outcomes data. MAIN OUTCOME MEASURES: Flap survival, adequacy of seal, and complications. RESULTS: Two patients with residual/recurrent pituitary adenomas met the inclusion criteria. The nasoseptal flap was unavailable in each case due to a prior septectomy. Salvage of the original nasoseptal flap was not possible, as it did not provide adequate coverage of the resultant defect due to contraction from healing. All PPITFs healed uneventfully and covered the entire defect. No complications were observed in the early post-operative period. Endoscopic techniques and limitations of the PPITF are also discussed. CONCLUSIONS: Our clinical experience supports the PPITF to be a viable alternative for reconstruction of the skull base in the absence of the nasoseptal flap. PMID- 23663899 TI - Epidemiology and mortality of burns in the Lucknow Region, India--a 5 year study. AB - Nearly 95% of global burn deaths and disabilities are estimated to occur in low and middle income countries of the world. Burns are extremely common and are a major public health problem in a developing country like India. The purpose of this study was to record and evaluate the causes and the magnitude of the fatal burns retrospectively. An analysis of autopsy records revealed 2225 (10.7%) cases of burns among the total autopsies done over 5 years period (1st January 2008 27th November 2012) in the mortuary of Forensic Medicine & Toxicology, K.G.M.U., Lucknow. The majority of deaths (88.8%) occurred between 10 and 49 years of age group with a preponderance of females (87.5%). The flame burns were seen in 60.1% of the victims. The majority of burn incidents were suicidal (38.6%) in nature followed by accidental (37.3%) and homicidal (24.1%) deaths. The percentages of burns with a total body surface area (TBSA) over 50% were observed in most of the cases (82.5%). In most of the cases deaths occurred within a week (82%) and most of the victims died from septicaemia and pneumonia (43.7%) followed by neurogenic shock (28.5%). The results of this study provide the necessary information to implement programmes for health education relating to prevention of burns focusing on the domestic setting. PMID- 23663900 TI - The impact of oxandrolone on length of stay following major burn injury: a clinical practice evaluation. AB - INTRODUCTION: The anabolic agent oxandrolone (OX) has been found to decrease length of stay (LOS) following 20-60% total body surface area (TBSA) burn injury. This study uses the Comprehensive Severity Index (CSI) to control for severity of illness and explores the relationship between OX and LOS in a more broadly selected sample of burn patients and a natural practice setting. METHODS: A practice-based evidence study was conducted at a single regional burn center. Maximum severity of illness (MCSIC) was measured using a burn-specific version of CSI. Data on 167 consecutive surviving patients with TBSA>=15% were analyzed using case-control matching for MCSIC, TBSA, and age. Thirty-eight patients received OX. RESULTS: Median patient age for the entire patient sample was 42.7 years. Using a 1:1 match based upon MCSIC, TBSA, then age, mean LOS for patients who received OX was 33.6 days, as opposed to 43.4 days for those who were not managed with OX (p=0.03). If patients were matched >1:1 for controls: cases, mean LOS was 40.9 days (controls) versus 31.6 days (cases). CONCLUSIONS: OX is associated with shorter LOS after controlling for MCSIC, TBSA, and age. Future comparative effectiveness studies should better define which patients derive the greatest benefits from receipt of OX during their recovery from major burn injury. PMID- 23663903 TI - [In cancer things are different and in fact different standards apply]. PMID- 23663902 TI - Evaluation of pharmacological activities, cytotoxicity and phenolic composition of four Maytenus species used in southern African traditional medicine to treat intestinal infections and diarrhoeal diseases. AB - BACKGROUND: Microbial infections and resulting inflammation and oxidative stress are common pathogenesis of gastrointestinal tract (GIT) disorders. In South Africa, several species of the genus Maytenus are used in traditional medicine to treat various infectious diseases. Most of the previous work on this genus was focused on nonpolar extracts from the root and bark. In this study, leaf extracts of polar extracts of Maytenus peduncularis, Maytenus procumbens, Maytenus senegalensis and Maytenus undata were evaluated for antimicrobial, anti inflammatory and antioxidant activities to determine their efficacy as therapeutic agents in GIT disorders. METHODS: Phenolic-enriched leaf extracts and fractions were prepared by extracting with acidified 70% methanol and solvent solvent fractionation. The activities of the fractions against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Enterococcus faecalis as well as clinical isolates of Aspergillus fumigatus, Candida albicans and Cryptococcus neoformans were determined using a serial microplate dilution method. Antioxidant activities were determined using 1,1-diphenyl-2 picrylhydrazyl (DPPH), 2,2'-azinobis(3-ethylbenzthiazoline-6-sulphonic acid) (ABTS), hydroxyl (OH) radical scavenging and linoleic acid peroxidation inhibitory assays. The phenolic composition as well as the cytotoxicity against Vero cell lines of the crude extracts was evaluated using various standard protocols. RESULTS: The antimicrobial activities were concentrated in the non polar fractions of hexane, dichloromethane and ethyl acetate (MICs 19-312 MUg/ml). The crude extracts and polar fractions (butanol and water) had moderate to poor antimicrobial activity (MICs 312 to above 2500 MUg/ml). The crude extracts and polar fractions had good antioxidant activity (EC50 values varied from 1.22 to 607 MUg/ml, 1.71 to 312 MUg/ml and 23 to 284 MUg/ml for DPPH, ABTS and OH respectively. Linoleic acid peroxidation inhibition EC50 values of the crude extracts ranged between 27 and 39 MUg/ml with relatively low toxicity against Vero cell lines (IC50 values 87 to 187 MUg/ml). Fractionation of a crude extract with low activity could lead to fractions with more potent activity. CONCLUSION: This study justifies the traditional use of leaf crude extracts and fractions from these four plants to remedy gastrointestinal disorders resulting from infection, inflammation and oxidative stress complications. The study also provides rationale for the use of leaf extracts with same beneficial effects in place of unsustainable root and bark harvest. PMID- 23663904 TI - ["The King of Diseases": the special attention that is paid to cancer patients and how it came about? An Essay]. AB - The history of cancer in the 20(th) century demonstrates that various factors have contributed to the perception of cancer as the "Emperor of All Maladies" although this has never been true from an epidemiological perspective. Depending on the geographical area, infectious diseases like tuberculosis or malaria or cardiovascular diseases still head the list of the most common illnesses. Within the group of chronic degenerative diseases, however, cancer has outdistanced the widespread classic infectious diseases as a result of the epidemiologic transition in 1900, at least in the more developed countries. Under the Nazi dictatorship (from 1933 to 1945), the perception of cancer in Germany got particularly promoted for propaganda purposes. In the Atomic Era cancer attracted strong public interest as a worthwhile object of research in radiation therapies using large-scale facilities (electron accelerators, "electron guns"). A further upsurge of interest in cancer could then be witnessed in the context of the debate about the pathogenic role of environmental factors. Notably, this increased perception of cancer has not yet been significantly associated with a sweeping success in cancer treatment, but rather with ideologies, hopes and innovation impulses. (As supplied by publisher). PMID- 23663905 TI - [Medical care of the cancer patient - Is it really so different?]. AB - Cancer deaths contribute to more than 25% of the overall mortality in Germany, which is only superseded by death from cardiovascular diseases. Apart from improving cancer prevention, the development of effective therapies for advanced cancer is a key task in oncology. Here we compare the criteria of clinical effectiveness that are applied to medical cancer therapies with those that are applied to therapies for cardiovascular diseases. (As supplied by publisher). PMID- 23663906 TI - [Cancer: Is it really so different? Particularities of oncologic drugs from the perspective of the pharmaceutical regulatory agency]. AB - For innovative oncological medicines the centralised procedure at the European Medicines Agency is mandatory for a marketing authorisation application for the European Union. As with other medical drugs, the marketing authorisation decision is based on the assessment of its efficacy, safety and pharmaceutical quality but does not consider price or reimbursement. More sophisticated diagnostic methods drive an increasing stratification of cancer into a multitude of different diseases. Regardless of their different pathogenesis and therapeutic options the most relevant clinical endpoints remain cure, overall survival and progression free survival. These endpoints include both efficacy and safety, as patient survival reflects the sum of the beneficial anti-tumour effects (increasing survival) AND the adverse effects (decreasing survival). The benefit of an anticancer medicine should be evident from both overall survival and progression free survival (e.g. used as primary and secondary endpoints). Mature data on overall survival may not be needed for marketing authorisation if a clear increase in progression free survival convincingly predicts a beneficial effect on overall survival. In these exceptional cases treatment of patients with an obviously beneficial medicine must not be delayed - possibly for years - until the exact size of the benefit has been established. The continued stratification of the disease cancer results in a lower prevalence for each of the newly distinguished disease entities and an ever increasing number of orphan designations for medicines for rare diseases. Incentives for the development of orphan medicines include market exclusivity for up to ten years. In specific circumstances, however, the orphan legislation may restrict the authorisation and marketing of competing generic products even beyond these ten years. Conditional approval and approval under exceptional circumstances may accelerate patients' access to a new medicine. Both postulate that the extent of the benefit cannot be determined with sufficient certainty at the time of marketing authorisation. This uncertainty may have a negative impact on price and reimbursement as these decisions may consider data or assessments from the marketing authorisation procedure. Therefore, marketing authorisation applications and subsequent pricing and reimbursement negotiations should not be regarded as completely independent processes, but be included in an overall strategy for the development of oncologic drugs. (As supplied by publisher). PMID- 23663907 TI - [HTA-Perspective: Challenges in the early assessment of new oncological drugs]. AB - Oncologic drug therapies have gained wide attention in the context of health policy priority setting for serious and socially significant diseases with high human and monetary costs. Due to uncertainties and scepticism about the actual therapeutic importance of newly approved oncology products, an early assessment programme was already established in Austria in 2007. The assessment of new oncology products is thereby faced with special challenges, since study populations are frequently not representative or the study design is laid out in such a manner that a definitive assessment of patient-relevant endpoints is not possible (cross-overs after interim assessments, surrogate parameters as primary endpoints, uncontrolled studies or those with unrealistic comparators, invalidated post-hoc identified biomarkers). On account of these major uncertainties, even the European Medicines Agency (EMA) is already contemplating multi-stage, "adaptive" approvals, and national reimbursement institutions are increasingly working with outcome-oriented, conditional reimbursement. (As supplied by publisher). PMID- 23663908 TI - [Thinking from the end - Does the diagnosis "cancer" make a difference to patients and carers?]. AB - The diagnosis of cancer is often associated with pain, suffering and dying. Many of these aspects also apply to patients dying from non-malignant disease. Being confronted with a malignancy posts an existential threat for many patients that is linked with loss of control, challenge of autonomy and fear of the future. In contrast, patients with non-malignant disease do not realise the scope of their diagnosis and the potentially life-limiting nature of their disease. The prognosis of patients with chronic organ failure is often shorter than that of some patients with malignancies. Patients with malignant and non-malignant disease suffer from pain and many other symptoms. Tumour-oriented therapies, side effects and changes of the body image add to the suffering of cancer patients. Although consequences of the disease and the therapies are often not visible in patients with non-malignant disease, the increasing functional decline, psychosocial burden, lack of co-ordination of care, and information needs burden patients. Wishes at the end of life are similar in cancer and non-cancer patients. Access to palliative care is much easier for cancer patients than for non-cancer patients. PMID- 23663909 TI - ["Is it possible to do less?" The current state of the debate in Sweden]. AB - The question "Is it possible to do less?" and the claim "Less is more!" can be answered and construed in different ways. One possible interpretation, which is well established in the Swedish health system, is "Accomplishing more (of the things that are important) by doing less (of the things that are dispensable)". Essentially, this is the basis of prioritisation in Swedish health care. While the concept of prioritisation is very well established in Sweden, the discussion about prioritising in Germany has always been difficult. It is, from a Swedish perspective, unclear why, of all things, health care should be exempted from prioritisation which otherwise is a necessity concerning all aspects of human and societal life. Some conditions complicate prioritisation in German health care, including the system of private and statutory health insurance and economic incentives which do not reward procedures based on indications. It will be argued that the Swedish health care system is more effective than the German not at least because of the system of prioritisation that allows for providing more necessary and essential health care instead of offering unnecessary and dubious procedures, thereby also improving patient outcome. (As supplied by publisher). PMID- 23663910 TI - [Less can be more - drug therapy in the elderly]. AB - A significant proportion of the elderly population is affected by multimorbidity and polypharmacy. Drug safety in this population is characterised by age associated changes in pharmacokinetics and pharmacodynamics, an increased risk for drug-drug interactions, an unmanageable situation of side effects and co morbidities, and a questionable adherence to complex therapies. Moreover, elderly multimorbid patients are usually not enrolled in clinical trials, and therefore the evidence for efficacy and safety of drugs is sparse. Many practice guidelines do not consider multimorbidity and age-associated changes in physical function, cognition and reduced life expectancy. Most published approaches to reducing polypharmacy such as algorithms and checklists have not yet been validated prospectively in randomised, controlled trials. However, some studies have shown the feasibility of stopping medications, in some cases accompanied by remarkable improvements of quality of life. (As supplied by publisher). PMID- 23663911 TI - [One does not need to have it all. Evidence in routine medical practice]. PMID- 23663912 TI - [Would you mind a little bit less? Methodological and ethical challenges posed by the reduction of overtreatment]. AB - The present paper outlines two central challenges that should be taken into account when making a concerted effort to reduce excessive medical care (overdiagnosis and overtreatment): first, the inevitability of value judgements in the risk-benefit assessment of medical treatment measures in conjunction with the need to go beyond the individual doctor-patient relationship and make these value judgements while, at least in part, assuming the role of acting deputy; and second, the need for a sufficient level of competence and trust in evidence-based medicine on the part of both physicians and patients. The paper will explain how one can say in a methodologically reasonable and ethically acceptable manner that a certain medical measure - in the context of the regular care setting - will objectively cause a "net harm" to the patient. Relevant institutions in the German healthcare system will be described that are currently conducting risk benefit assessments (by different means and with different purposes). Taking the known entity of clinical guidelines as an example, the paper will demonstrate that the subjects of overdiagnosis and overtreatment as well as shortage of medical care can be more explicitly communicated by employing certain additional methodological tools. Finally, some central implementation barriers to a successful application of "Less is more!" will be presented and critically discussed. (As supplied by publisher). PMID- 23663913 TI - [On the attractiveness, implementation and evaluation of guidelines]. AB - Principles and conditions for guideline implementation and evaluation were the subject of a workshop organised by the German Association of the Scientific Medical Societies (AWMF) and the German Network for Health Services Research (DNVF). This report reflects contents and discussions and suggests possible future activities. The workshop highlighted the need for conceptual frameworks, theory-driven research and concerted strategies. The reinforcement of strategic partnerships within the health care organisations is an indispensable prerequisite for successful guideline implementation and evaluation.(As supplied by author). PMID- 23663914 TI - [Quality Manager 2.0 in hospitals: A practical guidance for executive managers, medical directors, senior consultants, nurse managers and practicing quality managers]. AB - Aiming at the development of perspectives and recommendations for modern quality management in health services the GQMG conducted a study on the role and self conception of quality managers in hospitals. It seems obvious that the effectiveness of quality management clearly depends on the executive board's skilful installation of quality management, their support of quality managers and, particularly in larger-sized institutions on the coordination of staff units and cross-sectional functions.(As supplied by author). PMID- 23663915 TI - [Project report: Development of log books for the medical practical year at the Charite]. PMID- 23663916 TI - What else can brains do? AB - The approach Clark labels "action-oriented predictive processing" treats all cognition as part of a system of on-line control. This ignores other important aspects of animal, human, and robot intelligence. He contrasts it with an alleged "mainstream" approach that also ignores the depth and variety of AI/Robotic research. I don't think the theory presented is worth taking seriously as a complete model, even if there is much that it explains. PMID- 23663917 TI - Randomized trial of the effect of tailored versus standard use of the combined oral contraceptive pill on continuation rates at 1 year. AB - BACKGROUND: There is growing interest from women and clinicians in extended or tailored use of the combined oral contraceptive (COC) pill. Potential advantages include less bleeding, greater contraceptive efficacy and user satisfaction. We examined the effect of a tailored pill regimen, compared with the standard regimen, on continuation and satisfaction rates at 1 year and associated bleeding patterns. STUDY DESIGN: This was a randomized controlled trial with 503 women aged 18-45 years. Women were randomized to either the standard regimen (21 daily pills followed by a 7-day pill-free interval) or tailored regimen (daily pills until three consecutive days bleeding triggers a 3-day pill-free interval) of Microgynon 30(r) (ethinyl oestradiol 30 mcg, levonorgestrel 150 mcg). Primary outcome was COC continuation at 12 months; secondary outcomes included satisfaction with pill regimen regarding contraception and bleeding pattern. Daily electronic diaries were used to record women's pill use, switching to other contraceptive methods, menstrual bleeding patterns and satisfaction levels. RESULTS: Eighty-three percent of women were already taking the COC at recruitment, 13% were restarting the COC and 4% were first time COC users. Seventy-one percent of all women were followed up at 12 months. Continuation rates at 1 year were 82% in the tailored arm versus 80% in the standard arm [odds ratio (OR)=1.13; 95% confidence interval (CI)=0.67-1.91]. Satisfaction with contraceptive regimen was 86% (tailored) versus 94% (standard) (OR=0.37; 95% CI=0.17-0.79), and satisfaction with bleeding pattern was 79% versus 87%, respectively (OR=0.53; 95% CI=0.30-0.93). Median number of bleeding days per month was 2.4 (tailored) and 4.9 (standard). Incidence, duration and intensity of bleeding episodes were significantly lower in the tailored arm. CONCLUSIONS: In women familiar with standard use of the COC, switching to tailored COC use or continuing with standard use were both associated with high COC continuation rates and high satisfaction with contraceptive regimen and bleeding pattern. While significant differences tended to favor the standard group, tailored COC use was associated with significantly less bleeding, suited some women very well and can provide a suitable alternative to standard use. PMID- 23663918 TI - Pregnancy: not a disease but still a health risk. PMID- 23663919 TI - Hepatitis B virus and hepatitis C virus co-infection: a therapeutic challenge. PMID- 23663920 TI - Severe cholestasis due to disseminated histoplasmosis under adalimumab-containing immunosuppressive therapy. PMID- 23663922 TI - Nordic couples' decision-making processes during assisted reproduction treatments. AB - OBJECTIVE: To study couples' perceptions of their decision-making process during the first three years of infertility treatments. STUDY DESIGN: This study is a part of a larger project studying the decision-making processes of 22 infertile heterosexual couples, recruited from fertility clinics in all five Nordic countries, over a three year period. A descriptive qualitative method was used. MAIN OUTCOME MEASURES: Process of decision-making during assisted reproduction treatments. RESULTS: Seventeen couples had succeeded in becoming parents after approximately three years. Our study suggests that the decision-making process during fertility treatments has three phases: (i) recognizing the decisions to be made, with subcategories; the driving force, mutual project, (ii) gathering knowledge and experience about the options, with subcategories; trust, patient competence, personalized support, and (iii) adapting decisions to possible options, with subcategories; strategic planning, adaption. The core category was "maintaining control in a situation of uncertainty." CONCLUSIONS: Two parallel processes affect couples' decision-making process, one within themselves and their relationship, and the other in their contact with the fertility clinic. Couples struggle to make decisions, trusting clinic personnel for guidance, knowledge, and understanding. Nevertheless, couples expressed disappointment with the clinics' reactions to their requests for shared decision-making. PMID- 23663923 TI - Religiosity and sexuality: counseling provided by Brazilian Protestant pastors. AB - OBJECTIVE: This qualitative study aimed to explore counseling about sexuality and contraception provided to the church community. METHODS: The oral history method was performed. Data were collected through in-depth face-to-face interviews with 18 Brazilian Protestant pastors and were examined using thematic analysis. RESULTS: Four themes were identified from the data: (a) Counseling based on Christian doctrine provided to preserve the integrity of the family; (b) Adequate performance of gender roles is essential to preserve harmony in the family; (c) Recommendations for sex with pleasure and the free use of contraceptives in marriage; (d) Distinct positions regarding abortion: clearly forbidden versus permissible when authorized by law. CONCLUSIONS: The pastors provide traditional counselings regarding sexuality and the use of contraceptives is stimulated within the marriage. The main aim of the counselings given to the church community is the preservation of family integrity. The exploration of patients religious backgrounds and its consideration is essential in the planning and implementation of a culturally meaningful and non-conflicting healthcare. PMID- 23663924 TI - Dynamics of contraceptive use in India: apprehension versus future intention among non-users and traditional method users. AB - OBJECTIVE: This study examines the reasons for not using any method of contraception as well as reasons for not using modern methods of contraception, and factors associated with the future intention to use different types of contraceptives in India and its selected states, namely Uttar Pradesh, Assam and West Bengal. METHODS: Data from the third wave of District Level Household and Facility Survey, 2007-08 were used. Bivariate as well as logistic regression analyses were performed to fulfill the study objective. RESULTS: Postpartum amenorrhea and breastfeeding practices were reported as the foremost causes for not using any method of contraception. Opposition to use, health concerns and fear of side effects were reported to be major hurdles in the way of using modern methods of contraception. Results from logistic regression suggest considerable variation in explaining the factors associated with future intention to use contraceptives. CONCLUSION: Promotion of health education addressing the advantages of contraceptive methods and eliminating apprehension about the use of these methods through effective communication by community level workers is the need of the hour. PMID- 23663925 TI - Gynecological patients learning to perform the pelvic examination: a win-win concept. AB - OBJECTIVE: This study explored gynecological patient perceptions of previous pelvic examinations (PE), a learning session about PE prior to a scheduled PE consultation, and the impact of the learning session on the PE during the consultation. STUDY DESIGN: Twelve informants were purposefully sampled from women with scheduled gynecologist appointments at a Swedish University Hospital. The learning session preceded the consultation and provided information on female genital anatomy and the PE, and the informant performed a PE on a mannequin. Individual qualitative interviews followed the consultation. The interviews were transcribed verbatim and analyzed using a constant comparative analysis to acquire a deeper understanding of the women's experiences of the learning session and the subsequent PE. RESULTS: Three categories were identified in the analysis: 'Harmonizing the bad with the good' category, which primarily concerned the informants' previous experiences of the PE. 'Gaining self-confidence through knowledge', which depicted the informants' experiences of the learning session. 'Mental preparation enables bodily recapture', which was the summarizing category of informant experiences of the scheduled PE. The core category, 'active involvement triggers empowerment', was created from the categories, and constitutes the core of the empirical material. CONCLUSION: The informants' active participation during the learning session increased their knowledge, generated self-confidence, triggered an empowering process, and promoted interaction with the examiner during their subsequent PE. PMID- 23663926 TI - Pregnant women's perspectives on decision-making when a fetal malformation is detected by ultrasound examination. AB - OBJECTIVES: The aims of the study were to explore factors influencing the decision to continue or terminate pregnancy due to detection of fetal malformation following ultrasound examination, to elucidate the need for more information or other routines to facilitate the decision-making process and to assess satisfaction with the decision made. DESIGN: Descriptive study. SETTING: Four fetal care referral centres in Stockholm, Sweden. POPULATION: Pregnant women with a detected fetal malformation. METHODS: Data was collected by questionnaires. 134 women participated, 99 completing the questionnaire. Descriptive statistical analysis was performed. RESULTS: Both women who continued and those who terminated pregnancy based their decision on the severity of the malformation. Other reasons for terminating the pregnancy were aspects including socioeconomic considerations. None stated religious factors. The doctor at the fetal care unit also had an influence on the decision-making. The timeframe receiving information was regarded as long enough in duration but not the number of occasions. In both groups the women made the decision by themselves or together with their partners. The majority experienced that they had made the right decision. Women who terminated their pregnancy had a significant higher rate (51.2%) (p < or = 0.004) of previous abortions than those in the continuing group (23.2%). CONCLUSION: The decision to continue or terminate the pregnancy was to a great extent based on the severity of the malformation. Religious aspects did not seem to influence the decision. Many women expressed a need for additional occasion of information. The vast majority of women were satisfied with their decision. PMID- 23663927 TI - Cardiovascular toxicity evaluation of silica nanoparticles in endothelial cells and zebrafish model. AB - Environmental exposure to nanomaterials is inevitable as nanomaterials become part of our daily life, and as a result, nanotoxicity research is gaining attention. However, most investigators focus on the evaluation of overall toxicity instead of a certain organism system. In this regard, the evaluation of cardiovascular effects of silica nanoparticles was preformed in vitro and in vivo. It's worth noting that silica nanoparticles induced cytotoxicity as well as oxidative stress and apoptosis. ROS and apoptosis were considered as major factor to endothelial cells dysfunction, involved in several molecular mechanisms of cardiovascular diseases. In vivo study, mortality, malformation, heart rate and whole-embryo cellular death were measured in zebrafish embryos. Results showed that silica nanoparticles induced pericardia toxicity and caused bradycardia. We also examined the expression of cardiovascular-related proteins in embryos by western blot analysis. Silica nanoparticles inhibited the expression of p-VEGFR2 and p-ERK1/2 as well as the downregulation of MEF2C and NKX2.5, revealed that silica nanoparticles could inhibit the angiogenesis and disturb the heart formation and development. In summary, our results suggest that exposure to silica nanoparticles is a possible risk factor to cardiovascular system. PMID- 23663928 TI - The effect of decellularization of tracheal allografts on leukocyte infiltration and of recellularization on regulatory T cell recruitment. AB - Tracheal transplantation without immunosuppressive therapy has been accomplished with a tissue-engineering approach using decellularized biological scaffolds in combination with recipient progenitor cells. The mechanisms of immune response directed towards these tracheal allografts have not been fully determined. In this study, we evaluated the immunogenicity of these grafts at the protein level, and functionally, in vitro and in vivo in a large animal model. Long-segment circumferential tracheal allografts were decellularized using two different protocols and recellularized using recipient mesenchymal stromal cells (MSC) and tracheal epithelial progenitor cells (TEC). Residual MHCI and MHCII immunostaining was found surrounding the submucosal glands despite cyclical decellularization. In an in vitro lymphocyte proliferation assay, CD4+ T cells continued to proliferate on decellularized pieces and this proliferation was inhibited by co-culture with autologous MSC. Allografts were heterotopically transplanted under a muscle flap in the neck of the recipients and decellularization was found to delay leukocyte infiltration but resulted in eventual cartilage degradation. Recellularization prevented this infiltration up to 3 weeks post-transplantation and allowed for preservation of the cartilage. The immune cells found within these grafts included a significant number of CD4+CD25+Foxp3+ regulatory T cells. Furthermore, gene expression of anti inflammatory cytokines, such as IL-10 and TGF-beta1, involved in proliferation, differentiation and function of regulatory T cells was found in these grafts. These results indicate that the immunological modification induced by recellularized tracheal scaffolds is an active process involving the recruitment of immunosuppressive cells, rather than simply the removal of donor-derived antigenic components. PMID- 23663929 TI - Isolation and bioinformatic analysis of seven genes encoding potato apyrase. Bacterial overexpresssion, refolding and initial kinetic studies on some recombinant potato apyrases. AB - Here we have isolated seven apyrase encoding cDNA sequences (StAPY4-StAPY10) from the potato variety Saturna tuber cDNA library by affecting necessary modifications in the screening protocol. The cDNA sequences were identified with a pair of primers complementary to the most conserved sequences identified in potato variety Desiree apyrase genes. Our data strongly suggest the multigenic nature of potato apyrase. All deduced amino acid sequences contain a putative signal sequence, one transmembrane region at the amino terminus and five apyrase conserved regions (ACRs) (except StAPY6). Phylogenetic analysis revealed that encoded proteins shared high level of DNA sequence identity among themselves, representing a family of proteins markedly distinct from other eukaryotic as well as prokaryotic apyrases. Two cDNA sequences (StAPY4 and StAPY6) were overexpressed in bacteria and recombinant proteins were found accumulated in inclusion bodies, even thought they were fused with thioredoxin-tag. Additionally, we present the first successful in vitro attempt at reactivation and purification of recombinant potato apyrase StAPY6. The ratio of ATPase/ADPase hydrolysis of recombinant StAPY6 was determined as 1.5:1. Unlike other apyrases the enzyme lacked ACR5 and was endowed with lower molecular weight, high specificity for purine nucleotides and very low specificity for pyrimidine, suggesting that StAPY6 is a potato apyrase, not described so far. PMID- 23663930 TI - Potential sources of high value chemicals from leaves, stems and flowers of Miscanthus sinensis 'Goliath' and Miscanthus sacchariflorus. AB - Society demands chemicals from sustainable sources. Identification of commercially important chemicals in crops increases value in biorefineries and reduces reliance on petrochemicals. Miscanthus sinensis and Miscanthus sacchariflorus are high-yielding distinct plants, which are sources of high-value chemicals and bioethanol through fermentation. Cinnamates in leaves, stems and flowers were analysed by LC-ESI-MS(n). Free phenols were extracted and separated chromatographically. More than twenty hydroxycinnamates were identified by UV and LC-ESI-MS(n). Several cinnamate hexosides were detected in the M. sinensis flower and in M. sacchariflorus (leaf and stem). Hydroxybenzoic acids and their hexosides were observed in leaf and stem of M. sacchariflorus. Higher concentrations of 3-feruloylquinic acid were observed in M. sacchariflorus stem, suggesting a role in cell-wall biosynthesis. This technique can be used to screen plants in a mapping family to identify genotypes/species with high concentrations of phenols. Plants with low concentrations of antimicrobial phenols may be good feedstocks for fermentation. PMID- 23663931 TI - Introduction: Invertebrate neuropeptides XIII. PMID- 23663932 TI - Contribution of cardiopulmonary exercise testing to the identification of latent systolic dysfunction in chronic aortic regurgitation. AB - Chronic aortic regurgitation (AR) is a valvulopathy of slow and insidious evolution, and patients may remain asymptomatic for a long period of time. Exercise-induced systolic dysfunction occurs during the natural history of chronic AR and is related to changes in both preload and afterload. We describe the case of a 58-year-old woman with a diagnosis of chronic AR who reported progressive dyspnea of six years' duration. A cardiopulmonary exercise test to assess functional capacity showed flattening of both oxygen uptake and oxygen pulse curves, suggesting latent systolic dysfunction related to chronic AR, which was later confirmed by stress Doppler echocardiogram with dynamic physical exercise. PMID- 23663933 TI - Are gene loops the cause of transcriptional noise? AB - Expression levels of the same mRNA or protein vary significantly among the cells of an otherwise identical population. Such biological noise has great functional implications and is largely due to transcriptional bursting, the episodic production of mRNAs in short, intense bursts, interspersed by periods of transcriptional inactivity. Bursting has been demonstrated in a wide range of pro and eukaryotic species, attesting to its universal importance. However, the mechanistic origins of bursting remain elusive. A different type of phenomenon, which has also been suggested to be widespread, is the physical interaction between the promoter and 3' end of a gene. Several functional roles have been proposed for such gene loops, including the facilitation of transcriptional reinitiation. Here, I discuss the most recent findings related to these subjects and argue that gene loops are a likely cause of transcriptional bursting and, thus, biological noise. PMID- 23663934 TI - Bipolar disorder: at the extremes. PMID- 23663935 TI - Assessing the end of the UK's aid to South Africa. PMID- 23663936 TI - Compassionate release in the USA. PMID- 23663937 TI - Diagnosis of bipolar disorder: who is in a mixed state? PMID- 23663938 TI - Fast-track hip and knee arthroplasty. PMID- 23663940 TI - Nick Craddock: a world leader in psychiatric genetics. PMID- 23663941 TI - Statin and exercise prescription. PMID- 23663942 TI - Statin and exercise prescription. PMID- 23663943 TI - Statin and exercise prescription - Authors' reply. PMID- 23663944 TI - Statin and exercise prescription. PMID- 23663945 TI - Prescription of physical activity - Author's reply. PMID- 23663946 TI - Prescription of physical activity. PMID- 23663948 TI - World Oncology Forum and commercial sponsorship. PMID- 23663949 TI - Anaesthesia-related mortality in sub-Saharan Africa. PMID- 23663950 TI - Economic sanctions strangle Iranians' health, not just drug supply. PMID- 23663951 TI - Genetics of bipolar disorder. AB - Studies of families and twins show the importance of genetic factors affecting susceptibility to bipolar disorder and suggest substantial genetic and phenotypic complexity. Robust and replicable genome-wide significant associations have recently been reported in genome-wide association studies at several common polymorphisms, including variants within the genes CACNA1C, ODZ4, and NCAN. Strong evidence exists for a polygenic contribution to risk (ie, many risk alleles of small effect). A notable finding is the overlap of susceptibility between bipolar disorder and schizophrenia for several individual risk alleles and for the polygenic risk. By contrast, genomic structural variation seems to play a smaller part in bipolar disorder than it does in schizophrenia. Together, these genetic findings suggest directions for future studies to delineate the aetiology and pathogenesis of bipolar disorder, indicate the need to re-evaluate our diagnostic classifications, and might eventually pave the way for major improvements in clinical management. PMID- 23663952 TI - Bipolar disorder diagnosis: challenges and future directions. AB - Bipolar disorder refers to a group of affective disorders, which together are characterised by depressive and manic or hypomanic episodes. These disorders include: bipolar disorder type I (depressive and manic episodes: this disorder can be diagnosed on the basis of one manic episode); bipolar disorder type II (depressive and hypomanic episodes); cyclothymic disorder (hypomanic and depressive symptoms that do not meet criteria for depressive episodes); and bipolar disorder not otherwise specified (depressive and hypomanic-like symptoms that do not meet the diagnostic criteria for any of the aforementioned disorders). Bipolar disorder type II is especially difficult to diagnose accurately because of the difficulty in differentiation of this disorder from recurrent unipolar depression (recurrent depressive episodes) in depressed patients. The identification of objective biomarkers that represent pathophysiologic processes that differ between bipolar disorder and unipolar depression can both inform bipolar disorder diagnosis and provide biological targets for the development of new and personalised treatments. Neuroimaging studies could help the identification of biomarkers that differentiate bipolar disorder from unipolar depression, but the problem in detection of a clear boundary between these disorders suggests that they might be better represented as a continuum of affective disorders. Innovative combinations of neuroimaging and pattern recognition approaches can identify individual patterns of neural structure and function that accurately ascertain where a patient might lie on a behavioural scale. Ultimately, an integrative approach, with several biological measurements using different scales, could yield patterns of biomarkers (biosignatures) to help identify biological targets for personalised and new treatments for all affective disorders. PMID- 23663954 TI - Transmission of Aeromonas hydrophila by leeches. PMID- 23663955 TI - Tackling inequalities in obesity: a protocol for a systematic review of the effectiveness of public health interventions at reducing socioeconomic inequalities in obesity among adults. AB - BACKGROUND: Socioeconomic inequalities in obesity and associated risk factors for obesity are widening throughout developed countries worldwide. Tackling obesity is high on the public health agenda both in the United Kingdom and internationally. However, what works in terms of interventions that are able to reduce inequalities in obesity is lacking. METHODS/DESIGN: The review will examine public health interventions at the individual, community and societal level that might reduce inequalities in obesity among adults aged 18 years and over, in any setting and in any country. The following electronic databases will be searched: MEDLINE, EMBASE, CINAHL, PsycINFO, Social Science Citation Index, ASSIA, IBSS, Sociological Abstracts, and the NHS Economic Evaluation Database. Database searches will be supplemented with website and gray literature searches. No studies will be excluded based on language, country or publication date. Randomized and non-randomized controlled trials, prospective and retrospective cohort studies (with/without control groups) and prospective repeat cross sectional studies (with/without control groups) that have a primary outcome that is a proxy for body fatness and have examined differential effects with regard to socioeconomic status (education, income, occupation, social class, deprivation, poverty) or where the intervention has been targeted specifically at disadvantaged groups or deprived areas will be included. Study inclusion, data extraction and quality appraisal will be conducted by two reviewers. Meta analysis and narrative synthesis will be conducted. The main analysis will examine the effects of 1) individual, 2) community and 3) societal level public health interventions on socioeconomic inequalities in adult obesity. Interventions will be characterized by their level of action and their approach to tackling inequalities. Contextual information on how such public health interventions are organized, implemented and delivered will also be examined. DISCUSSION: The review will provide evidence, and reveal any gaps in the evidence base, of public health strategies which reduce and prevent inequalities in the prevalence of obesity in adults and provide information on the organization, implementation and delivery of such interventions. TRIAL REGISTRATION: PROSPERO registration number: CRD42013003612. PMID- 23663956 TI - Esophageal capsule endoscopy and Barrett's esophagus: where are we in 2013? PMID- 23663953 TI - Treatment of bipolar disorder. AB - We review recent developments in the acute and long-term treatment of bipolar disorder and identify promising future routes to therapeutic innovation. Overall, advances in drug treatment remain quite modest. Antipsychotic drugs are effective in the acute treatment of mania; their efficacy in the treatment of depression is variable with the clearest evidence for quetiapine. Despite their widespread use, considerable uncertainty and controversy remains about the use of antidepressant drugs in the management of depressive episodes. Lithium has the strongest evidence for long-term relapse prevention; the evidence for anticonvulsants such as divalproex and lamotrigine is less robust and there is much uncertainty about the longer term benefits of antipsychotics. Substantial progress has been made in the development and assessment of adjunctive psychosocial interventions. Long term maintenance and possibly acute stabilisation of depression can be enhanced by the combination of psychosocial treatments with drugs. The development of future treatments should consider both the neurobiological and psychosocial mechanisms underlying the disorder. We should continue to repurpose treatments and to recognise the role of serendipity. We should also investigate optimum combinations of pharmacological and psychotherapeutic treatments at different stages of the illness. Clarification of the mechanisms by which different treatments affect sleep and circadian rhythms and their relation with daily mood fluctuations is likely to help with the treatment selection for individual patients. To be economically viable, existing psychotherapy protocols need to be made briefer and more efficient for improved scalability and sustainability in widespread implementation. PMID- 23663957 TI - Home monitoring program reduces interstage mortality after the modified Norwood procedure. AB - BACKGROUND: From 2002 to 2005, the interstage mortality after a modified Norwood procedure was 7% in our program. An interstage home monitoring program (HMP) was established to identify Norwood procedure patients at increased risk of decompensation and to reduce interstage mortality. METHODS: Results of the first 5 years of the Norwood HMP were reviewed retrospectively. Interstage was defined as the time between Norwood hospital discharge and admission for second stage surgical palliation. In the HMP, families documented oxygen saturation, heart rate, weight, and feedings daily. Nurse practitioners called each family at least weekly, and when issues arose, action plans were determined based on symptom severity. RESULTS: Between October 2005 and October 2010 there were 46 Norwood procedure patients who survived to hospital discharge. All were enrolled in the HMP. Forty-five patients had a Norwood procedure with right ventricle to pulmonary artery conduit, and 1 patient had a modified Blalock-Taussig shunt. Interstage survival was 100%. Nineteen patients (41%) were admitted interstage; 5 patients were admitted twice, 1 patient was admitted 4 times. Seventeen patients (37%) required interstage interventions. Eight patients (17%) required major interventions: conduit stenting, aortic arch balloon angioplasty, emergent shunt, or early Glenn surgery. Minor interventions included supplemental oxygen, blood transfusion, intravenous hydration, diuresis, anti-arrhythmic therapy, or feeding adjustments. CONCLUSIONS: In the first 5 years of the HMP, all infants discharged after a modified Norwood procedure survived the interstage period. The HMP altered clinical management in 37% of patients. Home monitoring of oxygen saturation, heart rate, weight, and feedings, along with comprehensive care coordination, allowed timely interventions and reduced interstage mortality from 7% to 0%. PMID- 23663958 TI - Early treatment of aortic stenosis will prevent poor outcomes and save thousands of lives. PMID- 23663959 TI - Recycling and reuse of waste from electricity distribution networks as reinforcement agents in polymeric composites. AB - Of the waste generated from electricity distribution networks, wooden posts treated with chromated copper arsenate (CCA) and ceramic insulators make up the majority of the materials for which no effective recycling scheme has been developed. This study aims to recycle and reuse this waste as reinforcement elements in polymer composites and hybrid composites, promoting an ecologically and economically viable alternative for the disposal of this waste. The CCA wooden posts were cut, crushed and recycled via acid leaching using 0.2 and 0.4N H2SO4 in triplicate at 70 degrees C and then washed and dried. The ceramic insulators were fragmented in a hydraulic press and separated by particle size using a vibrating sieve. The composites were mixed in a twin-screw extruder and injected into the test specimens, which were subjected to physical, mechanical, thermal and morphological characterization. The results indicate that the acid treatment most effective for removing heavy metals in the wood utilizes 0.4NH2SO4. However, the composites made from wood treated with 0.2NH2SO4 exhibited the highest mechanical properties of the composites, whereas the use of a ceramic insulator produces composites with better thermal stability and impact strength. This study is part of the research and development project of ANEEL (Agencia Nacional de Energia Eletrica) and funded by CPFL (Companhia Paulista de Forca e Luz). PMID- 23663960 TI - Diversity of bacterial isolates during full scale rotary drum composting. AB - Bacterial diversity of full scale rotary drum composter from biodegradable organic waste samples were analyzed through two different approaches, i.e., Culture dependent and independent techniques. Culture-dependent enumerations for indigenous population of bacterial isolates mainly total heterotrophic bacteria (Bacillus species, Pseudomonas species and Enterobacter species), Fecal Coliforms, Fecal Streptococci, Escherichia coli, Salmonella species and Shigella species showed reduction during the composting period. On the other hand, Culture independent method using PCR amplification of specific 16S rRNA sequences identified the presence of Acinetobacter species, Actinobacteria species, Bacillus species, Clostridium species, Hydrogenophaga species, Butyrivibrio species, Pedobacter species, Empedobactor species and Flavobacterium species by sequences clustering in the phylogenetic tree. Furthermore, correlating physico chemical analysis of samples with bacterial diversity revealed the bacterial communities have undergone changes, possibly linked to the variations in temperature and availability of new metabolic substrates while decomposing organics at different stages of composting. PMID- 23663961 TI - Macromolecular assemblies. PMID- 23663962 TI - Exercise-induced hippocampal anti-inflammatory response in aged rats. AB - Aging is often accompanied by cognitive decline, memory impairment and an increased susceptibility to neurodegenerative disorders. Most of these age related alterations have been associated with deleterious processes such as changes in the expression of inflammatory cytokines. Indeed, higher levels of pro inflammatory cytokines and lower levels of anti-inflammatory cytokines are found in the aged brain. This perturbation in pro- and anti-inflammatory balance can represent one of the mechanisms that contribute to age-associated neuronal dysfunction and brain vulnerability. We conducted an experimental study to investigate whether an aerobic exercise program could promote changes in inflammatory response in the brains of aged rats. To do so, we evaluated the levels of tumor necrosis factor alpha (TNFalpha), interleukin 1 beta (IL1beta), interleukin 6 (IL6) and interleukin 10 (IL10) in the hippocampal formation of 18 month old rats that underwent treadmill training over 10 consecutive days. Quantitative immunoassay analyses showed that the physical exercise increased anti-inflammatory cytokine levels IL10 in the hippocampal formation of aged rats, when compared to the control group. The hippocampal levels of pro-inflammatory cytokines IL1beta, IL6 and TNFalpha were not statistically different between the groups. However, a significant reduction in IL1beta/IL10, IL6/IL10 and TNFalpha/IL10 ratio was observed in the exercised group in relation to the control group. These findings indicate a favorable effect of physical exercise in the balance between hippocampal pro- and anti-inflammatory during aging, as well as reinforce the potential therapeutic of exercise in reducing the risk of neuroinflammation-linked disorders. PMID- 23663964 TI - Structural, evolutionary, and assembly principles of protein oligomerization. AB - In the protein universe, 30-50% of proteins self-assemble to form symmetrical complexes consisting of multiple copies of themselves, called homomers. The prevalence of homomers motivates us to review many of their properties. In Section 1, we describe the methods and challenges associated with quaternary structure inference-these methods are indeed at the basis of any analysis on homomers. In Section 2, we describe the morphological properties of homomers, as well as the database 3DComplex, which provides a taxonomy for both homomeric and heteromeric protein complexes. In Section 3, we review interface properties of homomeric complexes. In Section 4, we then present recent findings on the evolution of homomer interfaces, which we link in Section 5 to the evolution of homomers as entire entities. In Section 6, we discuss mechanisms involved in their assembly and how these mechanisms can be linked to evolution. PMID- 23663965 TI - Physicochemical principles of protein aggregation. AB - This chapter provides a theoretical framework on the quantitative description of protein aggregation. The reader is provided with an overview of the fundamental theory of linear and helical polymers, as well as an introduction on the parameters governing evolution of aggregates over time. The models presented for the interpretation of the protein aggregation process take into account the contributions of different physicochemical parameters such as charge, hydrophobicity, and secondary structure propensity. Finally, we discuss our current understanding of how prediction of aggregation rates and identification of aggregation-prone protein regions are predicted from the information contained in the primary amino acid sequence. PMID- 23663963 TI - Evolutionary, physicochemical, and functional mechanisms of protein homooligomerization. AB - Protein homooligomers afford several important benefits for the cell; they mediate and regulate gene expression, activity of many enzymes, ion channels, receptors, and cell-cell adhesion processes. The evolutionary and physical mechanisms of oligomer formation are very diverse and are not well understood. Certain homooligomeric states may be conserved within protein subfamilies and between different subfamilies, therefore providing the specificity to particular substrates while minimizing interactions with unwanted partners. In addition, transitions between different oligomeric states may regulate protein activity and support the switch between different pathways. In this chapter, we summarize the biological importance of homooligomeric assemblies, physicochemical properties of their interfaces, experimental methods for their identification, their evolution, and role in human diseases. PMID- 23663966 TI - Structural aspects of amyloid formation. AB - Amyloid fibrils are highly organized and generally insoluble protein aggregates rich in beta secondary structure that can be formed by a wide range of sequences. They have been the object of intense scrutiny because their formation has been associated with a number of neurodegenerative disorders such as Alzheimer's, Parkinson's, Huntington's, and Creutzfeldt-Jakob's diseases. As a consequence of these efforts, much is now known about the properties of proteins that render them prone to form amyloid fibrils, about the mechanism of fibrillation, about the molecular structures of the fibrils, and about the forces that stabilize them. The relationship between the structural properties of the monomeric protein and those of the corresponding aggregate has been, in particular, intensively studied. In this chapter, we will provide an account of current knowledge on this intriguing relationship and provide the reader with key references about this topic. PMID- 23663967 TI - Quaternary structure predictions and structural communication features of GPCR dimers. AB - In spite of the ever-increasing evidence that G protein-coupled receptors (GPCRs) form dimers/oligomers, the biological role(s) and structural architecture of homologous and heterologous receptor aggregation are, however, far from being clarified. This chapter reviews the insights gained so far, at multiscale levels of resolution, on GPCR dimerization/oligomerization from in vitro experiments, structure predictions, and structure determinations. Focus is put on the achievement by the FiPD-based approach, which proved effective in predicting the supramolecular organization of membrane proteins including GPCRs. The combination of FiPD-based quaternary structure predictions with molecular simulations and analyses can be a valuable tool to infer the effects of dimerization on the structural communication features of a receptor dimer/oligomer bound to functionally different ligands. Ultimately, the integration between atomistic and mesoscopic simulations is expected to be a promising tool to unveil functioning mechanisms that involve intricate protein networks. PMID- 23663968 TI - Challenges in the development of heteromer-GPCR-based drugs. AB - G-protein-coupled receptors are targets of a variety of diseases. Drug screening has been classically performed assuming the occurrence of monomeric receptors. As more and more receptor heteromers are identified, the challenge is now to develop screening assays to select heteromer-specific drugs. These drugs may, for instance, be able to interact preferentially with prerather than with postsynaptic receptors. Heteromer-based drug discovery opens new perspectives in both Academic pursuits and for the Pharmaceutical industry. PMID- 23663969 TI - Di/oligomerization of GPCRs-mechanisms and functional significance. AB - Initially considered as strict and rigid monomers, GPCRs have shown an ever increasing flexibility in the number of intermolecular interactions they can participate in. Few rules can be applied to all members of this receptor superfamily, as the functional roles of resulting dimers or oligomers vary widely from biosynthesis, functional complementation, enhancement and control of signaling, positive and negative cooperativity, signal desensitization, membrane trafficking, and pharmacological diversity, among others. Receptor dimerization/oligomerization is a challenging phenomenon to disentangle even in vitro and thus in vivo evidence for its functional significance requires employment of a variety of cutting-edge techniques. Nevertheless, the evidence for GPCR di/oligomerization at the physiological level is mounting and has begun to shed light on an intricate network of interactions that challenge the previous knowledge on how this family of receptors function. Here, we summarize the evidence for GPCR di/oligomerization in living organisms with a particular focus of their involvement in health and disease. PMID- 23663972 TI - Social networking among voltage-activated potassium channels. AB - Voltage-activated potassium channels (Kv channels) are ubiquitously expressed proteins that subserve a wide range of cellular functions. From their birth in the endoplasmic reticulum, Kv channels assemble from multiple subunits in complex ways that determine where they live in the cell, their biophysical characteristics, and their role in enabling different kinds of cells to respond to specific environmental signals to generate appropriate functional responses. This chapter describes the types of protein-protein interactions among pore forming channel subunits and their auxiliary protein partners, as well as posttranslational protein modifications that occur in various cell types. This complex oligomerization of channel subunits establishes precise cell type specific Kv channel localization and function, which in turn drives a diverse range of cellular signal transduction mechanisms uniquely suited to the physiological contexts in which they are found. PMID- 23663970 TI - G protein-coupled receptor heterocomplexes in neuropsychiatric disorders. AB - G protein-coupled receptors (or GPCRs) represent the largest family of membrane proteins in the human genome and are the target of approximately half of all therapeutic drugs. GPCRs contain a conserved structure of seven transmembrane domains. Their amino terminus is located extracellularly, whereas the carboxy terminus extends into the cytoplasm. Accumulating evidence suggests that GPCRs exist and function as monomeric entities. Nevertheless, more recent findings indicate that GPCRs can also form dimers or even higher order oligomers. The differential pharmacological and signaling properties of GPCR heteromeric complexes hint that their physiological effects may be different as compared to those obtained in tissue cultures that express a particular GPCR. In this chapter, we review current data on the role of GPCR heteromerization in receptor signaling, as well as its potential implication in neuropsychiatric disorders such as schizophrenia, depression, and Parkinson's disease. PMID- 23663973 TI - Oligomerization of the mitochondrial protein VDAC1: from structure to function and cancer therapy. AB - The voltage-dependent anion channel (VDAC1), lying in the mitochondrial outer membrane (OMM), mediates the transport of ions and metabolites, thus controlling the cross talk between mitochondria and the rest of the cell. VDAC1 has also been recognized as a key protein in mitochondria-mediated apoptosis, is the proposed target for the pro- and antiapoptotic Bcl-2-family of proteins and is involved in apoptotic protein release from the mitochondria. Questions, however, remain as to if and how VDAC1 mediates the transfer of apoptotic proteins across the OMM. Our recent studies suggest that upon apoptosis induction, VDAC1 oligomerizes to form a new large pore allowing the passage of a folded protein, like cytochrome c. This review provides insight into the central role of VDAC1 in mammalian cell life and death and emphasizes VDAC1 function in apoptosis, focusing on VDAC1 oligomerization as a key step in mitochondria-mediated apoptosis and key structural features of VDAC1 that mediate its apoptotic function. PMID- 23663975 TI - Receptor heteromeric assembly-how it works and why it matters: the case of ionotropic glutamate receptors. AB - The composition and spatial arrangement of subunits in ion channels are essential for their function. Diverse stoichiometries are possible in a multitude of channels. These depend upon cell type-specific subunit expression, which can be tuned in a developmentally regulated manner and in response to activity, on subunit stability in the endoplasmic reticulum, intersubunit affinities, and potentially subunit diffusion within the ER membrane. In concert, these parameters shape channel biogenesis and ultimately tune cellular response properties. The complexity of this assembly process is particularly well illustrated by the ionotropic glutamate receptors, the main mediators of excitatory neurotransmission. These tetrameric cation channels predominantly assemble into heteromers, which is "obligatory" for some iGluR subfamilies but "preferential" for others. Here, we discuss recent insights into the rules underlying these two pathways, the role of individual domains based on an ever increasing list of crystal structures, and how these assembly parameters tune assembly across diverse receptor oligomers. PMID- 23663974 TI - Consequences of dimerization of the voltage-gated proton channel. AB - The human voltage-gated proton channel, hHV1, appears to exist mainly as a dimer. Teleologically, this is puzzling because each protomer retains the main properties that characterize this protein: proton conduction that is regulated by conformational (channel opening and closing) changes that occur in response to both voltage and pH. The HV1 dimer is mainly linked by C-terminal coiled-coil interactions. Several types of mutations produce monomeric constructs that open approximately five times faster than the wild-type dimeric channel but with weaker voltage dependence. Intriguingly, the quintessential function of the HV1 dimer, opening to allow H(+) conduction, occurs cooperatively. Both protomers undergo a conformational change, but both must undergo this transition before either can conduct. The teleological purpose of dimerization may be to steepen the voltage dependence of channel opening, at least in phagocytes. In other cells, the purpose is not understood. Finally, several single-celled species have HV that are likely monomeric. PMID- 23663971 TI - Disease-specific heteromerization of G-protein-coupled receptors that target drugs of abuse. AB - Drugs of abuse such as morphine or marijuana exert their effects through the activation of G-protein-coupled receptors (GPCRs), the opioid and cannabinoid receptors, respectively. Moreover, interactions between either of these receptors have been shown to be involved in the rewarding effects of drugs of abuse. Recent advances in the field, using a variety of approaches, have demonstrated that many GPCRs, including opioid, cannabinoid, and dopamine receptors, can form associations between different receptor subtypes or with other GPCRs to form heteromeric complexes. The formation of these complexes, in turn, leads to the modulation of the properties of individual protomers. The development of tools that can selectively disrupt GPCR heteromers as well as monoclonal antibodies that can selectively block signaling by specific heteromer pairs has indicated that heteromers involving opioid, cannabinoid, or dopamine receptors may play a role in various disease states. In this review, we describe evidence for opioid, cannabinoid, and dopamine receptor heteromerization and the potential role of GPCR heteromers in pathophysiological conditions. PMID- 23663977 TI - Oligomerization of dynamin superfamily proteins in health and disease. AB - Proteins of the dynamin superfamily are mechanochemical GTPases, which mediate nucleotide-dependent membrane remodeling events. The founding member dynamin is recruited to the neck of clathrin-coated endocytic vesicles where it oligomerizes into helical filaments. Nucleotide-hydrolysis-induced conformational changes in the oligomer catalyze scission of the vesicle neck. Here, we review recent insights into structure, function, and oligomerization of dynamin superfamily proteins and their roles in human diseases. We describe in detail the molecular mechanisms how dynamin oligomerizes at membranes and introduce a model how oligomerization is linked to membrane fission. Finally, we discuss molecular mechanisms how mutations in dynamin could lead to the congenital diseases, Centronuclear Myopathy and Charcot-Marie Tooth disease. PMID- 23663976 TI - The structural basis for the allosteric regulation of ribonucleotide reductase. AB - Ribonucleotide reductases (RRs) catalyze a crucial step of de novo DNA synthesis by converting ribonucleoside diphosphates to deoxyribonucleoside diphosphates. Tight control of the dNTP pool is essential for cellular homeostasis. The activity of the enzyme is tightly regulated at the S-phase by allosteric regulation. Recent structural studies by our group and others provided the molecular basis for understanding how RR recognizes substrates, how it interacts with chemotherapeutic agents, and how it is regulated by its allosteric regulators ATP and dATP. This review discusses the molecular basis of allosteric regulation and substrate recognition of RR, and particularly the discovery that subunit oligomerization is an important prerequisite step in enzyme inhibition. PMID- 23663978 TI - Multimerization of the dnmt3a DNA methyltransferase and its functional implications. AB - The Dnmt3a DNA cytosine-C5 methyltransferase has been recently shown to exhibit a complex oligomerization and multimerization potential, the structural basis and functional implications of which will be the subject of this contribution. The enzyme forms a linear heterotetramer with Dnmt3L, in which the interaction of Dnmt3a and 3L stimulates the catalytic activity of Dnmt3a. Isolated Dnmt3a forms protein filaments that bind to several DNA molecules oriented in parallel, which plays an essential role in the location of the enzyme to heterochromatin. Dnmt3L disrupts Dnmt3a protein filaments and leads to a redistribution of the enzyme in cells toward euchromatin. Finally, Dnmt3a complexes and Dnmt3a/3L heterotetramers cooperatively multimerize on DNA forming protein-DNA filaments. This leads to a preference of the enzyme for periodic methylation of DNA and supports its heterochromatic localization. PMID- 23663979 TI - Oligomerization in endoplasmic reticulum stress signaling. AB - Oligomerization of protein complexes has been involved in various mechanisms that play a major role in endoplasmic reticulum (ER) functions. In particular, in response to the accumulation of misfolded proteins in the ER, an adaptive response is activated and named the unfolded protein response (UPR). To facilitate recovery of ER homeostasis, both the inositol-requiring enzyme-1 (IRE1) and the protein kinase RNA-like ER kinase, two transmembrane ER stress transducers, oligomerize and activate UPR-specific transcription factors to adjust the folding and productive capacity of the ER, to direct misfolded proteins to ER-associated degradation or autophagy. Recent advances in the molecular characterization of how ER protein sensors transduce signals to orchestrate the adaptive cellular response have greatly unlocked the development of tools to dissect their functions in health and disease. Here, we focus on the advances concerning oligomerization of ER stress transducers and, in particular IRE1, describe the oligomerization-dependent mechanisms for modulating UPR signals on and off. PMID- 23663980 TI - Toll-IL-1-receptor-containing adaptor molecule-1: a signaling adaptor linking innate immunity to adaptive immunity. AB - The innate immune system senses microbial infections using pattern-recognition receptors and signals to activate adaptive immunity. Type I transmembrane protein Toll-like receptors (TLRs) play important roles in antimicrobial immune responses. Upon the recognition of pathogen-associated molecular patterns, TLRs homo- or heterodimerize and recruit distinct adaptor molecules to the intracellular TIR domains. Toll-IL-1-receptor-containing adaptor molecule-1 (TICAM-1) is a signaling adaptor downstream of TLRs 3 and 4 that recognizes virus derived double-stranded RNA and lipopolysaccharide, respectively. TLR3 is expressed on the endosomal membrane in myeloid DCs, where TLR3-mediated signaling is initiated. Once TICAM-1 is activated, transcription factors, IRF-3, NF-kappaB, and AP-1, are activated, leading to production of IFN-beta and proinflammatory cytokines and maturation of dendritic cells, which are capable of activating NK cells and cytotoxic T cells. Hence, TICAM-1 signaling appears to link innate immunity to adaptive immunity. In this review, we summarize the current knowledge on TICAM-1 and discuss its role in virus infection and antitumor immunity. PMID- 23663981 TI - Assembly of gamma-tubulin ring complexes: implications for cell biology and disease. AB - Microtubules are among the main constituents of the cytoskeleton. They are assembled from dimers of alpha- and beta-tubulin. This assembly occurs preferentially at organizing centers such as the centrosomes, catalyzed by multiprotein complexes of gamma-tubulin. At the beginning of mitosis, the amount of gamma-tubulin complexes at the centrosomes increases sharply, supporting the sudden formation of numerous spindle microtubules. Recent studies on the structure of gamma-tubulin complex proteins have advanced our understanding of the assembly process of gamma-tubulin complexes, and have pointed toward putative mechanisms of microtubule nucleation. Moreover, the discovery of novel proteins associated with gamma-tubulin complexes has illustrated the possibilities of how gamma-tubulin might be recruited and regulated at specific sites of microtubule organization. This chapter highlights recent developments in the field and discusses the potential of the gamma-tubulin complex as a pharmacological target, to control proliferation of cells. PMID- 23663983 TI - Oligomerization of rab/effector complexes in the regulation of vesicle trafficking. AB - Rabs comprise the largest member of the Ras superfamily of small GTPases with over 60 proteins in mammals and 11 proteins in yeast. Like all small GTPases, Rabs oscillate between an inactive GDP-bound conformation and an active GTP-bound state that is tethered to lipid membranes via a C-terminal prenylation site on conserved cysteine residues. In their active state, Rabs regulate various aspects of membrane trafficking, including vesicle formation, transport, docking, and fusion. The critical element of biological activity is the recruitment of cytosolic effector proteins to specific endomembranes by active Rabs. The importance of Rabs in cellular processes is apparent from their links to genetic disorders, immunodeficiency, cancer, and pathogen invasion. During the last decade, numerous structures of complexes have shed light on the molecular basis for Rab/effector specificity and their topological organization on subcellular membranes. Here, I review the known structures of Rab/effector complexes and their modes of oligomerization. This is followed by a brief discussion on the thermodynamics of effector recruitment, which has not been documented sufficiently in previous reviews. A summary of diseases associated with Rab/effector trafficking pathways concludes this chapter. PMID- 23663984 TI - Preface. In cells. PMID- 23663982 TI - Chemokine oligomerization in cell signaling and migration. AB - Chemokines are small proteins best known for their role in controlling the migration of diverse cells, particularly leukocytes. Upon binding to their G protein-coupled receptors on the leukocytes, chemokines stimulate the signaling events that cause cytoskeletal rearrangements involved in cell movement, and migration of the cells along chemokine gradients. Depending on the cell type, chemokines also induce many other types of cellular responses including those related to defense mechanisms, cell proliferation, survival, and development. Historically, most research efforts have focused on the interaction of chemokines with their receptors, where monomeric forms of the ligands are the functionally relevant state. More recently, however, the importance of chemokine interactions with cell surface glycosaminoglycans has come to light, and in most cases appears to involve oligomeric chemokine structures. This review summarizes existing knowledge relating to the structure and function of chemokine oligomers, and emerging methodology for determining structures of complex chemokine assemblies in the future. PMID- 23663985 TI - Antibacterial, antidiarrhoeal, and cytotoxic activities of methanol extract and its fractions of Caesalpinia bonducella (L.) Roxb leaves. AB - BACKGROUND: Caesalpinia bonducella is an important medicinal plant for its traditional uses against different types of diseases. Therefore, the present study investigated the antimicrobial, antidiarrhoeal, and cytotoxic activities of the methanol extract and ethyl acetate, chloroform, and petroleum ether (pet. ether) fractions of C. bonducella leaves. METHODS: The antibacterial potentialities of methanol extract and its fractions of C. bonducella leaves were investigated by the disc diffusion method against four gram-positive and five gram-negative bacteria at 300, 500 and 800 MUg/disc. Kanamycin (30 MUg/disc) was used as the standard drug. Antidiarrhoeal activities of leaf extracts were evaluated at two doses (200 and 400 mg/kg) and compared with loperamide in a castor oil-induced diarrhoeal model in rat. The fractions were subjected to a brine shrimp lethality test to evaluate their cytotoxicity. RESULTS: The methanol extract and other three fractions exhibited better activities at higher concentrations. Amongst, the chloroform fraction showed maximum activity at all three concentrations (300, 500, and 800 MUg/disc) against almost all bacteria. S. aureus and P. aeruginosa showed better sensitivities to all extracts at all three concentrations excluding the pet. ether fraction. Bacillus megaterium and Klebsiella spp. were two bacteria amongst nine that showed lowest sensitivity to the extracts. Maximum zone of inhibition (25-mm) was obtained by the methanol extract at an 800 MUg/disc concentration against S. aureus. In the antidiarrhoeal test, all fractions exhibited dose-dependent actions, which were statistically significant (p < 0.05). Ethyl acetate fraction exerted maximum inhibition (51.11%) against defecation, whereas 57.75% inhibition was obtained for loperamide. Moderate cytotoxicity was found for the methanol extract and its three fractions compared with the standard drug vincristine sulfate in the brine shrimp bioassay. In the present study, the LC50 values of the methanol crude extract and ethyl acetate, chloroform, pet. ether fractions and vincristine sulfate were 223.87, 281.84, 112.2, 199.53, and 12.59 MUg/mL, respectively. Therefore, the ethyl acetate fraction showed maximum cytotoxicity, whereas minimum cytotoxicity was observed for the chloroform fraction. CONCLUSION: The present study revealed that the ethyl acetate fraction of the C. bonducella leaves has significant antidiarrhoeal properties. The methanol extract and other three fractions of the C. bonducella leaves possess potent antibacterial activities along with moderate cytotoxicities that may lead to new drug development. PMID- 23663986 TI - Psychosocial measures used to assess the effectiveness of school-based nutrition education programs: review and analysis of self-report instruments for children 8 to 12 years old. AB - OBJECTIVE: To identify the psychometric properties of evaluation instruments that measure mediators of dietary behaviors in school-aged children. DESIGN: Systematic search of scientific databases limited to 1999-2010. MAIN OUTCOME MEASURES: Psychometric properties related to development and testing of self report instruments for children 8-12 years old. ANALYSIS: Systematic search of 189 articles and review of 15 instruments (20 associated articles) meeting the inclusion criteria. Search terms used included children, school, nutrition, diet, nutrition education, and evaluation. RESULTS: Fourteen studies used a theoretical framework to guide the instrument's development. Knowledge and self-efficacy were the most commonly used psychosocial measures. Twelve instruments focused on specific nutrition-related behaviors. Eight instruments included over 40 items and used age-appropriate response formats. Acceptable reliability properties were most commonly reported for attitude and self-efficacy measures. Although most of the instruments were reviewed by experts (n = 8) and/or pilot-tested (n = 9), only 7 were tested using both rigorous types of validity and with low-income youth. CONCLUSIONS AND IMPLICATIONS: Results from this review suggest that additional research is needed to develop more robust psychosocial measures for dietary behaviors, for low-income youth audiences. PMID- 23663987 TI - Considerations for planning and designing meta-analysis in oral medicine. AB - Evidence to address a scientific question is generated through the design of research aiming to answer it. Probably the most often sought design in epidemiologic research is a randomized clinical trial that offers the advantage of controlling for confounders, which may influence the trial outcome. In contrast, observational study designs test hypotheses when clinical trials are difficult to implement. The interest in clinical trials has led to an explosion of manuscripts testing interventions in health care, often yielding interesting results albeit in statistically underpowered samples. Thus, the clinician faces the challenge of making sense of multiple studies that produce results of variable strength when attempting to assess the evidence supporting a treatment. Meta-analytic methods represent an alternative to assess the evidence by pooling the results from multiple studies to increase statistical power. This manuscript describes considerations for planning and implementing meta-analysis in oral medicine. PMID- 23663988 TI - Bicycle-related maxillofacial injuries: a double-center study. AB - OBJECTIVE: Bicycle-related injuries account for an important proportion of road injuries all over the world. As only few reports have focused on the characteristics of maxillofacial fractures sustained in bicycle accidents, the purpose of this study was to present and compare epidemiological data about bicycle-related maxillofacial injuries in two European centers between 2001 and 2010. METHODS: Bicycle-related facial fractures occurred in 105 patients (79 males, 26 females) in Turin, with a percentage of 5.77 among all facial fractures, and in 103 patients (55 males, 50 females) in Amsterdam, with a percentage of 19.69. RESULTS: The major risk groups include young people between their first to third decades. The mandible is the most frequently involved facial bone. Among mandibular injuries the most commonly involved site was the condyle. CONCLUSIONS: Bicycle-related injuries must be considered an important etiological factor in maxillofacial fractures with typical patterns, such as a peculiar seasonal incidence. PMID- 23663989 TI - Open versus closed treatment of unilateral moderately displaced mandibular condylar fractures: a meta-analysis of randomized controlled trials. AB - PURPOSE: To compare the efficacy of operative and conservative treatment of displaced condylar fractures of the mandible, a meta-analysis was performed. STUDY DESIGN: PubMed, Cochrane Controlled Trials Register, EMBASE electronic databases were searched until 10 December 2012. English studies were restricted in randomized controlled trials (RCT). RESULTS: Four RCT with 177 patients were included. No significant difference was found between the 2 groups in the maximal interincisal opening (P = .32). However a statistically significant difference was seen that operative treatment statistically got better efficacy in lateral excursion movement, protrusion, malocclusion, and temporomandibular joint pain (P < .05). CONCLUSIONS: This meta-analysis confirms that both treatment options for unilateral displaced condylar fractures of the mandible yielded acceptable results. However, operative treatment was superior in most objective and subjective functional parameters. PMID- 23663990 TI - Filling the void about sperm function knowledge and how the -omics approach can close the circle. PMID- 23663991 TI - Introduction: male rejuvenation: what the reproductive specialist needs to know. AB - Androgens and other hormones are commonly being used by men in attempts to achieve a variety of health benefits that are often referred to "male rejuvenation." This series of articles will prepare the reproductive specialist to deal with these patients and their presented problems. PMID- 23663992 TI - Effect of rejuvenation hormones on spermatogenesis. AB - OBJECTIVE: To review the current literature for the effect of hormones used in rejuvenation clinics on the maintenance of spermatogenesis. DESIGN: Review of published literature. SETTING: Not applicable. PATIENT(S): Men who have undergone exogenous testosterone (T) and/or anabolic androgenic steroid (AAS) therapies. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Semen analysis, pregnancy outcomes, and time to recovery of spermatogenesis. RESULT(S): Exogenous testosterone and anabolic androgenic steroids suppress intratesticular testosterone production, which may lead to azoospermia or severe oligozoospermia. Therapies that protect spermatogenesis involve human chorionic gonadotropin (hCG) therapy and selective estrogen receptor modulators (SERMs). The studies examining the effect of human growth hormone (HGH) on infertile men are uncontrolled and unconvincing, but they do not appear to negatively impact spermatogenesis. At present, routine use of aromatase inhibitors is not recommended based on a lack of long-term data. CONCLUSION(S): The use of hormones for rejuvenation is increasing with the aging of the Baby Boomer population. Men desiring children at a later age may be unaware of the side-effect profile of hormones used at rejuvenation centers. Testosterone and anabolic androgenic steroids have well established detrimental effects on spermatogenesis, but recovery may be possible with cessation. Clomiphene citrate, human growth hormone (HGH)/insulin-like growth factor-1 (IGF-1), human chorionic gonadotropin (hCG), and aromatase inhibitors do not appear to have significant negative effects on sperm production, but quality data are lacking. PMID- 23663993 TI - Antimullerian hormone inhibits follicle-stimulating hormone-induced adenylyl cyclase activation, aromatase expression, and estradiol production in human granulosa-lutein cells. AB - OBJECTIVE: To investigate the effects of antimullerian hormone (AMH) on basal and FSH-induced cytochrome P450 aromatase (aromatase) expression and E2 production in human granulosa-lutein (hGL) cells, and to elucidate the mechanism by which AMH exerts its effects. DESIGN: Experimental study. SETTING: Academic medical center for reproductive science. PATIENT(S): The hGL cells were obtained from consenting patients undergoing IVF treatment. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Primary cultures of hGL cells were used to examine the effects of AMH (10 ng/mL) on basal and FSH (0.2 IU/mL)-stimulated E2 and intracellular cyclic adenosine 3':5' monophosphate (cAMP) accumulation, as well as aromatase and FSH receptor expression. Small interfering RNA targeting type II AMH receptor (AMHR2) was used to verify the specificity of the effects. RESULT(S): Treatment with AMH significantly reduced FSH-stimulated aromatase expression and E2 accumulation, whereas it had no measurable effects on basal and/or 8-Br-cAMP-stimulated levels. The FSH receptor messenger RNA and protein levels were not altered in AMH-treated cells. Cotreatment with AMH suppressed FSH-induced increases in intracellular cAMP. Knockdown of AMHR2 reversed the effects of AMH on aromatase expression. CONCLUSION(S): The AMH acts through AMHR2 to inhibit FSH-induced adenylyl cyclase activation, aromatase expression, and E2 production. PMID- 23663994 TI - Trends and determinants of use of long-acting reversible contraception use among young women in France: results from three national surveys conducted between 2000 and 2010. AB - OBJECTIVE: To investigate trends and determinants in the use of long-acting reversible contraceptives (LARCs), including intrauterine devices and implants, over the last decade among young women in France. DESIGN: Data drawn from three cross-sectional national probability surveys. SETTING: Not applicable. PATIENT(S): A total of 1,204 women, ages 15 to 29, who are at potential risk of an unintended pregnancy in 2000; 1,921 in 2005; and 1,281 in 2010. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Logistic regression models were used to explore trends in LARC use since 2000 and to examine determinants of LARC use in 2010. RESULT(S): A minority of women were using LARC methods, with a significant increase between 2000 and 2010, from 4.6% to 6.4%. The odds of LARC use in 2010 were higher among women 20 to 29 years, parous women, women with a history of unintended pregnancy, women in difficult financial situations, smokers, and women in the care of a gynecologist. CONCLUSION(S): This study shows that little progress has been made in LARC use among young women in France, despite these methods being widely available and reimbursed by the national health system. PMID- 23663995 TI - Training in embryo transfer: how should it be done? PMID- 23663996 TI - Decreases in adrenomedullin expression and ciliary beat frequency in the nasal epithelium in tubal pregnancy. AB - OBJECTIVE: To study adrenomedullin (ADM) expression and its relation to ciliary beat frequency (CBF) in the nasal mucociliated epithelium in tubal ectopic pregnancy (tEP). DESIGN: Experimental study. SETTING: University teaching hospital. PATIENT(S): Women with tEP and normal intrauterine pregnancy matched for age and gestational age were recruited. Healthy nonpregnant women were also recruited as nonpregnant controls. INTERVENTION(S): Nasal epithelial brushing. MAIN OUTCOME MEASURE(S): Adrenomedullin expression in nasal epithelium (measured by real-time reverse transcription-polymerase chain reaction, plasma ADM concentration (measured by ELISA), and CBF (measured by photometric method). RESULT(S): We have demonstrated a similar decrease in ADM expression and CBF in the nasal mucociliated epithelium, as well as in plasma ADM concentration, in women with tEP compared with normal pregnant women. Adrenomedullin up-regulates nasal CBF via the ADM receptor, as in the oviduct. There is significant correlation between nasal and oviductal CBF. CONCLUSION(S): Nasal epithelium ADM and CBF, as well as plasma ADM, are possible predictors of women at risk of tEP. PMID- 23663997 TI - Coital frequency and infertility: which male factors predict less frequent coitus among infertile couples? AB - OBJECTIVE: To determine the coital frequency among infertile couples and which factors are associated with less frequent coitus. DESIGN: Cross-sectional study. SETTING: Tertiary-level male infertility clinic. PATIENT(S): A total of 1,298 infertile men. INTERVENTION(S): Administration of computer-based survey, semen analysis, and serum hormone evaluation. MAIN OUTCOME MEASURE(S): Monthly coital frequency. RESULT(S): A total of 1,298 patients presented to clinic for infertility consultation and completed the computer-based survey. The median male age was 35 years (interquartile range [IQR] 32-39 years) and the median duration of infertility was 2 years (IQR 1-4 years) before consultation. Median monthly coital frequency was seven (IQR 5-10; range 0-40); 24% of couples were having intercourse <= 4 times per month. Overall, 0.6%, 2.7%, 4.8%, 5.8%, and 10.8% of the men reported having intercourse 0, 1, 2, 3, and 4 times per month, respectively. When simultaneously taking into account the influence of age, libido, erectile function, and semen volume on coital frequency, older patients had 1.05 times higher odds (per year of age) of less frequent coitus (odds ratio 1.05, 95% confidence interval 1.03-1.08). In addition, patients with better erectile function had 1.12 times higher odds (per point on Sexual Health Inventory for Men scale) of more frequent coitus (odds ratio 1.12, 95% confidence interval 1.09-1.18). CONCLUSION(S): Similar to the general population, most infertile couples report having coitus more than four times per month. Older male age and erectile dysfunction are independent risk factors for less frequent coitus among infertile men, which could have an impact on fertility. Coital frequency should be considered in infertility assessments. PMID- 23663998 TI - Whatever its variability, antimullerian hormone remains the most stable hormonal predictor. PMID- 23663999 TI - Reply of the authors. PMID- 23664000 TI - Brain dead yet mind alive: a positron emission tomography case study of brain metabolism in Cotard's syndrome. PMID- 23664002 TI - Interactions between cold ambient temperature and older age on haptic acuity and manual performance. AB - The impact of exposure to cold on individuals' motor skills demands a deeper understanding of the ways in which cold weather influences psychomotor and haptic performance. In this study, various facets of psychomotor performance were evaluated in order to determine the impacts of ambient cold exposure on older persons. Healthy younger and older persons performed a battery of haptic psychomotor tests at room (23 degrees C) and cold (1 degrees C) ambient temperatures. The results indicate that older individuals do not perform as well as younger persons across the battery of tests, with cold temperature further degrading their performance in dexterity tasks (in, for example, Minnesota Manual Dexterity test placing: F [1, 16] = 10.23, p < .01) and peak precision grip force generation (F [1, 16] = 18.97, p < .01). The results suggest that cold weather may have an impact on the occupations older persons are able to perform during the winter months. PMID- 23664003 TI - On the shape of the population ROC curve. AB - RATIONALE AND OBJECTIVES: Human observers often do not produce empirical operating points near the northeast corner of the receiver operating characteristic (ROC) plot, and thus the local shape of the population ROC curve is unknown. MATERIALS AND METHODS: We call attention to occult abnormalities and propose that considerations by human observers of the prior probability of occult abnormalities can cause the shape of the local population ROC curve to be convex, a straight line, or concave near the northeast corner of the ROC plot. We further conducted a set of simulated detection-task (without-search) experiments with human observers and, mathematically, with an ideal observer and a model observer. In the experiments, we used signals, pseudo-signals that were similar to signals, and random image noise. The relative frequency of occult signals was controlled in the experiments. RESULTS: In the simulated experiments, the population ROC curve of the ideal observer was always convex, but those of the model observer and of human observers were convex, a straight-line, or concave, depending on the relative frequency of occult signals. The population ROC curve for the model observer was identical to that for the ideal observer when knowing the relative frequency of occult signals was not important for the ideal observer, and it was similar to that for human observers otherwise. CONCLUSION: Observer consideration of the prior probability of occult abnormalities is important in ROC studies and could cause unexpected shapes of the local population ROC curve. Absence of empirical operating points near the northeast corner of the ROC plot may be caused by occult abnormalities. PMID- 23664001 TI - Sight and sound out of synch: fragmentation and renormalisation of audiovisual integration and subjective timing. AB - The sight and sound of a person speaking or a ball bouncing may seem simultaneous, but their corresponding neural signals are spread out over time as they arrive at different multisensory brain sites. How subjective timing relates to such neural timing remains a fundamental neuroscientific and philosophical puzzle. A dominant assumption is that temporal coherence is achieved by sensory resynchronisation or recalibration across asynchronous brain events. This assumption is easily confirmed by estimating subjective audiovisual timing for groups of subjects, which is on average similar across different measures and stimuli, and approximately veridical. But few studies have examined normal and pathological individual differences in such measures. Case PH, with lesions in pons and basal ganglia, hears people speak before seeing their lips move. Temporal order judgements (TOJs) confirmed this: voices had to lag lip-movements (by ~200 msec) to seem synchronous to PH. Curiously, voices had to lead lips (also by ~200 msec) to maximise the McGurk illusion (a measure of audiovisual speech integration). On average across these measures, PH's timing was therefore still veridical. Age-matched control participants showed similar discrepancies. Indeed, normal individual differences in TOJ and McGurk timing correlated negatively: subjects needing an auditory lag for subjective simultaneity needed an auditory lead for maximal McGurk, and vice versa. This generalised to the Stream-Bounce illusion. Such surprising antagonism seems opposed to good sensory resynchronisation, yet average timing across tasks was still near-veridical. Our findings reveal remarkable disunity of audiovisual timing within and between subjects. To explain this we propose that the timing of audiovisual signals within different brain mechanisms is perceived relative to the average timing across mechanisms. Such renormalisation fully explains the curious antagonistic relationship between disparate timing estimates in PH and healthy participants, and how they can still perceive the timing of external events correctly, on average. PMID- 23664004 TI - Vimentin is synthesized by mouse vascular trophoblast giant cells from embryonic day 7.5 onwards and is a characteristic factor of these cells. AB - INTRODUCTION: A few days after implantation, the embryo grows intensely and trophoblast giant cells (TGC) undergo cell rearrangement, especially of their cytoskeleton. Although we previously showed vimentin in mouse antimesometrial TGC at embryonic days (E) 8.5-10.5, by immunostaining, we did not demonstrate what is the first embryonic day that TGC synthesize vimentin and whether mouse chorioallantoic placental TGC express vimentin. This is of particular interest because cytokeratin is a marker for TGC in the placenta. METHODS: We performed in situ hybridization and immunolocalization, combined with histological and stereological techniques, to study vimentin expression between E6.5 and E12.5 and we investigated Vegf and Flt1/Vegfr1 expression in TGC. RESULTS: Analyses of morphologic parameters of TGC showed that the highest expansion of nuclear and cytoplasmic volumes (p <= 0.05) occurred at E7.5. We detected vimentin expression in TGC from E7.5 onwards; vimentin disappeared as TGC degeneration advanced. Primary and secondary TGC showed intense positive immunostaining for vimentin, Vegf and Flt1/Vegfr1 at E7.5. In the chorioallantoic placenta, parietal TGC (zone of giant cells), spiral artery-associated TGC, maternal blood canal-associated TGC and TGC within the sinusoidal spaces of the labyrinth exhibited an intense immunopositive-reaction for vimentin. DISCUSSION: At E7.5 TGC acquire vimentin, Vegf and Flt1/Vegfr1; at the same time, blood begins to drain from maternal vessels. Vimentin synthesis initiates during a differentiation process of TGC and continues throughout the stage of vascular TGC. CONCLUSIONS: We propose that vimentin is a characteristic factor of specialized (vascular) TGC, being a valuable tool for studying pathological pregnancies associated with defects in vascular trophoblasts in mice. PMID- 23664005 TI - Translating positron emission tomography studies in animals to stimulant addiction: promises and pitfalls. AB - Addiction is a chronically relapsing brain disorder that insidiously affects the motivational and cognitive control systems of susceptible individuals. Clinical research over the last two decades has profited from the technique of positron emission tomography (PET), a non-invasive imaging technique that allows the longitudinal assessment of addiction-relevant biomarkers in current and former drug users. The vast majority of this research has unsurprisingly focused on the brain dopamine (DA) systems given their pivotal role in primary drug reinforcement and the rich abundance of dopaminergic PET tracers. However, the provocative failure of dopaminergic medications in addiction has fuelled the search for alternative treatments. This article considers current controversies in this field as well as prospects for elucidating neurotransmitter mechanisms in addiction beyond DA. PMID- 23664006 TI - [New recommendations on the use of human albumin solutions in patients with severe sepsis and septic shock. A critical evaluation of the literature]. AB - The third edition of the Surviving Sepsis Campaign guidelines opens the door to the use of albumin for fluid resuscitation in patients with severe sepsis and septic shock. This recommendation is based on a recent meta-analysis that included studies with evidence of insufficient plasma expansion in the control group and studies performed in children with malaria with clear statistical heterogeneity (P for interaction=.02). After excluding pediatric studies, the confidence interval of the effect estimate was consistent with a mortality excess in the group treated with albumin (OR=.87 [95%CI: .71 to 1.07]). Two new randomized studies reported after publication of the meta-analysis found no benefit in patients treated with albumin. Given the uncertainty about the true effect of albumin (due to the existence of indirectness and imprecision) and its cost considerations, it is suggested not to use albumin in the initial resuscitation of patients with severe sepsis and septic shock (GRADE2C). PMID- 23664007 TI - [Severe community-acquired pneumonia: prognostic scales versus evolutive parameters in ICU admission decisions]. PMID- 23664009 TI - Animal welfare: an animal science approach. AB - Increasing world population and demand for animal-derived protein puts pressure on animal production to meet this demand. For this purpose animal breeding efforts were conducted to obtain the maximum yield that the genetic makeup of the animals permits. Under the influence of economics which is the driving force behind animal production, animal farming became more concentrated and controlled which resulted in rearing animals under confinement. Since more attention was given on economics and yield per animal, animal welfare and behavior were neglected. Animal welfare which can be defined as providing environmental conditions in which animals can display all their natural behaviors in nature started gaining importance in recent years. This does not necessarily mean that animals provided with good management practices would have better welfare conditions as some animals may be distressed even though they are in good environmental conditions. Consumers are willing to pay more for welfare-friendly products (e.g.: free range vs caged egg) and this will change the animal production practices in the future. Thus animal scientists will have to adapt themselves for the changing animal welfare rules and regulations that differ for farm animal species and countries. In this review paper, animal welfare is discussed from an animal science standpoint. PMID- 23664008 TI - Cerebrospinal fluid neopterin decay characteristics after initiation of antiretroviral therapy. AB - BACKGROUND: Neopterin, a biomarker of macrophage activation, is elevated in the cerebrospinal fluid (CSF) of most HIV-infected individuals and decreases after initiation of antiretroviral therapy (ART). We studied decay characteristics of neopterin in CSF and blood after commencement of ART in HIV-infected subjects and estimated the set-point levels of CSF neopterin after ART-mediated viral suppression. METHODS: CSF and blood neopterin were longitudinally measured in 102 neurologically asymptomatic HIV-infected subjects who were treatment-naive or had been off ART for >= 6 months. We used a non-linear model to estimate neopterin decay in response to ART and a stable neopterin set-point attained after prolonged ART. Seven subjects with HIV-associated dementia (HAD) who initiated ART were studied for comparison. RESULTS: Non-HAD patients were followed for a median 84.7 months. Though CSF neopterin concentrations decreased rapidly after ART initiation, it was estimated that set-point levels would be below normal CSF neopterin levels (<5.8 nmol/L) in only 60/102 (59%) of these patients. Pre-ART CSF neopterin was the primary predictor of set-point (P <0.001). HAD subjects had higher baseline median CSF neopterin levels than non-HAD subjects (P <0.0001). Based on the non-HAD model, only 14% of HAD patients were predicted to reach normal levels. CONCLUSIONS: After virologically suppressive ART, abnormal CSF neopterin levels persisted in 41% of non-HAD and the majority of HAD patients. ART is not fully effective in ameliorating macrophage activation in CNS as well as blood, especially in subjects with higher pre-ART levels of immune activation. PMID- 23664010 TI - Advances in the industrial production of halal and kosher red meat. AB - The worldwide volume and value of trade in halal and kosher meat and co-products are huge. Muslim countries alone consumed meat estimated to be worth USD 57.2 billion in 2008. The halal and kosher principles that govern the production of red meat have many similarities, as well as some fundamental differences. Perhaps the most significant difference is that at the time of slaughter, the animal needs only to be alive to meet the minimum halal requirement, but must be both alive and conscious for kosher. It is for this reason that reversible pre slaughter stunning is acceptable only for halal meat, although a compromise form of post-slaughter stunning is now considered kosher in some countries. Extensive research on animal physiology and welfare has characterised and optimised the methods for stunning livestock, and enabled advancement in associated technologies. This forms the basis for harmonising the religious and secular requirements for the protection of animal welfare at slaughter. These technologies and the associated processing practices for the industrial production of halal and kosher meat are reviewed in this paper. PMID- 23664011 TI - Optimizing dopaminergic differentiation of pluripotent stem cells for the manufacture of dopaminergic neurons for transplantation. AB - BACKGROUND AIMS: We have previously described a xeno-free scalable system to generate transplantable dopaminergic neurons from human pluripotent stem cells. However, several important questions remain to be answered about our cell therapy efforts. These include determining the exact time at which cells should be transplanted and whether cells at this stage can be frozen, shipped, thawed and injected without compromising their ability to mature and survive the transplantation procedure. We also needed to determine whether further optimization of the culture process could shorten the development time and reduce variability and whether a current Good Manufacture Practice (CGMP) facility could manufacture cells with fidelity. METHODS: We developed an optimized protocol that included modulating the sonic hedgehog homolog gradient with bone morphogenetic proteins (BMP2) and addition of activin to the culture medium, which shortened the time to generate Lmx1A and FoxA2 immunoreactive cells by 4-6 days. RESULTS: We showed that cells at this stage could be safely frozen and thawed while retaining an excellent ability to continue to mature in vitro and survive transplant in vivo. Importantly, we successfully adapted this process to a CGMP facility and manufactured two lots of transplant-ready dopaminergic neurons (>250 vials) under CGMP-compatible conditions. In vitro characterization, including viability/recovery on thawing, whole genome expression as well as expression of midbrain/dopaminergic markers, showed that the cells manufactured under GMP compatible conditions were similar to cells produced at lab scale. CONCLUSIONS: Our results suggest that this optimized protocol can be used to generate dopaminergic neurons for Investigational New Drug enabling studies. PMID- 23664012 TI - Tumour budding is a strong and independent prognostic factor in pancreatic cancer. Reply to comment. PMID- 23664014 TI - In vitro inhibition of canine distemper virus by flavonoids and phenolic acids: implications of structural differences for antiviral design. AB - Infection caused by canine distemper virus (CDV) is a highly contagious disease with high incidence and lethality in the canine population. Antiviral activity of flavonoids quercetin, morin, rutin and hesperidin, and phenolic cinnamic, trans cinnamic and ferulic acids were evaluated in vitro against the CDV using the time of addition assay to determine which step of the viral replicative cycle was affected. All flavonoids displayed great viral inhibition when they were added at the times 0 (adsorption) and 1h (penetration) of the viral replicative cycle. Both quercetin and hesperidin presented antiviral activity at the time 2h (intracellular). In the other hand, cinnamic acid showed antiviral activity at the times 0 and 2h while trans-cinnamic acid showed antiviral effect at the times -1h (pre-treatment) and 0 h. Ferulic acid inhibited CDV replicative cycle at the times 0 and 1h. Our study revealed promising candidates to be considered in the treatment of CDV. Structural differences among compounds and correlation to their antiviral activity were also explored. Our analysis suggest that these compounds could be useful in order to design new antiviral drugs against CDV as well as other viruses of great meaning in veterinary medicine. PMID- 23664013 TI - Feasibility and dose discovery analysis of zoledronic acid with concurrent chemotherapy in the treatment of newly diagnosed metastatic osteosarcoma: a report from the Children's Oncology Group. AB - AIM: Patients with metastatic osteosarcoma (OS) have a poor outcome with conventional therapies. Zoledronic acid (ZA) is a third-generation bisphosphonate that reduces skeletal-related events in many adult cancers, and pre-clinical data suggest a possible benefit in OS. This study assessed the maximum tolerated dose (MTD) and the feasibility of ZA when combined with chemotherapy in patients with metastatic OS. PATIENTS AND METHODS: Patients with a histological diagnosis of OS were eligible if they were <40 years of age, had initially metastatic disease and met organ function requirements. Treatment combined surgery and a conventional chemotherapy regimen. ZA was given concurrent with chemotherapy for a total of eight doses over 36 weeks. Three dose levels of ZA were tested: 1.2 mg/m(2) [max 2 mg], 2.3 mg/m(2) [max 4 mg] and 3.5 mg/m(2) [max 6 mg]. The MTD was determined during induction. Six patients were to be treated at each dose level, with an additional six patients treated with the MTD to help assess post-induction feasibility. RESULTS: Twenty-four patients (median age 13.5 years [range, 7-22]; 16 females) were treated. Five patients experienced dose-limiting toxicities (DLTs) during induction, including three patients treated with 3.5 mg/m(2). DLTs included hypophosphatemia, hypokalemia, hyponatremia, mucositis, limb pain and limb oedema. There were no reports of excessive renal toxicity or osteonecrosis of the jaw. The MTD was defined as 2.3 mg/m(2) (max 4 mg). CONCLUSIONS: ZA can be safely combined with conventional chemotherapy with an MTD of 2.3 mg/m(2) (max 4 mg) for patients with metastatic osteosarcoma. PMID- 23664015 TI - A novel indirect ELISA based on glycoprotein Gn for the detection of IgG antibodies against Rift Valley fever virus in small ruminants. AB - Rift Valley fever virus (RVFV) is an emerging zoonotic pathogen that causes high morbidity and mortality in humans and livestock. In this paper, we describe the cloning, expression and purification of RVFV glycoprotein Gn and its application as a diagnostic antigen in an indirect ELISA for the specific detection of RVF IgG antibodies in sheep and goats. The performance of this Gn based ELISA is validated using a panel of almost 2000 field samples from sheep and goats from Mozambique, Senegal, Uganda and Yemen. All serum samples were also tested by virus neutralization test (VNT), the gold standard method for RVFV serological testing. Compared to the VNT results the Gn based ELISA proved to have an excellent sensitivity (94.56%) and specificity (95.57%). Apart from establishing this new diagnostic assay, these results also demonstrate a close correlation between the presence of RVFV Gn and neutralizing antibodies. PMID- 23664016 TI - Blood phagocyte activity after race training sessions in Thoroughbred and Arabian horses. AB - Intensive exercise and exertion during competition promote many changes that may result in the impairment of immunity and increased susceptibility to infections. The aim of this study was to evaluate the activity of "the first line of defense": neutrophils and monocytes in racing Thoroughbred and Arabian horses after routine training sessions. Twenty-three (12 Thoroughbred and 11 Arabian) horses were examined. Routine haematological (number of red blood cells - RBC, haemoglobin concentration - HGB, haematocrit - HCT, total number of white blood cells - WBC), biochemical (creatine phosphokinase activity - CPK and total protein concentration - TP) parameters, cortisol concentration as well as phagocytic and oxidative burst activity of neutrophils and monocytes were determined. The values of basic parameters and the activity of phagocytes differed between breeds and distinct patterns of exercise-induced changes were observed. The training sessions did not produce the decrease in phagocyte activity that might lead to the suppression of immunity. PMID- 23664017 TI - Influence of horn flies (Haematobia irritans) on teat skin condition, intramammary infection, and serum anti-S. aureus antibody titres in holstein heifers. AB - Staphylococcus aureus remains a major mastitis-causing pathogen in growing dairy heifers, resulting in damage to developing milk secretory tissue. The purpose of this study was to evaluate the role of horn flies as vectors in the spread of S. aureus among dairy heifers immunized with a S. aureus bacterin. We analyzed the prevalence of mastitis among quarters, evaluated teat skin condition (as a result of biting flies) prior to and after insecticide administration, and measured serum anti-S. aureus antibody titres monthly after vaccination. Response to S. aureus immunization was poor; however, titres increased 2- to 3-fold during the period when fly populations increased drastically and teat skin condition worsened, especially front quarter teat condition. Presence of flies and the resulting teat lesions were associated with a high level of S. aureus mastitis. Use of an insecticidal pour-on reduced fly populations and healed teat lesions, but existing cases of mastitis required antibiotic therapy. PMID- 23664018 TI - Service-based health human resources planning for older adults. AB - OBJECTIVES: To test a service-based health human resources (HHR) planning approach for older adults in the context of home and long term care (LTC); to create a practical template/tools for use in various jurisdictions and/or health care settings. DESIGN: The most serious health needs of seniors in 2 Canadian jurisdictions were identified and linked to the specific services and associated competencies required of health care providers (HCPs) to address those needs. The amounts of each service required were quantified and compared against the capacity of HCPs to perform the services, measured using a self-assessment survey, by using a previously developed analytical framework. SETTING: Home and LTC sectors in Nova Scotia and Nunavut, Canada. PARTICIPANTS: Regulated and nonregulated HCPs were invited to complete either an online or paper-based competency self-assessment survey. RESULTS: Survey response rates in Nova Scotia and Nunavut were 11% (160 responses) and 20% (22 responses), respectively. Comparisons of the estimated number of seniors likely to need each service with the number who can be served by the workforces in each jurisdiction indicated that the workforces in both jurisdictions are sufficiently numerous, active, productive, and competent to provide most of the services likely to be required. However, significant gaps were identified in pharmacy services, ongoing client assessment, client/family education and involvement, and client/family functional and social supports. CONCLUSION: Service-based HHR planning is feasible for identifying gaps in services required by older adults, and can guide policy makers in planning hiring/recruitment, professional development, and provider education curricula. Implementation will require commitment of policy makers and other stakeholders, as well as ongoing evaluation of its effectiveness. More broadly, the ongoing effectiveness of the approach will depend on workforce planning being conducted in an iterative way, driven by regular reevaluation of population health needs and HHR effectiveness. PMID- 23664019 TI - Current Alzheimer's medications: effective treatment options, or expensive bottles of hope? PMID- 23664020 TI - Geriatric dermatology review: Major changes in skin function in older patients and their contribution to common clinical challenges. AB - There is a paucity of data to guide evidence-based treatment decisions in managing older dermatologic patients, in part because of the frequent exclusion of older adults from clinical trials. Hence, we provide a comprehensive review of important conditions in geriatric dermatology, or "dermatogeriatrics." It is our hope the field of "dermatogeriatrics" will become more evidence-based and recognized as a field in its own right so that we can better meet the needs of our growing numbers of older patients, now and in the future. PMID- 23664021 TI - Carabelli's trait in Croatian populations over 1800 years. AB - Examination and comparison of the morphological features of tooth crown in archaeological and recent samples can be difficult due to the different levels of tooth wear seen both within and between populations. These differences make the comparison of frequency data for Carabelli trait problematic. The aim of the present study is to detect the frequency and degree of expression of Carabelli's trait in Croatian populations from late antiquity to recent times and to use these data as supplementary evidence of complex population migration. A total of 1287 individuals from the late antiquity, medieval, early modern and modern periods were examined. Correlation between the presence of Carabelli's trait and tooth crown size was tested. The results of our analyses show that the frequency of Carabelli's trait is significantly greater in the early modern period (51.3%) and in the 21st century (43.1%) than in the late antiquity (20.4%) and medieval periods (23.4%). These results are consistent with historical evidence of migration and population change in the territory of present-day Croatia throughout the almost 1800 years covered by this study. The results also provide additional evidence for the complex nature of population change in the transition from the late antiquity to the early medieval period. PMID- 23664022 TI - Help youth with epilepsy to become competent and happy adults: Transition care. PMID- 23664023 TI - Environmental tobacco smoke exposure at home and smoking prevalence in the general Portuguese population--the INAsma study. AB - BACKGROUND: We aimed to: 1) estimate the prevalence of exposure to environmental tobacco smoke (ETS) at home in the Portuguese population; 2) estimate tobacco smoking prevalence in Portugal; 3) identify social and personal characteristics associated with smoking or exposure to ETS. METHODS: Nationwide, cross-sectional, population-based telephone survey. Overall, 6003 individuals completed the interview. ETS exposure at home was defined as exposure to at least one current smoker at home. A smoker was defined as someone with 15 years or older, smoking at least 1 cigarette per day during a year; a current smoker (CS) smoked in the last month. RESULTS: Exposure to ETS at home was reported by 26.6% (95%CI 25.5 27.7) of the participants. Living in households with >=4 persons (OR=2.31; 95%CI[1.81-2.96]), being a current smoker (OR=7.29; 95%CI[5.74-9.26]) or having current asthma (OR=2.06; 95%CI[1.45-2.94]) were factors positively associated with ETS exposure. When analyzed by gender, the effect of current asthma was only relevant to females. Currently 19.0% (95%CI 18.0-20.0) of the Portuguese population smokes tobacco and 17.2% (95%CI 16.2-18.2) are ex-smokers. CS prevalence is higher in males than females (26.5%versus 12.2%, p<0,001). The odds of being a CS were higher for males, the more educated, and those exposed to ETS at home. When analyzed by gender, school education only affected females. CONCLUSION: Exposure to ETS at home was higher than previously reported. Children/adolescents and asthma patients may have a higher risk of exposure. This report endorses a decreasing trend in the prevalence of tobacco smoking in Portuguese males, but a tendency to increase in females. PMID- 23664025 TI - Proceedings of the Seventh International Workshop on Waldenstrom Macroglobulinemia. PMID- 23664024 TI - Chronic obstructive pulmonary disease prevalence in Lisbon, Portugal: the burden of obstructive lung disease study. AB - BACKGROUND: There is a great heterogeneity in the prevalence of Chronic Obstructive Pulmonary Disease (COPD) demonstrates a great heterogeneity across the world. The Burden of Obstructive Lung Disease (BOLD) initiative was started to measure the prevalence of COPD in a standardized way. We aimed to estimate the prevalence of COPD in Portuguese adults aged 40 years or older of a target population of 2,700 000 in the Lisbon region, in accordance with BOLD protocol. METHODS: A stratified, multi-stage random sampling procedure was used which included 12 districts. The survey included a questionnaire with information on risk factors for COPD and reported respiratory disease and a post-bronchodilator spirometry performed at survey centres. RESULTS: For the 710 participants with questionnaires and acceptable spirometry, the overall weighted prevalence of GOLD stage I+ COPD was 14.2% (95% C.I. 11.1, 18.1), and stage II+ was 7.3% (95% C.I. 4.7, 11.3). Unweighted prevalence was 20.2% (95% C.I.17.4, 23.3) for stage I+ and 9.5% (95% C.I. 7.6, 11.9) for stage II+. Prevalence of COPD in GOLD stage II+ increased with age and was higher in men. The prevalence of GOLD stage I+ COPD was 9.2% (95% C.I. 5.9, 14.0) in never smokers versus 27.4% (95% C.I. 18.5, 38.5) in those who had smoked >20 pack-years. The agreement between previous doctor diagnosis and spirometric diagnosis was low, with 86.8% of underdiagnosed individuals. CONCLUSIONS: The 14.2% of COPD estimated prevalence indicates that COPD is a common disease in the Lisbon region. In addition, a large proportion of underdiagnosed disease was detected. The high prevalence of COPD with a high level of underdiagnosis, points to the need of raising awareness of COPD among health professionals, and requires more use of spirometry in the primary care setting. PMID- 23664026 TI - Challenges with serum protein electrophoresis in assessing progression and clinical response in patients with Waldenstrom macroglobulinemia. AB - Accurate determination of the immunoglobulin (Ig) M paraprotein concentration is crucial to evaluating response in patients with Waldenstrom macroglobulinemia (WM). In most clinical laboratories, M-spike quantitation is performed by serum protein electrophoresis, which is the same method used to quantitate IgG and IgA paraproteins in patients with multiple myeloma (MM). However, the migration pattern and propensity of IgM paraproteins to form higher-order complexes in serum makes laboratory evaluation of samples from patients with WM especially challenging. We review examples of patients whose IgM paraprotein is particularly ill-suited to M-spike quantitation by serum protein electrophoresis: a case of "sticky M," a case of IgM multimers that cannot be resolved, and a case of an IgM in the beta region. In these and similar cases, a method other than M-spike quantitation, such as IgM heavy chain nephelometry, should be considered in laboratory evaluation of paraprotein concentration. PMID- 23664027 TI - Comparative response assessment by serum immunoglobulin M M-protein and total serum immunoglobulin M after treatment of patients with Waldenstrom macroglobulinemia. AB - Serum immunoglobulin (Ig) M monoclonal protein determined by electrophoresis (sIgM-MP) and total serum IgM (sIgM) by nephelometry are widely used for response assessment in Waldenstrom macroglobulinemia (WM), although have not been compared for predicting changes in underlying disease burden. We, therefore, compared these serum markers with changes in bone marrow (BM) and extramedullary disease for 73 patients who were rituximab naive and treated with a rituximab-containing regimen. By linear regression analysis, reductions in sIgM-MP and sIgM showed moderate correlation with BM disease involvement (r = 0.4051 and r = 0.4490, respectively), and did not differ from one another as estimators of BM disease response (P = .3745). Neither sIgM-MP nor sIgM showed a strong correlation with BM disease response in patients with low (<1000 mg/dL) or high (>5000 mg/dL) IgM levels and extramedullary disease response. sIgM-MP and sIgM, therefore, are comparable response markers in WM. Development of newer, more accurate surrogate response markers are needed to better delineate treatment outcomes in patients with WM and with low or high IgM levels, and extramedullary disease. PMID- 23664028 TI - Comment on developmental alterations of the human retrotrapezoid nucleus homologue by Lavezzi et al. PMID- 23664029 TI - Exploring the effects of attitudinal and perception characteristics on drinking and driving non-compliant behaviour. AB - The objective of this paper is to examine a number of factors (observed and latent) that might have a causal effect on drinking and driving (D&D) behaviour. Face-to-face surveys were conducted among patrons at bars and cafeterias and 305 valid questionnaires were filled. A confirmatory factor analysis was performed so as to identify the latent constructs and a mixed structural equation model was developed. From the analysis it came up that non-compliant behaviour of D&D is limited at older ages, also associated with high levels of income and car availability. Though men are consuming more alcohol, women seem to be more prone in driving under the influence (DUI) of alcohol. Furthermore, it was found that people who strongly support the examined interventions in the study (e.g. better enforcement, more traffic safety campaigns, stricter penalties) are more unlikely to drive after drinking compare to those who have some objections. Finally, it was not found any statistically significant relation between individuals' level of awareness and D&D behaviour. PMID- 23664030 TI - Risk factors for predicting the occult nodal metastasis in T1-2N0M0 NSCLC patients staged by PET/CT: potential value in the clinic. AB - BACKGROUND AND OBJECTIVE: The aims of our study were to evaluate the occult nodal metastasis in clinical stage I patients by PET/CT, further investigate the potential risk factors for nodal involvement, since a successful prediction could be helpful in selection appropriate candidates for SABR or limited surgery. METHODS: We retrospectively reviewed the records of 189 patients who diagnosed as clinical stage I NSCLC by (18)F-FDG PET/CT from January 2004 to July 2011. All patients underwent lobectomy and systematic lymph node dissection and preoperative (18)F-FDG PET/CT scanning. The prevalence of occult nodal metastasis in patients as clinical N0 was analyzed according to clinicopathological factors such as tumor location, tumor size, tumor subtype, grade of differentiation and primary tumor SUV(max). Risk factors for occult nodal metastasis were defined by univariate and multivariate analysis. RESULTS: Occult nodal metastasis was detected in 18.0% (34/189) of the patients. SUV(max) of the primary tumor and tumor size were independent predictors of occult nodal metastasis for patients with clinical N(0)NSCLC by FDG PET/CT. Accordingly we divided our patients into three groups: group 1 (low-risk group) ~T <= 3 cm and SUV(max) <= 4.3; group 2 (moderate-risk group) ~T <= 3 cm and SUV(max) > 4.3 or SUV(max) <= 4.3 and T > 3 cm; group 3 (high-risk group) ~T > 3 cm and SUV(max) > 4.3. The occult lymph node metastasis rate in groups 1, 2, 3 was 1/82 (1.2%), 19/75 (25.3%) and 14/32 (43%) respectively. CONCLUSIONS: T(1-2N0M0) NSCLC patients by PET/CT showing larger tumor size and high SUV(max) constitute a high-risk group for occult nodal metastasis. The combined information of primary tumor SUV(max) and tumor size before treatment have potential values in the clinic. These findings would be helpful in selection of SABR or limited surgery candidates. PMID- 23664031 TI - Proposal on incorporating blood vessel invasion into the T classification parts as a practical staging system for stage I non-small cell lung cancer. AB - BACKGROUND: We investigated blood vessel invasion (BVI) as a possible negative prognostic factor in patients with stage I non-small cell lung cancer (NSCLC) according to the 7th edition of the TNM classification. METHODS: Between 1999 and 2007, a total of 694 consecutive patients with pathological stage I NSCLC underwent complete resection with systematic lymph node dissection at Tokyo Medical University Hospital. All sections of the specimens were stained by Elastica van Gieson to visualize elastic fibers and were examined to determine the prognostic symptoms of BVI. We statistically analyzed the association between BVI and clinicopathologic factors, as well as clinical outcomes. RESULTS: BVI was detected in 201 patients with stage I NSCLC (29.0%). The 5-year overall survival (OS) rates of the non-BVI and BVI patients were 90.5% and 66.0%, respectively (p < 0.0001). BVI was found to be a significant independent prognostic factor by multivariate survival analysis in stage IA and stage IB NSCLC (HR 2.591, p < 0.001; HR 2.347, p = 0.009, respectively). The 5-year OS rate of patients with BVI was significantly worse than that of patients without BVI in the T1a (94.5% vs 87.5%, p < 0.0001), T1b (82.7% vs 65.9%, p < 0.0001), and T2a (90.9% vs 61.8%, p < 0.0001) subgroups. CONCLUSION: We identified the presence of BVI as an independent poor prognostic factor in patients with stage I NSCLC. In the future revision of the TNM staging system, the routine use of elastic fiber stains in pathological evaluations of lung cancer for BVI determination might be recommended, and tumors with BVI should be upstaged to the higher current T staging. PMID- 23664032 TI - Patients' preconceptions of acupuncture: a qualitative study exploring the decisions patients make when seeking acupuncture. AB - BACKGROUND: Like any other form of healthcare, acupuncture takes place in a particular context which can enhance or diminish treatment outcomes (i.e. can produce contextual effects). Patients' expectations of acupuncture might be an important component of contextual effects, but we know relatively little about the origins and nature of patients' expectations or wider preconceptions about acupuncture. Our aim was to identify the processes the underpin patients' decisions to try acupuncture and thus begin to tease out the origins and nature of patients' preconceptions. METHODS: One-off semi-structured interviews were conducted with a purposive, varied sample of 35 adults who had tried acupuncture for various conditions. Interviews explored people's experiences of acupuncture treatment and techniques from framework and inductive thematic analysis were used to relate the data to the research question. RESULTS: We identified four distinct processes within participants' accounts of deciding to try acupuncture: establishing a need for treatment, establishing a need for a new treatment, deciding to try acupuncture, and finding an acupuncturist. Family, friends and health care professionals played a role in these processes, providing support, advice, and increasing people's general familiarity with acupuncture. When they came to their first acupuncture appointment, participants had hopes, concerns, and occasionally concrete expectations as to the nature of acupuncture treatment and its likely effects. CONCLUSIONS: Existing theories of how context influences health outcomes could be expanded to better reflect the psychological components identified here, such as hope, desire, optimism and open-mindedness. Future research on the context of acupuncture should consider these elements of the pre treatment context in addition to more established components such as expectations. There appears to be a need for accessible (i.e. well-disseminated), credible, and individualised, patient-centred materials that can allay people's concerns about the nature of acupuncture treatment and shape realistic hopes and expectations. PMID- 23664033 TI - [Research in health sciences, co-responsibility and social impact]. PMID- 23664034 TI - Re. 'Re. Provision of vascular surgery in England in 2012'. PMID- 23664035 TI - Centerline is not as accurate as outer curvature length to estimate thoracic endograft length. AB - BACKGROUND: To assess the accuracy of the aortic outer curvature length for thoracic endograft planning. METHODS: Seventy-four patients (58 men, 66.4 +/- 14 years) who underwent thoracic endovascular aortic repair between 2009 and 2011 treated with a Cook Medical endograft were enrolled in this retrospective study. Immediate postoperative CT scans were analysed using EndoSize software. Three vessel lengths were computed between two fixed landmarks placed at each end of the endograft: the straightline (axial) length, the centerline length and the outer curvature length. A tortuosity index was defined as the ratio of the centerline length/straightline length. A Student t test and a Pearson correlation coefficient were used to examine the results. RESULTS: We found a significant difference between the centerline length (135.4 +/- 24 mm) and that of the endograft (160 +/- 29 mm) (p < .0001). This difference correlates with the tortuosity index (r = .818, p < .0001), the endograft length (r = .587, p < .0001), and the diameter of the endograft (r = .53, p < .0001). However, the outer curvature length (161.3 +/- 29 mm) and the endograft length (160 +/- 29 mm) were similar (p = .792). CONCLUSION: The outer curvature length more accurately reflects that of the deployed endograft and may prove more accurate than centerlines in planning thoracic endografts. PMID- 23664036 TI - Antegrade eversion endarterectomy of the external iliac artery. AB - OBJECTIVE: We describe and present the results of our novel technique for eversion endarterectomy of the external iliac artery (EIA). METHODS: For our prospective follow-up study, antegrade eversion endarterectomy (AEEA) of the EIA was mostly performed as a bail-out procedure, if (endovascular-assisted) remote endarterectomy from the groin had failed. Postoperative clinical and hemodynamic changes were reported according to the recommendations of the Society for Vascular Surgery. To evaluate the data, we used the Kaplan-Meier product limit method. RESULTS: Thirty patients (mean age 65.5 years) underwent AEEA on 33 EIAs for atherosclerotic occlusive disease over a 10-year period. The mean follow-up was 50 months. The primary technical success rate was 100%. The 30-day mortality was 0. There were no early occlusions. Two patients required redo surgery for retroperitoneal haematomas. Postoperative improvement was marked in 30%, moderate in 64% and minimal in 6%, explained by 21 (64%) concomitant occlusions of the superficial femoral arteries. The 1-, 3- and 5-year primary patency rates were 100%, 96% and 90%, and primary assisted patency rates were 100%, 96% and 96% respectively. Fourteen patients (47%) died during the long follow-up period from unrelated causes. CONCLUSION: AEEA is a safe autologous surgical technique with promising results. PMID- 23664037 TI - The social construction of social problems: the case of elder abuse and neglect. AB - The interaction and inter-penetrability overlap of abuse and neglect has been previously described. Therefore, the question is not whether a distinction can be made between the two, but how specific events are constructed into abuse and/or neglect based on how each of the protagonists involved (researchers, professional workers, family members, and the older persons themselves) make sense of abuse and neglect. The purpose of this paper is to explore the social and psychological construction of elder abuse and neglect and illustrate the theoretical constructs using case material and its application to the field. PMID- 23664038 TI - CD11b expression correlates with monosomal karyotype and predicts an extremely poor prognosis in cytogenetically unfavourable acute myeloid leukemia. PMID- 23664039 TI - Does the change in Q angle magnitude in unilateral stance differ when comparing asymptomatic individuals to those with patellofemoral pain? AB - OBJECTIVE: To determine if Q angle changes in magnitude from bilateral stance when compared to unilateral stance and then if they are significantly different changes related to the presence of patellofemoral joint pain. DESIGN: Observational correlation. SETTING: University biomechanics laboratory. PARTICIPANTS: 60 Asymptomatic females and 12 females with patellofemoral joint pain. MAIN OUTCOME MEASURE: Bilateral and unilateral stance Q angle. RESULTS: Sixty females had their Q angles measured in bilateral and unilateral stance. Linear regressions showed predictive equations and positive correlations for unilateral and bilateral stance Q angles (r=0.81-0.89, p<0.001). The equations generated were used to predict unilateral Q angle from bilateral Q angle measurements in 12 patients with patellofemoral joint pain. The actual unilateral Q angle measurement of the symptomatic knee was significantly greater than that predicted for each individual (p=0.01), whilst the asymptomatic knee showed no significant difference (p=0.16). CONCLUSION: This study showed a strong positive relationship between bilateral and unilateral stance Q angles which could be represented in a positive linear regression equation. The linear regression equation was then used to predict the effect on the Q angle of moving from a bilateral to a unilateral stance. It has been found previously that patients with patellofemoral joint pain on loading the limb in unilateral stance in activities such as walking and stair descent have increased knee valgus angle. The current study supports those findings indicating that when taking up unilateral stance patients with patellofemoral joint pain demonstrate greater than expected increase in Q angle which could increase loading on the patellofemoral joint. PMID- 23664040 TI - The effects of light emitting diode therapy following high intensity exercise. AB - OBJECTIVE: To determine the effects of light emitting diode therapy (LEDT) irradiation on blood lactate concentration ([La]) clearance, peak power output and fatigue index (FI) following high intensity fatiguing exercise. DESIGN: Single-blinded randomised cross-over placebo controlled trial. SETTING: University College Dublin, Institute for Sport and Health, Human performance laboratory. PARTICIPANTS: Eighteen healthy male athletes were recruited from field-based sports (including soccer, hockey and rugby union) and participated in the present study. MAIN OUTCOME MEASURES: Dependent variables were the peak power output elicited during the Wingate Anaerobic Test (WAnT), FI and [La] before and after each exercise. WAnT performance was measured prior to high intensity fatiguing exercise (Yo-Yo IR2), prior to LEDT or placebo, and following LEDT or placebo. [La] was measured at baseline, immediately after the Yo-Yo IR2, and in the 3rd, 9th, and 15th min following LEDT or placebo condition. RESULTS: No significant group by treatment interactions were observed for any outcome measures (P > 0.05). CONCLUSION: We conclude that LEDT irradiation applied following high intensity exercise was not effective and has no immediate effect on [La] clearance, peak power and FI, and thus has no significant effect on muscle recovery in athletes at the intensity and irradiation parameters used in the present study. Further research using different parameters is required to determine how LEDT may contribute to post-exercise recovery. PMID- 23664041 TI - Consensus statement on Concussion in Sport - The 4th International Conference on Concussion in Sport held in Zurich, November 2012. PMID- 23664042 TI - Modifications in endoscopic practice for the elderly. PMID- 23664043 TI - Beta blocker treatment of heart failure patients with ongoing cocaine use. PMID- 23664045 TI - Role of euroSCORE II in predicting long-term outcome after percutaneous catheter intervention for coronary triple vessel disease or left main stenosis. AB - OBJECTIVES: The SYNTAX score (Ssc) assessing the complexity of coronary anatomy predicts survival after percutaneous coronary intervention (PCI). We tested the hypothesis that the newly developed euroSCORE II (eSC2) can improve the prediction of outcome after complex PCI by the Ssc. METHODS AND RESULTS: Our study comprised 1262 consecutive patients with triple vessel disease or left main stenosis, who were contacted 3 years after elective PCI with drug-eluting stents. We calculated eSC2, Ssc, logistic euroSCORE, and ACEF score. Prediction of 3-year all-cause mortality by these scores was assessed by Cox proportional hazard models. Models were compared by the Hosmer-Lemeshow test for calibration (HL), the C-statistics (AUC) for discrimination and by net reclassification indices (NRI). eSC2 and Ssc were significant predictors of 3-year mortality (unadjusted hazard ratios [95%-confidence limits], 1.050 [1.033-1.067], 1.180 [1.146-1.215], respectively, P<0.001). The predictive value of eSC2 was improved by logarithmic transformation. Adding eSC2 to the model with Ssc improved calibration (HL 7.4 vs. 11.1) and discrimination (increase in AUC [95%-confidence limits] 0.12 [0.07 to 0.17]) and yielded a significant NRI of 0.38 (95%-confidence limits 0.28 to 0.47). The absolute difference in 3-year mortality between strata of Ssc (<=22, >22-32, >32) was smaller with eSC2<1% (1.4%, 3.4%, 9.7%, respectively), than with eSC2>1.6% (11.2%, 20.2%, 30.6%, respectively). The predictive ability of eSC2 was similar to that of the other clinical scores. CONCLUSIONS: eSC2 predicts 3-year mortality after complex PCI and modifies the impact of angiographic complexity on outcome. PMID- 23664044 TI - Effect of farnesyltransferase inhibition on cardiac remodeling in spontaneously hypertensive rats. AB - BACKGROUND: Farnesyltransferase (FT), an essential enzyme at the downstream of mevalonate pathway, was reported to be upregulated in hypertrophic cardiomyocytes of spontaneously hypertensive rats (SHRs) compared with myocardium of Wistar Kyoto rats (WKYs). This upregulation was accompanied with cardiac remodeling. This study was designed to determine whether FT inhibition can alter cardiac remodeling in SHRs. METHODS: Twelve-week-old SHRs were randomized to receive infusion of either NS or FTI-276 (307 MUg/kg/d i.v. each n=10). WKY rats served as normal controls (n=6). Echocardiography was performed before and after intervention. SHR hearts were perfused ex vivo for the evaluation of cardiac performance, collagen deposition and biochemical changes (activation of Ras, extracellular-signal regulated kinases/ERK1/2, procollagen type I/SH, TGF-beta1, connective tissue growth factor/CTGF, and bone morphogenetic protein-7/BMP-7 expression). RESULTS: FTI-276 intervention decreased interventricular septum wall thickness at end- diastole (IVSd) and relative wall thickness (RWT) of SHRs (P<0.05). Three week intervention with FTI-276 attenuated hydroxyproline content (P<0.05), collagen deposition (P<0.01), Ras activation, ERK1/2 phosphorylation (P<0.01) and mRNA expression of procollagen type I, TGF-beta1 and CTGF and elevated mRNA expression of BMP-7 (P<0.05) in left ventricle of SHRs. CONCLUSION: The present study indicated that FT inhibition could attenuate myocardial fibrosis and partly improve cardiac remodeling in SHRs. The beneficial effects might be mediated through suppression of the activation of Ras and ERK1/2 phosphorylation pathway. The enhanced mRNA expression of BMP-7 with inhibition of TGF-beta1 and CTGF mRNA expression might be an important mechanism. PMID- 23664047 TI - Direct-aortic "evolute" self-expanding aortic bioprosthesis implantation. PMID- 23664046 TI - "The silence of lambs": Cardiac lesions in asymptomatic immune-mediated diseases detected by cardiovascular magnetic resonance. PMID- 23664048 TI - Relation of body mass index to mortality among patients with percutaneous coronary intervention longer than 5 years follow-up: a meta-analysis. PMID- 23664049 TI - Radial approach for patients with ST-segment elevation acute coronary syndrome: it is definitely the best access site. PMID- 23664050 TI - Intermittent manifestation of pre-excitation syndrome: "this door is not open 24/7". PMID- 23664051 TI - Non-cancer atherosclerotic effects associated with environmental and therapeutic radiation doses: the Chernobyl thyroid cancer children study. PMID- 23664052 TI - Mean platelet volume in patients with primary aldosteronism and its relation to left ventricular hypertrophy. PMID- 23664053 TI - Stress cardiac magnetic resonance reveals myocardial perfusion impairment in asymptomatic diabetes mellitus type I, missed by the routine non-invasive evaluation. PMID- 23664054 TI - [Endovascular treatment in acute ischaemic stroke. A stroke care plan for the region of Madrid]. AB - INTRODUCTION: Endovascular therapies (intra-arterial thrombolysis and mechanical thrombectomy) after acute ischaemic stroke are being implemented in the clinical setting even as they are still being researched. Since we lack sufficient data to establish accurate evidence-based recommendations for use of these treatments, we must develop clinical protocols based on current knowledge and carefully monitor all procedures. DEVELOPMENT: After review of the literature and holding work sessions to reach a consensus among experts, we developed a clinical protocol including indications and contraindications for endovascular therapies use in acute ischaemic stroke. The protocol includes methodology recommendations for diagnosing and selecting patients, performing revascularisation procedures, and for subsequent patient management. Its objective is to increase the likelihood of efficacy and treatment benefit and minimise risk of complications and ineffective recanalisation. Based on an analysis of healthcare needs and available resources, a cooperative inter-hospital care system has been developed. This helps to ensure availability of endovascular therapies to all patients, a fast response time, and a good cost-to-efficacy ratio. It includes also a prospective register which serves to monitor procedures in order to identify any opportunities for improvement. CONCLUSIONS: Implementation of endovascular techniques for treating acute ischaemic stroke requires the elaboration of evidence-based clinical protocols and the establishment of appropriate cooperative healthcare networks guaranteeing both the availability and the quality of these actions. Such procedures must be monitored in order to improve methodology. PMID- 23664055 TI - Sexsomnia: parasomnia associated with sexual behaviour during sleep. AB - INTRODUCTION: The purpose of our study is to describe 4 cases of sexsomnia, a form of parasomnia characterised by sexual behaviour during sleep. METHODS: Clinical history and video-polysomnography recordings from patients diagnosed with sexsomnia in the Multidisciplinary Sleep Unit at Hospital Clinic in Barcelona. RESULTS: Three men and one woman between 28 and 43 years of age reported sexual behaviours during sleep with progression times ranging from 9 months to 7 years. Episodes consisted of masturbation without seeking the participation of a sleeping partner (2 cases) and attempts at sexual intercourse with inappropriate and uncharacteristic vocalizations and behaviours (3 cases). The frequency of the episodes ranged from 4 isolated episodes to 2-3 per week. Patients were amnestic of these events and surprised by their partners' accounts of their behaviour. Medical histories revealed that 1 patient was a somnambulist, 2 had confusional arousals, and 1 experienced somniloquy. Video-polysomnography did not disclose sexual behaviours during sleep but revealed sleep apnoea in 2 cases and periodic leg movements in sleep in another. The only patient treated with clonazepam reported decreased frequency of both confusional arousals and sexsomnia episodes. CONCLUSIONS: Sexsomnia occurs in young adults and is characterised by masturbation and inappropriate attempts at achieving sexual intercourse followed by total amnesia of the events. It can be associated with other parasomnias such as sleepwalking and confusional arousals. Other sleep disorders, including sleep apnoea and periodic leg movement disorder, may trigger episodes of sexsomnia. PMID- 23664056 TI - Profiling the isokinetic shoulder rotator muscle strength in 13- to 36-year-old male and female handball players. AB - OBJECTIVES: To evaluate the external (ER) and internal rotator (IR) muscles' isokinetic peak torque and conventional and functional strength ratios in handball players and controls of different ages. DESIGN: Cross-sectional and descriptive analysis. SETTING: Exercise Physiology Laboratory. PARTICIPANTS: A total of 228 participants (108 athletes and 120 controls) were divided into five groups according to age, ranging from 13 to 36 years old. MAIN OUTCOME MEASURES: Isokinetic tests were performed concentrically at 60 and 300 deg s(-1) and eccentrically at 300 deg s(-1). RESULTS: The differences between the athletes and controls regarding the peak torque of the ER and IR muscles were significant in males older than 18 years. The peak torque of the IR and ER muscles increased significantly across age in male athletes, but not in female athletes, except in the case of ER peak torque, which differed significantly between 13 and 16 years old. The female athletes presented higher conventional ratios (0.81 +/- 0.07) than males (0.66 +/- 0.08). Values represent means and standard deviations. Athletes and controls showed mean functional strength ratios below 1.0. CONCLUSIONS: Although there were no muscular ratio differences between the athletes and the controls, their ratio values were below the literature recommended reference values to prevent shoulder injuries. PMID- 23664057 TI - Generation of functional antibodies for mammalian membrane protein crystallography. AB - Membrane proteins act as gateways to cells, and they are responsible for much of the communication between cells and their environments. Crystallography of membrane proteins is often limited by the difficulty of crystallization in detergent micelles. Co-crystallization with antibody fragments has been reported as a method to facilitate the crystallization of membrane proteins; however, it is widely known that the generation of mouse monoclonal antibodies that recognize the conformational epitopes of mammalian integral membrane proteins is typically difficult. Here, we present our protocols to generate functional mouse antibodies for the membrane protein crystallography, which have enabled us to solve crystal structures of mammalian receptors and transporters complexed with antibody fragments. PMID- 23664058 TI - Exposure to avian influenza H7N9 in farms and wet markets. PMID- 23664059 TI - Acute gastric necrosis and air in the hepatic-portal vein secondary to a strangulated paraumbilical hernia. PMID- 23664060 TI - Reducing exposure to avian influenza H7N9. PMID- 23664061 TI - [Iliac aneurysm rupture during preconditioning with levosimendan for coronary artery bypass graft]. AB - We present the case of a 77 year-old patient scheduled for coronary artery bypass. During the infusion of levosimendan as preconditioning for surgery, a rupture of right common iliac artery occurred. Surgery was delayed and an urgent aorto-bifemoral bypass was performed. We believe that the rupture of the artery was triggered by an increase in transmural pressure due to the inotropic effects of levosimendan in a dilated diseased vessel. To our knowledge, there are no cases of aneurysm rupture as a complication during levosimendan infusion, but the coincidence of events in time strongly suggests some kind of causal relationship. PMID- 23664062 TI - [Emergency cesarean section and craniectomy in a patient with rupture of a cerebral arteriovenous malformation]. AB - The intracerebral hemorrhage in pregnancy is a rare event, but can have catastrophic consequences for both mother and fetus. The management of non ruptured arteriovenous malformations in pregnancy is not free of controversy in the current literature, as there is the possibility of spontaneous bleeding and becoming a true emergency. We report the case of a pregnant patient of 35 weeks with a diagnosis of a cerebral arteriovenous malformation, who developed a sudden onset of headache, generalized tonic-clonic seizures, loss of consciousness, and hemiparesis with radiological images of an intracranial hematoma with a mass effect, and signs of herniation. The multidisciplinary management is discussed, emphasizing perioperative cesarean approach plus craniotomy and drainage of the hematoma, and subsequent management in intensive care, and definitive management by neuroradiology, with a successful outcome. PMID- 23664063 TI - Meta-analysis of joint preservation versus arthroplasty for the treatment of displaced 3- and 4-part fractures of the proximal humerus. AB - PURPOSE: This meta-analysis compares the clinical outcomes of joint preservation versus arthroplasty in the treatment of displaced proximal humerus fractures. METHODS: Medline, CINAHL, and EMBASE were searched for studies published between 1970 and 2011 reporting outcomes of the treatment of 3- or 4-part proximal humerus fractures using the Constant-Murley score in skeletally mature patients. Randomised and cohort studies with >= 1-year follow-up were included. Two individuals independently extracted data, and study results were divided into subgroups based on type of treatment. RESULTS: A meta-analysis with meta regressions was performed on the mean Constant score. Of 610 total participants in the studies analysed, 340 were treated with joint-preserving techniques. The random-effects mean Constant score across all treatment types was 62.7 (95% CI, 61.6-63.9, P<0.001), with joint-preserving treatments demonstrating higher scores than arthroplasty (70 vs. 49, P<0.001). The studies displayed significant heterogeneity (Q statistic=516, P<0.001, I(2)=94.8). In the meta-regression analyses, Constant scores decreased significantly with increasing age, fracture severity, and rate of osteonecrosis (P<0.001). CONCLUSIONS: In the existing literature, displaced proximal humerus fractures demonstrate improved Constant scores when treated with joint-preserving options. Age, fracture pattern, and complication rate are significant predictors of the Constant score independent of the selected treatment. Given the observed heterogeneity and variance in treatment techniques in the included studies, more comparative studies are needed to definitively recommend joint-preserving techniques versus arthroplasty for specific fracture patterns. PMID- 23664064 TI - Accountable care organizations: is the radiologist at risk? PMID- 23664065 TI - Immobilization of tetramethylguanidine on mesoporous SBA-15 silica: a heterogeneous basic catalyst for transesterification of soybean oil. AB - An active heterogeneous catalyst, namely 1,1,3,3-tetramethylguanidine (TMG) immobilized on mesoporous SBA-15 silica (SBA-15-pr-TMG), was prepared and the catalytic activity was investigated for transesterification of soybean oil with methanol. The heterogeneous catalysts were characterized using Hammett titration method, Fourier transform infrared spectra, X-ray diffraction, scanning electron microscopy, transmission electron microscopy, N2 adsorption-desorption, and X-ray photoelectron spectroscopy techniques. It is shown that the activity of the catalysts for the transesterification reaction is closely related to their basic properties. By using this catalyst, an environmentally benign process for biodiesel production in a heterogeneous manner was developed. When the reaction was carried out at reflux of methanol, with a molar ratio of methanol to soybean oil of 15:1, a reaction time 12h and a catalyst amount 5 wt%, the oil conversion of 91.7% was achieved. The catalyst could be recovered easily and reused without significant degradation in activity. PMID- 23664066 TI - Application of an electric field for pretreatment of a seeding source for dark fermentative hydrogen production. AB - In present study, an electric field was newly adopted as a pretreatment method for inoculum preparation in dark fermentative hydrogen production. Various voltages (5-20 V for 10 min) were applied, and the feasibility and efficiency of this method were compared with those of heat pretreatment (90 degrees C for 20 min). Both the highest H2 yield, 1.43 mol H2/mol hexoseadded, and the highest production rate, 101.4 mL H2/L/h, were observed at 10 V. While RNA concentration of above 100mg/L was maintained up to 10 V, it was decreased at an applied voltage of 20 V, where the worst performance was observed. Microbial analysis results confirmed that only H2 producing bacteria were detected with electric pretreatment, while non-H2 producing bacteria coexist with heat and electric (5 V) pretreatment. The results suggested that application of an electric field has reasonable potential as an alternative method for preparing inoculums for hydrogen production. PMID- 23664067 TI - Assessment of biomarkers in Mytilus edulis to determine good environmental status for implementation of MSFD in Ireland. AB - Candidate OSPAR/ICES recommended biomarkers at the level of the individual in Mytilus edulis for determination of good environmental status for MSFD were evaluated against contaminant levels at sites around Ireland. The sites chosen ranged from moderate to low pollution levels, but the actual ranking of the sites varied according to the contaminant levels present. At the most contaminated site, Cork, 4 out of 16 contaminants exceeded the EAC, while at Shannon, no EACs were exceeded. The SOS assay suggested that Cork was the healthiest site with a LT50 of 17.6 days, while SOS for Shannon was 15.6 days. Likewise, condition factors varied among sites and did not always correspond to contaminant-based status. There may be uncertainty in assigning status around the not good:good boundary. This raises potential difficulties not only in the biomarker/contaminant load relationship but also in the reliability of the biomarkers themselves and hence barriers meeting compliance levels. PMID- 23664068 TI - An ecotoxicological analysis of the sediment quality in a European Atlantic harbor emphasizes the current limitations of the Water Framework Directive. AB - The "PortoNovo" project was developed to standardize the methodologies for water quality management in the port areas of coastal Atlantic regions to improve the Water Frame Directive (WFD) for these specific water bodies. Under this scope, water and sediment samples were collected from five sites within the Port of Aveiro, Portugal. According to the physical and chemical parameters that were analyzed (i.e., metals, total organic carbon, polychlorinated biphenyls and polycyclic aromatic hydrocarbons), the sediments were not considered at risk based on European sediment quality laws. However, the bioassays that were performed on the sediment samples (Microtox(r)) and the standardized acute toxicity test using the marine rotifer, Brachionus plicatilis, on sediment elutriates revealed higher toxicity levels. The use of bioassays to assess sediment quality clearly complements more conservative approaches and highlights current gaps within the WFD. The approach presented here can be easily transferred to other port areas for more reliable water quality management. PMID- 23664069 TI - Transmission rate of African swine fever virus under experimental conditions. AB - African swine fever (ASF) is a highly lethal, viral disease of swine. No vaccine is available, so controlling an ASF outbreak is highly dependent on zoosanitary measures, such as stamping out infected herds and quarantining of affected areas. Information on ASF transmission parameters could allow for more efficient application of outbreak control measures. Three transmission experiments were carried out to estimate the transmission parameters of two ASF virus isolates: Malta'78 (in two doses) and Netherlands'86. Different criteria were used for onset of infectiousness of infected pigs and moment of infection of contact pigs. The transmission rate (beta), estimated by a Generalized Linear Model, ranged from 0.45 to 3.63 per day. For the infectious period, a minimum as well as a maximum infectious period was determined, to account for uncertainties regarding infectiousness of persistently infected pigs. While the minimum infectious period ranged from 6 to 7 days, the average maximum infectious period ranged from approximately 20 to nearly 40 days. Estimates of the reproduction ratio (R) for the first generation of transmission ranged from 4.9 to 24.2 for the minimum infectious period and from 9.8 to 66.3 for the maximum infectious period, depending on the isolate. A first approximation of the basic reproduction ratio (R0) resulted in an estimate of 18.0 (6.90-46.9) for the Malta'78 isolate. This is the first R0 estimate of an ASFV isolate under experimental conditions. The estimates of the transmission parameters provide a quantitative insight into ASFV epidemiology and can be used for the design and evaluation of more efficient control measures. PMID- 23664070 TI - [Thrombotic thrombocytopenic purpura associated with interferon therapy in a HIV and HCV co-infected woman]. AB - INTRODUCTION: Causes of acquired thrombotic thrombocytopenic purpura (TTP) are multiple and rarely iatrogenic. CASE REPORT: A 40-year-old, HIV and hepatitis C virus co-infected woman was treated with interferon and ribavirine and developed a TTP confirmed by the presence of anti-ADAMTS 13 antibodies. The outcome was favourable when treatment was discontinued and rituximab infusion administered. CONCLUSION: The occurrence of anemia and thrombocytopenia in patients treated with interferon and ribavirine is not always related to direct toxicities of these treatments. The ADAMS 13 testing may help the clinician to diagnose iatrogenic acquired TTP. PMID- 23664071 TI - Association of growth, feeding practices and exercise conditions with the severity of the osteoarticular status of limbs in French foals. AB - The aim of this study was to identify the risk factors for the severity of Juvenile OsteoChondral Conditions (JOCC) in limbs of French foals. Twenty-one farms in Normandy, France, were sampled and enrolled in a cohort study including 378 foals from three breeds, followed from the 8th month of pregnancy of the mares until the foals were approximately 6months old. Data on growth, feeding practices and exercise conditions were regularly collected. The carpus, the front and hind digits, the hock and the stifle of the foals were radiographed at the end of follow-up. JOCC severity in each foal was described using a global appraisal of its osteoarticular status (OAS) depending on the number and the severity of radiographic findings. Of the 378 foals, 53% had a good OAS, 34% had an intermediate OAS and 13% had a poor OAS. The breed (Selle Francais and French Trotter Standardbred vs. Thoroughbred), a high girth perimeter at early age and an irregular exercise were significantly associated with a poor OAS. This study contributes to the understanding of the development of JOCC. An increased growth and reduced or irregular physical activity during the first weeks of life would be responsible for more severe lesions. Growth and exercise conditions should be carefully monitored to reduce the prevalence of severe JOCC in foals. PMID- 23664072 TI - Implementing biosecurity on dairy farms: rewriting the 'cultural script'. PMID- 23664073 TI - Juvenile osteochondral conditions in the horse: a special issue. Introduction. PMID- 23664074 TI - Patellar clunk syndrome in a current high flexion total knee design. AB - This retrospective study of 208 (204 patients) total knee arthroplasties evaluated the incidence of patellar clunk syndrome for two high-flex posterior stabilized knee prostheses; a high-flex fixed bearing prosthesis and a high-flex mobile bearing prosthesis. Patients were followed for up to two years and were evaluated for patellar clunk and component position. Knees receiving the mobile bearing had a significantly higher (p < 0.001) incidence of patellar clunk (15%) than knees receiving the fixed bearing (0%). There was a significantly higher incidence of patellar clunk in males (34.1%; p < 0.01) compared to females (8.6%). Fibrous nodules were treated surgically in 11 of the knees with patellar clunk. The design of this particular mobile bearing knee seems to contribute to patellar clunk syndrome. PMID- 23664075 TI - Three-year follow up utilizing tantal cones in revision total knee arthroplasty. AB - There still is no consensus on the treatment of choice in revision knee arthroplasty associated with severe femoral and/or tibial bone loss. A total of 44 patients underwent revision knee arthroplasty procedures using porous tantalum cones (TM cones) to reconstruct tibial and/or femoral bone defects. At latest follow up after 37 months (32-48), 38 patients remained in the study. Tibial and femoral bone loss was categorized according to the AORI-Classification. The average preoperative KSS improved from 34 (range, 6-90) to 63 points (range, 7-90 points). The VAS improved from 7.5 to 4.8. Two patients required a re-revision due to aseptic loosening. There was no correlation between the different types of knee prosthesis implanted. Our study shows favourable clinical and radiological outcomes using TM cones in managing significant bone loss in revision total knee surgery. PMID- 23664076 TI - Image guided radiation therapy (IGRT) technologies for radiation therapy localization and delivery. PMID- 23664077 TI - Addressing a gap in current IMRT quality assurance. PMID- 23664078 TI - Hospitalization for hemorrhage among warfarin recipients prescribed amiodarone. AB - Amiodarone inhibits the hepatic metabolism of warfarin, potentiating its anticoagulant effect. However, the clinical consequences of this are not well established. Our objective in this study was to characterize the risk of hospitalization for a hemorrhage associated with the initiation of amiodarone within a cohort of continuous warfarin users in Ontario. We conducted a population-based retrospective cohort study among Ontario residents aged >=66 years receiving warfarin. Among patients with at least 6 months of continuous warfarin therapy, we identified those who were newly prescribed amiodarone and an equal number who were not, matching on age, gender, year of cohort entry, and a high-dimensional propensity score. The primary outcome was hospitalization for hemorrhage within 30 days of amiodarone initiation. Between July 1, 1994, and March 31, 2009, we identified 60,497 patients with at least 6 months of continuous warfarin therapy, of whom 11,665 (19%) commenced amiodarone. For 7,124 (61%) of these, we identified a matched control subject who did not receive amiodarone. Overall, 56 (0.8%) amiodarone recipients and 23 (0.3%) control patients were hospitalized for hemorrhage within 30 days of initiating amiodarone (adjusted hazard ratio 2.45; 95% confidence interval, 1.49-4.02). Seven of 56 (12.5%) patients hospitalized for a hemorrhage after starting amiodarone died in hospital. In conclusion, initiation of amiodarone among older patients receiving warfarin is associated with a more than twofold increase in the risk of hospitalization for hemorrhage, with a relatively high fatality rate. Physicians should closely monitor patients who initiate amiodarone while receiving warfarin. PMID- 23664079 TI - Study design and baseline characteristics of the national observational study of diagnostic and interventional cardiac catheterization by the French Society of Cardiology. AB - The national observational study of diagnostic and interventional cardiac catheterization (ONACI) is a prospective multicenter registry of the French Society of Cardiology including all interventional cardiology procedures performed from 2004. We aimed to evaluate "real-world" management of patients with coronary artery disease in France from this registry. The present study was focused on data collected from 2004 to 2008. Patient demographics and co morbidities, invasive parameters, treatment options, and procedural techniques were prospectively collected. Patients were recruited from 99 hospitals (55% of patients were hospitalized in private clinics and 45% in public institutions). During a 5-year period, a total of 298,105 patients underwent coronary angiography and 176,166 patients underwent percutaneous coronary intervention. Diagnosis was acute coronary syndrome in 22%, stable angina or silent ischemia in 23%, and atypical chest pain in 9% of cases. Normal coronary arteries or nonsignificant coronary narrowing were found in 26% of patients. Radial access was increasingly used over the years regardless of the indication. The average number of percutaneous coronary interventions per procedure was 1.5 +/- 0.7 (range, 1.3 +/- 0.7 to 1.5 +/- 0.7) and that of stents per procedure was 1.5 +/- 0.8 (range, 1.5 +/- 0.8 to 1.6 +/- 0.8). Drug-eluting stents were used in 45% (range, 34% to 62%), increasing from 2004 to 2006, and then decreasing after the 2006 controversy. In conclusion, ONACI is one of the largest catheterization registries during this period, providing a detailed and comprehensive global description of the spectrum and management of patients with suspected coronary artery disease undergoing cardiac catheterization. PMID- 23664080 TI - The state of scientific evidence on air pollution and human health in Nepal. AB - Air pollution has been linked to acute and chronic health effects. However, the majority of evidence is based in North America and Europe, with a growing number of studies in Asia and Latin America. Nepal is one of the many South Asian countries where little such research has been conducted. We summarized the state of scientific evidence and identify research gaps based on the existing literature on air pollution and human health in Nepal. We performed a systematic literature search to identify relevant studies. Studies were categorized as those that estimate: (1) health impacts of indoor air pollution, (2) health impacts of outdoor air pollution, (3) health burdens from outdoor air pollution in Nepal based on existing concentration-response relationships from elsewhere, or (4) exposure and air quality but do not link to health. We identified 89 studies, of which 23 linked air pollution to health impacts. The remainder focused on exposure and air quality, demonstrating high pollution levels. The few health studies focused mainly on indoor air (n=15), especially in rural areas and during cooking. Direct exposure measurements were for short time periods; most studies used indirect exposure methods (e.g., questionnaire). Most health studies had small sample sizes with almost all focusing on respiratory health. Although few studies have examined air pollution and health in Nepal, the existing studies indicate high pollution levels and suggest large health impacts. Nepal's dearth of scientific research on air pollution and health is not unique and likely is similar to that of many other developing regions. Future research with larger studies and more health outcomes is needed. Key challenges include data availability. PMID- 23664081 TI - Temporary cementation in total ankle arthroplasty. AB - Total ankle arthroplasty can be technically demanding in patients with poor bone quality. In bone fragile patients, the use of a temporary cementation technique ("biocementation") can assist in providing a stable, secure implant interface with native bone that is of poor quality. I report the short-term results of 9 ankles (7 consecutive patients) undergoing total ankle replacement with temporary cementation using a slowly resorbable injectable bone graft substitute composed of 75% calcium sulfate and 25% calcium phosphate. PMID- 23664082 TI - An unusual variety of simultaneous fracture dislocation pattern: medial swivel dislocation of talonavicular joint with displaced fractures of the fourth and fifth metatarsals. AB - In published studies, a very rare, special type of Chopart dislocation termed a swivel dislocation has been reported. This injury is characterized by dislocation of the talonavicular joint, but the calcaneocuboid joint remains intact. The foot creates a typical rotational movement without inversion or eversion. The axis of rotation is the interosseous talocalcaneal ligament, which remains intact. We report the case of an 18-year-old male who had experienced a medial swivel dislocation of the talonavicular joint associated with displaced fractures of the fourth and fifth metatarsals. The occurrence, features, and method of treatment of this rare injury are presented. PMID- 23664083 TI - Single-event multilevel acute total correction of complex equinocavovarus deformity in skeletally mature patients with spastic cerebral palsy hemiparesis. AB - Complex multiplanar ankle/foot deformity as equinocavovarus is a common problem in patients with spastic cerebral palsy hemiparesis. The data from 30 consecutive patients (30 feet), treated between March 2009 and March 2010, with equinocavovarus and toe clawing secondary to spastic cerebral palsy hemiparesis, aged 16 to 18 years, were analyzed clinically and radiographically. All the patients had received conservative physiotherapy treatment and ankle/foot orthoses before undergoing combined soft tissue and bony surgical procedures performed in a single session to correct the complex toe clawing, cavus, varus, and equinus deformities. Preoperative measurements of certain foot angles were compared with their corresponding postoperative values. A grading system for evaluation of the results using a point scoring system was used to accurately evaluate both the clinical and the radiographic results after an average follow up period of 2.5 years. Of the 30 patients (30 feet), 18 (60%) had excellent, 9 (30%) good, 3 (10%) fair, and 0 had poor outcomes. Neither vascular problems nor nonunion occurred. Significant improvement was seen postoperatively (p < .0333). Neither staged surgical procedures nor gradual distraction techniques using external fixators are ideal modalities to correct complex ankle/foot equinocavovarus deformity in patients with spastic cerebral palsy. Single-event, multilevel surgery with complete soft tissue and bony correction appears to be the treatment of choice in such cases. It shortens the treatment period and avoids patient dissatisfaction associated with multiple procedures, without major complications. PMID- 23664084 TI - Sex-specific effects of isolation stress and consumption of palatable diet during the prepubertal period on metabolic parameters. AB - OBJECTIVES: Social isolation during the prepubertal period may have long-term effects on metabolism. The exposure to stressful events is associated with increased palatable food intake, constituting reward-based eating. However, palatable food consumption in early life may lead to metabolic alterations later in life. We investigated whether isolation stress during early life can lead to metabolic alterations in male and female rats with or without exposure to a palatable diet. METHODS: Animals were stressed by isolation during one week after weaning, with or without exposure to a palatable diet. RESULTS: Stress and palatable diet induced increased caloric consumption. In females, there was a potentiation of consumption in animals exposed to stress and palatable diet, reflected by increased weight gain and triacylglycerol levels in juveniles, as well as increased adiponectin levels. Most of the effects had disappeared in the adults. Different effects were observed in males: in juveniles, stress increased unacylated ghrelin levels, and hypothalamic neuropeptide Y (NPY). Subsequently, adult males that were exposed to a palatable diet during prepuberty showed increased body weight and retroperitoneal fat deposition, increased glycemia, and decreased plasma adiponectin and hypothalamic NPY. Exposure to stress during prepuberty led to increased adrenals during adulthood, decreased LDL-cholesterol and increased triacylglycerol levels. CONCLUSION: Isolation stress and consumption of palatable diet changes metabolism in a sex-specific manner. Prepuberty female rats were more prone to stress effects on food consumption, while males showed more long-lasting effects, being more susceptible to a metabolic programming after the consumption of a palatable diet. PMID- 23664085 TI - Irisin: a renaissance in metabolism? PMID- 23664086 TI - A psychological pathway from insomnia to depression among older adults. AB - BACKGROUND: Higher levels of insomnia predict greater depression severity among older adults; however, the psychological mechanisms underlying this relationship are unclear. This study tested a path model that explored whether dysfunctional beliefs about sleep and hopelessness mediated the relationship from insomnia to depression. It was hypothesized that insomnia would predict depression, both directly and indirectly, via dysfunctional beliefs about sleep and hopelessness. METHODS: A community sample of 218 independent-living Australian older adults aged from 65 to 96 years completed a self-report questionnaire package. From the initial 218 participants, 171 completed a measure of depression three months later. RESULTS: Path analysis demonstrated that maladaptive sleep beliefs and hopelessness partly explained how insomnia influenced depression, irrespective of the presence of obstructive sleep apnea and/or restless legs syndrome. CONCLUSIONS: An older adult's beliefs about sleep and sense of hopelessness were important psychological factors that helped explain how insomnia related to depression. PMID- 23664087 TI - Dietary intake and health risk assessment of lead and cadmium via consumption of cow meat for an urban population in Enugu State, Nigeria. AB - The study assessed the dietary intake of lead and cadmium and health risk from consumption of various parts of cow meat by the urban population of Enugu State, Nigeria. Meat samples (n=150) comprising of muscle, liver, kidney, intestine and tripe were purchased from abattoirs in Nsukka and Enugu. The samples were dried, ground and two gram was digested with 3:2 HNO3:HClO4 v/v. The Cd and Pb concentrations were read with an atomic absorption spectrophotometer. The dietary intakes were estimated using a one week food frequency questionnaire administered to 755 subjects. The dietary intake of lead (ug/kg body weight/week) were in the following ranges; men [0.15 (kidney)-0.55(intestine)], non pregnant/non lactating women [0.16 (kidney)-0.62 (liver)], pregnant/lactating women [0.13 (kidney)-0.53 (intestine)], undergraduate students [0.12 (kidney)-0.62 (intestine)] and school children [0.29 (kidney)-1.16 (liver)]; cadmium: men [0.42 (liver)-1.21 (tripe)], non-pregnant/non-lactating women [0.53 (kidney)-1.20 (tripe)], pregnant/lactating women [0.43 (kidney)-0.90 (intestine)], undergraduate students [0.40 (kidney) 1.18 (tripe)] and school children [0.97 (kidney)-1.93 (tripe)]. The total dietary intakes of lead from the various cow meat parts by the groups were much lower than the provisional tolerable weekly intake (PTWI) guide line, but for cadmium, the intakes were quite appreciable when compared to the PTWI guideline while the intake for school children was very high, 113% of PTWI for the metal. The target hazard quotients were in the range of 0.05-0.10 for lead and 0.42-0.90 for cadmium. These values are less than one, indicating that the subjects are not exposed to any significant health risk via cow meat consumption. PMID- 23664088 TI - Screening of in vitro cytotoxicity, antioxidant potential and bioactivity of nano and micro-ZrO2 and -TiO2 particles. AB - Nanometal oxides are used in tissue engineering and implants. The increased use of nanoparticles suggests the need to study their adverse effects on biological systems. The present investigation explores in vitro cytotoxicity, antioxidant potential, and bioactivity of nano- and micro-particles such as zirconia (ZrO2) and titania (TiO2) on biological systems such as National Institute of Health (NIH) 3T3 mouse embryonic fibroblasts cell line, di(phenyl)-(2,4,6 trinitrophenyl) iminoazanium (DPPH) and simulated body fluid (SBF). The cell line viability % indicated that nano ZrO2 and TiO2 were less toxic than microparticles up to 200ugml(-1). DPPH assay revealed that the free radical scavenging potential of tested particles were higher for nano ZrO2 (76.9%) and nano TiO2 (73.3%) at 100mg than that for micron size particles. Calcium deposition percentage of micro and nano-ZrO2 particles, after SBF study, showed 0.066% and 0.094% respectively, whereas for micro- and nano-TiO2, it was 0.251% and 0.615% respectively. FTIR results showed a good bioactivity through hydroxyapatite formation. The present investigation clearly shows that nanoparticles possess good antioxidant potential and better biocompatibility under in vitro conditions which are dose and size dependent. Hence, cytotoxicity itself is not promising evaluation method for toxicity rather than particles individual characterisation using antioxidant and bioactivity analysis. PMID- 23664089 TI - Information literacy during entry to practice: information-seeking behaviors in student nurses and recent nurse graduates. AB - BACKGROUND: The ability to locate information pertinent to guide clinical practice is important for quality nursing care and patient safety. To date, little is known about the transfer of information literacy skills as student nurses transition to clinical practice as new graduates. This study begins to address this gap from the perspective of student nurses, recent nurse graduates (RNs), nurse leaders and library staff. OBJECTIVES: To describe the information seeking behaviors of student nurses and RNs within their clinical settings. DESIGN AND PARTICIPANTS: This is a descriptive study that included both cross sectional surveys and key informant interviews. Participants were senior-level undergraduate students and recently graduated RNs (graduated since 2008), and nurse leaders and library staff employed in one of the clinical sites accepting undergraduate students from the McMaster Mohawk and Conestoga BScN program. The study was completed in two large hospital corporations in Hamilton, Ontario, Canada. METHODS: Student nurses and RNs were invited to complete online surveys to assess their access to and use of information sources and resources within clinical practice. Students completed a survey comprised of five open-ended questions, while RNs completed a survey comprised of 13 fixed choice and open ended questions. Nurse leaders and library staff participated in qualitative interviews to verify the extent and availability of information resources. RESULTS: Eighteen RNs and 62 students completed their respective surveys. Three categories of information sources and resources were identified: electronic, print and interpersonal. Electronic sources of information were the most used resource by both students and RNs. More RNs reported using interpersonal sources, while students reported using more print sources of information. CONCLUSIONS: Recent RN graduates meet the Canadian Association of Schools of Nursing performance indicators related to information access for the entry to practice Nursing Informatics competencies. PMID- 23664090 TI - Transplantation of human mesenchymal stem cells loaded on collagen scaffolds for the treatment of traumatic brain injury in rats. AB - Studies have suggested that mesenchymal stem cells (MSCs) have therapeutic effects following traumatic brain injury (TBI). However, cell distribution and survival rate are two major barriers to their success as therapeutic treatment. The improvement of cell therapy using collagen delivery matrices had been reported. However, we know very little about the mechanisms. We labeled human bone marrow-derived mesenchymal stem cells (hMSCs) with a positron emission tomography (PET) tracer, 18F-fluoro-2-deoxy-D-glucose (FDG). hMSCs were transplanted with or without collagen scaffolds into rats with experimental TBI and the whole-body nuclear images were compared. Collagen scaffolds increased the retention of hBMSC in the lesion site and limited its distribution at the transplanted region. Significantly more hMSCs were detected in the brain when transplanted with collagen scaffolds. The results showed collagen scaffolds also efficiently improved cell survival and neurite outgrowth in vivo, resulting in better neural functional recovery. In addition, brain metabolism also improved in the collagen scaffold implanted group, as evaluated by PET. We speculated that collagen scaffolds would improve early engraftment and support the survival of grafted cells post-transplantation. PMID- 23664092 TI - New biologic therapy for systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a heterogenous multi-systemic autoimmune disease that is associated with considerable morbidity and mortality. Rituximab is one of the earliest biologic therapies used in SLE. It performed well in off label studies but failed to demonstrate efficacy in randomised controlled trials. Abatacept is a biologic developed for inflammatory arthritis but has shown promise in SLE. Belimumab is the first biologically approved therapy in fifty years for treatment of SLE. The development of biological therapies for SLE parallels the increasing understanding of the immunopathogenesis of SLE and looks promising. New drugs in development are those targeting the co-stimulatory modulation, cytokines and the B and T cells. Of interest are epratuzumab, the interferon antagonists and peptide-based therapies. PMID- 23664091 TI - Tumour heterogeneity and immune-modulation. AB - Recent advances in sequencing technologies have revealed extensive intratumour heterogeneity (ITH) both within individual tumours and between primary and metastatic tumours for different cancer types. Such genetic diversity may have clinical implications for both cancer diagnosis and treatment with increasing evidence linking ITH and therapeutic resistance. Nonetheless, whilst limiting the activity of targeted agents, tumour genetic heterogeneity may provide a new therapeutic opportunity through generation of neo-antigens that could be recognised and targeted by the patient's own immune system in response to immune modulatory therapies. Longitudinal genomic studies assessing tumour clonal architecture and its correlation with the underlying immune response to cancer in each particular patient are needed to follow tumour evolutionary dynamics over time and through therapy, in order to further understand the mechanisms behind drug resistance and to inform the development of new combinatorial therapeutic strategies. PMID- 23664093 TI - Clinical significance of surgery for gastric submucosal tumours with size enlargement during watchful waiting period. AB - BACKGROUND: The true impact of surgery for small, asymptomatic and biopsy negative gastric submucosal tumours (SMTs) with size enlargement during 'watchful waiting' period has not been fully understood. METHODS: From 2005 to 2012, 100 patients with gastric SMTs underwent surgery. Twenty-three of them with size enlargement during observation period were enrolled in the retrospective analysis. Data included clinicopathologic findings, genetic findings, operative outcomes and prognoses. RESULTS: All patients (13 males, 10 females), with median age of 54 (41-71), had their lesions detected by routine health check-up (n=21) or incidentally (2). The tumours were 1.8 (0.5-4.0)cm in size at their initial detection, and enlarged up to 3.2 (2.0-7.0)cm at the operation during 63.0 (14.6 233.7) months. As surgical procedure, laparoscopic partial gastrectomy accounted for the majority (78.3%). Histologic examination revealed gastrointestinal stromal tumour (GIST) (21) and schwannoma (2). Although 16 out of 21 GISTs were categorised into 'Very low' (1), and 'Low' (13) risk according to Fletcher's classification, 'Intermediate' (5) and 'High' (2) risk were identified in the series. No recurrences/metastases were noted in 23.2 (0.9-87) months of postoperative follow-up. CONCLUSION: Our study revealed the existence of high mitotic GISTs in asymptomatic, small gastric SMTs with size enlargement, and laparoscopic surgery was safely applied to majority of those cases. Prompt surgical intervention should therefore be considered for those lesions. PMID- 23664094 TI - Robust gene expression signature is not merely a significant P value. PMID- 23664095 TI - Characterization of interleukin-1beta in Helicobacter pylori-induced gastric inflammation and DNA methylation in interleukin-1 receptor type 1 knockout (IL 1R1(-/-)) mice. AB - Helicobacter pylori infection induced interleukin-1beta (IL-1beta) production and is associated with aberrant DNA methylation and gastric diseases. Here, we investigated the role of IL-1beta in H. pylori-induced gastric inflammation and DNA methylation using IL-1 receptor type 1 knockout (IL-1R1(-/-)) mice, and compared the therapeutic efficacy of antimicrobial therapy with IL-1 receptor antagonist (IL-1ra). IL-1R1(-/-) and wild-type (WT) mice were infected with H. pylori for 16, 24 and 32 weeks. Infected WT mice at 24 weeks were given either antimicrobial therapy or IL-1ra. Comparing to the IL-1R1(-/-) mice, infected WT mice with functional IL-1beta signaling had higher gastritis scores, higher IL 1beta and iNOS mRNA expression, higher nitric oxide (NO) production and increased frequency of E-cadherin (E-cad) methylation at all the time points analyzed. IL 1beta release was significantly elevated in infected WT mice than normal controls at 16 weeks post-infection (p<0.005). Treatment of infected mice with antimicrobial therapy and IL-1ra significantly reduced the degree of gastritis (p<0.005; p<0.05, respectively), iNOS expression (p<0.0001; p<0.01, respectively) and NO production (both p<0.001) compared with untreated controls. Mice receiving antimicrobial therapy had significantly lower IL-1beta expression than untreated controls (p<0.0001). Both treatments reduced the incidence of E-cad methylation in infected mice compared with controls, however, no statistical significance was observed. There was no significant alteration of total DNA methyltransferase (DNMT) activity. These results demonstrated that IL-1beta played a crucial role in H. pylori-induced gastric inflammation and DNA methylation. H. pylori eradication and IL-1ra administration could ameliorate inflammatory stress. PMID- 23664096 TI - Rare overexpression of anaplastic lymphoma kinase gene in inflammatory and non inflammatory breast cancer. PMID- 23664097 TI - Enhancement role of host 12/15-lipoxygenase in melanoma progression. AB - 12/15-Lipoxygenase (12/15-LOX) is a non-haeme iron-containing dioxygenase that forms 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) or 15(S)-HETE. Several biological mediators including cytokines, growth factors and lipid metabolites released during tumour cell-endothelial cell adhesion are associated with malignant tumour progression. Here we found that HETEs released from the host organ played a critical role in tumour metastasis. Intravenous injection of B16F10 melanoma cells caused lung nodule formation, which was markedly attenuated in 12/15-LOX null mice. Co-injection of melanoma cells with 12(S)-HETE increased the lung homing activity of B16F10 melanoma cells. In vitro studies showed that 12(S)-HETE and 15(S)-HETE treatment resulted in a concentration-dependent increase of adhesion of B16F10 cells on collagen or fibronectin. The melanoma cell adhesion was then evaluated in pulmonary primary cell culture isolated from wild-type (WT) and 12/15-LOX knockout (KO) mice. It was found that the adhesion of melanoma cells on the epithelial cells isolated from 12/15-LOX null mice was reduced in comparison with those isolated from WT mice. Treatment of 12(S)-HETE increased the pFAK in melanoma cells adhering on collagen-coated slide. The enhancement of adherence elicited by 12(S)-HETE in B16F10 cells could be antagonised by focal adhesion kinase (FAK) inhibitor 14 (FAK inhibitor) or PD98059 (extracellular signal-regulated kinase (ERK) inhibitor). 12(S)-HETE increased the phosphorylation of FAK and ERK in adhering melanoma cells. The FAK phosphorylation induced by 12(S)-HETE was further inhibited by PD98059, indicating that FAK is the downstream target of ERK. The adhesion and lung metastasis of human melanoma cells of C32 in NOD/SCID mice were also potentiated by co-treatment with 12(S)-HETE. These results demonstrate that 12(S)-HETE/15(S) HETE activates ERK and FAK signalling pathways, thereby upregulates the adhesion and metastatic potential of melanoma cells. The endogenous release of 12(S) HETE/15(S)-HETE in the host organ may affect the metastatic potential of melanoma. PMID- 23664098 TI - The strength of small: improved targeting of insulin-like growth factor-1 receptor (IGF-1R) with F(ab')2-R1507 fragments in Ewing sarcomas. AB - PURPOSE: To investigate whether F(ab')2-fragments of the monoclonal Insulin-like Growth Factor-1 Receptor (IGF-1R) antibody R1507 (F(ab')2-R1507) can successfully target IGF-1R in Ewing sarcomas (ES). MATERIALS AND METHODS: BALB/c nude mice were subcutaneously implanted with IGF-1R-expressing human ES xenografts (EW-5 and EW-8) which previously showed heterogeneous or no uptake of indium-111 labelled R1507 IgG ((111)In-R1507), respectively. Mice were injected with (111)In F(ab')2-R1507 or (111)In-R1507 as a reference. Biodistribution and immuno SPECT/computed tomography (CT) imaging studies were carried out 2, 4, 8 and 24 h post-injection (p.i.) for (111)In-F(ab')2-R1507 and 24 h p.i. for (111)In-R1507. RESULTS: Biodistribution studies showed specific accumulation of (111)In-F(ab')2 R1507 in EW-5 xenografts from t=2 h p.i. onwards (3.6 +/- 0.2%ID/g at t = 24 h p.i.) and (111)In-F(ab')2-R1507 immuno-SPECT showed almost homogeneous intratumoural distribution at t=24h p.i. Tumour-to-blood ratios of (111)In F(ab')2-R1507 were significantly higher than those of (111)In-R1507 at t=24 h p.i. (2.4 +/- 0.4 versus 0.5 +/- 0.1, respectively; p<0.05). More importantly, (111)In-F(ab')2-R1507 also specifically accumulated in EW-8 tumours (3.7 +/- 0.7%ID/g at t = 24 h p.i). In both EW-5 and EW-8 tumours, there was a good spatial correlation between IGF-1R expression and (111)In-F(ab')2-R1507 tumour distribution. CONCLUSION: (111)In-F(ab')2-R1507 fragments can successfully target IGF-1R in ES models and have superior tumour penetrating and IGF-1R-targeting properties as compared to (111)In-R1507. This suggests that anti-IGF-1R therapies in ES and other tumours may be improved by using smaller therapeutic compounds, although further in vivo studies addressing this topic are warranted. PMID- 23664099 TI - Design, synthesis, quantum chemical studies and biological activity evaluation of pyrazole-benzimidazole derivatives as potent Aurora A/B kinase inhibitors. AB - Novel pyrazole-benzimidazole derivatives have been designed and synthesized. The entire target compounds were determined against cancer cell lines U937, K562, A549, LoVo and HT29 and were screened for Aurora A/B kinase inhibitory activity in vitro. The compounds 7a, 7b, 7i, 7k and 7l demonstrated significant cancer cell lines and Aurora A/B kinase inhibitory activities. Molecular modeling studies suggested the derivatives have bound in the active site of Aurora A kinase through the formation of four hydrogen bonds. Quantum chemical studies were carried out on these compounds to understand the structural features essential for activity. The cellular activity of 7k was also tested by immunofluorescence. PMID- 23664100 TI - Opportunistic salpingectomy for women at low risk for development of ovarian carcinoma: the time has come. PMID- 23664101 TI - Photoperiod and melatonin treatments for controlling sperm parameters, testicular and accessory sex glands size in male Iberian ibex: A model for captive mountain ruminants. AB - This study examines whether photoperiod and/or melatonin treatments can improve sperm variables outside the breeding season in the Iberian ibex-a model species for wild mountain ruminants-thus helping in the collection of high quality sperm beyond the normal breeding season for depositing in genetic resource banks. Adult Iberian ibex males (n=17) were divided into four treatment groups: (1) controls under the natural photoperiod (control group; n=4), (2) treatment with melatonin implants on December 22nd, February 22nd and April 22nd (group WS-M; n=5), (3) treatment with short photoperiod cycles, i.e., 2 months of long days followed by melatonin implants (to emulate 2 months of short days) throughout the year (group PHPld+M; n=4), and (4) treatment with melatonin implants on June 22nd and August 22nd (group SS-M; n=4). The interaction treatment x season had a strong influence on testis size (P<0.05), the size of the seminal vesicles (P<0.001), the percentage of abnormal sperms (P<0.05), and percentage non-progressive (P<0.05) and progressive (P<0.001) sperm motility. In groups WS-M and PHPld+M, the normal springtime physiological reductions in testis size, non-progressive sperm motility and acrosome integrity were prevented. The values for the studied sperm variables were, however, reduced in the natural breeding season at the end of the experimental period in group PHPld+M, although not in group WS-M. The pattern of melatonin administration in group SS-M conferred no advantages on reproductive functionality. These results suggest that lengthening the short day period after the winter solstice (the WS-M treatment) extends reproductive activity in this species, allowing good quality sperm to be recovered for conservation purposes during the non-breeding season. PMID- 23664102 TI - Comparison of 2 minimally invasive routes for hysterectomy of large uteri. AB - OBJECTIVE: To compare the perioperative outcomes associated with 2 minimally invasive surgical routes for the hysterectomy of large fibroid uteri. METHODS: Retrospective review of 84 women undergoing hysterectomy via minilaparotomy (n=54) or robot-assisted laparoscopy (n=30) for uteri weighing at least 500g. Outcome measures included hemorrhage (blood loss of 500mL or more) and postoperative length of stay. RESULTS: Unadjusted mean blood loss (560.2+/ 507.4mL versus 165.0+/-257.5mL, P<0.001), rate of hemorrhage (40.7% versus 6.7%, P=0.001, odds ratio 6.1 [95% confidence interval 1.5-24.2]), and rate of blood transfusion (14.8% versus 0%, P=0.03 ) were all higher with minilaparotomy than with robot-assisted surgery, while the median postoperative stay was significantly shorter with robotic surgery (2 [range 1-4] days versus 1 [range 0 7] days, P<0.01). After adjusting for differences in uterine weight using a multivariate linear regression analysis, the mean blood loss and the rate of hemorrhage were no longer significantly different between the 2 groups. CONCLUSION: The minilaparotomy approach may be used to remove very large uteri and does not require specialized and expensive equipment, or advanced endoscopic training. The robotic approach, when feasible, allows for early postoperative discharge. PMID- 23664103 TI - Constitutional and occupational risk factors associated with bladder cancer. AB - OBJECTIVE: Bladder carcinoma (BC) is the fourth most common type of cancer in males from Western countries, with primary prevention an important healthcare challenge. We review the associated constitutional and occupational risk factors (RF), with greater or lesser scientific evidence, in the aetiology of BC. MATERIAL AND METHODS: Literature review of the last 25 years of the constitutional and occupational RF associated with BC, conducted on MedLine, CancerLit, Science Citation Index and Embase. The search profiles were Risk factors/Genetic factors/Genetic polymorphisms/Epidemiology/Occupational factors and Bladder cancer. RESULTS: The main RF were a) age and gender (diagnosed at age 65 and over, with a 4:1 ratio of males to females); b) race, ethnicity and geographic location (predominantly in Caucasians and in Southern European countries); c) genetic (N-acetyltransferase-2 and glutathione s-transferase M1 gene mutations, which significantly increase the risk for BC); d) occupational, which represent 5%-10% of BC RF; and f) occupations with high BC risk, such as aluminium production, the manufacture of dyes, paints and colourings, the rubber industry and the extraction and industrial use of fossil fuels. CONCLUSIONS: BC is the end result of the variable combination of constitutional and environmental RF, the majority of which are unknown. The most significant constitutional RF are related to age, gender, race, ethnicity geographic location and genetic polymorphisms. The main occupational RF are those related to aromatic amines and polycyclic aromatic hydrocarbons. PMID- 23664105 TI - High-risk populations for vision loss and eye care underutilization: a review of the literature and ideas on moving forward. AB - Much work has been done to highlight and understand the significant disparities in the use of eye care services, but they continue to exist. We review the existing literature on utilization in high-risk populations to provide a context for understanding what "high-risk" means, to understand the utilization patterns among high-risk populations, and to highlight barriers to appropriate eye care utilization. We also discuss potential approaches to reduce these disparities. PMID- 23664106 TI - Lifelong learning in nursing: a Delphi study. AB - BACKGROUND: In order to foster a culture of lifelong learning in nursing, it is important to identify what the concept means in the nursing profession as well as the characteristics of a lifelong learner. OBJECTIVES: The purpose of this Delphi study was to conceptualize lifelong learning from the perspective of nursing, and to identify characteristics and essential elements of lifelong learning. DESIGN AND METHOD: A Delphi Study technique in three phases was completed using an online survey tool. Data were analyzed for conceptual description, ratings of characteristics and attributes, and expert consensus in these three phases. SETTING: An online survey tool was used in this study. PARTICIPANTS: Recognized experts in nursing education, administration and public policy participated in this study. RESULTS: Lifelong learning in nursing is defined as a dynamic process, which encompasses both personal and professional life. This learning process is also both formal and informal. Lifelong learning involves seeking and appreciating new worlds or ideas in order to gain a new perspective as well as questioning one's environment, knowledge, skills and interactions. The most essential characteristics of a lifelong learner are reflection, questioning, enjoying learning, understanding the dynamic nature of knowledge, and engaging in learning by actively seeking learning opportunities. Keeping the mind active is essential to both lifelong learning and being able to translate knowledge into the capacity to deliver high quality nursing care. CONCLUSIONS: It is hoped that a clearer understanding of lifelong learning in nursing will foster more discussion and research about intentional, active inclusion of lifelong learning behaviors in nursing curricula. PMID- 23664107 TI - Assessing global partnerships in graduate nursing. AB - North-South partnerships in graduate nursing education can prepare students to address global healthcare issues, increase cultural competence, and build research capacity. However, the current literature does not include a critical and systematic assessment of partnerships using established guidelines. This paper has two objectives: 1) Find and refine a suitable measure to assess a North South inter-institutional research and clinical partnership in nursing; 2) Pilot test an assessment measure and describe the results of a systematic institutional self-evaluation of a developing North-South research and clinical partnership within a graduate nursing program. The first objective was addressed by searching for, examining and selecting an assessment measure. The second objective was obtained by applying the assessment measure to a developing graduate-level research and clinical partnership between a Canadian School of Nursing and a Malawian College of Nursing; qualitative data collected included information from a document review and subjective experiences of partners. Results showed that when appropriate revisions are made to an existing guideline, it is applicable to use as an assessment measure for North-South inter-institutional research and clinical partnerships. Recommendations for improvement were made, allowing the guideline to be more specific for research and clinical partnerships. Results demonstrated that the existing Canadian-Malawian partnership was strongest in the guideline category of "shaping the purpose and scope of the partnership," and weakest in "partnership implementation and context." This paper implies that: 1) evaluation can strengthen partnerships and enhance educational experience for nursing students; 2) research comparing and contrasting different genres of partnerships could help determine which type is the most appropriate for an institutions' particular outcome goals; and 3) effective establishment and maintenance of North-South partnership occurs through an on-going process of evaluation. PMID- 23664108 TI - [Toxicity by "chocho agua"]. PMID- 23664109 TI - [Multiple sebaceous hyperplasia secondary to ciclosporin in a heart transplant patient]. PMID- 23664110 TI - Country-specific young adult dual-energy X-ray absorptiometry reference data are warranted for T-score calculations in women: data from the peak-25 cohort. AB - The aims of this study were to provide normative data for dual-energy X-ray absorptiometry (DXA) in 25-yr-old women and evaluate whether young adult Swedish women have bone mineral density (BMD) comparable with DXA manufacturer reference values and other equivalent populations. BMD at all sites was measured in the population-based Peak-25 cohort (n = 1061 women; age, 25.5 +/- 0.2yr). BMD values were standardized (sBMD) and compared against the Third National Health and Nutrition Examination Survey (NHANES III) and other cohorts. Based on the DXA manufacturer-supplied reference values, Z-scores were 0.54 +/- 0.98 (femoral neck [FN]), 0.47 +/- 0.96 (total hip [TH]), and 0.32 +/- 1.03 (lumbar spine [LS]). In comparison with other studies, sBMD was higher in the Peak-25 cohort (FN, 1.5% 8.3%; TH, 3.9%-9.2%; and LS, 2.4%-6.5%) with the exception of trochanter-sBMD which was 2.5% lower compared with NHANES III. The concordance in identifying those in the lowest or highest quartile of BMD was highest between hip measurements (low, 71%-78% and high, 70%-84%), corresponding discordance of 0% 1%. At this age, the correlation between DXA sites was strong (r = 0.62-0.94). BMD in Swedish young adult women is generally higher than has been reported in other equivalently aged European and North American cohorts and suggests that the high fracture incidence in Sweden is not explained by lower peak bone mass. The use of nonregional-specific DXA reference data could contribute to misdiagnosed osteoporosis in elderly women. PMID- 23664111 TI - Potential sources of quantification error when retrospectively assessing metacarpal bone loss from historical radiographs by using digital X-ray radiogrammetry: an experimental study. AB - During the past 15 yr, digital X-ray radiogrammetry (DXR) has been used to measure metacarpal bone mineral density (BMD). BMD is often measured in existing cohorts where X-ray images were not acquired in accordance with the DXR imaging protocol (DIP). The purpose of the present study was to analyze how deviations from DIP in historical radiographs may affect the reproducibility of DXR-BMD measurements. Cadaver hand phantoms were used to conduct repeat measurements of deviations from DIP with respect to voltage, exposure, lateral displacement, supination, combination of lateral displacement and supination or rotation, extension of the wrist, and edge enhancement. Direct digital radiography (Aristos; Siemens Healthcare, Erlangen, Germany) was used for image acquisition and dxr-online (Sectra, Linkoping, Sweden) for DXR-BMD measurements. The influence of the tested deviations from DIP ranged from 0 to 32.5 mg/cm(2) (0 6.8%). On repetition with the same specimen, none of the deviations resulted in a within-specimen reproducibility error greater than 2 mg/cm(2) (0.4%, equivalent to a T-score of 0.042). Among the tested deviations, all except tube voltage had a magnitude greater than the normal measurement noise for the technique and must therefore be considered when planning a study based on historical images. PMID- 23664112 TI - Reducing the health consequences of opioid addiction in primary care. AB - Addiction to prescription opioids is prevalent in primary care settings. Increasing prescription opioid use is largely responsible for a parallel increase in overdose nationally. Many patients most at risk for addiction and overdose come into regular contact with primary care providers. Lack of routine addiction screening results in missed treatment opportunities in this setting. We reviewed the literature on screening and brief interventions for addictive disorders in primary care settings, focusing on opioid addiction. Screening and brief interventions can improve health outcomes for chronic illnesses including diabetes, hypertension, and asthma. Similarly, through the use of screening and brief interventions, patients with addiction can achieve improved health outcome. A spectrum of low-threshold care options can reduce the negative health consequences among individuals with opioid addiction. Screening in primary care coupled with short interventions, including motivational interviewing, syringe distribution, naloxone prescription for overdose prevention, and buprenorphine treatment are effective ways to manage addiction and its associated risks and improve health outcomes for individuals with opioid addiction. PMID- 23664113 TI - Computerizing natural history collections. AB - Computers are ubiquitous in the life sciences and are associated with many of the practical and conceptual changes that characterize biology's twentieth-century transformation. Yet comparatively little has been written about how scientists use computers. Despite this relative lack of scholarly attention, the claim that computers revolutionized the life sciences by making the impossible possible is widespread, and relatively unchallenged. How did the introduction of computers into research programs shape scientific practice? The Museum of Vertebrate Zoology (MVZ) at the University of California, Berkeley provides a tractable way into this under-examined question because it is possible to follow the computerization of data in the context of long-term research programs. PMID- 23664114 TI - The impact of pharmaceutical innovation on longevity and medical expenditure in France, 2000-2009. AB - Longitudinal, disease-level data are used to analyze the impact of pharmaceutical innovation on longevity (mean age at death) and medical expenditure in France during the period 2000-2009. The estimates imply that pharmaceutical innovation increased mean age at death by 0.29 years (3.43 months) during this period-about one-fifth of the total increase in longevity. This estimate is smaller than those obtained in previous studies of Germany and the U.S., but the rate of adoption of new drugs was lower in France. Longevity is much more strongly related to the number of drugs than it is to the number of drug classes. Pharmaceutical innovation during 2000-2009 is estimated to have increased per capita pharmaceutical expenditure by $125 (26%) in 2009, but most (87%) of this increase was offset by a reduction in hospital expenditure. The baseline estimate of the cost per life-year gained from pharmaceutical innovation in France during 2000 2009 is about $8100. This estimate is fairly close to the mean of estimates obtained ($10,800) from U.S., German, and Australian studies. PMID- 23664115 TI - Loss of fat-free mass over four years in adult cystic fibrosis is associated with high serum interleukin-6 levels but not tumour necrosis factor-alpha. AB - BACKGROUND & AIMS: Malnutrition is associated with poorer outcome in cystic fibrosis (CF). This follow-up study aimed to document nutritional status changes, including fat-free mass (FFM), in adults with CF; and to identify predictors of FFM loss. METHODS: Fifty-eight non-transplanted CF adults (mean +/- SD forced expiratory volume in one second (FEV1) 63.7 +/- 21.4%predicted; mean +/- SD age 30.3 +/- 7.7years at baseline) were studied at baseline and 3.6 +/- 0.4 years later. Body composition was measured using dual-energy X-ray absorptiometry. At follow-up, blood was analysed for interleukin-6 and tumour necrosis factor-alpha (TNF-alpha) on three occasions over six months and averaged for each participant. Associations with annual percentage change in FFM (ann%DeltaFFM), including cytokines, CF genotype and annual change in FEV1%predicted (annDeltaFEV1%), were determined. RESULTS: Mean FFM was 49.5 +/- 8.8 kg at baseline and 49.6 +/- 8.9 kg at follow-up (p = 0.66). Ann%DeltaFFM ranged from -2.0 to +3.6%. FEV1%predicted declined by 1.2 +/- 2.4% per year. Forty percent of participants had elevated average interleukin-6 levels. Ann%DeltaFFM was negatively correlated with interleukin-6 levels (rho -0.34, p = 0.008), but not TNF-alpha or annDeltaFEV1%. F508DEL homozygote or heterozygote participants had greater FFM loss than those carrying no F508DEL allele (p = 0.01). CONCLUSION: Higher serum interleukin-6 and presence of the F508DEL mutation, but not TNF-alpha, were associated with FFM loss in adults with CF. PMID- 23664116 TI - Mutations in BICD2, which encodes a golgin and important motor adaptor, cause congenital autosomal-dominant spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is a heterogeneous group of neuromuscular disorders caused by degeneration of lower motor neurons. Although functional loss of SMN1 is associated with autosomal-recessive childhood SMA, the genetic cause for most families affected by dominantly inherited SMA is unknown. Here, we identified pathogenic variants in bicaudal D homolog 2 (Drosophila) (BICD2) in three families afflicted with autosomal-dominant SMA. Affected individuals displayed congenital slowly progressive muscle weakness mainly of the lower limbs and congenital contractures. In a large Dutch family, linkage analysis identified a 9q22.3 locus in which exome sequencing uncovered c.320C>T (p.Ser107Leu) in BICD2. Sequencing of 23 additional families affected by dominant SMA led to the identification of pathogenic variants in one family from Canada (c.2108C>T [p.Thr703Met]) and one from the Netherlands (c.563A>C [p.Asn188Thr]). BICD2 is a golgin and motor-adaptor protein involved in Golgi dynamics and vesicular and mRNA transport. Transient transfection of HeLa cells with all three mutant BICD2 cDNAs caused massive Golgi fragmentation. This observation was even more prominent in primary fibroblasts from an individual harboring c.2108C>T (p.Thr703Met) (affecting the C-terminal coiled-coil domain) and slightly less evident in individuals with c.563A>C (p.Asn188Thr) (affecting the N-terminal coiled-coil domain). Furthermore, BICD2 levels were reduced in affected individuals and trapped within the fragmented Golgi. Previous studies have shown that Drosophila mutant BicD causes reduced larvae locomotion by impaired clathrin mediated synaptic endocytosis in neuromuscular junctions. These data emphasize the relevance of BICD2 in synaptic-vesicle recycling and support the conclusion that BICD2 mutations cause congenital slowly progressive dominant SMA. PMID- 23664117 TI - Mutations in B3GALT6, which encodes a glycosaminoglycan linker region enzyme, cause a spectrum of skeletal and connective tissue disorders. AB - Proteoglycans (PGs) are a major component of the extracellular matrix in many tissues and function as structural and regulatory molecules. PGs are composed of core proteins and glycosaminoglycan (GAG) side chains. The biosynthesis of GAGs starts with the linker region that consists of four sugar residues and is followed by repeating disaccharide units. By exome sequencing, we found that B3GALT6 encoding an enzyme involved in the biosynthesis of the GAG linker region is responsible for a severe skeletal dysplasia, spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMD-JL1). B3GALT6 loss-of-function mutations were found in individuals with SEMD-JL1 from seven families. In a subsequent candidate gene study based on the phenotypic similarity, we found that B3GALT6 is also responsible for a connective tissue disease, Ehlers-Danlos syndrome (progeroid form). Recessive loss-of-function mutations in B3GALT6 result in a spectrum of disorders affecting a broad range of skeletal and connective tissues characterized by lax skin, muscle hypotonia, joint dislocation, and spinal deformity. The pleiotropic phenotypes of the disorders indicate that B3GALT6 plays a critical role in a wide range of biological processes in various tissues, including skin, bone, cartilage, tendon, and ligament. PMID- 23664118 TI - Defective initiation of glycosaminoglycan synthesis due to B3GALT6 mutations causes a pleiotropic Ehlers-Danlos-syndrome-like connective tissue disorder. AB - Proteoglycans are important components of cell plasma membranes and extracellular matrices of connective tissues. They consist of glycosaminoglycan chains attached to a core protein via a tetrasaccharide linkage, whereby the addition of the third residue is catalyzed by galactosyltransferase II (beta3GalT6), encoded by B3GALT6. Homozygosity mapping and candidate gene sequence analysis in three independent families, presenting a severe autosomal-recessive connective tissue disorder characterized by skin fragility, delayed wound healing, joint hyperlaxity and contractures, muscle hypotonia, intellectual disability, and a spondyloepimetaphyseal dysplasia with bone fragility and severe kyphoscoliosis, identified biallelic B3GALT6 mutations, including homozygous missense mutations in family 1 (c.619G>C [p.Asp207His]) and family 3 (c.649G>A [p.Gly217Ser]) and compound heterozygous mutations in family 2 (c.323_344del [p.Ala108Glyfs(*)163], c.619G>C [p.Asp207His]). The phenotype overlaps with several recessive Ehlers Danlos variants and spondyloepimetaphyseal dysplasia with joint hyperlaxity. Affected individuals' fibroblasts exhibited a large decrease in ability to prime glycosaminoglycan synthesis together with impaired glycanation of the small chondroitin/dermatan sulfate proteoglycan decorin, confirming beta3GalT6 loss of function. Dermal electron microcopy disclosed abnormalities in collagen fibril organization, in line with the important regulatory role of decorin in this process. A strong reduction in heparan sulfate level was also observed, indicating that beta3GalT6 deficiency alters synthesis of both main types of glycosaminoglycans. In vitro wound healing assay revealed a significant delay in fibroblasts from two index individuals, pointing to a role for glycosaminoglycan defect in impaired wound repair in vivo. Our study emphasizes a crucial role for beta3GalT6 in multiple major developmental and pathophysiological processes. PMID- 23664119 TI - Molecular defects in the motor adaptor BICD2 cause proximal spinal muscular atrophy with autosomal-dominant inheritance. AB - The most common form of spinal muscular atrophy (SMA) is a recessive disorder caused by deleterious SMN1 mutations in 5q13, whereas the genetic etiologies of non-5q SMA are very heterogeneous and largely remain to be elucidated. In a Bulgarian family affected by autosomal-dominant proximal SMA, we performed genome wide linkage analysis and whole-exome sequencing and found a heterozygous de novo c.320C>T (p.Ser107Leu) mutation in bicaudal D homolog 2 (Drosophila) (BICD2). Further analysis of BICD2 in a cohort of 119 individuals with non-5q SMA identified a second de novo BICD2 mutation, c.2321A>G (p.Glu774Gly), in a simplex case. Detailed clinical and electrophysiological investigations revealed that both families are affected by a very similar disease course, characterized by early childhood onset, predominant involvement of lower extremities, and very slow disease progression. The amino acid substitutions are located in two interaction domains of BICD2, an adaptor protein linking the dynein molecular motor with its cargo. Our immunoprecipitation and localization experiments in HeLa and SH-SY5Y cells and affected individuals' lymphoblasts demonstrated that p.Ser107Leu causes increased dynein binding and thus leads to accumulation of BICD2 at the microtubule-organizing complex and Golgi fragmentation. In addition, the altered protein had a reduced colocalization with RAB6A, a regulator of vesicle trafficking between the Golgi and the endoplasmic reticulum. The interaction between p.Glu744Gly altered BICD2 and RAB6A was impaired, which also led to their reduced colocalization. Our study identifies BICD2 mutations as a cause of non-5q linked SMA and highlights the importance of dynein-mediated motility in motor neuron function in humans. PMID- 23664120 TI - Mutations in BICD2 cause dominant congenital spinal muscular atrophy and hereditary spastic paraplegia. AB - Dominant congenital spinal muscular atrophy (DCSMA) is a disorder of developing anterior horn cells and shows lower-limb predominance and clinical overlap with hereditary spastic paraplegia (HSP), a lower-limb-predominant disorder of corticospinal motor neurons. We have identified four mutations in bicaudal D homolog 2 (Drosophila) (BICD2) in six kindreds affected by DCSMA, DCSMA with upper motor neuron features, or HSP. BICD2 encodes BICD2, a key adaptor protein that interacts with the dynein-dynactin motor complex, which facilitates trafficking of cellular cargos that are critical to motor neuron development and maintenance. We demonstrate that mutations resulting in amino acid substitutions in two binding regions of BICD2 increase its binding affinity for the cytoplasmic dynein-dynactin complex, which might result in the perturbation of BICD2-dynein dynactin-mediated trafficking, and impair neurite outgrowth. These findings provide insight into the mechanism underlying both the static and the slowly progressive clinical features and the motor neuron pathology that characterize BICD2-associated diseases, and underscore the importance of the dynein-dynactin transport pathway in the development and survival of both lower and upper motor neurons. PMID- 23664121 TI - Cannabis use during a voluntary quit attempt: an analysis from ecological momentary assessment. AB - BACKGROUND: There is little research that has sought to identify factors related to quit success and failure among cannabis users. The current study examined affective, cognitive, and situational factors related to cannabis use among current cannabis users undergoing a voluntary, self-guided quit attempt. METHOD: The sample consisted of 30 (33% female) current cannabis users, 84% of whom evinced a current cannabis use disorder. Ecological momentary assessment was used to collect multiple daily ratings of cannabis withdrawal, negative affect, peer cannabis use, reasons for use, and successful coping strategies over two weeks. RESULTS: Findings from generalized linear models indicated that cannabis withdrawal and positive and negative affect were significantly higher during cannabis use than non-use episodes. Additionally, when negative and positive affect were entered simultaneously, negative affect, but not positive affect, remained significantly related to use. Participants were significantly more likely to use in social situations than when alone. When participants were in social situations, they were significantly more likely to use if others were using. Participants tended to use more behavioral than cognitive strategies to abstain from cannabis. The most common reason for use was to cope with negative affect. CONCLUSIONS: Overall, these novel findings indicate that cannabis withdrawal, affect (especially negative affect), and peer use play important roles in cannabis use among self-quitters. PMID- 23664123 TI - Methamphetamine-induced behavioral sensitization in a rodent model of posttraumatic stress disorder. AB - BACKGROUND: Single prolonged stress (SPS) is a rodent model of posttraumatic stress disorder (PTSD)-like characteristics. Given that PTSD is frequently comorbid with substance abuse and dependence, including methamphetamine (METH), the current study sought to investigate the effects of SPS on METH-induced behavioral sensitization. METHODS: In experiment 1, Sprague-Dawley rats were subject to SPS or control treatment and subsequently tested across four sessions of an escalating METH dosing paradigm. METH was injected (i.p.) in escalating doses (0, 0.032, 0.1, 0.32, 1.0, and 3.2mg/kg; dissolved in saline) every 15min and ambulatory activity was recorded. In experiment 2, SPS and control treated rats were injected (i.p.) with either saline or METH (5mg/kg) for five consecutive daily sessions and tested for stereotypy as well as ambulatory activity. Two days later, all animals were injected with a challenge dose of METH (2.5mg/kg) and again tested for activity. RESULTS: No differences in the acute response to METH were observed between SPS and controls. SPS enhanced METH induced ambulatory activity across sessions, compared to controls. METH-induced stereotypy increased across sessions, indicative of behavioral sensitization; however, SPS attenuated, not enhanced, this effect suggesting that SPS may prevent the development of stereotypy sensitization. CONCLUSIONS: Collectively, results show that SPS increases repeated METH-induced ambulatory activity while preventing the transition across sessions from ambulatory activity to stereotypy. These findings suggest that SPS alters drug-induced neuroplasticity associated with behavioral sensitization to METH, which may reflect an effect on the shared neurocircuitry underlying PTSD and substance dependence. PMID- 23664124 TI - How the states stack up: disparities in substance abuse outpatient treatment completion rates for minorities. AB - BACKGROUND: This study was an exploratory investigation of state-level minority disparities in successfully completing outpatient treatment, a major objective for attending substance abuse treatment and a known process outcome measure. METHOD: This was a retrospective analysis of state discharge and admission data from the 2006 to 2008 Treatment Episode Datasets-Discharge (TEDS-D). Data were included representing all discharges from outpatient substance abuse treatment centers across the United States. All first treatment episode clients with admission/discharge records meeting inclusion criteria who could be classified as White, Latino, or Black/African American were used (n=940,058). RESULTS: States demonstrated racial and ethnic disparities in their crude and adjusted completion rates, which also varied considerably among the states. Minorities typically showed a disadvantage. A few states showed significantly higher completion rates for Blacks or Latinos. CONCLUSIONS: Realistically, a variety of factors likely cause the state race/ethnic differences in successful completion rates. States should investigate their delivery systems to reduce completion disparities. PMID- 23664122 TI - Mind-body practices: an alternative, drug-free treatment for smoking cessation? A systematic review of the literature. AB - OBJECTIVE: The limited success of current smoking cessation therapies encourages research into new treatment strategies. Mind-body practices such as yoga and meditation have the potential to aid smoking cessation and become an alternative drug-free treatment option. The aim of this article is to assess the efficacy of yoga and other meditation-based interventions for smoking cessation, to identify the challenges of clinical trials applying mind-body treatments, and to outline directions for future research on these types of therapies to assist in smoking cessation. METHODS: A systematic review of the scientific literature. RESULTS: Fourteen clinical trials met the inclusion criteria defined for this review. Each article was reviewed thoroughly, and evaluated for quality, design, and methodology. Although primary outcomes differed between studies, the fourteen articles, most with limitations, reported promising effects supporting further investigation of the use of these practices to improve smoking cessation. CONCLUSIONS: The literature supports yoga and meditation-based therapies as candidates to assist smoking cessation. However, the small number of studies available and associated methodological problems require more clinical trials with larger sample sizes and carefully monitored interventions to determine rigorously if yoga and meditation are effective treatments. PMID- 23664125 TI - Injecting practices in sexual partnerships: hepatitis C transmission potentials in a 'risk equivalence' framework. AB - BACKGROUND: Evidence indicates minimal hepatitis C (HCV) sexual transmission risk among HIV negative heterosexual partners. Limited HCV literacy has been demonstrated among people who inject drugs, yet there is a dearth of research exploring perceptions of HCV heterosexual transmission risk among this high risk population. METHODS: We conducted a qualitative life history study with people who had been injecting drugs for over six years, to explore the social practices and conditions of long-term HCV avoidance. Participants were recruited through London drug services and drug user networks. The sample comprised 10 women and 27 men (n=37), of whom 22 were HCV antibody negative. Participants were aged from 23 to 57 years and had been injecting for 6 to 33 years. Twenty participants were in long term heterosexual partnerships. FINDINGS: The majority of participants in relationships reported 'discriminate' needle and syringe sharing with their primary sexual partner. Significantly, and in tension with biomedical evidence, participants commonly rationalised syringe sharing with sexual partners in terms of 'risk equivalence' with sexual practices in regard to HCV transmission. Participants' uncertain knowledge regarding HCV transmission, coupled with unprotected sexual practices perceived as being normative were found to foster 'risk equivalence' beliefs and associated HCV transmission potential. CONCLUSION: HCV prevention messages that 'add on' safe sex information can do more harm than good, perpetuating risk equivalence beliefs and an associated dismissal of safe injecting recommendations among those already practicing unprotected sex. PMID- 23664127 TI - Distant Harrington rod migration 35 years after implantation. AB - Harrington rods have been successfully implanted in thousands of patients for the correction of scoliotic deformity since the 1950s. An exceedingly rare complication of Harrington rod placement is loosening with resultant migration. The authors present a 50-year-old woman who had a single Harrington rod placed when she was 15 years old. Thirty-five years later, she presented with acute sensory changes in her lower extremities. Imaging revealed rod failure and migration of the hardware distally, resulting in penetration of the wall of the rectum. Due to the unique anatomical position of the migrated hardware, sigmoidoscopy was used to directly visualize and remove the rod. The patient ultimately made a full recovery. Rod migration is an exceedingly rare complication that has been described only a few times since the introduction of Harrington rods over 60 years ago. The case herein is particularly unique given the extensive period of time that passed before migration (35 years) and the use of sigmoidoscopy for hardware removal. PMID- 23664128 TI - Kleine-Levin syndrome with brain atrophy. AB - Kleine-Levin syndrome (KLS) is commonly described as a self-limiting disorder exhibiting episodes of hypersomnia and psychiatric symptoms, but without any enduring disabilities. Recently, reports have shown that persistent or even progressive memory deficits can also be associated with the disorder. Nevertheless, little has been reported about cognitive disturbances in KLS. Our report describes a rare patient with KLS and prominent brain atrophy. A 24-year old woman developed severe neurological and psychiatric features 12 years previously, 2 weeks after she was hit in the head. Although she has had no recurrence of the primary KLS symptoms, she continues to have a cognitive disorder, verbal disability, and whole brain atrophy. PMID- 23664126 TI - Intravenous prenatal nicotine exposure increases orexin expression in the lateral hypothalamus and orexin innervation of the ventral tegmental area in adult male rats. AB - BACKGROUND: Approximately 18% of pregnant women continue to smoke tobacco cigarettes throughout pregnancy. Offspring exposed to tobacco smoke in utero exhibit a higher incidence of drug use in later stages of development relative to non-exposed children. Animal models indicate that prenatal nicotine (PN) exposure alone alters the development of the mesocorticolimbic dopamine (DA) system, which, in part, organizes motivated behavior and reward. The orexin/hypocretin neuropeptide system, which originates in the lateral hypothalamus (LH), projects to key areas of the mesocorticolimbic DA pathway. Previous research suggests that orexin exerts a major influence on motivation and reward. METHODS: The present experiments determined if intravenous (IV) PN exposure alters (1) the expression of orexin neurons and melanin-concentrating hormone (MCH; positive control) in the LH; and (2) orexin projections from the LH onto DA neurons in the ventral tegmental area (VTA). Dams were injected with IV nicotine (0.05 mg/kg/injection) or saline 3*/day during gestational days 8-21. Tissues from adult male offspring (~130 days) were examined using immunohistochemistry. RESULTS: Relative to controls, offspring of IV PN exposure showed (1) increased numbers of orexin neurons in the LH, and no changes in the expression of MCH; and (2) increased orexin appositions on DA cells in the VTA. CONCLUSION: The findings indicate that the influence of PN exposure is enduring, and suggests that the PN-induced modification of orexin expression on mesolimbic circuitry may contribute to the reported changes in motivated behaviors related to food and drug reward observed in offspring prenatally exposed to nicotine. PMID- 23664129 TI - Central nervous system vasculitis secondary to systemic sclerosis. AB - Systemic sclerosis (SSc) or scleroderma is a connective tissue disease with a diverse array of clinical manifestations secondary to underlying fibrosis and autoimmunity. Central nervous system (CNS) impairment is uncommon in SSc. Here we report the fourth known patient with CNS vasculitis caused by SSc. In each previous report, the patient was a middle-aged to elderly female. Our patient was 24 years old at the time of presentation, significantly younger than the other reported patients. Importantly, our patient's rapidly progressive clinical course and poor response to immunosuppression have not been reported in patients with CNS vasculitis secondary to scleroderma. Although CNS vasculitis is extremely rare in SSc, our report suggests that clinicians should consider this diagnosis in the differential of SSc patients with neurologic impairment. PMID- 23664130 TI - Leptomeningeal metastasis of an intradural malignant peripheral nerve sheath tumor. AB - Malignant peripheral nerve sheath tumors (MPNST) are defined as any malignant tumor arising from or differentiating towards the peripheral nerve sheath. Intradural MPNST metastases are very rare. We report, to our knowledge, the first case of leptomeningeal metastasis of a MPNST to the spine and intracranial space. A 56-year-old woman with primary intradural MPNST of the S1 nerve root developed leptomeningeal metastases as well as brain metastases 19 months after diagnosis. The patient had a history of non-Hodgkins lymphoma for which she had received irradiation to the spine 15 years prior to this presentation. She had no stigmata of neurofibromatosis type 1. Patients with MPNST may also develop leptomeningeal metastases as demonstrated in this patient with intradural post-radiation MPNST. PMID- 23664131 TI - A further patient with parasitic myositis due to Haycocknema perplexum, a rare entity. AB - A new genus of nematode, Haycocknema perplexum, causing polymyositis in humans, was first described in two Australian patients from Tasmania in 1998. Three patients with myositis due to the same nematode were reported from northern Queensland in 2008. We report the sixth case from Australia, a 50-year-old man, also from Tasmania. He had a 2-year history of progressive weakness, weight loss of 10 kg and dysphagia. Muscle biopsy was initially interpreted as polymyositis with eosinophils. Maximum creatine kinase (CK) level was 5700 U/L and full blood examination was normal. He deteriorated after several months of treatment with prednisolone and methotrexate and review of the muscle biopsy showed intramyofibre parasites of H. perplexum. After 3 months of treatment with albendazole therapy, he made a very good clinical recovery and his CK decreased to 470 U/L. This uniquely Australian parasite can mimic polymyositis and leads to significant irreversible morbidity (two of the previous patients still have weakness and elevated CK after years) and even mortality (one died), if diagnosed late or after corticosteroids. Diagnosis can only be made by histopathology of muscle biopsy. PMID- 23664132 TI - Use of the O-arm(r) for skull base resection in a sphenoorbital meningioma. AB - Intraoperative imaging during skull base surgery allows the surgeon to evaluate surgical results and direct further bone resection prior to closure, avoiding the potential morbidity of inadequate surgical therapy or reoperation. Intraoperative CT (iCT) scanning has become widely available in recent years, but its neurosurgical applications have been limited mostly to spinal and functional operations. We report a patient with a sphenoorbital meningioma with adjacent hyperostosis causing proptosis and optic canal stenosis in which a portable iCT scanner (O-arm((r)); Medtronic, Fridley, MN, USA) was used to guide further resection. Postoperatively, the patient experienced resolution of her proptosis, and her vision remains clinically normal. The O-arm((r)) can be easily incorporated into standard operating rooms and is useful in tailoring bony skull base resections. PMID- 23664133 TI - Intravenous levetiracetam for treatment of neonatal seizures. AB - In this case series we report on eight neonates with refractory seizures who received intravenous levetiracetam when seizures did not respond to two or more conventional anticonvulsants. Six of the eight neonates had an excellent response with either cessation, or reduction in seizures by at least 80%. One neonate showed a partial response while one did not have any reduction in seizure frequency. We did not encounter any adverse effects that could be attributable to levetiracetam. PMID- 23664134 TI - Melkersson-Rosenthal syndrome: a review of seven patients. AB - Melkersson-Rosenthal syndrome (MRS) is a rare disorder consisting of a triad of persistent or recurrent orofacial edema, relapsing facial paralysis and fissured tongue. It is difficult to diagnose and treat. A retrospective review of our MRS patients was performed. The medical files, and treatment, radiologic and histopathologic records of these patients were reviewed. The study group consisted of seven male MRS patients. In four patients, the three classical manifestations were present simultaneously. Neuroimaging examinations found facial soft-tissue thickening and swelling in two patients. The indicators of the disease in our patients were as follows: two had family histories, two had elevated levels of protein in the cerebrospinal fluid, one had an increased immunoglobulin G level in the blood and one had reactive arthritis. All patients responded to systemic corticosteroid treatment. We discuss the genetic, infectious and immunologic factors in the etiology of MRS. Neuroimaging examinations were useful in determining the diagnosis and in determining whether the initial treatment of MRS should be with systemic corticosteroids. PMID- 23664135 TI - Cell type-specific function of TAK1 in innate immune signaling. AB - Transforming growth factor beta-activated kinase 1 (TAK1 or MAP3K7) is a key signaling component of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinase (MAPK) signaling pathways. Activation of TAK1 is tightly regulated through its binding partners and protein modifications. Although TAK1 functions as an essential and positive regulator of innate immune signaling and apoptosis in mouse embryonic fibroblasts (MEFs), T cells, and other cells, it negatively regulates cell development and activation of proinflammatory signaling pathways in neutrophils. However, the molecular mechanisms responsible for the opposite roles of TAK1 in different cell types remain to be addressed. In this article, we discuss the latest progresses in our understanding of TAK1 regulation, function, and mechanisms in a cell-type specific manner. PMID- 23664136 TI - On measurements and their quality: paper 1: reliability - history, issues and procedures. AB - This is the first in a short series of papers on measurement theory and practice with particular relevance to intervention research in nursing, midwifery, and healthcare. In this article I discuss reliability, its origins in classic measurement theory, important issues to consider when operationally defining reliability for a particular study, correlational procedures for assessing the reliability of data once collected, including test-retest reliability, split-half reliability, and Cronbach's coefficient alpha. Some important insights into reliability provided by attenuation theory are also offered. PMID- 23664137 TI - Routine health screens: a time for reflection. PMID- 23664138 TI - Personal reflections on the first 50 years of cardiovascular surgery. PMID- 23664139 TI - Defining surgical quality in gastric cancer: a RAND/UCLA appropriateness study. PMID- 23664140 TI - Health disparities analysis of critically ill pediatric trauma patients in Milwaukee, Wisconsin. AB - BACKGROUND: Injury is the leading cause of childhood morbidity and mortality in the US. The associated costs exceed $20 billion annually. This study examined disparities in disadvantaged populations of critically injured pediatric patients admitted to a level 1 pediatric trauma center. STUDY DESIGN: A retrospective study was conducted of all trauma patients admitted to the pediatric intensive care unit (PICU) at a level 1 pediatric trauma hospital from 2005 to 2009. RESULTS: Data on 324 patients were analyzed; 45% of patients were Caucasian, 33% were African American, 12% were Hispanic, and 10% were other. There was no difference in age, Glasgow Coma Scale (GCS), or Injury Severity Score (ISS) across ethnic groups. The mortality rate was 12%. A higher percentage of Caucasians were commercially insured and from the highest income quartile than non-Caucasians (p < 0.001). African Americans had the highest rate of penetrating trauma and intentional injury compared with other ethnicities (p < 0.001). Nearly 75% of firearm injuries were clustered in 7 ZIP codes with the lowest median household incomes. The home was the most common location for firearm injuries. Children involved in assaults were more likely to have a single parent (67%) than 2 parents (26%, p < 0.001). Both ethnicity and payer status were significantly associated with mortality. CONCLUSIONS: Significant disparities in socioeconomic status exist in severely injured pediatric patients treated in the PICU. Disparities were associated with adverse outcomes. These results should inform community and public health efforts to identify the areas and populations at highest risk for violence-related injuries. PMID- 23664141 TI - Pediatric specialist care is associated with a lower risk of bowel resection in children with intussusception: a population-based analysis. AB - BACKGROUND: Although previous studies have shown that radiologic intussusception reduction is more likely at children's hospitals, no study to date has compared outcomes among children advancing to surgical intervention. We hypothesized that rates of bowel resection would differ between hospitals with and without pediatric surgeons. STUDY DESIGN: We conducted a population-based retrospective cohort study using Washington State discharge records. All children younger than 18 years undergoing operative intussusception reduction between 1999 and 2009 were included (n = 327). Data were collected on demographics, disease severity, comorbidities, and concomitant gastrointestinal pathology. Multivariate logistic regression was used to estimate odds of intestinal resection during operative intussusception reduction. RESULTS: Pediatric hospitals treated a smaller proportion of children older than 4 years of age (12.1% vs 44.4%), as well as a greater proportion of Medicaid patients (50.9% vs 42.6%). Patients at pediatric hospitals had a lower prevalence of underlying intestinal anomalies or identifiable mass lesions (14.3% vs 16.7%). "Severe disease" (perforation, ischemia, acidosis) was more common at pediatric hospitals (17.6% vs 9.3%). Overall, bowel resection was more commonly performed at nonpediatric hospitals (59.3% vs 33.0%). On multivariate analysis, the odds of bowel resection were significantly lower at pediatric compared with nonpediatric hospitals (odds ratio [OR] 0.20, p < 0.001), and this association was strongest in younger patients. Adjusted odds of postoperative complications were greater for bowel resection patients (OR 2.83, p < 0.001). CONCLUSIONS: Bowel resection during operative intussusception reduction is more likely at hospitals without pediatric surgeons, and is associated with increased complications. Improved outcomes may be achieved by efforts aimed at standardizing care and decreasing variability in the treatment of pediatric intussusception. PMID- 23664142 TI - The role of work environment in keeping newly licensed RNs in nursing: a questionnaire survey. AB - BACKGROUND: In prior studies, newly licensed registered nurses (RNs) describe their job as being stressful. Little is known about how their perceptions of the hospital work environment affect their commitment to nursing. OBJECTIVES: To assess the influence of hospital work environment on newly licensed RN's commitment to nursing and intent to leave nursing. DESIGN: Correlational survey. SETTINGS: Newly licensed RNs working in hospitals in Florida, United States. PARTICIPANTS: 40% random sample of all RNs newly licensed in 2006. METHODS: The survey was mailed out in 2008. Dependent variables were indicators of professional commitment and intent to leave nursing. Independent variables were individual, organizational, and work environment characteristics and perceptions (job difficulty, job demands and job control). Statistical analysis used ordinary least squares regressions. Level of significance was set at p<0.05. RESULTS: Job difficulty and job demand were significantly related to a lower commitment to nursing and a greater intent to leave nursing, and vice versa for job control. The strongest ranked of the job difficulties items were: incorrect instructions, organizational rules, lack of supervisor support, and inadequate help from others. Workload and other items were significant, but ranked lower. The strongest ranked of the job pressure items were: "having no time to get things done" and "having to do more than can be done well." The strongest ranked of job control items were "ability to act independent of others." Nurses with positive orientation experiences and those working the day shift and more hours were less likely to intend to leave nursing and more likely to be committed to nursing. Significant demographic characteristics related to professional commitment were race and health. CONCLUSIONS: Negative perceptions of the work environment were strong predictors of intent to leave nursing and a lower commitment to nursing among newly licensed RNs. These results indicate that retention of newly licensed RNs in nursing can be improved through changes in the work environment that remove obstacles to care-giving, increase resources and autonomy, and reduce workload and other job pressure factors. PMID- 23664143 TI - Why do nursing students not want to work in geriatric care? A national questionnaire survey. AB - BACKGROUND: Given the severe shortage of nurses in geriatric care in Israel and the planned expansion of their role in the care of older people, the Israel Ministry of Health's Nursing Division decided to investigate the readiness of current students to work in geriatrics. OBJECTIVES: To gather last-year student nurses' views on geriatric nursing as a career choice and identify the factors behind those views. DESIGN: A cross-sectional questionnaire study was designed. SETTINGS AND PARTICIPANTS: 486 students (70% of the total last-year student nurse population) across the whole range of study settings completed the questionnaire in 2011. METHODS: On the basis of extensive data collection from focus groups of student nurses and working geriatric nurses a structured, self-administered questionnaire was compiled. The researchers distributed and collected the questionnaire in the students' classrooms. RESULTS: 61% of the 486 respondents had no intention of working in geriatrics while 12% considered the prospect favourably. 27% of the respondents were prepared to consider geriatric nursing as a career choice only after advanced specialist training in that field. 69% said that the planned expansion of the powers of geriatric nurses would incline them more favourably to work in geriatrics. A relatively high proportion of those interested in working in geriatrics were men. The students' appraisal of the content of their training programme and of the current state of geriatrics in Israel appeared not to influence career choice. Multiple regression analysis found that the factors most predictive of geriatric care as a career choice were a generally favourable attitude to older people, the expansion of nurse powers in the sector and previous experience in older people care. Studying on an academic programme as opposed to a diploma programme was a negative predictor. CONCLUSIONS: The non-influence of training programme content/design is the key finding. The chief recruitment effort should be invested in making the domain of geriatric nursing more attractive to nurses by improving its pay structure and expanding the powers of geriatric nurses to the level of Clinical Nurse Specialist, which would provide an attractive promotion track. PMID- 23664144 TI - Transthyretin and the human placenta. AB - Since its discovery, transthyretin (TTR) has been regarded as an important hepatically derived protein carrier of thyroid hormones and retinol in blood. However, in more recent years it has been shown that TTR has other important functions. TTR is abundant in cerebrospinal fluid, where it may be involved in transport of thyroid hormones into the brain. TTR derived amyloid is associated with diseases such as senile systemic amyloidosis, familial amyloid polyneuropathy and familial amyloid cardiomyopathy. Recently, synthesis, secretion and uptake of TTR by human placenta have been reported. TTR appears to play an important role in the delivery of maternal thyroid hormone to the developing fetus. This review explores the various proposed roles of TTR and more recent findings on TTR synthesis and expression in the placenta. PMID- 23664147 TI - Withdrawal of anti-epileptic medications during video EEG monitoring does not alter ECG parameters or HRV. AB - PURPOSE: To assess if anti-epileptic drug (AED) withdrawal/cessation results in changes in ECG parameters and/or measures of heart rate variability (HRV), in patients having VEEG monitoring, that might affect susceptibility to sudden death in epilepsy. METHODS: In this study, we included 36 patients with medically refractory epilepsy undergoing continuous video-EEG-ECG monitoring in hospital for pre-surgical assessment. We recorded and analysed multiple 10-min epochs of 2 lead ECG during periods when the subjects were awake and in REM and non-REM sleep, both on admission, and after the subjects had been partially or completely weaned from their AEDs. We compared ECG parameters and measures of HRV from these recorded epochs before and after AED reduction/cessation, with each patient acting as their own comparator. Epochs measured during awake, REM, and non-REM periods were analysed separately. In addition, we analysed a subgroup of patients who had been withdrawn from Na+-channel blocking medications specifically, to analyse the effect of this particular class of AEDs in isolation. KEY FINDINGS: Upon AED withdrawal, we observed a small increase in heart rate and shortening of the QT interval, when subjects were awake, but no other changes in ECG parameters were detected, nor did we find changes in any measure of HRV. In addition, no significant changes were found during sleep. Similar results were found in the analysis of the subgroup of patients withdrawn from Na+-channel blocking AEDs. SIGNIFICANCE: Our study does not support a prominent role for AEDs, and withdrawal/cessation of AEDs, in deranging cardiac physiology during video EEG monitoring in medically refractory epilepsy patients undergoing video EEG monitoring. PMID- 23664145 TI - Mass spectrometry techniques in the survey of steroid metabolites as potential disease biomarkers: a review. AB - Mass spectrometric approaches have been fundamental to the identification of metabolites associated with steroid hormones, yet this topic has not been reviewed in depth in recent years. To this end, and given the increasing relevance of liquid chromatography-mass spectrometry (LC-MS) studies on steroid hormones and their metabolites, the present review addresses this subject. This review provides a timely summary of the use of various mass spectrometry-based analytical techniques during the evaluation of steroidal biomarkers in a range of human disease settings. The sensitivity and specificity of these technologies are clearly providing valuable new insights into breast cancer and cardiovascular disease. We aim to contribute to an enhanced understanding of steroid metabolism and how it can be profiled by LC-MS techniques. PMID- 23664146 TI - Pharmacological concentrations of irisin increase cell proliferation without influencing markers of neurite outgrowth and synaptogenesis in mouse H19-7 hippocampal cell lines. AB - AIMS/HYPOTHESIS: Irisin is a novel, myocyte secreted, hormone that has been proposed to mediate the beneficial effects of exercise on metabolism. Irisin is expressed, at lower levels, in human brains and knock-down of the precursor of irisin, FNDC5, decreases neural differentiation of mouse embryonic stem cells. No previous studies have evaluated whether irisin may directly regulate hippocampal neurogenesis in mouse hippocampal neuronal (HN) cells. METHODS: Hippocampal neurogenesis and irisin signaling were studied in vitro using mouse H19-7 HN cell lines. RESULTS: We observed that cell proliferation is regulated by irisin in a dose-dependent manner in mouse H19-7 HN cells. Specifically, physiological concentrations of irisin, 5 to 10nmol/L, had no effect on cell proliferation when compared to control. By contrast, pharmacological concentrations of irisin, 50 to 100nmol/L, increased cell proliferation when compared to control. Similar to these results regarding irisin's effects on cell proliferation, we also observed that only pharmacological concentrations of irisin increased STAT3, but not AMPK and/or ERK, activation. Finally, we observed that irisin did not activate either microtubule-associated protein 2, a specific neurite outgrowth marker, or Synapsin, a specific synaptogenesis marker in mouse H19-7 HN cells. CONCLUSIONS/INTERPRETATIONS: Our data suggest that irisin, in pharmacological concentrations, increases cell proliferation in mouse H19-7 HN cells via STAT3, but not AMPK and/or ERK, signaling pathways. By contrast, neither physiological nor pharmacological concentrations of irisin alter markers of hippocampal neurogenesis in mouse H19-7 HN cell lines. PMID- 23664148 TI - The HPV16 oncogenes cause aberrant stem cell mobilization. AB - Human Papilloma Virus related epithelial cancers have been speculated to derive from virus-infected tissue stem cells. Stem cells also are thought to provide a reservoir of latently infected cells that can persist for long periods. In this study we have examined the effects of HPV16 E6 and E7 oncogenes on multipotent epithelial stem cells, using in vivo systems. Our results show that expression of HPV16 oncogenes reduces the number of bulge label-retaining cells within hair follicles at telogen suggesting aberrant mobilization, a result supported by increased mobilization upon acute anagen induction. Importantly the loss of relative quiescence, a hallmark feature of stem cells, occurs in the absence of a reduction in other stem cell markers. This points to an atypical stem cell compartment in the context of E6 and E7 expression. We hypothesize that this aberrant compartment may have important roles in the viral life cycle and/or ensuing carcinogenesis. PMID- 23664150 TI - Subfoveal fibrosis in eyes with neovascular age-related macular degeneration treated with intravitreal ranibizumab. AB - PURPOSE: To assess baseline and follow-up characteristics of choroidal neovascularization (CNV) lesions in age-related macular degeneration in relation to the development of subfoveal subretinal fibrosis. DESIGN: Retrospective, observational case series. METHODS: settings and study population: One hundred ninety-seven treatment-naive eyes in 197 patients with CNV in age-related macular degeneration without subfoveal fibrosis at first presentation who were treated with ranibizumab in a pro re nata regimen. main outcome measure: Subfoveal fibrosis at the conclusion follow-up of 24 months or fewer. RESULTS: The hazard ratio of any subfoveal fibrosis developing in eyes with predominantly classic CNV was 5.95 (95% confidence interval [CI], 3.25 to 10.90) compared with minimally classic and occult CNV, whereas the hazard ratio of fibrosis developing with foveal atrophy was 3.38 (95% CI, 1.47 to 7.81; mean follow-up, 1.80 years; 95% CI, 1.75 to 1.85 years). The hazard ratio of any fibrosis developing was 3.38 (95% CI, 1.10 to 10.38) in eyes with a baseline best-corrected visual acuity of 40 or worse using Early Treatment Diabetic Retinopathy Study letter scores, as compared with eyes with a baseline best-corrected visual acuity of 70 letters or more. An interval between diagnosis and treatment of 15 days or more was associated with a hazard ratio of any fibrosis developing of 2.24 (95% CI, 1.28 to 3.94) as compared with an interval of fewer than 15 days. Compared with eyes in which fibrosis did not develop, eyes in which prominent fibrosis or fibrosis developed with foveal atrophy lost 8.5 more Early Treatment Diabetic Retinopathy Study letters (95% CI, -1.0 to -15.9; P = .0242) and 10.3 more Early Treatment Diabetic Retinopathy Study letters (95% CI, -4.0 to -16.5; P = .0012), respectively. CONCLUSIONS: The development of subfoveal fibrosis in neovascular age-related macular degeneration was associated with predominantly classic CNV and poorer visual acuity at first presentation, a longer interval between diagnosis and treatment, and approximately 2 lines of additional visual loss at the conclusion follow-up. PMID- 23664151 TI - Assessment of retinal function before and after idiopathic macular hole surgery. AB - PURPOSE: To evaluate preoperative and postoperative retinal function in patients who underwent macular surgery for idiopathic macular hole. DESIGN: Prospective, comparative, interventional case series. METHODS: Thirty eyes of 30 patients with idiopathic macular hole were included in the study. Patients underwent pars plana vitrectomy and peeling of the internal limiting membrane (ILM). ILM visualization was improved in 15 patients by using triamcinolone acetonide and in the remaining 15 patients by using infracyanine green dye. Spectral-domain optical coherence tomography examination was performed to document macular hole closure. Retinal function was assessed preoperatively and postoperatively over a period of 12 months by best-corrected visual acuity (BCVA) measurement (ETDRS chart), MP-1 microperimetry, and focal electroretinogram recording (fERG). Focal electroretinograms were recorded in response to a sinusoidally modulated (41 Hz), uniform field presented to the macular (18 degrees) and foveal (2.25 degrees) region. RESULTS: Macular hole closure was achieved in all patients in both groups. At 12 months, visual acuity improved in both groups (P < .001), and there were no statistically significant differences between groups. Mean macular sensitivity within the central 2 and 8 degrees increased in both groups, and there were no statistically significant differences between groups at any follow up. In the triamcinolone acetonide group, 12 months after surgery the amplitude of the fERG's first harmonic (1F) increased both in the macular region (P < .001) and in the foveal region (P < .05). In the infracyanine green group, at 12 months the amplitude of the first harmonic (1F) decreased in both areas. The decrease was significant in the macular region (P < .05) and not significant in the foveal region (P = .095). CONCLUSION: Vitrectomy and ILM peeling assisted with either triamcinolone acetonide or infracyanine green staining improves visual acuity and mean macular sensitivity at 12 months in patients affected by idiopathic macular hole. However, triamcinolone acetonide staining is associated with an increase of fERG's first harmonic amplitude in the foveal and macular region, whereas in the case of infracyanine green staining it seems to decrease after surgery. The reduction of the amplitude of fERG's first harmonic suggests that infracyanine green may have a late toxic effect on photoreceptor cells. PMID- 23664152 TI - Accuracy and speed of electronic health record versus paper-based ophthalmic documentation strategies. AB - PURPOSE: To compare accuracy and speed of keyboard and mouse electronic health record (EHR) documentation strategies with those of a paper documentation strategy. DESIGN: Prospective cohort study. METHODS: Three documentation strategies were developed: (1) keyboard EHR, (2) mouse EHR, and (3) paper. Ophthalmology trainees recruited for the study were presented with 5 clinical cases and documented findings using each strategy. For each case-strategy pair, findings and documentation time were recorded. Accuracy of each strategy was calculated based on sensitivity (fraction of findings in actual case that were documented by subject) and positive ratio (fraction of findings identified by subject that were present in the actual case). RESULTS: Twenty subjects were enrolled. A total of 258 findings were identified in the 5 cases, resulting in 300 case-strategy pairs and 77 400 possible total findings documented. Sensitivity was 89.1% for the keyboard EHR, 87.2% for mouse EHR, and 88.6% for the paper strategy (no statistically significant differences). The positive ratio was 99.4% for the keyboard EHR, 98.9% for mouse EHR, and 99.9% for the paper strategy (P < .001 for mouse EHR vs paper; no significant differences between other pairs). Mean +/- standard deviation documentation speed was significantly slower for the keyboard (2.4 +/- 1.1 seconds/finding) and mouse (2.2 +/- 0.7 seconds/finding) EHR compared with the paper strategy (2.0 +/- 0.8 seconds/finding). Documentation speed of the mouse EHR strategy worsened with repetition. CONCLUSIONS: No documentation strategy was perfectly accurate in this study. Documentation speed for both EHR strategies was slower than with paper. Further studies involving total physician time requirements for ophthalmic EHRs are required. PMID- 23664153 TI - Short-term outcomes of aflibercept for neovascular age-related macular degeneration in eyes previously treated with other vascular endothelial growth factor inhibitors. AB - PURPOSE: To report results of aflibercept therapy in eyes with neovascular age related macular degeneration previously treated with bevacizumab, ranibizumab, or both. DESIGN: Retrospective, interventional, noncomparative, consecutive case series. METHODS: Ninety-six eyes from 85 patients with neovascular age-related macular degeneration who previously had received bevacizumab, ranibizumab, or both were treated with aflibercept monthly for 3 months followed by a fourth injection within 2 months. Outcomes were determined 4 +/- 1 months after the first aflibercept dose and included: proportion of patients gaining or losing 2 lines or more of best-corrected visual acuity, proportion remaining within a gain or loss of 1 line, mean change in logarithm of the minimal angle of resolution visual acuity, mean change in central foveal thickness, mean change in macular cube volume, and qualitative anatomic response as assessed by spectral-domain optical coherence tomography. RESULTS: At baseline, 82 (85%) eyes had signs of active exudation despite a mean of 17 previous anti-vascular endothelial growth factor injections. At final visit, 82 (85%) remained stable within a gain or loss of 1 line, 7 (7%) gained 2 lines or more, and 7 (7%) lost 2 lines or more of best corrected visual acuity. Mean logarithm of the minimal angle of resolution visual acuity showed minimal change 0.02 (range, -0.46 to 0.70; P = .14). Mean central foveal thickness decreased -18 MUm (range, -242 to 198 MUm; P = .06). Mean macular volume decreased -0.27 mm(3) (95% confidence interval, -0.4 to -0.1 mm(3); P = .004). On qualitative analysis, 4 (5%) eyes had complete resolution of exudative fluid, 40 (49%) showed partial resolution, 26 (32%) remained unchanged, and 12 (14%) showed worsened exudative fluid. CONCLUSIONS: Aflibercept seems to be an effective alternative for neovascular age-related macular degeneration patients previously treated with bevacizumab, ranibizumab, or both at 4 months of follow-up. Most treated eyes demonstrated stable visual acuity and anatomic improvements by spectral-domain optical coherence tomography. PMID- 23664154 TI - Painful Na-channelopathies: an expanding universe. AB - The universe of painful Na-channelopathies--human disorders caused by mutations in voltage-gated sodium channels--has recently expanded in three dimensions. We now know that mutations of sodium channels cause not only rare genetic 'model disorders' such as inherited erythromelalgia and channelopathy-associated insensitivity to pain but also common painful neuropathies. We have learned that mutations of NaV1.8, as well as mutations of NaV1.7, can cause painful Na channelopathies. Moreover, recent studies combining atomic level structural models and pharmacogenomics suggest that the goal of genomically guided pain therapy may not be unrealistic. PMID- 23664155 TI - Validation of a photogrammetric technique for computing equine hoof volume. AB - Assessment of equine foot conformation is often based on linear and angular measurements performed on lateral digital photographs. However, quantification of external foot conformation requires more comprehensive assessments to capture the shape of the entire foot. Volumetric measurements of the hoof capsule represent a summary measure quantifying foot shape. The aim of this study was to develop a method for computation of virtual foot models from digital foot images allowing precise and accurate volumetric measurements. This photogrammetric technique was then assessed for the characterization of foot volume changes associated with foot trimming. Using the technique, three different photographers imaged feet from 18 cadavers at different time points and one analyst processed their images to generate virtual computer models. Volumetric measurements were obtained from these models to determine their precision in the context of 'Photographer', 'Time' and the effect of 'Trimming'. Computed tomographic (CT) imaging was used to assess the accuracy of the photogrammetric method. Pre-trim photogrammetric measurements showed excellent precision and accuracy and the results did not depend on the person acquiring the images. The accuracy of post-trim photogrammetric measurements deteriorated in comparison with the average differences measured by CT imaging (19 cm(3)). Precise volumetric measurements were obtained using the photogrammetric method, but average differences in foot volume after trimming as measured by CT imaging are likely too small to be detected with confidence. PMID- 23664156 TI - Worms--a "license to kill". AB - Worm infections can cause severe harm and death to both humans and numerous domestic and wild animals. Despite the fact that there are many beneficial worm species, veterinarians, physicians and parasitologists have multiple reasons to combat parasitic worms. The pros and cons of various approaches for the discovery of new control methods are discussed, including novel anthelmintics, vaccines and genetic approaches to identify novel drug and vaccine targets. Currently, the mainstay of worm control remains chemotherapy and prophylaxis. The importance of knowledgeable and wise use of the available anthelmintics is highlighted. PMID- 23664157 TI - Parasiticidal activity of a novel synthetic peptide from the core alpha-helical region of NK-lysin. AB - NK-lysin is an anti-microbial peptide that plays a critical role in innate immunity against infectious pathogens through its selective membrane disruptive property. We previously expressed and purified a full-length chicken NK-lysin (cNKL) recombinant protein, and demonstrated its in vitro anti-parasitic activity against the apicomplexan protozoan, Eimeria, the etiologic agent of avian coccidiosis. This study evaluated the in vitro and in vivo anti-parasitic properties of a synthetic peptide (cNK-2) incorporating a predicted membrane permeating, amphipathic alpha-helix of the full-length cNKL protein. The cNK-2 peptide exhibited dose- and time-dependent in vitro cytotoxic activity against E. acervulina and E. tenella sporozoites. The cytotoxic activity of 1.5 MUM of cNK-2 peptide against E. acervulina following 6h incubation was equal to that of 2.5 MUM of melittin, the principal active component of apitoxin (bee venom) that also exhibits anti-microbial activity. Even greater activity was detected against E. tenella, where 0.3 MUM of cNK-2 peptide was equivalent to 2.5 MUM of melittin. Against Neospora caninum tacyzoites, however, the cytotoxic activity of cNK-2 peptide was inferior to that of melittin. Transmission electron microscopy of peptide-treated E. tenella sporozoites revealed disruption of the outer plasma membrane and loss of intracellular contents. In vivo administration of 1.5 MUM of cNK-2 peptide increased protection against experimental E. acervulina infection, as measured by greater body weight gain and reduced fecal oocyst shedding, compared with saline controls. These results suggest that the cNK-2 synthetic peptide is a novel anti-infective peptide that can be used for protection against avian coccidiosis during commercial poultry production. PMID- 23664158 TI - Generation and characterization of a recombinant chimeric protein (rCpLi) consisting of B-cell epitopes of a dermonecrotic protein from Loxosceles intermedia spider venom. AB - A chimeric protein was constructed expressing three epitopes of LiD1, a dermonecrotic toxin from the venom of Loxosceles intermedia spider. This species is responsible for a large number of accidents involving spiders in Brazil. We demonstrated that the chimeric protein (rCpLi) generated is atoxic and that antibodies previously developed in rabbits against synthetic epitopes reactive with rCpLi in ELISA and immunoblot assays. The antibody response in rabbits against the rCpLi was evaluated by ELISA and we have detected an antibody response in all immunized animals. Overlapping peptides covering the amino acid sequence of the rCpLi were synthesized on a cellulose membrane, and their recognition by rabbit anti-rCpLi serum assessed. Three different antigenic regions were identified. The percentage of inhibition of the dermonecrotic, hemorrhagic and edematogenic activities caused by the recombinant protein LiD1r in naive rabbits was assessed by pre-incubation with anti-rCpLi antibodies. Anti rCpLi induced good dermonecrotic and hemorrhagic protection. The levels of protection were similar to the antiboides anti-LiD1r. In summary, we have developed a polyepitope recombinant chimeric protein capable of inducing multiple responses of neutralizing antibodies in a rabbit model. This engineered protein may be a promising candidate for therapeutic serum development or vaccination. PMID- 23664159 TI - The influence of age, sex, and posture on the measurement of atlantodental interval in a normal population. AB - OBJECTIVE: The atlantodental interval (ADI) is used in assessing atlantoaxial stability. This measurement may potentially be affected by several features encountered during patient examination. This study examined the influence of 3 features: age, sex, and posture, on the measurement of ADI in a normal population. METHODS: The ADI was measured sequentially on 269 lateral cervical radiographs of adults with no demonstrated bony injury. Images were stratified by age and sex with equal representation in each age group. A further 25 asymptomatic adults were assessed for posture using craniovertebral angle measured from digital lateral photographs. The ADI was then measured from a lateral radiograph. The data were examined for correlation between age, craniovertebral angle, and ADI using Spearman rank correlation. The ADI of age groups was compared by Kruskal-Wallis test. The relationship between ADI and sex was examined using Wilcoxon rank sum test. Interaction between age and sex was explored using an interaction term in regression analysis. RESULTS: The ADI decreased with age, median measurements reducing from 2.07 to 0.85 mm across age groups (P < .01). No significant relationship was demonstrated between ADI and sex. No significant interaction was demonstrated between age and sex. Measurements of craniovertebral angle did not correlate with ADI (rho = 0.03, P = .90). CONCLUSION: The magnitude of ADI decreases with advancing age. Age should be considered a modifying factor when interpreting measurement of ADI, particularly in consideration of potential minor instabilities. Patient sex does not appear to influence ADI, either independently or in interaction with age. Craniocervical posture variation does not influence ADI in an asymptomatic adult population. PMID- 23664160 TI - Practice patterns in spine radiograph utilization among doctors of chiropractic enrolled in a provider network offering complementary care in the United States. AB - OBJECTIVE: Nonspecific back pain is associated with high use of diagnostic imaging in primary care, yet current evidence suggests that routine imaging of the spine is unnecessary. The objective of this study is to describe current practice patterns in spine radiograph utilization among doctors of chiropractic enrolled in an American provider network. METHODS: A cross-sectional analysis of administrative claims data from one of the largest providers of complementary health care networks for health plans in the United States was performed. Survey data containing provider demographics were linked with routinely collected data on spine radiograph utilization and patient characteristics aggregated at the provider level. We calculated rates and variations of spine radiographs over 12 months. Negative binomial regression was performed to identify significant predictors of high radiograph utilization and to estimate the associated incidence risk ratio. RESULTS: Complete data for 6946 doctors of chiropractic and 249193 adult patients were available for analyses. In 2010, claims were paid for a total of 91542 new patient examinations and 23369 spine radiographs (including 17511 ordered within 5 days of initial patient examination). The rate of spine radiographs within 5 days of an initial patient visit was 204 per 1000 new patient examinations. Significant predictors of higher radiograph utilization rates included the following: practicing in the Midwest or South US census regions, practicing in an urban or suburban setting, chiropractic school attended, and being a male provider in full-time practice with more than 20 years of experience. CONCLUSION: Chiropractic school attended and practice location were the most influential predictors of spine radiograph utilization among network chiropractors. This information may help to inform the development and evaluation of a tailored intervention to address overuse of radiograph utilization. PMID- 23664161 TI - A multicenter, prospective, randomized comparison of a novel signal transmission capsule endoscope to an existing capsule endoscope. AB - BACKGROUND: MiroCam, a capsule endoscope, uses a novel transmission technology, electric-field propagation, which uses the human body as a conduction medium for data transmission. OBJECTIVE: To compare the ability of the MiroCam (MC) and PillCam (PC) to identify sources of obscure GI bleeding (OGIB). DESIGN: Prospective, multicenter, comparative study. SETTING: Six academic hospitals. PATIENTS: A total of 105 patients with OGIB. INTERVENTION: Patients ingested both the MC and PC capsules sequentially in a randomized fashion. MAIN OUTCOME MEASUREMENTS: Concordance of rates in identifying a source of OGIB, operational times, and rates of complete small-bowel examination. RESULTS: Data analysis resulted in 43 (48%) "abnormal" cases identifying a source of OGIB by either capsule. Twenty-four cases (55.8%) were positive by both capsules. There was negative agreement in 46 of 58 cases (79.3%). The kappa index was 0.547 (chi(2) = 1.32; P = .36). In 12 cases, MC positively identified a source that was not seen on PC, whereas in 7 cases, PC positively identified a source that was not seen on MC. MC had a 5.6% higher rate of detecting small-bowel lesions (P = .54). MC captured images at 3 frames per second for 11.1 hours, and PC captured images at 2 frames per second for 7.8 hours (P < .0001). Complete small-bowel examination was achieved in 93.3% for MC and 84.3% for PC (P = .10). LIMITATIONS: Readers were not blinded to the particular capsule they were reading. CONCLUSION: A positive diagnostic finding for OGIB was identified by either capsule in 48% of cases. The concordance rate between the 2 capsules was comparable to that of prior studies in identifying sources of small-bowel bleeding. The longer operational time of the MC may result in higher rates of complete small-bowel examination, which may, in turn, translate into a higher rate of detecting small bowel lesions. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT00878982.). PMID- 23664162 TI - Role of endoscopy in the staging and management of colorectal cancer. PMID- 23664163 TI - A review of TMJ-related papers published in the British Journal of Oral and Maxillofacial Surgery in 2011 and 2012. AB - This review summarises the articles relating to the temporomandibular joint (TMJ) that were published in the British Journal of Oral and Maxillofacial Surgery (BJOMS) between January 2011 and December 2012. In total 24 papers were published. Of these, 16 (67%) were full-length articles, which included prospective, retrospective, and laboratory-based studies as well as reviews. The remaining 8 papers were short communications, technical notes, and letters to the editor, which report on, amongst other things, unusual cases, rare complications, and novel surgical techniques. PMID- 23664164 TI - Novel 1H-imidazol-2-amine derivatives as potent and orally active vascular adhesion protein-1 (VAP-1) inhibitors for diabetic macular edema treatment. AB - Novel thiazole derivatives were synthesized and evaluated as vascular adhesion protein-1 (VAP-1) inhibitors. Although we previously identified a compound (2) with potent VAP-1 inhibitory activity in rats, the human activity was relatively weak. Here, to improve the human VAP-1 inhibitory activity of compound 2, we first evaluated the structure-activity relationships of guanidine bioisosteres as simple small molecules and identified a 1H-benzimidazol-2-amine (5) with potent activity compared to phenylguanidine (1). Based on the structure of compound 5, we synthesized a highly potent VAP-1 inhibitor (37b; human IC50=0.019 MUM, rat IC50=0.0051 MUM). Orally administered compound 37b also markedly inhibited ocular permeability in streptozotocin-induced diabetic rats after oral administration, suggesting it is a promising compound for the treatment of diabetic macular edema. PMID- 23664165 TI - When nature meets nurture: persistent Yersinia infection. PMID- 23664166 TI - What's in her pocket: worsening diverticulitis. PMID- 23664168 TI - Identification of inflamed aortic plaque in conventional fluorodeoxyglucose positron emission tomography myocardial viability studies. AB - BACKGROUND: It has been shown that (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is useful in identifying inflamed plaque in major arteries. This study evaluated the feasibility of inflamed plaque detection with routinely acquired cardiac FDG-PET viability studies in patients with severe coronary artery disease and left ventricular dysfunction. METHODS: Clinically indicated myocardial viability scans using FDG and PET combined with computed tomography from 103 patients were retrospectively analyzed for FDG uptake in the proximal, ascending, and descending thoracic aorta. Aortic uptake was graded on the basis of peak and mean target-to-background ratio (TBR): grade 0, < 1; grade 1, 1.01-1.49; grade 2, 1.5-1.99; and grade 3, > 2. RESULTS: Of the 103 patients, 71 (68.9%) had a history of myocardial infarction, 88 (85.4%) were on statins, and 70 (68%) were on angiotensin-converting enzyme (ACE) inhibitors. Increased FDG uptake (mean TBR grade 1-3) was seen in 79 of 103 patients (77%), and grade 3 aortic uptake based on peak TBR was found in 12 of 103 patients (12%). CONCLUSIONS: Detection of inflamed atherosclerotic plaque in the aorta with conventional FDG viability scans is feasible. The rate of very positive uptake in this population of ischemic heart disease patients is low, possibly reflecting aggressive secondary risk factor modification including statin and ACE inhibitor use. PMID- 23664167 TI - Loss of runt-related transcription factor 3 induces gemcitabine resistance in pancreatic cancer. AB - BACKGROUND & AIM: Runt-related transcription factor 3 (RUNX3) is a tumor suppressor gene that is expressed in gastric and other cancers including pancreatic cancer. However, the precise function of RUNX3 in pancreatic cancer has not been fully elucidated. In this study, we aimed to determine the effect of decreased RUNX3 expression in pancreatic cancer. METHODS: This study included 36 patients with primary pancreatic cancer, who had undergone pancreaticoduodenectomy. All patients were treated with 1000 mg/m2 gemcitabine after the surgery. The pancreatic cancer cell lines PANC-1, MIAPaCa-2, BxPC-3, SUIT-2, and KLM-1 were used for immunoblotting analysis of RUNX3 and multidrug resistance protein (MRP) expressions. Ectopic RUNX3 expression was achieved by cDNA transfection of the cells, and small interfering RNA (siRNA) against RUNX3 was used to knock down endogenous RUNX3. Cell growth in the presence of gemcitabine was assessed using the MTT assay. RESULTS: Patients with RUNX3 positive and RUNX3-negative pancreatic cancer had a median survival of 1006 and 643 days, respectively. Exogenous RUNX3 expression reduced the expression of MRP1, MRP2, and MRP5 in endogenous RUNX3-negative cells, whereas RUNX3 siRNA increased the expressions of these genes in endogenous RUNX3-positive cells. Exogenous RUNX3 expression decreased gemcitabine IC50 in RUNX3-negative cells. CONCLUSION: Loss of RUNX3 expression contributes to gemcitabine resistance by inducing MRP expression, thereby resulting in poor patient survival. PMID- 23664169 TI - Novel nonsurgical left ventricular assist device and system. AB - Treatment options for advanced stages of congestive heart failure remain limited. Left ventricular assist devices (LVADs) have emerged as a means to support failing circulation. However, these devices are not without significant risk such as major open chest surgery. We utilized a novel approach for device placement at the aorto-left atria continuity as a site to create a conduit capable of accommodating a percutaneous LVAD system. We designed and developed an expandable nitinol based device for placement at this site to create a shunt between the LA and aorta. Our experiments support this anatomic location as an accessible and feasible site for accommodation of an entirely percutaneous LVAD. The novelty of this approach would bypass the left ventricle, and thereby minimize complications and morbidities associated with current LVAD placement. PMID- 23664170 TI - Heart failure. Foreword. PMID- 23664171 TI - Optimizing cardiac resynchronization therapy for congestive heart failure. AB - In patients with advanced systolic heart failure and mechanical dyssynchrony, cardiac resynchronization therapy (CRT) is an effective means of improving symptoms and reducing mortality. There are now several recognized approaches to optimize CRT. Imaging modalities can assist with identifying the myocardium with the latest mechanical activation for targeted left ventricular lead implantation. Device programming can be tailored to maximize biventricular pacing, and thereby is its benefit. Cardiac imaging has shown that atrioventricular and interventricular intervals can be adjusted to further reduce dyssynchrony. We review these various approaches that maximize the benefit derived from CRT. PMID- 23664172 TI - Prognosis of secondary acute myeloid leukemia. PMID- 23664173 TI - New insights into the machinery of blood digestion by ticks. AB - Blood-protein digestion is a key physiological process providing essential nutrients for ticks and is a prerequisite for the transmission of tick-borne pathogens. Recently, substantial progress has been made in determining the proteolytic machinery in tick gut tissue, which is based on a dynamic multienzyme network capable of processing a vast amount of host blood. In this article we summarize our current knowledge of the molecular mechanisms of tick hematophagy and their similarities to those of Platyhelminthes, nematodes, and Plasmodium. Future research perspectives, including the potential for rational control of ticks and transmitted diseases, are also discussed. PMID- 23664174 TI - Endobronchial ultrasonography added to endoscopic ultrasonography improves staging in esophageal cancer. AB - BACKGROUND: The gold standard for staging the local extension (T stage) and lymph node (LN) status (N stage) of esophageal cancer is endoscopic ultrasonography (EUS). When biopsy of the peritumoral LNs is performed using EUS, there is a risk of specimen contamination secondary to piercing the primary tumor; this shortcoming can be circumvented with endobronchial ultrasonography (EBUS). Moreover, EBUS allows for biopsy of LN stations not accessible with EUS. METHODS: The study consisted of a prospective clinical trial. Fifty-two consecutive patients with potentially resectable esophageal cancer referred for endoscopic staging were prospectively enrolled. Radial and convex EUS followed by convex EBUS were performed during a single staging procedure. The LNs not accessible by EUS were biopsied using EBUS. Results of the EBUS procedure were compared to those of EUS in terms of the addition of staging information, upstaging, and confirmation of stage. RESULTS: The combined EBUS-EUS procedure was performed in 42 patients. Ten patients were excluded. In all, 54 LNs were biopsied under EUS guidance and 48 LNs were biopsied under EBUS guidance. The EUS results were positive for metastatic esophageal cancer in 29 LNs (54%), and EBUS was positive in 10 LNs (21%). The addition of EBUS to EUS in the staging of esophageal cancer led to nodal and patient upstaging in 5 patients (12%) and confirmed the EUS stage with additional negative or positive LN sampling in 29 patients (69%). Positive EBUS that led to upstaging (5 patients) changed the treatment plan from potentially resectable to palliative. There was no morbidity related to EBUS. CONCLUSIONS: A combined EBUS-EUS staging procedure improves precision in staging, leads to upstaging, and can change the treatment plan in patients with esophageal cancer. PMID- 23664175 TI - Biosynthesis of benzylisoquinoline alkaloids in Corydalis bracteata: compartmentation and seasonal dynamics. AB - Numerous species of the genus Corydalis (Papaveraceae) produce a large spectrum of benzylisoquinoline alkaloids (BIA), some of which are of potential therapeutic value, but no information on sites of their biosynthesis and compartmentation is available. This study focuses on the biosynthesis, compartmentation and seasonal dynamics of BIA in Corydalis bracteata (Steph. ex Willd) Pers., a geophyte with a very short spring vegetation period, which for the rest of the year is represented by underground tubers with buds. It was found that all organs of C. bracteata contained high levels of BIA, the highest concentrations being detected in underground tuber buds in early autumn. Neither xylem nor phloem sap contained alkaloids throughout the year but BIA were present in the apoplastic wash fluid of the tuber. The absence of long-distance transport of alkaloids was confirmed by the experiment using an isotopically labeled tracer, [ring-(13)C6]-tyramine: when whole plants were fed with the tracer with via the roots, the alkaloids became labeled in the roots only and not in other organs. However, when detached roots, leaves, tubers and stems were exposed to [ring-(13)C6]-tyramine, the label was incorporated into alkaloids in all organs. We conclude that no long-distance translocation of alkaloids occurs between organs of C. bracteata, while in the tuber the cell-to-cell transport of alkaloids could occur via the apoplast. In contrast to other BIA-producing species, every organ of C. bracteata was found to be capable of de novo biosynthesis of the full complement of alkaloids. PMID- 23664176 TI - Seasonal and spatial variation in carbon based secondary compounds in green algal and cyanobacterial members of the epiphytic lichen genus Lobaria. AB - Acetone-extractable carbon based secondary compounds (CBSCs) were quantified in two epiphytic lichens to study possible effects of external factors (season and aspect) on secondary chemistry and to relate defense investments to biomass growth and changes in specific thallus mass (STM). At the end of four separate annual cycles starting in each of the four seasons, the cyanolichen Lobaria scrobiculata and the cephalolichen Lobaria pulmonaria (green algae as the primary photobiont and with localized Nostoc in internal cephalodia) were monitored in their natural forest habitats and after being transplanted at three contrasting aspects in open sites. Season strongly influenced most CBSCs. Medullary CBSCs in both species were twice as high in summer as in winter. Aspect hardly affected major CBSCs, whereas transplantation from forest to clear-cut slightly reduced these compounds. No major CBSCs in any species showed a trade-off with growth rate. Dry matter- as well as thallus area-based medullary CBSC contents increased with STM. The cortical usnic acid strongly increased with growth rate and followed spatial, but not seasonal variations in light exposure. Maximal CBSC levels during seasons with most herbivores is consistent with the hypothesis inferring that herbivory is a major selective force for CBSCs. Lack of trade-off between growth and defence investments suggests that these two processes do not compete for photosynthates. PMID- 23664177 TI - Effect of different temperatures on performance and membrane fouling in high concentration PAC-MBR system treating micro-polluted surface water. AB - A bench-scale immersed microfiltration coupled with 50 g/L PAC was developed to treat micro-polluted surface water (MPSW) under 10 and 20 degrees C and the effects of temperatures on the performance and the membrane fouling were also investigated. The low temperature (10 degrees C) delayed the time for the start up by 9 days and the complete nitrification by 10 days. In the stable operation, two systems both had high NH3-N removal efficiency (above 90%) and better removal of organic matters (10% DOC, 5% UV254 and 4% SUVA) at 10 degrees C. Polysaccharides (SMP) were the main membrane fouling matters at low temperature (10 degrees C) and low temperature (10 degrees C) didn't cause serious chemical irreversible membrane fouling. PMID- 23664178 TI - Engineering strategies for simultaneous enhancement of C-phycocyanin production and CO2 fixation with Spirulina platensis. AB - Spirulina platensis produces nutraceutical product C-phycocyanin (C-PC) and simultaneously mitigates CO2 emissions during its growth. Using a designed flat type photobioreactor, the S. platensis biomass production was markedly enhanced, leading to a CO2 removal rate and a biomass concentration of 0.23 g/L/d and 2.25 g/L, respectively. The cell growth, CO2 fixation rate and C-PC production of S. platensis were investigated when it was cultivated under different irradiation conditions. As the light intensity increased from 100 to 700 MUmol/m(2)/s, the overall biomass productivity, CO2 consumption rate and maximal C-PC productivity increased significantly to 0.74, 1.53 and 0.11 g/L/d, respectively. After determining the suitable light intensity, the nitrogen concentration was also adjusted to further enhance the performance of CO2 fixation and C-PC production. The results show that with an optimal nitrogen concentration of 0.045 M, the CO2 consumption rate and maximal C-PC productivity were further increased to 1.58 and 0.13 g/L/d, respectively. PMID- 23664179 TI - Use of a comprehensive polymerase chain reaction system for diagnosis of ocular infectious diseases. AB - PURPOSE: To measure the genomic DNA of ocular infectious pathogens in ocular fluids and to analyze the clinical relevance of these pathogens in uveitis and endophthalmitis. DESIGN: Prospective clinical case series. PARTICIPANTS: A total of 500 patients with infectious uveitis and endophthalmitis were examined at Tokyo Medical and Dental University, Tokyo Medical University, Kyushu University, Osaka University, and Kyoto Prefectural University, all in Japan. METHODS: Genomic DNA of bacteria, fungi, parasites, and viruses in collected intraocular samples were examined by comprehensive polymerase chain reaction (PCR). Samples were analyzed first by multiplex PCR and quantitative real-time PCR for human herpes viruses (HHVs) 1 through 8 and toxoplasma. Subsequently, samples were examined by broad-range real-time PCR for bacterial 16S and fungal 18S/28S ribosomal DNA (rDNA). MAIN OUTCOME MEASURES: Infectious uveitis and endophthalmitis diagnoses were obtained when using the PCR system. Calculations of the positivity and the diagnostic parameters such as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) also were evaluated. RESULTS: In all of the tested infectious uveitis and endophthalmitis patients, either herpes simplex virus type 1 (n = 18), herpes simplex virus type 2 (n = 4), varicella-zoster virus (n = 55), Epstein-Barr virus (n = 17), cytomegalovirus (n = 68), HHV type 6 (n = 2), toxoplasma (n = 6), bacterial 16S (n = 33), or fungal 18S/28S (n = 11) genome was detected. Neither HHV type 7 nor HHV type 8 DNA was detected in any of the samples. Of the 21 false-negative results found during the PCR analyses, 12 cases were negative for patients clinically suspected of having bacterial endophthalmitis. Conversely, false positive results for the comprehensive PCR examinations occurred in only 3 cases that subsequently were found to have bacterial 16S rDNA. Diagnostic parameters for the sensitivity, specificity, PPV, and NPV of our PCR examinations were 91.3%, 98.8%, 98.6%, and 92.4%, respectively. CONCLUSIONS: Use of our comprehensive PCR assay to examine ocular samples in patients with endophthalmitis and uveitis seems to be clinically useful for detecting infectious antigen DNA. Thus, this PCR method is a reliable tool for both diagnosing ocular disorders and further screening of patients for intraocular infections. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23664181 TI - Tuberculosis transmission by Mycobacterium bovis in a mixed cattle and goat herd. AB - A tuberculosis (TB) outbreak caused by Mycobacterium bovis occurred in a mixed herd of three cattle and eighteen goats in Northern Italy in 2005. All the cattle were removed, as opposed to the co-existing goats, who remained in the farm and were not subsequently tested by the official intradermal tuberculin test. At the beginning of May 2006, a 7-day old calf was introduced into the herd from an officially TB-free (OTF) farm. On October 2006, tuberculous lesions were detected at the slaughterhouse in the same animal. The following epidemiological investigation on the herd highlighted a clinical suspicion of TB in one goat out of 35, and visible lesions were found at necropsy in the respiratory and intestinal tracts. Bacteriological culture and molecular tests confirmed the presence of M. bovis in both animals. Spoligotyping and Mycobacterial Interspersed Repetitive Units - Variable Number of Tandem Repeats (MIRU-VNTR) showed the same genomic profile of the previous breakdown occurred in 2005. Since this profile has never been described in Italy, these findings suggest the probable transmission of TB within the farm among cattle and goats. The remaining 34 goats were also tested by single intradermal cervical comparative tuberculin (SICCT) test, Interferon (IFN)-gamma assay and ELISA for antibody to M. bovis. The SICCT test and the IFN-gamma showed a good concordance with 20 and 19 positive reactors, respectively. By ELISA we found 12Ab-positive animals, seven of which had not been detected by the tests for cell-mediated immunity. Finally, 15 goats were found positive for gross lesions at necropsy. The in vivo tests revealed a total of 27 positive animals out of 35, which highlights the usefulness of the serology in parallel with SICCT and IFN-gamma when an advanced stage of infection is suspected. Moreover, our results confirm the necessity for adopting the official tuberculin test on goats co-existing with cattle. PMID- 23664180 TI - A toxicokinetic comparison of two species of low larkspur (Delphinium spp.) in cattle. AB - Low larkspurs have different toxic potentials to livestock due to variation in the individual alkaloids present in the plants. Two species, Delphinium nuttallianum and Delphinium andersonii were dosed to 10 Holstein steers at 10mg and 12 mg toxic alkaloids/kg, respectively. Blood samples were collected periodically for 96 h, analyzed for serum alkaloid concentrations and toxicokinetic parameters calculated for 16-deacetylgeyerline, 14 deacetylnudicauline, methyllycaconitine and geyerline/nudicauline which co-eluted in the serum analysis. The maximum serum alkaloid concentrations and area under the curve values for 16-deacetylgeyerline and geyerline/nudicauline were significantly different between the two groups due to the concentrations of the alkaloids in each larkspur species. The alkaloid elimination half-lives were similar for the two larkspur species. These results suggest the elimination rates of norditerpene alkaloids from different larkspur species in cattle are similar regardless of plant alkaloid composition. The determining factor for larkspur toxicity is the individual alkaloid composition of the plant. PMID- 23664182 TI - Dabigatran in clinical practice--one-year experience at Skane University Hospital. PMID- 23664183 TI - Paramyxoviruses in reptiles: a review. AB - In 1972, an outbreak of neurorespiratory disease in a Swiss serpentarium formed the basis for the first description of a paramyxovirus isolated from a reptile. In the forty years since this outbreak, there have been over 50 published reports about reptilian paramyxoviruses from all over the world. The majority of these investigations have concerned themselves with ferlaviruses (sometimes previously referred to as ophidian paramyxoviruses, or OPMV). The biology of these viruses is reviewed and this is followed by a review of the clinical findings that are associated with ferlaviral infection and the various diagnostic tests that are used to identify infected reptiles. Recently, a second, and highly divergent, reptilian paramyxovirus, Sunshine virus, was described in Australian pythons, so it is an opportune time to reflect on the paramyxoviruses that infect reptiles. PMID- 23664184 TI - Changes of poultry faecal microbiota associated with Clostridium difficile colonisation. AB - Bacterial, fungal and archaeal microbiota was analysed in 143 chicken faecal samples from a single poultry farm. After DHPLC (denaturing high performance liquid chromatography) 15 bacterial groups, 10 fungal groups and a single archaeal species were differentiated. Samples were grouped into two clusters with significantly different frequencies of C. difficile positive and negative samples in each cluster. Acidaminococcus intestini, described here for the first time as a part of poultry faecal microbiota, was significantly more likely present in C. difficile negative samples, while presence/absence of some other microorganisms (Enterococcus cecorum, Lactobacillus galinarum, Moniliella sp. and Trichosporon asahii) was close to significance. Two other groups not reported previously for poultry, Coprobacillus sp. and Turicibacter sp. did not differ significantly between C. difficile positive and negative samples. Differences in microbiota diversity depend on animal age, but not on the presence of C. difficile. With machine learning (WEKA J48) we have defined specific combinations of microbial groups predictive for C. difficile colonisation. Microbial groups associated with C. difficile colonisation in poultry are different than those reported for humans and include bacteria as well as fungi. Also with this approach A. intestini was found to be most strongly related to C. difficile negative samples. PMID- 23664185 TI - Male rats transmit Brucella abortus biotype 1 through sexual intercourse. AB - The aim of this study was to evaluate transmission of Brucella abortus biotype 1 via sexual intercourse in rats. Male and female virgin Sprague-Dawley (SD) rats were experimentally infected intraperitoneally with 1*10(9)colony forming units (CFU) of B. abortus biotype 1, a Korean bovine isolate. At 14 days after infection, infected male rats (n=10) were housed with uninfected female rats (n=10) and infected female rats (n=10) were housed with uninfected male rats (n=10) for a period of one month. During this period all uninfected female rats became pregnant and 6 of 10 infected female rats became pregnant. Serum from two out of 10 female uninfected rats had positive reactions in the Rose Bengal Plate Agglutination Test (RBPAT), Tube Agglutination Test (TAT) or the Enzyme-Linked Immunosorbent Assay (ELISA); whereas none of the uninfected male rat had positive reactions in these tests. Using bacteriological culture and AMOS-PCR assay, B. abortus biotype 1 was isolated and identified from two uninfected female rats and all of the uninfected male rats were found negative for B. abortus biotype 1. It was concluded that transmission of B. abortus biotype 1 from infected male to uninfected female rats resulted from sexual intercourse. PMID- 23664186 TI - Biofilm-forming ability of Staphylococcus aureus strains isolated from human skin. AB - BACKGROUND: Staphylococcus aureus produces various toxins and enzymes, and its presence can exacerbate skin conditions. Previous studies have shown that S. aureus is involved in skin deterioration, even in normal tissue. Biofilm strains show much greater resistance to antimicrobial agents and therefore require a much higher concentration of biocide than planktonic counterparts. OBJECTIVE: As such, alternative strategies and more effective therapeutic agents against biofilm producing S. aureus in skin are of great interest. Therefore, we turned our attention to differences in 50 clinical biofilm strains isolated from human facial skin. METHODS: Based on S. aureus density on facial skin, we divided donors into two groups: relatively low density (LSG) and high density (HSG). In general, strong biofilm-forming strains were detected in the HSG donors. Two strains from each of the groups were submitted to gene microarray analysis to investigate expression differences and confirmed by RT-PCR. RESULTS: In total, 111 of 7775 genes were differentially expressed between low (SA2 and SA7) vs. high (SA10 and SA33) biofilm-forming clinical strains. These genes include already well-known as biofilm formation related genes like icaABCD and lrgAB, and newly identified genes (sdrC, sspBCP) by RT-PCR. Comparison of gene expression differences between the two groups available at NCBI Gene Expression Omnibus accession number GSE44268. CONCLUSION: Our results suggest that S. aureus density in the skin is closely related to biofilm-forming ability, and we have identified several potential target genes that may be involved in regulating biofilm formation in situ. PMID- 23664187 TI - Role of alpha5beta1 integrin and MIA (melanoma inhibitory activity) in the pathogenesis of vitiligo. PMID- 23664189 TI - Fukushima radionuclides in Vilnius/Lithuania aerosols: modelling of aerosol transport. AB - Measurements of activity concentrations of (131)I; (129 m)Te, (132)Te, (134)Cs and; (136)Cs, (137)Cs in aerosol were carried out in daily samples after the Fukushima accident during the period of March-April, 2011 in Vilnius. The maximum activity concentrations of (131)I and (137)Cs were found to be 3,700 MUBq m(-3) and 1,040 MUBq m(-3), respectively. Variations in activity ratios of (132)Te/(129 m)Te and (137)Cs/(136)Cs observed after the accident were explained by the decay of the short-lived isotopes, while those in (134)Cs/(137)Cs by the dilution effect of the Chernobyl-derived (137)Cs. It was found that different behaviours of highly volatile (131)I and (137)Cs resulted in enrichment of ground level aerosol particles by (131)I with respect to (137)Cs. Simulated activity concentrations of (137)Cs attached to aerosol particles for the Vilnius site reasonably agreed with measured activities in aerosol samples during the Fukushima accident. PMID- 23664188 TI - Invariant natural killer T cells are enriched at the site of cutaneous inflammation in lupus erythematosus. AB - BACKGROUND: Systemic lupus erythematosus (SLE) is associated with a numerical and functional reduction of peripheral blood (PB) invariant natural killer T (iNKT) cells. Limited information exists on the role of iNKT cells in the pathogenesis of lupus erythematosus. OBJECTIVE: To investigate the frequency and phenotype of iNKT cells in PB and dermal infiltrates from patients with SLE, subacute cutaneous lupus erythematosus (SCLE) and discoid lupus erythematosus (DLE). METHODS: PB was obtained from 23 SLE, 6 SCLE, and 11 DLE patients, and from 30 healthy controls. iNKT cell frequency and CCR4/CCR6 surface expression were assessed by flow cytometry. The frequency and phenotype of skin infiltrating Valpha24(+)Vbeta11(+) iNKT cells were investigated by immunofluorescence in lesional biopsies from 20 patients, unaffected skin from 3 patients, and from 6 healthy controls. RESULTS: Lupus erythematosus patients displayed significantly lower percentages of circulating CD3(+)6B11(+) iNKT cells compared to healthy controls. Whereas CCR6 expression on iNKT cells was enhanced in active SLE patients regardless of cutaneous involvement compared to healthy controls, CCR4 was exclusively increased in patients with active cutaneous lesions. Furthermore, iNKT cells were significantly enriched in lesional skin of SLE and DLE patients, but not in unaffected skin of lupus patients. The majority of lesional iNKT cells expressed IFN-gamma and CCR4. CONCLUSION: The deficiency in circulating iNKT cells in cutaneous lupus erythematosus is associated with an increase of iNKT cells at the site of cutaneous inflammation. These data underscore the importance of analyzing iNKT cells not only in PB, but also in the target tissues. PMID- 23664190 TI - Mitochondrial DNA sequence and copy number variants cannot be the only culprit in the pathogenesis of noncompaction. PMID- 23664191 TI - A cheaper method of corneal protection during periocular surgery: in response to: Kittur MA, Isaac R, Parkin IR. Physiological method of corneal protection during periocular surgery. Br J Oral Maxillofac Surg 2013;51:178-9. PMID- 23664192 TI - [Iodine intake during pregnancy: effects on thyroid function in mother and child]. AB - INTRODUCTION: Recent studies in Spain have shown an inadequate iodine intake in a significant proportion of pregnant women. Pregnancy increases thyroid hormone requirements, and adequate iodine intake is therefore needed. MATERIAL AND METHODS: One hundred and forty-seven women in their third trimester (week 37) of pregnancy provided a blood sample and a 24-hour urine sample to test serum and urine iodine levels and completed a food frequency questionnaire to assess iodine intake during pregnancy. Serum TSH levels were measured in the babies born to the 140 mothers in the postpartum group. RESULTS: Only 10.9% of pregnant women consumed more than 250 MUg iodine daily, and 24.4% of them consumed less than 100 MUg daily. Mean free T4 levels were 9.37 pmol/L, and 74 women (54.41%) had levels below the hypothyroxinemia threshold. TSH levels were normal in 135 newborns (96.4%), while 5 (3.6%) had levels higher than 5 MUU/mL. PMID- 23664193 TI - [Diabetes mellitus and depressive disorder, an undesirable association]. AB - Type 2 diabetes and depressive disorder are 2 chronic diseases highly prevalent in developed countries and with a negative impact on quality of life and life expectancy. In recent years, both conditions have been shown to be strongly associated. Thus, diabetics have an increased risk of suffering depressive disorder, as well as impaired glucose homeostasis, if they experience depression. In diabetic patients, concurrent depression is associated to greater difficulties in disease management and metabolic control, increased risk of developing chronic complications, decreased quality of life, and higher healthcare expenses. As a result, the interest of diabetic scientific societies in this association has increased, and they recommend regular mood assessment in diabetic patients. However, the limited clinical experience available and the conflicting results reported to date make it difficult to draw conclusions. PMID- 23664194 TI - [Some considerations about the consensus document "Detection of thyroid dysfunction in pregnant women: universal screening is justified"]. PMID- 23664195 TI - Portal venous gas emboli after accidental ingestion of concentrated hydrogen peroxide. AB - BACKGROUND: Hydrogen peroxide is a common household product. It is clear and odorless making it easy to confuse with water, especially when improperly stored. Concentrated formulations are also available for consumer purchase. OBJECTIVE: We report a case of hydrogen peroxide ingestion in a child and discuss the potential consequences and treatment of such an exposure. CASE REPORT: A 12-year-old boy accidentally ingested a sip of concentrated hydrogen peroxide. He rapidly developed hematemesis and presented to the Emergency Department. His initial work up was unremarkable, and his symptoms resolved quickly. However, diffuse gas emboli were found within the portal system on abdominal computed tomography. The child was treated with hyperbaric oxygen therapy and later found to have gastric irritation as well as an ulcer on endoscopy. He recovered fully from the incident. CONCLUSIONS: We present this case to increase awareness of the dangers of hydrogen peroxide ingestion in children. Fortunately, the child in this case recovered fully, but emergency physicians should be aware of the potential consequences and therapeutic options. PMID- 23664196 TI - Orolingual angioedema with alteplase administration for treatment of acute ischemic stroke. PMID- 23664197 TI - The role of muscle strength & activation patterns in patellofemoral pain. AB - BACKGROUND: To investigate the extent to which quadriceps muscle activation and strength are responsible for patellofemoral pain. METHODS: A pain on-off switch system synchronized with a force transducer and surface electromyography was utilized on 32 volunteer patellofemoral pain patients during maximal isometric and squat exercises. FINDINGS: There were 26 patients out of the 32 tested who complained of pain during the squat or isometric test, of these 20 subjects presented a significant advantage for the vastus lateralis compared to the vastus medialis obliquis activation and 12 patients had decreased quadriceps strength of the symptomatic compared to the non symptomatic leg. All patients who demonstrated weak vastus medialis obliquis activation during the isometric exercise possessed the same symptoms during the squat. On the other hand, 9 patients who showed diminished vastus medialis obliquis activation during the squat displayed equal activation between the vastus medialis obliquis and the vastus lateralis during the isometric task. With regard to the timing for the onset of muscle activation, there were only 4 patients who had a difference (P=0.03) between the symptomatic (0.042 s) and non-symptomatic legs (0.011 s). INTERPRETATION: Causes for patellofemoral pain vary and are not necessarily a result of quadriceps strength deficit or vastus medialis obliquis activation weakness. Patellofemoral pain patients who possess lower vastus medialis obliquis activation compared to the vastus lateralis do not necessarily have quadriceps weakness while patients presenting with quadriceps strength deficits do not always have an imbalance between vastus medialis obliquis and vastus lateralis activation. PMID- 23664198 TI - Anthropometric assessment of patients with cerebral palsy: which curves are more appropriate? AB - OBJECTIVE: To describe the nutritional assessment of children with cerebral palsy, verifying the correlation of growth curves specific for cerebral palsy with general curves, in addition to assessing the presence of digestive manifestations associated with nutritional problems. METHODS: This was a cross sectional study of 187 individuals with cerebral palsy, evaluating anthropometric data in curves commonly used in pediatrics and specific curves for cerebral palsy, in addition to the description of presence of dysphagia, constipation, and respiratory infections. RESULTS: 58% of patients were males, with a mean age of 5.6 +/- 3.5 years. Anthropometric data of weight below the 10th percentile occurred in 10% of the sample considering the cerebral palsy scale, versus 51% when considering the reference from the Centers for Disease Control and Prevention (p < 0.01; Kappa 0.19). The weight of most individuals with dysphagia, recurrent respiratory infections, and constipation was below the 50th percentile, with respective percentages of 67%, 75%, and 72%. CONCLUSION: The references commonly used in pediatrics tend to overestimate malnutrition in individuals with cerebral palsy, and their correlation with specific references for cerebral palsy is low. Digestive manifestations were mainly found in those individuals whose anthropometric measurements were below the 50th percentile. PMID- 23664199 TI - A prospective study of risk factors for neurological complications in childhood bacterial meningitis. AB - OBJECTIVE: To prospectively analyze the prognostic factors for neurological complications of childhood bacterial meningitis. METHODS: This prospective study enrolled 77 children from 1 month until 16 years of age, treated for bacterial meningitis during the period of January 1, 2009 through December 31, 2010. 16 relevant predictors were chosen to analyze their association with the incidence of neurological complications. p-values < 0.05 were considered statistically significant. RESULTS: Of the 77 children treated for bacterial meningitis, 33 patients developed neurological complications (43%), and two children died (2.6%). The etiology of bacterial meningitis cases was proven in 57/77 (74%) cases: 32 meningococci, eight pneumococci, six Gram-negative bacilli, five H. influenzae, five staphylococci, and one S. viridans isolates were found. Factors found to be associated with increased risk of development of neurological complications were age < 12 months, altered mental status, seizures prior to admission, initial therapy with two antibiotics, dexamethasone use, presence of focal neurological deficit on admission and increased proteins in cerebrospinal fluid (CSF) (p < 0.05). Initial pleocytosis > 5,000 cells/mm(3), pleocytosis > 5,000 cells/mm(3) after 48 hours, CSF/blood glucose ratio < 0.20, female gender, previous treatment with antibiotics, community-acquired infection, duration of illness > 48 hours, presence of comorbidity, and primary focus of infection were not associated with increased risk for the development of neurological complications. CONCLUSION: Age < 12 months and severity of clinical presentation at admission were identified as the strongest predictors of neurological complications and may be of value in selecting patients for more intensive care and treatment. PMID- 23664200 TI - Zinc and other micronutrients supplementation through the use of sprinkles: impact on the occurrence of diarrhea and respiratory infections in institutionalized children. AB - OBJECTIVE: To evaluate the incidence of diarrheal disease (DD) and acute respiratory infection (ARI) in children undergoing supplementation of zinc and other micronutrients through the use of sprinkles, as well as their acceptance by these patients. METHOD: This was a randomized double-blinded clinical trial of 143 healthy institutionalized children, aged 6 to 48 months. They were randomized into two groups and received daily zinc and micronutrients - test group (sprinkles), or micronutrients without zinc - control group. Children were supplemented for 90 days and followed regarding the outcomes of DD and ARI. RESULTS: Of the randomized children, 52.45% belonged to the test and 47.55% to the control group. The incidence of DD in the test group was 14.7% and was 19.1% in the control group. The test group showed a lower risk of developing DD when compared to controls, but this finding was not statistically significant (RR=0.77 [0.37 to 1.6], p=0.5088). ARI had high incidence in both groups, 60% in the test group and 48.5% in the control group, with an increased risk of developing the disease in the test group, but with no statistical significance (RR=1.24 [0.91 to 1.68], p=0.1825). Regarding acceptance, the mean percentage of consumption, in days, of the entire content of the sachets containing sprinkles was 95.72% (SD=4.9) and 96.4% (SD=6.2) for the test and control groups, respectively. CONCLUSIONS: Zinc supplementation through the use of sprinkles did not reduce the incidence of DD or ARI among the evaluated children. The sprinkles were well accepted by all study participants. PMID- 23664201 TI - Measures of cardiovascular risk and subclinical atherosclerosis in a cohort of women with a remote history of preeclampsia. AB - OBJECTIVE: We assessed for subclinical atherosclerosis using carotid intima-media thickness (CIMT) among women with and without a remote history of preeclampsia. Secondarily, we contrasted cardiovascular risk factors and electrocardiography between both groups. Women with a history of preeclampsia are at higher risk of future cardiovascular disease (CVD). The degree to which this is mediated by atherosclerosis is less understood, especially after several decades. METHODS: We performed a nested cohort study comprising 109 women with a remote history of preeclampsia 1:2 matched to 218 women with an uncomplicated pregnancy. After a median of 20 years since the index pregnancy, we measured blood pressure, height, weight, waist and hip circumference, and performed an oral 75 g glucose tolerance test (OGTT), fasting lipids, electrocardiography, albumin:creatinine ratio (ACR) and CIMT among all participants. RESULTS: While women with and without preeclampsia had similar family histories of CVD, those with preeclampsia had a higher rate of chronic hypertension (32% versus 10%, p < 0.0001), greater waist (p = 0.008) and hip circumferences (p = 0.001). No differences were seen on in OGTT, lipid or ACR measures. Average maximum CIMT was similar among those with versus without preeclampsia (0.831 mm versus 0.817, p = 0.38), and preeclampsia was not a significant predictor of CIMT in a multiple linear regression model (p = 0.63), despite more electrocardiograms compatible with coronary disease. CONCLUSION: Two decades after delivery, women with a remote history of preeclampsia had more CVD risk factors than women with unaffected pregnancies, but this was not reflected in a difference in CIMT. PMID- 23664202 TI - Increased lysophosphatidic acid levels in culprit coronary arteries of patients with acute coronary syndrome. AB - BACKGROUND: Lysophosphatidic acid (LPA) is a platelet activator and highly thrombogenic lipid constituent of atherosclerotic plaque. However, whether or not LPA locally released from culprit lesions is associated with acute coronary syndrome (ACS) remains unclear. METHODS: We studied 52 patients with ACS who were treated by emergency percutaneous coronary intervention and thrombectomy. Levels of LPA and other established biomarkers were enzymatically assayed in samples of culprit coronary arterial and systemic peripheral arterial blood. Levels of LPA and lysophosphatidylcholine (LPC) were measured in plasma, and those of autotaxin, soluble CD40 ligand (sCD40L), hs-CRP and Lp-PLA2 were measured in serum. RESULTS: Median LPA levels were significantly higher in coronary (CB) than in peripheral (PB) arterial blood (p = 0.009). Levels of sCD40L were higher in CB than in PB, but the difference did not reach statistical significance (p = 0.177). In contrast, autotaxin and Lp-PLA2 levels were significantly higher in PB than in CB (p = 0.005 and p = 0.038, respectively). Levels of LPC and hs-CRP were also higher in PB than in CB (p = 0.129 and p = 0.121, respectively). Levels of LPA in both CB and PB were positively and significantly associated with those of LPC (r = 0.632, p < 0.01 and r = 0.465, p < 0.001). CONCLUSIONS: Culprit coronary arteries of ACS contained significantly more LPA than the systemic arterial circulation. Higher LPA concentrations might be associated with the pathophysiology of ACS. PMID- 23664203 TI - Association between carotid intima-media thickness and retinal arteriolar and venular diameter in patients with hypertension: a cross-sectional study. AB - OBJECTIVE: Abnormalities in retinal vessels are frequent, but its association with findings in other vascular sites has been scarcely investigated. This study aimed to examine the association between ultrasound-measured carotid intima-media thickness (IMT) and retinal arteriolar and venular diameters, in hypertensive patients. METHODS: In this cross-section study, 173 hypertensive patients had both retinography taken and digitized to determine vessel diameters by an edge detecting computerized method and carotid ultrasound for semi-automated carotid IMT measurement. The association between the mean common carotid IMT and retinal arterioles and venules diameters was assessed by using multiple linear regression models. RESULTS: The mean (+/-SD) arteriolar and venular diameters were 102. 8 (+/-11.6) MUm and 128.9 (+/-15.5) MUm, respectively, and common carotid IMT was 0.87 (+/-0.19) mm. A significant and independent association was demonstrated for carotid IMT and retinal arteriolar caliber (adjusted beta -0.245, p = 0.001) and for carotid IMT and retinal venular caliber (adjusted beta 0.191, p = 0.009) after controlling for age, gender, systolic blood pressure, total cholesterol and HDL (high-density lipoprotein) cholesterol, prior cardiovascular disease, carotid plaque and the retinal fellow vessel. CONCLUSION: In patients with hypertension, carotid intima-media thickness, a marker of macrovascular damage, is significantly and independently associated with microvascular damage, determined by retinal arteriolar and venular calibers. PMID- 23664204 TI - Global output feedback control for a class of high-order feedforward nonlinear systems with input delay. AB - This paper investigates the problem of output feedback stabilization for a class of high-order feedforward nonlinear systems with time-varying input delay. First, a scaling gain is introduced into the system under a set of coordinate transformations. Then, the authors construct an observer and controller to make the nominal system globally asymptotically stable. Based on homogeneous domination approach and Lyapunov-Krasovskii functional, it is shown that the closed-loop system can be rendered globally asymptotically stable by the scaling gain. Finally, two simulation examples are provided to illustrate the effectiveness of the proposed scheme. PMID- 23664205 TI - Performance comparison of optimal fractional order hybrid fuzzy PID controllers for handling oscillatory fractional order processes with dead time. AB - Fuzzy logic based PID controllers have been studied in this paper, considering several combinations of hybrid controllers by grouping the proportional, integral and derivative actions with fuzzy inferencing in different forms. Fractional order (FO) rate of error signal and FO integral of control signal have been used in the design of a family of decomposed hybrid FO fuzzy PID controllers. The input and output scaling factors (SF) along with the integro-differential operators are tuned with real coded genetic algorithm (GA) to produce optimum closed loop performance by simultaneous consideration of the control loop error index and the control signal. Three different classes of fractional order oscillatory processes with various levels of relative dominance between time constant and time delay have been used to test the comparative merits of the proposed family of hybrid fractional order fuzzy PID controllers. Performance comparison of the different FO fuzzy PID controller structures has been done in terms of optimal set-point tracking, load disturbance rejection and minimal variation of manipulated variable or smaller actuator requirement etc. In addition, multi-objective Non-dominated Sorting Genetic Algorithm (NSGA-II) has been used to study the Pareto optimal trade-offs between the set point tracking and control signal, and the set point tracking and load disturbance performance for each of the controller structure to handle the three different types of processes. PMID- 23664206 TI - Survey of Korean pedestrians' natural preference for walking directions. AB - The primary objective of this study was to investigate the stereotypes of Koreans regarding preferred walking directions when encountering various public walking facilities, and to provide useful information to pedestrians and traffic policy legislators. To this end, this study was conducted in two phases. In the first phase, we conducted observational research on pedestrians' walking directions in ten different situations. In the second phase, six hundred Korean male and female subjects were selected to investigate the various statistics about their preferred walking directions and their employment characteristics in diverse walking facilities. The results showed that 59.3% abided by the Left-side Traffic rule while 40.7% abided by the Right-side rule. On the contrary, 73.7% of respondents showed preferences to the Right-side Traffic rule. Moreover, right handed people showed strong tendencies to walk on the right side of the road and vice versa, hence suggesting that the direction people naturally prefer in walking should be a crucial determinant when regulating traffic policies. PMID- 23664207 TI - Pyuria predicts poor prognosis in patients with non-muscle-invasive bladder cancer. AB - BACKGROUND: To evaluate the significance of inflammation in non-muscle-invasive bladder cancer (NMIBC), we assessed the presence of pyuria at time of diagnosis. PATIENTS AND METHODS: A cohort of 805 patients with newly diagnosed NMIBC between 1994 and 2007 at the Tokyo Metropolitan Tama Medical Center were enrolled in this retrospective study. Pyuria was defined as urine containing >= 10 white blood cells (WBCs) per high power field (HPF). RESULTS: One hundred ninety-nine (24%) of the patients with NMIBC had pyuria. The 3-year recurrence-free survival rates of patients with and without pyuria were 10.9 vs. 45.0%, respectively. The 5-year progression-free survival rates of patients with and without pyuria were 72.3% and 95.7%, respectively. Multivariate Cox proportional hazards regression models indicated that pyuria was an independent predictor of disease recurrence and progression. After dividing the sample according to the European Organization for Research and Treatment of Cancer (EORTC) risk tables, we further classified patients into subgroups according to the presence of pyuria. The recurrence-free survival rates were higher in the pyuria-negative subgroups of the low, intermediate-low, intermediate-high, and high risk for recurrence groups. Similarly, the progression-free survival rates at 5 years were higher in the pyuria-negative subgroups of the low, intermediate-low, and intermediate-high risk for progression groups. CONCLUSION: Patients with inflammatory NMIBC exhibited poor clinical outcomes. PMID- 23664208 TI - Photodynamic therapy versus combination therapy in polypoidal choroidal vasculopathy: changes of aqueous vascular endothelial growth factor. AB - PURPOSE: To investigate the influence of photodynamic therapy (PDT) and combination of PDT and ranibizumab on aqueous humor levels of vascular endothelial growth factor (VEGF) in polypoidal choroidal vasculopathy (PCV). DESIGN: Prospective randomized clinical trial. METHOD: We included 20 eyes with treatment-naive PCV and 20 eyes undergoing cataract surgery as controls. PCV eyes were randomized to treatment with PDT alone or to a combination of ranibizumab and PDT on the same day. During 3 months, retreatment was not performed. Aqueous humors were collected at baseline and at 1 week, 1 month, and 3 months after treatment in the PCV group and during cataract surgery in the control group. VEGF levels were measured using multiplex bead immunoassay. RESULTS: At baseline, VEGF levels were significantly increased in PCV eyes compared with control eyes. A significant decrease in VEGF levels was found at 1 week after PDT treatment (n = 8) and at all time points after combination treatment (n = 12). With combination treatment, VEGF levels were decreased to values below the detection limit in all eyes at 1 week and 1 month and in 7 of 12 eyes at 3 months. There was no difference in the clinical profiles among the 2 treatment groups at each time point. CONCLUSION: Decreased levels of VEGF detected 1 week after PDT for PCV seems to reflect acute damage of vascular endothelial cells, one of the VEGF expression sites in PCV. Concomitant ranibizumab resulted in a further decrease in VEGF to negligible levels, but this result did not affect the clinical results for 3 months. PMID- 23664209 TI - Contrast-induced nephropathy and dehydration. PMID- 23664210 TI - GOALDS--goal based damage ship stability and safety standards. AB - The new probabilistic damaged stability regulations for dry cargo and passenger ships (SOLAS 2009), which entered into force on January 1, 2009, represent a major step forward in achieving an improved safety standard through the rationalisation and harmonization of damaged stability requirements. There are, however, serious concerns regarding the adopted formulation for the calculation of the survival probability of passenger ships, particularly for ROPAX and large cruise vessels. The present paper outlines the objectives, the methodology of work and main results of the EU-funded FP7 project GOALDS (Goal Based Damaged Stability, 2009-2012), which aims to address the above shortcomings by state-of the-art scientific methods and by formulating a rational, goal-based regulatory framework, properly accounting for the damage stability properties of passenger ships and the risk of people onboard. PMID- 23664211 TI - Caffeic acid derivatives: a new type of influenza neuraminidase inhibitors. AB - Recently, many natural products, especially some plant-derived polyphenols have been found to exert antiviral effects against influenza virus and show inhibitory activities on neuraminidases (NAs). In our research, we took caffeic acid which contained two phenolic hydroxyl groups as the basic fragment to build a small compound library with various structures. The enzyme inhibition result indicated that some compounds exhibited moderate activities against NA and compound 15d was the best with IC50=7.2 MUM and 8.5 MUM against N2 and N1 NAs, respectively. The 3,4-dihydroxyphenyl group from caffeic acid was important for the activity according to the docking analysis. Besides, compound 15d was found to be a non competitive inhibitor with Ki=11.5+/-0.25 MUM by the kinetic study and also presented anti-influenza virus activity in chicken embryo fibroblast cells. It seemed promising to discover more potent NA inhibitors from caffeic acid derivatives to cope with influenza virus. PMID- 23664212 TI - Structural elucidation of novel degradation product of brotizolam. AB - When the drug product of brotizolam (1) is decomposed according to the interview form and patent, hydrolysate (2) is obtained, but its physicochemical data are still missing. To elucidate the structure based on a spectroscopic approach, the above-mentioned degradation product was isolated and applied to the structural analysis. As a result, the structure of decomposed product was found to be different from that of 2. In this report, its isolation and structure elucidation by NMR and MS spectra are described. PMID- 23664213 TI - Optimization of a novel potent and selective bacterial DNA helicase inhibitor scaffold from a high throughput screening hit. AB - Benzobisthiazole derivatives were identified as novel helicase inhibitors through high throughput screening against purified Staphylococcus aureus (Sa) and Bacillus anthracis (Ba) replicative helicases. Chemical optimization has produced compound 59 with nanomolar potency against the DNA duplex strand unwinding activities of both B. anthracis and S. aureus helicases. Selectivity index (SI=CC50/IC50) values for 59 were greater than 500. Kinetic studies demonstrated that the benzobisthiazole-based bacterial helicase inhibitors act competitively with the DNA substrate. Therefore, benzobisthiazole helicase inhibitors represent a promising new scaffold for evaluation as antibacterial agents. PMID- 23664214 TI - Aryl uracil inhibitors of hepatitis C virus NS5B polymerase: synthesis and characterization of analogs with a fused 5,6-bicyclic ring motif. AB - The synthesis and structure-activity relationships of a novel aryl uracil series which contains a fused 5,6-bicyclic ring unit for HCV NS5B inhibition is described. Several analogs display replicon cell culture potencies in the low nanomolar range along with excellent rat pharmacokinetic values. PMID- 23664215 TI - Discovery of new potent inhibitors for carbonic anhydrase IX by structure-based virtual screening. AB - Through structure-based virtual screening, some dozen of benzene sulfonamides with novel scaffolds are identified as potent inhibitors against carbonic anhydrase (CA) IX with IC50 values ranging from 2.86 to 588.34 nM. Among them, compounds 1 and 9 show high selectivity against tumor-target CA IX over CA II (the selectivity ratios are 21.3 and 136.6, respectively). The possible binding poses of hit compounds are also explored and the selectivity is elucidated by molecular docking simulations. The hit compounds discovered in this work would provide novel scaffolds for further hit-to-lead optimization. PMID- 23664216 TI - Nigella sativa seed extract: 1. Enhancement of sheep macrophage immune functions in vitro. AB - Nigella sativa (N. sativa) seed, Black cumin, immunomodulatory activity has been investigated in human and mice. Little is known about the immunomodulatory effect of Nigella sativa (N. sativa) seed extract on animals' immune cells, specifically, antigen presenting cells such as macrophages. This study focused on the immunomodulatory effect of N. sativa seed extract on sheep macrophage functions in vitro. Sheep peripheral blood monocytes were isolated and derived to macrophages (MDM). The MDM were cultured with N. sativa seed extract and their morphological changes, phagocytic activity, nitric oxide production, and microbicidal activity were investigated. Marked morphological changes were observed in MDM cultured with N. sativa seed extract including cell size enlargement; increase in both cytoplasmic space and cytoplasmic granules. Significant increases in phagocytic activity to Candida albicans yeast and in number of yeast engulfed per individual MDM were observed in cells cultured with seed extract. MDM capacity to produce nitric oxide was higher in the culture media of the seed extract-cultured cells compared to the control. Interestingly, prominent enhancement in MDM microbicidal activity to yeast or bacteria was observed in MDM cultured with N. sativa seed extract confirming the potent immunostimulatory effect of the extract. From this study, it could be concluded that N. sativa seed extract can enhance macrophages' important innate immune functions that could control infectious diseases and regulate adaptive immunity. PMID- 23664217 TI - [Caudal epidural anesthesia in a case of Fournier's gangrena]. PMID- 23664218 TI - [Takotsubo cardiomyopathy in the context of Staphylococcus aureus sepsis]. AB - Takotsubo cardiomyopathy consists of a transient dysfunction of the left ventricle. It is characterised by an impaired left ventricular segmentary contractility, without significant coronary lesions in the coronary angiography. It usually occurs after an episode of physical or emotional stress. We present the case of a 70 year-old woman, who, in the postoperative period of an ankle osteosynthesis, developed a Takotsubo cardiomyopathy in the context of a sepsis caused by Staphylococcus aureus. She presented with acute lung oedema and a clinical picture of low cardiac output. The echocardiogram showed left ventricular medioapical akinesia. Coronary angiography was normal. She was treated with supportive measures with good progress. At 33 days from onset she was able to be discharged from hospital to home with normal systolic function on echocardiography. PMID- 23664219 TI - Fertility preservation consultation for women with cancer: are we helping patients make high quality decisions? AB - Improved possibilities to protect and preserve fertility before gonadotoxic therapies allow us to help more women than in previous years. But to individually decide which preserving option and concept is possible and useful, one needs time for an intensive fertility preservation consultation. The counselling should be performed as soon as possible after having an exact diagnosis, an idea about the planned oncological adjuvant or neoadjuvant therapy and its potential toxicity on ovaries. After the fertility preservation consultation, patients must have enough time to decide and involved colleagues must have enough time to realize the individual concept after patients' decision. PMID- 23664220 TI - Stem cell therapeutic possibilities: future therapeutic options for male-factor and female-factor infertility? AB - Recent advances in assisted reproduction treatment have enabled some couples with severe infertility issues to conceive, but the methods are not successful in all cases. Notwithstanding the significant financial burden of assisted reproduction treatment, the emotional scars from an inability to conceive a child enacts a greater toll on affected couples. While methods have circumvented some root causes for male and female infertility, often the underlying causes cannot be treated, thus true cures for restoring a patient's fertility are limited. Furthermore, the procedures are only available if the affected patients are able to produce gametes. Patients rendered sterile by medical interventions, exposure to toxicants or genetic causes are unable to utilize assisted reproduction to conceive a child - and often resort to donors, where permitted. Stem cells represent a future potential avenue for allowing these sterile patients to produce offspring. Advances in stem cell biology indicate that stem cell replacement therapies or in-vitro differentiation may be on the horizon to treat and could cure male and female infertility, although significant challenges need to be met before this technology can reach clinical practice. This article discusses these advances and describes the impact that these advances may have on treating infertility. PMID- 23664221 TI - Optimal combination of radiotherapy and endocrine drugs in breast cancer treatment. AB - PURPOSE: Breast cancer is the most common cancer in women. Radiotherapy is considered a standard treatment option after surgery and adjuvant endocrine therapy is also universally used. Tamoxifen and letrozole are the current first line endocrine therapy drugs. However, information has been scarce about how best to sequence these therapies to maximize their effectiveness and keep toxic effects to a minimum. In this study, we observed the effect of different sequence combination of radiotherapy and endocrine drugs, tamoxifen or letrozole, to get the best treatment sequence. MATERIALS AND METHODS: The combination effect of radiotherapy and tamoxifen was observed on breast tumour cell line MCF-7, radiotherapy and letrozole on aromatase-expressing breast tumour cell line MCF 7CA. Irradiation was performed with 6Gy, except for doses ranging from 0 to 8Gy for clone formation assay. Tamoxifen or letrozole was added before or after irradiation, respectively. Radiosensitivity was evaluated by clonogenic assay, cell viability by 3-(4,-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4 sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. To explore the potential mechanism, cell apoptosis was determined by DNA-binding dye 4',6-diamidino-2 phenylindole dihydrochloride (DAPI) assay, the change of Bcl-2 and Bax expression was by western blot. RESULTS: Although no significant statistical difference was observed between different sequence, tamoxifen and letrozole both increased radiosensitivity. Furthermore, the above inhibitory effect was related with apoptosis signaling pathway, especially Bcl-2 and Bax. CONCLUSION: Taken together, these results suggested that endocrine drugs, such as tamoxifen and letrozole, have potential application with radiotherapy. PMID- 23664222 TI - Linear exophytic tumor on the dorsum of the tongue. PMID- 23664223 TI - Congenital subungual and periungual melanocytic nevus. PMID- 23664224 TI - Verruciform xanthoma associated with reactivation of Epstein-Barr virus. PMID- 23664226 TI - Albumin reduces the antibacterial activity of polyhexanide-biguanide-based antiseptics against Staphylococcus aureus and MRSA. AB - BACKGROUND: Wound infection is one of the major complications in acute and chronic wound healing. Antiseptic solutions and wound irrigating agents are routinely used for therapy and prevention in healthcare today. Even if wound exudate contains total protein concentrations up to 9.3% and albumin concentrations up to 2.7% its influence to the antibacterial efficacy of these agents is barely investigated. MATERIALS AND METHODS: This study analyzed the antibacterial effect of polyhexanide biguanide (PHMB) agents (PHMB-concentration 0.005-0.1%) against Staphylococcus aureus and methicillin-resistant-S. aureus (MRSA) after 2min incubation in presents of albumin in different concentrations (0-3%) in a standardized quantitative suspension assay. RESULTS: A significant decrease of the antibacterial activity against S. aureus was shown for a PHMB concentration of 0.005% from 0.3% albumin (p<0.05), respectively highly significant from 0.75% (p<0.01) on. Thereby the loss of antimicrobial effect was presented as a linear correlation to the rising concentration of albumin. Furthermore a reduction of the antibacterial activity against MRSA in comparison to S. aureus was presented, for albumin concentrations from 3% on highly significant (p<0.01). CONCLUSION: The study showed that albumin causes a significant decrease of the antibacterial potency of PHMB-based antiseptics. Furthermore a diminished potency of the investigated substances for MRSA contaminated wounds must be taken in consideration. If in vitro experiments show a significant decrease of antibacterial efficacy in the presence of albumin a sufficient activity of PHMB-based agents in clinical practice, especially in cases of exuding wounds or dried-up exudates, cannot be expected. PMID- 23664225 TI - The impact of severe burns on skeletal muscle mitochondrial function. AB - Severe burns induce a pathophysiological response that affects almost every physiological system within the body. Inflammation, hypermetabolism, muscle wasting, and insulin resistance are all hallmarks of the pathophysiological response to severe burns, with perturbations in metabolism known to persist for several years post injury. Skeletal muscle is the principal depot of lean tissue within the body and as the primary site of peripheral glucose disposal, plays an important role in metabolic regulation. Following a large burn, skeletal muscle functions as and endogenous amino acid store, providing substrates for more pressing functions, such as the synthesis of acute phase proteins and the deposition of new skin. Subsequently, burn patients become cachectic, which is associated with poor outcomes in terms of metabolic health and functional capacity. While a loss of skeletal muscle contractile proteins per se will no doubt negatively impact functional capacity, detriments in skeletal muscle quality, i.e. a loss in mitochondrial number and/or function may be quantitatively just as important. The goal of this review article is to summarise the current understanding of the impact of thermal trauma on skeletal muscle mitochondrial content and function, to offer direction for future research concerning skeletal muscle mitochondrial function in patients with severe burns, and to renew interest in the role of these organelles in metabolic dysfunction following severe burns. PMID- 23664227 TI - Patent ductus arteriosus in preterm infants is associated with cardiac autonomic alteration and predominant parasympathetic stimulation. AB - BACKGROUND: Hemodynamic disorders in patent ductus arteriosus (PDA) may alter the stimulation of the autonomic nervous system. AIM: The objective of this study was to analyze the orthosympathetic-parasympathetic balance in preterm infants with PDA. STUDY DESIGN AND SUBJECTS: Patients were included from consecutive admissions to Amiens University Hospital from 2009 to 2011. We defined a PDA group and a Control group (echographic criteria). For each patient, three 4 minutes segments of ECG were recorded during quiet sleep and the RR chronologic series were extracted, and spectral (Fourier Transform) and time-domain analyses were performed. For each parameter of heart rate variability (HRV), average of three measures was determined and analysed. RESULTS: Forty-four patients were included for analysis. The total HRV power, LF/HF ratio and SDNN were lower in the PDA group (n = 22, gestational age 28.2 w +/- 1.9) than in the Control group (n = 22, gestational age 28.8 w +/- 2). The decrease in LF power destabilized the autonomic balance in favour of parasympathetic stimulation. After adjustment for postconceptional age, PDA was still associated with parameters of autonomic neural stimulation. CONCLUSION: These results suggest association of PDA with predominance of parasympathetic stimulation in preterm infants. The mechanisms of homeostasis in patients with PDA are very complex and involve both circulatory adaptations and control by autonomic pathway. If confirmed, our results could be interesting for future researches aiming to verify the interest of new targeted therapies for the management of PDA. PMID- 23664228 TI - Anesthetic emergencies in oral surgery: malignant hyperthermia, endocrinopathy, and neurologic events. AB - Despite the impressive safety of office-based anesthesia, serious emergencies still occur. Early and appropriate treatment is likely to improve outcomes. This article discusses selected emergencies with backgrounds and rationale for emergent treatment. PMID- 23664229 TI - The failure of biologics in sepsis: where do we stand? AB - The failure of the PROWESS-SHOCK study of recombinant human activated protein C (drotrecogin alfa) has generated much scepticism about the future of immunomodulatory interventions in sepsis. This review presents a summary of the few remaining promising strategies for immunointervention. These comprise intravenous clarithromycin, haemoperfusion through a polymyxin B-embedded fibre device (PMX-B), recombinant thrombomodulin (rTM) and intravenous immunoglobulin preparations enriched in IgM and IgA (IgMA). The great heterogeneity in the pathophysiology of sepsis mandates a highly individualised approach. This approach comprises: septic shock and multiple organ dysfunction syndrome arising in the field of ventilator-associated pneumonia as an indication for intravenous clarithromycin; abdominal severe sepsis/shock for PMX-B haemoperfusion; sepsis and acute coagulopathy for rTM; and early septic shock for IgMA. However, specific diagnostic tools should be developed to make this personalised approach more robust. PMID- 23664230 TI - Application of the Bayesian approach for derivation of PDFs for concentration ratio values. AB - Concentration ratios (CRs) are used to derive activity concentrations in wild plants and animals. Usually, compilations of CR values encompass a wide range of element-organism combinations, extracted from different studies with statistical information reported at varying degrees of detail. To produce a more robust estimation of distribution parameters, data from different studies are normally pooled using classical statistical methods. However, there is inherent subjectivity involved in pooling CR data in the sense that there is a tacit assumption that the CRs under any arbitrarily defined biota category belong to the same population. Here, Bayesian inference has been introduced as an alternative way of making estimates of distribution parameters of CRs. This approach, in contrast to classical methods, is more flexible and also allows us to define the various assumptions required, when combining data, in a more explicit manner. Taking selected data from the recently compiled wildlife transfer database (http://www.wildlifetransferdatabase.org/) as a working example, attempts are made to refine the pooling approaches previously used and to consider situations when empirical data are limited. PMID- 23664231 TI - Implications for human and environmental health of low doses of ionising radiation. AB - The last 20 years have seen a major paradigm shift in radiation biology. Several discoveries challenge the DNA centric view which holds that DNA damage is the critical effect of radiation irrespective of dose. This theory leads to the assumption that dose and effect are simply linked - the more energy deposition, the more DNA damage and the greater the biological effect. This is embodied in radiation protection (RP) regulations as the linear-non-threshold (LNT) model. However the science underlying the LNT model is being challenged particularly in relation to the environment because it is now clear that at low doses of concern in RP, cells, tissues and organisms respond to radiation by inducing responses which are not readily predictable by dose. These include adaptive responses, bystander effects, genomic instability and low dose hypersensitivity, and are commonly described as stress responses, while recognizing that "stress" can be good as well as bad. The phenomena contribute to observed radiation responses and appear to be influenced by genetic, epigenetic and environmental factors, meaning that dose and response are not simply related. The question is whether our discovery of these phenomena means that we need to re-evaluate RP approaches. The so-called "non-targeted" mechanisms mean that low dose radiobiology is very complex and supra linear or sub-linear (even hormetic) responses are possible but their occurrence is unpredictable for any given system level. Issues which may need consideration are synergistic or antagonistic effects of other pollutants. RP, at present, only looks at radiation dose but the new (NTE) radiobiology means that chemical or physical agents, which interfere with tissue responses to low doses of radiation, could critically modulate the predicted risk. Similarly, the "health" of the organism could determine the effect of a given low dose by enabling or disabling a critical response. These issues will be discussed. PMID- 23664232 TI - Communicating risk of hereditary breast and ovarian cancer with an interactive decision support tool. AB - OBJECTIVE: Women with hereditary breast and ovarian cancer syndrome (HBOC) face a higher risk of earlier, more aggressive cancer. Because of HBOC's rarity, screening is recommended only for women with strong cancer family histories. However, most patients do not have accurate history available and struggle to understand genetic concepts. METHODS: Cancer in the Family, an online clinical decision support tool, calculated women's HBOC risk and promoted shared patient provider decisions about screening. A pilot evaluation (n=9 providers, n=48 patients) assessed the tool's impact on knowledge, attitudes, and screening decisions. Patients used the tool before wellness exams and completed three surveys. Providers accessed the tool during exams, completed exam checklists, and completed four surveys. RESULTS: Patients entered complete family histories (67%), calculated personal risk (96%), and shared risk printouts with providers (65%). HBOC knowledge increased dramatically for patients and providers, and many patients (75%) perceived tool results as valid. The tool prompted patient provider discussions about HBOC risk and cancer family history (88%). CONCLUSIONS: The tool was effective in increasing knowledge, collecting family history, and sparking patient-provider discussions about HBOC screening. PRACTICE IMPLICATIONS: Interactive tools can effectively communicate personalized risk and promote shared decisions, but they are not a substitute for patient-provider discussions. PMID- 23664233 TI - Acceptability of video recordings of consultations in HIV and genitourinary medicine (GUM). PMID- 23664234 TI - Do participation and personalization matter? A model-driven evaluation of an Internet-based patient education intervention for fibromyalgia patients. AB - OBJECTIVES: To evaluate the effectiveness of an Internet-based patient education intervention, which was designed upon principles of personalization and participatory design. METHODS: Fifteen months after the first release of the website, 209 fibromyalgia patients recruited through health professionals completed an online questionnaire to assess patients' use of the website, health knowledge, self-management behavior, and health outcomes. These constructs were combined into an a-priory model that was tested using a structural equation modeling approach. RESULTS: Results show that the usage of certain tools of the website - designed and personalized involving the end users - impacts patients' health knowledge, which in turn impacts self-management. Improvements in self management ultimately lower the impact of Fibromyalgia Syndrome leading to better health outcomes. CONCLUSION: This study empirically confirmed that the adoption of a participatory approach to the design of eHealth interventions and the use of personalized contents enhance the overall effectiveness of systems. PRACTICE IMPLICATIONS: More time and effort should be invested in involving patients in the preliminary phases of the development of Internet-based patient education interventions and in the definition of models that can guide the systems' evaluation beyond technology-related variables such as usability, accessibility or adoption. PMID- 23664235 TI - Meta-analysis of methylcobalamin alone and in combination with lipoic acid in patients with diabetic peripheral neuropathy. AB - AIMS: To compare the efficacy and safety of daily lipoic acid (300-600 mg i.v.) plus methylcobalamin (500-1000 mg i.v. or im.) (LA-MC) with that of methylcobalamin alone (MC) on diabetic peripheral neuropathy (DPN). METHODS: Electronic database were searched for studies published up to November 1, 2012 and study quality was assessed in duplicate. A random or a fixed effect model was used to analyse outcomes which were expressed as risk ratios (RRs) or mean difference (MD). I(2) statistic was used to assess heterogeneity. RESULTS: Seventeen studies were included. Combined data from all studies showed that the LA-MC combination therapy was significantly superior to MC monotherapy (RR=1.47; 95% CI: 1.37-1.58). Superiority of the LA-MC combination was shown in nerve conduction velocity (NCV) with WMDs of 6.89 (95% CI: 4.24-9.73) for median motor nerve conduction velocity (MNCV), 5.24 (4.14-6.34) for median sensory nerve conduction velocity (SNCV), 4.34 (3.03-5.64) for peroneal MNCV, and 4.53 (3.2 5.85) for peroneal SNCV. There were no serious adverse events associated with treatment. CONCLUSIONS: The results of the meta-analysis show that treatment with LA-MC for 2-4 weeks is associated with better outcomes in NCV and neuropathic symptoms relative to MC treatment. However larger well-designed studies are required to confirm this conclusion. PMID- 23664237 TI - Liver involvement in sphingosine 1-phosphate dynamism revealed by adenoviral hepatic overexpression of apolipoprotein M. AB - OBJECTIVES: Sphingosine 1-phosphate (S1P) is a vasoprotective lipid mediator that is mainly carried on HDL in the circulation and several anti-atherosclerotic properties of HDL is considered to be ascribed to S1P. Since S1P riding on HDL was recently shown to bind to apolipoprotein M (apoM), which is derived from liver, we analyzed the possible involvement of liver in S1P metabolism. METHODS AND RESULTS: Using adenoviruses, we overexpressed apoM in HepG2 cells and mice livers and found that both the medium/plasma and cell/liver S1P contents increased. Among lipoprotein subclasses, S1P contents increased mainly in HDL fractions. On the other hand, hepatectomy resulted in the reduction of plasma S1P levels in mice. The incubation of S1P in the conditional medium of apoM overexpressing HepG2 cells interfered with S1P degradation. Furthermore, adenoviral hepatic overexpression of apoM resulted in increase in the S1P level of plasma but not of blood cells, while combination of hepatic apoM overexpression and intraperitoneal administration of C17-sphingosine resulted in the increase in the C17-S1P level both in livers and in plasma, but again not in blood cells. CONCLUSIONS: Livers are involved in S1P dynamism, and it was suggested that apoM, produced from livers, increases circulating plasma S1P by augmenting the S1P output from livers and modifies extracellular S1P metabolism. PMID- 23664236 TI - The good-enough science-and-politics of anthropological collaboration with evidence-based clinical research: Four ethnographic case studies. AB - The apolitical legitimacy of "evidence-based medicine" offers a practical means for ethnography and critical social-science-and-humanities-of-health theory to transfer survival resources to structurally vulnerable populations and to engage policy and services audiences with urgent political problems imposed on the urban poor in the United States that harm health: most notably, homelessness, hyperincarceration, social service cut-backs and the War on Drugs. We present four examples of collaborations between ethnography and clinical research projects that demonstrate the potentials and limits of promoting institutional reform, political debate and action through distinct strategies of cross methodological dialog with epidemiological and clinical services research. Ethnographic methods alone, however, are simply a technocratic add-on. They must be informed by critical theory to contribute effectively and transformatively to applied health initiatives. Ironically, technocratic, neoliberal logics of cost effectiveness can sometimes render radical service and policy reform initiatives institutionally credible, fundable and capable of generating wider political support, even though the rhetoric of economic efficacy is a double-edged sword. To extend the impact of ethnography and interdisciplinary theories of political economic, cultural and disciplinary power relations into applied clinical and public health research, anthropologists - and their fellow travelers - have to be able to strategically, but respectfully learn to see through the positivist logics of clinical services research as well as epidemiological epistemology in order to help clinicians achieve - and extend - their applied priorities. In retrospect, these four very differently-structured collaborations suggest the potential for "good-enough" humble scientific and political strategies to work for, and with, structurally vulnerable populations in a punitive neoliberal era of rising social inequality, cutbacks of survival services, and hyperincarceration of the poor. PMID- 23664238 TI - The influence of size, clearance, cartilage properties, thickness and hemiarthroplasty on the contact mechanics of the hip joint with biphasic layers. AB - Computational models of the natural hip joint are needed to examine and optimise tissue sparing interventions where the natural cartilage remains part of the bearing surfaces. Although the importance of interstitial fluid pressurisation in the performance of cartilage has long been recognized, few studies have investigated the time dependent interstitial fluid pressurisation in a three dimensional natural hip joint model. The primary aim of this study was to develop a finite element model of the natural hip incorporating the biphasic cartilage layers that was capable of simulating the joint response over a prolonged physiological loading period. An initial set of sensitivity studies were also undertaken to investigate the influence of hip size, clearance, cartilage properties, thickness and hemiarthroplasty on the contact mechanics of the joint. The contact stress, contact area, fluid pressure and fluid support ratio were calculated and cross-compared between models with different parameters to evaluate their influence. It was found that the model predictions for the period soon after loading were sensitive to the hip size, clearance, cartilage aggregate modulus, thickness and hemiarthroplasty, while the time dependent behaviour over 3000s was influenced by the hip clearance and cartilage aggregate modulus, permeability, thickness and hemiarthroplasty. The modelling methods developed in this study provide a basic platform for biphasic simulation of the whole hip joint onto which more sophisticated material models or other input parameters could be added in the future. PMID- 23664239 TI - Validation of a finite element model of the human elbow for determining cartilage contact mechanics. AB - It is important to study joint contact mechanics to better understand the processes which lead to cartilage degradation. The purpose of this study was to develop and validate a finite element (FE) model of a human elbow capable of predicting joint contact area and stress. A cylindrical constrained elbow joint loading apparatus was used to measure the cartilage compression and contact area for a single cadaveric specimen. A computer model of the same joint was created based on computed tomography images of the specimen, and the same loading was simulated using FE contact analysis. The model-predicted joint compression and contact area corresponded closely with experiment-measured results (differences of -4.9% and +9.6%). A sensitivity analysis showed that the model results were sensitive to cartilage and bone material properties, as well as the cartilage thickness distribution. The results of this study underline the importance of using accurate material properties and physiological cartilage thickness distributions when simulating cartilage contact mechanics. PMID- 23664240 TI - The effect of sterilization on the dynamic mechanical properties of paired rabbit cortical bone. AB - The optimal sterilization method for load bearing allografts remains a clinical concern. Recently, supercritical carbon dioxide (SCCO2) treatments have been shown to be capable of terminally sterilizing a range of bacteria and viruses, while preserving the static mechanical properties of cortical bone. This study evaluated the effect of SCCO2 treatment compared with two doses of gamma irradiation, on clinically relevant dynamic mechanical properties of cortical bone. Quasi-static testing was also performed to compare the impairment of treatment. Whole paired adult rabbit humeri were dissected and randomly assigned into either SCCO2 Control, SCCO2 Additive or gamma irradiation at 10 or 25kGy treatment groups. The bones were treated and mechanically tested in three-point bending, with the lefts acting as controls for the treated rights. Maximum load, energy to failure and stiffness were evaluated from static tests. The number of cycles to failure was determined for fatigue at 6-60% of the ultimate load. This study found that SCCO2 treatment with or without additive did not alter static or dynamic mechanical properties. Gamma irradiation had a deleterious dose dependent effect, with statistically significant (p<0.05) reductions in all static mechanical parameters at 25kGy. This effect was increased in fatigue with statistically significant decreases in both the 10 and 25kGy dose groups. This study highlights the expediency of SCCO2 treatment for load bearing bone allograft processing as terminal sterilization can be achieved while maintaining both the quasi-static and dynamic mechanical properties of the graft. PMID- 23664241 TI - Clinical results after different operative treatment methods of radial head and neck fractures: a systematic review and meta-analysis of clinical outcome. AB - INTRODUCTION: There is no consensus on optimal treatment strategy for Mason type II-IV fractures. Most recommendations are based upon experts' opinion. METHODS: An OVID-based literature search were performed to identify studies on surgical treatment of radial head and neck fracture. Specific focus was placed on extracting data describing clinical efficacy and outcome by using the Mason classification and including elbow function scores. A total of 841 clinical studies were identified describing in total the clinical follow-up of 1264 patients. RESULTS: For type II radial head and neck fractures the significant best treatment option seems to be ORIF with an overall success rate of 98% by using screws or biodegradable (polylactide) pins. ORIF with a success rate of 92% shows the best results in the treatment of type III fractures and seem to be better than resection and implantation of a prosthesis. For this fracture type the ORIF with screws (96%), biodegradable (polylactide) pins (88%) and plates (83%) showed the best results. In the treatment of type IV fractures similar results could be found with a tendency of the best results after ORIF followed by resection and implantation of a prosthesis. If a prosthesis was implanted, the primary implantation seems to be associated with a better outcome after type III (87%) and IV (82%) fractures compared to the results after a secondary implantation. DISCUSSION: Recommendations for surgical treatment of radial head and neck fractures according to the Mason classification can now be given with the best available evidence. LEVEL OF EVIDENCE: IV. PMID- 23664242 TI - Wearable seismocardiography: towards a beat-by-beat assessment of cardiac mechanics in ambulant subjects. AB - Seismocardiogram (SCG) is the measure of the micro-vibrations produced by the heart contraction and blood ejection into the vascular tree. Over time, a large body of evidence has been collected on the ability of SCG to reflect cardiac mechanical events such as opening and closure of mitral and aortic valves, atrial filling and point of maximal aortic blood ejection. We recently developed a smart garment, named MagIC-SCG, that allows the monitoring of SCG, electrocardiogram (ECG) and respiration out of the laboratory setting in ambulant subjects. The present pilot study illustrates the results of two different experiments performed to obtain a first evaluation on whether a dynamical assessment of indexes of cardiac mechanics can be obtained from SCG recordings obtained by MagIC-SCG. In the first experiment, we evaluated the consistency of the estimates of two indexes of cardiac contractility, the pre-ejection period, PEP, and the left ventricular ejection time, LVET. This was done in the lab, by reproducing an experimental protocol well known in literature, so that our measures derived from SCG could have been compared with PEP and LVET reference values obtained by traditional techniques. Six healthy subjects worn MagIC-SCG while assuming two different postures (supine and standing); PEP was estimated as the time interval between the Q wave in ECG and the SCG wave corresponding to the opening of aortic valve; LVET was the time interval between the SCG waves corresponding to the opening and closure of the aortic valve. The shift from supine to standing posture produced a significant increase in PEP and PEP/LVET ratio, a reduction in LVET and a concomitant rise in the LF/HF ratio in the RR interval (RRI) power spectrum. These results are in line with data available in literature thus providing a first support to the validity of our estimates. In the second experiment, we evaluated in one subject the feasibility of the beat-by-beat assessment of LVET during spontaneous behavior. The subject was continuously monitored by the smart garment from 8 am to 8 pm during a workday. From the whole recording, three data segments were selected: while the subject was traveling to work (M1), during work in the office (O) and while traveling back home (M2). LVET was estimated on a beat-by-beat basis from SCG and the RRI influence was removed by regression analysis. The LVET series displayed marked beat-by-beat fluctuations at the respiratory frequency. The amplitude of these fluctuations changed in the three periods and was lower when the LF/HF RRI power ratio was higher, at O, thus suggesting a possible influence of the autonomic nervous system on LVET short-term variability. To the best of our knowledge this case report provides for the first time a representation of the beat-by-beat dynamics of a systolic time interval during daily activity. The statistical characterization of these findings remains to be explored on a larger population. PMID- 23664243 TI - Potential of adjustable height carts in reducing the risk of low back injury in grocery stockers. AB - While the workers of the Wholesale and Retail Trade industrial sector suffer from musculoskeletal disorders at an alarming rate, there have been few investigative studies into potential effective interventions to reduce the ergonomic stress. The objective of the study was to determine whether a cart with an adjustable shelf could reduce awkward postures and motions while stocking products in a grocery store. Fifteen workers at a small grocery store in Puerto Rico completed stocking tasks with two types of carts: traditional and adjustable height cart or Ergo Cart. Trunk kinematics, LBD risk index, NIOSH lifting index, subjective ratings, and productivity indicators were collected during four typical stocking tasks. The Adjustable Ergo Cart reduced the sagittal trunk flexion by 7 degrees and velocity by about 5 degrees /s but increased twisting by about 2 degrees and twist velocity by 4 degrees /s as compared to the traditional cart. The LBD risk index was reduced by a small 2.4% in probability although greater reductions were found for larger items (e.g. bags of dog food and 2-L of Soda). The consensus among workers was that the adjustable cart would be easier to use. Overall, the study provides objective evidence that an ergonomically designed cart (e.g. adjustable height) has some potential to reduce sagittal trunk flexion, LBD risk index, and the NIOSH lift index. Overall, the results indicate that any intervention such as an adjustable cart can only have marginal effectiveness unless the entire systems perspective is considered. PMID- 23664244 TI - Evaluation of thermal and evaporative resistances in cricket helmets using a sweating manikin. AB - The main objective of this study is to establish an approach for measuring the dry and evaporative heat dissipation cricket helmets. A range of cricket helmets has been tested using a sweating manikin within a controlled climatic chamber. The thermal manikin experiments were conducted in two stages, namely the (i) dry test and (ii) wet test. The ambient air temperature for the dry tests was controlled to ~ 23 degrees C, and the mean skin temperatures averaged ~ 35 degrees C. The thermal insulation value measured for the manikin with helmet ensemble ranged from 1.0 to 1.2 clo. The results showed that among the five cricket helmets, the Masuri helmet offered slightly more thermal insulation while the Elite helmet offered the least. However, under the dry laboratory conditions and with minimal air movement (air velocity = 0.08 +/- 0.01 ms(-1)), small differences exist between the thermal resistance values for the tested helmets. The wet tests were conducted in an isothermal condition, with an ambient and skin mean temperatures averaged ~ 35 degrees C, the evaporative resistance, Ret, varied between 36 and 60 m(2) Pa W(-1). These large variations in evaporative heat dissipation values are due to the presence of a thick layer of comfort lining in certain helmet designs. This finding suggests that the type and design of padding may influence the rate of evaporative heat dissipation from the head and face; hence the type of material and thickness of the padding is critical for the effectiveness of evaporative heat loss and comfort of the wearer. Issues for further investigations in field trials are discussed. PMID- 23664245 TI - A literature review on optimum and preferred joint angles in automotive sitting posture. AB - In this study, a survey of the scientific literature in the field of optimum and preferred human joint angles in automotive sitting posture was conducted by referring to thirty different sources published between 1940 and today. The strategy was to use only sources with numerical angle data in combination with keywords. The aim of the research was to detect commonly used joint angles in interior car design. The main analysis was on data measurement, usability and comparability of the different studies. In addition, the focus was on the reasons for the differently described results. It was found that there is still a lack of information in methodology and description of background. Due to these reasons published data is not always usable to design a modern ergonomic car environment. As a main result of our literature analysis we suggest undertaking further research in the field of biomechanics and ergonomics to work out scientific based and objectively determined "optimum" joint angles in automotive sitting position. PMID- 23664246 TI - ...And I would say thank you so much and see you soon! PMID- 23664247 TI - Impact of comorbidities in pulmonary rehabilitation outcomes in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) represents an increasing burden worldwide. COPD can no longer be considered a disease which only involves the lungs, its systemic consequences make it an important risk factor for other chronic comorbidities. AIM: To determine the frequency of comorbidities in patients with COPD undergoing a pulmonary rehabilitation program (PRP) and to evaluate the influence of baseline characteristics as well as comorbidities on the outcomes of PRP. METHODS: The present study included all COPD patients that were admitted to a PRP in our unit. The response to PR was measured by the improvement in exercise tolerance (6 minute walk test), dyspnea (Mahler's Dyspnea Index) and health status (St. George's Respiratory Questionnaire). RESULTS: 114 patients with COPD were included. Most patients (96,5%) had at least one comorbidity. Metabolic diseases (71.1%), cardiovascular diseases (67.5%), other respiratory conditions (57.9%) and anxiety/depression (21.1%) were the most prevalent ones. 64.9%, 64.9% and 51.1% of the patients improved in terms of exercise tolerance, quality of life and dyspnea, respectively. The overall results were similar in all levels of the disease and in all comorbid subgroups. Logistic regression analysis showed that respiratory failure and ischemic heart disease negatively influenced improvement in health status and anxiety/depression predicted lower improvement in dyspnea. CONCLUSION: PR was associated with improvements in all comorbid subgroups of patients, underlining the important role of exercise training in rehabilitation of those chronic diseases associated with COPD. On the other hand, the presence of comorbidities in COPD patients, if clinically controlled, should not preclude access to PR. PMID- 23664248 TI - Validation of two clinical prognostic models in patients with acute symptomatic pulmonary embolism. AB - OBJECTIVE: The aim of this study was to compare the predictive value of two clinical prognostic models, the Spanish score and the simplified Pulmonary Embolism Severity Index (sPESI), in an independent cohort of patients diagnosed of acute symptomatic pulmonary embolism (PE). METHODS: We performed a retrospective analysis of a cohort composed of 1447patients with acute symptomatic PE. The Spanish score and the sPESI were calculated for each patient according to different clinical variables. We assessed the predictive accuracy of these scores for 30-day mortality, and a composite of non fatal recurrent venous thromboembolism and non fatal major bleeding, using Cstatistic, which was obtained by means of logistic regression and ROC curves. RESULTS: Overall, 138 patients died (9.5%) during the first month of follow-up. Both scores showed an excellent predictive value for 30-day all-cause mortality (Cstatistic, 0.72 and 0.74), but the performance was poor for the secondary endpoint (Cstatistic, 0.60 and 0.59). The sPESI classified fewer patients as low risk (32% versus 62%; P<.001). Low-risk patients based on the sPESI had a lower 30-day mortality than those based on the Spanish score (1.1% versus 4.2%), while the 30-day rate of non fatal recurrent VTE or major bleeding was similar (2.2% versus 2.3%). CONCLUSIONS: Both scores provide excellent information to stratify the risk of mortality in patients treated of PE. The usefulness of these models for nonfatal adverse events is questionable. The sPESI identified low-risk patients with PE better than the Spanish score. PMID- 23664250 TI - Photosensitivity due to thiazides. AB - Thiazides are widely used diuretics that first became available in the 1950s. The first reports of photosensitivity reactions to thiazides were published shortly after the introduction of these drugs, but few cases have been described since. We review all the cases of photosensitivity due to thiazides published up to December 2011. We found 62 cases, 33 in women and 29 in men. The most common presentation was eczematous lesions in a photodistributed pattern, and the most common causative agent was hydrochlorothiazide. The results of photobiological studies were published in only some of the cases reviewed. In most cases, phototesting revealed an abnormal response to UV-A alone or to both UV-A and UV B. In some cases, the results of phototesting were normal and only photopatch testing yielded abnormal results. Diagnosis of photosensitivity due to thiazides requires a high degree of suspicion. Ideally, diagnosis should be confirmed by a photobiological study. PMID- 23664249 TI - Dynamics of oral microbial community profiling during severe early childhood caries development monitored by PCR-DGGE. AB - OBJECTIVE: To monitor the longitudinal changes in oral microbial diversity of children with severe early childhood caries (S-ECC) compared to caries free (CF) controls. METHODS: Dental plaque samples of 12 children in each group at 8, 14, 20, 26 and 32 months of age were analysed. Total microbial genomic DNA was isolated from each sample, and PCR-denaturing gradient gel electrophoresis (DGGE) analyses were carried out. RESULTS: The number of bands was significantly higher in the CF group (18.17+/-4.91 bands) than in the S-ECC group (14.54+/-5.56 bands) at 32 months of age (P<0.05). A total of 21 genera were identified in all subjects, and there were no significant differences between the two groups at genus level. DGGE profiles showed that most of the clusters were constructed from one individual over time in the both groups. CONCLUSIONS: The onset of S-ECC is accompanied by a decrease in microbial diversity. The overall composition of the microbiota is highly similar within an individual over time. PMID- 23664251 TI - Evaluating clinical dermatology practice in medical undergraduates. AB - The acquisition of competences (the set of knowledge, skills and attitudes required to perform a job to a professional level) is considered a fundamental part of medical training. Dermatology competences should include, in addition to effective clinical interviewing and detailed descriptions of skin lesions, appropriate management (diagnosis, differentiation, and treatment) of common skin disorders and tumors. Such competences can only be acquired during hospital clerkships. As a way of certifying these competences, we propose evaluating the different components as follows: knowledge, via clinical examinations or critical incident discussions; communication and certain instrumental skills, via structured workplace observation and scoring using a set of indicators; and attitudes, via joint evaluation by staff familiar with the student. PMID- 23664252 TI - Update on the treatment of chronic urticaria. AB - Chronic spontaneous urticaria, also known as chronic idiopathic urticaria or simply chronic urticaria, is a common disorder that has a prevalence in the general population that ranges between 0.5% and 1%. This condition negatively affects the patient's quality of life and has considerable impact on direct and indirect health-related costs. Chronic urticaria is difficult to manage. Nonsedating H1 antihistamines are the first line of therapy, but fewer than 50% of patients experience relief at recommended dosages. Although guidelines call for increasing the dosage when response is inadequate, some patients still do not achieve adequate control of symptoms. New treatment alternatives, with proven efficacy under the standards of evidence-based medical practice, must therefore be developed. PMID- 23664253 TI - Synergistic effect of ultrasonic pre-treatment combined with UV irradiation for secondary effluent disinfection. AB - The ultraviolet (UV) disinfection efficiency is often affected by suspended solids (SS). Given their high concentration or large particle size, SS can scatter UV light and provide shielding for bacteria. Thus, ultrasound is often employed as a pre-treatment process to improve UV disinfection. This work investigated the synergistic effect of ultrasound combined with UV for secondary effluent disinfection. Bench-scale experiments were conducted in using samples obtained from secondary sedimentation tanks. These tanks belonged to three wastewater treatment plants in Beijing that use different kinds of biological treatment methods. Several parameters may contribute to the changes in the efficiency of ultrasound and UV disinfection. Thus, the frequency and energy density of ultrasound, as well as the SS, were investigated. Results demonstrated that samples which have relatively higher SS concentrations or higher percentages of larger particles have less disinfection efficiency using UV disinfection alone. However, the presence of ultrasound could improve the disinfection efficiency because it has synergistic effect. Changes in the particle size distribution and SS concentration notably affected the efficiency of UV disinfection. The efficiency of Escherichia coli elimination can be decreased by 1.2 log units as the SS concentration increases from 16.9 mg/l to 25.4 mg/l at a UV energy density of 40 mJ/cm(2). UV disinfection alone reduced the E. coli population by 3.4 log units. However, the synergistic disinfection of ultrasound and UV could reach 5.4 log units during the reduction of E. coli at a 40 kHz frequency and an energy density of 2.64 kJ/l. The additional synergistic effect is 1.1 log units. PMID- 23664254 TI - Trastuzumab therapy in Australia: which patients with HER2+ metastatic breast cancer are assessed for cardiac function? AB - PURPOSE: To manage the potential trastuzumab mediated cardiotoxicity, clinical guidelines recommend pre-treatment cardiac function assessment and 3-monthly reassessment during therapy. This study examined rates of cardiac function assessment and predictors of assessment among patients receiving trastuzumab for HER2+ metastatic breast cancer treatment in routine clinical care. METHODS: Our cohort comprised 3418 women receiving trastuzumab for HER2+ metastatic breast cancer under Australia's nationally funded Herceptin Program (2001-2010). We examined rates of pre-treatment and during-treatment assessment. We used logistic regression and zero-inflated Poisson regression to examine predictors of pre treatment and during-treatment assessment respectively. RESULTS: 37.7% of patients were assessed pre-treatment, 50.4% during therapy, and 26.4% both before and during therapy. Among patients assessed for cardiac function, reassessment occurred regularly (median of 3.9 months). History of cardiovascular conditions and prior anthracycline use predicted pre-treatment assessment (OR = 1.32, 95% CI: 1.08-1.61; OR = 1.23, 95% CI: 1.05-1.44 respectively). Concurrent trastuzumab and taxane use, exposure to anthracyclines, and older age predicted during treatment assessment (IRR = 1.17, 95% CI: 1.06-1.29; IRR = 1.12, 95% CI: 1.02 1.23; and IRR = 1.05, 95% CI: 1.01-1.09 respectively). Patients with multi morbidities were less likely to receive during-treatment assessment. CONCLUSION: Over the last decade, cardiac function assessment in a large cohort of patients receiving trastuzumab was not consistent with guideline recommendations. The association between cardiac monitoring and risk factors for cardiac dysfunction suggest clinicians are triaging patients prior to implementing cardiac assessment. Efforts are needed to identify barriers to implementing current guidelines for cardiac monitoring in metastatic breast cancer patients undergoing trastuzumab treatment, particularly those with multi-morbidities. PMID- 23664255 TI - '23 h Model' for breast surgery: an early experience. AB - The principles of fast track surgery are well established in colorectal surgery. It is an evidence based model aimed at reducing length of stay, convalescence and morbidity by optimising both clinical and organisational factors. Despite this, the implementation of fast track surgery in breast cancer patients has been slow. The 23 h discharge model for breast cancer surgery patients has been outlined by the NHS Improvement Programme and is a breakthrough from traditional inpatient care. This paper outlines the early experience of implementation of this model in a single institution during a 3-month audit period. Over 80% of patients undergoing non-reconstructive breast surgery were discharged safely within '23 h'. This suggests that good communication links, reorganisation of existing resources, active user involvement (both patients and clinical team) and strong project management ensures fast-tracking to be safe for the patient with significant economic benefits for the hospital. PMID- 23664257 TI - Hanseniaspora opuntiae, Saccharomyces cerevisiae, Lactobacillus fermentum, and Acetobacter pasteurianus predominate during well-performed Malaysian cocoa bean box fermentations, underlining the importance of these microbial species for a successful cocoa bean fermentation process. AB - Two spontaneous Malaysian cocoa bean box fermentations (one farm, two plantation plots) were investigated. Physical parameters, microbial community dynamics, yeast and bacterial species diversity [mainly lactic acid bacteria (LAB) and acetic acid bacteria (AAB)], and metabolite kinetics were monitored, and chocolates were produced from the respective fermented dry cocoa beans. Similar microbial growth and metabolite profiles were obtained for the two fermentations. Low concentrations of citric acid were found in the fresh pulp, revealing low acidity of the raw material. The main end-products of the catabolism of the pulp substrates glucose, fructose, and citric acid by yeasts, LAB, and AAB were ethanol, lactic acid, acetic acid, and/or mannitol. Hanseniaspora opuntiae, Lactobacillus fermentum, and Acetobacter pasteurianus were the prevalent species of the two fermentations. Saccharomyces cerevisiae, Lactobacillus plantarum, Lactobacillus pentosus, and Acetobacter ghanensis were also found during the mid phase of the fermentation processes. Leuconostoc pseudomesenteroides and Acetobacter senegalensis were among the prevailing species during the initial phase of the fermentations. Tatumella saanichensis and Enterobacter sp. were present in the beginning of the fermentations and they could be responsible for the degradation of citric acid and/or the production of gluconic acid and lactic acid, respectively. The presence of facultative heterofermentative LAB during the fermentations caused a high production of lactic acid. Finally, as these fermentations were carried out with high-quality raw material and were characterised by a restricted microbial species diversity, resulting in successfully fermented dry cocoa beans and good chocolates produced thereof, it is likely that the prevailing species H. opuntiae, S. cerevisiae, Lb. fermentum, and A. pasteurianus were responsible for it. PMID- 23664256 TI - Reversal of moderate and intense neuromuscular block induced by rocuronium with low doses of sugammadex for intraoperative facial nerve monitoring. AB - We report two cases in which moderate and intense rocuronium-induced neuromuscular block was reversed intraoperatively with low sugammadex doses in order to facilitate electromyographic evaluation of facial nerve function during surgery of the parotid gland and the middle ear. Acceleromyography was used to assess reversal of neuromuscular block before starting electromyography monitoring. Rocuronium-induced neuromuscular block was reversed with sugammadex 0.22mgkg(-1) when the TOF ratio was 0.14 in the first patient, and with sugammadex 2mgkg(-1) during intense block (PTC 0) in the second patient. In each case, appropriate neuromuscular function (TOF ratio>=0.9) was established soon after sugammadex administration, and electromyographic evaluation of facial nerve was successfully conducted. The use of rocuronium and sugammadex, coupled with objective neuromuscular monitoring with acceleromyography, assured complete restoration of neuromuscular function and created the optimal conditions for the surgical team. PMID- 23664258 TI - Survey of Listeria monocytogenes, Salmonella spp. and Escherichia coli O157:H7 in raw ingredients and ready-to-eat products by commercial real-time PCR kits. AB - Real-time PCR (RTiPCR) assays including enrichment stage were evaluated for the rapid detection of Listeria monocytogenes, Salmonella spp. and Escherichia coli O157:H7 in raw ingredients and ready-to-eat products using molecular beacon probes available as commercial kits (WARNEX Genevision, Canada & AES Chemunex detection system, France). The accuracy of the assays was evaluated analyzing 1032 naturally contaminated food samples in combination to the conventional cultural methods. Presence/absence testing of the above pathogens was performed in 25 g samples of each product. In case of L. monocytogenes of 39 positive RTiPCR samples, 37 were confirmed by the cultural method (based on McNemar's test the difference between the two methods is insignificant). The highest incidence of L. monocytogenes in food products was found in desserts and the second highest in frozen pastries. None of the samples were cultural positive but negative in the RTiPCR test. One among the 343 investigated samples was positive for Salmonella spp. by RTiPCR and the cultural method. Out of 333 samples analyzed for E. coli O157:H7 no positive sample was detected. RTiPCR-based methods proved to be powerful tools for fast, sensitive and accurate pathogen detection in raw food ingredients and ready-to-eat products. PMID- 23664259 TI - Metabolic activity and symbiotic interactions of lactic acid bacteria and yeasts isolated from water kefir. AB - Water kefir is a mildly sour and alcoholic drink fermented by a stable microbial multispecies community. With its high sugar content and low amino acid concentration water kefir medium represents a demanding habitat. In this ecological niche only well adapted microorganisms which are fit to the consortium are able to grow and mutually provide essential nutrients. The synergism between main representatives of water kefir yeasts and lactobacilli was studied in a co culture model system. Co-cultivation of yeasts and lactobacilli in water kefir medium significantly increased cell yield of all interaction partners, delineating the interaction of these water kefir isolates as mutualism. The support of Zygotorulaspora (Z.) florentina was due to the acidification of the medium by the lactobacilli, whereas lactobacilli are improved in growth by the disposal of essential nutrients produced by yeasts. The trophic interaction between Lactobacillus (Lb.) hordei and yeasts is constituted by the release of amino acids and Vitamin B6 from yeasts, whereas Lb. nagelii is supported in growth by their production of amino acids. The interaction of Z. florentina and Lb. nagelii was further examined to reveal that co-cultivation induced the yeast to release arginine, which was essential for Lb. nagelii. PMID- 23664260 TI - Biodiversity and dynamics of the bacterial community of packaged king scallop (Pecten maximus) meat during cold storage. AB - The microbial biodiversity and dynamics of king scallops meat and coral during cold storage (cold chain rupture: 1/3 storage time at 4 degrees C followed by 2/3 at 8 degrees C), was assessed by combining culture-dependant and independent methods. Products were packaged as follows: aerobic, vacuum packed and 3 different CO2/N2 modified atmospheres and the impact of these conditions on the microbial communities was assessed. Results indicated that under air (current packaging condition), the dominant species corresponded to Brochothrix thermosphacta, Pseudomonas spp. and Shewanella spp. These species have regularly been associated in the literature with food (especially seafood), and product spoilage. Moellerella wisconsensis was the only species detected on VRBG medium, however, its impact on the food product is unclear. Packaging conditions influenced the ecosystem equilibrium and biodiversity. Except for day 8, the lowest counts for all studied flora were observed for modified atmosphere packaging (MAP) containing >80% CO2. Moreover, in these conditions, higher biodiversity by Temporal Temperature Gradient Gel Electrophoresis (TTGE) and the non-detection of specific flora (i.e. Pseudoalteromonas haloplanktis) were observed. At day 8, scallops packaged using these conditions were still acceptable from a sensorial point of view (odour), although the initial load of the king scallop was high (total psychrotrophic flora reached 5.5 log CFU/g). PMID- 23664261 TI - Effect of meat ingredients (sodium nitrite and erythorbate) and processing (vacuum storage and packaging atmosphere) on germination and outgrowth of Clostridium perfringens spores in ham during abusive cooling. AB - The effect of nitrite and erythorbate on Clostridium perfringens spore germination and outgrowth in ham during abusive cooling (15 h) was evaluated. Ham was formulated with ground pork, NaNO2 (0, 50, 100, 150 or 200 ppm) and sodium erythorbate (0 or 547 ppm). Ten grams of meat (stored at 5 degrees C for 3 or 24 h after preparation) were transferred to a vacuum bag and inoculated with a three strain C. perfringens spore cocktail to obtain an inoculum of ca. 2.5 log spores/g. The bags were vacuum-sealed, and the meat was heat treated (75 degrees C, 20 min) and cooled within 15 h from 54.4 to 7.2 degrees C. Residual nitrite was determined before and after heat treatment using ion chromatography with colorimetric detection. Cooling of ham (control) stored for 3 and 24 h, resulted in C. perfringens population increases of 1.46 and 4.20 log CFU/g, respectively. For samples that contained low NaNO2 concentrations and were stored for 3 h, C. perfringens populations of 5.22 and 2.83 log CFU/g were observed with or without sodium erythorbate, respectively. Residual nitrite was stable (p > 0.05) for both storage times. Meat processing ingredients (sodium nitrite and sodium erythorbate) and their concentrations, and storage time subsequent to preparation of meat (oxygen content) affect C. perfringens spore germination and outgrowth during abusive cooling of ham. PMID- 23664262 TI - Microbial origin of non proteolytic aminoacyl derivatives in long ripened cheeses. AB - Cheese ripening involves a complex series of biochemical events that contribute to the development of each cheese characteristic taste, aroma and texture. Proteolysis, which has been the subject of active research in the last decade, is the most complex of these biochemical events. However, also aminoacyl derivates of non-proteolytic origin (gamma-glutamyl-amino acids and lactoyl-amino acids) with interesting sensory properties have been identified in cheeses. In the present work, an enzymatic activity producing gamma-glutamyl-phenylalanine in Parmigiano-Reggiano water soluble extracts was observed. It was hypothesized that gamma-glutamyl-amino acids and lactoyl-amino acids could be originated by enzymes of bacterial origin. In order to confirm this hypothesis, Lactobacillus helveticus and Lactobacillus rhamnosus were chosen as representative of starter and non starter microbiota of Parmigiano Reggiano cheese. They were used as model bacteria, in the presence of suitable precursors, to verify their ability to produce gamma-glutamyl-phenylalanine and lactoyl-phenylalanine. The eventual abilities of these strains were tested both during growth and after cell lyses. While gamma-glutamyl-phenylalanine was produced only by lysed cells, lactoyl phenylalanine was produced either by growing or lysed cells in different amount depending on the species, the cells condition and the time of incubation. PMID- 23664263 TI - Growth inhibition of Cronobacter spp. strains in reconstituted powdered infant formula acidified with organic acids supported by natural stomach acidity. AB - Cronobacter is associated with outbreaks of rare, but life-threatening cases of meningitis, necrotizing enterocolitis, and sepsis in newborns. This study was conducted to determine the effect of organic acids on growth of Cronobacter in laboratory medium and reconstituted powdered infant formula (PIF) as well as the bacteriostatic effect of slightly acidified infant formula when combined with neonatal gastric acidity. Inhibitory effect of seven organic acids on four acid sensitive Cronobacter strains was determined in laboratory medium with broth dilution method at pH 5.0, 5.5 and 6.0. Acetic, butyric and propionic acids were most inhibitive against Cronobacter in the laboratory medium. The killing effect of these three acids was partially buffered in reconstituted PIF. Under neonatal gastric acid condition of pH 5.0, the slightly acidified formula which did not exert inhibition effect solely reduced significantly the Cronobacter populations. A synergistic effect of formula moderately acidified with organic acid combined with the physiological infant gastric acid was visible in preventing the rapid growth of Cronobacter in neonatal stomach. The study contributed to a better understanding of the inhibitory effect of organic acids on Cronobacter growth in different matrixes and provided new ideas in terms of controlling bacteria colonization and translocation by acidified formula. PMID- 23664264 TI - Metabolism of lactic acid in fermented cucumbers by Lactobacillus buchneri and related species, potential spoilage organisms in reduced salt fermentations. AB - Recent evidence suggests that Lactobacillus buchneri may play an important role in spoilage-associated secondary fermentation of cucumbers. Lactic acid degradation during fermented cucumber spoilage is influenced by sodium chloride (NaCl) concentration, pH, and presence of oxygen. Objectives were to evaluate these factors on lactic acid utilization by L. buchneri, and to compare the biochemical changes to those which occur during fermented cucumber spoilage. Effects of NaCl (0, 2, 4, and 6% w/w), pH (3.8 vs 5.0), and aerobic environment were investigated using fermented cucumber media (FC) inoculated with spoilage microorganisms. At pH 3.8, L. buchneri degraded lactic acid in all NaCl concentrations. The highest rate of lactic acid utilization occurred in FC with 2% NaCl (P < 0.05). Lactic acid utilization was nearly identical under aerobic and anaerobic conditions, indicating that oxygen does not influence lactate metabolism by L. buchneri. Lactic acid utilization was accompanied by increases in acetic acid and 1,2-propanediol, and Lactobacillus rapi was able to convert 1,2-propanediol to propionic acid and propanol. L. buchneri initiated spoilage in a wide range of environmental conditions that may be present in commercial cucumber fermentations, and L. rapi may act syntrophically with L. buchneri to produce the commonly observed spoilage metabolites. PMID- 23664265 TI - Transcriptional and functional responses of Escherichia coli O157:H7 growing in the lettuce rhizoplane. AB - Lettuce and spinach are increasingly implicated in foodborne illness outbreaks due to contamination by Escherichia coli O157:H7. While this bacterium has been shown to colonize and survive on lettuce leaf surfaces, little is known about its interaction with the roots of growing lettuce plants. In these studies, a microarray analyses, mutant construction and confocal microscopy were used to gain an understanding of structure and function of bacterial genes involved in the colonization and growth of E. coli O157:H7 on lettuce roots. After three days of interaction with lettuce roots, 94 and 109 E. coli O157:H7 genes were significantly up- and down-regulated at least 1.5 fold, respectively. While genes involved in biofilm modulation (ycfR and ybiM) were significantly up-regulated, 40 of 109 (37%) of genes involved in protein synthesis were significantly repressed. E. coli O157:H7 was 2 logs less efficient in lettuce root colonization than was E. coli K12. We also unambiguously showed that a DeltaycfR mutant of E. coli O157:H7 was unable to attach to or colonize lettuce roots. Taken together these results indicate that bacterial genes involved in attachment and biofilm formation are likely important for contamination of lettuce plants with Shiga toxin-producing E. coli strains. PMID- 23664266 TI - Perioperative antibiotics for surgical site infection in pancreaticoduodenectomy: does the SCIP-approved regimen provide adequate coverage? AB - INTRODUCTION: The Joint Commission Surgical Care Improvement Project (SCIP) includes performance measures aimed at reducing surgical site infections (SSI). One measure defines approved perioperative antibiotics for general operative procedures. However, there may be a subset of procedures not adequately covered with the use of approved antibiotics. We hypothesized that piperacillin tazobactam is a more appropriate perioperative antibiotic for pancreaticoduodenectomy (PD). METHODS: In collaboration with hospital epidemiology and the Division of Infectious Diseases, we retrospectively reviewed records of 34 patients undergoing PD between March and May 2008 who received SCIP approved perioperative antibiotics and calculated the SSI rate. After changing our perioperative antibiotic to piperacillin-tazobactam, we prospectively reviewed PDs performed between June 2008 and March 2009 and compared the SSI rates before and after the change. RESULTS: For 34 patients from March through May 2008, the SSI rate for PD was 32.4 per 100 cases. Common organisms from wound cultures were Enterobacter and Enterococcus (50.0% and 41.7%, respectively), and these were cefoxitin resistant. From June 2008 through March 2009, 106 PDs were performed. During this period, the SSI rate was 6.6 per 100 surgeries, 80% lower than during March through May 2008 (relative risk, 0.204; 95% confidence interval [CI], 0.086-0.485; P = .0004). CONCLUSION: Use of piperacillin-tazobactam as a perioperative antibiotic in PD may reduce SSI compared with the use of SCIP approved antibiotics. Continued evaluation of SCIP performance measures in relationship to patient outcomes is integral to sustained quality improvement. PMID- 23664267 TI - Intracellular cytokine production and cognition in healthy older adults. AB - Elevated concentrations of the pro-inflammatory cytokines IL-1beta and IL-6 have been associated with impaired cognitive performance. There are, however, few studies that have examined the relationship between cytokine production and specific aspects of cognition in healthy older individuals. Two-colour flow cytometry was used to determine intracellular cytokine production by activated monocytes, and neuropsychological tests were performed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) in 93 apparently healthy men and women aged 55-70 years. A series of hierarchical regression analyses was carried out to examine the contribution of IL-1beta and IL-6 (% expression and production (antibody binding capacity (ABC))) to recognition, attention and working memory, after controlling for socio-demographic variables (age, sex and social class). IL-1beta% expression and IL-6 production predicted aspects of working memory. Recognition memory was found to be sensitive to the affects of age and social class. The current study suggests that higher intracellular cytokine production by activated monocytes may be predictive of lower cognitive performance in working memory in healthy older individuals. These findings indicate that utilization of models for in vivo cytokine production upon immune challenge may be useful in studying specific aspects of memory affected during inflammatory responses, for example in individuals at risk for cognitive decline owing to age-related inflammatory disorders. PMID- 23664268 TI - Serum levels of brain-derived neurotrophic factor are unchanged after transcranial direct current stimulation in treatment-resistant depression. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) plays an important role in differentiation and repair of neurons in the adult brain. BDNF serum levels have been found to be lower in depressed patients than in healthy subjects. In a couple of studies, effective antidepressant treatment including electroconvulsive therapy led to an increase in BDNF serum levels. As transcranial direct current stimulation (tDCS) is currently discussed as novel therapeutic intervention in major depression, we investigated BDNF serum levels during tDCS in therapy resistant depression. METHODS: Twenty-two patients with a major depressive episode participated in a double-blind placebo-controlled trial and received randomized cross over treatment with 2 weeks active and 2 weeks sham tDCS (1 or 2 mA for 20 min, anode over the left dorsolateral prefrontal cortex, cathode right supraorbital cortex). RESULTS: Clinical assessment only showed a modest and non significant improvement in HAMD, BDI and CGI in both groups. BDNF serum levels were measured at baseline, after 2 and after 4 weeks. There was neither a significant change of BDNF levels following active tDCS, nor were severity of depressive symptoms and BDNF levels correlated. LIMITATIONS: The small sample size, its heterogeneity, the short observation period and a cross-over design without an interval between both conditions. CONCLUSIONS: tDCS did not change BDNF serum levels unlike other established antidepressant interventions in this treatment resistant sample. However, larger studies are needed. PMID- 23664270 TI - Authors' reply to: comment to "variation of quality of colonoscopy in Italy over five years: a nation-wide observational study". PMID- 23664269 TI - Author's reply to "comment on: predictors of clinical response of acid suppression in Chinese patients with gastrooesophageal reflux disease". PMID- 23664271 TI - Pre-selection by double layer density gradient centrifugation improves the fertilising capacity of frozen-thawed, capacitated stallion sperm. AB - The effect of combining double layer density gradient centrifugation (DL-DGC) with different capacitation treatments on the fertilising capacity of frozen thawed stallion sperm was examined via a heterologous assay involving in vitro matured, zona pellucida-free bovine oocytes. In a first experiment, aliquots of frozen-thawed stallion sperm were subjected to one of five capacitation treatments without DL-DGC - ionomycin at 1.0MUM, 0.1MUM, 0.05MUM or 0.01MUM, or caffeine at 200MUg/mL. The fertilising capacity of the semen was then assessed at 18h by staining the above oocytes with 4,6-diamidino-2-phenylindole (DAPI) and examining for sperm penetration, the number of penetrated spermatozoa per oocyte, and male pronucleus formation. In a second experiment, aliquots of frozen-thawed stallion sperm were subjected to DL-DGC selection - or not - and then further subjected to the two best capacitation treatments (0.1MUM and 0.05MUM ionomycin). The fertilising capacity of the semen was then determined as above. The DL DGC/capacitated sperm samples showed the highest mean penetration rates: 24.16% following capacitation with 0.1MUM ionomycin, and 12.21% following capacitation with 0.05MUM ionomycin. The capacitated but non-DL-DGC-selected sperm returned significantly lower values: 6.26% and 7.02% for the same ionomycin treatments respectively. These findings suggest that combining DL-DGC selection with ionomycin capacitation improves the fertilising capacity of frozen-thawed stallion sperm. PMID- 23664272 TI - The changing face of tuberculosis: trends in tuberculosis-associated skeletal changes. AB - Tuberculosis remains a major health problem in many areas of the world. Previous research suggested that the frequency of bone lesions has decreased in the modern (but pre-antibiotic) period, and that the predominantly spinal involvement have changed to affect other parts of the skeleton, in particular ribs. The purpose of this study was to investigate whether bone lesions associated with TB became more or less common in the post-antibiotic period, and if the pattern of skeletal involvement has changed. The skeletons of 147 individuals from South Africa who died from TB were assessed. These were divided into three groups - those dying before 1950 and presumed to have had no antibiotic intervention (n = 52); those dying between 1950 and 1985 presumed to have been treated with antibiotics (n = 34); and those dying after 1985 where co-infection with HIV and drug-resistant disease emerged (n = 61). Overall, 33.3% of all individuals showed signs that could be associated with TB, with corresponding figures in each of the three groups being 21.1%, 38.2% and 41.0%. The increase from group 1 to 3 was statistically significant. Rib lesions are becoming more common, while spinal lesions are decreasing. It may be suggested that patients are surviving for longer due to antibiotic treatment, allowing more time for the development of lesions. PMID- 23664273 TI - Superantigens induce IL-17 production from polarized Th1 clones. AB - Differentiation of naive CD4(+) T cells has been considered to be an irreversible event and, in particular, the plasticity is believed to be completely lost in Th1 subset in vitro after multiple stimulations. However, here we demonstrate that highly polarized myelin oligodendrocyte glycoprotein (MOG)- and herpes simples virus-specific Th1 clones were still capable of producing IL-17 upon superantigen stimulation. Anti-MHC class-II and anti-TCR alphabeta chains partially blocked superantigen-induced IL-17 production. These findings suggest that fully differentiated Th1 cells still have capability to produce cytokines of other Th subsets and production of IL-17 by MOG-specific Th1 cells may have implication in initiation and/or exacerbation of neurological autoimmune diseases. PMID- 23664274 TI - CXCL10 antagonism and plasma sDPPIV correlate with increasing liver disease in chronic HCV genotype 4 infected patients. AB - Egypt has the highest prevalence of hepatitis C virus infection worldwide. CXCL10 is a potent chemoattractant that directs effector lymphocytes to sites of inflammation. It has been reported that plasma CXCL10 is processed by dipeptidylpeptidase IV (DPPIV) thus leading to the generation of an antagonist form. Using Luminex-based immunoassays we determined the concentration of different forms of CXCL10 (total, agonist, and antagonist). We also evaluated plasma soluble DPPIV (sDPPIV) concentration and plasma dipeptidylpeptidase (DPP) activity. Using flow cytometry and immunohistochemistry, we analyzed the distribution of lymphocyte subsets. Plasma CXCL10 was elevated in chronic HCV patients, however the agonist form was undetectable. Increased sDPPIV concentration and DPP activity supported the NH2-truncation of CXCL10. Finally, we demonstrated an increased frequency of CXCR3(+) cells in the peripheral blood, and low numbers of CXCR3(+) cells within the lobular regions of the liver. These findings generalize the observation of chemokine antagonism as a mechanism of immune modulation in chronic HCV patients and may help guide the use of new therapeutic immune modulators. PMID- 23664275 TI - Endothelial PDGF-BB produced ex vivo correlates with relevant hemodynamic parameters in patients affected by chronic venous disease. AB - Surgical specimens of vein were obtained from the tertiary venous network and/or saphenous vein from patients (n=20) affected by chronic venous disease (CVD). Into the venous segments, which subsequently were surgically ablated, the following hemodynamic parameters were assessed by echo-color-doppler (ECD): peak systolic velocity, end diastolic velocity, whose combination allowed the calculation of the resistance index (RI) and the reflux time (RT). Highly purified venous endothelial cell (VEC) cultures derived from venous segments of these CVD patients were then characterized for the profile of cytokines and chemokines released in the culture supernatants. Among the 27 cytokines and chemokines examined, we found a positive and significant correlation (R=0.5; p=0.03) only between the spontaneous release of PDGF-BB by VEC cultures and the RT values of the patients from which the VEC were isolates. In addition, the release of PDGF-BB in the VEC culture supernatants was significantly (p<0.01) increased upon in vitro treatment with recombinant TNF-alpha. By using pharmacological inhibitors, specific for the main pathways, NF-kB, ERK1/2 and p38 MAPK, activated by exposure of endothelial cells to TNF-alpha, we found that only NF-kB appeared to be significantly involved in mediating the PDGF-BB induction by TNF-alpha. Of interest, the release of PDGF-BB in response to the in vitro inflammatory stimulation, maintained a positive and significant correlation with RT (R=0.6; p=0.01), while showing a negative correlation with RI (R=-0.5; p=0.03). The potential implications of our findings for the pathophysiology of CVD are discussed. PMID- 23664277 TI - Management of common carotid artery dissection due to extension from acute type A (DeBakey I) aortic dissection. AB - BACKGROUND: Acute type A aortic dissection can extend into arch vessels, including the common carotid arteries. Although several reports describe concomitant endovascular repair of common carotid artery dissection (CCAD) during open ascending aortic repair, the criteria for repair, natural history, and risk of stroke are unclear. We examine the literature and our experience with nonoperative management of CCAD after acute aortic dissection repair to determine the risk of stroke and the need for carotid revascularization. METHODS: We queried our cases of type A aortic dissection over a 10-year period from January 2002 to December 2011. Imaging was reviewed to determine the presence of CCAD and degree of true-lumen stenosis. Analysis was performed to determine risk of stroke and survival on initial presentation and during follow-up. Survival functions between excluded groups and those with and without CCAD were compared using log rank statistics. RESULTS: We repaired 288 cases of acute type A aortic dissection during the study period. Adequate carotid imaging was available in 179 patients and comprised the study group. We identified 43 cases with CCAD (group A, 24.0%) and 136 cases without it (group B, 76.0%). History of previous stroke was not a risk factor for new stroke in either group (P = .517). Bilateral CCAD occurred in 16 cases (37.2%). Stroke on initial presentation was more common in group A (18.6%) than in group B (8.1%; odds ratio, 2.6; 95% confidence interval, 0.97 6.95; P = .051). Degree of stenosis or false-lumen thrombosis did not affect rate of stroke on presentation. The degree of postoperative true-lumen stenosis ranged from 0% (resolution) to 90%. No patient with CCAD had stroke or required carotid revascularization after discharge on follow-up. The 5-year, stroke-free survival rates in groups A and B were 69.7% and 73.6% (P = .820), respectively. CONCLUSIONS: CCAD, due to extension from aortic arch dissection, has a low risk of subsequent stroke after the initial event. Based on current data, there is little evidence to suggest that aortic origin CCAD requires repair in the absence of recurrent symptoms, regardless of the degree of stenosis or false-lumen patency. Recommended optimal medical therapy includes either aspirin or anticoagulation for 6 months after initial presentation. Additional longitudinal studies are needed. PMID- 23664278 TI - Comparative numerical study on left ventricular fluid dynamics after dilated cardiomyopathy. AB - INTRODUCTION: The role of flow on the progression of left ventricular (LV) remodeling has been presumed, although measurements are still limited and the intraventricular flow pattern in remodeling hearts has not been evaluated in a clinical setting. Comparative evaluation of intraventricular fluid dynamics is performed here between healthy subjects and dilated cardiomyopathy (DCM) patients. METHODS: LV fluid dynamics is evaluated in 20 healthy young men and 8 DCM patients by combination of 3D echocardiography with direct numerical simulations of the equation governing blood motion. Results are analyzed in terms of quantitative global indicators of flow energetics and blood transit properties that are representative of the qualitative fluid dynamics behaviors. RESULTS: The flow in DCM exhibited qualitative differences due to the weakness of the formed vortices in the large LV chamber. DCM and healthy subjects show significant volumetric differences; these also reflect inflow properties like the vortex formation time, energy dissipation, and sub-volumes describing flow transit. Proper normalization permitted to define purely fluid dynamics indicators that are not influenced by volumetric measures. CONCLUSION: Cardiac fluid mechanics can be evaluated by a combination of imaging and numerical simulation. This pilot study on pathological changes in LV blood motion identified intraventricular flow indicators based on pure fluid mechanics that could potentially be integrated with existing indicators of cardiac mechanics in the evaluation of disease progression. PMID- 23664279 TI - Septic shock due to Rhodococcus equi in a patient with chronic myelomonocytic leukemia. PMID- 23664280 TI - Perioperative morbidity and mortality following bilateral total hip arthroplasty. AB - There is concern about safety of bilateral total hip arthroplasty (THA).This study aims to compare in-hospital complication rates between unilateral, simultaneous and staged bilateral THAs. The Nationwide Inpatient Sample from 2002 2010 was used. Patients and complications were identified using ICD-9-CM codes. In multivariate analysis, bilateral THA had higher risk of systemic complications (Odds ratio (OR): 2.1, P<0.001) compared to unilateral procedure, whereas no significant difference existed between simultaneous and staged bilateral THAs. The rate of local complications was higher in bilateral versus unilateral (4.96% versus 4.54%, P=0.009) and in staged versus simultaneous bilateral THAs (OR: 1.75, P=0.05). Bilateral THA increases risk of systemic complications compared to unilateral surgery and simultaneous bilateral THA appears to be safer than staging during one hospitalization. PMID- 23664281 TI - Utility of trephine reamers in revision hip arthroplasty. AB - Powered trephines used over a femoral component to disrupt the bone component interface can yield acceptable clinical and radiographic outcomes while minimizing direct mechanical injury and indirect thermal necrosis. Thirty-six patients required trephining for fractured stems (16), infection (8), malposition (7), modular junction failure (4), and acetabular exposure (1). Harris Hip Scores (HHS), radiographic healing, and complications were assessed at a follow-up of 50.01 mo. Mean HHS increased from 46.61 preoperatively to 87.78 postoperatively (p<.0001). Two patients suffered spontaneous postoperative periprosthetic fractures in the region of the trephined bone at 3 mo and 4 mo postoperatively. Despite undergoing ORIF with locked plates, they both re-fractured with necrotic bone observed at the time of revision. There is a 5.6% incidence of femoral shaft fractures near the region of trephined bone within 1 year of surgery. Given the location of these fractures, thermal necrosis may have occurred and consideration should be given to distally bypassing the region of the femur that has been trephined. PMID- 23664283 TI - [Tuberculosis and cinema]. PMID- 23664282 TI - Cerebrovascular disease is associated with outcomes after total knee arthroplasty: a US total joint registry study. AB - We assessed the association of cerebrovascular disease preoperatively with patient-reported outcomes (PROs) of moderate-severe activity limitation and moderate-severe pain at 2- and 5-years after primary total knee arthroplasty (TKA) using multivariable-adjusted logistic regression; 7139 primary and 4234 revision TKAs were included. Compared to the patients without cerebrovascular disease, those with cerebrovascular disease had a higher odds ratio (OR) of moderate-severe limitation at 2 years and 5 years, 1.32 (95% confidence interval [CI]: 1.02, 1.72; P = .04) and 1.83 (95% CI: 1.32, 2.55; P < .001), respectively. No significant associations were noted with moderate-severe pain at 2 years or 5 years. In conclusion, we found that cerebrovascular disease is independently associated with pain and function outcomes after primary TKA. This should be taken into consideration when discussing expected outcomes of TKA with patients. PMID- 23664284 TI - [Cystic fibrosis: new treatments targeting the CFTR protein]. AB - Cystic fibrosis is an autosomal recessive genetic disease due to mutations in the (cystic fibrosis transmembrane conductance regulator) CFTR gene. The CFTR protein is a chloride channel expressed at the surface of several epithelial cells. Defective function of the CFTR protein leads to a severe disease in which lung disease is the leading cause of death. Current treatments are symptomatic. Nevertheless, with specialist and holistic care in dedicated cystic fibrosis centres, the median survival has improved. But the average age of death remains 29 years. Innovative molecules aiming to correct the CFTR protein itself are under development. These will be personalised treatments depending on the genotype or the type of CFTR dysfunction. The first molecule, ivacaftor, has just been approved in Europe and the USA. Adults and children treated with ivacaftor in clinical trials had a 10% improvement in FEV1 that was maintained for more than a year. Although at present ivacaftor is approved for only a small percentage of patients, the therapeutic strategy of correcting CFTR protein has been proved a valid approach. Other molecules targeting other defects in the CFTR protein are under evaluation. PMID- 23664276 TI - The shared allelic architecture of adiponectin levels and coronary artery disease. AB - OBJECTIVE: A large body of epidemiologic data strongly suggests an association between excess adiposity and coronary artery disease (CAD). Low adiponectin levels, a hormone secreted only from adipocytes, have been associated with an increased risk of CAD in observational studies. However, these associations cannot clarify whether this relationship is causal or due to a shared set of causal factors or even confounding. Genome-wide association studies have identified common variants that influence adiponectin levels, providing valuable tools to examine the genetic relationship between adiponectin and CAD. METHODS: Using 145 genome wide significant SNPs for adiponectin from the ADIPOGen consortium (n = 49,891), we tested whether adiponectin-decreasing alleles influenced risk of CAD in the CARDIoGRAM consortium (n = 85,274). RESULTS: In single-SNP analysis, 5 variants among 145 SNPs were associated with increased risk of CAD after correcting for multiple testing (P < 4.4 * 10(-4)). Using a multi-SNP genotypic risk score to test whether adiponectin levels and CAD have a shared genetic etiology, we found that adiponectin-decreasing alleles increased risk of CAD (P = 5.4 * 10(-7)). CONCLUSION: These findings demonstrate that adiponectin levels and CAD have a shared allelic architecture and provide rationale to undertake a Mendelian randomization studies to understand if this relationship is causal. PMID- 23664285 TI - [Cardio-respiratory involvement in adult-onset Still's disease]. AB - Cardiopulmonary involvement in adult-onset Still's disease is not as common as cutaneous and articular involvement. Pleuropericarditis is the most frequent thoracic manifestation. Although difficult, diagnosis of other thoracic manifestations, which may reveal the disease, is crucial, due to the high risk to life and the efficacy of new immunosuppressive agents. The pathophysiology involves essentially immunological factors, Still's disease being increasingly seen as an autoimmune inflammatory disease. Pro-inflammatory cytokines such as interleukine (IL) 1, 6 and 18 play a crucial role in macrophage activation, which is central in the pathophysiology of adult Still's disease. The classification of cardiopulmonary manifestations is based on anatomy. Cardiac lesions may involve all the tissues of the heart and the pulmonary arteries. Respiratory lesions may involve the pleura, the lung parenchyma (organizing pneumonitis, infiltrative lung disease, alveolar damage, amyloidosis), and the respiratory muscles, including the diaphragm. Finally, some manifestations may be provoked by the treatment itself. Steroids, the first-line treatment, are very effective in pleuropericarditis. Methotrexate used to be prescribed when steroids failed, but biotherapies such as IL1 and IL6 inhibitors have transformed the prognosis of forms resistant to these drugs. PMID- 23664286 TI - [Cannabis use and impairment of respiratory function]. AB - Cannabis is the most commonly smoked illicit substance in many countries including France. It can be smoked alone in plant form (marijuana) but in our country it is mainly smoked in the form of cannabis resin mixed with tobacco. The technique of inhaling cannabis differs from that of tobacco, increasing the time that the smoke spends in contact with the bronchial mucosal and its impact on respiratory function. One cigarette composed of cannabis and tobacco is much more harmful than a cigarette containing only tobacco. In cannabis smokers there is an increased incidence of respiratory symptoms and episodes of acute bronchitis. Cannabis produces a rapid bronchodilator effect; chronic use provokes a reduction in specific conductance and increase in airways resistance. Studies on the decline of Forced Expiratory Volume are discordant. Cannabis smoke and tetrahydrocannabinol irritate the bronchial tree. They bring about histological signs of airways inflammation and alter the fungicidal and antibacterial activity of alveolar macrophages. Inhalation of cannabis smoke is a risk factor for lung cancer. Stopping smoking cannabis will bring about important benefits for lung function. This should encourage clinicians to offer patients support in quitting smoking. PMID- 23664287 TI - [The small airways: normal histology and the main histopathological lesions]. AB - Lesions of the small airway are observed in a wide variety of pulmonary conditions, most of which are due to infection, tobacco and connective tissue diseases. They are sometimes isolated or, more often, associated with involvement of other pulmonary structures such as the bronchi, the lung parenchyma and the pleura. The pathological spectrum of the bronchiolar response to injury is relatively limited. Thus, the same lesion is observed in various clinical settings. There is no correlation between the severity of the small airway involvement seen by the pathologist and the clinical and functional manifestations of bronchiolitis. The causes of bronchiolitis may be classified on a clinical basis, on aetiology or on histological appearance, yet no single classification appears to be suitable. An integrated clinical, radiological, functional and histological approach is needed. As they are seen by the pathologist microscopically, small airway lesions may be subdivided into three categories: (1) simple nonspecific lesions (bronchiolitis - cellular, follicular, granulomatous, obliterative, constrictive) that are never exclusively related to one clinical picture, (2) or displaying a more specific pattern like the respiratory bronchiolitis of the smoker or the histolgical changes of asthma, (3) bronchiolar lesions in conditions described as "interstitial", predominantly centrilobular, involving the small airways and the lung parenchyma, and visible radiologically. After recalling the normal histological appearances of the bronchioles, this review describes the diversity of the histopathological lesions of the small airways. PMID- 23664288 TI - [Specificity of the psychological undertaking of a patient in thoracic oncology]. AB - The question raised by the title calls for a balanced answer. As a matter of fact, like in many clinical situations in which an illness threatens the patient's survival, the singularity of each case makes any attempt of generalization simplistic. Writing about the speficity of the psychological undertaking in thoracic oncology has to avoid two pitfalls: denying any psychosociological specificity of thoracic cancerology, and thus not providing the reader's understanding with anything which could help them read the most frequent problematics. And secondly turn clinical qualitative data into generalities stuck on each case, and rejecting the singularity of the sick person as a subject. As we attempt to avoid both traps, the three next points will be tackled: the announcement of cancer is prototypical of a trauma, and calls up an intense affect of anguish. This affect can be read through social representations, which intervene within the exchange doctor - sick person. The subjectivation of this relation cannot be understood without taking the environment into account, and especially what the affected person knows about cancer owing to their belonging to a socius. In the traumatic atmosphere thus created, the rereading of the phenomenons - cropping up between a somatic symptom experienced by the patient and a traumatic language revolving around the compulsory term "cancer" - is achieved according recurrent thematic lines. As we do not wish to reach the exhaustiveness of the significant unities, neither their reassembly, we will limit ourselves to the development of one main line: that of the relation to time, to temporality, and to presentism. PMID- 23664289 TI - [Epidemiology, management and cost of bone metastases from lung cancer]. AB - In lung cancer, there is a significant incidence of bone metastases with skeletal complications affecting more than 50% of patients. The systematic detection of bone metastases should be included in the initial staging of lung cancer in order to begin their management at an early stage. Treatment is either pharmacological (analgesics, zoledronic acid, anti-rank ligand) or non-pharmacological (radiotherapy, interventional radiological techniques, surgery) especially when bone metastases become symptomatic or complicated. External beam radiation, used for both analgesia and strengthening, can be combined with percutaneous and surgical treatments. Prophylactic or restorative surgery for pathological fractures should be subject to multidisciplinary discussion. Finally, the medico economic impact of bone metastases is substantial. This is related to treatment of bone complications, which emphasises the importance of their prevention. CONCLUSION: Bone metastases from lung cancer cause complications which impact on patients' quality of life. Their management should be by a multidisciplinary approach in view of the numerous therapeutic options. PMID- 23664290 TI - [Ambrosia pollinosis]. AB - Pollinosis is now called seasonal allergic rhinitis by the international terminology but pollinosis includes many other symptoms and so we will use the term Ambrosia pollinosis in this article. The characteristics of ragweed pollinosis are: severity, duration from August to September and the presence of asthma and/or tracheitis in about 50% of cases. Ambrosia: phanerogam, dicotyledon, annual plant, monoic. In France, fields in the mid Rhone Valley are covered with Ambrosia artemisiifolia L. but Ambrosia trifida L. is rare. The French Foundation For Ragweed Study (AFEDA) reports here 30years of clinical and epidemiological studies, involving considerable expense, that describe the geographic distribution of this pollinosis in Europe, and applies a predictive model of Ambrosia pollination to an appropriate treatment thanks to a sensitive sensor (Cour pollen trap). The spreading of Ambrosia is partly due to the regulations of the Common Agricultural Policy. There are numerous allergens; recently the major allergen of mugwort has been identified in ragweed. Profilins cause hypersensitivity reactions to certain foods. Genetic predisposition to developing this pollinosis is discussed because sometimes: the disease starts late in life, no personal or family history of atopy is found, immunoglobulin levels are low. Some publications have discussed a genetic predisposition to allergies to Juniperus ashei (United-States) and Cryptomeria japonica (Japan). The clinical efficacy of sublingual specific immunotherapy is well established and well accepted by patients. PMID- 23664291 TI - [Cross reactions between pollens and vegetable food allergens]. AB - INTRODUCTION: The association of food allergies and pollinosis are numerous, implicating tree, grass and weed pollens on one hand and on the other, several plant foods which after ingestion can induce an oral syndrome or more severe reactions such as urticaria, Quincke's edema, asthma and even anaphylactic shock. BACKGROUND: The molecular basis of cross reactions between pollens and vegetable food allergens is increasingly understood. The principal allergens involved are those of the Bet v 1 family, and profilins found in all pollens as well as in many fruits and vegetables; these two groups of allergens are denatured by high temperatures and by gastric enzymes, in contrast to LTP, which is only found in weeds and some tree pollens. Other molecules can be involved in cross reactions such as Bet v 6 (an isoflavone reductase), 1 beta glucanases and thaumatine-like proteins. Inhibition experiments confirmed that the epitopes responsible for primary sensitization come mainly from pollen allergens; the cross-reactive molecular allergen is related to the geographic environment of the patients. CONCLUSIONS: The practical aspects of managing these patients are underlined: explanations of co-sensitization, explanations for the lack of efficacy of some extracts, usefulness of a molecular diagnosis obtained either by CAP or microarray, prediction of severe clinical reactions induced by specific molecular allergens and the effectiveness of pollen immunotherapy on the cross-related food allergy. PMID- 23664292 TI - [Human error: the most common cause of central line complications]. PMID- 23664293 TI - Effect of nitrogen doping on oxygen vacancies of titanium dioxide supported vanadium pentoxide for ammonia-SCR reaction at low temperature. AB - A V2O5/N-doped TiO2 catalyst has been developed by partly substituting the lattice oxygen of TiO2 support with nitrogen, which showed a remarkable increase in activity for the reduction of NO with NH3 at low temperature. The catalyst was characterized by Brunauer-Emmett-Teller (BET), transmission electron microscope (TEM), photoluminescence (PL), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and electron paramagnetic resonance (EPR). The results demonstrated that N doping cannot noticeably change the microscopic features but dramatically enhanced the formation of surface oxygen vacancies, which can play a vital role in the formation of superoxide ions to improve the SCR activity. The catalyst with [N]/[Ti]=1.0*10(-2) showed the highest NO removal efficiency in the SCR reaction at low temperature. Furthermore, the V1TiN1.0 catalyst showed better resistance to SO2 and H2O during the SCR of NO. PMID- 23664294 TI - Impact of age on long-term outcome after primary angioplasty with bare-metal or drug-eluting stent (from the DESERT cooperation). AB - Despite mechanical reperfusion, elderly patients with ST-segment elevation myocardial infarction (STEMI) still experience unsatisfactory outcomes. Drug eluting stents (DES) have significantly reduced target-vessel revascularization (TVR), but concerns have emerged about the higher risk of late stent thrombosis, which may be more pronounced in elderly patients. Therefore, the aim of this study was to evaluate the impact of age on outcome in patients with STEMI who underwent primary angioplasty with bare-metal stents (BMS) or DES. Our population comprised 6,298 patients who underwent primary angioplasty and stent implantation included in the Drug-Eluting Stent in Primary Angioplasty (DESERT) Cooperation database. Age was significantly associated with female gender (p <0.001), diabetes (p <0.001), hypertension (p <0.001), previous myocardial infarction (MI; p <0.001), ischemia time (p <0.001), and anterior MI (p <0.001) but inversely related to smoking (p <0.001). Elderly patients most often had infarct-related artery located in the descending artery (p = 0.014) and impaired postprocedural thrombolysis in myocardial infarction flow (p <0.001). Elderly patients were less often on clopidogrel at follow-up. At long-term follow-up, age was associated with a higher rate of death (hazard ratio [95% confidence interval] = 2.17 [1.97 to 2.39], p <0.0001), whereas no impact was observed on reinfarction (p = 0.36), stent thrombosis (p = 0.84), and TVR (p = 0.54). These results were confirmed in patients receiving both BMS and DES. The impact of age on mortality was confirmed after correction for baseline confounding factors (gender, diabetes hypertension, hypercholesterolemia, smoking, ischemia time, anterior MI, infarct-related artery location, and postprocedural thrombolysis in myocardial infarction 3 flow; adjusted hazard ratio [95% confidence interval] = 2.13 [1.78 to 2.56], p <0.001). In conclusion, this study shows that in patients with STEMI who underwent primary angioplasty, age is independently associated with higher mortality, observed with both BMS and DES, whereas no impact was observed on the rate of reinfarction, stent thrombosis, and TVR. PMID- 23664296 TI - Effects of low-dosed imidacloprid pulses on the functional role of the caged amphipod Gammarus roeseli in stream mesocosms. AB - Effects of two series of imidacloprid pulses on caged amphipods (Gammarus roeseli) and their shredder efficiency for litter decomposition were studied for 70 days as part of a comprehensive stream mesocosm experiment. The duration of each imidacloprid pulse of 12ugL(-1) was 12h. About 250mL cages with an initial stock of 10 adult gammarids together with different conditioned litter substrates were used. Beside alder leaves (Alnus glutinosa), straw (* Triticosecale) was also used in different trials and tested for its suitability to serve as litter substrate. Results from tracer and microprobe measurements approved the suitability of the test system under low-flow condition of 10cms(-1) in the surrounding stream water. Population development followed a logistic growth function with a carrying capacity of 200 Ind cage(-1) for alder and 161 for straw. In the course of the study, the F1 generation reached sexual maturity and F2 offspring appeared. Increased nitrogen contents of gammarid-free trials compared to stocked ones after 70 days indicated that biofilm on both substrates was an important food source for G. roeseli. However, increased shredding activity by gammarids was only detected for alder during the second pulse series. During the remaining time and also for straw, losses of coarse particular organic matter were quite constant and slow indicating the dominance of transport limited decomposition processes on the litter surfaces. No effect of imidacloprid pulses on population levels and litter decomposition could be detected. However, the number of brood carrying females was reduced in the treatments compared to the control groups in the last 3 weeks of the study. In conclusion, repeated low level and short-term exposition may have adverse long-term effects on G. roeseli in the field with regard to both the population size and the functional role as key shredder. PMID- 23664297 TI - Impaired ability to imagine future pleasant events is associated with apathy in schizophrenia. AB - Recent research has established that schizophrenia patients have difficulties envisioning the future. Although mental simulations have a clear adaptive value, little is known about the function of simulating future episodes, particularly emotional events. The aim of this study was to explore the relationships between apathy and future projection in schizophrenia. Twenty-five schizophrenia patients and 25 healthy controls were asked to imagine pleasant and unpleasant episodes that might happen to them in the future. Verbal descriptions were scored for specificity, and participants also completed the Memory Characteristics Questionnaire, which assesses phenomenal characteristics of imagined future events. Apathy was assessed with the Lille Apathy Rating Scale and the apathetic/social withdrawal item of the Positive and Negative Syndrome Scale. Results showed that schizophrenia patients' pleasant and unpleasant imagined future events were less specific and contained fewer phenomenal characteristics (e.g., amount of sensory details) than those of controls. In the schizophrenia group, difficulties imagining future pleasant events, and particularly poor self referential information for future pleasant events, were specifically associated with apathy, even after controlling for working memory. These results suggest that episodic future thinking impairments, especially for future events of pleasure, may partly underlie the motivational deficits characteristic of schizophrenia. PMID- 23664298 TI - Identifying high-school dance students who will develop an eating disorder: a 1 year prospective study. AB - This study examined the changes in eating disorder (ED) status over 1 year and identified risk factors for EDs among female dance students. In 2003, all students enrolled in each of the nation's 12 high schools with gifted dance programs participated in a two-phase survey. The same participants were invited to take part in a follow-up survey 1 year later. In all, 583 persons completed the phase 1 questionnaire survey, and 245 persons completed interviews twice at baseline and follow-up. Thirty-five females had a newly developed ED, and less than half of the ED cases found at baseline had recovered at follow-up. Being a grade 12 student carried a reduced risk of EDs, whereas higher baseline scores on the Bulimic Investigatory Test Edinburgh (BITE) increased risks of developing an ED after 1 year. A 10-item BITE questionnaire validly identified girl dance students who would develop EDs later in high school. EDs were more commonly developed during middle adolescence, and we suggest that prevention work against EDs begin in this period among the dance student population. The brief screening questionnaire might help detect intervention targets of a prevention program among adolescent dance students. PMID- 23664299 TI - The public health benefit of medicines: how it has been assessed in France? The principles and results of five years' experience. AB - Health technology assessment seeks to inform health policy- and decision-makers by promoting use of current best evidence and by addressing country specific factors, such as local context and values. In France, public health benefit (PHB) is one of the criteria used to inform decisions on the reimbursement of medicines. This article describes the methodological framework and the results after five years of assessment of PHB, by the French National Authority for Health. The semi-quantitative method used includes three dimensions that are: (1) the ability of a drug to improve the population's health status, (2) the drug's adequacy to cover public health needs, and; (3) the impact of the drug on the healthcare system. From 2005 to 2010, the PHB of 530 drugs was estimated, and 72% were assessed as having no PHB. The PHB was "low" for 88% of drugs expected to have a PHB, "medium" for 10%, and was considered to be "high" in only one case. The results of this experience show that it is feasible to assess the public health impact of drugs. But the high level of uncertainties at the time of a drug's first appraisal limits the assessment, which obviously has to be completed by reappraisal with post-marketing studies. PMID- 23664300 TI - Productivity and patient satisfaction in primary care--conflicting or compatible goals? AB - Following recent reforms in Swedish primary care, providers are accountable to both citizens and county councils, in their role as payers. Productivity and quality measurement is fundamental for ensuring health care providers accountability to payers and that resources are spent as intended. The purpose was to study productivity and patient satisfaction in Swedish primary care. One measure of productivity capturing volume of visits and one measure capturing individual's judgment about the quality of services in relation to allocated resources was estimated. The potential conflict between the two measures and variation with respect to different factors was analyzed. There was a great variation in both measures of productivity. No conflict between the two measures of productivity was found. Thus, most providers could increase their volume of services without adverse effects for the quality and vice versa. Providers are however faced with different conditions. Traditional productivity measures are not enough to assess whether allocated resources are used according to set priorities and generates value for money. Information about the length and content of visits and the distribution of services produced is also needed, in particular to assess if resources allocated based on expected great needs among certain groups actually benefits those individuals. Effects of services produced are also needed. This is particularly important to assess if resources allocated based on expected great needs among certain groups actually benefits those individuals. PMID- 23664301 TI - Transparency vs. closed-door policy: do process characteristics have an impact on the outcomes of coverage decisions? A statistical analysis. AB - The aim of this study was to analyze influences of process- and technology related characteristics on the outcomes of coverage decisions. Using survey data on 77 decisions from 13 countries, we examined whether outcomes differ by 14 variables that describe components of decision-making processes and the technology. We analyzed the likelihood of committees covering a technology, i.e. positive (including partial coverage) vs. negative coverage decisions. We performed non-parametric univariate tests and binomial logistic regression with a stepwise variable selection procedure. We identified a negative association between a positive decision and whether the technology is a prescribed medicine (p=0.0097). Other significant influences on a positive decision outcome included one disease area (p=0.0311) and whether a technology was judged to be (cost )effective (p<0.0001). The first estimation of the logistic regression yielded a quasi-complete separation for technologies that were clearly judged (cost )effective. In uncertain decisions, a higher number of stakeholders involved in voting (odds ratio=2.52; p=0.03) increased the likelihood of a positive outcome. The results suggest that decisions followed the lines of evidence-based decision making. Despite claims for transparent and participative decision-making, the phase of evidence generation seemed most critical as decision-makers usually adopted the assessment recommendations. We identified little impact of process configurations. PMID- 23664302 TI - Microbial contamination of hematopoietic progenitor cell products. AB - INTRODUCTION: Microbial screening for contamination is a part of hematopoietic progenitor cell (HPC) collection and infusion procedure. We aimed to find out our microbial contamination rates during collection, processing and infusion steps of HPC products. We also evaluated the clinical course of patients who received contaminated HPC products. PATIENTS-METHODS: We retrospectively analyzed microbial contamination records of HPC grafts between 2010 and 2012. HPC products of autologous donors were evaluated for contamination at three steps: at the end of mobilization, following processing with DMSO and just before stem cell infusion. Grafts of allogeneic donors were assessed only before HPC transplantation (HCT). Microbiological analysis of HPC samples were performed with an automated system (BacT/Alert(r)). RESULT: During the study period a total of 492 mobilization procedures were performed on 329 (214 autologous and 115 allogeneic) donors. Bacterial contamination has been detected in 103 of 1630 samples (6%). Ninety-seven out of 1162 blood samples (8%) from 265 patients who were treated with HCT were contaminated. Forty-six patients (41 autologous and 5 allogeneic) were transplanted with contaminated HPC products. During HCT 42 patients experienced febrile neutropenic attack and 34 of them had positive blood culture results. In none of these 34 patients the isolated pathogens were the same organisms with those found in the final contaminated stem cell product before stem cell infusion. None of the patients who received contaminated products died because of sepsis within the posttransplant 30days. There was no significant difference between patients who received contaminated and non contaminated products in terms of the first day of fever, duration of fever, engraftment kinetics and duration of hospitalization. CONCLUSION: Our results suggest that microbial contamination of HPC products is an issue to be prevented, although it may not have a major impact on the general success of HCT. PMID- 23664303 TI - [Salutogenesis, new perspectives to promote health]. PMID- 23664304 TI - Vibration amplitude and induced temperature limitation of high power air-borne ultrasonic transducers. AB - The acoustic impedances of matching layers, their internal loss and vibration amplitude are the most important and influential parameters in the performance of high power airborne ultrasonic transducers. In this paper, the optimum acoustic impedances of the transducer matching layers were determined by using a genetic algorithm, the powerful tool for optimizating domain. The analytical results showed that the vibration amplitude increases significantly for low acoustic impedance matching layers. This enhancement is maximum and approximately 200 times higher for the last matching layer where it has the same interface with the air than the vibration amplitude of the source, lead zirconate titanate-pizo electric while transferring the 1 kW is desirable. This large amplitude increases both mechanical failure and temperature of the matching layers due to the internal loss of the matching layers. It has analytically shown that the temperature in last matching layer with having the maximum vibration amplitude is high enough to melt or burn the matching layers. To verify suggested approach, the effect of the amplitude of vibration on the induced temperature has been investigated experimentally. The experimental results displayed good agreement with the theoretical predictions. PMID- 23664305 TI - The influence of elastic upstream artery length on fluid-structure interaction modeling: a comparative study using patient-specific cerebral aneurysm. AB - Fluid-structure interaction (FSI) simulations using a patient-specific geometry are carried out to investigate the influence the length of elastic parent artery and the position of constraints in the solid domain on the accuracy of patient specific FSI simulations. Three models are tested: Long, Moderate, and Short, based on the length of the elastic parent artery. All three models use same wall thickness (0.5 mm) and the elastic modulus (5 MPa). The maximum mesh displacement is the largest for the Long model (0.491 mm) compared to other models (0.3 mm for Moderate, and 0.132 mm for Short). The differences of hemodynamic and mechanical variables, aneurysm volume and cross-sectional area between three models are all found to be minor. In addition, the Short model takes the least amount of computing time of the three models (11h compared to 21 h for Long and 19 h for Moderate). The present results indicate that the use of short elastic upstream artery can shorten the time required for pati ent-specific FSI simulations without impacting the overall accuracy of the results. PMID- 23664306 TI - Experimental design for the optimization of the derivatization reaction in determining chlorophenols and chloroanisoles by headspace-solid-phase microextraction-gas chromatography/mass spectrometry. AB - The paper shows some tools (its interpretation and usefulness) to optimize a derivatization reaction and to more easily interpret and visualize the effect that some experimental factors exert on several analytical responses of interest when these responses are in conflict. The entire proposed procedure has been applied in the optimization of equilibrium/extraction temperature and extraction time in the acetylation reaction of 2,4,6-trichlorophenol; 2,3,4,6 tetrachlorophenol, pentachlorophenol and 2,4,6-tribromophenol as internal standard (IS) in presence of 2,4,6-trichloroanisole, 2,3,5,6-tetrachloroanisole, pentachloroanisole and 2,4,6-trichloroanisole-d5 as IS. The procedure relies on the second order advantage of PARAFAC (parallel factor analysis) that allows the unequivocal identification and quantification, mandatory according international regulations (in this paper the EU document SANCO/12495/2011), of the acetyl chlorophenols and chloroanisoles that are determined by means of a HS-SPME-GC/MS automated device. The joint use of a PARAFAC decomposition and a Doehlert design provides the data to fit a response surface for each analyte. With the fitted surfaces, the overall desirability function and the Pareto-optimal front are used to describe the relation between the conditions of the derivatization reaction and the quantity extracted of each analyte. The visualization by using a parallel coordinates plot allows a deeper knowledge about the problem at hand as well as the wise selection of the conditions of the experimental factors for achieving specific goals about the responses. In the optimal experimental conditions (45 degrees C and 25min) the determination by means of an automated HS-SPME-GC/MS system is carried out. By using the regression line fitted between calculated and true concentrations, it has been checked that the procedure has neither proportional nor constant bias. The decision limits, CCa, for probability a of false positive set to 0.05, vary between 0.221 and 0.420ugL(-1). PMID- 23664307 TI - Bacterial discrimination by dictyostelid amoebae reveals the complexity of ancient interspecies interactions. AB - BACKGROUND: Amoebae and bacteria interact within predator-prey and host-pathogen relationships, but the general response of amoeba to bacteria is not well understood. The amoeba Dictyostelium discoideum feeds on, and is colonized by, diverse bacterial species, including Gram-positive [Gram(+)] and Gram-negative [Gram(-)] bacteria, two major groups of bacteria that differ in structure and macromolecular composition. RESULTS: Transcriptional profiling of D. discoideum revealed sets of genes whose expression is enriched in amoebae interacting with different species of bacteria, including sets that appear specific to amoebae interacting with Gram(+) or with Gram(-) bacteria. In a genetic screen utilizing the growth of mutant amoebae on a variety of bacteria as a phenotypic readout, we identified amoebal genes that are only required for growth on Gram(+) bacteria, including one that encodes the cell-surface protein gp130, as well as several genes that are only required for growth on Gram(-) bacteria, including one that encodes a putative lysozyme, AlyL. These genes are required for parts of the transcriptional response of wild-type amoebae, and this allowed their classification into potential response pathways. CONCLUSIONS: We have defined genes that are critical for amoebal survival during feeding on Gram(+), or Gram( ), bacteria that we propose form part of a regulatory network that allows D. discoideum to elicit specific cellular responses to different species of bacteria in order to optimize survival. PMID- 23664308 TI - Osteomalacia induced by adefovir in patient with hepatitis B. AB - Osteomalacia is defined as a defect in mineralization of the bone matrix. We describe the case of a patient with chronic hepatitis B infection in whom treatment with adefovir induced renal phosphate loss with intense and sustained hypophosphatemia which derived in symptomatic osteomalacia. PMID- 23664309 TI - Structure and function of the major ampullate spinning duct of the golden orb weaver, Nephila edulis. AB - Silks are fibres produced by spiders, some insects and even a crustacean, and are formed from protein solution by a pulltrusion process that is not well understood. Here we describe three aspects of the functional anatomy of the spinning apparatus in a spider: (i) changes in the diameter of the duct of the silk gland along its length for individuals at different stages of development, (ii) the correlation between the morphology of the duct and size and (iii) changes in the thickness of the wall of the duct. We conclude that in the distal part of the duct both the lumen's geometry and change in diameter with distance remains remarkably constant as the duct increases in length from moult to moult as the spider grows. This suggests constancy in the region where the nascent silk filament is drawn down within the lumen of the duct, which is likely to be fundamental for forming strong and tough fibres. PMID- 23664310 TI - Malpighian tubules of adult flesh fly, Sarcophaga ruficornis Fab. (Diptera: Sarcophagidae): an ultrastructural study. AB - The Malpighian tubules of adult flesh fly, Sarcophaga ruficornis consist of principal and stellate cells. The principal cells reveal all the characteristics of transporting epithelia with well developed deep basal membrane infoldings forming a complex of interconnecting labyrinth of canaliculi and luminal microvilli, both of which are associated with mitochondria. The central cytoplasm of the cells contains a well developed nucleus, clear vacuoles or vacuoles filled with secretory material, mineral concretions or spherocrystals, lysosomes and a network of endoplasmic reticulum. The mineral concretions are also observed in the region of luminal microvilli and in the lumen of the tubule suggesting their extrusion into the lumen by exocytosis. Several formed bodies are also observed in the lumen. Stellate cells are characterized by simple membrane infoldings and luminal microvilli devoid of mitochondria. The cells are separated by septate junctions. The Malpighian tubules are richly supplied by tracheae and muscle fibers. PMID- 23664311 TI - The emotional journey of labour-women's perspectives of the experience of labour moving towards birth. AB - BACKGROUND: there has been minimal exploration of women's emotional flow during labour and towards birth. This research aimed to capture woman's remembered experiences of this process. METHOD: a critical feminist standpoint methodology guided this research which used in depth interviews to explore the perspectives of 18 women who had experienced a spontaneous labour and birth. These women all had continuity of care from a known midwife FINDINGS: women described labour and birth in terms of their emotions. These emotions flowed from excitement at the beginning, to calm as they waited for the labour to strengthen. This waiting time was variable in length and the women were often able to continue with many aspects of normal life. As the labour intensified women described moving into a 'zone' of timelessness and spacelessness; a time of letting go of control. The external world was shut out. Some women described feeling overwhelmed as the birth approached, others felt intensely tired. During the birth the women returned to a state of alertness. Some described shock or disbelief. They were surprised at how effectively their body had worked and taken them through labour. CONCLUSION AND IMPLICATION FOR PRACTICE: women described labour as defined by their emotions. The feelings described were linear and consistent and may be an indication of normal labour and birth physiology. These descriptions may be helpful when supporting women during labour and birth. PMID- 23664312 TI - Patients' and professionals' barriers and facilitators to external cephalic version for breech presentation at term, a qualitative analysis in the Netherlands. AB - OBJECTIVE: external cephalic version (ECV) is a relatively simple and safe manoeuvre and a proven effective approach in the reduction of breech presentation at term. There is professional consensus that ECV should be offered to all women with a fetus in breech presentation, but only up to 70% of women eligible for ECV undergo an ECV attempt. The aim of the study was to identify barriers and facilitators for ECV among professionals and women with a breech presentation at term. DESIGN: qualitative study with semi-structured interviews. SETTING: Dutch hospitals. PARTICIPANTS: pregnant women with a breech presentation who had decided on ECV, and midwives and gynaecologists treating women with a breech presentation. MEASUREMENTS: on the basis of national guidelines and expert opinions, we developed topic lists to guide the interviews and discuss barriers and facilitators in order to decide on ECV (pregnant women) or advice on ECV (midwives and gynaecologists). FINDINGS: among pregnant women the main barriers were fear, the preference to have a planned caesarean section (CS), incomplete information and having witnessed birth complications within the family or among friends. The main facilitators were the wish for a home birth, the wish for a vaginal delivery and confidence of the safety of ECV. Among professionals the main barriers were a lack of knowledge to fully inform and counsel patients on ECV, and the inability to counsel women who preferred a primary CS. The main facilitator was an unambiguous policy on (counselling for) ECV within the region. CONCLUSION: we identified several barriers and facilitators possibly explaining the suboptimal implementation of ECV for breech presentation in the Netherlands. This knowledge should be taken into account in designing implementation strategies for ECV to improve the uptake of ECV by professionals and patients. PMID- 23664313 TI - An experimental and theoretical analysis of unconfined compression of corneal stroma. AB - The cornea is a transparent connective tissue with dual functions of protecting the eye (mechanical properties) and refracting the light (optical properties). Both of these properties are derived from the corneal intricate and pseudo regular extracellular matrix, the stroma. From the mechanics point of view, the corneal extracellular matrix is a hydrated structure composed of collagen fibrils, proteoglycans, and the interstitial fluid. The objective of this study was to investigate compressive biomechanical properties of the cornea using an experimental and numerical framework. The unconfined compression stress relaxation tests were performed to measure the corneal behavior experimentally and the transversely isotropic biphasic theory was used to analyze the experimental data. It was observed that the behavior of the corneal stroma under stepwise stress-relaxation compression is similar to that of the other soft hydrated tissues and is composed of an immediate stiff response, a transient relaxation phase, and a final steady-state stage. Within the range of deformation considered in this study, maximum and equilibrium reaction stresses were linearly dependent on the compressive strain. The linear transversely isotropic biphasic model curve fitted experimental measurements with the coefficient of determination rfit(2)=0.98+/-0.01. The mechanical parameters of the porcine corneal stroma were calculated as a function of the engineering strain. The corneal out-of-plane modulus was almost independent of the compressive strain, the transverse Young's modulus linearly increased with increasing strain, and the permeability coefficient decayed exponentially with increasing strain. The average mechanical parameters under unconfined compression were found to be: the out-of-plane modulus E-z=5.61KPa, the transverse Young's modulus E-r=1.33MPa, and the permeability coefficient kappa-r=2.14*10(-14)m(4)/N.s. PMID- 23664314 TI - Difference in hemodynamic and wall stress of ascending thoracic aortic aneurysms with bicuspid and tricuspid aortic valve. AB - The aortic dissection (AoD) of an ascending thoracic aortic aneurysm (ATAA) initiates when the hemodynamic loads exerted on the aneurysmal wall overcome the adhesive forces holding the elastic layers together. Parallel coupled, two-way fluid-structure interaction (FSI) analyses were performed on patient-specific ATAAs obtained from patients with either bicuspid aortic valve (BAV) or tricuspid aortic valve (TAV) to evaluate hemodynamic predictors and wall stresses imparting aneurysm enlargement and AoD. Results showed a left-handed circumferential flow with slower-moving helical pattern in the aneurysm's center for BAV ATAAs whereas a slight deviation of the blood flow toward the anterolateral region of the ascending aorta was observed for TAV ATAAs. Blood pressure and wall shear stress were found key hemodynamic predictors of aneurysm dilatation, and their dissimilarities are likely associated to the morphological anatomy of the aortic valve. We also observed discontinues, wall stresses on aneurysmal aorta, which was modeled as a composite with two elastic layers (i.e., inhomogeneity of vessel structural organization). This stress distribution was caused by differences on elastic material properties of aortic layers. Wall stress distribution suggests AoD just above sinotubular junction. Moreover, abnormal flow and lower elastic material properties that are likely intrinsic in BAV individuals render the aneurysm susceptible to the initiation of AoD. PMID- 23664315 TI - Local axial compressive mechanical properties of human carotid atherosclerotic plaques-characterisation by indentation test and inverse finite element analysis. AB - The fibrous cap of an atherosclerotic plaque may be prone to rupture if the occurring stresses exceed the strength of the cap. Rupture can cause acute thrombosis and subsequent ischaemic stroke or myocardial infarction. A reliable prediction of the rupture probability is essential for the appropriate treatment of atherosclerosis. Biomechanical models, which compute stresses and strain, are promising to provide a more reliable rupture risk prediction. However, these models require knowledge of the local biomechanical properties of atherosclerotic plaque tissue. For this purpose, we examined human carotid plaques using indentation experiments. The test set-up was mounted on an inverted confocal microscope to visualise the collagen fibre structure during the tests. By using an inverse finite element (FE) approach, and assuming isotropic neo-Hookean behaviour, the corresponding Young's moduli were found in the range from 6 to 891kPa (median 30kPa). The results correspond to the values obtained by other research groups who analysed the compressive Young's modulus of atherosclerotic plaques. Collagen rich locations showed to be stiffer than collagen poor locations. No significant differences were found between the Young's moduli of structured and unstructured collagen architectures as specified from confocal collagen data. Insignificant differences between the middle of the fibrous cap, the shoulder regions, and remaining plaque tissue locations indicate that axial, compressive mechanical properties of atherosclerotic plaques are independent of location within the plaque. PMID- 23664316 TI - Factors associated with increasing functional decline in multimorbid independently living older people. AB - OBJECTIVES: With increasing age the levels of activities of daily living (ADL) deteriorate. In this study we aimed to investigate which demographic characteristics and disorders are associated with ADL disabilities in multi morbid older people. STUDY DESIGN: We performed a cross-sectional study with baseline patient data from a large Dutch trial in independently living multi morbid older people combined with the reimbursed healthcare data for the same subjects. MAIN OUTCOME MEASURES: The primary outcome of our study was the level of independence of activities of daily living (ADL) as assessed with the Modified Katz Activities of Daily Living (KATZ-15) scale. RESULTS: In our study we were able to include 1187 persons (63.0% female) for whom both questionnaire data and reimbursed healthcare data was available. In total, 59% had a Katz-15 score of 1 or higher. The strongest associations with ADL disabilities in women were psychiatric disorders, with prevalence rate (PR) estimates of 1.37 (95% confidence interval (CI): 1.17-1.60) and transient ischaemic attacks and cerebrovasculair accidents in men, with PR estimates of 1.94 (95% CI: 1.41-2.66). Although univariate analysis seemed to also reveal associations with socio demographic factors such as living together with a partner or the socio-economic status, these factors were not independently associated with ADL disabilities. CONCLUSIONS: In this cross-sectional study we found that 71% of the multi-morbid female elderly had a sub-optimal level of activities of daily living, as assessed with the Katz-15 scale. The results of our study show that multiple disorders are associated with ADL disabilities in multi-morbid older men and women. We found socio-demographic characteristics not to be independently associated ADL disabilities. PMID- 23664317 TI - Pregnancy-induced hypertension is associated with maternal history and a risk of cardiovascular disease in later life: Japanese cross-sectional study. AB - OBJECTIVE: To clarify the associations between pregnancy-induced hypertension (PIH) with heritability of PIH from mother to daughter and the risk of cardiovascular disease in later life in Japanese women. STUDY DESIGN: The Japan Nurses' Health Study (JNHS) is a cohort study of Japanese women's health. Data from the JNHS baseline survey between 2001 and 2007 were used to conduct a cross sectional analysis. Of the 49,927 respondents in the baseline survey, 10,456 parous women who were >=45 years old at baseline were included in the analysis. MAIN OUTCOME MEASURES: The age-adjusted odds ratio (OR) of PIH in women whose mother had a history of PIH, and the age-adjusted OR of PIH in participants for hypertension, hypercholesterolemia and diabetes mellitus (DM). RESULTS: The age adjusted OR of PIH was 2.72 (95% confidence interval [CI]: 2.14-3.46) in women whose mother had a history of PIH compared with those whose mother did not have PIH. PIH was a risk factor for hypertension (age adjusted OR: 2.85, 95% CI: 2.45 3.11), hypercholesterolemia (age-adjusted OR: 1.49, 95% CI: 1.29-1.72) and DM (age-adjusted OR: 1.53, 95% CI: 1.11-2.11), as determined by logistic regression analysis. CONCLUSIONS: In Japanese women, the risk of PIH is approximately 2.7 fold greater in those whose mothers also had PIH compared with those whose mothers did not. PIH is a risk factor for hypertension, hypercholesterolemia, and diabetes mellitus in later life. PMID- 23664319 TI - The histopathology of idiopathic pulmonary fibrosis in West Highland white terriers shares features of both non-specific interstitial pneumonia and usual interstitial pneumonia in man. AB - Idiopathic pulmonary fibrosis (IPF) in West Highland white terriers (WHWTs) is a breed-related, spontaneously arising disease that is a potential animal model for IPF in man. Histopathological similarity between IPF in WHWTs and usual interstitial pneumonia (UIP), the histopathological correlate for IPF in man, has not been confirmed and histological features of non-specific interstitial pneumonia (NSIP), another form of human idiopathic interstitial pneumonia, have been reported in WHWTs with IPF. This study describes the pulmonary histopathological findings in 18 WHWTs with IPF, including lobe-specific samples in nine of the dogs. The canine lesions and their distribution pattern are compared with histopathological characteristics in samples of human UIP and NSIP. Underlying diffuse mature fibrosis, resembling human NSIP more than UIP, was seen in the lungs of all dogs with IPF. Additionally, the majority of dogs with IPF showed multifocal areas of accentuated subpleural and peribronchiolar fibrosis with occasional 'honeycombing' and profound alveolar epithelial changes, reminiscent of human UIP and not commonly seen in NSIP. Interstitial fibroblastic foci, characteristic of UIP, were not seen in WHWTs with IPF. Progressive fibrosis, with intra-alveolar organizing fibrosis alongside interstitial mature collagen deposition, was present within the more severely affected areas of lung in WHWTs with IPF. Severe pulmonary lesions were seen more commonly in the caudal than in the cranial lung lobes. PMID- 23664318 TI - The DietCompLyf study: a prospective cohort study of breast cancer survival and phytoestrogen consumption. AB - DietCompLyf is a multi-centre prospective study designed to investigate associations between phytoestrogens - naturally occurring plant compounds with oestrogenic properties - and other diet and lifestyle factors with breast cancer recurrence and survival. 3159 women with grades I-III breast cancer were recruited 9-15 months post-diagnosis from 56 UK hospitals. Detailed information on clinico-pathological, diet, lifestyle and quality of life is collected annually up to 5 years. Biological samples have also been collected as a resource for subsequent evaluation. The characteristics of the patients and associations between pre-diagnosis intake of phytoestrogens (isoflavones and lignans; assessed using the EPIC-Norfolk UK 130 question food frequency questionnaire) and breast cancer (i) risk factors and (ii) prognostic factors are described for 1797 women who had complete data for all covariates and phytoestrogens of interest. Isoflavone intakes were higher in the patients who were younger at diagnosis, in the non-smokers, those who had breast-fed and those who took supplements. Lignan intakes were higher in patients with a higher age at diagnosis, in ex-smokers, those who had breast-fed, who took supplements, had a lower BMI at diagnosis, lower age at menarche and were nulliparous. No significant associations between pre-diagnosis phytoestrogen intake and factors associated with improved breast cancer prognosis were observed. The potential for further exploration of the relationship between phytoestrogens and breast cancer recurrence and survival, and for the establishment of evidence to improve dietary and lifestyle advice offered to patients following breast cancer diagnosis using DietCompLyf data is discussed. PMID- 23664320 TI - Diagnosis and management of fetal heart failure. AB - Congestive fetal heart failure, defined as inability of the heart to deliver adequate blood flow to organs such as the brain, liver, and kidneys, is a common final outcome of many intrauterine disease states that may lead to fetal demise. Advances in fetal medicine during the past 3 decades now provide the diagnostic tools to detect and also treat conditions that may lead to fetal heart failure. Fetal echocardiographic findings depend on severity of diastolic and systolic dysfunction of both ventricles. At an advanced stage, findings include cardiomegaly; valvar regurgitation; venous congestion; fetal edema and effusions; oligohydramnios; and preferential shunting of blood flow to the brain, heart, and adrenals in the distressed fetus. A useful diagnostic tool to quantify severity of heart failure is the cardiovascular profile score, which is a composite score based on 5 different echocardiographic parameters. To predict outcomes, the score should be interpreted in the context of the underlying disease, as different causes of intrauterine heart failure may have highly variable outcomes. Low fetal cardiac output may result from a myocardial disease (cardiomyopathy, myocarditis, ischemia), abnormal loading conditions (arterial hypertension, obstructive structural heart disease, atrioventricular malformations, twin-to-twin transfusion), arrhythmia, or external cardiac compression (pleural and/or pericardial effusions, cardiac tumours). Treatment options are available for several of these conditions. PMID- 23664323 TI - Nuclear NF-kappaB expression correlates with outcome among patients with head and neck squamous cell carcinoma treated with primary chemoradiation therapy. AB - BACKGROUND: To examine whether nuclear NF-kappaB expression correlates with outcome in patients with head and neck squamous cell carcinoma (HNSCC) treated with primary chemoradiation therapy (CRT). METHODS AND MATERIALS: Between 2007 and 2010, 101 patients with locally advanced primary HNSCC were treated with definitive simultaneous CRT. Pretreatment biopsy specimens were analyzed for NF kappaB p65 (RelA) nuclear immunoreactivity. A sample was assigned to be positive with more than 5% positive nuclear expression. The predictive relevance of NF kappaB and clinicopathologic factors for overall survival (OS), progression-free survival (PFS), local progression-free survival (LPFS), and metastasis-free survival (DMFS) was examined by univariate and multivariate analysis. RESULTS: No significant differences between the groups were observed with regard to age, sex, total radiation dose, fractionation mode, total chemotherapy applied, T stage or grading. Patients with p65 nuclear positive biopsy specimens showed significantly a higher rate of lymph node metastasis (cN2c or cN3 status, P=.034). Within a mean follow-up time of 25 months (range, 2.33-62.96 months) OS, PFS, and DMFS were significantly poorer in the p65 nuclear positive group (P=.008, P=.027, and P=.008, respectively). These correlations remained significant in multivariate analysis. CONCLUSION: NF-kappaB/p65 nuclear expression is associated with increased lymphatic and hematogenous tumor dissemination and decreased survival in HNSCC patients treated with primary CRT. Our results may foster further investigation of a predictive relevance of NF-kappaB/p65 and its role as a suitable target for a molecular-based targeted therapy in HNSCC cancer. PMID- 23664324 TI - A novel method for predicting late genitourinary toxicity after prostate radiation therapy and the need for age-based risk-adapted dose constraints. AB - BACKGROUND: There are no well-established normal tissue sparing dose-volume histogram (DVH) criteria that limit the risk of urinary toxicity from prostate radiation therapy (RT). The aim of this study was to determine which criteria predict late toxicity among various DVH parameters when contouring the entire solid bladder and its contents versus the bladder wall. The area under the histogram curve (AUHC) was also analyzed. METHODS AND MATERIALS: From 1993 to 2000, 503 men with prostate cancer received 3-dimensional conformal RT (median follow-up time, 71 months). The whole bladder and the bladder wall were contoured in all patients. The primary endpoint was grade >=2 genitourinary (GU) toxicity occurring >=3 months after completion of RT. Cox regressions of time to grade >=2 toxicity were estimated separately for the entire bladder and bladder wall. Concordance probability estimates (CPE) assessed model discriminative ability. Before training the models, an external random test group of 100 men was set aside for testing. Separate analyses were performed based on the mean age (<= 68 vs >68 years). RESULTS: Age, pretreatment urinary symptoms, mean dose (entire bladder and bladder wall), and AUHC (entire bladder and bladder wall) were significant (P<.05) in multivariable analysis. Overall, bladder wall CPE values were higher than solid bladder values. The AUHC for bladder wall provided the greatest discrimination for late bladder toxicity when compared with alternative DVH points, with CPE values of 0.68 for age <=68 years and 0.81 for age >68 years. CONCLUSION: The AUHC method based on bladder wall volumes was superior for predicting late GU toxicity. Age >68 years was associated with late grade >=2 GU toxicity, which suggests that risk-adapted dose constraints based on age should be explored. PMID- 23664325 TI - Interval to biochemical failure predicts clinical outcomes in patients with high risk prostate cancer treated by combined-modality radiation therapy. AB - PURPOSE: To validate the prognostic value of interval to biochemical failure (IBF) in patients with high-risk prostate cancer (HiRPCa) treated with combined modality radiation therapy (CMRT) with or without androgen deprivation therapy (ADT). METHODS AND MATERIALS: We conducted a retrospective review of HiRPCa (prostate-specific antigen >20 ng/mL, Gleason score [GS] 8-10, or clinical T stage T3-T4) treated with either dose-escalated external beam radiation therapy (EBRT) or CMRT. Interval to biochemical failure was classified as <=18 or >18 months from the end of all therapy to the date of biochemical failure (BF). Kaplan-Meier methods and Cox proportional hazards regression were used to evaluate the prognostic value of IBF <=18 months for distant metastasis (DM) and prostate cancer-specific mortality (PCSM). RESULTS: Of 958 patients with a median follow-up of 63.2 months, 175 patients experienced BF. In those with BF, there were no differences in pretreatment clinical characteristics between the EBRT and CMRT groups, except for a higher proportion of patients with GS 8-10 in the CMRT group (70% vs 52%, P=.02). Median IBF after all therapy was 24.0 months (interquartile range 9.6-46.0) in the EBRT group and 18.9 months (interquartile range 9.2-34.5) in the CMRT group (P=.055). On univariate analysis, IBF <=18 months was associated with increased risk of DM and PCSM in the entire cohort and the individual EBRT and CMRT groups. On multivariate analysis, only GS 9-10 and IBF <=18 months, but not the radiation therapy regimen or ADT use, predicted DM (hazard ratio [HR] 3.7, P<.01, 95% confidence interval [CI] 1.4-10.3 for GS 9-10; HR 3.9, P<.0001, 95% CI 2.4-6.5 for IBF <=18 months) and PCSM (HR 14.8, P<.009, 95% CI 2.0-110 for GS 9-10; HR 4.4, P<.0001, 95% CI 2.4-8.1 for IBF <=18 months). CONCLUSIONS: Short IBF was highly prognostic for higher DM and PCSM in patients with HiRPCa. The prognostic value of IBF for DM and PCSM was not affected by the radiation therapy regimen or ADT use. PMID- 23664326 TI - Pain flare is a common adverse event in steroid-naive patients after spine stereotactic body radiation therapy: a prospective clinical trial. AB - PURPOSE: To determine the incidence of pain flare after spine stereotactic body radiation therapy (SBRT) in steroid-naive patients and identify predictive factors. METHODS AND MATERIALS: Forty-one patients were treated with spine SBRT between February 2010 and April 2012. All patients had their pain assessed at baseline, during, and for 10 days after SBRT using the Brief Pain Inventory. All pain medications were recorded daily and narcotics converted to an oral morphine equivalent dose. Pain flare was defined as a 2-point increase in worst pain score as compared with baseline with no decrease in analgesic intake, a 25% increase in analgesic intake as compared with baseline with no decrease in worst pain score, or if corticosteroids were initiated at any point during or after SBRT because of pain. RESULTS: The median age and Karnofsky performance status were 57.5 years (range, 27-80 years) and 80 (range, 50-100), respectively. Eighteen patients were treated with 20-24 Gy in a single fraction, whereas 23 patients were treated with 24-35 Gy in 2-5 fractions. Pain flare was observed in 68.3% of patients (28 of 41), most commonly on day 1 after SBRT (29%, 8 of 28). Multivariate analysis identified a higher Karnofsky performance status (P=.02) and cervical (P=.049) or lumbar (P=.02) locations as significant predictors of pain flare. In those rescued with dexamethasone, a significant decrease in pain scores over time was subsequently observed (P<.0001). CONCLUSIONS: Pain flare is a common adverse event after spine SBRT and occurs most commonly the day after treatment completion. Patients should be appropriately consented for this adverse event. PMID- 23664327 TI - Ten-year survival results of a randomized trial of irradiation of internal mammary nodes after mastectomy. AB - PURPOSE: To evaluate the efficacy of irradiation of internal mammary nodes (IMN) on 10-year overall survival in breast cancer patients after mastectomy. METHODS AND PATIENTS: This multicenter phase 3 study enrolled patients with positive axillary nodes (pN+) or central/medial tumors with or without pN+. Other inclusion criteria were age <75 and a Karnofsky index >=70. All patients received postoperative irradiation of the chest wall and supraclavicular nodes and were randomly assigned to receive IMN irradiation or not. Randomization was stratified by tumor location (medial/central or lateral), axillary lymph node status, and adjuvant therapy (chemotherapy vs no chemotherapy). The prescribed dose of irradiation to the target volumes was 50 Gy or equivalent. The first 5 intercostal spaces were included in the IMN target volume, and two-thirds of the dose (31.5 Gy) was given by electrons. The primary outcome was overall survival at 10 years. Disease-free survival and toxicity were secondary outcomes. RESULTS: T total of 1334 patients were analyzed after a median follow-up of 11.3 years among the survivors. No benefit of IMN irradiation on the overall survival could be demonstrated: the 10-year overall survival was 59.3% in the IMN-nonirradiated group versus 62.6% in the IMN-irradiated group (P=.8). According to stratification factors, we defined 6 subgroups (medial/central or lateral tumor, pN0 [only for medial/central] or pN+, and chemotherapy or not). In all these subgroups, IMN irradiation did not significantly improve overall survival. CONCLUSIONS: In patients treated with 2-dimensional techniques, we failed to demonstrate a survival benefit for IMN irradiation. This study cannot rule out a moderate benefit, especially with more modern, conformal techniques applied to a higher risk population. PMID- 23664328 TI - In regard to Shah. PMID- 23664329 TI - Role of MRA in the detection of intracranial aneurysm in the acute phase of subarachnoid hemorrhage. AB - BACKGROUND: Magnetic resonance angiography (MRA) has been evaluated for the detection of unruptured intracranial aneurysms with favorable results at 3 Tesla (3T) and with similar diagnostic accuracy as both 3D time-of-flight (3D-TOF) and contrast-enhanced (CE-MRA) MRA. However, the diagnostic value and place of MRA in the detection of ruptured aneurysms has been little evaluated. Thus, the goal of this prospective single-center series was to assess the feasibility and diagnostic value of 3T 3D-TOF MRA and CE-MRA for aneurysm detection in acute non traumatic subarachnoid hemorrhage (SAH). METHODS: From March 2006 to December 2007, all consecutive patients admitted to our hospital with acute non-traumatic SAH (<=10 days) were prospectively included in this study evaluating MRA in the diagnostic workup of SAH. Feasibility of MRA and sensitivity/specificity of 3D TOF and CE-MRA were assessed compared with gold standard DSA. RESULTS: In all, 84 consecutive patients (45 women, 39 men; age 23-86 years) were included. The feasibility of MRA was low (43/84, 51.2%). The reasons given for patients not undergoing magnetic resonance imaging (MRI) examination were clinical status (27 patients), potential delay in aneurysm treatment (11 patients) and contraindications to MRI (three patients). In patients explored by MRA, the sensitivity of CE-MRA (95%) was higher compared with 3D-TOF (86%) with similar specificity (80%). Also, 3D-TOF missed five aneurysms while CE-MRA missed two. CONCLUSION: The value of MRA in the diagnostic workup of ruptured aneurysms is limited due to its low feasibility during the acute phase of bleeding. Sensitivity for aneurysm detection was good for both MRA techniques, but tended to be better with CE-MRA. PMID- 23664330 TI - CD8+ T cell help is required for efficient induction of EAE in Lewis rats. AB - The role of CD8+ T cells in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) is still unclear. We describe here significantly reduced disease activity of EAE both in Lewis rats depleted of CD8+ T cells by monoclonal antibodies and CD8 knockout rats, which was accompanied by reduced leukocyte infiltration into the spinal cord. We detected myelin basic protein (MBP) specific CD8+ T cells in peripheral lymphoid organs of CD8-depleted animals which, however, failed to differentiate into interferon-gamma-producing effector cells. Our results indicate that CD8+ T cells interact with myelin-specific CD8+ T cells early in EAE enabling them to differentiate into pathogenic effector cells. PMID- 23664331 TI - Porcine reproductive and respiratory syndrome virus activates inflammasomes of porcine alveolar macrophages via its small envelope protein E. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) infection results in extensive tissue inflammation and damage, which are believed to be responsible for increased susceptibility to secondary infection and even for death. However, its pathogenic mechanisms are not fully understood. To explore the mechanism underlying the PRRSV-induced tissue inflammation and damage, we investigated whether PRRSV activates porcine alveolar macrophage (PAM) inflammasomes which mediate por-IL-1beta maturation/release and subsequently induce tissue inflammation and injury. Our results showed that PRRSV and its small envelope protein E significantly increased IL-1beta release from LPS-primed PAMs; however, only PRRSV not protein E significantly increased IL-1beta release from no-LPS primed PAMs, which indicates PRRSV can activate inflammasomes of PAMs by its encoded protein E. These results provide a molecular basis for the pathogenic mechanism of PRRSV on inducing extensive tissue inflammation and damage, and suggest that the inflammasome may provide a potential therapeutic target for PRRS prevention and treatment. PMID- 23664332 TI - A benchmark for management of drug resistant HIV. PMID- 23664334 TI - Mortality indicators in community-acquired pneumonia requiring intensive care in Turkey. AB - BACKGROUND: Severe community-acquired pneumonia (SCAP) is a fatal disease. This study was conducted to describe an outcome analysis of the intensive care units (ICUs) of Turkey. METHODS: This study evaluated SCAP cases hospitalized in the ICUs of 19 different hospitals between October 2008 and January 2011. The cases of 413 patients admitted to the ICUs were retrospectively analyzed. RESULTS: Overall 413 patients were included in the study and 129 (31.2%) died. It was found that bilateral pulmonary involvement (odds ratio (OR) 2.5, 95% confidence interval (CI) 1.1-5.7) and CAP PIRO score (OR 2, 95% CI 1.3-2.9) were independent risk factors for a higher in-ICU mortality, while arterial hypertension (OR 0.3, 95% CI 0.1-0.9) and the application of non-invasive ventilation (OR 0.2, 95% CI 0.1-0.5) decreased mortality. No culture of any kind was obtained for 90 (22%) patients during the entire course of the hospitalization. Blood, bronchoalveolar lavage, and non-bronchoscopic lavage cultures yielded enteric Gram-negatives (n=12), followed by Staphylococcus aureus (n=10), pneumococci (n=6), and Pseudomonas aeruginosa (n=6). For 22% of the patients, none of the culture methods were applied. CONCLUSIONS: SCAP requiring ICU admission is associated with considerable mortality for ICU patients. Increased awareness appears essential for the microbiological diagnosis of this disease. PMID- 23664335 TI - Store-operated calcium entry and calcium influx via voltage-operated calcium channels regulate intracellular calcium oscillations in chondrogenic cells. AB - Chondrogenesis is known to be regulated by calcium-dependent signalling pathways in which temporal aspects of calcium homeostasis are of key importance. We aimed to better characterise calcium influx and release functions with respect to rapid calcium oscillations in cells of chondrifying chicken high density cultures. We found that differentiating chondrocytes express the alpha1 subunit of voltage operated calcium channels (VOCCs) at both mRNA and protein levels, and that these ion channels play important roles in generating Ca(2+) influx for oscillations as nifedipine interfered with repetitive calcium transients. Furthermore, VOCC blockade abrogated chondrogenesis and almost completely blocked cell proliferation. The contribution of internal Ca(2+) stores via store-operated Ca(2+) entry (SOCE) seems to be indispensable to both Ca(2+) oscillations and chondrogenesis. Moreover, this is the first study to show the functional expression of STIM1/STIM2 and Orai1, molecules that orchestrate SOCE, in chondrogenic cells. Inhibition of SOCE combined with ER calcium store depletion abolished differentiation and severely diminished proliferation, suggesting the important role of internal pools in calcium homeostasis of differentiating chondrocytes. Finally, we present an integrated model for the regulation of calcium oscillations of differentiating chondrocytes that may have important implications for studies of chondrogenesis induced in various stem cell populations. PMID- 23664336 TI - Understanding colloidal FeSx formation from iron phosphate precipitation sludge for optimal phosphorus recovery. AB - The use of sulfide to form iron sulfide precipitates is an attractive option for separation and recovery of phosphorus and ferric iron from ferric phosphate sludge generated in wastewater treatment. The key factors affecting the simultaneous generation and separation of iron sulfide precipitates and phosphate solution from ferric phosphate sludge have so far not been thoroughly investigated. This study therefore focuses on the recovery of phosphorus from synthetic sludge by controlled sulfide addition under different operating conditions. The factors that affect the phosphorus recovery, as well as the optimal process conditions to achieve an effective solid-liquid separation, were investigated. The separation of the FeSx particles is a significant challenge due to the colloidal nature of the particles formed. Faster separation and higher phosphorus recovery was achieved when operating at pH 4 with dosing times of at least 1h. At this pH, phosphorus recovery of 70+/-6% was reached at the stoichiometric S/Fe molar ratio of 1.5, increasing to over 90% recovery at a S/Fe molar ratio of 2.5. Zeta potential results confirmed the colloidal nature of the iron sulfide precipitate, with the isoelectric point around pH 4, explaining the fast separation of the FeSx particles at this pH. PMID- 23664333 TI - Efficacy and safety of raltegravir for treatment of HIV for 5 years in the BENCHMRK studies: final results of two randomised, placebo-controlled trials. AB - BACKGROUND: Two randomised, placebo-controlled trials-BENCHMRK-1 and BENCHMRK-2 investigated the efficacy and safety of raltegravir, an HIV-1 integrase strand transfer inhibitor. We report final results of BENCHMRK-1 and BENCHMRK-2 combined at 3 years (the end of the double-blind phase) and 5 years (the end of the study). METHODS: Integrase-inhibitor-naive patients with HIV resistant to three classes of drug and who were failing antiretroviral therapy were enrolled. Patients were randomly assigned (2:1) to raltegravir 400 mg twice daily or placebo, both with optimised background treatment. Patients and investigators were masked to treatment allocation until week 156, after which all patients were offered open-label raltegravir until week 240. The primary endpoint was previously assessed at 16 weeks. We assessed long-term efficacy with endpoints of the proportion of patients with an HIV viral load of less than 50 copies per mL and less than 400 copies per mL, and mean change in CD4 cell count, at weeks 156 and 240. FINDINGS: 1012 patients were screened for inclusion. 462 were treated with raltegravir and 237 with placebo. At week 156, 51% in the raltegravir group versus 22% in the placebo group (non-completer classed as failure) had viral loads of less than 50 copies per mL, and 54% versus 23% had viral loads of less than 400 copies per mL. Mean CD4 cell count increase (analysed by an observed failure approach) was 164 cells per MUL versus 63 cells per MUL. After week 156, 251 patients (54%) from the raltegravir group and 47 (20%) from the placebo group entered the open-label raltergravir phase; 221 (47%) versus 44 (19%) completed the entire study. At week 240, viral load was less than 50 copies per mL in 193 (42%) of all patients initially assigned to raltegravir and less than 400 copies per mL in 210 (45%); mean CD4 cell count increased by 183 cells per MUL. Virological failure occurred in 166 raltegravir recipients (36%) during the double-blind phase and in 17 of all patients (6%) during the open-label phase. The most common drug-related adverse events at 5 years in both groups were nausea, headache, and diarrhoea, and occurred in similar proportions in each group. Laboratory test results were similar in both treatment groups and showed little change after year 2. INTERPRETATION: Raltegravir has a favourable long term efficacy and safety profile in integrase-inhibitor-naive patients with triple-class resistant HIV in whom antiretroviral therapy is failing. Raltegravir is an alternative for treatment-experienced patients, particularly those with few treatment options. FUNDING: Merck Sharp & Dohme. PMID- 23664338 TI - Descriptive analysis and early-stage consumer acceptance of yogurts fermented with carrot juice. AB - This research explored the sensory characteristics and consumer acceptance of novel probiotic unsweetened yogurts. Yogurts were made with 4 carrot juice levels (8, 16, 24, and 32%), 2 firmness levels (regular, 45g/L milk solids; firm, 90g/L milk solids), and 2 starter cultures (C1, C2). The sensory profile characterized the color intensity (before and after stirring), carrot flavor, sourness, and 7 texture/mouth-feel attributes (astringency, chalkiness, mouth-coating, thickness, smoothness, creaminess, and graininess). The influence of carrot juice level and firmness level were evaluated using ANOVA, polynomial contrasts, and principal component analysis. Mean scores and standard errors were calculated. Consumer acceptance panels in Wolfville, Nova Scotia (n=56), and in Vancouver, British Columbia (Asian n=72, non-Asian n=72), evaluated the hedonic responses to the C1 and C2 formulations, respectively. We observed increases in color intensity, carrot flavor, creaminess, mouth-coating, and chalkiness with increasing carrot juice levels, as well as increases in color intensity, carrot flavor, creaminess, mouth-coating, thickness, and astringency with increasing milk solids concentrations of the C1 and C2 yogurts. Mean hedonic scores for color, appearance, and texture/mouth-feel were greater than hedonic scores for aroma, flavor/taste, and overall liking. This research identified the sensory qualities that need further development and demonstrated the importance of early-stage consumer acceptance research for directing new product development. PMID- 23664337 TI - [Association of muscle strength with early markers of cardiovascular risk in sedentary adults]. AB - OBJECTIVE: To assess the association between muscle strength and early cardiovascular risk (CVR) markers in sedentary adults. MATERIALS AND METHODS: A total of 176 sedentary subjects aged 18-30 years were enrolled. Body mass index and fat percentage were calculated, and waist circumference, grip strength by dynamometry, systolic blood pressure, diastolic blood pressure, mean arterial pressure, and maximal oxygen uptake by VO2max were measured as CVR markers. A multivariate logistic regression analysis was used to assess associations between muscle strength and CVR markers. RESULTS: Inverse correlations were found between muscle strength and adiposity (r=-.317; P=.001), waist circumference (r=-.309; P=.001), systolic blood pressure (r=-.401; P=.001), and mean arterial pressure (r=-.256; P=.001). Subjects with lower levels of muscle strength had a 5.79-fold (95% CI 1.57 to 9.34; P=.008) risk of having higher adiposity levels (>=25%) and a 9.67-fold (95% CI=3.86 to 19.22; P<.001) risk of having lower physical capacity values for VO2max (<=31.5mL/kg/min(-1)). CONCLUSIONS: In sedentary adults, muscle strength is associated to early manifestations of CVR. It is suggested that muscle strength testing is added to routine measurement of VO2max and traditional risk factors for prevention and treatment of cardiovascular risk. PMID- 23664339 TI - Concentrations of n-3 and n-6 fatty acids in Dutch bovine milk fat and their contribution to human dietary intake. AB - Weekly samples representative of Dutch milk were analyzed for concentrations of n 3 and n-6 fatty acids (FA). Concentrations of the n-3 FA alpha-linolenic acid (ALA), eicosatetraenoic acid, eicosapentaenoic acid, and docosapentaenoic acid were 0.495+/-0.027, 0.041+/-0.004, 0.067+/-0.005, and 0.086+/-0.008g per 100g of fat, respectively, whereas docosahexaenoic acid was absent or present in concentrations lower than 0.020g per 100g of fat. Concentrations of the n-6 FA linoleic acid (LeA), gamma-linoleic acid, dihomo-gamma-linoleic acid, and arachidonic acid were 1.428+/-0.068, 0.070+/-0.007, 0.066+/-0.004, and 0.089+/ 0.004g per 100g of fat, respectively; adrenic acid was present in concentrations lower than 0.020g per 100g of fat, whereas docosapentaenoic acid was absent in all samples. The concentrations of ALA and LeA were significantly higher in spring and summer, compared with autumn and winter. The concentrations of all other ALA- and LeA-derived n-3 and n-6 FA were not significantly different between seasons. The contribution of milk fat to the daily intake of eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid was calculated for human consumption levels in different countries. Milk fat contributed between 10.7 and 14.1% to the daily intake of eicosapentaenoic acid and between 23.5 and 34.2% to the intake of docosapentaenoic acid; whereas docosahexaenoic acid contribution was marginal. Arachidonic acid from milk fat contributed between 10.5 and 18.8% to the human intake of n-6 FA. PMID- 23664340 TI - Effect of pre- versus postmilking supplementation on traffic and performance of cows milked in a pasture-based automatic milking system. AB - Cows milked in a pasture-based automatic milking system tend to have a lower daily milking frequency in comparison with cows milked in indoor systems. Milking events with intervals beyond 16h have been reported to have a negative effect on milk yield and udder health, and therefore it is important to minimize their occurrence. As feed is the main incentive to encourage cow traffic around the system, a study was conducted to compare pre- (PRE) versus postmilking (POST) supplementary feed placement strategies in a pasture-based automatic milking system. We hypothesized that PRE cows would have a stronger incentive to walk voluntarily from the paddock to the dairy facility to get milked (due to the reward being more immediate), thereby reducing their milking interval and increasing daily milking frequency and milk yield. The PRE cows returned to the dairy facility sooner (PRE=11.9 vs. POST=13.27h) but had longer milking intervals (PRE=15.3 vs. POST=14.28h). This was due to the additional time spent in the prefeeding area (PRE=56 versus POST=23min) combined with a longer average time spent in the premilking waiting yard (PRE=97 versus POST=77min). Treatment did not affect daily milk yield per cow. The result of this study demonstrates the potential of manipulating feeding management strategies to influence cow behavior and traffic in voluntary milking systems. PMID- 23664341 TI - Prediction of bulk milk fatty acid composition based on farming practices collected through on-farm surveys. AB - The aim of this study was to predict the fatty acid (FA) composition of bulk milk using data describing farming practices collected via on-farm surveys. The FA composition of 1,248 bulk cow milk samples and the related farming practices were collected from 20 experiments led in 10 different European countries at 44 degrees N to 60 degrees N latitude and sea level to 2,000 m altitude. Farming practice-based FA predictions [coefficient of determination (R(2)) >0.50] were good for C16:0, C17:0, saturated FA, polyunsaturated FA, and odd-chain FA, and very good (R(2) >=0.60) for trans-11 C18:1, trans-10 + trans-11 C18:1, cis 9,trans-11 conjugated linoleic acid, total trans FA, C18:3n-3, n-6:n-3 ratio, and branched-chain FA. Fatty acids were predicted by cow diet composition and by the altitude at which milk was produced, whereas animal-related factors (i.e., lactation stage, breed, milk yield, and proportion of primiparous cows in the herd) were not significant in any of the models. Proportion of fresh herbage in the cow diet was the main predictor, with the highest effect in almost all FA models. However, models built solely on conserved forage-derived samples gave good predictions for odd-chain FA, branched-chain FA, trans-10 C18:1 and C18:3n-3 (R(2) >=0.46, 0.54, 0.52, and 0.70, respectively). These prediction models could offer farmers a valuable tool to help improve the nutritional quality of the milk they produce. PMID- 23664342 TI - Effect of estrus synchronization on daily somatic cell count variation in goats according to lactation number and udder health status. AB - Two repeated experiments were carried out in 2 different years to study the effect of estrus on somatic cell count (SCC) in dairy goats. In the first year, 36 Murciano-Granadina goats were used [12 primiparous and 24 multiparous; 22 healthy and 14 with an intramammary infection (IMI)] and, after a 6-d pre experimental period, were divided into 2 groups according to lactation number, udder health status, SCC, and milk production. One group was kept as a control, whereas the other received an estrus synchronization hormonal treatment lasting 11d. At 24, 48, and 72h after cessation of the hormone treatment, goats were placed in contact with a buck to confirm that they were in estrus. For 32 consecutive days (6 pre-experimental, 11 in hormone treatment, and 15 post treatment) the SCC per gland and udder were monitored in all animals. In the second year, we repeated the same experimental design using a total of 38 Murciano-Granadina breed goats (12 primiparous and 26 multiparous; 26 healthy and 12 with IMI). Throughout this experiment, milk yield and composition were also recorded daily for each goat. Upon termination of the hormonal treatment, the SCC in udder milk increased significantly in the treatment group compared with the control group over 3 consecutive days. This increase was observed for year (1 and 2), parity (primiparous and multiparous), and udder health status (healthy and IMI). The log10 SCC (cells/mL) increased from 5.5+/-0.09 before estrus to 6.04+/ 0.09 during treatment; therefore, the geometric mean of the SCC increased 3.5 times during treatment. The maximum values obtained in healthy glands of primiparous goats (geometric mean=0.37 million cells/mL) were lower than in healthy glands (1.1 million cells/mL) or infected glands (1.7 million cells/mL) of multiparous goats. The increase in SCC observed during estrus (200% increase in geometric means) could not be explained by the changes in milk production, which only fell by 13%. During estrus, the percentage of protein and dry matter in the milk also increased significantly. We concluded that it is necessary to consider the presence of estrus to correctly interpret milk SCC, as an indirect method for detecting IMI or as a commercial milk quality parameter. PMID- 23664343 TI - Invited review: heat stress effects during late gestation on dry cows and their calves. AB - In dairy cattle, late gestation is a critical period for fetal growth and physiological transition into the next lactation. Environmental factors, such as temperature and light, exert dramatic effects on the production, health, and well being of animals during this period and after parturition. The aim of this review was to introduce effects of heat stress during late gestation on dairy cattle, and discuss the biological mechanisms that underlie the observed production and health responses in the dam and her fetus. Relative to cooled cows, cows that are heat stressed during late gestation have impaired mammary growth before parturition and decreased milk production in the subsequent lactation. In response to higher milk yield, cows cooled prepartum undergo a series of homeorhetic adaptations in early lactation to meet higher demand for milk synthesis compared with heat-stressed cows, but no direct effect of environmental heat stress on metabolism exists during the dry period. Prepartum cooling improves immune status of transition cows and evidence suggests that altered prolactin signaling in immune cells mediates the effects of heat stress on immune function. Late-gestation heat stress compromises placental development, which results in fetal hypoxia, malnutrition, and eventually fetal growth retardation. Maternal heat stress may also have carryover effects on the postnatal growth of offspring, but direct evidence is still lacking. Emerging evidence suggests that offspring from prepartum heat-stressed cows have compromised passive immunity and impaired cell-mediated immune function compared with those from cooled cows. PMID- 23664344 TI - Reaction norm of fertility traits adjusted for protein and fat production level across lactations in Holstein cattle. AB - A total of 304,001 artificial insemination outcomes in up to 7 lactations from 142,389 Holstein cows, daughters of 5,349 sires and 101,433 dams, calving between January 1995 and December 2007 in 1,347 herds were studied by a reaction norm model. The (co)variance components for days to first service (DFS), days open, nonreturn rate in the first service (NRFS), and number of services per conception were estimated by 6 models: 3 Legendre polynomial degrees for the genetic effects and adjustment or not for the level of fat plus protein (FP) production recorded at day closest to DFS. For all traits and type of FP adjustment, a second degree polynomial showed the best fit. The use of the adjusted FP model did not increase the level of genetic (co)variance components except for DFS. The heritability for each of the traits was low in general (0.03-0.10) and increased from the first to fourth calving; nevertheless, very important variability was found for the estimated breeding value (EBV) of the sires. The genetic correlations (rg) were close to unity between adjacent calvings, but decreased for most distant parities, ranging from rg=0.36 (for DFS) to rg=0.63 (for NRFS), confirming the existence of heterogeneous genetic (co)variance components and EBV across lactations. The results of the eigen decomposition of rg shows that the first eigenvalue explained between 82 to 92% and the second between 8 to 14% of the genetic variance for all traits; therefore, a deformation of the overall mean trajectory for reproductive performance across the trajectory of the different calving could be expected if selection favored these eigenfunctions. The results of EBV for the 50 best sires showed a substantial reranking and variation in the shape of response across lactations. The more important aspect to highlight, however, is the difference between the EBV of the same sires in different calvings, a characteristic known as plasticity, which is particularly important for DFS and NRFS. This component of fertility adds another dimension to selection for fertility that can be used to change the negative genetic progress of reproductive performance presented in this population of Holstein cows. The use of a reaction norm model should allow producers to obtain more robust cows for maintenance of fertility levels along the whole productive life of the cows. PMID- 23664345 TI - Sexually active groups in cattle-a novel estrus sign. AB - The current study presents a novel objective measure for characterizing sexually active groups (SAG 3-5) and relates this measure to other behaviors of lactating Holstein-Friesian cows. Cows in SAG 3-5 were required to participate in a minimum of 1 estrus behavior per 5min while staying within 3m (2 cow lengths) of its partner(s) for a minimum of 5min. Twenty Holstein-Friesian cows were video monitored continuously through 1 complete estrous cycle (22d). Standing behavior, SAG 3-5, secondary estrus signs (SEC), and other social and agonistic behaviors were recorded continuously. The period of mounting estrus (MTE) was divided into the 3 parts: prestand, standing estrus (STE), and poststand. The mean durations of MTE, prestand, STE, and poststand period were 12.9+/-1.84, 4.0+/-1.93, 7.1+/ 1.44, and 1.8+/-0.57h (n=13). The fractions of time spent in SAG 3-5 during MTE, prestand, STE, and poststand period were 13, 8, 19, and 1% (n=11). During MTE, cows participated, on average, in 5.8+/-1.24 SAG 3-5 and initiated 9.5+/-2.99 mounts, with mean durations of 0.25+/-0.03h and 4.00+/-0.36s, respectively. The novel measure SAG 3-5 was a sign of long duration not confined only to groups of STE cows. On one day when no cows were in estrus and during the periods 4 to 24h before and after MTE, no SAG 3-5 behaviors were observed. Luteal-phase cows participated in SAG 3-5 only when the partner was a single cow in estrus. The time spent in SAG 3-5 increased between 1 and 3h before MTE and the prestand period (3 vs. 8%) and reached a peak level during STE. From STE to poststand, time spent in SAG 3-5 decreased considerably (19 vs. 1%). The observed decrease in nonmutual agonistic behaviors 4 to 24h before MTE is suggested as an early sign of pre-estrus. Changes in SAG 3-5, agonistic behaviors, and SEC are suggested as indicators of the specific stages of MTE. Increased SEC initiated and SAG 3-5 were indicators of late pre-estrus and early estrus (prestand). Peak levels of SAG 3-5, SEC, and social agonistic behaviors were indicators of STE. A sudden decrease in behaviors, preceded by frequent interactions, was indicative of late estrus (poststand). On the basis of the findings reported here, we propose that SAG 3-5, as well as proceptive and receptive patterns of SEC and agonistic behaviors, be included in estrus detection protocols. Updated knowledge of these behavioral interactions may assist when determining the stage of estrus and the optimal time to breed dairy cows. PMID- 23664346 TI - Estimate of serum immunoglobulin G concentration using refractometry with or without caprylic acid fractionation. AB - Objectives of this study were to develop a rapid calf-side test to determine serum IgG concentrations using caprylic acid (CA) fractionation, followed by refractometry of the IgG-rich supernatant and compare the accuracy of this method with results obtained using refractometry using raw serum. Serum samples (n=200) were obtained from 1-d-old calves, frozen (-20 degrees C), and shipped to the laboratory. Samples were allowed to thaw for 1h at room temperature. Fractionation with CA was conducted by adding 1mL of serum to a tube containing 45, 60, or 75uL of CA and 0.5, 1.0, or 1.5mL of 0.06 M acetic acid. The tube contents were mixed well, allowed to react for 1 min, and then centrifuged at 3,300 * g for 0, 10, or 20 min at 25 degrees C. The %Brix and refractive index of the fractionated supernatant were determined using a digital refractometer. Nonfractionated serum was analyzed for %Brix (BRn), refractive index (nDn), and IgG concentration by radial immunodiffusion. The mean serum IgG concentration was 19.0 mg/mL [standard deviation (SD)=9.7], with a range of 3.5 to 47.0 mg/mL. The mean serum BRn was 8.6 (SD=0.91), with a range of 6.8 to 11.0. The mean serum nDn was 1.34566 (SD=0.00140), with a range of 1.34300 to 1.34930. Serum nDn was positively correlated with IgG concentration (correlation coefficient=0.86; n=185). Fractionated samples treated with 1mL 0.6 M acetic acid and 60uL of CA and not centrifuged before analysis resulted in a strong relationship between the refractive index of the fractionated supernatant and IgG (correlation coefficient=0.80; n=45). Regression was used to determine cut points indicative of 10, 12, and 14 mg of IgG/mL to determine the sensitivity and specificity of refractometry to identify failure of passive transfer (serum IgG <10 mg/mL at 24 h old). The nDn were 1.34414, 1.34448, and 1.34480 to predict 10, 12, and 14 mg of IgG/mL of serum, respectively. The BRn cut points were 7.6, 7.8, and 8.0, respectively. The nDn cut points of 1.34448 and 1.34480 resulted in similar specificities (82.9%), whereas the 1.34414 cut point had a specificity of 60.0%. The BRn cut point of 7.6 and 7.8%Brix resulted in a similar percentage of correctly classified samples (89.7 and 90.8%, respectively); however, the 7.8% Brix cut point resulted in fewer false positives. These results suggest that Brix refractometry of nonfractionated calf serum provides a strong estimate of IgG concentration and 7.8% Brix may be used as the cut point to identify failure of passive transfer in 1-d-old calves. PMID- 23664347 TI - Prediction of urinary nitrogen and urinary urea nitrogen excretion by lactating dairy cattle in northwestern Europe and North America: a meta-analysis. AB - A meta-analysis was conducted on the effect of dietary and animal factors on the excretion of total urinary nitrogen (UN) and urinary urea nitrogen (UUN) in lactating dairy cattle in North America (NA) and northwestern Europe (EU). Mean treatment data were used from 47 trials carried out in NA and EU. Mixed model analysis was used with experiment included as a random effect and all other factors, consisting of dietary and animal characteristics, included as fixed effects. Fixed factors were nested within continent (EU or NA). A distinction was made between urinary excretions based on either urine spot samples or calculated assuming a zero N balance, and excretions that were determined by total collection of urine only. Moreover, with the subset of data based on total collection of urine, a new data set was created by calculating urinary N excretion assuming a zero N balance. Comparison with the original subset of data allowed for examining the effect of such an assumption on the relationship established between milk urea N (MUN) concentration and UN. Of all single dietary and animal factors evaluated to predict N excretion in urine, MUN and dietary crude protein (CP) concentration were by far the best predictors. Urinary N excretion was best predicted by the combination of MUN, CP, and dry matter intake, whereas UUN was best predicted by the combination of MUN and CP. All other factors did not improve or only marginally improved the prediction of UN or UUN. The relationship between UN and MUN differed between NA and EU, with higher estimated regression coefficients for MUN for the NA data set. Precision of UN and UUN prediction improved substantially when only UN or UUN data based on total collection of urine were used. The relationship between UN and MUN for the NA data set, but not for the EU data set, was substantially altered when UN was calculated assuming a zero N balance instead of being based on the total collection of urine. According to results of the present meta-analysis, UN and UUN are best predicted by the combination of MUN and CP and that, in regard to precision and accuracy, prediction equations for UN and UUN should be derived from the total collection of urine. PMID- 23664348 TI - The motivation of dairy cows for access to pasture. AB - Several factors influence whether dairy cattle prefer to be indoors or at pasture, including weather conditions and milk yield, but it is unclear how motivated cows are for access to pasture. One way to measure motivation is to require the animal to work (e.g., walk different distances) for access to a resource. This study investigated whether pasture access located 60, 140, or 260m from the indoor housing would affect the proportion of time dairy cows spent at pasture. Thirty-two Holstein-Friesian dairy cows were used during the study, which took place in the United Kingdom from May to July 2010. The experiment consisted of four 18-d experimental periods, with 8 cows in each period, which were further divided into 2 groups of 4 cows. Following a training period, the cows were randomly allocated to distances of 60, 140, or 260m to pasture over three 4-d measurement periods. A video camera was used to record time spent indoors and outdoors 24h/d, and manual behavior observations (0700 to 2200h) took place 6 times during each period to record how the cows spent their time in each location. The video data showed that cows spent, on average, 57.8% (+/-3.44) of their time outside (either at pasture or on the track). One-sample t-tests revealed that this value was different from 0% (t=16.80), 50% (t=2.26), and 100% (t=-12.28). Analysis of the percentage time spent outside revealed that distance did not influence nighttime pasture use (2100 to 0430h; F2,8=0.16; 81.0% vs. 81.0% vs. 76.7%, for 60m vs. 140m vs. 260m, respectively). In contrast, during the day (0700 to 2100h; from behavior observations), time spent at pasture declined as distance increased; that is, cows spent more time at pasture when they had to walk 60m (F2,80=10.09) than when they had to walk 140 or 260m (45.3% vs. 27.4% vs. 21.2%, respectively). Time spent at pasture decreased on rainy days (y=-1.0672x + 59.646, R(2)=0.09, n=48d), but the indoor temperature-humidity index (THI), the outdoor THI, and body condition score did not influence time spent outside. Under the climatic conditions of the current study in the United Kingdom, cows had a partial preference for pasture, which was influenced by distance to pasture during daytime but not at night. This shows that dairy cows were more motivated to access pasture at night compared with during the day. PMID- 23664349 TI - Aggregation and adhesion properties of 22 Lactobacillus strains. AB - In this paper, the autoaggregating, coaggregating, hydrophobicity, and adhering abilities of 22 Lactobacillus strains belonging to different species were assessed. No correlation existed between autoaggregation and adhesion of the strains belonging to different species, whereas a positive correlation existed between autoaggregation and adhesion of the strains belonging to the same species. After treating with guanidine HCl, the autoaggregating and adhering abilities of some Lactobacillus strains decreased, indicating that surface-bound proteins and other macromolecules played a role in the adhering and autoaggregating abilities. The strains Lactobacillus plantarum 20 and 66 had higher adhesion and coaggregation abilities and should be further studied for their probable probiotic properties. Aggregating, coaggregating, and adhering abilities of Lactobacillus strains could be used as the preliminary criteria for selecting strains having probiotic potential. PMID- 23664350 TI - Genetic associations of ketosis and displaced abomasum with milk production traits in early first lactation of Canadian Holsteins. AB - The aim of this study was to investigate the genetic associations of ketosis and displaced abomasum with milk production traits in early first lactation of Canadian Holsteins. Health data recorded by producers were available from the national dairy cattle health system in Canada. Test-day records of milk, fat, and protein yields were obtained from the routine milk recoding scheme. Ketosis and displaced abomasum were defined as binary traits (0 = healthy; 1 = sick) based on whether or not the cow had at least 1 case of the respective disease in the period from calving to 100 d after calving. Mean frequencies of ketosis and displaced abomasum were 4.1 and 2.7%, respectively. The following milk production traits were considered: milk yield, fat percentage (Fat%), protein percentage (Prot%), fat-to-protein (F:P) ratio, and F:P ratio >1.5. The trait F:P ratio >1.5 was scored as 1 or 0, based on whether or not the cow had an F:P ratio >1.5. For milk production traits, the first (5-30 d in milk) and the second (31-60 d in milk) test days were considered. Data were analyzed using bivariate linear animal models. Average heritabilities of 0.02 and 0.04 were obtained for ketosis and displaced abomasum, respectively. For milk production traits, the lowest heritabilities were obtained for F:P >1.5 (0.04 to 0.08), whereas the highest estimates were found for Prot% (0.27 to 0.38). Ketosis and displaced abomasum were genetically uncorrelated with milk yield in early lactation. Moderate favorable correlations were found between metabolic diseases and milk composition traits. Ketosis was significantly correlated with Fat% (0.33), F:P ratio (0.30), and F:P ratio >1.5 (0.35) at the first test day, whereas all genetic correlations with milk composition traits at the second test day were not significant and close to zero. Significant favorable genetic correlations were also found between displaced abomasum and F:P ratio (0.26), F:P ratio >1.5 (0.25) and Prot% (-0.19) at the first test day. Also, Prot% at the second test day was significantly correlated (-0.16) with displaced abomasum. Overall, a higher Fat% and F:P ratio and a lower Prot% at the first test day were associated with an increased susceptibility to metabolic diseases. As genetic correlations between metabolic diseases and F:P ratio were far from unity, dairy producers should be encouraged to keep accurate and complete health data. This will be expected to yield to more accurate genetic evaluations for metabolic diseases. PMID- 23664351 TI - Storage of refrigerated raw goat milk affecting the quality of whole milk powder. AB - The aim of this study was to evaluate the influence of the growth of lipolytic bacteria in raw goat milk stored under refrigeration for different periods on quality parameters of goat milk powder during its shelf life. Fresh goat milk (100L) was collected after milking, divided into 3 identical fractions, and stored at 4 degrees C for 1, 3, and 5d. On d 1, 3, and 5, one sample (1L) was collected and used for microbiological and chemical analysis, and the remaining fraction (almost 30L) was spray dried and stored at 25 degrees C. Milk powder was submitted to microbiological, chemical, and sensory analysis immediately after production, and on d 60, 120, and 180. Lipolytic psychrotrophic counts and total free fatty acid content did not increase in raw milk during storage. However, peroxide value, caprylic and capric acid concentrations, and total free fatty acid content of milk powder increased during 180d of storage, with higher levels found in milk powder manufactured with raw milk stored for 5d. Capric odor and rancid flavors increased in milk powder during storage, regardless the of storage of raw milk for 1, 3, or 5d. Heat treatments used during powder processing destroyed lipolytic psychrotrophic bacteria, but did not prevent lipolysis in milk powder. Results of this trial indicate that the storage of raw goat milk at 4 degrees C should not exceed 3d to preserve the quality of goat milk powder during its shelf life of 180d. PMID- 23664352 TI - Determination of gamma-hydroxybutyric acid in biofluids using a one-step procedure with "in-vial" derivatization and headspace-trap gas chromatography mass spectrometry. AB - A headspace-trap gas chromatography-mass spectrometry (HS-trap GC-MS) method was developed to determine GHB, a low molecular weight compound and drug of abuse, in various biological fluids. Combining this relatively novel and fully automated headspace technique with "in-vial" methylation of GHB allowed for a straightforward approach. One single method could be used for all biofluids (urine, plasma, serum, whole blood or lyzed blood), requiring only 100MUl of sample. Moreover, our approach involves mere addition of all reagents and sample into one vial. Following optimization of headspace conditions and trap settings, validation was performed. Although sample preparation only consists of the addition of salt and derivatization reagents directly to a 100MUl-sample in a HS vial, adequate method sensitivity and selectivity was obtained. Calibration curves ranged from 5 to 150MUg/ml GHB for urine, from 2 to 150MUg/ml for plasma, and from 3.5 to 200MUg/ml for whole blood. Acceptable precision and accuracy (<13% bias and imprecision) were seen for all quality controls (QC's) (LLOQ level, low, medium, high), including for the supplementary serum- and lyzed blood based QC's, using calibration curves prepared in plasma or whole blood, respectively. Incurred sample reanalysis demonstrated assay reproducibility, while cross-validation with another GC-MS method demonstrated that our method is a valuable alternative for GHB determination in toxicological samples, with the advantage of requiring only 100MUl and minimal hands-on time, as sample preparation is easy and injection automated. PMID- 23664353 TI - Water stable metal-organic framework packed microcolumn for online sorptive extraction and direct analysis of naproxen and its metabolite from urine sample. AB - The metal-organic framework MIL-101 was fabricated in a polyetheretherketone (PEEK) tube as micro-trapping device, and applied to sorptive extraction of naproxen and its metabolite in urine samples. The remarkable water stability of the MIL-101 characterizes the material as being different from other moisture sensitive metal-organic framework. It is therefore suitable for extraction of pharmaceuticals from biological fluids. The adsorption isotherms in aqueous solution showed that the adsorption of naproxen on MIL-101 is endothermic. Additionally, MIL-101 exhibited higher extraction capacity to naproxen than that of C18-bonded silica and multi-walled nanotube. A specially designed in-tube sorptive extraction (ITSE) device endows the extraction process with the characteristic of rapidness, convenience, and easy of conjunction with high performance liquid chromatography (HPLC). Finally the MIL-101 based ITSE method coupled with HPLC and fluorescence detection was applied to analysis of naproxen and 6-O-desmethylnaproxen in urine samples. Parameters that influence the online extraction procedure, including pH of the sample solution, flow rate of extraction, sample volume, desorption solvents and time were investigated. The method is proved to be highly sensitive with the linear range of 0.05-6.0MUgL(-1) and the limits of detection of 0.034 and 0.011MUgL(-1) for naproxen and 6-O desmethylnaproxen, respectively. The recoveries in urine samples were 85.3-98.3% for naproxen and 94.0-97.3% for 6-O-desmethylnaproxen with intra- and inter-day RSDs of 2.7-5.2% and 7.1-8.1%, respectively. Urine samples could be directly subjected to analysis without any additional sample pretreatment. The proposed method was demonstrated an efficient, flexible and versatile extraction tool which is ideally suitable for online conjunction with chromatographic methods. PMID- 23664354 TI - Incidence of irregular astigmatism eligible for contact lens fitting after Descemet membrane endothelial keratoplasty. AB - PURPOSE: To evaluate the incidence and causes of anterior corneal surface irregularities after successful Descemet membrane endothelial keratoplasty (DMEK) and the efficacy of contact lens fitting in these cases. SETTING: Tertiary referral center. DESIGN: Retrospective study of prospectively collected data. METHODS: Eyes with a subnormal visual outcome or monocular diplopia after successful DMEK were fitted with a contact lens. These cases were evaluated with Pentacam rotating Scheimpflug camera imaging preoperatively and 6 months postoperatively, and outcomes were compared with those in a randomly selected DMEK control group. RESULTS: In a series of 262 surgeries, 23 eyes (21 patients) were fitted with contact lenses; the control group comprised 23 eyes. Indications for contact lens fitting included (1) obvious corneal surface irregularities due to preexisting corneal scarring, (2) surface irregularities associated with longstanding preoperative stromal edema, and (3) undetectable optical imperfections. The postoperative corrected distance visual acuity (CDVA) with spectacles improved after contact lens correction (P<.001). Preoperative and postoperative irregularity indices were significantly higher in the contact lens group than in the DMEK control group (P<.05). Positive correlations were found between the duration of preoperative stromal edema and postoperative Scheimpflug camera indices (P<.02). CONCLUSIONS: After successful DMEK, 23 of 262 eyes (9%) showed subnormal spectacle CDVA and/or monocular diplopia due to corneal scarring, surface irregularities, or undetectable optical imperfections that could be managed by contact lens fitting. Prolonged preoperative corneal edema for more than 12 months may be a risk factor for diffuse irregular astigmatism after DMEK. FINANCIAL DISCLOSURE: Dr. Melles is a consultant to DORC International BV/Dutch Ophthalmic USA. No author has a financial or proprietary interest in any material or method mentioned. PMID- 23664355 TI - Posterior chamber phakic intraocular lens to correct myopia: long-term follow-up. AB - PURPOSE: To evaluate the long-term safety and efficacy of a refractive phakic intraocular lens (pIOL) (PRL) to correct moderate to high myopia. SETTING: Department of Ophthalmology, University Medicine Charite Berlin, Berlin, Germany. DESIGN: Retrospective cohort study. METHODS: Uncorrected (UDVA) and corrected (CDVA) distance visual acuities, refraction, intraocular pressure, endothelial cell loss, and adverse events were evaluated. RESULTS: The study enrolled 53 eyes (mean spherical equivalent [SE] -12.17 diopters [D] +/- 4.12 [SD]) of 29 patients. The mean age was 34.6 +/- 9.2 years and the mean follow-up, 86 +/- 21.2 months. The mean UDVA improved from 1.37 +/- 0.28 logMAR preoperatively to 0.14 +/- 0.19 logMAR at the last postoperative visit (P<.05). The mean CDVA improved from 0.10 +/- 0.18 logMAR to -0.01 +/- 0.09 logMAR (P<.05). The overall mean efficacy index and mean safety index were 0.9 and 1.21, respectively, at the last follow-up visit. The mean endothelial cell loss at the last follow-up was 6.4%. The complications were slight posterior chamber (PC) pIOL decentration (5 eyes, 9.4%), severe PC pIOL decentration resulting in pIOL removal (1 eye, 1.8%), glaucoma (4 eyes, 7.5%), clinically significant cortical lens opacification resulting in cataract surgery (4 eyes, 7.5%), clinically asymptomatic anterior subcapsular cataract formation (6 eyes, 11.3%), and retinal detachment (2 eyes, 3.8%). CONCLUSIONS: Posterior chamber phakic pIOL implantation to correct moderate to high myopia provided predictable and stable refractive results but with a high rate of serious complications over the long term. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23664356 TI - In vivo analysis of glued intraocular lens position with ultrasound biomicroscopy. AB - PURPOSE: To report ultrasound biomicroscopic (UBM) findings of glued transscleral fixated posterior chamber intraocular lenses (IOLs) in eyes with inadequate capsules. SETTING: Dr. Agarwal's Eye Hospital and Eye Research Centre, Chennai, India. DESIGN: Case series. METHODS: Eyes with glued IOLs for inadequate capsule support were examined with UBM. Optic tilt was measured in relation to the iris plane. Haptic location, iris-IOL contact, vitreous incarceration, and central anterior chamber depth (ACD) were measured and correlated clinically with vision and refractive error. RESULTS: The mean follow-up was 24.6 months +/- 14.3 (SD). Of the 46 eyes, 8 (17.4%) showed optic tilt and 38 (82.6%) showed no optic tilt. Of 92 haptics examined, 85 (92.4%) were in the ciliary sulcus and 7 (7.6%) in the pars plicata. There was no significant association between the presence of optic tilt and haptic location (P=.585, chi-square test). The mean ocular residual astigmatism (ORA) was 0.5 +/- 0.2 diopter (D). There was no significant difference in ORA between eyes with tilt and eyes without tilt (P=.079). There was no significant correlation between ORA and IOL position. There was no correlation of optic tilt and postoperative vision or cylinder. Other features included iris-IOL contact (6.5%), vitreous incarceration (5.4%), and ACD difference (P=.002). CONCLUSIONS: No significant IOL optic tilt affecting the postoperative vision was detected with glued transscleral-fixated IOLs. The technique reliability was good, with the haptics located in the intended position in more than 90% of eyes. FINANCIAL DISCLOSURE: Dr. Amar Agarwal is a paid consultant to Staar Surgical Co. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 23664357 TI - Laser in situ keratomileusis in United States Naval aviators. AB - PURPOSE: To evaluate the safety and efficacy of femtosecond-assisted wavefront guided laser in situ keratomileusis (LASIK) as well as higher-order aberrometric changes in a population of active-duty United States Naval aviators. SETTING: Navy Refractive Surgery Centers, San Diego, California, and Portsmouth, Virginia, USA. DESIGN: Prospective noncomparative 2-site study. METHODS: In this study of femtosecond-assisted wavefront-guided LASIK, 3 groups were differentiated according to the refractive status: myopia, mixed astigmatism, and hyperopia. Uncorrected (UDVA) and corrected (CDVA) distance visual acuities, refraction, mesopic low-contrast CDVA, higher-order aberrations (HOAs), and patient satisfaction were evaluated during a 3-month follow-up. RESULTS: The study enrolled, treated, and included for analysis 548 eyes with myopia, 60 eyes with mixed astigmatism, and 25 eyes with hyperopia. The UDVA was 20/20 or better in 98.3% of eyes with myopia and mixed astigmatism at all postoperative visits and in 95.7% of hyperopic eyes 3 months postoperatively. The gain in CDVA was 1 or more lines in 39.2%, 41.1%, and 30.4% of myopic, mixed astigmatic and hyperopic eyes, respectively. Loss of 2 lines of CDVA after surgery occurred in 2 myopic eyes (0.4%). At 3 months, a mean change of +0.03 MUm +/- 0.10 (SD) and +0.05 +/- 0.08 MUm was observed in higher-order root mean square and primary spherical aberration, respectively. Of the patients, 95.9% said they believed that LASIK had helped their effectiveness as Naval aviators and 99.6% would recommend the same treatment to others. CONCLUSION: Femtosecond-assisted wavefront-guided LASIK was an efficacious and safe option for refractive correction in Naval aviators, enabling a quick return to flight status. FINANCIAL DISCLOSURE: Drs. Tanzer and Schallhorn are consultants to Abbott Medical Optics, Inc. No author has a financial or proprietary interest in any material or method mentioned. PMID- 23664358 TI - Brotherhood brings orphans in from the cold. AB - Detection and classification of related proteins significantly aids in prioritizing structural determination targets. In this issue of Structure, Rubinstein and colleagues describe an improved method for categorizing members of variable protein families and demonstrate its utility for the immunoglobulin superfamily. PMID- 23664359 TI - Sphingosine kinase: a closer look at last. AB - Sphingosine-1-phosphate is a potent sphingolipid mediator, and the kinase that produces it, sphingosine kinase 1 (SphK1), has been implicated in cancer progression, inflammation, and cardiovascular diseases. In this issue of Structure, Wang and colleagues provide the scientific community with the long awaited structure of SphK1. PMID- 23664360 TI - Encapsulating bacteria. AB - In this issue, Bushell and colleagues report the structure of Escherichia coli Wzi, an outer membrane protein, and provide evidence that it functions as a lectin for K30 capsule polysaccharide, thereby anchoring it to the cell surface. PMID- 23664362 TI - Fatigue is frequent and multifactorial in Friedreich's ataxia. PMID- 23664361 TI - Neurotransmitter transporters: structure meets function. AB - At synapses, sodium-coupled transporters remove released neurotransmitters, thereby recycling them and maintaining a low extracellular concentration of the neurotransmitter. The molecular mechanism underlying sodium-coupled neurotransmitter uptake is not completely understood. Several structures of homologs of human neurotransmitter transporters have been solved with X-ray crystallography. These crystal structures have spurred a plethora of computational and experimental work to elucidate the molecular mechanism underlying sodium-coupled transport. Here, we compare the structures of GltPh, a glutamate transporter homolog, and LeuT, a homolog of neurotransmitter transporters for the biogenic amines and inhibitory molecules GABA and glycine. We relate these structures to data obtained from experiments and computational simulations, to draw conclusions about the mechanism of uptake by sodium-coupled neurotransmitter transporters. Here, we propose how sodium and substrate binding is coupled and how binding of sodium and substrate opens and closes the gates in these transporters, thereby leading to an efficient coupled transport. PMID- 23664363 TI - Suicide prevention in correctional facilities: reflections and next steps. AB - Data from a recent national study of inmate suicides indicates that the suicide rate in county jails throughout the United States has steadily decreased. Despite this progress, the author argues that rather than developing and maintaining comprehensive policies and practices, policymakers and correctional administrators appear preoccupied with the notion that suicides can only be prevented when inmates are on suicide precautions. Measures such as closed circuit television monitoring, suicide-resistant jail cells, safety smocks, and new technology are popular tools to keep certain inmates safe. There is more to suicide prevention than simply observing suicidal inmates and waiting for them to attempt suicide. The author argues that suicides are prevented and suicide rates reduced when correctional facilities provide a comprehensive array of programming that identifies suicidal inmates who are otherwise difficult to identify, ensures their safety on suicide precautions, and provides a continuity of care throughout confinement. PMID- 23664364 TI - Malingering in the correctional system: does incentive affect prevalence? AB - Incentives to malinger vary greatly dependent on the context, as does the prevalence. Malingering in the medico-legal context of the criminal courts is generally for one of two purposes: to present as incompetent to stand trial or to successfully plead not guilty by reason of insanity. Estimates of the prevalence of malingering in these contexts vary between 8 and 21%. The prevalence of malingering increases dramatically in a general offender sample, where the external incentive is likely to be substantially different. Malingering in this context can be as high as 56% and generally occurs to obtain a more desirable housing situation or desired medications. Our study examined data from two distinct samples to evaluate incentives to malinger: patients found incompetent to stand trial (IST) and sent to a state hospital for restoration and jail inmates seeking psychiatric services (JPS). Our results indicate that the rate of malingering in the IST sample was consistent with rates published in comparable samples (17.5%) and the rate for the JPS sample was substantially higher (64.5%). Only in the IST sample was rate of malingering associated with offense severity: patients found IST for murder and robbery evidenced malingering rates more than double the sample as a whole. Offense severity bore no relationship to malingering in the JPS sample. PMID- 23664365 TI - Successful early surgical treatment in neonatal compartment syndrome: case report. AB - Neonatal compartment syndrome is rare, and the diagnosis is often missed or delayed because other ischemic diseases can mimic clinical signs observed on the skin. A premature newborn infant presented with skin lesions during the first hours of life that were recognized as the sentinel finding in compartment syndrome of the newborn. We restored normal function by emergency surgery. The authors highlight the importance of effective collaboration between pediatricians and surgeons to improve the management of this neonatal condition. PMID- 23664366 TI - The PPARgamma agonist efatutazone increases the spectrum of well-differentiated mammary cancer subtypes initiated by loss of full-length BRCA1 in association with TP53 haploinsufficiency. AB - Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have anticancer activity and influence cell differentiation. We examined the impact of the selective PPARgamma agonist efatutazone on mammary cancer pathogenesis in a mouse model of BRCA1 mutation. Mice with conditional loss of full-length BRCA1 targeted to mammary epithelial cells in association with germline TP53 insufficiency were treated with efatutazone through the diet starting at age 4 months and were euthanized at age 12 months or when palpable tumor reached 1 cm(3). Although treatment did not reduce percentage of mice developing invasive cancer, it significantly reduced prevalence of noninvasive cancer and total number of cancers per mouse and increased prevalence of well-differentiated cancer subtypes not usually seen in this mouse model. Invasive cancers from controls were uniformly estrogen receptor alpha negative and undifferentiated, whereas well-differentiated estrogen receptor alpha-positive papillary invasive cancers appeared in efatutazone-treated mice. Expression levels of phosphorylated AKT and CDK6 were significantly reduced in the cancers developing in efatutazone treated mice. Efatutazone treatment reduced rates of mammary epithelial cell proliferation and development of hyperplastic alveolar nodules and increased expression levels of the PPARgamma target genes Adfp, Fabp4, and Pdhk4 in preneoplastic mammary tissue. Intervention efatutazone treatment in mice with BRCA1 deficiency altered mammary cancer development by promoting development of differentiated invasive cancer and reducing prevalence of noninvasive cancer and preneoplastic disease. PMID- 23664367 TI - [The "2013 Seville Document" on allogeneic blood transfusion alternatives: a consensus document and an example of mutidisciplinary medical cooperation]. PMID- 23664368 TI - Bilateral orbital preseptal cellulitis after combined adenotonsillectomy and strabismus surgery--case report and pathogenetic hypothesis. AB - The first case of bilateral orbital preseptal cellulitis complicating combined adenotonsillectomy and strabismus surgery is reported. The issues of antimicrobial prophylaxis are discussed. The authors speculate about the possible routes of surgical site infection. Transient bacteraemia secondary to adenotonsillectomy may be theoretically a source of distant surgical site infection to the orbit, raising the issue of distant surgical site contamination during multidisciplinary surgery. Combined adenotonsillectomy and eye surgery might benefit from prophylactic systemic antibiotic administration. PMID- 23664369 TI - Towards a European Brain-Health Union. PMID- 23664371 TI - Cooling of children with severe traumatic brain injury. PMID- 23664370 TI - Comparison of hypothermia and normothermia after severe traumatic brain injury in children (Cool Kids): a phase 3, randomised controlled trial. AB - BACKGROUND: On the basis of mixed results from previous trials, we assessed whether therapeutic hypothermia for 48-72 h with slow rewarming improved mortality in children after brain injury. METHODS: In this phase 3, multicenter, multinational, randomised controlled trial, we included patients with severe traumatic brain injury who were younger than 18 years and could be enrolled within 6 h of injury. We used a computer-generated randomisation sequence to randomly allocate patients (1:1; stratified by site and age [<6 years, 6-15 years, 16-17 years]) to either hypothermia (rapidly cooled to 32-33 degrees C for 48-72 h, then rewarmed by 0.5-1.0 degrees C every 12-24 h) or normothermia (maintained at 36.5-37.5 degrees C). The primary outcome was mortality at 3 months, assessed by intention-to-treat analysis; secondary outcomes were global function at 3 months after injury using the Glasgow outcome scale (GOS) and the GOS-extended pediatrics, and the occurrence of serious adverse events. Investigators assessing outcomes were masked to treatment. This trial is registered with ClinicalTrials.gov, number NCT00222742. FINDINGS: The study was terminated early for futility after an interim data analysis on data for 77 patients (enrolled between Nov 1, 2007, and Feb 28, 2011): 39 in the hypothermia group and 38 in the normothermia group. We detected no between-group difference in mortality 3 months after injury (6 [15%] of 39 patients in the hypothermia group vs two [5%] of 38 patients in the normothermia group; p=0.15). Poor outcomes did not differ between groups (in the hypothermia group, 16 [42%] patients had a poor outcome by GOS and 18 [47%] had a poor outcome by GOS extended paediatrics; in the normothermia group, 16 [42%] patients had a poor outcome by GOS and 19 [51%] of 37 patients had a poor outcome by GOS-extended paediatrics). We recorded no between-group differences in the occurrence of adverse events or serious adverse events. INTERPRETATION: Hypothermia for 48 h with slow rewarming does not reduce mortality of improve global functional outcome after paediatric severe traumatic brain injury. FUNDING: National Institute of Neurological Disorders and Stroke and National Institutes of Health. PMID- 23664372 TI - The influence of simulated rotator cuff tears on the risk for impingement in handbike and handrim wheelchair propulsion. AB - BACKGROUND: Rotator cuff tears strongly affect the biomechanics of the shoulder joint in their role to regulate the joint contact force needed to prevent the joint from dislocation. The aim of this study was to investigate the influence of simulated progressed rotator cuff tears on the (in)stability of the glenohumeral joint and the risk for impingement during wheelchair and handbike propulsion. METHODS: The Delft Shoulder and Elbow Model was used to calculate the magnitude of the glenohumeral joint reaction force and the objective function J, which is an indication of the effort needed to complete the task. Full-thickness tears were simulated by virtually removing muscles from the model. FINDINGS: With larger cuff tears the joint reaction force was higher and more superiorly directed. Also extra muscle force was necessary to balance the external force such that the glenohumeral joint did not dislocate. INTERPRETATION: A tear of only the supraspinatus leads only to a minor increase in muscle forces and a minor shift of the force on the glenoid, indicating that it is possible to function well with a torn supraspinatus muscle. A massive tear shifts the direction of the joint reaction force to the superior border of the glenoid, increasing the risk for impingement. PMID- 23664373 TI - Argonaute reformatting. AB - In this issue of Molecular Cell, De et al. (2013) report that highly complementary targets promote release of small RNAs from effector Argonaute complexes, thus providing mechanistic insights into regulation of small RNA stability and implications for siRNA design. PMID- 23664374 TI - Adenosine: essential for life but licensed to kill. AB - In this issue of Molecular Cell,Long and Crighton (2013) report a cell death priming mechanism activated by p53 that senses extracellular adenosine accumulated following chemotherapy or hypoxia, providing a novel connection between adenosine signaling and apoptosis. PMID- 23664377 TI - Asymmetric radial expansion and contraction of rat carotid artery observed using a high-resolution ultrasound imaging system. AB - The geometry of carotid artery bifurcation is of high clinical interest because it determines the characteristics of blood flow that is closely related to the formation and development of atherosclerotic plaque. However, information on the dynamic changes in the vessel wall of carotid artery bifurcation during a pulsatile cycle is limited. This pilot study investigated the cyclic changes in carotid artery geometry caused by blood flow pulsation in rats. A high-resolution ultrasound imaging system with a broadband scanhead centered at 40 MHz was used to obtain longitudinal images of the rat carotid artery. A high frame rate retrospective B-scan imaging technique based on the use of electrocardiogram to trigger signal acquisition was used to examine precisely the fast arterial wall motion. Two-dimensional geometry data obtained from nine rats showed that the rat carotid artery asymmetrically contracts and dilates during each cardiac cycle. Systolic/diastolic vessel diameters near the upstream and downstream regions from the bifurcation were 0.976 +/- 0.011/0.825 +/- 0.015 mm and 0.766 +/- 0.015/0.650 +/- 0.016 mm, respectively. Their posterior/anterior wall displacement ratios in the radial direction were 41.0 +/- 14.9% and 2.9 +/- 1.6%, respectively. These results indicate that in the vicinity of bifurcation, the carotid artery favorably expands to the anterior side during the systolic phase. This phenomenon was observed to be more prominent in the downstream region near the bifurcation. The cyclic variation pattern in wall movement varies depending on the measurement site, which shows different patterns at far upstream and downstream of the bifurcation. The asymmetric radial expansion and contraction of the rat carotid artery observed in this study may be useful in studying the hemodynamic etiology of cardiovascular diseases because the pulsatile changes in vessel geometry may affect the local hemodynamics that determines the spatial distribution of wall shear stress, one of important cardiovascular risk factors. Further systematic study is needed to clarify the effects of wall elasticity, branch angle and vessel diameter ratio on the asymmetric wall motion of carotid artery bifurcation. PMID- 23664375 TI - The AID-induced DNA damage response in chromatin. AB - Chemical modifications to the DNA and histone protein components of chromatin can modulate gene expression and genome stability. Understanding the physiological impact of changes in chromatin structure remains an important question in biology. As one example, in order to generate antibody diversity with somatic hypermutation and class switch recombination, chromatin must be made accessible for activation-induced cytidine deaminase (AID)-mediated deamination of cytosines in DNA. These lesions are recognized and removed by various DNA repair pathways but, if not handled properly, can lead to formation of oncogenic chromosomal translocations. In this review, we focus the discussion on how chromatin modifying activities and -binding proteins contribute to the native chromatin environment in which AID-induced DNA damage is targeted and repaired. Outstanding questions remain regarding the direct roles of histone posttranslational modifications and the significance of AID function outside of antibody diversity. PMID- 23664376 TI - Highly complementary target RNAs promote release of guide RNAs from human Argonaute2. AB - Argonaute proteins use small RNAs to guide the silencing of complementary target RNAs in many eukaryotes. Although small RNA biogenesis pathways are well studied, mechanisms for removal of guide RNAs from Argonaute are poorly understood. Here we show that the Argonaute2 (Ago2) guide RNA complex is extremely stable, with a half-life on the order of days. However, highly complementary target RNAs destabilize the complex and significantly accelerate release of the guide RNA from Ago2. This "unloading" activity can be enhanced by mismatches between the target and the guide 5' end and attenuated by mismatches to the guide 3' end. The introduction of 3' mismatches leads to more potent silencing of abundant mRNAs in mammalian cells. These findings help to explain why the 3' ends of mammalian microRNAs (miRNAs) rarely match their targets, suggest a mechanism for sequence specific small RNA turnover, and offer insights for controlling small RNAs in mammalian cells. PMID- 23664378 TI - Novel slanted incidence air-coupled ultrasound method for delamination assessment in individual bonding planes of structural multi-layered glued timber laminates. AB - Non-destructive assessment of delaminations in glued laminated timber structures is required during their full life cycle. A novel air-coupled ultrasound (ACU) method has been developed, which is able to separately detect delaminations in individual bonding planes of arbitrarily high and long laminated stacks and typically 200 mm wide. The 120 kHz ACU transmitter-receiver pair is positioned at two opposite lateral faces of the sample, with a small inclination with respect to the inspected bonding planes, so that an ultrasound beam is excited at a user defined refraction angle within the sample, interacting with defects in a limited height portion of the stack. The attenuation of the ultrasound beam transmitted across the defect (negative detection) provided better sensitivity to defects than the scattered fields (positive detection), which are masked by spurious fields. Dedicated finite-difference time-domain (FDTD) simulations provided understanding on the wave propagation and defect detectability limits, with respect to the heterogeneous anisotropic material structure introduced by the curvature of the annual rings in individual timber lamellas. A simplified analytical expression was derived to calculate refraction angles in timber in function of insonification angle and ring angle. Experimental results show that the method is able to detect >20% wide defects in both isotropic material and in glulam with straight year rings, and >50% wide and 100mm long defects in commercial glulam beams. The discrimination of defects from background variability is optimized by normalizing the images with respect to reference defect-free sample sections (normalization) or previous measurements (difference imaging), and by combining readings obtained with distinct ultrasound beam refraction angles (spatial diversity). Future work aims at the development of a tomographic defect inspection by combining the described theoretical and experimental methods. PMID- 23664379 TI - Effect of multiparity on morphometry and oestrogen receptor expression of pelvic and perineal striated muscles in rabbits: is serum oestradiol relevant? AB - OBJECTIVE: To determine changes in morphometry and expression of oestrogen receptors (OR) in the pubococcygeus and bulbospongiosus muscles, and the concentration of serum oestradiol associated with multiparity. STUDY DESIGN: Twelve chinchilla-breed female rabbits were divided into multiparas who had undergone four consecutive deliveries and age-matched virgin nulliparas. Pubococcygeus and bulbospongiosus muscles were surgically removed from each rabbit and processed histologically. Fibre cross-sectional area, number of peripheral nuclei, and expression of ORalpha and ORbeta were measured for each muscle. Serum samples were obtained and the concentration of serum oestradiol was quantified. RESULTS: Multiparity increased (p <= 0.05) fibre cross-sectional area and the number of peripheral nuclei per fibre in pubococcygeus muscle, but not in bulbospongiosus muscle. Expression of both ORalpha and ORbeta was high (p <= 0.05) in both muscles from multiparous rabbits. A rise in serum oestradiol was measured at the end of the second pregnancy, which was absent (p <= 0.05) at the end of the fourth pregnancy. The concentration of serum oestradiol was similar (p > 0.05) in nulliparous and multiparous rabbits. CONCLUSIONS: Multiparity caused morphometric changes in pubococcygeus muscle but not in bulbospongiosus muscle. As OR expression was high for both muscles, some properties related to fibre composition or muscle physiology could be affected. The finding that serum oestradiol was not elevated at the end of the fourth pregnancy could be related to changes in pelvic and perineal muscles associated with multiparity. PMID- 23664380 TI - Birth of a healthy infant after preimplantation genetic diagnosis by sequential blastomere and trophectoderm biopsy for beta-thalassemia and HLA genotyping. AB - BACKGROUND: Preimplantation genetic diagnosis (PGD) is a widely used technique for couples at genetic risk and involves the diagnosis and transfer of unaffected embryos generated through in vitro fertilization (IVF) techniques. STUDY DESIGN: For those couples who are at risk of transmitting a genetic disease to their offspring, preimplantation embryos can be selected according to their genetic status as well as human leukocyte antigen (HLA) compatibility with the affected child. Stem cells from the resulting baby's umbilical cord blood can be used for transplantation to the affected sibling without graft rejection. RESULTS: Here we report successful hematopoietic stem cell transplantation (HSCT) after the birth of a healthy infant, who was born after successful PGD testing with both cleavage stage and blastocyst stage biopsy for the purpose of diagnosis of beta thalassemia and HLA compatibility. CONCLUSION: The specific feature of this work is not only to have the first successful HSCT achieved in Bulgaria after using preimplantation HLA typing technique, it also demonstrates how to accomplish this success via cross-border collaboration of different units, which makes the application of these sophisticated methods possible in hospitals not having the necessary equipments and expertise. PMID- 23664381 TI - Combined ipsilateral neck and axillary lymphadenectomy for metastatic skin cancers: a case series and surgical tips. AB - In the absence of distant disease simultaneous skin cancer metastasis to neck and axillary lymph nodes necessitates both an axillary and neck en block lymphadenectomy. A combined ipsilateral neck and axillary lymph node dissection should involve an in-continuity dissection through the cervicoaxillary canal for optimal lymphatic and oncological clearance. Review of the literature reveals little published instruction on the procedure since the radical surgery performed by Bowden over 50 years ago. We present 4 cases where ipsilateral axillary and neck lymph node dissections were performed for metastatic melanoma and a case of apical axillary node dissection via a neck incision approach. Our surgical tips include performing apical axillary node dissection via the neck incision and consideration of clavicular osteotomy or clavicular excision. A transclavicular approach was taken in one patient who had an excellent functional outcome after a plate and screw fixation. One elderly patient required a middle third claviculectomy which reduced shoulder elevation but was not associated with functional impairment. We conclude the surgery is safe and associated with the usual morbidity ascribed with either an axillary or neck dissection undertaken in isolation. However, patients have a significant risk of disease relapse as would be expected due to the duel metastatic sites, multiple lymph node and neck involvement which are known to be independent poor prognostic factors on melanoma survival and relapse. PMID- 23664382 TI - Evidence for long-term effectiveness of cranial distraction osteogenesis for syndromic craniosynostosis. PMID- 23664383 TI - Cutaneous lymphadenoma with unusual localization. PMID- 23664384 TI - Application of Mefix dressing: a technical tip. PMID- 23664385 TI - Skin-reducing mastectomy and one-stage implant reconstruction with a myodermal flap: a safe and effective technique in risk-reducing and therapeutic mastectomy. AB - INTRODUCTION: Immediate reconstruction following mastectomy for breast cancer has been shown to be oncologically safe and associated with improved psychosocial outcomes for patients. Bostwick described a technique for one-stage implant based reconstruction, combining skin-sparing mastectomy with concurrent reduction of the skin envelope. This report reviews the experience of a single centre using skin-reducing mastectomy and one-stage implant reconstruction in both early stage breast cancer and risk-reducing mastectomy, with specific reference to frequency of complications, implant loss and oncological outcomes. METHODS AND RESULTS: A retrospective review was undertaken to identify women who had undergone skin reducing mastectomy and one-stage implant reconstruction using a de epithelialised dermal flap, between October 2008 and October 2012. One hundred and four consecutive mastectomies, with reconstruction, were performed by two surgeons on 64 patients. No complications were seen in 43.8% of patients. At three months, four implants were lost (3.8% of breast reconstructions, 6.3% of patients), due to either peri-implant infection or mastectomy skin flap necrosis. One patient required unplanned return to theatre for evacuation of a haematoma. Minor mastectomy skin flap necrosis was seen in 10 breasts (9.6% of reconstructed breasts) and superficial wound infection in 8 breasts (7.7% of reconstructed breasts). All of these complications were managed conservatively and none required operative intervention. At a median follow up of 35 months (4-53 months) there had been one episode of ipsilateral axillary nodal recurrence. CONCLUSION: One-stage implant reconstruction using a myo-dermal flap technique following skin reducing mastectomy is safe and should be considered in selected patients. Most complications are minor and will resolve with conservative management. Major complications such as implant failure or immediate reoperation, were relatively uncommon (6.3% patients, 3.8% of reconstructed breasts). Early follow-up suggests that oncological outcomes are satisfactory, but longer follow-up is required to substantiate this. PMID- 23664386 TI - Clitoroplasty: a blunt technique for patients with lichen sclerosis. PMID- 23664387 TI - Pedicle particulars. PMID- 23664388 TI - Physicochemical studies of mixed surfactant microemulsions with isopropyl myristate as oil. AB - The present study is focused on evaluation of interfacial compositions and thermodynamic properties of w/o mixed surfactant [(sodium dodecylsulfate, SDS/polyoxyethylene (23) lauryl ether, Brij-35)/1-pentanol (Pn)/isopropyl myristate (IPM)] microemulsions under various physicochemical conditions by the dilution method. The number of moles of Pn at the interface (n(a)(i)) and bulk oil (n(a)(o)), and various thermodynamic parameters [viz. standard Gibbs free energy (DeltaG(o->i)(0)), standard enthalpy (DeltaH(o->i)(0)), and standard entropy (DeltaS(o->i)(0)) of the transfer of Pn from bulk oil to the interface] have been found to be dependent on the molar ratio of water to surfactant (omega), concentration of Brij-35 (X(Brij-35)), and temperature. Temperature insensitive microemulsions with zero specific heat capacity (DeltaC(p)(0))(o->i) have been formed at specific compositions. The intrinsic enthalpy change of the transfer process (DeltaH(0))(o->i)* has been evaluated from linear correlation between DeltaH(o->i)(0) and DeltaS(o->i)(0) at different experimental temperatures. The present report also aims at a precise characterization on the basis of molecular interactions between the constituents and provides insight into the nature of the oil/water interfaces of these systems by conductivity and dynamic light scattering studies as a function of omega and X(Brij-35). Conductivity studies reveal that incorporation of Brij-35 in non-percolating water/SDS/Pn/IPM systems makes them favorable for omega-induced percolation behavior up to X(Brij-35) <= 0.5. But further addition of Brij-35 causes a decrease in conductivity with increasing omega. Furthermore, the hydrodynamic diameters of the microemulsion droplets increase with increase in both X(Brij-35) and omega. Correlations of the results in terms of the evaluated physicochemical parameters have been attempted. PMID- 23664389 TI - Gelatin-assisted hydrothermal synthesis of single crystalline zinc oxide nanostars and their photocatalytic properties. AB - Biotemplate-assisted approach is simple and friendly to the environment. With the assistance of gelatin as a soft biotemplate and a structure-directing agent, star like zinc oxide (ZnO) nanostructures have been prepared by assembly of well defined nanorods under hydrothermal conditions. Their morphology and structures were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), and transmission electron microscopy (TEM). The growth mechanism of the ZnO nanostars is also investigated. The as-prepared ZnO nanostars display high photocatalytic activity toward the degradation of methyl orange (MO) under ultraviolet (UV) irradiation. PMID- 23664390 TI - The enhancement of electron-phonon coupling in glutathione-protected Au25 clusters. AB - Glutathione-protected Au25 clusters (Au25@GSH) are prospective for biological applications due to their biocompatibility and near infrared fluorescence. The weak electron-phonon coupling, however, restricts their applications in bioanalysis and therapeutics. Here we modify the properties of Au25@GSH by changing their ligands. The temperature dependent fluorescence shows that conjugation with different ligands results in modified temperature behavior. In particular, Au25@GSH-MPA evidently exhibits enhanced phonon coupling, therefore, resulting in a decrease in the emission energy and an increase in bandwidth upon increasing temperatures. The enhanced phonon coupling in modified Au25@GSH sheds new light on the future application of nanoclusters from early diagnosis towards therapeutics. PMID- 23664391 TI - Palladium or palladium hydride nanoparticles synthesized by laser ablation of a bulk palladium target in liquids. AB - Laser ablation of a bulk Pd target in DIW, acetone or ethanol was carried out for the production of nanoparticles colloidal solutions. The size distribution of the nanoparticles follows log-normal function for all three liquids, with a median diameter of 3, 1.1 and 1.5 nm and standard deviation of 0.65, 1 and 1, respectively. Amorphous carbon is found on the nanoparticles synthesized in the hydrocarbons (acetone or ethanol). In DIW pure Pd nanoparticles were generated while ablation in acetone or ethanol lead to the synthesis of palladium hydride (PdHx) nanoparticles. These nanoparticles can be used in hydrogen storage applications. PMID- 23664392 TI - SPR studies of the adsorption of silver/bovine serum albumin nanoparticles (Ag/BSA NPs) onto the model biological substrates. AB - The primary objective of this study is to investigate the interactive forces that promote the adsorption of bio-conjugated nanoparticles onto proteins. To elucidate the interactive forces, we demonstrate an approach using synthetic and model biological surfaces to study adsorption of bio-conjugated nanoparticles. Real-time adsorption of BSA conjugated silver nanoparticles (Ag/BSA NPs) on the immobilized substrates was followed by surface plasmon resonance (SPR). The extent of adsorption of the nanoparticles on the synthetic surface was found to be larger for self-assembled monolayers (SAMs) with ionizable terminal groups and lower for SAMs with unionizable terminal groups. For model biological substrate, the extent of nanoparticles adsorption was found to relate to the pKa of immobilized proteins. For collagen immobilized substrate, the adsorption of Ag/BSA nanoparticles showed a significantly higher SPR response than that of free BSA. The extent of nanoparticles adsorption on the collagen immobilized substrate was also influenced by the type and concentration of electrolyte used in dispersing nanoparticles. Our findings indicate that the adsorption of nanoparticles to immobilized surface has contributions from electrostatic interactions, hydrophobic, and/or hydrogen bonding. This work provides the framework to study interactions that may arise when bio-conjugated nanoparticles are transported in biological systems. PMID- 23664393 TI - Surface chemistry and spectroscopy studies on 1,4-naphthoquinone in cell membrane models using Langmuir monolayers. AB - Investigating the role of drugs whose pharmaceutical activity is associated with cell membranes is fundamental to comprehending the biochemical processes that occur on membrane surfaces. In this work, we examined the action of 1,4 naphthoquinone in lipid Langmuir monolayers at the air-water interface, which served as a model for half of a membrane, and investigated the molecular interactions involved with tensiometry and vibrational spectroscopy. The surface pressure-area isotherms exhibited a noticeable shift to a lower area in relation to 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dihexadecanoyl-sn glycero-3-phospho-l-serine (DPPS) lipid monolayers, which indicated a disruption of the monolayer structure and solubilisation of the lipids towards the aqueous subphase. To better correlate to the action of this drug in biological membrane events, cell cultures that represented tumorigenic and non-tumorigenic cells were spread onto the air-water interface, and 1,4-naphthoquinone was then incorporated. While only slight changes were observed in the non-tumorigenic cells upon drug incorporation, significant changes were observed in the tumorigenic cells, on which the organisation of the Langmuir monolayers was disrupted as evidenced by tensiometry and vibrational spectroscopy. This work then shows that this drug interacts preferentially for specific surfaces. In simplified models, it has a higher effect for the negative charged DPPS rather than the zwitterionic DPPC; and for complex cell cultures, 1,4-naphthoquinone presents a more significant effect for that representing tumorigenic cells. PMID- 23664394 TI - Facile and fast synthesis of polyaniline-coated poly(glycidyl methacrylate) core shell microspheres and their electro-responsive characteristics. AB - Electro-responsive core-shell structured particles were fabricated in two steps. In the first step, a spherical and monodisperse poly(glycidyl methacrylate) (PGMA) core was prepared by dispersion polymerization with an epoxy group, which was then functionalized with an amine functional group (ami-PGMA) via an epoxide amine reaction with ethylenediamine. In the second step, a conducting polyaniline (PANI) shell was grafted onto the ami-PGMA surface via the in situ polymerization of an aniline monomer with a uniform thickness. The epoxy group on the PGMA microspheres provided a simple and fast way to react with amine functional groups without the need for a further swelling or grafting process. The morphology of the core-shell structure was confirmed by scanning election microscopy and transmission electron microscopy. The electrorheological properties of the PGMA/PANI particles-based suspension were examined using a Couette-type rotational rheometer under an applied electric field. The shear stress curves were fitted to the Cho-Choi-Jhon (CCJ) model of the rheological equation of state. PMID- 23664395 TI - Tunable macromolecular-based materials for the adsorption of perfluorooctanoic and octanoic acid anions. AB - The sorption properties of tunable urethane-based copolymer materials containing beta-cyclodextrin (beta-CD) were evaluated with perfluorooctanoic acid (PFOA) and octanoic acid (OA) anions in aqueous solutions, respectively. The copolymer materials are herein referred to as macromolecular imprinted materials (MIMs) since their design strategy incorporates a porogen macromolecule (beta-CD) within a cross-linked hexamethylene diisocyanate (HDI) framework. We report the tunable uptake of OA and PFOA anions from aqueous solution with variable adsorption modes, in accordance with the composition of the MIMs. The sorption results with granular activated carbon (GAC) were compared at 295 K and pH values exceeding the pKa values of each adsorbate. The BET and Sips models provided estimates of the monolayer sorption capacity (Qm) and related equilibrium sorption parameters. The Qm value for GAC with PFOA was ~1.4 mmol/g; whereas, a greater Qm value for PFOA (up to 2.6 mmol/g) was observed with the MIMs. GAC displays greater sorption capacity toward PFOA at relatively low Ce values and saturation of the monolayer occurs at Ce~0.5 mM. The MIMs/PFOA system displays monolayer completion at values of Ce~1 mM and multilayer sorption when Ce>1mM. Equilibrium sorption of PFOA onto MIMs occurs at the inclusion sites of beta-CD and interstitial binding sites of the polymeric framework. Surface adsorption of the PFOA anion occurs between the PFOA carboxylate head group and dipolar interstitial domains of the cross-linker framework. The MIMs sorbents display tunable and favorable binding with PFOA and OA anions where the uptake (per mg MIMs) with PFOA was ~5-33% (5 MUM-5 mM) and with OA was ~0.5-5% (1-20 mM). The overall sorptive uptake of OA and PFOA anions by the MIMs sorbents meets or exceeds those observed for GAC. PMID- 23664396 TI - Extracolonic findings on CT colonography: does the benefit outweigh the cost? PMID- 23664397 TI - Combined diffusion-weighted, blood oxygen level-dependent, and dynamic contrast enhanced MRI for characterization and differentiation of renal cell carcinoma. AB - PURPOSE: To investigate a multiparametric magnetic resonance imaging (MRI) approach comprising diffusion-weighted imaging (DWI), blood oxygen-dependent (BOLD), and dynamic contrast-enhanced (DCE) MRI for characterization and differentiation of primary renal cell carcinoma (RCC). MATERIAL AND METHODS: Fourteen patients with clear-cell carcinoma and four patients with papillary RCC were examined with DWI, BOLD MRI, and DCE MRI at 1.5T. The apparent diffusion coefficient (ADC) was calculated with a monoexponential decay. The spin-dephasing rate R2* was derived from parametric R2* maps. DCE-MRI was analyzed using a two compartment exchange model allowing separation of perfusion (plasma flow [FP] and plasma volume [VP]), permeability (permeability surface area product [PS]), and extravascular extracellular volume (VE). Statistical analysis was performed with Wilcoxon signed-rank test, Pearson's correlation coefficient, and receiver operating characteristic curve analysis. RESULTS: Clear-cell RCC showed higher ADC and lower R2* compared to papillary subtypes, but differences were not significant. FP of clear-cell subtypes was significantly higher than in papillary RCC. Perfusion parameters showed moderate but significant inverse correlation with R2*. VE showed moderate inverse correlation with ADC. Fp and Vp showed best sensitivity for histological differentiation. CONCLUSION: Multiparametric MRI comprising DWI, BOLD, and DCE MRI is feasible for assessment of primary RCC. BOLD moderately correlates to DCE MRI-derived perfusion. ADC shows moderate correlation to the extracellular volume, but does not correlate to tumor oxygenation or perfusion. In this preliminary study DCE-MRI appeared superior to BOLD and DWI for histological differentiation. PMID- 23664398 TI - Regional cerebral perfusion alterations in patients with mild cognitive impairment and Alzheimer disease using dynamic susceptibility contrast MRI. AB - RATIONALE AND OBJECTIVES: The purpose of this study was to assess regional cerebral perfusion distribution in patients with Alzheimer disease (AD) or mild cognitive impairment (MCI) using dynamic susceptibility contrast magnetic resonance imaging. MATERIALS AND METHODS: Regional changes of perfusion were evaluated in 34 patients with AD, 51 patients with MCI, and 23 healthy controls (HCs). Using region of interest analyses, regional cerebral blood flow (CBF), cerebral blood volume, and mean transit time were measured bilaterally in the hippocampus; the temporal, temporoparietal, frontal, and sensomotoric cortices; the anterior and posterior cingulate gyri; the lentiform nucleus; and the cerebellum. RESULTS: A significant reduction of CBF in patients with AD compared to HCs was shown in the frontal and temporoparietal cortices bilaterally, the lentiform nuclei bilaterally, the left posterior cingulate gyrus, and the cerebellum. Compared with patients with MCI, patients with AD presented a reduction of CBF in the frontal cortices bilaterally, the left temporoparietal cortex, and the left anterior and posterior cingulate gyrus. In both hippocampi and the posterior cingulate gyrus, a trend to a slight increase of CBF in patients with MCI was noticed with a decrease in patients with AD. CONCLUSIONS: Using dynamic susceptibility contrast magnetic resonance imaging, pathologic alterations of regional brain perfusion can be demonstrated in patients with AD compared to patients with MCI or HCs. PMID- 23664399 TI - The effect of JPEG2000 compression on detection of skull fractures. AB - RATIONAL AND OBJECTIVES: To investigate the effect of the Joint Photographic Experts Group (JPEG2000) 30:1 and 60:1 lossy compression on the detection of cranial vault fractures when compared to JPEG2000 lossless compression. MATERIALS AND METHODS: Fifty cranial computed tomography (CT) images were processed with three different level of JPEG2000 compression (lossless, 30:1 lossy, and 60:1 lossy) creating three sets of images. These were presented to five musculoskeletal specialists and five neuroradiologists. Each reader read at two of the three compression levels. Twenty-two cases contained a single fracture; the remaining 28 cases contained no fractures. Observers were asked to identify the presence or absence of a fracture, to locate its site, and rate their degree of confidence. Receiver operating characteristic (ROC), jackknife free-response receiver operating characteristic (JAFROC) and the Dorfman-Berbaum-Metz multiple reader multiple case (DBM-MRMC) analyses were used to explore differences between the lossless and lossy compressed images. RESULTS: JPEG2000 lossless and 30:1 lossy compression demonstrated no significant difference in their performance with JAFROC and DBM-MRMC analysis (P < .416); however, JPEG2000 30:1 lossy compression demonstrated significantly better performance than 60:1 lossy compression (P < .016). A significant increase in misplaced confidence ratings was also seen with 60:1 (P < .037) over 30:1 lossy and lossless compression. CONCLUSION: JPEG2000 60:1 compression degrades the detection of skull fractures significantly while increasing the confidence with which readers rate fractures compared with 30:1 lossy and lossless compression. JPEG2000 30:1 lossy compression does not significantly change performance when compared to JPEG2000 lossless for the detection of skull fractures on CT. PMID- 23664400 TI - Establishing a gold standard for test sets: variation in interpretive agreement of expert mammographers. AB - RATIONALE AND OBJECTIVES: Test sets for assessing and improving radiologic image interpretation have been used for decades and typically evaluate performance relative to gold standard interpretations by experts. To assess test sets for screening mammography, a gold standard for whether a woman should be recalled for additional workup is needed, given that interval cancers may be occult on mammography and some findings ultimately determined to be benign require additional imaging to determine if biopsy is warranted. Using experts to set a gold standard assumes little variation occurs in their interpretations, but this has not been explicitly studied in mammography. MATERIALS AND METHODS: Using digitized films from 314 screening mammography exams (n = 143 cancer cases) performed in the Breast Cancer Surveillance Consortium, we evaluated interpretive agreement among three expert radiologists who independently assessed whether each examination should be recalled, and the lesion location, finding type (mass, calcification, asymmetric density, or architectural distortion), and interpretive difficulty in the recalled images. RESULTS: Agreement among the three expert pairs for recall/no recall was higher for cancer cases (mean 74.3 +/- 6.5) than for noncancers (mean 62.6 +/- 7.1). Complete agreement on recall, lesion location, finding type and difficulty ranged from 36.4% to 42.0% for cancer cases and from 43.9% to 65.6% for noncancer cases. Two of three experts agreed on recall and lesion location for 95.1% of cancer cases and 91.8% of noncancer cases, but all three experts agreed on only 55.2% of cancer cases and 42.1% of noncancer cases. CONCLUSION: Variability in expert interpretive is notable. A minimum of three independent experts combined with a consensus should be used for establishing any gold standard interpretation for test sets, especially for noncancer cases. PMID- 23664402 TI - Template-driven computed tomography radiation dose reporting: implementation of a radiology housestaff quality improvement project. AB - RATIONALE AND OBJECTIVES: Radiation exposure from medical imaging has received increasing attention in recent years. Ongoing calls to report radiation doses received during radiology studies as a means of recording cumulative exposure and identifying rare over-exposures have culminated in the State of California passing a mandatory reporting requirement effective July 1, 2012. Herein we describe a radiology housestaff-led quality improvement project to track radiation dose reporting a full year prior to state reporting mandates using a template-driven reporting system and our results over the first 12 months of its implementation. MATERIALS AND METHODS: Effective July 2011, all radiology trainees were instructed to use a standard computed tomography (CT) report template that included a CT dose measurement derived from dose information routinely displayed on our picture archiving and communication system. Consecutive reports from July 1, 2011, to June 30, 2012, of patients who underwent CT examinations at our institution were then retrospectively reviewed. Compliance of each study with the reporting requirement was assessed based on the presence or absence of a radiation dose statement within the finalized report. RESULTS: A total of 36,217 eligible consecutive CT reports were identified within the review period. Of these, 91.9% reported the radiation dose for the examination, greatly exceeding the initial goal of 80% compliance with the dose reporting requirement. CONCLUSION: Successful reporting of CT radiation doses resulted from template-driven reporting, readily accessible calculation tools to facilitate dose calculation, and minimization of reporting burden on the radiologist a full year prior to state regulatory mandates. PMID- 23664401 TI - Redox imaging of human breast cancer core biopsies: a preliminary investigation. AB - RATIONALE AND OBJECTIVES: The clinical gold standard for breast cancer diagnosis relies on invasive biopsies followed by tissue fixation for subsequent histopathological examination. This process renders the specimens to be much less suitable for biochemical or metabolic analysis. Our previous metabolic imaging data in tumor xenograft models showed that the mitochondrial redox state is a sensitive indicator that can distinguish between normal and tumor tissue. In this study, we investigated whether the same redox imaging technique can be applied to core biopsy samples of human breast cancer and whether the mitochondrial redox state may serve as a novel metabolic biomarker that may be used to distinguish between normal and malignant breast tissue in the clinic. Our long-term objective was to identify novel metabolic imaging biomarkers for breast cancer diagnosis. MATERIALS AND METHODS: Both normal and cancerous tissue specimens were collected from the cancer-bearing breasts of three patients shortly after surgical resection. Core biopsies and tissue blocks were obtained from tumor and normal adjacent breast tissue, respectively. All specimens were snap-frozen with liquid nitrogen, embedded in chilled mounting medium with flavin adenine dinucleotide and reduced nicotinamide adenine dinucleotide reference standards adjacently placed, and scanned using the Chance redox scanner (ie, cryogenic nicotinamide adenine dinucleotide/oxidized flavoprotein fluorescence imager). RESULTS: Our preliminary data showed cancerous tissues had up to 10-fold higher oxidized flavoprotein signals and had elevated oxidized redox state compared to the normal tissues from the same patient. A high degree of tumor tissue heterogeneity in the redox indices was observed. CONCLUSIONS: Our finding suggests that the identified redox imaging indices could differentiate between cancer and noncancer breast tissues without subjecting tissues to fixatives. We propose that this novel redox scanning procedure may assist in tissue diagnosis in freshly procured biopsy samples before tissue fixation. PMID- 23664404 TI - Learning to handle conflict: insights from chimps and bonobos. PMID- 23664403 TI - Enhancing patients' experiences in radiology: through patient-radiologist interaction. AB - In this survey-based study, we attempted to gain deeper insights into the perspectives of patients in a contemporary radiology department. How well do they understand the role of radiologists in their care? What role(s) would they like radiologists to play? Specifically, do they value the opportunity to interact directly with radiologists? And what effect do such encounters have on their assessments of the quality of their care experiences in the radiology department? PMID- 23664405 TI - Driving deeper learning by assessment: an adaptation of the Revised Bloom's Taxonomy for medical imaging in gross anatomy. AB - RATIONALE AND OBJECTIVES: As medical imaging continues to grow as a central modality by which physicians of all specialties visualize anatomy, so, too, is its role in medical student education. However, no study to our knowledge has attempted to categorize the necessary cognitive skills. Here, we assess a tool to identify those skills and their possible hierarchical nature that reflects deeper understanding of radiological anatomy. MATERIALS AND METHODS: We adapted the revision of Bloom's Taxonomy of Educational Objectives to create examination questions and teaching points for normal radiological anatomy in a medical anatomy course in 2008. All six previously established levels of cognitive processes were adapted, ranging from Remembering to Create. Reliability and validity were assessed. RESULTS: Of 102 eligible students, 98 (98%) consented to participate, and 108 examination questions were assessed. Cronbach alpha assessing reliability ranged from poor (.197) to moderate (.571) with most categories being moderate. Score means for the levels of cognitive processes were statistically distinct [F(4, 102) = 180.63, P < .001] and tended to decrease as the level of cognitive process increased [Spearman rho(5) = -.800, P = .104], consistent with a valid hierarchical structure. CONCLUSIONS: A radiological anatomy adaptation of the revised taxonomy demonstrated generally adequate reliability and acceptable validity to establish evaluations that test different depths of cognitive processes. This is a critical first step to create a fundamental curricular tool by which medical imaging education-both normal and pathological-may be taught and assessed in the future. PMID- 23664406 TI - Half a century of work for radiology. PMID- 23664407 TI - Superficial siderosis of the central nervous system due to chronic hemorrhage from a giant invasive prolactinoma. AB - Superficial siderosis of the central nervous system (CNS) is a rare disorder caused by deposition of hemosiderin in neuronal tissue in the subpial layer of the CNS due to slow subarachnoid or intraventricular hemorrhage. The most common neurologic manifestations include progressive gait ataxia, sensorineural hearing loss, and corticospinal tract signs. We present a case of superficial siderosis in a 43-year-old man who presented to the Emergency Department with sudden onset bilateral visual deterioration and a loss of consciousness. A hemorrhagic giant prolactinoma was diagnosed based on brain CT scan, T1-weighted MRI, and an endocrine blood examination. Susceptibility-weighted non-contrast MRI showed pathognomonic signs of superficial siderosis in the form of a hypointensity rim surrounding the brainstem, cerebellar fissures, and cranial nerves VII and VIII. This report demonstrates that superficial siderosis can be caused by pituitary apoplexy. PMID- 23664408 TI - Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing caused by a pituitary adenoma. AB - Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) syndrome is a rare primary headache syndrome first described in 1978. We report on a 43-year-old man with a 10 year history of SUNCT in whom a pituitary macroadenoma was eventually detected. His pain rapidly improved with medical treatment of the prolactinoma and we propose that this is a case of symptomatic SUNCT. PMID- 23664409 TI - Hyperdense middle cerebral artery sign is associated with increased risk of hemorrhagic transformation after intravenous thrombolysis for patients with acute ischaemic stroke. AB - Haemorrhagic transformation (HT) is an infrequent but serious complication of intravenous thrombolysis therapy (IVT) for acute ischemic stroke. The hyperdense middle cerebral artery sign (HMCAS) is a possible radiological predictor. We aimed to assess the association between HMCAS and HT in a retrospective study. We included all patients with acute anterior circulation ischaemic stroke who received IVT between October 2007 and December 2011. Baseline characteristics were collected, including demographics, stroke risk factors and stroke type. Presence of HMCAS on baseline CT scans was evaluated. Follow-up CT scans were examined for HT, categorised according to the European Australasian Acute Stroke Study (ECASS) classification. The presence of symptomatic intracerebral haemorrhage (sICH) was defined according to Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST) criteria. The association between HT and HMCAS was assessed by univariate and multivariate logistic regression analysis. We included 182 consecutive patients treated with IVT in this study. HMCAS was present in 70 patients (38.5%). Patients with HMCAS had higher baseline National Institutes of Health Stroke Scale scores (p<0.001) and more frequent early ischaemic changes on baseline CT scan (p<0.001) than those without HMCAS. We identified 49 instances (26.9%) of HT in 182 follow-up CT scans. HMCAS was associated with HT in univariate analysis (unadjusted odds ratio [OR]=4.151, 95% confidence interval [CI]: 2.081-8.279, p<0.001) and remained an independent risk factor of HT in multivariate analysis (adjusted OR=2.691, 95% CI: 1.231-5.882, p=0.013). There was no statistically significant difference in the frequency of sICH between the HMCAS group and the non-HMCAS group. We concluded that HMCAS is common in anterior circulation infarction and is independently predictive of HT after thrombolytic therapy. PMID- 23664410 TI - Swedish review strengthens grounds for concluding that radiation from cellular and cordless phones is a probable human carcinogen. AB - With 5.9 billion reported users, mobile phones constitute a new, ubiquitous and rapidly growing exposure worldwide. Mobile phones are two-way microwave radios that also emit low levels of electromagnetic radiation. Inconsistent results have been published on potential risks of brain tumors tied with mobile phone use as a result of important methodological differences in study design and statistical power. Some studies have examined mobile phone users for periods of time that are too short to detect an increased risk of brain cancer, while others have misclassified exposures by placing those with exposures to microwave radiation from cordless phones in the control group, or failing to attribute such exposures in the cases. In 2011, the World Health Organization, International Agency for Research on Cancer (IARC) advised that electromagnetic radiation from mobile phone and other wireless devices constitutes a "possible human carcinogen," 2B. Recent analyses not considered in the IARC review that take into account these methodological shortcomings from a number of authors find that brain tumor risk is significantly elevated for those who have used mobile phones for at least a decade. Studies carried out in Sweden indicate that those who begin using either cordless or mobile phones regularly before age 20 have greater than a fourfold increased risk of ipsilateral glioma. Given that treatment for a single case of brain cancer can cost between $100,000 for radiation therapy alone and up to $1 million depending on drug costs, resources to address this illness are already in short supply and not universally available in either developing or developed countries. Significant additional shortages in oncology services are expected at the current growth of cancer. No other environmental carcinogen has produced evidence of an increased risk in just one decade. Empirical data have shown a difference in the dielectric properties of tissues as a function of age, mostly due to the higher water content in children's tissues. High resolution computerized models based on human imaging data suggest that children are indeed more susceptible to the effects of EMF exposure at microwave frequencies. If the increased brain cancer risk found in young users in these recent studies does apply at the global level, the gap between supply and demand for oncology services will continue to widen. Many nations, phone manufacturers, and expert groups, advise prevention in light of these concerns by taking the simple precaution of "distance" to minimize exposures to the brain and body. We note than brain cancer is the proverbial "tip of the iceberg"; the rest of the body is also showing effects other than cancers. PMID- 23664411 TI - Role of molting on the biodistribution of CeO2 nanoparticles within Daphnia pulex. AB - As all arthropods, microcrustaceans shed their chitinous exoskeleton (cuticule, peritrophic membrane) to develop and grow. While the molting is the most crucial stage in their life cycle, it remains poorly investigated in term of pollutant biodistribution within the organisms. In this paper, we used optical, electronic, and X ray-based microscopies to study the uptake and release of CeO2 nanoparticles by/from Daphnia pulex over a molting stage. We measured that D. pulex molts every 59 +/- 21 h (confidence interval) with growth rates about 1.1 or 1.8 MUm per stage as a function of the pieces measured. Ingestion via food chain was the main route of CeO2 nanoparticles uptake by D. pulex. The presence of algae during the exposure to nanoparticles (sub-lethal doses) enhanced by a factor of 3 the dry weight concentration of Ce on the whole D. pulex. Nanoparticles were localized in the gut content, in direct contact with the peritrophic membrane, and on the cuticle. Interestingly, the depuration (24 h with Chlorella pseudomonas) was not efficient to remove the nanoparticles from the organisms. From 40% to 100% (depending on the feeding regime during exposure) of the CeO2 taken up by D. pulex is not release after the depuration process. However, we demonstrated for the first time that the shedding of the chitinous exoskeleton was the crucial mechanism governing the released of CeO2 nanoparticles regardless of the feeding regime during exposure. PMID- 23664412 TI - Photodynamic therapy in mycosis fungoides. AB - Photodynamic therapy involves the topical application of a photosensitizer to a lesion, which is then subsequently exposed to a light source. It is mainly used in the nonsurgical treatment of nonmelanoma skin cancer, in which it achieves good response and an excellent cosmetic result. In the last 10 years, photodynamic therapy has also been used with some success in the treatment of plaque-stage mycosis fungoides and has emerged as an alternative to skin-directed therapies. Its main advantages are the good response to treatment, lack of toxicity, and excellent cosmetic results. This article reviews the literature and the practical application of photodynamic therapy in mycosis fungoides. PMID- 23664413 TI - Spectral analysis of intracranial pressure signals recorded during infusion studies in patients with hydrocephalus. AB - Hydrocephalus includes a number of disorders characterised by clinical symptoms, enlarged ventricles (observable using neuroimaging techniques) and altered cerebrospinal fluid (CSF) dynamics. Infusion tests are one of the available procedures to study CSF circulation in patients with clinical and radiological features of hydrocephalus. In them, intracranial pressure (ICP) is deliberately raised and CSF circulation disorders evaluated through measurements of the resulting ICP. In this study, we analysed seventy-seven ICP signals recorded during infusion tests using four spectral-based parameters: median frequency (MF) and relative power (RP) in three frequency bands. These measures provide a novel perspective for the analysis of ICP signals in the frequency domain. Each signal was divided into four artefact-free epochs (corresponding to the basal, early infusion, plateau and recovery phases of the infusion study). The four spectral parameters were calculated for each epoch. We analysed differences between epochs of the infusion test and correlations between these epochs and patient data. Statistically significant differences (p < 1.7 * 10(-3), Bonferroni-corrected Wilcoxon signed-rank tests) were found between epochs of the infusion test using MF and RP. Furthermore, some spectral parameters (MF in the basal phase, RP for the first frequency band and in the early infusion phase, RP for the second frequency band and in all phases of the infusion study and RP in the third frequency band and in the basal phase) revealed significant correlations (p < 0.01) between epochs of the infusion test and signal amplitude in the basal and plateau phases. Our results suggest that spectral analysis of ICP signals could be useful for understanding CSF dynamics in hydrocephalus. PMID- 23664415 TI - Regulation of cytoskeletal dynamics by phospholipase D and phosphatidic acid. AB - Plants respond to diverse biotic and abiotic stimuli as well as to endogenous developmental cues. Many of these stimuli result in altered activity of phospholipase D (PLD), an enzyme that hydrolyzes structural phospholipids producing phosphatidic acid (PA). PA is a key signaling intermediate in animals, but its targets in plants are relatively uncharacterized. Recent studies have demonstrated that the cytoskeleton is a major target of PLD-PA signaling and identified a positive feedback loop between actin turnover and PLD activity. Moreover, two cytoskeletal proteins, capping protein and MAP65-1, have been identified as PA-binding proteins regulating actin and microtubule organization and dynamics. In this review, we highlight the role of the PLD-PA module as an important hub for housekeeping and stress-induced regulation of membrane associated cytoskeletal dynamics. PMID- 23664414 TI - Brain serotonin 1A receptor binding as a predictor of treatment outcome in major depressive disorder. AB - BACKGROUND: We previously reported higher serotonin 1A receptor (5-HT1A) binding in subjects with major depressive disorder (MDD) during a major depressive episode using positron emission tomography imaging with [(11)C]WAY-100635. 5-HT1A receptor binding is also associated with treatment outcome after nonstandardized antidepressant treatment. We examined whether pretreatment 5-HT1A binding is associated with treatment outcome following standardized escitalopram treatment in MDD. We also compared 5-HT1A binding between all MDD subjects in this cohort and a sample of healthy control subjects. METHODS: Twenty-four MDD subjects in a current major depressive episode and 51 previously studied healthy control subjects underwent positron emission tomography scanning with [(11)C]WAY-100635, acquiring a metabolite-corrected arterial input function and free-fraction measurement to estimate 5-HT1A binding potential (BPF = Bmax/KD, where Bmax = available receptors and KD = dissociation constant). Major depressive disorder subjects then received 8 weeks of treatment with escitalopram; remission was defined as a posttreatment 24-item Hamilton Depression Rating Scale <10 and >= 50% reduction in Hamilton Depression Rating Scale. RESULTS: Remitters to escitalopram had 33% higher baseline 5-HT1A binding in the raphe nuclei than nonremitters (p = .047). Across 12 cortical and subcortical regions, 5-HT1A binding did not differ between remitters and nonremitters (p = .86). Serotonin 1A receptor binding was higher in MDD than control subjects across all regions (p = .0003). Remitters did not differ from nonremitters in several relevant clinical measures. CONCLUSIONS: Elevated 5-HT1A binding in raphe nuclei is associated with subsequent remission with the selective serotonin reuptake inhibitor escitalopram; this is consistent with data from a separate cohort receiving naturalistic antidepressant treatment. We confirmed our previous findings of higher 5-HT1A binding in current MDD compared with control subjects. PMID- 23664416 TI - United for strength and growth. PMID- 23664417 TI - Strengthening nursing's voice. PMID- 23664418 TI - Response to 60th anniversary issue of Nursing Outlook. PMID- 23664419 TI - Stress and nurses' horizontal mobbing: moderating effects of group identity and group support. AB - Horizontal mobbing is a process of systematic and repeated aggression towards a worker by coworkers. Among others, stress has been pointed out as one of the antecedents that favors the onset of horizontal mobbing, whereas group support to the target could act as a buffer. Moreover, the social identity approach emphasizes that group identity is an antecedent of group support. This study explores the interaction of group support and group identity in the explanation of horizontal mobbing in a sample (N = 388) of registered nurses and licensed practical nurses employed at two large hospitals in Madrid and Navarre (Spain). The results show that stress is positively associated to horizontal mobbing, whereas group support and group identity were negative predictors of horizontal mobbing. Furthermore, the combination of low group identity and low group support precipitated HM among nurses. PMID- 23664420 TI - Screening for maternal coeliac disease as a potential risk factor for orofacial clefts--a pilot study. AB - There is increasing evidence that dietary folic acid deficiency in utero may increase the risk of developing the 'cleft lip with or without cleft palate' (CL+/-P) variant of orofacial cleft. Coeliac disease is a common cause of folic acid malabsorption, and in the majority of cases remains undiagnosed. This pilot study assessed the seroprevalence of undiagnosed coeliac disease in a cohort of mothers of infants with CL+/-P in the Hyderabad area of India. The seroprevalence of coeliac disease of 1.15% (95% confidence interval 0.37-2.66%) was little different from the expected figure based on published population studies, making a clinically significant association unlikely. PMID- 23664421 TI - Hereditary spherocytosis, elliptocytosis, and other red cell membrane disorders. AB - Hereditary spherocytosis and elliptocytosis are the two most common inherited red cell membrane disorders resulting from mutations in genes encoding various red cell membrane and skeletal proteins. Red cell membrane, a composite structure composed of lipid bilayer linked to spectrin-based membrane skeleton is responsible for the unique features of flexibility and mechanical stability of the cell. Defects in various proteins involved in linking the lipid bilayer to membrane skeleton result in loss in membrane cohesion leading to surface area loss and hereditary spherocytosis while defects in proteins involved in lateral interactions of the spectrin-based skeleton lead to decreased mechanical stability, membrane fragmentation and hereditary elliptocytosis. The disease severity is primarily dependent on the extent of membrane surface area loss. Both these diseases can be readily diagnosed by various laboratory approaches that include red blood cell cytology, flow cytometry, ektacytometry, electrophoresis of the red cell membrane proteins, and mutational analysis of gene encoding red cell membrane proteins. PMID- 23664422 TI - A prospective patient-centred evaluation of urethroplasty for anterior urethral stricture using a validated patient-reported outcome measure. AB - BACKGROUND: Studies of interventions for urethral stricture have inferred patient benefit from clinician-driven outcomes or questionnaires lacking scientifically robust evidence of their measurement properties for men with this disease. OBJECTIVE: To evaluate urethral reconstruction from the patients' perspective using a validated patient-reported outcome measure (PROM). DESIGN, SETTING, AND PARTICIPANTS: Forty-six men with anterior urethral stricture at four UK urology centres completed the PROM before (baseline) and 2 yr after urethroplasty. INTERVENTION: A psychometrically robust PROM for men with urethral stricture disease. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Lower urinary tract symptoms (LUTS), health status, and treatment satisfaction were measured, and paired t and Wilcoxon matched-pairs tests were used for comparative analysis. RESULTS AND LIMITATIONS: Thirty-eight men underwent urethroplasty for bulbar stricture and eight for penile stricture. The median (range) follow-up was 25 (20 30) mo. Total LUTS scores (0 = least symptomatic, 24 = most symptomatic) improved from a median of 12 at baseline to 4 at 2 yr (mean [95% confidence interval (CI)] of differences 6.6 [4.2-9.1], p < 0.0001). A total of 33 men (72%) felt their urinary symptoms interfered less with their overall quality of life, 8 (17%) reported no change, and 5 (11%) were worse 2 yr after urethroplasty. Overall, 40 men (87%) remained "satisfied" or "very satisfied" with the outcome of their operation. Health status visual analogue scale scores (100 = best imaginable health, 0 = worst) 2 yr after urethroplasty improved from a mean of 69 at baseline to 79 (mean [95% CI] of differences 10 [2-18], p = 0.018). Health state index scores (1 = full health, 0 = dead) improved from 0.79 at baseline to 0.89 at 2 yr (mean [95% CI] of differences 0.10 [0.02-0.18), p = 0.012]). CONCLUSIONS: This is the first study to prospectively evaluate urethral reconstruction using a validated PROM. Men reported continued relief from symptoms with related improvements in overall health status 2 yr after urethroplasty. These data can be used as a provisional reference point against which urethral surgeons can benchmark their performance. PMID- 23664424 TI - Up-regulation of matrix metalloproteinases-2 and -9 via an Erk1/2/NF-kappaB pathway in murine mast cells infected with Toxoplasma gondii. AB - Mast cells are key effectors in inflammation and contain proteinases that are released on activation. This study investigates associations between extracellular signal-regulated kinase (Erk)1/2, nuclear factor (NF)-kappaB, matrix metalloproteinase (MMP)-2 and MMP-9 in mast cells infected with Toxoplasma gondii tachyzoites. T. gondii infection led to increased mast cell degranulation. Phosphorylated (p)-Erk1/2 and p-NF-kappaB were increased significantly in mast cells infected with T. gondii. Pretreatment with the Erk kinase inhibitor PD98059 significantly decreased the expression of p-Erk1/2, p-NF-kappaB, MMP-2 and MMP-9. Treatment with MG132, an indirect NF-kappaB inhibitor, effectively reduced p IkappaBalpha, p-NF-kappaB, MMP-2 and MMP-9 expression. Collectively, these data show that suppression of an Erk1/2/NF-kappaB signalling pathway caused a reduction in MMP-2 and -9 activities. Inhibiting this signalling pathway for MMP 2 and MMP-9 expression might offer a potential way to control early T. gondii infection. This pathway for the generation of MMP-2 and MMP-9 is important for mast cell secretion and the NF-kappaB/Erk1/2 signalling pathway may be key in MMP 2 and MMP-9 production in host defense against toxoplasmosis. PMID- 23664423 TI - A systematic review of the volume-outcome relationship for radical prostatectomy. AB - CONTEXT: Due to the complexity and challenging nature of radical prostatectomy (RP), it is likely that both short- and long-term outcomes strongly depend on the cumulative number of cases performed by the surgeon as well as by the hospital. OBJECTIVE: To review systematically the association between hospital and surgeon volume and perioperative, oncologic, and functional outcomes after RP. EVIDENCE ACQUISITION: A systematic review of the literature was performed, searching PubMed, Embase, and Scopus databases for original and review articles between January 1, 1995, and December 31, 2011. Inclusion and exclusion criteria comprised RP, hospital and/or surgeon volume reported as a predictor variable, a measurable end point, and a description of multiple hospitals or surgeons. EVIDENCE SYNTHESIS: Overall 45 publications fulfilled the inclusion criteria, where most data originated from retrospective institutional or population-based cohorts. Studies generally focused on hospital or surgeon volume separately. Although most of these analyses corroborated the impact of increasing volume with better outcomes, some failed to find any significant effect. Studies also differed with respect to the proposed volume cut-off for improved outcomes, as well as the statistical means of evaluating the volume-outcome relationship. Five studies simultaneously compared hospital and surgeon volume, where results suggest that the importance of either hospital or surgeon volume largely depends on the end point of interest. CONCLUSIONS: Undeniable evidence suggests that increasing volume improves outcomes. Although it would seem reasonable to refer RP patients to high-volume centers, such regionalization may not be entirely practical. As such, the implications of such a shift in practice have yet to be fully determined and warrant further exploration. PMID- 23664425 TI - Immunohistochemical characterization of the hepatic progenitor cell compartment in medaka (Oryzias latipes) following hepatic injury. AB - Laboratory fish species are used increasingly in biomedical research and are considered robust models for the study of regenerative processes. Studies investigating the response of the fish liver to injury have demonstrated the presence of a ductular reaction and oval-like cells in injured and regenerating liver. To date, however, it is unclear if this cell population is the piscine equivalent of oval cells (OCs) or intermediate hepatobiliary cells (IHBCs) identified in rodents and man, respectively. The present study defines the process of OC differentiation in fish liver using histopathology, immunohistochemistry and transmission electron microscopy. To generate OC proliferation in Japanese medaka (Oryzias latipes), hepatic injury was induced by exposure of adult fish to either microcystin LR or dimethylnitrosamine. A transgenic strain of medaka expressing a red fluorescent protein (RFP) exclusively in hepatocytes was used. The morphological response to injury was characterized by a ductular reaction comprised of cytokeratin (CK) AE1/AE3(+) OCs progressing to IHBCs variably positive for CK and RFP and finally mature RFP(+) hepatocytes and CK(+) cholangiocytes. These observations support a bipotential differentiation pathway of fish OCs towards hepatocytes and cholangiocytes. Ultrastructural morphology confirmed the presence of OCs and differentiation towards hepatocytes. These results demonstrated clear similarities between patterns of reaction to injury in fish and mammalian livers. They also confirm the presence of, and support the putative bipotential lineage capabilities of, the fish OC. PMID- 23664426 TI - Expression of the thrombopoietin gene in tissues from healthy dogs. AB - Thrombopoietin (THPO) is the major cytokine that regulates megakaryopoiesis and platelet production. Several human and murine studies have demonstrated that THPO is primarily synthesized in the liver, but the kidney, spleen and bone marrow are also sites of expression. The aim of this study was to determine THPO mRNA levels in a range of canine tissues by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). Samples of bone marrow (n = 5), liver (n = 10), lung (n = 10), renal cortex (n = 10), renal medulla (n = 5) and spleen (n = 10) were obtained from 10 healthy, hound-cross dogs aged 6-8 months. The highest THPO mRNA levels were found in the liver, followed by the bone marrow, spleen, lung and kidney. There was a 13-fold difference in expression between liver and kidney. The bone marrow showed high levels of THPO mRNA in the absence of disease. The liver and bone marrow are likely to be the major sites of THPO production in the dog. PMID- 23664427 TI - Clinical and radiological results of femoral head structural allograft for severe bone defects in revision TKA--a minimum 8-year follow-up. AB - BACKGROUND: Proper treatment of bone loss is essential for the long term durability of revision TKA. However, the method of choice in managing large bone defects is still under debate. We therefore assessed the mid to long term clinical and radiographic results of revision TKA using a fresh frozen femoral head allograft and a standard condylar implant or varus-valgus constrained prosthesis with a diaphyseal-engaging stem. METHODS: We retrospectively reviewed the records of 27 patients who had undergone revision TKA between August 1997 and March 2003 using a fresh frozen femoral head allograft and a standard condylar implant or varus-valgus constrained prosthesis with a diaphyseal-engaging stem. The median follow-up period was 107 months (range, 96-157 months). RESULTS: Clinical evaluation revealed that the mean range of motion had increased from 71 degrees to 113 degrees and the mean Hospital for Special Surgery knee score had improved from 46 to 83 points. The overall tibio-femoral angle improved from varus 7.3 degrees to valgus 6.l degrees . In 26 out of 27 knees, union was demonstrated at an average of seven months postoperatively, and there were no cases of collapse, disease transmission or stress fractures. In one knee, an infection recurred. CONCLUSIONS: Our results demonstrate that femoral head allografts in treatment of severe bone defects are reliable and durable. If possible, less constrained prostheses with diaphyseal-engaging stems should be chosen for increased durability. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 23664428 TI - [Colorectal cancer in Spain: Temporary disability and preventive occupational strategies]. AB - BACKGROUND: Colorectal cancer is one of the most frequent cancers in both sexes and the most frequent in the developed countries, if men and women are considered together as a group. It has an important associated morbidity and mortality in all countries and constitutes a public health problem with a high direct and indirect economic cost. The number of workdays lost due to temporary disability (TD) is one of the quantifiable references of these indirect costs. AIMS: To determine the indirect cost associated with TD due to colorectal cancer in Spain during the year 2011, a cost that aids in the prevention cost/benefit estimation. METHODS: The number of TD processes, the number of workdays lost due to TD, and the mean duration of those processes, based on the CIE 9-MC codes related to this pathology, as well as the calculated cost, using the Spanish minimum wage as a reference, during the period of January to December 2011, were all reviewed. RESULTS: Colorectal cancer in Spain during 2011 represented 1,046 TD processes, 202,784 workdays lost, and a mean process duration of 194 days/year. The resulting cost of the pathology due to TD was 4,335,521.92 euros. CONCLUSIONS: These results are beneficial for evaluating the usefulness of implementing public health support strategies for a greater reduction in colorectal cancer prevalence and mortality, and an improvement in quality of life of the affected individuals and their families, together with an economic savings resulting from a reduction in TD as a consequence of this disease. PMID- 23664429 TI - [Mexican consensus on portal hypertension]. AB - The aim of the Mexican Consensus on Portal Hypertension was to develop documented guidelines to facilitate clinical practice when dealing with key events of the patient presenting with portal hypertension and variceal bleeding. The panel of experts was made up of Mexican gastroenterologists, hepatologists, and endoscopists, all distinguished professionals. The document analyzes themes of interest in the following modules: preprimary and primary prophylaxis, acute variceal hemorrhage, and secondary prophylaxis. The management of variceal bleeding has improved considerably in recent years. Current information indicates that the general management of the cirrhotic patient presenting with variceal bleeding should be carried out by a multidisciplinary team, with such an approach playing a major role in the final outcome. The combination of drug and endoscopic therapies is recommended for initial management; vasoactive drugs should be started as soon as variceal bleeding is suspected and maintained for 5 days. After the patient is stabilized, urgent diagnostic endoscopy should be carried out by a qualified endoscopist, who then performs the corresponding endoscopic variceal treatment. Antibiotic prophylaxis should be regarded as an integral part of treatment, started upon hospital admittance and continued for 5 days. If there is treatment failure, rescue therapies should be carried out immediately, taking into account that interventional radiology therapies are very effective in controlling refractory variceal bleeding. These guidelines have been developed for the purpose of achieving greater clinical efficacy and are based on the best evidence of portal hypertension that is presently available. PMID- 23664430 TI - Intrascrotal lipoblastoma: a report of two cases and a review of the literature. AB - Lipoblastomas are rare benign mesenchymal tumors of fetal white fat tissue appearing most commonly in children under 3 years of age, and usually affecting the extremities. Only nine cases of intrascrotal lipoblastoma have been reported to our knowledge, and although they are benign, in one case an orchidectomy was performed. We describe two new cases of intrascrotal lipoblastoma, and review the literature. PMID- 23664431 TI - Management of external ear melanoma: the same or something different? AB - BACKGROUND: The external ear represents a site with high ultraviolet exposure and thin skin overlying cartilage. The aim of this study was to determine if ear melanomas have different characteristics than cutaneous melanomas in other anatomic sites. METHODS: The evaluation of patients treated at a tertiary care center. RESULTS: Sixty patients were treated for ear melanoma (87% male, mean age = 56.7, mean thickness = 1.65 mm). Seven of thirty-two patients (22%) who underwent sentinel lymph node biopsy had positive nodes. Twenty (33%) patients had recurrence including 6 patients with negative sentinel lymph nodes (SLNs) and 5 patients with positive SLNs. Three of 10 patients (30%) treated with Mohs surgery had local recurrence. CONCLUSIONS: The overall local and systemic recurrences are similar to those previously reported. There is a higher recurrence rate than expected in patients with a negative SLN and a high local recurrence rate after Mohs surgery. Our data suggest that SLN evaluation may be less accurate in ear melanomas and that Mohs surgery may be associated with a relatively high local recurrence rate. PMID- 23664432 TI - Dynamic time warping improves sewer flow monitoring. AB - Successful management and control of wastewater and storm water systems requires accurate sewer flow measurements. Unfortunately, the harsh sewer environment and insufficient flow meter calibration often lead to inaccurate and biased data. In this paper, we improve sewer flow monitoring by creating redundant information on sewer velocity from natural wastewater tracers. Continuous water quality measurements upstream and downstream of a sewer section are used to estimate the travel time based on i) cross-correlation (XCORR) and ii) dynamic time warping (DTW). DTW is a modern data mining technique that warps two measured time series non-linearly in the time domain so that the dissimilarity between the two is minimized. It has not been applied in this context before. From numerical experiments we can show that DTW outperforms XCORR, because it provides more accurate velocity estimates, with an error of about 7% under typical conditions, at a higher temporal resolution. In addition, we can show that pre-processing of the data is important and that tracer reaction in the sewer reach is critical. As dispersion is generally small, the distance between the sensors is less influential if it is known precisely. Considering these findings, we tested the methods on a real-world sewer to check the performance of two different sewer flow meters based on temperature measurements. Here, we were able to detect that one of two flow meters was not performing satisfactorily under a variety of flow conditions. Although theoretical analyses show that XCORR and DTW velocity estimates contain systematic errors due to dispersion and reaction processes, these are usually small and do not limit the applicability of the approach. PMID- 23664433 TI - Intrapartum care could be improved according to Swedish fathers: mode of birth matters for satisfaction. AB - BACKGROUND: Intrapartum care is expected to be shaped by parents' need and preferences. AIM: The aim was to explore Swedish fathers' intrapartum care quality experiences, with a specific focus on care deficiencies in relation to birth mode. A secondary aim was to explore which issues of quality that contributed most to dissatisfaction with the overall assessment of the care. METHODS: Cross-sectional design, part of a prospective longitudinal survey in Sweden. A quality of care index was developed, based on perceived reality and subjective importance of given intrapartum care. Two months after birth 827 fathers answered nine questions related to quality of care. Descriptive statistics and logistic regression analysis were used. RESULTS: Dissatisfaction with overall intrapartum care was related to deficiencies in partner's medical care (OR 5.6; 2.7-11.2), involvement in decision-making during childbirth (OR 2.6; 1.3-4.9), midwives presence in the labour room (OR 2.4; 1.2-4.7), and ability to discuss the birth afterwards (OR 2.0; 1.1-3.8). After emergency caesarean section 46% judged the partner's medical intrapartum care as most deficient (OR 1.73; 1.05-2.86), and after elective caesarean section 40% of the fathers judged involvement in decision-making as deficient (OR 4.07; 1.95-8.50). When the fathers had participated in a spontaneous vaginal birth they were dissatisfied with the presence of the midwife in the labour room (OR 1.72; 1.03 2.87). CONCLUSIONS: Deficiencies existed in the intrapartum care and were judged differently depending on mode of birth. The fathers needed to feel secure about the women's medical care, and wanted to be involved and supported. PMID- 23664434 TI - Lead perforation: an uncommon cause of chest pain in a patient with pacemaker. PMID- 23664435 TI - Letter to the Editor in response to the Carlomagno et al. article regarding the serum sST2 and IL-33 levels in patients with PAH. PMID- 23664437 TI - A Novel use of the dedicated sideguard nitinol self expanding Cappella stent for the treatment of left main stem bifurcation. PMID- 23664436 TI - Assessing the impact of dabigatran and warfarin on health-related quality of life: results from an RE-LY sub-study. AB - BACKGROUND: Anticoagulation is recommended in patients with atrial fibrillation (AF) to prevent strokes. Vitamin K antagonists, such as warfarin, are associated with numerous practical limitations--frequent anticoagulation monitoring, lifestyle and dietary restrictions--that complicate patient management and may impact health-related quality of life (HRQoL). This study derived HRQoL estimates for AF patients receiving warfarin or dabigatran etexilate (dabigatran), a new oral anticoagulant not requiring anticoagulation monitoring, during one year of stable treatment, i.e. in the absence of outcome events, such as strokes or major bleedings. METHODS: Changes in HRQoL over time and between treatments were assessed using the EQ-5D (utility and Visual Analogue Scale (VAS) scores) at baseline, 3 and 12 months in a sub-group of 1435 patients participating in the RE LY trial. RE-LY was a phase III study that compared the safety and efficacy of warfarin, dabigatran 150 mg bid and dabigatran 110 mg bid for stroke prevention in patients with AF. RESULTS: Utilities ranged from 0.805 (dabigatran 150 mg bid) to 0.811 (dabigatran 110 mg bid) at baseline, and did not change over the one year observation period. No differences between the dabigatran groups and warfarin were statistically significant except for the dabigatran 150 mg bid group at 3 months. Similarly, none of the within-group or between-group differences in VAS scores were statistically significant. CONCLUSIONS: Over the course of one year, all anticoagulated patients without outcome events (e.g. strokes or major bleedings) had stable HRQoL. Scores between dabigatran and warfarin were comparable, which was unexpected given the known complexities of warfarin treatment. PMID- 23664438 TI - The role of thrombospondin-1 in cardiovascular health and pathology. AB - Cardiovascular diseases (CVDs) remain a leading cause of morbidity and mortality in the developed world and are becoming increasingly prevalent in the developing world. Although a range of therapies already exist for established CVDs, there is a significant interest in further understanding disease pathogenesis in order to improve treatment. Thrombospondin (TSP)-1 is an important extracellular matrix component that influences the function of vascular smooth muscle cells, endothelial cells, fibroblasts and inflammatory cells with important implications for CVDs. TSP-1 regulates matrix production and organisation thereby influencing tissue remodelling and promoting the generation of T regulatory cells that control the inflammatory response. Reported findings from in vitro and animal studies are conflicting and suggest differing effects of TSP-1 on various cellular mechanisms, depending on the experimental setting. Vascular cells express a number of TSP-1 receptors, such as CD36, proteoglycans and several integrins, which are regulated by specific contextual signals which may explain the varying effects that TSP-1 elicits in different environments. Different domains of TSP-1 activate distinct signalling pathways eventually resulting in quite different cellular phenotypes and tissue specific effects. The sum total of the various pathways activated likely determines the overall effect on angiogenesis or proliferation in a specific tissue. Hence defining a common mechanism of action of TSP-1 in CVD is complicated. Increasing the understanding of the role of TSP-1 in various CVDs will potentially provide new opportunities for therapeutic intervention using peptides derived from its various domains currently under evaluation in other diseases. PMID- 23664439 TI - Association between levels of serum perfluorooctane sulfate and carotid artery intima-media thickness in adolescents and young adults. AB - BACKGROUND: Perfluorinated chemicals (PFCs) have been widely used for years in a variety of products worldwide. Although epidemiological findings have shown that PFC levels are positively associated with cholesterol and uric acid levels, it is unknown whether PFCs are associated with atherosclerosis. METHODS: We recruited 664 subjects (12-30 years) from a population-based sample of adolescents and young adults based on a mass urine screening to determine the relationship between serum levels of PFCs and carotid intima-media thickness (CIMT). RESULTS: The median concentrations and ranges of perfluorooctanoic acid (PFOA), perfluorooctane sulfate (PFOS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFUA) were 3.49 (0.75-52.2) ng/mL, 8.65 (0.11-85.90) ng/mL, 0.38 (0.38-25.4) ng/mL, and 6.59 (1.50-105.7) ng/mL, respectively. After controlling for age, gender, smoking status, systolic blood pressure, body mass index, low-density lipoprotein cholesterol, triglyceride, high-sensitivity C reactive protein, and homeostasis model assessment of insulin resistance, multiple linear regression analysis revealed that CIMT increased significantly across quartiles of PFOS (0.434 mm, 0.446 mm, 0.458 mm, 0.451 mm; P for trend <0.001). Subpopulation analysis showed the association between PFOS and CIMT was more evident and significant in females, non-smokers, subjects of age 12-19 years, BMI<24, and those with APOE genotype of E2 carrier and E3/E3. CONCLUSIONS: Higher serum concentrations of PFOS were associated with an increase of carotid IMT in this cohort of adolescents and young adults. Further studies are warranted to clarify the causal relationship between PFOS and atherosclerosis. PMID- 23664440 TI - Utility of intracardiac echocardiography for catheter ablation of an anteroseptal accessory pathway from the non-coronary aortic cusp. PMID- 23664441 TI - Microvascular coronary disease in women: role of the cardiopulmonary exercise testing. PMID- 23664442 TI - iPhone ECG monitoring--the gateway to the new paradigm of STEMI therapy. PMID- 23664443 TI - Induced pluripotent stem cell models of long QT syndrome. PMID- 23664444 TI - Silent atrial fibrillation: a clinical conundrum. PMID- 23664445 TI - Impact of potassium permanganate on cyanobacterial cell integrity and toxin release and degradation. AB - Potassium permanganate (KMnO4) is commonly used as a pre-treatment oxidant to remove soluble manganese (Mn) and iron (Fe) which can contribute to dirty water in drinking water supplies. Because Mn and Fe problems are commonly associated with thermal stratification in summer and autumn, they frequently coincide with the presence of cyanobacteria. The use of KMnO4 as an oxidant for Mn and Fe control therefore needs to consider the potential impacts on cyanobacterial cell integrity and toxin release. This study aims to assess the effect of KMnO4 on cyanobacteria cell integrity, toxin release and toxin oxidation. A toxic strain of Microcystis aeruginosa was exposed to various concentrations of KMnO4 and the cell integrity of cyanobacteria was measured with flow cytometry. Further the intra- and extra-cellular toxin concentrations were quantified and it was apparent that KMnO4 reduced both the intra- and extra-cellular toxins at low initial concentrations of 1 and 3 mg L(-1) without complete cell lysis. However, the cell integrity of cyanobacteria was compromised at KMnO4 concentrations of 5 mg L(-1) and 10 mg L(-1) and led to intracellular toxin release. In the 10 mg L( 1) KMnO4 treatment, the total toxin was oxidised after 7h contact time. A model describing the two step process of release and degradation was developed and may provide a tool to assess the risk water quality posed by toxin release. Consequently, it may be possible to use KMnO4 as a pre-treatment for Mn and Fe at concentrations<3 mg L(-1) and short contact time when cyanobacteria are also present. PMID- 23664446 TI - EML4-ALK translocation in both metachronous second primary lung sarcomatoid carcinoma and lung adenocarcinoma: a case report. AB - The EML4-ALK gene translocation was described in a non small cell lung cancer (NSCLC) subset, with a potent oncogenic activity. It represents one of the newest molecular targets in NSCLC. We report on the case of a metachronous second primary lung sarcomatoid carcinoma after resection of lung adenocarcinoma both with ALK translocation, in a non-smoking patient. EML4-ALK rearrangement was detected with immunohistochemistry and confirmed with fluorescent in situ hybridization (FISH). To assess the clonal relationship between the two tumors, both adenocarcinoma and sarcomatoid carcinoma were analyzed by array comparative genomic hybridization (aCGH). We observed different genomic profiles suggesting that the tumors arose independently and were thus multiple primaries. To the best of our knowledge, this is the first report concerning the presence of the EML4 ALK fusion gene in a sarcomatoid carcinoma of the lung. Crizotinib, the ALK tyrosine kinase inhibitor, is highly effective in ALK-rearranged NSCLC; therefore, it may be imperative to identify all NSCLC that harbor ALK translocations in the near future. Starting from our evidence, tumors with sarcomatoid histology may need to be screened for the presence of EML4-ALK rearrangement. PMID- 23664447 TI - Genetic and epigenetic alterations of the LKB1 gene and their associations with mutations in TP53 and EGFR pathway genes in Korean non-small cell lung cancers. AB - INTRODUCTION: Liver kinase 1 (LKB1) plays a critical barrier role in lung tumorigenesis by controlling initiation, differentiation and metastasis. We searched for genetic and epigenetic alterations of the LKB1 gene in Korean non small cell lung cancers (NSCLCs) and correlated the results with clinicopathological features. We also investigated the relationship between genetic and epigenetic alterations of LKB1 and mutations in the TP53 gene and epidermal growth factor receptor (EGFR) pathway genes. METHODS: A total of 159 NSCLCs were analyzed for loss of heterozygosity (LOH) at microsatellite loci D19S886, and D19S878. Mutations and methylation status of LKB1 were examined by direct sequencing and a methylation-specific polymerase chain reaction, respectively. RESULTS: A somatic mutation was found in one of the 159 tumors. LOH and promoter methylation was detected in 19.5% (31/159) and 13.2% (21/159) of the tumors, respectively. Four of the 159 tumors had concomitant LOH and methylation of LKB1. In total, 30.2% of the 159 NSCLCs harbored LKB1 LOH or promoter methylation, which were correlated with down-regulation of gene expression. LKB1 LOH was more frequent in males, smokers, and tumors with a TP53 mutation than in females, never-smokers, and tumors without a TP53 mutation, respectively. However, no significant correlation between LKB1 alterations and mutations in EGFR pathway genes was found. CONCLUSION: These results suggest that the prevalence of LKB1 genetic and epigenetic alterations in NSCLCs vary depending on patient ethnicity. Our results show that LKB1 alterations often occur simultaneously with mutations in EGFR pathway genes. PMID- 23664448 TI - Clinical perspective of afatinib in non-small cell lung cancer. AB - Reversible ATP-competitive inhibitors targeting the epidermal growth factor receptor (EGFR) have been established as the most effective treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring "activating" mutations in exons 19 and 21 of the EGFR gene. However, clinical activity is limited by acquired resistance which on average develops within 10 months of continued treatment. The mechanisms for acquired resistance include selection of the EGFR T790M mutation in approximately 50% of cases, and MET gene amplification, PIK3CA gene mutation, transdifferentiation into small-cell lung cancer and additional rare or unkown mechanisms. Afatinib is a small molecule covalently binding and inhibiting the EGFR, HER2 and HER4 receptor tyrosine kinases. In preclinical studies, afatinib not only inhibited the growth of models with common activating EGFR mutations, but was also active in lung cancer models harboring wild-type EGFR or the EGFR L858R/T790M double mutant. Clinical efficacy of afatinib has been extensively studied in the LUX-Lung study program. These trials showed promising efficacy in patients with EGFR-mutant NSCLC or enriched for clinical benefit from EGFR tyrosine kinase inhibitors gefitinib or erlotinib. Here we review the current status of clinical application of afatinib in NSCLC. We also discuss clinical aspects of resistance to afatinib and strategies for its circumvention. PMID- 23664449 TI - Favorable prognosis of operable non-small cell lung cancer (NSCLC) patients harboring an increased expression of tumor endothelial markers (TEMs). AB - Genome analyses of endothelial cells identified genes specifically expressed by tumor endothelial cells, called tumor endothelial markers (TEMs). Currently there are no data available concerning the role of TEMs in non-small cell lung cancer (NSCLC). Therefore, the aim of this study was to investigate the role of TEMs in NSCLC in vitro and in vivo. First we evaluated the expression of various TEMs (Robo4, Clec14 and ECSCR) by qRT-PCR and Western blot analyses in three NSCLC cell lines (A549, Calu1, Colo699) and compared them to human umbilical vein endothelial cells (HUVECs), endothelial colony forming cells (ECFCs) and human bronchial epithelial cells (HBEpCs). Next the expression of TEMs was measured in resected tumor tissue of NSCLC patients (n = 63) by qRT-PCR and compared to adjacent non-cancerous lung tissue (n = 52). Further, immunohistochemical analysis of Robo4 expression in tumor tissue (n = 33) and adjacent non-cancerous tissue (n = 27) was performed. We found that NSCLC cell lines and HBEpC did not express TEMs on the mRNA level compared to HUVECs (p = 0.001). In the contrary, a significant up-regulation of Robo4 and Clec14 was found in tumor samples (Robo4 p = 0.03, Clec14 p = 0.002). Both facts clearly indicate that these proteins are allocated to the tumor stromal department. Correlation with clinical data showed that increased TEM expression correlated with prolonged overall survival of operated NSCLC patients (Robo4 high 120.5 vs. Robo4 low 47.6 months, Clec14 high 108.1 vs. Clec14 low 54.5 months and ECSCR high 120.5 vs. ECSCR low 42.2 months). In summary, we found that TEMs are overexpressed in NSCLC stromal tissue and that an increased TEM expression correlated with an increased overall survival in early stage NSCLC. PMID- 23664450 TI - Global localization of 3D anatomical structures by pre-filtered Hough forests and discrete optimization. AB - The accurate localization of anatomical landmarks is a challenging task, often solved by domain specific approaches. We propose a method for the automatic localization of landmarks in complex, repetitive anatomical structures. The key idea is to combine three steps: (1) a classifier for pre-filtering anatomical landmark positions that (2) are refined through a Hough regression model, together with (3) a parts-based model of the global landmark topology to select the final landmark positions. During training landmarks are annotated in a set of example volumes. A classifier learns local landmark appearance, and Hough regressors are trained to aggregate neighborhood information to a precise landmark coordinate position. A non-parametric geometric model encodes the spatial relationships between the landmarks and derives a topology which connects mutually predictive landmarks. During the global search we classify all voxels in the query volume, and perform regression-based agglomeration of landmark probabilities to highly accurate and specific candidate points at potential landmark locations. We encode the candidates' weights together with the conformity of the connecting edges to the learnt geometric model in a Markov Random Field (MRF). By solving the corresponding discrete optimization problem, the most probable location for each model landmark is found in the query volume. We show that this approach is able to consistently localize the model landmarks despite the complex and repetitive character of the anatomical structures on three challenging data sets (hand radiographs, hand CTs, and whole body CTs), with a median localization error of 0.80 mm, 1.19 mm and 2.71 mm, respectively. PMID- 23664451 TI - Explaining moral religions. AB - Moralizing religions, unlike religions with morally indifferent gods or spirits, appeared only recently in some (but not all) large-scale human societies. A crucial feature of these new religions is their emphasis on proportionality (between deeds and supernatural rewards, between sins and penance, and in the formulation of the Golden Rule, according to which one should treat others as one would like others to treat oneself). Cognitive science models that account for many properties of religion can be extended to these religions. Recent models of evolved dispositions for fairness in cooperation suggest that proportionality based morality is highly intuitive to human beings. The cultural success of moralizing movements, secular or religious, could be explained based on proportionality. PMID- 23664452 TI - Learned regulation of brain metabolism. AB - Self-regulation and voluntary control of circumscribed brain regions using real time functional MRI (rt-fMRI) allows the establishment of a causal functional link between localized brain activity and behavior and cognition. A long tradition of research has clearly shown the brain's ability to learn volitional control of its own activity and effects on behavior. Yet, the underlying neural mechanism of self-regulation is still not fully understood. Here, we propose that self-regulation of brain activity is akin to skill learning and thus may depend on an intact subcortical motor system. We elaborate on the critical role of the basal ganglia in skill learning and neurofeedback, and clarify that brain-self regulation need not be an explicit and conscious process as often mistakenly held. PMID- 23664453 TI - Social cognition in the rodent: nothing to be sniffed at. AB - The rat is emerging as a powerful model for studying cognition and its neural bases. Extending this work to the social domain requires understanding better how rats transmit and interpret social information. A recent study highlights a novel role for sniffing as a channel for such social communication. PMID- 23664454 TI - Promoting palliative care in patients with motor neuron disease in Taiwan. PMID- 23664455 TI - Evaluation of rule effectiveness and positive predictive value of clinical rules in a Dutch clinical decision support system in daily hospital pharmacy practice. AB - INTRODUCTION: Our advanced clinical decision support (CDS) system, entitled 'adverse drug event alerting system' (ADEAS), is in daily use in our hospital pharmacy. It is used by hospital pharmacists to select patients at risk of possible adverse drug events (ADEs). The system retrieves data from several information systems, and uses clinical rules to select the patients at risk of ADEs. The clinical rules are all medication related and are formulated using seven risk categories. OBJECTIVE: This studies objectives are to 1) evaluate the use of the CDS system ADEAS in daily hospital pharmacy practice, and 2) assess the rule effectiveness and positive predictive value (PPV) of the clinical rules incorporated in the system. SETTING: Leiden University Medical Center, The Netherlands. All patients admitted on six different internal medicine and cardiology wards were included. MEASURES: Outcome measures were total number of alerts, number of patients with alerts and the outcome of these alerts: whether the hospital pharmacist gave advice to prevent a possible ADE or not. Both overall rule effectiveness and PPV and rule effectiveness and PPV per clinical rule risk category were scored. STUDY DESIGN: During a 5 month study period safety alerts were generated daily by means of ADEAS. All alerts were evaluated by a hospital pharmacist and if necessary, healthcare professionals were subsequently contacted and advice was given in order to prevent possible ADEs. RESULTS: During the study period ADEAS generated 2650 safety alerts in 931 patients. In 270 alerts (10%) the hospital pharmacist contacted the physician or nurse and in 204 (76%) cases this led to an advice to prevent a possible ADE. The remaining 2380 alerts (90%) were scored as non-relevant. Most alerts were generated with clinical rules linking pharmacy and laboratory data (1685 alerts). The overall rule effectiveness was 0.10 and the overall PPV was 0.08. Combination of rule effectiveness and PPV was highest for clinical rules based upon the risk category "basic computerized physician order entry (CPOE) medication safety alerts fine-tuned to high risk patients" (rule efficiency=0.17; PPV=0.14). CONCLUSION: ADEAS can effectively be used in daily hospital pharmacy practice to select patients at risk of potential ADEs, but to increase the benefits for routine patient care and to increase efficiency, both rule effectiveness and PPV for the clinical rules should be improved. Furthermore, clinical rules would have to be refined and restricted to those categories that are potentially most promising for clinical relevance, i.e. "clinical rules with a combination of pharmacy and laboratory data" and "clinical rules based upon the basic CPOE medication safety alerts fine-tuned to high risk patients". PMID- 23664456 TI - Torsion of parasitic myoma in the mesentery after myomectomy. PMID- 23664457 TI - Single-port vs. conventional multi-port access laparoscopy-assisted vaginal hysterectomy: comparison of surgical outcomes and complications. AB - OBJECTIVE: To compare surgical outcomes and complications between single-port access (SPA) and multi-port access (MPA) laparoscopy-assisted vaginal hysterectomy (LAVH). STUDY DESIGN: A retrospective review of medical records was performed in patients who underwent LAVH for non-malignant gynaecological diseases at Eun Hospital between April 2010 and April 2012. One hundred and twenty women underwent SPA LAVH using a transumbilical three-channel single-port system and 130 women underwent conventional MPA LAVH. Surgical outcomes and complications were compared between the two groups. RESULTS: The outcomes of the SPA-LAVH group vs. the conventional MPA-LAVH group were as follows: mean+/ standard deviation total operative time (73.1+/-24.3 vs. 70.3+/-22.1min, p=0.349), largest dimension of uterus (10.7+/-2.3 vs. 10.8+/-2.8cm, p=0.847), weight of extirpated uterus (311+/-185 vs. 339+/-234g, p=0.298) and change in haemoglobin (1.7+/-0.8 vs. 2.0+/-0.9g/dl, p=0.025). The incidence of complications was similar in each group (20 vs. 16 patients, p=0.327). Unplanned intra-operative laparotomy was not necessary in either group, and there were no cases of bowel injury or main vessel injury in either group. In total, there were three bladder injuries: one in the SPA-LAVH group and two in the MPA-LAVH group. The postoperative course was uneventful in most patients, but six patients had a transient paralytic ileus (four in the SPA-LAVH group and two in the MPA-LAVH group) and 10 patients had a pelvic haematoma (five in each group), all of whom recovered following conservative management. Port-related complications were rare, but one patient in the SPA-LAVH group had a port-site umbilical hernia. CONCLUSION: Use of SPA and MPA LAVH has similar results in terms of surgical outcomes and complications. PMID- 23664458 TI - Dehydroepiandrosterone supplementation improves predictive markers for diminished ovarian reserve: serum AMH, inhibin B and antral follicle count. AB - OBJECTIVE: To evaluate the effect of dehydroepiandrosterone (DHEA) supplementation on ovarian reserve by measuring markers such as antral follicle count, serum anti-Mullerian hormone (AMH) and inhibin B in patients with diminished ovarian reserve. STUDY DESIGN: This prospective study was undertaken at Dr. Zekai Tahir Burak Women's Health Research and Education Hospital, Ankara, Turkey. Forty-one patients with diminished ovarian reserve were included in the study and received supplementation with DHEA 25mg, t.i.d., for at least 6 weeks. Serum AMH, inhibin B, follicle-stimulating hormone (FSH) and oestradiol, and antral follicle count were determined before and after DHEA supplementation. Baseline ovarian reserve parameters such as antral follicle count, FSH, oestradiol, AMH, inhibin B, clinical and laboratory IVF outcomes, and pregnancy rates were studied. RESULTS: There were significant differences in day 3 FSH, oestradiol, antral follicle count, AMH and inhibin B levels before and after DHEA supplementation in all patients (p=0.001, 0.001, 0.002, 0.001 and 0.001, respectively). The study population was divided into two age groups (<35 and >=35 years) to determine whether there was a difference in the effect of DHEA supplementation between younger and older patients with diminished ovarian reserve. Significant differences were found in all of the parameters in both study groups (p<0.05). CONCLUSIONS: DHEA supplementation is an effective option for patients with diminished ovarian reserve. Prior to assisted reproductive technology, patients with diminished ovarian reserve should be offered DHEA supplementation as an alternative to oocyte donation. PMID- 23664459 TI - Emerging health issues from chronic pesticide exposure: innovative methodologies and effects on molecular cell and tissue level. PMID- 23664460 TI - Cerebral infarction in a case of Parry-Romberg syndrome. AB - Our objective is to report a rare coexistence of Parry-Romberg disease and ischemic stroke. Here, we report the case of a 34-year-old woman with Parry Romberg syndrome who developed cerebral infarction. This patient developed sudden left-sided weakness and was admitted to our hospital. Magnetic resonance imaging revealed acute cerebral infarction in the posterior limb of the right internal capsule. The patient had been diagnosed with Parry-Romberg syndrome at the age of 12, and she had a history of migraine without aura. Transesophageal echocardiography revealed a patent foramen ovale, but no atrial septal aneurysm or deep vein thrombosis was observed in the lower extremities. She was treated with 200 mg of aspirin and 10 mg of atorvastatin. Her symptoms gradually improved, and she was discharged 10 days after admission. Parry-Romberg syndrome is a rare disease of progressive hemifacial atrophy with unknown etiology. The potential risk factors for ischemic stroke in Parry-Romberg syndrome include ipsilateral cerebrovascular abnormality or migraine. In addition, patent foramen ovale was identified as a concomitant risk factor in our case. PMID- 23664461 TI - Elderly age, bilateral lesions, and severe neurological deficit are correlated with stroke-associated pneumonia. AB - Causative factors for pneumonia and their impact on prognosis were investigated in patients with acute ischemic stroke. Patient characteristics, swallowing function, lesions, and the presence or absence of intervention by dysphagia rehabilitation were assessed in 292 patients with acute cerebral infarction to determine the association of these factors with pneumonia. As a result, 52 patients (17.8%) experienced pneumonia. Of these, 14 developed pneumonia within 3 days of hospital admission and 38 developed the disease after 4 days or later. Pneumonia was frequently seen among elderly patients, those with severe neurological symptoms or cognitive disorders and those with bilateral multiple lesions, and was associated with prolonged length of stay and decline in activities of daily living at hospital discharge. In conclusion, elderly age, bilateral lesions, and severe neurological deficit were significantly associated with pneumonia. Pneumonia in turn strongly predicted inability to take food orally and be discharged from hospital to home. PMID- 23664462 TI - Plasma levels of second-generation antipsychotics and clinical response in acute psychosis: a review of the literature. AB - OBJECTIVE: The objective of the study is to assess the relationships between plasma concentrations (Cps) of second-generation antipsychotics (SGAs) and clinical outcome in order to establish the clinical value of therapeutic drug monitoring. METHOD: In April 2012, we searched PubMed and MEDLINE databases for English-language articles using the keywords risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, paliperidone, iloperidone, asenapine, lurasidone, therapeutic drug monitoring, serum level, and plasma level. One hundred and ninety-one articles were retrieved from the initial search. Articles were selected for inclusion if they involved an attempt to correlate Cps with efficacy measures, if they were prospective in nature, and if they examined patients experiencing an acute exacerbation of a psychotic illness. Ultimately 11 articles were selected. RESULTS: Of the nine compounds involved in the search, only four were included in relevant articles, and only two of these were involved in multiple trials. No studies involving the most recently developed compounds (paliperidone, iloperidone, asenapine, and lurasidone) were identified. Studies varied widely in methodology, with only four studies adopting a fixed-dose model. Results differed considerably between studies regarding both clinical and adverse effects, with 6 of the 11 studies revealing a positive correlation between Cps and response. CONCLUSIONS: The utility of therapeutic drug monitoring of SGAs (other than clozapine) remains an open question, although limited evidence from fixed-dose studies is encouraging. We discuss the potentially significant clinical value of antipsychotic Cps and the consequent need for further research in this area. PMID- 23664463 TI - [Migraine]. PMID- 23664464 TI - A population-based survey of the prevalence and types of glaucoma in central Iran: the Yazd eye study. AB - PURPOSE: To describe the prevalence and types of glaucoma in Yazd, central Iran. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: Iranian adults aged 40 to 80 years, residing in Yazd, Iran, in 2010 and 2011. METHODS: Eligible samples were selected using cluster random sampling. Each participant underwent an interview and ophthalmologic examinations, including refraction, determination of uncorrected and best-corrected visual acuity, slit-lamp biomicroscopy, Goldmann applanation tonometry, gonioscopy, dilated fundus examination, central corneal thickness measurement, visual field testing, and stereoscopic fundus photography. MAIN OUTCOME MEASURES: Prevalence of different types of glaucoma. RESULTS: Of 2320 eligible individuals, 2098 (response rate, 90.4%) participated in the study and 1990 completed all evaluations for glaucoma diagnosis. Overall, 47 persons (2.4%) were categorized with ocular hypertension, 32 persons (1.6%) were categorized with primary angle-closure suspect (PACS), and 16 persons (0.8%) were categorized with primary angle closure (PAC). The total number of subjects with glaucoma was 87 (4.4%; 95% confidence interval, 3.3-5.4), consisting of primary open-angle glaucoma (POAG, 3.2%, including high-tension glaucoma [1.7%] and normal-tension glaucoma [NTG], 1.5%]), primary angle-closure glaucoma (PACG, 0.4%), pseudoexfoliation glaucoma (0.4%), and other secondary glaucomas (0.4%). The mean age of subjects with glaucoma was 63.3 +/- 11 years, and 57.5% of them were female. Seventy-eight individuals (89.7%) were unaware of their disease. Positive family history of glaucoma was present in 6.9% of glaucoma subjects. CONCLUSIONS: The prevalence of glaucoma in Yazd (4.4%) is comparable to that in other population-based studies in Asia, with POAG accounting for the majority of cases. Most affected subjects were unaware of their disease. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23664465 TI - Impairment of lacrimal secretion in the unaffected fellow eye of patients with recurrent unilateral herpetic keratitis. AB - PURPOSE: To assess the impact of recurrent unilateral herpetic keratitis (HK) on the tear secretion of the unaffected fellow eye. DESIGN: Prospective, noninterventional study. PARTICIPANTS AND CONTROLS: Thirty-five patients with a history of recurrent unilateral HK (clinically quiescent for at least 3 months) (HK group) and 35 patients who were age- and sex-matched with no history of corneal disease (control group). METHODS: Tear osmolarity, tear instability (tear break-up time [TBUT]), tear reflex (Schirmer's I test), and central corneal sensitivity with the Cochet-Bonnet esthesiometer (Luneau, France) were measured in the HK and control groups. MAIN OUTCOME MEASURES: Tear osmolarity, TBUT, Schirmer's I, and central corneal sensitivity were compared between the affected and unaffected eyes of the HK and control groups. RESULTS: Tear osmolarity and tear secretion reflex were similar between the affected and unaffected eyes of the HK group. Corneal sensitivity and TBUT were statistically lower in the affected eyes compared with the unaffected eyes in the HK group (P = 0.001 and P<0.001, respectively). The central corneal sensitivity of unaffected eyes in the HK group was not significantly different from that in the control group (P>0.05). The tear stability and tear secretion reflex were decreased and tear osmolarity was increased in the unaffected eyes of the HK group compared with the control group (P<0.05, all cases). The difference between unaffected and control eyes varied according to the type of HK. All 4 tests were modified in patients with neurotrophic keratitis (KN). In the keratouveitis subgroup, only corneal sensitivity was normal, whereas Schirmer's I results were also normal in patients with archipelago keratitis. Tear osmolarity was consistently affected in both eyes of herpetic patients. CONCLUSIONS: Tear function is impaired in the unaffected eyes of patients with unilateral recurrent HK, even when the disease is apparently quiescent. The higher severity of results in the unaffected fellow eye of patients with KN in comparison with other herpes subgroups suggests that recurrent HK induces a reduction in the afferent pathways of the tear secretion reflex from the affected eye, leading to tear dysfunction in the unaffected eye. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23664466 TI - Analysis of choroidal morphologic features and vasculature in healthy eyes using spectral-domain optical coherence tomography. AB - OBJECTIVE: To analyze the morphologic features and vasculature of the choroid in healthy eyes using spectral-domain (SD) optical coherence tomography (OCT). DESIGN: Cross-sectional retrospective review. PARTICIPANTS: Forty-two healthy subjects (42 eyes) with no ocular disease who underwent high-definition scanning with Cirrus high-definition OCT (Carl Zeiss Meditec, Inc., Dublin, CA) at the New England Eye Center, Boston, Massachusetts, between November 2009 and September 2010. METHODS: The SD OCT images were evaluated for morphologic features of the choroid, including the shape of the choroid-scleral border, location of the thickest point of choroid, and regions of focal choroidal thinning. Total choroidal thickness and large choroidal vessel layer thickness were measured by 2 independent observers experienced in analyzing OCT images using the Cirrus linear measurement tool at the fovea, 750 MUm nasal and temporal to the fovea. Custom software was used to calculate the ratio of choroidal stroma to the choroidal vessel lumen. MAIN OUTCOME MEASURES: Qualitative assessment of the choroidal morphologic features, quantitative analysis of choroidal vasculature, and use of novel automated software to determine the ratio of choroidal stromal area to the area of choroidal vessel lumen. RESULTS: The 42 subjects had a mean age of 51.6 years. All subjects (100%) had a so-called bowl or convex shape to the choroid sclera junction, and the thickest point of the choroid was under the fovea in 88.0% of the subjects. The mean choroidal thickness was 256.8 +/- 75.8 MUm, mean thickness of the large choroidal vessel layer was 204.3 +/- 65.9 MUm, and that of the medium choroidal vessel layer-choriocapillaris layer was 52.9 +/- 20.6 MUm beneath the fovea. The ratio of large choroidal vessel layer thickness to the total choroidal thickness beneath the fovea was 0.7 +/- 0.06. The software generated ratio of choroidal stromal area to the choroidal vessel lumen area was 0.27 +/- 0.08, suggesting that choroidal vessel lumen forms a greater proportion of the choroid than the choroidal stroma in healthy eyes. CONCLUSIONS: This is the first study to describe the morphologic features and vasculature of the choroid in healthy eyes from 1-line raster scans obtained using SD OCT. The method described holds promise and has immediate clinical usefulness in recognizing subtle changes in choroidal morphologic features and the role of choroidal angiopathy in various disease states that, in the future, may inform new treatment methods. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 23664467 TI - American Joint Committee on Cancer classification of posterior uveal melanoma (tumor size category) predicts prognosis in 7731 patients. AB - PURPOSE: To evaluate the clinical features and prognosis of posterior uveal (ciliary body and choroid) melanoma based on the American Joint Committee on Cancer (AJCC) classification (7th edition) of primary tumor (T). DESIGN: Retrospective, interventional case series. PARTICIPANTS: Seven thousand seven hundred thirty-one patients. INTERVENTION: Ocular management including plaque radiotherapy, enucleation, local resection, or laser therapy. MAIN OUTCOME MEASURES: Melanoma-related metastasis and death. RESULTS: Of 7731 patients with posterior uveal melanoma, the AJCC classification based on T was category T1 in 3557 (46%), T2 in 2082 (27%), T3 in 1599 (21%), and T4 in 493 (6%). Based on tumor categories T1, T2, T3, and T4, respectively, features that showed significant increase with tumor category included patient age at presentation (57, 58, 58, and 61 years; P<0.001), tumor base (8, 12, 15, and 20 mm; P<0.001), tumor thickness (3.5, 5.2, 8.9, and 11.4 mm; P<0.001), mushroom configuration (8%, 20%, 38%, and 39%; P<0.001), associated subretinal fluid (64%, 80%, 82%, and 83%; P<0.001), intraocular hemorrhage (5%, 12%, 17%, and 18%; P<0.001), rupture of Bruch's membrane (9%, 24%, 40%, and 40%; P<0.001), and extraocular extension (1%, <1%, 4%, and 12%; P<0.001). After therapy, Kaplan-Meier estimates of metastasis at 5, 10, and 20 years were 8%, 15%, and 25% for category T1, 14%, 25%, and 40% for category T2, 31%, 49%, and 62% for category T3, and 51%, 63%, and 69% for category T4, respectively (P<0.001). Kaplan-Meier estimates of death at 5, 10, and 20 years were 4%, 8%, and 11% for category T1, 8%, 13%, and 24% for category T2, 19%, 27%, and 36% for category T3, and 30%, 43%, and 51% for category T4, respectively (P<0.001). Compared with category T1, the hazard ratio for metastasis and death for T2 was 1.8 and 1.9, respectively, that for T3 was 4.5 and 4.7, respectively, and that for T4 was 8.2 and 8.8, respectively. CONCLUSIONS: Based on the AJCC classification, increasing tumor category was associated with older age, larger tumor, and greater incidence of subretinal fluid, hemorrhage, and extraocular extension. Compared with uveal melanoma classified as T1, the rate of metastasis and death was 2 times greater for T2, 4 times greater for T3, and 8 times greater for T4. The risk for metastasis and death increased 2-fold with each increasing melanoma category. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23664468 TI - Correction of visual impairment by cataract surgery and improved survival in older persons: the Blue Mountains Eye Study cohort. AB - OBJECTIVE: We assessed whether correction of visual impairment (VI) by cataract surgery was associated with improved long-term survival in an older Australian population. DESIGN: Population-based cohort study. PARTICIPANTS: In the Blue Mountains Eye Study, 354 participants, aged >= 49 years, had both cataract and VI or had undergone cataract surgery before baseline examinations. They were subsequently examined after 5- and 10-year follow-ups. METHODS: Associations between the mortality risk and the surgical correction of VI (visual acuity [VA] <20/40, attributable to cataract) were assessed in Cox proportional hazard regression models, after multivariate adjustment, using time-dependent variables for the study factor. MAIN OUTCOME MEASURES: All-cause mortality. RESULTS: The 15 year crude mortality of participants who had undergone cataract surgery at baseline with no subsequent VI (71.8%) was relatively similar to that in participants with cataract-related VI who had not yet undergone surgery (79.4%). However, after adjusting for age and sex, participants who underwent cataract surgery before baseline or during follow-up and no longer had VI had significantly lower long-term mortality risk (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.46-0.77) than participants with VI due to cataract who had not undergone cataract surgery. This lower mortality risk in the group with surgically corrected VI (HR, 0.54; 95% CI, 0.41-0.73) persisted after further adjustment for smoking, body mass index, home ownership, qualifications, poor self-rated health, the presence of poor mobility, hypertension, diabetes, self-reported history of angina, myocardial infarction, stroke, cancer, asthma, and arthritis. This finding remained significant (HR, 0.55; 95% CI, 0.41-0.73) after additional adjustment for the number of medications taken (continuous variable) and the number (>= 5 vs. <5) of comorbid conditions (poor mobility, hypertension, diabetes, angina, myocardial infarction, stroke, cancer, asthma, or arthritis) as indicators of frailty. CONCLUSIONS: Surgical correction of VI due to cataract was associated with significantly better long-term survival of older persons after accounting for known cataract and mortality risk factors, and indicators of general health. Whether some uncontrolled factors (frailty or general health) could have influenced decisions not to perform cataract surgery in some participants is unknown. However, this finding strongly supports many previous reports linking VI with poor survival. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 23664469 TI - Utility and uncorrected refractive error. AB - PURPOSE: To investigate utility (a preference-based quality of life [QoL] measure) associated with uncorrected refractive error (URE). DESIGN: Cross sectional study. PARTICIPANTS: A cohort of 341 consecutive patients 40 to 65 years of age with refractive error and no ocular disease impairing vision worse than 20/25 (0.1 logarithm of the minimum angle of resolution [logMAR] units) in the better eye. Without vision correction, 30 had no vision impairment, 65 had only distance vision impairment (DVI), 97 had only near vision impairment (NVI), 112 had moderate amounts of both distance and near vision impairment (DNVI), and 37 had severe impairment (distance or near worse than 20/200 [>1.0 logMAR]) in the better eye. METHODS: All participants underwent a comprehensive eye examination with refraction, aided and unaided visual acuity (VA) at 6 m and 40 cm, and ocular health assessment. Utilities were elicited for a number of scenarios using a standardized, face-to-face time trade-off (TTO) interview method. MAIN OUTCOME MEASURES: The main outcome measure was TTO utility for the participant's own uncorrected vision state. Utilities ranged from 0 to 1, where 0 = death and 1 = perfect vision, and were scaled to account for comorbidities so that 1 = perfect health (adjusted utility). RESULTS: Unaided VA was 0.50 +/- 0.24 logMAR at distance in the DVI group, 0.43 +/- 0.17 logMAR at near in the NVI group, and 0.72 +/- 0.36 and 0.56 +/- 0.29 at distance and near, respectively, in the DNVI group. Adjusted utilities for the 3 groups were 0.82 +/- 0.16 in the DVI group, 0.81+/-0.17 in the NVI group, and 0.68 +/- 0.25 in the DNVI group. The DVI and NVI group utilities (adjusted and unadjusted) did not differ significantly (P = 0.73 and P = 0.77, respectively). The DNVI utility was significantly worse than that of the DVI and NVI groups (adjusted and unadjusted, P<0.01). CONCLUSIONS: The URE is associated with measurable reductions in utility (and therefore QoL). Reductions are similar regardless of whether near or distance vision is impaired, but worse when both are impaired. The results underscore the significance of the effect of URE on QoL, particularly with respect to uncorrected presbyopia, which has been a relatively neglected area in research and policy. The utility figures in this study can be used as inputs for cost-effectiveness studies relating to URE to assist resource allocation decisions. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23664470 TI - Ocular adnexal lymphoma: assessment of a tumor-node-metastasis staging system. AB - PURPOSE: To assess distribution, correlations, and prognostic effect of tumor (T), node (N), and metastasis (M) staging on relapse and survival. DESIGN: Retrospective clinical review. PARTICIPANTS: Sixty-three patients diagnosed with primary ocular adnexal lymphoma (OAL) between January 1986 and November 2011. METHODS: Complete ocular examination and systemic evaluation were performed. Patients were staged according to the American Joint Committee on Cancer (AJCC) seventh edition tumor-node-metastasis (TNM) clinical staging system for OAL and followed every 6 to 12 months (median follow-up, 27.9 months). MAIN OUTCOME MEASURES: Relapse defined as lymphoma recurrence in the initial site of presentation, the contralateral ocular adnexal structures, or other systemic site and overall survival. RESULTS: There were 40 men (63.5%). The median age was 65 years (range, 24-85 years). The affected site was the conjunctiva in 27 patients (42.9%), orbit in 38 patients (60.3%), and eyelid in 3 patients (4.8%). The histologic subtype was extranodal marginal zone lymphoma (EMZL) in 51 patients (81.0%). A total of 14 patients (23.3%) had T1, 42 patients (70.0%) had T2, 1 patient (1.7%) had T3, and 3 patients (5.0%) had T4 disease. A total of 48 patients (82.8%) had N0 disease, and 10 patients (17.2%) had N1-4 disease. M stage was M0 in 47 patients (81.0%) and M1 in 11 patients (19.0%). With advanced T stage, there was an increase in both N1-4 (P = 0.045) and M1 disease (P = 0.041). M1 disease was greater among patients with N1-4 disease compared with N0 stage (50.0% vs. 12.5%, P = 0.003). Overall, 18 patients (28.6%) relapsed and 6 patients (9.5%) died. In Cox analysis, relapse was not associated with T stage (hazard ratio [HR], 1.14 per 1 level increase, P = 0.71), N stage (HR, 1.47; P = 0.51 N1-4 vs. N0), or M stage (HR, 1.22; P = 0.76 M1 vs. M0). T stage was not associated with survival (HR, 0.86; P = 0.81), whereas N1-4 had marginally worse survival than N0 (HR, 5.35; P = 0.07), and M1 had worse survival than M0 (HR, 9.27; P = 0.008). CONCLUSIONS: The TNM staging system for primary OAL is useful for precise characterization of extent of local disease. Although T stage does not predict relapse or survival, N1-4 and M1 stages indicated less favorable survival. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23664471 TI - Ocular demodicosis as a risk factor of pterygium recurrence. AB - PURPOSE: To evaluate ocular demodicosis as a potential risk factor in pterygium recurrence. DESIGN: Cross-sectional study to correlate clinical findings with laboratory data. PARTICIPANTS: We retrospectively reviewed 94 patients (43 with primary and 51 with recurrent pterygia), among whom 68 patients received surgical correction, and prospectively enrolled another 23 pterygium patients and 14 nonpterygium controls for measuring the tear level of interleukin (IL)-17. METHODS: All patients had microscopically confirmed ocular demodicosis. Statistical correlations were analyzed among age, sex, aqueous tear deficiency, dry eye, ocular demodicosis, follow-up period, surgical outcome, and tear levels of IL-17 measured by enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: Correlation between ocular demodicosis or IL-17 levels and pterygium recurrence. RESULTS: Among 94 patients, ocular demodicosis was more prevalent in patients with recurrent pterygium than those with primary pterygium (P = 0.015). During follow-up of 16.5 +/- 11.5 months, 68 postsurgical patients developed 7 corneal recurrences, which constituted 7.4% of primary and 12.2% of recurrent pterygium (P = 0.820). They also developed 8 conjunctival recurrences. Kaplan-Meier survival analysis showed combined (P = 0.000), corneal (P = 0.044), and conjunctival (P = 0.002) recurrence was significantly higher among patients with demodicosis than those without. Conjunctival recurrence occurred within 6 months in eyes without demodicosis but extended beyond 6 months in eyes with demodicosis. In 34 postsurgical patients with demodicosis, the mite count of 14 patients with recurrence was significantly higher than that of 20 without (P = 0.005). The IL-17 level was significantly higher in patients with either pterygium or demodicosis than controls (P = 0.049 and 0.040, respectively), and the IL-17 level was further elevated in patients with both pterygium and demodicosis (all P<0.05). CONCLUSIONS: Ocular demodicosis is a risk factor for pterygium recurrence, especially for conjunctival recurrence, presumably by perpetuating chronic inflammation mediated by T-helper (Th)17 lymphocytes. PMID- 23664472 TI - Evaluation of the effect of silver nanoparticles and silver ions using stress responsive gene expression in Chironomus riparius. AB - Silver nanoparticles (AgNPs) are extensively used in many commercial products because of their antimicrobial properties and they are therefore released into the environment from various products. A number of genes, especially those representing antioxidant and detoxification pathways, have potential application for studying mechanism of action of environmental pollutants at molecular level. In the present study, the stress responsive transcription of antioxidant and detoxification genes in response to AgNPs and Ag(+) ions exposure is studied in the ecotoxicologically important model species Chironomus riparius. The selected genes were superoxide dismutases (CuZnSOD and MnSOD), catalase (CAT), phospholipid hydroperoxide glutathione peroxidase 1 (PHGPx1), thioredoxin reductase 1 (TrxR1), and delta-3, sigma-4 and epsilon-1 classes of glutathione S transferases (GSTs). The mRNA expression levels of each gene were determined after exposure of animals for 24h to three different AgNP and Ag(+) ion concentrations using Real-Time PCR method. Significant up-regulation of CuZnSOD and MnSOD was found after exposure to Ag(+) ions and AgNPs, respectively. The transcript levels of CAT, PHGPx1 and TrxR1 were significantly up-regulated only after exposure to AgNPs and no significant change was observed after exposure to Ag(+) ions. The expression levels of all the GSTs were more pronounced after exposure to AgNPs as compared to Ag(+) ions. The overall results suggest that AgNPs led to pronounced induction of genes related to oxidative stress and detoxification than Ag(+) ions. PMID- 23664473 TI - Lethal and sublethal effects of four essential oils on the egg parasitoids Trissolcus basalis. AB - The essential oils from leaves of Schinus molle var. areira, Aloysia citriodora, Origanum vulgare and Thymus vulgaris have showed potential as phytoinsecticides against the green stink bug, Nezara viridula. In this work were evaluated their toxicological and behavioral effects on the parasitoid Trissolcus basalis, a biological control agent of this pest insect. Essential oils were obtained via hydrodestillation from fresh leaves. Insecticide activity in T. basalis females was evaluated in direct contact and fumigation bioassays. Behavioral effects were evaluated in olfactometer bioassays. To evaluate the residual toxicity, females of the parasitoids were exposed to oil residues; in these insects, the sublethal effects were evaluated (potential parasitism and survivorship of immature stages). The essential oils from O. vulgare and T. vulgaris proved to be highly selective when used as fumigant and did not change parasitoid behavior. After one week, the residues of these oils were harmless and did not show sublethal effects against T. basalis. According with these results, essential oils have potential applications for the integrated management of N. viridula. PMID- 23664474 TI - Effects of methyltestosterone, letrozole, triphenyltin and fenarimol on histology of reproductive organs of the copepod Acartia tonsa. AB - The marine calanoid copepod Acartia tonsa was exposed to methyltestosterone (MET, 1.6-126 MUg L(-1)), letrozole (LET, 10-1000 MUg L(-1)), triphenyltin chloride (TPT, 0.0014-0.0088 MUg L(-1) TPT-Sn) and fenarimol (FEN, 2.8-105 MUg L(-1)) for 21 d covering a full life-cycle. All four compounds investigated are known to act as androgens in vertebrates. The digestive tract, musculature, nervous system, reproductive organs, gonad and accessory sexual glands were examined by light microscopy after routine staining and immune-labelling for detection of apoptosis and determination of proliferation activities. MET induced an inhibition of oogenesis, oocyte maturation and yolk formation, respectively, which was most pronounced at the lowest concentrations tested. In LET exposed males, spermatogenesis was enhanced with very prominent gamete stages; in some stages apoptosis occurred. The spermatophore was hypertrophied and displayed deformations. In females, LET induced a disorder of oogenesis and disturbances in yolk synthesis. TPT stimulated the male reproductive system at 0.0014 and 0.0035 MUg TPT-SnL(-1), whereas inhibiting effects were observed in the female gonad at 0.0088 MUg TPT-SnL(-1). In FEN exposed females proliferation of gametes was reduced and yolk formation showed irregular features at 2.8-105 MUgL(-1). In FEN exposed males an elevated proliferation activity was observed. No pathological alterations in other organ systems, e.g. the digestive tract including the hindgut acting as respiratory organ, the nervous system, or the musculature were seen. This indicates that the effects on gonads might be caused rather by disturbance of endocrine signalling or interference with hormone metabolism than by general toxicity. PMID- 23664475 TI - Hybridization of natural systems with advanced treatment processes for organic micropollutant removals: new concepts in multi-barrier treatment. AB - Organic micropollutants (OMPs) represent a major constraint in drinking water supply. In the past, emphasis has been on individual treatment processes comprising conventional treatment (coagulation, sedimentation, and filtration) followed by advanced treatment processes (adsorption, ion-exchange, oxidation, and membrane separation). With the depletion of water resources and high demand for power and chemical usage, efforts need to be made to judiciously use advanced treatment processes. There is a new interest in multiple barriers with synergies in which two coupled processes can function as a hybrid process. Within the context of this paper, the hybrid processes include a natural treatment process coupled with an advanced process. Pilot/full-scale studies have shown efficient removal of OMPs by these hybrid processes. With this hybridization, the usage of resources such as power and chemicals can be reduced. In this study, coupling/hybridization of aquifer recharge and recovery (ARR) with oxidation (O3), advanced oxidation process which involves OH radicals (AOP), nanofiltration (NF), reverse osmosis (RO) and granular activated carbon (GAC) adsorption for OMP removal was studied. O3 or AOP as a pre-treatment and GAC, NF, RO, or UV/chlorination as a post-treatment to ARR was studied. NF can be replaced by RO for removal of OMPs since studies have shown similar performance of NF to RO for removal of many OMPs, thereby reducing costs and providing a more sustainable approach. PMID- 23664476 TI - A coupled biological and photocatalysis pretreatment system for the removal of crystal violet from wastewater. AB - The efficiency of a coupled photocatalytic-biological system for removing crystal violet (CV) from an aqueous solution was assessed. Initial experiments demonstrated that the optimal operating parameters for the photoreactor were a 1.5-h reaction time, pH 7.0, and a 2.0-min retention time. Under these conditions, the photocatalytic reaction reduced the toxicity of the CV solution by 94%. Subsequent evaluation of the performance and characteristics of the coupled photocatalytic-biological system in terms of CV removal revealed that the coupled system successfully removed and efficiently mineralized CV in a semi continuous mode when the CV concentration was <150mgL(-1). Based on our analysis of the degradation products, CV degradation in this coupled system involved stepwise demethylation and aromatic ring opening. Phylogenetic analysis of the bioreactor effluent showed that the predominant phyla were Proteobacteria, followed by Bacteroidetes and Actinobacteria, suggesting that this coupled system is conducive for such processes as demethylation, aromatic ring opening, carbon oxidation, and nitrification. These results were verified in a GC-MS analysis. To our knowledge, this is the first report on CV removal using a coupled system. PMID- 23664477 TI - Comment on "photolysis of Enrofloxacin in aqueous systems under simulated sunlight irradiation: kinetics, mechanism and toxicity of photolysis products [Li et al., Chemosphere 85 (2011) 892-897]". PMID- 23664478 TI - Biodegradation of nitroglycerin in porous media and potential for bioaugmentation with Arthrobacter sp. strain JBH1. AB - Nitroglycerin (NG) is a toxic explosive found as a contaminant of soil and groundwater. Several microbial strains are capable of partially reducing the NG molecule to dinitro or mononitroesters. Recently, a strain capable of growing on NG as the sole source of carbon and nitrogen (Arthrobacter sp. strain JBH1) was isolated from contaminated soil. Despite the widespread presence of microbial strains capable of transforming NG in contaminated soils and sediments, the extent of NG biodegradation at contaminated sites is still unknown. In this study column experiments were conducted to investigate the extent of microbial degradation of NG in saturated porous media, specifically after bioaugmentation with JBH1. Initial experiments using sterile, low sorptivity sand, showed mineralization of NG after bioaugmentation with JBH1 in the absence of sources of carbon and nitrogen other than NG. Results could be modeled using a first order degradation rate of 0.14d(-1). Further experiments conducted using contaminated soil with high organic carbon content (highly sorptive) resulted in column effluents that did not contain NG although high dinitroester concentrations were observed. Bioaugmentation with JBH1 in sediments containing strains capable of partial transformation of NG resulted in complete mineralization of NG and faster degradation rates. PMID- 23664479 TI - In silico investigations of anti-androgen activity of polychlorinated biphenyls. AB - Polychlorinated biphenyls (PCBs) have attracted great concern as global environmental pollutants and representative endocrine disruptors. In this work, a molecular model study combining three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, and molecular dynamics (MD) simulations was performed to explore the structural requirement for the anti androgen activities of PCBs and to reveal the binding mode between the PCBs and androgen receptor (AR). The best comparative molecular similarity indices analysis (CoMSIA) model, obtained from receptor-based alignment, shows leave-one out cross-validated correlation coefficient (q(2)) of 0.665 and conventional correlation coefficient (R(2)) of 0.945. The developed model has a highly predictive ability in both internal and external validation. Furthermore, the interaction mechanisms of PCBs to AR were analyzed by molecular docking and MD simulation. Molecular docking indicated that all the PCBs in the data set docked in a hydrophobic pocket. The Binding free energies calculated by Molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) not only exhibited a good correlation with the experimental activity, but also could explain the activity difference of the studied compounds. The binding free energy decomposition analysis indicates that the van der Waals interaction is the major driving force for the binding process. PMID- 23664480 TI - Canopy carbon budget of Siebold's beech (Fagus crenata) sapling under free air ozone exposure. AB - To determine the effects of ozone (O3) on the canopy carbon budget, we investigated photosynthesis and respiration of leaves of Siebold's beech saplings under free air O3 exposure (60 nmol mol(-1), during daytime) in relation to the within-canopy light gradient; we then calculated the canopy-level photosynthetic carbon gain (PCG) and respiratory carbon loss (RCL) using a canopy photosynthesis model. Susceptibilities of photosynthesis and respiration to O3 were greater in leaves of upper canopy than in the lower canopy. The canopy net carbon gain (NCG) was reduced by O3 by 12.4% during one growing season. The increased RCL was the main factor for the O3-induced reduction in NCG in late summer, while contributions of the reduced PCG and the increased RCL to the NCG were almost the same in autumn. These results indicate contributions of changes in PCG and RCL under O3 to NCG were different between seasons. PMID- 23664481 TI - Advancing socio-technical systems thinking: a call for bravery. AB - Socio-technical systems thinking has predominantly been applied to the domains of new technology and work design over the past 60 years. Whilst it has made an impact, we argue that we need to be braver, encouraging the approach to evolve and extend its reach. In particular, we need to: extend our conceptualization of what constitutes a system; apply our thinking to a much wider range of complex problems and global challenges; and engage in more predictive work. To illustrate our agenda in novel domains, we provide examples of socio-technical perspectives on the management of crowd events and environmental sustainability. We also outline a research and development agenda to take the area forward. PMID- 23664482 TI - [Peritoneal gistosis: role of cytoreductive surgery and perioperative intraperitoneal chemotherapy]. PMID- 23664484 TI - Predictors of rehospitalization among elderly patients admitted to a rehabilitation hospital: the role of polypharmacy, functional status, and length of stay. AB - OBJECTIVES: Rehospitalizations for elderly patients are an increasing health care burden. Nonetheless, we have limited information on unplanned rehospitalizations and the related risk factors in elderly patients admitted to in-hospital rehabilitation facilities after an acute hospitalization. SETTING: In-hospital rehabilitation and aged care unit. DESIGN: Retrospective cohort study. PARTICIPANTS: Elderly patients 65 years or older admitted to an in-hospital rehabilitation hospital after an acute hospitalization between January 2004 and June 2011. MEASUREMENTS: The rate of 30-day unplanned rehospitalization to hospitals was recorded. Risk factors for unplanned rehospitalization were evaluated at rehabilitation admission: age, comorbidity, serum albumin, number of drugs, decline in functional status, delirium, Mini Mental State Examination score, and length of stay in the acute hospital. A multivariable Cox proportional regression model was used to identify the effect of these risk factors for time to event within the 30-day follow-up. RESULTS: Among 2735 patients, with a median age of 80 years (interquartile range 74-85), 98 (4%) were rehospitalized within 30 days. Independent predictors of 30-day unplanned rehospitalization were the use of 7 or more drugs (hazard ratio [HR], 3.94; 95% confidence interval, 1.62 9.54; P = .002) and a significant decline in functional status (56 points or more at the Barthel Index) compared with the month before hospital admission (HR 2.67, 95% CI: 1.35-5.27; P = .005). Additionally, a length of stay in the acute hospital of 13 days or more carried a twofold higher risk of rehospitalization (HR 2.67, 95% CI: 1.39-5.10); P = .003). CONCLUSIONS: The rate of unplanned rehospitalization was low in this study. Polypharmacy, a significant worsening of functional status compared with the month before acute hospital admission, and hospital length of stay are important risk factors. PMID- 23664483 TI - Site of death among nursing home residents in the United States: changing patterns, 2003-2007. AB - CONTEXT: The proportion of US deaths occurring in nursing homes (NHs) has been increasing in the past 2 decades and is expected to reach 40% by 2020. Despite being recognized as an important setting in the provision of end-of-life (EOL) care, little is known about the quality of care provided to dying NH residents. There has been some, but largely anecdotal evidence suggesting that many US NHs transfer dying residents to hospitals, in part to avoid incurring the cost of providing intensive on-site care, and in part because they lack resources to appropriately serve the dying residents. We assessed longitudinal trends and geographic variations in place of death among NH residents, and examined the association between residents' characteristics, treatment preferences, and the probability of dying in hospitals. METHODS: We used the Minimum Data Set (NH assessment records), Medicare denominator (eligibility) file, and Medicare inpatient and hospice claims to identify decedent NH residents. In CY2003-2007, there were 2,992,261 Medicare-eligible NH decedents from 16,872 US Medicare- and/or Medicaid-certified NHs. Our outcome of interest was death in NH or in a hospital. The analytical strategy included descriptive analyses and multiple logistic regression models, with facility fixed effects, to examine risk-adjusted temporal trends in place of death. FINDINGS: Slightly more than 20% of decedent NH residents died in hospitals each year. Controlling for individual-level risk factors and for facility fixed effects, the likelihood of residents dying in hospitals has increased significantly each year between 2003 through 2007. CONCLUSIONS: This study fills a significant gap in the current literature on EOL care in US nursing homes by identifying frequent facility-to-hospital transfers and an increasing trend of in-hospital deaths. These findings suggest a need to rethink how best to provide care to EOL nursing home residents. PMID- 23664485 TI - Tubular adenoma of the urinary tract: a newly described entity. AB - Tubular adenomas in the urinary tract with the same appearance as those in the gastrointestinal tract have not yet been described in the literature. We herein report 4 cases of tubular adenomas in the urinary tract encountered within our consult practice. This lesion was defined by the presence of a collection of small round tubular glands with intestinal-type epithelium showing moderate dysplasia, identical to the histology of tubular adenomas in the intestinal tract. Patients ranged in age from 37 to 63 years (mean, 45 years), with 3 of the 4 being male (male-to-female ratio, 3:1). The locations were urinary bladder, prostatic urethra and ureter with hematuria, polyps, and obstructive mass as their presentations, respectively. One lesion was large measuring 1.4 cm associated with pseudoinvasion as well as invasive adenocarcinoma. Immunohistochemically, the tubular adenomas stained positive for CDX2 and CK20, while negative for GATA3 and CK7. One case showed positive nuclear beta-catenin staining. Tubular adenoma of the urinary tract is a rare lesion, and recognition of this entity will encourage further reports and help to better understand the relation of tubular adenoma to concurrent and subsequent urinary tract malignancies. PMID- 23664486 TI - "Old" is "new" in diagnostic pathology. PMID- 23664487 TI - CD44 standard form expression is correlated with high-grade and advanced-stage ovarian carcinoma but not prognosis. AB - Single-chain glycoprotein CD44 is a major cell surface receptor for hyaluronan and mediates epithelial cell adhesion by its involvement in cell-cell and cell matrix interactions. Recently, CD44 has been identified as a biomarker of cancer stem cells in many malignancies including ovarian carcinoma. However, its clinical significance in human ovarian carcinoma has been controversial until recently. The aim of our current study was to clarify the clinical role of CD44 expression in human ovarian carcinoma. Immunohistochemical staining of 483 primary ovarian carcinoma and 27 paired primary and recurrent ovarian carcinoma samples for CD44 standard form (CD44s) was performed using tissue microarray. The associations between CD44s expression and clinical factors (histologic types, tumor grade, International Federation of Gynecology and Obstetrics stage, and response to chemotherapy), and overall or disease-free survivals were analyzed. We observed CD44s expression in 38% of the ovarian carcinoma samples. Results of the Fisher exact test suggested that CD44s expression was associated with high grade carcinoma (P = .013), advanced International Federation of Gynecology and Obstetrics stage (III-IV; P < .001), age at diagnosis less than 60 years (P = .011), and transitional cell carcinoma (P = .039). However, CD44s expression was not associated with overall survival (P = .529) or disease-free survival (P = .218) by the log-rank test. Moreover, there was no statistical difference in CD44s expression between the primary and recurrent ovarian carcinomas. Our results showed that CD44s expression is not a prognostic predictor in ovarian cancer. PMID- 23664488 TI - Differential expression of ubiquitin carboxy-terminal hydrolase L1 in breast carcinoma and its biological significance. AB - Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme that hydrolyzes ubiquitin. Previous reports have shown both tumorigenic and antitumorigenic roles for UCHL1. However, the expression patterns of UCHL1 protein, an area that is critical for validating its clinicopathologic roles among subtypes of breast cancer, is still lacking. Here we examined the expression of UCHL1 by immunohistochemistry in 243 breast carcinomas of various subtypes. We found expression of UCHL1 in 8.3% of invasive ductal carcinomas but not in other carcinoma subtypes, except for metaplastic carcinomas of the breast, which showed UCHL1 staining in 61.9% of cases, with the sarcomatous components being more intensely stained. UCHL1 expression in invasive ductal carcinomas significantly correlated with a high histologic grade (P = .001), the triple negative phenotype (P = .02), and the basal-like phenotype (P <.001); furthermore, it was associated with poorer overall survival by univariate and multivariate analyses. Knockdown of UCHL1 in an invasive Snail variant transfected MCF7 cells with high endogenous UCHL1 protein level significantly reduced invasion and anchorage-independent growth. Conclusively, our results demonstrate a role for UCHL1 in aggressive phenotypes in breast carcinoma. The high expression of UCHL1 in metaplastic carcinomas of the breast, which is pathogenically related to epithelial-mesenchymal transition, may implicate an association between UCHL1 expression and the epithelial-mesenchymal transition in breast cancer. PMID- 23664489 TI - Establishing a geochemical heterogeneity model for a contaminated vadose zone- aquifer system. AB - A large set of sediment samples from a 1600 m2 experimental plot within a 2.2 km2 vadose zone and groundwater uranium (VI) plume was subject to physical, chemical, and mineralogic characterization. The plot is being used for field experimentation on U(VI) recharge and transport processes within a persistent groundwater plume that exists in the groundwater-river interaction zone of the Columbia River at the U.S. DOE Hanford site. The samples were obtained during the installation of 35 tightly spaced (10 m separation) groundwater monitoring wells. The characterization measurements for each sample included total contaminant concentrations (U and Cu primarily), bicarbonate extractable U(VI), sequential 238U(VI) contaminant desorption Kd, 233U(VI) adsorption K(d), grain size distribution, surface area, extractable poorly crystalline Fe(III) oxides, and mineralogy. The characterization objective was to inform a conceptual model of coupled processes controlling the anomalous longevity of the plume, and to quantify the spatial heterogeneity of the contaminant inventory and the primary properties effecting reactive transport. Correlations were drawn between chemical, physical, and reaction properties, and Gaussian simulation was used to compute multiple 3-D realizations of extractable U(VI), the 233U(VI) adsorption K(d), and the distribution of the reactive <2 mm fraction. Adsorbed contaminant U(VI) was highest in the vadose zone and the zone of seasonal water table fluctuation lying at its base. Adsorbed U(VI) was measureable, but low, in the groundwater plume region where very high hydraulic conductivities existed. The distribution of adsorbed U(VI) displayed no apparent correlation with sediment physical or chemical properties. Desorption [238U(IV)] and adsorption [233U(VI)] K(d) values showed appreciable differences due to mass transfer controlled surface complexation and the effects of long subsurface residence times. The 233U(VI) adsorption K(d), a combined measure of surface complexation strength and site concentration, was relatively uniform throughout the domain, displaying correlation with fines distribution and surface area. The characterization results revealed U(VI) supplied to the groundwater plume through spatially heterogeneous recharge from residual contamination in the zone of seasonal water table fluctuation, and transport of U(VI) controlled by weak, kinetically controlled surface complexation in the coarse-textured saturated zone. Geostatistical relationships for the adsorbed contaminant U distribution in the characterization domain allow an extrapolation to inventory at the plume scale, a critical unknown for remedial action. PMID- 23664490 TI - Assessing demographic and epidemiologic parameters of rural dog populations in India during mass vaccination campaigns. AB - Mass vaccination of dogs is a mainstay for efforts to control rabies and other viral pathogens. The success of such programs is a function of the ability to vaccinate sufficient proportions of animals to develop herd immunity. However, fully assessing success in reaching target vaccination-levels and in understanding the outcome of mass vaccination efforts is hindered if insufficient information is available on the demographics of dog populations and the prevalence of the targeted pathogens. While such information can sometimes be gained from questionnaire surveys, greater precision requires direct assessment of the dog populations. Here we show how such information can be gained from surveys of dogs conducted in association with mass-vaccination programs. We conducted surveys of dogs in six villages in rural Maharashtra, India, between February and July 2011 as part of an effort to reduce the risk of human rabies and virus transmission from dogs to wildlife. Mass vaccination efforts were conducted in each village, and paired with blood sample collection and photographic mark-recapture approaches to gain epidemiologic and demographic data. This data in turn facilitated estimates of dog abundance, population density and structure, vaccination coverage, and seroprevalence of antibodies against canine adenovirus (CAV), canine parvovirus (CPV), and canine distemper virus (CDV). The median dog population size for the six villages was 134 (range 90-188), the median dog population density was 719 dogs per km(2) (range 526 969), and the median human:dog ratio for these six villages was 34 (range 30-47). The median household:dog ratio for the six villages was 6 (range 5-8). Following vaccination efforts, the median vaccination coverage achieved was 34% (range 24 42%). The dog populations consisted mostly of adult dogs (67-86%) and the median sex ratio for the study area was male biased (1.55 males per female; range 0.9 2.5). The seroprevalence of antibodies against CAV, CPV and CDV was 68, 88 and 73%, respectively. Mass vaccination campaigns provide an opportunity to obtain vital epidemiological and demographic data, and develop a clearer understanding of the threats and impacts of diseases and disease control measures. PMID- 23664491 TI - Trans-lamina terminalis approach for third ventricle and suprasellar tumours. AB - BACKGROUND: The trans-lamina terminalis (TLT) approach to the suprasellar region and third ventricle is complex, with risks of visual and hormonal deficits. However, the postoperative deficits might not be directly related to opening of the lamina terminalis but to the close relationship of tumours with vital neural and vascular structures. The analysis of results using this approach was the objective of this study. MATERIAL AND METHODS: The TLT approach was used in 29 patients (18 craniopharyngiomas, 5 astrocytomas, 5 germinomas and 1 ganglioglioma). The extent of tumour removal, mortality and morbidity (especially visual or hormonal deficits) were studied. RESULTS: Complete tumour removal was achieved in 15 patients, subtotal extensive removal (more than 90%) in 9 cases and partial removal in 5 cases. Panhypopituitarism developed in 22 patients. Total tumour removal was associated with the development of endocrinological disturbances. There was worsening or the onset of new visual field defects in 4 cases. Postoperative endocrine and visual deficits were in the range generally described regarding surgery for tumours in this region. CONCLUSION: The TLT approach allows for extensive removal of third ventricle and suprasellar tumours, without increased risks of visual and hormonal deficits, compared to those described regarding surgery for lesions in this region. PMID- 23664492 TI - Chemistry and combustion of fit-for-purpose biofuels. AB - From the inception of internal combustion engines, biologically derived fuels (biofuels) have played a role. Nicolaus Otto ran a predecessor to today's spark ignition engine with an ethanol fuel blend in 1860. At the 1900 Paris world's fair, Rudolf Diesel ran his engine on peanut oil. Over 100 years of petroleum production has led to consistency and reliability of engines that demand standardized fuels. New biofuels can displace petroleum-based fuels and produce positive impacts on the environment, the economy, and the use of local energy sources. This review discusses the combustion, performance and other requirements of biofuels that will impact their near-term and long-term ability to replace petroleum fuels in transportation applications. PMID- 23664493 TI - Optimal type I and type II error pairs when the available sample size is fixed. AB - OBJECTIVE: To model how to select the optimal pair of type I and type II errors that maximize study value when there are constrains on the available study sample size. STUDY DESIGN AND SETTING: Correct inferences [true positives (TPs) and true negatives (TNs)] increase and wrong inferences (false positives and false negatives) decrease the value of a study. We model the composite value of a study based on these four inferences, their relative importance, and relative frequency using multiplicative and additive models. Numerical examples are presented for randomized trials, epidemiologic studies, and agnostic omics investigations with massive testing and variable sample size constraints. RESULTS: The optimal choice of type I and type II errors varies a lot according to the available sample size and the plausible effect sizes in each field. We show how equations can be streamlined for special applications: when the value of all four inferences is considered equal, when the identification of TNs carries no value, and when a study carries no value unless at least one TP is discovered. CONCLUSION: The proposed optimization equations can be used to guide the selection of the optimal type I and type II errors of future studies in which sample size is constrained. PMID- 23664494 TI - Anticancer effect of altersolanol A, a metabolite produced by the endophytic fungus Stemphylium globuliferum, mediated by its pro-apoptotic and anti-invasive potential via the inhibition of NF-kappaB activity. AB - Altersolanol A, a natural product from the endophytic fungus Stemphylium globuliferum isolated from the medicinal plant Mentha pulegium (Lamiaceae) growing in Morocco, shows cytotoxic, cytostatic, anti-inflammatory and anti migrative activity against human chronic myeloid K562 leukemia and A549 lung cancer cells in a dose dependent manner without affecting the viability of non cancerous cells. Altersolanol A induces cell death by apoptosis through the cleavage of caspase-3 and -9 and through the decrease of anti-apoptotic protein expression. Moreover, we report here the importance of the distinct structural features of altersolanol A by testing other related anthracene derivatives in order to identify preliminary structure-activity relationships. Acetylation of altersolanol A did not improve activity where other derivatives such as tetrahydroaltersolanol B and ampelanol that differ from altersolanol A by reduction of one of a carbonyl group and removal of hydroxyl substituents were inactive in comparison. Altogether our results suggest that altersolanol A may be considered as an interesting lead for further development of chemotherapeutic agents. PMID- 23664495 TI - Synthesis and anticancer activity of acyl thioureas bearing pyrazole moiety. AB - In this work novel organic based compounds, acyl thiourea derivatives were synthesized and their anticancer activities were investigated. A new series of acyl thiourea derivatives containing pyrazole ring were prepared in good yield through one pot reaction of 4-benzoyl-1, 5-diphenyl-1H-pyrazole-3-carbonyl chloride with ammonium thiocyanate and various amines. The structures of the newly synthesized compounds were confirmed by IR, (1)H NMR, (13)C NMR and elemental analysis. Anticancer activities of synthesized compounds were evaluated on human colon, liver and leukemia cancer cell lines. Cell culture studies have demonstrated significant toxicity of the compounds on the cell lines, and the levels of toxicity have altered in the presence of various side groups. These results confirm that novel pyrazolyl acyl thioureas derived compounds may be utilized for cancer treatment. Furthermore, these compounds have a great potential and significance for further investigations. PMID- 23664496 TI - Synthesis of spin-labeled riboswitch RNAs using convertible nucleosides and DNA catalyzed RNA ligation. AB - Chemically stable nitroxide radicals that can be monitored by electron paramagnetic resonance (EPR) spectroscopy can provide information on structural and dynamic properties of functional RNA such as riboswitches. The convertible nucleoside approach is used to install 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) and 2,2,5,5-tetramethylpyrrolidin-1-oxyl (proxyl) labels at the exocyclic N(4)-amino group of cytidine and 2'-O-methylcytidine nucleotides in RNA. To obtain site-specifically labeled long riboswitch RNAs beyond the limit of solid phase synthesis, we report the ligation of spin-labeled RNA using an in vitro selected deoxyribozyme as catalyst, and demonstrate the synthesis of TEMPO labeled 53 nt SAM-III and 118 nt SAM-I riboswitch domains (SAM=S adenosylmethionine). PMID- 23664497 TI - Protein conjugation with genetically encoded unnatural amino acids. AB - The site-specific incorporation of unnatural amino acids with orthogonal chemical reactivity into proteins enables the synthesis of structurally defined protein conjugates. Amino acids containing ketone, azide, alkyne, alkene, and tetrazine side chains can be genetically encoded in response to nonsense and frameshift codons. These bio-orthogonal chemical handles allow precise control over the site and stoichiometry of conjugation, and have enabled medicinal chemistry-like optimization of the physical and biological properties of protein conjugates, especially the next-generation protein therapeutics. PMID- 23664499 TI - The relationship between age and risky injecting behaviours among a sample of Australian people who inject drugs. AB - BACKGROUND: Limited evidence suggests that younger people who inject drugs (PWID) engage in high-risk injecting behaviours. This study aims to better understand the relationships between age and risky injecting behaviours. METHODS: Data were taken from 11 years of a repeat cross-sectional study of sentinel samples of regular PWID (The Australian Illicit Drug Reporting System, 2001-2011). Multivariable Poisson regression was used to explore the relationship between age and four outcomes of interest: last drug injection occurred in public, receptive needle sharing (past month), experiencing injecting-related problems (e.g. abscess, dirty hit; past month), and non-fatal heroin overdose (past six months). RESULTS: Data from 6795 first-time study participants were analysed (median age: 33 years, interquartile range [IQR]: 27-40; median duration of injecting: 13 years [IQR: 7-20]). After adjusting for factors including duration of injecting, each five year increase in age was associated with significant reductions in public injecting (adjusted incidence rate ratio [AIRR]: 0.90, 95% confidence interval [CI]: 0.88-0.92), needle sharing (AIRR: 0.84, 95% CI: 0.79-0.89) and injecting-related problems (AIRR: 0.96, 95% CI: 0.95-0.97). Among those who had injected heroin in the six months preceding interview, each five year increase in age was associated with an average 10% reduction in the risk of heroin overdose (AIRR: 0.90, 95% CI: 0.85-0.96). CONCLUSIONS: Older PWID report significantly lower levels of high-risk injecting practices than younger PWID. Although they make up a small proportion of the current PWID population, younger PWID remain an important group for prevention and harm reduction. PMID- 23664498 TI - Non-colorectal intestinal tract carcinomas in inflammatory bowel disease: results of the 3rd ECCO Pathogenesis Scientific Workshop (II). AB - Patients with inflammatory bowel diseases (IBD) have an excess risk of certain gastrointestinal cancers. Much work has focused on colon cancer in IBD patients, but comparatively less is known about other more rare cancers. The European Crohn's and Colitis Organization established a pathogenesis workshop to review what is known about these cancers and formulate proposals for future studies to address the most important knowledge gaps. This article reviews the current state of knowledge about small bowel adenocarcinoma, ileo-anal pouch and rectal cuff cancer, and anal/perianal fistula cancers in IBD patients. PMID- 23664500 TI - The relation of autonomic function to physical fitness in patients suffering from alcohol dependence. AB - BACKGROUND: Reduced cardio-vascular health has been found in patients suffering from alcohol dependence. Low cardio-respiratory fitness is an independent predictor of cardio-vascular disease. METHODS: We investigated physical fitness in 22 alcohol-dependent patients 10 days after acute alcohol withdrawal and compared results with matched controls. The standardized 6-min walk test (6 MWT) was used to analyze the relationship of autonomic dysfunction and physical fitness. Ventilatory indices and gas exchanges were assessed using a portable spiroergometric system while heart rate recordings were obtained separately. We calculated walking distance, indices of heart rate variability and efficiency parameters of heart rate and breathing. In addition, levels of exhaled carbon monoxide were measured in all participants to account for differences in smoking behaviour. Multivariate analyses of variance (MANOVA) were performed to investigate differences between patients and controls with regard to autonomic and efficiency parameters. RESULTS: Patients walked a significantly shorter distance in comparison to healthy subjects during the 6 MWT. Significantly decreased heart rate variability was observed before and after the test in patients when compared to controls, while no such difference was observed during exercise. The efficiency parameters indicated significantly reduced efficiency in physiological regulation when the obtained parameters were normalized to the distance. DISCUSSION: The 6 MWT is an easily applied instrument to measure physical fitness in alcohol dependent patients. It can also be used during exercise interventions. Reduced physical fitness, as observed in our study, might partly be caused by autonomic dysfunction, leading to less efficient regulation of physiological processes during exercise. PMID- 23664501 TI - Point of care troponin testing: rules and regulations. PMID- 23664502 TI - [Multimodal rehabilitation program in elective colorectal surgery: Impact on hospital costs]. AB - INTRODUCTION: Multimodal rehabilitation (MMRH) programs in surgery have proven to be beneficial in functional recovery of patients. The aim of this study is to evaluate the impact of a MMRH program on hospital costs. METHOD: A comparative study of 2 consecutive cohorts of patients undergoing elective colorectal surgery has been designed. In the first cohort, we analyzed 134 patients that received conventional perioperative care (control group). The second cohort included 231 patients treated with a multimodal rehabilitation protocol (fast-track group). Compliance with the protocol and functional recovery after fast-track surgery were analyzed. We compared postoperative complications, length of stay and readmission rates in both groups. The cost analysis was performed according to the system "full-costing". RESULTS: There were no differences in clinical features, type of surgical excision and surgical approach. No differences in overall morbidity and mortality rates were found. The mean length of hospital stay was 3 days shorter in the fast-track group. There were no differences in the 30-day readmission rates. The total cost per patient was significantly lower in the fast-track group (fast-track: 8.107 +/- 4.117 euros vs. control: 9.019 +/- 4.667 Euros; P=.02). The main factor contributing to the cost reduction was a decrease in hospitalization unit costs. CONCLUSION: The application of a multimodal rehabilitation protocol after elective colorectal surgery decreases not only the length of hospital stay but also the hospitalization costs without increasing postoperative morbidity or the percentage of readmissions. PMID- 23664504 TI - 4th Intercontinental Cooperative ITP Study Group (ICIS) expert meeting in Montreux, Switzerland, September 2012. PMID- 23664505 TI - Commentary on session: Immune thrombocytopenia nomenclature, guidelines, and natural history. AB - Two presentations discussed different aspects of immune thrombocytopenia (ITP) management. The first considered active monitoring for occult hemorrhage in the gastrointestinal tract, urinary tract, and brain. Participants generally did not feel that these would be useful in determining management of children with ITP since serious bleeding was likely to manifest itself. A single historical paper had suggested that microscopic cranial bleeding may result in chronic brain disturbance, but overall experience of ITP does not support this. Participants considered ways of studying this possibility but noted the considerable difficulties in setting up a formal study and suggested that the established registries should be alerted to capture long-term data on school performance. The second presentation focused on the extent to which recent papers are using the new terminology and guidelines. Participants noted the two new guidelines gave discrepant advice with regard to splenectomy. Management of ITP is not necessarily straightforward and needs to be tailored to the individual. PMID- 23664503 TI - Behavioral intervention technologies: evidence review and recommendations for future research in mental health. AB - OBJECTIVE: A technical expert panel convened by the Agency for Healthcare Research and Quality and the National Institute of Mental Health was charged with reviewing the state of research on behavioral intervention technologies (BITs) in mental health and identifying the top research priorities. BITs refers to behavioral and psychological interventions that use information and communication technology features to address behavioral and mental health outcomes. METHOD: This study on the findings of the technical expert panel. RESULTS: Videoconferencing and standard telephone technologies to deliver psychotherapy have been well validated. Web-based interventions have shown efficacy across a broad range of mental health outcomes. Social media such as online support groups have produced disappointing outcomes when used alone. Mobile technologies have received limited attention for mental health outcomes. Virtual reality has shown good efficacy for anxiety and pediatric disorders. Serious gaming has received little work in mental health. CONCLUSION: Research focused on understanding reach, adherence, barriers and cost is recommended. Improvements in the collection, storage, analysis and visualization of big data will be required. New theoretical models and evaluation strategies will be required. Finally, for BITs to have a public health impact, research on implementation and application to prevention is required. PMID- 23664506 TI - Autoimmunity and novel therapies in immune-mediated thrombocytopenia. AB - Immune-mediated thrombocytopenic purpura (ITP) is recognized as a cell-specific autoimmune disorder, yet, multifactorial in origin. The development of thrombocytopenia is well proven to be mediated by both humoral (anti-platelet antibodies) and cellular (T-cell) mediated mechanisms. In some cases other autoantibodies are also induced, eg, antinuclear antibody (ANA), anti-dsDNA, and anti-cardiolipin, in addition to anti-platelet antibodies. The persistance of these autoantibodies during the course of ITP could herald future development of another autoimmune disease, eg, systemic lupus erythematosus (SLE) or anti phospholipid syndrome (APS). Due to the better understanding of the pathophysiology of ITP, new novel therapies were introduced aiming to achieve long-lasting remissions. In this review we will focus on the autoimmune nature of the disease and on some of the mechanisms of action of these new therapies. PMID- 23664507 TI - Cell death in immune thrombocytopenia: novel insights and perspectives. AB - Immune thrombocytopenia (ITP) is a complex disease. The pathogenic and clinical heterogeneity of ITP is reflected by reports on variability in patient history and treatment response, in concert with recent evidence from mechanistic studies. Programmed cell death (PCD) pathways are thought to play a peculiar role in the megakaryocyte lineage in terms of hemostasis and the generation and function of megakaryocytes and platelets; unbalanced genetic or environmental disturbances of these tightly regulated pathways may cause thrombocytopenia. Dysregulated PCD has also been linked to peripheral platelet destruction, intramedullary apoptosis, and inefficient thrombopoiesis in ITP. In this article, we discuss novel and controversial findings on the role of PCD in the megakaryocyte lineage and their potential implications in terms of pathogenesis, diagnosis, and treatment of ITP. PMID- 23664508 TI - DNA methylation and primary immune thrombocytopenia. AB - DNA methylation is a heritable, stable, and also reversible way of DNA modification; it can regulate gene expression without changing the nucleotide sequences. Because it takes part in regulation of immune responses, the loss of methylation homeostasis in immune cells will result in autoimmune disease by inducing aberrant gene expression. Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease with many immune deficiencies. Recently, it was well documented that abnormal DNA methylation is also involved in the etiology of ITP. In this review, we elucidate the role of DNA methylation in autoimmune diseases by summarizing the DNA methylation-sensitive genes and the relationship between DNA methylation and ITP. PMID- 23664509 TI - To treat or not to treat--from guidelines to individualized patient management. AB - Immune thrombocytopenia (ITP) is a rare disorder. Evidence-based guidelines provide important information for hematologists, as well as diagnostic and therapeutic recommendations to other physicians with limited expertise in the field. However, guidelines in pediatric and adult ITP do not answer some imperative questions: which patient is at risk of severe bleeding and requires pharmacologic treatment? Who will recover spontaneously? Is splenectomy still an appropriate second-line treatment for all chronic or persistent ITP patients? This review summarizes the current approach to these important issues, the patients' perspective, and how we can improve individual patient management. PMID- 23664511 TI - Three decades of experience in managing immune thrombocytopenia in children in Arab countries. AB - There are scattered and limited data in the literature on immune thrombocytopenia (ITP) in children from the Arab region. The aim of the current review is to present data from this region on the diagnosis, therapy, and morbidity associated with ITP. The first report was published three decades ago. It was assumed that there was a different disease pattern of ITP, but this was later discovered to be inaccurate and the frequencies of different ITP patterns were not different from other regions. The initial work-up for diagnosis of newly diagnosed ITP included routine bone marrow evaluation for all patients in most studies; however, a limited need for bone marrow for the initial evaluation was reported. An Egyptian multicenter study on the morbidity and mortality of intracranial hemorrhage (ICH) with other sporadic data was reported. Neither regional nor national guidelines for ITP management in most Arab countries have been reported. However, the use of initial intravenous immunoglobulin (IVIG) therapy in the Arabian Gulf region in contrast to corticosteroids in most other countries was obvious. Limited data on the use of anti-CD20, avoidance of unnecessary splenectomy, and the use of thrombopoietin receptor analogue in chronic ITP were published recently. A unified consensus for ITP management in the Arab region is essential but not yet realistic. More publications from this region are needed. PMID- 23664510 TI - Thrombopoietin receptor agonists in primary immune thrombocytopenia. AB - Thrombopoietin (TPO) regulates thrombopoiesis through activation of TPO receptors on the megakaryocyte cell surface, resulting in increased platelet production. The TPO receptor agonists are novel treatments for patients with chronic ITP aimed at increasing platelet production through interactions with the TPO receptor on megakaryocytes. Two TPO receptor agonists, romiplostim and eltrombopag, have received regulatory approval. In patients with chronic ITP who remain at risk of bleeding following treatment with first-line therapies, these agents have been shown to increase platelet counts, decrease bleeding events, and reduce the need for adjunctive or rescue treatments. The TPO receptor agonists are well-tolerated, though uncertainty remains regarding the risk of thromboembolism and bone marrow fibrosis. Comparative clinical trial data addressing the efficacy, safety, cost-effectiveness, and impact on health-related quality of life of TPO receptor agonists relative to other second-line treatment options are needed to guide treatment decisions in chronic ITP patients who fail first-line therapies. PMID- 23664512 TI - Occult hemorrhage in immune thrombocytopenia. AB - Assessing clinical bleeding in patients with immune thrombocytopenia (ITP) and predicting future risk of major hemorrhage has proven to be a complicated task given the heterogeneity in bleeding manifestations. Although bleeding scales have been used for this purpose, they fail to account for occult or subclinical hemorrhage. Little is known about the frequency and clinical significance of occult hemorrhage in ITP and no formal investigations have been published on the subject. However, determining the prevalence and incidence of occult hemorrhage may shed light on our understanding of bleeding severity in both children and adults. This review explores the potential clinical significance, sites and methods of testing of subclinical microbleeding in ITP. PMID- 23664513 TI - Selected topics of the 4th International Cooperative Study Group meeting on immune thrombocytopenia revisited. AB - The Intercontinental Cooperative immune thrombocytopenia (ITP) Study Group (ICIS) held its 4th Expert Meeting in September 2012 in Montreux, Switzerland. The program reunited researchers and clinicians from all over the globe and was organized with lectures and seminars for real-time exchange of latest information. Platelets target victims of autoimmune disease on their own, participating under physiological conditions in the immune network; these small cells are more immunologically savvy than previously thought. Currently, researchers focus their attention on regulatory T and regulatory B cells, ie, cells that might have a decisive impact on how ITP spontaneously resolves or evolves into chronic disease. Diagnostic criteria and prognosis are increasingly benefiting from molecular biological tests, and therapy has evolved with the availability of biosimilar agents and recombinant hormones or blockers of their receptors. PMID- 23664514 TI - Standardized clinical assessment and management plans (SCAMPs): perspectives on a new method to understand treatment decisions and outcomes in immune thrombocytopenia. AB - Modern evidence based guidelines in immune thrombocytopenia (ITP) are mostly based on expert opinion. Standardized clinical assessment and management plans (SCAMPs) are flexible, feedback-based practice guidelines that could be valuable for both managing patients with ITP and understanding treatment decisions and outcomes. At Boston Children's Hospital, we have implemented a SCAMP for patients with newly diagnosed and persistent ITP. To develop the algorithm, a group of local ITP experts devised an initial guideline, which was then modified by the attending hematologists who care for ITP patients until consensus was reached. Since deviations from the algorithm are encouraged, all clinicians did not need to agree with all aspects of the algorithm. At each clinic visit, clinicians fill out data collection forms explaining practice deviations. The goals of this process are to decrease practice variation and resource utilization and learn from the outcomes and deviations that occur to continually improve our practice. SCAMPs are an innovative approach to improve quality of care in ITP. PMID- 23664515 TI - Understanding the importance of using patient-reported outcome measures in patients with immune thrombocytopenia. AB - Incorporating patient-reported outcomes (PROs) when studying patients with immune thrombocytopenia (ITP) is essential since treatment decisions are complex and using platelet count only partly explains disease burden. Since most symptoms are only experienced subjectively and are seldom captured during clinician-based evaluations, using self-report is crucial for early symptom detection. However, capturing the patient's illness experience necessitates using well-developed and validated instruments. This article provides insight on the importance of using PROs in ITP, summarizes the methodological steps to develop PRO instruments, and discusses challenges related to integrating PROs into research and clinical practice. PMID- 23664516 TI - CD4+CD25+Foxp3+ regulatory T cells in the pathophysiology of immune thrombocytopenia. AB - Regulatory T cells characterized by CD4, CD25, and transcription factor forkhead box P3, called Tregs, are a subpopulation of CD4(+) T cells specialized for immune suppression. Tregs contribute to maintenance of peripheral immune tolerance, and their defects are thought to play a role in the pathogenesis of various autoimmune diseases. Immune thrombocytopenia (ITP) is an autoimmune disease characterized by increased platelet destruction and reduced platelet production, resulting in decreased platelet count. Recently, a series of studies in adults and children with ITP have found that the frequency of Tregs is reduced in circulation, bone marrow, and spleen, and Treg function is impaired. Treg dysregulation is improved after platelet count is recovered by treatment with dexamethasone, rituximab, or thrombopoietin receptor agonists. In addition, a critical role of Tregs in preventing the anti-platelet autoimmune response has been demonstrated in mice deficient in functional Tregs. Thrombocytopenia observed in Treg-deficient mice is mediated through production of IgG anti platelet autoantibodies, which is analogous to human ITP. Further studies evaluating mechanisms of Treg dysregulation in ITP patients are necessary to elucidate the pathogenesis of ITP and develop novel therapeutic strategies that suppress anti-platelet autoimmune response. PMID- 23664517 TI - Immune thrombocytopenia nomenclature, consensus reports, and guidelines: what are the consequences for daily practice and clinical research? AB - New insights into the pathophysiology and the natural history of immune thrombocytopenia (ITP) and new therapeutical approaches have emerged in the last 10 years that have made necessary the update of previous guidelines. An important step towards the harmonization on both the definition of the disease and the phases of the disease, the objectives of treatment, and the criteria of response to be used in clinical trials has been first made possible throughout the International Working group on ITP. This important step has been followed by an international consensus report and the updated American Society of Hematology (ASH) guidelines focused on the investigation and management of ITP taking into account the data from the most recent clinical trials in the field. In this article, the consequences and translation that these guidelines may have or not on daily practice and on future clinical trials are discussed and the few controversies are pointed out. Whereas these guidelines are helpful for the investigation of ITP and for the harmonization of clinical trials, some area of uncertainties do remain for the best management of ITP and especially the choice of the best second-line strategy in persistent ITP is still far from being consensual. PMID- 23664518 TI - Individualized treatment for immune thrombocytopenia: predicting bleeding risk. AB - Treatment of patients with immune thrombocytopenia (ITP) is often directed at increasing the platelet count and preventing significant hemorrhage even when there is minimal bleeding present. This approach, however, requires that a large number of patients receive prophylactic treatment to prevent major bleeding events. Identification of initial risk factors for development of severe bleeding would allow for more directed and personalized therapy. This review provides a summary of the current literature with the intent to explore various clinical and laboratory risk factors for severe bleeding including mucosal bleeding, platelet count, and aspects of platelet function. PMID- 23664519 TI - Chronic immune thrombocytopenia in children: who needs splenectomy? AB - In the field of emerging innovative therapies, such as thrombopoietin mimetics, the question of who needs splenectomy remains highly relevant. Removal of the spleen is an accepted and potentially curative treatment of immune thrombocytopenia (ITP) after decades with a favorable economical-effect ratio but with relevant morbidity particularly in the young patients. ITP is rare and splenectomy is performed in a minority of children, which makes its research almost impossible, resulting in a poor standardization of the procedure. Hence, in children, recommendation and decision for splenectomy is individually based and rests on expert opinions. Furthermore, local practice and availability of health products affect the frequency of splenectomy. Current guidelines agree on one point: splenectomy should be postponed for at least 12 months after the initial diagnosis of ITP, due to the high probability of improvement or even spontaneous remission. However, evidence-based data are lacking and splenectomy remains controversial. This article reviews the current literature and delineates controversies and complexities of splenectomy in children with ITP. There is an urgent need for consensus of this procedure in pediatric patients. PMID- 23664520 TI - Immune dysregulation in immune thrombocytopenia. AB - Immune thrombocytopenia (ITP) is a bleeding disorder characterized by low platelet counts due to decreased platelet production as well as increased platelet destruction by autoimmune mechanisms. A shift toward Th1 and possibly Th17 cells together with impaired regulatory compartment, including T-regulatory (Tregs) and B-regulatory (Bregs) cells, have been reported, suggesting a generalized immune dysregulation in ITP. Interestingly, several treatments including the use of thrombopoietic agents appear to be associated with improvement in the regulatory compartment. Understanding how Th1/Th17/Treg differentiation and expansion are controlled is central to uncovering how autoimmunity may be sustained in chronic ITP and reversed following response to therapy. In this review, we will summarize the recent findings on the state of the Breg and Treg compartments in ITP, the role of monocyte subsets in the control of Th/Treg expansion, and our working model of how the regulatory compartment may impact response to treatment and the means by which this information may guide therapy in ITP patients in the future. PMID- 23664522 TI - Childhood immune thrombocytopenia--who will spontaneously recover? AB - Although the majority of children with immune thrombocytopenia (ITP) have a short duration of the disease, the very rare but significant complications of the disease often cause fear and anxiety among families of children with ITP. Added to the reduced quality of life (QoL) of those children are restrictions imposed on daily activities to avoid trauma. Treatment decisions in chronic ITP and especially regarding splenectomy are hampered by the inability to predict when recovery will take place. Identification of predictors of recovery would be beneficial for improving treatment decisions and QoL of both children and families. This literature review focuses on clinical parameters and emerging genetic biomarkers for prediction of duration of childhood ITP. Higher recovery rates were found among infants with newly diagnosed ITP. In contrast onset of the disease at adolescence was associated with worse recovery rates. Six clinical features were found to be associated with short duration of disease; the most prominent ones were abrupt onset of bleeding symptoms (<2 weeks) and age at onset <= 10 years. Two genetic biomarkers have been suggested as predictors of chronic disease: overexpression of vanin-1 (VNN-1), an oxidative stress sensor, and the Q63R missense variant of the gene encoding the cannabinoid receptor type 2. To be clinically useful each of those predictors requires further validation in larger studies. Genetic biomarkers will potentially offer direct and early prognosis estimation. PMID- 23664521 TI - Innate and adaptive immunity in immune thrombocytopenia. AB - Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by both accelerated clearance of autoantibody-sensitized platelets and suboptimal platelet production. A number of studies have provided evidence of disturbed innate and adaptive immune responses in patients with ITP. This brief review will highlight some of the more recent work in this field and highlight other findings that provide a potential link between ITP, systemic lupus erythematosus (SLE), and autoimmune hemolytic anemia (AHA). PMID- 23664523 TI - B-cell depletion in immune thrombocytopenia. AB - B cells play an important role in the immune response and can lead to the development of autoimmune diseases and particularly immune thrombocytopenia (ITP). A rational approach to ITP treatment could involve B-cell depletion such as with rituximab. Rituximab is a chimeric monoclonal antibody directed against CD20 molecule. It has direct effects on antibody production and indirect effects on cellular immunity. Rituximab demonstrated an overall response rate of 62.5% that lasted from 2-48 months. The ability of rituximab as an effective splenectomy-avoiding option was recently confirmed in a meta-analysis of randomized clinical trials and observational studies including 368 patients with an overall response rate of 57%. However, the estimated 5- year response is only 21% in adults. Rituximab appears to be well tolerated, but we lack studies of long-term tolerance. The optimal time to administer rituximab for ITP remains unclear. There is consensus to administer corticosteroids or intravenous immunoglobulin (IVIg) as first-line therapy in ITP. A panel of experts was unable to formulate a clear strategy for the respective place of splenectomy, thrombopoietin-receptor agonists, and rituximab as second-line treatment. Among new-generation CD20-targeted therapy, only veltuzumab has been tested for ITP. Preliminary study suggests that it could have similar efficacy to rituximab. Options other than anti-CD20 treatment may modulate and/or inhibit the B-cell compartment. Several monoclonal antibodies (MoAbs) directed against different B lymphocyte receptors or structures implicated in the cooperation between B and T lymphocytes have been successfully tested in various autoimmune diseases. Testing these options in ITP will be an exciting challenge. PMID- 23664524 TI - Immune thrombocytopenia patients requiring anticoagulation--maneuvering between Scylla and Charybdis. AB - Immune thrombocytopenia (ITP) is no longer a disorder of young people. Half of the patients are older than 50 and comorbidities become more common with age. Anticoagulation has to be discussed when an ITP patient develops atrial fibrillation, venous or arterial thromboembolism, myocardial infarction, or stroke. At the same time low platelet counts often prohibit therapeutic anticoagulation. Guidelines do not give guidance for these situations. This article summarizes experiences from case reports and small series and suggests an approach to ITP patients with thrombocytopenia and an indication for anticoagulation. PMID- 23664525 TI - Immune thrombocytopenia and B-cell-activating factor/a proliferation-inducing ligand. AB - Primary immune thrombocytopenia (ITP) is an organ-specific autoimmune disorder characterized by autoantibody-mediated enhanced platelet destruction and dysmegakaryocytopoiesis. B cells have been demonstrated to play critical roles in the pathophysiology of ITP. B-cell-activating factor (BAFF) and a proliferation inducing ligand (APRIL) are crucial cytokines supporting survival and differentiation of B cells, and dysregulation of BAFF/APRIL is involved in the pathogenesis of B-cell related autoimmune diseases including ITP. Currently ongoing clinical trials using BAFF and/or APRIL-blocking agents have yielded positive results in human systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), further confirming the pathological role of BAFF/APRIL in autoimmunity. This review will describe the function of BAFF/APRIL and address the feasibility of BAFF/APRIL inhibition in the management of ITP. PMID- 23664526 TI - Decreased incidence of cytomegalovirus infection with sirolimus in a post hoc randomized, multicenter study in lung transplantation. AB - BACKGROUND: Cytomegalovirus (CMV) is the most common opportunistic infection in lung transplantation. A recent multicenter, randomized trial (the AIRSAC study) comparing sirolimus to azathioprine in lung transplant recipients showed a decreased incidence of CMV events in the sirolimus cohort. To better characterize this relationship of decreased incidence of CMV events with sirolimus, we examined known risk factors and characteristics of CMV events from the AIRSAC database. METHODS: The AIRSAC database included 181 lung transplant patients from 8 U.S.-based lung transplant centers that were randomized to sirolimus or azathioprine at 3 months post-transplantation. CMV incidence, prophylaxis, diagnosis and treatment data were all prospectively collected. Prophylaxis and treatment of CMV were at the discretion of each institution. RESULTS: The overall incidence of any CMV event was decreased in the sirolimus arm when compared with the azathioprine arm at 1 year after lung transplantation (relative risk [RR] = 0.67, confidence interval [CI] 0.55 to 0.82, p < 0.01). This decreased incidence of CMV events with sirolimus remained significant after adjusting for confounding factors of CMV serostatus and CMV prophylaxis. CONCLUSIONS: These data support results from other solid-organ transplantation studies and suggest further investigation of this agent in the treatment of lung transplant recipients at high risk for CMV events. PMID- 23664527 TI - Frequency of coronary artery fistulae is increased after orthotopic heart transplantation. PMID- 23664528 TI - Expressed in high metastatic cells (Ehm2) is a positive regulator of keratinocyte adhesion and motility: The implication for wound healing. AB - BACKGROUND: Multiple factors have been shown to delay dermal wound healing. These resultant wounds pose a significant problem in terms of morbidity and healthcare spend. Recently, an increasing volume of research has focused on the molecular perturbations underlying non-healing wounds. OBJECTIVES: This study investigates the effect of a novel cancer promoter, Ehm2, in wound healing. Ehm2 belongs to the FERM family of proteins, known to be involved in membrane-cytoskeletal interactions, and has been shown to promote cancer metastasis in melanoma, prostate cancer and breast cancer. METHODS: Ehm2 mRNA levels were analysed using qRT-PCR, standardised to GAPDH, from either acute or chronic wounds, and normal skin. IHC analysis was also undertaken from wound edge biopsies. An anti-Ehm2 transgene was created and transfected into the HaCaT cell line. The effect of Ehm2 knockdown on migration, adhesion, growth, cell cycle progression and apoptosis was analysed using standard laboratory methods. Western Blot analysis was used to investigate potential downstream protein interactions. RESULTS: Ehm2 is expressed nearly three times higher in acute wound tissues, compared to chronic wound tissues. Increased Ehm2 expression is found in wounds undergoing healing, especially at the leading wound edge. In vitro, Ehm2 knockdown reduces cellular adhesion, migration and motility, without affecting growth, cell cycle and apoptosis. Finally, Ehm2 knockdown results in reduced NWasp protein expression. CONCLUSION: These results suggest Ehm2 may be an important player in the wound healing process, and show that Ehm2 knockdown downregulates the expression of NWasp, through which it may have its effect on cellular migration. PMID- 23664529 TI - Possible roles of barrier-to-autointegration factor 1 in regulation of keratinocyte differentiation and proliferation. AB - BACKGROUND: Barrier-to-autointegration factor 1 (BANF1) is an essential component of the nuclear lamina. Recent studies have clarified that BANF1 is a causative molecule of Nestor-Guillermo progeria syndrome. Despite recent progress in studies on BANF1, the role of BANF1 in keratinocytes has not been addressed at all. OBJECTIVE: This study aims to determine the localization of BANF1 in psoriatic epidermal keratinocytes as well as in normal keratinocytes and to clarify its possible function in those keratinocytes. METHODS: Immunohistochemistry of BANF1 was performed on 10 cases of psoriasis and 10 healthy control individuals. Expression of molecules associated with inflammation of the skin by HSC-1, a human skin squamous cell carcinoma cell line, stimulated by TPA and treated with siRNA to BANF1 were analyzed with quantitative PCR and Western blot. RESULTS: Strong nuclear-dominant immunostaining of BANF1 was seen in the epidermal keratinocytes of psoriatic lesions, although in the normal epidermis, all the KCs in the upper epidermis showed cytoplasmic-dominant staining of BANF1. By BANF1 knockdown in TPA-stimulated HSC-1 cells, the mRNA levels of S100A9 were significantly elevated compared with those of control HSC-1 cells treated with siRNA to CD4. The protein expression level of S100A9 and phosphorylated c-Jun was elevated by BANF1 knockdown. CONCLUSION: BANF1 is translocated onto the nuclear envelope in the psoriatic epidermal keratinocytes, suggesting that BANF1 is associated with upregulated proliferation of keratinocytes in psoriatic lesions. Activation of BANF1 possibly suppresses S100A9 expression and inactivates c-Jun, resulting in suppression of cutaneous inflammation. PMID- 23664530 TI - Clinical features distinguishing lymphoma development in primary Sjogren's Syndrome--a retrospective cohort study. AB - OBJECTIVE: The objective is to determine the relationship between clinical features and non-Hodgkin lymphoma (NHL) development in primary Sjogren's Syndrome (pSS), taking recently designed disease activity/severity scores into account. METHODS: Medical charts of pSS patients were retrospectively analyzed, scoring first and last visits with the (cumulative) EULAR Sjogren's Syndrome Disease Activity Index and counting extraglandular manifestations, comparing patients with and without NHL. RESULTS: One hundred ninety-five patients were analyzed with a median follow-up of 92 months (range 12-256). Twenty-one patients (11%) had NHL. Associations of parotid gland enlargement (OR 2.84) and low C4 (OR 7.71) with NHL were confirmed. In NHL patients, development of purpura, peripheral neuropathy (PNP), and glomerulonephritis (GN) concurred with lymphoma in 3/3, 5/7, and 2/2 of cases, respectively. Otherwise, purpura and PNP were not associated with NHL later on. This suggests that these symptoms might represent paraneoplastic events (in 16%, 24%, and 100% of our cases, respectively). Presence of IgM-kappa clonal components was associated with lymphoma in 64% of cases. Disease activity/severity scores at first visit could not predict lymphoma development, nor was the pSS disease course significantly worse in patients with NHL. CONCLUSIONS: In our cohort, no clinical manifestation or disease score could clearly select patients with subsequent lymphoma development. Presence of IgM kappa clonal components and development of purpura, PNP, and GN should alert the clinician for the presence of lymphoma. PMID- 23664532 TI - Comparison of laparoscopic versus open adrenalectomy: results from American College of Surgeons-National Surgery Quality Improvement Project. AB - BACKGROUND: Although the existing literature suggests that laparoscopic adrenalectomy may be associated with less postoperative morbidity than open adrenalectomy, a comparison of the two approaches has not been published using American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) data. The objective of our analysis was to compare the 30-d outcomes after laparoscopic versus open adrenalectomy using this data source. METHODS: The ACS NSQIP Participant User Files for 2005-2010 were used for this retrospective analysis, which included all patients with (1) a primary Current Procedural Terminology code for open or laparoscopic adrenalectomy and (2) a postoperative International Classification of Diseases, Ninth Revision (ICD-9) code for adrenal gland pathology. Primary outcomes were 30-d postoperative mortality, overall complication rate, and length of postoperative hospitalization. The association between surgical approach and primary outcomes were determined after adjusting for a comprehensive array of patient- and procedure-related factors. RESULTS: A total of 3100 patients were included for analysis (644 undergoing open versus 2456 undergoing laparoscopic adrenalectomy). Patients undergoing a laparoscopic procedure had significantly lower postoperative morbidity and shorter length of stay than patients undergoing an open procedure after adjustment for patient- and procedure-related factors. Similar findings were demonstrated for all indications, including malignancy. CONCLUSIONS: To our knowledge, the present study represents the largest comparison to date of laparoscopic versus open adrenalectomy. Our findings suggest that the laparoscopic approach is associated with sizeable reductions in postoperative morbidity and length of postoperative hospitalization. PMID- 23664533 TI - Tumor necrosis factor-alpha preconditioning attenuates liver ischemia/reperfusion injury through preserving sarco/endoplasmic reticulum calcium-ATPase function. AB - BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional cytokine. In this study, we investigated the role of TNF-alpha preconditioning in liver ischemia/reperfusion injury (IRI). METHODS: After IRI, serum alanine aminotransferase, protein levels of SERCA-3, and Caspase-3 in liver were analyzed. In vitro study, primary hepatocytes were isolated from mice and cultured in hypoxic media with or without TNF-alpha. The levels of SERCA-3, Caspase-3, and intracellular calcium were evaluated after 24-h incubation. In addition, protease inhibitors were adopted to determine the role of SERCA-3 in TNF-alpha preconditioning. RESULTS: Low dose of TNF-alpha preconditioning protected liver from IRI, which was described by reduced serum alanine aminotransferase, Capase-3, and elevated SERCA-3 compared with the animals without TNF-alpha treatment. The in vitro test confirmed the protective effect of TNF-alpha through maintaining homeostasis of intracellular calcium. However, the effect of TNF-alpha was deprived by protease inhibitors. CONCLUSIONS: In this study, we demonstrated that IRI reduced SERCA-3 expression in liver. Low dose of TNF-alpha preconditioning protected against SERCA-3 reducing, promoted intercellular calcium storage, and attenuated liver IRI. PMID- 23664535 TI - Axillary ultrasound in patients with clinically node-negative breast cancer: which features are predictive of disease? AB - BACKGROUND: Axillary ultrasound is used in the evaluation of breast cancer patients to identify subclinical node-positive disease. The study aim was to identify whether certain radiologic characteristics correlate with cytology and final pathology. METHODS: We retrospectively reviewed ultrasound images of 110 women with clinically node-negative breast cancer and suspicious axillary ultrasound to identify specific anatomic characteristics previously shown to be more commonly associated with metastatic involvement. Results were compared with cytology and final pathology. We used descriptive statistics for data summary. RESULTS: Of the 110 patients, cytology was positive in 71 (68%) and final pathology was positive in 80 (73%). The most common indication for biopsy was lymph node cortex characterized by thickening or eccentric contour (N = 40). Loss of the fatty hilum was described in 17 patients, and 9 patients had lymph nodes with both abnormal cortical and hilar features. Of 43 patients with "suspicious" disease without specific criteria, the most common indication for biopsy was disparity in size of one or more lymph nodes compared with others. Maximum cortical thickness was greater in patients with positive cytology compared with those with negative cytology (7.6 versus 6.2 mm; P = 0.047). Ultrasound characteristics such as lymph node size, cortical morphology, contour, and hilar fat were not individually predictive of final cytology and pathology. CONCLUSIONS: Axillary ultrasound is a valuable tool that accurately predicted malignant axillary disease in 73% of patients with clinically node-negative breast cancer. Elaboration of standard criteria for nodal evaluation will improve usefulness of this imaging modality in preoperative staging of the axilla. PMID- 23664534 TI - Rehabilitation after trauma; does age matter? AB - BACKGROUND: Variability exits in the ability to predict overall recovery after trauma and inpatient rehabilitation. The aim of this study was to identify factors predicting functional improvement in trauma patients undergoing inpatient rehabilitation. METHODS: We performed a 3-y retrospective cohort analysis on a prospectively collected database of all trauma patients discharged from a level I trauma center to a single inpatient rehabilitation center. Patient's Functional Independence Measures (FIM) scores on hospital discharge and on discharge from the rehabilitation center were collected. Delta FIM was defined as the difference in FIM between rehabilitation center discharge and hospital discharge. Multiple linear regressions were performed to identify hospital admission factors associated with delta FIM. RESULTS: We included 160 patients, 69% were male, mean age 54.6 +/- 22 y, and median Injury Severity Score 14 [10-50]. Based on rehabilitation admission FIM scores, 29 were totally dependent and 131 were partially dependent. The mean change in FIM was 39.4 +/- 13. Age, gender, Glasgow Coma Scale on presentation, Injury Severity Score, systolic blood pressure on presentation, and intensive care unit length of stay were not predictive of delta FIM. Hospital length of stay and head Abbreviated Injury Score on hospital admission were negative predictors of delta FIM. CONCLUSIONS: In our study, age as an independent factor was not predictive of functional outcome after injury. The extent of head injury continues to negatively affect the overall functional improvement based on FIM. PMID- 23664536 TI - Sensitivity and predictive value of ultrasound in pediatric cholecystitis. AB - BACKGROUND: Ultrasonography has a high sensitivity and positive predictive value (PPV) for diagnosing cholecystitis in adults. The objective of this study was to determine the sensitivity and PPV of ultrasonography in the diagnosis of pediatric cholecystitis. METHODS: We performed a single-institution retrospective review of the records of all patients undergoing cholecystectomy with a preoperative ultrasound during 2005-2010. We calculated sensitivity, specificity, and PPV using pathologic findings as the standard for the diagnosis of cholecystitis. RESULTS: In the 223 included patients, the median (interquartile range) age was 14 y (11-16 y); and 64% were female. Preoperative symptoms of abdominal pain were reported in 98% of patients. A diagnosis of cholecystitis was reported in 10% (23 of 223) of ultrasound readings. Pathologic diagnosis of cholecystitis was present in 80% (179 of 223) of cholecystectomy specimens, with 8% (15 of 179) having acute cholecystitis, 83% (148 of 179) chronic cholecystitis, and 9% (16 of 179) both. Sensitivity of ultrasound findings ranged from 6% for Murphy's sign to 66% for cholelithiasis. Positive predictive values ranged from 67% for Murphy's sign to 87% for gallbladder sludge. Presence of any one ultrasound sign had a sensitivity of 82% and PPV of 80%. CONCLUSIONS: Ultrasound findings in pediatric cholecystitis have lower sensitivities and PPVs than reported in adults. These differences may be explained by the higher prevalence of chronic cholecystitis in children, which suggests that children may have milder episodes of self-limited gallbladder inflammation compared with adults, which may lead to a delay in treatment. PMID- 23664537 TI - Immunohistochemical evaluation of TMPRSS2-ERG gene fusion in adenosis of the prostate. AB - Adenosis (atypical adenomatous hyperplasia) is a benign lesion that morphologically mimics prostate adenocarcinoma, although the relationship between these 2 lesions is still debated. The TMPRSS2-ERG fusion is a common chromosomal rearrangement that occurs early in the development of invasive adenocarcinoma of the prostate and results in the expression of a truncated ERG protein. This fusion is present in 50% of adenocarcinomas and in 20% of high-grade prostate intraepithelial lesions. Until recently, fluorescent in situ hybridization was the only method available to detect these rearrangements. A specific anti-ERG antibody is now available for detecting ERG protein expression and serves as a useful marker for ERG rearrangements. Formalin-fixed, paraffin-embedded tissue sections of adenosis from cases of prostate biopsies (n = 30), transurethral resections of the prostate (n = 12), and radical prostatectomies (n = 3) were analyzed via immunohistochemistry for ERG. None (0%) of the foci of adenosis were positive for ERG protein expression. Of 40 cases of Gleason score 6 adenocarcinoma on a tissue microarray, 22 (55%) were positive for ERG protein. Of the positive cases, 14 (63.6%) were moderate in intensity, with the remaining 36.4% being weak. The lack of ERG expression in adenosis supports the notion that it is not a precursor lesion of adenocarcinoma. Moreover, it suggests that immunohistochemistry for ERG expression could be a useful tool to differentiate adenosis from adenocarcinoma. PMID- 23664538 TI - TWIST1 promoter methylation is associated with prognosis in tonsillar squamous cell carcinoma. AB - Tonsillar squamous cell carcinomas (TSCC) frequently present with locally advanced diseases and cervical metastases, which are associated with poor prognoses. Epithelial-mesenchymal transition (EMT) is critical for tumor invasiveness and metastatic potential. Recent studies have shown that TWIST1 inducing EMT is overexpressed and hypermethylated in several cancers, indicating disease progression. The aim of the present study was to determine the clinical and prognostic significance of TWIST1 hypermethylation and EMT-related protein expression in TSCC. Methylation levels of TWIST1 promoter were analyzed by quantitative real-time methylation-specific polymerase chain reaction. Immunohistochemical analyses of TWIST1, Snail, and SMAD nuclear interacting protein-1 (SNIP1) were performed in 65 formalin-fixed, paraffin-embedded blocks of surgically resected specimens. TWIST1 promoter hypermethylation was found in 27.7% (18/65) of TSCCs. TWIST1 promoter hypermethylation was associated with poor differentiation (P = .012). Contralateral cervical lymph node metastasis was more frequently observed in TWIST1-methylated tumors (P = .029). High protein expressions of TWIST1, Snail, and SNIP1 were observed in 14 TSCC specimens (21.5%), 21 TSCC specimens (32.3%), and 38 TSCC specimens (58.5%), respectively. SNIP1 expression correlated significantly with TWIST1 methylation (P = .001), whereas TWIST1 protein expression did not. Contralateral cervical lymph node metastasis was an independent risk factor of the decreased overall survival rate (P = .002). TWIST1 methylation (P = .031) and pN stage (P = .037) were independent factors of poor prognoses affecting disease-free survival. TWIST1 promoter hypermethylation may be a useful molecular marker for predicting prognoses and contralateral cervical lymph node metastases in patients with TSCC. PMID- 23664539 TI - Expression of group IIA phospholipase A2 is an independent predictor of favorable outcome for patients with gastric cancer. AB - Growing evidence suggests that phospholipase A2 (PLA2) plays a pivotal role in tumorigenesis in human gastrointestinal cancer. One of the well-studied isoforms of PLA2, group IIA PLA2 (PLA2G2A), appears to exert its protumorigenic or antitumorigenic effects in a tissue-specific manner. The present study was designed to determine the expression profile and prognostic value of PLA2G2A in gastric cancer in a large Chinese cohort. By using real-time polymerase chain reaction, the amount of PLA2G2A messenger RNA in 60 pairs of fresh gastric tumors and adjacent noncancerous mucosa was measured. The immunostaining of PLA2G2A in 866 gastric cancers with paired noncancerous tissues was assayed. No expression of PLA2G2A was found in normal gastric mucosa, and focal expression of PLA2G2A was noticed in intestinal metaplasia, whereas significantly increased expression of PLA2G2A was observed in the cytoplasm of gastric cancer cells. Furthermore, the extent of PLA2G2A expression was associated with tumor size (P < .001), tumor differentiation (P = .001), T class (P < .001), N class (P < .001), and TNM stage (P < .001) of gastric cancer. Multivariate analysis showed that PLA2G2A expression was an independent predictor of survival for patients with gastric cancer (P = .024). Expression of PLA2G2A seems to be protective for patients with gastric cancer (hazard ratio, 1.423; 95% confidence interval, 1.047-1.935), and it may be a target for achieving better treatment outcomes. PMID- 23664540 TI - Expression of FGFR3 and FGFR4 and clinical risk factors associated with progression-free survival in synovial sarcoma. AB - Although rare, synovial sarcoma (SS) is one of the most common soft tissue sarcomas affecting young adults. To investigate potential tumor markers related to synovial sarcoma prognosis, we carried out a single-institution retrospective analysis of 103 patients diagnosed with SS between 1980 and 2009. Clinical outcome data were obtained from medical records, and archived tissue samples were used to evaluate the relationship between progression-free survival (PFS) and several prognostic factors, including tumor expression of FGFR3 and FGFR4. No associations were found between PFS and gender, body mass index, tumor site, SS18 SSX translocation, or FGFR4 expression. As seen in previous studies, age at diagnosis (<35, 63% versus >=35 years, 31% 10-year PFS; P = .033), histologic subtype (biphasic, 75% versus monophasic 34% 10-year PFS; P = .034), and tumor size (<=5 cm, 70% versus >5 cm, 22% 10-year PFS; P < .0001) were associated with PFS in SS patients. In addition, in a subset of patients with available archived tumor samples taken prior to chemotherapy or radiation (n = 34), higher FGFR3 expression was associated with improved PFS (P = .030). To the best of our knowledge, this is the largest study of SS to date to suggest a potential clinical role for FGFR3. While small numbers make this investigation somewhat exploratory, the findings merit future investigation on a larger scale. PMID- 23664541 TI - Oncogene abnormalities in a series of primary melanomas of the sinonasal tract: NRAS mutations and cyclin D1 amplification are more frequent than KIT or BRAF mutations. AB - Primary malignant melanoma of sinonasal tract is a rare but severe form of melanoma. We retrospectively analyzed 17 cases and focused on the histologic presentation and the expression of c-Kit, epidermal growth factor receptor (EGFR), cyclin D1/Bcl-1, PS100, and HMB45 and searched for BRAF, NRAS, and KIT mutations that are known to be associated with melanoma subtypes, together with amplifications of KIT, cyclin D1, cyclin-dependent kinase 4, MDM2, and microphthalmia-associated transcription factor using quantitative polymerase chain reaction. In most cases (78%), an in situ component was evidenced. Invasive components were composed of diffuse areas of rhabdoid, epithelioid, or spindle cells and, in most cases, lacked inflammatory reaction, suggesting that an immune escape phenomenon probably develops when the disease progresses. EGFR was rarely and weakly expressed in the in situ component of 2 cases. None of the investigated case showed BRAF V600E, but 1 had a D594G mutation. NRAS mutations in exon 2 (G12D or G12A) were found in 3 cases (18%), and a KIT mutation in exon 11 (L576P), in 1, whereas c-Kit was expressed at the protein level in half of the cases. Amplifications of cyclin D1 were evidenced in 5 cases, confirmed in 3 by fluorescence in situ hybridization, but this was not always correlated with protein expression, found in 8 patients (62.5%), 3 having no significant amplification. In conclusion, primary malignant melanoma of sinonasal tract is not associated with BRAF V600E mutations. Instead, NRAS or KIT mutations and cyclin D1 amplification can be found in a proportion of cases, suggesting that primary malignant melanoma of sinonasal tract is heterogeneous at the molecular level and should not be sensitive to therapeutic approaches aiming at BRAF. PMID- 23664542 TI - Usefulness of significant morphologic characteristics in distinguishing between Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative Merkel cell carcinomas. AB - Merkel cell polyomavirus (MCPyV) monoclonally integrates into genomes of approximately 80% of Merkel cell carcinomas (MCCs) and undergoes mutation. We previously demonstrated statistically significant differences in tumor cell morphology and biology between MCPyV-positive and MCPyV-negative MCCs. We reassessed the usefulness of our morphologic criteria in differentiating MCPyV negative and MCPyV-positive MCCs for practical diagnosis. Two trainees and 4 pathologists challenged estimations (5-point confidence scale) of MCPyV infection in MCCs using hematoxylin and eosin-stained slides of 43 new MCC cases and 2 morphologic criteria: (1) nuclear polymorphism is higher and cytoplasm is more abundant in MCPyV-negative MCC cells, and (2) MCC combined with squamous cell carcinoma is defined as MCPyV negative, regardless of tumor cell morphology of MCC. Subsequently, immunohistochemistry for MCPyV large T antigen and polymerase chain reaction for MCPyV DNA yielded concordant results (MCPyV positivity was 30/43 and 32/43, respectively) for 41 (96%) of 43 cases. The mean accuracy, sensitivity, and specificity of the trainees and pathologists were 92.4% +/- 1.5% and 81.5% +/- 11.0%, 95.6% +/- 6.2% and 90.2% +/- 8.3%, and 83.3% +/- 11.8% and 74.6% +/- 14.1%, respectively. Values of the areas under the curve were 0.80 to 0.95, indicating good informative scores. Using our morphologic criteria, observers can predict the absence of MCPyV infection and diagnose MCPyV-negative MCCs with poor prognosis. Unexpectedly, the performance of trainees was superior to that of pathologists, implying that our morphologic criteria are useful even for practitioners having little experience. Our morphologic criteria will provide pathologists with convenient and reliable hallmarks for accurate MCC diagnosis. PMID- 23664543 TI - Oncocytic glioblastoma: a glioblastoma showing oncocytic changes and increased mitochondrial DNA copy number. AB - Ten cases of glioblastomas showing oncocytic changes are described. The tumors showed mononuclear to multinuclear cells and abundant, granular, eosinophilic cytoplasm. The cytoplasm of these same cells was filled by strongly immunoreactive mitochondria. At ultrastructure, numerous mitochondria, some of which were large, were evidenced in the cytoplasm of neoplastic cells. Finally, 9 of 10 of these cases had a significantly high mitochondrial DNA content compared with control tissue (P < .01). It seems that, for these tumors, the designation of oncocytic glioblastoma is appropriate. To the best of our knowledge, oncocytic changes have not been previously reported in such neoplasms. Oncocytic glioblastomas have to be added to the long list of various tumors that can manifest "unexpected" oncocytic changes in different organs. Albeit failing to show statistical significance (log-rank test, P = .597; Wilcoxon test, P = .233), we observed a trend for longer median survival in oncocytic glioblastomas, when compared with "ordinary" glioblastomas (median survival of 16 versus 8.7 months). Thus, it seems that the definition of neoplasms showing oncocytic changes, currently based on classic morphological parameters (ie, histology, ultrastructure, and immunohistochemistry), can be expanded by including the quantitative assessment of mitochondrial DNA content. PMID- 23664544 TI - High interleukin-10 expression within the central nervous system may be important for initiation of recovery of Dark Agouti rats from experimental autoimmune encephalomyelitis. AB - Dark Agouti (DA) rats are highly susceptible to induction of experimental autoimmune encephalomyelitis (EAE), still they completely recover from the disease. Here, we were interested to determine contribution of major anti inflammatory cytokines transforming growth factor (TGF)-beta and interleukin (IL) 10 to the recovery of DA rats from EAE. To that extent we determined CNS expression of these cytokines in DA rats at different phases of EAE and compared data to those obtained in EAE-resistant Albino Oxford (AO) rats. Higher expression of TGF-beta was persistently observed in the CNS of AO rats, even if rats were not immunized. This implied that high TGF-beta within the CNS is important for resistance of AO rats to EAE induction. On the contrary, IL-10 expression was consistently higher in DA than in AO rats and it culminated at the peak of EAE. Methylprednisolone suppressed EAE and expression of IL-10 in spinal cord homogenates, while IL-10 was increased in CNS-infiltrating immune cells. This implied that IL-10 might have a significant role in recovery of DA rats from the disease. Thus, we next explored effects of IL-10 on astrocytes, glial cells that largely contribute to control of CNS inflammation. IL-10 stimulated astrocytic expression of an important regulator of neuroinflammation, CXCL12. Thus, IL-10 might contribute to recovery of DA rats from EAE through induction of CXCL12 expression in astrocytes. PMID- 23664546 TI - AA amyloidosis associated with systemic-onset juvenile idiopathic arthritis. AB - We report a 12-year-old boy with nephrotic syndrome due to renal AA amyloidosis. The AA amyloidosis was associated with a 3-year history of systemic-onset juvenile idiopathic arthritis. The presence of serum amyloid A protein was confirmed by laser microdissection of Congo Red-positive glomeruli and vessels followed by liquid chromatography and tandem mass spectrometry; this analysis excluded hereditary and familial amyloidosis. Aggressive management of the systemic-onset juvenile idiopathic arthritis resulted in improvement in clinical and laboratory parameters. The case represents an unusual cause of nephrotic syndrome in children. Early diagnosis of renal amyloidosis and management of systemic-onset juvenile idiopathic arthritis is paramount to preventing progression of kidney disease. PMID- 23664545 TI - Peripheral administration of translation inhibitors reverses increased hyperalgesia in a model of chronic pain in the rat. AB - Chronic pain is extremely difficult to manage, in part due to lack of progress in reversing the underlying pathophysiology. Since translation of messenger ribonucleic acids (mRNAs) in the peripheral terminal of the nociceptor plays a role in the transition from acute to chronic pain, we tested the hypothesis that transient inhibition of translation in the peripheral terminal of the nociceptor could reverse hyperalgesic priming, a model of transition from acute to chronic pain. We report that injection of translation inhibitors rapamycin and cordycepin, which inhibit translation by different mechanisms, at the peripheral terminal of the primed nociceptor produces reversal of priming in the rat that outlasted the duration of action of these drugs to prevent the development of priming. These data support the suggestion that interruption of translation in the nociceptor can reverse a preclinical model of at least 1 form of chronic pain. PERSPECTIVE: This study provides evidence that ongoing protein translation in the sensory neuron terminals is involved in pain chronification, and local treatment that transiently interrupts this translation may be a useful therapy to chronic pain. PMID- 23664547 TI - Out-of-hospital use of proton pump inhibitors and hypomagnesemia at hospital admission: a nested case-control study. AB - BACKGROUND: Case series suggest that long-term use of proton pump inhibitors (PPIs) is associated with hypomagnesemia, but the current literature lacks systematically collected data. Our aim was to examine whether hypomagnesemia at the time of hospital admission is associated with out-of-hospital use of PPIs. STUDY DESIGN: Nested case-control study matched for age and sex. SETTING & PARTICIPANTS: Data were collected retrospectively from a tertiary acute-care facility. Eligible cases consisted of 402 adults with hypomagnesemia (serum magnesium <1.4 mEq/L) at the time of hospital admission to medical services, age- and sex-matched with 402 control individuals with normal serum magnesium levels (1.4-2.0 mEq/L). PREDICTOR: Out-of-hospital PPI use was identified in the hospital record. An omeprazole equivalent dose was calculated when possible. Covariates included the Charlson-Deyo comorbidity index, diabetes, diuretic use, estimated glomerular filtration rate, and gastroesophageal reflux. OUTCOME: Multivariable conditional logistic regression analyses were used to examine the association of PPI use with hypomagnesemia at the time of hospital admission. RESULTS: PPI use was not associated with hypomagnesemia (adjusted OR, 0.82; 95% CI, 0.61-1.11). Neither PPI type nor omeprazole equivalent daily dose was associated with hypomagnesemia. Sensitivity analyses of PPI use restricted to patients with esophageal disorders (adjusted OR, 1.00; 95% CI, 0.69-1.45), severe hypomagnesemia (magnesium, <=1.0 mEq/L; adjusted OR, 0.78; 95% CI, 0.13-4.61), or estimated glomerular filtration rate >=60 mL/min/1.73 m(2) (adjusted OR, 0.84; 95% CI, 0.53-1.34) were unrevealing. LIMITATIONS: Exposure misclassification; hospitalized patients on medical services may not be representative of a broader ambulatory-based population. CONCLUSIONS: In a hospital-based adult population, out-of-hospital PPI use is not associated with hypomagnesemia at the time of hospital admission to medical services. In light of these inconclusive results, prospective cohort studies are needed to address this rare potential medication related adverse effect. PMID- 23664548 TI - Blood pressure, proteinuria, and phosphate as risk factors for progressive kidney disease: a hypothesis. AB - Chronic kidney disease (CKD) affects approximately 500 million people worldwide and is increasingly common in both industrialized and emerging countries. Although the mechanisms underlying the inexorable progression of CKD are incompletely defined, recent discoveries may pave the way to a more comprehensive understanding of the pathophysiology of CKD progression and the development of new therapeutic strategies. In particular, there is accumulating evidence indicating a key role for the complex and yet incompletely understood system of divalent cation regulation, which includes phosphate metabolism and the recently discovered fibroblast growth factor 23 (FGF-23)/klotho system, which seems inextricably associated with vitamin D deficiency. The aim of this review is to discuss the links between high blood pressure, proteinuria, phosphate levels, and CKD progression and explore new therapeutic strategies to win the fight against CKD. PMID- 23664549 TI - Tripterygium preparations for the treatment of CKD: a systematic review and meta analysis. AB - BACKGROUND: Preparations of the herb Tripterygium wilfordii Hook F are used widely for the treatment of chronic kidney disease in China. The efficacy and safety of Tripterygium preparations still have not been fully identified. STUDY DESIGN: Systematic review and meta-analysis. SETTING & POPULATION: Patients with chronic kidney disease. SELECTION CRITERIA FOR STUDIES: Randomized controlled trials. INTERVENTION: Tripterygium preparations (Tripterygium glycoside tablets, Tripterygium hypoglaucum Hutch tablets, and Tripterygium granules or extracts) versus placebo, standard care, or other immunosuppressive treatment. OUTCOMES: Weighted mean difference and summary estimates of relative risk (RR) reductions with 95% CIs were calculated with a random-effects model. Outcomes analyzed included change in proteinuria, serum creatinine level, and creatinine clearance rate, as well as remission and relapse rate and drug-related adverse events. RESULTS: We identified 75 trials that included 4,386 participants. Overall, Tripterygium therapy reduced proteinuria by protein excretion of 628 (95% CI, 736 to -521) mg/d and reduced serum creatinine level by 0.12 (95% CI, -0.17 to 0.06) mg/dL compared with controls (both P < 0.001) in a range of kidney conditions. Tripterygium preparations also increased the rate of complete remission by 56% (95% CI, 32%-85%; P < 0.001) and of complete or partial remission by 24% (95% CI, 17%-31%; P < 0.001) while reducing relapse by 58% (95% CI, 42%-69%; P < 0.001). Tripterygium preparations increased the rate of liver function test result abnormalities (RR, 4.03; 95% CI, 2.24-7.25; P < 0.001) and altered menstruation (RR, 5.29; 95% CI, 2.09-13.38; P < 0.001). LIMITATIONS: Suboptimal study quality, significant heterogeneity in the primary outcome. CONCLUSIONS: Tripterygium preparations may have nephroprotective effects, but high-quality trials are required to reliably determine the balance of benefits and harms. PMID- 23664550 TI - Age estimation standards for a Western Australian population using the coronal pulp cavity index. AB - Age estimation is a vital aspect in creating a biological profile and aids investigators by narrowing down potentially matching identities from the available pool. In addition to routine casework, in the present global political scenario, age estimation in living individuals is required in cases of refugees, asylum seekers, human trafficking and to ascertain age of criminal responsibility. Thus robust methods that are simple, non-invasive and ethically viable are required. The aim of the present study is, therefore, to test the reliability and applicability of the coronal pulp cavity index method, for the purpose of developing age estimation standards for an adult Western Australian population. A total of 450 orthopantomograms (220 females and 230 males) of Australian individuals were analyzed. Crown and coronal pulp chamber heights were measured in the mandibular left and right premolars, and the first and second molars. These measurements were then used to calculate the tooth coronal index. Data was analyzed using paired sample t-tests to assess bilateral asymmetry followed by simple linear and multiple regressions to develop age estimation models. The most accurate age estimation based on simple linear regression model was with mandibular right first molar (SEE +/-8.271 years). Multiple regression models improved age prediction accuracy considerably and the most accurate model was with bilateral first and second molars (SEE +/-6.692 years). This study represents the first investigation of this method in a Western Australian population and our results indicate that the method is suitable for forensic application. PMID- 23664551 TI - Robo3-driven axon midline crossing conditions functional maturation of a large commissural synapse. AB - During the formation of neuronal circuits, axon pathfinding decisions specify the location of synapses on the correct brain side and in correct target areas. We investigated a possible link between axon midline crossing and the subsequent development of output synapses formed by these axons. Conditional knockout of Robo3 in the auditory system forced a large commissural synapse, the calyx of Held, to be exclusively formed on the wrong, ipsilateral side. Ipsilateral calyx of Held synapses showed strong transmission defects, with reduced and desynchronized transmitter release, fewer fast-releasable vesicles, and smaller and more variable presynaptic Ca(2+) currents. Transmission defects were not observed in a downstream inhibitory synapse, and some defects persisted into adulthood. These results suggest that axon midline crossing conditions functional maturation of commissural synapses, thereby minimizing the impact of mislocalized synapses on information processing. This mechanism might be relevant to human disease caused by mutations in the ROBO3 gene. PMID- 23664553 TI - Commentary: Is a two-staged anterior-posterior vertebral column resection (VCR) safer than a posterior-only VCR approach for severe pediatric deformities? PMID- 23664554 TI - Commentary: Minimally invasive spine surgery: new standard or transient fashion? PMID- 23664552 TI - Temporal and mosaic Tsc1 deletion in the developing thalamus disrupts thalamocortical circuitry, neural function, and behavior. AB - Tuberous sclerosis is a developmental genetic disorder caused by mutations in TSC1, which results in epilepsy, autism, and intellectual disability. The cause of these neurological deficits remains unresolved. Imaging studies suggest that the thalamus may be affected in tuberous sclerosis patients, but this has not been experimentally interrogated. We hypothesized that thalamic deletion of Tsc1 at distinct stages of mouse brain development would produce differential phenotypes. We show that mosaic Tsc1 deletion within thalamic precursors at embryonic day (E) 12.5 disrupts thalamic circuitry and alters neuronal physiology. Tsc1 deletion at this early stage is unique in causing both seizures and compulsive grooming in adult mice. In contrast, only a subset of these phenotypes occurs when thalamic Tsc1 is deleted at a later embryonic stage. Our findings demonstrate that abnormalities in a discrete population of neurons can cause global brain dysfunction and that phenotype severity depends on developmental timing and degree of genetic mosaicism. PMID- 23664555 TI - Commentary: Patient satisfaction in spinal surgery: should we be addressing customer service or health improvement? PMID- 23664556 TI - Considering the diagnosis of occipitocervical dissociation. PMID- 23664557 TI - Bone grafting techniques in idiopathic scoliosis: a confirmation that allograft is as good as autograft but dispels the purported pain associated with the iliac crest bone graft harvest. PMID- 23664558 TI - Three- and 4-year-old children's response tendencies to various interviewers. AB - Unlike young preschoolers, older preschoolers may exhibit a response bias under social pressure from authoritative interviewers. To examine this, 3- and 4-year old preschoolers were asked yes-no questions about familiar and unfamiliar objects in three conditions. In one condition an adult asked them questions in a live interaction, in a second condition an adult asked questions via video, and in a third condition a robot asked questions via video. The 3-year-olds exhibited a yes bias-a tendency to say "yes"-in nearly all conditions. The only exception was when they were asked questions about unfamiliar objects by the human interviewer via video, where they did not respond in a biased manner. The 4-year olds exhibited a yes bias in only one condition-when they were questioned by a live human interviewer about both objects. They also exhibited a nay-saying bias when asked questions about unfamiliar objects in both video conditions, and they did not show any response bias in other conditions. The results suggest that the social pressure from an authoritative adult in a live interaction is problematic. PMID- 23664559 TI - Methotrexate therapy may prevent the onset of uveitis in juvenile idiopathic arthritis. AB - OBJECTIVE: To evaluate whether early treatment with methotrexate (MTX) prevents the onset of uveitis in children with juvenile idiopathic arthritis. STUDY DESIGN: The clinical charts of all consecutive patients seen between January 2002 and February 2011 who had a disease duration <1 year at first visit and had received a stable management for at least 2 years with or without MTX were reviewed. Patients who were given systemic medications other than MTX (except nonsteroidal anti-inflammatory drugs) were excluded. Patients with systemic arthritis, rheumatoid factor-positive arthritis, or enthesitis-related arthritis were also excluded. In each patient, the 2-year follow-up period after first visit was examined to establish whether uveitis had occurred. RESULTS: A total of 254 patients with a median disease duration of 0.3 year were included. Eighty-six patients (33.9%) were treated with MTX, whereas 168 patients (66.1%) did not receive MTX. During the 2-year follow-up, 211 patients (83.1%) did not develop uveitis, whereas 43 patients (16.9%) had uveitis a median of 1.0 year after the first visit. The frequency of uveitis was lower in MTX-treated than in MTX untreated patients (10.5% vs 20.2%, respectively, P = .049). Survival analysis confirmed that patients treated with MTX had a lower probability of developing uveitis. CONCLUSION: Early MTX therapy may prevent the onset of uveitis in children with juvenile idiopathic arthritis. Because our study may be affected by confounding by indication, the potential of MTX to reduce the incidence of ocular disease should be investigated in a randomized controlled trial. PMID- 23664560 TI - Characterization of xanthatin: anticancer properties and mechanisms of inhibited murine melanoma in vitro and in vivo. AB - Anti-cancer investigations on Xanthatin mainly focus on in vitro experiments. We herein reported the anti-tumor effects of Xanthatin both in vitro and in vivo. MTS assay results showed that Xanthatin had a remarkable anti-proliferative effect on B16-F10 cells. Moreover, the expression of beta-catenin was up regulated both in vitro and in vivo. Animal studies further revealed that Xanthatin killed the tumor cells around the blood vessels which contributes to reduce microvascular density extremely. All these results indicate that Xanthatin inhibited murine melanoma B16-F10 cell proliferation possibly associated with activation of Wnt/beta-catenin pathway and its activity against melanoma tumor might also be relevant to inhibition of angiogenesis. PMID- 23664561 TI - Evolution of symmetric upbeat into dissociated torsional-upbeat nystagmus in internuclear ophthalmoplegia. PMID- 23664562 TI - Effective, selective and specific inhibition of COX-1 may overcome the "aspirin paradox". PMID- 23664563 TI - Serum des-R prothrombin activation peptide fragment 2: a novel prognostic marker for disseminated intravascular coagulation. AB - INTRODUCTION: Disseminated intravascular coagulation (DIC) is diagnosed based on the combination of predisposing underlying conditions and laboratory tests for plasma coagulation markers. Because the collection of blood plasma samples is a fastidious procedure, the serum sample method may be preferred for measurement of coagulation markers when feasible. MATERIALS AND METHODS: The novel serum marker des-R prothrombin activation peptide fragment 2 (des-R F2) was measured using a sandwich enzyme-linked immunosorbent assay in 181 patients suspected of having DIC. Thrombin generation potential was estimated with a calibrated automated thrombogram. RESULTS: Serum des-R F2 was generated with an in vitro clotting process within a serum separation tube after blood collection. Carboxypeptidase inhibitor inhibited the formation of des-R F2 during in vitro clotting. Low levels of prothrombin and thrombin generation potential resulted in low serum des R F2 levels. Serum des-R F2 was significantly decreased in overt DIC. Levels of des-R F2 correlated with DIC severity and other coagulation markers. Of note, the decrease in serum des-R F2 levels was a significant marker for predicting mortality. CONCLUSIONS: The serum marker, des-R F2, can be used for the investigation of DIC severity and prognosis. It should be considered a useful marker, especially when only serum samples are available. PMID- 23664564 TI - Six novel missense mutations causing factor X deficiency and application of thrombin generation test. AB - INTRODUCTION: Inherited factor X (FX) deficiency is a rare hemorrhagic condition characterized by a variable clinical presentation weakly correlating with laboratory phenotype and genotype. Thrombin generation test (TGT) offers potential clinical advantages in the evaluation of hypocoagulable states. MATERIALS AND METHODS: Five FX assays were performed using clotting, chromogenic and immunological methods. The factor X gene (F10) defects were analyzed by direct sequencing. Thrombin generation (TG) was measured using a standard procedure with commercial reagents at 1 pM and 5 pM of tissue factor (TF). The influence of contact activation on TG at the two TF concentrations was analyzed by the addition of corn trypsin inhibitor (CTI). RESULTS: Seven missense mutations were identified in the F10 of the four probands with FX deficiency, six of which (Ser425Pro, Ala-29Pro, Phe324Leu, Ala235Thr, Cys111Arg and Met362Thr) were novel and associated with type I FX deficiency. TG measurements at 1 pM TF need the addition of CTI in both healthy individuals and FX-deficient patients. TG parameters of ETP, Peak and Rate correlated well with the FX:C levels and the clinical expressions of the FX-deficient patients at 1 pM TF with CTI. There is a higher sensitivity for FX deficiency at 1 pM TF compared with 5 pM TF in FX deficient patients. CONCLUSIONS: TGT may serve as a useful laboratory tool to assess the individual clinical manifestation of the patients with FX deficiency and 1 pM TF concentration in the presence of CTI is recommended. PMID- 23664565 TI - The change of insulin levels after six weeks antidepressant use in drug-naive major depressive patients. AB - BACKGROUND: A reciprocal relationship between diabetes risk and depression has been reported. There are few studies investigating glucose-insulin homeostasis before and after short-term antidepressant treatment in drug-naive major depressive disorder (MDD) patients. METHODS: This study included 104 healthy controls and 50 drug-naive MDD patients diagnosed according to the DSM-IV criteria. These MDD patients were randomly assigned to receive fluoxetine or venlafaxine for six weeks. Depressive symptoms, body mass index, fasting plasma levels of glucose and insulin were measured. RESULTS: Compared to the healthy controls, the fasting plasma insulin and the homeostasis model of assessment for pancreatic beta-cell secretory function (HOMA-beta) was significantly lower in the MDD patients before antidepressant treatment (7.7+/-4.8 MUIU/mL vs. 5.1+/-4.2 MUIU/mL, p=0.006; 114.2+/-72.3% vs. 74.8+/-52.0%, p=0.005, respectively). However, these indices were not correlated with depression severity. After 6 weeks of fluoxetine or venlafaxine treatment, the level of HOMA-beta borderline significantly increased (108.1+/-75.5%, p=0.059). LIMITATIONS: The study was limited by the follow-up duration and lack of a placebo group. CONCLUSIONS: Antidepressants might affect insulin secretion independently of the therapeutic effects on MDD. Further studies are needed to investigate the long-term effects of antidepressants on insulin regulation in MDD patients. PMID- 23664566 TI - To a broader concept of remission: rating the health-related quality of life in bipolar disorder. AB - BACKGROUND: The relationship between remission and quality of life in bipolar disorder is incompletely understood. This study aimed to determine cut-points on the 36-item Short-Form Health Survey (SF-36) and the European Quality of Life Index (EQ-5D) that corresponded with an objective clinical measure of remission in bipolar disorder patients. METHODS: Data from a 2-year prospective observational study of bipolar and schizoaffective patients were analysed. Concordant with previous research, the Clinical Global Impression-Bipolar Version (CGI-BP) was used as an index of remission, specifically the severity scores of 1 (normal, not at all ill) and 2 (borderline mentally ill). The mean SF-36 standardized mental component (SMC) and standardized physical component (SPC) total scores as well as the EQ-5D index score that corresponded with a CGI-BP severity score of 1 or 2 were determined. RESULTS: The mean SF-36 score that corresponded with a CGI-BP severity score of 1 or 2, was below 50 for the SPC (49.3) and below 49 for the SMC (48.3). The mean EQ-5D score that corresponded with a CGI-BP severity score of 1 or 2 was below 0.88 (0.87). LIMITATIONS: Although the initial sample is sufficiently large (n=240), 49 patients scored 1 and 2 on the CGI-S, of which 12 had schizoaffective disorder. CONCLUSIONS: This study suggests that a cut-off score of >=50 for the SPC and >=49 for the SMC of the SF-36 and >=0.88 for the EQ-5D index approximates a CGI-BP definition of remission. PMID- 23664567 TI - Mood and metabolic consequences of sleep deprivation as a potential endophenotype' in bipolar disorder. AB - It has been commonly recognized that circadian rhythm and sleep/wake cycle are causally involved in bipolar disorder. There has been a paucity of systematic research considering the relations between sleep and mood states in bipolar disorder. The current study examines the possible influences of sleep deprivation on mood states and endocrine functions among first-degree relatives of patients with bipolar disorder and healthy controls. Blood samples were taken at two time points in the consecutive mornings at predeprivation and postdeprivation periods. Participants simultaneously completed the Profiles of Mood States at two time points after giving blood samples. Plasma T3 and TSH levels increased after total sleep deprivation in both groups. Sleep deprivation induced TSH levels were reversely associated with depression-dejection among healthy controls. A paradoxical effect was detected for only the first-degree relatives of the patients that changes in plasma cortisol levels negatively linked to depression dejection and anger-hostility scores after total sleep deprivation. Plasma DHEA levels became correlated with vigor-activity scores after sleep deprivation among first-degree relatives of bipolar patients. On the contrary, significant associations of depression-dejection, anger-hostility, and confusion-bewilderment with the baseline plasma DHEA levels became statistically trivial in the postdeprivation period. Findings suggested that first-degree relatives of patients with bipolar disorder had completely distinct characteristics with respect to sleep deprivation induced responses in terms of associations between endocrine functions and mood states as compared to individuals whose relatives had no psychiatric problems. Considering the relationships between endocrine functions and mood states among relatives of the patients, it appears like sleep deprivation changes the receptor sensitivity which probably plays a pivotal role on mood outcomes among the first-degree relatives of patients with bipolar disorder. PMID- 23664568 TI - "My appointment received the sanction of the Admiralty": why Charles Darwin really was the naturalist on HMS Beagle. AB - For decades historians of science and science writers in general have maintained that Charles Darwin was not the 'naturalist' or 'official naturalist' during the 1831-1836 surveying voyage of HMS Beagle but instead Captain Robert FitzRoy's 'companion', 'gentleman companion' or 'dining companion'. That is, Darwin was primarily the captain's social companion and only secondarily and unofficially naturalist. Instead, it is usually maintained, the ship's surgeon Robert McCormick was the official naturalist because this was the default or official practice at the time. Although these views have been repeated in countless accounts of Darwin's life, this essay aims to show that they are incorrect. PMID- 23664569 TI - Standardization of the depression screener patient health questionnaire (PHQ-9) in the general population. AB - BACKGROUND: The nine-item depression module from the Patient Health Questionnaire (PHQ-9) is widely used as an open access screening instrument for depression in different health care and community settings; thus far, normative data from the general population are still scarce. The objectives of the study were to generate normative data and to further investigate the construct validity and factor structure of the PHQ-9 in the general population. METHODS: Nationally representative face-to face household surveys were conducted in Germany between 2003 and 2008 (n=5018). The survey questionnaires included the PHQ-9, the Satisfaction with Life Scale, the 12-item Short Form Health Survey (SF-12) for the measurement of health-related quality of life and demographic characteristics. RESULTS: Normative data for the PHQ-9 were generated for both genders (53.6% female) and different age levels [mean age (S.D.) of 48.9 (18.1) years]. Women had significantly higher mean (S.D.) scores compared with men [3.1 (3.5) vs. 2.7 (3.5)]. A prevalence rate of moderate to high severity of depressive symptoms of 5.6% was identified. Intercorrelations with depression were highest for the Mental Component Scale of the SF-12, followed by the Physical Component Scale of health-related quality of life, and life satisfaction. Results supported a one-factor model of depression. CONCLUSIONS: The normative data provide a framework for the interpretation and comparisons of depression with other populations. Evidence supports reliability and validity of the unidimensional PHQ-9 as a measure of depression in the general population. PMID- 23664571 TI - Alexithymia in the medically ill. Analysis of 1190 patients in gastroenterology, cardiology, oncology and dermatology. AB - OBJECTIVE: To use the Diagnostic Criteria for Psychosomatic Research (DCPR) for characterizing alexithymia in a large and heterogeneous medical population, in conjunction with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and other DCPR criteria. METHOD: Of 1305 patients recruited from 4 medical centers in the Italian Health System, 1190 agreed to participate. They all underwent an assessment with DSM-IV and DCPR structured interviews. A total of 188 patients (15.8%) were defined as alexithymic by using the DCPR criteria. Data were submitted to cluster analysis. RESULTS: Five clusters of patients with alexithymia were identified: (1) alexithymia with no psychiatric comorbidity (29.3% of cases); (2) depressed somatization with alexithymic features (23.4%); (3) alexithymic illness behavior (17.6%); (4) alexithymic somatization (17%) and (5) alexithymic anxiety (12.8%). CONCLUSIONS: The results indicate that DCPR alexithymia is associated with a comorbid mood or anxiety disorder in about one third of cases; it is related to various forms of somatization and abnormal illness behavior in another third and may occur without psychiatric comorbidity in another subgroup. Identification of alexithymic features may entail major prognostic and therapeutic differences among medical patients who otherwise seem to be deceptively similar since they share the same psychiatric and/or medical diagnosis. PMID- 23664570 TI - Can familial factors account for the association of body mass index with poor mental health in men or women? AB - OBJECTIVE: This study examined if associations between body mass index (BMI) and mental and physical health were independent of genetic and familial factors. METHOD: Data from 2831 twins (66% female) were used in an epidemiological co-twin control design with measures of BMI and mental and physical health outcomes. Generalized estimating equation regressions assessed relationships between BMI and health outcomes controlling for interdependency among twins and demographics. Within-pair regression analyses examined the association of BMI with health outcomes controlling for genetic and familial influences. RESULTS: Adjusted analyses with individual twins found associations in women between BMI and perceived stress (P=.01) and depression (P=.002), and the link between BMI and depression (P=.03) was significant in men. All physical health outcomes were significantly related to BMI. Once genetic and familial factors were taken into account, mental health outcomes were no longer significantly associated with BMI. BMI in women remained related to ratings of physical health (P=.01) and body pain (P=.004), independent of genetic and familial influences. CONCLUSION: These findings suggest that genetic and familial factors may account for the relationship between increased weight and poor mental health. PMID- 23664572 TI - Family-centred care during midface advancement with a rigid external device: what do families need? AB - Midface advancement with distraction osteogenesis using the rigid external device (RED) is an effective but invasive treatment to correct the hypoplastic midface. This study draws up an inventory of the stressors, needs and coping strategies of families during this treatment, to determine the best conditions for family centred care. Data were collected by reviewing the patients' files and administering semi-structured interviews. The data were analysed using the software program Atlas.ti and were re-analysed by an independent researcher. Parents and patients were interviewed separately. Fourteen families participated. Four patients had an absolute indication for surgery. All families were eager to have the patient's facial appearance improved. Nevertheless, despite psychological counselling, they experienced stress when confronted with the changed facial appearance. Another stressor was weight loss. Six patients were in a state of acute malnutrition and needed supplementary feeding. We conclude that the best conditions for family-centred care should be aligned to the different phases of treatment. Leading up to surgery it is important to screen families' expectations regarding aesthetic, functional and social outcomes and to assess their capacity to cope with the long treatment and effects of changed facial appearance. Peer contact and psychosocial training to increase self-esteem are tools to enhance co-operation and satisfaction. During the distraction and stabilisation phase, we advise the monitoring of nutritional intake and weight. During all phases of treatment easy accessibility to the team is recommended. PMID- 23664573 TI - Nipple reconstruction after implant-based breast reconstruction: a "matched-pair" outcome analysis focusing on the effects of radiotherapy. AB - BACKGROUND: The major focus of research when addressing nipple reconstruction has been on developing new techniques to provide for long-lasting nipple projection. Rarely, has the outcome of nipple reconstruction as it relates to postoperative morbidity, particularly after implant-based breast reconstruction, been analyzed. METHODS: A "matched-pair" study was designed to specifically answer the question whether a history of radiotherapy predisposes to a higher complication rate after nipple reconstruction in patients after implant-based breast reconstruction. Only patients with a history of unilateral radiotherapy who underwent bilateral mastectomy and implant-based breast reconstruction followed by bilateral nipple reconstruction were included in the study. RESULTS: A total of 17 patients (i.e. 34 nipple reconstructions) were identified who met inclusion criteria. The mean age of the study population was 43.5 years (range, 23-69). Complications were seen after a total of 8 nipple reconstructions (23.5 percent). Of these, 7 complications were seen on the irradiated side (41.2 percent) (p = 0.03). CONCLUSION: While nipple reconstruction is a safe procedure after implant-based breast reconstruction in patients without a history of radiotherapy the presence of an irradiated field converts it to a procedure with a significant increase in postoperative complication rate. PMID- 23664574 TI - Primary breast augmentation clinical trial outcomes stratified by surgical incision, anatomical placement and implant device type. AB - BACKGROUND: Clinical evidence concerning the potential risks and benefits associated with surgical incision, anatomical pocket and implant device type in primary breast augmentation is lacking. OBJECTIVES: This study assesses relative risk (RR) of adverse events stratified by surgical incision, anatomical pocket and breast implant device in primary augmentation patients enrolled in Core (NCT00689871, round/silicone devices) and 410 (NCT00690339, anatomically shaped/highly cohesive silicone devices) long-term clinical trials. METHODS: RR for time-to-first-event of Baker grade 3-4 capsular contracture (CC), moderate severe malposition, and secondary procedure were calculated using multivariate time-to-event regression analysis. RESULTS: Risk of CC was increased with periareolar (unadjusted model only) and with axillary (adjusted model) versus inframammary incision. Risk of CC was significantly reduced with subpectoral versus subglandular placement (adjusted model), and with textured surface/round/silicone-filled devices and textured surface/shaped/highly cohesive silicone-filled devices versus smooth surface/round/silicone-filled devices (adjusted model). Risk of CC was significantly reduced with textured surface devices independent of subpectoral or subglandular placement (adjusted model). In a number-needed-to-treat analysis, 7-9 patients needed to be treated with a textured surface device to prevent one Baker grade 3-4 CC over 10 years. Risk of moderate-severe malposition was significantly increased with periareolar (adjusted model) and axillary (adjusted model) versus inframammary incision; and significantly lower with textured surface/shaped/highly cohesive silicone-filled devices than with smooth surface/round/silicone-filled devices (adjusted model). Risk of secondary procedures was significantly increased with periareolar (adjusted model) and axillary (adjusted model) versus inframammary incision; and significantly reduced with textured surface/shaped/highly cohesive silicone filled devices versus smooth surface/round/silicone-filled devices (adjusted model). CONCLUSIONS: In primary breast augmentation, surgical incision, anatomical pocket, and device were significant predictors of clinical outcomes: capsular contracture, malposition and secondary procedure. PMID- 23664575 TI - Reanimation of facial palsy following tumor extirpation in pediatric patients: our experience with 16 patients. AB - The aim of this study was to present our experience with reanimation of facial palsy (FP) following tumor extirpation in pediatric patients and to analyze the functional outcomes based on different types of procedures performed considering demographic and electrophysiological data of the patients. Sixteen patients with FP post-tumor extirpation who underwent facial reanimation were reviewed. Three independent assessors evaluated the preoperative and postoperative videos using the Terzis' grading scale for eye closure, smile, depressor and overall esthetic and functional outcomes. Preoperative and postoperative electromyographic interpretations and the effect of demographic variables were also evaluated. There was significant improvement in all the patients regarding overall esthetic and functional outcomes (p < 0.0001). Good and excellent overall esthetic and functional outcomes were observed in 62.50% of the patients (n = 10). The difference between preoperative and postoperative EMG results was of statistical significance (p < 0.0001 for each target re-innervated). Better results were observed in younger patients (<=10 years) (p = 0.014) and in early cases (denervation time <=2 years) (p = 0.033). Functional results were significantly better if surgery was performed within 2 years and the patient was younger than 10 years. Augmentation of the paretic facial musculature in pediatric patients with post-tumor FP was feasible with the use of dynamic and/or static procedures. Advanced microsurgical techniques, such as the use of free muscle transfers, should be kept in mind in late cases (denervation time over 2 years). PMID- 23664576 TI - Late extrusion of a temporomandibular joint prosthesis masquerading as a sebaceous cyst. AB - Complications of temporomandibular joint prostheses are not uncommon and have been well documented. We report a very late and rare complication following silastic TMJ replacement, believed to be the first implant extrusion through healthy skin. We are reminded that these implants can still cause problems to patients many years after initial surgery. PMID- 23664577 TI - Craniofacial disorders that have phenotypic overlap with Treacher Collins syndrome. PMID- 23664578 TI - Clostridium difficile infections: do we know the real dimensions of the problem? AB - Clostridium difficile infection (CDI) is the primary cause of nosocomial diarrhoea in industrialised countries, usually occurring as a complication of antibiotic therapy in elderly patients. Landmark events contributed to boosting interest in CDI over the last 10 years, including the emergence of unusually severe and recurrent CDI due to the NAP1/BI/027 strain, as well as reports suggesting that CDI is also significantly encountered in patients previously considered at no risk, such as community-acquired CDI in patients with no recent antibiotic use, or CDI during pregnancy. Despite this growing interest from the medical community, we do not know the real dimensions of the disease for the following reasons: (i) despite comprehensive guidelines published in Europe and in the USA, most laboratories still use diagnostic tests with suboptimal sensitivity as a 'rule-out' test, hence a significant proportion of CDIs remain undiagnosed; (ii) use of PCR as a stand-alone test by others will probably overestimate the real incidence of CDI and jeopardise any comparison between institutions with different diagnostic procedures; and (iii) transversal studies, with optimum design and diagnostic tests, are rapidly outdated due to the dramatic changes in CDI epidemiology that may occur from one year to another. To get an accurate picture of the real dimensions of the CDI issue, we need more systematic use of an adequate and homogeneous diagnostic strategy in the field as well as the implementation of continuous monitoring of CDI incidence through surveillance programmes. PMID- 23664579 TI - Management of candidaemia and invasive candidiasis in critically ill patients. AB - Critically ill patients in the intensive care unit (ICU) are at increased risk of encountering bloodstream infections (BSIs) with Candida spp., associated with an elevated crude mortality rate. This supports the significance of early detection of infection and identification of the most effective management approach. A review of the various antifungal treatments and an evaluation of the diverse management approaches for invasive candidiasis in critically ill patients is necessary for guiding evidence-based decision-making. Different early detection schemes for invasive candidiasis are well documented in the literature. Other than the common use of blood cultures, new methods entail the use of risk prediction scores and biomarker tests. Regarding management strategies, different options are currently supported. These include prophylaxis, empirical therapy, pre-emptive therapy, and treatment of culture-documented infections. The choice of treatment is greatly dependent on several factors related to the patient and/or to the surrounding environment. Attention needs to be given to previous exposure to azoles, epidemiological data on dominant Candida spp. in local ICUs, severity of illness and associated morbidities. This paper summarises the most recent literature as well as the guidelines issued by the Infectious Diseases Society of America. The objective is to identify the best diagnosis and management approaches for serious Candida infections in critically ill patients. In addition, this article addresses an important aspect associated with managing candidaemia in critically ill patients pertaining to the decision for intravenous catheter removal. PMID- 23664580 TI - Treatment of bacteraemia: meticillin-resistant Staphylococcus aureus (MRSA) to vancomycin-resistant S. aureus (VRSA). AB - Around the world, Staphylococcus aureus remains a dominant cause of bacteraemia. Whilst meticillin resistance remains the major phenotype of concern, various levels of reduced glycopeptide susceptibility are emerging with increasing frequency. The most common MRSA phenotypes now have raised vancomycin MICs within the susceptible range (MICs of 1-2mg/L). This phenomenon, known as MIC creep, is hotly contested and often denied. Key to detecting MIC creep may be to examine isolates fresh, as freezing can allow reversion to wild-type MIC, presumably by loss of mutations. Treatment failure is common with vancomycin and it is uncertain whether higher doses are beneficial. At the other extreme, when enough mutations have accumulated, full VISA status is achieved, although this can also be unstable on storage. Heteroresistant and VISA strains can be considered the inevitable end result of continued MIC creep and are even more likely to fail glycopeptide treatment. Currently full vancomycin resistance is uncommon, with only approximately 20 strains described and confirmed worldwide. Empirical treatment for patients with undefined Gram-positive sepsis can undoubtedly be improved by knowledge of MRSA status, so this is a potential advantage of hospital admission screening. If a patient is risk-assessed or screen-positive for MRSA, and infection is not serious, then vancomycin or teicoplanin is appropriate empirical therapy, providing loading doses are given to achieve therapeutic concentrations immediately (trough 15 mg/L). For life-threatening infections, the glycopeptides are inadequate unless the isolate is likely to be fully susceptible (Etest<1.5mg/L). If not, daptomycin (8-10mg/L) can be used as monotherapy but the MIC should be measured as soon as possible. PMID- 23664581 TI - Dissemination of the KPC-2 carbapenemase in non-Klebsiella pneumoniae enterobacterial isolates from Colombia. AB - Klebsiella pneumoniae carbapenemase (KPC)-type enzymes have largely disseminated worldwide among K. pneumoniae isolates. In this study, 11 non-K. pneumoniae KPC producing enterobacterial isolates from four hospitals located in different Colombian cities were genetically investigated. All isolates were multidrug resistant and harboured the bla(KPC-2) gene along with several other acquired beta-lactamase genes. The bla(KPC-2) gene was associated with transposon Tn4401b inserted in different loci of plasmids varying in size and replicon type. The presence of KPC-2 in different enterobacterial species from different cities within Colombia underlines the spread of KPC beyond K. pneumoniae. PMID- 23664582 TI - Expression of HvHMA2 in tobacco modifies Zn-Fe-Cd homeostasis. AB - HvHMA2 is a plasma membrane P1B-ATPase from barley that functions in Zn/Cd root to-shoot transport. To assess the usefulness of HvHMA2 for modifying the metal content in aerial plant parts, it was expressed in tobacco under the CaMV35S promoter. Transformation with HvHMA2 did not produce one unique pattern of Zn and Cd accumulation; instead it depended on external metal supply. Thus Zn and Cd root-to-shoot translocation was facilitated, but not at all applied Zn/Cd concentrations. Metal uptake was restricted in HvHMA2-transformed plants and the level in the shoot was not enhanced. It was shown that HvHMA2 localizes to the plasma membrane of tobacco cells, and overloads the apoplast with Zn, which could explain the overall decrease in metal uptake observed. Despite the lower levels in the shoot, HvHMA2 transformants showed increased Zn sensitivity. Moreover, introduction of HvHMA2 into tobacco interfered with Fe metabolism and Fe accumulation was modified in HvHMA2-transformants in a Zn- and Cd-concentration dependent manner. The results indicate that ectopic expression of the export protein HvHMA2 in tobacco interferes with tobacco metal Zn-Cd-Fe cross homeostasis, inducing internal mechanisms regulating metal uptake and tolerance. PMID- 23664583 TI - Glutathione S-transferase (GST) family in barley: identification of members, enzyme activity, and gene expression pattern. AB - Barley (Hordeum vulgare) is one of the most important cereals in many developing countries where drought stress considerably diminishes agricultural production. Glutathione S-transferases (GSTs EC 2.5.1.18) are multifunctional enzymes which play a crucial role in cellular detoxification and oxidative stress tolerance. In this study, 84 GST genes were identified in barley by a comprehensive in silico approach. Sequence alignment and phylogenetic analysis grouped these HvGST proteins in eight classes. The largest numbers of the HvGST genes (50) were included in the Tau class followed by 21 genes in Phi, five in Zeta, two in DHAR, two in EF1G, two in Lambda, and one each in TCHQD and Theta classes. Phylogenetic analysis of the putative GSTs from Arabidopsis, rice, and barley indicated that major functional diversification within the GST family predated the monocot/dicot divergence. However, intra-specious duplication seems to be common. Expression patterns of five GST genes from Phi and Tau classes were investigated in three barley genotypes (Yusof [drought-tolerant], Moroc9-75 [drought-sensitive], and HS1 [wild ecotype]) under control and drought-stressed conditions, during the vegetative stage. All investigated genes were up-regulated significantly under drought stress and/or showed a higher level of transcripts in the tolerant cultivar. Additionally, GST enzyme activity was superior in Yusof and induced in the extreme-drought-treated leaves, while it was not changed in Moroc9-75 under drought conditions. Moreover, the lowest and highest levels of lipid peroxidation were observed in the Yusof and Moroc9-75 cultivars, respectively. Based on the achieved results, detoxification and antioxidant activity of GSTs might be considered an important factor in the drought tolerance of barley genotypes for further investigations. PMID- 23664585 TI - Elevated serum protein oxidative stress in siblings of patients with schizophrenia. PMID- 23664584 TI - Analysis of factors influencing sensitization of Japanese cedar pollen in asymptomatic subjects. AB - OBJECTIVE: Japanese cedar pollinosis is increasing rapidly in Japan. Although analysis has been made concerning the factors influencing the development of the cedar pollinosis, analysis concerning the risk factors influencing the sensitization in asymptomatic subjects has not been done. METHODS: Risk factors for sensitization to Japanese cedar pollen were analyzed among 73 subjects (32 men and 41 women) who do not develop symptoms of pollinosis at the time of Japanese cedar pollen scattering. Their ages ranged from 18 to 60 years with the mean of 34.1 years. Possible factors influencing sensitization were investigated through a written questionnaire and doctors' questioning. Japanese cedar-specific IgE titers and Dermatophagoides pteronyssinus-specific IgE titers in the serum were measured by CAP-FEIA (fluorescent enzyme immunoassay). RESULTS: Of the 73 subjects, 26 were sensitized to the Japanese cedar pollen, for a 36% sensitization rate. Among the eleven factors examined, only one factor was shown to significantly influence the sensitization rate to Japanese cedar pollen. It was sensitization to house dust mites (56.5% vs. 26.0% chi(2) value=6.27, p=0.012). The sensitization rate to the pollen did not correlate to the presence of other allergic diseases, history of rhinosinusitis, family history of Japanese cedar pollinosis, food preference, presence or absence of cedar trees in the surroundings, present living circumstances, childhood circumstances, age, sex, or smoking habits. We calculated odds ratios in order to estimate how much those factors influence the sensitization to Japanese cedar pollen. Significantly high odds ratio for sensitization to house dust mite (6.63; 95% confidence interval (CI): 1.76-32.2) was found. CONCLUSION: The present study indicates that sensitization to the pollen in the subjects without pollinosis is influenced by sensitization to house dust mite. PMID- 23664586 TI - Affect recognition and functioning in putatively prodromal individuals. PMID- 23664587 TI - Facial emotion perception abnormality in patients with early schizophrenia. AB - BACKGROUND: Deficit in facial emotion perception is an important social cognitive impairment in schizophrenic patients, and it is one of the key determinants of functional outcome in schizophrenia. However, the moderating effect of social context and the boundary of perceptual categories of facial emotion perception remain unclear. METHOD: A total of 36 schizophrenic outpatients in their early stage of illness and 43 healthy controls were recruited for evaluation of social and clinical characteristics, neurocognitive profiles, and facial emotion categorization (FEC) performance. FEC was assessed by a computer-based program with 120 trials, in which social context was presented in the form of a preceding question, in order to simulate the conditions of being praised (positive), blamed (negative), or inquiry (neutral), while the participants were asked to judge a photograph derived from one of the five facial images in a happy-angry emotion continuum. The FEC data was inserted into a logistic function model with subsequent analysis by repeated measures ANOVA and the shift point and slope as outcome measures. RESULTS: Schizophrenic patients were significantly more likely to perceive ambiguous and subtle facial expressions as happy, rather than angry, in all three social contexts. However, the interaction effects between group and context for FEC performance was not significant. CONCLUSIONS: Schizophrenic patients, even in their early stage of illness, appear to have abnormal perceptions of facial emotion categories, which may explain some of their abnormal social interactions and disabilities. This study provides additional information in understanding social cognitive deficits among schizophrenic patients. PMID- 23664588 TI - Failure of attention focus and cognitive control in schizophrenia patients with auditory verbal hallucinations: evidence from dichotic listening. AB - Auditory verbal hallucinations (AVHs) are speech perceptions that lack an external source, phenomenologically experienced as "hearing voices". A perceptual origin of an AVH experience in patients with schizophrenia can however not explain why the "voices" drain the attentional and cognitive capacity of the patients, making them unable to direct attention away from the "voices" and to cognitively suppress the experience. We recently reported how AVHs interfere with the perception of speech sounds, using a dichotic listening experimental paradigm. We now extend this finding by reporting on the interference caused by AVHs on attention and cognitive control, using a slight variation of the same dichotic listening paradigm. The patients (N=148) were instructed to pay attention to and report from either the right or left ear syllable of the dichotic pair. We then correlated their PANSS score for the hallucination item (P3) with the performance score on the dichotic listening task. The results showed that AVHs interfered with the ability to report the right ear syllable when instructed to pay attention to the right side, which is a marker of inability to attend to an external speech stimulus. When instructed to pay attention to the left side, AVHs interfered with the ability to report the left ear syllable, which is a marker of inability to use cognitive control to suppress attending to the "voices". The corresponding correlations for the emotional withdrawal (N2) negative symptom were all non-significant. The correlations were substantiated in an ANOVA with corresponding significant group differences between high versus low symptom score groups. The results thus extend our previous findings of a perceptual origination for AVHs by showing that AVHs interfere with the ability to attend to the outer world around the patient, and the ability to inhibit, or suppress, the "voices" once they occur. Future research should pin down the neuronal basis of both the origination and the attentional and cognitive control aspects of AVHs. PMID- 23664589 TI - In vivo 7 Tesla imaging of the dentate granule cell layer in schizophrenia. AB - PURPOSE: The hippocampus is central to the pathophysiology of schizophrenia. Histology shows abnormalities in the dentate granule cell layer (DGCL), but its small size (~100 MUm thickness) has precluded in vivo human studies. We used ultra high field magnetic resonance imaging (MRI) to compare DGCL morphology of schizophrenic patients to matched controls. METHOD: Bilateral hippocampi of 16 schizophrenia patients (10 male) 40.7 +/- 10.6 years old (mean +/- standard deviation) were imaged at 7 Tesla MRI with heavily T2*-weighted gradient-echo sequence at 232 MUm in-plane resolution (0.08 MUL image voxels). Fifteen matched controls (8 male, 35.6 +/- 9.4 years old) and one ex vivo post mortem hippocampus (that also underwent histopathology) were scanned with same protocol. Three blinded neuroradiologists rated each DGCL on a qualitative scale of 1 to 6 (from "not discernible" to "easily visible, appearing dark gray or black") and mean left and right DGCL scores were compared using a non-parametric Mann-Whitney test. RESULTS: MRI identification of the DGCL was validated with histopathology. Mean right and left DGCL ratings in patients (3.2 +/- 1.0 and 3.5 +/- 1.2) were not statistically different from those of controls (3.9 +/- 1.1 and 3.8 +/- 0.8), but patients had a trend for lower right DGCL score (p = 0.07), which was significantly associated with patient diagnosis (p = 0.05). The optimal 48% sensitivity and 80% specificity for schizophrenia were achieved with a DGCL rating of <=2. CONCLUSION: Decreased contrast in the right DGCL in schizophrenia was predictive of schizophrenia diagnosis. Better utility of this metric as a schizophrenia biomarker may be achieved in future studies of patients with homogeneous disease subtypes and progression rates. PMID- 23664590 TI - General intellectual ability does not explain the general deficit in schizophrenia. AB - Patients with schizophrenia demonstrate a generalized deficit across multiple cognitive domains. However, it is unknown whether this deficit is largely due to lower intelligence, or if there is an impact of schizophrenia which cannot be accounted for by measures of general intellectual ability (GIA). We created four IQ-matched strata of equal width between 89 healthy volunteers (HC) and 77 patients with schizophrenia (SZ) who had very similar IQ and reading scores within each stratum, then compared each stratum's performance on the MATRICS Consensus Cognitive Battery (MCCB). We hypothesized that any patient impairment on the MCCB after matching on IQ would be evidence that GIA does not fully explain the general deficit seen in schizophrenia. We found that patients showed evidence of greater neuropsychological impairment than what would be expected based solely on their IQ and reading ability scores. Further, this deficit was stronger in some cognitive domains than others, namely, processing speed and social cognition. These results suggest the presence of a distinction between GIA and generalized neuropsychological impairment that was consistent in magnitude across all patients, regardless of IQ. PMID- 23664591 TI - Experimental (FT-IR, FT-Raman, 1H, 13C NMR) and theoretical study of alkali metal syringates. AB - In this work the influence of lithium, sodium, potassium, rubidium and cesium on the electronic system of the syringic acid (4-hydroxy-3,5-dimethoxybenzoic acid) was studied. This paper presents spectroscopic vibrations (FT-IR, FT-Raman) and NMR ((1)H and (13)C) study of the series of alkali metal syringates from lithium to cesium syringates. Characteristic shifts of band wavenumbers and changes in band intensities along the metal series were observed. Optimized geometrical structures of the studied compounds were calculated by the B3LYP method using the 6-311++G(**) basis set. Aromaticity indices, atomic charges, dipole moments and energies were also calculated. The theoretical wavenumbers and intensities of IR and NMR spectra were obtained. The calculated parameters were compared to experimental characteristics of studied compounds. PMID- 23664592 TI - Bilateral near-infrared spectroscopy for detecting traumatic vascular injury. AB - BACKGROUND: Extremity wounds account for most battlefield injuries. Clinical examination may be unreliable by medics or first responders, and continuous assessment by experienced practitioners may not be possible on the frontline or during transport. Near-infrared spectroscopy (NIRS) provides continuous, noninvasive monitoring of tissue oxygen saturation (StO2), but its use is limited by inter-patient and intra-patient variability. We tested the hypothesis that bilateral NIRS partially addresses the variability problem and can reliably identify vascular injury after extremity trauma. MATERIALS AND METHODS: This prospective study consisted of 30 subjects: 20 trauma patients with extremity injury and 10 healthy volunteers. Bilateral StO2 tissue sensors were placed on the thenar eminence or medial plantar surface. Injured and non-injured extremities within the same patient (DeltaStO2) were compared using Wilcoxon signed ranks test. Receiver operating characteristic curves were generated and areas under the curve (AUCs) were calculated for DeltaStO2 of 6, 10, and 15. Values are expressed as median (interquartile range). RESULTS: Trauma patients were age 31 y (23 y), 85% male, with injury severity score of 9 (5). There were seven arterial and three venous injuries. Most involved the lower extremity (n = 16; 80%) and resulted from a penetrating mechanism (n = 14; 70%). DeltaStO2 between limbs was 20.4 (10.4) versus 2.4 (3.0) (P < 0.001) for all patients with vascular injury versus patients and volunteers with no vascular injury. DeltaStO2 reliably identified any vascular injury (AUC, 0.975; P < 0.001), whereas pulse examination alone or in combination with Doppler exam could detect only arterial injury. A DeltaStO2 of 6 had the greatest sensitivity and specificity (AUC, 0.900; P < 0.001). CONCLUSIONS: Continuous monitoring of bilateral limbs with NIRS detects changes in perfusion resulting from arterial or venous injury and may offer advantages over serial manual measurements of pulses or Doppler signals. This technique may be most relevant in military and disaster scenarios or during transport, in which the ability to monitor limb perfusion is difficult or experienced clinical judgment is unavailable. PMID- 23664593 TI - Soluble FGL2 induced by tumor necrosis factor-alpha and interferon-gamma in CD4+ T cells through MAPK pathway in human renal allograft acute rejection. AB - BACKGROUND: Acute rejection (AR), initiated by alloreactive CD4(+) T cells, hampers allograft survival. Soluble fibrinogen-like protein 2 (sFGL2) is a novel effector of CD4(+) T cells. We previously found that serum sFGL2 significantly increased in renal allograft recipients with AR. In this study, sFGL2 secretion by CD4(+) T cells and its mechanism were further explored both in vivo and in vitro. MATERIALS AND METHODS: Forty cases of living-related renal transplant recipients with biopsy-proven AR or stable renal function were collected and detected serum sFGL2, tumor necrosis factor (TNF)-alpha and interferon (IFN) gamma, and peripheral CD4(+) T cells. In vitro, the isolated human CD4(+) T cells were stimulated by TNF-alpha or IFN-gamma. sFGL2 in the supernatant and mitogen activated protein kinase (MAPK) proteins in the CD4(+) T cells were investigated. Approval for this study was obtained from the Ethics Committee of Fudan University. RESULTS: sFGL2, TNF-alpha, IFN-gamma, and CD4(+) T cells were significantly increased in the peripheral blood of renal allograft recipients with AR. Stimulation with 1000 U/mL TNF-alpha or 62.5 U/mL IFN-gamma for 48 h provided an optimal condition for CD4(+) T cells to secrete sFGL2 in vitro. Phosphorylated (p-) c-Jun N-terminal kinase was remarkably upregulated in the activated CD4(+) T cells, whereas no significant changes were found in p-p38 MAPK or p-ERK1/2 expression. Furthermore, inhibition of c-Jun N-terminal kinase significantly reduced sFGL2 secretion by CD4(+) T cells. CONCLUSIONS: sFGL2 secretion by CD4(+) T cells can be induced with TNF-alpha and IFN-gamma stimulation through MAPK signaling in renal allograft AR. Our study suggests that sFGL2 is a potential mediator in the pathogenesis of allograft rejection. PMID- 23664594 TI - Intraperitoneal 1.5% Delflex improves intestinal blood flow in necrotizing enterocolitis. AB - BACKGROUND: Necrotizing enterocolitis (NEC) alters intestinal microvascular control mechanisms causing significant vasoconstriction. Our prior work with intraperitoneal 2.5% dextrose solution demonstrated increased intestinal perfusion in experimentally induced NEC. In the current study, we examine whether a buffered solution with lower glucose and osmolar loads similarly increases intestinal blood flow. We hypothesized that buffered 1.5% dextrose solution would increase ileal blood flow compared with baseline in NEC. METHODS: We randomly assigned pregnant Sprague-Dawley rats to control (n = 103) or NEC (n = 123) groups, by litter. We induced NEC by previously published methods. Control pups were vaginally delivered and dam-fed. We used laser Doppler flowmetry to evaluate perfusion in the terminal ileum at 12, 24, 48, 72, or 96 h after delivery at baseline and after application of topical 1.5% dextrose solution. We evaluated differences between groups and time points by analysis of variance and Tukey post hoc test. RESULTS: Baseline blood flow in the terminal ileum increased with gestational age in both groups (P < 0.05). Control groups had significantly greater baseline blood flow than NEC groups (P < 0.05), and topical application of buffered 1.5% dextrose solution increased blood flow compared with baseline in both groups at all time points (P < 0.05). CONCLUSIONS: Topical 1.5% dextrose solution significantly enhanced blood flow in the terminal ileum to the same degree as 2.5% dextrose solution. Thus, the use of buffered 1.5% dextrose solution might be more beneficial in treating clinical NEC, because it places a lower glucose and osmotic load on NEC-injured intestine. PMID- 23664595 TI - Omega-3 fatty acids are inversely related to callous and unemotional traits in adolescent boys with attention deficit hyperactivity disorder. AB - A number of research studies have reported abnormal plasma fatty acid profiles in children with ADHD along with some benefit of n-3 to symptoms of ADHD. However, it is currently unclear whether (lower) long chain-polyunsaturated fatty acids (LC-PUFAs) are related to ADHD pathology or to associated behaviours. The aim of this study was to test whether (1) ADHD children have abnormal plasma LC-PUFA levels and (2) ADHD symptoms and associated behaviours are correlated with LC PUFA levels. Seventy-two, male children with (n=29) and without a clinical diagnosis of ADHD (n=43) were compared in their plasma levels of LC-PUFA. Plasma DHA was higher in the control group prior to statistical correction. Callous unemotional (CU) traits were found to be significantly negatively related to both eicosapentaenoic acid (EPA), and total omega-3 in the ADHD group. The findings unveil for the first time that CU and anti-social traits in ADHD are associated with lower omega-3 levels. PMID- 23664598 TI - Parameters that influence the isolation of multipotent mesenchymal stromal cells from human umbilical cord blood. AB - BACKGROUND AND OBJECTIVES: Umbilical cord blood is an important source of stem cells. However, isolating multipotent mesenchymal stromal cells (MSCs) from umbilical cord blood presents methodological challenges. We compared the effectiveness of six approaches to improve the success rate of MSC isolation and proliferation from umbilical cord blood. METHODS: Thirty umbilical cord blood units underwent investigation. In 10 samples, MNCs from each sample were divided into four groups to test the effect of negative immunodepletion (NI) alone (group A); NI plus basic fibroblastic growth factor (bFGF) supplementation together (group B); bFGF supplementation alone (group C); and culture with neither NI nor bFGF (group D). The cells of each group were isolated from 10mL of umbilical cord blood. For investigating the effect of sample volume (group E) and MesenCult Proliferation Kits (group F), cells were isolated from 45+/-2ml. MSCs were identified on the basis of morphological, flow cytometric and differentiation potential characteristics. RESULTS: In groups of A-D, one week after the initial seeding, the cells showed a rounded appearance, and in the fourth week, many of them died. MSCs outgrowth was seen in 40% of the samples from group F, and this yield was further enhanced to 60% in cultures done with the MesenCult Proliferation Kit (group F). The fibroblast-like cells expanded rapidly and showed features of MSCs. CONCLUSION: Sample volume was the parameter that showed the greatest influence on the isolation yield of MSCs from umbilical cord blood. This could be further enhanced by adding the MesenCult Proliferation Kit. PMID- 23664597 TI - Stearidonic and gamma-linolenic acids in echium oil improves glucose disposal in insulin resistant monkeys. AB - Echium oil (EO) contains stearidonic acid (18:4), a n-3 polyunsaturated fatty acids (PUFAs), and gamma-linolenic acids (18:3), a n-6 PUFA that can be converted to long chain (LC)-PUFAs. We aimed to compare a safflower oil (SO)-enriched diet to EO- and fish oil (FO)-enriched diets on circulating and tissue PUFAs levels and glycemic, inflammatory, and cardiovascular health biomarkers in insulin resistant African green monkeys. In a Latin-square cross-over study, eight monkeys consumed matched diets for 6 weeks with 3-week washout periods. Monkeys consuming FO had significantly higher levels of n-3 LC-PUFAs and EO supplementation resulted in higher levels of circulating n-3 LC-PUFAs and a significant increase in dihomo-gamma linolenic acid (DGLA) in red blood cells and muscle. Glucose disposal was improved after EO consumption. These data suggest that PUFAs in EO supplementation have the capacity to alter circulating, RBC and muscle LC-PUFA levels and improve glucose tolerance in insulin-resistant monkeys. PMID- 23664596 TI - Effects of low-dose aspirin and fish oil on platelet function and NF-kappaB in adults with diabetes mellitus. AB - INTRODUCTION: Many diabetics are insensitive to aspirin's platelet anti aggregation effects. The possible modulating effects of co-administration of aspirin and fish oil in subjects with diabetes are poorly characterized. PARTICIPANTS AND METHODS: Thirty adults with type 2 diabetes mellitus were treated with aspirin 81 mg/d for 7 days, then with fish oil 4 g/day for 28 days, then the combination of fish oil and aspirin for another 7 days. RESULTS: Aspirin alone and in combination with fish oil reduced platelet aggregation in most participants. Five of 7 participants classified as aspirin insensitive 1 week after daily aspirin ingestion were sensitive after the combination. Although some platelet aggregation measures correlated positively after aspirin and fish oil ingestion alone and (in combination) in all individuals, correlation was only observed in those who were aspirin insensitive after ingestion of the combination. CONCLUSIONS: Co-administration of aspirin and fish oil may reduce platelet aggregation more than aspirin alone in adults with diabetes mellitus. PMID- 23664599 TI - Do favic patients resume fava beans ingestion later in their life, a study for this, and a new hypothesis for favism etiology. AB - BACKGROUND AND OBJECTIVES: The etiology of favism remains unclear and the fate of favic patients has not previously been studied. Therefore, individuals who had experienced an episode of favism were studied regarding subsequent fava bean ingestion, including the reason for fava bean ingestion after the initial favic attack and any adverse reactions. In addition, a new hypothesis for the etiology of favism is proposed. PATIENTS AND METHODS: From June 2005 to June 2012, a total of 38 patients with a history of favism were included in this study. Circumstances regarding the initial favic attack were obtained from medical records and patient interviews, and subsequent fava bean ingestion and recurrence of symptoms were investigated. RESULTS: Three of the 38 patients (7.9%) were female, and 35 (92.1%) were male. The mean age was 27.9 years (14-63 years). The first attack of favism occurred before 10 years of age for 31 patients (81.6%) and in the springtime for 35 patients (92.1%). Thirty-three patients (86.7%) regularly ate fava beans before the attack, and 35 (92.1%) resumed eating fava beans within 1-17 years after the attack without symptoms. Two patients (5.2%) experienced a single recurrence of symptoms. No evidence of hemolysis was found in the four patients checked after fava bean re-ingestion. CONCLUSIONS: Patients resumed eating fava bean for various reasons, and the recurrence of symptoms was uncommon. An infectious agent such as a virus may play a role in the development of favism. PMID- 23664601 TI - Overexpression of LC3A autophagy protein in follicular and diffuse large B-cell lymphomas. AB - BACKGROUND AND OBJECTIVES: Autophagy is a self-degradation mechanism induced under stress conditions in all eukaryotic cells. Its activity in human lymphomas has not been studied as yet. METHODS: In this study, the autophagic activity of lymphoid cells was investigated in follicular lymphomas (FL; 48 cases), diffuse large B-cell lymphomas (DLBCL; 78 cases), and in reactive follicular hyperplasias (41 cases), using the light chain 3A (LC3A) antibody and a standard immunohistochemical technique. RESULTS: In all cases, the pattern of LC3A reactivity was uniformly diffuse cytoplasmic, but expressed more frequently in FLs (68.8%) than in DLBCLs (41%) (p=0.02), and much more commonly in DLBCLs than in reactive lymph nodes (24.3%) (p<0.006). Interestingly, FLs expressing LC3A in >10% of lymphoid cells (high reactivity) were associated with the hypoxia-related protein HIF1alpha and the enzyme of anaerobic metabolism lactate dehydrogenase LDH5 (p=0.004 and p=0.003, respectively). Such associations, however, were not a feature in DLBCLs of increased LC3A activity. CONCLUSIONS: LC3A expression in FLs is hypoxia-induced, whereas its expression in DLBCLs may be regulated by other molecular mechanisms. The current study provides a tool for further assessment of autophagic activity in translational and autophagy targeting therapy studies. PMID- 23664600 TI - Hematopoietic stem cell transplantation practice variation among centers in the Eastern Mediterranean Region (EMRO): Eastern Mediterranean Bone Marrow Transplantation (EMBMT) group survey. AB - INTRODUCTION: This practice survey is conducted to analyze clinical hematopoietic stem cell transplantation (HSCT) practice variability among centers in the WHO Eastern Mediterranean Region (EMRO), as represented by the Eastern Mediterranean Blood and Marrow Transplantation (EMBMT) group. METHOD: This internet based survey was completed by the medical program directors of the EMBMT centers; 17 centers participated. The survey collected data on various clinical aspects of HSCT practice. RESULTS: Consistency in pre HSCT cardiac (100%), pulmonary (82%) and viral screen (100%) was observed. Obtaining informed consent was universal. Pre-HSCT psychological assessment is practiced in 50% of the centers. All centers used single-bedded rooms with HEPA filters. Visitor policy during neutropenic phase and the use of gowns, masks or gloves when examining patients varied among centers. MRSA/VRE screen and use of low bacterial diet were applied in 65% and 82%, respectively. Anti-bacterial prophylaxis is employed in 58% (Auto-SCT) and 60% (Allo-SCT) of the centers. Drug choice varied (cotrimoxazole, ciprofloxacin, levofloxacin, piperacillin-tazobactam); 60% of the centers used penicillin prophylaxis in GVHD patients. PCP prophylaxis is applied in 58% (Auto-SCT) and 87% (Allo-SCT) of the centers; cotrimoxazole is usually used. Anti-viral prophylaxis with acyclovir or, less commonly, valacyclovir is used in 70% (Auto SCT) and 93% (Allo-SCT) of centers. Anti-fungal prophylaxis is applied in 70% (Auto-SCT), 93% (myeloablative Allo-SCT) and 87% (reduced intensity [RIC] Allo SCT). Fluconazole is used in all Auto-SCT and majority of Allo-SCT recipients; few centers used other agents (itraconazole, voriconazole, amphotericin B) in Allo-SCT. Prophylactic GCSF use varied among centers: Auto-SCT 77%, myeloablative Allo-SCT 33%, RIC Allo-SCT 27%. Use of ursodeoxycholic acid for venoocclusive disease (VOD) prophylaxis is variable: 60% (Allo-SCT) and 12% (Auto-SCT). Cyclosporine/methotrexate is the most commonly used GVHD prophylaxis in myeloablative Allo-SCT (93%); heterogeneity was seen in RIC SCT. Treatment of steroid refractory acute GVHD varied (ATG 53%, higher steroid dose 40%). CMV monitoring varied between antigenemia (53%) and PCR (40%) techniques. Pre-emptive anti CMV therapy is used in 86% of the centers, while 7% used routine CMV prophylaxis; 7% had no specific CMV management policy. CONCLUSION: Consistency was observed in areas of pre-SCT work up, use of single rooms, HEPA filters and GVHD prophylaxis. Heterogeneity is observed in other practice aspects including other isolation measures, anti-microbial prophylaxis, VOD prophylaxis, growth factor use and treatment of steroid refractory GVHD. Further studies are needed to probe the impact of such practice variations on post-transplant outcome and to ascertain the best clinical practice approach. PMID- 23664602 TI - Orbital myeloid sarcoma presenting as massive proptosis. AB - A 10-year-old boy presented with right proptosis for 8 months. The eyeball was grossly pushed down, with diffuse corneal haze and non-reactive pupil. Systemic examination was normal. Previous investigations in another centre included a computerized tomography scan, which showed a well-defined enhancing retro-bulbar mass, a non-contributory fine needle aspiration cytology and a biopsy showing fibrocollagenous tissue with moderate lympho-monocytic infiltrate suggestive of non-specific inflammation. PET-CT scan revealed the presence of enlarged fluoro deoxyglucose-avid cervical and mesenteric lymph nodes. Biopsy of the retro-bulbar mass was repeated in our centre. It showed fibrocollagenous and skeletal muscle tissue infiltrated by lymphoid follicles, dispersely lying lymphocytes and plasma cells, and admixed large atypical cells with vesicular nuclei, prominent nucleoli and scanty cytoplasm, strongly positive for myeloperoxidase, CD43 and CD99 immunohistochemistry. Hemogram was normal. Bone marrow aspiration/biopsy and CSF showed no evidence of acute myeloid leukemia. The child received chemotherapy in another centre and is in complete remission 6 months after completion. PMID- 23664603 TI - Adenocarcinoma of the colon in children: case series and mini-review of the literature. AB - Colon cancer is extremely rare in children. This article reports three cases of adenocarcinoma of the colon. A 12-year-old boy, a 13-year-old boy, and a 13-year old girl presented with constipation and abdominal enlargement over a two-month duration. Abdominal ultrasound and barium enema confirmed a stenotic segment at the rectum with obvious shouldering. Adenocarcinoma was diagnosed following colonoscopic biopsy and laparotomy. We conclude that any child presenting with unexplained persistent constipation, abdominal distension or bleeding per rectum, colon cancer should be suspected and investigated with endoscopy or barium enema. PMID- 23664604 TI - Hematopoietic stem cell transplant versus chemotherapy plus tyrosine kinase inhibitor in the treatment of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). AB - BACKGROUND: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) remained until recently the molecular genetic abnormality associated with the worst outcome. Hematopoietic stem cell transplant (HSCT) was considered the treatment of choice, however, recent data have indicated that chemotherapy plus tyrosine kinase inhibitor (TKI) maybe an alternative effective therapy. METHODS: We conducted a retrospective analysis of children (<18 years) with Ph+ ALL who were treated at King Hussein Cancer Center (KHCC) from January 2003 till December 2011. RESULTS: Over a 9 year period, 411 children were diagnosed and treated for ALL at KHCC. Twenty three (6.6%) had Ph+ ALL; 16 males and 7 females. Median age at diagnosis was 9.5 years (range 1.67-17). The median white blood cell count was 58.6*10(3)/MUL (range 1.6-459). Twelve patients underwent HSCT from a full matched related donor; and 10 were treated with intensive chemotherapy plus TKI (imatinib). Those who underwent HSCT were significantly older (P=0.004) and had a higher leukocyte count at diagnosis (P=0.53). After a median follow up of 42.2 months (range 12.7-107), the estimated 5 year event free survival (EFS) and overall survival (OS) were 75% and 91.6%, respectively, for those who underwent HSCT as primary therapy and 49.3% and 83.3%, respectively, for those treated with chemotherapy plus imatinib. There was no significant difference in EFS (P=0.98) or OS (P=1) between the two treatment modalities. CONCLUSIONS: Our results indicate that chemotherapy plus TKI may be a reasonable treatment option for some children with Ph+ ALL. PMID- 23664605 TI - A rare case with typical acute promyelocytic leukemia morphology associated with isolated isochromosome 17q without RARalpha rearrangement. AB - Isolated isochromosome 17q has rarely been reported in hematologic tumor patients. A 37-year-old man was admitted with fever and weakness. Blood routine test showed anemia and thrombocytopenia. The morphology and immunology of bone marrow cells conform to classic acute promyelocytic leukemia (APL). But the karyotype showed isolated isochromosome 17q without t(15;17) (q22;q12). Rverse transcriptase polymerase chain reaction (RT-PCR) for PML -RARa was negative and fluorescence in situ hybridization (FISH) analysis showed no RARa gene rearrangements.The patient responded poorly to all trans retinoic acid and traditional chemotherapy with daunorubicin and cytarabine and survived only 43 days after diagnosis. The pathogenesis and the best treatment choice for this kind of patients are not clear currently. PMID- 23664606 TI - Metastatic squamous cell carcinoma in a bone marrow transplant recipient. AB - We report a case of 53year old female with history of acute myelogenous leukemia, for which she underwent allogeneic peripheral blood stem cell transplant; her course was complicated by chronic graft versus host disease. Seven years later she presents with squamous cell carcinoma of the skin which metastasize to her heart. Here, in this case we tend to highlight the aggressive nature of the squamous cell carcinoma in an immunocompromised individual. PMID- 23664607 TI - RAN translation: fragile X in the running. AB - In this issue of Neuron, Todd et al. (2013) reveal that noncanonical repeat associated non-AUG (RAN) translation occurs on nonexpanded (CGG)30-50 and premutation (CGG)59-160 repeats, associated with the FMR1 gene, suggesting that the polyglycine and polyalanine products might have natural and pathogenic roles. PMID- 23664608 TI - Evidence for a common endocannabinoid-related pathomechanism in autism spectrum disorders. AB - In this issue of Neuron, Foldy et al. (2013) report that endocannabinoid-mediated signaling at inhibitory synapses is dysregulated in mouse models of autism associated Neuroligin-3 mutations. These findings carry implications regarding the pathophysiology of autism spectrum disorders and the development of treatment strategies. PMID- 23664609 TI - Fear and anxiety regulation by conserved affective circuits. AB - In this issue of Neuron, Yamaguchi et al. (2013) demonstrated that inactivation of two parallel neural pathways connecting the posterior septum with the medial habenula differentially affects fear and anxiety in mice, providing insights into how animals choose defensive behaviors under threats. PMID- 23664610 TI - Reinforcing rhythms in the sleeping brain with a computerized metronome. AB - Sleep has many inherent benefits, including an important role in memory consolidation. In this issue of Neuron, Ngo et al. (2013b) demonstrate that appropriately timed sounds delivered during sleep can invigorate electrophysiological oscillations conducive to memory stabilization. PMID- 23664611 TI - Temporal processing in the olfactory system: can we see a smell? AB - Sensory processing circuits in the visual and olfactory systems receive input from complex, rapidly changing environments. Although patterns of light and plumes of odor create different distributions of activity in the retina and olfactory bulb, both structures use what appears on the surface similar temporal coding strategies to convey information to higher areas in the brain. We compare temporal coding in the early stages of the olfactory and visual systems, highlighting recent progress in understanding the role of time in olfactory coding during active sensing by behaving animals. We also examine studies that address the divergent circuit mechanisms that generate temporal codes in the two systems, and find that they provide physiological information directly related to functional questions raised by neuroanatomical studies of Ramon y Cajal over a century ago. Consideration of differences in neural activity in sensory systems contributes to generating new approaches to understand signal processing. PMID- 23664612 TI - The cell-autonomous role of excitatory synaptic transmission in the regulation of neuronal structure and function. AB - The cell-autonomous role of synaptic transmission in the regulation of neuronal structural and electrical properties is unclear. We have now employed a genetic approach to eliminate glutamatergic synaptic transmission onto individual CA1 pyramidal neurons in a mosaic fashion in vivo. Surprisingly, while electrical properties are profoundly affected in these neurons, as well as inhibitory synaptic transmission, we found little perturbation of neuronal morphology, demonstrating a functional segregation of excitatory synaptic transmission from neuronal morphological development. PMID- 23664613 TI - Plum, an immunoglobulin superfamily protein, regulates axon pruning by facilitating TGF-beta signaling. AB - Axon pruning during development is essential for proper wiring of the mature nervous system, but its regulation remains poorly understood. We have identified an immunoglobulin superfamily (IgSF) transmembrane protein, Plum, that is cell autonomously required for axon pruning of mushroom body (MB) gamma neurons and for ectopic synapse refinement at the developing neuromuscular junction in Drosophila. Plum promotes MB gamma neuron axon pruning by regulating the expression of Ecdysone Receptor-B1, a key initiator of axon pruning. Genetic analyses indicate that Plum acts to facilitate signaling of Myoglianin, a glial derived TGF-beta, on MB gamma neurons upstream of the type-I TGF-beta receptor Baboon. Myoglianin, Baboon, and Ecdysone Receptor-B1 are also required for neuromuscular junction ectopic synapse refinement. Our study highlights both IgSF proteins and TGF-beta facilitation as key promoters of developmental axon elimination and demonstrates a mechanistic conservation between MB axon pruning during metamorphosis and the refinement of ectopic larval neuromuscular connections. PMID- 23664614 TI - Three mechanisms assemble central nervous system nodes of Ranvier. AB - Rapid action potential propagation in myelinated axons requires Na+ channel clustering at nodes of Ranvier. However, the mechanism of clustering at CNS nodes remains poorly understood. Here, we show that the assembly of nodes of Ranvier in the CNS involves three mechanisms: a glia-derived extracellular matrix (ECM) complex containing proteoglycans and adhesion molecules that cluster NF186, paranodal axoglial junctions that function as barriers to restrict the position of nodal proteins, and axonal cytoskeletal scaffolds (CSs) that stabilize nodal Na+ channels. We show that while mice with a single disrupted mechanism had mostly normal nodes, disruptions of the ECM and paranodal barrier, the ECM and CS, or the paranodal barrier and CS all lead to juvenile lethality, profound motor dysfunction, and significantly reduced Na+ channel clustering. Our results demonstrate that ECM, paranodal, and axonal cytoskeletal mechanisms ensure robust CNS nodal Na+ channel clustering. PMID- 23664615 TI - Competition between alpha-actinin and Ca2+-calmodulin controls surface retention of the L-type Ca2+ channel Ca(V)1.2. AB - Regulation of neuronal excitability and cardiac excitation-contraction coupling requires the proper localization of L-type Ca2+ channels. We show that the actin binding protein alpha-actinin binds to the C-terminal surface targeting motif of alpha11.2, the central pore-forming Ca(V)1.2 subunit, in order to foster its surface expression. Disruption of alpha-actinin function by dominant-negative or small hairpin RNA constructs reduces Ca(V)1.2 surface localization in human embryonic kidney 293 and neuronal cultures and dendritic spine localization in neurons. We demonstrate that calmodulin displaces alpha-actinin from their shared binding site on alpha11.2 upon Ca2+ influx through L-type channels, but not through NMDAR, thereby triggering loss of Ca(V)1.2 from spines. Coexpression of a Ca2+-binding-deficient calmodulin mutant does not affect basal Ca(V)1.2 surface expression but inhibits its internalization upon Ca2+ influx. We conclude that alpha-actinin stabilizes Ca(V)1.2 at the plasma membrane and that its displacement by Ca2+-calmodulin triggers Ca2+-induced endocytosis of Ca(V)1.2, thus providing an important negative feedback mechanism for Ca2+ influx. PMID- 23664616 TI - Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis. AB - Neural circuits are regulated by activity-dependent feedback systems that tightly control network excitability and which are thought to be crucial for proper brain development. Defects in the ability to establish and maintain network homeostasis may be central to the pathogenesis of neurodevelopmental disorders. Here, we examine the function of the tuberous sclerosis complex (TSC)-mTOR signaling pathway, a common target of mutations associated with epilepsy and autism spectrum disorder, in regulating activity-dependent processes in the mouse hippocampus. We find that the TSC-mTOR pathway is a central component of a positive feedback loop that promotes network activity by repressing inhibitory synapses onto excitatory neurons. In Tsc1 KO neurons, weakened inhibition caused by deregulated mTOR alters the balance of excitatory and inhibitory synaptic transmission, leading to hippocampal hyperexcitability. These findings identify the TSC-mTOR pathway as a regulator of neural network activity and have implications for the neurological dysfunction in disorders exhibiting deregulated mTOR signaling. PMID- 23664617 TI - Robust gamma coherence between macaque V1 and V2 by dynamic frequency matching. AB - Current theories propose that coherence of oscillatory brain activity in the gamma band (30-80 Hz) constitutes an avenue for communication among remote neural populations. However, reports documenting stimulus dependency and time variability of gamma frequency suggest that distant neuronal populations may, at any one time, operate at different frequencies precluding synchronization. To test this idea, we recorded from macaque V1 and V2 simultaneously while presenting gratings of varying contrast. Although gamma frequency increased with stimulus contrast in V1 and V2 (by ~25 Hz), V1-V2 gamma coherence was maintained for all contrasts. Moreover, while gamma frequency fluctuated by ~15 Hz during constant contrast stimulation, this fluctuation was highly correlated between V1 and V2. The strongest coherence connections showed a layer-specific pattern, matching feedforward anatomical connectivity. Hence, gamma coherence among remote populations can occur despite large stimulus-induced and time-dependent changes in gamma frequency, allowing communication through coherence to operate without a stimulus independent, fixed-frequency gamma channel. PMID- 23664618 TI - Motion-dependent representation of space in area MT+. AB - How is visual space represented in cortical area MT+? At a relatively coarse scale, the organization of MT+ is debated; retinotopic, spatiotopic, or mixed representations have all been proposed. However, none of these representations entirely explain the perceptual localization of objects at a fine spatial scale- a scale relevant for tasks like navigating or manipulating objects. For example, perceived positions of objects are strongly modulated by visual motion; stationary flashes appear shifted in the direction of nearby motion. Does spatial coding in MT+ reflect these shifts in perceived position? We performed an fMRI experiment employing this "flash-drag" effect and found that flashes presented near motion produced patterns of activity similar to physically shifted flashes in the absence of motion. This reveals a motion-dependent change in the neural representation of object position in human MT+, a process that could help compensate for perceptual and motor delays in localizing objects in dynamic scenes. PMID- 23664620 TI - When do we dare to stop biological or immunomodulatory therapy for Crohn's disease? Results of a multidisciplinary European expert panel. AB - BACKGROUND: Safety and economic issues have increasingly raised concerns about the long term use of immunomodulators or biologics as maintenance therapies for Crohn's disease (CD). Despite emerging evidence suggesting that stopping therapy might be an option for low risk patients, criteria identifying target groups for this strategy are missing, and there is a lack of recommendations regarding this question. METHODS: Multidisciplinary European expert panel (EPACT-II Update) rated the appropriateness of stopping therapy in CD patients in remission. We used the RAND/UCLA Appropriateness Method, and included the following variables: presence of clinical and/or endoscopic remission, CRP level, fecal calprotectin level, prior surgery for CD, and duration of remission (1, 2 or 4 years). RESULTS: Before considering withdrawing therapy, the prerequisites of a C reactive protein (CRP) and fecal calprotectin measurement were rated as "appropriate" by the panellists, whereas a radiological evaluation was considered as being of "uncertain" appropriateness. Ileo-colonoscopy was considered appropriate 1 year after surgery or after 4 years in the absence of prior surgery. Stopping azathioprine, 6-mercaptopurine or methotrexate mono-therapy was judged appropriate after 4 years of clinical remission. Withdrawing anti-TNF mono therapy was judged appropriate after 2 years in case of clinical and endoscopic remission, and after 4 years of clinical remission. In case of combined therapy, anti-TNF withdrawal, while continuing the immunomodulator, was considered appropriate after two years of clinical remission. CONCLUSION: A multidisciplinary European expert panel proposed for the first time treatment stopping rules for patients in clinical and/or endoscopic remission, with normal CRP and fecal calprotectin levels. PMID- 23664619 TI - Social manipulation of preference in the human brain. AB - Our preferences are influenced by what other people like, but depend critically on how we feel about those people, a classical psychological effect called "cognitive balance." Here, we manipulated preferences for goods by telling participants the preferences of strongly liked or disliked groups of other people. Participants' preferences converged to those of the liked group, but diverged from the disliked group. Activation of dorsomedial prefrontal cortex (dmPFC) tracked the discrepancy between one's own preference and its social ideal and was associated with subsequent preference change (toward the liked and away from the disliked group), even several months later. A follow-up study found overlapping activation in this same region of dmPFC with negative monetary outcomes, but no overlap with nearby activations induced by response conflict. A single social encounter can thus result in long-lasting preference change, a mechanism that recruits dmPFC and that may reflect the aversive nature of cognitive imbalance. PMID- 23664621 TI - Anxiety is associated with impaired tolerance of colonoscopy preparation in inflammatory bowel disease and controls. AB - BACKGROUND AND AIM: Pain and nausea are often reported during bowel cleansing (BC) for ileocolonoscopy (IC). We aimed to explore putative mechanisms associated with impaired tolerance to BC. METHODS: A 1:1 (100 IBD and 100 controls) sex and age matched case-control study was performed. Patients completed the hospital anxiety and depression scale (HADS-A/HADS-D), visceral sensitivity index (VSI) and state-trait anxiety inventory, state scale (STAI-S), in addition to self assessment of BC and abdominal pain and nausea ratings during BC. Endoscopists reported the Mayo score, Harvey Bradshaw index (HBI), simple endoscopic score for Crohn's disease, and Boston bowel preparation scale (BBPS). RESULTS: Higher VSI and depression scores were observed in IBD patients. VSI (P<0.0001) and age (P=0.008) showed a positive and negative association with abdominal pain during BC, respectively. HADS-A (P=0.009) and female sex (P=0.02) were positively associated with nausea during BC, while age (P=0.02) showed a negative association. Disease activity was not associated with worse BBPS or nausea during BC, while a higher HBI was associated with more pain during BC (P=0.0006). Nausea (P=0.007) and abdominal pain (P=0.003) during BC, and less previous ICs (P=0.03) were independently associated with anxiety prior to IC (STAI-S). Significant correlations were found between VSI and STAI-S and disease activity. CONCLUSION: Higher gastrointestinal-specific anxiety and co-morbid anxiety are associated with increased pain and nausea during BC, respectively. Pain and nausea during BC were in turn associated with higher anxiety levels at the moment of IC, potentially creating a "vicious circle". Measures taken to reduce anxiety could improve BC and IC tolerance. PMID- 23664622 TI - Response to the letter by J.-C. Vogt. PMID- 23664623 TI - A flagellated motile Salmonella Gallinarum mutant (SG Fla+) elicits a pro inflammatory response from avian epithelial cells and macrophages and is less virulent to chickens. AB - Salmonella enterica subspecies enterica serovar Gallinarum biovar Gallinarum (SG) is a non-flagellated bacterium which causes fowl typhoid, a systemic disease associated with high mortality in birds. It has been suggested that the absence of flagella in SG is advantageous in the early stages of systemic infection through absence of TLR-5 activation. In order to investigate this hypothesis in more detail a flagellated and motile SG mutant (SG Fla(+)) was constructed. The presence of flagella increased invasiveness for chicken kidney cells (CKC) while its presence did not alter survival in HD11 macrophages. SG Fla(+) induced higher levels of CXCLi2, IL-6 and iNOS mRNA expression in CKC than the SG parent strain. The expression of genes responsible for immune response mediators in infected HD11 macrophages were not related to the presence of flagella. Mortality rates were lower in birds challenged with SG Fla(+) when compared with the SG parent. SG Fla(+) was recovered from caecal contents which showed pathological changes suggestive of inflammation and suggested increased colonization ability. PMID- 23664624 TI - Myth making in the measurement of blood pressure. PMID- 23664625 TI - Dissociable attentional and affective circuits in medication-naive children with attention-deficit/hyperactivity disorder. AB - Current neurocognitive models of attention-deficit/hyperactivity disorder (ADHD) suggest that neural circuits involving both attentional and affective processing make independent contributions to the phenomenology of the disorder. However, a clear dissociation of attentional and affective circuits and their behavioral correlates has yet to be shown in medication-naive children with ADHD. Using resting-state functional connectivity MRI (rs-fcMRI) in a cohort of medication naive children with (N=22) and without (N=20) ADHD, we demonstrate that children with ADHD have reduced connectivity in two neural circuits: one underlying executive attention (EA) and the other emotional regulation (ER). We also demonstrate a double dissociation between these two neural circuits and their behavioral correlates such that reduced connectivity in the EA circuit correlates with executive attention deficits but not with emotional lability, while on the other hand, reduced connectivity in the ER circuit correlates with emotional lability but not with executive attention deficits. These findings suggest potential avenues for future research such as examining treatment effects on these two neural circuits as well as the potential prognostic and developmental significance of disturbances in one circuit vs the other. PMID- 23664626 TI - Dating violence perpetration and victimization among U.S. adolescents: prevalence, patterns, and associations with health complaints and substance use. AB - PURPOSE: This research identified conceptually cohesive latent classes of youth dating violence (DV) and examined associations between covariates and classes by gender. METHODS: A nationally representative sample of 2,203 10th grade students completed assessments of physical and verbal DV victimization and perpetration, depressive symptoms, health complaints, and substance use. A Factor Mixture Model was used to identify patterns of DV. Gender differences among classes were examined for depressive symptoms, health complaints, and substance use. RESULTS: Prevalence of DV victimization was 35% and perpetration was 31%. A three-class model fit adequately and provided conceptual cohesion: Class 1 = non-involved (65%); Class 2 = victims/perpetrators of verbal DV (30%); and Class 3 = victims/perpetrators of verbal and physical DV (5%). Compared with Class 1 adolescents, those in Classes 2 and 3 were more likely to report depressive symptoms, psychological complaints, and alcohol use. Females in Classes 2 and 3 were also more likely to report physical complaints, cigarette use, and marijuana use. Among females involved in DV, those in Class 3 compared with Class 2 reported more depressive symptoms, physical and psychological complaints, and cigarette and marijuana use. CONCLUSIONS: The three-class model distinguished involvement in verbal acts from involvement in verbal and physical acts. Adolescents involved in DV had similar probabilities of reporting perpetration and victimization, suggesting violence within relationships may be mutual. Involvement in DV was associated with more health issues and concurrent problem behaviors. For females in particular, the increased involvement in DV was associated with other health indicators. PMID- 23664627 TI - Interest in over-the-counter access to oral contraceptives among women in the United States. AB - BACKGROUND: A growing body of evidence indicates that over-the-counter (OTC) access to oral contraceptive pills (OCPs) is safe and effective. STUDY DESIGN: We performed a nationally representative survey of adult women at risk of unintended pregnancy using a probability-based online panel. In November-December 2011, 2046 eligible women completed the survey. Weighted proportions were calculated, and logistic regression was used to identify covariates associated with support for and interest in using an OTC OCP. RESULTS: A total of 62.2% said they were strongly (31.4%) or somewhat (30.9%) in favor of OCPs being available OTC. A total of 37.1% of participants reported being likely to use OCPs if available OTC, including 58.7% of current users, 28.0% using no method and 32.7% using a less effective method. Covariates associated with a higher odds of reporting interest in using OTC OCPs were younger age; being divorced, being separated or living with a partner (versus married); being uninsured or having private insurance (versus public insurance); living in the south (versus northeast); and current use of OCPs or less effective methods, or nonuse of contraception (versus use of another hormonal method or intrauterine device). Among respondents who said they were likely to use OTC OCPs, the highest amount they were willing to pay was on average $20. CONCLUSIONS: US women are supportive of OTC access to OCPs, and many would obtain refills OTC or start using OCPs if they were available OTC. PMID- 23664628 TI - Keratoacanthomas arising in association with prurigo nodules in pruritic, actinically damaged skin. AB - BACKGROUND: There is no known association between the development of keratoacanthomas and prurigo nodules. OBJECTIVE: We report a case series of 7 patients with a long-standing history of actinic damage, pruritus, and prurigo nodularis who developed widespread keratoacanthomas within the same affected area. METHODS: This was a retrospective case series assessing the clinical characteristics of patients with multiple keratoacanthomas arising in association with prurigo nodules. RESULTS: All 7 patients were elderly Caucasian women (mean age 79 +/- 3.7 years) with actinically damaged skin and a long-standing history of widespread pruritus and prurigo nodules. All patients had histologically confirmed keratoacanthomas, or squamous cell carcinomas with the clinical appearance of a keratoacanthoma, that developed within the field of prurigo nodules. All 7 patients had a clinical response to acitretin with a decrease in the number of lesions. Four patients had an associated eczematous dermatitis and were also treated with cyclosporine with improvement in pruritus and prurigo nodules and no increase in keratoacanthomas. LIMITATIONS: The retrospective design and small number of patients are limitations to this study. CONCLUSION: Our case series represents a distinct subset of elderly individuals with extensive actinic damage who we believe are predisposed to developing both prurigo nodules and keratoacanthomas. PMID- 23664629 TI - Does the use of antipyretics in children who have acute infections prolong febrile illness? A systematic review and meta-analysis. AB - OBJECTIVE: To review the literature and test the hypothesis that the use of antipyretic drugs in children with acute infections slows recovery. STUDY DESIGN: A systematic review and meta-analysis of the literature was undertaken to investigate the effect of antipyretic drugs upon recovery from infectious diseases in children. A search of Medline (1946 until November 2012) and EMBASE (1980 until November 1, 2012) was undertaken to identify studies in which the authors compared the use of antipyretic medications with nonpharmacologic treatments for fever. RESULTS: Six papers were identified, 5 of which were included in the meta-analysis. Three studies focused on children with malaria and the other 3 considered general viral and respiratory infections and varicella. The pooled mean difference in time to fever clearance was 4.16 hours and was faster in those receiving antipyretics compared with those not (95% CI -6.35 to 1.96 hours; P = .0002). There was little evidence of statistical heterogeneity (chi(2) 4.84; 4 df; P = .3; I(2) 17%). CONCLUSION: There is no evidence from these studies that the use of antipyretics slows the resolution of fever in children. PMID- 23664630 TI - Histological characteristics of the fetal inflammatory response associated with neurodevelopmental impairment and death in extremely preterm infants. AB - OBJECTIVE: To test the hypothesis that increasing severity of the fetal inflammatory response (FIR) would have a dose-dependent relationship with severe neurodevelopmental impairment or death in extremely preterm infants. STUDY DESIGN: We report 347 infants of 23-28 weeks gestational age admitted to a tertiary neonatal intensive care unit between 2006 and 2008. The primary outcome was death or neurodevelopmental impairment at the 18- to 22-month follow-up. Exposure status was defined by increasing stage of funisitis (stage 1, phlebitis; stage 2, arteritis with or without phlebitis; stage 3, subacute necrotizing funisitis) and severity of chorionic plate vasculitis (inflammation with or without thrombosis). RESULTS: A FIR was detected in 110 placentas (32%). The rate of severe neurodevelopmental impairment/death was higher in infants with subacute necrotizing funisitis compared with infants without placental/umbilical cord inflammation (60% vs 35%; P < .05). Among infants with stage 1 or 2 funisitis, the presence of any chorionic vasculitis was associated with a higher rate of severe neurodevelopmental impairment/death (47% vs 23%; P < .05). After adjustment for confounding factors, only subacute necrotizing funisitis (risk ratio, 1.87; 95% CI, 1.04-3.35; P = .04) and chorionic plate vasculitis with thrombosis (risk ratio, 2.21; 95% CI, 1.10-4.46; P = .03) were associated with severe neurodevelopmental impairment/death. CONCLUSION: Severe FIR, characterized by subacute necrotizing funisitis and severe chorionic plate vasculitis with thrombosis, is associated with severe neurodevelopmental impairment/death in preterm infants. PMID- 23664632 TI - Effectiveness of deep vein thrombosis screening on admission to a rehabilitation hospital: a prospective study in 1043 consecutive patients. AB - INTRODUCTION: The diagnosis and treatment of deep vein thrombosis/pulmonary embolism (DVT/PE) are important issues not only in acute-care hospitals, but also in rehabilitation hospitals. To test the hypothesis that DVT/PE occurring at rehabilitation hospitals is carried over from acute-care hospitals, we evaluated a method of DVT screening on admission that combined D-dimer (D-D) measurement and compression ultrasound (CUS). MATERIAL AND METHODS: This prospective single center observational study included 1043 patients who were admitted to our rehabilitation hospital between August 1, 2007, and August 1, 2011, after excluding those meeting the exclusion criteria. We screened patients on admission and observed the occurrence of DVT/PE until discharge. RESULTS: Of the 1043 patients, 152 (14.6%) had a D-D level of >= 3.0 MUg/mL on admission. CUS was performed for these patients and indicated the presence of DVT in 15 patients (1.4%), who were subsequently treated. Of these 15 patients, six (40%) had no DVT symptoms, and five of these six patients had spinal cord injury. Of 137 patients who were CUS negative, two developed DVT/PE within 8 days of hospitalization, and recovery was achieved by treatment. No subsequent occurrence was observed. CONCLUSIONS: These results indicated all cases were carried over from acute-care hospitals. Six out of 15 patients had no symptoms of DVT/PE. Thus, this method of DVT screening on admission to a rehabilitation hospital is useful for risk management. PMID- 23664631 TI - Disorders of protein misfolding: alpha-1-antitrypsin deficiency as prototype. PMID- 23664633 TI - In vitro effects of recombinant activated factor VII on thrombin generation and coagulation following inhibition of platelet procoagulant activity by prasugrel. AB - INTRODUCTION: Prasugrel is a thienopyridyl P2Y12 antagonist with potent antiplatelet effects. At present, little is known about its effects on thrombin generation or what strategies may emergently reverse its anticoagulant effects. In the current study we evaluated whether recombinant activated factor VII may reverse prasugrel induced effects and increase thrombin generation in an in vitro model. METHODS: The effect of prasugrel active metabolite, PAM (R-138727), was evaluated on platelet aggregation, thrombin generation, and rotational thromboelastometry parameters using blood from 20 healthy volunteers. Additionally, we evaluated the effects of adenosine diphosphate (ADP) and recombinant activated factor VII on restoring these parameters towards baseline values. RESULTS: PAM reduced maximum platelet aggregation and led to platelet disaggregation. It also decreased peak thrombin, increased lag time, and increased time to peak thrombin. Treatment with recombinant activated factor VII restored all three parameters of thrombin generation towards baseline. ADP decreased lag time and time to peak thrombin, but had no effect on peak thrombin. When recombinant activated factor VII and ADP were combined they had a greater effect on thrombin parameters than either drug alone. PAM also increased thromboelastometric clotting time and clot formation time, but had no effect on maximum clot firmness. Treatment with either recombinant activated factor VII or ADP restored these values towards baseline. CONCLUSIONS: Recombinant activated factor VII restores thrombin generation in the presence of PAM. In patients taking prasugrel with life-threatening refractory bleeding it has the potential to be a useful therapeutic approach. Additional clinical studies are needed to validate our findings. PMID- 23664634 TI - The biomedical model of mental disorder: a critical analysis of its validity, utility, and effects on psychotherapy research. AB - The biomedical model posits that mental disorders are brain diseases and emphasizes pharmacological treatment to target presumed biological abnormalities. A biologically-focused approach to science, policy, and practice has dominated the American healthcare system for more than three decades. During this time, the use of psychiatric medications has sharply increased and mental disorders have become commonly regarded as brain diseases caused by chemical imbalances that are corrected with disease-specific drugs. However, despite widespread faith in the potential of neuroscience to revolutionize mental health practice, the biomedical model era has been characterized by a broad lack of clinical innovation and poor mental health outcomes. In addition, the biomedical paradigm has profoundly affected clinical psychology via the adoption of drug trial methodology in psychotherapy research. Although this approach has spurred the development of empirically supported psychological treatments for numerous mental disorders, it has neglected treatment process, inhibited treatment innovation and dissemination, and divided the field along scientist and practitioner lines. The neglected biopsychosocial model represents an appealing alternative to the biomedical approach, and an honest and public dialog about the validity and utility of the biomedical paradigm is urgently needed. PMID- 23664635 TI - Droplet breakup in subsea oil releases--part 2: predictions of droplet size distributions with and without injection of chemical dispersants. AB - A new method for prediction of droplet size distributions from subsea oil and gas releases is presented in this paper. The method is based on experimental data obtained from oil droplet breakup experiments conducted in a new test facility at SINTEF. The facility is described in a companion paper, while this paper deals with the theoretical basis for the model and the empirical correlations used to derive the model parameters from the available data from the test facility. A major issue dealt with in this paper is the basis for extrapolation of the data to full scale (blowout) conditions. Possible contribution from factors such as buoyancy flux and gas void fraction are discussed and evaluated based on results from the DeepSpill field experiment. PMID- 23664636 TI - Chemical dispersion of oil with mineral fines in a low temperature environment. AB - The increasing risks of potential oil spills in the arctic regions, which are characterized by low temperatures, are a big challenge. The traditional dispersant method has shown limited effectiveness in oil cleanup. This work studied the role of mineral fines in the formation of oil-mineral aggregates (OMAs) at low temperature (0-4 degrees C) environment. The loading amount of minerals and dispersant with different dispersant and oil types were investigated under a full factorial design. The shapes and sizes of OMAs were analyzed. Results showed that the behavior of OMA formation differs when dispersant and mineral fines are used individually or together. Both the experimental and microscopic results also showed the existence of optimal dispersant to oil ratios and mineral to oil ratios. In general, poor oil removal performance was observed for more viscous oil. Corexit 9500 performed better than Corexit 9527 with various oils, in terms of oil dispersion and OMA formation. PMID- 23664637 TI - In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation. AB - BACKGROUND: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is accompanied by activation of immuno-inflammatory pathways, increased bacterial translocation and autoimmune responses to serotonin (5-HT). Inflammation is known to damage 5-HT neurons while bacterial translocation may drive autoimmune responses. This study has been carried out to examine the autoimmune responses to 5-HT in ME/CFS in relation to inflammation and bacterial translocation. METHODS: We examined 5-HT antibodies in 117 patients with ME/CFS (diagnosed according to the centers for disease control and prevention criteria, CDC) as compared with 43 patients suffering from chronic fatigue (CF) but not fulfilling the CDC criteria and 35 normal controls. Plasma interleukin-1 (IL-1), tumor necrosis factor (TNF)alpha, neopterin and the IgA responses to Gram-negative bacteria were measured. Severity of physio-somatic symptoms was measured using the fibromyalgia and chronic fatigue syndrome rating scale (FF scale). RESULTS: The incidence of positive autoimmune activity against 5-HT was significantly higher (p<0.001) in ME/CFS (61.5%) than in patients with CF (13.9%) and controls (5.7%). ME/CFS patients with 5-HT autoimmune activity displayed higher TNFalpha, IL-1 and neopterin and increased IgA responses against LPS of commensal bacteria than those without 5-HT autoimmune activity. Anti-5-HT antibody positivity was significantly associated with increased scores on hyperalgesia, fatigue, neurocognitive and autonomic symptoms, sadness and a flu-like malaise. DISCUSSION: The results show that, in ME/CFS, increased 5-HT autoimmune activity is associated with activation of immuno-inflammatory pathways and increased bacterial translocation, factors which are known to play a role in the onset of autoimmune reactions. 5-HT autoimmune activity could play a role in the pathophysiology of ME/CFS and the onset of physio-somatic symptoms. These results provide mechanistic support for the notion that ME/CFS is a neuro-immune disorder. PMID- 23664638 TI - National study of suicide method in violent criminal offenders. AB - BACKGROUND: Gaining a greater knowledge of the mechanisms and means by which violent offenders die by suicide can inform tailored preventive strategies. METHODS: Using interlinked national Danish registry data we constructed a nested case-control study dataset of all adult suicides during 1994-2006: N=9708 cases and N=188,134 age and gender matched living controls. Completely ascertained International Classification of Diseases 10th revision cause-specific mortality codes were examined, with all criminal charges since 1980, and covariate information on psychiatric treatment and socio-demographics. Self-poisonings were classified as 'nonviolent' suicide and all other methods as being 'violent' ones. RESULTS: Compared with the general population, risk among male and female violent offenders was strongly and significantly elevated for suicide by either a violent or a nonviolent method, although the relative risk was greater for nonviolent suicide. These patterns were also observed among nonviolent offenders, albeit with smaller effect sizes. Risk was especially raised for self-poisoning with narcotics & hallucinogens. We could only examine the full range of suicide methods in male violent offenders. In these men, hanging was the most frequently used method, although risk was markedly and significantly elevated virtually across the entire range of regularly used suicide methods. LIMITATIONS: We lacked sufficient statistical power for undertaking a detailed profiling of specific suicide methods among female violent offenders. CONCLUSIONS: Our findings indicate that comprehensive and broadly-based preventive approaches are needed for tackling the markedly raised risk of suicide by both violent and nonviolent means in this population. Their high relative risk for self-poisoning by illicit or illegal drugs underlines the importance of access to means and of prevailing subculture. PMID- 23664639 TI - Immune response phenotype of allergic versus clinically tolerant pigs in a neonatal swine model of allergy. AB - The prevalence of childhood food allergy and the duration of these allergies, particularly those considered to be transient, like egg and milk allergy, are increasing. The identification of allergic individuals using minimally invasive, non-anaphylaxis-threatening methods is therefore of increasing importance. In this experiment, correlates were sought of an allergic immune response (IR) phenotype in pigs. Using pigs pre-treated with heat-killed bacteria or bacterial components before allergic sensitization with the egg white protein ovomucoid (Ovm), differences were determined in IR phenotype of pigs in the categories treated-allergic, treated-tolerant, control-allergic (CA) and control-tolerant. Phenotype was established by measuring immunoglobulin (Ig)-associated antibody activity (AbA), cytokine profiles and the proportion of blood T-regulatory cells (T-regs) and observing late-phase allergen-specific skin tests (ST). Although 100% of pigs became sensitized to Ovm, only 33% of pigs had clinical signs of allergy after oral challenge with egg white. Pigs without clinical signs were classified as clinically tolerant. Sixty-seven percent of allergic pigs had a positive, late-phase ST classified as very strong or strong, while 84% of clinically tolerant pigs did not have late-phase ST. Treated-allergic pigs and CA pigs had greater total antibody IgG (H+L), IgE and IgG1 AbA than clinically tolerant pigs. Cytokine profiles of allergic pigs and the proportion of circulating T-regs, did not differ significantly between allergic and clinically tolerant pigs. Therefore, measurement of allergen-specific IgG, IgG1 and/or IgE activity and evaluation of late-phase ID ST may be useful in identifying allergic IR phenotypes in swine models of food allergy, which may be extended toward human use. PMID- 23664641 TI - Prevalence of isolated left ventricular non-compaction in a medicine ward. PMID- 23664640 TI - Prefrontal cortical dysfunction after overexpression of histone deacetylase 1. AB - BACKGROUND: Postmortem brain studies have shown that HDAC1-a lysine deacetylase with broad activity against histones and nonhistone proteins-is frequently expressed at increased levels in prefrontal cortex (PFC) of subjects diagnosed with schizophrenia and related disease. However, it remains unclear whether upregulated expression of Hdac1 in the PFC could affect cognition and behavior. METHODS: Using adeno-associated virus, an Hdac1 transgene was expressed in young adult mouse PFC, followed by behavioral assays for working and long-term memory, repetitive activity, and response to novelty. Prefrontal cortex transcriptomes were profiled by microarray. Antipsychotic drug effects were explored in mice treated for 21 days with haloperidol or clozapine. RESULTS: Hdac1 overexpression in PFC neurons and astrocytes resulted in robust impairments in working memory, increased repetitive behaviors, and abnormal locomotor response profiles in novel environments. Long-term memory remained intact. Over 300 transcripts showed subtle but significant changes in Hdac1-overexpressing PFC. Major histocompatibility complex class II (MHC II)-related transcripts, including HLA DQA1/H2-Aa, HLA-DQB1/H2-Ab1, and HLA-DRB1/H2-Eb1, located in the chromosome 6p21.3-22.1 schizophrenia and bipolar disorder risk locus, were among the subset of genes with a more robust (>1.5-fold) downregulation in expression. Hdac1 levels declined during the course of normal PFC development. Antipsychotic drug treatment, including the atypical clozapine, did not affect Hdac1 levels in PFC but induced expression of multiple MHC II transcripts. CONCLUSIONS: Excessive HDAC1 activity, due to developmental defects or other factors, is associated with behavioral alterations and dysregulated expression of MHC II and other gene transcripts in the PFC. PMID- 23664642 TI - Left ventricular hypertrophy detected by echocardiography in HIV-infected patients. AB - BACKGROUND: Left ventricular hypertrophy (LVH) is a predictor of overall mortality in the general population. The most sensitive diagnostic method is transthoracic echocardiography (TTE). In this study, we describe the prevalence of LVH, and the factors associated with it, in a group of patients with HIV infection. METHODS: TTE was offered to all patients attending the outpatient clinic of the Hospital Costa del Sol (Marbella, Spain) between 1 December 2009 and 28 February 2011. The corresponding demographic and clinical data were obtained. The left ventricular mass (LVM) was calculated and indexed by height(2.7). LVH was defined as LVM >48g/m(2.7) in men or >44g/m(2.7) in women. RESULTS: We examined 388 individuals (75.5% male, mean age 45.38years). Of these, 76.1% were receiving HAART; 11.9% had hypertension, 6.2% had diabetes mellitus, 23.2% had dyslipidaemia and 53.6% were tobacco users. The risk of cardiovascular disease at 10years (RV10) was 12.15% (95%CI: 10.99-13.31%). 19.1% of these patients had a high RV10. A total of 69 patients (19.8%) presented high LVM. Age, hypertension, dyslipidaemia, RV10 and the use of nevirapine were associated with a greater presence of LVH in the univariate analysis. In the logistic regression analysis performed, the factors retained in the model were the presence of high RV10 (OR: 2.92, 95%CI: 1.39-6.15) and the use of nevirapine (OR 2.20, 95%CI: 1.18 4.14). CONCLUSIONS: In this group of patients, the use of nevirapine and the presence of high RV10 were associated with LVH. The use of nevirapine might be related to its prescription for patients with higher RV10. PMID- 23664643 TI - Genetic polymorphisms in the IL22 gene are associated with psoriasis vulgaris in a Japanese population. PMID- 23664644 TI - Regional treatment margins for prostate brachytherapy. AB - PURPOSE: This study quantified the treatment margin (TM) around the prostate that received 100% of the prescribed dose and analyzed postimplant dosimetry in different regions of the prostate for (125)I seed implants. METHODS AND MATERIALS: An average target volume (ATV) was created from postoperative MRI scan contours drawn independently by five radiation oncologists in 40 patients. The MRI was fused with the postoperative CT for dosimetry purposes. The TM, defined as the radial distance between the ATV and the 100% isodose line, was measured at 16 points at the base, midgland, and apex. The ATV was divided into four quadrants: anterior-superior, posterior-superior, anterior-inferior, and posterior-inferior quadrants. The values of the dose that covers 90% of the ATV (D90) and the percentage of the ATV receiving the prescribed dose (V100) received by the whole prostate and its four quadrants were documented. RESULTS: The range of the mean TM, in millimeter, was -8.88 to 3.68, 1.12 to 10.42, and 6.27 to 18.25 at the base, midgland, and apex, respectively. The mean D90 was 135.8, 162.8, 191.0, and 194.6 Gy for the anterior-superior, posterior-superior, anterior-inferior, and posterior-inferior quadrants, respectively. CONCLUSIONS: Despite having a relatively uniform preoperative planning target volume, this study identified variable TMs postoperatively in different regions of the prostate. In particular, the anterior base is most underdosed, whereas the lateral regions of the midgland and apex have generous TMs. Postimplant dosimetric parameters were lowest in the anterior-inferior quadrant. PMID- 23664645 TI - Failure modes and effects analysis applied to high-dose-rate brachytherapy treatment planning. AB - PURPOSE: To apply failure modes and effects analysis to high-dose-rate treatment planning to identify the most likely and significant sources of error in the process. METHODS: We have made a list of 25 failure modes grouped into six categories (imaging, catheter reconstruction, dwell position activity, dose points/normalization, optimization/dose, and evaluation). Each mode was rated on a one to five scale for severity, likelihood of occurrence, and probability of escaping detection. An overall ranking was formed from the product of the three scores. The authors assigned scores independently and the resulting rankings were averaged. We also analyzed 44 reported medical events related to high-dose-rate treatment planning listed on the Nuclear Regulatory Commission Web site and compared them with our own rankings. RESULTS: Failure modes associated with image sets, catheter reconstruction, indexer length, and incorrect dose points had the highest ranking in our analysis (scores higher than 20). The most often cited failure modes in the Nuclear Regulatory Commission reports examined were indexer length (20/44) and incorrect dose points (6/44). Several of our high-ranking modes are not associated with reported events. CONCLUSION: It is a useful exercise to identify failure modes locally and analyze the efficacy of the local quality assurance program. Comparison with nationally reported failures can help direct the local analysis, but the absence or small number of reports for failure modes with a high score may be owing to low detectability. Such modes obviously cannot be ignored. PMID- 23664646 TI - Long-term outcome for prostate cancer using pseudo pulse-dosed rate brachytherapy, external beam radiotherapy, and hormones. AB - PURPOSE: We report the long-term outcomes of pulse-dose rate (PDR) brachytherapy used in a nonstandard style (pseudo-PDR) with an high-dose rate brachytherapy technique in conjunction with external beam radiotherapy (EBRT) and hormonal manipulation on prostate cancer (PC). METHODS AND MATERIALS: We treated 253 patients with Stage T1-T3 N0M0 PC, between December 1999 and March 2006. All patients received neoadjuvant androgen deprivation for a median 6 months. Treatment consisted of three pulses of pseudo-PDR brachytherapy to a median dose of 18Gy with 50.4Gy in 28 fractions of EBRT. RESULTS: At a median 6 years followup, (range, 1-11 years), 5-year overall survival was 92%, and PC-specific survival was 96%. The 5-year biochemical control (biochemical no evidence of disease) by the Phoenix definition for low-, intermediate-, and high-risk groups was 95%, 90%, and 71%, respectively (p<0.00001). At 6 years, the incidence of Radiotherapy Oncology Group Grade 2 and 3 genitourinary toxicity was 1% and 6%; Radiotherapy Oncology Group Grade 2 and 3 gastrointestinal toxicity was 4% and 0%. Erectile preservation at 3 years was 58%. The Phoenix definition best predicted clinical failure with a high specificity (94%). CONCLUSIONS: Pseudo-PDR brachytherapy plus EBRT with limited neoadjuvant hormonal manipulation is an effective treatment option in localized PC, with minimal and tolerable morbidity and provides excellent control. This technique of a modified PDR-delivery technique appears as effective as high-dose rate therapy. PMID- 23664647 TI - CT enteroclysis in the developing world: how we do it, and the pathology we see. AB - INTRODUCTION: Imaging and diagnosis of small bowel disease is challenging, especially in developing countries where access to supplementary imaging equipment is not readily available. Imaging of the small bowel has evolved from small bowel follow-through to the first enteroclysis by Pesquera in 1929. This technique evolved over time with advances in enteral intubation catheters, enteral contrast media and techniques for infusing enteral contrast. OBJECTIVE: (1) Describe our modification of performing CTE and (2) to show pathology and discuss its relevance in our clinical practice. MATERIALS AND METHODS: This was a retrospective study that included 73 patients since the introduction of our modified technique of performing CT enteroclysis (CTE) using saline vaculitres, intravenous line connection sets and a drip stand. We recorded patient data in Microsoft Corporation Excel 2007 to include indications for the CTE, patient demographics and imaging findings related to small bowel pathology with associated extra luminal findings and incidental extra-intestinal non small bowel findings that was statistically analyzed. RESULTS: Of the 73 patients included in the study 42 where females and 31 males. 15 (20.5%) had small bowel pathology and 12 (16.4%) had non-small bowel pathology that could explain the clinical symptoms. Malabsorption/chronic diarrhea group was the largest indication for referral (26% of referrals). Most prevalent small bowel findings were in the inflammatory bowel subgroups where 30% had imaging features of active inflammatory bowel disease. CONCLUSION: Decades of experience have shown that only small bowel examinations that uniformly distend the small bowel lumen can confidently confirm or rule out small bowel pathology. With our modified technique performed, with readily available and affordable infusion equipment and enteral contrast we achieve diagnostic quality small bowel distention to demonstrate and diagnose with confidence small bowel pathology in our population. This is of particular value in developing countries where we are resource limited and expensive equipment and contrast material is often not available. PMID- 23664648 TI - Segmentation and volumetric analysis of the caudate nucleus in Alzheimer's disease. AB - OBJECTIVES: A quantitative volumetric analysis of caudate nucleus can provide valuable information in early diagnosis and prognosis of patients with Alzheimer's diseases (AD). Purpose of the study is to estimate the volume of segmented caudate nucleus from MR images and to correlate the variation in the segmented volume with respect to the total brain volume. We have also tried to evaluate the caudate nucleus atrophy with the age related atrophy of white matter (WM), gray matter (GM) and cerebrospinal fluid (CSF) in a group of Alzheimer's disease patients. METHODS: 3D fast low angle shot (3D FLASH) brain MR images of 15 AD patients, 15 normal volunteers and 15 patients who had normally diagnosed MR images were included in the study. Brain tissue and caudate nuclei were segmented using the statistical parametric mapping package and a semi-automatic tool, respectively and the volumes were estimated. Volume of segmented caudate nucleus is correlated with respect to the total brain volume. Further, the caudate nucleus atrophy is estimated with the age related atrophy of WM, GM and CSF in a group of AD patients. RESULTS: Significant reduction in the caudate volume of AD patients was observed compared to that of the normal volunteers. Statistical analysis also showed significant variation in the volume of GM and CSF of AD patients. Among the patients who had normal appearing brain, 33% showed significant changes in the caudate volume. We hypothesize that these changes can be considered as an indication of early AD. CONCLUSION: The method of volumetric analysis of brain structures is simple and effective way of early diagnosis of neurological disorders like Alzheimer's disease. We have illustrated this with the observed changes in the volume of caudate nucleus in a group of patients. A detailed study with more subjects will be useful in correlating these results for early diagnosis of AD. PMID- 23664649 TI - High-resolution computed tomographic findings of Aspergillus infection in lung transplant patients. AB - OBJECTIVE: The aim of this study was to assess high-resolution computed tomographic (HRCT) findings at presentation in lung transplant patients diagnosed with pulmonary Aspergillus infection. MATERIALS AND METHODS: We retrospectively reviewed HRCT findings from 23 patients diagnosed with pulmonary aspergillosis. Imaging studies were performed 2-5 days after the onset of symptoms. The patient sample comprised 12 men and 11 women aged 22-59 years (mean age, 43.6 years). All patients had dyspnea, tachypnea, and cough. Diagnoses were established with Platelia Aspergillus enzyme immunoassays for galactomannan antigen detection in bronchoalveolar lavage and recovery of symptoms, and HRCT findings after voriconazole treatment. The HRCT scans were reviewed independently by two observers who reached a consensus decision. RESULTS: The main HRCT pattern, found in 65% (n=15) of patients, was centrilobular tree-in-bud nodules associated with bronchial thickening. This pattern was described in association with areas of consolidation and ground-glass opacities in 13% (n=3) of patients. Consolidation and ground-glass opacities were the main pattern in 22% (n=5) of patients. The pattern of large nodules with and without the halo sign was observed in 13% (n=3) of patients, and were associated with consolidation and ground-glass opacities in one case. CONCLUSION: The predominant HRCT findings in lung transplant patients with pulmonary aspergillosis were bilateral bronchial wall thickening and centrilobular opacities with the tree-in-bud pattern. Ground-glass opacities and/or bilateral areas of consolidation were also common findings. Pulmonary nodules with the halo sign were found in only 13% of patients. PMID- 23664650 TI - Oxytocin stimulated release of PGF2alpha and its inhibition by a cyclooxygenase inhibitor and an oxytocin receptor antagonist from equine endometrial cultures. AB - Uterine inflammation results in a poor uterine environment and early embryonic loss in the mare due to an inhibition of maternal recognition of pregnancy caused from increased prostaglandin F2alpha (PGF2alpha). Oxytocin binds to endometrial cell receptors to activate prostaglandin synthesis. An oxytocin receptor antagonist (Atosiban) and a cyclooxygenase inhibitor (indomethacin) both decrease PGF2alpha production. The aim of this study was to evaluate the in vitro effects of Atosiban and indomethacin on equine uterine prostaglandin secretion. Equine endometrial explants were harvested on day two of behavioral estrus. Endometrial explant cultures were challenged with oxytocin (250nM) and PGF2alpha concentrations were measured over time. Explants were also cultured with Atosiban and indomethacin for 6h to determine the influence on PGF2alpha secretion. When endometrial explants were challenged with oxytocin, PGF2alpha concentrations were greater (P<0.0001) at each time point over the 24h of culture as compared to controls. Oxytocin failed (P<0.001) to elicit PGF2alpha release in explants cultured with either Atosiban or indomethacin. These findings show equine endometrial explants can be stimulated with oxytocin to increase secretion of PGF2alpha and this secretion can be inhibited through an oxytocin receptor antagonist and a Cox inhibitor, suggesting that this response to oxytocin involves an oxytocin receptor mediated event that activates the prostaglandin synthesis cascade through cyclooxygenase. Furthermore, this data suggests a role for the use of these inhibitors in vivo to decrease uterine PGF2alpha secretion and prevent early luteal regression and embryonic loss. PMID- 23664651 TI - Antioxidative effects of melatonin on kinetics, microscopic and oxidative parameters of cryopreserved bull spermatozoa. AB - Reactive oxygen species generated during the freeze-thawing process may reduce sperm quality. This study evaluates the effects of melatonin supplementation as an antioxidant in the semen extender on post-thaw parameters of bull spermatozoa. Melatonin was added to the citrate-egg yolk extender to yield six different final concentrations: 0, 0.1, 1, 2, 3 and 4mM. Ejaculates were collected from six proven Holstein bulls. Semen was diluted in the extender packaged in straws, which was frozen with liquid nitrogen. The semen extender supplemented with various doses of melatonin increased (p<0.05) total motility, progressive motility, linearity, sperm track straightness, lateral head displacement, viability, integrity of the sperm membrane and total normal morphology of sperm after the freeze-thawing process. The most effective concentration of melatonin in microscopic evaluations of the bull sperm freezing extender was 2mM. The highest (p<0.05) value of total antioxidant capacity (48.9+/-2.7) and the lowest value of lipid peroxidation (2.7+/-0.8) were achieved by inclusion of 3mM concentration of melatonin in the semen extender and the highest activity of catalase (0.7+/-0.1) was obtained by 2mM melatonin. Four millimolar concentration of melatonin were reduced (p<0.05) the progressive motility and straight linear velocity. In conclusion, supplementation of 2 or 3mM concentration of melatonin in the semen extender improved the quality of post-thawed semen, which may associate with a reduction in lipid peroxidation as well as an increase in the total antioxidant capacity and antioxidant enzyme activity. PMID- 23664652 TI - Sex determination of bovine preimplantation embryos by oligonucleotide microarray. AB - The aim has been to set up a rapid and accurate microarray assay using sandwich mode for sex determination of bovine preimplantation embryos. Twelve sequence specific oligonucleotide capture probes used to discriminate 12 samples were spotted onto the aldehyde-modified glass slides by Arrayer. The 2 recognition probes used to identify coding regions of the sex-determining region of the Y chromosome gene (SRY) and beta-casein (CSN2) reference gene were coupled with biotin. The assay was optimized by using genomic DNA extracted from blood samples of known sex individuals. Polymerase chain reaction (PCR) was used to amplify the fragments in the HMG box region of SRY gene and CSN2 gene with sequence-specific primers. The sex of samples was identified by detecting both the SRY and CSN2 genes simultaneously in 2 reaction cells of microarrays, with the male having SRY and CSN2 signals and the female only CSN2. The sex of 20 bovine preimplantation embryos was determined by oligonucleotide microarray. The protocol was run with a blind test that showed a 100% (82/82) specificity and accuracy in sexing of leukocytes. The bovine embryos were transferred into 20 bovine recipients, with a pregnant rate of 40% (8/20). Three calves were born at term, and 5 fetuses were miscarried. Their sexes were fully in accordance with the embryonic sex predetermination predicted by oligonucleotide microarray. This suggests that the oligonucleotide microarray method of SRY gene analysis can be used in early sex prediction of bovine embryos in breeding programs. PMID- 23664653 TI - Inhibitory effects of neural stem cells derived from human embryonic stem cells on differentiation and function of monocyte-derived dendritic cells. AB - Neural stem cells (NSCs) possess immunosuppressive characteristics, but effects of NSCs on human dendritic cells (DCs), the most important antigen presenting cells, are less well studied. We used an in vitro approach to evaluate the effects of human NSCs on differentiation of human blood CD14(+) monocytes into DCs. NSCs derived from H1 human embryonic stem cells (hESC-NSCs) and human ReNcell NSC line, as well as human bone marrow derived mesenchymal stem cells (MSCs), were tested. We observed that in response to treatment with interleukin-4 and granulocyte macrophage colony-stimulating factor CD14(+) monocytes co cultured with NSCs were able to down-regulate CD14 and up-regulate the differentiation marker CD1a, whereas MSC co-culture strongly inhibited CD1a expression and supported prolonged expression of CD14. A similar difference between NSCs and MSCs was noted when lipopolysaccharides were included to induce maturation of monocyte-derived DCs. However, when effects on the function of derived DCs were investigated, NSCs suppressed the elevation of the DC maturation marker CD83, although not the up-regulation of costimulatory molecules CD80, CD86 and CD40, and impaired the functional capacity of the derived DCs to stimulate alloreactive T cells. We did not observe any obvious difference between hESC-NSCs and ReNcell NSCs in inhibiting DC maturation and function. Our data suggest that although human NSCs are less effective than human MSCs in suppressing monocyte differentiation into DCs, these stem cells can still affect the function of DCs, ultimately regulating specific immune responses. PMID- 23664654 TI - Natural course of acute neck and low back pain in the general population: the HUNT study. AB - In this prospective cohort study we aimed to describe the natural course of acute neck and low back pain in a general population of Norway. We screened 9056 subjects aged 20-67 years who participated in a general health survey for a new episode of neck or low back pain the previous month. The screening identified 219 subjects who formed the cohort for this study. Pain intensity was reported on a numeric rating scale (0-10) at 1, 2, 3, 6, and 12 months after start of the new pain episode. The course of pain was described for neck and low back pain, different baseline pain levels, age groups, and number of pain sites at baseline. Use of medication and health care was described and associations between pain intensity and seeking health care were estimated. Pain declined rapidly within 1 month after a new pain episode, with a reduction of 0.91 (95% confidence interval [CI] 0.50-1.32) for neck pain and 1.40 (95% CI 0.82-1.99) for low back pain with little change thereafter. However, pain remained unchanged over the follow-up year for those with equal pain in the neck and low back areas at baseline and for those reporting 4 or more pain sites at baseline. Only 1 in 5 sought health care for their complaints. Still, the course of pain was comparable to effect sizes reported in interventional studies. This study thus contributes natural course reference data for comparisons of pain outcome in clinical trials and practice. PMID- 23664655 TI - Disturbances in slow-wave sleep are induced by models of bilateral inflammation, neuropathic, and postoperative pain, but not osteoarthritic pain in rats. AB - Preclinical assessment of pain has typically relied on measuring animal responses to evoked stimulation. Because of inherent limitations of these assays, there is a need to develop measures of animal pain/discomfort that are objective, not experimentally evoked, and mimic the human condition. Patients with chronic pain manifest a variety of co-morbidities, one of which is disturbances in sleep. We used electroencephalography to objectively assess 4 rat models of pain (inflammatory/complete Freund's adjuvant [CFA], neuropathic/chronic constriction injury [CCI], postoperative/skin incision, osteoarthritis/monosodium iodoacetate [MIA]) for the occurrence of sleep disturbances. Four different measures of slow wave sleep (SWS) were examined: amplitude of 1- to 4-Hz waves, total time spent in SWS, time spent in SWS-1, and time spent in SWS-2. Bilateral injuries were more likely to induce a sleep disturbance than unilateral injuries in the CFA, CCI, and skin incision assays. Sleep disturbances occurred in the deeper stage of SWS, as the amplitude of 1- to 4-Hz waves and time spent in SWS-2 were significantly decreased in all models except the osteoarthritis model. Sleep disturbances lasted for approximately 3 to 14days, depending on the model, and were resolved despite continued hypersensitivity to evoked stimulation. Morphine, gabapentin, diclofenac, and ABT-102 (TRPV1 antagonist) all improved sleep in the bilateral CFA assay at doses that did not significantly alter SWS in uninjured rats. Preclinical assessment of compounds should follow the path of clinical studies and take into account diverse aspects of the "pain condition." This would include evaluating nociceptive thresholds as well as other endpoints, such as cognition and sleep, that may be affected by the pathological state. PMID- 23664656 TI - Development of numerical model for predicting heat generation and temperatures in MSW landfills. AB - A numerical modeling approach has been developed for predicting temperatures in municipal solid waste landfills. Model formulation and details of boundary conditions are described. Model performance was evaluated using field data from a landfill in Michigan, USA. The numerical approach was based on finite element analysis incorporating transient conductive heat transfer. Heat generation functions representing decomposition of wastes were empirically developed and incorporated to the formulation. Thermal properties of materials were determined using experimental testing, field observations, and data reported in literature. The boundary conditions consisted of seasonal temperature cycles at the ground surface and constant temperatures at the far-field boundary. Heat generation functions were developed sequentially using varying degrees of conceptual complexity in modeling. First a step-function was developed to represent initial (aerobic) and residual (anaerobic) conditions. Second, an exponential growth decay function was established. Third, the function was scaled for temperature dependency. Finally, an energy-expended function was developed to simulate heat generation with waste age as a function of temperature. Results are presented and compared to field data for the temperature-dependent growth-decay functions. The formulations developed can be used for prediction of temperatures within various components of landfill systems (liner, waste mass, cover, and surrounding subgrade), determination of frost depths, and determination of heat gain due to decomposition of wastes. PMID- 23664657 TI - Simultaneous personnel and vehicle shift scheduling in the waste management sector. AB - Urban waste management is becoming an increasingly complex task, absorbing a huge amount of resources, and having a major environmental impact. The design of a waste management system consists in various activities, and one of these is related to the definition of shift schedules for both personnel and vehicles. This activity has a great incidence on the tactical and operational cost for companies. In this paper, we propose an integer programming model to find an optimal solution to the integrated problem. The aim is to determine optimal schedules at minimum cost. Moreover, we design a fast and effective heuristic to face large-size problems. Both approaches are tested on data from a real-world case in Southern Italy and compared to the current practice utilized by the company managing the service, showing that simultaneously solving these problems can lead to significant monetary savings. PMID- 23664658 TI - Implanted medical devices or other strong sources of interference are not barriers to magnetoencephalographic recordings in epilepsy patients. AB - OBJECTIVE: Localization accuracy in magnetoencephalography (MEG) recordings is highly dependent on signal to noise ratio, which is difficult to control. METHODS: We have post-processed our data in order to reduce noise to a level permitting adequate source localization with equivalent current dipole methods. In 30 consecutive epilepsy patients, MEG was recorded using a whole-head MEG system consisting of 204 planar gradiometer and 102 magnetometers, with simultaneous EEG. Data were reviewed to identify interictal spikes. The initial analysis was done after employing a spatiotemporal signal space separation (tSSS) method. A total of 18 dipole clusters in 15 patients were reanalyzed without tSSS, to compare the number, goodness of fit, and locations of acceptable dipoles before and after processing. RESULTS: In 8 of 18 clusters, although acceptable dipole clusters were captured before processing, there was a clear improvement of all parameters with tSSS. In another 5 clusters, all from patients with vagus nerve stimulators, there were few or no acceptable dipoles before processing, but sufficient dipole clusters were obtained with tSSS. CONCLUSION: In contrast to volunteer research subjects, clinical patients cannot be expected to cooperate as fully, and their MEG data are likely to include more interference. This study demonstrates that processing the MEG data with a method to eliminate artifact arising from outside the brain significantly improves the data. SIGNIFICANCE: In some cases, this improvement can mean the difference between satisfactory dipole fits vs no possible localization. PMID- 23664659 TI - The role of triphasic waves in the care of critically ill patients. PMID- 23664661 TI - Expression of Opa interacting protein 5 (OIP5) is associated with tumor stage and prognosis of clear cell renal cell carcinoma. AB - Opa interacting protein 5 (OIP5), overexpressed in some types of human cancers, has been reported to be associated with the carcinogenesis of human cancer. However, the biological function and clinical significance of OIP5 in human Clear Cell Renal Cell Carcinoma (CCRCC) remains unknown. In the present study, we found the expression of OIP5 was markedly upregulated in surgical CCRCC specimens and CCRCC cell lines. Immunohistochemical analysis revealed that paraffin-embedded archival CCRCC specimens exhibited higher levels of OIP5 expression than normal renal tissues. Further statistical analysis suggested the upregulation of OIP5 was positively correlated with the Fuhrman grade (P = 0.02), T classification (P = 0.015), N classification (P = 0.018) and clinical stage (P = 0.035). Also, patients with high OIP5 expression dramatically exhibited shorter survival time (P = 0.001). In addition, the OIP5 expression was an independent prognostic marker of overall survival of CCRCC patients in a multivariate analysis (P = 0.008). Experimentally, we demonstrated that silencing OIP5 in CCRCC cell lines by specific siRNA clearly inhibited cell growth. In conclusion, our findings suggested that OIP5 could be a valuable marker of CCRCC progression and prognosis, and a promising therapeutic target for CCRCC. PMID- 23664660 TI - T-cell immunity to human alphaherpesviruses. AB - Human alphaherpesviruses (alphaHHV) - herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus (VZV) - infect mucosal epithelial cells, establish a lifelong latent infection of sensory neurons, and reactivate intermittingly to cause recrudescent disease. Although chronic alphaHHV infections co-exist with brisk T-cell responses, T-cell immune suppression is associated with worsened recurrent infection. Induction of alphaHHV-specific T-cell immunity is complex and results in poly-specific CD4 and CD8 T-cell responses in peripheral blood. Specific T-cells are localized to ganglia during the chronic phase of HSV infection and to several infected areas during recurrences, and persist long after viral clearance. These recent advances hold promise in the design of new vaccine candidates. PMID- 23664662 TI - Reply: To PMID 22705258. PMID- 23664663 TI - Effectiveness of risk communication interventions on the medical follow-up of youth treated with antidepressants. AB - Following reports of a potential association between antidepressants (ADs) and suicidal behaviour in youth, regulatory warnings were issued in May 2004, and clinical recommendations on medical follow-up were published in November 2007. Our study aimed at assessing the association between these communication interventions and medical follow-up of children (age 10-14) and adolescents (age 15-19) who initiate an AD treatment. A retrospective cohort study (1998-2008) was conducted among youth members of the Quebec public drug plan. Study outcomes consisted of adequate follow-up practice, defined as at least 1 medical visit per month during the first 3 months of treatment. The effect of each intervention on follow-up practices was determined through multivariate logistic regression analysis. The cohort included 4576 children and 12,419 adolescents. Two thirds of both children and adolescents had at least one medical visit during the first trimester of treatment, but only 20% had a frequency of at least one visit per month (i.e. adequate). The occurrence and frequency of visits did not change after either the warning nor the publication of the guidelines. Further interventions designed to optimize monitoring practices should be envisaged. PMID- 23664665 TI - Validation of the Yale-Brown Obsessive-Compulsive Severity Scale in African Americans with obsessive-compulsive disorder. AB - The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) is widely used in the assessment of obsessive-compulsive disorder (OCD), but the psychometric properties of the instrument have not been examined in African Americans with OCD. Therefore, the purpose of this study is to explore the properties of the Y BOCS severity scale in this population. Participants were 75 African American adults with a lifetime diagnosis of OCD. They completed the Y-BOCS, the Beck Anxiety Inventory (BAI), the Beck Depression Inventory-II (BDI-II), and the Multigroup Ethnic Identity Measure (MEIM). Evaluators rated OCD severity using the Clinical Global Impression Scale (CGI) and their global assessment of functioning (GAF). The Y-BOCS was significantly correlated with both the CGI and GAF, indicating convergent validity. It also demonstrated good internal consistency (alpha=0.83) and divergent validity when compared to the BAI and BDI II. Confirmatory factor analyses tested five previously reported models and supported a three-factor solution, although no model exhibited excellent fit. An exploratory factor analysis was conducted, supporting a three-factor solution. A linear regression was conducted, predicting CGI from the three factors of the Y BOCS and the MEIM, and the model was significant. The Y-BOCS appears to be a valid measure for African American populations. PMID- 23664664 TI - Hypothetical decision making in schizophrenia: the role of expected value computation and "irrational" biases. AB - The aim of the present study was to examine the contributions to decision making (DM) deficits in schizophrenia (SZ) patients of expected value (EV) estimation and loss aversion. Patients diagnosed with SZ (n=46) and healthy controls (n=34) completed two gambling tasks. In one task, participants chose between two options with the same EV across two conditions: Loss frames and Keep frames. A second task involved accepting or rejecting gambles, in which gain and loss amounts varied, determining the EV of each trial. SZ patients showed a reduced "framing effect" relative to controls, as they did not show an increased tendency to gamble when faced with a certain loss. SZ patients also showed a reduced tendency to modify behavior as a function of EV. The degree to which choices tracked EV correlated significantly with several cognitive measures in both patients and controls. SZ patients show distinct deviations from normal behavior under risk when their decisions are based on prospective outcomes. These deviations are two fold: cognitive deficits prevent value-based DM in more-impaired patients, and in less-impaired patients there is a lack of influence from well-established subjective biases found in healthy people. These abnormalities likely affect everyday DM strategies in schizophrenia patients. PMID- 23664666 TI - Herpes zoster eye complications: rates and trends. AB - PURPOSE: To provide population-based data on the risk, types, and outcomes of eye involvement in herpes zoster (HZ). METHODS: A cohort study based on review of the medical records of patients in whom HZ was diagnosed between January 1, 1980, and December 31, 2007, was performed. Herpes zoster was confirmed by the presence of the typical rash and symptoms or by laboratory testing, and eye involvement was confirmed by ophthalmologists' evaluation. Information was collected on all eye diagnoses and on HZ eye-related visits, treatments, procedures, and outcomes. RESULTS: Of the 2035 individuals with HZ in any dermatome, 184 (9.0%) had eye involvement. The mean age of the 184 was 62.6 years, and 5 cases occurred in patients younger than 21. Overall, 6.5% (12) were immunosuppressed at the time of the eye complications. The rate of increase in HZ eye involvement was 23% by decade from 1980 to 2007. Common eye complications were keratitis (n=144, 76.2%), uveitis/iritis (n=88, 46.6%), and conjunctivitis (n=67, 35.4%). Recurrent keratitis and recurrent iritis/uveitis occurred in 6.9% (13) and 7.4% (14), respectively. Outcomes included 6 patients (3.3%) with new vision decrements to 20/200 or worse. Two individuals had successful corneal transplants. Another 6 individuals (3.3%) had lid ptosis that affected vision, including 1 elderly woman with permanent unilateral tarsorrhaphy. Severe HZ eye pain was reported to be directly responsible for 1 unsuccessful suicide attempt. Acute retinal necrosis did not develop in any individual. A mean of 10.8 eye visits per patient with HZ and eye involvement was reported to continue for a mean of 308 days. CONCLUSION: Eye complications are common and result in considerable health care use and permanent vision decrement in about 6.6% (6) of individuals with HZ eye involvement. Most health care use and long-term adverse outcomes occurred in patients in whom prevention of HZ with the zoster vaccine would be possible. PMID- 23664667 TI - Response to "Increased risks of upper tract urothelial carcinoma in male and female Chinese herbalists". PMID- 23664668 TI - Toward clinical application of the Keap1-Nrf2 pathway. AB - The Keap1-Nrf2 pathway plays a crucial role in determining the sensitivity of cells to chemical and/or oxidative insults by regulating the basal and inducible expression of detoxification and antioxidant enzymes, ABC transporters, and other stress response enzymes and/or proteins. Increasing attention has been focused on the roles that the Keap1-Nrf2 pathway plays in the protection of our body against drug toxicity and stress-induced diseases. Simultaneously, Nrf2 has been recognized to promote oncogenesis and resistance to chemotherapeutic drugs. Cancer cells hijack Nrf2 activity to support their malignant growth and thus Nrf2 has emerged as a therapeutic target. Translational studies of the Keap1-Nrf2 system, from mechanistic understanding to clinical applications, are now important to improve human health. PMID- 23664669 TI - Cooperation and communication challenges in small-scale eHealth development projects. AB - AIM: In eHealth development there is an increasing focus on user participation inspired by the information systems field of practice and research. There are, however, many other challenges in developing information systems that fit healthcare practices. One of these is the challenge of cooperation and communication in development projects that are initiated and managed by clinicians e.g. cooperating with IT professionals in 'bottom up' health informatics projects that have been initiated and are managed by healthcare professional project managers. METHOD: The analysis and results are drawn from a qualitative case study on a systems development project that was managed by a local, non-technical, healthcare professional and the complex blend and interactions with the IT professionals in the phases of ideas, design, development, implementation, maintenance and distribution. RESULTS: We analyze the challenges of cooperation and communication using perspectives from information systems research and the concepts of 'language-games' and 'shared design spaces', and thereby exploring the boundaries between the different communication, practice and culture of the IT professionals and the healthcare professionals. CONCLUSION: There is a need to (a) develop a better understanding of the development process from the point of view of the 'user' and (b) tools for making technical knowledge explicit in the development process. Cooperative and communicative methods are needed that support and develop the shared design spaces between IT professionals and the clinical context in order to strengthen small-scale health information systems projects. PMID- 23664670 TI - Neural dynamics of neglected targets in patients with right hemisphere damage. AB - We studied the neural correlates of target omissions in five patients with right hemisphere damage and varying signs of left spatial neglect. Benefiting from the high temporal resolution of magneto-encephalography, we directly compared brain regional synchrony events of detected and omitted left-sided targets. Results showed that before stimulus presentation, a low beta synchronization activity was specifically increased within left frontal areas before pathological response omissions of left-sided targets. In the same pre-stimulus period, there were no such beta oscillations when patients correctly detected the target, or when no target was presented. Our findings emphasize the importance of neural activity during the pre-stimulus period on subsequent stimulus processing, and highlight the consequences of episodic interruptions of large-scale interhemispheric networks on target detection. Furthermore, our data suggest that prefrontal activity is not necessarily beneficial to target detection, but can be detrimental to it. PMID- 23664671 TI - Forced expiratory decay in asthmatic preschool children--is it adult type? AB - BACKGROUND: The forced expiratory decay in healthy preschool children portrays a convex shape that differs from the linear decay in the older healthy population. The "adult-type" expiratory decay during airway obstruction is concave. The study objective was to determine if the expiratory decay in young asthmatic children is "adult-type". METHODS: Among 245 children (age 3-7 yrs), 178 had asthma (asthmatics) and 67 were non-asthmatic (controls). The expiratory flow decay was inspected by FEF25-75/FVC ratio (=1.0 when linear). Values were compared to those of our formerly studied (n = 108) healthy children. A meaningful obstruction in FEF25-75/FVC ratio was defined as 2-zScores from healthy. A meaningful response to bronchodilators was related to non-asthmatics. RESULTS: In healthy subjects FEF25-75/FVC ratio declined with age from 1.73 +/- 0.17 to 1.28 +/- 0.11. Non asthmatics portrayed ratio values similar to those of healthy subjects. In asthmatics, 118/178 displayed a convex to linear expiratory decay (FEF25-75/FVC = 1.33 +/- 0.22). Sixty/178 asthmatics portrayed concavity (FEF25-75/FVC-0.79 +/- 0.16) that appeared when FEF50 was 43.4 +/- 12%healthy. Concavity appearance was also age-dependent (30.4% of 3-4 y old and 59.1% of 6-7 y). Vital-Capacity decreased in either decays, forming a visually petit curve. Most asthmatic children respond to bronchodilators by a meaningful elevation in FEF25-75/FVC values and by a visual change in the shape of the curve. Other common spirometry indices also increased meaningfully. CONCLUSION: Most asthmatic preschool children portray convex to linear expiratory decay with diminished vital capacity, resulting in a visually smaller than healthy curve, with seemingly normal expiratory decay. These curves may be misinterpreted as "normal" or as "no cooperation" and may lead to misinterpretation. In response to bronchodilators, FEF25-75/FVC value increases in asthmatics and the curve changes from concave to linear or from linear to convex contour. PMID- 23664672 TI - Increased plasma agmatine levels in patients with schizophrenia. AB - Agmatine is an endogenous substance, synthesized from l-arginine, and it is proposed to be a new neurotransmitter. Preclinical studies indicated that agmatine may have an important role in the pathophysiology of schizophrenia. This study was organized to investigate plasma agmatine in patients with schizophrenia and in healthy controls. Eighteen patients with schizophrenia and 19 healthy individuals constituted the subjects. Agmatine levels in the plasma were measured using the HPLC method. The S100B protein level, which is a peripheral biomarker for brain damage, was also measured using the ELISA method. While plasma levels of agmatine in patients with schizophrenia were significantly increased (p < 0.0001) compared to those of healthy individuals (control), there were no significant changes in the levels of S100B protein (p = 0.660). An ROC (receiver operating characteristic) curve analysis revealed that measuring plasma agmatine levels as a clinical diagnostic test would significantly differentiate between patients with schizophrenia and those in the control group (predictive value: 0.969; p < 0.0001). The predictive value of S100B measurements was not statistically significant (p > 0.05). A multiple regression analysis revealed that the age of the patient and the severity of the illness, as indicated by the PANSS score, significantly contributed the plasma agmatine levels in patients with schizophrenia. These results support the hypothesis that an excess agmatine release is important in the development of schizophrenia. The findings also imply that the plasma agmatine level may be a potential biomarker of schizophrenia. PMID- 23664673 TI - Antipsychotic augmentation of selective serotonin reuptake inhibitors in resistant tic-related obsessive-compulsive disorder in children and adolescents: a naturalistic comparative study. AB - The aim of this study is to assess efficacy of augmentation of SSRIs with risperidone or aripiprazole in youths with tic-related Obsessive-Compulsive Disorder (OCD) non responders to an SSRI monotherapy. 120 consecutive patients (age range 7-18 years) were treated with an SSRI monotherapy for at least 12 weeks, 51 (42.5%) were responders, and the 69 non-responders (mean age 13.7 +/- 2.4 years) were included in this study. 35 patients received an augmentation with risperidone (1.7 +/- .8 mg/day), and 34 with aripiprazole (8.9 +/- 3.1 mg/day) for 12 weeks. Regarding the OCD symptomatology, at the endpoint the Clinical Global Impression-Severity score (CGI-S) improved from 5.6 +/- .8 (severely ill), to 3.2 +/- .9 (mild to moderately ill) (p < .0001), and the Children-Global Assessment Scale (C-GAS) from 40.3 +/- 5.2 to 53.8 +/- 9.2 (p < .0001). Thirty nine patients (56.5%) were responders in OCD symptomatology (CGI-I score 1 or 2, CGI-S score 3 or less and C-GAS score 50 or more during three consecutive months after a 12-week treatment). Compared to non responders, they were less impaired at the baseline in CGI-S (p < .0001) and C-GAS (p < .0001). Subtypes of OCD and comorbidity did not affect the response. No differences were found between risperidone and aripiprazole augmentation. 47 patients (68.1%) significantly improved tics, without differences between risperidone and aripiprazole. None discontinued medications because of side effects, but risperidone was associated with weight gain and sedation, and aripiprazole to mild/moderate agitation. In tic-related pediatric OCD, augmentation of SSRIs with risperidone or aripiprazole was tolerated and effective in about half of the patients non responding to an SSRI. PMID- 23664674 TI - Synergistic activity of rifampicin and ethambutol against slow-growing nontuberculous mycobacteria is currently of questionable clinical significance. AB - A key issue in the treatment of disease caused by slow-growing nontuberculous mycobacteria is the limited association between in vitro minimum inhibitory concentrations (MICs) of rifampicin and ethambutol alone and the in vivo outcome of treatment with these drugs. Combined susceptibility testing to rifampicin and ethambutol could provide a more realistic view of the efficacy of these drugs. In this study, Mycobacterium avium (n = 5), Mycobacterium chimaera (n = 6), Mycobacterium intracellulare (n = 4), Mycobacterium xenopi (n = 4), Mycobacterium malmoense (n = 3) and Mycobacterium simiae (n = 2) clinical isolates were selected and the MICs of rifampicin and ethambutol alone and in combination were measured using the Middlebrook 7H10 agar dilution method. Synergy was defined as a fractional inhibitory concentration index <= 0.5. Rifampicin and ethambutol showed synergistic activity against the majority of M. avium (4/5), M. chimaera (5/6) and M. intracellulare (3/4) isolates and 1 of 2 eligible M. malmoense isolates. No synergistic activity was measured against M. xenopi and M. simiae. Synergy was neither universal for all species nor for all isolates of one species; it thus needs to be tested for rather than assumed. Even if this synergy exists in vivo, it is questionable whether the MICs to the combined drugs can be overcome by the drug exposure attained by current regimens at the recommended dosages. New dosing strategies for rifampicin and ethambutol should be studied to increase the exposure to these drugs and thus maximise their impact. PMID- 23664675 TI - Epigenetics in sepsis: targeting histone deacetylases. AB - Severe sepsis and septic shock are lethal complications of infection, characterised by dysregulated inflammatory and immune responses. Our understanding of the pathogenesis of sepsis has improved markedly in recent years, but unfortunately has not been translated into efficient treatment strategies. Epigenetic mechanisms such as covalent modification of histones by acetylation are master regulators of gene expression under physiological and pathological conditions, and strongly impact on inflammatory and host defence responses. Histone acetylation is controlled by histone acetyltransferases and histone deacetylases (HDACs), which affect gene expression also by targeting non histone transcriptional regulators. Numerous HDAC inhibitors (HDACi) are being tested in clinical trials, primarily for the treatment of cancer. We performed the first comprehensive study of the impact of HDACi on innate immune responses in vitro and in vivo. We showed that HDACi act essentially as negative regulators of the expression of critical immune receptors and antimicrobial pathways in innate immune cells. In agreement, HDACi impaired phagocytosis and killing of bacteria by macrophages, and increased susceptibility to non-severe bacterial and fungal infections. Strikingly, proof-of-principle studies demonstrated that HDACi protect from lethal toxic shock and septic shock. Overall, our observations argue for a close monitoring of the immunological and infection status of patients treated with HDACi, especially immunocompromised cancer patients. They also support the concept of pharmacological inhibitors of HDACs as promising drugs to treat inflammatory diseases, including sepsis. PMID- 23664676 TI - Controversies in the management of the critically ill: the role of probiotics. AB - Probiotics are commercially available, viable, non-pathogenic micro-organisms that, when ingested in sufficient quantities, exert a health benefit to the host derived through modification of the gut flora, local release of antimicrobial factors, maintenance of integrity of the gut barrier, competition for epithelial adherence, prevention of bacterial translocation, and modulation of the local immune response. In critically ill patients, probiotics appear to lead to decreased susceptibility to antibiotic-associated diarrhoea, Clostridium difficile infections, ventilator-associated pneumonia, necrotising enterocolitis, acute severe pancreatitis, sepsis and multiple organ dysfunction syndrome as well as a shortened duration of infections. Current scientific evidence supporting the use of probiotics is not conclusive and is mainly derived from single-centre, not very well designed trials that are limited by many factors including small sample sizes, heterogeneity in the probiotic strains used, effectiveness of the combined strains, optimum dose regimens, frequency and duration of administration, and certainly incomplete knowledge of the mechanism of action of each strain. Probiotics appear to be well tolerated, whilst adverse events are very rare. The most commonly reported adverse events include bacteraemia, fungaemia and sepsis. At present, based on the available evidence and although helpful and relatively safe for certain disease conditions, routine use of probiotics in the critically ill is not recommended. PMID- 23664677 TI - Assessment of extended-spectrum beta-lactamase, KPC carbapenemase and porin resistance mechanisms in clinical samples of Klebsiella pneumoniae and Enterobacter spp. AB - The emergence and spread of resistance mechanisms in Gram-negative bacilli has complicated the treatment of serious nosocomial infections. Current automated systems for detection of Klebsiella pneumoniae carbapenemase (KPC)-producing isolates are unreliable. One possible straightforward alternative method is evaluation of ertapenem resistance. However, the accuracy of this method is affected by other resistance mechanisms such as AmpC gene expression or extended spectrum beta-lactamase production associated with porin loss. This study included 128 samples of K. pneumoniae and Enterobacter spp. that were non susceptible to ertapenem. The disk diffusion and Etest method were applied to determine susceptibility to imipenem, meropenem and ertapenem. Isolates exhibiting intermediate or complete resistance to ertapenem were evaluated for resistance mechanisms. bla(TEM), bla(SHV), bla(CTX-M), bla(CTX-M-2) and bla(KPC) genes were tested for by PCR, and the presence of outer membrane protein was investigated by dot-blot assay. bla(TEM) was detected in 52.9% and 10.3%, bla(SHV) in 29.4% and 0.94%, bla(CTX-M) in 41.4% and 1.9% and bla(CTX-M-2) in 23.5% and 1.9% of K. pneumoniae and Enterobacter cloacae isolates, respectively. The bla(KPC) gene was present in 12.6% of Enterobacter spp. isolates. OmpC and OmpF were present in 6.6% of E. cloacae isolates. These results indicate that several resistance mechanisms contribute to potential therapeutic failure of carbapenem therapy and point to the need for better detection methods and surveillance strategies. PMID- 23664678 TI - Effect of ribosome-targeting antibiotics on streptomycin-resistant Mycobacterium mutants in the rpsL gene. AB - Streptomycin (Sm) was the first antibiotic used against Mycobacterium tuberculosis, the aetiological agent of tuberculosis (TB). However, point mutations in the rpsL gene can generate resistance to Sm, which is why spontaneous resistance to this antibiotic emerges so rapidly during treatment. Here we examine the interaction between Sm resistance and sensitivity to other ribosome-targeting antibiotics. Levels of resistance of rpsL mutants to the ribosome-affecting antibiotics chloramphenicol, tetracycline, gentamicin and erythromycin were tested, both singly and in combination. For this purpose, Mycobacterium smegmatis was used, which is commonly used in laboratory experiments as a model for TB. Generally, Sm-resistant mutants were as sensitive to the ribosome-affecting antibiotics as the wild-type strain. Combinations of different ribosome-affecting antibiotics were occasionally more potent than either of the single drugs, with better inhibition of both wild-type and mutant strains. Combining different ribosome-affecting drugs could represent an additional strategy in treating mycobacterial infections, including those resistant to newer drugs such as isoniazid or ethambutol. PMID- 23664679 TI - Parotid perfusion in nasopharyngeal carcinoma patients in early-to-intermediate stage after low-dose intensity-modulated radiotherapy: evaluated by fat-saturated dynamic contrast-enhanced magnetic resonance imaging. AB - PURPOSE: To investigate parotid perfusion in early-to-intermediate stage after parotid-sparing radiation dose using fat-saturated DCE-MRI, and to verify whether the perfusion alteration was related to radiation dose and the PSV. METHODS AND MATERIALS: Thirty-two parotid glands from 16 consecutive patients with pathologically proven nasopharyngeal carcinoma treated by IMRT were examined. The parotid glands received a radiation dose of 28.9+/-3.9Gy with a PSV of 43.1%+/ 13.9%. Perfusion parameters were calculated using time-shifted Brix model from fat-saturated DCE-MRI data before (pre-RT) and in early-to-intermediate stage after (post-RT) IMRT. Paired t-test was used to evaluate perfusion changes, while Pearson's correlation test was used to examine perfusion dependency on radiation dose and PSV. For multiple comparisons Bonferroni correction was applied. RESULTS: Successful fat saturation was achieved in 29 of 32 parotid glands. Compared with pre-RT, the post-RT parotid glands showed significantly higher A, peak enhancement, and wash-in slope, plus a lower Kel, suggesting a mixed effect of increased vascular permeability and acinar loss. Linear regression showed that peak enhancement was positively associated with radiation dose in post-RT parotid glands. Kel and slope were negatively associated with PSV, while time-to-peak was positively associated with PSV significantly. CONCLUSIONS: Our results suggest that time-shifted Brix model is feasible for quantifying parotid perfusion using DCE-MRI. The perfusion alterations in early-to-intermediate stage after IMRT might be related to a mixed effect of increased vascular permeability and acinar loss with dose and PSV dependencies. PMID- 23664681 TI - a-tDCS differential modulation of corticospinal excitability: the effects of electrode size. AB - BACKGROUND: Novel noninvasive brain stimulation techniques such as transcranial direct current stimulation (tDCS) have been developed in recent years. tDCS induced corticospinal excitability changes depend on two important factors: current density and electrodes size. Despite clinical success with existing tDCS parameters; optimal protocols are still not entirely set. OBJECTIVE: The current study aimed to investigate the effects of anodal tDCS (a-tDCS) with three electrode sizes on corticospinal excitability. METHODS: a-tDCS was applied with three active electrode sizes of 12, 24 and 35 cm(2) with a constant current density of 0.029 mA/cm(2) on twelve right handed healthy individuals (mean age: 34.5 +/- 10.32 years) in different sessions at least 48 h apart. a-tDCS was applied continuously for 10 min, with a constant reference electrode size of 35 cm(2). The corticospinal excitability of extensor carpi radialis muscle (ECR) was measured before and immediately after the intervention and at 10, 20 and 30 min thereafter. RESULTS: We found that smaller electrode may produce more focal current density and could lead to more effective and localized neural modulation than the larger ones. Post hoc comparisons showed that active electrode of 12 cm(2) size induces the biggest increase in the corticospinal excitability compared to bigger electrode sizes, 24 cm(2) (P = 0.002) and 35 cm(2) (P = 0.000). There was no significant difference between two larger electrode sizes (24 cm(2) and 35 cm(2)) (P = 0.177). a-tDCS resulted in significant excitability enhancement lasting for 30 min after the end of stimulation in the 12 and 24 cm(2) electrode size conditions (P < 0.005). However, in 35 cm(2) electrode size condition, the MEP amplitudes of the ECR did not differ significantly from baseline value in 20 and 30 min post stimulation (P > 0.005). CONCLUSION: Reducing stimulation electrode size to one third of the conventional one results in spatially more focused stimulation and increases the efficacy of a-tDCS for induction of larger corticospinal excitability. This may be due to the fact that larger electrodes stimulate nearby cortical functional areas which can have inhibitory effects on primary motor cortex. PMID- 23664680 TI - Balanced steady state free precession for arterial spin labeling MRI: Initial experience for blood flow mapping in human brain, retina, and kidney. AB - We implemented pseudo-continuous ASL (pCASL) with 2D and 3D balanced steady state free precession (bSSFP) readout for mapping blood flow in the human brain, retina, and kidney, free of distortion and signal dropout, which are typically observed in the most commonly used echo-planar imaging acquisition. High resolution functional brain imaging in the human visual cortex was feasible with 3D bSSFP pCASL. Blood flow of the human retina could be imaged with pCASL and bSSFP in conjunction with a phase cycling approach to suppress the banding artifacts associated with bSSFP. Furthermore, bSSFP based pCASL enabled us to map renal blood flow within a single breath hold. Control and test-retest experiments suggested that the measured blood flow values in retina and kidney were reliable. Because there is no specific imaging tool for mapping human retina blood flow and the standard contrast agent technique for mapping renal blood flow can cause problems for patients with kidney dysfunction, bSSFP based pCASL may provide a useful tool for the diagnosis of retinal and renal diseases and can complement existing imaging techniques. PMID- 23664682 TI - Response to the letter to the editor of pain by S. Canavero. PMID- 23664683 TI - Hypnotic susceptibility modulates brain activity related to experimental placebo analgesia. AB - Identifying personality traits and neural signatures that predict placebo responsiveness is important, both on theoretical and practical grounds. In the present functional magnetic resonance imaging (fMRI) study, we performed multiple regression interaction analysis to investigate whether hypnotic susceptibility (HS), a cognitive trait referring to the responsiveness to suggestions, explains interindividual differences in the neural mechanisms related to conditioned placebo analgesia in healthy volunteers. HS was not related to the overall strength of placebo analgesia. However, we found several HS-related differences in the patterns of fMRI activity and seed-based functional connectivity that accompanied placebo analgesia. Specifically, in subjects with higher HS, the placebo response was related to increased anticipatory activity in a right dorsolateral prefrontal cortex focus, and to reduced functional connectivity of that focus with brain regions related to emotional and evaluative pain processing (anterior mid-cingulate cortex/medial prefrontal cortex); an opposite pattern of fMRI activity and functional connectivity was found in subjects with lower HS. During pain perception, activity in the regions reflecting attention/arousal (bilateral anterior thalamus/left caudate) and self-related processing (left precuneus and bilateral posterior temporal foci) was negatively related to the strength of the analgesic placebo response in subjects with higher HS, but not in subjects with lower HS. These findings highlight HS influences on brain circuits related to the placebo analgesic effects. More generally, they demonstrate that different neural mechanisms can be involved in placebo responsiveness, depending on individual cognitive traits. PMID- 23664684 TI - The radiology sweat shop, or how holding on to our past is jeopardizing our future. PMID- 23664685 TI - [Mass spectrometry-extended neonatal screening in tandem: is more better?]. PMID- 23664686 TI - [Risk of hypercalcemia and hipervitaminosis D induced by calcifediol. Review of cases reported to the Spanish Pharmacovigilance System]. PMID- 23664687 TI - [Cat bite-induced cellulitis: Bergeyella zoohelcum]. PMID- 23664688 TI - [Oral secondary effects of radiotherapy and chemotherapy in cancer of the cervicofacial region]. PMID- 23664689 TI - [Othello syndrome secondary to zonisamide]. PMID- 23664690 TI - Test-retest repeatability of quantitative cardiac 11C-meta-hydroxyephedrine measurements in rats by small animal positron emission tomography. AB - INTRODUCTION: The norepinephrine analogue (11)C-meta-hydroxyephedrine (HED) has been used to interrogate sympathetic neuronal reuptake in cardiovascular disease. Application for longitudinal studies in small animal models of disease necessitates an understanding of test-retest variability. This study evaluated the repeatability of multiple quantitative cardiac measurements of HED retention and washout and the pharmacological response to reuptake blockade and enhanced norepinephrine levels. METHODS: Small animal PET images were acquired over 60 min following HED administration to healthy male Sprague Dawley rats. Paired test and retest scans were undertaken in individual animals over . Additional HED scans were conducted following administration of norepinephrine reuptake inhibitor desipramine or continuous infusion of exogenous norepinephrine. HED retention was quantified by retention index, standardized uptake value (SUV), monoexponential and one-compartment washout. Plasma and cardiac norepinephrine were measured by high performance liquid chromatography. RESULTS: Test retest variability was lower for retention index (15% +/- 12%) and SUV (19% +/- 15%) as compared to monoexponential washout rates (21% +/- 13%). Desipramine pretreatment reduced myocardial HED retention index by 69% and SUV by 85%. Chase treatment with desipramine increased monoexponential HED washout by 197% compared to untreated controls. Norepinephrine infusion dose-dependently reduced HED accumulation, reflected by both retention index and SUV, with a corresponding increase in monoexponential washout. Plasma and cardiac norepinephrine levels correlated with HED quantitative measurements. CONCLUSION: The repeatability of HED retention index, SUV, and monoexponential washout supports its suitability for longitudinal PET studies in rats. Uptake and washout of HED are sensitive to acute increases in norepinephrine concentration. PMID- 23664691 TI - Transcarotid endoaortic balloon occlusion of the stent graft during reintervention on the thoracoabdominal aorta after thoracic endovascular aortic repair. PMID- 23664692 TI - Aortic wall papillary fibroelastoma. PMID- 23664693 TI - Aquaporin 4 molecular mimicry and implications for neuromyelitis optica. AB - Neuromyelitis optica (NMO) is associated with antibodies to aquaporin 4 (AQP4). We hypothesized that antibodies to AQP4 can be triggered by exposure to environmental proteins. We compared human AQP4 to plant and bacterial proteins to investigate the occurrence of significantly similar structures and sequences. High similarity to a known epitope for NMO-IgG, AQP4(207-232), was observed for corn ZmTIP4-1. NMO and non-NMO sera were assessed for reactivity to AQP4(207-232) and the corn peptide. NMO patient serum showed reactivity to both peptides as well as to plant tissue. These findings warrant further investigation into the role of the environment in NMO etiology. PMID- 23664694 TI - The long pentraxin PTX3 as a correlate of cancer-related inflammation and prognosis of malignancy in gliomas. AB - Inflammation is a component of glioma microenvironment. PTX3 is a component of the humoral arm of innate immunity and a candidate marker of inflammation. In the present study we assessed the expression of PTX3 in gliomas by immunohistochemistry. PTX3 expression differed across low and high-grade tumors based on histopathological diagnosis and clinical severity, positively correlating with tumor grade and severity. In a multivariate logistic regression model, only the PTX3 score was significantly associated with the presence of a high-grade tumor. Thus, PTX3 may represent a new marker of cancer-related inflammation and glioma malignancy. PMID- 23664695 TI - Mechanism and novel therapeutic approaches to wasting in chronic disease. AB - Cachexia is a multifactorial syndrome defined by continuous loss of skeletal muscle mass - with or without loss of fat mass - which cannot be fully reversed by conventional nutritional support and which may lead to progressive functional impairment and increased death risk. Its pathophysiology is characterized by negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism. Muscle wasting is encountered in virtually all chronic disease states in particular during advanced stages of the respective illness. Several pre-clinical and clinical studies are ongoing to ameliorate this clinical problem. The mechanisms of muscle wasting and cachexia in chronic diseases such as cancer, chronic heart failure, chronic obstructive pulmonary disease and chronic kidney disease are described. We discuss therapeutic targets and such potential modulators as appetite stimulants, selective androgen receptor modulators, amino acids and naturally occurring peptide hormones. PMID- 23664696 TI - Two-year survival and neurological outcome of in-hospital cardiac arrest patients rescued by extracorporeal cardiopulmonary resuscitation. AB - BACKGROUND: The clinical benefit of extracorporeal cardiopulmonary resuscitation (E-CPR) has been proved in short-term follow-up studies. However, the benefit of E-CPR beyond 1 year has been not known. We investigated 2-year outcome of patients who received E-CPR or conventional CPR (C-CPR). METHODS: We analyzed a total of 406 adult in-hospital cardiac arrest victims who underwent CPR for more than 10 min from 2003 to 2009. The two-year survival and neurological outcome of E-CPR (n=85) and C-CPR (n=321) were compared using propensity score-matched analysis. RESULTS: The 2-year survival with minimal neurological impairment was 4 fold higher in the E-CPR group than the C-CPR group (23.5% versus 5.9%, hazard ratio (HR)=0.57, 95% confidence interval (CI)=0.43-0.75, p<0.001) by unadjusted analysis. After propensity-score matching, it was still 4-fold higher in the E CPR group than the C-CPR group (20.0% versus 5.0%, HR=0.53, 95% CI=0.36-0.80, p=0.002). In the E-CPR group, the independent predictors associated with minimal neurological impairment were age <=65 years (HR=0.46; 95% CI=0.26-0.81; p=0.008), CPR duration <=35 min (HR=0.37; 95% CI=0.18-0.76; p=0.007), and subsequent cardiovascular intervention including coronary intervention or cardiac surgery (HR=0.36; 95% CI=0.18-0.68; p=0.002). CONCLUSIONS: The initial survival benefit of E-CPR for cardiac arrest patients persisted at 2 years. PMID- 23664697 TI - Extra-deep guide-catheter intubation for direct thromboaspiration. PMID- 23664698 TI - Coronary AVM: abnormal communication is the issue. PMID- 23664699 TI - Novel single-beat full-volume capture real-time three-dimensional echocardiography and auto-contouring algorithm for quantification of left ventricular volume: validation with cardiac magnetic resonance imaging. PMID- 23664700 TI - Mortality after transradial approach in ST-segment elevation myocardial infarction. Do we see the forest for the trees? PMID- 23664701 TI - Challenging ticagrelor's claimed reduction in the rate of definite stent thrombosis versus clopidogrel: insights from the FDA reports. AB - Ticagrelor has been promoted to reduce the rate of definite stent thrombosis compared to clopidogrel from the The Platelet Inhibition and Patient Outcomes (PLATO) trial. However, several issues prevent this statement from being accurate, (1) stent thrombosis was an exploratory endpoint in PLATO--cases were retrospectively and prospectively adjudicated, (2) Sampling/ascertainment bias most likely lead to these conclusions, (3) Stent thromboses were not confirmed by an angiographic core lab (a requirement by the ARC definition for 'definite stent thrombosis'), (4) The integrity of the mortality and MI data from the PLATO trial have recently been challenged. A statement that ticagrelor reduces definite stent thrombosis versus clopidogrel cannot be justified. PMID- 23664702 TI - Hybrid management of acute type A aortic dissection presenting as acute coronary syndrome. PMID- 23664704 TI - Recent developments in fast pyrolysis of ligno-cellulosic materials. AB - Pyrolysis is a thermochemical process to convert ligno-cellulosic materials into bio-char and pyrolysis oil. This oil can be further upgraded or refined for electricity, transportation fuels and chemicals production. At the time of writing, several demonstration factories are considered worldwide aiming at maturing the technology. Research is focusing on understanding the underlying processes at all relevant scales, ranging from the chemistry of cell wall deconstruction to optimization of pyrolysis factories, in order to produce better quality oils for targeted uses. Among the several bio-oil applications that are currently investigated the production and fermentation of pyrolytic sugars explores the promising interface between thermochemistry and biotechnology. PMID- 23664703 TI - A unified coding strategy for processing faces and voices. AB - Both faces and voices are rich in socially-relevant information, which humans are remarkably adept at extracting, including a person's identity, age, gender, affective state, personality, etc. Here, we review accumulating evidence from behavioral, neuropsychological, electrophysiological, and neuroimaging studies which suggest that the cognitive and neural processing mechanisms engaged by perceiving faces or voices are highly similar, despite the very different nature of their sensory input. The similarity between the two mechanisms likely facilitates the multi-modal integration of facial and vocal information during everyday social interactions. These findings emphasize a parsimonious principle of cerebral organization, where similar computational problems in different modalities are solved using similar solutions. PMID- 23664705 TI - Microorganism contamination of mezuzahs in a tertiary care hospital in Brooklyn, New York City. PMID- 23664706 TI - Is there a standard induction regimen for patients with AML? PMID- 23664707 TI - Homoharringtonine-based induction regimens for patients with de-novo acute myeloid leukaemia: a multicentre, open-label, randomised, controlled phase 3 trial. AB - BACKGROUND: Homoharringtonine-based induction regimens have been widely used in China for patients with acute myeloid leukaemia. However, their efficacy has not been tested in a multicentre randomised controlled trial in a large population. We assessed the efficacy and safety of homoharringtonine-based induction treatment for management of newly diagnosed acute myeloid leukaemia. METHODS: This open-label, randomised, controlled, phase 3 study was done in 17 institutions in China between September, 2007, and July, 2011. Untreated patients aged 14-59 years with acute myeloid leukaemia were randomly assigned (by a computer-generated allocation schedule without stratification) to receive one of three induction regimens in a 1:1:1 ratio: homoharringtonine 2 mg/m(2) per day on days 1-7, cytarabine 100 mg/m(2) per day on days 1-7, and aclarubicin 20 mg/day on days 1-7 (HAA); homoharringtonine 2 mg/m(2) per day on days 1-7, cytarabine 100 mg/m(2) per day on days 1-7, and daunorubicin 40 mg/m(2) per day on days 1-3 (HAD); or daunorubicin 40-45 mg/m(2) per day on days 1-3 and cytarabine 100 mg/m(2) per day on days 1-7 (DA). Patients in complete remission were offered two cycles of intermediate-dose cytarabine (2 g/m(2) every 12 h on days 1-3). The primary endpoints were the proportion of patients who achieved complete remission after two cycles of induction treatment and event-free survival in the intention to-treat population. The trial is registered in the Chinese Clinical Trial Register, number ChiCTR-TRC-06000054. FINDINGS: We enrolled 620 patients, of whom 609 were included in the intention-to-treat analysis. 150 of 206 patients (73%) in the HAA group achieved complete remission versus 125 of 205 (61%) in the DA group (p=0.0108); 3-year event-free survival was 35.4% (95% CI 28.6-42.2) versus 23.1% (95% CI 17.4-29.3; p=0.0023). 133 of 198 patients (67%) in the HAD group had complete remission (vs DA, p=0.20) and 3-year event-free survival was 32.7% (95% CI 26.1-39.5; vs DA, p=0.08). Adverse events were much the same in all groups, except that more patients in the HAA (12 of 206 [5.8%]) and HAD (13 of 198 [6.6%]) groups died within 30 days than in the DA group (two of 205 [1%]; p=0.0067 vs HAA; p=0.0030 vs HAD). INTERPRETATION: A regimen of homoharringtonine, cytarabine, and aclarubicin is a treatment option for young, newly diagnosed patients with acute myeloid leukaemia. FUNDING: Chinese National High Tech Programme, Key Special Research Foundation of the Ministry of Science and Technology of China, National Nature Science Foundation of China, National Clinical Key Specialty Construction Project. PMID- 23664708 TI - Effects of a programme of interventions on regional comprehensive palliative care for patients with cancer: a mixed-methods study. AB - BACKGROUND: Improvement of palliative care is an important public health issue, but knowledge about how to deliver palliative care throughout a region remains inadequate. We used surveys and in-depth interviews to assess changes in the quality of palliative care after regional interventions and to gain insights for improvement of palliative care at a regional level. METHODS: In this mixed methods study, a comprehensive programme of interventions for regional palliative care for patients with cancer was implemented from April 1, 2008, to March 31, 2011 in Tsuruoka, Kashiwa, Hamamatsu, and Nagasaki in Japan. Interventions included education, specialist support, and networking. We surveyed patients, bereaved family members, physicians, and nurses before and after the interventions were introduced. We also did qualitative interviews with health care professionals after the interventions were introduced. Primary endpoints were numbers of home deaths, coverage of specialist services, and patient reported and family-reported qualities of care. This trial is registered with UMIN Clinical Trial Registry, Japan (UMIN000001274). FINDINGS: 859 patients, 1110 bereaved family members, 911 physicians, and 2378 nurses provided analysable preintervention surveys; 857 patients, 1137 bereaved family members, 706 physicians, and 2236 nurses provided analysable postintervention surveys. Proportions of home deaths increased significantly, from 348 of 5147 (6.76%) before the intervention programme to 581 of 5546 (10.48%) after the intervention programme (p<0.0001). Furthermore, 194 of 221 (87.78%) family members of patients who died at home answered that these patients had wanted to die at home. The ratio of patients who received palliative care services to all patients who died of cancer increased significantly (from 0.31 to 0.50; p<0.0001). The patient reported (effect size 0.14; adjusted p=0.0027) and family-reported (0.23; p<0.0001) qualities of care were significantly better after interventions than before interventions. Physician-reported and nurse-reported difficulties decreased significantly after the introduction of the interventions. Qualitative interviews showed improved communication and cooperation between health-care professionals because of greater opportunities for interactions at various levels. INTERPRETATION: A regional programme of interventions could improve the quality of palliative care. Improvement of communication between health-care professionals is key to improvement of services. FUNDING: Third Term Comprehensive Control Research for Cancer Health and Labor Sciences Research Grants of the Ministry of Health, Labour and Welfare of Japan. PMID- 23664709 TI - Genetic epidemiology of Sarcoptes scabiei in the Iberian wolf in Asturias, Spain. AB - BACKGROUND: During the last decades, attempts have been made to understand the molecular epidemiology of Sarcoptes scabiei, and to detect and clarify the differences between isolates from different hosts and geographic regions. Two main phenomena have been described: (i) host-taxon derived-Sarcoptes mite infection in European wild animals (revealing the presence of three separate clusters, namely herbivore-, carnivore- and omnivore-derived Sarcoptes populations in Europe) and (ii) prey-to-predator Sarcoptes mite infection in the Masai Mara ecosystem. RESULTS: Using one multiplex of 9 microsatellite markers and Sarcoptes mite samples from sympatric Pyrenean chamois, red deer, red fox and Iberian wolf, different population structure analyses revealed concordance with the host-taxon law described for wild animals in Europe, with two main host derived Sarcoptes mite populations, herbivore- and carnivore-derived. Surprisingly, Iberian wolf derived Sarcoptes populations had the highest genetic diversity among the other populations, including two different subpopulations: one similar to the herbivore-derived Sarcoptes populations, and another similar to carnivore (fox)-derived Sarcoptes mite population. CONCLUSIONS: The host-taxon effect in wild animals is still supported with the maintenance of carnivore- and herbivore-derived Sarcoptes clusters' separation in analyzed mites. However, this phenomenon could be modified with the inclusion of a large predator as wolf in the present work, revealing prey-to-predator Sarcoptes mite infection between the studied host-taxa and suggesting the importance of wolf's immune system for explaining the high variability reported in C. lupus derived mites. Further studies of host diet, behavior and movement, and regarding the role played by its immune system, would be of great help to clarify interactions between the two hypotheses, host-taxon and prey-to-predator. PMID- 23664710 TI - Development of an antibody-ELISA for seroprevalence of Trypanosoma evansi in equids of North and North-western regions of India. AB - The importance of Trypanosoma evansi as the etiological agent for surra is often overlooked due to difficulty in accurate diagnosis of the disease. In the present study, an antibody-ELISA was developed using whole cell lysate antigen prepared from purified trypanosomes and used for seroprevalence study of T. evansi in equids. A total of 3695 equids were surveyed and blood samples were collected from each animal during September 2009 to August 2011. Out of these, 420 serum samples were found positive for presence of antibodies against T. evansi collected from equids of six agro-climatic zones of North and North-western regions of India comprising eight states viz., Gujarat (36/479), Haryana (11/275), Himachal Pradesh (14/83), Jammu and Kashmir (32/221), Punjab (1/38), Rajasthan (90/1148), Uttarakhand (141/753), and Uttar Pradesh (65/330). The maximum seroprevalence (19.69%) for T. evansi infection was observed in equids of Uttar Pradesh state with an overall seroprevalence of 11.36% in North and North western regions of India. The results indicated that surra is endemic in equids of North and North-western parts of India. PMID- 23664711 TI - Macroparasite communities in stray cat populations from urban cities in Peninsular Malaysia. AB - The occurrence of macroparasites was studied from 543 stray cats in four urban cities from the west (Kuala Lumpur), east (Kuantan), north (Georgetown) and south (Malacca) of Peninsular Malaysia from May 2007 to August 2010. Five ectoparasites species were recovered namely, Ctenocephalides felis, Felicola subrostratus, Haemaphysalis bispinosa, Heterodoxus spiniger and Lynxacarus radovskyi. Two cats from Georgetown were infested with the dog louse, H. spiniger and this represented the first host record for this species in Malaysia. Up to nine species of helminths were recovered with overall high prevalences of infection of 83% in Kuantan, followed by 75.1% in Kuala Lumpur, 71.6% in Georgetown and 68% in Malacca. The helminth species comprised five nematodes, Toxocara malaysiensis, Toxocara cati, Ancylostoma braziliensis, Ancylostoma ceylanicum, Physaloptera praeputialis, two cestodes Taenia taeniaeformis, Dipylidium caninum and one trematode, Playtnosomum fastosum. The majority of helminths were present in the four study sites except for the absence of P. praeputialis in Kuala Lumpur. The prevalence and abundance of infections were analysed taking intrinsic (host age and sex) and extrinsic (season) factors into consideration. Levels of infection and infestation were mainly influenced by host age and to a lesser extent sex and season, whereas four nematode species exhibited significant interactions within the intestine of the cat host. The potential for transmission of some macroparasite species from stray cats to the human population in urban areas is discussed. PMID- 23664713 TI - Commentary on "Regulatory issues in drug development programs targeting cognitive impairment in schizophrenia". PMID- 23664712 TI - Auditory P3 in antidepressant pharmacotherapy treatment responders, non responders and controls. AB - Event-related potentials (ERPs), derived from electroencephalographic (EEG) recordings, can index electrocortical activity related to cognitive operations. The fronto-central P3a ERP is involved in involuntary processing of novel auditory information, whereas the parietal P3b indexes controlled attention processing. The amplitude of the auditory P3b has been found to be decreased in major depressive disorder (MDD). However, few studies have examined the relations between the P3b, the related P3a, and antidepressant treatment response. We tested 53 unmedicated individuals (25 females) with MDD, as well as 43 non depressed controls (23 females) on the novelty oddball task, wherein infrequent deviant (target) and frequent standard (non-target) tones were presented, along with infrequent novel (non-target/distractor) sounds. The P3a and P3b ERPs were assessed to novel and target sounds, respectively, as were their accompanying behavioral performance measures. Depression ratings and the antidepressant response status were assessed following 12 weeks of pharmacotherapy with three different regimens. Antidepressant treatment non-responders had smaller baseline P3a/b amplitudes than responders and healthy controls. Baseline P3b amplitude also weakly predicted the extent of depression rating changes by week 12. Females exhibited larger P3a/b amplitudes than males. With respect to task performance, controls had more target hits than treatment non-responders. ERP measures correlated with clinical changes in males and with behavioral measures in females. These results suggest that greater (or control-like) baseline P3a/b amplitudes are associated with a positive antidepressant response, and that gender differences characterize the P3 and, by extension, basic attentive processes. PMID- 23664714 TI - Cerebral infarction in an HIV-infected patient with combined protein S and C deficiency and a patent foramen ovale. AB - A 41-year-old male with a history of human immunodeficiency virus (HIV) infection developed motor aphasia, dysarthria, and right hemiparesis. A magnetic resonance imaging scan of the brain revealed a cerebral infarction in the territory of the left middle cerebral artery. The laboratory data showed decreased levels of protein S and protein C. Transesophageal contrast-enhanced echocardiography revealed a patent foramen ovale (PFO). Prothrombotic states, such as protein S and C deficiency, have been reported in HIV-infected patients. In addition, previous studies have reported prothrombotic states to be risk factors for PFO related cerebral infarction. An association between combined protein S and C deficiency caused by HIV infection and PFO-related cerebral infarction was suggested in our patient. PMID- 23664715 TI - Broncholithiasis with post-obstructive pneumonia and empyema. PMID- 23664716 TI - Progressive visual loss in an otherwise healthy male. PMID- 23664717 TI - A "stable" coronary plaque rupture documented by repeated OCT studies. PMID- 23664718 TI - Stress CMR reduces revascularization, hospital readmission, and recurrent cardiac testing in intermediate-risk patients with acute chest pain. AB - OBJECTIVES: The aim of this study was to determine the effect of stress cardiac magnetic resonance (CMR) imaging in an observation unit (OU) on revascularization, hospital readmission, and recurrent cardiac testing in intermediate-risk patients with possible acute coronary syndromes (ACS). BACKGROUND: Intermediate-risk patients commonly undergo hospital admission with high rates of coronary revascularization. It is unknown whether OU-based care with CMR is a more efficient alternative. METHODS: A total of 105 intermediate risk participants with symptoms of ACS but without definite ACS on the basis of the first electrocardiogram and troponin were randomized to usual care provided by cardiologists and internists (n = 53) or to OU care with stress CMR (n = 52). The primary composite endpoint of coronary artery revascularization, hospital readmission, and recurrent cardiac testing at 90 days was determined. The secondary endpoint was length of stay from randomization to index visit discharge; safety was measured as ACS after discharge. RESULTS: The median age of participants was 56 years (range 35 to 91 years), 54% were men, and 20% had pre existing coronary disease. Index hospital admission was avoided in 85% of the OU CMR participants. The primary outcome occurred in 20 usual care participants (38%) versus 7 OU CMR participants (13%) (hazard ratio: 3.4; 95% confidence interval: 1.4 to 8.0, p = 0.006). The OU CMR group experienced significant reductions in all components: revascularizations (15% vs. 2%, p = 0.03), hospital readmissions (23% vs. 8%, p = 0.03), and recurrent cardiac testing (17% vs. 4%, p = 0.03). Median length of stay was 26 h (interquartile range: 23 to 45 h) in the usual care group and 21 h (interquartile range: 15 to 25 h) in the OU CMR group (p < 0.001). ACS after discharge occurred in 3 usual care participants (6%) and no OU CMR participants. CONCLUSIONS: In this single-center trial, management of intermediate-risk patients with possible ACS in an OU with stress CMR reduced coronary artery revascularization, hospital readmissions, and recurrent cardiac testing, without an increase in post-discharge ACS at 90 days. (Randomized Investigation of Chest Pain Diagnostic Strategies; NCT01035047). PMID- 23664719 TI - Clinical and echocardiographic variables associated with LA septal pouch. PMID- 23664721 TI - Affected in the nightclub. A case study of regular clubbers' conflictual practices in nightclubs. AB - The nightclub as a space is presented as a free and hedonistic place for pleasure. This space is also part of a wider socio-spatial-economic framework in which various forms of regulation apply to clubbers and the cultivation of affects. This paper researches marginal and contested forms of experiences within a club as a way of understanding the complexities of pleasure. The study does so by addressing experiences through the concept of affects, which is situated within a framework of a non-representational theory of space. Anxiety, pride, anger, shame and embarrassment are embodied simultaneously with the affects of love, joy, sympathy and so on. Alcohol, illicit drugs, bouncers, music and other human or non-human actants are part of the place. It is within this heterogeneous assemblage that affects become embodied. The data consists of 273 cases from a large Copenhagen nightclub where guests have complained about being rejected or being given quarantine. The paper suggests that if the space of the club is approached as being more than a mono-affectual space of either risk or pleasure, then it would be possible to reduce conflicts and produce more inclusive spaces. PMID- 23664720 TI - Visceral and subcutaneous fat quality and cardiometabolic risk. AB - OBJECTIVES: The aim of this study was to evaluate whether computed tomography (CT) attenuation, as a measure of fat quality, is associated with cardiometabolic risk factors above and beyond fat quantity. BACKGROUND: Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) are pathogenic fat depots associated with cardiometabolic risk. Adipose tissue attenuation in CT images is variable, similar to adipose tissue volume. However, whether the quality of abdominal fat attenuation is associated with cardiometabolic risk independent of the quantity is uncertain. METHODS: Participants were drawn from the Framingham Heart Study CT substudy. The VAT and SAT volumes were acquired by semiquantitative assessment. Fat quality was measured by CT attenuation and recorded as mean Hounsfield unit (HU) within each fat depot. Sex-specific linear and logistic multivariable regression models were used to assess the association between standard deviation (SD) decrease in HU and each risk factor. RESULTS: Lower CT attenuation of VAT and SAT was correlated with higher body mass index levels in both sexes. Risk factors were generally more adverse with decreasing HU values. For example, in women, per 1 SD decrease in VAT HU, the odds ratio (OR) was increased for hypertension (OR: 1.80), impaired fasting glucose (OR: 2.10), metabolic syndrome (OR: 3.65), and insulin resistance (OR: 3.36; all p < 0.0001). In models that further adjusted for VAT volume, impaired fasting glucose, metabolic syndrome, and insulin resistance remained significant. Trends were similar but less pronounced for SAT and for men. There was evidence of an interaction between HU and fat volume among both women and men. CONCLUSIONS: Lower CT attenuation of VAT and SAT is associated with adverse cardiometabolic risk above and beyond total adipose tissue volume. Qualitative indices of abdominal fat depots may provide insight regarding cardiometabolic risk independent of fat quantity. PMID- 23664722 TI - Preoperative chemotherapy is effective for stage III resectable non--small-cell lung cancer: metaanalysis of 16 trials. AB - BACKGROUND: The benefit of preoperative chemotherapy for resectable non-small cell lung cancer is still controversial. PATIENTS AND METHODS: We conducted fixed model metaanalysis including randomized controlled trials comparing 'preoperative chemotherapy plus surgery' and 'surgery alone' as a primary study with sufficient data to provide a hazard ratio for overall survival. MEDLINE and Cochrane databases were used for the study search. RESULTS: We found 16 studies. Seven included only stage III disease cases, and 9 were conducted without stage limitation. Sixteen trials involving 3728 samples observing 2326 deaths yielded a pooled hazard ratio for overall survival of 0.84 (95% confidence interval [CI], 0.77-0.91; P < .001) with moderate heterogeneity (I(2) = 40%). In sensitivity analysis, strong heterogeneity (I(2) = 69%) was found between the 7 trials covering only stage III disease and 9 trials without stage limitation. The 7 studies evaluating only stage III disease involving 1447 samples and 1068 deaths yielded a pooled hazard ratio of 0.77 (95% CI, 0.68-0.87; P < .001) with nonsignificant low heterogeneity (I(2) = 17%). No publication bias was observed throughout this study. The effect of preoperative chemotherapy differs among stages. The pooled hazard ratio comparing 'preoperative chemotherapy plus surgery' and 'surgery alone' for patients with stage III disease in our study was 0.77, which is slightly better than the pooled hazard ratio of 0.83 in the Lung Adjuvant Cisplatin Evaluation study that compared 'surgery plus postoperative chemotherapy' and 'surgery alone.' CONCLUSION: Preoperative chemotherapy plus surgery for stage III disease is more effective than previously considered. PMID- 23664723 TI - Polymorphisms of CYP2D6 gene and gefitinib-induced hepatotoxicity. AB - INTRODUCTION: Gefitinib induces severe hepatotoxicity in approximately a quarter of Japanese patients with epidermal growth factor receptor (EGFR) mutation positive non-small-cell lung cancer (NSCLC). Gefitinib is metabolized by cytochrome P450 (CYP) enzymes--including CYP3A4/5, CYP1A1, and CYP2D6--in the liver. We hypothesized that polymorphisms of the CYP2D6 gene may account for gefitinib-induced hepatotoxicity. PATIENTS AND METHODS: Polymorphisms of the CYP2D6 gene were analyzed in 55 patients with NSCLC who experienced grade >= 2 transaminase elevation from gefitinib. The distribution of the CYP2D6 genotype was compared with that of the healthy Japanese population. The correlations between the nonfunctional allele *5 or the reduced-function allele *10 and hepatotoxicity-related clinical factors were also examined. RESULTS: The distribution of the CYP2D6 genotype in the study participants was not different from that of the general Japanese population, reported previously. Existence of allele *5 or *10 did not correlate with clinical factors such as onset of hepatotoxicity within 2 months, grade >= 3 serum transaminase elevation, and tolerability to dose reduction or rechallenge of gefitinib. However, in 7 patients taking CYP3A4-inhibitory drugs, rechallenge of gefitinib again caused hepatotoxicity in 4 patients with allele *5 or *10 but not in 3 patients with normal alleles (P = .029). Moreover, switching to erlotinib did not cause hepatotoxicity in any of 17 patients with allele *5 or *10 but did in 3 of 8 patients without these alleles (P = .024). CONCLUSION: Reduced function of CYP2D6 may partly account for gefitinib-induced hepatotoxicity when CYP3A4 is inhibited. Erlotinib could be safely used in patients with decreased CYP2D6 activity even after they experienced gefitinib-induced hepatotoxicity. PMID- 23664724 TI - Effect of leptin treatment on mitochondrial function in obese leptin-deficient ob/ob mice. AB - OBJECTIVE: Leptin stimulates peripheral lipid oxidation, but the influence on mitochondrial function is partly unknown. We investigated tissue-specific mitochondrial function in leptin-deficient obese C57BL/6J-ob/ob mice compared to lean littermates following leptin treatment. MATERIALS AND METHODS: Lean and obese ob/ob mice were treated with saline or leptin for 5 days. At day six, liver, extensor digitorum longus (EDL) and soleus muscle were dissected and mitochondrial respiration analyzed in freshly dissected tissues. Expression of key proteins in the regulation of mitochondrial function was determined. RESULTS: In liver, mitochondrial respiration was reduced in ob/ob mice compared to lean mice. Expression of mitochondrial transcription factor A (TFAM) was decreased in ob/ob mice, but increased with leptin treatment. In glycolytic EDL muscle, mitochondrial respiration was increased in ob/ob mice. Protein markers of complex II, IV and ATP synthase were increased in EDL muscle from both saline- and leptin treated ob/ob mice. TFAM protein abundance was decreased, while dynamin-1-like protein was increased in EDL muscle from saline-treated ob/ob mice and restored by leptin treatment. In oxidative soleus muscle, mitochondrial respiration and electron transport system protein abundance were unchanged, while TFAM was reduced in ob/ob mice. CONCLUSIONS: In conclusion, leptin-deficient ob/ob mice display tissue-specific mitochondrial adaptations under basal conditions and in response to leptin treatment. Mitochondrial respiration was decreased in liver, increased in glycolytic muscle and unaltered in oxidative muscle from ob/ob mice. Insight into the tissue-specific regulation of mitochondrial function in response to energy supply and demand may provide new opportunities for the treatment of insulin resistance. PMID- 23664725 TI - Lack of correlation between the size of HIV proviral DNA reservoir and the level of immune activation in HIV-infected patients with a sustained undetectable HIV viral load for 10 years. AB - BACKGROUND: The persistence of HIV residual replication in patients with an undetectable plasma viral load (pVL) may limit immune recovery and facilitate inflammation-induced comorbidities. OBJECTIVE: The objective was to evaluate any correlation between immune restoration and intracellular [IC] HIV-DNA in cART treated patients with a sustained undetectable pVL. STUDY DESIGN: This retrospective cross sectional study included 62 patients with a median duration of undetectable pVL of 10.3 years. IC HIV DNA in peripheral mononuclear blood cells (PBMCs) and T cell subsets were measured at the last visit. pVL, CD4(+) and CD8(+) T cell counts were retrospectively collected from the onset of long-term inhibition by antiretroviral treatment. The patients were separated into two groups: 27 non-blippers (sustained pVL< threshold value during all the visits) and 35 blippers ( >= 1 episodes of pVL> threshold but < 1000 copies/ml). The median pVL in blippers was 115 copies/ml. RESULTS: The median IC HIV DNA rate was 34 copies/10(6) PBMCs (71% >= 20 copies/10(6) PBMCs) with no significant difference between the groups. The proportion of CD8(+)CD38(+) and CD8(+)DR(+) T cells was higher in blipper patients, but the difference was only significant for the CD8(+)DR(+) marker (p = 0.036). No correlation was found between markers of immune activation on CD4(+) and CD8(+) T cells and the IC HIV-DNA level. CONCLUSION: No relation was found between the size of HIV reservoirs and immune activation in patients with sustained undetectable pVL. Mechanisms of immune activation have to be better understood in order to define specific therapeutic interventions. PMID- 23664726 TI - Evidence of the megavirome in humans. AB - BACKGROUND: Megavirales is a proposed new virus order composed of Mimivirus, Marseillevirus and closely related viruses, as well as members of the families Poxviridae, Iridoviridae, Ascoviridae, Phycodnaviridae and Asfarviridae. The Megavirales virome, which we refer to as the megavirome, has been largely neglected until now because of the use of technical procedures that have jeopardized the discovery of giant viruses, particularly the use of filters with pore sizes in the 0.2-0.45-MUm range. Concurrently, there has been accumulating evidence supporting the role of Mimivirus, discovered while investigating a pneumonia outbreak using amoebal coculture, as a causative agent in pneumonia. OBJECTIVES: In this paper, we describe the detection of sequences related to Mimivirus and Marseillevirus in the gut microbiota from a young Senegalese man. We also searched for sequences related to Megavirales in human metagenomes publicly available in sequence databases. RESULTS: We serendipitously detected Mimivirus- and Marseillevirus-like sequences while using a new metagenomic approach targeting bacterial DNA that subsequently led to the isolation of a new member of the family Marseilleviridae, named Senegalvirus, from human stools. This discovery demonstrates the possibility of the presence of giant viruses of amoebae in humans. In addition, we detected sequences related to Megavirales members in several human metagenomes, which adds to previous findings by several groups. CONCLUSIONS: Overall, we present convergent evidence of the presence of mimiviruses and marseilleviruses in humans. Our findings suggest that we should re-evaluate the human megavirome and investigate the prevalence, diversity and potential pathogenicity of giant viruses in humans. PMID- 23664727 TI - Longitudinal assessment of immunological and oral clinical conditions in patients undergoing anticancer treatment for leukemia. AB - OBJECTIVE: The aim of this study was to evaluate the evolution of the immunological and oral clinical conditions of children and adolescents undergoing anticancer treatment for leukemia (ATL). METHODS: Twenty patients aged 3-15 years undergoing chemotherapy seen at a referral center for cancer treatment in the State of Maranhao, Brazil, from 2008 to 2009, were evaluated at baseline (1st). Twenty-two controls were selected in public schools. Oral lesions, caries experience (deft and DMFT), plaque index (PI), gingival index (GI) and salivary IgA were analyzed. Patients and controls were evaluated after 6 months (2nd). The Shapiro Wilk, Mann-Whitney, Wilkoxon and Spearman correlation tests were carried out (alpha=5%). RESULTS: Gingivitis and mucositis were the most frequent manifestations in oral mucosae during the two phases. The mean DMFT index increased from 3.9 +/- 4.2 (1st) to 4.4 +/- 4.3 (2nd) (p = 0.04). The mean deft index was the same in the 1st (1.9 +/- 2.7) and 2nd (1.9 +/- 2.7) evaluation (p = 0.86). The GI also did not vary between assessments: 1st (1.3 +/- 0.4) and 2nd (1.3 +/- 0.3) - (p = 0.12), except on the lingual and distal surfaces, where increased from the 1st to 2nd evaluation (p < 0.01). The PI varied from 0.9 to 1.1, but this difference was not significant (p = 0.48), except for the lingual surface, where increased from 0.6 to 1.0 (p = 0.04). There was a reduction in salivary IgA levels from 2.9 to 1.9 MUg/mL (p = 0.04), and mean IgA was significantly higher in the control group (5.4 MUg/mL) if compared to cases (p < 0.01). CONCLUSION: The clinical and immunological oral conditions of children and adolescents undergoing ATL presented an unfavorable evolution. This study highlights the need for monitoring oral conditions during the ATL and draws attention to the additional responsibility of the otolaryngologist in referring ATL patients to the dentist, especially in the presence of clinical evidence of oral problems. We suggest that the planning of ATL take into account the oral health, in a multidisciplinary oncology team. PMID- 23664728 TI - Structure of the capsular polysaccharides and lipopolysaccharides from Haemophilus parasuis strains ER-6P (serovar 15) and Nagasaki (serovar 5). AB - Haemophilus parasuis is a Gram-negative bacterium from the family Pasteurellaceae and a swine pathogen. H. parasuis is found in the upper respiratory tract of piglets and produces Glasser's disease, an invasive disease characterized by polyserositis. H. parasuis contains a short lipopolysaccharide (LPS) or lipooligosaccharide (LOS) reported to play a partial role in interaction with host cells. The presence of capsule has been phenotypically demonstrated in certain H. parasuis strains and its role in virulence has been suggested, but the chemical structure of the surface polysaccharides of this bacterium was unknown. The structure of capsular polysaccharide (CPS) and LOS from virulent strains ER 6P and Nagasaki was studied by NMR spectroscopy, mass spectrometry and chemical methods. CPS from both strains had the same main chain with disaccharide repeating unit, substituted with alpha-Neu5R-(2-3)-alpha-GalNAc-(1-P-(strain ER 6P) or alpha-Neu5R-(2-3)-alpha-Gal-(1-P-strain Nagasaki) side chains, where R is the N-acetyl or N-glycolyl group. Glycolyl-neuraminic acid is widely found in animal glycoproteins, but it apparently has not been found in bacteria before, and might be important for the biology of this microorganism. Ac and Gc were present in equal amounts in the strain ER-6P but Nagasaki contained only about 20% of Gc substituent. Both strains produced the same LPS of a rough type with a single phosphorylated Kdo linking core and lipid A parts. LOS structure was similar to some strains of H. influenzae and contained a globotetraose terminal sequence. PMID- 23664729 TI - Reinvestigation of the structure of Brucella O-antigens. AB - O-Specific polysaccharides of Brucella contain two antigenic determinants, called A and M. Most of the strains express epitope A with a small amount of epitope M, whereas Brucella melitensis strain 16 M expresses longer polymer consisting mostly of M-type epitopes. Proposed explanation was that epitope A is defined by 1-2-linked homopolymer of N-formylperosamine (Rha4NFo), while epitope M is a pentasaccharide with four 2- and one 3-substituted Rha4NFo. We reinvestigated both types of structures by 2D NMR and showed that M-epitope is a tetrasaccharide, missing one of the 2-linked Rha4NFo as compared to the previously proposed structure. Polysaccharide from B. melitensis 16 M contains a fragment of 1-2-linked polymer, capped with M-type polymer. Other strains contain one or two M-type units at the non-reducing end of the 1-2-linked O-chain. PMID- 23664730 TI - Quantitative measures of functional outcomes and quality of life in patients with C5 palsy. AB - BACKGROUND: It is generally understood that postoperative C5 palsy can occur with anterior or posterior decompression surgery, but functional measures of the palsy have not been well documented. This study aimed to investigate the incidence of C5 palsy in different surgical procedures, examine the correlations between muscle strength, upper extremity functional measures, and health-related quality of life, and to observe potential risk factors contributing to C5 palsy. METHODS: Our investigation involved a retrospective study design. A total of 364 patients who underwent decompression surgery were indicated within the selected exclusion criteria. Additionally, 12 C5 palsy patients were recruited. The relationships between the manual muscle test (MMT), the action research arm test (ARAT), the Jebsen test of hand function (JTHF), and the European quality of life-5 dimensions (EQ-5D) were studied, and univariate analyses were performed to search possible risk factors and recovery investigation. RESULTS: The data analyzed in the 12 cases and C5 palsy incidences (3.3%) were: 0.7% in anterior procedures (n = 2), 8.8% in posterior procedures (n = 6), and 36.4% in combined procedures (n = 4). Moderate-to-high correlations were observed between the ARAT, JTHF, EQ-5D visual analog scale scores, and MMT (r = 0.636-0.899). There were significant differences in patient age, etiology of cervical lesion, variable decompression procedures, and the number of decompression levels between the C5 palsy and non C5 palsy groups. For female patients (p = 0.018) and number of decompression levels (p = 0.028), there were significant differences between the complete recovery and the incomplete recovery groups. CONCLUSION: Patients undergoing combined anterior-posterior decompression surgery had the highest incidence of C5 palsy, and correlations between the ARAT, JTHF, EQ-5D visual analog scale clinical tools, and MMT scores supported these findings. Female status and lower decompression levels could also be predictive factors for complete recovery, although additional research is needed to substantiate these findings. PMID- 23664731 TI - Unusual giant intraspinal teratoma in an infant. AB - There are few cases of giant pediatric intraspinal teratoma. We report a case of a 4-month-old female baby with giant intraspinal teratoma. Magnetic resonance imaging (MRI) of the spine revealed a large intradural tumor from the C7 to S2 level, with solid, cystic, and fatty components. Partial surgical removal of the tumor showed pathology of a mature cystic teratoma. The imaging diagnosis of intraspinal teratoma included the location, solid and cystic component, and fatty content. The MR techniques adopted included gradient echo sequences as used to detect teeth or calcification. The difficulties in surgical resection of this case are also presented. PMID- 23664732 TI - Double coronary artery thrombosis presenting as acute extensive anterior ST segment elevation myocardial infarction. AB - Simultaneous thrombosis of more than one coronary artery is an uncommon angiographic finding in acute ST-segment elevation myocardial infarction (STEMI), and usually leads to cardiogenic shock or even sudden cardiac death. We reported a 56-year-old man presenting with persistent chest tightness and ST-segment elevation over precordial leads in electrocardiography (ECG). Emergent coronary angiogram showed total occlusion of both the proximal right coronary artery (RCA) and the proximal left anterior descending artery (LAD). We performed thrombus aspiration and stenting over the LAD with thrombolysis in myocardial infarction (TIMI) III flow to the distal LAD. However, diminishing collateral flow to the distal RCA complicated with complete atrioventricular block (CAVB) and cardiogenic shock developed thereafter. Because distal embolization of the collateral circulation from the LAD to the distal RCA was suspected, thrombus aspiration and stenting over the proximal RCA were performed. After reperfusion of the RCA, the patient's hemodynamic status stabilized and he recovered uneventfully. PMID- 23664733 TI - C5 palsy after cervical spine decompression surgery. PMID- 23664734 TI - No enlargement of the right internal jugular vein of the dialysis patients in the Trendelenburg position. AB - BACKGROUND: The Trendelenburg position has been suggested for right internal jugular vein (RIJV) catheterization. However, this position can sometimes be functionally intolerable for chronic kidney disease patients. We conducted an ultrasound study to further investigate the efficacy of the use of the Trendelenburg position during tunneled dialysis catheter insertion via the RIJV in chronic kidney disease patients. METHODS: We recruited into our study patients without a history of prior tunneled dialysis catheter insertion or neck surgery. Those patients with stenosis or thrombus in the RIJV were excluded. Serial ultrasound images were acquired with patients in the supine position, with the head rotated 30 degrees to the left: Stage 0, table flat; Stage T, Trendelenburg tilt. Then, measurements of patient RIJV transverse diameter, anteroposterior (AP) diameter, and cross-sectional area (CSA) were obtained. RESULTS: Fifty dialysis patients and 40 healthy volunteers completed the study. There were no significant differences in the lateral diameter, AP diameter, or AP/lateral diameter ratio between the dialysis patients and healthy volunteers, whether in the supine or the Trendelenburg position. However, the CSA of the RIJV of the healthy volunteers in the Trendelenburg position was significantly larger than that in dialysis patients. The change in CSA from the supine to the Trendelenburg position was also significantly different between the two groups. CONCLUSION: In contrast to healthy volunteers, there was no enlargement of the RIJV when dialysis patients were in the Trendelenburg position. The reason for this phenomenon may be multifactorial, with diastolic dysfunction being the most likely cause, and further investigation is required to clarify the cause. Our investigation suggests that the supine position for central venous catheterization in dialysis patients is superior to the Trendelenburg position. PMID- 23664735 TI - Using modern teaching strategies to teach upper abdominal sonography to medical students. AB - BACKGROUND: Upper abdominal sonography can help physicians to confirm the diagnosis of various hepatobiliary diseases. Teaching sonography skills to medical students is important because it may enhance their level of knowledge and overall development during their gastroenterology section rotation. Sonographic imaging is abstract and students can be easily confused when scanning the abdominal structures from different sites and directions. We used several modern teaching strategies to facilitate the learning of sonography skills. METHODS: The year five medical students beginning a gastroenterology section rotation for their first-year clerkship were taught abdominal sonography skills. Abstract sonographic images were related to concrete objects and the surrounding structures were further indicated. Each of the images was given a specific name and was sorted according to the scanning site. A mnemonics system was designed to help students to memorize the names of these images. A badge was created to recognize the achievement of being able to complete a basic upper abdominal sonography. Students were free (i.e., not obligated) to request a demonstration opportunity to show their skills within 2 weeks after receiving tutelage. We recorded the number of students who received training and were able to successfully complete the task; these individuals then received a badge to be pinned onto their white coats. RESULTS: Sixty-three of 68 students (92.6%) requested evaluation and all of them passed. CONCLUSION: We have greatly simplified the process of learning about upper abdominal sonography by using andragogy to enhance learning, mnemonics to help memory, and a pin-badge reward system to stimulate incentives. PMID- 23664736 TI - The benefits of estrogen or selective estrogen receptor modulator on kidney and its related disease-chronic kidney disease-mineral and bone disorder: osteoporosis. AB - An umbrella concept addressing the relationship between chronic kidney disease (CKD) and mineral and bone disorders has been developed in recent years. Given the high prevalence of osteoporosis-related fractures in postmenopausal women with CKD, especially those undergoing chronic hemodialysis, the strategy used in the prevention and management of CKD and its associated osteoporosis in these postmenopausal women has become a topic of substantial debate. This controversy has ongoing relevance because osteoporosis results in a significant economic burden secondary to increased morbidity and mortality. The perfect goal of treatment and prevention includes both bone protection and renal protection, or at least protection of one disease without compromising the other disease. Both CKD and osteoporosis are frequently observed in the same patients, and often have parallel progression in postmenopausal women. Estrogen, the main female hormone during reproductive age, has been reported to have a protective effect on kidney fibrosis in several animal models, and is also considered one of the most effective drugs in the management of postmenopausal women with osteoporosis and prevention of osteoporosis. However, due to the many adverse events associated with the use of estrogen with and without progestin, some of which have contributed to significant morbidity and mortality, drug modification, which has had fewer reported incidences of adverse events without compromising the protective effect on both the kidney and bone, may have an easier road to acceptance. Therapeutic alternatives, such as the selective estrogen receptor modulators (SERMs), have shown the benefits of estrogen on bone, serum lipid levels, and renal protection, without any adverse effects on the breast and endometrium. The Multiple Outcomes of Raloxifene Evaluation trial (MORE) and its extension-Continuing Outcomes Relevant to Evista (CORE), a double-blind, randomized clinical trial encompassing postmenopausal women with osteoporosis, showed promising results in both bone and renal studies. Raloxifene increased bone mineral density (BMD) in the spine and femoral neck and reduced the risk of vertebral fracture. In addition, raloxifene slowed the increase in the rate of serum creatinine and also significantly slowed the decrease in the estimated glomerular filtration rate; of most importance, raloxifene use was associated with significantly fewer kidney-related adverse events. Hemodialyzed women on raloxifene treatment demonstrated increased trabecular BMD, a decrease in bone resorption markers, and a decrease in the low-density lipoprotein-cholesterol value. Thus, raloxifene and, most likely, other SERMs could be better in place of estrogen in the management of postmenopausal women with CKD and its associated osteoporosis, although much evidence should be provided in the advanced-stage CKD, especially in the Stage 5 CKD patients on dialysis. PMID- 23664737 TI - The additional value of live/real-time three-dimensional transesophageal echocardiography over two-dimensional transesophageal echocardiography for assessing mitral regurgitation with eccentric jets. AB - BACKGROUND: Two-dimensional transesophageal echocardiography (2D TEE) Doppler color flow imaging is the gold standard for assessing the severity of mitral regurgitation (MR). Severe MR with very eccentric jet may involve more than one mitral leaflet lesion and can be missed by 2D TEE. The purpose of this study was to assess the usefulness and the incremental value of real-time three-dimensional (RT 3D) TEE over 2D TEE findings in the evaluation of patients suffering eccentric MR with more than one mitral leaflet lesion. METHODS: Intraoperative 2D TEE and RT 3D TEE examinations were performed on 168 patients with Carpenter II MR who underwent surgery. MR was defined as either central, free-standing eccentric jet or very eccentric jet. 2D TEE and RT 3D TEE finding were compared with surgical findings. RESULTS: Of these 168 MR patients, 25 patients (14.9%) had central jets and 143 patients (85.1%) had eccentric jets. Among 143 patients with eccentric jets, 47 patients (32.9%) had free-standing eccentric MR jets, and 96 (67.1%) patients had very eccentric jets. 3D TEE diagnosed the severity and location of MR lesions correctly in all patients; this was not the case with 2D TEE, which had significant diagnostic misses in nine patients (9.4%, p < 0.001) having MR with very eccentric jets. These nine patients had lesions on both mitral leaflets, which were missed during 2D TEE examination owing to the highly turbulent flows produced by very eccentric jets from one mitral leaflet lesion and impinging the opposite mitral leaflet lesion. CONCLUSION: The severity of MR with very eccentric jet was more accurately and comprehensively assessed by 3D TEE than by 2D TEE. Therefore, intraoperative RT 3D TEE provides incremental information that is generally superior to 2D TEE in patients with complex MR due to very eccentric jets. PMID- 23664738 TI - Modeling exposures to organophosphates and pyrethroids for children living in an urban low-income environment. AB - Pesticide exposure in urban low-income residential environments may be elevated as a result of persistent application due to severe pest infestation. Children living in this environment may be a sensitive subpopulation for these non-dietary exposures, due to their physiological and behavioral differences. In this study, we provide an exposure modeling framework to simulate exposures for children in this environment and assess dominant exposure routes and sources of exposure variability, in order to characterize factors that influence risk. We use a dataset of pesticide measurements collected in 42 low-income dwellings, including vacuum dust and floor wipe samples from kitchens and living rooms. We fit distributions to the concentration measurements for the organophosphates measured, chlorpyrifos and diazinon, and the most prevalent pyrethroids (permethrin, cypermethrin, and cyfluthrin), and simulated 1000 homes from the distributions. Concentration measurements were then connected with activity pattern data, short-term dermal and ingestion exposures and absorbed doses were simulated for children ages 1-5 years. For both pesticide groups, exposure values ranged widely, with concentration values contributing most significantly to exposure variability, although approximately 20-fold variability was attributable to exposure factors alone. In addition, upper percentile exposed children usually had both higher concentrations as well as greater influences from exposure and dose factors. Differences were also seen across pesticide groups in dominant exposure pathways. Our analyses indicate a profile of factors that describe individuals likely to receive high doses of one or multiple pesticides and could allow for more targeted intervention strategies. More generally, this work provides a standard framework to evaluate and describe exposures to prevalent residential pesticides via multiple pathways. PMID- 23664739 TI - Zoonotic disease risk perceptions and infection control practices of Australian veterinarians: call for change in work culture. AB - This study was conducted to determine the perceptions of zoonotic disease risk among Australian veterinarians, the infection control practices they use to protect themselves from zoonotic diseases, and the factors influencing their use of these protective practices. A questionnaire was designed and piloted prior to its administration to veterinarians at the annual Australian Veterinary Association Conference in May 2011. The questionnaire comprised 21 closed, semi closed and open questions. Data from the questionnaire were analyzed using ordinal logistic regression analyses to determine significant factors for veterinarians' use of personal protective equipment (PPE). A total of 344 veterinarians completed the questionnaire of which 63.7% were women, 63.2% worked in small/companion animal practice, and 79.9% worked in private veterinary practice. Of the respondents, 44.9% reported contracting a zoonosis during their careers with 19.7% reporting a suspected case and 25.2% reporting a confirmed incidence. Around 40-60% of veterinarians perceived exposure to zoonosis likely or very likely in a variety of situations. With reference to current national industry guidelines, the reported use of PPE was less than "adequate" for most scenarios except for performing postmortems, surgery or dental procedures. No PPE was used by 60-70% of veterinarians for treating respiratory and neurological cases and by 40-50% when treating gastrointestinal and dermatological cases. Workplace conditions need improvement as 34.8% of workplaces did not have isolation units for infected animals, 21.1% did not have separate eating areas for staff, and 57.1% did not have complete PPE kits for use. Veterinarians were more likely to use PPE if they had undertaken postgraduate education, perceived that zoonosis exposure from animals and procedures was likely, consciously considered PPE use for every case they dealt with and believed that liability issues and risks encouraged use of PPE. In contrast, those working in private practices, those who tended to 'just hope for the best' when trying to avoid zoonotic diseases, and those who were not aware of industry guidelines were less likely to use PPE. The results suggest that veterinarians' perceptions and workplace policies and culture substantially influence their use of PPE. Efforts should be made to encourage veterinarians and their workplaces to use infection control practices to protect themselves and their staff from zoonotic diseases. PMID- 23664740 TI - Minimalist shoe injuries: three case reports. AB - Running in minimalist shoes continues to increase in popularity and multiple mainstream shoe companies now offer minimalist shoes. While there is no evidence that traditional running shoes prevent injuries, there are concerns that the designs of minimalist shoes may increase injury risk. However, reports of injuries in runners wearing minimalist shoes are rare. We present three injuries occurring in runners that were wearing minimalist shoes at the time of injury. All three of the runners switched immediately to the minimalist shoes with no transition period. We recommend that any transition to minimalist shoe gear be performed gradually. It is our contention that these injuries are quite common and will continue to become more prevalent as more runners change to these shoes. PMID- 23664741 TI - Increased expression of USP22 is associated with disease progression and patient prognosis of salivary duct carcinoma. AB - OBJECTIVES: Ubiquitin-specific protease 22 (USP22) could exhibit a critical function in pathological processes, including oncogenesis and cell cycle progression. This study examines the protein expression of USP22 in salivary duct carcinoma (SDC) in association with patient survival and other clinicopathologic parameters. MATERIALS AND METHODS: Quantitative RT-PCR and immunohistochemistry (IHC) were used to determine the expression of USP22 protein in 44 SDCs in comparison with 20 non-cancerous salivary tissues. Furthermore, we analyzed the correlation between the expression of the USP22 protein and various clinicopathologic factors including survival status of patients with SDC. RESULTS: The incidence of positive USP22 expression was 63.7% in 44 SDC tissues. The mRNA level of USP22 expression in SDC samples was significantly higher than that in non-cancerous salivary tissues (P < 0.001), which was consistent with the IHC result (P < 0.001). Moreover, statistical analysis showed that positive USP22 expression was positively related to pT classification, pN classification and AJCC stage. Notably, high USP22 expression was significantly associated with shorter overall survival (P = 0.023) and disease-specific survival (P = 0.019). Multivariate Cox regression analysis revealed that USP22 expression level was an independent prognostic factor for both overall survival (P < 0.001) and disease free survival (P < 0.001). CONCLUSION: Our results indicate that activation of USP22 correlates with SDC progression and therapy failure. Overexpression of USP22 may contribute to the progression of SDC and thus may serve as a new molecular marker to predict the prognosis of SDC patients. PMID- 23664742 TI - Contribution of osseous and muscular stabilizing effects with the Latarjet procedure for anterior instability without glenoid bone loss. AB - BACKGROUND: The Latarjet procedure is used to treat anterior shoulder instability. Authors contend that the main concept of the operation is using the conjoined tendon as a sling to lower the subscapularis, reinforcing the anteroinferior capsule. The effects of the "sling," as well as stability and range of motion (ROM), after the Latarjet procedure have not been documented. In this study, we test the Latarjet procedure, attempting to account for the effect of the conjoined tendon. We also use the model to characterize the kinematic effects and stabilizing mechanism of the Latarjet procedure. MATERIALS AND METHODS: Six cadaveric shoulders were tested in the intact state, after anterior capsulotomy, and after the Latarjet procedure. An apparatus was designed that allowed for loading of the conjoined tendon. ROM and translation were quantified. After conclusion of testing in the Latarjet group, the conjoined tendon was released and specimens were retested to determine stability attributable to the sling effect versus the osseous effect alone. RESULTS: We found no statistically significant differences with regard to ROM after the Latarjet procedure. The Latarjet procedure did significantly decrease anteroinferior translation. However, when the conjoined tendon was unloaded, there was a significantly decreased resistance to anterior translation. After conjoined tendon release, there was no effect on inferior translation. CONCLUSION: This study confirmed that the Latarjet procedure successfully decreases anteroinferior translation while maintaining ROM. It did not support the belief that inferior stability is provided by the sling effect. The model developed can serve as the basis for future testing. LEVEL OF EVIDENCE: basic science study, biomechanics. PMID- 23664743 TI - Linking of total elbow prosthesis during surgery; a biomechanical analysis. AB - BACKGROUND: Presently, 2 types of elbow prostheses are used: unlinked and linked. The Latitude total elbow prosthesis allows the surgeon to decide during the implantation whether the prosthesis is placed unlinked or linked, and whether the native radial head is retained, resected, or replaced. The purpose of this study is to assess and to compare the varus and valgus laxity of the unlinked and linked version of the latitude total elbow prosthesis with: (1) the native radial head preserved, (2) the native radial head excised, and (3) the native radial head replaced by a radial head component. METHODS: Biomechanical testing was performed on 14 fresh-frozen upper limb specimens. RESULTS: Linking the prosthesis predominantly influences the valgus laxity of the elbow. DISCUSSION/CONCLUSION: Linking the Latitude total elbow prosthesis results in increased valgus stability. In the linked version of the total elbow prosthesis, the radial head only plays a small part in both valgus and varus stability. An unlinked situation is not advised in absence of a native radial head or in case of inability to replace the radial head. PMID- 23664744 TI - Regarding "Is shoulder pain for three months or longer correlated with depression, anxiety, and sleep disturbance?". PMID- 23664745 TI - Evaluation of cartilage degeneration in a rat model of rotator cuff tear arthropathy. AB - BACKGROUND AND HYPOTHESIS: Rotator cuff tears are the most common injury seen by shoulder surgeons. Glenohumeral osteoarthritis develops in many late-stage rotator cuff tear patients as a result of torn cuff tendons, termed "cuff tear arthropathy." However, the mechanisms of cuff tear arthropathy have not been fully established. It has been hypothesized that a combination of synovial and mechanical factors contribute equally to the development of cuff tear arthropathy. The goal of this study was to assess the utility of this model in investigating cuff tear arthropathy. MATERIALS AND METHODS: We used a rat model that accurately reflects rotator cuff muscle degradation after massive rotator cuff tears through either infraspinatus and supraspinatus tenotomy or suprascapular nerve transection. Using a modified Mankin scoring system, we found significant glenohumeral cartilage damage after both rotator cuff tenotomy and suprascapular nerve transection after only 12 weeks. RESULTS: Cartilage degeneration was similar between groups and was present on both the humeral head and the glenoid. Denervation of the supraspinatus and infraspinatus muscles without opening the joint capsule caused cartilage degeneration similar to that found in the tendon transection group. CONCLUSIONS: Our results suggest that altered mechanical loading after rotator cuff tears is the primary factor in cartilage degeneration after rotator cuff tears. Clinically, understanding the process of cartilage degeneration after rotator cuff injury will help guide treatment decisions in the setting of rotator cuff tears. LEVEL OF EVIDENCE: Basic science study, animal model. PMID- 23664746 TI - The medial-ridge sign as an indicator of anterior glenoid bone loss. AB - BACKGROUND: The goal of this study was to investigate the incidence of a medial bony ridge at the scapular neck in patients with recurrent anterior shoulder instability and analyze its reliability in identifying anterior glenoid rim bone loss. METHODS: A total of 109 shoulders in 105 consecutive patients underwent primary surgical stabilization for recurrent anterior shoulder instability with preoperative 2-dimensional and 3-dimensional computed tomography (CT) evaluation. The CT images of each affected shoulder were analyzed for the extent of anterior glenoid bone loss and the presence of a "medial-ridge sign." The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the medial-ridge sign were calculated for different sizes of glenoid rim defects. RESULTS: A positive medial-ridge sign was detected in 77.1% of the shoulders. The sensitivity of the medial-ridge sign ranged from 81.6% (95% confidence interval [CI], 73.0%-87.9%) for defects greater than 0% to 100% (95% CI, 82.4%-100%) for defects >=20%. The PPV of the medial-ridge sign decreased from 100% for defects >0% to 11.9% for defects >=25%. The specificity of the medial-ridge sign decreased from 100% (95% CI, 61.0-100%) for defects >0%, to 25.3% (95% CI, 17.7%-34.6%) for defects >=25%. The NPV of the medial-ridge sign increased from 24.0% for defects >0% to 100% for defects >20%. CONCLUSION: The medial-ridge sign represents a CT-based radiologic sign with high sensitivity and NPV for identification of significant anterior glenoid rim defects in case of recurrent anterior shoulder instability. PMID- 23664747 TI - Complications and revision rate compared by type of total elbow arthroplasty. AB - BACKGROUND: This study evaluates the long-term results, including complication and revision rates, of different types of total elbow arthroplasty (TEA) with an average follow up of 13 years. METHODS: Since 1984, a total of 84 primary TEAs have been performed in 77 patients at our institution. The patient's average age was 54.2 years. We performed unlinked TEA in 35 cases (Pritchard ERS since 1984 [n = 18], Kudo type 3 since 1991 [n = 17]), and semi-linked TEA in 49 cases (Pritchard Mark II since 1997 [n = 14], Coonrad-Morrey since 2001 [n = 35]). We assessed the patients for compliance to daily living guidelines (not to exceed 2.25 kg for repetitive lifting and 4.5 kg for single episode lifting), and followed up with them for an average of 13 years after primary TEA. We analyzed their results with regard to complication and revision rates as the type of TEA. RESULTS: The mean Mayo Elbow Performance Score (MEPS) improved from preoperative 34 points to postoperative 84 points. The active flexion-extension elbow motion increased from 25 degrees -94 degrees preoperative to 12 degrees -130 degrees postoperative. The overall complication rate was 44.0% (37/84 cases); the rate was statistically higher in the unlinked group (62.9%, 22/35 cases) than in the semi-linked group (30.6%, 15/49 cases). The overall revision rate was 27.4% (23/84 cases); the rate was higher in the unlinked group (34.3%, 12/35 cases) than in the semi-linked group (22.4%, 11/49 cases). CONCLUSION: Semi-linked TEA has better outcomes than unlinked TEA with respect to complication and revision rates; but continuous efforts to develop a new TEA design for longevity, improved cementing technique, and supporting activities of daily living are needed to reduce complication and revision rates in the future. PMID- 23664748 TI - Suprascapular nerve entrapment isolated to the spinoglenoid notch: surgical technique and results of open decompression. AB - BACKGROUND: Entrapment of the suprascapular nerve (SSN) at the spinoglenoid notch (SGN) specifically affects the infraspinatus, and isolated external rotation (ER) weakness can result. We describe the technique of open SSN decompression at the SGN for infraspinatus involvement and report the results of a consecutive series. MATERIALS AND METHODS: Twenty-nine shoulders underwent SSN decompression at the SGN. The mean age was 44 years (range, 15-69 years), and the mean follow-up was 4.3 years (range, 1-7 years). On manual muscle testing, ER strength was abnormal in all patients: 2/5 in 3, 3/5 in 21, and 4/5 in 5. The mean preoperative American Shoulder and Elbow Surgeons (ASES) score was 48 (range, 23-83). Atrophy of the infraspinatus was visible or palpable in 72% of shoulders. Magnetic resonance imaging showed ganglion cysts at the SGN in only 20.7% of shoulders. RESULTS: Of the patients, 19 (66%) regained full ER strength, 9 (31%) improved to 4/5, and 1 (3%) had ER strength of 3/5. The mean ASES score improved to 75 (range, 60-100) (P < .05). Of 29 shoulders, 23 (79%) showed improved ER strength within 1 week of surgery. All ganglion cyst cases regained full ER strength within a mean of 6 weeks. In all cases, ER strength improved by at least 1 full strength grade. DISCUSSION: A ganglion cyst is not necessary to produce SSN compression at the SGN. SSN compression at the SGN can present as an isolated entity or can occur in conjunction with rotator cuff pathology or a ganglion cyst. An index of suspicion, physical examination, magnetic resonance imaging, and electromyography confirm the diagnosis. The described operative approach detaches no muscle and allows rapid recovery, and in all cases, ER strength improved to normal or by 1 full grade. PMID- 23664749 TI - Effect of anatomic bone grafting in post-traumatic recurrent anterior shoulder instability on glenoid morphology. AB - BACKGROUND: Shoulder stability primarily depends on concavity compression, which relies on the concave shape of the glenoid not mere glenoid width. This study analyzed the effect of anatomic glenoid reconstruction surgery on concavity morphology. METHODS: Thirty-one consecutive patients with recurrent anterior shoulder instability and glenoid bone loss underwent surgical stabilization using the J-bone graft. Twenty patients were available for preoperative, postoperative, and 1-year follow-up computed tomography scans. On standardized axial images, the change over time of the glenoid concavity extent, depth, version, and step formation was measured and compared with the unaffected side. RESULTS: The mean preoperative concavity extent was 82.3% and increased (P < .001) after surgery to 113.1% before decreasing (P < .001) to 99.2% at follow-up concordant to the contralateral side (P = .75). The mean concavity depth was 56.6% preoperatively, increased to 226.4% postoperatively (P < .001), and diminished to 149.2% at follow-up (P < .001). Affected glenoids showed an average loss of -6.0 degrees of retroversion preoperatively, with an increase to +5.6 degrees postoperatively (P < .001) and a decrease to +0.2 degrees at follow-up (P < .001). The average step-formation on the articular surface after graft insertion diminished significantly, from 2.3 mm postoperatively to 0.3 mm at follow-up (P < .001). CONCLUSION: Anatomic glenoid reconstruction surgery using the J-bone graft provides temporary overcorrection of the glenoid concavity extent, depth, and version, with subsequent normalization due to physiologic remodeling processes. PMID- 23664750 TI - Achieving fixation in glenoids with superior wear using reverse shoulder arthroplasty. AB - BACKGROUND: Superior glenoid wear is a common challenge with reverse shoulder arthroplasty and, if left uncorrected, can result in superior glenoid tilt, which increases the risk of aseptic glenoid loosening. This study evaluates the impact of an E2 superior defect on reverse shoulder glenoid fixation in composite scapulae after correction of glenoid tilt by use of 2 different glenoid reaming techniques: eccentric reaming and off-axis reaming. MATERIALS AND METHODS: A superior glenoid defect was created in 14 composite scapulae. The superior defect was corrected by 2 different glenoid reaming techniques: (1) eccentric reaming with implantation of a standard glenoid baseplate and (2) off-axis reaming with implantation of a superior-augment glenoid baseplate. Each corrected superior defect scapula was then cyclically loaded (along with a control group consisting of 7 non-worn scapulae) for 10,000 cycles at 750 N; glenoid baseplate displacement was measured for each group to quantify fixation before and after cyclic loading. RESULTS: Regardless of the glenoid reaming technique or the glenoid baseplate type, each standard and superior-augment glenoid baseplate remained well fixed in this superior-defect model scenario after cyclic loading. No differences in baseplate displacement were observed either before or after cyclic loading between groups. DISCUSSION: Our results suggest that either glenoid reaming technique may be used to achieve fixation in the clinically challenging situation of superior wear with reverse shoulder arthroplasty. LEVEL OF EVIDENCE: Basic science, biomechanical study. PMID- 23664752 TI - The management of pneumonia in internal medicine. AB - Pneumonia generates a high workload for internal medicine departments. Management of this disease is challenging, because patients are usually elderly and have multiple comorbid conditions. Furthermore, the interpretation and adherence to guidelines are far from clear in this setting. We report the opinion of 43 internists especially interested in infectious diseases that were questioned at the 2011 XXXII National Conference of Spanish Society of Internal Medicine about the main issues involved in the management of pneumonia in the internal medicine departments, namely, classification, admission criteria, microbiological workup, therapeutic management, discharge policy, and prevention of future episodes. Participants were asked to choose between 2 options for each statement by 4 investigators. Consensus could not be reached in many cases. The most controversial issues concerned recognition and management of healthcare associated pneumonia (HCAP). Most participants were aware of the differences in terms of underlying diseases, etiological distribution, and outcome of HCAP compared with community-acquired pneumonia, but only a minority agreed to manage HCAP as hospital-acquired pneumonia, as suggested by some guidelines. A clinical patient-to-patient approach proved to be the option preferred by internists in the management of HCAP. PMID- 23664754 TI - Hedging, knowledge and interaction: Doctors' and clients' talk about medical information and client experiences in genetic counseling. AB - OBJECTIVES: The article starts from the observation that professionals in genetic counseling deploy the strategy of 'hedging'. It shows how hedging is used in a particular sequential position: doctors' responses to clients' presentations of personal information during information delivery sequences. METHODS: The data consist of video-recorded sessions of genetic counseling. The methodology is based on ethnomethodological conversation analysis. The analysis identifies interactional patterns in the counseling sessions. RESULTS: In their responses doctors display an orientation to different access to different kinds of knowledge. In particular, the doctors tread carefully when commenting on the situation of a particular client vis-a-vis the symptoms and prognosis of genetic conditions. Furthermore, the article shows that the doctors' responses and hedging devices in them are fitted to the form and function of the clients' presentations of personal experience. CONCLUSION: While the focus of the article is narrow in that it concentrates on one type of an interactional sequence, its strength is that it shows how the doctor's talk can be intertwined with the client's contributions. PRACTICE IMPLICATIONS: The results make it possible for genetic counselors to identify an interactional task they recurrently face and reflect on alternative ways of responding to it. PMID- 23664755 TI - A non-epileptiform event in the course of rTMS: a case for close physician monitoring. PMID- 23664753 TI - TDP-43 pathology in a patient carrying G2019S LRRK2 mutation and a novel p.Q124E MAPT. AB - Leucine-rich repeat kinase 2 (LRRK2) mutation is the most common cause of genetic related parkinsonism and is usually associated with Lewy body pathology; however, tau, alpha-synuclein, and ubiquitin pathologies have also been reported. We report the case of a patient carrying the LRRK2 G2019S mutation and a novel heterozygous variant c.370C>G, p.Q124E in exon 4 of the microtubule-associated protein tau (MAPT). The patient developed parkinsonism with good levodopa response in her 70s. Neuropathological analysis revealed nigral degeneration and Alzheimer-type tau pathology without Lewy bodies. Immunohistochemical staining using phospho-TDP-43 antibodies identified occasional TDP-43 pathology in the hippocampus, temporal neocortex, striatum, and substantia nigra. However, TDP-43 pathology was not identified in another 4 archival LRRK2 G2019S cases with Lewy body pathology available in the Queen Square Brain Bank. Among other published cases of patients carrying LRRK2 G2019S mutation, only 3 were reportedly evaluated for TDP-43 pathology, and the results were negative. The role of the MAPT variant in the clinical and pathological manifestation in LRRK2 cases remains to be determined. PMID- 23664756 TI - Long lasting effects of daily theta burst rTMS sessions in the human amblyopic cortex. AB - BACKGROUND: It has been reported that a single session of 1 Hz or 10 Hz repetitive transcranial magnetic stimulation (rTMS) of the visual cortex can temporarily improve contrast sensitivity in adults with amblyopia. More recently, continuous theta burst stimulation (cTBS) of the visual cortex has been found to improve contrast sensitivity in observers with normal vision. OBJECTIVE/HYPOTHESIS: The aims of this study were to assess whether cTBS of the visual cortex could improve contrast sensitivity in adults with amblyopia and whether repeated sessions of cTBS would lead to more pronounced and/or longer lasting effects. METHODS: cTBS was delivered to the visual cortex while patients viewed a high contrast stimulus with their non-amblyopic eye. This manipulation was designed to bias the effects of cTBS toward inputs from the amblyopic eye. Contrast sensitivity was measured before and after stimulation. The effects of one cTBS session were measured in five patients and the effects of five consecutive daily sessions were measured in four patients. Three patients were available for follow-up at varying intervals after the final session. RESULTS: cTBS improved amblyopic eye contrast sensitivity to high spatial frequencies (P < 0.05) and there was a cumulative improvement across sessions with asymptotic improvement occurring after 2 daily sessions of stimulation. The contrast sensitivity improvements were stable over a period of up to 78 days. CONCLUSIONS: These initial results in a small number of patients indicate the cTBS may allow for enduring visual function improvements in adults with amblyopia. PMID- 23664757 TI - Opposing functions of psoriasin (S100A7) and koebnerisin (S100A15) in epithelial carcinogenesis. AB - The S100 protein family is involved in epithelial cell maturation and inflammation. Some S100 members are dysregulated during carcinogenesis and have been established as tumor markers. Psoriasin (S100A7) and koebnerisin (S100A15) are highly homologous proteins that have been first described in psoriasis, which is characterized by disturbed epidermal maturation and chronic inflammation. Despite their homology, both S100 proteins are distinct in expression and function through different receptors but synergize as chemoattractants and pro inflammatory 'alarmins' to promote inflammation. Psoriasin and koebnerisin are further regulated with tumor progression in epithelial cancers. In tumor cells, high cytoplasmic expression of psoriasin and koebnerisin may prevent oncogenic activity, whereas their nuclear translocation and extracellular secretion are associated with tumor progression and poor prognosis. The present review outlines these opposing effects of psoriasin and koebnerisin in multifunctional pathways and mechanisms that are known to affect tumor cells ('seeds'), tumor environment ('soil') and tumor cell metastasis ('seeding') thereby influencing epithelial carcinogenesis. PMID- 23664758 TI - Anti-viral agents: potential utility in exacerbations of asthma. AB - Asthma is the most common chronic respiratory disease and its prevalence is on the increase. Respiratory viral infections in early life have been suggested to increase the risk of development of asthma in later life and virus infection remains the single greatest precipitant of asthma exacerbations. The development of effective anti-viral treatments remains a key target for therapeutic intervention. Here we discuss the role of respiratory viral infection in asthma exacerbation and highlight current and potential anti-viral agents and their mechanisms of action. PMID- 23664759 TI - Methodology for solid state NMR study of cross relaxation and molecular dynamics in heteronuclear systems. AB - This work presents the theoretical analysis of cross-relaxation and its applications to the study of molecular dynamics in the solid state heteronuclear systems in the laboratory frame. The solid state NMR experiments were carried out on a homemade pulse spectrometer operating at the frequency of 30.2 MHz and 28.411 MHz for protons and fluorines, respectively. It is worth noting that this spectrometer includes a specially designed probe which simultaneously works at two slightly differing frequencies for protons and fluorine nuclei with complete absence of their interference. Contrary to a large number of previous cross relaxation studies, in our experiments proton spins can be polarized in the magnetic field B0 or excited by rf pulses, while fluorine spins are continuously saturated for a long time. The saturation of fluorines is maintained throughout the whole duration of the experiment. It leads to a simplification of the mathematical analysis of the experimental results. PMID- 23664760 TI - The use of lung donors older than 55 years: a review of the United Network of Organ Sharing database. AB - BACKGROUND: Current lung transplantation guidelines stipulate that the ideal donor is aged younger than 55 years, but several institutions have reported that outcomes using donors aged 55 years and older are comparable with those of younger donors. METHODS: We retrospectively reviewed the United Network for Organ Sharing (UNOS) database to identify all adult lung transplants between 2000 and 2010 in the United States. Patients were stratified by donor age 18 to 34 (reference), 35 to 54, 55 to 64, and >= 65 years. Primary outcomes included survival at 30 days and at 1, 3, and 5 years and rates of bronchiolitis obliterans syndrome (BOS). Survival was assessed using the Kaplan-Meier method. Risk factors for mortality were identified by multivariable Cox and logistic regression. RESULTS: We identified 10,666 recipients with median follow-up of 3 years (range, 0-10 years). Older donors were more likely to have died of cardiovascular or cerebrovascular causes, but there were no differences in recipient diagnosis, lung allocation score, or incidence of BOS as a function of donor age. The use of donors aged 55 to 64 years was not a risk factor for mortality at 1 year (odds ratio, 1.1; p = 0.304) or 3 years (odds ratio, 0.923; p = 0.571) compared with the reference group; however, use of donors aged > 65 years was associated with increased mortality at both time points (odds ratio, 2.8 and 2.4, p < 0.02). CONCLUSIONS: Outcomes after lung transplantation using donors aged 55 to 64 years were similar to those observed with donors meeting conventional age criteria. Donors aged >= 65 years, however, were associated with decreased intermediate-term survival, although there was no increased risk of BOS for this group. PMID- 23664761 TI - Impact of nutritional state on lung transplant outcomes. AB - BACKGROUND: When high-risk lung transplant candidates are evaluated, nutritional state is often neglected. We evaluated the prevalence of markers reflecting pre transplant malnutrition and their association with post-operative complications and death. METHODS: From January 2005 to July 2010, 453 patients underwent primary lung transplantation at our institution. Pre-operative nutrition-related variables, including body mass index and weight/height ratio, reflecting cachexia, and albumin, total protein, immunoglobulins, and absolute lymphocyte count were considered in identifying risk factors for time-related major post operative complications (renal failure requiring dialysis, respiratory failure requiring tracheostomy), pulmonary or bloodstream infections, and death. RESULTS: Forty-eight patients had BMI <18.5 kg/m(2), 41 had a weight/height ratio <= 0.3, 102 had albumin <3.5 g/dl, 110 had total protein <6 g/dl, and 112 had an absolute lymphocyte count <1,000/MUl, indicative of a malnourished state. At 6 months, 30% had experienced pulmonary infection, with lower total serum protein concentration an important risk (p = 0.02). One-year actuarial mortality was 15%; risk factors included lower serum albumin (p = 0.004), particularly when <3 g/dl. In contrast, variables reflecting nutritional state were not statistically significantly correlated with dialysis, respiratory failure requiring tracheostomy, or bloodstream infections. CONCLUSION: Although malnutrition is uncommon in lung transplant patients, those at extremes of low serum albumin and total protein have worse survival and increased risk of post-operative infection. Strategies to improve nutrition of these high-risk candidates awaiting lung transplantation should be developed. PMID- 23664762 TI - Cystic dystrophy of the gastroduodenal wall in heterotopic pancreas. PMID- 23664763 TI - Transcriptional and epigenetic dynamics during specification of human embryonic stem cells. AB - Differentiation of human embryonic stem cells (hESCs) provides a unique opportunity to study the regulatory mechanisms that facilitate cellular transitions in a human context. To that end, we performed comprehensive transcriptional and epigenetic profiling of populations derived through directed differentiation of hESCs representing each of the three embryonic germ layers. Integration of whole-genome bisulfite sequencing, chromatin immunoprecipitation sequencing, and RNA sequencing reveals unique events associated with specification toward each lineage. Lineage-specific dynamic alterations in DNA methylation and H3K4me1 are evident at putative distal regulatory elements that are frequently bound by pluripotency factors in the undifferentiated hESCs. In addition, we identified germ-layer-specific H3K27me3 enrichment at sites exhibiting high DNA methylation in the undifferentiated state. A better understanding of these initial specification events will facilitate identification of deficiencies in current approaches, leading to more faithful differentiation strategies as well as providing insights into the rewiring of human regulatory programs during cellular transitions. PMID- 23664765 TI - An integrated microfluidic device in marine microalgae culture for toxicity screening application. AB - Algal assay using marine microalgae has emerged as an important method to evaluate the toxicity of chemicals, which is currently undertaken using conventional culture and additional detection of physiological cellular endpoints. While effective, this approach can be labor-intensive and thus could benefit from a more streamlined, integrated approach. Microfluidics offers a way to accomplish this goal. Here, we demonstrate a microfluidic device which consists of a concentration gradient generator (CGG), diffusible culturing module and power-free valve system. It allows the processes of chemical liquid dilution and diffusion, micro-scale microalgal culture (in batch or chemostatic conditions), cell stimulation and on-lined screening to be integrated into a single device. Using the device, marine microalgae were successfully cultured and stressed on-chip. The simple assay provides multi-biological response measurements of cell division rate, autofluorescence and esterase activity. This work showed promising in developing a microfluidic platform for toxicity screening based on marine microalgal culture. PMID- 23664764 TI - Epigenomic analysis of multilineage differentiation of human embryonic stem cells. AB - Epigenetic mechanisms have been proposed to play crucial roles in mammalian development, but their precise functions are only partially understood. To investigate epigenetic regulation of embryonic development, we differentiated human embryonic stem cells into mesendoderm, neural progenitor cells, trophoblast like cells, and mesenchymal stem cells and systematically characterized DNA methylation, chromatin modifications, and the transcriptome in each lineage. We found that promoters that are active in early developmental stages tend to be CG rich and mainly engage H3K27me3 upon silencing in nonexpressing lineages. By contrast, promoters for genes expressed preferentially at later stages are often CG poor and primarily employ DNA methylation upon repression. Interestingly, the early developmental regulatory genes are often located in large genomic domains that are generally devoid of DNA methylation in most lineages, which we termed DNA methylation valleys (DMVs). Our results suggest that distinct epigenetic mechanisms regulate early and late stages of ES cell differentiation. PMID- 23664766 TI - Bioaccumulation of polychlorinated biphenyls and organochlorine pesticides in young-of-the-year bluefish (Pomatomus saltatrix) in the vicinity of a Superfund Site in New Bedford Harbor, Massachusetts, and in the adjacent waters. AB - Spatial gradients of polychlorinated biphenyls (PCBs) and organochlorine pesticides were examined in the young-of-the-year (YOY) bluefish (Pomatomus saltatrix) in the vicinity of a PCB Superfund Site in New Bedford Harbor, Massachusetts, and in the adjacent waters. PCB concentrations in bluefish varied between different locations, and also among fish from a given location. A generally decreasing gradient in PCB concentrations was evident as the bluefish were collected away from the Superfund Site. The average sum of PCB concentrations were highest for bluefish collected in the Upper Harbor between Interstate-195 Bridge and Coggeshall Street Bridge (Upper Harbor), followed by bluefish in Lower Harbor from north of Popes Island Bridge (Lower Harbor), and bluefish from Outer Harbor south of Hurricane Barrier (Outer Harbor). The levels of PCBs in bluefish from Clarks Cove and PCBs in bluefish from Buzzards Bay were similar and lowest among all bluefish specimens analyzed in the present study. Pesticide concentrations were about one order of magnitude or lower than the PCB concentrations, and the gradient of pesticide concentrations generally followed the gradient of PCB concentrations. Some of the commonly detected pesticides in the order of decreasing concentrations included DDTs and metabolites, heptachlor epoxide, endosulfan sulfate, and alpha-chlordane. Distribution of PCBs and organochlorine pesticides were examined in the tissues of YOY bluefish from Clarks Cove. PCBs and lipids in the brain samples of YOY bluefish were generally numerically greater than PCBs in the liver samples, but these differences were not statistically significant. PCBs and lipids in hypaxial muscle samples were numerically greater than PCBs in epaxial muscle samples, although these two groups of tissues were not statistically different. Despite the higher susceptibility of lighter PCB homologs to geophysical and biogeochemical weathering processes, the relative dominance of lighter homologs in the Upper Harbor and Lower Harbor samples suggested ongoing or recent sources of these lighter PCBs, particularly Aroclor 1242 and Aroclor 1016 in this area. The presence of heavier homologs in the Upper Harbor and Lower Harbor bluefish samples could be attributed to Aroclor 1252 and Aroclor 1254 that were being used in relatively smaller quantities in the manufacture of electrical components in addition to Aroclor 1242 and Aroclor 1016. The concentration of heavier PCB homologs appears to increase in YOY bluefish the further away from the PCB Superfund Site in the Acushnet Estuary the samples were collected. Principal component analyses of PCB 153 normalized concentrations of the individual PCB congeners resulted in two general groupings; a relatively tight group comprised of YOY bluefish from Upper Harbor, Lower Harbor, and Outer Harbor, and a rather loose and more dispersed group comprised of Buzzards Bay bluefish and the tissue samples of bluefish from Clarks Cove. Principal component analyses of major pesticides suggested close groupings of bluefish from Clarks Cove and bluefish from Buzzards Bay. Pesticides in bluefish from Upper Harbor, Lower Harbor, and Outer Harbor formed a loose group, with some bluefish from these locations populating close to Clarks Cove and Buzzards Bay bluefish. Although PCBs have been implicated in various behavioral and health effects in the experimental and field studies, the deleterious effects of chronic exposure to high concentrations of PCBs and the potential for recruitment of New Bedford Harbor YOY bluefish population to the adult stock remains obscure. Adaptive or evolutionary resistance to contaminants have been documented in resident species in some highly contaminated estuaries, however similar responses have not been investigated in the migratory species like bluefish. The results of the present study provide a reference baseline for YOY bluefish for "before-and-after" comparative studies and other toxicological studies for the New Bedford Harbor Superfund Site that is currently being remediated. PMID- 23664767 TI - Evaluation of lung function and deposition of aerosolized bronchodilators carried by heliox associated with positive expiratory pressure in stable asthmatics: a randomized clinical trial. AB - While administration of medical aerosols with heliox and positive airway pressure are both used clinically to improve aerosol delivery, few studies have differentiated their separate roles in treatment of asthmatics. The aim of this randomized, double blinded study is to differentiate the effect of heliox and oxygen with and without positive expiratory pressure (PEP), on delivery of radiotagged inhaled bronchodilators on pulmonary function and deposition in asthmatics. 32 patients between 18 and 65 years of age diagnosed with stable moderate to severe asthma were randomly assigned into four groups: (1) Heliox + PEP (n = 6), (2) Oxygen + PEP (n = 6), (3) Heliox (n = 11) and (4) Oxygen without PEP (n = 9). Each group received 1 mg of fenoterol and 2 mg of ipratropium bromide combined with 25 mCi (955 Mbq) of Technetium-99m and 0.9% saline to a total dose volume of 3 mL placed in a Venticis II nebulizer attached to a closed, valved mask with PEP of 0 or 10 cm H2O. Both gas type and PEP level were blinded to the investigators. Images were acquired with a single-head scintillation camera with the longitudinal and transverse division of the right lung as regions of interest (ROIs). While all groups responded to bronchodilators, only group 1 showed increase in FEV1%predicted and IC compared to the other groups (p < 0.04). When evaluating the ROI in the vertical gradient we observed higher deposition in the middle and lower third in groups 1 (p = 0.02) and 2 (p = 0.01) compared to group 3. In the horizontal gradient, a higher deposition in the central region in groups 1 (p = 0.03) and 2 (p = 0.02) compared to group 3 and intermediate region of group 2 compared to group 3. We conclude that aerosol deposition was higher in groups with PEP independent of gas used, while bronchodilator response with Heliox + PEP improved FEV1 % and IC compared to administration with Oxygen, Oxygen with PEP and Heliox alone. Trial registration NCT01268462. PMID- 23664768 TI - Comparisons of sarcopenia defined by IWGS and EWGSOP criteria among older people: results from the I-Lan longitudinal aging study. AB - OBJECTIVE: To compare clinical characteristics of sarcopenia defined by the International Working Group on Sarcopenia (IWGS) and European Working Group on Sarcopenia in Older People (EWGSOP) criteria among older people in Taiwan. DESIGN: A prospective population-based community study. SETTING: I-Lan County of Taiwan. PARTICIPANTS: A total of 100 young healthy volunteers and 408 elderly people. INTERVENTION: None. MEASUREMENTS: Anthropometry, skeletal muscle mass measured by dual x-ray absorptiometry, relative appendicular skeletal muscle index (RASM), percentage skeletal muscle index (SMI), 6-meter walking speed, and handgrip strength. RESULTS: The prevalence of sarcopenia was 5.8% to 14.9% in men and 4.1% to 16.6% in women according to IWGS and EWGSOP criteria by using RASM or SMI as the muscle mass indices. The agreement of sarcopenia diagnosed by IWGS and EWGSOP criteria was only fair by using either RASM or SMI (kappa = 0.448 by RASM, kappa = 0.471 by SMI). The prevalence of sarcopenia was lower by the IWGS definition than the EWGSOP definition, but it was remarkably lower by using RASM than SMI in both criteria. Overall, sarcopenic individuals defined by SMI were older, had a higher BMI but similar total skeletal muscle mass, and had poorer muscle strength and physical performance than nonsarcopenic individuals. However, by using RASM, sarcopenic individuals had less total skeletal muscle mass but similar BMI than nonsarcopenic individuals. Multivariable logistic regression showed that age was the strongest associative factor for sarcopenia in both IWGS and EWGSOP criteria. Obesity played a neutral role in sarcopenia when it is defined by using RASM, but significantly increased the risk of sarcopenia in both criteria by using SMI. CONCLUSION: The agreement of sarcopenia defined by IWGS and EWGSOP was only fair, and the prevalence varied largely by using different skeletal muscle mass indices. Proper selections for cutoff values of handgrip strength, walking speed, and skeletal muscle indices with full considerations of gender and ethnic differences were of critical importance to reach the universal diagnostic criteria for sarcopenia internationally. PMID- 23664769 TI - Evaluation of a nursing home medical director's curriculum for geriatric medicine fellows. AB - OBJECTIVES: To describe the evaluation of a nursing home medical directorship curriculum for geriatric medicine fellows. DESIGN: Six first-year geriatric medicine fellows from the University of Hawaii program participated in this educational intervention. INTERVENTION: A medical directorship curriculum based on the American Medical Directors Association's description of the roles and responsibilities of the medical director. Seven 1-hour sessions covering core topics were delivered in case-based format, with the opportunity to practice application. MEASUREMENTS: The curriculum's impact on learner's knowledge, attitudes, skills, and abilities was evaluated using pretests and posttests. The curriculum was evaluated using a structured individual feedback interview after the completion of this curriculum. Pre-post mean scores for attitudes and skills/ability items were compared using paired t tests. A summary of comments from fellows' interviews was tabulated. RESULTS: Fellows showed a significant improvement in knowledge scores after the intervention (63.33% correct before the intervention and 76.67% correct after the intervention, mean change = 13.33%, P = .03). The mean overall scores for attitudes and skills/ability items increased from 4.72 to 5.33 (change = 0.61, P = .11), and 2.67 to 3.83 (change = 1.17, P = .009), respectively. Comments from the interviews were positive and fell into 3 categories. First, fellows felt that they achieved a good knowledge base. Second, they gained a better understanding of the roles and responsibilities. Last, all participants felt the curriculum was very practical and helped them feel more prepared to become medical directors. CONCLUSIONS: An innovative curriculum for nursing home medical direction provided for first-year geriatric medicine fellows had a significantly positive impact on their knowledge, ability, and skills. The curriculum was effective in helping fellows better understand and apply what they learned regarding the roles and responsibilities in medical direction. PMID- 23664770 TI - RETRACTED: Increases in inflammatory mediators in DRG implicate in the pathogenesis of painful neuropathy in Type 2 diabetes. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal).This article has been retracted at the request of the Editor-in-Chief.Image duplication has been observed within Figure 1g-h. The corresponding author has been asked to provide an acceptable explanation for this duplication but has not been able to do so neither have the original source files been supplied. PMID- 23664771 TI - Administration of IL-1 trap prolongs survival of transplanted pancreatic islets to type 1 diabetic NOD mice. AB - We previously reported that IL-1 Trap (a hybrid molecule consisting of the extracellular domain of IL-1 receptor accessory protein and IL-1 receptor type 1 arranged inline and fused to the Fc-portion of IgG1) can protect rat pancreatic islets in vitro against noxious effects induced by IL-1beta. In this study we tested the effect of administration of a murine IL-1 Trap on the recurrence of disease (ROD) model in non-obese diabetic (NOD) mice. Spontaneously diabetic female NOD mice received implantation of a curative number (600) of syngeneic pancreatic islets beneath their left kidney capsule from young healthy NOD mouse donors. Once a day, the mice were injected subcutaneously with IL-1 Trap (30mg/kg bodyweight), or an equimolar dose Fc-control protein (8.4mg/kg bodyweight) or saline. The treatments were maintained until ROD (i.e. a blood glucose value ?11.1mM for 2 consecutive days) or until 5days after transplantation. 3 out of 11 mice treated with IL-1 Trap showed a significantly increased graft survival compared to all other mice, and analysis of relative cytokine mRNA levels in isolated spleen cells showed elevated IL-4 mRNA levels, but no differences in FoxP3 or iNOS staining of grafts, from mice treated with IL-1 Trap, at both endpoints, compared to both control groups. Administration of IL-1 Trap counteracts islet cell destruction in the NOD mouse model of type 1 diabetes. In part this could be due to a shift towards Th2 cytokine production seen in IL-1 Trap treated animals. PMID- 23664773 TI - Prophylactic ketamine to prevent shivering in parturients undergoing Cesarean delivery during spinal anesthesia. AB - STUDY OBJECTIVE: To compare the efficacy and safety of ketamine 0.25 mg/kg with ketamine 0.5 mg/kg to prevent shivering in patients undergoing Cesarean delivery. DESIGN: Prospective, randomized, double-blinded, placebo-controlled study. SETTING: Operating rooms and postoperative recovery rooms. PATIENTS: 120 ASA physical status 1 and 2 pregnant women scheduled for Cesarean delivery during spinal anesthesia. MEASUREMENTS: Patient characteristics, anesthetic and surgical details, Apgar scores at 1 and 5 minutes, and side effects of the study drugs were recorded. Heart rate, mean arterial pressure, oxygen saturation via pulse oximetry, tympanic temperature, severity of shivering, and degree of sedation were recorded before intrathecal injection and thereafter every 5 minutes. Patients were randomized to three groups: saline (Group C, n=30), intravenous (IV) ketamine 0.25 mg/kg (Group K-0.25, n=30), or IV ketamine 0.5 mg/kg (Group K 0.5, n=30). Grade 3 or 4 shivering was treated with IV meperidine 25 mg and the prophylaxis was regarded as ineffective. MAIN RESULTS: The number of shivering patients was significantly less in Group K-0.25 and in Group K-0.5 than in Group C (P = 0.001, P = 0.001, respectively). The tympanic temperature values of Group C were lower at all times of the study than in either ketamine group. Median sedation scores of Group K-0.5 were significantly higher than in Group K-0.25 or Group C at 10, 20, 30, and 40 minutes after spinal anesthesia. CONCLUSIONS: Prophylactic IV ketamine 0.25 mg/kg was as effective as IV ketamine 0.5 mg/kg in preventing shivering in patients undergoing Cesarean section during spinal anesthesia. PMID- 23664774 TI - Identification of predictors of early infection in acute burn patients. AB - Burn patients are at high risk for infections; however, common indicators of infection are unreliable in this population and can lead to unnecessary use of antibiotics. The study objective was to determine if predictors of early infection in adult acute burn patients are identified to provide clinicians with a practical tool to aid in the diagnosis of infection, thereby minimizing unnecessary exposure to antimicrobials. A retrospective chart review of all adult acute burn injury patients admitted over a 1 year period to the burn centre at Sunnybrook Health Sciences Centre was conducted. Early infection was defined as one that occurred within the first 10 days after injury and in accordance with American Burn Association guidelines. Those without infection were compared to patients with infection generally and also to patients with sepsis specifically. The period prevalence of early infection and sepsis in our patients was 50% (56/111) and 16% (18/111), respectively. It was determined that heart rate >=110 bpm, systolic blood pressure <=100 mmHg and intubation were the best predictors of sepsis (p<0.05); and fraction of inhaled oxygen >25% and maximum temperature >=39 degrees C were the best predictors of infection (p<0.05). This pilot project identified significant predictors of early infection and sepsis in acute burns and will be validated in a prospective study. PMID- 23664775 TI - Antimicrobial susceptibility of bacterial isolates from burn units in Gaza. AB - BACKGROUND: Bacterial infections continue to be a leading cause of morbidity and mortality among burn patients despite intensive prophylaxis and treatment. Often treatment is complicated by the emergence of antimicrobial resistance pathogens. There are no reports or published data on the susceptibility profiles of bacteria isolated from burn patients in the Gaza strip. PATIENTS AND METHODS: A cross sectional study was performed in the two burn units of Al-Shifa and Naser hospitals for 6 months from October 2010 to March 2011. A total of 118 wound samples from burn patients, 97 environmental samples and 28 samples from health care workers (HCWs) were collected and cultured according to the standard microbiological procedures. The bacterial isolates were identified by conventional methods and the antibiotic susceptibility profiles were determined by the standard disc diffusion method according to CLSI guidelines. RESULTS: The overall percentage of positive cultures from both hospitals was 45.8%, where Nasser burn unit revealed higher positive cultures than Al-Shifa burn unit. Pseudomonas aeruginosa was the most common pathogen isolated (50%) followed by Enterobacter cloacae (28.3%). Meanwhile, fingers and nasal samples that collected from HCWs showed 78.6% and 32.3% positive cultures respectively, where P. aeruginosa was the highest pathogen isolated (32.3%), followed by Coagulase Negative Staphylococci (CoNS) (29%). Environmental samples also showed higher isolation rate of Pseudomonas and CoNS. Pseudomonas isolates from patients samples were found to be resistant to most of antimicrobials used except for piperacillin-tazobactam. The family Enterobacteriaceae isolated from patients and environmental samples were resistant to most of the tested antimicrobials. However, the Enterobacteriaceae isolates from HCWs samples were sensitive to the most of the tested antimicrobials. The incidence of methicillin-resistant Staphylococci according to oxacillin sensitivity test was 60% in patient's samples, 77.8% in HCWs samples and 90% in environmental samples. CONCLUSION: High percentage of resistance was found among clinical isolates in general to the commonly used antibiotics with a notable increase in MRSA incidence among both patients and environmental samples as well as HCWs. PMID- 23664776 TI - Development of a national position paper for chronic care: example of Belgium. AB - The management of chronic diseases is a prime challenge of most 21st century health care systems. Many Western countries have invested heavily in care plans oriented towards specific conditions and diseases, such as dementia and cancer. The major downside of this narrowly focused approach is that treatment of multimorbidity is ignored. This paper describes the development and main stance of a national position that proposes streamlined reforms of the Belgian health care system to improve care for patients with multiple chronic diseases. We used a combination of methods to develop this stance: literature review and stakeholders' consultation. The latter identified areas for improvement: efficiency of the health care system, coordination of care, investments in human care resources, informal caregivers' support, better accessibility, and changes in the financial payment system. The position paper list 20 recommendations that are translated into about 50 action points to reform the health care system. Chronic care tailored to the patient's needs, including implementation of multidisciplinary teamwork, new functions, task delegation in primary care, and empowerment of the patient and informal caregivers are some major areas discussed. In addition, improved support, revised payment mechanisms, and setting up a quality system, along with the tailoring of patient care, can all facilitate delivery of high quality care in patients with chronic comorbidities. PMID- 23664778 TI - Not-so-incidental findings: the ACMG recommendations on the reporting of incidental findings in clinical whole genome and whole exome sequencing. PMID- 23664780 TI - Measuring determinants of career satisfaction of anesthesiologists: validation of a survey instrument. AB - STUDY OBJECTIVE: To measure the parameter of job satisfaction among anesthesiologists. DESIGN: Survey instrument. SETTING: Academic anesthesiology departments in the United States. SUBJECTS: 320 anesthesiologists who attended the annual meeting of the ASA in 2009 (95% response rate). MEASUREMENTS AND MAIN RESULTS: The anonymous 50-item survey collected information on 26 independent demographic variables and 24 dependent ranked variables of career satisfaction among practicing anesthesiologists. Mean survey scores were calculated for each demographic variable and tested for statistically significant differences by analysis of variance. Questions within each domain that were internally consistent with each other within domains were identified by Cronbach's alpha >= 0.7. P-values <= 0.05 were considered statistically significant. Cronbach's alpha analysis showed strong internal consistency for 10 dependent outcome questions in the practice factor-related domain (alpha = 0.72), 6 dependent outcome questions in the peer factor-related domain (alpha = 0.71), and 8 dependent outcome questions in the personal factor-related domain (alpha = 0.81). Although age was not a variable, full-time status, early satisfaction within the first 5 years of practice, working with respected peers, and personal choice factors were all significantly associated with anesthesiologist job satisfaction. CONCLUSIONS: Improvements in factors related to job satisfaction among anesthesiologists may lead to higher early and current career satisfaction. PMID- 23664777 TI - ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. AB - Zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) comprise a powerful class of tools that are redefining the boundaries of biological research. These chimeric nucleases are composed of programmable, sequence-specific DNA-binding modules linked to a nonspecific DNA cleavage domain. ZFNs and TALENs enable a broad range of genetic modifications by inducing DNA double-strand breaks that stimulate error-prone nonhomologous end joining or homology-directed repair at specific genomic locations. Here, we review achievements made possible by site-specific nuclease technologies and discuss applications of these reagents for genetic analysis and manipulation. In addition, we highlight the therapeutic potential of ZFNs and TALENs and discuss future prospects for the field, including the emergence of clustered regulatory interspaced short palindromic repeat (CRISPR)/Cas-based RNA-guided DNA endonucleases. PMID- 23664781 TI - Bilateral sagittal split osteotomy in cadaveric pig mandibles: evaluation of the lingual fracture line based on the use of splitters and separators. AB - OBJECTIVE: To analyze the splitting pathways of the (lingual) fracture lines during a bilateral sagittal split osteotomy (BSSO) in cadaveric pig mandibles. STUDY DESIGN: A BSSO was performed using splitters and separators. Special attention was paid to end the horizontal medial cut at the deepest point of the entrance of the mandibular foramen. RESULTS: Of all lingual fractures, 95% ended in the mandibular foramen. Forty percent of these fractures extended through the mandibular canal and 40% extended inferiorly along the mandibular canal. CONCLUSION: Almost all lingual fracture lines ended in the mandibular foramen, most likely due to the placement of the medial cut in the concavity of the mandibular foramen. The mandibular foramen and canal could function as the path of least resistance in which the splitting pattern is seen. We conclude that a consistent splitting pattern was achieved without increasing the incidence of possible sequelae. PMID- 23664782 TI - Severe destruction of the temporomandibular joint with complete resorption of the condyle associated with synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome. AB - The synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome consists of a combination of inflammatory bone disorders and dermatologic pathology. Bone lesions as a form of diffuse sclerosing osteomyelitis in the mandible occur in the posterior body and ramus. Bone lesions rarely spread to the temporomandibular joint (TMJ) where ankylosis may result. Herein we present an unusual case of SAPHO syndrome with TMJ involvement in which severe destruction of the TMJ occurred. We observed an extension of the invasive soft tissue lesion into the infratemporal fossa from the TMJ with complete resorption of the condyle. In contrast to other previously reported cases, in our case the condyle was strongly suspected as the primary site of the bone lesion with subsequent extension to the ramus and infratemporal fossa. The destructive nature and related symptoms resembled a malignant tumor. PMID- 23664783 TI - Performance of Luffa cylindrica as immobilization matrix in bioconversion reactions by Nicotiana tabacum BY-2. AB - The dry fruit of Luffa cylindrica was investigated as an immobilization matrix for Nicotiana tabacum cells in bioconversion reactions of exogenous substrates. Immobilized cells show high biocatalytic activity under high substrate levels. Cell growth on the dry fruit can be maintained until reaching an immobilization capacity of 1.8 g cells/g(Luffa). PMID- 23664784 TI - Clinical nurses' perception of continuing professional education as a tool for quality service delivery in public hospitals Calabar, Cross River State, Nigeria. AB - This study was conducted to determine the perception of nurses on various aspects of continuing professional education (CPE). A mixed method design (quantitative/qualitative) was adopted. A self-explanatory, semi-structured questionnaire was validated and used to collect data in addition to unstructured interview. One hundred and fifty nurses were selected through stratified random sampling from two hospitals in Calabar, Nigeria and served as participants. Participants generally perceived CPE as valuable and worthwhile and participated because it is mandatory and helps them to retain their jobs. The content of CPE were perceived to be more relevant for clinicians than for nurse educators; clinical skills and quantitative research methodology were adequately covered while evidence-based practice, attitudinal issues, nursing theories and patient safety were inadequately covered. CPE was perceived to be fragmented without gaining points, follow-up monitoring and evaluation after CPE which make it difficult to objectively assess the influence of CPE on quality of care. It is recommended that nurse leaders in Nigeria should develop online CPE modules for nursing, and allocate points to them so that participation may contribute to career progression. Effective monitoring and evaluation systems should be put in place to assess impact of CPE on staff competence and patient outcomes. PMID- 23664785 TI - Daytime physical activity patterns and physical fitness in institutionalized elderly women: an exploratory study. AB - This study investigated the relationship between daytime physical activity patterns and physical fitness in elderly women. The subjects comprised 19 elderly women who resided in a nursing home. Time spent lying, sitting, standing and walking and the number of steps taken during the daytime from 10:00 to 16:00 were measured to determine physical activity patterns. Physical fitness measures included muscle strength, balance, flexibility and physical performance. The elderly women spent 18.3% of their daytime walking, 7.31% in a standing position, 56.9% sitting and 17.4% lying down. Our results showed that the time spent in walking or standing positions was significantly associated with balance and physical performance such as walking speed, while the time spent in a sitting position was inversely associated with muscle strength, balance and physical performance. The results of this study suggest that the time the elderly spend on weight-bearing activities and in sedentary behavior are associated with physical fitness. PMID- 23664786 TI - The Higher Care At Discharge Index (HCDI): identifying older patients at risk of requiring a higher level of care at discharge. AB - A screening index, administered at admission, can be useful in identifying older hospitalised patients at risk of requiring a higher level care at discharge. The objective of this study was to describe the development of a risk stratification index for allocating patients into lower and higher risk of requiring higher level care at discharge. A prospective cohort study of general medical patients, aged >=70 years admitted to three metropolitan acute care hospitals in Brisbane, Australia was conducted. Derivation cohort (n=360) was used to: identify significant predictive factors associated with discharge to a higher level care; and develop a screening index to stratify patients into lower and higher risk. Predictive performance of the index was examined in the validation cohort (n=142). Five independent factors associated with requiring higher level care (identified using stepwise logistic regression analysis) were used to develop the HCDI: no support person to assist with living in the community; received assistance with finances; received assistance with hygiene; short term memory problems; hospitalised in 90 days prior to current hospital admission. Sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) of the dichotomised risk scores of the HCDI were: 76.3%; 73.3%; 36.0%; and 94.0% respectively; correctly classified 73.8%. In the validation cohort, sensitivity was 81.8%; specificity 68.7%; PPV 18.0%; NPV 97.8%, correctly classified 69.7%. Requirement for a higher level care at discharge has important consequences for health service delivery. The HCDI can be used to identify patients at higher risk. PMID- 23664787 TI - Comparison of functional autonomy with associated sociodemographic factors, lifestyle, chronic diseases (CD) and neuropsychiatric factors in elderly patients with or without the metabolic syndrome (MS). AB - The objective of this study was to compare autonomy and its associated factors in the elderly with and without MS. This study was a cross-sectional evaluation comprised of 402 subjects aged 60 years or older, of both sexes, consulting at the Family Health program, in Vicosa/MG. Autonomy was classified according to the Group of Latin American Development to Maturity (GDLAM) protocol and MS according to classification of the International Diabetes Federation. The independent variables were sociodemographic gender, age, marital status, education, those related to lifestyle including levels of physical activity and sedentary behavior, neuropsychological aspects included depressive symptoms, level of cognition and the presence of CD. A multiple linear regression model was used to estimate associations of variables with autonomy in the elderly with or without the MS. In the elderly group without MS, autonomy was associated with increasing age, sedentary behavior and depressive symptoms. In the group of elderly patients with MS, in addition to these factors, autonomy was also associated with being illiterate, not being physically active and presenting chronic illness. It was concluded that the presence of MS worsened the functional autonomy of elderly persons. PMID- 23664788 TI - Injection drug users' involvement in drug dealing in the downtown eastside of Vancouver: social organization and systemic violence. AB - BACKGROUND: Illicit drug markets are a key component of the risk environment surrounding injection drug use. However, relatively few studies have explored how injection drug users' (IDUs) involvement in drug dealing shapes their experiences of drug market-related harm. This exploratory qualitative study aims to understand IDUs' dealing activities and roles, as well as the perceived benefits and risks related to participation in illicit drug markets, including experiences of drug market violence. METHODS: Ten IDUs with extensive involvement in drug dealing activities were recruited from the Vancouver Injection Drug User Study (VIDUS) and participated in semi-structured qualitative interviews, which elicited discussion of experiences dealing drugs, perceived benefits and hazards related to dealing, and understandings of drug market violence. RESULTS: Participant's involvement in drug market activities included corporate sales, freelance or independent sales, and opportunistic sales termed "middling" as well as drug market-related hustles entailing selling bogus drugs and robbing dealers. Participants primarily dealt drugs to support their own illicit drug use, and we found that arrest and criminal justice involvement, hazards stemming from drug debts, and drug market-related violence were key risks related to dealing activities. CONCLUSION: The challenges of managing personal consumption while selling drugs exacerbates the hazards associated with drug dealing. Efforts to address drug dealing among IDUs should consider both drug dependency and the material conditions that propel drug users towards dealing activities. Interventions should explore the potential of combining enhanced drug treatment programs with low threshold employment and alternative income generation opportunities. PMID- 23664789 TI - Methods for population size estimation of problem drug users using a single registration. AB - BACKGROUND: The number of problem drug users is used as a key indicator to monitor the drug situation in the European Union. An alternative approach to estimate the number of problem drug users is given by 'the one-source capture recapture analysis' that uses a single registration. METHODS: Two variants of the one-source capture-recapture analysis were applied to a single registration: the truncated Poisson regression model (TPR) and the Zelterman regression model. These models were applied to data about clinical drug-related hospital admissions derived from the Dutch Hospital Registration (LMR). The TPR accounts for heterogeneity in capture probabilities by allowing for covariates and the Zelterman regression model relies on the problem drug users that were seen only once or twice in the hospital; the latter model is known to be robust against unobserved heterogeneity. RESULTS: The TPR model was found to have a bad fit due to unobserved heterogeneity. The Zelterman regression model estimated the population size at 10,415 problem drug users (95% CI is 8400-12,429). This figure is an estimate of the number of problem drug users who are at risk of a clinical hospital admission due to the medical consequences of their drug use. The model can also provide estimates of different subgroups of problematic drug users. CONCLUSION: The method presented here offers a promising alternative for estimating the number of problem drug users, including different subgroups of drug users. In addition, observed and unobserved heterogeneity can be accounted for in these estimates. PMID- 23664790 TI - Neurokinin-1 receptor-expressing neurons that contain serotonin and gamma aminobutyric acid in the rat rostroventromedial medulla are involved in pain processing. AB - The rostroventromedial medulla (RVM) is an important area of the endogenous pain regulating system, in which 5-hydroxytryptamine (5-HT) and gamma-aminobutyric acid (GABA) are 2 main transmitters involved in pain modulation. However, whether 5-HT and GABA are colocalized is poorly understood. By using glutamate decarboxylase 67-green fluorescence protein (GAD67-GFP) knock-in mouse, we confirmed the colocalization of 5-HT and GABA in the RVM, with a main distribution in the raphe magnus nucleus and paragigantocellular reticular nucleus. Interestingly, more than half (51.6%) of the 5-HT/GABA-immunoreactive (ir) neurons expressed neurokinin-1 receptors (NK-1R) and one-third (30.1%) of the 5-HT/GABA/NK-1R-ir neurons projected to the spinal cord, suggesting that substance P (SP) should regulate the activity of 5-HT/GABA-ir spinal cord projecting neurons. By combining retrograde and anterograde tracing methods, we observed that the cuneiform nucleus, dorsal raphe nucleus, and lateral periaqueductal gray are the main origin nuclei for the SP-ir fibers and terminals in the RVM. Finally, after formalin injection into the mice hind paw, 29.2% SP-ir RVM-projecting neurons from supra-RVM nuclei and 33.1% NK-1R-ir spinal cord projecting neurons in the RVM were activated. The present study provides potent morphological evidence that 5-HT and GABA are coexistent in RVM-spinal cord projecting neurons that are also regulated by SPergic projections. PERSPECTIVE: The results will greatly enhance our understanding for the modulation of nociceptive information in the descending pain-regulating system. PMID- 23664791 TI - Beta-ketothiolase deficiency and pregnancy. PMID- 23664792 TI - Human ghrelin decreases pituitary response to GnRH in superovulated ewes. AB - In addition to its metabolic role, ghrelin has been found to suppress luteinizing hormone secretion in many species acting mainly at the hypothalamic level. The objectives of the present study were to test the hypothesis that besides its effects on the hypothalamic level, ghrelin exerts a direct action on the pituitary. Twelve cycling ewes were synchronized, using progestagen intravaginal sponges and superovulated using eCG. At the time of sponge withdrawal, animals were allocated into two groups, ghrelin-treated (Gh) and control. Two days after the sponge removal, GnRH was given to synchronize ovulations. Simultaneously with GnRH treatment, animals of the Gh group received the first of four treatments of acylated human ghrelin at a dose of 6 MUg/kg body weight iv; three additional treatments of ghrelin iv were given every 15 minutes thereafter. Control animals received saline iv. Blood samples were collected before challenge (-30 and 0 minutes) and at 30, 60, 75, 90, 105, 120, 135, 150, and 180 minutes after GnRH treatment, and were analyzed for LH, FSH, estradiol, progesterone, insulin, and insulin-like growth factor-I concentrations. Ghrelin treatment attenuated GnRH induced a preovulatory surge of both gonadotrophins, with the effect being greater for LH. No difference was detected for insulin, estradiol, and progesterone concentrations, and insulin-like growth factor-I levels were increased in the Gh group. Our results imply that in sheep, ghrelin conducts specific regulatory effects on the GnRH/LH axis, and provide for the first time strong evidence that besides its central action, ghrelin might regulate gonadotrophin release acting at the pituitary level. PMID- 23664793 TI - An earlier rise in systemic progesterone and increased progesterone in the uterine vein during early pregnancy are associated with enhanced embryonic survival in the ewe. AB - Improved livestock production efficiency through greater embryonic survival (ES) is of economic and animal welfare benefit. Physiological characterization of animals that are extreme outliers for ES provides a valuable opportunity to identify a naturally occurring mechanism by which this trait may be enhanced. The objective was to determine the likely cause for the lifetime history of enhanced or reduced ES in a line of ewes selected for high fecundity. To address this question, progesterone concentrations in peripheral plasma as well as ovarian and uterine venous plasma samples were compared between groups of ewes with a lifetime history of either enhanced or reduced ES. The ability of the uterus to synthesize progesterone de novo at Day 5 of gestation was also tested. Ewes with enhanced ES had an earlier rise in progesterone concentration after estrus, irrespective of pregnancy status. In addition, there were increased concentrations of progesterone in the uterine vein in enhanced ES compared with reduced ES ewes on Day 5 of gestation (8.3 +/- 0.8 ng/mL and 3.9 +/- 1.4 ng/mL, respectively, P < 0.05). However, there were no differences in ovarian venous plasma (enhanced ES, 1725 +/- 166 ng/mL; reduced ES, 1665 +/- 268 ng/mL) at Day 5 of gestation. Although the endometrial tissue of some ewes (3/8) at Day 5 of gestation expressed three of the key genes necessary for regulation of de novo synthesis of progesterone, expression was not present exclusively in either of the two ES groups and therefore was unlikely to explain differences in the uterine vein progesterone concentrations between the enhanced and reduced ES groups. Collectively, the earlier rise in progesterone concentrations in peripheral plasma during the first week of gestation in the enhanced ES animals was independent of the presence of an embryo. Moreover, increased progesterone concentrations were also observed in the uterine vein at Day 5 of gestation of the enhanced ES ewes. It is proposed that the difference in uterine vein progesterone concentration was likely due to the differences in ovarian venous blood supply rather than de novo synthesis by the uterus. PMID- 23664794 TI - Influence of semen collection on salivary cortisol release, heart rate, and heart rate variability in stallions. AB - The aim of this study was to evaluate the stress response of stallions (n = 16) aged 3-13 years with previous sexual experience to semen collection by determination of heart rate, heart rate variability, and cortisol in saliva. Recordings were done on two consecutive days. The time intervals from leaving the box until arrival in the collection barn and from first exposure to the teaser mare until ejaculation as well as the number of mounts until ejaculation were neither affected by collection day nor by age, sexual experience (i.e., the number of breeding seasons the stallion experienced), or sexual workload of the stallion (i.e., the mean number of semen collections per week). Heart rate was continuously determined from 30 minutes before to 30 minutes after ejaculation and significantly increased in response to the semen collection procedure (P < 0.001). Changes in heart rate were significantly influenced by sexual experience (P < 0.01) and sexual workload (P < 0.05) but not by the age of the stallions. Day of semen collection did not have any effects. The heart rate variability variable root mean square of successive RR differences was not affected by semen collection procedures. Cortisol concentration in saliva was determined from 60 minutes before to 120 minutes after ejaculation and did not change significantly. The results indicate that semen collection is perceived as not more than a modest temporary stressor in sexually experienced and well-trained stallions. PMID- 23664795 TI - Sperm morphology, motility, and velocity in naturally occurring polyploid European weatherfish (Misgurnus fossilis L.). AB - Spontaneous polyploidy has been frequently documented in various fish species. This process may lead to disruption in testicular development and function. In the present study, sperm morphology and motility, elements critical to male fertility, were characterized in the naturally occurring triploid (3n) and tetraploid (4n) European weatherfish, Misgurnus fossilis L. (Teleostei, Cobitidae) inhabiting the upper reaches of the Luznice River in the Czech Republic. Sperm with smaller heads, shorter flagella, and a lower number of mitochondria was observed in 3n specimens compared with 4n, but no differences were observed in size of midpiece or ultrastructure of sperm. Similar to most teleosts, the European weatherfish spermatozoon lacked an acrosome and consisted of a head (containing DNA), a midpiece (containing mitochondria and proximal and distal centrioles), and a flagellum with 9 + 2 microtubular structure. Sperm velocity was significantly lower in individuals with 4n compared with 3n, whereas no difference in sperm motility was observed. The stepwise linear regression reported significant negative correlations between sperm velocity and length of sperm head (r = -0.92, P < 0.01). In conclusion, the data reported no effect of polyploidy on sperm ultrastructure and motility in the European weatherfish, although it can affect sperm velocity, possibly through differences in head size and the number of mitochondria, which provide ATP for sperm movement. PMID- 23664796 TI - Pitfalls in animal reproduction research: how the animal guards nature's secrets. AB - The estrous cycles of heifers and mares are used for illustrating pitfalls at the animal level in research in reproductive biology. Infrequent monitoring for characterizing the change in hormone concentrations or for detecting a reproductive event can be a pitfall when the interval for obtaining data exceeds the interval between events. For example, hourly collection of blood samples has shown that the luteolytic period (decreasing progesterone) encompasses 24 hours in heifers and mares. Collection of samples every 6-24 hours results in the illusion that luteolysis requires 2-3 days, owing to the occurrence of luteolysis on different days in individuals. A single treatment with PGF2alpha that causes complete regression of the corpus luteum is an example of an overdose pitfall. A nonphysiological progesterone increase occurs and will be misleading if used for making interpretations on the nature of luteolysis. A pitfall can also occur if a chosen reference point or end point is a poor representation of a physiological event. For example, if on a selected day after ovulation the animals in treatment A are closer on average to luteolysis than animals in treatment B, treatment A will appear to have had an earlier luteolytic effect. Among the techniques that are used directly in the animal, ultrasonography appears to be most prone to research pitfalls. Research during a given month can be confounded by seasonal effects, even in species that ovulate throughout the year. The presence of unknown factors or complex interactions among factors and the sensitivity of the animal to a research procedure separate from the direct effect of a treatment are also research challenges. A hidden factor should be considered nature's challenge to open-minded biologists but a pitfall for the close-minded. PMID- 23664797 TI - Operator experience reduces the risk of second trimester amniocentesis-related adverse outcomes. AB - OBJECTIVE: To investigate the impact of operator experience on amniocentesis related adverse outcomes. STUDY DESIGN: Retrospective study of mid-trimester amniocenteses performed by the same operator on singleton pregnancies in a single private institution during 1994-2007. Outcomes were hemorrhagic or dark amniotic fluid aspiration, insufficient volume aspiration, repeated puncture and fetal loss. Rates were estimated annually, as well as for every 10% of procedures up to the total number. The association of each outcome with epidemiological aspects was also examined. RESULTS: In total, 5913 amniocenteses were performed. The overall rate of adverse outcomes was 5.4%. The total adverse outcome rate reduced from 10.2% in the first 10% of cases to 3.0% in the last 10% (P=.001). The rate of hemorrhagic fluid gradually decreased from 4.4% to 1.5% (P=.05) over the same intervals. The fetal loss rate was also reduced from 0.5% during the first half to 0.3% in the second half of the study period (P=NS). Logistic regression analysis indicated no significant correlations between adverse outcomes with any of epidemiological parameters of women undergoing amniocentesis. CONCLUSION: Operator experience has a beneficial impact on preventing procedure-related adverse outcomes. PMID- 23664798 TI - Reliable support: Measuring calibration of likelihood ratios. AB - Calculation of likelihood ratios (LR) in evidence evaluation still presents major challenges in many forensic disciplines: for instance, an incorrect selection of databases, a bad choice of statistical models, low quantity and bad quality of the evidence are factors that may lead to likelihood ratios supporting the wrong proposition in a given case. However, measuring performance of LR values is not straightforward, and adequate metrics should be defined and used. With this objective, in this work we describe the concept of calibration, a property of a set of LR values. We highlight that some desirable behavior of LR values happens if they are well calibrated. Moreover, we propose a tool for representing performance, the Empirical Cross-Entropy (ECE) plot, showing that it can explicitly measure calibration of LR values. We finally describe some examples using speech evidence, where the usefulness of ECE plots and the measurement of calibration is shown. PMID- 23664799 TI - Usefulness of surgical glove dressing: a novel technique for skin graft fixation after hand burns. PMID- 23664800 TI - Accurately costing unilateral delayed DIEP flap breast reconstruction. AB - INTRODUCTION: Free tissue transfer for breast reconstruction is widely practiced in the UK and its availability forms part of the NICE guidelines in treating breast cancer. Free flap reconstruction scores highly on patient reported outcome measures for both immediate and delayed procedures. However there are significant resource implications and a concern that the financial burden is not adequately met by the fixed price tariff system (Payment by Results). This study aims to compare the cost of treatment with both local financial estimates and reimbursement. METHOD: We conducted a prospective costing analysis for 10 consecutive delayed unilateral DIEP breast reconstructions from August 2011 by a single surgeon in Frenchay Hospital, Bristol. Comparison was made to both the hospital's costing estimates and the Health Resource Group (HRG) tariffs received for 27 similar cases performed by the same surgeon in the 2010-11 financial year. RESULTS: The mean treatment cost for performing a delayed unilateral DIEP procedure was L7628 (+/-L754 Standard Deviation). This compared to an estimate from the financial department of L8072+/-(L1683 SD). These values were not significantly different (p=0.27). The HRG tariff was L8792 (+/-L423 SD). There was an average net income of L720 per case. Personnel in theatre represented the largest cost area at an average of 73% of total cost. CONCLUSIONS: This study highlights that the costs of this procedure have been estimated accurately by the financial department and that the current HRG code provides adequate reimbursement. The new HRG code for 2012-13, HRG JA14z, provides significantly less reimbursement at L7012 and measures need to be taken to address this. This study has identified that personnel costs are the greatest contributor to overall cost and allowed us to recognise and implement changes to improve efficiency. PMID- 23664801 TI - Single-stage management of huge desmoplastic ameloblastoma of the anterior mandible. PMID- 23664802 TI - Three-dimensional facial anthropometry of unilateral cleft lip infants with a structured light scanning system. AB - BACKGROUND: Cleft lip in the presence or absence of a cleft palate is a major public health problem. However, few studies have been published concerning the soft-tissue morphology of cleft lip infants. Currently, obtaining reliable three dimensional (3D) surface models of infants remains a challenge. The aim of this study was to investigate a new way of capturing 3D images of cleft lip infants using a structured light scanning system. In addition, the accuracy and precision of the acquired facial 3D data were validated and compared with direct measurements. STUDY DESIGN: Ten unilateral cleft lip patients were enrolled in the study. Briefly, 3D facial images of the patients were acquired using a 3D scanner device before and after the surgery. Fourteen items were measured by direct anthropometry and 3D image software. The accuracy and precision of the 3D system were assessed by comparative analysis. RESULTS: The anthropometric data obtained using the 3D method were in agreement with the direct anthropometry measurements. All data calculated by the software were 'highly reliable' or 'reliable', as defined in the literature. The localisation of four landmarks was not consistent in repeated experiments of inter-observer reliability in preoperative images (P<0.05), while the intra-observer reliability in both pre- and postoperative images was good (P>0.05). CONCLUSIONS: The structured light scanning system is proven to be a non-invasive, accurate and precise method in cleft lip anthropometry. PMID- 23664803 TI - RPM tracing for the detection of changes in lung tumor position: in response to Alderliesten et al. Radiother Oncol 2012;105(2):155-60. PMID- 23664805 TI - [Femoral vein and femoral artery catheters: complications associated with insertion and technical alternatives for prevention]. PMID- 23664804 TI - Intentional retrieval suppression can conceal guilty knowledge in ERP memory detection tests. AB - Brain-activity markers of guilty knowledge have been promoted as accurate and reliable measures for establishing criminal culpability. Tests based on these markers interpret the presence or absence of memory-related neural activity as diagnostic of whether or not incriminating information is stored in a suspect's brain. This conclusion critically relies on the untested assumption that reminders of a crime uncontrollably elicit memory-related brain activity. However, recent research indicates that, in some circumstances, humans can control whether they remember a previous experience by intentionally suppressing retrieval. We examined whether people could use retrieval suppression to conceal neural evidence of incriminating memories as indexed by Event-Related Potentials (ERPs). When people were motivated to suppress crime retrieval, their memory related ERP effects were significantly decreased, allowing guilty individuals to evade detection. Our findings indicate that brain measures of guilty knowledge may be under criminals' intentional control and place limits on their use in legal settings. PMID- 23664806 TI - Risk factors of recurrent seizure, co-morbidities, and mortality in new onset seizure in elderly. AB - OBJECTIVE: To determine the risk factors of seizure recurrence and the most common comorbidities in elderly patients with epilepsy. METHOD: We did a retrospective study of 278 patients older than 65 years with first seizure. We evaluated electrolytes, blood glucose, urea and creatinine levels, and performed electrocardiography (ECG), and routine electroencephalogram (EEG) on all patients. We evaluated seizure recurrence and comorbidities at 2 years. RESULTS: Univariate analysis found that significant (P<0.05) factors affecting seizure recurrence were etiology of seizure, EEG, and status epilepticus at first presentation. In multivariate regression analysis, etiology of seizure and EEG were significant statistical factors in seizure recurrence at 2 years follow up. Age, sex, duration of time between first seizure and diagnosis of seizure, seizure type, misdiagnosis of non-epileptic seizure, and use of antiepileptic drugs were not significant factors for predicting seizure recurrence. Depression and anxiety were the most common comorbidities in our study, followed by sleep related disorders and stroke. There were no statistically significantly differences in comorbidities between patients who remained seizure free and patients who had recurrent seizure. CONCLUSION: Most of the new onset seizures in our elderly patients were focal onset. Acute symptomatic etiology, remote symptomatic etiology, progressive symptomatic etiology and abnormal EEG features were powerful predictors of seizure recurrence, and mood disorder, sleep disorder and stroke were the common comorbidities. PMID- 23664807 TI - Etiologies of epilepsy and health-seeking itinerary of patients with epilepsy in a resource poor setting: analysis of 342 Nigerian Africans. AB - PURPOSE: The understanding of causation of epilepsy, especially in resource poor African countries where prevalence rates are very high, would aid strategies for primary prevention. This study sought to determine the causes of epilepsy in Nigerian Africans and health-itinerary of patients with epilepsy. METHOD: This was an observational, cross-sectional descriptive study of consecutive newly diagnosed adult patients with epilepsy using a mixed-methods approach of face-to face in-depth interview of patients' parents and relations, health care personnel who had given medical attention at any time and telephone interview. A structured interview schedule was used to obtain demographic information, details of seizure variables, health seeking itinerary and history of previous hospitalizations. Data was analyzed descriptively with SPSS version 17. RESULTS: Three hundred and forty-two patients with epilepsy with a mean age of 31.4+/-11.98 years participated in the study. Most of the patients (68.1%; 233/342) were unemployed and students. There were 270 (78.9%) patients with generalized epilepsy. No identifiable etiology was found in 37.7%, but of the remaining 62.3%, the commonest causes included post traumatic (19.6%), recurrent childhood febrile convulsions (13.2%), post-stroke (6.7%), brain tumors (5.9%), neonatal jaundice (5.3%), birth-related asphyxia (5%) and history of previous CNS infections (4.7%). Family history of epilepsy was obtained in 9.9%, all of whom had primarily generalized seizures. 61.4% of them sought initial attention from the traditional healers or in prayer houses. CONCLUSION: This study showed the pattern of causes of epilepsy in Nigerian Africans. The health seeking behavior and itinerary of the PWE revealed a preference for traditional healers. There is need for health policies and epilepsy awareness campaigns to prevent causes of seizures and improve the knowledge of the public respectively. PMID- 23664808 TI - Translumbar hemodialysis catheters in patients with limited central venous access: does patient size matter? AB - PURPOSE: To describe a single institutional experience with translumbar tunneled dialysis catheters (TDC) and compare outcomes between patients with normal and abnormal body mass index (BMI). MATERIALS AND METHODS: Translumbar TDCs placed between January 2002 and July 2011 were reviewed retrospectively. There were 33 patients; 18 had a normal BMI<25, and 15 had an abnormal BMI>25. Technical outcome, complications, indications for exchange or removal, and BMI were recorded. Catheter dwell time, catheter occlusion rate, frequency of malposition, and infection rates were collected. RESULTS: There were 92 procedures (33 initial placements) with 7,825 catheter days. The technical success rate was 100%. Two minor (2.2%) and three major (3.3%) complications occurred. The complication rate did not differ significantly between patients with a normal BMI and patients with an abnormal BMI. Median catheter time in situ (interquartile range) for all patients was 61 (113) days, for patients with normal BMI was 66 (114) days, and for patients with abnormal BMI was 56 (105) days (P = .9). Primary device service intervals for all patients, patients with normal BMI, and patients with abnormal BMI were 47 (96) days, 63 (98) days, and 39 (55) days (P = .1). Secondary device service intervals for all patients, patients with normal BMI, and patients with abnormal BMI were 147 (386) days, 109 (124) days, and 409 (503) days (P = .23). Catheter-related central venous thrombosis rate was 0.01 per 100 catheter days (n = 1). CONCLUSIONS: Translumbar TDC placement can provide effective hemodialysis in patients with limited venous reserve regardless of the patient's BMI. An abnormal BMI (>25) does not significantly affect complication rate, median catheter time in situ, or primary or secondary device service interval of translumbar TDCs. PMID- 23664809 TI - Adjuvant liposomal doxorubicin markedly affects radiofrequency ablation-induced effects on periablational microvasculature. AB - PURPOSE: To evaluate the effects of radiofrequency (RF) ablation without and with adjuvant intravenous (IV) liposomal doxorubicin (Doxil) on microvessel morphology and patency and intratumoral drug delivery and retention. MATERIALS AND METHODS: There were 133 tumors/animals used in this experiment. First, single subcutaneous tumors (R3230 in Fischer rats and 786-0 in nude mice) were randomly assigned to receive RF ablation alone or no treatment and sacrificed 0-72 hours after treatment. Next, combined RF ablation and liposomal doxorubicin (1 mg given 15 min after RF ablation) was studied in R3230 tumors at 0-72 hours after treatment. Histopathologic assessment, including immunohistochemical staining for cleaved caspase-3, heat-shock protein 70, and CD34, was performed to assess morphologic vessel appearance, vessel diameter, and microvascular density. Subsequently, tumors were randomly assigned to receive RF ablation alone, RF ablation and liposomal doxorubicin, or no treatment (control tumors), followed by IV fluorescent-labeled liposomes (a surrogate marker) given 0-24 hours after RF ablation to permit qualitative assessment. RESULTS: RF ablation alone resulted in enlarged and dysmorphic vessels from 0-4 hours, peaking at 12-24 hours after RF ablation, occurring preferentially closer to the electrode. The addition of doxorubicin resulted in earlier vessel contraction (mean vessel area, 47,539 MUm(2)+/-9,544 vs 1,854 MUm(2)+/-458 for RF ablation alone at 15 min; P<.05). Combined RF ablation and liposomal doxorubicin produced similar fluorescence 1 hour after treatment (40.88 AU/MUm(2)+/-33.53 vs 22.1 AU/MUm(2)+/-13.19; P = .14) but significantly less fluorescence at 4 hours (24.3 AU/MUm(2)+/-3.65 vs 2.8 AU/MUm(2)+/-3.14; P<.002) compared with RF ablation alone denoting earlier reduction in microvascular patency. CONCLUSIONS: RF ablation induces morphologic changes to vessels within the ablation zone lasting 12-24 hours after treatment. The addition of liposomal doxorubicin causes early vessel contraction and a reduction in periablational microvascular patency. Such changes would likely need to be considered when determining optimal drug administration and imaging paradigms. PMID- 23664811 TI - Peptides and peptide-derived molecules targeting the intracellular domains of Cx43: gap junctions versus hemichannels. AB - About a decade ago, the molecular determinants controlling the opening and closing of Cx43 gap junction channels have been identified. Advanced biophysical approaches revealed a critical role for structural rearrangements in the cytoplasmic loop and dimerization of the C-terminal tail, resulting in binding of the C-terminal tail to the cytoplasmic loop and Cx43 gap junction channel closure during cellular acidosis. This has spurred the development of Cx43-mimetic peptides and peptidomimetics that interfere with these loop/tail interactions, thereby preventing the closure of Cx43 gap junctions, e.g. in the heart upon ischemia. Recently, we found that loop/tail interactions control Cx43-hemichannel activity but with an opposite effect. Binding of the C-terminal tail to the cytoplasmic loop is a requisite for the opening of Cx43 hemichannels in response to different stimuli, like decreased extracellular [Ca2+], increased intracellular [Ca2+], positive membrane potentials or ischemia. Strikingly, peptides that favor the open state of Cx43 gap junctions like the L2 peptide inhibit Cx43-hemichannel opening. These tools now provide unprecedented opportunities to selectively inhibit Cx43 hemichannels while maintaining Cx43 gap junction communication, impossible to achieve with siRNA or knockdown approaches both affecting gap junctions and hemichannels. These tools not only are very helpful to unravel the role of Cx43 hemichannels in complex biological systems, but also hold therapeutic potential to counteract excessive Cx43-hemichannel activity like in ischemia/reperfusion in the brain and the heart or to prevent Cx43 hemichannel-mediated gliotransmitter release in the basal amygdala during memory consolidation in response to emotional events. This article is part of the Special Issue Section entitled 'Current Pharmacology of Gap Junction Channels and Hemichannels'. PMID- 23664810 TI - Neurocircuitry of drug reward. AB - In recent years, neuroscientists have produced profound conceptual and mechanistic advances on the neurocircuitry of reward and substance use disorders. Here, we will provide a brief review of intracranial drug self-administration and optogenetic self-stimulation studies that identified brain regions and neurotransmitter systems involved in drug- and reward-related behaviors. Also discussed is a theoretical framework that helps to understand the functional properties of the circuitry involved in these behaviors. The circuitry appears to be homeostatically regulated and mediate anticipatory processes that regulate behavioral interaction with the environment in response to salient stimuli. That is, abused drugs or, at least, some may act on basic motivation and mood processes, regulating behavior-environment interaction. Optogenetics and related technologies have begun to uncover detailed circuit mechanisms linking key brain regions in which abused drugs act for rewarding effects. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23664812 TI - Differential roles of mGlu(7) and mGlu(8) in amygdala-dependent behavior and physiology. AB - Glutamate transmission and synaptic plasticity in the amygdala are essential for the learning and expression of conditioned fear. Glutamate activates both ionotropic glutamate receptors and eight subtypes of metabotropic glutamate receptors (mGlu1-8). In the present study, we investigated the roles of mGlu7 and mGlu8 in amygdala-dependent behavior and synaptic plasticity. We show that ablation of mGlu7 but not mGlu8 attenuates long-term potentiation (LTP) at thalamo-lateral amygdala (LA) synapses where a strong association between LTP and learning has been demonstrated. mGlu7-deficient mice express a general deficit in conditioned fear whereas mGlu8-deficient mice show a dramatic reduction in contextual fear. The mGlu7 agonist AMN082 reduced thalamo-LA LTP and intra amygdala administration blocked conditioned fear learning. In contrast, the mGlu8 agonist DCPG decreased synaptic transmission but not LTP at thalamo-LA synapses. Intra-amygdala DCPG selectively reduced the expression of contextual fear but did not affect the acquisition and expression of cued fear. Taken together, these data revealed very different roles for mGlu7 and mGlu8 in amygdala synaptic transmission, fear learning and its expression. These receptors seem promising targets for treating anxiety disorders with different underlying pathologies with exaggerated fear learning (mGlu7) or contextual fear (mGlu8). PMID- 23664813 TI - Shaping neurons: Long and short range effects of mature and proBDNF signalling upon neuronal structure. AB - Both mature BDNF and its precursor, proBDNF, play a crucial role in shaping neurons and contributing to the structural basis for neuronal connectivity. They do so in a largely opposing manner, and through differential engagement with their receptors. In this review, we will summarise the evidence that BDNF modulates neural circuit formation in vivo both within the central and peripheral nervous systems, through the control of neuronal morphology. The underlying intracellular mechanisms that translate BDNF signalling into changes of neuronal cell shape will be described. In addition, the signalling pathways that act either locally at the site of BDNF action, or over long distances to influence gene transcription will be discussed. These mechanisms begin to explain the diversity of actions that BDNF carries out on neuronal morphology. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'. PMID- 23664814 TI - Effect of tapentadol on neurons in the locus coeruleus. AB - Tapentadol is a novel centrally acting drug that combines mu-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI), producing analgesic effects in various painful conditions. We investigated the acute effects of tapentadol in the locus coeruleus (LC), a central nucleus regulated by the noradrenergic and opioid systems that is critical in pain modulation. In single unit extracellular recordings of LC neurons from anaesthetized male Sprague Dawley rats, tapentadol clearly inhibited the spontaneous electrophysiological activity of LC neurons in a dose-dependent manner (ED50 = 0.8 mg/kg). This inhibitory effect was reversed by RX821002 (an alpha2-adrenoceptor antagonist) and naloxone (a mu-opioid receptor antagonist) by 96.7% and 28.2%, respectively. Pretreatment with RX821002, N-ethoxycarbonyl-2-ethoxy-1-2-dihydroquinoline (EEDQ, an irreversible alpha2-adrenoceptor antagonist) or naloxone shifted the tapentadol dose-effect curve to the right (ED50 = 2.2 mg/kg, 2.0 mg/kg and 2.1 mg/kg, respectively). Furthermore, tapentadol inhibited the LC response to mechanical stimulation of the hindpaw in a dose-dependent manner. In summary, we demonstrate that acute administration of tapentadol inhibits LC neurons in vivo, mainly due to the activation of alpha2-adrenoceptors. These data suggest that both the noradrenergic and opioid systems participate in the inhibitory effect of tapentadol on LC neurons, albeit to different extents, which may account for its potent analgesic effect and mild opioidergic side-effects. PMID- 23664815 TI - Gay men seeking surrogacy to achieve parenthood. AB - Assisted reproduction technologies have developed at an extraordinary rate in recent years. This, combined with the changing landscape of legal, technical and social possibilities, enables gay men to consider their options for fatherhood as new opportunities emerge for them to create families. Media coverage of gay celebrities embracing surrogacy as a way of having a family and high-profile legal cases have raised awareness of surrogacy across the world. However, gay fatherhood achieved through assisted reproduction is a highly under-researched area, both in the UK and internationally. The research that currently exists on gay fatherhood is largely related to gay men who become parents through processes such as adoption and fostering and children conceived through previous heterosexual relationships. Much of this evidence has centred on parenting experiences, the outcomes for children or the legal perspectives. This paper outlines the different types of surrogacy and the legal issues facing gay men who choose this route to parenthood, summarizes the limited research on gay men and surrogacy and discusses gaps in the current knowledge base. PMID- 23664816 TI - Karyotype determination and reproductive guidance for short stature women with a hidden Y chromosome fragment. AB - Two unrelated couples came to the Reproductive and Genetic Hospital of Citic Xiangya to ask for reproductive guidance. One couple had an affected son and the other couple had secondary infertility. Conventional GTG banding showed that the women in both couples had a 46,X,add(X)(p22) karyotype. Further molecular cytogenetic studies showed that both women had a 46,X,der(X)t(X;Y)(p22;q11.2) karyotype and that the affected boy had inherited the derivative X chromosome, which resulted in an Xp contiguous gene syndrome. After an assessment of reproductive risk, the first couple conceived naturally and opted for prenatal diagnosis (PND) by amniocentesis. No abnormal karyotypes were found for the twin pregnancy and healthy twin girls were born after a full-term normal pregnancy. The second couple chose to undergo IVF with preimplantation genetic diagnosis (PGD). Two PGD cycles were performed by fluorescence in-situ hybridization. In the first PGD cycle, all three embryos had abnormal hybridization signals. In the second cycle, a male embryo with normal hybridization signals was transferred into the womb and a normal pregnancy was achieved. The results show the importance of detecting the derivative chromosome followed by PND or PGD if a woman carries an Xp;Yq translocation. PMID- 23664817 TI - Ovarian stimulation leads to a severe implantation defect in mice. AB - The aim of the present study was to evaluate whether ovarian stimulation could induce embryo implantation dysfunction in mice and to explore the possible mechanisms involved. Ovarian stimulation was performed with intraperitoneal injections of 0, 2.5, 5.0, 7.5 and 10.0 IU pregnant mare serum gonadotrophin followed by the same dose of human chorionic gonadotrophin 48h later. A dose dependent implantation defect in stimulated mice was demonstrated, which can be mainly explained by premature luteolysis and secondary endometrial changes induced by an imbalance in oestradiol and progesterone. PMID- 23664818 TI - Convergence of FPR-rs3-expressing neurons in the mouse accessory olfactory bulb. AB - In the mouse, most members of the FPR receptor family are expressed by vomeronasal sensory neurons. The neural circuitry corresponding to this class of chemical sensors is unknown. Taking advantage of the presence of FPR-rs3 on both vomeronasal dendrites and axonal fibers, we visualized the distribution of sensory cells expressing this member of the FPR family, and their corresponding axonal projections in the olfactory bulb. We found a rostrocaudal gradient of receptor choice frequency in the vomeronasal sensory neuroepithelium, and observed a convergence of FPR-rs3 axons into multiple, linked and deeply located glomeruli. These were homogenously innervated, and spatially restricted to the basal portion of the rostral accessory olfactory bulb. This organization, reminiscent of the one that characterizes axonal projections of V1R-expressing neurons, supports a role played by these receptors in the perception of semiochemicals. PMID- 23664819 TI - Intraductal therapy of ductal carcinoma in situ: a presurgery study. AB - INTRODUCTION: Ductal carcinoma in situ (DCIS) is a noninvasive breast cancer wherein malignant cells are confined within a ductal lobular unit. Although less than half the cases of DCIS will progress to invasive disease, most women are treated aggressively with surgery, radiation, and/or hormone therapy due to the inability to clinically evaluate the extent and location of the disease. Intraductal therapy, in which a drug is administered directly into the mammary duct through the nipple, is a promising approach for treating DCIS, but the feasibility of instilling drug into a diseased duct has not been established. PATIENTS AND METHODS: Four to 6 weeks before their scheduled surgery, 13 women diagnosed with DCIS were subjected to cannulation of the affected duct. After both the absence of perforation and presence of dye in the duct were confirmed by ductogram, pegylated liposomal doxorubicin was instilled. Histopathologic assessment was performed after surgery to assess the treatment effects. RESULTS: Of the 13 women enrolled in the study, 6 had their DCIS duct successfully cannulated without perforation and instilled with the drug. The treatment was well tolerated, and no serious adverse events have been reported. Biomarker studies indicated a general decrease in Ki-67 levels but an increase in annexin-1 and 8-hydroxydeoxyguanosine in the lumen of DCIS-containing ducts, which suggests a local response to pegylated liposomal doxorubicin treatment. CONCLUSIONS: Intraductal therapy offers a nonsurgical strategy to treat DCIS at the site of disease, potentially minimizing the adverse effects of systemic treatment while preventing development of invasive cancer. PMID- 23664820 TI - A negative confirmatory biopsy among men on active surveillance for prostate cancer does not protect them from histologic grade progression. AB - BACKGROUND: Many men (21-52%) are reported to have no cancer on the second, also known as the confirmatory, biopsy (B2) for prostate cancer active surveillance (AS). If these men had a reduced risk of pathologic progression, particularly grade related, the intensity of their follow-up could be decreased. OBJECTIVE: To investigate if men with no cancer on B2 are less likely to undergo subsequent pathologic progression. DESIGN, SETTING, AND PARTICIPANTS: Men were identified from our tertiary care center AS prostate cancer database (1995-2012). Eligibility criteria were prostate-specific antigen (PSA) <= 10, cT2 or lower, no Gleason grade 4 or 5, three or fewer positive cores, and no core >50% involved. Only patients with three or more biopsies were selected and then dichotomized on cancer status (yes or no) at B2. INTERVENTION AS OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Pathologic progression was defined as grade (advancement in Gleason score) and/or volume (more than three positive cores, >50% core involved). Progression-free survival was compared. Predictors of progression were investigated using a Cox proportional hazards model. RESULTS AND LIMITATIONS: Of the 286 patients remaining on AS after B2, 149 (52%) had no cancer and 137 (48%) had cancer. The median follow-up after B2 was 41 mo (interquartile range [IQR]: 26.5-61.9). Progression-free survival at 5 yr was 85.2% versus 67.3% for negative B2 versus cancer on B2, respectively (p = 0.002). Men with no cancer at B2 had a 53% reduction in risk of subsequent progression (hazard ratio [HR]: 0.47; 95% confidence interval [CI], 0.29-0.77; p = 0.003). Subanalysis showed prognostic indicators of volume-related progression were absence of cancer (HR: 0.36; 95% CI, 0.20-0.62; p = 0.0006) and PSA density (HR: 1.79; 95% CI, 1.12-2.89; p = 0.01). The only predictor of grade-related progression was age (HR: 1.05; 95% CI, 1.00-1.10; p = 0.04). Retrospective analysis was the major limitation of the study. CONCLUSIONS: Absence of cancer on B2 is associated with a significantly decreased risk of volume-related but not grade-related progression. This must be considered when counseling men on AS. PMID- 23664822 TI - Uterine sarcomas: review of 26 years at The Instituto Nacional de Cancerologia of Mexico. AB - Uterine sarcomas are a group of uncommon tumors that account for approximately 1% of malignant neoplasms of the female genital tract and between 3 and 8.4% of malignant uterine neoplasms. OBJECTIVE: To evaluate the factors associated with the clinical behavior of uterine sarcomas. MATERIALS AND METHODS: In the period from October 1983 to December 2009, clinical files of patients with a confirmed diagnosis of uterine sarcoma at the National Institute of Cancerology of Mexico (INCan) were reviewed and evaluated. RESULTS: We identified 77 cases with complete information; average age at presentation was 51.6 years (range, 14-78 years); most frequent histology was leiomyosarcoma (LMS) in 53/77 (68.8%) cases; most frequent symptom reported at the time of diagnosis was abnormal vaginal bleeding in 36/77 (46.7%) cases, and the most frequent clinical stage was clinical stage (CS) I in 31/77 (40.2%) cases. Initial treatment was total abdominal hysterectomy (TAH) and bilateral salpingo-oophrectomy (BSO) in 53/77 (68.9%) cases. Disease-free period was 27.8 months (range, 0-184 months), with disease recurrence in 33/77 (42.85%) cases, most frequent site as lung in 13/33 (39.39%) cases. Management of recurrences was surgery and chemotherapy (CT) in 5/33 (15.15%) and CT in 10/33 (30.30%) of cases. At present, 40.3% of the patients (31/77) are found to be Disease-free. CONCLUSION: Notwithstanding that uterine sarcomas are aggressive neoplasms, most accepted management to date is TAH + BSO, observing that the fact that this procedure is not performed by oncologists does not affect the DFP nor OS, contrary to what occurs in other gynecological neoplasms. PMID- 23664823 TI - False positive control of activated voxels in single fMRI analysis using bootstrap resampling in comparison to spatial smoothing. AB - Functional magnetic resonance imaging (fMRI) is an effective tool for the measurement of brain neuronal activities. To date, several statistical methods have been proposed for analyzing fMRI datasets to select true active voxels among all the voxels appear to be positively activated. Finding a reliable and valid activation map is very important and becomes more crucial in clinical and neurosurgical investigations of single fMRI data, especially when pre-surgical planning requires accurate lateralization index as well as a precise localization of activation map. Defining a proper threshold to determine true activated regions, using common statistical processes, is a challenging task. This is due to a number of variation sources such as noise, artifacts, and physiological fluctuations in time series of fMRI data which affect spatial distribution of noise in an expected uniform activated region. Spatial smoothing methods are frequently used as a preprocessing step to reduce the effect of noise and artifacts. The smoothing may lead to a shift and enlargement of activation regions, and in some extend, unification of distinct regions. In this article, we propose a bootstrap resampling technique for analyzing single fMRI dataset with the aim of finding more accurate and reliable activated regions. This method can remove false positive voxels and present high localization accuracy in activation map without any spatial smoothing and statistical threshold setting. PMID- 23664821 TI - Neural structures underlying set-shifting: roles of medial prefrontal cortex and anterior cingulate cortex. AB - Impaired attentional set-shifting and inflexible decision-making are problems frequently observed during normal aging and in several psychiatric disorders. To understand the neuropathophysiology of underlying inflexible behavior, animal models of attentional set-shifting have been developed to mimic tasks such as the Wisconsin Card Sorting Task (WCST), which tap into a number of cognitive functions including stimulus-response encoding, working memory, attention, error detection, and conflict resolution. Here, we review many of these tasks in several different species and speculate on how prefrontal cortex and anterior cingulate cortex might contribute to normal performance during set-shifting. PMID- 23664824 TI - MRI allows for longitudinal quantitative analysis of body fat composition in rats: an analysis of sibutramine-associated changes at the group level. AB - PURPOSE: Body fat distribution changes are associated with multiple alterations in metabolism. Therefore, the assessment of body fat compartments by MRI in animal models is a promising approach to obesity research. Standard T1-weighted (T1w) whole body MRI was used here to quantify different effects in the subcutaneous and visceral fat compartments in rats under treatment with an anorexiant. MATERIALS AND METHODS: Twenty rats on a high caloric diet were investigated by the identical MRI protocol at baseline and after seven weeks. Ten rats received a treatment with sibutramine, 10 rats served as vehicle control group. To longitudinally assess body fat components, MRI analysis was used with two approaches: 2D slicewise graphic analysis (SGA) was compared with an automated 3D analysis algorithm (3DA). RESULTS: At the group level, fat volume differences showed a longitudinal increase of subcutaneous and visceral fat volumes for the control group, whereas the sibutramine group showed stable subcutaneous fat volumes and decrease in visceral fat volumes. SGA and 3DA volume determination showed significant correlations for subcutaneous fat volume (C=0.85, p<0.001), visceral fat volume (C=0.87, p<0.001), and total fat volume (C=0.90, p<0.001). CONCLUSION: It could be demonstrated that computer-based analysis of T1w MRI could be used to longitudinally assess changes in body fat compartments in rats at the group level. In detail, it was possible to investigate the effect of sibutramine separate on the fat compartments in rats. PMID- 23664825 TI - Cupulolithiasis of the posterior semicircular canal. AB - BACKGROUND: We sometimes experience patients with persistent torsional/vertical (upbeating) positional nystagmus in the head-hanging position. We have been convinced of the existence of cupulolithiasis of the posterior semicircular canal because such cases reveal persistent torsional/vertical (downbeating) positional nystagmus in the nose-down position. PURPOSE: In order to confirm the validity of Ewald's third law, we quantified the difference between positional nystagmus in the head-hanging position and that in the nose-down position. METHODS: The subjects were 10 patients with posterior cupulolithiasis, 9 female and 1 male, with a mean age of 58.9years. Nystagmus was recorded using an infrared camera and the findings were converted to digital data. Using ImageJ, we performed three dimensional video-oculography and measured the maximum slow-phase velocity (MSV) of three components. RESULTS: In the horizontal component, the mean value of MSV in the head-hanging position was 3 degrees /s, and that in the nose-down position was 2.7 degrees /s. There was no significant difference between the two positions. In the vertical component, the mean value of MSV in the head-hanging position was 4.3 degrees /s, and that in the nose-down position was 6 degrees /s. There was no significant difference between the two positions. In the torsional component, the mean value of MSV in the head-hanging position was 4.4 degrees /s, and that in the nose-down position was 1.4 degrees /s. The former was significantly greater than the latter (p<0.01). CONCLUSIONS: Although we could not confirm the validity of Ewald's third law, the torsional component in the head-hanging position was significantly greater than that in the nose-down position. PMID- 23664826 TI - "Do no harm": fortifying MDT collaboration in changing technological times. AB - PURPOSE: To examine the changes in multidisciplinary medical team activity and practices, with respect to the amount of patient cases, the information needs and technology used, with up to 10 multidisciplinary teams (MDTs) in a large teaching hospital over a 10-year period. METHODS: An investigation of MDT meeting activity was undertaken in November 2005 and repeated in November 2012 for the MDTs at a large university teaching hospital. Analysis of data from 8 MDTs was informed through long-term ethnographical study, and supplemented with 38 semi-structured interviews and a survey from 182 staff members of MDTs. RESULTS: Work rhythms change over time as a function of the volume of work and technology changes, such as the use of a picture archive and communication system (PACS), videoconferencing and an electronic patient record (EPR). Maintaining cohesive teamwork, system dependability, and patient safety in the context of rapid change is challenging. CONCLUSIONS: Benefits of MDT work are in evidence, but the causes are not fully understood. Instead of asking 'how can technology support more MDT activity?', we ask 'how can we preserve the benefits of human-human interaction in an increasingly technological environment?' and 'how can we ensure that we do no harm?' when introducing technology to support an increasingly demanding collaborative work setting. Introducing technology to streamline work might instead threaten the experienced improvement in patient services. PMID- 23664827 TI - In vivo skin biophysical behaviour and surface topography as a function of ageing. AB - Normal skin ageing is characterised by an alteration of the underlying connective tissue with measurable consequences on global skin biophysical properties. The cutis laxa syndrome, a rare genetic disorder, is considered as an accelerated ageing process since patients appear prematurely aged due to alterations of dermal elastic fibres. In the present study, we compared the topography and the biomechanical parameters of normal aged skin with an 17 year old cutis laxa patient. Skin topography analyses were conducted on normal skin at different ages. The results indicate that the skin relief highly changes as a function of ageing. The cutaneous lines change from a relatively isotropic orientation to a highly anisotropic orientation. This reorganisation of the skin relief during the ageing process might be due to a modification of the skin mechanical properties, and particularly to a modification of the dermis mechanical properties. A specific bio-tribometer, based on the indentationtechnique under light load, has been developed to study the biophysical properties of the human skin in vivo through two main parameters: the physico-chemical properties of the skin surface, by measuring the maximum adhesion force between the skin and the bio-tribometer; and the bulk mechanical properties. Our results show that the pull-off force between the skin and the biotribometer as well as the skin Young's modulus decrease with age. In the case of the young cutis laxa patient, the results obtained were similar to those observed for aged individuals. These results are very interesting and encouraging since they would allow the monitoring of the cutis laxa skin in a standardised and non-invasive way to better characterize either the evolution of the disease or the benefit of a treatment. PMID- 23664828 TI - Microdeletion syndromes. AB - The recent explosion in the implementation of genome-wide microarray technology to discover rare, pathogenic genomic rearrangements in a variety of diseases has led to the discovery of numerous microdeletion syndromes. It is now clear that these microdeletions are associated with extensive phenotypic heterogeneity and incomplete penetrance. A subset of recurrent microdeletions underpin diverse phenotypes, including intellectual disability, autism, epilepsy and neuropsychiatric disorders. Recent studies highlight a role for additional low frequency variants, or 'second hits' to account for this variability. The implementation of massively parallel sequencing and epigenetic models may provide a powerful prospective approach to the delineation of microdeletion syndrome phenotypes. PMID- 23664829 TI - [Immunophenotypic classification of 3 cases of hepatocellular adenoma. Differential diagnosis with focal nodular hyperplasia]. AB - Interest in adenomas has been renewed by the discovery of the molecular changes in these tumors. The latest World Health Organization publication on gastrointestinal tract tumors (2010) includes four types of hepatic adenomas, which are well characterized immunohistochemically, genotypically and phenotypically. In these tumors, medical history and morphological behavior play an important role in determining the risk of malignancy, mainly in adenomas with a b-catenin mutation. The presence of steatosis, inflammation, vascular changes linked to response to L-FABP, serum amyloid A, and glutamyl synthetase help to classify these tumors into four groups: hepatocellular adenomas with the HNF1A mutation (H-HCA), those with the b-catenin mutation (b-HCA), inflammatory HCA (IHCA), and HCA without markers. The absence of glypican 3 expression, HSP 70 and perivenular mapping of glutamyl synthetase helps to distinguish these tumors from well differentiated hepatocellular carcinoma. We describe the clinical, morphological and immunophenotypic features of three patients diagnosed with hepatic adenomas in a 2-year period. PMID- 23664830 TI - Apocynin, an NADPH oxidase inhibitor, suppresses progression of prostate cancer via Rac1 dephosphorylation. AB - Recently, considerable evidence has been generated that oxidative stress contributes to the etiology and pathogenesis of prostate cancer. The present study focused on the effects of apocynin, an inhibitor of the NADPH oxidase which generates intracellular superoxide, on a rat androgen-independent prostate cancer cell line (PLS10) in vitro and in vivo. Apocynin significantly inhibited cell proliferation of PLS10 cells via G1 arrest of the cell cycle in vitro. Surprisingly, it did not affect reactive oxygen species (ROS) but inhibited phosphorylation of Rac1, one component of the NADPH oxidase complex. A Rac1 inhibitor, NSC23766, also inhibited cell proliferation, and both apocynin and NSC23766 reduced phosphorylation of Rac1 and NF-kappaB, as well as cyclin D1. Furthermore, in a xenograft model of prostate cancer with PLS10, apocynin suppressed tumor growth and metastasis in a dose dependent manner in vivo, with reduction of cell proliferation and vessel number in the tumors. Expression and secretion of vascular endothelial growth factor (VEGF) were reduced by apocynin treatment in vivo and in vitro, respectively. In conclusion, despite no apparent direct relationship with oxidative stress, apocynin inhibited growth of androgen independent prostate cancer in vitro and in vivo. Apocynin thus warrants further attention as a potential anti-tumor drug. PMID- 23664831 TI - Adaptive colouration in amphibians. AB - Amphibians, i.e. salamanders, frogs and caecilians show a wide range of bright colours in combination with contrasting patterns. There is variation among species, populations and also within species and populations. Furthermore, individuals often change colours during developmental stages or in response to environmental factors. This extraordinary variation means that there are excellent opportunities to test hypotheses of the adaptive significance of colours using amphibian species as models. We review the present view of functions of colouration in amphibians with the main focus on relatively unexplored topics. Variation in colouration has been found to play a role in thermoregulation, UV protection, predator avoidance and sexual signalling. However, many proposed cases of adaptive functions of colouration in amphibians remain virtually scientifically unexplored and surprisingly few genes influencing pigmentation or patterning have been detected. We would like to especially encourage more studies that take advantage of recent developments in measurement of visual properties of several possible signalling receivers (e.g. predators, competitors or mates). Future investigations on interactions between behaviour, ecology and vision have the potential to challenge our current view of the adaptive function of colouration in amphibians. PMID- 23664832 TI - IRF4 transcription-factor-dependent CD103(+)CD11b(+) dendritic cells drive mucosal T helper 17 cell differentiation. AB - CD103(+)CD11b(+) dendritic cells (DCs) represent the major migratory DC population within the small intestinal lamina propria (SI-LP), but their in vivo function remains unclear. Here we demonstrate that intestinal CD103(+)CD11b(+) DC survival was dependent on interferon regulatory factor 4 (IRF4). Mice with a DC deletion in Irf4 displayed reduced numbers of intestinal interleukin 17 (IL-17) secreting helper T 17 (Th17) cells and failed to support Th17 cell differentiation in draining mesenteric lymph nodes (MLN) following immunization. The latter was associated with a selective reduction in CD103(+)CD11b(+) MLN DCs and DC derived IL-6. Immunized Il6(-/-) mice failed to support Th17 cell differentiation in MLN in vivo and CD103(+)CD11b(+) MLN DCs supported IL-6 dependent Th17 cell differentiation in vitro. Together, our results suggest a central role for IRF4-dependent, IL-6 producing CD103(+)CD11b(+) DCs in intestinal Th17 cell differentiation. PMID- 23664833 TI - The encoding of vowels and temporal speech cues in the auditory cortex of professional musicians: an EEG study. AB - Here, we applied a multi-feature mismatch negativity (MMN) paradigm in order to systematically investigate the neuronal representation of vowels and temporally manipulated CV syllables in a homogeneous sample of string players and non musicians. Based on previous work indicating an increased sensitivity of the musicians' auditory system, we expected to find that musically trained subjects will elicit increased MMN amplitudes in response to temporal variations in CV syllables, namely voice-onset time (VOT) and duration. In addition, since different vowels are principally distinguished by means of frequency information and musicians are superior in extracting tonal (and thus frequency) information from an acoustic stream, we also expected to provide evidence for an increased auditory representation of vowels in the experts. In line with our hypothesis, we could show that musicians are not only advantaged in the pre-attentive encoding of temporal speech cues, but most notably also in processing vowels. Additional "just noticeable difference" measurements suggested that the musicians' perceptual advantage in encoding speech sounds was more likely driven by the generic constitutional properties of a highly trained auditory system, rather than by its specialisation for speech representations per se. These results shed light on the origin of the often reported advantage of musicians in processing a variety of speech sounds. PMID- 23664834 TI - Cell and tissue mechanics in cell migration. AB - Migrating cells generate traction forces to counteract the movement-resisting forces arising from cell-internal stresses and matrix adhesions. In the case of collective migration in a cell colony, or in the case of 3-dimensional migration through connective tissue, movement-resisting forces arise also from external stresses. Although the deformation of a stiffer cell or matrix causes larger movement-resisting forces, at the same time a larger stiffness can also promote cell migration due to a feedback between forces, deformations, and deformation speed that is mediated by the acto-myosin contractile machinery of cells. This mechanical feedback is also important for stiffness sensing, durotaxis, plithotaxis, and collective migration in cell colonies. PMID- 23664835 TI - Negative feedback regulation of Homer 1a on norepinephrine-dependent cardiac hypertrophy. AB - Homers are scaffolding proteins that modulate diverse cell functions being able to assemble signalling complexes. In this study, the presence, sub-cellular distribution and function of Homer 1 was investigated. Homer 1a and Homer 1b/c are constitutively expressed in cardiac muscle of both mouse and rat and in HL-1 cells, a cardiac cell line. As judged by confocal immunofluorescence microscopy, Homer 1a displays sarcomeric and peri-nuclear localization. In cardiomyocytes and cultured HL-1 cells, the hypertrophic agonist norepinephrine (NE) induces alpha1 adrenergic specific Homer 1a over-expression, with a two-to-three-fold increase within 1h, and no up-regulation of Homer 1b/c, as judged by Western blot and qPCR. In HL-1 cells, plasmid-driven over-expression of Homer 1a partially antagonizes activation of ERK phosphorylation and ANF up-regulation, two well established, early markers of hypertrophy. At the morphometric level, NE-induced increase of cell size is likewise and partially counteracted by exogenous Homer 1a. Under the same experimental conditions, Homer 1b/c does not have any effect on ANF up-regulation nor on cell hypertrophy. Thus, Homer 1a up-regulation is associated to early stages of cardiac hypertrophy and appears to play a negative feedback regulation on molecular transducers of hypertrophy. PMID- 23664836 TI - Quercetin and epigallocatechin gallate inhibit glucose uptake and metabolism by breast cancer cells by an estrogen receptor-independent mechanism. AB - In this study we characterized (3)H-2-deoxy-d-glucose ((3)H -DG) uptake by the estrogen receptor (ER)-positive MCF7 and the ER-negative MDA-MB-231 human breast cancer cell lines and investigated the effect of quercetin (QUE) and epigallocatechin gallate (EGCG) upon (3)H-DG uptake, glucose metabolism and cell viability and proliferation. In both MCF7 and MDA-MB-231 cells (3)H-DG uptake was (a) time-dependent, (b) saturable with similar capacity (Vmax) and affinity (Km), (c) potently inhibited by cytochalasin B, an inhibitor of the facilitative glucose transporters (GLUT), (d) sodium-independent and (e) slightly insulin stimulated. This suggests that (3)H-DG uptake by both cell types is mediated by members of the GLUT family, including the insulin-responsive GLUT4 or GLUT12, while being independent of the sodium-dependent glucose transporter (SGLT1). QUE and EGCG markedly and concentration-dependently inhibited (3)H-DG uptake by MCF7 and by MDA-MB-231 cells, and both compounds blocked lactate production by MCF7 cells. Additionally, a 4h-treatment with QUE or EGCG decreased MCF7 cell viability and proliferation, an effect that was more potent when glucose was available in the extracellular medium. Our results implicate QUE and EGCG as metabolic antagonists in breast cancer cells, independently of estrogen signalling, and suggest that these flavonoids could serve as therapeutic agents/adjuvants even for ER-negative breast tumors. PMID- 23664838 TI - Substrate elasticity as biomechanical modulator of tissue homeostatic parameters in corneal keratinocytes. AB - This study aimed at identifying putative modulations of tissue homeostatic parameters in corneal keratinocytes in response to biomechanical cues as basis for innovative cornea biomechanical-tailored biomaterials. Since cornea epithelial biomechanics is already described for contacts on nanostructures, we herein analyzed cell response to mechanical substrate elasticity. Therefore, corneal keratinocytes were established on physiologically-relevant elastic substrates of 40kPa, 130kPa but also on non-physiological stiff substrates of 1.74MPa for 3 days. qPCR revealed that changes in gene expression were only marginal between 40kPa and 130kPa, while significant modulations were seen on 1.74MPa substrates for most tissue-innate biomarkers under study. Gene expression fairly coincided with the protein, with differentiation progression biomarkers involucrin and fillagrin being already significantly increased between elasticities of 40kPa and 130kPa. Regarding focal adhesions, reinforcement was seen for beta1 integrin and phospho- p(125FAK) between 40kPa and 130kPa, while from 130kPa to 1.74MPa actin redistributed and phospho-p(125FAK) was strikingly up-regulated. These findings suggest elasticity dependence for differentiation progression and focal adhesion dynamics of corneal keratinocytes, supporting the concept of biomechanics governed regulation of tissue homeostasis. Moreover, this concept in turn can be translated into prospective cornea-tailored biomaterials for therapeutic approaches in ophthalmology. PMID- 23664837 TI - Fibroblast morphogenesis on 3D collagen matrices: the balance between cell clustering and cell migration. AB - Fibroblast clusters have been observed in tissues under a variety of circumstances: in fibrosis and scar, in the formation of hair follicle dermal papilla, and as part of the general process of mesenchymal condensation that takes place during development. Cell clustering has been shown to depend on features of the extracellular matrix, growth factor environment, and mechanisms to stabilize cell-cell interactions. In vitro studies have shown that increasing the potential for cell-cell adhesion relative to cell-substrate adhesion promotes cell clustering. Experimental models to study fibroblast clustering have utilized centrifugation, hanging drops, and substrata with poorly adhesive, soft and mechanically unstable properties. In this review, we summarize work on a new, highly tractable, cell clustering research model in which human fibroblasts are incubated on the surfaces of collagen matrices. Fibroblast clustering occurs under procontractile growth factor conditions (e.g., serum or the serum lipid agonist lysophosphatidic acid) but not under promigratory growth factor conditions (e.g., platelet-derived growth factor) and can be reversed by switching growth factor environments. Cell contraction plays a dual role in clustering to bring cells closer together and to stimulate cells to organize fibronectin into a fibrillar matrix. Binding of fibroblasts to a shared fibronectin fibrillar matrix stabilizes clusters, and fragmentation of the fibrillar matrix occurs when growth factor conditions are switched to promote cell dispersal. PMID- 23664840 TI - regEfmtool: speeding up elementary flux mode calculation using transcriptional regulatory rules in the form of three-state logic. AB - Despite the considerable progress made in recent years, the computation of the complete set of elementary flux modes of large or even genome-scale metabolic networks is still impossible. We present regEfmtool which is an extension to efmtool that utilizes transcriptional regulatory networks for the computation of elementary flux modes. The implemented extension significantly decreases the computational costs for the calculation of elementary flux modes, such as runtime, memory usage and disk space by omitting biologically infeasible solutions. Hence, using the presented regEfmtool pushes the size of metabolic networks that can be studied by elementary flux modes to new limits. PMID- 23664839 TI - Developmental windows of breast cancer risk provide opportunities for targeted chemoprevention. AB - The magnitude of the breast cancer problem implores researchers to aggressively investigate prevention strategies. However, several barriers currently reduce the feasibility of breast cancer prevention. These barriers include the inability to accurately predict future breast cancer diagnosis at the individual level, the need for improved understanding of when to implement interventions, uncertainty with respect to optimal duration of treatment, and negative side effects associated with currently approved chemoprevention therapies. None-the-less, the unique biology of the mammary gland, with its postnatal development and conditional terminal differentiation, may permit the resolution of many of these barriers. Specifically, lifecycle-specific windows of breast cancer risk have been identified that may be amenable to risk-reducing strategies. Here, we argue for prevention research focused on two of these lifecycle windows of risk: postpartum mammary gland involution and peri-menopause. We provide evidence that these windows are highly amenable to targeted, limited duration treatments. Such approaches could result in the prevention of postpartum and postmenopausal breast cancers, correspondingly. PMID- 23664841 TI - Response competition and response inhibition during different choice discrimination tasks: evidence from ERP measured inside MRI scanner. AB - We investigated the neural correlates underlying response inhibition and conflict detection processes using ERPs and source localization analyses simultaneously acquired during fMRI scanning. ERPs were elicited by a simple reaction time task (SRT), a Go/NoGo task, and a Stroop-like task (CST). The cognitive conflict was thus manipulated in order to probe the degree to which information processing is shared across cognitive systems. We proposed to dissociate inhibition and interference conflict effects on brain activity by using identical Stroop-like congruent/incongruent stimuli in all three task contexts and while varying the response required. NoGo-incongruent trials showed a larger N2 and enhanced activations of rostral anterior cingulate cortex (ACC) and pre-supplementary motor area, whereas Go-congruent trials showed a larger P3 and increased parietal activations. Congruent and incongruent conditions of the CST task also elicited similar N2, P3 and late negativity (LN) ERPs, though CST-incongruent trials revealed a larger LN and enhanced prefrontal and ACC activations. Considering the stimulus probability and experimental manipulation of our study, current findings suggest that NoGo N2 and frontal NoGo P3 appear to be more associated to response inhibition rather than a specific conflict monitoring, whereas occipito-parietal P3 of Go and CST conditions may be more linked to a planned response competition between the prepared and required response. LN, however, appears to be related to higher level conflict monitoring associated with response choice-discrimination but not when the presence of cognitive conflict is associated with response inhibition. PMID- 23664842 TI - Cryomicroscopy of radiation sensitive specimens on unmodified graphene sheets: reduction of electron-optical effects of charging. AB - Images of radiation-sensitive specimens obtained by electron microscopy suffer a reduction in quality beyond that expected from radiation damage alone due to electron beam-induced charging or movement of the specimen. For biological specimens, charging and movement are most severe when they are suspended in an insulating layer of vitreous ice, which is otherwise optimal for preserving hydrated specimens in a near native state. We image biological specimens, including a single particle protein complex and a lipid-enveloped virus in thin, vitreous ice films over suspended sheets of unmodified graphene. We show that in such preparations, the charging of ice, as assessed by electron-optical perturbation of the imaging beam, is eliminated. We also use the same specimen supports to record high resolution images at liquid nitrogen temperature of monolayer paraffin crystals grown over graphene. PMID- 23664843 TI - First report of the activity of predatory fungi on Angiostrongylus cantonensis (Nematoda: Angiostrongylidae) first-stage larvae. AB - The nematode Angiostrongylus cantonensis causes eosinophilic meningoencephalitis in humans and thus alternative methods of control should be studied. The objective of this work was to evaluate the predatory capacity of eight fungal isolates of the species Duddingtonia flagrans (AC001, CG768 and CG722), Monacrosporium thaumasium (NF34), M. sinense (SF53) and Arthrobotrys robusta (I31), A. cladodes (CG719) and A. conoides (I40) on first-stage larvae (L1) of A. cantonensis under laboratory conditions. The treated groups contained 1000 conidia of the fungal isolates and 1000 A. cantonensis L1 in Petri dishes containing 2% water-agar medium (2% WA). The control group (without fungi) contained only 1000 A. cantonensis L1 in 2% WA. Evidence of predation was observed at the end of 7 days. Percentage reductions in L1 were: AC001, 82.8%; CG768, 71.0%; CG722, 72.8%; NF34, 86.7%; SF53, 89.7%; I40, 48.3%; CG719, 84.7%; and I31, 80.4%. No significant difference was observed (p>0.01) between the actions of the isolates used; however, a difference was noted (p<0.01) in relation to the control group. The results of the present work, confirm previous reports of the effectiveness of the fungi D. flagrans, M. thaumasium, M. sinense and A. robusta in controlling larvae of potentially zoonotic nematodes, this being the first report on A. cantonensis L1. PMID- 23664845 TI - Huntington's disease: the road to progress. PMID- 23664844 TI - Predictors of phenotypic progression and disease onset in premanifest and early stage Huntington's disease in the TRACK-HD study: analysis of 36-month observational data. AB - BACKGROUND: TRACK-HD is a multinational prospective observational study of Huntington's disease (HD) that examines clinical and biological findings of disease progression in individuals with premanifest HD (preHD) and early-stage HD. We aimed to describe phenotypic changes in these participants over 36 months and identify baseline predictors of progression. METHODS: Individuals without HD but carrying the mutant huntingtin gene (classed as preHD-A if >=10.8 years and preHD-B if <10.8 years from predicted onset), participants with early HD (classed as HD1 if they had a total functional capacity score of 11-13 and HD2 if they had a score of 7-10), and healthy control individuals were assessed at four study sites in the Netherlands, the UK, France, and Canada. We measured 36-month change for 3T MRI, clinical, cognitive, quantitative motor, and neuropsychiatric assessments and examined their prognostic value. We also assessed the relation between disease progression and the combined effect of CAG repeat length and age. All participants were analysed according to their baseline subgroups. Longitudinal results were analysed using a combination of repeated-measure weighted least squares models and, when examining risk of new diagnosis, survival analysis. FINDINGS: At baseline, 366 participants were enrolled between Jan 17, and Aug 26, 2008, and of these 298 completed 36-month follow-up: 97 controls, 58 participants with preHD-A, 46 with preHD-B, 66 with HD1, and 31 with HD2. In the preHD-B group, several quantitative motor and cognitive tasks showed significantly increased rates of decline at 36 months, compared with controls, whereas few had at 24 months. Of the cognitive measures, the symbol digit modality test was especially sensitive (adjusted mean loss 4.11 points [95% CI 1.49-6.73] greater than controls; p=0.003). Among psychiatric indicators, apathy ratings specifically showed significant increases (0.34 points [95% CI 0.02-0.66] greater than controls; p=0.038). There was little evidence of reliable change in non-imaging measures in the preHD-A group, with the exception of the speeded tapping inter-tap interval (0.01 s [95% CI 0.01-0.02] longer than controls; p=0.0001). Several baseline imaging, quantitative motor, and cognitive measures had prognostic value, independent of age and CAG repeat length, for predicting subsequent clinical diagnosis in preHD. Of these, grey-matter volume and inter tap interval were particularly sensitive (p=0.013 and 0.002, respectively). Longitudinal change in these two measures was also greater in participants with preHD who received a diagnosis of HD during the study compared with those who did not, after controlling for CAG repeat length and age-related risk (p=0.006 and 0.0003, respectively). In early HD, imaging, quantitative motor, and cognitive measures were predictive of decline in total functional capacity and tracked longitudinal change; also, neuropsychiatric changes consistent with frontostriatal pathological abnormalities were associated with this loss of functional capacity (problem behaviours assessment composite behaviour score p<0.0001). Age and CAG repeat length explained variance in longitudinal change of multimodal measures, with the effect more prominent in preHD. INTERPRETATION: We have shown changes in several outcome measures in individuals with preHD over 36 months. These findings further our understanding of HD progression and have implications for clinical trial design. FUNDING: CHDI Foundation. PMID- 23664846 TI - Regio- and stereocontrolled synthesis of novel steroidal isoxazolines: a new route to the formation of selectively modified steroid side chains. AB - 1,3-Dipolar cycloaddition reaction of acetonitrile oxide to cis- and trans-22 hydroxy-24-alkoxycarbonyl-Delta(23)-steroids is investigated. An unusual stereochemical course of the cycloaddition, leading to the same set of the isoxazoline adducts for both (Z)- and (E)-disubstituted olefins is revealed. It is shown, the reaction is regioselective and all possible 4',5'-diastereoisomers of resulting isoxazolines can be prepared as major products by cycloaddition to the suitable alkene. The structure of the key compounds is confirmed by X-ray and 2D NMR analysis. PMID- 23664847 TI - Cenani-Lenz syndrome restricted to limb and kidney anomalies associated with a novel LRP4 missense mutation. AB - Cenani-Lenz syndrome (CLS) is a rare autosomal recessive developmental disorder of the limbs. The disorder is characterized by complete syndactyly with metacarpal fusions and/or oligodactyly sometimes accompanied by radioulnar synostosis. The clinical expression is variable and kidney agenesis/hypoplasia, craniofacial dysmorphism and teeth abnormalities are frequent features as well as lower limb involvement. CLS was recently associated with mutations in the low density lipoprotein receptor-related protein 4 (LRP4) gene and dysregulated canonical WNT signaling. We have identified a large consanguineous Pakistani pedigree with 9 members affected by CLS. The affected individuals present with a consistent expression of the syndrome restricted to the limbs and kidneys. Symptoms from the lower limb are mild or absent and there were no radioulnar synostosis or craniofacial involvement. Genetic analysis using autozygosity mapping and sequencing revealed homozygosity for a novel missense mutation c.2858T > C (p.L953P) in the LRP4 gene. The mutation is located in a region encoding the highly conserved low-density lipoprotein receptor repeat class B domain of LRP4. Our findings add to the genotype-phenotype correlations in CLS and support kidney anomalies as a frequent associated feature. PMID- 23664848 TI - Meta-analysis: accuracy of 18FDG PET-CT for distant metastasis staging in lung cancer patients. AB - BACKGROUND: We undertook a meta-analysis to evaluate the accuracy of (18)FDG PET CT for diagnosis of distant metastases in lung cancer patients. METHODS: Studies about (18)FDG PET-CT for diagnosis of distant metastases in patients with lung cancer were systematically searched in the MEDLINE and EMBASE databases. We calculated sensitivities, specificities, positive likelihood ratios and negative likelihood ratios, and constructed summary receiver operating characteristic curves using bivariate regression models for (18)FDG PET-CT. RESULTS: Across 9 studies (780 patients), the sensitivity, specificity, positive likelihood ratio and negative likelihood ratio of (18)FDG PET-CT were 0.93 (95% confidence interval [CI] = 0.88-0.96), 0.96 (95% CI = 0.95-0.96), 28.4 (95% CI = 14.0-57.5), and 0.08 (95% CI = 0.02-0.37), respectively. Overall weighted area under the curve was 0.98 (95% CI = 0.96-0.99). CONCLUSION: (18)FDG PET-CT has excellent diagnostic performance for diagnosis of distant metastases in patients with lung cancer. PMID- 23664849 TI - Evaluation of clinical tools and their diagnostic use in distal symmetric polyneuropathy. AB - AIMS: To compare the diagnostic usefulness of tuning fork, monofilament, biothesiometer and skin biopsies in peripheral neuropathy in individuals with varying glucose metabolism. METHODS: Normoglycaemic, impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) individuals were recruited. Nerve conduction studies (NCS) and thermal threshold tests were performed. Vibrotactile sense was tested with a biothesiometer and a 128-Hz tuning fork. Touch/pressure perception was examined with a 10-g monofilament. Skin biopsies were performed and intraepidermal nerve fibres were quantified. Distal symmetric polyneuropathy (DSPN) was defined as neuropathy disability score >=2 and abnormal NCS. Thermal threshold tests were used to define small nerve fibre neuropathy (sDSPN) in cases where NCS (large nerve fibres) were normal. RESULTS: The prevalence of DSPN and sDSPN in the whole group (n=119) was 18% and 23%, respectively. For the biothesiometer, a cut-off of >=24.5V had a sensitivity of 82% and specificity of 70% (AUC=0.81, 95% CI 0.71-0.91) when evaluating DSPN. An intraepidermal nerve fibre density cut-off of <=3.39fibres/mm showed a sensitivity of 74% and specificity of 70% in the detection of sDSPN, whereas the sensitivity of the tuning fork and the biothesiometer were relatively low, 46% and 67%, respectively. When combining skin biopsies with the tuning fork, 10 more sDSPN cases were identified. Adding skin biopsy to the combination of the tuning fork and biothesiometer increased the sensitivity of finding sDSPN cases, but not DSPN, from 81% to 93%. CONCLUSION: Using a biothesiometer in clinical routine might be a sensitive method to detect large nerve fibre dysfunction in the lower extremity, whereas skin biopsies in combination with methods measuring vibrotactile sense could increase the diagnostic sensitivity of detecting peripheral neuropathy at an early stage. PMID- 23664850 TI - Phages bearing affinity peptides to severe acute respiratory syndromes-associated coronavirus differentiate this virus from other viruses. AB - BACKGROUND: Transmission of SARS-associated coronavirus (SARS-CoV) is now well controlled, nevertheless, it is important to develop effective methods to identify this virus from other pathogens. OBJECTIVES: The purpose of this study was to identify potential ligands and develop a novel diagnostic test to SARS-CoV using phage display technology. STUDY DESIGN: The SARS-CoV spike 1 (S1) protein containing the receptor binding region (RBD) was used as an immobilized target followed by incubation with a 12-mer phage display random peptide library. After four rounds of biopanning, 10 monoclonal phages with specific binding activity to the S1-RBD protein were obtained and subjected to binding and diagnostic assays. RESULTS: DNA sequencing showed that two phage displayed peptides HHKTWHPPVMHL (phage-H) and SQWHPRSASYPM (phage-S) that were specific ligands to the S1 protein. Moreover, the selected phage-H and phage-S were capable of differentiating SARS-CoV from other coronaviruses in indirect enzyme-linked immunosorbent assays. CONCLUSION: The peptides identified in this study are useful reagents for detection of SARS-CoV. PMID- 23664851 TI - Spatio-temporal microhabitat use by two co-occurring species of scorpions in Atlantic rainforest in Brazil. AB - With the increasing devastation of the tropical rain forest, there is a critical need to understand how animal forest communities are structured and how habitat degradation will affect these communities. We conducted a field survey to investigate the microhabitat preferences of two co-occurring species of scorpions (Tityus pusillus and Ananteris mauryi) in a fragment of Atlantic rainforest, as well as their abundance and their ecological niche, during both the dry and rainy seasons. Behavioural aspects related to the use of the environment and the proportions of juveniles and adults are also described. The occurrence of intra- and interspecific coexistence was assessed by active search. In addition, pitfall catches were used to assess the structure of the population in the dry and rainy seasons. The differential patterns of spatial distribution in the litter layers provided evidence of partial niche partitioning between the two coexisting scorpion species depending on age and climatic conditions. Abundance, foraging behaviour and age structure (juveniles and adults) were seasonally influenced. We conclude that the diverse and subtle behaviours involved in interaction and habitat use may facilitate species coexistence. Resource partitioning and refuge sharing on a temporal and/or spatial scale, as well as predation pressure, may drive the dynamics and spatial distribution of scorpion species in the rain forest environment. PMID- 23664852 TI - Determination of free fatty acids in pharmaceutical lipids by 1H NMR and comparison with the classical acid value. AB - Indices like acid value, peroxide value, and saponification value play an important role in quality control and identification of lipids. Requirements on these parameters are given by the monographs of the European pharmacopeia. (1)H NMR spectroscopy provides a fast and simple alternative to these classical approaches. In the present work a new (1)H NMR approach to determine the acid value is described. The method was validated using a statistical approach based on a variance components model. The performance under repeatability and in-house reproducibility conditions was assessed. We applied this (1)H NMR assay to a wide range of different fatty oils. A total of 305 oil and fat samples were examined by both the classical and the NMR method. Except for hard fat, the data obtained by the two methods were in good agreement. The (1)H NMR method was adapted to analyse waxes and oleyloleat. Furthermore, the effect of solvent and in the case of castor oil the effect of the oil matrix on line broadening and chemical shift of the carboxyl group signal are discussed. PMID- 23664853 TI - Pentacyclic triterpenes from Manilkara bidentata resin. Isolation, identification and biological properties. AB - Three pentacyclic triterpenes were isolated for the first time from resinous plant Manilkara bidentata. Ultrasound-assisted extraction with ethanol was chosen after a comparison of various extraction methods. Analysis of the extract was performed by HPLC with evaporative light scattering detection and semi preparative HPLC has enabled us to isolate two urs-12-enes (3beta-O-acetyl-alpha amyrin and 3beta-O-trans cinnamyl-alpha-amyrin) and a lupane-type derivative (3beta-O-trans cinnamyl lupeol). Structures were elucidated on the basis of HRESIMS, atmospheric pressure photoionization MS, and homo- and heteronuclear correlation NMR experiments. Antioxidant and anti-inflammatory activities were determined on Manilkara extract and isolated fractions. We have also investigated their action on collagen and fibronectin synthesis, two very important proteins of the extracellular matrix. Thus, Manilkara extract was able to decrease IL 1beta and IL-8 pro-inflammatory cytokines. These activities exhibit the potential use of Manilkara extract as an anti-inflammatory and anti-aging ingredient for pharmaceutical and cosmetic industries. PMID- 23664854 TI - Repeated lumbar puncture in adults with pneumococcal meningitis: an observational study. PMID- 23664855 TI - A nationwide study of comorbidity and risk of reinfection after Staphylococcus aureus bacteraemia. AB - BACKGROUND: Data on risk factors and rates of reinfection associated with Staphylococcus aureus bacteraemia (SAB) are sparse. METHODS: We conducted a nationwide cohort study of cases of SAB diagnosed between 1995 and 2008. Reinfection was defined as an episode of SAB more than 90 days after the initial episode of SAB. Comorbidity was evaluated by the Charlson Comorbidity Index (CCI). Cox proportional hazards modelling was used to estimate hazard rates (HR). RESULTS: Of 10,891 eligible patients, 774 (7.1%) experienced reinfection a median of 458 days (range 90-5021 days) after their primary SAB episode corresponding to a reinfection rate of 1459 (95% confidence interval (CI): 1357-1562) per 100,000 personyears. In multivariate analysis, sex, origin, a vascular or peritoneal device, endocarditis and comorbidity were associated with reinfection. The association was more than two-fold higher among patients in dialysis and for patients with severe comorbidity (CCI >= 2). HIV infection (Hazard ratio (HR) 6.18, 95% CI: 4.17-9.16), renal disease (HR 3.92, 95% CI: 3.22-4.78), diabetes with complications (HR 2.11, 95% CI: 1.69-2.62), diabetes without complications (HR 1.61, 95% CI: 1.34-1.93), mild (HR: 1.94, 95% CI: 1.36-2.76) and severe liver disease (HR 2.08, 95% CI: 1.08-4.03), peptic ulcer (HR 1.33, 95% CI: 1.03-1.72), and paraplegia (HR 2.15, 95% CI: 1.02-4.54) were each associated with an increased risk of reinfection. CONCLUSIONS: Patients with previous SAB have a 60 fold higher risk of SAB compared to the general population. Patients with HIV infection, renal disease, diabetes, liver disease, peptic ulcer and paraplegia had the highest rates of reinfection. PMID- 23664856 TI - Rituximab-associated progressive multifocal leukoencephalopathy after lung transplantation. PMID- 23664857 TI - In vivo gamma-irradiation low dose threshold for suppression of DNA double strand breaks below the spontaneous level in mouse blood and spleen cells. AB - There is a considerable controversy as to whether DNA damage induced by low doses and low dose rates of ionizing radiation is treated by cellular defence mechanisms in ways similar to that induced at high doses and high dose rates, and what downstream delayed effects may be caused by low doses compared to moderate and high doses. This constitutes the major challenge for the linear no-threshold model currently used for radiological risk estimates. Among the various DNA lesions induced by ionizing radiation, DNA double strand breaks (DSBs) are considered the most important due to their potential to cause cell death, mutagenesis and carcinogenesis. This study examined the accumulation of DNA DSBs in mouse blood leucocytes and splenocytes after long-term, chronic low dose gamma irradiation in vivo, and how this exposure may alter cell sensitivity to acute high dose irradiation. Animals were irradiated for 40, 80 or 120 days at a dose rate of 0.15mGy/h, with total accumulated doses of 144, 288 and 432mGy. DNA DSBs were measured in blood leucocytes and splenocytes using the neutral comet assay. We found that after an initial slight increase in the level of DNA DSBs at 40 days of exposure compared to controls, there was a subsequent drop after either 80 (P<0.01) or 120 days of exposure (P=0.066 for blood leucocytes; P=0.024 for splenocytes). Interestingly, the DNA breaks level after both 80 and 120 days of exposure was lower than in control. Similarly, the cells exposed to the chronic radiation for 80 and 120 days were less sensitive to the induction of DNA DSBs by acute 4Gy irradiation, whereas 40 days of exposure did not significantly modify the radiosensitivity. Our results indirectly indicate that low level ionizing radiation in vivo may trigger inducible repair of both endogenous and exogenous DNA DSBs, and that there is a dose threshold for this inducible defence mechanism, below which it does not occur. These data provide new evidence, now at the molecular level in vivo, that the dose-response for DNA DSBs at very low doses and dose rates is not linear. PMID- 23664858 TI - Pirfenidone attenuates IL-1beta-induced COX-2 and PGE2 production in orbital fibroblasts through suppression of NF-kappaB activity. AB - The aim of this study was to determine the effect of pirfenidone on interleukin (IL)-1beta-induced cyclooxygenase (COX)-2 and prostaglandin (PG)E2 expression in orbital fibroblasts from patients with thyroid-associated ophthalmopathy (TAO). Primary cultures of orbital fibroblasts from patients with TAO (n = 4) and non TAO subjects (n = 4) were prepared. The level of PGE2 in orbital fibroblasts treated with IL-1beta in the presence or absence of pirfenidone was measured using an enzyme-linked immunosorbent assay. The effect of pirfenidone on IL-1beta induced COX-2 expression in orbital fibroblasts from patients with TAO was evaluated by reverse transcription-polymerase chain reaction (PCR) and quantitative real-time PCR analyses, and verified by Western blot. Activation of nuclear factor-kappaB (NF-kappaB) was evaluated by immunoblotting for inhibitor of kappaB (IkappaB)alpha and phosphorylated IkappaBalpha, and DNA-binding activity of p50/p65 NF-kappaB was analyzed by electrophoretic mobility shift assay. In addition, IL-1 receptor type 1 (IL-1R1) expression was assessed by RT PCR in IL-1beta-treated cells with or without pirfenidone. Pirfenidone significantly attenuated IL-1beta-induced PGE2 release in both TAO and non-TAO cells. IL-1beta-induced COX-2 mRNA and protein expression decreased significantly following co-treatment with pirfenidone. IL-1beta-induced IkappaBalpha phosphorylation and degradation decreased in the presence of pirfenidone and led to decreased nuclear translocation and DNA binding of the active NF-kappaB complex. In our system, neither IL-1beta nor pirfenidone co-treatment influenced IL-1R1 expression. Our results suggest that pirfenidone attenuates the IL-1beta induced PGE2/COX-2 production in TAO orbital fibroblasts, which is related with suppression of the NF-kappaB activation. PMID- 23664859 TI - Inverse computational analysis of in vivo corneal elastic modulus change after collagen crosslinking for keratoconus. AB - Corneal collagen crosslinking with riboflavin photosensitization and ultraviolet irradiation is a novel approach to limiting the progression of keratoconus in patients by increasing the elastic modulus of the degenerate cornea. Beneficial reductions in corneal steepness and aberrations after crosslinking also frequently occur. In a previous study, we described a computational modeling approach to simulating topographic progression in keratoconus and regression of disease with corneal collagen crosslinking. In the current study, this model has been expanded and applied to the inverse problem of estimating longitudinal time dependent changes in the corneal elastic modulus after crosslinking using in vivo measurements from 16 human eyes. Topography measured before crosslinking was used to construct a patient-specific finite element model with assumed hyperelastic properties. Then the properties of the cornea were altered using an inverse optimization method to minimize the difference between the model-predicted and in vivo corneal shape after crosslinking. Effects of assumptions regarding sclera-to cornea elastic modulus ratio and spatial attenuation of treatment effect due to ultraviolet beam characteristics on the predicted change in elastic modulus were also investigated. Corneal property changes computed by inverse finite element analysis provided excellent geometric agreement with clinical topography measurements in patient eyes post-crosslinking. Over all post-treatment time points, the estimated increase in corneal elastic modulus was 110.8 +/- 48.1%, and slightly less stiffening was required to produce the same amount of corneal topographic regression of disease when the sclera-to-cornea modulus ratio was increased. Including the effect of beam attenuation resulted in greater estimates of stiffening in the anterior cornea. Corneal shape responses to crosslinking varied considerably and emphasize the importance of a patient-specific approach. PMID- 23664860 TI - Stanniocalcin-1 and -2 promote angiogenic sprouting in HUVECs via VEGF/VEGFR2 and angiopoietin signaling pathways. AB - The members of stanniocalcins (STCs: STC-1 and STC-2) family are known to be involved in tumor progression and metastasis. Although current evidences suggest the involvement of STCs in vascular biology, the functional roles of STCs in angiogenesis have not yet been elucidated. The objective of this study was to decipher the roles of STCs in angiogenesis of human umbilical vascular endothelial cells (HUVECs). We prepared STC1 or STC2 lentiviral particles to transduce the cells to reveal their effects on the processes of cell proliferation, migration and tube formation. The stimulatory effects of STCs on these processes were demonstrated, supporting the notion of STCs in angiogenesis. To dissect the molecular components involved, STC1 or STC2 transduction led to significant increases in the expression levels of cell cycle regulators (i.e. cyclin-D and phospho-retinoblastoma), matrix metalloproteinase (MMP)-2 but a decrease of tissue inhibitors of metalloproteases (TIMP)-1. The expression levels of the cell adhesion/junctional proteins vimentin and VE-cadherin, were significantly induced. Moreover the transduction induced both mRNA and protein levels of eNOS, VEGF and VEGFR2 (KDR mRNA and pKDR), highlighting the stimulatory effects of STCs on VEGF-signaling pathway. Furthermore STC2 transduction but not STC1, activated angiopoietin (Ang)-2 pathway. Taken together, STC1 and STC2 play positive roles in angiogenic sprouting. The action of STC1 was mediated via VEGF/VEGFR2 pathway while STC2 were mediated via VEGF/VEGFR2 and Ang-2 pathways. PMID- 23664861 TI - Effects of estrogen and estrogenic compounds, 4-tert-octylphenol, and bisphenol A on the uterine contraction and contraction-associated proteins in rats. AB - We examined the effects of estradiol (E2), 4-tert-octylphenol (OP), and bisphenol A (BPA) on uterine contractions in immature rats. The expression and localization of contraction-associated proteins (CAPs), and contractility of rat uterus with a collagen gel contraction assay were analyzed. E2, OP, and BPA all increased oxytocin (OT)-related pathway, while the prostaglandin-related signaling was reduced. Interestingly, E2 and estrogenic compounds showed distinct effects on the contractile activity of uterine cells. E2 enhanced the contractility, while OP and BPA significantly decreased it. Immunohistochemical analysis of CAPs showed distinct regulation of prostaglandin F receptor localization by E2 and estrogenic compounds, which may explain the different contractile activities of those reagents. In summary, we demonstrate that E2, OP, and BPA regulate CAP expression in a similar manner in the immature rat uterus, however, the effects on contractile activity were modulated differently. These findings suggest that OP and BPA interfere with uterine contractility. PMID- 23664862 TI - G13 controls angiogenesis through regulation of VEGFR-2 expression. AB - At sites of angiogenesis, the expression of the key angiogenesis regulator vascular endothelial growth factor (VEGF) and its main receptor, VEGF receptor 2 (VEGFR-2), are strongly upregulated. Whereas the processes controlling VEGF expression are well described, the mechanisms underlying VEGFR-2 upregulation have remained unclear. We found that endothelial VEGFR-2 expression is strongly reduced in the absence of the G protein G13, resulting in an impaired responsiveness to VEGF-A, a phenotype that can be rescued by normalization of VEGFR-2 levels. G13-mediated VEGFR-2 expression involved activation of the small GTPase RhoA and transcription factor NF-kappaB, the latter acting via a specific binding site at position -84 of the VEGFR-2 promoter. Mice with endothelial cell specific loss of G13 showed reduced VEGFR-2 expression at sites of angiogenesis and attenuated VEGF effects, resulting in impaired retinal angiogenesis and tumor vascularization. Taken together, we identified G-protein-mediated signaling via G13 as a critical regulator of VEGFR-2 expression during angiogenesis. PMID- 23664863 TI - Viral infection controlled by a calcium-dependent lipid-binding module in ALIX. AB - ALIX plays a role in nucleocapsid release during viral infection, as does lysobisphosphatidic acid (LBPA). However, the mechanism remains unclear. Here we report that LBPA is recognized within an exposed site in ALIX Bro1 domain predicted by MODA, an algorithm for discovering membrane-docking areas in proteins. LBPA interactions revealed a strict requirement for a structural calcium tightly bound near the lipid interaction site. Unlike other calcium- and phospholipid-binding proteins, the all-helical triangle-shaped fold of the Bro1 domain confers selectivity for LBPA via a pair of hydrophobic residues in a flexible loop, which undergoes a conformational change upon membrane association. Both LBPA and calcium binding are necessary for endosome association and virus infection, as are ALIX ESCRT binding and dimerization capacity. We conclude that LBPA recruits ALIX onto late endosomes via the calcium-bound Bro1 domain, triggering a conformational change in ALIX to mediate the delivery of viral nucleocapsids to the cytosol during infection. PMID- 23664864 TI - Multisynaptic projections from the ventrolateral prefrontal cortex to hand and mouth representations of the monkey primary motor cortex. AB - Different sectors of the prefrontal cortex have distinct neuronal connections with higher-order sensory areas and/or limbic structures and are related to diverse aspects of cognitive functions, such as visual working memory and reward based decision-making. Recent studies have revealed that the prefrontal cortex (PF), especially the lateral PF, is also involved in motor control. Hence, different sectors of the PF may contribute to motor behaviors with distinct body parts. To test this hypothesis anatomically, we examined the patterns of multisynaptic projections from the PF to regions of the primary motor cortex (MI) that represent the arm, hand, and mouth, using retrograde transsynaptic transport of rabies virus. Four days after rabies injections into the hand or mouth region, particularly dense neuron labeling was observed in the ventrolateral PF, including the convexity part of ventral area 46. After the rabies injections into the mouth region, another dense cluster of labeled neurons was seen in the orbitofrontal cortex (area 13). By contrast, rabies labeling of PF neurons was rather sparse in the arm-injection cases. The present results suggest that the PF MI multisynaptic projections may be organized such that the MI hand and mouth regions preferentially receive cognitive information for execution of elaborate motor actions. PMID- 23664866 TI - Characterization and functional analysis of serine proteinase and serine proteinase homologue from the swimming crab Portunus trituberculatus. AB - Serine proteases (SPs), with their homologues (SPHs), a family of multifunctional proteins, play a crucial role in innate immune system. In our present study, we made an appropriate correction: serine protease homologue PtcSPH (Li et al., [1]) obtained from the swimming crab Portunus trituberculatus was actually a serine protease and re-designated as PtcSP. Sequence analysis revealed PtcSP and PtSP (Li et al., [2]) might be encoded by the same genomic locus and generated by alternative splicing of the pre-mRNA. Eight exons were identified in genomic DNA sequence of PtcSP. A comprehensive phylogenetic analysis was made combined with our previous reports (Cui et al., [3]; Li et al., [1,2]). The result showed SPs and SPHs of P. trituberculatus had different origins in gene evolution. To further characterize the function(s) of proteins, the recombinant serine proteases or homologues were assayed for various biological functions: proteinase activity, antimicrobial activity and microorganisms binding activity. The recombinant protein PtcSP exhibited trypsin-like protease activity and antibacterial activity. PtSPH1 (Li et al., [2]) lacked proteolytic activity but displayed binding activity to yeast and the crab pathogenic bacterium, Vibrio alginolyticus. Further, the N-terminal clip domain of PtcSP had antibacterial activity and the C-terminal SP-like domain had trypsin-like protease activity. PMID- 23664865 TI - Channelrhodopsins: visual regeneration and neural activation by a light switch. AB - The advent of optogenetics provides a new direction for the field of neuroscience and biotechnology, serving both as a refined investigative tool and as potential cure for many medical conditions via genetic manipulation. Although still in its infancy, recent advances in optogenetics has made it possible to remotely manipulate in vivo cellular functions using light. Coined Nature Methods' 'Method of the Year' in 2010, the optogenetic toolbox has the potential to control cell, tissue and even animal behaviour. This optogenetic toolbox consists of light sensitive proteins that are able to modulate membrane potential in response to light. Channelrhodopsins (ChR) are light-gated microbial ion channels, which were first described in green algae. ChR2 (a subset of ChR) is a seven transmembrane alpha helix protein, which evokes membrane depolarization and mediates an action potential upon photostimulation with blue (470 nm) light. By contrast to other seven-transmembrane proteins that require second messengers to open ion channels, ChR2 form ion channels themselves, allowing ultrafast depolarization (within 50 milliseconds of illumination). It has been shown that integration of ChR2 into various tissues of mice can activate neural circuits, control heart muscle contractions, and even restore breathing after spinal cord injury. More compellingly, a plethora of evidence has indicated that artificial expression of ChR2 in retinal ganglion cells can reinstate visual perception in mice with retinal degeneration. PMID- 23664867 TI - Teleost T and NK cell immunity. AB - The main function of the immune system is to maintain the organism's homeostasis when invaded by foreign material or organisms. Prior to successful elimination of the invader it is crucial to distinguish self from non-self. Most pathogens and altered cells can be recognized by immune cells through expressed pathogen- or danger-associated molecular patterns (PAMPS or DAMPS, respectively), through non self (e.g. allogenic or xenogenic cells) or missing major histocompatibility (MHC) class I molecules (some virus-infected target cells), and by presenting foreign non-self peptides of intracellular (through MHC class I-e.g. virus infected target cells) or extracellular (through MHC class II-e.g. from bacteria) origin. In order to eliminate invaders directly or by destroying their ability to replicate (e.g. virus-infected cells) specialized immune cells of the innate and adaptive responses appeared during evolution. The first line of defence is represented by the evolutionarily ancient macrophages and natural killer (NK) cells. These innate mechanisms are well developed in bony fish. Two types of NK cell homologues have been described in fish: non-specific cytotoxic cells and NK like cells. Adaptive cell-mediated cytotoxicity (CMC) requires key molecules expressed on cytotoxic T lymphocytes (CTLs) and target cells. CTLs kill host cells harbouring intracellular pathogens by binding of their T cell receptor (TCR) and its co-receptor CD8 to a complex of MHC class I and bound peptide on the infected host cell. Alternatively, extracellular antigens are taken up by professional antigen presenting cells such as macrophages, dendritic cells and B cells to process those antigens and present the resulting peptides in association with MHC class II to CD4(+) T helper cells. During recent years, genes encoding MHC class I and II, TCR and its co-receptors CD8 and CD4 have been cloned in several fish species and antibodies have been developed to study protein expression in morphological and functional contexts. Functional assays for innate and adaptive lymphocyte responses have been developed in only a few fish species. This review summarizes and discusses recent results and developments in the field of T and NK cell responses with focus on economically important and experimental model fish species in the context of vaccination. PMID- 23664868 TI - Touchdown digital polymerase chain reaction for quantification of highly conserved sequences in the HIV-1 genome. AB - Digital polymerase chain reaction (PCR) is an emerging absolute quantification method based on the limiting dilution principle and end-point PCR. This methodology provides high flexibility in assay design without influencing quantitative accuracy. This article describes an assay to quantify HIV DNA that targets a highly conserved region of the HIV-1 genome that hampers optimal probe design. To maintain high specificity and allow probe binding and hydrolysis of a probe with low melting temperature, a two-stage touchdown PCR was designed with a first round of amplification at high temperature and a subsequent round at low temperature to allow accumulation of fluorescence. PMID- 23664869 TI - Cavities in the compact bone in tetrapods and fish and their effect on mechanical properties. AB - Bone includes cavities in various length scales, from nanoporosities occurring between the collagen fibrils and the mineral crystals all the way to macrocavities like the medullary cavity. In particular, bone is permeated by a vast number of channels (the lacunar-canalicular system), that reduce the stiffness and, more importantly, the strength of the bone that they permeate. These consequences are presumably a price worth paying for the ability of the lacunar-canalicular system to detect changes in the strain environment within the bone material and, when deleterious, to trigger processes like modeling or remodeling which 'rectify' it. Here we review the size and density of the various types of cavities in bone, and discuss their effect on the mechanical properties of cortical bone. In this respect the bones of advanced teleost fish species (probably the majority of all vertebrate species) are an unsolved conundrum because they lack bone cells (and therefore lacunae and canaliculi) in their skeleton. Yet, despite being acellular, some of these fish can undergo considerable remodeling in at least some parts of their skeleton. We address, but do not solve this mystery. PMID- 23664870 TI - Change in single cystathionine beta-synthase domain-containing protein from a bent to flat conformation upon adenosine monophosphate binding. AB - Cystathionine beta-synthase (CBS) domains are small intracellular modules that can act as binding domains for adenosine derivatives, and they may regulate the activity of associated enzymes or other functional domains. Among these, the single CBS domain-containing proteins, CBSXs, from Arabidopsis thaliana, have recently been identified as redox regulators of the thioredoxin system. Here, the crystal structure of CBSX2 in complex with adenosine monophosphate (AMP) is reported at 2.2A resolution. The structure of dimeric CBSX2 with bound-AMP is shown to be approximately flat, which is in stark contrast to the bent form of apo-CBSXs. This conformational change in quaternary structure is triggered by a local structural change of the unique alpha5 helix, and by moving each loop P into an open conformation to accommodate incoming ligands. Furthermore, subtle rearrangement of the dimer interface triggers movement of all subunits, and consequently, the bent structure of the CBSX2 dimer becomes a flat structure. This reshaping of the structure upon complex formation with adenosine-containing ligand provides evidence that ligand-induced conformational reorganization of antiparallel CBS domains is an important regulatory mechanism. PMID- 23664872 TI - Evaluation of bioactivities of chlorokojic acid derivatives against dermatophytes couplet with cytotoxicity. AB - In an attempt to find novel antifungal agents with improved activity, a series of compounds bearing 6-chloromethyl-3-hydroxy-2-substituted 4H-pyran-4-one moiety were synthesized and examined for their cytotoxic evaluation and antifungal activities against both standard and isolated dermatophytic fungal species Microsporum gypseum, Trichophyton mentagrophytes var. erinacei and Epidermophyton floccosum. PMID- 23664871 TI - Development of a triclosan scaffold which allows for adaptations on both the A- and B-ring for transport peptides. AB - The enoyl acyl-carrier protein reductase (ENR) enzyme is harbored within the apicoplast of apicomplexan parasites providing a significant challenge for drug delivery, which may be overcome through the addition of transductive peptides, which facilitates crossing the apicoplast membranes. The binding site of triclosan, a potent ENR inhibitor, is occluded from the solvent making the attachment of these linkers challenging. Herein, we have produced 3 new triclosan analogs with bulky A- and B-ring motifs, which protrude into the solvent allowing for the future attachment of molecular transporters for delivery. PMID- 23664873 TI - Ligand-inducible formation of RNA pseudoknot. AB - Here, we demonstrate that a series of naphthyridine derivatives, naphthyridine carbamate tetramer (NCTn), can bind to the RNA CGG/CGG triad comprised of two single-stranded regions of a hairpin loop and a tail. Complete suppression of the binding by a single mutation indicated simultaneous binding of NCTn between hairpin loop and single stranded tail, leading to the formation of NCTn-induced pseudoknot. PMID- 23664874 TI - Discovery of TAK-960: an orally available small molecule inhibitor of polo-like kinase 1 (PLK1). AB - Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies. PMID- 23664875 TI - A bioassay-driven discovery of an unexpected selenophene and its cytotoxicity. AB - During the reaction of methyl 3beta-acetoxy-glycyrrhetinate (1) with SeO2 significant amounts of a cytotoxic hitherto unprecedented triterpenoic selenophene 3 are formed. This compound stops cell proliferation and acts by apoptosis. PMID- 23664876 TI - Solid phase synthesis and biological evaluation of probestin as an angiogenesis inhibitor. AB - Probestin is a potent aminopeptidase N (APN) inhibitor originally isolated from the bacterial culture broth. Here, we report probestin synthesis by solid phase peptide synthesis (SPPS) method and evaluated its activity to inhibit angiogenesis using a chicken embryo chorioallantoic membrane (CAM) assay and a CAM tumor xenograft model. Results from these studies demonstrate that probestin inhibits the angiogenic activity and tumor growth. PMID- 23664877 TI - Synthesis of novel strobilurin-pyrimidine derivatives and their antiproliferative activity against human cancer cell lines. AB - A series of new strobilurin-pyrimidine analogs were designed and synthesized based on the structures of our previously discovered antiproliferative compounds I and II. Biological evaluation with two human cancer cell lines (A549 and HL60) showed that most of these compounds possessed moderate to potent antiproliferative activity. Two potent candidates (8f, IC50=2.2 nM and 11d, IC50=3.4 nM) were identified with nanomolar activity against leukemia cancer cell line HL60 for further development. This activity represents a 1000- to 2500-fold improvement compared to the parent compounds I and II and is 20- to 30-fold better than the chemotherapy drug, doxorubicin. The present work provides strong incentive for further development of these strobilurin-pyrimidine analogs as potential antitumor agents for the treatment of leukemia. PMID- 23664878 TI - A convenient synthesis of GDP-D-rhamnose: the donor substrate for D rhamnosyltransferase WbpZ from Pseudomonas aeruginosa PAO1. AB - Gram negative bacteria have lipopolysaccharides (LPS) that are critical for their survival. LPS molecules are composed of antigenic exopolysaccharide chains (O antigens). We are interested in discovering the enzymes involved in the biosynthesis of O antigens in Pseudomonas aeruginosa. The common polysaccharide antigen contains alpha-linked D-rhamnose residues. We have now synthesized GDP-D rhamnose by a convenient synthesis in aqueous solution, and have shown that it can be used without extensive purification as the donor substrate for D rhamnosyltransferase (WbpZ) from the P. aeruginosa strain PAO1. The availability of this nucleotide sugar preparation allows for characterization of D rhamnosyltransferases. PMID- 23664879 TI - Discovery of 1-(1,3,5-triazin-2-yl)piperidine-4-carboxamides as inhibitors of soluble epoxide hydrolase. AB - 1-(1,3,5-Triazin-yl)piperidine-4-carboxamide inhibitors of soluble epoxide hydrolase were identified from high through-put screening using encoded library technology. The triazine heterocycle proved to be a critical functional group, essential for high potency and P450 selectivity. Phenyl group substitution was important for reducing clearance, and establishing good oral exposure. Based on this lead optimization work, 1-[4-methyl-6-(methylamino)-1,3,5-triazin-2-yl]-N {[[4-bromo-2-(trifluoromethoxy)]-phenyl]methyl}-4-piperidinecarboxamide (27) was identified as a useful tool compound for in vivo investigation. Robust effects on a serum biomarker, 9, 10-epoxyoctadec-12(Z)-enoic acid (the epoxide derived from linoleic acid) were observed, which provided evidence of robust in vivo target engagement and the suitability of 27 as a tool compound for study in various disease models. PMID- 23664880 TI - Development of indole/indazole-aminopyrimidines as inhibitors of c-Jun N-terminal kinase (JNK): optimization for JNK potency and physicochemical properties. AB - A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties. PMID- 23664881 TI - The effects of belongingness on the Simultaneous Lightness Contrast: a virtual reality study. AB - Simultaneous Lightness Contrast (SLC) is the phenomenon whereby a grey patch on a dark background appears lighter than an equal patch on a light background. Interestingly, the lightness difference between these patches undergoes substantial augmentation when the two backgrounds are patterned, thereby forming the articulated-SLC display. There are two main interpretations of these phenomena: The mid-level interpretation maintains that the visual system groups the luminance within a set of contiguous frameworks, whilst the high-level one claims that the visual system splits the luminance into separate overlapping layers corresponding to separate physical contributions. This research aimed to test these two interpretations by systematically manipulating the viewing distance and the horizontal distance between the backgrounds of both the articulated and plain SLC displays. An immersive 3D Virtual Reality system was employed to reproduce identical alignment and distances, as well as isolating participants from interfering luminance. Results showed that reducing the viewing distance resulted in increased contrast in both the plain- and articulated-SLC displays and that, increasing the horizontal distance between the backgrounds resulted in decreased contrast in the articulated condition but increased contrast in the plain condition. These results suggest that a comprehensive lightness theory should combine the two interpretations. PMID- 23664882 TI - Superior renoprotective effects of the combination of breviscapine with enalapril and its mechanism in diabetic rats. AB - Breviscapine is a flavonoid extracted from a Chinese herb Erigeron breviscapus, previously it was shown that treatment with breviscapine attenuated renal injury in the diabetic rats. The purpose of this study was to investigate whether breviscapine combined with enalapril (an ACE inhibitor) have superior renoprotective effects against diabetic nephropathy. Rats were randomly separated into five groups: control, diabetes, diabetes treated with enalapril, diabetes treated with breviscapine, or diabetes treated with combined enalapril with breviscapine. Twenty-four hours urinary AER and the levels of 3-NT in renal tissue and MDA in renal tissue and urine as well as activities and expression of PKC in renal tissue were determined, and renal tissue morphology were observed by light microscopy after 8 weeks. Expression of TGFbeta1 protein was performed by immunohistochemistry method. Increased AER and kidney pathologic injury were attenuated by treatment with either enalapril or breviscapine and further reduced by the combination of the two. Elevated 3-NT in renal tissue and MDA levels in renal tissue and urine were reduced by enalapril or breviscapine and, more effectively, by combined enalapril with breviscapine. PKC activities and expression were higher in renal tissue in diabetic rats than those of the control group, which were reduced by both monotherapies, and further abrogated by combination therapy in both cases. Overexpression of TGFbeta1 protein observed in the glomeruli and tubulointerstitium of diabetic rats was attenuated by enalapril or breviscapine to a similar lever and further reduced by the combination of the two. The combination of enalapril and breviscapine confers superiority over monotherapies on renoprotection, which mechanism may be at least partly correlated with synergetic suppression on increased oxidative stress and PKC activities as well as overexpression of TGFbeta1 in renal tissue. PMID- 23664883 TI - Transgenic indica rice lines, expressing Brassica juncea Nonexpressor of pathogenesis-related genes 1 (BjNPR1), exhibit enhanced resistance to major pathogens. AB - Brassica juncea Nonexpressor of pathogenesis-related genes 1 (BjNPR1) has been introduced into commercial indica rice varieties by Agrobacterium-mediated genetic transformation. Transgenic rice plants were regenerated from the phosphinothricin-resistant calli obtained after co-cultivation with Agrobacterium strain LBA4404 harbouring Ti plasmid pSB111-bar-BjNPR1. Molecular analyses confirmed the stable integration and expression of BjNPR1 in various transgenic rice lines. Transgenes NPR1 and bar were stably inherited and disclosed co segregation in subsequent generations in a Mendelian fashion. Homozygous transgenic rice lines expressing BjNPR1 protein displayed enhanced resistance to rice blast, sheath blight and bacterial leaf blight diseases. Rice transformants with higher levels of NPR1 revealed notable increases in plant height, panicle length, flag-leaf length, number of seeds/panicle and seed yield/plant as compared to the untransformed plants. The overall results amply demonstrate the profound impact of BjNPR1 in imparting resistance against major pathogens of rice. The multipotent BjNPR1, as such, seems promising as a prime candidate gene to fortify crop plants with durable resistance against various pathogens. PMID- 23664884 TI - Development of a Stress-Inducible Controlled Expression (SICE) system in Lactococcus lactis for the production and delivery of therapeutic molecules at mucosal surfaces. AB - In recent years, recombinant lactic acid bacteria (LAB) have been successfully used as safe mucosal delivery vectors. Herein, we report on the development of a Stress-Inducible Controlled Expression (SICE) system in L. lactis for the production and delivery of proteins of health interest (both therapeutic and vaccine related) at mucosal surfaces. This system is episomal in nature and is composed of a vector carrying an expression cassette under the transcriptional control of a stress-inducible promoter. The functionality of the SICE system was validated in vivo using two different routes of administration: oral and intranasal, and in two different murine models of human pathologies: (i) a model of therapy against inflammatory bowel diseases (IBD) and (ii) a model of vaccination against human papillomavirus type-16 (HPV-16). PMID- 23664885 TI - A three-dimensional tissue culture model of bone formation utilizing rotational co-culture of human adult osteoblasts and osteoclasts. AB - Living bone is a complex, three-dimensional composite material consisting of numerous cell types spatially organized within a mineralized extracellular matrix. To date, mechanistic investigation of the complex cellular level cross talk between the major bone-forming cells involved in the response of bone to mechanical and biochemical stimuli has been hindered by the lack of a suitable in vitro model that captures the "coupled" nature of this response. Using a novel rotational co-culture approach, we have generated large (>4mm diameter), three dimensional mineralized tissue constructs from a mixture of normal human primary osteoblast and osteoclast precursor cells without the need for any exogenous osteoconductive scaffolding material that might interfere with such cell-cell interactions. Mature, differentiated bone constructs consist of an outer region inhabited by osteoclasts and osteoblasts and a central region containing osteocytes encased in a self-assembled, porous mineralized extracellular matrix. Bone constructs exhibit morphological, mineral and biochemical features similar to remodeling human trabecular bone, including the expression of mRNA for SOST, BGLAP, ACP5, BMP-2, BMP-4 and BMP-7 within the construct and the secretion of BMP 2 protein into the medium. This "coupled" model of bone formation will allow the future investigation of various stimuli on the process of normal bone formation/remodeling as it relates to the cellular function of osteoblasts, osteoclasts and osteocytes in the generation of human mineralized tissue. PMID- 23664886 TI - Fluorescent non-porous silica nanoparticles for long-term cell monitoring: cytotoxicity and particle functionality. AB - Inorganic nanoparticles such as silica particles offer many exciting possibilities for biomedical applications. However, the possible toxicity of these particles remains an issue of debate that seriously impedes their full exploitation. In the present work, commercially available fluorescent silica nanoparticles 25, 45 and 75 nm in diameter optimized for cell labelling (C Spec(r) particles) are evaluated with regard to their effects on cultured cells using a novel multiparametric setup. The particles show clear concentration and size-dependent effects, where toxicity is caused by the number and total surface area of cell-associated particles. Cell-associated particles generate a short burst of oxidative stress that, next to inducing cell death, affects cell signalling and impedes cell functionality. For cell labelling purposes, 45 nm diameter silica particles were found to be optimally suited and no adverse effects were noticeable at concentrations of 50 MUg ml(-1) or below. At this safe concentration, the particles were found to still allow fluorescence tracking of cultured cells over longer time periods. In conclusion, the data shown here provide a suitable concentration of silica particles for fluorescent cell labelling and demonstrate that at safe levels, silica particles remain perfectly suitable for fluorescent cell studies. PMID- 23664887 TI - Do behaviour-change techniques contribute to the effectiveness of exercise therapy in patients with intermittent claudication? A systematic review. AB - This systematic narrative review of randomised controlled trials (RCTs) identifies and evaluates the efficacy of behaviour-change techniques explicitly aimed at walking in individuals with intermittent claudication. An electronic database search was conducted up to December 2012. RCTs were included comparing interventions incorporating behaviour-change techniques with usual care, walking advice or exercise therapy for increasing walking in people with intermittent claudication. Studies were evaluated using the Cochrane Collaboration risk of bias tool. The primary outcome variable was maximal walking ability at least 3 months after the start of an intervention. Secondary outcome variables included pain-free walking ability, self-report walking ability and daily walking activity. A total of 3,575 records were retrieved. Of these, six RCTs met the inclusion criteria. As a result of substantial heterogeneity between studies, no meta-analysis was conducted. Overall, 11 behaviour-change techniques were identified; barrier identification with problem solving, self-monitoring and feedback on performance were most frequently reported. There was limited high quality evidence and findings were inconclusive regarding the utility of behaviour-change techniques for improving walking in people with intermittent claudication. Rigorous, fully powered trials are required that control for exercise dosage and supervision in order to isolate the effect of behaviour change techniques alongside exercise therapy. PMID- 23664888 TI - Antitumoral effects of vasoactive intestinal peptide in human renal cell carcinoma xenografts in athymic nude mice. AB - We studied antitumor effect of VIP in human renal cell carcinoma (RCC) (A498 cells xenografted in immunosuppressed mice). VIP-treated cells gave resulted in p53 upregulation and decreased nuclear beta-catenin translocation and NFkappaB expression, MMP-2 and MMP-9 activities, VEGF levels and CD-34 expression. VIP led to a more differentiated tubular organization in tumours and less metastatic areas. Thus, VIP inhibits growth of A498-cell tumours acting on the major issues involved in RCC progression such as cell proliferation, microenvironment remodelling, tumour invasion, angiogenesis and metastatic ability. These antitumoral effects of VIP offer new therapeutical possibilities in RCC treatment. PMID- 23664890 TI - Multifunctional superparamagnetic iron oxide nanoparticles: promising tools in cancer theranostics. AB - Iron-oxide nanoparticles of small dimensions that have superparamagnetic properties show immense potential to revolutionize the future of cancer theranostics, the combinatorial diagnosis and therapeutic approach towards cancer. Superparamagnetic iron-oxide nanoparticles (SPIONs) have unique magnetic properties, due to which they show excellent tumor-targeting efficiency, and this paves the way for effective personalized cancer treatment. The aim of this review is to focus on the ability of SPIONs to perform multiple roles in the field of cancer biology, such as in diagnosis, monitoring, targeting and therapy. Also, other topics are discussed, including the synthesis of SPIONs, the challenges and recent advances. PMID- 23664889 TI - Synergistic combination therapy with nanoliposomal C6-ceramide and vinblastine is associated with autophagy dysfunction in hepatocarcinoma and colorectal cancer models. AB - Autophagy, a catabolic survival pathway, is gaining attention as a potential target in cancer. In human liver and colon cancer cells, treatment with an autophagy inducer, nanoliposomal C6-ceramide, in combination with the autophagy maturation inhibitor, vinblastine, synergistically enhanced apoptotic cell death. Combination treatment resulted in a marked increase in autophagic vacuole accumulation and decreased autophagy maturation, without diminution of the autophagy flux protein P62. In a colon cancer xenograft model, a single intravenous injection of the drug combination significantly decreased tumor growth in comparison to the individual treatments. Most importantly, the combination treatment did not result in increased toxicity as assessed by body weight loss. The mechanism of combination treatment-induced cell death both in vitro and in vivo appeared to be apoptosis. Supportive of autophagy flux blockade as the underlying synergy mechanism, treatment with other autophagy maturation inhibitors, but not autophagy initiation inhibitors, were similarly synergistic with C6-ceramide. Additionally, knockout of the autophagy protein Beclin-1 suppressed combination treatment-induced apoptosis in vitro. In conclusion, in vitro and in vivo data support a synergistic antitumor activity of the nanoliposomal C6-ceramide and vinblastine combination, potentially mediated by an autophagy mechanism. PMID- 23664891 TI - The "gout of the Medici": making the modern diagnosis using paleopathology. AB - Documentary sources show that painful joint disease afflicted several members of the Medici family, which dominated Renaissance Florence in Italy. The term frequently reported in contemporary archives to indicate these morbid episodes is "gout." Paleopathology allows us to verify the nosological information obtained from the written documents and to clarify the nature of the rheumatological condition that afflicted the Medici. A paleopathological study carried out on the skeletal remains of several members of the Medici family buried in the basilica of S. Lorenzo in Florence demonstrated that the "gout" of the Medici was truly a uric acid gout only in Ferdinand I (1549-1609), whose left foot showed peculiar lesions. Genetic and environmental factors, with particular regard to diet, may have been involved in the etiology of this disease, which in Ferdinand was associated with diffuse idiopatic skeletal hyperostosis (DISH). DISH was observed also in the column of Cosimo the Elder (1389-1464) and Cosimo I (1519-1574); a link between the incidence of DISH and high social status, especially in terms of lifestyle and nutritional patterns, has been suggested and the present study seems to further confirm this association. Finally, rheumatoid arthritis (RA) was diagnosed in Cosimo the Elder, Piero "the Gouty" (1416-1469) and Cardinal Carlo (1596-1666); as for Carlo, macroscopic and radiological findings were supported by molecular results which revealed that he was bearing the specificity HLA-DR4 predisposing to RA. The coexistence of DISH and RA attested in Cosimo the Elder can be interpreted as coincidental. In conclusion, the term "gout" as used in Renaissance texts has to be regarded as the clinical manifestation of a number of different joint diseases. In the case of the Medici family in Florence, these included DISH, rheumatoid arthritis and uric acid gout. PMID- 23664892 TI - Lgr5 expression as stem cell marker in human gastric gland and its relatedness with other putative cancer stem cell markers. AB - To explore Lgr5 as the possible stem cell marker in human gastric tissue, 259 normal gastric tissues and dissected gastric adenocarcinoma were analyzed by immunohistochemistry, immunofluorescence double staining and qRT-PCR. The results demonstrated that Lgr5 was expressed in the bottom of the normal gastric gland units, and showed a differential expression in gastric adenocarcinoma with varying differentiation. Lgr5 and Bmi1 were co-expressed within the same cells of gastric glands. CD26+, CD44+, ALDH1+ and CD133+ cells co-existed with Lgr5+ cells in the stem cell zone of adjacent normal gastric mucosa, and they were detectable in gastric adenocarcinoma but behaved differently. We concluded that Lgr5 may be the adult stem cell marker in human gastric epithelium; Lgr5 and Bmi1 may belong to the same stem cell population; Lgr5, CD26, CD44, ALDH1, and CD133 may be functionally-associated. PMID- 23664894 TI - Choosing Wisely and the perceived drivers of endoscopy use. PMID- 23664893 TI - Identification, expression, and taxonomic distribution of alternative oxidases in non-angiosperm plants. AB - Alternative oxidase (AOX) is a terminal ubiquinol oxidase present in the respiratory chain of all angiosperms investigated to date, but AOX distribution in other members of the Viridiplantae is less clear. We assessed the taxonomic distribution of AOX using bioinformatics. Multiple sequence alignments compared AOX proteins and examined amino acid residues involved in AOX catalytic function and post-translational regulation. Novel AOX sequences were found in both Chlorophytes and Streptophytes and we conclude that AOX is widespread in the Viridiplantae. AOX multigene families are common in non-angiosperm plants and the appearance of AOX1 and AOX2 subtypes pre-dates the divergence of the Coniferophyta and Magnoliophyta. Residues involved in AOX catalytic function are highly conserved between Chlorophytes and Streptophytes, while AOX post translational regulation likely differs in these two lineages. We demonstrate experimentally that an AOX gene is present in the moss Physcomitrella patens and that the gene is transcribed. Our findings suggest that AOX will likely exert an influence on plant respiration and carbon metabolism in non-angiosperms such as green algae, bryophytes, liverworts, lycopods, ferns, gnetophytes, and gymnosperms and that further research in these systems is required. PMID- 23664895 TI - Brachytherapy-based partial breast irradiation is associated with low rates of complications and excellent cosmesis. AB - BACKGROUND: Recent retrospective, claims-based analyses have suggested a potential increased rate of toxicities associated with brachytherapy-based accelerated partial breast irradiation (APBI). The purpose of this analysis was to examine cosmesis and toxicity data from the prospective American Society of Breast Surgeons (ASBS) breast brachytherapy registry trial to compare to the findings from the claims analyses. METHODS: The ASBS breast brachytherapy registry is a prospective nonblinded multi-institutional registry trial. Patients with Stage 0-II breast cancer undergoing breast conserving therapy were eligible. A total of 1665 patients were enrolled and 1449 treated between 2002 and 2004 with a median followup of 63 months. All patients were treated with the MammoSite (Hologic, Inc.) single-lumen device to deliver adjuvant APBI (34Gy in 3.4Gy fractions). RESULTS: The rate of excellent/good cosmesis was 90.6% at 84 months. The rate of a complication (symptomatic seroma, infection, fat necrosis, telangiectasias) at 1 year/any time point was 24.2%/38.5%, whereas the rate of noninfectious complications at 1 year/any time point was 14.8%/28.9%. The rate of symptomatic seroma, fat necrosis, infection, and telangiectasia at any time was 13.4%, 2.5%, 9.6%, and 13.0%, respectively. CONCLUSIONS: The final toxicity analysis from ASBS breast brachytherapy registry trial confirms the previously noted excellent cosmesis and toxicity profiles and fails to confirm retrospective claims analyses that have suggested higher rates of toxicity for brachytherapy based APBI. PMID- 23664896 TI - Profile of pediatric Crohn's disease in Belgium. AB - AIM: A Belgian registry for pediatric Crohn's disease, BELCRO, was created. This first report aims at describing disease presentation and phenotype and determining associations between variables at diagnosis and registration in the database. METHODS: Through a collaborative network, children with previously established Crohn's disease and newly diagnosed children and adolescents (under 18 y of age) were recruited over a 2 year period. Data were collected by 23 centers and entered in a database. Statistical association tests analyzed relationships between variables of interest at diagnosis. RESULTS: Two hundred fifty-five patients were included. Median age at diagnosis was 12.5 y (range: 1.6 18 y); median duration of symptoms prior to diagnosis was 3 m (range: 1-12 m). Neonatal history and previous medical history did not influence disease onset nor disease behavior. Fifty three % of these patients presented with a BMI z-score < 1. CRP was an independent predictor of disease severity. Steroids were widely used as initial treatment in moderate to severe and extensive disease. Over time, immunomodulators and biological were prescribed more frequently, reflecting a lower prescription rate for steroids and 5-ASA. A positive family history was the sole significant determinant for earlier use of immunosuppression. CONCLUSION: In Belgium, the median age of children presenting with Crohn's disease is 12.5 y. Faltering growth, extensive disease and upper GI involvement are frequent. CRP is an independent predictive factor of disease activity. A positive family history appears to be the main determinant for initial treatment choice. PMID- 23664897 TI - Colorectal cancer in inflammatory bowel disease: results of the 3rd ECCO pathogenesis scientific workshop (I). AB - Epidemiological studies demonstrate an increased risk of colorectal cancer in patients with inflammatory bowel disease (IBD). A detailed literature review was conducted on epidemiology, risk factors, pathophysiology, chemoprevention and outcomes of colorectal cancer (CRC) in IBD as part of the 3rd ECCO scientific pathogenesis workshop. PMID- 23664898 TI - Dorsolateral frontal cortex and peripheral muscarinic receptors participation in the discriminative stimulus properties of scopolamine in rats. AB - Organisms are capable of making decisions based on their ability to discriminate between different stimuli. This principle is fundamental for the adaptation of organisms to their environment, by emitting appropriate behaviors based on a previously acquired discriminative process. The present study analyzed the participation of the peripheral nervous system, the M1 muscarinic receptor subtype, as well as the contribution of the dorsolateral frontal cortex to discrimination process using scopolamine as discriminative stimulus. Male Wistar rats were trained to discriminate between scopolamine (1.0 mg/kg) and saline injections (i.p.) using a two-lever operant procedure. Once discrimination was acquired, generalization curves for scopolamine, methylscopolamine, pirenzepine, dorsolateral frontal cortex lesion and control conditions were obtained. Results showed that rats were able to discriminate and generalize its responses to different doses of scopolamine but not for methylscopolamine or pirenzepine, thus the data suggest that discriminative properties of scopolamine are processed in CNS and that the M1 receptor does not participate in this process. Dorsolateral frontal cortex lesion did not produce any statistically significant difference in the generalization curve, which suggests that a system different from the dorsolateral prefrontal cortex may be responsible for the control of stimulus produced by scopolamine. PMID- 23664900 TI - Anticonvulsant effect of kaurenoic acid isolated from the root bark of Annona senegalensis. AB - CONTEXT: The herbal preparations of Annona senegalensis Pers. (Annonaceae) root bark are used in Nigerian ethnomedicine for the treatment of epilepsy and febrile seizures. The scientific evidence for this effect has been reported. OBJECTIVE: The aim of this study was to identify and characterize the active constituent responsible for the anticonvulsant effect. MATERIALS AND METHODS: Bioactive guided fractionation of the methanol-methylene chloride root bark extract (MME) of A. senegalensis using pentylenetetrazole (PTZ)-induced seizures in mice, afforded a potent anticonvulsant ethyl-acetate fraction (EF). Further fractionation of the EF yielded eight sub-fractions (F1-F8) which were tested for anticonvulsant activity. The sub-fraction F2 yielded white crystals that were purified to obtain A. senegalensis crystals, AS2. The AS2, which exhibited potent anticonvulsant effects, was characterized by 1D and 2D NMR spectroscopy, mass spectroscopy and X-ray crystallography. RESULTS: The AS2 was characterized as kaur-16-en-19-oic acid (KA), a diterpenoid. The AS2 indicated an oral LD50 of 3800 mg/kg. The results showed that the MME, EF and AS2 significantly (P<0.05) and dose-dependently delayed the onset of myoclonic spasms and tonic-clonic phases of seizures induced by PTZ and maximal electroshock seizures (MES). DISCUSSION AND CONCLUSION: Kaurenoic acid was identified as the anticonvulsant principle in the root bark extract of A. senegalensis. The anticonvulsant effect of the MME, EF and AS2 is most likely being mediated through central inhibitory mechanisms. PMID- 23664899 TI - Anxiolytic effects of the GABA(A) receptor partial agonist, L-838,417: impact of age, test context familiarity, and stress. AB - The partial alpha2,3,5 GABA(A) receptor agonist, L-838,417 has been reported to have anxiolytic effects in adult rodents. Although maturational differences exist for the GABA(A) receptor subunits, the anxiolytic effects of L-838,417 have not been tested in younger animals. The goal of the present experiments was to determine whether L-838,417 reverses anxiety-like behavior induced by either an unfamiliar environment (Experiment 1) or repeated restraint stress (Experiment 2) differentially in adolescent and adult, male and female Sprague-Dawley rats using a modified social interaction test. In Experiment 1, rats were injected with 0, 0.5, 1.0, 2.0, or 4.0 mg/kg L-838,417, i.p. and tested 30 min later in an unfamiliar test context for 10 min. In Experiment 2, rats were exposed to restraint stress (90 min daily for 5 days). Immediately after the last restraint session, animals were injected with L-838,417 and placed alone for 30 min in the test apparatus to familiarize them to this context prior to the 10 min social interaction test. In Experiment 1, L-838,417 produced anxiolytic effects in adults at 1.0 mg/kg, as indexed by a transformation of social avoidance into preference and an increase in social investigation. In adolescents, a dose of 2.0 mg/kg eliminated social avoidance, but had no anxiolytic effects on social investigation. Testing under familiar circumstances (Experiment 2) after repeated restraint stress eliminated age differences in sensitivity to L-838,417, with 0.5 mg/kg reversing the anxiogenic effects of prior stress regardless of age, but with doses >= 1 mg/kg decreasing social investigation, an effect possibly due in part to locomotor-impairing effects of this compound. Although locomotor activity was suppressed in both experiments, higher doses of L-838,417 were necessary to suppress locomotor activity in Experiment 1. Thus, anxiolytic effects of L 838,417 were found to be context-, age-, and stress-dependent. PMID- 23664901 TI - Dopamine agonist-induced penile erection and yawning: a comparative study in outbred Roman high- and low-avoidance rats. AB - The effects on penile erection and yawning of subcutaneous (SC) injections of the mixed dopamine D1/D2-like agonist apomorphine (0.02-0.2 mg/kg) were studied in outbred Roman high- (RHA) and low-avoidance (RLA) male rats, two lines selectively bred for their respectively rapid versus poor acquisition of the active avoidance response in the shuttle-box, and compared with the effects observed in male Sprague-Dawley (SD) rats. Apomorphine dose-response curves were bell-shaped in all rat lines/strains. Notably, more penile erections and yawns were recorded mainly in the ascending part of these curves (e.g., apomorphine 0.02-0.08 mg/kg) in both RLA and RHA rats compared to SD rats, with RLA rats showing the higher response (especially for yawning) with respect to RHA rats. Similar results were found with PD-168,077 (0.02-0.2 mg/kg SC), a D4 receptor agonist, which induced penile erection but not yawning. In all rat lines/strains, apomorphine responses were markedly reduced by the D2 antagonist L-741,626, but not by the D3 antagonist, SB277011A, whereas the D4 antagonists L-745,870 and FAUC213 elicited a partial, yet statistically significant, inhibitory effect. In contrast, the pro-erectile effect of PD-168,077 was completely abolished by L 745,870 and FAUC213, as expected. The present study confirms and extends previously reported differences in dopamine transmission between RLA and RHA rats and between the SD strain and the Roman lines. Moreover, it confirms previous studies supporting the view that dopamine receptors of the D2 subtype play a predominant role in the pro-yawning and pro-erectile effect of apomorphine, and that the selective stimulation of D4 receptors induces penile erection. PMID- 23664902 TI - Water dispersible magnetite nanoparticles influence the efficacy of antibiotics against planktonic and biofilm embedded Enterococcus faecalis cells. AB - The objective of this study was to investigate the potential of magnetic nanoparticles to potentiate, but also to accomplish a sustained and controlled drug release and subsequently improve the efficacy of antibiotics against Enterococcus faecalis, one of the most resistant opportunistic pathogens, that poses a threat to chronically infected or immunocompromised patients and is difficult to eradicate from medical devices. To our knowledge, this is the first study trying to investigate the ability of magnetite nanoparticles to improve the anti-bacterial activity of the current antibiotics against planktonic and biofilm growing E. faecalis. Our results are suggesting that the magnetite nanoparticles may be considered an effective aminoglycoside antibiotics carrier, but a complete understanding of the way in which they selectively interact with different antibiotics and with the bacterial cell is needed, in order to obtain improved strategies for elimination of E. faecalis biofilms on biomedical devices or human tissues. PMID- 23664903 TI - Severe narrowing of left cavernous carotid artery associated with Fusobacterium necrophorum infection. AB - Severe oropharyngeal infection can result in Lemierre's disease, a syndrome with high mortality secondary to inflammation and thrombosis of cervical and intracranial veins with involvement of contiguous structures; however arterial involvement is rare. We report a case of Lemierre's disease in a 12 year old boy with severe narrowing of the left cavernous carotid artery. PMID- 23664904 TI - Oxygen deprivation affects the antimicrobial action of LL-37 as determined by microplate real-time kinetic measurements under anaerobic conditions. AB - Some agents, including Escherichia coli and group A Streptococcus pyogenes cause infections in oxygen depleted sites. LL-37 is a human host defence peptide shown previously to play an important role in controlling infections caused by these bacteria. However, the effect of oxygen levels on the antimicrobial activity of LL-37 remains obscure. In order to test the effect of oxygen (or lack thereof) on LL-37's activity against E. coli and S. pyogenes, a method for adapting commonly used microtiter plates for real-time growth-kinetic (and growth-inhibition) measurements under anaerobic conditions was developed. Using the proposed method, anaerobic conditions were attained in the microplate within 30 min and were maintained for at least five days. Anaerobiosis was further confirmed by comparing the growth of two anaerobic oral species (Porphyromonas gingivalis and Fusobacterium nucleatum) in anaerobic compartments of microtiter plates versus aerobic ones. Both species grew only in the anaerobic compartments of the plates as indicated by the growth curves generated. The sensitivities of E. coli and S. pyogenes to LL-37 were tested under anaerobic conditions and compared to those in aerobic ones. The oxygen facultative E. coli grew to a higher density under aerobic conditions and its sensitivity to LL-37 was increased under anaerobiosis. The microaerophilic pathogen S. pyogenes grew faster and to a higher density under anaerobic conditions and was much more resistant to LL-37 under oxygen deprivation. Our results suggest that resistance to antimicrobial agents of microbes infecting anaerobic-microaerophilic sites should be tested under oxygen restricted conditions. PMID- 23664905 TI - Identification of Veillonella tobetsuensis in tongue biofilm by using a species specific primer pair. AB - Veillonella atypica, Veillonella denticariosi, Veillonella dispar, Veillonella parvula, and Veillonella rogosae have been reported to be isolated from human oral cavities. The recently detected Veillonellatobetsuensis in human tongue biofilms was proposed as a novel Veillonella sp. In this study, to determine the distribution and frequency of V. tobetsuensis, we established a method for the detection and identification of V. tobetsuensis by using polymerase chain reaction (PCR) using a species-specific primer pair. The primer pair for V. tobetsuensis was designed on the basis of the nucleotide sequence of the 70-kDa heat shock protein (dnaK) gene of V. tobetsuensis JCM 17976(T) (=ATCC BAA 2400(T)). The primer pair generated a specific PCR product for V. tobetsuensis but not for other oral Veillonella spp. With the PCR procedure using the primer pair, we could detect less than 10 ng of genomic DNA extracted from V. tobetsuensis. Thus, the PCR method using this primer pair is suitable for the specific detection and identification of V. tobetsuensis. The distribution and frequency of V. tobetsuensis were investigated by PCR using this species-specific primer pair. V. tobetsuensis was detected in 5 of 27 subjects. V. tobetsuensis was recovered from 19% (5/27) of subjects with other Veillonella species. And, prevalence of V. tobetsuensis ranged from 7.6% to 20.0% in these subjects. V. tobetsuensis is likely to coexist with other Veillonella spp. in tongue biofilm. In this study, the species-specific PCR primer pair for V. tobetsuensis was designed using partial sequences of the dnaK gene. This is the first report using a species-specific primer pair for PCR to determine the distribution and frequency of V. tobetsuensis in tongue biofilm. PMID- 23664906 TI - Transposon mutagenesis of Bacteroides fragilis using a mariner transposon vector. AB - The mariner transposon vector pYV07 was tested for use in the mutagenesis of Bacteroides fragilis 638R. The transposon vector efficiently generated mutants in B. fragilis 638R. The transposon disrupted genes were scattered throughout the genome of B. fragilis 638R. This method serves as a powerful tool to study B. fragilis. PMID- 23664907 TI - Edible lipid nanoparticles: digestion, absorption, and potential toxicity. AB - Food-grade nanoemulsions are being increasingly used in the food and beverage industry to encapsulate, protect, and deliver hydrophobic functional components, such as oil-soluble flavors, colors, preservatives, vitamins, and nutraceuticals. These nanoemulsions contain lipid nanoparticles (radius <100 nm) whose physicochemical characteristics (e.g., composition, dimensions, structure, charge, and physical state) can be controlled by selection of appropriate ingredients and fabrication techniques. Nanoemulsions have a number of potential advantages over conventional emulsions for applications within the food industry: higher stability to particle aggregation and gravitational separation; higher optical transparency; and, increased bioavailability of encapsulated components. On the other hand, there are also some risks associated with consumption of lipid nanoparticles that should be considered before they are widely utilized, such as their ability to alter the fate of bioactive components within the gastrointestinal tract and the potential toxicity of some of the components used in their fabrication (e.g., surfactants and organic solvents). This article provides an overview of the current status of the biological fate and potential toxicity of food-grade lipid nanoparticles suitable for utilization within the food and beverage industry. PMID- 23664908 TI - Two duplicated chicken-type lysozyme genes in disc abalone Haliotis discus discus: molecular aspects in relevance to structure, genomic organization, mRNA expression and bacteriolytic function. AB - Lysozymes are crucial antibacterial proteins that are associated with catalytic cleavage of peptidoglycan and subsequent bacteriolysis. The present study describes the identification of two lysozyme genes from disc abalone Haliotis discus discus and their characterization at sequence-, genomic-, transcriptional- and functional-levels. Two cDNAs and BAC clones bearing lysozyme genes were isolated from abalone transcriptome and BAC genomic libraries, respectively and sequences were determined. Corresponding deduced amino acid sequences harbored a chicken-type lysozyme (LysC) family profile and exhibited conserved characteristics of LysC family members including active residues (Glu and Asp) and GS(S/T)DYGIFQINS motif suggested that they are LysC counterparts in disc abalone and designated as abLysC1 and abLysC2. While abLysC1 represented the homolog recently reported in Ezo abalone [1], abLysC2 shared significant identity with LysC homologs. Unlike other vertebrate LysCs, coding sequence of abLysCs were distributed within five exons interrupted by four introns. Both abLysCs revealed a broader mRNA distribution with highest levels in mantle (abLysC1) and hepatopancreas (abLysC2) suggesting their likely main role in defense and digestion, respectively. Investigation of temporal transcriptional profiles post LPS and -pathogen challenges revealed induced-responses of abLysCs in gills and hemocytes. The in vitro muramidase activity of purified recombinant (r) abLysCs proteins was evaluated, and findings indicated that they are active in acidic pH range (3.5-6.5) and over a broad temperature range (20-60 degrees C) and influenced by ionic strength. When the antibacterial spectra of (r)abLysCs were examined, they displayed differential activities against both Gram positive and Gram negative strains providing evidence for their involvement in bacteriolytic function in abalone physiology. PMID- 23664909 TI - Immunological responses of the mangrove oysters Crassostrea gasar naturally infected by Perkinsus sp. in the Mamanguape Estuary, Paraiba state (Northeastern, Brazil). AB - Perkinsus genus includes protozoan parasites of marine mollusks, especially bivalves. In the last four years, this parasite has been detected in mangrove oysters Crassostrea rhizophorae and Crassostrea gasar from the Northeastern region of Brazil. Hemocytes are the key cells of the oyster immune system, being responsible for a variety of cellular and humoral reactions, such as phagocytosis, encapsulation and the release of several effector molecules that control the invasion and proliferation of microorganisms. In Brazil, there is little information on perkinsosis and none on the immune responses of native oysters' species against Perkinsus spp. The objective of this study was to determine the effects of natural infection by Perkinsus sp. on the immunological parameters of mangrove oysters C. gasar cultured in the Mamanguape River Estuary (Paraiba, Brazil). Adults oysters (N = 40/month) were sampled in December 2011, March, May, August and October 2012. Gills were removed and used to determine the presence and intensity of the Perkinsus sp. infection, according to a scale of four levels (1-4), using the Ray's fluid thioglycollate medium assay. Immunological parameters were measured in hemolymph samples by flow cytometry, including: total hemocyte count (THC), differential hemocyte count (DHC), cell mortality, phagocytic capacity, and production of Reactive Oxygen Species (ROS). The plasma was used to determine the hemagglutination activity. The results showed the occurrence of Perkinsus sp. with the highest mean prevalence (93.3%) seen so far in oyster populations in Brazil. Despite that, no oyster mortality was associated. In contrast, we observed an increase in hemocyte mortality and a suppression of two of the main defense mechanisms, phagocytosis and ROS production in infected oysters. The increase in the percentage of blast-like cells on the hemolymph, and the increase in THC in oysters heavily infected (at the maximum intensity, 4) suggest an induction of hemocytes proliferation. The immunological parameters varied over the studied months, which may be attributed to the dynamics of infection by Perkinsus sp. The results of the present study demonstrate that Perkinsus sp. has a deleterious effect on C. gasar immune system, mainly in high intensities, which likely renders oysters more susceptible to other pathogens and diseases. PMID- 23664910 TI - The link between selenium binding protein from Sinonovacula constricta and environmental pollutions exposure. AB - Selenium binding proteins (SeBPs) play a crucial role in controlling the oxidation/reduction in many physiological processes. Here we reported the isolation and characterization of a cDNA of SeBP gene from Sinonovacula constricta (denoted as ScSeBP). The full-length cDNA of ScSeBP was of 2345 bp, consisting of a 5'UTR of 246 bp, a 3' UTR of 626 bp, and a complete ORF of 1473 bp encoding a polypeptide with 491 amino acid residues. The predicted molecular mass of deduced amino acid of ScSeBP was 54.85 kDa and the theoretical pI was 6.44. Tissue distribution analysis of the ScSeBP revealed that the mRNA transcripts of ScSeBP were constitutively expressed in all examined tissues with the higher expressions in gill, gonad and the haemocytes. The temporal expression of ScSeBP in gill and haemocytes after B[alpha]P and heavy metals exposure were recorded by qPCR. B[alpha]P exposure at 0.5 and 5 mg L(-1) caused significant increase in mRNA expression of ScSeBP in haemocytes, but down-regulated ScSeBP mRNA expression in gill. Concerning heavy metals stresses, the suppressed expression patterns were detected in gill and haemocyte except lower concentration of PbCl2 exposure in haemocytes at 12 h. All our results indicated that ScSeBP was one of key effectors in mediating B[alpha]P and heavy metals exposure. PMID- 23664911 TI - Phagocytosis and respiratory burst activity of haemocytes from the ivory snail, Babylonia areolata. AB - Haemocytes from the ivory snail, Babylonia areolata phagocytized Saccharomyces cerevisiae and Vibrio parahaemolyticus after 30 min. Haemocytes phagocytized V. parahaemolyticus at a greater rate than they phagocytized S. cerevisiae. The phagocytic rate (PP) of V. parahaemolyticus by granulocytes to was a little higher than that of S. cerevisiae. The phagocytic index (PI) of V. parahaemolyticus by granulocytes was significantly higher than that of S. cerevisiae. The same was true of hyalinocytes. The PP of granulocytes was significantly higher than that of hyalinocytes for each pathogen. No difference in PI was observed in granulocytes and hyalinocytes. Two defense mechanisms of B. areolata were quantified using flow cytometry. Haemocyte phagocytosis was quantified using fluorescent microbeads and respiratory burst activity was measured using H2O2 increases detected by 2', 7'-dichlorofluorescein diacetate. Both phagocytosis and respiratory burst activity of the haemocytes increased over time. After 90 min the phagocytic rate no longer increased. In the case of respiratory burst, the greatest increase in fluorescence occurred between 30 and 120 min, no further increase was seen after 120 min. These results showed unequivocally that a native (unstimulated) haemocyte oxidative burst was active in B. areolata. The aim of this study was to further the knowledge of immunology in gastropods. PMID- 23664912 TI - A tailless Dscam from Eriocheir sinensis diversified by alternative splicing. AB - Dscam (Down syndrome cell adhesion molecule), a member of the immunoglobulin superfamily (IgSF), plays an essential role in pathogen recognition and further involves in the innate defense of invertebrates. In the present study, the cDNA of a Dscam from Chinese mitten crab Eriocheir sinensis (designated EsDscam) was cloned and characterized. It contained a 5-terminal untranslated region (UTR) of 60 bp, a 3-UTR of 216 bp with a poly (A) tail, and an open reading frame (ORF) of 4848 bp encoding a polypeptide of 1615 amino acids with the putative molecular mass of 178.4 kDa and theoretical isoelectric point of 6.31. The EsDscam protein shared higher sequence identities and similar domain architecture with Dscams from other invertebrate, including typical 10 immunoglobulin (Ig) domains, 6 fibronectin type 3 domains (FNIII) and one cell attachment sequence (RGD) in extracellular region, while it lacked the expected transmembrane domain and cytoplasmic tail compared with other members of Dscam family. After sequencing 80 separate clones of Ig2, 3 and Ig7 regions from pooled cDNA libraries constructed from normal and bacterial-infected crabs, 44 alternative sequences were detected in the N-terminal of Ig2, 39 ones in Ig3, and 31 ones in Ig7 domain, suggesting that EsDscam could potentially encode at least 53196 unique isoforms. Furthermore, two 3'UTR isoforms and two 5'UTR isoforms of EsDscam were also identified by RACE strategy. EsDscam mRNA was most abundantly expressed in the tissues of nerve, muscle, hepatopancreas and gill, and weakly expressed in heart, gonad and hemocytes. Western blotting and immunofluorescence analysis revealed that EsDscam protein was mainly distributed in serum, and few on the membrane of crab hemocytes. These results suggested that this tailless EsDscam was one member of crustacean Dscam family, and the generation of diverse isoforms through alternative splicing allowed it to recognize various pathogens and play an active role in immune defense of crabs. PMID- 23664913 TI - Diversity of lectins in Macrobrachium rosenbergii and their expression patterns under spiroplasma MR-1008 stimulation. AB - Lectins play important roles in crustacean innate immunity through recognition of foreign pathogens. In this study, 20 lectins including C-type lectins [dual carbohydrate recognition domain (CRD) type and single-CRD type], L-type lectin, and lectin with low-density lipoprotein class A (LDLa) domain were identified from the freshwater prawn Macrobrachium rosenbergii. The tissue distribution and expression patterns of these lectins under spiroplasma strain MR-1008 challenge were investigated. Most of the lectins were found to be mainly distributed in the hepatopancreas. Lectin5, Lectin14, Lectin17, and Lectin18 exhibited the highest expression level in the hemocytes, nerve, intestine, and heart, respectively. MrLec1 to MrLec6 (dual-CRD lectins) in the hepatopancreas were up-regulated by spiroplasma challenge. Single-CRD lectins reached the highest level at 72 h after spiroplasma challenge. Lectin9 and Lectin15 both belong to L-type lectins. At post-spiroplasma challenge, Lectin9 expression was up-regulated, whereas Lectin15 expression was down-regulated. Lectin11 with LDLa domain showed the highest level after 12 h Lectin18 and Lectin20, namely, CD209, were also up-regulated by spiroplasma challenge. Lectin14, a C-type lectin, quickly reached the highest level after 2 h Lectin16 showed the highest level after 72 h Lectin5 reached the highest level in cultured hemocytes after 6 h Lectin17 in the intestine and Lectin14 in the nerve were slightly up-regulated after 6 and 2 h, respectively. Our research results indicate that lectins may play important roles in early or late immune responses against spiroplasma challenge. PMID- 23664914 TI - Lactobacillus planarum subsp. plantarum JCM 1149 vs. Aeromonas hydrophila NJ-1 in the anterior intestine and posterior intestine of hybrid tilapia Oreochromis niloticus ? * Oreochromis aureus ?: an ex vivo study. AB - To investigate the ex vivo interactions of probiotic-pathogen-host in warm-water fish, hybrid tilapia (Oreochromis niloticus? * Oreochromis aureus?) were sacrificed to isolate anterior and posterior intestine for incubation with phosphate-buffered saline (PBS; pH 7.2) as the control, Lactobacillus plantarum JCM 1149 at 1.0 * 10(9) CFU/ml, Aeromonas hydrophila NJ-1 at 1.0 * 10(8) CFU/ml, or the both combination. Denaturing Gradient Gel Electrophoresis (DGGE) fingerprint and consequent sequence analysis confirmed anterior intestine sac was more prone to the colonization of L. plantarum JCM 1149 and A. hydrophila NJ-1 than the posterior part. L. plantarum JCM 1149 and A. hydrophila NJ-1 inhibited the population each other in anterior or posterior sac, indicating their competition for the colonization. The induced expression of HSP70, IL-1beta and TNF-alpha in the anterior sac by the addition of L. plantarum JCM 1149 or A. hydrophila NJ-1 demonstrated the activity and a local immune response of ex vivo anterior sac. Compared with posterior intestine, higher population colonization and more sensitive immune response of anterior sac indicated differential patterns for the probiotic-pathogen-host interactions. Scanning electronic microscopy (SEM) observation showed that pathogen A. hydrophila NJ-1 damaged the anterior intestine, which was alleviated by the pretreatment of L. plantarum JCM 1149, showing its probiotic effect. PMID- 23664915 TI - Development of a novel candidate subunit vaccine against Grass carp reovirus Guangdong strain (GCRV-GD108). AB - Grass carp reovirus Guangdong 108 strain (GCRV-GD108) was recently isolated in Guangdong province, China. M6 gene of GCRV-GD108 was speculated encoding virus major outer capsid protein VP4. Blast analysis showed that the amino acid sequence of GCRV-GD108 VP4 was homologous to the structural protein VP4 of known Aquareoviruses (27.3-32.9%). Immunogenicity prediction by DNAStar software revealed there were multiple B cell epitopes on GCRV-GD108 VP4. Prokaryotic expression vector pET32a was used to express VP4 recombinant protein (rVP4) in E. coli BL21(DE3) strain. As expected, the molecular weight of recombinant VP4 was about 87 kDa showed by SDS-PAGE result. Neutralization assay demonstrated that the rabbit polyclonal antibody of rVP4 could prevent virus infection efficiently. After 14 days immunization with the rVP4, grass carps were challenged with GCRV GD108, the results showed that different doses of rVP4 (1 MUg/g, 3 MUg/g and 5 MUg/g) all provided protection against virus infection (47-82%). The relative percent survival reached 82% in the group immunized with 3 MUg/g of rVP4. ELISA revealed rVP4 induced high antibody titer in immunized fish. IgM expression levels in head kidney of grass carp were detected by RT-PCR, and the results showed that IgM expressed at a significantly higher level in immunization groups than in blank control, indicating the rVP4 can induce strong immune response. In conclusion, rVP4 is a candidate vaccine against GCRV-GD108. PMID- 23664916 TI - Intramuscular challenge of rainbow trout (Oncorhynchus mykiss) with two Norwegian field strains of Flavobacterium psychrophilum. AB - In recent years there has been an increasing occurrence of Flavobacterium psychrophilum infections in farmed salmonids in Norway. The current study describes two field isolates of F. psychrophilum collected from farmed rainbow trout (Oncorhynchus mykiss) fingerlings and post smolts in Norway. Virulence of the two isolates was tested in vivo by intramuscular (IM) and/or intraperitoneal (IP) challenge of disease free, un-vaccinated rainbow trout. The isolates were concluded to be highly virulent compared to a reference isolate as they yielded high mortality after IM challenge even at low challenge doses. The more virulent of the two isolates was further used to establish a challenge model to evaluate the efficacy of vaccines against infections with F. psychrophilum. Three groups were included in the vaccination-challenge study; a vaccinated group given a 6 antigen (Ag) component vaccine containing F. psychrophilum antigens (6 Ag/F.psy(+)), a control vaccinated group administered a similar 5 antigen component vaccine without F. psychrophilum antigens (5 Ag/F.psy(-)), and a non injected negative control group. Results from the IM challenge demonstrated that 1) our challenge model is able to discriminate between protected and unprotected experimental groups and 2) that the vaccine induced protection is specific against F. psychrophilum as mortality in the 5 Ag/F.psy(-) group was equally high as in the negative control, while the 6 Ag/F.psy(+) induced a high level of protection (RPS60 = 86.7%). The present study is one of the first to describe protection against F. psychrophilum infections induced by a multicomponent injection vaccine. PMID- 23664917 TI - Transplatin enhances effect of cisplatin on both single DNA molecules and live tumor cells. AB - Cisplatin is the main platinum antitumor drug applied in clinical settings. However, its trans isomer, transplatin, is known to have an ineffective antitumor activity. Despite intensive studies in this field, the structural and biophysical properties of DNA molecules reacting with these two platinum complexes have not been fully elucidated. In the present study, we observed that transplatin made efficient cross-linking of DNA in the vicinity of cisplatin adducts. High resolution atomic force microscopy studies revealed that the transplatin-induced cross-linkings of nucleotides flanking cisplatin adducts were characterized by kinked-loop structures with rod-like shapes of nanometer scales (~10-60nm). The results were further confirmed by denaturing gel electrophoresis and single molecule experiment using magnetic tweezers. In vivo studies revealed that transplatin and cisplatin co-treatment could induce a considerable amount of kinked loops with smaller sizes (~15nm) in cellular DNA. Furthermore, compared with cisplatin treatment alone, the co-treatment resulted in enhanced cytotoxicity, increased amount of interstrand cross-links, and cell lesions more reluctant to cellular repair system. The results of the present study provide a new clue for understanding the stepwise reactions of DNA with platinum drugs and might serve as a basis for the development of a new antitumor strategy. PMID- 23664918 TI - Recovery from hind limb ischemia enhances rhBMP-2-mediated segmental bone defect repair in a rat composite injury model. AB - Although severe extremity trauma is often inclusive of skeletal and vascular damage in combination, segmental bone defect repair with concomitant vascular injury has yet to be experimentally investigated. To this end, we developed a novel rat composite limb injury model by combining a critically-sized segmental bone defect with surgically-induced hind limb ischemia (HLI). Unilateral 8mm femoral defects were created alone (BD) or in combination with HLI (BD + HLI), and all defects were treated with rhBMP-2 via a hybrid biomaterial delivery system. Based on reported clinical and experimental observations on the importance of vascular networks in bone repair, we hypothesized that HLI would impair bone regeneration. Interestingly, the BD+HLI group displayed improved radiographic bridging, and quantitative micro-CT analysis revealed enhanced bone regeneration as early as week 4 (p < 0.01) that was sustained through week 12 (p < 0.001) and confirmed histologically. This effect was observed in two independent studies and at two different doses of rhBMP-2. Micro-CT angiography was used to quantitatively evaluate vascular networks at week 12 in both the thigh and the regenerated bone defect. No differences were found between groups in total blood vessel volume in the thigh, but clear differences in morphology were present as the BD+HLI group possessed a more interconnected network of smaller diameter vessels (p < 0.001). Accordingly, while the overall thigh vessel volume was comparable between groups, the contributions to vessel volume based on vessel diameter differed significantly. Despite this evidence of a robust neovascular response in the thigh of the BD + HLI group, differences were not observed between groups for bone defect blood vessel volume or morphology. In total, our results demonstrate that a transient ischemic insult and the subsequent recovery response to HLI significantly enhanced BMP-2-mediated segmental bone defect repair, providing additional complexity to the relationship between vascular tissue networks and bone healing. Ultimately, a better understanding of the coupling mechanisms may reveal important new strategies for promoting bone healing in challenging clinical scenarios. PMID- 23664919 TI - Photocatalytic degradation of trimethoprim by metallic nanoparticles supported on TiO2-P25. AB - The effect of Au, Ag, Cu and Ni nanoparticles deposited on TiO2-P25 was studied on the photodegradation of trimethoprim, a commonly used antibiotic. The synthesized materials were characterized by ICP, EDS, XRD, BET, UV-vis, TEM and TPR. The metal loading was 0.5 wt.% and the average particle size was about 2 nm in all the studied samples. The deposition of metallic particles on TiO2-P25 produces an enhancement of the activity of the bare semiconductor; when the degradation of trimethoprim was carried out by pure TiO2-P25, the mineralization reached only 50% of the organic matter, while by using metallic nanoparticles deposited on TiO2-P25, the mineralization of organic matter increased up to 80% for the same reaction conditions and reaction time. The evaluation of the photocatalytic activity was made for solutions containing trimethoprim in concentrations of 40 ppm under UV light irradiation using a lamp with primary emission at 254 nm and 2.2 mW/cm(2). It is shown that the ability of the photocatalyst to mineralize trimethoprim depends on the electron affinity and the electronegativity of the deposited metal. PMID- 23664920 TI - Placental concentrations of manganese and the risk of fetal neural tube defects. AB - Manganese (Mn) is an essential trace element required for normal growth, development, and cellular homeostasis, but excess Mn is toxic to the central nervous system. The present pilot study examined whether the level of Mn in the placenta was associated with the risk of fetal neural tube defects (NTDs). A case control study was conducted. Cases were 80 fetuses or newborns with NTDs, and controls were 50 healthy, nonmalformed newborns. Placental Mn, zinc, copper, iron, and selenium were determined with inductively coupled plasma-mass spectrometry. The median Mn concentration was significantly higher in case placentas than in controls: cases, 131.60 ng/g (95% confidence interval [CI], 99.25-166.76); controls, 101.54 ng/g (95% CI, 80.14-119.79). Mn concentrations above the median were associated with a 4-fold (95% CI, 1.23-14.79) increased risk for any NTDs and a 7-fold (95% CI, 1.52-39.64) increased risk for spina bifida after other confounding factors were controlled. Elevated Mn levels were associated with an increased risk of anencephaly, although the adjusted odds ratio did not reach statistical significance. The association between higher Mn concentrations and risk of NTDs showed a clear dose-response relationship. Risk of NTDs increased to 1.51 (95% CI, 0.65-3.52) and 5.03 (95% CI, 1.89-13.33) for those whose placental Mn level was in the second and third tertiles, respectively, compared with the lowest tertile. Elevated placental concentrations of Mn may be associated with increased risks of NTDs in this population. PMID- 23664921 TI - Copper/zinc and copper/selenium ratios, and oxidative stress as biochemical markers in recurrent aphthous stomatitis. AB - PROJECT: Recurrent aphthous stomatitis (RAS) is a common oral mucosal disorder characterized by recurrent, painful oral aphthae, and oxidative stress presumably contributes to its pathogenesis. The aim of this study is to scrutinize the relationship between oxidative stress and serum trace elements (copper, Cu; zinc, Zn; selenium, Se), and to evaluate the ratios of Cu/Zn and Cu/Se in this disorder. PROCEDURE: Patients with RAS (n = 33) and age- and sex-matched healthy control subjects (n = 30) were enrolled in this study. Malondialdehyde (MDA) concentrations in plasma and the activities of superoxide dismutase (SOD1; CuZnSOD), glutathione peroxidase (GPx) and catalase (CAT) in erythrocyte were determined as spectrophotometric. Also, the levels of Se, Zn and Cu in serum were determined on flame and furnace atomic absorption spectrophotometer using Zeeman background correction. RESULTS AND CONCLUSIONS: Oxidative stress was confirmed by the significant elevation in plasma MDA, and by the significant decrease in CAT, SOD1, and GPx (p < 0.05). When compared to controls, Zn and Se levels were significantly lower in patients, whereas Cu levels was higher in RAS patients than those in controls (p < 0.05). In addition, the correlation results of this study were firstly shown that there were significant and positive correlations between Se-CAT, Se-GPx, and Cu-MDA parameters, but negative correlations between Se-Cu, Se-MDA, Cu-CAT, Cu-SOD1 and Cu-GPx parameters in RAS patients. Furthermore, the ratios of Cu/Zn and Cu/Se were significantly higher in the patients than the control subjects (p < 0.05). Our results indicated that lipid peroxidation associated with the imbalance of the trace elements seems to play a crucial role in the pathogenesis of RAS. Furthermore, the serum Cu/Zn and Cu/Se ratios may be used as biochemical markers in these patients. PMID- 23664922 TI - Trace elements (copper, zinc, selenium and molybdenum) as markers in oral sub mucous fibrosis and oral squamous cell carcinoma. AB - Oral cancer is a major cause of cancer morbidity and mortality worldwide and is prevalent in most areas where tobacco related practices are observed. Essential elements play a role in many biochemical reactions as a micro-source and there is growing evidence that their concentrations are altered on the onset and progress of malignant disease. In this study the levels of copper (Cu), zinc (Zn), selenium (Se) and molybdenum (Mo) in serum of patients with oral sub mucous fibrosis (OSMF) (n = 30) and oral squamous cell carcinoma (OSCC) (n = 30); were determined and the alterations of these critical parameters were analyzed in comparison with controls (n = 30) to identify predictors amongst these parameters for disease occurrence and progression. The serum Cu and Zn were established using Flame Atomic Absorption Spectrometry. Serum estimation of Se and Mo was done by graphite furnace atomic absorption spectrometry (GFAAS). Data analysis revealed a marked, progressive and significant increase in Cu levels in precancer (OSMF) and cancer (OSCC) groups as compared to the normal group. The level of Zn in serum was slightly elevated in OSMF and OSCC though not statistically significant. Cu/Zn ratio was slightly but not significantly elevated. Serum levels of Se and Mo were significantly decreased in the precancer and cancer groups as compared to the normals. PMID- 23664923 TI - [Sugammadex and profound rocuronium neuromuscular blockade induced by magnesium sulphate]. PMID- 23664924 TI - Patient attitudes towards undergoing additional breast biopsy for research. AB - BACKGROUND: Acquisition of additional breast tissue has become integral to breast oncology research. This questionnaire study examines patient willingness to undergo research-dedicated breast biopsies either at time of diagnostic biopsy (T1) or after carcinoma diagnosis has been confirmed and eligibility for a specific study established (T2), and influencing factors thereof. METHODS: Prior to consultation, patients attending breast clinics were recruited to complete a questionnaire examining willingness to undergo an extra fine needle aspirate (FNA) and/or core needle biopsy (CNB) for research either at T1 or T2. Descriptions of FNA and CNB procedures were supplied to those with no prior experience. Patient perspectives towards donating surplus tissue remaining from a diagnostic procedure and/or surgery for future research were also explored. FINDINGS: A total of 100 patients were recruited, 42% with prior history of breast carcinoma (BC), 22% with family history of BC (FHBC) and 65%/42% with previous experience of CNB/FNA respectively. Overall, 57% were willing to undergo additional biopsy at one or both time points. Willingness to undergo additional biopsy was greater for T1 than T2, but equivalent for CNB and FNA (willingness CNB T1, 50% vs T2, 26%, willingness FNA T1 50% vs T2 29%). A statistically significant increase in willingness to undergo CNB and/or FNA at T1 and/or T2 was seen in association with prior diagnosis of BC, FHBC, previous visit to breast clinic and prior experience of breast biopsy. 83% of patients expressed a willingness to allow surplus tissue to be stored in a biobank for future research. INTERPRETATION: Where possible patients should be approached to undergo baseline research biopsies at time of diagnostic process rather than subsequently. Patients do not find FNA more acceptable than core biopsy. Prior exposure to the biopsy procedure increases willingness to undergo research dedicated biopsies. PMID- 23664925 TI - Isradipine prevents rotenone-induced intracellular calcium rise that accelerates senescence in human neuroblastoma SH-SY5Y cells. AB - Previous research demonstrated that rotenone (RT) induces neuronal injury partially by increasing intracellular Ca(2+) concentrations ([Ca(2+)]i), and inducing oxidative stress, leading to a neurodegenerative disorder. However, the mechanism of RT-induced injury remains elusive. Recent work revealed that Ca(2+) signaling is important for RT-induced senescence in human neuroblastoma SH-SY5Y cells. In the present study, we found that in SH-SY5Y cells, RT increased [Ca(2+)]i, senescence associated beta-galactosidase activity, aggregation of lipofuscin, production of reactive oxygen species, G1/G0 cell cycle arrest, and activation of p53/p21 signaling proteins. In addition, RT decreased the expression of the signaling proteins for cell proliferation and survival, Cyclin dependent kinase 2 (CDK2), cyclin D1, and Akt. Pretreatment of SH-SY5Y cells with isradipine, an L-type Ca(2+) channel blocker, or EGTA antagonized these effects of RT. These results suggested that application of isradipine might be a novel approach to prevent RT-induced neurodegenerative disorder such as Parkinson's disease. PMID- 23664926 TI - ArtPathDesign: rational heterologous pathway design system for the production of nonnative metabolites. AB - In silico platform named ArtPathDesign was developed to design and select heterologous pathways. By integrating previously developed pathway search algorithm and scoring heterologous pathways using codon usage information, we successfully screened heterologous reactions suitable for the production of value added chemicals by microorganisms. PMID- 23664927 TI - Biochemical characterization and cooperation with co-chaperones of heat shock protein 90 from Schizosaccharomyces pombe. AB - The characterization of Hsp90 from the fission yeast Schizosaccharomyces pombe was performed. Hsp90 of S. pombe existed as a dimer and exhibited ATP-dependent conformational changes. It captured unfolded proteins in the ATP-free open conformation and protected them from thermal aggregation. Hsp90 of S. pombe was also able to refold thermally denatured firefly luciferase. The co-chaperones Sti1 and Aha1 bound Hsp90 and modulated its activity. Because the affinity of Sti1 was higher than that of Aha1, the effect of Sti1 appeared to dominate when both co-chaperones existed simultaneously. PMID- 23664928 TI - A balanced de novo inv(7)(p14.3q22.3) disrupting PDE1C and ATXN7L1 in a 14-year old developmentally delayed boy. AB - We report a 14 year old male patient ascertained for developmental delay, carrying a de novo pericentric inversion on chr(7)(p14.3q22.3). Sequencing revealed that the breakpoints overlap a LTR sequence on 7q22.3 and a LINE on 7p14.3. A TTTAAA motif was found in proximity of the breakpoints on both arms. In addition the sequencing detected several small micro-rearrangements, deletion, duplication, insertion, at the breakpoints. No significant sequence identity exists between the 7p14.3 and 7q22.3 breakpoints. These features at the breakpoint junctions suggest that the inversion was triggered by the TTTAAA motif, LTR and LINE and healed by a Non Homologous End Joining (NHEJ) mechanism. The genes ATXN7L1 and PDE1C are disrupted by the inversion. PDE1C is responsible for the hydrolysis of the second messenger molecules cAMP and cGMP and is highly expressed in the human heart and certain brain regions. In mice, Pde1c is expressed in migrating neuronal cells within the central nervous system during early embryo development. Although neuronal migration disorder was not seen in our patient, this is the first patient described with haploinsufficiency of PDE1C possibly causing developmental delay. PMID- 23664929 TI - Exome sequencing released a case of X-linked adrenoleukodystrophy mimicking recessive hereditary spastic paraplegia. AB - Genetic heterogeneity is common in many Mendelian disorders such as hereditary spastic paraplegia (HSP), which makes the genetic diagnosis more complicated. The goal of this study was to investigate a Chinese family with recessive hereditary spastic paraplegia, of which causative mutations could not be identified using the conventional PCR-based direct sequencing. Next-generation sequencing of all the transcripts of whole genome exome, after on-array hybrid capture, was performed on two affected male subjects (the proband and his brother). A missense mutation (c.1661G>A, p.R554H) was identified in ABCD1. Subsequently, PCR-based direct sequencing of other family members revealed that the mutation was co segregating with the disease, indicating that ABCD1 mutation was the pathogenic event for this family. Very long-chain fatty acids (VLCFA) assay in the two affected cases confirmed X-ALD. Our study suggests exome sequencing can be used not only to find a novel causative gene, but also to quickly identify mutations of known genes when the clinical elements are etiologically misleading. PMID- 23664930 TI - Synthesis, optimization and characterization of acetylated corn starch with the high degree of substitution. AB - Acetylated corn starch (ACS) was synthesized by the reaction of native corn starch (NCS) with acetic anhydride (AA) and acetic acid in an aqueous medium in the presence of p-toluenesulfonic acid (PTSA) as a catalyst. The factors that could affect the degree of substitution (DS) of corn starch were investigated which included the reaction temperature and time, the volume ratio of AA to acetic acid and the usage of the catalyst PTSA. The optimal DS of 2.85 was obtained. Fourier transform infrared (FTIR) spectrometry showed new bands at 1733, 1375 and 1252cm(-1). As DS increased, the bands at 3400cm(-1) and 1083cm( 1) were gradually weakened. The scanning electron microscopy (SEM) of the ACS indicated that the exterior and interior of native starch were destroyed by the esterification. Wide angle X-ray diffraction revealed that the peaks at 15 degrees , 18 degrees , 20 degrees and 23 degrees were diminished, while the peak at 21 degrees became more distinct as the DS increased. Differential scanning calorimetry (DSC) thermograms exhibited that ACS had some lower gelatinization temperatures and enthalpies than NCS. PMID- 23664931 TI - Utilization of chitosan nanoparticles as a green finish in multifunctionalization of cotton textile. AB - Chitosan nanoparticles were synthesized through polymerization of CS at different concentrations with methacrylic acid (MAA) using K2S2O8 as initiator. This polymerization gave rise to suspension which was ice-cooled then subjected to severe centrifuging and the supernatant discarded to yield CS nanoparticles. Major characteristics of the so prepared CS nanoparticles namely size/distribution of the particles, their structural features, surface description and thermal stability were examined using DLS, FTIR, SEM and TGA, respectively. When CS nanoparticles were used as a finish for cotton fabrics with a crosslinking agent, the fabric displayed improved dyeability and thermal stability as well as antibacterial activity and UV protection. These latter two functionalities were significantly increased by post treatment of fabric with copper sulfate. PMID- 23664932 TI - Effects of carboxymethylpachymaran on signal molecules in chicken immunocytes. AB - The study was carried out to investigate the immunomodulation mechanism of carboxymethylpachymaran (CMP). Chicken splenic lymphocytes were cultured in medium alone or with CMP at the final concentration of 50mg/L, 100mg/L, 200mg/L or 400mg/L in vitro for 4h, 8h, 12h or 24h, respectively. The supernatants at different culture periods were analyzed for changes in levels of 6-keto prostaglandin F1alpha (6-keto-PGF1alpha), thromboxane B2 (TXB2) and nitric oxide (NO). The cells were collected to determine contents of oxidized glutathione (GSSG), reduced glutathione (GSH), cyclic AMP (cAMP) and cyclic GMP (cGMP). The results showed that CMP increase the values of NO, 6-keto-PGF1alpha, TXB2, and the ratio of 6-keto-PGF1alpha to TXB2 in supernatants. The contents of intracellular GSH, cAMP, cGMP and the ratio of cAMP to cGMP were increased in the cells treated with CMP. The results suggested that CMP enhanced immune functions by increasing the contents of GSH and by regulating arachidonic acid signal transduction systems in chicken splenic lymphocytes. The signal pathway of NO cGMP plays an important role in CMP-induced activation of chicken splenic lymphocytes. PMID- 23664933 TI - Characterization of new exopolysaccharides produced by coculturing of L. kefiranofaciens with yoghurt strains. AB - This project was designed to study the coculturing affect of exopolysaccharide (EPS) producing strains Lactobacillus kefiranofaciens (L.k) ZW3, with non EPS producing strains L. bulgaricus (L.b) and Streptococcus thermophilus (S.t) in three different combinations: L.k+L.b, L.k+S.t, and L.k+L.b+S.t. FTIR analysis revealed presence of strong stretch in regions of 3400, 2900 and 1647cm(-1) which is characteristic of a typical polysaccharide. Co-cultured EPSs were composed of glucose, galactose, arabinose and xylose; and their sugar compositions were different from ZW3 polysaccharide that was mainly composed of gluco-galactan. Peak temperature for L.k+L.b, L.k+S.t, L.k+S.t+L.b and ZW3 polymers were 90.59, 87.61, 95.18 and 97.38 degrees C, respectively. Thermal analysis revealed degradation temperature of 326.44, 294.6, 296.7 and 299.62 degrees C for L.k+L.b, L.k+S.t, L.k+S.t+L.b and ZW3 polymers, respectively. SEM and AFM analysis divulged that three cocultured EPSs had different surface morphology than ZW3 polymer. Since co-cultured polymers have different structure than the polymer produced exclusively by EPS producing strain, it can be safely concluded from the study that co-culturing can be one way to change the structure of polymers. Coculturing of L. kefiranofaciens with non-EPS producing strains resulted in yoghurt with increased viscosity and delayed syneresis. PMID- 23664934 TI - Molecular heterogeneity of arabinogalactan-protein from Coffea arabica instant coffee. AB - Arabinogalactan-protein complex (AGP), isolated from freeze-dried instant coffee powder of Coffea arabica beans, was subjected to ion-exchange chromatography. Stepwise elution with water and solutions of sodium chloride with increasing ionic strength afforded eight fractions (F1-F8). Chemical analyses have shown that compositions of individual conjugates varied in carbohydrate and protein contents, molecular mass and slightly in monosaccharide composition. Protein content was increasing by increasing ionic strength of the eluent and it was confirmed also by FT-IR spectra. NMR study has shown that carbohydrate moieties in individual ion exchange fractions differed in the degree of backbone and side chains branching. Performed study has confirmed a molecular heterogeneity of arabinogalactan-protein complex present in a commercial instant coffee. PMID- 23664935 TI - Synthesis of N-furoyl chitosan and chito-oligosaccharides and evaluation of their antioxidant activity in vitro. AB - N-furoyl chitosan (NF-CS) and N-furoyl chitosan oligosaccharide (NF-COS) were prepared via acylation of chitosan and chitosan oligosaccharide. Their chemical structures and physical properties were characterized by Fourier transform infrared spectroscopy, (1)H NMR, X-ray diffraction, and elemental analysis. Results showed that the degrees of substitution of the derivatives were 0.68 and 0.72, respectively. Their antioxidant activities in vitro were further studied. The inhibition concentration of NF-CS at 50% (IC50) and the scavenging effect of NF-COS on DPPH were 1.3 and 0.76mgmL(-1), respectively. The derivatives also exhibited higher antioxidant activities than chitosan based on the reducing power and hydroxyl radical scavenging activities. PMID- 23664936 TI - Characterization of esterified cassava starch with long alkyl side chains and different substitution degrees. AB - The present work describes the characterization and thermal properties of hydrophobic starch obtained by the esterification of cassava starch with acyl imidazoles, acid chlorides and methyl ester derivatives of fatty acids with n alkyl chains with 12-22 carbon atoms, in order to compare the dependence of their properties as a function of the length of the side chain and the methodology used for their synthesis. The n-acyl starches presented degrees of substitution (DS) between 0.06 and 1.2. Most of the derivatives obtained with acyl imidazoles were found to be stable at temperatures up to 300 degrees C, whereas those synthesized with acid chlorides or methyl ester decomposed below. Finally, when the n-acyl starches were substituted with n-alkyl side chains of 16 or more carbon atoms, they were capable to crystallize in separate paraffinic phases independent of the starch backbone. PMID- 23664937 TI - Effects of beta-cyclodextrin on the intestinal absorption of berberine hydrochloride, a P-glycoprotein substrate. AB - The major objective of this work is to investigate the enhancing effect of beta cyclodextrin on the intestinal absorption of berberine hydrochloride, a P glycoprotein (Pgp) substrate. The inclusion complexation behavior of BBH with beta-CD was investigated by phase-solubility diagram, Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray powder diffractometry, NMR spectroscopy, and molecular modeling studies. Results indicated that the 1,3 benzodioxole of BBH was included into the cavity of beta-CD to form an inclusion complex which exhibited higher dissolution rate than BBH in vitro. The intestinal absorption of the inclusion complex in rats was significantly higher than the free drug due to its solubilizing effect and Pgp modulatory activity. The mechanisms of beta-CD on Pgp modulation were demonstrated by modifying the Pgp ATPase activity, the Pgp mRNA level and the Pgp expression. PMID- 23664938 TI - An arabino(glucurono)xylan isolated from immunomodulatory active hemicellulose fraction of Salvia officinalis L. AB - From the aerial parts of sage (Salvia officinalis L.) an arabino-(4-O-methyl glucurono)-xylan (AGX) was isolated by alkaline extraction followed by precipitation with barium hydroxide solution. Polymer was isolated from sage as a light brown polysaccharide material of molecular mass (Mp) 84,000. Compositional analyses of sage AGX revealed xylose (81%), arabinose (10%), glucuronic acid (8%) and small amounts of hexoses (1%). Linkage sugar analyses showed the (1->4) linked xylopyranosyl backbone with low degree of substitution (9-10%) at O-2 and O-3. Arabinofuranose residues were found as the terminal, 1,3-, 1,5- and 1,3,5 linked. NMR structural analyses of acidic oligomers, generated by partial acidic hydrolysis of AGX, confirmed a substitution of xylose residues by glucuronic acid and its 4-O-methyl derivate at O-2 at an average on every fourteenth xylose residue. NMR and FT-IR measurements, as well as a high negative optical rotation confirmed the beta configuration of glycosidic linkages in AGX backbone. PMID- 23664939 TI - Chitosan/alginate crosslinked hydrogels: preparation, characterization and application for cell growth purposes. AB - Chitosan hydrogels may be formed by various mechanisms. In this study, we aimed to form hybrid polymer networks of chitosan with alginate using a crosslinker which enabled the covalent binding of the two macromolecules. The structural and thermal characterization of these hydrogels was performed by using Fourier transform infrared (FTIR) and differential scanning calorimeter (DSC). The morphological analysis of the crosslinked material was investigated by scanning electron microscopy (SEM) and a scanning probe microscope with atomic force microscope (AFM) attachment. The swelling properties of these gels were analyzed in water and in phosphate buffered saline (PBS) solution. The presence of alginate in a chitosan/alginate hydrogel was shown to support the hydrogel stability. Compared to chitosan/alginate (1/2) hydrogel prepared with 1wt% DCC, the swelling of chitosan/alginate (1/2) hydrogels prepared with 3wt% DCC was limited. To measure the degree of cell proliferation, the hydrogels were seeded with L929 mouse fibroblasts and cell numbers measured by neutral red uptake assay. The cell attachment was also followed by (SEM) photography. It was observed that chitosan/alginate (1/2) hydrogels with 1wt% (DCC) provides a better environment for cell attachment and proliferation. This study presents functional hydrogel formation by crosslinked chitosan and alginate, a novel biomaterial which also supports cell growth. PMID- 23664940 TI - Reduced toxicity conditioning and allogeneic stem cell transplantation in adults using fludarabine, carmustine, melphalan, and antithymocyte globulin: outcomes depend on disease risk index but not age, comorbidity score, donor type, or human leukocyte antigen mismatch. AB - Although reduced-intensity conditioning has become standard of care for patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplantation (HCT), the optimum regimen has yet to be defined, and may depend on pretransplantation patient- and/or disease-specific risk factors. We report here results in 100 adults, ages 18 to 69, with high-risk hematologic malignancy who received conditioning with fludarabine, carmustine, melphalan, and rabbit antithymocyte globulin (FBM-A). Outcomes were stratified using the disease risk index (DRI) as published by Armand et al. (Blood 2012;120:905-913). Median age was 56, and patients were ineligible for standard myeloablative conditioning because of age, organ dysfunction, or prior autologous HCT. Patients underwent transplantation for myeloid (acute myelogenous leukemia, n = 40; myelodysplastic syndrome, n = 24; myelofibrosis, n = 13; other myeloid, n = 2) or lymphoid (acute lymphoblastic leukemia, n = 8; non-Hodgkin lymphoma, n = 8; Hodgkin lymphoma, n = 4, chronic lymphocytic leukemia, n = 1) malignancy. Donors were related in 26 patients (22 matched, 4 mismatched at 1 antigen) and unrelated in 74 (mismatched at 1 or 2 HLA loci in 33); grafts were peripheral blood stem cells in 97 patients, bone marrow in 2, and double cord in 1. According to the DRI, 68 patients were classified as low (n = 1) or intermediate risk (n = 67), and 32 were classified as high (n = 28) or very high risk (n = 4). With a median follow up of surviving patients of 18 months, the Kaplan-Meier estimate of overall survival at 2 years for patients in the low/intermediate risk group is 80%, compared with 66% in the high/very high group (P = .11). Two-year cumulative incidence of relapse and nonrelapse mortality in the low/intermediate group are 9.9% and 15%, versus 25% and 19% in the high/very high group (respective P values .07 and .81). The cumulative incidence of acute graft-versus-host (GVHD) grades III to IV at 100 days was 8.1%, and the incidence of National Institutes of Health-defined moderate to severe chronic GVHD was 22% at 2 years. No deaths were attributable to chronic GVHD. Survival was not influenced by age, hematopoietic comorbidity index score, donor type, donor gender, or presence of mismatch. We conclude that FBM-A is an effective and safe conditioning regimen for adults up to age 69 with hematologic malignancies who have low-, intermediate-, or high risk scores according to the DRI. PMID- 23664941 TI - A review of emergency medical services events in US national parks from 2007 to 2011. AB - OBJECTIVE: Outdoor recreation is growing in the United States, with more than 279 million annual visitors to areas controlled by the National Park Service (NPS). Emergency medical needs in these parks are overseen by the National Park's rangers within the NPS Emergency Medical Services (EMS) system. This study examines medical and traumatic emergencies throughout the NPS over a 5-year period to better understand the types of events and fatalities rangers encounter, both regionally and on a national scale. METHODS: This is a retrospective review of the annual EMS reports published by the 7 NPS regions from 2007 to 2011. The following were compared and examined at a regional and national level: medical versus traumatic versus first aid events, cardiac events and outcomes, use of automated external defibrillators, and medical versus traumatic fatalities. RESULTS: The national incidence of EMS events was 45.9 events per 1 million visitors. Medical, traumatic, and first aid events composed 29%, 28%, and 43% of reports, respectively. Of medical episodes, 1.8% were cardiac arrests, of which 64.2% received automated external defibrillator treatment; 29.1% of cardiac arrests survived to hospital discharge. Of fatalities, 61.4% were traumatic in nature and the remaining 38.5% were nontraumatic (medical). Regional differences were found for all variables. CONCLUSIONS: On a national level, the NPS experiences an equal number of medical and traumatic EMS events. This differs from past observed trends that reported a higher incidence of traumatic events than medical events in wilderness settings. Cardiac events and automated external defibrillator usage are relatively infrequent. Traumatic fatalities are more common than medical fatalities in the NPS. Regional variations in events likely reflect differences in terrain, common activities, proximity to urban areas, and access to definitive care between regions. These data can assist the NPS in targeting the regions with the greatest number of incidents and fatalities for prevention, ranger training, and visitor education. PMID- 23664942 TI - Generation of realistic HMPAO SPECT images using a subresolution sandwich phantom. AB - Traditional interpretation of rCBF SPECT data is of a qualitative nature and is dependent on the observer's understanding of the normal distribution of the tracer. The use of a normal database in quantitative regional analysis facilitates the detection of functional abnormality in individual and group studies by accounting for inter-subject variability. The ability to simulate realistic images would allow various important areas related to the use of normal databases to be studied. These include the optimisation of the detection of abnormal blood flow and the portability of normal databases between gamma camera systems. To investigate this further we have constructed a hardware phantom and scanned various configurations of radioactive brain patterns and simulated skull configurations. METHODS: A subresolution sandwich phantom was constructed with a simulated skull which was assembled using a high-resolution segmented MR scan printed with a (99m)TcO4 - mixture and scanned using a double-headed gamma camera with parallel-hole collimators. Various different grey-to-white matter (GM:WM) ratios and aluminium simulated skull configurations were used. A single difference measure between the phantom data and a control database mean image was used for optimisation. The realism of phantom data was assessed using statistical parametric mapping (SPM) and ROI analysis. RESULTS: Optimisation was achieved with a range of WM:GM ratios from 1.9 to 2.4:1 with various simulated skull configurations. CONCLUSION: The ability to simulate realistic HMPAO SPECT scans has been demonstrated using a subresolution sandwich phantom. Further work, involving scanning the optimised phantom on different gamma camera systems and comparison with camera-specific normal databases should further refine the phantom configuration. PMID- 23664943 TI - Classic EEG motor potentials track the emergence of value-based decisions. AB - Making a value-based decision is a cognitively complex phenomenon and divisible into several sub-processes, such as the perception, evaluation, and final selection of choice options. Although previous research has attempted to dissociate these processes in the brain, there is emerging evidence that late action selection mechanisms are influenced continuously throughout the entire decision act. We used electroencephalography (EEG) and an established sequential decision making paradigm to investigate the extent to which the readiness potential (RP) and the lateralized readiness potential (LRP), two classic preparatory EEG motor components, reflect the ongoing evaluation process in value based choices. During the task, human participants sequentially sampled probabilistic information to buy or reject offers of unknown value (using both hands) and were allowed to respond at any time. The pressure to respond was manipulated by charging low or high costs for collecting information. We modeled how and when decisions were made and found that participants adaptively lowered their threshold for required evidence with information costs and elapsed time. These shifts were accompanied by an increased RP-like signal during the decision process. The RP was further influenced by the amount of accumulated evidence. In addition, an LRP could be measured from the start of the decision process, well in advance and independent of the final decision. Our results are consistent with a continuous involvement of the brain's motor system in emerging value-based decisions and advocate using classic EEG motor potentials for studying neurocognitive theories of decision making. PMID- 23664944 TI - Multiple synergistic effects of emotion and memory on proactive processes leading to scene recognition. AB - Visual scene recognition is a proactive process through which contextual cues and top-down expectations facilitate the extraction of invariant features. Whether the emotional content of the scenes exerts a reliable influence on these processes or not, however, remains an open question. Here, topographic ERP mapping analysis and a distributed source localization method were used to characterize the electrophysiological correlates of proactive processes leading to scene recognition, as well as the potential modulation of these processes by memory and emotion. On each trial, the content of a complex neutral or emotional scene was progressively revealed, and participants were asked to decide whether this scene had previously been encountered or not (delayed match-to-sample task). Behavioral results showed earlier recognition for old compared to new scenes, as well as delayed recognition for emotional vs. neutral scenes. Electrophysiological results revealed that, ~400 ms following stimulus onset, activity in ventral object-selective regions increased linearly as a function of accumulation of perceptual evidence prior to recognition of old scenes. The emotional content of the scenes had an early influence in these areas. By comparison, at the same latency, the processing of new scenes was mostly achieved by dorsal and medial frontal brain areas, including the anterior cingulate cortex and the insula. In the latter region, emotion biased recognition at later stages, likely corresponding to decision making processes. These findings suggest that emotion can operate at distinct and multiple levels during proactive processes leading to scene recognition, depending on the extent of prior encounter with these scenes. PMID- 23664945 TI - The neural basis of cognitive change: reappraisal of emotional faces modulates neural source activity in a frontoparietal attention network. AB - Emotions can be regulated effectively via cognitive change, as evidenced by cognitive behavioural therapy. The neural correlates of cognitive change were investigated using reappraisal, a strategy that involves the reinterpretation of emotional stimuli. Hemodynamic studies revealed cortical structures involved in reappraisal and highlighted the role of the prefrontal cortex in regulating subcortical affective processing. Studies using event-related potentials elucidated the timing of reappraisal by showing effective modulation of the Late Positive Potential (LPP) after 300ms but also even earlier effects. The present study investigated the spatiotemporal dynamics of the cortical network underlying cognitive change via inverse source modelling based on whole-head magnetoencephalography (MEG). During MEG recording, 28 healthy participants saw angry and neutral faces and followed instructions designed to down- or up regulate emotions via reappraisal. Differences between angry and neutral face processing were specifically enhanced during up-regulation, first in the parietal cortex during M170 and across the whole cortex during LPP-M, with particular involvement of the parietal and dorsal prefrontal cortex regions. Thus, our data suggest that the reappraisal of emotional faces involves specific modulations in a frontoparietal attention network. PMID- 23664946 TI - You can't stop the music: reduced auditory alpha power and coupling between auditory and memory regions facilitate the illusory perception of music during noise. AB - Our brain has the capacity of providing an experience of hearing even in the absence of auditory stimulation. This can be seen as illusory conscious perception. While increasing evidence postulates that conscious perception requires specific brain states that systematically relate to specific patterns of oscillatory activity, the relationship between auditory illusions and oscillatory activity remains mostly unexplained. To investigate this we recorded brain activity with magnetoencephalography and collected intracranial data from epilepsy patients while participants listened to familiar as well as unknown music that was partly replaced by sections of pink noise. We hypothesized that participants have a stronger experience of hearing music throughout noise when the noise sections are embedded in familiar compared to unfamiliar music. This was supported by the behavioral results showing that participants rated the perception of music during noise as stronger when noise was presented in a familiar context. Time-frequency data show that the illusory perception of music is associated with a decrease in auditory alpha power pointing to increased auditory cortex excitability. Furthermore, the right auditory cortex is concurrently synchronized with the medial temporal lobe, putatively mediating memory aspects associated with the music illusion. We thus assume that neuronal activity in the highly excitable auditory cortex is shaped through extensive communication between the auditory cortex and the medial temporal lobe, thereby generating the illusion of hearing music during noise. PMID- 23664947 TI - Genetic and environmental contributions to brain activation during calculation. AB - Twin studies have long suggested a genetic influence on inter-individual variations in mathematical abilities, and candidate genes have been identified by genome-wide association studies. However, the localization of the brain regions under genetic influence during number manipulation is still unexplored. Here we investigated fMRI data from a group of 19 MZ (monozygotic) and 13 DZ (dizygotic) adult twin pairs, scanned during a mental calculation task. We examined both the activation and the degree of functional lateralization in regions of interest (ROIs) centered on the main activated peaks. Heritability was first investigated by comparing the respective MZ and DZ correlations. Then, genetic and environmental contributions were jointly estimated by fitting a ACE model classically used in twin studies. We found that a subset of the activated network was under genetic influence, encompassing the bilateral posterior superior parietal lobules (PSPL), the right intraparietal sulcus (IPS) and a left superior frontal region. An additional region of the left inferior parietal cortex (IPC), whose deactivation correlated with a behavioral calculation score, also presented higher similarity between MZ than between DZ twins, thus offering a plausible physiological basis for the observable inheritance of math scores. Finally, the main impact of the shared environment was found in the lateralization of activation within the intraparietal sulcus. These maps of genetic and environmental contributions provide precise candidate phenotypes for further genetic association analyses, and illuminate how genetics and education shape the development of number processing networks. PMID- 23664949 TI - Mean-based neural coding of voices. AB - The social significance of recognizing the person who talks to us is obvious, but the neural mechanisms that mediate talker identification are unclear. Regions along the bilateral superior temporal sulcus (STS) and the inferior frontal cortex (IFC) of the human brain are selective for voices, and they are sensitive to rapid voice changes. Although it has been proposed that voice recognition is supported by prototype-centered voice representations, the involvement of these category-selective cortical regions in the neural coding of such "mean voices" has not previously been demonstrated. Using fMRI in combination with a voice identity learning paradigm, we show that voice-selective regions are involved in the mean-based coding of voice identities. Voice typicality is encoded on a supra individual level in the right STS along a stimulus-dependent, identity independent (i.e., voice-acoustic) dimension, and on an intra-individual level in the right IFC along a stimulus-independent, identity-dependent (i.e., voice identity) dimension. Voice recognition therefore entails at least two anatomically separable stages, each characterized by neural mechanisms that reference the central tendencies of voice categories. PMID- 23664948 TI - Functional specialization within the supplementary motor area: a fNIRS study of bimanual coordination. AB - Bimanual movements can be performed by flexing and extending the target effectors (e.g., hand muscles) in unison, or by flexing units on one side in unison with extension of the same units on the opposite side. The former movement patterns are generally referred to as in-phase or parallel, whereas the latter patterns are often termed anti-phase movements. It is well known that anti-phase patterns are unstable and tend to spontaneously transition to in-phase movements at higher repetition rates, but the mechanisms and brain regions involved are not fully understood. In the current study, we utilized functional near-infrared spectroscopy (fNIRS) to evaluate whether anterior/posterior subdivisions of the supplementary motor complex (SMA) have distinct functional roles in maintaining in-phase and anti-phase movement patterns. Twelve healthy adult participants completed a bimanual coordination task comprised of anti-phase and in-phase trials as 24-channel fNIRS data was recorded from dorsal-medial motor areas. We examined the relative concentrations of oxygenated and deoxygenated hemoglobin in the channels that were located over the anterior SMA (e.g., pre-SMA) and the SMA proper. Our most interesting results indicated that oxygenated hemoglobin responses were greater in the anterior SMA during performance of anti-phase compared to in-phase movements. In the SMA proper, oxygenated hemoglobin responses did not differ between the two movement patterns. These data suggest that the anterior SMA is critical to programming and maintaining the less stable anti-phase movement patterns, and support the conceptual framework of an anterior directed gradient of progressively more complex functionality in the SMA. PMID- 23664950 TI - Brain oscillatory subsequent memory effects differ in power and long-range synchronization between semantic and survival processing. AB - Memory crucially depends on the way information is processed during encoding. Differences in processes during encoding not only lead to differences in memory performance but also rely on different brain networks. Although these assumptions are corroborated by several previous fMRI and ERP studies, little is known about how brain oscillations dissociate between different memory encoding tasks. The present study therefore compared encoding related brain oscillatory activity elicited by two very efficient encoding tasks: a typical deep semantic item feature judgment task and a more elaborative survival encoding task. Subjects were asked to judge words either for survival relevance or for animacy, as indicated by a cue presented prior to the item. This allowed dissociating pre item activity from item-related activity for both tasks. Replicating prior studies, survival processing led to higher recognition performance than semantic processing. Successful encoding in the semantic condition was reflected by a strong decrease in alpha and beta power, whereas successful encoding in the survival condition was related to increased alpha and beta long-range phase synchrony. Moreover, a pre-item subsequent memory effect in theta power was found which did not vary with encoding condition. These results show that measures of local synchrony (power) and global long range-synchrony (phase synchronization) dissociate between memory encoding processes. Whereas semantic encoding was reflected in decreases in local synchrony, increases in global long range synchrony were related to elaborative survival encoding, presumably reflecting the involvement of a more widespread cortical network in this task. PMID- 23664951 TI - Transcranial cerebellar direct current stimulation (tcDCS): motor control, cognition, learning and emotions. AB - The neurological manifestations of cerebellar diseases range from motor to cognitive or behavioral abnormalities. Experimental data in healthy subjects extend the cerebellar role to learning, emotional and mood control. The need for a non-invasive tool to influence cerebellar function in normal and pathological conditions led researchers to develop transcranial cerebellar direct current stimulation (tcDCS). tcDCS, like tDCS, depends on the principle that weak direct currents delivered at around 2mA for minutes over the cerebellum through surface electrodes induce prolonged changes in cerebellar function. tcDCS modulates several cerebellar skills in humans including motor control, learning and emotional processing. tcDCS also influences the cerebello-brain interactions induced by transcranial magnetic stimulation (TMS), walking adaptation, working memory and emotional recognition. Hence tcDCS is a simple physiological tool that can improve our physiological understanding of the human cerebellum, and should prove useful also in patients with cerebellar dysfunction or psychiatric disorders and those undergoing neurorehabilitation to enhance neuroplasticity. PMID- 23664953 TI - SWIFT: a novel method to track the neural correlates of recognition. AB - Isolating the neural correlates of object recognition and studying their fine temporal dynamics have been a great challenge in neuroscience. A major obstacle has been the difficulty to dissociate low-level feature extraction from the actual object recognition activity. Here we present a new technique called semantic wavelet-induced frequency-tagging (SWIFT), where cyclic wavelet scrambling allowed us to isolate neural correlates of object recognition from low level feature extraction in humans using EEG. We show that SWIFT is insensitive to unrecognized visual objects in natural images, which were presented up to 30s, but is highly selective to the recognition of the same objects after their identity has been revealed. The enhancement of object representations by top-down attention was particularly strong with SWIFT due to its selectivity for high level representations. Finally, we determined the temporal dynamics of object representations tracked by SWIFT and found that SWIFT can follow a maximum of between 4 and 7 different object representations per second. This result is consistent with a reduction in temporal capacity processing from low to high level brain areas. PMID- 23664954 TI - Tactile stimulation and hemispheric asymmetries modulate auditory perception and neural responses in primary auditory cortex. AB - Although multisensory integration has been an important area of recent research, most studies focused on audiovisual integration. Importantly, however, the combination of audition and touch can guide our behavior as effectively which we studied here using psychophysics and functional magnetic resonance imaging (fMRI). We tested whether task-irrelevant tactile stimuli would enhance auditory detection, and whether hemispheric asymmetries would modulate these audiotactile benefits using lateralized sounds. Spatially aligned task-irrelevant tactile stimuli could occur either synchronously or asynchronously with the sounds. Auditory detection was enhanced by non-informative synchronous and asynchronous tactile stimuli, if presented on the left side. Elevated fMRI-signals to left sided synchronous bimodal stimulation were found in primary auditory cortex (A1). Adjacent regions (planum temporale, PT) expressed enhanced BOLD-responses for synchronous and asynchronous left-sided bimodal conditions. Additional connectivity analyses seeded in right-hemispheric A1 and PT for both bimodal conditions showed enhanced connectivity with right-hemispheric thalamic, somatosensory and multisensory areas that scaled with subjects' performance. Our results indicate that functional asymmetries interact with audiotactile interplay which can be observed for left-lateralized stimulation in the right hemisphere. There, audiotactile interplay recruits a functional network of unisensory cortices, and the strength of these functional network connections is directly related to subjects' perceptual sensitivity. PMID- 23664952 TI - Neurovascular coupling in normal aging: a combined optical, ERP and fMRI study. AB - Brain aging is characterized by changes in both hemodynamic and neuronal responses, which may be influenced by the cardiorespiratory fitness of the individual. To investigate the relationship between neuronal and hemodynamic changes, we studied the brain activity elicited by visual stimulation (checkerboard reversals at different frequencies) in younger adults and in older adults varying in physical fitness. Four functional brain measures were used to compare neuronal and hemodynamic responses obtained from BA17: two reflecting neuronal activity (the event-related optical signal, EROS, and the C1 response of the ERP), and two reflecting functional hemodynamic changes (functional magnetic resonance imaging, fMRI, and near-infrared spectroscopy, NIRS). The results indicated that both younger and older adults exhibited a quadratic relationship between neuronal and hemodynamic effects, with reduced increases of the hemodynamic response at high levels of neuronal activity. Although older adults showed reduced activation, similar neurovascular coupling functions were observed in the two age groups when fMRI and deoxy-hemoglobin measures were used. However, the coupling between oxy- and deoxy-hemoglobin changes decreased with age and increased with increasing fitness. These data indicate that departures from linearity in neurovascular coupling may be present when using hemodynamic measures to study neuronal function. PMID- 23664955 TI - Preclinical evaluation of [(18)F]JNJ42259152 as a PET tracer for PDE10A. AB - Phosphodiesterase-10A (PDE10A) is implicated in several neuropsychiatric disorders involving basal ganglia neurotransmission, such as schizophrenia, obsessive-compulsive disorder and Huntington's disease. To confirm target engagement and exposure-occupancy relationships of clinical candidates for treatment, and to further explore the in vivo biology of PDE10A, non-invasive imaging using a specific PET ligand is warranted. Recently we have reported the in vivo evaluation of [(18)F]JNJ41510417 which showed specific binding to PDE10A in rat striatum, but with relatively slow kinetics. A chemically related derivative JNJ42259152 was found to have a similar in vivo occupancy, but lower lipophilicity and lower PDE10A in vitro inhibitory activity compared to JNJ41510417. (18)F-labeled JNJ42259152 was therefore evaluated as a potential PDE10A PET radiotracer. Baseline PET in rats and monkey showed specific retention in the PDE10A-rich striatum, and fast wash-out, with a good contrast to non specific binding, in other brain regions. Pretreatment and chase experiments in rats with the selective PDE10A inhibitor MP-10 showed that tracer binding was specific and reversible. Absence of specific binding in PDE10A knock-out (KO) mice further confirmed PDE10A specificity. In vivo radiometabolite analysis using high performance liquid chromatography (HPLC) showed presence of polar radiometabolites in rat plasma and brain. In vivo imaging in rat and monkey further showed faster brain kinetics, and higher striatum-to-cerebellum ratios for [(18)F]JNJ42259152 compared to [(18)F]JNJ41510417. The arterial input function corrected for radiometabolites was determined in rats and basic kinetic modeling was established. For a 60-min acquisition time interval, striatal binding potential of the intact tracer referenced to the cerebellum showed good correlation with corresponding binding potential values of a Simplified Reference Tissue Model and referenced Logan Plot, the latter using a population averaged reference tissue-to-plasma clearance rate and offering the possibility to generate representative parametric binding potential images. In conclusion we can state that in vivo imaging in PDE10A KO mice, rats and monkey demonstrates that [(18)F]JNJ42259152 provides a PDE10A-specific signal in the striatum with good pharmacokinetic properties. Although presence of a polar radiometabolite in rat brain yielded a systematic but reproducible underestimation of the striatal BPND, a Logan reference tissue model approach using 60 min acquisition data is appropriate for quantification. PMID- 23664956 TI - Metallothionein prevention of arsenic trioxide-induced cardiac cell death is associated with its inhibition of mitogen-activated protein kinases activation in vitro and in vivo. AB - Cardiotoxicity induced by arsenic trioxide has become a serious blockade of clinical applications of this effective anticancer agent. The general mechanism responsible for arsenic cardiotoxicity has been attributed to its induction of oxidative stress. Metallothionein (MT) has been extensively proven to be a potent endogenous antioxidant that protects heart against oxidative stress-induced cardiac damage. To investigate whether and how MT protects against arsenic cardiotoxicity, MT-overexpressing H9c2 (MT-H9c2) cardiac cells and transgenic (MT TG) mice with their corresponding controls were exposed to the clinical relevant dose of arsenic trioxide. Cardiac cell apoptosis was detected by molecular indices, including the cleavage of caspase 3 and caspase 12, Bax/Bcl2 expression ratio, CHOP expression and/or confirmed by a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. Arsenic trioxide dose- and time-dependently induced cardiac cell death in H9c2 cells with a significant activation of major MAPK subfamily members such as ERK1/2, JNK and p38, but not in MT-H9c2 cells. Importantly, the protective effect of MT on arsenic trioxide induced apoptotic cell death was completely recaptured in the heart of MT-TG with a significant prevention of MAPKs activation. These results indicate that arsenic trioxide-upregulated MAPKs might play important role in arsenic trioxide-induced apoptotic cell death in cardiac cells both in vivo and in vitro, and MT's suppression of arsenic trioxide apoptotic effect was associated with the inhibition of MAPK activation. Therefore, selective elevation of cardiac MT levels with pharmacological approaches may be a potential strategy for the prevention of arsenic cardiotoxicity. PMID- 23664957 TI - Sensory and sensorimotor features in violinists and violists with neck pain. AB - OBJECTIVE: To investigate sensory and sensorimotor function in violin and viola players with and without neck pain. DESIGN: Prospective, cross-sectional study. SETTING: University laboratory. PARTICIPANTS: Convenience sample of violin players with playing-related neck pain (n=22), violinists without neck pain (n=21), and healthy nonmusician comparison subjects (n=21). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Measures include thermal pain thresholds (cold and heat) and pressure pain thresholds (PPTs) over the cervical spine and over a remote region (tibialis anterior muscle). Motor performance tests including reaction times, speed of movement, accuracy, coordination, and tapping speed assessed with a special upper-limb test battery. RESULTS: Musicians with neck pain had significantly lower heat and elevated cold pain thresholds as well as lower PPTs over C5-6 (P<.01) and over the tibialis anterior (P<.05). Motor performance tests revealed no differences between the symptomatic and asymptomatic musicians and nonmusician comparison groups (P>.05). CONCLUSIONS: Violin players with neck pain demonstrated signs of sensory impairment, suggesting that playing-related neck pain may be associated with augmented central pain processing consistent with findings in other neck pain groups. No differences were evident in the motor performance tests. Fine motor skills of violin players may be better assessed in the context of playing their musical instruments before definitive conclusions can be drawn about the presence or not of sensorimotor impairments in this group of musicians with playing-related neck pain. PMID- 23664958 TI - Potential strategies for control of bluetongue, a globally emerging, Culicoides transmitted viral disease of ruminant livestock and wildlife. AB - Bluetongue (BT) is a non-zoonotic arboviral disease of certain wild and domestic species of cloven-hoofed ungulates. The causative agent, bluetongue virus (BTV), is spread through temperate and tropical regions of the world by biting Culicoides midges. Control of BTV infection is complicated by the plurality of virus serotypes and the ubiquity and opportunistic feeding behavior of its midge vector. The global distribution of BTV infection has recently altered, perhaps driven in part by climatic influences on midge species resident in different regions. The goal of this review is to evaluate realistic strategies that might be utilized to control or prevent future outbreaks of BT and other Culicoides transmitted diseases. Importantly, optimal control of emerging, rapidly evolving arbovirus diseases such as BT will require integrated countermeasures that mitigate all aspects of the virus's transmission cycle. This will best be accomplished using preventative, rather than purely reactive strategies. PMID- 23664959 TI - Increased SMA-M1 coherence in Parkinson's disease - Pathophysiology or compensation? AB - Parkinson's disease (PD) is a common neurodegenerative disorder owing to loss of dopaminergic cells. Akinesia - one of the core symptoms of PD - is associated with exaggerated oscillations at beta frequency (13-30 Hz) within the subthalamic nucleus (STN). Thus, enhanced oscillations below 30 Hz are assumed to represent a pathophysiological marker of PD. However, recent data suggest that OFF medication exaggerated beta oscillations within basal ganglia (BG) cortical networks may serve for the compensation of BG dysfunctions. The STN is functionally connected to mesial prefrontal areas like the supplementary motor area (SMA). But, it is still not fully understood how enhanced beta oscillations within the BG exert dominance over the primary motor cortex (M1) thereby yielding motor impairment. The present study, therefore, investigates the effect of dopaminergic state on SMA-M1 functional connectivity using Magnetoencephalography (MEG). MEG data were recorded in 7 patients suffering from PD with preponderance of akinesia during isometric contraction of the right forearm and during rest. Coherence as a measure of functional connectivity between M1 and SMA was calculated OFF and ON medication and correlated with the motor part of the Unified Parkinson's Disease Rating Scale (UPDRS III) and with disease duration. During rest a significant positive correlation between disease duration and SMA-M1 coherence was found ON but not OFF medication. Conversely, during isometric contraction SMA-M1 coherence and UPDRS III were inversely correlated OFF but not ON medication explaining more than 80% of variance. The results favor the hypothesis that OFF medication exaggerated cortical coherence at beta frequency represents a compensatory mechanism rather than a pathophysiological marker per se. PMID- 23664960 TI - Axonal degeneration in the peripheral nervous system: implications for the pathogenesis of amyotrophic lateral sclerosis. AB - Axons are the anatomical link between neuronal cell bodies and their target organs, and thus axonal degeneration is the pathological substrate that underlies neurological dysfunction in a large number of neurological conditions. Recent advances in the field of axonal biology demonstrate that axons possess programs for survival and degeneration that are distinct from those of the cell body, indicating that therapeutic strategies must consider protection of both the cell body and the axon. This review discusses axonal degeneration in the peripheral nervous system (PNS) with a focus on amyotrophic lateral sclerosis, examining both the underlying mechanisms, and the cellular and disease models of axonal degeneration that relate to disease pathogenesis. PMID- 23664961 TI - Dopamine receptor activation increases glial cell line-derived neurotrophic factor in experimental stroke. AB - Treatment with levodopa enhances functional recovery after experimental stroke but its mechanisms of action are elusive. Reactive astrocytes in the ischemic hemisphere are involved in mechanisms promoting recovery and also express dopamine 1 (D1) and dopamine 2 (D2) receptors. Here we investigated if the activation of astrocytic dopamine receptors (D1 and D2) regulates the expression of glial cell line-derived neurotrophic factor (GDNF) after combined in vitro hypoxia/aglycemia (H/A) and studied the expression of GDNF in the ischemic brain after treatment with levodopa/benserazide following transient occlusion of the middle cerebral artery (tMCAO) in the rat. Twenty-four hours after H/A, GDNF levels were upregulated in exposed astrocytes compared to normoxic control cultures and further elevated by the addition of the selective D1 receptor agonist (R)-(+)-SKF-38393 hydrochloride while D1 receptor antagonism by R(+)-SCH 23390 hydrochloride significantly reduced GDNF. No effect on GDNF levels was observed by the application of the D2 receptor agonist R(-)-2,10,11-trihydroxy-N propyl-noraporphine hydrobromide hydrate or S-(-)-eticlopride hydrochloride (D2 receptor antagonist). After tMCAO, GDNF was upregulated in D1 expressing reactive astrocytes in the peri-infarct area. In addition, treatment with levodopa/benserazide significantly increased GDNF levels in the infarct core and peri-infarct area after tMCAO without affecting the expression of glial fibrillar acidic protein (GFAP), an intermediate filament and marker of reactive gliosis. After stroke, GDNF levels increase in the ischemic hemisphere in rats treated with levodopa, implicating GDNF in the mechanisms of tissue reorganization and plasticity and in l-DOPA enhanced recovery of lost brain function. Our results support levodopa treatment as a potential recovery enhancing therapy in stroke patients. PMID- 23664962 TI - Mobilisation of the splenic monocyte reservoir and peripheral CX3CR1 deficiency adversely affects recovery from spinal cord injury. AB - Macrophages in the injured spinal cord originate from resident microglia and blood monocytes. Whether this diversity in origins contributes to their seemingly dual role in immunopathology and repair processes has remained poorly understood. Here we took advantage of Cx3cr1(gfp) mice to visualise monocyte-derived macrophages in the injured spinal cord via adoptive cell transfer and bone marrow (BM) chimera approaches. We show that the majority of infiltrating monocytes at 7 days post-injury originate from the spleen and only to a lesser extent from the BM. Prevention of early monocyte infiltration via splenectomy was associated with improved recovery at 42 days post-SCI. In addition, an increased early presence of infiltrating monocytes/macrophages, as a result of CX3CR1 deficiency within the peripheral immune compartment, correlated with worsened injury outcomes. Adoptive transfer of identified Cx3cr1(gfp/+) monocytes confirmed peak infiltration at 7 days post-injury, with inflammatory (Ly6C(high)) monocytes being most efficiently recruited. Focal SCI also changed the composition of the two major monocyte subsets in the blood, with more Ly6C(high) cells present during peak recruitment. Adoptive transfer experiments further suggested high turnover of inflammatory monocytes in the spinal cord at 7 days post-injury. Consistent with this, only a small proportion of infiltrating cells unequivocally expressed polarisation markers for pro-inflammatory (M1) or alternatively activated (M2) macrophages at this time point. Our findings offer new insights into the origins of monocyte-derived macrophages after SCI and their contribution to functional recovery, providing a basis for further scrutiny and selective targeting of Ly6C(high) monocytes to improve outcomes from neurotraumatic events. PMID- 23664963 TI - Dose reporting legislation in California: are we placing the idea of patient safety ahead of reality? PMID- 23664964 TI - Graduate medical education in the era of health care reform. AB - Medicare is the primary source of funding for graduate medical education (GME) in the United States. The growing deficit, a sluggish economy, and rising health care costs have focused attention on cutting spending, and GME reimbursement from Medicare is being considered among the entitlement programs for spending reduction. At the same time, health care reform will place new demands on residency training. The authors review the history of GME financing, the potential impact of GME spending cuts and health care reform on radiology training, and the new skills residents will need to practice in the era of health reform. As health care financing evolves, so must resident education. PMID- 23664965 TI - The re-education of the referring physician. PMID- 23664966 TI - Retooling nuclear medicine education in diagnostic radiology: interactive strategies using audience response system technology. PMID- 23664967 TI - Estimating the survival functions for right-censored and interval-censored data with piecewise constant hazard functions. AB - The exponential distribution is frequently used to model the survival time of a patient population, which assumes the hazard rate to be a constant over time. This assumption is often violated as the hazard function may vary over time and exhibit one or more change points in its values. Several methods exist in the literature for detecting a single change point in a piecewise constant hazard function for right-censored data. A sequential testing approach to detecting multiple change points in the hazard function using likelihood ratio statistics and resampling is proposed, which is applicable to both right-censored and interval-censored data. Numerical results based on simulated survival data and a real example show that the proposed approach can accurately detect the change points in the hazard function for both right-censored and interval-censored data. PMID- 23664969 TI - Prediction of nanoparticle prodrug metabolism by pharmacokinetic modeling of biliary excretion. AB - Pharmacokinetic modeling and simulation is a powerful tool for the prediction of drug concentrations in the absence of analytical techniques that allow for direct quantification. The present study applied this modeling approach to determine active drug release from a nanoparticle prodrug formulation. A comparative pharmacokinetic study of a nanoscale micellar docetaxel (DTX) prodrug, Procet 8, and commercial DTX formulation, Taxotere, was conducted in bile duct cannulated rats. The nanoscale (~40nm) size of the Procet 8 formulation resulted in confinement within the plasma space and high prodrug plasma concentrations. Ex vivo prodrug hydrolysis during plasma sample preparation resulted in unacceptable error that precluded direct measurement of DTX concentrations. Pharmacokinetic modeling of Taxotere and Procet 8 plasma concentrations, and their associated biliary metabolites, allowed for prediction of the DTX concentration profile and DTX bioavailability, and thereby evaluation of Procet 8 metabolism. Procet 8 plasma decay and in vitro plasma hydrolytic rates were identical, suggesting that systemic clearance of the prodrug was primarily metabolic. The Procet 8 and Taxotere plasma profiles, and associated docetaxel hydroxy-tert-butyl carbamate (HDTX) metabolite biliary excretion, were best fit by a two compartment model, with both linear and non-linear DTX clearance, and first order Procet 8 hydrolysis. The model estimated HDTX clearance rate agreed with in vitro literature values, supporting the predictability of the proposed model. Model simulation at the 10mg DTX equivalent/kg dose level predicted DTX formation rate limited kinetics and a peak plasma DTX concentration of 39ng/mL at 4h for Procet 8, in comparison to 2826ng/mL for Taxotere. As a result of nonlinear DTX clearance, the DTX AUCinf for the Procet 8 formulation was predicted to be 2.6 times lower than Taxotere (775 vs. 2017h*ng/mL, respectively), resulting in an absolute bioavailability estimate of 38%. As DTX clearance in man is considered linear, this low bioavailability is likely species-dependent. These data support the use of pharmacokinetic modeling and simulation in cases of complex formulations, where analytical methods for direct measurement of free (released) drug concentrations are unavailable. Uses of such models may include interpretation of preclinical toxicology studies, selection of first in man dosing regimens, and PK/PD model development. PMID- 23664970 TI - The cerebellum optimizes perceptual predictions about external sensory events. AB - Perception and action are governed not only by sensory information but also by prior predictions about sensory events. These sensory predictions allow one to react more rapidly to predictable information in the environment and to perceptually distinguish self-produced and externally produced sensations. In order to be accurate, however, all sensory predictions need continuous recalibration to match the changing properties of the environment, the sensorimotor system, or both. Earlier studies showed that the cerebellum is crucial for the recalibration of sensory predictions capturing the sensory consequences of one's motor behavior. Here we asked whether the cerebellum, a structure intimately linked to plasticity within the motor domain, also accounts for the recalibration of sensory predictions about external sensory events within the perceptual domain in a nonmotor task. Cerebellar patients and healthy controls were equally able to predict the time of reappearance of a moving target that temporarily disappeared behind an occluder. However, patients were significantly impaired in recalibrating this spatiotemporal prediction to account for an experimentally added delay. This suggests that the cerebellum plays a domain-general role in fine tuning predictive models. PMID- 23664971 TI - Locomotion controls spatial integration in mouse visual cortex. AB - Growing evidence indicates that responses in sensory cortex are modulated by factors beyond direct sensory stimulation. In primary visual cortex (V1), for instance, responses increase with locomotion. Here we show that this increase is accompanied by a profound change in spatial integration. We recorded from V1 neurons in head-fixed mice placed on a spherical treadmill. We characterized spatial integration and found that the responses of most neurons were suppressed by large stimuli. As in primates, this surround suppression increased with stimulus contrast. These effects were captured by a divisive normalization model, where the numerator originates from a central region driving the neuron and the denominator originates from a larger suppressive field. We then studied the effects of locomotion and found that it markedly reduced surround suppression, allowing V1 neurons to integrate over larger regions of visual space. Locomotion had two main effects: it increased spontaneous activity, and it weakened the suppressive signals mediating normalization, relative to the driving signals. We conclude that a fundamental aspect of visual processing, spatial integration, is controlled by an apparently unrelated factor, locomotion. This control might operate through the mechanisms that are in place to deliver surround suppression. PMID- 23664972 TI - The tumor suppressor Rb critically regulates starvation-induced stress response in C. elegans. AB - How animals coordinate gene expression in response to starvation is an outstanding problem closely linked to aging, obesity, and cancer. Newly hatched Caenorhabditis elegans respond to food deprivation by halting development and promoting long-term survival (L1 diapause), thereby providing an excellent model for the study of starvation response. Through a genetic search, we have discovered that the tumor suppressor Rb critically promotes survival during L1 diapause and most likely does so by regulating the expression of genes in both insulin-IGF-1 signaling (IIS)-dependent and -independent pathways mainly in neurons and the intestine. Global gene expression analyses suggested that Rb maintains the "starvation-induced" transcriptome and represses the "refeeding induced" transcriptome, including the repression of many pathogen-, toxin-, and oxidative-stress-inducible and metabolic genes, as well as the activation of many other stress-resistant genes, mitochondrial respiratory chain genes, and potential IIS receptor antagonists. Notably, the majority of genes dysregulated in starved L1 Rb(-) animals were not found to be dysregulated in fed conditions. Altogether, these findings identify Rb as a critical regulator of the starvation response and suggest a link between functions of tumor suppressors and starvation survival. These results may provide mechanistic insights into why cancer cells are often hypersensitive to starvation treatment. PMID- 23664973 TI - Environmental alkalinity sensing mediated by the transmembrane guanylyl cyclase GCY-14 in C. elegans. AB - Survival requires that living organisms continuously monitor environmental and tissue pH. Animals sense acidic pH using ion channels and G-protein-coupled receptors (GPCRs), but monitoring of alkaline pH is not well understood. We report here that in the nematode Caenorhabditis elegans, a transmembrane receptor type guanylyl cyclase (RGC), GCY-14, of the ASEL gustatory neuron, plays an essential role in the sensing of extracellular alkalinity. Activation of GCY-14 opens a cGMP-gated cation channel encoded by tax-2 and tax-4, resulting in Ca(2+) entry into ASEL. Ectopic expression of GCY-14 in other neurons indicates that it accounts for the alkalinity sensing capability. Domain-swapping and site-directed mutagenesis of GCY-14 reveal that GCY-14 functions as a homodimer, in which histidine of the extracellular domains plays a crucial role in alkalinity detection. These results argue that in addition to ion channels and GPCRs, RGCs also play a role in pH sensation in neurons. PMID- 23664974 TI - Neural response phase tracks how listeners learn new acoustic representations. AB - Humans are remarkable at rapidly learning regularities through experience from a dynamic environment. For example, long-lasting memories are formed even for auditory noise patterns after short, repeated exposure in an unsupervised manner. Although animal neurophysiological and human studies demonstrate adaptive cortical plasticity after sensory learning and memory formation, the mechanisms by which the auditory system extracts and encodes holistic patterns from random noise, which contains neither semantic labels nor prominent acoustic features to facilitate encoding, remains unknown. Here we combined magnetoencephalography (MEG) with psychophysics to address the issue. We demonstrate that the establishment of a reliable neuronal phase pattern in low-frequency (3-8 Hz) auditory cortical responses mirrors the noise memory formation process. Specifically, with repeated exposure, originally novel noise patterns are memorized, as reflected in behavior, and gradually produce robust phase responses in auditory cortex. Moreover, different memorized noises elicit distinguishable phase responses, suggesting their specificity to noise structure. The results indicate that the gradual establishment of low-frequency oscillatory phase patterns in auditory neuronal responses mediates the implicit learning process by which originally undifferentiated noises become new auditory objects. PMID- 23664975 TI - Spatial population expansion promotes the evolution of cooperation in an experimental Prisoner's Dilemma. AB - Cooperation is ubiquitous in nature, but explaining its existence remains a central interdisciplinary challenge. Cooperation is most difficult to explain in the Prisoner's Dilemma game, where cooperators always lose in direct competition with defectors despite increasing mean fitness. Here we demonstrate how spatial population expansion, a widespread natural phenomenon, promotes the evolution of cooperation. We engineer an experimental Prisoner's Dilemma game in the budding yeast Saccharomyces cerevisiae to show that, despite losing to defectors in nonexpanding conditions, cooperators increase in frequency in spatially expanding populations. Fluorescently labeled colonies show genetic demixing of cooperators and defectors, followed by increase in cooperator frequency as cooperator sectors overtake neighboring defector sectors. Together with lattice-based spatial simulations, our results suggest that spatial population expansion drives the evolution of cooperation by (1) increasing positive genetic assortment at population frontiers and (2) selecting for phenotypes maximizing local deme productivity. Spatial expansion thus creates a selective force whereby cooperator enriched demes overtake neighboring defector-enriched demes in a "survival of the fastest." We conclude that colony growth alone can promote cooperation and prevent defection in microbes. Our results extend to other species with spatially restricted dispersal undergoing range expansion, including pathogens, invasive species, and humans. PMID- 23664976 TI - Avoiding coral reef functional collapse requires local and global action. AB - Coral reefs face multiple anthropogenic threats, from pollution and overfishing to the dual effects of greenhouse gas emissions: rising sea temperature and ocean acidification. While the abundance of coral has declined in recent decades, the implications for humanity are difficult to quantify because they depend on ecosystem function rather than the corals themselves. Most reef functions and ecosystem services are founded on the ability of reefs to maintain their three dimensional structure through net carbonate accumulation. Coral growth only constitutes part of a reef's carbonate budget; bioerosion processes are influential in determining the balance between net structural growth and disintegration. Here, we combine ecological models with carbonate budgets and drive the dynamics of Caribbean reefs with the latest generation of climate models. Budget reconstructions using documented ecological perturbations drive shallow (6-10 m) Caribbean forereefs toward an increasingly fragile carbonate balance. We then projected carbonate budgets toward 2080 and contrasted the benefits of local conservation and global action on climate change. Local management of fisheries (specifically, no-take marine reserves) and the watershed can delay reef loss by at least a decade under "business-as-usual" rises in greenhouse gas emissions. However, local action must be combined with a low carbon economy to prevent degradation of reef structures and associated ecosystem services. PMID- 23664977 TI - Alternative splicing generates a truncated isoform of human TNFRSF11A (RANK) with an altered capacity to activate NF-kappaB. AB - Alternative splicing (AS) is a major post-transcriptional modification taking place in all cells. Many members of the TNF receptor superfamily modulate their function through protein isoforms produced by alternative splicing. TNFRSF11A (RANK) gene, through alternative splicing produces multiple isoforms truncated in their intracellular domain, with distinct functions. Here, we report the identification and characterization of a novel human TNFRSF11A (RANK) variant from human normal brain, named RANK-e5a (TNFRSF11A_e5a). The novel variant lacks 42 nucleotides from exon 5, giving rise to a novel shorter form of exon 5, named exon 5a. The incorporation of the novel exon 5a in RANK mRNA does not affect the open reading frame, producing a truncation of thirteen amino acids of the third and fourth TNFR motifs of the extracellular part of the receptor. By western blot analysis and immunofluorescence staining we were able to further characterize the RANK-e5a isoform at the protein level. In addition, we performed an ELISA assay to characterize RANK/RANKL and RANK-e5a/RANKL binding capacities, and we identified a reduced affinity of RANK-e5a to bind RANKL. Finally, when RANK-e5a is stimulated by RANK ligand, its capability to activate NF-kappaB is reduced compared to the wild type RANK receptor. Overall, our data provide a novel regulatory mechanism for the RANK/RANKL system, at the RANK receptor level. PMID- 23664978 TI - Genetic structure of Mexican Mestizos with type 2 diabetes mellitus based on three STR loci. AB - BACKGROUND: The aims of this population genetics study were: 1) to ascertain whether Mexicans with type 2 diabetes mellitus (DM) were genetically homogeneous and 2) to compare the genetic structure of this selected population with the previously reported data of four random populations (Nuevo Leon, Hispanics, Chihuahua, and Central Region of Mexico). METHODS: A sample of 103 unrelated individuals with DM and whose 4 grandparents were born in five zones of Mexico was interviewed in 32 Medical Units in the Mexican Institute of Social Security (IMSS). The non-coding STRs D16S539, D7S820, and D13S317 were analyzed. RESULTS: Genotype distribution was in agreement with Hardy-Weinberg expectations for all three markers. Allele frequencies were found to be similar between the selected population and the four random populations. Gene diversity analysis suggested that more than 99.57% of the total gene diversity could be attributed to variation between individuals within the population and 0.43% between the populations. CONCLUSIONS: According to the present and previous studies using molecular and non-molecular nuclear DNA markers not associated with any disease, the Mexican Mestizo population is found to be genetically homogeneous and therefore the genetic causes of DM are less heterogeneous, thereby simplifying genetic epidemiological studies as has been found in a previous study with the same design in Mexican women with breast cancer. PMID- 23664979 TI - Complete genome sequencing and analysis of an anti-tumor Newcastle disease virus strain. AB - HBNU/LSRC/F3, a Newcastle disease virus (NDV) strain stored in our lab, exhibited an anti-tumor ability in our previous studies. Nonetheless, very little is known about its genome sequence, which is vital for further study. Here, the complete HBNU/LSRC/F3 genome was fully sequenced and compared with other NDV sequences. Its genome contained 15,192 nucleotides (nt) consisting of two termini and six genes in the following order: 3'-Le-NP-P-M-F-HN-L-Tr-5'. Phylogenetic analysis indicated that this NDV strain belonged to the Class II genotype IX group. A multibasic amino acid (aa) sequence was found at the cleavage site ((112)RRQRR?F(117)) within the fusion (F) protein, and a 6 nt insertion was present in the 5' non-coding region of the NP gene. The whole genome sequence was highly similar to other genotype IX NDV genomes reported in China. Overall, this study provides insight into the sequence characteristics of genotype IX NDVs, which will be useful for subsequent investigations. PMID- 23664980 TI - Two Delta6-desaturase-like genes in common carp (Cyprinus carpio var. Jian): structure characterization, mRNA expression, temperature and nutritional regulation. AB - Delta6-Desaturase is the rate-limiting enzyme involved in highly unsaturated fatty acid (HUFA) biosynthesis. There is very little information on the evolution and functional characterization of Delta6Fad-a and Delta6Fad-b in common carp (Cyprinus carpio var. Jian). In the present study, the genomic sequences and structures of two putative Delta6-desaturase-like genes in common carp genome were obtained. We investigated the mRNA expression patterns of Delta6Fad-a and Delta6Fad-b in tissue, hatching carp embryos, larvae by temperature shock and juveniles under nutritional regulation. Our results showed that the two Delta6Fad genes had identical coding exon structures, being comprised of 12 coding exons, and with introns of distinct size and sequence composition. They were not allelic variants of a single gene. Both Delta6Fad genes were highly expressed in liver, intestine (pyloric caeca) and brain. The Delta6Fad-a and Delta6Fad-b mRNAs showed an increase in expression from newly hatched to 25 days after hatching. The expression levels of Delta6Fad-a were obviously regulated by temperature, whereas Delta6Fad-b was not affected by temperature. The regulation of Delta6Fad-a and Delta6Fad-b in response to dietary fatty acid composition was determined in liver, brain and intestine (pyloric caeca) of common carp fed with diets: diet1with fish oil (FO) rich in n-3 HUFA, diet2 with corn oil (CO, 18:2n-6) and diet3 with linseed oil (LO, 18:3n-3). The differential expression of Delta6Fad-a and Delta6Fad-b genes in liver, brain and intestine in common carps was fed with different oil sources, respectively. Further work is in progress to determine the mechanism of differential expression of the Delta6Fad-a and Delta6Fad-b genes in different tissues and the roles of transcription factors in regulating HUFA synthesis. PMID- 23664981 TI - Ambiguous external genitalia due to defect of 5-alpha-reductase in seven Iraqi patients: prevalence of a novel mutation. AB - We report on seven Iraqi patients with 46,XY karyotype and ambiguous genitalia characterized by perineo-scrotal hypospadias, bifid scrotum, clitoris like phallus, palpable testes in inguinal canal and pseudovagina. Patients were raised five as females and two as males. They are all unrelated with the exception of two couples of brothers. The diagnosis of 5-alpha-reductase-2 deficiency syndrome was first hypothesized on clinical grounds and then confirmed by molecular analysis. Direct sequencing analysis of the SRD5A2 gene revealed in five patients a novel homozygous frame-shift mutation (c.453delC) and in two related patients a previous reported missense mutation. The presence of the same mutation in unrelated patients of the same population suggests a possible founder effect. This report brings the 5-alpha-reductase-2 deficiency syndrome to the attention of clinical geneticists and child surgeons and discusses the appropriate clinical and surgical strategies for treating these patients. PMID- 23664982 TI - Base composition and nucleosome density in exonic and intronic regions in genes of the filamentous ascomycetes Aspergillus nidulans and Aspergillus oryzae. AB - We sequenced nucleosomal DNA fragments of the filamentous ascomycetes Aspergillus nidulans and Aspergillus oryzae and then mapped those sequences on their genomes. We compared the GC content and nucleosome density in the exonic and intronic regions in the genes of A. nidulans and A. oryzae. Although the GC content and nucleosome density in the exonic regions tended to be higher than those in the intronic regions, the difference in the distribution of the GC content was more notable than that of the nucleosome density. Next, we compared the GC content and nucleosome density in the exonic regions of 9616 orthologous gene pairs. In both Aspergillus species, the GC content did not correlate with the nucleosome density. In addition, the Spearman's rank correlation coefficient (rho=0.51) between the GC content of the exonic regions of the 9616 orthologous gene pairs was higher than that (rho=0.31) of the nucleosome densities of A. nidulans and A. oryzae. These results strongly suggest that the GC content in the exons of the orthologous gene pairs has been conserved during evolution but the nucleosome density has varied throughout. PMID- 23664983 TI - Indigenous and foreign Y-chromosomes characterize the Lingayat and Vokkaliga populations of Southwest India. AB - Previous studies have shown that India's vast coastal rim played an important role in the dispersal of modern humans out of Africa but the Karnataka state, which is located on the southwest coast of India, remains poorly characterized genetically. In the present study, two Dravidian populations, namely Lingayat (N=101) and Vokkaliga (N=102), who represent the two major communities of the Karnataka state, were examined using high-resolution analyses of Y-chromosome single nucleotide polymorphisms (Y-SNPs) and seventeen short tandem repeat (Y STR) loci. Our results revealed that the majority of the Lingayat and Vokkaliga paternal gene pools are composed of four Y-chromosomal haplogroups (H, L, F* and R2) that are frequent in the Indian subcontinent. The high level of L1-M76 chromosomes in the Vokkaligas suggests an agricultural expansion in the region, while the predominance of R1a1a1b2-Z93 and J2a-M410 lineages in the Lingayat indicates gene flow from neighboring south Indian populations and West Asia, respectively. Lingayat (0.9981) also exhibits a relatively high haplotype diversity compared to Vokkaliga (0.9901), supporting the historical record that the Lingayat originated from multiple source populations. In addition, we detected ancient lineages such as F*-M213, H*-M69 and C*-M216 that may be indicative of genetic signatures of the earliest settlers who reached India after their migration out of Africa. PMID- 23664984 TI - Prevalence of antibiotic resistance genes and their relationship with antibiotics in the Huangpu River and the drinking water sources, Shanghai, China. AB - The prevalence of antibiotic resistance genes (ARGs) and their relationship with antibiotics in the surface waters of the Huangpu River and the drinking water sources of Shanghai, China, were investigated. 39 ARGs, including four sulfonamide ARGs, 23 tetracycline ARGs, four chloramphenicol ARGs, five beta lactam ARGs and three penicillin ARGs were targeted in this study. Two sulfonamide ARGs (sul I and sul II), eight tetracycline ARGs (tet(A), tet(B), tet(C), tet(G), tet(M), tet(O), tet(W) and tet(X)), and one beta-lactam ARG (TEM) were detected to be present in water samples by polymerase chain reaction (PCR), with the detection frequencies ranging from 42.86% to 100%. The average concentrations of the 11 ARGs ranged from 3.66*10(1) copy/mL (tet(B)) to 1.62*10(5) copy/mL (sul II), quantified by quantitative real-time PCR (QPCR). The number of detected ARGs and the ARG concentrations were generally higher in suburban sampling sites than in urban sites. Being in or near suburban rural areas, some raw drinking water sources were observed to have comparatively higher ARG contamination, drawing an urgent attention for the concern of public health. Generally consistent relations were observed between the concentrations of tet genes and the tetracycline levels and between the concentrations of sul genes and the sulfonamide levels. PMID- 23664985 TI - Characterization of non-exhaust coarse and fine particles from on-road driving and laboratory measurements. AB - We investigated the physical and chemical properties of non-exhaust coarse and fine particles generated by on-road driving and in a laboratory setting using a mobile sampling system. The on-road driving and laboratory measurements performed under constant speed driving revealed that particles produced by tire wear had a size distribution in the range of 2-3 MUm, while roadway particles (RWPs) measured behind the front tire during on-road driving largely comprised crustal materials such as road surface wear particles and road dust as well as tire wear particles (TWPs). The mode diameters of particles obtained from on-road driving under cornering conditions were similar to those obtained under constant speed conditions, but with higher concentrations of crustal elements. Under braking conditions, the particulate matter (PM) concentrations of brake wear particles (BWPs) sampled near the brake pad increased significantly and were much higher than the concentration of RWPs during deceleration, indicating that BWPs are one of the main sources of non-exhaust emissions. In addition, BWPs observed from on road and laboratory measurements had a broader PM size range (1-10 MUm) than RWPs. Size-segregated chemical analysis of PM samples indicated that the concentrations of Fe and Ca were highest in the coarse fraction emitted under constant speed and cornering conditions, while Fe, Ba, and Ti were most abundant in the fine fraction emitted during braking events. PMID- 23664986 TI - Evaluation of Brucella abortus S19 vaccines commercialized in Brazil: immunogenicity, residual virulence and MLVA15 genotyping. AB - Live attenuated Brucella abortus S19 is the most effective vaccine against brucellosis in cattle. The assessment of the immunological parameters is essential to guarantee the biological quality of live anti-bacteria vaccines. The evaluation of genetic stability of live bacterial vaccines is also important in quality control. The aims of the present study were to compare (i) the immunogenicity and residual virulence, and (ii) the genotypic profile (MLVA15) of the eight S19 vaccines commercialized in Brazil to the USDA S19 reference strain. Two batches of each of the eight S19 commercial vaccines used in Brazil (A-H) were tested. They were submitted to the potency and residual virulence in vivo tests recommended by OIE and typed by the multiple-locus variable-number tandem repeat (VNTR) analysis (MLVA) described for Brucella spp. Our results demonstrated that all S19 vaccines commercialized in Brazil would be approved by Brazilian and OIE recommendations for potency and residual virulence. Furthermore, the S19 vaccine is genetically very homogeneous, as all but two batches (from the same manufacturer) tested showed identical MLVA15 profile. The two batches with different profiles presented six repeat units in locus Bruce07, instead of the five found in all other strains, including the USDA S19 reference strain. Although presenting a slightly different profile, this vaccine was also protective, as demonstrated by the immunogenicity and residual virulence assays performed. Therefore, the commercial Brazilian S19 vaccines were in accordance to Brazilian and international standards for immunogenicity and residual virulence tests. Moreover, our results also show that MLVA could be a useful inclusion to the list of in vitro tests required by the official control authorities to be applied to the commercial S19 vaccines, as an efficient assay to guarantee the quality and stability of the vaccine strains. PMID- 23664988 TI - Prospective cost-benefit analysis of a two-dimensional barcode for vaccine production, clinical documentation, and public health reporting and tracking. AB - In the United States recording accurate vaccine lot numbers in immunization records is required by the National Childhood Vaccine Injury Act and is necessary for public health surveillance and implementation of vaccine product recalls. However, this information is often missing or inaccurate in records. The Food and Drug Administration (FDA) requires a linear barcode of the National Drug Code (NDC) on vaccine product labels as a medication verification measure, but lot number and expiration date must still be recorded by hand. Beginning in 2011, FDA permitted manufacturers to replace linear barcodes with two-dimensional (2D) barcodes on unit-of-use product labels. A 2D barcode can contain the NDC, expiration date, and lot number in a symbol small enough to fit on a unit-of-use label. All three data elements could be scanned into a patient record. To assess 2D barcodes' potential impacts, a mixed-methods approach of time-motion data analysis, interview and survey data collection, and cost-benefit analysis was employed. Analysis of a time-motion study conducted at 33 practices suggests scanning 2D-barcoded vaccines could reduce immunization documentation time by 36 39 s per dose. Data from an internet survey of primary care providers and local health officials indicate that 60% of pediatric practices, 54% of family medicine practices, and 39% of health departments would use the 2D barcode, with more indicating they would do so if they used electronic health records. Inclusive of manufacturer and immunization provider costs and benefits, we forecast lower bound net benefits to be $310-334 million between 2011 and 2023 with a benefit-to cost ratio of 3.1:1-3.2:1. Although we were unable to monetize benefits for expected improved immunization coverage, surveillance, or reduced medication errors, based on our findings, we expect that using 2D barcodes will lower vaccine documentation costs, facilitate data capture, and enhance immunization data quality. PMID- 23664987 TI - Safety and immunogenicity of IMVAMUNE(r) smallpox vaccine using different strategies for a post event scenario. AB - INTRODUCTION: Reintroduction of Variola major as an agent of bioterrorism remains a concern. A shortened dosing schedule of Bavarian Nordic's (BN) IMVAMUNE((r)) (modified vaccinia Ankara vaccine against smallpox) was compared to the currently recommended 0- and 28-day schedule for non-inferiority by evaluating the magnitude and kinetics of the immune responses. METHODS: Subjects were assigned to receive IMVAMUNE or placebo administered subcutaneously on Days 0 and 7, Days 0 and 28, or Day 0. Blood was collected for antibody and cell-mediated immune assays. Subjects were followed for safety for 12 months after last vaccination. RESULTS: The primary endpoint of this study was the geometric mean antibody titers (GMT) at 14 days post last vaccination. Of 208 subjects enrolled, 191 received vaccine (Group: 0+7, Group: 0+28 and Group: 0) and 17 received placebo. Moderate/severe systemic reactogenicity after any vaccination were reported by 31.1%, 25.4%, and 28.6% of the subjects for Group: 0+7, Group: 0+28, and Group: 0, respectively (Chi-square test, P=0.77). Based on BN's Plaque Reduction Assay GMTs, Group: 0+7 was non-inferior to Group: 0+28 at Day 4, 180, and 365 after the second vaccination. On Day 14, Group: 0+7 and Group: 0+28 GMT were 10.8 (CI: 9.0, 12.9) and 30.2 (CI: 22.1, 41.1), respectively. Based on BN's Enzyme-linked immunosorbent assay, the proportion of subjects with positive titers for Group: 0+28 was significantly greater than that for Group: 0+7 after second vaccination at Days 4 and 180. By Day 14 after the second dose, the IFN-gamma enzyme-linked immunosorbent spot (ELISPOT) responses were similar for Group: 0+28 and Group: 0+7. CONCLUSION: Overall, a standard dose of IMVAMUNE (0.5 mL of 1 x 10(8) TCID/mL) administered subcutaneously was safe and well tolerated. A second dose of IMVAMUNE at Day 28 compared to Day 7 provided greater antibody responses and the maximal number of responders. By Day 14 after the second dose, IFN-gamma ELISPOT responses were similar for Group: 0+28 and Group: 0+7. PMID- 23664989 TI - Immunogenicity of sequences around HIV-1 protease cleavage sites: potential targets and population coverage analysis for a HIV vaccine targeting protease cleavage sites. AB - Developing an effective preventative vaccine against HIV-1 has proved to be a great challenge. The classical and proven vaccine approach has failed so far or produced a modest effect, new approaches are needed. In this study we evaluated the immunogenicity of the sequences around the protease cleavage sites (PCS) and the population coverage of a vaccine targeting HIV-1 PCS. The sequence conservation was evaluated by comparing entropy score of sequences around PCS with Gag and Pol. The immunogenicity of sequences around the 12 PCS (+10/-10 amino acids) was analyzed by identifying epitopes of HLA class I alleles in PCS region using four approaches: (1) identification of previously reported HLA class I allele epitopes around PCS region; (2) screening and validating epitopes of 8 HLA class I alleles common to most world populations using iTopia Epitope Discovery system and IFN-gamma ELISpot assays; (3) screening of 151 patients of Pumwani cohort for PBMC IFN-gamma ELISPOT responses to the subtype A and D consensus around PCS region; and (4) prediction of HLA alleles with epitopes around the PCS using NetMHCpan. Population coverage was calculated using the web based analysis tool of the Immune Epitope Database based on HLA class I genotype frequencies from dbMHC database. The results showed that many HLA class I alleles have multiple epitopes in the 12 PCS regions, indicating sequence immunogenicity around PCS. Multiple epitopes of many HLA class I alleles common to >95% world populations have been identified around the 12 PCS region. Targeting these sites is a feasible vaccine approach. PMID- 23664990 TI - Correlates of HPV vaccination among adolescent females from Appalachia and reasons why their parents do not intend to vaccinate. AB - Limited research has examined HPV vaccination in Appalachia, a region with cervical cancer disparities. We analyzed 2008-2010 National Immunization Survey Teen data for adolescent females ages 13-17 from Appalachia (n=1951) to identify correlates of HPV vaccination and reasons why their parents do not intend to vaccinate. HPV vaccine initiation was 40.8%, completion was 27.7%, and follow through was 67.8%. Vaccination outcomes tended to be higher among females who were older, had visited their healthcare provider in the last year, or whose parents reported receiving a provider recommendation to vaccinate. Only 41.0% of parents with unvaccinated daughters intended to vaccinate in the next year. The most common reasons for not intending to vaccinate were believing vaccination is not needed or not necessary (21.5%) and lack of knowledge (18.5%). Efforts to reduce missed opportunities for vaccination at healthcare visits and address reasons why parents are not vaccinating may help increase HPV vaccination in Appalachia. PMID- 23664991 TI - Modeling the impact of quadrivalent HPV vaccination on the incidence of Pap test abnormalities in the United States. AB - BACKGROUND: We present data on Pap test results and HPV prevalence from the HPV Sentinel Surveillance project, a multiyear surveillance project enrolling women from a diverse set of 26 clinics throughout the US from 2003 to 2005. We use mathematical modeling to illustrate the potential timing and magnitude of decreases in Pap test abnormalities in sexually transmitted disease (STD), family planning, and primary care clinics in the US as a result of HPV vaccination. METHODS: The probability of an abnormal Pap result was based on three factors: (1) infection with HPV 16/18, or both; (2) infection with high-risk HPV types other than HPV 16/18; and (3) infection with HPV 6/11, or both. We estimated the relative reduction in the probability of an abnormal Pap result over the first 25 years of a female-only, quadrivalent HPV vaccination program, compared to a scenario of no HPV vaccination in which the probability of abnormal Pap results was assumed constant. RESULTS: The probability of an abnormal Pap result ranged from 7.0% for the lowest risk group (those without any high-risk HPV types and without HPV 6/11) to 45.2% for the highest risk group (those with HPV 16/18 and at least one other high-risk HPV type). Estimated reductions in abnormal Pap results among women in the 21- to 29-year age group were 0.8%, 10.2%, and 11.3% in years 5, 15, and 25 of the vaccine program respectively, in the lower vaccine coverage scenario, and 7.4%, 21.4%, and 22.2%, respectively, in the higher coverage scenario. CONCLUSIONS: Our results suggest that HPV vaccination will have a discernable impact on the probability of Pap abnormalities, but the timing and magnitude of the reduction will depend substantially on vaccine coverage and the degree of cross-protection against high risk HPV types other than HPV 16/18. PMID- 23664992 TI - Characterization of the carbohydrate binding and ADP-ribosyltransferase activities of chemically detoxified pertussis toxins. AB - Pertussis toxin (PTx) is an essential component of the acellular pertussis (aP) vaccine. However, because PTx in its native form is considered too toxic for human vaccine use, it must be inactivated into a stable, nontoxic form by treatment with chemical detoxifying agents or by genetic modification. Therefore, testing for the residual PTx in the aP vaccine is a major quality control step for vaccine manufacturers and regulatory authorities. The histamine sensitization test is currently the standard safety test method for all aP vaccines, regardless of the vaccine formula or the detoxification process, except for those with genetically modified PTx. However, test result variability and ethical concerns regarding animal use necessitate an alternative method. In vitro assays based on the biochemical properties of PTx have been considered as potential alternatives to the histamine sensitization test. In this study, the suitability of assays based on the ADP-ribosyltransferase and carbohydrate binding activities of PTx was assessed for PTx after treatment with formaldehyde, glutaraldehyde or both denaturants in sequence. The results indicated a distinctive pattern of the biochemical activities depending on the detoxification methods and storage conditions. These results suggest that although a more careful study is needed, these in vitro biochemical assays can be considered potential alternatives to the histamine sensitization test, as they might provide more specific safety information of aP vaccines. PMID- 23664993 TI - Desirability for a typhoid fever vaccine among rural residents, Pemba Island, Tanzania. AB - BACKGROUND: Surveillance data indicate that Salmonella enterica serotype Typhi (S. Typhi) is a significant cause of morbidity and mortality in Africa. With limited anticipated short-term improvements in sanitation and water infrastructure, targeted vaccination campaigns may be an important prevention tool for typhoid fever. METHODS: A cross-sectional survey was conducted with 435 randomly selected households in four rural villages on Pemba Island, Tanzania. A dichotomous 'readiness to pay' variable was created to assess vaccine desirability. Data analyses included univariate and bivariate descriptive statistics and binary logistic regression. Bivariate outcomes (ANOVA, t-tests, and chi-square) and odds ratios with 95% confidence intervals are reported. RESULTS: A total of 66% respondents stated that they would pay for a typhoid fever vaccine in the future. Readiness to pay was not significantly associated with household expenditures. Readiness to pay was associated with use of local Primary Health Care Units (PHCUs) compared to use of cottage or district hospitals (OR 1.8 [95% CI, 1.2-2.7]: p=.007) and with knowledge of someone being sick from typhoid fever (OR 2.2 [95% CI, 1.0-4.5]: p=.039). Respondents perceiving prevention measures as more effective (OR 1.0 [95% CI, 1.0-1.2]: p=.009) were also more likely ready to pay. Preferred methods of communication of information about a typhoid fever vaccine included broadcasting via microphone ('miking'), radio, and door-to-door visits. CONCLUSIONS: With rapid increase in numbers of licensed and promising vaccines, policy makers and health administrators are faced with decisions regarding allocation of scarce health resources for competing interventions. Community residents need to be informed about diseases which may not be readily recognized, diagnosed, and treated. Perceived vulnerability to the disease may increase likelihood of vaccine desirability. A better local understanding of typhoid fever is needed for general prevention measures, increasing treatment access, and future vaccination campaigns. PMID- 23664994 TI - Protective immunity induced by immunization with a live, cultured Anaplasma marginale strain. AB - Despite significant economic losses resulting from infection with Anaplasma marginale, a tick-transmitted rickettsial pathogen of cattle, available vaccines provide, at best, only partial protection against clinical disease. The green fluorescent protein expressing mutant of the A. marginale St. Maries strain is a live, marked vaccine candidate (AmStM-GFP). To test whether AmStM-GFP is safe and provides clinical protection, a group of calves was vaccinated, and clinical parameters, including percent parasitized erythrocytes (PPE), packed cell volume (PCV) and days required to reach peak bacteremia, were measured following inoculation and following tick challenge with wild type St. Maries strain (AmStM). These clinical parameters were compared to those obtained during infection with the A. marginale subsp. centrale vaccine strain (A. centrale) or wild type AmStM. AmStM-GFP resulted in similar clinical parameters to A. centrale, but had a lower maximum PPE, smaller drop in PCV and took longer to reach peak bacteremia than wild type AmStM. AmStM-GFP provided clinical protection, yielding a stable PCV and low bacteremia following challenge, whereas A. centrale only afforded partial clinical protection. PMID- 23664995 TI - Increased IgG but normal IgA anti-pneumococcal protein antibodies in lung of HIV infected adults. AB - PspA and pneumolysin (Ply) are important protein vaccine candidates. HIV infection is associated with increased susceptibility to pneumococcal pneumonia and concomitantly high pneumococcal carriage rates. Pneumococcal exposure is immunizing at the mucosa in healthy adults and so we wished to determine if the increased pneumococcal exposure in HIV-infected adults would be associated with altered pneumococcal specific antibody responses. We measured serum and bronchoalveolar lavage (BAL) fluid immunoglobulin (Ig)G and IgA to PspA and Ply in HIV-infected and healthy age-matched adults. Naturally generated anti-Ply and anti-PspA IgG levels but not IgA were significantly increased in HIV-infected subjects in BAL independent of the hyperglobulinaemia commonly associated with HIV. There was therefore no evidence of a defect in mucosal responses to pneumococcal protein antigens among HIV-infected adults. With regard to future vaccination strategies, simply increasing mucosal anti-pneumococcal protein Ig levels, without addressing functional protective response, is not likely to be effective in preventing pneumococcal pneumonia in HIV-infected individuals. PMID- 23664996 TI - Parental and societal support for adolescent immunization through school based immunization programs. AB - OBJECTIVES: Adolescent immunizations such as human papillomavirus vaccine have been implemented through school based immunization programs (SBIPs) in Australia. We assessed community attitudes toward immunization of adolescents though SBIPs. METHODS: A cross-sectional population survey of rural and metropolitan households in South Australia in 2011. Univariate and multiple regression analyses identified predictors of support for a SBIP. RESULTS: Participation rate was 57.3% with 1926 adults interviewed. Overall, 75.9% regarded school as the best place to offer adolescent immunizations, with 16.4% preferring the family physician. Parents of high school students were most supportive (88.4%) of a SBIP with 87.9% of their adolescents reported as having participated in the program. Adults 18-34 years (79.4%) were more likely to support a SBIP compared to older adults (68.7% of >55 years) [adjusted OR=2.39, p=0.002] and men were more supportive (80.3%) than women (71.7%) [adjusted OR=1.54, p=0.003]. Reasons for participation in the SBIP included convenience (39.9%), public funding for the service (32.4%), and confidence in immunization recommendations (21.0%). CONCLUSIONS: Public support for the SBIP was very high particularly amongst parents whose adolescent/s had participated in the program. PMID- 23664997 TI - Different kinetics of circulating antibody-secreting cell responses after primary and booster oral immunizations: a tool for assessing immunological memory. AB - We show that the kinetics of circulating IgA as well as IgG antibody-secreting cell (ASC) responses differs considerably after primary and booster vaccination with the oral cholera vaccine Dukoral((r)), as determined by the antibody in lymphocyte supernatant (ALS) as well as ELISPOT methods. Thus, whereas the antitoxin ASC responses did not peak until 7-9 days after primary vaccination, peak responses to a second dose given after two weeks, or a single booster dose given 6 months to 14 years later, were recorded already after 4-5 days and then rapidly declined. Our results indicate that many previous studies reporting ASC results 7-10 days after repeated immunization may have substantially underestimated the magnitudes of the responses. The results also suggest that detection of peak ASC responses at an early time point after booster immunization can be used as a simple tool to assess immunological memory. PMID- 23664998 TI - Nonmedical exemptions to immunization requirements in California: a 16-year longitudinal analysis of trends and associated community factors. AB - BACKGROUND: Rates of nonmedical exemptions to kindergarten-entry immunization requirements have increased over the past 2 decades, especially in states that permit philosophical exemptions and/or have easier administrative policies for obtaining nonmedical exemptions. We evaluated trends in school personal belief exemption rates over the period 1994-2009 in California, and associated school and community characteristics. METHODS: We used data on personal belief exemptions from 6392 public and private elementary schools from the California Department of Public Health, as well as census tract and school demographic data. Generalized estimating equations were used to model annual mean increases in personal belief exemption rates, and to identify school and community characteristics associated with personal belief exemption rates. RESULTS: Over the study period, the average school personal belief exemption rate increased from 0.6% in 1994 to 2.3% in 2009, an average of 9.2% (95% CI: 8.8-9.6%) per year. The average personal belief exemption rate among private schools over the entire study period was 1.77 (95% CI: 1.55-2.01) times that among public schools. The annual rate of increase was slightly higher among private schools (10.1%, 95% CI: 9.1-11.1%) than among public schools (8.8%, 95% CI: 8.4-9.2%). Schools located within census tracts classified as rural had 1.66 (95% CI: 1.26-2.08) times higher personal belief exemption rates than schools located within urban census tracts. Exemption rates were also associated with race, population density, education, and income. CONCLUSIONS: This study confirms concerns about increasing rates of nonmedical exemptions to kindergarten vaccine requirements within the state of California, using data collected over a 16-year period. PMID- 23664999 TI - Factors predicting response to hepatitis B vaccination in patients with inflammatory bowel disease. AB - Hepatitis-B-seronegative patients with inflammatory bowel disease (IBD) should be vaccinated. However, response to vaccination in this population seems to be poorer than in healthy people. The aim of this study is to assess which clinical, analytical and immunosuppressive therapy parameters affect the response to hepatitis B vaccination in patients with IBD. A follow-up including monitoring of the immunosuppressive therapy of a cohort of 123 patients with IBD was carried out after each round of vaccination against hepatitis B virus. The recombinant HBsAg vaccine (20 MUg) was administered using the standard regimen (0, 1 and 6 months). Anti-HBs values >10I U/L after 1-3 months post-vaccination were considered as a successful response to vaccination. One hundred and five patients (85.5%) completed the programme and response to vaccination was observed in 50 (47.6%) patients. Multivariate analysis showed an independent relationship, with weaker response to vaccination, for IBD duration equal to or longer than 110 months [adjusted OR (95% CI): 0.282 (0.114-0.701)], serum albumin levels below 3.6 mg/dl at the beginning of vaccination [adjusted OR (95% CI): 0.336 (0.112 1.009)], and corticosteroid therapy in more than one vaccination dose [adjusted OR (95% CI): 0.333 (0.135-0.820)]. This study confirms the poor response to hepatitis B vaccination in patients with IBD, being particularly weak in individuals with long-term IBD progression, low serum albumin levels and those on corticosteroid therapy. PMID- 23665001 TI - Proteomic and immunological characterization of a new food allergen from hazelnut (Corylus avellana). AB - Hazelnuts (Corylus avellana) are one of the most common sources of life-long IgE mediated food allergies. In this study, we investigated the IgE-reactivity pattern of children with hazelnut allergy (N=15) from Regione Campania, located in Southern Italy, and addressed proteomic strategies for characterizing IgE binding proteins. For all of the patients (15/15), the predominant IgE-reactive component was a minor ~55kDa protein not previously described. Similar to the hazelnut 11S globulin Cor a 9 allergen, the immunoreactive protein consisted of two subunits linked via a disulfide bridge. In contrast to Cor a 9, only the 20.7kDa alkaline subunit exhibited IgE-affinity. The immunogenic subunit was purified by a two-step chromatographic procedure, but peptide mass fingerprinting was unsuccessful in identifying it, due to the incompleteness of the annotated hazelnut genome. Several tryptic peptides were de novo sequenced by tandem mass spectrometry and showed a high degree of homology with the 11S globulin storage proteins from other seeds, some of which have already been reported as food allergens. The structural characterization suggests that the new putative allergen is a divergent isoform of the hazelnut 11S globulin. These results provide a new platform for developing innovative diagnostic and therapeutic intervention plans. BIOLOGICAL SIGNIFICANCE: Over the years, at least five proteins have been reported as potential food hazelnut allergens. The predominance of specific allergens appears to be strictly related to the geographical origin of the allergic subjects. The complex patterns of the IgE reactivity of hazelnut storage proteins result in a poor diagnostic and prognostic accuracy. In the perspective of a component-resolved "molecular approach" to the hazelnut allergy we investigated the immune-reactivity patterns to hazelnuts of 15 patients (14 in the pediatric age range) from Region Campania, located in Southern Italy. For all the patients the predominant IgE-reactive component was a minor ~55kDa protein not previously annotated in either protein or genomic databases. The putative allergen was isolated, partially characterized by MS/MS de novo sequencing and appears to be an isoallergen of the hazelnut 11S globulin Cor a 9. Like this latter, the immunoreactive protein consisted of two subunits linked via a disulfide. In contrast to Cor a 9, only the 20.7kDa alkaline subunit exhibited IgE-affinity, in analogy to 11S allergens from other seeds (pistachio, cashew, soybean). We believe that the application of combined immunochemical and proteomic strategies to characterize the new food allergen could be of interest for the readers of Journal of Proteomics. In addition, the results of this study have functional worth in providing a new platform to plan innovative diagnostic and therapeutic intervention approaches to treat hazelnut allergy. PMID- 23665000 TI - Moving from unsequenced to sequenced genome: reanalysis of the proteome of Leishmania donovani. AB - The kinetoplastid protozoan parasite, Leishmania donovani, is the causative agent of kala azar or visceral leishmaniasis. Kala azar is a severe form of leishmaniasis that is fatal in the majority of untreated cases. Studies on proteomic analysis of L. donovani thus far have been carried out using homology based identification based on related Leishmania species (L. infantum, L. major and L. braziliensis) whose genomes have been sequenced. Recently, the genome of L. donovani was fully sequenced and the data became publicly available. We took advantage of the availability of its genomic sequence to carry out a more accurate proteogenomic analysis of L. donovani proteome using our previously generated dataset. This resulted in identification of 17,504 unique peptides upon database-dependent search against the annotated proteins in L. donovani. These peptides were assigned to 3999 unique proteins in L. donovani. 2296 proteins were identified in both the life stages of L. donovani, while 613 and 1090 proteins were identified only from amastigote and promastigote stages, respectively. The proteomic data was also searched against six-frame translated L. donovani genome, which led to 255 genome search-specific peptides (GSSPs) resulting in identification of 20 novel genes and correction of 40 existing gene models in L. donovani. BIOLOGICAL SIGNIFICANCE: Leishmania donovani genome sequencing was recently completed, which permitted us to use a proteogenomic approach to map its proteome and to carry out annotation of it genome. This resulted in mapping of 50% (3999 proteins) of L. donovani proteome. Our study identified 20 novel genes previously not predicted from the L. donovani genome in addition to correcting annotations of 40 existing gene models. The identified proteins may help in better understanding of stage-specific protein expression profiles in L. donovani and to identify novel stage-specific drug targets in L. donovani which could be used in the treatment of leishmaniasis. This article is part of a Special Issue entitled: Trends in Microbial Proteomics. PMID- 23665003 TI - The gastric fluid proteome as a potential source of gastric cancer biomarkers. AB - Gastric cancer is a significant cause of death in many parts of the world. Although timely intervention is associated with better clinical outcome, early gastric cancer detection is frequently not possible given its asymptomatic nature. As such, sensitive and specific gastric cancer biomarkers are highly sought after as diagnostic surrogates that may replace invasive endoscopic and histological examinations. Unlike gastric cancer tissue and serum which are heterogeneous and overloaded with abundant proteins, the gastric fluid contains a concentrated molecular biopsy of the stomach that accurately reflects gastric oncology. This review attempts to (i) summarise the state of proteomics-based gastric cancer biomarker discovery from patient gastric fluids, (ii) outline key considerations in working with the body fluid, and (ii) discuss how the challenges in gastric cancer diagnosis may be overcome with new perspectives in gastric cancer screening. PMID- 23665002 TI - Identification of proteomic signatures associated with lung cancer and COPD. AB - Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) commonly coexist in smokers, and the presence of COPD increases the risk of developing LC. The aim of this study was to identify distinct proteomic profiles able to discriminate these two pathological entities. Protein content was assessed in the bronchoalveolar lavage (BAL) of 60 patients classified in four groups: COPD, COPD and LC, LC without COPD, and control with neither COPD nor LC. Proteins were separated into spots by bidimensional polyacrylamide gel electrophoresis (2D PAGE) and examined by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/TOF). A total of 40 proteins were differentially expressed in the LC and/or COPD groups as compared with the control group. Distinct protein profiles were identified and validated for each pathological entity (LC and COPD). The main networks involved were related to inflammatory signalling, free radical scavenging and oxidative stress response, and glycolysis and gluconeogenesis pathways. The most relevant signalling link between LC and COPD was through the NF-kappaB pathway. In conclusion, the protein profiles identified contribute to elucidate the underlying pathogenic pathways of both diseases, and provide new tools of potential use as biomarkers for the early diagnosis of LC. BIOLOGICAL SIGNIFICANCE: Sequence coverage. The protein sequence coverage (95%) was estimated for specific proteins by the percentage of matching amino acids from the identified peptides having confidence greater than or equal to 95% divided by the total number of amino acids in the sequence. Ingenuity Pathways Analysis. Mapping of our proteins onto biological pathways and disease networks demonstrated that 22 proteins were linked to inflammatory signalling (p value: 1.35 10(-08)-1.42 10(-02)), 15 proteins were associated with free radical scavenging and oxidative stress response (p-value: 4.93 10(-11)-1.27 10(-02)), and 9 proteins were related with glycolysis and gluconeogenesis pathways (p value: 7.39 10(-09)-1.58 10(-02)). PMID- 23665004 TI - Avian CD4(+)CD25(+) regulatory T cells: properties and therapeutic applications. AB - Regulatory T cells (Tregs) are a subset of T cells that specialize in immune suppression. CD4(+)CD25(+)FoxP3(+) T cells have been characterized as Tregs and extensively studied in mammals. In the absence of a putative FoxP3 ortholog in avians, CD4(+)CD25(+) cells is characterized as Tregs in avians. Avian CD4(+)CD25(+) cells produce high amounts of IL-10, TGF-beta, CTLA-4, and LAG-3 mRNA; lack IL-2 mRNA; and suppress T cell proliferation in vitro through both contact-dependent and -independent pathways. Depleting avian CD4(+)CD25(+) cells increases the proliferation of, IL-2 amount, and IFNgamma mRNA amount of CD4(+)CD25(-) cells. Avian CD4(+)CD25(+) cells lose their suppressive properties immediately after inflammation and acquire supersuppressive properties once inflammation subsides. Although Treg activity could be beneficial to the host, Tregs simultaneously inhibit host immunity and cause persistent infections of certain pathogens. Therapy targeted toward alleviating Treg mediated immune suppression can improve host immunity against those persistent pathogens and benefit poultry production. PMID- 23665005 TI - Strand-seq: a unifying tool for studies of chromosome segregation. AB - Non random segregation of sister chromatids has been implicated to help specify daughter cell fate (the Silent Sister Hypothesis [1]) or to protect the genome of long-lived stem cells (the Immortal Strand Hypothesis [2]). The idea that sister chromatids are non-randomly segregated into specific daughter cells is only marginally supported by data in sporadic and often contradictory studies. As a result, the field has moved forward rather slowly. The advent of being able to directly label and differentiate sister chromatids in vivo using fluorescence in situ hybridization [3] was a significant advance for such studies. However, this approach is limited by the need for large tracks of unidirectional repeats on chromosomes and the reliance on quantitative imaging of fluorescent probes and rigorous statistical analysis to discern between the two competing hypotheses. A novel method called Strand-seq which uses next-generation sequencing to assay sister chromatid inheritance patterns independently for each chromosome [4] offers a comprehensive approach to test for non-random segregation. In addition Strand-seq enables studies on the deposition of chromatin marks in relation to DNA replication. This method is expected to help unify the field by testing previous claims of non-random segregation in an unbiased way in many model systems in vitro and in vivo. PMID- 23665006 TI - Advanced drug delivery in motion. AB - After 50 years of research on advanced drug delivery systems the time has come to critically reflect upon the past achievements. Despite some successes, many hurdles still need to be overcome before we can quantitatively deliver therapeutically relevant amounts of drug molecules to any desired location within the human body. In this commentary, I give my opinion on how to improve the current generation of nanocarriers for drug delivery. In addition, I speculate on which direction the drug delivery field should be going in order to fulfill the "magic bullet" dream in the long run. PMID- 23665007 TI - Molecular weight controls the elongation of oblate-shaped degradable poly(gamma benzyl-L-glutamate)nanoparticles. AB - The shape of nanoparticles in drug targeting applications has been recently suggested as being an interesting parameter for modulating their fate in the body after delivery. In view of investigating the incidence of this parameter on in vivo distribution, poly(gamma-benzyl-L-glutamate) (PBLG) has been selected for preparing non-spherical nanoparticles. PBLG is a degradable polymer forming alpha helices rods, which can easily self-assemble by nanoprecipitation into oblate shaped nanoparticles. Varying the molecular weight of the polymer from 28 to 85 kg mol(-1) resulted in elongation ratios between 1.5 and 3.5, respectively, while the nanoparticles exhibited a fairly constant particle volume. Their non spherical shape was attributed to an ordered packing of the PBLG rods resulting in a liquid crystal-like self organization of PBLG rods with varying lengths. This set of morphological characteristics makes these nanoparticles a valuable tool for gaining a better understanding of their fate in biological fluids, mechanisms of interactions with cells and in vivo distribution studies. PMID- 23665008 TI - "Catarrhal physiognomy" and Koplik's spots. PMID- 23665009 TI - Genetic polymorphism and immune response to tuberculosis in indigenous populations: a brief review. AB - We systematically reviewed studies of the immune response to tuberculosis and the genetic polymorphisms associated with Th1- or Th2-mediated cytokine expression in indigenous populations. A bibliographic search was performed on the Medline and ISI databases and included studies published between January 1980 and October 2011. The search terms were tuberculosis, American Indians, Amerindian, indigenous, Indians, native people, aboriginal, immun*, host immune, immune response, cytokine*, polymorphism*, and gene. Regardless of their design, studies that evaluated immunoglobulin, cytokine levels and genetic polymorphisms that altered cytokine expression were included. Thirteen studies met the inclusion criteria. The majority of studies were performed in Latin America, and five investigated the Warao ethnic group of Venezuela. Most of the investigations indirectly evaluated the immune response. Higher anergy to the tuberculin skin test, higher IgG4 and IgM levels, higher IL-5 production and lower TNF-alpha, IL 12p40 and IFN-gamma production were found in the indigenous populations. The studies also reported a predominantly Th2-type response in these populations and a possibly higher susceptibility to tuberculosis. A better understanding of the relevant genetic polymorphisms and their role in immune regulation would help to clarify the immunogenetic mechanisms of TB infection in these populations. This information would be useful for identifying new treatments and preventing infection and progression to active disease. PMID- 23665010 TI - Gestational toxoplasmosis in Parana State, Brazil: prevalence of IgG antibodies and associated risk factors. AB - The aim of the present study was to verify the association between seropositivity for IgG anti-Toxoplasma gondii antibodies and social, economic and environmental variables of pregnant women attending the public health centers of Parana, Brazil. From January 2007 to July 2010, 2226 pregnant women were interviewed and detection of anti-T. gondii specific IgG and IgM antibodies was performed by chemiluminescence test. Seropositivity for anti-T. gondii IgG was observed in 1151 (51.7%) pregnant women, 29 of which (1.3%) presented IgM reagent with IgG of high avidity. The variables associated with the presence of IgG were residency in the rural area, more than one pregnancy, less than or equal to eight years schooling, low per capita income, age group, raw or poorly cooked meat ingestion, and contact with the soil. There was neither association with raw fruit and vegetable ingestion nor with the presence of cats in the residencies. PMID- 23665011 TI - Direct detection of bla(OXA-23) gene from endotracheal aspirates by real time PCR. PMID- 23665013 TI - Oxygen-dependent secretion of a bioactive hepcidin-GFP chimera. AB - Hepcidin, a hepatic hormone, regulates serum iron levels by controlling both intestinal iron absorption and iron release from macrophages. Although transcription of hepcidin is controlled by diverse stimuli, it remains elusive if post-transcriptional steps of its production are also regulated. To address this issue, GFP was fused to the C-terminus of hepcidin and the chimeric hepcidin-GFP protein was expressed in hepatoma Huh7 cells. Expression and secretion of hepcidin-GFP were analyzed by fluorescence microscopy or western blotting and its activity was assessed by in vitro biological assays. Transient over-expression of hepcidin-GFP resulted in production and secretion of premature forms. On the other hand, stable low-level expression led to synthesis and secretion of a properly matured hepcidin-GFP. This form was biologically active since it affected appropriately the levels of IRP2 and ferritin in human THP1 monocytes and targeted ferroportin in mouse J774 macrophages. Treatment of hepcidin-GFP expressing cells with hypoxia (0.1% O2) altered the subcellular distribution of pro-hepcidin-GFP and significantly reduced the secretion of mature hepcidin-GFP. Our hepcidin-GFP expression system allows the investigation of post transcriptional processing of hepcidin and implicates hypoxia in its secretion control. PMID- 23665012 TI - Strategies to reduce mortality and morbidity due to AIDS-related cryptococcal meningitis in Latin America. AB - Latin America is the region with the third most AIDS-related cryptococcal meningitis infections globally. Highly active antiretroviral therapy (HAART) has reduced the number of infections; however, the number of deaths and the case fatality rate continues to be unacceptable. In this review, we focus on the burden of AIDS-related cryptococcosis in Latin America and discuss potential strategies to reduce early mortality from Cryptococcus. In this review, we highlight the importance of: (1) earlier HIV diagnosis and HAART initiation with retention-in-care to avoid AIDS; (2) pre-HAART cryptococcal antigen (CRAG) screening with preemptive fluconazole treatment; (3) better diagnostics (e.g. CRAG testing); and (4) optimal treatment with aggressive management of intracranial pressure and induction therapy with antifungal combination. Implementation of these strategies can reduce cryptococcal-related deaths, improve care, and reduce healthcare costs. PMID- 23665014 TI - Nerve injury-induced upregulation of miR-21 in the primary sensory neurons contributes to neuropathic pain in rats. AB - Neuropathic pain is intractable chronic pain caused by damage to the somatosensory system. Peripheral nerve injury of the primary sensory neurons changes expressions of multiple microRNAs that affect many aspects of cellular functions by regulating specific gene expressions. miR-21, a well-characterized oncogenic miRNA, is consistently upregulated after peripheral nerve injury in the dorsal root ganglion (DRG), where cell bodies of primary sensory neurons exist. However, their causal relationship to the pain is fully unknown. In this study, we therefore investigated the miR-21 expression in the DRGs along with the time course of neuropathic pain and its involvement in the neuropathic pain. Neuropathic pain was induced in rats by specific ligation of the left fifth lumbar spinal nerve. After the injury, miR-21 expression in the injured DRG neurons, but not in the neighboring uninjured DRG neurons, was persistently upregulated following the pain development. Intrathecal administration of interleukin-1beta also increased the miR-21 expression in the DRG. Both mechanical allodynia and thermal hyperalgesia in the neuropathic pain were attenuated by intrathecal administration of miR-21 inhibitor. miR-21 is specifically upregulated in the injured DRG neurons and causally involved in the late phase of neuropathic pain. Therefore, miR-21 and its modulatory system may be a therapeutic target for intractable chronic neuropathic pain. PMID- 23665015 TI - MUDENG is cleaved by caspase-3 during TRAIL-induced cell death. AB - MUDENG, also known as AP5M1, was originally identified as an adaptin domain containing gene that induced cell death in lymphoma cell lines. However, little is known of the mechanism responsible for MUDENG-mediated cell death. In this study, we investigated MUDENG changes during TRAIL-induced cell death. We found that MUDENG is rapidly processed in response to TRAIL in Jurkat and BJAB cells with time line similar to that of caspase activation. Caspase-3-mediated MUDENG cleavage was confirmed by an in vitro cleavage assay using recombinant active caspase proteins. Caspase cleavage sites (D276 and D290) were located in the adaptin domain of MUDENG, and cleaved MUDENG showed the reduced killing activity. These results suggest that the adaptin domain plays a key role in MUDENG-mediated cell death. PMID- 23665016 TI - The SNAI1 and SNAI2 proteins occupy their own and each other's promoter during chondrogenesis. AB - Two Snail family genes, Snai1 and Snai2, encode E2 box-binding transcriptional repressors that are important for cartilage development during long bone formation in mice. We demonstrated previously that the Snai1 and Snai2 genes function redundantly, and compensate for each other's loss during mouse chondrogenesis in vivo. A prediction from this genetic data is that the SNAI1 and SNAI2 proteins can bind to each other's promoter to regulate gene expression. Here we demonstrate that expression of Snai1 and Snai2 RNA and protein is induced during chondrogenic differentiation of cultured mouse ATDC5 cells. Using chromatin immunoprecipitation assays, we then show that endogenous SNAI1 and SNAI2 proteins bind to a subset of E2 boxes in both their own and each other's promoter in differentiating ATDC5 cells. Together with our previous genetic data, these results support the model that expression of the Snai1 and Snai2 genes is negatively regulated by their protein products occupying each other's promoter during chondrogenesis, and help provide an explanation for the genetic redundancy observed in the mouse loss of function models. PMID- 23665017 TI - beta-Arrestin 1 mediates non-canonical Wnt pathway to regulate convergent extension movements. AB - beta-Arrestins are multifaceted proteins that play critical roles in termination of G protein-coupled receptor (GPCR) signaling by inducing its desensitization and internalization as well as in facilitation of many intracellular signaling pathways. Here, we examine using Xenopus embryos whether beta-arrestin 1 might act as a mediator of beta-catenin-independent Wnt (non-canonical) signaling. Xenopus beta-arrestin 1 (xbetaarr1) is expressed in the tissues undergoing extensive cell rearrangements in early development. Gain- and loss-of-function analyses of xbetaarr1 revealed that it regulates convergent extension (CE) movements of mesodermal tissue with no effect on cell fate specification. In addition, rescue experiments showed that xbetaarr1 controls CE movements downstream of Wnt11/Fz7 signal and via activation of RhoA and JNK. In line with this, xbetaarr1 associated with key Wnt components including Ryk, Fz, and Dishevelled. Furthermore, we found that xbetaarr1 could recover CE movements inhibited by xbetaarr2 knockdown or its endocytosis defective mutant. Overall, these results suggest that beta-arrestin 1 and 2 share interchangeable endocytic activity to regulate CE movements downstream of the non-canonical Wnt pathway. PMID- 23665018 TI - AG490 inhibits NFATc1 expression and STAT3 activation during RANKL induced osteoclastogenesis. AB - Commonly, JAK/STAT relays cytokine signals for cell activation and proliferation, and recent studies have shown that the elevated expression of JAK/STAT is associated with the immune rejection of allografts and the inflammatory processes of autoimmune disease. However, the role which JAK2/STAT3 signaling plays in the receptor activator of nuclear factor-kappaB ligand (RANKL)-mediated osteoclastogenesis is unknown. In this study, we investigated the effects of AG490, specific JAK2 inhibitor, on osteoclast differentiation in vitro. AG490 significantly inhibited osteoclastogenesis in murine osteoclast precursor cell line RAW264.7 induced by RANKL. AG490 suppressed cell proliferation and delayed the G1 to S cell cycle transition. Furthermore, AG490 also suppressed the expression of nuclear factor of activated T cells (NFAT) c1 but not c-Fos in RAW264.7. Subsequently, we investigated various intracellular signaling components associated with osteoclastogenesis. AG490 had no effects on RANKL induced activation of Akt, ERK1/2. Interestingly, AG490 partly inhibited RANKL induced phosphorylation of Ser(727) in STAT3. Additionally, down-regulation of STAT3 using siRNA resulted in suppression of TRAP, RANK and NFATc1 expression. In conclusion, we demonstrated that AG490 inhibited RANKL-induced osteoclastogenesis by suppressing NFATc1 production and cell proliferation via the STAT3 pathway. These results suggest that inhibition of JAK2 may be useful for the treatment of bone diseases characterized by excessive osteoclastogenesis. PMID- 23665019 TI - Cooperative and non-cooperative conformational changes of F-actin induced by cofilin. AB - Cofilin is an actin-binding protein that promotes F-actin depolymerization. It is well-known that cofilin-coated F-actin is more twisted than naked F-actin, and that the protomer is more tilted. However, the means by which the local changes induced by the binding of individual cofilin proteins proceed to the global conformational changes of the whole F-actin molecule remain unknown. Here we investigated the cofilin-induced changes in several parts of F-actin, through site-directed spin-label electron paramagnetic resonance spectroscopy analyses of recombinant actins containing single reactive cysteines. We found that the global, cooperative conformational changes induced by cofilin-binding, which were detected by the spin-label attached to the Cys374 residue, occurred without the detachment of the D-loop in subdomain 2 from the neighboring protomer. The two processes of local and global changes do not necessarily proceed in sequence. PMID- 23665020 TI - Crystal structure of GTPase-activating domain from human MgcRacGAP. AB - Cytokinesis in animal cells relies on a centralspindlin complex consisting of male germ cell RacGap (MgcRacGAP) and mitotic kinesin-like protein 1 (MKLP1). Rho GTPases act as molecular switches to regulate the actin cytoskeleton for cytokinesis, of which Rac1 is regulated by MgcRacGAP. In this study, we determined the crystal structure of the GTPase-activating protein (GAP) domain of MgcRacGAP at a resolution of 1.9A. The conformation of Arg385, which is a key residue for GAP activity, was found to be different from that of previously reported GAP proteins, and MgcRacGAP (residues 348-546) was found to exist as a monomer in solution, according to Stokes radii. We also measured the GAP activity of MgcRacGAP mutants for Rac1. PMID- 23665021 TI - Inhibition of sorbitol dehydrogenase by nucleosides and nucleotides. AB - Sorbitol dehydrogenase inhibitors have been found to prevent, or alleviate, various secondary complications of diabetes mellitus. In the present study, the effects of nucleosides and nucleotides on the rate of sorbitol oxidation catalyzed by the sheep liver enzyme were studied by steady-state kinetics at pH 7.4. Various such compounds, including ATP and the 2'-deoxy-analogues of ATP, ADP and AMP, reversibly inhibit enzyme activity by formation of enzyme-coenzyme inhibitor ternary complexes. In each case, no deviations from linearity were seen in the double-reciprocal plots using sorbitol or NAD(+) as the varied substrate and there was a linear relationship between inhibitor concentration and the observed inhibitory effects. Sorbitol was docked into a model of the sheep SDH NAD(+) complex based upon the structure of the human SDH-NAD(+) holoenzyme. The resulting structure of the ternary complex of sheep SDH, NAD(+) and sorbitol (PMDB ID code PM 0078068) shows that the reactive C-2 hydroxyl group of sorbitol is oriented toward the 4'-position of the nicotinamide moiety of the coenzyme, and that the adjacent primary hydroxyl group of sorbitol interacts with the catalytic zinc. The results indicate that the ribose moiety of the inhibitor structures is an important determinant for the observed effects. Specifically, the 2'-position of the ribose ring exerts an effect with respect to inhibitor potency. PMID- 23665022 TI - Activin A inhibits activities of lipopolysaccharide-activated macrophages via TLR4, not of TLR2. AB - Activin A, a member of TGF-beta superfamily, is involved in either pro inflammatory or anti-inflammatory responses. Our previous studies have reported that lipopolysaccharide (LPS) can simulate activin A secretion from macrophage, and activin A can induce rest macrophage activation in mice, but inhibit the activities of the activated macrophages. However, the relationship of activin and LPS actions and their mechanism are not well characterized. In the present study, the results showed that both activin A and LPS promoted the phagocytic activities of mouse peritoneal macrophages in vivo and in vitro, but activin A inhibited the phagocytosis of LPS-activated macrophages. Simultaneously, the results revealed that activin A inhibited the Toll-like receptor 4 (TLR4) expression on LPS activated mouse peritoneal macrophages in vivo and in vitro, whereas there was no obvious change of TLR2 expression. Moreover, the results showed that activin A obviously reduced the TLR4 mRNA and protein expressions in LPS-activated macrophage cell line RAW264.7 cells, and the inhibitory effect of activin A on the TLR4 expression was significantly attenuated in Smad3 knock-down RAW264.7 cells. Interestingly, LPS promoted the expression of activin type IIA receptor (ActRIIA) on mouse peritoneal macrophages in vivo, and also up-regulated ActRIIA and activin signal molecules Smad2, 3 mRNA expressions. These data suggest that activin A inhibits LPS action on macrophages in vivo via suppressing TLR4 expression, and LPS further augments the negative feedback action of activin A via up-regulating activin signaling transduction. PMID- 23665023 TI - Bacillus thuringiensis Cry4Ba toxin employs two receptor-binding loops for synergistic interactions with Cyt2Aa2. AB - We previously demonstrated that co-expression in Escherichia coli of Bacillus thuringiensis (Bt) subsp. israelensis Cry4Ba and Bt subsp. darmstadiensis Cyt2Aa2 shows high synergistic toxicity against target mosquito larvae. Here, further insights into synergistic interactions between these two toxins were revealed through bioactivity restoration of particular inactive Cry4Ba-mutant toxins altered within the receptor-binding domain. Specific mutations at beta2-beta3 (Y332A) or beta4-beta5 (F364A) loops, but neither at three other beta-hairpin loops (beta6-beta7, beta8-beta9 and beta10-beta11) of Cry4Ba, adversely affect toxicity restoration by Cyt2Aa2. Binding analysis using quartz crystal microbalance verified a decrease in binding of these two bioinactive-mutant toxins (Y332A and F364A) to the immobilized Cyt2Aa2. This suggests that Cry4Ba utilizes these two critical aromatic loop-residues, Tyr(332) and Phe(364), for synergistic toxicity with its alternative receptor-Cyt2Aa2. PMID- 23665024 TI - Fasudil inhibits ER stress-induced VCAM-1 expression by modulating unfolded protein response in endothelial cells. AB - The process of atherosclerosis is affected by interactions among numerous biological pathways. Accumulating evidence shows that endoplasmic reticulum (ER) stress plays a crucial role in the development of atherosclerosis. Rho-kinase is an effector of small GTP-binding protein Rho, and has been implicated as an atherogenic factor. Previous studies demonstrated that fasudil, a specific Rho kinase inhibitor, exerts a cardioprotective effect by downregulating ER stress signaling. However, the molecular link between ER stress and Rho-kinase in endothelial cells has not been elucidated. In this study, we investigated the mechanisms by which fasudil regulates endothelial inflammation during ER stress. Tunicamycin, an established ER stress inducer, increased vascular cellular adhesion molecule (VCAM)-1 expression in endothelial cells. Intriguingly, fasudil inhibited VCAM-1 induction. From a mechanistic stand point, fasudil inhibited expression of activating transcription factor (ATF)4 and subsequent C/EBP homologous protein (CHOP) induction by tunicamycin. Furthermore, fasudil attenuated tunicamycin-induced phophorylation of p38MAPK that is crucial for the atherogenic response during ER stress. These findings indicate that Rho-kinase regulates ER stress-mediated VCAM-1 induction by ATF4- and p38MAPK-dependent signaling pathways. Rho-kinase inhibition by fasudil would be an important therapeutic approach against atherosclerosis, in particular, under conditions of ER stress. PMID- 23665025 TI - Silencing of the STAT3 signaling pathway reverses the inherent and induced chemoresistance of human ovarian cancer cells. AB - Ovarian cancer is the leading cause of gynecologic cancer deaths among women. Although platinum-based chemotherapy is the first-line treatment for human ovarian cancer, chemoresistance remains a major obstacle to successful treatment, and there are currently no approved molecularly targeted therapies. Recent evidence indicates that signal transducer and activator of transcription-3 (STAT3) is a determinant of chemoresistance and is related to tumor recurrence in a large number of solid malignancies. In this study, we demonstrated that high levels of pSTAT3 were associated with chemoresistance in human ovarian cancer cells. Targeting STAT3 by siRNA technology markedly enhanced cisplatin-induced apoptosis in cisplatin-resistant ovarian cancer cells that expressed a high level of pSTAT3. Interleukin-6 (IL-6) could induce STAT3 activation in cisplatin sensitive ovarian cancer cells and led to protection against cisplatin. The STAT3 siRNA treatment also blocked IL-6-induced STAT3 phosphorylation, resulting in the attenuation of the anti-apoptotic activity of IL-6. We found that the combination of cisplatin and STAT3 siRNA resulted in the collapse of the mitochondrial membrane potential, attenuated the expression of Bcl-xL and Bcl-2, and increased the release of cytochrome C and expression of Bax. Taken together, these results suggest that the pharmacological inhibition of STAT3 may be a promising therapeutic strategy for the management of chemoresistance in ovarian cancer. PMID- 23665026 TI - Outcomes of two surgical revision techniques for recurrent anterior shoulder instability following selective capsular repair. AB - INTRODUCTION: Conventional capsulolabral reconstruction for anterior shoulder instability fails with recurrent instability in up to 23% of cases. Few studies have evaluated surgical revision strategies and outcomes. The objective of this study was to evaluate clinical and radiographic outcomes in a homogeneous series of surgical revisions after selective capsular repair (SCR). HYPOTHESIS: Observed anatomic lesions can guide the choice between repeat SCR and coracoid transfer (Latarjet procedure). MATERIALS AND METHODS: From January 2005 to January 2009, 11 patients with trauma-related recurrent anterior shoulder instability (episodes of subluxation and/or dislocation) after SCR were included. Mean age was 31 years (range, 19-45 years). At revision, a glenoid bony defect was present in six patients. Repeat SCR was performed in five patients and coracoid transfer in six patients. RESULTS: After a mean follow-up of 40 months (range, 24-65 months), no patient had experienced further episodes of instability. However, four patients had a positive apprehension test. External rotation decreased significantly by more than 20 degrees after both techniques. The Simple Shoulder Test, Walch Duplay, and Rowe scores were 10.5, 79, and 85, respectively. No patient had a subscapularis tear. Of these 11 patients, nine were able to resume their sporting activities and eight reported being satisfied or very satisfied with the subjective outcome. Radiographs showed fibrous non-union of the coracoid transfer in one patient. CONCLUSION: In patients with recurrent anterior shoulder instability after SCR, repeat SCR and coracoid transfer produce similarly satisfactory outcomes. The size of the glenoid bone defect may be the best criterion for choosing between these two procedures. However, open revision surgery may decrease the range of motion, most notably in external rotation. LEVEL OF EVIDENCE: Level IV. PMID- 23665027 TI - Effects of lixisenatide once daily on gastric emptying in type 2 diabetes- relationship to postprandial glycemia. AB - OBJECTIVES: To determine the effects of lixisenatide, a new once-daily (QD) glucagon-like peptide-1 receptor agonist, on postprandial glucose (PPG) and gastric emptying, and the relationship between these effects in patients with type 2 diabetes mellitus (T2DM). METHODS: Data were obtained from a randomized, double-blind, placebo-controlled, parallel-group study with treatment duration of 28 days in patients with T2DM receiving <=2 oral antidiabetic drugs. Lixisenatide was injected subcutaneously using an ascending dose range (5-20 MUg) increased every fifth day in increments of 2.5 MUg. Blood glucose was determined before and after three standardized meals (breakfast, lunch, and dinner). Gastric emptying of the standardized breakfast was determined by a (13)C-octanoic acid breath test at baseline (Day-1) and at Day 28. RESULTS: A total of 21 and 22 patients were randomized to lixisenatide 20 MUg QD and placebo, respectively. With lixisenatide 20 MUg QD, there was a reduction in PPG when compared with placebo after breakfast (p<0.0001), lunch (p<0.001) and dinner (p<0.05). Hence, lixisenatide 20 MUg administered in the morning exhibited a pharmacodynamic effect on blood glucose throughout the day. Gastric emptying (50% emptying time) increased substantially from baseline with lixisenatide 20 MUg QD, but not with placebo (change from baseline +/- SD: -24.1 +/- 133.1 min for placebo and 211.5 +/- 278.5 min for lixisenatide; p<0.01). There was an inverse relationship between PPG area under the curve after breakfast and gastric emptying with lixisenatide 20 MUg QD (n=17, r(2)=0.51, p<0.05), but not with placebo. CONCLUSIONS: In this study, lixisenatide at a dose of 20 MUg QD reduced postprandial glycemic excursions in patients with T2DM, possibly as a result of sustained slowing of gastric emptying. PMID- 23665028 TI - CDK inhibitors suppress Th17 and promote iTreg differentiation, and ameliorate experimental autoimmune encephalomyelitis in mice. AB - Th17 cells, which have been implicated in autoimmune diseases, require IL-6 and TGF-beta for early differentiation. Several Smad-independent pathways including the JNK and the RhoA-ROCK pathways have been implicated in the induction of RORgammat, the master regulator of Th17, however, molecular mechanisms underlying Smad-independent pathway remain largely unknown. To identify novel pathways involved in Th17 differentiation, we screened 285 chemical inhibitors for known signaling pathways. Among them, we found that Kenpaullone, a GSK3-beta and CDK inhibitor, efficiently suppressed TGF-beta-mediated RORgammat induction and enhanced Foxp3 induction in primary T cells. Another CDK inhibitor, Roscovitine, but not other GSK3-beta inhibitors, suppressed Th17 differentiation and enhanced iTreg development. Kenpaullone and Roscovitine suppressed experimental autoimmune encephalomyelitis (EAE), a typical Th17-mediated autoimmune disease model. These two compounds enhanced STAT5 phosphorylation and restored IL-2 production in the presence of TGF-beta. These data suggest that CDK inhibitors modulate TGF-beta signaling pathways, which restore TGF-beta-mediated suppression of IL-2 production, thereby modifying the Th17/iTreg balance. PMID- 23665029 TI - The effect of an acidic cleanser versus soap on the skin pH and micro-flora of adult patients: a non-randomised two group crossover study in an intensive care unit. AB - OBJECTIVES: To test the effects of two different cleansing regimens on skin surface pH and micro-flora, in adult patients in the intensive care unit (ICU). RESEARCH METHODOLOGY: Forty-three patients were recruited from a 23-bed tertiary medical/surgical ICU. The nineteen patients in Group One were washed using soap for daily hygiene care over a four week period. In Group 2, 24 patients were washing daily using an acidic liquid cleanser (pH 5.5) over a second four week period. Skin pH measurements and bacterial swabs were sampled daily from each for a maximum of ten days or until discharged from the ICU. MAIN OUTCOME MEASURES: Skin surface pH and quantitative skin cultures (colony forming units). FINDINGS: Skin pH measurements were lower in patients washed with pH 5.5 cleanser than those washed with soap. This was statistically significant for both the forearm (p = 0.0068) and leg (p = 0.0015). The bacterial count was not statistically significantly different between the two groups. Both groups demonstrated that bacterial counts were significantly affected by the length of stay in ICU (p = 0.0032). CONCLUSION: This study demonstrated that the product used in routine skin care significantly affects the skin pH of ICU patients, but not the bacterial colonisation. Bacterial colonisation of the skin increases with length of stay. PMID- 23665030 TI - The immunomodulatory effects of statins in community-acquired pneumonia: a systematic review. AB - OBJECTIVE: To evaluate the potential immunomodulatory effects of statins in community-acquired pneumonia. METHODS: We performed a systematic review of available literature on experimental and clinical studies. We used a PubMed/MEDLINE and EMBASE search to identify potential articles. RESULTS: We identified 34 original studies, 17 experimental and 17 clinical studies, published up to March 2013. CONCLUSIONS: Statins attenuated pulmonary inflammation by modulating neutrophil function, by reducing cytokine expression and release, and by protecting against disruption of pulmonary integrity. However, additional experimental studies are needed to fully elucidate the exact mechanisms. Several clinical studies suggested a decreased risk of CAP or a reduction in mortality due to CAP for current statin users, but the mostly observational design of these studies hampers the interpretation of their results. Therefore, appropriately designed studies, such as randomised controlled trials, are required to demonstrate the usefulness of statins in the prevention and treatment of CAP. PMID- 23665032 TI - Rapid IgG heavy chain cleavage by the streptococcal IgG endopeptidase IdeS is mediated by IdeS monomers and is not due to enzyme dimerization. AB - Streptococcus pyogenes employs an IgG specific endopeptidase, IdeS, to counteract the effector functions of specific IgG. The physiological significant step in disarming specific IgG is the cleavage of one IgG heavy chain. So far, characterizations of IdeS enzymatic activity have employed techniques that failed to differentiate between the first and the second cleavage step. The present data demonstrate that IdeS is active as a monomer and that IdeS activity follows classical Michaelis-Menten kinetics arguing against the previously proposed formation of a functional IdeS dimer. Our results show that IdeS inactivates IgG 100-fold faster than previously reported. PMID- 23665031 TI - Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation. AB - Mutations in with-no-lysine (K) kinase 4 (WNK4) and a ubiquitin E3 ligase complex component kelch-like 3 (KLHL3) both cause pseudohypoaldosteronism II (PHAII), a hereditary form of hypertension. We determined whether WNK4 or its effector is regulated by KLHL3 in Xenopus oocytes. KLHL3 inhibited the positive effect of WNK4 on Na(+)-Cl(-) cotransporter (NCC) by decreasing WNK4 protein abundance without decreasing that of NCC and the downstream kinase OSR1 directly. Ubiquitination and degradation of WNK4 were induced by KLHL3. The effect of KLHL3 on WNK4 degradation was blocked by a dominant negative form of cullin 3. All five PHAII mutations of KLHL3 tested disrupted the regulation on WNK4. We conclude that KLHL3 is a substrate adaptor for WNK4 in a ubiquitin E3 ligase complex. PMID- 23665033 TI - In search of novel highly active mitochondria-targeted antioxidants: thymoquinone and its cationic derivatives. AB - Since the times of the Bible, an extract of black cumin seeds was used as a medicine to treat many human pathologies. Thymoquinone (2-demethylplastoquinone derivative) was identified as an active antioxidant component of this extract. Recently, it was shown that conjugates of plastoquinone and penetrating cations are potent mitochondria-targeted antioxidants effective in treating a large number of age-related pathologies. This review summarizes new data on the antioxidant and some other properties of membrane-penetrating cationic compounds where 2-demethylplastoquinone substitutes for plastoquinone. It was found that such a substitution significantly increases a window between anti- and prooxidant concentrations of the conjugates. Like the original plastoquinone derivatives, the novel compounds are easily reduced by the respiratory chain, penetrate through model and natural membranes, specifically accumulate in mitochondria in an electrophoretic fashion, and strongly inhibit H2O2-induced apoptosis at pico- and nanomolar concentrations in cell cultures. At present, cationic demethylplastoquinone derivatives appear to be the most promising mitochondria targeted drugs of the quinone series. PMID- 23665034 TI - The most important thing is the tail: multitudinous functionalities of intrinsically disordered protein termini. AB - Many functional proteins do not have well-folded structures in their substantial parts, representing hybrids that possess both ordered and disordered regions. Disorder is unevenly distributed within these hybrid proteins and is typically more common at protein termini. Disordered tails are engaged in a wide range of functions, some of which are unique for termini and cannot be found in other disordered parts of a protein. This review covers some of the key functions of disordered protein termini and emphasizes that these tails are not simple flexible protrusions but are evolved to serve. PMID- 23665035 TI - Utility of COI, CAD and morphological data for resolving relationships within the genus Sarcophaga (sensu lato) (Diptera: Sarcophagidae): a preliminary study. AB - Currently there are ~ 3000 known species of Sarcophagidae (Diptera), which are classified into 173 genera in three subfamilies. Almost 25% of sarcophagids belong to the genus Sarcophaga (sensu lato) however little is known about the validity of, and relationships between the ~ 150 (or more) subgenera of Sarcophaga s.l. In this preliminary study, we evaluated the usefulness of three sources of data for resolving relationships between 35 species from 14 Sarcophaga s.l. subgenera: the mitochondrial COI barcode region, ~ 800 bp of the nuclear gene CAD, and 110 morphological characters. Bayesian, maximum likelihood (ML) and maximum parsimony (MP) analyses were performed on the combined dataset. Much of the tree was only supported by the Bayesian and ML analyses, with the MP tree poorly resolved. The genus Sarcophaga s.l. was resolved as monophyletic in both the Bayesian and ML analyses and strong support was obtained at the species level. Notably, the only subgenus consistently resolved as monophyletic was Liopygia. The monophyly of and relationships between the remaining Sarcophaga s.l. subgenera sampled remain questionable. We suggest that future phylogenetic studies on the genus Sarcophaga s.l. use combined datasets for analyses. We also advocate the use of additional data and a range of inference strategies to assist with resolving relationships within Sarcophaga s.l. PMID- 23665036 TI - Testing monophyly without well-supported gene trees: evidence from multi-locus nuclear data conflicts with existing taxonomy in the snake tribe Thamnophiini. AB - Ideally, existing taxonomy would be consistent with phylogenetic estimates derived from rigorously analyzed data using appropriate methods. We present a multi-locus molecular analysis of the relationships among nine genera in the North American snake tribe Thamnophiini in order to test the monophyly of the crayfish snakes (genus Regina) and the earth snakes (genus Virginia). Sequence data from seven genes were analyzed to assess relationships among representatives of the nine genera by performing multi-locus phylogeny and species tree estimations, and we performed constraint-based tests of monophyly of classic taxonomic designations on a gene-by-gene basis. Estimates of concatenated phylogenies demonstrate that neither genera are monophyletic, and this inference is supported by a species tree estimate, though the latter is less robust. These taxonomic findings were supported using gene tree constraint tests and Bayes Factors, where we rejected the monophyly of both the crayfish snakes (genus Regina) and the earth snakes (genus Virginia); this method represents a potentially useful tool for taxonomists and phylogeneticists when available data is less than ideal. PMID- 23665037 TI - Diversification of the monoterpene synthase gene family (TPSb) in Protium, a highly diverse genus of tropical trees. AB - Plant monoterpenes are a diverse class of secondary metabolites mediating biotic and abiotic interactions with direct effects on plant fitness. To evaluate the hypothesis that monoterpene diversity is related to functional diversification after gene duplication, we reconstructed the evolutionary history of monoterpene synthases (TPSb)--the genes underlying monoterpene synthesis--in Protium, a taxonomically and chemically diverse genus of tropical trees. We isolated multiple copies of TPSb genes from chemically divergent Protium species, reconstructed the phylogeny of this gene family, used maximum-likelihood estimation of selection coefficients, and inferred residues evolving under positive selection. We found evidence for one ancient and multiple more recent duplication events giving rise to three, and potentially five, copies of TPSb genes currently present in Protium. There was evidence for adaptive evolution in one copy with a positively selected residue likely involved in protein folding and product specificity. All other copies were inferred to be evolving under a combination of stabilizing and/or relaxed selection. Although gene copy number is consistent with the extensive phenotypic diversity in monoterpenes shown in Protium, selection analyses suggest that not all copies are undergoing divergent selection consistent with a coevolutionary arms race with enemies, but instead may be under stabilizing and relaxed selection consistent with signaling or physiological stress functionality. PMID- 23665038 TI - The evolution and biogeography of the austral horse fly tribe Scionini (Diptera: Tabanidae: Pangoniinae) inferred from multiple mitochondrial and nuclear genes. AB - Phylogenetic relationships within the Tabanidae are largely unknown, despite their considerable medical and ecological importance. The first robust phylogenetic hypothesis for the horse fly tribe Scionini is provided, completing the systematic placement of all tribes in the subfamily Pangoniinae. The Scionini consists of seven mostly southern hemisphere genera distributed in Australia, New Guinea, New Zealand and South America. A 5757 bp alignment of 6 genes, including mitochondrial (COI and COII), ribosomal (28S) and nuclear (AATS and CAD regions 1, 3 and 4) genes, was analysed for 176 taxa using both Bayesian and maximum likelihood approaches. Results indicate the Scionini are strongly monophyletic, with the exclusion of the only northern hemisphere genus Goniops. The South American genera Fidena, Pityocera and Scione were strongly monophyletic, corresponding to current morphology-based classification schemes. The most widespread genus Scaptia was paraphyletic and formed nine strongly supported monophyletic clades, each corresponding to either the current subgenera or several previously synonymised genera that should be formally resurrected. Molecular results also reveal a newly recognised genus endemic to New Zealand, formerly placed within Scaptia. Divergence time estimation was employed to assess the global biogeographical patterns in the Pangoniinae. These analyses demonstrated that the Scionini are a typical Gondwanan group whose diversification was influenced by the fragmentation of that ancient land mass. Furthermore, results indicate that the Scionini most likely originated in Australia and subsequently radiated to New Zealand and South American by both long distance dispersal and vicariance. The phylogenetic framework of the Scionini provided herein will be valuable for taxonomic revisions of the Tabanidae. PMID- 23665039 TI - Evolutionary events in Lilium (including Nomocharis, Liliaceae) are temporally correlated with orogenies of the Q-T plateau and the Hengduan Mountains. AB - The Hengduan Mountains (H-D Mountains) in China flank the eastern edge of the Qinghai-Tibet Plateau (Q-T Plateau) and are a center of great temperate plant diversity. The geological history and complex topography of these mountains may have prompted the in situ evolution of many diverse and narrowly endemic species. Despite the importance of the H-D Mountains to biodiversity, many uncertainties remain regarding the timing and tempo of their uplift. One hypothesis is that the Q-T Plateau underwent a final, rapid phase of uplift 8-7 million years ago (Mya) and that the H-D Mountains orogeny was a separate event occurring 4-3 Mya. To evaluate this hypothesis, we performed phylogenetic, biogeographic, divergence time dating, and diversification rate analyses of the horticulturally important genus Lilium, including Nomocharis. The Lilium-Nomocharis complex is distributed throughout the temperate Northern Hemisphere but is most diverse within the H-D Mountains and Q-T Plateau. Our matK and ITS phylogenies support previous studies showing that Nomocharis is nested within Lilium. However, we detected incongruence between the two gene trees which may result from hybridization. Dating analyses performed using the ITS dataset showed that the evolution of major lineages within Lilium-Nomocharis may be temporally coincident with Q-T Plateau uplift occurring 8-7 Mya and H-D Mountains uplift approximately 4-3 Mya. Our analyses of diversification times and rates among Lilium-Nomocharis clades are less conclusive. However, these do suggest high extinction rates among H-D Mountains lineages. PMID- 23665041 TI - Activated human hepatic stellate cells induce myeloid derived suppressor cells from peripheral blood monocytes in a CD44-dependent fashion. AB - BACKGROUND & AIMS: Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of cells associated with the suppression of immunity. However, little is known about how or where MDSCs are induced and from which cells they originate. The liver is known for its immune regulatory functions. Here, we investigated the capacity of human hepatic stellate cells (HSCs) to transform peripheral blood monocytes into MDSCs. METHODS: We cultured freshly isolated human monocytes from healthy donors on primary human HSCs or an HSC cell-line and characterized the phenotype and function of resulting CD14(+)HLA-DR(-/low) monocytes by flow cytometry, quantitative PCR, and functional assays. We analyzed the molecular mechanisms underlying the induction and function of the CD14(+)HLA DR(-/low) cells by using blocking antibodies or knock-down technology. RESULTS: Mature peripheral blood monocytes co-cultured with HSCs downregulated HLA-DR and developed a phenotypic and functional profile similar to MDSCs. Only activated but not freshly isolated HSCs were capable of inducing CD14(+)HLA-DR(-/low) cells. Such CD14(+)HLA-DR(-/low) monocyte-derived MDSCs suppressed T-cell proliferation in an arginase-1 dependent fashion. HSC-induced development of CD14(+)HLA-DR(-/low) monocyte-derived MDSCs was not mediated by soluble factors, but required physical interaction and was abrogated by blocking CD44. CONCLUSIONS: Our study shows that activated human HSCs convert mature peripheral blood monocytes into MDSCs. As HSCs are activated during chronic inflammation, the subsequent local induction of MDSCs may prevent ensuing excessive liver injury. HSC-induced MDSCs functionally and phenotypically resemble those isolated from liver cancer patients. Thus, our data suggest that local generation of MDSCs by liver-resident HSCs may contribute to immune suppression during inflammation and cancer in the liver. PMID- 23665040 TI - Genetic diversity, phylogeny and evolution of alkaloid sequestering in Cuban miniaturized frogs of the Eleutherodactylus limbatus group. AB - The miniaturized frogs of the Eleutherodactylus limbatus group, endemic to Cuba, have recently been shown to contain alkaloids in their skin, representing the fifth independent evolutionary origin of alkaloid sequestering in anurans. Based on a comprehensive sampling of all known species of the group we here assess their range-wide phylogeography using DNA sequences of the mitochondrial cytochrome b and the nuclear Rag-1 gene. We found E. etheridgei, E. cubanus, and E. orientalis to be genetically highly distinct, with uncorrected pair-wise distances >12% in the cytochrome b gene and >5% in the 16S rRNA gene, and without haplotype sharing in the Rag-1 gene. On the contrary, E. iberia, E. jaumei, E. limbatus, and one unnamed lineage from Gran Piedra mountains had lower mitochondrial divergences to each other (<6% in cytochrome b; <3% in 16S) and extensive Rag-1 haplotype sharing, suggesting that their species status requires careful revision. All species and lineages of the group occur in the mountain areas of eastern Cuba and only one of them, E. limbatus, colonized central and western Cuba. Populations of this latter lineage are only weakly genetically differentiated, and its range expansion to western Cuba is probably Pleistocenic, demonstrating that also miniaturized frog species are able of considerable range expansions (over hundreds of kilometers) in short time spans. A phylogeny based on about 5 kb of mitochondrial and nuclear genes places, with maximum support, E. etheridgei basalmost in the group, followed by E. cubanus, E. orientalis, and the E. iberia-jaumei-limbatus clade. The screening of skin alkaloids revealed the presence of alkaloids in all lineages of the group, but alkaloids known to be sequestered by other anurans were not found in the basalmost E. etheridgei. Furthermore, individuals of the derived lineages of the E. iberia-jaumei-limbatus clade had a much larger variety of different alkaloid compounds (3-18) than the other three species (0-4). Traces of alkaloids were found in other species only remotely related to the E. limbatus group, i.e., E. caspari, E. goini, E. ricordii, and E. tetajulia. According to these findings, it can be hypothesized that the capacity to sequester dietary alkaloids into the skin evolved first in an ancestral, litter-dwelling and small-sized Cuban Eleutherodactylus, followed by evolution of miniaturization and diurnality in the early representatives of the E. limbatus group, and eventually by increased brightness of color with probable aposematic function and a highly efficient mechanism of alkaloid sequestering. PMID- 23665042 TI - Portal uptake function in veno-occlusive regions evaluated by real-time fluorescent imaging using indocyanine green. PMID- 23665043 TI - Hepatocyte nuclear factor 4alpha regulates the expression of the murine pyruvate carboxylase gene through the HNF4-specific binding motif in its proximal promoter. AB - Pyruvate carboxylase (PC) is the first regulatory enzyme of gluconeogenesis. Here we report that the proximal promoter of the murine PC gene contains three binding sites for hepatocyte nuclear factor 4alpha (HNF4alpha). These sites include the classical direct repeat 1 (DR1) (-386/-374), non-perfect DR1 (-118/-106) and HNF4alpha-specific binding motif (H4-SBM) (-26/-14). Under basal conditions, mutation of the non-perfect DR1 decreased promoter activity by 50%, whereas mutation of neither the DR1 nor the H4-SBM had any effect. In marked contrast, only mutation of the H4-SBM decreased HNF4alpha-transactivation of the promoter activity by 65%. EMSA revealed that HNF4alpha binds to the DR1site and H4-SBM with similar affinity while it binds poorly to the non-perfect DR1. Interestingly, this non-perfect DR1 also coincides with two E-boxes. Mutation of the non-perfect DR1 together with the nearby E-box reduced USF1- but not USF2 transactivation of promoter activity, suggesting that USF1 partly contributes to the basal activity of the promoter. Substitution of the H4-SBM with the DR1 marginally reduced the basal promoter activity but did not eliminate HNF4alpha transactivation, suggesting that HNF4alpha can exert its effect via DR1 within this promoter context. ChIP-assay confirmed that HNF4alpha is associated with the H4-SBM. Suppression of HNF4alpha expression in AML12 cells down-regulated PC mRNA and PC protein by 60% and 50%, respectively, confirming that PC is a target of HNF4alpha. We also propose a model for differential regulation of P1 promoter of PC gene in adipose tissue and liver. PMID- 23665044 TI - Host metabolism promotes growth of Chlamydia pneumoniae in a low oxygen environment. AB - Chlamydia pneumoniae infections of the respiratory tract are common and are associated with acute and chronic diseases such as community-acquired pneumonia (CAP) and chronic obstructive pulmonary disease (COPD). Recent studies have shown that reduced environmental oxygen availability promotes chlamydial growth in infected host cells. The underlying mechanisms remain unclear. We performed a targeted siRNA screen coupled with an automated high-throughput microscopic analysis to identify key host cell genes that play a role in promoting the hypoxic growth of C. pneumoniae. A total of 294 siRNAs - targeting 98 selected genes including central mediators of metabolic, trafficking and signaling pathways - were tested on chlamydial inclusion formation in C. pneumoniae infected A549 cells under normoxic (20% O2) and hypoxic (2% O2) conditions 48 h post infection. Evaluation of the different functional clusters of genes revealed that under hypoxic conditions, enhanced growth of C. pneumoniae was centrally mediated by the host cell glycolytic pathway. Inhibition of the phosphofructokinase (PFK), lactate dehydrogenase (LDH), glycerol-3-phosphate dehydrogenase (GPD2) and the forkheadbox O3 (FOXO3) gene-expression by siRNAs abrogated chlamydial progeny. The pivotal role of host cell glycolysis in chlamydial development under hypoxia was further confirmed by pharmacological inhibition of the pathway by 2-fluoro-deoxy-glucose. The results indicate that the microenvironment of the host cell determines the fate of C. pneumoniae by controlling pathogen-induced metabolic pathways. PMID- 23665045 TI - Diosmin abrogates chemically induced hepatocarcinogenesis via alleviation of oxidative stress, hyperproliferative and inflammatory markers in murine model. AB - Hepatocellular carcinoma (HCC) is a global health problem and is fourth leading cause of cancer related deaths. Now-a-days new strategies have been accounted for the chemoprevention of liver cancer due to ineffective traditional treatments against HCC. In the present study, we have shown that diosmin attenuates 2-AAF induced hepatic toxicity and early tumor promotion markers (ODC, PCNA and Ki67), its chemopreventive efficacy against DEN initiated and 2-AAF promoted hyper proliferation and hepatocarcinogenesis in Wistar rats. Hepatocarcinogenesis has been characterized by the presence of apparent hepatic nodules, hepatic proliferation, elevation in the levels of proliferation markers (PCNA and Ki67), and inflammatory markers (COX-2 and iNOS) in DEN and 2-AAF administered rats. Protective efficacy of diosmin has been investigated in terms of its potential in reducing the percentage of visible hepatic nodules and the restoration of early tumor markers (PCNA, Ki67 and ODC), oxidative stress biomarkers, serum cytotoxicity markers (AST, ALT and LDH), cell necrosis markers (NF-kappa B and TNF-alpha) and inflammatory markers (COX-2 and iNos). Our study demonstrates that the inhibition of cell proliferation and down regulation of inflammatory markers may be, at least in part, the underlying mechanisms related to the liver tumor inhibition by diosmin. The present study allows us to conclude that diosmin being a dietary supplement, could be used as chemopreventive agent to prevent hepatocarcinogenesis. PMID- 23665046 TI - Evidence that adrenal hexose-6-phosphate dehydrogenase can effect microsomal P450 cytochrome steroidogenic enzymes. AB - The role of adrenal hexose-6-phosphate dehydrogenase in providing reducing equivalents to P450 cytochrome steroidogenic enzymes in the endoplasmic reticulum is uncertain. Hexose-6-phosphate dehydrogenase resides in the endoplasmic reticulum lumen and co-localizes with the bidirectional enzyme 11beta hydroxysteroid dehydrogenase 1. Hexose-6-phosphate dehydrogenase likely provides 11beta-hydroxysteroid dehydrogenase 1 with NADPH electrons via channeling. Intracellularly, two compartmentalized reactions generate NADPH upon oxidation of glucose-6-phosphate: cytosolic glucose-6-phosphate dehydrogenase and microsomal hexose-6-phosphate dehydrogenase. Because some endoplasmic reticulum enzymes require an electron donor (NADPH), it is conceivable that hexose-6-phosphate dehydrogenase serves in this capacity for these pathways. Besides 11beta hydroxysteroid dehydrogenase 1, we examined whether hexose-6-phosphate dehydrogenase generates reduced pyridine nucleotide for pivotal adrenal microsomal P450 enzymes. 21-hydroxylase activity was increased with glucose-6 phosphate and, also, glucose and glucosamine-6-phosphate. The latter two substrates are only metabolized by hexose-6-phosphate dehydrogenase, indicating that requisite NADPH for 21-hydroxylase activity was not via glucose-6-phosphate dehydrogenase. Moreover, dihydroepiandrostenedione, a non-competitive inhibitor of glucose-6-phosphate dehydrogenase, but not hexose-6-phosphate dehydrogenase, did not curtail activation by glucose-6-phosphate. Finally, the most compelling observation was that the microsomal glucose-6-phosphate transport inhibitor, chlorogenic acid, blunted the activation by glucose-6-phosphate of both 21 hydroxylase and 17-hydroxylase indicating that luminal hexose-6-phosphate dehydrogenase can supply NADPH for these enzymes. Analogous kinetic observations were found with microsomal 17-hydroxylase. These findings indicate that hexose-6 phosphate dehydrogenase can be a source, but not exclusively so, of NADPH for several adrenal P450 enzymes in the steroid pathway. Although the reduced pyridine nucleotides are produced intra-luminally, these compounds may also slowly transverse the endoplasmic reticulum membrane by unknown mechanisms. PMID- 23665047 TI - Internal ribosome entry site-mediated translational regulation of ATF4 splice variant in mammalian unfolded protein response. AB - Activating transcription factor 4 (ATF4) is a master regulator of genes involved in unfolded protein response (UPR) and its translation is regulated through reinitiation at upstream open reading frames. Here, we demonstrate internal ribosome entry site (IRES)-mediated translation of an alternatively spliced variant of human ATF4. This variant that contains four upstream open reading frames in the 5' leader region was expressed in leukocytes and other tissues. mRNA and protein expression of this variant was activated in the UPR. Its translation was neither inhibited by steric hindrance nor affected by eIF4G1 inactivation, indicating a cap-independent and IRES-dependent mechanism not mediated by ribosome scanning-reinitiation. The IRES activity mapped to a highly structured region that partially overlaps with the third and fourth open reading frames was unlikely attributed to cryptic promoter or splicing, but was activated by PERK-induced eIF2alpha phosphorylation. Taken together, our findings reveal a new mechanism for translational regulation of ATF4 in mammalian UPR. PMID- 23665048 TI - A novel actin cytoskeleton-dependent noncaveolar microdomain composed of homo oligomeric caveolin-2 for activation of insulin signaling. AB - The role of caveolin-2 (cav-2), independently of caveolin-1 (cav-1) and caveolae, has remained elusive. Our data show that cav-2 exists in the plasma membrane (PM) in cells lacking cav-1 and forms homo-oligomeric complexes. Cav-2 did not interact with cavin-1 and cavin-2 in the PM. Rab6-GTP was required for the microtubule-dependent exocytic transport of cav-2 from the Golgi to the PM independently of cav-1. The cav-2-oligomerized noncaveolar microdomain was unaffected by cholesterol depletion and protected from shearing of silica-coated PM. Activation of insulin receptor (IR) was processed in the microdomain. Actin depolymerization affected the formation and sustenance of cav-2-oligomerized noncaveolar microdomain and attenuated IR recruitment to the microdomain thereby inhibiting IR signaling activation. Cav-2 shRNA stable cells and the cells ectopically expressing an oligomerization domain truncation mutant, cav-2?47-86 exhibited retardation of IR signaling activation via the noncaveolar microdomain. Elevation in status of cav-2 expression rendered the noncaveolar activation of IR signaling in cav-1 down-regulated or/and cholesterol-depleted cells. Our findings reveal a novel homo-oligomeric cav-2 microdomain responsible for regulating activation of IR signaling in the PM. PMID- 23665049 TI - Exhaled nitric oxide is associated with cyclic changes in sexual hormones. AB - BACKGROUND: We hypothesized that changes in the levels of sexual hormones during the menstrual cycle influence the concentration of nitric oxide in the exhaled air (FeNO) and alveolar exhaled nitric oxide (CANO). METHODS: Twelve healthy, non allergic women in their reproductive age (age range 25-37 years) were recruited. Subjects were studied, on alternate days, over the course of their menstrual cycle. At each visit, measurements of FeNO and CANO were performed. Progesterone and 17-beta-estradiol concentrations were measured in salivary samples. RESULTS: Eight subjects completed the study. The levels of FeNO and CANO were 13 +/- 4.7 pbb and 3.5 +/- 1.9 pbb, respectively (mean +/- SD). The mean salivary concentration of progesterone was 65.1 +/- 16.2 pg/ml (mean +/- SD), with a range of 32.4-107.7 pg/ml, and the concentration of 17 beta-estradiol was 6.0 +/- 1.6 pg/ml, with a range of 3.1-12.9 pg/ml. The Generalized Estimating Equations procedure demonstrated that levels of progesterone influenced both FeNO and CANO (Wald chi2 = 11.60, p = 0.001; and Wald chi2 = 87.55, p = 0.001, respectively). On the contrary, the salivary levels of 17 beta-estradiol were not significantly associated with FeNO (Wald chi2 = 0.087, p = 0.768) or CANO (Wald chi2 = 0.58, p = 0.448). CONCLUSION: In healthy women, the menstrual cycle-associated hormonal fluctuations selectively influence the levels of bronchial and alveolar NO. The current findings may have important clinical implications for the interpretation of eNO levels, by identifying a patient-related factor that influences the eNO measurements. PMID- 23665051 TI - Effects of body posture and exercise training on cardiorespiratory responses to exercise. AB - The primary aims of the present study were to evaluate cardiorespiratory responses to incremental head down tilt exercise and to determine if the cardiorespiratory adaptations obtained from endurance training in the head down tilt posture transfer to the upright posture. 22 men (25+/-3 years) performed VO2peak cycle exercise tests in the upright and head down tilt postures. Of these, 11 men were endurance trained on a cycle ergometer in the upright posture for 8 weeks (upright training group; UTG) or in the upright posture for 4 weeks followed by 4 weeks in the head down tilt posture (head down training group; HTG). During acute exercise, VO2peak was decreased in the head down tilt posture compared to upright (2.01+/-0.51 vs. 2.32+/-0.61l/min respectively, P<0.05). Stroke volume (SV) at 100 W was greater during head down tilt cycling compared to the upright (77+/-5 vs. 71+/-4 ml/beat, P<0.05). Following training VO2peak increased in both groups during upright exercise. However, VO2peak during head down tilt cycling was only increased in the HTG. Sub-maximal and peak SV in the HTG increased in both upright and head down tilt postures. SV in the UTG increased only in the upright posture and was unchanged during head down tilt cycling. In conclusion, acute head down tilt exercise increases sub-maximal SV compared to upright exercise. Furthermore, training in the head down tilt posture induces cardiorespiratory adaptations in both upright and head down tilt postures, while the adaptations to upright exercise training are primarily observed when upright exercise was performed. PMID- 23665050 TI - Circadian dependence of receptors that mediate wake-related excitatory drive to hypoglossal motoneurons. AB - Serotonin (5-HT), norepinephrine and orexins (ORX) are the three best established mediators of wake-related activation of hypoglossal (XII) motoneurons that innervate the muscles of the tongue. Since the tongue's use is temporarily closely aligned with the rest-activity cycle, we tested whether expression of mRNA for relevant 5-HT, norepinephrine and ORX receptors varies in the XII nucleus with the rest-activity cycle. Adult rats (n=7-9/group) were decapitated at 8-9 am (near rest period onset) or at 6-7 pm (near active period onset). Tissue micropunches were extracted from medullary slices containing the XII motor and sensory external cuneate (ECN) nuclei. 5-HT2A, alpha1-adrenergic and ORX type 2 receptor mRNAs were quantified using RT-PCR. Only 5-HT2A receptor mRNA levels differed between the two time points and were higher at the active period onset; no differences were detected in the ECN. Consistent with the mRNA results, 5-HT2A protein levels were also higher in the XII nucleus at the active period onset than at rest onset. Thus, the endogenous serotonergic excitatory drive to XII motoneurons may be enhanced through circadian- or activity-dependent mechanisms that increase the availability of 5-HT2A receptors prior to the active period. Conversely, reduced levels of 5-HT2A receptors during the rest-sleep period may exacerbate the propensity for sleep-disordered breathing in subjects with anatomically compromised upper airway. PMID- 23665052 TI - The anti-apoptotic effect of hydrogen sulfide attenuates injuries to the medullary respiratory centers of neonatal rats subjected to in utero cigarette smoke exposure. AB - H2S may serve as an important neuroprotectant. The present experiments were performed to determine whether H2S could attenuate the injuries sustained by the medullary respiratory centers of neonatal rats that were subjected to cigarette smoke exposure (CS) in utero. Pregnant SD rats were divided into 4 exposure groups: control, CS, CS+NaHS (donor of H2S) and NaHS. Hypoxia decreased the burst frequencies of the hypoglossal rootlets of the medullary slices in CS neonatal rats, and NaHS offset the hypoxia-induced respiratory suppression. Nissl staining indicated that NaHS alleviated the injuries that were sustained by neurons after CS in utero. NaHS also decreased the number of TUNEL-positive neurons and the expression of activated caspase-3 protein in the medulla oblongata of CS neonatal rats. Furthermore, NaHS promoted Bcl-2 protein expression and reduced Bax protein and mRNA expression in the medulla oblongata of CS neonatal rats. Therefore, the present study indicates that the anti-apoptotic effect of H2S protects rat medullary respiratory centers from injuries that would otherwise be sustained from in utero CS exposure. PMID- 23665054 TI - Expression of LC3 and Beclin 1 in the spinal dorsal horn following spinal nerve ligation-induced neuropathic pain. AB - Impaired spinal GABAergic inhibitory function is known to be pivotal in neuropathic pain (NPP). At present, data concerning time-dependent alterations in cell type and cell death in the spinal dorsal horn are highly controversial, likely related to the experimental NPP model used. In this study, we examined the expression of autophagy using a L5 spinal nerve ligation (SNL)-induced neuropathic pain rat model. Following ligation of the spinal nerve, neuropathic pain behavior, such as mechanical allodynia, was induced rapidly and maintained for 14 days. After testing for mechanical allodynia, we assessed the changes in expression of LC3 and Beclin 1 in the spinal cord following SNL. Immunohistochemical analysis showed that the levels of LC3 and Beclin 1 protein in the ipsilateral L5 spinal dorsal horn were significantly elevated on day 14 following SNL. Double immunohistochemical analysis further confirmed increases in LC3 and Beclin 1 in mostly neurons and a few astrocytes following SNL. LC3 and Beclin 1 expressions were upregulated in GABAergic interneurons of spinal dorsal horn after SNL, while the loss of GABAergic interneurons did not change significantly. Our results suggest that autophagic disruption in GABAergic interneurons and astrocytes following peripheral nerve injury might be involved in the induction and maintenance of neuropathic pain. PMID- 23665055 TI - Ethnobotany of medicinal plants used in Xalpatlahuac, Guerrero, Mexico. AB - ETHNOPHARMACOLOGICAL IMPORTANCE: Medicinal plants have been used for centuries for the empirical treatment of many diseases. This study documented the use of plant species in traditional medicine in the municipality of Xalpatlahuac, Guerrero, Mexico. MATERIALS AND METHODS: Direct interviews were performed with inhabitants from Xalpatlahuac. The interviews were analyzed with two quantitative tools: (a) the informant consensus factor (ICF) that estimates the level of agreement about which medicinal plants may be used for each category and (b) the relative importance (RI) that determines the extent of potential utilization of each species. RESULTS: A total of 67 plant species with medicinal purposes, belonging to 36 families and used to treat 55 illnesses and 3 cultural filiations were reported by interviewees. Nineteen mixtures with medicinal plants were reported by the interviewers. Mentha piperita was the most used plant for combinations (4 mixtures). The results of the ICF showed that diseases of the respiratory and digestive systems had the greatest agreement. The most versatile species according to their RI are Marrubium vulgare, Mimosa albida and Psidium guajava.. CONCLUSION: This study demonstrates that plant species play an important role in healing practices and magical-religious rituals among inhabitants from Xalpatlahuac, Guerrero, Mexico. Furthermore, pharmacological, phytochemical and toxicological studies with medicinal flora, including mixtures, are required for the experimental validation of their traditional uses. PMID- 23665056 TI - Comparative assessment of dermal wound healing potentials of various Trifolium L. extracts and determination of their isoflavone contents as potential active ingredients. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Trifolium species are used in Turkish folk medicine as a wound healing agent, expectorant, antiseptic, sedative and to alleviate pain in rheumatism. In the present study, the aqueous methanolic extracts (80%) of 13 Trifolium species (Trifolium ambigum, Trifolium arvense var. arvense, Trifolium campestre, Trifolium canescens, Trifolium hybridum var. anatolicum, Trifolium hybridum var. hybridum, Trifolium pannonicum, Trifolium pratense var. pratense, Trifolium purpureum var. purpureum, Trifolium repens var. repens, Trifolium resupinatum var. microcephalum, Trifolium spadiceum and Trifolium trichocephalum) collected from different regions of Anatolia were evaluated for their in vivo wound healing effects. MATERIALS AND METHODS: In vivo wound healing activities of the plant aqueous methanolic extracts were evaluated by linear incision and circular excision wound models subsequent to histopathological analysis. Active constituents were determined by a validated high performance liquid chromatographic method. Precision of the method was performed by the evaluation of intra-day and inter-day variations of the each standard at limits of quantification (LOQ) levels. RESULTS: The aqueous methanolic extracts of Trifolium canescens and Trifolium pretense var. pratense possessed better wound healing activity compared to the other extracts and control groups. The animal groups treated with the Trifolium canescens extract demonstrated increased contraction (48.96%) on excision and a significant increase in wound tensile strength (35.6%) on incision models. The main compounds were detected as genistein and biochanin A for Trifolium canescens. CONCLUSION: The results of the present study revealed the wound healing potential of Trifolium canescens. This might be due to the combined effect of the isoflavones genistein, formononetin, daidzein, and biochanin A present in the extract. PMID- 23665053 TI - Identification and distribution of projections from monoaminergic and cholinergic nuclei to functionally differentiated subregions of prefrontal cortex. AB - The prefrontal cortex (PFC) is implicated in a variety of cognitive and executive functions and is composed of several distinct networks, including anterior cingulate cortex (ACC), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). These regions serve dissociable cognitive functions, and are heavily innervated by acetylcholine, dopamine, serotonin and norepinephrine systems. In this study, fluorescently labeled retrograde tracers were injected into the ACC, mPFC, and OFC, and labeled cells were identified in the nucleus basalis (NB), ventral tegmental area (VTA), dorsal raphe nucleus (DRN) and locus coeruleus (LC). DRN and LC showed similar distributions of retrogradely labeled neurons such that most were single labeled and the largest population projected to mPFC. VTA showed a slightly greater proportion of double and triple labeled neurons, with the largest population projecting to OFC. NB, on the other hand, showed mostly double and triple labeled neurons projecting to multiple subregions. Therefore, subsets of VTA, DRN and LC neurons may be capable of modulating individual prefrontal subregions independently, whereas NB cells may exert a more unified influence on the three areas simultaneously. These findings emphasize the unique aspects of the cholinergic and monoaminergic projections to functionally and anatomically distinct subregions of PFC. PMID- 23665057 TI - Ethnobotanical survey of medicinally important wild edible fruits species used by tribal communities of Lesser Himalayas-Pakistan. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Present survey was conducted to explore ethnomedicinal uses and cultural importance of wild edible fruits species by the inhabitants of Lesser Himalayas-Pakistan. MATERIALS AND METHODS: Information was obtained through informed consent semi-structured interviews, questionnaires, market survey, focus group conversation, unceremonious dialogue and village walks with key informants. Cultural significance of each species was calculated based on use report by participants at each study site. RESULTS: A total of 35 wild edible fruits belonging to 21 genera and 17 families were used for the treatment of various ailments and consumed. Rosaceae was found dominating family with (8 spp.), followed by Moraceae (6 spp.), Rhamnaceae (5 spp.), Palmae and Vitaceae (2 spp. each) and remaining families were represented by one species each. Fruits (48%) were found highly utilized plant parts, followed by leaves (34%), bark, flowers and seeds (4% each), branches, latex and roots (2% each). Water was used as a medium for preparation while milk, ghee, oil, egg and butter are used for application. Modes of preparation were fall into seven categories like fresh parts eaten raw (38%), powder (24%), decoction (20%), extract (12 %), paste (4%), juice and latex (2% each). Based on cultural important index (CI) Morus nigra was found most significant species within top ten fruit plants followed by Morus alba, Olea ferruginea, Berberis lycium, Pyrus pashia, Ficus carica, Ficus palmata, Ziziphus mauritiana, Diospyros lotus and Ziziphus nummularia. CONCLUSIONS: Traditional uses of wild edible plant depend mainly on socio economic factors rather than climatic conditions or wealth of flora. Use reports and citation demonstrated that there is a common cultural heritage regarding the gathered food plants. Further investigation is required for Antioxidant study, essential and toxic components, pharmacological applications; dietary requirements and biotechnological techniques to improve yields. PMID- 23665058 TI - Management of failed low colorectal and coloanal anastomosis. AB - The most serious early complication after rectal resection with low anastomosis is anastomotic leakage (AL). AL may compromise the long-term conservation of the anastomosis and also worsen oncological results. The aim of this review was to identify those factors that contribute to the prevention of AL and to delineate the various treatment options (endoscopic, perineal surgical approach, abdominal surgical approach) for chronic AL or anastomotic stricture. Treatments for AL or anastomotic stricture should be protected by proximal diversion of fecal flow, ideally by a diverting stoma created at the time of the initial proctectomy. Local approaches to surgical treatment should include perineal examination under general anesthesia by the surgeon and drainage of the fistula. Trans-abdominal interventions should be reserved for high AL and for failure of perineal procedures. Although they have only limited indications for the treatment of AL, endoscopic treatments can be used in a complementary manner to surgical treatment. Balloon dilation is the first-line treatment for anastomotic strictures. PMID- 23665059 TI - Is port-site resection necessary in the surgical management of gallbladder cancer? AB - INTRODUCTION: Gallbladder carcinoma is frequently discovered incidentally on pathologic examination of the specimen after laparoscopic cholecystectomy (LC) performed for presumed "benign" disease. The objective of the present study was to assess the role of excision of port-sites from the initial LC for patients with incidental gallbladder carcinoma (IGBC) in a French registry. METHODS: Data on patients with IGBC identified after LC between 1998 and 2008 were retrospectively collated in a French multicenter database. Among those patients undergoing re-operation with curative intent, patients with port-site excision (PSE) were compared with patients without PSE and analyzed for differences in recurrence patterns and survival. RESULTS: Among 218 patients with IGBC after LC (68 men, 150 women, median age 64 years), 148 underwent re-resection with curative intent; 54 patients had PSE and 94 did not. Both groups were comparable with regard to demographic data (gender, age > 70, co-morbidities), surgical procedures (major resection, lymphadenectomy, main bile duct resection) and postoperative morbidity. In the PSE group, depth of tumor invasion was T1b in six, T2 in 24, T3 in 22, and T4 in two; this was not significantly different from patients without PSE (P = 0.69). Port-site metastasis was observed in only one (2%) patient with a T3 tumor who died with peritoneal metastases 15 months after resection. PSE did not improve the overall survival (77%, 58%, 21% at 1, 3, 5 years, respectively) compared to patients with no PSE (78%, 55%, 33% at 1, 3, 5 years, respectively, P = 0.37). Eight percent of patients developed incisional hernia at the port-site after excision. CONCLUSION: In patients with IGBC, PSE was not associated with improved survival and should not be considered mandatory during definitive surgical treatment. PMID- 23665061 TI - Increased heat shock transcription factor 1 in the cerebellum reverses the deficiency of Purkinje cells in Alzheimer's disease. AB - Alzheimer's disease (AD) is one of the most debilitating neurodegenerative nerve diseases, seriously affecting one's ability to carry out daily activities. AD is both progressive and incurable, but molecular studies have begun to shed light on the mechanisms that underlie it. Immunochemical staining showed that cell bodies of Purkinje cells in the cerebellum were significantly reduced in AD rats compared with normal rats. Heat shock protein 70 (HSP70) was found to prevent polyglutamine aggregation in Huntington's disease and spinocerebellar ataxias (SCAs) and to relieve symptoms in SCAs and Parkinson's disease. Recently, AD related phenotypes were found to be suppressed in HSP70 transgenic rats. However, the effects of other HSPs and the mechanisms of HSP-triggered changes in AD are unknown. In this study, we found that expression levels of HSP60, -70, and -90 were downregulated in the cerebella of rats with AD. Furthermore, heat shock factor 1 (HSF1), a key transcription factor for the expression of HSP genes, was found to be greatly decreased in the cerebella of AD rats. Even more interesting, injection of lentivirus vector-HSF1 into the cerebella of AD rats significantly increased HSF1 and HSP expression levels and induced an increase in the number of Purkinje cell bodies. Our findings provide novel evidence that low expression of HSPs in AD rats is dependent on the low expression of HSF1, and increased expression of HSF1 contributes to the reversal of cerebellar Purkinje cell deficiency in AD. Therefore, increasing HSF1 expression is a potential new strategy for the treatment of AD. PMID- 23665060 TI - Sexually dimorphic intracellular responses after cocaine-induced conditioned place preference expression. AB - Sex differences in cocaine's mechanisms of action and behavioral effects have been widely reported. However, little is known about how sex influences intracellular signaling cascades involved with drug-environment associations. We investigated whether ERK/CREB intracellular responses in the mesocorticolimbic circuitry underlying cocaine environmental associations are sexually dimorphic. We used a standard 4 day conditioned place preference (CPP) paradigm using 20mg/kg cocaine-a dose that induced CPP in male and female Fischer rats. In the nucleus accumbens (NAc) following CPP expression, cocaine treated animals showed increased phosphorylated ERK (pERK), phosphorylated CREB (pCREB) and DeltaFosB protein levels. In the hippocampus (HIP) and caudate putamen (CPu), pERK and FosB/DeltaFosB levels were also increased, respectively. Cocaine females had a larger change in HIP pERK and CPu DeltaFosB levels than cocaine males; partly due to lower protein levels in saline female rats when compared to saline males. Prefrontal cortex (PfC) pCREB levels increased in cocaine males, but not females, whereas PfC pERK levels were increased in cocaine females, but not males. CPP scores were positively correlated to NAc pERK, HIP pERK and CPu FosB protein levels, suggesting that similar to males, the ERK/CREB intracellular pathway in mesocorticolimbic regions undergoes cocaine induced neuroplasticity in female rats. However, there seem to be intrinsic (basal) sexual dimorphisms in this pathway that may contribute to responses expressed after cocaine-CPP. Taken together, our results suggest that cellular responses associated with the expression of learned drug-environment associations may play an important role in sex differences in cocaine addiction and relapse. PMID- 23665062 TI - A review of contemporary options for medical management of hemangiomas, other vascular tumors, and vascular malformations. AB - Vascular anomalies include vascular tumors and vascular malformations. With growing pharmacologic options and parallels to cancer treatment and biology, the hematologist-oncologist has assumed a more prominent role in clinical care and research relating to these diagnoses. This also is a growing area for targeted therapies and drug repositioning. We performed a review of contemporary options for medical management of these lesions. PubMed was searched for "vascular anomaly", "hemangioma", "vascular malformation", "arteriovenous malformation", "capillary malformation", "cerebral cavernous malformation", "lymphatic malformation", and "venous malformation", each with "drug treatment" as a modifier. Manuscripts were reviewed to verify diagnoses, indications for treatment, dose-schedules, evidence of effectiveness, toxicities, and mechanisms of action. ClinicalTrials.gov also was reviewed for relevant trials. More than 20 agents were identified which have been used to treat vascular anomalies. Rigorous studies are lacking for many of these. The rarity of these tumors has limited development of medical approaches to treatment. Cooperative group trials will be needed to prove the effectiveness of drugs which have shown promise in cases and small series. The observant clinician remains a powerful tool for identifying potential new treatments for vascular tumors and malformations. PMID- 23665063 TI - Pattern description and reliability parameters of six force-time related indices measured with plantar pressure measurements. AB - BACKGROUND: Functional interpretation of plantar pressure measurements is commonly done through the use of ratios and indices which are preceded by the strategic combination of a subsampling method and selection of physical quantities. However, errors which may arise throughout the determination of these temporal indices/ratio calculations (T-IRC) have not been quantified. The purpose of the current study was therefore to estimate the reliability of T-IRC following semi-automatic total mapping (SATM). METHODS: Using a repeated-measures design, two experienced therapists performed three subsampling sessions on three left and right pedobarographic footprints of ten healthy participants. Following the subsampling, six T-IRC were calculated: Rearfoot-Forefoot_fti, Rearfoot Midfoot_fti, Forefoot medial/lateral_fti, First ray_fti, Metatarsal 1-Metatarsal 5_fti, Foot medial-lateral_fti. FINDINGS: Patterns of the T-IRC were found to be consistent and in good agreement with corresponding knowledge from the literature. The inter-session errors of both therapists were similar in pattern and magnitude. The lowest peak inter-therapist error was found in the First ray_fti (6.5 a.u.) whereas the highest peak inter-therapist error was observed in the Forefoot medial/lateral_fti (27.0 a.u.) The magnitude of the inter-session and inter-therapist error varied over time, precluding the calculation of a simple numerical value for the error. The difference between both error parameters of all T-IRC was negligible which underscores the repeatability of the SATM protocol. CONCLUSION: The current study reports consistent patterns for six T-IRC and similar inter-session and inter-therapist error. The proposed SATM protocol and the T-IRC may therefore serve as basis for functional interpretation of footprint data. PMID- 23665064 TI - Normative values for the foot posture index between right and left foot: a descriptive study. AB - BACKGROUND: The foot posture index (FPI) is a commonly used method to quantify standing foot posture. No normative data have, however, been presented to establish the range of a normal difference and asymmetrical differences between FPI score in the right foot and in the left foot. PURPOSE: The purpose of the present study was to establish normative values for the difference between the FPI scores across the two feet. METHODS: Among 930 healthy adults, FPI score was quantified in both feet. Difference between the two feet was calculated as FPI score on the right foot minus the FPI score on the left foot. Based on a normal distribution of the differences, asymmetry was defined as values below or above one standard deviation (SD) from the mean. Severe asymmetry was below and above +/-2SD from the mean. Normal difference was defined as the range between +/-1SD. RESULTS: A reference range for normal difference in FPI score between left foot and right foot was -2 to +2. Asymmetry scores ranged from -2 to -4 and +2 to +4, while severe asymmetry was <-4 and >4. CONCLUSION: Normative values for the difference between FPI scores in right foot and left foot have been presented from a large sample of healthy adults. These normative values can be used to identify a normal difference or an asymmetrical difference in foot posture across feet in one individual. PMID- 23665065 TI - Dual tasking affects lateral trunk control in healthy younger and older adults. AB - Assessing the effects of attention-demanding tasks on trunk movement provides useful insights into postural control while walking in an attention-split situation, such as occurs in daily life. The coefficient of attenuation of acceleration (CoA) at the trunk is a useful gait index to assess whole trunk movements. We investigated the effect of attention-demanding tasks on CoA to assess the role of attention on trunk control during walking. Thirty healthy, community-dwelling older adults (70.1+/-5.6 years) and 38 younger adults (22.1+/ 3.4 years) participated in this study. Participants walked 20 m at a self selected speed (slow, normal, fast) and while performing an attention-demanding cognitive task. Trunk acceleration was measured using triaxial accelerometers attached to the lower (L3 spinous process) and upper (C7 spinous process) trunk and used to compute CoA (the reduction in acceleration from the lower to upper trunk). Results showed that an attention-demanding task significantly decreased CoA in the medio-lateral (ML) direction in both age groups (p<0.001), whereas it did not affect CoA in the vertical (VT) and anterior-posterior (AP) directions. Our findings suggest that the priority of whole trunk control in the ML direction may be higher than in other directions and be strongly associated with attention, whereas whole trunk control in the VT and AP directions may be passively regulated and require minimal attentional control. PMID- 23665066 TI - Collision avoidance between two walkers: role-dependent strategies. AB - This paper studies strategies for collision avoidance between two persons walking along crossing trajectories. It has been previously demonstrated that walkers are able to anticipate the risk of future collision and to react accordingly. The avoidance task has been described as a mutual control of the future distance of closest approach, MPD (i.e., Mininum Predicted Distance). In this paper, we studied the role of each walker in the task of controlling MPD. A specific question was: does the walker giving way (2nd at the crossing) and the one passing first set similar and coordinated strategies? To answer this question, we inspected the effect of motion adaptations on the future distance of closest approach. This analysis is relevant in the case of collision avoidance because subtle anticipatory behaviors or large last moment adaptations can finally yield the same result upon the final crossing distance. Results showed that collision avoidance is performed collaboratively and the crossing order impacts both the contribution and the strategies used: the participant giving way contributes more than the one passing first to avoid the collision. Both walkers reorient their path but the participant giving way also adapts his speed. Future work is planned to investigate the influence of crossing angle and TTC on adaptations as well as new types of interactions, such as intercepting or meeting tasks. PMID- 23665067 TI - Estimating the contribution of inhalation exposure to di-2-ethylhexyl phthalate (DEHP) for PVC production workers, using personal air sampling and urinary metabolite monitoring. AB - Because of troubling reports of high urinary metabolite levels and adverse reproductive health effects in workers exposed to di(2-ethylhexyl)phthalate (DEHP) in occupational settings, concern about exposure to DEHP in occupational settings is increasing. However, the contributions of different routes of exposure to DEHP are unclear. We used personal air sampling and biomonitoring to determine the contribution of inhalation exposure to the body burden of DEHP in the workplace. Eighty-nine workers (high-exposure group: 66 raw-materials workers; low-exposure group: 23 administrative workers) were recruited from three polyvinyl chloride (PVC) factories. Urinary levels of mono(2-ethylhexyl) phthalate (MEHP), (mono(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono(2-ethyl-5 hydroxyhexyl) phthalate (MEHHP) were measured in pre-shift and post-shift samples. The geometric means of airborne concentrations of DEHP were 5.3 MUg/m3 (low-exposure group) and 32.7 MUg/m3 (high-exposure group) (P<0.01). Correlation analysis showed a consistently significant association between airborne DEHP concentration and urinary DEHP metabolite levels in the high-exposure group. Calculating daily DEHP intake based on total urinary metabolite levels showed that the geometric means of total daily urinary metabolite levels of DEHP were 9.2 MUg/kg/day (low-exposure group) and 15.5 MUg/kg/day (high-exposure group) (P<0.01). A quartile analysis of all workers showed a significant trend toward an association between the individual contribution of inhalation exposure to DEHP and urinary DEHP metabolite levels, for which the mean inhalation contribution was 46.7% in the highest quartile. We conclude that inhalation-absorbed airborne DEHP significantly increased the total body burden of DEHP in these occupationally exposed workers. PMID- 23665068 TI - Specific detection and identification of [Actinobacillus] muris by PCR using primers targeting the 16S-23S rRNA internal transcribed spacer regions. AB - [Actinobacillus] muris represents along with [Pasteurella] pneumotropica the most prevalent Pasteurellaceae species isolated from the laboratory mouse. Despite the biological and economic importance of Pasteurellaceae in relation to experimental animals, no molecular based methods for the identification of [A.] muris are available. The aim of the present investigation was to develop a PCR method allowing detection and identification of [A.] muris. In this assay, a Pasteurellaceae common forward primer based on a conserved region of the 16S rRNA gene was used in conjunction with two different reverse primers specific for [A.] muris, targeting the 16S-23S internal transcribed spacer sequences. The specificity of the assay was tested against 78 reference and clinical isolates of Pasteurellaceae, including 37 strains of [A.] muris. In addition, eight other mice associated bacterial species which could pose a diagnostic problem were included. The assay showed 100% sensitivity and 97.95% specificity. Identification of the clinical isolates was validated by ITS profiling and when necessary by 16S rRNA sequencing. This multiplex PCR represents the first molecular tool able to detect [A.] muris and may become a reliable alternative to the present diagnostic methods. PMID- 23665069 TI - A radish seed antifungal peptide with a high amyloid fibril-forming propensity. AB - The amyloid fibril-forming ability of two closely related antifungal and antimicrobial peptides derived from plant defensin proteins has been investigated. As assessed by sequence analysis, thioflavin T binding, transmission electron microscopy, atomic force microscopy and X-ray fiber diffraction, a 19 amino acid fragment from the C-terminal region of Raphanus sativus antifungal protein, known as RsAFP-19, is highly amyloidogenic. Further, its fibrillar morphology can be altered by externally controlled conditions. Freezing and thawing led to amyloid fibril formation which was accompanied by loss of RsAFP-19 antifungal activity. A second, closely related antifungal peptide displayed no fibril-forming capacity. It is concluded that while fibril formation is not associated with the antifungal properties of these peptides, the peptide RsAFP-19 is of potential use as a controllable, highly amyloidogenic small peptide for investigating the structure of amyloid fibrils and their mechanism of formation. PMID- 23665071 TI - Peroral endoscopic myotomy for the treatment of achalasia: an international prospective multicenter study. AB - Pilot studies have indicated that peroral endoscopic myotomy (POEM) might be a safe and effective treatment for achalasia. We performed a prospective, international, multicenter study to determine the outcomes of 70 patients who underwent POEM at 5 centers in Europe and North America. Three months after POEM, 97% of patients were in symptom remission (95% confidence interval, 89%-99%); symptom scores were reduced from 7 to 1 (P < .001) and lower esophageal sphincter pressures were reduced from 28 to 9 mm Hg (P < .001). The percentage of patients in symptom remission at 6 and 12 months was 89% and 82%, respectively. POEM was found to be an effective treatment for achalasia after a mean follow-up period of 10 months. PMID- 23665072 TI - Low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) reverses Abeta(1-42)-mediated memory deficits in rats. AB - Accumulating evidence shows the disruption of hippocampal neurotrophins secretion leads to memory deficits in Alzheimer's disease (AD) animal models. Invasive injection of exogenous neurotrophins into hippocampus reverses spatial memory deficits, but its clinical application is limited by traumatic brain injury during the injection procedure. Notably, recent studies have demonstrated that noninvasive repetitive transcranial magnetic stimulation (rTMS) increases endogenous neurotrophins contents in the brain of normal rats. Whether low frequency rTMS can reverse Abeta(1-42)-mediated decrease in hippocampal neurotrophins contents and spatial memory impairment is still unclear. Here, we reported that severe deficit in long-term potentiation (LTP) and spatial memory were observed in an Abeta(1-42)-induced toxicity rat model. Furthermore, neurotrophins (NGF and BDNF) and NMDA-receptor levels were decreased after Abeta injection. However, low-frequency rTMS markedly reversed the decrease in neurotrophins contents. And the rTMS-induced increment of neurotrophins up regulated hippocampal NMDA-receptor expression. Moreover, low-frequency rTMS rescued deficits in LTP and spatial memory of rats with Abeta-injection. These results indicate that low-frequency rTMS noninvasively and effectively increases hippocampal neurotrophins and NMDA-receptor contents in Abeta(1-42)-induced toxicity model rats, which helps to enhance hippocampal LTP and reverses Abeta(1 42)-mediated memory deficits. PMID- 23665073 TI - Some euryhalinity may be more common than expected in marine elasmobranchs: the example of the South American skate Zapteryx brevirostris (Elasmobranchii, Rajiformes, Rhinobatidae). AB - Elasmobranchs are essentially marine, but ~15% of the species occur in brackish or freshwater. The Brazilian marine coastal skate Zapteryx brevirostris, non reported in nearby estuaries, was submitted to 35, 25, 15, and 5 psu, for 6 or 12h (n=6). Plasma was assayed for osmolality, urea, and ions (Na(+), Cl(-), K(+), Mg(2+)). Muscle water content was determined, and the rectal gland, kidney and gills were removed for carbonic anhydrase (CA) and Na(+),K(+)-ATPase (NKA) activities. The skate survived to all treatments. Plasma osmolality and urea levels decreased respectively by 27% and 38% after 12h in 5 psu (with respect to levels when in seawater), but plasma Na(+), Cl(-), and Mg(2+) were well regulated. Plasma K(+) showed some conformation after 12h. Muscle hydration was maintained. Branchial CA and NKA did not respond to salinity. Rectal gland NKA decreased upon seawater dilution, while renal NKA increased. This skate was shown to be partially euryhaline. The analysis of plasma urea of elasmobranchs in brackish and freshwater versus salinity and time-allied to the widespread occurrence of some euryhalinity in the group-led us to revisit the hypothesis of a brackish water habitat for elasmobranch ancestors. PMID- 23665074 TI - Zinc transferrin stimulates red blood cell formation in the head kidney of common carp (Cyprinus carpio). AB - The common carp is one of the few fish able to tolerate extremely low oxygen levels. These fish store zinc in their digestive tract tissue and head kidney at concentrations of 300-500MUg/g of fresh tissue, which is 5-10 times higher than in other fish. Previous studies have indicated a link between the high zinc levels in the common carp and stress erythropoiesis. In this report, using suspension-cultured common carp head kidney cells with or without ZnCl2 supplementation, we found that zinc stimulated the proliferation of immature red blood cells; however, this effect was only observed when the culture was supplemented with carp serum. We identified the active component of carp serum to be transferrin. The zinc-transferrin complex interacts with the transferrin receptor and stimulates the proliferation of immature red blood cells. In addition, the growth rate of the immature red blood cells was regulated by the supplied ZnCl2 concentration. Under stress, the zinc in the common carp digestive tract tissue was released and used as a signal to induce red blood cell formation in the head kidney. This cell culture system might provide a means for exploring the regulatory role of zinc in hematopoietic cell growth. PMID- 23665075 TI - Differential regulation of the glutamate transporter variants GLT-1a and GLT-1b in the cortex and spinal cord of transgenic rats expressing hSOD1(G93A). AB - Altered expression and activity of GLT-1 have been characterized in amyotrophic lateral sclerosis (ALS) patients and in animal models of the disease. Data suggest that the expression of two C-terminus splice variants of GLT-1 (namely GLT-1a and GLT-1b) can be differentially regulated in this pathological context. We herein characterized the expression of GLT-1a and GLT-1b mRNA and the glutamate uptake activity in the fronto-temporal cortex and the lumbar spinal cord of transgenic rats expressing hSOD1(G93A) at various stages of the disease. We also investigated the expression and activity of the other key glutamate transporters GLAST and EAAC1. While the progression of the disease was associated with a reduction of the overall GLT-1 activity in both cortex and spinal cord, the regulation of GLT-1a and GLT-1b transcripts showed different profiles. In the cortex, GLT-1a mRNA which appears as the most abundant isoform at a pre symptomatic stage was strongly decreased during the progression of the disease while GLT-1b mRNA increased to reach a similar level as GLT-1a at end-stage. In the lumbar spinal cord of transgenic rats, both GLT-1a and GLT-1b mRNAs, expressed at the same levels before the symptom onset, were strongly decreased in the ventral horns. While no modification of GLAST was detected, EAAC1 mRNA was highly increased at a pre-symptomatic stage in transgenic animals, explaining a higher activity of glutamate transporters at this age. These results demonstrate that glutamate transporters are differentially expressed in nervous structures of wild-type and transgenic animals although the total GLT-1 activity was constantly decreased during the disease progression. PMID- 23665076 TI - Exploring information chaos in community pharmacy handoffs. AB - BACKGROUND: A handoff is the process of conveying necessary information in order to transfer primary responsibility for providing safe and effective drug therapy to a patient from one community pharmacist to another, typically during a shift change. The handoff information conveyed in pharmacies has been shown to be unstructured and variable, leading to pharmacist stress and frustration, prescription delays, and medication errors. OBJECTIVE: The purpose of this study was to describe and categorize the information hazards present in handoffs in community pharmacies. METHODS: A qualitative research approach was used to elicit the subjective experiences of community pharmacists. Community pharmacists who float or work in busy community pharmacies were recruited and participated in a face to face semi-structured interview. Using a systematic content data analysis, the study identified five categories of information hazards that can lead to information chaos, a framework grounded in human factors and ergonomics. RESULTS: Information hazards including erroneous information and information overload, underload, scatter, and conflict, are experienced routinely by community pharmacists during handoff communication and can result in information chaos. The consequences of information chaos include increased mental workload, which can precipitate problematic prescriptions "falling between the cracks." This can ultimately impact patient care and pharmacist quality of working life. CONCLUSIONS: The results suggest that handoffs in community pharmacies result in information hazards. These information hazards can distract pharmacists from their primary work of assessing prescriptions and educating their patients. Further research on how handoffs are conducted can produce information on how hazards in the system can be eliminated. PMID- 23665077 TI - Pharmacists' adoption into practice of newly reclassified medicines from diverse therapeutic areas in Scotland: a quantitative study of factors associated with decision-making. AB - BACKGROUND: In the UK, over 90 medicines that were previously available only through prescription have been reclassified to allow over-the-counter (OTC) availability via pharmacies. Pharmacists are personally responsible for undertaking or supervising the sales and supplies of these OTC 'pharmacy only' (P) medicines. Reclassification facilitates pharmacy management of a wide range of conditions. OBJECTIVE: This research aimed to evaluate Scottish community pharmacists' perspectives of newly reclassified 'P' medicines from diverse therapeutic areas and to identify factors associated with their adoption into practice of these medicines. METHODS: A cross-sectional postal survey of all community pharmacies in Scotland (N = 1138) was undertaken. The questionnaire was mailed to the pharmacist responsible for OTC medicines. Four newly reclassified 'P' medicines: omeprazole, naproxen, simvastatin and chloramphenicol eye drops were evaluated. Outcomes of interests included pharmacist support for the reclassified status, perceived adoption into practice of these medicines (i.e., how often they supplied each of these medicines) and factors associated with decision-making. Analyses included descriptive, bivariate correlation, principal component factor and binary regression. RESULTS: Five hundred sixty-three pharmacists responded (response rate: 49.5%). Newly reclassified medicines studied had been adopted into practice by the respondent pharmacists to varying degrees. A high majority of the respondents expressed support for the reclassified status (82.4%) and perceived that the level of adoption into practice of OTC chloramphenicol was high (92.1%). In contrast, over 80% of respondents had not yet made a supply of OTC simvastatin to patients, mainly owing to pharmacists' perceptions of lack of evidence of efficacy of the OTC dose and patient demand. Decision-making was influenced by factors such as perceived benefits to patients and pharmacy practice; e.g., respondents who agreed that reclassified naproxen was a good opportunity to develop their professional role were significantly more likely to rate their support for the reclassified status highly than those who were unsure or disagreed (odds ratio = 3.7 (95% confidence interval: 2.1-6.7); P value <0.001). CONCLUSIONS: Key factors informing decisions to adopt the reclassified medicines into pharmacists' practice relate to perceptions regarding the benefits of reclassification to patient care and their professional roles. The results have relevance to future reclassification decisions. PMID- 23665078 TI - Antibiotic dispensing in Egyptian community pharmacies: an observational study. AB - BACKGROUND: Antibiotics are commonly dispensed medications from community pharmacies, and they are frequently prescribed for inappropriate indications. In many countries, they are easily accessible without prescriptions. The inappropriate use of antibiotics results in the emergence of resistant bacterial strains, which represents a considerable public health problem, particularly in developing countries. OBJECTIVE: This study aimed to describe the pattern of antibiotics dispensing from Egyptian community pharmacies and to collect baseline descriptive data on the antibiotics dispensed and their appropriateness. METHODS: A cross-sectional, observational study of antibiotic dispensing encounters was conducted at 36 randomly selected pharmacies in Greater Cairo, Egypt. Data were collected during one shift at each pharmacy. Structured questionnaires recording patient demographics, antibiotics dispensed and reasons for dispensing were completed for each antibiotic dispensing encounter. The data were descriptively analysed. RESULTS: Overall, 1158 antibiotics were dispensed during the study period with a total cost of L.E. 24,487 (approximately 3,673 $USD). While self medication and purchasing without medical prescriptions were common, representing around 23.3% of the antibiotics (n = 270), most antibiotics were prescribed by a doctor or dentist (n = 736, 63.6%). Pharmacist recommendations accounted for the remainder (n = 152, 13.1%). The main reasons for antibiotic use were respiratory tract ailments and gastroenteritis symptoms. The antibiotics most commonly dispensed were: penicillins, erythromycin, metronidazole, neomycin, clotrimoxazole and tetracyclines. Approximately 70% of the antibiotics dispensed on prescriptions were judged to be appropriate for the indications while this percentage was around 61% for antibiotics dispensed on pharmacist recommendation and patient's request. CONCLUSIONS: The results of this study show that antibiotics are frequently dispensed from community pharmacies in Egypt without appropriate prescriptions and for inappropriate indications. These findings support the need for strict enforcement of pharmacy laws through improved inspection processes. They highlight the need for evidence-based guidelines and educational interventions to improve antibiotic prescribing and dispensing practices. PMID- 23665079 TI - Measurement of dehydroepiandrosterone sulphate (DHEAS): a comparison of Isotope Dilution Liquid Chromatography Tandem Mass Spectrometry (ID-LC-MS/MS) and seven currently available immunoassays. AB - BACKGROUND: Dehydroepiandrosterone sulphate (DHEAS) is an important marker of the adrenal gland. Its measurement is required in several adrenal diseases, such as adrenal tumours, adrenal insufficiency and congenital adrenal hyperplasia. Most clinical laboratories measure DHEAS using commercially available immunoassays. The aim of the present study was to investigate the accuracy of currently available DHEAS methods. METHODS: Seven commercially available DHEAS assays were compared to Isotope-Dilution Liquid Chromatography Tandem Mass Spectrometry (ID LC-MS/MS) by measuring 75 serum samples (concentration range 0.06-20.6 MUmol/L measured by ID-LC-MS/MS) with each method. Moreover, recovery and linearity experiments were performed. Data from our present study were compared to DHEAS data of the Dutch, German and British External Quality Assessment Schemes (EQAS's). RESULTS: Three methods agreed well with ID-LC-MS/MS (R between 0.93 and 0.99 and slopes ranging from 0.92 to 1.07) and showed good recoveries. Four methods showed standardization problems (slopes were 0.84, 1.14, 1.20 and 1.28). Linearity was good in all methods. Intra-assay coefficient of variation was 4.1% using ID-LC-MS/MS and below 5.5% in immunometric methods; one assay had an unacceptably high intra-assay coefficient of variation of 18%. Our data are in agreement with data obtained in three EQAS's. CONCLUSION: Some of the commercially available DHEAS methods show standardization problems and/or a high imprecision. These problems may potentially have clinically adverse consequences. We advise the manufacturers to improve their assays and laboratory specialists to scrutinize the DHEAS method they employ. PMID- 23665081 TI - Vestibular schwannoma mimicking horizontal cupulolithiasis. AB - Positional vertigo and nystagmus can be due to canalithiasis, cupulolithiasis and less commonly, an underlying peripheral or central vestibular disorder. We present a patient with vestibular schwannoma who initially sought treatment for positioning vertigo. Video-oculography on the roll-test revealed direction changing horizontal apogeotropic nystagmus, consistent with horizontal cupulolithiasis. However, further audio-vestibular investigations and imaging confirmed a right vestibulopathy attributable to a schwannoma of the right vestibular nerve. This case report suggests that vestibular schwannoma should be considered as another potential mimicker of horizontal cupulolithiasis. PMID- 23665080 TI - A multi-site comparison of in vivo safety pharmacology studies conducted to support ICH S7A & B regulatory submissions. AB - INTRODUCTION: Parts A and B of the ICH S7 guidelines on safety pharmacology describe the in vivo studies that must be conducted prior to first time in man administration of any new pharmaceutical. ICH S7A requires a consideration of the sensitivity and reproducibility of the test systems used. This could encompass maintaining a dataset of historical pre-dose values, power analyses, as well as a demonstration of acceptable model sensitivity and robust pharmacological validation. During the process of outsourcing safety pharmacology studies to Charles River Laboratories, AstraZeneca set out to ensure that models were performed identically in each facility and saw this as an opportunity to review the inter-laboratory variability of these essential models. METHODS: The five in vivo studies outsourced were the conscious dog telemetry model for cardiovascular assessment, the rat whole body plethysmography model for respiratory assessment, the rat modified Irwin screen for central nervous system assessment, the rat charcoal meal study for gastrointestinal assessment and the rat metabolic cage study for assessment of renal function. Each study was validated with known reference compounds and data were compared across facilities. Statistical power was also calculated for each model. RESULTS: The results obtained indicated that each of the studies could be performed with comparable statistical power and could achieve a similar outcome, independent of facility. DISCUSSION: The consistency of results obtained from these models across multiple facilities was high thus providing confidence that the models can be run in different facilities and maintain compliance with ICH S7A and B. PMID- 23665082 TI - Intracranial hemorrhage due to intracranial hypertension caused by the superior vena cava syndrome. AB - We report a patient with intracranial hemorrhage secondary to venous hypertension as a result of a giant aortic pseudoaneurysm that compressed the superior vena cava and caused obstruction of the venous return from the brain. To our knowledge, this is the first patient reported to have an intracranial hemorrhage secondary to a superior vena cava syndrome. The condition appears to be caused by a reversible transient rise in intracranial pressure, as a result of compression of the venous return from the brain. Treatment consisted of surgery for the aortic pseudoaneurysm, which led to normalization of the intracranial pressure and resorption of the intracranial hemorrhage. PMID- 23665083 TI - Antibacterial properties of cyclodextrin-antiseptics-complexes determined by microplate laser nephelometry and ATP bioluminescence assay. AB - Cyclodextrins (CDs) are able to form inclusion complexes with other molecules, thereby, protecting these guest molecules from degradation, enhancing their biocompatibility or influencing their physiological distribution while retaining their activity. Here, antibacterial effects of CD-complexes with the antiseptics chlorhexidine diacetate (CHX), iodine (IOD) and polihexanide (PHMB) were determined using two different in vitro methods, microplate laser nephelometry and an ATP bioluminescence assay. Laser nephelometry is a direct method for monitoring and evaluating growth of micro-organisms by measurement of the turbidity of the solution. In contrast, the ATP bioluminescence assay determines specifically the amount of metabolic active bacterial cells. The antibacterial effects of CD-antiseptics-complexes were examined for Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus and Staphylococcus epidermidis and the results of both methods were compared in respect of calculated means of half maximal inhibitory concentrations (IC50) and statistical evaluated Pearson's correlation coefficients (r). It could be demonstrated that both methods showed a high comparability although they differ in the parameters tested. This study revealed that CD-complexes with CHX and PHMB were most effective against E. coli and the tested staphylococci. While CD-IOD complexes obtained high activity against K. pneumoniae, P. aeruginosa was distinctly more resistant compared to the other bacteria. PMID- 23665084 TI - Characterization of the semi-interpenetrated network based on collagen and poly(N isopropyl acrylamide-co-diethylene glycol diacrylate). AB - The study is devoted to the characterization of the semi-interpenetrating polymeric network (semi-IPN) structures, prepared as dual sensitive networks, based on poly(N-isopropyl acrylamide-co-diethylene glycol diacrylate) inserted into a collagen porous membrane with potential biomedical-applications. The pharmaceutical applications are related to the possibility of using the semi synthetic networks for inclusion, retention, transportation and release of drug molecules. The insertion and the homogeneity distribution of the drug into the polymeric network were evaluated by near infrared-chemical imaging (NIR-CI) technique. The drug release was investigated from the kinetically viewpoint in simulated biological environment by using UV-vis spectrophotometric technique. The zeta potential measurement results showed meaningful change of the electric potential of the network surface at the interfacial double layer with the environment in the interdependence with the network composition and environment characteristics. The biodegradable character of the semi-synthetic network, also presented, undergoes with tissue engineering request for achievement of tissue substituents. Texture analysis of the semi-IPN was realized in order to evidence the potential applications of the prepared compounds in tissue engineering. The adhesion properties reveal the possibility to control the surface adhesion by: network composition, the ratio between the polymer types, and the crosslinking degree of polymeric networks. The evaluation of the semi-IPN characteristics in medical terms, concerned the surface electrical charge, the loading, retention and release properties of an active compound, the adhesion properties and the effect of collagenase enzyme over the collagen fibres as component in semi-IPN, and from the pharmaceutical terms emphasizes the potential applications of the new polymeric semi-IPN networks. PMID- 23665085 TI - Evaluation of antioxidant efficacy of vanadium-3-hydroxyflavone complex in streptozotocin-diabetic rats. AB - Since 1985, when Heyliger et al., first demonstrated that oral administration of sodium orthovanadate (0.8mg/ml) to STZ induced diabetic rats resulted in normoglycemia, numerous extensive studies have been reported on the antidiabetic actions of vanadium. The acceptance of vanadium compounds as promising therapeutic antidiabetic drugs has been slowed due to the concern for chronic toxicity associated with vanadium accumulation. In order to circumvent the toxic effects of vanadium, a combinational approach wherein a novel V3HF complex was synthesized, characterized and its toxic as well as antidiabetic potential were evaluated in STZ diabetic rats. Experimental and clinical studies suggest that hyperglycemia-induced oxidative stress primarily contributes to the pathogenesis and progression of both primary as well as secondary complications of diabetes. It is possible to reduce the risks caused by excessive generation of free radicals by either enhancing the body's natural antioxidant defenses or by supplementing with proven antioxidants. The present study was aimed to study the role of V3HF complex on hyperglycemia mediated oxidative stress in STZ-diabetic rats and the results indicate that the complex improves pancreatic beta cell function. Histological and ultrastructural studies also evidenced that the complex protect the beta cells from hyperglycemia-induced oxidative stress. PMID- 23665086 TI - Mathematical methods to model rodent behavior in the elevated plus-maze. AB - The elevated plus maze is a widely used experimental test to study anxiety-like rodent behavior. It is made of four arms, two open and two closed, connected at a central area forming a plus shaped maze. The whole apparatus is elevated 50 cm from the floor. The anxiety of the animal is usually assessed by the number of entries and duration of stay in each arm type during a 5-min period. Different mathematical methods have been proposed to model the mechanisms that control the animal behavior in the maze, such as factor analysis, statistical inference on Markov chains and computational modeling. In this review we discuss these methods and propose possible extensions of them as a direction for future research. PMID- 23665087 TI - Filiform polyps and filiform polyp-like lesions are common in defunctioned or diverted colorectum resection specimens. AB - We describe filiform polyps (FPs) in a series of defunctioned rectums with diversion colitis. A 6-year search of all defunctioned rectal resection specimens revealed 8 cases with 17 macroscopically observed FPs. They occurred in 4 females and 4 males aged between 12 and 64 years. Four had defunctioning colostomies for ulcerative colitis, 3 for Crohn disease and 1 for diverticular disease. Multiple lesions were seen in 6 of 8 cases: 1 case having 4 FPs, 1 patient with 3 lesions, and 4 cases with 2 lesions. The FP varied in length from 4 to 11 mm; mean length was 7.8 mm. No evidence of mucosal prolapse was seen in any of the polypoid lesions. In 65 cases without grossly observed polypoid lesions, prominent mucosal polypoid projections in keeping with FP were seen in 47 cases. These were observed in nonulcerated sections and were histologically identical to the 17 macroscopically observed FPs ranging from 3 to 8 mm, and 3 to 5 such polypoid lesions were seen in 20 cases. We suggest that FP and FP-like lesions are commonly encountered in defunctioned resection specimens. PMID- 23665088 TI - Endocervical glandular involvement, multicentricity, and extent of the disease are features of high-grade cervical intraepithelial neoplasia. AB - This study aimed to evaluate the rate of endocervical glandular involvement, positive surgical margins, multicentricity, and disease extent between low-grade and high-grade cervical intraepithelial lesions after loop electrosurgical excision procedure (LEEP). Pathology medical records of patients who underwent LEEP were reviewed retrospectively. Patients with negative LEEP results were excluded. Loop electrosurgical excision procedure reports of patients with cervical intraepithelial neoplasia (CIN) 1, 2, and 3 were compared. There was no statistically significant difference between patients with CIN 1 (n=24), CIN 2 (n=27), and CIN 3 (n=64) when age and surgical margin positivity were considered. Endocervical glandular involvement, multicentricity, and disease extent were higher in patients with CIN 3 (P=.001, P=.002, and P=.001, respectively). In conclusion, we recommend that patients with endocervical glandular involvement, lesions involving more than two-thirds of the LEEP specimen, and multicentricity be followed up more closely. PMID- 23665089 TI - Differential expression of matrix metalloproteinase-13 in mucinous and nonmucinous colorectal carcinomas. AB - Colorectal carcinoma (CRC) is a major health problem all over the world. Mucinous CRCs are known to have a peculiar behavior and genetic derangements. This study aimed to investigate matrix metalloproteinase (MMP)-13 expression in mucinous and nonmucinous CRCs. We studied tumor tissue specimens from 150 patients with mucinous and nonmucinous CRC who underwent radical surgery from January 2007 to January 2012. High-density manual tissue microarrays were constructed using a modified mechanical pencil tip technique, and paraffin sections were submitted for immunohistochemistry using MMP-13. Statistical analysis was performed for clinical and pathological data of all studied cases together with MMP-13 expression in mucinous and nonmucinous groups. Mucinous carcinoma was significantly associated with young age, more depth of invasion, lymph node metastasis, and less peritumoral and intratumoral neutrophils. Nonmucinous carcinomas showed higher MMP-13 expression compared with mucinous carcinomas. Despite the negative or low expression of MMP-13, mucinous carcinomas had more depth of invasion and more frequency of lymph node metastasis than did nonmucinous carcinomas. PMID- 23665090 TI - Kinetics and mechanism of reactions of the drug tiopronin with platinum(IV) complexes. AB - Tiopronin, a synthetic thiol-containing drug being used in treatments of cystinuria and certain types of rare arthritis, is also a hepatoprotective and a detoxifying agent. Many analytical methods have been developed based on its redox chemistry with metal ions/complexes, but the kinetic and mechanistic aspects are poorly understood. In this work, the oxidation of tiopronin by cisplatin prodrug and a model compound, cis-[Pt(NH3)2Cl4] and trans-[PtCl2(CN)4](2-), was investigated. The oxidation kinetics was followed by a stopped-flow spectrophotometer over a wide pH range under the pseudo first-order conditions of [Tiopronin]?[Pt(IV)]. Time-resolved spectra were also recorded for both Pt(IV) complexes, enabling to establish an overall second-order rate law: d[Pt(IV)]/dt=k'[Tiopronin][Pt(IV)], where k' pertains to observed second-order rate constants. Under the kinetic conditions, tiopronin was oxidized to form the tiopronin-disulfide exclusively as identified by mass spectrometry. A reaction mechanism was proposed, involving parallel reductions of the Pt(IV) complexes by the three protolytic tiopronin species as rate-determining steps. The rate constants for the rate-determining steps were derived. The fully deprotonated tiopronin is about 4*10(4) more reactive than its corresponding thiol form for both Pt(IV) complexes; the huge reactivity difference orchestrates closely with the fact that the nucleophilicity of thiolate is much higher than the corresponding thiol. Hence, the attack of the sulfur atom in thiol/thiolate of tiopronin on the axially-coordinated chloride in the Pt(IV) complexes is nucleophilic in nature in the rate-determining steps, resulting in a bridge formation and a subsequent bridged electron-transfer. PMID- 23665091 TI - Adsorptive stripping voltammetry determination of methyldopa on the surface of a carboxylated multiwall carbon nanotubes modified glassy carbon electrode in biological and pharmaceutical samples. AB - In the present work, a simple carboxylated multiwall carbon nanotubes (CMWCNTs) modified glassy carbon electrode was developed for sensitive determination of methyldopa (MTD). The study of modified electrode and MTD electrochemical behavior at its surface was investigated employing SEM, adsorptive stripping voltammetry, electrochemical impedance spectroscopy and chronocoulometry. These studies show that the oxidation of MTD is facilitated at the surface of GCE which is casted with CMWCNTs and remarkably peak current enhanced comparing to the bare electrode due to its adsorption on the electrode surface. Also, because of the catalytic property of modified electrode onset potential decreased for oxidation of MTD. Under optimized conditions, the calibration curve was linear in two concentration ranges of 0.1-30 and 30.0-300.0 MUM with a detection limit of 0.08 MUM and relative standard deviation (R.S.D.%) lower than 3.0% (n=5). This modified electrode was used as a sensor for determination of MTD in pharmaceutical and human urine samples with satisfactory results. PMID- 23665092 TI - Preferential localization of Lactococcus lactis cells entrapped in a caseinate/alginate phase separated system. AB - This study aimed to entrap bioprotective lactic acid bacteria in a sodium caseinate/sodium alginate aqueous two-phase system. Phase diagram at pH=7 showed that sodium alginate and sodium caseinate were not miscible when their concentrations exceeded 1% (w/w) and 6% (w/w), respectively. The stability of the caseinate/alginate two-phase system was also checked at pH values of 6.0 and 5.5. Lactococcus lactis subsp. lactis LAB3 cells were added in a 4% (w/w) caseinate/1.5% (w/w) alginate two-phase system at pH=7. Fluorescence microscopy allowed to observe that the caseinate-rich phase formed droplets dispersed in a continuous alginate-rich phase. The distribution of bacteria in such a system was observed by epifluorescence microscopy: Lc. lactis LAB3 cells stained with Live/Dead((r)) Baclight kitTM were located exclusively in the protein phase. Since zeta-potential measurements indicated that alginate, caseinate and bacterial cells all had an overall negative charge at pH 7, the preferential adhesion of LAB cells was assumed to be driven by hydrophobic effect or by depletion phenomena in such biopolymeric systems. Moreover, LAB cells viability was significantly higher in the ternary mixture obtained in the presence of both caseinate and alginate than in single alginate solution. Caseinate/alginate phase separated systems appeared thus well suited for Lc. lactis LAB3 cells entrapment. PMID- 23665093 TI - Association between physical activity and metabolic syndrome among Malay adults in a developing country, Malaysia. AB - OBJECTIVES: Metabolic syndrome is a highly prevalent health problem within the adult population in developing countries. We aimed to study the association of physical activity levels and metabolic risk factors among Malay adults in Malaysia. DESIGN: Cross-sectional. METHODS: Body mass index, waist circumference, and systolic/diastolic blood pressure, fasting blood glucose, fasting triglyceride and high-density lipoprotein cholesterol levels were measured in 686 Malay participants (aged 35-74 years). Self-reported physical activity was obtained with the validated International Physical Activity Questionnaire (Malay version) and categorized into low, moderate or high activity levels. RESULTS: Individuals who were classified as overweight and obese predominated (65.6%). On the basis of the modified NCEP ATP III criteria, metabolic syndrome was diagnosed in 31.9% of all participants, of whom 46.1% were men and 53.9% were women. The prevalence of metabolic syndrome among participants with low, moderate or high activity levels was 13.3%, 11.7% and 7.0%, respectively (p<0.001). Statistically significant negative associations were found between a number of metabolic risk factors and activity categories (p<0.05). The odds ratios for metabolic syndrome in the moderate and high activity categories were 0.42 (95% CI: 0.27-0.65) and 0.52 (95% CI: 0.35-0.76), respectively, adjusted for gender. CONCLUSIONS: Moderate and high activity levels were each associated with reduced odds for metabolic syndrome independent of gender. Although a slightly lower prevalence of metabolic syndrome was associated with high activity than with moderate activity, potential health benefits were observed when moderate activity was performed. PMID- 23665094 TI - The "subjective" pupil old/new effect: is the truth plain to see? AB - Human memory is an imperfect process, prone to distortion and errors that range from minor disturbances to major errors that can have serious consequences on everyday life. In this study, we investigated false remembering of manipulatory verbs using an explicit recognition task and pupillometry. Our results replicated the "classical" pupil old/new effect as well as data in false remembering literature that show how items must be recognize as old in order for the pupil size to increase (e.g., "subjective" pupil old/new effect), even though these items do not necessarily have to be truly old. These findings support the strength-of-memory trace account that affirms that pupil dilation is related to experience rather than to the accuracy of recognition. Moreover, behavioral results showed higher rates of true and false recognitions for manipulatory verbs and a consequent larger pupil diameter, supporting the embodied view of language. PMID- 23665095 TI - Effects of nitric oxide on cell proliferation: novel insights. AB - Nitric oxide (NO) has been suggested to be a pathophysiological modulator of cell proliferation, cell cycle arrest, and apoptosis. In this context, NO can exert opposite effects under diverse conditions. Indeed, several studies have indicated that low relative concentrations of NO seem to favor cell proliferation and antiapoptotic responses and higher levels of NO favor pathways inducing cell cycle arrest, mitochondria respiration, senescence, or apoptosis. Here we report the effects of NO on both promotion and inhibition of cell proliferation, in particular in regard to cardiovascular disease, diabetes, and stem cells. Moreover, we focus on molecular mechanisms of action involved in the control of cell cycle progression, which include both cyclic guanosine monophosphate dependent and -independent pathways. This growing field may lead to broad and novel targeted therapies against cardiovascular diseases, especially concomitant type 2 diabetes, as well as novel bioimaging NO-based diagnostic tools. PMID- 23665096 TI - Rotor ablation: around and around we go. PMID- 23665097 TI - The assault on the left atrial appendage in perspective. PMID- 23665098 TI - Percutaneous left atrial appendage closure with the AMPLATZER cardiac plug device in patients with nonvalvular atrial fibrillation and contraindications to anticoagulation therapy. AB - OBJECTIVES: The aim of this study was to evaluate the results associated with left atrial appendage closure (LAAC) with the AMPLATZER Cardiac Plug (ACP) (St. Jude Medical, Minneapolis, Minnesota) in patients with nonvalvular atrial fibrillation and absolute contraindications to anticoagulation therapy. BACKGROUND: Few data exist on the late outcomes after LAAC in patients with absolute contraindications to warfarin. METHODS: A total of 52 patients with nonvalvular atrial fibrillation underwent LAAC with the ACP device in 7 Canadian centers. Most patients received short-term (1 to 3 months) dual-antiplatelet therapy after the procedure and single-antiplatelet therapy thereafter. A transesophageal echocardiography was performed in 74% of patients at the 6-month follow-up. No patient was lost to follow-up (>= 12 months in all patients). RESULTS: The mean age and median (interquartile range) CHADS2 score were 74 +/- 8 years and 3 (2 to 4), respectively. The procedure was successful in 98.1% of the patients, and the main complications were device embolization (1.9%) and pericardial effusion (1.9%), with no cases of periprocedural stroke. At a mean follow-up of 20 +/- 5 months, the rates of death, stroke, systemic embolism, pericardial effusion, and major bleeding were 5.8%, 1.9%, 0%, 1.9%, and 1.9%, respectively. The presence of mild peridevice leak was observed in 16.2% of patients at the 6-month follow-up as evaluated by transesophageal echocardiography. There were no cases of device thrombosis. CONCLUSIONS: In patients with nonvalvular atrial fibrillation at high risk of cardioembolic events and absolute contraindications to anticoagulation, LAAC using the ACP device followed by dual-/single-antiplatelet therapy was associated with a low rate of embolic and bleeding events after a mean follow-up of 20 months. No cases of severe residual leak or device thrombosis were observed at the 6-month follow up. PMID- 23665099 TI - Aggregate risk score based on markers of inflammation, cell stress, and coagulation is an independent predictor of adverse cardiovascular outcomes. AB - OBJECTIVES: This study sought to determine an aggregate, pathway-specific risk score for enhanced prediction of death and myocardial infarction (MI). BACKGROUND: Activation of inflammatory, coagulation, and cellular stress pathways contribute to atherosclerotic plaque rupture. We hypothesized that an aggregate risk score comprised of biomarkers involved in these different pathways-high sensitivity C-reactive protein (CRP), fibrin degradation products (FDP), and heat shock protein 70 (HSP70) levels-would be a powerful predictor of death and MI. METHODS: Serum levels of CRP, FDP, and HSP70 were measured in 3,415 consecutive patients with suspected or confirmed coronary artery disease (CAD) undergoing cardiac catheterization. Survival analyses were performed with models adjusted for established risk factors. RESULTS: Median follow-up was 2.3 years. Hazard ratios (HRs) for all-cause death and MI based on cutpoints were as follows: CRP >=3.0 mg/l, HR: 1.61; HSP70 >0.625 ng/ml, HR; 2.26; and FDP >=1.0 MUg/ml, HR: 1.62 (p < 0.0001 for all). An aggregate biomarker score between 0 and 3 was calculated based on these cutpoints. Compared with the group with a 0 score, HRs for all-cause death and MI were 1.83, 3.46, and 4.99 for those with scores of 1, 2, and 3, respectively (p for each: <0.001). Annual event rates were 16.3% for the 4.2% of patients with a score of 3 compared with 2.4% in 36.4% of patients with a score of 0. The C statistic and net reclassification improved (p < 0.0001) with the addition of the biomarker score. CONCLUSIONS: An aggregate score based on serum levels of CRP, FDP, and HSP70 is a predictor of future risk of death and MI in patients with suspected or known CAD. PMID- 23665101 TI - Radiation dose in close proximity to patients after myocardial perfusion imaging: potential implications for hospital personnel and the public. PMID- 23665100 TI - Effects of bariatric surgery on human small artery function: evidence for reduction in perivascular adipocyte inflammation, and the restoration of normal anticontractile activity despite persistent obesity. AB - OBJECTIVES: The aim of this study was to investigate the effects of bariatric surgery on small artery function and the mechanisms underlying this. BACKGROUND: In lean healthy humans, perivascular adipose tissue (PVAT) exerts an anticontractile effect on adjacent small arteries, but this is lost in obesity associated conditions such as the metabolic syndrome and type II diabetes where there is evidence of adipocyte inflammation and increased oxidative stress. METHODS: Segments of small subcutaneous artery and perivascular fat were harvested from severely obese individuals before (n = 20) and 6 months after bariatric surgery (n = 15). Small artery contractile function was examined in vitro with wire myography, and perivascular adipose tissue (PVAT) morphology was assessed with immunohistochemistry. RESULTS: The anticontractile activity of PVAT was lost in obese patients before surgery when compared with healthy volunteers and was restored 6 months after bariatric surgery. In vitro protocols with superoxide dismutase and catalase rescued PVAT anticontractile function in tissue from obese individuals before surgery. The improvement in anticontractile function after surgery was accompanied by improvements in insulin sensitivity, serum glycemic indexes, inflammatory cytokines, adipokine profile, and systolic blood pressure together with increased PVAT adiponectin and nitric oxide bioavailability and reduced macrophage infiltration and inflammation. These changes were observed despite the patients remaining severely obese. CONCLUSIONS: Bariatric surgery and its attendant improvements in weight, blood pressure, inflammation, and metabolism collectively reverse the obesity-induced alteration to PVAT anticontractile function. This reversal is attributable to reductions in local adipose inflammation and oxidative stress with improved adiponectin and nitric oxide bioavailability. PMID- 23665102 TI - Initial reactivity and magnitude of the acute stress response associated with personality in wild great tits (Parus major). AB - Phenotypic correlations, such as those between functionally distinct behavioral traits, can emerge through the action of selection on individual traits, on trait combinations, and through pleiotropic mechanisms. Steroid hormones are known to have pleiotropic effects on a suite of behavioral and physiological traits, including stable individual differences in coping with stress. Characterizing the stress axis in relation to personality, however, has typically focused on estimating baseline and peak levels of glucocorticoids, principally in captive animals. In contrast, the reactivity of the stress response-how quickly it turns on and persists-may better indicate the ability of an individual to cope with challenges, particularly in free-living animals. Using wild great tits (Parus major) we tested the hypothesis that cautious individuals respond to a standardized stressor with a more reactive stress response compared to bolder individuals. Wild birds were captured and tested for exploration behavior in a novel environment-an operational measure of personality in this species-and assessed separately for their glucocorticoid response to a standardized stressor. Slower explorers exhibited a greater elevation in glucocorticoid levels within the first three minutes after capture. Further, slower explorers reached a higher maximum CORT concentration and had higher total exposure to glucocorticoids during the stressor period. These data provide evidence that the temporal reactivity of the endocrine stress response, specifically its speed and magnitude, is associated with stable behavioral traits in free-living animals. PMID- 23665103 TI - Development of a multiplex gene expression assay for components of the endocrine growth axis in coho salmon. AB - This study explores the efficacy of the Quantigene plex (QGP) technology for measuring a panel of endocrine growth-related transcripts in coho salmon, Oncorhynchus kisutch. The QGP technology permits the simultaneous quantification of multiple targeted mRNAs within a single tissue homogenate using sequence specific probes and requires no reverse transcription (RT) or amplification as is required for RT-quantitative PCR (RT-qPCR). Using liver homogenates from coho salmon under fed and fasted conditions, we compared the detectable fold differences of steady-state mRNA levels between the QGP and probe-based RT-qPCR assays for insulin-like growth factors (igf1 and igf2), insulin-like growth factor binding proteins (igfbp1b, igfbp2a, and igfbp2b), somatolactin receptor (slr), and growth hormone receptors (ghr1 and ghr2). Significant, positive correlations for all genes between the two assays were found. In addition, the relatively low variance of results from the QGP assay suggests that this is a suitable method for a comprehensive analysis of endocrine growth-related transcripts and could potentially be used to develop assays for other gene networks in teleosts. PMID- 23665104 TI - Induced erythropoiesis during acute anemia in Atlantic salmon: a transcriptomic survey. AB - Anemia is a common pathophysiological response to stressors, malnutrition and infections in salmonid fish. In order to improve our understanding of the molecular mechanisms and markers associated with induced erythropoiesis (EP) during acute anemia in Atlantic salmon (Salmo salar L.), we performed transcriptome analysis of fish injected with the hemolytic compound phenylhydrazine (PHZ). Treatment with a low dose of PHZ resulted in moderate but significant reduction of hematocrit (Hct) and increased transcription of cardiac erythropoietin (epo) at 2 days post challenge (dpc), and epo receptor (epor) in spleen from 2 to 4 dpc. Oligonucleotide microarrays were used to characterize the events of EP in the spleen, an important organ for expansive EP during acute erythropoietic stress in rodents, and these were compared to gene expression profiles of untreated mature red blood cells (RBC) in order to search for erythroid-specific genes. Splenic responses suggested a prevalence of protective mechanisms at the first stage, characterized by induced xenobiotic metabolism and responses to oxidative and protein stress. Erythroid-specific regulation was evident at 2 dpc and enhanced by 4 dpc, and gene expression profiles witnessed a rapid establishment of RBC phenotype although Hct levels remained low. A large group of genes showed a strong correlation to globins by expression profiles. In addition to epor this included genes of heme and iron metabolism, scavengers of free radicals and chaperones, channels and transporters, markers of erythrocytes, regulators of proliferation and cell cycle arrest and many genes with unidentified roles in RBC differentiation. Induced EP in spleen was characterized by specific features, such as upregulation of innate antiviral immune genes and sustained high expression of proapoptotic genes including caspases. Transcriptome changes suggested an association between EP and suppression of several developmental programs including adaptive immune responses. In conclusion, acute hemolysis and resulting anemia rapidly induced EP in the spleen of Atlantic salmon, which showed both common characteristics for all vertebrates as well as fish-specific properties. PMID- 23665105 TI - Transcriptomic profiling of progesterone in the male fathead minnow (Pimephales promelas) testis. AB - P4 is a hormone with diverse functions that include roles in reproduction, growth, and development. The objectives of this study were to examine the effects of P4 on androgen production in the mature teleost testis and to identify molecular signaling cascades regulated by P4 to improve understanding of its role in male reproduction. Fathead minnow (FHM) testis explants were treated in vitro with two concentrations of P4 (10(-8) and 10(-6) M) for 6 and 12 h. P4 significantly increased testosterone (T) production in the FHM testis but did not affect 11-ketotestosterone. Gene network analysis revealed that insulin growth factor (Igf1) and tumor necrosis factor receptor (Tnfr) signaling was significantly depressed with P4 treatment after 12h. There was also a 20% increase in a gene network for follicle-stimulating hormone secretion and an 18% decrease in genes involved in vasopressin signaling. Genes in steroid metabolism (e.g. star, cyp19a, 11bhsd) were not significantly affected by P4 treatments in this study, and it is hypothesized that pre-existing molecular machinery may be more involved in the increased production of T rather than the de novo expression of steroid-related transcripts and receptors. There was a significant decrease in prostaglandin E synthase 3b (cytosolic) (ptges3b) after treatment with P4, suggesting that there is cross talk between P4 and prostaglandin pathways in the reproductive testis. P4 has a role in regulating steroid production in the male testis and may do so by modulating gene networks related to endocrine pathways, such as Igf1, Tnfr, and vasopressin. PMID- 23665106 TI - Synthesis and antiproliferative activity of 4-substituted-piperazine-1 carbodithioate derivatives of 2,4-diaminoquinazoline. AB - A novel series of 4-substituted-piperazine-1-carbodithioate derivatives of 2,4 diaminoquinazoline were synthesized and tested for their antiproliferative activities against five human cancer cell lines including A549 (lung cancer), MCF 7 (breast adenocarcinoma), HeLa (cervical carcinoma), HT29 and HCT-116 (colorectal cancer). Most of the synthesized compounds showed broad spectrum antiproliferative activity (IC50 1.47-11.83 MUM), of which 8f, 8m and 8q were the most active members with IC50 values in the range of 1.58-2.27, 1.84-3.27 and 1.47-4.68 MUM against five cancer cell lines examined, respectively. Further investigations revealed that compounds 8f, 8m and 8q exhibited weak inhibition against dihydrofolate reductase and no activity against thymidylate synthase, while induced DNA damage and activated the G2/M checkpoint in HCT-116 cells. PMID- 23665108 TI - Homocysteine induces cerebral endothelial cell death by activating the acid sphingomyelinase ceramide pathway. AB - Homocysteine (Hcy) levels may rise after a stroke, but the mechanism of Hcy induced cerebral endothelial cell (CEC) dysfunction has not been explored. In this study we examined the role of the acid sphingomyelinase (Asm)-ceramide pathway in the molecular mechanism of Hcy-induced CEC dysfunction. Murine CECs were prepared from fresh mouse brains. CECs were treated with 50-500 MUM Hcy and 30-100 MUM C2-ceramide for 48 h. Sphingomyelinase assays were performed to determine Asm activity. Quantitative assessments of cell survival and death by the MTT reduction and LDH release were conducted. Treatment of murine CECs with Hcy and ceramide caused cell death in a dose-dependent manner as determined by LDH and MTT assays. 250 MUM Hcy and 50 MUM C2-ceramide caused 50% cell death. Hcy induced murine CEC death also occurred in a time-dependant manner with substantial cell death noted as early as 24h after Hcy exposure. C2-ceramide induced murine CEC death occurred earlier than Hcy-induced cell death by about 18h. Hcy treatment increased Asm activity and intracellular ceramide accumulation. This study demonstrated that Hcy and C2-ceramide can cause murine CEC death. Hcy induces CEC death possibly by activating the Asm-ceramide pathway. PMID- 23665107 TI - A proposal for refining the forced swim test in Swiss mice. AB - The forced swim test (FST) is a preclinical test to the screening of antidepressants based on rats or mice behaviours, which is also sensitive to stimulants of motor activity. This work standardised and validated a method to register the active and passive behaviours of Swiss mice during the FST in order to strength the specificity of the test. Adult male Swiss mice were subjected to the FST for 6 min without any treatment or after intraperitoneal injection of saline (0.1 ml/10 g), antidepressants (imipramine, desipramine, or fluoxetine, 30 mg/kg) or stimulants (caffeine, 30 mg/kg or apomorphine, 10mg/kg). The latency, frequency and duration of behaviours (immobility, swimming, and climbing) were scored and summarised in bins of 6, 4, 2 or 1 min. Parameters were first analysed using Principal Components Analysis generating components putatively related to antidepressant (first and second) or to stimulant effects (third). Antidepressants and stimulants affected similarly the parameters grouped into all components. Effects of stimulants on climbing were better distinguished of antidepressants when analysed during the last 4 min of the FST. Surprisingly, the effects of antidepressants on immobility were better distinguished from saline when parameters were scored in the first 2 min. The method proposed here is able to distinguish antidepressants from stimulants of motor activity using Swiss mice in the FST. This refinement should reduce the number of mice used in preclinical evaluation of antidepressants. PMID- 23665109 TI - The adhesive skin exudate of Notaden bennetti frogs (Anura: Limnodynastidae) has similarities to the prey capture glue of Euperipatoides sp. velvet worms (Onychophora: Peripatopsidae). AB - The dorsal adhesive secretion of the frog Notaden bennetti and the prey-capture "slime" ejected by Euperipatoides sp. velvet worms look and handle similarly. Both consist largely of protein (55-60% of dry weight), which provides the structural scaffold. The major protein of the onychophoran glue (Er_P1 for Euperipatoides rowelli) and the dominant frog glue protein (Nb-1R) are both very large (260-500 kDa), and both give oddly "turbulent" electrophoresis bands. Both major proteins, which are rich in Gly (16-17 mol%) and Pro (7-12 mol%) and contain 4-hydroxyproline (Hyp, 4 mol%), have the composition of intrinsically unstructured proteins. Their propensities for elastomeric or amyloid structures are discussed in light of Er_P1's large content of intrinsically disordered long tandem repeats. The low carbohydrate content of both glues is consistent with conventional protein glycosylation, which in the N. bennetti adhesive was explored by 2D PAGE. The N-linked sugars of Nb-1R appear to prevent inappropriate self-aggregation. Some peptide sequences from Nb-1R are presented. Overall, there are enough similarities between the frog and the velvet worm glues to suspect that they employ related mechanisms for setting and adhesion. A common paradigm is proposed for amphibian and onychophoran adhesives, which, if correct, points to convergent evolution. PMID- 23665110 TI - Peripheral antinociceptive efficacy and potency of a novel opioid compound 14-O MeM6SU in comparison to known peptide and non-peptide opioid agonists in a rat model of inflammatory pain. AB - This study compared the peripheral analgesic effects of a novel opioid agonist 14 O-methylmorphine-6-O-sulfate (14-O-MeM6SU), to that of non-peptide (morphine, fentanyl) and peptide opioid agonists (Met-enkephalin; met-ENK and beta endorphin; beta-END) in a model of localized inflammatory pain evoked by intraplantar (i.pl.) Freund's complete adjuvant (FCA). Nociceptive responses to local opioid agonists were measured by pressure paw-withdrawal procedures. In addition, the antinociceptive efficacy and potency of these test compounds in vivo was compared to that in vitro using the rat vas deferens (RVD) bioassay. Intraplantar 14-O-MeM6SU (0.32-2.53 nmol/rat), morphine (14.95-112.15 nmol/rat), fentanyl (0.19-2.36 nmol/rat), met-ENK (0.10-10 nmol/rat) and beta-END (0.77-5.00 nmol/rat) dose dependently increased paw pressure thresholds exclusively in inflamed hindpaws. At higher doses analgesic effects were also seen in noninflamed paws for 14-O-MeM6SU, morphine and fentanyl but not for met-ENK or beta-END. The maximal possible local analgesic effect (%) measured in inflamed paws was 50.6 +/- 2.7, 18.23 +/- 1.78, 37.44 +/- 2.17, 36.00 +/- 1.43, and 40.69 +/- 0.91 for 14-O-MeM6SU, morphine, fentanyl, met-ENK and beta-END, respectively. Interestingly, i.pl. administered opioid peptides met-ENK and beta-END displayed a peripheral analgesic ceiling effect. This local antinociception was antagonized by co-administered opioid antagonist naloxone-methiodide (NAL-M). Similar to the analgesic testing, the RVD showed the following efficacy order of the test compounds: 14-O-MeM6SU>beta-END>fentanyl>met-ENK?morphine. Taken together, 14-O MeM6SU was more potent than morphine, fentanyl and met-ENK and beta-END and displayed superiority in the maximum antinociceptive effects. The superiority of local antinociceptive effects of 14-O-MeM6SU might be due to both pharmacodynamic and pharmacokinetic factors. PMID- 23665111 TI - Pregnenolone sulfate modulates glycinergic transmission in rat medullary dorsal horn neurons. AB - The neurosteroid pregnenolone sulfate (PS), a representative excitatory neuromodulator, has a variety of neuropharmacological actions, such as memory enhancement and convulsant effects. In this study, the effects of PS on glycinergic transmission, such as glycinergic spontaneous miniature inhibitory postsynaptic currents (mIPSCs), were investigated in acutely isolated medullary dorsal horn neurons by use of a conventional whole-cell patch-clamp technique. PS significantly increased the frequency but decreased the amplitude of glycinergic mIPSCs in a concentration-dependent manner. PS also accelerated the decay time constant of glycinergic mIPSCs. The PS-induced decrease in mIPSC amplitude was due to the direct postsynaptic inhibition of glycine receptors because PS inhibited the glycine-induced Cl(-) currents in a noncompetitive manner. The PS induced increase in mIPSC frequency was not due to the activation of alpha7 nicotinic acetylcholine, NMDA, sigma1 receptors and voltage-dependent Ca(2+) channels, which are known to be molecular targets of PS. On the other hand, the PS-induced increase in mIPSC frequency was completely attenuated either in the Ca(2+)-free external solution or in the presence of transient receptor potential (TRP) channel blockers, suggesting that PS elicits an increase in Ca(2+) concentration within glycinergic nerve terminals via the activation of putative TRP channels. The PS-mediated modulation of glycinergic synaptic transmission, such as the enhancement of presynaptic glycine release and direct inhibition of postsynaptic glycine receptors, might have a broad impact on the excitability of medullary dorsal horn neurons and therefore affect the processing of nociceptive transmission from orofacial tissues. PMID- 23665112 TI - Secalonic acid A protects dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+)-induced cell death via the mitochondrial apoptotic pathway. AB - Secalonic acid A (SAA) is a natural compound found in marine fungi. We have reported that SAA can attenuate the cytotoxicity of colchicine in rat cortical neurons. Whether SAA can also inhibit the neurotoxicity of 1-methyl-4 phenylpyridinium (MPP(+)) in dopaminergic neurons has not been investigated. Here, we show that pretreatment with 1 MUM SAA significantly rescued tyrosine hydroxylase (TH)-positive neurons from MPP(+)-induced neurotoxicity in primary dopaminergic neuron culture. Moreover, SAA at doses of 0.15 mg/kg and 0.75 mg/kg increased the number of dopaminergic neurons and upregulated striatal dopamine in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mice experiments. We also show that SAA significantly attenuated cytotoxicity induced by 2.5 mM MPP(+) in SH-SY5Y cells. These results indicate that the activation of JNK, p38 mitogen activated protein kinase (MAPK) and caspase-3 during apoptosis triggered by MPP(+) could be suppressed by SAA; on the other hand, an MPP(+)-induced increase in the expression of Bax in SH-SY5Y cells was blocked by SAA. These results indicate that inhibition of the phosphorylation of JNK and p38 MAPK, down-regulation of Bax expression, and suppression of caspase-3 activation are involved in the protective effects of SAA against MPP(+) toxicity in SH-SY5Y cells. SAA may rescue dopaminergic neurons from MPP(+)-induced cell death through the mitochondrial apoptotic pathway. PMID- 23665114 TI - HZ08 inhibits the multi-drug resistance on multiple sites as the substrate of p glycoprotein. AB - Overexpression of p-glycoprotein (p-gp) leads to the production of multi-drug resistance (MDR) which could discharge various anti-tumor chemicals with structural heterogeneity. HZ08, a novel tetrahydroisoquinoline derivate, was discovered to modulate the MDR. What was confirmed is its definite inhibition of multi-drug resistance caused by p-gp and its promotion for the intracellular cytotoxins accumulation in the previous study. In order to explore whether HZ08 is the substrate of p-gp and on which sites it exerts its function, RNAi to mdr1 was introduced and the interaction between HZ08 and some classic agents (verapamil, rhodamine 123) with clearly binding sites was also investigated. Experimental results revealed that HZ08 is the most probable substrate of p-gp and may share the same modulation sites located at the p-gp with verapamil. Data obtained also indicated that there is a common binding site shared by rhodamine 123 and HZ08, but negative competition showed between HZ08 and adriamycin. In conclusion, HZ08 may be the substrate of p-gp and acts as a multiple target modulator to invert the efflux function of p-gp. PMID- 23665113 TI - PAC1 receptors mediate positive chronotropic responses to PACAP-27 and VIP in isolated mouse atria. AB - PACAP and VIP have prominent effects on cardiac function in several species, but little is known about their influence on the murine heart. Accordingly, we evaluated the expression of PACAP/VIP receptors in mouse heart and the response of isolated atria to peptide agonists. Quantitative PCR demonstrated that PAC1, VPAC1, and VPAC2 receptor mRNAs are present throughout the mouse heart. Expression of all three receptor transcripts was low, PAC1 being the lowest. No regional differences in expression were detected for individual receptor mRNAs after normalization to L32. Pharmacological effects of PACAP-27, VIP, and the selective PAC1 agonist maxadilan were evaluated in isolated, spontaneously beating atria from C57BL/6 mice of either sex. Incremental additions of PACAP-27 at 1 min intervals caused a concentration-dependent tachycardia with a logEC50= 9.08 +/- 0.15 M (n=7) and a maximum of 96.3 +/- 5.9% above baseline heart rate. VIP and maxadilan also caused tachycardia but their potencies were about two orders of magnitude less. Increasing the dosing interval to 5 min caused a leftward shift of the concentration-response curve to maxadilan but no changes in the curves for PACAP-27 or VIP. Under this condition, neither the potency nor the efficacy of maxadilan differed from those of PACAP-27. Neither PACAP-27 nor maxadilan caused tachyphylaxis, and maximal responses to maxadilan were maintained for at least 2 h. We conclude that all three VIP/PACAP family receptors are expressed by mouse cardiac tissue, but only PAC1 receptors mediate positive chronotropic responses to PACAP-27 and VIP. PMID- 23665115 TI - BK viremia precedes hemorrhagic cystitis in children undergoing allogeneic hematopoietic stem cell transplantation. AB - BK virus is associated with hemorrhagic cystitis after hematopoietic stem cell transplantation (HSCT), although evidence supporting a causal relationship remains limited. Although BK viruria is common after HSCT, BK viremia may better predict clinically significant cystitis, similar to its predictive value for nephropathy after kidney transplantation. We hypothesized that BK viremia would precede hemorrhagic cystitis in a cohort of 88 consecutive children prospectively enrolled to originally study thrombotic microangiopathy in the first 100 days after allogeneic HSCT. Cox regression models with time-varying covariates assessed the association between different BK viremia cutoffs and the development of hemorrhagic cystitis, defined as at least macroscopic hematuria. Subjects with a peak plasma BK viral load 1 to 9999 copies/mL had an adjusted hazard ratio of 4.2 (95% confidence interval (CI), 1.3 to 13.7) for the development of hemorrhagic cystitis. Those with peak BK viremia >100,000 copies/mL had an adjusted hazard ratio of 116.8 (95% CI, 12 to 1136) for cystitis. Other independent risk factors for hemorrhagic cystitis included age >7 years and HHV-6 viremia. Neither graft-versus-host disease nor achieving engraftment increased the risk for cystitis. If therapeutic strategies are found to be effective, these observations may support screening for BK viremia after HSCT, as currently recommended for other DNA viruses. PMID- 23665116 TI - A mechanism for effective cell-seeding in rigid, microporous substrates. AB - Seeding cells into porous ceramic substrates has been shown to improve outcomes in surgical repair of large bone defects, but the physics underlying cellular ingress into such scaffolds remains elusive. This paper demonstrates capillary forces as a novel, yet simple, self-loading or self-seeding mechanism for rigid, microporous substrates. Capillary forces were found to draw cells through a microporous network with interconnections smaller than the diameter of the cells in suspension. Work here emphasizes CaP-based bone scaffolds containing both macroporosity (>100MUm) and microporosity (5-50MUm); these have been shown to improve bone formation in vivo as compared to their macroporous counterparts and also performed better than microporous scaffolds containing BMP-2 by some measures of bone regeneration. We hypothesize that capillary force driven self seeding in both macro- and micropores may underlie this improvement, and present a mathematical model and experiments that support this hypothesis. The cell localization and penetration depth within these two-dimensional substrates in vitro depends upon both the cell type (size and stiffness) and the capillary forces generated by the microstructure. Additional experiments showing that cell penetration depth in vitro depends on cell size and stiffness suggest that microporosity could be tailored to optimize cell infiltration in a cell-specific way. Endogenous cells are also drawn into the microporous network in vivo. Results have important implications for design of scaffolds for the healing of large bone defects, and for controlled release of drugs in vivo. PMID- 23665117 TI - Micelle formation of sodium hyodeoxycholate. AB - Sodium hyodeoxycholate (NaHDC) is the main component of hog bile salts, which play a role in the absorption of sparingly soluble materials in the intestinal solution. The biosurfactant has an amphiphilic molecular structure, similar to that of ursodeoxycholate from bear gallbladder. Micelle formation from hyodeoxycholate was studied at 308.2K using pyrene fluorescence probe to determine critical micelle concentrations (cmc) at various NaCl concentrations. The change in the fluorescence spectrum peak ratios with NaHDC concentration indicated two steps for bile salt aggregation. The first step was the formation of small micelles (cmc) at 5mM, and the second step was the formation of stable aggregates at 14 mM in aqueous solution. The aggregation of hyodeoxycholate, analyzed using the stepwise association model, was found to grow its aggregation number from 4 to 7 with increasing concentration. The aggregation number in aqueous solution was also confirmed by the static light scattering method. The average measured aggregation number of the micelles was 6.7. The micellar size was relatively small as measured by either method, but it was covered by general aggregation number of human bile salts. The degree of counterion binding to the micelles, determined using a sodium ion-selective electrode, was ca. 0.5 for the NaHDC micelles. This value was relatively high among typical bile salts. Moreover, the solubilization capacity of the NaHDC micelles was assessed using cholesterol. It became clear that NaHDC micelles hardly solubilized cholesterol compared to typical human bile salts. The maximum solubilization by NaHDC was equivalent only to that by sodium ursodeoxycholate. PMID- 23665118 TI - In vitro catheter and sorbent-based method for clearance of radiocontrast material during cerebral interventions. AB - BACKGROUND: Contrast-induced acute kidney injury is a severe condition resulting from the use of radiology contrast in patients with predisposing factors. HYPOTHESIS: We hypothesized that a novel system including a device containing polymer resin sorbent beads and a custom-made suctioning catheter could efficiently remove contrast from an in vitro novel model of circulatory system (MOCS) mimicking the cerebral circulation. METHODS: A custom-made catheter was built and optimized for cerebral venous approach. The efficiency of a system made of a polymer resin sorbent beads column (CST 401, Cytosorbents) and this particular catheter was tested in the MOCS running a solution composed of 0.9% saline and radio-contrast. During two series of 18 cycles of first-pass experiments we assessed the catheter's suctioning efficiency and the system's ability to clear radio-contrast injected into the MOCS's cerebral arterial segment. We also assessed the functioning and reliability of the MOCS. RESULTS: Mean suctioning efficiency of the catheter was 84% +/- 24%. The polymer sorbent column contrast removal rate was initially 96% and gradually decreased with subsequent cycles in a linear fashion during an experiment lasting approximately 90 minutes. The MOCS had a reliability of 0.9946*min(-1) where 1 * min(-1) was the optimum value. CONCLUSION: A system including a polymer resin sorbent beads column and a custom-made suctioning catheter had an excellent initial efficiency in quickly removing contrast from an artificial MOCS mimicking the cerebral circulation. MOCS is an inexpensive and relatively reliable custom-made system that can be used for training or testing purposes. PMID- 23665119 TI - Automated home cage assessment shows behavioral changes in a transgenic mouse model of spinocerebellar ataxia type 17. AB - Spinocerebellar Ataxia type 17 (SCA17) is an autosomal dominantly inherited, neurodegenerative disease characterized by ataxia, involuntary movements, and dementia. A novel SCA17 mouse model having a 71 polyglutamine repeat expansion in the TATA-binding protein (TBP) has shown age related motor deficit using a classic motor test, yet concomitant weight increase might be a confounding factor for this measurement. In this study we used an automated home cage system to test several motor readouts for this same model to confirm pathological behavior results and evaluate benefits of automated home cage in behavior phenotyping. Our results confirm motor deficits in the Tbp/Q71 mice and present previously unrecognized behavioral characteristics obtained from the automated home cage, indicating its use for high-throughput screening and testing, e.g. of therapeutic compounds. PMID- 23665120 TI - ROS production and NF-kappaB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. AB - The Adenomatous Polyposis Coli (APC) gene is mutated in the majority of colorectal cancers (CRCs). Loss of APC leads to constitutively active WNT signaling, hyperproliferation, and tumorigenesis. Identification of pathways that facilitate tumorigenesis after APC loss is important for therapeutic development. Here, we show that RAC1 is a critical mediator of tumorigenesis after APC loss. We find that RAC1 is required for expansion of the LGR5 intestinal stem cell (ISC) signature, progenitor hyperproliferation, and transformation. Mechanistically, RAC1-driven ROS and NF-kappaB signaling mediate these processes. Together, these data highlight that ROS production and NF-kappaB activation triggered by RAC1 are critical events in CRC initiation. PMID- 23665122 TI - Time between the first and second operations for staged total knee arthroplasties when the interval is determined by the patient. AB - BACKGROUND: The purpose of this study was to evaluate the interval between the first and second operations for staged total knee arthroplasties (TKAs) in patients with bilateral knee osteoarthritis. Depending on satisfactory preoperative health status, the patients determined the timing of the second operation. We also analysed correlations between the interval and patient characteristics. METHODS: Eighty-six patients with bilateral knee osteoarthritis were analysed. The mean follow-up time from the first TKA was 96 months. The side of the first TKA was chosen by the patients. The timing of the second TKA was determined by the patients, depending on their perceived ability to tolerate the additional pain and limitations to activities of daily living. RESULTS: The median interval between the first and second operations was 12.5 months, with a range of 2 to 113 months. In 43 (50%) patients, the interval was <12 months. There was no difference in the interval between females and males (p=0.861), and no correlation between the interval and body mass index or age. There was weak correlation between the year of the first TKA and the interval (R=-0.251, p=0.020), with the interval getting significantly shorter as the years progressed (p=0.032). CONCLUSIONS: The median interval between the first and second operations in patients who underwent staged TKAs for bilateral knee osteoarthritis was about 1 year. The results of the current study may help patients and physicians to plan effective treatment strategies for staged TKAs. LEVELS OF EVIDENCE: Level II. PMID- 23665123 TI - Post-operative complications following primary ACL reconstruction using allogenic and autogenic soft tissue grafts: increased relative morbidity risk is associated with increased graft diameter. AB - BACKGROUND: The purpose of this study is to compare the risk of peri-operative complication events associated with allogenic and autogenic grafts during routine follow-up for six months after primary arthroscopic anterior cruciate ligament (ACL) reconstruction surgery. METHODS: A retrospective cohort study identified patients that underwent ACL reconstruction via an arthroscopically assisted single tunnel technique. Fixation was primarily cortical suspension (endobutton) from the femora and bicortical fixation (Washer-loc) in the tibia. Patients were monitored for six months following surgery. Morbidity was defined as complications during this period requiring medical or surgical intervention. Risk of complications was compared according to tissue type and patient characteristics. The Cochran-Mantel-Haenszel method was applied to estimate risk ratios (RR) and confidence intervals (CI) as the measure of association between graft type and morbidity risk. RESULTS: The cohort included 413 eligible patients. Sixty six percent received allograft tissue, while the remainder received autograft tissue. Morbidity risk was 7.0% among patients receiving allograft tissue and 2.8% among patients receiving autograft tissue. Allograft demonstrated elevated risk of complication versus autograft (RR=2.3 (95% CI: 0.9 7.2)), though the data are of borderline significance (p=0.11). Complications were associated with larger graft diameter in comparison to patients who experienced no complication (9.0+/-1.2 mm v. 8.4+/-1.0mm, p=0.005). CONCLUSION: The relative morbidity risk was about two-fold greater among patients receiving allograft tissue. Regardless of tissue type, graft size was larger among patients who experienced a complication. LEVEL OF EVIDENCE: Level III. PMID- 23665121 TI - Genome-wide chromatin interactions of the Nanog locus in pluripotency, differentiation, and reprogramming. AB - The chromatin state of pluripotency genes has been studied extensively in embryonic stem cells (ESCs) and differentiated cells, but their potential interactions with other parts of the genome remain largely unexplored. Here, we identified a genome-wide, pluripotency-specific interaction network around the Nanog promoter by adapting circular chromosome conformation capture sequencing. This network was rearranged during differentiation and restored in induced pluripotent stem cells. A large fraction of Nanog-interacting loci were bound by Mediator or cohesin in pluripotent cells. Depletion of these proteins from ESCs resulted in a disruption of contacts and the acquisition of a differentiation specific interaction pattern prior to obvious transcriptional and phenotypic changes. Similarly, the establishment of Nanog interactions during reprogramming often preceded transcriptional upregulation of associated genes, suggesting a causative link. Our results document a complex, pluripotency-specific chromatin "interactome" for Nanog and suggest a functional role for long-range genomic interactions in the maintenance and induction of pluripotency. PMID- 23665124 TI - Pain control after primary total knee replacement. A prospective randomised controlled trial of local infiltration versus single shot femoral nerve block. AB - BACKGROUND: We report a prospective blinded randomised trial of local infiltration versus femoral nerve block in patients undergoing primary total knee replacement (TKR), in accordance with the CONSORT statement 2010. METHODS: Fifty patients in a teaching hospital were consented for the study. The study arms were intraoperative local anaesthesia (150ml 0.2% ropivacaine/1ml 1:1000 adrenaline/30mg ketolorac) and femoral nerve block (30ml 0.2% ropivacaine) with a primary outcome of pain score at 4h post operatively. Secondary outcomes were pain at 2h, pain scores before and after physiotherapy on day one, total opiate administered, time to physiotherapy goals and length of stay. Randomisation was by sealed envelope. The assessor was blinded and the patients partially blinded to the intervention. RESULTS: Ten patients were excluded, eight before randomisation. The trial is complete. Forty patients were analysed for the primary outcome measure. The local infiltration group had significantly lower pain scores at 4h post-operatively; mean [SD] score 2.1 [2.6] versus 6.8 [3.2], p<0.00001 and on post-operative day one prior to physiotherapy; mean score 2.4 [2.3] versus 4.4 [2.3], p<0.05. Total opiate use was also significantly lower in the local infiltration group; mean total 115 [50.3]mg versus 176.5 [103.5]mg, p<0.01. There was no difference in any other outcome. There were no harms as a result of either intervention. CONCLUSION: Intraoperative local infiltration gives superior pain relief compared to single shot femoral nerve block over the first 24h following primary TKR and minimises post-operative opiate use. PMID- 23665125 TI - The incentive salience of courtship vocalizations: hormone-mediated 'wanting' in the auditory system. AB - Conspecific vocalizations differ from many other sounds in that they have natural incentive salience. Our thinking about auditory responses to vocalizations may therefore benefit from models originally developed to understand reward. According to those models, the brain attributes incentive salience to rewarding stimuli via the activity of monoaminergic neuromodulators. These neuromodulators, in turn, mediate the effects of experience and internal state. Songbirds lend themselves well to this discussion because the natural incentive salience of song is clearly modulated by both factors. Their auditory responses have been well studied, particularly the song-induced expression of plasticity-associated genes such as ZENK. Here I review evidence that ZENK responses to song are regulated by monoamine neuromodulators, and I interpret this evidence in the context of incentive salience. First, hearing conspecific song engages monoaminergic activity in the auditory system and elsewhere. Second, in females this activity may be regulated by the same hormones that regulate behavioral preferences for song. Finally, much of the evidence thought to implicate neuromodulators in song discrimination and memory suggests that they may affect incentive salience. Expanding the study of incentive salience beyond the mesolimbic reward system may reveal some new ways of thinking about its underlying neural basis. This article is part of a Special Issue entitled "Communication Sounds and the Brain: New Directions and Perspectives". PMID- 23665126 TI - Cloning and characterization of new transcript variants of insulin-like growth factor-I in Sika deer (Cervus elaphus). AB - Insulin-like growth factor I (IGF-I) is a multi-promoter gene that has complex biological functions and plays an important role in cell differentiation and proliferation, animal growth and metabolism. IGF-I function is of particular importance in embryonic development. In this study, 5' and 3' RACE techniques were used to clone full-length cDNA of the IGF-I gene from the deer liver for the first time. Six transcript variants were identified: Class-1-Ea, Class-1-Eb, Class-1-Ec, Class-2-Ea, Class-2-Eb and Class-2-Ec. Analysis of amino acid sequence alignments indicated that different transcript variants of IGF-I from deer are highly conserved with other mammals and show high homology with Ovis aries, Capra hircus and Bos taurus. The IGF-I transcript variants show low homology with Mus musculus, Rattus norvegicuc and Canis familiaris. A rooted phylogenetic tree was constructed and suggested that the evolutionary molecular relationship of deer was closest to O. aries and farthest from M. musculus and R. norvegicuc. The results from semi-quantitative RT-PCR showed that in adult deer, the tissue expression level of IGF-I was high in liver and spleen and low in heart, lung, kidney and duodenum. The tissue expression level of Class-1-Ea IGF-I mRNA was higher than that of other transcript variants, while class-1 IGF-I mRNA tissue expression was higher than class-2 IGF-I mRNA tissue expression in liver and spleen. In fetal deer, only Class-1-Ea IGF-I mRNA was expressed, and the tissue expression level in the liver, lung, kidney and duodenum was higher than the tissue expression level in the heart and spleen. These results implied that transcript variants of the IGF-I gene have different roles in embryonic development and animal growth in deer. PMID- 23665127 TI - Parasitological and immunological aspects of early Ascaris spp. infection in mice. AB - Studies related to the immunobiological aspects of an Ascaris spp. infection are still scarce, especially those that aim to elucidate the early events of the immune response. In this study, we demonstrated a novel standardized method for early experimental Ascaris infection, providing additional information about the infectivity of eggs embryonated in vitro as well as the influence of host age on development of the infection. Finally, we characterised the immunopathology of early infection, focusing on the tissue and systemic cytokine profiles and the histopathology of infection in the lungs of BALB/c mice. Our results demonstrated that the highest egg infectivity occurred on the 100th and 200th days of in vitro embryonation and that 8 week-old BALB/c mice were more susceptible to infection than 16 week-old mice. Ascaris-infected mice showed an early, significant level of IL-5 production in the lungs 4 days p.i., followed by an increase in the level of neutrophils in the inflammatory infiltrate at 8 days p.i, which was correlated with the peak of larval migration in the tissue and a significant level of IL-6 production. The inflammatory infiltrate in the lungs was gradually replaced by mononuclear cells and eosinophils on the 10th and 12th days p.i., respectively, and an increase in TNF levels was observed. The downmodulation of systemic TCD4(+) cell numbers might suggest that T cell hyporesponsiveness was induced by the Ascaris spp. larvae, contributing to safeguarding parasite survival during larval migration. Taken together, the novel aspects of Ascaris infection presented here enabled a better understanding of the immunopathological events during larval migration, providing insight for further studies focused on immunisation and immunoprophylatic assays. PMID- 23665128 TI - Identification and significance of Naegleria fowleri isolated from the hot spring which related to the first primary amebic meningoencephalitis (PAM) patient in Taiwan. AB - Naegleria fowleri can cause primary amoebic meningoencephalitis, a rapidly developing and highly lethal infectious disease. The first confirmed case of primary amoebic meningoencephalitis in Taiwan was reported in November 2011, in which the patient visited a thermal spring recreational area 1 week prior to hospitalisation. Water sampling was performed to verify the presence of Naegleria at the facility. According to our results, 32% and 20% of recreational water samples were contaminated with Naegleria spp. and Acanthamoeba spp., respectively. The genotypes of Naegleria identified at the hot spring included N. fowleri, Naegleria australiensis and Naegleria lovaniensis. Using PCR, it was determined that the strain of N. fowleri in one sample possessed the same genotype 2 as the clinical isolate. Thus, the thermal spring was suggested to be the likely source of infection. This is the first known instance of simultaneously isolating N. fowleri from both a patient as well as from a hot spring in Taiwan. Following this initial study, the pools at the thermal spring recreational area were drained, scrubbed and disinfected, and a follow-up study was performed 1 month later. Naegleria fowleri was not detected in follow-up testing; however, other Naegleria spp. were identified. We postulate that the biofilm in the waterlines may have provided a reservoir for free-living amoebae. The presence/absence of Acanthamoeba and Naegleria spp. did not differ significantly with any measured parameters related to water quality; however, a high percentage of the thermal water pool samples were contaminated with Naegleria or Acanthamoeba. Thus, amoebic contamination may present a serious threat to the health of humans who engage in leisure activities at thermal springs. PMID- 23665129 TI - Potentiometric sensing of nuclease activities and oxidative damage of single stranded DNA using a polycation-sensitive membrane electrode. AB - A simple, general and label-free potentiometric method to measure nuclease activities and oxidative DNA damage in a homogeneous solution using a polycation sensitive membrane electrode is reported. Protamine, a linear polyionic species, is used as an indicator to report the cleavage of DNA by nucleases such as restriction and nonspecific nucleases, and the damage of DNA induced by hydroxyl radicals. Measurements can be done with a titration mode or a direct detection mode. For the potentiometric titration mode, the enzymatic cleavage dramatically affects the electrostatical interaction between DNA and protamine and thus shifts the response curve for the potentiometric titration of the DNA with protamine. Under the optimized conditions, the enzyme activities can be sensed potentiometrically with detection limits of 2.7*10(-4)U/uL for S1 nuclease, and of 3.9*10(-4)U/uL for DNase I. For the direct detection mode, a biocomplex between protamine and DNA is used as a substrate. The nuclease of interest cleaves the DNA from the protamine/DNA complex into smaller fragments, so that free protamine is generated and can be detected potentiometrically via the polycation-sensitive membrane electrode. Using a direct measurement, the nuclease activities could be rapidly detected with detection limits of 3.2*10(-4)U/uL for S1 nuclease, and of 4.5*10(-4)U/uL for DNase I. Moreover, the proposed potentiometric assays demonstrate the potential applications in the detection of hydroxyl radicals. It is anticipated that the present potentiometric strategy will provide a promising platform for high-throughput screening of nucleases, reactive oxygen species and the drugs with potential inhibition abilities. PMID- 23665130 TI - Technological, biological, and acoustical constraints to music perception in cochlear implant users. AB - Despite advances in technology, the ability to perceive music remains limited for many cochlear implant users. This paper reviews the technological, biological, and acoustical constraints that make music an especially challenging stimulus for cochlear implant users, while highlighting recent research efforts to overcome these shortcomings. The limitations of cochlear implant devices, which have been optimized for speech comprehension, become evident when applied to music, particularly with regards to inadequate spectral, fine-temporal, and dynamic range representation. Beyond the impoverished information transmitted by the device itself, both peripheral and central auditory nervous system deficits are seen in the presence of sensorineural hearing loss, such as auditory nerve degeneration and abnormal auditory cortex activation. These technological and biological constraints to effective music perception are further compounded by the complexity of the acoustical features of music itself that require the perceptual integration of varying rhythmic, melodic, harmonic, and timbral elements of sound. Cochlear implant users not only have difficulty perceiving spectral components individually (leading to fundamental disruptions in perception of pitch, melody, and harmony) but also display deficits with higher perceptual integration tasks required for music perception, such as auditory stream segregation. Despite these current limitations, focused musical training programs, new assessment methods, and improvements in the representation and transmission of the complex acoustical features of music through technological innovation offer the potential for significant advancements in cochlear implant mediated music perception. PMID- 23665131 TI - Pazopanib as second-line treatment after sunitinib or bevacizumab in patients with advanced renal cell carcinoma: a Sarah Cannon Oncology Research Consortium Phase II Trial. AB - BACKGROUND: This phase II trial examined the activity and toxicity of second-line treatment with pazopanib after failure of first-line single-agent treatment with sunitinib or bevacizumab in patients with advanced clear cell renal carcinoma. PATIENTS AND METHODS: Fifty-five patients with metastatic clear cell renal carcinoma who had previously received first-line treatment with sunitinib (39 patients) or bevacizumab (16 patients) were enrolled. Patients received pazopanib 800 mg orally daily and were evaluated for response after 8 weeks of treatment. Responses were measured using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, and confirmed with repeated scans after 8 weeks. Patients with objective response or stable disease continued treatment until disease progression or unacceptable toxicity occurred. RESULTS: Fifteen of 55 patients (27%) had objective response to pazopanib. An additional 27 patients (49%) had stable disease, for a disease control rate of 76%. After a median follow-up of 16.7 months, the median progression-free survival for the entire group was 7.5 months (95% confidence interval, 5.4-9.4 months). Similar progression-free survival was observed regardless of whether previous treatment was with sunitinib or bevacizumab. The estimated overall survival rate for the entire group at 24 months was 43%. CONCLUSION: Pazopanib is an active agent for the treatment of advanced clear cell renal carcinoma, even after failure of sunitinib or bevacizumab. Treatment with pazopanib should be considered early in the sequence of therapy for patients with advanced renal cell carcinoma. PMID- 23665133 TI - Curability of poor-risk metastatic sarcomatoid renal cell carcinoma with the combination of gemcitabine, 5-fluorouracil, and interferon-alfa: a case report of a 55-year-old man with a 10-year complete remission. PMID- 23665132 TI - Preoperative neutrophil-lymphocyte ratio as an independent prognostic marker for patients with upper urinary tract urothelial carcinoma. AB - BACKGROUND: To predict the prognosis, we evaluated the significance of the preoperative neutrophil-lymphocyte ratio (NLR) in patients with upper urinary tract urothelial carcinoma (UUTUC). PATIENTS AND METHODS: A cohort of 137 patients diagnosed with UUTUC from 1994 to 2008 at Tokyo Metropolitan Tama Medical Center was enrolled in this retrospective study. Log-rank test and Cox proportional hazards regression models were used for univariate and multivariate analyses. RESULTS: On univariate analysis, pathologic T stage, grade, lymphovascular invasion, C-reactive protein (CRP) level, and NLR were significantly associated with recurrence-free survival (RFS) and cancer-specific survival (CSS). The RFS rates for an NLR < 2.5 and for one >= 2.5 at 5 years were 74.3% and 30.4%, respectively. The CSS rates for an NLR < 2.5 and for one >= 2.5 at 5 years were 81.3% and 29.4%, respectively. The multivariate Cox proportional hazards regression models showed that the NLR could be an independent predictor for RFS and CSS. Based on the results of multivariate analysis, the scoring model was developed. RFS and CSS rates at 5 years were as follows: 0 risk factor, 97.1% and 97.0%, respectively; 1 risk factor, 91.1% and 90.9%, respectively; 2 risk factors, 39.5% and 58.6%, respectively; 3 risk factors, 26.6% and 28.6%, respectively; and 4 risk factors, 6.0% and 5.6%, respectively. CONCLUSIONS: The preoperative NLR is an independent prognostic predictor. The model based on the NLR and pathologic factors can be useful in clinical practice. PMID- 23665134 TI - Use of a clinical assistant to screen patients with genitourinary cancer to encourage entry into clinical trials and use of supportive medication: a pilot project at a Canadian cancer center. AB - BACKGROUND: The central goal of cancer care is to improve patient outcomes through advancing medical knowledge. Therefore, participation in clinical trials is encouraged to demonstrate efficacy and understand toxicities of medical interventions. In the oncology setting, these interventions are also frequently accompanied by clinical care to maintain bone health throughout the course of disease. In this study we examined the use of a study screener to enhance accrual and highlight bone health issues in a tertiary referral cancer center. PATIENTS AND METHODS: A study screener was introduced into 4 separate genitourinary clinics in a tertiary referral cancer center. Over a retrospective and subsequent prospective 10-week period, clinical trial accrual and bone health parameters were measured. RESULTS: There were no statistically significant differences between the retrospective and prospective periods in probability of approaching a patient for clinical trials (P = .60), accrual rates (P = .80), or proportion of patients later found ineligible (P = .31). The difference in initiation of calcium and vitamin D between the retrospective and prospective patients was statistically significant (P < .0001) and the difference between cohorts for starting treatment with zoledronic acid or denosumab was statistically significant (P = .02) and approached significance for the prostate cancer patients (P = .12). CONCLUSION: This pilot study suggests that in an academic setting, there is appropriate physician awareness of clinical trial availability, however the use of medication to improve bone health is suboptimal, and requires further research to identify and remove barriers to appropriate use including additional evidence of beneficial toxicity-benefit and cost-benefit ratios. PMID- 23665135 TI - Living and dying for inflammation: neutrophils, eosinophils, basophils. AB - Neutrophils, eosinophils, and basophils play essential roles during microbe induced and sterile inflammation. The severity of such inflammatory processes is controlled, at least in part, by factors that regulate cell death and survival of granulocytes. In recent years, major progress has been made in understanding the molecular mechanisms of granulocyte cell death and in identifying novel damage- and pathogen-associated molecular patterns as well as regulatory cytokines impacting granulocyte viability. Furthermore, an increased interest in innate immunity has boosted our overall understanding of granulocyte biology. In this review, we describe and compare factors and mechanisms regulating neutrophil, eosinophil, and basophil lifespan. Because dysregulation of death pathways in granulocytes can contribute to inflammation-associated immunopathology, targeting granulocyte lifespan could be therapeutically promising. PMID- 23665136 TI - Penicillin-induced epileptiform activity elevates focal brain temperature in anesthetized rats. AB - To elucidate a relationship between changes in focal brain temperature and severity of abnormal brain activity, epileptiform discharges and behavioral seizures were induced by Penicillin G in anesthetized rats, and focal brain temperature was measured. Penicillin G was injected into the right primary sensorimotor cortex (400IU/MUl). After the injection, epileptiform discharges induced a temperature increase gradually by 0.65+/-0.24 degrees C. Moreover, when behavioral seizures were induced by reducing the anesthesia level, the temperature was raised by 0.26+/-0.22 degrees C. These results suggest that elevation of the focal brain temperature is associated with the severity of epileptic activity. PMID- 23665137 TI - Effect of treadmill exercise on the BDNF-mediated pathway in the hippocampus of stressed rats. AB - A growing body of evidence suggests that exercise enhances hippocampal plasticity and function through BDNF up-regulation, which is potentiated by antidepressant treatment. However, little is known about the molecular mechanisms mediating the effect of exercise. The present study investigated the effect of treadmill exercise on PI3K/Akt signaling, which mediates synaptic plasticity in the hippocampus of stressed rats. Rats were subjected to immobilization stress 2h/day for 7 days. The rats were run on the treadmill at a speed of 15m/min, 30min/day, for 5 days. Western blotting was used to assess changes in the levels of phospho tyr(490)-Trk receptor, phospho-ser(473)-Akt, phospho-ser(9)-GSK-3beta, phospho ser(2448)- mTOR, and phosphor-thr(389)-p70S6K, and in BDNF and various synaptic proteins. Immobilization stress significantly decreased BDNF expression and phosphorylation of Trk receptor, Akt, GSK-3beta, mTOR, and p70S6K in the hippocampus of rats; furthermore, synaptophysin, PSD-95, neuroligin 1, and beta neurexin were decreased. Treadmill exercise significantly attenuated the decreased expression of these proteins. Moreover, exercise significantly increased PI3K/Akt signaling in the absence of immobilization stress. These results suggest that treadmill exercise reverses stress-induced changes in the rat hippocampus via an increase in PI3K/Akt signaling and may induce a functional reconnection of hippocampal synapses that mediate antidepressant actions. PMID- 23665138 TI - Prefrontal cortex activity during motor tasks with additional mental load requiring attentional demand: a near-infrared spectroscopy study. AB - Functional near-infrared spectroscopy (fNIRS) is suitable for investigating cerebral oxygenation changes during motor and/or mental tasks. In the present study, we investigated how an additional mental load during a motor task at two submaximal loadings affects the fNIRS-measured brain activation over the right prefrontal cortex (PFC). Fifteen healthy males performed isometric grasping contractions at 15% and 30% of the maximal voluntary contraction (MVC) with or without an additional mental (i.e., arithmetic) task. Mental performance, force variability, fNIRS and subjective perception responses were measured in each condition. The performance of the mental task decreased significantly while the force variability increased significantly at 30% MVC as compared to 15% MVC, suggesting that performance of dual-task required more attentional resources. PFC activity increased significantly as the effort increased from 15% to 30% MVC (p<.001). Although a larger change in the deoxyhemoglobin was observed in dual task conditions (p=.051), PFC activity did not change significantly as compared to the motor tasks alone. In summary, participants were unable to invest more attention and effort in performing the more difficult levels in order to maintain adequate mental performance. PMID- 23665139 TI - Validation of inhibitors of an ABC transporter required to transport lipopolysaccharide to the cell surface in Escherichia coli. AB - The presence of lipopolysaccharide (LPS) in the outer leaflet of the outer membrane (OM) of Gram-negative bacteria creates a permeability barrier that prevents the entry of most currently available antibiotics. The seven lipopolysaccharide transport (Lpt) proteins involved in transporting and assembling this glycolipid are essential for growth and division in Escherichia coli; therefore, inhibiting their functions leads to cell death. LptB, the ATPase that provides energy for LPS transport and assembly, forms a complex with three other inner membrane (IM) components, LptC, F, and G. We demonstrate that inhibitors of pure LptB can also inhibit the full IM complex, LptBFGC, purified in detergent. We also compare inhibition of LptB and the LptBFGC complex with the antibiotic activity of these compounds. Our long-term goal is to develop tools to study inhibitors of LPS biogenesis that could serve as potentiators by disrupting the OM permeability barrier, facilitating entry of clinically used antibiotics not normally used to treat Gram-negative infections, or that can serve as antibiotics themselves. PMID- 23665140 TI - Synthesis of new 18F-radiolabeled silicon-based nitroimidazole compounds. AB - The syntheses of new nitroimidazole compounds using silicon-[(18)F]fluorine chemistry for the potential detection of tumor hypoxia are described. [(18)F]silicon-based compounds were synthesized by coupling 2-nitroimidazole with silyldinaphtyl or silylphenyldi-tert-butyl groups and labeled by fluorolysis or isotopic exchange. Dinaphtyl compounds (6, 10) were labeled in 56-71% yield with a specific activity of 45 GBq/MUmol, however these compounds ([(18)F]7 and [(18)F]11) were not stable in plasma. Phenyldi-tert-butyl compounds were labeled in 70% yield with a specific activity of 3 GBq/MUmol by isotopic exchange, or in 81% yield by fluorolysis of siloxanes with a specific activity of 45 GBq/MUmol. The labeled compound [(18)F]18 was stable in plasma and excreted by the liver and kidneys in vivo. In conclusion, the fluorosilylphenyldi-tert-butyl (SiFA) group is more stable in plasma than fluorosilyldiphenyl moiety. Thus, compound [(18)F]18 is suitable for further in vivo assessments. PMID- 23665142 TI - New nitric oxide donating 1,2,4-triazole/oxime hybrids: synthesis, investigation of anti-inflammatory, ulceroginic liability and antiproliferative activities. AB - A series of novel nitric oxide (NO) donating triazole/oxime hybrids was prepared and evaluated for their anti-inflammatory activity. Most of the tested compounds showed significant anti-inflammatory activity using carrageenan-induced rat paw edema method compared to indomethacin. Calculation of the ulcer indices and histopathological investigation indicated that the prepared NO-donating oximes exhibited less ulcerogenicity compared to their intermediate ketones and indomethacin. The NO-donating oxime 6i revealed significant activity against renal cancer A498 cell lines with 50.52 cell growth inhibition. PMID- 23665141 TI - Programmable DNA-binding small molecules. AB - Aberrant gene expression is responsible for a myriad of human diseases from infectious diseases to cancer. Precise regulation of these genes via specific interactions with the DNA double helix could pave the way for novel therapeutics. Pyrrole-imidazole polyamides are small molecules capable of binding to pre determined DNA sequences up to 16 base pairs with affinity and specificity comparable to natural transcription factors. In the three decades since their development, great strides have been made relating to synthetic accessibility and improved sequence specificity and binding affinity. This perspective presents a brief history of early seminal developments in the field and highlights recent reports of the utility of polyamides as both genetic modulators and molecular probes. PMID- 23665143 TI - Manzamine A, a marine-derived alkaloid, inhibits accumulation of cholesterol ester in macrophages and suppresses hyperlipidemia and atherosclerosis in vivo. AB - The formation of foam cells in macrophages plays an essential role in the progression of early atherosclerotic lesions and therefore its prevention is considered to be a promising target for the treatment of atherosclerosis. We found that an extract of the marine sponge Acanthostrongylophora ingens inhibited the foam cell formation induced by acetylated low-density lipoprotein (AcLDL) in human monocyte-derived macrophages, as measured based on the accumulation of cholesterol ester (CE). Bioassay-guided purification of inhibitors from the extract afforded manzamines. Manzamine A was the most potent inhibitor of foam cell formation, and also suppressed CE formation in Chinese hamster ovary cells overexpressing acyl-CoA:cholesterol acyl-transferase (ACAT)-1 or ACAT-2. In addition, manzamine A inhibited ACAT activity. Next, we orally administered manzamine A to apolipoprotein E (apoE)-deficient mice for 80 days, and found that total cholesterol, free cholesterol, LDL-cholesterol, and triglyceride levels in serum were significantly reduced and the area of atherosclerotic lesions in the aortic sinus was also substantially diminished. These findings clearly suggest that manzamine A suppresses hyperlipidemia and atherosclerosis in apoE-deficient mice by inhibiting ACAT and is therefore a promising lead compound in the prevention or treatment of atherosclerosis. Although manzamine A has been reported to show several biological activities, this is the first report of a suppressive effect of manzamine A on atherosclerosis in vivo. PMID- 23665144 TI - Immunoglobulin gene rearrangements and mutational status in argentinian patients with chronic lymphocytic leukemia. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease. The mutational status of the immunoglobulin heavy chain variable (IGHV) region represents one of the best prognostic markers and defines 2 disease subgroups: mutated (M-CLL) and unmutated (UM-CLL), with different clinical course. MATERIALS AND METHODS: IGHV-D-J gene rearrangements and mutational status were analyzed in 73 Argentinian patients with CLL, 22 previously treated, by reverse transcriptase-polymerase chain reaction and bidirectional sequencing. The results were compared with those reported in other geographic regions. Fluorescence in situ hybridization analysis was also performed. RESULTS: A total of 43 (58.9%) cases were of patients with M-CLL, and 30 (41.1%) were patients with UM-CLL. Deletion of chromosome 13q14 as a single alteration was more frequently observed in the M-CLL group (48%) than in the UM-CLL group (24%). In the M-CLL group, the proportion of cases with deletion of chromosome 13q14 was significantly higher than those with +12 and those with deletions of chromosomes 17p and 11q (P = .003). The most frequently used IGHV families were IGHV3 > IGHV1 > IGHV4, which are different from those observed in Asian, Brazilian, and Uruguayan series. The IGHV3-23 gene (10.8%) was the most commonly used, followed by IGHV1-69 (9.5%), IGHV4-59 and IGHV2-5 (6.8% each), and IGHV3-21 and IGHV3-30 (5.4% each). IGHV4-34 showed the lowest frequency (2.7%) in our cohort compared with published data, whereas IGHV4-59, IGHV3-72, and IGHV2-5 were overexpressed in our series. Stereotyped HCDR3 (heavy chain complementary determining region 3) was found in 9.5% of patients. CONCLUSIONS: Our results showed that Argentinian patients with CLL display an IGHV gene usage that resembles that observed in Western countries and exhibited interesting similarities and differences with respect to published series from other Latin American populations, which reflect variations in the genetic background. PMID- 23665146 TI - Paget's disease of the nipple treated successfully with cryosurgery: a series of cases report. AB - INTRODUCTION: Paget's disease of the nipple is a rare form of breast malignancy. Underlying breast cancer, either in situ or invasive accompanies lesions of the nipple in most of the cases. The connection between both entities and their exact origin remains unclear. Nevertheless, underlying ductal breast cancer is often confined to the central, subareolar part of the breast. Radical mastectomy, although successful, seems to be too mutilating treatment in the era of breast sparing surgery. Studies describing breast conserving surgery performed without adjuvant treatment are rare and the patients not numerous. Due to low incidence of the disease, there are no randomised trials conducted which could show the optimal method of treatment. MATERIALS AND METHODS: We performed cryosurgery of the affected nipple-areola complex (NAC) in treatment of six patients with Paget's disease of the nipple who presented general contraindications or lack of consent for surgery. RESULTS: With a follow up ranging from 60 to 121 months (average 94) we obtained very good results in terms of disease specific survival: there were two cases of recurrent disease, confined to the scar and treated successfully with cryosurgery again; four patients are alive without disease. Death was not related to cancer in the remained two cases. CONCLUSIONS: Cryotherapy is successful form of treatment of localised Paget's disease of the nipple--especially in face of contraindications for surgery or lack of patient's agreement for operational treatment. PMID- 23665145 TI - Crystal structures of Plasmodium falciparum cytosolic tryptophanyl-tRNA synthetase and its potential as a target for structure-guided drug design. AB - Malaria, most commonly caused by the parasite Plasmodium falciparum, is a devastating disease that remains a large global health burden. Lack of vaccines and drug resistance necessitate the continual development of new drugs and exploration of new drug targets. Due to their essential role in protein synthesis, aminoacyl-tRNA synthetases are potential anti-malaria drug targets. Here we report the crystal structures of P. falciparum cytosolic tryptophanyl tRNA synthetase (Pf-cTrpRS) in its ligand-free state and tryptophanyl-adenylate (WAMP)-bound state at 2.34 A and 2.40 A resolutions, respectively. Large conformational changes are observed when the ligand-free protein is bound to WAMP. Multiple residues, completely surrounding the active site pocket, collapse onto WAMP. Comparison of the structures to those of human cytosolic TrpRS (Hs cTrpRS) provides information about the possibility of targeting Pf-cTrpRS for inhibitor development. There is a high degree of similarity between Pf-cTrpRS and Hs-cTrpRS within the active site. However, the large motion that Pf-cTrpRS undergoes during transitions between different functional states avails an opportunity to arrive at compounds which selectively perturb the motion, and may provide a starting point for the development of new anti-malaria therapeutics. PMID- 23665147 TI - A comparative proteomic analysis of Vibrio cholerae O1 wild-type cells versus a phoB mutant showed that the PhoB/PhoR system is required for full growth and rpoS expression under inorganic phosphate abundance. AB - PhoB/PhoR is a two-component system originally described as involved in inorganic phosphate (Pi) transport and metabolism under Pi limitation. In order to disclose other roles of this system, a proteomic analysis of Vibrio cholerae 569BSR and its phoB/phoR mutant under high Pi levels was performed. Most of the proteins downregulated by the mutant have roles in energy production and conversion and in amino acid transport and metabolism. In contrast, the phoB/phoR mutant upregulated genes mainly involved in adaptation to atypical conditions, indicating that the absence of a functional PhoB/PhoR caused increased expression of a number of genes from distinct stress response pathways. This might be a strategy to overcome the lack of RpoS, whose expression in the stationary phase cells of V. cholerae seems to be controlled by PhoB/PhoR. Moreover, compared to the wild-type strain the phoB/phoR mutant presented a reduced cell density at stationary phase of culture in Pi abundance, lower resistance to acid shock, but higher tolerance to thermal and osmotic stresses. Together our findings show, for the first time, the requirement of PhoB/PhoR for full growth under high Pi level and for the accumulation of RpoS, indicating that PhoB/PhoR is a fundamental system for the biology of V. cholerae. BIOLOGICAL SIGNIFICANCE: Certain V. cholerae strains are pathogenic to humans, causing cholera, an acute dehydrating diarrhoeal disease endemic in Southern Asia, parts of Africa and Latin America, where it has been responsible for significant mortality and economical damage. Its ability to grow within distinct niches is dependent on gene expression regulation. PhoB/PhoR is a two-component system originally described as involved in inorganic phosphate (Pi) transport and metabolism under Pi limitation. However, Pho regulon genes also play roles in virulence, motility and biofilm formation, among others. In this paper we report that the absence of a functional PhoB/PhoR caused increased expression of a number of genes from distinct stress response pathways, in Pi abundance. Moreover, we showed, for the first time, that the interrelationship between PhoB-RpoS-(p)ppGpp-poly(P) in V. cholerae, is somewhat diverse from the model of inter-regulation between those systems, described in Escherichia coli. The V. cholerae dependence on PhoB/PhoR for the RpoS mediated stress response and cellular growth under Pi abundance, suggests that this system's roles are broader than previously thought. PMID- 23665148 TI - The effect of peptide adsorption on signal linearity and a simple approach to improve reliability of quantification. AB - Peptide quantification using MS often relies on the comparison of peptide signal intensities between different samples, which is based on the assumption that observed signal intensity has a linear relationship to peptide abundance. A typical proteomics experiment is subject to multiple sources of variance, so we focussed here on properties affecting peptide linearity under simple, well defined conditions. Peptides from a standard protein digest were analysed by multiple reaction monitoring (MRM) MS to determine peptide linearity over a range of concentrations. We show that many peptides do not display a linear relationship between signal intensity and amount under standard conditions. Increasing the organic content of the sample solvent increased peptide linearity by increasing the accuracy and precision of quantification, which suggests that peptide non-linearity is due to concentration-dependent surface adsorption. Using multiple peptides at various dilutions, we show that peptide non-linearity is related to observed retention time and predicted hydrophobicity. Whereas the effect of adsorption on peptide storage has been investigated previously, here we demonstrate the deleterious effect of peptide adsorption on the quantification of fresh samples, highlight aspects of sample preparation that can minimise the effect, and suggest bioinformatic approaches to enhance the selection of peptides for quantification. BIOLOGICAL SIGNIFICANCE: Accurate quantification is central to many aspects of science, especially those examining dynamic processes or comparing molecular stoichiometries. In biological research, the quantification of proteins is an important yet challenging objective. Large-scale quantification of proteins using MS often depends on the comparison of peptide intensities with only a single-level calibrant (as in stable isotope labelling and absolute quantification approaches) or no calibrants at all (as in label-free approaches). For these approaches to be reliable, it is essential that the relationship between signal intensity and concentration is linear, without a significant intercept. Here, we show that peptide adsorption can severely affect this relationship, even under controlled conditions, and we demonstrate simple methodologies that can be used to moderate and predict this effect. These findings thus enable the quantification of proteins with increased robustness and reliability. PMID- 23665149 TI - Identification of new protein coding sequences and signal peptidase cleavage sites of Helicobacter pylori strain 26695 by proteogenomics. AB - Correct annotation of protein coding genes is the basis of conventional data analysis in proteomic studies. Nevertheless, most protein sequence databases almost exclusively rely on gene finding software and inevitably also miss protein annotations or possess errors. Proteogenomics tries to overcome these issues by matching MS data directly against a genome sequence database. Here we report an in-depth proteogenomics study of Helicobacter pylori strain 26695. MS data was searched against a combined database of the NCBI annotations and a six-frame translation of the genome. Database searches with Mascot and X! Tandem revealed 1115 proteins identified by at least two peptides with a peptide false discovery rate below 1%. This represents 71% of the predicted proteome. So far this is the most extensive proteome study of Helicobacter pylori. Our proteogenomic approach unambiguously identified four previously missed annotations and furthermore allowed us to correct sequences of six annotated proteins. Since secreted proteins are often involved in pathogenic processes we further investigated signal peptidase cleavage sites. By applying a database search that accommodates the identification of semi-specific cleaved peptides, 63 previously unknown signal peptides were detected. The motif LXA showed to be the predominant recognition sequence for signal peptidases. BIOLOGICAL SIGNIFICANCE: The results of MS-based proteomic studies highly rely on correct annotation of protein coding genes which is the basis of conventional data analysis. However, the annotation of protein coding sequences in genomic data is usually based on gene finding software. These tools are limited in their prediction accuracy such as the problematic determination of exact gene boundaries. Thus, protein databases own partly erroneous or incomplete sequences. Additionally, some protein sequences might also be missing in the databases. Proteogenomics, a combination of proteomic and genomic data analyses, is well suited to detect previously not annotated proteins and to correct erroneous sequences. For this purpose, the existing database of the investigated species is typically supplemented with a six-frame translation of the genome. Here, we studied the proteome of the major human pathogen Helicobacter pylori that is responsible for many gastric diseases such as duodenal ulcers and gastric cancer. Our in-depth proteomic study highly reliably identified 1115 proteins (FDR<0.01%) by at least two peptides (FDR<1%) which represent 71% of the predicted proteome deposited at NCBI. The proteogenomic data analysis of our data set resulted in the unambiguous identification of four previously missed annotations, the correction of six annotated proteins as well as the detection of 63 previously unknown signal peptides. We have annotated proteins of particular biological interest like the ferrous iron transport protein A, the coiled-coil-rich protein HP0058 and the lipopolysaccharide biosynthesis protein HP0619. For instance, the protein HP0619 could be a drug target for the inhibition of the LPS synthesis pathway. Furthermore it has been proven that the motif "LXA" is the predominant recognition sequence for the signal peptidase I of H. pylori. Signal peptidases are essential enzymes for the viability of bacterial cells and are involved in pathogenesis. Therefore signal peptidases could be novel targets for antibiotics. The inclusion of the corrected and new annotated proteins as well as the information of signal peptide cleavage sites will help in the study of biological pathways involved in pathogenesis or drug response of H. pylori. PMID- 23665151 TI - Coupling the cell cycle to development and regeneration of the inner ear. AB - Cell cycle exit and acquirement of a postmitotic state is essential for the proper development of organs. In the present review, we examine the role of the cell cycle control in the sensory epithelia of the mammalian inner ear. We describe the roles of the core cell cycle regulators in the proliferation of prosensory cells and in the initiation and maintenance of terminal mitosis of the sensory epithelia. We also discuss how other intracellular signalling may influence the cell cycle. Finally, we address the question of whether manipulations of the cell cycle may have the potential to create replacement cells for the damaged inner sensory epithelia. PMID- 23665150 TI - Colour variation in cichlid fish: developmental mechanisms, selective pressures and evolutionary consequences. AB - Cichlid fishes constitute one of the most species-rich families of vertebrates. In addition to complex social behaviour and morphological versatility, they are characterised by extensive diversity in colouration, both within and between species. Here, we review the cellular and molecular mechanisms underlying colour variation in this group and the selective pressures responsible for the observed variation. We specifically address the evidence for the hypothesis that divergence in colouration is associated with the evolution of reproductive isolation between lineages. While we conclude that cichlid colours are excellent models for understanding the role of animal communication in species divergence, we also identify taxonomic and methodological biases in the current research effort. We suggest that the integration of genomic approaches with ecological and behavioural studies, across the entire cichlid family and beyond it, will contribute to the utility of the cichlid model system for understanding the evolution of biological diversity. PMID- 23665152 TI - Genetics of colouration in birds. AB - Establishing the links between phenotype and genotype is of great importance for resolving key questions about the evolution, maintenance and adaptive function of phenotypic variation. Bird colouration is one of the most studied systems to investigate the role of natural and sexual selection in the evolution of phenotypic diversity. Given the recent advances in molecular tools that allow discovering genetic polymorphisms and measuring gene and protein expression levels, it is timely to review the literature on the genetics of bird colouration. The present study shows that melanin-based colour phenotypes are often associated with mutations at melanogenic genes. Differences in melanin based colouration are caused by switches of eumelanin to pheomelanin production or by changes in feather keratin structure, melanoblast migration and differentiation, as well as melanosome structure. Similar associations with other types of colourations are difficult to establish, because our knowledge about the molecular genetics of carotenoid-based and structural colouration is quasi inexistent. This discrepancy stems from the fact that only melanin-based colouration shows pronounced heritability estimates, i.e. the resemblance between related individuals is usually mainly explained by genetic factors. In contrast, the expression of carotenoid-based colouration is phenotypically plastic with a high sensitivity to variation in environmental conditions. It therefore appears that melanin-based colour traits are prime systems to understand the genetic basis of phenotypic variation. In this context, birds have a great potential to bring us to new frontiers where many exciting discoveries will be made on the genetics of phenotypic traits, such as colouration. In this context, a major goal of our review is to suggest a number of exciting future avenues. PMID- 23665153 TI - Muscle wasting in heart failure: An overview. AB - Patients with heart failure are frequently limited in their exercise capacity. Although this clinical phenomenon is mostly attributed to the failing myocardium, the effects of skeletal muscle wasting should not be underestimated. Muscle wasting may present in the form of loss of muscle mass and function, termed sarcopenia in healthy aging, or in the form of cachexia. Only cachexia is associated with loss of body weight. The mechanisms involved embrace an anabolic /catabolic imbalance with increased degradation of myofibrils and myocyte apoptosis. Clinical effects include reduced muscle mass, strength and consequently reduced exercise capacity. This article describes the terminology, molecular pathways, prevalence, clinical implications and possible treatment approaches to muscle wasting in patients with heart failure. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. PMID- 23665154 TI - Protein breakdown in muscle wasting: role of autophagy-lysosome and ubiquitin proteasome. AB - Skeletal muscle adapts its mass as consequence of physical activity, metabolism and hormones. Catabolic conditions or inactivity induce signaling pathways that regulate the process of muscle loss. Muscle atrophy in adult tissue occurs when protein degradation rates exceed protein synthesis. Two major protein degradation pathways, the ubiquitin-proteasome and the autophagy-lysosome systems, are activated during muscle atrophy and variably contribute to the loss of muscle mass. These degradation systems are controlled by a transcription dependent program that modulates the expression of rate-limiting enzymes of these proteolytic systems. The transcription factors FoxO, which are negatively regulated by Insulin-Akt pathway, and NF-kappaB, which is activated by inflammatory cytokines, were the first to be identified as critical for the atrophy process. In the last years a variety of pathways and transcription factors have been found to be involved in regulation of atrophy. This review will focus on the last progress in ubiquitin-proteasome and autophagy-lysosome systems and their involvement in muscle atrophy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. PMID- 23665155 TI - Pre-training evaluation and feedback improved skills retention of basic life support in medical students. AB - BACKGROUND: Pre-training evaluation and feedback have been shown to improve medical students' skills acquisition of basic life support (BLS) immediately following training. The impact of such training on BLS skills retention is unknown. This study was conducted to investigate effects of pre-training evaluation and feedback on BLS skills retention in medical students. METHODS: Three hundred and thirty 3rd year medical students were randomized to two groups, the control group (C group) and pre-training evaluation and feedback group (EF group). Each group was subdivided into four subgroups according to the time of retention-test (at 1-, 3-, 6-, 12-month following the initial training). After a 45-min BLS lecture, BLS skills were assessed (pre-training evaluation) in both groups before training. Following this, the C group received 45 min training. 15 min of group feedback corresponding to students' performance in pre-training evaluation was given only in the EF group that was followed by 30 min of BLS training. BLS skills were assessed immediately after training (post-test) and at follow up (retention-test). RESULTS: No skills difference was observed between the two groups in pre-training evaluation. Better skills acquisition was observed in the EF group (85.3 +/- 7.3 vs. 68.1 +/- 12.2 in C group) at post-test (p<0.001). In all retention-test, better skills retention was observed in each EF subgroup, compared with its paired C subgroup. CONCLUSIONS: Pre-training evaluation and feedback improved skills retention in the EF group for 12 months after the initial training, compared with the control group. PMID- 23665156 TI - Shaping synaptic plasticity: the role of activity-mediated epigenetic regulation on gene transcription. AB - Learning and memory are basic functions of the brain that allowed human evolution. It is well accepted that during learning and memory formation the dynamic establishment of new active synaptic connections is crucial. Persistent synaptic activation leads to molecular events that include increased release of neurotransmitters, increased expression of receptors on the postsynaptic neuron, thus creating a positive feedback that results in the activation of distinct signaling pathways that temporally and permanently alter specific patterns of gene expression. However, the epigenetic changes that allow the establishment of long term genetic programs that control learning and memory are not completely understood. Even less is known regarding the signaling events triggered by synaptic activity that regulate these epigenetic marks. Here we review the current understanding of the molecular mechanisms controlling activity-dependent gene transcription leading synaptic plasticity and memory formation. We describe how Ca(2+) entry through N-methyl-d-aspartate-type glutamate neurotransmitter receptors result in the activation of specific signaling pathways leading to changes in gene expression, giving special emphasis to the recent data pointing out different epigenetic mechanisms (histone acetylation, methylation and phosphorylation as well as DNA methylation and hydroxymethylation) underlying learning and memory. PMID- 23665157 TI - A practical access to glucose- and allose-based (5+5) 3-spiropseudonucleosides from a common intermediate. AB - A practical access to glucose-based and allose-based spirooxazolidinones is reported. The synthetic sequence consisting of TEMPO-catalyzed oxidation of 1,2:5,6-di-O-isopropylidene-alpha-D-glucofuranose, Henry reaction, and reduction provides amino alcohol with allo-configuration on a multigram scale. Alternatively, water elimination from Henry products followed by a rehydration gives an access to diastereomerically pure glucose-based nitro alcohol which upon reduction provides complementary amino alcohol with gluco-configuration. The latter amino alcohols are transformed into spirooxazolidinones (3 spiropseudonucleosides) via their N-Cbz or N-phenylcarbamate derivatives. The title compounds easily undergo N-derivatization and give highly crystalline materials. Two of the newly obtained (5+5) 3-spiropseudonucleosides are characterized by X-ray crystallography. PMID- 23665158 TI - Host specificity and colony impacts of the fire ant pathogen, Solenopsis invicta virus 3. AB - An understanding of host specificity is essential before pathogens can be used as biopesticides or self-sustaining biocontrol agents. In order to define the host range of the recently discovered Solenopsis invicta virus 3 (SINV-3), we exposed laboratory colonies of 19 species of ants in 14 genera and 4 subfamilies to this virus. Despite extreme exposure during these tests, active, replicating infections only occurred in Solenopsis invicta Buren and hybrid (S. invicta*S. richteri) fire ant colonies. The lack of infections in test Solenopsis geminata fire ants from the United States indicates that SINV-3 is restricted to the saevissima complex of South American fire ants, especially since replicating virus was also found in several field-collected samples of the black imported fire ant, Solenopsis richteri Forel. S. invicta colonies infected with SINV-3 declined dramatically with average brood reductions of 85% or more while colonies of other species exposed to virus remained uninfected and healthy. The combination of high virulence and high host specificity suggest that SINV-3 has the potential for use as either a biopesticide or a self-sustaining biocontrol agent. PMID- 23665159 TI - Aptamer biosensor for label-free impedance spectroscopy detection of potassium ion based on DNA G-quadruplex conformation. AB - Herein, a label-free and highly sensitive electrochemical impedance spectroscopy (EIS) aptasensor for the detection of potassium ion (K+) was developed based on a conformational change in which a K+-stabilized single stranded DNA (ssDNA) with G rich sequence was used as the recognition element. In the measurement of K+ ions, the change in interfacial electron transfer resistance (R(ct)) of the sensor using a redox couple of [Fe(CN)6]3-/4- as the probe was monitored. In the presence of K+, the G-rich DNA folded into the G-quadruplex structure, and then K+ can bind to the G-quadruplex structure, leading to an increase in the R(ct). The Rct increased with K+ concentration, and the plot of R(ct) against the logarithm of K+ concentration is linear over the range from 0.1 nM to 1 mM with a detection limit of 0.1 nM. Other metal ions, such as Ca2+, Mg2+, Na+, Li+, Al3+, Zn2+, Cu2+, and Ni2+ caused no notable interference on the detection of K+. The scheme reported herein is applicable to the detection of other kinds of G-rich aptamer-binding chemicals and biomolecules. PMID- 23665160 TI - Predicting parkinsonism: new opportunities from Gaucher disease. PMID- 23665162 TI - Antimicrobial and acetylcholinesterase inhibitory activities of Buddleja salviifolia (L.) Lam. leaf extracts and isolated compounds. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Buddleja salviifolia leaves are used for the treatment of eye infections and neurodegenerative conditions by various tribes in South Africa. AIM OF STUDY: This study was designed to isolate the phenolic constituents from the leaf extracts of Buddleja salviifolia and evaluate their antimicrobial and acetylcholinesterase (AChE) activities. MATERIAL AND METHODS: Three phenolic compounds were isolated from the ethyl acetate fraction of a 20% aqueous methanol leaf extract of Buddleja salviifolia using Sephadex LH-20 and silica gel columns. Structure elucidation of the isolated compounds was carried out using spectroscopic techniques: mass spectrometry (ESI-TOF-MS) and NMR (1D and 2D). The extracts and isolated compounds were evaluated for antimicrobial and acetylcholinesterase activities using the microdilution technique. The bacteria used for the antimicrobial assays were Gram-positive Bacillus subtilis and Staphylococcus aureus and Gram-negative Escherichia coli and Klebsiella pneumoniae. RESULTS: The isolated compounds were characterized as: 4' hydroxyphenyl ethyl vanillate (1) a new natural product, acteoside (2) and quercetin (3). The crude extract, fractions and the isolated compounds from the leaves of the plant exhibited a broad spectrum of antibacterial activity. The EtOAc fraction exhibited good activity against Bacillus subtilis and Staphylococcus aureus with MIC values ranging from 780.0 to 390.0 ug/mL. Isolated compound 2 exhibited good activity against Staphylococcus aureus with an MIC value of 62.5 ug/mL. The hexane and DCM fractions of leaves showed the best activity against Candida albicans with MIC and MFC values of 390.0 ug/mL. In the AChE inhibitory test, among the tested extracts, the hexane fraction was the most potent with an IC50 value of 107.4 ug/mL, whereas for the isolated compounds, it was compound (3) (quercetin) with an IC50 value of 66.8 ug/mL. CONCLUSIONS: Activities demonstrated by the extracts and isolated compounds support the ethnopharmacological use of Buddleja salviifolia against eye infections and neurodegenerative diseases. PMID- 23665163 TI - Anti-oxidative stress effect of red ginseng in the brain is mediated by peptidyl arginine deiminase type IV (PADI4) repression via estrogen receptor (ER) beta up regulation. AB - AIM OF THE STUDY: Ginseng has been used as an anti-stress agent, and its active ingredient, ginsenoside, is similar in structure to estrogen. However, the effect of ginseng on the stressed brain is not completely understood. The aim of this study is to understand systematically how red ginseng (RG) affects gene expressions in the brain of immobilization (IMO) stressed mice to elucidate its underlying mechanism. MATERIALS AND METHODS: For in vivo experiments, mice were stressed by immobilization for 30, 45, or 60 min, and gene expression in the mice brain was analyzed by microarray and system biology. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling (TUNEL) staining, and gene expression by Western blot or qPCR. For in vitro study, the SK-N-SH neuroblastoma cells were stressed by H2O2 exposure. The resultant cytotoxicity was measured by MTT assay, and gene expression by Western blot, ELISA, or qPCR. RESULTS: Microarray analysis of genes in IMO stressed mice brains showed that RG administration prior to IMO stress downregulated >40 genes including peptidyl arginine deiminase type 4 (PADI4). Interestingly, PADI4 was up regulated by various stresses such as H2O2, acrylamide, and tunicamycin in neuroblastoma SK-N-SH cells but inhibited by RG. IMO stress and in vitro H2O2 stress depressed the estrogen receptor (ER)-beta expression but not ERalpha. However, RG treatment increased ERbeta expression both in vivo and in vitro. Comparative analysis regarding the networks by systems biology revealed that TNF alpha plays a critical role in IMO stress, and the cell death associated network was much higher than other categories. Consistently, the IMO stress induced TNF alpha and Cox-2 expressions, malondialdehyde (MDA), and cell death in the brain, whereas RG administration inhibited these inductions in vivo. siRNA and transient expression studies revealed that ERbeta inhibited the PADI4 expression. CONCLUSION: PADI4 could be used as an oxidative stress marker. RG seems to inhibit oxidative stress-inducible PADI4 by up-regulating ERbeta expression in the brain thus protecting brain cells from apoptosis. PMID- 23665164 TI - Argyreia nervosa (Burm. f.): receptor profiling of lysergic acid amide and other potential psychedelic LSD-like compounds by computational and binding assay approaches. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The convolvulacea Argyreia nervosa (Burm. f.) is well known as an important medical plant in the traditional Ayurvedic system of medicine and it is used in numerous diseases (e.g. nervousness, bronchitis, tuberculosis, arthritis, and diabetes). Additionally, in the Indian state of Assam and in other regions Argyreia nervosa is part of the traditional tribal medicine (e.g. the Santali people, the Lodhas, and others). In the western hemisphere, Argyreia nervosa has been brought in attention as so called "legal high". In this context, the seeds are used as source of the psychoactive ergotalkaloid lysergic acid amide (LSA), which is considered as the main active ingredient. AIM OF THE STUDY: As the chemical structure of LSA is very similar to that of lysergic acid diethylamide (LSD), the seeds of Argyreia nervosa (Burm. f.) are often considered as natural substitute of LSD. In the present study, LSA and LSD have been compared concerning their potential pharmacological profiles based on the receptor binding affinities since our recent human study with four volunteers on p.o. application of Argyreia nervosa seeds has led to some ambiguous effects. MATERIAL AND METHODS: In an initial step computer-aided in silico prediction models on receptor binding were employed to screen for serotonin, norepinephrine, dopamine, muscarine, and histamine receptor subtypes as potential targets for LSA. In addition, this screening was extended to accompany ergotalkaloids of Argyreia nervosa (Burm. f.). In a verification step, selected LSA screening results were confirmed by in vitro binding assays with some extensions to LSD. RESULTS: In the in silico model LSA exhibited the highest affinity with a pKi of about 8.0 at alpha1A, and alpha1B. Clear affinity with pKi>7 was predicted for 5-HT1A, 5-HT1B, 5-HT1D, 5-HT6, 5-HT7, and D2. From these receptors the 5-HT1D subtype exhibited the highest pKi with 7.98 in the prediction model. From the other ergotalkaloids, agroclavine and festuclavine also seemed to be highly affine to the 5-HT1D-receptor with pKi>8. In general, the ergotalkaloids of Argyreia nervosa seem to prefer serotonin and dopamine receptors (pKi>7). However, with exception of ergometrine/ergometrinine only for 5-HT3A, and histamine H2 and H4 no affinities were predicted. Compared to LSD, LSA exhibited lower binding affinities in the in vitro binding assays for all tested receptor subtypes. However, with a pKi of 7.99, 7.56, and 7.21 a clear affinity for 5-HT1A, 5-HT2, and alpha2 could be demonstrated. For DA receptor subtypes and the alpha1-receptor the pKi ranged from 6.05 to 6.85. CONCLUSION: Since the psychedelic activity of LSA in the recent human study was weak and although LSA from Argyreia nervosa is often considered as natural exchange for LSD, LSA should not be regarded as LSD-like psychedelic drug. However, vegetative side effects and psychotropic effects may be triggered by serotonin or dopamine receptor subtypes. PMID- 23665161 TI - Review of clinical presentation and diagnosis of mucopolysaccharidosis IVA. AB - Mucopolysaccharidosis type IVA (MPS IVA) was described in 1929 by Luis Morquio from Uruguay and James Brailsford from England, and was later found as an autosomal recessive lysosomal storage disease. MPS IVA is caused by mutations in the gene encoding the enzyme, N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Reduced GALNS activity results in impaired catabolism of two glycosaminoglycans (GAGs), chondroitin-6-sulfate (C6S) and keratan sulfate (KS). Clinical presentations of MPS IVA reflect a spectrum of progression from a severe "classical" phenotype to a mild "attenuated" phenotype. More than 180 different mutations have been identified in the GALNS gene, which likely explains the phenotypic heterogeneity of the disorder. Accumulation of C6S and KS manifests predominantly as short stature and skeletal dysplasia (dysostosis multiplex), including atlantoaxial instability and cervical cord compression. However, abnormalities in the visual, auditory, cardiovascular, and respiratory systems can also affect individuals with MPS IVA. Diagnosis is typically based on clinical examination, skeletal radiographs, urinary GAG, and enzymatic activity of GALNS in blood cells or fibroblasts. Deficiency of GALNS activity is a common assessment for the laboratory diagnosis of MPS IVA; however, with recently increased availability, gene sequencing for MPS IVA is often used to confirm enzyme results. As multiple clinical presentations are observed, diagnosis of MPS IVA may require multi-system considerations. This review provides a history of defining MPS IVA and how the understanding of the disease manifestations has changed over time. A summary of the accumulated knowledge is presented, including information from the International Morquio Registry. The classical phenotype is contrasted with attenuated cases, which are now being recognized and diagnosed more frequently. Laboratory based diagnoses of MPS IVA are also discussed. PMID- 23665166 TI - Glutamatergic activities in neonatal rat spinal cord heterogeneously regulate single-fiber splanchnic nerve discharge. AB - Kynurenic acid (KYN) is a metabolite of tryptophan and is involved in various neurological disorders. Using whole-bundle nerve recording techniques, we previously observed that applications of KYN to block endogenous ionotropic glutamate receptor activities in neonatal rat spinal cords in vitro cause a reversible fluctuation of splanchnic sympathetic nerve discharge (SND). We hypothesized that the SND fluctuation was due to a heterogeneous single-fiber response. To detail individual fiber activities, we used the so-called 'oligofiber recordings'. Spontaneous single-fiber activities were recorded from the collagenase-dissociated splanchnic nerve fascicles. Applications of KYN increased, decreased or did not change firing rates. The heterogeneous responses in spontaneous spiking activities were confirmed by applications of APV or CNQX, suggesting an effect mediated by endogenous NMDA- or non-NMDA receptor activities. In addition to changes in firing rates, apparent drug-induced changes in firing patterns were also observed in some fiber activities. Using the oligofiber recording techniques, we confirmed a differential role of endogenous ionotropic glutamate receptor activities in regulating sympathetic outflows from the spinal cord of neonatal rats. Fine-tuning of ionotropic glutamate receptor activities in the spinal cord may serve as a simple way for heterogeneous regulation of various sympathetic-targeting tissues. PMID- 23665167 TI - Fast prediction of deleterious angiogenin mutations causing amyotrophic lateral sclerosis. AB - Certain single nucleotide polymorphisms causing missense mutations in angiogenin result in its loss-of-function and onset of amyotrophic lateral sclerosis (ALS). Although several such associations are reported across diverse ethnic groups, no method is available for predicting if a new mutation is deleterious. We present here a fast molecular dynamics based method for determining the mechanisms of functional loss caused by mutations, and attributes to ascertain whether a mutation causes ALS. PMID- 23665165 TI - Parabrachial nucleus involvement in multiple system atrophy. AB - Multiple system atrophy (MSA) is associated with respiratory dysfunction, including sleep apnea, respiratory dysrhythmia, and laryngeal stridor. Neurons of the parabrachial nucleus (PBN) control respiratory rhythmogenesis and airway resistance. OBJECTIVES: The objective of this study is to determine whether there was involvement of putative respiratory regions of the PBN in MSA. METHODS: We examined the pons at autopsy in 10 cases with neuropathologically confirmed MSA and 8 age-matched controls. Sections obtained throughout the pons were processed for calcitonin-gene related peptide (CGRP) and Nissl staining to identify the lateral crescent of the lateral PBN (LPB) and the Kolliker-Fuse nucleus (K-F), which are involved in respiratory control. Cell counts were performed using stereology. RESULTS: There was loss of CGRP neurons in the PBN in MSA (total estimated cell counts for the external LPB cluster was 12,584 +/- 1146 in controls and 5917 +/- 389 in MSA, p<0.0001); for the external medial PBN (MPB) cluster it was 15,081 +/- 1758 in controls and 7842 +/- 466 in MSA, p<0.001. There was also neuronal loss in putative respiratory regions of the PBN, including the lateral crescent of the LPB (13,039 +/- 1326 in controls and 4164 +/- 872 in MSA, p<0.0001); and K-F (5120 +/- 495 in controls and 999 +/- 308 in MSA, p<0.0001). CONCLUSIONS: There is involvement of both CGRP and putative respiratory cell groups in the PBN in MSA. Whereas the clinical implications of CGRP cell loss are still undetermined, involvement of the LPB and K-F may contribute to respiratory dysfunction in this disorder. PMID- 23665168 TI - Structures of Down syndrome kinases, DYRKs, reveal mechanisms of kinase activation and substrate recognition. AB - Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinases (DYRKs) play key roles in brain development, regulation of splicing, and apoptosis, and are potential drug targets for neurodegenerative diseases and cancer. We present crystal structures of one representative member of each DYRK subfamily: DYRK1A with an ATP-mimetic inhibitor and consensus peptide, and DYRK2 including NAPA and DH (DYRK homology) box regions. The current activation model suggests that DYRKs are Ser/Thr kinases that only autophosphorylate the second tyrosine of the activation loop YxY motif during protein translation. The structures explain the roles of this tyrosine and of the DH box in DYRK activation and provide a structural model for DYRK substrate recognition. Phosphorylation of a library of naturally occurring peptides identified substrate motifs that lack proline in the P+1 position, suggesting that DYRK1A is not a strictly proline-directed kinase. Our data also show that DYRK1A wild-type and Y321F mutant retain tyrosine autophosphorylation activity. PMID- 23665169 TI - Structural basis for the unique heterodimeric assembly between cerebral cavernous malformation 3 and germinal center kinase III. AB - Defects in cerebral cavernous malformation protein CCM3 result in cerebral cavernous malformation (CCM), a common vascular lesion of the human CNS. CCM3 functions as an adaptor protein that interacts with various signal proteins. Among these partner proteins, germinal center kinase III (GCKIII) proteins have attracted significant interest because GCKIII-CCM3 interactions play essential roles in vascular physiology. Here, we report the crystal structures of CCM3 in complex with the C-terminal regulatory domains of GCKIII (GCKIIIct) at 2.4 A resolution. Our results reveal that GCKIIIct adopts a fold closely resembling that of the CCM3 N-terminal dimeric domain. GCKIIIct heterodimerizes with CCM3 in a manner analogous to CCM3 homodimerization. The remarkable structural rearrangement of CCM3 induced by GCKIIIct binding and the ensuing interactions within CCM3 are characterized as the structural determinants for GCKIIIct-CCM3 heterodimerization. Taken together, these findings provide a precise structural basis for GCKIIIct-CCM3 heterodimerization and the functional performance of GCKIII mediated by CCM3. PMID- 23665170 TI - Structure of rhomboid protease in complex with beta-lactam inhibitors defines the S2' cavity. AB - Rhomboids are evolutionarily conserved serine proteases that cleave transmembrane proteins within the membrane. The increasing number of known rhomboid functions in prokaryotes and eukaryotes makes them attractive drug targets. Here, we describe structures of the Escherichia coli rhomboid GlpG in complex with beta lactam inhibitors. The inhibitors form a single bond to the catalytic serine and the carbonyl oxygen of the inhibitor faces away from the oxyanion hole. The hydrophobic N-substituent of beta-lactam inhibitors points into a cavity within the enzyme, providing a structural explanation for the specificity of beta lactams on rhomboid proteases. This same cavity probably represents the S2' substrate binding site of GlpG. We suggest that the structural changes in beta lactam inhibitor binding reflect the state of the enzyme at an initial stage of substrate binding to the active site. The structural insights from these enzyme inhibitor complexes provide a starting point for structure-based design for rhomboid inhibitors. PMID- 23665171 TI - An autoinhibited conformation of LGN reveals a distinct interaction mode between GoLoco motifs and TPR motifs. AB - LGN plays essential roles in asymmetric cell divisions via its N-terminal TPR motif-mediated binding to mInsc and NuMA. This scaffolding activity requires the release of the autoinhibited conformation of LGN by binding of Galpha(i) to its C terminal GoLoco (GL) motifs. The interaction between the GL and TPR motifs of LGN represents a distinct GL/target binding mode with an unknown mechanism. Here, we show that two consecutive GL motifs of LGN form a minimal TPR-motif-binding unit. GL12 and GL34 bind to TPR0-3 and TPR4-7, respectively. The crystal structure of a truncated LGN reveals that GL34 forms a pair of parallel alpha helices and binds to the concave surface of TPR4-7, thereby preventing LGN from binding to other targets. Importantly, the GLs bind to TPR motifs with a mode distinct from that observed in the GL/Galpha(i).GDP complexes. Our results also indicate that multiple and orphan GL motif proteins likely respond to G proteins with distinct mechanisms. PMID- 23665172 TI - Co-infection with hepatitis B does not alter treatment response in chronic hepatitis C. AB - BACKGROUND/AIM: To investigate the clinical features and treatment response in patients with hepatitis B (HBV) and hepatitis C virus (HCV) co-infection receiving anti-HCV therapy. PATIENTS AND METHOD: Patients with HBV/HCV co infection, who were eligible for anti-HCV therapy, were included in the study. Patients had detectable HBsAg for at least 6 months and detectable HCV-RNA before the initiation of therapy. Primary end-point was the proportion of patients achieving sustained virological response (SVR). HBV serology and HBV-DNA results obtained during the follow-up were assessed to determine HBV clearance or reactivation after anti-HCV therapy. RESULTS: There were 612 patients in the HCV cohort and 52 (8.5%) of them were HBV/HCV co-infected. Twenty-eight patients (20 male, mean age: 47 +/- 12) received anti-HCV treatment and followed-up for a mean duration of 53 months (12-156). Fifteen patients received peginterferon/ribavirin combination while the remaining patients received standard interferon/ribavirin combination (n=6) or standard interferon monotherapy (n=7). Patients receiving interferon monotherapy were under chronic hemodialysis therapy. SVR was achieved in 14 (50%) patients at the end of follow-up. The proportion of patients with SVR in three treatment arms were not significantly different (P=0.78). Eight of 11 patients with detectable HBV-DNA cleared HBV-DNA during treatment. Seven (25%) patients experienced a rebound in HBV-DNA, and one patient experienced an acute hepatitis flare which was controlled by tenofovir therapy. Two (7%) patients cleared HBsAg and one of them was seroconverted to anti-HBs. CONCLUSION: Co infection with HBV does not have a negative impact on the efficacy of anti-HCV treatment, but HBV-DNA should be monitored to overcome the risk of HBV exacerbation. PMID- 23665175 TI - Evolution of the insect terminal patterning system--insights from the milkweed bug, Oncopeltus fasciatus. AB - The anterior and posterior ends of the insect embryo are patterned through the terminal patterning system, which is best known from the fruitfly Drosophila melanogaster. In Drosophila, the RTK receptor Torso and its presumed co-activator Torso-like initiate a signaling cascade, which activates two terminal gap genes, tailless and huckebein. These in turn interact with various patterning genes to define terminal structures. Work on other insect species has shown that this system is poorly conserved, and not all of its components have been found in all cases studied. We place the variability of the system within a broader phylogenetic framework. We describe the expression and knock-down phenotypes of the homologues of terminal patterning genes in the hemimetabolous Oncopeltus fasciatus. We have examined the interactions among these genes and between them and other patterning genes. We demonstrate that all of these genes have different roles in Oncopeltus relative to Drosophila; torso-like is expressed in follicle cells during oogenesis and is involved in the invagination of the blastoderm to form the germ band, and possibly also in defining the growth zone; tailless is regulated by orthodenticle and has a role only in anterior determination; huckebein is expressed only in the middle of the blastoderm; finally, torso was not found in Oncopeltus and its role in terminal patterning seems novel within holometabolous insects. We then use our data, together with published data on other insects, to reconstruct the evolution of the terminal patterning gene network in insects. We suggest that the Drosophila terminal patterning network evolved recently in the lineage leading to the Diptera, and represents an example of evolutionary "tinkering", where pre-existing pathways are co-opted for a new function. PMID- 23665173 TI - Zebrafish Zic2a and Zic2b regulate neural crest and craniofacial development. AB - Holoprosencephaly (HPE), the most common malformation of the human forebrain, is associated with defects of the craniofacial skeleton. ZIC2, a zinc-finger transcription factor, is strongly linked to HPE and to a characteristic set of dysmorphic facial features in humans. We have previously identified important functions for zebrafish Zic2 in the developing forebrain. Here, we demonstrate that ZIC2 orthologs zic2a and zic2b also regulate the forming zebrafish craniofacial skeleton, including the jaw and neurocranial cartilages, and use the zebrafish to study Zic2-regulated processes that may contribute to the complex etiology of HPE. Using temporally controlled Zic2a overexpression, we show that the developing craniofacial cartilages are sensitive to Zic2 elevation prior to 24hpf. This window of sensitivity overlaps the critical expansion and migration of the neural crest (NC) cells, which migrate from the developing neural tube to populate vertebrate craniofacial structures. We demonstrate that zic2b influences the induction of NC at the neural plate border, while both zic2a and zic2b regulate NC migratory onset and strongly contribute to chromatophore development. Both Zic2 depletion and early ectopic Zic2 expression cause moderate, incompletely penetrant mispatterning of the NC-derived jaw precursors at 24hpf, yet by 2dpf these changes in Zic2 expression result in profoundly mispatterned chondrogenic condensations. We attribute this discrepancy to an additional role for Zic2a and Zic2b in patterning the forebrain primordium, an important signaling source during craniofacial development. This hypothesis is supported by evidence that transplanted Zic2-deficient cells can contribute to craniofacial cartilages in a wild-type background. Collectively, these data suggest that zebrafish Zic2 plays a dual role during craniofacial development, contributing to two disparate aspects of craniofacial morphogenesis: (1) neural crest induction and migration, and (2) early patterning of tissues adjacent to craniofacial chondrogenic condensations. PMID- 23665174 TI - PI3K regulates branch initiation and extension of cultured mammary epithelia via Akt and Rac1 respectively. AB - The tree-like architecture of the mammary gland is generated by branching morphogenesis, which is regulated by many signals from the microenvironment. Here we examined how signaling downstream of phosphoinositide 3-kinase (PI3K) regulates different steps of mammary branching using three-dimensional culture models of the mammary epithelial duct. We found that PI3K was required for both branch initiation and elongation. Activated Akt was enhanced at branch initiation sites where its negative regulator, PTEN, was blocked by signaling via Sprouty2 (SPRY2); inhibiting Akt prevented branch initiation. The pattern of SPRY2 expression, and thus of Akt activation and branch initiation, was controlled by mechanical signaling from endogenous cytoskeletal contractility. In contrast, activated GTP-bound Rac1 localized to the leading edge of nascent branches and was required for branch elongation. These data suggest that the PI3K network integrates mechanical and biochemical signaling to control branching morphogenesis of mammary epithelial cells. PMID- 23665176 TI - Anger and selective attention to reward and punishment in children. AB - Anger is a negative emotion associated with approach motivation and may influence children's attention preference. Three experiments examined the effect of anger on the attentional biases accompanying reward versus punishment cues in Chinese 5 and 6-year-olds. Experiment 1 tested children who were prone to report angry feelings in an unfair game. Experiment 2 measured children who were rated by parents and teachers for temperamental anger. Experiment 3 explored children who reported angry feelings in a frustrating attention task with rigged and noncontingent feedback after controlling for temperament anger. Results suggested that both the angry and anger-prone children were faster to engage attention toward the reward cues than toward the punishment cues in the three experiments. Furthermore, the angry children in the frustrating attention task (and those with poor attention focusing by parental report) were slower in disengaging attention away from the reward versus punishment cues (especially after negative feedback). Results support the approach motivation of anger, which can facilitate children's attention toward the appetitive approach-related information. The findings are discussed in terms of the adaptive and maladaptive function of anger. PMID- 23665177 TI - Early number knowledge and cognitive ability affect early arithmetic ability. AB - Previous literature suggests that early number knowledge is important for the development of arithmetic calculation ability. The domain-general ability of verbal working memory also has an impact on arithmetic ability. This longitudinal study tested the impact of early number knowledge and verbal working memory on the arithmetic calculation ability of children in preschool (N=315) and then later in Grade 1 using structural equation modeling. Three models were used to test hypotheses drawn from previous literature. The current study demonstrates that both early number knowledge and the domain-general ability of verbal working memory affect preschool and Grade 1 arithmetic ability. Early number knowledge had a direct impact on the growth of arithmetic ability, whereas verbal working memory had only an indirect effect via number knowledge and preschool arithmetic ability. These results fit well with von Aster and Shalev's developmental model of numerical cognition (Developmental Medicine & Child Neurology, 2007, Vol. 49, pp. 868-873) and highlight the importance of considering arithmetic ability as independent from early number knowledge. Results also emphasize the importance of training early number knowledge before school entry to promote the development of arithmetic ability. PMID- 23665178 TI - Working memory and social functioning in children. AB - This study extends previous research and examines whether working memory (WM) is associated with multiple measures of concurrent social functioning (peer rejection, overall social competence, relational aggression, physical aggression, and conflict resolutions skills) in typically developing fourth- and fifth-grade children (N=116). Poor central executive WM was associated with both broad social impairments (peer rejection and poor overall social competence) and specific social impairments (physical aggression, relational aggression, and impaired conflict resolution skills); poor verbal storage was associated only with greater peer rejection, and spatial storage was not associated with any measures of social impairment. Analyses also examined whether specific impairments in aggressive behavior and conflict resolution skills mediated the association between central executive and broad measures of social functioning. Greater physical aggression and impaired conflict resolution skills were both significant mediators; relational aggression was not. Implications for theory and future research are discussed. PMID- 23665179 TI - How to bet on a memory: developmental linkages between subjective recollection and decision making. AB - The current study investigated the development of subjective recollection and its role in supporting decisions in 6- and 7-year-olds, 9- and 10-year-olds, and adults (N=78). Participants encoded items and details about them. Later, they were asked to recognize the items, recall the details, and report on subjective feelings of recollection and familiarity for test items. Critically, they were required to select a subset of trials to be evaluated for the possibility of a reward. All age groups were more likely to report subjective recollection when they accurately recalled details, demonstrating an ability to introspect on subtle differences in subjective memory states, although 6- and 7-year-olds could do so reliably only for color details. However, only 9- and 10-year-olds and adults were more likely to select trials that were associated with subjective recollection, suggesting that a connection between this subjective experience and decision making emerges later during middle childhood. PMID- 23665180 TI - The genetic and environmental etiologies of individual differences in early reading growth in Australia, the United States, and Scandinavia. AB - This first cross-country twin study of individual differences in reading growth from post-kindergarten to post-second grade analyzed data from 487 twin pairs from the United States, 267 twin pairs from Australia, and 280 twin pairs from Scandinavia. Data from two reading measures were fit to biometric latent growth models. Individual differences for the reading measures at post-kindergarten in the United States and Australia were due primarily to genetic influences and to both genetic and shared environmental influences in Scandinavia. In contrast, individual differences in growth generally had large genetic influences in all countries. These results suggest that genetic influences are largely responsible for individual differences in early reading development. In addition, the timing of the start of formal literacy instruction may affect the etiology of individual differences in early reading development but have only limited influence on the etiology of individual differences in growth. PMID- 23665181 TI - IFN-gamma production by human natural killer cells in response to HCV-infected hepatoma cells is dependent on accessory cells. AB - BACKGROUND & AIMS: Interferon-gamma (IFN-gamma), a cytokine produced by activated natural killer cells (NK) and T lymphocytes, is an important regulator of innate and adaptive immunity during hepatitis C virus (HCV) infection. However, the cellular sources and mechanisms of IFN-gamma induction in HCV-infection are not fully understood. METHODS: We cultured normal human peripheral blood mononuclear cells (PBMCs) with different populations of immune cells and JFH-1 HCV-infected HuH7.5 (JFH-1/HuH7.5) cells. RESULTS: We found that PBMCs produced large amounts of IFN-gamma after co-culture with JFH-1/HuH7.5 cells. Using intracellular cytokine staining, we confirmed that NK cells and NKT cells (to a lesser extent) were the major IFN-gamma producers within PBMCs. Purified NK/NKT cells did not produce IFN-gamma in response to JFH-1/HuH7.5 cells and depletion of accessory (HLA-DR(+)) cells prevented IFN-gamma induction in PBMCs. Through selective cell depletion of dendritic cells or monocytes from PBMCs, we determined that plasmacytoid dendritic cells (pDCs) were indispensable for NK-IFN-gamma induction and the presence of monocytes was needed for maximal NK-IFN-gamma induction. We further revealed that NK-IFN-gamma induction depended on pDC-derived IFN-alpha while other IFN-gamma inducing cytokines, IL-12, and IL-18, played minimal roles. Close contact between JFH-1/HuH7.5 cells and NK cells was required for IFN-gamma production and monocyte-derived IL-15 significantly augmented IFN-gamma induction. CONCLUSIONS: We discovered a novel mechanism where NK cells interact with pDCs and monocytes, efficiently producing IFN-gamma in response to HCV infected cells. This indicates that co-operation between NK cells and accessory cells is critical for IFN-gamma production and regulation of immunity during HCV infection. PMID- 23665183 TI - Mother-to-infant transmission of hepatitis B virus infection: significance of maternal viral load and strategies for intervention. PMID- 23665182 TI - Differential impact of hyponatremia and hepatic encephalopathy on health-related quality of life and brain metabolite abnormalities in cirrhosis. AB - BACKGROUND & AIMS: Hyponatremia (HN) and hepatic encephalopathy (HE) together can impair health-related quality of life (HRQOL) and cognition in cirrhosis. We aimed at studying the effect of hyponatremia on cognition, HRQOL, and brain MR spectroscopy (MRS) independent of HE. METHODS: Four cirrhotic groups (no HE/HN, HE alone, HN alone (sodium <130 mEq/L), HE+HN) underwent cognitive testing, HRQOL using Sickness Impact Profile (SIP: higher score is worse; has psychosocial and physical sub-scores) and brain MRS (myoinositol (mI) and glutamate+glutamine (Glx)), which were compared across groups. A subset underwent HRQOL testing before/after diuretic withdrawal. RESULTS: 82 cirrhotics (30 no HE/HN, 25 HE, 17 HE+HN, and 10 HN, MELD 12, 63% hepatitis C) were included. Cirrhotics with HN alone and without HE/HN had better cognition compared to HE groups (median abnormal tests no-HE/HN: 3, HN: 3.5, HE: 6.5, HE+HN: 7, p=0.008). Despite better cognition, HN only patients had worse HRQOL in total and psychosocial SIP while both HN groups (with/without HE) had a significantly worse physical SIP (p<0.0001, all comparisons). Brain MRS showed the lowest Glx in HN and the highest in HE groups (p<0.02). mI levels were comparably decreased in the three affected (HE, HE+HN, and HN) groups compared to no HE/HN and were associated with poor HRQOL. Six HE+HN cirrhotics underwent diuretic withdrawal which improved serum sodium and total/psychosocial SIP scores. CONCLUSIONS: Hyponatremic cirrhotics without HE have poor HRQOL despite better cognition than those with concomitant HE. Glx levels were lowest in HN without HE but mI was similar across affected groups. HRQOL improved after diuretic withdrawal. Hyponatremia has a complex, non-linear relationship with brain Glx and mI, cognition and HRQOL. PMID- 23665184 TI - Pleiotropic effects of methionine adenosyltransferases deregulation as determinants of liver cancer progression and prognosis. AB - Downregulation of liver-specific MAT1A gene, encoding S-adenosylmethionine (SAM) synthesizing isozymes MATI/III, and upregulation of widely expressed MAT2A, encoding MATII isozyme, known as MAT1A:MAT2A switch, occurs in hepatocellular carcinoma (HCC). Being inhibited by its reaction product, MATII isoform upregulation cannot compensate for MATI/III decrease. Therefore, MAT1A:MAT2A switch contributes to decrease in SAM level in rodent and human hepatocarcinogenesis. SAM administration to carcinogen-treated rats prevents hepatocarcinogenesis, whereas MAT1A-KO mice, characterized by chronic SAM deficiency, exhibit macrovesicular steatosis, mononuclear cell infiltration in periportal areas, and HCC development. This review focuses upon the pleiotropic changes, induced by MAT1A/MAT2A switch, associated with HCC development. Epigenetic control of MATs expression occurs at transcriptional and post transcriptional levels. In HCC cells, MAT1A/MAT2A switch is associated with global DNA hypomethylation, decrease in DNA repair, genomic instability, and signaling deregulation including c-MYC overexpression, rise in polyamine synthesis, upregulation of RAS/ERK, IKK/NF-kB, PI3K/AKT, and LKB1/AMPK axis. Furthermore, decrease in MAT1A expression and SAM levels results in increased HCC cell proliferation, cell survival, and microvascularization. All of these changes are reversed by SAM treatment in vivo or forced MAT1A overexpression or MAT2A inhibition in cultured HCC cells. In human HCC, MAT1A:MAT2A and MATI/III:MATII ratios correlate negatively with cell proliferation and genomic instability, and positively with apoptosis and global DNA methylation. This suggests that SAM decrease and MATs deregulation represent potential therapeutic targets for HCC. Finally, MATI/III:MATII ratio strongly predicts patients' survival length suggesting that MAT1A:MAT2A expression ratio is a putative prognostic marker for human HCC. PMID- 23665185 TI - Evaluation of the Acute Kidney Injury Network criteria in hospitalized patients with cirrhosis and ascites. AB - BACKGROUND & AIMS: For several years hepatologists have defined acute renal failure in patients with cirrhosis as an increase in serum creatinine (sCr) >= 50% to a final value of sCr>1.5mg/dl (conventional criterion). Recently, the Acute Kidney Injury Network (AKIN) defined acute renal failure as acute kidney injury (AKI) on the basis of an absolute increase in sCr of 0.3mg/dl or a percentage increase in sCr >= 50% providing also a staging from 1 to 3. AKIN stage 1 was defined as an increase in sCr >= 0.3mg/dl or increase in sCr >= 1.5 fold to 2-fold from baseline. AKI diagnosed with the two different criteria was evaluated for the prediction of in-hospital mortality. METHODS: Consecutive hospitalized patients with cirrhosis and ascites were included in the study and evaluated for the development of AKI. RESULTS: Conventional criterion was found to be more accurate than AKIN criteria in improving the prediction of in-hospital mortality in a model including age and Child-Turcotte-Pugh score. The addition of either progression of AKIN stage or a threshold value for sCr of 1.5mg/dl further improves the value of AKIN criteria in this model. More in detail, patients with AKIN stage 1 and sCr<1.5mg/dl had a lower mortality rate (p=0.03), a lower progression rate (p=0.01), and a higher improvement rate (p=0.025) than patients with AKIN stage 1 and sCr >= 1.5mg/dl. CONCLUSIONS: Conventional criterion is more accurate than AKIN criteria in the prediction of in-hospital mortality in patients with cirrhosis and ascites. The addition of either the progression of AKIN stage or the cut-off of sCr >= 1.5mg/dl to the AKIN criteria improves their prognostic accuracy. PMID- 23665186 TI - Reply to: Mother-to-infant transmission of hepatitis B virus infection: significance of maternal viral load and strategies for intervention. PMID- 23665187 TI - Care coordination for patients with cirrhosis: a "win-win" solution for patients, caregivers, providers, and healthcare expenditures. PMID- 23665188 TI - Transcriptomic analysis of the interactions between Agaricus bisporus and Lecanicillium fungicola. AB - Agaricus bisporus is susceptible to a number of diseases, particularly those caused by fungi, with Lecanicillium fungicola being the most serious. Control of this disease is important for the security of crop production, however given the lack of knowledge about fungal-fungal interactions, such disease control is rather limited. Exploiting the recently released genome sequence of A. bisporus, here we report studies simultaneously investigating both the host and the pathogen, focussing on transcriptional changes associated with the cap spotting lesions typically seen in this interaction. Forward-suppressive subtractive hybridisation (SSH) analysis identified 68 A. bisporus unigenes induced during infection. Chitin deacetylase showed the strongest response, with almost 1000 fold up-regulation during infection, so was targeted for down-regulation by silencing to see if it was involved in defence against L. fungicola. Transgenic lines were made expressing hairpin RNAi constructs, however no changes in susceptibility to L. fungicola were observed. Amongst the other up-regulated genes there were none with readily apparent roles in resisting infection in this susceptible interaction. Reverse-SSH identified 72 unigenes from A. bisporus showing reduced expression, including two tyrosinases, several genes involved in nitrogen metabolism and a hydrophobin. The forward-SSH analysis of infected mushrooms also yielded 64 unigenes which were not of A. bisporus origin and thus derived from L. fungicola. An EST analysis of infection-mimicking conditions generated an additional 623 unigenes from L. fungicola including several oxidoreductases, cell wall degrading enzymes, ABC and MFS transporter proteins and various other genes believed to play roles in other pathosystems. Together, this analysis shows how both the pathogen and the host modify their gene expression during an infection-interaction, shedding some light on the disease process, although we note that some 40% of unigenes from both organisms encode hypothetical proteins with no ascribed function which highlights how much there is still to discover about this interaction. PMID- 23665189 TI - Genes associated with lignin degradation in the polyphagous white-rot pathogen Heterobasidion irregulare show substrate-specific regulation. AB - The pathogenic white-rot basidiomycete Heterobasidion irregulare is able to remove lignin and hemicellulose prior to cellulose during the colonization of root and stem xylem of conifer and broadleaf trees. We identified and followed the regulation of expression of genes belonging to families encoding ligninolytic enzymes. In comparison with typical white-rot fungi, the H. irregulare genome has exclusively the short-manganese peroxidase type encoding genes (6 short-MnPs) and thereby a slight contraction in the pool of class II heme-containing peroxidases, but an expansion of the MCO laccases with 17 gene models. Furthermore, the genome shows a versatile set of other oxidoreductase genes putatively involved in lignin oxidation and conversion, including 5 glyoxal oxidases, 19 quinone oxidoreductases and 12 aryl-alcohol oxidases. Their genetic multiplicity and gene specific regulation patterns on cultures based on defined lignin, cellulose or Norway spruce lignocellulose substrates suggest divergent specificities and physiological roles for these enzymes. While the short-MnP encoding genes showed similar transcript levels upon fungal growth on heartwood and reaction zone (RZ), a xylem defense tissue rich in phenolic compounds unique to trees, a subset of laccases showed higher gene expression in the RZ cultures. In contrast, other oxidoreductases depending on initial MnP activity showed generally lower transcript levels on RZ than on heartwood. These data suggest that the rate of fungal oxidative conversion of xylem lignin differs between spruce RZ and heartwood. It is conceivable that in RZ part of the oxidoreductase activities of laccases are related to the detoxification of phenolic compounds involved in host defense. Expression of the several short-MnP enzymes indicated an important role for these enzymes in effective delignification of wood by H. irregulare. PMID- 23665190 TI - Individual variations in the micronucleus assay for biological dosimetry after high dose exposure. AB - The micronucleus assay is widely used as a biological dosimeter. Due to an inhibitory effect of radiation on cell proliferation the assay yields satisfactory results only when the absorbed dose is below about 5Gy. In 2002 Muller and Rode suggested that a modified version of the test, based on the analysis of the ratio of trinucleated to tetranucleated cells and the frequency of micronuclei (Mn) in binucleated cells containing at least one Mn, can be applied to detect a dose reaching 15Gy (Mutat. Res. 502 (2002) 47-51). Their conclusion was based on the results of experiments with lymphocytes from one donor and nothing is known about the possible influence of individual variability on the applicability of the Mn test to detect high doses of radiation. The aim of the present study was to validate the modified micronucleus assay with lymphocytes of 5 donors. Their blood was exposed to 0, 5, 10, 15 and 20Gy of (60)Co gamma rays. The levels of Mn and of cell proliferation were assessed using various approaches. A strong inter-individual variability was observed for all endpoints. The results clearly show that the assessment of cell proliferation is essential for the interpretation of results. Unfortunately, it was not possible to identify one single proliferation marker that gives all necessary information. PMID- 23665191 TI - Improved 1,3-propanediol production by engineering the 2,3-butanediol and formic acid pathways in integrative recombinant Klebsiella pneumoniae. AB - In the biotechnological process, insufficient cofactor NADH and multiple by products restrain the final titer of 1,3-propanediol (1,3-PD). In this study, 1,3 PD production was improved by engineering the 2,3-butanediol (2,3-BD) and formic acid pathways in integrative recombinant Klebsiella pneumoniae. The formation of 2,3-BD is catalysed by acetoin reductase (AR). An inactivation mutation of the AR in K. pneumoniae CF was generated by insertion of a formate dehydrogenase gene. Inactivation of AR and expression of formate dehydrogenase reduced 2,3-BD formation and improved 1,3-PD production. Fermentation results revealed that intracellular metabolic flux was redistributed pronouncedly. The yield of 1,3-PD reached 0.74 mol/mol glycerol in flask fermentation, which is higher than the theoretical yield. In 5 L fed-batch fermentation, the final titer and 1,3-PD yield of the K. pneumoniae CF strain reached 72.2 g/L and 0.569 mol/mol, respectively, which were 15.9% and 21.7% higher than those of the wild-type strain. The titers of 2,3-BD and formic acid decreased by 52.2% and 73.4%, respectively. By decreasing the concentration of all nonvolatile by-products and by increasing the availability of NADH, this study demonstrates an important strategy in the metabolic engineering of 1,3-PD production by integrative recombinant hosts. PMID- 23665192 TI - Induction and construct UV protective yeast plasmid. AB - In this study, we apply concepts of synthetic biology in combination with conventional methods to assemble different genetic components to construct yeast resistant to UV radiation, and to induce production of anti-UV proteins. This work combines sequences of different promoters, STRESS-proteins, heat shock protein (HSP), kinase proteins, alcohol dehydrogenase protein (ADH), ribosomal binding sites, fluorescent reporter proteins, terminators, and a synthetic ribosomal switch. The aim of this investigation was to induce an anti-UV proteins, and to construct an anti-UV yeast plasmid to be used for protection of skin cells against UV radiation. This investigation demonstrates induction and construction of anti-UV genes and production of their corresponding proteins. Cultures of Saccharomyces cerevisiae (ATCC # 66348) were exposed to short-wave UV radiation and were then subjected to time-PCR to assess specific gene expression. Proteins were identified using two dimensional difference gel electrophoresis (2D DIGE) and LC-MS/MS. Different up-regulated and down-regulated proteins were identified. Highly expressed identified proteins were cloned into S. cerevisiae using a synthetic biology approach. Extracts from UV-induced genetically transformed yeasts were used to protect skin cell cultures (ATCC #2522-CRL) in vitro. Both microscopic analysis and an apoptosis assay showed protection of the skin cell cultures against UV radiation. PMID- 23665193 TI - Genome-wide identification of the targets for genetic manipulation to improve L lactate production by Saccharomyces cerevisiae by using a single-gene deletion strain collection. AB - To identify genome-wide targets for gene manipulation for increasing L-lactate production in recombinant Saccharomyces cerevisiae strains, we transformed all available single-gene deletion strains of S. cerevisiae with a plasmid carrying the human L-lactate dehydrogenase gene, and examined L-lactate production in the obtained transformants. The thresholds of increased or decreased L-lactate production were determined based on L-lactate production by the standard strain in repetitive experiments. L-lactate production data for 4802 deletion strains were obtained, and deletion strains with increased or decreased L-lactate production were identified. Functional category analysis of genes whose deletion increased L-lactate production revealed that ribosome biogenesis-related genes were overrepresented. Most deletion strains for genes related to ribosome biogenesis exhibited increased L-lactate production in 200-ml batch cultures. We deleted the genes related to ribosome biogenesis in a recombinant strain of S. cerevisiae with a genetic background different from that of the above deletion strains, and examined the effect of target gene deletion on L-lactate production. We observed that deletion of genes related to ribosome biogenesis leads to increased L-lactate production by recombinant S. cerevisiae strains, and the single-gene deletion strain collection could be utilized in identifying target genes for improving L-lactate production in S. cerevisiae recombinant strains. PMID- 23665194 TI - The development of next-generation sequencing assays for the mitochondrial genome and 108 nuclear genes associated with mitochondrial disorders. AB - Sanger sequencing of multigenic disorders can be technically challenging, time consuming, and prohibitively expensive. High-throughput next-generation sequencing (NGS) can provide a cost-effective method for sequencing targeted genes associated with multigenic disorders. We have developed a NGS clinical targeted gene assay for the mitochondrial genome and for 108 selected nuclear genes associated with mitochondrial disorders. Mitochondrial disorders have a reported incidence of 1 in 5000 live births, encompass a broad range of phenotypes, and are attributed to mutations in the mitochondrial and nuclear genomes. Approximately 20% of mitochondrial disorders result from mutations in mtDNA, with the remaining 80% found in nuclear genes that affect mtDNA levels or mitochondrion protein assembly. In our NGS approach, the 16,569-bp mtDNA is enriched by long-range PCR and the 108 nuclear genes (which represent 1301 amplicons and 680 kb) are enriched by RainDance emulsion PCR. Sequencing is performed on Illumina HiSeq 2000 or MiSeq platforms, and bioinformatics analysis is performed using commercial and in-house developed bioinformatics pipelines. A total of 16 validation and 13 clinical samples were examined. All previously reported variants associated with mitochondrial disorders were found in validation samples, and 5 of the 13 clinical samples were found to have mutations associated with mitochondrial disorders in either the mitochondrial genome or the 108 nuclear genes. All variants were confirmed by Sanger sequencing. PMID- 23665195 TI - Molecular inversion probe array for the genetic evaluation of stillbirth using formalin-fixed, paraffin-embedded tissue. AB - Array comparative hybridization has been used successfully to identify genomic alterations in stillbirth material; however, high DNA quantity and quality requirements may limit its utility in some fetal samples. Molecular inversion probe (MIP) array analysis of FFPE stillbirth autopsy samples circumvents the challenges associated with karyotype and short-term fetal cell culture, requires limited DNA input, and allows for retrospective evaluation of fetal loss. We performed MIP analysis on archival FFPE autopsy tissue to identify underlying genetic abnormalities not previously detected using traditional cytogenetic methods. Archival FFPE stillbirth cases (>=20 weeks gestation) were identified with the following characteristics: i) the phenotype suggested underlying genomic alterations; ii) the karyotype was either normal or not available and there were no other known genetic abnormalities; or iii) previous microarray testing was not performed. Genomic DNA (75 ng) was processed onto a 330,000-feature MIP array. Twenty-seven of 29 (93.1%) FFPE samples had passing MIP quality control scores. Abnormalities were seen in 3 of 27 (11%) archival samples (deletion of 17q12, trisomy 18, and a case of 4qter duplication and 13qter deletion arising from an unbalanced 4q;13q translocation), which, if identified at the time of autopsy, may have changed the course of medical management. This study highlights the benefits of using MIP array analysis for identification of genomic alterations in FFPE stillbirth autopsy tissue. PMID- 23665196 TI - Neurofeedback and standard pharmacological intervention in ADHD: a randomized controlled trial with six-month follow-up. AB - The present study is a randomized controlled trial that aims to evaluate the efficacy of Neurofeedback compared to standard pharmacological intervention in the treatment of attention deficit/hyperactivity disorder (ADHD). The final sample consisted of 23 children with ADHD (11 boys and 12 girls, 7-14 years old). Participants carried out 40 theta/beta training sessions or received methylphenidate. Behavioral rating scales were completed by fathers, mothers, and teachers at pre-, post-treatment, two-, and six-month naturalistic follow-up. In both groups, similar significant reductions were reported in ADHD functional impairment by parents; and in primary ADHD symptoms by parents and teachers. However, significant academic performance improvements were only detected in the Neurofeedback group. Our findings provide new evidence for the efficacy of Neurofeedback, and contribute to enlarge the range of non-pharmacological ADHD intervention choices. To our knowledge, this is the first randomized controlled trial with a six-month follow-up that compares Neurofeedback and stimulant medication in ADHD. PMID- 23665197 TI - Perception of illusory contours forms intermodulation responses of steady state visual evoked potentials as a neural signature of spatial integration. AB - Perception of illusory contours was shown to be a consequence of neural activity related to spatial integration in early visual areas. Candidates for such filling in phenomena are long-range horizontal connections of neurons in V1/V2, and feedback from higher order visual areas. To get a direct measure of spatial integration in early visual cortex, we presented two differently flickering inducers, which evoked steady-state visual evoked potentials (SSVEPs) while manipulating the formation of an illusory rectangle. As a neural marker of integration we tested differences in amplitudes of intermodulation frequencies i.e. linear combinations of the driving frequencies. These were significantly increased when an illusory rectangle was perceived. Increases were neither due to changes of any of the two driving frequencies nor in the frequency that tagged the processing of the compound object, indicating that results are not a consequence of paying more attention to inducers when the illusory rectangle was visible. PMID- 23665198 TI - Effects of Aggregatibacter actinomycetemcomitans leukotoxin on endothelial cells. AB - Aggregatibacter actinomycetemcomitans is a human pathogen that produces leukotoxin (LtxA) as a major virulence factor. In this study the effect of LtxA on microvascular endothelial cell viability and phenotype was studied. High doses of single LtxA treatment (500 ng/ml to 5 MUg/ml) significantly and irreversibly decreased cell proliferation and induced apoptosis, as assessed by tetrazolium salt and annexin V assay, respectively. Apoptosis was partially inhibited by the pan-caspase inhibitor, z-VAD-fmk. LtxA caused a cell cycle arrest in the G2/M phase after 72 h. Between 500 ng/ml and 5 MUg/ml, after long- or short-term stimulation LtxA increased the expression of ICAM-1 and VCAM-1, as well as the percentages of endothelial cells expressing these adhesion molecules. Thus, A. actinomycetemcomitans LtxA has substantial pro-inflammatory effects on human brain endothelial cells by upregulation of ICAM-1 and VCAM-1. Furthermore, LtxA in higher concentration was found to decrease proliferation and induces apoptosis in microvascular endothelial cells. PMID- 23665200 TI - Positioning ganglioside D3 as an immunotherapeutic target in lymphangioleiomyomatosis. AB - Tumors that develop in lymphangioleiomyomatosis (LAM) as a consequence of biallelic loss of TSC1 or TSC2 gene function express melanoma differentiation antigens. However, the percentage of LAM cells expressing these melanosomal antigens is limited. Here, we report the overexpression of ganglioside D3 (GD3) in LAM. GD3 is a tumor-associated antigen otherwise found in melanoma and neuroendocrine tumors; normal expression is largely restricted to neuronal cells in the brain. We also observed markedly reduced serum antibody titers to GD3, which may allow for a population of GD3-expressing LAM cells to expand within patients. This is supported by the demonstrated sensitivity of cultured LAM cells to complement mediated cytotoxicity via GD3 antibodies. GD3 can serve as a natural killer T (NKT) cell antigen when presented on CD1d molecules expressed on professional antigen-presenting cells. Although CD1d-expressing monocyte derivatives were present in situ, enhanced NKT-cell recruitment to LAM lung was not observed. Cultured LAM cells retained surface expression of GD3 over several passages and also expressed CD1d, implying that infiltrating NKT cells can be directly cytotoxic toward LAM lung lesions. Immunization with antibodies to GD3 may thus be therapeutic in LAM, and enhancement of existing NKT-cell infiltration may be effective to further improve antitumor responses. Overall, we hereby establish GD3 as a suitable target for immunotherapy of LAM. PMID- 23665199 TI - Frequent genetic alterations in EGFR- and HER2-driven pathways in breast cancer brain metastases. AB - Current standard systemic therapies for treating breast cancer patients with brain metastases are inefficient. Targeted therapies against human epidermal growth factor receptors are of clinical interest because of their alteration in a subset of breast cancers (BCs). We analyzed copy number, mutation status, and protein expression of epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER2), phosphatase and tensin homologue (PTEN), and PI3K catalytic subunit (PIK3CA) in 110 ductal carcinoma in situ, primary tumor, and metastatic BC samples. Alterations in EGFR, HER2, and PTEN, alone or in combination, were found in a significantly larger fraction of breast cancer brain metastases tumor tissue compared with samples from primary tumors with good prognosis, bone relapse, or other distant metastases (all P < 0.05). Primary tumor patients with a subsequent brain relapse showed almost equally high frequencies of especially EGFR and PTEN alteration as the breast cancer brain metastases patients. PIK3CA was not associated with an increased risk of brain metastases. Genetic alterations in both EGFR and PTEN were especially common in triple-negative breast cancer patients and rarely were seen among HER2-positive patients. In conclusion, we identified two independent high-risk primary BC subgroups for developing brain metastases, represented by genetic alterations in either HER2 or EGFR/PTEN-driven pathways. In contrast, none of these pathways was associated with an increased risk of bone metastasis. These findings highlight the importance of both pathways as possible targets in the treatment of brain metastases in breast cancer. PMID- 23665201 TI - Combination of oxidative stress and FOXM1 inhibitors induces apoptosis in cancer cells and inhibits xenograft tumor growth. AB - Tumor cells accumulate high level of reactive oxygen species (ROS) because they are metabolically more active than normal cells. Elevated ROS levels increase tumorigenecity but also render cancer cells more vulnerable to oxidative stress than normal cells. The oncogenic transcription factor Forkhead Box M1 (FOXM1), which is overexpressed in a wide range of human cancers, was reported to protect cancer cells from the adverse effects of oxidative stress by up regulating the expression of scavenger enzymes. We therefore hypothesized that the combination of FOXM1 ablation and ROS inducers could selectively eradicate cancer cells. We show that RNA interference-mediated knockdown of FOXM1 further elevates intracellular ROS levels and increases sensitivity of cancer cells to ROS mediated cell death after treatment with ROS inducers. We also demonstrate that the combination of ROS inducers with FOXM1/proteasome inhibitors induces robust apoptosis in different human cancer cells. In addition, we show evidence that FOXM1/proteasome inhibitor bortezomib in combination with the ROS inducer beta phenylethyl isothiocyanate efficiently inhibits the growth of breast tumor xenografts in nude mice. We conclude that the combination of ROS inducers and FOXM1 inhibitors could be used as a therapeutic strategy to selectively eliminate cancer cells. PMID- 23665202 TI - Spdef null mice lack conjunctival goblet cells and provide a model of dry eye. AB - Goblet cell numbers decrease within the conjunctival epithelium in drying and cicatrizing ocular surface diseases. Factors regulating goblet cell differentiation in conjunctival epithelium are unknown. Recent data indicate that the transcription factor SAM-pointed domain epithelial-specific transcription factor (Spdef) is essential for goblet cell differentiation in tracheobronchial and gastrointestinal epithelium of mice. Using Spdef(-/-) mice, we determined that Spdef is required for conjunctival goblet cell differentiation and that Spdef(-/-) mice, which lack conjunctival goblet cells, have significantly increased corneal surface fluorescein staining and tear volume, a phenotype consistent with dry eye. Microarray analysis of conjunctival epithelium in Spdef( /-) mice revealed down-regulation of goblet cell-specific genes (Muc5ac, Tff1, Gcnt3). Up-regulated genes included epithelial cell differentiation/keratinization genes (Sprr2h, Tgm1) and proinflammatory genes (Il1-alpha, Il-1beta, Tnf-alpha), all of which are up-regulated in dry eye. Interestingly, four Wnt pathway genes were down-regulated. SPDEF expression was significantly decreased in the conjunctival epithelium of Sjogren syndrome patients with dry eye and decreased goblet cell mucin expression. These data demonstrate that Spdef is required for conjunctival goblet cell differentiation and down-regulation of SPDEF may play a role in human dry eye with goblet cell loss. Spdef(-/-) mice have an ocular surface phenotype similar to that in moderate dry eye, providing a new, more convenient model for the disease. PMID- 23665204 TI - CD147 in regulatory T cells. AB - CD147 or EMMPRIN belongs to the immunoglobulin superfamily of membrane receptors and is expressed in epithelial cells, cancer cells and T cells of the immune system. In T cells CD147 functions as a receptor for soluble cyclophilins and is involved in chemotaxis. We recently reported its expression to high levels and association with suppressive function in regulatory T cells. Here, we discuss its potential application as a marker of activated regulatory T cells. PMID- 23665203 TI - FAM190A deficiency creates a cell division defect. AB - Like the p16, SMAD4, and RB1 genes, FAM190A (alias CCSER1) lies at a consensus site of homogeneous genomic deletions in human cancer. FAM190A transcripts in 40% of cancers also contain in-frame deletions of evolutionarily conserved exons. Its gene function was unknown. We found an internal deletion of the FAM190A gene in a pancreatic cancer having prominent focal multinuclearity. The experimental knockdown of FAM190A expression by shRNA caused focal cytokinesis defects, multipolar mitosis, and multinuclearity as observed in time-lapse microscopy. FAM190A was localized to the gamma-tubulin ring complex of early mitosis and to the midbody in late cytokinesis by immunofluorescence assay and was present in the nuclear fraction of unsynchronized cells by immunoblot. FAM190A interacted with EXOC1 and Ndel1, which function in cytoskeletal organization and the cell division cycle. Levels of FAM190A protein peaked 12 hours after release from thymidine block, corresponding to M-phase. Slower-migrating phosphorylated forms accumulated toward M-phase and disappeared after release from a mitotic block and before cytokinesis. Studies of FAM190A alterations may provide mechanistic insights into mitotic dysregulation and multinuclearity in cancer. We propose that FAM190A is a regulator or structural component required for normal mitosis and that both the rare truncating mutations and common in-frame deletion alteration of FAM190A may contribute to the chromosomal instability of cancer. PMID- 23665205 TI - Myeloperoxidase (MPO)-specific CD4+ T cells contribute to MPO-anti-neutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis. AB - Autoimmunity to the neutrophil enzyme myeloperoxidase (MPO) is an important cause of rapidly progressive glomerulonephritis, but the relative roles of MPO-specific anti-neutrophil cytoplasmic antibodies (MPO-ANCA) and autoreactive effector MPO specific CD4(+) T cells are unclear. We confirmed that passive transfer of murine MPO-ANCA to agammaglobulinemic MUMT mice immunized with OVA induces glomerular injury with capillary wall thickening, fibrinoid necrosis, mesangial cell proliferation, and periglomerular cell infiltration. Preimmunization of MUMT mice with MPO induced MPO-specific CD4(+) T cells and significantly enhanced renal injury after MPO-ANCA transfer. CD4(+) T cell depletion prevented this augmentation of injury, confirming the importance of effector T cells in the development of MPO-ANCA associated glomerulonephritis. Therefore, MPO-ANCA can induce glomerulonephritis through both direct humoral mechanisms (recruitment of neutrophils and deposition of MPO) and indirectly by initiating MPO deposition in glomeruli, thereby directing effector CD4(+) T cell mediated injury. To confirm and support this data, we transferred T cells from MPO-immunized Mpo(-/-)MUMT mice into Rag1(-/-) mice (control mice received ovalbumin specific T cells) and triggered injury by passive MPO-ANCA. Renal injury was significantly greater in mice transferred with T cells from MPO-immunized mice. These current studies demonstrate that MPO-ANCA induces injury via both humoral and cell mediated immune mechanisms. PMID- 23665206 TI - Effects of tolerogenic dendritic cells generated by siRNA-mediated RelB silencing on immune defense and surveillance functions of T cells. AB - Dendritic cells (DCs) can initiate immune responses or induce immune tolerance, according to their level of maturation. In this study, we inhibited RelB expression in immature (im)DCs using small interfering RNA (siRNA) to maintain their immature status. RelB-silenced DCs induced donor-specific hyporesponsiveness in T cells. In contrast, T cells primed by RelB-silenced DCs maintained normal proliferation and cytokine secretion when stimulated by influenza virus antigen. Proliferation was similar between T cells stimulated with syngeneic tumor antigen or donor-specific antigen stimulation, but was significantly lower compared with T cells stimulated with influenza virus antigen. Moreover, an altered pattern of micro181a and micro155 transcriptional levels in T cells was involved in the differential regulation. This study demonstrates that RelB-silenced DCs could induce donor-specific hyporesponsiveness and slightly impair immune surveillance of T cells, while retaining their immune defense functions. PMID- 23665207 TI - Perception without self-matching in conditional tag based cooperation. AB - We consider a model for the evolution of cooperation in a population where individuals may have one of a number of different heritable and distinguishable markers or tags. Individuals interact with each of their neighbors on a square lattice by either cooperating by donating some benefit at a cost to themselves or defecting by doing nothing. The decision to cooperate or defect is contingent on each individual's perception of its interacting partner's tag. Unlike in other tag-based models individuals do not compare their own tag to that of their interaction partner. That is, there is no self-matching. When perception is perfect the cooperation rate is substantially higher than in the usual spatial prisoner's dilemma game when the cost of cooperation is high. The enhancement in cooperation is positively correlated with the number of different tags. The more diverse a population is the more cooperative it becomes. When individuals start with an inability to perceive tags the population evolves to a state where individuals gain at least partial perception. With some reproduction mechanisms perfect perception evolves, but with others the ability to perceive tags is imperfect. We find that perception of tags evolves to lower levels when the cost of cooperation is higher. PMID- 23665208 TI - Heterogeneous distribution of mechanical stress in human lung: a mathematical approach to evaluate abnormal remodeling in IPF. AB - Idiopathic pulmonary fibrosis (IPF) is the most common and severe form of idiopathic interstitial pneumonia. A recently proposed pathogenic model suggests that the concurrent action of cell senescence, exposure to cigarette smoke and mechanical stress due to respiratory lung movements lead to a localized exhaustion of tissue renewal capacity with eventual alveolar loss and abnormal lung remodeling. In this study we have compared the distribution of IPF lesions, as shown by TC radiological images, with the hypothetical distribution of maximal mechanical stress obtained by a simplified mathematical model. The geometry and distribution of stress as determined by our simulation are closely similar to those demonstrated in vivo in the lungs of patients with idiopathic pulmonary fibrosis using high resolution CT scan radiological imaging. These data argue in favor of the recently proposed contribution of mechanical stress to progressive damage and remodeling of lung parenchyma in IPF. The parameters of the model can be tuned on the age of the patients. PMID- 23665209 TI - Can cell mortality determine division of labor in tissue organization? AB - Tissue organization comes from the emergence of cell cooperation where cell homeostasis and function are performed as a trade-off of two excluding proliferative and differentiated cellular states. By introducing function in a population dynamics approach, I study the role of division of labor in tissue optimality when cell turn-over and limitation of space and resources are imposed as natural restrictions of a living tissue. The results indicate that although cell turn-over imposes a inevitable reduction in function abilities, the penalty is smaller when division of labor is at work, especially when a rapid cell turnover and high cell density is a requirement for the tissue, as occurred in epithelia hierarchical tissues. Analytic results are in agreement with the experimental data available in literature. The study provides an explanation about why homogeneous tissues for which proliferative and functional tasks are performed by a same cell type are unlikely to be observed under high cell-renewal requirements. PMID- 23665210 TI - Reply: To PMID 23624205. PMID- 23665211 TI - Static and dynamic approaches yield similar estimates of the thermal sensitivity of insect metabolism. AB - Thermal sensitivity of metabolism (estimated by the temperature coefficient, Q10) is important for understanding ectotherm responses to temperature, but can only be measured empirically. Several strategies can be used to estimate thermal sensitivity. Static temperature respirometry uses measurements of metabolic rate taken at a series of temperatures, either by using different individuals at each temperature (independent STR, iSTR), or the same individual at several different temperatures (repeated STR, rSTR). Q10 can also be estimated from measurements of metabolic rate during a monotonic change in temperature (dynamic temperature respirometry, DTR), using either upwards (uDTR) or downwards (dDTR) temperature ramps. We compared estimates of Q10 of metabolic rate in adult females of the fall field cricket, Gryllus pennsylvanicus, derived from measurements made between 8 and 35 degrees C, using iSTR, rSTR, dDTR and uDTR. We also controlled for aging effects during rSTR, and for ramp rate during DTR. We found that all measurement methods yielded statistically comparable measures of Q10. However, DTR provided higher absolute estimates of metabolic rate than STR. Thus, it appears that the different methods provide comparable estimates of Q10, allowing meta-analyses to utilize estimates of Q10 derived from different methods, and for the measurement strategy to be tailored to the characteristics of the organism. PMID- 23665212 TI - Exploring sensitive boundaries in nursing education: attitudes of undergraduate student nurses providing intimate care to patients. AB - BACKGROUND: Nursing students often feel challenged and intimidated to provide intimate care to patients in the health care setting. Student nurses in particular are faced with social, professional, academic and peer expectations and experience high levels of stress when providing this intimate care. OBJECTIVE: Explore student nurses attitudes to providing intimate care. METHODS: Year two and year three students of a three year undergraduate nursing programme completed a descriptive Nursing Students Intimate Care (NSIC) survey with open ended questions. This study discusses student responses to the question: Did you feel it was appropriate for a nurse to provide intimate care to a patient of the opposite sex? RESULTS: Three major themes were identified: societal and self determined role expectations, comfort and discomfort providing intimate care, and age and gender of the carer and recipient. CONCLUSIONS: Student nurses face numerous challenges when having to provide intimate care to patients. These challenges are influenced by the age, gender, levels of comfort of the nurse and the patient and is related to the nature of intimate care being provided. Student nurses will benefit from pre-clinical simulated training experiences in providing intimate care. This training needs to specifically consider being sensitive to the needs of the patient, maintaining patient dignity, negotiating, accommodating and implementing plan of care while being competent and professional in their approach to providing intimate care. PMID- 23665214 TI - Alteration of muscle membrane excitability in sepsis: possible involvement of ciliary nervous trophic factor (CNTF). AB - One of the main factor involved neuromyopathy acquired in intensive care unit (ICU) appears to be sepsis. It induces the release of many pro- and anti inflammatory factors which can directly modulate the muscle excitability. We have studied the effects of one of them: the ciliary nervous trophic factor (CNTF) which is a cytokine released in the early phase of sepsis. CNTF induces a decrease in the sodium current and an increase in resting potential as in sodium inversion potential. These effects could participate to the hypo-excitability observed during sepsis and could be involved in the ICU acquired neuromyopathy. As for TNFalpha, this early effect is mainly mediated by protein kinase C (PKC) activation and appears to be a reversible post-transcriptional effect. PMID- 23665215 TI - Evaluation of ligninolytic enzymes, ultrasonication and liquid hot water as pretreatments for bioethanol production from cotton gin trash. AB - Cotton gin trash (CGT) is a ubiquitous cotton-production-waste resource which can be used for ethanol production. In this research, seven combinations of three pretreatments; ultrasonication, liquid hot water and ligninolytic enzymes were evaluated on CGT to select the best pretreatments combination that increased the cellulose conversion and the ethanol yield in the saccharification and fermentation processes, respectively. The structural changes in the cellulose, hemicellulose and lignin from CGT were followed using FT-IR after each pretreatment. All the pretreatment combinations modified the CGT's structure and composition compared with the unpretreated CGT, and the majority of them improved release of sugars originally present in the CGT. The best results were achieved by the sequential combination of ultrasonication, hot water, and ligninolytic enzymes with an improvement of 10% in the ethanol yield and cellulose conversion compared to the other pretreatments. These results are a contribution to develop a feasible bioethanol production from CGT. PMID- 23665216 TI - Structural properties of pretreated biomass from different acid pretreatments and their effects on simultaneous saccharification and ethanol fermentation. AB - The aim of this study was to investigate the effects of different acid pretreatments on the hydrolysis of biomass and ethanol production. Maleic, oxalic, and sulfuric acids were used individually as catalysts. The fermentable sugar concentration in hydrolysate was high at more than 30 g/L, which obtained at the dicarboxylic acid pretreatment. On the structural change of pretreated biomass, the S/G ratio ranged from 1.7 to 2.0, which was lower than that of raw material. The amount of phenolic OH group was significantly increased by acid pretreatment, which ranged 17.5-32.8%, compared to 4.7% of the raw material. The amounts of phenolic OH group in lignin sensitively affected simultaneous saccharification and fermentation. The maleic acid pretreated biomass, which included 17.5% of the phenolic OH group, was very effective for attaining high glucose yields and ethanol yield, after simultaneous saccharification and fermentation. At the same time, the highest ethanol yield was 0.48. PMID- 23665217 TI - Sequential nitrification-denitrification process for nitrogenous, sulfurous and phenolic compounds removal in the same bioreactor. AB - The kinetic and metabolic behavior of an aerobic granular sludge to nitrify, denitrify and nitrify-denitrify was evaluated in batch cultures. In nitrification control, ammonium, 4-methylphenol and sulfide were consumed efficiently (~100%) and recovered as NO3(-), CO2, S(0) and SO4(2-), respectively. In denitrification control, S(0) and nitrate were efficiently consumed and recovered as SO4(2-) and N2, respectively. Sequential nitrification-denitrification process was evaluated by applying oxic/anoxic conditions. Ammonium, 4-methylphenol and sulfide were oxidized to nitrate, CO2 and mainly S(0), respectively, under aerobic conditions. After that, anoxic conditions were established where S(0) reduced all nitrate to N2, with molecular nitrogen yield (YN2) of 1.03 +/- 0.06 mg/mg NH4(+)-N consumed. This is the first study to show the capability of an aerobic granular sludge in simultaneous removal of ammonium, 4-methylphenol and sulfide by sequential nitrification-denitrification process in the same bioreactor. PMID- 23665218 TI - p53 efficiently suppresses tumor development in the complete absence of its cell cycle inhibitory and proapoptotic effectors p21, Puma, and Noxa. AB - Activation of apoptosis through transcriptional induction of Puma and Noxa has long been considered to constitute the critical (if not sole) process by which p53 suppresses tumor development, although G1/S boundary cell-cycle arrest via induction of the CDK inhibitor p21 has also been thought to contribute. Recent analyses of mice bearing mutations that impair p53-mediated induction of select target genes have indicated that activation of apoptosis and G1/S cell-cycle arrest may, in fact, be dispensable for p53-mediated tumor suppression. However, the expression of Puma, Noxa, and p21 was not abrogated in these mutants, only reduced; therefore, the possibility that the reduced levels of these critical effectors of p53-mediated apoptosis and G1/S-cell-cycle arrest sufficed to prevent tumorigenesis could not be excluded. To resolve this important issue, we have generated mice deficient for p21, Puma, and Noxa (p21-/-puma-/-noxa-/- mice). Cells from these mice were deficient in their ability to undergo p53 mediated apoptosis, G1/S cell-cycle arrest, and senescence. Nonetheless, these animals remained tumor free until at least 500 days, in contrast to p53-deficient mice, which had all succumbed to lymphoma or sarcoma by 250 days. Interestingly, DNA lesions induced by gamma-irradiation persisted longer in p53-deficient cells compared to wild-type or p21-/-puma-/-noxa-/- cells, and the former failed to transcriptionally activate several p53 target genes implicated in DNA repair. These results demonstrate beyond a doubt that the induction of apoptosis, cell cycle arrest, and possibly senescence is dispensable for p53-mediated suppression of spontaneous tumor development and indicate that coordination of genomic stability and possibly other processes, such as metabolic adaptation, may instead be critical. PMID- 23665219 TI - The bacterial SMC complex displays two distinct modes of interaction with the chromosome. AB - The bacterial SMC (structural maintenance of chromosomes) complex binds nonspecifically to DNA in vitro and forms two discrete subcellular centers in vivo, one in each cell half. How this distribution is maintained is unclear. We show by time-lapse imaging of single molecules that the localization is achieved through limited, yet rapid movement of the SMC subunits through the nucleoid. Accessory ScpAB subunits mediate the arrest of 20% of SMC molecules at the center of a cell half and do not move together with the 80% mobile SMC molecules. Only free SMC, but not the preformed SMC/ScpAB complex, was able to bind to DNA in vitro, revealing distinct functions of SMC fractions. Thus, whereas SMC alone dynamically interacts with many sites on the chromosome, it forms static assemblies together with ScpAB complex partners. Our findings reveal two distinct modes of interaction of SMC with the chromosome and indicate that limited diffusion within a confined space and transient arrest may be a general mechanism for positioning proteins within a chromosome and within a noncompartmentalized cell. PMID- 23665221 TI - Differential phosphorylation of Smad1 integrates BMP and neurotrophin pathways through Erk/Dusp in axon development. AB - Sensory axon development requires concerted actions of growth factors for the precise control of axonal outgrowth and target innervation. How developing sensory neurons integrate different cues is poorly understood. We demonstrate here that Smad1 activation is required for neurotrophin-mediated sensory axon growth in vitro and in vivo. Through differential phosphorylation, Smad1 exerts transcriptional selectivity to regulate the expression and activity of Erk1 and Erk2-two key neurotrophin effectors. Specifically, bone morphogenetic proteins (BMPs) signal through carboxy-terminal phosphorylation of Smad1 (pSmad1C) to induce Erk1/2 transcription for enhanced neurotrophin responsiveness. Meanwhile, neurotrophin signaling results in linker phosphorylation of Smad1 (pSmad1L), which in turn upregulates an Erk-specific dual-specificity phosphatase, Dusp6, leading to reduced pErk1/2 and constituting a negative-feedback loop for the prevention of axon overgrowth. Together, the BMP and neurotrophin pathways form a tightly regulated signaling network with a balanced ratio of Erk1/2 and pErk1/2 to direct the precise connections between sensory neurons and peripheral targets. PMID- 23665220 TI - Identifying network motifs that buffer front-to-back signaling in polarized neutrophils. AB - Neutrophil polarity relies on local, mutual inhibition to segregate incompatible signaling circuits to the leading and trailing edges. Mutual inhibition alone should lead to cells having strong fronts and weak backs or vice versa. However, analysis of cell-to-cell variation in human neutrophils revealed that back polarity remains consistent despite changes in front strength. How is this buffering achieved? Pharmacological perturbations and mathematical modeling revealed a functional role for microtubules in buffering back polarity by mediating positive, long-range crosstalk from front to back; loss of microtubules inhibits buffering and results in anticorrelation between front and back signaling. Furthermore, a systematic, computational search of network topologies found that a long-range, positive front-to-back link is necessary for back buffering. Our studies suggest a design principle that can be employed by polarity networks: short-range mutual inhibition establishes distinct signaling regions, after which directed long-range activation insulates one region from variations in the other. PMID- 23665222 TI - Discovering RNA-protein interactome by using chemical context profiling of the RNA-protein interface. AB - RNA-protein (RNP) interactions generally are required for RNA function. At least 5% of human genes code for RNA-binding proteins. Whereas many approaches can identify the RNA partners for a specific protein, finding the protein partners for a specific RNA is difficult. We present a machine-learning method that scores a protein's binding potential for an RNA structure by utilizing the chemical context profiles of the interface from known RNP structures. Our approach is applicable even when only a single RNP structure is available. We examined 801 mammalian proteins and find that 37 (4.6%) potentially bind transfer RNA (tRNA). Most are enzymes involved in cellular processes unrelated to translation and were not known to interact with RNA. We experimentally tested six positive and three negative predictions for tRNA binding in vivo, and all nine predictions were correct. Our computational approach provides a powerful complement to experiments in discovering new RNPs. PMID- 23665223 TI - p53 DNA binding cooperativity is essential for apoptosis and tumor suppression in vivo. AB - Four molecules of the tumor suppressor p53 assemble to cooperatively bind proapoptotic target genes. The structural basis for cooperativity consists of interactions between adjacent DNA binding domains. Mutations at the interaction interface that compromise cooperativity were identified in cancer patients, suggesting a requirement of cooperativity for tumor suppression. We report on an analysis of cooperativity mutant p53E177R mice. Apoptotic functions of p53 triggered by DNA damage and oncogenes were abolished in these mice, whereas functions in cell-cycle control, senescence, metabolism, and antioxidant defense were retained and were sufficient to suppress development of spontaneous T cell lymphoma. Cooperativity mutant mice are nevertheless highly cancer prone and susceptible to different oncogene-induced tumors. Our data underscore the relevance of DNA binding cooperativity for p53-dependent apoptosis and tumor suppression and highlight cooperativity mutations as a class of p53 mutations that result in a selective loss of apoptotic functions due to an altered quaternary structure of the p53 tetramer. PMID- 23665224 TI - The Phr1 ubiquitin ligase promotes injury-induced axon self-destruction. AB - Axon degeneration is an evolutionarily conserved process that drives the loss of damaged axons and is an early event in many neurological disorders, so it is important to identify the molecular constituents of this poorly understood mechanism. Here, we demonstrate that the Phr1 E3 ubiquitin ligase is a central component of this axon degeneration program. Loss of Phr1 results in prolonged survival of severed axons in both the peripheral and central nervous systems, as well as preservation of motor and sensory nerve terminals. Phr1 depletion increases the axonal level of the axon survival molecule nicotinamide mononucleotide adenyltransferase 2 (NMNAT2), and NMNAT2 is necessary for Phr1 dependent axon stability. The profound long-term protection of peripheral and central mammalian axons following Phr1 deletion suggests that pharmacological inhibition of Phr1 function may be an attractive therapeutic candidate for amelioration of axon loss in neurological disease. PMID- 23665225 TI - Structural basis for recognition of the pore-forming toxin intermedilysin by human complement receptor CD59. AB - Pore-forming proteins containing the structurally conserved membrane attack complex/perforin fold play an important role in immunity and host-pathogen interactions. Intermedilysin (ILY) is an archetypal member of a cholesterol dependent cytolysin subclass that hijacks the complement receptor CD59 to make cytotoxic pores in human cells. ILY directly competes for the membrane attack complex binding site on CD59, rendering cells susceptible to complement lysis. To understand how these bacterial pores form in lipid bilayers and the role CD59 plays in complement regulation, we determined the crystal structure of human CD59 bound to ILY. Here, we show the ILY-CD59 complex at 3.5 A resolution and identify two interfaces mediating this host-pathogen interaction. An ILY-derived peptide based on the binding site inhibits pore formation in a CD59-containing liposome model system. These data provide insight into how CD59 coordinates ILY monomers, nucleating an early prepore state, and suggest a potential mechanism of inhibition for the complement terminal pathway. PMID- 23665226 TI - Cationized IVIg as a potential substitute to IVIg for the treatment of experimental immune thrombocytopenia. AB - In this study, we evaluated the possibility of using cationized IVIg (cIVIg) instead of IVIg as a more effective therapy for the treatment of experimental immune thrombocytopenia in mice. The pharmacokinetics (PK) and biodistribution of cIVIg and IVIg in mice were compared. cIVIg displayed a shorter plasma half-life and an increased organ uptake in both the spleen and liver compared to IVIg, suggesting that cIVIg could be more potent than IVIg to prevent platelet clearance in a mouse model of thrombocytopenia. However, although the biodistribution of cIVIg in the spleen and liver was improved, its ability to prevent platelet clearance in mice remained similar to that of IVIg. Altogether, our data demonstrate the possibility of using chemical cationization of IVIg preparations to increase organ uptake, and also highlight the challenges of developing effective substitutes to IVIg. PMID- 23665227 TI - A transcriptome-wide RNAi screen in the Drosophila ovary reveals factors of the germline piRNA pathway. AB - The Drosophila piRNA pathway provides an RNA-based immune system that defends the germline genome against selfish genetic elements. Two interrelated branches of the piRNA system exist: somatic cells that support oogenesis only employ Piwi, whereas germ cells utilize a more elaborate pathway centered on the three gonad specific Argonaute proteins (Piwi, Aubergine, and Argonaute 3). While several key factors of each branch have been identified, our current knowledge is insufficient to explain the complex workings of the piRNA machinery. Here, we report a reverse genetic screen spanning the ovarian transcriptome in an attempt to uncover the full repertoire of genes required for piRNA-mediated transposon silencing in the female germline. Our screen reveals key factors of piRNA mediated transposon silencing, including the piRNA biogenesis factors CG2183 (GASZ) and Deadlock. Our data uncover a previously unanticipated set of factors preferentially required for repression of different transposon types. PMID- 23665228 TI - A genome-wide RNAi screen draws a genetic framework for transposon control and primary piRNA biogenesis in Drosophila. AB - A large fraction of our genome consists of mobile genetic elements. Governing transposons in germ cells is critically important, and failure to do so compromises genome integrity, leading to sterility. In animals, the piRNA pathway is the key to transposon constraint, yet the precise molecular details of how piRNAs are formed and how the pathway represses mobile elements remain poorly understood. In an effort to identify general requirements for transposon control and components of the piRNA pathway, we carried out a genome-wide RNAi screen in Drosophila ovarian somatic sheet cells. We identified and validated 87 genes necessary for transposon silencing. Among these were several piRNA biogenesis factors. We also found CG3893 (asterix) to be essential for transposon silencing, most likely by contributing to the effector step of transcriptional repression. Asterix loss leads to decreases in H3K9me3 marks on certain transposons but has no effect on piRNA levels. PMID- 23665229 TI - Ubiquitin binding by a CUE domain regulates ubiquitin chain formation by ERAD E3 ligases. AB - Ubiquitin-binding domains (UBDs) differentially recognize ubiquitin (ub) modifications. Some of them specifically bind mono-ub, as has been shown for the CUE domain. Interestingly, so far no significant ubiquitin binding has been observed for the CUE domain of yeast Cue1p. Cue1p is receptor and activator of the ubiquitin-conjugating enzyme Ubc7p. It integrates Ubc7p into endoplasmic reticulum (ER) membrane-bound ubiquitin ligase complexes, and thus, it is crucial for ER-associated protein degradation (ERAD). Here we show that the CUE domain of Cue1p binds ubiquitin chains, which is pivotal for the efficient formation of K48 linked polyubiquitin chains in vitro. Mutations that abolish ubiquitin binding by Cue1p affect the turnover of ERAD substrates in vivo. Our data strongly imply that the CUE domain facilitates substrate ubiquitylation by stabilizing growing ubiquitin chains at the ERAD ubiquitin ligases. Hence, we demonstrate an unexpected function of a UBD in the regulation of ubiquitin chain synthesis. PMID- 23665230 TI - A structurally unique E2-binding domain activates ubiquitination by the ERAD E2, Ubc7p, through multiple mechanisms. AB - Cue1p is an integral component of yeast endoplasmic reticulum (ER)-associated degradation (ERAD) ubiquitin ligase (E3) complexes. It tethers the ERAD ubiquitin conjugating enzyme (E2), Ubc7p, to the ER and prevents its degradation, and also activates Ubc7p via unknown mechanisms. We have now determined the crystal structure of the Ubc7p-binding region (U7BR) of Cue1p with Ubc7p. The U7BR is a unique E2-binding domain that includes three alpha-helices that interact extensively with the "backside" of Ubc7p. Residues essential for E2 binding are also required for activation of Ubc7p and for ERAD. We establish that the U7BR stimulates both RING-independent and RING-dependent ubiquitin transfer from Ubc7p. Moreover, the U7BR enhances ubiquitin-activating enzyme (E1)-mediated charging of Ubc7p with ubiquitin. This demonstrates that an essential component of E3 complexes can simultaneously bind to E2 and enhance its loading with ubiquitin. These findings provide mechanistic insights into how ubiquitination can be stimulated. PMID- 23665231 TI - The genetic makeup of the Drosophila piRNA pathway. AB - The piRNA (PIWI-interacting RNA) pathway is a small RNA silencing system that acts in animal gonads and protects the genome against the deleterious influence of transposons. A major bottleneck in the field is the lack of comprehensive knowledge of the factors and molecular processes that constitute this pathway. We conducted an RNAi screen in Drosophila and identified ~50 genes that strongly impact the ovarian somatic piRNA pathway. Many identified genes fall into functional categories that indicate essential roles for mitochondrial metabolism, RNA export, the nuclear pore, transcription elongation, and chromatin regulation in the pathway. Follow-up studies on two factors demonstrate that components acting at distinct hierarchical levels of the pathway were identified. Finally, we define CG2183/Gasz as an essential primary piRNA biogenesis factor in somatic and germline cells. Based on the similarities between insect and vertebrate piRNA pathways, our results have far-reaching implications for the understanding of this conserved genome defense system. PMID- 23665232 TI - Metabolic control of persister formation in Escherichia coli. AB - Bacterial persisters are phenotypic variants that form from the action of stress response pathways triggering toxin-mediated antibiotic tolerance. Although persisters form during normal growth from native stresses, the pathways responsible for this phenomenon remain elusive. Here we have discovered that carbon source transitions stimulate the formation of fluoroquinolone persisters in Escherichia coli. Further, through a combination of genetic, biochemical, and flow cytometric assays in conjunction with a mathematical model, we have reconstructed a molecular-level persister formation pathway from initial stress (glucose exhaustion) to the activation of a metabolic toxin-antitoxin (TA) module (the ppGpp biochemical network) resulting in inhibition of DNA gyrase activity, the primary target of fluoroquinolones. This pathway spans from initial stress to antibiotic target and demonstrates that TA behavior can be exhibited by a metabolite-enzyme interaction (ppGpp-SpoT), in contrast to classical TA systems that involve only protein and/or RNA. PMID- 23665234 TI - Enhancing the efficiency of direct reprogramming of human mesenchymal stem cells into mature neuronal-like cells with the combination of small molecule modulators of chromatin modifying enzymes, SMAD signaling and cyclic adenosine monophosphate levels. AB - Advances in cell reprogramming technologies to generate patient-specific cells of a desired type will revolutionize the field of regenerative medicine. While several cell reprogramming methods have been developed over the last decades, the majority of these technologies require the exposure of cell nuclei to reprogramming large molecules via transfection, transduction, cell fusion or nuclear transfer. This raises several technical, safety and ethical issues. Chemical genetics is an alternative approach for cell reprogramming that uses small, cell membrane penetrable substances to regulate multiple cellular processes including cell plasticity. Recently, using the combination of small molecules that are involved in the regulation chromatin structure and function and agents that favor neural differentiation we have been able to generate neural like cells from human mesenchymal stem cells. In this study, to improve the efficiency of neuronal differentiation and maturation, two specific inhibitors of SMAD signaling (SMAD1/3 and SMAD3/5/8) that play an important role in neuronal differentiation of embryonic stem cells, were added to our previous neural induction recipe. Results demonstrated that human mesenchymal stem cells grown in this culture conditions exhibited higher expression of several mature neuronal genes, formed synapse-like structures and exerted electrophysiological properties of differentiating neural stem cells. Thus, an efficient method for production of mature neuronal-like cells from human adult bone marrow derived mesenchymal stem cells has been developed. We concluded that specific combinations of small molecules that target specific cell signaling pathways and chromatin modifying enzymes could be a promising approach for manipulation of adult stem cell plasticity. PMID- 23665235 TI - MiR-224 impairs adipocyte early differentiation and regulates fatty acid metabolism. AB - MicroRNAs (miRNAs) are small ~22 nucleotide regulatory RNAs that regulate the stability and translation of cognate messenger RNAs (mRNAs). MicroRNAs participate in the regulation of adipogenesis and identification of the full repertoire of MicroRNAs expressed in adipose tissue is likely to improve our understanding of adipose tissue growth and development significantly. In the present study, it is found that miR-224-5p abundance decreases first and then increases during adipogenesis of 3T3-L1 cells. And early growth response 2 (EGR2) and Acyl-CoA synthetase long-chain family member 4 (ACSL4) are direct targets of miR-224-5p. Further studies in mouse 3T3-L1 cell-line shows that miR-224-5p is a novel negative regulator of adipocyte differentiation through post transcriptional regulation of early growth response 2 during early adipogenesis. Furthermore, miR-224-5p could regulate fatty acid metabolism through Acyl-CoA synthetase long-chain family member 4 at terminal differentiation. It indicates that miR-224 plays different roles on different stages of adipogenesis. PMID- 23665236 TI - EVI1 targets DeltaNp63 and upregulates the cyclin dependent kinase inhibitor p21 independent of p53 to delay cell cycle progression and cell proliferation in colon cancer cells. AB - Several lines of evidence suggest that specific transcriptional events are involved in cell cycle, proliferation and differentiation processes; however, their deregulation by proto-oncogenes are involved in the development of leukemia and tumors. One such proto-oncogene is ecotropic viral integration site I which can differentially effect cell cycle progression and proliferation, in cell types of different origin. Our data for the first time shows that ecotropic viral integration site I binds to DeltaNp63 promoter element directly and down regulates its expression. Down regulation of DeltaNp63 induces the expression of p21 in HT-29 cells and also in colon carcinoma cells that do not express p53 including patient samples expressing low level of p53, that eventually delay cell cycle progression at G0/G1 phase. Concomitant silencing of ecotropic viral integration site I from the cells or introduction of DeltaNp63 to the cells significantly rescued this phenotype, indicating the growth defect induced by DeltaNp63 deficiency to be, at least in part, attributable to ecotropic viral integration site I function. The mutual regulation between ecotropic viral integration site I and DeltaNp63 may constitute a novel axis which might affect the downstream pathways in cells that do not express functional p53. PMID- 23665237 TI - Lipid raft regulates the initial spreading of melanoma A375 cells by modulating beta1 integrin clustering. AB - Cell adhesion and spreading require integrins-mediated cell-extracellular matrix interaction. Integrins function through binding to extracellular matrix and subsequent clustering to initiate focal adhesion formation and actin cytoskeleton rearrangement. Lipid raft, a liquid ordered plasma membrane microdomain, has been reported to play major roles in membrane motility by regulating cell surface receptor function. Here, we identified that lipid raft integrity was required for beta1 integrin-mediated initial spreading of melanoma A375 cells on fibronectin. We found that lipid raft disruption with methyl-beta-cyclodextrin led to the inability of focal adhesion formation and actin cytoskeleton rearrangement by preventing beta1 integrin clustering. Furthermore, we explored the possible mechanism by which lipid raft regulates beta1 integrin clustering and demonstrated that intact lipid raft could recruit and modify some adaptor proteins, such as talin, alpha-actinin, vinculin, paxillin and FAK. Lipid raft could regulate the location of these proteins in lipid raft fractions and facilitate their binding to beta1 integrin, which may be crucial for beta1 integrin clustering. We also showed that lipid raft disruption impaired A375 cell migration in both transwell and wound healing models. Together, these findings provide a new insight for the relationship between lipid raft and the regulation of integrins. PMID- 23665233 TI - Nutrition knowledge is associated with higher adherence to Mediterranean diet and lower prevalence of obesity. Results from the Moli-sani study. AB - A Mediterranean dietary pattern has been associated with reducing the risk of cardiovascular and chronic disease. The aim of this study was to evaluate the role of nutrition knowledge in determining possible differences among dietary patterns in a general population from a Mediterranean region. We conducted a cross-sectional study on a subsample of 744 subjects enrolled in the population based cohort of the Moli-sani Project. A 92-item questionnaire on nutrition knowledge was elaborated, validated and administered. Dietary information were obtained from the EPIC food frequency questionnaire and adherence to a Mediterranean dietary pattern was evaluated both by the a priori Greek Mediterranean diet score and the a posteriori approach obtained by principal component analysis. Nutrition knowledge was significantly associated with higher adherence to a Mediterranean dietary pattern. The odds of having higher adherence to a Mediterranean dietary pattern increased with greater nutrition knowledge. The odds ratio of being obese significantly decreased with increasing nutrition knowledge levels. The results showed that nutrition knowledge was significantly associated with higher adherence to a Mediterranean dietary pattern and with lower prevalence of obesity in a Southern Italian region with Mediterranean diet tradition independently from education and other socioeconomic factors. PMID- 23665238 TI - Intestinal caveolin-1 is important for dietary fatty acid absorption. AB - How dietary fatty acids are absorbed into the enterocyte and transported to the ER is not established. We tested the possibility that caveolin-1 containing lipid rafts and endocytic vesicles were involved. Apical brush border membranes took up 15% of albumin bound (3)H-oleate whereas brush border membranes from caveolin-1 KO mice took up only 1%. In brush border membranes, the (3)H-oleate was in the detergent resistant fraction of an OptiPrep gradient. On OptiPrep gradients of intestinal cytosol, we also found the (3)H-oleate in the detergent resistant fraction, separate from OptiPrep gradients spiked with (3)H-oleate or (3)H triacylglycerol. Caveolin-1 immuno-depletion of cytosol removed 91% of absorbed (3)H-oleate whereas immuno-depletion using IgG, or anti-caveolin-2 or -3 or anti clathrin antibodies removed 20%. Electron microscopy showed the presence of caveolin-1 containing vesicles in WT mouse cytosol that were 4 fold increased by feeding intestinal sacs 1mM oleate. No vesicles were seen in caveolin-1 KO mouse cytosol. Caveolin-1 KO mice gained less weight on a 23% fat diet and had increased fat in their stool compared to WT mice. We conclude that dietary fatty acids are absorbed by caveolae in enterocyte brush border membranes, are endocytosed, and transported in cytosol in caveolin-1 containing endocytic vesicles. PMID- 23665239 TI - Differential protein expression in mussels Mytilus galloprovincialis exposed to nano and ionic Ag. AB - Ag NPs are one of the most commonly used NPs in nanotechnology whose environmental impacts are to date unknown and the information about bioavailability, mechanisms of biological uptake and toxic implications in organisms is scarce. So, the main objective of this study was to investigate differences in protein expression profiles in gills and digestive gland of mussels Mytilus galloprovincialis exposed to Ag NPs and Ag(+) (10 MUg L(-1)) for a period of 15 days. Protein expression profiles of exposed gills and digestive glands were compared to those of control mussels using two-dimensional electrophoresis to discriminate differentially expressed proteins. Different patterns of protein expression were obtained for exposed mussels, dependent not only on the different redox requirements of each tissue but also to the Ag form used. Unique sets of differentially expressed proteins were affected by each silver form in addition to proteins that were affected by both Ag NPs and Ag(+). Fifteen of these proteins were subsequently identified by MALDI-TOF-TOF and database search. Ag NPs affected similar cellular pathways as Ag(+), with common response mechanisms in cytoskeleton and cell structure (catchin, myosin heavy chain), stress response (heat shock protein 70), oxidative stress (glutathione s transferase), transcriptional regulation (nuclear receptor subfamily 1G), adhesion and mobility (precollagen-P) and energy metabolism (ATP synthase F0 subunit 6 and NADH dehydrogenase subunit 2). Exposure to Ag NPs altered the expression of two proteins associated with stress response (major vault protein and ras partial) and one protein involved in cytoskeleton and cell structure (paramyosin), while exposure to Ag(+) had a strong influence in one protein related to stress response (putative c1q domain containing protein) and two proteins involved in cytoskeleton and cell structure (actin and alpha-tubulin). Protein identification showed that Ag NPs toxicity is mediated by oxidative stress-induced cell signalling cascades (including mitochondria and nucleus) that can lead to cell death. This toxicity represents the cumulative effect of Ag(+) released from the particles and other properties as particle size and surface reactivity. This study helped to unravel the molecular mechanisms that can be associated with Ag NPs toxicity; nevertheless, some additional studies are required to investigate the exact interaction between these NPs and cellular components. PMID- 23665240 TI - Biomarkers and transcription levels of cancer-related genes in cockles Cerastoderma edule from Galicia (NW Spain) with disseminated neoplasia. AB - Disseminated neoplasia (DN) is a pathological condition reported for several species of marine bivalves throughout the world, but its aetiology has not yet been satisfactorily explained. It has been suggested that chemical contamination could be a factor contributing to neoplasia. The aim of the present study was to compare cell and tissue biomarkers and the transcription level of cancer-related genes in cockles (Cerastoderma edule) affected by DN with those of healthy cockles in relation to chemical contaminant burdens. For this, cockles were collected from a natural bed in Cambados (Ria de Arousa, Galicia) in May 2009. The prevalence of DN was 12.36% and 3 degrees of DN severity were distinguished. No significant differences in metal accumulation, non-specific inflammatory responses and parasites were observed between healthy and DN-affected cockles. Lysosomal membrane stability was significantly reduced in cockles affected by DN, which indicates a poorer health condition. Very low frequencies of micronuclei were recorded and no significant differences were detected between DN severity groups. Haemolymph analyses showed a higher frequency of mitotic figures and binucleated cells in cockles affected by moderate and heavy DN than in healthy ones. Neoplastic animals showed significantly higher transcription levels of p53 and ras than healthy cockles and mutational alterations in ras gene sequence were detected. Low concentrations of metals, polycyclic aromatic hydrocarbons, polychlorinated biphenyls and phthalate esters were measured in cockles from Cambados. In conclusion, cockles affected by DN suffer a general stress situation and have altered patterns of cancer-related gene transcription. Further studies are in progress to elucidate mechanisms of carcinogenesis in this species. PMID- 23665241 TI - Discussion: 'Tachysystole in term labor,' by Heuser et al. AB - In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. PMID- 23665242 TI - Planned home birth: the professional responsibility response--a midwifery response. PMID- 23665243 TI - Hide and seek: surgeons discovered multiple omental tumors during a hysterectomy. PMID- 23665244 TI - Body image, regret, and satisfaction following colpocleisis. AB - OBJECTIVE: Colpocleisis is a definitive surgical treatment for prolapse resulting in vaginal obliteration. We sought to evaluate body image, regret, satisfaction, and pelvic floor symptoms following this procedure. STUDY DESIGN: This was a prospective multicenter study through the Fellows' Pelvic Research Network. All women electing colpocleisis for management of pelvic organ prolapse were screened for enrollment. The Pelvic Floor Impact Questionnaire, Pelvic Floor Distress Inventory, and the modified Body Image Scale (BIS) were completed preoperatively and 6 weeks following surgery. Additionally, the Decision Regret Scale and the Satisfaction with Decision Scale were administered at the 6-week postoperative visit. A sample size of 88 subjects was calculated to evaluate change in the BIS score. RESULTS: In all, 87 patients were analyzed. Mean age was 79 years (SD 5.8) with a mean body mass index of 27 (SD 5.3). The majority (89.3%) was Caucasian. Six weeks after surgery, significant improvements were noted in all parameters. Mean BIS scores decreased from 4.8 to 1.2 (P < .001), signifying improved body image. Indeed, the overall number of subjects with BIS scores in the normal range doubled after surgery. Pelvic Floor Distress Inventory and Pelvic Floor Impact Questionnaire scores decreased significantly (P < .001 and P < .001), suggesting a positive impact on bladder, bowel, and prolapse symptoms. Finally, low levels of regret (mean score 1.35) and concurrent high satisfaction (mean score 4.73) were documented. CONCLUSION: Colpocleisis improves body image and pelvic floor symptoms while giving patients a definitive surgical option that results in low regret and high satisfaction. PMID- 23665245 TI - Risk-reducing salpingectomy as a new and safe strategy to prevent ovarian cancer. PMID- 23665246 TI - Reply: To PMID 23333546. PMID- 23665247 TI - ST analysis reviewed. PMID- 23665248 TI - Reply: To PMID 23151491. PMID- 23665249 TI - Reply: To PMID 23583217. PMID- 23665250 TI - Three-way tie: the umbilical cord insertion site was different for each member of a set of triplets. PMID- 23665252 TI - Imatinib methanesulfonate reduces hippocampal amyloid-beta and restores cognitive function following repeated endotoxin exposure. AB - Alzheimer's disease (AD) is characterized, in part, by atrophy of the adult brain and increased presence of extracellular amyloid-beta (Abeta) plaques. Previous studies in our lab have shown that peripheral inflammation can lead to increased central Abeta and deficits in learning and memory. In order to determine whether Abeta accumulation in the brain is responsible for the learning deficits, we attempted to decrease peripheral production of Abeta in order to reduce central Abeta accumulation. It has previously been shown that Abeta is produced in large quantities in the liver, and is transferred across the blood-brain barrier (BBB). Recent research has shown that peripheral treatment with imatinib methanesulfonate salt (IM), known to interfere with the interaction between gamma (gamma)-secretase and the gamma-secretase activating protein (GSAP), decreases the cleavage of peripheral amyloid precursor protein into Abeta. Because IM poorly penetrates the BBB, we hypothesized that co-administration of IM with LPS would decrease peripheral production of Abeta in the presence of LPS-induced inflammation, leading to a decrease in Abeta accumulation in the hippocampus. We show that peripheral IM treatment eliminates hippocampal Abeta elevation that follows LPS-induced peripheral inflammation. Importantly, IM also eliminates the cognitive impairment seen following seven consecutive days of LPS administration, implicating Abeta peptides as a likely cause of these cognitive deficits. PMID- 23665253 TI - Television viewing, C-reactive protein, and depressive symptoms in older adults. AB - There is emerging evidence for a link between sedentary behavior and mental health, although the mechanisms remain unknown. We tested if an underlying inflammatory process explains the association between sedentary behavior and depressive symptoms. We conducted a two year follow-up of 4964 (aged 64.5+/-8.9 years) men and women from the English Longitudinal Study of Ageing, a cohort of community dwelling older adults. Self-reported TV viewing time was assessed at baseline as a marker of leisure time sedentary behavior. The eight-item Centre of Epidemiological Studies Depression (CES-D) scale was administered to measure depressive symptoms at follow-up. At baseline, TV time was associated with C reactive protein (CRP), adjusted geometric mean CRP values were 2.94 mg/L (<2 h/d TV); 3.04 mg/L (2-4 h/d TV); 3.29 mg/L (4-6 h/d TV); 3.23 mg/L (>6 h/d TV). We observed both a direct association of TV time on CES-D score at follow-up (B=0.08, 95% CI, 0.05, 0.10) and indirect effects (B=0.07, 95% CI, 0.05, 0.08). The indirect effects were largely explained through lack of physical activity, smoking, and alcohol, but not by CRP or body mass index. PMID- 23665255 TI - Oral delivery of taurocholic acid linked heparin-docetaxel conjugates for cancer therapy. AB - We have synthesized taurocholic acid (TCA) linked heparin-docetaxel (DTX) conjugates for oral delivery of anticancer drug. The ternary biomolecular conjugates formed self-assembly nanoparticles where docetaxel was located inside the core and taurocholic acid was located on the surface of the nanoparticles. The coupled taurocholic acid in the nanoparticles had enhanced oral absorption, presumably through the stimulation of a bile acid transporter of the small intestine. The oral absorption profile demonstrated that the concentration of the conjugates in plasma is about 6 fold higher than heparin alone. An anti-tumor study in MDA-MB231 and KB tumor bearing mice showed significant tumor growth inhibition activity by the ternary biomolecular conjugates. Ki-67 histology study also showed evidence of anticancer activity of the nanoparticles. Finally, noninvasive imaging using a Kodak Molecular Imaging System demonstrated that the nanoparticles were accumulated efficiently in tumors. Thus, this approach for oral delivery using taurocholic acid in the ternary biomolecular conjugates is promising for treatment of various types of cancer. PMID- 23665256 TI - Functionalized nanoparticles provide early cardioprotection after acute myocardial infarction. AB - Recent developments in nanotechnology have created considerable potential toward diagnosis and cancer therapy. In contrast, the use of nanotechnology in tissue repair or regeneration remains largely unexplored. We hypothesized that intramyocardial injection of insulin-like growth factor (IGF)-1-complexed poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (PLGA-IGF-1 NPs) increases IGF-1 retention, induces Akt phosphorylation, and provides early cardioprotection after acute myocardial infarction (MI). We synthesized 3 different sizes of PLGA particles (60 nm, 200 nm, and 1 MUm) which were complexed with IGF-1 using electrostatic force to preserve the biological function of IGF-1. Afterward, we injected PLGA-IGF-1 NPs in the heart after MI directly. Compared with the other two larger particles, the 60 nm-sized PLGA-IGF-1 NPs carried more IGF-1 and induced more Akt phosphorylation in cultured cardiomyocytes. PLGA-IGF-1 NPs also prolonged Akt activation in cardiomyocytes up to 24h and prevented cardiomyocyte apoptosis induced by doxorubicin in a dose-dependent manner. In vivo, PLGA-IGF-1 NP treatment significantly retained more IGF-1 in the myocardium than the IGF-1 alone treatment at 2, 6, 8, and 24 h. Akt phosphorylation was detected in cardiomyocytes 24h post-MI only in hearts receiving PLGA-IGF-1 NP treatment, but not in hearts receiving injection of PBS, IGF-1 or PLGA NPs. Importantly, a single intramyocardial injection of PLGA-IGF-1 NPs was sufficient to prevent cardiomyocyte apoptosis (P<0.001), reduce infarct size (P<0.05), and improve left ventricle ejection fraction (P<0.01) 21 days after experimental MI in mice. Our results not only demonstrate the potential of nanoparticle-based technology as a new approach to treating MI, but also have significant implications for translation of this technology into clinical therapy for ischemic cardiovascular diseases. PMID- 23665254 TI - Infusion of imaging and therapeutic molecules into the plant virus-based carrier cowpea mosaic virus: cargo-loading and delivery. AB - This work is focused on the development of a plant virus-based carrier system for cargo delivery, specifically 30nm-sized cowpea mosaic virus (CPMV). Whereas previous reports described the engineering of CPMV through genetic or chemical modification, we report a non-covalent infusion technique that facilitates efficient cargo loading. Infusion and retention of 130-155 fluorescent dye molecules per CPMV using DAPI (4',6-diamidino-2-phenylindole dihydrochloride), propidium iodide (3,8-diamino-5-[3-(diethylmethylammonio)propyl]-6 phenylphenanthridinium diiodide), and acridine orange (3,6 bis(dimethylamino)acridinium chloride), as well as 140 copies of therapeutic payload proflavine (PF, acridine-3,6-diamine hydrochloride), is reported. Loading is achieved through interaction of the cargo with the CPMV's encapsidated RNA molecules. The loading mechanism is specific; empty RNA-free eCPMV nanoparticles could not be loaded. Cargo-infused CPMV nanoparticles remain chemically active, and surface lysine residues were covalent modified with dyes leading to the development of dual-functional CPMV carrier systems. We demonstrate cargo delivery to a panel of cancer cells (cervical, breast, and colon): CPMV nanoparticles enter cells via the surface marker vimentin, the nanoparticles target the endolysosome, where the carrier is degraded and the cargo is released allowing imaging and/or cell killing. In conclusion, we demonstrate cargo infusion and delivery to cells; the methods discussed provide a useful means for functionalization of CPMV toward its application as drug and/or contrast agent delivery vehicle. PMID- 23665257 TI - Expansion of the lymphatic vasculature in cancer and inflammation: new opportunities for in vivo imaging and drug delivery. AB - Over the last 15 years, discovery of key growth factors and specific molecular markers for lymphatic vessels has enabled a new era of molecular research on the lymphatic vascular system. As a result, it has been found that lymphangiogenesis, the expansion of existing lymphatic vessels, plays an important role in tumor progression and in the control of chronic inflammation. At the same time, technical advancements have been made to improve the visualization of the lymphatic system. We have recently developed liposomal and polymer-based formulations of near-infrared lymphatic-specific imaging tracers for the non invasive quantitative in vivo imaging of lymphatic vessel function. Using these tracers, a near-infrared stereomicroscope system allows imaging of initial and collecting lymphatic vessels with high spatial and temporal resolution in mice. In addition, we have developed a new method, using antibodies to a lymphatic specific marker and positron emission tomography, to sensitively detect lymphatic expansion in lymph nodes as the earliest sign of cancer metastasis. These imaging methods have great potential to provide non-invasive measures to assess the functionality of the lymphatic system and to assess the efficiency of lymphatic drug delivery. PMID- 23665259 TI - Description and phylogeny of Zelenkaia trichopterae gen. et sp. nov. (Microsporidia), an aquatic microsporidian parasite of caddisflies (Trichoptera) forming spore doublets. AB - Two novel microsporidia infecting the fat body tissues in larvae of two hosts, Halesus digitatus and Micropterna sequax (Trichoptera, Limnephilidae), were investigated using light and electron microscopy and rDNA sequence analyses. The molecular and morphological characters of these isolates warrant creation of a new microsporidian genus, Zelenkaia gen. n., with two species, one named herein. Developmental stages of Zelenkaia spp. have single nuclei. In sporogony, a plasmodium with four nuclei gives rise by rosette-like budding to two pairs of uninucleate sporoblasts, each within a thin-walled, subpersistent sporophorous vesicle. Sporoblasts and mature spores adhere temporary together, forming doublets oriented in parallel, within the sporophorous vesicle. Spores are long oval and uninucleate, and those of the type species Z. trichopterae measure 10.3*3.5MUm and have 24-25 polar filament coils. Phylogenetic analysis based on rDNA places Zelenkaia spp. within the aquatic clade of microsporidia and, more specifically, in the clade containing some microporidia from amphipod hosts. PMID- 23665258 TI - Biodegradable hybrid polymer micelles for combination drug therapy in ovarian cancer. AB - The co-delivery of drug combination at a controlled ratio via the same vehicle to the cancer cells is offering the advantages such as spatial-temporal synchronization of drug exposure, synergistic therapeutic effects and increased therapeutic potency. In an attempt to develop such multidrug vehicle this work focuses on functional biodegradable and biocompatible polypeptide-based polymeric micelles. Triblock copolymers containing the blocks of ethylene glycol, glutamic acid and phenylalanine (PEG-PGlu-PPhe) were successfully synthesized via NCA based ring-opening copolymerization and their composition was confirmed by (1)H NMR. Self-assembly behavior of PEG-PGlu90-PPhe25 was utilized for the synthesis of hybrid micelles with PPhe hydrophobic core, cross-linked ionic PGlu intermediate shell layer, and PEG corona. Cross-linked (cl) micelles were about 90nm in diameter (xi-potential=-20mV), uniform (narrow size distribution), and exhibited nanogels-like behavior. Degradation of cl-micelles was observed in the presence of proteolytic enzymes (cathepsin B). The resulting cl-micelles can incorporate the combination of drugs with very different physical properties such as cisplatin (15 w/w% loading) and paclitaxel (9 w/w% loading). Binary drug combination in cl-micelles exhibited synergistic cytotoxicity against human ovarian A2780 cancer cells and exerted a superior antitumor activity by comparison to individual drug-loaded micelles or free cisplatin in cancer xenograft model in vivo. Tunable composition and stability of these hybrid biodegradable micelles provide platform for drug combination delivery in a broad range of cancers. PMID- 23665260 TI - Increasing organizational evidence based practice capacity through an evidence based practice scholars program. PMID- 23665261 TI - A fully-automated one-pot synthesis of [18F]fluoromethylcholine with reduced dimethylaminoethanol contamination via [18F]fluoromethyl tosylate. AB - INTRODUCTION: A novel one-pot method for preparing [(18)F]fluoromethylcholine ([(18)F]FCH) via in situ generation of [(18)F]fluoromethyl tosylate ([(18)F]FCH2OTs), and subsequent [(18)F]fluoromethylation of dimethylaminoethanol (DMAE), has been developed. METHODS: [(18)F]FCH was prepared using a GE TRACERlab FXFN, although the method should be readily adaptable to any other fluorine-(18) synthesis module. Initially ditosylmethane was fluorinated to generate [(18)F]FCH2OTs. DMAE was then added and the reaction was heated at 120 degrees C for 10 min to generate [(18)F]FCH. After this time, reaction solvent was evaporated, and the crude reaction mixture was purified by solid-phase extraction using C(18)-Plus and CM-Light Sep-Pak cartridges to provide [(18)F]FCH formulated in USP saline. The formulated product was passed through a 0.22 um filter into a sterile dose vial, and submitted for quality control testing. Total synthesis time was 1.25 h from end-of-bombardment. RESULTS: Typical non-decay-corrected yields of [(18)F]FCH prepared using this method were 91 mCi (7% non-decay corrected based upon ~1.3 Ci [(18)F]fluoride), and doses passed all other quality control (QC) tests. CONCLUSION: A one-pot liquid-phase synthesis of [(18)F]FCH has been developed. Doses contain extremely low levels of residual DMAE (31.6 ug/10 mL dose or ~3 ppm) and passed all other requisite QC testing, confirming their suitability for use in clinical imaging studies. PMID- 23665262 TI - [The decalogue on the arteriovenous malformation]. PMID- 23665263 TI - [A simple and reliable technique for the treatment of rhinoliquorrhoea from small defects: Free nasal mucosa overlay graft]. AB - INTRODUCTION: Cerebrospinal fluid leaks to the sinonasal cavities (rhinoliquorrhoea) represent a process with diagnostic and therapeutic difficulties. The endoscopic transnasal approach is the method of choice, but with many possible variants. The purpose of this paper was to make a critical review of our diagnostic and therapeutic protocol used for 11years. MATERIAL AND METHODS: We operated on 31patients. The diagnosis was based on the biochemical analysis of rhinorrhoea, CT and MRI. TREATMENT: endoscopic nasal surgery after preoperative intrathecal injection of 5% fluorescein (2cc). Closure was performed using a free overlay graft from middle turbinate mucosa. RESULTS: Two patients had meningitis as the first sign. All patients were diagnosed by biochemical analysis of rhinorrhoea. CT and MRI gave clear evidence of the leakage location. The skull base defect was always less than 1cm. Fluorescein allowed clear visualisation of the fistulous area without other instruments and produced no side effects. One patient had a postoperative frontal abscess, which evolved favourably. All fistulas were closed and there was only one recurrence at 10years, which debuted as pneumococcal meningitis. DISCUSSION AND CONCLUSIONS: Our surgical protocol, based on the use of intrathecal fluorescein and free grafting of middle turbinate mucosa overlay onto the fistulous area, achieves successful long-term results in the management of rhinoliquorrhoea secondary to small skull base defects. PMID- 23665264 TI - Efficacy of a sperm-selection chamber in terms of morphology, aneuploidy and DNA packaging. AB - Since most current techniques analysing spermatozoa will inevitably exclude these gametes from further use, attempts have been made to enrich semen samples with physiological spermatozoa with good prognosis using special sperm-processing methods. A particular sperm-selection chamber, called the Zech-selector, was found to be effective in completely eliminating spermatozoa with DNA strand breaks. The aim of this study was to further analyse the subgroup of spermatozoa accumulated using the Zech-selector. In detail, the potential of the chamber to select for proper sperm morphology, DNA status and chromatin condensation was tested. Two samples, native and processed semen, of 53 patients were analysed for sperm morphology (*1000, *6300), DNA packaging (fragmentation, chromatin condensation) and chromosomal status (X, Y, 18). Migration time (the time needed for proper sperm accumulation) was significantly correlated to fast progressive motility (P=0.002). The present sperm-processing method was highly successful with respect to all parameters analysed (P<0.001). In particular, spermatozoa showing numeric (17.4% of patients without aneuploidy) or structural chromosomal abnormalities (90% of patients without strand-breaks) were separated most effectively. To summarize, further evidence is provided that separating spermatozoa without exposure to centrifugation stress results in a population of highly physiological spermatozoa. PMID- 23665265 TI - Mutational analysis of SKP2 and P27 in Chinese Han women with premature ovarian failure. AB - P27 and SKP2, a major regulator of P27, play a crucial role in ovarian function in mice. Both P27-deficient and SKP2-deficient female mice develop premature ovarian failure (POF). The coding regions of SKP2 and P27 were examined in 200 Chinese women with POF and 200 control volunteers. This study is the first to investigate SKP2 in POF. No plausible pathogenic mutations were detected. The results suggest that mutations in SKP2 and P27 are not common in Chinese Han women with POF. PMID- 23665266 TI - Calcium lignosulphonate: re-evaluation of relevant endpoints to re-confirm validity and NOAEL of a 90-day feeding study in rats. AB - A 90-day feeding study in Han/Wistar rats with calcium lignosulphonate was evaluated by the EFSA. The study was considered to be inadequate due to potentially impaired health status of the animals based upon a high incidence of minimal lymphoid hyperplasia in mesenteric/mandibular lymph nodes and Peyer's patches, and minimal lymphoid cell infiltration in the liver in all animals. The EFSA Panel further disagreed with the conclusion that the treatment-related observation of foamy histiocytosis in mesenteric lymph nodes was non-adverse and asked whether this observation would progress to something more adverse over time. A PWG was convened to assess the sections of lymph nodes, Peyer's patches and liver. In addition, all lymphoid tissues were re-examined. The clinical pathology and animal colony health screening data were re-evaluated. The question whether the foamy histiocytosis could progress to an adverse finding with increasing exposure duration was addressed by read-across. In conclusion, the animals on the 90-day feeding study were in good health, the study was adequate for safety evaluation, and the foamy histiocytes in the mesenteric lymph nodes were not considered adverse, but rather an adaptive response that was considered unlikely to progress to an adverse condition with time. The NOAEL was re-affirmed to be 2000 mg/kgbw/d. PMID- 23665267 TI - Interference control in 6-11 year-old children with and without ADHD: behavioral and ERP study. AB - Event-related potentials (ERPs) were recorded during a hybrid Simon-spatial Stroop task. We compared interference control and conflict monitoring in children with and without attention-deficit/hyperactivity disorder (ADHD), to examine developmental functional patterns. We found that children with ADHD exhibited lower accuracy rates and longer and more variable reaction time (RT) in both tasks, especially in the incongruent condition. In both controls and ADHD children, the accuracy rate increased and RT decreased with age. Major development in interference control occurred from 6-7 to 8 years in ADHD children and controls, yet only occurred from 9 to 10-11 years in normal children. The ERP results revealed that the N2 potentials were not significantly different from age matched controls in the two tasks and that the development pattern of conflict monitoring was not different in school age children with and without ADHD. Children with ADHD had normal conflict monitoring ability. PMID- 23665268 TI - Insight into the binding mode and the structural features of the pyrimidine derivatives as human A2A adenosine receptor antagonists. AB - The interaction of 278 monocyclic and bicyclic pyrimidine derivatives with human A2A adenosine receptor (AR) was investigated by employing molecular dynamics, thermodynamic analysis and three-dimensional quantitative structure-activity relationship (3D-QSAR) approaches. The binding analysis reveals that the pyrimidine derivatives are anchored in TM2, 3, 5, 6 and 7 of A2A AR by the aromatic stacking and hydrogen bonding interactions. The key residues involving Phe168, Glu169, and Asn253 stabilize the monocyclic and bicyclic cores of inhibitors. The thermodynamic analysis by molecular mechanics/Poisson Boltzmann surface area (MM-PBSA) approach also confirms the reasonableness of the binding modes. In addition, the ligand-/receptor-based comparative molecular similarity indices analysis (CoMSIA) models of high statistical significance were generated and the resulting contour maps correlate well with the structural features of the antagonists essential for high A2A AR affinity. A minor/bulky group with negative charge at C2/C6 of pyrimidine ring respectively enhances the activity for all these pyrimidine derivatives. Particularly, the higher electron density of the ring in the bicyclic derivatives, the more potent the antagonists. The obatined results might be helpful in rational design of novel candidate of A2A adenosine receptor antagonist for treatment of Parkinson's disease. PMID- 23665269 TI - Do ethnic patterns in cryptorchidism reflect those found in testicular cancer? AB - PURPOSE: There are established variations in testicular cancer incidence between ethnic groups within countries. It is currently unclear whether the occurrence of cryptorchidism-a known risk factor for testicular cancer-follows similar patterns. In New Zealand Maori have unusually high rates of testicular cancer compared to individuals of European ancestry. We hypothesized that ethnic trends in the incidence of cryptorchidism would reflect those for testicular cancer in this setting. MATERIALS AND METHODS: We followed 318,441 eligible male neonates born in New Zealand between 2000 and 2010 for the incidence of orchiopexy confirmed cryptorchidism and the incidence of known risk factors for cryptorchidism (low birth weight, short gestation, small size for gestational age) using routine maternity, hospitalization and mortality records. Logistic regression was used to calculate odds ratios for the presence of known risk factors for cryptorchidism by ethnic group. Poisson regression was used to calculate relative risk of cryptorchidism by ethnicity, adjusted for risk factors. RESULTS: Ethnic patterns of cryptorchidism incidence in New Zealand closely mirrored those previously observed for testicular cancer. Maori had higher rates of cryptorchidism than all other ethnic groups (adjusted RR 1.2 [95% CI 1.11-1.3]), with Pacific (0.89 [0.8-0.99]) and Asian groups (0.68 [0.59-0.79]) having the lowest rates (European/other, referent). CONCLUSIONS: Since the principal risk factors for cryptorchidism are present in utero, the results of the current study strengthen the likelihood that the ethnic patterning of testicular cancer is at least partly due to prenatal risk factors. PMID- 23665270 TI - Male breast cancer and 5alpha-reductase inhibitors finasteride and dutasteride. AB - PURPOSE: We examined the association between 5alpha-reductase inhibitors and male breast cancer. MATERIALS AND METHODS: Study participants were men 40 to 85 years old, with prescription and medical coverage, enrolled in the United States IMS LifeLinkTM Health Plan claims database between 2001 and 2009. Cases required a primary breast cancer diagnosis (ICD-9-CM 175.x) on 2 different dates and a procedural code for mastectomy or lumpectomy/partial mastectomy with evidence of continuous care (radiation/chemotherapy or diagnoses in 2 or more months). Eligible controls were within 5 years in age and had duration of prior health care enrollment within 6 weeks. Risk set sampling selected 20 controls per case. We assessed the rate ratio for male breast cancer with 5alpha-reductase inhibitor exposure using conditional logistic regression. Analyses were stratified by duration of health care enrollment before diagnosis (1 year or more, 2 years or more and 3 years or more), each incremental 180 and 365 days of cumulative 5alpha reductase inhibitor exposure, and period specific time frames before diagnosis (years 1, 2 and 3). RESULTS: We identified 339 breast cancer cases matched to 6,780 controls. No statistically significant associations were observed between 5alpha-reductase inhibitors and breast cancer regardless of exposure assessment before the index date (1 year or more-RR 0.70, 95% CI 0.34-1.45; 2 years or more RR 0.59, 95% CI 0.24-1.48; or 3 years or more-RR 0.75, 95% CI 0.27-2.10). Each subsequent 180 days (RR 1.02, 95% CI 0.67-1.53) and 365 days (RR 1.03, 95% CI 0.45-2.37) of cumulative 5alpha-reductase inhibitor therapy and period specific rate ratios also showed null associations. CONCLUSIONS: The lack of an association in our study suggests that the development of breast cancer should not influence the prescribing of 5alpha-reductase inhibitor therapy. PMID- 23665271 TI - Spondin-2, a secreted extracellular matrix protein, is a novel diagnostic biomarker for prostate cancer. AB - PURPOSE: SPON2 belongs to the F-spondin family of secreted extracellular matrix proteins. It is deregulated in some tumors, including prostate cancer. In this prospective study we assessed the role of serum SPON2 as a biomarker for prostate cancer diagnosis as well as any association between SPON2 levels and clinicopathological features. We also compared the diagnostic performance of this biomarker to that of serum sarcosine, and percent free-to-total and total prostate specific antigen. MATERIALS AND METHODS: SPON2 was measured using a sandwich enzyme linked immunosorbent assay in serum samples from 286 patients with prostate cancer and 68 with no evidence of malignancy, as confirmed by 10 to 12-core ultrasound guided prostate biopsy. Nonparametric statistical tests and ROC analysis were done to assess the diagnostic performance of SPON2 vs the other biomarkers. RESULTS: Median serum SPON2 was significantly higher in patients with prostate cancer than in those with no evidence of malignancy (77.5 vs 23.6 ng/ml, p<0.0001). ROC analysis showed a higher predictive value of SPON2 (AUC 0.952) than of serum sarcosine (AUC 0.674), percent free-to-total prostate specific antigen (AUC 0.806) and total prostate specific antigen (AUC 0.561). Moreover, patients with low grade prostate cancer had higher median SPON2 levels (p=0.001). Spearman rank correlation confirmed a negative association with Gleason score (rs=-0.29, p=0.0005). CONCLUSIONS: We found evidence that SPON2 levels were significantly higher in patients with prostate cancer than in healthy individuals. Moreover, this biomarker had better diagnostic performance than serum sarcosine, and percent free-to-total and total prostate specific antigen. This greater accuracy was also present in a subset of patients with normal prostate specific antigen. PMID- 23665272 TI - Castration-resistant prostate cancer: AUA Guideline. AB - PURPOSE: This Guideline is intended to provide a rational basis for the management of patients with castration-resistant prostate cancer based on currently available published data. MATERIALS AND METHODS: A systematic review and meta-analysis of the published literature was conducted using controlled vocabulary supplemented with keywords relating to the relevant concepts of prostate cancer and castration resistance. The search strategy was developed and executed by reference librarians and methodologists to create an evidence report limited to English-language, published peer-reviewed literature. This review yielded 303 articles published from 1996 through 2013 that were used to form a majority of the guideline statements. Clinical Principles and Expert Opinions were used for guideline statements lacking sufficient evidence-based data. RESULTS: Guideline statements were created to inform clinicians on the appropriate use of observation, androgen-deprivation and antiandrogen therapy, androgen synthesis inhibitors, immunotherapy, radionuclide therapy, systemic chemotherapy, palliative care and bone health. These were based on six index patients developed to represent the most common scenarios encountered in clinical practice. CONCLUSIONS: As a direct result of the significant increase in FDA approved therapeutic agents for use in patients with metastatic CRPC, clinicians are challenged with a multitude of treatment options and potential sequencing of these agents that, consequently, make clinical decision-making more complex. Given the rapidly evolving nature of this field, this guideline should be used in conjunction with recent systematic literature reviews and an understanding of the individual patient's treatment goals. In all cases, patients' preferences and personal goals should be considered when choosing management strategies. PMID- 23665273 TI - Optical spectroscopy in turbid media using an integrating sphere: mitochondrial chromophore analysis during metabolic transitions. AB - Recent evidence suggests that the activity of mitochondrial oxidative phosphorylation complexes (MOPCs) is modulated at multiple sites. Here, a method of optically monitoring electron distribution within and between MOPCs is described using a center-mounted sample in an integrating sphere (to minimize scattering effects) with a rapid-scanning spectrometer. The redox-sensitive MOPC absorbances (~465-630 nm) were modeled using linear least squares analysis with individual chromophore spectra. Classical mitochondrial activity transitions (e.g., ADP-induced increase in oxygen consumption) were used to characterize this approach. Most notable in these studies was the observation that intermediates of the catalytic cycle of cytochrome oxidase are dynamically modulated with metabolic state. The MOPC redox state, along with measurements of oxygen consumption and mitochondrial membrane potential, was used to evaluate the conductances of different sections of the electron transport chain. This analysis then was applied to mitochondria isolated from rabbit hearts subjected to ischemia/reperfusion (I/R). Surprisingly, I/R resulted in an inhibition of all measured MOPC conductances, suggesting a coordinated down-regulation of mitochondrial activity with this well-established cardiac perturbation. PMID- 23665274 TI - Young women with polycystic liver disease respond best to somatostatin analogues: a pooled analysis of individual patient data. AB - BACKGROUND & AIMS: Clinical trials have shown that in patients with polycystic liver disease (PLD), short-term treatment with somatostatin analogues (SAs) reduces liver volumes by 4.5%-5.9%, compared with placebo. However, the effects of SA therapy vary among individuals. We collected data from individual patients with PLD to identify subgroups that benefit most from SA therapy. METHODS: We analyzed data from 107 patients with PLD from 3 randomized placebo-controlled trials (67 received SAs, 52 received placebo). We used multiple linear regression analysis to determine the effects of SAs based on patients' age, sex, baseline liver volume, and diagnosis (autosomal dominant polycystic liver or kidney disease). The primary outcome was change in liver volume after 6-12 months of treatment. RESULTS: The effects of SA therapy did not differ significantly among patients with different diagnoses or baseline liver volumes; the overall difference in liver volume between groups receiving SAs therapy vs placebo was 5.3% (P < .001). Among subjects given placebo, young women (48 years old or younger) had the greatest increase in polycystic liver volume (4.8%; 95% confidence interval: 2.2%-7.4%), and mean liver volumes did not increase in older women and men. Women 48 years old or younger had a greater response to therapy (a reduction in liver volume of 8.0% compared with placebo; P < .001) than older women (a reduction in liver volume of 4.1% compared with placebo; P = .022). CONCLUSIONS: Based on a pooled analysis of data from individual patients with PLD, treatment with somatostatin analogues is equally effective for patients with autosomal dominant polycystic kidney disease or polycystic liver disease; efficacy does not depend on size of the polycystic liver. Young female patients appear to have the greatest benefit from 6-12 months of SA therapy, which might avert the progressive course of the disease in this specific group. PMID- 23665275 TI - Associations between colorectal cancer molecular markers and pathways with clinicopathologic features in older women. AB - BACKGROUND & AIMS: Colorectal tumors have a large degree of molecular heterogeneity. Three integrated pathways of carcinogenesis (ie, traditional, alternate, and serrated) have been proposed, based on specific combinations of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in BRAF and KRAS. We used resources from the population-based Iowa Women's Health Study (n = 41,836) to associate markers of colorectal tumors, integrated pathways, and clinical and pathology characteristics, including survival times. METHODS: We assessed archived specimens from 732 incident colorectal tumors and characterized them as microsatellite stable (MSS), MSI high or MSI low, CIMP high or CIMP low, CIMP negative, and positive or negative for BRAF and/or KRAS mutations. Informative marker data were collected from 563 tumors (77%), which were assigned to the following integrated pathways: traditional (MSS, CIMP negative, BRAF mutation negative, and KRAS mutation negative; n = 170), alternate (MSS, CIMP low, BRAF mutation negative, and KRAS mutation positive; n = 58), serrated (any MSI, CIMP high, BRAF mutation positive, and KRAS mutation negative; n = 142), or unassigned (n = 193). Multivariable adjusted Cox proportional hazards regression models were used to assess the associations of interest. RESULTS: Patients' mean age (P = .03) and tumors' anatomic subsite (P = .0001) and grade (P = .0001) were significantly associated with integrated pathway assignment. Colorectal cancer (CRC) mortality was not associated with the traditional, alternate, or serrated pathways, but was associated with a subset of pathway-unassigned tumors (MSS or MSI low, CIMP negative, BRAF mutation negative, and KRAS mutation positive) (n = 96 cases; relative risk = 1.76; 95% confidence interval, 1.07-2.89, compared with the traditional pathway). CONCLUSIONS: We identified clinical and pathology features associated with molecularly defined CRC subtypes. However, additional studies are needed to determine how these features might influence prognosis. PMID- 23665277 TI - The virtue of translational PKPD modeling in drug discovery: selecting the right clinical candidate while sparing animal lives. AB - Translational pharmacokinetic-pharmacodynamic (PKPD) modeling has been fully implemented at AstraZeneca's drug discovery unit for central nervous system and pain indications to facilitate timely progression of the right compound to clinical studies, simultaneously assuring essential preclinical efficacy and safety knowledge. This review illustrates the impact of a translational PKPD paradigm with examples from drug discovery programs. Paradoxically, laboratory animal use decreased owing to better understanding of in vitro-in vivo relationships, optimized in vivo study designs, meta-analyses and hypothesis testing using simulations. From an ethical and effectivity perspective, we advocate that translational PKPD approaches should be implemented more broadly in drug discovery. PMID- 23665276 TI - Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. AB - BACKGROUND & AIMS: Short-chain fatty acids (SCFAs), the most abundant microbial metabolites in the intestine, activate cells via G-protein-coupled receptors (GPRs), such as GPR41 and GPR43. We studied regulation of the immune response by SCFAs and their receptors in the intestines of mice. METHODS: Inflammatory responses were induced in GPR41(-/-), GPR43(-/-), and C57BL6 (control) mice by administration of ethanol; 2, 4, 6-trinitrobenzene sulfonic-acid (TNBS); or infection with Citrobacter rodentium. We examined the effects of C rodentium infection on control mice fed SCFAs and/or given injections of antibodies that delay the immune response. We also studied the kinetics of cytokine and chemokine production, leukocyte recruitment, intestinal permeability, and T-cell responses. Primary colon epithelial cells were isolated from GPR41(-/-), GPR43(-/-), and control mice; signaling pathways regulated by SCFAs were identified using immunohistochemical, enzyme-linked immunosorbent assay, and flow cytometry analyses. RESULTS: GPR41(-/-) and GPR43(-/-) mice had reduced inflammatory responses after administration of ethanol or TNBS compared with control mice, and had a slower immune response against C rodentium infection, clearing the bacteria more slowly. SCFAs activated intestinal epithelial cells to produce chemokines and cytokines in culture and mice after administration of ethanol, TNBS, or C rodentium. These processes required GPR41 and GPR43 and were required to recruit leukocytes and activate effector T cells in the intestine. GPR41 and GPR43 activated extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase signaling pathways in epithelial cells to induce production of chemokines and cytokines during immune responses. CONCLUSIONS: SCFAs activate GPR41 and GPR43 on intestinal epithelial cells, leading to mitogen-activated protein kinase signaling and rapid production of chemokines and cytokines. These pathways mediate protective immunity and tissue inflammation in mice. PMID- 23665278 TI - Effects of steroid hormones on reproduction- and detoxification-related gene expression in adult male mosquitofish, Gambusia affinis. AB - The molecular mechanisms that mediate fish reproduction and detoxification in response to steroid hormones were studied by using adult male western mosquitofish (Gambusia affinis) as sentinel species. The expression patterns of three vitellogenins (VtgA, VtgB and VtgC), two estrogen receptors (ERalpha and ERbeta), two androgen receptors (ARalpha and ARbeta), metallothionein (MT) and cytochrome P450 1A (CYP1A) in the liver and testis of adult male mosquitofish were assessed through exposure treatments with progesterone (P), testosterone (T) and 17beta-estradiol (E2), alone and in combination for eight days. The results showed that expression patterns of Vtg subtype, ER subtype, AR subtype, MT and CYP1A genes in male mosquitofish varied according to tissue and specific hormone stress. Vtg subtype mRNA expression was induced in the liver in E2-added treatments, and an up-regulation of ERalpha mRNA expression was also observed. In addition, hormone treatments increased three Vtg subtype mRNA expression levels in the testis, at least to some extent. All hormone treatments significantly inhibited ERalpha, ERbeta and ARbeta mRNA expression in the testis. Some of hormone treatments could affect MT and CYP1A gene expression in mosquitofish. In general, multiple hormone treatments showed different effects on target gene expression compared with corresponding hormone alone. The results from the present study provided valuable information on the toxicological effects of steroid hormones in mosquitofish. PMID- 23665280 TI - Retrotransposons: a new and credible source of inherited and somatically acquired hepatocellular carcinoma mutations. PMID- 23665281 TI - CHOP is a critical regulator of acetaminophen-induced hepatotoxicity. AB - BACKGROUND & AIMS: The liver is a major site of drug metabolism and elimination and as such is susceptible to drug toxicity. Drug induced liver injury is a leading cause of acute liver injury, of which acetaminophen (APAP) is the most frequent causative agent. APAP toxicity is initiated by its toxic metabolite NAPQI. However, downstream mechanisms underlying APAP induced cell death are still unclear. Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have recently emerged as major regulators of metabolic homeostasis. UPR regulation of the transcription repressor CHOP promotes cell death. We analyzed the role of UPR and CHOP in mediating APAP hepatotoxicity. METHODS: A toxic dose of APAP was orally administered to wild type (wt) and CHOP knockout (KO) mice and damage mechanisms were assessed. RESULTS: CHOP KO mice were protected from APAP induced damage and exhibited decreased liver necrosis and increased survival. APAP metabolism in CHOP KO mice was undisturbed and glutathione was depleted at similar kinetics to wt. ER stress and UPR activation were overtly seen 12h following APAP administration, a time that coincided with strong upregulation of CHOP. Remarkably, CHOP KO but not wt mice exhibited hepatocyte proliferation at sites of necrosis. In vitro, large T immortalized CHOP KO hepatocytes were protected from APAP toxicity in comparison to wt control cells. CONCLUSIONS: CHOP upregulation during APAP induced liver injury compromises hepatocyte survival in various mechanisms, in part by curtailing the regeneration phase following liver damage. Thus, CHOP plays a pro-damage role in response to APAP intoxication. PMID- 23665279 TI - Complement in animal development: unexpected roles of a highly conserved pathway. AB - The complement pathway is most famous for its role in immunity, orchestrating an exquisitely refined system for immune surveillance. At its core lies a cascade of proteolytic events that ultimately serve to recognise microbes, infected cells or debris and target them for elimination. Mounting evidence has shown that a number of the proteolytic intermediaries in this cascade have, in themselves, other functions in the body, signalling through receptors to drive events that appear to be unrelated to immune surveillance. It seems, then, that the complement system not only functions as an immunological effector, but also has cell-cell signalling properties that are utilised by a number of non-immunological processes. In this review we examine a number of these processes in the context of animal development, all of which share a requirement for precise control of cell behaviour in time and space. As we will see, the scope of the complement system's function is indeed much greater than we might have imagined only a few years ago. PMID- 23665282 TI - Food-derived peroxidized fatty acids may trigger hepatic inflammation: a novel hypothesis to explain steatohepatitis. AB - BACKGROUND & AIMS: Obesity and hepatic steatosis are frequently associated with the development of a non-alcoholic steatohepatitis (NASH). The mechanisms driving progression of a non-inflamed steatosis to NASH are largely unknown. Here, we investigated whether ingestion of peroxidized lipids, as being present in Western style diet, triggers the development of hepatic inflammation. METHODS: Corn oil containing peroxidized fatty acids was administered to rats by gavage for 6 days. In a separate approach, hepatocytes (HC), endothelial (EC) and Kupffer cells (KC) were isolated from untreated livers, cultured, and incubated with peroxidized linoleic acid (LOOH; linoleic acid (LH) being the main fatty acid in corn oil). Samples obtained from in vivo and in vitro studies were mainly investigated by qRT-PCR and biochemical determinations of lipid peroxidation products. RESULTS: Rat treatment with peroxidized corn oil resulted in increased hepatic lipid peroxidation, upregulation of nitric oxide synthetase-2 (NOS-2), cyclooxygenase-2 (COX-2), interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNFalpha), elevation of total nitric oxides, and increase in cd68-, cd163-, TNFalpha-, and/or COX-2 positive immune cells in the liver. When investigating liver cell types, LOOH elevated the secretion of TNFalpha, p38MAPK phosphorylation, and mRNA levels of NOS-2, COX-2, and TNFalpha, mainly in KC. The elevation of gene expression could be abrogated by inhibiting p38MAPK, which indicates that p38MAPK activation is involved in the pro-inflammatory effects of LOOH. CONCLUSIONS: These data show for the first time that ingestion of peroxidized fatty acids carries a considerable pro-inflammatory stimulus into the body which reaches the liver and may trigger the development of hepatic inflammation. PMID- 23665283 TI - Irisin is inversely associated with intrahepatic triglyceride contents in obese adults. AB - BACKGROUND & AIMS: Obesity is closely related to non-alcoholic fatty liver disease (NAFLD), which has become an important public health problem because of its high prevalence and association with metabolic syndromes. Irisin was recently identified as a novel peptide to improve obesity and glucose homeostasis, and considered to be therapeutic for human metabolic diseases. The aim of this study was to examine the association of serum irisin concentration and liver triglyceride contents in obese Chinese adults. METHODS: Serum irisin levels were measured and liver fat contents determined by (1)H MRS in 296 obese adults. Anthropometric parameters and blood biochemical indexes including liver enzymes, glucose, and lipid profiles were detected. The liver triglyceride contents of subjects were measured by (1)H MRS. The protein levels of irisin were determined by quantitative ELISA. RESULTS: We found that serum irisin levels were reduced in obese adults with NAFLD. By dividing the distribution of intrahepatic triglyceride (IHTG) contents into quartiles, serum irisin levels were reduced gradually with the increase of IHTG contents (p<0.01). Higher serum irisin levels were associated with preferable TG levels. Serum ALT and AST concentrations were inversely correlated with serum irisin levels. Multivariate linear regression analysis demonstrated that serum irisin levels were independently associated with liver fat (p<0.01). By logistic regression analysis, the odds ratio for higher IHTG contents was reduced by 12.4% per 1 SD increase in serum irisin concentrations after adjustment for multivariate metabolic factors [OR (95% CI); 0.876 (0.777-0.987)]. CONCLUSIONS: These results demonstrated that serum irisin concentrations were inversely associated with the triglyceride contents in the liver and liver enzymes in obese Chinese adults. PMID- 23665284 TI - MiR-20a triggers metastasis of gallbladder carcinoma. AB - BACKGROUND & AIMS: The dysfunction of miRNAs has been demonstrated to participate in the development of various tumors. However, whether miRNAs are involved in metastasis and progression of gallbladder carcinoma (GBC) remains unknown. METHODS: A new designed gain-of-function miRNA screening technology was applied to filter out pro-metastatic miRNAs in GBC. Their expression in GBC tissues was validated by real-time PCR. The biological functions of miRNAs were intensively studied by transwell, immunoblot, immunohistochemical, and in situ hybridization assays. Tumorigenicity and liver metastasis were further examined in nude mice. RESULTS: Of 880 miRNAs, 17 were filtered out as the prominent metastatic inducers of GBCs. Among them, the upregulation of pro-metastatic miR-20a was closely associated with local invasion, distant metastasis, and poor prognosis of 67 followed-up GBC patients, clinically. Patients with higher miR-20a expression exhibited worse overall survival (OS and median OS time was 5 and 20 months, respectively) than the lower expression group. A dramatically increased TGF-beta1 level was found in GBC patients, which was responsible for the elevation of miR 20a. The ectopic expression of miR-20a could induce epithelial-mesenchymal transition and enhance metastasis of GBC cells in vitro and in vivo, by directly targeting the 3' UTR of Smad7, and subsequently promoting nuclear translocation of beta-catenin. Conversely, the blockage of miR-20a by specific antagomir effectively restored the expression of Smad7 and attenuated TGF-beta-induced cell metastasis. CONCLUSIONS: TGF-beta1-mediated activation of the miR-20a/Smad7/beta catenin axis plays a pivotal role in the pathogenesis and worse prognosis of GBCs and may serve as a potential therapeutic target in the future. PMID- 23665285 TI - SUOX is a promising diagnostic and prognostic biomarker for hepatocellular carcinoma. AB - BACKGROUND & AIMS: To investigate diagnostic and prognostic values of sulfite oxidase (SUOX) in patients with hepatocellular carcinoma (HCC) who underwent curative resection. METHODS: We investigated immunohistochemically the expression dynamics of SUOX, aldo-ketoreductase family 1 member B10 (AKR1B10) and CD34 at different stages of HCC. The differential diagnostic performance of three markers or their combinations in high-grade dysplastic nodules (HGDNs) and well differentiated small HCC (WD-sHCC) were investigated by logistic regression models and validated in an independent testing set. Overall survival (OS) and time to recurrence (TTR) were evaluated in 300 patients with HCC as the testing cohort, and validated in 198 patients with HCC. RESULTS: SUOX was decreased and AKR1B10 and CD34 were increased with the stepwise progression of hepatocarcinogenesis. For differential diagnosis of WD-sHCC from HGDNs, the sensitivity and specificity of the SUOX+AKR1B10+CD34 combination for WD-sHCC detection were 93.8% and 95.2%, respectively, and overall accuracy was much higher than any of the three individual markers and two marker combinations. In addition, SUOX, but not AKR1B10 and CD34, was an independent prognostic factor for OS and TTR, and showed better correlation with OS and TTR if combined with serum alpha-fetoprotein (AFP) for both the testing and validation cohorts. CONCLUSIONS: SUOX+AKR1B10+CD34 combination could make a substantial contribution to hepatic immunopathological diagnosis to distinguish WD-sHCC from HGDNs. Meanwhile, SUOX combined with serum AFP may predict postoperative outcome and tumor recurrence risk. PMID- 23665286 TI - Impaired CD4+ T cell stimulation of NK cell anti-fibrotic activity may contribute to accelerated liver fibrosis progression in HIV/HCV patients. AB - BACKGROUND & AIMS: HIV/HCV co-infection is characterized by a faster progression to liver fibrosis compared to HCV mono-infection. Epidemiologic studies found an association between low CD4(+) T cell counts and advanced stages of liver fibrosis. However, the mechanisms underlying this association remain unclear. CD4(+) T cells critically modulate NK cell activity. Of note, NK cells have been shown to display anti-fibrotic activity via killing of activated hepatic stellate cells (HSC). Thus, we speculated that CD4(+) T cells might modulate fibrosis progression by interacting with NK cells. METHODS: NK cells from HCV(+) (n=35), HIV(+)/HCV(+) (n=28), HIV(+) (n=8) patients, and healthy controls (n=30) were used in this study. NK cells were cultured in the presence or absence of supernatants from CD3/CD28-stimulated CD4(+) cells. Then, NK cells were co incubated with activated HSC and studied for degranulation, IFN-gamma secretion, and induction of HSC apoptosis. RESULTS: Following incubation with CD4(+) T cell supernatants, NK cells displayed a significantly increased activity against primary HSC as compared to unstimulated NK cells. This effect was, at least in part, mediated via an IL-2 dependent upregulation of NKG2D expression. HCV/HIV co infection was associated with an impaired IL-2 secretion of CD4(+) T cells resulting in an ineffective stimulation of anti-fibrotic NK cell function. CONCLUSIONS: Here, we show that CD4(+) T cells are able to stimulate anti fibrotic NK cell activity via IL-2 mediated upregulation of NKG2D. HIV-induced loss of CD4(+) T cells together with an impaired activity of CD4(+) T cells may contribute to accelerate progression of liver fibrosis observed in co-infection. PMID- 23665287 TI - Comparative genetic analyses point to HCP5 as susceptibility locus for HCV associated hepatocellular carcinoma. AB - BACKGROUND & AIMS: Recently, genetic variations in MICA (lead single nucleotide polymorphism [SNP] rs2596542) were identified by a genome-wide association study (GWAS) to be associated with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) in Japanese patients. In the present study, we sought to determine whether this SNP is predictive of HCC development in the Caucasian population as well. METHODS: An extended region around rs2596542 was genotyped in 1924 HCV-infected patients from the Swiss Hepatitis C Cohort Study (SCCS). Pair wise correlation between key SNPs was calculated both in the Japanese and European populations (HapMap3: CEU and JPT). RESULTS: To our surprise, the minor allele A of rs2596542 in proximity of MICA appeared to have a protective impact on HCC development in Caucasians, which represents an inverse association as compared to the one observed in the Japanese population. Detailed fine-mapping analyses revealed a new SNP in HCP5 (rs2244546) upstream of MICA as strong predictor of HCV-related HCC in the SCCS (univariable p=0.027; multivariable p=0.0002, odds ratio=3.96, 95% confidence interval=1.90-8.27). This newly identified SNP had a similarly directed effect on HCC in both Caucasian and Japanese populations, suggesting that rs2244546 may better tag a putative true variant than the originally identified SNPs. CONCLUSIONS: Our data confirms the MICA/HCP5 region as susceptibility locus for HCV-related HCC and identifies rs2244546 in HCP5 as a novel tagging SNP. In addition, our data exemplify the need for conducting meta-analyses of cohorts of different ethnicities in order to fine map GWAS signals. PMID- 23665289 TI - Cortical geometry may influence placement of interface between Par protein domains in early Caenorhabditis elegans embryos. AB - During polarization, proteins and other polarity determinants segregate to the opposite ends of the cell (the poles) creating biochemically and dynamically distinct regions. Embryos of the nematode worm Caenorhabditis elegans (C. elegans) polarize shortly after fertilization, creating distinct regions of Par protein family members. These regions are maintained through to first cleavage when the embryo divides along the plane specified by the interface between regions, creating daughter cells with different protein content. In wild type single cell embryos the interface between these Par protein regions is reliably positioned at approximately 60% egg length, however, it is not known what mechanisms are responsible for specifying the position of the interface. In this investigation, we use two mathematical models to investigate the movement and positioning of the interface: a biologically based reaction-diffusion model of Par protein dynamics, and the analytically tractable perturbed Allen-Cahn equation. When we numerically simulate the models on a static 2D domain with constant thickness, both models exhibit a persistently moving interface that specifies the boundary between distinct regions. When we modify the simulation domain geometry, movement halts and the interface is stably positioned where the domain thickness increases. Using asymptotic analysis with the perturbed Allen Cahn equation, we show that interface movement depends explicitly on domain geometry. Using a combination of analytic and numeric techniques, we demonstrate that domain geometry, a historically overlooked aspect of cellular simulations, may play a significant role in spatial protein patterning during polarization. PMID- 23665288 TI - A systematic review of follow-up biopsies reveals disease progression in patients with non-alcoholic fatty liver. AB - BACKGROUND & AIMS: Disease progression in non-alcoholic fatty liver disease (NAFLD) is not well understood and there is controversy about whether non alcoholic fatty liver (NAFL, i.e., steatosis alone or with mild inflammation not qualifying for steatohepatitis) can evolve towards steatohepatitis (NASH) with fibrosis. METHODS: We reviewed 70 patients with untreated NAFLD and with two biopsies performed more than one year apart. Clinical and biological data were recorded at the time of both biopsies. Alcohol consumption did not change during follow-up. RESULTS: Initially 25 patients had NAFL and 45 had NASH and/or advanced fibrosis. After a mean follow-up of 3.7 years (s.d. 2.1), 16 NAFL patients developed NASH, eight with severe ballooning and six with bridging fibrosis on the follow-up biopsy. Patients with mild lobular inflammation or any degree of fibrosis were at higher risk of progression than those with steatosis alone. Those with unambiguous disease progression were older and had worsening of their metabolic risk factors (higher weight and more diabetes at baseline and during follow-up). In the whole cohort, ballooning progression and bridging fibrosis often occurred together and co-existed with a reduction in ALT, higher weight gain, and a higher incidence of diabetes during follow-up. CONCLUSIONS: A substantial proportion of patients with NAFL can progress towards well-defined NASH with bridging fibrosis, especially if metabolic risk factors deteriorate. Even mild inflammation or fibrosis could substantially increase the risk of progression when compared to steatosis alone. Current monitoring practices of these patients should be revised. PMID- 23665290 TI - Curcumin ameliorates memory deficits via neuronal nitric oxide synthase in aged mice. AB - A number of neuroprotective effects of curcumin have been demonstrated in recent years. However, whether curcumin exerts any beneficial effects on age-related impaired cognition and memory has not been well characterized; nor was there any detailed data on the molecular pathways activated by curcumin. The present study attempts to investigate the effects of curcumin on memory decline of aged mice with a focus upon the possible contribution of the neuronal nitric oxide synthase (nNOS)/nitric oxide (NO) pathway in the memory amelioration effect of curcumin. The results showed that chronic administration of curcumin (50mg/kg, i.p., 21 days) significantly ameliorated the memory acquisition ability of aged male mice in the novel object recognition and passive avoidance tasks. Immunoblotting revealed that chronic treatment of curcumin increased nNOS expression in the prefrontal cortex, amygdala and hippocampus, as well as the enhancement of nNOS activity and NO concentration. This enhancement was suppressed by pre-treatment with 7-nitroindazole (7-NI), a specific inhibitor of neuronal nitric oxide synthase (nNOS). Furthermore, inhibition of nNOS synthase by 7-NI also prevented the memory improvement effects of curcumin in aged mice. Taken together, the results of the present study suggest that the amelioration of memory deficits by curcumin in aged mice was mediated, at least in part, by activating the nNOS activity in specific brain regions. These findings reveal the therapeutic potential of curcumin as a preventive agent upon the deterioration of cognitive faculties. PMID- 23665291 TI - Evaluation of the elastinolytic activity and protective effect of Leptallo I, a protein composed by metalloprotease and FA5/8C domains, from Leptospira interrogans Copenhageni. AB - Leptospirosis is a re-emergent zoonosis, caused by pathogenic spirochetes from the genus Lepstospira. To date, there is no protein described to be involved in leptospiral hemorrhagic manifestations, although several proteases have been reported for other bacterial infections. In this study we identified 12 putative metalloproteases from the genome of Leptospira interrogans, and characterized for the first time a putative metalloprotease, here named Leptallo I, as a potential Zn(2+) dependent glycylglycine protease belonging to the M23 metalloendopeptidase family. The native protein was detected in extracts from several pathogenic Leptospira species and further shown to be secreted to the culture medium. We expressed the recombinant protein and its C-terminal fragment containing the metalloprotease domain, and both presented regular secondary structures. The sera of humans with leptospirosis were able to recognize rLeptallo I, indicating that the native protein is expressed and presented to the immune system during infection. The recombinant proteins displayed a significant, though relatively low, elastinolytic activity, and the challenge of hamsters immunized with rLeptallo I conferred 33% protection, suggesting a significant importance of this protein in the pathogenesis. The elastinolytic activity may be important for leptospires-host interaction, because elastin constitutes a significant proportion of total lung and blood vessel proteins. PMID- 23665292 TI - [Non-Hodgkin lymphoma of maxillofacial soft tissue: a report of two cases and review of the literature]. AB - The extranodal non-Hodgkin lymphomas of maxillofacial soft tissues are rare. We report two cases of maxillofacial soft tissue non-Hodgkin lymphoma treated with chemotherapy followed by localized radiotherapy with complete remission after 3 and 6 months. We study the clinical, radiological and histopathological features as well as the treatment and the prognosis of extranodal non-Hodgkin lymphomas maxillofacial muscles. PMID- 23665294 TI - Guest editorial: special issue on zebrafish and other model organisms in comparative endocrine research. PMID- 23665295 TI - Surface plasmon resonance spectroscopy for characterisation of membrane protein ligand interactions and its potential for drug discovery. AB - Surface plasmon resonance (SPR) spectroscopy is a rapidly developing technique for the study of ligand binding interactions with membrane proteins, which are the major molecular targets for validated drugs and for current and foreseeable drug discovery. SPR is label-free and capable of measuring real-time quantitative binding affinities and kinetics for membrane proteins interacting with ligand molecules using relatively small quantities of materials and has potential to be medium-throughput. The conventional SPR technique requires one binding component to be immobilised on a sensor chip whilst the other binding component in solution is flowed over the sensor surface; a binding interaction is detected using an optical method that measures small changes in refractive index at the sensor surface. This review first describes the basic SPR experiment and the challenges that have to be considered for performing SPR experiments that measure membrane protein-ligand binding interactions, most importantly having the membrane protein in a lipid or detergent environment that retains its native structure and activity. It then describes a wide-range of membrane protein systems for which ligand binding interactions have been characterised using SPR, including the major drug targets G protein-coupled receptors, and how challenges have been overcome for achieving this. Finally it describes some recent advances in SPR based technology and future potential of the technique to screen ligand binding in the discovery of drugs. This article is part of a Special Issue entitled: Structural and biophysical characterisation of membrane protein-ligand binding. PMID- 23665296 TI - The scaling of contact rates with population density for the infectious disease models. AB - Contact rates and patterns among individuals in a geographic area drive transmission of directly-transmitted pathogens, making it essential to understand and estimate contacts for simulation of disease dynamics. Under the uniform mixing assumption, one of two mechanisms is typically used to describe the relation between contact rate and population density: density-dependent or frequency-dependent. Based on existing evidence of population threshold and human mobility patterns, we formulated a spatial contact model to describe the appropriate form of transmission with initial growth at low density and saturation at higher density. We show that the two mechanisms are extreme cases that do not capture real population movement across all scales. Empirical data of human and wildlife diseases indicate that a nonlinear function may work better when looking at the full spectrum of densities. This estimation can be applied to large areas with population mixing in general activities. For crowds with unusually large densities (e.g., transportation terminals, stadiums, or mass gatherings), the lack of organized social contact structure deviates the physical contacts towards a special case of the spatial contact model - the dynamics of kinetic gas molecule collision. In this case, an ideal gas model with van der Waals correction fits well; existing movement observation data and the contact rate between individuals is estimated using kinetic theory. A complete picture of contact rate scaling with population density may help clarify the definition of transmission rates in heterogeneous, large-scale spatial systems. PMID- 23665298 TI - Effect of duck meat consumption on thyroid hormone concentrations and energy metabolism of Sprague-Dawley rats. AB - The two diets, a duck meat diet (DMD) and a control casein diet (CD) were isocaloric (15.9 kJ/g dry matters), and contained 18.3% protein, 7.4% fat, 60.0% carbohydrate. The selenium contents in casein, duck meat powder, CD and DMD were 0.061, 0.549, 0.123 and 0.225 mg/kg. Rats in the DMD group had higher serum selenium concentrations (p<0.05) and liver 5'-deiodinase activities (p<0.05). As a result, duck meat consumption increased serum tri-iodothryonine (T3) concentrations (p<0.05) and decreased serum thyroxine (T4) concentrations (p<0.05). The lower serum T4 concentrations (p<0.05) were also supported by the lower total content of tyrosine and phenylalanine in duck meat powder compared to casein (7.72 vs 10.13). Compared to casein, duck meat powder had higher total content of glutamic acid, leucine, aspartic acid, serine, and alanine (44.68 vs 49.21), which led to higher serum TBG concentrations (p<0.05) in the DMD group. Hence, the DMD group had lower serum free T4 (FT4) concentrations (p<0.05), and lower serum free T3 (FT3) concentrations on day 14 (p<0.05), which significantly decreased the energy expenditure of rats in the DMD group, with lower liver Na,K ATPase and Ca-ATPase activities (p<0.05), lower OCRs and rectal temperature, especially on day 13 (p<0.05), higher body weight (p<0.05), and body-weight gain (p<0.05). We concluded that duck meat consumption decreased the energy metabolism of rats by multiple-step regulation of THs. PMID- 23665297 TI - Frequency of acute myeloid leukaemia-associated mouse chromosome 2 deletions in X ray exposed immature haematopoietic progenitors and stem cells. AB - Exposure to ionising radiation can lead to an increased risk of cancer, particularly leukaemia. In radiation-induced acute myeloid leukaemia (rAML), a partial hemizygous deletion of mouse chromosome 2 is a common feature in several susceptible strains. The deletion is an early event detectable 24h after exposure in bone marrow cells using cytogenetic techniques. Expanding clones of bone marrow cells with chromosome 2 deletions can be detected less than a year after exposure to ionising radiation in around half of the irradiated mice. Ultimately, 15-25% of exposed animals develop AML. It is generally assumed that leukaemia originates in an early progenitor cell or haematopoietic stem cell, but it is unknown whether the original chromosome damage occurs at a similar frequency in committed progenitors and stem cells. In this study, we monitored the frequency of chromosome 2 deletions in immature bone marrow cells (Lin(-)) and haematopoietic stem cells/multipotent progenitor cells (LSK) by several techniques, fluorescent in situ hybridisation (FISH) and through use of a reporter gene model, flow cytometry and colony forming units in spleen (CFU-S) following ex vivo or in vivo exposure. We showed that partial chromosome 2 deletions are present in the LSK subpopulation, but cannot be detected in Lin(-) cells and CFU-S12 cells. Furthermore, we transplanted irradiated Lin(-) or LSK cells into host animals to determine whether specific irradiated cell populations acquire an increased proliferative advantage compared to unirradiated cells. Interestingly, the irradiated LSK subpopulation containing cells carrying chromosome 2 deletions does not appear to repopulate as well as the unirradiated population, suggesting that the chromosomal deletion does not provide an advantage for growth and in vivo repopulation, at least at early stages following occurrence. PMID- 23665299 TI - Food label education does not reduce sodium intake in people with type 2 diabetes mellitus. A randomised controlled trial. AB - BACKGROUND: Sodium intake is high in people with type 2 diabetes (T2DM). The aim of this study was to investigate whether urinary sodium excretion can be reduced by educating people with T2DM to read food labels and choose low sodium products. METHOD: In a 3 month randomised controlled trial, 78 men (n=49) and women (n=29) with T2DM were recruited from a Diabetes Centre at a University teaching hospital. The intervention group was educated in a single session to use the nutrition information panel on food labels to choose products which complied with the Food Standards Australia New Zealand (FSANZ) guideline of <120 mg sodium/100 g food. The control group continued on their usual diet. The primary outcome measure was 24h urinary sodium excretion which was performed at baseline and 3 months. Data was analysed using repeated measures analysis of variance, independent samples t-test and Pearson's correlations. RESULTS: At 3 months mean urinary sodium excretion was unchanged in the intervention (174+/-13 mmol/24 h and 175+/-13 mmol/24 h) and control group (167+/-15mmol/24h and 161+/-13 mmol/24 h), and there was no between group difference (p>0.05). CONCLUSION: Sodium excretion was not reduced following the label reading education provided to this group of people with T2DM. PMID- 23665300 TI - TRAK ontology: defining standard care for the rehabilitation of knee conditions. AB - In this paper we discuss the design and development of TRAK (Taxonomy for RehAbilitation of Knee conditions), an ontology that formally models information relevant for the rehabilitation of knee conditions. TRAK provides the framework that can be used to collect coded data in sufficient detail to support epidemiologic studies so that the most effective treatment components can be identified, new interventions developed and the quality of future randomized control trials improved to incorporate a control intervention that is well defined and reflects clinical practice. TRAK follows design principles recommended by the Open Biomedical Ontologies (OBO) Foundry. TRAK uses the Basic Formal Ontology (BFO) as the upper-level ontology and refers to other relevant ontologies such as Information Artifact Ontology (IAO), Ontology for General Medical Science (OGMS) and Phenotype And Trait Ontology (PATO). TRAK is orthogonal to other bio-ontologies and represents domain-specific knowledge about treatments and modalities used in rehabilitation of knee conditions. Definitions of typical exercises used as treatment modalities are supported with appropriate illustrations, which can be viewed in the OBO-Edit ontology editor. The vast majority of other classes in TRAK are cross-referenced to the Unified Medical Language System (UMLS) to facilitate future integration with other terminological sources. TRAK is implemented in OBO, a format widely used by the OBO community. TRAK is available for download from http://www.cs.cf.ac.uk/trak. In addition, its public release can be accessed through BioPortal, where it can be browsed, searched and visualized. PMID- 23665301 TI - Risk factors for renal cell carcinoma in the VITAL study. AB - PURPOSE: The incidence of renal cell carcinoma is increasing worldwide. Cited risk factors include obesity, smoking and hypertension but few others have been confirmed in prospective studies. We used a prospective cohort to validate established renal cell carcinoma risk factors and evaluate more controversial risk factors for incident renal cell carcinoma. MATERIALS AND METHODS: A total of 77,260 residents of Washington 50 to 76 years old completed a questionnaire between 2000 and 2002 on demographic, lifestyle and health data. Incident renal cell carcinoma cases were determined by linkage to the regional cancer registry through December 31, 2009. Multivariate methods using covariates and cutoffs selected a priori were applied to analyze the association between renal cell carcinoma and previously studied factors related to lifestyle (body mass index, smoking and alcohol/fruit/vegetable consumption) and health (hypertension, diabetes, kidney disease and viral hepatitis). RESULTS: There were 249 incident cases of renal cell carcinoma. Independent renal cell carcinoma risk factors in the fully adjusted model were body mass index (35 or greater vs less than 25 kg/m2 HR 1.71, 95% CI 1.06-2.79), smoking (greater than 37.5 pack-years vs never HR 1.58, 95% CI 1.09-2.29), hypertension (HR 1.70, 95% CI 1.30-2.22), kidney disease (HR 2.58, 95% CI 1.21-5.50) and viral hepatitis (HR 1.80, 95% CI 1.03 3.14). Diabetes was associated with renal cell carcinoma (HR 1.83, 95% CI 1.26 2.65) in a base model adjusting for age and gender but not in the multivariate model. We found no association between alcohol, fruit or vegetable intake and renal cell carcinoma. CONCLUSIONS: We identified a significant association of renal cell carcinoma with obesity, smoking, hypertension, renal disease and viral hepatitis. Identifying risk factors offers an opportunity for targeted education and intervention. PMID- 23665302 TI - Rapid clearance of intranasally administered DNA from rat tissues. AB - The cold-adapted (ca) live attenuated influenza vaccine (LAIV) strains are manufactured in embryonated hens' eggs. Recently, a clonal isolate from Madin Darby Canine Kidney (MDCK) cells was derived and characterized to assess its utility as a potential cell substrate for the manufacturing of LAIV [1]. Since MDCK cells are a transformed continuous cell line [2], and low levels of residual cellular components (DNA and protein) are found in the intermediates and final filled vaccine, we sought to characterize the uptake and clearance of MDCK DNA from tissues in order to assess theoretical risks associated with manufacturing LAIV in MDCK cell culture. In order to address this concern, MDCK DNA uptake and clearance studies were performed in Sprague Dawley rats. DNA extracted from MDCK Master Cell Bank (MCB) cells was administered via an intranasal (IN) or intramuscular (IM) route. Tissue distribution and clearance of MDCK DNA were then examined in fourteen selected tissue types at selected time points post administration using a quantitative PCR assay specific for canine (SINE) DNA. Results from these studies demonstrate that the uptake and clearance of MDCK DNA from tissues vary depending on the route of administration. When DNA was administered intranasally, as compared to intramuscularly, detectable DNA levels were lower at all time points. Thus, the intranasal route of vaccine administration appears to reduce potential risk associated with residual host cell DNA that may be present in cell culture produced final vaccine products. PMID- 23665304 TI - Safety of the production process of SURFACEN((r)) to inactivate and remove virus. AB - SURFACEN((r)) is a biological product produced from pig lungs. Since these animals can be potential sources of microbial pathogens such as viruses, the manufacturing process of this product should guarantee safety from health hazards. The SURFACEN((r)) production procedure is capable of effective viral clearance (inactivation/removal) by involving two stages of organic solvent extraction followed by acetone precipitation and heat treatment. In this study, we evaluated the clearance capacity of these four stages for a wide range of viruses by performing spiking experiments. Residual contamination was assessed using a Tissue Culture Infectious Dose assay (log10 TCID50). The validation study demonstrated that, for all viruses tested, the TCID50 titers were reduced by more than 2 log10 in each stage. Total log reduction values achieved were between >=17.82 log10 and >=27.93 log10, depending on the virus physical properties, titer, and the number of processing stages applied. Results indicated that the production procedure of SURFACEN((r)) can inactivate or remove contaminant viruses from the raw material. PMID- 23665303 TI - Serogroup quantitation of multivalent polysaccharide and polysaccharide-conjugate meningococcal vaccines from China. AB - The active components of most meningococcal vaccines are four antigenic serogroup capsular polysaccharides (A, C, Y, W135). The vaccines, monovalent or multivalent mixtures of either free polysaccharides or polysaccharides conjugated to antigenic carrier proteins, may be in liquid or lyophilised formulations, with or without excipients. Acid hydrolysis and chromatographic methods for serogroup quantitation, which were previously optimised and qualified using polysaccharide based standards and a narrow range of real vaccines, are here challenged with multiple lots of a broad assortment of additional multivalent polysaccharide based meningococcal vaccine products. Centrifugal filtration successfully removed all interfering lactose excipient without loss of polysaccharides to allow for the determination of Y and W135 serogroups. Replicate operations by three different analysts indicated high method reproducibility. Results indicated some lot-to-lot and product-to-product variations. However, all vaccines were within general specifications for each serogroup polysaccharide, with the exception of all lots of one polysaccharide vaccine - which by these methods were found to be deficient in the serogroup A component only. These robust techniques are very useful for the evaluation of antigen content and consistency of manufacture. The deformulation, hydrolysis and chromatographic methods may be adaptable for the evaluation of other types of polysaccharide-based vaccines. PMID- 23665305 TI - Ambulatory continuous posterior lumbar plexus blocks following hip arthroscopy: a review of 213 cases. AB - STUDY OBJECTIVE: To evaluate complications associated with ambulatory continuous lumbar plexus blocks. DESIGN: Retrospective review of all patients who received a continuous lumbar plexus block for analgesia following arthroscopic hip surgery from January 2004 to July 2009. SETTING: Academic medical center. MEASUREMENTS: Data from 213 patients who were discharged home with a continuous lumbar plexus block following hip arthroscopy were studied. Side effects and complications, including impaired ambulation, systemic local anesthetic toxicity, abnormal local anesthetic spread, and neurologic injury, were recorded. MAIN RESULTS: Of the 281 patients who received a continuous lumbar plexus block following hip arthroscopy, 213 were discharged home with the continuous lumbar plexus block. Significant complications occurred in 3.8% of patients (8/213). Twenty of 213 patients (9.4%) reported prolonged sensory or motor deficits after the continuous lumbar plexus block was removed. Most of these deficits were minor and resolved spontaneously, but 4 patients (1.9%) experienced persistent neurologic symptoms. One patient had a fall, one patient was readmitted for possible bilateral spread from the continuous lumbar plexus block, and two patients experienced symptoms of local anesthetic systemic toxicity (LAST). CONCLUSIONS: While complications associated with hip arthroscopy with ambulatory continuous lumbar plexus blocks do occur, significant complications are uncommon. Most complications are managed easily on an outpatient basis. However, nearly 1% of patients presented with symptoms concerning for LAST and were treated without any hemodynamic compromise. PMID- 23665306 TI - Family income and child health in the UK. AB - Recent studies examining the relationship between family income and child health in the UK have produced mixed findings. We re-examine the income gradient in child general health and its evolution with child age in this country, using a very large sample of British children. We find that there is no correlation between income and child general health at ages 0-1, that the gradient emerges around age 2 and is constant from age 2 to age 17. In addition, we show that the gradient remains large and significant when we reduce the endogeneity of income. Furthermore, our results indicate that the gradient in general health reflects a greater prevalence of chronic conditions among low-income children and a greater severity of these conditions. Taken together, these findings suggest that income does matter for child health in the UK and may play a role in the intergenerational transmission of socioeconomic status. PMID- 23665307 TI - MicroRNA regulation of endothelial homeostasis and commitment-implications for vascular regeneration strategies using stem cell therapies. AB - Human embryonic (hESC) and induced pluripotent (hiPSC) stem cells have broad therapeutic potential in the treatment of a range of diseases, including those of the vascular system. Both hESCs and hiPSCs have the capacity for indefinite self renewal, in addition to their ability to differentiate into any adult cell type. These cells could provide a potentially unlimited source of cells for transplantation and, therefore, provide novel treatments, e.g. in the production of endothelial cells for vascular regeneration. MicroRNAs are short, noncoding RNAs that act posttranscriptionally to control gene expression and thereby exert influence over a wide range of cellular processes, including maintenance of pluripotency and differentiation. Expression patterns of these small RNAs are tissue specific, and changes in microRNA levels have often been associated with disease states in humans, including vascular pathologies. Here, we review the roles of microRNAs in endothelial cell function and vascular disease, as well as their role in the differentiation of pluripotent stem cells to the vascular endothelial lineage. Furthermore, we discuss the therapeutic potential of stem cells and how knowledge and manipulation of microRNAs in stem cells may enhance their capacity for vascular regeneration. PMID- 23665308 TI - Effects of ozone exposure on the ocular surface. AB - Changes in the ocular surface induced by ozone have received limited research attention. Here, we investigate the effects of ozone exposure on the integrity of the ocular surface, the production of inflammatory cytokines in tears, and changes in mucin-secreting cells in a mouse model. In addition, ozone-induced nuclear factor-kappaB (NF-kappaB)-mediated inflammatory processes were evaluated in cultured human conjunctival epithelial cells. In vivo, ozone induced the breakdown of corneal epithelial integrity, decreased the number of mucin secreting cells, and induced the production of inflammatory cytokines, without altering tear volume. In vitro, ozone exposure led to increases in NF-kappaB nuclear translocation, kappaB-dependent transcriptional activity, NF-kappaB inhibitor alpha (IkappaBalpha) proteolysis, and expression of phosphorylated IkappaBalpha (p-IkappaBalpha), but did not cause cytotoxicity or cellular apoptosis. In addition, ozone induced the expression of inflammatory cytokines, Toll-like receptors, and C-C chemokine receptors, but decreased the expression of mucins. Furthermore, inhibition of NF-kappaB with pyrrolidine dithiocarbamate before exposure of cultured human conjunctival epithelial cells to ozone prevented changes in IkappaBalpha and p-IkappaBalpha levels in association with a decrease in the levels of inflammatory cytokines. Therefore, we conclude that ozone exposure interferes with ocular surface integrity and induces inflammation involving NF-kappaB-mediated processes at the level (and/or upstream) of IkappaBalpha. Understanding the role of ozone in the initiation of inflammatory processes on the animal ocular surface and in cultured human conjunctival epithelial cells can help elucidate the pathogenesis of ocular surface damage and suggest protective strategies for preserving a healthy ocular surface against ozone exposure. PMID- 23665309 TI - [Foreign body reaction in osteoarthritis of the trapeziometacarpal joint treated by trapezectomy and interposition of a L-polylactic acid "anchovy" (Arex(r)615R). A series of eight cases]. AB - Osteoarthritis of the trapeziometacarpal joint is a common pathology. When the trapezium is not large enough to allow using a total joint arthroplasty or in case of peritrapezial osteoarthrosis, the authors used a trapeziectomy with interposition of an absorbable L-polylactic acid anchovy (Arex((r))615R). This technique is simple and fast. From 2006 to 2010, out of 68 implants, nine displayed a prolonged inflammatory reaction, both clinically and radiologically abnormal, leading the patients to undergo revision surgery for removal of the implant before the end of the third postoperative year. Histological analysis highlighted in all the cases a resorptive gigantocellular immune foreign body reaction. PMID- 23665310 TI - [Fingertip injuries in children]. AB - Traumatisms of distal extremities are frequent in children. They can associate fingertip skin, bone and nail complex injuries. Their severity level is very variable, from simple subungual bruise to distal amputation. Initial care needs careful repair of injured structures. Secondary treatment of sequelae is much more difficult. PMID- 23665311 TI - Bilateral rupture of the extensor pollicis longus tendon. A case report. AB - Bilateral rupture of the extensor pollicis longus (EPL) is a rare entity and the few cases that have been reported were associated with an underlying systemic condition such as rheumatoid arthritis or following an injury. We present the case of a patient who was referred to us with a spontaneous rupture of the EPL tendon of the right wrist and that of the left side observed 2 months after tenosynovectomy. The patient had not any pathologic condition or evidence of trauma in both wrists. In the left side, he was operated on and a tenolysis and subcutaneous tendon transposition was performed. Despite this preventive surgery, the patient suffered from a tendon rupture. The possible causes of surgery failure are discussed. PMID- 23665313 TI - Hydrogen peroxide-induced necrotic cell death in cardiomyocytes is independent of matrix metalloproteinase-2. AB - Matrix metalloproteinase-2 (MMP-2) is well known to proteolyse both extracellular and intracellular proteins. Reactive oxygen species activate MMP-2 at both transcriptional and post-translational levels, thus MMP-2 activation is considered an early event in oxidative stress injury. Although hydrogen peroxide is widely used to trigger oxidative stress-induced cell death, the type of cell death (apoptosis vs. necrosis) in cardiomyocytes is still controversial depending on the concentration used and the exposure time. We carefully investigated the mode of cell death in neonatal rat cardiomyocytes induced by different concentrations (50-500 MUM) of hydrogen peroxide at various time intervals after exposure and determined whether MMP-2 is implicated in hydrogen peroxide-induced cardiomyocyte death. Treating cardiomyocytes with hydrogen peroxide led to elevated MMP-2 level/activity with maximal effects seen at 200 MUM. Hydrogen peroxide caused necrotic cell death by disrupting the plasmalemma as evidenced by the release of lactate dehydrogenase in a concentration- and time-dependent manner as well as the necrotic cleavage of PARP-1. The absence of both caspase-3 cleavage/activation and apoptotic cleavage of PARP-1 illustrated the weak contribution of apoptosis. Pre-treatment with selective MMP inhibitors did not protect against hydrogen peroxide-induced necrosis. In conclusion hydrogen peroxide increases MMP-2 level/activity in cardiomyocytes and induces necrotic cell death, however, the later effect is MMP-2 independent. PMID- 23665312 TI - Myelophil attenuates brain oxidative damage by modulating the hypothalamus pituitary-adrenal (HPA) axis in a chronic cold-stress mouse model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Myelophil is composed of Astragali Radix and Salviae Miltiorrhizae Radix, according to the long traditional pharmacological practices, and it has been used for patients with chronic fatigue-associated symptoms including concentration problem or memory loss. AIM OF THE STUDY: This study aimed to evaluate the clinical relevance of Myelophil on brain oxidative damage using a chronic cold stress mice model. MATERIAL AND METHODS: Balb/c mice were subjected to cold stress (4 degrees C for 4h) six times per week for 2 weeks with or without oral administration of Myelophil (50, 100, or 200mg/kg), or ascorbic acid (50mg/kg). RESULTS: Chronic cold stress induced histopathological hippocampal apoptosis with drastically increased serum levels of total reactive oxygen species and nitric oxide, as well as brain lipid peroxidation levels, protein carbonyl, and caspase-3/7 activity. These alterations were significantly ameliorated by Myelophil treatment. Myelophil administration significantly recovered the depleted glutathione and its enzymes, superoxide dismutase activity, and catalase protein and gene expression levels. Serum levels of corticosterone, dopamine, and adrenaline were notably altered by chronic cold stress but were significantly ameliorated by Myelophil treatment. Myelophil also normalized alterations in tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-10 gene expression and protein levels. Chronic cold stress up-regulated gene expression levels of phenylethanolamine N-methyltransferase and monoamine oxidase-B, and glucocorticoid receptors in the hypothalamus and hippocampus, respectively, whereas Myelophil treatment completely normalized these levels. CONCLUSIONS: These results suggest that Myelophil has potent pharmaceutical effects against chronic cold-stress-induced brain damage by relieving oxidative stress and inflammation and regulating stress hormones in mice. PMID- 23665314 TI - Therapeutic potential of curcumin in experimentally induced allergic rhinitis in guinea pigs. AB - In the present experiments, the possible role of curcumin in ovalbumin induced allergic rhinitis in guinea pig model was investigated. Various allergic rhinitis symptoms viz sneezing, rubbing frequencies, lacrimation and nasal congestion at various humidity conditions as well as on repeated sensitization were studied. The biochemical changes like serum IgE, IL-4 and nitric oxide (NO) in nasal lavage and eosinophil peroxidase activity in nasal homogenates were determined in allergic rhinitis. Curcumin treatment significantly reduced the symptoms (sneezing, rubbing frequencies, lacrimation and nasal congestion) and improved the histopathological alterations (reduction in inflammatory cells infiltration) of nasal mucosa in allergic rhinitis. Furthermore, curcumin treatment prevented significantly elevation of serum IgE, IL-4, NO in nasal lavage and eosinophil peroxidase in nasal homogenate. In the present experimental findings, we suggest that curcumin is a promising anti-allergic agent that may be useful in the clinical management of allergic rhinitis. PMID- 23665315 TI - Vasoprotective effect of vitamin E: rescue of ethanol-induced atherosclerosis and inflammatory stress in rat vascular wall. AB - Chronic ethanol consumption increases the incidence of cardiovascular disease. The mechanisms underlying ethanol-induced susceptibility to cardiovascular disease continue to be defined. This study examines the hypothesis that chronic ethanol consumption plausibly induces vascular wall abnormalities via inflammatory reactions. In addition, it intends to find out whether vitamin E inhibits the abnormalities induced by ethanol in rats' vascular wall. Twenty four male Wistar rats were divided into three groups (n=8): Control (c), ethanol (E), and vitamin E treated ethanol (VETE) group. After 6weeks, the aortic and coronary wall changes, vascular endothelial growth factor (VEGF), alpha-1 glycoprotein and haptoglobin amounts in plasma, C-reactive protein levels(CRP), as well as the amount of aortic IL-6 were evaluated. The results revealed the elevation of polymorphonuclear (PMN) leukocyte in the vascular wall, disorganization of endothelium with ballooning of cells, proliferation of vasa-vasorum with an increase in the IL-6, CRP, as well as a decrease in VEGF and an increase in alpha 1 glycoprotein and haptoglobin in the ethanol group compared to the control group. Significant amelioration of aortic and coronary wall changes, along with the restoration of elevated level of IL6, CRP, and the decreased level of VEGF compared to that of the controls were found in vitamin E-treated animals. These findings strongly support the idea that heavy and chronic ethanol consumption initiates atherosclerosis by inflammatory stress, and that these effects can be alleviated by vitamin E as an anti-inflammatory agent. PMID- 23665316 TI - Nano-titanium dioxide induced cardiac injury in rat under oxidative stress. AB - Heart diseases, which are related to oxidative stress (OS), negatively affect millions of people from kids to the elderly. Titanium dioxide (TiO2) has widespread applications in our daily life, especially nanoscale TiO2. Compared to the high risk of particulate matter (<=2.5MUm) in air to heart disease patients, related research of TiO2 on diseased body is still unknown, which suggest us to explore the potential effects of nanoscale and microscale TiO2 to heart under OS conditions. Here, we used alloxan to induce OS conditions in rat, and investigated the response of heart tissue to TiO2 in healthy and alloxan treated rats. Compared with NMs treatment only, the synergistic interaction between OS conditions and nano-TiO2 significantly reduced the heart-related function indexes, inducing pathological changes of myocardium with significantly increased levels of cardiac troponin I and creatine kinase-MB. In contrast with the void response of micro-TiO2 to heart functions in alloxan treated rats, aggravation of OS conditions might play an important role in cardiac injury after alloxan and nano-TiO2 dual exposure. Our results demonstrated that OS conditions enhanced the adverse effects of nano-TiO2 to heart, suggesting that the use of NMs in stressed conditions (e.g., drug delivery) needs to be carefully monitored. PMID- 23665317 TI - Involvement of lipid droplets in hepatic responses to lipopolysaccharide treatment in mice. AB - Infection and inflammation induce important changes in lipid metabolism, which result in increased free fatty acids and triacylglycerol in plasma and altered high density lipoprotein (HDL) metabolism. Our aim was to elucidate whether hepatic lipid droplets (LDs) are involved in the adaptations of lipid metabolism to endotoxemia. We characterized the lipid content and several enzymatic activities in subcellular fractions and subpopulations of LDs from livers of mice 24h after lipopolysaccharide (LPS) treatment and analyzed the expression of key genes involved in lipid management. Endotoxemic mice showed lower lipid content in LDs with decreased molar fraction of cholesteryl ester and higher diacylglycerol/triacylglycerol ratio as compared to their controls. They also showed a decrease in cytosolic triacylglycerol hydrolase activity, specifically in dense LDs, and in microsomal and cytosolic diacylglycerol hydrolase activity; concomitantly neutral lipid biosynthetic capacity and triacylglycerol levels in plasma lipoproteins increased. Together with the overexpression of genes involved in lipogenesis and HDL formation our results suggest that altered hepatic management of LD lipids in LPS-treated mice might be related to the channeled mobilization of triacylglycerol for very low density lipoprotein assembly and to the induction of cholesterol export. PMID- 23665318 TI - Histone deacetylases inhibitor trichostatin A modulates the extracellular release of APE1/Ref-1. AB - Apurinic/apyrimidinic endonuclease 1/Redox factor-1 (APE1/Ref-1) can be acetylated via post-translational modification. We investigated the effect of an inhibitor of histone deacetylases on the extracellular release of APE1/Ref-1 in HEK293 cells. Trichostatin A (TSA), an inhibitor of histone deacetylases, induced APE1/Ref-1 secretion without changing cell viability. In a fluorescence quantitative assay, the secreted APE1/Ref-1 was estimated to be about 10 ng/mL in response to TSA (1 MUM). However, TSA did not induce the secretion of lysine mutated APE1/Ref-1 (K6R/K7R). TSA also caused nuclear to cytoplasmic translocation of APE1/Ref-1. Taken together, these findings suggest that APE1/Ref 1 is a protein whose secretion is governed by lysine acetylation. PMID- 23665319 TI - Myc binds the pluripotency factor Utf1 through the basic-helix-loop-helix leucine zipper domain. AB - In order to elucidate the function of Myc in the maintenance of pluripotency and self-renewal in mouse embryonic stem cells (mESCs), we screened for novel ESC specific interactors of Myc by mass spectrometry. Undifferentiated embryonic cell transcription factor 1 (Utf1) was identified in the screen as a putative Myc binding protein in mESCs. We found that Myc and Utf1 directly interact. Utf1 is a chromatin-associated factor required for maintaining pluripotency and self renewal in mESCs. It can also replace c-myc during induced pluripotent stem cell (iPSC) generation with relatively high efficiency, and shares target genes with Myc in mESCs highlighting a potentially redundant functional role between Myc and Utf1. A large region of Utf1 was found to be necessary for direct interaction with N-Myc, while the basic helix-loop-helix leucine zipper domain of N-Myc is necessary for direct interaction with Utf1. PMID- 23665320 TI - The expression of IL-6 and STAT3 might predict progression and unfavorable prognosis in Wilms' tumor. AB - PURPOSE: To investigate the expression profiles of IL-6 and STAT3 in Wilms' tumor (WT) and their relationship with disease progression. METHODS: Immunohistochemistry was used to examine IL-6 and STAT3 expression in 58 primary tumors and 18 invasive/metastatic ones. RESULTS: Positive expression rate of IL 6/STAT3 was 39.7% (23/58)/29.3% (17/58) in primary WT tissues, while 61.1% (11/18)/33.3% (6/18) in associated invasive/metastatic tissues. The expression rate of IL-6 and STAT3 was higher in primary WT tumors of invasive/metastatic group than that of non-invasive/metastatic group (P=0.033; P=0.012). There was a positive correlation between IL-6 and STAT3 expression in 76 WT tissues (P<0.001, r=0.444). The expression of IL-6 /STAT3 between primary WT and matched invasive/metastatic tissues was concordance (P=0.727; P=0.99). IL-6 expression status and histopathological type were associated with disease-free survival (DFS) and overall survival (OS) (P<0.05), while STAT3 was only correlated with DFS (P<0.05). CONCLUSIONS: IL-6 and STAT3 expression in WT might be correlated with progression and predict unfavorable prognosis, highlighting a new therapy target for invasive or metastatic WTs. PMID- 23665321 TI - Arginase inhibition reduces interleukin-1beta-stimulated vascular smooth muscle cell proliferation by increasing nitric oxide synthase-dependent nitric oxide production. AB - We investigated whether arginase inhibition suppressed interleukin (IL)-1beta stimulated proliferation in vascular smooth muscle cells (VSMCs) and the possible mechanisms involved. IL-1beta stimulation increased VSMC proliferation, while the arginase inhibitor BEC and transfection of the antisense (AS) oligonucleotide against arginase I decreased VSMC proliferation and was associated with increased protein content of the cell cycle regulator p21Waf1/Cip1. IL-1beta incubation induced inducible nitric oxide synthase (iNOS) mRNA expression and protein levels in a dose-dependent manner, but did not affect arginase I and II expression. Consistent with this data, IL-1beta stimulation resulted in increase in NO production that was significantly augmented by arginase inhibition. The specific iNOS inhibitor 1400W abolished IL-1beta-mediated NO production and further accentuated IL-1beta-stimulated cell proliferation. Incubation with NO donors GSNO and DETA/NO in the presence of IL-1beta abolished VSMCs proliferation and increased p21Waf1/Cip1 protein content. Furthermore, incubation with the cGMP analogue 8-Br-cGMP prevented IL-1beta-induced VSMCs proliferation. In conclusion, arginase inhibition augmented iNOS-dependent NO production that resulted in suppression of IL-1beta-induced VSMCs proliferation in a cGMP-dependent manner. PMID- 23665323 TI - Importance of muscle biopsy in diagnosis of muscle diseases. PMID- 23665322 TI - Gambogic acid induces EGFR degradation and Akt/mTORC1 inhibition through AMPK dependent-LRIG1 upregulation in cultured U87 glioma cells. AB - Glioblastoma multiforme (GBM) is the most common malignant tumor in adults' central nervous system (CNS). The development of novel anti-cancer agents for GBM is urgent. In the current study, we found that gambogic acid induced growth inhibition and apoptosis in cultured U87 glioma cells, which was associated with Akt/mTORC1 (mTOR complex 1) signaling in-activation. To restore Akt activation by introducing a constitutively active (CA) Akt attenuated gambogic acid-induced cytotoxicity against U87 cells. For mechanism study, we found that gambogic acid induced LRIG1 (leucine-rich repeat and Ig-like domain-containing-1) upregulation, which was responsible for EGFR (epidermal growth factor receptor) degradation and its downstream Akt/mTORC1 inhibition. Further, we provided evidence to support that AMPK (AMP-activated protein kinase) activation mediated gambogic acid induced LRIG1 upregulation, U87 cell apoptosis and growth inhibition, while AMPK inhibition by shRNA or compound C reduced gambogic acid-induced EGFR/Akt inhibition and cytotoxicity in U87 cells. We here proposed novel signaling mechanism mediating gambogic acid-induced cytotoxic effects in glioma cells. PMID- 23665324 TI - Acetylcholine receptors regulate gene expression that is essential for primitive streak formation in murine embryoid bodies. AB - Muscarinic acetylcholine receptors (mAchRs) are critical components of the cholinergic system, which is the key regulator of both the central and peripheral nervous systems in mammals. Interestingly, several components of the cholinergic system, including mAchRs and choline acetyltransferase (ChAT), have recently been found to be expressed in mouse embryonic stem (ES) cells and human placenta. These results raise the intriguing possibility that mAchRs play physiological roles in the regulation of early embryogenesis. Early embryogenesis can be mimicked in vitro using an ES cell-based culture system in which the cells form a primitive streak-like structure and efficiently develop into mesodermal progenitors. Here we report that chemical inhibitors specifically targeting mAchRs suppressed the expression of genes essential for primitive streak formation, including Wnt3, and thereby blocked mesodermal progenitor differentiation. Interestingly, mAchR inhibitors also reduced the expression of Cyp26a1, an enzyme involved in the catabolism of retinoic acid (RA). RA is an important regulator of Wnt3 signaling. Our study presents evidence indicating that mAchRs influence RA signaling necessary for the induction of the primitive streak. To our knowledge, this is the first report showing that mAchRs have important functions not only in adult mammals but also during early mammalian embryogenesis. PMID- 23665326 TI - Sac-1004, a novel vascular leakage blocker, enhances endothelial barrier through the cAMP/Rac/cortactin pathway. AB - The maintenance of endothelial barrier is critical for the vascular homeostasis and is maintained by the interaction of adherens junction (AJ) and tight junction (TJ) proteins between adjacent cells. This interaction is stabilized by actin cytoskeleton forming cortical actin ring. Here, we developed a novel vascular leakage blocker, Sac-1004 and investigated its mechanism of action in endothelial cells (ECs). Sac-1004 inhibited endothelial hyperpermeability induced by vascular endothelial growth factor, histamine and thrombin via stabilization of cortical actin ring and AJ proteins at the cell-cell junction. Treatment of Sac-1004 in ECs increased cAMP levels and activated Rac, both of which are known to strengthen endothelial barrier. Furthermore, Sac-1004 induced phosphorylation of cortactin and its localization at cell membrane that is essential for the stabilization of cortical actin ring. These effects of Sac-1004 on ECs were significantly abrogated by dideoxyadenosine (adenylyl cyclase inhibitor) and NSC23766 (Rac inhibitor). Taken together, our findings indicate that Sac-1004 blocks vascular leakage by enhancing endothelial integrity via the cAMP/Rac/cortactin pathway and imply the potential usefulness of Sac-1004 in the development of therapeutic means for vascular leakage-related diseases. PMID- 23665325 TI - NEK9 depletion induces catastrophic mitosis by impairment of mitotic checkpoint control and spindle dynamics. AB - NEK9 is known to play a role in spindle assembly and in the control of centrosome separation, but the consequences of NEK9 targeting in cancer cells remain to be elucidated. In this study, we used siRNA to investigate the consequences of targeting NEK9 in glioblastoma and kidney cancer cells as a first step in assessing its potential as an anti-cancer therapeutic target. Live cell imaging revealed that NEK9 depletion of U1242 glioblastoma and Caki2 kidney carcinoma cells resulted in failure of cytokinesis. Interestingly, NEK9-depleted Caki2 cells overrode mitosis under incorrect chromosome alignment and were converted to a micronucleated phenotype, leading to cell death. Whereas, the RPE1 normal epithelium cell line was refractory to abnormal mitosis upon NEK9 knockdown. Nocodazole-induced mitotic arrest was compromised after NEK9 depletion, indicating that NEK9 has an important role in mitotic checkpoint system. Taken together, we propose that NEK9 inhibition represents a novel anti-cancer strategy by induction of mitotic catastrophe via impairment of spindle dynamics, cytokinesis and mitotic checkpoint control. PMID- 23665327 TI - Ubiquitination of the heterotrimeric G protein alpha subunits Galphai2 and Galphaq is prevented by the guanine nucleotide exchange factor Ric-8A. AB - The cytosolic protein Ric-8A acts as a guanine nucleotide exchange factor for Galpha subunits of the Gi, Gq, and G12/13 classes of heterotrimeric G protein in vitro, and is also known to increase the amounts of these Galpha proteins in vivo. The mechanism whereby Ric-8 regulates Galpha content, however, has not been fully understood. Here we show that Ric-8 Astabilizes Galphai2 and Galphaq by preventing their ubiquitination. Ric-8A interacts with and stabilizes Galphai2, Galphaq, Galpha12, but not Galphas, when expressed in COS-7 cells. The protein levels of Galphai2 and Galphaq appear to be controlled via the ubiquitin proteasome degradation pathway, because these Galpha subunits undergo polyubiquitination and are stabilized with the proteasome inhibitor MG132. The ubiquitination of Galphai2 and Galphaq is suppressed by expression of Ric-8A. The suppression likely requires Ric-8A interaction with these Galpha proteins; the C terminal truncation of Galphaq and Galphai2 completely abrogates their interaction with Ric-8A, their stabilization by Ric-8A, and Ric-8A-mediated inhibition of Galpha ubiquitination. PMID- 23665329 TI - Hepatitis B virus e antigen induces activation of rat hepatic stellate cells. AB - Chronic hepatitis B virus infection is a major cause of hepatic fibrosis, leading to liver cirrhosis and hepatocellular carcinoma. Hepatitis B virus e antigen (HBeAg) is an accessory protein of HBV, not required for viral replication but important for natural infection in vivo. Hepatic stellate cells (HSCs) are the major producers of excessive extracellular matrix during liver fibrogenesis. Therefore, we examined the influence of HBeAg on HSCs. The rat HSC line HSC-T6 was transfected with HBeAg plasmids, and expression of alpha-smooth muscle actin, collagen I, transforming growth factor-beta1 (TGF-beta), and tissue inhibitors of metalloproteinase 1 (TIMP-1) was investigated by quantitative real-time PCR. The proliferation of HSCs was determined by MTS analysis. HBeAg transduction induced up-regulation of these fibrogenic genes and proliferation of HSCs. We found that HBeAg induced TGF-beta secretion in HSCs, and the activation of HSCs was prevented by a neutralizing anti-TGF-beta antibody. Depletion and addition of HBeAg protein in conditioned medium from HSC-T6 cells transduced with HBeAg indicated that HBeAg directly induced the activation and proliferation of rat primary HSCs. Taken together, HBeAg induces the activation and proliferation of HSCs, mainly mediated by TGF-beta, and HBeAg protein purified from cell medium can directly activate HSCs. PMID- 23665330 TI - Rapamycin targeting mTOR and hedgehog signaling pathways blocks human rhabdomyosarcoma growth in xenograft murine model. AB - Rhabdomyosarcomas (RMS) represent the most common childhood soft-tissue sarcoma. Over the past few decades outcomes for low and intermediate risk RMS patients have slowly improved while patients with metastatic or relapsed RMS still face a grim prognosis. New chemotherapeutic agents or combinations of chemotherapies have largely failed to improve the outcome. Based on the identification of novel molecular targets, potential therapeutic approaches in RMS may offer a decreased reliance on conventional chemotherapy. Thus, identification of effective therapeutic agents that specifically target relevant pathways may be particularly beneficial for patients with metastatic and refractory RMS. The PI3K/AKT/mTOR pathway has been found to be a potentially attractive target in RMS therapy. In this study, we provide evidence that rapamycin (sirolimus) abrogates growth of RMS development in a RMS xenograft mouse model. As compared to a vehicle-treated control group, more than 95% inhibition in tumor growth was observed in mice receiving parenteral administration of rapamycin. The residual tumors in rapamycin-treated group showed significant reduction in the expression of biomarkers indicative of proliferation and tumor invasiveness. These tumors also showed enhanced apoptosis. Interestingly, the mechanism by which rapamycin diminished RMS tumor growth involved simultaneous inhibition of mTOR and hedgehog (Hh) pathways. Diminution in these pathways in this model of RMS also inhibited epithelial mesenchymal transition (EMT) which then dampened the invasiveness of these tumors. Our data provide bases for using rapamycin either alone or in combination with traditional chemotherapeutic drugs to block the pathogenesis of high risk RMS. PMID- 23665328 TI - Heme oxygenase-1 induction alters chemokine regulation and ameliorates human immunodeficiency virus-type-1 infection in lipopolysaccharide-stimulated macrophages. AB - We have elucidated a putative mechanism for the host resistance against HIV-1 infection of primary human monocyte-derived macrophages (MDM) stimulated with lipopolysaccharide (LPS). We show that LPS-activated MDM both inhibited HIV-1 entry into the cells and were refractory to post-entry productive viral replication. LPS-treated cells were virtually negative for mature virions as revealed by transmission electron microscopy. LPS activation of MDM markedly enhanced the expression of heme oxygenase-1 (HO-1), a potent inducible cytoprotective enzyme. Increased HO-1 expression was accompanied by elevated production of macrophage inflammatory chemokines (MIP1alpha and MIP1beta) by LPS activated MDM, significantly decreased surface chemokine receptor-5 (CCR-5) expression, and substantially reduced virus replication. Treatment of cells with HO-1 inhibitor SnPP IX (tin protoporphyrin IX) attenuated the LPS-mediated responses, HIV-1 replication and secretion of MIP1alpha, MIP1beta, and LD78beta chemokines with little change in surface CCR-5 expression. These results identify a novel role for HO-1 in the modulation of host immune response against HIV infection of MDM. PMID- 23665331 TI - Picropodophyllin inhibits epithelial ovarian cancer cells in vitro and in vivo. AB - Epithelial ovarian cancer (EOC) is one of the leading causes of gynecological cancer death. Approximately 70% of the patients experience recurrence accompanied by the development of drug resistance 2-3 years after chemotherapy. Picropodophyllin (PPP) is a newly identified insulin-like growth factor-1 receptor (IGF-1R) inhibitor that has been shown to have anticancer properties. In this study, we investigated the effect of PPP on EOC growth in vitro and in vivo. The EOC cell line SKOV-3 was treated with increasing concentrations of PPP or cisplatin, and cell viability and apoptosis were evaluated. To study the effects of PPP on EOC growth, apoptosis, and toxicity in vivo, a BALB/c nude mouse xenograft model was established. Mice were treated with normal saline (controls), PPP, cisplatin, or PPP in combination with cisplatin. In addition, the expression of phosphorylated IGF-1R (pIGF-1R) was examined in vitro and in vivo. PPP induced a dose-dependent decrease in SKOV-3 cell viability in vitro and reduced tumor volume and weight in the in vivo xenograft model. Furthermore, PPP in combination with cisplatin was more effective in inhibiting the growth of SKOV-3 cells and xenografts than either drug alone. PPP-mediated growth inhibition was associated with apoptosis induction in vitro and in vivo. PPP was well tolerated in vivo and exerted its effects with minimal hepatotoxicity and renal toxicity. PPP downregulated the expression of pIGF-1R in vitro and in vivo, an effect that appeared to be associated with its growth inhibitory properties. Our results indicate that PPP may have therapeutic application in the treatment of EOC. PMID- 23665332 TI - Involvement of circadian oscillation(s) in the photoperiodic time measurement and the induction of reproductive diapause in a northern Drosophila species. AB - An ability to predict forthcoming changes in environmental conditions and get prepared for them in advance is crucial for the survival and reproduction of organisms living in a seasonally changing environment. We have studied the possible involvement of circadian oscillator(s) in the photoperiodic timer controlling seasonal responses by tracing Drosophila montana females' diapause induction in constant darkness and in a classical Nanda-Hamner experiment. Nearly all females developed ovaries in continuous darkness, which shows the direct development to be their default developmental pathway in the absence of photoperiods. In Nanda-Hamner experiment the females' diapause incidence was close to zero in light:dark cycle 12:4 (photoperiod 16 h) and increased to nearly 100% in 12:8 and 12:12 (photoperiods 20 and 24 h). In longer photoperiods (28-72 h) the females' diapause percentages decreased gradually along with an increase in the length of the dark period, showing no peaks of high diapause incidence in the multiples of 24h. These findings suggest that the photoperiodic timer of D. montana is based on heavily damping circadian oscillator(s) or that it lacks strong oscillators. Damping of the photoperiodic timer under prolonged nights and constant darkness fits well with our earlier finding that these flies lose their locomotor activity rhythm in constant darkness, and suggests that the mechanisms underlying females' photoperiodic diapause response and their free-running locomotor activity rhythm may be partly based on same oscillators. PMID- 23665333 TI - Functional characterizations of one odorant binding protein and three chemosensory proteins from Apolygus lucorum (Meyer-Dur) (Hemiptera: Miridae) legs. AB - Chemoreception plays an important role in insects for sensing information when searching for host and oviposition sites. An understanding of the chemosensory mechanism could aid in the development of new methods to effectively prevent damage from insects in agriculture. We have constructed a legs cDNA library for Apolygus lucorum and sequenced 1584 ESTs, from which we identified 669 unigenes. From this collection we identified one putative odorant binding protein (AlucOBP5) and three chemosensory proteins (AlucCSP2, AlucCSP3, AlucCSP4) genes. Using real-time PCR method, we assessed the expression of these genes in the head, thorax, abdomen, wing, antenna and mouthparts. Results indicate that the expression of these genes had tissue- and gender-specificity. AlucCSP2 and AlucCSP3 were specifically expressed in female wings. AlucCSP4 was expressed relatively highly in female wings but also expressed in other tissues. AlucOBP5 was expressed in female abdomen and male legs with high levels in the latter. Expression vectors for these proteins were constructed and expressed in BL21(DE3). The purified proteins were then tested for binding properties using bis-ANS as the fluorescent ligand. AlucOBP5 could bind strongly with phenyl acetaldehyde, 1-hexanol, 3-hexenal and beta-ionone. AlucCSP2 and AlucCSP3 had low affinity with all general odorants. AlucCSP4 did not bind with any of the standards. All four proteins could bind with gossypol, meletin with high affinity and could also bind with rutin hydrate, although AlucCSP4 had weak binding capacity. AlucCSP3 and AlucCSP4 could bind weakly with catechin, while AlucCSP2 and AlucOBP5 could not. PMID- 23665334 TI - The clock gene cycle plays an important role in the circadian clock of the cricket Gryllus bimaculatus. AB - To dissect the molecular oscillatory mechanism of the circadian clock in the cricket Gryllus bimaculatus, we have cloned a cDNA of the clock gene cycle (Gb'cyc) and analyzed its structure and function. Gb'cyc contains four functional domains, i.e. bHLH, PAS-A, PAS-B and BCTR domains, and is expressed rhythmically in light dark cycles, peaking at mid night. The RNA interference (RNAi) of Clock (Gb'Clk) and period (Gb'per) reduced the Gb'cyc mRNA levels and abolished the rhythmic expression, suggesting that the rhythmic expression of Gb'cyc is regulated by a mechanism including Gb'Clk and Gb'per. These features are more similar to those of mammalian orthologue of cyc (Bmal1) than those of Drosophila cyc. A single treatment with double-stranded RNA (dsRNA) of Gb'cyc effectively knocked down the Gb'cyc mRNA level and abolished its rhythmic expression. The cyc RNAi failed to disrupt the locomotor rhythm, but lengthened its free-running period in constant darkness (DD). It is thus likely that Gb'cyc is involved in the circadian clock machinery of the cricket. The cyc RNAi crickets showed a rhythmic expression of Gb'per and timeless (Gb'tim) in the optic lobe in DD, explaining the persistence of the locomotor rhythm. Surprisingly, cyc RNAi revealed a rhythmic expression of Gb'Clk in DD which is otherwise rather constitutively expressed in the optic lobe. These facts suggest that the cricket might have a unique clock oscillatory mechanism in which both Gb'cyc and Gb'Clk are rhythmically controlled and that under abundant expression of Gb'cyc the rhythmic expression of Gb'Clk may be concealed. PMID- 23665335 TI - A randomized clinical trial of the health evaluation and referral assistant (HERA): research methods. AB - The Health Evaluation and Referral Assistant (HERA) is a web-based program designed to facilitate screening, brief intervention, and referral to treatment (SBIRT) for tobacco, alcohol, and drug abuse. After the patient completes a computerized substance abuse assessment, the HERA produces a summary report with evidence-based recommended clinical actions for the healthcare provider (the Healthcare Provider Report) and a report for the patient (the Patient Feedback Report) that provides education regarding the consequences of use, personally tailored motivational messages, and a tailored substance abuse treatment referral list. For those who provide authorization, the HERA faxes the individual's contact information to a substance abuse treatment provider matched to the individual's substance use severity and personal characteristics, like insurance and location of residence (dynamic referral). This paper summarizes the methods used for a randomized controlled trial to evaluate the HERA's efficacy in leading to increased treatment initiation and reduced substance use. The study was performed in four emergency departments. Individual patients were randomized into one of two conditions: the HERA or assessment only. A total of 4269 patients were screened and 1006 participants enrolled. The sample was comprised of 427 tobacco users, 212 risky alcohol users, and 367 illicit drug users. Forty-two percent used more than one substance class. The enrolled sample was similar to the eligible patient population. The study should enhance understanding of whether computer-facilitated SBIRT can impact process of care variables, such as promoting substance abuse treatment initiation, as well as its effect on subsequent substance abuse and related outcomes. PMID- 23665336 TI - A review of phase II trial designs for initial marker validation. AB - Phase II clinical trials aim to identify promising experimental regimens for further testing in phase III trials. In this review article, we focus on phase II designs for initial predictive biomarker validation to determine if a drug should be developed for an unselected patient population or for a biomarker-defined patient subset only. Several prospective designs for biomarker-directed therapy have been proposed, differing primarily in the study population, or randomization scheme, or both. The design choice is driven by scientific rationale, marker prevalence, strength of preliminary evidence, assay performance, and turn-around times for marker assessment. The enrichment design is most appropriate when compelling preliminary evidence suggests treatment benefit in only certain marker defined subgroups, the all-comers design is useful when preliminary evidence regarding treatment effects in marker subgroups is unclear, and adaptive designs have the most potential in the setting of multiple treatment options and multiple marker-defined subgroups. We recently proposed a 2-stage phase II design that has the option for direct assignment (i.e., stop randomization and assign all patients to the experimental arm in stage 2) based on interim analysis (IA) results. This design not only recognizes the need for randomization but also acknowledges the possibility of promising but inconclusive results after pre planned IA. Simulation studies demonstrated that the direct assignment-option design has minimal power loss, marginal increase in type I error rates, and reasonable robustness to population shift effects. Systematic evaluation and implementation of these design strategies in the phase II setting are essential for accelerating the clinical validation of biomarker guided-therapy. PMID- 23665338 TI - Insight into hypoxic preconditioning and ischemic injury through determination of nPKCepsilon-interacting proteins in mouse brain. AB - Cerebral hypoxic preconditioning (HPC) provides neuroprotection by intracellular signaling pathways. We previously demonstrated that novel protein kinase Cepsilon (nPKCepsilon) activation participated in cerebral HPC development. In this study, we explore the role of nPKCepsilon in HPC-induced neuroprotection against middle cerebral artery occlusion (MCAO)-induced ischemic injury and identify its possible signaling molecules. A total of 131 adult male BALB/c mice were divided into eight groups: normoxic control (n=9), HPC (n=9), HPC+epsilonV1-2 (n=13), Sham (n=19), HPC+sham (n=6), Ischemia (I, 6h MCAO, n=31), HPC+I (n=25) and HPC+epsilonV1-2+I (n=19). nPKCepsilon specific inhibitor epsilonV1-2 was administered via intracerebroventricular injection. Western blot, 2,3,5 triphenyltetrazolium chloride staining and terminal deoxynucleotidyl transferase mediated dUTP nick end labeling were applied to determine nPKCepsilon membrane translocation, infarction volume and programmed cell death (PCD), respectively. Two-dimensional gel electrophoresis (2-De) and matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) were used to identify nPKCepsilon-interacting proteins, followed by bioinformatics analysis of genee ontology (GO) to predict nPKCepsilon-specific signaling pathways. Our results showed that HPC attenuates MCAO-induced brain injuries and stabilized nPKCepsilonmembrane translocation in peri-infarct region, which was abolished by nPKCepsilon-speecific inhibitor epsilonV1-2. Proteomics analysis revealed 8 up- and 3 down-regulated nPKCepsilon-interacting proteins both in cytosolic and particulate fractions of HPC mouse brain. GO analysis predicted 25 significant nPKCepsilon-specific signaling pathways among the 16 identified nPKCepsilon interacting proteins in brain of HPC mice. This study is the first to report multiple nPKCepsilon-interacting proteins and their signaling pathways in HPC mouse brain, suggesting that nPKCepsilon signaling molecules is responsible for HPC-induced neuroprotection against cerebral ischemic injuries of mice. PMID- 23665337 TI - Neuroimaging biomarkers for epilepsy: advances and relevance to glial cells. AB - Glial cells play an important role in normal brain function and emerging evidence would suggest that their dysfunction may be responsible for some epileptic disease states. Neuroimaging of glial cells is desirable, but there are no clear methods to assess neither their function nor localization. Magnetic resonance imaging (MRI) is now part of a standardized epilepsy imaging protocol to assess patients. Structural volumetric and T2-weighted imaging changes can assist in making a positive diagnosis in a majority of patients. The alterations reported in structural and T2 imaging is predominantly thought to reflect early neuronal loss followed by glial hypertrophy. MR spectroscopy for myo-inositol is a being pursued to identify glial alterations along with neuronal markers. Diffusion weighted imaging (DWI) is ideal for acute epileptiform events, but is not sensitive to either glial cells or neuronal long-term changes found in epilepsy. However, DWI variants such as diffusion tensor imaging or q-space imaging may shed additional light on aberrant glial function in the future. The sensitivity and specificity of PET radioligands, including those targeting glial cells (translocator protein) hold promise in being able to image glial cells. As the role of glial function/dysfunction in epilepsy becomes more apparent neuroimaging methods will evolve to assist the clinician and researcher in visualizing their location and function. PMID- 23665339 TI - A novel tetrameric gp350 1-470 as a potential Epstein-Barr virus vaccine. AB - Infectious mononucleosis and B-cell transformation in response to infection with Epstein-Barr virus (EBV) is dependent upon binding of the EBV envelope glycoprotein gp350 to CD21 on B-cells. Gp350-specific antibody comprises most of the EBV neutralizing activity in the serum of infected patients, making this protein a promising target antigen for a prophylactic EBV vaccine. We describe a novel, tetrameric gp350-based vaccine that exhibits markedly enhanced immunogenicity relative to its monomeric counterpart. Plasmid DNA was constructed for synthesis, within transfected CHO cells, of a tetrameric, truncated (a.a. 1 470) gp350 protein (gp350(1-470)). Tetrameric gp350(1-470) induced ~ 20-fold higher serum titers of gp350(1-470)-specific IgG and >19-fold enhancements in neutralizing titers at the highest dose, and was >25-fold more immunogenic on a per-weight basis than monomeric gp350(1-470). Further, epidermal immunization with plasmid DNA encoding gp350(1-470) tetramer induced 8-fold higher serum titers of gp350(1-470)-specific IgG relative to monomer. Tetrameric gp350(1-470) binding to human CD21 was >24-fold more efficient on a per-weight basis than monomer, but neither tetramer nor monomer mediated polyclonal human B-cell activation. Finally, the introduction of strong, universal tetanus toxoid (TT) specific CD4+ T-cell epitopes into the tetrameric gp350(1-470) had no effect on the gp350(1-470)-specific IgG response in naive mice, and resulted in suppressed gp350(1-470)-specific IgG responses in TT-primed mice. Collectively, these data suggest that tetrameric gp350(1-470) is a potentially promising candidate for testing as a prophylactic EBV vaccine, and that protein multimerization, using the approach described herein, is likely to be clinically relevant for enhancing the immunogenicity of other proteins of vaccine interest. PMID- 23665340 TI - Lyme disease vaccination: are we ready to try again? PMID- 23665341 TI - Safety and immunogenicity of a novel multivalent OspA vaccine against Lyme borreliosis in healthy adults: a double-blind, randomised, dose-escalation phase 1/2 trial. AB - BACKGROUND: Lyme borreliosis is caused by Borrelia burgdorferi sensu stricto in the USA and by several Borrelia species in Europe and Asia, but no human vaccine is available. We investigated the safety and immunogenicity of adjuvanted and non adjuvanted vaccines containing protective epitopes from Borrelia species outer surface protein A (OspA) serotypes in healthy adults. METHODS: Between March 1, 2011, and May 8, 2012, we did a double-blind, randomised, dose-escalation phase 1/2 study at four sites in Austria and Germany. Healthy adults aged 18-70 years who were seronegative for B. burgdorferi sensu lato were eligible for inclusion. Participants were recruited sequentially and randomly assigned to one of six study groups in equal ratios via an electronic data capture system. Participants and investigators were masked to group allocation. Participants received three vaccinations containing 30 MUg, 60 MUg, or 90 MUg OspA antigen with or without an adjuvant, with intervals of 28 days, and a booster 9-12 months after the first immunisation. The coprimary endpoints were the frequency and severity of injection-site and systemic reactions within 7 days of each vaccination, and the antibody responses to OspA serotypes 1-6, as established by ELISA. This study is registered with ClinicalTrials.gov, number NCT01504347. FINDINGS: 300 participants were randomly assigned: 151 to adjuvanted vaccines (50 to 30 MUg, 51 to 60 MUg, and 50 to 90 MUg doses), and 149 to non-adjuvanted vaccines (50 to 30 MUg, 49 to 60 MUg, and 50 to 90 MUg doses). Adverse reactions were predominantly mild, and no vaccine-related serious adverse events were reported. The risk of systemic reactions (risk ratio 0.54 [95% CI 0.41-0.70]; p<0.0001) and of moderate or severe systemic reactions (0.35 [0.13-0.92]; p=0.034) was significantly lower for adjuvanted than non-adjuvanted formulations. The 30 MUg adjuvanted formulation had the best tolerability profile; only headache (five [10%, 95% CI 4 20] of 50), injection-site pain (16 [32%, 21-45]), and tenderness (17 [34%, 23 47]) affected more than 6% of patients. All doses and formulations induced substantial mean IgG antibody titres against OspA serotypes 1-6 after the first three vaccinations (range 6944-17,321) and booster (19,056-32,824) immunisations. The 30 MUg adjuvanted formulation induced the highest antibody titres after the booster: range 26,143 (95% CI 18,906-36,151) to 42,381 (31,288-57,407). INTERPRETATION: The novel multivalent OspA vaccine could be an effective intervention for prevention of Lyme borreliosis in Europe and the USA, and possibly worldwide. Larger confirmatory formulation studies will need to be done that include individuals seropositive for Borrelia burgdorferi sensu lato before placebo-controlled phase 3 efficacy studies can begin. FUNDING: Baxter. PMID- 23665342 TI - The influence of vitamin D supplementation on melatonin status in patients with multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) incidence is higher in geographic regions with less sunlight exposure. Both vitamin D and melatonin are essential mediators of the effect of sunlight in health, and as such are candidates to play a key role in MS. We hypothesized that vitamin D and melatonin may have related influences in patients with MS. METHODS: In a randomized, double blind study of 40 IFN-beta treated MS patients, 21 patients were assigned to 800 IU of vitamin D3 per day (low dose), while 19 patients received 4,370 IU vitamin D3 per day (high dose) for one year. Serum 25-hydroxy-vitamin-D (25-OH-D) and nighttime urine melatonin metabolite, 6-sulphatoxy-melatonin (6-SMT), were measured at baseline, 3 months and 1 year from enrolment. RESULTS: After 3 months supplementation, 25-OH-D levels increased and nighttime melatonin secretion decreased significantly in the high dose group, but not in the low dose group. After 1 year, a decrease in 25-OH-D levels, accompanied by an increase of urine nighttime 6-SMT were observed in the high dose group. Percent change in serum 25 OH-D was significantly and negatively correlated with percent change in urine 6 SMT after 3 months and between 3 months to 1 year. 25-OH-D levels by the end of the study were significantly and negatively correlated to BMI. CONCLUSIONS: Melatonin secretion is negatively correlated with alterations in serum 25-OH-D in IFN-beta treated patients with MS. The finding suggests that melatonin should be considered as a potential mediator of vitamin D neuro-immunomodulatory effects in patients with MS. PMID- 23665344 TI - Efficient isolation of polymorphic microsatellites from high-throughput sequence data based on number of repeats. AB - Transcriptome data are a good resource to develop microsatellites due to their potential in targeting candidate genes. However, developing microsatellites can be a time-consuming enterprise due to the numerous primer pairs to be tested. Therefore, the use of methodologies that make it efficient to identify polymorphic microsatellites is desirable. Here we used a 62,038 contigs transcriptome assembly, obtained from pyrosequencing a peacock blenny (Salaria pavo) multi-tissue cDNA library, to mine for microsatellites and in silico evaluation of their polymorphism. A total of 4190 microsatellites were identified in 3670 unique unigenes, and from these microsatellites, in silico polymorphism was detected in 733. We selected microsatellites based either on their in silico polymorphism and annotation results or based only on their number of repeats. Using these two approaches, 28 microsatellites were successfully amplified in twenty-six individuals, and all but 2 were found to be polymorphic, being the first genetic markers for this species. Our results showed that the strategy of selection based on number of repeats is more efficient in obtaining polymorphic microsatellites than the strategy of in silico polymorphism (allelic richness was 8.2+/-3.85 and 4.56+/-2.45 respectively). This study demonstrates that combining the knowledge of number of repeats with other predictors of variability, for example in silico microsatellite polymorphism, improves the rates of polymorphism, yielding microsatellites with higher allelic richness, and decreases the number of monomorphic microsatellites obtained. PMID- 23665343 TI - Investigations into the involvement of NMDA mechanisms in recognition memory. AB - This review will focus on evidence showing that NMDA receptor neurotransmission is critical for synaptic plasticity processes within brain regions known to be necessary for the formation of object recognition memories. The aim will be to provide evidence concerning NMDA mechanisms related to recognition memory processes and show that recognition memory for objects, places or associations between objects and places depends on NMDA neurotransmission within the perirhinal cortex, temporal association cortex medial prefrontal cortex and hippocampus. Administration of the NMDA antagonist AP5, selectively into each of these brain regions has revealed that the extent of the involvement NMDA receptors appears dependent on the type of information required to solve the recognition memory task; thus NMDA receptors in the perirhinal cortex are crucial for the encoding of long-term recognition memory for objects, and object-in-place associations, but not for short-term recognition memory or for retrieval. In contrast the hippocampus and medial prefrontal cortex are required for both long term and short-term recognition memory for places or associations between objects and places, or for recognition memory tasks that have a temporal component. Such studies have therefore confirmed that the multiple brain regions make distinct contributions to recognition memory but in addition that more than one synaptic plasticity process must be involved. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'. PMID- 23665345 TI - Evaluating and improving the quality of time-dependent, diffuse reflectance spectroscopic signals measured from in vivo brain during craniotomy. AB - BACKGROUND: Optical spectroscopy can be used to assess the pathophysiological characteristics of diseased and injured biological tissue in vivo in a non destructive way. It is often used in conjunction with a contact optical probe for the purposes of operating and sensing in a sterile field. Since the probe is often held by the hand of an investigator during data acquisition, any hand instability can affect the quality of acquired data and, hence, degrade the accuracy of diagnosis. This study was designed to quantitatively characterize these artifacts, and then propose an effective engineering solution to remove them. METHODS: Time-dependent diffuse reflectance spectra (Rd(lambda,t)) were acquired from the normal cortex region of pediatric patients undergoing epilepsy surgery. They were acquired at a rate of 33 Hz, and their range was 400 and 900 nm. Two distinct ways of collecting data were tested: one with the fiber optical probe held by the surgeon's hand during data acquisition, and the other with the probe held by a specially designed probe holder. The probe holder was designed and constructed to minimize the variations in probe contact pressure and contact point for the full duration of any given investigation. Spectral data acquired using versus not using the probe holder were characterized and compared in the time, wavelength, and frequency domains, using both descriptive and inferential statistics. RESULTS: Hand motion manifested as strong random variations in Rd(lambda,t) which impacted temporal and frequency characteristics of Rd(lambda,t). The percentage standard deviation %STD of Rd(lambda,t) acquired without probe holder could be as high as 60%, and they are significantly higher than those with probe holder at all wavelengths. This difference is especially prominent between 400 and 600 nm. Rd(lambda,t) acquired without the probe holder also processed a higher spectral power energy in the frequency domain than those with the probe holder. The correlation analysis revealed that the hand motions induced synchronistic variations in Rd(lambda,t) between 600 and 800 nm, but this synchronicity is not obvious between 400 and 600 nm. CONCLUSION: The results of this investigation demonstrate the nature and the magnitude of hand motion induced artifacts in in vivo diffuse reflectance spectra and propose one potential solution (i.e., a probe holder) to remove them. These findings allow us to improve the quality of time-dependent, diffuse reflectance signals acquired to study the dynamic characteristics of biological tissues, like brain, in vivo. PMID- 23665347 TI - Ultrasonography-guided intracardiac injection: an improvement for quantitative brain colonization assays. AB - Brain metastasis is a frequent occurrence in patients with cancer, with devastating consequences. The current animal models for brain metastasis are highly variable, leading to a need for improved in vivo models that recapitulate the clinical disease. Herein, we describe an experimental brain metastasis model that uses ultrasonographic guidance to perform intracardiac injections. This method is easy to perform, giving consistent and quantitative results. Demonstrating the utility of this method, we have assessed a variety of metastatic cell lines for their ability to develop into brain metastases. Those cell lines that were competent at brain colonization could be detected in the brain vasculature 4 hours after intracardiac injection, and a few adherent cells persisted until colonization occurred. In contrast, those cell lines that were deficient in brain colonization were infrequently found 4 hours after introduction into the arterial circulation and were not detected at later time points. All of these cells were capable of brain colonization after intraparenchymal injection. We propose that adherence to the brain vasculature may be the key limiting step that determines the ability of a cancer cell to form brain metastases successfully. Identifying brain endothelium-specific adhesion molecules may enable development of screening modalities to detect brain colonizing cancer cells and therapies to prevent these metastatic cells from seeding the brain. PMID- 23665346 TI - Regulation of lung injury and fibrosis by p53-mediated changes in urokinase and plasminogen activator inhibitor-1. AB - Alveolar type II epithelial cell (ATII) apoptosis and proliferation of mesenchymal cells are the hallmarks of idiopathic pulmonary fibrosis, a devastating disease of unknown cause characterized by alveolar epithelial injury and progressive fibrosis. We used a mouse model of bleomycin (BLM)-induced lung injury to understand the involvement of p53-mediated changes in urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) levels in the regulation of alveolar epithelial injury. We found marked induction of p53 in ATII cells from mice exposed to BLM. Transgenic mice expressing transcriptionally inactive dominant negative p53 in ATII cells showed augmented apoptosis, whereas those deficient in p53 resisted BLM-induced ATII cell apoptosis. Inhibition of p53 transcription failed to suppress PAI-1 or induce uPA mRNA in BLM-treated ATII cells. ATII cells from mice with BLM injury showed augmented binding of p53 to uPA, uPA receptor (uPAR), and PAI-1 mRNA. p53-binding sequences from uPA, uPAR, and PAI-1 mRNA 3' untranslated regions neither interfered with p53 DNA binding activity nor p53-mediated promoter transactivation. However, increased expression of p53-binding sequences from uPA, uPAR, and PAI-1 mRNA 3' untranslated regions in ATII cells suppressed PAI-1 and induced uPA after BLM treatment, leading to inhibition of ATII cell apoptosis and pulmonary fibrosis. Our findings indicate that disruption of p53-fibrinolytic system cross talk may serve as a novel intervention strategy to prevent lung injury and pulmonary fibrosis. PMID- 23665348 TI - Pharmacologic inhibition of IkappaB kinase activates immediate hypersensitivity reactions in mice. AB - Pharmacologic inhibitors of IkappaB kinase (IKK), especially IKK-beta, have been developed to treat inflammatory diseases. However, their interactions with components of the NF-kappaB pathways are not fully known in allergic diseases. To examine whether IKK is involved in immediate hypersensitivity reactions and to determine whether counterregulatory mechanisms in the NF-kappaB activation system were active, we examined the role played by IKK components on mast cell degranulation using a murine ocular immediate hypersensitivity reaction model. Pharmacologic inhibition of IKK in mice caused paradoxical aggravation of the mast cell-mediated immediate hypersensitivity reaction and up-regulation in the expression of inflammatory cytokines. Downstream analyses showed that B-cell deficiency or treatment by IL-1 receptor antagonist corrected the aberrant activation of tissue-resident mast cells, which would indicate contribution by activated B cells. Analyses of co-cultures of tissue-resident mast cells showed the contribution of activated B cells to activation of mast cells and secretion of inflammatory cytokines. Aberrant activation of the NF-kappaB promoter in isolated B cells was induced exclusively by IKK-beta inhibition and was negated by ablating IKK-alpha. Aggravated mast cell degranulation by pharmacologic IKK inhibition in the murine immediate hypersensitivity reaction was corrected by B cell-targeted inhibition of IKK-alpha. Thus, IKK-beta limits B-cell-mediated mast cell activation and inflammatory cytokine induction in immediate hypersensitivity by counterbalancing the activity of IKK-alpha. PMID- 23665349 TI - Regulation of liver growth by glypican 3, CD81, hedgehog, and Hhex. AB - Previous studies from our laboratory have found glypican 3 (GPC3) as a negative regulator of growth. CD81 was found to be a binding partner for GPC3, and its expression and co-localization with GPC3 increased at the end of hepatocyte proliferation. However, the mechanisms through which these two molecules might regulate liver regeneration are not known. We tested the hypothesis that GPC3 down-regulates the hedgehog (HH) signaling pathway by competing with patched-1 for HH binding. We found decreased GPC3-Indian HH binding at peak proliferation in mice followed by increase in glioblastoma 1 protein (effector of HH signaling). We performed a yeast two-hybrid assay and identified hematopoietically expressed homeobox (Hhex, a known transcriptional repressor) as a binding partner for CD81. We tested the hypothesis that Hhex binding to CD81 keeps it outside the nucleus. However, when GPC3 binds to CD81, CD81-Hhex binding decreases, resulting in nuclear translocation of Hhex and transcriptional repression. In support of this, we found decreased GPC3-CD81 binding at hepatocyte proliferation peak, increased CD81-Hhex binding, and decreased nuclear Hhex. GPC3 transgenic mice were used as an additional tool to test our hypothesis. Overall, our data suggest that GPC3 down-regulates cell proliferation by binding to HH and down-regulating the HH signaling pathway and binding with CD81, thus making it unavailable to bind to Hhex and causing its nuclear translocation. PMID- 23665351 TI - Pharmacodynamic study of the 7,8-dihydroxy-4-methylcoumarin-induced selective cytotoxicity toward U-937 leukemic cells versus mature monocytes: cytoplasmic p21(Cip1/WAF1) as resistance factor. AB - The development of tumor-selective drugs with low systemic toxicity has always been a major challenge in cancer treatment. Our group previously identified the 7,8-dihydroxy-4-methylcoumarin (DHMC) as a potential chemotherapeutic agent due to its potent, selective anti-proliferative and apoptosis-inducing effects on several cancer cell lines over peripheral blood mononuclear cells. However, there are still no published reports that can explain such selectivity of action. Herein, we addressed this question by using the U-937 promonocytic leukemia cell line, which can be forced to differentiate into a monocyte-like phenotype in vitro. U-937 cells differentiation is dependent on the nuclear expression of p21(Cip1/WAF1), a protein that is absent in immature U-937 cells but present in both the nucleus and the cytoplasm of normal DHMC-resistant monocytes. Considering that induction of differentiation rendered U-937 cells resistant to DHMC, we evaluated the possible causal role of cytoplasmic p21(Cip1/WAF1) in the onset of such resistance by employing U-937 cells stably transfected with a ZnCl2 inducible p21(Cip1/WAF1) variant lacking the nuclear localization signal (U 937/CB6-DeltaNLS-p21 cells). Expression of cytoplasmic p21(Cip1/WAF1) did not induce differentiation of the cells but turned them resistant to DHMC through inhibition of JNK, a crucial mediator of DHMC-induced apoptosis in U-937 cells. Sub-acute toxicity evaluation of DHMC in Balb/c mice indicated that DHMC administered intraperitoneally at doses up to 100mg/kg induced no systemic damage. Collectively, our results explain for the first time the selective cytotoxicity of DHMC for tumor cells over normal monocytes, and encourage further in vivo studies on this compound as potential anti-leukemic agent. PMID- 23665350 TI - Mineralization/anti-mineralization networks in the skin and vascular connective tissues. AB - Ectopic mineralization has been linked to several common clinical conditions with considerable morbidity and mortality. The mineralization processes, both metastatic and dystrophic, affect the skin and vascular connective tissues. There are several contributing metabolic and environmental factors that make uncovering of the precise pathomechanisms of these acquired disorders exceedingly difficult. Several relatively rare heritable disorders share phenotypic manifestations similar to those in common conditions, and, consequently, they serve as genetically controlled model systems to study the details of the mineralization process in peripheral tissues. This overview will highlight diseases with mineral deposition in the skin and vascular connective tissues, as exemplified by familial tumoral calcinosis, pseudoxanthoma elasticum, generalized arterial calcification of infancy, and arterial calcification due to CD73 deficiency. These diseases, and their corresponding mouse models, provide insight into the pathomechanisms of soft tissue mineralization and point to the existence of intricate mineralization/anti-mineralization networks in these tissues. This information is critical for understanding the pathomechanistic details of different mineralization disorders, and it has provided the perspective to develop pharmacological approaches to counteract the consequences of ectopic mineralization. PMID- 23665352 TI - Oxysterols and related sterols: implications in pharmacology and pathophysiology. PMID- 23665353 TI - Stereo specific platelet inhibition by the natural LXR agonist 22(R)-OH cholesterol and its fluorescence labelling with preserved bioactivity and chiral handling in macrophages. AB - Two synthetic LXR agonists were recently reported to inhibit collagen-induced platelet aggregation and thrombus formation in mice. We therefore studied whether also natural LXR agonists inhibit human platelet activation and whether they can be fluorescence-labelled preserving their bioactivity for LXR-related functional imaging. The natural LXR agonist 22(R)-OH-cholesterol - but not its stereoisomer 22(S)-OH-cholesterol - inhibited collagen induced platelet shape change and aggregation similar to synthetic LXR agonists in a concentration- and time dependent manner. First exposure to 22(S)-OH-cholesterol prevented the subsequent inhibition of platelets by 22(R)-OH-cholesterol but not vice versa. 22(R)- and 22(S)-OH-cholesterol could be fluorescence-labelled as 22(R)- and 22(S)-OH cholesteryl-3-dodecanoic-3-BODIPY esters with high yield and purity using the Steglich acylation. Labelled 22(R)- and 22(S)-OH-cholesterol esters retained the stereo specific bioactivity of their parent compounds, were metabolically stable and not cytotoxic at LXR agonistic concentrations. Live staining with labelled 22(R)- or 22(S)-OH-cholesterol esters demonstrated stereo specific inhibition of platelet spreading and chiral handling by macrophages that reflect LXR activation. The rapid inhibition of platelet reactivity to collagen by natural and pharmacologic LXR agonists offers a mechanism that could attenuate platelet activation by denuded plaques that expose collagen and LXR agonistic oxysterols. Stable fluorescence labelled 22(R)- and 22(S)-OH-cholesterol analogues with preserved stereo specific bioactivity and staining characteristics provide valuable tools for LXR-related functional imaging in pathophysiologic studies, for binding assays and for LXR-targeted drug development. PMID- 23665354 TI - Can adherence to dietary guidelines address excess caloric intake? An empirical assessment for the UK. AB - The facilitation of healthier dietary choices by consumers is a key element of government strategies to combat the rising incidence of obesity in developed and developing countries. Public health campaigns to promote healthier eating often target compliance with recommended dietary guidelines for consumption of individual nutrients such as fats and added sugars. This paper examines the association between improved compliance with dietary guidelines for individual nutrients and excess calorie intake, the most proximate determinant of obesity risk. We apply quantile regressions and counterfactual decompositions to cross sectional data from the National Diet and Nutrition Survey (2000-01) to assess how excess calorie consumption patterns in the UK are likely to change with improved compliance with dietary guidelines. We find that the effects of compliance vary significantly across different quantiles of calorie consumption. Our results show that compliance with dietary guidelines for individual nutrients, even if successfully achieved, is likely to be associated with only modest shifts in excess calorie consumption patterns. Consequently, public health campaigns that target compliance with dietary guidelines for specific nutrients in isolation are unlikely to have a significant effect on the obesity risk faced by the population. PMID- 23665355 TI - The psychostimulant modafinil enhances gap junctional communication in cortical astrocytes. AB - Sleep-wake cycle is characterized by changes in neuronal network activity. However, for the last decade there is increasing evidence that neuroglial interaction may play a role in the modulation of sleep homeostasis and that astrocytes have a critical impact in this process. Interestingly, astrocytes are organized into communicating networks based on their high expression of connexins, which are the molecular constituents of gap junction channels. Thus, neuroglial interactions should also be considered as the result of the interplay between neuronal and astroglial networks. Here, we investigate the effect of modafinil, a wakefulness-promoting agent, on astrocyte gap junctional communication. We report that in the cortex modafinil injection increases the expression of mRNA and protein of connexin 30 but not those of connexin 43, the other major astroglial connexin. These increases are correlated with an enhancement of intercellular dye coupling in cortical astrocytes, which is abolished when neuronal activity is silenced by tetrodotoxin. Moreover, gamma hydroxybutyric acid, which at a millimolar concentration induces sleep, has an opposite effect on astroglial gap junctions in an activity-independent manner. These results support the proposition that astroglia may play an important role in complex physiological brain functions, such as sleep regulation, and that neuroglial networking interaction is modified during sleep-wake cycle. This article is part of the Special Issue Section entitled 'Current Pharmacology of Gap Junction Channels and Hemichannels'. PMID- 23665357 TI - Errors in motion processing amongst older drivers may increase accident risk. AB - Accident statistics highlight that older drivers are more frequently involved in right-of-way collisions than younger drivers. Accurately gauging vehicle speed is critical for judgement of when to pull out from a junction safely in front of oncoming traffic. We used psychophysical methods to measure drivers' ability to discriminate between different rates of looming presented by vehicles approaching at different speeds. We demonstrate that sensitivity to approach speed reduces by between 2.8 and 3.4 mph, dependent upon vehicle type, for every decade that age increases. We show that perceptual limitations for drivers over the age of 75 years can lead to a 50% reduction in time available to perform traffic manoeuvres, which may contribute in part to their overrepresentation in casualty statistics at junction. Results are discussed in terms of implications for road safety policy. PMID- 23665356 TI - Molecular and behavioral pharmacology of two novel orally-active 5HT2 modulators: potential utility as antipsychotic medications. AB - BACKGROUND: Desired serotonin 5HT2 receptor pharmacology for treatment of psychoses is 5HT2A antagonism and/or 5HT2C agonism. No selective 5HT2A antagonist has been approved for psychosis and the only approved 5HT2C agonist (for obesity) also activates 5HT2A and 5HT2B receptors, which can lead to clinical complications. Studies herein tested the hypothesis that a dual-function 5HT2A antagonist/5HT2C agonist that does not activate 5HT2B receptors would be suitable for development as an antipsychotic drug, without liability for weight gain. METHODS: The novel compounds (+)- and (-)-trans-4-(4'-chlorophenyl)-N,N-dimethyl 2-aminotetralin (p-Cl-PAT) were synthesized, characterized in vitro for affinity and functional activity at human 5HT2 receptors, and administered by intraperitoneal (i.p.) and oral (gavage) routes to mice in behavioral paradigms that assessed antipsychotic efficacy and effects on feeding behavior. RESULTS: (+)- and (-)-p-Cl-PAT activated 5HT2C receptors, with (+)-p-Cl-PAT being 12-times more potent, consistent with its higher affinity across 5HT2 receptors. Neither p Cl-PAT enantiomer activated 5HT2A or 5HT2B receptors at concentrations up to 300 times greater than their respective affinity (Ki), and (+)-p-Cl-PAT was shown to be a 5HT2A competitive antagonist. When administered i.p. or orally, (+)- and (-) p-Cl-PAT attenuated the head-twitch response (HTR) in mice elicited by the 5HT2 agonist (-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and reduced intake of a highly palatable food in non-food-deprived mice, with (+)-p-Cl-PAT being more potent across behavioral assays. CONCLUSIONS: The novel in vitro pharmacology of (+)-p Cl-PAT (5HT2A antagonism/5HT2C agonism without activation of 5HT2B) translated in vivo to an orally-active drug candidate with preclinical efficacy to treat psychoses without liability for weight gain. PMID- 23665359 TI - Selection pressures give composite correlated random walks Levy walk characteristics. AB - Composite correlated random walks have been posited as a strong alternative to Levy walks as models of multi-scale forager movement patterns. Here it is shown that if plastic then intrinsic composite correlated random walks will, under selection pressures, evolve to resemble optimal Levy walks when foraging is non destructive. The fittest composite correlated random walkers are found to be those that come closest to being optimal Levy walkers. This may explain why such a diverse range of foragers have movement patterns that can be approximated by optimal Levy walks and shows that the 'Levy-flight foraging' hypothesis has a broad hinterland. The new findings are consistent with recent observations of mussels Mytilus edulis and the Australian desert ant Melophorus bagoti which suggest that animals approximate a Levy walk by adopting an intrinsic composite movement strategy with different modes. PMID- 23665358 TI - Breaking the symmetry: immune enhancement increases persistence of dengue viruses in the presence of asymmetric transmission rates. AB - The dengue viruses exist as four antigenically distinct serotypes. These four serotypes co-circulate and interact with each other through multiple immune mediated mechanisms. Though the majority of previous efforts to understand the transmission dynamics of dengue have assumed identical characteristics for these four serotypes, empirical data suggests that they differ from one another in important ways. Here, we examine dynamics and persistence in models that do not assume symmetry between the dengue viruses. We find that for serotype transmission rates that are only slightly asymmetric, increased transmissibility of secondary infections through immune enhancement increases the persistence of all dengue viruses in opposition to findings in symmetric models. We identify an optimal magnitude of immune enhancement that maximizes the probability of persistence of all four serotypes. In contrast to other pathogen systems where heterogeneity between serotypes in transmissibility facilitates competitive exclusion (Bremmermann and Thieme, 1989), here we find that in the presence of Antibody Dependent Enhancement (ADE) heterogeneity can increase the persistence of multiple serotypes of dengue. PMID- 23665360 TI - Leveraging concept-based approaches to identify potential phyto-therapies. AB - The potential of plant-based remedies has been documented in both traditional and contemporary biomedical literature. Such types of text sources may thus be sources from which one might identify potential plant-based therapies ("phyto therapies"). Concept-based analytic approaches have been shown to uncover knowledge embedded within biomedical literature. However, to date there has been limited attention towards leveraging such techniques for the identification of potential phyto-therapies. This study presents concept-based analytic approaches for the retrieval and ranking of associations between plants and human diseases. Focusing on identification of phyto-therapies described in MEDLINE, both MeSH descriptors used for indexing and MetaMap inferred UMLS concepts are considered. Furthermore, the identification and ranking consider both direct (i.e., plant concepts directly correlated with disease concepts) and inferred (i.e., plant concepts associated with disease concepts based on shared signs and symptoms) relationships. Based on the two scoring methodologies used in this study, it was found that a Vector Space Model approach outperformed probabilistic reliability based inferences. An evaluation of the approach is provided based on therapeutic interventions catalogued in both ClinicalTrials.gov and NDF-RT. The promising findings from this feasibility study highlight the challenges and applicability of concept-based analytic strategies for distilling phyto-therapeutic knowledge from text based knowledge sources like MEDLINE. PMID- 23665361 TI - Physicochemical characterization of the staphylolytic LysK enzyme in complexes with polycationic polymers as a potent antimicrobial. AB - Staphylococcus aureus causes many serious visceral, skin, and respiratory diseases. About 90% of its clinical strains are multi-drug resistant, but the use of bacteriophage lytic enzymes offers a viable alternative to antibiotic therapy. LysK, the phage K endolysin, can lyse S. aureus when purified and exposed externally. It has been investigated in its complexes with polycationic polymers (poly-l-lysines (PLLs) of molecular weights 2.5, 9.6, and 55.2 kDa and their block copolymers with polyethylene glycol PLL10-PEG114, PLL30-PEG114, and PLL30 PEG23) as a basis for creating active and stable antimicrobial. Complexing with polycationic PLLs produces a stabilizing effect on LysK due to structure ordering in its molecules and break-down of aggregates as a result of electrostatic interaction. The stability of LysK in the presence of PLL-PEG block copolymers improves by both electrostatic and hydrophobic mechanisms. Complexes of LysK with 2.5, 9.6, 55.2 kDa poly-l-lysines and PLL30-PEG114 have demonstrated sufficient stability at the temperatures of physiological activity (37 degrees C) and storage (4 degrees C and 22 degrees C). PMID- 23665362 TI - Effects on performance and carcass and meat quality attributes following immunocastration with the gonadotropin releasing factor vaccine Bopriva or surgical castration of Bos indicus bulls raised on pasture in Brazil. AB - Bos indicus bulls 20 months of age grazed on pasture in Minas Gerais, Brazil either received 2 doses of the GnRF vaccine Bopriva at d0 and d91 (group IC, n=144) or were surgically castrated on d91 (group SC, n=144). Slaughter on d280, was 27 weeks after castration. Adverse safety issues in 8% of group SC bulls following surgery contrasted with 0% in group IC bulls. At d105 testosterone levels were suppressed to similar levels in both groups. Importantly, group IC bulls had higher live weight, hot carcass weight, ADG (P<0.005) and dressing percentage (P<0.0001) compared to group SC animals. There were no negative effects on carcass or meat quality traits, thus immunocastration was concluded to offer a safe and effective method that provides production gains, and improves animal welfare in Bos indicus beef bulls without impacting meat and carcass quality. PMID- 23665363 TI - Aspiration thrombectomy: it's about time. PMID- 23665365 TI - Glycemic control and risk of cardiovascular disease hospitalization and all-cause mortality. AB - OBJECTIVES: This study sought to evaluate the relationship between glycemic control and cardiovascular disease (CVD) hospitalizations and all-cause mortality among patients with type 2 diabetes in a real-world setting. BACKGROUND: Clinical trials have not established that tight glycemic control reduces CVD events and may be associated with increased mortality. Observational studies of specific cohorts have reported increased risk of those outcomes at both high and low glycosylated hemoglobin (HbA1c) levels. METHODS: Using the mean of all HbA1c measures over a mean follow-up of 6 years, we created categories of HbA1c (<6.0%, 6.0% to 6.4%, 6.5% to 6.9%, 7.0% to 7.4%, 7.5% to 7.9%, 8.0% to 8.4%, 8.5% to 8.9%, and >= 9.0%) to estimate the risk of CVD hospitalization and all-cause mortality associated with glycemic control, adjusting for demographic and clinical characteristics among 26,673 members of Kaiser Permanente Northwest with type 2 diabetes. RESULTS: Compared with patients with mean HbA1c levels 7.0% to 7.4%, those with mean HbA1c levels <6.0% had a 68% increased risk of CVD hospitalization (hazard ratio [HR]: 1.68 [95% confidence interval (CI): 1.39 to 2.04], p < 0.001) after adjustment for demographic and clinical characteristics. Those with HbA1c levels 6.0% to 6.4% (HR: 1.18 [95% CI: 1.00 to 1.40], p = 0.048) and 6.5% to 6.9% (HR: 1.18 [95% CI: 1.02 to 1.37], p = 0.031) also had significantly higher risk relative to the reference group of 7.0% to 7.4%, as did patients with HbA1c levels 8.5% to 8.9% (HR: 1.55 [95% CI: 1.24 to 1.94], p < 0.001) and >= 9.0% (HR: 1.83 [95% CI: 1.50 to 2.22], p < 0.001). Risk of all cause mortality was significantly greater than the reference group among HbA1c categories <6.0%, 6.0% to 6.4%, 6.5% to 6.9%, and >= 9.0%. CONCLUSIONS: The relationship between mean HbA1c and CVD hospitalizations and all-cause mortality was U-shaped, with greater risk at both higher and lower HbA1c levels. PMID- 23665366 TI - Paved with good intentions and marred by half-truths. PMID- 23665364 TI - 4-year results of a randomized controlled trial of percutaneous repair versus surgery for mitral regurgitation. AB - OBJECTIVES: This study sought to evaluate 4-year outcomes of percutaneous repair versus surgery for mitral regurgitation. BACKGROUND: Transcatheter therapies are being developed to treat valvular heart disease. In the EVEREST (Endovascular Valve Edge-to-Edge Repair Study) II trial, treatment of mitral valve regurgitation (MR) with a novel percutaneous device was compared with surgery and showed superior safety, but less reduction in MR at 1 year overall. We report the 4-year outcomes from the EVEREST II trial. METHODS: Patients with grade 3+ or 4+ MR were randomly assigned to percutaneous repair with the MitraClip (Abbott, Menlo Park, California) device or conventional mitral valve surgery in a 2:1 ratio (184:95). Patients prospectively consented to 5 years of follow-up. RESULTS: At 4 years, the rate of the composite endpoint of freedom from death, surgery, or 3+ or 4+ MR in the intention-to-treat population was 39.8% versus 53.4% in the percutaneous repair group and surgical groups, respectively (p = 0.070). Rates of death were 17.4% versus 17.8% (p = 0.914), and 3+ or 4+ MR was present in 21.7% versus 24.7% (p = 0.745) at 4 years of follow-up, respectively. Surgery for mitral valve dysfunction, however, occurred in 20.4% versus 2.2% (p < 0.001) at 1 year and 24.8% versus 5.5% (p < 0.001) at 4 years. CONCLUSIONS: Patients treated with percutaneous repair of the mitral valve more commonly required surgery to treat residual MR; however, after the first year of follow up, there were few surgeries required after either percutaneous or surgical treatment and no difference in the prevalence of moderate-severe and severe MR or mortality at 4 years. (Endovascular Valve Edge-to-Edge Repair Study [EVEREST II]; NCT00209274). PMID- 23665367 TI - ACCF/AHA/SCAI 2013 update of the clinical competence statement on coronary artery interventional procedures: a report of the American College of Cardiology Foundation/American Heart Association/American College of Physicians Task Force on Clinical Competence and Training (Writing Committee to Revise the 2007 Clinical Competence Statement on Cardiac Interventional Procedures). PMID- 23665368 TI - Exercise training in patients with heart failure and preserved ejection fraction: findings awaiting discovery. PMID- 23665369 TI - Can we measure how hot the plaque is? Not yet, but... PMID- 23665370 TI - Effect of endurance exercise training on endothelial function and arterial stiffness in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial. AB - OBJECTIVES: The study sought to evaluate the effects of endurance exercise training (ET) on endothelial-dependent flow-mediated arterial dilation (FMD) and carotid artery stiffness, and their potential contributions to the training related increase in peak exercise oxygen consumption (Vo2) in older patients with heart failure with preserved ejection fraction (HFPEF). BACKGROUND: Elderly HFPEF patients have severely reduced peak Vo2, which improves with ET, however, the mechanisms of this improvement are unclear. FMD and arterial distensibility are critical components of the exercise response and are reduced with aging. However, it is unknown whether these improve with ET in elderly HFPEF or contribute to the training-related improvement in peak Vo2. METHODS: A total of 63 HFPEF patients (age 70 +/- 7 years) were randomized to 16 weeks of ET (walking, arm and leg ergometry, n = 32) or attention control (CT) (n = 31). Peak Vo2, brachial artery FMD in response to cuff ischemia, carotid artery distensibility by high resolution ultrasound, left ventricular function, and quality of life were measured at baseline and follow-up. RESULTS: ET increased peak Vo2 (ET: 15.8 +/- 3.3 ml/kg/min vs. CT: 13.8 +/- 3.1 ml/kg/min, p = 0.0001) and quality of life. However, brachial artery FMD (ET: 3.8 +/- 3.0% vs. CT: 4.3 +/- 3.5%, p = 0.88), and carotid arterial distensibility (ET: 0.97 +/- 0.56 vs. CT: 1.07 +/- 0.34 * 10(-3) mm.mm Hg(-2); p = 0.65) were unchanged. Resting left ventricular systolic and diastolic function were unchanged by ET. CONCLUSIONS: In elderly HFPEF patients, 16 weeks of ET improved peak Vo2 without altering endothelial function or arterial stiffness. This suggests that other mechanisms, such as enhanced skeletal muscle perfusion and/or oxygen utilization, may be responsible for the ET-mediated increase in peak Vo2 in older HFPEF patients. (Prospective Aerobic Reconditioning Intervention Study [PARIS]; NCT01113840). PMID- 23665371 TI - Cause of death within 30 days of percutaneous coronary intervention in an era of mandatory outcome reporting. AB - OBJECTIVES: This study sought to ascertain causes of death and the incidence of percutaneous coronary intervention (PCI)-related mortality within 30 days. BACKGROUND: Public reporting of 30-day mortality after PCI without clearly identifying the cause may result in operator risk avoidance and affect hospital reputation and reimbursements. Death certificates, utilized by previous reports, have poor correlation with actual cause of death and may be inadequate for public reporting. METHODS: All patients who died within 30 days of a PCI from January 2009 to April 2011 at a tertiary care center were included. Causes of death were identified through detailed chart review using Academic Research Consortium consensus guidelines and compared with reported death certificates. The causes of death were divided into cardiac and noncardiac and PCI and non-PCI-related categories. RESULTS: Of the 4,078 PCI, 81 deaths (2%) occurred within 30 days. Of these, 58% died of cardiac and 42% of noncardiac causes. However, only 42% of 30 day deaths were attributed to PCI-related complications. Patients with non-PCI related, compared with PCI-related, death presented with a higher incidence of cardiogenic shock (15 of 47 [32%] vs. 2 of 34 [6%]; p < 0.01) and cardiac arrest (19 of 47 [40%] vs. 1 of 34 [3%]; p < 0.01). Death certificates had only 58% accuracy (95% confidence interval: 45% to 72%) for classifying patients as experiencing cardiac versus noncardiac death. CONCLUSIONS: Less than one-half of 30-day deaths are attributed to a PCI-related complication. Death certificates are inaccurate and do not report PCI-related deaths, which may represent a better marker of PCI quality. PMID- 23665372 TI - Role of aspiration and mechanical thrombectomy in patients with acute myocardial infarction undergoing primary angioplasty: an updated meta-analysis of randomized trials. AB - OBJECTIVES: This meta-analysis was designed to update data on clinical outcomes with aspiration thrombectomy or mechanical thrombectomy before primary percutaneous coronary intervention (PCI) compared with conventional primary PCI alone. BACKGROUND: The clinical efficacy of thrombectomy in acute myocardial infarction (AMI) remains uncertain. METHODS: Clinical trials that randomized AMI patients to aspiration (18 trials, n = 3,936) or mechanical thrombectomy (7 trials, n = 1,598) before PCI compared with conventional PCI alone were included. RESULTS: The weighted mean duration of clinical follow-up was 6 months. Aspiration thrombectomy vs. conventional primary PCI (18 trials, n=3,936): Major adverse cardiac events (MACE) (risk ratio [RR]: 0.76; 95% confidence interval [CI]: 0.63 to 0.92; p = 0.006) and all-cause mortality (RR: 0.71; 95% CI: 0.51 to 0.99; p = 0.049) were significantly reduced with aspiration thrombectomy. Beneficial trends were noted for recurrent MI (p = 0.11) and target vessel revascularization (p = 0.06). Final infarct size (p = 0.64) and ejection fraction (p = 0.32) at 1 month were similar. ST-segment resolution (STR) at 60 min (RR: 1.31; 95% CI: 1.16 to 1.48; p < 0.0001) and Thrombolysis In Myocardial Infarction blush grade (TBG) 3 post-procedure (RR: 1.37; 95% CI: 1.19 to 1.59; p < 0.0001) were both improved with aspiration thrombectomy. Mechanical thrombectomy vs. conventional primary PCI (7 trials, n = 1,598): there was no difference between the mechanical thrombectomy and conventional primary PCI arms in the incidence of MACE (RR: 1.10; 95% CI: 0.59 to 2.05; p = 0.77), mortality (p = 0.57), recurrent MI (p = 0.32), target vessel revascularization (p = 0.19), or final infarct size (p = 0.47). A benefit in STR at 60 min (RR: 1.25; 95% CI: 1.06 to 1.47; p = 0.007), but not TBG 3 (RR: 1.09; 95% CI: 0.86 to 1.38; p = 0.48) was noted. CONCLUSIONS: Thrombectomy during AMI by manual catheter aspiration, but not mechanically, is beneficial in reducing MACE, including mortality, at 6 to 12 months compared with conventional primary PCI alone. PMID- 23665373 TI - Good fat, bad fat: the increasingly complex interplay of adipose tissue and the cardiovascular system. PMID- 23665374 TI - Alternative TLRs are stimulated by bacterial ligand to induce TLR2-unresponsive colon cell response. AB - Although pathogenic bacteria penetrate colonic cells causing infection, the role of its surface molecules serving as key Toll-like receptor (TLR) ligands and triggering response remains unexplored. We show that TLR2-ligand porin up regulated TLR4 on HT-29 cells, which the TLR4-ligand LPS could not. TLR1 that co express with TLR2 got stimulated with TLR4. Besides the two TLRs, MD-2 was expressed revealing that the TLR4 co-receptor is not exclusive for LPS signaling. SARM-1 that mostly down-regulates TLR-signaling, demonstrated central role in signaling by engaging IRF-3 and NF-kappaB for cell activity. Porin induced type 1 chemokines particularly MCP-3, while porin-stimulated HT-29 culture supernatant displayed PBMC migration, collectively suggesting that the chemokines influence colon and immune cell cross-talk. In TLR2 down-regulated HT-29 cells, we found TLR1 and TLR4 as substitute TLRs to identify porin and orchestrate signaling. Thus, TLR replacement for PAMP recognition demonstrates specificity of ligand.TLR association can compromise and is a necessary alternative for successful execution of immune responses. PMID- 23665376 TI - The ameliorative effect of various antioxidants on Adriamycin-induced fetal renal abnormalities. AB - OBJECTIVE: To examine the efficacy of nine antiapoptotic compounds in preventing the development of Adriamycin-induced fetal renal abnormalities or ameliorating the resultant renal damage in a rat model. METHODS: Thirty-three Sprague-Dawley rats were randomly divided into sham-control, Adriamycin and prevention groups. The prevention group was divided into 9 subgroups. The rats were time mated and experimental rats were injected with Adriamycin on gestational day 7-9. Sham control rats were injected with saline on the same days. The preventive medications were administered to the prevention group from 7 days prior to mating to the end of pregnancy. Samples were prepared from fetuses for histological and biochemical analyses. RESULTS: A total of 331 fetuses were recovered. There were no resorptions in the Deferoxamine, Amifostine and sham-control groups. Significant decrease of antioxidant activities was noted in the Adriamycin group compared to the sham-control group. In all prevention groups, antioxidant activities were significantly increased compared to the Adriamycin group. The highest rate of hydronephrosis was observed in the Adriamycin group (82%). The lowest rates of renal abnormalities were noted with Deferoxamine and Amifostine: 8% and 11%. CONCLUSION: Oxidant injury plays a critical role in the development and progression of Adriamycin-induced fetal renal abnormalities. Some antiapoptotic medications, notably Deferoxamine and Amifostine, may have preventive and therapeutic potential in the management of fetal renal abnormalities. PMID- 23665375 TI - Neural predictors and mechanisms of cognitive behavioral therapy on threat processing in social anxiety disorder. AB - Cognitive behavioral therapy (CBT) is "gold standard" psychotherapy for social anxiety disorder (SAD). Cognitive models posit that preferential processing of threat mediates excessive forms of anxiety, which is supported by exaggerated amygdala, insula, and cortical reactivity to threatening socio-emotional signals in SAD. However, little is known about neural predictors of CBT success or the mechanisms by which CBT exerts its therapeutic effects. Functional magnetic resonance imaging (fMRI) was conducted during responses to social signals of threat (fearful/angry faces) against positive signals (happy faces) in 14 patients with SAD before and after 12 weeks of CBT. For comparison, 14 healthy control (HC) participants also underwent two fMRI scans, 12 weeks apart. Whole brain voxel-wise analyses showed therapeutic success was predicted by enhanced pre-treatment activation to threatening faces in higher-order visual (superior and middle temporal gyrus), cognitive, and emotion processing areas (dorsal anterior cingulate cortex, dorsomedial prefrontal cortex). Moreover, a group by time interaction was revealed in prefrontal regions (dorsomedial, medial gyrus) and insula. The interaction was driven by relatively greater activity during threat processing in SAD, which significantly reduced after CBT but did not significantly predict response to CBT. Therefore, pre-treatment cortical hyperactivity to social threat signals may serve as a prognostic indicator of CBT success in SAD. Collectively, CBT-related brain changes involved a reduction in activity in insula, prefrontal, and extrastriate regions. Results are consistent with cognitive models, which associate decreases in threat processing bias with recovery. PMID- 23665377 TI - Long-term outcome of male genital reconstruction in childhood. AB - Hypospadias, epispadias with or without exstrophy, and disorders of sex development are among the most common anomalies of genitalia that occur during childhood. Considering the tremendous effect of genitourinary reconstruction on adult life, the evaluation of the long-term results of different techniques of genitoplasty in pediatrics is of the utmost importance. After reviewing the literature, the authors summarize the available long-term outcomes of genitoplasty in childhood, specifically focusing on the cosmetic, psychosocial, psychosexual and functional results, and emphasize that, contrary to the widely available data on early outcomes of genital reconstruction in the pediatric population, very few well described controlled studies have evaluated the long term effect of genitoplasty in puberty and adulthood, in the sense that the surgeon should describe the peroperative findings in more detail and also be more structured in evaluating the postoperative result at follow-up visits. Finally, the authors conclude that more attention should be paid to the impact of these techniques on cosmetic aspects and psychosexual development in these patients after puberty, as they play a crucial role in their adult quality of life. PMID- 23665378 TI - Modulation of effective connectivity during vocalization with perturbed auditory feedback. AB - The integration of auditory feedback with vocal motor output is important for the control of voice fundamental frequency (F0). We used a pitch-shift paradigm where subjects respond to an alteration, or shift, of voice pitch auditory feedback with a reflexive change in F0. We presented varying magnitudes of pitch shifted auditory feedback to subjects during vocalization and passive listening and measured event related potentials (ERPs) to the feedback shifts. Shifts were delivered at +100 and +400 cents (200 ms duration). The ERP data were modeled with dynamic causal modeling (DCM) techniques where the effective connectivity between the superior temporal gyrus (STG), inferior frontal gyrus and premotor areas were tested. We compared three main factors: the effect of intrinsic STG connectivity, STG modulation across hemispheres and the specific effect of hemisphere. A Bayesian model selection procedure was used to make inference about model families. Results suggest that both intrinsic STG and left to right STG connections are important in the identification of self-voice error and sensory motor integration. We identified differences in left-to-right STG connections between 100 cent and 400 cent shift conditions suggesting that self- and non-self voice error are processed differently in the left and right hemisphere. These results also highlight the potential of DCM modeling of ERP responses to characterize specific network properties of forward models of voice control. PMID- 23665379 TI - Left parietal TMS disturbs priming between symbolic and non-symbolic number representations. AB - An amodal number representation activated by all types of numerical input, irrespective of the input notation, has often been proposed to be located in the left or right intraparietal sulcus (IPS). Two cross-notational priming experiments were carried out to test the existence of a notation-independent magnitude representation in the left or right parietal lobes. In Experiment 1, stimuli were Arabic digits and number words. Results revealed no significant effect of repetitive transcranial magnetic stimulation (rTMS) over left or right IPS during prime presentation. In contrast, in Experiment 2, digits and dot patterns were intermixed and here the priming distance effect (PDE) was reduced in the right TMS condition and absent for stimulation over left IPS. These findings suggest: (1) that TMS over left but not right IPS disrupts processes that are crucial for priming when symbolic and non-symbolic stimuli are intermixed, and (2) that disruption of the left IPS on its own is not sufficient to disrupt cross-notational priming when purely symbolic number notations are used. Our results point towards a crucial role of the left hemisphere for the mapping between small symbolic and non-symbolic numerosities. PMID- 23665380 TI - Molecular characterization of the dimer formation of Fcalpha/MU receptor (CD351). AB - Fcalpha/MUR (CD351) is an Fc receptor for both IgA and IgM and forms an atypical dimer that is resistant to reduction by 2-mercaptoethanol or boiling. We previously demonstrated that the cytoplasmic portion of Fcalpha/MUR is required for dimer formation and for its efficient cell-surface expression. However, the biochemical nature of these phenomena has not been determined. By using a BW5147 mouse cell line expressing deletion mutants of the cytoplasmic region of Fcalpha/MUR, we found that the region spanning amino acids 504-523 was required for efficient cell-surface expression, whereas the region spanning amino acids 481-490 was required for dimmer formation. Immunoblotting analyses of transfectants simultaneously expressing Flag-tagged Fcalpha/MUR and hemagglutinin tagged Fcalpha/MUR suggested that Fcalpha/MUR does not form homodimers. Instead, our data suggest that Fcalpha/MUR forms heterodimers with an as-yet-unknown molecule with a molecular weight of 60-70 kDa. PMID- 23665382 TI - NFATc2 recruits cJun homodimers to an NFAT site to synergistically activate interleukin-2 transcription. AB - Transcription of interleukin-2 (IL-2), a pivotal cytokine in the mammalian immune response, is induced by NFAT and AP-1 transcriptional activators in stimulated T cells. NFATc2 and cJun drive high levels of synergistic human IL-2 transcription, which requires a unique interaction between the C-terminal activation domain of NFATc2 and cJun homodimers. Here we studied the mechanism by which this interaction contributes to synergistic activation of IL-2 transcription. We found that NFATc2 can recruit cJun homodimers to the -45 NFAT element, which lacks a neighboring AP-1 site. The bZip domain of cJun is sufficient to interact with the C-terminal activation domain of NFATc2 in the absence of DNA and this interaction is inhibited by AP-1 DNA. When the -45 NFAT site was replaced by either an NFAT/AP-1 composite site or a single AP-1 site the specificity for cJun homodimers in synergistically activating IL-2 transcription was lost, and cJun/cFos heterodimers strongly activated transcription. These studies support a model in which IL-2 transcriptional synergy is mediated by the unique recruitment of a cJun homodimer to the -45 NFAT site by NFATc2, where it acts as a co activator for IL-2 transcription. PMID- 23665381 TI - The constant region affects antigen binding of antibodies to DNA by altering secondary structure. AB - We previously demonstrated an important role of the constant region in the pathogenicity of anti-DNA antibodies. To determine the mechanisms by which the constant region affects autoantibody binding, a panel of isotype-switch variants (IgG1, IgG2a, IgG2b) was generated from the murine PL9-11 IgG3 autoantibody. The affinity of the PL9-11 antibody panel for histone was measured by surface plasmon resonance (SPR). Tryptophan fluorescence was used to determine wavelength shifts of the antibody panel upon binding to DNA and histone. Finally, circular dichroism spectroscopy was used to measure changes in secondary structure. SPR analysis revealed significant differences in histone binding affinity between members of the PL9-11 panel. The wavelength shifts of tryptophan fluorescence emission were found to be dependent on the antibody isotype, while circular dichroism analysis determined that changes in antibody secondary structure content differed between isotypes upon antigen binding. Thus, the antigen binding affinity is dependent on the particular constant region expressed. Moreover, the effects of antibody binding to antigen were also constant region dependent. Alteration of secondary structures influenced by constant regions may explain differences in fine specificity of anti-DNA antibodies between antibodies with similar variable regions, as well as cross-reactivity of anti-DNA antibodies with non-DNA antigens. PMID- 23665383 TI - Molecular mechanisms of reactive oxygen species-related pulmonary inflammation and asthma. AB - Asthma is a highly relevant disorder that can be induced by many environmental factors such as allergens and pollutants. One of the most critical pathological symptoms of asthma is airway inflammation. In order to identify a cause of respiratory inflammation, we thoroughly examine the unique role of reactive oxygen species (ROS). Evidence supports that the inhalation of aggravating compounds such as allergens can promote the increased generation of ROS. Accordingly, ROS have a proven role in the cellular signaling cascades of many respiratory diseases that cause respiratory inflammation, including asthma. Although there is no known cure for asthma, current treatments effectively lessen the inflammation symptom. Based on the investigations of asthma pathogenesis and the mechanism of ROS formation, we have identified several novel anti inflammatory therapeutic treatments, shedding light on a fundamental understanding for the cure of this disorder. In this review, we will outline the pathogenesis of asthma and its relationship to ROS, oxidative stress, and pulmonary inflammation. PMID- 23665384 TI - Evolution of Staphylococcus aureus and MRSA during outbreaks. AB - Investigation of Staphylococcus aureus outbreaks, and particularly those due to methicillin-resistant S. aureus (MRSA) in hospitals, can identify infection reservoirs and prevent further colonization and infection. During outbreaks, S. aureus genomes develop single nucleotide polymorphisms (SNPs), small genetic rearrangements, and/or acquire and lose mobile genetic elements (MGE) encoding resistance and virulence genes. Whole genome sequencing (WGS) is the most powerful method for discriminating between related isolates and deciding which are involved in an outbreak. Isolates with only minor variations are detectable and can identify MRSA transmission routes and identify reservoirs. Some patients may carry 'clouds' of related isolates, and this has consequences for how we interpret the data from outbreak investigations. Different clones of MRSA are evolving at different rates, influencing their typability. S. aureus genome variation reveals the importance of antibiotic resistance in the long term evolution of successful hospital clones, contributing to strategies to prevent the spread of successful MRSA clones. PMID- 23665385 TI - Ablation targets in reentrant ventricular tachycardia. PMID- 23665386 TI - Goldilocks and the importance of AV intervals in cardiac resynchronization--how to best find the AV interval that is not too long, not too short, but just right for patients. PMID- 23665387 TI - Hand-held ultrasonography to assess external chest compressions on a fresh cadaver. PMID- 23665388 TI - An unexplained cardiac arrest, always re-check the "A" after resuscitation. PMID- 23665390 TI - Modeling complex responses of FM-sensitive cells in the auditory midbrain using a committee machine. AB - Frequency modulation (FM) is an important building block of complex sounds that include speech signals. Exploring the neural mechanisms of FM coding with computer modeling could help understand how speech sounds are processed in the brain. Here, we modeled the single unit responses of auditory neurons recorded from the midbrain of anesthetized rats. These neurons displayed spectral temporal receptive fields (STRFs) that had multiple-trigger features, and were more complex than those with single-trigger features. Their responses have not been modeled satisfactorily with simple artificial neural networks, unlike neurons with simple-trigger features. To improve model performance, here we tested an approach with the committee machine. For a given neuron, the peri-stimulus time histogram (PSTH) was first generated in response to a repeated random FM tone, and peaks in the PSTH were segregated into groups based on the similarity of their pre-spike FM trigger features. Each group was then modeled using an artificial neural network with simple architecture, and, when necessary, by increasing the number of neurons in the hidden layer. After initial training, the artificial neural networks with their optimized weighting coefficients were pooled into a committee machine for training. Finally, the model performance was tested by prediction of the response of the same cell to a novel FM tone. The results showed improvement over simple artificial neural networks, supporting that trigger-feature-based modeling can be extended to cells with complex responses. This article is part of a Special Issue entitled Neural Coding 2012. This article is part of a Special Issue entitled Neural Coding 2012. PMID- 23665389 TI - Use of rapid sequence intubation predicts improved survival among patients intubated after out-of-hospital cardiac arrest. AB - OBJECTIVE: Some observational studies indicate that endotracheal intubation is associated with a worse outcome compared to bag-mask ventilation after out-of hospital cardiac arrest in emergency medical services (EMS) systems without rapid sequence intubation (RSI). We evaluated the role of RSI in airway management following cardiac arrest. METHODS: We conducted a cohort study of all non traumatic arrest patients treated by a metropolitan EMS system from 2007 to 2011. Advanced airway management information was obtained from a prospective airway registry and linked to a cardiac arrest registry. We used multivariate logistic regression to estimate the association between attempted intubation status and survival to hospital discharge. RESULTS: Of 3133 patients, 82% underwent attempted intubation without RSI, 15% underwent attempted RSI, and 3% experienced no intubation attempt. Survival to hospital discharge differed by attempted intubation status: 11% (n=291/2576) for intubation without RSI, 48% (n=226/471) for RSI, and 71% (n=61/86) for "no intubation." Compared to the intubation without RSI group, the adjusted odds ratios of survival were 5.6 (95% CI 4.3, 7.2) for the RSI group and 15 (95% CI 9, 27) for the "no intubation" group. CONCLUSION: In this population-based cohort of out-of-hospital cardiac arrest, RSI was used in 15% of patients and associated with a better prognosis than intubation attempted without paralytics. Because this subset with a favorable prognosis may not be readily intubated in systems without paralytics, these findings could help to explain the adverse relationship between intubation and survival observed in prior studies. PMID- 23665391 TI - Olfactory ensheathing cells of hamsters, rabbits, monkeys, and mice express alpha smooth muscle actin. AB - Olfactory ensheathing cells (OECs) are the chief glial population of the mammalian olfactory nervous system, residing in the olfactory mucosa and at the surface of the olfactory bulb. We investigated the neurochemical features of OECs in a variety of mammalian species (including adult hamsters, rabbits, monkeys, and mice, as well as fetal pigs) using three biomarkers: alpha-smooth muscle actin (alphaSMA), S100beta, and glial fibrillary acidic protein (GFAP). Mucosal and bulbar OECs from all five mammalian species express S100beta. Both mucosal and bulbar OECs of monkeys express alphaSMA, yet only bulbar OECs of hamsters and only mucosal OECs of rabbits express alphaSMA as well. Mucosal OECs, but not bulbar OECs, also express GFAP in hamsters and monkeys; mice, by comparison, have only a sparse population of OECs expressing GFAP. Though alphaSMA immunostaining is not detected in OECs of adult mice, GFAP-expressing mucosal OECs isolated from adult mice do coexpress alphaSMA in vitro. Moreover, mucosal OECs from adult mutant mice lacking alphaSMA expression display perturbed cellular morphology (i.e., fewer cytoplasmic processes extending among the hundreds of olfactory axons in the olfactory nerve fascicles and nuclei having degenerative features). In sum, these findings highlight the efficacy of alphaSMA and S100beta as biomarkers of OECs from a variety of mammalian species. These observations provide definitive evidence that mammalian OECs express the structural protein alphaSMA (at various levels of detection), which appears to play a pivotal role in their ensheathment of olfactory axons. PMID- 23665392 TI - A simple method to quickly and simultaneously purify and enrich intact rat brain microcapillaries and endothelial and glial cells for ex vivo studies and cell culture. AB - The blood-brain barrier is morphologically composed of cerebral microcapillary endothelium through its tight junctions. It serves as a mechanical, metabolic and cellular barrier and can also protect the brain from pathogen invasion. Many brain diseases involve a disturbance of blood-brain barrier function either as a consequence of a noxa or as primary failure. In vitro models of the blood-brain barrier are suitable tools to study drug transport, pathogen transmigration and leukocyte diapedesis across the cerebral endothelium. Such models have previously been derived mainly from porcine or bovine brain tissues. We describe here a simple method by which rat cerebral microcapillaries and cells of glial origin can be quickly and simultaneously purified. By using a capillary fragment size restriction method based on glass bead columns different fractions can be separated: vital, long capillary fragments for ex vivo uptake studies and smaller capillary fragments for endothelial culture. Furthermore, fractions can be obtained for astroglial and oligodendroglial cell cultures. With this method both microcapillary enrichment and glial cell purification are quickly achieved, which reduces expenditure, number of required animals and laboratory working time. PMID- 23665393 TI - An fMRI study on sunk cost effect. AB - Sunk cost effect (also called escalation of commitment, etc) is a pervasive, interesting and famous decision bias, which has been intensively discussed in psychology, economics, management, political science, zoology, etc. To date, little has been known about the neural basis of this phenomenon. We investigated it by using functional magnetic resonance imaging (fMRI) to monitor healthy subjects' brain activities when they made decisions in a task wherein sunk cost and incremental cost were systematically manipulated. Higher sunk cost only increased activity of some brain areas (mainly lateral frontal and parietal cortices, which are involved in risk-taking), whereas lower incremental cost mainly increased activity of some brain areas (including striatum and medial prefrontal cortex, which are sensitive to rewards). No overlapping brain areas were found to respond to both sunk cost and incremental cost. These results favor certainty effect over self-justification or diminishing sensitivity as account of sunk cost effect. PMID- 23665394 TI - Reductive stress in young healthy individuals at risk of Alzheimer disease. AB - Oxidative stress is a hallmark of Alzheimer disease (AD) but this has not been studied in young healthy persons at risk of the disease. Carrying an Apo epsilon4 allele is the major genetic risk factor for AD. We have observed that lymphocytes from young, healthy persons carrying at least one Apo epsilon4 allele suffer from reductive rather than oxidative stress, i.e., lower oxidized glutathione and P p38 levels and higher expression of enzymes involved in antioxidant defense, such as glutamylcysteinyl ligase and glutathione peroxidase. In contrast, in the full blown disease, the situation is reversed and oxidative stress occurs, probably because of the exhaustion of the antioxidant mechanisms just mentioned. These results provide insights into the early events of the progression of the disease that may allow us to find biomarkers of AD at its very early stages. PMID- 23665396 TI - SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative damage. AB - Progressive accumulation of defective mitochondria is a common feature of aged cells. SIRT3 is a NAD(+)-dependent protein deacetylase that regulates mitochondrial function and metabolism in response to caloric restriction and stress. FOXO3 is a direct target of SIRT3 and functions as a forkhead transcription factor to govern diverse cellular responses to stress. Here we show that hydrogen peroxide induces SIRT3 to deacetylate FOXO3 at K271 and K290, followed by the upregulation of a set of genes that are essential for mitochondrial homeostasis (mitochondrial biogenesis, fission/fusion, and mitophagy). Consequently, SIRT3-mediated deacetylation of FOXO3 modulates mitochondrial mass, ATP production, and clearance of defective mitochondria. Thus, mitochondrial quantity and quality are ensured to maintain mitochondrial reserve capacity in response to oxidative damage. Maladaptation to oxidative stress is a major risk factor underlying aging and many aging-related diseases. Hence, our finding that SIRT3 deacetylates FOXO3 to protect mitochondria against oxidative stress provides a possible direction for aging-delaying therapies and disease intervention. PMID- 23665397 TI - Redox metabolism in Trypanosoma cruzi: functional characterization of tryparedoxins revisited. AB - Tryparedoxins (TXNs) are multipurpose oxidoreductases from trypanosomatids that transfer reducing equivalents from trypanothione to various thiol proteins. In Trypanosoma cruzi, two genes coding for TXN-like proteins have been identified: TXNI, previously characterized as a cytoplasmic protein, and TXNII, a putative tail-anchored membrane protein. In this work, we performed a comparative functional characterization of T. cruzi TXNs. Particularly, we cloned the gene region coding for the soluble version of TXNII for its heterologous expression. The truncated recombinant protein (without its 22 C-terminal transmembrane amino acids) showed TXN activity. It was also able to transfer reducing equivalents from trypanothione, glutathione, or dihydrolipoamide to various acceptors, including methionine sulfoxide reductases and peroxiredoxins. The results support the occurrence and functionality of a second tryparedoxin, which appears as a new component in the redox scenario for T. cruzi. PMID- 23665398 TI - Hyperuricemia influences tryptophan metabolism via inhibition of multidrug resistance protein 4 (MRP4) and breast cancer resistance protein (BCRP). AB - Hyperuricemia is related to a variety of pathologies, including chronic kidney disease (CKD). However, the pathophysiological mechanisms underlying disease development are not yet fully elucidated. Here, we studied the effect of hyperuricemia on tryptophan metabolism and the potential role herein of two important uric acid efflux transporters, multidrug resistance protein 4 (MRP4) and breast cancer resistance protein (BCRP). Hyperuricemia was induced in mice by treatment with the uricase inhibitor oxonic acid, confirmed by the presence of urate crystals in the urine of treated animals. A transport assay, using membrane vesicles of cells overexpressing the transporters, revealed that uric acid inhibited substrate-specific transport by BCRP at clinically relevant concentrations (calculated IC50 value: 365+/-13MUM), as was previously reported for MRP4. Moreover, we identified kynurenic acid as a novel substrate for MRP4 and BCRP. This finding was corroborated by increased plasma levels of kynurenic acid observed in Mrp4(-/-) (107+/-19nM; P=0.145) and Bcrp(-/-) mice (133+/-10nM; P=0.0007) compared to wild type animals (71+/-11nM). Hyperuricemia was associated with >1.5 fold increase in plasma kynurenine levels in all strains. Moreover, hyperuricemia led to elevated plasma kynurenic acid levels (128+/-13nM, P=0.005) in wild type mice but did not further increase kynurenic acid levels in knockout mice. Based on our results, we postulate that elevated uric acid levels hamper MRP4 and BCRP functioning, thereby promoting the retention of other potentially toxic substrates, including kynurenic acid, which could contribute to the development of CKD. PMID- 23665399 TI - Follow-up for Clinically Localized Renal Neoplasms: AUA Guideline. AB - PURPOSE: The purpose of this guideline is to provide a clinical framework for follow-up of clinically localized renal neoplasms undergoing active surveillance, or following definitive therapy. MATERIALS AND METHODS: A systematic literature review identified published articles in the English literature between January 1999 and 2011 relevant to key questions specified by the Panel related to kidney neoplasms and their follow-up (imaging, renal function, markers, biopsy, prognosis). Study designs consisting of clinical trials (randomized or not), observational studies (cohort, case-control, case series) and systematic reviews were included. RESULTS: Guideline statements provided guidance for ongoing evaluation of renal function, usefulness of renal biopsy, timing/type of radiographic imaging and formulation of future research initiatives. A lack of studies precluded risk stratification beyond tumor staging; therefore, for the purposes of postoperative surveillance guidelines, patients with localized renal cancers were grouped into strata of low- and moderate- to high-risk for disease recurrence based on pathological tumor stage. CONCLUSIONS: Evaluation for patients on active surveillance and following definitive therapy for renal neoplasms should include physical examination, renal function, serum studies and imaging and should be tailored according to recurrence risk, comorbidities and monitoring for treatment sequelae. Expert opinion determined a judicious course of monitoring/surveillance that may change in intensity as surgical/ablative therapies evolve, renal biopsy accuracy improves and more long-term follow-up data are collected. The beneficial impact of careful follow-up will also need critical evaluation as further study is completed. PMID- 23665395 TI - Glutathione metabolism and Parkinson's disease. AB - It has been established that oxidative stress, defined as the condition in which the sum of free radicals in a cell exceeds the antioxidant capacity of the cell, contributes to the pathogenesis of Parkinson disease. Glutathione is a ubiquitous thiol tripeptide that acts alone or in concert with enzymes within cells to reduce superoxide radicals, hydroxyl radicals, and peroxynitrites. In this review, we examine the synthesis, metabolism, and functional interactions of glutathione and discuss how these relate to the protection of dopaminergic neurons from oxidative damage and its therapeutic potential in Parkinson disease. PMID- 23665400 TI - Intravesical gemcitabine for high risk, nonmuscle invasive bladder cancer after bacillus Calmette-Guerin treatment failure. AB - PURPOSE: We report our experience with intravesical gemcitabine for bladder cancer after failed bacillus Calmette-Guerin treatment. MATERIALS AND METHODS: We retrospectively reviewed the records of patients at our cancer center treated with intravesical gemcitabine after bacillus Calmette-Guerin failure. We estimated progression-free, recurrence-free and cancer specific survival using the cumulative incidence function, considering death from another cause as a competing risk. Comparisons were made using the Gray test. Overall survival was estimated using the Kaplan-Meier method and differences were compared with the log rank test. RESULTS: Of 69 patients treated with intravesical gemcitabine 37 had bacillus Calmette-Guerin refractory disease. Median followup in progression free patients was 3.3 years. Progression-free and cancer specific survival were similar in patients with refractory disease and those with other types of bacillus Calmette-Guerin failure. Overall survival was lower in patients with refractory disease (58% vs 71%) but this was not statistically significant (p=0.096). Of the patients 27 patients experienced a complete response. Progression-free, cancer specific and overall survival did not differ significantly between patients with and without a complete response. Cystectomy was subsequently performed in 20 patients. Those with a complete response had a delayed time to cystectomy and no muscle invasive bladder cancer at cystectomy. There were no serious adverse events and only a minority of patients discontinued treatment due to adverse events. CONCLUSIONS: In our experience intravesical gemcitabine should be considered after bacillus Calmette-Guerin failure in patients with bladder cancer who refuse radical cystectomy or who are not candidates for major surgery. PMID- 23665401 TI - Alterations in acetylcholine, PGE2 and IL6 release from urothelial cells following treatment with pyocyanin and lipopolysaccharide. AB - The effects of pseudomonal virulence factor pyocyanin, and LPS from Pseudomonas aeruginosa and Escherichia coli on urothelial mediator release and cytokine production were examined. RT4 urothelial cells were treated with pyocyanin (1-100 MUM) or LPS (1-100 ng/mL) for 24-h. Effects were measured in terms of changes in cell viability, basal and stretch-induced acetylcholine (Ach) and PGE2 release, and inflammatory cytokines (IL-6 and IL-12) production. Twenty-four hour pyocyanin (100 MUM) treatment significantly decreased urothelial cell viability, while stretch-induced Ach release response was inhibited. E. coli LPS (100 ng/mL) produced a similar response with an additional significant increase in basal Ach release. All three virulence factors significantly increased urothelial PGE2 release; under basal release for pyocyanin (100 MUM), stretch-induced release for pseudomonal LPS (>= 10 ng/mL) and both basal and stimulated release for E. coli LPS (>= 10 ng/mL). IL-6 and IL-12 were not detected in control samples, however 24h treatment with pyocyanin (100 MUM) or LPS (100 ng/mL) resulted in IL-6 release from urothelial cells. The changes in urothelial Ach and PGE2, and release of inflammatory cytokine IL-6 induced by exposure to the bacterial virulence factors may play a role in the symptoms of pain and urinary urgency experienced with urinary tract infections. PMID- 23665402 TI - Enkephalin and dynorphin mRNA expression are associated with resilience or vulnerability to chronic social defeat stress. AB - There are important and enduring differences between individuals in the magnitude of all aspects of the stress response. Among the neuropeptide systems, the endogenous opioids enkephalin (ENK) and dynorphin (DYN), are very interesting candidates to participate in the naturally occurring variations in coping styles and to determine the individual capacity for adaptation during chronic stress exposure. Under chronic social stress exposure, we hypothesize that changes in the ENKergic vs DYNergic neuronal systems within specific nuclei of the basal forebrain contribute to naturally occurring variations in coping styles and will determine individual capacities for stress adaptation. Sprague-Dawley rats were exposed to a resident-intruder model of defeat for 7 days. The average latency to be defeated over seven consecutive days was calculated for each intruder rat. Based on this distribution, we chose an average defeat latency of 350s as a cutoff criterion to define resilient and vulnerable rats. A subpopulation assumed a subordinate posture in a relatively short latency (<350s, SL) and the other subpopulation resisted defeat resulting in longer latencies (>350s, LL) to assume this posture and were identified as being vulnerable and resilient respectively. Rats were euthanized 24h after the last stress session. ENK mRNA expression was lower in the basolateral nucleus of the amygdala in vulnerable compared to control and resilient individuals. In contrast, there was no difference between resilient and control individuals. DYN mRNA is increased only within the dorsal and medial shell of the NAc of vulnerable rats compared to control individuals. There was no difference between resilient and control individuals. DYN mRNA is increased in resilient individuals in the central area of the striatum, caudal part, compared to control individuals. DYN is also increased in medial area of the striatum, caudal part in resilient and vulnerable compared to control individuals. These results have broad implications for understanding the functional roles of opioid neurotransmission following repeated social stress and suggest that ENK could facilitate the adaptation of behavioral responses by opposition to the DYN neurotransmission that appears to promote maladaptive behavioral response to chronic social stress. PMID- 23665403 TI - A general method for diagonal peak suppression in homonuclear correlated NMR spectra by spatially and frequency selective pulses. AB - Homonuclear two- and multidimensional NMR spectra are standard experiments for the structure determination of small to medium-sized molecules. In the large majority of homonuclear correlated spectra the diagonal contains the most intense peaks. Cross-peaks near the diagonal could overlap with huge tails of diagonal peaks and can therefore be easily overlooked. Here we present a general method for the suppression of peaks along the diagonal in homonuclear correlated spectra. It is based on a spatially selective excitation followed by the suppression of magnetization which has not changed the frequency during the mixing process. In addition to the auto correlation removal, these experiments are also less affected by magnetic field inhomogeneities due to the slice selective excitation, which on the other side leads to a reduced intensity compared to regular homonuclear correlated spectra. PMID- 23665404 TI - [Determining factors in body mass index of Spanish schoolchildren based on the National Health Surveys]. AB - INTRODUCTION: Spanish National Health Surveys do not establish synergistic relations between variables. The purpose of this study was to perform a deeper historical analysis of body mass index (BMI) and its relation to other parameters included in the questionnaire for children. MATERIAL AND METHODS: Data from interviews conducted (between 1987 and 2006) to parents and guardians of schoolchildren aged 9-15 years were analyzed. Height and weight reported by parents were selected and used to calculate BMI. Subjects were stratified by age, gender, time spent sleeping and watching television and, finally, frequency of physical activity. The historical trend of BMI and its dependence on the above factors were analyzed using ANOVA tests. RESULTS AND CONCLUSIONS: Significant weight and height increases were seen, which were more marked in boys aged 12 to 15 years. Influence of physical activity on BMI was shown, but decreased (P<.001) as exercise time increased. By contrast, BMI increased (P<.001) as time spent watching television increased. On the other hand, the role of sleep as modulator of body size was confirmed, since schoolchildren aged 9-11 years who slept over 9h had lower BMIs (P<.001). In subjects aged 12 to 15, BMI decreased (P<.001) from 6h of sleep. PMID- 23665405 TI - Reduced complication rate after modified binding purse-string-mattress sutures pancreatogastrostomy versus duct-to-mucosa pancreaticojejunostomy. AB - BACKGROUND AND PURPOSE: A 2011 metaanalysis demonstrated no difference in postoperative complications between pancreatogastrostomy and pancreaticojejunostomy after pancreaticoduodenectomy with the limitation of heterogeneity among the analysed studies. The present study compares postoperative complications after duct-to-mucosa pancreaticojejunostomy with a modified binding purse-string-mattress sutures pancreatogastrostomy in a teaching hospital. METHODS: One-hundred consecutive pancreaticoduodenectomies were reconstructed either by pancreaticojejunostomy (n = 50, 2004-2008) or modified pancreatogastrostomy (n = 50, 2008-2011). Prospective patients' data was retrospectively analysed for postoperative complications. MAIN FINDINGS: Complications occurred significantly less after modified pancreatogastrostomy compared to pancreaticojejunostomy (p = 0.016). This was mainly due to a significantly lower rate of pancreatic fistula (p = 0.029), especially a lower rate of clinically relevant B and C fistulas (p = 0.011). In particular, the fistula rate was reduced in patients with a soft, non-fibrotic pancreas (p = 0.0231). Postoperative mortality was also lower after modified pancreatogastrostomy (p = 0.042). Uni- and multivariate analyses revealed a soft, non-fibrotic pancreatic texture (odds ratio 5.4, p = 0.028), a non-dilatated pancreatic duct (p = 0.047) and pancreaticojejunostomy (odds ratio 10.7, p = 0.026) as independent, negative factors for pancreatic fistula. CONCLUSION: In a teaching hospital, modified pancreatogastrostomy seems to be superior to pancreaticojejunostomy regarding pancreatic fistula, especially in patients with a soft, non-fibrotic pancreas and/or a small duct. An ongoing prospective randomised multicentre trial (RECOPANC) might confirm these results. PMID- 23665406 TI - Combined quantification of corticotropin-releasing hormone, cortisol-to-cortisone ratio and progesterone by liquid chromatography-Tandem mass spectrometry in placental tissue. AB - With mid-gestation the production of placental corticotropin-releasing hormone (CRH) starts to steadily increase. The fetal peptide CRH excerts direct functions at the feto-maternal interface (vasodilatation, timing of birth) via its interaction with progesterone and indirectly ensures maturation and growth of fetal organ systems for delivery by driving fetal cortisol production via its induction of adrenocorticotropic hormone release. This feedback loop is tightly controlled by the amount of enzymatic cortisol/cortisone turnover in the placental syncytiotrophoblast by 11beta-hydroxy-steroid dehydrogenase type 2 (11beta-HSD2). Traditionally, placental tissue hormones have been quantified by immunological methods (e.g. RIA or ELISA), which have the drawback of possible cross-reactivity and tissue perturbations. Most importantly, it is not possible to quantify CRH and steroid hormones, such as cortisol, cortisone and progesterone together in the same sample with these methods. Hence, we aimed to develop and validate a quantitative mass spectrometry (MS) method for multi-modal quantification of these placental hormones: While CRH was readily detectable throughout the placenta, the placental levels of progesterone and especially cortisol and cortisone were higher at the placental base facing the maternal side. The HPLC-MS/MS procedure showed excellent selectivity and sufficient limit of quantification in placental tissue homogenates to allow for simultaneous detection of CRH, cortisol and cortisone, and progesterone. PMID- 23665407 TI - Synthesis and cytotoxicity of some novel 21E-benzylidene steroidal derivatives. AB - A series of novel derivatives of 21E-benzylidene-pregn-1,4-diene-3,20-dione 7a-g and 21E-benzylidene-4-chloro-pregn-1,4-diene-3,20-dione 8a-g was synthesized from the commercially available progesterone. These title compounds were evaluated for their cytotoxic activity against brine shrimp (Artemia salina) and murine Lewis lung carcinoma cells (LLC). It was found that compounds 7a-g exhibited stronger activities than 8a-g against the brine shrimps, and some of the tested compounds possessed weak inhibition of LLC cells. PMID- 23665408 TI - Bioaccessibility of metals in fish, shellfish, wild game, and seaweed harvested in British Columbia, Canada. AB - Fish, shellfish, wild game, and seaweed are important traditional foods that are essential to the physical and cultural well-being of Indigenous peoples in Canada. The goal of this study was to measure the concentration and bioaccessibility of As, Cd, Hg, Se, Cu and Mn in 45 commonly consumed traditional foods collected by harvested by the First Nations Food, Nutrition, and Environment Study (FNFNES) from 21 First Nations communities in British Columbia, Canada, in 2008-2009. A significant and negative correlation was observed between Hg concentration and Hg bioaccessibility. Metal bioaccessibility tended to be high; median values ranging between 52% (Mn) and 83% (Cu). The notable exceptions were observed for As in wild game organs (7-19%) and rabbit meat (4%) as well as Hg in salmon eggs (10%). Results of Principal Components Analysis confirmed the unique pattern of bioaccessibility of As and Hg in traditional foods, suggesting that, unlike other metals, As and Hg bioaccessibility are not simply controlled by food digestibility under the operating conditions of the in vitro model. These data provide useful information for dietary contaminant risk assessment and intake assessments of essential trace elements. PMID- 23665409 TI - Potential role of ATP-binding cassette transporters in the intestinal transport of rhein. AB - Rhein, a lipophilic anthraquinone, exhibits anti-inflammatory and anti-tumor activities; however, it is hepatotoxic. ATP-binding cassette transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated protein 2 (MRP2), can pump toxicants from gut epithelial cells back into the intestinal lumen to prevent poisoning. We investigated their roles in rhein transport using a rat intestinal perfusion model and Caco-2, MDCKII-MDR1 (high expression of P-gp), MDCKII-BCRP (high expression of BCRP) and MDCKII-MRP2 (high expression of MRP2) cell models. The permeability of rhein in the duodenum significantly increased with increasing perfused concentration of rhein in the rat model, suggesting that efflux transporters were involved in rhein transport. In the Caco-2 cells, the permeability of rhein from the basolateral (B) to the apical (A) was significantly higher than that from A to B. In the presence of BCRP or MRP2 inhibitor, the permeability of rhein significantly decreased from B to A direction. In the MDCKII-BCRP cells, rhein was more permeable in B to A side than that in the opposite side. However, no significant differences of rhein permeability were observed in two directions in both MDCKII-MDR1 and MDCKII-MRP2 cells. Taken together, these results suggested that only BCRP was involved in rhein transport. PMID- 23665410 TI - Scientific and ethical issues related to stem cell research and interventions in neurodegenerative disorders of the brain. AB - Should patients with Parkinson's disease participate in research involving stem cell treatments? Are induced pluripotent stem cells (iPSC) the ethical solution to the moral issues regarding embryonic stem cells? How can we adapt trial designs to best assess small numbers of patients in receipt of invasive experimental therapies? Over the last 20 years there has been a revolution in our ability to make stem cells from different sources and use them for therapeutic gain in disorders of the brain. These cells, which are defined by their capacity to proliferate indefinitely as well as differentiate into selective phenotypic cell types, are viewed as being especially attractive for studying disease processes and for grafting in patients with chronic incurable neurodegenerative disorders of the CNS such as Parkinson's disease (PD). In this review we briefly discuss and summarise where our understanding of stem cell biology has taken us relative to the clinic and patients, before dealing with some of the major ethical issues that work of this nature generates. This includes issues to do with the source of the cells, their ownership and exploitation along with questions about patient recruitment, consent and trial design when they translate to the clinic for therapeutic use. PMID- 23665411 TI - Overcoming therapeutic obstacles in inflammatory bowel diseases: a comprehensive review on novel drug delivery strategies. AB - Inflammatory bowel diseases (IBDs) are a group of debilitating inflammatory complications specially inflicting colonic tissue in which full long term remission with current standardized treatments is yet intangible. Therapeutic side effects and efficacy considerations necessitate the development of more effective systems which lower the required drug doses, reduce systemic adverse effects and deliver the drug specifically to the desired site of action in colon. The large surface area in large intestine is suitable for drug absorption but the primary approaches to treatment depend on the gastrointestinal (GI) condition and its movements. Hereafter, there are novel GI-independent targeted drug delivery systems or therapeutic approaches, including micro- and nanoparticles that have been developed for IBD treatment and have the potential to overcome some of the current drawbacks of conventional IBD therapy. This review provides broad but concise information over the arena of the evolving systems aimed at different targets involved in IBD which are being studied in animal or in vitro models of this complication, while comparing these to conventional treatments. It further discusses important pros and cons of therapeutic approaches against IBD while helping to better understand and evaluate the future impact of novel drug delivery systems on human IBD and assisting in focusing the future research in this topic, on strategies which could provide maximum remission in IBD patients. PMID- 23665412 TI - Statins modulate feedback regulation mechanisms between advanced glycation end products and C-reactive protein: evidence in patients with acute myocardial infarction. AB - OBJECTIVE: High sensitivity C-reactive protein (hsCRP) and advanced glycation end products (AGEs) have been proposed as mediators in inflammation and atherosclerosis. Therefore, we studied the relation between AGE and hsCRP in patients with acute myocardial infarction (AMI). METHODS: Patients with AMI diagnosis and satisfying our inclusion criteria were included during 2009-2011 in an unicentre registry of AMI patients for a cross-sectional study. The final cohort was composed of 156 patients (46.2% STEMI and 27.6% with type-2 diabetes). AGE and hsCRP were measured in plasma. RESULTS: Diabetic patients were older than non-diabetics (68.6 +/- 10.6 vs. 60.4 +/- 13.9 years; p<0.05), presented more incidence of hypertension (62.8 vs. 36.3%; p<0.05) and were in a higher Killip class (p<0.05). The mean values of fluorescent AGE and hsCRP levels were 61.3 +/- 49.8 AU and 2.4 +/- 4.0 mg/L, respectively, and there were no differences in these parameters between diabetic and non-diabetic patients. A direct association between AGE and hsCRP levels was observed, mainly in diabetic patients (r=0.258; p=0.018). Importantly, this association disappeared in patients who had been treated with statins before their AMI (r=-0.055; p=0.845), but it was maintained in non-diabetic patients naive for statins treatment (r=0.634; p<0.001), independently of other treatments and confounding parameters. CONCLUSIONS: This is the first evidence in humans of a feedback regulation mechanism between CRP and the AGE-RAGE axis modulated by statins. PMID- 23665413 TI - A novel manganese complex, Mn-(II) N-(2-hydroxy acetophenone) glycinate overcomes multidrug-resistance in cancer. AB - Multidrug resistance (MDR) remains a significant problem for effective cancer chemotherapy. In spite of considerable advances in drug discovery, most of the cancer cases still stay incurable because of resistance to chemotherapy. We synthesized a novel, Mn (II) complex (chelate), viz., manganese N-(2-hydroxy acetophenone) glycinate (MnNG) that exhibits considerable efficacy to overcome drug resistant cancer. The antiproliferative activity of MnNG was studied on doxorubicin resistant and sensitive human T lymphoblastic leukemia cells (CEM/ADR 5000 and CCRF/CEM). MnNG induced apoptosis significantly in CEM/ADR 5000 cells probably through generation of reactive oxygen species. Moreover, intraperitoneal (i.p.) application of MnNG at non-toxic doses caused significant increase in the life-span of Swiss albino mice bearing sensitive and doxorubicin resistant subline of Ehrlich ascites carcinoma cells. PMID- 23665414 TI - Topographical study of O(6)-alkylguanine DNA alkyltransferase repair activity and N7-methylguanine levels in resected lung tissue. AB - BACKGROUND: Tobacco specific nitrosamines such as 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone (NNK) are genotoxic alkylating agents found within cigarette smoke that induce lung adenocarcinomas in animal models. In humans, adenocarcinomas originate most frequently in the lung periphery. The aim of this study was to determine whether peripheral lung has increased susceptibility to the genotoxic effects of alkylating agents by comparing DNA alkylation damage (N7 methylguanine: N7-meG) and repair (O(6)-alkylguanine DNA alkyltransferase: MGMT) in peripheral relative to central lung tissue. METHODS: Macroscopically normal lung tissue, resected from patients undergoing surgery for lung cancer, was sampled at equidistant points from central to peripheral lung along a bronchus. N7-meG levels were determined using an immunoslotblot technique and MGMT activity with a [32P]-labelled oligodeoxynucleotide cleavage assay. RESULTS: A total of 20 subjects were recruited, 12 males and 8 females with a mean age of 68.7+/ 5.8years. There were 14 former and 6 current smokers with a mean smoking exposure of 34.0+/-18.3packyears. N7-meG (mean 0.75+/-0.57/10(6)dG, n=65 samples from 14 patients) and MGMT repair (geometric mean 9.57+/-1.62fmol/MUg DNA, n=79 samples from 16 patients) were detected in all samples assayed. MGMT activity increased towards the lung periphery (r=0.28, p=0.023; n=16) with a highly significant association in current (r=0.53, p=0.008; n=6) but not former smokers (r=0.13; p=0.41; n=10). No correlation was seen with N7-meG levels and lung position (r= 0.18; p=0.21; n=14). N7-meG levels were higher in current compared to former smokers reaching significance in two lung positions including peripheral lung (p=0.047). CONCLUSIONS: The findings in this study do not support the hypothesis that peripheral tissue is more susceptible to the genotoxic effects of alkylating agents than central lung tissue. In addition exposure to cigarette smoke reduced the level of MGMT in central bronchial tissue possibly through increased alkylating agent exposure. PMID- 23665415 TI - Alterations in hepatic metabolism of sulfur amino acids in non-obese type-2 diabetic Goto-Kakizaki rats. AB - Elevated plasma homocysteine has been identified as a risk factor for cardiovascular disease and non-alcoholic liver disease, which are major complications of diabetes. Hence, hepatic homocysteine metabolism has become a major focus of diabetes research. However, little information is available regarding plasma homocysteine levels in non-obese diabetic animals. Therefore, we investigated the hepatic metabolism of sulfur-amino acids in non-obese type-2 diabetic Goto-Kakizaki rats. The experiments were performed using 9-week-old Goto Kakizaki rats and age-matched Wistar rats. The major finding of this study is that homocysteine levels in the liver and plasma are maintained by a balance between the up-regulation of betaine homocysteine methyltransferase and the inhibition of cystathionine beta-synthase in non-obese type-2 diabetic rats. Hepatic levels of cysteine and its metabolites, such as hypotaurine, taurine, and glutathione, were increased despite inhibition of the transsulfuration of homocysteine to cysteine. The elevated hepatic taurine and glutathione levels may be attributed to the up-regulation of cysteine dioxygenase expression and increased cysteine availability for glutathione synthesis. Inhibition of hepatic methionine adenosyltransferase activity in Goto-Kakizaki rats was associated with a decrease in hepatic S-adenosylmethionine, which serves as an allosteric activator of cystathionine beta-synthase. The non-obese type-2 diabetic condition results in profound changes in hepatic sulfur-amino acid metabolism and raises the possibility that sulfur-amino acid metabolism may be regulated by obesity- as well as diabetes-associated factors. Further study to elucidate the pathological significance of sulfur-amino acid metabolism in chronic liver disease in type-2 diabetic animals is underway in this laboratory. PMID- 23665417 TI - Toxicity of organic and inorganic nanoparticles to four species of white-rot fungi. AB - The rapid development of nanoparticles (NP) for industrial applications and large volume manufacturing, with its subsequent release into the environment, raised the need to understand and characterize the potential effects of NP to biota. Accordingly, this work aimed to assess sublethal effects of five NP to the white rot fungi species Trametes versicolor, Lentinus sajor caju, Pleurotus ostreatus, and Phanerochaete chrysosporium. Each species was exposed to serial dilutions of the following NP: organic-vesicles of SDS/DDAB and of Mo/NaO; gold-NP, quantum dot CdSe/ZnS, and Fe/Co. Fungi growth rate was monitored every day, and at the end of assay the mycelium from each replicate was collected to evaluate possible changes in its chemical composition. For all NP-suspensions the following parameters were characterized: hydrodynamic diameter, surface charge, aggregation index, zeta potential, and conductivity. All tested NP tended to aggregate when suspended in aqueous media. The obtained results showed that gold-NP, CdSe/ZnS, Mo/NaO, and SDS/DDAB significantly inhibited the growth of fungi with effects on the mycelium chemical composition. Among the tested NP, gold-NP and CdSe/ZnS were the ones exerting a higher effect on the four fungi. Finally to our knowledge, this is the first study reporting that different types of NP induce changes in the chemical composition of fungi mycelium. PMID- 23665416 TI - Potential adverse health effects of persistent organic pollutants on sea turtles: evidences from a cross-sectional study on Cape Verde loggerhead sea turtles. AB - The Cape Verde nesting population of loggerhead sea turtles (Caretta caretta) is the third largest population of this species in the world. For conservation purposes, it is essential to determine how these reptiles respond to different types of anthropogenic contaminants. We evaluated the presence of organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and polycyclic aromatic hydrocarbons (PAHs) in the plasma of adult nesting loggerheads from Boa Vista Island, Cape Verde, and studied the effects of the contaminants on the health status of the turtles using hematological and biochemical parameters. All turtles had detectable levels of non-dioxin like PCBs, whereas dioxin-like congeners (DL PCBs) were detected in only 30% of the turtles. Packed cell volume decreased with higher concentrations of PCBs, which suggests that PCB exposure could result in anemia in sea turtles. In addition, a negative association between some OCPs and white blood cells (WBC) and thrombocyte estimate was noted. The DDT-metabolite, p,p'-DDE was negatively correlated with the Na/K ratio and, additionally, a number of correlations between certain PAHs and electrolyte balances were found, which suggest that exposure to these environmental contaminants could affect the kidneys and salt glands in sea turtles. Additionally, several correlations were observed between these environmental pollutants (OCPs and PAHs) and enzyme activity (GGT, ALT, ALP and amylase) and serum protein levels, pointing to the possibility that these contaminants could induce adverse metabolic effects in sea turtles. Our results indicate that anthropogenic pollutants are present in the Cape Verde loggerhead turtle nesting population and could exert negative effects on several health parameters. Because of the importance of this loggerhead nesting population, protective regulations at national and international levels as well as international action are necessary for assuring the conservation of this population. PMID- 23665418 TI - Developmental reelin expression and time point-specific alterations from lead exposure in zebrafish. AB - Reelin (RELN) is a large glycoprotein that plays critical roles during and after neuronal development. In a previous study utilizing developing zebrafish, the RELN ortholog was in a subset of genes associated with neuronal function that was altered following exposure to 100ppb Pb at 72h post-fertilization (hpf). Although RELN is associated with neurodevelopment and neurological diseases, it represents a previously uncharacterized target for developmental Pb neurotoxicity. To further investigate Pb-induced expression decrease of RELN, a more detailed analysis was done using in situ hybridization and quantitative PCR (qPCR) on developing zebrafish at multiple developmental time points and at different exposure concentrations. Time points included in the analysis were 24, 36, 48, 60, 72 and 96hpf. The four exposure conditions tested were 10, 50 or 100ppb Pb as well as a control. In situ hybridization demonstrated concentrated expression of the gene in the telencephalon and in midbrain, hindbrain and spinal cord. Expression was less spatially restricted early in development but became isolated to specific cell populations in the central nervous system by 48hpf. The telencephalon demonstrated a high degree of expression throughout development. Pb exposure did not affect the observed location of expression at any of the time points tested. However, qPCR analysis demonstrated that reln expression statistically decreased in embryos exposed to the highest concentration compared to controls at 60hpf. No changes in brain morphology as assessed by measuring brain length and no significant increase in the number of apoptotic cells in the brain were observed at the highest exposure concentration. These data demonstrate that a decrease in reln expression occurs following Pb exposure at a concentration below one that results in changes in brain length or in the number of apoptotic cells in the zebrafish model system during a short window and is likely linked to concurrent developmental processes. PMID- 23665419 TI - Prenatal smoke exposure: effects on infant auditory system and placental gene expression. AB - Prenatal smoke exposure has been shown to change cochlear echo response amplitudes and auditory brainstem response (ABR) wave latencies in newborns. Since gene expression changes are often synchronized in different tissue types, the goal of the present work was to determine the relationships between prenatal smoke exposure induced changes in hearing responses with changes in placental gene expression. Results showed significant cotinine level elevations in mothers who smoked >=10cigarettes/day during their pregnancy compared to no detectable cotinine in nonsmoking mothers. Cochlear echo response amplitudes in the 2-8kHz range and ABR wave latencies, specifically wave V and interpeak interval I-V, were also significantly reduced in newborns of smoking mothers. Functional pathway analysis of upregulated placental genes using the Database for Annotation, Visualization and Integrated Discovery (DAVID) online software showed significant enrichment of terms associated with neurodevelopmental processes including glutamatergic and cholinergic systems and a number of wingless type proteins in the top two tiers with corrected enrichment p-values of <=0.05. Other relevant functional pathways were significant at unadjusted enrichment p-values of 0.001-0.11 and included calcium signaling, neurotransmission/neurological processes and oxidative stress. The neurological process clusters included 7 genes (EML2, OTOR, SLC26A5, TBL1X, TECTA, USH1C and USH1G) known to modulate cochlear outer hair cell motility. We localized proteins encoded by the top two regulated genes, TBL1X and USH1C, using immunohistochemistry to placental stem and anchoring villi associated with active contractile function. These placental genes may mediate active contraction and relaxation in the placental villi, for example, during maternal-fetal perfusion matching, similar to the active lengthening and shortening of the cochlear outer hair cells during sensory transduction. Thus, the functional consequence of their alteration in the cochlea would be reflected as a decline in cochlear echoes as shown in this study. Such parallel changes suggest the potential utility of placental gene expression as a surrogate for evaluating changes in the developing cochlea related to potential aberrant cochlear function in newborns with prenatal smoke exposure. PMID- 23665420 TI - Ultrabright fluorescent mesoporous silica nanoparticles for prescreening of cervical cancer. AB - We report on the first functional use of recently introduced ultrabright fluorescent mesoporous silica nanoparticles, which are functionalized with folic acid, to distinguish cancerous and precancerous cervical epithelial cells from normal cells. The high brightness of the particles is advantageous for fast and reliable identification of both precancerous and cancerous cells. Normal and cancer cells were isolated from three healthy women and three cancer patients. Three precancerous cell lines were derived by immortalization of primary cultures of normal cells with human papillomavirus type-16 (HPV-16) DNA. We observed substantially different particle internalization by normal and cancerous/precancerous cells after a short incubation time of 15 minutes. Compared to HPV-DNA and cell pathology tests, which are currently used for prescreening of cervical cancer, we demonstrated that the specificity of our method was similar (94-95%), whereas its sensitivity was significantly better (95 97%) than the sensitivity of those currently used tests (30-80%). FROM THE CLINICAL EDITOR: This team of investigators reports on the development of a new screening test for cervical cancer using ultrabright fluorescent mesoporous silica nanoparticles functionalized with folic acid, enabling significantly better sensitivity (95-97% vs. 30-80%) and maintained specificity (94-95%) compared with current clinical tests. This test should find a way to clinical use in the near future. PMID- 23665421 TI - Regulation of the osteogenesis of pre-osteoblasts by spatial arrangement of electrospun nanofibers in two- and three-dimensional environments. AB - Orientation of extracellular matrix (ECM) fibrils contributes to the anisotropy of bones, but little is known about how fibril orientation induces osteoblastic responses. Here, biomimetic polycaprolactone/type I collagen (PCL/COL-1) nanofibers with aligned and random fiber arrangements were used as models to study their effects on pre-osteoblasts. Elongated cell morphology, accelerated cell migration, elevated alkaline phosphatase activity and calcium content, up regulated expression of osteogenic markers and differential expression of integrins were observed for cells cultured on two-dimensional (2D) aligned nanofibers. To emulate in vivo tissue structure, three-dimensional (3D) cell/nanofiber constructs with cells embedded among nanofiber layers were built via layer-by-layer assembly. These showed that aligned nanofibers in the 3D constructs continuously induced cell polarization and promoted osteogenesis. These findings revealed that nanofiber alignment favored osteogenic differentiation of pre-osteoblasts, and demonstrated the potential of 3D cell/nanofiber construct as a model to study specific cell-material interactions in a physiologically relevant environment. FROM THE CLINICAL EDITOR: In this novel study, biomimetic polycaprolactone/type I collagen nanofibers with aligned and random fiber arrangements were used to demonstrate their effects on pre osteoblasts with an overall goal of improved orientation of extracellular matrix fibrils to optimize osteoblastic responses and improve osteogenesis for future therapeutic exploitation. PMID- 23665422 TI - Hypermethylations of RASAL1 and KLOTHO is associated with renal dysfunction in a Chinese population environmentally exposed to cadmium. AB - Exposure to cadmium (Cd) can affect both DNA methylation and renal function, but there are few examples of the association between epigenetic markers and Cd induced kidney damage. It has been suggested that hypermethylation of the genes RASAL1 and KLOTHO is associated with renal fibrogenesis. To investigate whether hypermethylation of RASAL1 and KLOTHO in peripheral blood DNA can be associated with Cd exposure and/or Cd-induced renal dysfunction, the degrees of methylation of RASAL1 and KLOTHO in peripheral blood DNA from 81 residents in Cd-polluted and non-polluted areas were measured using bisulfate-PCR-pyrosequencing. Changes in blood cadmium (BCd), urinary cadmium (UCd), and kidney parameters were measured, and the glomerular filtration rate (eGFR) was estimated. The levels of BCd and UCd correlated positively with the levels of DNA methylation in RASAL1 and in KLOTHO. The more heavily exposed residents (BCd, 4.23-13.22MUg/L; UCd, 8.65 32.90MUg/g creatinine) exhibited obvious renal dysfunction. Notably, when Cd concentration in blood and urine was adjusted, the increased methylation level in RASAL1 was inversely correlated with eGFR (P<0.01) but the relationship between hypermethylation of KLOTHO and eGFR was not statistically significant. The methylation of RASAL1 increased along with the increased abnormal prevalence of eGFR. Our findings suggest that Cd exposure can induce the hypermethylation of RASAL1 and KLOTHO. Hypermethylation of RASAL1 may be an indicator of the progress for chronic kidney disease. PMID- 23665423 TI - Anti-inflammatory and anti-oxidant activities of olmesartan medoxomil ameliorate experimental colitis in rats. AB - Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) driven through altered immune responses with production of proinflammatory cytokines. Many therapies are used, but side effects and loss of response limit long-term effectiveness. New therapeutic strategies are thus needed for patients who don't respond to current treatments. Recently, there is suggested involvement of the proinflammatory hormone angiotensin II in inflammatory bowel disease. The aim of this study was to investigate the possible role of olmesartan medoxomil (OLM-M), an angiotensin II receptor blocker in ameliorating ulcerative colitis. Colitis was induced in male Wistar rats by administration of 5% dextran sodium sulphate (DSS) in drinking water for 5days. OLM-M (1, 3 and 10mg/kg) was administered orally during 21days prior to the induction of colitis, and for 5days after. Sulfasalazine (500mg/kg) was used as reference drug. All animals were tested for changes in colon length, disease activity index (DAI) and microscopic damage. Colon tissue concentration/activity of tumor necrosis alpha (TNF-alpha), myeloperoxidase (MPO), prostaglandin E2 (PGE2), reduced glutathione (GSH) and malondialdehyde (MDA) were assessed. Results showed that the OLM-M dose dependently ameliorated the colonic histopathological and biochemical injuries, an effect that is comparable or even better than that of the standard sulfasalazine. These results suggest that olmesartan medoxomil may be effective in the treatment of UC through its anti-inflammatory and antioxidant effects. PMID- 23665424 TI - An in vitro investigation of endocrine disrupting effects of the mycotoxin alternariol. AB - Alternariol (AOH) is a mycotoxin commonly produced by Alternaria alternata on a wide range of foods. Few studies to date have been performed to evaluate the effects of AOH on endocrine activity. The present study makes use of in vitro mammalian cellular based assays and gene expression to investigate the ability of AOH to act as an endocrine disruptor by various modes of action. Reporter gene assays (RGAs), incorporating natural steroid hormone receptors for oestrogens, androgens, progestagens and glucocorticoids were used to identify endocrine disruption at the level of nuclear receptor transcriptional activity, and the H295R steroidogenesis assay was used to assess endocrine disruption at the level of gene expression and steroid hormone production. AOH exhibited a weak oestrogenic response when tested in the oestrogen responsive RGA and binding of progesterone to the progestagen receptor was shown to be synergistically increased in the presence of AOH. H295R cells when exposed to 0.1-1000ng/ml AOH, did not cause a significant change in testosterone and cortisol hormones but exposure to 1000ng/ml (3.87MUM) AOH resulted in a significant increase in estradiol and progesterone production. In the gene expression study following exposure to 1000ng/ml (3.87MUM) AOH, only one gene NR0B1 was down-regulated, whereas expression of mRNA for CYP1A1, MC2R, HSD3B2, CYP17, CYP21, CYP11B2 and CYP19 was up-regulated. Expression of the other genes investigated did not change significantly. In conclusion AOH is a weak oestrogenic mycotoxin that also has the ability to interfere with the steroidogenesis pathway. PMID- 23665425 TI - Wnt signaling: role in LTP, neural networks and memory. AB - Wnt components are key regulators of a variety of developmental processes, including embryonic patterning, cell specification, and cell polarity. The Wnt signaling pathway participates in the development of the central nervous system and growing evidence indicates that Wnts also regulates the function of the adult nervous system. In fact, most of the key components including Wnts and Frizzled receptors are expressed in the adult brain. Wnt ligands have been implicated in the regulation of synaptic assembly as well as in neurotransmission and synaptic plasticity. Deregulation of Wnt signaling has been associated with several pathologies, and more recently has been related to neurodegenerative diseases and to mental and mood disorders. In this review, we focus our attention on the Wnt signaling cascade in postnatal life and we review in detail the presence of Wnt signaling components in pre- and postsynaptic regions. Due to the important role of Wnt proteins in wiring neural circuits, we discuss recent findings about the role of Wnt pathways both in basal spontaneous activities as well as in activity dependent processes that underlie synaptic plasticity. Finally, we review the role of Wnt in vivo and we finish with the most recent data in literature that involves the effect of components of the Wnt signaling pathway in neurological and mental disorders, including a special emphasis on in vivo studies that relate behavioral abnormalities to deficiencies in Wnt signaling, as well as the data that support a neuroprotective role of Wnt proteins in relation to the pathogenesis of Alzheimer's disease. PMID- 23665426 TI - Oral administration of d-limonene controls inflammation in rat colitis and displays anti-inflammatory properties as diet supplementation in humans. AB - AIMS: To further explore the anti-inflammatory properties of d-Limonene. MAIN METHODS: A rat model was used to compare evolution of TNBS (2,5,6-trinitrobenzene sulfonic acid)-induced colitis after oral feeding with d-Limonene compared to ibuprofen. Peripheral levels of TNF-alpha (Tumor Necrosis Factor alpha) were assessed in all animals. Cell cultures of fibroblasts and enterocytes were used to test the effect of d-Limonene respectively on TNFalpha-induced NF-kappaB (nuclear factor-kappa B) translocation and epithelial resistance. Finally, plasmatic inflammatory markers were examined in an observational study of diet supplementation with d-Limonene-containing orange peel extract (OPE) in humans. KEY FINDINGS: Administered per os at a dose of 10mg/kg p.o., d-Limonene induced a significant reduction of intestinal inflammatory scores, comparable to that induced by ibuprofen. Moreover, d-Limonene-fed rats had significantly lowered serum concentrations of TNF-alpha compared to untreated TNBS-colitis rats. The anti-inflammatory effect of d-Limonene also involved inhibition of TNFalpha induced NF-kappaB translocation in fibroblast cultures. The application of d Limonene on colonic HT-29/B6 cell monolayers increased epithelial resistance. Finally, inflammatory markers, especially peripheral IL-6, markedly decreased upon OPE supplementation of elderly healthy subjects submitted or not to 56 days of dietary supplementation with OPE. SIGNIFICANCE: In conclusion, d-Limonene indeed demonstrates significant anti-inflammatory effects both in vivo and in vitro. Protective effects on the epithelial barrier and decreased cytokines are involved, suggesting a beneficial role of d-Limonene as diet supplement in reducing inflammation. PMID- 23665428 TI - A role for spermine oxidase as a mediator of reactive oxygen species production in HIV-Tat-induced neuronal toxicity. AB - Chronic oxidative stress, which occurs in brain tissues of HIV-infected patients, is involved in the pathogenesis of HIV-associated dementia. Oxidative stress can be induced by HIV-1-secreted proteins, either directly or indirectly through the release of cytotoxic factors. In particular, HIV-1 Tat is able to induce neuronal death by interacting with and activating the polyamine-sensitive subtype of the NMDA receptor (NMDAR). Here, we focused on the role of polyamine catabolism in Tat-induced oxidative stress in human neuroblastoma (SH-SY5Y) cells. First, Tat was found to induce reactive oxygen species production and to affect cell viability in SH-SY5Y cells, these effects being mediated by spermine oxidase (SMO). Second, Tat was observed to increase SMO activity as well as decreasing the intracellular spermine levels. Third, Tat-induced SMO activation was completely prevented by the NMDAR antagonist MK-801, clearly indicating an involvement of NMDAR stimulation. Finally, pretreatment of cells with N acetylcysteine, a scavenger of H2O2, and with MK-801 was able to completely inhibit reactive oxygen species formation and to restore cell viability. Altogether, these data strongly suggest a role for polyamine catabolism-derived H2O2 in neurotoxicity as elicited by Tat-stimulated NMDAR. PMID- 23665429 TI - Reverse correlation reveals how observers sample visual information when estimating three-dimensional shape. AB - Human observers exhibit large systematic distance-dependent biases when estimating the three-dimensional (3D) shape of objects defined by binocular image disparities. This has led some to question the utility of disparity as a cue to 3D shape and whether accurate estimation of 3D shape is at all possible. Others have argued that accurate perception is possible, but only with large continuous perspective transformations of an object. Using a stimulus that is known to elicit large distance-dependent perceptual bias (random dot stereograms of elliptical cylinders) we show that contrary to these findings the simple adoption of a more naturalistic viewing angle completely eliminates this bias. Using behavioural psychophysics, coupled with a novel surface-based reverse correlation methodology, we show that it is binocular edge and contour information that allows for accurate and precise perception and that observers actively exploit and sample this information when it is available. PMID- 23665427 TI - Translocation of iron from lysosomes to mitochondria during ischemia predisposes to injury after reperfusion in rat hepatocytes. AB - The mitochondrial permeability transition (MPT) initiated by reactive oxygen species (ROS) plays an essential role in ischemia-reperfusion (IR) injury. Iron is a critical catalyst for ROS formation, and intracellular chelatable iron promotes oxidative injury-induced and MPT-dependent cell death in hepatocytes. Accordingly, our aim was to investigate the role of chelatable iron in IR-induced ROS generation, MPT formation, and cell death in primary rat hepatocytes. To simulate IR, overnight-cultured hepatocytes were incubated anoxically at pH 6.2 for 4h and reoxygenated at pH 7.4. Chelatable Fe(2+), ROS, and mitochondrial membrane potential were monitored by confocal fluorescence microscopy of calcein, chloromethyldichlorofluorescein, and tetramethylrhodamine methyl ester, respectively. Cell killing was assessed by propidium iodide fluorimetry. Ischemia caused progressive quenching of cytosolic calcein by more than 90%, signifying increased chelatable Fe(2+). Desferal and starch-desferal 1h before ischemia suppressed calcein quenching. Ischemia also induced quenching and dequenching of calcein loaded into mitochondria and lysosomes, respectively. Desferal, starch desferal, and the inhibitor of the mitochondrial Ca(2+) uniporter (MCU), Ru360, suppressed mitochondrial calcein quenching during ischemia. Desferal, starch desferal, and Ru360 before ischemia also decreased mitochondrial ROS formation, MPT opening, and cell killing after reperfusion. These results indicate that lysosomes release chelatable Fe(2+) during ischemia, which is taken up into mitochondria by MCU. Increased mitochondrial iron then predisposes to ROS dependent MPT opening and cell killing after reperfusion. PMID- 23665430 TI - The validation of a scale to measure cognitive development in Chinese preschool children. AB - The present study aimed to evaluate the reliability and validity of the cognitive sub-test of the Preschool Developmental Assessment Scale (PDAS) for Hong Kong Chinese children. Participants included 378 children (189 boys and 189 girls) aged 3-6 years old, with 324 children with typical development and 54 children with developmental disabilities. They were administered the cognitive sub-test of the PDAS and the Wechsler Preschool and Primary Scale of Intelligence - Revised (WPPSI-R). The PDAS cognitive sub-test total scores correlated positively with the WPPSI-R scores. It could differentiate children from different age groups, with younger children attaining significantly lower scores than older children. The sub-test could also differentiate children with typical development from those with developmental disabilities, with the latter attaining significantly lower scores. The sensitivity and specificity were around 80%. Internal consistency (KR-20) was .93 and test-retest reliability was .81. The cognitive sub-test of the PDAS was found to be a promising screening tool for the identification of preschool children with developmental disabilities. PMID- 23665432 TI - Disseminated pediatric herpes zoster. PMID- 23665431 TI - ADHD among adolescents with intellectual disabilities: pre-pathway influences. AB - Children and adolescents with intellectual disabilities (ID) are at heightened risk for developing ADHD. However, the validity of ADHD as a diagnosis for youth with ID remains controversial. To advance research on validity, the present study examined the hypothesized precursors to ADHD in typically developing adolescents (TD) and adolescents with ID, specifically with regard to family history of ADHD, molecular genetics, and neuropsychological functioning. Results indicated that youth ADHD symptoms were related to parental ADHD symptoms regardless of the adolescent's cognitive functioning. Additionally, findings suggested that the DRD4 genetic variant and adolescent set-shifting abilities were related to adolescent ADHD symptoms independent of cognitive functioning. This study provides an initial investigation of the biological correlates of ADHD among youth with ID. PMID- 23665433 TI - Varicella complicated by rhabdomyolysis. PMID- 23665434 TI - Health-related quality of life, patient satisfaction, and adherence to treatment in patients with moderate or severe atopic dermatitis on maintenance therapy: the CONDA-SAT study. AB - OBJECTIVE: To evaluate health-related quality of life (HRQOL), patient satisfaction, and adherence to treatment in patients with moderate or severe atopic dermatitis on maintenance therapy. MATERIAL AND METHODS: We performed a national, multicenter, cross-sectional, epidemiological study in adults and children with moderate or severe atopic dermatitis of at least 16 months' duration who were receiving maintenance therapy. We used the Dermatology Life Quality Index (DLQI), the children's version of this scale (cDLQI), and the Morisky medication adherence scale. Visual analog scales were used to measure treatment satisfaction. We used the Mann-Whitney U test to compare HRQOL between patients with moderate and severe disease and the Wilcoxon test to compare the frequency and duration of flares before and after the start of maintenance therapy. RESULTS: We studied 141 children and 141 adults; the prevalence of moderate AD in these groups was 85.8% and 79.4%, respectively. The impact of AD on HRQOL was mild to moderate. Maintenance therapy led to a significant decrease in the frequency and duration of flares (P < .001). While treatment satisfaction was high in both groups, adherence was poor (18.4%-42.6% in children and 14.9% 27.0% in adults). CONCLUSIONS: Patients with moderate and severe AD receiving maintenance therapy experience a reduction in the number and duration of flares and an improvement in HRQOL. While treatment satisfaction is high, adherence rates could be improved. PMID- 23665435 TI - Reference centers for epidermolysis bullosa and ichthyosis: an urgent need in Spain. PMID- 23665436 TI - Rituximab in dermatology. AB - Rituximab was introduced into clinical practice as a medication with considerable potential. Its use in patients with B-cell lymphoma and rheumatoid arthritis revealed numerous indications in autoimmune diseases, many of which involve the skin, thus requiring dermatologists to become familiar with both the characteristics of anti-CD20 antibodies and the role of B cells in multiple skin diseases. Thanks to these developments, we will be able to use rituximab more frequently and appropriately in our patients and draw up consensus guidelines based on large case series. In other words, establishing the indications for rituximab will make it possible to shorten disease course and reduce morbidity due to more specific drugs. PMID- 23665437 TI - Nodular lesion on a woman's earlobe. PMID- 23665438 TI - Dysregulated expression of T cell immunoglobulin and mucin domain 3 is associated with the disease severity and the outcome of patients with spontaneous intracerebral hemorrhage. AB - OBJECTIVES: We aimed to investigate the expression of T cell immunoglobulin and mucin domain 3 (Tim-3) on peripheral blood cells in spontaneous intracerebral hemorrhage (ICH) patients and to analyze its clinical significance. DESIGN AND METHODS: Tim-3 expression on peripheral immunocytes from ICH patients and healthy volunteers was measured by flow cytometry. The correlation between Tim-3 expression and the clinical indices was estimated using linear regression. RESULTS: Tim-3 expressions on peripheral CD3+ T cells and CD8+ T cells in ICH patients are significantly downregulated, while Tim-3 expressions on CD14+ monocytes and CD16+CD56+ NK cells are increased. Furthermore, Tim-3 expression on peripheral CD8+ cells was negatively correlated with the inflammatory response, the disease severity and the outcome of ICH patients. However, there was no relationship between Tim-3 expression and blood glucose concentration. CONCLUSIONS: Altered expression of Tim-3 might play an important role in the pathogenesis of ICH, demonstrating that Tim-3 might be a novel candidate molecule for prognosis evaluation of ICH patients. PMID- 23665439 TI - Development of test strips for rapid buprenorphine detection in vitro. AB - OBJECTIVES: Buprenorphine (BUP) is the primary treatment for narcotic addiction, but it is often abused by opioid-dependent patients in many countries. For timely and effective detection and controlling the amount of BUP used in therapy, a rapid and sensitive test is needed. In the present study, we describe the development of test strips using monoclonal antibodies (MAbs) for the detection of BUP. DESIGN AND METHODS: The MAbs were generated from hybridomas, and purified MAbs were used to create colloidal gold-antibody conjugates that were placed in the test strips. RESULTS: The BUP test strips had a limit of detection (LOD) of 12.5 ng/mL and did not cross-react with other drugs tested at physiological levels. CONCLUSIONS: Therefore, this assay has sufficient sensitivity and specificity for BUP detection in urine specimens so that the dosage of BUP given to individuals being treated for opioid dependence can be monitored. PMID- 23665440 TI - SNAP-Ed Steps to Health inspires third graders to eat smart and move more. PMID- 23665441 TI - Androgen (dihydrotestosterone)-mediated regulation of food intake and obesity in female mice. AB - To better understand how elevated androgen levels regulate food intake and obesity in females, we treated ovariectomized female mice with dihydrotestosterone (DHT) (non-aromatazable androgen), measured food intake and body weight, and evaluated physiological changes in liver function, glucose tolerance, and leptin resistance. Ovariectomized mice were treated with DHT or placebo. Mice were then fed a high fat diet under free-feeding or pair-feeding conditions for 3 months. We found that when DHT-treated ovariectomized mice had free access to food (free-feeding), they had increased food intake and higher body weight compared with control animals. These mice also had a significantly greater accumulation of fat in the liver and exhibited increased fasting glucose, impaired glucose tolerance, and resistance to leptin. However, when these mice were placed on a restricted diet and fed the same caloric amounts as controls (pair-feeding), their body weight increased at the same rate as control animals. This suggests that androgen regulates food intake through altered leptin sensitivity, and this increase of food intake could significantly contribute to an obesity phenotype. In summary, we demonstrated a role for androgen in the regulation of food intake and weight gain in females using a mouse model. This model will be useful to further elucidate the role of elevated androgen in females. PMID- 23665442 TI - Nonmuscle myosin II-B (myh10) expression analysis during zebrafish embryonic development. AB - Nonmuscle myosin II (NM II) is the name given to the multi-subunit protein product of three genes (myh9, myh10, and myh14) encoding different nonmuscle myosin heavy chains. The three NM II isoforms share a very similar molecular structure and play important roles in a variety of fundamental biological processes. NM II-B (myh10) has been shown to be essential for the formation of mouse neural system and heart. But so far the complete knowledge for its expression in developing zebrafish embryos is lacking. In current study, we proved the conservation of zebrafish NM II-B in vertebrate evolution by in silicon analysis. Afterwards the NM II-B (myh10) expression was demonstrated to initiate after gastrulation stage. At 20 hpf, the expression is mainly restricted in central nervous system (CNS). It was maintained and expanded to sensor organ including eye, otic vesicle, and olfactory bulb at 36 hpf and later. We also detected myh10 mRNA hybridization signal in 48 hpf zebrafish heart. In addition, we investigated myh9a and myh9b mRNA distribution in zebrafish developing embryos. It was shown that myh10 and myh9 have distinct expression pattern, with myh9s not in neural system but in epidermis, enveloping layer (EVL). Our study provides new insight into the NM II expression and the use of this model organism to tackle future studies on the role of NM II in embryo development. PMID- 23665443 TI - Spatiotemporal expression of Notch receptors and ligands in developing mouse placenta. AB - Notch signaling is involved in cell lineage specification in many developing organs. In mice there are four known Notch receptor genes (Notch1-4) and five ligands genes (Dll1, 3, 4 and Jagged1 and 2). Notch2 is essential for development of placenta, an organ that mediates feto-maternal nutrient and gas exchange as well as maternal adaptations to pregnancy. However the role of other Notch receptors and ligands in placentation is not known. In order to gain better insight into the role of Notch signaling in mouse placenta we thoroughly analyzed mRNA expression of all Notch receptors and ligands in all trophoblast cell types from the embryonic day (E) 7.5 to E12.5, the period during which all of the substructures of the placenta develop. Here we show that Notch receptors and ligands are specifically and dynamically expressed in multiple cell layers of developing placenta. We found that the Notch2 receptor and Jagged1 and Jagged2 ligand genes are complementarily expressed in trophoblast cells of the chorion and its later derivatives in the labyrinth. Dll4 and Notch2 expression complement each other in the ectoplacental cone, while Dll1 and Notch2 are expressed in an ectoplacental cone derivative, the junctional zone. Moreover Dll4 and Notch2 are expressed at the ectoplacental cone-decidua interface at early stages of placentation. Additionally we show that Notch2 is dynamically expressed in all trophoblast giant cell subtypes, which is consistent with previous reports. Overall these expression pattern results suggest that Notch signaling may play several diverse roles during placenta development. PMID- 23665444 TI - Expression of the murine transcription factor SOX3 during embryonic and adult neurogenesis. AB - Previous studies have shown that Sox3 is expressed in nascent neuroprogenitor cells and is functionally required in mammals for development of the dorsal telencephalon and hypothalamus. However, Sox3 expression during embryonic and adult neurogenesis has not been examined in detail. Using a SOX3-specific antibody, we show that murine SOX3 expression is maintained throughout telencephalic neurogenesis and is restricted to progenitor cells with neuroepithelial and radial glial morphologies. We also demonstrate that SOX3 is expressed within the adult neurogenic regions and is coexpressed extensively with the neural stem cell marker SOX2 indicating that it is a lifelong marker of neuroprogenitor cells. In contrast to the telencephalon, Sox3 expression within the developing hypothalamus is upregulated in developing neurons and is maintained in a subset of differentiated hypothalamic cells through to adulthood. Together, these data show that Sox3 regulation is region-specific, consistent with it playing distinct biological roles in the dorsal telencephalon and hypothalamus. PMID- 23665445 TI - Identification of aggregation breakers for bevacizumab (Avastin(r)) self association through similarity searching and interaction studies. AB - Aggregation is a common challenge in the optimization of therapeutic antibody formulations. Since initial self-association of two monomers is typically a reversible process, the aim of this study is to identify different excipients that are able to shift this equilibrium to the monomeric state. The hypothesis is that a specific interaction between excipient and antibody may hinder two monomers from approaching each other, based on previous work in which dexamethasone phosphate showed the ability to partially reverse formed aggregates of the monoclonal IgG1 antibody bevacizumab back into monomers. The current study focuses on the selection of therapeutically inactive compounds with similar properties. Adenosine monophosphate, adenosine triphosphate, sucrose-6-phosphate and guanosine monophosphate were selected in silico through similarity searching and docking. All four compounds were predicted to bind to a protein-protein interaction hotspot on the Fc region of bevacizumab and thereby breaking dimer formation. The predictions were supported in vitro: An interaction between AMP and bevacizumab with a dissociation constant of 9.59+/-0.15 mM was observed by microscale thermophoresis. The stability of the antibody at elevated temperature (40 degrees C) in a 51 mM phosphate buffer pH 7 was investigated in presence and absence of the excipients. Quantification of the different aggregation species by asymmetrical flow field-flow fractionation and size exclusion chromatography demonstrates that all four excipients are able to partially overcome the initial self-association of bevacizumab monomers. PMID- 23665446 TI - Osmotic pressure driven protein release from viscous liquid, hydrophobic polymers based on 5-ethylene ketal epsilon-caprolactone: potential and mechanism. AB - In this study, the potential of low molecular weight, viscous liquid polymers based on 5-ethylene ketal epsilon-caprolactone for localized delivery of proteins via an osmotic pressure release mechanism was investigated. Furthermore, the osmotic release mechanism from viscous liquid polymers was elucidated. 5-Ethylene ketal epsilon-caprolactone was homopolymerized or copolymerized with D,L-lactide (DLLA) by ring-opening polymerization. Polymer hydrophobicity was adjusted by choice of initiator; hydrophobic polymers were prepared by initiating with octan 1-ol, while more hydrophilic polymers were prepared by initiating with 350 g/mol methoxy poly(ethylene glycol) (PEG). Particles consisting of bovine serum albumin (BSA) as a model protein drug were co-lyophilized with trehalose at 50:50 and 10:90 (w/w) ratios and were mixed into the polymers at 1% and/or 5% (w/w) particle loading. The release and mechanism of release of BSA from the polymers were assessed in vitro. BSA was released in a sustained manner, with a near zero order release profile and with minimal burst effect for 5-80 days depending on the polymer's hydrophilicity; the release was faster from the PEG initiated polymers than from the octan-1-ol initiated polymers. Increasing the particle loading from 1% to 5% (w/w) resulted in a more noticeable burst effect, but did not significantly increase the mass fraction release rate. This release behavior was determined to proceed as follows. Release from the polymer was triggered by the water activity gradient between the surrounding aqueous medium and the saturated solution, which forms when water is absorbed from the surrounding medium to dissolve a given particle. The generated pressure initiates swelling around the particle/polymer interface and creates a superhydrated polymer region through which the solute is transported by convection, at a rate determined by the osmotic pressure generated. PMID- 23665447 TI - Raman spectroscopy and multivariate analysis for the rapid discrimination between native-like and non-native states in freeze-dried protein formulations. AB - This study investigates whether Raman spectroscopy combined with multivariate analysis (MVA) enables a rapid and direct differentiation between two classes of conformational states, i.e., native-like and non-native proteins, in freeze-dried formulations. A data set comprising of 99 spectra, both from native-like and various types of non-native freeze-dried protein formulations, was obtained by freeze-drying lactate dehydrogenase (LDH) as model protein under various conditions. Changes in the secondary structure in the solid freeze-dried proteins were determined through visual interpretation of the blank corrected second derivative amide I band in the ATR-FTIR spectra (further called FTIR spectra) and served as an independent reference to assign class labels. Exploratory analysis and supervised classification, using Principal Components Analysis (PCA) and Partial Least Squares - Linear Discriminant Analysis (PLS-LDA), respectively, revealed that Raman spectroscopy is with 95% accuracy able to correctly discriminate between native-like and non-native states in the tested freeze-dried LDH formulations. Backbone (i.e., amide III) and side chain sensitive spectral regions proved important for making the discrimination between both classes. As discrimination was not influenced by the spectral signals from the tested excipients, there was no need for blank corrections. The Raman model may allow direct and automated analysis of the investigated quality attribute, opening possibilities for a real time and in-line quality indication as a future step. However, the sensitivity of the method should be further investigated and where possible improved. PMID- 23665448 TI - Application of in vitro biopharmaceutical methods in development of immediate release oral dosage forms intended for paediatric patients. AB - Biopharmaceutics is routinely used in the design and development of medicines to generate science based evidence to predict in vivo performance; the application of this knowledge specifically to paediatric medicines development is yet to be explored. The aim of this review is to present the current status of available biopharmaceutical tools and tests including solubility, permeability and dissolution that may be appropriate for use in the development of immediate release oral paediatric medicines. The existing tools used in adults are discussed together with any limitations for their use within paediatric populations. The results of this review highlight several knowledge gaps in current methodologies in paediatric biopharmaceutics. The authors provide recommendations based on existing knowledge to adapt tests to better represent paediatric patient populations and also provide suggestions for future research that may lead to better tools to evaluate paediatric medicines. PMID- 23665449 TI - Cytotoxic activity of extracts from Hypochaeris radicata. AB - Pasture-associated stringhalt is an acquired equine disease characterized by peripheral neuropathy and hyperflexion of the pelvic limbs. The disease occurs most commonly during periods of drought in horses grazing pastures heavily contaminated by Hypochaeris radicata. We hypothesized that stringhalt is caused by neurotoxins elaborated by H. radicata in response to the stress of drought conditions. Supernates were collected from H. radicata that were stressed (or not) by immersion in copper chloride solution, then extracted with ethyl acetate and dried. Dilutions of extracts from stressed (SE) and control, unstressed (UE) plants were incubated with myelinating spinal cord cultures (MSCC) established from fetal Swiss mice, and with spinal ganglion cultures (SGC) and dermal fibroblast cultures derived from neonatal mouse tissues. Cytotoxicity in culture monolayers was evaluated both morphologically by microscopy and by release of lactate dehydrogenase activity into culture supernates. Three different SGC preparations were exposed to a single H. radicata extract and single preparations of fibroblasts and MSCC were exposed to three different extracts. Repin, a plant derived sesquiterpene lactone neurotoxin, was included as a positive control. Significant dose-dependent cytotoxicity was seen within 24 h in all three culture types when incubated with SE or repin. Complete morphologic destruction of culture monolayers was induced by the highest concentrations tested of SE (100 MUg/mL) and repin (30 MUg/mL). Cytotoxic effect of SE was significantly greater than that of UE for all three cell types and was not due to copper contamination of the extract. This study has identified a cytotoxic activity in leaf exudates of H. radicata that was upregulated by the model stressor, copper chloride. PMID- 23665450 TI - Proteinaceous toxins from three species of scorpaeniform fish (lionfish Pterois lunulata, devil stinger Inimicus japonicus and waspfish Hypodytes rubripinnis): close similarity in properties and primary structures to stonefish toxins. AB - The crude toxins from three species of venomous fish (lionfish Pterois lunulata, devil stinger Inimicus japonicus and waspfish Hypodytes rubripinnis) belonging to the order Scorpaeniformes exhibited mouse-lethal, hemolytic, edema-forming and nociceptive activities. In view of the antigenic cross-reactivity with the stonefish toxins, the primary structures of the stonefish toxin-like toxins from the three scorpaeniform fish were determined by cDNA cloning using primers designed from the highly conserved sequences of the stonefish toxins. Based on the data obtained in gel filtration, immunoblotting and cDNA cloning, each toxin was judged to be a 160 kDa heterodimer composed of 80 kDa alpha- and beta subunits. The three scorpaeniform fish toxins contain a B30.2/SPRY domain (~200 amino acid residues) in the C-terminal region of each subunit, as reported for the toxins from two species of lionfish and two species of stonefish. With respect to the amino acid sequence similarity, the scorpaeniform fish toxins are divided into the following two groups: toxins from three species of lionfish and those from devil stinger, two species of stonefish and waspfish. The phylogenetic tree generated also clearly supports the classification of the toxins. PMID- 23665451 TI - Efficient transduction of human hematopoietic repopulating cells with a chimeric HIV1-based vector including SIV capsid. AB - Innate immune factors, such as TRIM5alpha and cyclophilin A (CypA), act as a major restriction factor of retroviral infection among species. When HIV1 infects human cells, HIV1 capsid binds to human CypA to escape from human TRIM5alpha restriction. However, in rhesus cells, the mismatch between HIV1 capsid and rhesus CypA is recognized by rhesus TRIM5alpha to reduce HIV1 infectivity through proteasomal degradation. To circumvent this block, we previously developed a chimeric HIV1 vector (chiHIV) that substituted HIV1 capsid with SIV capsid, and it significantly increased transduction efficiency for nonhuman primate cells. In this study, we evaluated whether the chiHIV vector efficiently transduces human cells, and the transduction efficiency might increase by a CypA inhibitor (cyclosporine) and a proteasome inhibitor (MG132). The chiHIV vector could transduce human CD34+ cells, as efficiently as the HIV1 vector, in vitro and in xenograft mice, even in the mismatch between SIV capsid and human CypA. Cyclosporine decreased transduction efficiency with the HIV1 vector, whereas it slightly increased transduction efficiency with the chiHIV vector in human CD34+ cells. MG132 increased transduction efficiency with both chiHIV and HIV1 vectors in the same manner. However, MG132 was toxic to human CD34+ cells at high concentrations, and both drugs had a small range of effective dosage. These findings demonstrate that both chiHIV and HIV1 vectors have similar transduction efficiency for human hematopoietic repopulating cells, suggesting that the chiHIV vector escapes from TRIM5alpha restriction, which is independent of human CypA. PMID- 23665452 TI - How to perform cardiopulmonary resuscitation: an opportunity for technology development. PMID- 23665453 TI - Travelling waves for a velocity-jump model of cell migration and proliferation. AB - Cell invasion, characterised by moving fronts of cells, is an essential aspect of development, repair and disease. Typically, mathematical models of cell invasion are based on the Fisher-Kolmogorov equation. These traditional parabolic models cannot be used to represent experimental measurements of individual cell velocities within the invading population since they imply that information propagates with infinite speed. To overcome this limitation we study combined cell motility and proliferation based on a velocity-jump process where information propagates with finite speed. The model treats the total population of cells as two interacting subpopulations: a subpopulation of left-moving cells, L(x,t), and a subpopulation of right-moving cells, R(x,t). This leads to a system of hyperbolic partial differential equations that includes a turning rate, Lambda?0, describing the rate at which individuals in the population change direction of movement. We present exact travelling wave solutions of the system of partial differential equations for the special case where Lambda=0 and in the limit that Lambda->infinity. For intermediate turning rates, 00.05). In general, values for sperm characteristics found after thawing at 37 degrees C were better preserved than at 70 degrees C (P<0.05), both in the use of 0.25 mL or 0.50 mL straws, which were similar for semen packaging (P>0.05). The evaluation of the kinematic parameters of sperm motility confirmed these results at values varying from 20% to 30% motile sperm for the samples tha wed at 37 degrees C, and values fewer than 12% motile sperm for samples thawed at 70 degrees C (P<0.05). In conclusion, we recommend the use of a fast freezing curve that reduces the time spent on the cryopreservation of collared peccary semen, which could be packaged both in 0.25 mL or 0.50 mL straws, but the thawing should be conducted at 37 degrees C/1 min. PMID- 23665463 TI - Further evidence of hepatitis B virus genotype I circulation in Northeast India. AB - Hepatitis B virus (HBV) genotypes have known to show a geographical pattern in their distribution and have been used to trace the migration of populations from geographically distant regions. Novel recombinants between HBV genotypes A, G and C referred as genotype I has been recently reported from Eastern India. In our investigation to characterise antiviral resistance mutations, we identified a rare case of HBV genotype I infection in chronic hepatitis B subject. We encountered confounding results of this emerging genotype 'designated as genotype G' in three widely used HBV sequence database for genotype determination. The recombinant fragment of genotype G largely occupies the surface gene sequence of the newly identified genotype I and could hence lead to misclassification of genotype I. Additionally, recombination analysis of the generated sequences in Simplot and jpHMM model showed two different patterns of recombination events. In conclusion, the increasing recognition of genotype I in this population suggests that further studies may reveal uncommon genotypes from other geographically distant regions. Our observation of potential genotype I misclassification despite the use of public HBV sequence database and other recombination analysis tools highlights the need for updating and validating public sequence domains of diagnostic importance. PMID- 23665464 TI - PRP8 intein in cryptic species of Histoplasma capsulatum: evolution and phylogeny. AB - The PRP8 intein is the most widespread intein among the Kingdom Fungi. This genetic element occurs within the prp8 gene, and is transcribed and translated simultaneously with the gene. After translation, the intein excises itself from the Prp8 protein by an autocatalytic splicing reaction, subsequently joining the N and C terminals of the host protein, which retains its functional conformation. Besides the splicing domain, some PRP8 inteins also have a homing endonuclease (HE) domain which, if functional, makes the intein a mobile element capable of becoming fixed in a population. This work aimed to study (1) The occurrence of this intein in Histoplasma capsulatum isolates (n=99) belonging to different cryptic species collected in diverse geographical locations, and (2) The functionality of the endonuclease domains of H. capsulatum PRP8 inteins and their phylogenetic relationship among the cryptic species. Our results suggest that the PRP8 intein is fixed in H. capsulatum populations and that an admixture or a probable ancestral polymorphism of the PRP8 intein sequences is responsible for the apparent paraphyletic pattern of the LAmA clade which, in the intein phylogeny, also encompasses sequences from LAmB isolates. The PRP8 intein sequences clearly separate the different cryptic species, and may serve as an additional molecular typing tool, as previously proposed for other fungi genus, such as Cryptococcus and Paracoccidioides. PMID- 23665465 TI - High phylogeographic structure in sylvatic vectors of Chagas disease of the genus Mepraia (Hemiptera: Reduviidae). AB - The hematophagous Hemiptera of the subfamily Triatominae are a very diverse group with a variety of morphs, behaviors and distributions. They have great epidemiological importance because many of its members are vectors of the protozoan Trypanosoma cruzi, the agent of Chagas disease. Mepraia is a genus of Triatominae endemic to Chile responsible for transmitting T. cruzi in the sylvatic cycle. Mepraia includes three species, M. gajardoi (18 degrees 30'-26 degrees 30' S) M. spinolai (26 degrees 30'-34 degrees 20' S) and the recently described M. parapatrica in intermediate zones (24 degrees 36'-26 degrees 51' S). Using mitochondrial DNA sequences, we inferred historical processes that led to the current structure of populations. Phylogeographic analyses identified three lineages, congruent with current taxonomy, and populations were highly structured. The times to the most recent common ancestor suggest that M. spinolai is the oldest lineage. We discuss the taxonomic and biogeographic implications of our results. PMID- 23665466 TI - Spatial distribution and population genetics of Leishmania infantum genotypes in Sao Paulo State, Brazil, employing multilocus microsatellite typing directly in dog infected tissues. AB - This study investigated the genetic characteristics of Leishmania infantum samples from Sao Paulo (SP) State, Brazil in order to collaborate with information about the possible origins of the parasites, as well as, the introduction and spread of visceral leishmaniasis in this Brazilian State. Multilocus microsatellite typing (MLMT) was performed using a set of 17 microsatellite markers. DNA was extracted from 250 samples collected from dogs diagnosed with visceral leishmaniasis and 112 (45%) were genotyped: 67 from the northwest region (NWSP), and 29 from the southeast region (SESP) of SP. The results were correlated with other 16 samples from Mato Grosso do Sul State (MS) (which borders NWSP). Although, a small portion of samples was genotyped, it was possible to genotype multiple loci using small amounts of Leishmania DNA extracted directly from dog tissues. Despite the fact that MLMT analysis defined 33 different genotypes, a low polymorphism was detected within the parasites studied with 10 polymorphic loci. There are two main genetic clusters circulating in SP with strong genetic differentiation, one (POP-A) is composed by samples from SESP and NWSP and presented a weak signal of geographical substructure. The other, belongs to the same cluster found in the state of MS (POP-B), which was the main one. The majority (93.75%) of MS parasite genotypes belonged to POP-B, with just one sample (6.25%) grouped in POP-A. POP-B also comprised 10.34% of SESP and 26.87% of NWSP samples. Besides one sample from MS, POP-A is composed by 73.13% of NWSP and 89.66% of SESP samples. The MLMT analysis supported the idea of canine visceral leishmaniasis being introduced in the Northwest region of SP State by the traffic of humans and dogs from MS. In the southeast region of SP occurred an introduction of a new L. infantum genetic cluster. Probably the transmission was spread by traffic of infected dogs from other Brazilian regions, or by introduction of imported dogs from other countries. All these data together contributed to the detection of the genetic profile of L. infantum population in SP State. PMID- 23665467 TI - Comparison of diagnostic sensitivity of C-arm CT, DSA and CT in detecting small HCC. AB - BACKGROUND/AIMS: To compare the detection rate of 64-slice CT, digital subtraction angiography (DSA) and C-arm computed tomography (C-arm CT) in small lesions with a diameter <=3.0 cm of hepatocellular carcinoma (HCC). METHODOLOGY: Sixty-six patients with HCC underwent 64-slice CT, DSA, and C-arm CT, and were followed up by lipiodol CT two weeks after transcatheter arterial chemoembolization (TACE). Whose result was used as diagnostic reference. The number of detected lesions with diameter <=3.0 cm in each imaging modality was counted independently by 4 radiologists. RESULTS: A total of 174 lesions out of the 66 patients were confirmed by lipiodol CT, among which 47.7% were detected by 64-slice CT, 82.2% by DSA, and 97.1% by C-arm CT. McNemar test showed the statistical difference in detection rate between each two methods of CT, DSA and C-arm CT (all p<0.0001). All lesions were further classified into 3 groups (group A, B, C) according to the diameter (<=1cm, 1-2cm, 2-3cm), where C-arm CT showed significantly higher diagnostic sensitivity in group A and B. CONCLUSIONS: Compared to 64-slice CT and DSA, C-arm CT has the best sensitivity by detecting small lesions of HCC, and thus may play a guiding role in TACE procedure. PMID- 23665468 TI - Bayesian ARTMAP for regression. AB - Bayesian ARTMAP (BA) is a recently introduced neural architecture which uses a combination of Fuzzy ARTMAP competitive learning and Bayesian learning. Training is generally performed online, in a single-epoch. During training, BA creates input data clusters as Gaussian categories, and also infers the conditional probabilities between input patterns and categories, and between categories and classes. During prediction, BA uses Bayesian posterior probability estimation. So far, BA was used only for classification. The goal of this paper is to analyze the efficiency of BA for regression problems. Our contributions are: (i) we generalize the BA algorithm using the clustering functionality of both ART modules, and name it BA for Regression (BAR); (ii) we prove that BAR is a universal approximator with the best approximation property. In other words, BAR approximates arbitrarily well any continuous function (universal approximation) and, for every given continuous function, there is one in the set of BAR approximators situated at minimum distance (best approximation); (iii) we experimentally compare the online trained BAR with several neural models, on the following standard regression benchmarks: CPU Computer Hardware, Boston Housing, Wisconsin Breast Cancer, and Communities and Crime. Our results show that BAR is an appropriate tool for regression tasks, both for theoretical and practical reasons. PMID- 23665469 TI - Homocysteine is a novel risk factor for suboptimal response of blood platelets to acetylsalicylic acid in coronary artery disease: a randomized multicenter study. AB - The incomplete inhibition of platelet function by acetylsalicylic acid (ASA), despite the patients are receiving therapeutic doses of the drug ('aspirin resistance'), is caused by numbers of risk factors. In this study we verified the idea that plasma homocysteine (Hcy) contributes to 'aspirin-resistance' in patients with coronary artery disease (CAD) and with or without type 2 diabetes mellitus (T2DM). A cross-designed randomized controlled intervention study has been performed (126 CAD pts incl. 26 with T2DM) to determine whether increasing ASA dose from 75mg to 150mg daily may result in the increased antiplatelet effect, in the course of four-week treatment. Platelet response to collagen (coll) or arachidonic acid (AA) was monitored with whole blood aggregometry, plasma thromboxane (Tx), and Hcy levels were determined immunochemically. The ASA mediated reductions in platelet response to coll (by 12+/-3%) or AA (by 10+/-3%) and in plasma Tx (by 20+/-9%; p<0.02 or less) were significantly greater for higher ASA dose and significantly correlated with plasma Hcy, which was significantly lower in "good" ASA responders compared to "poor" responders (p<0.001). Higher plasma Hcy appeared a significant risk factor for blood platelet refractoriness to low ASA dose (OR=1.11; +/-95%CI: 1.02-1.20, p<0.02, adjusted to age, sex and CAD risk factors). Hcy diminished in vitro antiplatelet effect of low ASA concentration and augmented platelet aggregation (by up to 62% (p<0.005) for coll and up to 15% (p<0.005) for AA), whereas its acetyl derivative acted oppositely. Otherwise, Hcy intensified antiplatelet action of high ASA. Hyperhomocysteinaemia may be a novel risk factor for the suppressed blood platelet response to ASA, and homocysteine may act as a specific sensitizer of blood platelets to some agonists. While homocysteine per se acts as a proaggregatory agent to blood platelets, its acetylated form is able to reverse this effect. Thus, these findings reveal a possibly new challenging potential of the acetylating properties of ASA therapy. PMID- 23665471 TI - Investigation of the association behaviors between bovine serum albumin and 2-(4 methylphenyl)-3-(N-acetyl)-5-(2,4-dichlorophenoxymethyl)-1,3,4-oxodiazoline. AB - The study was designed to examine the interaction between 2-(4-methylphenyl)-3-(N acetyl)-5-(2,4-dichlorophenoxymethyl)-1,3,4-oxodiazoline (MPNDO) and bovine serum albumin (BSA) under physiological conditions by using fluorescence spectroscopy, ultraviolet absorption spectroscopy, FT-IR spectroscopy and circular dichroism spectroscopy and atomic force microscope. Spectroscopic analysis of the fluorescence emission quenching and ultraviolet absorption revealed that the quenching mechanism of bovine serum albumin by MPNDO was static quenching procedure. The binding constant and binding sites number at different temperatures were measured. The average binding distances between donor (BSA) and acceptor (MPNDO) was estimated to be 1.46 nm (301 K), based on the Foster non radioactive energy transfer theory. An average size of 3.1 nm had a high proportion and these dots might be ascribed to BSA, some other dots with an average size of 6.6 nm might result from BSA-MPNDO bioconjugates while the average diameter of MPNDO was 1.6 nm, which was reasonable to conclude that one BSA-MPNDO bioconjugates consisted of one BSA and one MPNDO. The thermodynamic parameters, enthalpy change (DeltaH), entropy change (DeltaS) and free energy change (DeltaG) were calculated, which indicated that the action force was mainly van der Waals forces. The data collected through synchronous fluorescence, FT-IR spectroscopy and circular dichroism spectroscopy demonstrated that the conformation of BSA was not affected obviously in the presence of MPNDO. PMID- 23665470 TI - Cytosolic NADPH homeostasis in glucose-starved procyclic Trypanosoma brucei relies on malic enzyme and the pentose phosphate pathway fed by gluconeogenic flux. AB - All living organisms depend on NADPH production to feed essential biosyntheses and for oxidative stress defense. Protozoan parasites such as the sleeping sickness pathogen Trypanosoma brucei adapt to different host environments, carbon sources, and oxidative stresses during their infectious life cycle. The procyclic stage develops in the midgut of the tsetse insect vector, where they rely on proline as carbon source, although they prefer glucose when grown in rich media. Here, we investigate the flexible and carbon source-dependent use of NADPH synthesis pathways in the cytosol of the procyclic stage. The T. brucei genome encodes two cytosolic NADPH-producing pathways, the pentose phosphate pathway (PPP) and the NADP-dependent malic enzyme (MEc). Reverse genetic blocking of those pathways and a specific inhibitor (dehydroepiandrosterone) of glucose-6 phosphate dehydrogenase together established redundancy with respect to H2O2 stress management and parasite growth. Blocking both pathways resulted in ~10 fold increase of susceptibility to H2O2 stress and cell death. Unexpectedly, the same pathway redundancy was observed in glucose-rich and glucose-depleted conditions, suggesting that gluconeogenesis can feed the PPP to provide NADPH. This was confirmed by (i) a lethal phenotype of RNAi-mediated depletion of glucose-6-phosphate isomerase (PGI) in the glucose-depleted Deltamec/Deltamec null background, (ii) an ~10-fold increase of susceptibility to H2O2 stress observed for the Deltamec/Deltamec/(RNAi)PGI double mutant when compared with the single mutants, and (iii) the (13)C enrichment of glycolytic and PPP intermediates from cells incubated with [U-(13)C]proline, in the absence of glucose. Gluconeogenesis-supported NADPH supply may also be important for nucleotide and glycoconjugate syntheses in the insect host. PMID- 23665472 TI - Real-time in vivo monitoring of circadian E-box enhancer activity: a robust and sensitive zebrafish reporter line for developmental, chemical and neural biology of the circadian clock. AB - The circadian clock co-ordinates physiology and behavior with the day/night cycle. It consists of a transcriptional-translational feedback loop that generates self-sustained oscillations in transcriptional activity with a roughly 24h period via E-box enhancer elements. Numerous in vivo aspects of core clock feedback loop function are still incompletely understood, including its maturation during development, tissue-specific activity and perturbation in disease states. Zebrafish are promising models for biomedical research due to their high regenerative capacity and suitability for in vivo drug screens, and transgenic zebrafish lines are valuable tools to study transcriptional activity in vivo during development. To monitor the activity of the core clock feedback loop in vivo, we created a transgenic zebrafish line expressing a luciferase reporter gene under the regulation of a minimal promoter and four E-boxes. This Tg(4xE-box:Luc) line shows robust oscillating reporter gene expression both under light-dark cycles and upon release into constant darkness. Luciferase activity starts to oscillate during the first days of development, indicating that the core clock loop is already functional at an early stage. To test whether the Tg(4xE-box:Luc) line could be used in drug screens aimed at identifying compounds that target the circadian clock in vivo, we examined drug effects on circadian period. We were readily able to detect period changes as low as 0.7h upon treatment with the period-lengthening drugs lithium chloride and longdaysin in an assay set-up suitable for large-scale screens. Reporter gene mRNA expression is also detected in the adult brain and reveals differential clock activity across the brain, overlapping with endogenous clock gene expression. Notably, core clock activity is strongly correlated with brain regions where neurogenesis takes place and can be detected in several types of neural progenitors. Our results demonstrate that the Tg(4xE-box:Luc) line is an excellent tool for studying the regulation of the circadian clock and its maturation in vivo and in real time. Furthermore, it is highly suitable for in vivo screens targeting the core clock mechanism that take into account the complexity of an intact organism. Finally, it allows mapping of clock activity in the brain of a vertebrate model organism with prominent adult neurogenesis and high regeneration capacity. PMID- 23665473 TI - The G alpha subunit Galpha8 inhibits proliferation, promotes adhesion and regulates cell differentiation. AB - Heterotrimeric G protein-mediated signal transduction plays a pivotal role in both vegetative and developmental stages in the eukaryote Dictyostelium discoideum. Here we describe novel functions of the G protein alpha subunit Galpha8 during vegetative and development stages. Galpha8 is expressed at low levels during vegetative growth. Loss of Galpha8 promotes cell proliferation, whereas excess Galpha8 expression dramatically inhibits growth and induces aberrant cytokinesis on substrates in a Gbeta-dependent manner. Overexpression of Galpha8 also leads to increased cell-cell cohesion and cell-substrate adhesion. We demonstrate that the increased cell-cell cohesion is mainly caused by induced CadA expression, and the induced cell-substrate adhesion is responsible for the cytokinesis defects. However, the expression of several putative constitutively active mutants of Galpha8 does not augment the phenotypes caused by intact Galpha8. Galpha8 is strongly induced after starvation, and loss of Galpha8 results in decreased expression of certain adhesion molecules including CsA and tgrC1. Interestingly, Galpha8 is preferentially distributed in the upper and lower cup of the fruiting body. Lack of Galpha8 decreases the expression of the specific marker of the anterior-like cells, suggesting that Galpha8 is required for anterior-like cell differentiation. PMID- 23665475 TI - A temporal mechanism that produces neuronal diversity in the Drosophila visual center. AB - The brain consists of various types of neurons that are generated from neural stem cells; however, the mechanisms underlying neuronal diversity remain uncertain. A recent study demonstrated that the medulla, the largest component of the Drosophila optic lobe, is a suitable model system for brain development because it shares structural features with the mammalian brain and consists of a moderate number and various types of neurons. The concentric zones in the medulla primordium that are characterized by the expression of four transcription factors, including Homothorax (Hth), Brain-specific homeobox (Bsh), Runt (Run) and Drifter (Drf), correspond to types of medulla neurons. Here, we examine the mechanisms that temporally determine the neuronal types in the medulla primordium. For this purpose, we searched for transcription factors that are transiently expressed in a subset of medulla neuroblasts (NBs, neuronal stem cell like neural precursor cells) and identified five candidates (Hth, Klumpfuss (Klu), Eyeless (Ey), Sloppy paired (Slp) and Dichaete (D)). The results of genetic experiments at least explain the temporal transition of the transcription factor expression in NBs in the order of Ey, Slp and D. Our results also suggest that expression of Hth, Klu and Ey in NBs trigger the production of Hth/Bsh-, Run and Drf-positive neurons, respectively. These results suggest that medulla neuron types are specified in a birth order-dependent manner by the action of temporal transcription factors that are sequentially expressed in NBs. PMID- 23665474 TI - A distant, cis-acting enhancer drives induction of Arf by Tgfbeta in the developing eye. AB - The Arf tumor suppressor represents one of several genes encoded at the Cdkn2a and Cdkn2b loci in the mouse. Beyond its role blunting the growth of incipient cancer cells, the Arf gene also plays an essential role in development: its gene product, p19(Arf), is induced by Tgfbeta2 in the developing eye to dampen proliferative signals from Pdgfrbeta, which effect ultimately fosters the vascular remodeling required for normal vision in the mouse. Mechanisms underlying Arf induction by Tgfbeta2 are not fully understood. Using the chr4(Delta70 kb/Delta70 kb) mouse, we now show that deletion of the coronary artery disease (CAD) risk interval lying upstream of the Cdkn2a/b locus represses developmentally-timed induction of Arf resulting in eye disease mimicking the persistent hyperplastic primary vitreous (PHPV) found in Arf-null mice and in children. Using mouse embryo fibroblasts, we demonstrate that Arf induction by Tgfbeta is blocked in cis to the 70 kb deletion, but Arf induction by activated RAS and cell culture "shock" is not. Finally, we show that Arf induction by Tgfbeta is derailed by preventing RNA polymerase II recruitment following Smad 2/3 binding to the promoter. These findings provide the first evidence that the CAD risk interval, located at a distance from Arf, acts as a cis enhancer of Tgfbeta2-driven induction of Arf during development. PMID- 23665476 TI - Identification of ta-siRNAs and cis-nat-siRNAs in cassava and their roles in response to cassava bacterial blight. AB - Trans-acting small interfering RNAs (ta-siRNAs) and natural cis-antisense siRNAs (cis-nat-siRNAs) are recently discovered small RNAs (sRNAs) involved in post transcriptional gene silencing. ta-siRNAs are transcribed from genomic loci and require processing by microRNAs (miRNAs). cis-nat-siRNAs are derived from antisense RNAs produced by the simultaneous transcription of overlapping antisense genes. Their roles in many plant processes, including pathogen response, are mostly unknown. In this work, we employed a bioinformatic approach to identify ta-siRNAs and cis-nat-siRNAs in cassava from two sRNA libraries, one constructed from healthy cassava plants and one from plants inoculated with the bacterium Xanthomonas axonopodis pv. manihotis (Xam). A total of 54 possible ta siRNA loci were identified in cassava, including a homolog of TAS3, the best studied plant ta-siRNA. Fifteen of these loci were induced, while 39 were repressed in response to Xam infection. In addition, 15 possible cis-natural antisense transcript (cis-NAT) loci producing siRNAs were identified from overlapping antisense regions in the genome, and were found to be differentially expressed upon Xam infection. Roles of sRNAs were predicted by sequence complementarity and our results showed that many sRNAs identified in this work might be directed against various transcription factors. This work represents a significant step toward understanding the roles of sRNAs in the immune response of cassava. PMID- 23665477 TI - Fast and reliable prediction of domain-peptide binding affinity using coarse grained structure models. AB - Domain-peptide recognition and interaction are fundamentally important for eukaryotic signaling and regulatory networks. It is thus essential to quantitatively infer the binding stability and specificity of such interaction based upon large-scale but low-accurate complex structure models which could be readily obtained from sophisticated molecular modeling procedure. In the present study, a new method is described for the fast and reliable prediction of domain peptide binding affinity with coarse-grained structure models. This method is designed to tolerate strong random noises involved in domain-peptide complex structures and uses statistical modeling approach to eliminate systematic bias associated with a group of investigated samples. As a paradigm, this method was employed to model and predict the binding behavior of various peptides to four evolutionarily unrelated peptide-recognition domains (PRDs), i.e. human amph SH3, human nherf PDZ, yeast syh GYF and yeast bmh 14-3-3, and moreover, we explored the molecular mechanism and biological implication underlying the binding of cognate and noncognate peptide ligands to their domain receptors. It is expected that the newly proposed method could be further used to perform genome-wide inference of domain-peptide binding at three-dimensional structure level. PMID- 23665478 TI - Self-assembled magnetic resonance imaging nanoprobes based on arachidyl chitosan for cancer diagnosis. AB - Arachidyl chitosan (chitosan oligosaccharide-arachidic acid; CSOAA)-based self assembled nanoprobes for magnetic resonance imaging (MRI) of neoplastic lesions was developed and evaluated in vitro. Diethylenetriaminepentaacetic dianhydride (DTPA) was conjugated to chitosan oligosaccharide (CSO) and Gd(3+) was chelated to the resulting ligand. DTPA conjugation and Gd(3+) chelation were confirmed primarily by Fourier transform infrared spectroscopy (FT-IR) and zeta potential measurement. A spherical nanoprobe of around 150 nm mean diameter in the tested concentration range was formed in an aqueous environment by simple dissolution. The critical aggregation concentration (CAC) of the CSOAA-based nanoprobe was 3.86 MUg/ml, indicating its stability after dilution in body fluid. The nanoprobe had negligible toxicity in head and neck cancer cell lines (Hep-2 and FaDu cells). The amount of Cy5.5-labeled nanoprobe taken-up by cells, as observed by confocal laser scanning microscopy (CLSM), increased according to incubation time (up to 12h). A phantom study showed a T1-positive contrast-enhancing effect of the developed CSOAA-based nanoprobe, compared to that of the commercial formulation (Gd-DTPA; Magnevist). These results indicate that the CSOAA-based nanoprobe can be used for efficient MR imaging of neoplastic cells. PMID- 23665479 TI - Propolis induced antibacterial activity and other technical properties of cotton textiles. AB - Propolis is a gum gathered by honey bees from various plants; the honey bees use propolis to seal holes in their honey combs, smooth out the internal wall and protect the entrance against intruders. It is composed of 50% resin (flavonoids and related phenolic acid), 30% wax, 10% essential oils, 5% pollen and 5% various organic components. As a natural mixture, propolis is widely used in medicine, cosmetics and food. So far no attempts have been yet made to make use of propolis in the realm of textile finishing. Current work presents the first systemic study targeted to build up a scientific basis for production of cotton textiles having antibacterial activity and other useful properties by making use of propolis as eco-friendly finish within the scope of green strategy. Propolis extract solution (70/30 ethanol/water) of 10% concentration was prepared as the stock. Different amounts of the latter were used along with a crosslinking agent and catalyst for treatment of cotton fabrics as per pad-dry-cure technique. Antibacterial activity of the so treated fabrics was obtained through monitoring the efficiency of the interaction of propolis with cotton cellulose. This interaction was expressed as inhibition zone diameter after the treated fabrics were exposed to (G+ve) and (G ve) bacteria. Other properties include crease recovery, tensile strength and elongation at break. Factors affecting these properties such as type, nature and concentration of the crosslinking agent, concentration of propolis, and conditions of curing were investigated. In addition characterization of the propolis containing modified cotton fabrics including demonstration of the antibacterial activity, SEM, FTIR, durability to washing, UV protection and water repellency were performed. Based on results obtained, it is concluded that application of propolis along with glyoxal and Al2(SO4)3catalyst using pad-dry (3min/80 degrees C), cure (5/140 degrees C) bring about cotton textile with superior antibacterial activity, water repellent and ease of care characteristics as well as UV protection. Tentative mechanism of the reaction of propolis with cotton in the presence of glyoxal was also reported. PMID- 23665480 TI - Comparison of behavioral effects of the NMDA receptor channel blockers memantine and ketamine in rats. AB - Memantine and ketamine block N-methyl-D-aspartate (NMDA) receptors with similar affinity and kinetics, yet their behavioral consequences differ: e.g., memantine is used to alleviate symptoms of Alzheimer's disease, whereas ketamine reproduces symptoms of schizophrenia. The two drugs exhibit different pharmacokinetics, which may play a principal role in their differential behavioral effects. To gain insight into the drugs' behavioral consequences, we treated adult male rats acutely with varying doses (0-40 mg/kg i.p.) of memantine or ketamine and assessed exploratory behavior and spatial working memory. To examine the importance of pharmacokinetics, we assessed behavior either 15 or 45 min after drug administration. Both drugs decreased ambulation, fine movements, and rearing at the beginning of the exploratory activity test; however, at the end of the test, high doses of only memantine increased ambulation and fine movements. High doses of both drugs disrupted spontaneous alternation, a measure of working memory, but high doses of only memantine elicited perseverative behavior. Surprisingly, ketamine's effects were influenced by the delay between drug administration and testing no more frequently than were memantine's. Our findings show that, regardless of test delay, memantine and ketamine evoke similar behavioral effects at lower doses, consistent with NMDA receptors being both drugs' principal site of action, but can have divergent effects at higher doses. Our results suggest that the divergence of memantine's and ketamine's behavioral consequences is likely to result from differences in mechanisms of NMDA receptor antagonism or actions at other targets. PMID- 23665481 TI - The extracellular matrix locally regulates asynchronous concurrent lactation in tammar wallaby (Macropus eugenii). AB - Asynchronous concurrent lactation (ACL) is an extreme lactation strategy in macropod marsupials including the tammar wallaby, that may hold the key to understanding local control of mammary epithelial cell function. Marsupials have a short gestation and a long lactation consisting of three phases; P2A, P2B and P3, representing early, mid and late lactation respectively and characterised by profound changes in milk composition. A lactating tammar is able to concurrently produce phase 2A and 3 milk from adjacent glands in order to feed a young newborn and an older sibling at heel. Physiological effectors of ACL remain unknown and in this study the extracellular matrix (ECM) is investigated for its role in switching mammary phenotypes between phases of tammar wallaby lactation. Using the level of expression of the genes for the phase specific markers tELP, tWAP, and tLLP-B representing phases 2A, 2B and 3 respectively we show for the first time that tammar wallaby mammary epithelial cells (WallMECs) extracted from P2B acquire P3 phenotype when cultured on P3 ECM. Similarly P2A cells acquire P2B phenotype when cultured on P2B ECM. We further demonstrate that changes in phase phenotype correlate with phase-specific changes in ECM composition. This study shows that progressive changes in ECM composition in individual mammary glands provide a local regulatory mechanism for milk protein gene expression thereby enabling the mammary glands to lactate independently. PMID- 23665482 TI - Identification of a Ninein (NIN) mutation in a family with spondyloepimetaphyseal dysplasia with joint laxity (leptodactylic type)-like phenotype. AB - Spondyloepimetaphyseal dysplasia with joint laxity-leptodactylic type (SEMDJL2) is an autosomal dominant skeletal dysplasia which is characterized by midface hypoplasia, short stature, joint laxity with dislocations, genua valga, progressive scoliosis, and slender fingers. Recently, heterozygous missense mutations in KIF22, a gene which encodes a member of the kinesin-like protein family, have been identified in sporadic as well as familial cases of SEMDJL2. In the present study homozygosity mapping and whole-exome sequencing were combined to analyze a consanguineous family with a phenotype resembling SEMDJL2. We identified homozygous missense mutations in the two nearby genes NIN (Ninein) and POLE2 (DNA polymerase epsilon subunit B) which segregate with the disease in the family and were not present in 500 healthy control individuals and in the 1094 control individuals contained within the 1000-genomes database. We present several lines of evidence that mutant Ninein is most likely causative for the SEMDJL2-like phenotype. The centrosomal protein NIN shows a functional relationship with KIF22 and other proteins associated with chromosome congression/movement, centrosomal function, and ciliogenesis, which have been associated with skeletal dysplasias. Moreover, compound heterozygous missense mutations at more N-terminal positions of Ninein have very recently been identified in a family with microcephalic primordial dwarfism. Together with the present report this strongly supports a fundamental role of Ninein in skeletal development. PMID- 23665483 TI - Simple and fast PO-CL method for the evaluation of antioxidant capacity of hydrophilic and hydrophobic antioxidants. AB - A simple and fast procedure is described for evaluating the antioxidant activity of hydrophilic and hydrophobic compounds by using the peroxyoxalate chemiluminescence (PO-CL) reaction of Bis(2,4,6-trichlorophenyl) oxalate (TCPO) with hydrogen peroxide in the presence of di(tert-butyl)2-(tert-butylamino)-5 [(E)-2-phenyl-1-ethenyl]3,4-furandicarboxylate as a highly fluorescent fluorophore. The IC50 values of the well-known antioxidants were calculated and the results were expressed as gallic equivalent antioxidant capacity (GEAC). It was found that the proposed method is free of physical quenching and oxidant interference, for this reason, proposed method is able to determine the accurate scavenging activity of the antioxidants to the free radicals. Finally, the proposed method was applied to the evaluation of antioxidant activity of complex real samples such as soybean oil and sunflower oil (as hydrophobic samples) and honey (as hydrophilic sample). To the best of our knowledge, this is the first time that total antioxidant activity can be determined directly in soybean oil, sunflower oil and honey (not in their extracts) using PO-CL reactions. PMID- 23665484 TI - Strain rate dependent properties of human craniovertebral ligaments. AB - Craniovertebral ligaments were tested to failure under tensile loading. Ligaments tested included: transverse ligament, anterior atlanto occipital membrane, posterior atlanto occipital membrane, capsular ligaments between Skull-C1 and C1 C2, anterior atlantoaxial membrane, posterior atlantoaxial membrane and the tectorial membrane/vertical cruciate/apical/alar ligament complex. The objective of this study was to obtain mechanical properties of craniovertebral ligaments of a younger population, at varying strain rates representative of automotive crash scenarios, and investigate rate and gender effects for use in numerical models of the cervical spine. There have been few studies conducted on the mechanical properties of human craniovertebral ligaments. Only one study has tested all of the ligaments, and previous studies use older age specimens (mean age 67, from most complete study). Further, tests were often not performed at elongation rates representative of car crash scenarios. Previous studies did not perform tests in an environment resembling in vivo conditions, which has been shown to have a significant effect on ligament tensile behaviour. Fifty-four craniovertebral ligaments were isolated from twenty-one spines, and tested to failure in tension under simulated in vivo temperature and hydration levels, at quasi-static (0.5 s( 1)) and high strain rates (150 s(-1)). Values for failure force, failure elongation, stiffness, and toe region elongation were obtained from force displacement curves. Values were analyzed for strain rate and gender effects. Increased strain rate produced several significant effects including: higher failure forces for the transverse ligament and capsular ligament (Skull-C1), lower failure elongation for the tectorial membrane complex, higher stiffness for the tectorial membrane complex and capsular ligament (Skull-C1), and lower toe region elongation for capsular ligament (Skull-C1). Gender effects were limited. Ligament tests demonstrated expected rate effects. Younger specimens had a higher failure force and stiffness and failed at lower elongations than older specimens from previous studies. Gender effects suggest there may be a difference between male and female properties, but require further testing to establish greater significance. PMID- 23665485 TI - Modulation of the nano-tensile mechanical properties of co-blended amphiphilic alginate fibers as oradurable biomaterials for specialized biomedical application. AB - The modulation of the mechanical properties of monolithic fibers by plasticizing and crosslinking enables the dynamic control of the nano-tensile forces, thereby obtaining optimized Young's modulus and ultimate strain for specialized application in the treatment of periodontal disease. In this work, drug-loaded crosslinked and plasticized alginate fibers (cl-PAFs) were prepared by extrusion gelification with the aim of designing oradurable biomaterials for placement within the periodontal pocket and provide prolonged drug delivery. Mechanical properties of drug-free cl-PAFs were determined using a nanoTensileTM 5000 instrument and subsequently optimized versus the quantity of plasticizer and crosslinker as formulation variables employing a Box-Behnken experimental design strategy. Mechanically optimized fibers obtained (Young's Modulus=314.04 MPa, yield stress=5.80 MPa, ultimate strength=10.05 MPa, ultimate strain=0.29 MPa and toughness=2.39 J cm(-3)) were loaded with the model drugs ciprofloxacin and diclofenac both individually and simultaneously. The Young's modulus of cl-PAFs loaded with either drug individually exhibited a steep decline. However, in the case of cl-PAFs loaded with both drugs simultaneously, Young's modulus regained the original value which may be attributed to the cohesive energy density, porosity and space filling. The effect of various formulation variables on the drug entrapment and release characteristics of the alginate fibers was elucidated at pH 4.0 and pH 6.8. Furthermore, a previously established atomistic computational model based on energy refinements was employed to mechanistically describe the fiber performance. The effect of varying the plasticizer and crosslinking ion concentration on Young's modulus and ultimate strain of the linear elastic polymer matrix and the performance of the ciprofloxacin and/or diclofenac loaded optimized fiber was elucidated and conceptualized using molecular mechanics energy relationships (MMER) via the geometrical conformation and positioning of the molecular architectures. PMID- 23665486 TI - Lipidomic characterization of streptozotocin-induced heart mitochondrial dysfunction. AB - Myocardial mitochondria dysfunction seems to represent an important pathogenic factor underlying cardiomyopathy, a common complication of type 1 diabetes mellitus (T1DM). Despite significant progress in the understanding of the molecular mechanisms of mitochondrial function in the heart, the interplay between phospholipids and membrane proteins of this organelle is still poorly comprehended. Using a well-characterized animal model of T1DM obtained by the administration of streptozotocin, phospholipid profiling of isolated mitochondria was performed using MS-based approaches, which was analyzed together with oxidative phosphorylation (OXPHOS) complexes activities and their susceptibility to oxidation, and the expression of cytochrome c, the uncoupling protein UCP-3 and the mitochondrial transcription factor Tfam. Although in higher amounts, mitochondria from T1DM heart presented lower OXPHOS activity and lower transcription ability. This profile was related to phospholipid (PL) remodeling characterized by higher phosphatidylcholine levels, lower phosphatidylglycerol, phosphatidylinositol and sphingomyelin content, higher amounts of long fatty acyl side chains and increased lipid peroxidation, particularly of cardiolipin (CL). CL peroxidation was paralleled by lower cytochrome c content. Though in higher levels, UCP-3 does not seem to protect heart mitochondrial PL and membrane proteins from the oxidative damage induced by four weeks of hyperglycemia. Taken together, our data suggest that PL remodeling of heart mitochondria is an early event in T1DM pathogenesis and is related with OXPHOS dysfunction. PMID- 23665487 TI - Mitochondrial haplotypes may modulate the phenotypic manifestation of the LHON associated m.14484T>C (MT-ND6) mutation in Chinese families. AB - Mitochondrial m.14484T>C (MT-ND6) mutation has been associated with Leber's hereditary optic neuropathy. Previous investigations revealed that the m.14484T>C mutation is a primary factor underlying the development of optic neuropathy but is not sufficient to produce a clinical phenotype. However, mitochondrial haplogroups have been proposed to modulate the phenotypic manifestation of the m.14484T>C mutation. Here, we performed the clinical, genetic evaluation and complete mitochondrial genome sequence analysis of 41 Han Chinese pedigrees carrying the m.14484T>C mutation. These families exhibited a wide range of penetrances and expressivities of optic neuropathy. The average ratio between affected male/female matrilineal relatives from 41 families was 2:1. The penetrance of optic neuropathy in these Chinese pedigrees ranged from 5.6% to 100%, with the average of 23.8%. Furthermore, the age-of-onset for optic neuropathy varied from 4 to 44 years, with the average of 19.3 years. Sequence analysis of their mitochondrial genomes identified distinct sets of polymorphisms belonging to ten Eastern Asian haplogroups, indicating that the m.14484T>C mutation occurred through recurrent origins and founder events. We showed that mitochondrial haplogroups M9, M10 and N9 increased the penetrance of optic neuropathy in these Chinese families. In particular, these mitochondrial haplogroup specific variants: m.3394T>C (MT-ND1), m.14502T>C (MT-ND4) and m.14693A>G (MT-TE) enhanced the penetrance of visual loss in these Chinese families. These data provided the direct evidence that mitochondrial modifiers modulate the variable penetrance and expressivity of optic neuropathy among Chinese pedigrees carrying the m.14484T>C mutation. PMID- 23665488 TI - Inhibitory effects of sulfated 20(S)-ginsenoside Rh2 on the release of pro inflammatory mediators in LPS-induced RAW 264.7 cells. AB - Ginsenoside Rh2 is one of the most important ginsenosides in ginseng with anti inflammatory and antitumor effects. However, the extremely poor oral bioavailability induced by its low water solubility greatly limits the potency of Rh2 in vivo. In the previous study, we sulfated 20(S)-ginsenoside Rh2 with chlorosulfonic acid and pyridine method, and got one novel derivative, Rh2-B1, with higher water solubility and greater immunologic enhancement than Rh2. However, the anti-inflammatory effect of Rh2-B1 remains unclear. We therefore investigated the effects of Rh2-B1 on lipopolysaccharide (LPS)-induced proinflammatory mediators in RAW 264.7 macrophages. We found that Rh2-B1 dramatically inhibited LPS-induced overproduction of nitric oxide, prostaglandin E2, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6. Consistently, the protein and mRNA expression levels of inducible nitric oxide synthase and cyclooxygenase-2 were remarkably decreased by Rh2-B1. In addition, Rh2-B1 significantly suppressed the phosphorylations of p38, c-Jun N-terminal kinase, and extracellular signal receptor-activated kinase 1/2 induced by LPS. Rh2-B1 was further shown to inhibit NF-kappaB p65 translocation into the nucleus by suppressing IkappaBalpha degradation. In conclusion, we demonstrate that Rh2 B1 inhibits the release of LPS-induced pro-inflammatory mediators through blocking mitogen-activated protein kinases and NF-kappaB signaling pathways, suggesting that sulfated ginsenosides could be potential agents for anti inflammatory therapies. PMID- 23665489 TI - Functional evaluation of the receptors mediating vasoconstriction of rat aorta by trace amines and amphetamines. AB - Trace amines including beta-phenylethylamine (beta-PEA) and amphetamines classically exert pharmacological actions via indirect sympathomimetic mechanisms. However, there is evidence for other mechanisms and this study explores the receptors mediating vasoconstriction in rat aorta. beta-PEA, d amphetamine, MDMA, cathinone and methylphenidate caused concentration-dependent contractions of rat isolated aortic rings which were unaffected by prazosin (1 MUM), ICI-118,551 (1 MUM), cocaine (10 MUM) and pargyline (10 MUM), to inhibit alpha1- and beta2-adrenoceptors, neuronal transport and monoamine oxidase (MAO), respectively. Octopamine concentration-response curves, however, were shifted to the right. In the presence of the inhibitors, the rate of onset of octopamine contractions was slowed. Lineweaver-Burk analysis of the kinetics of the response generated different KM values for octopamine in the absence (2.35 * 10(-6)M) and presence (6.09 * 10(-5)M) of inhibitors, indicating mediation by different receptors. Tryptamine-induced vasoconstriction also resisted blockade by adrenergic inhibitors and the 5-HT1A, 1B, 1D and 5-HT2A receptor antagonists, methiothepin (50 nM) and ketanserin (30 nM), respectively. Trace amines and amphetamines therefore exert vasoconstriction independently of adrenoceptors, neuronal transport and 5-HT receptor activation. There was no evidence of tachyphylaxis or cross-tachyphylaxis of the vasoconstriction to these amines. Tyramine was a partial agonist and in its presence, beta-PEA, d-amphetamine and octopamine were antagonised indicating that they all act through a common receptor for which tyramine serves as an antagonist. We conclude that the vasoconstriction is via TAAR-1, because of structural similarities between amines, ability to stimulate recombinant trace amine-associated receptor 1 (TAAR 1) and the presence of TAAR-1 in rat aorta. PMID- 23665490 TI - Asymmetric dimethylarginine regulates the lipopolysaccharide-induced nitric oxide production in macrophages by suppressing the activation of NF-kappaB and iNOS expression. AB - Two major effector systems are frequently implicated in the immune and endothelial cell alternations associated with inflammation. They include the enhanced production of reactive oxygen species and diminished bioavailability of nitric oxide (NO). Importantly, these processes can be regulated by endogenously produced methylarginines, inhibitors for NO derived from macrophages and endothelial cells. Therefore, the aim of this study was to show the potential pharmacological intervention of methylarginines (N(G)-methyl-L-arginine, L-NMMA; N(G), N(G)'-dimethyl-L-arginine-symmetric dimethylarginine, SDMA; and N(G), N(G) dimethyl-L-arginine-asymmetric dimethylarginine, ADMA) in activation of murine peritoneal (RAW 264.7) and alveolar (MHS) macrophages with lipopolysaccharide from Gram-negative bacteria (LPS). The data presented in this study clearly declare that L-NMMA (1-50MUM) and ADMA (10-50 MUM) significantly inhibited the LPS-induced NO production from macrophages in a concentration-dependent manner. It was demonstrated, for the first time, that the ADMA- and L-NMMA-induced down regulation of NO production was accompanied by reduced expression of mRNA and protein for inducible NO synthase as well as decreased activation of nuclear factor-kappaB. Importantly, we found a negative correlation between the ADMA dependent reduction of NO production and ADMA-increased superoxide formation, which indicates that ADMA can negatively affect the balance in LPS-induced macrophage-derived production of reactive mediators. The only effect of SDMA was observed for LPS-triggered superoxide production, which was significantly decreased in its highest concentration (50 MUM). In summary, L-NMMA and ADMA can mediate their effects on macrophage activation via regulation of intracellular signaling pathways, which can affect critical functions in activated macrophages. PMID- 23665491 TI - Antinociceptive response in transgenic mice expressing rat tonin. AB - Angiotensin II (Ang II) may be produced directly from angiotensinogen by tonin. Studies have demonstrated that Ang II and its metabolite Ang-(1-7) produce antinociception in pain animal models. The aim of the present study was to determine whether the transgenic mice that express rat tonin (TGM(rTon)) show altered nociceptive behavior and investigate the possible involvement of angiotensin metabolites. Nociception was evaluated using the thermal tail-flick and chemical acetic acid writhing tests, and the drugs were administered by intracerebroventricular and subcutaneous pathways, respectively. Probabilities less than 5% (P<0.05) were considered to be statistically significant (t test; ANOVA/Bonferroni's test). The results demonstrate that the transgenic mice showed an antinociceptive effect in the tail-flick and acetic acid writhing tests. In addition, it was observed that losartan, an AT1 receptor antagonist and A-779 (D Ala7-Ang-(1-7)), a Mas receptor antagonist attenuated the antinociceptive behavior. Our data suggest that the Ang II produced in TGM(rTon) induces antinociception via the AT1 receptor, while the Ang-(1-7) produced from Ang II induced antinociception via the Mas receptor. PMID- 23665492 TI - Arginase inhibition reduces infarct size via nitric oxide, protein kinase C epsilon and mitochondrial ATP-dependent K+ channels. AB - Reduced bioavailability of nitric oxide (NO) contributes to the development of myocardial ischemia-reperfusion (I/R) injury. Increased activity of arginase is a potential factor that reduces NO bioavailability by competing for the substrate L arginine. The aim of the study was to test the hypothesis that inhibition of arginase after coronary artery occlusion protects from I/R injury and to explore possible mechanisms behind this effect. Male Sprague-Dawley rats subjected to 30 min of coronary artery ligation and 2h reperfusion were given i.v. before the reperfusion: 1) saline; 2) the arginase inhibitor N-omega-hydroxy-nor-L-arginine (nor-NOHA); 3) nor-NOHA with the NO synthase (NOS) inhibitor N(G)-monomethyl-L arginine (L-NMMA); 4) nor-NOHA with the mitochondrial ATP-dependent K(+) (mitoKATP) channel blocker 5-hydroxydecanoic acid (5-HD); 5) nor-NOHA with the protein kinase C epsilon (PKCepsilon) inhibitor epsilon-V1-2 or 6) epsilon-V1-2 alone. Infarct size in the control groups was 61+/-3% and it was reduced to 47+/ 3% (P<0.01) by nor-NOHA. The cardioprotective effect was blocked by the NOS inhibitor L-NMMA. PKCepsilon expression was reduced by I/R and this reduction was attenuated by nor-NOHA. Furthermore, the PKCepsilon inhibitor epsilon-V1-2 abolished the protective effect of nor-NOHA (infarct size 69+/-6%). In addition, the cardioprotective effect of nor-NOHA was also abolished following blockade of the mitoKATP channel (infarct size 62+/-1%). Inhibition of arginase before reperfusion protects the heart from I/R injury via a NOS-dependent pathway, increased expression of PKCepsilon and activation of mitoKATP channels. PMID- 23665493 TI - Diminazene aceturate improves autonomic modulation in pulmonary hypertension. AB - We have previously demonstrated that diminazene aceturate (DIZE), a putative angiotensin 1-7 converting enzyme activator, protects rats from monocrotaline (MCT)-induced pulmonary hypertension (PH). The present study was conducted to determine if the beneficial effects of DIZE are associated with improvements in autonomic nervous system (ANS) modulation. PH was induced in male rats by a single subcutaneous injection of MCT (50 mg/kg). A subset of MCT rats were treated with DIZE (15 mg/kg/day) for a period of 21 days, after which the ANS modulation was evaluated by spectral and symbolic analysis of heart rate variability (HRV). MCT administration resulted in a significant (P<0.001) increase in the right ventricular systolic pressure (62 +/- 14 mmHg) when compared with other experimental groups (Control: 26 +/- 6; MCT + DIZE: 31 +/- 7 mmHg), while DIZE treatment was able to decrease this pressure. Furthermore MCT treated rats had significantly reduced total power of HRV than the controls. On the other hand, although not significant, a trend towards increased HRV was observed in the MCT + DIZE group (Control: 108 +/- 47; MCT: 12 +/- 8.86 and MCT + DIZE: 40 +/- 14), suggesting an improvement of the cardiac autonomic modulation. This observation was further confirmed by the low-frequency/high-frequency index of spectral analysis (Control: 0.74 +/- 0.62; MCT: 1.45 +/- 0.78 and MCT + DIZE: 0.34 +/- 0.49) which showed that DIZE treatment was able to recover the ANS imbalance observed in the MCT-induced pulmonary hypertensive rats. Collectively, our results demonstrate that MCT-induced PH is associated with a significant increase in sympathetic modulation and a decrease in HRV, which are markedly improved by DIZE treatment. PMID- 23665494 TI - Male hypogonadism induced by high fat diet and low dose streptozotocin is mediated by activated endoplasmic reticulum stress and IkappaBbeta and attenuated by argirein and valsartan. AB - Male hypogonadism is frequently accompanied with type 2 diabetes due to testicular dysfunction, but the origin of the pathogenesis is not known. We measured whether pro-inflammatory factors including endoplasmic reticulum (ER) stress chaperones and inhibitory kappaBbeta (IkappaBbeta) contribute to testis damage in type 2 diabetic rats produced by a high-fat diet (HFD) and low dose streptozotocin (STZ). We determined whether these can be attenuated by the anti inflammatory activity of argirein a derivative of rhein as compared to valsartan. Reduced testosterone and LH (luteinizing hormone) levels in serum were significant in association with a decrease in the levels of mRNA and steroidogenic acute regulatory protein (StAR), insulin receptor substrate (IRS 1), activated IkappaBbeta and ER stress chaperone C/EBP homologous protein (CHOP) in the diabetic testis and sperm count, motility and sexual behaviors were reduced in vivo. Additionally, Leydig cells cultured with high glucose showed upregulated IkappaBbeta, ER stress sensor PERK (PKR-like ER kinase) and p-Akt/Akt in vitro. These changes may be due to a component of inflammation linked to activated NADPH oxidase and were significantly alleviated by either argirein or valsartan. In conclusion, diabetic testopathy induced by a HFD and low STZ is characterized by an entity of inflammation and is alleviated by argirein and valsartan through normalizing activated IkappaBbeta and ER stress. PMID- 23665495 TI - The memory stages of a spatial Y-maze task are not affected by a low dose of ketamine/midazolam. AB - Anesthetics, such as the ketamine/midazolam combination, are used in research with animals and in human clinical practice; thus, it is essential to clarify the potential effects of these anesthetics on memory. This study aimed to evaluate how a low dose of the ketamine/midazolam combination affects the acquisition, consolidation, or recall of a spatial memory task. Thirty-three adult male C57BL/6 mice were divided into four treatment groups: unanesthetized control animals and three groups of animals treated with 40 mg/kg of ketamine and 10mg/kg of midazolam administered in a single intraperitoneal injection. The different treatment groups received the same anesthetic dose at different time points, to study the acquisition, consolidation, and recall of spatial memory in the Y-maze task. The percentage of correct choices was measured. Six mice were killed 4 days and 12 days after anesthesia for histopathological analyses. There were no differences between treatment and control groups regarding the acquisition of spatial memory, measured as the slope of the learning curve, or in the percentage of correct choices in the consolidation or recall periods of the task. Similarly, no differences were detected between groups regarding the number of cells per square millimeter in the visual and retrosplenial cortex, in the dentate gyrus, and in the CA1 and CA3 regions of the hippocampus. Hence, a low dose of the ketamine/midazolam combination did not impair memory processes or brain integrity in adult mice, suggesting that this combination is unlikely to cause cognitive complications. PMID- 23665496 TI - Pentamethylquercetin ameliorates fibrosis in diabetic Goto-Kakizaki rat kidneys and mesangial cells with suppression of TGF-beta/Smads signaling. AB - Pentamethylquercetin (PMQ) has been shown to possess glucose-lowering properties, but its effect on renal fibrosis in diabetes is still unclear. This study was designed to investigate the effect of PMQ on renal fibrosis and the underlying mechanisms in spontaneous type II diabetic Goto-Kakizaki rats and mesangial cells in high glucose. We found that in Goto-Kakizaki rats, PMQ treatment attenuated glomerular volume, glycogen deposition, renal collagen and fibronectin accumulation, in addition to amelioration of diabetic symptoms, including reduction of urine volume and urine glucose levels. In mesangial cells, PMQ remarkably inhibited the cell proliferation and total collagen accumulation, and suppressed cell hypertrophy. Further experiments showed that PMQ treatment down regulated the expression of TGF-beta1, up-regulated Smad7 and inhibited Smad2/3 activation in vivo and vitro. Our results demonstrated that PMQ ameliorated renal fibrosis in diabetes, which may be associated with suppressed TGF-beta/Smads signaling. PMID- 23665497 TI - Up-regulation of monoamine oxidase activity in the striatum of rats following chronic treatment of thienorphine. AB - Thienorphine is a new, non-selective partial agonist of opioid receptors. In our previous study using microdialysis, thienorphine persistently increased the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum of rats, without affecting the level of dopamine. This finding suggested that monoamine oxidase (MAO) activity in the striatum of rats increased by chronic thienorphine treatment. In the present study, we investigated whether chronic treatment of thienorphine affected MAO activity in the striatum of rats compared with morphine. Rats were treated subcutaneously (three times/day) with either saline (control), morphine, thienorphine, or a pre-treatment of thienorphine followed by morphine, for 3 or 5 continuous days. A 20-min naloxone challenge given to a sub-group of animals from each group occurred at the end of their 5-day treatment. The results showed that repeated administration of thienorphine significantly elevated MAO activity in the striatum, thus restoring MAO activity, which was inhibited by chronic morphine treatment. These results suggest that increased activity of MAO in the striatum may accelerate the metabolism of dopamine, leading to the elevations of DOPAC and HVA. Furthermore, these findings implicate the involvement of MAO in the pharmacological characteristics of thienorphine. PMID- 23665498 TI - Synergistic, but not separate, stimulation of accumbal beta1- and beta2 adrenoceptors alters the accumbal dopamine efflux in freely moving rats. AB - The effects of intra-accumbal infusion of selective agonists for the beta adrenoceptor subtypes on the noradrenaline and dopamine efflux in the nucleus accumbens of freely moving rats were investigated, using in vivo microdialysis. Neither beta1-(dobutamine: 0.06 and 0.12 pmol) nor beta2-adrenoceptor agonist (salbutamol: 0.36 and 3.6 pmol) altered the basal noradrenaline and dopamine efflux in the nucleus accumbens. Co-administration of 0.06 pmol of dobutamine with salbutamol (3.6 pmol) did not affect the noradrenaline levels, but it increased the dopamine efflux to approximately 120%. Co-administration of 0.12 pmol of dobutamine with salbutamol (0.36 or 3.6pmol) also increased DA efflux to approximately 120% without affecting noradrenaline levels. The non-selective beta adrenoceptor antagonist l-propranolol (1200 pmol) that did not alter the basal noradrenaline and dopamine levels, suppressed the dopamine efflux, induced by co administration of dobutamine (0.12 pmol) and salbutamol (3.6 pmol). The doses mentioned are the total amount of drug over the 60-min infusion period. The present results support our previously reported conclusion that stimulation of accumbal beta-adrenoceptors which are suggested to be postsynaptically located on accumbal dopaminergic terminals, can enhance the dopamine efflux in the nucleus accumbens. The present study also provides in vivo neurochemical evidence that concomitant, but not separate, activation of accumbal beta1- and beta2 adrenoceptors synergistically increases the accumbal dopamine efflux. PMID- 23665499 TI - Time course of the effects of lipopolysaccharide on prepulse inhibition and brain nitrite content in mice. AB - The systemic administration of lipopolysaccharide (LPS) induces time-dependent behavioral alterations, which are related to sickness behavior and depression. The time-course effects of LPS on prepulse inhibition (PPI) remain unknown. Furthermore, the time-dependent effects of LPS on central nitrite content had not been investigated. Therefore, we studied alterations induced by single LPS (0.5mg/kg, i.p.) administration to mice on parameters, such as PPI, depressive- and anxiety-like behaviors, working memory, locomotor activity and motor coordination, 1.5 and 24h post-LPS administration. IL-1beta and TNFalpha in the blood and brain as well as brain nitrite levels were evaluated in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST). An overall hypolocomotion was observed 1.5h post-LPS, along with depressive-like behaviors and deficits in working memory. Increments in IL-1beta content in plasma and PFC, TNFalpha in plasma and decreases in nitrite levels in the ST and PFC were also verified. Twenty-four hours post-LPS treatment, depressive-like behaviors and working memory deficits persisted, while PPI levels significantly reduced along with increases in IL-1beta content in the PFC and a decrease in nitrite levels in the HC, ST and PFC. Our data demonstrate that a delayed increase (i.e., 24h post-LPS) in PPI levels ensue, which may be useful behavioral parameter for LPS-induced depression. A decrease in nitrergic neurotransmission was associated with these behavioral findings. PMID- 23665500 TI - Phosphoinositide-specific phospholipase C beta 1b (PI-PLCbeta1b) interactome: affinity purification-mass spectrometry analysis of PI-PLCbeta1b with nuclear protein. AB - Two isoforms of inositide-dependent phospholipase C beta1 (PI-PLCbeta1) are generated by alternative splicing (PLCbeta1a and PLCbeta1b). Both isoforms are present within the nucleus, but in contrast to PLCbeta1a, the vast majority of PLCbeta1b is nuclear. In mouse erythroid leukemia cells, PI-PLCbeta1 is involved in the regulation of cell division and the balance between cell proliferation and differentiation. It has been demonstrated that nuclear localization is crucial for the enzymatic function of PI-PLCbeta1, although the mechanism by which this nuclear import occurs has never been fully characterized. The aim of this study was to characterize both the mechanism of nuclear localization and the molecular function of nuclear PI-PLCbeta1 by identifying its interactome in Friend's erythroleukemia isolated nuclei, utilizing a procedure that coupled immuno affinity purification with tandem mass spectrometry analysis. Using this procedure, 160 proteins were demonstrated to be in association with PI-PLCbeta1b, some of which have been previously characterized, such as the splicing factor SRp20 (Srsf3) and Lamin B (Lmnb1). Co-immunoprecipitation analysis of selected proteins confirmed the data obtained via mass spectrometry. Of particular interest was the identification of the nuclear import proteins Kpna2, Kpna4, Kpnb1, Ran, and Rangap1, as well as factors involved in hematological malignancies and several anti-apoptotic proteins. These data give new insight into possible mechanisms of nuclear trafficking and functioning of this critical signaling molecule. PMID- 23665501 TI - Cloning and characterization of the glycoside hydrolases that remove xylosyl groups from 7-beta-xylosyl-10-deacetyltaxol and its analogues. AB - Paclitaxel, a natural antitumor compound, is produced by yew trees at very low concentrations, causing a worldwide shortage of this important anticancer medicine. These plants also produce significant amounts of 7-beta-xylosyl-10 deacetyltaxol, which can be bio-converted into 10-deacetyltaxol for the semi synthesis of paclitaxel. Some microorganisms can convert 7-beta-xylosyl-10 deacetyltaxol into 10-deacetyltaxol, but the bioconversion yield needs to be drastically improved for industrial applications. In addition, the related beta xylosidases of these organisms have not yet been defined. We set out to discover an efficient enzyme for 10-deacetyltaxol production. By combining the de novo sequencing of beta-xylosidase isolated from Lentinula edodes with RT-PCR and the rapid amplification of cDNA ends, we cloned two cDNA variants, Lxyl-p1-1 and Lxyl p1-2, which were previously unknown at the gene and protein levels. Both variants encode a specific bifunctional beta-d-xylosidase/beta-d-glucosidase with an identical ORF length of 2412 bp (97% identity). The enzymes were characterized, and their 3.6-kb genomic DNAs (G-Lxyl-p1-1, G-Lxyl-p1-2), each harboring 18 introns, were also obtained. Putative substrate binding motifs, the catalytic nucleophile, the catalytic acid/base, and potential N-glycosylation sites of the enzymes were predicted. Kinetic analysis of both enzymes showed kcat/Km of up to 1.07 s(-1)mm(-1) against 7-beta-xylosyl-10-deacetyltaxol. Importantly, at substrate concentrations of up to 10 mg/ml (oversaturated), the engineered yeast could still robustly convert 7-beta-xylosyl-10-deacetyltaxol into 10 deacetyltaxol with a conversion rate of over 85% and a highest yield of 8.42 mg/ml within 24 h, which is much higher than those reported previously. Therefore, our discovery might lead to significant progress in the development of new 7-beta-xylosyl-10-deacetyltaxol-converting enzymes for more efficient use of 7-beta-xylosyltaxanes to semi-synthesize paclitaxel and its analogues. This work also might lead to further studies on how these enzymes act on 7-beta xylosyltaxanes and contribute to the growing database of glycoside hydrolases. PMID- 23665502 TI - Feasibility of corneal drug delivery of cysteamine using vitamin E modified silicone hydrogel contact lenses. AB - Cystinosis is an inherited genetic disease characterized by the accumulation of cystine crystals in several tissues including the cornea. The corneal manifestations of cystinosis are treated by hourly instillation of cysteamine eye drops each day while awake. The high frequency of eye drop instillation along with the long duration of treatment leads to poor compliance in many patients. We have combined in vitro experiments with mathematical modeling to investigate the feasibility of daily use of cysteamine loaded contact lenses to replace the hourly instillation of drops. Our approach was based on incorporation of vitamin E diffusion barriers into commercially available contact lenses to increase the duration of drug release. Contact lenses were first soaked in a solution of vitamin E in ethanol. Subsequently, the lenses were soaked in an aqueous solution of cysteamine to load the drug. The drug release profiles from vitamin E treated lenses were measured under sink conditions. In addition, drug oxidation rates were measured after exposing drug loaded contact lenses to humidified room air. To study further the feasibility of using contact lenses for the delivery of cysteamine, a mass transfer model was used to determine the rates at which the drug loaded in the lens is delivered to the cornea. The results show that vitamin E loading increases the release duration from 10 min to about 3 h in solution, thus allowing the possibility of extended drug delivery. In addition to improving the release profiles, vitamin E loading also improved the drug stability by reducing the oxidation rates. The mathematical modeling of drug transport in the eye suggested that the vitamin E loaded contact lens can provide the daily therapeutic dose without causing toxicity, while significantly increasing the bioavailability compared to eye drops. Based on the in vitro experimental results and the mathematical modeling, it is likely that a single contact lens worn for about 2h could achieve the same therapeutic effects as hourly instillation of eye drops. PMID- 23665503 TI - Process of prototyping coronary stents from biodegradable Fe-Mn alloys. AB - Biodegradable stents are considered to be a recent innovation, and their feasibility and applicability have been proven in recent years. Research in this area has focused on materials development and biological studies, rather than on how to transform the developed biodegradable materials into the stent itself. Currently available stent technology, the laser cutting-based process, might be adapted to fabricate biodegradable stents. In this work, the fabrication, characterization and testing of biodegradable Fe-Mn stents are described. A standard process for fabricating and testing stainless steel 316L stents was referred to. The influence of process parameters on the physical, metallurgical and mechanical properties of the stents, and the quality of the produced stents, were investigated. It was found that some steps of the standard process such as laser cutting can be directly applied, but changes to parameters are needed for annealing, and alternatives are needed to replace electropolishing. PMID- 23665504 TI - Initiated chemical vapor deposition of thermoresponsive poly(N-vinylcaprolactam) thin films for cell sheet engineering. AB - Poly(N-vinylcaprolactam) (PNVCL) is a thermoresponsive polymer known to be nontoxic, water soluble and biocompatible. Here, PNVCL homopolymer was successfully synthesized for the first time by use of a one-step vapor-phase process, termed initiated chemical vapor deposition (iCVD). Fourier transform infrared spectroscopy results showed that radical polymerization took place from N-vinylcaprolactam monomers without damaging the functional caprolactam ring. A sharp lower critical solution temperature transition was observed at 31 degrees C from the iCVD poly(N-vinylcaprolactam) (PNVCL) film. The thermoresponsive PNVCL surface exhibited a hydrophilic/hydrophobic alteration with external temperature change, which enabled the thermally modulated attachment and detachment of cells. The conformal coverage of PNVCL film on various substrates with complex topography, including fabrics and nanopatterns, was successfully demonstrated, which can further be utilized to fabricate cell sheets with aligned cell morphology. The advantage of this system is that cells cultured on such thermoresponsive surfaces could be recovered as an intact cell sheet by simply lowering the temperature, eliminating the need for conventional enzymatic treatments. PMID- 23665506 TI - Inhibition of mortalin expression reverses cisplatin resistance and attenuates growth of ovarian cancer cells. AB - The heat shock protein mortalin is frequently overexpressed in human malignancies. In this study, an assessment of mortalin expression using ovarian cancer tissue microarrays suggested that mortalin overexpression might be related to drug resistance. Using a short hairpin (sh) RNA approach, we evaluated the effect of reducing mortalin expression in vitro and in vivo. The results of our study show that elevated levels of mortalin expression increase cancer cell resistance to cisplatin-induced cytotoxicity and identify mortalin as a potential therapeutic target for improved treatment of drug-resistant ovarian cancer. PMID- 23665505 TI - IGFBP5 domains exert distinct inhibitory effects on the tumorigenicity and metastasis of human osteosarcoma. AB - Osteosarcoma (OS) is the most common primary malignancy of bone. We investigated the roles of insulin-like growth factor binding protein 5 (IGFBP5) domains in modulating OS tumorigenicity and metastasis. The N-terminal (to a lesser extent the C-terminal) domain inhibited cell proliferation and induced apoptosis while the C-terminal domain inhibited cell migration and invasion. The Linker domain had no independent effects. In vivo, the N-terminal domain decreased tumor growth without affecting pulmonary metastases while the C-terminal domain inhibited tumor growth and metastases. In summary, the N- and C-terminal domains modulated OS tumorigenic phenotypes while the C-terminal domain inhibited OS metastatic phenotypes. PMID- 23665507 TI - The role of microRNAs in mitochondria in cancer. AB - Reprogramming of the energy metabolism in cancer cell presents progressive field of cancer research. This feature is associated mainly with the mitochondria, which is major energy source of eukaryotic cells. These organelles are essential to the cell homeostasis maintenance, play an important role in intrinsic apoptotic pathway and their dysfunction is associated with multiple diseases including cancer. Recently, it was described that microRNAs (miRNAs) regulate important signaling pathways in mitochondria and many of these miRNAs are deregulated in various cancers. Here we summarize current knowledge about miRNAs involved in mitochondrial functioning with focus on cellular energy metabolism, apoptosis and mitophagy. PMID- 23665509 TI - WITHDRAWN: Overview of Drosophila immunity: A historical perspective. AB - This article has been withdrawn at the request of the author. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 23665508 TI - Expression of cytoskeleton-associated protein 4 is related to lymphatic metastasis and indicates prognosis of intrahepatic cholangiocarcinoma patients after surgery resection. AB - The objective of the study was to investigate the clinical significance of CKAP4 in intrahepatic cholangiocellular carcinoma (ICC). CKAP4 expression was determined in a cohort containing 173 cases of ICC patients. We found that CKAP4 was overexpressed in the majority of ICC cases and was significantly associated with tumor size, distant metastasis, lymph node metastasis, UICC and TNM stage features. Kaplan-Meier and Cox regression data indicated that CKAP4 was correlated with favorable clinical outcome and was an independent predictor for overall survival (HR, 0.646; 95% CI, 0.463-0.900 [p=0.010]). Thus, CKAP4 may serve as a prognostic marker of ICC patients. PMID- 23665510 TI - A bi-Poisson model for clustering gene expression profiles by RNA-seq. AB - With the availability of gene expression data by RNA-seq, powerful statistical approaches for grouping similar gene expression profiles across different environments have become increasingly important. We describe and assess a computational model for clustering genes into distinct groups based on the pattern of gene expression in response to changing environment. The model capitalizes on the Poisson distribution to capture the count property of RNA-seq data. A two-stage hierarchical expectation-maximization (EM) algorithm is implemented to estimate an optimal number of groups and mean expression amounts of each group across two environments. A procedure is formulated to test whether and how a given group shows a plastic response to environmental changes. The impact of gene-environment interactions on the phenotypic plasticity of the organism can also be visualized and characterized. The model was used to analyse an RNA-seq dataset measured from two cell lines of breast cancer that respond differently to an anti-cancer drug, from which genes associated with the resistance and sensitivity of the cell lines are identified. We performed simulation studies to validate the statistical behaviour of the model. The model provides a useful tool for clustering gene expression data by RNA-seq, facilitating our understanding of gene functions and networks. PMID- 23665511 TI - Integrating bioinformatics into senior high school: design principles and implications. AB - Bioinformatics is an integral part of modern life sciences. It has revolutionized and redefined how research is carried out and has had an enormous impact on biotechnology, medicine, agriculture and related areas. Yet, it is only rarely integrated into high school teaching and learning programs, playing almost no role in preparing the next generation of information-oriented citizens. Here, we describe the design principles of bioinformatics learning environments, including our own, that are aimed at introducing bioinformatics into senior high school curricula through engaging learners in scientifically authentic inquiry activities. We discuss the bioinformatics-related benefits and challenges that high school teachers and students face in the course of the implementation process, in light of previous studies and our own experience. Based on these lessons, we present a new approach for characterizing the questions embedded in bioinformatics teaching and learning units, based on three criteria: the type of domain-specific knowledge required to answer each question (declarative knowledge, procedural knowledge, strategic knowledge, situational knowledge), the scientific approach from which each question stems (biological, bioinformatics, a combination of the two) and the associated cognitive process dimension (remember, understand, apply, analyze, evaluate, create). We demonstrate the feasibility of this approach using a learning environment, which we developed for the high school level, and suggest some of its implications. This review sheds light on unique and critical characteristics related to broader integration of bioinformatics in secondary education, which are also relevant to the undergraduate level, and especially on curriculum design, development of suitable learning environments and teaching and learning processes. PMID- 23665512 TI - Helical conformation endows poly-l-lactic acid fibers with a piezoelectric charge under tensile stress. AB - Poly-l-lactic acid (PLLA) has been clinically used as a bioabsorbable material and attains a piezoelectric charge upon molecular orientation by the application of a shear force to the C-axis of the crystal line region. Previous studies showed that implanted drawn PLLA films or rods accelerate the ossification due to piezoelectric effect. In this study, we originally designed helically-twisted PLLA fiber to produce piezoelectricity in bioabsorbable suture upon tensile stress. The piezoelectricity of the helical PLLA fibers was evaluated using a lock-in amplifier system in vitro. The ossification induced by helical PLLA fibers was examined by implanting them in the rat patellar ligament supporting a physiological tensile load. We observed that 57 degrees and 45 degrees twisted PLLA fibers generated a higher piezoelectric potential than did 27 degrees twisted fibers. The animal experiment showed that the formation of osseous tissue around helical PLLA fibers was more significant than around non-helical control fibers at 4 weeks after their implantation. These results suggest that helical PLLA fiber may be useful for the surgical suture or artificial ligament, which connects to the bone. PMID- 23665513 TI - Seroprevalence of Trypanosoma evansi infection in water buffaloes from the mountainous region of North Vietnam and effectiveness of trypanocidal drug treatment. AB - Water buffalo (WB) is an important domestic animal in Vietnam. This study utilized a card agglutination test to investigate seroprevalence of surra in WB population. Sera were collected from 585 WB from 4 different regions in Cao Bang and Thai Nguyen Provinces. Among them, 131 samples (22.4%) were positive for surra. The highest prevalence (24.6%) was found among 3 to 5 years old WB. Buffaloes less than 3 years old had the lowest prevalence (15.6%). Among 27 abortion cases, 9 WB (33.3%) were surra positive. For treatment of surra, Berenil(r) demonstrated a 100% cure rate, while that of Trypamidium(r) was only 40%. Our findings suggest that the current control strategy has not succeeded in reducing prevalence of surra in Vietnam. PMID- 23665514 TI - The unusual adequate development of a child with severe central hypothyroidsm negative at neonatal thyrotropin screening. PMID- 23665515 TI - Vaginal effects of ospemifene in the ovariectomized rat preclinical model of menopause. AB - Ospemifene is a unique tissue-selective estrogen agonist/antagonist (also known as a selective estrogen receptor modulator [SERM]) with demonstrated efficacy in Phase 3 studies of postmenopausal women with vulvar and vaginal atrophy (VVA). This report describes preclinical studies on the effects of ospemifene in the ovariectomized (OVX) rat model of menopause. Ospemifene (10mg/kg/day) and the SERM comparator, raloxifene (10mg/kg/day) were administered for 2 weeks and both increased vaginal weight; ospemifene was more effective than raloxifene. In addition, ospemifene had a greater effect on increasing vaginal epithelial height compared with raloxifene. The effect on uterine weight was less pronounced for both ospemifene and raloxifene. The ED50 of ospemifene on vaginal epithelial height was 0.39mg/kg/day and the magnitude was nearly the same as was seen with the positive control, 17alpha-ethinyl estradiol (EE2). In a histological analysis of ospemifene-treated rat vaginas, basal cells were overlaid by 2 to 3 cell layers of thickened goblet-like mucified cells apically; however, the cornification observed with EE2 was absent. Estrogenic activity of ospemifene was confirmed by upregulation of progesterone receptors in vaginal epithelium and stroma. Ospemifene showed similar affinity for estrogen receptor (ER)-alpha and ER-beta, but an overall lower affinity than estradiol. Ospemifene antagonized estrogen response element (ERE)-mediated transactivation on MCF-7 cells, confirming its anti-estrogenic activity in breast cancer cells. The dose response for ospemifene in the rat is consistent with that observed in clinical studies of ospemifene 30 and 60mg, showing that the OVX rat is a highly predictive model of SERM activity in postmenopausal VVA. PMID- 23665516 TI - Nitritation versus full nitrification of ammonium-rich wastewater: comparison in terms of nitrous and nitric oxides emissions. AB - The processes of nitritation and full nitrification of synthetic reject wastewater were compared in terms of N2O and NO emissions. Two lab-scale sequencing batch reactors (SBR1 and SBR2) were enriched with Nitrosomonas (ammonia-oxidizing bacteria) and Nitrobacter (nitrite-oxidizing bacteria), as shown by fluorescence in situ hybridization (FISH) and high-resolution 16S rRNA tag pyrosequencing. Stable conversion of ammonium to nitrite and nitrite to nitrate was achieved in SBR1 and SBR2 respectively. Biomass from SBR2 was added in SBR1 in order to achieve full nitrification. Under nitritation, 1.22% of the converted-N was emitted as N2O, and 0.066% as NO. During the transition from nitritation to full nitrification, effluent nitrite concentrations decreased but nitrogen oxides were emitted at levels similar to the nitritation period. Gas emissions decreased sharply under full nitrification conditions (0.54% N2O N/converted-N; 0.021% NO-N/converted-N), probably as a result of the combined effect of lower nitrite and ammonium concentrations in the bioreactor. PMID- 23665517 TI - Influence of cell properties on rheological characterization of microalgae suspensions. AB - The influences of algal cell size and surface charge on rheological properties of microalgae suspensions were investigated. The effective viscosity of two microalgae suspensions, i.e., the freshwater Chlorella sp. and the marine Chlorella sp., was measured as a function of their volume fractions in the range of 0.70-4.31%. The hydrodynamic diameters of the freshwater Chlorella sp. and the marine Chlorella sp. were measured to be 3.13 and 6.00 MUm, respectively. The Zeta potentials of these two algal cells were measured to be -23.73 and -81.81 mV, respectively. The intrinsic viscosities of these two microalgae suspensions were further determined to be 24.7 and 16.1, respectively. Combining with theoretical models, these results indicated that the algal cell size has a predominant effect over cell surface charge in affecting rheological properties of microalgae suspensions. Smaller algal cells result in a higher effective viscosity of the microalgae suspension. PMID- 23665518 TI - Influence of anode potentials on selection of Geobacter strains in microbial electrolysis cells. AB - Through their ability to directly transfer electrons to electrodes, Geobacter sp. are key organisms for microbial fuel cell technology. This study presents a simple method to reproducibly select Geobacter-dominated anode biofilms from a mixed inoculum of bacteria using graphite electrodes initially poised at -0.25, 0.36 and -0.42 V vs. Ag/AgCl. The biofilms all produced maximum power density of approximately 270 m Wm(-2) (projected anode surface area). Analysis of 16S rRNA genes and intergenic spacer (ITS) sequences found that the biofilm communities were all dominated by bacteria closely related to Geobacter psychrophilus. Anodes initially poised at -0.25 V reproducibly selected biofilms that were dominated by a strain of G. psychrophilus that was genetically distinct from the strain that dominated the -0.36 and -0.42 V biofilms. This work demonstrates for the first time that closely related strains of Geobacter can have very different competitive advantages at different anode potentials. PMID- 23665519 TI - Alkaline hydrogen peroxide pretreatment of cashew apple bagasse for ethanol production: study of parameters. AB - The alkaline hydrogen peroxide (AHP) pretreatment of cashew apple bagasse (CAB) was evaluated based on the conversion of the resultant cellulose into glucose. The effects of the concentration of hydrogen peroxide at pH 11.5, the biomass loading and the pretreatment duration performed at 35 degrees C and 250 rpm were evaluated after the subsequent enzymatic saccharification of the pretreated biomass using a commercial cellulase enzyme. The CAB used in this study contained 20.56 +/- 2.19% cellulose, 10.17 +/- 0.89% hemicellulose and 35.26 +/- 0.90% lignin. The pretreatment resulted in a reduced lignin content in the residual solids. Increasing the H2O2 concentration (0-4.3% v/v) resulted in a higher rate of enzymatic hydrolysis. Lower biomass loadings gave higher glucose yields. In addition, no measurable furfural and hydroxymethyl furfural were produced in the liquid fraction during the pretreatment. The results show that alkaline hydrogen peroxide is effective for the pretreatment of CAB. PMID- 23665521 TI - Lymphocyte responses: stand by for action! PMID- 23665520 TI - Regulation of innate and adaptive immunity by Notch. AB - Coordinated function of the innate and adaptive arms of the immune system in vertebrates is essential to promote protective immunity and to avoid immunopathology. The Notch signalling pathway, which was originally identified as a pleiotropic mediator of cell fate in invertebrates, has recently emerged as an important regulator of immune cell development and function. Notch was initially shown to be a key determinant of cell-lineage commitment in developing lymphocytes, but it is now known to control the homeostasis of several innate cell populations. Moreover, the roles of Notch in adaptive immunity have expanded to include the regulation of T cell differentiation and function. The aim of this Review is to summarize the current status of immune regulation by Notch. A better understanding of Notch function in both innate and adaptive immunity will hopefully provide multiple avenues for therapeutic intervention in disease. PMID- 23665522 TI - Current concepts on the pathogenesis and etiology of congenital diaphragmatic hernia. AB - This review outlines research that has advanced our understanding of the pathogenesis and etiology of congenital diaphragmatic hernia (CDH). The majority of CDH cases involve incomplete formation of the posterolateral portion of the diaphragm, clinically referred to as a Bochdalek hernia. The hole in the diaphragm allows the abdominal viscera to invade the thoracic cavity, thereby impeding normal lung development. As a result, newborns with CDH suffer from a combination of severe pulmonary hypoplasia and pulmonary hypertension. Despite advances in neonatal intensive care, mortality and serious morbidity remain high. Systematic studies using rat and transgenic mouse models in conjunction with analyses of human tissue are providing insights into the embryological origins of the diaphragmatic defect associated with CDH and abnormalities of developmentally regulated signaling cascades. PMID- 23665523 TI - Trans-vivo delayed type hypersensitivity assay for antigen specific regulation. AB - Delayed-type hypersensitivity response (DTH) is a rapid in vivo manifestation of T cell-dependent immune response to a foreign antigen (Ag) that the host immune system has experienced in the recent past. DTH reactions are often divided into a sensitization phase, referring to the initial antigen experience, and a challenge phase, which usually follows several days after sensitization. The lack of a delayed-type hypersensitivity response to a recall Ag demonstrated by skin testing is often regarded as an evidence of anergy. The traditional DTH assay has been effectively used in diagnosing many microbial infections. Despite sharing similar immune features such as lymphocyte infiltration, edema, and tissue necrosis, the direct DTH is not a feasible diagnostic technique in transplant patients because of the possibility of direct injection resulting in sensitization to donor antigens and graft loss. To avoid this problem, the human to-mouse "trans-vivo" DTH assay was developed (1,2). This test is essentially a transfer DTH assay, in which human peripheral blood mononuclear cells (PBMCs) and specific antigens were injected subcutaneously into the pinnae or footpad of a naive mouse and DTH-like swelling is measured after 18-24 hr (3). The antigen presentation by human antigen presenting cells such as macrophages or DCs to T cells in highly vascular mouse tissue triggers the inflammatory cascade and attracts mouse immune cells resulting in swelling responses. The response is antigen-specific and requires prior antigen sensitization. A positive donor reactive DTH response in the Tv-DTH assay reflects that the transplant patient has developed a pro-inflammatory immune disposition toward graft alloantigens. The most important feature of this assay is that it can also be used to detect regulatory T cells, which cause bystander suppression. Bystander suppression of a DTH recall response in the presence of donor antigen is characteristic of transplant recipients with accepted allografts (2,4-14). The monitoring of transplant recipients for alloreactivity and regulation by Tv-DTH may identify a subset of patients who could benefit from reduction of immunosuppression without elevated risk of rejection or deteriorating renal function. A promising area is the application of the Tv-DTH assay in monitoring of autoimmunity(15,16) and also in tumor immunology (17). PMID- 23665524 TI - Update on management of herpes keratitis in children. AB - PURPOSE OF REVIEW: To summarize the articles published in 2012 pertaining to the clinical presentation, diagnosis, and treatment of herpetic keratitis, with specific attention to pediatric population. RECENT FINDINGS: Liu et al. confirm prior literature that herpetic keratitis has higher recurrence rate in children than adults. Recurrences are more likely to occur as stromal disease. Vision loss in children is from corneal scarring leading to deprivation and/or refractive amblyopia. Acyclovir is safe and well tolerated as a treatment in pediatric population, and preferable to difficult and toxic eye-drop regimens.Immunochromatographic assay is an effective diagnostic tool to confirm diagnosis of herpes simplex virus-1 (HSV) in corneal scrapings with high specificity but poorer sensitivity.Real time PCR can be employed to follow changes in HSV viral load in patients where resistance is suspected. SUMMARY: Delays in treatment related to misdiagnosis, as well as resistance to current antiviral therapeutics, can lead to visually devastating corneal opacification. In the pediatric population, already at risk for amblyopia, this can be especially damaging. Children are unique with regards to the way in which they manifest herpetic keratitis, making rapid diagnosis and treatment even more challenging. PMID- 23665525 TI - Update on diagnosis and management of Descemet's membrane detachment. AB - PURPOSE OF REVIEW: Descemet's membrane detachment (DMD) is commonly encountered after intraocular surgery and ocular trauma. Although its occurrence has been known for a long time, the disease course and its optimal management is not yet fully understood. This review aims to present an update on current trends in diagnosis and management of DMD. RECENT FINDINGS: Different causes as well as a variable course of disease exist for DMD. Although some DMDs reattach spontaneously with a good visual outcome, some corneas clear without the need for an attached membrane and a few corneas do not clear in spite of an attached Descemet's membrane. DMDs may be treated either conservatively or surgically, with many surgeons favouring an early surgical intervention especially for scrolled, extensive and sight-disabling DMDs. However, due to an unknown course of the disease, exact timing and nature of surgical intervention could not yet been fully defined. SUMMARY: Most DMDs can now be recognized and managed successfully with good visual outcome. However, optimal timing and treatment strategy for different DMDs remain an area to be explored for the best visual recovery for patients. PMID- 23665526 TI - Evolution in the use of intrastromal corneal ring segments for corneal ectasia. AB - PURPOSE OF REVIEW: To report the recent advances in the use of intrastromal corneal ring segments (ICRS) for treating patients with corneal ectasia. RECENT FINDINGS: ICRS improve visual, refractive, and keratometric parameters in patients with keratoconus and postlaser in-situ keratomileusis ectasia. ICRS have been made safer, quicker, and more precise with the use of femtosecond lasers for ring insertion. ICRS produce better visual outcomes in patients with poor preoperative corrected distance visual acuity compared with patients with less preoperative visual impairment. Standard ICRS do not improve vision in patients with stage 3-4 keratoconus (Amsler-Krumeich classification), but newer models of ICRS, such as Intacs SK, appear promising for these patients. ICRS have been successfully combined with treatments such as corneal collagen cross-linking (CXL), penetrating keratoplasty, and photorefractive keratectomy. SUMMARY: ICRS variably improve visual acuity. Numerous questions concerning ICRS remain, including the duration of the effects of ICRS and the changes that ICRS induce on a biomechanical level. The optimal method for combined CXL and ICRS placement has not yet been determined. Further well-designed randomized controlled studies with long-term follow-up are needed for clarification. PMID- 23665527 TI - Proton magnetic resonance spectroscopy measures related to short-term symptomatic outcome in chronic schizophrenia. AB - INTRODUCTION: Proton magnetic resonance spectroscopy (1H MRS) enables the evaluation of in vivo brain function. The purpose of the study was to compare 1H MRS measurements in schizophrenic patients, who were clinical responders after short-term antipsychotic treatment, with non-responders and healthy controls. METHODS: We investigated a group of 47 patients diagnosed with schizophrenia. Patients were examined twice--once after a period of at least 7 days without neuroleptics and the second time at least 4 weeks after therapy with stable doses of medication. The follow-up was available in 42 patients. Baseline MRS measurements of clinical responders were compared with non-responders and the group of healthy controls (N=26). We assessed the following metabolite ratios: NAA (N-acetylaspartate), Glx (complex of GABA, glutamine and glutamate), Cho (choline) and mI (myo-inositol) to creatinine (Cr) in the left frontal and temporal lobes and the thalamus. RESULTS: Responders showed a significantly lower baseline frontal Glx/Cr level than non-responders. Both groups had a significantly lower NAA/Cr ratio in the frontal lobe than the controls, but only non-responders had a significantly lower NAA/Cr ratio in the thalamus. CONCLUSIONS: Our results confirm the relationship between the glutamatergic system and pathophysiology of schizophrenia and suggest a significant value of 1H MRS examination in the assessment of the future treatment effect. PMID- 23665528 TI - Modulation of cortical activity in response to visually induced postural perturbation: combined VR and EEG study. AB - There is evidence from EEG studies that unexpected perturbations to standing posture induce a differential modulation of cortical activity compared to self initiated and/or predictable conditions. However, the neural correlates of whole body postural response to visually induced perturbations on standing posture have not been examined. Here we employ a novel experimental paradigm via combined virtual reality (VR) and EEG measures to examine the effects of visually induced perturbations on the dynamics of postural responses. Twelve Penn State student athletes without prior history of neurologic disorders and/or orthopaedic injuries participated in this study. There were no differences in response/reaction time measures between both spatially and temporally unpredictable and fully predictable conditions (p>.05). However, significantly stronger modulation of frontal-central EEG theta activity was present prior to onset of unpredictable postural perturbations (p<.05). It is postulated that enhanced EEG theta in unpredictable conditions reflects increased effort to recruit additional brain resources to meet the demands of the postural tasks. PMID- 23665529 TI - Prevalence and characteristics of Salmonella spp. isolated from poultry slaughterhouses in Korea. AB - Poultry products have consistently been identified as important sources of Salmonella infection in humans, because vertical transfer of infection from breeding hens to progeny is an important aspect of the epidemiology of Salmonella spp. infection within the poultry industry. The aim of this study was to estimate the prevalence of Salmonella contamination in poultry products from 15 different located geographical areas from among the 50 poultry slaughterhouses authorized to operate in Korea and to characterize all the isolates by genotyping, phage typing and antibiotic resistance pattern. Salmonella was isolated from 10 (66.7%) of the first and 5 (33.3%) of the last chilling waters and from 32 (42.7%) carcasses originating from 9 slaughterhouses. The major prevalent serotypes of Salmonella originating from 2 duck slaughterhouses and 13 chicken slaughterhouses tested were S. Typhimurium and S. Enteritidis, respectively. Regarding the characteristics of their antibiotic resistance, 8 of the 11 ampicillin resistant (AmR) isolates carried blaTEM only, two carried blaTEM and blaCTX-M-14 and one carried blaCTX-M-3 and only one AmR isolate with the blaCTX-M-3 beta-lactamase gene was an ESBL-producing Salmonella strain. Twenty-seven Salmonella isolates showed nalidixic acid resistance with a mutation at amino acid codon Asp87 in gyrA and no mutation in the parC gene. In all the phenotypic and genotypic properties of the 18 S. Enteritidis and 8 S. Typhimurium based on PFGE, phage types and antibiotic resistance pattern, the predominant patterns were XEI/BEI PT32a-NaR (n = 5) and XTI/BTI-RNDC-no resistant antibiotics (n = 6), respectively. PMID- 23665530 TI - Multilocus sequence typing and DNA similarity analysis implicates that a Borrelia valaisiana-related sp. isolated in Japan is distinguishable from European B. valaisiana. AB - Lyme disease Borrelia spp. are transmitted by Ixodes ticks, and more than 10 species of borreliae have been identified around the world. Recently, another Borrelia sp. has been reported in Asia (Japan, Korea, China, Taiwan and Thailand) as Borrelia valaisiana-related sp. In the present study, we obtained and genetically characterized 19 B. valaisiana-related sp. strains from mammals and ticks. Genetic analyses showed that the Borrelia strains were distinct from B. valaisiana found in Europe. Multilocus sequence typing revealed that these Borrelia isolates formed a monophyletic group with B. yangtze strains in China. Some of the strains were isolated from the bladders of small mammals, and also two strains were experimentally confirmed to be infectious in C3H/HeN mice. We observed that the Borrelia sp. was maintained in the Ixodes granulatus tick after molting. These results suggested that small mammals and I. granulatus were possible reservoir hosts and the vector tick for the Borrelia sp., respectively. B. valaisiana, originally found in Europe, was transmitted mainly by I. ricinus, and birds were mainly thought to be reservoir hosts. Our results suggested that Japanese isolates of B. yangtze (formerly B. valaisiana-related sp.) were distinguishable from B. valaisiana according to the reservoir host and its vector tick. In this study, we also deposited borrelia strain Okinawa-CW62 into bioresource centers as a reference strain of B. yangtze(=DSM 24625, JCM 17189). PMID- 23665531 TI - ACR appropriateness Criteria(r) first trimester bleeding. AB - Vaginal bleeding is not uncommon in the first trimester of pregnancy. Ultrasound is the foremost modality for evaluating normal development of the gestational sac and embryo and for discriminating the causes of bleeding. While correlation with quantitative betaHCG and clinical presentation is essential, sonographic criteria permit diagnosis of failed pregnancies, ectopic pregnancy, gestational trophoblastic disease and spontaneous abortion. The American College of Radiology Appropriateness Criteria guidelines have been updated to incorporate recent data. A failed pregnancy may be diagnosed when there is absence of cardiac activity in an embryo exceeding 7 mm in crown rump length or absence of an embryo when the mean sac diameter exceeds 25 mm. In a stable patient with no intrauterine pregnancy and normal adnexae, close monitoring is advised. The diagnosis of ectopic pregnancy should be based on positive findings rather than on the absence of an intrauterine sac above a threshold level of betaHCG. Following abortion, ultrasound can discriminate retained products of conception from clot and arteriovenous fistulae. The American College of Radiology Appropriateness Criteria(r) are evidence-based guidelines for specific clinical conditions that are reviewed every two years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 23665532 TI - Quantitative analysis of autophagy using advanced 3D fluorescence microscopy. AB - Prostate cancer is the leading form of malignancies among men in the U.S. While surgery carries a significant risk of impotence and incontinence, traditional chemotherapeutic approaches have been largely unsuccessful. Hormone therapy is effective at early stage, but often fails with the eventual development of hormone-refractory tumors. We have been interested in developing therapeutics targeting specific metabolic deficiency of tumor cells. We recently showed that prostate tumor cells specifically lack an enzyme (argininosuccinate synthase, or ASS) involved in the synthesis of the amino acid arginine(1). This condition causes the tumor cells to become dependent on exogenous arginine, and they undergo metabolic stress when free arginine is depleted by arginine deiminase (ADI)(1,10). Indeed, we have shown that human prostate cancer cells CWR22Rv1 are effectively killed by ADI with caspase-independent apoptosis and aggressive autophagy (or macroautophagy)(1,2,3). Autophagy is an evolutionarily-conserved process that allows cells to metabolize unwanted proteins by lysosomal breakdown during nutritional starvation(4,5). Although the essential components of this pathway are well-characterized(6,7,8,9), many aspects of the molecular mechanism are still unclear - in particular, what is the role of autophagy in the death response of prostate cancer cells after ADI treatment? In order to address this question, we required an experimental method to measure the level and extent of autophagic response in cells - and since there are no known molecular markers that can accurately track this process, we chose to develop an imaging-based approach, using quantitative 3D fluorescence microscopy(11,12). Using CWR22Rv1 cells specifically-labeled with fluorescent probes for autophagosomes and lysosomes, we show that 3D image stacks acquired with either widefield deconvolution microscopy (and later, with super-resolution, structured illumination microscopy) can clearly capture the early stages of autophagy induction. With commercially available digital image analysis applications, we can readily obtain statistical information about autophagosome and lysosome number, size, distribution, and degree of colocalization from any imaged cell. This information allows us to precisely track the progress of autophagy in living cells and enables our continued investigation into the role of autophagy in cancer chemotherapy. PMID- 23665533 TI - Problems with measuring peripheral oxytocin: can the data on oxytocin and human behavior be trusted? AB - Research on the neurobiological and behavioral effects of oxytocin (OT), as well as on its possible therapeutic applications, has intensified in the past decade. Accurate determination of peripheral OT levels is essential to reach meaningful conclusions and to motivate, support and inform clinical interventions. Different, but concordant, methods for measuring plasma OT have been developed over the past four decades, but since 2004 several commercially available methods have been favored in research with humans. Evaluation of these methods reveals that they lack reliability when used on unextracted samples of human fluids, and that they tag molecules in addition to OT, yielding estimates that are wildly discrepant with an extensive body of earlier findings that were obtained using methods that are well validated, but more laborious. An accurate, specific, and readily available method for measuring OT that can be adopted as the standard in the field is urgently needed for advances in our understanding of OT's roles in cognition and behavior. PMID- 23665534 TI - Pre-transplant donor specific anti-HLA antibody is associated with antibody mediated rejection, progressive graft dysfunction and patient death. AB - BACKGROUND: The long term effect of donor specific antibodies (DSA) detected by Luminex Single Antigen Bead (SAB) assay in the absence of a positive complement dependant cytotoxicity (CDC) crossmatch is unclear. DSA at the time of transplant were determined retrospectively in 258 renal transplant recipients from 2003 to 2007 and their relationship with rejection and graft function prospectively evaluated. After a median of 5.6 years follow-up 9% of patients had antibody mediated rejection (AMR) (DSA 11/37 (30%), DSA-Neg 13/221 (6%), HR 6.6, p<0.001). Patients with anti-HLA class II (HR 6.1) or both class I+II (HR 10.1) DSA had the greatest risk for AMR. The Mean Fluorescent Intensity (MFI) of the DSA was significantly higher in patients with AMR than those with no rejection (p=0.006). Moreover, the strength of the antibody was shown to be important, with the risk of AMR significantly greater in those with DSA >8000 MFI than those with DSA <8000 MFI (HR 23, p<0.001). eGFR progressively declined in patients with DSA but was stable in those without DSA (35.7 +/- 20.4 mls/min vs 48.5 +/- 22.7) and composite patient and graft survival was significantly worse in those with class II (HR 2.9) or both class I+II (HR 3.7) but not class I DSA. Class II DSA alone, or in combination with class I DSA had the strongest association with graft loss and patient death. Patients with DSA not only have increased rates of acute AMR, but also chronic graft dysfunction, graft loss and death. Antibody burden quantified by SAB assay may identify patients at highest immunological risk and therefore influence patient management and improve long-term patient outcome. PMID- 23665535 TI - Improvement of insulin resistance following transsphenoidal surgery in patients with acromegaly: correlation with serum IGF-I levels. AB - AIM: The aim of this study was to determine the correlation between the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis and glucose intolerance in acromegaly during the early postoperative period. SUBJECTS AND METHODS: The study included 20 patients with acromegaly caused by GH-secreting pituitary adenoma who received transsphenoidal surgery in our hospital. Glucose tolerance was evaluated with oral glucose tolerance tests (OGTTs) performed during pre- and early postoperative periods (9 [7-18] days after surgery). Homeostasis model assessment of insulin resistance (HOMA-IR) and insulinogenic index (IGI) were calculated, and correlation analyses were performed between these values and the GH-IGF-I axis. Patients were divided according to postoperative changes of the axis, and glucose tolerance was compared between the groups. RESULTS: In preoperative OGTTs, nine patients had impaired glucose tolerance and two had diabetes mellitus patterns. Postoperatively, significant reduction was observed both in fasting plasma glucose levels (p<0.01) and in HOMA-IR (p<0.01), whereas IGI showed no significant change. HOMA-IR was significantly correlated with serum IGF-I levels both before (r=0.83, p<0.01) and after (r=0.57, p<0.01) surgery, although it was not correlated with serum GH levels. Patients who achieved more than 50% postoperative reduction in serum IGF-I levels showed significant improvement in OGTTs results (p<0.05). CONCLUSIONS: In patients with acromegaly, serum IGF-I levels, but not GH levels, were significantly correlated with insulin resistance. Early postoperative improvement of glucose tolerance is observed in patients who achieved postoperative reduction in serum IGF-I levels. PMID- 23665536 TI - Structural and biochemical characterization of the broad substrate specificity of Bacteroides thetaiotaomicron commensal sialidase. AB - Sialidases release the terminal sialic acid residue from a wide range of sialic acid-containing polysaccharides. Bacteroides thetaiotaomicron, a symbiotic commensal microbe, resides in and dominates the human intestinal tract. We characterized the recombinant sialidase from B. thetaiotaomicron (BTSA) and demonstrated that it has broad substrate specificity with a relative activity of 97, 100 and 64 for 2,3-, 2,6- and 2,8-linked sialic substrates, respectively. The hydrolysis activity of BTSA was inhibited by a transition state analogue, 2-deoxy 2,3-dehydro-N-acetyl neuraminic acid, by competitive inhibition with a Ki value of 35MUM. The structure of BSTA was determined at a resolution of 2.3A. This structure exhibited a unique carbohydrate-binding domain (CBM) at its N-terminus (a.a. 23-190) that is adjacent to the catalytic domain (a.a. 191-535). The catalytic domain has a conserved arginine triad with a wide-open entrance for the substrate that exposes the catalytic residue to the surface. Unlike other pathogenic sialidases, the polysaccharide-binding site in the CBM is near the active site and possibly holds and positions the polysaccharide substrate directly at the active site. The structural feature of a wide substrate-binding groove and closer proximity of the polysaccharide-binding site to the active site could be a unique signature of the commensal sialidase BTSA and provide a molecular basis for its pharmaceutical application. PMID- 23665537 TI - Metal-organic frameworks-based biosensor for sequence-specific recognition of double-stranded DNA. AB - A simple, cost-efficient, sensitive and selective fluorescence sensor is developed for sequence-specific recognition of duplex DNA (ds-DNA) in vitro using metal-organic framework (MOF) as the sensing platform. N,N-Bis(2-hydroxy ethyl)dithiooxamidatocopper(II) (H(2)dtoaCu) was chosen as the example MOF, because it strongly chemisorbs the dye-labeled probe TFO (triplex-forming oligonucleotide), and quenches fluorescence from the dye. In the presence of target ds-DNA (the PPT of HIV RNA, a 16-bp ds-DNA sequence), the TFO could interact with the major groove in ds-DNA (via Hoogsteen hydrogen bonding) to form a rigid triplex structure, resulting in fluorescence recovery. The enhanced fluorescence signal has a relationship with the ds-DNA concentration, the detection limit is as low as 1.3 nmol L(-1) (S/N = 3) with good selectivity, which is lower than that based on a graphene oxide platform and electrochemical DNA sensor. PMID- 23665538 TI - The effects of medical school on health outcomes: evidence from admission lotteries. AB - This paper estimates the effects of attending medical school on health outcomes by exploiting that admission to medical school in the Netherlands is determined by a lottery. Among the applicants for medical school, people who attended medical school have on average 1.5 more years of completed education than people who did not. They are also more likely to have been exposed to a health-related education curriculum. The results show only modest impacts on health outcomes. Attending medical school reduces alcohol consumption and being underweight somewhat, and has a small positive impact on self-reported health status. It has, however, a small negative effect on the frequency of physical exercise and no significant impact on smoking, and being overweight or obese. Attending medical school does have a large positive impact on the probability of being registered for donations of organs. PMID- 23665539 TI - Sick but satisfied: the impact of life and health satisfaction on choice between health scenarios. AB - Preference elicitation methods require respondents to predict the impact a change in health might have on their future selves. The focus on the change in health is at the possible expense of other experiences of life once in that health state. We analyse personal preferences to a pairwise choice task involving trade-offs between quality and length of life, where satisfaction levels with life or health are introduced in the description of the health states. We find that a health scenario including low levels of satisfaction increases the likelihood of preferring to die sooner in full health, whereas scenarios including high levels of satisfaction increase the likelihood of preferring to live for longer in poor health. The differences highlight the sensitivity of preferences to what is described in health states and therefore show the importance of on-going discussions about precisely what respondents should be asked to consider in preference elicitation studies. PMID- 23665540 TI - Decoding human gene expression signatures in the brain. AB - The evolution of higher cognitive functions in humans is thought to be due, at least in part, to the molecular evolution of gene expression patterns specific to the human brain. In this article, we explore recent and past findings using comparative genomics in human and non-human primate brain to identify these novel human patterns. We suggest additional directions and lines of experimentation that should be taken to improve our understanding of these changes on the human lineage. Finally, we attempt to put into context these genomic changes with biological phenotypes and diseases in humans. PMID- 23665541 TI - The great repression: chromatin and cryptic transcription. AB - The eukaryotic chromatin structure is essential in correctly defining transcription units. Impairing this structure can activate cryptic promoters, and lead to the accumulation of aberrant RNA transcripts. Here we discuss critical pathways that are responsible for the repression of cryptic transcription and the maintenance of genome integrity. PMID- 23665542 TI - Chirality-dependent balance between hydrogen bonding and London dispersion in isolated (+/-)-1-indanol clusters. AB - The aggregation behavior of racemic and enantiopure 1-indanol has been studied by FTIR spectroscopy, resonant ion dip IR spectroscopy, and spontaneous Raman scattering in supersonic jets. This triple experimental approach, augmented by homology to related molecular fragments and dispersion-corrected DFT predictions, allows disentangling the complex spectroscopic signature in the OH stretch range. Evidence for chirality-sensitive aggregation via isolated OH...pi bonds in competition with cooperative ...OH...OH...pi patterns is collected. An accurate description of London dispersion forces provides the key to its explanation. PMID- 23665543 TI - Pretransplant and posttransplant treatment of hepatitis C virus infection with protease inhibitors. AB - PURPOSE OF REVIEW: Considering the impact of recurrent hepatitis C after liver transplantation on patient and graft survival, we examine the current and potential use of protease inhibitors in the prevention and treatment of recurrent hepatitis C. RECENT FINDINGS: In genotype-1-infected patients in the waiting list, triple therapy with boceprevir or telaprevir should be considered in compensated cirrhotics. However, tolerability of therapy is low, and side effects are frequent and potentially life-threatening. In posttransplant hepatitis C, available data suggest that triple therapy substantially increases the virological response. Interactions of protease inhibitors with immunosuppressants are considerable, especially between tacrolimus and telaprevir. Anemia seems to be particularly frequent with triple therapy after liver transplantation. Interferon (IFN)-free regimens seem to achieve a high antiviral effect with an excellent safety profile and will probably replace the current IFN-based treatments in a few years from now. SUMMARY: Antiviral therapy with protease inhibitors will substantially increase the number of patients achieving sustained hepatitis C virus eradication, either before or after liver transplantation. However, side effects and drug-drug interactions will possibly hamper their applicability in both settings; thus, a careful selection and management of patients will be crucial. In the near future, combination of direct-acting antivirals will allow shorter, safer, and more effective IFN-free regimens. PMID- 23665544 TI - Autologous gastrointestinal reconstructive surgery: complement or alternative to intestinal transplantation. AB - PURPOSE OF REVIEW: Autologous intestinal reconstructive surgery has evolved over the past 3 decades from rescue to main surgical procedure in the multidisciplinary approach to short bowel syndrome (SBS) patients with intestinal failure. The purpose of this review is to clarify the actual place of intestinal reconstructive surgical techniques in the management of intestinal failure related to SBS and their relationship with intestinal transplantation. RECENT FINDINGS: Recent reports from centers of excellence in intestinal rehabilitation underline the efficacy and safety of autologous intestinal reconstructive surgery in patients with SBS. Outcome parameters as survival, parenteral nutrition weaning, and clinical conditions were improved in SBS patients treated by gastrointestinal reconstructive surgery. SUMMARY: Autologous intestinal reconstructive procedures are pivotal to achieve enteral autonomy in patients with intestinal failure related to SBS. They should be considered mutually supportive and not antagonistic to intestinal transplantation. PMID- 23665545 TI - Technical aspects of intestinal transplantation. AB - PURPOSE OF REVIEW: Intestinal transplantation includes an heterogeneous group of procedures in which different compositions of organs are transplanted. The current classification includes four groups according to the inclusion of the liver and/or the stomach in the graft: isolated intestinal transplantation, liver intestinal transplantation, multivisceral transplantation, and modified multivisceral transplantation. Variants exist, the technical evolution having been slow, yet constant over years. RECENT FINDINGS: The most relevant early technical improvements were aimed at achieving better feasibility and safety of the most difficult aspects of the different procedures, such as removal of the recipient's diseased organs, performing of vascular reconstructions and prevention of complications as with retention of the donor's duodenum and pancreas in liver-intestine transplantation. More recently, apart from a clear definition of the classification of the procedures, progress has been more directed in a conservative direction such as the preservation of the native spleen with and without the pancreas in multivisceral transplants. SUMMARY: After achieving consistent satisfactory short-term results, the technical interest in intestinal transplantation is now moved to solutions that, in spite of a possible increased difficulty, may offer better opportunities of mid-term and long-term successes, both in terms of survival and quality of life. PMID- 23665546 TI - Genetic aberrations of signaling pathways in lymphomagenesis: revelations from next generation sequencing studies. AB - Next generation sequencing (NGS) technology has led to a burst of disease relevant molecular information in a variety of lymphoid tumors, including chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, Burkitt lymphoma, Waldenstrom macroglobulinemia, hairy cell leukemia, and splenic marginal zone lymphoma. Beside disclosing comprehensive catalogs of somatic mutations and new insights into the genes that contribute to cellular transformation, NGS has also provided molecular clues useful for addressing a number of unmet clinical needs in the field of B-cell tumor management, including biomarkers for disease diagnosis and classification improvement (i.e. mutations of BRAF, MYD88 and NOTCH2), and new targets to be translated into therapeutic interventions (i.e. BCR, TLR, NOTCH, NF-kappaB and MAPK signaling pathways). This review summarizes the molecular lesions of signaling pathways that have been discovered in B-cell lymphoproliferative disorders by NGS studies. PMID- 23665547 TI - Selection of Vibrio harveyi-resistant Litopenaeus vannamei via a three-round challenge selection with a pathogenic strain of V. harveyi. AB - To obtain Vibrio harveyi-resistant Litopenaeus vannamei shrimp used for study on immune response of shrimp avoid vibriosis, a three-round challenge selection procedure was applied. In this procedure, resistant shrimp were selected gradually via three rounds challenge experiment with a pathogenic strain of V. harveyi at a median and controllable lethal dose of 96-h LD50 (the median lethal dose). After this procedure, the cumulative mortality of selected shrimp during 96 h after injection of V. harveyi at 2.0 * 10(6) cfu shrimp(-1) significantly decreased from 93.3% to 26.7%, the hours of beginning of death and the hours of attaining of the maximum cumulative mortality of shrimp prolonged from 4 h and 10 h to 8 h and 24 h, respectively. The LD50 of 6 h, 12 h, 24 h, 48 h and 96 h of selected shrimp significantly increased to 1.4 +/- 0.1 * 10(7) (p < 0.01), 5.5 +/ 0.4 * 10(6) (p < 0.01), 3.1 +/- 0.2 * 10(6) (p < 0.01), 2.7 +/- 0.1 * 10(6) (p < 0.01) and 2.7 +/- 0.1 * 10(6) cfu shrimp(-1) (p < 0.01), about 15.9, 15.3, 9.4, 10.0 and 10.4 times of that of normal shrimp, respectively. In conclusion, the resistance of shrimp to Vibrio significantly increased after the three-round challenge selection procedure. PMID- 23665548 TI - A single whey acidic protein domain containing protein (SWD) inhibits bacteria invasion and dissemination in shrimp Marsupenaeus japonicus. AB - The single whey acidic protein (WAP) domain containing proteins (SWDs) in crustacean belong to type III crustins and have antiprotease activities and/or antimicrobial activities. Their functions in vivo in crustacean immunity need to be clarify. In this study, a new single WAP domain containing protein (SWD) was obtained from Marsupenaeus japonicus, designated as MjSWD. The full-length cDNA of MjSWD was 522 bp.The open reading frame of MjSWD encoded a protein of 79 amino acids, with a 24 amino acid signal peptide and a WAP domain. Tissue distribution analysis revealed that MjSWD transcripts were generally expressed in all the tested tissues, including hemocytes, heart, hepatopancreas, gill, stomach and intestine. The time course expression of MjSWD was analyzed by quantitative real time PCR, and the results exhibited that MjSWD was upregulated after bacteria (Vibrio anguillarum, Staphylococcus aureus) and white spot syndrome virus (WSSV) challenge in gills and stomach of the shrimp. The purified recombinant protein of MjSWD could bind to several Gram-negative and Gram-positive bacteria though binding to microbial polysaccharides (peptidoglycan). MjSWD could inhibit the activity of Subtilisin A and Proteinase K and bacteria-secreted proteases. The results of natural infection with MjSWD incubated bacteria showed that the inhibition of MjSWD against bacterial secreted proteases was contributed to inhibiting bacteria invasion and dissemination in the shrimp. The MjSWD is, thus, involved in the shrimp antibacterial innate immunity. PMID- 23665550 TI - Disturbed balance in three subpopulations of CD4(+)Foxp3(+) regulatory T cells in Stevens-Johnson syndrome and toxic epidermal necrolysis patients. PMID- 23665549 TI - T helper-17 activation dominates the immunologic milieu of both amyotrophic lateral sclerosis and progressive multiple sclerosis. AB - MS (multiple sclerosis) and ALS (amyotrophic lateral sclerosis) differ in important respects, but common pathogenic features seem to be shared in these two diseases. To shed light on such features, immunophenotypic and functional analysis were performed in peripheral monocytes and T lymphocytes of ALS and primary progressive (PP) MS patients and healthy controls (HC). Results showed that TH1-, TH17-, and IL-6-driven inflammation characterize both diseases; this is unsuccessfully hampered by TH2 activation and, possibly, BDNF secretion. Results herein clarify the pathogenic similarities between ALS and PP-MS and could be helpful for the design of novel diagnostic and therapeutic approaches to ALS. PMID- 23665551 TI - [ATP hydrolysis-driven gating of an ABC transporter CFTR channel: from stills to movies]. PMID- 23665552 TI - [From stills to movies - attempts with protein X-ray crystallography]. PMID- 23665553 TI - [Dimerization of heregulin receptor as observed using single-molecule imaging in living cells]. PMID- 23665554 TI - [Immuno-EM in solution using the Atmospheric Scanning Electron Microscope (ASEM)]. PMID- 23665555 TI - [Roles of ERK5 in neuronal cells]. PMID- 23665556 TI - [Potency of carotenoids found in vegetables and fruits]. PMID- 23665557 TI - [Light microscopy techniques for live cell and animal imaging using fluorescent proteins]. PMID- 23665558 TI - [Change the world through business partnering - commercialization of biotechnology and open-innovation]. PMID- 23665559 TI - [Pharmacological and clinical profile of golimumab (Simponi(r))]. PMID- 23665560 TI - [Mycoplasma pneumoniae]. PMID- 23665561 TI - [Lymphangiogenesis]. PMID- 23665562 TI - Synip arrests soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-dependent membrane fusion as a selective target membrane SNARE binding inhibitor. AB - The vesicle fusion reaction in regulated exocytosis requires the concerted action of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) core fusion engine and a group of SNARE-binding regulatory factors. The regulatory mechanisms of vesicle fusion remain poorly understood in most exocytic pathways. Here, we reconstituted the SNARE-dependent vesicle fusion reaction of GLUT4 exocytosis in vitro using purified components. Using this defined fusion system, we discovered that the regulatory factor synip binds to GLUT4 exocytic SNAREs and inhibits the docking, lipid mixing, and content mixing of the fusion reaction. Synip arrests fusion by binding the target membrane SNARE (t-SNARE) complex and preventing the initiation of ternary SNARE complex assembly. Although synip also interacts with the syntaxin-4 monomer, it does not inhibit the pairing of syntaxin-4 with SNAP-23. Interestingly, synip selectively arrests the fusion reactions reconstituted with its cognate SNAREs, suggesting that the defined system recapitulates the biological functions of the vesicle fusion proteins. We further showed that the inhibitory function of synip is dominant over the stimulatory activity of Sec1/Munc18 proteins. Importantly, the inhibitory function of synip is distinct from how other fusion inhibitors arrest SNARE dependent membrane fusion and therefore likely represents a novel regulatory mechanism of vesicle fusion. PMID- 23665563 TI - A ubiquitin-like domain recruits an oligomeric chaperone to a retrotranslocation complex in endoplasmic reticulum-associated degradation. AB - The Bag6-Ubl4A-Trc35 complex is a multifunctional chaperone that regulates various cellular processes. The diverse functions of Bag6 are supported by its ubiquitous localization to the cytoplasm, the nucleus, and membranes of the endoplasmic reticulum (ER) in cells. In ER-associated degradation (ERAD) pathways, Bag6 can interact with the membrane-associated ubiquitin ligase gp78 via its ubiquitin-like (UBL) domain, but the relative low affinity of this interaction does not reconcile with the fact that a fraction of Bag6 is tightly bound to the membranes. Here, we demonstrate that the UBL domain of Bag6 is required for interaction with the ER membranes. We find that in addition to gp78, the Bag6 UBL domain also binds a UBL-binding motif in UbxD8, an essential component of the gp78 ubiquitinating machinery. Importantly, Bag6 contains a proline-rich (PR) domain termed PDP (Proline rich-DUF3587-Proline rich) that forms homo-oligomer, allowing the UBL domain to form multivalent interactions with gp78 and UbxD8, which are essential for recruitment of Bag6 to the ER membrane. Furthermore, the PR domain comprises largely intrinsically disordered segments, which are sufficient for interaction with an unfolded substrate. We propose that simultaneous association with multiple ERAD factors helps to anchor a disordered chaperone oligomer to the site of retrotranslocation to prevent protein aggregation in ERAD. PMID- 23665566 TI - What future for palliative care education? PMID- 23665564 TI - Reinterpreting the action of ATP analogs on K(ATP) channels. AB - Neuroendocrine-type K(ATP) channels, (SUR1/Kir6.2)4, couple the transmembrane flux of K(+), and thus membrane potential, with cellular metabolism in various cell types including insulin-secreting beta-cells. Mutant channels with reduced activity are a cause of congenital hyperinsulinism, whereas hyperactive channels are a cause of neonatal diabetes. A current regulatory model proposes that ATP hydrolysis is required to switch SUR1 into post-hydrolytic conformations able to antagonize the inhibitory action of nucleotide binding at the Kir6.2 pore, thus coupling enzymatic and channel activities. Alterations in SUR1 ATPase activity are proposed to contribute to neonatal diabetes and type 2 diabetes risk. The regulatory model is partly based on the reduced ability of ATP analogs such as adenosine 5'-(beta,gamma-imino)triphosphate (AMP-PNP) and adenosine 5'-O (thiotriphosphate) (ATPgammaS) to stimulate channel activity, presumably by reducing hydrolysis. This study uses a substitution at the catalytic glutamate, SUR(1E1507Q), with a significantly increased affinity for ATP, to probe the action of these ATP analogs on conformational switching. ATPgammaS, a slowly hydrolyzable analog, switches SUR1 conformations, albeit with reduced affinity. Nonhydrolyzable AMP-PNP and adenosine 5'-(beta,gamma-methylenetriphosphate) (AMP PCP) alone fail to switch SUR1, but do reverse ATP-induced switching. AMP-PCP displaces 8-azido-[(32)P]ATP from the noncanonical NBD1 of SUR1. This is consistent with structural data on an asymmetric bacterial ABC protein that shows that AMP-PNP binds selectively to the noncanonical NBD to prevent conformational switching. The results imply that MgAMP-PNP and MgAMP-PCP (AMP-PxP) fail to activate K(ATP) channels because they do not support NBD dimerization and conformational switching, rather than by limiting enzymatic activity. PMID- 23665567 TI - ehospice: palliative care news, views, and inspiration from around the world. PMID- 23665565 TI - Cosmogenic (7)Be and (22)Na in ground level air in Switzerland (1994-2011). AB - We report monthly averages of weekly (7)Be and (22)Na concentrations in aerosol samples collected with high volume aerosol filters at 5 sampling sites in Switzerland from 1994 to 2011 ((7)Be) and from 2000 to 2011 ((22)Na). Monthly average concentrations of the two cosmogenic isotopes varied between 2600 and 4600 MUBq/m(3) for (7)Be and between 0.2 MUBq/m(3) and 0.5 MUBq/m(3) for (22)Na. The (22)Na concentration in ground level air strongly increased from March to May, while a corresponding (7)Be increase was seen from March until July. The observed variations of the (7)Be and (22)Na activities together with the changes in the (7)Be/(22)Na ratio indicate input of stratospheric air between March and May, increased mixing of upper tropospheric air from June to August, and less exchange between the upper and lower troposphere in autumn and winter. Additionally, the 11-year solar cycle is clearly seen in the annual averages of the (7)Be concentrations. PMID- 23665568 TI - Transitions between care settings after enrollment in a palliative care service in Italy: a retrospective analysis. AB - This study was a retrospective analysis of prospectively collected data that aimed to map patients' care transitions following admission to a specialist palliative care service in Italy called Antea Centre. Patients' data was extracted from the Antea local database from 2007 to 2011. External transitions were defined as a change in the setting of care, with the patient no longer being cared for by Antea staff. Internal transitions were defined as a change in the setting of care, with the care still being provided by Antea staff. A total of 1123 patients out of 5313 admitted to the palliative service (21%) experienced transitions. Patients who experienced no transitions after their admission to the palliative care service were more likely to have a Karnofsky Performance Scale Index <30, to have been referred by a hospital physician, to have a shorter survival time, and to have home as their place of death (P<0.001). Although the patients with no transitions had worse clinical conditions, organisations should pay attention to reducing the possible negative effects of transitions, such as discontinuity of care and poor coordination. PMID- 23665569 TI - Outcomes of a nurse-delivered psychosocial intervention for weight- and eating related distress in family carers of patients with advanced cancer. AB - BACKGROUND: International expert consensus is that psychosocial intervention is likely to help advanced cancer patients and their family carers affected by weight loss and poor appetite. PURPOSE: To investigate the potential for a psychosocial intervention, the Macmillan Approach to Weight and Eating (MAWE), to mitigate weight- and eating-related distress in carers of patients with advanced cancer. METHOD: A controlled before and after study was conducted with carers of advanced cancer patients living in the community in the South of England in 2006 7. It used mixed methods to compare carers exposed to MAWE (n=12) with a control group (n=14). RESULTS: Weight- and eating-related distress improved in carers exposed to MAWE. Qualitative analysis found that MAWE may help carers by providing information, reassurance, and support for self-management. CONCLUSION: This preliminary study of MAWE suggests that it provides benefits as a supportive intervention. Further testing is warranted using a more robust experimental design. PMID- 23665570 TI - Cancer pain in Jordan: prevalence and adequacy of treatment. AB - BACKGROUND: Despite the introduction of numerous guidelines and pharmacological interventions to manage cancer pain, poor assessment and under-medication remain common. AIM: To estimate the prevalence of cancer pain and the adequacy of its management in Jordan. METHOD: A convenience sample of 162 cancer patients from two hospitals participated in a cross-sectional survey using an Arabic version of the Brief Pain Inventory-short form (BPI). RESULTS: 73.3% of the patients had pain severe enough to merit rating on the BPI. The mean of the worst pain scores in the past 24 hours was high at 7.5 out of 10 (standard deviation (SD) 2.7). 31% of patients with pain had not been treated for their pain, and the mean Pain Management Index score was -1.20 (SD 1.0). CONCLUSION: These cancer patients were experiencing high levels of pain, which was undertreated. Providing adequate pain management is a priority, hence more education, training, and resources are needed in Jordan to reduce cancer patients' suffering. PMID- 23665571 TI - Facilitating advance care planning in community palliative care: conversation starters across the client journey. AB - This paper describes the development of a tool for palliative care nurses to initiate and facilitate advance care planning (ACP) conversations in community palliative care practice. Seven community palliative care services located across Australia participated in a multi-site action research project. Data included participant observation, individual and focus group interviews with palliative care health professionals, and medical record audit. A directed content analysis used a pre-established palliative care practice framework of referral, admission, ongoing management, and terminal/discharge care. From this framework a Conversation Starter Tool for ACP was developed. The Tool was then used in orientation and continuing nurse education programmes. It provided palliative care nurses the opportunity to introduce and progress ACP conversations. PMID- 23665572 TI - Geriatric rehabilitation for patients with advanced COPD: programme characteristics and case studies. AB - Considering the worldwide ageing of populations, there is a growing need for rehabilitation programmes specifically designed for geriatric patients. The authors developed and implemented a post-acute geriatric rehabilitation programme in a skilled nursing facility for patients with advanced chronic obstructive pulmonary disease (COPD)-the GR-COPD programme. This paper describes the characteristics of the programme and presents three case studies to illustrate its possible benefits for individual patients. The case studies show that integration of rehabilitation and palliative care components is essential, as patients with advanced COPD admitted to hospital for an acute exacerbation often suffer from high symptom burden, deteriorating quality of life, and poor prognosis. Development and implementation of a post-acute GR-COPD programme is feasible and can offer substantial benefits for patients with advanced COPD admitted to hospital for an acute exacerbation. PMID- 23665573 TI - An evaluation of the activity of a 7-day, nurse-led specialist palliative care service in an acute district general hospital. AB - INTRODUCTION: This report describes the activity of a new 7-day-per-week, nurse led palliative care service in an acute district general hospital in the UK. METHODS: The service is based in a hospital with an integral cancer centre. On the weekends, one clinical nurse specialist (CNS) is present within the hospital, with a consultant providing telephone support. The data for this report was obtained by reviewing the team's clinical database and the patients' individual clinical assessments. RESULTS: During the first year, the CNSs undertook 651 face to-face weekend consultations. Overall, 25% of the total consultations and 18% of new patient consultations were undertaken on the weekends. The primary reasons for reviewing patients on the weekends were pain (46%), other symptoms (27.5%), and patient on the Liverpool Care Pathway (17%). Overall, 23% of new patients died over the weekend or in the early hours of the Monday morning. CONCLUSIONS: This service evaluation provides evidence of the value of having a 7-day-per-week palliative care service in an acute district general hospital. PMID- 23665575 TI - Relative effect potency estimates of dioxin-like activity for dioxins, furans, and dioxin-like PCBs in adults based on two thyroid outcomes. AB - BACKGROUND: Toxic equivalency factors (TEFs) are an important component in the risk assessment of dioxin-like human exposures. At present, this concept is based mainly on in vivo animal experiments using oral dosage. Consequently, the current human TEFs derived from mammalian experiments are applicable only for exposure situations in which oral ingestion occurs. Nevertheless, these "intake" TEFs are commonly-but incorrectly-used by regulatory authorities to calculate "systemic" toxic equivalents (TEQs) based on human blood and tissue concentrations, which are used as biomarkers for either exposure or effect. OBJECTIVES: We sought to determine relative effect potencies (REPs) for systemic human concentrations of dioxin-like mixture components using thyroid volume or serum free thyroxine (FT4) concentration as the outcomes of interest. METHODS: We used a benchmark concentration and a regression-based approach to compare the strength of association between each dioxin-like compound and the thyroid end points in 320 adults residing in an organochlorine-polluted area of eastern Slovakia. RESULTS: REPs calculated from thyroid volume and FT4 were similar. The regression coefficient (beta)-derived REP data from thyroid volume and FT4 level were correlated with the World Health Organization (WHO) TEF values (Spearman r = 0.69, p = 0.01 and r = 0.62, p = 0.03, respectively). The calculated REPs were mostly within the minimum and maximum values for in vivo REPs derived by other investigators. CONCLUSIONS: Our REPs calculated from thyroid end points realistically reflect human exposure scenarios because they are based on chronic, low-dose human exposures and on biomarkers reflecting body burden. Compared with previous results, our REPs suggest higher sensitivity to the effects of dioxin like compounds. PMID- 23665576 TI - Fluorescent molecularly imprinted polymer thin films for specific protein detection prepared with dansyl ethylenediamine-conjugated O-acryloyl L hydroxyproline. AB - Protein-imprinted polymers, capable of specific transduction of protein binding events into fluorescent signal change, were designed and synthesized by using dansyl ethylenediamine-conjugated O-acryloyl L-hydroxyproline (Hyp-En-Dans). Human serum albumin (HSA) was used as a model target protein and HSA-imprinted polymers (HSA-IP) were prepared on glass substrates. Specific fluorescence change was observed for HSA binding on the imprinted polymer thin film, whereas a weaker response was observed for other proteins, including bovine serum albumin, chymotrypsin, lysozyme, and avidin. The binding specificity was found to derive from the rigid structure of the hydrogen-bondable pyrrolidine moiety. Compared with SPR measurements, the non-specific binding caused by the polymer matrix and/or randomly located fluorescent monomer residues that did not compose specific binding sites did not contribute to the observed fluorescence change. These results revealed that the proposed protein-imprinting technique using Hyp En-Dans could provide a highly selective protein-sensing platform, in which only specific binding events would be detected by fluorescent measurements. PMID- 23665577 TI - An electrochemiluminescence aptasensor for thrombin using graphene oxide to immobilize the aptamer and the intercalated [Formula: see text] probe. AB - The immobilization of aptamer and the introduction of signal molecule are two keys for the development of electrochemiluminescence (ECL) aptasensor. Herein, the immobilization strategy with graphene oxide (GO) and a functional oligonucleotide (FO) are used to develop a sensitive aptasensor with the detection of thrombin as a model. After GO is attached on glass carbon or gold electrodes through physical adsorption, the amino-tagged aptamer is immobilized on the electrode surface via an amide linkage between the amino group at the end of aptamer and the carboxyl groups on GO. The FO is designed to contain two parts: the complementary strand and an intermolecular duplex for the intercalation of Ru(phen)32+ as ECL probe. The hybridization between aptamer and its complementary part at FO achieves the introduction of Ru(phen)32+ probe onto the electrode surface for high ECL emission. The hybrid between aptamer and thrombin leads to the release of FO containing the intercalated Ru(phen)32+ probe. Correspondingly, the decreased ECL emission is used to quantify thrombin. The concentration-dependent response of thrombin is observed between 0.90 pM and 226 pM with a detection limit of 0.40 pM. While GO is used to immobilize the aptamer with various electrodes, such as glass carbon electrode and gold electrode in this work, GO can also preconcentrate TPrA on its surface to improve the sensitivity. The well-designed label-free ECL aptasensor strategy can be easily extended to other targets via the selection of their aptamers. PMID- 23665578 TI - A new cytotoxic triterpene saponin from Lysimachia nummularia L. AB - A new glycosylated triterpene 1 (named nummularoside) was isolated from the underground parts of Lysimachia nummularia L. Its chemical structure was elucidated as 3-O-beta-{{[beta-D-xylopyranosyl-(1->2)]-[beta-D-xylopyranosyl-(1 >4)]-beta-D-glucopyranosyl-(1->4)}-[beta-D-glucopyranosyl-(1->2)-]-alpha-L arabinopyranosyl]}, protoprimulagenin A on the basis of extensive NMR and MS spectral data. The saponin showed significant activity against prostate cancer cells DU145 and PC3 (EC50 1.2 and 7.4 MUg/mL, respectively), while it did not affect normal cells (EC50 30 MUg/mL), in contrast to the reference compound (mitoxanthrone, EC50 0.45 MUg/mL). Glioblastoma cells were also significantly affected by the tested saponin (EC50 6.0 MUg/mL), whereas the activity against melanoma cells was moderate (EC50 17.5-23.2 MUg/mL). PMID- 23665579 TI - The chemorepulsive axon guidance protein semaphorin3A is a constituent of perineuronal nets in the adult rodent brain. AB - In the adult rodent brain, subsets of neurons are surrounded by densely organised extracellular matrix called perineuronal nets (PNNs). PNNs consist of hyaluronan, tenascin-R, chondroitin sulphate proteoglycans (CSPGs), and the link proteins Crtl1 and Bral2. PNNs restrict plasticity at the end of critical periods and can be visualised with Wisteria floribunda agglutinin (WFA). Using a number of antibodies raised against the different regions of semaphorin3A (Sema3A) we demonstrate that this secreted chemorepulsive axon guidance protein is localised to WFA-positive PNNs around inhibitory interneurons in the cortex and several other PNN-bearing neurons throughout the brain and co-localises with aggrecan, versican, phosphacan and tenascin-R. Chondroitinase ABC (ChABC) was injected in the cortex to degrade glycosaminoglycans (GAGs) from the CSPGs, abolishing WFA staining of PNNs around the injection site. Sema3A-positive nets were no longer observed in the area devoid of WFA staining. In mice lacking the link protein Crtl1 in the CNS only vestigial PNNs are present, and in these mice there were no Sema3A-positive PNN structures. A biochemical analysis shows that Sema3A protein binds with high-affinity to CS-GAGs and aggrecan and versican extracted from PNNs in the adult rat brain, and a significant proportion of Sema3A is retrieved in brain extracts that are enriched in PNN-associated GAGs. The Sema3A receptor components PlexinA1 and A4 are selectively expressed by inhibitory interneurons in the cortex that are surrounded by Sema3A positive PNNs. We conclude that the chemorepulsive axon guidance molecule Sema3A is present in PNNs of the adult rodent brain, bound to the GAGs of the CSPGs. These observations suggest a novel concept namely that chemorepulsive axon guidance molecules like Sema3A may be important functional attributes of PNNs in the adult brain. PMID- 23665580 TI - Nonsense-mediated mRNA decay occurs during eIF4F-dependent translation in human cells. AB - The nonsense-mediated mRNA decay (NMD) pathway degrades mRNAs undergoing premature termination of translation. It has been argued that in human cells, NMD is restricted to a pioneer round of translation initiated on mRNAs associated with the cap-binding complex (CBC) and that the exchange of the CBC for the eIF4F translation initiation complex renders mRNAs immune to NMD. Here, we demonstrate that human mRNAs undergoing eIF4F-dependent translation are not immune to NMD. First, prolonged translation inhibition does not render an NMD substrate resistant to NMD, despite allowing exchange of CBC for eIF4F. Second, eIF4F inhibitors stabilize NMD substrates undergoing cap-dependent translation. Third, the eIF4E-associated pool of an NMD substrate degrades as rapidly as the overall pool of the mRNA. Thus, eIF4F-dependent translation supports NMD in human cells, allowing for the possibility that NMD could be activated upon cellular cues on already translating mRNAs. PMID- 23665581 TI - eIF4E-bound mRNPs are substrates for nonsense-mediated mRNA decay in mammalian cells. AB - Eukaryotic mRNAs with premature translation termination codons (PTCs) are recognized and degraded through a process termed nonsense-mediated mRNA decay (NMD). The evolutionary conservation of the core NMD factors UPF1, UPF2 and UPF3 implies a similar basic mechanism of PTC recognition in all eukaryotes. However, while PTC-containing mRNAs in yeast seem to be available to NMD at each round of translation, mammalian NMD has been reported to be restricted to cap-binding complex (CBC)-bound mRNAs during the pioneer round of translation. Here, we compared decay kinetics of two NMD reporter genes in mRNA fractions bound to either CBC or the eukaryotic initiation factor 4E (eIF4E) in human cells and demonstrate that NMD destabilizes eIF4E-bound transcripts as efficiently as those associated with CBC. These results corroborate an emerging unified model for NMD substrate recognition, according to which NMD can ensue at every aberrant translation termination event. PMID- 23665582 TI - Phosphatidylinositol 4,5-bisphosphate clusters act as molecular beacons for vesicle recruitment. AB - Synaptic-vesicle exocytosis is mediated by the vesicular Ca(2+) sensor synaptotagmin-1. Synaptotagmin-1 interacts with the SNARE protein syntaxin-1A and acidic phospholipids such as phosphatidylinositol 4,5-bisphosphate (PIP2). However, it is unclear how these interactions contribute to triggering membrane fusion. Using PC12 cells from Rattus norvegicus and artificial supported bilayers, we show that synaptotagmin-1 interacts with the polybasic linker region of syntaxin-1A independent of Ca(2+) through PIP2. This interaction allows both Ca(2+)-binding sites of synaptotagmin-1 to bind to phosphatidylserine in the vesicle membrane upon Ca(2+) triggering. We determined the crystal structure of the C2B domain of synaptotagmin-1 bound to phosphoserine, allowing development of a high-resolution model of synaptotagmin bridging two different membranes. Our results suggest that PIP2 clusters organized by syntaxin-1 act as molecular beacons for vesicle docking, with the subsequent Ca(2+) influx bringing the vesicle membrane close enough for membrane fusion. PMID- 23665583 TI - Turning catalytically inactive human Argonaute proteins into active slicer enzymes. AB - Argonaute proteins interact with small RNAs that guide them to complementary target RNAs, thus leading to inhibition of gene expression. Some but not all Argonaute proteins are endonucleases and can cleave the complementary target RNA. Here, we have mutated inactive human Ago1 and Ago3 and generated catalytic Argonaute proteins. We find that two short sequence elements at the N terminus are important for activity. In addition, PIWI-domain mutations in Ago1 may misarrange the catalytic center. Our work helps in understanding of the structural requirements that make an Argonaute protein an active endonucleolytic enzyme. PMID- 23665584 TI - Analysis of SEMA6B gene expression in breast cancer: identification of a new isoform. AB - BACKGROUND: SEMA6B is a member of the semaphorins axon-guidance family. A growing body of evidence has been accumulated describing the role of semaphorin molecules in cancer development and the involvement of SEMA6B in cancer progression has recently been proposed. METHODS: Our analysis, based on real-time PCR, focused on the expression of SEMA6B in a panel of breast cancer tissues, compared to the normal counterpart. RESULTS: In cancer tissues we found a significantly strong down-modulation of this transcript. Moreover we identified and characterized a novel SEMA6B isoform, named SEMA6Ba. This isoform has a novel splice junction, created by the usage of alternative donor and acceptor splice sites internal to the exon 17. By in silico analysis we found that the new transcript 3' UTR lacks some highly-conserved miRNA binding sites, suggesting possible consequences on both spatial and temporal expression of SEMA6Ba. The translated sequence of SEMA6Ba lacks the cytoplasmic tail, crucial for triggering the reverse signaling described for the transmembrane semaphorins. We also demonstrated, by immunofluorescence analysis of endogenous and overexpressed SEMA6Ba, that the protein clearly localized to the endoplasmic reticulum and plasma membrane. In conclusion, SEMA6B gene products are strongly down modulated in breast cancer tissues and a new isoform named SEMA6Ba has been described and characterized. GENERAL SIGNIFICANCE: Our work states a clear relation among breast cancer and SEMA6B expression; moreover we describe for the first time the SEMA6Ba protein and report here the analysis of SEMA6Ba RNA messenger, the protein expression and the cellular localization. PMID- 23665585 TI - Albumin-drug interaction and its clinical implication. AB - BACKGROUND: Human serum albumin acts as a reservoir and transport protein for endogenous (e.g. fatty acids or bilirubin) and exogenous compounds (e.g. drugs or nutrients) in the blood. The binding of a drug to albumin is a major determinant of its pharmacokinetic and pharmacodynamic profile. SCOPE OF REVIEW: The present review discusses recent findings regarding the nature of drug binding sites, drug albumin binding in certain diseased states or in the presence of coadministered drugs, and the potential of utilizing albumin-drug interactions in clinical applications. MAJOR CONCLUSIONS: Drug-albumin interactions appear to predominantly occur at one or two specific binding sites. The nature of these drug binding sites has been fundamentally investigated as to location, size, charge, hydrophobicity or changes that can occur under conditions such as the content of the endogenous substances in question. Such findings can be useful tools for the analysis of drug-drug interactions or protein binding in diseased states. A change in protein binding is not always a problem in terms of drug therapy, but it can be used to enhance the efficacy of therapeutic agents or to enhance the accumulation of radiopharmaceuticals to targets for diagnostic purposes. Furthermore, several extracorporeal dialysis procedures using albumin containing dialysates have proven to be an effective tool for removing endogenous toxins or overdosed drugs from patients. GENERAL SIGNIFICANCE: Recent findings related to albumin-drug interactions as described in this review are useful for providing safer and efficient therapies and diagnoses in clinical settings. This article is part of a Special Issue entitled Serum Albumin. PMID- 23665586 TI - The challenges of using fluorescent probes to detect and quantify specific reactive oxygen species in living cells. AB - BACKGROUND: Small molecule fluorescent probes are vital tools for monitoring reactive oxygen species in cells. SCOPE OF REVIEW: The types of probe available, the extent to which they are specific or quantitative and complications in interpreting results are discussed. MAJOR CONCLUSIONS: Most commonly used probes (e.g. dihydrodichlorofluorescein, dihydrorhodamine) have some value in providing information on changes to the redox environment of the cell, but they are not specific for any one oxidant and the response is affected by numerous chemical interactions and not just increased oxidant generation. These probes generate the fluorescent end product by a free radical mechanism, and to react with hydrogen peroxide they require a metal catalyst. Probe radicals can react with oxygen, superoxide, and various antioxidant molecules, all of which influence the signal. Newer generation probes such as boronates act by a different mechanism in which nucleophilic attack by the oxidant on a blocking group releases masked fluorescence. Boronates react with hydrogen peroxide, peroxynitrite, hypochlorous acid and in some cases superoxide, so are selective but not specific. They react with hydrogen peroxide very slowly, and kinetic considerations raise questions about how the reaction could occur in cells. GENERAL SIGNIFICANCE: Data from oxidant-sensitive fluorescent probes can provide some information on cellular redox activity but is widely misinterpreted. Recently developed non-redox probes show promise but are not generally available and more information on specificity and cellular reactions is needed. We do not yet have probes that can quantify cellular production of specific oxidants. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn. PMID- 23665587 TI - Calorimetric analysis of the plasma proteome: identification of type 1 diabetes patients with early renal function decline. AB - BACKGROUND: Microalbuminuria (MA) has been questioned as a predictor of progressive renal dysfunction in patients with type 1 diabetes (T1D). Consequently, new clinical end points are needed that identify or predict patients that are at risk for early renal function decline (ERFD). The potential clinical utility of differential scanning calorimetry (DSC) analysis of blood plasma and other biofluids has recently been reported. This method provides an alternate physical basis with which to study disease-associated changes in the bulk plasma proteome. METHODS: DSC analysis of blood plasma was applied to identify unique signatures of ERFD in subjects enrolled in the 1st Joslin Study of the Natural History of Microalbuminuria in Type 1 Diabetes, a prospective cohort study of T1D patients. Recent data suggests that differences in the plasma peptidome of these patients correlate with longitudinal measures of renal function. Differences in DSC profile (thermogram) features were evaluated between T1D MA individuals exhibiting ERFD (n=15) and matched control subjects (n=14). RESULTS: The average control group thermogram resembled a previously defined healthy thermogram. Differences were evident between ERFD and control individuals. Heat capacity values of the main two transitions were found to be significant discriminators of patient status. CONCLUSIONS: Results from this pilot study suggest the potential utility of DSC proteome analysis to prognostic indicators of renal disease in T1D. GENERAL SIGNIFICANCE: DSC shows sensitivity to changes in the bulk plasma proteome that correlate with clinical status in T1D providing additional support for the utility of DSC profiling in clinical diagnostics. PMID- 23665588 TI - Zebrafish transforming growth factor-beta-stimulated clone 22 domain 3 (TSC22D3) plays critical roles in Bmp-dependent dorsoventral patterning via two deubiquitylating enzymes Usp15 and Otud4. AB - BACKGROUND: Osmotic stress transcription factor 1/transforming growth factor-beta stimulated clone 22 domain 3 (Ostf1/Tsc22d3) is a transcription factor that plays an osmoregulatory role in euryhaline fishes. Its mRNA and protein levels are up regulated under hyperosmotic stress. However, its osmoregulatory and developmental functions have not been studied in any stenohaline freshwater fishes. Zebrafish is an excellent model to perform such study to unfold the functional role of Tsc22d3. METHODS: We identified the zebrafish Tsc22d3 and performed knockdown studies using morpholino antisense oligonucleotide (MO). RESULTS: Zebrafish Tsc22d3 did not response to hypertonic stress and ts22d3 knockdown or overexpression by injecting MO or capped RNA did not change the transcriptional levels of any of the known ionocyte markers. To reveal the unknown function of zebrafish Tsc22d3, we performed several in situ molecular marker studies on tsc22d3 morphants and found that Tsc22d3 plays multi-functional roles in dorsoventral (DV) patterning, segmentation, and brain development. We then aimed to identify the mechanism of Tsc22d3 in the earliest stages of DV patterning. Our results demonstrated that tsc22d3 is a ventralizing gene that can stimulate the transcription of bone morphogenetic protein 4 (bmp4) and, thus, has a positive effect on the Bmp signaling pathway. Furthermore, we showed that Tsc22d3 interacts with deubiquitylating enzymes, ubiquitin-specific protease 15 (Usp15) and ovarian tumor domain containing protein 4 (Otud4). In addition, the interruption of Bmp4 signaling by double knockdown of usp15 and otud4 reduced the ventralized effects in tsc22d3-overexpressing embryos. CONCLUSIONS: This is the first study to identify new developmental functions of Tsc22d3 in zebrafish. GENERAL SIGNIFICANCE: Zebrafish tsc22d3 is a ventralizing gene and plays a role in early embryogenesis. PMID- 23665589 TI - Efficient chromatin immunoprecipitation using limiting amounts of biomass. AB - Chromatin immunoprecipitation (ChIP) is a widely-used method for determining the interactions of different proteins with DNA in chromatin of living cells. Examples include sequence-specific DNA binding transcription factors, histones and their different modification states, enzymes such as RNA polymerases and ancillary factors, and DNA repair components. Despite its ubiquity, there is a lack of up-to-date, detailed methodologies for both bench preparation of material and for accurate analysis allowing quantitative metrics of interaction. Due to this lack of information, and also because, like any immunoprecipitation, conditions must be re-optimized for new sets of experimental conditions, the ChIP assay is susceptible to inaccurate or poorly quantitative results. Our protocol is ultimately derived from seminal work on transcription factor:DNA interactions(1,2) , but incorporates a number of improvements to sensitivity and reproducibility for difficult-to-obtain cell types. The protocol has been used successfully(3,4) , both using qPCR to quantify DNA enrichment, or using a semi quantitative variant of the below protocol. This quantitative analysis of PCR amplified material is performed computationally, and represents a limiting factor in the assay. Important controls and other considerations include the use of an isotype-matched antibody, as well as evaluation of a control region of genomic DNA, such as an intergenic region predicted not to be bound by the protein under study (or anticipated not to show changes under the experimental conditions). In addition, a standard curve of input material for every ChIP sample is used to derive absolute levels of enrichment in the experimental material. Use of standard curves helps to take into account differences between primer sets, regardless of how carefully they are designed, and also efficiency differences throughout the range of template concentrations for a single primer set. Our protocol is different from others that are available(5-8) in that we extensively cover the later, analysis phase. PMID- 23665590 TI - Quantitative proteomics reveals the temperature-dependent proteins encoded by a series of cluster genes in thermoanaerobacter tengcongensis. AB - Comprehensive and quantitative information of the thermophile proteome is an important source for understanding of the survival mechanism under high growth temperature. Thermoanaerobacter tengcongensis (T. tengcongensis), a typical anaerobic thermophilic eubacterium, was selected to quantitatively evaluate its protein abundance changes in response to four different temperatures. With optimized procedures of isobaric tags for relative and absolute quantitation quantitative proteomics (iTRAQ), such as peptide fractionation with high-pH reverse phase (RP) high performance liquid chromatography (HPLC), tandem MS acquisition mode in LTQ Orbitrap Velos MS, and evaluation of the quantification algorithms, high quality of the quantitative information of the peptides identified were acquired. In total, 1589 unique proteins were identified and defined 251 as the temperature-dependent proteins. Analysis of genomic locations toward the correspondent genes of these temperature-dependent proteins revealed that more than 30% were contiguous units with relevant biological functions, which are likely to form the operon structures in T. tengcongensis. The RNA sequencing (RNA-seq) data further demonstrated that these cluster genes were cotranscribed, and their mRNA abundance changes responding to temperature exhibited the similar trends as the proteomic results, suggesting that the temperature-dependent proteins are highly associated with the correspondent transcription status. Hence, the operon regulation is likely an energy-efficient mode for T. tengcongensis survival. In addition, evaluation to the functions of differential proteomes indicated that the abundance of the proteins participating in sulfur-respiration on the plasma membrane was decreased as the temperature increased, whereas the glycolysis-related protein abundance was increased. The energy supply in T. tengcongensis at high temperature is, therefore, speculated not mainly through the respiration chain reactions. PMID- 23665592 TI - The Association Between Hospital-Treated Injuries and ADHD Symptoms in Childhood and Adolescence: A Follow-Up Study in the Northern Finland Birth Cohort 1986. AB - OBJECTIVE: We examined the risk of hospital-treated injuries related to the symptoms/diagnosis of ADHD. METHOD: The study population (N = 6,111) was composed from the Northern Finland Birth Cohort 1986. At the age of 8, symptoms of hyperactivity and at the age of 15, symptoms of ADHD were assessed by the parents while the clinical diagnoses of ADHD were set in adolescence. Information on injuries was obtained from national register. RESULTS: The risk for hospital treated injuries during ages 0 to 7 was 1.7-fold increased among those with symptoms of hyperactivity assessed at age 8. Also, injuries during ages 7 to 15 years were more common among those with symptoms of ADHD at age 15 with respect to any injury, fractures, and intracranial injuries, and among those with the diagnosis of ADHD with respect to any injury. CONCLUSION: The present study shows an association between hospital-treated injuries and symptoms of ADHD in a large epidemiological sample of 0- to 15-year-old children. PMID- 23665591 TI - Temporal analysis of the magnaporthe oryzae proteome during conidial germination and cyclic AMP (cAMP)-mediated appressorium formation. AB - Rice blast disease caused by Magnaporthe oryzae is one of the most serious threats to global rice production. During the earliest stages of rice infection, M. oryzae conidia germinate on the leaf surface and form a specialized infection structure termed the appressorium. The development of the appressorium represents the first critical stage of infectious development. A total of 3200 unique proteins were identified by nanoLC-MS/MS in a temporal study of conidial germination and cAMP-induced appressorium formation in M. oryzae. Using spectral counting based label free quantification, observed changes in relative protein abundance during the developmental process revealed changes in the cell wall biosynthetic machinery, transport functions, and production of extracellular proteins in developing appressoria. One hundred and sixty-six up-regulated and 208 down-regulated proteins were identified in response to cAMP treatment. Proteomic analysis of a cAMP-dependent protein kinase A mutant that is compromised in the ability to form appressoria identified proteins whose developmental regulation is dependent on cAMP signaling. Selected reaction monitoring was used for absolute quantification of four regulated proteins to validate the global proteomics data and confirmed the germination or appressorium specific regulation of these proteins. Finally, a comparison of the proteome and transcriptome was performed and revealed little correlation between transcript and protein regulation. A subset of regulated proteins were identified whose transcripts show similar regulation patterns and include many of the most strongly regulated proteins indicating a central role in appressorium formation. A temporal quantitative RT-PCR analysis confirmed a strong correlation between transcript and protein abundance for some but not all genes. Collectively, the data presented here provide the first comprehensive view of the M. oryzae proteome during early infection-related development and highlight biological processes important for pathogenicity. PMID- 23665593 TI - Novel tetranuclear triarylantimony(V) complexes with (+/-)-mandelic acid ligands: synthesis, characterization, in vitro cytotoxicity and DNA binding properties. AB - Four novel tetranuclear organoantimony(V) complexes [R3SbL]4, in which LH = (+/-) mandelic acid and R = phenyl (1), 4-fluorophenyl (2), 3-fluorophenyl (3), 3,4,5 trifluorophenyl (4), were synthesized and characterized. The complexes displayed rapid, low micromolar in vitro cytotoxicity against a range of epithelial tumour cells and efficient CT-DNA binding. PMID- 23665594 TI - Effects of O2 pressure on the oxidation of VO(x)/Pt(111). AB - Vanadium oxide (VO(x)) has been extensively used in many oxidation and selective oxidation reactions. In this study, VO(x) thin films were prepared in an ultra high vacuum (UHV) chamber by evaporating V onto a Pt(111) surface followed by subsequent oxidation at 623 K in 1 * 10(-7) Torr O2, and further oxidized in the 'high-pressure' reaction cell with 1 Torr O2. The film quality and structure were investigated by high-resolution electron energy loss spectroscopy (HREELS), X-ray photoelectron spectroscopy (XPS), low energy electron diffraction (LEED), low energy ion scattering spectroscopy (LEIS), Auger electron spectroscopy (AES), and in situ infrared reflection absorption spectroscopy (IRAS). On the Pt(111) surface, VO(x) forms isolated O=VO(x) (x = 0-3) species, surface two-dimensional (2D) (2 * 2)-V2O3 domains, a bi-layer structure with a (3?3 * 6) arrangement, and a complicated tri-layer structure as the coverage increases from submonolayer to multilayer. Under the UHV conditions, the oxidation state of V is mainly +3 and the stability was found to be surface V2O3 > bi-layer V2O3 > tri-layer one. After exposing to 0.3-1 Torr O2, VO(x) can be oxidized to higher oxidation states, mainly V2O5, as evidenced by the shifts of the core-level binding energies and presence of V=O. These results indicate that thorough oxidation of VO(x) requires sufficiently high O2 pressure, and that vanadium-based catalysts may possess higher oxidation states under most reaction conditions in the presence of O2. PMID- 23665596 TI - Bilirubin nomogram, a prediction tool or natural history profile? PMID- 23665597 TI - The journal grows Dr. OP Ghai as editor from 1973-75. PMID- 23665598 TI - Lactobacillus rhamnosus GG supplementation for preventing respiratory infections in children: a meta-analysis of randomized, placebo-controlled trials. AB - OBJECTIVE: To systematically review the effectiveness of administering Lactobacillus rhamnosus GG (LGG) for preventing respiratory infections in children. DESIGN: Systematic Review and Meta-analysis. DATA SOURCES: Electronic databases and trial registries. RESULTS: Four RCTs involving 1805 participants met the inclusion criteria. Compared with placebo, LGG administration was associated with a reduced incidence of acute otitis media (four RCTs, n=1805, RR 0.76, 95% CI 0.64-0.91, fixed effects model, NNT 17, 95% CI 11-46), a reduced risk of upper respiratory infections (one RCT, n=281, RR 0.62, 95% CI 0.50-0.78, NNT 4, 95% CI 3-8) and antibiotic treatments (four RCTs, n=1805, RR 0.80, 95% CI 0.71-0.91, fixed effects model). There was no significant difference between the LGG and the control groups in the risk of overall respiratory infections and the incidence of lower respiratory infections. However, subgroup analysis of two studies on children older than 1 year showed significant reduction in the risk of overall respiratory infections (two RCTs, n=794, RR 0.73, 95% CI 0.57-0.92, random effects model, NNT 8, 95% CI 5-14). Adverse effects were similar in both groups. No serious adverse events were reported. CONCLUSION: The administration of Lactobacillus rhamnosus GG compared with placebo has the potential to reduce the incidence of acute otitis media, the upper respiratory infections and antibiotic use in children. PMID- 23665599 TI - Consensus Statement of the Indian Academy of Pediatrics on integrated management of severe acute malnutrition. AB - JUSTIFICATION: Severe acute malnutrition (SAM) is a major public health issue. It afflicts an estimated 8.1 million under-five children in India causing nearly 0.6 million deaths. The improved understanding of pathophysiology of SAM as well as new internationally accepted growth charts and newer modalities of integrated intervention have necessitated a relook at IAP recommendations. PROCESS: A National Consultative Meeting on Integrated Management of Severe Acute Malnutrition was held in Mumbai on 16th and 17th October, 2010. It was attended by the invited experts in the field. Extensive discussions were held as per the program. The participants were then divided into six groups for detailed discussions. The groups deliberated on various issues pertaining to the task assigned and presented recommendations of the groups in a plenary session. The participants made a list of recommendations after extensive discussions. A Writing Committee was formed and was entrusted with the task of drawing a Consensus Statement on the basis of these Recommendations. After multiple deliberations, the following Consensus Statement was adopted. OBJECTIVES: To critically evaluate the current global evidence to formulate a consensus among stakeholders regarding diagnosis and management of SAM. RECOMMENDATIONS: An integrated management of malnutrition is likely to yield more dividends. Thus, management of SAM should constitute an important component of Integrated Management of Neonatal and Childhood Illnesses (IMNCI) program. Determination of SAM on the basis of Z-scores using WHO Growth charts is considered statistically more appropriate than cut-offs based on percentage weight deficit of the median. Considering the fact that many children with SAM can be successfully managed on outpatient basis and even in the community, it is no more considered necessary to advise admission of all children with SAM to a healthcare facility. Management of SAM should not be a stand-alone program. It should integrate with community management therapeutic programs and linkages with child treatment center, district hospitals and tertiary level centers offering inpatient management for SAM and include judicious use of ready-to-use-therapeutic Food (RUTF). All sections of healthcare providers need to be trained in the integrated management of SAM. PMID- 23665600 TI - Short syndrome-an expanding phenotype. AB - The phenotypic description of SHORT syndrome (OMIM- 269880) is expanding since its initial description in 1975. There have been 26 case reports till date but the genetic locus of this syndrome is elusive. Involvement of PITX2 gene initially envisaged is probably is not the only gene involved but has an important role to play in ocular development. Our case did not demonstrate mutation in PITX2 gene. Here, we report a case of SHORT syndrome with two new unreported features deviated nasal septum and cryptorchidism and stress on lipodystrophy, a cardinal feature but not a part of the pneumonic SHORT. PMID- 23665601 TI - Apparent mineralocorticoid excess (AME) syndrome. AB - Apparent mineralocorticoid excess (AME) syndrome is a rare autosomal recessive disorder due to the deficiency of 11b hydroxysteroid dehydrogenase type 2 enzyme (11beta-HSD2). Mutations in this gene affect the enzymatic activity resulting to an excess of cortisol, which causes its inappropriate access to mineralocorticoid receptor leading to inherited hypertension.This is a potentially fatal but treatable disorder. We present clinical and molecular studies on two sisters diagnosed as AME. PMID- 23665602 TI - Fulminant Epstein Barr virus encephalitis. AB - Epstein Barr virus (EBV) encephalitis is rare in children but can have severe neurological complications and sometimes fatal. It can manifest with varied neurological presentations like meningoencephalitis, brain stem encephalitis, GBS etc. This can appear alone or with clinical picture of infectious mononucleosis. Establishing a diagnosis of EBV encephalitis is difficult and consequently molecular, serological and imaging techniques should be used when investigating a child with encephalitis. To highlight this entity we report two fatal cases of EBV meningoencephalitis presenting with sole neurological manifestations. PMID- 23665603 TI - Ectopic thyroid in presumed thyroglossal duct cyst. AB - We report a case of an eight year old female child with a midline neck mass for seven years. Since its early presentation, this midline mass has recently increased in size. A presumptive diagnosis of thyroglossal duct cyst was made clinically and planned for surgery. Preoperative evaluation revealed hypothyroidism, hence she was referred to us for the management of the same prior to excision. On further evaluation 99 Tc-thyroid scan showed that this midline mass was in fact the only functioning thyroid tissue and ultrasonography revealed no thyroid tissue in usual location, therefore no surgery was performed. This case demonstrates the essential role of a thyroid scan and ultrasonography in the preoperative evaluation of a midline neck mass. PMID- 23665604 TI - Continuous glucose monitoring system for congenital hyperinsulinemia. AB - Blood glucose monitoring is a way of testing the concentration of glucose in the blood. The most recent advance is the development of continuous glucose monitoring system (CGMS) which gives 24 hour trend of blood sugar levels thus helping both the patient and the physician in achieving better glycemic control. CGMS in pediatric population is generally used for those on insulin pumps and those who are having fluctuating blood glucose levels. This case highlights the use of CGMS for a child with congenital hyperinsulinemia. It helped in close monitoring of blood glucose levels thereby identifying recurrent hypoglycemia, leading to a better control of blood glucose levels. PMID- 23665605 TI - Angioedema following ingestion of fried flying red fire ants. AB - Red ants sting anaphylaxis was rarely reported from India. But angioedema due to ingestion of fried flying red fire ants in children is almost never reported from India and also very rarely reported from outside India. We report a case of recurrent non allergic angioedema following ingestion of fried flying red ants. PMID- 23665606 TI - Precocious puberty as initial presentation in mediastinal tumour. AB - Numerous disorders can cause precocious puberty in children, and germ cell tumours (GCT) are one of the rare causes . We report two cases of mediastinal malignant GCTs who presented with precocious puberty. Both patients had bulky and advanced disease, were aggressively treated with neo-adjuvant chemotherapy and surgery, and are surviving and free of disease. PMID- 23665607 TI - Profile of children with poor school performance in Mumbai. AB - We report on the etiology of poor school performance (PSP) in children assessed at a learning disability clinic in western India over 12 months. Specific learning disabilities (dyslexia, dysgraphia and dyscalculia) were the commonest cause of PSP (72.76%), followed by borderline intellectual functioning (8.94%), language barrier (8.54%), and mental retardation (4.88%). PMID- 23665608 TI - Acute demyelinating encephalomyelitis in malaria. PMID- 23665609 TI - Glibenclamide for neonatal diabetes. PMID- 23665610 TI - Vitamin d intoxication: too much of a good thing! PMID- 23665611 TI - Gemcitabine induced skin rash. PMID- 23665612 TI - Unusual Migration of VP Shunt. PMID- 23665613 TI - The long and short of PKC modulation of the L-type calcium channel. PMID- 23665614 TI - Pannexins after stroke: knocking-out membrane channels to improve neurological function. PMID- 23665615 TI - An improved lectin-based method for the detection of mucin-type O-glycans in biological samples. AB - Mucins and mucin-type glycoproteins, collectively referred to as mucin-type O glycans, are implicated in many important biological functions and pathological conditions, including malignancy. Presently, there is no reliable method to measure the total mucin-type O-glycans of a sample, which may contain one or more of these macromolecules of unknown structures. We report the development of an improved microassay that is based on the binding of lectins to the unique and constant GalNAc-Ser/Thr structural feature of mucin-type O-glycans. Since the sugar-amino acid linkage in the mucin-type O-glycans is invariably cryptic, we first chemically removed the heterogeneous peripheral and core saccharides of model glycoconjugates before examining for their interactions using an enzyme linked lectin assay (ELLA). Desialylation of the model glycoconjugates led to maximal binding of the lectins but additional treatments such as Smith degradation did not result in increased binding. Of the lectins tested for their ability to probe the desialylated O-glycans, jacalin showed the highest sensitivity followed by champedak galactose binding (CGB) lectin and Vicia villosa agglutinin. Further improvement in the sensitivity of ELLA was achieved by using microtiter plates that were pre-coated with the CGB lectin, which increased the specificity of the assay to mucin-type O-glycans. Finally, the applicability of the developed sandwich ELLA to crude samples was demonstrated by estimating trace quantities of the mucin-type O-glycans in the human serum. PMID- 23665616 TI - Design, characterization, teratogenicity testing, antibacterial, antifungal and DNA interaction of few high spin Fe(II) Schiff base amino acid complexes. AB - In this study, new Fe(II) Schiff base amino acid chelates derived from the condensation of o-hydroxynaphthaldehyde with L-alanine, L-phenylalanine, L aspartic acid, L-histidine and L-arginine were synthesized and characterized via elemental, thermogravimetric analysis, molar conductance, IR, electronic, mass spectra and magnetic moment measurements. The stoichiometry and the stability constants of the complexes were determined spectrophotometrically. Correlation of all spectroscopic data suggested that Schiff bases ligands exhibited tridentate with ONO sites coordinating to the metal ions via protonated phenolic-OH, azomethine-N and carboxylate-O with the general formulae [Fe(HL)2].nH2O. But in case of L-histidine, the ligand acts as tetradentate via deprotonated phenolic OH, azomethine-N, carboxylate-O and N-imidazole ring ([FeL(H2O)2].2H2O), where HL=mono anion and L=dianion of the ligand. The structure of the prepared complexes is suggested to be octahedral. The prepared complexes were tested for their teratogenicity on chick embryos and found to be safe until a concentration of 100 MUg/egg with full embryos formation. Moreover, the interaction between CT DNA and the investigated complexes were followed by spectrophotometric and viscosity measurements. It was found that, the prepared complexes bind to DNA via classical intercalative mode and showed a different DNA activity with the sequence: nhi>nari>nali>nasi>nphali. Furthermore, the free ligands and their complexes are screened for their in vitro antibacterial and antifungal activity against three types of bacteria, Escherichia coli, Pseudomonas aeruginosa and Bacillus cereus and three types of anti fungal cultures, Penicillium purpurogenium, Aspergillus flavus and Trichotheium rosium in order to assess their antimicrobial potential. The results show that the metal complexes are more reactive with respect to their corresponding Schiff base amino acid ligands. PMID- 23665617 TI - Hexachlorocyclohexanes (HCHs) in placenta and umbilical cord blood and dietary intake for women in Beijing, China. AB - Placenta and umbilical cord blood are important media for investigating maternal fetal exposure to environmental pollutants. Historically hexachlorocyclohexanes (HCHs) were once widely-used in China. In this study, residues of HCHs were measured in placenta and umbilical cord blood samples for 40 women from Beijing. The measured median values of HCHs were 62.0 and 68.8 ng/g fat in placenta and umbilical cord blood, respectively. Concentrations of HCHs in placenta and umbilical cord blood of urban cohort were higher than those of rural group due to enhanced consumption of fish, meat, and milk. Residues of HCHs in placenta were significantly correlated with total food consumption, dietary intake, and maternal age, and could be predicted using the parameters dependent upon ingestion of meat and milk. The transplacental exposure of fetuses to HCHs was revealed by a close association between the residual levels in the paired placenta and the paired umbilical cord blood samples. PMID- 23665618 TI - Protective role of fine silts for PAH in a former industrial soil. AB - An original combined organic geochemistry and soil science approach was used to elucidate PAH availability controlling factors in a multi-contaminated industrial soil. Water granulodensimetric fractionation was applied to obtain five water stable material fractions. These were characterized by elemental, molecular and mineral analysis, and microscopic observations. Among the different fractions, fine silts distinguished themselves by higher carbon and nitrogen contents, lower C/N ratio, an enrichment in total PAH and especially high molecular weight compounds, a coal tar signature and the lowest PAH availability. This fine silt fraction seemed to play a protective role for PAH that might be explained by its size and/or its specific reactivity. The mineral phases present in this fraction were proposed to explain the protection of organic matter. This led to a specific molecular signature of OM, having higher sorption properties both processes (sorption and mineral-bound protection) resulting in a lower PAH availability. PMID- 23665619 TI - Vertical eddy diffusion as a key mechanism for removing perfluorooctanoic acid (PFOA) from the global surface oceans. AB - Here we estimate the importance of vertical eddy diffusion in removing perfluorooctanoic acid (PFOA) from the surface Ocean and assess its importance as a global sink. Measured water column profiles of PFOA were reproduced by assuming that vertical eddy diffusion in a 3-layer ocean model is the sole cause for the transport of PFOA to depth. The global oceanic sink due to eddy diffusion for PFOA is high, with accumulated removal fluxes over the last 40 years of 660 t, with the Atlantic Ocean accounting for 70% of the global oceanic sink. The global oceans have removed 13% of all PFOA produced to a depth greater than 100 m via vertical eddy diffusion; an additional 4% has been removed via deep water formation. The top 100 m of the surface oceans store another 21% of all PFOA produced (~1100 t). PMID- 23665620 TI - An SH2 domain-based tyrosine kinase assay using biotin ligase modified with a terbium(III) complex. AB - Src homology 2 (SH2) domains are modules of approximately 100 amino acids and are known to bind phosphotyrosine-containing sequences with high affinity and specificity. In the present work, we developed an SH2 domain-based assay for Src tyrosine kinase using a unique biotinylation reaction from archaeon Sulfolobus tokodaii. S. tokodaii biotinylation has a unique property that biotin protein ligase (BPL) forms a stable complex with its biotinylated substrate protein (BCCP). Here, an SH2 domain from lymphocyte-specific tyrosine kinase was genetically fused to a truncated BCCP, and the resulting fusion protein was labeled through biotinylation with BPL carrying multiple copies of a luminescent Tb(3+) complex. The labeled SH2 fusion proteins were employed to detect a phosphorylated peptide immobilized on the surface of the microtiter plate, where the phosphorylated peptide was produced by phosphorylation to the substrate peptide by Src tyrosine kinase. Our assay allows for a reliable determination of the activity of Src kinase lower than 10 pg/MUL by a simple procedure. PMID- 23665621 TI - Highly sensitive fluorescent immunoassay of human immunoglobulin G based on PbS nanoparticles and DNAzyme. AB - This paper reports a highly sensitive fluorescent immunoassay for the detection of human immunoglobulin G based on PbS nanoparticles and DNAzyme. A sandwich immunoassay format was performed on a microtiter plate. Goat anti-human IgG was coated onto the polystyrene microtiter plate. The human IgG analyte was first captured by the goat anti-human IgG, and then sandwiched by a goat anti-human IgG antibody labeled with PbS nanoparticles. After being dissolved with HNO3, the released Pb(2+) made the substrate chain of the DNAzyme labeled with the fluorophore dissociate from the enzyme strand of the DNAzyme labeled with the quencher, which resulted in fluorescence recovery. Then, the human IgG could be detected indirectly from the fluorescent signals. Under the optimized conditions, the linear range of the developed immunosensor was from 1 ng mL(-1) to 10 MUg mL( 1) with a detection limit of 0.8 ng mL(-1). This immunosensor could be used to detect the amount of human IgG in human serum samples. PMID- 23665622 TI - Simple determination of L-ascorbic acid on TLC by visual detection using autocatalytic reaction. AB - The L-ascorbic acid concentration in beverages was measured after separation by silica gel thin layer chromatography (TLC) by visually determining the time in autocatalytic reaction for the L-ascorbic acid spot to turn the same yellow color of the background and disappear (the end time of the induction period) after spraying the slide with a 3,6-dihydroxyxanthane solution. There was a good linear relationship between the end time of the induction period and the concentration of L-ascorbic acid for concentrations in the range of 5.0 - 20 mM (r(2) = 0.9944). In addition, there was a good relationship expressed by a quadratic equation in the concentration range of 0.1 - 5.0 mM (r(2) = 0.9975). The relative standard deviations of the L-ascorbic acid values for 3 beverages (2.2 - 8.6 mM) were less than 5% (n = 5), and the recovery of 5.0 mM L-ascorbic acid from 4 beverages (0.7 - 7 mM) was 97 - 110%. A good correlation was also observed between the L-ascorbic acid values of 23 beverages (0 - 86 mM) determined by the proposed TLC method and the colorimetric method contained in a commercially available kit for L-ascorbic acid (r(2) = 0.9945). PMID- 23665623 TI - A simple HPLC method for determining the purine content of beer and beer-like alcoholic beverages. AB - Several methods for quantifying the purine content in food and drink have been described using high-performance liquid chromatography (HPLC). We have developed an improved HPLC method that is based on a method reported by Kaneko et al. and that is more sensitive yet simple, and suitable for determining the purine content of beer and beer-like alcoholic beverages. Quantitative HPLC separation was performed on a Shodex Asahi Pak GS-320HQ column with an isocratic elution of 150 mmol/L sodium phosphate buffer (H(3)PO(4)/NaH(2)PO(4) = 20:100 (v/v)). The retention times for the four analytes, namely, adenine, guanine, hypoxanthine and xanthine, were 19.9, 25.0, 29.3 and 43.0 min, respectively. The resolution was good, and there was no excessive interference from the other compounds in the beverages at these retention times. Furthermore, the detection limit for all the analytes was improved to less than 0.0075 mg/L, and all the calibration curves showed good linearity (r(2) > 0.999) between 0.013 and 10 mg/L for adenine and guanine, and between 0.025 and 10 mg/L for hypoxanthine and xanthine. The pretreatment was simplified by removing some procedures and optimizing the perchloric acid hydrolysis and the enzymatic peak-shift assay. We reduced the sample dilution rate by almost 50%, and the time spent on pretreatment from 4 days to only 180 min. The recovery of the analytes from spiked samples was 94.8 - 103.8%. This method may be useful for evaluating quantitative and qualitative differences in the purine content of beer and beer-like alcoholic beverages. PMID- 23665624 TI - Rapid on-site air sampling with a needle extraction device for evaluating the indoor air environment in school facilities. AB - A rapid on-site air sampling technique was developed with a miniaturized needle type sample preparation device for a systematic evaluation of the indoor air environments in school facilities. With the in-needle extraction device packed with a polymer particle of divinylbenzene and activated carbon particles, various types of volatile organic compounds (VOCs) were successfully extracted. For evaluating the indoor air qualities in school facilities, air samples in renovated rooms using organic solvent as a thinner of the paint were analyzed along with measurements of several VOCs in indoor air samples taken in newly built primary schools mainly using low-VOCs materials. After periodical renovation/maintenance, the time-variation profile of typical VOCs found in the school facilities has also been monitored. From the results, it could be observed that the VOCs in most of the rooms in these primary schools were at a quite low level; however, a relatively higher concentration of VOCs was found in some specially designed rooms, such as music rooms. In addition, some non-regulated compounds, including benzyl alcohol and branched alkanes, were detected in these primary schools. The results showed a good applicability of the needle device to indoor air analysis in schools, suggesting a wide range of future employment of the needle device, especially for indoor air analysis in other types of facilities and rooms including hospitals and hotels. PMID- 23665625 TI - Microextraction in a packed syringe for the analysis of olive biophenols in rat plasma using CMK-3 nanoporous sorbent. AB - A carbon-based nanoporous sorbent was first used for microextraction in a packed syringe (MEPS) before HPLC/UV analysis of some biophenols in rat plasma. A laboratory-made programmable apparatus was designed and used for automation of the extraction procedure. The MEPS syringe was packed with 2 mg of CMK-3 sorbent, between the barrel and the injection needle, and mounted on an apparatus for programming of the conditioning, sampling, washing, elution and cleaning steps. All steps of the microextraction procedure were carefully optimized on the system. For optimization of important factors, such as the number of adsorption and elution cycles, elution volume and pH, a multivariate central composite design method was used. The highest recoveries were obtained for 24 and 10 times of adsorption and elution cycles, respectively, using 100 MUL of acetonitrile as the eluent and a sample pH of 2. Good results were obtained in terms of the precision (RSD 1.6, 2.5 and 2.3%) and detection limit (0.7, 4.7 and 0.25 MUM) for caffeic acid, tyrsol and oleuropein, respectively. The method was simple, efficient and appropriate for sample clean up before analysis by HPLC, and was successfully applied to the determination of biophenols in the plasma of several rats that received an olive leaves extract either by a gavage or an intraperitoneal injection method. A positive correlation was found between the amount of olive extract's feeding of the rats and the level of their plasma biophenols. PMID- 23665626 TI - A rapid procedure for the determination of C60 and C70 fullerenes in soil and sediments by ultrasound-assisted extraction and HPLC-UV. AB - In this work, a rapid and sensitive method, based on ultrasound-assisted extraction of samples with a small volume of toluene, has been developed for the quantification of C60 and C70 fullerenes in soil and sediments. Good extraction efficiencies were obtained at all of the fortification levels studied (200, 100, 20 and 2 ng/g), which ranged from 72 to 104%. An important effect of the extraction temperature was observed on C60 recoveries, and an acceptable decrease in the recovery rates was observed in aged samples. In the case of wet samples, the extraction can be done by percolating a small volume of acetonitrile before extraction. The extraction yields of the developed method for the extraction of C60 and C70 from soil were compared with those obtained by pressurized liquid extraction. Finally, analyses of fullerenes in agricultural and industrial soils and sediments were carried out, but no fullerene residues were found. PMID- 23665627 TI - Optimization of an online post-column derivatization system for ultra high performance liquid chromatography (UHPLC) and its applications to analysis of biogenic amines. AB - We investigated the efficacy and utility of a post-column derivatization method for the detection of amines with o-phthalaldehyde (OPA) in ultra high-performance liquid chromatography (UHPLC). Since it was anticipated that a derivatization reaction system placed downstream of the column would give considerable band broadening to narrow peaks generated by a UHPLC column, we examined the contributions of the dimensions of the reaction tube, the fluorescence (FL) detector flow cell, and the column to the extra-column peak broadening, and optimized the post-column derivatization system in UHPLC. We successfully separated amines within 6 min with gradient elution by using the post-column derivatization system connected to a UHPLC system. The analysis time was reduced by a factor of 7 compared with that by conventional HPLC. The detection limits were 18.0 - 105.7 fmol, depending on the compounds; the reproducibilities were 0.11 - 0.82% RSD for the retention times and 0.78 - 1.66% RSD for the peak areas (n = 10), respectively. The linear dynamic ranges were up to 12, 20, and 40 pmol/MUL, depending on the compounds, respectively. PMID- 23665628 TI - Determination of acid dissociation constant of degradable tetrabromophenolphthalein ethyl ester by capillary zone electrophoresis. AB - An acid dissociation constant of tetrabromophenolphthalein ethyl ester (TBPE) was determined through the measurement of electrophoretic mobility by capillary zone electrophoresis (CZE). Although TBPE is degradable in acidic pH region and it gradually degraded at pH conditions around and below its pKa values in the time scale of the CZE measurement, equilibrium species of interest were detected as a peak-shaped signal with tailing of the degraded species. Changes in electrophoretic mobility of the equilibrium species of TBPE were analyzed at its detectable pH range in the presence of phenol red as a mobility standard. An acid dissociation constant of 3.47 +/- 0.06 (pK(a), I = 0.01, 25 degrees C, standard error) was determined for TBPE. PMID- 23665629 TI - Dissociation kinetic analysis of Ce(III) complex with Quin2 by microchip capillary electrophoretic reactor. AB - Dissociation kinetic analysis of a complex of Ce(3+) with a polyaminocarboxylic ligand, 8-amino-2-[(2-amino-5-methylphenoxyl)methyl]-6-methoxyquinoline N,N,N',N',-tetraacetic acid (Quin2), was studied by microchip capillary electrophoretic reactor. Dissociation rate constants, k(d), of Ce(3+)-Quin2 complex in alkaline conditions at pH 8.3 - 9.8 were determined. The linear relationship of k(d) with the concentration of hydroxide ion indicates the existence of a hydroxide ion-assisted path in the dissociation reaction of Ce(3+) Quin2 complex in alkaline conditions. The solvolytic dissociation rate constant, and the hydroxide ion-assisted dissociation rate constant of Ce(3+)-Quin2 complex were determined to be 1.55 * 10(-3) and 3.24 * 10(2) s(-1) in the analysis of the dependence of k(d) with the concentration of hydroxide ion, respectively. PMID- 23665630 TI - A single FIA system coupled with reduction and distillation processes for the determination of sulfate ion by spectrophotometry. AB - In the present work, all steps of the sulfate reduction procedures, such as reduction, distillation and sulfate determination were joined in only one FIA system. The formed sulfide was on-line determined by employ the Fisher reaction. The proposed method presented a LOD of 1.00 MUg L(-1) and a LOQ of 3.33 MUg L( 1), well lower than the most commonly used turbidimetric determination, with no significant interferences. Additionally, we reached an analytical frequency of 6 measurements per hour, including all steps, beginning with the introduction of the sample up to the signal reading. Therefore, it revealed very fast, low reagent/sample consumption, agreeing with green-chemistry statements. This method has also a wide linear range (3.33 up to 1000 MUg L(-1)), being useful for both low and high sulfate concentrations. PMID- 23665631 TI - Flow-injection spectrophotometric determination of bromate in bottled drinking water samples using chlorpromazine reagent and a liquid waveguide capillary cell. AB - In this work, aiming to develop a simple, inexpensive method for the determination of low bromate levels in water samples, a liquid waveguide capillary cell (LWCC) was coupled to a FIA system. The long optical path (100 cm) of the LWCC was used to improve the sensitivity and the limit of detection without resorting to any off-line or in-line preconcentration processes. The spectrophotometric determination was based on the oxidation of chlorpromazine by bromate in an acidic medium, resulting in the formation of a colored radical product. Sulfamic acid was added to the reagent for minimizing the interference of nitrite, and a chelating ion exchange resin was used to remove major cationic interferences. The developed system allowed the determination of bromate within the range between 1 - 20 MUg L(-1) with a detection limit of 0.2 MUg L(-1). PMID- 23665632 TI - Determination of lead by square wave anodic stripping voltammetry using an electrochemical sensor. AB - A novel electrochemical assay for lead (Pb(2+)) detection was developed in this study, involving the use of screen-printed electrodes (SPEs). The sensor was used with selected supporting electrolytes in conjunction with square wave anodic stripping voltammetry (ASV) to study the redox characteristics of lead. Good response currents were obtained using a supporting electrolyte comprising acetate buffer pH 5.0 with 0.5 mol L(-1) NH4Cl. Without a deposition process, the anodic peaks for higher lead concentrations (ranging from 0.7 to 10 mg L(-1)) were sharp and symmetrical on the bare electrode surface. Optimal ASV conditions were obtained with a well-defined stripping peak for 200 MUL deposition solution volumes, a deposition potential of -1.2 V for Ag/AgCl, and a deposition time of either 300 or 400 s. Under optimal conditions, a calibration curve ranging from 6.25 to 500 MUg L(-1) was obtained for lead determination. Furthermore, the performance of a Hg-free sensor for Pb(2+) determination was compared with that of a Hg-coated electrode, and the detection limits were approximately 0.9 - 1.5 MUg L(-1). PMID- 23665633 TI - Characterization of Sb-doped Bi(2)UO(6) solid solutions by X-ray diffraction and X-ray absorption spectroscopy. AB - The preparation and characterization of Sb-doped Bi(2)UO(6) solid solutions, in a limited composition range, is reported for the first time. The solid solutions were prepared by solid-state reactions of Bi(2)O(3), Sb(2)O(3) and U(3)O(8) in the required stoichiometry. The reaction products were characterized by X-ray diffraction (XRD) and X-ray absorption spectroscopy (XAS) measurements at the Bi and U L(3) edges. The XRD patterns indicate the precipitation of additional phases in the samples when Sb doping exceeds 4 at%. The chemical shifts of the Bi absorption edges in the samples, determined from the XANES spectra, show a systematic variation only up to 4 at% of Sb doping and support the results of XRD measurements. These observations are further supported by the local structure parameters obtained by analysis of the EXAFS spectra. The local structure of U is found to remain unchanged upon Sb doping indicating that Sb(+3) ions replace Bi(+3) during the doping of Bi(2)UO(6) by Sb. PMID- 23665634 TI - Spatially resolved observation of a radio-frequency-powered glow discharge plasma for emission spectrometric analysis. AB - In glow discharge optical emission spectrometry, two-dimensional emission images for iron atomic lines were measured by using an imaging spectrograph equipped with a CCD detector, when a radio-frequency (r.f.) power source was employed for excitation. Emission images at the Fe I 371.99-nm and the Fe I 375.82-nm lines, having different excitation energies, were analyzed by the two-line method to obtain the spatial distribution of the excitation temperature in the plasma. Their emission intensities had a concentric-circle-like distribution along the radial direction of the plasma to become weaker towards the surrounding portion, which was very similar to a direct-current (d.c.) glow discharge plasma. On the other hand, the spatial distribution in the excitation temperature became relatively uniform over the central portion of the plasma, also being analogous between the r.f. and the d.c. glow discharge plasmas. These results imply that there is a major excitation process that occurs in a glow discharge plasma regardless of the power modes. PMID- 23665636 TI - Plasmonic nanoprobes for intracellular sensing and imaging. AB - Recent advances in integrating nanotechnology and optical microscopy offer great potential in intracellular applications with improved molecular information and higher resolution. Continuous efforts in designing nanoparticles with strong and tunable plasmon resonance have led to new developments in biosensing and bioimaging, using surface-enhanced Raman scattering and two-photon photoluminescence. We provide an overview of the nanoprobe design updates, such as controlling the nanoparticle shape for optimal plasmon peak position; optical sensing and imaging strategies for intracellular nanoparticle detection; and addressing practical challenges in cellular applications of nanoprobes, including the use of targeting agents and control of nanoparticle aggregation. PMID- 23665637 TI - Decreased L-tryptophan concentration in distinctive brain regions of mice treated repeatedly with phencyclidine. AB - It has been reported that repeated phencyclidine (PCP) treatment induces schizophrenia-like behavior in mice. L-Tryptophan (Trp) concentrations in brain tissues of control (n = 8) and PCP-treated mice (10 mg/kg/day, s.c., 14 days, n = 10) were determined using high-performance liquid chromatography (HPLC) with fluorescence detection. The HPLC method involved pre-column fluorescence derivatization with (R)-(-)-4-(N,N-dimethylaminosulfonyl)-7-(3 isothiocyanatopyrrolidin-1-yl)-2,1,3-benzoxadiazole (DBD-PyNCS). Eight different parts of the brain, namely, the frontal cortex, nucleus accumbens, striatum, hippocampus, amygdala, thalamus, hypothalamus, and cerebellum, of both groups were investigated. A significant decrease in the L-Trp concentration in the nucleus accumbens (p = 0.024) and hippocampus (p = 0.027) was observed in PCP treated mice, suggesting that alteration of the L-Trp metabolism might occur in these brain parts. PMID- 23665639 TI - Non-denaturating isoelectric focusing gel electrophoresis for uranium-protein complexes quantitative analysis with LA-ICP MS. AB - A non-denaturating isoelectric focusing (ND-IEF) gel electrophoresis protocol has been developed to study and identify uranium (U)-protein complexes with laser ablation-inductively coupled plasma mass spectrometry (LA-ICP MS) and electrospray ionization mass spectrometry (ESI-MS). The ND-IEF-LA-ICP MS methodology set-up was initiated using in vitro U-protein complex standards (i.e., U-bovine serum albumin and U-transferrin) allowing the assessment of U recovery to 64.4 +/- 0.4 %. This methodology enabled the quantification of U protein complexes at 9.03 +/- 0.23, 15.27 +/- 0.36, and 177.31 +/- 25.51 nmol U L(-1) in digestive gland cytosols of the crayfish, Procambarus clarkii, exposed respectively to 0, 0.12, and 2.5 MUmol of waterborne depleted U L(-1) during 10 days. ND-IEF-LA-ICP MS limit of detection was 19.3 pmol U L(-1). Elemental ICP MS signals obtained both in ND-IEF electropherograms and in size exclusion chromatograms of in vivo U-protein complexes revealed interactions between U- and Fe- and Cu-proteins. Moreover, three proteins (hemocyanin, pseudohemocyanin-2, and arginine kinase) out of 42 were identified as potential uranium targets in waterborne-exposed crayfish cytosols by microbore reversed phase chromatography coupled to molecular mass spectrometry (uRPC-ESI-MS/MS) after ND-IEF separation. PMID- 23665638 TI - Capillary electrophoretic analysis of hydroxyl radicals produced by respiring mitochondria. AB - Here, we report the use of a capillary electrophoretic method with laser-induced fluorescence detection to evaluate hydroxyl radicals produced by respiring mitochondria. The probe, hydroxyphenylfluorescein (HPF), is separated from the product, fluorescein, in under 5 min with zeptomole and attomole limits of detection for fluorescein and HPF, respectively. Purification of the probe with a C-18 SPE column is necessary to reduce the fluorescein impurity in the probe stock solution from 0.4% to less than 0.001%. HPF was responsive to hydroxyl radicals produced by isolated mitochondria from L6 cells, and this signal was blunted when DMSO was added to scavenge hydroxyl radicals and when carbonyl cyanide m-chlorophenylhydrazone was added to depolarize the mitochondria. The method was used to compare hydroxyl radical levels in mitochondria isolated from brown adipose tissue of lean and obese mice. Mitochondria from obese mice produced significantly more hydroxyl radicals than those from lean mice. PMID- 23665640 TI - Efficacy of the histamine 3 receptor (H3R) antagonist pitolisant (formerly known as tiprolisant; BF2.649) in epilepsy: dose-dependent effects in the human photosensitivity model. AB - A new class of drugs, the nonimidazole histamine 3 receptor (H3R) antagonists, has been developed in the past decade for treatment of various brain diseases. Pitolisant is such a drug. We studied the pharmacodynamic effect of pitolisant in patients with epilepsy in early Phase II, using the photosensitivity proof of concept model. A total of 14 adult patients (11 females and 3 males; 5 drug naive) were studied for three days to evaluate the effect of a single oral dose of pitolisant on EEG photosensitivity ranges. All patients showed repeatedly a generalized photoparoxysmal response (PPR) prior to drug administration on placebo Day 1. A statistically significant suppressive effect (standardized photosensitive response [SPR] reduction as measured with paired t-tests) for 20-, 40-, or 60-mg doses of pitolisant was seen in 9/14 (64%) patients of whom 6/14 (43%) showed abolition of the response to intermittent photic stimulation (IPS). Patients on the highest dosage (60 mg) showed the strongest effect with an effect lasting up to 28 h. Thus, full-scale Phase II studies with this novel H3R antagonist, pitolisant, in patients with epilepsy are warranted. PMID- 23665641 TI - Flashbulb memories in patients with temporal lobe epilepsy. AB - PURPOSE: Flashbulb memories (FMs) are vivid and stable autobiographical memories associated with learning surprising news of high emotional impact. Patients with temporal lobe epilepsy (TLE) can have autobiographical memory deficits. This is the first investigation of FMs in TLE applying a consistency measure of FM quality controlling for confabulation. METHOD: A sample of 12 patients with TLE and a matched group of 15 healthy controls (HCs) were tested on an FM test including a retest procedure. Scores of FM consistency were obtained by comparing answers across both testing occasions. RESULTS: In patients with TLE, FM consistency scores were significantly lower than in HCs. Exploratory subgroup analyses revealed FM deficits in both patients with left TLE and patients with right TLE compared with HCs. CONCLUSION: The present study indicates that the FMs of patients with TLE are less consistent than those of healthy control subjects. Future investigations with larger samples are desirable, especially regarding separate analyses of patients with left TLE and patients with right TLE. PMID- 23665642 TI - Does a history of physical exposures at work affect hand-grip strength in midlife? A retrospective cohort study in Denmark. AB - OBJECTIVE: The aim of this cohort study was to examine associations between physical exposures throughout working life and hand-grip strength (HGS) in midlife. METHODS: The Copenhagen Aging and Midlife Biobank (CAMB) provided data about employment and HGS for 3843 Danes. Individual job histories, including duration of employment in specific jobs, were assigned exposures from a job exposure matrix. Exposures were standardized to ton-years (lifting 1000 kg each day in one year), stand-years (standing/walking for six hours each day in one year) and kneel-years (kneeling for one hour each day in one year). The effects of exposure-years on HGS were analyzed as linear effects and cubic splines in multivariate regression models, adjusted for potential confounders. RESULTS: Mean age was 59 years among both genders and HGS was 49.19 kg [standard deviation (SD) 8.42] and 30.61 kg (SD 5.49) among men and women, respectively. Among men, exposure to kneel-years was associated with higher HGS [>0.030 kg (P=0.007) per exposure-year]. Ton- and stand-years were not associated with HGS among either men or women in linear analyses. In spline regression analyses, associations between ton- and stand-years and HGS were non-linear and primarily positive among men. Among women, the associations were non-linear and, according to ton-years, primarily negatively associated with HGS but statistically insignificant. CONCLUSION: A history of physical exposures at work explained only a minor part of the variation in HGS, though exposure to kneeling throughout working life was associated with a slightly higher HGS among men. Exposure to lifting and standing/walking was not associated with HGS. PMID- 23665643 TI - Combination effect of antibiotics against bacteria isolated from keratitis using fractional inhibitory concentration index. AB - PURPOSE: To study the in vitro interaction of fluoroquinolones such as levofloxacin (LVFX), gatifloxacin (GFLX), or moxifloxacin (MFLX) in combination with tobramycin (TOB) or cefmenoxime (CMX) against clinical isolates of bacteria from keratitis. METHODS: The activity of each drug alone was determined by an agar dilution method. Checkerboard synergy testing was then performed against 47 isolates, including Staphylococcus species, Streptococcus species, and Pseudomonas aeruginosa. Antimicrobial combinations were classified as synergistic, additive, indifferent, or antagonistic, according to their fractional inhibitory concentration. RESULTS: The average fractional inhibitory concentration indexes of combined use of LVFX/CMX or GFLX/CMX in Staphylococcus species and Streptococcus species, and LVFX/CMX, GFLX/CMX, MFLX/CMX in gram negative rods were low. The additive activity of the following drug combinations were seen in more than 70% of isolates: LVFX/CMX and GFLX/CMX against gram positive cocci and LVFX/CMX, GFLX/CMX, MFLX/CMX against gram-negative rods. No consistent synergistic or antagonistic effect was observed with the combinations used. CONCLUSION: The combination of LVFX/CMX or GFLX/CMX was predominantly additive for all tested isolates. PMID- 23665644 TI - Correlation of anterior and posterior corneal shape in keratoconus. AB - PURPOSE: To evaluate the correlation of the mean curvature and shape factors of both corneal surfaces for different corneal diameters measured with the Scheimpflug photography-based system in keratoconus eyes. METHODS: A total of 61 keratoconus eyes of 61 subjects, aged 14 to 64 years, were included in this study. All eyes received a comprehensive ophthalmologic examination including anterior segment and corneal analysis with the Sirius system (CSO): anterior and posterior mean corneal radius for 3, 5, and 7 mm (aKM, pKM), anterior and posterior mean shape factor for 4.5 and 8 mm (ap, pp), central and minimal corneal thickness, and anterior chamber depth. RESULTS: Mean aKM/pKM ratio around 1.20 (range, 0.95-1.48) was found for all corneal diameters (P = 0.24). Weak but significant correlations of this ratio with pachymetric parameters were found (r between -0.28 and -0.34, P < 0.04). The correlation coefficient between aKM and pKM was >= 0.92 for all corneal diameters. A strong and significant correlation was also found between ap and pp (r >= 0.86, P < 0.01). The multiple regression analysis revealed that central pKM was significantly correlated with aKM, central corneal thickness, anterior chamber depth, and spherical equivalent (R >= 0.88, P < 0.01) and that 8 mm pp was significantly correlated with 8 mm ap and age (R = 0.89, P < 0.01). CONCLUSIONS: Central posterior corneal curvature and shape factor in the keratoconus eye can be consistently predicted from the anterior corneal curvature and shape factor, respectively, in combination with other anatomical and ocular parameters. PMID- 23665645 TI - Assessment of tear osmolarity and other dry eye parameters in post-LASIK eyes. AB - PURPOSES: To assess the tear osmolarity using the TearLab device after laser in situ keratomileusis (LASIK) and to compare the values with those obtained by traditional tear film tests before and after the procedure. METHODS: Thirty eyes of 15 refractive surgery candidates (5 men and 10 women of mean age: 30.55 +/- 11.79 years) were examined. Using a special questionnaire (Ocular Surface Disease Index), subjective dry eye complaints were evaluated, and then, the tear osmolarity was measured with the TearLab system (TearLab Corporation) and conventional dry eye tests were carried out. Examinations were performed preoperatively and at 1, 30, and 60 days after the surgery. RESULTS: The mean value of tear osmolarity was 303.62 +/- 12.29 mOsm/L before the surgery and 303.58 +/- 20.14 mOsm/L at 60 days after the treatment (P = 0.69). Mean lid parallel conjunctival folds value was 0.68 +/- 0.68 before the procedure and 0.58 +/- 0.65 subsequent to surgery (P = 0.25). Meibomian gland dysfunction was not detected. No significant deviation was observed in the values of Schirmer test, corneal staining, tear break-up time, and lid parallel conjunctival folds when compared with postoperatively obtained values during the follow-up period (P > 0.05). CONCLUSIONS: During LASIK flap creation, intact corneal innervation is damaged, and the ocular surface lacrimal functional unit can be impaired. In our study, no abnormal dry eye test results were observed before or after the procedure. Based on our results, LASIK treatment is safe for dry eye involving the administration of adequate artificial tears for a minimum of 3 months. PMID- 23665646 TI - Contamination risk of 100% autologous serum eye drops in management of ocular surface diseases. AB - PURPOSE: To evaluate the sterility and safety of 100% nonpreserved, autologous, serum eye drop treatment in patients with ocular surface diseases. METHODS: A total of 147 autologous serum bottles (294 samples) from 21 patients with ocular surface diseases were included. Seven bottles with autologous serum were prepared for each patient, and each bottle was used for only 1 day, then discarded. Two samples from each bottle were taken (before use and after 24 hours of use) and then cultured in standard media. The culture plates were held for at least 6 weeks or until no growth could be confirmed. To monitor safety, all patients were admitted and evaluated for the occurrence of infection. RESULTS: In the pretreatment group, 4 samples from 4 patients (1.36%) were positive for bacteria and 7 samples from 7 patients (2.38%) were positive for fungi. In the 24-hour after-treatment group, 1 culture (0.34%) was positive for bacteria, and 6 samples (2.04%) from 6 patients were positive for fungi. Aspergillus spp and Fonsecaea spp were the most common organisms identified in any of the cultures. Neither clinical nor microbiological evidence of infection was demonstrated in any patient during the treatment or follow-up periods. CONCLUSIONS: Although no ocular surface infection was observed, the patients under 100% autologous serum eye drops therapy should be closely monitored for clinical evidence of fungal and bacterial infections. PMID- 23665647 TI - Clinical effectiveness of topical cyclosporine a 0.05% after laser epithelial keratomileusis. AB - PURPOSE: To evaluate the effect of topical cyclosporine A 0.05% after laser epithelial keratomileusis (LASEK). METHODS: This retrospective nonrandomized comparative analysis was performed in 40 patients (80 eyes) with myopia who underwent flap-off LASEK. Twenty patients (group A) were treated with topical cyclosporine A 0.05% in combination with conventional treatment, and 20 patients (group B) received conventional treatment only. In each group, 10 patients had preoperative dry eye. Uncorrected visual acuity, refractive error, corneal haze grade, symptom score, and ocular surface parameters were measured in both groups before LASEK and at 1, 2, 4, and 8 weeks postoperatively. RESULTS: There were no significant differences between the groups in postoperative uncorrected visual acuity, spherical equivalent, corneal haze grade, Schirmer test values, and keratoepitheliopathy scores. Group A had lower symptom scores (0.80 +/- 0.52 vs.1.35 +/- 0.49; P < 0.01) and higher tear film break-up time (BUT) (8.05 +/- 1.39 vs. 6.55 +/- 1.39 seconds; P < 0.01) compared with group B at 4 weeks after LASEK. In addition, in preoperative dry eye patients, symptom scores and tear film BUT returned to preoperative level at 4 weeks postoperatively in group A, whereas they returned to preoperative level at 8 weeks in group B. CONCLUSIONS: Treatment with topical cyclosporine A 0.05% can improve ocular discomfort and increase tear film BUT during the early postoperative period, especially in patients with preoperative dry eye. PMID- 23665648 TI - Preconditioned donor corneal thickness for microthin endothelial keratoplasty. AB - PURPOSE: To describe a novel surgical technique to produce thin endothelial grafts for Descemet stripping automated endothelial keratoplasty (DSAEK). METHODS: Thirteen human cadaveric corneas in organ culture were randomized into conventional (n = 7) and microthin (n = 6) DSAEK groups. Grafts in the conventional DSAEK group were prepared using the conventional DSAEK technique of a single microkeratome pass with a 350-MUm cutting head. Corneas in the microthin group were preconditioned to achieve a target central thickness of 530 MUm before graft dissection with a 350-MUm microkeratome head. Preconditioning involved stromal dehydration under pachymetric control using sterile airflow for 15-second increments. Donor and graft thicknesses were assessed with optical coherence tomography, and endothelial viability with trypan blue and alizarin red staining. RESULTS: Mean endothelial graft thickness obtained using the microthin DSAEK technique was 106 MUm (SD, 32 MUm) compared with 177 MUm (SD, 33 MUm) obtained using conventional DSAEK technique (P = 0.0024). Donor preconditioning yielded a predicted reduction of 100 MUm in graft stromal thickness at a rate of 1.5 MUm/s and mean duration of 72 seconds. The average anterior lamella thickness (cut depth) obtained in microthin and conventional DSAEK groups were 424 and 431 MUm, respectively (P = 0.84). There was no difference in endothelial viability between the 2 groups. There were no corneal perforations during graft preparation in this study. CONCLUSIONS: Donor preconditioning by pachymetry-controlled stromal dehydration achieved significantly thinner endothelial grafts compared with the conventional DSAEK technique without compromise to endothelial viability or graft wastage. PMID- 23665649 TI - Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus keratitis in rabbits. AB - PURPOSE: To compare the efficacy of topical linezolid (LZD) 1 mg/mL or 2 mg/mL to vancomycin (VA) 50 mg/mL for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) keratitis in rabbits. METHODS: One hundred colony forming unit (CFU) MRSA bacteria were injected intrastromally into rabbit corneas. Sixteen hours after the injection, 24 rabbits were randomly divided into 4 groups. Rabbit eyes were treated with 1 drop of topical LZD 1 mg/mL, LZD 2 mg/mL, VA 50 mg/mL, or isotonic saline every 15 minutes for 5 doses and then every 30 minutes for 14 doses. Eyes were examined before and after the treatment using slit-lamp biomicroscopy by 2 observers blinded to the study for the determination of clinical severity. Then, corneas were harvested for the quantification of bacteria and histopathology. RESULTS: There were no differences in clinical severity among the groups before and after the treatment in each eye. The mean CFU * 10(6) of MRSA recovered from the LZD 1 mg/mL, LZD 2 mg/mL, and VA 50 mg/mL groups were significantly lower than that recovered from corneas treated with isotonic saline. There was no statistically significant difference among the treatment groups in terms of CFU * 10(6). Epithelial erosion in the VA 50 mg/mL group was significantly worse than that in the other groups. LZD 2 mg/mL group had the lowest mean epithelial erosion values. CONCLUSIONS: Topical LZD showed activity against MRSA that was comparable to fortified VA in this experimental keratitis model. PMID- 23665650 TI - Impact of collagen cross-linking for keratoconus on corneal sensitivity. PMID- 23665651 TI - Warm compresses and the risks of elevated corneal temperature with massage. AB - PURPOSES: To quantify the changes in corneal temperature resulting from intensive warm compress (WC) application with minimal pressure and to review the significance of these changes within the context of the peer-reviewed literature. METHODS: WC were applied intensively and unilaterally at 45 +/- 0.5 degrees C for 30 minutes with the contralateral eye serving as a control. Outer upper eyelid and central corneal surface temperatures were measured using an Infrared pyrometer at baseline. The WC were removed for repeat measurements of the outer upper eyelid surface and central corneal temperatures every 2 minutes and replaced with a new WC heated to 45 +/- 0.5 degrees C. Lid and corneal temperatures were monitored for 10 minutes after the final WC application. RESULTS: The mean age of the subjects was 37.1 +/- 15.0 years (n = 12). The mean maximum outer upper lid temperature of 42.2 +/- 1.3 degrees C was reached after 6 minutes. The mean maximum corneal temperature of 39.4 +/- 0.7 degrees C was reached after 8 minutes of heating. The control eye showed no significant change in temperature from baseline throughout the experimental period. CONCLUSIONS: These data show that WC use for lid warming, even when only minimal contact pressure is applied, also transfers significant heat to the cornea. Corneal temperatures reach peak temperature after about 8 minutes of WC application. Recent reports discussing the increased potential for transient and long-term corneal molding subsequent to the heat and pressure of WC application are briefly reviewed. PMID- 23665652 TI - Influence of axial length on conjunctivochalasis. AB - PURPOSE: To investigate the relation between the severity of conjunctivochalasis and the axial length (AL) of the eyeball. METHODS: A prospective nonrandomized study was performed on 165 patients aged 51 to 88 years. The age, gender, medical history, ocular history, grade and other parameters of inferior conjunctivochalasis (classified as nasal, middle, and temporal), and AL were determined in all patients. Patients were divided into a short AL group (<= 22.0 mm), a medium AL group (>22.0 to <= 24.0 mm), and a long AL group (>24.0 mm). RESULTS: The short AL group tended to have higher grades of temporal and nasal conjunctivochalasis compared with the medium and long AL groups. Multivariate logistic regression analysis showed that the total conjunctivochalasis score (the sum of the scores for the temporal, middle, and nasal regions) was significantly associated with the age [odds ratio (OR) = 1.32, P = 0.001] and the AL (OR = 0.81, P = 0.029). In addition, the AL was independently associated with the grade of conjunctivochalasis after adjustment for age (OR = 0.80, P = 0.020). CONCLUSIONS: This was the first assessment of the relationship between the AL and the grade of conjunctivochalasis. Our findings suggest that the severity of conjunctivochalasis is dependent on the AL, with a short AL contributing to the pathogenesis of conjunctivochalasis. PMID- 23665653 TI - Triage in surgery: from theory to practice, the Medecins Sans Frontieres experience. AB - Establishing triage is necessary in mass casualty events. If the concept of triage itself is easy, its application in the field encounters many difficulties at times unforseen. MSF offers a list of the main obstacles encountered when establishing an efficient triage system. PMID- 23665654 TI - The risk of dislocation after total hip arthroplasty for fractures is decreased with retentive cups. AB - PURPOSE: Total hip arthroplasty (THA) has been efficacious for treating hip fractures in healthy older patients. However, in those patients with fractures a widely variable prevalence of dislocation has been reported, partly because of varying durations of follow up for this specific end-point. The purpose of the present study was to determine the cumulative risk of dislocation in these patients with fractures and to investigate if retentive cups decrease the risk of dislocation. METHODS: Between 2000 and 2005, 325 patients with neck fracture underwent primary THA using a retentive (325 hips) cup. The results of these 325 acetabular cups were compared to 180 THA without retentive cups performed for neck fractures in the same hospital between 1995 and 2000 by the same surgical team. The mean age of the 505 patients was 75 years (range 65-85). All patients were followed for a minimum of five years for radiographic evidence of implant failure. The patients were followed at routine intervals and were specifically queried about dislocation. The cumulative risk of dislocation and recurrent dislocation was calculated with use of the Kaplan-Meier method. RESULTS: For patients without retentive cups, the cumulative risk of a first-time dislocation was 5 % at one month and 12 % at one year and then rose at a constant rate of approximately 1 % every year to 16 % at five years. For patients with retentive cups, the cumulative risk of a first-time dislocation was 1 % at one month, 2 % at one year and then did not changed at five years. There were no differences in the mortality rates or in loosening rates among the treatment groups. The rate of secondary surgery was highest in the group without retentive (10 % for recurrent dislocation) compared with 1 % in the group treated with retentive cups. In absence of retentive cups, multivariate analysis revealed that the relative risk of dislocation for female patients (as compared with male patients) was 2.1 and that the relative risk for patients who were 80 years old or more (as compared with those who were less than 80 years old) was 1.5. Two underlying diagnoses occurring during follow up-cognitively impaired patients or neurologic disease were also associated with a significantly greater risk of dislocation in absence of retentive cup. For these patients the risk was also decreased with a retentive cup. CONCLUSION: With standard cups the incidence of dislocation is highest in the first year after arthroplasty and then continues at a relatively constant rate for the life of the arthroplasty. Patients at highest risk are old female patients and those with a diagnosis of neurologic disease. Retentive cups in these patients are an effective technique to prevent post-operative hip dislocation. PMID- 23665655 TI - Comment on Zeng et al.: Vascularised greater trochanter bone graft, combined free iliac flap and impaction bone grafting for osteonecrosis of the femoral head. PMID- 23665656 TI - Comment on Kritsaneephaiboon et al.: Minimally invasive plate osteosynthesis of distal tibial fracture using a posterolateral approach: a cadaveric study and preliminary report. PMID- 23665657 TI - Not precisely accurate. PMID- 23665658 TI - Focused rigidity casts: an overview. AB - Focused rigidity casts (FRCs) are a novel treatment made from polymer semi flexible cast material, used in the management of plantar foot ulceration to offload the site of ulceration. Current anecdotal evidence suggests that use of FRCs helps achieve quicker healing time. While FRCs were first used in the treatment of fractures, previous reports suggest that the FRC may be effective in the treatment of plantar foot ulceration. Although there is a paucity of evidence to support the use of FRCs in the treatment of foot ulceration, current evidence demonstrates a decrease in both wound healing time and plantar pressure. The aim of the paper is to examine the importance of offloading plantar ulcerations and introduce FRCs. PMID- 23665659 TI - Patient perspectives of their leg ulcer journey. AB - OBJECTIVE: To understand the personal impact of venous leg ulceration from the patients' perspective. METHOD: Face-to-face, unstructured interviews were conducted with nine patient participants with venous leg ulcers. The interviews were digitally recorded, transcribed verbatim and, using thematic analysis, the themes and subthemes which impacted on quality of life were identified. RESULTS: Four core themes were identified: the ulcer, symptoms, wound management and effects on daily life, with 16 subthemes that negatively impacted on quality of life (QoL) also identified. CONCLUSION: This qualitative study offers a valuable insight into the complex issues that impact on daily living for this patient group. The implications of the findings are far reaching and suggest that proactive symptom management and the fostering of a patient focus to consultations may improve QoL and encourage the patient to engage as an active partner in his/her management plan; both of which are explored in the subsequent phases of the larger study. DECLARATION OF INTEREST: This study was funded by West Midlands Strategic Health Authority. The authors have no conflicts of interest to declare. PMID- 23665660 TI - Pyoderma gangrenosum: guideline for wound practitioners. AB - Pyoderma gangrenosum (PG) is an atypical ulceration of the skin with unknown aetiology, usually associated with autoimmune systemic illnesses and haematological malignancies. Diagnosis is based on clinical suspicion and exclusion of other conditions. Treatment options vary greatly, ranging from conservative local and systemic immunosuppression to surgical measures, including amputation, but none is shown to be universally effective. Currently no guideline regarding escalation of treatment exists. Based on a review of the current literature and three illustrative cases of PG, a working treatment guideline is presented for wound practitioners. PMID- 23665661 TI - Melanoma arising in chronic ulceration associated with lymphoedema. AB - Chronic ulceration can be complicated by development of a malignancy. The most frequent associated malignances are squamous cell carcinoma and basal cell carcinoma, although melanoma, leiomyosarcoma and adenocarcinoma are less commonly seen. Chronic lymphoedema may also predispose to development of some malignancies, including lymphangiosarcoma, squamous cell carcinoma and Kaposi's sarcoma. Here, we report the case of a 77-year-old man with primary lymphoedema, who developed melanoma in a chronic foot ulcer of 60 years' duration. The patient underwent wide excision for the melanoma, and remains free from metastases at 1 year follow up. PMID- 23665662 TI - The Explorer study: the first double-blind RCT to assess the efficacy of TLC-NOSF on DFUs. AB - Urgo Medical recently announced the launch of the Explorer study, a large, Europe wide, clinical study on the efficacy and tolerability of UrgoStart Contact, a lipidocolloid technology dressing impregnated with nano-oligosaccharide factor, in the treatment of diabetic foot ulceration. The number of patients, investigating centres and countries involved, as well as the length of treatment and patient follow-up, make this an ambitious, double-blind, randomised controlled trial. PMID- 23665663 TI - Skin grafting the contaminated wound bed: reassessing the role of the preoperative swab. AB - OBJECTIVE: To investigate use of the preoperative wound swab to predict graft failure compared with establishing the indication for skin grafting on clinical grounds alone. METHOD: Patients requiring meshed split-thickness skin grafting were prospectively included; the indication for grafting was established on clinical grounds exclusively. A preoperative swab of the wound bed was taken, but its result was concealed to prevent it influencing clinical decision-making. Negative pressure wound therapy (NPWT) was used for both wound bed preparation and graft fixation.After 2 months, graft area take percentage was measured using digital image processing software and the results validated against the result of the preoperative wound swab. RESULTS: Eighty-seven wounds were included in the study. Mean graft area take percentage was 88%,with five grafts considered complete failures(< 25% take).A posteriori analysis of the wound cultures showed that 53% had been contaminated on grafting, but these did not fare any worse than near-sterile wounds. Qualitative analysis of cultures showed that wounds containing either Pseudomonas aeruginosa or Staphylococcus aureus did have inferior outcome (mean take percentage 78.9% vs 91.3%; p=0.038).Diabetes was also a deteriorating factor (mean take percentage 83.0% vs 90.7%; p=0.004). CONCLUSION: Establishing the indication for skin grafting on clinical grounds exclusively does not yield grossly inferior results. In light of recent advances in skin grafting, including use of NPWT as adjuvant therapy, the requirement for routine preoperative wound swabs may be questioned. PMID- 23665664 TI - Repeatability and clinical utility in stereophotogrammetric measurements of wounds. AB - OBJECTIVE: To investigate the hypothesis that stereophotogrammetric wound size monitoring shows suitable inter-observer reliability and user acceptance for clinical practice use. METHOD: Veterans admitted for conservative management of severe pressure ulcers were eligible for inclusion in the study. Three dimensional (3D) digital wound images were independently captured by two expert and two non-expert nurse-observers using a commercially available stereophotogrammetry system,weekly for 6 weeks.A double-blinded analyst generated 3D wound reconstructions, using software to determine geometry. Clinical opinion of wound progression was provided by an expert physician. RESULTS: Thirteen wounds were assessed with more than 80% of all images being readable. Interclass correlation of 0.9867 (p < 0.000 I) was observed. Compared with clinical opinion, 3D wound measurement was sensitive between improving and static wounds for wound perimeter, volume, depth and length. CONCLUSION: These preliminary findings suggest that 3D wound measurement minimises differences in wound measurement between expert and non-expert observers, suggesting it could be implemented with high reliability in health-care settings where several observers are involved in wound care management. PMID- 23665665 TI - Your Turn pressure ulcer campaign. PMID- 23665666 TI - Back to basics: an introduction to economic evaluation. PMID- 23665667 TI - Purification of recombinant vaccinia virus-expressed monomeric HIV-1 gp120 to apparent homogeneity. AB - Vaccinia virus (VV) has been used to express a variety of heterologous proteins, including HIV envelope (Env) glycoproteins. The Env protein is synthesized as a precursor molecule, gp160, which is cleaved into the surface antigen gp120 and the transmembrane protein gp41. Even though production of gp160 by the VV expression system has been described, its use for gp120 production is not well documented. Here we report a new procedure for the purification of gp120 from serum-containing culture supernatant of VV-infected cells. The gp120 protein was enriched to a purity better than 60% on a snowdrop (Galanthus nivalis) lectin affinity column in the presence of 0.25% zwitterionic detergent Empigen BB. After additional DEAE anion exchange and Superdex size exclusion chromatography steps, the gp120 monomer was purified free of contamination as determined by SDS-PAGE. The retention of structural integrity was confirmed by determining the affinity constant of purified gp120s to soluble CD4 and a monoclonal antibody IgG1b12, using surface plasmon resonance analysis. The purification procedure is robust and reproducible, and may find general use for glycoprotein purifications from sources where the presence of serum is desirable. PMID- 23665668 TI - Hepcidin as a predictor of disease severity in acute pancreatitis: a single center prospective study. AB - BACKGROUND/AIMS: Predicting the severity of acute pancreatitis is limited to clinical, laboratory and radiological risk factors. Hepcidin levels increase in acute inflammation. We aimed to assess the relationship between hepcidin and C reactive protein (CRP), white blood cells (WBC) and multi-detector computerized tomography (MDCT) in predicting the severity of pancreatitis. METHODOLOGY: We undertook a prospective review of 59 consecutive patients with acute pancreatitis admitted to our clinic. Biochemical values were measured from blood samples taken within 2 hours of admission and from between 2 and 72 hours related to the time of symptom onset. RESULTS: In predicting severe acute pancreatitis, hepcidin was superior to CRP and WBC (Area Under the Curve (AUC)=0.79, p=0.003; AUC=0.69, p=NS; AUC=0.53, p=NS, respectively). CONCLUSIONS: In this study, hepcidin was found to be superior to CRP in predicting the severity of pancreatitis. PMID- 23665669 TI - Microfluidic-based electrotaxis for on-demand quantitative analysis of Caenorhabditis elegans' locomotion. AB - The nematode Caenorhabditis elegans is a versatile model organism for biomedical research because of its conservation of disease-related genes and pathways as well as its ease of cultivation. Several C. elegans disease models have been reported, including neurodegenerative disorders such as Parkinson's disease (PD), which involves the degeneration of dopaminergic (DA) neurons (1). Both transgenes and neurotoxic chemicals have been used to induce DA neurodegeneration and consequent movement defects in worms, allowing for investigations into the basis of neurodegeneration and screens for neuroprotective genes and compounds (2,3). Screens in lower eukaryotes like C. elegans provide an efficient and economical means to identify compounds and genes affecting neuronal signaling. Conventional screens are typically performed manually and scored by visual inspection; consequently, they are time-consuming and prone to human errors. Additionally, most focus on cellular level analysis while ignoring locomotion, which is an especially important parameter for movement disorders. We have developed a novel microfluidic screening system (Figure 1) that controls and quantifies C. elegans' locomotion using electric field stimuli inside microchannels. We have shown that a Direct Current (DC) field can robustly induce on-demand locomotion towards the cathode ("electrotaxis") (4). Reversing the field's polarity causes the worm to quickly reverse its direction as well. We have also shown that defects in dopaminergic and other sensory neurons alter the swimming response (5). Therefore, abnormalities in neuronal signaling can be determined using locomotion as a read-out. The movement response can be accurately quantified using a range of parameters such as swimming speed, body bending frequency and reversal time. Our work has revealed that the electrotactic response varies with age. Specifically, young adults respond to a lower range of electric fields and move faster compared to larvae (4). These findings led us to design a new microfluidic device to passively sort worms by age and phenotype (6). We have also tested the response of worms to pulsed DC and Alternating Current (AC) electric fields. Pulsed DC fields of various duty cycles effectively generated electrotaxis in both C. elegans and its cousin C. briggsae (7). In another experiment, symmetrical AC fields with frequencies ranging from 1 Hz to 3 KHz immobilized worms inside the channel (8). Implementation of the electric field in a microfluidic environment enables rapid and automated execution of the electrotaxis assay. This approach promises to facilitate high-throughput genetic and chemical screens for factors affecting neuronal function and viability. PMID- 23665670 TI - ENT-HNS education: what undergraduate students want? PMID- 23665671 TI - Preemptive peritonsillar infiltration with lidocaine for relief of bipolar adult post-tonsillectomy pain: a randomized, double-blinded clinical study. AB - There are discordant results in the studies of the peritonsillar infiltration in adults undergoing the tonsillectomy. The study is to compare the effect of the preemptive peritonsillar infiltration with lidocaine in bipolar tonsillectomy in adult. 172 adult patients were randomly located into five groups before tonsillectomy: group 0: without the peritonsillar infiltration, group 1: for 3 ml normal saline with 1:200,000 epinephrine per tonsil, group 2: for 3 ml 1 %lidocaine with 1:200,000 epinephrine per tonsil, group 3: for 8 ml normal saline with 1:200,000 epinephrine per tonsil, group 4: for 8 ml lidocaine with 1:200,000 epinephrine per tonsil. The post-operative pain in the following 7 days was assessed by visual analog scale. Operation time and post-operative bleeding were also recorded. No significant differences were found between operative times, post-tonsillectomy hemorrhage between the five groups. The differences between pain scores of the group 0, group 1 and group 2 were not statistically significant (P > 0.05). The differences between pain scores of group 3, group 4 against group 0, group 1, group 2 were statistically significant (P < 0.05). We found the volume of peritonsillar infiltration might contribute to the relief of pain of the bipolar post-tonsillectomy. PMID- 23665672 TI - A prospective study of arsenic exposure, arsenic methylation capacity, and risk of cardiovascular disease in Bangladesh. AB - BACKGROUND: Few prospective studies have evaluated the influence of arsenic methylation capacity on cardiovascular disease (CVD) risk. OBJECTIVE: We evaluated the association of arsenic exposure from drinking water and arsenic methylation capacity with CVD risk. METHOD: We conducted a case-cohort study of 369 incident fatal and nonfatal cases of CVD, including 211 cases of heart disease and 148 cases of stroke, and a subcohort of 1,109 subjects randomly selected from the 11,224 participants in the Health Effects of Arsenic Longitudinal Study (HEALS). RESULTS: The adjusted hazard ratios (aHRs) for all CVD, heart disease, and stroke in association with a 1-SD increase in baseline well-water arsenic (112 ug/L) were 1.15 (95% CI: 1.01, 1.30), 1.20 (95% CI: 1.04, 1.38), and 1.08 (95% CI: 0.90, 1.30), respectively. aHRs for the second and third tertiles of percentage urinary monomethylarsonic acid (MMA%) relative to the lowest tertile, respectively, were 1.27 (95% CI: 0.85, 1.90) and 1.55 (95% CI: 1.08, 2.23) for all CVD, and 1.65 (95% CI: 1.05, 2.60) and 1.61 (95% CI: 1.04, 2.49) for heart disease specifically. The highest versus lowest ratio of urinary dimethylarsinic acid (DMA) to MMA was associated with a significantly decreased risk of CVD (aHR = 0.54; 95% CI: 0.34, 0.85) and heart disease (aHR = 0.54; 95% CI: 0.33, 0.88). There was no significant association between arsenic metabolite indices and stroke risk. The effects of incomplete arsenic methylation capacity- indicated by higher urinary MMA% or lower urinary DMA%--with higher levels of well-water arsenic on heart disease risk were additive. There was some evidence of a synergy of incomplete methylation capacity with older age and cigarette smoking. CONCLUSIONS: Arsenic exposure from drinking water and the incomplete methylation capacity of arsenic were adversely associated with heart disease risk. PMID- 23665674 TI - ER stress induced impaired TLR signaling and macrophage differentiation of human monocytes. AB - Endoplasmic reticulum (ER) stress causes impairment of the intracellular protein synthesis machinery, affecting various organ functions and homeostasis systems, including immunity. We found that ER stress induced by the N-linked glycosylation inhibitor, tunicamycin, caused susceptibility to apoptosis in the human monocytic cell line, THP-1 cells. Importantly, prior to tunicamycin-induced apoptosis, the proinflammatory response to toll-like receptor (TLR) 4 ligand lipopolysaccharide (LPS) stimulation was attenuated with respect to the expression of the proinflammatory cytokines. This impaired expression of proinflammatory cytokines was a consequence of the inhibition of NF-kappaB activation. Moreover, tunicamycin-induced ER stress disturbed the differentiation of THP-1 cells into macrophages induced by phorbol-12-myristate-13-acetate treatment. We also confirmed that ER stress affected the response of primary human monocytes to TLR ligand and their ability to differentiate into macrophages. These data suggest that ER stress imposes an important pathological insult to the immune system, affecting the crucial functions of monocytes. PMID- 23665673 TI - Effects of cigarette smoke extract on primary activated T cells. AB - Tobacco smoking predisposes the development of diseases characterized by chronic inflammation and T cell dysfunction. In this study, we aimed to determine the direct effects of cigarette smoke on primary T cells and to identify the corresponding molecular mediators. Activated T cells cultured in the presence of cigarette smoke extract (CSE) displayed a dose-dependent decrease in cell proliferation, which associated with the induction of cellular apoptosis. T cell apoptosis by CSE was independent of caspases and mediated through reactive oxygen and nitrogen species endogenously contained within CSE. Additional results showed that exposure of T cells to CSE induced phosphorylation of the stress mediator eukaryotic-translation-initiation-factor 2 alpha (eIF2alpha). Inhibition of the phosphorylation of eIF2alpha in T cells prevented the cellular apoptosis induced by CSE. Altogether, the results show the direct effects of CSE on T cells, which advance in the understanding of how cigarette smoking promotes chronic inflammation and immune dysfunction. PMID- 23665675 TI - Protein lysine acetylation guards metabolic homeostasis to fight against cancer. AB - Properly coordinated metabolism and maintained metabolite homeostasis are important because altered metabolite homeostasis has a causal role in many human diseases, including cancer. Metabolite homeostasis is maintained by fine-tuned coordination of metabolite generation and utilization. Metabolite deregulation has recently been shown to alter the signaling pathways and reprogram epigenetic factors associated with tumorigenesis. Protein lysine acetylation is emerging as a metabolism-coordinating mechanism. Mechanistic studies have shown that acetylation may have roles in nutrient adaptation and in maintaining metabolite homeostasis by exerting regulatory effects on metabolic enzymes, metabolic pathways and metabolic networks. Here we review recent progress in the determination of the role of acetylation regulation in metabolism coordination. In particular, we review links between deregulated acetylation in metabolic enzymes and tumorigenesis. We further hypothesize on applications of the mediation of acetylation to restore deregulated metabolism coordination and thus develop novel means of cancer treatment. PMID- 23665677 TI - Theileria induces oxidative stress and HIF1alpha activation that are essential for host leukocyte transformation. AB - Complex links between infection and cancer suggest that we still can learn much about tumorigenesis by studying how infectious agents hijack the host cell machinery. We studied the effects of an intracellular parasite called Theileria that infects bovine leukocytes and turns them into invasive cancer-like cells. We investigated the host cells pathways that are deregulated in infected leukocytes and might link infection and lymphoproliferative disease. We show that intracellular Theileria parasites drive a Warburg-like phenotype in infected host leukocytes, characterized by increased expression of metabolic regulators, increased glucose uptake and elevated lactate production, which were lost when the parasite was eliminated. The cohabitation of the parasites within the host cells leads to disruption of the redox balance (as measured by reduced/oxidized glutathione ratio) and elevated ROS (reactive oxygen species) levels, associated with chronic stabilization of the hypoxia-inducible factor 1 alpha (HIF1alpha). Inhibition of HIF1alpha (pharmacologically or genetically), or treatment with antioxidants, led to a marked reduction in expression of aerobic glycolytic genes and inhibited the transformed phenotype. These data show that stabilization of HIF1alpha, following increased ROS production, modulates host glucose metabolism and is critical for parasite-induced transformation. Our study expands knowledge about the molecular strategy used by the parasite Theileria to induce the transformed phenotypes of infected cells via reprogramming of glucose metabolism and redox signaling. PMID- 23665676 TI - Tumor-derived mural-like cells coordinate with endothelial cells: role of YKL-40 in mural cell-mediated angiogenesis. AB - Tumor neo-vasculature is characterized by spatial coordination of endothelial cells with mural cells, which delivers oxygen and nutrients. Here, we explored a key role of the secreted glycoprotein YKL-40, a mesenchymal marker, in the interaction between endothelial cells and mesenchymal mural-like cells for tumor angiogenesis. Xenotransplantation of tumor-derived mural-like cells (GSDCs) expressing YKL-40 in mice developed extensive and stable blood vessels covered with more GSDCs than those in YKL-40 gene knockdown tumors. YKL-40 expressed by GSDCs was associated with increased interaction of neural cadherin/beta catenin/smooth muscle alpha actin; thus, mediating cell-cell adhesion and permeability. YKL-40 also induced the interaction of vascular endothelial cadherin/beta-catenin/actin in endothelial cells (HMVECs). In cell co-culture systems, YKL-40 enhanced both GSDC and HMVEC contacts, restricted vascular leakage, and stabilized vascular networks. Collectively, the data inform new mechanistic insights into the cooperation of mural cells with endothelial cells induced by YKL-40 during tumor angiogenesis, and also enhance our understanding of YKL-40 in both mural and endothelial cell biology. PMID- 23665678 TI - TGF-beta1 suppression of microRNA-450b-5p expression: a novel mechanism for blocking myogenic differentiation of rhabdomyosarcoma. AB - Transforming growth factor beta 1 (TGF-beta1) is the most potent inhibitor of myogenic differentiation (MyoD) of rhabdomyosarcoma (RMS); however, the underlying mechanisms of this inhibition remain unclear. In this study, we identified novel TGF-beta1-related microRNAs (miRNAs); among these, miR-450b-5p is significantly regulated by TGF-beta1. We provide evidence that TGF-beta1 exerts it function by suppressing miR-450b-5p. Both in cultured cells and tumor implants, miR-450b-5p significantly arrested the growth of RMS and promoted its MyoD. Utilizing a bioinformatics approach, we identified miR-450b-5p target mRNAs. Among these candidates, only the expression of ecto-NOX disulfide-thiol exchanger 2 (ENOX2) and paired box 9 (PAX9) was augmented by miR-450b-5p knockdown examined by western blot; the engineered inhibition antagonized TGF beta1-mediated differentiation inhibition. Furthermore, we found that the Smad3 and Smad4 pathways, but not Smad2, are the principal mediator of TGF-beta1 suppression of miR-450b-5p. Taken together, these results suggest that disrupting the TGF-beta1 suppression of miR-450b-5p, or knockdown of ENOX2 and PAX9, are effective approaches in inducing RMS MyoD. PMID- 23665679 TI - Proof-of-concept rare cancers in drug development: the case for rhabdomyosarcoma. AB - Rare diseases typically affect fewer than 200,000 patients annually, yet because thousands of rare diseases exist, the cumulative impact is millions of patients worldwide. Every form of childhood cancer qualifies as a rare disease-including the childhood muscle cancer, rhabdomyosarcoma (RMS). The next few years promise to be an exceptionally good era of opportunity for public-private collaboration for rare and childhood cancers. Not only do certain governmental regulation advantages exist, but these advantages are being made permanent with special incentives for pediatric orphan drug-product development. Coupled with a growing understanding of sarcoma tumor biology, synergy with pharmaceutical muscle disease drug-development programs, and emerging publically available preclinical and clinical tools, the outlook for academic-community-industry partnerships in RMS drug development looks promising. PMID- 23665680 TI - Met-induced membrane blebbing leads to amoeboid cell motility and invasion. AB - Met tyrosine kinase has been implicated in tumorigenesis and metastasis; its overexpression and deregulation is often observed in cancer. Although Met's functions in cell motility has been studied extensively, its involvement in bleb based, amoeboid motility is yet to be determined. The aim of this work is to study the role of Met in amoeboid cell motility and invasion. We show that aggressive breast cancer cells expressing high levels of endogenous Met, as well as HEK293T cells over expressing fluorescent Met, exhibit constitutive, ligand independent Met activation, leading to Met-dependent membrane blebbing and amoeboid cell motility; HEK293T cells over expressing fluorescent Met were able to invade in three-dimensional matrix. Hyper-activated Met mutant significantly enhances blebbing and cell motility. Met inhibition by either a Met-specific inhibitor or by exogenous expression of a dominant-negative Met remarkably repressed membrane blebbing and invasion. Inhibition of Rho signaling pathway by a ROCK inhibitor also represses Met-induced blebbing, suggesting that Met regulates the blebbing machinery through Rho-ROCK pathway, which controls the actin-myosin contractile force. Either de-polymerization or hyper-polymerization of the actin cytoskeleton abrogates Met-induced blebbing, signifying that actin polymerization has a role in halting and retracting Met-induced mature blebs. Indeed, when blebs retract, membrane wrinkles containing high levels of Met and actin are generated, indicating localized formation of Met-signaling microdomains. We suggest that this bleb-based activity is induced by amplification of Met signaling in unique membrane domains generated by bleb retraction. Our results indicate that Met-induced blebbing has an important role in cell detachment, amoeboid motility and invasion ability, which are utilized by cancer cells for migration and metastasis. PMID- 23665681 TI - Intramolecular hydrogen-bonding activation in cysteines: a new effective radical scavenger. AB - The challenge of developing organic molecules with improved antioxidant activities for a competitive marketplace requires, given the great amount of possibilities, much laboratory work. Nowadays, the ability of methodologies based on quantum chemistry to determine the influence of different modifications on a molecule core provides a powerful tool for selecting the most useful derivatives to be synthesized. Here, we report the results of the assessment of antioxidant activity for quaternary amino acids, specifically for cysteine derivatives. The effect of introducing different substituents on the cysteine core is evaluated by using DFT to obtain an adequate structure-antioxidant activity relationship. This theoretical study shows a small panel of targets among which (R)-N-acetyl-2 methylcysteine methyl ester 15 exhibits special features and relevant antioxidant activity. The conformational (1)H NMR study of this synthesized compound indicates the existence of an intramolecular C7 member ring involving S-HO[double bond, length as m-dash]C substructure, which is reported for the first time in the literature for this amino acid unit. This unusual conformation seems to be the reason for the high antioxidant capacity experimentally found for this compound. PMID- 23665682 TI - Experimental evidences for a new model in the description of the adsorption coupled reduction of Cr(VI) by protonated banana skin. AB - This work reports experimental evidences, not previously considered, to evaluate the Cr(VI) removal by protonated banana skin biomass. Variations in the number of hydroxyl groups, quantified by potentiometric titrations, and CO2 evolution during experiments, were attributed mainly to the oxidation of hydroxylic entities present in the studied material. The results indicate that these groups together with the carboxylic moieties are the main functionalities involved on the adsorption-coupled reduction process. The column experiment carried out provides a new approach to obtain the maximum reduction capacity of the material (3.72 mmol g(-1)). Moreover, we hereby propose a model that reports the first evidence for the instant bound of Cr(III) species to the material used, formed after the reduction of Cr(VI) present in solution. The removal process was quantified carrying out experiments under various pHs, biomass doses and Cr(VI) concentrations, and the mechanism underlying chromium removal was identified. PMID- 23665683 TI - A novel process for recovery of fermentation-derived succinic acid: process design and economic analysis. AB - Recovery and purification of organic acids produced in fermentation constitutes a significant fraction of total production cost. In this paper, the design and economic analysis of a process to recover succinic acid (SA) via dissolution and acidification of succinate salts in ethanol, followed by reactive distillation to form succinate esters, is presented. Process simulation was performed for a range of plant capacities (13-55 million kg/yr SA) and SA fermentation titers (50-100 kg/m(3)). Economics were evaluated for a recovery system installed within an existing fermentation facility producing succinate salts at a cost of $0.66/kg SA. For a SA processing capacity of 54.9 million kg/yr and a titer of 100 kg/m(3) SA, the model predicts a capital investment of $75 million and a net processing cost of $1.85 per kg SA. Required selling price of diethyl succinate for a 30% annual return on investment is $1.57 per kg. PMID- 23665684 TI - Thermogravimetric characteristics and pyrolysis kinetics of alga Sagarssum sp. biomass. AB - Alga Sagarssum sp. can be converted to bio-oil, gas, and char through pyrolysis. In this study, the pyrolysis characteristics and kinetics of Sagarssum sp. were investigated using a thermogravimetric analyzer and tubing reactor, respectively. Sagarssum sp. decomposed below 550 degrees C, but the majority of materials decomposed between 200 and 350 degrees C at heating rates of 5-20 degrees C/min. The apparent activation energy increased from 183.53 to 505.57 kJ mol(-1) with increasing pyrolysis conversion. The kinetic parameters of Sagarssum sp. pyrolysis were determined using nonlinear least-squares regression of the experimental data, assuming second-order kinetics. The proposed lumped kinetic model represented the experimental results well and the kinetic rate constants suggested a predominant pyrolysis reaction pathway from Sagarssum sp. to bio-oil, rather than from Sagarssum sp. to gas. The kinetic rate constants indicated that the predominant reaction pathway was A (Sagarssum sp.) to B (bio-oil), rather than A (Sagarssum sp.) to C (gas; C1-C4). PMID- 23665685 TI - Separation and characterization of effective demulsifying substances from surface of Alcaligenes sp. S-XJ-1 and its application in water-in-kerosene emulsion. AB - The main goal of this work was to analyze the effect of surface substances on demulsifying capability of the demulsifying strain Alcaligenes sp. S-XJ-1. The demulsifying substances were successfully separated from the cell surface with dichloromethane-alkali treatment, and exhibited 67.5% of the demulsification ratio for water-in-kerosene emulsions at a dosage of 356mg/L. FT-IR, TLC and ESI MS analysis confirmed the presence of a carbohydrate-protein-lipid complex in the demulsifying substances with the major molecular ions from mass-to-charge ratio (m/z) 165 to 814. After the substances separated, the cell morphology changed from aggregated to dispersed, and the concentration of cell surface functional groups decreased. Cell surface hydrophobicity and the ability of cell adhesion to hydrophobic surface of the treated cells was also reduced compared with original cell. It was proved that the demulsifying substances had a significant effect on cell surface properties and accordingly with demulsifying capability of Alcaligenes sp. S-XJ-1. PMID- 23665686 TI - Production of novel microbial flocculants by Klebsiella sp. TG-1 using waste residue from the food industry and its use in defecating the trona suspension. AB - A microbial-flocculants-producing (MBF-producing) bacterium, named TG-1, was isolated from waste water of a starch factory, and identified as Klebsiella sp. TG-1. The microbial flocculants (MBF) produced by TG-1, named as MBF-TG-1, was applied to defecating the strong basic trona suspension in the trona industry. After optimizing medium and culturing conditions with single-factor and orthogonal designs, the highest flocculation rate of 86.9% was achieved. Chemical analysis showed that the purified microbial flocculants (MBF-TG-1) was mainly composed of polysaccharides (84.6%), with a small amount of protein or amino acid (11.1%). Bridging mechanism was supposed as the main flocculation mechanism by analyzing the flocculation process and the biochemistry properties of MBF-TG-1. The high flocculation rate (84%) was also achieved with a low-cost medium (the solid residue of tofu production from food industry). PMID- 23665687 TI - Consolidated bioprocessing of untreated switchgrass to hydrogen by the extreme thermophile Caldicellulosiruptor saccharolyticus DSM 8903. AB - The abilities of the extreme thermophilic bacterium Caldicellulosiruptor saccharolyticus DSM 8903 to ferment switchgrass (SWG), microcrystalline cellulose (MCC) and glucose to hydrogen (H2) in one-step were examined. Hydrogen production from glucose reached the theoretical maximum for dark fermentation of 4 mol H2/mol glucose. The H2 yield on MCC and SWG after 6 days of fermentation was 23.2 mmol H2/L or 9.4 mmol H2/g MCC and 14.3 mmol H2/L or 11.2 mmol H2/g SWG, respectively. The rate of H2 formation however was higher on MCC (0.7 mmol/Lh) than SWG (0.1 mmol/Lh). C. saccharolyticus DSM 8903 was able to produce H2 directly from mechanically-comminuted SWG without any physicochemical or biological pretreatment. Combining four processing steps (pretreatment, enzyme production, saccharification and fermentation) into a single biorefinery operation makes C. saccharolyticus DSM 8903 a promising candidate for consolidated bioprocessing (CBP) of lignocellulosic biomass. PMID- 23665688 TI - Steam reforming of tar derived from lignin over pompom-like potassium-promoted iron-based catalysts formed on calcined scallop shell. AB - In order to understand the improvement effect of potassium (K) on the catalytic activity of iron-loaded calcined scallop shell (CS) for the steam reforming tar derived from biomass, various K precursors were applied for the catalyst preparation. It is found that pompom-like iron-based particles with a mesoporous structure were easily formed on the surface of calcined scallop shell (CS) when K2CO3 was used as K precursor while no such kind of microsphere was formed when other kinds of K precursors such as KOH and KNO3 were applied. The optimum K loading amount for the preparation of this catalyst was investigated. Based on the experimental results obtained, a mechanism for the formation of these microspheres was proposed. This pompom-like potassium-promoted iron-based catalyst showed a better catalytic activity and reusability for the steam reforming of tar derived from lignin. PMID- 23665689 TI - Development and characterization of the partial nitrification aerobic granules in a sequencing batch airlift reactor. AB - In this study, partial nitrifying (PN) aerobic granules were developed in a sequencing batch airlift reactor by controlling the airflow rate and NH4(+) loading rate. The PN reactor produced an effluent with a NO2(-)/NH4(+) ratio of approximately one and with an NH4(+) conversion rate of 1.22 kg N m(-3)day(-1). More than 95% of the total organic carbon was removed during the process. On the basis of clone library analysis and fluorescence in situ hybridization, ammonia oxidizing bacteria (AOB) closely related to Nitrosomonas eutropha and putative heterotrophic denitrifiers were mainly present near the surface of the PN aerobic granules. Microelectrode measurements revealed that both NH4(+) and NO2(-) were consumed near the surface (<200 MUm), whereas no nitrate (NO3(-)) accumulation was observed throughout the granules. These results indicate that PN by AOB and nitrite denitrification by heterotrophs, but not nitrite oxidation, simultaneously occurred near the surface of the PN aerobic granules. PMID- 23665690 TI - Performance of photoperiod and light intensity on biogas upgrade and biogas effluent nutrient reduction by the microalgae Chlorella sp. AB - Biogas is an environment-friendly fuel but that must be upgraded before being utilized. The method about removing CO2 from biogas by microalgal culturing using biogas effluent as nutrient medium in this study could effectively upgrade biogas and simultaneously reduce the biogas effluent nutrient. Results showed that the optimum parameters for microalgal growth and biogas effluent nutrient reduction was moderate light intensity with middle photoperiod. While low light intensity with long photoperiod and moderate light intensity with middle photoperiod obtained the best biogas CO2 removal and biogas upgrade effects. Therefore, the optimal parameters were moderate light intensity 350 MUmol m(-2)s(-1) with middle photoperiod 14 h light:10h dark. Under this condition, the microalgal dry weight, CH4 concentration, reduction efficiency of chemical oxygen demand, total nitrogen, and total phosphorus was 615.84 +/- 33.07 mg L(-1), 92.16 +/- 2.83% (v/v), 88.74 +/- 3.45%, 83.94 +/- 3.51%, and 80.43 +/- 4.17%, respectively. PMID- 23665691 TI - Techno-economic analysis of bioethanol production from lignocellulosic residues in Colombia: a process simulation approach. AB - In this study a techno-economic analysis of the production of bioethanol from four lignocellusic (Sugarcane bagasse, Coffee cut-stems, Rice Husk, and Empty Fruit Bunches) residues is presented for the Colombian case. The ethanol production was evaluated using Aspen Plus and Aspen Process Economic Analyzer carrying out the simulation and the economic evaluation, respectively. Simulations included the composition of lignocellulosic residues, which was determined experimentally. It was found that empty fruit bunches presents the highest ethanol yield from a dry basis point of view (313.83 L/t), while rice husk produced less ethanol (250.56 L/t). The ethanol production cost was assessed for the standalone ethanol plant and the ethanol plant coupled with a cogeneration system. Moreover, ethanol production cost using EFB was the lowest with (0.49 US$/L) and without (0.58 US$/L) cogeneration scheme. PMID- 23665692 TI - In situ ethyl ester production from wet algal biomass under microwave-mediated supercritical ethanol conditions. AB - An in situ transesterification approach was demonstrated for converting lipid rich wet algae (Nannochloropsis salina) into fatty acid ethyl esters (FAEE) under microwave-mediated supercritical ethanol conditions, while preserving the nutrients and other valuable components in the algae. This single-step process can simultaneously and effectively extract the lipids from wet algae and transesterify them into crude biodiesel. Experimental runs were designed to optimize the process parameters and to evaluate their effects on algal biodiesel yield. The algal biomass characterization and algal biodiesel analysis were carried out by using various analytical instruments such as FTIR, SEM-EDS, TLC, GC-MS and transmission electron microscopy (TEM). The thermogravimetric analysis (TGA) under nitrogen and oxygen environments was also performed to examine the thermal and oxidative stability of ethyl esters produced from wet algae. This simple in situ transesterification process using a green solvent and catalyst free approach can be a potentially efficient route for algal biodiesel production. PMID- 23665693 TI - Biodiesel production from waste chicken fat with low free fatty acids by an integrated catalytic process of composite membrane and sodium methoxide. AB - An integrated process of catalytic composite membranes (CCMs) and sodium methoxide was developed to produce biodiesel from waste chicken fat. The free fatty acids (FFAs) in the chicken oil were converted to methyl esters by esterification with methanol using a novel sulfonated polyethersulfone (SPES)/PES/non-woven fabric (NWF) CCMs in a flow-through catalytic membrane reactor. The CCM is that the NWF fibers were fully embedded in SPES/PES with a homogeneous and microporous structure. The oil obtained after esterification was carried out by transesterification of sodium methoxide. The results showed that the FFAs conversion obtained by CCMs with the acid capacity of 25.28 mmol (H(+)) was 92.8% at the residence time 258s. The CCMs present a good stability during the continuous running of 500 h. The conversion of transesterification was 98.1% under the optimum conditions. The quality of the biodiesel met the international standards. PMID- 23665694 TI - Thermochemical conversion of crude glycerol to biopolyols for the production of polyurethane foams. AB - This study aimed to produce biopolyols from crude glycerol via a novel thermochemical conversion process. The effect of operational parameters, including sulfuric acid loading and reaction temperature and time, on the properties of the produced biopolyols was investigated. Biopolyols produced under preferred reaction conditions of 200 degrees C, 90 min, and 3% sulfuric acid loading showed a hydroxyl number of around 481 mg KOH/g, an acid number of around 5mg KOH/g, and a viscosity of around 25.0 Pas. The resulting polyurethane (PU) foams showed a compressive strength of around 184.5 kPa and a density of around 43.0 kg/m(3), comparable to those of some petroleum-based analogs. Characterization of the biopolyols via pyrolysis-gas chromatography-mass spectrometry (Py-GC-MS), gas chromatography (GC), and thermogravimetrical analysis (TGA) showed that the major reactions of this process were the formation of monoglycerides and diglycerides through the esterification and transesterification of different components in crude glycerol. PMID- 23665695 TI - Effects of sawdust-CPAM on textile dyeing sludge dewaterability and filter cake properties. AB - Sawdust was used as a filter aid for the textile dyeing sludge dewatering in this study. Results showed that sawdust conditioning in conjunction with cationic polyacrylamide (CPAM) presented much better dewaterability than CPAM alone. The optimal sawdust and CPAM dosage for the best dewaterability was found to be 60 wt.% (mass percent) and 15 kg/t DS (dry solid), the time to filter (TTF) and the yield at 90% degree of the filtration completion (YN90) were 5s and 15.6 kg/m(2)h under the conditions, respectively. TTF and YN90 were more appropriate parameters than specific resistance to filtration (SRF) for assessing the sludge dewaterability as affected by physical conditioners. The moisture content of various filter cake layers gradually became the same with the increase of sawdust dosage. The flocculated sludge cake became relatively incompressible after sawdust conditioning. Sawdust acts to maintain the permeability during the compressed filtration by resisting cake compression. PMID- 23665696 TI - A novel chemoenzymatic synthesis of propyl caffeate using lipase-catalyzed transesterification in ionic liquid. AB - Propyl caffeate has the highest antioxidant capacity in the caffeate alkyl esters family, but industrial production of propyl caffeate is hindered by low yields using either the chemical or enzymatic catalysis method. To set up a high-yield process for obtaining propyl caffeate, a novel chemoenzymatic synthesis method using lipase-catalyzed transesterification of an intermediate methyl caffeate or ethyl caffeate and 1-propanol in ionic liquid was established. The maximum propyl caffeate yield of 98.5% was obtained using lipase-catalyzed transesterification under the following optimal conditions: Novozym 435 as a biocatalyst, [Bmim][CF3SO3] as a medium, a molar ratio of methyl caffeate to 1-propanol of 1:5, a mass ratio of methyl caffeate to lipase of 1:20, and a reaction temperature of 60 degrees C. The two-step conversion of caffeic acid to propyl caffeate via methyl caffeate is an efficient way to prepare propyl caffeate with an overall yield of 82.7%. PMID- 23665697 TI - An automated method for baseline correction, peak finding and peak grouping in chromatographic data. AB - An automated method (FastChrom) for baseline correction, peak detection and assignment (grouping) of similar peaks across samples has been developed. The method has been tested both on artificial data and a dataset obtained from gas chromatograph analysis of wine samples. As part of the automated approach, a new method for baseline estimation has been developed and compared with other methods. FastChrom has been shown to perform at least as well as conventional software. However, compared to other approaches, FastChrom finds more peaks in the chromatograms and not only those with retention times defined by the user. FastChrom is fast and easy to use and offers the possibility of applying a retention time index which facilitates the identification of peaks and the comparison between experiments. PMID- 23665698 TI - Severe bradycardia and prolonged hypotension in ciguatera. AB - Ciguatera results when ciguatoxin-contaminated coral reef fish from tropical or subtropical waters are consumed. The clinical features that present in affected persons are mainly gastrointestinal, neurological, general, and much less commonly, cardiovascular. We report the case of a 50-year-old man who developed the characteristic combination of acute gastrointestinal and neurological symptoms after the consumption of an unidentified coral reef fish head. In addition to those symptoms, he developed dizziness, severe bradycardia (46 bpm) and prolonged hypotension, which required the administration of intravenous atropine and over three days of intravenous fluid replacement with dopamine infusion. Patients with ciguatera can develop severe bradycardia and prolonged hypotension. Physicians should recognise the possible cardiovascular complications of ciguatera and promptly initiate treatment with intravenous atropine, intravenous fluid replacement and inotropic therapy if such complications are observed. PMID- 23665700 TI - New insight into singlet oxygen generation at surface modified nanocrystalline TiO2--the effect of near-infrared irradiation. AB - The generation of singlet oxygen in aqueous colloids of nanocrystalline TiO2 (anatase) modified by organic chelating ligands forming surface Ti(IV) complexes was studied. Detailed studies revealed a plausible and to date unappreciated influence of near-infrared irradiation on singlet oxygen generation at the surface of TiO2. To detect (1)O2, direct and indirect methods have been applied: a photon counting technique enabling time-resolved measurements of (1)O2 phosphorescence, and fluorescence measurements of a product of singlet oxygen interaction with Singlet Oxygen Sensor Green (SOSG). Both methods proved the generation of (1)O2. Nanocrystalline TiO2 modified with salicylic acid appeared to be the most efficient photosensitizer among the tested materials. The measured quantum yield reached the value of 0.012 upon irradiation at 355 nm, while unmodified TiO2 colloids appeared to be substantially less efficient generators of singlet oxygen with the corresponding quantum yield of ca. 0.003. A photocatalytic degradation of 4-chlorophenol, proceeding through oxidation by OH, was also monitored. The influence of irradiation conditions (UV, vis, NIR or any combination of these spectral ranges) on the generation of both singlet oxygen and hydroxyl radicals has been tested and discussed. Simultaneous irradiation with visible and NIR light did not accelerate OH formation; however, for TiO2 modified with catechol it influenced (1)O2 generation. Singlet oxygen is presumably formed according to Nosaka's mechanism comprising O2(-) oxidation with a strong oxidant (hole, an oxidized ligand); however, the energy transfer from NIR-excited titanium(iii) centers (trapped electrons) plays also a plausible role. PMID- 23665701 TI - Decreased fasting blood glucose is associated with impaired hepatic glucose production in thyroid-stimulating hormone receptor knockout mice. AB - Our previous study reported that thyroid-stimulating hormone (TSH) promotes cholesterol synthesis via the cyclic adenosine monophosphate/protein kinase A/cAMP regulatory element-binding protein (cAMP/PKA/CREB) pathway after binding to TSH receptors (TSHR) in the liver. The hepatic cAMP/PKA/CREB pathway also plays an important role in maintaining fasting glucose homeostasis. These findings implied a possible role for TSH in hepatic glucose metabolism. In this study, we used TSH receptor knockout mice (Tshr-ko mice) to clarify the effect of Tshr deletion on hepatic glucose metabolism, and investigated whether the effects of TSH directly regulate hepatic gluconeogenesis in HepG2 cells. Tshr-ko mice exhibited decreased fasting blood glucose levels, increased insulin sensitivity but normal level of fasting plasma insulin. Tshr deletion impaired hepatic glucose production by down-regulating the expression of glucose-6-phosphatase (G6P) and phosphoenolpyruvate pyruvate carboxylase (PEPCK) mRNA, two rate limiting enzymes in hepatic gluconeogenesis, and enhancing the abundance of hepatic glucokinase (GK), the first enzyme regulating glycogen synthesis. Moreover, Tshr deletion inhibited the protein expression of hepatic phospho-CREB and increased the protein expression of hepatic phospho-AMP-activated protein kinase (p-AMPK), two up-stream regulators of PEPCK and G6P mRNA. In HepG2 cells, TSH increased the expression of G6P and PEPCK at mRNA level. These results indicated the simulative effects of TSH on hepatic glucose production in vivo and in vitro, suggesting a novel role for TSH in hepatic glucose metabolism. PMID- 23665702 TI - Aedes aegypti disregard humidity-related conditions with adequate nutrition. AB - Weather variations have clear associations with the epidemiology of dengue fever and populations of Aedes aegypti mosquitoes. Data on humidity associations, however, lags with respect to its effect on host-biting, nectar-seeking and survival. This experimental study on Ae. aegypti, sourced from the arid tropics, investigated the effect of low and high relative humidity and diet in relation to host-biting, temporal variations in feeding frequency, and mosquito mortality. In each environmental setting, 10 replicates, containing one male and five female mosquitoes, were challenged with different nutritional sources every six hours over 12 days. Results showed that host-biting did not diminish in low humidity and was six times higher than expected. Sucrose feeding was observed to significantly moderate host-biting and water alone was inadequate for survival. The high host-biting rates help to explain the intensity of dengue epidemics, while the ability of the mosquito to disregard adverse humidity-related conditions helps to explain how dengue epidemics in arid tropical regions can be just as devastating as those in the wet tropics. PMID- 23665703 TI - Chemical composition and in vitro antitrypanosomal activity of fractions of essential oil from Cymbopogon nardus L. AB - Essential oil from Cymbopogon nardus was evaluated for activity against Trypanosoma brucei brucei BS221 (IC50 = 0.31 +/- 0.03 MUg/mL) and cytotoxic effect on normal kidney (Vero) cells (IC50 = >100 MUg/mL). The crude essential oil was subjected to various chromatography techniques afforded active sub fractions with antitrypanosomal activity; F4 (IC50 = 0.61 +/- 0.06 MUg/mL), F6 (IC50= 0.73 +/- 0.33 MUg/mL), F7 (IC50 = 1.15 +/- 0 MUg/mL) and F8 (IC50 = 1.11 +/- 0.01 MUg/mL). These active fractions did not exhibit any toxic effects against Vero cell lines and the chemical profiles investigation indicated presence of alpha-and gamma-eudesmol, elemol, alpha-cadinol and eugenol by GC/MS analysis. PMID- 23665704 TI - Molecular characterization of Fasciola species isolated from imported sheep in Taif region (Saudi Arabia). AB - Accurate identification of Fasciola species, followed by biological and ecological characterization, is important with concern to the planning for field control. Because there are many variations in morphological characteristics, exact distinguishing of Fasciola species is usually difficult by simple traditional microscopic measurements and, therefore, the morphometric characterization may be insufficient for the species identification. Hence, the present work was proposed to collect 100 liver samples from 100 imported sheep from Sudan from slaughterhouses in Taif region. The samples were firstly examined macroscopically and microscopically to ensure the presence or absence of infection. The collected worms were subjected for RAPD-PCR analysis using different primers and ITS1 sequences for accurate identification. Using RAPD-PCR analysis, two primers were selected to amplify the DNA of each Fasciola. The results show that the amplification fragments were between 500 and 1500 bp and, the use of random genetic markers allowed to discriminate among the different collected species. Using Internal transcribed spacer region (ITS) sequencing, the imported sheep in Taif region consisted of 630 bps including complete ITS1, partial 18S and 5.8S and had 5 variable nucleotide positions. This is the first demonstration of the existence of both F. hepatica, F. gigantica and hybrid and/or introgressed populations of liver flukes bearing genetic material from both F. hepatica and F. gigantica in the imported sheep in Saudi Arabia by a genetic approach. PMID- 23665705 TI - Mosquito larvicidal and ovicidal activity of puffer fish extracts against Anopheles stephensi, Culex quinquefasciatus and Aedes aegypti (Diptera: Culicidae). AB - The extracts of liver (LE), ovary (OE), skin (SE) and muscle (ME) tissues of four species of puffer fishes viz., Arothron hispidus, Lagocephalus inermis, Lagocephalus scleratus and Chelonodon patoca were evaluated against larvae and eggs of three mosquito vectors, Anopheles stephensi, Culex quinquefasciatus and Aedes aegypti. The LC50 values were 1194.26, 1382.73 (LE); 1421.42, 1982.73 (OE); 7116.86, 15038.98 (ME) and 10817.8 ppm (SE) for An. stephensi and Cx. quinquefasciatus respectively for A. hispidus. In the case of L. inermis, the LC50 values were 1163.83, 1556.1 and 2426.38 (LE); 1653.53, 2734.74 (OE); 6067.47 (ME) and 10283.04 ppm (SE) for An. stephensi, Cx. quinquefasciatus and Ae. aegypti respectively. The LC50 values were 1509.98, 1608.69 (LE) and 1414.9, 2278.69 ppm (OE) for An. stephensi and Cx. quinquefasciatus respectively for the extracts of L. scleratus. In the case C. patoca extracts the LC50 values were 1182.29, 1543.00, 2441.03 (LE) and 1076.13, 2582.11 ppm (OE) for An. stephensi, Cx. quinquefasciatus and Ae. aegypti respectively. OE and LE of all puffer fishes exhibited zero percent egg hatchability from 600 to 1000 ppm against eggs of An. stephensi and Cx. quinquefasciatus. This study shows that puffer toxins are effective in killing the larvae and eggs of mosquitoes. PMID- 23665706 TI - Vertical distribution of Aedes mosquitoes in multiple storey buildings in Selangor and Kuala Lumpur, Malaysia. AB - The aim of the present study was to determine the vertical distribution and abundance of Aedes mosquitoes in multiple storey buildings in Selangor and Kuala Lumpur, Malaysia. Ovitrap surveillance was conducted for 4 continuous weeks in multiple storey buildings in 4 residential areas located in Selangor [Kg. Baiduri (KB)] and Kuala Lumpur [Student Hostel of University of Malaya (UM), Kg. Kerinchi (KK) and Hang Tuah (HT)]. The results implied that Aedes mosquitoes could be found from ground floor to highest floor of multiple storey buildings and data from different elevation did not show significant difference. Ovitrap index for UM, KB, HT and KK ranged from 0 - 29.17%, 0 - 55.56%, 8.33 - 83.33% and 0 - 91.17% respectively. Aedes aegypti and Aedes albopictus were found breeding in HT, KK and KB; while only Ae. albopictus was obtained from UM. The results indicate that the invasion of Aedes mosquitoes in high-rise apartments could facilitate the transmission of dengue virus and new approaches to vector control in this type of residential area should be developed. PMID- 23665707 TI - Identification and antimicrobial activity of actinobacteria from soils in southern Thailand. AB - The aim of this research was to study on the identification and antimicrobial activity of actinobacteria from six soil samples collected around Krung Ching waterfall, Nakhon Si Thammarat province, the southern part of Thailand. Thirty one isolates of actinobacteria were isolated using the dilution plating method on modified starch casein nitrate agar plates and potato starch-glycerol agar plates. On the primary screening, 9 isolates exhibited the antimicrobial activity against Bacillus subtilis, 8 isolates against Kocuria rhizophila, 6 isolates against Mucor racemosus, 2 isolates against Escherichia coli and Candida albicans and 5 isolates against Xanthomonas campestris pv. oryzae. All the isolates were identified based on their morphological and cultural characteristics including the 16S rRNA gene sequence analysis. Eighteen isolates were identified as Streptomyces, 8 isolates as Nocardia, 2 isolates as Kitasatospora, one of each isolate as Amycolatopsis, Rhodococcus and Gordonia. PMID- 23665708 TI - Gastrointestinal helminths of camels (Camelus dromedarius) in center of Iran. AB - Camels are multipurpose animals in Iran. As parasitic diseases are the major cause of impaired meat and milk production in this animal, the present study aimed at determining gastrointestinal helminthic infections of Iranian camels in the center of the country. Gastrointestinal (GI) tract of 144 carcasses of one humped camels (Camelus dromedarius) slaughtered in Yazd, Esfahan and Kerman provinces' abattoirs were examined for adult helminths. Camels were from both sexes and different ages. Recovered parasites were identified according to described keys by light microscope. Of 144 tested camels, 117 were infected with at least one helminth species (81.3%). A total of 28 worm species from 14 genera were identified in the digestive tract of infected animals, including 26 species of nematodes and two species of cestodes. The infection rates in stomach, small intestine, and caecum/large intestine were 86.3%, 91.5% and 11.1%, respectively. However, no worm was found in the oesophagus. The recovered worms with infection rates are discussed in this paper. In the present study, Haemonchus tataricus, Trichostrongylus hamatus and Trichuris infundibulus are reported from Iranian dromedaries for the first time. Regarding high prevalence of infection, using anthelminthic drugs seemed necessary to improve the health and productivity of camels. On the other hand, the high rate of zoonotic species indicated that camels have important role in maintaining and transmitting infection to humans. PMID- 23665709 TI - Epidemiological survey of helminths of goats in southern Punjab, Pakistan. AB - The main purpose of this study was to investigate the prevalence of helminths of goats such as Fasciola hepatica, Haemonchus contortus, Paramphistomum cervi, Oesophagostomum columbian, Cotylophoron cotylophorum, Monezia expansa, Oestertagia oestertagi and Oestertagia circumcincta. The overall prevalence of all species of helminthes was 52% in goat. The study was designed to investigate the factors of helminths prevalence on the basis of sex and age of goat with the help of Chi-square. All the results obtained were non-significant due to some factors which directly affects the prevalence of helminths. PMID- 23665710 TI - Wild rodents and their ectoparasites in Baluchistan area, southeast of Iran. AB - During 2008-2009 a total of 67 individuals of rodents, Tetera indica, Meriones hurrianae, Meriones libycus and Gerbillus nanus were trapped in three areas, Bampor, Daman and Qasre Qand from Iranshahr and Nikshahr districts. There is a significant difference between comparative abundance of four species (P<0.05). A total of 1422 ectoparasites collected including 299 mites (21%), 127 fleas (8.9%), 972 lice (68.4%) and 24 ticks (1.7%). Significant findings amongst the ectoparasites is the lice group with three species identified, Laelaps accuninata, Andralaelaps hermophrodita and Paracheylaellaps pyriformis being the first record in the study areas. All four captured genera of rodents are known as main/ potential reservoir hosts of zoonotic cutaneous leishmaniasis. The migration habit of rodents may affect the spatial distribution of parasitic ticks and their transmitted diseases like CCHF, which has been reported in recent years from Sistan and Baluchestan province. Monitoring of rodent populations and their ectoparasites will help to predict the potential of zoonotic arthropod-borne diseases. PMID- 23665711 TI - Intestinal parasitic infections among expatriate workers in Al-Madina Al Munawarah, Kingdom of Saudi Arabia. AB - Al Madinah Al Munawarah, Kingdom of Saudi Arabia (KSA) has one of the largest number of expatriate workers. Most of them are from Sri-Lanka, Indonesia, Philippines, India and Bangladesh. These countries are considered as endemic areas for intestinal parasites. A total of 2732 stool samples were screened for intestinal parasites. Positive cases were recorded among 407 stool samples (14.9%). The common parasitic infections were encountered among 20-29 age groups (18.5%) while, the lowest infection rate was among individual >= 50 years (11.8%). According to the nationality, the highest infections were recorded among Pakistanis (23.2%), followed by Philippines (22.2%), Sudanese workers (18.7%), and the lowest infection rates were recorded among Bangladeshi individuals. The infected persons were farmers, food handlers and shepherds. The detected intestinal parasites were Giardia lamblia (21.9%), Entamoeba histolytica/Entamoeba coli (17.8%), Trichuris trichiura (16.2%), Ascaris lumbricoides (15.8%), hookworm (13%), Hymenolepis nana (8.9%), Strongyloides sterocoralis (3.5%), Schistosoma mansoni (2.2%), and Enterobius vermicularis (0.43%). In conclusion, the high prevalence of parasites among expatriates may produce health problem among the Saudi society due to the nature of the expatriates' work. PMID- 23665712 TI - Bone marrow Penicillium marneffei infection in acquired immunodeficiency syndrome patients: report of 35 cases. AB - Penicilliosis is a tropical disease occurring mostly in Southeast Asia. The incidence of Penicillium marneffei infection in acquired immunodeficiency syndrome (AIDS) patients is increasing due to the infection of the HIV in the population in recent years. In this report, the bone marrow smears of 331 AIDS patients have been examined for the evidence of P. marneffei infection, and 35 (10.6%) of whom were found positive, showing the existing of pathogen in the bone marrow smears. This result indicates that bone marrow P. marneffei infection is a serious complication in HIV infected patients and the inspection of bone marrow should be considered as a routine procedure during treatment. PMID- 23665713 TI - Pelvic and retroperitoneal hydatid cysts superinfected with Brucella sp. and review of infected hydatid cysts. AB - Hydatid disease is a zoonotic infection resulting from the tissue infestation of the larval stage of the parasite Echinococcus granulosus. Hydatid cysts superinfected with pyogenic organisms have been reported previously. Brucellosis is more prevalent in people with close contact to animals and those consuming fresh milk or fresh milk products. Although these two disorders have some similar epidemiological features, we did not encounter any hydatid cyst cases superinfected with Brucella species (sp.) in a search of medical literature (Pubmed). Here, we present a case of hydatid cyst disease superinfected with Brucella and review the literature on other hydatid cyst cases superinfected with pyogenic organisms. We conclude that in regions where brucellosis and hydatid cysts are endemic, cysts may be infected with Brucella sp. PMID- 23665714 TI - Ecological attributes of Hepatozoon lacertilis Gupta et al., 2011 susceptibility in Indian lizards, Hemidactylus flaviviridis (Gekkonidae) and Calotes versicolor (Agamidae). AB - Ecological attributes of haematozoan parasites are poorly understood. In this study, we report haematozoan prevalence in two species of Indian lizards, Hemidactylus flaviviridis (Family: Gekkonidae) and Calotes versicolor (Family: Agamidae) under three macro-environmental variables: host location, weight and seasonal variations. Hemidactylus flaviviridis (n= 199) and Calotes versicolor (n= 34) were sampled from Bareilly, Chandausi and Mirzapur, Uttar Pradesh, India belonging to different weight groups [Group I (0-5 gm), Group II (5-10 gm) and Group III (10-15 gm)] and during various seasons [Summer (May-July), Rainy (August-October), Winter (November-January), Spring (February-April)] of the year. A haemogregarine, Hepatozoon Miller, 1908 was discovered from both host species. Test for identity of the parasites was conducted by feeding infected Culex quinquefasciatus (Diptera: Culicidae) on infection-free H. flaviviridis and C. versicolor and blood examinations on 22(nd) day (H. flaviviridis) and 25(th) day (C. versicolor) post feeding (pf) revealed similar haematozoan parasites and were identified as Hepatozoon lacertilis Gupta et al., 2011. Infectivity from different locations indicated a prevalence of 5.26% (Bareilly) and 16.36% (Mirzapur) in H. flaviviridis whereas infectivity was comparatively higher (19.23%) in C. versicolor. In different weight groups, Group III indicated highest infectivity in both lizards being 21.42% (C. versicolor) and 17.85% (H. flaviviridis). Parasites showed highest prevalence during spring season (H. flaviviridis : 9.52%; C. versicolor : 25%). Values of significance were determined by chi-square test to compare the prevalence within different variables (host location, weight and season). The study has importance for its contribution to the knowledge on the diversity of reptilian hosts infected by haemogregarines. It is the first record of Hepatozoon infectivity in both lizard species with respect to the three macro-environmental variables. PMID- 23665715 TI - Bovine carriers of Anaplasma marginale and Anaplasma bovis in South India. AB - Carriers of bovine anaplasmosis in Northern Kerala, South India were detected using conventional microscopical and molecular techniques. PCR-RFLP and nested PCR techniques were used for detection of Anaplasma marginale and Anaplasma bovis respectively and the PCR products were confirmed by sequencing. Out of 150 samples tested, 25 were detected positive for A. marginale and five for A. bovis based on molecular tests. The inclusion bodies of A. marginale could be detected by microscopy in two blood smears after staining by giemsa while acridine orange staining detected three smears positive. The data clearly suggest the higher sensitivity of molecular techniques for diagnosis of these diseases. PMID- 23665716 TI - Detection of Dientamoeba fragilis among diarrheal patients referred to Tabriz health care centers by nested PCR. AB - Dientamoeba fragilis is a protozoan parasite of the human large intestine which is implicated as a cause of gastrointestinal diseases. The diagnosis of this parasite in direct smear preparations is difficult due to the lack of a cyst stage. The permanent staining method is generally used for diagnosis of D. fragilis, but the technique is laborious and time consuming. The purpose of this study was to evaluate the performance of PCR for detection of D. fragilis in clinical specimen of health care center in Tabriz, northwest of Iran. Stool samples of 1000 patients were collected from different laboratories and were immediately examined via wet mount and permanent staining methods. All positive samples and 55 randomly selected negative samples were studied by PCR technique. Using direct smear examination, no positive sample was found among 1000 stool samples, whereas 21 (2.1%) positive and 26 suspicious cases were reported in stained smears. PCR screening indicated that from 21 positive cases, 17 were positive by primary PCR, whereas nested PCR detected all 21 positive cases as well as 3 new positive samples from the suspicious cases (overall 24 (2.4%) positive samples), yet all negative cases remained negative through both stages of PCR amplifications. In comparison with nested PCR (if considered as gold standard), primary PCR showed 81% sensitivity and 100% specificity and those of microscopy was determined to be 87.5% and 100%, respectively. Considering the favorable sensitivity and specificity of nested PCR and its other advantages such as relative simplicity and speed this technique is proposed for rapid diagnosis of D. fragilis in clinical samples. PMID- 23665717 TI - DNA typing of Calliphorids collected from human corpses in Malaysia. AB - Estimation of post-mortem interval (PMI) is crucial for time of death determination. The advent of DNA-based identification techniques forensic entomology saw the beginning of a proliferation of molecular studies into forensically important Calliphoridae (Diptera). The use of DNA to characterise morphologically indistinguishable immature calliphorids was recognised as a valuable molecular tool with enormous practical utility. The local entomofauna in most cases is important for the examination of entomological evidences. The survey of the local entomofauna has become a fundamental first step in forensic entomological studies, because different geographical distributions, seasonal and environmental factors may influence the decomposition process and the occurrence of different insect species on corpses. In this study, calliphorids were collected from 13 human corpses recovered from indoors, outdoors and aquatic conditions during the post-mortem examination by pathologists from the government hospitals in Malaysia. Only two species, Chrysomya megacephala and Chrysomya rufifacies were recovered from human corpses. DNA sequencing was performed to study the mitochondrial encoded COI gene and to evaluate the suitability of the 1300 base pairs of COI fragments for identification of blow fly species collected from real crime scene. The COI gene from blow fly specimens were sequenced and deposited in GenBank to expand local databases. The sequenced COI gene was useful in identifying calliphorids retrieved from human corpses. PMID- 23665718 TI - Species composition and pyrethroid susceptibility status of Anopheles mosquitoes from two different locations in Malaysia. AB - A 14-months survey was carried out to identify the species composition of Anopheles mosquitoes from Kampung Bongor, Grik, Perak. Adding to that, a preliminary one month mosquito population screening was done at Kampung Tepin, Serian, Sarawak. Consequently, the insecticide susceptibility status of a pyrethroid was tested against two selected species of Anopheles collected from these two locations in Malaysia. A total of 4,497 Anopheles from 11 species were identified from collections in Kampung Bongor, whereas 2,654 An. letifer were collected from Kampung Tepin. The An. maculatus of Kampung Bongor and An. letifer of Kampung Tepin were then selected and tested using WHO standard diagnostic test kits and impregnated papers with 0.75% permethrin. The response values of KT50 and KT95 for An. maculatus were recorded at 28.09 minutes and 62.98 minutes respectively. Anopheles letifer recorded much slower response values of KT50 and KT95, which was at 35.09 minutes and 73.03 minutes respectively. Both An. maculatus and An. letifer showed 100% mortality after 24 hours holding period. The results indicate that both species were still susceptible to the tested pyrethroid. For effective vector control and resistance management, accurate and periodic insecticide resistance monitoring should be undertaken especially in rural areas with agricultural usage of insecticides. PMID- 23665719 TI - Acanthamoeba genotype T4 detected in naturally-infected feline corneas found to be in homology with those causing human keratitis. AB - A total of 10 out of 65 cornea swab samples from cats with eye symptoms showed Acanthamoeba-like morphology after cultivation. By PCR and DNA sequencing of Acanthamoeba diagnostic fragment 3 (DF3), all 10 isolates from the positive samples were categorized into two homologous groups of AfC1 (PM1, PM2, PM3, PF6, KM7, KF8, KMK9) and AfC2 (PM4, PM5, KFK10) due to the presence of bases A(354) and G(354), respectively. Furthermore, DF3 of AfC1 and AfC2 showed 100% similarity with Genbank reference isolates with the accession numbers DQ087314, EU146073 and U07401, GU808323, which were Acanthamoeba castellanii strains genotype T4 originating from human keratitis. This finding suggests that A. castellani strains have the capability to infect cats and human under favorable conditions. PMID- 23665720 TI - Cockroach fauna in the Ogasawara Chain Islands of Japan and analysis of their habitats. AB - A survey of cockroach fauna was carried out on the 3 inhabited islands of the Ogasawara chain island of Japan, namely, Chichijima island, Hahajima island and Iwo island. Seven species, namely, Periplaneta americana (Linnaeus, 1758), Periplaneta australasiae (Fabricius, 1775), Blattella lituricollis (Walker, 1868), Onychostylus vilis (Brunner von Wattenwyl, 1865), Supella longipalpa (Fabricius, 1798), Pycnoscelus surinamensis (Linnaeus, 1758) and Opisthoplatia orientalis (Burmeister, 1838), were collected on Chichijima island. Four species, namely, P. americana, P. australasiae, O. vilis and P. surinamensis were collected on Hahajima island and 6 species, namely, P. americana, P. australasiae, B. lituricollis, O. vilis, P. surinamensis and Neostylopyga rhombifolia were collected on Iwo island. This is the first record of N. rhombifolia and Onychostylus orientalis on the Ogasawara chain islands. Our study increases the recorded taxon of cockroaches on the Ogasawara from 3 families, 5 genera 10 species to 4 families, 7 genera, 12 species. A list of the cockroach species on Ogasawara islands reported to date as well as a key for their identification is also presented. Periplaneta americana and P. australasiae, being the dominant species, together with S. longipalpa, were collected mostly in the indoor environment, indicating their preference for this habitat. Pycnoscelus surinamensis, which is considered as an outdoor insect has been found in semi household environments such as greenhouse and shed, indicating their new adaptation to the changing environment. PMID- 23665721 TI - First report of family infestation with pubic louse (Pthirus pubis; Insecta: Anoplura: Pthiridae) in Iran--a case report. AB - The sucking lice including the head, body and pubic louse infest humans and so they are of high hygienic importance. Pubic lice are transmitted during sexual contact in adults. Thus, infestation of children with pubis louse is very rare. A case of infestation with pubic louse (Pthirus pubis) in a family in Kashan was seen. On examination of family members, the parasites were collected and observed under the light microscope. Infestation of eyelashes with P. pubis lice was confirmed. Since this parasite can be observed on the skin, infestation with this louse has always been one of the concerns of human communities. Pthiriasis has frequently been reported in many parts of the world; however, there are few reports on this infestation in Iran, especially familial infestation with this louse. Hence, this article could be the first report on the familial infestation with P. pubis in Iran and it can be suggested that infestation with pubic lice occurs in sporadic form in all over the country. PMID- 23665722 TI - Occurrence of Campylobacter and Salmonella in ducks and duck eggs in Selangor, Malaysia. AB - The importance of Campylobacter and Salmonella as foodborne pathogens is well recognised globally. A recent work in Penang found ducks in commercial farms were infected with these organisms. The aim of the study was to detect the presence of Campylobacter and Salmonella in ducks and Salmonella in duck eggs in farms in a small part of Selangor. Cloacal swabs were obtained from 75 ducks and 30 duck eggs from three farms. The isolation and identification of Campylobacter and Salmonella were done using conventional methods. Twelve percent of Campylobacter and 16.0% of Salmonella were isolated from the ducks sampled. Salmonella was absent on and in eggs. Campylobacter isolates consisted of 22% Campylobacter jejuni and the remaining was Campylobacter coli. Three Salmonella serovars identified were Salmonella Agona, S. Braenderup and S. Corvallis. The presence of Campylobacter and Salmonella in ducks may cause contamination of the meat during processing and handling which can constitute public health hazard. Moreover, the farm workers may be exposed to the organisms through contact with the infected animals. PMID- 23665723 TI - New locality record of Isomyia paurogonita Fang & Fan, 1986 (Diptera: Calliphoridae) from Peninsular Malaysia and Borneo. AB - Isomyia paurogonita Fang & Fan, 1986 (Diptera: Calliphoridae), a rare species of the subfamily Rhiniinae (tribe Cosminini) was recorded for the first time in Malaysia. We collected one male and two females during a field trip conducted at Genting Highland, Pahang, peninsular Malaysia in May 2011. A 3-day old cow liver was offered as attractant and dipterans collected were transferred to the laboratory for specimens processing and identification. The adults of I. paurogonita were attracted to the odour and then captured by using a sweep net. Isomyia paurogonita was also recorded from two other localities in Peninsular and Malaysian Borneo, namely Gombak Utara, Selangor and Sibu, Sarawak. PMID- 23665724 TI - Rapid development of a lumbar juxtafacet cyst causing conus medullaris syndrome. PMID- 23665725 TI - Impact of anterior clinoidectomy on visual function after resection of meningiomas in and around the optic canal. AB - BACKGROUND: Meningiomas of the anterior and middle skull base frequently involve the optic nerve and cause progressive visual impairment. Surgical decompression of the optic nerve is the only option to preserve visual function. Depending on the invaded structures, optic nerve decompression can be part of a complete tumor removal or the main surgical intention in terms of local debulking. However, bony decompression of the optic canal including anterior clinoidectomy for optic nerve decompression is still a surgical maneuver under discussion. METHODS: From 2006 to 2011, 46 consecutive patients with skull base meningiomas in and around the optic canal were operated. The pterional approach was tailored for each patient. Resection included bony decompression of the optic canal with or without anterior clinoidectomy. Visual acuity and fields were evaluated pre- and postoperatively. RESULTS: Fifty-three percent of patients underwent anterior clinoidectomy, 23 % optic canal unroofing, and 24 % any bony decompression. In 21 patients (46 %), gross total resection (GTR, Simpson grade I or II) was achieved, while 25 patients (54 %) received subtotal resection (STR, Simpson grade III or IV). Sixty three percent of patients presented with preoperative visual impairment. Postoperative visual changes were significantly related to preoperative visual function. While all patients with normal preoperative vision remained unchanged, in patients with impaired vision, surgery caused improvement in 70 % and deterioration in 10 % of patients (p < 0.0001). In patients with anterior clinoidectomy, vision improved more frequently than without anterior clinoidectomy (p < 0.05). CONCLUSIONS: Anterior clinoidectomy is safe and may improve visual outcome in meningiomas in and around the optic canal. PMID- 23665726 TI - Nasal nitric oxide is a marker of poor asthma control. AB - Asthma control, evaluated by symptoms, exacerbations rate and lung function may be greatly influenced by comorbidities, particularly chronic rhinosinusitis (CRS). Measurement of nasal nitric oxide (nNO) is a simple way to assess the severity of CRS. We aimed to analyze the relationship between asthma control and nasal NO. All patients with moderate-to-severe asthma on regular follow-up at our Outpatients' Clinic between November 2009 and April 2010 were included into the study. All patients were evaluated for asthma control by asthma control questionnaire (ACQ) and comorbidities (rhinitis, chronic rhinosinusitis with (CRSwNP) or without nasal polyps, obesity). Exhaled nitric oxide and nNO were obtained in all patients. Eighty-two patients were enrolled (mean age: 48 years, range: 21-80; 42 females). According to ACQ, 53 patients (64.6%) reported controlled asthma. Patients with uncontrolled asthma had lower nNO and higher prevalence of CRSwNP, with a significant correlation between nNO and ACQ. nNO is a biomarker negatively related to asthma control. As low nNO values were associated to CRSwNP, our results indicate that asthma control is highly influenced by this comorbidity. PMID- 23665727 TI - The challenge of integrity. PMID- 23665729 TI - Clinical and cost-effectiveness of absorbent dressings in the treatment of highly exuding VLUs. AB - OBJECTIVE: To estimate the clinical effectiveness and cost effectiveness of using a sodium carboxymethylcellulose dressing (CMC [Aquacel]) and four super absorbent dressings (DryMax Extra[DM], Flivasorb [F], Kerramax [K] and sachet S [S]) in the treatment of highly exuding chronic venous leg ulcers (VLUs) in the UK, from the perspective of the National Health Service (NHS). METHOD: A decision model was constructed depicting the patient pathways and associated management of a cohort of 439 patients with highly exuding chronic VLUs of;;: 3 months of age. The model was based on the case records of a cohort of matched patients from The Health Improvement Network (THIN)database (a nationally representative database of patients registered with general practitioners (GPs) in the UK) who were treated with one of the five dressings. The model estimated the costs and outcomes of patient management over 6 months and the relative cost-effectiveness of using each dressing. RESULTS: Patients' mean age was 73.1 years, and 46% were female. Between 39% and 56% ofVLUs healed by 6 months. CMC-treated wounds that remained unhealed increased in size by 43% over the study period, whereas unhealed wounds treated with the other dressings decreased in size by a mean 34%. Consequently, CMC was excluded from the cost-effectiveness analysis. The 6-monthly NHS cost of managing a VLU with S was L3700 per patient, which was 15-28% lower than the cost of managing patients with the other three super absorbents. Additionally, use of S improved patients' health status to a greater extent than the other three super absorbents, since S-treated patients accrued 0.3-3% more QALYs. Starting treatment with S was the preferred strategy followed by DM, K and Fin that order. CONCLUSION: Within the limitations of the data set,S affords the NHS a cost effective treatment for managing highly exuding chronic VLUs of >=3 months of age, compared with DM, F, K and CMC. PMID- 23665730 TI - SAP-containing dressings exhibit sustained antimicrobial effects over 7 days in vitro. AB - OBJECTIVE: To investigate the antimicrobial activity of SAP-containing wound dressings in vitro over a prolonged period of time (7 days) and to assess their ability to sustain the antimicrobial effect. METHOD: SAP dressings were tested according to the JIS L 1902:2002 against the pathogens Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli and Candida albicans.Additionally, effect on S. aureus and P. aeruginosa growth was investigated after a prolonged incubation period of 7 days. Furthermore, both SAP dressings were repeatedly inoculated with P. aeruginosa suspension and, after 7 days, microbial growth under the dressings was evaluated. RESULTS: Both SAP containing wound dressings tested exhibited a significant to strong antimicrobial activity against Staphylococcus aureus, MRSA, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Candida albicans in vitro. Moreover, it could be shown that they were able to sustain antibacterial efficacy over a prolonged period of time. Using a direct incubation method with repeated re-inoculation of the dressing samples, it could be shown that growth of P. aeruginosa was reduced after 4 days of treatment and completely inhibited after 7 days. No significant differences were observed between the two SAP-dressings tested. CONCLUSION: These in vitro experiments impressively demonstrated the antimicrobial mechanism of SAP containing wound dressings: rapid up-take of fluid, binding of microorganisms to the SAP-core, and retention of the bacteria inside the dressing. Moreover, it could be shown that they are able to exhibit their antimicrobial activity over a prolonged period of time unless the amount of fluid present exceeds their fluid handling capacity. PMID- 23665731 TI - Clinical outcomes of WF10 adjunct to standard treatment of diabetic foot ulcers. AB - OBJECTIVE: To study clinical outcomes and safety of WF I 0 as an adjunct to standard treatment for diabetic foot ulcers (DFU) and to determine the optimal number of WF I 0 cycles that should be administered. METHOD: A prospective, open label study of WF I 0 adjunct to standard treatment for severe DFU but salvageable foot was carried out between July 2009 and June 20 I 0. Patients were classified into three groups, according to common clinical presentations: neuropathic ulcer, ischaemic ulcer and severely infected ulcer. Ulcer assessments were monitored using the wound severity score (WSS; range 0-16).The clinical outcomes at 24 weeks were defined as 'good' (ulcer achieved endpoint [WSS=0-1 ]), 'fair'(improved from baseline [WSS=2-4]) and 'poor' (not improved or worsened [WSS > 4]). RESULTS: From a total of 129 patients, 21 ( 16%) presented with neuropathic ulcers, 49 (38%) with ischaemic ulcers and 59 (46%) with severely infected ulcers.AII neuropathic ulcers achieved either a good or fair outcome, with 81% achieving a good outcome, as did 49% and 81% of ischaemic and severely infected ulcers, respectively. Minor amputations were necessary for 14 patients (I I%), but no major amputation was required. Twenty seven patients (21 %) had transient reduction of haematocrit after WF I 0 therapy. One hundred and one patients (78 %) received only I cycle of WF I 0. CONCLUSION: WF I 0 as an adjunct to standard DFU treatment showed good clinical outcomes in the neuropathic ulcer group and the severely infected ulcer group. A side effect of WF I 0, transient reduction of haematocrit, was observed in 21% of patients. Most patients required only one cycle of WF I 0. PMID- 23665732 TI - Orthopaedic nurses' knowledge about pressure ulcers in Iran: a cross-sectional study. AB - OBJECTIVE: To assess nurses' knowledge about pressure ulcers in an Iranian orthopaedic ward. METHOD: A cross-sectional, self-report questionnaire study using Pieper's Pressure Ulcer Knowledge Test (PUKT). Orthopaedic nurses' knowledge about pressure ulcers was examined in two teaching hospitals in Iran. The questionnaire consisted of 41 true or false assertions, categorised according to pressure ulcer classification and onset, wound characteristics and preventive measure. RESULTS: Of 68 nurses, 57 participated in this study (response rate of 84%); of the respondents, 68%(n=39) were women and 32% (n= 18) were men. Mean age of participants was 30.2 +/- 5.1 years and mean years of experience was 6.9 +/- 4.6 years. The overall rate of correct responses by nurses was 70.1%.Nurses had the highest level of knowledge in the pressure ulcer prevention category and the lowest in the pressure ulcer categorisation and onset section. No relationship was found between level of knowledge and nurses' years of experience. CONCLUSION: Pressure ulcer prevention is one of the most important roles of nurses in an orthopaedic setting. The results of this study suggest that orthopaedic nurses in Iran were not sufficiently knowledgeable about pressure ulcers. Therefore, there is a need to improve their knowledge with some targeted, educational programmes. PMID- 23665733 TI - Wound 'dechronification' with negatively-charged polystyrene microspheres: a double-blind RCT. AB - OBJECTIVE: To compare the efficacy and safety of negatively-charged polystyrene microspheres (NCM)with controls (saline soaks) in the treatment of hard-to-heal wounds of various aetiologies. METHOD: Patients with one or more hard-to-heal wounds, defined as refractory to healing for at least 4 weeks, or those with exposed bone, tendon or ligament, were eligible for inclusion and were randomised to either NCM (PolyHeal; MediWound Ltd.) or controls, both applied twice daily for 4 weeks. Patients were monitored bi-weekly for an additional 8 weeks, while treated by standard wound care, at the investigators' discretion, and were re evaluated 2 years after inclusion. The primary endpoint was defined as coverage of> 75% of the wound area by light-red granulation tissue after 4 weeks of treatment. RESULTS: Fifty-eight patients completed the study, 32 in the NCM group and 26 in the control group. The two most common wound types were those with primary etiologies of venous insufficiency and postoperative/post trauma. In the NCM group 47% of patients achieved > 75% light red granulation tissue after 4 weeks compared with 15% of patients in the control group (p=O.O I). The mean wound surface area in the NCM group was reduced by 39.0% after 4 weeks compared with 14.9% in the control group (p=0.02).The achievement of> 75% light red granulation tissue and reduction of mean wound surface area was also observed in the two main sub-groups (venous insufficiency and postoperative/post trauma), although it was not statistically significant, possibly due to the small sample size in each sub-group. CONCLUSION: This study demonstrates that compared to control treatment, NCM treatment of hard to-heal and chronic wounds improves formation of healthy granulation tissue and reduces wound size thus in fact 'kick starting' the healing process and 'dechronifying' chronic wounds. PMID- 23665734 TI - Use of 3D photography in complex-wound assessment. AB - OBJECTIVE: To review the evidence to support three-dimensional (3D) photographic imaging in wound care and undertake a feasibility evaluation of one device in the clinical environment. METHOD: A literature review was undertaken of the role of stereophotogrammetry in wound care.Subsequently, a 3D imaging and data storage system was selected and evaluated in two representative case studies within the clinical environment of the Royal Centre for Defence Medicine. RESULTS: The review suggested that 3D imaging has the potential to provide more accurate data on which to base treatment decisions. In practice, the device was found to be relatively easy to operate and sufficiently robust to handle the demands of clinical practice. However, the high initial cost of the unit and the time taken to download images to the database meant that its benefits were limited to more complex wound types. CONCLUSION: Three-dimensional photography has the potential to play a role in management options;however, current technical issues limit its potential and the incorporation of a highly defined image (similar to that of a standard digital 2D photograph) within its 3D representation would make it more powerful. PMID- 23665735 TI - Handling the sequelae of breast cancer treatment: use of NPWT to enhance patient independence. AB - A cancer diagnosis can be an overwhelming experience and has devastating implications for an individual, their family and friends. Radical treatment, although often essential, can have its own health consequences. This case study describes the management of a 38-year-old woman with a portable, non-electrical negative pressure wound therapy device, suggesting benefits in terms of healing, patient independence and improved quality of life. The case study also highlights the importance of effective communication, patient involvement and empowerment in clinical decision-making, showing that an effective client-clinician relationship can help overcome the physical and emotional sequelae of this diagnosis. PMID- 23665736 TI - Cell trafficking of endothelial progenitor cells in tumor progression. AB - Blood vessel formation plays an essential role in many physiologic and pathologic processes, including normal tissue growth and healing, as well as tumor progression. Endothelial progenitor cells (EPC) are a subtype of stem cells with high proliferative potential that are capable of differentiating into mature endothelial cells, thus contributing to neovascularization in tumors. In response to tumor-secreted cytokines, EPCs mobilize from the bone marrow to the peripheral blood, home to the tumor site, and differentiate to mature endothelial cells and secrete proangiogenic factors to facilitate vascularization of tumors. In this review, we summarize the expression of surface markers, cytokines, receptors, adhesion molecules, proteases, and cell signaling mechanisms involved in the different steps (mobilization, homing, and differentiation) of EPC trafficking from the bone marrow to the tumor site. Understanding the biologic mechanisms of EPC cell trafficking opens a window for new therapeutic targets in cancer. PMID- 23665737 TI - Use of multiple endpoints and approval paths depicts a decade of FDA oncology drug approvals. AB - This study explores the historic use of different endpoints to support regular and accelerated approval of cancer drugs between 2002 and 2012. In the past 10 years, two thirds of oncology regular approvals were based on endpoints other than overall survival. More than three quarters of accelerated approvals were based on response rates. The accelerated approval program has been heavily used over this time period, with one third of all approved oncology indications receiving accelerated approval. At times, critics have characterized the agency as rigid and unpredictable. This research describes the degree of regulatory flexibility that U.S. Food and Drug Administration and drug sponsors have used over the past decade in the development of new treatments for cancer. PMID- 23665738 TI - Electric-double-layer field-effect transistors with ionic liquids. AB - Charge carrier control is a key issue in the development of electronic functions of semiconductive materials. Beyond the simple enhancement of conductivity, high charge carrier accumulation can realize various phenomena, such as chemical reaction, phase transition, magnetic ordering, and superconductivity. Electric double layers (EDLs), formed at solid-electrolyte interfaces, induce extremely large electric fields. This results in a high charge carrier accumulation in the solid, much more effectively than solid dielectric materials. In the present review, we describe recent developments in the field-effect transistors (FETs) with gate dielectrics of ionic liquids, which have attracted much attention due to their wide electrochemical windows, low vapor pressures, and high chemical and physical stability. We explain the capacitance effects of ionic liquids, and describe the various combinations of ionic liquids and organic and inorganic semiconductors that are used to achieve such effects as high transistor performance, insulator-metal transitions, superconductivity, and ferromagnetism, in addition to the applications of the ionic-liquid EDL-FETs in logic devices. We discuss the factors controlling the mobility and threshold voltage in these types of FETs, and show the ionic liquid dependence of the transistor performance. PMID- 23665739 TI - Vaginal approaches to pelvic organ prolapse repair. AB - PURPOSE OF REVIEW: Changes in perception regarding the safety of mesh require a review of vaginal approaches for pelvic organ prolapse surgery with and without mesh. The purpose of this article is to examine the implications of the negative stigma toward mesh and review the outcomes of different vaginal approaches to pelvic organ prolapse repair. RECENT FINDINGS: Defining a successful outcome of pelvic organ prolapse surgery from a symptomatic perspective instead of an anatomic perspective reveals that native tissue repairs and graft repairs are equivalent. In the posterior and apical compartments, a review of multiple studies shows that native tissue and graft transvaginal repairs have similar anatomic results except that native tissue repairs do not carry the risk of mesh extrusion. After failure of a native tissue repair, the majority of surgeons will use a graft-augmented repair. SUMMARY: Controversy exists about how to define a successful outcome after pelvic organ prolapse surgery. Native tissue repairs require a more individualized approach than mesh-augmented repairs because native tissue requires the surgeon to closely examine the patient to determine the exact compartment and location that is affected before deciding on a surgical approach. PMID- 23665740 TI - Defining high-risk prostate cancer. AB - PURPOSE OF REVIEW: High-risk prostate cancer often represents a lethal disease requiring timely diagnosis and effective therapy. Standardized criteria that define high-risk prostate cancer have yet to be established, rendering the discrimination of high-risk from nonhigh-risk patients a challenge. This review summarizes the contemporary definitions of high-risk prostate cancer and their clinical utility. RECENT FINDINGS: As currently defined, high-risk prostate cancer constitutes a heterogeneous group of tumors with varying pathological features and inconsistent outcomes. Some high-risk patients may harbor systemic disease and relapse after local definitive therapy, whereas a substantial proportion have localized cancers and may be cured by surgery alone. If properly identified, these high-risk patients should be deemed candidates for curative treatment and spared the morbidity of systemic therapy. Additional information derived from systematic prostate biopsy, magnetic resonance findings, and, possibly, pretreatment prostate-specific antigen kinetics may be incorporated into the currently available models to yield a better prediction and to allow more informed decision-making. SUMMARY: The quandary of how to define high-risk prostate cancer is pertinent. Various contemporary definitions of high-risk prostate cancer are available, most of which lack adequate sensitivity and specificity. Patients with high-risk clinically localized prostate cancer, by any of the current definitions, should not be uniformly disqualified from local definitive therapy with curative intent. PMID- 23665741 TI - Future prospects: who is the patient who still dies of prostate cancer following local treatment of high-risk prostate cancer? Can we prolong their lives using modern treatment approaches? AB - PURPOSE OF REVIEW: Prostate cancer remains the commonest nondermatological cause of cancer in Western men and the second leading cause of cancer death in these men. While low and intermediate-risk prostate cancers make up the vast bulk of prostate cancer diagnoses, it is high-risk prostate cancer that is a much larger killer. Management paradigms for such disease are changing and thus we review the current state of play with the management of these cancers and what the future might hold. RECENT FINDINGS: High-risk prostate cancer is a heterogeneous beast, with huge variations in disease severity. Hence, management of these cases must be tailored based on specific risk factors of individual patients, and the role for surgery especially in the lower end of the spectrum is increasing. SUMMARY: The increasing use of radical extirpative surgery might negatively impact functional outcomes but are likely to prolong lives of high-risk prostate cancer sufferers, though more research from well conducted randomized controlled trials is needed to exactly define which patient subpopulations should receive which therapies, in which orders, and at what times. PMID- 23665742 TI - Results of hormone therapy as first-line treatment for high-risk prostate cancer. AB - PURPOSE OF REVIEW: To assess the current place for androgen deprivation therapy as single modality in locally advanced nonmetastatic situations. RECENT FINDINGS: One standard of care for node negative locally advanced disease is a combination of external beam with androgen deprivation treatment. Several recent randomized trials have confirmed the key role of a local treatment combined to a systemic one in terms of specific and overall survival. The specific morbidity of this combined modality appears to be minimal. Retrospective data also suggest that a local treatment should be considered in case of positive nodes. Finally, the real place of immediate single hormonal treatment has also been clarified. The limited survival benefit has to be balanced with the side-effects. Therefore, this single modality should be limited to the most aggressive situations when no local treatment is planned. SUMMARY: Single hormonal treatment for nonmetastatic advanced prostate cancer appears to be limited to the few patients unfit or unwilling for a local treatment and having a high prostate-specific antigen and a short prostate-specific antigen doubling time. In all other situations, it might represent a clear undertreatment. PMID- 23665743 TI - Associations between traffic-related black carbon exposure and attention in a prospective birth cohort of urban children. AB - BACKGROUND: Ambient air pollution may have neurotoxic effects in children. Data examining associations between traffic-related air pollution and attention domains remain sparse. OBJECTIVES: We examined associations between black carbon (BC), a marker of traffic particles, and attention measures ascertained at 7-14 years of age among 174 children in a birth cohort based in the Boston, Massachusetts, area. METHODS: We estimated BC levels using a validated spatial temporal land-use regression model based on residence during children's lifetime. Children completed the Conner's Continuous Performance Test (CPT) measuring omission errors, commission errors, and hit reaction time (HRT), with higher scores indicating increased errors or slower reaction time. Multivariable adjusted linear regression analyses were used to examine associations between BC and each attention outcome. RESULTS: Children were primarily Hispanic (56%) and Caucasian (41%); 53% were boys. We found a positive association between higher BC levels with increased commission errors and slower HRT, adjusting for child IQ, age, sex, blood lead level, maternal education, pre- and postnatal tobacco smoke exposure, and community-level social stress. Notably, the association was weaker, though still positive, for the highest BC quartile relative to the middle two quartiles. Sex-stratified analysis demonstrated statistically significant associations between BC and both commission errors and HRT in boys, but BC was not significantly associated with any of the CPT outcomes in girls. CONCLUSIONS: In this population of urban children, we found associations between BC exposure and higher commission errors and slower reaction time. These associations were overall more apparent in boys than girls. PMID- 23665744 TI - Patient specific or routine preoperative workup in septoplasty: which one is cost effective? AB - This study aimed at determining the limits of preoperative investigation and calculate estimated cost analysis in septoplasty with and without turbinate surgery. A retrospective chart review. The study was conducted at secondary referral center. A retrospective chart review of patients who have undergone septoplasty over a 1-year period was performed. The need for routine (battery testing) versus patient specific preoperative workup of 380 septoplasty patients was evaluated. Mean age of the patients was 31.5 +/- 4.6. The patients were classified into three groups according to preoperative routine laboratory testing results: (1) normal group (2) abnormal group and (3) abnormal out of action limit group. Medical records were revaluated by an anesthesiologist and ear nose throat doctor according to preoperative American Society of Anesthesiologists guidelines to calculate estimated possible costs in case of patient specific preoperative workup. Three hundred seventy-seven patients were within ASA 1 group and three patients were within ASA 2. According to preoperative battery testing results, 5.8% of the patients (n = 22) were in group 1, 93.4% (n = 355) were in group 2, 0.8% (n = 3) were in group 3. Surgery was postponed due to concomitant pathologies for about 44 days (10-180 days) in four patients (1.1%). Preoperative routine laboratory testing costs were calculated as $41.08 +/- 6.69 (40.25 128.78) per patient. When medical records were reevaluated retrospectively, estimated cost per patient would be $8.91 +/- 10.40 (7.18-79.91) if patient specific preoperative workup were done. Individual preoperative testing would save $12,226.78 annually and total cost would decrease from $15,612.41 to $3,385.62. (p = 0.001). Patient-specific preoperative workup is more cost effective than routine battery testing in septoplasty with and without turbinate surgery. PMID- 23665746 TI - Does rheumatoid arthritis have an effect on audiovestibular tests? AB - The study aimed to determine the characteristics of hearing loss, vestibular responses and the incidence of vestibular disturbances in RA patients. This prospective study was performed at the Otolaryngology Department of Bozok University School of Medicine between May and November 2012. Eighty-one RA patients (69 women and 12 men) with a mean age of 40.8 +/- 13.4 years (23-67 years) and 81 healthy controls (67 women and 14 men) with a mean age of 41.3 +/- 13.8 years (24-66 years). Each subject was tested with low and high-frequency audiometry by a single experienced investigator under standard audiometric testing conditions. For each set of tests, mean values of air and bone conduction at each frequency and tympanometric values were calculated for the study groups. Videonystagmography (VNG) including smooth pursuit, saccade, positional, and caloric tests were also performed. The mean air conduction threshold values at high frequencies (4,000, 6,000, and 8,000 Hz) in RA group were lower than control groups. The difference between mean air conduction threshold values of the control groups against RA group at high frequencies were statistically significant (p < 0.05). There was no statistically significance between the two groups in tympanometric values (p < 0.05). VNG testing revealed central abnormalities in twenty patients (24.69%), peripheral abnormalities in five patients (6.17%), and mixed abnormalities in six patients (7.4%). There was no association between VNG abnormalities in patients with RA and age, sex, duration of disease, accompanying vertigo complaint, the laboratory findings and hearing levels (p < 0.05). Our findings suggest an association of RA and audiovestibular system dysfunction regardless clinical and demographic situation of patients. We assume the hearing and vestibular disturbances in RA are more prevalent than previously recognized. Also hearing losses in high frequencies in RA patients may be considered as an indicator of cochlear involvement in this disease. PMID- 23665745 TI - Drug-induced sleep endoscopy: a two drug comparison and simultaneous polysomnography. AB - The purpose of the present study was to compare pharyngeal and polysomnographical findings during drug-induced sleep endoscopy (DISE) performed with either propofol or midazolam as a single sedative agent. It is prospective, non randomized, double-blinded case series study. Sixteen patients with sleep disordered breathing were sedated first with propofol and after full wake up with midazolam. Simultaneous polysomnography (PSG) was performed. We compared the zones of obstruction and vibration found with both drugs using the VOTE classification. Simultaneous PSG findings are also compared. There were 15 men and one woman; the mean age was 42.7 years old, mean body mass index 26.9 kg/m(2). Average DISE duration was 20 min with Propofol and 14.3 min with Midazolam. The induced sleep stage obtained was N2 with both drugs. Outpatient physical exam did not correlate with drug-induced sleep findings. There was a good correlation between DISE results with both drugs in all the areas of collapse except the velum (p < 0.005). Using a continuous perfusion, there is a good agreement in the findings observed in DISE performed with propofol and midazolam and PSG. PMID- 23665747 TI - Role of transnasal oesophagoscopy in diagnosis of early malignancy in the area of the oesophagus and hypopharynx. A review of the literature. PMID- 23665748 TI - Visual presentation of hand image modulates visuo-tactile temporal order judgment. AB - Perceptual systems can distinguish among a variety of inputs in the temporal domain, including even different sensory inputs. This process has been investigated mainly by using a temporal task (temporal order judgment: TOJ). For example, studies have reported estimated critical limits (just noticeable difference: JND) of the TOJ between a visual stimulus and a tactile stimulus (visuo-tactile TOJ, e.g., flashes and vibrations) fell within a certain temporal range. Recent studies have also suggested that the visual presentation of a hand image could modulate visuo-tactile integrations in the temporal domain, but these studies did not thoroughly examine such effects by using temporal tasks. Here, we investigated the effect of visual presentation of a hand image on visuo-tactile TOJ. In our experiments, a visual stimulus was presented on the index finger of a hand image and a tactile stimulus was presented on the index finger of a participant's hand. We found that the JND of visuo-tactile TOJ became larger when a forward hand image was presented than when inverted hand or arrow images were presented. However, this effect was not observed for the TOJ between an auditory stimulus and a visual stimulus. Thus, the visual presentation of a hand image whose angle corresponds to that of one's own hand could selectively degrade visuo tactile TOJ. This finding indicates that visual hand images implicitly enhance the internal proximity between the visual and tactile stimuli and make them difficult to distinguish from each other in the temporal domain. PMID- 23665749 TI - Temporal processing of self-motion: modeling reaction times for rotations and translations. AB - In this paper, we show that differences in reaction times (RT) to self-motion depend not only on the duration of the profile, but also on the actual time course of the acceleration. We previously proposed models that described direction discrimination thresholds for rotational and translational motions based on the dynamics of the vestibular sensory organs (otoliths and semi circular canals). As these models have the potential to describe RT for different motion profiles (e.g., trapezoidal versus triangular acceleration profiles or varying profile durations), we validated these models by measuring RTs in human observers for a direction discrimination task using both translational and rotational motions varying in amplitude, duration and acceleration profile shape in a within-subjects design. In agreement with previous studies, amplitude and duration were found to affect RT, and importantly, we found an influence of the profile shape on RT. The models are able to fit the measured RTs with an accuracy of around 5 ms, and the best-fitting parameters are similar to those found from identifying the models based on threshold measurements. This confirms the validity of the modeling approach and links perceptual thresholds to RT. By establishing a link between vestibular thresholds for self-motion and RT, we show for the first time that RTs to purely inertial motion stimuli can be used as an alternative to threshold measurements for identifying self-motion perception models. This is advantageous, since RT tasks are less challenging for participants and make assessment of vestibular function less fatiguing. Further, our results provide strong evidence that the perceived timing of self-motion stimulation is largely influenced by the response dynamics of the vestibular sensory organs. PMID- 23665750 TI - Right but not left angular gyrus modulates the metric component of the mental body representation: a tDCS study. AB - The parietal lobes contribute to body-space representation. The present work aims at characterizing the functional role of the inferior parietal lobe in body-space representation and at studying the different roles of the angular gyrus in the right and left hemisphere. We conducted three separate transcranial direct current stimulation (tDCS) experiments using "tactile distance task" as an implicit measure of body representation. Whereas anodal tDCS on the right angular gyrus influences vocal reaction times (vRT) for stimuli delivered on the ipsilateral body parts without changes of accuracy, right tDCS improved both vRT and accuracy for tactile stimuli on the contralateral limbs. Sham or left parietal anodal tDCS had no effect. These evidences support the view that right parietal areas have a crucial role in the metric component of the body representation. PMID- 23665751 TI - Quantifying connectivity via efferent and afferent pathways in motor control using coherence measures and joint position perturbations. AB - The applicability of corticomuscular coherence (CMC) as a connectivity measure is limited since only 40-50 % of the healthy population presents significant CMC. In this study, we applied continuous joint position perturbations to obtain a more reliable measure of connectivity in motor control. We evaluated the coherence between joint position perturbations and EEG (position-cortical coherence, PCC) and CMC. Healthy subjects performed two isotonic force tasks against the handle of a wrist manipulator. The baseline task was isometric; in the perturbed task, the handle moved continuously with small amplitude. The position perturbation signal covered frequencies between 5 and 29 Hz. In the perturbed task, all subjects had significant PCC and 86 % of the subjects had significant CMC, on both stimulus and non-stimulus frequencies. In the baseline task, CMC was present in only 45 % of the subjects, mostly on beta-band frequencies. The position perturbations during an isotonic force task elicited PCC in all subjects and elicited CMC in most subjects on both stimulus and non-stimulus frequencies. Perturbed CMC possibly arises by two separate processes: an intrinsic process, similar to the process in an unperturbed task, involving both efferent and afferent pathways; and a process related to the excitation of the afferent and efferent pathways by the perturbation. These processes cannot be separated. PCC, however, reflects connectivity via the afferent pathways only. As PCC was present in all healthy subjects, we propose this coherence as a reliable measure for connectivity in motor control via the afferent pathways. PMID- 23665752 TI - Adaptation of motor control strategies to environmental cues in a pursuit tracking task. AB - Visually guided tracking paradigms can provide insight into the adaptability of motor control strategies. We argue that the question of whether a sensorimotor process, or its absence, is beneficial or detrimental for performance is one that needs to be answered relative to the sensory cues available in the environment and the given task constraints. In this paper, we describe how and when environmental cues have task-dependent benefits. We used a new pursuit-tracking paradigm and added, removed, or replaced cues within the same tracking task in either predictable or unpredictable environments to investigate the use and adaptability of different control strategies. Participants were invited to perform a tracking task over six blocks in six different conditions. Compared to a condition where both target and control cursor (cues) were visible, performance was maintained when a cue was added and decreased when a cue was removed. Our results show that participants only learned to use new cues if the old one was removed and the replacement was valid. This means that the sensorimotor system adapts only if forced to do so instead of constantly exploiting optimization strategies. PMID- 23665753 TI - "Self pop-out": agency enhances self-recognition in visual search. AB - In real-life situations, we are often required to recognize our own movements among movements originating from other people. In social situations, these movements are often correlated (for example, when dancing or walking with others) adding considerable difficulty to self-recognition. Studies from visual search have shown that visual attention can selectively highlight specific features to make them more salient. Here, we used a novel visual search task employing virtual reality and motion tracking to test whether visual attention can use efferent information to enhance self-recognition of one's movements among four or six moving avatars. Active movements compared to passive movements allowed faster recognition of the avatar moving like the subject. Critically, search slopes were flat for the active condition but increased for passive movements, suggesting efficient search for active movements. In a second experiment, we tested the effects of using the participants' own movements temporally delayed as distractors in a self-recognition discrimination task. We replicated the results of the first experiment with more rapid self-recognition during active trials. Importantly, temporally delayed distractors increased reaction times despite being more perceptually different than the spatial distractors. The findings demonstrate the importance of agency in self-recognition and self-other discrimination from movement in social settings. PMID- 23665755 TI - Selenium bioaccumulation in stocked fish as an indicator of fishery potential in pit lakes on reclaimed coal mines in Alberta, Canada. AB - Pit lakes are a common reclamation strategy for open pit mines; however, there is a concern about their water quality and suitability as fish habitat because they are often contaminated by metals or metalloids. This study assessed the exposure of fish and invertebrates to selenium (Se) and other metals and metalloids in pit lakes formed by open pit coal mining in Tertiary (thermal coal) and in Cretaceous (metallurgical coal) bedrock. Juvenile hatchery rainbow trout, Oncorhynchus mykiss, and brook trout, Salvelinus fontinalis, were stocked into two thermal coal pit lakes (water Se < 2 MUg/L, low water Se) and two metallurgical coal pit lakes (water Se > 15 MUg/L, high water Se). Se accumulation in stocked fish and concentrations in invertebrates were characterized over a period of 2 years. In the metallurgical pits, invertebrates had higher Se concentrations and fish accumulated Se to higher levels (exceeding USEPA tissue Se guidelines) than biota in the thermal pits. Rainbow and brook trout accumulated similar concentrations of Se in their muscle and exhibited a similar relationship between whole-body and muscle Se concentrations. These results may be used by resource managers to assess compliance with whole-body tissue Se guidelines and to determine if pit lakes in coal mining areas pose a significant Se risk to wildlife or human health. The high Se exposure in metallurgical coal pits indicates that under the current mining and reclamation strategy, these lakes are not suitable for management as recreational "put and take" fisheries. PMID- 23665756 TI - Fishing farmers or farming fishers? Fishing typology of inland small-scale fishing households and fisheries management in singkarak lake, west sumatra, indonesia. AB - Technical and socio-economic characteristics are known to determine different types of fishers and their livelihood strategies. Faced with declining fish and water resources, small-scale fisheries engage into transformations in livelihood and fishing practices. The paper is an attempt to understand these changes and their socio-economic patterns, in the case of Singkarak Lake in West Sumatra, Indonesia. Based upon the hypothesis that riparian communities have diverse, complex yet structured and dynamic livelihood systems, the paper's main objective is to study, document and model the actual diversity in livelihood, practices and performance of inland small-scale fisheries along the Singkarak Lake, to picture how households are adapted to the situation, and propose an updated, workable model (typology) of those for policy. Principal component analysis and cluster analysis were used to develop a typology of fishing households. The results show that small-scale fishers can be classified into different types characterized by distinct livelihood strategies. Three household types are identified, namely "farming fishers" households (type I, 30 %), "fishing farmers" households (type II, 30 %), and "mainly fishers" households (type III, 40 %). There are significant differences among these groups in the number of boats owned, annual fishing income, agriculture income and farming experience. Type I consists of farming fishers, well equipped, with high fishing costs and income, yet with the lowest return on fishing assets. They are also landowners with farming income, showing the lowest return on land capital. Type II includes poor fishing farmers, landowners with higher farming income; they show the highest return on land asset. They have less fishing equipment, costs and income. Type III (mainly fishers) consists of poorer, younger fishers, with highest return on fishing assets and on fishing costs. They have little land, low farming income, and diversified livelihood sources. The nature of their livelihood strategies is discussed for each identified group. This helps to understand the complexity and diversity of small-scale fishers, particularly in the study area which is still poorly known. This paper concludes with policy implication and possible management initiatives for environmentally prudent policy aiming at improvement of fishers' livelihood. PMID- 23665757 TI - Assessment of the effectiveness of protected areas management in Iran: case study in Khojir National Park. AB - The requirement to assess the management effectiveness (ME) in protected areas (PAs) is increasing around the world to help improve management and accountability. An evaluation of ME for Khojir National Park (KNP), one of the Iran's oldest PAs, was conducted using a multi-method approach that consisted of structured interviews, open interviews, and site visits. This was the first ME evaluation in Iran. The structured interview was based on the management effectiveness tracking tool methodology. KNP received an average score of 43 %, which is lower than the global average, illustrating that its general management was in the low-intermediate level. The indices of legal status, resource inventory, planning for land and water use, regulations, and objectives received the highest average scores, whereas education and awareness, community co management, regular work plan, boundary demarcation, visitor facilities, budget sources, staff training, protection systems, and management plan received the lowest ones. The management system of KNP was generally established, but many problems of the management still need to be resolved. To improve ME, some countermeasures should be taken, such as increasing funding, strengthening capacity building, planning, and adaptive management, and implementing community participation. PMID- 23665758 TI - The impact of early adequate antimicrobial therapy on 14-day mortality in patients with monomicrobial Pseudomonas aeruginosa and Acinetobacter baumannii bacteremia. AB - The impact of colistin therapy for early adequate antimicrobial therapy on clinical outcomes has rarely been evaluated in patients with Pseudomonas aeruginosa bacteremia (PAB) or Acinetobacter baumannii bacteremia (ABB). We investigated the impact of early adequate antimicrobial therapy on 14-day mortality in 149 patients with monomicrobial PAB and ABB at two medical centers where colistin treatment was frequently used. Patients who survived the first 14 days of PAB/ABB received adequate antimicrobial therapy within 3 days of bacteremia more frequently than those who died (53.3 vs. 38.6%), although this finding is not statistically significant (p = 0.10). After excluding patients who received adequate colistin therapy, the difference was statistically significant (94.6 vs. 58.8%, p = 0.001). In a multiple regression model excluding patients who received colistin therapy, adequate antimicrobial therapy within 3 days of bacteremia was a preventive factor for 14-day mortality (adjusted OR = 0.23, 95% CI = 0.07-0.80, p = 0.02). In another multiple regression model including patients who received colistin, compared to inadequate antimicrobial therapy, adequate non-colistin therapy was a preventive factor for 14-day mortality (aOR = 0.22, 95% CI = 0.07-0.78, p = 0.019), but adequate colistin therapy was not (aOR = 8.20, 95% CI = 1.07-62.90, p = 0.043). The favorable impact of early adequate antimicrobial therapy on 14-day mortality in patients with monomicrobial PAB/ABB may be lessened in the clinical practice of using colistin frequently. Further studies may be needed to evaluate the clinical impact of colistin therapy in patients with PAB or ABB. PMID- 23665759 TI - Long-term differences in urinary, bowel and sexual function among men treated with surgery versus radiation for prostate cancer. PMID- 23665761 TI - The average shape of the closed trefoil knot fluctuating on a floppy rope. AB - The average shape of the trefoil knot tied on a floppy, hard rope subject to thermal fluctuations has been determined. The fluctuations of the shape of knots were performed by random bending. As a result of the changing shape procedure large sets of deformed conformations of the initial knot were obtained. Afterwards, these sets were subject to the shape-fitting procedure. It has been found that the conformation is different from the ideal conformation of the knot. PMID- 23665760 TI - Breast cancer resistance protein (Bcrp) and the testis--an unexpected turn of events. AB - Breast cancer resistance protein (Bcrp) is an ATP-dependent efflux drug transporter. It has a diverse spectrum of hydrophilic and hydrophobic substrates ranging from anticancer, antiviral and antihypertensive drugs, to organic anions, antibiotics, phytoestrogens (e.g., genistein, daidzein, coumestrol), xenoestrogens and steroids (e.g., dehydroepiandrosterone sulfate). Bcrp is an integral membrane protein in cancer and normal cells within multiple organs (e.g., brain, placenta, intestine and testis) that maintains cellular homeostasis by extruding drugs and harmful substances from the inside of cells. In the brain, Bcrp is a major component of the blood-brain barrier located on endothelial cells near tight junctions (TJs). However, Bcrp is absent at the Sertoli cell blood testis barrier (BTB); instead, it is localized almost exclusively to the endothelial TJ in microvessels in the interstitium and the peritubular myoid cells in the tunica propria. Recent studies have shown that Bcrp is also expressed stage specifically and spatiotemporally by Sertoli and germ cells in the seminiferous epithelium of rat testes, limited only to a testis-specific cell adhesion ultrastructure known as the apical ectoplasmic specialisation (ES) in stage VI-early VIII tubules. These findings suggest that Bcrp is equipped by late spermatids and Sertoli cells to protect late-stage spermatids completing spermiogenesis. Furthermore, Bcrp was found to be associated with F (filamentous) actin and several actin regulatory proteins at the apical ES and might be involved in the organisation of actin filaments at the apical ES in stage VII VIII tubules. These findings will be carefully evaluated in this brief review. PMID- 23665762 TI - Helix-coil transition in terms of Potts-like spins. AB - In the spin model of a helix-coil transition in polypeptides a preferred value of spin has to be assigned to the helical conformation, in order to account for different symmetries of the helical vs. the coil states, leading thus to the Generalized Model of Polypeptide Chain (GMPC) Hamiltonian as opposed to the Potts model Hamiltonian, both with many-body interactions. Comparison of explicit transfer matrix secular equations of the Potts model and the GMPC model reveals that the largest eigenvalue of the Potts model with Delta many-body interactions coincides with the largest eigenvalue of the GMPC model with Delta - 1 many-body interactions, indicating the identity of both free energies. In distinction, the second largest eigenvalues in both models do not coincide, indicating a different behavior for the spatial correlation length that in its turn defines the width of the helix-coil transition interval. We explore in detail the thermodynamic consequences, resulting from spin models with and without the built-in spin anisotropy, that should indicate which model to favour as a more appropriate description of the equilibrium physical properties pertaining to the helix-coil transition. PMID- 23665763 TI - Does congenital cytomegalovirus infection lead to hearing loss by inducing mutation of the GJB2 gene? AB - BACKGROUND: Congenital cytomegalovirus (CMV) infection and mutation of the gap junction beta-2 (GJB2) gene are important causes of sensorineural hearing loss (SNHL). This study aims to determine if congenital CMV infection leads to deafness by inducing GJB2 mutation. METHODS: GJB2 gene sequencing and auditory brainstem response testing were performed in 159 neonates (63 with and 96 without CMV infection) from August 2008 to August 2011. For neonates with GJB2 mutation, their parents were further screened for GJB2 sequence. RESULTS: The incidence of SNHL was 12.7% in CMV-infected but 0% in uninfected children aged 1-1.5 y (P = 0.000). Similar mutation rates of the GJB2 gene were observed in neonates with or without CMV infection (34.9 vs. 32.3%, respectively, P = 0.734). No significant difference in the mutation rate of GJB2 was found among neonates with CMV infection and SNHL, those with CMV infection and normal hearing, and uninfected newborns with normal hearing (P = 0.438). Mutations 79G>A, 109G>A, 341A>G, and 608T>C were found in neonates with and without CMV infection. All of the above mutations were also found in both or one of the corresponding parents. CONCLUSION: Congenital CMV infections may cause deafness in neonates, but this might be independent of GJB2 gene mutation. PMID- 23665764 TI - Optimizing the relaxivity of GdIII complexes appended to InP/ZnS quantum dots by linker tuning. AB - Three bimodal MRI/optical nanosized contrast agents with high per-nanoparticle relaxivity (up to 2523 mM(-1) s(-1) at 35 MHz and 932 mM(-1) s(-1) at 200 MHz) have been prepared connecting up to 115 tris-aqua Gd(III) complexes to fluorescent non-toxic InP/ZnS quantum dots. The structure of the linker has an important effect on the relaxivity of the final multimeric contrast agent. PMID- 23665765 TI - Analysis of the main dosimetric peak of Al2O3:C compounds with a model of interacting traps. AB - The glow curve of Al2O3:C compounds has been analyzed by employing a model consisting of two active traps, thermally disconnected traps and one recombination centre. The analysis takes into account interaction among traps and the thermal quenching of the thermoluminescent emission. PMID- 23665766 TI - Absolute determination of power density in the VVER-1000 mock-up on the LR-0 research reactor. AB - The work presents a detailed comparison of calculated and experimentally determined net peak areas of selected fission products gamma lines. The fission products were induced during a 2.5 h irradiation on the power level of 9.5 W in selected fuel pins of the VVER-1000 Mock-Up. The calculations were done with deterministic and stochastic (Monte Carlo) methods. The effects of different nuclear data libraries used for calculations are discussed as well. The Net Peak Area (NPA) may be used for the determination of fission density across the mock up. This fission density is practically identical to power density. PMID- 23665767 TI - Experimental infection of non-human primates with avian influenza virus (H9N2). AB - Several cases of humans infected with the H9N2 avian influenza virus (AIV) have been described since 1999; however, the infectivity and pathogenicity of H9N2 in humans is not well defined. A non-human primate model in rhesus macaques was developed to study H9N2 virus infections as a means of better understanding the pathogenesis and virulence of this virus, in addition to testing antiviral drugs. Rhesus macaques inoculated with H9N2 AIV presented with biphasic fever and viral pneumonia. H9N2 was recovered from nasal washes and pharyngeal samples up to days 7-9 postinfection, followed by an increase in HI (hemagglutination inhibition) antibody titers. Tissue tropism and immunohistochemistry indicated that H9N2 AIV replicated in the upper respiratory tract (turbinate, trachea, and bronchus) and in all lobes of the lung. Our data suggest that rhesus macaques are a suitable animal model to study H9N2 influenza virus infections, particularly in the context of viral evolution and pathogenicity. PMID- 23665768 TI - A loop-mediated isothermal amplification method for the detection of members of the genus Ranavirus. AB - A loop-mediated isothermal amplification (LAMP) method was developed for detection of members of the genus Ranavirus. The optimum reaction mixture contained 2.5 MUL of each inner primer, RV-FIP (20 pmol/MUL) and RV-BIP (20 pmol/MUL), 0.5 MUL of each outer primer, RV-F3 (10 pmol/MUL) and RV-B3 (10 pmol/MUL), 1.25 MUL of each loop primer, RV-LF (20 pmol/MUL) and RV-LB (20 pmol/MUL), 3.5 MUL dNTP mix (10 mM each), 8 MUL MgSO4 (25 mM), 1 MUL of Bst DNA polymerase (8 U/mL, large fragment; New England Biolabs Inc., Beverly, MA, USA), 2.5 MUL 10 * supplied buffer, and 1 MUL of template DNA in a final volume of 25 MUL. The optimum reaction conditions were 63 degrees C for 60 min. This LAMP method could detect Andrias davidianus iridovirus (ADIV), soft-shelled turtle iridovirus (STIV), and epizootic hematopoietic necrosis virus (EHNV), all of which belong to the genus Ranavirus, but it could not detect other viruses such as koi herpes virus (KHV), channel catfish virus (CCV), infectious spleen and kidney necrosis virus (ISKNV) and white spot syndrome virus (WSSV). The detection limit of the LAMP method was 100 copies of STIV DNA segment, and the sensitivity was 10 times higher than that of the polymerase chain reaction (PCR) assay. The results could be estimated visually by eye when calcein was added. PMID- 23665769 TI - Complete genome sequence of a novel potato virus S strain infecting Solanum phureja in Colombia. AB - Potato virus S (PVS) (genus Carlavirus, family Betaflexiviridae) is one of the most prevalent viruses in potato crops (Solanum tuberosum and S. phureja) around the world, causing reductions in crop yields between 10 and 20 %. Symptoms of PVS infection may include leaf mottling, rugosity of leaves, deepening of the veins and reductions in crop yields between 10 and 20 %. Virions are flexuous rods of 610-710 nm with a positive-sense ssRNA genome of approximately 8500 nt comprising six ORFs, a 5'CAP and a 3'poly-A tail. PVS has been classified into two groups: PVS(O) (Ordinary) and PVS(A) (Andean). PVSA induces severe symptoms in infected plants, such as premature senescence and defoliation, and is more efficiently transmitted by aphids than PVS(O). To date, only five PVS genomes have been completely sequenced, including those of three PVS(O) and two PVS(A) strains. Currently, there are no reports of complete PVS genome sequences from Andean South America. In this work, we present the complete genomic sequence of a novel PVS strain infecting S. phureja that is clearly distinct from currently known PVS isolates. PMID- 23665770 TI - Ljungan virus is endemic in rodents in the UK. AB - Ljungan virus is a recently identified member of the family Picornaviridae that was isolated from bank voles in Sweden. LjV has been associated with [corrected] type 1 diabetes-like symptoms and myocarditis in bank voles (Myodes glareolus), and it has been suggested that it has zoonotic potential. Here, we show for the first time that Ljungan virus is prevalent (20-27 % positive by PCR) in four species of UK rodent (Myodes glareolus [bank vole], Apodemus sylvaticus [wood mouse], Microtus agrestis [field vole] and Mus musculus [house mouse]). Sequence analysis showed that Ljungan virus of genotypes 1 and 2 were present, although genotype 1 was more prevalent and more frequently associated with brain tissue. This study highlights the prevalence of Ljungan virus in the UK and the need for assessment [corrected] of its zoonotic potential. PMID- 23665772 TI - A combinatorial approach to the peptide feature matching problem for label-free quantification. AB - MOTIVATION: Label-free quantification is an important approach to identify biomarkers, as it measures the quantity change of peptides across different biological samples. One of the fundamental steps for label-free quantification is to match the peptide features that are detected in two datasets to each other. Although ad hoc software tools exist for the feature matching, the definition of a combinatorial model for this problem is still not available. RESULTS: A combinatorial model is proposed in this article. Each peptide feature contains a mass value and a retention time value, which are used to calculate a matching weight between a pair of features. The feature matching is to find the maximum weighted matching between the two sets of features, after applying a to-be computed time alignment function to all the retention time values of one set of the features. This is similar to the maximum matching problem in a bipartite graph. But we show that the requirement of time alignment makes the problem NP hard. Practical algorithms are also provided. Experiments on real data show that the algorithm compares favorably with other existing methods. CONTACT: binma@uwaterloo.ca SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23665771 TI - GAGE-B: an evaluation of genome assemblers for bacterial organisms. AB - MOTIVATION: A large and rapidly growing number of bacterial organisms have been sequenced by the newest sequencing technologies. Cheaper and faster sequencing technologies make it easy to generate very high coverage of bacterial genomes, but these advances mean that DNA preparation costs can exceed the cost of sequencing for small genomes. The need to contain costs often results in the creation of only a single sequencing library, which in turn introduces new challenges for genome assembly methods. RESULTS: We evaluated the ability of multiple genome assembly programs to assemble bacterial genomes from a single, deep-coverage library. For our comparison, we chose bacterial species spanning a wide range of GC content and measured the contiguity and accuracy of the resulting assemblies. We compared the assemblies produced by this very high coverage, one-library strategy to the best assemblies created by two-library sequencing, and we found that remarkably good bacterial assemblies are possible with just one library. We also measured the effect of read length and depth of coverage on assembly quality and determined the values that provide the best results with current algorithms. CONTACT: salzberg@jhu.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23665774 TI - Boosted CO2 reaction with methanol to yield dimethyl carbonate over Mg-Al hydrotalcite-silica lyogels. AB - Nonimmobilized and immobilized Mg-Al hydrotalcite-like materials on silica lyogels were prepared and activated by calcination to be tested as catalysts in the direct carboxylation reaction of methanol. The HTs supported on silica lyogels showed an important improvement and high stability in the direct synthesis reaction of DMC from CO2 and MeOH. PMID- 23665773 TI - A statistical framework for power calculations in ChIP-seq experiments. AB - MOTIVATION: ChIP-seq technology enables investigators to study genome-wide binding of transcription factors and mapping of epigenomic marks. Although the availability of basic analysis tools for ChIP-seq data is rapidly increasing, there has not been much progress on the related design issues. A challenging question for designing a ChIP-seq experiment is how deeply should the ChIP and the control samples be sequenced? The answer depends on multiple factors some of which can be set by the experimenter based on pilot/preliminary data. The sequencing depth of a ChIP-seq experiment is one of the key factors that determine whether all the underlying targets (e.g. binding locations or epigenomic profiles) can be identified with a targeted power. RESULTS: We developed a statistical framework named CSSP (ChIP-seq Statistical Power) for power calculations in ChIP-seq experiments by considering a local Poisson model, which is commonly adopted by many peak callers. Evaluations with simulations and data-driven computational experiments demonstrate that this framework can reliably estimate the power of a ChIP-seq experiment at different sequencing depths based on pilot data. Furthermore, it provides an analytical approach for calculating the required depth for a targeted power while controlling the false discovery rate at a user-specified level. Hence, our results enable researchers to use their own or publicly available data for determining required sequencing depths of their ChIP-seq experiments and potentially make better use of the multiplexing functionality of the sequencers. Evaluation of power for multiple public ChIP-seq datasets indicate that, currently, typical ChIP-seq studies are powered well for detecting large fold changes of ChIP enrichment over the control sample, but they have considerably less power for detecting smaller fold changes. AVAILABILITY: Available at www.stat.wisc.edu/~zuo/CSSP. CONTACT: keles@stat.wisc.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23665775 TI - A case of malignant insulinoma: successful control of glycemic fluctuation by replacing octreotide injections with octreotide LAR injections. AB - A 73-year-old woman with malignant insulinoma was treated with 100 MUg/day octreotide for unresected insulinoma and liver metastases. The daily administration of the drug induced hyperglycemia after dinner in addition to existing fasting hypoglycemia possibly because this drug suppressed both insulin and glucagon secretion and its blood concentration was unstable. After replacing a daily injection of octreotide with a monthly injection of octreotide long acting repeatable (LAR), blood glucose levels stabilized within the normal range. The findings of the present study showed that octreotide LAR could be useful for the long-term treatment of unresectable insulinomas. PMID- 23665776 TI - Direct electrical stimulation of the somatosensory cortex in humans using electrocorticography electrodes: a qualitative and quantitative report. AB - OBJECTIVE: Recently, electrocorticography-based brain-computer interfaces have been successfully used to translate cortical activity into control signals for external devices. However, the utility of such devices would be greatly enhanced by somatosensory feedback. Direct stimulation of somatosensory cortex evokes sensory perceptions, and is thus a promising option for closing the loop. Before this can be implemented in humans it is necessary to evaluate how changes in stimulus parameters are perceived and the extent to which they can be discriminated. APPROACH: Electrical stimulation was delivered to the somatosensory cortex of human subjects implanted with electrocorticography grids. Subjects were asked to discriminate between stimuli of different frequency and amplitude as well as to report the qualitative sensations elicited by the stimulation. MAIN RESULTS: In this study we show that in humans implanted with electrocorticography grids, variations in the amplitude or frequency of cortical electrical stimulation produce graded variations in percepts. Subjects were able to reliably distinguish between different stimuli. SIGNIFICANCE: These results indicate that direct cortical stimulation is a feasible option for sensory feedback with brain-computer interface devices. PMID- 23665778 TI - Compassion, care, dignity and respect: the NHS needs a culture change. PMID- 23665777 TI - HIV-1 outcompetes HIV-2 in dually infected Senegalese individuals with low CD4+ cell counts. AB - OBJECTIVE: Dual infection with HIV-1 and HIV-2, which is not uncommon in West Africa, has implications for transmission, progression, and antiretroviral therapy (ART). Few studies have examined viral dynamics in this setting. Our objective was to directly compare HIV-1 and HIV-2 viral loads and to examine whether this relationship is associated with CD4+ cell count. STUDY DESIGN: This is a retrospective analysis of data from observational cohort studies. METHODS: We compared HIV-1 and HIV-2 viral loads from 65 dually infected, ART-naive Senegalese individuals. Participants provided blood, oral fluid, and cervicovaginal lavage (CVL) or semen samples for virologic and immunologic testing. We assessed relationships between HIV-1 and HIV-2 levels using linear regression with generalized estimating equations to account for multiple study visits. RESULTS: After adjusting for CD4+ cell count, age, sex, and commercial sex work, HIV-1 RNA levels were significantly higher than HIV-2 levels in semen, CVL, and oral fluids. Despite similar peripheral blood mononuclear cell DNA levels among individuals with CD4+ cell counts above 500 cells/MUl, individuals with CD4+ cell counts below 500 cells/MUl had higher HIV-1 and lower HIV-2 DNA levels. Individuals with high CD4+ cell counts had higher mean HIV-1 plasma RNA viral loads than HIV-2, with HIV-1 levels significantly higher and HIV-2 levels trending toward lower mean viral loads among individuals with low CD4+ cell counts. CONCLUSION: Our data are consistent with the hypothesis that with disease progression, HIV-1 outcompetes HIV-2 in dually infected individuals. This finding helps explain differences in prevalence and outcomes between HIV-1, HIV-2, and HIV-dual infection. PMID- 23665779 TI - Subacute onset encephalopathy: a rare clinical syndrome with many aetiologies. PMID- 23665781 TI - Treatment of articular cartilage defects of the knee. PMID- 23665782 TI - Traumatic injuries to the biliary tree. PMID- 23665783 TI - Resuscitation beyond Advanced Trauma Life Support: damage control. PMID- 23665784 TI - Coronary chronic total occlusions and percutaneous coronary intervention. PMID- 23665785 TI - Where next for the Cancer Drugs Fund? PMID- 23665786 TI - Managing impulse control behaviours in Parkinson's disease: practical guidelines. PMID- 23665787 TI - Mortality in a teaching hospital during junior doctor changeover: a regional and national comparison. AB - Concerns about whether the junior doctor changeover in the UK is associated with an increased risk of death have been reawakened by a retrospective study (Jen et al, 2009). Examination of overall mortality data has consistently failed to demonstrate any increase in mortality during the changeover. However, regional and national trends may mask this increase, so a study was undertaken to compare mortality in a busy London teaching hospital with regional and national trends. No evidence of an increase in mortality in August was found for any of the time periods examined, even after comparison with regional and national trends. The authors conclude that examination of overall mortality data is a blunt and impractical instrument for settling the question of whether an increase in morbidity and mortality occurs. Preventable morbidity and mortality should be audited. PMID- 23665788 TI - Acute presentation of rapidly progressive probable Creutzfeldt-Jakob disease. PMID- 23665789 TI - Subacute sclerosing panencephalitis: rapidly progressive cognitive decline in a young patient. PMID- 23665790 TI - Jonathan Hutchinson: surgeon and remarkable generalist. PMID- 23665791 TI - Pulmonary nodule biopsy: also consider bronchoscopic techniques. PMID- 23665793 TI - Is 6% tetrastarch 130kDa (hydroxyethyl starch 130/0.4 or 130/0.42) suitable for severe sepsis? PMID- 23665794 TI - Inverse interaction between tropomyosin and phosphorylated myosin in the presence or absence of caldesmon. AB - In the present study, co-sedimentation assay, intrinsic fluorescence intensity measurement, and Mg2+-ATPase activity analysis were carried out to investigate the direct effect of tropomyosin (TM) on unphosphorylated myosin (UM) or phosphorylated myosin (PM) in the presence or absence of caldesmon (CaD). Results showed that TM significantly decreased the sedimentation, intrinsic fluorescence intensity, and the Mg2+-ATPase activity of PM, but not UM. In the presence of CaD, TM also significantly decreased these parameters irrespective of myosin phosphorylation, suggesting that the interaction between TM and CaD abolished the effects of TM on PM or UM and that there was an inverse interaction between TM and PM, characterized by the decreased PM sedimentation and intrinsic fluorescence intensity. PMID- 23665795 TI - Explaining differences in remuneration rates of nursing homes in Germany. AB - Remuneration rates of German nursing homes are prospectively negotiated between long-term care insurance (LTCI) and social assistance on the one side and nursing homes on the other. They differ considerably across regions while there is no evidence for substantial differences in care provision. This article explains the differences in the remuneration rates by observable characteristics of the nursing home, its residents and its region with a special focus on the largest federal state of North Rhine Westphalia, in which the most expensive nursing homes are located. We use data from the German Federal Statistical Office for 2005 on all nursing homes that offer full-time residential care for the elderly. We find that differences in remuneration rates can partly be explained by exogenous factors. Controls for residents, nursing homes and district characteristics explain roughly 30 % of the price difference; 40 % can be ascribed to a regionally different kind of negotiation between nursing homes and LTCI. Thirty percent of the raw price difference remains unexplained by observable characteristics. PMID- 23665796 TI - Cervical screening, high-grade squamous lesions, and cervical cancer in illicit drug users. AB - BACKGROUND AND PURPOSE: Women who use illicit drugs ("drug users") are exposed to human papillomaviruses (HPVs) from lifestyle risks that include sex risk behaviors, human immunodeficiency virus infection, and high levels of tobacco smoking. Both HPVs and tobacco smoking are recognized causes of cervical cancer, but little is known about risk in drug users. We sought to examine risk of cervical neoplasia and to estimate cervical screening prevalence in drug users compared to non-drug-users in Australia. METHODS: Our study linked hospital admission records of women aged 20-54 in 2000-2007 to Pap Test Register and Cancer Registry records for 19,699 with an illicit drug-related admission and 194,089 without. We designed a nested case-control study of risk of cervical intraepithelial neoplasia (CIN) 2/3 and cervical cancer and a cross-sectional study of screening prevalence in this cohort of women. RESULTS: Drug users were less likely than non-users to be screened in the past 3 years (crude prevalence 47 vs 58%; prevalence ratio 0.80; 95% CI 0.78-0.81). Odds ratios (ORs) in drug users, adjusted for cervical screening history and smoking, were 1.13 (95% CI 1.04-1.23) for CIN 2/3 and 1.43 (95% CI 0.96-2.15) for cervical cancer. The adjusted ORs in each case were similar in cannabinoid users and users of other drugs. CONCLUSIONS: The increased risks of CIN 2/3 and cervical cancer we observed are probably due to sex risk behaviors and their associated high risk of HPV. Interventions in drug users, such as HPV vaccination and barrier contraception and more cervical screening, might reduce the risk of cervical neoplasia. PMID- 23665797 TI - Synthesis, interaction with DNA, cytotoxicity, cell cycle arrest and apoptotic inducing properties of ruthenium(II) molecular "light switch" complexes. AB - In an endeavor toward the development of metal-based anticancer drugs, we present here the design, synthesis and characterization of three ruthenium(II) functionalized phenanthroline complexes with extended pi-conjugation. These complexes have been shown to act as promising CT-DNA intercalators as evidenced by UV-visible, luminescence, emission quenching by [Fe(CN)6](4-), DNA competitive binding with ethidium bromide and salt dependent studies. All three complexes [Ru(Hdpa)2PPIP](2+) (1), [Ru(Hdpa)2PIP](2+) (2), [Ru(Hdpa)24HEPIP](2+) (3) clearly demonstrated that they can bind to DNA through the intercalation mode. Cell viability experiments indicated that all complexes showed significant dose dependent cytotoxicity in selected cell lines. The apoptosis and cell cycle arrest were also investigated. The complexes were docked into DNA-base-pairs using the 'GOLD' (Genetic Optimization for Ligand Docking), docking program. PMID- 23665798 TI - Coumarin chalcone fibrates: a new structural class of lipid lowering agents. AB - In our continuing search for safe and efficacious antidyslipidemic agents, structurally interesting coumarin-chalcone fibrates were synthesized and evaluated in triton WR-1339 induced hyperlipidemic rats. The most active compound 41 decreased the total cholesterol (TC), phospholipids (PL) and triglycerides (TG), of hyperlipidemic rats by 26, 24, and 25% respectively. In addition, the compound 41 significantly reversed the levels of VLDL, LDL HDL and also increased the LPL activity. Altogether, our data suggests that these novel hybrids would be a potential new class of therapeutic agents against dyslipidemia. PMID- 23665799 TI - Synthesis and activity evaluation of tilorone analogs as potential anticancer agents. AB - Tilorone is an interferon inducer with anticancer activity. Twenty-two novel tilorone analogs were synthesized by improvements of fluorenone skeleton, side chains and amino groups to screen new anticancer agents. In vitro evaluation showed that ten new compounds had better anticancer activities than tilorone. Among them, 2c (IC50 < 7 MUM against cancer cell lines and IC50 > 35 MUM against non-cancer cell lines) and 5d (IC50 < 10 MUM against cancer cell lines and IC50 > 53 MUM against non-cancer cell lines) exhibited the best anticancer activities and selectivities. Pharmacophore modeling of highly active compounds was carried out by Molecular Operating Environment (MOE) to generate a visualized model for compound design in future study. PMID- 23665800 TI - Synthesis and preliminary in vitro biological evaluation of 7alpha-testosterone chlorambucil hybrid designed for the treatment of prostate cancer. AB - The synthesis of 7alpha-testosterone-chlorambucil hybrid is reported. This compound is made from testosterone in a 6 step reaction sequence and with 23% overall yield. An alternative convergent reaction sequence yielded the same hybrid through a Grubbs metathesis reaction between chlorambucil allyl ester and 7alpha-allyltestosterone with 35% overall yield. MTT assays showed that the hybrid is selective towards hormone-dependent prostate cancer cell line (LNCaP (AR+)) and shows similar activity than the parent drug, chlorambucil. Thus, the new hybrid shows promising potential for drug targeting of hormone-dependent prostate cancer through its capacity of delivering chlorambucil directly to the site of treatment. This could extend the use of chlorambucil to prostate cancer in the future. PMID- 23665801 TI - 3-Biphenylimidazo[1,2-a]pyridines or [1,2-b]pyridazines and analogues, novel Flaviviridae inhibitors. AB - Using Ttou 84 as starting point, a novel class of biphenyl derivatives of imidazo[1,2-a]pyridine and imidazo[1,2-b]pyridazine was designed to optimize the inhibitory properties on the replication of the bovine viral diarrhoea virus (BVDV) and hepatitis C virus (HCV). Three sites of pharmacomodulation were chosen i.e. positions 2, 3 and 6 on the central heterocyclic core structure. From the 49 analogues tested, only compound 18j (3-(2'-hydroxybiphen-3-yl)-2-(2 methoxyphenyl)-6-(thien-3-yl)imidazo[1,2-b]pyridazine) showed antiviral activity in the HCV replicon system reminiscent of selective inhibition (60-70% inhibition). Compound 4f (3-(biphen-3-yl)-2-(4-fluorophenyl)-6 phenylthioimidazo[1,2-a]pyridine) proved to be the most selective inhibitor of BVDV replication and showed no or only marginal cross-resistance with known inhibitors of pestivirus replication. The cross-resistance profile of 4f might indicate that 4f does not interact with the same binding site as BPIP, VP32947, AG110 or LZ37. From 42 analogues tested against both viruses, QSAR studies were discussed in regard to BVDV antiviral activity. PMID- 23665803 TI - Uncertainty of testing methods--what do we (want to) know? AB - It is important to stimulate innovation for regulatory testing methods. Scrutinizing the knowledge of (un)certainty of data from actual standard in vivo methods could foster the interest in new testing approaches. Since standard in vivo data often are used as reference data for model development, improved uncertainty accountability also would support the validation of new in vitro and in silico methods, as well as the definition of acceptance criteria for the new methods. Hazard and risk estimates, transparent for their uncertainty, could further support the 3Rs, since they may help focus additional information requirements on aspects of highest uncertainty. Here we provide an overview on the various types of uncertainties in quantitative and qualitative terms and suggest improving this knowledge base. We also reference principle concepts on how to use uncertainty information for improved hazard characterization and development of new testing methods. PMID- 23665802 TI - Mechanistic validation. AB - Validation of new approaches in regulatory toxicology is commonly defined as the independent assessment of the reproducibility and relevance (the scientific basis and predictive capacity) of a test for a particular purpose. In large ring trials, the emphasis to date has been mainly on reproducibility and predictive capacity (comparison to the traditional test) with less attention given to the scientific or mechanistic basis. Assessing predictive capacity is difficult for novel approaches (which are based on mechanism), such as pathways of toxicity or the complex networks within the organism (systems toxicology). This is highly relevant for implementing Toxicology for the 21st Century, either by high throughput testing in the ToxCast/Tox21 project or omics-based testing in the Human Toxome Project. This article explores the mostly neglected assessment of a test's scientific basis, which moves mechanism and causality to the foreground when validating/qualifying tests. Such mechanistic validation faces the problem of establishing causality in complex systems. However, pragmatic adaptations of the Bradford Hill criteria, as well as bioinformatic tools, are emerging. As critical infrastructures of the organism are perturbed by a toxic mechanism we argue that by focusing on the target of toxicity and its vulnerability, in addition to the way it is perturbed, we can anchor the identification of the mechanism and its verification. PMID- 23665804 TI - A 155-plex high-throughput in vitro coregulator binding assay for (anti )estrogenicity testing evaluated with 23 reference compounds. AB - To further develop an integrated in vitro testing strategy for replacement of in vivo tests for (anti-)estrogenicity testing, the ligand-modulated interaction of coregulators with estrogen receptor alpha was assessed using a PamChip(r) plate. The relative estrogenic potencies determined, based on ERalpha binding to coregulator peptides in the presence of ligands on the PamChip(r) plate, were compared to the relative estrogenic potencies as determined in the in vivo uterotrophic assay. The results show that the estrogenic potencies predicted by the 57 coactivators on the peptide microarray for 18 compounds that display a clear E2 dose-dependent response (goodness of fit of a logistic dose-response model of 0.90 or higher) correlated very well with their in vivo potencies in the uterotrophic assay, i.e., coefficient of determination values for 30 coactivators higher than or equal to 0.85. Moreover, this coregulator binding assay is able to distinguish ER agonists from ER antagonists: profiles of selective estrogen receptor modulators, such as tamoxifen, were distinct from those of pure ER agonists, such as dienestrol. Combination of this coregulator binding assay with other types of in vitro assays, e.g., reporter gene assays and the H295R steroidogenesis assay, will frame an in vitro test panel for screening and prioritization of chemicals, thereby contributing to the reduction and ultimately the replacement of animal testing for (anti-)estrogenic effects. PMID- 23665805 TI - Serum-reduced and serum-free media for differentiation of Caco-2 cells. AB - Human intestinal Caco-2 cells were differentiated using serum-reduced medium with fetal bovine serum (FBS) added only to the basolateral (BL) medium, and four serum-free media, containing insulin, transferrin, selenium (ITS), or MITO+TM serum extender (ITS plus growth factors), with or without addition of a lipid mixture, respectively. Differentiation was assessed by monitoring monolayer permeability, alkaline phosphatase and sucrase activities, and the transport of digoxin and cephalexin. Notably, the serum-reduced protocol produced results that were comparable to cells differentiated in the control medium and should be recommended as an alternative to the use of 10% FBS in both apical (AP) and BL media. ITS serum-free medium elicited permeability values and cephalexin transport similar to control cells. MITO+TM medium was the most efficient in promoting the two transport activities investigated, and it should be further evaluated with a larger set of substances, although its undisclosed composition represents a limit that may override these advantages. PMID- 23665806 TI - Evidence for the detection of non-endotoxin pyrogens by the whole blood monocyte activation test. AB - Threats of pyrogenicity were discovered more than a century ago. Measures to determine the safety of parenterals and, more recently, medical devices and cell therapies for human use have been in place for 70 years. Currently, there are three testing possibilities available: the Rabbit Pyrogen Test, the Limulus Amebocyte Lysate test (Bacterial Endotoxin Test), and test systems using human whole blood or human monocytes, called Monocyte Activation Test (MAT). The MAT is based on the human fever reaction and thus most closely reflects the human situation. Unfortunately, regulations and testing guidelines are not fully harmonized, despite formal international validation. Furthermore, data showing that the MAT is capable of covering the totality of possible pyrogens relevant to humans were not included in the MAT validations of the last decade. For this review we collate evidence from published literature, unpublished data of our own, and results from the international validation study to show that there is overwhelming scientific evidence to conclude that the whole blood MAT reliably detects non-endotoxin pyrogens. Therefore, further validation exercises do not seem warranted. PMID- 23665808 TI - Reprint: Inflammatory findings on species extrapolations: humans are definitely no 70-kg mice. AB - Modern toxicology has embraced in vitro methods, and major hopes are based on the omics technologies and systems biology approaches they bring along (Hartung and McBride, 2011; Hartung et al., 2012). A culture of stringent validation has been developed for such approaches (Leist et al., 2010, 2012a,b), while the quality and usefulness of animal experiments have been little scrutinized. A new study (Seok et al., 2013) now shows the low predictivity of animal responses in the field of inflammation. These findings corroborate earlier findings from comparisons in the fields of neurodegeneration, stroke and sepsis. The low predictivity of animal experiments in research areas allowing direct comparisons of mouse versus human data puts strong doubt on the usefulness of animal data as key technology to predict human safety. PMID- 23665809 TI - Alternative in vitro methods to characterize the role of Endocrine Active Substances (EASs) in hormone-targeted tissues. PMID- 23665807 TI - Metabolomics in toxicology and preclinical research. AB - Metabolomics, the comprehensive analysis of metabolites in a biological system, provides detailed information about the biochemical/physiological status of a biological system, and about the changes caused by chemicals. Metabolomics analysis is used in many fields, ranging from the analysis of the physiological status of genetically modified organisms in safety science to the evaluation of human health conditions. In toxicology, metabolomics is the -omics discipline that is most closely related to classical knowledge of disturbed biochemical pathways. It allows rapid identification of the potential targets of a hazardous compound. It can give information on target organs and often can help to improve our understanding regarding the mode-of-action of a given compound. Such insights aid the discovery of biomarkers that either indicate pathophysiological conditions or help the monitoring of the efficacy of drug therapies. The first toxicological applications of metabolomics were for mechanistic research, but different ways to use the technology in a regulatory context are being explored. Ideally, further progress in that direction will position the metabolomics approach to address the challenges of toxicology of the 21st century. To address these issues, scientists from academia, industry, and regulatory bodies came together in a workshop to discuss the current status of applied metabolomics and its potential in the safety assessment of compounds. We report here on the conclusions of three working groups addressing questions regarding 1) metabolomics for in vitro studies 2) the appropriate use of metabolomics in systems toxicology, and 3) use of metabolomics in a regulatory context. PMID- 23665810 TI - Towards evidence-based translational research: the pros and cons of conducting systematic reviews of animal studies. PMID- 23665811 TI - Advanced tests for skin and respiratory sensitization assessment. AB - Sens-it-iv is an FP6 Integrated Project that finished in March 2011 after 66 months of activity, thanks to 12 million ? of funding. The ultimate goal of the Sens-it-iv project was the development of a set of in vitro methods for the assessment of the skin and respiratory sensitization potential of chemicals and proteins. The level of development was intended to be at the point to enter the pre-validation phase. At the end of the project it can be concluded that the goal has been largely accomplished. Several advanced methods were evaluated extensively, and for some of them a detailed Standard Operating Procedure (SOP) was established. Other, less advanced methods also contributed to our understanding of the mechanisms driving sensitization. The present contribution, which has been prepared with the support of CAAT-Europe, represents a short summary of what was discussed during the 3-day end congress of the Sens-it-iv project in Brussels. It presents a list of methods that are ready for skin sensitization hazard assessment. Potency evaluation and the possibility of distinguishing skin from respiratory sensitizers are also well advanced. PMID- 23665812 TI - Photoswitchable interactions between photochromic organic diarylethene and surface plasmon resonance of gold nanoparticles in hybrid thin films. AB - Hybrid materials combining gold nanoparticles (GNP) of variable diameter and an organic thin layer of photochromic diarylethenes were achieved. Solid-state photoswitching based on ring-closure/ring-opening reaction was carried out under alternate UV and visible irradiations. In addition to the spectral changes due to the photochromism itself, the surface plasmon resonance related to the GNP is significantly modified, influenced by a photoinduced change in the refractive index of its environment. These two contributions were sorted out, showing the possibility of probing a photochromic switch by following the plasmon band. The shape change of the plasmon band was consistently compared to calculations based on the Mie theory. Additionally, with one given diarylethene compound, both UV visible spectroscopy and surface enhanced Raman scattering (SERS) spectroscopy showed an acceleration of the ring-opening photochromic reaction in the presence of GNP. PMID- 23665813 TI - Reducing health risks from indoor exposures in rapidly developing urban China. AB - BACKGROUND: Over the past two decades there has been a large migration of China's population from rural to urban regions. At the same time, residences in cities have changed in character from single-story or low-rise buildings to high-rise structures constructed and furnished with many synthetic materials. As a consequence, indoor exposures (to pollutants with outdoor and indoor sources) have changed significantly. OBJECTIVES: We briefly discuss the inferred impact that urbanization and modernization have had on indoor exposures and public health in China. We argue that growing adverse health costs associated with these changes are not inevitable, and we present steps that could be taken to reduce indoor exposures to harmful pollutants. DISCUSSION: As documented by China's Ministry of Health, there have been significant increases in morbidity and mortality among urban residents over the past 20 years. Evidence suggests that the population's exposure to air pollutants has contributed to increases in lung cancer, cardiovascular disease, pulmonary disease, and birth defects. Whether a pollutant has an outdoor or an indoor source, most exposure to the pollutant occurs indoors. Going forward, indoor exposures can be reduced by limiting the ingress of outdoor pollutants (while providing adequate ventilation with clean air), minimizing indoor sources of pollutants, updating government policies related to indoor pollution, and addressing indoor air quality during a building's initial design. CONCLUSIONS: Taking the suggested steps could lead to significant reductions in morbidity and mortality, greatly reducing the societal costs associated with pollutant derived ill health. PMID- 23665814 TI - Comparison of the genetic background of different Colombian populations using the SNPforID 52plex identification panel. AB - Various strategies for analysing SNP markers and genotyping have been published with the goal of obtaining informative profiles from biological samples that contain only small amounts of template and/or degraded DNA. In this study, a multiplex assay of 52 autosomal single-nucleotide polymorphisms (SNPs) was used to analyse 438 individuals from urban populations from different regions of Colombia, as well as a sample of 50 Native American individuals of the Pastos ethnic group from Narino. To determine if significant differences in these 52 SNPs exist between the distinct regions of Colombia, genetic distance and admixture analyses were performed based on the available data for 17 different Colombian population groups and for population groups from Africa, Europe and America. The results demonstrate significant differences between the populations from the Southwest Andean, Central-West Andean, Central-East Andean, Orinoquian and northern Colombian Pacific Coast regions. Most of the regions exhibited a European and Native American admixture. One exception is the population from the region of Choco (on the northern Pacific Coast), which exhibits a high proportion of African admixture (54 %). From the observed genetic backgrounds, it is possible to conclude that a single reference database for the entire country would not be suitable for forensic purposes. The allele frequencies and the forensically relevant parameters were calculated for all of the markers in each Colombian region with significant values for the combined matching probability (power of discrimination >=0.99999999999999990) and the combined probability of exclusion (>=0.9990) in trios that were obtained from all of the population groups. PMID- 23665816 TI - Efficacy of cholestyramine ointment in reduction of postoperative pain and pain during defecation after open hemorrhoidectomy: results of a prospective, single center, randomized, double-blind, placebo-controlled trial: reply. PMID- 23665815 TI - Amebic acute appendicitis: systematic review of 174 cases. AB - BACKGROUND: This study aimed to determine the clinical and demographic features of acute amebic appendicitis by reviewing the reported cases. METHODS: The PubMed and MEDLINE databases were searched to identify articles related to amebic appendicitis using key words. The search included all articles published between 1935 and 2012 without restricting language, journal, or country. RESULTS: A total of 174 cases of amebic appendicitis reported in 42 articles were analyzed. The mean age of the patients was 23.5 years (range 2 months-83 years). The majority of patients were male (74.0 %), and the majority of cases were reported from countries with high/moderate risk for amebiasis (76.5 %). A history of traveling to a high/moderate-risk country was cited in 64.0 % of the overall cases. The interval between travel and onset of clinical symptoms ranged from months to years. History of or coexisting dysenteric diarrhea was present in only 7.0 and 14.0 % of overall cases, respectively. A preoperative diagnosis of amebiasis was cited for only five cases (3.0 %). Complicated appendicitis was present in 30.7 % of cases, some of which required colon resection. Severe postoperative intraabdominal complications (e.g., liver abscess, abdominal sepsis, gastrointestinal fistula, hemorrhage) occurred in 19.4 % of surgery-treated patients. The overall mortality rate was 3.2 %. CONCLUSION: Appendectomy specimens should be routinely sent for histopathologic examination. In the case of suspected amebic acute appendicitis, extra precautions-early appendectomy, metronidazole for antibiotic prophylaxis, wet-preparation examination, obtaining a timely pathology result, increasing the awareness of uncommon complications of appendectomy-can hasten appropriate therapeutic intervention and improve outcome. PMID- 23665817 TI - Patient attitudes toward transaxillary robot-assisted thyroidectomy. AB - BACKGROUND: The transaxillary robot-assisted technique constitutes an acceptable treatment option for patients requiring thyroidectomy. However, patients' attitudes toward this new technique have not yet been analyzed. METHODS: A sample of 596 randomly selected patients who underwent thyroidectomy between January 2000 and March 2010 was assessed. We evaluated patients' attitudes toward transaxillary robot-assisted thyroidectomy, taking into account the validated Patient Scar Assessment Questionnaire, the SF-36 Health Survey Questionnaire, and 11 sociodemographic and surgical patient characteristics. RESULTS: Only 11.6 % of the patients would prefer to have been treated with the transaxillary method. Most patients had concerns that it would be a more painful procedure (39.2 %), and they expressed satisfaction with the existing esthetic outcome (29.1 %); other concerns were that the robotic approach would be of longer duration (25.4 %) and at higher cost (15.5 %). Nevertheless, the worse the appearance of the neck scar the more preferable is the new method (p = 0.025), a result that holds true irrespective of patients' physical health, the invasive procedure attained (conventional or minimal), and the presence of postoperative complications, among other characteristics. Patients diagnosed with a benign or uncertain neoplasm (p = 0.022) and younger patients (p = 0.003) held a more positive view of the new method. CONCLUSIONS: Patients who have undergone conventional thyroidectomy via the usual neck incision do not express a preference for the transaxillary method. The reasons given include various perceived disadvantages of the robotic procedure (increased pain, longer operative times, and higher cost). Younger patients, patients with poor appearance of their neck scar, and patients with benign thyroid pathology seem to hold a more positive attitude toward the robotic approach. PMID- 23665818 TI - Hepatectomy for huge hepatocellular carcinoma: single institute's experience. AB - BACKGROUND: The surgical resection of huge hepatocellular carcinoma (HCC) is still controversial. This study was designed to introduce our experience of liver resection for huge HCC and evaluate the safety and outcomes of hepatectomy for huge HCC. METHODS: A total of 258 hepatic resections for the patients with huge HCC were analysed retrospectively from December 2002 to December 2011. The operative outcomes were compared with 293 patients with HCC >5.0 cm but <10.0 cm in diameter. Prognostic factors for long-term survival were evaluated by univariate and multivariate analyses. RESULTS: The 1-, 3-, 5-year overall survival rates after liver resection were 84, 62, and 33 %. Overall survival and disease-free survival in huge HCC group and HCC >5.0 cm but <10.0 cm group were similar (P = 0.751, P = 0.493). Solitary huge HCC group has significantly a more longer overall and disease-free survival time than nodular huge HCC (P = 0.026, P = 0.022). Univariate and multivariate analysis revealed that the types of tumour, vascular invasion, and UICC stage were independent prognostic factors for overall survival (P = 0.047, P = 0.037, P = 0.033). CONCLUSIONS: Hepatic resection can be performed safely for huge HCC with a low mortality and favorable survival outcomes. Solitary huge HCC has the better surgical outcomes than nodular huge HCC. PMID- 23665819 TI - Comorbidity burden in patients with chronic GVHD. AB - Chronic GVHD (cGVHD) is associated with mortality, disability and impaired quality of life. Understanding the role of comorbidity in patients with cGVHD is important both for prognostication and potentially for tailoring treatments based on mortality risks. In a prospective cohort study of patients with cGVHD (n=239), we examined the performance of two comorbidity scales, the Functional Comorbidity Index (FCI) and the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI). Both scales detected a higher number of comorbidities at cGVHD cohort enrollment than pre-hematopoietic cell transplant (HCT) (P<0.001). Higher HCT-CI scores at the time of cGVHD cohort enrollment were associated with higher non relapse mortality (HR: 1.21:1.04-1.42, P=0.01). For overall mortality, we detected an interaction with platelet count. Higher HCT-CI scores at enrollment were associated with an increased risk of overall mortality when the platelet count was <= 100,000/MUL (HR: 2.01:1.20-3.35, P=0.01), but not when it was >100,000/MUL (HR: 1.05:0.90-1.22, P=0.53). Comorbidity scoring may help better to predict survival outcomes in patients with cGVHD. Further studies to understand vulnerability unrelated to cGVHD activity in this patient population are needed. PMID- 23665820 TI - Reduced-intensity vs myeloablative conditioning allogeneic hematopoietic SCT for patients aged over 45 years with ALL in remission: a study from the Adult ALL Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT). AB - In this study, outcomes for 575 adult ALL patients aged >=45 years who underwent first allo-SCT in CR were analyzed according to the type of conditioning regimen (myeloablative conditioning (MAC) for 369 patients vs reduced-intensity conditioning (RIC) for 206 patients). Patients in the RIC group were older (median age, 58 vs 51 years, P<0.0001). There were no statistically significant differences in 3-year OS, disease-free survival (DFS) and non-relapse mortality (NRM): 51% vs 53%, 47% vs 39% and 38% vs 36%, respectively. Multivariate analysis showed that CR2 and HLA mismatching were associated with poor OS (P=0.002 and P=0.019, respectively). HLA mismatching was associated with lower rate of relapse (P=0.016), but was associated with higher rate of NRM (P=0.001). RIC was associated with good OS and DFS in patients who received HLA-mismatch transplantation and were aged >=55 years compared with MAC by multivariate analysis for each event with interaction (hazard ratio (HR) and 95% confidence interval 0.35 and 0.15-0.81, P=0.014 for OS and 0.36 and 0.16-0.81, P=0.013 for DFS). Therefore, patients >=55 years of age with HLA-mismatch transplantation should be candidates for RIC rather than MAC. PMID- 23665821 TI - Prospective qualitative and quantitative non-invasive evaluation of intestinal acute GVHD by contrast-enhanced ultrasound sonography. AB - Intestinal acute GVHD (I-aGVHD) is a life-threatening complication after allografting. Non-invasive bed-side procedures to evaluate extension and treatment response are still lacking. We hypothesized that, during I-aGVHD, contrast-enhanced ultrasound sonography (CEUS) could detect microcirculation changes (MVC) of the bowel wall (BW) and help to monitor treatment response. We prospectively employed CEUS in 83 consecutive patients. Of these, 14 patients with biopsy-proven intestinal GVHD (I-GVHD) were defined as the study group, whereas 16 patients with biopsy-proven stomach GVHD (U-GVHD) without intestinal symptoms, 6 normal volunteers and 4 patients with neutropenic enterocolitis were defined as the control group. All patients were evaluated with both standard ultrasonography (US) and CEUS at the onset of intestinal symptoms, during clinical follow-up and at flare of symptoms. Standard US revealed BW thickening of multiple intestinal segments, useful to determine the extension of GVHD. CEUS showed MVC, which correlated with GVHD activity, treatment response, and predicted flare of intestinal symptoms. US and CEUS findings were superimposable at diagnosis and in remission. CEUS was, however, more sensitive and specific to identify subclinical activity in patients with clinical relevant improvement. These findings were not observed in the control groups. CEUS is a non-invasive, easily reproducible bed-side tool useful to monitor I-aGVHD. PMID- 23665822 TI - Late mortality after hematopoietic SCT for a childhood malignancy. AB - Hematopoietic SCT (HSCT) has been used as a curative therapy for pediatric malignancies. Survivors of HSCT are at risk for disease recurrence, late morbidity and mortality. We assessed late mortality (>=2 years post-HSCT) in a population-based cohort of children who underwent HSCT for a malignancy. Mortality outcomes were determined by linking a clinical transplant database with the Canadian province of Ontario's pediatric cancer mortality files. Seven hundred and fifty-four children underwent HSCT (371 allogeneic, 383 autologous). Of the 479 (63.5%) who were alive >=2 years post HSCT, 98 (20.5%) suffered a late death. Late mortality in the allogeneic HSCT group was 14.9% (median follow-up 10.0 years; range: 2.0-25.6 years), mainly due to relapse of the primary malignancy (64.7%). Chronic GVHD and second malignancies were not major causes of late mortality. A total of 25.5% suffered a late death following autologous HSCT (median follow-up 6.7 years; range: 2.0-22.2 years). Recurrence of the primary malignancy accounted for 87.5% of these deaths. Recurrence of the primary malignancy is the predominant cause of late mortality after HSCT. In contrast to studies of adult patients, non-relapse mortality is less common in children, and death due to chronic GVHD and secondary malignancies is uncommon. PMID- 23665824 TI - Testicular hemangioma: a series of 8 cases. AB - Testicular hemangioma is a very rare neoplasm with only 25 cases reported in the English literature. We describe 8 cases of testicular hemangioma encountered at our institution between 1992 and 2012. Of the 7 consult cases, 4 were malignant, 1 a Leydig cell tumor, and 2 were recognized as hemangiomas. The patients' ages ranged from 9 to 54 years (mean 32; median 30). Seven patients presented with self-detected palpable masses, and 2 patients reported pain. Six hemangiomas involved the right testis, and 2 were left sided. Ultrasonography recognized hypervascularity in 3 cases. History of pelvic irradiation, chemotherapy, and remote scrotal trauma was present in 3 patients. Preoperative serum tumor markers were negative (2/2 cases). The average size was 1.7 cm (median 1.8; range, 0.5 to 3.0). Six cases were infiltrative within the testis and entrapped benign seminiferous tubules, and 3 tumors invaded the tunica albuginea. Three hemangiomas were epithelioid, 2 anastomosing, 1 cellular capillary, 1 capillary, and 1 cavernous. Mitoses were sparse in all but 1 case, which reached up to 5 per 10 HPF. In 6 cases, seminiferous tubules adjacent to the hemangioma were atrophic without spermatogenesis. Immunohistochemical analysis was performed in 6 cases, and tumors stained with CD31, CD34, FVIII-related protein, and FLI-1 but not with pancytokeratin AE1/3, epithelial membrane antigen, keratin 8/18, placental alkaline phosphatase, human herpes virus 8, human chorionic gonadotropin, c-kit, melan-A, or p53. In cases with follow-up, there were no recurrences in 7 patients (mean 21 mo; median 12 mo; range, 1 to 72 mo). In summary, testicular hemangioma is a rare neoplasm with different morphologies having in common an infiltrative growth pattern with entrapment of seminiferous tubules, which should not be considered a feature of malignancy. Clinical and radiologic findings may preoperatively suggest a vascular tumor. PMID- 23665823 TI - Prognostic value of dual-source multidetector computed tomography coronary angiography in patients with stent implantation. AB - We aim to evaluate the prognostic value of dual-source 64-slice multidetector computed tomography (MDCT) in patients with coronary stents. The study included 173 patients [mean age 59.9 +/- 10.1 years, 76.7 % male] with previous stent implantation who underwent MDCT for evaluation of CAD and stent patency. Coronary imaging was performed via dual-source MDCT scanner. Stented vessel segment was evaluated as patent without neointimal hyperplasia (NIH), nonobstructive NIH (<50 % luminal narrowing), or obstructive NIH (>50 % luminal narrowing). Patients were evaluated for major cardiovascular events (MACEs) to demonstrate association between stent patency and clinical outcome. MACEs that were originating from non stented segments were excluded. A total of 213 coronary stents were evaluated in our study. During mean of 21.2 +/- 13.6 months' follow-up, 25 patients experienced MACEs [1 (4.0 %) cardiac death, 5 (20.0 %) nonfatal MI, and 19 (76.0 %) unstable angina pectoris requiring hospitalization and target vessel revascularization] associated with stented segment of coronary arteries. One hundred of 105 patients (95.2 %) with a patent stent without NIH detected by MDCT had no cardiac event associated with stented segments during mean 2 years' follow up period. These data indicate that patients with a patent stent without NIH as determined by MDCT have a good prognosis as opposed to an increased rate of events among patients with either nonobstructive or obstructive NIH as determined with MDCT, supporting MDCT as a reliable tool to evaluate patients after coronary stenting. PMID- 23665825 TI - Contact dermatitis from unexpected exposure to rosin from a toilet seat. PMID- 23665826 TI - Contact allergy to shoe components in professionals and nonprofessionals of the shoe industry. PMID- 23665827 TI - Persistent photosensitivity after allergic contact dermatitis to epoxy resin. AB - BACKGROUND: Persistent photosensitivity after allergic contact dermatitis (ACD) to epoxy resin has rarely been described. OBJECTIVE: The aim of this study was to create awareness that ACD to epoxy may be a trigger for persistent photosensitivity. METHODS: We present a series of 5 patients who developed ACD to epoxy resin and later a photodistributed eczematous eruption when exposed to sunlight, with a documented decrease in minimal erythema dose to UVA and UVB. RESULTS: The age of patients ranged from 34 to 71 years, and there were 3 men and 2 women. Each patient had occupational exposure to epoxy. Symptoms of epoxy ACD preceded photosensitivity by 5 months to 12 years in 3 cases and occurred simultaneously in 2 cases. Patch testing to epoxy resin was positive in all patients. Phototesting revealed a decreased minimal erythema dose to UVA and UVB in each of the 3 patients who were phototested. Photopatch testing was positive for epoxy resin in 1 of the 2 patients tested. All patients remained photosensitive for at least 2 years after diagnosis, with only 1 case of photosensitivity resolving with extended avoidance of epoxy. CONCLUSIONS: There is an association between ACD to epoxy resin and development of persistent photosensitivity. Possible mechanisms to explain the relationship between the 2 phenomena are discussed. PMID- 23665828 TI - Benzoyl peroxide in topical acne preparations: an underreported contact allergen? PMID- 23665829 TI - Budesonide allergic contact dermatitis "by proxy"? PMID- 23665830 TI - Is dermatitis palmaris sicca an irritant contact dermatitis? AB - BACKGROUND: Dermatitis palmaris sicca (DPS) is a common dry-fissured palmar dermatitis in Asian women. It may be an irritant contact dermatitis, but the immunophenotype of the cells in its infiltrate is unknown. OBJECTIVE: The aim of this study was to evaluate the role of inflammatory cells in the pathogenesis of DPS. METHODS: Patch testing was done in 68 patients with DPS, 87 subjects with hand eczema, and 31 healthy subjects. Immunophenotyping of cutaneous inflammatory cells was performed in 8 patients with DPS, 10 subjects with hand eczema, and 8 healthy individuals. RESULTS: Positive patch rates were higher in patients with DPS and those with hand eczema compared with healthy controls, but strong positive (++ or +++) reactions in DPS were fewer compared with hand eczema. Density of CD3, CD4, CD8, and CD68 cells in skin lesions of DPS and hand eczema was significantly higher than that in normal skin. Sparse CD20 cells were present only in hand eczema. Compared with hand eczema, the number of CD3, CD8, CD68, and dermal CD1a cells decreased, but epidermal CD1a cells and CD4/CD8 ratio increased in DPS. CONCLUSIONS: The absolute lack of CD20 cells and relative scarcity of dermal CD8 and CD1a cells in skin lesions might be insufficient to induce contact hypersensitivity, so DPS may be an irritant but not allergic contact dermatitis. PMID- 23665831 TI - Chlorhexidine: uses and adverse reactions. AB - Chlorhexidine is increasingly being used not only as an antiseptic to prevent hospital infections and an adjuvant in oral hygiene but also as a preservative in personal care products. As exposure to the agent becomes more widespread, reports of adverse reactions to it are increasing. Complications range from mild irritant contact dermatitis to life-threatening anaphylaxis. Allergic contact dermatitis in some cases precedes anaphylaxis. It is imperative that physicians be aware of the many possible sources of contact with this antiseptic and be alert to recognize the potentially debilitating and catastrophic reactions that may occur because of chlorhexidine sensitization. PMID- 23665832 TI - Hand and upper extremity function in workers with hand dermatitis. AB - BACKGROUND: Traditional methods of assessing impairment associated with skin conditions focus on clinical severity, medication usage, activities of daily living, and quality of life. Assessment of function and ability to work may provide important additional information when determining readiness to work. OBJECTIVES: The objective was to gain an understanding of the functional impairment of the hand and upper extremity associated with hand dermatitis and the impact of hand dermatitis on quality of life, work instability, and productivity. METHODS: Sixty-two patients with suspected contact dermatitis of the hands participated in physical and functional assessments of the upper extremity and patient-reported questionnaires including Dermatology Life Quality Index, Short Form 36 Health Survey, Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH), Work Instability Scale, and Work Limitations Questionnaire. RESULTS: Numbness and finger joint restrictions were moderate to severe in 29% and 30% of the workers, respectively. Positive Tinel and/or Phalen signs occurred in 25%. Forty-eight percent reported moderate-to-high work instability, and 31% reported a greater than 10% decrease in work productivity. Thirty-five percent missed work in the past year, 19% were doing a different job, and 9% were not working. CONCLUSIONS: Patients with hand dermatitis demonstrate significant functional compromise of the hand and a decrease in ability to work. PMID- 23665833 TI - Diagnosis and prevalence of lanolin allergy. AB - BACKGROUND: Current evaluation of suspected allergic contact dermatitis to lanolin includes patch testing to lanolin alcohol (30% in petrolatum). Using this method, the prevalence of lanolin allergy is low (1.8%-2.5%). OBJECTIVE: The objective of this study was to determine whether patch testing to a single lanolin derivative results in underdiagnosis compared with patch testing to 12 lanolin derivatives. METHODS: Patients were prospectively patch tested to (1) lanolin alcohol (30% in petrolatum) in our standard allergen series; (2) Amerchol L101 (50% in petrolatum) in our cosmetic series; and (3) 10 lanolin derivatives (using concentrations and vehicles recommended in the literature) in a supplemental series. RESULTS: Of 286 patients, the overall prevalence of positive reactions to lanolin in at least 1 of the 3 patch test series was 6.29% (95% confidence interval [CI], 3.48%-9.11%) (n = 18). The prevalence rates of lanolin allergy using the standard, cosmetic, and supplemental series were 1.05% (95% CI, 0%-2.23%), 3.85% (95% CI, 1.62%-6.07%), and 3.85% (95% CI, 1.62%-6.07%), respectively. Amerchol L101 was associated with increased reaction rates compared with the standard (odds ratio, 3.81; P = 0.007) and supplemental (odds ratio, 8.85; P < 0.001) series, whereas reaction rates were similar for the standard and supplemental series (P = 0.78). CONCLUSIONS: Amerchol L101 and patients' own products should be added to a standard patch testing allergen series to adequately identify lanolin allergy. PMID- 23665834 TI - The role of patch testing in the evaluation of orthopedic implant-related adverse effects: current evidence does not support broad use. AB - In recent years, there has been a growing interest in the use of skin patch testing to evaluate patients for orthopedic, implant-related adverse effects. This may be done preoperatively to avoid implanting a material to which an individual may be allergic or postoperatively to implicate sensitivity as a cause for implant failure. There is emerging evidence that patch testing might have utility in the workup of implant-related adverse events; however, the level of evidence at the present time is weak and based only on a collection of case reports, series, and retrospective cohort studies (level IV evidence as per United States Department of Health and Human Services guidelines); there are no randomized controlled trials (level I evidence) with which to guide medical decision making. Recent reports have advocated that patch testing be broadly used in the preoperative evaluation of all patients self-reporting a history of metal sensitivity. In addition, several authors have advocated that patch test results should guide preoperative implant selection and postoperative implant removal. It is the opinion of this author that these recommendations are premature, lacking robust clinical evidence, and unfeasible given the broad-reaching logistical impact and societal costs involved. More robust clinical data are needed, and thorough cost-benefit analyses must be performed before such far-reaching and costly systematic practices should be broadly implemented. PMID- 23665835 TI - Patch testing and hypersensitivity reactions to metallic implants: still many open questions. PMID- 23665836 TI - Commentary on Crawford, et al, The role of patch testing in the evaluation of orthopedic implant-related adverse effects: current evidence does not support broad use. PMID- 23665837 TI - Pragmatism and the evaluation of metal hypersensitivity reactions. AB - Evaluating patients with potential metal hypersensitivity reactions is challenging. Clear evidence-based guidelines based on randomized studies are lacking. A pragmatic approach to evaluation of these patients is useful due to this lack of evidence. Patch testing remains the gold standard for evaluating type IV reactions on the skin and is also likely the best test for metal reactions to implanted devices until more hard data is available. PMID- 23665838 TI - Constructing lanthanide [Nd(III), Er(III) and Yb(III)] complexes using a tridentate N,N,O-ligand for near-infrared organic light-emitting diodes. AB - A novel type of NIR-emitting lanthanide complexes Ln(PND)3 (Ln = Nd, Er and Yb) was designed and synthesized based on a tridentate monoanionic N,N,O-ligand 6 (pyridin-2-yl)-1,5-naphthyridin-4-ol (PND). Such complex owns definite charge neutral, coordination-saturated and mononuclear structure that is proved by X-ray single crystal diffraction of Nd(PND)3. Photophysical studies on the ligand and complexes reveal that the PND ligand has suitable energy level to sensitize the near-infrared (NIR) emitting lanthanide ions (Nd(3+), Er(3+), and Yb(3+)). Among the three compounds, Yb(PND)3 shows the highest photoluminescence quantum yield up to 0.9% in a mixture of acetonitrile and methanol solution (10 : 1, v/v, 10( 4) M). Thermal measurements indicate that these compounds have high decomposition (Td) and glass transition (Tg) temperature up to 420 and 265 degrees C, respectively, implying great advantage for constructing organic electronic devices via vacuum deposition method. At last, NIR organic light-emitting diodes (OLEDs) with simple three-layer structure were fabricated to test their electroluminescent performance, showing maximum NIR irradiance and maximum external quantum efficiency (EQE) of 25 MUW cm(-2) and 0.019% for Nd(3+), 0.46 MUW cm(-2) and 0.004% for Er(3+), and 86 MUW cm(-2) and 0.14% for Yb(3+), respectively. PMID- 23665839 TI - Facile one-pot synthesis of organic dye-complexed microgels for optical detection of glucose at physiological pH. AB - With a rational design of functional co-monomers, low-cost dye-complexed microgels, capable of continuous glucose detection at physiological pH, were readily synthesized in one-pot via precipitation polymerization in water. PMID- 23665840 TI - Lectin-like oxidized low-density lipoprotein receptor-1 plays an important role in vascular inflammation in current smokers. AB - AIM: Smoking induces vascular inflammation and increases the risk of cardiovascular events. Lectinlike oxidized low-density lipoprotein receptor-1 (LOX-1) is a scavenger receptor that is induced by oxidative stress and is associated with atherosclerotic plaque formation and destabilization. LOX-1 interacts with C-reactive protein (CRP) and plays an important role in inflammatory diseases. We therefore hypothesized that LOX-1 may be involved in the onset of smoking-induced vascular inflammation. METHODS: We measured the soluble LOX-1 (sLOX-1) levels in sera obtained from 207 current smokers. RESULTS: The serum sLOX-1 levels positively correlated with various smoking variables, such as the number of cigarettes smoked per day (r= 0.150, p<0.05), the expired air carbon monoxide (CO) concentrations (r= 0.198, p<0.005) and the Fagerstrom test for nicotine dependence scores (r= 0.190, p<0.01). The serum levels of sLOX 1 also correlated with those of a representative inflammatory marker, the serum high-sensitivity CRP level (hsCRP; r= 0.232, p<0.005). A multivariate regression analysis revealed the independent determinants of the serum sLOX-1 level to be the expired air CO concentration (beta= 0.182, p<0.05) and the hsCRP level (beta= 0.213, p<0.01). CONCLUSIONS: The serum sLOX-1 level was found to increase in close association with both the smoking-related variables and the inflammatory marker hsCRP. These findings suggest that LOX-1 may therefore play an important role in the onset of smoking-induced inflammation and atherosclerosis in humans. PMID- 23665841 TI - The apolipoprotein B/A1 ratio is associated with reactive oxygen metabolites and endothelial dysfunction in statin-treated patients with coronary artery disease. AB - AIM: The prognostic significance of the apolipoprotein B/A1 (ApoB/A1) ratio in statintreated patients with coronary artery disease (CAD) is unknown. We aimed to evaluate the association of the ApoB/A1 ratio with oxidative stress and endothelial dysfunction in these patients. METHODS: We enrolled 62 consecutive statin-treated patients who underwent percutaneous coronary intervention (PCI). Their lipid profiles, diacron-reactive oxygen metabolites (d-ROMs), as a marker of oxidative stress, flow-mediated dilatation (FMD), as a marker of vascular endothelial function, and C-reactive protein (CRP) levels, as a marker of inflammation, were measured. RESULTS: Our study population comprised 44 men and 18 women (mean age, 70.5 +/- 2.5 years). The ApoB/A1 ratio was positively correlated with the results of the d-ROMs test (p=0.004, r=0.36) and CRP level (p=0.02, r=0.30) and negatively correlated with the %FMD (p=0.005, r=-0.40). A multivariate logistic regression analysis showed that the most powerful predictive factor for the d-ROMs was the ApoB/A1 ratio (p=0.026). We therefore divided patients into two groups according to the cutoff point reported by the INTERHEART study: a low ApoB/A1 ratio (<0.641, n=26) and a high ApoB/A1 ratio (>0.641, n=36). The patients with a high ApoB/A1 ratio had higher levels of d ROMs and CRP, and tended to have a lower %FMD. CONCLUSION: The ApoB/A1 ratio was associated with the d-ROMs, a marker of oxidative stress, endothelial dysfunction and inflammation, and could be useful as a residual atherosclerotic risk marker to help prevent CAD in statin-treated patients. PMID- 23665842 TI - N-terminal pro-B-type natriuretic peptide is associated with arterial stiffness measured using the cardio-ankle vascular index in renal transplant recipients. AB - AIM: Arterial stiffness is an established cardiovascular risk marker and an independent predictor of cardiovascular events and mortality in various groups of patients, including renal transplant recipients. Recent studies have noted that B type natriuretic peptide (BNP) acts as a local paracrine molecule that modulates endothelial permeability and regeneration. The aim of this study was to evaluate the relationship between the serum N-terminal pro-BNP (NT-pro-BNP) level and arterial stiffness in renal transplant recipients. METHODS: Fasting blood samples were obtained from 66 renal transplant recipients. The cardio-ankle vascular index was calculated using the waveform device (CAVI-VaSera VS-1000). The serum NTpro-BNP levels were measured using an electrochemiluminescence immunoassay. A CAVI value of >=9 was used to define a high level of arterial stiffness. RESULTS: Thirty-two patients (48.5%) were classified into the high arterial stiffness group. Diabetes (p=0.030), smoking (p<0.001), duration of kidney transplantation (p=0.001), body weight (p=0.014), waist circumference (p=0.022), body mass index (p=0.001) and the fasting glucose (p=0.021) and serum NT-pro-BNP (p<0.001) levels were higher in the high arterial stiffness group than in the low arterial stiffness group. A multivariate forward stepwise linear regression analysis showed that the log-NT-pro-BNP level (beta: 0.459, p<0.001) remained an independent predictor of the CAVI value in the renal transplant recipients. CONCLUSIONS: The serum fasting NT-pro-BNP level is associated with arterial stiffness in renal transplant recipients. PMID- 23665843 TI - Microfluidic chemotaxis platform for differentiating the roles of soluble and bound amyloid-beta on microglial accumulation. AB - Progressive microglial accumulation at amyloid-beta (Abeta) plaques is a well established signature of the pathology of Alzheimer's disease, but how and why microglia accumulate in the vicinity of Abeta plaques is unknown. To understand the distinct roles of Abeta on microglial accumulation, we quantified microglial responses to week-long lasting gradients of soluble Abeta and patterns of surface bound Abeta in microfluidic chemotaxis platforms. We found that human microglia chemotaxis in gradients of soluble Abeta42 was most effective at two distinct concentrations of 23 pg.mL(-1) and 23 ng.mL(-1) Abeta42 in monomers and oligomers. We uncovered that while the chemotaxis at higher Abeta concentrations was exclusively due to Abeta gradients, chemotaxis at lower concentrations was enhanced by Abeta-induced microglial production of MCP-1. Microglial migration was inhibited by surface-bound Abeta42 in oligomers and fibrils above 45 pg.mm( 2). Better understanding of microglial migration can provide insights into the pathophysiology of senile plaques in AD. PMID- 23665844 TI - MetPP: a computational platform for comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry-based metabolomics. AB - MOTIVATION: Due to the high complexity of metabolome, the comprehensive 2D gas chromatography time-of-flight mass spectrometry (GC*GC-TOF MS) is considered as a powerful analytical platform for metabolomics study. However, the applications of GC*GC-TOF MS in metabolomics are not popular owing to the lack of bioinformatics system for data analysis. RESULTS: We developed a computational platform entitled metabolomics profiling pipeline (MetPP) for analysis of metabolomics data acquired on a GC*GC-TOF MS system. MetPP can process peak filtering and merging, retention index matching, peak list alignment, normalization, statistical significance tests and pattern recognition, using the peak lists deconvoluted from the instrument data as its input. The performance of MetPP software was tested with two sets of experimental data acquired in a spike-in experiment and a biomarker discovery experiment, respectively. MetPP not only correctly aligned the spiked-in metabolite standards from the experimental data, but also correctly recognized their concentration difference between sample groups. For analysis of the biomarker discovery data, 15 metabolites were recognized with significant concentration difference between the sample groups and these results agree with the literature results of histological analysis, demonstrating the effectiveness of applying MetPP software for disease biomarker discovery. AVAILABILITY: The source code of MetPP is available at http://metaopen.sourceforge.net CONTACT: xiang.zhang@louisville.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23665845 TI - Biodegradation of carbamate pesticides by natural river biofilms in different seasons and their effects on biofilm community structure. AB - This study investigated the ability of natural river biofilms from different seasons to degrade the carbamate pesticides methomyl, carbaryl and carbofuran in single and multiple pesticide systems, and the effects of these pesticides on algal and bacterial communities within biofilms. Spring biofilms had the lowest biomass of algae and bacteria but showed the highest methomyl degradation (>99%) and dissipation rates, suggesting that they might contain microorganisms with high methomyl degradation abilities. Degradation of carbofuran (54.1-59.5%) by biofilms in four seasons was similar, but low degradation of carbaryl (0-27.5%) was observed. The coexistence of other pesticides was found to cause certain effects on pesticide degradation and primarily resulted in lower diversity of diatoms and bacteria than when using a single pesticide. The tolerant diatoms and bacteria potentially having the ability to degrade test pesticides were identified. River biofilms could be suitable biomaterials or used to isolate degraders for bioremediating pesticide-contaminated water. PMID- 23665846 TI - Diasteroisomer and enantiomer-specific profiles of hexabromocyclododecane and tetrabromobisphenol A in an aquatic environment in a highly industrialized area, South China: vertical profile, phase partition, and bioaccumulation. AB - Tetrabromobisphenol A (TBBPA) and hexabromocyclododecanes (HBCDs) were determined in water, sediments, sediment cores, and three fish species from a river running through a highly industrialized area in South China. TBBPA concentrations exceeded those of HBCDs in the sediment and the dissolved phase of water and its levels in fish were at the high end of worldwide figures. 26% of HBCDs and 99% of TBBPA were found in dissolved phase of water. Plecostomus occupying high trophic level exhibited higher HBCD levels and higher abundance of alpha-HBCD than mud carp and nile tilapia which occupy low trophic level. An enrichment of (+)-alpha HBCD in three fish species but (-)-alpha-HBCD in sediment was observed. As for gamma-HBCD, most of sediment exhibited racemic while a species-dependence in fish sample was found. No clear trend was found for vertical distribution of enantiomeric profile for gamma-HBCD, suggesting that the enantioselectivity of degradation of gamma-HBCD is limited. PMID- 23665847 TI - Electrical stimulation with a penetrating optic nerve electrode array elicits visuotopic cortical responses in cats. AB - OBJECTIVE: A visual prosthesis based on penetrating electrode stimulation within the optic nerve (ON) is a potential way to restore partial functional vision for blind patients. We investigated the retinotopic organization of ON stimulation and its spatial resolution. APPROACH: A five-electrode array was inserted perpendicularly into the ON or a single electrode was advanced to different depths within the ON (~1-2 mm behind the eyeball, 13 cats). A sparse noise method was used to map ON electrode position and the visual cortex. Cortical responses were recorded by a 5 * 6 array. The visuotopic correspondence between the retinotopic position of the ON electrode was compared with the visual evoked cortical map and the electrical evoked potentials elicited in response to ON stimulation. MAIN RESULTS: Electrical stimulation with penetrating ON electrodes elicited cortical responses in visuotopographically corresponding areas of the cortex. Stimulation of the temporal side of the ON elicited cortical responses corresponding to the central visual field. The visual field position shifted from the lower to central visual field as the electrode penetrated through the depth of the ON. A spatial resolution of ~ 2 degrees to 3 degrees within a limited cortical visuotopic representation could be obtained by this approach. SIGNIFICANCE: Visuotopic electrical stimulation with a relatively fine spatial resolution can be accomplished using penetrating electrodes implanted at multiple sites and at different depths within the ON just behind the globe. This study also provides useful experimental data for the design of electrode density and the distribution of penetrating ON electrodes for a visual prosthesis. PMID- 23665848 TI - Molecular detection of human H7N9 influenza A virus causing outbreaks in China. AB - BACKGROUND: A novel subtype of influenza A virus (H7N9) was recently identified in humans. The virus is a reassortant of avian viruses, but these human isolates contain mutations [hemagglutinin (HA) Q226L and PB2 E627K] that might make it easier for the virus to adapt to mammalian hosts. Molecular tests for rapid detection of this virus are urgently needed. METHODS: We developed a 1-step quantitative real-time reverse-transcription PCR assay to detect the novel human H7N9 virus. The primer set was specific to the hemagglutinin (HA) gene of the H7N9 viruses currently causing the outbreak in China and had mismatches to all previously known avian or mammalian H7 HA sequences. In addition, the assay was evaluated using influenza A viruses of various genetic backgrounds and other negative controls. RESULTS: The detection limit of the assay was approximately 0.04 TCID50 (median tissue culture infective dose) per reaction. The assay specificity was high and all negative control samples, including 8 H7 viruses not closely related to the human H7N9 virus, tested negative. CONCLUSIONS: The established assay allows rapid detection of the novel human H7N9 virus, thereby allowing better pandemic preparedness. PMID- 23665850 TI - The role of community centre-based arts, leisure and social activities in promoting adult well-being and healthy lifestyles. AB - Developed countries are experiencing high levels of mental and physical illness associated with long term health conditions, unhealthy lifestyles and an ageing population. Given the limited capacity of the formal health care sector to address these public health issues, attention is turning to the role of agencies active in civil society. This paper sought to evaluate the associations between participation in community centre activities, the psycho-social wellbeing and health related behaviours. This was based on an evaluation of the South West Well being programme involving ten organisations delivering leisure, exercise, cooking, befriending, arts and crafts activities. The evaluation consisted of a before-and-after study with 687 adults. The results showed positive changes in self-reported general health, mental health, personal and social well-being. Positive changes were associated with diet and physical activity. Some activities were different in their outcomes-especially in cases where group activities were combined with one-to-one support. The results suggest that community centre activities of this nature offer benefits that are generically supportive of health behaviour changes. Such initiatives can perform an important role in supporting the health improvement objectives of formal health care services. For commissioners and partner agencies, accessibility and participation are attractive features that are particularly pertinent to the current public health context. PMID- 23665849 TI - Swine dysentery: aetiology, pathogenicity, determinants of transmission and the fight against the disease. AB - Swine Dysentery (SD) is a severe mucohaemorhagic enteric disease of pigs caused by Brachyspira hyodysenteriae, which has a large impact on pig production and causes important losses due to mortality and sub-optimal performance. Although B. hyodysenteriae has been traditionally considered a pathogen mainly transmitted by direct contact, through the introduction of subclinically infected animals into a previously uninfected herd, recent findings position B. hyodysenteriae as a potential threat for indirect transmission between farms. This article summarizes the knowledge available on the etiological agent of SD and its virulence traits, and reviews the determinants of SD transmission. The between-herds and within herd transmission routes are addressed. The factors affecting disease transmission are thoroughly discussed, i.e., environmental survival of the pathogen, husbandry factors (production system, production stage, farm management), role of vectors, diet influence and interaction of the microorganism with gut microbiota. Finally, prophylactic and therapeutic approaches to fight against the disease are briefly described. PMID- 23665852 TI - Significant signals--versatile interpreters. PMID- 23665851 TI - The anti-inflammatory action of Bothrops jararaca snake antithrombin on acute inflammation induced by carrageenan in mice. AB - OBJECTIVE AND DESIGN: Antithrombin is known as the most important natural coagulation inhibitor and has been shown to have anti-inflammatory properties. The present study aimed to investigate the effects of Bothrops jararaca antithrombin on acute inflammation induced by carrageenan in mice. METHODS: We evaluated the anti-inflammatory activity of antithrombin on models of paw edema formation, cell migration and leukocyte-endothelium interaction in mice (Swiss; n = 5). Acute inflammation was induced by the administration of carrageenan (15 mg kg-1). RESULTS: Treatment with B. jararaca antithrombin (1 mg kg-1) 1 h before or after carrageenan administration significantly inhibited paw edema formation, reduced cell influx to the peritoneal cavity due to reduction in the migration of polymorphonuclear cells, and attenuated leukocyte rolling in the microcirculation of the cremaster muscle.The effects of antithrombin on vascular and cellular events of inflammation were completely abolished by treatment with the cyclo oxygenase inhibitor indomethacin (4 mg kg-1), suggesting the involvement of prostacyclin in the mechanism of inflammation inhibition by B. jararaca antithrombin. CONCLUSION: This work showed for the first time the anti inflammatory properties of B. jararaca antithrombin on vascular and cellular events of inflammation. These findings suggest that antithrombin is effective in preventing paw edema formation, cell migration and leukocyte rolling induced by carrageenan in mice. PMID- 23665853 TI - Phylogeny and systematics of Micranthes (Saxifragaceae): an appraisal in European territories. AB - Recent phylogenetic studies have shown that Saxifraga, as currently understood, must be divided into two genera: Saxifraga L. sensu stricto and Micranthes Haw. To better understand the evolutionary history of these two genera, we performed phylogenetic analyses inferred from the nuclear ribosomal sequences from the internal transcribed spacer and the sequences of the plastid DNA (rbcL). Our molecular data confirmed the monophyly of the genus Micranthes and the consistency of the existing systematic treatments based on morphological criteria. Moreover, Micranthes species native from the Iberian Peninsula (i.e. M. clusii, M. lepismigena and M. stellaris) should be included into Micranthes sect. Arabisa. PMID- 23665855 TI - Rewards and incentives for the provision of human tissue for research. AB - The Nuffield Council on Bioethics' 2011 report, Human Bodies: Donation for Medicine and Research, proposes a system for examining the ethical implications of different types of incentives for the provision of human tissue for use in medicine and research. The cornerstone of this system is the principle of altruism which, the Council recommends, should, where possible, remain the starting point for any such tissue provision. Using the Council's example of ova provision for research as an area in which altruism-based rewards might be departed from, this article argues that such a system has the potential to become inconsistent and unnecessarily complex. It suggests that the outcomes-focussed and motivations-focussed justifications the Council provides do not sit easily within the fast-paced and unpredictable area of biotechnology research. Further, it may undermine the focus on autonomy that is enshrined in the relevant legislation. This article suggests that a fair system for incentivising and rewarding the provision of human tissue in research should be developed, which focuses on elements of this role that are common to all tissue providers. PMID- 23665854 TI - Understanding and managing zoonotic risk in the new livestock industries. AB - BACKGROUND: In many parts of the world, livestock production is undergoing a process of rapid intensification. The health implications of this development are uncertain. Intensification creates cheaper products, allowing more people to access animal-based foods. However, some practices associated with intensification may contribute to zoonotic disease emergence and spread: for example, the sustained use of antibiotics, concentration of animals in confined units, and long distances and frequent movement of livestock. OBJECTIVES: Here we present the diverse range of ecological, biological, and socioeconomic factors likely to enhance or reduce zoonotic risk, and identify ways in which a comprehensive risk analysis may be conducted by using an interdisciplinary approach. We also offer a conceptual framework to guide systematic research on this problem. DISCUSSION: We recommend that interdisciplinary work on zoonotic risk should take into account the complexity of risk environments, rather than limiting studies to simple linear causal relations between risk drivers and disease emergence and/or spread. In addition, interdisciplinary integration is needed at different levels of analysis, from the study of risk environments to the identification of policy options for risk management. CONCLUSION: Given rapid changes in livestock production systems and their potential health implications at the local and global level, the problem we analyze here is of great importance for environmental health and development. Although we offer a systematic interdisciplinary approach to understand and address these implications, we recognize that further research is needed to clarify methodological and practical questions arising from the integration of the natural and social sciences. PMID- 23665856 TI - Legislative regulation and ethical governance of medical research in different European Union countries. AB - OBJECTIVE: To obtain information about the similarities and differences in regulating different types of medical research in the European Union (EU). METHODS: Web searches were performed from September 2009 to January 2011. Notes on pre-determined topics were systematically taken down from the web pages. The analysis relied only on documents and reports available on the web, reflecting the situation at the end of 2010. RESULTS: In several countries, regulatory legislation applied only to clinical trials on drugs and medical devices, in other states various types of research were also regulated but by laws different from those concerning trials, and in many countries, some research areas were not controlled by legislation at all. In very few countries was all medical research handled similarly from a legal point of view. The number of research ethics committees (RECs) in a single country varied from one to 264. Their areas of responsibility, working principles and length of time to grant research permission varied as well as the rules for obtaining informed consent from vulnerable groups. In 10 EU countries, there was no appeal mechanism after a negative decision by an REC. The RECs were not accountable to any organisation in five EU countries. CONCLUSIONS: There is a need for a fundamental debate regarding whether and which kinds of changes are needed for the further harmonisation of medical research governance in the EU and how cross-country medical research could be facilitated in the future. PMID- 23665857 TI - Separation of cobalt and nickel by solvent extraction with two mutually immiscible ionic liquids. AB - The proof-of-principle for the separation of metals by solvent extraction using two mutually immiscible ionic liquids is given. Cobalt was extracted from the ionic liquid 1-ethyl-3-methylimidazolium chloride to the ionic liquid trihexyl(tetradecyl)phosphonium bis(2,4,4-trimethylpentyl)phosphinate. A distribution ratio of 44 was obtained. Cobalt could be selectively separated from nickel, with a separation factor of 207. The extraction mechanism was elucidated using UV-VIS absorption measurements. The mutual solubility between the two ionic liquids was determined by (1)H NMR. Processing steps such as washing, stripping and regeneration of the ionic liquid phases are discussed. PMID- 23665858 TI - Magnetization states of all-oxide spin valves controlled by charge-orbital ordering of coupled ferromagnets. AB - Charge-orbital ordering is commonly present in complex transition metal oxides and offers interesting opportunities for novel electronic devices. In this work, we demonstrate for the first time that the magnetization states of the spin valve can be directly manipulated by charge-orbital ordering. We investigate the interlayer exchange coupling (IEC) between two epitaxial magnetite layers separated by a nonmagnetic epitaxial MgO dielectric. We find that the state of the charge-orbital ordering in magnetite defines the strength, and even the sign of the IEC. First-principles calculations further show that the charge-orbital ordering modifies the spin polarized electronic states at the Fe(3)O(4)/MgO interfaces and results in a sufficiently large phase shift of wave function which are responsible for the observed IEC sign change across Verwey temperature. Our findings may open new interesting avenues for the electric field control of the magnetization states of spin valves via charge-orbital ordering driven IEC sign change. PMID- 23665859 TI - Neurointerventional treatment in acute stroke. Whom to treat? (Endovascular treatment for acute stroke: utility of THRIVE score and HIAT score for patient selection). AB - PURPOSE: Intra-arterial therapy (IAT) is used increasingly as a treatment option for acute stroke caused by central large vessel occlusions. Despite high rates of recanalization, the clinical outcome is highly variable. The authors evaluated the Houston IAT (HIAT) and the totaled health risks in vascular events (THRIVE) score, two predicting scores designed to identify patients likely to benefit from IAT. METHODS: Fifty-two patients treated at the Stavanger University Hospital with IAT from May 2009 to June 2012 were included in this study. We combined the scores in an additional analysis. We also performed an additional analysis according to high age and evaluated the scores in respect of technical efficacy. RESULTS: Fifty-two patients were evaluated by the THRIVE score and 51 by the HIAT score. We found a strong correlation between the level of predicted risk and the actual clinical outcome (THRIVE p = 0.002, HIAT p = 0.003). The correlations were limited to patients successfully recanalized and to patients <80 years. By combining the scores additional 14.3 % of the patients could be identified as poor candidates for IAT. Both scores were insufficient to identify patients with a good clinical outcome. CONCLUSIONS: Both scores showed a strong correlation to poor clinical outcome in patients <80 years. The specificity of the scores could be enhanced by combining them. Both scores were insufficient to identify patients with a good clinical outcome and showed no association to clinical outcome in patients aged >=80 years. PMID- 23665860 TI - Interventional exclusion of iliac artery aneurysms using the flow-diverting multilayer stent. AB - PURPOSE: This study was designed to evaluate retrospectively the results of complex iliac artery aneurysm (IAA) exclusion using the Cardiatis-Multilayer Stent. METHODS: Between October 2010 and August 2012, ten IAAs were treated in eight males (mean age 75 (59-91) years) using the Multilayer Stent. All IAA exceeded a diameter of 3 cm or were symptomatic. Follow-up (FU) examinations included CT or MR angiography, sonography, and clinical assessment up to 2 years. RESULTS: Primary stent placement was technically successful in eight of ten cases. In two cases, severe stent retraction during deployment necessitated placement of an additional stent. Immediately after stent placement, a marked reduction of flow within the sac was observed in all cases (peri-interventional mortality 0%). During FU, there were two thrombotic stent occlusions, making reintervention necessary (primary patency rate 80%, secondary patency 100%). Four IAA were completely occluded at FU, whereas the original vessel and covered branches (n = 8) were patent. In four IAA, there was still residual perfusion. In one patient, IAA diameter decreased slightly, while it remained constant in seven (mean imaging FU 195 (range 1-695) days). There were no adverse events on clinical FU (mean FU 467 (range 101-695) days). CONCLUSIONS: Other studies showed the Cardiatis-Multilayer-Stent to be a technically relatively simple treatment option for complex IAA with inadequate landing zones, especially in patients with multiple comorbidities to avoid ipsilateral IIA obstruction. However, in our series complication rate was high. Incomplete sac exclusion, stent-shortening, and thrombotic occlusion can complicate treatment, making meticulous patient selection necessary. Close imaging surveillance is mandatory especially in the early postinterventional period. PMID- 23665861 TI - Interest of electrostimulation of peripheral motor nerves during percutaneous thermal ablation. AB - PURPOSE: We present our experience of utilizing peripheral nerve electrostimulation as a complementary monitoring technique during percutaneous thermal ablation procedures; and we highlight its utility and feasibility in the prevention of iatrogenic neurologic thermal injury. METHODS: Peripheral motor nerve electrostimulation was performed in 12 patients undergoing percutaneous image-guided thermal ablations of spinal/pelvic lesions in close proximity to the spinal cord and nerve roots. Electrostimulation was used in addition to existing insulation (active warming/cooling with hydrodissection, passive insulation with CO2 insufflation) and temperature monitoring (thermocouples) techniques. Impending neurologic deficit was defined as a visual reduction of muscle response or need for a stronger electric current to evoke muscle contraction, compared with baseline. RESULTS: Significant reduction of the muscle response to electrostimulation was observed in three patients during the ablation, necessitating temporary interruption, followed by injection of warm/cool saline. This resulted in complete recovery of the muscle response in two cases, while for the third patient the response did not improve and the procedure was terminated. No patient experienced postoperative motor deficit. CONCLUSION: Peripheral motor nerve electrostimulation is a simple, easily accessible technique allowing early detection of impending neurologic injury during percutaneous image-guided thermal ablation. It complements existing monitoring techniques and provides a functional assessment along the whole length of the nerve. PMID- 23665862 TI - Long-term outcomes of percutaneous venoplasty and Gianturco stent placement to treat obstruction of the inferior vena cava complicating liver transplantation. AB - PURPOSE: Evaluation of long-term outcomes of venoplasty and Gianturco stents to treat inferior vena cava (IVC) obstruction after liver transplantation. METHODS: We retrospectively analyzed records from 33 consecutive adult patients referred with the intent to treat suspected IVC obstruction after liver transplantation. Treatment was performed for occlusion or stenosis with a gradient exceeding 3 mmHg. The primary treatment was venoplasty and, if refractory, Gianturco stent placement. Recurrence prompted repeat venoplasty or stent placement. RESULTS: Of the 33 patients, 25 (aged 46.9 +/- 12.2 years) required treatment at a mean of 2.3 years (14 days to 20.3 years) after transplantation. For technically successful cases, primary treatment was venoplasty alone (14) or with stent placement (10). Technical success was 96 % (24 of 25) reflecting failure to cross one occlusion. Clinical success was 88 % (22 of 25) reflecting the technical failure and two that died of unrelated complications within 5 weeks. Cumulative primary patencies were 57.1 % at 6 months (n = 21) and 51.4 % at 1 (n = 10), 3 (n = 7), 5 (n = 6), and 7 (n = 5) years. Cumulative primary assisted patency was 95.2 % at 6 months (n = 21) and at 1 (n = 15), 3 (n = 9), 5 (n = 8), and 7 (n = 8) years. The 17 patients stented for refractory (n = 10) or recurrent (n = 7) stenosis had cumulative primary and primary assisted patencies of 86.0 and 100 %, respectively, from 6 months (n = 14) to 7 years (n = 3). No major complications occurred; one fractured stent was observed after 11.6 years. CONCLUSION: For IVC obstruction following liver transplantation, excellent long-term outcomes can be achieved by venoplasty and Gianturco stent placement. PMID- 23665863 TI - Multiple intravitreal injections of ganciclovir for cytomegalovirus retinitis after stem-cell transplantation. AB - BACKGROUND: Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality in patients after hematopoietic stem cell transplantation (HSCT). Although much effort has been put into dealing with CMV retinitis secondary to acquired immunodeficiency syndrome (AIDS), the few reports which have been published have mainly focused on treatment of CMVR after HSCT. METHODS: This clinical interventional retrospective study included 14 patients (eight men; mean age 23.89 +/- 12.09; 23 eyes) who suffered from CMV retinitis after stem-cell transplantation, in order to evaluate the efficacy and safety of multiple intravitreal injections of ganciclovir (IVG) for patients with CMV retinitis. All patients received 4 injections of IVG of 1 mg at 1 week intervals, and were followed up weekly for at least 2 months with measurement of best-corrected visual acuity (BCVA) and CMV levels in anterior aqueous humor with real-time polymerase chain reaction. Anterior aqueous humor was obtained before each injection. RESULTS: The levels of CMV in anterior aqueous humor showed significant decrease from (6.34 +/- 15.78) * 10(5) copies/ml at baseline to (5.22 +/- 12.15) * 10(3) copies/ml at 1 month (P < 0.001, Mann-Whitney U test). CMV couldn't be detected in 11 eyes (47.8 %) after two injections, and this rose to 18 eyes (78.3 %) at 1 month. The mean logMAR BCVA was 0.659 +/- 0.572 at baseline and 0.680 +/- 0.527 at 2 months, which suggested no significant improvement (P = 0.736, Mann-Whitney U test) during the procedure. All patients experienced improved vitreous opacity and diminished area of the lesion under funduscopy after 4 injections of IVG. No severe complications developed. CONCLUSIONS: Multiple IVG seemed to be beneficial for patients with CMV retinitis after stem cell transplantation, in reducing CMV levels in aqueous humor. Further study to optimize the dose of ganciclovir is needed in order to achieve better treatment outcomes. PMID- 23665864 TI - Intracameral concentrations of the fibrinolytic system components in patients with age-related macular degeneration. AB - PURPOSE: To detect the intracameral concentrations and activities of plasminogen and other components of the fibrinolytic system, and to investigate whether those concentrations and activities are higher in patients with age-related macular degeneration (AMD) in comparison to healthy controls. METHODS: Prospective case series of 93 patients scheduled for standard phacoemulsification. RESULTS: Mean plasminogen activity in patients with non-exsudative AMD (n = 24) revealed to be 0.06%N, in patients with exudative AMD (n = 7) 0.03%N and in healthy controls (n = 43) 0.02%N (p = 0.38, ANOVA). Plasminogen activator inhibitor I (PAI-1) was detected in neither group. Alpha2-antiplasmin activity was 1.61 U/ml in the non exudative AMD group (n = 27), 0 U/ml in the exudative AMD group (n = 7) and 0.54 U/ml in the control group (n = 48) (p = 0.1, ANOVA). Concentrations of plasmin-a2 antiplasmin complex (PAP) were detected at levels of 17.91 ng/ml in the non exudative AMD group (n = 11), of 16.6 ng/ml in the exudative AMD group (n = 5), and of 17.43 ng/ml in the control group (n = 14) (p = 0.92, ANOVA). CONCLUSIONS: Plasminogen is present with a very low activity in aqueous humor. There are no significant differences in aqueous humor concentrations or activities of plasminogen and other components of the fibrinolytic system between patients with non-exudative AMD, exudative AMD, and healthy controls. Further studies should investigate vitreous samples instead of aqueous humor samples. A careful and accurate workup of obtained intraocular fluids is needed to detect the low concentrations and activities of the parameters analyzed. PMID- 23665865 TI - Clopidogrel does not work following cardiopulmonary resuscitation. PMID- 23665867 TI - Response to "CYP3A5 genotype, but not CYP3A4*1b, CYP3A4*22, or hematocrit, predicts tacrolimus dose requirements in Brazilian renal transplant patients". PMID- 23665866 TI - A phase I trial of bortezomib in combination with epirubicin, carboplatin and capecitabine (ECarboX) in advanced oesophagogastric adenocarcinoma. AB - PURPOSE: The protease inhibitor bortezomib attenuates the action of NF-kappaB and has shown preclinical activity alone and in combination with chemotherapy. DESIGN: A Phase I dose-escalation study was performed administering bortezomib (0.7, 1.0, 1.3 and 1.6 mg m(-2) on days 1 and 8 from cycle 2 onwards) in combination with Epirubicin 50 mg m(-2) intravenously on day 1, Carboplatin AUC 5 day 1 and Capecitabine 625 mg m(-2) BD days 1-21 every 21 days (VECarboX regimen), in patients with advanced oesophagogastric adenocarcinoma. The primary objective was to define the maximum tolerated dose (MTD) of Bortezomib when combined with ECarboX. RESULTS: 18 patients received bortezomib 0.7 (n = 6), 1.0 (n = 3), 1.3 (n = 6) and 1.6 mg m(-2) (n = 3) and a protocol amendment reducing the capecitabine dose to 500 mg m(-2) BD was enacted due to myelotoxicity. Common treatment-related non-haematological adverse events of any grade were fatigue (83.3 %), anorexia (55.6 %), constipation (55.6 %) and nausea (55.6 %). Common Grade 3/4 haematological toxicities were neutropenia (77.8 %) and thrombocytopenia (44.4 %). Objective responses were achieved in 6 patients (33.3 %) and a further 5 patients (27.8 %) had stable disease for >8 weeks. CONCLUSIONS: The addition of Bortezomib to ECarboX is well tolerated and response rates are comparable with standard chemotherapy. PMID- 23665868 TI - A meta-analysis of CYP2D6 metabolizer phenotype and metoprolol pharmacokinetics. AB - Metoprolol, a commonly prescribed beta-blocker, is primarily metabolized by cytochrome P450 2D6 (CYP2D6), an enzyme with substantial genetic heterogeneity. Several smaller studies have shown that metoprolol pharmacokinetics is influenced by CYP2D6 genotype and metabolizer phenotype. To increase robustness of metoprolol pharmacokinetic estimates, a systematic review and meta-analysis of pharmacokinetic studies that administered a single oral dose of immediate-release metoprolol were performed. Pooled analysis (n = 264) demonstrated differences in peak plasma metoprolol concentration, area under the concentration-time curve, elimination half-life, and apparent oral clearance that were 2.3-, 4.9-, 2.3-, and 5.9-fold between extensive and poor metabolizers, respectively, and 5.3-, 13 , 2.6-, and 15-fold between ultrarapid and poor metabolizers (all P < 0.001), respectively. Enantiomer-specific analysis revealed genotype-dependent enantio selective metabolism, with nearly 40% greater R- than S-metoprolol metabolism in ultrarapid and extensive metabolizers. This study demonstrates a marked effect of CYP2D6 metabolizer phenotype on metoprolol pharmacokinetics and confirms enantiomer-specific metabolism of metoprolol. PMID- 23665869 TI - PAHs in the Chinese environment: levels, inventory mass, source and toxic potency assessment. AB - This paper presents a systematic but preliminary study on the levels, inventory mass, emission sources and risk of exposure to PAHs in China by examining 14 polycyclic aromatic hydrocarbons (from the 16 priority PAHs listed by the U.S. EPA, excluding naphthalene and acenaphthylene) in four main environmental media (air, water, soil and sediment). The concentration of individual PAHs in the air, soil, freshwater, seawater, freshwater sediment and marine sediment of China was compared with the global concentration range (GCR) of PAHs from a large number of studies. The PAH levels were found at the high end of the GCR in the air, at the upper middle of the GCR in the water body, and at the middle of the GCR in the soil and sediment. These indicate that PAHs still are emitted heavily in China. About 530 000 tons of Sigma14PAH was estimated to be distributed into these four media in China. Soil possesses the highest proportion of the PAHs (60%), and the air has the lowest proportion (<0.5%). Therefore, the soil and sediment play an important role in the storage of PAHs. More than 10 thousand tons of PAHs are emitted from all kinds of sources. Firewood, straw, domestic and coking were considered as the main emissions of PAHs in the energy supply. A benzo[a]pyrene (BaP) based hazard quotient (HQ) was introduced to assess the potential toxic risk of exposure. The terrestrial water environment was found to have a high BaP exposure. The HQ value was more than 1 for 58% of freshwater and 39% of freshwater sediment samples. Urban and developed sites were considered to have high BaP exposure risk. PMID- 23665872 TI - Novel activity of KRAB domain that functions to reinforce nuclear localization of KRAB-containing zinc finger proteins by interacting with KAP1. AB - Previously, we found that two isoforms of the ZNF268 gene (ZNF268a and ZNF268b2, with and without the KRAB domain, respectively) might play distinct roles in normal epithelia and in cervical cancer. Here we further investigated that KRAB domain defined the function disparity in part by reinforcing nuclear localization of ZNF268a. We found that the A-box of KRAB alone retained major specific nuclear localization activity. In contrast, the B-box alone did not have nuclear localization activity but enhanced it significantly. Consistent with the critical function of the A-box, each mutation of six conserved residues (V9, V11, F13, E16, E17 and W18) in the A-box dramatically impaired nuclear localization activity. Furthermore, the unique nuclear localization activity of KRAB was verified in seven additional KRAB-containing zinc finger proteins (KRAB-ZFPs), suggesting that it is a universal feature of KRAB-ZFPs. Finally, KRAB exerted its unique nuclear localization activity by interacting with the RBCC domain of its corepressor KAP1. Our results have revealed a novel mechanism by which the KRAB domain reinforces nuclear localization of KRAB-ZFPs by interacting with KAP1. Our study also suggests that loss of the KRAB domain in KRAB-ZFPs due to aberrant alternative splicing might contribute to carcinogenesis. PMID- 23665871 TI - Mechanical forces in lymphatic vascular development and disease. AB - The lymphatic vasculature is essential for fluid homeostasis and transport of immune cells, inflammatory molecules, and dietary lipids. It is composed of a hierarchical network of blind-ended lymphatic capillaries and collecting lymphatic vessels, both lined by lymphatic endothelial cells (LECs). The low hydrostatic pressure in lymphatic capillaries, their loose intercellular junctions, and attachment to the surrounding extracellular matrix (ECM) permit passage of extravasated blood plasma from the interstitium into the lumen of the lymphatic capillaries. It is generally thought that interstitial fluid accumulation leads to a swelling of the ECM, to which the LECs of lymphatic capillaries adhere, for example via anchoring filaments. As a result, LECs are pulled away from the vascular lumen, the junctions open, and fluid enters the lymphatic vasculature. The collecting lymphatic vessels then gather the plasma fluid from the capillaries and carry it through the lymph nodes to the blood circulation. The collecting vessels contain intraluminal bicuspid valves that prevent fluid backflow, and are embraced by smooth muscle cells that contribute to fluid transport. Although the lymphatic vessels are regular subject to mechanical strain, our knowledge of its influence on lymphatic development and pathologies is scarce. Here, we discuss the mechanical forces and molecular mechanisms regulating lymphatic vascular growth and maturation in the developing mouse embryo. We also consider how the lymphatic vasculature might be affected by similar mechanomechanisms in two pathological processes, namely cancer cell dissemination and secondary lymphedema. PMID- 23665870 TI - The role of inflammation in sporadic and familial Parkinson's disease. AB - The etiology of Parkinson's disease (PD) is complex and most likely involves numerous environmental and heritable risk factors. Interestingly, many genetic variants, which have been linked to familial forms of PD or identified as strong risk factors, also play a critical role in modulating inflammatory responses. There has been considerable debate in the field as to whether inflammation is a driving force in neurodegeneration or simply represents a response to neuronal death. One emerging hypothesis is that inflammation plays a critical role in the early phases of neurodegeneration. In this review, we will discuss emerging aspects of both innate and adaptive immunity in the context of the pathogenesis of PD. We will highlight recent data from genetic and functional studies that strongly support the theory that genetic susceptibility plays an important role in modulating immune pathways and inflammatory reactions, which may precede and initiate neuronal dysfunction and subsequent neurodegeneration. A detailed understanding of such cellular and molecular inflammatory pathways is crucial to uncover pathogenic mechanisms linking sporadic and hereditary PD and devise tailored neuroprotective interventions. PMID- 23665873 TI - Genetic bypass of Aspergillus nidulans crzA function in calcium homeostasis. AB - After dephosphorylation by the phosphatase calcineurin, the fungal transcription factor CrzA enters the nucleus and activates the transcription of genes responsible for calcium homeostasis and many other calcium-regulated activities. A lack of CrzA confers calcium-sensitivity to the filamentous fungus Aspergillus nidulans. To further understand calcium signaling in filamentous fungi and to identify genes that interact genetically with CrzA, we selected for mutations that were able to suppress crzADelta calcium intolerance and identified three genes. Through genetic mapping, gene sequencing, and mutant rescue, we were able to identify these as cnaB (encoding the calcineurin regulatory subunit), folA (encoding an enzyme involved in folic acid biosynthesis, dihydroneopterin aldolase), and scrC (suppression of crzA(-), encoding a hypothetical protein). By using a calcium indicator, Fluo-3, we were able to determine that the wild-type and the suppressor strains were either able to regulate intracellular calcium levels or were able to take up and or store calcium correctly. The increased expression of calcium transporters, pmcA and/or pmcB, in suppressor mutants possibly enabled tolerance to high levels of calcium. Our results suggest that a cnaB suppressor mutation confers calcium tolerance to crzADelta strains through restoration of calcium homeostasis. These results stress that in A. nidulans there are calcineurin-dependent and CrzA-independent pathways. In addition, it is possible that CrzA is able to contribute to the modulation of folic acid biosynthesis. PMID- 23665874 TI - How good are indirect tests at detecting recombination in human mtDNA? AB - Empirical proof of human mitochondrial DNA (mtDNA) recombination in somatic tissues was obtained in 2004; however, a lack of irrefutable evidence exists for recombination in human mtDNA at the population level. Our inability to demonstrate convincingly a signal of recombination in population data sets of human mtDNA sequence may be due, in part, to the ineffectiveness of current indirect tests. Previously, we tested some well-established indirect tests of recombination (linkage disequilibrium vs. distance using D' and r(2), Homoplasy Test, Pairwise Homoplasy Index, Neighborhood Similarity Score, and Max chi(2)) on sequence data derived from the only empirically confirmed case of human mtDNA recombination thus far and demonstrated that some methods were unable to detect recombination. Here, we assess the performance of these six well-established tests and explore what characteristics specific to human mtDNA sequence may affect their efficacy by simulating sequence under various parameters with levels of recombination (rho) that vary around an empirically derived estimate for human mtDNA (population parameter rho = 5.492). No test performed infallibly under any of our scenarios, and error rates varied across tests, whereas detection rates increased substantially with rho values > 5.492. Under a model of evolution that incorporates parameters specific to human mtDNA, including rate heterogeneity, population expansion, and rho = 5.492, successful detection rates are limited to a range of 7-70% across tests with an acceptable level of false-positive results: the neighborhood similarity score incompatibility test performed best overall under these parameters. Population growth seems to have the greatest impact on recombination detection probabilities across all models tested, likely due to its impact on sequence diversity. The implications of our findings on our current understanding of mtDNA recombination in humans are discussed. PMID- 23665875 TI - A dynamic database of microarray-characterized cell lines with various cytogenetic and genomic backgrounds. AB - The Human Genetic Cell Repository sponsored by the National Institute of General Medical Sciences (NIGMS) contains more than 11,000 cell lines and DNA samples collected from numerous individuals. All of these cell lines and DNA samples are categorized into several collections representing a variety of disease states, chromosomal abnormalities, heritable diseases, distinct human populations, and apparently healthy individuals. Many of these cell lines have previously been studied with detailed conventional cytogenetic analyses, including G-banded karyotyping and fluorescence in situ hybridization. This work was conducted by investigators at submitting institutions and scientists at Coriell Institute for Medical Research, where the NIGMS Repository is hosted. Recently, approximately 900 cell lines, mostly chosen from the Chromosomal Aberrations and Heritable Diseases collections, have been further characterized in detail at the Coriell Institute using the Affymetrix Genome-Wide Human SNP Array 6.0 to detect copy number variations and copy number neutral loss of heterozygosity. A database containing detailed cytogenetic and genomic information for these cell lines has been constructed and is freely available through several sources, such as the NIGMS Repository website and the University of California at Santa Cruz Genome Browser. As additional cell lines are analyzed and subsequently added into it, the database will be maintained dynamically. PMID- 23665876 TI - The rate and effects of spontaneous mutation on fitness traits in the social amoeba, Dictyostelium discoideum. AB - We performed a mutation accumulation (MA) experiment in the social amoeba Dictyostelium discoideum to estimate the rate and distribution of effects of spontaneous mutations affecting eight putative fitness traits. We found that the per-generation mutation rate for most fitness components is 0.0019 mutations per haploid genome per generation or larger. This rate is an order of magnitude higher than estimates for fitness components in the unicellular eukaryote Saccharomyces cerevisiae, even though the base-pair substitution rate is two orders of magnitude lower. The high rate of fitness-altering mutations observed in this species may be partially explained by a large mutational target relative to S. cerevisiae. Fitness-altering mutations also may occur primarily at simple sequence repeats, which are common throughout the genome, including in coding regions, and may represent a target that is particularly likely to give fitness effects upon mutation. The majority of mutations had deleterious effects on fitness, but there was evidence for a substantial fraction, up to 40%, being beneficial for some of the putative fitness traits. Competitive ability within the multicellular slug appears to be under weak directional selection, perhaps reflecting the fact that slugs are sometimes, but not often, comprised of multiple clones in nature. Evidence for pleiotropy among fitness components across MA lines was absent, suggesting that mutations tend to act on single fitness components. PMID- 23665877 TI - Sequence-based mapping of the polyploid wheat genome. AB - The emergence of new sequencing technologies has provided fast and cost-efficient strategies for high-resolution mapping of complex genomes. Although these approaches hold great promise to accelerate genome analysis, their application in studying genetic variation in wheat has been hindered by the complexity of its polyploid genome. Here, we applied the next-generation sequencing of a wheat doubled-haploid mapping population for high-resolution gene mapping and tested its utility for ordering shotgun sequence contigs of a flow-sorted wheat chromosome. A bioinformatical pipeline was developed for reliable variant analysis of sequence data generated for polyploid wheat mapping populations. The results of variant mapping were consistent with the results obtained using the wheat 9000 SNP iSelect assay. A reference map of the wheat genome integrating 2740 gene-associated single-nucleotide polymorphisms from the wheat iSelect assay, 1351 diversity array technology, 118 simple sequence repeat/sequence tagged sites, and 416,856 genotyping-by-sequencing markers was developed. By analyzing the sequenced megabase-size regions of the wheat genome we showed that mapped markers are located within 40-100 kb from genes providing a possibility for high-resolution mapping at the level of a single gene. In our population, gene loci controlling a seed color phenotype cosegregated with 2459 markers including one that was located within the red seed color gene. We demonstrate that the high-density reference map presented here is a useful resource for gene mapping and linking physical and genetic maps of the wheat genome. PMID- 23665878 TI - Generalized admixture mapping for complex traits. AB - Admixture mapping is a popular tool to identify regions of the genome associated with traits in a recently admixed population. Existing methods have been developed primarily for identification of a single locus influencing a dichotomous trait within a case-control study design. We propose a generalized admixture mapping (GLEAM) approach, a flexible and powerful regression method for both quantitative and qualitative traits, which is able to test for association between the trait and local ancestries in multiple loci simultaneously and adjust for covariates. The new method is based on the generalized linear model and uses a quadratic normal moment prior to incorporate admixture prior information. Through simulation, we demonstrate that GLEAM achieves lower type I error rate and higher power than ANCESTRYMAP both for qualitative traits and more significantly for quantitative traits. We applied GLEAM to genome-wide SNP data from the Illumina African American panel derived from a cohort of black women participating in the Healthy Pregnancy, Healthy Baby study and identified a locus on chromosome 2 associated with the averaged maternal mean arterial pressure during 24 to 28 weeks of pregnancy. PMID- 23665879 TI - Molecular population genetics of inversion breakpoint regions in Drosophila pseudoobscura. AB - Paracentric inversions in populations can have a profound effect on the pattern and organization of nucleotide variability along a chromosome. Regions near inversion breakpoints are expected to have greater levels of differentiation because of reduced genetic exchange between different gene arrangements whereas central regions in the inverted segments are predicted to have lower levels of nucleotide differentiation due to greater levels of genetic flux among different karyotypes. We used the inversion polymorphism on the third chromosome of Drosophila pseudoobscura to test these predictions with an analysis of nucleotide diversity of 18 genetic markers near and away from inversion breakpoints. We tested hypotheses about how the presence of different chromosomal arrangements affects the pattern and organization of nucleotide variation. Overall, markers in the distal segment of the chromosome had greater levels of nucleotide heterozygosity than markers within the proximal segment of the chromosome. In addition, our results rejected the hypothesis that the breakpoints of derived inversions will have lower levels of nucleotide variability than breakpoints of ancestral inversions, even when strains with gene conversion events were removed. High levels of linkage disequilibrium were observed within all 11 breakpoint regions as well as between the ends of most proximal and distal breakpoints. The central region of the chromosome had the greatest levels of linkage disequilibrium compared with the proximal and distal regions because this is the region that experiences the highest level of recombination suppression. These data do not fully support the idea that genetic exchange is the sole force that influences genetic variation on inverted chromosomes. PMID- 23665880 TI - Spatial profiling of nuclear receptor transcription patterns over the course of Drosophila development. AB - Previous work has shown that many of the 18 family members of Drosophila nuclear receptor transcription factors function in a temporal hierarchy to coordinate developmental progression and growth with the rate limiting process of metabolism. To gain further insight into these interactions and processes, we have undertaken a whole-family analysis of nuclear receptor mRNA spatial expression patterns over the entire process of embryogenesis, as well as the 3rd instar wandering larva stage, by using high-resolution fluorescence in situ hybridization. Overall, the patterns of expression are remarkably consistent with previously mapped spatial activity profiles documented during the same time points, with similar hot spots and temporal profiles in endocrine and metabolically important tissues. Among the more remarkable of the findings is that the majority of mRNA expression patterns observed show striking subcellular distributions, indicating potentially critical roles in the control of protein synthesis and subsequent subcellular distributions. These patterns will serve as a useful reference for future studies on the tissue-specific roles and interactions of nuclear receptor proteins, partners, cofactors and ligands. PMID- 23665881 TI - Executive summary of the Japan Atherosclerosis Society (JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan 2012 version. PMID- 23665882 TI - Direct renin inhibitor induced renal failure. AB - Aliskiren, a direct renin inhibitor, is a novel antihypertensive agent with placebo-like tolerability. The patient developed acute renal failure after addition of aliskiren to combination of diuretic, angiotensin-converting enzyme inhibitor and aldosterone antagonist. This case highlights the point that acute renal failure can occur as an adverse effect of aliskiren. Because there is no conclusive evidence about the safety of aliskiren when used in combination with multiple drugs that inhibit renin angiotensin aldosterone system, caution should be exercised while initiating this drug in patients already on combination of diuretic, angiotensin-converting enzyme inhibitor and aldosterone antagonist. PMID- 23665883 TI - Comparison of the analgesic efficacy of dexketoprofen trometamol and meperidine HCl in the relief of renal colic. AB - In this study, the analgesic effects of dexketoprofen trometamol and meperidine hydrochloride were compared in patients diagnosed with renal colic. This study was a prospective, randomized, double-blind study. Fifty-two patients, between the ages of 18 and 70 years who were diagnosed with renal colic, were enrolled in the study after obtaining ethics committee approval. Before drug injection, dexketoprofen trometamol and meperidine hydrochloride were placed in closed envelopes, and the patients were randomly given a single dose of intravenous infusion for 20 minutes. Severity of pain and symptoms was evaluated with the numerical rating scale and renal colic symptom score for each patient immediately before administration of drugs and 30 minutes after the end of the application. At the same time, systolic arterial blood pressure, diastolic arterial pressure, respiratory rate, heart rate, nausea, vomiting, and reactions due to drug administration were recorded before and after drug administration. In statistical methods, t test, analysis of variance, and repeated measure analysis were used for the analysis of normally distributed continuous variables and the Mann Whitney U, Kruskal-Wallis and Friedman tests were used for analysis of not normally distributed continuous variables. In the analysis of discrete variables, the chi test was used. In both groups, a significant decrease was found in numerical rating scale values measured 30 minutes after drug administration, but the decline in dexketoprofen trometamol group (P = 0.02) was found to be more. Although a significant decrease was found in the renal colic symptom score (P < 0.001) values measured after drug administration in the dexketoprofen trometamol group, no significant decrease was found in the meperidine HCl (P = 0.058) group. After drug administration, a statistically significant decrease was found in the systolic arterial blood pressure, heart rate, and respiratory rate in both groups. Also, a statistically significant decrease was found in the diastolic arterial pressure in the meperidine group. But these changes in vital findings were not serious enough to disrupt patients' clinical status. With this study, we concluded that dexketoprofen trometamol, from the nonsteroidal anti-inflammatory drug group, can be within the primary treatment options for renal colic because of better analgesic efficacy, being well tolerated by patients compared with meperidine hydrochloride. PMID- 23665884 TI - Vildagliptin with metformin once-daily regimen-insights from a single-center analysis. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors have been well established as an adjunctive treatment to metformin. Most guidelines recommend treatment with a DPP 4 inhibitor, vildagliptin, in addition to metformin in a twice-daily regimen. However, the twice-daily regimen has difficulty with medication adherence, increased cost of therapy, and possibility of more side effects. Our objective was to evaluate, by means of retrospective analysis, the efficacy of once-daily metformin and vildagliptin (a DPP-4 inhibitor) in reducing blood glucose for patients on combination therapy. We analyzed data from our database of outpatients attending the diabetic clinic at a tertiary care center in Kolkata, India. We had data on once-daily combination of metformin and vildagliptin for 154 patients between September 2008 and May 2012. We followed up these patients for a median of 17.6 months and evaluated posttherapy glucose levels and hemoglobin A1c. Continuous variables were compared with t tests. Once-daily metformin-vildagliptin combination was found to be associated with a mean reduction of 27.52 mg/dL of fasting plasma glucose, 71.70 mg/dL of postprandial plasma glucose, and 1.41% reduction of HbA1c (P < 0.05 for all). Metformin vildagliptin combination in a once-daily regimen seems to be associated with significant reductions in plasma glucose and HbA1c and may be a viable and cost effective alternative to a twice-daily regimen as starting therapy. PMID- 23665885 TI - A Taurolidine-Citrate-Heparin Lock Solution Effectively Eradicates Pathogens From the Catheter Biofilm in Hemodialysis Patients. AB - Catheter-related bacteremia (CRB) is a typical complication of hemodialysis catheter use. Catheter lumen colonization by pathogens is regarded as a direct cause of CRB. Once settled, the catheter biofilm increases the risk of developing infection, thus necessitating insertion replacement and antibiotic treatment. The study assessed the self-sufficient efficacy of taurolidine-citrate-heparin lock solution in eradicating catheter biofilm bacteria and keeping it sterile in patients on hemodialysis. Twenty-nine chronic patients on hemodialysis with tunneled and nontunneled catheters locked with a heparin filling (the mean time of heparin lock use -30.1 +/- 2.0 days) and subsequently converted to a taurolidine-citrate-heparin filling were included. Peripheral vein and catheter lumen blood cultures were obtained before the filling change and after taurolidine-citrate-heparin lock use (mean time 33.8 +/- 7.6 days). Twenty-four participants with tunneled and nontunneled catheters locked with taurolidine citrate-heparin filling served as the control group. During the heparin-locking period, CRB was diagnosed in 3 cases (only nontunneled catheters). The catheter blood cultures findings were positive in 23 patients (10 temporary and 13 permanent catheters), whereas both the catheter and peripheral vein blood cultures were sterile in 3 of 29 subjects (only permanent catheters). Irrespective of catheter type (tunneled or nontunneled), repeated culture revealed no pathogens in any of the 23 patients with initial positive catheter blood culture, after the use of taurolidine-citrate-heparin filling. No positive blood culture was noted in the control group. The taurolidine-citrate-heparin lock solution effectively eradicated pathogens from nontunneled and tunneled catheter biofilms and helped to maintain catheter lumen sterility. PMID- 23665886 TI - Fatal sepsis and systemic inflammatory response syndrome after off-label prasugrel: a case report. AB - Aggressive dual antiplatelet therapy is associated not only with more bleeding, impaired wound healing, and potentially more solid cancer rates but it also causes higher infection risks including sepsis, and systemic inflammatory response syndrome (SIRS). This may be especially true considering the alarming off-label use of prasugrel. A 65-year-old white male patient with a history of myocardial infarction treated with percutaneous coronary intervention and implantation of 2 bare metal stents, was treated with off-label clopidogrel for 4 years, including a double daily dose (150 mg) for the initial 13 months. Still on clopidogrel, the patient was hospitalized with suspected pneumonia. A diagnostic cardiac catheterization revealed a 60%-70% blockage of the mid left anterior descending, but there was no need for coronary intervention. At discharge, clopidogrel 75 mg/d was switched over to off-label prasugrel 10 mg/d on top of aspirin (81 mg/d). On day 3 after prasugrel was given, a football-sized bruise appeared on the patient's lower right abdomen, but computed tomography results were unremarkable. On day 6 after administration of prasugrel, the patient became dizzy, disoriented, confused, experienced difficulty breathing, severe headache, weakness, intensive petechial rash covering the entire body, and breathing difficulty requiring ventilation. Within 24 hours, the patient was unable to correctly identify his age; his eyes were pale in color to almost colorless and when hearing a sound he would turn his entire head toward the sound and he appeared to be blind. His lungs, liver, and kidneys began to show signs of failure over the next 5-9 days. Sixteen days after the administration of the first prasugrel dose, the patient died of sepsis complicated with SIRS. Aggressive off-label use of clopidogrel (double dose for 13 months, and >4 years overall duration), followed by off-label switchover to the highest daily dose (10 mg) prasugrel may trigger sepsis and fatal SIRS. The mechanism responsible for such harmful association is probably indirect, and involves the weakening of platelet-neutrophil-endothelial crosstalk necessary to combat infections, and/or keep inflammation from spreading. PMID- 23665887 TI - Trials of acupuncture for drug dependence: a recommendation for hypotheses based on the literature. AB - OBJECTIVES: After initial promising research into acupuncture for withdrawal from drugs of dependence, two large negative trials were published in 2002 and the use of acupuncture in US rehabilitation facilities fell. However, subsequently it has been maintained, despite a lack of support from systematic reviews. This suggests a mismatch between research and clinical observation, which could be due to the acupuncture technique used, choice of controls or outcome measures. This study aims to explore the mismatch. METHODS: An exploratory review of all 48 clinical trials on alcohol, cocaine, nicotine or opioid dependence included in current reviews. RESULTS: Studies with sham controls (that could be active) were less likely to be positive (33%) than those with non-acupuncture controls (75%). Positive results were more likely when measuring craving (56%) or withdrawal symptoms (58%) than when measuring abstinence (31%) or attrition (31%). Three treatment variables appeared to be associated with positive results: (1) body acupuncture, used in 13 studies, was associated with positive outcomes for craving and withdrawal symptoms but not for abstinence or attrition; (2) electroacupuncture, used in seven studies, was associated with positive results with all four outcomes; and (3) bilateral needling in 20 studies was associated with effects on abstinence, craving and withdrawal symptoms. CONCLUSIONS: The current evidence suggests that acupuncture may have some effects on drug dependence that have been missed because of choice of outcome in many previous studies, and future studies should use outcomes suggested by clinical experience. Body points and electroacupuncture, used in the original clinical observation, justify further research. PMID- 23665888 TI - Acupuncture in preventing postoperative anaesthesia-related sore throat: a comparison with no acupuncture. AB - BACKGROUND: Postoperative sore throat occurs frequently in surgical patients as a result of tracheal intubation. Despite advances in medical and anaesthetic care, the incidence of postoperative sore throat remains high. Our study aimed to assess the efficacy of acupuncture in the prevention of postoperative sore throat following general anaesthesia. METHODS: A non-randomised clinical study (NRS) was carried out in a tertiary care hospital in Tehran, Iran on 228 consecutive patients undergoing elective surgeries under general anaesthesia. Of these, 114 patients were assigned to the acupuncture group and treated with body acupuncture at the PC6 point, while the remaining 114 patients received no preventive care and were treated with routine medical treatment where necessary. The incidence of sore throat within the first 24 h postoperatively was then compared between the two study groups. RESULTS: Of the 114 patients in the acupuncture group, 16 patients (14%) experienced sore throat within the first 24 h postoperatively, which was significantly lower compared to the 34 patients (29.8%) with sore throat in the medical treatment group (p<0.05). However, the frequency of patients with severe sore throat requiring medical treatment did not differ significantly (12.3% vs 16.7%, p>0.05). CONCLUSIONS: Our study suggests that acupuncture could be considered as an option in prevention of postoperative anaesthesia-related sore throat. PMID- 23665889 TI - A visible multi-digit DNA keypad lock based on split G-quadruplex DNAzyme and silver microspheres. AB - A novel visible multi-digit DNA keypad lock system was fabricated based on split G-quadruplex DNAzyme and silver microspheres. The final result of the keypad lock can be easily recognized by the naked eye and the number of inputs for the keypad lock can be flexibly adjusted. This molecular platform showed excellent scalability and flexibility. PMID- 23665890 TI - Proteomic analysis of the biological response of MG63 osteoblast-like cells to titanium implants. AB - Understanding of the interaction between human MG63 osteoblast-like cells and surfaces is necessary in the field of tissue engineering and biomaterials. Various titanium surfaces are widely used as not only implant materials, but also as miniscrews in orthodontics. Our goal was to assess the proteomic response of MG63 osteoblast-like cells to different titanium surfaces. MG63 osteoblast-like cells were cultured on three different titanium surfaces: a smooth surface (S), a sandblasted with large grit and acid-etched surface (SLA), and a surface coated with a thin layer of hydroxyapatite (HA). Cells grown on the rougher surfaces (SLA and HA) exhibited downregulated cell proliferation and morphological changes. In the proteomic analysis, cells grown on the SLA surface showed upregulated expression of protocadherin-beta3 precursor, kinase insert domain receptor, fibroblast growth factor receptor-3, and insulin-like growth factor I, while the expression levels of cell adhesion kinase, collagen alpha-1(I) chain precursor, collagen type XI alpha2, and cadherin-11 were upregulated in cells grown on the HA surface. These proteins are known to be involved in osteoblast adhesion, growth, and differentiation. Thus, the surface properties of dental materials can influence the expression of proteins involved in osseointegration related processes. Proteomic analysis may reveal changes in novel proteins that explain why osseointegration varies depending on surface properties. PMID- 23665891 TI - Metabolite profiling of astilbin in rat sera using UPLC/MS(E) and impact of its metabolites on immunosuppressive activity. AB - Astilbin, a natural flavonoid, has been shown to have a selective immunosuppressive activity on activated T lymphocytes. In our previous study, 3' O-methylastilbin was identified as an active metabolite in vivo. However, more comprehensive information regarding the kinetics and metabolic characteristics of astilbin is yet unknown. Here, we isolated and identified 4 metabolites after incubating astilbin with rat liver microsomal/cytosolic fractions. Besides 3'-O methylastilbin, 4'-O-methylastilbin was firstly identified and detected in the rat plasma after either oral or intravenous administration of astilbin. And phenotypic differences in the metabolic profile were observed between the two administration routes when using UPLC/MS(E) to measure the metabolites in the plasma. Moreover, 4'-O-methylastilbin decreased serum transaminases elevation in mice with concanavalin A-induced liver injury and reduced the mRNA expression of TNF-alpha and IFN-gamma in primed lymph cells upon antigen restimulation. The immunosuppressive activity of 4'-O-methylastilbin appears weaker than astilbin and 3'-O-methylastilbin. Taken together, the characterization of the comprehensive metabolic profile of astilbin confirmed 3'-O-methylastilbin as the major active form of astilbin metabolites, revealed 4'-O-methylastilbin as a minor active form, and helped us to evaluate the route of astilbin administration, which is beneficial for the treatment of human immune diseases. PMID- 23665892 TI - Simultaneous determination of bioactive components in essential oil of Xiang-Fu Si-Wu Formula in Beagle dog plasma by UPLC-MS/MS and its application to pharmacokinetics. AB - A highly sensitive and rapid ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) has been developed and validated for simultaneous quantification of the three main bioactive compounds, i.e., ligustilide, dehydrocostuslactone and alpha-cyperone in dog plasma after oral administration of the essential oil of Xiang-Fu-Si-Wu Formula (XEO). Clarithromycin was used as an internal standard (IS). Plasma samples were processed by protein precipitation with methanol. The separation was performed on an Acquity BEH C18 column (100mm*2.1mm, 1.7MUm) at a flow rate of 0.4mLmin(-1), using 0.1% formic acid acetonitrile as mobile phase. The MS/MS ion transit ions monitored were 190.5 >90.9 for ligustilide, 231.1->185.1 for dehydrocostuslactone, 219.2->123.0 for alpha-cyperone and 748.5->158.1 for IS. Method validation was performed as per Food and Drug Administration guidelines and the results met the acceptance criteria. The lower limit of quantification (LLOQ) achieved was 5.12ng/mL for ligustilide, 1.06ng/mL for dehydrocostuslactone and 1.89ng/mL for alpha-cyperone, respectively, and the calibration curves obtained were linear (r>0.99) over the concentration range approximately 1-1000ng/mL. The intra- and inter-day precision was less than 15% and the accuracy was within +/-9.2%. After validation, this method was successfully applied to a pharmacokinetic study where dogs were orally given 0.3g/kg XEO, equivalent to 183.6mg/kg of ligustilide, 5.0mg/kg of dehydrocostuslactone and 26.2mg/kg of alpha-cyperone, respectively. PMID- 23665893 TI - vsiRNAs derived from the miRNA-generating sites of pri-tae-miR159a based on the BSMV system play positive roles in the wheat response to Puccinia striiformis f. sp. tritici through the regulation of taMyb3 expression. AB - Plants live in a complex environment, exposed to stresses, such as unsuitable climates, pests and pathogenic microorganisms. Pathogens are one of the most serious factors that threaten plant growth. Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is one of the most destructive diseases worldwide. Virus-induced gene silencing (VIGS) is a popular tool for the functional analysis of wheat genes, generating abundant small RNAs (sRNAs). sRNAs are key components in gene regulatory networks, silencing corresponding genes at the post-transcriptional level. In this study, we transduced pri-tae-miR159a into plant tissues using the barley stripe mosaic virus (BSMV) system, and demonstrated that vsiRNAs were generated from the same miRNAs generating sites of pri-tae-miR159a, with the function of Dicer RNase III-like classes of endonucleases (DCL4). In addition, the accumulation of vsiRNAs in wheat leaves challenged with Pst Chinese yellow rust 23 (CYR23), resulted in a resistant phenotype, and in the compatible interaction, the sporation of Pst was limited. Whereas, infection with a control construct had no effect on the resistance or susceptibility. The results of the histological observation also supported these phenotype changes. Interestingly, vsiRNAs were also involved in the interactions between wheat and Pst through the tae-miR159-mediated regulation of taMyb3 expression. Moreover, these results also supported the speculation that vsiRNAs were generated from the same sites of pri-tae-miR159a. These studies indicated that vsiRNAs from miRNAs generating sites of pri-tae-miR159a based on the BSMV system play positive roles in the wheat response to Pst through the regulation of taMyb3 expression. PMID- 23665894 TI - Majorana fermions in semiconductor nanowires: fundamentals, modeling, and experiment. AB - After a recent series of rapid and exciting developments, the long search for the Majorana fermion-the elusive quantum entity at the border between particles and antiparticles-has produced the first positive experimental results, but is not over yet. Originally proposed by E Majorana in the context of particle physics, Majorana fermions have a condensed matter analogue in the zero-energy bound states emerging in topological superconductors. A promising route to engineering topological superconductors capable of hosting Majorana zero modes consists of proximity coupling semiconductor thin films or nanowires with strong spin-orbit interaction to conventional s-wave superconductors in the presence of an external Zeeman field. The Majorana zero mode is predicted to emerge above a certain critical Zeeman field as a zero-energy state localized near the order parameter defects, namely, vortices for thin films and wire ends for the nanowire. These Majorana bound states are expected to manifest non-Abelian quantum statistics, which makes them ideal building blocks for fault-tolerant topological quantum computation. This review provides an update on the current status of the search for Majorana fermions in semiconductor nanowires by focusing on the recent developments, in particular the period following the first reports of experimental signatures consistent with the realization of Majorana bound states in semiconductor nanowire-superconductor hybrid structures. We start with a discussion of the fundamental aspects of the subject, followed by considerations on the realistic modeling, which is a critical bridge between theoretical predictions based on idealized conditions and the real world, as probed experimentally. The last part is dedicated to a few intriguing issues that were brought to the fore by the recent encouraging experimental advances. PMID- 23665895 TI - Polycistronic lentivirus induced pluripotent stem cells from skin biopsies after long term storage, blood outgrowth endothelial cells and cells from milk teeth. AB - The generation of human induced pluripotent stem cells (hiPSCs) requires the collection of donor tissue, but clinical circumstances in which the interests of patients have highest priority may compromise the quality and availability of cells that are eventually used for reprogramming. Here we compared (i) skin biopsies stored in standard physiological salt solution for up to two weeks (ii) blood outgrowth endothelial cells (BOECs) isolated from fresh peripheral blood and (iii) children's milk teeth lost during normal replacement for their ability to form somatic cell cultures suitable for reprogramming to hiPSCs. We derived all hiPSC lines using the same reprogramming method (a conditional (FLPe) polycistronic lentivirus) and under similar conditions (same batch of virus, fetal calf serum and feeder cells). Skin fibroblasts could be reprogrammed robustly even after long-term biopsy storage. Generation of hiPSCs from juvenile dental pulp cells gave similar high efficiencies, but that of BOECs was lower. In terms of invasiveness of biopsy sampling, biopsy storage and reprogramming efficiencies skin fibroblasts appeared best for the generation of hiPSCs, but where non-invasive procedures are required (e.g., for children and minors) dental pulp cells from milk teeth represent a valuable alternative. PMID- 23665896 TI - Rab27 GTPases distribute extracellular nanomaps for invasive growth and metastasis: implications for prognosis and treatment. AB - The Rab27 family of small GTPases regulates exocytosis of distinct vesicle types including multivesicular endosomes, which results in the release of exosomes. Exosomes are nanometer-sized membrane vesicles that enclose soluble factors such as proteins and nucleic acids within a lipid bilayer and can travel toward distant tissues to influence multiple aspects of cell behavior. In our view that tumors are endocrine organs producing exosomes, Rab27 GTPases and their effector proteins are critical determinants for invasive growth and metastasis. Rab27 proteins and their effectors may serve as prognostic biomarkers or as targets for patient-tailored therapy. PMID- 23665897 TI - Combining coarse-grained protein models with replica-exchange all-atom molecular dynamics. AB - We describe a combination of all-atom simulations with CABS, a well-established coarse-grained protein modeling tool, into a single multiscale protocol. The simulation method has been tested on the C-terminal beta hairpin of protein G, a model system of protein folding. After reconstructing atomistic details, conformations derived from the CABS simulation were subjected to replica-exchange molecular dynamics simulations with OPLS-AA and AMBER99sb force fields in explicit solvent. Such a combination accelerates system convergence several times in comparison with all-atom simulations starting from the extended chain conformation, demonstrated by the analysis of melting curves, the number of native-like conformations as a function of time and secondary structure propagation. The results strongly suggest that the proposed multiscale method could be an efficient and accurate tool for high-resolution studies of protein folding dynamics in larger systems. PMID- 23665899 TI - Molecular dynamics simulation of tryptophan hydroxylase-1: binding modes and free energy analysis to phenylalanine derivative inhibitors. AB - Serotonin is a neurotransmitter that modulates many central and peripheral functions. Tryptophan hydroxylase-1 (TPH1) is a key enzyme of serotonin synthesis. In the current study, the interaction mechanism of phenylalanine derivative TPH1 inhibitors was investigated using molecular dynamics (MD) simulations, free energy calculations, free energy decomposition analysis and computational alanine scanning. The predicted binding free energies of these complexes are consistent with the experimental data. The analysis of the individual energy terms indicates that although the van der Waals and electrostatics interaction contributions are important in distinguishing the binding affinities of these inhibitors, the electrostatic contribution plays a more crucial role in that. Moreover, it is observed that different configurations of the naphthalene substituent could form different binding patterns with protein, yet lead to similar inhibitory potency. The combination of different molecular modeling techniques is an efficient way to interpret the interaction mechanism of inhibitors and our work could provide valuable information for the TPH1 inhibitor design in the future. PMID- 23665900 TI - Posttranslational modifications of GLUT4 affect its subcellular localization and translocation. AB - The facilitative glucose transporter type 4 (GLUT4) is expressed in adipose and muscle and plays a vital role in whole body glucose homeostasis. In the absence of insulin, only ~1% of cellular GLUT4 is present at the plasma membrane, with the vast majority localizing to intracellular organelles. GLUT4 is retained intracellularly by continuous trafficking through two inter-related cycles. GLUT4 passes through recycling endosomes, the trans Golgi network and an insulin sensitive intracellular compartment, termed GLUT4-storage vesicles or GSVs. It is from GSVs that GLUT4 is mobilized to the cell surface in response to insulin, where it increases the rate of glucose uptake into the cell. As with many physiological responses to external stimuli, this regulated trafficking event involves multiple posttranslational modifications. This review outlines the roles of posttranslational modifications of GLUT4 on its function and insulin-regulated trafficking. PMID- 23665898 TI - Cationic antimicrobial polymers and their assemblies. AB - Cationic compounds are promising candidates for development of antimicrobial agents. Positive charges attached to surfaces, particles, polymers, peptides or bilayers have been used as antimicrobial agents by themselves or in sophisticated formulations. The main positively charged moieties in these natural or synthetic structures are quaternary ammonium groups, resulting in quaternary ammonium compounds (QACs). The advantage of amphiphilic cationic polymers when compared to small amphiphilic molecules is their enhanced microbicidal activity. Besides, many of these polymeric structures also show low toxicity to human cells; a major requirement for biomedical applications. Determination of the specific elements in polymers, which affect their antimicrobial activity, has been previously difficult due to broad molecular weight distributions and random sequences characteristic of radical polymerization. With the advances in polymerization control, selection of well defined polymers and structures are allowing greater insight into their structure-antimicrobial activity relationship. On the other hand, antimicrobial polymers grafted or self-assembled to inert or non inert vehicles can yield hybrid antimicrobial nanostructures or films, which can act as antimicrobials by themselves or deliver bioactive molecules for a variety of applications, such as wound dressing, photodynamic antimicrobial therapy, food packing and preservation and antifouling applications. PMID- 23665901 TI - Microarray analysis of transcriptional responses to abscisic acid and salt stress in Arabidopsis thaliana. AB - Abscisic acid (ABA) plays a crucial role in plant responses to abiotic stress. To investigate differences in plant responses to salt and ABA stimulus, differences in gene expression in Arabidopsis in response to salt and ABA were compared using an Agilent oligo microarray. A total of 144 and 139 genes were significantly up- and downregulated, respectively, under NaCl stress, while 406 and 381 genes were significantly up- and downregulated, respectively, under ABA stress conditions. In addition, 31 genes were upregulated by both NaCl and ABA stresses, and 23 genes were downregulated by these stressors, suggesting that these genes may play similar roles in plant responses to salt and ABA stress. Gene ontology (GO) analysis revealed four subgroups of genes, including genes in the GO categories "Molecular transducer activity", "Growth", "Biological adhesion" and "Pigmentation", which were expressed in response to ABA stress but not NaCl stress. In addition, genes that play specific roles during salt or ABA stress were identified. Our results may help elucidate differences in the response of plants to salt and ABA stress. PMID- 23665902 TI - A novel colorimetric immunoassay utilizing the peroxidase mimicking activity of magnetic nanoparticles. AB - A simple colorimetric immunoassay system, based on the peroxidase mimicking activity of Fe3O4 magnetic nanoparticles (MNPs), has been developed to detect clinically important antigenic molecules. MNPs with ca. 10 nm in diameter were synthesized and conjugated with specific antibodies against target molecules, such as rotaviruses and breast cancer cells. Conjugation of the MNPs with antibodies (MNP-Abs) enabled specific recognition of the corresponding target antigenic molecules through the generation of color signals arising from the colorimetric reaction between the selected peroxidase substrate, 3,3',5,5' tetramethylbenzidine (TMB) and H2O2. Based on the MNP-promoted colorimetric reaction, the target molecules were detected and quantified by measuring absorbance intensities corresponding to the oxidized form of TMB. Owing to the higher stabilities and economic feasibilities of MNPs as compared to horseradish peroxidase (HRP), the new colorimetric system employing MNP-Abs has the potential of serving as a potent immunoassay that should substitute for conventional HRP based immunoassays. The strategy employed to develop the new methodology has the potential of being extended to the construction of simple diagnostic systems for a variety of biomolecules related to human cancers and infectious diseases, particularly in the realm of point-of-care applications. PMID- 23665904 TI - Genome-wide gene expression profiles in antioxidant pathways and their potential sex differences and connections to vitamin C in mice. AB - Vitamin C (VC) is well known as an antioxidant in humans, primates and guinea pigs. Studies have suggested gender differences in VC requirements in humans, and gender differences in oxidant injury vulnerability in early life may represent a biological mechanism contributing to gender disparity in later life. Using spontaneous bone fracture (sfx) mice, which lack the gene for L-Gulonolactone oxidase (Gulo), we studied the potential sex difference in expression profiles of oxidative genes at the whole-genome level. Then, we analyzed data of gene expressions in a mouse population of recombinant inbred (RI) strains originally derived by crossing C57BL/6J (B6) and DBA/2J (D2) mice. Our data indicated that there were sex differences in the regulation of pre- and pro-oxidative genes in sfx mice. The associations of expression levels among Gulo, its partner genes and oxidative genes in the BXD (B6 * D2) RI strains showed a sex difference. Transcriptome mapping suggests that Gulo was regulated differently between female and male mice in BXD RI strains. Our study indicates the importance of investigating sex differences in Gulo and its oxidative function by using available mouse models. PMID- 23665903 TI - Multiple functions of the RNA-binding protein HuR in cancer progression, treatment responses and prognosis. AB - The human embryonic lethal abnormal vision-like protein, HuR, is a member of the Hu family of RNA-binding proteins. Over the past decade, this ubiquitously expressed protein has been extensively investigated in cancer research because it is involved in the regulation of mRNA stability and translation in many cell types. HuR activity and function is associated with its subcellular distribution, transcriptional regulation, translational and post-translational modifications. HuR regulation of target mRNAs is based on the interaction between the three specific domains of HuR protein and one or several U- or AU-rich elements (AREs) in the untranslated region of target mRNAs. A number of cancer-related transcripts containing AREs, including mRNAs for proto-oncogenes, cytokines, growth factors, and invasion factors, have been characterized as HuR targets. It has been proposed that HuR has a central tumorigenic activity by enabling multiple cancer phenotypes. In this review, we comprehensively survey the existing evidence with regard to the diverse functions of HuR in caner development and progression. The current data also suggest that HuR might be a novel and promising therapeutic target and a marker for treatment response and prognostic evaluation. PMID- 23665905 TI - Melatonin effects on hard tissues: bone and tooth. AB - Melatonin is an endogenous hormone rhythmically produced in the pineal gland under the control of the suprachiasmatic nucleus (SCN) and the light/dark cycle. This indole plays an important role in many physiological processes including circadian entrainment, blood pressure regulation, seasonal reproduction, ovarian physiology, immune function, etc. Recently, the investigation and applications of melatonin in the hard tissues bone and tooth have received great attention. Melatonin has been investigated relative to bone remolding, osteoporosis, osseointegration of dental implants and dentine formation. In the present review, we discuss the large body of published evidence and review data of melatonin effects on hard tissues, specifically, bone and tooth. PMID- 23665906 TI - The role of E3 ubiquitin ligase Cbl proteins in beta-elemene reversing multi-drug resistance of human gastric adenocarcinoma cells. AB - Recent studies indicate that beta-elemene, a compound isolated from the Chinese herbal medicine Curcuma wenyujin, is capable of reversing tumor MDR, although the mechanism remains elusive. In this study, beta-Elemene treatment markedly increased the intracellular accumulation of doxorubicin (DOX) and rhodamine 123 in both K562/DNR and SGC7901/ADR cells and significantly inhibited the expression of P-gp. Treatment of SGC7901/ADR cells with beta-elemene led to downregulation of Akt phosphorylation and significant upregulation of the E3 ubiquitin ligases, c-Cbl and Cbl-b. Importantly, beta-elemene significantly enhanced the anti-tumor activity of DOX in nude mice bearing SGC7901/ADR xenografts. Taken together, our results suggest that beta-elemene may target P-gp-overexpressing leukemia and gastric cancer cells to enhance the efficacy of DOX treatment. PMID- 23665907 TI - Vascular endothelial growth factor induces CXCL1 chemokine release via JNK and PI 3K-dependent pathways in human lung carcinoma epithelial cells. AB - Lung cancer cells express different chemokines and chemokine receptors that modulate leukocyte infiltration within tumor microenvironment. In this study we screened several mediators/growth factors on CXCL1 release in human carcinoma epithelial cells. Of the tested mediators, VEGF was found to have a robust increase in causing CXCL1 release. VEGF stimulated CXCL1 release and mRNA expression in a time- and concentration-dependent manner. The release was inhibited by the VEGF receptor antagonists and the JNK, PI-3K, tyrosine kinase, and transcription inhibitors. In parallel, VEGF induced JNK, PI3K and Akt activation. Strikingly, among these inhibitors only the JNK inhibitor could reduce VEGF-induced CXCL1 mRNA expression, suggesting that JNK participated in VEGF-induced CXCL1 synthesis, whereas PI-3K was responsible for cellular CXCL1 secretory process. In addition, the steroid dexamethasone and TGF-beta suppressed CXCL1 release through a transcriptional regulation. We also showed that cells stimulated with VEGF significantly attracted monocyte migration, which could be abolished by CXCL1 B/N Ab, CXC receptor 2 antagonist, TGF-beta, and dexamethasone. In summary, we provide here evidence showing JNK activation for VEGF-induced CXCL1 DNA transcription and PI-3K pathway for extracellular CXCL1 release in human carcinoma epithelial cells. The released CXCL1 was functionally linked to recruiting monocytes into lung cancer cell microenvironment. PMID- 23665908 TI - Native high density lipoproteins (HDL) interfere with platelet activation induced by oxidized low density lipoproteins (OxLDL). AB - Platelets and lipoproteins play a crucial role in atherogenesis, in part by their ability to modulate inflammation and oxidative stress. While oxidized low density lipoproteins (OxLDL) play a central role in the development of this disease, high density lipoproteins (HDL) represent an atheroprotective factor of utmost importance. As platelet function is remarkably sensitive to the influence of plasma lipoproteins, it was the aim of this study to clarify if HDL are able to counteract the stimulating effects of OxLDL with special emphasis on aspects of platelet function that are relevant to inflammation. Therefore, HDL were tested for their ability to interfere with pro-thrombotic and pro-inflammatory aspects of platelet function. We are able to show that HDL significantly impaired OxLDL induced platelet aggregation and adhesion. In gel-filtered platelets, HDL decreased both the formation of reactive oxygen species and CD40L expression. Furthermore, HDL strongly interfered with OxLDL-induced formation of platelet neutrophil aggregates in whole blood, suggesting that platelets represent a relevant and sensitive target for HDL. The finding that HDL effectively competed with the binding of OxLDL to the platelet surface might contribute to their atheroprotective and antithrombotic properties. PMID- 23665909 TI - N-6-adenine-specific DNA methyltransferase 1 (N6AMT1) polymorphisms and arsenic methylation in Andean women. AB - BACKGROUND: In humans, inorganic arsenic is metabolized to methylated metabolites mainly by arsenic (+3 oxidation state) methyltransferase (AS3MT). AS3MT polymorphisms are associated with arsenic metabolism efficiency. Recently, a putative N-6-adenine-specific DNA methyltransferase 1 (N6AMT1) was found to methylate arsenic in vitro. OBJECTIVE: We evaluated the role of N6AMT1 polymorphisms in arsenic methylation efficiency in humans. METHODS: We assessed arsenic methylation efficiency in 188 women exposed to arsenic via drinking water (~ 200 ug/L) in the Argentinean Andes by measuring the relative concentrations of arsenic metabolites in urine [inorganic arsenic, methylarsonic acid (MMA), and dimethylarsinic acid] by high-performance liquid chromatography coupled with hydride generation and inductively coupled plasma mass spectrometry. We performed genotyping for N6AMT1 and AS3MT polymorphisms by Taqman assays, and gene expression (in blood; n = 63) with Illumina HumanHT-12 v4.0. RESULTS: Five N6AMT1 single nucleotide polymorphisms (SNPs; rs1997605, rs2205449, rs2705671, rs16983411, and rs1048546) and two N6AMT1 haplotypes were significantly associated with the percentage of MMA (%MMA) in urine, even after adjusting for AS3MT haplotype. %MMA increased monotonically according to the number of alleles for each SNP (e.g., for rs1048546, mean %MMA was 7.5% for GG, 8.8% for GT, and 9.7% for TT carriers). Three SNPs were in linkage disequilibrium (R2 > 0.8). Estimated associations for joint effects of N6AMT1 (haplotype 1) and AS3MT (haplotype 2) were generally consistent with expectations for additive effects of each haplotype on %MMA. Carriers of N6AMT1 genotypes associated with lower %MMA showed the lowest N6AMT1 expression, but associations were monotonic according to copy number for only one genotype and one haplotype. CONCLUSIONS: N6AMT1 polymorphisms were associated with arsenic methylation in Andean women, independent of AS3MT. N6AMT1 polymorphisms may be susceptibility markers for arsenic-related toxic effects. PMID- 23665910 TI - Orbital-based insights into parallel-displaced and twisted conformations in pi-pi interactions. AB - Dispersion and electrostatics are known to stabilize pi-pi interactions, but the preference for parallel-displaced (PD) and/or twisted (TW) over sandwiched (S) conformations is not well understood. Orbital interactions are generally believed to play little to no role in pi-stacking. However, orbital analysis of the dimers of benzene, pyridine, cytosine and several polyaromatic hydrocarbons demonstrates that PD and/or TW structures convert one or more pi-type dimer MOs with out-of phase or antibonding inter-ring character at the S stack to in-phase or bonding in the PD/TW stack. This change in dimer MO character can be described in terms of a qualitative stack bond order (SBO) defined as the difference between the number of occupied in-phase/bonding and out-of-phase/antibonding inter-ring pi type MOs. The concept of an SBO is introduced here in analogy to the bond order in molecular orbital theory. Thus, whereas the SBO of the S structure is zero, parallel displacement or twisting the stack results in a non-zero SBO and overall bonding character. The shift in bonding/antibonding character found at optimal PD/TW structures maximizes the inter-ring density, as measured by intermolecular Wiberg bond indices (WBIs). Values of WBIs calculated as a function of the parallel-displacement are found to correlate with the dispersion and other contributions to the pi-pi interaction energy determined by the highly accurate density-fitting DFT symmetry adapted perturbation theory (DF-DFT-SAPT) method. These DF-DFT-SAPT calculations also suggest that the dispersion and other contributions are maximized at the PD conformation rather than the S when conducted on a potential energy curve where the inter-ring distance is optimized at fixed slip distances. From these results of this study, we conclude that descriptions of the qualitative manner in which orbitals interact within pi stacking interactions can supplement high-level calculations of the interaction energy and provide an intuitive tool for applications to crystal design, molecular recognition and other fields where non-covalent interactions are important. PMID- 23665911 TI - Impact of economic crisis on mental health of migrant workers: what happened with migrants who came to Spain to work? AB - OBJECTIVES: To assess changes in mental health in a sample of migrant workers after the eruption of the economic crisis in Spain. METHODS: 318 migrant workers were interviewed. Mental health, sociodemographic, and economic crisis related variables were obtained through face-to-face (2008) and phone (2011) interviews. Prevalence of poor mental health (PMH) was compared (2011-2008) and multivariate logistic regression models were fitted. RESULTS: Change in prevalence of PMH was higher in men (aOR 4.63; 95 % CI 2.11-10.16). Subgroups of men showing the largest detrimental mental health effects were: unemployed, with low salaries (<=1,200 euros) and those reporting family burden. An increase of PMH was found in women, without significant associations. CONCLUSIONS: Mental health of migrant workers in Spain has worsened during the economic crisis. PMID- 23665912 TI - O-GlcNAcylation involvement in high glucose-induced cardiac hypertrophy via ERK1/2 and cyclin D2. AB - Continuous hyperglycemia is considered to be the most significant pathogenesis of diabetic cardiomyopathy, which manifests as cardiac hypertrophy and subsequent heart failure. O-GlcNAcylation has attracted attention as a post-translational protein modification in the past decade. The role of O-GlcNAcylation in high glucose-induced cardiomyocyte hypertrophy remains unclear. We studied the effect of O-GlcNAcylation on neonatal rat cardiomyocytes that were exposed to high glucose and myocardium in diabetic rats induced by streptozocin. High glucose (30 mM) incubation induced a greater than twofold increase in cell size and increased hypertrophy marker gene expression accompanied by elevated O-GlcNAcylation protein levels. High glucose increased ERK1/2 but not p38 MAPK or JNK activity, and cyclin D2 expression was also increased. PUGNAc, an inhibitor of beta-N acetylglucosaminidase, enhanced O-GlcNAcylation and imitated the effects of high glucose. OGT siRNA and ERK1/2 inhibition with PD98059 treatment blunted the hypertrophic response and cyclin D2 upregulation. OGT inhibition also prevented ERK1/2 activation. We also observed concentric hypertrophy and similar changes of O-GlcNAcylation level, ERK1/2 activation and cyclin D2 expression in myocardium of diabetic rats induced by streptozocin. In conclusion, O-GlcNAcylation plays a role in high glucose-induced cardiac hypertrophy via ERK1/2 and cyclin D2. PMID- 23665913 TI - Magnesium: is there a signal in the noise? PMID- 23665914 TI - Low-dose sugammadex reversal: there is no such thing as a free lunch. PMID- 23665915 TI - Reversal of neuromuscular blockade with sugammadex at the reappearance of four twitches to train-of-four stimulation. AB - BACKGROUND: Doses of sugammadex required to reverse deep, moderate, and shallow rocuronium-induced neuromuscular blockade have been established. However, no adequate doses for the reversal of reappearance of four twitches of train-of-four (TOF) stimulation (threshold TOF-count-four) have been established. METHODS: This single-center, randomized, controlled, double-blind, four-groups parallel-arm study included 80 patients undergoing general anesthesia with propofol, sevoflurane, fentanyl, and rocuronium. Neuromuscular monitoring was performed with calibrated acceleromyography. Once rocuronium-induced neuromuscular blockade recovered spontaneously to threshold TOF-count-four, patients randomly received 0.5, 1.0, 2.0 mg/kg of sugammadex or 0.05 mg/kg of neostigmine. The time between study drug injection and reversal of TOF ratios to 1.0 was measured. Rapid reversal (<=2.0 min average, upper limit of 5.0 min) was the primary endpoint and slower reversal (<=5.0 min average, upper limit of 10 min) was the secondary endpoint of the study. RESULTS: Sugammadex, in doses of 1.0 and 2.0 mg/kg, reversed threshold TOF-count-four to TOF ratios of 1.0 in 2.1+/-0.8 min (mean+/ SD) and 1.8+/-0.9 min, respectively. Sugammadex, 0.5 mg/kg, induced a similar degree of reversal in 4.1+/-1.9 min (P<0.001 vs. 1.0 and 2.0 mg/kg). Neostigmine, 0.05 mg/kg, reversed TOF ratios to 1.0 in 8.5+/-3.5 min (P<0.001 vs. sugammadex groups). CONCLUSION: Sugammadex, 1.0 mg/kg, rapidly and effectively reverses rocuronium-induced block that has recovered spontaneously to a threshold TOF count-four. A dose of 0.5 mg/kg was equally effective, but satisfactory antagonism took as long as 8 min to take place. PMID- 23665916 TI - C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements. AB - Mechanisms regulating transcription factor interaction with chromatin in intact mammalian tissues are poorly understood. Exploiting an adrenalectomized mouse model with depleted endogenous glucocorticoids, we monitor changes of the chromatin landscape in intact liver tissue following glucocorticoid injection. Upon activation of the glucocorticoid receptor (GR), proximal regions of activated and repressed genes are remodelled, and these remodelling events correlate with RNA polymerase II occupancy of regulated genes. GR is exclusively associated with accessible chromatin and 62% percent of GR-binding sites are occupied by C/EBPbeta. At the majority of these sites, chromatin is preaccessible suggesting a priming function of C/EBPbeta for GR recruitment. Disruption of C/EBPbeta binding to chromatin results in attenuation of pre-programmed chromatin accessibility, GR recruitment and GR-induced chromatin remodelling specifically at sites co-occupied by GR and C/EBPbeta. Collectively, we demonstrate a highly cooperative mechanism by which C/EBPbeta regulates selective GR binding to the genome in liver tissue. We suggest that selective targeting of GR in other tissues is likely mediated by the combined action of cell-specific priming proteins and chromatin remodellers. PMID- 23665917 TI - Unconventional protein secretion: an evolving mechanism. AB - The process by which proteins are secreted without entering the classical endoplasmic reticulum (ER)-Golgi complex pathway, in eukaryotic cells, is conveniently called unconventional protein secretion. Recent studies on one such protein called Acb1 have revealed a number of components involved in its secretion. Interestingly, conditions that promote the secretion of Acb1 trigger the biogenesis of a new compartment called CUPS (Compartment for Unconventional Protein Secretion). CUPS form near the ER exit site but lack ER-specific proteins. Other proteins that share some of the features common with the secretion of Acb1 are interleukin-1beta and tissue transglutaminase. Here I will review recent advances made in the field and propose a new model for unconventional protein secretion. PMID- 23665918 TI - Antisense now makes sense: dual modulation of androgen-dependent transcription by CTBP1-AS. PMID- 23665920 TI - Patterning of regional gene expression in autism: new complexity. AB - Autism is a common and often severe neurodevelopmental disorder for which diverse pathophysiological processes have been proposed. Recent gene expression data comparing autistic and control brains suggest that the normal differential gene expression between frontal and temporal cortex is attenuated in autistic brains. It is unknown if regional de-differentiation occurs elsewhere in autistic brain. Using high resolution, genome-wide RNA expression microarrays and brain specimens meeting stringent selection criteria we evaluated gene expression data of two other regions: Brodmann area 19 (occipital cortex) and cerebellar cortex. In contrast to frontal/temporal cortical data, our data do not indicate an attenuation of regional specialization between occipital and cerebellar cortical regions in autistic brains. PMID- 23665919 TI - Attenuation of insulin signalling contributes to FSN-1-mediated regulation of synapse development. AB - A neuronal F-box protein FSN-1 regulates Caenorhabditis elegans neuromuscular junction development by negatively regulating DLK-mediated MAPK signalling. In the present study, we show that attenuation of insulin/IGF signalling also contributes to FSN-1-dependent synaptic development and function. The aberrant synapse morphology and synaptic transmission in fsn-1 mutants are partially and specifically rescued by reducing insulin/IGF-signalling activity in postsynaptic muscles, as well as by reducing the activity of EGL-3, a prohormone convertase that processes agonistic insulin/IGF ligands INS-4 and INS-6, in neurons. FSN-1 interacts with, and potentiates the ubiquitination of EGL-3 in vitro, and reduces the EGL-3 level in vivo. We propose that FSN-1 may negatively regulate insulin/IGF signalling, in part, through EGL-3-dependent insulin-like ligand processing. PMID- 23665921 TI - Synthesis and characterization of thiolated carboxymethyl chitosan-graft cyclodextrin nanoparticles as a drug delivery vehicle for albendazole. AB - A new strategy for the synthesis of thiolated carboxymethyl chitosan-g cyclodextrin nanoparticles by an ionic-gelation method is presented. The synthetic approach was based on the utilization of 1,6-hexamethylene diisocyanate during cyclodextrin grafting onto carboxymethyl chitosan. The use of the 1,6 hexamethylene diisocyanate resulted in reactions between cyclodextrin and active sites at the C6-position of chitosan, and preserved amino groups of chitosan for subsequent reactions with thioglycolic acid, as the thiolating agent, and tripolyphosphate, as the gelling counterion. Various methods such as scanning electron microscopy, rheology and in vitro release studies were employed to exhibit significant features of the nanoparticles for mucosal albendazole delivery applications. It was found that the thiolated carboxymethyl chitosan-g cyclodextrin nanoparticles prepared using an aqueous solution containing 1 wt% of tripolyphosphate and having 115.65 (MUmol/g polymer) of grafted thiol groups show both the highest mucoadhesive properties and the highest albendazole entrapment efficiency. The latter was confirmed theoretically by calculating the enthalpy of mixing of albendazole in the above thiolated chitosan polymer. PMID- 23665923 TI - Photoswitchable NHC-promoted ring-opening polymerizations. AB - The UV-induced photocyclization of a dithienylethene-annulated N-heterocyclic carbene precatalyst enabled photoswitchable ring-opening polymerizations of epsilon-caprolactone and delta-valerolactone. The polymerizations proceeded efficiently in ambient light, however UV irradiation attenuated the reaction rate (k(amb)/k(UV) = 59). Subsequent visible light exposure reversed the photocyclization and restored catalytic activity. PMID- 23665924 TI - Non-invasive monitoring of therapeutic carbon ion beams in a homogeneous phantom by tracking of secondary ions. AB - Radiotherapy with narrow scanned carbon ion beams enables a highly accurate treatment of tumours while sparing the surrounding healthy tissue. Changes in the patient's geometry can alter the actual ion range in tissue and result in unfavourable changes in the dose distribution. Consequently, it is desired to verify the actual beam delivery within the patient. Real-time and non-invasive measurement methods are preferable. Currently, the only technically feasible method to monitor the delivered dose distribution within the patient is based on tissue activation measurements by means of positron emission tomography (PET). An alternative monitoring method based on tracking of prompt secondary ions leaving a patient irradiated with carbon ion beams has been previously suggested. It is expected to help in overcoming the limitations of the PET-based technique like physiological washout of the beam induced activity, low signal and to allow for real-time measurements. In this paper, measurements of secondary charged particle tracks around a head-sized homogeneous PMMA phantom irradiated with pencil-like carbon ion beams are presented. The investigated energies and beam widths are within the therapeutically used range. The aim of the study is to deduce properties of the primary beam from the distribution of the secondary charged particles. Experiments were performed at the Heidelberg Ion Beam Therapy Center, Germany. The directions of secondary charged particles emerging from the PMMA phantom were measured using an arrangement of two parallel pixelated silicon detectors (Timepix). The distribution of the registered particle tracks was analysed to deduce its dependence on clinically important beam parameters: beam range, width and position. Distinct dependencies of the secondary particle tracks on the properties of the primary carbon ion beam were observed. In the particular experimental set-up used, beam range differences of 1.3 mm were detectable. In addition, variations in the beam width could be measured with a precision of 0.9 mm. Furthermore, shifts of the lateral beam position could be monitored with a sub-millimetre precision. The presented investigations demonstrate experimentally that the non-invasive measurement and analysis of secondary ion distributions around head-sized homogeneous objects provide information on the actual beam delivery. Beam range, width and position could be monitored with a precision attractive for therapeutic situations. PMID- 23665922 TI - The Histochemistry and Cell Biology compendium: a review of 2012. AB - The year 2012 was another exciting year for Histochemistry and Cell Biology. Innovations in immunohistochemical techniques and microscopy-based imaging have provided the means for advances in the field of cell biology. Over 130 manuscripts were published in the journal during 2012, representing methodological advancements, pathobiology of disease, and cell and tissue biology. This annual review of the manuscripts published in the previous year in Histochemistry and Cell Biology serves as an abbreviated reference for the readership to quickly peruse and discern trends in the field over the past year. The review has been broadly divided into multiple sections encompassing topics such as method advancements, subcellular components, extracellular matrix, and organ systems. We hope that the creation of this subdivision will serve to guide the reader to a specific topic of interest, while simultaneously providing a concise and easily accessible encapsulation of other topics in the broad area of Histochemistry and Cell Biology. PMID- 23665925 TI - Food washing and placer mining in captive great apes. AB - Sweet potato washing and wheat placer mining in Japanese macaques (Macaca fuscata) are among the most well known examples of local traditions in non-human animals. The functions of these behaviors and the mechanisms of acquisition and spread of these behaviors have been debated frequently. Prompted by animal caretaker reports that great apes [chimpanzees (Pan troglodytes), bonobos (Pan paniscus), gorillas (Gorilla gorilla), and orangutans (Pongo abelii)] at Leipzig Zoo occasionally wash their food, we conducted a study of food washing behaviors that consisted of two parts. In the first part we assessed the current distribution of the behavior on the basis of caretaker reports. In the second (experimental) part, we provided subjects individually with a water basin and two types of food (apples and cereal) that was either clean or covered/mixed with sand. We found that subjects of all species (except gorillas) placed apples in the water before consumption, and that they did so more often when the apples were dirty than when they were clean. Several chimpanzees and orangutans also engaged in behaviors resembling wheat placer mining. PMID- 23665926 TI - Genotype variations in cadmium and lead accumulations of leafy lettuce (Lactuca sativa L.) and screening for pollution-safe cultivars for food safety. AB - Heavy-metals in polluted soils can accumulate in plants and threaten crop safety. To evaluate the risk of heavy-metal pollution in leafy lettuce (Lactuca sativa L.), two pot experiments were conducted to investigate Cd and Pb accumulation and transfer potential in 28 cultivars of lettuce and to screen for low-Cd and low-Pb accumulative cultivars. In the three treatments, 5.2-fold, 4.8-fold and 4.8-fold differences in the shoot Cd concentration were observed between the cultivars with the highest and the lowest Cd concentrations, respectively. This genotype variation was sufficiently large to identify low-Cd accumulative genotypes to reduce Cd contamination in food. Cadmium accumulation in the low-Cd accumulative genotypes was significantly positively correlated with Pb accumulation. At the cultivar level, Cd and Pb accumulation in lettuce was stable and genotype dependent. High Pb soil levels did not affect shoot Cd accumulation in lettuce. Lettuce was concluded to be at high risk for Cd pollution and low risk for Pb pollution. Among the tested cultivars, cvs. SJGT, YLGC, N518, and KR17 had the lowest Cd and Pb accumulation abilities in shoots and are thus important parental material for breeding pollution-safe cultivars to minimize Cd and Pb accumulation. PMID- 23665927 TI - Molecular characterization of beta-thalassemia in four communities in South Gujarat--codon 30 (G -> A) a predominant mutation in the Kachhiya Patel community. AB - Different thalassemia mutations have been reported in various ethnic groups and geographical regions in India. In this study, we have investigated Kachhiya Patel, Dhodia Patel, Modh Bania, and Muslim communities of Surat, Gujarat to identify molecular defects causing beta-thalassemia in them. Covalent reverse dot blot hybridization technique was used to detect six common Indian beta thalassemia mutations while the seventh mutation (619-bp deletion) was identified by PCR. The less common mutations were detected by amplification refractory mutation and the uncharacterized samples were directly sequenced. Characterization of beta-thalassemia mutations was carried out in a total of 175 unrelated beta-thalassemia trait cases. We identified IVS 1 nt 5 (G -> C) in 31 out of 65 Muslims, codon (Cd) 41/42 (-CTTT) in 14 out of 16 in Modh Banias, Cd 15 (G -> A) in 19 out of 24 Dhodia Patels. The most significant observation was an uncommon mutation; Cd 30 (G -> A) detected in 61 out of 70 Kachhiya Patels. The 619-bp deletion was detected in 6 out of 10 Muslim-Memons. Many other rare mutations like Cd 15 (-T), Cd 8 (-AA), -88 (C -> A), Capsite +1 (A -> C), Cd 16( C), and Cd 5 (-CT) were detected. To our knowledge, our study is the first to characterize beta-thalassemia mutations in the Kachhiya Patel community. This study will facilitate molecular analysis and prenatal diagnosis in these four communities. PMID- 23665928 TI - Pharmaceuticals in tap water: human health risk assessment and proposed monitoring framework in China. AB - BACKGROUND: Pharmaceuticals are known to contaminate tap water worldwide, but the relevant human health risks have not been assessed in China. OBJECTIVES: We monitored 32 pharmaceuticals in Chinese tap water and evaluated the life-long human health risks of exposure in order to provide information for future prioritization and risk management. METHODS: We analyzed samples (n = 113) from 13 cities and compared detected concentrations with existing or newly-derived safety levels for assessing risk quotients (RQs) at different life stages, excluding the prenatal stage. RESULTS: We detected 17 pharmaceuticals in 89% of samples, with most detectable concentrations (92%) at < 50 ng/L. Caffeine (median maximum, nanograms per liter: 24.4-564), metronidazole (1.8-19.3), salicylic acid (16.6-41.2), clofibric acid (1.2-3.3), carbamazepine (1.3-6.7), and dimetridazole (6.9-14.7) were found in >= 20% of samples. Cities within the Yangtze River region and Guangzhou were regarded as contamination hot spots because of elevated levels and frequent positive detections. Of the 17 pharmaceuticals detected, 13 showed very low risk levels, but 4 (i.e., dimetridazole, thiamphenicol, sulfamethazine, and clarithromycin) were found to have at least one life-stage RQ >= 0.01, especially for the infant and child life stages, and should be considered of high priority for management. We propose an indicator-based monitoring framework for providing information for source identification, water treatment effectiveness, and water safety management in China. CONCLUSION: Chinese tap water is an additional route of human exposure to pharmaceuticals, particularly for dimetridazole, although the risk to human health is low based on current toxicity data. Pharmaceutical detection and application of the proposed monitoring framework can be used for water source protection and risk management in China and elsewhere. PMID- 23665930 TI - Interaction of 9,10-phenanthraquinone with dithiol causes oxidative modification of Cu,Zn-superoxide dismutase (SOD) through redox cycling. AB - 9,10-Phenanthraquinone (9,10-PQ) is abundant in diesel exhaust particles (DEP) and causes oxidative protein modification in cells. We previously reported that redox cycling of 9,10-PQ with dithiols leads to the generation of an excess of superoxide (O2*-). Cu,Zn-superoxide dismutase (Cu,Zn-SOD), which dismutates O2*- to hydrogen peroxide (H2O2), is sensitive to its own product, H2O2. In this study, incubating 9,10-PQ with dithiols, but not monothiols, for 24 hr, resulted in the conversion of native Cu,Zn-SOD to its charge isomers, some of which did not show enzyme activity. Exposing Cu,Zn-SOD to 9,10-PQ in the presence of dihydrolipoic acid (DHLA), a model for low molecular weight endogenous dithiols, caused a concentration-dependent decrease in the enzyme activity. Under these conditions, copper release from the active site and Cu,Zn-SOD oxidation were detected, the evidence for which was carbonyl formation. Experiments using agents that scavenge reactive oxygen species (ROS) indicated that the hydroxyl radical (*OH) derived from H2O2 plays a critical role in the fragmentation of the enzyme. The findings presented suggest that Cu,Zn-SOD readily undergoes oxidative modification associated with activity loss, caused by ROS generated by the redox cycling of 9,10-PQ with endogenous dithiols such as DHLA and, presumably, proximal protein thiols. PMID- 23665929 TI - TO901317, a potent LXR agonist, is an inverse agonist of CAR. AB - The basal transcriptional activity of unliganded human constitutive androstane receptor (hCAR) was shown to be repressed by the potent liver X receptor (LXR) agonist, TO901317, in a concentration-dependent manner using a reporter assay in cultured cells. TO901317 also repressed the basal transcriptional activity of both mouse and rat CAR. The certified hCAR agonist, CITCO, partially reversed this repressive effect of TO901317 on hCAR basal activity. Unlike hCAR, a three alanine insertion mutant and the splice variant 2 of hCAR require agonists, such as CITCO, to become transcriptionally active and the CITCO-induced reporter activity was repressed by TO901317. As has been previously shown for the typical hCAR inverse agonist, PK11195, TO901317 blocked the interaction of hCAR with steroid receptor co-activator 1 (SRC1). In contrast, the interaction between hCAR and nuclear receptor corepressor 1 (NCoR1) was promoted by PK11195 and TO901317. Furthermore, the hCAR-mediated basal induction of endogenous cytochrome P450 2B6 (CYP2B6) mRNA was adversely affected by co-treatment with TO901317. PMID- 23665931 TI - Phenylhydroquinone induces loss of thymocytes through cell cycle arrest and apoptosis elevation in p53-dependent pathway. AB - ortho-Phenylphenol has been employed in post-harvest treatment of citrus fruits. Although o-phenylphenol has been reported to cause carcinomas in the urinary tract in rats, toxicity to the immune organs is still unknown. Herein, we report that administration of o-phenylphenol induces thymic atrophy and loss of thymocytes in female BALB/c mice. The influence seems to result from inhibition of the thymocyte development, because increased and decreased populations of the CD4- CD8- double-negative and CD4+ CD8+ double-positive thymocytes were observed in the o-phenylphenol-administered mice, respectively. ortho-Phenylphenol is metabolized to phenylhydroquinone by cytochrome P450 monooxygenases. Phenylhydroquinone made cell cycle of thymocytes to be arrested through reduced expression of the genes associated with G2/M phase and through phosphorylation of p53 at Ser15. Phosphorylation of p53 at Ser15 was upregulated by activation of not only ATR but also Erk1/2 and p38, leading to increase of apoptosis. Gene expression of cytochrome P450 1A1 (CYP1A1) was promoted in thymocytes from the o phenylphenol-administered mice. Overall, our results suggest that o-phenylphenol induces CYP1A1 expression and is metabolized into phenylhydroquinone by the expressed CYP1A1 in thymocytes. The produced phenylhydroquinone in turn induces inhibition of thymocyte development through cell cycle arrest and apoptosis in the p53-dependent pathway. PMID- 23665932 TI - Marijuana smoke condensate induces p53-mediated apoptosis in human lung epithelial cells. AB - Since the largely abused worldwide used of marijuana, there have been many ongoing debates regarding the adverse health effects of marijuana smoking. Marijuana smoking was recently proved to cause pulmonary toxicity by inducing genotoxic effects or generating reactive oxygen species. Because p53, a tumor suppressor gene, has an important pathophysiologic role in the regulation of lung epithelial cell DNA damage responses, we hypothesized that p53 may be involved in the oxidative stress-mediated apoptosis induced by marijuana smoking. First, we confirmed that marijuana smoke condensate (MSC) induces oxidative stress in BEAS 2B cells. We observed that reactive oxygen species (ROS) generation was increased by MSC in the DCFH-DA assay. Also, antioxidant enzyme (superoxide dismutase, catalase) activity and their mRNA expressions were up-regulated by MSC. Second, we investigated p53 involvement in the MSC-induced apoptotic pathway in BEAS-2B cells. The results showed that MSC increased caspase-3 activation and DNA fragmentation as markers of apoptosis. In addition, the mRNA levels of apoptosis related genes (p53 and Bax) were increased by MSC and phospho-p53, along with the increase of Bax protein expression by MSC. Apoptosis and apoptosis-related gene expression were partially blocked by an inhibitor of p53-dependent transcriptional activation (pifithrin-alpha). The results indicate that p53 plays a role in MSC-induced apoptosis. Taken together, the findings of the present study suggest that MSC partially induces p53-mediated apoptosis through ROS generation in human lung epithelial cells and this may have broader implications for our understanding of pulmonary diseases. PMID- 23665934 TI - Correlations between BRCA1 defect and environmental factors in the risk of breast cancer. AB - The risk factors for breast cancer, the most common female malignant cancer, include environmental factors such as radiation, tobacco, a high-fat diet, and xenoestrogens as well as hormones. In addition, BRCA1 and BRCA2 are the most well known genetic factors that increase risk for breast cancer. Coincidence of those environmental and genetic factors might augment the risk of tumorigenesis of breast. To verify this hypothesis, we briefly evaluated the carcinogenic potency of various environmental factors in the absence or presence of BRCA1 as a genetic factor in a normal mammary epithelial cell line, MCF10A. Many environmental factors tested increased cellular ROS level in the absence of other insult. In addition, TCDD, DMBA, 3MC, and BPA enhanced the BaP-induced ROS production. BRCA1 knockdown (BRCA1-KD) cells by siRNA significantly induced cellular accumulation of ROS compared to control cells. In this setting, the addition of paraquat, TCDD, DMBA, 2OHE2 or 4OHE2 significantly augmented ROS generation in BRCA1-KD MCF10A cells. Measurements of BaP-DNA adduct formation as a marker of DNA damage also revealed that BRCA1 deficiency leads increased DNA damage. In addition, TCDD and DMBA significantly increased BaP-DNA adduct formation in the absence of BRCA1. These results imply that elevated level of ROS is correlated with increase of DNA damage in BRCA1 defective cells. Taken together, our study suggests that several environmental factors might increase the risk of tumorigenesis in BRCA1 defective breast epithelial cells. PMID- 23665935 TI - Prenatal exposure to zinc oxide particles alters monoaminergic neurotransmitter levels in the brain of mouse offspring. AB - Zinc oxide (ZnO) nano-sized particles (NPs) are beneficial materials used for sunscreens and cosmetics. Although ZnO NPs are widely used for cosmetics, the health effects of exposure during pregnancy on offspring are largely unknown. Here we investigated the effects of prenatal exposure to ZnO NPs on the monoaminergic system of the mouse brain. Subcutaneous administration of ZnO NPs to the pregnant ICR mice (total 500 MUg/mouse) were carried out and then measured the levels of dopamine (DA), serotonin (5-HT), and noradrenalin, and their metabolites in 9 regions of the brain of offspring (6-week-old) using high performance liquid chromatography (HPLC). HPLC analysis demonstrated that DA levels were increased in hippocampus in the ZnO NP exposure group. In the levels of DA metabolites, homovanillic acid was increased in the prefrontal cortex and hippocampus, and 3, 4-dihydroxyphenylacetic acid was increased in the prefrontal cortex by prenatal ZnO NP exposure. Furthermore, DA turnover levels were increased in the prefrontal cortex, neostriatum, nucleus accumbens, and amygdala in the ZnO NP exposure group. We also found changes of the levels of serotonin in the hypothalamus, and of the levels of 5-HIAA (5-HT metabolite) in the prefrontal cortex and hippocampus in the ZnO NP-exposed group. The levels of 5-HT turnover were increased in each of the regions except for the cerebellum by prenatal ZnO NP exposure. The present study indicated that prenatal exposure to ZnO NPs might disrupt the monoaminergic system, and suggested the possibility of detrimental effects on the mental health of offspring. PMID- 23665933 TI - CYP3A4 intron 6 C>T polymorphism (CYP3A4*22) is associated with reduced CYP3A4 protein level and function in human liver microsomes. AB - Effects of the CYP3A4 intron 6 C>T (CYP3A4*22) polymorphism, which has recently been reported to have a critical role in vivo, were investigated by measuring CYP3A4 protein expression levels and CYP3A4-dependent drug oxidation activities in individual human liver microsomes in vitro. Prior to protein analysis, analysis of DNA samples indicated that 36 Caucasian subjects were genotyped as CYP3A4*1/*1 and five subjects were CYP3A4*1/*22, with a CYP3A4*22 allelic frequency of 6.1%. No CYP3A4*22 alleles were found in the Japanese samples (106 alleles). Individual differences in CYP2D6-dependent dextromethorphan O demethylation activities in liver microsomes from Caucasians were not affected by either the CYP3A4*1/*22 or CYP3A5*1/*3 genotype. Liver microsomes genotyped as CYP3A4*1/*22 (n = 4) showed significantly lower CYP3A-dependent dextromethorphan N-demethylation, midazolam 1'-hydroxylation, and testosterone 6beta-hydroxylation activities, as well as lower expression levels of CYP3A protein (28% of control), compared with those of the CYP3A4*1/*1 group (n = 19). The other polymorphism, CYP3A5*1/*3, did not show these differences (n = 4). The CYP3A4*22 polymorphism was associated with reduced CYP3A4 protein expression levels and resulted in decreased CYP3A4-dependent activities in human livers. The present results suggest an important role of low expression of CYP3A4 protein associated with the CYP3A4*22 allele in the individual differences in drug clearance. PMID- 23665936 TI - Epigallocatechin gallate protects against nitric oxide-induced apoptosis via scavenging ROS and modulating the Bcl-2 family in human dental pulp cells. AB - Nitric oxide (NO) is produced by three different isoforms of the enzyme NO synthase (NOS). NOS isoforms are expressed in many cell types, including human dental pulp cells (HDPC). NO acts as an intracellular messenger at physiological levels although it can be cytotoxic at higher concentrations. Epigallocatechin gallate (EGCG), a major green tea polyphenol, has diverse pharmacological activities in cell growth and death. This study is aimed to investigate the apoptotic mechanism by NO and effects of EGCG on NO-induced apoptosis in HDPC. Sodium nitroprusside (SNP), an NO donor, decreased the cell viability of HDPC in a dose- and time-dependent manner. EGCG was administered for 1 hr before the SNP treatment, resulting in increased cell viability and reactive oxygen species (ROS) production inhibition. Expression of Bax, a pro-apoptotic Bcl-2 family, was upregulated, whereas expression of Bcl-2, an anti-apoptotic Bcl-2 family, was downregulated in SNP-treated HDPC. SNP augmented the release of cytochrome c from mitochondria into cytosol and enhanced caspase-9, and -3 activities, a marker of the apoptotic executing stage. EGCG ameliorated caspase-9 and -3 activities and cytochrome c release increased by SNP. These results suggest that EGCG has a protective effect against NO-induced apoptosis in HDPC by scavenging ROS and modulating the Bcl-2 family. PMID- 23665937 TI - Eicosapentaenoic acid attenuates hepatic accumulation of cholesterol esters but aggravates liver injury and inflammation in mice fed a cholate-supplemented high fat diet. AB - The administration of a sodium cholate-supplemented high-fat (CAHF) diet in mice induced the predominant accumulation of cholesterol esters (CE) in the liver and biochemical and histological features of liver injury. Cholesteryl oleate was the most abundant CE found in the liver of the mice fed the CAHF diet. We examined the effect of ethyl eicosapentaenoate (EPA) on hepatic CE accumulation and liver injury in the mice fed the CAHF diet. The EPA supplementation suppressed the elevation in the level of cholesteryl oleate in the liver. The expression levels of sterol O-acyltransferase-2 and stearoyl-CoA desaturase-1 mRNA in the liver were elevated in the mice fed the CAHF diet, but they were normalized by the EPA supplementation. However, the elevation in serum transaminase activity, the sign of inflammatory cell exudation and inflammatory gene responses in the liver of the mice fed the EPA-supplemented diet were enhanced compared with those of the mice fed the CAHF diet. We demonstrated that EPA supplementation attenuated CE accumulation but aggravated liver injury and liver inflammation in the mice fed the CAHF diet. PMID- 23665938 TI - Comparative gene expression analysis of the amygdala in autistic rat models produced by pre- and post-natal exposures to valproic acid. AB - Gene expression profiles in the amygdala of juvenile rats were compared between the two autistic rat models for mechanistic insights into impaired social behavior and enhanced anxiety in autism. The rats exposed to VPA by intraperitoneal administration to their dams at embryonic day (E) 12 were used as a model for autism (E2IP), and those by subcutaneous administration at postnatal day (P) 14 (P14SC) were used as a model for regressive autism; both of the models show impaired social behavior and enhanced anxiety as symptoms. Gene expression profiles in the amygdala of the rats (E12IP and P14SC) were analyzed by microarray and compared to each other. Only two genes, Neu2 and Mt2a, showed significant changes in the same direction in both of the rat models, and there were little similarities in the overall gene expression profiles between them. It was considered that gene expression changes per se in the amygdala might be an important cause for impaired social behavior and enhanced anxiety, rather than expression changes of particular genes. PMID- 23665939 TI - Liver tumor promoting effect of orphenadrine in rats and its possible mechanism of action including CAR activation and oxidative stress. AB - Orphenadrine (ORPH), an anticholinergic agent, is a cytochrome P450 (CYP) 2B inducer. CYP2B inducers are known to have liver tumor-promoting effects in rats. In this study, we performed a rat two-stage liver carcinogenesis bioassay to examine the tumor-promoting effect of ORPH and to clarify its possible mechanism of action. Male rats were given a single intraperitoneal injection of N diethylnitrosamine (DEN) as an initiation treatment. Two weeks after DEN administration, rats were fed a diet containing ORPH (0, 750, or 1,500 ppm) for 6 weeks. One week after the ORPH-administration rats were subjected to two-thirds partial hepatectomy for the acceleration of hepatocellular proliferation. The number and area of glutathione S-transferase placental form-positive foci significantly increased in the DEN-ORPH groups. Real-time RT-PCR revealed increased mRNA expression levels of Cyp2b1/2, Mrp2 and Cyclin D1 in the DEN-ORPH groups and of Gpx2 and Gstm3 in the DEN-High ORPH group. Microsomal reactive oxygen species (ROS) production and oxidative stress markers such as thiobarbituric acid-reactive substances and 8-hydroxydeoxyguanosine were increased in the DEN-High ORPH group. Immunohistochemically, constitutively active/androstane receptor (CAR) were clearly localized in the nuclei of hepatocytes in the DEN-ORPH groups. These results suggest that ORPH causes nuclear translocation of CAR resulting in the induction of the liver tumor promoting activity. Furthermore, oxidative stress resulting from ROS production is also involved in the liver tumor-promoting activity of ORPH. PMID- 23665940 TI - Enhanced liver tumor promotion activity in rats subjected to combined administration of phenobarbital and orphenadrine. AB - Phenobarbital (PB) and orphenadrine (ORPH) are cytochrome P450 (CYP) 2B inducers and have liver tumor-promoting effects in rats. In this study, we performed a rat two-stage liver carcinogenesis bioassay to examine the tumor-promoting effect of PB and ORPH co-administration. Twelve male rats per group were given an intraperitoneal injection of N-diethylnitrosamine (DEN) for initiation. Two-week after DEN administration, rats were given PB (60 or 120 ppm in drinking water), ORPH (750 or 1,500 ppm in diet) or 60 ppm PB+750 ppm ORPH for 6-week. One-week after the PB/ORPH treatment, all rats were subjected to two-thirds partial hepatectomy. To evaluate the effect of the combined administration, we used two statistical models: a heteroadditive model and an isoadditive model. In the heteroadditive model, the net values of the number and area of glutathione S transferase placental form (GST-P) positive foci, Cyp2b1/2, Gstm3 and Gpx2 mRNA levels, microsomal reactive oxygen species (ROS) production and thiobarbituric acid-reactive substances level in the PB+ORPH group were significantly higher than the sum of the net values of those in the Low PB and Low ORPH groups. In the isoadditive model, the average values of the area of GST-P positive foci and PCNA positive hepatocyte ratio and Gstm3 mRNA level in the PB+ORPH group were significantly higher than the average values of those in the High PB and High ORPH groups. These results suggest that PB and ORPH co-administration causes synergistic effects in liver tumor-promoting activity in rats resulting from oxidative stress due to enhanced microsomal ROS production. PMID- 23665941 TI - beta-N-methylamino-L-alanine induces changes in both GSK3 and TDP-43 in human neuroblastoma. AB - beta-N-methylamino-L-alanine (L-BMAA) is a neurotoxic amino acid produced by most cyanobacteria, which are extensively distributed in different environments all over the world. L-BMAA has been linked to a variety of neurodegenerative diseases. This work aims to analyze the toxicological action of L-BMAA related to alterations observed in different neurodegenerative illness as Alzheimer disease and amyotrophic lateral sclerosis. Our results demonstrate that neuroblastoma cells treated with L-BMAA show an increase in glycogen synthase kinase 3 beta (GSk3beta) and induce accumulation of TAR DNA-binding protein 43 (TDP-43) truncated forms (C-terminal fragments), phosphorylated and high molecular weight forms of TDP-43, that appears frequently in some neurodegenerative diseases. PMID- 23665942 TI - Methacarn as a whole brain fixative for gene and protein expression analyses of specific brain regions in rats. AB - For molecular analysis in anatomically-specific brain regions for rodent studies, it is necessary to establish a fast and accurate procedure for tissue sampling to achieve high integrity and expression fidelity of extracted molecules. The present study was performed to examine suitability of whole brain fixation with methacarn and subsequent tissue sampling using punch-biopsy devices for gene expression analysis in rats. After fixation, each specific region, i.e., hippocampal dentate gyrus, corpus callosum, cingulate cortex or cerebellar vermis was collected, and the integrity and variability of expression data of extracted total RNAs and polypeptides were examined. Methacarn fixation, acetone fixation, and unfixed tissues were compared. Methacarn fixation resulted in high integrity of total RNAs sufficient for conducting global expression analysis and superior in terms of uniformity in the integrity among brain regions to that of acetone fixation. Extracted polypeptide after methacarn fixation revealed similar integrity to that without fixation or with acetone fixation. Methacarn fixation resulted in lower mRNA expression variability between samples than acetone fixation in microarray analysis. The fidelity of polypeptide expression was mostly equivalent between methacarn and acetone fixation in 2-dimensional differential in-gel electrophoresis, although the expression levels of a small number of polypeptides from acetone-fixed tissues were affected. These results suggest that whole brain fixation with methacarn retains advantages for global analyses of mRNAs and polypeptides in rodent studies. PMID- 23665943 TI - Biochemical evaluation of the neurotoxicity of MPTP and MPP+ in embryonic and newborn mice. AB - One of the toxicities caused by 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) is damage to dopaminergic neurons. When injected into C57BL/6J mice, MPTP penetrates into the brain and is converted to 1-methyl-4-phenylpyridinium (MPP+) by monoamine oxidase (MAO)-B in astrocytes. MPP+ has high affinity for the dopamine transporter (DAT) on dopaminergic neurons, and is taken up into the cell to cause cell death. There have been relatively few researches on the acute MPTP toxicity to embryonic or newborn mice. In the present study, we attempted to evaluate the influence of MPTP and MPP+ on embryonic and newborn mice by measuring sequential changes in major indexes of MPTP toxicity and MPTP metabolism; levels of Tyrosine Hydroxylase (TH), DAT, MAO-A and MAO-B. In addition, we measured the levels of dopamine and its metabolites, 3,4-dihydroxy phenylacetic acid (DOPAC) and homovanillic acid (HVA), in the brain of newborn mice. A single injection of MPTP and MPP+ reduced the levels of dopamine and its metabolites, DOPAC and HVA, in the brain of newborn mice about 6-12 hr after the injection. Similarly the levels of mRNAs and proteins of DAT and TH were lowered in the brain of embryonic and newborn mice as well. The levels of these indexes were generally recovered at 24 hr after injection, indicating that the neurotoxicity induced by a single injection of MPTP or MPP+ is temporary and recoverable in embryonic and newborn mice. By contrast, no significant changes in the expression levels of MAO-A and MAO-B were observed in either MPTP- or MPP+ treated mice. PMID- 23665944 TI - Assessment of the safety of hydrogenated resistant maltodextrin: reverse mutation assay, acute and 90-day subchronic repeated oral toxicity in rats, and acute no effect level for diarrhea in humans. AB - A series of safety assessments were performed on hydrogenated resistant maltodextrin prepared by converting the reducing terminal glucose of resistant maltodextrin into sorbitol. The reverse mutation assay did not show mutagenicity. Acute and 90-day subchronic oral toxicity studies in rats showed no death was observed in any groups, including the group receiving the highest single dose of 10 g/kg body weight or the highest dose of 5 g/kg body weight per day for 90 days. Mucous or watery stools were observed in the hydrogenated resistant maltodextrin treatment group on the acute study, which were transient and were associated with the osmotic pressure caused by intake of the high concentrations. Subchronic study showed dose-dependent increases in the weights of cecum alone, cecal contents alone, and cecum with cecal contents as well as hypertrophy of the cecal mucosal epithelium, which are considered to be common physiological responses after intake of indigestible carbohydrates. These results indicated that the no observed adverse effect level (NOAEL) of hydrogenated resistant maltodextrin was 10 g/kg body weight or more on the acute oral toxicity study and 5.0 g/kg body weight/day or more on the 90-day subchronic repeated oral toxicity study in rats. Further study performed in healthy adult humans showed that the acute no-effect level of hydrogenated resistant maltodextrin for diarrhea was 0.8 g/kg body weight for men and more than 1.0 g/kg body weight for women. The results of the current safety assessment studies suggest that hydrogenated resistant maltodextrin is safe for human consumption. PMID- 23665945 TI - The equilibria between monovalent ions and phosphatidylcholine monolayer at the air/water interface. AB - The effect of monovalent ion (Li+, Na+, Cs+) interaction with monolayers of phosphatidylcholine (lecithin, PC) was investigated at the air/water interface. We present surface tension measurements of lipid monolayers obtained using a Langmuir method as a function of monovalent ion concentration. Measurements were carried out at 22 degrees C using a Teflon trough and a Nima 9000 tensiometer. Interactions between lecithin and monovalent ions result in significant deviations from the additivity rule. An equilibrium theory to describe the behavior of monolayer components at the air/water interface was developed in order to obtain the stability constants and area occupied by one molecule of PC monovalent ion complexes (PC-Me+). PMID- 23665946 TI - Freiburg neuropathology case conference: contrast-enhancing white matter lesion adjacent to the lateral ventricle. PMID- 23665947 TI - Assessing crossmodal matching of abstract auditory and visual stimuli in posterior superior temporal sulcus with MEG. AB - Associating crossmodal auditory and visual stimuli is an important component of perception, with the posterior superior temporal sulcus (pSTS) hypothesized to support this. However, recent evidence has argued that the pSTS serves to associate two stimuli irrespective of modality. To examine the contribution of pSTS to crossmodal recognition, participants (N=13) learned 12 abstract, non linguistic pairs of stimuli over 3weeks. These paired associates comprised four types: auditory-visual (AV), auditory-auditory (AA), visual-auditory (VA), and visual-visual (VV). At week four, participants were scanned using magnetoencephalography (MEG) while performing a correct/incorrect judgment on pairs of items. Using an implementation of synthetic aperture magnetometry that computes real statistics across trials (SAMspm), we directly contrasted crossmodal (AV and VA) with unimodal (AA and VV) pairs from stimulus-onset to 2s in theta (4-8Hz), alpha (9-15Hz), beta (16-30Hz), and gamma (31-50Hz) frequencies. We found pSTS showed greater desynchronization in the beta frequency for crossmodal compared with unimodal trials, suggesting greater activity during the crossmodal pairs, which was not influenced by congruency of the paired stimuli. Using a sliding window SAM analysis, we found the timing of this difference began in a window from 250 to 750ms after stimulus-onset. Further, when we directly contrasted all sub-types of paired associates from stimulus onset to 2s, we found that pSTS seemed to respond to dynamic, auditory stimuli, rather than crossmodal stimuli per se. These findings support an early role for pSTS in the processing of dynamic, auditory stimuli, and do not support claims that pSTS is responsible for associating two stimuli irrespective of their modality. PMID- 23665949 TI - Study on electrochemiluminescence spectra of ZnO flakes. AB - The electrochemiluminescence spectra of ZnO were recorded to investigate the surface states of the samples prepared from hydrothermal synthesis and electrochemical deposition, respectively. Photoluminescence spectra and electrochemiluminescence-potential curves were applied to study the effect of the preparation procedure and particle sizes on the surface electronic structure of products. The results indicated that the preparation conditions and the particle sizes have a small influence on the surface band gap. PMID- 23665948 TI - Differential brain shrinkage over 6 months shows limited association with cognitive practice. AB - The brain shrinks with age, but the timing of this process and the extent of its malleability are unclear. We measured changes in regional brain volumes in younger (age 20-31) and older (age 65-80) adults twice over a 6 month period, and examined the association between changes in volume, history of hypertension, and cognitive training. Between two MRI scans, 49 participants underwent intensive practice in three cognitive domains for 100 consecutive days, whereas 23 control group members performed no laboratory cognitive tasks. Regional volumes of seven brain structures were measured manually and adjusted for intracranial volume. We observed significant mean shrinkage in the lateral prefrontal cortex, the hippocampus, the caudate nucleus, and the cerebellum, but no reliable mean change of the prefrontal white matter, orbital-frontal cortex, and the primary visual cortex. Individual differences in change were reliable in all regions. History of hypertension was associated with greater cerebellar shrinkage. The cerebellum was the only region in which significantly reduced shrinkage was apparent in the experimental group after completion of cognitive training. Thus, in healthy adults, differential brain shrinkage can be observed in a narrow time window, vascular risk may aggravate it, and intensive cognitive activity may have a limited effect on it. PMID- 23665950 TI - Phase I study of sunitinib plus S-1 and cisplatin in Japanese patients with advanced or metastatic gastric cancer. AB - BACKGROUND: This phase I, dose-finding study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of sunitinib plus S 1/cisplatin in Japanese patients with advanced/metastatic gastric cancer. PATIENTS AND METHODS: Patients received oral sunitinib on a continuous daily dosing (CDD) or 2-weeks-on/2-weeks-off schedule (Schedule 2/2; 25 mg/day or 37.5 mg/day), plus S-1 (80-120 mg/day)/cisplatin 60 mg/m(2). RESULTS: Twenty-seven patients received treatment, including 26 patients treated per protocol (sunitinib 25 mg/day CDD schedule, n = 4; sunitinib 25 mg/day Schedule 2/2, n = 16 [dose-limiting toxicity (DLT) cohort, n = 6 plus expansion cohort, n = 10]; sunitinib 37.5 mg/day Schedule 2/2, n = 6). One patient erroneously self administered sunitinib 12.5 mg/day and was excluded from the analyses. The MTD was sunitinib 25 mg/day on Schedule 2/2. DLTs were reported for: 2/4 patients given sunitinib 25 mg/day on the CDD schedule; 1/6 patients administered sunitinib 25 mg/day on Schedule 2/2 (grade [G] 3 neutropenic infection, G4 thrombocytopenia, and S-1 dose interruption >=5 days), and 3/6 patients given sunitinib 37.5 mg/day on Schedule 2/2. Results below are for the overall MTD cohort (n = 16). The most frequently reported G3/4 adverse events were neutropenia (93.8 %) and leukopenia (75.0 %). The objective response rate was 37.5 %; six additional patients experienced no disease progression for >=24 weeks. Median progression-free survival was 12.5 months. No pharmacokinetic drug drug interactions were observed between sunitinib/S-1/cisplatin and S 1/cisplatin. CONCLUSIONS: The MTD of sunitinib was 25 mg/day on Schedule 2/2 combined with cisplatin/S-1 in patients with advanced/metastatic gastric cancer. This regimen had a manageable safety profile and preliminary antitumor activity. PMID- 23665952 TI - Correction for misclassification of caries experience in the absence of internal validation data. AB - OBJECTIVES: To quantify the effects of risk factors and/or determinants on disease occurrence, it is important that the risk factors as well as the variable that measures the disease outcome are recorded with the least error as possible. When investigating the factors that influence a binary outcome, a logistic regression model is often fitted under the assumption that the data are collected without error. However, most categorical outcomes (e.g., caries experience) are accompanied by misclassification and this needs to be accounted for. The aim of this research was to adjust for binary outcome misclassification using an external validation study when investigating factors influencing caries experience in schoolchildren. MATERIALS AND METHODS: Data from the Signal Tandmobiel((r)) study were used. A total of 500 children from the main and 148 from the validation study were included in the analysis. Regression models (with several covariates) for sensitivity and specificity were used to adjust for misclassification in the main data. RESULTS: The use of sensitivity and specificity modeled as functions of several covariates resulted in a better correction compared to using point estimates of sensitivity and specificity. Age, geographical location of the school to which the child belongs, dentition type, tooth type, and surface type were significantly associated with the prevalence of caries experience. CONCLUSIONS: Sensitivity and specificity calculated based on an external validation study may resemble those obtained from an internal study if conditioned on a rich set of covariates. CLINICAL RELEVANCE: Main data can be corrected for misclassification using information obtained from an external validation study when a rich set of covariates is recorded during calibration. PMID- 23665951 TI - Improved adeno-associated virus (AAV) serotype 1 and 5 vectors for gene therapy. AB - Despite significant advancements with recombinant AAV2 or AAV8 vectors for liver directed gene therapy in humans, it is well-recognized that host and vector related immune challenges need to be overcome for long-term gene transfer. To overcome these limitations, alternate AAV serotypes (1-10) are being rigorously evaluated. AAV5 is the most divergent (55% similarity vs. other serotypes) and like AAV1 vector is known to transduce liver efficiently. AAV1 and AAV5 vectors are also immunologically distinct by virtue of their low seroprevalence and minimal cross reactivity against pre-existing AAV2 neutralizing antibodies. Here, we demonstrate that targeted bio-engineering of these vectors, augment their gene expression in murine hepatocytes in vivo (up to 16-fold). These studies demonstrate the feasibility of the use of these novel AAV1 and AAV5 vectors for potential gene therapy of diseases like hemophilia. PMID- 23665953 TI - Association of MTHFR gene C677T mutation with recurrent aphthous stomatitis and number of oral ulcers. AB - OBJECTIVES: Recurrent aphthous stomatitis (RAS) is a common ulcerative disease of the oral mucosa. Methylenetetrahydrofolate reductase (MTHFR) gene variants are associated with thrombophilia and vasculopathy that may result in oral ulceration. Oral ulcers are also the most common feature of Behcet's disease (BD). Association of MTHFR gene C677T mutation with BD has been reported in different populations. The aim of the present study was to investigate the possible association between MTHFR gene C677T mutation and RAS and evaluate if there was an association with clinical features in a relatively large cohort of Turkish patients. MATERIALS AND METHODS: The study included 188 patients affected by RAS and 200 healthy controls. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) assay for the MTHFR gene C677T mutation. RESULTS: The genotype and allele frequencies of C677T mutation showed statistically significant differences between RAS patients and controls (p = 0.002 and p = 0.0004, respectively). After stratifying RAS patients according to clinical characteristics of oral ulcers, a significant association was observed between C677T mutation and number of oral ulcers of RAS patients (p = 0.006). CONCLUSIONS: As a result, a high association between MTHFR gene C677T mutation and RAS was observed in the present study. Also number of oral ulcers was found to be associated with MTHFR C677T mutation in RAS patients. CLINICAL RELEVANCE: If our observation can be substantiated with further studies, evaluation for MTHFR mutations and perhaps folate supplementation may become necessary in selected patients. PMID- 23665955 TI - Biosynthesis and PBAN-regulated transport of pheromone polyenes in the winter moth, Operophtera brumata. AB - The trienoic and tetraenoic polyenes, (3Z,6Z,9Z)-3,6,9-nonadecatriene, (3Z,6Z,9Z) 3,6,9-henicosatriene, and (3Z,6Z,9Z)-1,3,6,9-henicosatetraene were found in the abdominal cuticle and pheromone gland of the winter moth Operophtera brumata L. (Lepidoptera: Geometridae), in addition to the previously identified single component sex pheromone (3Z,6Z,9Z)-1,3,6,9-nonadecatetraene. The pheromone biosynthesis activating neuropeptide (PBAN) is involved in the regulation of polyene transport from abdominal cuticle to the pheromone gland. In vivo deuterium labeling experiments showed that (11Z,14Z,17Z)-11,14,17-icosatrienoic acid, the malonate elongation product of linolenic acid, (9Z,12Z,15Z)-9,12,15 octadecatrienoic acid, is used to produce (3Z,6Z,9Z)-3,6,9-nonadecatriene and (3Z,6Z,9Z)-1,3,6,9-nonadecatetraene. PMID- 23665956 TI - Lifting the veil: a typological survey of the methodological features of Islamic ethical reasoning on biomedical issues. AB - We survey the meta-ethical tools and institutional processes that traditional Islamic ethicists apply when deliberating on bioethical issues. We present a typology of these methodological elements, giving particular attention to the meta-ethical techniques and devices that traditional Islamic ethicists employ in the absence of decisive or univocal authoritative texts or in the absence of established transmitted cases. In describing how traditional Islamic ethicists work, we demonstrate that these experts possess a variety of discursive tools. We find that the ethical responsa-i.e., the products of the application of the tools that we describe-are generally characterized by internal consistency. We also conclude that Islamic ethical reasoning on bioethical issues, while clearly scripture-based, is also characterized by strong consequentialist elements and possesses clear principles-based characteristics. The paper contributes to the study of bioethics by familiarizing non-specialists in Islamic ethics with the role, scope, and applicability of key Islamic ethical concepts, such as "aims" (maqasid), "universals" (kulliyyat), "interest" (maslaha), "maxims" (qawa'id), "controls" (dawabit), "differentiators" (furuq), "preponderization" (tarjih), and "extension" (tafri'). PMID- 23665954 TI - Vascular endothelium leaves fingerprints on the surface of erythrocytes. AB - Gliding of red blood cells (RBC) through blood vessels is mediated by the negatively charged glycocalyx located on the surfaces of both RBC and endothelial cells (EC). In various vasculopathies, EC gradually lose this protective surface layer. As a consequence, RBC come into close physical contact with the vascular endothelium. It is hypothesized that the RBC glycocalyx could be adversely affected by a poor EC glycocalyx. This hypothesis was tested by evaluating the RBC and EC surface layers with atomic force microscopy techniques. In the first series of experiments, EC monolayers grown in culture were exposed to rhythmic drag forces exerted from a blood overlay (drag force treatment), and thereafter, the EC surface was investigated in terms of thickness and adhesiveness. In the second series, the glycocalyx of the EC monolayers was disturbed by enzymatic cleavage of negatively charged heparan sulfates before drag force treatment, and thereafter, the RBC surface was evaluated. In the third series, the RBC glycocalyx of the blood overlay was enzymatically disturbed before drag force treatment, and thereafter, the EC surface was evaluated. A strong positive correlation between the RBC and EC surface properties was found (r (2) = 0.95). An enzymatically affected EC glycocalyx lead to the shedding of the RBC glycocalyx and vice versa. It is concluded that there is physical interaction between the blood and endothelium. Apparently, the RBC glycocalyx reflects properties of the EC glycocalyx. This observation could have a significant impact on diagnosis and treatment of cardiovascular diseases. PMID- 23665957 TI - Photoprotective bioactivity present in a unique marine bacteria collection from Portuguese deep sea hydrothermal vents. AB - Interesting biological activities have been found for numerous marine compounds. In fact, screening of phylogenetically diverse marine microorganisms from extreme environments revealed to be a rational approach for the discovery of novel molecules with relevant bioactivities for industries such as pharmaceutical and cosmeceutical. Nevertheless, marine sources deliverables are still far from the expectations and new extreme sources of microbes should be explored. In this work, a marine prokaryotic collection from four Mid-Atlantic Ridge (MAR) deep sea hydrothermal vents near the Azores Islands, Portugal, was created, characterized and tested for its photoprotective capacity. Within 246 isolates, a polyphasic approach, using chemotaxonomic and molecular typing methods, identified 23 related clusters of phenetically similar isolates with high indexes of diversity. Interestingly, 16S rRNA gene sequencing suggested the presence of 43% new prokaryotic species. A sub-set of 139 isolates of the prokaryotic collection was selected for biotechnological exploitation with 484 bacterial extracts prepared in a sustainable upscalling manner. 22% of the extracts showed an industrially relevant photoprotective activity, with two extracts, belonging to new strains of the species Shewanella algae and Vibrio fluvialis, uniquely showing UV-A, UV-B and UV-C protective capacity. This clearly demonstrates the high potential of the bacteria MAR vents collection in natural product synthesis with market applications. PMID- 23665958 TI - Tetroazolemycins A and B, two new oxazole-thiazole siderophores from deep-sea Streptomyces olivaceus FXJ8.012. AB - Two new oxazole/thiazole derivatives, named tetroazolemycins A (1) and B (2), have been isolated from the acetone extract of the mycelium of Streptomyces olivaceus FXJ8.012 derived from deep-sea water, together with three known compounds, spoxazomicins A-C (3-5), isolated from the fermentation supernatant. The planar structure and relative configuration of tetroazolemycins were elucidated by a combination of spectroscopic analyses, including 1D- and 2D-NMR techniques, and showed to be new pyochelin-type antibiotics. Both compounds showed metal ion-binding activity and their Zn2+ complexes exhibited weak activity against pathogenic bacteria Klebsiella pneumoniae. PMID- 23665960 TI - Crystal structure of a nitrate/nitrite exchanger. AB - Mineral nitrogen in nature is often found in the form of nitrate (NO3(-)). Numerous microorganisms evolved to assimilate nitrate and use it as a major source of mineral nitrogen uptake. Nitrate, which is central in nitrogen metabolism, is first reduced to nitrite (NO2(-)) through a two-electron reduction reaction. The accumulation of cellular nitrite can be harmful because nitrite can be reduced to the cytotoxic nitric oxide. Instead, nitrite is rapidly removed from the cell by channels and transporters, or reduced to ammonium or dinitrogen through the action of assimilatory enzymes. Despite decades of effort no structure is currently available for any nitrate transport protein and the mechanism by which nitrate is transported remains largely unknown. Here we report the structure of a bacterial nitrate/nitrite transport protein, NarK, from Escherichia coli, with and without substrate. The structures reveal a positively charged substrate-translocation pathway lacking protonatable residues, suggesting that NarK functions as a nitrate/nitrite exchanger and that protons are unlikely to be co-transported. Conserved arginine residues comprise the substrate-binding pocket, which is formed by association of helices from the two halves of NarK. Key residues that are important for substrate recognition and transport are identified and related to extensive mutagenesis and functional studies. We propose that NarK exchanges nitrate for nitrite by a rocker switch mechanism facilitated by inter-domain hydrogen bond networks. PMID- 23665959 TI - De novo mutations in histone-modifying genes in congenital heart disease. AB - Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent-offspring trios. CHD cases show a significant excess of protein altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left-right organizer. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes 'poised' promoters and enhancers, which regulate expression of key developmental genes. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD. PMID- 23665961 TI - Architecture and evolution of a minute plant genome. AB - It has been argued that the evolution of plant genome size is principally unidirectional and increasing owing to the varied action of whole-genome duplications (WGDs) and mobile element proliferation. However, extreme genome size reductions have been reported in the angiosperm family tree. Here we report the sequence of the 82-megabase genome of the carnivorous bladderwort plant Utricularia gibba. Despite its tiny size, the U. gibba genome accommodates a typical number of genes for a plant, with the main difference from other plant genomes arising from a drastic reduction in non-genic DNA. Unexpectedly, we identified at least three rounds of WGD in U. gibba since common ancestry with tomato (Solanum) and grape (Vitis). The compressed architecture of the U. gibba genome indicates that a small fraction of intergenic DNA, with few or no active retrotransposons, is sufficient to regulate and integrate all the processes required for the development and reproduction of a complex organism. PMID- 23665962 TI - Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells. AB - Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells through large, heterogeneous vesicles known as macropinosomes. Oncogenic Ras proteins have been shown to stimulate macropinocytosis but the functional contribution of this uptake mechanism to the transformed phenotype remains unknown. Here we show that Ras transformed cells use macropinocytosis to transport extracellular protein into the cell. The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism. Accordingly, the dependence of Ras-transformed cells on free extracellular glutamine for growth can be suppressed by the macropinocytic uptake of protein. Consistent with macropinocytosis representing an important route of nutrient uptake in tumours, its pharmacological inhibition compromises the growth of Ras transformed pancreatic tumour xenografts. These results identify macropinocytosis as a mechanism by which cancer cells support their unique metabolic needs and point to the possible exploitation of this process in the design of anticancer therapies. PMID- 23665963 TI - Multidimensional prognostic risk assessment identifies association between IL12B variation and surgery in Crohn's disease. AB - BACKGROUND: The ability to identify patients with Crohn's disease (CD) at highest risk of surgery would be invaluable in guiding therapy. Genome-wide association studies have identified multiple IBD loci with unknown phenotypic consequences. The aims of this study were to: (1) identify associations between known and novel CD loci with early resective CD surgery and (2) develop the best predictive model for time to surgery using a combination of phenotypic, serologic, and genetic variables. METHODS: Genotyping was performed on 1,115 subjects using Illumina based genome-wide technology. Univariate and multivariate analyses tested genetic associations with need for surgery within 5 years. Analyses were performed by testing known CD loci (n = 71) and by performing a genome-wide association study. Time to surgery was analyzed using Cox regression modeling. Clinical and serologic variables were included along with genotype to build predictive models for time to surgery. RESULTS: Surgery occurred within 5 years in 239 subjects at a median time of 12 months. Three CD susceptibility loci were independently associated with surgery within 5 years (IL12B, IL23R, and C11orf30). Genome-wide association identified novel putative loci associated with early surgery: 7q21 (CACNA2D1) and 9q34 (RXRA, COL5A1). The most predictive models of time to surgery included genetic and clinical risk factors. More than a 20% difference in frequency of progression to surgery was seen between the lowest and highest risk groups. CONCLUSIONS: Progression to surgery is faster in patients with CD with both genetic and clinical risk factors. IL12B is independently associated with need and time to early surgery in CD patients and justifies the investigation of novel and existing therapies that affect this pathway. PMID- 23665964 TI - Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients. AB - BACKGROUND: To evaluate the safety of thiopurines in patients with inflammatory bowel disease. To identify predictive factors associated with the development of thiopurine-induced adverse events. METHODS: Long-term incidence of adverse events was estimated in patients from a prospectively maintained Spanish nationwide database using Kaplan-Meier analysis. Cox regression analysis was performed to identify potential predictive factors of adverse events. RESULTS: Three thousand nine hundred and thirty-one patients were included. Ninety-five percent of patients were on azathioprine. The median follow-up with thiopurines was 44 months (range, 0-420). Adverse events occurred at a median of 1 month after starting treatment. The cumulative incidence of adverse events was 26%, with an annual risk of 7% per patient-year of treatment. Most frequent adverse events were nausea (8%), hepatotoxicity (4%), myelotoxicity (4%), and pancreatitis (4%). Four patients had lymphoma. Female and Crohn's disease increased the risk of having nausea. The risk of hepatotoxicity was lower in females and higher in Crohn's disease. The risk of myelotoxicity was significantly higher in patients treated with mercaptopurine and in females. The risk of pancreatitis was higher in Crohn's disease. Overall, 17% of patients discontinued thiopurine treatment due to adverse events. Thirty-seven percent of these patients started thiopurines again and 40% of them had adverse events again. CONCLUSIONS: As many as 1 of 4 patients on thiopurine therapy had adverse events during follow-up. A relatively high proportion of patients (17%) had to discontinue the treatment with thiopurines due to adverse events. However, more than half of patients that restarted thiopurine treatment after its discontinuation due to adverse events tolerated it. Several predictive factors for some adverse events have been identified. PMID- 23665965 TI - 52-week efficacy of adalimumab in patients with moderately to severely active ulcerative colitis who failed corticosteroids and/or immunosuppressants. AB - BACKGROUND: The results of an open-label follow-up until week 52 of patients with moderately to severely active ulcerative colitis who participated in a double blind placebo-controlled adalimumab induction trial (ULTRA 1, NCT00385736) are reported. METHODS: The study included adult anti-tumor necrosis factor-naive patients who completed double-blind adalimumab induction under an amended protocol (intent-to-treat [ITT]-A3 population) or any version of the protocol (ITT-E). Patients randomized to placebo received adalimumab beginning at week 8; patients randomized to adalimumab continued every other week dosing. Weekly dosing was allowed beginning at week 14 (original protocol) or week 12 (amended protocol). Clinical remission (Mayo score <=2, no subscore >1), clinical response (decrease in Mayo score >=3 points and >=30% from baseline, plus decrease in rectal bleeding subscore >=1 or absolute rectal bleeding subscore <=1), mucosal healing (endoscopy subscore <=1), escalation to weekly dosing, and reduction in corticosteroid use were assessed at week 52 in the pooled ITT-A3 and pooled ITT-E populations, using modified nonresponder imputation. RESULTS: Rates of clinical remission, clinical response, and mucosal healing at week 52 for the ITT-A3 population (N = 390) were 29.5%, 53.6%, and 46.7%, respectively; 38.8% of week 8 responders achieved clinical remission at week 52. Of patients using baseline corticosteroids (N = 234), 56.0% were corticosteroid-free at week 52 (26.1% in clinical remission). Results of the ITT-E population were similar. No new safety issues were identified. CONCLUSIONS: In this open-label study, adalimumab was effective for maintaining clinical remission in anti-tumor necrosis factor-naive patients with moderately to severely active ulcerative colitis who did not adequately respond to conventional therapy. PMID- 23665966 TI - Effect of ursodeoxycholic acid use on the risk of colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory bowel disease: a systematic review and meta-analysis. AB - BACKGROUND: Ursodeoxycholic acid (UDCA) may modify the risk of inflammatory bowel disease (IBD)-associated colorectal cancer. We performed a systematic review and meta-analysis of studies evaluating the effect of UDCA on the risk of IBD associated colorectal neoplasia (CRN) (defined as colorectal cancer and/or dysplasia) in patients with primary sclerosing cholangitis with concomitant IBD (PSC-IBD). METHODS: We conducted a systematic search of Medline, Embase, and Web of Science and manually reviewed the literature. Studies were included if they: (1) evaluated exposure to UDCA in patients with PSC-IBD, (2) reported IBD associated CRN as outcome, and (3) reported relative risks or odds ratios (ORs) or provided data for their calculation. Summary OR estimates with 95% confidence intervals (CIs) were calculated using the random-effects model. RESULTS: Eight studies (5 observational, 3 randomized controlled trials) reporting 177 cases of CRN in 763 patients with PSC-IBD were included in the analysis. Overall, meta analysis showed no significant protective association between UDCA use and CRN (OR, 0.81; 95% CI, 0.41-1.61). However, there was a significant chemopreventive effect on the risk of advanced CRN (colorectal cancer and/or high-grade dysplasia) (OR, 0.35; 95% CI, 0.17-0.73). In a subgroup analysis, low-dose UDCA use (8-15 mg/kg/d) was associated with significant risk reduction of CRN (OR, 0.19; 95% CI, 0.08-0.49). CONCLUSIONS: UDCA, particularly at low doses, may reduce the risk of advanced CRN in patients with PSC-IBD. However, results should be interpreted with caution, given limited reporting of cancer-related outcomes, primarily from tertiary care centers. PMID- 23665967 TI - The increasing prevalence of inflammatory bowel diseases among Jewish adolescents and the sociodemographic factors associated with diagnosis. AB - BACKGROUND: We investigated the prevalence and sociodemographic factors associated with diagnosis of inflammatory bowel diseases (IBD) among Jewish Israeli adolescents. METHODS: A total of 953,684 Jewish Israeli adolescents (57.8% men) who underwent a general health examination at mean age 17.3 +/- 0.5 years from 1998 to 2010 were included. A definite diagnosis of IBD was based on laboratory, endoscopy, and pathology reports. Covariate data included socioeconomic status (SES) as defined by the Israel Central Bureau Statistics, and origin and number of children in household. RESULTS: A total of 2021 patients with IBD were identified (0.21%) in 13 annual cohorts. The prevalence of IBD increased from 149.4 cases per 100,000 to 301.0 cases per 100,000 in the first and last cohort (Ptrend = 0.003). Independent factors associated with occurrence of IBD were SES (high: odds ratio [OR] = 1.84, 95% confidence interval [CI]: 1.60 2.1, P < 0.001; medium: OR = 1.47, 95% CI: 1.3-1.69, P < 0.001; low: reference), Western origin (OR = 1.71, 95% CI: 1.53-1.90, P < 0.001; Asia Africa: reference), and male gender (OR = 1.21, 95% CI: 1.10-1.33, P < 0.001; female: reference). Four or more children in the household were associated with reduced OR for IBD [N >= 4: OR = 0.70, 95% CI: 0.62-0.72, P < 0.001, N = 1-3: reference]. The OR among adolescents of Western origin-high SES was 2.95 times higher compared with adolescents of Asia-African origin with low SES. CONCLUSIONS: The prevalence of IBD doubled during the 13 years of the study period. Among this large cohort of Jewish adolescents, for each origin, higher SES was associated with increased occurrence of IBD. PMID- 23665968 TI - Cardiorespiratory fitness predicts mortality and hospital length of stay after major elective surgery in older people. AB - OBJECTIVE: This study aimed to define the relationship between cardiorespiratory fitness and age in the context of postsurgery mortality and morbidity in older people. BACKGROUND: Postsurgery mortality and morbidity increase with age. Cardiorespiratory fitness also declines with age, and the independent and linked associations between cardiorespiratory fitness and age on postsurgical mortality and morbidity remain to be determined. METHODS: An unselected consecutive group of 389 adults with a mean age of 66 years (range 26-86 years) underwent cardiorespiratory exercise testing before major hepatobiliary surgery at a single center. Mortality and critical care unit and hospital lengths of stay were collected from patient records. Primary outcomes were in-hospital all-cause mortality after surgery and hospital and critical care lengths of stay. RESULTS: Anaerobic threshold was the most significant independent predictor for postoperative mortality (P = 0.003; beta = -0.657 and odds ratio = 0.52) in 18 of 389 (4.6%) patients who died during their in-hospital stay. Age was not a significant predictor in this model. Older people with normal cardiorespiratory fitness spent the same number of days in the hospital or critical care unit as younger people with similar cardiorespiratory fitness (13 vs 12; P = 0.08 and 1 vs 1; P = 0.103). Patients older than 75 years with low cardiorespiratory fitness spent a median of 11 days longer in hospital (23 vs 12; P < 0.0001) and 2 days longer in critical care (2.9 vs 0.9; P < 0.0001) when compared with patients with adequate cardiorespiratory fitness. CONCLUSIONS: Cardiorespiratory fitness is an independent predictor of mortality and length of hospital stay and provides significantly more accurate prognostic information than age alone. Clinicians should consider both the prognostic value of cardiorespiratory testing and techniques to preserve cardiorespiratory function before elective surgery in older people. PMID- 23665969 TI - The Holy Grail of geriatric surgery. PMID- 23665970 TI - Quality of life after gastrectomy for adenocarcinoma: a prospective cohort study. AB - BACKGROUND: Gastrectomy remains a major operation with potential for significant deterioration in patients' health-related quality of life (QOL). This study assessed differences in QOL among patients after distal (DG), proximal (PG), or total (TG) gastrectomy. METHODS: We prospectively enrolled patients undergoing gastrectomy at our institution between 2002 and 2007. Participants completed the European Organization for Research and Treatment of Cancer cancer (QLQ-C30) and gastric (QLQ-STO22) questionnaires preoperatively and at 5 postoperative intervals up to 18 months. We compared changes from baseline in patients based on extent of resection (proximal, distal, or total) using generalized linear models, adjusting for age, stage of disease, and (neo)adjuvant therapy. We converted QOL raw scores to reflect the proportion of patients with clinically significant deterioration based on the minimal important difference. RESULTS: We included 134 patients: 82 DG, 16 PG, and 36 TG. In the immediate postoperative period, 55% of patients suffered significant impairment in their global QOL. This improved in most patients by 6 months, although 20% to 35% continued to have substantially worse QOL than before surgery. Patients who underwent PG suffered from significantly more clinical reflux [70% vs 35% (DG), 40% (TG)], nausea/vomiting (60% vs 25%, 30%), and global QOL impairment (60% vs 30%, 30%) than patients who underwent DG or TG, whose QOL scores were similar. These differences persisted up to 18 months postoperatively. CONCLUSIONS: Surgeons should discuss expectations of QOL impairment with their patients before gastrectomy and reassure them that most symptoms resolve by 6 months after operation. Patients who undergo PG suffer from worse QOL impairment than patients who undergo DG or TG. PMID- 23665971 TI - MACC1 mRNA levels predict cancer recurrence after resection of colorectal cancer liver metastases. AB - OBJECTIVE: Upon colon cancer metastasis resection in liver, disease outcome is heterogeneous, ranging from indolent to very aggressive, with early recurrence. The aim of this study is to investigate the capability of metastasis associated in colon cancer 1 (MACC1) levels measured in liver metastasis specimens to predict further recurrence of the disease. METHODS: Gene expression and gene dosage of MACC1, hepatocyte growth factor (HGF), and hepatocyte growth factor receptor (MET) were assessed using quantitative realtime polymerase chain reaction on a cohort of 64 liver metastasis samples from patients with complete follow-up of 36 months and detailed clinical annotation. The most relevant mutations associated to prognosis in colorectal cancer, KRAS, and PIK3CA were assessed on the same specimens with Sanger sequencing. RESULTS: Receiver operating characteristic (ROC) analysis revealed that MACC1 mRNA abundance is a good indicator of metastatic recurrence (AUC = 0.65, P < 0.05), whereas no such results were obtained with MET and HGF, nor with gene dosage. Generation of MACC1 based risk classes was capable of successfully separating patients into poor and good prognosis subgroups [hazard ratio (HR) = 5.236, 95% confidence interval (CI) = 1.2068-22.715, P < 0.05]. Also KRAS mutation was significantly associated with higher risk of recurrence (HR = 2.07, 95% CI = 1.048-4.09, P < 0.05). Cox regression multivariate analysis supported the independence of MACC1, but not KRAS, from known prognostic clinical information (Node Size HR = 3.155, 95% CI = 1.4418-6.905, P < 0.001, Preoperative carcinoembryonic antigen HR = 2.359, 95% CI = 1.0203-5.452, P < 0.05, MACC1 HR = 7.2739, 95% CI = 1.6584-31.905, P < 0.01). CONCLUSIONS: MACC1, a new easily detectable biomarker in cancer, is an independent prognostic factor of recurrence after liver resection of colorectal cancer metastasis. PMID- 23665972 TI - The transpelvic vertical rectus abdominis flap: one interdisciplinary approach to reduce postoperative complications after surgery for rectal cancer. PMID- 23665973 TI - "Endometriosis"--the role of radical surgery in a regional pain syndrome. PMID- 23665974 TI - Letter re: "Complete surgery for low rectal endometriosis: long-term results of a 100-case prospective study". PMID- 23665975 TI - Reply to letter: "For patients with early esophageal cancer endoscopic mucosa resection is not the end of the story!". PMID- 23665976 TI - Does duration of perioperative antibiotic prophylaxis matter in cardiac surgery? PMID- 23665977 TI - Reply to letter: "The ALPPS procedure for extended indications in liver surgery: an old finding applied in surgical oncology". PMID- 23665978 TI - Fast benchtop visualization of graphene grain boundaries using adhesive properties of defects. AB - Highly adhesive properties of graphene grain boundaries to permanganate lead to a very quick, easy and convenient method to visualize the grain boundaries simply using an optical microscope, which would be vital to improve specific properties of graphene. PMID- 23665979 TI - Treatment results at 1 year of ranibizumab therapy for polypoidal choroidal vasculopathy in eyes with good visual acuity. AB - PURPOSE: To evaluate the efficacy of intravitreal ranibizumab (IVR) for subfoveal polypoidal choroidal vasculopathy (PCV) in eyes with a best corrected visual acuity (BCVA) of 0.6 (logMAR 0.22) or better. METHODS: Fifty eyes with BCVA between 0.6 (logMAR 0.22) and 1.0 (logMAR 0) and subfoveal PCV were treated with IVR for 3 consecutive months. Additional IVR was given at subsequent monthly visits, if needed, up to 11 months after the initial injection. The patients were followed-up prospectively for 12 months, and changes in mean BCVA, central retinal thickness (CRT), serous retinal detachment (SRD), hemorrhage, and number of polypoidal lesions were evaluated. RESULTS: Mean BCVA improved significantly at the 3-, 6-, 9-, and 12-month follow-up visits and CRT decreased significantly at 1, 2, 3, 6, 9, and 12 months after the initial treatment as compared with the baseline. SRD was observed in 10 and 21 eyes at 3 and 12 months. Hemorrhage was observed in 6 eyes at 3 months and 3 eyes at 12 months. All polypoidal lesions had completely regressed in 19 % and the size of network vessels was either unchanged or enlarged in 98 % of the eyes at 12 months. CONCLUSION: Based on the maintenance of vision improvement for at least 12 months, IVR for PCV proved useful for eyes with BCVAs of 0.6 (logMAR 0.22) to 1.0 (logMAR 0), despite a low regression rate of polypoidal lesions and minimal network size reduction. PMID- 23665980 TI - Children and adolescents with follicular lymphoma have an excellent prognosis with either limited chemotherapy or with a "Watch and wait" strategy after complete resection. AB - Data on clinical features and outcome in pediatric follicular lymphoma (pFL) are scarce. The aim of this retrospective study including 13 EICNHL and/or i-BFM study group members was to assess clinical characteristics and course in a series of 63 pFL patients. pFL was found to be associated with male gender (3:1), older age (72 % >=10 years old), low serum LDH levels (<500 U/l in 75 %), grade 3 histology (in 88 %), and limited disease (87 % stage I/II disease), mostly involving the peripheral lymph nodes. Forty-four out of sixty-three patients received any polychemotherapy and 1/63 rituximab only, while 17/63 underwent a "watch and wait" strategy. Of 36 stage I patients, 30 had complete resections. Only one patient relapsed; 2-year event-free survival and overall survival were 94 +/- 5 and 100 %, respectively, after a median follow-up of 2.2 years. Conclusively, treatment outcome in pFL seems to be excellent with risk-adapted chemotherapy or after complete resection and an observational strategy only. PMID- 23665981 TI - Microstructure-induced helical vortices allow single-stream and long-term inertial focusing. AB - Fluid inertia has been used to position microparticles in confined channels because it leads to precise and predictable particle migration across streamlines in a high-throughput manner. To focus particles, typically two inertial effects have been employed: inertial migration of particles in combination with geometry induced secondary flows. Still, the strong scaling of inertial effects with fluid velocity or channel flow rate have made it challenging to design inertial focusing systems for single-stream focusing using large-scale microchannels. Use of large-scale microchannels (>=100 MUm) reduces clogging over long durations and could be suitable for non-single-use flow cells in cytometry systems. Here, we show that microstructure-induced helical vortices yield single-stream focusing of microparticles with continuous and robust operation. Numerical and experimental results demonstrate how structures contribute to improve focusing in these larger channels, through controllable cross-stream particle migration, aided by locally tuned secondary flows from sequential obstacles that act to bring particles closer to a single focusing equilibrium position. The large-scale inertial focuser developed here can be operated in a high-throughput manner with a maximum throughput of approximately 13,000 particles per s. PMID- 23665982 TI - A quick and robust method for measurement of signal-to-noise ratio in MRI. AB - A novel method is proposed for the measurement of signal-to-noise ratio (SNR) for the purpose of quality assurance (QA) in MRI. A boxcar filtering technique is applied which allows estimation of signal and noise from a single image. The method has been used to estimate SNR in a large set of images acquired in a consistent manner using various scanner models, coils and phantoms. Performance is evaluated by comparison with the double-image subtraction technique incorporating temporal instability correction. The limits of agreement between the techniques are comparable to typical variability in daily SNR, and significantly superior to the performance of other single-image methods published to date. Single-image methods are preferable as they halve the image acquisition time of the recommended double-image approach. Major inaccuracies are identified in methods of SNR measurement currently used for QA in MRI. PMID- 23665983 TI - [Comparison of standard Euroscore, logistic Euroscore and Euroscore II in prediction of early mortality following coronary artery bypass grafting]. AB - OBJECTIVE: EuroSCORE is the most widely used risk prediction system. Standard EuroSCORE, which had been published in 1999, was revised as a Logistic EuroSCORE in 2003. Further, it was reconsidered and published as EuroSCORE II in 2011. In this study we compared Standard, Logistic EuroSCORE and EuroSCORE II in prediction of early mortality following coronary artery bypass grafting. METHODS: We retrospectively analyzed 406 patients who underwent coronary artery bypass grafting operation between 2011-1012. Standard, Logistic and new version were compared with ROC analysis. RESULTS: In general population, mean standard EuroSCORE was 3.25+/-1.05, mean logistic EuroSCORE was found 2.48+/-0.58, mean EuroSCORE II was found 1.30 +/- 0.09 and overall mortality was 10 (10/406 2.46%). Area under curve (AUC) was found 0.992 95% CI: 0.978-0.998 for standard EuroSCORE, 0.992 95% CI: 0.977-0.998 for logistic EuroSCORE and 0.990 95% CI: 0.975-0.997 for EuroSCORE II. In high risk patients (patients with standard EuroSCORE >= 6) AUC was found 0.870 95% CI 0.707-0.961 for standard EuroSCORE, 0.857 95% CI 0.691-0.954 for logistic EuroSCORE, and 0.961 95% CI: 0.829-0.998 for EuroSCORE II. CONCLUSION: Standard, Logistic EuroSCORE and EuroSCORE II are similarly successful in mortality prediction. EuroSCORE II may be better in high risk patients which needs confirmation in large prospective studies. PMID- 23665984 TI - The effect of incremental endurance exercise training on left ventricular mechanics: a prospective observational deformation imaging study. AB - OBJECTIVE: Exercise training has been known to cause structural and functional alterations in the heart called athletes heart. We aimed to investigate the effects of incremental endurance exercise training (IEET) on the left ventricular (LV) mechanics in healthy subjects. METHODS: This prospective observational study included 34 healthy young men who participated in competitive sports. The participants were subjected to a six-month IEET program. The LV mechanics measured using two-dimensional speckle tracking echocardiography was recorded while the participants were in an inactive state before and at the end of the six months. To compare continuous variables before and after IEET, Wilcoxon or paired t test were used. RESULTS: Baseline and post training echocardiographic measurements showed that there was no significant change in LV ejection fraction (%) (p=0.64) and there were an increase in end-systolic and end-diastolic diameters, posterior and septal wall thickness, relative wall thickness and LV mass index (p<0.05, for all). LV mechanical parameters such as global strain (S) (19.8+/-1.33% vs. 20.4+/-1.26%, p=0.001), apical four -chamber S (19.4+/-1.96% vs. 20.1+/-1.86%, p=0.01), apical two- chamber S (19.9+/-1.75% vs. 20.7+/-1.75%, p=0.003), apical (23.0+/-3.1% vs. 23.6+/-3.2%, p=0.03), and basal circumferential S (21.1+/-2.2 % vs. 21.6+/-2.5%, p=0.03), and apical rotation (degree) (7.9+/ 0.95 vs. 8.4+/-0.74, p=0.001) values were significantly increased by IEET. CONCLUSION: We demonstrated that IEET has led to exercise related cardiac structural and functional changes such as LV dilatation and LV hypertrophy, accompanied by a significant increase in LV systolic S and LV twist measurements. PMID- 23665985 TI - The effects of cardiac resynchronization treatment on autonomic functions aside from functional status in heart failure. AB - OBJECTIVE: Cardiac resynchronization therapy (CRT) improves heart rate variability (HRV) and heart rate turbulence (HRT) parameters. Herein, our aim was to compare these parameters with intracardiac-cardioverter defibrillator (ICD) patients with similar functional status to detect possible additional benefits of CRT on autonomic functions. METHODS: Patients who had systolic HF (NYHA class II and III) with an ejection fraction <35% were enrolled in this observational, cross-sectional study. These patients were implanted either an ICD or a CRT device. A 24-hour Holter recording was obtained to assess HRV and HRT parameters in 2 groups. Unpaired t-test and Chi-square test were used for comparisons between 2 groups. Logistic regression analysis was performed to determine the variables affecting functional status. RESULTS: Of 105 patients included in the study; 55 had CRT and 50 had ICD device. The baseline characteristics of the patients were similar in both groups. SDNN, SDANN, SDNN index, and LFnu were similar in both groups; however, RMSSD, pNN50, HFnu, LF/HF ratio, turbulence slope and albeit to a non-significant value turbulence onset were better in CRT group. When the HRV and HRT parameters were compared according to functional status, patients in functional class II had significantly better HRV and HRT parameters when compared to the ones in class III (p<0.05 for all). Regression analysis showed that only SDNN was associated with functional class [OR: 0.89 (95% CI: 0.80-0.98), p=0.03]. After the covariance analysis to eliminate the effects of functional status on HRV and HRT parameters; the parameters mostly related with the parasympathetic system activity, namely RMSSD, pNN50, HFnu, LF/HF ratio, turbulence onset and turbulence slope were still better in CRT group. CONCLUSION: The most striking finding in our study is that HRV and HRT values related with parasympathetic activation are better in CRT patients when compared to ICD patients with similar functional status. Therefore, upgrading to CRT may have additional benefits on autonomic functions, which needs further investigation. PMID- 23665986 TI - Effect of lifestyle modifications on diastolic functions and aortic stiffness in prehypertensive subjects: a prospective cohort study. AB - OBJECTIVE: Prehypertension is one of the primary causes of major cardiovascular events independent from other cardiovascular risk factors. The aim of the study was to evaluate the effect of therapeutic lifestyle modifications (LSMs) on cardiac diastolic function and aortic stiffness in prehypertensive subjects. METHODS: This study designed as a prospective cohort study. Sixty-one prehypertensive adults were included in this study. The goals of LMS were weight loss of at least 5 kg in subjects with a BMI >=25 kg/m2 and moderate-intensity physical activity at least 180 minutes per week. We evaluated left ventricular (LV) diastolic function and aortic stiffness parameters at baseline and after 6 months by conventional and tissue Doppler imaging (TDI) echocardiography. Statistical analyses were performed using Wilcoxon-signed rank test and the paired sample t test. RESULTS: Transmitral early velocity (E), the ratio of E to transmitral late velocity (E/A), TDI diastolic early septal velocity (septal E), TDI systolic septal velocity (septal S), TDI early lateral velocity (lateral E), the ratio of septal E to TDI late septal (septal A) velocity (septal E/A) and the ratio of lateral E to late lateral (lateral A) velocity (lateral E/A) were found to be significantly increased after the LSMs (p<0.05 for all). The beta stiffness index was decreased (12.07 vs. 6.33; p<0.001) and the aortic compliance (0.02 cm/mmHg vs. 0.05 cm/mmHg; p<0.001) and the aortic strain (3.28% vs. 7.02%; p<0.001) were increased significantly after the LSMs. CONCLUSION: LSMs improve conventional and TDI echocardiographic parameters and aortic stiffness measurements in subjects with prehypertension. PMID- 23665987 TI - Can single cIMT measurement during echocardiography affect further investigation decision for coronary artery disease? AB - OBJECTIVE: This study was aimed to evaluate whether there is any potential role of the measurement of the carotid intima-media thickness (cIMT) in patients with suspected coronary artery disease (CAD) during the echocardiography session on decision-making to refer patients for further diagnostic evaluation such as gated myocardial perfusion imaging (gMPI). METHODS: cIMT of 199 consecutive patients was measured during the echocardiography session and all patients underwent gMPI. According to gMPI results, patients were divided into two groups as CAD and normal groups and according to cIMT measurements patients were divided into four subgroups. RESULTS: Although, there was a good correlation between the age and cIMT values of the patients (r=0.546, p<0.001), the correlation between the summed stress scores and the age of the patients was very weak (r=0.142, p=0.045) and the correlation between the summed stress scores and the cIMT values was very weak (r=0.107, p=0.131). The cIMT measurements of the CAD group (0.74+/-0.17 mm) were significantly higher than those of the normal group (0.67+/-0.16 mm) (p=0.012), but after the age correction, the significance between the cIMT measurements of the CAD and the normal groups was not found (p=0.131). Besides, the relationship between the categorical cIMT values of both the CAD and the normal groups was insignificant (p=0.059) and the correlation between the increasing cIMT values and the presence of detectable CAD was also very weak (r=0.187, p=0.08). CONCLUSION: cIMT can predict occurrence of cardiovascular events in subjects, but single cIMT measurement during echocardiographic examination does not seem to have potential role on decision making for further investigation in patients with suspected CAD. PMID- 23665988 TI - Validity of the Turkish version of the European Heart Failure Self-Care Behavior Scale. AB - OBJECTIVE: The specific purpose of this study was to investigate the validity of the Turkish version of the European Heart Failure Self-care Behavior Scale by applying to 494 Turkish Heart Failure Patients. METHODS: The study was conducted as a cross-sectional sample survey, between October 2012 and January 2013. The 494 patients who applied with a diagnosis of heart failure were included in the study after determining the clinical diagnosis and type of treatment. Cronbach's alpha coefficient was used to evaluate the validity and reliability of the scale. Exploratory and confirmatory factor analyses were applied for the determination of the sub-factors of the scale in Turkish adaptation; content, item and factor adaption. Structural Equation Modeling was used for the purpose of creation and supervision of the structural models of the scale. RESULTS: Cronbach's alpha coefficient of internal consistency of Turkish version of the Scale was found to be 0.69. According to the results of the factor analysis, it was determined that the data is in a form suitable for factor analysis and the data have the assumption of multivariate normal distribution. The goodness of fit measures used for the validity of Structural Equation Modeling were obtained to be RMSEA=0.047 (CI=0.00-0.079), AGFI=0.83, GFI=0.91 respectively. CONCLUSION: The scale is divided into 4 sub-factors according to the Structural Equation Modeling. The European Heart Failure Self-care Behavior Scale is a scale that easily applied to measure the behavior of self-care in heart failure patients. In addition, the scale reaches the conclusion as soon as possible and does not require additional training for researchers. Further, patients can apply themselves the scale easily. PMID- 23665989 TI - The paradox of NKp46+ natural killer cells: drivers of severe hepatitis C virus induced pathology but in-vivo resistance to interferon alpha treatment. AB - OBJECTIVE: There is evidence that natural killer (NK) cells help control persistent viral infections including hepatitis C virus (HCV). The phenotype and function of blood and intrahepatic NK cells, in steady state and after interferon (IFN) alpha treatment has not been fully elucidated. DESIGN: We performed a comparison of NK cells derived from blood and intrahepatic compartments in multiple paired samples from patients with a variety of chronic liver diseases. Furthermore, we obtained serial paired samples from an average of five time points in HCV patients treated with IFNalpha. RESULTS: Liver NK cells demonstrate a distinct activated phenotype compared to blood manifested as downregulation of the NK cell activation receptors CD16, NKG2D, and NKp30; with increased spontaneous degranulation and IFN production. In contrast, NKp46 expression was not downregulated. Indeed, NKp46-rich NK populations were the most activated, correlating closely with the severity of liver inflammation. Following initiation of IFNalpha treatment there was a significant increase in the proportion of intrahepatic NK cells at days 1 and 3. NKp46-rich NK populations demonstrated no reserve activation capacity with IFNalpha treatment and were associated with poor viral control on treatment and treatment failure. CONCLUSIONS: NKp46 marks out pathologically activated NK cells, which may result from a loss of homeostatic control of activating receptor expression in HCV. Paradoxically these pathological NK cells do not appear to be involved in viral control in IFNalpha treated individuals and, indeed, predict slower rates of viral clearance. PMID- 23665991 TI - A cross-sectional study of the association between working hours and sleep duration among the Japanese working population. AB - OBJECTIVES: This study aimed to clarify the association between long working hours and short sleep duration among Japanese workers. METHODS: We selected 4,000 households from across Japan by stratified random sampling and conducted an interview survey of a total of 662 participants (372 men; 290 women) in November 2009. Logistic regression analyses were performed using "sleep duration <6 hours per day" as a dependent variable to examine the association between working hours/overtime hours and short sleep duration. RESULTS: When male participants who worked for >=7 but <9 hours per day were used as a reference, the odds ratio (OR) for short sleep duration in those who worked for >= 11 hours was 8.62 (95% confidence interval [CI]: 3.94-18.86). With regard to overtime hours among men, when participants without overtime were used as a reference, the OR for those whose period of overtime was >= 3 hours but <4 hours was 3.59 (95% CI: 1.42 9.08). For both men and women, those with long weekday working hours tended to have a short sleep duration during weekdays and holidays. CONCLUSIONS: It is essential to avoid working long hours in order to prevent short sleep duration. PMID- 23665990 TI - Randomised clinical trial comparing sequential and concomitant therapies for Helicobacter pylori eradication in routine clinical practice. AB - OBJECTIVES: No trial has compared non-bismuth quadruple 'sequential' and 'concomitant' regimens in settings with increasing clarithromycin rates. The study aims to compare the effectiveness and safety of these therapies for Helicobacter pylori treatment. DESIGN: Prospective randomised clinical trial in 11 Spanish hospitals. Patients naive to eradication therapy with non investigated/functional dyspepsia or peptic ulcer disease were included. Randomised (1:1) to sequential (omeprazole (20 mg/12 h) and amoxicillin (1 g/12 h) for 5 days, followed by 5 days of omeprazole (20 mg/12 h), clarithromycin (500 mg/12 h) and metronidazole (500 mg/12 h)), or concomitant treatment (same drugs taken concomitantly for 10 days). Eradication was confirmed with (13)C-urea breath test or histology 4 weeks after treatment. Adverse events (AEs) and compliance were evaluated with questionnaires and residual medication count. RESULTS: 338 consecutive patients were randomised. Mean age was 47 years, 60% were women, 22% smokers and 20% had peptic ulcer. Concomitant and sequential eradication rates were, respectively, 87% vs 81% by intention-to-treat (p=0.15) and 91% vs 86% (p=0.131) per protocol. Respective compliances were 83% vs 82%. Treatment-emergent AEs were reported in 59% of patients (no differences found between treatments). AEs were mostly mild (60%), and average length was 6.1 days, causing discontinuation only in 12 patients. Multivariate analysis: 'concomitant' treatment showed an OR of 1.5 towards better eradication rate in a borderline significance CI (95% CI 0.9 to 2.8). CONCLUSIONS: Concomitant therapy led to a non-statistically significant advantage (5%) over sequential therapy, coming closer to 90% cure rates. Both therapies showed an acceptable safety profile. ClincialTrials.gov: NCT01273441. PMID- 23665992 TI - Effects of implementing an ergonomic work schedule on heart rate variability in shift-working nurses. AB - OBJECTIVES: The aim of this study was to compare the psychophysiological strain related to a conventional shift schedule and new ergonomically improved two- and three-shift schedules using heart rate variability (HRV) analysis. The specific aim was to determine whether the introduced ergonomic shift arrangement had any positive effects on the psychophysiological strain such as increased HRV or decrease in the sympathovagal balance of the autonomic nervous system (ANS). METHODS: Questionnaire data and 24-hour HRV recordings were gathered from 48 female shift-working nurses once while working the conventional shift schedule (baseline) and again after one year working an ergonomic shift schedule during the morning shift. RESULTS: Comparisons between conventional and ergonomic shift schedules (baseline and follow-up, respectively) revealed significant differences in frequency-domain parameters. Implementing an ergonomic shift schedule resulted in decreased normalized low frequency (LF) power, increased normalized high frequency (HF) power, and decreased LF/HF ratio at the beginning of the shift. Furthermore, at baseline, mean RR interval, root mean square of successive RR interval differences (RMSSD) and normalized HF power were increased at the end of the shift compared with the values at the beginning of the morning shift. In contrast, at the follow-up, LF power was increased between the end and beginning of the morning shift. CONCLUSIONS: The psychophysiological strain measured by HRV analysis was lower at the beginning of the work shift for the ergonomic shift schedules compared with the conventional schedule. This indicates that an ergonomic shift schedule may have a positive effect on the ANS recovery occurring between successive work shifts. PMID- 23665993 TI - Regulation of bcl-2 transcription by estrogen receptor-alpha and c-Jun in human endometrium. AB - The estrogen-estrogen receptor (ER) signaling pathway plays crucial physiologic roles in not only the control of reproduction, but also in the generation of cancer in the breast and uterus. While some ER target genes have been identified containing the estrogen-responsive element (ERE), others are activated eventually by ER via protein-protein interaction without binding to ERE. In a previous study, we identified that the proliferative phase-specific expression of the bcl 2 gene in glandular cells could be regulated by the binding of c-Jun to its motifs in the promoter. Results from our present study indicate that the menstrual cyclic expression of bcl-2 could be controlled by either direct binding of ERalpha to ERE in the c-Jun promoter or the interaction of ERalpha with c-Jun that binds to its motifs in the bcl-2 gene. Intriguingly, the transcriptionally active form of c-Jun phosphorylated at Ser63 was identified binding to its motifs in the bcl-2 gene in a menstrual cyclic non-specific manner. Our study revealed a novel mechanism that transcriptionally regulates the expression of bcl-2 in the normal human endometrium. PMID- 23665995 TI - One-pot, sequential four-component synthesis of benzo[c]pyrano[3,2-a]phenazine, bis-benzo[c]pyrano[3,2-a]phenazine and oxospiro benzo[c]pyrano[3,2-a]phenazine derivatives using 1,4-diazabicyclo[2.2.2]octane (DABCO) as an efficient and reusable solid base catalyst. AB - 1,4-Diazabicyclo[2.2.2]octane (DABCO) has been used as an efficient and reusable solid base catalyst for the one-pot, two-step, four-component synthesis of pyrano[3,2-a]phenazine derivatives by the condensation reaction of 2-hydroxy-1,4 naphthoquinone, 1,2-diamines, carbonyl compounds and alkylmalonates under conventional heating as well as microwave irradiation. This procedure has also been applied successfully for the synthesis of novel bis- benzo[c]pyrano[3,2 a]phenazine and oxospiro benzo[c]pyrano[3,2-a]phenazine derivatives. Using this procedure, all the products were obtained in good to excellent yields. The catalyst has been recovered and reused several times without any loss of reactivity. PMID- 23665994 TI - Retrograde trafficking of AB5 toxins: mechanisms to therapeutics. AB - Bacterial AB5 toxins are a clinically relevant class of exotoxins that include several well-known members such as Shiga, cholera, and pertussis toxins. Infections with toxin-producing bacteria cause devastating human diseases that affect millions of individuals each year and have no definitive medical treatment. The molecular targets of AB5 toxins reside in the cytosol of infected cells, and the toxins reach the cytosol by trafficking through the retrograde membrane transport pathway that avoids degradative late endosomes and lysosomes. Focusing on Shiga toxin as the archetype member, we review recent advances in understanding the molecular mechanisms involved in the retrograde trafficking of AB5 toxins and highlight how these basic science advances are leading to the development of a promising new therapeutic approach based on inhibiting toxin transport. PMID- 23665996 TI - Climate change matters. AB - One manifestation of climate change is the increasingly severe extreme weather that causes injury, illness and death through heat stress, air pollution, infectious disease and other means. Leading health organisations around the world are responding to the related water and food shortages and volatility of energy and agriculture prices that threaten health and health economics. Environmental and climate ethics highlight the associated challenges to human rights and distributive justice but rarely address health or encompass bioethical methods or analyses. Public health ethics and its broader umbrella, bioethics, remain relatively silent on climate change. Meanwhile global population growth creates more people who aspire to Western lifestyles and unrestrained socioeconomic growth. Fulfilling these aspirations generates more emissions; worsens climate change; and undermines virtues and values that engender appreciation of, and protections for, natural resources. Greater understanding of how virtues and values are evolving in different contexts, and the associated consequences, might nudge the individual and collective priorities that inform public policy toward embracing stewardship and responsibility for environmental resources necessary to health. Instead of neglecting climate change and related policy, public health ethics and bioethics should explore these issues; bring transparency to the tradeoffs that permit emissions to continue at current rates; and offer deeper understanding about what is at stake and what it means to live a good life in today's world. PMID- 23665997 TI - Systematic review and metasummary of attitudes toward research in emergency medical conditions. AB - Emergency departments are challenging research settings, where truly informed consent can be difficult to obtain. A deeper understanding of emergency medical patients' opinions about research is needed. We conducted a systematic review and meta-summary of quantitative and qualitative studies on which values, attitudes, or beliefs of emergent medical research participants influence research participation. We included studies of adults that investigated opinions toward emergency medicine research participation. We excluded studies focused on the association between demographics or consent document features and participation and those focused on non-emergency research. In August 2011, we searched the following databases: MEDLINE, EMBASE, Google Scholar, Scirus, PsycINFO, AgeLine and Global Health. Titles, abstracts and then full manuscripts were independently evaluated by two reviewers. Disagreements were resolved by consensus and adjudicated by a third author. Studies were evaluated for bias using standardised scores. We report themes associated with participation or refusal. Our initial search produced over 1800 articles. A total of 44 articles were extracted for full-manuscript analysis, and 14 were retained based on our eligibility criteria. Among factors favouring participation, altruism and personal health benefit had the highest frequency. Mistrust of researchers, feeling like a 'guinea pig' and risk were leading factors favouring refusal. Many studies noted limitations of informed consent processes in emergent conditions. We conclude that highlighting the benefits to the participant and society, mitigating risk and increasing public trust may increase research participation in emergency medical research. New methods for conducting informed consent in such studies are needed. PMID- 23665998 TI - The kindest cut? Surgical castration, sex offenders and coercive offers. AB - The European Committee for the Prevention of Torture and Inhuman or Degrading Treatment or Punishment (CPT) have conducted visits and written reports criticising the surgical castration of sex offenders in the Czech Republic and Germany. They claim that surgical castration is degrading treatment and have called for an immediate end to this practice. The Czech and German governments have published rebuttals of these criticisms. The rebuttals cite evidence about clinical effectiveness and point out this is an intervention that must be requested by the sex offender and cannot occur without informed consent. This article considers a number of relevant arguments that are not discussed in these reports but which are central to how we might assess this practice. First, the article discusses the possible ways in which sex offenders could be coerced into castration and whether this is a decisive moral problem. Then, it considers a number of issues relevant to determining whether sex offenders are harmed by physical castration. The article concludes by arguing that sex offenders should not be coerced into castration, be that via threats or offers, but that there is no reason to think that this is occurring in the Czech Republic or Germany. In some cases, castration might be useful for reconfiguring a life that has gone badly awry and where there is no coercion, the European Committee for the Prevention of Torture and Inhuman or Degrading Treatment or Punishment are mistaken about this being degrading treatment. PMID- 23665999 TI - Spinal cord stimulation modulates cerebral neurobiology: a proton magnetic resonance spectroscopy study. AB - INTRODUCTION: Although spinal cord stimulation (SCS) is a widely used treatment for chronic neuropathic pain secondary to spinal surgery, little is known about the underlying physiological mechanisms. METHODS: The primary aim of this study is to investigate the neural substrate underlying short-term SCS by means of (1)H MR spectroscopy with short echo time, in 20 patients with failed back surgery syndrome. RESULTS: Marked increase of gamma-aminobutyric acid (GABA) and decrease in glucose in the ipsilateral thalamus were found between baseline situation without SCS and after 9' of SCS, indicating the key role of the ipsilateral thalamus as a mediator of chronic neuropathic pain. In addition, this study also showed a progressive decrease in glucose in the ipsilateral thalamus over time, which is in line with the findings of previous studies reporting deactivation in the ipsilateral thalamic region. CONCLUSIONS: The observation of GABA increase and glucose decrease over time in the ipsilateral thalamus may be the causal mechanism of the pain relief due to SCS or an epiphenomenon. PMID- 23666001 TI - Characterization of phenolic constituents from ephedra herb extract. AB - Nine known compounds: trans-cinnamic acid, catechin, syringin, epicatechin, symplocoside, kaempferol 3-O-rhamnoside 7-O-glucoside, isovitexin 2-O-rhamnoside, herbacetin 7-O-glucoside, and pollenitin B and a new flavonoid glycoside, characterized as herbacetin 7-O-neohesperidoside (1) on the basis of spectroscopic analysis and chemical evidence, were isolated from a traditional crude drug, "Ephedra herb extract". Compound 1 had no effects on HGF-induced motility, whereas herbacetin, which is an aglycone of 1, significantly inhibited it. PMID- 23666000 TI - Population genetics of Lymnaea stagnalis experimentally exposed to cocktails of pesticides. AB - Freshwater invertebrates may be regularly exposed to pesticides in agricultural landscapes, as water bodies such as ditches and ponds are the final recipient of many chemicals, through various transfer pathways. Local evolutionary impacts may hence be expected on populations, especially for species with a completely aquatic life cycle. We tested the hypothesis that exposure to combinations of pesticides used in crop protection programmes could increase the effect of random genetic drift in a non-target species, via demographic impacts. To do so, experimental populations of the freshwater snail Lymnaea stagnalis were created from a common genetic pool and exposed for three successive generations to treatments corresponding to two different crop protection plans (conventional and low pesticide input). Population genetic parameters were estimated in each generation on the basis of ten polymorphic microsatellite loci. Effects consistent with increased random genetic drift were observed for one sampling campaign performed in the third generation, i.e., decreased genetic variability and increased population differentiation in the group of populations exposed to the treatment programme whose demographic impact was the most effective on L. stagnalis. Otherwise, no clear pattern emerged and even opposed effects could be observed. All populations were found significantly inbred, mostly due to biparental inbreeding. Conversely, selfing was generally not significant, and did not express preferentially under high pesticide pressure. We conclude from this study that population genetics should be used very cautiously in the context of ecological risk assessment, especially when applied to natural populations. PMID- 23666002 TI - Chelator-accelerated one-pot 'click' labeling of small molecule tracers with 2 [18F]fluoroethyl azide. AB - 2-[18F]Fluoroethyl azide ([18F]FEA) can readily be obtained by nucleophilic substitution of 2-azidoethyl-4-toluenesulfonate with [18F]fluoride (half-life 110 min), and has become widely used as a reagent for 'click' labeling of PET tracers. However, distillation of [18F]FEA is typically required, which is time consuming and unpractical for routine applications. In addition, copper(I) catalyzed cycloaddition of [18F]FEA with non-activated alkynes, and with substrates containing labile functional groups, can be challenging. Herein, we report a highly efficient and practical ligand-accelerated one-pot/two-step method for 'click' labeling of small molecule tracers with [18F]FEA. The method exploits the ability of the copper(I) ligand bathophenanthrolinedisulfonate to accelerate the rate of the cycloaddition reaction. As a result, alkynes can be added directly to the crude reaction mixture containing [18F]FEA, and as cyclisation occurs almost immediately at room temperature, the reaction is tolerant to labile functional groups. The method was demonstrated by reacting [18F]FEA with a series of alkyne-functionalized 6-halopurines to give the corresponding triazoles in 55-76% analytical radiochemical yield. PMID- 23666003 TI - Diterpenylhydroquinones from natural ent-labdanes induce apoptosis through decreased mitochondrial membrane potential. AB - In this study, we examined the cytotoxic effects of seven ent-labdane derivatives 1-7 (0-100 MUM) in different human cancer cell lines. Our results showed that compounds 1-3 exhibited significant dose-dependent inhibition on the growth of the three different human cell lines, according to the sulphorhodamine B assay and produced morphological changes consistent with apoptosis, as confirmed by Hoestch 3342 staining analysis. They induced apoptosis in various cancer cell lines, as shown by nuclear condensation and fragmentation and caspase 3 activation. Such induction was associated with the depletion of mitochondrial membrane potential. These activities led to the cleavage of caspases and the trigger of cell death process. Overall, the compounds showed potent proapoptotic effects on the two different cancer cell lines, suggesting that the compounds deserve more extensive investigation of their potential medicinal applications. PMID- 23666004 TI - Oxidative debromination and degradation of tetrabromo-bisphenol A by a functionalized silica-supported iron(III)-tetrakis(p-sulfonatophenyl)porphyrin catalyst. AB - Tetrabromobisphenol A (TBBPA), a commonly used brominated flame retardant, also functions as an endocrine disruptor. Thus, the degradation of TBBPA has attracted considerable interest among the scientific community. Iron(III)-porphyrin complexes are generally regarded as "green" catalysts and have been reported to catalyze the efficient degradation and dehalogenation of halogenated phenols in environmental wastewaters. However, they are quickly deactivated due to self degradation in the presence of an oxygen donor, such as KHSO5. In the present study, an iron(III)-tetrakis (p-sulfonatophenyl)-porphyrin (FeTPPS) was immobilized on imidazole-modified silica (FeTPPS/IPS) via coordination of the Fe(III) with the nitrogen atom in imidazole to suppress self-degradation and thus enhance the catalyst reusability. The oxidative degradation and debromination of TBBPA and the influence of humic acid (HA), a major component in leachates, on the oxidation of TBBPA was investigated. More than 95% of the TBBPA was degraded in the pH range from 3 to 8 in the absence of HA, while the optimal pH for the reaction was at pH 8 in the presence of HA. Although the rate of degradation was decreased in the presence of HA, over 95% of the TBBPA was degraded within 12 h in the presence of 28 mg-C L-1 of HA. At pH 8, the FeTPPS/IPS catalyst could be reused up to 10 times without any detectable loss of activity for TBBPA for degradation and debromination, even in the presence of HA. PMID- 23666005 TI - From selenium- to tellurium-based glass optical fibers for infrared spectroscopies. AB - Chalcogenide glasses are based on sulfur, selenium and tellurium elements, and have been studied for several decades regarding different applications. Among them, selenide glasses exhibit excellent infrared transmission in the 1 to 15 um region. Due to their good thermo-mechanical properties, these glasses could be easily shaped into optical devices such as lenses and optical fibers. During the past decade of research, selenide glass fibers have been proved to be suitable for infrared sensing in an original spectroscopic method named Fiber Evanescent Wave Spectroscopy (FEWS). FEWS has provided very nice and promising results, for example for medical diagnosis. Then, some sophisticated fibers, also based on selenide glasses, were developed: rare-earth doped fibers and microstructured fibers. In parallel, the study of telluride glasses, which can have transmission up to 28 um due to its atom heaviness, has been intensified thanks to the DARWIN mission led by the European Space Agency (ESA). The development of telluride glass fiber enables a successful observation of CO2 absorption band located around 15 um. In this paper we review recent results obtained in the Glass and Ceramics Laboratory at Rennes on the development of selenide to telluride glass optical fibers, and their use for spectroscopy from the mid to the far infrared ranges. PMID- 23666006 TI - Curcumin and its carbocyclic analogs: structure-activity in relation to antioxidant and selected biological properties. AB - Curcumin is the major phenolic compound present in turmeric (Curcuma longa L.). Curcumin and 15 novel analogs were investigated for their antioxidant and selected biological activities. Strong relationships between the structure and evaluated activity revealed that the compounds with specific functional groups and carbon skeleton had specific biological profiles. Among the compounds tested, the derivatives (E)-2-(3,4-dimethoxybenzylidene)-5-((E)-3-(3,4 dimethoxyphenyl)acryloyl)cyclopentanone (3e), and (E)-2-(4-hydroxy-3 methoxybenzylidene)-5-((E)-3-(4-hydroxy-3-methoxyphenyl)acryloyl)-cyclopentanone (3d) and the parent compound curcumin exhibited the strongest free radical scavenging and antioxidant capacity. Concerning the other biological activities studied the compound (E)-2-(4-hydroxy-3-methoxybenzylidene)-5-((E)-3-(4-hydroxy-3 methoxy-phenyl)-acryloyl)cyclopentanone (3d) was the most potent angiotensin converting enzyme (ACE) inhibitor, while the derivatives (E)-2-(4 hydroxybenzylidene)-6-((E)-3-(4-hydroxyphenyl)acryloyl)cyclohexanone (2b), (E)-2 (3,4-dimethoxybenzylidene)-6-((E)-3-(3,4-dimethoxyphenyl)acryloyl)cyclohexanone (2e) and (E)-2-(3,4-dimethoxybenzylidene)-5-((E)-3-(3,4 dimethoxyphenyl)acryloyl)cyclopentanone (3e) exhibited strong tyrosinase inhibition. Moreover, (E)-2-(3,4-dimethoxybenzylidene)-6-((E)-3-(3,4 dimethoxyphenyl)-acryloyl)cyclohexanone (2e) was also found to be the strongest human HIV-1 protease inhibitor in vitro among the tested compounds. Cytotoxicity studies using normal human lung cells revealed that the novel curcumin as well as its carbocyclic analogs are not toxic. PMID- 23666007 TI - Antagonist effects of veratric acid against UVB-induced cell damages. AB - Ultraviolet (UV) radiation induces DNA damage, oxidative stress, and inflammatory processes in human epidermis, resulting in inflammation, photoaging, and photocarcinogenesis. Adequate protection of skin against the harmful effect of UV irradiation is essential. In recent years naturally occurring herbal compounds such as phenolic acids, flavonoids, and high molecular weight polyphenols have gained considerable attention as beneficial protective agents. The simple phenolic veratric acid (VA, 3,4-dimethoxybenzoic acid) is one of the major benzoic acid derivatives from vegetables and fruits and it also occurs naturally in medicinal mushrooms which have been reported to have anti-inflammatory and anti-oxidant activities. However, it has rarely been applied in skin care. This study, therefore, aimed to explore the possible roles of veratric acid in protection against UVB-induced damage in HaCaT cells. Results showed that veratric acid can attenuate cyclobutane pyrimidine dimers (CPDs) formation, glutathione (GSH) depletion and apoptosis induced by UVB. Furthermore, veratric acid had inhibitory effects on the UVB-induced release of the inflammatory mediators such as IL-6 and prostaglandin-E2. We also confirmed the safety and clinical efficacy of veratric acid on human skin. Overall, results demonstrated significant benefits of veratric acid on the protection of keratinocyte against UVB-induced injuries and suggested its potential use in skin photoprotection. PMID- 23666008 TI - Synthesis, characterization and activity evaluation of matrinic acid derivatives as potential antiproliferative agents. AB - A series of new matrinic acid derivatives 5a-e was synthesized. The chemical structures of the synthesized compounds were confirmed by 1H-NMR, 13C-NMR, and electrospray ionization mass spectroscopy. The anti-tumor activities were also investigated in vitro by evaluating the effect of synthesized compounds on the proliferation of A375, A549, HeLa, and HepG2 cells. Compound 5e was found to be the most potent against A375 and HeLa cells, with IC50 values of 37 and 75.5 MUg/mL, respectively. Compounds 5b, 5c, 5g, and 5h also exhibited antiproliferative activities against A549 cells, with IC50 values within the 36.2 47 MUg/mL range. For HepG2 cells, 5e and 5i, with IC50 values of 78.9 and 61 MUg/mL, respectively, showed higher antiproliferative activity than taxol. PMID- 23666009 TI - Camphor--a fumigant during the Black Death and a coveted fragrant wood in ancient Egypt and Babylon--a review. AB - The fragrant camphor tree (Cinnamomum camphora) and its products, such as camphor oil, have been coveted since ancient times. Having a rich history of traditional use, it was particularly used as a fumigant during the era of the Black Death and considered as a valuable ingredient in both perfume and embalming fluid. Camphor has been widely used as a fragrance in cosmetics, as a food flavourant, as a common ingredient in household cleaners, as well as in topically applied analgesics and rubefacients for the treatment of minor muscle aches and pains. Camphor, traditionally obtained through the distillation of the wood of the camphor tree, is a major essential oil component of many aromatic plant species, as it is biosynthetically synthesised; it can also be chemically synthesised using mainly turpentine as a starting material. Camphor exhibits a number of biological properties such as insecticidal, antimicrobial, antiviral, anticoccidial, anti-nociceptive, anticancer and antitussive activities, in addition to its use as a skin penetration enhancer. However, camphor is a very toxic substance and numerous cases of camphor poisoning have been documented. This review briefly summarises the uses and synthesis of camphor and discusses the biological properties and toxicity of this valuable molecule. PMID- 23666010 TI - Optimization and characterization of chitosan films for transdermal delivery of ondansetron. AB - The aim of this study was to develop novel transdermal films of ondansetron HCl with high molecular weight chitosan as matrix polymer and 2-(2-ethoxy-ethoxy) ethanol (Transcutol(r)) as plasticizer. In this context, firstly the physicochemical properties of gels used to formulate transdermal films were characterized and, physicochemical properties and bioadhesiveness of the transdermal films prepared with chitosan gels were assessed. The impact of three different types of terpenes, namely limonene, nerolidol and eucalyptol on in vitro skin permeation of ondansetron from transdermal films were also examined. ATR-FTIR measurements were performed to investigate the effects of the chitosan film formulations on in vitro conformational order of stratum corneum intercellular lipids after 24 h permeation study. The results showed that the chitosan gels consisting of Transcutol(r) as plasticizer and terpenes as penetration enhancer may be used to prepare transdermal films of ondansetron due to the good mechanical properties and bioadhesiveness of the transdermal films. Eucalyptol (1%) showed higher permeation enhancer effect than the other terpenes and control. ATR-FTIR data confirmed that finding in which eucalyptol induced a blue shift in the both CH2 asymmetric and symmetric absorbance peak positions indicating increased lipid fluidity of stratum corneum. PMID- 23666011 TI - Zwitterionic hydrogels implanted in mice resist the foreign-body reaction. AB - The performance of implantable biomedical devices is impeded by the foreign-body reaction, which results in formation of a dense collagenous capsule that blocks mass transport and/or electric communication between the implant and the body. No known materials or coatings can completely prevent capsule formation. Here we demonstrate that ultra-low-fouling zwitterionic hydrogels can resist the formation of a capsule for at least 3 months after subcutaneous implantation in mice. Zwitterionic hydrogels also promote angiogenesis in surrounding tissue, perhaps owing to the presence of macrophages exhibiting phenotypes associated with anti-inflammatory, pro-healing functions. Thus, zwitterionic hydrogels may be useful in a broad range of applications, including generation of biocompatible implantable medical devices and tissue scaffolds. PMID- 23666012 TI - TALEN-mediated editing of the mouse Y chromosome. AB - The functional study of Y chromosome genes has been hindered by a lack of mouse models with specific Y chromosome mutations. We used transcription activator-like effector nuclease (TALEN)-mediated gene editing in mouse embryonic stem cells (mESCs) to produce mice with targeted gene disruptions and insertions in two Y linked genes--Sry and Uty. TALEN-mediated gene editing is a useful tool for dissecting the biology of the Y chromosome. PMID- 23666013 TI - Polyoxometalate-based supramolecular gel. AB - Self-assemblyings of surfactant-encapsulated Wells-Dawson polyoxometalates (SEPs) nanobuilding blocks in butanone and esters yielded supramolecular gels showing thermo and photo responsive properties. The gels can be further polymerized if unsaturated esters were used and subsequently electrospinned into nanowires and non-woven mats. The as-prepared non-woven mats have a Young's modulus as high as 542.55 MPa. It is believed that this supramolecular gel is a good platform for polyoxometalates processing. PMID- 23666014 TI - Mechanism of NO2 storage in ceria studied using combined in situ Raman/FT-IR spectroscopy. AB - In situ Raman spectroscopy combined with quantitative FT-IR gas phase analysis was used to elucidate the mechanism of NO2 storage in ceria. At room temperature, NO2 exposure induces an immediate increase in the degree of ceria reduction accompanying nitrate formation. Two parallel reaction pathways for nitrate formation are identified. The presence of steam strongly influences the storage behavior by favoring the formation of free nitrates over bidentate/bridging nitrates. At 200 degrees , faster free nitrate formation and gas phase NO formation is observed, while the NOx storage capacity of ceria is reduced from 0.27 to 0.16 mmol g(-1) CeO2. PMID- 23666015 TI - Performance status and symptom scores of women with gynecologic cancer at the end of life. AB - OBJECTIVE: The Palliative Performance Scale (PPS), which measures performance status (100 = best performance to 0 = dead), and the Edmonton Symptom Assessment System (ESAS), which measures severity of 9 symptoms, are routinely collected at ambulatory cancer visits in Ontario. This study describes the trajectory of scores in patients with gynecologic cancer in the last 6 months of life. METHODS: An observational study was conducted between 2007 and 2010. Patients had ovarian/fallopian tube, uterine, and cervical cancer and required 1 or more PPS or ESAS assessment in the 6 months before death. Outcomes were the average PPS and ESAS scores per week before death. Using logistic regression, we analyzed the odds ratio of reporting a moderate to severe score for each symptom. RESULTS: Seven hundred ninety-five (PPS) and 1299 (ESAS) patients were included. The average PPS score started at 70 and ended at 30, rapidly declining in the last 2 months. For ESAS symptoms, drowsiness, decreased well-being, lack of appetite, and tiredness increased in severity closer to death and were prevalent in more than 70% of patients in the last week of life. Patients with cervical cancer had increased odds of moderate to severe pain (1.74; 95% confidence interval, 1.30 2.32) compared with ovarian cancer. CONCLUSIONS: Trajectories of mean performance status had not reached the "end-of-life" phase until 1 week before death. A large proportion of the gynecologic cancer patients reported moderate to severe symptom scores as death approached. Pain was uniquely elevated in the cervical cancer cohort as death approached. Adequately managing the symptom burden appears to be a significant issue in end-of-life gynecologic care. PMID- 23666016 TI - Treatment patterns, health care utilization, and costs of ovarian cancer in Central and Eastern Europe using a Delphi panel based on a retrospective chart review. AB - OBJECTIVE: Despite the considerable disease burden of ovarian cancer, there were no cost studies in Central and Eastern Europe. This study aimed to describe treatment patterns, health care utilization, and costs associated with treating ovarian cancer in Hungary, Poland, Serbia, and Slovakia. METHOD: Overall clinical practice for management of epithelial ovarian cancer was investigated through a 3 round Delphi panel. Experts completed a survey based on the chart review (n = 1542). The survey was developed based on clinical guidelines and the International Federation of Gynecology and Obstetrics Annual Report. Means, ranges, and outlier values were discussed with the experts during a telephone interview. Finally, consensus estimates were obtained in face-to-face workshops. Based on these results, overall cost of ovarian cancer was estimated using a Markov model. RESULTS: The patients included in the chart review were followed up from presurgical diagnosis and in each phase of treatment, that is, surgical staging and primary surgery, chemotherapy and chemotherapy monitoring, follow-up, and palliative care. The 5-year overall cost per patient was ?14,100 to ?16,300 in Hungary, ?14,600 to ?15,800 in Poland, ?7600 to ?8100 in Serbia, and ?12,400 to ?14,500 in Slovakia. The main components were chemotherapy-associated costs (68%-74% of the total cost), followed by cost of primary treatment with surgery (15%-21%) and palliative care (3%-10%). CONCLUSIONS: Patients with ovarian cancer consume considerable health care resources and incur substantial costs in Central and Eastern Europe. These findings may prove useful for clinicians and decision makers in understanding the economic implications of managing ovarian cancer in Central and Eastern Europe and the need for innovative therapies. PMID- 23666017 TI - Cost-effectiveness of BRCA1 and BRCA2 mutation testing to target PARP inhibitor use in platinum-sensitive recurrent ovarian cancer. AB - OBJECTIVES: (1) To determine whether use of a PARP inhibitor or (2) BRCA1/2 mutation testing followed by a PARP inhibitor for test positives is potentially cost-effective for maintenance treatment of platinum-sensitive recurrent high grade serous ovarian cancer. METHODS: A modified Markov decision analysis compared 3 strategies: (1) observe; (2) olaparib to progression; (3) BRCA1/2 mutation testing; treat mutation carriers with olaparib to progression. Progression-free survival and rates of adverse events were derived from a phase 2 randomized trial. Key assumptions are as follows: (1) 14% of patients harbor a BRCA1/2 mutation; (2) progression-free survival of individuals treated with olaparib is improved for BCRA1/2 carriers compared with noncarriers (estimated hazard ratio, approximately 0.4). Costs derived from national data were assigned to treatments, adverse events, and BRCA1/2 test. Monte Carlo probabilistic sensitivity analysis was performed. RESULTS: Global olaparib was the most effective strategy, followed by BRCA1/2 testing and no olaparib. BRCA1/2 testing had an incremental cost-effectiveness ratio (ICER) of $193,442 per progression free year of life saved (PF-YLS) compared to no olaparib, whereas global olaparib had an ICER of $234,128 per PF-YLS compared to BRCA1/2 testing. At a 52% lower than-baseline olaparib cost estimate of $3000 per month, BRCA1/2 testing became potentially cost-effective compared with observation, with an ICER of $100,000 per PF-YLS. When strategy (1) was removed from the analysis, BRCA1/2 testing was the preferred strategy. CONCLUSIONS: The use of maintenance olaparib in women with high-grade serous ovarian cancer is not cost-effective regardless of whether BRCA1/2 testing is used to direct treatment. However, BRCA1/2 testing is a preferred strategy compared to global maintenance olaparib alone. PMID- 23666018 TI - Individual variability in compensatory eating following acute exercise in overweight and obese women. AB - BACKGROUND: While compensatory eating following acute aerobic exercise is highly variable, little is known about the underlying mechanisms that contribute to the alterations in exercise-induced eating behaviour. METHODS: Overweight and obese women (body mass index=29.6+/-4.0 kg/m(2)) performed a bout of cycling individually tailored to expend 400 kcal (EX) or a time-matched no exercise control condition in a randomised, counter-balanced order. 60 min after the cessation of exercise, an ad libitum test meal was provided. Substrate oxidation and subjective appetite ratings were measured during exercise/time-matched rest, and during the period between the cessation of exercise and food consumption. RESULTS: While ad libitum energy intake (EI) did not differ between EX and the control condition (666.0+/-203.9 vs 664.6+/-174.4 kcal, respectively; ns), there was a marked individual variability in compensatory EI. The difference in EI between EX and the control condition ranged from -234.3 to 278.5 kcal. Carbohydrate oxidation during exercise was positively associated with postexercise EI, accounting for 37% of the variance in EI (r=0.57; p=0.02). CONCLUSIONS: These data indicate that the capacity of acute exercise to create a short-term energy deficit in overweight and obese women is highly variable. Furthermore, exercise-induced CHO oxidation can explain a part of the variability in acute exercise-induced compensatory eating. Postexercise compensatory eating could serve as an adaptive response to facilitate the restoration of carbohydrate balance. PMID- 23666019 TI - Sedentary behaviour and risk of mortality from all-causes and cardiometabolic diseases in adults: evidence from the HUNT3 population cohort. AB - BACKGROUND: Sedentary behaviour is a potential risk factor for chronic-ill health and mortality, that is, independent of health-enhancing physical activity. Few studies have investigated the risk of mortality associated with multiple contexts of sedentary behaviour. OBJECTIVE: To examine the prospective associations of total sitting time, TV-viewing time and occupational sitting with mortality from all causes and cardiometabolic diseases. METHODS: Data from 50,817 adults aged >=20 years from the Nord-Trondelag Health Study 3 (HUNT3) in 2006-2008 were linked to the Norwegian Cause of Death Registry up to 31 December 2010. Cox proportional hazards models examined all-cause and cardiometabolic disease related mortality associated with total sitting time, TV-viewing and occupational sitting, adjusting for multiple potential confounders including physical activity. RESULTS: After mean follow-up of 3.3 years (137,315.8 person-years), 1068 deaths were recorded of which 388 were related to cardiometabolic diseases. HRs for all-cause mortality associated with total sitting time were 1.12 (95% CI 0.89 to 1.42), 1.18 (95% CI 0.90 to 1.57) and 1.65 (95% CI 1.24 to 2.21) for total sitting time 4-<7, 7-<10 and >=10 h/day, respectively, relative to <4 h/day after adjusting for confounders (p-trend=0.001). A similar pattern of associations was observed between total sitting time and mortality from cardiometabolic diseases, but TV-viewing time and occupational sitting showed no or borderline significant associations with all-cause or cardiometabolic disease related mortality over the same follow-up period. CONCLUSIONS: Total sitting time is associated with all-cause and cardiometabolic disease-related mortality in the short term. However, prolonged sitting in specific contexts (ie, watching TV, at work) do not adversely impact health in the same timeframe. These findings suggest that adults should be encouraged to sit less throughout the day to reduce their daily total sitting time. PMID- 23666020 TI - The challenge of managing tendinopathy in competing athletes. AB - Managing tendinopathy in season is a challenge for all sports medicine practitioners. Many of the strategies employed to treat tendinopathy in a rehabilitation setting are not suitable because of the time taken to recover. Management strategies that control pain and maintain performance are required. These include load management, both reducing aggravating loads and introducing pain-relieving loads, medications and adequate monitoring to detect a deteriorating tendon. Other interventions such as intratendinous injection therapies and other direct tendon modalities can be provocative at worst and without effect at best. Research to improve the understanding of management in athletes in season is compromised by ethical considerations and access to willing participants. It is likely to remain an area where clinical advances guide future treatments. PMID- 23666021 TI - Risk factors and successful interventions for cricket-related low back pain: a systematic review. AB - BACKGROUND: Low back pain (LBP) is highly prevalent in cricketers, particularly in adolescent fast bowlers. Numerous modifiable risk factors for and interventions to address LBP in cricketers have been proposed in the literature. AIM: Summarise and critique studies evaluating LBP risk factors in cricketers, and evaluate the effectiveness of interventions designed to prevent or treat such LBP. STUDY DESIGN: Systematic literature review. METHODS: MEDLINE, ISI Web of Knowledge, CINAHL, SportDiscus and the Cochrane Library were searched from inception using key terms relating to risk factors and interventions in LBP in cricketers. Quality of included studies was assessed using the Downs and Black Quality Index, data were extracted to complete the effect size and OR calculations and evidence levels were established using van Tulder's criteria. RESULTS: 12 studies (6 of high quality) investigating the factors associated with LBP in cricketers and 5 low-quality studies evaluating the interventions for the treatment/prevention of LBP in cricketers were identified. Moderate evidence indicates the presence of acute MRI bone stress as a risk factor for developing lumbar stress fractures. Additionally, moderate evidence indicates increased shoulder counter rotation (associated with mixed bowling actions) and decreased anterior abdominal fascial slide may be associated with LBP in cricketers. CONCLUSIONS: Screening for bone stress on MRI should be considered by clinicians managing developing cricketers to identify the risk of lumbar stress fracture development. Numerous associative factors were outlined, although causality needs establishing to further guide interventions in cricketers with LBP. Intervention studies were of insufficient quality to generate concrete conclusions and these research failings require rapid attention. PMID- 23666022 TI - [Is physical activity an elixir?]. AB - Physical exercise has systemic effects, and it can regulate all the organs. The relative maximal aerobic oxygen uptake (VO2max) could have been important in the evolution of humans, since higher VO2max meant better hunting abilities for the Stone Age man. However, it appears that high level of VO2max is also important today, in the 21st century to prevent cardiovascular diseases, cancer and neurodegenerative diseases. High level of VO2max is not just preventive against a wide spectrum of diseases, but it associated with better function of many organs. Relevant data suggest that high level of VO2max is a key factor in prevention of diseases and survival even at the modern civilized world. PMID- 23666023 TI - [Prevalence of gastric polypoid lesions at an endoscopic facility]. AB - BACKGROUND: The prevalence of gastric polyps is unknown in Hungary. AIM: The aim of the authors was to assess the prevalence of polypoid lesions of the stomach in the endoscopic centre of the 2nd Department of Medicine, Semmelweis University. METHODS: Results of upper gastrointestinal endoscopies carried out between March 2010 and June 2011 were analysed. RESULTS: 193 cases with polyps were diagnosed in 4174 endoscopies (4.62%). Hyperplastic polyps, fundic gland polyps and malignant lesion were detected in 33.67%, 31.09% and 2.07% of the cases, respectively. Proton pump inhibitor use was more frequent among patients diagnosed with fundus gland polyps (p = 0.007), while hyperplastic polyps were diagnosed more frequently in patients with chronic gastritis (p = 0.032). CONCLUSIONS: The frequency of gastric polyps was higher than expected from data published in the literature. Long-term proton pump-inhibitor use and chronic gastritis were associated with fundus gland and hyperplastic polyps, respectively. PMID- 23666024 TI - [Comparison of the effectiveness of two internationally recommended screening methods for the diagnosis of gestational diabetes]. AB - INTRODUCTION: Early diagnosis and adequate care of gestational diabetes is of great importance for both the mother and her fetus. Although several national and international guidelines are known on the methodology for screening gestational diabetes, a not negligible part of the cases remain unrecognized when applying even the most widely used criteria recommended by the World Health Organization (1st recommendation). A connection has been found between the maternal blood glucose values and the prevalence of still-birth, preeclampsia and large for gestational age neonates in several studies, from which the Hyperglycaemia and Adverse Pregnancy Outcomes study has come into prominence. According to conclusions of this study the International Association of Diabetic Pregnancy Study Groups suggested new numeric criteria for the evaluation of the 75-gram oral glucose tolerance test (2nd recommendation), which differs from the evaluation used in the aforementioned screening system. AIMS: The aim of the study was to compare the effectiveness of the two screening systems by evaluation of the pregnancy outcomes. METHODS: By following non-twin pregnancies of 1107 pregnant mothers (831 with normal glucose tolerance, 276 with gestational diabetes based on any of the applied screening methods) the maternal (pre- and post-term birth, caesarean section, toxaemia) and newborns pregnancy outcomes (infants small and large for gestational age, hypoglycaemia) were analysed. RESULTS: With the exception of the prevalence of large for gestational age infants - which was higher among women screened by the new evaluation - no substantial difference in the efficacy of the two investigated methods was found. CONCLUSION: The decision whether the screening of gestational diabetes using the new criteria results in safer recognition of the disturbances of glucose metabolism during pregnancy requires further investigations including a large number of cases. PMID- 23666025 TI - [Quality of life in Hungarian patients with cystic fibrosis]. AB - INTRODUCTION: Cystic fibrosis is a progressive multisystemic disease which affects the quality of life of patients. AIM: The aim of the study was to evaluate quality of life in Hungarian patients with cystic fibrosis. METHODS: Validated Hungarian translation of The Cystic Fibrosis Questionnaire - Revised was used to measure quality of life. Clinical severity was determined on the basis of Shwachman-Kulczycki score. Lung function was measured using spirometry. RESULTS: 59 patients were included from five centres in Hungary. The relationships between 8-13 year-old children self-report and parent proxy report was 0.77 (p<0.001) in physical functioning, 0.07 (p<0.001) in emotional functioning, 0.51 (p<0.001) in eating, 0.21 (p<0.001) in treatment burden, 0.54 (p<0.001) in body image, 0.49 (p<0.001) in respiratory symptoms and 0.40 (p<0.001) in digestive symptoms domains. CONCLUSIONS: In contrast to physical domains weak correlations were observed between answers obtained from children and their parents in psychosocial domains. The perception of both patients and their parents should be assessed when measuring quality of life in paediatric patients with cystic fibrosis. PMID- 23666026 TI - [Gabor Pavai Vajna (1850-1913)--pioneer of the fight against tuberculosis in Pressburg, a forgotten disciple of Frigyes Koranyi]. PMID- 23666027 TI - [To the Editors regarding Veronika Meszaros et al., "Coping with work-related stress in healthcare professionals -- strategies for prevention of burnout and depression"]. PMID- 23666028 TI - Light trapping to amplify metal enhanced fluorescence with application for sensing TNT. AB - Metal Enhanced Fluorescence (MEF) typically produces enhancement factors of 10 to 50. By using a polymer layer as the dielectric spacer enhancements as high as 1,600 can be observed. The effect occurs with a variety of different polymers and substrates, all of which act to trap light in the dielectric layer. This allows the fabrication of sensors with improved sensitivity as demonstrated for detection of trinitrotoluene (TNT). PMID- 23666030 TI - A conceptual basis to encode and detect organic functional groups in XML. AB - A conceptual basis to define and detect organic functional groups is developed. The basic model of a functional group is termed as a primary functional group and is characterized by a group center composed of one or more group center atoms bonded to terminal atoms and skeletal carbon atoms. The generic group center patterns are identified from the structures of known functional groups. Accordingly, a chemical ontology 'Font' is developed to organize the existing functional groups as well as the new ones to be defined by the chemists. The basic model is extended to accommodate various combinations of primary functional groups as functional group assemblies. A concept of skeletal group is proposed to define the characteristic groups composed of only carbon atoms to be regarded as equivalent to functional groups. The combination of primary functional groups with skeletal groups is categorized as skeletal group assembly. In order to make the model suitable for reaction modeling purpose, a Graphical User Interface (GUI) is developed to define the functional groups and to encode in XML format appropriate to detect them in chemical structures. The system is capable of detecting multiple instances of primary functional groups as well as the overlapping poly-functional groups as the respective assemblies. PMID- 23666029 TI - 2-ketogluconic acid secretion by incorporation of Pseudomonas putida KT 2440 gluconate dehydrogenase (gad) operon in Enterobacter asburiae PSI3 improves mineral phosphate solubilization. AB - Enterobacter asburiae PSI3 is known to efficiently solubilize rock phosphate by secretion of approximately 50 mM gluconic acid in Tris-buffered medium in the presence of 75 mM glucose and in a mixture of seven aldosugars each at 15 mM concentration, mimicking alkaline vertisol soils. Efficacy of this bacterium in the rhizosphere requires P release in the presence of low amount of sugars. To achieve this, E. asburiae PSI3 has been manipulated to express gluconate dehydrogenase (gad) operon of Pseudomonas putida KT 2440 to produce 2 ketogluconic acid. E. asburiae PSI3 harboring gad operon had 438 U of GAD activity, secreted 11.63 mM 2-ketogluconic and 21.65 mM gluconic acids in Tris rock phosphate-buffered medium containing 45 mM glucose. E. asburiae PSI3 gad transformant solubilized 0.84 mM P from rock phosphate in TRP-buffered liquid medium. In the presence of a mixture of seven sugars each at 12 mM, the transformant brought about a drop in pH to 4.1 and released 0.53 mM P. PMID- 23666031 TI - The derivation of a chiral substituent code for secondary alcohols and its application to the prediction of enantioselectivity. AB - A chiral substituent code was proposed based on the features of secondary alcohols, in which a chiral center is attached to two substituents in addition to OH and H substituents. The new chirality code, which was generated by predefining positional information of four substituents attached to stereocenter, was applied to two datasets composed of secondary alcohols as the enantioselective products of asymmetric reactions. In the first dataset, the chemical reaction was catalyzed by a biocatalyst, lipase from Candida rugosa. The catalyst for the second dataset was (-)-diisopinocampheylchloroborane. The structure enantioselectivity relationship models were constructed using random forests with the chiral substituent code as the input. The resulting models were assessed both in terms of single enantiomers and pairs of enantiomers. Satisfactory results were obtained for both datasets. Although the chiral substituent code was specifically developed for secondary alcohols, it can easily be extended to represent chiral compounds possessing a specific chiral center bonded to two variable substituents. PMID- 23666032 TI - Insight into structural and biochemical determinants of substrate specificity of PFI1625c: correlation analysis of protein-peptide molecular models. AB - Bioinformatics and sequence comparison indicate PFI1625c as a putative metalloprotease present in plasmodium genome. The structure of PFI1625c consists of two domains with nearly identical folding topology. The active site of PFI1625c is located in a large central cavity between the two domains. Substrate binding regions of PFI1625c are lined by E-136, D-140 which provides negatively charged patches whereas F-53 facilitates binding of bulky hydrophobic residues of substrates. Probing PFI1625c active site with 199 different peptides from a combinatorial peptide library indicates preference of PFI1626c toward hydrophobic residue substituted peptides. Correlation analysis of each position of the peptide indicates that Ser 2 is the most crucial residue and no significant improvement was observed until it is mutated to a hydrophobic residue. The peptide P550 (LVIVAKRA) exhibits significantly better interaction within the active site than a template peptide (LSRVAKRA). The molecular dynamic's simulation studies confirms integrity of the complex, with all structures well within the qualitative limit of compactness and stability during the simulation time. There are structural and biochemical differences between PFI1625c with human metalloprotease and these are sufficient enough to allow us to exploit PFI1625c as drug targets. These computationally obtained insights provided clues about substrate selectivity in PFI1625c and it can be used to exploit PFI1625c as a target for future anti-malarial development. PMID- 23666033 TI - Relativistic theoretical studies on hydrogen bonds and the electronic structure of aqueous solvated bis(uranyl) complex: an insight into explicit and/or implicit solvent effects. AB - To understand the chemical behavior of uranyl complexes in water, a bis-uranyl [(phen)(UO2)(MU2-F)(F)]2 (A; phen = phenanthroline, MU2 = doubly bridged) and its hydrated form A.(H2O)n (n = 2, 4 and 6) were examined using scalar relativistic density functional theory. The addition of water caused the phen ligands to deviate slightly from the U2(MU2-F)2 plane, and red-shifts the U-F-terminal and U = O stretching vibrations. Four types of hydrogen bonds are present in the optimized hydrated A.(H2O)n complexes; their energies were calculated to fall within the range 4.37-6.77 kcal mol(-1), comparable to the typical values of 5.0 kcal mol(-1) reported for hydrogen bonds. An aqueous environment simulated by explicit and/or implicit models lowers and re-arranges the orbitals of the bis uranyl complex. PMID- 23666034 TI - NEMA NU-4 performance evaluation of PETbox4, a high sensitivity dedicated PET preclinical tomograph. AB - PETbox4 is a new, fully tomographic bench top PET scanner dedicated to high sensitivity and high resolution imaging of mice. This manuscript characterizes the performance of the prototype system using the National Electrical Manufacturers Association NU 4-2008 standards, including studies of sensitivity, spatial resolution, energy resolution, scatter fraction, count-rate performance and image quality. The PETbox4 performance is also compared with the performance of PETbox, a previous generation limited angle tomography system. PETbox4 consists of four opposing flat-panel type detectors arranged in a box-like geometry. Each panel is made by a 24 * 50 pixelated array of 1.82 * 1.82 * 7 mm bismuth germanate scintillation crystals with a crystal pitch of 1.90 mm. Each of these scintillation arrays is coupled to two Hamamatsu H8500 photomultiplier tubes via a glass light guide. Volumetric images for a 45 * 45 * 95 mm field of view (FOV) are reconstructed with a maximum likelihood expectation maximization algorithm incorporating a system model based on a parameterized detector response. With an energy window of 150-650 keV, the peak absolute sensitivity is approximately 18% at the center of FOV. The measured crystal energy resolution ranges from 13.5% to 48.3% full width at half maximum (FWHM), with a mean of 18.0%. The intrinsic detector spatial resolution is 1.5 mm FWHM in both transverse and axial directions. The reconstructed image spatial resolution for different locations in the FOV ranges from 1.32 to 1.93 mm, with an average of 1.46 mm. The peak noise equivalent count rate for the mouse-sized phantom is 35 kcps for a total activity of 1.5 MBq (40 uCi) and the scatter fraction is 28%. The standard deviation in the uniform region of the image quality phantom is 5.7%. The recovery coefficients range from 0.10 to 0.93. In comparison to the first generation two panel PETbox system, PETbox4 achieves substantial improvements on sensitivity and spatial resolution. The overall performance demonstrates that the PETbox4 scanner is suitable for producing high quality images for molecular imaging based biomedical research. PMID- 23666035 TI - Highly sensitive fluorescent detection of small molecules, ions, and proteins using a universal label-free aptasensor. AB - A facile and universal aptamer-based label-free approach for highly selective and sensitive fluorescence detection of a broad range of targets including small molecules, inorganic ions and proteins was developed by using PicoGreen to transduce the fluorescent signal of the double stranded DNA duplex formed between a free aptamer and its complementary strand. PMID- 23666036 TI - Pursuit of Complementary and Alternative Medicine Treatments in Adolescents With Cerebral Palsy. AB - This study determined the extent to which parents of adolescents with cerebral palsy seek out complementary and alternative medicine services. A regional sample of 166 adolescents (15.5 +/- 2.4 years) with cerebral palsy were recruited. Parents completed a questionnaire identifying the complementary and alternative medicine services received over the past year. Most (73.2%) did not currently utilize any of the listed services; 7.3% used 2 or more services. The most commonly used services were massage (15.4%), hyperbaric oxygen (9.6%), and osteopathy (5.7%). Youth with limited hand function were more likely (P = .01) to undergo hyperbaric oxygen. Massage therapy services were more frequent in youth with greater activity limitations (P < .005). Sociodemographic factors were not predictive of use. Approximately one quarter of families sought out these services for their adolescents with cerebral palsy. Many are expensive privately funded treatments. Physicians should openly discuss these options with families, highlighting the current state of knowledge on their efficacy. PMID- 23666037 TI - Implications of dietary therapy into the 21st century: conclusion to special issue. AB - The concept of dietary therapy for epilepsy has played an important role in the approach to the treatment of seizures for centuries--particularly with the development and utilization of the classic ketogenic diet over the past 90 years. Recently, there has been developing interest in the utilization of diet in other medical disorders, including autism spectrum disorders, traumatic brain injury, degenerative neurologic disorders, and cancer. As the utilization of dietary therapy expands, there are several issues that need to be addressed and better characterized to better understand the role of diet in the treatment of epilepsy and other disease. PMID- 23666038 TI - Hypomyelination with T2-hypointense globi pallidi in a child with fucosidosis. AB - A 4-year-old boy presented with progressive neurodegeneration, mild coarsening of facies and spasticity. The classical neuroimaging guided the subsequent investigation of enzyme assay which confirmed the diagnosis of fucosidosis. PMID- 23666039 TI - Autism and dietary therapy: case report and review of the literature. AB - We report the history of a child with autism and epilepsy who, after limited response to other interventions following her regression into autism, was placed on a gluten-free, casein-free diet, after which she showed marked improvement in autistic and medical symptoms. Subsequently, following pubertal onset of seizures and after failing to achieve full seizure control pharmacologically she was advanced to a ketogenic diet that was customized to continue the gluten-free, casein-free regimen. On this diet, while still continuing on anticonvulsants, she showed significant improvement in seizure activity. This gluten-free casein-free ketogenic diet used medium-chain triglycerides rather than butter and cream as its primary source of fat. Medium-chain triglycerides are known to be highly ketogenic, and this allowed the use of a lower ratio (1.5:1) leaving more calories available for consumption of vegetables with their associated health benefits. Secondary benefits included resolution of morbid obesity and improvement of cognitive and behavioral features. Over the course of several years following her initial diagnosis, the child's Childhood Autism Rating Scale score decreased from 49 to 17, representing a change from severe autism to nonautistic, and her intelligence quotient increased 70 points. The initial electroencephalogram after seizure onset showed lengthy 3 Hz spike-wave activity; 14 months after the initiation of the diet the child was essentially seizure free and the electroencephalogram showed only occasional 1-1.5 second spike-wave activity without clinical accompaniments. PMID- 23666040 TI - High-fat and ketogenic diets in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis is a fatal neurodegenerative disease. Epidemiologic data suggest that malnutrition is a common feature in amyotrophic lateral sclerosis and being overweight or obese confers a survival advantage in this patient population. In amyotrophic lateral sclerosis mouse models, a high-fat diet has been shown to lead to weight gain and prolonged survival. However, little research has been conducted to test whether nutritional interventions might ameliorate the disease course in humans. Here we review the currently available evidence supporting the potential role of dietary interventions as a therapeutic tool for amyotrophic lateral sclerosis. Ultimately, determining whether a high-fat or ketogenic diet could be beneficial in amyotrophic lateral sclerosis will require large randomized, placebo-controlled clinical trials. PMID- 23666041 TI - Pallidal stimulation in children: comparison between cerebral palsy and DYT1 dystonia. AB - The authors compared the outcomes of 17 children aged 7 to 15 years with DYT1 dystonia or cerebral palsy following deep brain stimulation. While patients with cerebral palsy presented with significantly greater motor disability than the DYT1 cohort at baseline, both groups demonstrated improvement at 1 year (cerebral palsy = 24%; DYT1 = 6%). The group as a whole demonstrated significant improvement on the Barry-Albright Dystonia Scale across time. Gains in motor function were apparent in both axial and appendicular distributions involving both upper and lower extremities. Gains achieved by 6 months were sustained in the cerebral palsy group, whereas the DYT1 group demonstrated continued improvement with ongoing pallidal stimulation beyond 18 months. Young patients with dystonia due to cerebral palsy responded comparably to patients with DYT1 dystonia. The severity of motor impairment in patients with cerebral palsy at baseline and follow-up raises the issue of even earlier intervention with neuromodulation in this population to limit long-term motor impairments due to dystonia. PMID- 23666042 TI - Clinicians' views on antiepileptic medication management in nonepileptic seizures. AB - Discontinuation of antiepileptic drugs should be a first step in treatment of nonepileptic seizures without comorbid epilepsy. However, clinical practices vary and standardized guidelines are not available. The aim of this study was to survey members of the American Epilepsy and Child Neurology Societies about factors that influence their decision about antiepileptic drug management in patients with nonepileptic seizures. A total of 236 respondents completed this survey, of whom 84% were academic pediatric neurologists and 96.2% were very willing to discontinue antiepileptic drugs in these patients. Clinicians with sufficient knowledge about nonepileptic seizures had fewer concerns about the potential for medical errors, were less influenced by requests made by patients or parents to continue antiepileptic drugs, and were comfortable making this decision if patients receive ongoing psychiatric care. Results of this survey highlight the need to examine if the same factors are involved in a large sample of community clinicians. PMID- 23666044 TI - Glut1 deficiency syndrome and novel ketogenic diets. AB - The classical ketogenic diet has been used for refractory childhood epilepsy for decades. It is also the treatment of choice for disorders of brain energy metabolism, such as Glut1 deficiency syndrome. Novel ketogenic diets such as the modified Atkins diet and the low glycemic index treatment have significantly improved the therapeutic options for dietary treatment. Benefits of these novel diets are increased palatability, practicability, and thus compliance-at the expense of lower ketosis. As high ketones appear essential to meet the brain energy deficit caused by Glut1 deficiency syndrome, the use of novel ketogenic diets in this entity may be limited. This article discusses the current data on novel ketogenic diets and the implications on the use of these diets in regard to Glut1 deficiency syndrome. PMID- 23666043 TI - Long-term outcome and risk factors for uncontrolled seizures after a first seizure in children with hematological malignancies. AB - Long-term outcomes of seizures that develop during treatment of childhood hematological malignancies have not been described. We analyzed seizure outcome in 62 children with leukemia or lymphoma treated at our institution. There was a median follow-up of 6.5 years since first seizure. Seizure etiology included intrathecal or systemic methotrexate in 24, leucoencephalopathy in 11, brain hemorrhage or thrombosis in 11, meningitis in 4, and no identifiable cause in 12. Seizures remained uncontrolled in 18, and risk factors for poor control included female sex (P = .02), no seizure control with first antiseizure drug (P = .08), and longer interval between cancer diagnosis and seizure onset (P = .09). Poor seizure control after initial antiseizure drug also predicted recurrent seizure after drug withdrawal (P = .04). In conclusion, seizures are controlled with medications in a majority of patients with hematological cancer. After a period without seizures, antiseizure drug withdrawal in appropriately selected patient has a high success rate. PMID- 23666045 TI - Congenital lymphocytic choriomeningitis virus: when to consider the diagnosis. AB - Lymphocytic choriomeningitis virus is a rodent-borne arenavirus that can cause congenital infection affecting the developing central nervous system. When the infection occurs during pregnancy, the virus targets the fetal brain and retina, potentially causing ventriculomegaly, hydrocephalus, chorioretinitis, and neurodevelopmental abnormalities. It has been previously suggested that lymphocytic choriomeningitis virus be added to the list of congenital infections currently included in the TORCH acronym (toxoplasmosis, rubella, cytomegalovirus, herpes, and syphilis). We present 2 neonates with antenatally known ventriculomegaly that were diagnosed with congenital lymphocytic choriomeningitis virus infection after birth. In addition to ventriculomegaly, one had nonimmune hydrops fetalis and the other had intracranial hemorrhage. In view of the seroprevalence of lymphocytic choriomeningitis virus (4.7%-10%), our findings suggest that screening for congenital lymphocytic choriomeningitis virus infection should be considered in fetuses and newborns with ventriculomegaly as well as other abnormal neuroimaging findings such as intracranial hemorrhage. PMID- 23666046 TI - Subcutaneous interferon Beta-1a in pediatric multiple sclerosis: a retrospective study. AB - To expand current knowledge, we examined the safety and tolerability of subcutaneous interferon beta-1a in patients with pediatric-onset multiple sclerosis. Records from 307 patients who had received at least 1 injection of subcutaneous interferon beta-1a for demyelinating events when aged younger than 18 years were reviewed. Overall, 168 (54.7%) patients had at least 1 prespecified medical event related to or under close monitoring with subcutaneous interferon beta-1a or specific to pediatric patients, 184 (59.9%) had nonserious medical events related to treatment or of unknown causality, and 12 (3.9%) had serious medical events irrespective of causality. The most common laboratory abnormalities were increased alanine (74/195; 37.9%) and aspartate aminotransferase levels (59/194; 30.4%). Annualized relapse rates were 1.79 before treatment and 0.47 during treatment. In conclusion, adult doses of subcutaneous interferon beta-1a (44 and 22 MUg, 3 times weekly) were well tolerated in pediatric patients and were associated with reduced relapse rates. PMID- 23666047 TI - Intake of vinegar beverage is associated with restoration of ovulatory function in women with polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is one of major causes of irregular menstruation. It is defined as a condition involving the combination of hyperandrogenism and chronic oligomenorrhea or anovulation, and is thought to have a variety of etiologies. Insulin resistance (impaired insulin sensitivity) has been suggested to be one of the etiologies of PCOS. PCOS patients often need to take medication to treat anovulation and infertility. Therefore, it would be beneficial to patients if simple non-pharmacological treatments can be developed. Recently the efficacy of vinegar to improve insulin resistance has been reported. To study the effect of vinegar on metabolic and hormonal indices and ovulatory function in PCOS, seven patients seeking a non-pharmacological treatment for PCOS took a beverage containing 15 g of apple vinegar daily for 90 to 110 days. Ovulation, the menstrual interval, fasting serum glucose level, fasting serum insulin level, luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone were compared before and after intake of the vinegar beverage. Intake of the vinegar beverage resulted in a decrease of the homeostasis model assessment insulin resistance index (HOMA-R) in six patients, as well as a decrease of the LH/FSH ratio in five of seven patients. Ovulatory menstruation was observed within 40 day in four of seven patients. These findings suggest the possibility of vinegar to restore ovulatory function through improving insulin sensitivity in PCOS patients, thus, avoiding pharmacological treatment. Intake of vinegar might reduce medical cost and treatment time for insulin resistance, anovulation, and infertility in patients with PCOS. PMID- 23666048 TI - Inflammatory markers are elevated in Eisenmenger syndrome. AB - Inflammation may be an important contributing factor to the progression of Eisenmenger syndrome (ES). Markers of systemic inflammation in ES have not been systematically studied. Inflammatory markers including high-sensitivity C reactive protein (hs-CRP), interleukin-2 (IL-2), IL-6, and interferon-gamma (IFN gamma) were measured in 42 consecutive ES patients (mean age, 24.3 +/- 10.6 years) compared with their levels in 22 healthy control subjects. The patients were followed up for a mean duration of 16.3 +/- 13.7 months. The levels of inflammatory markers were correlated with clinical and hemodynamic variables at baseline and the outcomes of death, hospitalization, and worsening World Health Organization (WHO) functional class at follow-up evaluation. Compared with the control subjects, ES patients showed a significant elevation in hs-CRP (2.99 +/- 3.5 vs 1.1 +/- 0.9 mg/dl; p = 0.002) and IFN-gamma (41.3 +/- 43.6 vs 10.4 +/- 6.9 pg/ml; p < 0.001) levels. The levels of IL-2 and IL-6 also were elevated but did not differ significantly from those in the control subjects. The patients with hs CRP levels higher than 3 mg/dl were significantly older (28.9 +/- 10.6 vs 21.5 +/ 9.8 years) and had a significantly shorter 6-min walk distance (421.5 +/- 133.2 vs 493.3 +/- 74.8 m). The levels of inflammatory markers did not correlate with baseline parameters or clinical outcomes. To conclude, the levels of hs-CRP and IFN-gamma are significantly elevated in ES. Elevated hs-CRP in ES was associated with older age and shorter 6-min walk distance, but the levels of inflammatory markers were not predictive of clinical events. PMID- 23666049 TI - Long-distance transport of Hg, Sb, and As from a mined area, conversion of Hg to methyl-Hg, and uptake of Hg by fish on the Tiber River basin, west-central Italy. AB - Stream sediment, stream water, and fish were collected from a broad region to evaluate downstream transport and dispersion of mercury (Hg) from inactive mines in the Monte Amiata Hg District (MAMD), Tuscany, Italy. Stream sediment samples ranged in Hg concentration from 20 to 1,900 ng/g, and only 5 of the 17 collected samples exceeded the probable effect concentration for Hg of 1,060 ng/g, above which harmful effects are likely to be observed in sediment-dwelling organisms. Concentrations of methyl-Hg in Tiber River sediment varied from 0.12 to 0.52 ng/g, and although there is no established guideline for sediment methyl-Hg, these concentrations exceeded methyl-Hg in a regional baseline site (<0.02 ng/g). Concentrations of Hg in stream water varied from 1.2 to 320 ng/L, all of which were below the 1,000 ng/L Italian drinking water Hg guideline and the 770 ng/L U.S. Environmental Protection Agency (USEPA) guideline recommended to protect against chronic effects to aquatic wildlife. Methyl-Hg concentrations in stream water varied from <0.02 to 0.53 ng/L and were generally elevated compared to the baseline site (<0.02 ng/L). All stream water samples contained concentrations of As (<1.0-6.2 MUg/L) and Sb (<0.20-0.37 MUg/L) below international drinking water guidelines to protect human health (10 MUg/L for As and 20 MUg/L for Sb) and for protection against chronic effects to aquatic wildlife (150 MUg/L for As and 5.6 MUg/L for Sb). Concentrations of Hg in freshwater fish muscle ranged from 0.052 0.56 MUg/g (wet weight), mean of 0.17 MUg/g, but only 17 % (9 of 54) exceeded the 0.30 MUg/g (wet weight) USEPA fish muscle guideline recommended to protect human health. Concentrations of Hg in freshwater fish in this region generally decreased with increasing distance from the MAMD, where fish with the highest Hg concentrations were collected more proximal to the MAMD, whereas all fish collected most distal from Hg mines contained Hg below the 0.30 MUg/g fish muscle guideline. Data in this study indicate some conversion of inorganic Hg to methyl Hg and uptake of Hg in fish on the Paglia River, but less methylation of Hg and Hg uptake by freshwater fish in the larger Tiber River. PMID- 23666050 TI - An opto-thermocapillary cell micromanipulator. AB - An opto-thermocapillary micromanipulator (OTMm) capable of single-cell manipulation and patterning is presented here. The OTMm uses a near-infrared laser focused on an ITO substrate to induce thermocapillary convection that can trap and transport living cells with forces of up to 40 pN. The OTMm complements other cell-manipulation technologies, such as optical tweezers and dielectrophoresis, as it is less dependent upon the optical and electrical properties of the working environment, and can function in many types of cell culture media. The OTMm was used to construct single-cell matrices in two popular hydrogels: PEGDA and agarose. High viability rates were observed in both hydrogels, and cells patterned in agarose spread and migrated during subsequent culturing. PMID- 23666051 TI - SLCO2B1 genetic polymorphisms in a Korean population: pyrosequencing analyses and comprehensive comparison with other populations. AB - SLCO2B1, also known as OATP2B1 (Organic Anion Transporter) or OATP-B or SLC21A9, is an organic anion uptake transporter that is encoded by the SLCO2B1 gene. In this study we assessed the frequencies of SLCO2B1 polymorphisms in a Korean population using newly developed pyrosequencing methods and compared their frequencies with those in other ethnic groups. We developed pyrosequencing methods to identify the following six SLCO2B1 non-synonymous polymorphisms: c.1175C > T (rs1621378), c.1457C > T (rs2306168), c.43C > T (rs56837383), c.935G > A (rs12422149), c.601G > A (rs35199625) and c.644A > T (rs72559740). The allele frequencies of these polymorphisms were analyzed in 227 Korean subjects. The allele frequencies of SLCO2B1 polymorphisms in the population tested were as follows: 0.0 for c.1175C > T, c.43C > T and c.644A > T; 0.2687 for c.1457C > T; 0.4273 for c.935G > A; and 0.0727 for c. 601G > A. Even though the allele frequencies of the c.1175C > T and c.1457C > T polymorphisms were comparable to those in Japanese subjects, the frequencies in this Korean population differed from those in other ethnic groups. The developed pyrosequencing methods are rapid and reliable for detecting non-synonymous SLCO2B1 polymorphisms. Large ethnic differences in the frequency of SLCO2B1 genetic polymorphisms were noted among ethnic groups. The SLCO2B1 polymorphisms at c.1175C > T, c.43C > T and c.644A > T were not found in the Korean population while c.1457C > T, c.935G > A and c.601G > A exhibited mostly higher frequencies in Koreans compared with Finnish, Caucasian and African-American populations. PMID- 23666052 TI - HLA genetic profile of Mapuche (Araucanian) Amerindians from Chile. AB - Amerindian Mapuche (Araucanians) are now living in Chile and Argentina at both sides of Andean Mountains. They are anthropologically and genetically different from southernmost South America Patagonian Amerindians. Most of the HLA alleles found in our Mapuche sample are frequent or very frequent in North and South America Amerindians: (1) Class I: A*02:01, A*03:01, A*68:01, B*39:09, B*51:01, (2) Class II: DRB1*03:01, DRB1*04:03, DRB1*07:01, DRB1*08:02, DRB1*14:02, DRB1*16:02. One of the nine most frequent extended haplotypes seems to be from European origin, suggesting the existence of a degree of admixture with Europeans in our Mapuche sample. It has been calculated of about 11 % admixture. Three of the extended haplotypes are also found in other Amerindians and five of them are newly found in Mapuche Amerindians: A*68:01-B*39:09-DRB1*08:02-DQB1*04:02; A*68:01-B*51:01-DRB1*04:03-DQB1*03:02; A*29:01-B*08:01-DRB1*03:01-DQB1*02:01; A*02:01-B*15:01-DRB1*04:03-DQB1*03:02; A*33:01-B*14:02-DRB1*07:01-DQB1*03:03. The medical importance of calculating HLA profile is discussed on the diagnostic (HLA and disease) and therapeutical bases of HLA pharmacogenomics and on the construction of a virtual transplantation HLA list profile. Also, anthropological conclusions are drawn. PMID- 23666053 TI - Polymorphisms and haplotypes in MyD88 are associated with the development of sarcoidosis: a candidate-gene association study. AB - Sarcoidosis is considered as a disorder of protracted immune response to an as yet unidentified causative agent that leads to granuloma formation. Material from M. tuberculosis and P. acne has been repeatedly detected in the sarcoidosis lesions, implying the involvement of the Toll-like receptor2 (TLR2) gene that responds to these intracellular pathogens. Since TLR2 association studies have produced controversial results, we sought to investigate whether the downstream signalling molecule MyD88 could be linked to disease susceptibility. We analyzed a total of 93 cases with sarcoidosis and of 89 controls for the most common MyD88 SNPs: -938C>A (rs4988453) and 1944C>G (rs4988457). There is evidence that the genotype distributions of both variants are associated with the development of sarcoidosis (p = 0.038 for -938C>A and p = 0.026 for 1944C>G). In particular, 938A and 1944G carriers were associated with risk of sarcoidosis [OR = 2.48 (1.23 5.02) and OR = 0.33 (0.14-0.76)], respectively, indicating dominance of the mutant alleles; however, the adjustment of the effect size for age and sex diminished the significance. The haplotype analysis showed association for the 938A/1944G haplotype (p < 0.001). Since genetic association studies have linked MyD88 to Hodgkin's lymphoma it is tempting to speculate that MyD88 may contribute to the granuloma formation that characterizes sarcoidosis. PMID- 23666054 TI - Cyclic chalcone analogue KRP6 as a potent modulator of cell proliferation: an in vitro study in HUVECs. AB - In the present investigation a novel series of chalcone analogues were synthesized and evaluated for their anti-proliferative activity in human umbilical vein endothelial cells (HUVECs). Among 14 tested compounds, chalcone analogue (E)-3-(2'-methoxybenzylidene)-4-chromanone (KRP6) exhibited the most potent activity with IC50 19 MUM. Moreover, HUVECs exhibited divergent, even opposing concentration-dependent responses to KRP6. This compound was the most potent inhibitor of cell proliferation and extracellular matrix formation (fibronectin and type IV collagen) at higher concentrations (20-50 MUM). In contrast, KRP6 stimulated the compensatory increase in proliferative activity including extracellular matrix formation at low concentrations (1, 10 MUM). KRP6 concentration-dependently modulated phosphorylation of Akt and mitogen-activated protein kinases such as extracellular signal-regulated kinase-1/-2 and p38 kinase, suggesting that these pathways play a role in the effect mediated by this compound. In addition, we found a selective effect on activated endothelial cells, in particular with resting endothelial cells. In conclusion, KRP6 is a potent modulator of selected steps of the angiogenic process in vitro. Accordingly, further in vivo research should be performed to facilitate its use in clinical practice. PMID- 23666055 TI - Genome-wide identification and transcription analysis of soybean carotenoid oxygenase genes during abiotic stress treatments. AB - Carotenoid oxygenase is a key enzyme in carotenoid metabolism leading to the synthesis of two phytohormones, abscisic acid (ABA) and strigolactone, as well as norisoprenoids. Few studies have analyzed inter-relationship of the metabolic networks of these three substances. In this present paper, soybean carotenoid oxygenase genes were identified to reveal their phylogenetic relationships, and the transcriptional response of these genes to four abiotic stresses (NaCl, PEG, high and low temperature) and ABA treatment were investigated to characterize their potential roles in plant resistance. Positive selection was found in the branches of carotenoid cleavage dioxygenase (CCD1), CCD8 and NCED (9-cis epoxycarotenoid oxygenase), indicating an adaptive evolution in these clades. In soybean eight carotenoid oxygenase genes were identified. The transcriptional responses of almost all of them under stress and ABA conditions were significantly altered when assessed by quantitative polymerase chain reaction. Notably, CCD1 and CCD4, previously known as the key genes in norisoprenoids metabolism, showed especially strong responses to the abiotic stresses and ABA treatment. Furthermore, transcription levels of CCD7 and CCD8, key genes for the strigolactone pathway, highly increased during ABA treatment providing further evidence that ABA is involved in regulating strigolactone metabolism. All of the carotenoid oxygenase genes in soybean are involved in plant abiotic stress physiology, and ABA is presumed to be a core regulatory substance. These findings provide some insights into the mechanisms that underlie the regulation of tolerance response to abiotic stresses in soybean. PMID- 23666056 TI - Polymorphic genetic variation in immune system genes: a study of two populations of Espirito Santo, Brazil. AB - Mapping single nucleotide polymorphisms (SNPs) in genes potentially involved in immune responses may help understand the pathophysiology of infectious diseases in specific geographical regions. In this context, we have aimed to analyze the frequency of immunogenetic markers, focusing on genes CD209 (SNP -336A/G), FCgammaRIIa (SNP -131H/R), TNF-alpha (SNP -308A/G) and VDR (SNP Taq I) in two populations of the Espirito Santo State (ES), Brazil: general and Pomeranian populations. Peripheral blood genomic DNA was extracted from one hundred healthy individuals of the general population and from 59 Pomeranians. Polymorphic variant identification was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). SNP genotype frequencies were in Hardy Weinberg Equilibrium. There was no statistically significant difference in allelic and genotypic distributions between the two populations studied. Statistically significant differences were observed for SNP genotype distribution in genes CD209, TNF-alpha and VDR when comparing the ES populations with other Brazilian populations. This is the first report of CD209, FcgammaRIIa, TNF-alpha and VDR allelic frequencies for the general and Pomeranian populations of ES. PMID- 23666057 TI - Cloning, in silico characterization and induction of TiKpp2 MAP kinase in Tilletia indica under the influence of host factor(s) from wheat spikes. AB - In order to understand the molecular mechanism(s) associated with floret specificity, morphogenetic and disease development of Karnal bunt (KB) pathogen in wheat spikes, host factor(s) was isolated from KB prone susceptible stage of wheat spikes. An orthologue of Kpp2 gene involved in pheromone response and fungal development was isolated from Tilletia indica for analyzing its role in fungal development. The maximum expression of TiKpp2 gene was observed at 14th day and decreased thereafter. To investigate whether the fungus alters the expression levels of same kinase upon interaction with plants, T. indica cultures were treated with 1% of host factor(s). Such treatment induced the expression of TiKpp2 gene in time dependent manner. Host factor(s) treatment tends to increase the myelination in fungal cultures by lowering the sporidial production. Increase in myelination led to impose more pathogenicity levels in the host and prolific multiplication of pathogen inside host causing more damage to developing grains. In silico characterization and protein-protein interaction studies further suggests that isolated gene showed similarity with Ustilago maydis Kpp2 and induction of TiKpp2 might further activate a downstream transcription factor Prf1. The results of present study clearly suggest that host factor(s) derived from wheat spikes provide certain signal(s) which activate TiKpp2 gene during morphogenetic development of T. indica and affect the fungal growth and pathogenicity. In turn it also provides a plausible explanation for floret specificity of KB fungus in wheat. PMID- 23666058 TI - Genetic differ in TLR4 gene polymorphisms and expression involved in Salmonella natural and artificial infection respectively in Chinese native chicken breeds. AB - Salmonella enteritidis (SE) is a foodborne pathogen that negatively affects both animal and human health. Genetic variations in response to pathogenic SE colonization or to SE vaccination were measured in chicken resource populations. Toll-like receptor 4 (TLR4) is part of a group of evolutionarily conserved pattern recognition receptors involved in the activation of the immune system in response to various pathogens and in the innate defense against infection. In this study, TLR4 was investigated the association of TLR4 gene polymorphisms with Salmonella natural infection situation of birds from two distinct Chinese genetic breeds. One SNP G1894C in the second intron of chicken TLR4 (chTLR4) was scanned in the two hens breed, which showed significant association with Salmonella natural infection situation (P<0.05). Genetic variations in response to pathogenic SE colonization also existed in distinct Chinese chicken resource population. In this study, mRNA expression of TLR4 was detected to investigate the association with the effect of artificial SE challenge in heterophil granulocytes and spleen of chicks from two distinct Chinese genetic breeds at 1, 3 and 10 day post-infection during the acute infection period. It clearly showed that young chicks' response to SE infection was regulated by TLR4 mRNA expression. The results suggest that genetics, time, gender, and interactions among these factors, play important roles in TLR4 mRNA basic values and copies modulation of SE mediated immune response in distinct Chinese chickens. PMID- 23666059 TI - Nutlin-3a, an MDM2 antagonist and p53 activator, helps to preserve the replicative potential of cancer cells treated with a genotoxic dose of resveratrol. AB - Resveratrol is a natural compound that has been intensely studied due to its role in cancer prevention and potential as an anti-cancer therapy. Its effects include induction of apoptosis and senescence-like growth inhibition. Here, we report that two cancer cell lines (U-2 OS and A549) differ significantly in their molecular responses to resveratrol. Specifically, in U-2 OS cells, the activation of the p53 pathway is attenuated when compared to the activation in A549 cells. This attenuation is accompanied by a point mutation (458: CGA->TGA) in the PPM1D gene and overexpression of the encoded protein, which is a negative regulator of p53. Experimentally induced knockdown of PPM1D in U-2 OS cells resulted in slightly increased activation of the p53 pathway, most clearly visible as stronger phosphorylation of p53 Ser37. When treated with nutlin-3a, a non genotoxic activator of p53, U-2 OS and A549 cells both responded with substantial activation of the p53 pathway. Nutlin-3a improved the clonogenic survival of both cell lines treated with resveratrol. This improvement was associated with lower activation of DNA-damage signaling (phosphorylation of ATM, CHK2, and histone H2AX) and higher accumulation of cells in the G1 phase of the cell cycle. Thus, the hyperactivation of p53 by nutlin-3a helps to preserve the replicative potential of cells exposed to resveratrol. PMID- 23666060 TI - Evaluation of polymorphism, hypermethylation and expression pattern of CTLA4 gene in a sample of Iranian patients with schizophrenia. AB - The cytotoxic T lymphocyte-associated antigen 4 gene (CTLA4) has a crucial role in regulation of T cell proliferation and mediates T cell apoptosis by encoding the T cell receptor. Schizophrenia (SCZ) patients often have abnormalities in terms of the function and development of the immune system. The aim of the present study was to investigate promoter variation and expression profile of the CTLA4 gene in patients with SCZ. We isolated genomic DNA from peripheral blood of 94 individuals with SCZ and 99 healthy control subjects. Genotypic analysis of CTLA4 (-318) was done by Tetra-ARMS-PCR. Methylation-specific polymerase chain reaction (MS-PCR) was used to estimate promoter hypermethylation of the CTLA4 gene. In addition, we investigated CTLA4 mRNA levels in 34 blood samples from cases and healthy controls using real-time reverse transcription PCR. The CT genotype of CTLA4 has a significantly protective effect on the risk to SCZ (OR=0.44; 95% CI 0.18-1.06, P=0.007) in comparison with the wild CC genotype. Promoter methylation of the CTLA4 gene increased the risk of disease statistically (OR=3.82, 95% CI 1.34-10.9, P=0.015) in cases when compared to healthy controls in blood samples. The mRNA expression level results showed statistically significant differences (P<0.0001) between cases (n=17) and healthy controls (n=17). To the best of our knowledge, this is the first evidence showing that promoter methylation of the CTLA4 gene along with transition of C to T was linked to a significantly higher expression of CTLA4 mRNA levels in patients with SCZ. PMID- 23666062 TI - Spatiotemporal expression profile of a putative beta propeller WDR72 in laying hens. AB - The purpose of this study is to characterize the expression profile of a novel gene WDR72 in laying hens. Sixty-week old Hy-line Brown layers with similar laying sequence, egg weight, and shell strength, were selected and divided into 5 groups. The oviduct segments, such as magnum, white isthmus, and uterus, were sampled from each group of hens which were killed at 3 h post-oviposition (3 h P.O.), 4.15-4.5 h P.O., 8.5-9 h P.O., 12 h P.O. and 18 h P.O., respectively. To the 8.5-9 h P.O. hens, additional organs were also sampled besides oviduct tissues. Moreover, another group of hens with weak shell strength were selected and their oviduct segments were sampled at 12 h P.O. Then the expression profile of WDR72 was analyzed using real-time quantitative RT-PCR. The results showed as follows. (1) WDR72 transcripts specifically distributed in parts of organs investigated. At 8.5-9 h P.O., WDR72 appeared to be much more abundantly expressed in hens' oviduct sections, then followed in turn by brain, kidney, lung, glandular stomach and spleen. However, there were almost no WDR72 transcripts expressed in pectoral muscle, liver, heart and jejunum. (2) During the process of an "egg" passing through an oviduct, the expression of WDR72 in the magnum was greatly superior to that in the other two oviduct segments at 3 h P.O., 8.5-9 h P.O., and 12 h P.O.; while it was white isthmus in which WDR72 transcript levels were the highest at 4.15-4.5 h P.O. and 18 h P.O. (3) To any oviduct segment, not only uterus but also magnum and white isthmus, the expression of WDR72 in which was significantly up-regulated at the stages of active calcification. (4) WDR72 transcript levels in any oviduct segments of strong-shell hens were significantly higher than that of weak-shell layers (P < 0.01), which arose the possibility that WDR72 was positively associated with chicken eggshell strength. In conclusion, the expression profile of WDR72 gene in laying hens has been characterized, which would facilitate to further probe into its functions. PMID- 23666061 TI - Comparative gene expression analysis in a highly anthocyanin pigmented mutant of colorless chrysanthemum. AB - In this study, we investigated differentially expressed genes between the original chrysanthemum cultivar 'Argus' with white flower color and its gamma-ray irradiated mutant 'ARTI-purple' with purple flower color. The expression levels of anthocyanin biosynthetic genes were not associated with anthocyanin accumulations of Argus and ARTI-purple. Expressed sequence tags (ESTs) analysis was performed to identify a novel cDNAs encoding enzymes of specific plant metabolic pathways and the biological effects of gamma-ray mutation through alterations in expression in each flower. A total of 796 unigenes were isolated from chrysanthemum ray florets. These unigenes were functionally classified using gene ontologies and tentative pathway associations were established to 99 sequences in the Kyoto encyclopedia of genes and genomes. The expressions of the isolated ESTs were screened by cDNA dot blot hybridization. Seven differentially expressed genes were identified as being involved in carbohydrate and lipid metabolic pathways and five as transcription factor or signal transduction genes. Of particular note, decreased expression of CmMYB1 was identified at the 'ARTI purple'. The CmMYB1 shared high similarity with AtMYB4 and AtMYBL2 which is a negative regulator of anthocyanin and flavonol accumulation. Furthermore, two genes involved in lipid metabolism, enoyl-ACP reductase and [acyl-carrier protein] S-malonyltransferase, were decreased in the 'ARTI-purple' flower. Our results suggest that the purple pigmentation of the 'ARTI-purple' is not just dependent on the expression of anthocyanin synthesis genes, and that the pigmentation may also affect other metabolic processing and the plant cell environment. PMID- 23666063 TI - ZRANB2 localizes to supraspliceosomes and influences the alternative splicing of multiple genes in the transcriptome. AB - Alternative splicing is a major source of protein diversity in humans. The human splicing factor zinc finger, Ran-binding domain containing protein 2 (ZRANB2) is a splicing protein whose specific endogenous targets are unknown. Its upregulation in grade III ovarian serous papillary carcinoma could suggest a role in some cancers. To determine whether ZRANB2 is part of the supraspliceosome, nuclear supernatants from human embryonic kidney 293 cells were prepared and then fractioned on a glycerol gradient, followed by Western blotting. The same was done after treatment with a tyrosine kinase to induce phosphorylation. This showed for the first time that ZRANB2 is part of the supraspliceosome, and that phosphorylation affects its subcellular location. Studies were then performed to understand the splicing targets of ZRANB2 at the whole-transcriptome level. HeLa cells were transfected with a vector containing ZRANB2 or with a vector-only control. RNA was extracted, converted to cDNA and hybridized to Affymetrix GeneChip((r)) Human Exon 1.0 ST Arrays. At the FDR <=1.3 significance level we found that ZRANB2 influenced the alternative splicing of primary transcripts of CENTB1, WDR78, C10orf18, CABP4, SMARCC2, SPATA13, OR4C6, ZNF263, CAPN10, SALL1, ST18 and ZP2. Several of these have been implicated in tumor development. In conclusion ZRANB2 is part of the supraspliceosome and causes differential splicing of numerous primary transcripts, some of which might have a role in cancer. PMID- 23666064 TI - Cancer targeting gene-viro-therapy for pancreatic cancer using oncolytic adenovirus ZD55-IL-24 in immune-competent mice. AB - Cancer targeting gene-viro-therapy (CTGVT) may prove to be an effective treatment for pancreatic cancer (PC). This study was intended to explore the anti-tumor effect of ZD55-IL-24 (oncolytic adenovirus ZD55 harboring IL-24) on PC in immune competent mice. The expression of gene harbored by oncolytic adenovirus ZD55 in PC cells was detected by reporter-gene assays. The in vitro anti PC ability of ZD55-IL-24 was tested by MTT, crystal violet staining and apoptosis assays. The in vivo anti PC effect of ZD55-IL-24 was further observed in an immune-competent mice model by detecting anti-tumor immunity and induction of apoptosis. The expression of gene harbored by ZD55 in PC cells was significantly higher than that harbored by the replicated-deficient adenovirus, and the amount of gene expression was time-dependent and dose-dependent. Both ZD55-IL-24 and ZD55 inhibited PC cells growth, but the anti-tumor effect of ZD55-IL-24 was significantly stronger than that of ZD55, and the ability of ZD55-IL-24 in inducing PC apoptosis was significantly stronger than that of ZD55. The tumor forming rate of group ZD55-IL-24 was the lowest, and the tumor-growing rate was also significantly lower than that of group ZD55 in immune-competent PC models. Moreover, ZD55-IL-24 mediated more anti-cancer immunity effects by induction of stronger T-lymphocytes response to PC cells, higher levels of gamma-IFN and IL-6 cytokines. ZD55-IL-24-mediated CTGVT could inhibit PC growth not only by inducing oncolysis and apoptosis but enhancing the anti-cancer immune effects by inducing T cell response to PC and up-regulating gamma-IFN and IL-6 cytokine in immune competent mice. This may serve as a candidate therapeutic approach for the treatment of PC. PMID- 23666065 TI - Factors influencing survival duration and choice of virgin queens in the stingless bee Melipona quadrifasciata. AB - In Melipona quadrifasciata, about 10% of the females develop into queens, almost all of which are killed. Occasionally, a new queen replaces or supersedes the mother queen or heads a new colony. We investigated virgin queen fate in queenright and queenless colonies to determine the effects of queen behaviour, body mass, nestmate or non-nestmate status, queenright or queenless colony status, and, when queenless, the effect of the time a colony had been queenless, on survival duration and acceptance. None of 220 virgin queens observed in four observation hives ever attacked another virgin queen nor did any of 88 virgin queens introduced into queenright colonies ever attack the resident queen. A new queen was only accepted in a queenless colony. Factors increasing survival duration and acceptance of virgin queens were to emerge from its cell at 2 h of queenlessness, to hide, and to avoid fights with workers. In this way, a virgin queen was more likely to be available when a colony chooses a new queen, 24-48 h after resident queen removal. Running, walking or resting, antennating or trophallaxis, played little or no role, as did the factors body mass or nestmate. "Queen choice" took about 2 h during which time other virgin queens were still being killed by workers. During this agitated process, the bees congregated around the new queen. She inflated her abdomen and some of the workers deposited a substance on internal nest surfaces including the glass lid of the observation hive. PMID- 23666066 TI - Zhang-Rice physics and anomalous copper states in A-site ordered perovskites. AB - In low dimensional cuprates several interesting phenomena, including high Tc superconductivity, are deeply connected to electron correlations on Cu and the presence of the Zhang-Rice (ZR) singlet state. Here, we report on direct spectroscopic observation of the ZR state responsible for the low-energy physical properties in two isostructural A-site ordered cuprate perovskites, CaCu(3)Co(4)O(12) and CaCu(3)Cr(4)O(12) as revealed by resonant soft x-ray absorption spectroscopy on the Cu L(3,2)- and O K-edges. These measurements reveal the signature of Cu in the high-energy 3+ (3d(8)), the typical 2+ (3d(9)), as well as features of the ZR singlet state (i.e., 3d(9)L, L denotes an oxygen hole). First principles GGA + U calculations affirm that the B-site cation controls the degree of Cu-O hybridization and, thus, the Cu valency. These findings introduce another avenue for the study and manipulation of cuprates, bypassing the complexities inherent to conventional chemical doping (i.e. disorder) that hinder the relevant physics. PMID- 23666068 TI - Optical properties of biological tissues: a review. AB - A review of reported tissue optical properties summarizes the wavelength dependent behavior of scattering and absorption. Formulae are presented for generating the optical properties of a generic tissue with variable amounts of absorbing chromophores (blood, water, melanin, fat, yellow pigments) and a variable balance between small-scale scatterers and large-scale scatterers in the ultrastructures of cells and tissues. PMID- 23666067 TI - IgG4-related disease of the ureter: report of two cases and review of the literature. AB - IgG4-related disease (IgG4-RD) is a recently recognized multi-organ fibro inflammatory lesion characterized by elevated IgG4 serum levels and mass-forming lesions. This condition shows similar histological features independently of the site of origin including storiform fibrosis, obliterative phlebitis, and dense lymphoplasmacytic infiltrate with a conspicuous IgG4-positive plasma cell component. Since this disease has only recently been categorized as a single specific nosologic entity, lesions with these typical morphological features have previously been named in different ways, creating some confusion and making it difficult to identify cases published in the literature. Lesions with features suggesting IgG4-RDs have very rarely been reported in the ureter, and they have been named using the terms "inflammatory pseudotumor" and "idiopathic segmental ureteritis." Herein, we describe the clinicopathological features of ureteral IgG4-RD found in two different patients. An 82-year-old female and a 77-year-old male underwent ureteral resection due to severe ureteral wall thickness and lumen stenosis suggestive of urothelial carcinoma. However, histological examinations showed transmural fibro-inflammatory lesions, with abundant IgG4 plasma cells intermixed with histiocytes, lymphocytes, fibroblasts, and scattered eosinophils. We have also accurately reviewed the literature in order to identify, among lesions diagnosed with different names, examples of ureteral IgG4-related lesions to give the reader a comprehensive overview of this relatively rare inflammatory disease. We suggest using the name "ureteral IgG4-RD" for those lesions showing the same morphological features as IgG4-RDs located elsewhere. PMID- 23666069 TI - Pluri-energy analysis of livestock systems--a comparison of dairy systems in different territories. AB - This paper introduces a generic assessment method called pluri-energy analysis. It aims to assess the types of energy used in agricultural systems and their conversion efficiencies. Four types of energy are considered: fossil energy, gross energy contained in the biomass, energy from human and animal labor and solar energy. The method was applied to compare smallholder low-input dairy production systems, which are common in developing countries, to the high-input systems encountered in OECD countries. The pluri-energy method is useful for analyzing the functioning of agricultural systems by highlighting their modes of energy management. Since most dairy systems in South Mali (SM) are low-input systems, they are primarily based on solar and labor energy types and do not require substantial fossil-energy inputs to produce milk. Farms in Poitou Charentes (PC) and Bretagne (BR) show intermediate values of fossil-energy use for milk production, similar to that found in the literature for typical European systems. However, fossil-energy use for milk production is higher on PC than BR farms because of a higher proportion of maize silage in the forage area; grazing pastures are more common on BR farms. Farms on Reunion Island (RI) require a relatively large amount of fossil energy to produce milk, mainly because the island context limits the amount of arable land. Consequently, milk production is based on large imports of concentrated feed with a high fossil-energy cost. The method also enables assessment of fossil-energy-use efficiency in order to increase the performance of biological processes in agricultural systems. Comparing the low-input systems represented by SM to the high-input systems represented by RI, PC and BR, an increase in solar-energy conversion, and thus land productivity, was observed due to intensification via increased fossil energy use. Conversely, though fossil-energy use at the herd level increased milk productivity, its effect on gross-energy conversion by the herd was less evident. Partitioning the total on-farm gross energy produced among animal co-products (milk, meat and manure) highlights the major functions of SM herds, which are managed to produce organic crop fertilizers. PMID- 23666070 TI - Estimation of awareness and perception of water scarcity among farmers in the Guanzhong Plain, China, by means of a structural equation model. AB - This paper applies a structural equation model (SEM) to analyze the formation of awareness and perception of water scarcity, based on a cross-sectional dataset of 446 farmers in the Guanzhong Plain, Shaanxi Province, China. We find that age, percentage of time spent on farming and social network are the main determinants of awareness. Water price and drought experience are the most important explanatory variables of perception. In addition, awareness and perception strongly interact. The results obtained in this paper are relevant for policymaking, since environmental behavior, which includes efficient use of natural resources, tends to improve if supported by internalization of social norms, which in its turn, is promoted by awareness and perception. From the analysis it follows that spreading information via social networks, rather than via the media, is an important vehicle to enhance awareness and perception and thus to improve irrigation water use efficiency. Special attention should be paid to part-time farmers who are limited in directly perceiving water scarcity. Finally, more use should be made of the price mechanism to strengthen perception and awareness. PMID- 23666071 TI - Constructing a ladder of transnational partnership working in support of marine spatial planning: thoughts from the Irish Sea. AB - This paper adds to the growing body of literature on partnerships and Marine Spatial Planning (MSP) by constructing a ladder of transnational partnership working which can act as an aid to partnership development. The first part draws upon partnership working and co-management literature and identifies 5 levels of transnational partnership working: Information Sharing; Administration Sharing; Agreed Joint Rules; Combined Organisation; and Combined Constitution and illustrates what these might entail with reference to established maritime partnerships. The second part of the paper then explores how these generic levels may be used to structure transnational partnership development in a particular marine setting. This draws upon the outputs of two Irish Sea Transnational Partnership Working events which were funded by the UK's Economic and Social Research Council, and in particular on the exploration of motivations for collaboration which was a key point of discussion. In conclusion the paper considers the strengths and weaknesses of the ladder and how it may be enhanced and used more widely to better understand and analyse existing transnational partnership activity and guide the development of new transnational partnerships in support of MSP. PMID- 23666072 TI - Role of sol with iron oxyhydroxide/sodium dodecyl sulfate composites on Fenton oxidation of sorbed phenanthrene in sand. AB - In situ Fenton oxidation has been recently used to oxidize sorbed organic contaminants in soil. The objective of present contribution was to study the role of sodium dodecyl sulfate (SDS) as anionic surfactant and sol with iron oxyhydroxide/SDS for Fenton oxidation of sorbed phenanthrene in sand. The most effective experimental condition for phenanthrene oxidation was the Fenton-like reaction system with 0.35% H2O2, 30 mM SDS, and 4 mM FeCl2. The Fenton-like reactions under these experimental conditions resulted in the production and sustenance of a stable sol with iron oxyhydroxide/SDS composites over 24 h. The formation of iron oxyhydroxide/SDS composites resulted in stabilization of H2O2, and then the Fenton-like reactions were sustained over 24 h. Furthermore, the sol of iron oxyhydroxide/SDS composites gave suitable sites to sustain oxidations of dissolved phenanthrene over a prolonged reaction span, which is required for in situ chemical oxidation. PMID- 23666073 TI - Analysis of social attitude to the new end use of recycled water for household laundry in Australia by the regression models. AB - Recycled water for household laundry can be regarded as a promising strategy to alleviate the current demand on scarce water supplies. Public acceptability becomes fairly important to ensure the successful establishment and development of this new end use. To address the issue, this study conducted social surveys in two locations of Australia, Port Macquarie and Melbourne, where respondents were asked 17 questions. The regression models provide conclusions about which characteristics are more likely to lead to the acceptance of recycled water from society. Three attitudinal variables (RWAlterDW, Attitude and Cost) and three psychological variables (Odour, Reading and SmallUnit) were found to be the key driving forces behind domestic water reuse behaviour. These findings could drive the future research direction to achieve better public perception of this new end use of recycled water. PMID- 23666074 TI - Motivating green public procurement in China: an individual level perspective. AB - Green public procurement (GPP) practices have been recognized as an effective policy tool for sustainable production and consumption. However, GPP practices adoption, especially in developing countries, is still an issue. Seeking to help understand these adoption issues, we develop a conceptual model which hypothesizes moderation effects of GPP knowledge on the relationships between GPP drivers and practices. Using primary data collected from 193 Chinese government officials, we find that regulations, rewards & incentive gains, and stakeholders exert pressure to motivate adoption of GPP practices. Knowledge of GPP regulations, responsibilities and experiences in developed countries is found to be limited. The study also found that voluntary regulations may actually be demotivating GPP practices. This study contributes to further theoretical and practical understanding of GPP practices. The findings can be helpful for policy makers, especially those in developing countries, to establish promotion and diffusion mechanisms for GPP practices as an important sustainable development tool. PMID- 23666075 TI - Oxidatively stable polyaniline:polyacid electrodes for electrochemical energy storage. AB - Conjugated polymers, such as polyaniline, have been widely explored as sensors, electrodes, and conductive fillers. As an electrode material in electrochemical energy storage systems, polyaniline can be subject to irreversible oxidation that reduces cycle life and electrode capacity, thus, limiting its widespread application. Here we present a simple route to produce and prepare polyaniline based electrodes that are oxidatively stable up to 4.5 V vs. Li/Li(+). The route uses a polyacid to stabilize the fully oxidized pernigraniline salt form of polyaniline, which is normally highly unstable as a homopolymer. The result is an organic electrode of exceptionally high capacity, energy density, power density, and cycle life. We demonstrate that the polyaniline:polyacid electrode stores 230 mA h g(-1) of polyaniline for over 800 cycles, far surpassing homopolymer polyaniline under equivalent conditions. This approach provides a highly stable, electrochemically reversible replacement for conventional polyaniline. PMID- 23666076 TI - Synthesis, fluorescence properties and theoretical calculations of novel stilbene derivatives based on 1,3,4-oxadiazole bearing anthracene core. AB - Two novel stilbene derivatives bearing anthracene core based on 1,3,4-oxadiazole were efficiently synthesized and characterized by (1)H-NMR, mass spectrometry and elemental analysis. The optical properties of the title compounds were investigated by UV-vis absorption and fluorescence emission spectra in different solvents. Chemical calculations were performed by density functional theory (DFT) at the (B3LYP)/6-31G* level. The results show the two compounds exhibit strong green fluorescence emission ranged from 489-493 nm, and the fluorescence quantum yield ranged from 0.78-0.92. Their HOMO and LUMO levels are (-5.44 eV, -2.25 eV) and (-5.45 eV, -2.28 eV), respectively. The influence of the solvent on the fluorescence intensities was also discussed. PMID- 23666077 TI - Role of aminoacyl-tRNA synthetases in infectious diseases and targets for therapeutic development. AB - Aminoacyl-tRNA synthetases (AARSs) play a pivotal role in protein synthesis and cell viability. These 22 "housekeeping" enzymes (1 for each standard amino acid plus pyrrolysine and o-phosphoserine) are specifically involved in recognizing and aminoacylating their cognate tRNAs in the cellular pool with the correct amino acid prior to delivery of the charged tRNA to the protein synthesis machinery. Besides serving this canonical function, higher eukaryotic AARSs, some of which are organized in the cytoplasm as a multisynthetase complex of nine enzymes plus additional cellular factors, have also been implicated in a variety of non-canonical roles. AARSs are involved in the regulation of transcription, translation, and various signaling pathways, thereby ensuring cell survival. Based in part on their versatility, AARSs have been recruited by viruses to perform essential functions. For example, host synthetases are packaged into some retroviruses and are required for their replication. Other viruses mimic tRNA like structures in their genomes, and these motifs are aminoacylated by the host synthetase as part of the viral replication cycle. More recently, it has been shown that certain large DNA viruses infecting animals and other diverse unicellular eukaryotes encode tRNAs, AARSs, and additional components of the protein-synthesis machinery. This chapter will review our current understanding of the role of host AARSs and tRNA-like structures in viruses and discuss their potential as anti-viral drug targets. The identification and development of compounds that target bacterial AARSs, thereby serving as novel antibiotics, will also be discussed. Particular attention will be given to recent work on a number of tRNA-dependent AARS inhibitors and to advances in a new class of natural "pro drug" antibiotics called Trojan Horse inhibitors. Finally, we will explore how bacteria that naturally produce AARS-targeting antibiotics must protect themselves against cell suicide using naturally antibiotic resistant AARSs, and how horizontal gene transfer of these AARS genes to pathogens may threaten the future use of this class of antibiotics. PMID- 23666078 TI - Molecular chirality: language, history, and significance. AB - In this chapter some background material concerning molecular chirality and enantiomerism is presented. First some basic chemical-molecular aspects of chirality are reviewed, after which certain relevant terminology whose use in the literature has been problematic is discussed. Then an overview is provided of some of the early discoveries that laid the foundations of the science of molecular chirality in chemistry and biology, including the discovery of the phenomenon of molecular chirality by L. Pasteur, the proposals for the asymmetric carbon atom by J.H. van 't Hoff and J.A. Lebel, Pasteur's discovery of biological enantioselectivity, the discovery of enantioselectivity at biological receptors by A. Piutti, the studies of enzymatic stereoselectivity by E. Fischer, and the work on enantioselectivity in pharmacology by A. Cushny. Finally, the role of molecular chirality in pharmacotherapy and new-drug development, arguably one of the main driving forces for the current intense interest in the phenomenon of molecular chirality, is discussed. PMID- 23666079 TI - Beyond pentacenes: synthesis and properties of higher acenes. AB - Acenes consist of linearly annulated benzene rings. Their reactivity increases quickly with increasing chain length. Therefore acenes longer than pentacene are very sensitive towards oxygen in the presence of light and thus these molecules have not been well studied or have remained elusive in spite of synthetic efforts dating back to the 1930s. This review gives an historical account of the development of the chemistry of acenes larger than pentacene and summarizes the recent progress in the field including strategies for stabilization of higher acenes up to nonacene. PMID- 23666080 TI - Differentiation of enantiomers by capillary electrophoresis. AB - Capillary electrophoresis (CE) has matured to one of the major liquid phase enantiodifferentiation techniques since the first report in 1985. This can be primarily attributed to the flexibility as well as the various modes available including electrokinetic chromatography (EKC), micellar electrokinetic chromatography (MEKC), and microemulsion electrokinetic chromatography (MEEKC). In contrast to chromatographic techniques, the chiral selector is mobile in the background electrolyte. Furthermore, a large variety of chiral selectors are available that can be easily combined in the same separation system. In addition, the migration order of the enantiomers can be adjusted by a number of approaches. In CE enantiodifferentiations the separation principle is comparable to chromatography while the principle of the movement of the analytes in the capillary is based on electrophoretic phenomena. The present chapter will focus on mechanistic aspects of CE enantioseparations including enantiomer migration order and the current understanding of selector-selectand structures. Selected examples of the basic enantioseparation modes EKC, MEKC, and MEEKC will be discussed. PMID- 23666081 TI - Enantiomeric differentiation by synthetic helical polymers. AB - Recent advances in the synthesis of helical polymers and their applications as chiral materials, in particular chiral stationary phases (CSPs), for high performance liquid chromatography (HPLC) are reviewed with an emphasis on the key role of the helical conformations with one-handedness for the prominent chiral recognition of enantiomers. The historical background of artificial optically active helical polymers is also briefly described. PMID- 23666082 TI - Salient features of enantioselective gas chromatography: the enantiomeric differentiation of chiral inhalation anesthetics as a representative methodological case in point. AB - The enantiomeric differentiation of the volatile chiral inhalation anesthetics enflurane, isoflurane, and desflurane by analytical and preparative gas chromatography on various modified cyclodextrins is described. Very large enantioseparation factors alpha are obtained on the chiral selector octakis(3-O butanoyl-2,6-di-O-pentyl)-gamma-cyclodextrin (Lipodex E). The gas chromatographically observed enantioselectivities are corroborated by NMR spectroscopy using Lipodex E as chiral solvating agent and by various sensor devices using Lipodex E as sensitive chiral coating layer. The assignment of the absolute configuration of desflurane is clarified. Methods are described for the determination of the enantiomeric distribution of chiral inhalation anesthetics during narcosis in clinical trials. The quantitation of enantiomers in a sample by the method of enantiomeric labeling is outlined. Reliable thermodynamic parameters of enantioselectivity are determined by using the retention-increment R' approach for the enantiomeric differentiation of various chiral halocarbon selectands on diluted cyclodextrin selectors. PMID- 23666083 TI - Atrioventricular valve regurgitation in the fetus with atrioventricular canal defect: transition from prenatal to postnatal life. AB - Atrioventricular valve regurgitation (AVVR) is a clinically important element of the common atrioventricular canal defect. Cardiac preload and afterload increase from prenatal to postnatal life. These hemodynamic changes may increase the degree of regurgitation and affect management and prognosis. We sought to investigate the frequency of change in degree of AVVR from fetal to postnatal life in this patient population. Subjects who underwent both fetal and postnatal echocardiography within 4 weeks of life between January 2008 and September 2010 were included in the study. Degree of AVVR was assessed by color Doppler imaging and scored as 0 (no regurgitation), 1 (hemodynamically insignificant regurgitation), and 2 (hemodynamically important regurgitation). Forty-nine subjects were included. Mean gestational age at fetal echocardiogram was 34 +/- 2.8 weeks; age at postnatal echocardiogram was a median of <24 h of age (range 0 24). After birth, 69 % subjects had no change, 8 % of subjects had a decrease, and 22 % subjects had an increase in AVVR grade. Five patients progressed from a fetal score 0 or 1 to postnatal score 2. Neither trisomy 21 nor heterotaxy syndrome were risk factors for progression of AVVR. In patients with AV canal defects, 90 % demonstrate no hemodynamically significant change in AVVR from fetal to postnatal life, whereas 10 % display a hemodynamically significant change. AVVR appreciated in utero is predictive of neonatal regurgitation in the majority of patients. These findings have implications for the counseling and management of the fetus with AV canal defect. PMID- 23666084 TI - Centrosome amplification causes microcephaly. AB - Centrosome amplification is a hallmark of human tumours. In flies, extra centrosomes cause spindle position defects that result in the expansion of the neural stem cell (NSC) pool and consequently in tumour formation. Here we investigated the consequences of centrosome amplification during mouse brain development and homeostasis. We show that centrosome amplification causes microcephaly due to inefficient clustering mechanisms, where NSCs divide in a multipolar fashion producing aneuploid cells that enter apoptosis. Importantly, we show that apoptosis inhibition causes the accumulation of highly aneuploid cells that lose their proliferative capacity and differentiate, thus depleting the pool of progenitors. Even if these conditions are not sufficient to halt brain development, they cause premature death due to tissue degeneration. Our results support an alternative concept to explain the etiology of microcephaly and show that centrosome amplification and aneuploidy can result in tissue degeneration rather than overproliferation and cancer. PMID- 23666086 TI - Carbon catabolite repression-independent and pH-dependent production of indoles by Rubrivivax benzoatilyticus JA2. AB - Rubrivivax benzoatilyticus JA2 produces indole derivatives (indoles) from aniline, anthranilate or L-tryptophan. Glucose repressed indole production in R. benzoatilyticus JA2, while malate had no effect. Growth of R. benzoatilyticus JA2 on glucose resulted in decrease in culture pH (6.4) compared with malate (8.4). Growth of R. benzoatilyticus JA2 on sugar carbon sources decreased culture pH (6.4-6.6) and indole production. Further, culture pH of 6.4 repressed the indole production, and pH 8.4 promoted the production irrespective of carbon sources used for growth. Moreover, correlation between indole production and culture pH was observed, where acidic pH inhibited indole production, while alkaline pH promoted the production, suggesting the role of pH in indole production. Tryptophan-catabolizing enzyme activities are significantly high in malate-grown cultures (pH 8.4) compared with that of the glucose (pH 6.4)-grown cultures and corroborated well with indole production, indicating their role in indole production. These results confirm that indole production in R. benzoatilyticus JA2 is pH dependent rather than carbon catabolite repression. PMID- 23666085 TI - Synergy between XMAP215 and EB1 increases microtubule growth rates to physiological levels. AB - In cells, a complex network of proteins regulates the dynamic growth of microtubules that is essential for division and migration. In vitro approaches with purified components have so far been unable to reconstitute fast microtubule growth observed in vivo . Here we show that two well-studied plus-end-binding proteins-end-tracking protein EB1 and microtubule polymerase XMAP215-act together to strongly promote microtubule growth to cellular rates. Unexpectedly, the combined effects of XMAP215 and EB1 are highly synergistic, with acceleration of growth well beyond the product of the individual effects of either protein. The synergistic growth promotion does not rely on any of the canonical EB1 interactions, suggesting an allosteric interaction through the microtubule end. This hypothesis is supported by the finding that taxol and XMAP215, which have non-overlapping binding sites on tubulin, also act synergistically on growth. The increase in growth rates is accompanied by a strong enhancement of microtubule catastrophe by EB1, thereby rendering the fast and dynamic microtubule behaviour typically observed in cells. PMID- 23666087 TI - Size-dependent Auger spectra and two-hole Coulomb interaction of small supported Cu-clusters. AB - Auger (L3M4,5M4,5) and X-ray photoionization spectra (2p, 3d) of mass-selected CuN-clusters supported by a thin natural silica layer are presented in the size range N = 8-55 atoms per cluster. The Auger spectra of all clusters are shifted to a lower kinetic energy with respect to the spectrum of the bulk. Furthermore the Auger energy decreases systematically with decreasing cluster size. The binding energies of the 2p and 3d valence states are higher than the corresponding bulk values. Using the energy of the Auger main line, the corresponding core hole peak and the centroid of the self-convoluted 3d valence band the on-site Coulomb interaction energy Udd of the two-hole final state as a function of cluster size has been determined. PMID- 23666088 TI - Microbial production of isoquinoline alkaloids as plant secondary metabolites based on metabolic engineering research. AB - Plants produce a variety of secondary metabolites that possess strong physiological activities. Unfortunately, however, their production can suffer from a variety of serious problems, including low levels of productivity and heterogeneous quality, as well as difficulty in raw material supply. In contrast, microorganisms can be used to produce their primary and some of their secondary metabolites in a controlled environment, thus assuring high levels of efficiency and uniform quality. In an attempt to overcome the problems associated with secondary metabolite production in plants, we developed a microbial platform for the production of plant isoquinoline alkaloids involving the unification of the microbial and plant metabolic pathways into a single system. The potential applications of this system have also been discussed. PMID- 23666089 TI - Long-term depression and other synaptic plasticity in the cerebellum. AB - Cerebellar long-term depression (LTD) is a type of synaptic plasticity and has been considered as a critical cellular mechanism for motor learning. LTD occurs at excitatory synapses between parallel fibers and a Purkinje cell in the cerebellar cortex, and is expressed as reduced responsiveness to transmitter glutamate. Molecular induction mechanism of LTD has been intensively studied using culture and slice preparations, which has revealed critical roles of Ca(2+), protein kinase C and endocytosis of AMPA-type glutamate receptors. Involvement of a large number of additional molecules has also been demonstrated, and their interactions relevant to LTD mechanisms have been studied. In vivo experiments including those on mutant mice, have reported good correlation of LTD and motor learning. However, motor learning could occur with impaired LTD. A possibility that cerebellar synaptic plasticity other than LTD compensates for the defective LTD has been proposed. PMID- 23666090 TI - Estimation of the total population moving into and out of the 20 km evacuation zone during the Fukushima NPP accident as calculated using "Auto-GPS" mobile phone data. AB - The first objective data showing the geographical locations of people in Fukushima after the Fukushima Dai-ichi nuclear power plant accident, obtained by an analysis of GPS (Global Positioning System)-enabled mobile phone logs, are presented. The method of estimation is explained, and the flow of people into and out of the 20 km evacuation zone during the accident is visualized. PMID- 23666092 TI - Automatic detection, localization, and volume estimation of ischemic infarcts in noncontrast computed tomographic scans: method and preliminary results. AB - OBJECTIVES: Sensitivity of noncontrast computed tomography (NCCT) in detecting hyperacute (< 8 hours) and acute (< 24 hours) cerebral infarction is low. We propose an automatic method to detect and localize ischemic infarct and to assess its volume from a single NCCT scan. MATERIALS AND METHODS: The method automatically determines attenuation value ranges of cerebrospinal fluid and white and gray matter, separates the brain scan into the left and right hemispheres, and by analyzing hemisphere attenuation value distributions using percentile difference ratios, it detects, localizes, and quantifies the infarct without its segmentation. The method performance was evaluated on 576 patients with clinically confirmed stroke through NCCT scans acquired at 4 centers to measure how it matched with that of experts in detection, localization, and assessment of infarct volume. The time from the onset of symptoms ranged from 1.5 to 72 hours for 450 scans and more than 72 hours for 82 scans, most with pathologic findings in addition to cerebral infarction; the time was unavailable for 44 scans. In addition, the method was compared with the novice's (with 52 scans) and experienced readers' infarct detection (with 21 * 2 scans) in early ischemia detection (with the time from the onset of symptoms ranging from 1.5 to 7 hours). RESULTS: The method matches 100% the expert's infarct detection when chronic infarcts, leukoaraiosis cases, and infarct volumes less than 2 cm (determined by detection accuracy simulation) are excluded from the analysis. For all cases excluding infarct volumes less than 2 cm, the method detection accuracy is 95.7%. Overall, the method detection accuracy is 83.2%. The early method detection accuracy (<= 3 hours) is 78.4%. The novice detection accuracy is 27.8% (<= 3 hours), 37.5% (3 < to <= 8 hours), and 77.8% (> 8 hours), whereas the expert detection accuracy for these cases is 100%. Moreover, the method detected all 21 early infarcts, of which 15 were missed by the stroke experts and 14 of 15 were missed by a general radiologist. The method performs automatic analysis in approximately 7 seconds. CONCLUSIONS: The results demonstrate potential benefits of our method for enhancing expert's performance because it quickly localizes the infarct and detects cases missed by experts, and it is to be considered as an aid in the emergency department because it substantially outperforms novice readers (100% vs 27%) in infarct detection on NCCT. PMID- 23666091 TI - Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease. AB - Non-alcoholic fatty liver disease is marked by hepatic fat accumulation not due to alcohol abuse. Several studies have demonstrated that NAFLD is associated with insulin resistance leading to a resistance in the antilipolytic effect of insulin in the adipose tissue with an increase of free fatty acids (FFAs). The increase of FFAs induces mitochondrial dysfunction and development of lipotoxicity. Moreover, in subjects with NAFLD, ectopic fat also accumulates as cardiac and pancreatic fat. In this review we analyzed the mechanisms that relate NAFLD with metabolic syndrome and dyslipidemia and its association with the development and progression of cardiovascular disease. PMID- 23666093 TI - Dynamic contrast-enhanced computed tomography to assess antitumor treatment effects: comparison of two contrast agents with different pharmacokinetics. AB - OBJECTIVE: Dynamic contrast-enhanced computed tomography (CT) is a sensitive method to evaluate functional changes of the tumor microvasculature after antitumor therapy by monitoring the kinetics of the contrast agent (CA) passage. Therefore, the pharmacokinetic properties of the CA possess a central role: iodinated x-ray CAs are small molecules that distribute rapidly within the extravascular extracellular space, whereas larger macromolecular compounds have a prolonged vascular phase and a restricted volume of distribution. The aim of this animal study was to compare the x-ray CA iopromide and the experimental gadolinium-based dendrimeric Gadomer in the assessment of early therapy response after a single dose of the novel multikinase inhibitor regorafenib. MATERIALS AND METHODS: For the study, an experimental GS9L rat glioma model was used. For each CA, the animals were divided randomly into a therapy (n = 8) and a placebo group (n = 4). All animals underwent a baseline CT and a second examination 24 hours after therapy with regorafenib (10 mg/kg body weight, oral) and placebo, respectively. The CAs were administered intravenously at a dosage of 0.5 g I or Gd per kg body weight and dynamic CT scans (80 kV, 160 mAseff, no table feed) of the tumor region were performed up to 404 seconds post injection (p.i.). Image evaluation was done by analyzing tumor time-density curves, the area under the curve (AUC), and the results of the 2-compartment Patlak modeling. RESULTS: Significant differences in the time-density curves, the AUC, and the Patlak transfer constant (Ktrans) were observed 24 hours after the regorafenib therapy but not after the placebo treatment. The treatment effects visualized with iopromide were most pronounced at early time points (<100 seconds p.i.), whereas imaging with Gadomer was most effective at a later time window (300-404 seconds p.i.). Comparable reductions of the AUC to 0.69 +/- 0.12 (iopromide) and 0.76 +/- 0.11 (Gadomer) were found 24 hours after the therapy. A significant higher Ktrans was detected with iopromide (14.3 +/- 2.7 mL per 100 mL/min) compared with Gadomer (1.8 +/- 0.2 mL per 100 mL/min). However, the relative reduction in Ktrans to 67% +/- 11% (iopromide) and to 68% +/- 7% (Gadomer) 24 hours after the therapy was similar. CONCLUSIONS: Dynamic contrast-enhanced CT detects early treatment effects on tumor microvasculature after a single dose of regorafenib, independently of the used CA. Gadomer showed a later optimal imaging window than iopromide did. However, the efficacy of Gadomer- and iopromide-enhanced imaging is equivalent. The results demonstrate the potential of dynamic contrast-enhanced CT using clinically available x-ray CA in the assessment of early treatment response after administration of novel antitumor therapeutic agents. PMID- 23666095 TI - Multivisceral resection in colorectal cancer: a systematic review. AB - BACKGROUND: The objective of this study was to critically evaluate current literature on outcomes following multivisceral resection (MVR) in colorectal cancer (CRC). Adequate surgical resection with clear margins is imperative in achieving long-term survival in colorectal cancer. Where there is adherence to or invasion of adjacent organs, (MVR) may be needed to achieve complete disease clearance. METHODS: A systematic review of MVR in CRC was performed. Pubmed/Medline and Cochrane databases were searched for English language articles from 1995 to 2012 using a predefined strategy. Retrieved abstracts were independently screened for relevance and data extracted from selected studies by 2 researchers. Results are reported as weighted means. RESULTS: Included were 22 studies comprising 1575 patients (87.0% primary colorectal cancer; 13.0% recurrent, 63.8% rectal; 36.2% colon). The most common organs resected were the bladder and reproductive organs. The perioperative mortality was 4.2% with morbidity of 41.5% (95% CI, 40.8-42.2%). The overall 5-year survival rate was 50.3% (95% CI, 49.9-50.8%). Surgery for recurrence was associated with worse outcomes than primary tumors with 5-year survival 19.5% (95% CI, 17.8-21.1%) for recurrent rectal cancer and primary rectal tumors 5-year overall survival 52.8% (95% CI, 52.0-53.8%). R0 resection was the strongest factor associated with long term survival. CONCLUSIONS: Multivisceral resection provides the best possibility of long-term survival in locally advanced primary colorectal cancer in which a clear margin has been achieved. PMID- 23666096 TI - A systematic review of evidence-informed practices for patient care rounds in the ICU*. AB - OBJECTIVES: Patient care rounds are a key mechanism by which healthcare providers communicate and make patient care decisions in the ICU but no synthesis of best practices for rounds currently exists. Therefore, we systematically reviewed the evidence for facilitators and barriers to patient care rounds in the ICU. DATA SOURCES: Search of Medline, Embase, CINAHL, PubMed, and the Cochrane library through September 21, 2012. STUDY SELECTION: Original, peer-reviewed research studies (no methodological restrictions) were selected, which described current practices, facilitators, or barriers to healthcare provider rounding in the ICU. DATA EXTRACTION: Two authors with methodological and content expertise independently abstracted data using a prespecified abstraction tool. DATA SYNTHESIS: The literature search identified 7,373 citations. Reviews of abstracts led to the retrieval of 136 full text articles for assessment; 43 articles in three languages (English, German, Spanish) were selected for review. Of these, 13 were ethnographic studies and 15 uncontrolled before-after studies. Six studies used control groups, including one cross-over randomized, one time-series, three cohort, and one controlled before-after study. A total of 13 facilitators and 9 barriers to patient care rounds were identified through a narrative and meta synthesis of included studies. Identified facilitators suggest that the quality of rounds is improved when conducted by a multidisciplinary group of providers, with explicitly defined roles, using a standardized structure and goal-oriented approach that includes a best practices checklist. Barriers to quality patient care rounds include poor information retrieval and documentation, interruptions, long rounding times, and allied healthcare provider perceptions of not being valued by rounding physicians. CONCLUSIONS: Although the evidence base for best practices of patient care rounds in the ICU is limited, several practical and low risk practices can be considered for implementation. PMID- 23666097 TI - Extracorporeal versus conventional cardiopulmonary resuscitation after ventricular fibrillation cardiac arrest in rats: a feasibility trial. AB - OBJECTIVES: Extracorporeal cardiopulmonary resuscitation with cardiopulmonary bypass potentially provides cerebral reperfusion, cardiovascular support, and temperature control for resuscitation from cardiac arrest. We hypothesized that extracorporeal cardiopulmonary resuscitation is feasible after ventricular fibrillation cardiac arrest in rats and improves outcome versus conventional cardiopulmonary resuscitation. DESIGN: Prospective randomized study. SETTING: University laboratory. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Rats (intubated, instrumented with arterial and venous catheters and cardiopulmonary bypass cannulae) were randomized to conventional cardiopulmonary resuscitation, extracorporeal cardiopulmonary resuscitation with/without therapeutic hypothermia, or sham groups. After 6 minutes of ventricular fibrillation cardiac arrest, resuscitation was performed with drugs (epinephrine, sodium bicarbonate, and heparin), ventilation, either cardiopulmonary resuscitation or extracorporeal cardiopulmonary resuscitation, and defibrillation. Temperature was maintained at 37.0 degrees C or 33.0 degrees C for 12 hours after restoration of spontaneous circulation. Neurologic deficit scores, overall performance category, histological damage scores (viable neuron counts in CA1 hippocampus at 14 days; % of sham), and microglia proliferation and activation (Iba-1 immunohistochemistry) were assessed. RESULTS: Extracorporeal cardiopulmonary resuscitation induced hypothermia more rapidly than surface cooling (p<0.05), although heart rate was lowest in the extracorporeal cardiopulmonary resuscitation hypothermia group (p<0.05). Survival, neurologic deficit scores, overall performance category, and surviving neurons in CA1 did not differ between groups. Hypothermia significantly reduced neuronal damage in subiculum and thalamus and increased the microglial response in CA1 at 14 days (all p<0.05). There was no benefit from extracorporeal cardiopulmonary resuscitation versus cardiopulmonary resuscitation on damage in any brain region and no synergistic benefit from extracorporeal cardiopulmonary resuscitation with hypothermia. CONCLUSIONS: In a rat model of 6-minute ventricular fibrillation cardiac arrest, cardiopulmonary resuscitation or extracorporeal cardiopulmonary resuscitation leads to survival with intact neurologic outcomes. Twelve hours of mild hypothermia attenuated neuronal death in subiculum and thalamus but not CA1 and, surprisingly, increased the microglial response. Resuscitation from ventricular fibrillation cardiac arrest and rigorous temperature control with extracorporeal cardiopulmonary resuscitation in a rat model is feasible, regionally neuroprotective, and alters neuroinflammation versus standard resuscitation. The use of experimental extracorporeal cardiopulmonary resuscitation should be explored using longer insult durations. PMID- 23666098 TI - In silico metabolic engineering of Bacillus subtilis for improved production of riboflavin, Egl-237, (R,R)-2,3-butanediol and isobutanol. AB - Bacillus subtilis is a Gram-positive sporiferous bacterium widely used in a variety of industrial fields as a producer of high-quality vitamins, enzymes and proteins. Many genetic modifications and evolutionary engineering optimisations aiming at obtaining a better performing strain for its products have been studied. As genome-scale metabolic network models have gained significant popularity as effective tools in metabolic phenotype studies, we reconstructed a genome-scale metabolic network of B. subtilis-iBsu1147. The accuracy of iBsu1147 is validated by growth on various carbon sources, single gene knockout and large fragment non-essential gene knockout simulations. The model is used for the in silico metabolic engineering design of reactions over/underexpressed or knockout for increasing the production of four important products of B. subtilis: riboflavin, cellulase Egl-237, (R,R)-2,3-butanediol and isobutanol. The simulation predicted candidate reactions related to the improvement of strain performance on related products. The prediction is partly supported by previously published results. Due to the complexity of the biological system, it is difficult to manually find the factors that are not directly related to the production of the target compounds. The in silico predictions provide more choices for further strain improvement for these products. PMID- 23666099 TI - Bifidobacterium breve B-3 exerts metabolic syndrome-suppressing effects in the liver of diet-induced obese mice: a DNA microarray analysis. AB - We previously reported that supplementation with Bifidobacterium breve B-3 reduced body weight gain and accumulation of visceral fat in a dose-dependent manner, and improved serum levels of total cholesterol, glucose and insulin in a mouse model of diet-induced obesity. In this study, we investigated the expression of genes in the liver using DNA microarray analysis and q-PCR to reveal the mechanism of these anti-obesity effects in this mouse model. Administration of B. breve B-3 led to regulated gene expression of pathways involved in lipid metabolism and response to stress. The results indicate that these regulations in the liver are related to the anti-metabolic syndrome effects of B. breve B-3. PMID- 23666100 TI - Increased bacterial putrescine has no impact on gut morphology and physiology in gnotobiotic adolescent mice. AB - Gut bacteria influence host anatomy and physiology. It has been proposed that bacterial metabolites including polyamines are responsible for intestinal maturation and mucosal growth. We have hypothesised that bacterially produced polyamines act as trophic factors and thereby influence large intestinal crypt depth and thickness of the different gut layers. For that purpose, germ-free mice were associated with two different microbial consortia. One group was colonised with a simplified human microbiota (SIHUMI). The second group was associated with SIHUMI + Fusobacterium varium (SIHUMI + Fv), which is known to produce high amounts of polyamines. Polyamine concentrations were measured by HPLC and morphological parameters were determined microscopically. Germ-free and conventional mice served as controls. The caecal putrescine concentration of the SIHUMI + Fv was 61.8 MUM (47.6-75.5 MUM), whereas that of conventional and SIHUMI mice was 28.8 MUM (1.3-41.7 MUM) and 24.5 MUM (16.8-29.1 MUM), respectively. The caecal putrescine concentration of germ-free mice was only 0.6 MUM (0-1.0 MUM). Caecal crypt depth and thickness of the different caecal layers revealed no significant differences between SIHUMI and SIHUMI + Fv mice. However, the crypt depth in the caeca of conventional, SIHUMI and SIHUMI + Fv mice was increased by 48.6% (P<0.001), 39.7% (P<0.001) and 28.5% (P<0.05), respectively, compared to germ-free mice. These findings indicate that increased intestinal putrescine concentrations do not influence gut morphology in our gnotobiotic adolescent mice. PMID- 23666101 TI - Expression of three beta-type carbonic anhydrases in tomato fruits. AB - Carbonic anhydrase (CA) and phosphoenolpyruvate carboxylase (PEPC) activity were found in different Solanum lycopersicum fruit tissues, predominantly in the locular parenchyma and pericarp. The distribution of the CA and PEPC proteins in the tomato fruit tissues was examined by immunohistolocalization. CA and PEPC proteins were found in all fruit tissues examined as well as in the seeds. Three full length cDNA clones designated SlCA1, SlCA2 and SlCA3 coding for beta carbonic anhydrases (CA; EC 4.2.1.1) were identified and characterized from tomato fruit. SlCA1 and SlCA3 encode two putative cytosolic isoforms whereas SlCA2 encodes a putative plastidial isoform. Quantitative real time RT-PCR analysis revealed that accumulation of SlCA1 mRNA transcripts was detected in all examined tomato fruit tissues or organs, whereas SlCA2 gene transcripts were found in abundance in leaves. Stems also had SlCA2 transcripts, with transcript levels being higher in flowers than in stems. The SlCA3 gene transcripts were found only in the flowers and the roots. The SlPEPC1 and SlPEPC2 gene transcript levels in different fruit tissues of the tomato were also examined. Tauhe possible role of CA isoforms in relation to PEPC in tomato fruit is discussed. PMID- 23666102 TI - Genetic diversity assessment of summer squash landraces using molecular markers. AB - Plant identification, classification, and genotyping within a germplasm collection are essential elements for establishing a breeding program that enhances the probability of plants with desirable characteristics in the market place. In this study, random amplified polymorphic DNA (RAPD) was used as a molecular tool to assess the diversity and relationship among 20 summer squash (Curcubita pepo L.) landraces traditionally used to treat hypertension and prostate hyperplasia. A total of 10 RAPD primers produced 65 reproducible bands of which 46 (70.77 %) were polymorphic, indicating a large number of genotypes within the summer squash lines. Cluster analysis divided the summer squash germplasm into two groups, one including one landrace and a second containing 19 landraces that could be divided into five sub-groups. Results of this study indicate the potential of RAPD markers for the identification and assessment of genetic variations among squash landraces and provide a number of choices for developing a successful breeding program to improve summer squash. PMID- 23666103 TI - Association between LEPR and MC4R genes polymorphisms and composition of milk from sows of dam line. AB - The polymorphisms of LEPR and MC4R genes are involved in appetite control mechanisms and indirectly associated with level of fat content in pig carcasses. Therefore, the aim of our study was to determine if both polymorphisms have an effect on components of colostrum and milk of sows. In our study we used gilts of two Polish breeds: Polish Landrace and Polish Large White, which belong to dam line in Polish breeding. Colostrum and milk of sows were collected in 7, 14 and 21 day of lactation to assay solids, total protein, fat and lactose. The obtained results showed, that the observed mutation (G/A 1426 MC4R) had a significant effect mainly on the fat and solids content of colostrum. Animals with the MC4R (AA) genotype had 2.13 and 1.91 % (P <= 0.01) lower fat content of colostrum compared to sows with the MC4R (GG) genotype and heterozygous MC4R (AG). The presence of the MC4R (A) allele in the animals' genotype contributed to a decrease in fat and solids content of colostrum. The LEPR/HpaII mutation was found to have a considerable effect on the level of most colostrum components (fat, protein and solids) in both pig breeds. Significant decrease in the value of the colostrum components (except lactose) was observed only for animals with the allele LEPR (B). The results obtained suggest that these genes might be used in selection of dam-line pigs as genetic markers of milk quality. PMID- 23666104 TI - DNMT1, DNMT3A and DNMT3B gene variants in relation to ovarian cancer risk in the Polish population. AB - Studies have demonstrated that changes in DNA methylation of cancer related genes can be an elementary process accounting for ovarian tumorigenesis. Therefore, we evaluated the possible association of single nucleotide polymorphisms (SNPs) of DNA methyltransferases (DNMTs) genes, including DNMT1, DNMT3B, and DNMT3A, with ovarian cancer development in the Polish population. Using PCR-RFLP and HRM analyses, we studied the prevalence of the DNMT1 rs8101626, rs2228611 and rs759920, DNMT3A rs2289195, 7590760, rs13401241, rs749131 and rs1550117, and DNMT3B rs1569686, rs2424913 and rs2424932 SNPs in patients with ovarian cancer (n=159) and controls (n=180). The lowest p values of the trend test were observed for the DNMT1 rs2228611 and rs759920 SNPs in patients with ovarian cancer (p trend=0.0118 and p trend=0.0173, respectively). Moreover, we observed, in the recessive inheritance model, that the DNMT1 rs2228611 and rs759920 SNPs are associated with an increased risk of ovarian cancer development [OR 1.836 (1.143 2.949), p=0.0114, p corr=0.0342, and OR 1.932 (1.185-3.152), p=0.0078, p cor=0.0234, respectively]. However, none of other nine studied SNPs displayed significant contribution to the development of ovarian cancer. Furthermore, haplotype and multifactor dimensionality reduction analysis of the studied DNMT1, DNMT3B, and DNMT3A polymorphisms did not reveal either SNP combinations or gene interactions to be associated with the risk of ovarian cancer development. Our results may suggest that DNMT1 variants may be risk factors of ovarian cancer. PMID- 23666105 TI - Genetic polymorphims of estrogen receptor alpha -397 PvuII (T>C) and -351 XbaI (A>G) in a portuguese population: prevalence and relation with breast cancer susceptibility. AB - Estrogen receptor alpha (ERalpha), that mediates the biologic effects of estrogen in estrogen-sensitive tissues like breast, is genetically polymorphic. To evaluate the association between -397 PvuII (T>C) and -351 XbaI (A>G) restriction fragment length polymorphisms (RFLPs) in intron 1 of ERalpha gene and susceptibility of breast cancer, we undertook a case-control study in BRCA1 185delAG and 5382insC/BRCA2 6174delT negative Portuguese women. The study population consisted of 107 patients with histological diagnosis of breast cancer and 121 women with no history of breast cancer. Genomic DNA was extracted from blood samples and genotyping analyses were performed by PCR-RFLP. XbaI polymorphism was associated with a significant reduced risk of breast cancer for carriers of the x allele in homozygozity (OR 0.178; 95% CI 0.070-0.456; P<0.001) or heterozigozity (OR 0.223; 95% CI 0.089-0.561; P=0.001). The PvuII polymorphism was associated with a non-significantly reduced risk. The combined analysis of PvuII and XbaI polymorphisms revealed none synergistic effect of the two genotypes, except for simultaneous carriers of pp and xx genotypes, that have a reduced risk of breast cancer (OR 0.226; 95% CI 0.049-1.035; P=0.044). The combination of PvuII and XbaI genotypes into haplotypes showed that carriers of two copies of the px (ppxx) haplotype had a reduced risk of breast cancer (OR 0.405; 95% CI 0.194-0.843; P=0.014), compared with PX (PPXX+PPXx+PpXX+PpXx) haplotypes. PvuII and XbaI polymorphisms were in linkage disequilibrium both in cases (D=0.044, r2=0.049, X2=5.216, P=0.022) and controls (D=0.090, r2=0.139, X2=16.819, P<0.001), but not in the entire sample population analyzed as a whole (D=0.087, r2=0.0076, X2=1.733, P=0.188). In conclusion, in this case-control study we found that ERalpha gene XbaI polymorphism may modify individual susceptibility for breast cancer in this population. PMID- 23666106 TI - Phylogeography of the white-clawed crayfish (Austropotamobius italicus) in Spain: inferences from microsatellite markers. AB - The white-clawed crayfish (Austropotamobius italicus), a cornerstone of Spain's aquatic ecosystems, was once widely distributed throughout much of the country. Unfortunately, its populations have suffered very strong declines over the last 40 years due to the spread of introduced species (red swamp and signal crayfishes), diseases, habitat loss and other anthropogenic impacts. The present work examines the genetic variation in 23 Spanish and four Italian populations of white-clawed crayfish via the analysis of microsatellite loci. The data show genetic variation in the Spanish populations to be affected by drastic and successive bottlenecks. Notwithstanding, the diversity of these Spanish populations in terms of observed heterozygosity is similar to or even higher than that recorded for other European populations studied using these same markers. North-central Spanish populations are clearly differentiated from the country's remaining populations; they should be considered distinct management units. Processes occurred in historical and recent times, such as genetic drift and translocations, contribute greatly to this genetic structure. These data provide useful information for conservation of this species, since the preservation of its population structure and genetic variability should be goals for management decisions. PMID- 23666108 TI - SEMI-SUPERVISED OBJECT RECOGNITION USING STRUCTURE KERNEL. AB - Object recognition is a fundamental problem in computer vision. Part-based models offer a sparse, flexible representation of objects, but suffer from difficulties in training and often use standard kernels. In this paper, we propose a positive definite kernel called "structure kernel", which measures the similarity of two part-based represented objects. The structure kernel has three terms: 1) the global term that measures the global visual similarity of two objects; 2) the part term that measures the visual similarity of corresponding parts; 3) the spatial term that measures the spatial similarity of geometric configuration of parts. The contribution of this paper is to generalize the discriminant capability of local kernels to complex part-based object models. Experimental results show that the proposed kernel exhibit higher accuracy than state-of-art approaches using standard kernels. PMID- 23666107 TI - Interaction of 9-O-(omega-amino) alkyl ether berberine analogs with poly(dT).poly(dA)*poly(dT) triplex and poly(dA).poly(dT) duplex: a comparative study. AB - Isoquinoline alkaloids and their analogs represent an important class of molecules for their broad range of clinical and pharmacological utility. These compounds are of current interest owing to their low toxicity and excellent chemo preventive properties. These alkaloids can play important role in stabilising the nucleic acid triple helices. The present study has focused on the interaction of five 9-O-(omega-amino) alkyl ether berberine analogs with the DNA triplex poly(dT).poly(dA)*poly(dT) and the parent duplex poly(dA).poly(dT) studied using various biophysical techniques. Scatchard analysis of the spectral data indicated that the analogs bind both to the duplex and triplex in a non-cooperative manner in contrast to the cooperative binding of berberine to the DNA triplex. Strong intercalative binding to the DNA triplex structure was revealed from ferrocyanide quenching, fluorescence polarization and viscosity results. Thermal melting studies demonstrated higher stabilization of the Hoogsteen base paired third strand of the DNA triplex compared to the Watson-Crick strand. Circular dichroism studies suggested a stronger perturbation of the DNA triplex conformation by the alkaloid analogs compared to the duplex. The binding was entropy-driven in each case and the entropy contribution to free energy increased as the length of the alkyl side chain increased. The analogs exhibited stronger binding affinity to the triple helical structure compared to the parent double helical structure. PMID- 23666109 TI - Measurement of indium concentration profiles and segregation efficiencies from high-angle annular dark field-scanning transmission electron microscopy images. AB - We investigated segregation of indium in an InxGa1-xAs/GaAs heterostructure via high-angle annular dark field-scanning transmission electron microscopy (HAADF STEM), where contrast strongly depends on the nuclear charges of the scattering atoms (Z-contrast). Indium concentration maps have been deduced from HAADF-STEM images by comparing normalized measured intensities with multislice simulations in the frozen lattice approach. Segregation coefficients were derived following the segregation model of Muraki et al.. This is demonstrated for HAADF-STEM images recorded in [100] and [110] zone-axes. Determined indium concentrations and segregation coefficients are compared with results from composition analysis by lattice fringe analysis (CELFA) measurements and energy-dispersive X-ray analysis (EDX). PMID- 23666110 TI - Prevalence and risk factor analysis of feline haemoplasma infection in New Zealand domestic cats using a real-time PCR assay. AB - Haemotropic mycoplasmas (haemoplasmas) are small epierythrocytic bacteria that have the potential to cause severe, life-threatening haemolytic anaemia. The aim of the current study was to evaluate feline haemoplasma prevalence using real time polymerase chain reaction (PCR) from a convenience sample of New Zealand domestic cats, including blood film examination and a risk factor analysis. DNA was extracted from 200 blood samples submitted to a diagnostic laboratory for routine haematology over a 12-month period. Species-specific real-time PCR assays identified 62 cats that were positive for haemoplasma DNA, giving an overall prevalence of 31%. Twelve of the positive cats had dual infections. The prevalence of the three feline haemoplasmas was 25% for 'Candidatus Mycoplasma haemominutum', 7.5% for Mycoplasma haemofelis and 4.5% for 'Candidatus Mycoplasma turicensis' (CMt). All samples were positive for an internal control (feline 28S rDNA) by real-time PCR. Sensitivity and specificity of blood smear examination for haemoplasma infection in this study was 9.7% and 97.8%, respectively. Retroviral infection was tested using the Idexx Snap Feline Triple test on all samples. Twenty cats (10%) were feline immunodeficiency virus (FIV) positive and 11 cats (5.5%) were feline leukaemia virus (FeLV) positive. Statistical comparisons, using multivariate logistic regression, indicated that positive FIV status, male gender and non-pedigree breed were significantly (P <0.05) associated with haemoplasma infection, with odds ratios of 10.16, 5.04 and 3.03, respectively. The results of this study demonstrate the prevalence of the three main feline haemoplasma species in New Zealand for the first time, with prevalences correlating with previous overseas studies. This is the first report of CMt in New Zealand. PMID- 23666111 TI - Divergent mating patterns and a unique mode of external sperm transfer in Zoraptera: an enigmatic group of pterygote insects. AB - A remarkable external sperm transfer is described for the first time in a species of a group of winged insects (Pterygota), the enigmatic Zoraptera. Mating and sperm transfer of two species of the order were examined in detail, documented, and compared with each other and with patterns described for other species belonging to the order. The behavior differs strikingly in Zorotypus impolitus and Zorotypus magnicaudelli. A copula is performed by males and females of the latter, as it is also the case in other zorapteran species and generally in pterygote insects. In striking contrast to this, males of Z. impolitus do not copulate but deposit small (100 MUm in diameter) spermatophores externally on the abdomen of the female. Each spermatophore contains only one giant spermatozoon (3 mm long and 3 MUm wide), a unique feature in the entire Hexapoda. External sperm transfer in Pterygota is a highly unusual case of evolutionary reversal. The very small relict group Zoraptera displays a uniform general morphology but exhibits very different reproductive structures and patterns of mating behavior. This may be an extreme form of a more general situation in insects, with a specific form of selection resulting in an accelerated rate of evolution in the reproductive system. PMID- 23666112 TI - High performance thylakoid bio-solar cell using laccase enzymatic biocathodes. AB - Thylakoid membranes have previously been used for electrochemical solar energy conversion, but the current output and open circuit voltage are low, in part due to limitations of the cathode. In this paper, a thylakoid bioanode and laccase biocathode were combined in the construction of a bio-solar cell capable of light induced generation of electrical power. This two-compartment cell showed a greater than 5-fold increase in short circuit current density and an open circuit voltage 0.275 V larger than that of a thylakoid bio-solar cell incorporating an air-breathing Pt cathode. The electrodes were then tested in several solutions of varying pH to evaluate the possibility of constructing a compartment-less bio solar cell. This membrane-less cell, operating at pH 5.5, generated a short circuit photocurrent density of 14.0 +/- 1.8 MUA cm(-2) which is 25% larger than the two-compartment cell and a similar open circuit voltage of 0.720 +/- 0.018 V. PMID- 23666113 TI - Development of patients with 47,XX,+13/45,X mosaics: case report and review of the literature. AB - Very few cases of mosaic trisomy 13 combined with a monosomy X have been reported. It can be assumed that most likely the zygote was 47,XX,+13 and 2 chromosomes (13 and X) were lost simultaneously during an early postzygotic division. Here, we reported a 3-year-old girl with mosaicism of trisomy 13 and monosomy X. The child had a short neck, hypertelorism, depressed nasal ridge, epicanthal fold, mid-facial hypoplasia, thin upper lip, long philtrum, ear anomalies, postaxial polydactyly, atrial septal defect, hydronephrosis, and sensorineural hearing loss. Her weight and length were consistently below the fifth centile. She demonstrated global developmental delay when evaluated at 10 and 16 months. The range of developmental quotients (DQs) was from 0.6 to 1.1; the personal-social part was the best, and gross motor development was the worst. When evaluated at 31 months, the DQs of motor development were from 0.52 to 0.69, the object manipulation subscale was 0.52, the visual-motor integration subscale was 0.59 and the mental DQ was 0.52. Her social-behavior part was the best, language was the worst and the DQs had dropped with growth. CONCLUSION: This is a case report of global development in a girl with mosaicism of trisomy 13 and monosomy X. The majority of physical anomalies observed tend to be mild and non life threatening. Her DQs dropped with growth, and the language and mental development were significantly delayed after 30 months. PMID- 23666114 TI - Family communication of BRCA1/2 results and family uptake of BRCA1/2 testing in a diverse population of BRCA1/2 carriers. AB - Previous studies examining communication of BRCA1/2 results with relatives and family uptake of BRCA1/2 testing have sampled from predominantly white, high SES cohorts ascertained solely from tertiary care centers. No studies have focused on family communication and testing among relatives of diverse BRCA1/2 carriers. We conducted structured interviews with 73 BRCA1/2 carriers identified at a public hospital and a tertiary cancer center. We asked participants if each first- and second-degree relative was aware of their BRCA1/2 results and whether or not each relative had tested. Generalized estimating equations identified rates and predictors of family communication and testing. Participants disclosed their test results to 73 % of 606 eligible relatives and 31 % of 514 eligible relatives tested. Communication and testing rates were similar for relatives of participants from the public hospital and the tertiary cancer center. Hospital site was not a significant predictor of either result disclosure or relative uptake of testing. African American and Asian/Pacific Islander participants were significantly less likely to disclose their results to their relatives; relatives of African American participants were significantly less likely to test. Addressing these disparities will require further research into the best ways to facilitate family communication and counsel at-risk relatives of racially and socioeconomically diverse BRCA1/2 mutation carriers. PMID- 23666115 TI - Effect of radiographic contrast media (Iodixanol, Iopromide) on the spectrin/actin-network of the membranous cytoskeleton of erythrocytes. AB - Red blood cells demonstrate a unique ability for repeated large deformation. Under the influence of a variety of agents, shapes other than the discocyte--e.g. stomatocytes or echinocytes--can be observed. Some radiographic agents induce shape changes from discocytic to echinocytic cells. Especially the echinocyte formation is associated with a rigidification of the cells bearing the risk of a hindered capillary passage of the echinocytes. The mechanisms leading to the formation of echinocytes are not well understood assuming that the membrane cytoskeleton is a key player. That is why this examination was focused on the participation of components of the membrane cytoskeleton in the formation of echinocytes and the protrusions accompanying the formation of echinocytes. Two radiographic contrast media approved for intra-arterial application were used to study echinocyte formation (Iodixanol320; Iopromide370). In the in vitro study serious changes in the membrane cytoskeleton were only found in those erythrocytes incubated in plasma supplemented with Iopromide370 (30%v/v). The shape of the spectrin net was completely altered; from the more homogeneous distribution--typical of cells in autologous plasma and also of cells in plasma supplemented with Iodixanol320--to a distribution of spectrin concentrated in the membrane-near regions with the appearance of spectrin-actin co-localization. Co localized spectrin with actin was also found around the membranous roots of protrusions which resemble exocytotic processes. In central parts of the cells there was a pronounced dissociation of spectrin and actin; green coloured condensed spectrin bundles originating from the cell membrane reached up to the root of the protrusions. Separate from this there were also fine long actin fibres passing through the whole cell. The incubation of erythrocytes in plasma supplemented with Iopromide370 induced rounded bubble-like protrusions from the cell membrane containing almost completely long bundles of actin fibres. The examination confirmed earlier studies showing that some radiographic contrast media are able to induce echinocyte formation. Furthermore, subcellular mechanisms were revealed explaining the different effects of Iodixanol in comparison to Iopromide. PMID- 23666116 TI - Chemically inducible diffusion trap at cilia reveals molecular sieve-like barrier. AB - Primary cilia function as specialized compartments for signal transduction. The stereotyped structure and signaling function of cilia inextricably depend on the selective segregation of molecules in cilia. However, the fundamental principles governing the access of soluble proteins to primary cilia remain unresolved. We developed a methodology termed 'chemically inducible diffusion trap at cilia' to visualize the diffusion process of a series of fluorescent proteins ranging in size from 3.2 nm to 7.9 nm into primary cilia. We found that the interior of the cilium was accessible to proteins as large as 7.9 nm. The kinetics of ciliary accumulation of this panel of proteins was exponentially limited by their Stokes radii. Quantitative modeling suggests that the diffusion barrier operates as a molecular sieve at the base of cilia. Our study presents a set of powerful, generally applicable tools for the quantitative monitoring of ciliary protein diffusion under both physiological and pathological conditions. PMID- 23666118 TI - The use of a bite fork to help mobilize the maxilla after downfracture during the Le Fort I osteotomy. A technical note. AB - INTRODUCTION: The Le Fort I osteotomy is indicated to reposition the maxilla in the surgical correction of dentofacial deformities. Although it is a known surgical step, like any surgical procedure, it can have complications and difficulties; among these, the initial mobility of the jaw is very common after completing all corticotomies. METHODS: The authors present a technique in which the bite fork is used as an auxiliary tool in maxilla downfracture, especially in cases of maxillary impaction where vertical space is created on the walls of the corticotomy. FINDINGS: As the bite fork acts as a scraper with a long leverage arm, an advantage would be the better distribution of forces along the corticotomy, minimizing the risk of bad fracture and facilitating maxillary downfracture movement. PMID- 23666117 TI - Mechanism-based corrector combination restores DeltaF508-CFTR folding and function. AB - The most common cystic fibrosis mutation, DeltaF508 in nucleotide binding domain 1 (NBD1), impairs cystic fibrosis transmembrane conductance regulator (CFTR) coupled domain folding, plasma membrane expression, function and stability. VX 809, a promising investigational corrector of DeltaF508-CFTR misprocessing, has limited clinical benefit and an incompletely understood mechanism, hampering drug development. Given the effect of second-site suppressor mutations, robust DeltaF508-CFTR correction most likely requires stabilization of NBD1 energetics and the interface between membrane-spanning domains (MSDs) and NBD1, which are both established primary conformational defects. Here we elucidate the molecular targets of available correctors: class I stabilizes the NBD1-MSD1 and NBD1-MSD2 interfaces, and class II targets NBD2. Only chemical chaperones, surrogates of class III correctors, stabilize human DeltaF508-NBD1. Although VX-809 can correct missense mutations primarily destabilizing the NBD1-MSD1/2 interface, functional plasma membrane expression of DeltaF508-CFTR also requires compounds that counteract the NBD1 and NBD2 stability defects in cystic fibrosis bronchial epithelial cells and intestinal organoids. Thus, the combination of structure guided correctors represents an effective approach for cystic fibrosis therapy. PMID- 23666119 TI - Association between leptin and systemic lupus erythematosus. AB - Leptin, the product of ob gene, is a 16-kDa nonglycosylated peptide hormone produced by adipocytes that regulates appetite and energy expenditure at the hypothalamic level. As is known to be a satiety factor that can regulate body weight by inhibiting food intake and stimulating energy expenditure, leptin is a pleiotropic hormone whose multiple effects include regulation of endocrine function, reproduction and immunity. Since leptin has been considered to be a pro inflammatory cytokine, investigations of leptin in the pathogenesis of autoimmune diseases have been detected, such as systemic lupus erythematosus, rheumatoid arthritis and osteoarthritis. Recently, the role of leptin in the modulation of immune response and inflammation has been discussed in the autoimmune diseases increasingly but less in systemic lupus erythematosus (SLE). Therefore, this article will focus on the current understanding of the role of leptin with such similar pathogenic mechanism in SLE in order to provide insights which may assist in the development of leptin-based approaches for the treatment of SLE. PMID- 23666120 TI - Consumer exposure to pesticide residues in apples from the region of south eastern Poland. AB - The production of apples in Poland is the largest among the countries of the European Union, and therefore, the consumption of these fruits is high in our country. The aim of this study was to determine the presence of pesticide residues in Polish apples and to assess if these residues pose a risk to the health of the consumer. Furthermore, compliance with legal regulations concerning the use of plant protection products in crop cultivation was ascertained. Pesticide residues were found in 192 samples (61.5% of tested samples). In six samples (1.9%), residues exceeded maximum residue limits. Violations concerned the insecticides: indoxacarb, diazinon and fenitrothion. The highest long-term consumer exposure was found in the case of consumption of apples with diazinon residue for both groups, adults and toddlers [4% acceptable daily intake (ADI), adults; 21% ADI, toddlers]. The highest values of short-term exposure were obtained in the case of consumption of apples with indoxacarb [5% acute reference dose (ARfD), adults; 27% ARfD, toddlers] and fenitrothion (4% ARfD, adults; 23% ARfD, toddlers). Although fungicides are the pesticides found most often in apples, the consumption of apples with insecticide residues constitutes the greatest hazard to human health. PMID- 23666121 TI - Dredging and contaminant exposure to tree swallows nesting on the upper Mississippi River. AB - In 2008 and 2009, dredge material from the Mississippi River in Pool 8 south of Brownsville, Minnesota was used to construct nearby islands. Chemical analysis of sediment in 2001 and 2002 in the area to be dredged indicated detectable concentrations of organic and inorganic contaminants. Tree swallows (Tachycineta bicolor), whose diet is mainly aquatic invertebrates, were used to evaluate contaminant exposure in both the dredged and newly created habitat. Organic and inorganic contaminant data were collected from tree swallows in 2007 through 2010 at one study site near the dredging operation, a reference study site upriver from the dredging activity, one study site down river from the dredging activity, and one study site on a newly created island (2009 and 2010 only). Organic and element concentrations were at background levels in all samples. Polychlorinated biphenyl and p,p'-dichlorodiphenyldichloroethylene concentrations in tree swallow nestlings decreased at all study sites over the period 2007 to 2010 including the island study site between 2009 and 2010. Element concentrations in tree swallow livers for the non-island study sites did not show a trend among years in relation to the dredging. Selenium concentrations at the newly created island were higher and cadmium concentrations were lower in 2010 than 2009. Hatching success of eggs in successful nests was not associated with dredging activities. PMID- 23666123 TI - Theoretical prediction of p-type transparent conductivity in Zn-doped TiO2. AB - It is very difficult and yet extremely important to fill the wide technological gap in developing transparent conducting oxides (TCOs) that exhibit excellent p type conducting characteristics. Here, on the basis of extensive first-principles calculations, we discover for the first time potentially promising p-type transparent conductivity in Zn-doped TiO2 under oxygen rich conditions. Efforts have been made to elaborate the effects of possible defects and their interaction with Zn doping on the p-type transparent conductivity. This work offers a fundamental road map for cost-effective development of p-type TCOs based on TiO2, which is a cheap and stable material system of large natural resources. PMID- 23666122 TI - Human vasculogenic cells form functional blood vessels and mitigate adverse remodeling after ischemia reperfusion injury in rats. AB - Cell-based therapies to restore heart function after infarction have been tested in pre-clinical models and clinical trials with mixed results, and will likely require both contractile cells and a vascular network to support them. We and others have shown that human endothelial colony forming cells (ECFC) combined with mesenchymal progenitor cells (MPC) can be used to "bio-engineer" functional human blood vessels. Here we investigated whether ECFC + MPC form functional vessels in ischemic myocardium and whether this affects cardiac function or remodeling. Myocardial ischemia/reperfusion injury (IRI) was induced in 12-week old immunodeficient rats by ligation of the left anterior descending coronary artery. After 40 min, myocardium was reperfused and ECFC + MPC (2 * 10(6) cells, 2:3 ratio) or PBS was injected. Luciferase assays after injection of luciferase labeled ECFC + MPC showed that 1,500 ECFC were present at day 14. Human ECFC lined perfused vessels were directly visualized by femoral vein injection of a fluorescently-tagged human-specific lectin in hearts injected with ECFC + MPC but not PBS alone. While infarct size at day 1 was no different, LV dimensions and heart weight to tibia length ratios were lower in cell-treated hearts compared with PBS at 4 months, suggesting post-infarction remodeling was ameliorated by local cell injection. Fractional shortening, LV wall motion score, and fibrotic area were not different between groups at 4 months. However, pressure-volume loops demonstrated improved cardiac function and reduced volumes in cell-treated animals. These data suggest that myocardial delivery of ECFC + MPC at reperfusion may provide a therapeutic strategy to mitigate LV remodeling and cardiac dysfunction after IRI. PMID- 23666124 TI - A passive wireless multi-sensor SAW technology device and system perspectives. AB - This paper will discuss a SAW passive, wireless multi-sensor system under development by our group for the past several years. The device focus is on orthogonal frequency coded (OFC) SAW sensors, which use both frequency diversity and pulse position reflectors to encode the device ID and will be briefly contrasted to other embodiments. A synchronous correlator transceiver is used for the hardware and post processing and correlation techniques of the received signal to extract the sensor information will be presented. Critical device and system parameters addressed include encoding, operational range, SAW device parameters, post-processing, and antenna-SAW device integration. A fully developed 915 MHz OFC SAW multi-sensor system is used to show experimental results. The system is based on a software radio approach that provides great flexibility for future enhancements and diverse sensor applications. Several different sensor types using the OFC SAW platform are shown. PMID- 23666125 TI - An intelligent automated door control system based on a smart camera. AB - This paper presents an innovative access control system, based on human detection and path analysis, to reduce false automatic door system actions while increasing the added values for security applications. The proposed system can first identify a person from the scene, and track his trajectory to predict his intention for accessing the entrance, and finally activate the door accordingly. The experimental results show that the proposed system has the advantages of high precision, safety, reliability, and can be responsive to demands, while preserving the benefits of being low cost and high added value. PMID- 23666126 TI - DNA hairpins as temperature switches, thermometers and ionic detectors. AB - Temperature is of major importance in most branches of science and technology as well as in everyday life, and with the miniaturization of electronic devices and the increasing ability to make research into small-scale systems, a specific need for very small thermostats and thermometers has been created. Here we describe how DNA molecules can be used as nanoscale sensors to meet these requirements. We illustrate how the hybridization kinetics between bases in DNA molecules combined with conformational changes of the DNA backbone can be exploited in the construction of simple but versatile temperature switches and thermometers, which can be built into electronic systems. DNA based sensors are at the same time applicable as ion detectors to monitor the chemical environment of a specific system. PMID- 23666127 TI - Design of a soil cutting resistance sensor for application in site-specific tillage. AB - One objective of precision agriculture is to provide accurate information about soil and crop properties to optimize the management of agricultural inputs to meet site-specific needs. This paper describes the development of a sensor equipped with RTK-GPS technology that continuously and efficiently measures soil cutting resistance at various depths while traversing the field. Laboratory and preliminary field tests verified the accuracy of this prototype soil strength sensor. The data obtained using a hand-operated soil cone penetrometer was used to evaluate this field soil compaction depth profile sensor. To date, this sensor has only been tested in one field under one gravimetric water content condition. This field test revealed that the relationships between the soil strength profile sensor (SSPS) cutting force and soil cone index values are assumed to be quadratic for the various depths considered: 0-10, 10-20 and 20-30 cm (r2 = 0.58, 0.45 and 0.54, respectively). Soil resistance contour maps illustrated its practical value. The developed sensor provides accurate, timely and affordable information on soil properties to optimize resources and improve agricultural economy. PMID- 23666128 TI - Current trends in wireless mesh sensor networks: a review of competing approaches. AB - Finding a complete mesh-based solution for low-rate wireless personal area networks (LR-WPANs) is still an open issue. To cope with this concern, different competing approaches have emerged in the Wireless Mesh Sensor Networks (WMSNs) field in the last few years. They are usually supported by the IEEE 802.15.4 standard, the most commonly adopted LR-WPAN recommendation for point-to-point topologies. In this work, we review the most relevant and up-to-date WMSN solutions that extend the IEEE 802.15.4 standard to multi-hop mesh networks. To conduct this review, we start by identifying the most significant WMSN requirements (i.e., interoperability, robustness, scalability, mobility or energy efficiency) that reveal the benefits and shortcomings of each proposal. Then, we re-examine thoroughly the group of proposals following different design guidelines which are usually considered by end-users and developers. Among all of the approaches reviewed, we highlight the IEEE 802.15.5 standard, a recent recommendation that, in its LR-WPAN version, fully satisfies the greatest number of WMSN requirements. As a result, IEEE 802.15.5 can be an appropriate solution for a wide-range of applications, unlike the majority of the remaining solutions reviewed, which are usually designed to solve particular problems, for instance in the home, building and industrial sectors. In this sense, a description of IEEE 802.15.5 is also included, paying special attention to its efficient energy saving mechanisms. Finally, possible improvements of this recommendation are pointed out in order to offer hints for future research. PMID- 23666129 TI - Air-coupled piezoelectric transducers with active polypropylene foam matching layers. AB - This work presents the design, construction and characterization of air-coupled piezoelectric transducers using 1-3 connectivity piezocomposite disks with a stack of matching layers being the outer one an active quarter wavelength layer made of polypropylene foam ferroelectret film. This kind of material has shown a stable piezoelectric response together with a very low acoustic impedance (<0.1 MRayl). These features make them a suitable candidate for the dual use or function proposed here: impedance matching layer and active material for air coupled transduction. The transducer centre frequency is determined by the l/4 resonance of the polypropylene foam ferroelectret film (0.35 MHz), then, the rest of the transducer components (piezocomposite disk and passive intermediate matching layers) are all tuned to this frequency. The transducer has been tested in several working modes including pulse-echo and pitch-catch as well as wide and narrow band excitation. The performance of the proposed novel transducer is compared with that of a conventional air-coupled transducers operating in a similar frequency range. PMID- 23666130 TI - An implantable neural sensing microsystem with fiber-optic data transmission and power delivery. AB - We have developed a prototype cortical neural sensing microsystem for brain implantable neuroengineering applications. Its key feature is that both the transmission of broadband, multichannel neural data and power required for the embedded microelectronics are provided by optical fiber access. The fiber-optic system is aimed at enabling neural recording from rodents and primates by converting cortical signals to a digital stream of infrared light pulses. In the full microsystem whose performance is summarized in this paper, an analog-to digital converter and a low power digital controller IC have been integrated with a low threshold, semiconductor laser to extract the digitized neural signals optically from the implantable unit. The microsystem also acquires electrical power and synchronization clocks via optical fibers from an external laser by using a highly efficient photovoltaic cell on board. The implantable unit employs a flexible polymer substrate to integrate analog and digital microelectronics and on-chip optoelectronic components, while adapting to the anatomical and physiological constraints of the environment. A low power analog CMOS chip, which includes preamplifier and multiplexing circuitry, is directly flip-chip bonded to the microelectrode array to form the cortical neurosensor device. PMID- 23666131 TI - A methodology and a web platform for the collaborative development of context aware systems. AB - Information and services personalization is essential for an optimal user experience. Systems have to be able to acquire data about the user's context, process them in order to identify the user's situation and finally, adapt the functionality of the system to that situation, but the development of context aware systems is complex. Data coming from distributed and heterogeneous sources have to be acquired, processed and managed. Several programming frameworks have been proposed in order to simplify the development of context-aware systems. These frameworks offer high-level application programming interfaces for programmers that complicate the involvement of domain experts in the development life-cycle. The participation of users that do not have programming skills but are experts in the application domain can speed up and improve the development process of these kinds of systems. Apart from that, there is a lack of methodologies to guide the development process. This article presents as main contributions, the implementation and evaluation of a web platform and a methodology to collaboratively develop context-aware systems by programmers and domain experts. PMID- 23666132 TI - Sensing solutions for collecting spatio-temporal data for wildlife monitoring applications: a review. AB - Movement ecology is a field which places movement as a basis for understanding animal behavior. To realize this concept, ecologists rely on data collection technologies providing spatio-temporal data in order to analyze movement. Recently, wireless sensor networks have offered new opportunities for data collection from remote places through multi-hop communication and collaborative capability of the nodes. Several technologies can be used in such networks for sensing purposes and for collecting spatio-temporal data from animals. In this paper, we investigate and review technological solutions which can be used for collecting data for wildlife monitoring. Our aim is to provide an overview of different sensing technologies used for wildlife monitoring and to review their capabilities in terms of data they provide for modeling movement behavior of animals. PMID- 23666133 TI - A self-sensing piezoelectric microcantilever biosensor for detection of ultrasmall adsorbed masses: theory and experiments. AB - Detection of ultrasmall masses such as proteins and pathogens has been made possible as a result of advancements in nanotechnology. Development of label-free and highly sensitive biosensors has enabled the transduction of molecular recognition into detectable physical quantities. Microcantilever (MC)-based systems have played a widespread role in developing such biosensors. One of the most important drawbacks of all of the available biosensors is that they all come at a very high cost. Moreover, there are certain limitations in the measurement equipments attached to the biosensors which are mostly optical measurement systems. A unique self-sensing detection technique is proposed in this paper in order to address most of the limitations of the current measurement systems. A self-sensing bridge is used to excite piezoelectric MC-based sensor functioning in dynamic mode, which simultaneously measures the system's response through the self-induced voltage generated in the piezoelectric material. As a result, the need for bulky, expensive read-out equipment is eliminated. A comprehensive mathematical model is presented for the proposed self-sensing detection platform using distributed-parameters system modeling. An adaptation strategy is then implemented in the second part in order to compensate for the time-variation of piezoelectric properties which dynamically improves the behavior of the system. Finally, results are reported from an extensive experimental investigation carried out to prove the capability of the proposed platform. Experimental results verified the proposed mathematical modeling presented in the first part of the study with accuracy of 97.48%. Implementing the adaptation strategy increased the accuracy to 99.82%. These results proved the measurement capability of the proposed self-sensing strategy. It enables development of a cost effective, sensitive and miniaturized mass sensing platform. PMID- 23666134 TI - A wearable mobile sensor platform to assist fruit grading. AB - Wearable computing is a form of ubiquitous computing that offers flexible and useful tools for users. Specifically, glove-based systems have been used in the last 30 years in a variety of applications, but mostly focusing on sensing people's attributes, such as finger bending and heart rate. In contrast, we propose in this work a novel flexible and reconfigurable instrumentation platform in the form of a glove, which can be used to analyze and measure attributes of fruits by just pointing or touching them with the proposed glove. An architecture for such a platform is designed and its application for intuitive fruit grading is also presented, including experimental results for several fruits. PMID- 23666135 TI - Algorithms based on CWT and classifiers to control cardiac alterations and stress using an ECG and a SCR. AB - This paper presents the results of using a commercial pulsimeter as an electrocardiogram (ECG) for wireless detection of cardiac alterations and stress levels for home control. For these purposes, signal processing techniques (Continuous Wavelet Transform (CWT) and J48) have been used, respectively. The designed algorithm analyses the ECG signal and is able to detect the heart rate (99.42%), arrhythmia (93.48%) and extrasystoles (99.29%). The detection of stress level is complemented with Skin Conductance Response (SCR), whose success is 94.02%. The heart rate variability does not show added value to the stress detection in this case. With this pulsimeter, it is possible to prevent and detect anomalies for a non-intrusive way associated to a telemedicine system. It is also possible to use it during physical activity due to the fact the CWT minimizes the motion artifacts. PMID- 23666136 TI - Hydrothermal synthesis of various hierarchical ZnO nanostructures and their methane sensing properties. AB - Hierarchical flower-like ZnO nanorods, net-like ZnO nanofibers and ZnO nanobulks have been successfully synthesized via a surfactant assisted hydrothemal method. The synthesized products were characterized by X-ray powder diffraction and field emission scanning electron microscopy, respectively. A possible growth mechanism of the various hierarchical ZnO nanostructures is discussed in detail. Gas sensors based on the as-prepared ZnO nanostructures were fabricated by screen printing on a flat ceramic substrate. Furthermore, their gas sensing characteristics towards methane were systematically investigated. Methane is an important characteristic hydrocarbon contaminant found dissolved in power transformer oil as a result of faults. We find that the hierarchical flower-like ZnO nanorods and net-like ZnO nanofibers samples show higher gas response and lower operating temperature with rapid response-recovery time compared to those of sensors based on ZnO nanobulks. These results present a feasible way of exploring high performance sensing materials for on-site detection of characteristic fault gases dissolved in transformer oil. PMID- 23666137 TI - Mitochondrial haplogroups are associated with clinical pattern of AIDS progression in HIV-infected patients. AB - We performed a cross-sectional study in 469 HIV-infected patients, whose mitochondrial haplogroups were genotyped to study their association with the clinical pattern of AIDS progression. The chance of not having an AIDS progression was 1.45 [95% of confidence interval (CI) = 1.02 to 2.05, P = 0.035) times greater in patients with cluster HV and 1.51 (95% CI = 1.06 to 2.18, P = 0.021) times greater in patients with haplogroup H. However, we only found significant values for haplogroup H (odds ratio = 1.52, 95% CI = 1.01 to 2.32, P = 0.049) in an ordinal logistic regression adjusted by gender, age at HIV infection, intravenous drug users, and hepatitis C virus infection. These data suggest that mitochondrial haplogroups might play a significant role in AIDS progression. PMID- 23666138 TI - Pre-antiretroviral therapy plasma levels of CCL2 may aid in the prediction of tuberculosis-associated immune reconstitution inflammatory syndrome in HIV patients after they commence antiretroviral therapy. PMID- 23666139 TI - Antiretroviral drugs in Africa: a public health versus a market approach. PMID- 23666140 TI - An innovative approach to improve the quality of prevention of mother-to-child transmission of HIV programs through nurse clinical mentoring in South Africa. PMID- 23666141 TI - Higher Veterans Aging Cohort Study (VACS) index scores in HIV-positive adults with CD4 counts <200 cells/mm3 despite viral suppression. PMID- 23666142 TI - A maintenance dose of atazanavir/ritonavir 200/100 mg once daily is effective in virologically suppressed HIV-1-infected patients. PMID- 23666143 TI - Revisiting the methodology of measuring HIV community viral load. PMID- 23666144 TI - Measuring the unknown: calculating community viral load among HIV-infected MSM unaware of their HIV status in San Francisco from National HIV Behavioral Surveillance, 2004-2011. PMID- 23666145 TI - Therapeutic mobilities: walking and 'steps' to wellbeing and health. AB - There is now an extensive literature on therapeutic landscapes, those settings and places that can contribute to wellbeing and good health. Less attention has been paid to the therapeutic qualities of the act of moving from one place to another. The recent emergence of a significant mobilities 'turn' in social science is welcome, but this has as yet had relatively little to say about the consequences of mobility for health and wellbeing. This paper maps the relations between one form of mobility - walking - and wellbeing and health. Such relations may be theorised as 'therapeutic mobilities', a concept that sits comfortably alongside that of therapeutic landscapes. I explore three elements of such relations: activity; connection; and context. Although only one form of mobility is considered, the notion of therapeutic mobilities can be extended to other forms of travel. PMID- 23666146 TI - Nature's good for you: sir Truby King, Seacliff Asylum, and the greening of health care in New Zealand, 1889-1922. AB - Sir Frederic Truby King's work at Seacliff Asylum in New Zealand, between 1889 and 1922, illustrates a prominent role of agriculture in relationship to human health and the environment. King utilized farming practices, a rural setting, occupational therapy, dietary changes and moves towards self-sufficiency as examples of asylum management practices, but these also ensured patient health and well-being. In this article, we analyze King's practices at Seacliff as a genealogical precursor to today's green care and care farming movements. PMID- 23666147 TI - Continuous graphene films synthesized at low temperatures by introducing coronene as nucleation seeds. AB - In this paper, we systematically studied the effects of coronene as nucleation seeds for graphene synthesis at low temperatures by chemical vapor deposition. Naphthalene was used as a solid carbon source which is capable of producing graphene at temperatures down to 300 degrees C. The experimental results showed clear evidence that coronene seeds work as preferred nucleation sites, through which the nucleation density and graphene domain size could be modulated. The introduction of the seeds greatly improved the homogeneity of monolayer graphene by suppressing uncontrolled nucleation and multilayer growth of graphene domains. The obtained carrier mobility of graphene fabricated at 400 degrees C by the seed-assisted process reached ~912 cm(2) V(-1) s(-1), which is considerably higher than that of ~300 cm(2) V(-1) s(-1) measured on graphene prepared without seeding. Besides offering cost advantages for large scale application, the technique proposed in this study may find significant applications in graphene/copper hybrid interconnects and graphene based flexible electronics. PMID- 23666148 TI - The regulation of testicular descent and the effects of cryptorchidism. AB - The first half of this review examines the boundary between endocrinology and embryonic development, with the aim of highlighting the way hormones and signaling systems regulate the complex morphological changes to enable the intra abdominal fetal testes to reach the scrotum. The genitoinguinal ligament, or gubernaculum, first enlarges to hold the testis near the groin, and then it develops limb-bud-like properties and migrates across the pubic region to reach the scrotum. Recent advances show key roles for insulin-like hormone 3 in the first step, with androgen and the genitofemoral nerve involved in the second step. The mammary line may also be involved in initiating the migration. The key events in early postnatal germ cell development are then reviewed because there is mounting evidence for this to be crucial in preventing infertility and malignancy later in life. We review the recent advances in what is known about the etiology of cryptorchidism and summarize the syndromes where a specific molecular cause has been found. Finally, we cover the recent literature on timing of surgery, the issues around acquired cryptorchidism, and the limited role of hormone therapy. We conclude with some observations about the differences between animal models and baby boys with cryptorchidism. PMID- 23666149 TI - The angiotensinogen gene M235T polymorphism and acute myocardial infarction risk: a meta-analysis of 22 studies. AB - Angiotensinogen, one of the most important proteins in the renin-angiotensin system, plays a key role in the progress of coronary heart disease and myocardial infarction (MI). Many studies have investigated the association between angiotensinogen gene M235T polymorphism and MI risk, but the results were inconsistent. We performed a meta-analysis of 22 studies on M235T polymorphism and MI risk published before November 2012. This meta-analysis included a total of 4,606 MI cases and 4,918 controls. Overall, the per-allele odds ratio (OR) of the 235T variant for total MI risk was 1.04 (95 % CI 0.92-1.17). When a recessive model was evaluated, the OR was 1.06 (95 % CI 0.96-1.17) and under a dominant model, the OR was 0.96 (95 % CI 0.82-1.11). Under pairwise comparisons, non significant associations were found between M235T polymorphism and MI risk (MT vs. MM, OR, 0.96, 95 % CI 0.87-1.06; TT vs. MM, OR, 1.03, 95 % CI 0.83-1.28). Subgroup analyses in the different ethnic groups and different control sources were performed and no significant association was found also. Based on the available evidence, no association between M235T polymorphism and MI risk was observed, even in the sub-analysis concerning different races and control sources. The direction of further research should focus not only on the simple relationship of M235T polymorphism and MI risk, but also on gene-gene and gene environment interaction. PMID- 23666150 TI - Recombinant beta-1,3-1,4-glucanase from Theobroma cacao impairs Moniliophthora perniciosa mycelial growth. AB - In this work, we identified a gene from Theobroma cacao L. genome and cDNA libraries, named TcGlu2, that encodes a beta-1,3-1,4-glucanase. The TcGlu2 ORF was 720 bp in length and encoded a polypeptide of 239 amino acids with a molecular mass of 25.58 kDa. TcGlu2 contains a conserved domain characteristic of beta-1,3-1,4-glucanases and presented high protein identity with beta-1,3-1,4 glucanases from other plant species. Molecular modeling of TcGlu2 showed an active site of 13 amino acids typical of glucanase with beta-1,3 and 1,4 action mode. The recombinant cDNA TcGlu2 obtained by heterologous expression in Escherichia coli and whose sequence was confirmed by mass spectrometry, has a molecular mass of about 22 kDa (with His-Tag) and showed antifungal activity against the fungus Moniliophthora perniciosa, causal agent of the witches' broom disease in cacao. The integrity of the hyphae membranes of M. perniciosa, incubated with protein TcGlu2, was analyzed with propidium iodide. After 1 h of incubation, a strong fluorescence emitted by the hyphae indicating the hydrolysis of the membrane by TcGlu2, was observed. To our knowledge, this is the first study of a cacao beta-1,3-1,4-glucanase expression in heterologous system and the first analysis showing the antifungal activity of a beta-1,3-1,4-glucanase, in particular against M. perniciosa. PMID- 23666151 TI - Intensity correction method customized for multi-animal abdominal MR imaging with 3T clinical scanner and multi-array coil. AB - PURPOSE: Simultaneous magnetic resonance (MR) imaging of multiple small animals in a single session increases throughput of preclinical imaging experiments. Such imaging using a 3-tesla clinical scanner with multi-array coil requires correction of intensity variation caused by the inhomogeneous sensitivity profile of the coil. We explored a method for correcting intensity that we customized for multi-animal MR imaging, especially abdominal imaging. METHOD: Our institutional committee for animal experimentation approved the protocol. We acquired high resolution T1-, T2-, and T2*-weighted images and low resolution proton density weighted images (PDWIs) of 4 rat abdomens simultaneously using a 3T clinical scanner and custom-made multi-array coil. For comparison, we also acquired T1-, T2-, and T2*-weighted volume coil images in the same rats in 4 separate sessions. We used software created in-house to correct intensity variation. We applied thresholding to the PDWIs to produce binary images that displayed only a signal producing area, calculated multi-array coil sensitivity maps by dividing low-pass filtered PDWIs by low-pass filtered binary images pixel by pixel, and divided uncorrected T1-, T2-, or T2*-weighted images by those maps to obtain intensity corrected images. We compared tissue contrast among the liver, spinal canal, and muscle between intensity-corrected multi-array coil images and volume coil images. RESULTS: Our intensity correction method performed well for all pulse sequences studied and corrected variation in original multi-array coil images without deteriorating the throughput of animal experiments. Tissue contrasts were comparable between intensity-corrected multi-array coil images and volume coil images. CONCLUSION: Our intensity correction method customized for multi-animal abdominal MR imaging using a 3T clinical scanner and dedicated multi-array coil could facilitate image interpretation. PMID- 23666152 TI - Ring-shaped lateral ventricular nodules detected with brain MR imaging. AB - PURPOSE: We evaluated the prevalence and imaging characteristics of ring-shaped lateral ventricular nodules (RSLVNs) detected by postcontrast brain magnetic resonance (MR) imaging. MATERIALS AND METHODS: We retrospectively reviewed cranial MR images of 1,241 patients who underwent contrast-enhanced brain imaging between January 1, 2008 and March 31, 2011, excluded images of inadequate quality of 130 patients, and ultimately analyzed images of 1,111 patients (544 male, 567 female). We assessed location, shape, and signal intensity of RSLVNs on T1 weighted (T1WIs), T2-weighted (T2WIs), fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted (DWIs) images and characteristics of contrast enhancement. RESULTS: In 5 patients, we found 6 RSLVNs (0.45%), four in the frontal horn and two in the roof of the body. Three RSLVNs were round, two were oval, and one was lobular on axial images. All 6 RSLVNs were isointense with adjacent brain parenchyma on T1WI, T2WI, and DWI but slightly hyperintense on FLAIR images; none showed enhancement on postcontrast MR imaging. Five nodules serially examined (range, 8 to 24 months) showed no interval changes. CONCLUSIONS: Our MR imaging findings of a 0.45% prevalence of RSLVNs shows they are not so rare as previously reported. Except for configuration, all nodules had similar intensity, and none showed contrast enhancement. Absence of changes during the follow-up period seemed to indicate that the nodules have no clinical significance. However, their clear differentiation avoids unnecessary surgery. PMID- 23666153 TI - Rapid high resolution MR neurography with a diffusion-weighted pre-pulse. AB - PURPOSE: To introduce, optimize, and assess the feasibility of a new scheme to rapidly acquire high-resolution volumetric neurographic images using a three dimensional turbo spin-echo sequence combined with a diffusion-weighted pre-pulse called improved motion-sensitized driven equilibrium (iMSDE): Diffusion-prepared MR Neurography (D-prep MRN). METHODS: In order to optimize the signal suppression of blood vessels and muscle at D-prep MRN, coronal lumbosacral plexus images were acquired in five volunteers at 3T, and the following parameters were examined: iMSDE gradient-strength (b-value) of 0, 2 and 10 s/mm2 (with the aim to suppress blood vessels) and iMSDE preparation duration (iMSDEprep-time) of 18, 50 and 100 ms (with the aim to suppress muscle signal). Subsequently, the feasibility of the optimized D-prep MRN sequence in visualizing the brachial plexus, lumbosacral plexus, and cranial nerves was evaluated in 5 healthy volunteers. RESULTS: A higher b-value of 10 s/mm2 was better in signal suppression of blood vessels, whereas an intermediate iMSDEprep-time of 50 ms provided the best compromise between suppression of muscle signal and minimization of signal loss of nerves. With these parameters, the normal nerve structures showed high signal intensity, while the blood vessels and muscles were effectively suppressed. The optimized D prep MRN sequence clearly showed the three-dimensional trajectory of the brachial plexus, lumbosacral plexus, and cranial nerves. CONCLUSION: D-prep MRN was introduced and optimized, and clearly showed detailed anatomy of the brachial plexus, lumbosacral plexus, and cranial nerves. These results suggest that the D prep MRN can be used for fast, high-resolution, volumetric imaging of the peripheral nervous system. PMID- 23666154 TI - Deconvolution analyses with tent functions reveal delayed and long-sustained increases of BOLD signals with acupuncture stimulation. AB - We used deconvolution analysis to examine temporal changes in brain activity after acupuncture stimulation and assess brain responses without expected reference functions. We also examined temporal changes in brain activity after sham acupuncture (noninsertive) and scrubbing stimulation. We divided 26 healthy right-handed adults into a group of 13 who received real acupuncture with manual manipulation and a group of 13 who received both tactical stimulations. Functional magnetic resonance imaging (fMRI) sequences consisted of four 15-s stimulation blocks (ON) interspersed between one 30-s and four 45-s rest blocks (OFF) for a total scanning time of 270 s. We analyzed data by using Statistical Parametric Mapping 8 (SPM8), MarsBaR, and Analysis of Functional NeuroImages (AFNI) software. For statistical analysis, we used 3dDeconvolve, part of the AFNI package, to extract the impulse response functions (IRFs) of the fMRI signals on a voxel-wise basis, and we tested the time courses of the extracted IRFs for the stimulations. We found stimulus-specific impulse responses of blood oxygen level dependent (BOLD) signals in various brain regions. We observed significantly delayed and long-sustained increases of BOLD signals in several brain regions following real acupuncture compared to sham acupuncture and palm scrubbing, which we attribute to peripheral nocireceptors, flare responses, and processing of the central nervous system. Acupuncture stimulation induced continued activity that was stronger than activity after the other stimulations. We used tent function deconvolution to process fMRI data for acupuncture stimulation and found delayed increasing and delayed decreasing changes in BOLD signal in the somatosensory areas and areas related to pain perception. Deconvolution analyses with tent functions are expected to be useful in extracting complicated and associated brain activity that is delayed and sustained for a long period after various stimulations. PMID- 23666155 TI - 1H NMR spectroscopic quantification of plasma metabolites in dialysate during hemodialysis. AB - We used 1H nuclear magnetic resonance (NMR) spectroscopy to assess metabolic responses in patients undergoing hemodialysis (HD). We collected 71 samples of plasma and dialysate from 10 patients before, during, and after HD. We used the dialysate as a possible substitute for blood plasma to quantify small metabolites by 1H NMR. We confirmed TSP (sodium 3-(trimethylsilyl) propionate 2, 2, 3, 3-d4) as a reference of NMR intensity in dialysate. We examined TSP sensitivities in various dialysate spectra and the correlation between signal intensities and added quantities of TSP. We used integrations of signal areas on 1H NMR spectra of plasma and dialysate to quantify concentrations of creatinine, lactate, alanine, and valine and calculate their ratios between plasma and dialysate. The ratios of metabolites in plasma to dialysate were 3.2+/-0.4 (creatinine), 3.6+/ 0.5 (valine), 3.8+/-0.7 (alanine), and 4.0+/-0.8 (lactate) mM (mean+/-standard deviation [SD]). The broader distributions of ratios in levels of lactate and alanine suggested their de novo production during the HD session. Estimation of blood metabolite levels using dialysate is useful for quantitative analysis of metabolic status in blood during HD. PMID- 23666156 TI - Visualization of endolymphatic hydrops in Meniere's disease after intravenous administration of single-dose gadodiamide at 1.5T. PMID- 23666157 TI - Three-dimensional visualization of endolymphatic hydrops after intravenous administration of single-dose gadodiamide. AB - Endolymphatic hydrops can be visualized with high contrast-to-noise ratio even after intravenous injection of single-dose gadolinium-based contrast material (IV SD-GBCM) using HYDROPS-Mi2 images. We applied 3-dimensional rendering software to process HYDROPS-Mi2 images of 15 ears with and without suspected Meniere's disease and separately visualized the volumes of endo- and perilymph in patients with Meniere's disease even after IV-SD-GBCM. Such dimensional visualization will aid understanding of the pathophysiology of Meniere's disease. PMID- 23666158 TI - MR-based measurements of portal vein flow and liver stiffness for predicting gastroesophageal varices. AB - OBJECTIVES: We evaluated flow parameters measured by phase-contrast magnetic resonance (MR) imaging (PC-MRI) of the portal venous system and liver stiffness measured by MR elastography (MRE) to determine the usefulness of these methods in predicting gastroesophageal varices (GEV) in patients with chronic liver disease (CLD). METHODS: In patients with CLD and controls, we performed PC-MRI on the portal (PV) and superior mesenteric veins; calculated mean velocity (V, cm/s), cross-sectional area (S, mm2), and flow volume (Q, mL/min); and determined markers of liver fibrosis (liver stiffness [kPa]) and aspartate aminotransferase (AST) platelet ratio index [APRI]). We visually assessed GEV and development of collateral pathways of the PV on routine contrast-enhanced dynamic MR imaging and compared patient characteristics, flow parameters, liver stiffness markers, and visual analysis among 3GEV groups, those with mild, severe, or no GEV with reference to endoscopic findings. RESULTS: Child-Pugh grade, VPV, SPV, liver stiffness, APRI, and visually identified GEV (visible GEV) differed significantly among the 3 groups (P<0.05). We investigated VPV, SPV, liver stiffness, and visible GEV as independent markers to distinguish patients with and without GEV and examined VPV and visible GEV to predict severe GEV. Visible GEV showed low sensitivity (14 to 30%) and high specificity (98%) for predicting GEV in patients with CLD. A subgroup analysis that excluded cases with collateral pathway demonstrated slightly improved diagnostic performance of VPV and liver stiffness. CONCLUSIONS: Portal vein flow parameters and liver stiffness can be useful markers for predicting GEV in patients with CLD. PMID- 23666159 TI - Consecutive acquisition of time-resolved contrast-enhanced MR angiography and perfusion MR imaging with added dose of gadolinium-based contrast agent aids diagnosis of suspected brain metastasis. AB - PURPOSE: Time-resolved contrast-enhanced magnetic resonance (MR) angiography (TCMRA) and perfusion MR imaging (PWI) have been used to assess the hemodynamics of brain tumors. We assessed the feasibility and value of consecutive performance of these techniques to evaluate suspected brain metastasis following supplementary injection of gadolinium-based contrast medium. METHODS: In 69 patients with suspected brain metastasis, we obtained precontrast MR images followed by TCMRA and postcontrast T1-weighted images after administration of 0.1 mmol/kg gadoteridol. When findings were negative or equivocal, we injected an additional 0.1-mmol/kg dose of gadoteridol and obtained PWI and second postcontrast T1-weighted images. We used a 3-point scale to grade perfusion maps and TCMRA and assessed whether these techniques added information to conventional MR imaging in the differential diagnosis. We also evaluated whether the second contrast injection improved the conspicuity and/or number of enhancing lesions and used a 4-point scoring system to quantitatively analyze diagnostic yield of TCMRA and PWI. RESULTS: We could assess tumor hemodynamics on PWI maps and TCMRA images in all 69 patients. In 14 cases (20%), PWI and/or TCMRA added information to conventional MR findings. After second injection of contrast medium, lesion conspicuity improved in 58 of the 69 cases (84%), and the number of detected lesions increased in 11 of 31 cases diagnosed with metastatic disease (36%). Quantitative analysis revealed TCMRA and PWI provided significant additional diagnostic information (Kruskal-Wallis test, P<0.0001). CONCLUSION: Consecutive acquisition of TCMRA and PWI using supplementary contrast injection can facilitate differential diagnosis of suspected brain metastasis and improve the number and conspicuity of detected lesions. PMID- 23666160 TI - Intrahepatic bile duct adenoma mimicking hepatic metastasis: case report and review of the literature. AB - We present a case of bile duct adenoma that mimicked hepatic metastasis from gastric cancer. The adenoma exhibited prolonged enhancement on dynamic computed tomography, hyperintensity on diffusion-weighted imaging, and diminished uptake of superparamagnetic iron oxide and gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid on magnetic resonance imaging, resembling those of adenocarcinomas. Knowledge of the imaging findings of this rare entity may aid correct diagnosis. PMID- 23666161 TI - Using business plan development as a capstone project for MPH programs in Canada: validation through the student perspective. AB - Master of Public Health (MPH) programs have been developed across Canada as a response to the need for adequately trained individuals to work in the public health sector. Educational institutions that deliver MPH programs have a responsibility to ensure that graduates of their program have the essential knowledge, skills and attitudes to begin a successful career in public health. The Public Health Agency of Canada has created the core competencies for public health to guide the development, delivery and evaluation of MPH programs. In Canada, a capstone project is the recommended method of evaluating the MPH graduate's ability to demonstrate proficiency in the public health core competencies. A business plan that develops the framework for a public health program is an ideal capstone project currently used in practice within the University of Guelph MPH program. This group assignment incorporates all 36 of the public health core competencies while providing students with a real-world public health experience, and should be considered for inclusion within MPH programs across Canada. Business planning provides students the opportunity to engage in practice-based learning, applying theoretical knowledge to practice. Further, the ability to develop realistic but financially feasible public health problems is an invaluable skill for MPH graduates. As the development of programs becomes more restricted and the continuation of other programs are under constant threat, the ability to develop a sound business plan is a required skill for individuals entering the public health sector, and will ensure students are able to maximize outcomes given tight fiscal budgets and limited resources. PMID- 23666162 TI - High glycolytic potential does not predict low ultimate pH in pork. AB - Extent of postmortem pH decline influences meat quality development. To better understand physiological determination of ultimate pH (pHu), we utilized female and castrated male pigs from a line whose selection index includes differentiated pHu. All genotypes of AMP-activated protein kinase gamma3 subunit (AMPKgamma3) V199I site were present. The mutant 199II genotype increased pHu, but only in castrated males. Genotype affected glycolytic potential (GP), but GP was weakly associated with pHu. A subset of animals was selected based on low (-Gly) and high (+Gly) residual glycogen content, and compared with AMPKgamma3 200Q, which is associated with low pHu. Both +Gly and 200Q muscle contained glycolytic substrate at 24h; however, 200Q muscle generated low pHu and greater lactate compared to +Gly. Additionally,-Gly and +Gly groups exhibited similar pHu despite a large difference in GP. In conclusion, high GP does not appear to directly impact the extent of postmortem pH decline. PMID- 23666163 TI - Evaluation of feedlot cattle working chute behavior relative to temperament, tenderness, and postmortem proteolysis. AB - The objective was to investigate if the association between working chute behavior and beef tenderness found in our previous study is related to protein degradation and calpain system activity. Crossbred steers (n=183) allotted to 16 pens were weighed every 28 d. Temperament was evaluated as exit velocity (EV), chute score (CS), and catch score (CAPS). Between 14 and 16 mo of age (606+/-52 kg), steers were harvested. Strip steaks were collected and aged for 14 d. Subsamples were collected at 36 h and 7d postmortem and analyzed for calpastatin activity, MU-calpain autolysis, and troponin-T degradation. Shear force (WBSF) was correlated (P<0.05) with calpastatin activity and measurements of troponin-T. Calpastatin activity, MU-calpain autolysis, and troponin-T measurements did not correlate with the measurements of EV, CS, and CAPS. Therefore, activation of the calpain system or differences in protein degradation did not appear to influence the differences in tenderness that are correlated with working chute behavior. PMID- 23666164 TI - The Austrian experience with trabectedin in non-selected patients with metastatic soft tissue sarcoma (STS). AB - PURPOSE: The purpose of this retrospective analysis was to assess efficacy and tolerability of trabectedin in soft tissue sarcoma (STS) in the routine clinical setting. PATIENTS AND METHODS: Efficacy and safety data of trabectedin were retrospectively evaluated in patients with advanced STS who had started treatment with trabectedin at six institutions in Austria between January 2008 and May 2012. RESULTS: Data of 101 adult patients were included in the present analysis. Patients had a median age of 56 years; 59 and 41% received trabectedin as <=2nd and >=3rd chemotherapy line for advanced disease, respectively. Median progression-free survival (PFS) and overall survival (OS) were 3.9 and 11.6 months. Median PFS and OS were different in patients who received trabectedin as <=2nd- or >=3rd-line treatment: median PFS was 3.9 versus 3.6 months and OS was 15.2 versus 24.8 months, respectively. The extent and severity of trabectedin induced toxicity were low and manageable. CONCLUSIONS: The activity and tolerability of trabectedin in the routine clinical setting is comparable to outcomes reported in phase II trials already published. Regardless of whether trabectedin was given earlier or later in the course of disease, outcomes did not differ in the cohort of analysed patients. PMID- 23666165 TI - Pan American Health Organization and World Health Organization: concerns regarding tobacco use. PMID- 23666166 TI - Long-term exposure to traffic-related air pollution and insulin resistance in children: results from the GINIplus and LISAplus birth cohorts. AB - AIMS/HYPOTHESIS: Epidemiological studies that have examined associations between long-term exposure to traffic-related air pollution and type 2 diabetes mellitus in adults are inconsistent, and studies on insulin resistance are scarce. We aimed to assess the association between traffic-related air pollution and insulin resistance in children. METHODS: Fasting blood samples were collected from 397 10 year-old children in two prospective German birth cohort studies. Individual level exposures to traffic-related air pollutants at the birth address were estimated by land use regression models. The association between air pollution and HOMA of insulin resistance (HOMA-IR) was analysed using a linear model adjusted for several covariates including birthweight, pubertal status and BMI. Models were also further adjusted for second-hand smoke exposure at home. Sensitivity analyses that assessed the impact of relocating, study design and sex were performed. RESULTS: In all crude and adjusted models, levels of insulin resistance were greater in children with higher exposure to air pollution. Insulin resistance increased by 17.0% (95% CI 5.0, 30.3) and 18.7% (95% CI 2.9, 36.9) for every 2SDs increase in ambient NO2 and particulate matter <=10 MUm in diameter, respectively. Proximity to the nearest major road increased insulin resistance by 7.2% (95% CI 0.8, 14.0) per 500 m. CONCLUSIONS/INTERPRETATION: Traffic-related air pollution may increase the risk of insulin resistance. Given the ubiquitous nature of air pollution and the high incidence of insulin resistance in the general population, the associations examined here may have potentially important public health effects despite the small/moderate effect sizes observed. PMID- 23666169 TI - Comment to: First laparoscopic totally extraperitoneal repair of Laugier's hernia: a case report. Ates M, Dirican A, Kose E, Isik B, Yilmaz S. Hernia 2013; 17:121-123. PMID- 23666167 TI - Semaphorin 3C is a novel adipokine linked to extracellular matrix composition. AB - AIMS/HYPOTHESIS: Alterations in white adipose tissue (WAT) function, including changes in protein (adipokine) secretion and extracellular matrix (ECM) composition, promote an insulin-resistant state. We set out to identify novel adipokines regulated by body fat mass in human subcutaneous WAT with potential roles in adipose function. METHODS: Adipose transcriptome data and secretome profiles from conditions with increased/decreased WAT mass were combined. WAT donors were predominantly women. In vitro effects were assessed using recombinant protein. Results were confirmed by quantitative PCR/ELISA, metabolic assays and immunochemistry in human WAT and adipocytes. RESULTS: We identified a hitherto uncharacterised adipokine, semaphorin 3C (SEMA3C), the expression of which correlated significantly with body weight, insulin resistance (HOMA of insulin resistance [HOMAIR], and the rate constant for the insulin tolerance test [KITT]) and adipose tissue morphology (hypertrophy vs hyperplasia). SEMA3C was primarily found in mature adipocytes and had no direct effect on human adipocyte differentiation, lipolysis, glucose transport or the expression of beta-oxidation genes. This could in part be explained by the significant downregulation of its cognate receptors during adipogenesis. In contrast, in pre-adipocytes, SEMA3C increased the production/secretion of several ECM components (fibronectin, elastin and collagen I) and matricellular factors (connective tissue growth factor, IL6 and transforming growth factor-beta1). Furthermore, the expression of SEMA3C in human WAT correlated positively with the degree of fibrosis in WAT. CONCLUSIONS/INTERPRETATION: SEMA3C is a novel adipokine regulated by weight changes. The correlation with WAT hypertrophy and fibrosis in vivo, as well as its effects on ECM production in human pre-adipocytes in vitro, together suggest that SEMA3C constitutes an adipocyte-derived paracrine signal that influences ECM composition and may play a pathophysiological role in human WAT. PMID- 23666168 TI - Phenobarbital-enhanced hepatobiliary scintigraphy in the diagnosis of biliary atresia: two decades of experience at a tertiary center. AB - BACKGROUND: Hepatobiliary scintigraphy is highly sensitive for diagnosing biliary atresia; however, its specificity has varied in the literature from 35% to 97%. OBJECTIVE: The purpose of this study was to re-evaluate the accuracy of phenobarbital-enhanced hepatobiliary scintigraphy in differentiating biliary atresia from other causes of neonatal cholestasis. MATERIALS AND METHODS: We retrospectively reviewed all hepatobiliary scans of infants with cholestasis at our institution from December 1990 to May 2011. Per our routine protocol the scans were obtained after pretreatment with phenobarbital (5 mg/kg/day for 5 days) to achieve a serum level of >=15 mcg/ml. Normal hepatic uptake with no biliary excretion by 24 h was considered consistent with biliary atresia. RESULTS: One hundred eighty-six infants with 210 hepatobiliary scans composed the study group. Forty-three (23%) infants had the final diagnosis of biliary atresia. Hepatobiliary scintigraphy was 100% sensitive, 93% specific and 94.6% accurate in diagnosing biliary atresia. Of the 186, 39/111 (35.1%) term and 2/68 (2.9%) preterm infants had biliary atresia; two of seven children with unknown gestational age also had biliary atresia. Other diagnoses included neonatal hepatitis, total parenteral nutrition cholestasis, Alagille syndrome, cystic fibrosis, choledochal cyst, hypothyroidism, alpha-1 antitrypsin deficiency and persistent cholestasis of unknown etiology. CONCLUSION: Phenobarbital-enhanced hepatobiliary scintigraphy is highly accurate in differentiating biliary atresia from other causes of neonatal cholestasis. Biliary atresia is rare in premature infants. PMID- 23666170 TI - Association between interleukin 6 gene haplotype and Alzheimer's disease: a Brazilian case-control study. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease that takes the form of a local overexpression of cytokines and other inflammatory molecules. We investigated three single-nucleotide polymorphisms (SNP) of the interleukin 6 gene (IL-6) promoter region [-174G/C (rs 1800795), -572C/G (rs 1800796), and 597G/A (rs 1800797)] in 200 patients with late-onset AD and 165 elderly controls in a Brazilian case-control population sample. Genotyping was carried out from blood cells using PCR-RFLP techniques. Statistical analysis was performed to evaluate the Hardy-Weinberg equilibrium and to compare frequencies between groups. No association was found between any IL-6 polymorphism and AD; however the haplotype composed of the -597 A allele and the -174G allele indicated a crude odds ratio (OR) of 0.15 (p = 0.0021) and a significantly adjusted OR (adjusted for the APOE E4 allele value) of 0.15 (p = 0.00294). Linkage disequilibrium was D' = 0.68 among the three SNPs. Our findings revealed a protective effect of AG (-597A, -174G) haplotype, which worked independently of the APOE E4 allele in our Brazilian population sample. Thus, the promoter region of IL-6 gene probably exerts an effect through gene linkage and/or gene interaction. PMID- 23666171 TI - Diagnostic power of 24S-hydroxycholesterol in cerebrospinal fluid: candidate marker of brain health. AB - We evaluated the diagnostic potential of 24S-hydroxycholesterol (24OHC) in cerebrospinal fluid. At a memory clinic, we investigated subjects with subjective cognitive impairment (SCI, n = 33), mild cognitive impairment (MCI) patients (n = 27), MCI patients with later progression into Alzheimer dementia at follow up (n = 10), and patients with AD (n = 24). We also had a control group of healthy volunteers who did not later develop cognitive problems (n = 13). The fraction of the population with pathological levels of 24OHC was 8% in controls, 34% in SCI, 37% in MCI, 80% in MCI with progression, and 42% in AD. The corresponding fractions for T-tau, P-tau, and Abeta42 were lower in the case of SCI and MCI but higher in the case of controls and AD. In case of MCI with progression, the fraction of pathological levels of 24OHC and Abeta42 were 80% and 63% respectively. We also studied a population of old healthy subjects age 75-99 years (n = 25). The fraction of individuals in this population with pathological levels of 24OHC was 0% whereas the fraction of individuals with pathological level of at least one of the other three biomarkers was 40%. The diagnostic power of 24OHC in cerebrospinal fluid seems to be similar to or lower than that of the established biomarkers T-tau, P-tau, and Abeta42 in the diagnosis of established AD. Our data suggest that 24OHC may be more sensitive than the classical biomarkers in an early phase of the neurodegenerative process and a better marker for "brain health" in old age. PMID- 23666172 TI - Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer's disease brain tissue. AB - The aim of this study was to establish a link between periodontal disease and Alzheimer's disease (AD) with a view to identifying the major periodontal disease bacteria (Treponema denticola, Tannerella forsythia, and Porphyromonas gingivalis) and/or bacterial components in brain tissue from 12 h postmortem delay. Our request matched 10 AD cases for tissue from Brains for Dementia Research alongside 10 non-AD age-related controls with similar or greater postmortem interval. We exposed SVGp12, an astrocyte cell line, to culture supernatant containing lipopolysaccharide (LPS) from the putative periodontal bacteria P. gingivalis. The challenged SVGp12 cells and cryosections from AD and control brains were immunolabeled and immunoblotted using a battery of antibodies including the anti-P. gingivalis-specific monoclonal antibody. Immunofluorescence labeling demonstrated the SVGp12 cell line was able to adsorb LPS from culture supernatant on its surface membrane; similar labeling was observed in four out of 10 AD cases. Immunoblotting demonstrated bands corresponding to LPS from P. gingivalis in the SVGp12 cell lysate and in the same four AD brain specimens which were positive when screened by immunofluorescence. All controls remained negative throughout while the same four cases were consistently positive for P. gingivalis LPS (p = 0.029). This study confirms that LPS from periodontal bacteria can access the AD brain during life as labeling in the corresponding controls, with equivalent/longer postmortem interval, was absent. Demonstration of a known chronic oral-pathogen-related virulence factor reaching the human brains suggests an inflammatory role in the existing AD pathology. PMID- 23666173 TI - Cortical and subcortical cerebrovascular resistance index in mild cognitive impairment and Alzheimer's disease. AB - BACKGROUND: Reduced regional cerebral blood flow (rCBF) is a well-established finding in Alzheimer's disease (AD), although fewer studies have examined the role of increased regional cerebrovascular resistance. By calculating the ratio of mean arterial pressure to rCBF, it is possible to estimate an index of regional cerebrovascular resistance (CVRi) that may be a sensitive measure of occult cerebrovascular disease. OBJECTIVE: To compare probable AD patients to mild cognitive impairment (MCI) and normal control (NC) participants on CVRi, the ratio of mean arterial pressure to rCBF. METHODS: Eighty-one participants (12 AD, 23 MCI, 46 NC) were compared on CVRi using voxel-wise analyses. Region-of interest analyses examined correlations between subcortical CVRi and both cognition and white matter lesion (WML) volume. RESULTS: Voxel-wise analyses revealed CVRi elevation in AD relative to NCs (subcortical, medial temporal, posterior cingulate, precuneus, inferior parietal, superior temporal) and MCI (subcortical, posterior cingulate). MCI participants exhibited intermediate CVRi values within cortical and medial temporal areas. Significant CVRi clusters were larger and more widespread than those of parallel CBF analyses. Among MCI and AD participants, subcortical CVRi elevation was associated with lower Dementia Rating Scale score (r = -0.52, p = 0.001, for both thalamus and caudate), and caudate CVRi correlated with WML volume (r = 0.45, p = 0.001). CONCLUSIONS: Cortical and subcortical CVRi is elevated in AD, particularly within the caudate and thalamus, where it is associated with decreased cognitive performance and increased WMLs. Findings suggest CVRi may play a role in cognitive decline and cerebrovascular disease in MCI and AD. PMID- 23666174 TI - Cerebrospinal fluid Abeta1-40 improves differential dementia diagnosis in patients with intermediate P-tau181P levels. AB - It is assumed that the concentration of amyloid-beta1-40 (Abeta1-40) in cerebrospinal fluid (CSF) reflects the total amount of Abeta protein in the brain and thus allows a better interpretation of inter-individual differences in Abeta quantity than the Abeta1-42 concentration. In this study, Abeta1-40 was added to the existing CSF biomarker panel of Abeta1-42, total tau (T-tau), and phosphorylated tau (P-tau181P) in order to test whether the accuracy of the differential dementia diagnosis improved. The concentration of Abeta1-40 (INNOTEST(r) beta-amyloid(1-40) prototype version, Innogenetics NV, Belgium) and the other biomarkers (INNOTEST(r)) was determined in CSF samples from 80 Alzheimer's disease (AD) patients, 75 non-AD dementia patients, and 30 controls. A large proportion of the study population had autopsy-confirmed neurodegeneration (AD: 73/80 = 91%; non-AD: 38/75 = 51%). The levels of Abeta1-40 were decreased in AD (10856 +/- 4745 pg/mL) and non-AD patients (10519 +/- 4491 pg/mL) when compared to controls (14760 +/- 7846 pg/mL) (p = 0.002 and p = 0.001). The Abeta1-42/Abeta1-40 ratio was significantly decreased in AD (0.043 +/ 0.021) as compared to non-AD patients (0.064 +/- 0.027; p < 0.001) and controls (0.053 +/- 0.023; p < 0.001). In order to differentiate AD from non-AD patients, a decision tree was constructed. The diagnostic accuracy of the decision tree that contained Abeta1-42, Abeta1-40, P-tau181P, and the Abeta1-42/Abeta1-40 ratio was significantly better than the diagnostic accuracy (80% versus 74%) of the decision tree without Abeta1-40 and the Abeta1-42/Abeta1-40 ratio (p < 0.001). In conclusion, no difference in Abeta1-40 CSF levels was found between AD and non-AD patients, but adding CSF Abeta1-40 and the CSF Abeta1-42/Abeta1-40 ratio to a biomarker-based decision tree, might have an added value for discriminating AD from non-AD patients in case of intermediate CSF P-tau181P values. PMID- 23666175 TI - Correlation between topographic N400 anomalies and reduced cerebral blood flow in the anterior temporal lobes of patients with dementia. AB - In Alzheimer's disease (AD) patients, episodic memory impairments are apparent, yet semantic memory difficulties are also observed. While the episodic pathology has been thoroughly studied, the neurophysiological mechanisms of the semantic impairments remain obscure. Semantic dementia (SD) is characterized by isolated semantic memory deficits. The present study aimed to find an early marker of mild AD and SD by employing a semantic priming paradigm during electroencephalogram recordings. Event-related potentials (ERP) of early (P1, N1) and late (N400) word processing stages were obtained to measure semantic memory functions. Separately, baseline cerebral blood flow (CBF) was acquired with arterial spin labeling. Thus, the analysis focused on linear regressions of CBF with ERP topographical similarity indices in order to find the brain structures that showed altered baseline functionality associated with deviant ERPs. All participant groups showed semantic priming in their reaction times. Furthermore, decreased CBF in the temporal lobes was associated with abnormal N400 topography. No significant CBF clusters were found for the early ERPs. Taken together, the neurophysiological results suggested that the automatic spread of activation during semantic word processing was preserved in mild dementia, while controlled access to the words was impaired. These findings suggested that N400-topography alterations might be a potential marker for the detection of early dementia. Such a marker could be beneficial for differential diagnosis due to its low cost and non-invasive application as well as its relationship with semantic memory dysfunctions that are closely associated to the cortical deterioration in regions crucial for semantic word processing. PMID- 23666176 TI - Neuropathologic correlates of cognition in a population-based sample. AB - Many cognitively normal older adults have underlying neuropathologic changes of Alzheimer's disease (AD), vascular brain injury (VBI), or Lewy body disease (LBD), which confer an increased risk of dementia. The current study focused on the association between multiple neuropathologic indices and performance on specific cognitive domains in a community sample of older adults. Of 438 participants in the Adult Changes in Thought population-based study of brain aging who were autopsied, 363 subjects had cognitive testing at their final study visit and were included. Associations were measured between performance on the Cognitive Abilities Screening Instrument prior to death and neuropathologic endpoints, including AD neuropathologic changes, LBD, cerebral amyloid angiopathy, and measures of VBI. Braak stage for neurofibrillary tangles, lower brain weight, and VBI as measured by cerebral cortical microvascular lesions (MUVBI) explained a significant proportion of the variance associated with global cognitive test performance (R2 = 0.31, p < 0.0001) both in the entire sample and when analysis was restricted to non-demented subjects (R2 = 0.23, p < 0.0001). Specific cognitive domains were differentially related to neuropathologic lesion type: memory and executive function with AD pathologic changes and cortical MUVBI, executive function with subcortical MUVBI, and visuospatial construction with LBD. Thus, neuropathologic lesions of LBD and MUVBI are associated with poorer cognitive performance over and above AD neuropathologic changes in subjects without dementia in this cohort. These findings underscore that cognitive impairment is a complex convergent trait that has important implications for clinical investigation and medical management of older adults. PMID- 23666177 TI - The development of an in vivo gamma-secretase assay using zebrafish embryos. AB - Aberrant proteolytic processing of amyloid-beta protein precursor by gamma secretase complexes may result in an imbalance between production and clearance of the Abeta proteolytic product and promote neuronal dysfunction and death. Presenilin proteins form the catalytic core of gamma-secretase complexes. The zebrafish, Danio rerio, is a versatile vertebrate model for investigating the molecular basis of Alzheimer's disease pathology. It possesses genes orthologous to human PSEN1 and PSEN2 (psen1 and psen2 respectively), and AbetaPP (appa and appb that are duplicates of an ancestral AbetaPP orthologue). Currently there is no in vivo assay appropriate for directly monitoring gamma-secretase activity. Here, we describe such an assay in which the level of a gamma-secretase substrate (a modified form of Appa protein) is observed in zebrafish embryos by western immunoblotting relative to a co-expressed protein not subject to gamma-secretase activity. We have used the assay to analyze the effects on gamma-secretase activity of blocking translation of transcripts of zebrafish psen1 and/or psen2. PMID- 23666178 TI - Overexpression of Down syndrome cell adhesion molecule impairs precise synaptic targeting. AB - Fragile X syndrome is caused by the loss of Fragile X mental retardation protein (FMRP), an RNA-binding protein that suppresses protein translation. We found that FMRP binds to Down syndrome cell adhesion molecule (Dscam) RNA, a molecule that is involved in neural development and has been implicated in Down syndrome. Elevated Dscam protein levels in FMRP null Drosophila and in flies with three copies of the Dscam gene both produced specific and similar synaptic targeting errors in a hard-wired neural circuit, which impaired the flies' sensory perception. Reducing Dscam levels in FMRP null flies reduced synaptic targeting errors and rescued behavioral responses. Our results indicate that excess Dscam protein may be a common molecular mechanism underlying altered neural wiring in intellectual disabilities such as Fragile X and Down syndromes. PMID- 23666179 TI - Responses of pulvinar neurons reflect a subject's confidence in visual categorization. AB - When we recognize a sensory event, we experience a confident feeling that we certainly know the perceived world 'here and now'. However, it is unknown how and where the brain generates such 'perceptual confidence'. Here we found neural correlates of confidence in the primate pulvinar, a visual thalamic nucleus that has been expanding markedly through evolution. During a categorization task, the majority of pulvinar responses did not correlate with any 'perceptual content'. During an opt-out task, pulvinar responses decreased when monkeys chose 'escape' options, suggesting less confidence in their perceptual categorization. Functional silencing of the pulvinar increased monkeys' escape choices in the opt out task without affecting categorization performance; this effect was specific to the contralateral visual target. These data were supported by a theoretical model of confidence, indicating that pulvinar activities encode a subject's certainty of visual categorization and contribute to perceptual confidence. PMID- 23666180 TI - Convergent cortical innervation of striatal projection neurons. AB - Anatomical studies have led to the assertion that intratelencephalic and pyramidal tract cortical neurons innervate different striatal projection neurons. To test this hypothesis, we measured the responses of mouse striatal neurons to optogenetic activation of intratelencephalic and pyramidal tract axons. Contrary to expectation, direct and indirect pathway striatal spiny projection neurons responded to both intratelencephalic and pyramidal tract activation, arguing that these cortical networks innervate both striatal projection neurons. PMID- 23666181 TI - Selective and graded coding of reward uncertainty by neurons in the primate anterodorsal septal region. AB - Natural environments are uncertain. Uncertainty of emotional outcomes can induce anxiety and raise vigilance, promote and signal the opportunity for learning, modulate economic choice and regulate risk-seeking. Here we demonstrate that a subset of neurons in the anterodorsal region of the primate septum (ADS) are primarily devoted to processing uncertainty in a highly specific manner. Those neurons were selectively activated by visual cues indicating probabilistic delivery of reward (for example, 25%, 50% and 75% reward) and did not respond to cues indicating certain outcomes (0% and 100% reward). The average ADS uncertainty response was graded with the magnitude of reward uncertainty and selectively signaled uncertainty about rewards rather than punishments. The selective and graded information about reward uncertainty encoded by many neurons in the ADS may underlie modulation of uncertainty of value- and sensorimotor related areas to regulate goal-directed behavior. PMID- 23666182 TI - Sexual partnerships with men and women among men who have sex with men in Beijing and Chongqing, China, 2010. AB - HIV is spreading among Chinese MSM and may possibly lead to infection of female partners. Pressure to marry may drive a greater proportion of Chinese MSM to have female partners than MSM elsewhere in the world. Measurement of the size of the potential risk to female partners of Chinese MSM is inconsistent in the literature. From samples of MSM in two Chinese cities, we documented numbers of sexual partners and sexual activity with those partners. About 500 MSM were sampled in each city. 11.0 and 12.6 % of men reported having any female partners in the past 6 months in Chongqing and Beijing, respectively. Men also reported that only 7.3 and 6.7 % of their entire partnerships were with women in Chongqing and Beijing, respectively. Defining transmission risk accounting for receptive anal sex among men and condom non-use with both male and female partners, 3.4 % of MSM in both Chongqing and Beijing would have the potential to transmit HIV to female partners. Only 9 (1.8 ) men in Chongqing and 2 (0.4 %) in Beijing were HIV positive and also had unprotected intercourse with females. The majority of HIV transmission risk among MSM in China is not from MSM to females. PMID- 23666183 TI - From research to practice: lay adherence counsellors' fidelity to an evidence based intervention for promoting adherence to antiretroviral treatment in the Western cape, South Africa. AB - In the Western Cape, lay counsellors are tasked with supporting antiretroviral (ARV) adherence in public healthcare clinics. Thirty-nine counsellors in 21 Cape Town clinics were trained in Options for Health (Options), an evidence-based intervention based on motivational interviewing (MI). We evaluated counsellors' ability to deliver Options for addressing poor adherence following 5 days training. Audio-recordings of counselling sessions collected following training were transcribed and translated into English. Thirty-five transcripts of sessions conducted by 35 counsellors were analysed for fidelity to the Options protocol, and using the Motivational Interviewing Treatment and Integrity (MITI) code. Counsellors struggled with some of the strategies associated with MI, such as assessing readiness-to-change and facilitating change talk. Overall, counsellors failed to achieve proficiency in the approach of MI according to the MITI. Counsellors were able to negotiate realistic plans for addressing patients' barriers to adherence. Further efforts aimed at strengthening the ARV adherence counselling programme are needed. PMID- 23666185 TI - The case for nursing: proving our worth. PMID- 23666186 TI - Transfusion-associated necrotizing enterocolitis: translating knowledge into nursing practice. AB - Necrotizing enterocolitis (NEC) is a leading cause of prolonged hospitalizations for premature infants in the United States. In a recent large retrospective study, a significant proportion of NEC cases were shown to occur within 48 hours of packed red blood cell (PRBC) transfusion, especially in growing preterm neonates of older postnatal age. A small body of evidence consistently demonstrates that 25-35 percent of NEC cases are temporally associated with PRBC transfusion and that cases of NEC associated with transfusion are generally more severe with a higher rate of surgical intervention and mortality. Awareness of this association is vital for potential prevention and early recognition of NEC. The neonatal nurse has a primary role in care strategies that may affect NEC. This review of literature was compiled to educate neonatal nurses about the existence of transfusion-associated necrotizing enterocolitis and guide the translation of knowledge into nursing practice at the bedside. PMID- 23666184 TI - Protein SUMOylation and plant abiotic stress signaling: in silico case study of rice RLKs, heat-shock and Ca(2+)-binding proteins. AB - Plants respond to stress conditions through early stress-response factors (ESRF), which serve the function of stress sensing and/or signal transduction. These mainly comprise qualitative and/or quantitative flux in the redox molecules, calcium ions (Ca(2+)), phosphatidic acid, hexose sugars and phytohormones. The role of resident proteins such as phytohormone receptors and G-proteins as first messengers under stress is well established. Yet, within the modern omics context, most of the stress response at the protein level is injudiciously attributed to substantial up- or down-regulation of expression measured at the RNA or protein level. Proteins such as kinases and transcription factors (TFs) that exhibit cascade effects are primary candidates for studies in plant stress tolerance. However, resident-protein post-translational modification (PTM), specifically in response to particular conditions such as stress, is a candidate for immediate and potent 'quick reaction force' (QRF) kind of effects. Stress mediated SUMOylation of TFs and other proteins have been observed. SUMOylation can change the rate of activity, function or location of the modified protein. Early SUMOylation of resident proteins can act in the stress signal transduction or in adaptive response. Here, we consider brief background information on ESRFs to establish the crosstalk between these factors that impinge on PTMs. We then illustrate connections of protein SUMOylation to phytohormones and TFs. Finally, we present results of an in silico analysis of rice Receptor-Like Kinases, heat shock and calcium-binding proteins to identify members of these gene families, whose basal expression under drought but potential SUMOylation presents them as QRF candidates for roles in stress signaling/response. PMID- 23666187 TI - Human milk banking. AB - Forms of human milk banking and donation have been present for more than a century worldwide, but, since 1985, the Human Milk Banking Association of North America (HM BANA) has established guidelines to make the use of donor's breast milk safe and the second best form of feeding to maternal breast milk for a neonatal intensive care unit (NICU) infant. The Indiana Mother's Human Milk Bank provides an extensive and meticulous process of selecting breast milk donors. The process begins with a phone interview with a potential donor and includes the review of the donor's medical records, blood laboratory screening, medication and dietary intake, as well as consent from the donor's pediatrician. The milk bank follows steps of collecting, storing, and receiving the breast milk in accordance with the guidelines of the HM BANA. Pasteurization is the method used to ensure the proper heating and cooling of breast milk. Despite the rigorous pasteurization method, the donor's breast milk will not lose most of the important beneficial components needed for sick or ill NICU infants. Every batch of pasteurized breast milk will be cultured for any possible contamination and shipped to NICUs after it has been cleared by laboratory testing. PMID- 23666188 TI - Neonatal bioethical perspectives: practice considerations. AB - Over the past 30 years, there has been a modest improvement in the survival rates of U.S. infants.The public health impact of associated economic and technological advances raises questions regarding neonatal care and end-of-life decisions for those caring for this population. Nurses have an obligation to remain abreast of neonatal ethical standards because they are intimately involved in caring for these patients. Therefore, the aim of this article is to (a) summarize the extant neonatal bioethical literature to appreciate the complex ethical issues that translate into practice challenges, (b) present a framework that guides the assessment of the benefits and burdens of neonatal intensive care in the clinical setting to solicit and provoke dialogue, and (c) provide examples that advocate for educational training for neonatal healthcare providers in support of ethically sound care to affected families and infants. PMID- 23666189 TI - Vitamin K prophylaxis in the newborn: indications and controversies. PMID- 23666190 TI - Bronze baby syndrome. AB - An in-depth review of jaundice in the newborn was covered in this column in the September/October 2007 issue. This article will include a brief review of bilirubin formation and discuss what is currently known about bronze baby syndrome (BBS). This column will include a short review of bilirubin formation and conclude with an unusual case study of a patient who developed BBS in the absence of direct hyperbilirubinemia. PMID- 23666191 TI - Finding the evidence. PMID- 23666192 TI - Facilitating breastfeeding in the neonatal intensive care unit: identifying barriers. PMID- 23666193 TI - Grandparents have a special role in the NICU. PMID- 23666195 TI - Hypothermia treatment following perinatal asphyxia-a parental perspective. PMID- 23666197 TI - BiP negatively affects ricin transport. AB - The AB plant toxin ricin binds both glycoproteins and glycolipids at the cell surface via its B subunit. After binding, ricin is endocytosed and then transported retrogradely through the Golgi to the endoplasmic reticulum (ER). In the ER, the A subunit is retrotranslocated to the cytosol in a chaperone dependent process, which is not fully explored. Recently two separate siRNA screens have demonstrated that ER chaperones have implications for ricin toxicity. ER associated degradation (ERAD) involves translocation of misfolded proteins from ER to cytosol and it is conceivable that protein toxins exploit this pathway. The ER chaperone BiP is an important ER regulator and has been implicated in toxicity mediated by cholera and Shiga toxin. In this study, we have investigated the role of BiP in ricin translocation to the cytosol. We first show that overexpression of BiP inhibited ricin translocation and protected cells against the toxin. Furthermore, shRNA-mediated depletion of BiP enhanced toxin translocation resulting in increased cytotoxicity. BiP-dependent inhibition of ricin toxicity was independent of ER stress. Our findings suggest that in contrast to what was shown with the Shiga toxin, the presence of BiP does not facilitate, but rather inhibits the entry of ricin into the cytosol. PMID- 23666198 TI - Feasibility of video clip analysis on effect of botulinum toxin-A injection for post-stroke upper limb spasticity. AB - Existing functional evaluation tools do not accurately reveal the improved function following botulinum toxin A (BTX-A) injection for post-stroke upper limb spasticity. With the aim of developing an alternate method of measuring functional improvement following BTX-A injection, this study tested the feasibility, validity and reliability of video clip analysis performed by the clinicians. Seventy-nine patients administered BTX-A due to post-stroke upper limb spasticity, were retrospectively evaluated using video clip analysis. Pre- and post-injection video clips recorded at 1-month intervals were randomly allocated and sent to three blinded physician evaluators who were asked to choose the one that seemed more improved in terms of hand motion and associated upper limb reaction during gait. The three physicians chose the post-injection video clip as depicting improved hand motion (82.3%, 79.7%, and 72.2%) and associated upper limb reaction during gait (73.4%, 70.9%, and 70.9%). Kappa and intraclass correlation coefficient as a measure of interrater reliability among the three physicians was 0.86 and 0.79 for the hand, and 0.92 and 0.92 for associated upper limb reaction during gait, respectively. The percent overall agreement of the physicians was 78.1% and 71.7% for hand function and associated upper limb reaction, respectively. Retrospective pre- and post-BTX-A injection video clip analyses is a clinically feasible alternative method to evaluate the improvement following BTX-A injection for post-stroke upper limb spasticity, especially in busy clinical practice setting. PMID- 23666199 TI - Brain ischemia induces regeneration of interneurons but not projection neurons. AB - PURPOSE: How injured long-distance neural tracts are reestablished following ischemic brain injury remains unclear. Theories surrounding reconnection include the growth of newly formed axons from newborn neurons, modification of local circuits and a beneficial influence from neurotrophic factors. This research aimed to find the developing new born neurons and the neurotrophic factors they secreted in a middle cerebral artery occlusion (MCAO) rat model to explain the roles of neural progenitor cells in post-ischemic neurogenesis. METHODS: Fifty three male Sprague-Dawley rats underwent the MCAO procedure or sham operation. Double labeling of specific neuron markers (calbindin and N-200) and a dividing cell marker (BrdU) were used to identify newly formed neurons. Neurotrophic factors were examined in the cerebrospinal fluid in post-ischemic rats using enzyme-linked immunosorbent assay. RESULTS: Ischemic injury induced activation of neurogenesis. The newborn neurons differentiated into calbindin-positive interneurons, but not N-200 positive projection neurons. The concentration of neurotrophic factors was elevated and was in accordance with the neurogenesis seen in ischemic animal models. CONCLUSION: Our research indicates that the recovery of neural function is not ascribed to the reestablishment of damaged projection tracts, but to the modulation of local circuits and beneficial effects of neurotrophins produced by neural progenitor cells. PMID- 23666200 TI - Combination treatment with progesterone and rehabilitation training further promotes behavioral recovery after acute ischemic stroke in mice. AB - PURPOSE: The present study was aimed to investigate whether combination treatment with progesterone and rehabilitation training would be more effective than monotherapy after cerebral ischemia. METHODS: C57BL/6 mice were subjected to focal ischemia by photothrombosis and were treated with progesterone (2 mg/kg), rehabilitation training or their combination. 2,3,5-triphenyltetrazolium chloride (TTC) staining and Nissl staining were used to measure infarct size at day 3 and day 7 after surgery, and rotarod test and grip strength test were conducted to evaluate behavioral outcomes. RESULTS: TTC staining indicated that progesterone, rehabilitation training and their combination produced a different degree of reduction in infarct volume compared with vehicle control at day 3 after ischemia (progesterone: 16.70 +/- 0.93 mm3, p < 0.01, rehabilitation training: 22.19 +/- 0.93 mm3, p < 0.05, progesterone + rehabilitation training: 14.76 +/- 0.92 mm3, p < 0.01, vehicle control: 28.73 +/- 1.05 mm3). Nissl staining revealed that prolonged treatment of progesterone, rehabilitation training and their combination led to a significant decrease in infarct volume at day 7 after ischemia (progesterone: 18.64 +/- 1.83 mm3, p < 0.01, rehabilitation training: 25.07 +/- 1.70 mm3, p < 0.05, progesterone + rehabilitation training: 17.09 +/- 0.92 mm3, p < 0.01, vehicle control: 30.31 +/- 1.36 mm3). No accumulative effect in the reduction of infarct volume was observed in combination therapy at both day 3 and day 7 after ischemia. However, combination therapy significantly improved behavioral performances in the first week after photothrombosis. Combination treatment significantly enhanced rotarod performance and forelimb grip strength at all time points within 7 days after ischemia compared with rehabilitation alone, and significantly improved rotarod performance and forelimb grip strength from day 2 after ischemia compared with progesterone alone. CONCLUSION: Our results suggested that combination treatment with progesterone and rehabilitation training had no additive effect in reducing infarct volume, but combination therapy exhibited enhanced efficacy in promoting functional recovery after ischemic stroke, suggesting progesterone and rehabilitation training may exert their effects via different mechanisms. PMID- 23666201 TI - A systematic review of naturalistic interventions in refugee populations. AB - Naturalistic interventions with refugee populations examine outcomes following mental health interventions in existing refugee service organisations. The current review aimed to examine outcomes of naturalistic interventions and quality of the naturalistic intervention literature in refugee populations with the view to highlight the strengths and limitations of naturalistic intervention studies. Database search was conducted using the search terms 'refugee', 'asylum seeker', 'treatment', 'therapy' and 'intervention. No date limitations were applied, but searches were limited to articles written in English. Seven studies were identified that assessed the outcome of naturalistic interventions on adult refugees or asylum seekers in a country of resettlement using quantitative outcome measures. Results showed significant variation in the outcomes of naturalistic intervention studies, with a trend towards showing decreased symptomatology at post-intervention. However, conclusions are limited by methodological problems of the studies reviewed, particularly poor documentation of intervention methods and lack of control in the design of naturalistic intervention studies. Further examination of outcomes following naturalistic interventions is needed with studies which focus on increasing the rigour of the outcome assessment process. PMID- 23666202 TI - Histopathological correlates with survival in reoperated glioblastomas. AB - The addition of concomitant and adjuvant chemotherapy to radiation therapy after surgical resection has increased significantly the survival of patients with glioblastoma (GB). In conjunction, there has been an increasing fraction of patients who present with new enlarged areas of contrast enhancement and edema on post-treatment imaging that improve without further treatment. It remains to be established how this phenomenon, commonly termed pseudoprogression, can be distinguished from true tumor recurrence defined as the histological presence of active high-grade tumor, as well as its prognostic significance. Data for over 500 patients undergoing surgery for recurrent GB were reviewed. Pathological specimens were categorized as those that contained active high-grade glioma in any amount, and those that did not. Patient survival was compared between these two groups, and independent associations were assessed using Cox proportionate hazards regression analysis. 59 patients met the study criteria including complete pathological and follow-up data. Mean age was 53 +/- 11 years. Median survival from suspected recurrence and initial diagnosis were 8 [5-14] and 20 [12 30] months. Seventeen patients (29 %) had no evidence of active high-grade tumor and 42 (71 %) had at least focal active high-grade glioma. Pathologic pseudoprogression at re-operation (p = 0.03) and gross total resection (p = 0.01) were independently associated with survival. The histopathological features defined here and used to assess the tumor at reoperation were independently associated with survival. These findings may be important in designing treatment strategies and clinical trial endpoints for patients with GB. PMID- 23666204 TI - Prediagnostic body weight and survival in high grade glioma. AB - Greater adiposity has been linked to an increased risk and/or poorer survival in a variety of cancers. We examined whether prediagnostic body weight 1-5 years prior to diagnosis is associated with survival in patients with high grade glioma. The analysis was based on a series of patients with high-grade glioma (N = 853) enrolled in a US-based multicenter case-control study. Subjects reported height and weight 1-5 years prior to interview and at age 21. BMI was categorized according to WHO criteria as underweight (BMI <18.5 kg/m(2)), normal weight (BMI 18.5-24.9 kg/m(2)), overweight (BMI 25-29.9 kg/m(2)) and obese (BMI >=30 kg/m(2)). Proportional hazards regression was used to estimate hazard ratios (HR) and 95 % confidence intervals (CIs) for glioma-related death according to body mass index (BMI, kg/m(2)). Overall survival was reduced among patients underweight (median survival: 12.0 months) or obese (median: 13.6 months) when compared to patients of normal weight (median: 17.5 months) prior to glioma diagnosis (p = 0.004). In a multivariate model controlling for other prognostic factors, an excess mortality was observed in patients reporting obese body weights 1-5 years prior to study interview when compared to patients with a normal BMI (HR = 1.32; 95 % CI 1.04-1.68). Consistent patterns of association with excess body weight were observed in men and women, and all findings were similar regardless of treatment for glioma. A lower than optimal body weight was associated with a nonsignificant excess mortality in multivariate analysis. Premorbid obesity was significantly associated with a poor patient outcome independent of treatment and established prognostic factors. Excess body weight may be an adverse prognostic factor in glioma, a relationship observed across a spectrum of cancer types. The current findings linking prediagnostic body weight with mortality in high-grade glioma warrant further research. PMID- 23666205 TI - Enantioselective phase-transfer catalytic alpha-alkylation of 2-methylbenzyl tert butyl malonates. AB - A new asymmetric synthetic method to prepare alpha,alpha-dialkylmalonates for the construction of a quaternary carbon center via phase-transfer catalytic (PTC) alkylation has been developed. Enantioselective alpha-alkylation of 2 methylbenzyl tert-butyl alpha-methylmalonates under phase-transfer catalytic conditions in the presence of (S,S)-3,4,5-trifluorophenyl-NAS bromide () afforded the corresponding alpha,alpha-dialkylmalonates in high chemical (up to 99%) and optical yields (up to 91% ee), which were selectively hydrolyzed to malonic monoacids under alkali basic conditions for conversion to versatile chiral intermediates. PMID- 23666203 TI - Curcumin acts anti-proliferative and pro-apoptotic in human meningiomas. AB - Meningiomas, the most frequent benign intracranial and intraspinal types of tumors are normally removed by surgery. Complications can occur when the tumor is critically localized and cannot be completely removed or when comorbidities of the mostly elder patients increase the general surgical risk. Thus, alternate medical treatment concepts for the therapy of meningiomas would be desirable. Curcumin, the active ingredient of the spice plant Curcuma longa has shown anti tumorigenic actions in many different types of tumors and therefore, its effect on growth and apoptosis of meningioma cells was studied in the present paper. In vitro, treatment of the human Ben-Men-1 meningioma cell line and of a series of 21 primary human meningioma cell cultures with curcumin (1-20 MUM) strongly reduced the proliferation in all cases in a dose dependent manner. Cell cycle analysis by fluorescence-activated cell sorting showed growth arrest at G2/M phase, which was confirmed by demonstrating the corresponding modulation of proteins involved in G2/M arrest by immunoblotting and/or confocal laser microscopy. High dosages (20, 50 MUM) of curcumin induced a significant increase of apoptosis in Ben-Men-1 and primary meningioma cell cultures as demonstrated by morphological changes of cell nuclei, DNA fragmentation, translocation of cell membrane associated phosphatidyl serine and the induction of apoptotic-acting cleaved caspase-3. Our results suggest that the multi-targeting drug curcumin has potent anti-tumorigenic actions in meningioma cells and might therefore be a putative candidate for the pharmacological treatment of meningiomas. PMID- 23666207 TI - Analysis of fatty infiltration and inflammation of the pelvic and thigh muscles in boys with Duchenne muscular dystrophy (DMD): grading of disease involvement on MR imaging and correlation with clinical assessments. AB - BACKGROUND: Prior reports focus primarily on muscle fatty infiltration in Duchenne muscular dystrophy (DMD). However, the significance of muscle edema is uncertain. OBJECTIVE: To evaluate the frequency and degree of muscle fat and edema, and correlate these with clinical function. MATERIALS AND METHODS: Forty two boys (ages 5-19 years) with DMD underwent pelvic MRI. Axial T1- and fat suppressed T2-weighted images were evaluated to grade muscle fatty infiltration (0-4) and edema (0-3), respectively. Degree and frequency of disease involvement were compared to clinical evaluations. RESULTS: Gluteus maximus had the greatest mean fatty infiltration score, followed by adductor magnus and gluteus medius muscles, and had the most frequent and greatest degree of fatty infiltration. Gluteus maximus also had the greatest mean edema score, followed by vastus lateralis and gluteus medius muscles. These muscles had the most frequent edema, although the greatest degree of edema was seen in other muscles. There was correlation between cumulative scores of fatty infiltration and all clinical evaluations (P < 0.05). CONCLUSION: In DMD, the muscles with the most frequent fatty infiltration had the greatest degree of fatty infiltration and correlated with patient function. However, the muscles with the most frequent edema were different from those with the greatest degree of edema. Thus, edema may not predict patient functional status. PMID- 23666206 TI - Role of diffusion-weighted imaging in differentiating benign and malignant pediatric abdominal tumors. AB - BACKGROUND: Solid malignant tumors are more highly cellular than benign lesions and hence have a restricted diffusion of water molecules. OBJECTIVE: To evaluate whether diffusion-weighted MR imaging (DWI) can differentiate between benign and malignant pediatric abdominal tumors. MATERIALS AND METHODS: We retrospectively analyzed DWI scans of 68 consecutive children with 39 benign and 34 malignant abdominal masses. To calculate the apparent diffusion coefficient (ADC) maps and ADC values, we used 1.5-T sequences at TR/TE/b-value of 5,250-7,500/54-64/b = 0, 500 and 3-T sequences at 3,500-4,000/66-73/b = 0, 500, 800. ADC values were compared between benign and malignant and between data derived at 1.5 tesla (T) and at 3 tesla magnetic field strength, using the Mann-Whitney-Wilcoxon test, ANOVA and a receiver operating curve (ROC) analysis. RESULTS: There was no significant difference in ADC values obtained at 1.5 T and 3 T (P = 0.962). Mean ADC values (* 10(-3) mm(2)/s) were 1.07 for solid malignant tumors, 1.6 for solid benign tumors, 2.9 for necrotic portions of malignant tumors and 3.1 for cystic benign lesions. The differences between malignant and benign solid tumors were statistically significant (P = 0.000025). ROC analysis revealed an optimal cut off ADC value for differentiating malignant and benign solid tumors as 1.29 with excellent inter-observer reliability (alpha score 0.88). CONCLUSION: DWI scans and ADC values can contribute to distinguishing between benign and malignant pediatric abdominal tumors. PMID- 23666208 TI - Identification of a Tibetan-specific mutation in the hypoxic gene EGLN1 and its contribution to high-altitude adaptation. AB - Tibetans are well adapted to high-altitude hypoxic conditions, and in recent genome-wide scans, many candidate genes have been reported involved in the physiological response to hypoxic conditions. However, the limited sequence variations analyzed in previous studies would not be sufficient to identify causal mutations. Here we conducted resequencing of the entire genomic region (59.4 kb) of the hypoxic gene EGLN1 (one of the top candidates from the genome wide scans) in Tibetans and identified 185 sequence variations, including 13 novel variations (12 substitutions and 1 insertion or deletion). There is a nonsynonymous mutation (rs186996510, D4E) showing surprisingly deep divergence between Tibetans and lowlander populations (Fst = 0.709 between Tibetans and Han Chinese). It is highly prevalent in Tibetans (70.9% on average) but extremely rare in Han Chinese, Japanese, Europeans, and Africans (0.56-2.27%), suggesting that it might be the causal mutation of EGLN1 contributing to high-altitude hypoxic adaptation. Neutrality test confirmed the signal of Darwinian positive selection on EGLN1 in Tibetans. Haplotype network analysis revealed a Tibetan specific haplotype, which is absent in other world populations. The estimated selective intensity (0.029 for the C allele of rs186996510) puts EGLN1 among the known genes that have undergone the strongest selection in human populations, and the onset of selection was estimated to have started at the early Neolithic (~8,400 years ago). Finally, we detected a significant association between rs186996510 and hemoglobin levels in Tibetans, suggesting that EGLN1 contributes to the adaptively low hemoglobin level of Tibetans compared with acclimatized lowlanders at high altitude. PMID- 23666209 TI - Sequence comparative analysis using networks: software for evaluating de novo transcript assembly from next-generation sequencing. AB - DNA sequencing technology is becoming more accessible to a variety of researchers as costs continue to decline. As researchers begin to sequence novel transcriptomes, most of these data sets lack a reference genome and will have to rely on de novo assemblers. Making comparisons across assemblies can be difficult: each program has its strengths and weaknesses, and no tool exists to comparatively evaluate these data sets. We developed software in R, called Sequence Comparative Analysis using Networks (SCAN), to perform statistical comparisons between distinct assemblies. SCAN uses a reference data set to identify the most accurate de novo assembly and the "good" transcripts in the user's data. We tested SCAN on three publicly available transcriptomes, each assembled using three assembly programs. Moreover, we sequenced the transcriptome of the oomycete Achlya hypogyna and compared de novo assemblies from Velvet, ABySS, and the CLC Genomics Workbench assembly algorithms. One thousand one hundred twenty-eight of the CLC transcripts were statistically similar to the reference, compared with 49 of the Velvet transcripts and 937 of the ABySS transcripts. SCAN's strength is providing statistical support for transcript assemblies in a biological context. However, SCAN is designed to compare distinct node sets in networks, therefore it can also easily be extended to perform statistical comparisons on any network graph regardless of what the nodes represent. PMID- 23666210 TI - Genetic signatures reveal high-altitude adaptation in a set of ethiopian populations. AB - The Tibetan and Andean Plateaus and Ethiopian highlands are the largest regions to have long-term high-altitude residents. Such populations are exposed to lower barometric pressures and hence atmospheric partial pressures of oxygen. Such "hypobaric hypoxia" may limit physical functional capacity, reproductive health, and even survival. As such, selection of genetic variants advantageous to hypoxic adaptation is likely to have occurred. Identifying signatures of such selection is likely to help understanding of hypoxic adaptive processes. Here, we seek evidence of such positive selection using five Ethiopian populations, three of which are from high-altitude areas in Ethiopia. As these populations may have been recipients of Eurasian gene flow, we correct for this admixture. Using single-nucleotide polymorphism genotype data from multiple populations, we find the strongest signal of selection in BHLHE41 (also known as DEC2 or SHARP1). Remarkably, a major role of this gene is regulation of the same hypoxia response pathway on which selection has most strikingly been observed in both Tibetan and Andean populations. Because it is also an important player in the circadian rhythm pathway, BHLHE41 might also provide insights into the mechanisms underlying the recognized impacts of hypoxia on the circadian clock. These results support the view that Ethiopian, Andean, and Tibetan populations living at high altitude have adapted to hypoxia differently, with convergent evolution affecting different genes from the same pathway. PMID- 23666213 TI - [Stem cell research using large animals]. PMID- 23666214 TI - [Significance of clonal hematopoiesis in patients with acquired aplastic anemia]. PMID- 23666211 TI - Thyroid autoimmunity in relation to islet autoantibodies and HLA-DQ genotype in newly diagnosed type 1 diabetes in children and adolescents. AB - AIMS/HYPOTHESIS: The aim of this work was to investigate, in children newly diagnosed with type 1 diabetes: (1) the prevalence of autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TGAb); and (2) the association between TPOAb, TGAb or both, with either islet autoantibodies or HLA-DQ genes. METHODS: Blood samples from 2,433 children newly diagnosed with type 1 diabetes were analysed for TPOAb and TGAb in addition to autoantibodies against arginine zinc transporter 8 (ZnT8RA), tryptophan zinc transporter 8 (ZnT8WA), glutamine zinc transporter 8 (ZnT8QA), glutamic acid decarboxylase (GADA), insulin (IAA), insulinoma-associated protein-2 (IA-2A), HLA-DQA-B1 genotypes, thyroid stimulating hormone (TSH) and free thyroxine (T4). RESULTS: At type 1 diabetes diagnosis, 12% of the children had thyroid autoantibodies (60% were girls; p < 0.0001). GADA was positively associated with TPOAb (p < 0.001) and with TGAb (p < 0.001). In addition, ZnT8A was associated with both TPOAb (p = 0.039) and TGAb (p = 0.015). DQB1*05:01 in any genotype was negatively associated with TPOAb (OR 0.55, 95% CI 0.37, 0.83, p value corrected for multiple comparisons (p c) = 0.012) and possibly with TGAb (OR 0.55, 95% CI 0.35, 0.87, p c = 0.07). Thyroid autoimmunity in children newly diagnosed with type 1 diabetes was rarely (0.45%) associated with onset of clinical thyroid disease based on TSH and free T4. CONCLUSIONS/INTERPRETATION: GADA and ZnT8A increased the risk for thyroid autoimmunity at the time of clinical diagnosis of type 1 diabetes, while HLA DQB1*05:01 reduced the risk. However, the associations between thyroid autoimmunity and HLA-DQ genotype were weak and did not fully explain the co occurrence of islet and thyroid autoimmunity. PMID- 23666215 TI - [Pathophysiology and diagnosis of primary immune thrombocytopenia]. PMID- 23666216 TI - [Current management of primary immune thrombocytopenia in Japan]. PMID- 23666217 TI - [Secondary immune thrombocytopenia associated with primary immunodeficiency]. PMID- 23666218 TI - [Relationship between red blood cell transfusion volume and posttransfusional iron overload in hematological diseases]. AB - We retrospectively investigated the status of transfusional iron overload at Kinki University Hospital. One hundred and sixty three patients received more than 10 red blood cell (RBC) units per year in 2009 and 2010. Myelodysplastic syndrome (37.4%) and aplastic anemia (11.0%) accounted for about 50% of the underlying diseases. At the time of receiving a total of 20 RBC units, 90.8% and 66.2% of the 65 patients evaluated had more than 500 and 1,000 ng/ml of serum ferritin, respectively. The frequency of organ dysfunction associated with iron overload was 56.9% of all the patients assessed, 37.8% of patients with serum ferritin levels of 500~999 ng/ml, and 67.4% of patients with serum ferritin levels >1,000 ng/ml. Although the Japanese guidelines propose 40 units of RBC transfusion and/or a serum ferritin level of 1,000 ng/ml as a good point to start iron chelation therapy, our results suggest that iron overload and consequent organ dysfunction may occur earlier than this. Therefore, it may be necessary to start iron chelation therapy earlier than that suggested by the Japanese guidelines. PMID- 23666219 TI - [The feasibility of Erwinia asparaginase for pediatric patients who developed an allergic reaction to E.coli asparaginase during treatment of acute lymphoblastic leukemia]. AB - Asparaginase (ASNase) is one of the most important key drugs in the treatment of acute lymphoblastic leukemia (ALL). However, clinical hypersensitivity reactions often occur and lead to the discontinuation of ASNase treatment. Here, we report a retrospective study of 68 Erwinia ASNase (Erw-ASNase) administrations in 11 patients with childhood ALL who developed allergic reactions to E.coli-ASNase in our hospital between 2006 and 2012. The median age of the patients was 6 (range, 0 to 14). Erw-ASNase purchased overseas by the patients' guardians had already been administered when we obtained informed consent from the guardians. In all patients, fibrinogen and/or anti-thrombin III levels were decreased, but thrombosis did not develop. There was only one mild adverse event (grade 2 urticaria) in one patient, in whom Erw-ASNase could be continued after increasing the doses of premedication with antihistamine and prednisolone. Erw-ASNase could be safely administered to all patients. PMID- 23666220 TI - [Transfusion-related acute lung injury during the treatment of EBV-associated hemophagocytic lymphohistiocytosis]. AB - Transfusion-related acute lung injury (TRALI) is a severe pulmonary complication following blood transfusions. We experienced a case of possible TRALI during the course of EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). A 19-year old woman was admitted to our hospital suffering from fever and abdominal pain. Her laboratory data revealed pancytopenia, liver damage, coagulopathy, and a high titer of EBV-DNA. Computed tomography showed hepatosplenomegaly and bone marrow aspiration revealed hemophagocytosis and the proliferation of atypical lymphocytes. A diagnosis of EBV-HLH was made and plasma exchange was performed. Severe hypoxia due to pulmonary edema developed two hours after starting the plasma transfusion. Methylprednisolone pulse therapy and non-invasive positive pressure ventilation ameliorated her respiratory condition. Anti-HLA class I and II antibodies were detected in donor sera and a cross-match test between patient lymphocytes and donor plasma was positive. To the best of our knowledge, this is the first case report of TRALI complicated with EBV-HLH. It is possible that hypercytokinemia accompanied by HLH was associated with the onset of TRALI. PMID- 23666221 TI - [Refractory acute myeloid leukemia developed malignancy-associated hemophagocytic lymphohistiocytosis during treatment of invasive fungal infection]. AB - We here report a 2-year-old female with relapsed acute myeloid leukemia (AML) with MLL gene rearrangement in the bone marrow and central nervous system. The 3' RACE (Rapid Amplification of cDNA Ends) method identified the MLLT10 gene as a fusion partner of the MLL gene. The patient was complicated with hemophagocytic lymphohistiocytosis (HLH) and invasive aspergillosis (IPA) after re-induction treatment with FLAG-IDA following etoposide, cytarabine, and mitoxantrone. Although treatment with systemic anti-fungal drugs was effective for IPA, HLH did not improve. We considered tumor-associated HLH to be initiated from leukemic stem cells (LSCs) in the bone marrow niche because reverse transcription polymerase chain reaction (RT-PCR) analysis of a bone marrow biopsy sample was positive for MLL-MLLT10. Gemtuzumab ozogamicin and sorafenib had no major effect on acquiring complete remission, and the patient died of progressive AML with an exacerbation of HLH and aspergillosis. LSCs are known to be resistant to conventional chemotherapy due to their quiescence in the cell cycle. Novel therapeutic concepts are important to eradicate LSCs in order to cure AML patients. PMID- 23666222 TI - [The appearance of t(9;22)(q34;q11.2) in BJP-lambda type multiple myeloma during maintenance therapy including lenalidomide]. AB - A 61-year-old man, who was diagnosed with Bence-Jones protein (BJP)-lambda type multiple myeloma, was treated with bortezomib. Although maintenance therapy including lenalidomide was continued, t(9;22)(q34;q11.2) was detected in the marrow cells by a cytogenetic study. The increased incidence of a secondary malignancy after treatment with lenalidomide for multiple myeloma has been highlighted in previous clinical trials; however, reports on the presence of t(9;22)(q34;q11.2) or the onset of chronic myelogenous leukemia have yet to be found. Although the cause of chronic myelogenous leukemia with the lenalidomide treatment is not yet clear, it is an interesting case. PMID- 23666223 TI - [Primary diffuse large B-cell lymphoma of the uterus complicated with hydronephrosis]. AB - Malignant lymphoma sometimes originates from extranodal sites; however, the uterus has rarely been reported as the site of the primary lesion. We present a patient with malignant lymphoma of the uterus complicating bilateral hydronephrosis. A 67-year-old previously healthy woman was seen at a clinic because of massive genital bleeding. She was referred to our hospital for further examination of a uterine tumor. Computed tomography scans revealed a pelvic tumor invading to the retroperitoneal region, which caused bilateral obstruction of the ureters and hydronephrosis. No lymph node swelling was detected. Magnetic resonance imaging showed a bulky uterine tumor that was homogenously low on T1 weighted imaging and isointense on T2-weighted imaging, while the endometrium was intact. A pathological examination of the biopsy specimen from the uterine cervix revealed diffuse infiltration of CD20-positive atypical large lymphoid cells, which was compatible with diffuse large B-cell lymphoma (DLBCL). Since the tumor expanded from the uterus and no other abnormal lesion was observed in imaging studies including gallium scintigraphy, a diagnosis of DLBCL of the uterus, clinical stage IE was made. The patient received six cycles of rituximab plus CHOP chemotherapy followed by involved field irradiation. She achieved complete remission and has been alive for more than two years without relapse. PMID- 23666224 TI - [Acute myeloid leukemia with monosomy 7 and inv(3)(q21q26.2) complicated with central diabetes insipidus]. AB - A 20-year-old female presented with thirst, polyposia, and polyuria and was referred to our hospital because of leukocytosis and anemia. Bone marrow aspiration revealed 66.8% myeloperoxidase-positive blasts and trilineage myelodysplasia. The karyotype was 45, XX, inv(3)(q21q26.2), -7[19]. Therefore, a diagnosis of AML with inv(3)(q21q26.2) complicated by -7 was made. Moreover, hyposthenuria and a low anti-diuretic hormone (ADH) level were observed. Although cerebrospinal fluid analysis was normal, magnetic resonance imaging (MRI) revealed the absence of hyperintensity in the neurohypophysis in T1-weighted images. Therefore, she was also diagnosed with diabetes insipidus. After she was administered a desmopressin nasal spray, the volume of urine produced decreased. Following treatment with second induction therapy containing high-dose cytarabine for AML, she achieved complete remission in the bone marrow. Moreover, when the abnormality on MRI and the volume of urine were normalized, she discontinued desmopressin. Although diabetes insipidus is a rare complication of AML, the majority of AML patients who have diabetes insipidus have the abnormal karyotypes with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and monosomy 7. Further study is required to clarify the pathogenesis and develop a strategy for the treatment of this category of AML. PMID- 23666225 TI - Complex three-dimensional polymer-metal core-shell structures towards emission control. AB - We report the fabrication of three-dimensional periodic metal nickel nanostructures achieved by the combination of femtosecond laser-induced two photon polymerization and electroless plating technology. We can control the deposition speed of 10 nm per second by adjusting the reaction time. The thermal stability is good under 500 degrees C for the three-dimensional graphite-lattice polymer structure with 200 nm nickel film. Optical reflectivity and thermal emission measurements under 550 degrees C showed that the fabricated metallic structure was thermally excited and emitted light at lambda = 4.50, 4.95 MUm. The emission peak wavelengths agree with the absorption peaks. These data demonstrate that creating metallic photonic crystals by incorporation of metals to laser fabricated templates is a simple and cost-efficient method. The emitters can work at such low temperatures, which is more important for realistic operation in applications. PMID- 23666226 TI - Evaluation of bioartificial renal tubule device prepared with human renal proximal tubular epithelial cells cultured in serum-free medium. AB - Bioartificial renal tubule devices (BTD) use cell therapy to improve conditions commonly observed in recipients of artificial kidneys for treatment of kidney diseases. We previously reported significant improvement of the condition of acute kidney injury (AKI) animals after treatment with BTD prepared with lifespan extended human renal proximal tubular cells (hRPTEC). However, a major obstacle to use of BTD for patients is their biological safety, because hRPTEC are cultured in medium containing fetal calf serum. To establish the biological safety of BTD, we prepared BTD with lifespan-extended hRPTEC cultured in a newly developed serum-free medium and compared these with BTD prepared with hRPTEC cultured in serum-containing conventional medium. Lifespan-extended hRPTEC cultured in serum-free medium (hRPTEC-SFM) can proliferate similar to hRPTEC cultured in serum-containing conventional medium (hRPTEC-CM). Comparison of leakage and of reabsorption of small molecules for BTD prepared with hRPTEC-SFM (BTD-SFM) with those for our previous BTD prepared with hRPTEC-CM (BTD-CM) showed transportation in these two types of BTD was almost identical. When AKI goats were treated with BTD-SFM for 26 h, increase of survival time and reduction of cytokine expression in blood cells were almost same as for AKI goats treated with BTD-CM. Quantification of the expression of some genes of hRPTEC in BTD revealed significant changes during BTD treatment for AKI goats. In conclusion, lifespan extended hRPTEC-SFM work as well as hRPTEC-CM, and the biological safety of BTD for patients could be elevated without loss of function by preparation from hRPTEC-SFM. PMID- 23666227 TI - Neospora caninum NC-6 Argentina induces fetopathy in both serologically positive and negative experimentally inoculated pregnant dams. AB - Neospora caninum infection is a major cause of abortion in cattle. The objectives of this study were to genetically characterize the N. caninum NC-6 Argentina isolate using a multilocus microsatellite analysis approach and to study its biological behavior by experimental inoculations into seronegative and seropositive pregnant cattle, evaluating the humoral and cellular immune response elicited and the occurrence of transplacental transmission and fetopathy. Pregnant cows (65 days of gestation) seropositive and seronegative to N. caninum were intravenously inoculated with tachyzoites of the NC-6 Argentina N. caninum strain and slaughtered at 108 +/- 2 days of gestation. Serum samples were analyzed for N. caninum antibodies by indirect fluorescent antibody test. The cellular immune response was analyzed by detection of gamma interferon (gammaIFN) production in blood cells. Tissue samples from dams, fetuses, and placental cotyledons were processed by histopathological and immunohistochemical techniques and examined for N. caninum DNA by PCR. Positive DNA samples were further analyzed by multilocus microsatellite typing for N. caninum. Inoculated animals had significantly higher N. caninum antibody titers and gammaIFN production than control animals. One seropositive inoculated cow aborted, one seronegative cow had a non-viable fetus, and the remaining fetuses from the experimentally inoculated dams had histopathologic lesions. The PCR was positive in 3/4 fetuses from seronegative inoculated cows and in 2/3 fetuses from seropositive inoculated cows. Multilocus microsatellite analysis revealed that the N. caninum DNA present in fetuses and placentas had an identical pattern to NC-6 Argentina strain. The NC-6 Argentina strain proved to be able to cross the placenta and to induce fetopathy in both the seropositive and seronegative dams. PMID- 23666228 TI - Hematological alterations caused by high intensity of L3 larvae of Contracaecum sp Railliet & Henry, 1912 (Nematoda, Anisakidae) in the stomach of Hoplias malabaricus in lakes in Pirassununga, Sao Paulo. AB - The objective of the present study was to discover the hematological indices of Hoplias malabaricus infected by larvae of Contracaecum sp. A total of 105 fish were collected from two lakes located in the municipal district of Pirassununga, Sao Paulo, Brazil, of which 95.2% were infested by L3 larvae of Contracaecum sp., with an average intensity of 348.7 +/- 231.55 helminths/fish. A total of 76 fish were analyzed to establish hematological parameters. Following analysis, it was found that there was a significant difference between hematological parameters Hct, erythrocytes (Er), thrombocytopenia (p = 0.01), and Hb (p = 0.02) in lakes A and B, while there was no significant difference for leukocyte (p = 0.68), mean corpuscular volume, mean corpuscular hemoglobin (p = 0.06), and mean corpuscular hemoglobin concentration (p = 0.47). The intensity of infection correlated negatively with Er (r(s) = -0.42; p < 0.01) and positively for (r(s) = 0.48; p < 0.01). The high intensity of infection by Contracaecum sp. in H. malabaricus did not affect the health of the fish despite causing alterations in hematological variables. PMID- 23666229 TI - Serological and molecular detection of Strongyloides stercoralis infection among an Orang Asli community in Malaysia. AB - Detection of Strongyloides stercoralis infection particularly in asymptomatic individuals is often hampered due to the lack of standard diagnostic tools. In this study, the use of serological and molecular approaches were investigated for the detection of S. stercoralis infection among an Orang Asli (indigenous) community following a preliminary detection by microscopic examination of faecal samples. Out of 54 individuals studied, 17/54 (31.5%) were detected to be positive for S. stercoralis infection by enzyme-linked immunosorbent assay (ELISA), compared to 0/54 (0%) by faecal examination. Further confirmation performed by a nested polymerase chain reaction (PCR) using DNA extracted from faecal samples of these 17 individuals yielded 3/17 (17.6%) positives for S. stercoralis DNA amplification. No amplification was seen with the other 37 faecal samples, which were negative by microscopy and ELISA. As the high ELISA positive results were suspected to be false-positives, ELISA is not recommended for use as a detection tool but may be beneficial for evaluating the effectiveness of anti Strongyloides drugs. The present finding indicated that PCR should be considered as an alternative diagnostic tool for the detection of S. stercoralis infection. PMID- 23666232 TI - Advanced oxidation using Fe(3)O(4) magnetic nanoparticles and its application in mercury speciation analysis by high performance liquid chromatography-cold vapor generation atomic fluorescence spectrometry. AB - A novel, green and efficient post-column oxidation method using Fe(3)O(4) magnetic nanoparticles (MNPs) was developed to on-line convert hydride generation/cold vapor generation (HG/CV) inactive species to their active species without microwave/UV irradiation. It was applied to high performance liquid chromatography HG/CV atomic fluorescence spectrometry (HPLC-HG/CV-AFS) to enable sensitive speciation analysis of both HG/CV inactive and active species. Inorganic mercury (Hg(2+)), methylmercury (MeHg), ethylmercury (EtHg) and phenylmercury (PhHg) were selected as model compounds to validate the methodology. Separation of these mercury species was accomplished on a RP-C18 column with a mixture of acetonitrile and water (10 : 90) at pH 6.8 containing 0.12% (m/v) L-cysteine as the mobile phase. In the presence of 0.6% (v/v) H(2)O(2), on-line conversion of the organomercury species eluted from the HPLC column to Hg(2+) was obtained using the advanced oxidation method at pH 2.0. Optimum conditions for the separation, oxidation and cold vapor generation were carefully investigated. The limits of detection (LODs) were 0.7, 1.1, 0.8 and 0.9 MUg L(-1) (as Hg) for Hg(2+), MeHg, EtHg and PhHg, respectively, corresponding to 14, 22, 16 and 18 pg absolute detection limits for Hg(2+), MeHg, EtHg and PhHg by using a 20 MUL sample loop, which are comparable to or better than those previously reported. National Research Council Canada DORM-2 fish muscle tissue and several real water samples were analyzed to validate the accuracy of the proposed method. PMID- 23666231 TI - Phenotypic heterogeneity of hereditary gynecologic cancers: a report from the Creighton hereditary cancer registry. AB - To determine the validity of observations suggesting a significant dichotomy of gynecologic cancers determined by linkage to specific genetic defects associated with two major autosomal dominant hereditary cancer syndromes; the Creighton University Hereditary Cancer Registry was searched for female carriers of germ line mutations in BRCA1 and BRCA2, associated with the Hereditary Breast Ovarian Cancer syndrome, and in the mismatch repair (MMR) genes MLH1, MSH2 and MSH6, associated with Lynch syndrome, who were registered with invasive uterine, ovarian, fallopian tube or peritoneal cancers between January 1, 1959 and December 31, 2010. From 217 such cases, a total of 174 subjects, consisting of 95 BRCA1 and BRCA2 mutation carriers and 79 carriers of mutations in MMR genes, were identified who had current signed Health Insurance Portability and Accountability Act forms and complete primary diagnostic pathology reports and clinical records. Data meticulously extracted from these cases were categorized and statistically analyzed. There were highly significant differences between carriers of BRCA1 and BRCA2 mutations and carriers of MMR gene mutations in the proportion of serous carcinomas compared with endometrioid carcinomas of the uterus, including cervix and endometium (p < 0.002), ovaries (p < 0.001) and overall, including fallopian tube and peritoneum cancers (p < 0.001). Endometrioid carcinoma was found in one and transitional carcinoma in another of the 14 BRCA1 mutation carriers with fallopian tube cancer, and endometrioid carcinoma was found in two of four MMR gene mutation carriers with fallopian tube cancers. All other fallopian tube cancers were serous carcinomas. Seven BRCA1 and one BRCA2 mutation carriers were diagnosed with primary peritoneal serous carcinoma; no peritoneal carcinomas were registered in MMR gene mutation carriers. Nine of 14 gynecologic cancers with associated endometriosis in mutation carriers were endometrioid or endometrioid mixed carcinomas compared with just three of other histologic types. Primary breast cancers, that characterize the HBOC syndrome, were much more frequent in BRCA1 and BRCA2 mutation carriers; while multiple gynecologic cancers and associated colorectal and urinary tract cancers, which are features of Lynch syndrome, were more common in MMR gene mutation carriers. Both serous and endometrioid carcinomas were diagnosed in MMR gene mutation carriers at significantly younger ages than in BRCA1 and BRCA2 mutation carriers (p < 0.0006). These findings confirm a clear dichotomy of uterine, ovarian and fallopian tube cancers associated with inheritance of mutations in BRCA1 and BRCA2 contrasted with inheritance of MMR gene mutations. This opens possibilities for new approaches to molecular genetic research into carcinogenic pathways and raises important new considerations regarding counseling, screening, prophylaxis and treatment of mutation carriers. PMID- 23666233 TI - Intravoxel incoherent motion model-based liver lesion characterisation from three b-value diffusion-weighted MRI. AB - OBJECTIVE: To evaluate intravoxel incoherent motion (IVIM) model-based liver lesion characterisation from three b-value diffusion-weighted imaging (DWI). METHODS: The 1.5-T DWI data from a respiratory gated spin-echo echo-planar magnetic resonance imaging sequence (b = 0, 50, 800 s/mm(2)) were retrospectively analysed in 38 patients with different liver lesions. Conventional apparent diffusion coefficient ADC = ADC(0,800) as well as IVIM-based parameters D' = ADC(50,800), ADC_low = ADC(0,50), and f' were calculated voxel-wise. Sixty-one regions of interest in hepatocellular carcinomas (HCCs, n = 24), haemangiomas (HEMs, n = 11), focal nodular hyperplasias (FNHs, n = 11), and healthy liver tissue (REFs, n = 15) were analysed. Group differences were investigated using Student's t-test and receiver-operating characteristic (ROC) analysis. RESULTS: Mean values +/- standard deviations of ADC, D', ADC_low (in 10(-5) mm(2)/s), and f' (in %) for REFs/FNHs/HEMs/HCCs were 130 +/- 11/143 +/- 27/168 +/- 16/113 +/- 25, 104 +/- 12/123 +/- 25/162 +/- 18/102 +/- 23, 518 +/- 66/437 +/- 97/268 +/- 69/283 +/- 120, and 18 +/- 3/14 +/- 4/6 +/- 3/9 +/- 5, respectively. Differences between lesions and REFs were more significant for IVIM-based parameters than for conventional ADC. ROC analysis showed the best discriminability between HCCs and FNHs for ADC_low and f' and between HEMs and FNHs or HCCs for D'. CONCLUSION: Three instead of two b-value DWI enables a numerically stable and voxel-wise IVIM based analysis for improved liver lesion characterisation with tolerable acquisition time. KEY POINTS: * Quantitative analysis of diffusion-weighted MRI helps liver lesion characterisation. * Analysis of intravoxel incoherent motion is superior to apparent diffusion coefficient determination. * Only three b values enable separation of diffusion and microcirculation effects. * The method presented is numerically stable, with voxel-wise results and short acquisition times. PMID- 23666234 TI - Brain metastatic volume and white matter lesions in advanced cancer patients. AB - Brain white matter T2 hyperintensities (WMH) are a frequent MRI finding in adults, both in asymptomatic and in cancer patients. The aim of our study is to determine the relationship between quantitative measures of the volume of WMH and the volume of brain metastatic lesions at the first MRI diagnosis of brain metastases in a population of advanced cancer patients. Brain MRI examinations of 162 consecutive patients were included and 984 brain metastases at first diagnosis were studied. Axial FLAIR images were used to visualize peri-lesional edema and to segment WMH; multiplanar contrast-enhanced T1-weighted TSE images were used to detect, count, segment and measure metastatic lesions. Segmentation of WMH on FLAIR images was performed after linear image registration to eliminate peri-lesional edema from the WMH masks. The distribution of the volumes of metastatic lesions was significantly different (ANOVA, p = 0.003) among all patients and among lung cancer patients (ANOVA, p = 0.003), with higher volumes of metastatic lesions in a higher proportion of patients when WMH were absent. There were no significant differences among groups at the 10 cc threshold of WMH. We found that volumes of brain metastases at the first MR diagnosis in a sample of advanced cancer patients and in the group of lung cancer patients were significantly lower if WMH were present; we suggest that WMH may represent a clinical MRI bio-marker of brain micro-environment resistance to the occurrence of brain metastases. PMID- 23666236 TI - Reduced glutathione export during programmed cell death of Neurospora crassa. AB - In a previous study, we demonstrated that staurosporine (STS) induces programmed cell death (PCD) in the fungus Neurospora crassa and that glutathione has the capability of inhibiting both STS-induced reactive oxygen species (ROS) formation and cell death. Here, we further investigated the role of glutathione in STS induced PCD in N. crassa and observed an efflux of reduced glutathione (GSH) together with a change in the cell internal redox state to a more oxidative environment. This event was also observed with another PCD inducer, phytosphingosine (PHS), although externally added GSH did not prevent PHS-induced PCD. The nature of ROS, detected under the experimental conditions at which GSH export occurred, is also different in the two systems, predominantly superoxide in the case of STS and hydrogen peroxide in the case of PHS. In both cases, GSH export preceded the alterations in the plasma membrane that lead to selective dye permeation. We conclude that glutathione export in the context of PCD is not exclusive of certain mammalian cells and can be extended to Fungi, being an early PCD event in N. crassa. In addition, STS and PHS induce different PCD pathways in this fungus and the role of GSH export in each of them is likely different. PMID- 23666235 TI - Phase I study of temozolomide combined with oral etoposide in children with malignant glial tumors. AB - The treatment of children with malignant glioma remains challenging. The aim of this multicenter phase I study is to establish the recommended dose (RD) of the combination therapy with temozolomide (TMZ) and oral etoposide (VP-16) in children with relapsed or refractory malignant glioma and brainstem glioma at diagnosis. A phase I trial was conducted to establish the maximum tolerated dose (MTD) of TMZ and oral VP-16. This orally administered combination was investigated by a classical 3 + 3 design. Cohorts of patients were enrolled at 4 different levels: (1) TMZ 120 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1 8; (2) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-8; (3) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-10; (4) TMZ 150 mg/m(2) on days 1-5 and VP-16 50 mg/m(2) on days 1-12. Therapy was administered in 28-day courses. A total of 118 courses were administered to 18 patients with a median age of 11.2 years. At dose level 1, none displayed toxicity. Of the 6 patients at dose level 2, 1 patient had dose limiting toxicity (DLT). None of the 3 patients at dose level 3 had DLT. At dose level 4, grade III/IV thrombocytopenia and neutropenia were observed in 2 out of the 6 patients enrolled. Therefore, the MTD was established at dose level 3. The RD for phase II trial in children with malignant glial is TMZ 150 mg/m(2) for 5 days and VP-16 50 mg/m(2) for 10 days every 28 days. PMID- 23666237 TI - Perceptions of family physician trainees and trainers regarding the usefulness of a virtual community of practice. AB - BACKGROUND: Training for Australian general practice, or family medicine, can be isolating, with registrars (residents or trainees) moving between rural and urban environments, and between hospital and community clinic posts. Virtual communities of practice (VCoPs), groups of people sharing knowledge about their domain of practice online and face-to-face, may have a role in overcoming the isolation associated with general practice training. OBJECTIVE: This study explored whether Australian general practice registrars and their supervisors (trainers) would be able to use, and would be interested in using, a VCoP in the form of a private online network for work and training purposes. It also sought to understand the facilitators and barriers to intention to use such a community, and considers whether any of these factors may be modifiable. METHODS: A survey was developed assessing computer, Internet, and social media access and usage, confidence, perceived usefulness, and barriers, facilitators, and intentions to use a private online network for training purposes. The survey was sent by email link to all 139 registrars and 224 supervisors in one of Australia's 17 general practice training regions. Complete and usable responses were received from 131 participants (response rate=0.4). RESULTS: Most respondents had access to broadband at home (125/131, 95.4%) and at work (130/131, 99.2%). Registrars were more likely to spend more than 2 hours on the Internet (P=.03), and to use social media sites for nonwork purposes (P=.01). On a 5-point Likert scale, confidence was high (mean 3.93, SD 0.63) and was negatively associated with higher age (P=.04), but not associated with training stage. Social media confidence was lower, with registrars more confident than supervisors for almost all social media activities. On a 5-point Likert scale, overall usefulness was scored positively (n=123, mean 3.63, SD 0.74), and was not significantly associated with age or training level. The main concerns of respondents were worries about privacy (registrar: 61/81, 75.3%; supervisor: 30/50, 60.0%) and insufficient time (registrar: 41/81, 50.6%; supervisor: 36/50, 72.0%). Using a multivariate generalized linear regression model, training stage and perceived usefulness were positively predictive, and concerns about privacy and time were negatively predictive of intention to use a private online network. CONCLUSIONS: General practice registrars and supervisors are interested in using a private online network, or VCoP, for work and training purposes. Important considerations are the extent to which concerns such as privacy and usefulness may be overcome by training and support to offset some other concerns, such as time barriers. Participants at an early stage in their training are more receptive to using an online network. More senior registrars and supervisors may benefit from more training and promotion of the online network to improve their receptiveness. PMID- 23666238 TI - Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis. AB - Adolescent idiopathic scoliosis (AIS) is the most common pediatric skeletal disease. We previously reported a locus on chromosome 10q24.31 associated with AIS susceptibility in Japanese using a genome-wide association study (GWAS) consisting of 1,033 cases and 1,473 controls. To identify additional AIS associated loci, we expanded the study by adding X-chromosome SNPs in the GWAS and increasing the size of the replication cohorts. Through a stepwise association study including 1,819 cases and 25,939 controls, we identified a new susceptibility locus on chromosome 6q24.1 in Japanese (P = 2.25 * 10(-10); odds ratio (OR) = 1.28). The most significantly associated SNP, rs6570507, was in GPR126 (encoding G protein-coupled receptor 126). Its association was replicated in Han Chinese and European-ancestry populations (combined P = 1.27 * 10(-14); OR = 1.27). GPR126 was highly expressed in cartilage, and the knockdown of gpr126 in zebrafish caused delayed ossification of the developing spine. Our results should provide insights into the etiology and pathogenesis of AIS. PMID- 23666239 TI - Meta-analysis identifies four new loci associated with testicular germ cell tumor. AB - We conducted a meta-analysis to identify new susceptibility loci for testicular germ cell tumor (TGCT). In the discovery phase, we analyzed 931 affected individuals and 1,975 controls from 3 genome-wide association studies (GWAS). We conducted replication in 6 independent sample sets comprising 3,211 affected individuals and 7,591 controls. In the combined analysis, risk of TGCT was significantly associated with markers at four previously unreported loci: 4q22.2 in HPGDS (per-allele odds ratio (OR) = 1.19, 95% confidence interval (CI) = 1.12 1.26; P = 1.11 * 10(-8)), 7p22.3 in MAD1L1 (OR = 1.21, 95% CI = 1.14-1.29; P = 5.59 * 10(-9)), 16q22.3 in RFWD3 (OR = 1.26, 95% CI = 1.18-1.34; P = 5.15 * 10( 12)) and 17q22 (rs9905704: OR = 1.27, 95% CI = 1.18-1.33; P = 4.32 * 10(-13) and rs7221274: OR = 1.20, 95% CI = 1.12-1.28; P = 4.04 * 10(-9)), a locus that includes TEX14, RAD51C and PPM1E. These new TGCT susceptibility loci contain biologically plausible genes encoding proteins important for male germ cell development, chromosomal segregation and the DNA damage response. PMID- 23666240 TI - Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14. AB - Testicular germ cell tumor (TGCT) is the most common cancer in young men and is notable for its high familial risks. So far, six loci associated with TGCT have been reported. From genome-wide association study (GWAS) analysis of 307,291 SNPs in 986 TGCT cases and 4,946 controls, we selected for follow-up 694 SNPs, which we genotyped in a further 1,064 TGCT cases and 10,082 controls from the UK. We identified SNPs at nine new loci (1q22, 1q24.1, 3p24.3, 4q24, 5q31.1, 8q13.3, 16q12.1, 17q22 and 21q22.3) showing association with TGCT (P < 5 * 10(-8)), which together account for an additional 4-6% of the familial risk of TGCT. The loci include genes plausibly related to TGCT development. PRDM14, at 8q13.3, is essential for early germ cell specification, and DAZL, at 3p24.3, is required for the regulation of germ cell development. Furthermore, PITX1, at 5q31.1, regulates TERT expression and is the third TGCT-associated locus implicated in telomerase regulation. PMID- 23666241 TI - Quantitative 3D model of light transmittance through translucent rocks applied to the hypolithic microbial community. AB - In extreme desert environments, photosynthetic microorganisms often live on the buried undersides of translucent rocks. Computing the light level reaching these locations requires 3D modeling of a finite rock. We report on Monte Carlo calculations of skylight and sunlight transmission through a partially buried flat cylindrical rock using one billion photons per simulation. Transmitted light level drops inversely with increasing rock opacity, as expected for purely scattering media. For a half-buried rock with an extinction coefficient of 0.1 cm(-1) (opacity of 0.2), transmission at the bottom is 64 % for sunlight at a solar zenith angle of 60 degrees and 82 % for skylight. Transmitted light level increases slowly with increasing scattering asymmetry factor of the rock independent of illumination or depth buried. Transmitted sunlight at zenith through a thick half-buried rock (opacity of 0.6) is six times brighter at the bottom than the subsurface sides. Skylight transmits equally to the subsurface sides and bottom. When the sun is not straight overhead, the sunward side of the rock is brighter than the underside of the rock. Compared to the sunlight transmitted to the bottom, transmitted sunlight inclined at 60 degrees is 24 times brighter at the subsurface side towards the sun and 14 times brighter at the subsurface side 70 degrees away from the sun. Transmitted sunlight emitted from zenith and skylight is uniformly bright at the bottom regardless of how deeply the rock is buried. Sunlight not at zenith transmits preferentially to the sunward bottom edge depending on the depth the rock is buried. PMID- 23666242 TI - Influence of age on the outcome of rehabilitation after total hip replacement. AB - BACKGROUND: This publication compares the results of physiotherapy after total hip replacement in two groups, each consisting of 50 subjects, differing in age by 10 years. MATERIAL AND METHODS: A group of 100 patients after total hip replacement was divided into two subgroups consisting of 50 subjects each, with mean age difference of 10 years. The first group included patients aged 47-60 years, the other 61-69 years. Patients were assessed at 6 weeks and reevaluated at 10 weeks after surgery during a 4-week in-hospital rehabilitation program. The study was based on a questionnaire, physical examination, 6-minute walking test and a test on stabilometric platform. RESULTS: In the younger group we observed easier and faster resolution of pain in the operated joint. In group II, which included patients aged 61 to 69 years, improvement in hip joint mobility was less pronounced than in the younger group. Six-minute walking test showed less improvement in walking distance in group II than group I. Among group II patients we noted less pronounced increase in weight bearing on the operated limb (by 2%, while 4% improvement was noted in group I), while final degree of weight-bearing was greater in group II than in group I and amounted to 48%. CONCLUSIONS: Younger patients recover faster, hip pain subsides easier, hip function returns more readily and to a greater extent. During a 4-week course of in-hospital rehabilitation older patients may regain hip function in a manner that brings them closer to the younger group. PMID- 23666243 TI - Photophysical study of a polyoxo ethylene linked naphthalene-based fluorescent chemosensor for Mg2+ and Ca2+ detection. AB - A naphthalene-based bichromophoric fluorescent sensor 2,2'-[oxy-bis(2 oxatetramethyleneoxy)]-bis[N-(2-naphthyl)-benzamide)] (1) was synthesized and characterized. Fluorescence decay for 1 in alcoholic solvents in the region of 415-460 nm revealed bi-exponential behavior. The faster component of the decay can be attributed to the formation of dimers. Above 480 nm, besides the dimer, there is also a little excimer formation and this excimer emits at longer wavelengths than the dimer. The observation of the change of the fluorescence emission spectra upon addition of water in EtOH-water mixtures is in line with the formation of water-bridged complexes preventing excimer formation. The sensor shows an increase in fluorescence intensity upon increasing Mg(2+) or Ca(2+) concentration in EtOH because the formation of the excimer can be hindered upon complexation with Mg(2+) or Ca(2+) ions. Because of the competition between hydrated metal ions and the water-bridged complex, spectral changes by complexation with Mg(2+) or Ca(2+) in EtOH-H2O (9 : 1 v/v) are quite different from those in neat ethanol. The ground-state dissociation constant K(d) estimated for the complex with Mg(2+) or Ca(2+) was found to be around 2.0 mM in EtOH-H2O (9 : 1 v/v), which makes it suitable for the measurement of the concentrations of these ions in physiologically relevant concentration ranges. PMID- 23666244 TI - Efficient sequencing of Anuran mtDNAs and a mitogenomic exploration of the phylogeny and evolution of frogs. AB - Anura (frogs and toads) constitute over 88% of living amphibian diversity but many important questions about their phylogeny and evolution remain unresolved. For this study, we developed an efficient method for sequencing anuran mitochondrial DNAs (mtDNAs) by amplifying the mitochondrial genome in 12 overlapping fragments using frog-specific universal primer sets. Based on this method, we generated 47 nearly complete, new anuran mitochondrial genomes and discovered nine novel gene arrangements. By combining the new data and published anuran mitochondrial genomes, we assembled a large mitogenomic data set (11,007 nt) including 90 frog species, representing 39 of 53 recognized anuran families, to investigate their phylogenetic relationships and evolutionary history. The resulting tree strongly supported a paraphyletic arrangement of archaeobatrachian (=nonneobatrachian) frogs, with Leiopelmatoidea branching first, followed by Discoglossoidea, Pipoidea, and Pelobatoidea. Within Neobatrachia, the South African Heleophrynidae is the sister-taxon to all other neobatrachian frogs and the Seychelles-endemic Sooglossidae is recovered as the sister-taxon to Ranoidea. These phylogenetic relationships agree with many nuclear gene studies. The chronogram derived from two Bayesian relaxed clock methods (MultiDivTime and BEAST) suggests that modern frogs (Anura) originated in the early Triassic about 244 Ma and the appearance of Neobatrachia took place in the late Jurassic about 163 Ma. The initial diversifications of two species-rich superfamilies Hyloidea and Ranoidea commenced 110 and 133 Ma, respectively. These times are older than some other estimates by approximately 30-40 My. Compared with nuclear data, mtDNA produces compatible time estimates for deep nodes (>150 Ma), but apparently older estimates for more shallow nodes. Our study shows that, although it evolves relatively rapidly and behaves much as a single locus, mtDNA performs well for both phylogenetic and divergence time inferences and will provide important reference hypotheses for the phylogeny and evolution of frogs. PMID- 23666245 TI - Structural valve deterioration of porcine bioprosthesis soon after mitral valve repair and replacement. AB - An 81-year-old woman, who had undergone mitral valve replacement (MVR) with a porcine bioprosthesis after mitral valve repair, presented with hemolysis 4 years and 6 months after MVR. Transthoracic echocardiography (TTE) revealed trivial mitral regurgitation, which was diagnosed based on the observed perivalvular leakage. Hemolysis gradually increased, and she developed dyspnea and edema 2 years after the appearance of mitral regurgitation. We performed a reoperation. Intraoperative transesophageal echocardiography (TEE) after intubation showed no perivalvular leakage of the mitral prosthesis, but transvalvular leakage through a leaflet perforation was present. The leaflets of the bioprosthesis had slit shaped perforations at their hinges. There was no sign of infection on the leaflet or annulus. We implanted a new bioprosthesis after removal of the deteriorated valve. The postoperative course was uneventful. Microscopic examination verified collagen degeneration, histiocyte infiltration, and hyalinization. It is important to perform TEE to rule out structural valve deterioration (SVD) even when regurgitation occurs soon after valve replacement. PMID- 23666246 TI - Paravalvular abscess of the mitral valve with fistula to the left ventricle and detachment of the coronary sinus in a young woman. AB - Infective endocarditis (IE) of the mitral valve (MV) manifesting paravalvular abscess (PA) is challenging. A 30-year-old woman presented with PA fistulating to the left ventricle, detachment of the coronary sinus and systemic embolization. During a course of fever of unknown origin, the patient received laparoscopic surgery under the diagnosis of strangulating intestinal obstruction due to colitis. Following abdominal surgery, abscess having blood flow within it from the left ventricle was pointed out at the left ventriculo-atrial junction by transthoracic echocardiography. Emergency surgery was performed under the diagnosis of PA of MV. Abscess debridement followed by reconstruction of the mitral annulus and coronary sinus with fresh autologous pericardium and mitral valve replacement (MVR) using a mechanical prosthetic valve were successfully performed. Timely and accurate diagnosis followed by the early surgical intervention with aggressive debridement of abscess and reconstruction with autologous pericardium should improve the outcome of this high-risk disease. PMID- 23666247 TI - Thoracoscopic wedge resection through a single incision using a thin puncture device. AB - Video-assisted thoracic surgery (VATS) has been enthusiastically used as a less invasive diagnostic or therapeutic surgical procedure in recent years. VATS results in considerably less postoperative pain than traditional thoracotomy incisions. The current trend is to reduce the number of ports and minimize the length of incisions to further reduce postoperative pain, chest wall paresthesia, and length of hospitalization. Although several accounts of reduced port surgery, such as single-incision laparoscopic surgery (SILS), have been reported, there are few descriptions of single-incision thoracoscopic surgery (SITS) using a thin puncture device for a variety of diseases. Herein, we describe a minimally invasive SITS technique using a thin puncture device. PMID- 23666248 TI - Hyperglycemia or high hemoglobin A1C: Which one is more associated with morbidity and mortality after coronary artery bypass graft surgery? AB - PROPOSE: Our aim was to determine which criterion- hyperglycemia or high levels of glycosylated hemoglobin (HbA1C) is more associated with increased mortality and morbidity after coronary artery bypass graft (CABG). METHODS: Two hundred and sixteen patients who underwent elective CABG were enrolled in this prospective study. In order to compare postoperative outcomes regarding HbA1c and fasting blood sugar (FBS) levels, the patients were divided into two groups based on plasma HbA1c levels >7% or <=7% and FBS >126 mg/dl or <=126 mg/dl. RESULTS: Of 216 studied patients, 165 and 51 cases had levels of HbA1C <=7% and HbA1c >7% respectively. Furthermore, 129 and 87 patients had levels of FBS of <=126 mg/dl and FBS of >126 mg/dl respectively. Multivariate analyses revealed that patients with high HbA1C levels experienced significantly higher rates of postoperative re intubation [P = 0.001, OR (95% CI) = 8.15 (2.88-23.09)], wound infection [P = 0.001, OR (95% CI) = 8.15 (2.88-23.09)] and bleeding [P = 0.027, OR (95% CI) = 2.18 (1.10-4.35)]. In addition, hyperglycemic patients had a higher frequency of arrhythmias [P = 0.001, OR (95% CI) = 3.07 (1.69-5.59)], atelectasis [P = 0.029, OR (95% CI) = 1.88 (1.07-3.30)] and wound infection [P = 0.001, OR (95% CI) = 8.75 (2.45-31.25)]. CONCLUSION: Higher levels of both HbA1C and FBS contribute to the increased risk of morbidity but not mortality rates in post-CABG surgery patients; yet further studies are required to distinguish "a better predictor" of postoperative adverse events. PMID- 23666249 TI - Mineralocorticoid receptor throughout the vessel: a key to vascular dysfunction in obesity. PMID- 23666250 TI - Neurohormonal and clinical sex differences in heart failure. AB - AIMS: Despite disparities in pathophysiology and disease manifestation between male and female patients with heart failure, studies focusing on sex differences in biomarkers are scarce. The purpose of this study was to assess sex-specific variation in clinical characteristics and biomarker levels to gain more understanding of the potential pathophysiological mechanisms underlying sex differences in heart failure. METHODS AND RESULTS: Baseline demographic and clinical characteristics, multiple biomarkers, and outcomes were compared between men and women in 567 patients. The mean age of the study group was 71 +/- 11 years and 38% were female. Women were older, had a higher body mass index and left ventricular ejection fraction, more hypertension, and received more diuretic and antidepressant therapy, but less ACE-inhibitor therapy compared with men. After 3 years, all-cause mortality was lower in women than men (37.0 vs. 43.9%, multivariable hazard ratio = 0.64; 95% confidence interval 0.45-0.92, P = 0.016). Levels of biomarkers related to inflammation [C-reactive protein, pentraxin 3, growth differentiation factor 15 (GDF-15), and interleukin 6] and extracellular matrix remodelling (syndecan-1 and periostin) were significantly lower in women compared with men. N-terminal pro-brain natriuretic peptide, TNF-alphaR1a, and GDF-15 showed the strongest interaction between sex and mortality. CONCLUSION: Female heart failure patients have a distinct clinical presentation and better outcomes compared with male patients. The lower mortality was independent of differences in clinical characteristics, but differential sex associations between several biomarkers and mortality might partly explain the survival difference. PMID- 23666252 TI - Chiral high-performance liquid chromatographic separation of evodiamine enantiomers and rutaecarpine, isolated from Evodiae fructus. AB - A rapid, simple and sensitive chiral HPLC method was developed and validated for quantification of biologically important alkaloids namely evodiamine enantiomers and rutaecarpine in Evodiae fructus using diphenhydramine as the internal standard (IS). Chromatographic separations were performed on a Chiralpak AD-H column (250 mm * 4.6 mm i.d., 5 MUm) with elution of n-hexane-2-propanol-ethanol (70:20:10, v/v/v) in a flow rate of 0.7 ml/min and at lambdamax 225 nm. To identify the order of elution, small quantities of the each evodiamine enantiomer were isolated by semi preparative HPLC method. Extraction samples were prepared by a simple solid phase extraction (SPE) method. All calibration curves showed good linearity (r(2)>=0.999) within the test ranges. The LOD and LOQ were lower than 0.05 and 0.1 MUg/ml, respectively. The RSDs of intra- and interday for relative peak areas of three analytes to IS were less than 3.2 and 2.5%, respectively, and the recoveries were 98.0-103.7%. The validated method was successfully applied to the quantitative analysis of three constituents in 13 batches of samples collected from market. The results showed that S-(+) evodiamine was the main component while R-(-)-evodiamine was present in low concentration. This study provides a qualitative and quantitative method for analysis of evodiamine enantiomers and rutaecarpine, and should be extendable to pharmacological and toxicological studies of the individual evodiamine enantiomers. PMID- 23666251 TI - Cardiovascular complications of radiation therapy for thoracic malignancies: the role for non-invasive imaging for detection of cardiovascular disease. AB - Radiation exposure to the thorax is associated with substantial risk for the subsequent development of cardiovascular disease. Thus, the increasing role of radiation therapy in the contemporary treatment of cancer, combined with improving survival rates of patients undergoing this therapy, contributes to a growing population at risk of cardiovascular morbidity and mortality. Associated cardiovascular injuries include pericardial disease, coronary artery disease, valvular disease, conduction disease, cardiomyopathy, and medium and large vessel vasculopathy-any of which can occur at varying intervals following irradiation. Higher radiation doses, younger age at the time of irradiation, longer intervals from the time of radiation, and coexisting cardiovascular risk factors all predispose to these injuries. The true incidence of radiation-related cardiovascular disease remains uncertain due to lack of large multicentre studies with a sufficient duration of cardiovascular follow-up. There are currently no consensus guidelines available to inform the optimal approach to cardiovascular surveillance of recipients of thoracic radiation. Therefore, we review the cardiovascular consequences of radiation therapy and focus on the potential role of non-invasive cardiovascular imaging in the assessment and management of radiation-related cardiovascular disease. In doing so, we highlight characteristics that can be used to identify individuals at risk for developing post-radiation cardiovascular disease and propose an imaging-based algorithm for their clinical surveillance. PMID- 23666253 TI - LC-MS/MS method for the quantification of almotriptan in dialysates: application to rat brain and blood microdialysis study. AB - A sensitive LC-MS/MS method was developed and validated for the quantification of almotriptan in rat brain and blood dialysates. Almotriptan is a 5HT1B/1D receptor agonist used for the treatment of migraine pain. Method consists of rapid gradient elution program with 10mM ammonium formate (pH 3) and acetonitrile on a Xbridge column. The MRM transitions monitored were m/z 336.2-58.1 for almotriptan and m/z 448.2-285.3 for the IS. The assay was linear in the range of 0.1-20 ng/ml, with acceptable precision and accuracy along with adequate sensitivity. The between batch accuracy was in the range of 99.0-104.3% with precision in between 0.6% and 5.8%. Microdialysis is an important sampling technique, with the capability of capturing the concentrations of various analytes in different bio fluids, at a single time point. This method was applied to quantify brain and blood dialysate samples obtained from a microdialysis study of rats treated with almotriptan (10mg/kg, p.o.). In vivo recovery experiments were performed to correct the dialysate concentrations into extracellular concentrations. Mean peak dialysate concentrations of almotriptan were found to be 152 +/- 78 and 7.4 +/- 1.0 ng/ml in blood and prefrontal cortex, respectively. The brain penetration of almotriptan is characterized by the AUCbrain/AUCblood found to be 0.07 +/- 0.05. The results revealed the importance of measuring the unbound almotriptan concentrations in the brain over the blood for understanding its PK/PD relationship. PMID- 23666254 TI - Identification of senkyunolide I metabolites in rats using ultra performance liquid chromatography/quadrupole-time-of-flight tandem mass spectrometry. AB - Ligusticum chuanxiong Hort. (Umbelliferae) has been widely prescribed to treat cardiovascular disease in China for centuries. Senkyunolide I is one of the major bioactive components in L. chuanxiong, which shows pharmacological activities against migraines and oxidative damage. In this paper, ultra performance liquid chromatography/quadrupole-time-of-flight tandem mass spectrometry (UPLC/Q-TOF-MS) was applied for the rapid analysis of senkyunolide I metabolites in rats after its intravenous administration. The non-metabolized parent compound and eighteen metabolites from drug-treated samples in rat plasma, urine and bile were identified. Our analysis indicated that methylation, hydration, epoxidation, glucuronidation and glutathione conjugation were the major pathways of senkyunolide I metabolism in vivo. This study provides important information regarding the metabolism of senkyunolide I, which will be helpful for understanding its mechanism of action. Furthermore, this work demonstrates the potential of using UPLC/Q-TOF-MS for the rapid and reliable characterization of the metabolites of natural products. PMID- 23666255 TI - Patients with anaemia can shift from kidney to liver production of erythropoietin as shown by glycoform analysis. AB - The primary production site of erythropoietin (EPO) is shifted from the liver to the kidney shortly after birth. Under conditions of lost or reduced kidney production, it is valuable to measure the production capacity of the liver. However, there is a lack of urine or serum based methods that can distinguish endogenous EPO produced in different cell types. Here is presented a method based on chromatographic interaction with the lectin wheat germ agglutinin (WGA) that can distinguish presumably liver-produced EPO, found in anaemic patients receiving epoetin and darbepoetin, from kidney-produced EPO found in healthy individuals. All the tested samples from haemodialysis patients with end-stage renal disease showed a presence of liver EPO. In some samples, the liver-produced EPO made up 90-100% of total EPO at a concentration of 8-10 ng/L in urine, which indicates that the liver has a quite high production capacity, although not adequate for the degree of anaemia. This glycoform analysis has made it possible to affirm that some anaemic patients can increase their liver-production of EPO. The use of such a method can give better insight into the regulation of non-renal endogenous EPO production, a potential source of EPO intended to replace administration of exogenous EPO. PMID- 23666256 TI - Quantification and structural elucidation of potential impurities in agomelatine active pharmaceutical ingredient. AB - Seven impurities in agomelatine drug substance were determined by a newly developed RP-HPLC method. Structures of potential impurities were confirmed by NMR and IR analysis. Efficient chromatographic separation was achieved on Hypersil BDS C18 column (250 mm * 4.6 mm, 5 MUm) in gradient mode by using a binary mixture of potassium dihydrogen phosphate (15 mM, pH adjusted to 3.0) and acetonitrile at a flow rate of 1.0 ml/min. A photodiode array detector set at 230 nm was used for detection. Forced degradation studies showed that the proposed method was specific, and agomelatine was found to be susceptible to acidic and alkaline conditions. The method was validated according to ICH guidelines with respect to specificity, sensitivity, precision, linearity, accuracy, robustness and system suitability. Detection limit of impurities was in the range of 0.0008 0.0047%. Regression analysis showed correlation coefficient value greater than 0.999 for agomelatine and its seven impurities. Accuracy of the method was established based on the recovery obtained between 94.4% and 106.7% for all impurities. The validation results demonstrated that the developed method was suitable for the quantitative determination of potential impurities in agomelatine. A possible mechanism for the formation of impurities was proposed. PMID- 23666257 TI - Nucleic acid aptamers as high affinity ligands in biotechnology and biosensorics. AB - Aptamers are small nucleic acid molecules capable of binding to a wide range of target molecules with high affinity and specificity. They have been developed and widely used not only as research tools, but also as biosensors, specific antagonists, and diagnostic markers and as protein purification platform for many pharmaceutical and clinical applications. Here, in this paper we will explore biochemical aspects of aptamer-target interactions and show why aptamers rival antibodies in target recognition and purification procedures. This review will focus on strategies of using aptamers as affinity ligands for molecules of therapeutic and pharmaceutical interest including applications in chromatography and capillary electrophoresis for protein and small molecule purification. Moreover, we will also discuss aptamers whose binding parameters can be controlled on demand for diagnostic approaches and used as sensitive receptors in biosensorics. Aptamers have opened up exciting fields in basic and applied research of pharmaceutical and biotechnological interest. PMID- 23666258 TI - KERNEL-BASED HIGH-DIMENSIONAL HISTOGRAM ESTIMATION FOR VISUAL TRACKING. AB - We propose an approach for non-rigid tracking that represents objects by their set of distribution parameters. Compared to joint histogram representations, a set of parameters such as mixed moments provides a significantly reduced size representation. The discriminating power is comparable to that of the corresponding full high-dimensional histogram yet at far less spatial and computational complexity. The proposed method is robust in the presence of noise and illumination changes, and provides a natural extension to the use of mixture models. Experiments demonstrate that the proposed method outperforms both full color mean-shift and global covariance searches. PMID- 23666260 TI - Contamination of metals in different tissues of rohu (Labeo rohita, Cyprinidae) collected from the Indian River Ganga. AB - In the present paper, accumulation of zinc (Zn), iron (Fe), copper (Cu), chromium (Cr), nickel (Ni), manganese (Mn) and lead (Pb) was determined in different tissues (skin, muscles, liver, gills, kidney and brain) of rohu (Labeo rohita) collected from the River Ganga in Varanasi, India. Concentrations of Cu (except gills), Fe and Cr (except brain for Cr) in most of the tissues were above the permissible safe limits for human consumption suggested by the Food and Agricultural Organization (FAO 1983). Concentrations of all metals were higher in River Ganga fish than those from the University fish farm. With the exception of Zn in skin, muscle and brain tissue, the studied metals were bioaccumulated in all tissues. The total metal accumulation or metal pollution index was highest in liver (20.8 +/- 0.50) followed by kidney (16.8 +/- 0.44), gills (15.2 +/- 0.15), muscles (12.1 +/- 0.08), skin (10.5 +/- 0.53) and brain (7.0 +/- 0.02). PMID- 23666261 TI - Retraction note to: Cardiac glycoside induces cell death via FasL by activating calcineurin and NF-AT, but apoptosis initially proceeds through activation of caspases. PMID- 23666259 TI - Genome-wide profiling of in vivo LPS-responsive genes in splenic myeloid cells. AB - Lipopolysaccharide (LPS), the major causative agent of bacterial sepsis, has been used by many laboratories in genome-wide expression profiling of the LPS response. However, these studies have predominantly used in vitro cultured macrophages (Macs), which may not accurately reflect the LPS response of these innate immune cells in vivo. To overcome this limitation and to identify inflammatory genes in vivo, we have profiled genome-wide expression patterns in non-lymphoid, splenic myeloid cells extracted directly from LPS-treated mice. Genes encoding factors known to be involved in mediating or regulating inflammatory processes, such as cytokines and chemokines, as well as many genes whose immunological functions are not well known, were strongly induced by LPS after 3 h or 8 h of treatment. Most of the highly LPS-responsive genes that we randomly selected from the microarray data were independently confirmed by quantitative RT-PCR, implying that our microarray data are quite reliable. When our in vivo data were compared to previously reported microarray data for in vitro LPS-treated Macs, a significant proportion (~20%) of the in vivo LPS responsive genes defined in this study were specific to cells exposed to LPS in vivo, but a larger proportion of them (~60%) were influenced by LPS in both in vitro and in vivo settings. This result indicates that our in vivo LPS-responsive gene set includes not only previously identified in vitro LPS-responsive genes but also novel LPS-responsive genes. Both types of genes would be a valuable resource in the future for understanding inflammatory responses in vivo. PMID- 23666262 TI - Disparities in lifestyle habits and health related factors of Montreal immigrants: is immigration an important exposure variable in public health? AB - Study disparities in lifestyle habits and health characteristics of Canadian born population and immigrants with different duration of residence. Data are extracted from 2009 to 2010 public use micro-data files of Canadian Community Health Survey representing about 1.5 million people. Sixty-one percent of the study sample was born in Canada; 49 % males and 59 % below age 50. Amongst lifestyle habits, recent immigrants were less likely to be regular smokers, RR (95 % CI) 0.56 (0.36-0.88) and frequent consumers of alcohol 0.49 (0.27-0.89), but more likely to consume less fruits and vegetables 1.26 (1.04-1.53) than those born in Canada. Amongst health related factors, recent immigrants were less likely to be overweight 0.79 (0.62-0.99) and suffer from chronic diseases 0.59 (0.44-0.80), but more likely to have limited access to family medicine 1.24 (1.04 1.47) than Canada-born population. Immigration status is an important population characteristic which influenced distribution of health indicators. Prevention and promotion strategies should consider immigration status as an exposure variable in the development and implementation of public health programs. PMID- 23666263 TI - A supervised learning framework of statistical shape and probability priors for automatic prostate segmentation in ultrasound images. AB - Prostate segmentation aids in prostate volume estimation, multi-modal image registration, and to create patient specific anatomical models for surgical planning and image guided biopsies. However, manual segmentation is time consuming and suffers from inter-and intra-observer variabilities. Low contrast images of trans rectal ultrasound and presence of imaging artifacts like speckle, micro-calcifications, and shadow regions hinder computer aided automatic or semi automatic prostate segmentation. In this paper, we propose a prostate segmentation approach based on building multiple mean parametric models derived from principal component analysis of shape and posterior probabilities in a multi resolution framework. The model parameters are then modified with the prior knowledge of the optimization space to achieve optimal prostate segmentation. In contrast to traditional statistical models of shape and intensity priors, we use posterior probabilities of the prostate region determined from random forest classification to build our appearance model, initialize and propagate our model. Furthermore, multiple mean models derived from spectral clustering of combined shape and appearance parameters are applied in parallel to improve segmentation accuracies. The proposed method achieves mean Dice similarity coefficient value of 0.91 +/- 0.09 for 126 images containing 40 images from the apex, 40 images from the base and 46 images from central regions in a leave-one-patient-out validation framework. The mean segmentation time of the procedure is 0.67 +/- 0.02 s. PMID- 23666264 TI - Predicting cortical ROIs via joint modeling of anatomical and connectional profiles. AB - Localization of cortical regions of interests (ROIs) in structural neuroimaging data such as diffusion tensor imaging (DTI) and T1-weighted MRI images has significant importance in basic and clinical neurosciences. However, this problem is considerably challenging due to the lack of quantitative mapping between brain structure and function, which relies on the availability of multimodal training data including benchmark task-based functional MRI (fMRI) images and effective machine learning algorithms. This paper presents a novel joint modeling approach that learns predictive models of ROIs from concurrent task-based fMRI, DTI, and T1-weighted MRI datasets. In particular, the effective generalized multiple kernel learning (GMKL) algorithm and ROI coordinate principal component analysis (PCA) model are employed to infer the intrinsic relationships between anatomical T1-weighted MRI/connectional DTI features and task-based fMRI-derived functional ROIs. Then, these predictive models of cortical ROIs are evaluated by cross validation studies, independent datasets, and reproducibility studies. Experimental results are promising. We envision that these predictive models can be potentially applied in many scenarios that have only DTI and/or T1-weighted MRI data, but without task-based fMRI data. PMID- 23666265 TI - The function of P2X3 receptor and NK1 receptor antagonists on cyclophosphamide induced cystitis in rats. AB - PURPOSE: The purpose of the study is to explore the function of P2X3 and NK1 receptors antagonists on cyclophosphamide (CYP)-induced cystitis in rats. METHODS: Sixty female Sprague-Dawley (SD) rats were randomly divided into three groups. The rats in the control group were intraperitoneally (i.p.) injected with 0.9% saline (4 ml/kg); the rats in the model group were i.p. injected with CYP (150 mg/kg); and the rats in the intervention group were i.p. injected with CYP with subsequently perfusion of bladder with P2X3 and NK1 receptors' antagonists, Suramin and GR 82334. Spontaneous pain behaviors following the administration of CYP were observed. Urodynamic parameters, bladder pressure-volume curve, maximum voiding pressure (MVP), and maximum cystometric capacity (MCC), were recorded. Pathological changes in bladder tissue were observed. Immunofluorescence was used to detect the expression of P2X3 and NK1 receptors in bladder. RESULTS: Cyclophosphamide treatment increased the spontaneous pain behaviors scores. The incidence of bladder instability during urine storage period of model group was significantly higher than intervention group (chi(2) = 7.619, P = 0.007) and control group (chi(2) = 13.755, P = 0.000). MCC in the model group was lower than the control and intervention groups (P < 0.01). Histological changes evident in model and intervention groups rats' bladder included edema, vasodilation, and infiltration of inflammatory cells. In model group, the expression of P2X3 receptor increased in urothelium and suburothelium, and NK1 receptor increased in suburothelium, while the expression of them in intervention group was lower. CONCLUSIONS: In CYP-induced cystitis, the expression of P2X3 and NK1 receptors increased in urothelium and/or suburothelium. Perfusion of bladder with P2X3 and NK1 receptors antagonists ameliorated the bladder function. PMID- 23666267 TI - Self-management of chemotherapy-related nausea and vomiting: a cross-sectional survey of Chinese cancer patients. AB - BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) remain prevalent among cancer patients despite pharmacological advances in CINV therapy. Patients can initiate nonpharmacologic strategies, which potentially play an important role as adjuncts to pharmacological agents in alleviating CINV. Some studies have explored nausea and vomiting self-management (NVSM) behaviors among patients in Western settings; however, little is known about the NVSM behaviors of patients in China. OBJECTIVES: This study examines NVSM behaviors of Chinese cancer patients. METHODS: A cross-sectional survey was conducted in a specialist cancer hospital in southeast China. RESULTS: A sample of 255 cancer patients was recruited. A mean of 8.56 (+/-3.15) NVSM behaviors was reported. Most NVSM behaviors were rated as moderately effective and were implemented with moderate self-efficacy. Higher distress levels, better functional status, previous similar symptom experiences, receiving chemotherapy as an inpatient, and greater support from multiple levels were related to greater engagement in NVSM; higher self efficacy levels pertaining to NVSM behaviors were associated with reports of more relief from specific NVSM behaviors. CONCLUSIONS: A range of NVSM strategies was initiated by Chinese cancer patients and provided some relief. A range of individual, health status, and environmental factors influenced engagement with and relief from NVSM behaviors. IMPLICATIONS FOR PRACTICE: To enhance Chinese patients' NVSM, patients should be supported to engage in behaviors including taking antiemetics, modifying their diet, using psychological strategies, and creating a pleasant environment. The findings highlight the importance of enhancing patients' self-efficacy in NVSM, alleviating symptom distress, and improving social support to achieve better outcomes. PMID- 23666266 TI - Improving intracellular doxorubicin delivery through nanoliposomes equipped with selective tumor cell membrane permeabilizing short-chain sphingolipids. AB - PURPOSE: To improve nanoliposomal-doxorubicin (DoxNL) delivery in tumor cells using liposome membrane-incorporated short-chain sphingolipids (SCS) with selective membrane-permeabilizing properties. DoxNL bilayers contained synthetic short-chain derivatives of known membrane microdomain-forming sphingolipids; C8 glucosylceramide (C8-GluCer), C8-galactosylceramide (C8-GalCer) or C8 lactosylceramide (C8-LacCer). METHODS: DoxNL enriched with C8-GluCer or C8-GalCer were developed, optimized and characterized with regard to size, stability and drug retention. In vitro cytotoxic activity was studied in a panel of human tumor cell lines and normal cells. Intracellular Dox delivery was measured by flow cytometry and visualized by fluorescence microscopy. For a further understanding of the involved drug delivery mechanism confocal microscopy studies addressed the cellular fate of the nanoliposomes, the SCS and Dox in living cells. RESULTS: C8 LacCer-DoxNL aggregated upon Dox loading. In tumor cell lines SCS-DoxNL with C8 GluCer or C8-GalCer demonstrated strongly increased Dox delivery and cytotoxicity compared to standard DoxNL. Surprisingly, this effect was much less pronounced in normal cells. Nanoliposomes were not internalized, SCS however transfered from the nanoliposomal bilayer to the cell membrane and preceded cellular uptake and subsequent nuclear localization of Dox. CONCLUSION: C8-GluCer or C8-GalCer incorporated in DoxNL selectively improved intracellular drug delivery upon transfer to tumor cell membranes by local enhancement of cell membrane permeability. PMID- 23666268 TI - The Latin American Center for Pediatric Oncology Nursing Education: development, implementation, and accomplishments. AB - BACKGROUND: Pediatric oncology nurses in low- and middle-income countries have limited access to specialized education and clinical training. This is a major impediment for treating children with cancer and contributes to the disparity in survival rates between high- and low-income countries. The International Outreach Nursing Program at St Jude Children's Research Hospital established full-time nurse educator positions at partner sites throughout Latin America. Experienced nurses were hired as educators; however, they had no formal pediatric oncology education, limited teaching experience, and no mentors as this was a new nursing role in low- and middle-income countries. OBJECTIVE: Our objective was to create a regional education center to prepare nurse educators to succeed in this pioneering role. INTERVENTIONS: The Latin American Center for Pediatric Oncology Nursing Education was created at Calvo Mackenna Hospital in Santiago, Chile, to provide education, resources, and support to educators. Education resources, including a comprehensive orientation program and courses in chemotherapy and central venous line care, were developed. A 4-week on-site comprehensive educator course and an organized support system were implemented. RESULTS: Education, resources, and support have been provided to 13 nurse educators representing 7 Latin American countries. The educators have provided pediatric oncology education to more than 1000 nurses. CONCLUSIONS: The center promotes excellence in pediatric oncology nursing by preparing and supporting educators, who in turn educate the entire nursing staff at partner sites. IMPLICATIONS FOR PRACTICE: Nurse educators equipped with knowledge and skills can improve the quality of care and ultimately survival of patients throughout Latin America. PMID- 23666269 TI - A randomized clinical trial of the efficacy of a self-care intervention to improve cancer pain management. AB - BACKGROUND: The undertreatment of cancer pain remains a significant clinical problem. OBJECTIVE: The aim of this randomized controlled trial was to evaluate the efficacy of the PRO-SELF Pain Control Program that was modified for Norwegian cancer patients in decreasing pain and increasing opioid intake compared with control care. INTERVENTIONS/METHODS: Oncology outpatients with pain from bone metastasis were randomized into the PRO-SELF (n = 87) or control (n = 92) groups. A nurse visited patients in the PRO-SELF group in their home at weeks 1, 3, and 6 and conducted telephone interviews at weeks 2, 4, and 5. Patients in both groups completed a daily diary of pain intensity ratings and analgesic intake. RESULTS: For both groups, significant decreases in pain intensity scores and in hours per day in pain (both, P < .001) were found over the 6 weeks of the study. However, no significant group * time interactions were found for any of the pain measures. In both groups, total dose of opioid taken increased over time. However, no significant group * time interactions were found for changes over time in the total dose, around-the-clock dose, or as-needed dose of opioid analgesics taken. CONCLUSIONS: Possible reasons for the lack of efficacy include an inadequate dose of the psychoeducational intervention, inadequate changes in analgesic prescriptions, and/or the impact of attention provided to the control group. IMPLICATIONS FOR PRACTICE: Coaching, nursing support, and the use of a pain diary may be important interventions to reduce pain intensity. PMID- 23666270 TI - Environment-related adaptive changes of gut commensal microbiota do not alter colonic toll-like receptors but modulate the local expression of sensory-related systems in rats. AB - Pathogenic and protective roles have been attributed to gut commensal microbiota (GCM) in gastrointestinal inflammatory and functional disorders. We have shown that the adaptation to a new environment implies specific changes in the composition of GCM. Here we assessed if environment-related adaptive changes of GCM modulate the expression of colonic Toll-like receptors (TLRs) and sensory related systems in rats. Adult male SD rats were maintained under different environmental conditions: barrier-breed-and-maintained, barrier-breed adapted to conventional conditions or conventional-breed-and-maintained. Fluorescent in situ hybridization and real-time quantitative PCR (qPCR) were used to characterize luminal ceco-colonic microbiota. Colonic expression of TLR2, TLR4, TLR5, and TLR7, cannabinoid receptors (CB1/CB2), MU-opioid receptor (MOR), transient receptor potential vanilloid (TRPV1, TRPV3, and TRPV4), protease-activated receptor 2 (PAR-2), and calcitonin gene-related peptide were quantified by RT qPCR. CB1, CB2 and MOR expression, was evaluated also by immunohistochemistry. In rats, housing-related environmental conditions induce specific changes of GCM, without impact on the expression of TLR-dependent bacterial recognition systems. Expression of sensory-related markers (MOR, TRPV3, PAR-2, and CB2) decreased with the adaptation to a conventional environment, correlating with changes in Bacteroides spp., Lactobacillus spp., and Bifidobacterium spp. counts. This suggests an interaction between GCM and visceral sensory mechanisms, which might be part of the mechanisms underlying the beneficial effects of some bacterial groups on functional and inflammatory gastrointestinal disorders. PMID- 23666271 TI - Synthesis and in vitro antifungal activities of new 2-aryl-6,7-methylenedioxy-3,4 dihydroisoquinolin-2-ium bromides. AB - 2-Aryl-3,4-dihydroisoquinolin-2-iums might be considered as a class of simple analogues of natural quaternary benzo[c]phenanthridine alkaloids. In this paper, 26 new 2-aryl-6,7-methylenedioxy-3,4-dihydroisoquinolin-2-ium bromides with various substituents in N-aromatic ring were synthesized from commercially available 1,3-benzodioxole in good to excellent yields. All the compounds were elucidated by MS, high resolution (HR)-MS, IR, (1)H- and (13)C-NMR analysis, and evaluated for antifungal activities in vitro against Alternaria alternate, Curvularia lunata and Fusarium oxysporum sp. niveum at 50 ug/mL. Most of the compounds showed higher activities against all the test fungi than their natural model compounds sanguinarine and chelerythrine. For A. alternate and Curvularia lunata, most of them were also more active than thiabendazole, a commercial fungicide standard. The structure-activity relationship indicated that the substituent in N-aromatic ring and its position had significant effect on the activity. The general trend was that halogen atoms and CF3 remarkably enhanced the activity while CH3 and OCH3 decreased the activity. Generally, o-substituted isomers were more active than m- and p-substituted isomer. The present results suggest that the title compounds are potential for the development of new isoquinoline antimicrobial agents. PMID- 23666273 TI - Community context and healthcare quality: the impact of community resources on licensing and accreditation of substance abuse treatment agencies. AB - This study examines variation in healthcare quality among substance abuse treatment agencies. Using an organizations framework, the authors predict that resource advantages benefit certain types of healthcare organizations, especially those located in affluent communities. As a result, levels of licensing and accreditation of substance abuse treatment agencies will differ across United States counties. The authors model these resources at both the organizational and community levels in an effort to understand the variability of licensing and accreditation between agencies and their local contexts. In multivariate models, the findings confirm that organizational characteristics such as private ownership (compared to public ownership), managed care contracts, inpatient and residential programs (compared to outpatient settings), as well as socioeconomic, racial/ethnic, and healthcare system advantage promote higher levels of licensing and accreditation. Public ownership and outpatient settings, as well as socioeconomic, racial/ethnic, and healthcare system disadvantage, are associated with lower levels of licensing and accreditation. PMID- 23666276 TI - Obesity in hospitalized type 2 diabetes patients: a descriptive study. AB - BACKGROUND: The association between obesity and type 2 diabetes has been well documented in epidemiological studies. Patients with type 2 diabetes have a higher body weight than control populations. Relatively few studies, however, have examined the prevalence of obesity in a cohort of hospitalized type 2 diabetes mellitus patients using an electronic health records database. This study measured the prevalence of obesity in hospitalized type 2 diabetes patients and described demographic and clinical characteristics using electronic health records from Convergence CT sites located in the southwestern United States. MATERIAL AND METHODS: Hospitalized patients with type 2 diabetes mellitus were identified in electronic health records from the Convergence Global Research Network. Demographic and clinical characteristics were examined for hospitalized patients with type 2 diabetes. Comparisons were made between males and females across different clinical characteristics as well as between obese patients (BMI >=30 kg/m2) and patients with BMI <30 kg/m2. RESULTS: Approximately 26.8% of hospitalized type 2 diabetes patients were overweight (BMI=25-29.9 kg/m2) and 57.7% were obese (BMI >=30 kg/m2). A higher percentage of females (61.3%) were obese compared to males (54.6%) (p=0.002). Obese patients with type 2 diabetes were younger, appeared to have inadequate glycemic control, exhibited higher blood pressure, and had worse lipid profiles compared to type 2 diabetes patients with BMI <30 kg/m2. CONCLUSIONS: Approximately 84.5% of the hospitalized type 2 diabetes patients identified in this study were overweight or obese (BMI >=25 kg/m2), suggesting the need for effective weight loss intervention in this population. PMID- 23666274 TI - CoQ10 and endothelial function in Asians from Korea compared to Asians born in the United States and US born Caucasians. AB - BACKGROUND: The vascular endothelium is the interface between the blood and vascular smooth muscle in arteries. It is easily damaged by oxidative stress. Recent studies show that Asians are more susceptible than Caucasians to impairment of endothelial function. This study examined endothelial function in US-born Caucasians, Asians from Korea, and US-born Asians (almost all Korean decent) and examined the effect of coenzyme Q10 (CoQ10) on endothelial function. MATERIAL AND METHODS: Twenty Caucasians and 30 Asians participated (<35 years old, males and females). Endothelial function was assessed by the skin blood flow response to local heat using a thermode for 6 minutes at 44 degrees C and by vascular occlusion for 4 minutes followed by release and measurement of skin blood flow for 2 minutes. In the US-born subjects, the experiments were repeated after 2-week administration of CoQ10 or a placebo. RESULTS: When applying 6 minutes of local heat at 44 degrees C, the skin blood flows were significantly higher in Caucasians than both Asian groups Asians. Likewise after vascular occlusion, the blood flow response was greater in Caucasians compared to Asians. Asians born in Asia had the lowest response of the 3 groups of subjects. Administering CoQ10 for 2 weeks eliminated much of the difference between the groups, whereas there was no difference with a placebo. CONCLUSIONS: These findings suggest that Asians either born in Asia or the US may have lower endothelial function than Caucasians. This may be explained, in part, by genetic variations causing increased oxidative stress from westernized diets in Asians. Co enzyme Q10 administration narrows the difference between the groups. PMID- 23666275 TI - Comparison of effects of epidural bupivacaine and intravenous meperidine analgesia on patient recovery following elective abdominal aortic surgery. AB - BACKGROUND: The efficacy of epidural anesthesia and analgesia in management of perioperative stress has been established. Perioperative pain management strategies decrease surgical complications and aid recovery. In this study, we aimed to document and compare the efficacy of epidural bupivacaine and intravenous meperidine on recovery of patients with elective abdominal aortic surgery performed under general anesthesia. MATERIAL AND METHODS: Patients undergoing elective abdominal aortic surgery between February 2009 and November 2011 were studied prospectively. Patients were randomized into epidural bupivacaine (n=40) and intravenous meperidine (n=40) groups regarding postoperative analgesia strategy. The preoperative demographic characteristics, perioperative outcomes, postoperative adverse effects of analgesia strategy, time to initiate oral intake, sedation scores, visual analogue scale results, and mobility scores were compared. RESULTS: The mean ages of the patients were 61.7+/ 8.1 in the epidural group and 59.4+/-9.7 in the intravenous group (p>0.05). The preoperative demographic characteristics of the patients were comparable between the groups. There were no statistically significant differences between groups regarding anesthesia times, intubation times, intensive care unit stay, hospital length of stay, postoperative vomiting, and postoperative cardiac, renal, and cerebral complications. Postoperative nausea was more prevalent in the meperidine group (p<0.05). In the epidural group, time to begin oral intake was shorter, sedation scores and visual analogue scale results were lower, and mobility scores were higher (p<0.05 each). CONCLUSIONS: Epidural analgesia allowed earlier recovery compared to intravenous analgesia in patients undergoing elective abdominal aortic surgery, but did not affect postoperative outcomes and complications. PMID- 23666278 TI - [Interdisciplinary dialogue on the etiology and prevention of suicide in Quebec]. PMID- 23666279 TI - [Epigenetic: a link between environment and genome]. AB - Adversity during childhood has for long been known to increase the risk of developing mental health problems in adulthood. Yet, it is only recently that epigenetic mechanisms have been identified as representing an interface on which the environment acts upon to induce behavioral changes. These changes affecting the expression of certain genes, without however modifying DNA sequences, particularly interfere with the functioning of systems regulating response to stress. In the long term, adversity during childhood, by inducing these epigenetic changes, predisposes some individuals in developing mental health problems in adulthood. This article examines the epigenetic impact of adversity during childhood and its behavioral consequences on mental health. PMID- 23666277 TI - Replication and fine mapping of asthma-associated loci in individuals of African ancestry. AB - Asthma originates from genetic and environmental factors with about half the risk of disease attributable to heritable causes. Genome-wide association studies, mostly in populations of European ancestry, have identified numerous asthma associated single nucleotide polymorphisms (SNPs). Studies in populations with diverse ancestries allow both for identification of robust associations that replicate across ethnic groups and for improved resolution of associated loci due to different patterns of linkage disequilibrium between ethnic groups. Here we report on an analysis of 745 African-American subjects with asthma and 3,238 African-American control subjects from the Candidate Gene Association Resource (CARe) Consortium, including analysis of SNPs imputed using 1,000 Genomes reference panels and adjustment for local ancestry. We show strong evidence that variation near RAD50/IL13, implicated in studies of European ancestry individuals, replicates in individuals largely of African ancestry. Fine mapping in African ancestry populations also refined the variants of interest for this association. We also provide strong or nominal evidence of replication at loci near ORMDL3/GSDMB, IL1RL1/IL18R1, and 10p14, all previously associated with asthma in European or Japanese populations, but not at the PYHIN1 locus previously reported in studies of African-American samples. These results improve the understanding of asthma genetics and further demonstrate the utility of genetic studies in populations other than those of largely European ancestry. PMID- 23666280 TI - [The sociology of gender: an original perspective for a better understanding of suicide in men]. AB - There is a general consensus that suicide is a social problem. But what exactly is the contribution of sociology to research on suicide? This paper proposes a brief overview of the historical bases of the sociology of suicide and its evolution through the study of deviance and exclusion. On the level of application, the sociology of gender contributed to better understand how some aspects of male socialisation, such as the rigid relations with norms of the male role, may act as suicide risk factors or as a path to recovery. PMID- 23666281 TI - [What can microscopy teach us on suicide?]. AB - The fine neuroanatomy of mood disorders and suicide is a relatively recent field of investigation. Together with neuroimaging, molecular biology and biochemistry, histological analyses of post-mortem brain regions implicated in mood regulation allow gaining a better understanding of the cellular and molecular mechanisms underlying major depression and suicide. In this article, the author discusses recent studies conducted in his laboratory on the fine neuroanatomy of the anterior cingular cortex (ACC). In particular, he presents data showing that ACC white matter fibrous astrocytes are hypertrophic in depressed suicides compared to matched sudden-death controls. These data are interpreted in the context of the neuroimmune hypothesis of major depression and suicide. PMID- 23666282 TI - [Suicide and nutrition: a bio-psychosocial approach]. AB - This article proposes a new bio-psychosocial perspective on the links between mental health, more specifically suicide, and nutrition. We first discuss the links between nutrition, its social role and suicide. The act of eating is studied as a social integrator and regulator, in the light of Durkheim's theorization. Nutrition is also examined as self-destruction, with particular cases of "diet-related suicide." De-structuring of meals and alienating foods are identified as contributing factors to the de-structuring of "nutrition models." We then discuss the place of food within the psychopathology, and finally, the links between biological parameters reflected in food and suicide risk. Avenues of research and intervention along this bio-psychosocial approach are also proposed. PMID- 23666283 TI - [The contribution of research in psychology in the complex comprehension of the etiology of suicide]. AB - If certain risk factors are known to increase suicidal behaviors, the question is to determine the differential weight of these various risk factors, on which individuals, in which context and in what period of their lives? We have put to test a model that explains different life trajectories leading to suicide. This research allows to surpass a correlation model of identification of risk factors and to target four distinct sub-groups of individuals for whom the developmental history seems quite different. It is clear that suicide is a complex, multidimensional and multilevel issue. Being at the crossroads of many scientific disciplines, psychology may help integrate and connect knowledge with other disciplines in order to clarify the contexts that affect suicidal individuals differently. This knowledge may help in identifying specific prevention interventions that could modify this chain of events leading ultimately to suicide. PMID- 23666284 TI - [Predicting suicide or predicting the unpredictable in an uncertain world: Reinforcement Learning Model-Based analysis]. AB - In general, it appears that the suicidal act is highly unpredictable with the current scientific means available. In this article, the author submits the hypothesis that predicting suicide is complex because it results in predicting a choice, in itself unpredictable. The article proposes a Reinforcement learning model-based analysis. In this model, we integrate on the one hand, four ascending modulatory neurotransmitter systems (acetylcholine, noradrenalin, serotonin, and dopamine) with their regions of respective projections and afferences, and on the other hand, various observations of brain imaging identified until now in the suicidal process. PMID- 23666285 TI - [Suicidality and musical preferences: a possible link?]. AB - Music is an important part of young people's lives. In this article, we attempt to answer two questions on the links between music et suicide. First, we examine if certain types of music favor suicidal process (ideation and acting out); and, secondly, we examine if music can constitute a tool to reduce the risk of suicide. Several factors possibly involved in links between musical preferences and the suicidal process are developed: the Velten effect and the musical mood induction procedure, the identification and the learning by imitation, the media influence as well as the individual characteristics. A multifactor approach is necessary to understand the complex and birectional links that unite musical preferences and suicide risk. PMID- 23666286 TI - [Suicide in the elderly: age-related specificities?]. AB - Suicide in the elderly raises the question of our relationship with aging and death. Suicide rate is relatively high in this group and is significantly related to depression widely under-diagnosed in the elderly. Suicidal behaviour in the elderly has clinical specificities including high intentionality and lethality, usually little personal history of suicidal behaviour and low levels of impulsivity-aggression. Suicidal vulnerability could rely on etiopathogenic mechanisms both common and different according to age; for example, a preponderance of early developmental factors and impulsivity-aggression in adolescents and young adults vs. pathological aging in older adults, but partly similar neurocognitive deficits leading individuals not to respond adequately to their environment (itself different with age). Direct comparisons between elderly and younger subjects would be required. The article concludes with a summary of the principles of recognition and management of suicide risk. PMID- 23666287 TI - [Suicidal behaviors in adolescents and young adults with Autism Spectrum Disorder (ASD) without intellectual disability]. AB - The Autistic Spectrum Disorders (ASD) are characterized by an atypical sociability, alterations in communication, restricted interests and stereotypies, with adding affective and adaptative disabilities. The suicidal behaviors are frequently observed in the adolescents and adults with an ASD without intellectual deficience. However, the clinical research on the topic is limited and the diagnosis not assessed in the emergency units. Among the individual risk factors of the suicidal behavior in ASD patients, mood and anxiety disorders are found as well as a familial affective disorder history. The intimidation and the lack of socio-professional integration were also reported as environnemental risk factors. Laters tudies taking into account the cognitive characteristics would permit to investigate the suicidal phenomenology in ASD patients. PMID- 23666288 TI - [Adolescents at suicide risk: nursing care they consider helpful]. AB - This qualitative study explores "helpful" nursing care from the perspective of adolescents at risk for suicide. While hospital-based nurses have a high level of direct and continuous contact with suicidal teens, little is known about the nursing care offered to this population. The purpose of this research is to explore the perceptions of suicidal adolescents regarding helpful nursing care during hospital treatment on a mental health unit. Nine patients, aged 15-18 years, participated in individualized, semi-structured interviews. Results affirm the importance of personalized, human caring interactions combined with nurse accompaniment across situations of daily living as well as during acute crisis, illness and suffering. The nurse's role and contribution in creating a therapeutic milieu is described, and the impact of a health-promoting hospital environment on patient care and recovery is highlighted. PMID- 23666289 TI - [Social work: A long tradition of intervention in suicidal crisis]. AB - This article examines the place of social work in identifying intervention in suicide. Divided in three parts, the article describes the paradox of social work regarding suicide, the contributions of social work in the field of research and intervention on suicide and finally, presents an example from a study by the author on depression in men. PMID- 23666290 TI - [Portrait of the use of mental health services before and after a suicide attempt requiring hospitalization]. AB - Health care systems play an important role in suicide prevention. Medical and administrative data allow analysis of patterns of mental health service use before and after hospitalization following a suicide attempt among Montreal residents diagnosed with schizophrenia or depression. Some results tend to show improvement in suicide prevention, especially among men with comorbid substance abuse disorders known to be particularly vulnerable. However, other observations are somewhat worrisome. The emergency room as an introduction to mental health services did not ensure adequate aftercare. Interventions are needed to improve access and coordination between different health care services. PMID- 23666291 TI - [Suicide prevention from a public health perspective]. AB - Suicide and suicide prevention represent major public health challenges. The public health perspective juxtaposes a multifactor understanding of society's health phenomena to a mobilization around determinants on which actions can be taken. Public health has encountered success with infectious diseases as well as chronic diseases such as hypertension. In this article, the phenomenon of suicide is detailed with data drawn from Quebec, Canada and international research. Population-based suicide prevention policies are generally multimodal, and often involve strategies aiming at improving mental health services. The success of these strategies lies in their steady application and in the close surveillance of this application. PMID- 23666292 TI - [In the name of the human being: reflections on suicide within its root causes]. AB - In this article, presented as an anthropological essay on the human condition, the author proposes some thoughts likely to support our reflection on the question of suicide, be it biological, sociological or psychological in nature. The framework suggests an invitation to question ourselves on what is the depth of the human being, the ambiguity that marks us, the inherent contradictions that constitutes us, as we are torn between life and death, between positivity and negativity, and the ideology of the "all positive" that tends to generate a dangerous internalization of the "negative." Suicide in its most diversified forms, from substance abuse of all kind, to chronic depression and self destruction, is thus examined within this fundamental ambiguity which is the mark of our human condition. Experts who attempt to comprehend suicidal behavior are invited to acknowledge our common, always tragic humanity that makes us all human beings. PMID- 23666293 TI - VAMP7 controls T cell activation by regulating the recruitment and phosphorylation of vesicular Lat at TCR-activation sites. AB - The mechanisms by which Lat (a key adaptor in the T cell antigen receptor (TCR) signaling pathway) and the TCR come together after TCR triggering are not well understood. We investigate here the role of SNARE proteins, which are part of protein complexes involved in the docking, priming and fusion of vesicles with opposing membranes, in this process. Here we found, by silencing approaches and genetically modified mice, that the vesicular SNARE VAMP7 was required for the recruitment of Lat-containing vesicles to TCR-activation sites. Our results indicated that this did not involve fusion of Lat-containing vesicles with the plasma membrane. VAMP7, which localized together with Lat on the subsynaptic vesicles, controlled the phosphorylation of Lat, formation of the TCR-Lat signaling complex and, ultimately, activation of T cells. Our findings suggest that the transport and docking of Lat-containing vesicles with target membranes containing TCRs regulates TCR-induced signaling. PMID- 23666294 TI - Targeting of a natural killer cell receptor family by a viral immunoevasin. AB - Activating and inhibitory receptors on natural killer (NK) cells have a crucial role in innate immunity, although the basis of the engagement of activating NK cell receptors is unclear. The activating receptor Ly49H confers resistance to infection with murine cytomegalovirus by binding to the 'immunoevasin' m157. We found that m157 bound to the helical stalk of Ly49H, whereby two m157 monomers engaged the Ly49H dimer. The helical stalks of Ly49H lay centrally across the m157 platform, whereas its lectin domain was not required for recognition. Instead, m157 targeted an 'aromatic peg motif' present in stalks of both activating and inhibitory receptors of the Ly49 family, and substitution of this motif abrogated binding. Furthermore, ligation of m157 to Ly49H or Ly49C resulted in intracellular signaling. Accordingly, m157 has evolved to 'tackle the legs' of a family of NK cell receptors. PMID- 23666295 TI - Epidemiology of atrial fibrillation in Turkey: preliminary results of the multicenter AFTER study. AB - OBJECTIVES: Although atrial fibrillation (AF) is one of the most common rhythm disorders observed in clinical practice, a multicenter epidemiological study has not been conducted in our country. This study aimed to assess our clinical approach to AF based upon the records of the first multicenter prospective Atrial Fibrillation in Turkey: Epidemiologic Registry (AFTER) study. STUDY DESIGN: Taking into consideration the distribution of the population in our country, 2242 consecutive patients with at least one AF attack determined by electrocardiographic examination in 17 different tertiary health care centers were included in the study. Inpatients and patients that were admitted to emergency departments were excluded from the study. Epidemiological data of the patients and the treatment administered were assessed. RESULTS: The mean age of the patients was determined as 66.8 +/- 12.3 years with female patients representing 60% of the study population. While the most common AF type in the Turkish population was non-valvular AF (78%), persistent/permanent AF was determined in 81% of all patients. Hypertension (%67) was the most common co morbidity in patients with AF. While a stroke or transient ischemic attack or history of systemic thromboembolism was detected in 15.3% of the patients, bleeding history was recorded in 11.2%. Also, 50% of the patients were on warfarin treatment and 53% were on aspirin treatment at the time of the study. The effective INR level was detected in 41.3% of the patients. The most frequent cause of not receiving anticoagulant therapy was physician neglect. CONCLUSION: These results demonstrate the necessity for improved quality of physician care of patients with AF, especially with regards to antithrombotic therapy. PMID- 23666297 TI - Standing the test of time: exercise testing for heart failure prognosis in the beta-blocker era. PMID- 23666296 TI - The prognostic value of the cardiopulmonary exercise test in patients with heart failure who have been treated with beta-blockers. AB - OBJECTIVES: The prevalence of chronic heart failure and a reduced ejection fraction (CHF-REF) has increased over the last decade. The cardiopulmonary exercise test (CPET) is an established tool for managing these patients. For patients who are administered beta-blockers, its predictive value is debated. The aim of this study was to assess the prognostic values of several parameters in patients with CHF-REF who were on beta-blockers. STUDY DESIGN: 390 patients with CHF-REF underwent CPET after cardiac rehabilitation and were followed for two years. RESULTS: The primary endpoints were all-cause mortality, cardiac-related mortality and major cardiovascular events (hospitalization for HF, heart transplantation and acute coronary syndrome or arrhythmia). The mean beta blockers dosage was 68.9% of the target dose. The two-year mortality rate was 13%, while the mean age of the population was 57.1 years. In addition, most of the patients were men (85.5% vs. 14.5%). The resting LVEF was 35.7 +/- 9.4 and the maximal oxygen uptake (peak VO2) was 19.5 ml/kg/min. The peak VO2, VE/VCO2 slope and circulatory power were significant predictors of risk. The prognosis was better when the initial linear VE/VCO2 slope was lower than 30, and the final steeper VE/VCO2 slope was lower than 32. There was no difference between the two slopes. The oxygen uptake efficiency slope, oxygen uptake, heart rate recovery, VE/VCO2/VO2 index and ventilatory threshold had no prognostic value. CONCLUSION: The peak VO2, circulatory power and VE/VCO2 slope were prognostic indicators for patients with CHF-REF who were on beta-blockers. PMID- 23666298 TI - Association of epicardial adipose tissue thickness by echocardiography and hypertension. AB - OBJECTIVES: Epicardial adipose tissue (EAT) is a component of visceral adiposity with endocrine and paracrine effects. It is also associated with metabolic syndrome (MetS). In this study, we investigated the relationship between EAT thickness and hypertension that is a component of MetS. STUDY DESIGN: Enrolled in this study were 140 hypertensive patients and 60 age- and sex-similar normotensive controls. EAT thickness was measured using 2-D echocardiography from the parasternal long- and short-axis views. EAT thicknesses were compared between patients with hypertension and controls. The effects of hypertension on EAT thickness were evaluated like other components of MetS. RESULTS: EAT thickness was increased in hypertensive patients compared to normotensive controls (6.3 +/- 1.7 mm vs. 5.3 +/- 1.6 mm; p<0.001). EAT thickness correlated with systolic and diastolic blood pressures (r=0.233, p=0.001; r=0.144, p=0.047, respectively). EAT thickness was further increased in patients with uncontrolled hypertension than in those with controlled hypertension (6.6 +/- 1.7 mm vs. 5.9 +/- 1.8 mm, p=0.046). When linear regression analysis was performed to assess the effect of hypertension on EAT thickness like the other components of MetS, hypertension (p=0.009, 95% CI 0.236-1.619), waist circumference (p=0.003, 95%CI 0.339-1.640), HDL-cholesterol (p=0.046, 95% CI, -0.054 - 0.001) and blood glucose levels (p=0.007, 95% CI, 0.003-0.002) were found to be independent correlates of EAT thickness. CONCLUSION: EAT thickness is associated with hypertension. Hypertension could be contributing factor for the development of EAT thickness like the other components of MetS. PMID- 23666299 TI - Association of neutrophil to lymphocyte ratio with presence of isolated coronary artery ectasia. AB - OBJECTIVES: Coronary artery ectasia (CAE) has been defined as a dilated artery luminal diameter that is at least 50% greater than the diameter of the normal portion of the artery. Isolated CAE is defined as CAE without significant coronary artery stenosis and isolated CAE has more pronounced inflammatory symptoms. Neutrophil to lymphocyte ratio (NLR) is widely used as a marker of inflammation and an indicator of cardiovascular outcomes in patients with coronary artery disease. We examined a possible association between NLR and the presence of isolated CAE. STUDY DESIGN: In this study, 2345 patients who underwent coronary angiography for suspected or known ischemic heart disease were evaluated retrospectively. Following the application of exclusion criteria, our study population consisted of 81 CAE patients and 85 age- and gender-matched subjects who proved to have normal coronary angiograms. Baseline neutrophil, lymphocyte and other hematologic indices were measured routinely prior to the coronary angiography. RESULTS: Patients with angiographic isolated CAE had significantly elevated NLR when compared to the patients with normal coronary artery pathology (3.39 +/- 1.36 vs. 2.25 +/- 0.58, p<0.001). A NLR level >= 2.37 measured on admission had a 77% sensitivity and 63% specificity in predicting isolated CAE at ROC curve analysis. In the multivariate analysis, hypercholesterolemia (OR=2.63, 95% CI 1.22-5.65, p=0.01), obesity (OR=3.76, 95% CI 1.43-9.87, p=0.007) and increased NLR (OR=6.03, 95% CI 2.61-13.94, p<0.001) were independent predictors for the presence of isolated CAE. CONCLUSION: Neutrophil to lymphocyte ratio is a readily available clinical laboratory value that is associated with the presence of isolated CAE. PMID- 23666300 TI - [Cardiac device related infective endocarditis; analysis of 15 cases]. AB - OBJECTIVES: We aimed to investigate the demographic and clinical characteristics, echocardiographic and microbiologic features, and outcomes of patients with permanent pacemaker (PM) and implantable cardioverter-defibrillator (ICD) endocarditis in this study. STUDY DESIGN: The study population consisted of 15 patients with permanent PM and ICD endocarditis. Data on demographics, medications, clinical procedures, microbiology, echocardiography, surgery, and outcome were collected. RESULTS: The mean age of the patients was 57 +/- 16. Seven patients (47%) were female. Of the 15 permanent PM and ICD endocarditis patients, 5 died during hospital follow-up (33%). Four patients (27%) experienced a pulmonary embolism. Culture-negative endocarditis was seen in 5 cases (33%). Staphylococci were the most common causative organisms (60%). Three patients had undergone surgical treatment (20%). CONCLUSION: Cardiac device-related endocarditis remain a rare but potentially fatal complication of device implantation. PMID- 23666301 TI - [Anxiety levels and quality of life assessment in patients that underwent an electrophysiologic study due to unexplained palpitations]. AB - OBJECTIVES: To compare the quality of life and anxiety levels of patients with normal and abnormal results detected during an electrophysiological study (EPS) that was performed due to undocumented palpitations. STUDY DESIGN: Patients (n=128) who underwent EPS without documented arrhythmia of unexplained palpitations were included in the study. The quality of life and anxiety levels of patients with abnormal EPS results were compared with those with normal results by using the 26-item short form of the World Health Organization quality of life scale and state-trait anxiety inventory. RESULTS: SVT was found in 72 patients by diagnostic EPS. Quality of life scores were significantly poorer in the SVT group than of the normal EPS group (p=0.000-0.001). Likewise, the anxiety scores of the patients in the SVT group were higher than normal in the EPS group (p=0.000). Age, physical quality of life, psychological quality of life, state anxiety and trait anxiety were found to be independent predictors of SVT in multivariate regression analysis. CONCLUSION: The level of anxiety was found to be higher and quality of life was found to be lower in patients with palpitations due to SVT. In clinical practice it should be kept in mind that noticed psychiatric symptoms may be secondary to an underlying arrhythmia in the evaluation of patients with palpitations. PMID- 23666302 TI - Obstruction of superior vena cava flow during transcatheter atrial septal defect closure with the Atriasept ASD occluder. AB - In this paper, we describe a patient with a large secundum atrial septal defect ASD (26 mm) with adequate rims that were suitable for percutaneous closure. While closing this ASD, the superior vena cava (SVC) was occluded with the right atrial disc of the Atriasept ASD occluder (Cardia) and thus the device was retrieved before its release. After retrieval of this device, an Amplatzer ASD occluder was successfully implanted without disturbing the caval flow. PMID- 23666303 TI - [Percutaneous closure of the coronary artery-pulmonary artery fistula in a patient with apical hypertrophic cardiomyopathy]. AB - A fifty-four-year-old female patient was admitted to our unit with exertional chest pain of six months duration. Transthoracic echocardiography showed apical hypertrophy. Upon further investigation, cardiac magnetic resonance imaging revealed apical hypertrophic cardiomyopathy. The patient underwent myocardial perfusion scintigraphy which showed anterior ischemia. Coronary angiography revealed an arteriovenous fistula (AVF) from the left anterior descending artery to the pulmonary artery. The patient's chest pain was attributed to a coronary steal syndrome secondary to the coronary AVF. The AVF fistula was closed with a coil and the patient's chest pain improved. In conclusion, coronary steal syndrome may lead to myocardial ischemia in patients with a coronary AVF. PMID- 23666304 TI - [Percutaneous transcatheter atrial septal defect closure with Amplatzer septal occluder device using three different techniques in three adult patients with complex ostium secundum type atrial defects]. AB - Complex ostium secundum type atrial septal defect (ASD) is a definition used for large (stretched diameter over 26 mm with deficient rim) or multiple ASDs or multi-fenestrated septum or ASDs with redundant and aneurysmal septal rims. Compared to simple defects, transcatheter ASD closure with Amplatzer septal occluder (ASO) is relatively challenging in these cases, and different techniques have been defined to increase procedure success. We report three adult patients with complex ostium secundum type ASDs that were closed with ASO device using three different techniques. The first case was a 36-year-old female patient with complaints of dyspnea, palpitation and fatigue. A complex ostium secundum type ASD was diagnosed, and the defect was closed with a 36 mm ASO device using a left upper pulmonary vein technique. The second case was a 47-year-old female patient with complaints of dyspnea and palpitation. A large and complex ASD was detected, and the defect was closed with a 28 mm device using a left atrial roof technique supported by non-inflated balloon. The third case was a 40-year-old female patient who presented with complaints of dyspnea and palpitation. Complex ASD was diagnosed, and the defect was closed with a 32 mm device using a partially inflated balloon technique. In large and complex ASDs, the classical implantation technique of an ASO device may fail at any time. The knowledge and application of different techniques that orient the left atrial disc parallel to the septum may increase the procedure success and decrease complications. PMID- 23666305 TI - Cardiac metastasis of renal cell carcinoma without inferior vena cava involvement: case report. AB - We report the case of a 51-year-old man with advanced renal cell carcinoma (RCC), without inferior vena cava (IVC) involvement, who was treated with chemotherapy. Computed tomography of the thorax and abdomen revealed metastatic invasion of the liver, mediastinal lymph nodes, right adrenal gland, and the head of pancreas. Heart involvement via the IVC is a well-known pattern of metastasis during RCC progression. There are very few cases worldwide that have reported RCC with cardiac metastasis without IVC involvement. PMID- 23666306 TI - Chronic pericardial effusion secondary to a influenza virus A (H1N1)/2009 infection. AB - We report, to our knowledge, the first successful treatment of novel Influenza A (H1N1)/2009 chronic pericardial effusion in an adult. This patient presented on admission respiratory failure and cardiac tamponade which required non invasive ventilation and drainage. Pericardial fluid polymerase chain reaction sequences were positive for Influenza A (H1N1)/2009 virus. Any other etiologies were discarded. Recidivating pericardial effusion after medical treatment, firstly with Oseltamivir, and afterwards, with colchicine and corticosteroids during six months, was solved with pericardiectomy. PMID- 23666307 TI - Balloon valvuloplasty for critical aortic stenosis in a fetus: a case report. AB - The mortality and morbidity of fetal aortic stenosis (AS) depend on the degree of the hemodynamic effects of the stenosis, and left ventricular (LV) adaptation, development and function during fetal life. In the case of critical AS, the development of hydrops and death in utero are well recognized entities. A 23-week gestation fetus was diagnosed with critical severe AS, cardiomegaly, a dilated LV with very poor contractility, and mitral regurgitation. There was a reversal of flow in the aortic arch through the ductus arteriosis and a reversed a-wave in the ductus venosus on Doppler examination. The fetus had hydrops with ascites, and massive scalp, face and skin edema. Fetal amniocentesis was normal. Aortic valvuloplasty was performed under general anesthesia and echocardiographic guidance. Pericardial effusion was not observed after the procedure. However, LV function could not be ameliorated and continued to diminish. There was no cardiac activity in the fetus two hours after the intervention. Aortic valvuloplasty in utero for AS is technically feasible. Mortality is mainly associated with technical errors, LV function, and the degree of endofibroelastosis in the effected fetuses. PMID- 23666308 TI - [Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents]. AB - The novel oral P2Y12 inhibitors (prasugrel and ticagrelor) have been incorporated into the recently updated acute coronary syndrome (ACS) guidelines, as an adjunct antiplatelet treatment to aspirin. The studies involving the use of new oral antiplatelet agents that are more potent, predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint (cardiovascular death, non-lethal myocardial infarction, stroke) for both prasugrel and ticagrelor compared to clopidogrel. The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups: (1) Mortality was reduced with ticagrelor; (2) Ticagrelor is especially more effective in intermediate-and high-risk non-ST elevation ACS patients in whom early invasive strategy is selected; (3) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention (PCI) after diagnostic angiography; and (4) Prasugrel is more effective in diabetic patients. While clopidogrel is recommended for ACS patients who are followed with a non-invasive strategy or who have not undergone percutaneous revascularization, it is the last line choice or an alternative to the P2Y12 inhibitor therapy for patients undergoing invasive strategy. PMID- 23666309 TI - [How temporary pacemaker electrode is implanted without using fluoroscopy?]. PMID- 23666310 TI - [Chronic left anterior descending artery occlusion due to giant left main coronary artery aneurysm thrombosis in a young patient with a history of Kawasaki disease]. PMID- 23666311 TI - Multiple coronary artery-pulmonary artery fistulas presenting with cardiac arrest. PMID- 23666312 TI - Giant pseudoaneurysm caused by left ventricle free-wall rupture leading left to right shunting: a rare case. PMID- 23666313 TI - Mitral valve Libman-Sacks endocarditis evaluated by two and three-dimensional transesophageal echocardiography. PMID- 23666314 TI - Porcelain thoracic aorta in a patient with rheumatoid arthritis. PMID- 23666315 TI - Theoretical spectroscopy using molecular dynamics: theory and application to CH5(+) and its isotopologues. AB - Infrared spectroscopy is a powerful technique to unravel the structure and dynamics of molecular systems of ever increasing complexity. For isolated molecules in the gas phase theoretical approaches that directly rely on solving the Schrodinger equation, either approximately or quasi-exactly, are well established. A distinctly different approach to compute infrared spectra can be based on advanced molecular dynamics, itself being based on classical Newtonian dynamics, in conjunction with concurrent first principles electronic structure calculations. At variance with traditional methods, which are formulated in terms of the Schrodinger representation of quantum mechanics, the molecular dynamics approach stems from Heisenberg's representation and thus relies on computing thermal expectation values of time-correlation functions. Crucial in addition to generating the spectra themselves is their decomposition in terms of modes, which can be assigned to correlated atomic motion. This ab initio molecular dynamics route to compute infrared spectra, and its recent extension to quasiclassical techniques relying on approximate path integral dynamics, is covered in the review part of this Perspective. The usefulness of this unconventional approach, which can be generalized beyond infrared spectroscopy, is demonstrated in detail by applying the full machinery in computing and assigning the infrared spectra of protonated methane and its isotopologues. This particular molecule is often considered to be the most prominent member of the class of floppy or fluxional molecules. CH5(+) has been a longstanding challenge for theoretical infrared spectroscopy because it undergoes intricate large-amplitude motion, which is also reviewed. Molecular dynamics based infrared spectroscopy is general and can be applied to diverse systems such as molecular complexes in the gas phase, chromophores in biomolecular environments, and solute-solvent systems in the liquid phase. PMID- 23666316 TI - Induction of response with etanercept-methotrexate therapy in patients with moderately active rheumatoid arthritis in Central and Eastern Europe in the PRESERVE study. AB - Biologics have mainly been assessed in patients with severe rheumatoid arthritis (RA) globally. Less attention has been paid to moderately active disease, especially in Central and Eastern Europe (CEE). Access to biologics and the disease features of RA patients may differ in CEE, relative to other regions. We assessed the clinical and patient-reported outcomes (PROs) of treatment from CEE patients in the multinational PRESERVE study ( NCT00565409 ). Patients with moderate RA 28-joint disease activity score ((DAS28) erythrocyte sedimentation rate (ESR) >3.2 and <=5.1) despite methotrexate (MTX) treatment received open label etanercept (ETN) 50 mg QW + MTX for 36 weeks. Low disease activity (DAS28 low disease activity (LDA) <=3.2) and remission (DAS28 ESR <2.6) were assessed. PROs included Health Assessment Questionnaire Disability Index (HAQ-DI), patient global assessment (PGA), EuroQol-5 Dimension (EQ-5D), pain visual analogue scale (VAS), Medical Outcomes Study sleep questionnaire (MOS Sleep), Functional Assessment of Chronic Illness Therapy (FACIT), and Work Productivity and Activity Impairment for RA (WPAI-RA). Descriptive summary statistics were employed. Of the 834 enrolled patients, 302 were from CEE. At baseline, CEE patients had similar disease states versus the overall population. By week 36, LDA was achieved by 87 %, remission by 67 %, and normal HAQ-DI (<=0.5) by 53 % of patients. Mean scores (SDs) for PROs significantly improved by week 36 as follows: HAQ-DI total by -0.6 (0.5); PGA by -2.4 (2.1); EQ-5D total index by 0.2 (0.2). Pain VAS, MOS Sleep, FACIT, and WPAI-RA also showed significant improvements. In conclusion, induction therapy with ETN + MTX led to DAS28 LDA, remission, and improvements in PROs in most CEE patients with moderately active RA despite treatment with MTX. These results are similar to the overall study population in the PRESERVE trial. PMID- 23666317 TI - Severe Guillain-Barre syndrome in a patient receiving anti-TNF therapy. Consequence or coincidence. A case-based review. AB - The adverse effects of anti-tumour necrosis factor alpha (TNFalpha) drugs include an increase in the risk of infections, congestive heart failure, lupus-like syndrome, and the onset or worsening of various demyelinating diseases such as, multiple sclerosis, optic neuritis, and Guillain-Barre syndrome (GBS), among others. We describe the case of a patient who developed GBS while she was on treatment with adalimumab. A 50-year-old woman with rheumatoid arthritis (RA) was admitted to the hospital due to progressive severe bilateral symmetric weakness of the legs, which quickly extended to the upper limbs and to the respiratory muscles. Adalimumab was started 13 months before. GBS was diagnosed and the anti TNFalpha therapy discontinued. The serological test for Campylobacter jejuni was positive. She required invasive mechanical ventilatory support for 9 months. Twelve months later, the patient was using a wheelchair following a rehabilitation programme, and at 24 months she was walking a few steps with assistive devices. The relevant literature on the relationship between GBS and anti-TNFalpha is reviewed. Twenty three cases of GBS occurring during anti TNFalpha therapy have been reported so far in the literature. In several cases, there was no clear temporal association, more than half had a possible previous infection, and in two cases the drug was reintroduced without recurrence of GBS. Our case, which is best explained by C. jejuni infection, as well as some of the cases described are probably not a direct result of anti-TNFalpha treatment, but an accidental coincidence. We also discuss the potential therapeutic options after anti-TNFalpha discontinuation. PMID- 23666318 TI - Chinese herbal medicine for gout: a systematic review of randomized clinical trials. AB - Patients with gout referring to Chinese herbal medicine are not rare in China, and a great number of clinical trials on herbal medicine have been published. However, there has not been a systematic review to summarize the evidence of Chinese herbal medicine for gout. The aim of this study is to evaluate the evidence for the effectiveness and safety of Chinese herbal medicine for gout. We searched for randomized clinical trials on Chinese herbal medicine for gout till December 2012. Cochrane risk of bias tool was used to assess the methodological quality. RevMan 5.2 was used to synthesize the results. We included 57 trials involving 4,527 gout patients. The quality of trials was generally poor. No trial reported health-related quality of life in patients. There is not enough evidence showing that herbal medicine was statistically more effective than conventional medications in pain relief [mean difference (MD), -0.03; 95% confidence interval (CI), -0.06, 0.00], but herbal medicine combined with conventional medicines may have better effectiveness (MD, -0.33; 95% CI, -0.59, -0.07). Trials that reported function limitation relief found herbal medicine more effective than conventional medications (MD, -0.23; 95% CI, -0.32, -0.15). There was no evidence showing that herbal medicine prevents gout recurrence better. Twenty-five out of 41 trials, involving 23 different herbal prescriptions, found statistical significance in lowering serum uric acid level, and the overall effect from Chinese herbal medicine in inflammation relief is better than conventional therapies in 19 trials with 17 different prescriptions. The current data show that herbal medicine leads to fewer side reactions compared to conventional therapies [risk ratio (RR), 0.11; 95% CI, 0.08 to 0.15]. Chinese herbal medicine may have clinical effectiveness for functional recovery in patients with gout, and lead to a safe control of serum uric acid level and inflammation severity. Due to low quality of trials, trials with higher methodological quality and less heterogeneity are needed in the future. PMID- 23666319 TI - Frequency and specificity of antibodies against nuclear and cytoplasmic antigens in healthy individuals by classic and new methods. PMID- 23666320 TI - Pulmonary and latent tuberculosis screening in opiate drug users: an essential and neglected approach for harm-reduction facilities. AB - OBJECTIVES: Opiates drug users are at much higher risk of developing tuberculosis (TB) infection than general population. We conducted this study to determine the susceptibility for pulmonary and latent TB infection in opiates drug users. METHODS: In this cross-sectional study, all opiates drug users referred to drop in centers, methadone maintenance clinics, and harm-reduction facilities affiliated with Shiraz University of Medical Sciences in southern Iran were screened for pulmonary and latent TB infection. RESULTS: The participation rate of opiate drug users was 87.66% (263 of 300). Mean age was 37.37 +/- 8.33 (range, 20-65) years. Two hundred twenty-six (85.93%) were male and 197 (74.90%) were injection drug users (IDUs). One hundred sixty-three (61.97%) had TB-related symptoms. Culture for TB was positive in 3 patients (1.14%) (2 non-IDUs and 1 IDU). Two patients (0.76%) showed acid-fast bacilli in the direct sputum smear. Eighty-five of 244 patients (34.83%) had a 5- to 10-mm induration in the skin TB test. Twenty-nine of 223 patients (13%) had abnormal findings from chest x-ray films. CONCLUSIONS: The prevalence of smear-positive pulmonary TB in opiate drug users is more than 100 times in the general population in Iran. Therefore, active and appropriate screening to detect pulmonary TB infection should be integrated into routine activities at all harm-reduction facilities for drug users, irrespective of their route of drug use or human immunodeficiency virus status, in this country. PMID- 23666321 TI - Lifestyle and depressive risk factors associated with problematic internet use in adolescents in an Arabian Gulf culture. AB - BACKGROUND: The use of the Internet has increased around the world but more so in the Middle Eastern countries, particularly in the Arabian Gulf region. This has also produced problematic Internet use (PIU) with potential detrimental effects on physical, mental, and psychosocial health. AIM: To determine the prevalence of PIU and its association with Beck Depression Inventory (BDI), comorbid, and lifestyle factors among adolescent and young adult (12- to 25-year-old) Qatari population. DESIGN: A cross-sectional survey. SETTING: All public and private schools and university under the Supreme Council of Education and Higher Education in Doha, Qatar. SUBJECTS AND METHODS: A total of 3000 students (12-25 years of age) were selected through multistage stratified random sampling from public and private schools and university under the overall administration of Qatar Supreme Council of Education. Among them, 2298 students (76.6%) consented to participate in the study during September 2009 to October 2010. Data were collected using a structured questionnaire including sociodemographic details, lifestyle, and dietary habits. Problematic Internet use and depressive tendencies were measured through validated Internet Addiction Test (IAT) and BDI. RESULTS: Of 2298, 71.6% were males and 28.4% were females. The overall prevalence of PIU was 17.6%. This study revealed that a significantly larger proportion of males (64.4%; P = 0.001) and Qatari students (62.9%; P < 0.001) had PIU. Students with PIU slept significantly less number of hours (6.43 +/- 1.70) than non-PIU group (6.6 +/- 1.80; P = 0.027). The proportion of students participating in moderate physical activity was significantly lower among those with PIU than in other group (47.8% vs 55.7%; P = 0.005). Qatari nationality (odds ratio [OR] = 1.82; P < 0.001), male sex (OR = 1.40; P < 0.001), having nonworking mother (housewife) (OR = 1.34; P = 0.009), eating fast foods (OR = 1.57; P < 0.001), and BDI score (OR = 1.14; P = 0.003) were positively associated with PIU, whereas moderate and mild physical activity were negatively associated with PIU (OR = 0.73, P = 0.002; OR, 0.77, P = 0.003, respectively). CONCLUSIONS: This study adds to the growing body of evidence linking PIU with negative lifestyle and depressive risk factors, among vulnerable adolescent and young adult. Problematic Internet use is becoming a significant public health issue that requires urgent attention. PMID- 23666322 TI - Interactions between alcohol and the antiretroviral medications ritonavir or efavirenz. AB - OBJECTIVE: Alcohol abuse occurs frequently in those with human immunodeficiency virus (HIV) infection. Alcohol has been linked to poor response to HIV treatment and more rapid progression of HIV. One possible contributor to such observations is drug interactions between alcohol and antiretroviral (ARV) medications. This study examined drug interactions between antiretroviral therapies (ARTs) containing either efavirenz or ritonavir with alcohol. METHODS: Human immunodeficiency virus-infected individuals not currently receiving ARTs participated in a randomized, double-blind, placebo-controlled study in which alcohol (or placebo) was administered and followed by blood sampling for pharmacokinetics, subjective, cardiovascular, and neuropsychological responses obtained at predetermined times. Antiretroviral therapy was then initiated and alcohol (or placebo) sessions were repeated after at least 2 weeks of observed ART. RESULTS: Blood alcohol concentrations (BAC) were lower after ART in a pattern consistent with decreased bioavailability. No effect of alcohol on ritonavir or efavirenz pharmacokinetics was observed. A pharmacodynamic interaction between alcohol and efavirenz was observed as evidenced by no change in intoxication or drowsiness before and after efavirenz ART despite lower BAC. CONCLUSIONS: These results show the effectiveness of implementing ART and its role in diminution of BAC, which could be associated with decreased risk of physiological toxicities related to alcohol consumption relative to those with untreated HIV infection. A potential pharmacodynamic interaction between alcohol and efavirenz was observed as demonstrated by a lack of decline in ratings of intoxication and drowsiness despite decreased BAC. Alcohol consumption did not alter the pharmacokinetics of ritonavir or efavirenz. PMID- 23666323 TI - Potentiation effect of metolachlor on toxicity of organochlorine and organophosphate insecticides in earthworm Eisenia andrei. AB - Acetylcholinesterase, glutathione-S-transferase and catalase activities were determined in earthworms Eisenia andrei exposed to insecticides (endosulfan, temephos, malathion, pirimiphos-methyl) alone and in a binary combination with the herbicide metolachlor. Metolachlor individually was not acutely toxic, even at high concentrations applied; however, in the treated earthworms metolachlor enhanced the toxicity of endosulfan and temephos by significantly reducing the acetylcholinesterase activity. In binary combination with malathion and pirimiphos-methyl, metolachlor did not increase toxicity. The potentiation character of metolachlor is specific rather than general, and probably depends on the chemical structure of pesticides in the mixture. PMID- 23666324 TI - An assessment of heavy metal bioaccumulation in Asian swamp eel, Monopterus albus, during plowing stages of a paddy cycle. AB - Livers and muscles of swamp eels (Monopterus albus) were analyzed for bioaccumulation of heavy metals during the plowing stage of a paddy cycle. Results showed heavy metals were bioaccumulated more highly in liver than muscle. Zinc (Zn) was the highest bioaccumulated metal in liver (98.5 +/- 8.95 MUg/g) and in muscle (48.8 +/- 7.17 MUg/g). The lowest bioaccumulated metals were cadmium (Cd) in liver (3.44 +/- 2.42 MUg/g) and copper (Cu) in muscle (0.65 +/- 0.20 MUg/g). In sediments, Zn was present at the highest mean concentration (52.7 +/- 2.85 MUg/g), while Cd had the lowest mean concentration (1.04 +/- 0.24 MUg/g). The biota-sediment accumulation factor (BSAF) for Cu, Zn, Cd and nickel (Ni) in liver tissue was greater than the corresponding BSAF for muscle tissue. For the three plowing stages, metal concentrations were significantly correlated between liver and muscle tissues in all cases, and between sediment and either liver or muscle in most cases. Mean measured metal concentrations in muscle tissue were below the maximum permissible limits established by Malaysian and U.S. governmental agencies, and were therefore regarded as safe for human consumption. PMID- 23666325 TI - Arsenic bioremediation by biogenic iron oxides and sulfides. AB - Microcosms containing sediment from an aquifer in Cambodia with naturally elevated levels of arsenic in the associated groundwater were used to evaluate the effectiveness of microbially mediated production of iron minerals for in situ As remediation. The microcosms were first incubated without amendments for 28 days, and the release of As and other geogenic chemicals from the sediments into the aqueous phase was monitored. Nitrate or a mixture of sulfate and lactate was then added to stimulate biological Fe(II) oxidation or sulfate reduction, respectively. Without treatment, soluble As concentrations reached 3.9 +/- 0.9 MUM at the end of the 143-day experiment. However, in the nitrate- and sulfate plus-lactate-amended microcosms, soluble As levels decreased to 0.01 and 0.41 +/- 0.13 MUM, respectively, by the end of the experiment. Analyses using a range of biogeochemical and mineralogical tools indicated that sorption onto freshly formed hydrous ferric oxide (HFO) and iron sulfide mineral phases are the likely mechanisms for As removal in the respective treatments. Incorporation of the experimental results into a one-dimensional transport-reaction model suggests that, under conditions representative of the Cambodian aquifer, the in situ precipitation of HFO would be effective in bringing groundwater into compliance with the World Health Organization (WHO) provisional guideline value for As (10 ppb or 0.13 MUM), although soluble Mn release accompanying microbial Fe(II) oxidation presents a potential health concern. In contrast, production of biogenic iron sulfide minerals would not remediate the groundwater As concentration below the recommended WHO limit. PMID- 23666326 TI - Garvicin A, a novel class IId bacteriocin from Lactococcus garvieae that inhibits septum formation in L. garvieae strains. AB - Lactococcus garvieae 21881, isolated in a human clinical case, produces a novel class IId bacteriocin, garvicin A (GarA), which is specifically active against other L. garvieae strains, including fish- and bovine-pathogenic isolates. Purification from active supernatants, sequence analyses, and plasmid-curing experiments identified pGL5, one of the five plasmids found in L. garvieae [M. Aguado-Urda et al., PLoS One 7(6):e40119, 2012], as the coding plasmid for the structural gene of GarA (lgnA), its putative immunity protein (lgnI), and the ABC transporter and its accessory protein (lgnC and lgnD). Interestingly, pGL5-cured strains were still resistant to GarA. Other putative bacteriocins encoded by the remaining plasmids were not detected during purification, pointing to GarA as the main inhibitor secreted by L. garvieae 21881. Mode-of-action studies revealed a potent bactericidal activity of GarA. Moreover, transmission microscopy showed that GarA seems to act by inhibiting septum formation in L. garvieae cells. This potent and species-specific inhibition by GarA holds promise for applications in the prevention or treatment of infections caused by pathogenic strains of L. garvieae in both veterinary and clinical settings. PMID- 23666327 TI - Use of agent-based modeling to explore the mechanisms of intracellular phosphorus heterogeneity in cultured phytoplankton. AB - There can be significant intraspecific individual-level heterogeneity in the intracellular P of phytoplankton, which can affect the population-level growth rate. Several mechanisms can create this heterogeneity, including phenotypic variability in various physiological functions (e.g., nutrient uptake rate). Here, we use modeling to explore the contribution of various mechanisms to the heterogeneity in phytoplankton grown in a laboratory culture. An agent-based model simulates individual cells and their intracellular P. Heterogeneity is introduced by randomizing parameters (e.g., maximum uptake rate) of daughter cells at division. The model was calibrated to observations of the P quota of individual cells of the centric diatom Thalassiosira pseudonana, which were obtained using synchrotron X-ray fluorescence (SXRF). A number of simulations, with individual mechanisms of heterogeneity turned off, then were performed. Comparison of the coefficient of variation (CV) of these and the baseline simulation (i.e., all mechanisms turned on) provides an estimate of the relative contribution of these mechanisms. The results show that the mechanism with the largest contribution to variability is the parameter characterizing the maximum intracellular P, which, when removed, results in a CV of 0.21 compared to a CV of 0.37 with all mechanisms turned on. This suggests that nutrient/element storage capabilities/mechanisms are important determinants of intrapopulation heterogeneity. PMID- 23666328 TI - Occurrence of the transferable copper resistance gene tcrB among fecal enterococci of U.S. feedlot cattle fed copper-supplemented diets. AB - Copper, an essential micronutrient, is supplemented in the diet at elevated levels to reduce morbidity and mortality and to promote growth in feedlot cattle. Gut bacteria exposed to copper can acquire resistance, which among enterococci is conferred by a transferable copper resistance gene (tcrB) borne on a plasmid. The present study was undertaken to investigate whether the feeding of copper at levels sufficient to promote growth increases the prevalence of the tcrB gene among the fecal enterococci of feedlot cattle. The study was performed with 261 crossbred yearling heifers housed in 24 pens, with pens assigned randomly to a 2*2 factorial arrangement of treatments consisting of dietary copper and a commercial linseed meal-based energy protein supplement. A total of 22 isolates, each identified as Enterococcus faecium, were positive for tcrB with an overall prevalence of 3.8% (22/576). The prevalence was higher among the cattle fed diets supplemented with copper (6.9%) compared to normal copper levels (0.7%). The tcrB positive isolates always contained both erm(B) and tet(M) genes. Median copper MICs for tcrB-positive and tcrB-negative enterococci were 22 and 4 mM, respectively. The transferability of the tcrB gene was demonstrated via a filter mating assay. Multilocus variable number tandem repeat analysis revealed a genetically diverse population of enterococci. The finding of a strong association between the copper resistance gene and other antibiotic (tetracycline and tylosin) resistance determinants is significant because enterococci remain potential pathogens and have the propensity to transfer resistance genes to other bacteria in the gut. PMID- 23666329 TI - ProP is required for the survival of desiccated Salmonella enterica serovar typhimurium cells on a stainless steel surface. AB - Consumers trust commercial food production to be safe, and it is important to strive to improve food safety at every level. Several outbreaks of food-borne disease have been caused by Salmonella strains associated with dried food. Currently we do not know the mechanisms used by Salmonella enterica serovar Typhimurium to survive in desiccated environments. The aim of this study was to discover the responses of S. Typhimurium ST4/74 at the transcriptional level to desiccation on a stainless steel surface and to subsequent rehydration. Bacterial cells were dried onto the same steel surfaces used during the production of dry foods, and RNA was recovered for transcriptomic analysis. Subsequently, dried cells were rehydrated and were again used for transcriptomic analysis. A total of 266 genes were differentially expressed under desiccation stress compared with a static broth culture. The osmoprotectant transporters proP, proU, and osmU (STM1491 to STM1494) were highly upregulated by drying. Deletion of any one of these transport systems resulted in a reduction in the long-term viability of S. Typhimurium on a stainless steel food contact surface. The proP gene was critical for survival; proP deletion mutants could not survive desiccation for long periods and were undetectable after 4 weeks. Following rehydration, 138 genes were differentially expressed, with upregulation observed for genes such as proP, proU, and the phosphate transport genes (pstACS). In time, this knowledge should prove valuable for understanding the underlying mechanisms involved in pathogen survival and should lead to improved methods for control to ensure the safety of intermediate- and low-moisture foods. PMID- 23666330 TI - Malonate catabolism does not drive N2 fixation in legume nodules. AB - Malonyl-coenzyme A (CoA) decarboxylase, malonyl-CoA synthetase, and malonate transporter mutants of Rhizobium leguminosarum bv. viciae and trifolii fixed N2 at wild-type rates on pea and clover, respectively. Thus, malonate does not drive N2 fixation in legume nodules. PMID- 23666331 TI - Identification of a new P335 subgroup through molecular analysis of lactococcal phages Q33 and BM13. AB - Lactococcal dairy starter strains are under constant threat from phages in dairy fermentation facilities, especially by members of the so-called 936, P335, and c2 species. Among these three phage groups, members of the P335 species are the most genetically diverse. Here, we present the complete genome sequences of two P335 type phages, Q33 and BM13, isolated in North America and representing a novel lineage within this phage group. The Q33 and BM13 genomes exhibit homology, not only to P335-type, but also to elements of the 936-type phage sequences. The two phage genomes also have close relatedness to phages infecting Enterococcus and Clostridium, a heretofore unknown feature among lactococcal P335 phages. The Q33 and BM13 genomes are organized in functionally related clusters with genes encoding functions such as DNA replication and packaging, morphogenesis, and host cell lysis. Electron micrographic analysis of the two phages highlights the presence of a baseplate more reminiscent of the baseplate of 936 phages than that of the majority of members of the P335 group, with the exception of r1t and LC3. PMID- 23666332 TI - Investigation of the relationship between lactococcal host cell wall polysaccharide genotype and 936 phage receptor binding protein phylogeny. AB - Comparative genomics of 11 lactococcal 936-type phages combined with host range analysis allowed subgrouping of these phage genomes, particularly with respect to their encoded receptor binding proteins. The so-called pellicle or cell wall polysaccharide of Lactococcus lactis, which has been implicated as a host receptor of (certain) 936-type phages, is specified by a large gene cluster, which, among different lactococcal strains, contains highly conserved regions as well as regions of diversity. The regions of diversity within this cluster on the genomes of lactococcal strains MG1363, SK11, IL1403, KF147, CV56, and UC509.9 were used for the development of a multiplex PCR system to identify the pellicle genotype of lactococcal strains used in this study. The resulting comparative analysis revealed an apparent correlation between the pellicle genotype of a given host strain and the host range of tested 936-type phages. Such a correlation would allow prediction of the intrinsic 936-type phage sensitivity of a particular lactococcal strain and substantiates the notion that the lactococcal pellicle polysaccharide represents the receptor for (certain) 936-type phages while also partially explaining the molecular reasons behind the observed narrow host range of such phages. PMID- 23666333 TI - Transkingdom genetic transfer from Escherichia coli to Saccharomyces cerevisiae as a simple gene introduction tool. AB - Transkingdom conjugation (TKC) permits transfer of DNA from bacteria to eukaryotic cells using a bacterial conjugal transfer system. However, it is not clear whether the process of DNA acceptance in a recipient eukaryote is homologous to the process of conjugation between bacteria. TKC transfer requires mobilizable shuttle vectors that are capable of conjugal transfer and replication in the donor and recipient strains. Here, we developed TKC vectors derived from plasmids belonging to the IncP and IncQ groups. We also investigated forms of transfer of these vectors from Escherichia coli into Saccharomyces cerevisiae to develop TKC as a simple gene introduction method. Both types of vectors were transferred precisely, conserving the origin of transfer (oriT) sequences, but IncP-based vectors appeared to be more efficient than an IncQ-based vector. Interestingly, unlike in agrobacterial T-DNA (transfer DNA) transfer, the efficiency of TKC transfer was similar between a wild-type yeast strain and DNA repair mutants defective in homologous recombination (rad51Delta and rad52Delta) or nonhomologous end joining (rad50Delta, yku70Delta, and lig4Delta). Lastly, a shuttle vector with two repeats of IncP-type oriT (oriT(P)) sequences flanking a marker gene was constructed. TKC transfer of this vector resulted in precise excision of both the oriT(P) loci as well as the marker gene, albeit at a low frequency of 17% of all transconjugants. This feature would be attractive in biotechnological applications of TKC. Taken together, these results strongly suggest that in contrast to agrobacterial T-DNA transfer, the circularization of vector single-stranded DNA occurs either before or after transfer but requires a factor(s) from the donor. TKC is a simple method of gene transfer with possible applications in yeast genetics and biotechnology. PMID- 23666334 TI - An MSH4 homolog, stpp1, from Pleurotus pulmonarius is a "silver bullet" for resolving problems caused by spores in cultivated mushrooms. AB - The enormous number of spores produced by fruiting bodies during cultivation of mushrooms can lead to allergic reactions of workers, reduction of commercial value, spread of mushroom disease, pollution of facilities, and depletion of genetic diversity in natural populations. A cultivar harboring a sporulation deficient (sporeless) mutation would be very useful for preventing these problems, but sporeless commercial cultivars are very limited in usefulness because sporeless traits are often linked with traits that are unfavorable for commercial cultivation. Thus, identifying a causal gene of a sporeless phenotype not linked to the adverse traits in breeding and cultivation is crucial for the establishment of sporeless breeding using a strategy employing targeting induced local lesions in genomes (TILLING) in cultivated mushrooms. We used a Pleurotus pulmonarius (Fr.) Quel. sporeless strain to identify and characterize the single recessive gene controlling the mutation. The 3,853-bp stpp1 gene encodes a protein of 854 amino acids and belongs to the MutS homolog (MSH) family associated with mismatch repair in DNA synthesis or recombination in meiosis. Gene expression analysis of the fruiting body showed that this gene is strongly expressed in the gills. Phenotypic analysis of disruptants formed by gene targeting suggested a reproducible sporeless phenotype. Mutants deficient in a functional copy of this gene have no unfavorable traits for sporeless cultivar breeding, so this gene will be an extremely useful target for efficient and versatile sporeless breeding in P. pulmonarius and various other cultivated mushrooms. PMID- 23666335 TI - Characterization of a novel dye-decolorizing peroxidase (DyP)-type enzyme from Irpex lacteus and its application in enzymatic hydrolysis of wheat straw. AB - Irpex lacteus is a white rot basidiomycete proposed for a wide spectrum of biotechnological applications which presents an interesting, but still scarcely known, enzymatic oxidative system. Among these enzymes, the production, purification, and identification of a new dye-decolorizing peroxidase (DyP)-type enzyme, as well as its physico-chemical, spectroscopic, and catalytic properties, are described in the current work. According to its N-terminal sequence and peptide mass fingerprinting analyses, I. lacteus DyP showed high homology (>95%) with the hypothetical (not isolated or characterized) protein cpop21 from an unidentified species of the family Polyporaceae. The enzyme had a low optimal pH, was very stable to acid pH and temperature, and showed improved activity and stability at high H2O2 concentrations compared to other peroxidases. Other attractive features of I. lacteus DyP were its high catalytic efficiency oxidizing the recalcitrant anthraquinone and azo dyes assayed (kcat/Km of 1.6 * 10(6) s(-1) M(-1)) and its ability to oxidize nonphenolic aromatic compounds like veratryl alcohol. In addition, the effect of this DyP during the enzymatic hydrolysis of wheat straw was checked. The results suggest that I. lacteus DyP displayed a synergistic action with cellulases during the hydrolysis of wheat straw, increasing significantly the fermentable glucose recoveries from this substrate. These data show a promising biotechnological potential for this enzyme. PMID- 23666336 TI - Generic Escherichia coli contamination of spinach at the preharvest stage: effects of farm management and environmental factors. AB - The objective of this study was to determine the effects of farm management and environmental factors on preharvest spinach contamination with generic Escherichia coli as an indicator of fecal contamination. A repeated cross sectional study was conducted by visiting spinach farms up to four times per growing season over a period of 2 years (2010 to 2011). Spinach samples (n = 955) were collected from 12 spinach farms in Colorado and Texas as representative states of the Western and Southwestern United States, respectively. During each farm visit, farmers were surveyed about farm-related management and environmental factors using a questionnaire. Associations between the prevalence of generic E. coli in spinach and farm-related factors were assessed by using a multivariable logistic regression model including random effects for farm and farm visit. Overall, 6.6% of spinach samples were positive for generic E. coli. Significant risk factors for spinach contamination with generic E. coli were the proximity (within 10 miles) of a poultry farm, the use of pond water for irrigation, a >66 day period since the planting of spinach, farming on fields previously used for grazing, the production of hay before spinach planting, and the farm location in the Southwestern United States. Contamination with generic E. coli was significantly reduced with an irrigation lapse time of >5 days as well as by several factors related to field workers, including the use of portable toilets, training to use portable toilets, and the use of hand-washing stations. To our knowledge, this is the first report of an association between field workers' personal hygiene and produce contamination with generic E. coli at the preharvest level. Collectively, our findings support that practice of good personal hygiene and other good farm management practices may reduce produce contamination with generic E. coli at the preharvest level. PMID- 23666337 TI - Genetic variability of vancomycin-resistant Enterococcus faecium and Enterococcus faecalis isolates from humans, chickens, and pigs in Malaysia. AB - Vancomycin-resistant enterococci (VRE) have been reported to be present in humans, chickens, and pigs in Malaysia. In the present study, representative samples of VRE isolated from these populations were examined for similarities and differences by using the multilocus sequence typing (MLST) method. Housekeeping genes of Enterococcus faecium (n = 14) and Enterococcus faecalis (n = 11) isolates were sequenced and analyzed using the MLST databases eBURST and goeBURST. We found five sequence types (STs) of E. faecium and six STs of E. faecalis existing in Malaysia. Enterococcus faecium isolates belonging to ST203, ST17, ST55, ST79, and ST29 were identified, and E. faecium ST203 was the most common among humans. The MLST profiles of E. faecium from humans in this study were similar to the globally reported nosocomial-related strain lineage belonging to clonal complex 17 (CC17). Isolates from chickens and pigs have few similarities to those from humans, except for one isolate from a chicken, which was identified as ST203. E. faecalis isolates were more diverse and were identified as ST4, ST6, ST87, ST108, ST274, and ST244, which were grouped as specific to the three hosts. E. faecalis, belonging to the high-risk CC2 and CC87, were detected among isolates from humans. In conclusion, even though one isolate from a chicken was found clonal to that of humans, the MLST analysis of E. faecium and E. faecalis supports the findings of others who suggest VRE to be predominantly host specific and that clinically important strains are found mainly among humans. The infrequent detection of a human VRE clone in a chicken may in fact suggest a reverse transmission of VRE from humans to animals. PMID- 23666338 TI - Environmental dissolved organic matter governs biofilm formation and subsequent linuron degradation activity of a linuron-degrading bacterial consortium. AB - It was examined whether biofilm growth on dissolved organic matter (DOM) of a three-species consortium whose members synergistically degrade the phenylurea herbicide linuron affected the consortium's integrity and subsequent linuron degrading functionality. Citrate as a model DOM and three environmental DOM (eDOM) formulations of different quality were used. Biofilms developed with all DOM formulations, and the three species were retained in the biofilm. However, biofilm biomass, species composition, architecture, and colocalization of member strains depended on DOM and its biodegradability. To assess the linuron-degrading functionality, biofilms were subsequently irrigated with linuron at 10 mg liter( 1) or 100 MUg liter(-1). Instant linuron degradation, the time needed to attain maximal linuron degradation, and hence the total amount of linuron removed depended on both the DOM used for growth and the linuron concentration. At 10 mg liter(-1), the final linuron degradation efficiency was as high as previously observed without DOM except for biofilms fed with humic acids which did not degrade linuron. At 100 MUg liter(-1) linuron, DOM-grown biofilms degraded linuron less efficiently than biofilms receiving 10 mg liter(-1) linuron. The amount of linuron removed was more correlated with biofilm species composition than with biomass or structure. Based on visual observations, colocalization of consortium members in biofilms after the DOM feed appears essential for instant linuron-degrading activity and might explain the differences in overall linuron degradation. The data show that DOM quality determines biofilm structure and composition of the pesticide-degrading consortium in periods with DOM as the main carbon source and can affect subsequent pesticide-degrading activity, especially at micropollutant concentrations. PMID- 23666339 TI - Zirex: a novel zinc-regulated expression system for Lactococcus lactis. AB - Here, we report a new zinc-inducible expression system for Lactococcus lactis, called Zirex, consisting of the pneumococcal repressor SczA and PczcD. PczcD tightly regulates the expression of green fluorescent protein in L. lactis. We show the applicability of Zirex together with the nisin-controlled expression system, enabling simultaneous but independent regulation of different genes. PMID- 23666341 TI - A novel differential mobility analyzer as a VOC detector and multivariate techniques for identification and quantification. AB - A Differential Mobility Analyser (DMA) is a specific configuration of an Ion Mobility Spectrometer (IMS) where ions with different electrical mobilities are separated in space, instead of in time of drift, as in classical drift-time IMS. This work presents results obtained with a parallel plate DMA instrument, with crucial differences in the sheath flow and the detection system when compared to other instruments in the market. These differences improve the resolving powers and sensitivities of the instrument. Additionally, datasets from IMS or DMA instruments are typically processed with univariate techniques when only qualitative detection is of interest. However, good performance in quantitative measurements can be achieved using multivariate data processing. This work presents for the first time, measurements with a stand-alone DMA instrument and the multivariate data processing related to VOCs and environmentally interesting samples. PMID- 23666340 TI - A universally applicable and rapid method for measuring the growth of streptomyces and other filamentous microorganisms by methylene blue adsorption desorption. AB - Quantitative assessment of growth of filamentous microorganisms, such as streptomycetes, is generally restricted to determination of dry weight. Here, we describe a straightforward methylene blue-based sorption assay to monitor microbial growth quantitatively, simply, and rapidly. The assay is equally applicable to unicellular and filamentous bacterial and eukaryotic microorganisms. PMID- 23666342 TI - Skeletal muscle adaptations to physical inactivity and subsequent retraining in young men. AB - Skeletal muscle structure and function are markedly affected by chronic disuse. With unloading, muscle mass is lost at rate of about 0.4 %/day but little is known about the recovery of muscle mass and strength following disuse. Here we report an extensive data set describing in detail skeletal muscle adaptations in structure and function in response to both disuse and retraining. Eight young men (23 +/- 2.2 years) underwent 3 weeks of unilateral lower limb suspension (ULLS) followed by a 3-week resistance training recovery program. Knee extensor isometric torque, voluntary activation, quadriceps femoris (QF) muscle volume (QFvol), fascicle length (Lf) and pennation angle (theta), physiological cross sectional area (PCSA) of all four heads of the QF muscle, were measured before, after ULLS, and post-ULLS-resistance training. Needle biopsies were taken from the vastus lateralis muscle of a subgroup (n = 6) of the same subjects and cross sectional area of individual muscle s and myosin content of muscle samples were determined. Following 3 weeks of ULLS, isometric torque decreased by 26 %, PCSA by 3 %, QFvol by 10 %. Lf and theta of all four heads of QF significantly decreased (p <= 0.05). Following the 3-week retraining period, isometric torque, PCSA, QFvol, Lf and theta of all four heads of QF were all fully restored to pre ULLS values. CSA of individual muscle fibres and myosin content of muscle samples decreased by 26 and 35 % respectively (post-ULLS) and recovered to almost pre ULLS values following retraining. There were no significant changes in voluntary activation of the quadriceps muscles in response to either ULLS or subsequent retraining. These results indicate that: (1) the loss of muscle force with 3-week unloading in humans is mostly explained by muscle atrophy and by a decrease in myosin content and, (2) all the neuromuscular changes induced by this model of disuse can be fully restored after a resistance training intervention of equal duration. PMID- 23666343 TI - Circulating levels of adipokines and IGF-1 are associated with skeletal muscle strength of young and old healthy subjects. AB - It is known that adipose tissue mass increases with age, and that a number of hormones, collectively called adipokines, are produced by adipose tissue. For most of them it is not known whether their plasmatic levels change with age. Moreover, it is known that adipose tissue infiltration in skeletal muscle is related to sarcopenia and loss of muscle strength. In this study we investigated the age-related changes of representative adipokines and insulin-like growth factor (IGF)-1 and their effect on muscle strength. We studied the association between circulating levels of adiponectin, leptin, resistin and IGF-1 and muscle strength. This cross-sectional study included 412 subjects of different age (152 subjects aged 18-30 years and 260 subjects aged 69-81 years) recruited within the framework of the European research network project "Myoage". The levels of adiponectin (both in male and female subjects) and leptin (only in males) were significantly higher in old subjects compared to young, while those of IGF-1 were lower in old subjects. In old subjects adiponectin, resistin and the resistin/IGF 1 ratio (but not IGF-1 alone) were inversely associated with quadriceps torque, while only adiponectin was inversely associated with handgrip strength independently from percentage of fat mass, height, age, gender and geographical origin. The ratio of leptin to adiponectin was directly associated with handgrip strength in both young and old subjects. These results suggest that in humans the age-associated loss of strength is associated with the levels of representative adipokines and IGF-1. PMID- 23666345 TI - Effect of estrogens on base excision repair in brain and liver mitochondria of aged female rats. AB - Changes in the endocrine system have been suggested to act as signaling factors in the regulation of age-related events. Among the different hormones that have been linked to the aging process, estrogens have been widely investigated. They have been associated with inflammatory and oxidative processes and several investigations have established a relationship between the protective effects of estrogens and the mitochondrial function. Mitochondrial DNA is subjected to continuous oxidative attack by free radicals, and the base excision repair (BER) pathway is the main DNA repair route present in mitochondria. We have investigated the effect of estrogen levels on some of the key enzymes of BER in brain and liver mitochondria. In both tissues, depletion of estrogens led to an increased mitochondrial AP endonuclease (mtAPE1) activity, while restoration of estrogen levels by exogenous supplementation resulted in restitution of control APE1 activity only in liver. Moreover, in hepatic mitochondria, changes in estrogen levels affected the processing of oxidative lesions but not deaminations. Our results suggest that changes in mtAPE1 activity are related to specific translocation of the enzyme from the cytosol into the mitochondria probably due to oxidative stress changes as a consequence of changes in estrogen levels. PMID- 23666346 TI - Excited state behavior of pyrrole 2-carboxyldehyde: theoretical and experimental study. AB - Photophysical and photochemical dynamics of excited state proton transfer reaction have been reported for Pyrrole 2-carboxyldehyde (PCL). Experimental and theoretical observations yield all possible signatures of intramolecular and intermolecular proton transfer in an excited state. Dual emission (~325 nm, ~375 nm) on photo excitation indicates the existence of more than one species in an excited state. Computed reaction pathway and two-dimensional potential energy profile in the ground state reveals a single minimum corresponding to normal form (E). Dual minima in excited state energy profile shows the existence of two species, one normal and other zwitterionic (Z*) species. A large Stokes shifted emission at ~375 nm in hydrocarbon medium reveals the existence of zwitterionic species due to Excited state intramolecular proton transfer (ESI(ra)PT). Excited State Intermolecular proton transfer (ESI(er)PT) is observed in a hydroxylic environment around 430-490 nm. pH variation in hydroxylic medium suggests the formation of anion (A((-))) from Z*. PMID- 23666347 TI - A new Schiff base fluorescent probe for imaging Cu2+ in living cells. AB - A novel probe based on ferrocenyl-1,3,4-thiadiazol-containing Schiff base was synthesized by the reaction of 5-ferrocenyl-1,3,4-thiadiazol-2-amine and 4 (diethylamino)salicylaldehyde, and characterized by IR, NMR, HRMS and X-ray analysis. UV-vis spectral and fluorescence property of the probe were investigated. The probe can be used to colorimetric sensitive and selective fluorescent recognition of Cu(2+) in buffer solution. Moreover, the probe can detect Cu(2+) by electrochemical method. Additionally, the Schiff base was successfully used as a selective and sensitive fluorescent probe for monitoring Cu(2+) ions in living cells. PMID- 23666348 TI - Molecular structure and vibrational spectra of N4-acetylcytosine. AB - The infrared and FT-Raman spectra of N4-acetylcytosine in the solid phase have been recorded, and the molecular geometrical parameters were optimized using B3LYP and MP2 methods with 6-311++G(d,p) basis set. The theoretical calculations indicate the presence of four stable conformers of N4-acetylcytosine, and the one containing an intramoleuclar six-membered ring is the most stable. The vibrational wavenumbers, infrared intensities, Raman scattering activities and the corresponding assignments of the observed bands based on the most optimized conformer were performed by B3LYP methods using the aug-cc-pvtz basis set. The observed and calculated frequencies are found to be in good agreement. PMID- 23666349 TI - The solvation dynamics at millisecond scale of Pd(II)-meso-tetra(4 carboxyphenyl)porphine in solid imidazolium-sulfonate-based ionic liquids. AB - The phosphorescence behavior and solvation dynamics of Pd(II)-meso-tetra(4 carboxyphenyl)porphine (Pd-TCPP) in three imidazolium ionic liquids (ILs) has been studied. The phosphorescence excitation and emission position of Pd-TCPP are dependent on the polarity, constituent ions and structure of the ILs. The phosphorescence decay of Pd-TCPP in these ILs is bi-exponential, and the average lifetimes decrease in the following order: 0.844 ms in 1-butylimidazolium p toluenesulfonate (HBIMTS)>0.472 ms in 1-butylimidazolium trifluoromethane sulfonate (HBIMTfO)>0.412 ms in 1-butyl-3-methylimidazolium p-toluenesulfonate (BMIMTS). The time-resolved phosphorescence emission spectra (TRPES) of Pd-TCPP display apparently blue-shifts with increasing time. The normalized Stokes shift correlation functions C(t) of Pd-TCPP in these ILs are mono-exponential, and the solvation relaxation times are 2.97, 47.7 and 12.1 ms in HBIMTfO, HBIMTS and BMIMTS, respectively. The solvation dynamics may be attributed to the collective motion of the ion pairs composed of imidazolium cations and counter anions to the area surrounding Pd-TCPP. PMID- 23666344 TI - Age-dependent alteration in muscle regeneration: the critical role of tissue niche. AB - Although adult skeletal muscle is composed of fully differentiated fibers, it retains the capacity to regenerate in response to injury and to modify its contractile and metabolic properties in response to changing demands. The major role in the growth, remodeling and regeneration is played by satellite cells, a quiescent population of myogenic precursor cells that reside between the basal lamina and plasmalemma and that are rapidly activated in response to appropriate stimuli. However, in pathologic conditions or during aging, the complete regenerative program can be precluded by fibrotic tissue formation and resulting in functional impairment of the skeletal muscle. Our study, along with other studies, demonstrated that although the regenerative program can also be impaired by the limited proliferative capacity of satellite cells, this limit is not reached during normal aging, and it is more likely that the restricted muscle repair program in aging is presumably due to missing signals that usually render the damaged muscle a permissive environment for regenerative activity. PMID- 23666350 TI - Growth, spectral, thermal, dielectric, mechanical, linear and nonlinear optical, birefringence, laser damage threshold studies of semi-organic crystal: dibrucinium sulfate heptahydrate. AB - Dibrucinium sulfate heptahydrate (DBSH), a semi-organic nonlinear optical material, has been synthesized and single crystals were grown from water-ethanol solution at room temperature up to dimensions of 10*7*2 mm(3). The unit cell parameters were determined from single crystal and powder X-ray diffraction studies. The structural perfection of the grown crystal has been analyzed by high resolution X-ray diffraction (HRXRD) study. FTIR and Raman studies were performed to identify the functional groups present in the title compound. The activation energy (E), entropy (DeltaS), enthalpy (DeltaH) and Gibbs free energy (DeltaG), of the thermal decomposition reaction have been derived from thermo gravimetric (TGA) and differential thermal (DTA) analysis curves, using Coats-Redfern method. The variation of dielectric properties of the grown crystal with respect to frequency has been investigated at different temperatures. Microhardness measurements revealed the mechanical strength of grown crystal. The optical parameters, the optical band gap E(g) and width of localized states Eu were determined using the transmittance data in the spectral range 200-800 nm. The relative second harmonic efficiency of the compound is found to be 1.4 times greater than that of KDP. Birefringence and Laser damage threshold studies were carried out for the grown crystal. PMID- 23666351 TI - Vibrational spectroscopic investigations and computational study of 5-chloro-2-[4 (trifluoromethyl)phenylcarbamoyl]phenyl acetate. AB - The optimized molecular structure, vibrational frequencies and corresponding vibrational assignments of 5-Chloro-2-[4-(trifluoromethyl)phenylcarbamoyl]phenyl acetate have been investigated experimentally and theoretically using Gaussian09 software package. Potential energy distribution of the normal modes of the vibrations was done using GAR2PED program. The HOMO and LUMO analysis is used to determine the charge transfer within the molecule. The stability of the molecule arising from hyper conjugative interaction and charge delocalization have been analyzed using NBO analysis. The calculated geometrical parameters are in agreement with that of similar derivatives. The calculated first hyperpolarizability is comparable with the reported values of similar derivatives and is an attractive object for future studies of nonlinear optics. The red shift of the NH stretching wave number in the IR spectrum with a strong intensity from the computed wave number indicates the weakening of the NH bond resulting in proton transfer to the neighboring oxygen. PMID- 23666352 TI - Molecular structure and spectroscopic characterization of ethyl 4-aminobenzoate with experimental techniques and DFT quantum chemical calculations. AB - The FT-IR and FT-Raman spectra of ethyl 4-aminobenzoate (EAB) in the solid phase were recorded. The fundamental vibrational wavenumbers, intensities of vibrational bands and the optimized geometrical parameters of the compound were evaluated using DFT (B3LYP) method with 6-311++G(d,p) basis set. The stable geometry of the compound was determined from the potential energy surface scan. Complete vibrational assignments and Natural Bond Orbital (NBO) analysis for the title compound were carried out. The assignments of the vibrational spectra were carried out with the help of normal co-ordinate analysis (NCA) following the Scaled Quantum Mechanical Force Field (SQMFF) methodology. The molecule orbital contributions were studied by using the total (TDOS), partial (PDOS), and overlap population (OPDOS) density of states. UV-visible spectrum of the compound was recorded and the electronic properties, such as HOMO and LUMO energies were performed by time-dependent DFT (TD-DFT) approach. Mulliken population analysis on atomic charges were also calculated. Besides, molecular electrostatic potential (MEP) and thermodynamic properties were performed. PMID- 23666353 TI - A combined experimental and theoretical (DFT and AIM) studies on synthesis, molecular structure, spectroscopic properties and multiple interactions analysis in a novel ethyl-4-[2-(thiocarbamoyl)hydrazinylidene]-3,5-dimethyl-1H-pyrrole-2 carboxylate and its dimer. AB - In the present work, ethyl-4-[2-(thiocarbamoyl)hydrazinylidene]-3,5-dimethyl-1H pyrrole-2-carboxylate (3) has been synthesized and characterized by (1)H NMR, UV Vis, FT-IR and Mass spectroscopy. The formation of the compound and its properties have also been evaluated by quantum chemical calculations using DFT, B3LYP functional and 6-31G(d,p) as basis set. The calculated thermodynamic parameters show that the formation of 3 is an exothermic and spontaneous reaction at room temperature. (1)H NMR chemical shifts are calculated using gauge including atomic orbitals (GIAO) approach in DMSO-d6 as solvent. Time dependent density functional theory (TD-DFT) is used to calculate the energy (E), oscillator strength (f) and wavelength absorption maxima (lambda(max)) of various electronic transitions and their nature within the molecule. NBO analysis is carried out to investigate the charge transfer or charge delocalization in various intra- and intermolecular interactions of molecular system. The vibrational analysis indicates the formation of dimer in the solid state by intermolecular heteronuclear hydrogen bonding (NH...O). Topological parameters at bond critical points (BCP) are calculated to analyze the strength and nature of various types of intra and intermolecular interactions in dimer by Bader's 'Atoms in molecules' AIM theory in detail. The binding energy of intermolecular multiple interactions is calculated to be 15.54 kcal/mol, using AIM calculation. The local reactivity descriptors such as Fukui functions (f(k)(+),f(k)(-)), local softnesses (s(k)(+),s(k)(-)) and electrophilicity indices (omega(k)(+),omega(k)( )) analyses are performed to determine the reactive sites within molecule. PMID- 23666354 TI - Molecular structure and vibrational spectra studies on antipyrine derivative, 4 (2,3,4-trihydroxybenzylideneamino) antipyrine. AB - The molecular geometry, theoretical harmonic frequencies and infrared intensities of 4-(2,3,4-trihydroxybenzylideneamino) antipyrine (THBAP) were calculated using different density functional methods (LSDA, mPW1PW91, B3LYP and HCTH) with various basic sets, including 3-21G, 6-311G, LanL2DZ, and SDD. The purpose of this research is to compare the performance of different density functional theory (DFT) methods at different basis sets in predicting geometry and vibration spectrum of THBAP. The optimized geometric band lengths and bond angles obtained by using mPW1PW91 at both LanL2DZ and SDD basic sets show the best agreement with the experimental data. A comparison between the observed fundamental vibrational frequencies of THBAP and the calculated results has been made and the result indicates that the mPW1PW91/6-311G level is superior to all the remaining levels for predicting all the vibration spectra on average for THBAP. PMID- 23666355 TI - Enthused research on DNA-binding and DNA-cleavage aptitude of mixed ligand metal complexes. AB - Five new Mn(II), Co(II), Ni(II), Cu(II) and Zn(II) mixed ligand complexes have been synthesized using a Schiff base precursor (obtained by the condensation of N (4-aminophenyl)acetamide and 4-chlorobenzaldehyde) as main ligand and 1,10 phenanthroline as co-ligand. They have been characterized by microanalytical data, IR, UV-Vis, magnetic moment values, conductivity and electrochemical measurements. The spectral data reveal that all the complexes exhibit octahedral geometry. The high electrical conductance of the complexes supports their electrolytic nature. The monomeric nature of the complexes has been assessed from their magnetic susceptibility values. These complexes are better antimicrobial active agents than the free ligands. DNA (CT) binding properties of these complexes have been explored by UV-Vis., viscosity measurements, cyclic voltammetry, and differential pulse voltammetry measurements. The oxidative cleavage activity of the complexes has been studied using supercoiled pUC19 DNA by gel electrophoresis. The experimental results show that the complexes are good intercalators. PMID- 23666356 TI - Spectroscopic studies on H2O2 damaging BSA induced by 1,2-dihydroxy-9, 10 anthraquinone-3-aminomethyl-N, N-diacetate-ferrous(III). AB - The interaction between 1,2-dihydroxy-9, 10-anthraquinone-3-aminomethyl-N, N diacetate-Ferrous(III) (Alizarin-DA-Fe(III)) and bovine serum albumin (BSA) was studied by using UV-vis and fluorescence spectra. And then, the H2O2 damage of BSA induced by Alizarin-DA-Fe(III) was examined. The results show that due to the interaction the fluorescence of BSA solution can be obviously quenched by Alizarin-DA-Fe(III) and that the quenching process belongs to the static quenching. In addition, in the presence of Alizarin-DA-Fe(III) the BSA molecules were markedly damaged by H2O2. Meanwhile, the effects of the standing time, Alizarin-DA-Fe(III) concentration and H2O2 concentration on the damage of BSA molecules were also researched. The experimental results demonstrate that the damage degree increase with the increase of standing time, Alizarin-DA-Fe(III) concentration and H2O2 concentration. Finally, the generation of reactive oxygen species (ROS) from H2O2 induced by Alizarin-DA-Fe(III) as Fenton-like reagent was estimated by some quenchers. Because the Iminodiacetic-Ferrous(III) (IDA-Fe(III)) and Nitrilotriacetic-Ferrous(III) (NTA-Fe(III)) can be thought of as the active part of Alizarin-DA-Fe(III), they were used to compare the catalytic activity with Alizarin-DA-Fe(III). Owing to the special plane structure, the experiment results showed that the Alizarin-DA-Fe(III) exhibited higher damage ability than IDA-Fe(III) and NTA-Fe(III). Perhaps, the Alizarin-DA-Fe(III) may be used as a new antitumor compound to induce peroxides in body to kill cancer cells. PMID- 23666357 TI - Thermodynamics of adduct formation of cobalt(II) tetraaza Schiff base complexes with organotin(IV)trichlorides. AB - UV-Vis. spectrophotometric study of the adduct formation of organotin(IV)trichlorides i.e. PhSnCl3 and MeSnCl3 as acceptors with Co(II) tetraaza complexes, such as [Co(ampen)] [N,N'-ethylenebis-(o-amino-alpha phenylbenzylideneiminato)cobalt(II)], [Co(campen)] [N,N'-ethylenebis-(5-chloro-o amino-alpha-phenylbenzylideneiminato)cobalt(II)], [Co(amaen)] [N,N'-ethylenebis (o-amino-alpha-methylbenzylideneiminato)cobalt(II)], [Co(amppn)] [N,N'-propylene bis-(5-chloro-o-amino-alpha-phenylbenzylideneiminato)cobalt(II)] and [Co(camppn)] [N,N'-propylenebis-(5-chloro-o-amino-alpha-phenylbenzylideneiminato)cobalt(II)] as donors were studied spectrophotometrically under N2 atmosphere and in N,N' dimethylformamide solvent. The formation constants and thermodynamic parameters were measured using spectrophotometric titration of adduct formation at various temperatures. The trend of the adduct formations of the cobalt(II) tetraaza complexes with a given organotintrichloride acceptor decreases as follow: [Co(amaen)]>[Co(amppn)]>[Co(ampen)]>[Co(camppn)]>[Co(campen)]. The trend of the formation constants for the studied organotintrichlorides with a given cobalt(II) tetraaza complexes is as follow: PhSnCl3>MeSnCl3. PMID- 23666358 TI - A method for electroporation to study gene function in mammary gland development. AB - To reveal the specific functions of various genes during embryonic development, the manipulation of genes using techniques such as electroporation is of fundamental importance for providing direct evidence concerning function or downstream activation of signaling networks. In vitro embryo culture and electroporation are useful techniques to introduce foreign genes, for developmental biology studies. Among the various mammalian culture techniques, Trowell culture is suitable for studies of embryonic mammary gland development because of its stability and ease of use in conjunction with electroporation technique application. The manipulation of gene expression using electroporation is a useful technique for the functional analysis of a particular gene. In this protocol, full steps for electroporation and in vitro embryo culture have been described for use in embryonic mammary gland development research. PMID- 23666359 TI - Assessment of pathogenic bacteria in treated graywater and irrigated soils. AB - Reuse of graywater (GW) for irrigation is recognized as a sustainable solution for water conservation. One major impediment for reuse of GW is the possible presence of pathogenic microorganisms. The presence and abundance of six pathogens and indicators were investigated in three GW recirculating vertical flow constructed wetland treatment systems and their respective irrigated yard soils. The treated GW and soils were monitored once every two months for six months using real-time quantitative PCR. As a control, samples from four soils irrigated with fresh water (FW) were similarly analyzed for pathogens and indicators. Comparable types of pathogens and fecal indicator bacteria, including Escherichia coli, Klebsiella pneumoniae, Salmonella enterica, Pseudomonas aeruginosa, Enterococcus faecalis, and Shigella spp., were found in the treated GW, their corresponding irrigated soils and the FW-irrigated soils. Moreover, the abundance of these bacteria in the GW- and FW-irrigated soils was of the same order of magnitude, suggesting that the source of the pathogens cannot be established. Our results suggest that GW irrigation has no effect on the diversity and abundance of the tested pathogens and indicators in yard soils. PMID- 23666361 TI - The changing contexts of health promotion. PMID- 23666360 TI - Fine mapping of the Bmgr5 quantitative trait locus for allogeneic bone marrow engraftment in mice. AB - To identify novel mechanisms regulating allogeneic hematopoietic cell engraftment, we used forward genetics and previously described identification, in mice, of a bone marrow (BM) engraftment quantitative trait locus (QTL), termed Bmgr5. This QTL confers dominant and large allele effects for engraftment susceptibility. It was localized to chromosome 16 by quantitative genetic techniques in a segregating backcross bred from susceptible BALB.K and resistant B10.BR mice. We now report verification of the Bmgr5 QTL using reciprocal chromosome 16 consomic strains. The BM engraftment phenotype in these consomic mice shows that Bmgr5 susceptibility alleles are not only sufficient but also indispensable for conferring permissiveness for allogeneic BM engraftment. Using panels of congenic mice, we resolved the Bmgr5 QTL into two separate subloci, termed Bmgr5a (Chr16:14.6-15.8 Mb) and Bmgr5b (Chr16:15.8-17.6 Mb), each conferring permissiveness for the engraftment phenotype and both fine mapped to an interval amenable to positional cloning. Candidate Bmgr5 genes were then prioritized using whole exome DNA sequencing and microarray gene expression data. Further studies are warranted to elucidate the genetic interaction between the Bmgr5a and Bmgr5b QTL and identify causative genes and underlying gene variants. This may lead to new approaches for overcoming the problem of graft rejection in clinical hematopoietic cell transplantation. PMID- 23666362 TI - Genome-wide identification of cancer-related polyadenylated and non polyadenylated RNAs in human breast and lung cell lines. AB - Eukaryotic mRNAs consist of two forms of transcripts: poly(A)+ and poly(A)-, based on the presence or absence of poly(A) tails at the 3' end. Poly(A)+ mRNAs are mainly protein coding mRNAs, whereas the functions of poly(A)- mRNA are largely unknown. Previous studies have shown that a significant proportion of gene transcripts are poly(A)- or bimorphic (containing both poly(A)+ and poly(A)- transcripts). We compared the expression levels of poly(A)- and poly(A)+ RNA mRNAs in normal and cancer cell lines. We also investigated the potential functions of these RNA transcripts using an integrative workflow to explore poly(A)+ and poly(A)- transcriptome sequences between a normal human mammary gland cell line (HMEC) and a breast cancer cell line (MCF-7), as well as between a normal human lung cell line (NHLF) and a lung cancer cell line (A549). The data showed that normal and cancer cell lines differentially express these two forms of mRNA. Gene ontology (GO) annotation analyses hinted at the functions of these two groups of transcripts and grouped the differentially expressed genes according to the form of their transcript. The data showed that cell cycle-, apoptosis-, and cell death-related functions corresponded to most of the differentially expressed genes in these two forms of transcripts, which were also associated with the cancers. Furthermore, translational elongation and translation functions were also found for the poly(A)- protein-coding genes in cancer cell lines. We demonstrate that poly(A)- transcripts play an important role in cancer development. PMID- 23666363 TI - Risk stratification of patients with non-ST-elevation acute coronary syndromes by assessing global longitudinal strain. AB - Noninvasive detection of left main/three-vessel diseases (LM/3VD) among patients with non-ST-elevation acute coronary syndromes (NSTEACS) has been difficult using echocardiography. However, two-dimensional (2D) strain/strain-rate analysis is more sensitive in quantitatively assessing contractile abnormality. Accordingly, we aimed to clarify the usefulness of 2D strain/strain-rate analysis for risk stratification of NSTEACS. A total of 50 patients with NSTEACS underwent echocardiography and coronary angiography. We evaluated global longitudinal peak strain (global PS), peak systolic strain rate (global SSR), early diastolic global peak strain rate (global ESR), time from aortic valve closure to peak strain (TAVC-global PS), and global ESR (TAVC-global ESR) in apical four-, two-, and three-chamber views. Patients were divided into two groups according to coronary angiographic findings, the high-risk group (n = 15) with either of left main or three-vessel disease, and the low-risk group (n = 35). There were no significant differences in global SSR and global ESR between the two groups. The amplitude of global PS was significantly reduced in high-risk patients with LM/3VD in comparison with low-risk patients (-17.5 +/- 2.4% vs -19.8 +/- 2.7%, P = 0.007, respectively). TAVC-global PS and TAVC-global ESR were significantly prolonged in high-risk patients with LM/3VD in comparison with low-risk patients (15.3 +/- 25.7 ms vs -36.8 +/- 32.7 ms, P < 0.0001 and 162.8 +/- 32.7 ms vs 135.7 +/- 41.5 ms, P < 0.03, respectively). Receiver-operating characteristic analysis demonstrated that TAVC-global PS most strongly detected high-risk patients with sensitivity of 100% and specificity of 74.3% (area under the curve = 0.938, 95 % confidence interval 0.832-0.986, P = 0.0001). Temporal analysis of 2D strain appeared to be useful in detecting high-risk patients with LM/3VD among patients with NSTEACS. PMID- 23666365 TI - Stem cell therapy in inflammatory bowel disease: which, when and how? AB - PURPOSE OF REVIEW: Stem cell therapy has emerged as a promising therapeutic strategy for inflammatory bowel diseases (IBDs). Currently, stem cell therapy is not part of the standard of care and is usually only performed as a part of clinical trials. In this review, clinical results, proposed underlying mechanisms, and future research directions will be discussed. RECENT FINDINGS: Administration of mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) has been evaluated for IBD treatment over the past years. MSC therapy is being explored as a treatment option for fistulizing Crohn's disease and for luminal Crohn's disease. It is shown to be well tolerated, but results on efficacy are inconsistent. HSC transplantation seems to be very effective, but serious adverse events are common. Therefore, future research should focus on improving efficacy of MSC therapy, and on improvement of safety of HSC therapy. SUMMARY: Both MSC and HSC therapy offer clinical potential, but currently are not routinely used for IBD treatment. MSC therapy seems well tolerated but results on efficacy are conflicting. HSC transplantation is shown to be effective but safety concerns remain. Nonetheless, for severe refractory IBD cases, stem cell therapy could well become the next-generation treatment option. PMID- 23666364 TI - High-dose cytarabine (HD araC) in the treatment of leukemias: a review. AB - Cytarabine (araC) has served as the backbone of acute myeloid leukemia (AML) treatment for nearly forty years. High-dose cytarabine (HD araC) therapy resulted from a theoretical model developed in the 1970s that attempted to maximize the anti-leukemia effect of cytarabine. Since that time, HD araC has been utilized mostly in consolidation therapy for AML and in patients with relapsed or resistant AML. The development of araC and HD araC preceded our current understanding of AML biology-that it is a heterogeneous disease, not a single clinical entity. Thus, the optimal dose, schedule, and clinical setting for the use of cytarabine in hematologic malignancies remain uncertain. Research is now better defining the optimal use of HD araC based on leukemia cell karyotype and molecular signature. Here we review the pharmacodynamics of araC, the landmark studies that established the role of HD araC in AML, and research defining the role of HD araC based on the unique biologic properties of the leukemia cell. PMID- 23666366 TI - An evolutionary perspective on the causes and treatment of inflammatory bowel disease. AB - PURPOSE OF REVIEW: To use insights from evolutionary biology to assess the current evidence for the causes, treatment, and prevention of inflammatory bowel disease (IBD). RECENT FINDINGS: When analyzed in the context of evolutionary adaptation, recent assessments of genetic, microbial, and environmental associations with IBD implicate infectious causation. SUMMARY: An evolutionary perspective provides insight into the causes of IBD, interpretation of its manifestations, and assessment of interventions. The evidence implicating infectious causation suggests that future studies of IBD would benefit from increased focus on infectious causes and interventions that prevent or inhibit them. PMID- 23666367 TI - Inflammatory bowel disease: evolutionary concepts in biology, epidemiology, mechanisms and therapy. PMID- 23666368 TI - Development of a novel class of tubulin inhibitors with promising anticancer activities. AB - We have developed a novel class (2-amino-4-phenyl-4H-chromene-3-carboxylate) of inhibitors of tubulin assembly by modifying HA14-1, which is a Bcl-2 inhibitor discovered by our group. Three of these compounds, mHA1, mHA6, and mHA11, showed in vitro cytotoxicities against tumor cells that were more potent and more stable than the backbone compound HA14-1, with nM IC50 values. In contrast, the cytotoxic effects of these compounds on normal cells were minimal. Computational docking, colchicine-tubulin competitive binding, and tubulin polymerization studies demonstrated that these compounds bind at the colchicine-binding site on tubulin and inhibit the formation of microtubules. Treatment of HL-60/Bcl-2 leukemia and CRL5908 lung cancer cells with these mHA compounds led to pronounced microtubule density decreases, G2/M cell cycle arrest, and apoptosis, as determined by immunofluorescence microscopy, flow cytometry, and DNA fragmentation analysis. Combined, these data identify a novel class of compounds that inhibit tubulin assembly and limit cancer cell phenotypes. IMPLICATIONS: This study supports the continued development of novel anti-tubulin assembly inhibitors as potential anticancer agents. PMID- 23666369 TI - miR-155-deficient bone marrow promotes tumor metastasis. AB - Infiltration of immune cells in primary tumors and metastatic sites is known to influence tumor progression and metastasis. Macrophages represent the most abundant immune cells in the tumor microenvironment, and evidence has shown that macrophages promote seeding, extravasation, and persistent growth of tumor cells at metastatic sites. miR-155 plays an essential role in immune cell development/function, and its aberrant expression is associated with lymphomas and several solid tumor types. However, it is unknown how miR-155 expression in immune cells affects solid tumor growth and metastasis. To this end, bone marrow transplantation was performed using miR-155-deficient mice as bone marrow donors and wild-type (WT) mice as recipients, and the chimeric mice were inoculated with tumor cells. We demonstrate that bone marrow lacking miR-155 significantly enhanced lung metastasis without a substantial effect on primary tumor growth. Relative to mice with WT bone marrow, miR-155-deficient bone marrow accumulated more macrophages in the spleen and lungs. Further analysis revealed that miR-155 deficient macrophages in metastatic sites exhibited a tumor-promoting M2 phenotype. In vitro study suggested that miR-155-null macrophages were prone to M2 polarization upon incubation with tumor cell-conditioned medium, due to elevated expression of C/EBPbeta, an identified miR-155 target. These data, for the first time, demonstrate that miR-155 in host immune cells plays a vital role in modulating solid tumor metastasis by affecting the recruitment and polarization of bone marrow-derived macrophages. IMPLICATIONS: Targeted inhibition of miR-155 delays tumor development but inhibition in host immune cells may encourage metastasis. PMID- 23666370 TI - What is more damaging to vascular endothelial function: Diabetes, age, high BMI, or all of the above? AB - BACKGROUND: It is well established that there is a reduction in the skin blood flow (SBF) in response to heat with age and diabetes. While it is known that high BMI creates a stress on the cardiovascular system and increases the risk of all cause of morbidity and mortality, little is known of the effect of high BMI on SBF response to heat. Since diabetes is associated with age and a higher BMI, the interrelationship between age, BMI and SBF needs to be investigated to better understand the contribution diabetes alone has to endothelial impairment. MATERIAL AND METHODS: This study examined the SBF to heat in young and old people with low and high BMI and people with diabetes with high BMI to determine the contribution these variables have on SBF. Subjects were ten young and older people with BMI <20 and ten young and older people with BMI >20 and ten subjects with diabetes with BMI >20. The SBF response, above the quadriceps, was determined during a 6 minutes exposure to heat at 44 degrees C. RESULTS: Even in young people, SBF after the stress of heat exposure was reduced in subjects with a high BMI. The effect of BMI was greatest in young people and lowest in older people and people with diabetes; in people with diabetes, BMI was a more significant variable than diabetes in causing impairment of blood flow to heat. BMI, for example, was responsible for 49% of the reduction in blood flow after stress heat exposure (R=-0.7) while ageing only accounted for 16% of the blood flow reduction (R=-0.397). CONCLUSIONS: These results would suggest the importance of keeping BMI low not only in people with diabetes to minimize further circulatory vascular damage, but also in young people to diminish long term circulatory vascular compromise. PMID- 23666371 TI - Can synchronizing feather-based measures of corticosterone and stable isotopes help us better understand habitat-physiology relationships? AB - Physiological mechanisms link the environment with population dynamics, and glucocorticoid hormones are of particular interest because they respond adaptively to environmental change and can influence vertebrate reproduction and fitness. We tested a novel approach of synchronizing feather-based measures of corticosterone (the primary avian glucocorticoid; CORTf) and ratios of stable isotopes (SIs) of C (delta(13)C) and N (delta(15)N) to provide information about environmental conditions and an integrated physiological response to those conditions over the same period of feather synthesis. Using a fragmented metapopulation of Dupont's larks Chersophilus duponti, an endangered steppe songbird, we analyzed interrelationships among CORTf, delta(13)C, delta(15)N, and the physical environment, including measures of habitat loss and fragmentation. CORTf was not related to any habitat variable measured directly. However, we detected a significant spatial structure to CORTf values and food availability, with greater similarity in both at smaller spatial scales. Using SIs as proxies for the local environment, we found CORTf was negatively related to delta(13)C. Values of CORTf, delta(13)C, and the relationship between the two were likely driven by variation in agricultural land use surrounding lark habitat patches. Our feather-based approach revealed that individual physiology was sensitive to environmental conditions (e.g., an interaction of food availability and variation in habitat) at a local scale, but not patch or landscape scales. Combining CORTf and SIs may be a promising tool because it can provide individual-based information about habitat, physiology, and their relationship during the same time period. PMID- 23666372 TI - Supplementation of microbial levan in the diet of Cyprinus carpio fry (Linnaeus, 1758) exposed to sublethal toxicity of fipronil: effect on growth and metabolic responses. AB - A 60-day feeding trial was conducted to study the effect of dietary microbial levan on growth performance and metabolic responses of Cyprinus carpio fry exposed to sublethal dose (1/10th LC50) of fipronil [(+/-)-5-amino-1-(2,6 dichloro-alpha,alpha,alpha-trifluoro-p-tolyl)-4-trifluoromethylsulfinylpyrazole-3 carbonitrile]. Two hundred and twenty five fry were randomly distributed in five treatments in triplicates. Four purified diets were prepared with graded levels of microbial levan. Five different treatment groups were levan control L0P0 (basal feed + 0 % levan without exposure to pesticide); pesticide control L0P1 (basal feed + 0 % levan with exposure to pesticide); L0.25P1 (basal feed + 0.25 % levan with exposure to pesticide); L0.50P1 (basal feed + 0.50 % levan with exposure to pesticide); and L0.75P1 (basal feed + 0.75 % levan with exposure to pesticide). Weight gain% and specific growth rate were significantly higher (p < 0.05) in levan fed groups compared to their non-levan fed counterpart. Highest (p < 0.05) content of ascorbic acid in muscle, liver and brain tissues was observed with higher level of dietary levan. Glucose-6-phosphate dehydrogenase activity decreased with the increasing level of dietary levan in the liver and muscle. Aspartate aminotransferase activity exhibited a second order polynomial relationship with the dietary levan, both in liver (Y = -1.001x2 + 5.366x + 5.812, r2 = 0.887) and muscle (Y = -0.566x2 + 2.833x + 6.506, r2 = 0.858) while alanine aminotransferase activity showed third order polynomial relationship both in liver (Y = 1.195x3 - 12.30x2 + 35.23x + 9.874, r2 = 0.879) and muscle (Y = 0.527x3 - 8.429x2 + 31.80x + 8.718, r2 = 0.990). Highest (p < 0.05) superoxide dismutase activity in gill was observed in the group fed with 0.75 % levan supplemented diet. Overall results indicated that dietary microbial levan at 0.75 % in C. carpio fry ameliorated the negative effects of fipronil and augmented the growth. PMID- 23666373 TI - Synthesis and antiproliferative effect of novel curcumin analogues. AB - Novel curcumin analogues with alpha,beta-unsaturated ketone moiety and/or alpha,beta-saturated ketone structure were synthesized from curcumin via alkylation at the central carbon and the phenolic hydroxy groups, and hydrogenation of alpha,beta-unsaturated ketone moiety. The antiproliferative activities were tested in five human solid tumor cell lines in vitro. Most of the compounds exhibited increased antiproliferative activities comparing with that of curcumin. Structure-activity relationship (SAR) analysis revealed that the alpha,beta-unsaturated ketone structure was not required for antiproliferative activity of these curcumin analogues. Among these compounds, 1,7-bis(3-methoxy-4 (3-(4-methylpiperazinyl-1-yl)propoxy)phenyl)-4,4-dibenzylheptane-3,5-dione (16f) was the most effective one with IC50 value below 1 uM, which was 9- to 81-fold more potent than curcumin. PMID- 23666374 TI - Editorial comment: Growing experience with ex vivo lung perfusion: many ways leading to the same goal. PMID- 23666375 TI - Early results in transplantation of initially rejected donor lungs after ex vivo lung perfusion: a case-control study. AB - OBJECTIVES: An increasing number of studies have shown that ex vivo lung perfusion (EVLP) is safe and that rejected donor lungs can be resuscitated and used for lung transplantation (LTx). Early clinical outcomes in patients transplanted with reconditioned lungs at our centre were reviewed and compared with those of contemporary non-EVLP controls. METHODS: During 18 months starting January 2011, 11 pairs of donor lungs initially deemed unsuitable for transplantation underwent EVLP. Haemodynamic (pulmonary flow, vascular resistance and artery pressure) and respiratory (peak airway pressure and compliance) parameters were analysed during evaluation. Lungs that improved (n = 11) to meet International Society of Heart and Lung Transplantation criteria were transplanted and compared with patients transplanted with non-EVLP lungs (n = 47) during the same time period. RESULTS: Donor lungs were initially rejected due to either inferior PaO2/FiO2 ratio (n = 9), bilateral infiltrate on chest X-ray (n = 1) or ongoing extra corporeal membrane oxygenation (n = 1). The donor lungs improved from a mean PaO2/FiO2 ratio of 27.9 kPa in the donor to a mean of 59.6 kPa at the end of the EVLP (median improvement 28.4 kPa, range 21.0-50.7 kPa). Two single lungs were deemed unsuitable and not used for LTx. Eleven recipients from the regular waiting list underwent either single (n = 3) LTx or double (n = 8) LTx with EVLP-treated lungs. The median time to extubation (12 (range, 3-912) vs 6 (range, 2-1296) h) and median intensive care unit (ICU) stay (152 (range, 40 625) vs 48 (range, 22-1632) h) were longer in the EVLP group (P = 0.05 and P = 0.01, respectively). There were no differences in length of hospital stay (median 28 (range 25-93) vs 28 (18-209), P = 0.21). Two patients in the EVLP group and 6 in the control group had primary graft dysfunction >Grade 1 at 72 h postoperatively. Three patients in the control group died before discharge. All recipients of EVLP lungs were discharged alive from hospital. CONCLUSIONS: The use of EVLP seems safe and indicates that lungs otherwise refused for LTx can be recovered and subsequently used for transplantation, although time to extubation and ICU stay were longer for the EVLP group. PMID- 23666376 TI - Excessive negative venous line pressures and increased arterial air bubble counts during miniaturized cardiopulmonary bypass: an experimental study comparing miniaturized with conventional perfusion systems. AB - OBJECTIVES: Miniaturized cardiopulmonary bypass (MCPB) is increasingly used in cardiac surgery, because it can lower clinically significant complications such as systemic inflammatory response, haemolysis and high transfusion requirements. A limitation of MCPB is the risk of excessive negative pressure in the venous line during volume depletion, probably leading to gaseous microembolism. METHODS: In an experimental study with 24 pigs, we compared conventional open cardiopulmonary bypass (CCPB group, n = 11) with MCPB (n = 13). The same pump and identical tubing materials were used in both groups. Primary endpoints were pressure values in the venous line and the right atrium as well as the amount of air bubbles >500 um. Secondary endpoints were biochemical parameters of systemic inflammatory response, ischaemia, haemodilution and haemolysis. RESULTS: Nearly 20% of venous pressure values were below -150 mmHg and approximately 10% of the right atrial pressure values were below -100 mmHg in the MCPB group, during the experiment. No such low values were observed in the CCPB group. In addition, the number of large arterial air bubbles was higher in the MCPB group compared with the CCPB group (mean +/- standard deviation [SD]: 13 444 +/- 5709 vs 0.9 +/- 0.6, respectively; P < 0.001). Bubble volume was also significantly larger during MCPB compared with CCPB (mean +/- SD: 1522 +/- 654 vs 4.1 +/- 2.5 ul, respectively; P < 0.001). Blood levels of interleukin-6, free haemoglobin and creatine kinase were significantly higher in the CCPB group compared with the MCPB group. CONCLUSIONS: Despite the benefits of MCPB regarding systemic inflammatory response and haemolysis, this technique is associated with excessive negative venous line pressures and a significant increase in the number and volume of arterial air bubbles compared with CCPB. Mini-perfusion systems and the management of MCPB require further refinements to avoid such adverse effects. PMID- 23666379 TI - No difference in effectiveness between focused and radial shockwave therapy for treating patellar tendinopathy: a randomized controlled trial. AB - PURPOSE: The aim of the study was to compare the effectiveness of focused shockwave therapy (FSWT) and radial shockwave therapy (RSWT) for treating patellar tendinopathy. METHODS: Patients were randomized into two groups. One group received three sessions of FSWT, and the other group received three sessions of RSWT. Both groups also received an eccentric training programme. Follow-up measurements took place 1, 4, 7 and 14 weeks after the final shockwave treatment. The primary outcome measure was the Victorian Institute of Sport Assessment-Patella (VISA-P) questionnaire. Secondary outcome measures were pain during ADL, sports activities and the decline squat. RESULTS: Forty-three subjects (57 tendons) were included in the study. Twenty-one subjects (31 tendons) received FSWT, and 22 subjects (26 tendons) received RSWT. Both groups improved significantly on the VISA-P score, but there were no differences in improvement between the FSWT group (15 points on the VISA-P) and the RSWT group (9.6 points, n.s.). This was also the case for the secondary outcome measures. CONCLUSION: There were no statistically significant differences in effectiveness between FSWT and RSWT. It is therefore not possible to recommend one treatment over the other on grounds of outcome. Both groups improved significantly, although it is questionable whether this difference is clinically relevant. LEVEL OF EVIDENCE: II. PMID- 23666378 TI - Implantation of tissue-engineered cartilage-like tissue for the treatment for full-thickness cartilage defects of the knee. AB - PURPOSE: The purposes of this study were to evaluate early- to midterm clinical results after implantation of tissue-engineered cartilage-like tissue for the treatment for full-thickness cartilage defects of the knee and to identify the factors affecting the final clinical results. METHODS: Tissue-engineered cartilage-like tissue was prepared by culturing autologous chondrocytes in atelocollagen gel for 3-4 weeks. A total of 73 knees of 72 patients with full thickness cartilage defects were implanted with this tissue-engineered cartilage like tissue. The follow-up of these patients for >5 years (range 5-11 years, median 8.0 years) is reported. The patients were evaluated clinically using a rating scale, as well as arthroscopically, biomechanically, and histologically. A modified magnetic resonance observation of cartilage repair tissue (MOCART) system was used to quantify the magnetic resonance imaging (MRI) findings of the lesions. The patient or defect factors influencing the final clinical outcomes were also investigated. RESULTS: Clinical rating improved significantly after implantation of tissue-engineered cartilage-like tissue. Arthroscopic findings at 2 years after implantation were graded as normal or nearly normal according to the International Cartilage Repair Society (ICRS) scale in 64 of 73 knees (87.7%). Biomechanically, stiffness of the graft almost equalled the surrounding normal cartilage (87.9-102.5%) at 2 years after implantation. Histologically, overall assessment of the repaired tissue by ICRS Visual Assessment Scale II was 70.4 +/- 20.8. The average MOCART score was 13.5 +/- 11.3 (0-45) preoperatively, 66.6 +/- 16.8 (10-90) at 1 year after implantation, 70.4 +/- 16.1 (15-90) at 2 years after implantation, and 72.5 +/- 17.4 (15-95) at the final follow-up, indicating that MRI results were maintained. Among the factors investigated, only arthroscopic grade of the repaired lesion at 2 years after implantation was significantly correlated with the final clinical scores. CONCLUSIONS: Implantation of tissue-engineered cartilage-like tissue for the cartilage defects of the knee was effective in short- to midterm post-operatively. This procedure can be proposed as one option for repairing full-thickness cartilage defect of the knee. LEVEL OF EVIDENCE: IV. PMID- 23666380 TI - The effect of sex and fatigue on lower limb kinematics, kinetics, and muscle activity during unanticipated side-step cutting. AB - PURPOSE: To determine how sex and fatigue affect lower limb kinematics, kinetics, and muscle activity during unanticipated side-step cutting. METHODS: Twenty-three physically active subjects (men 11, women 12) performed 10 successful trials of cutting manoeuvres each to either side under unanticipated conditions in response to 2 light emitting diodes before and after fatigue conditions. Data were analysed and compared regarding sex and fatigue conditions using two-way repeated measures analysis of variance. RESULTS: After fatigue-inducing exercise, women demonstrated larger impulses of ground reaction force (IGRF) during the first 50 ms (2.4 +/- 0.8 vs. 2.1 +/- 0.9, P < 0.05) than did men. Significant primary effects of sex indicated that women showed a smaller hip flexion angle at initial contact (40.4 +/- 6.9 degrees vs. 49.7 +/- 9.1 degrees , P < 0.05) and at maximum flexion angle (41.3 +/- 7.7 degrees vs. 51.4 +/- 9.0 degrees , P < 0.05) compared with men. Significant primary effects of fatigue were observed in the gluteus maximus muscle during 50 ms before initial contact (+21.5 +/- 48.3 %, P < 0.05) and in the semimembranosus muscle during 50 ms before initial contact (-6.2 +/- 20.1 %, P < 0.05) and the first 50 ms of side-step cutting (-7.9 +/- 26.6 %, P < 0.05). CONCLUSIONS: Our results suggest that sex differences, especially larger IGRF in a fatigue state combined with less hip flexion angle, lead to women having a higher risk for anterior cruciate ligament (ACL) injury. These findings may contribute to understanding the underlying mechanism of injury and development of preventive exercises against ACL injury. PMID- 23666381 TI - My patient is thrombocytopenic! Is (s)he? Why? And what shall I do? A practical approach to thrombocytopenia. AB - Solving the riddle of a thrombocytopenic patient is a difficult and fascinating task. The spectrum of possible aetiologies is wide, ranging from an in vitro artefact to severe treatment-resistant thrombocytopenic bleeding conditions, or even life-threatening prothrombotic states. Moreover, thrombocytopenia by itself does not protect from thrombosis and sometimes a patient with a low platelet count requires concomitant antithrombotic treatment as well. In order to identify and treat the cause and the effects of the thrombocytopenia, you have to put together several pieces of information, solving a unique jig-jaw puzzle. The present work is not a textbook article about thrombocytopenia, rather a collection of differential diagnostic thoughts, treatment concepts, and some basic knowledge, that you can retrieve when facing your next thrombocytopenic patient. Enjoy reading it, but most importantly enjoy taking care of patients with a low platelet count. I bet the present work will assist you in this challenging and rewarding clinical task. PMID- 23666382 TI - The molecular clusters in a supercritical fluid-solid system should be considered as a phase-thermodynamic principle and evidence. AB - In this work we propose a new thermodynamic principle in which a supercritical fluid (SCF)-solid system is divided into a solid phase, a cluster phase, and a bulk fluid phase, i.e., the molecular clusters in the system are considered as an individual phase. The phase equilibria of various SCF-solid systems are calculated using this principle in combination with Monte Carlo simulation and the Peng-Robinson equation of state (PR-EOS). It is shown that in the critical region of the supercritical (SC) solvents where the clustering is significant, the results calculated using this thermodynamic principle are much more consistent with the experimental data than those calculated using the conventional thermodynamic principle, confirming the validity of the principle proposed in this work. PMID- 23666383 TI - Proton trapping in yttrium-doped barium zirconate. AB - The environmental benefits of fuel cells have been increasingly appreciated in recent years. Among candidate electrolytes for solid-oxide fuel cells, yttrium doped barium zirconate has garnered attention because of its high proton conductivity, particularly in the intermediate-temperature region targeted for cost-effective solid-oxide fuel cell operation, and its excellent chemical stability. However, fundamental questions surrounding the defect chemistry and macroscopic proton transport mechanism of this material remain, especially in regard to the possible role of proton trapping. Here we show, through a combined thermogravimetric and a.c. impedance study, that macroscopic proton transport in yttrium-doped barium zirconate is limited by proton-dopant association (proton trapping). Protons must overcome the association energy, 29 kJ mol(-1), as well as the general activation energy, 16 kJ mol(-1), to achieve long-range transport. Proton nuclear magnetic resonance studies show the presence of two types of proton environment above room temperature, reflecting differences in proton dopant configurations. This insight motivates efforts to identify suitable alternative dopants with reduced association energies as a route to higher conductivities. PMID- 23666385 TI - Health-related quality of life in family members of patients with burns. AB - A severe burn not only affects the patients, but may also have a great impact on the lives of family members. It is known that family members of patients with burns experience psychological distress, but health-related quality of life (HRQoL) has not been studied in this group. The aim was to study predictors of HRQoL in family members of patients with burns. Forty-four family members of adult patients treated in a burn center, between 2000 and 2007, completed questionnaires during care, and at 3, 6, and 12 months after injury. HRQoL was assessed with the EuroQol 5D (EQ-5D), which consists of the dimensions: mobility, self-care, usual activities, pain, and anxiety/depression. The questionnaire generates an EQ-5D index and a visual analog scale (VAS) score. Overall, the EQ 5D index was similar to that of the general population. A slight improvement in HRQoL was found in the VAS scores and in the anxiety/depression dimension over time. In regression models, HRQoL was primarily predicted by earlier life events, symptoms of post-traumatic stress disorder, and HRQoL, assessed during the patients' hospitalization. In summary, HRQoL assessed with VAS scores increased slightly during the first year postburn, and early screening for life events and psychological symptoms, and HRQoL might be useful in identifying family members in need of support. PMID- 23666384 TI - Delayed topical p38 MAPK inhibition attenuates full-thickness burn wound inflammatory signaling. AB - Inflammatory signaling pathways, such as p38 mitogen-activated protein kinase (MAPK) play a central role in host responses to injury. In previous studies by the authors, topical p38 MAPK inhibitors effectively attenuated inflammatory signaling in a partial-thickness scald burn model, when applied to the burn wound immediately after injury. However, clinically relevant full-thickness scald burn wounds may act as a barrier to topical immune modulators, and delayed application of topical p38 MAPK inhibitors may not be effective. In this study, the authors evaluate the efficacy of topical p38 MAPK inhibition on full-thickness scald burns with immediate and delayed treatment. C57/BL6 mice received "Sham" or 30% TBSA full-thickness scald burn injury. After injury, the burn wounds were treated with a topical p38 MAPK inhibitor or vehicle. The treatment group received topical p38 MAPK inhibitor either immediately after burn or 4 hours (delayed) after injury. All animals were killed at 12 or 24 hours. Burn wounds underwent histological analyses. Skin and plasma were analyzed by enzyme-linked immunosorbent assay or real-time quantitative polymerase chain reaction for cytokine expression. Full-thickness scald burns resulted from immersion in 62 degrees C water for 25 seconds. Topical p38 MAPK inhibitor attenuated dermal interleukin (IL)-6, MIP-2, and IL-1beta expression and plasma IL-6 and MIP-2 cytokine expression. In addition, delayed application of topical p38 MAPK inhibitors significantly reduced dermal and plasma cytokine expression compared with vehicle control. Topical p38 MAPK inhibitors remain potent in reducing full thickness burn wound inflammatory signaling, even when treatment is delayed by several hours postinjury. Topical application of p38 MAPK inhibitor may be a clinically viable treatment after burn injury. PMID- 23666386 TI - ABA Southern Region Burn disaster plan: the process of creating and experience with the ABA southern region burn disaster plan. AB - The Southern Region of the American Burn Association began to craft a regional plan to address a surge of burn-injured patients after a mass casualty event in 2004. Published in 2006, this plan has been tested through modeling, exercise, and actual events. This article focuses on the process of how the plan was created, how it was tested, and how it interfaces with other ongoing efforts on preparedness. One key to success regarding how people respond to a disaster can be traced to preexisting relationships and collaborations. These activities would include training or working together and building trust long before the crisis. Knowing who you can call and rely on when you need help, within the context of your plan, can be pivotal in successfully managing a disaster. This article describes how a coalition of burn center leaders came together. Their ongoing personal association has facilitated the development of planning activities and has kept the process dynamic. This article also includes several of the building blocks for developing a plan from creation to composition, implementation, and testing. The plan discussed here is an example of linking leadership, relationships, process, and documentation together. On the basis of these experiences, the authors believe these elements are present in other regions. The intent of this work is to share an experience and to offer it as a guide to aid others in their regional burn disaster planning efforts. PMID- 23666387 TI - Detection of carbapenemase-encoding genes among clinical isolates of Pseudomonas aeruginosa in a Chinese burn unit. AB - The carbapenemases have recently emerged as molecules implicated in one of the most feared bacterial resistance mechanisms because of their ability to hydrolyze virtually all lactamase agents and their highly mobile genes. This study aimed to investigate the prevalence of carbapenemase and antimicrobial susceptibilities of Pseudomonas aeruginosa isolated from burn patients in Chongqing, China. Antimicrobial susceptibility of 111 isolates was determined by the disc agar diffusion test and the agar dilution method. Random Amplification of Polymorphic DNA polymerase chain reaction analysis revealed 111 P. aeruginosa 42 genotypes. Carbapenemase genes were amplified by polymerase chain reaction and the sequence verified by blast. Ninety-three of 111 (83.8%) isolates were resistant to imipenem; all of them had developed multidrug resistance and exhibited higher resistant rates compared with the imipenem-susceptible Pseudomonas. Ciprofloxacin was the most effective antipseudomonal agent. Thirty-three of the isolates were identified to contain the metallo-beta-lactamase blaIMP-4 gene and belong to different Random Amplification of Polymorphic DNA polymerase chain reactiongenotypes. In conclusion, the high prevalence of multidrug resistance (94.6%) and the production of blaIMP-4 genes in P. aeruginosa isolates in burn patients highlight the necessity of considering these issues in burn hospitals. PMID- 23666388 TI - Health-related quality of life in patients with brain tumors: limitations and additional outcome measures. AB - Health-related quality of life (HRQOL) is a multidimensional concept used to measure patients' functioning and well-being. In recent decades, HRQOL has become an important (secondary) outcome measure in clinical trials for brain tumor patients. It could be questioned, however, whether HRQOL is the only useful outcome measure for assessing the level of functioning and well-being of these patients. As described in this review, several general methodological issues can hamper the interpretation of HRQOL data collected in the oncology setting. Additionally, because brain tumor patients have a progressive brain disease resulting in cognitive impairments, patient-reported outcomes may not always be the most informative and accurate measures of HRQOL in brain tumor patients. Supplementary or alternative measures, such as proxy-rated HRQOL measures and measures of instrumental activities of daily living, may provide a more complete picture of brain tumor patients' functioning in daily life. PMID- 23666389 TI - Positional variations in mammary gland development and cancer. AB - Most mammals develop their mammary glands in pairs of which the two counterparts are symmetrically displaced away from the ventral midline. Based on this symmetry and the same functional outcome as a milk-producing organ, the mammary glands are easily presumed to be mere copies of one another. Based on our analysis of published data with inclusion of new results related to mammary development and pathology in mice, we argue that this presumption is incorrect: Between and within pairs, mammary glands differ from one another, and tumor incidence and biology depend on the position along the anterior-posterior and the left-right axis as well. This insight has implications for experimental designs with mouse models and for data extrapolation between mammary glands within and between species. We suggest that improved documentation of location-specific mammary gland features will lead to more insights into the molecular mechanisms of mammary gland development and cancer biology in both mice and humans. PMID- 23666390 TI - HIV vaccine research and discovery in the nonhuman primates model: a unified theory in acquisition prevention and control of SIV infection. AB - PURPOSE OF REVIEW: Here we highlight the latest advances in HIV vaccine concepts that will expand our knowledge on how to elicit effective acquisition-prevention and/or control of simian immunodeficiency virus (SIV) replication in the nonhuman primate (NHP) model. RECENT FINDINGS: In the context of the promising analyses from the RV144 Thai Trial and the effective control of SIV replication exerted by rhCMV-(SIV) elicited EM CD8 T cells, the HIV field has recently shifted toward vaccine concepts that combine protection from acquisition with effective control of SIV replication. Current studies in the NHP model have demonstrated the efficacy of HIV-neutralizing antibodies via passive transfer, the potential importance of the CD4 Tfh subset, the ability to effectively model the RV144 vaccine trial and the capacity of an Ad26 prime and modified vaccinia Ankara virus boost to elicit Env-specific antibody and cellular responses that both limit acquisition and control heterologous SIVmac251 challenge. SUMMARY: The latest work in the NHP model suggests that the next generation HIV-1 vaccines should aim to provoke a comprehensive adaptive immune response for both prevention of SIV acquisition as well as control of replication in breakthrough infection. PMID- 23666392 TI - Advances in antiretroviral therapy. AB - PURPOSE OF REVIEW: To review recent data about advances in ART. RECENT FINDINGS: In the last 2 years, clinical trials have demonstrated the safety and efficacy of three integrase transfer inhibitors [raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG)], one new nonnucleoside reverse transcriptase inhibitor [rilpivirine (RIL)] and a new extended release formulation of nevirapine in antiretroviral-naive and experienced patients. Cobicistat (COBI), a new pharmacologic enhancer without antiretroviral activity has been studied as a booster of EVG and atazanavir (ATV). Two new single-pill fixed-dose combinations (FDCs) have been approved by regulatory agencies: RIL/tenofovir (TDF) difumarate/emtricitabine and elvitegravir/COBI/TDF difumarate/emtricitabine. A new prodrug of TDF is going to be evaluated in phase III clinical trials with the goal of showing less bone and renal toxicity. Ongoing trials are evaluating the use of nucleoside sparing regimens in antiretroviral-naive patients. Generic formulations of multiple antiretrovirals would become available in the immediate future. The efficacy and price reduction associated with generic antiretrovirals remains to be elucidated. SUMMARY: In the last 2 years, the antiretroviral armamentarium has been significantly expanded by the advent of the integrase transfer inhibitors RAL, EVG and DTG, by a new nonnucleoside reverse transcriptase inhibitor, RIL and by two new single-pill FDCs. PMID- 23666391 TI - Using nonhuman primates to model HIV transmission. AB - PURPOSE OF REVIEW: One of the major obstacles in fully understanding HIV transmission comes from the impracticality of studying transmission in humans. Because of this encumbrance, the early phases of HIV transmission and systemic dissemination are poorly understood. In order to fully comprehend these critical steps in HIV infection, animal models must be devised to accurately reflect HIV's mode of action. This review seeks to highlight the essential nature of modelling HIV transmission in nonhuman primates (NHPs). RECENT FINDINGS: Recently, it was discovered that HIV infection is established in newly infected recipients by a single or few transmitted/founder variants. This has reshaped how animal modelling is conducted with researchers currently recapitulating a physiologically relevant, low-titre infection. Pertinent animal models have been established for the most common routes of infection, including rectal, vaginal and penile transmission; models for intravenous and oral transmission are still in developmental stages. SUMMARY: These limited dose models now accurately reflect HIV transmission in humans and provide a realistic experimental platform for vaccine development and other intervention strategies that can be used to inform vaccine development in humans. Using information obtained in NHP and human trials, it is conceivable to envision effective prevention modalities in the near future. PMID- 23666393 TI - Interaction between dietary marine-derived n-3 fatty acids intake and J-point elevation on the risk of cardiac death: a 24-year follow-up of Japanese men. AB - OBJECTIVE: Higher marine-derived n-3 fatty acids (MDn3FAs) intake reduces the risk of sudden cardiac death via antiarrhythmic effects. The article evaluates whether MDn3FAs intake attenuates the increased risk of cardiac death associated with J-point elevation (JPE), characterised by an elevation of QRS-ST junction (J point) >=0.1 mV on electrocardiography. DESIGN: A prospective population-based cohort study. SETTING: The National Survey on Circulatory Disorders and the National Nutrition Survey of Japan. PARTICIPANTS: A total of 4348 community dwelling men (mean age 49.3 years), without cardiovascular diseases at baseline, from randomly selected areas across Japan. MAIN OUTCOME MEASURES: Cardiac death (200 men) during the 24-year follow-up. RESULTS: Dietary MDn3FAs intake was assessed using a dietary method to estimate individual intake of household-based weighed food records for 3 days. Cox models were used to calculate HRs and 95% CIs adjusted for possible confounding factors. JPE was present in 340 participants (7.8%). The median daily intake of MDn3FAs was 0.35%kcal (0.92 g/day). The risk of cardiac death was significantly higher in participants with JPE than in those without JPE in the low intake group (<0.35%kcal; adjusted HR 3.51; 95% CI 1.84 to 6.73; p<0.001), but not in the high intake group (>=0.35%kcal; adjusted HR 1.09; 95% CI 0.56 to 2.16; p=0.795). The interaction between dietary MDn3FAs intake and JPE on the risk of cardiac death was statistically significant (p=0.006). CONCLUSIONS: The increased risk of cardiac death associated with JPE may be attenuated by higher dietary MDn3FAs intake. PMID- 23666394 TI - PCR-based screening for the most prevalent alpha 1 antitrypsin deficiency mutations (PI S, Z, and Mmalton) in COPD patients from Eastern Tunisia. AB - It is generally agreed that the protease inhibitor (PI) alleles PI*S (Val264Glu) and PI*Z (Lys342Glu) are the most common alpha 1 antitrypsin deficiency variants worldwide, but the PI*Mmalton allele (DeltaPhe52) prevails over these variants in some Mediterranean regions. In eastern Tunisia (Mahdia), we screened 100 subjects with chronic obstructive pulmonary disease for these variants. The PI*S and PI*Z alleles were genotyped by the previously described SexAI/Hpgamma99I RFLP-PCR. We provide here a new method for PI*Mmalton genotyping using mismatched RFLP-PCR. These methods are suitable for routine clinical application and can easily be reproduced by several laboratories, since they do not require extensive optimization, unlike the previously described bidirectional allele-specific amplification PCR for PI*Mmalton genotyping. Our results were in agreement with previous reports from central Tunisia (Kairouan), suggesting that the PI*Mmalton mutation is the most frequent alpha 1 antitrypsin deficiency-related mutation in Tunisia. PMID- 23666395 TI - Selective sensing of vapors of similar dielectric constants using peptide-capped gold nanoparticles on individual multivariable transducers. AB - Peptide-capped AYSSGAPPMPPF gold nanoparticles were demonstrated for highly selective chemical vapor sensing using individual multivariable inductor capacitor-resistor (LCR) resonators. Their multivariable response was achieved by measuring their resonance impedance spectra followed by multivariate spectral analysis. Detection of model toxic vapors and chemical agent simulants, such as acetonitrile, dichloromethane and methyl salicylate, was performed. Dichloromethane (dielectric constant epsilonr = 9.1) and methyl salicylate (epsilonr = 9.0) were discriminated using a single sensor. These sensing materials coupled to multivariable transducers can provide numerous opportunities for tailoring the vapor response selectivity based on the diversity of the amino acid composition of the peptides, and by the modulation of the nature of peptide nanoparticle interactions through designed combinations of hydrophobic and hydrophilic amino acids. PMID- 23666396 TI - Ex vivo live imaging of single cell divisions in mouse neuroepithelium. AB - We developed a system that integrates live imaging of fluorescent markers and culturing slices of embryonic mouse neuroepithelium. We took advantage of existing mouse lines for genetic cell lineage tracing: a tamoxifen-inducible Cre line and a Cre reporter line expressing dsRed upon Cre-mediated recombination. By using a relatively low level of tamoxifen, we were able to induce recombination in a small number of cells, permitting us to follow individual cell divisions. Additionally, we observed the transcriptional response to Sonic Hedgehog (Shh) signaling using an Olig2-eGFP transgenic line (1-3) and we monitored formation of cilia by infecting the cultured slice with virus expressing the cilia marker, Sstr3-GFP (4). In order to image the neuroepithelium, we harvested embryos at E8.5, isolated the neural tube, mounted the neural slice in proper culturing conditions into the imaging chamber and performed time-lapse confocal imaging. Our ex vivo live imaging method enables us to trace single cell divisions to assess the relative timing of primary cilia formation and Shh response in a physiologically relevant manner. This method can be easily adapted using distinct fluorescent markers and provides the field the tools with which to monitor cell behavior in situ and in real time. PMID- 23666397 TI - Long-tailed macaques (Macaca fascicularis) understand what conspecifics can see in a competitive situation. AB - Visual perspective taking (VPT), an understanding of what others can see, is a prerequisite for theory of mind (ToM). While VPT in apes is proven, its presence in monkeys is much-debated. Several different paradigms have been developed to test its existence, but all face interpretational problems since results can be explained by simpler cognitive mechanisms than VPT. Therefore, we adjusted one method where two individuals compete for access to food, visible or invisible for the dominant competitor, to preclude cognitively simpler mechanisms. The subordinate long-tailed macaques tested, selected significantly more often the food item invisible than the item visible to the dominant. In most trials, subjects retrieved only one food item and preferred the invisible food item. Surprisingly, they occasionally adopted an alternative strategy to obtain both food items, by first choosing the visible, most at risk food item. Faster animals adopted this strategy proportionally more often than slower ones. Contrary to previous research, our results cannot be explained by simpler cognitive mechanisms, since behavioural reading was prevented by a one-way mirror between the competitor and the food, and accessibility was equal to both food items. This is the first unequivocal evidence of VPT in a monkey species, suggesting that this precursor to ToM is an evolutionarily conserved capacity present in monkeys, apes and humans. PMID- 23666398 TI - Significance of the neutrophil myeloperoxidase index in patients with atherosclerotic diseases. AB - The pattern of changes in the neutrophil myeloperoxidase (MPO) levels in various atherosclerotic conditions was analyzed by assessing the mean myeloperoxidase index (MPXI), which is calculated during the routine complete blood count (CBC) performed using the flow-cytochemistry blood autoanalyzer ADVIA120/2120 (Siemens), and plasma MPO concentrations. MPXI values of ischemic heart disease (IHD) patients did not differ from those of healthy volunteers. However, MPXI values of IHD patients with arteriosclerosis obliterans (ASO) (-6.1 +/- 1.8) were significantly lower than those of IHD patients without ASO (0.8 +/- 0.5). In contrast, the MPO values in IHD patients with ASO were significantly elevated. In subjects without IHD, while the MPXI values in mild cases of ASO (Fontaine's stages I/II, 3.4 +/- 0.8) were significantly higher than those of healthy volunteers (0.4 +/- 0.4), the values of those with severe ASO (stages III/IV, 0.3 +/- 0.8) were significantly lower than those of mild cases. However, when ASO patients developed IHD, the MPXI values dramatically decreased (stages I/II, -7.3 +/- 1.9; stages III/IV, -5.2 +/- 1.6). These results indicate that MPXI is elevated in mild, but not in severe, ASO cases, and that MPXI decreases dramatically when ASO patients develop IHD. MPXI may constitute an informative independent biomarker for diagnosis and follow-up of IHD complicated by ASO. PMID- 23666399 TI - Less invasive new vaginoplasty using laparoscopy, atelocollagen sponge, and hand made mould. AB - OBJECTIVE: The purpose of this study was to validate the therapeutic efficacy of the innovative surgical approach using laparoscopy, atelocollagen sponge, and hand-made mould on the achievement of a satisfactory neovagina in patients with vaginal agenesis. STUDY DESIGN: The current study involved four patients diagnosed as having Mayer-Rokitansky-Kuster-Hauser syndrome. After creating a vaginal tunnel, the mould wrapped with atelocollagen sponge was placed within the neovagina. The hand-made mould made of expanded polystyrene was started to insert into the neovagina at 7 days after operation. Since this mould is lighter and easier to adjust compared with the previous commercialized ones, it was less stressful for the patients to master the procedure than previous methods. RESULTS: Average operation time was 124 minutes with average blood loss being 45 ml. Average hospital stay was 23 days. The mean length of the neovagina one week postoperation was 8 cm with two fingers in width in all patients. No remarkable postoperative complications were noted. At two months after surgery, the neovagina was confirmed to be completely epithelialized in all patients, assessed by Schiller's test. CONCLUSIONS: This innovative surgical procedure using a mould wrapped with atelocollagen sponge may be a more useful approach for the treatment of vaginal agenesis. PMID- 23666400 TI - Classification of caregiving families according to the Family Caregivers' Appraisal Checklist. AB - This study aimed to classify caregiving families according to the Family Caregivers' Appraisal Checklist (FACL; Horiguchi et al., 2012), which was originally developed to evaluate the probability of continuing caregiving. After nationwide targeting in Japan, the selected survey candidates included 1279 families utilizing domiciliary nursing services chosen by stratified two-stage sampling, and available data were obtained from 945 out of 1020 returned responses (return ratio: 79.8%). Scores for the seven components of FACL were cluster analyzed, and the following six clusters were extracted: Cluster A (12.8%) yielded high scores for all components; Cluster B (34.0%) yielded average scores; Cluster C (20.7%) scored mostly average but low for "quality of care service"; Cluster D (15.8%) showed relatively low scores for all components; Cluster E (11.4%) yielded low scores for all components except for "quality of care service" and "preparedness for emergencies"; and Cluster F (5.3%) scored significantly poorly for all components except for "preparedness for emergencies". Significant intercluster differences were observed for care recipient's age, the number of medical care, employment status, principal caregiver's subjective health, and the advice from family and friends. Caregiving duration was significantly associated with "positive appraisal of family caregiving", the number of medical care and the number of care types, and marginally with the level of care stipulated by the public long-term care insurance program (p < 0.07). Implications of classification of family type according to the FACL and the importance of positive appraisal of caregiving are discussed along with the future direction of use of the FACL. PMID- 23666401 TI - Feasibility, safety, and indications for surgical biopsy of intrinsic brainstem tumors in children. AB - PURPOSE: Diffuse intrinsic pontine gliomas (DIPGs) are rapidly progressive and aggressive tumors that usually arise in children. Their anatomic location makes gross total surgical resection impossible, and fewer than 10% of patients survive more than 2 years after diagnosis. Often, these lesions are treated based on imaging characteristics alone. However, despite aggressive chemotherapy and radiation treatments available, prognosis remains poor. There is therefore a need for new therapies directed by biologic profiling. This necessitates a tissue diagnosis and, therefore, surgical biopsy. We have reviewed the results of biopsy for DIPGs in children at a single institution and compared our results to those available in the literature to elucidate the utility of biopsy for DIPGs. METHODS: A historical cohort study was performed using medical records of patients under the age of 18 who underwent surgical biopsy of a DIPG at a single institution. RESULTS: Nine patients were included, four males and five females. Age at presentation ranged from 8 months to 10 years (average 5.7 years). Pathologic diagnoses included five high grade (WHO grade III or IV) gliomas and four low grade (WHO grade II) astrocytomas. There were no intraoperative complications, and only one patient developed a new postoperative neurologic deficit. CONCLUSIONS: Stereotactic biopsy of DIPGs is essential to obtain a pathologic diagnosis and is associated with low morbidity. This technique is important to elucidate biological characteristics of these tumors in order to direct multidisciplinary treatment plans possibly involving chemotherapy, radiation therapy, or other future clinical trial interventions for children with DIPGs. PMID- 23666402 TI - Influence of ligand presentation density on the molecular recognition of mannose functionalised glyconanoparticles by bacterial lectin BC2L-A. AB - Polyvalent carbohydrate-protein interactions play a key role in bio- and pathological processes, including cell-cell communication and pathogen invasion. In order to study, control and manipulate these interactions gold nanoparticles have been employed as a 3D scaffold, presenting carbohydrate ligands in a multivalent fashion for use as high affinity binding partners and a model system for oligosaccharide presentation at biomacromolecular surfaces. In this study, the binding of a series of mannose-functionalised gold nanoparticles to the dimeric BC2L-A lectin from Burkholderia cenocepacia has been evaluated. BC2L-A is known to exhibit a high specificity for (oligo)mannosides. Due to the unique structure and binding nature of this lectin, it provides a useful tool to study (oligo)saccharides presented on multivalent scaffolds. Surface plasmon resonance and isothermal titration calorimetric assays were used to investigate the effect of ligand presentation density towards binding to the bacterial lectin. We show how a combination of structural complementarities between ligand presentation and lectin architecture and statistical re-binding effects are important for increasing the avidity of multivalent ligands for recognition by their protein receptors; further demonstrating the application of glyconanotechnology towards fundamental glycobiology research as well as a potential towards biomedical diagnostics and therapeutic treatments. PMID- 23666403 TI - Chryseobacterium yeoncheonense sp. nov., with ginsenoside converting activity isolated from soil of a ginseng field. AB - A Gram-staining negative, aerobic, non-motile, non-flagellate, yellow-pigmented, rod-shaped bacterial strain, designated strain DCY67(T), was isolated from ginseng field in Republic of Korea. Strain DCY67(T) contained beta-glucosidase activity which converts ginsenoside Rb1 to compound K. Optimum growth of DCY67(T) occurred at 30 degrees C and pH 6.0-6.5. Analysis of the 16S rRNA gene sequences revealed that strain DCY67(T) belonged to the family Flavobacteriaceae and was most closely related to Chryseobacterium ginsenosidimutans THG 15(T) (97.5 %). The genomic DNA G+C content was 36.1 mol%. The predominant quinones were MK-6 (90.9 %) and MK-7 (9.15 %). The major fatty acids were iso-C15:0, summed feature 3 (containing C16:1 omega7c and/or C16:1 omega6c) and iso-C17:0 3-OH. On the basis of these phenotypic, genotypic and chemotaxonomic studies, strain DCY67(T) represents a novel species of the genus Chryseobacterium, for which, name Chryseobacterium yeoncheonense sp. nov. proposed the type strain is DCY67(T) (=KCTC 32090(T) = JCM 18516(T)). PMID- 23666404 TI - Imaging biomarkers and the role of neuroinflammation in neuropathic pain. AB - The papers from this thematic issue followed a translational research workshop, Imaging Neuroinflammation and Neuropathic Pain, that focused on the search for neuroimaging biomarkers to assess neuroinflammation associated with neuropathic pain. The topics covered in this issue include overviews of the historical and current knowledge regarding neuropathic pain, the potential mechanisms involved, the often under-recognized clinical presentations that can delay diagnosis, the various neuroimaging techniques that have been applied to evaluate neuropathic pain and neuroinflammation, to case series illustrating novel treatments of neuropathic pain. Furthermore, the use of telemedicine to disseminate knowledge and improve the diagnosis and treatment of pain syndromes is also discussed. PMID- 23666405 TI - The Identification of Seniors at Risk (ISAR) score to predict clinical outcomes and health service costs in older people discharged from UK acute medical units. AB - BACKGROUND: tools are required to identify high-risk older people in acute emergency settings so that appropriate services can be directed towards them. OBJECTIVE: to evaluate whether the Identification of Seniors At Risk (ISAR) predicts the clinical outcomes and health and social services costs of older people discharged from acute medical units. DESIGN: an observational cohort study using receiver-operator curve analysis to compare baseline ISAR to an adverse clinical outcome at 90 days (where an adverse outcome was any of death, institutionalisation, hospital readmission, increased dependency in activities of daily living (decrease of 2 or more points on the Barthel ADL Index), reduced mental well-being (increase of 2 or more points on the 12-point General Health Questionnaire) or reduced quality of life (reduction in the EuroQol-5D) and high health and social services costs over 90 days estimated from routine electronic service records. SETTING: two acute medical units in the East Midlands, UK. PARTICIPANTS: a total of 667 patients aged >=70 discharged from acute medical units. RESULTS: an adverse outcome at 90 days was observed in 76% of participants. The ISAR was poor at predicting adverse outcomes (AUC: 0.60, 95% CI: 0.54-0.65) and fair for health and social care costs (AUC: 0.70, 95% CI: 0.59 0.81). CONCLUSIONS: adverse outcomes are common in older people discharged from acute medical units in the UK; the poor predictive ability of the ISAR in older people discharged from acute medical units makes it unsuitable as a sole tool in clinical decision-making. PMID- 23666406 TI - The predictive properties of frailty-rating scales in the acute medical unit. AB - BACKGROUND: older people are at an increased risk of adverse outcomes following attendance at acute hospitals. Screening tools may help identify those most at risk. The objective of this study was to compare the predictive properties of five frailty-rating scales. METHOD: this was a secondary analysis of a cohort study involving participants aged 70 years and above attending two acute medical units in the East Midlands, UK. Participants were classified at baseline as frail or non-frail using five different frailty-rating scales. The ability of each scale to predict outcomes at 90 days (mortality, readmissions, institutionalisation, functional decline and a composite adverse outcome) was assessed using area under a receiver-operating characteristic curve (AUC). RESULTS: six hundred and sixty-seven participants were studied. Frail participants according to all scales were associated with a significant increased risk of mortality [relative risk (RR) range 1.6-3.1], readmission (RR range 1.1 1.6), functional decline (RR range 1.2-2.1) and the composite adverse outcome (RR range 1.2-1.6). However, the predictive properties of the frailty-rating scales were poor, at best, for all outcomes assessed (AUC ranging from 0.44 to 0.69). CONCLUSION: frailty-rating scales alone are of limited use in risk stratifying older people being discharged from acute medical units. PMID- 23666407 TI - F-actin and a type-II myosin are required for efficient clustering of the ER stress sensor Ire1. AB - Endoplasmic reticulum (ER) stress causes the ER-resident transmembrane protein Ire1 to self-associate, leading to the formation of large oligomeric clusters. In yeast cells, this induces strong unfolded protein response (UPR) through splicing of HAC1 mRNA. Here, we demonstrate that highly ER-stressed yeast cells exhibited poor Ire1 clustering in the presence of the actin-disrupting agent latrunculin-A. Under these conditions, Ire1 may form smaller oligomers because latrunculin-A only partially diminished the Ire1-mediated splicing of HAC1 mRNA. Ire1 cluster formation was also impaired by deletion of the type-II myosin gene MYO1 or SAC6, which encodes the actin-bundling protein fimbrin. Finally, we demonstrated that Ire1 clusters are predominantly located on or near actin filaments. Therefore, we propose that actin filaments play an important role in ER stress-induced clustering of Ire1. PMID- 23666408 TI - Photoelectron spectroscopy of aromatic compound clusters of the B12 all-boron benzene: B12Au- and B12(BO)-. AB - We report a photoelectron spectroscopy and density-functional theory study of the B12Au(-) and B13O(-) clusters and their neutrals, which are shown to be six pi electron aromatic compounds between the quasi-planar all-boron B12 benzene analogue and a monovalent Au or BO ligand. Electron affinities of B12Au and B13O are measured to be 3.48 +/- 0.04 and 3.90 +/- 0.04 eV, respectively. Structural searches are performed for B12Au(-) and B13O(-), which are compared with the isovalent B12H(-) cluster. The global minima of B12Au(-) and B13O(-) both feature an almost intact B12 cluster with the Au and BO ligands bonded to its periphery, respectively. For B12Au(-), a low-lying isomer is also identified, which is only 0.4 kcal mol(-1) above the global minimum, in agreement with the experimental observation of a weakly populated isomer in the cluster beam of B12Au(-). These aromatic compound clusters provide new examples for the Au/H isolobal analogy and the boronyl (BO) chemistry. PMID- 23666409 TI - Formative evaluation of ontology learning methods for entity discovery by using existing ontologies as reference standards. AB - OBJECTIVE: Developing a two-step method for formative evaluation of statistical Ontology Learning (OL) algorithms that leverages existing biomedical ontologies as reference standards. METHODS: In the first step optimum parameters are established. A 'gap list' of entities is generated by finding the set of entities present in a later version of the ontology that are not present in an earlier version of the ontology. A named entity recognition system is used to identify entities in a corpus of biomedical documents that are present in the 'gap list', generating a reference standard. The output of the algorithm (new entity candidates), produced by statistical methods, is subsequently compared against this reference standard. An OL method that performs perfectly will be able to learn all of the terms in this reference standard. Using evaluation metrics and precision-recall curves for different thresholds and parameters, we compute the optimum parameters for each method. In the second step, human judges with expertise in ontology development evaluate each candidate suggested by the algorithm configured with the optimum parameters previously established. These judgments are used to compute two performance metrics developed from our previous work: Entity Suggestion Rate (ESR) and Entity Acceptance Rate (EAR). RESULTS: Using this method, we evaluated two statistical OL methods for OL in two medical domains. For the pathology domain, we obtained 49% ESR, 28% EAR with the Lin method and 52% ESR, 39% EAR with the Church method. For the radiology domain, we obtain 87% ESA, 9% EAR using Lin method and 96% ESR, 16% EAR using Church method. CONCLUSION: This method is sufficiently general and flexible enough to permit comparison of any OL method for a specific corpus and ontology of interest. PMID- 23666410 TI - The Caenorhabditis elegans Lifespan Machine. AB - The measurement of lifespan pervades aging research. Because lifespan results from complex interactions between genetic, environmental and stochastic factors, it varies widely even among isogenic individuals. The actions of molecular mechanisms on lifespan are therefore visible only through their statistical effects on populations. Indeed, survival assays in Caenorhabditis elegans have provided critical insights into evolutionarily conserved determinants of aging. To enable the rapid acquisition of survival curves at an arbitrary statistical resolution, we developed a scalable imaging and analysis platform to observe nematodes over multiple weeks across square meters of agar surface at 8-MUm resolution. The automated method generates a permanent visual record of individual deaths from which survival curves are constructed and validated, producing data consistent with results from the manual method of survival curve acquisition for several mutants in both standard and stressful environments. Our approach permits rapid, detailed reverse-genetic and chemical screens for effects on survival and enables quantitative investigations into the statistical structure of aging. PMID- 23666411 TI - High-throughput tetrad analysis. AB - Tetrad analysis has been a gold-standard genetic technique for several decades. Unfortunately, the need to manually isolate, disrupt and space tetrads has relegated its application to small-scale studies and limited its integration with high-throughput DNA sequencing technologies. We have developed a rapid, high throughput method, called barcode-enabled sequencing of tetrads (BEST), that uses (i) a meiosis-specific GFP fusion protein to isolate tetrads by FACS and (ii) molecular barcodes that are read during genotyping to identify spores derived from the same tetrad. Maintaining tetrad information allows accurate inference of missing genetic markers and full genotypes of missing (and presumably nonviable) individuals. An individual researcher was able to isolate over 3,000 yeast tetrads in 3 h, an output equivalent to that of almost 1 month of manual dissection. BEST is transferable to other microorganisms for which meiotic mapping is significantly more laborious. PMID- 23666412 TI - Improving the efficiency of antioxidant extraction from mango peel by using microwave-assisted extraction. AB - The purpose of this study was to analyze the extraction efficiency of antioxidants from mango peel by comparing two techniques: microwave-assisted (MAE) and traditional solvent (TE) extraction. The number of extraction steps, water content in the extractant, peel weight-to-solvent volume ratio in extractions and extraction time all had an influence on obtaining extracts with high antioxidant capacity, but the extraction technique and the water content in the extractant were the factors with the greatest effect. Using three steps, a water content of 50 % in the ethanol:water extractant, an extraction time of 60 min and a weight-to-volume ratio of 1:10 or 1:50 (w/v) led to the highest antioxidant activity and phytochemicals content in extracts. The extraction time needed to extract phytochemicals from mango peel was similar when MAE and TE were used. However, the antioxidant capacity and phytochemical content were around 1.5 6.0 times higher in the extracts obtained by MAE. PMID- 23666413 TI - The role of the gastrointestinal tract in phosphate homeostasis in health and chronic kidney disease. AB - PURPOSE OF REVIEW: For a number of years, there has been increasing interest in the concept of directly targeting intestinal phosphate transport to control hyperphosphatemia in chronic kidney disease. However, progress has been slow due to the paucity of information on the mechanisms involved in intestinal phosphate absorption. This editorial highlights the most recent developments in our understanding of this process and the role of the intestine in the maintenance of phosphate balance. RECENT FINDINGS: Recent studies in NaPi-IIb knockout mice have confirmed that this transport protein plays a significant role in intestinal phosphate absorption and is critical in the proposed feed-forward mechanism between the small intestine and kidney, which helps to maintain normal phosphate balance and steady-state plasma phosphate concentrations. In addition, renal failure-induced hyperphosphatemia is attenuated in NaPi-IIb knockout mice, confirming that NaPi-IIb is a suitable target in the prevention and treatment of hyperphosphatemia. SUMMARY: Recent findings suggest that consumption of processed foods containing phosphate preservatives may lead to excessive phosphate exposure (if not overload), toxicity, and cardiovascular disease in the general population, as well as in patients with declining renal function. Therefore, establishing more effective ways of targeting the intestine to limit dietary phosphate absorption could have wide-reaching health benefits. PMID- 23666414 TI - Circadian regulation of renal function and potential role in hypertension. AB - PURPOSE OF REVIEW: Previous studies have shown that a variety of specific renal functions exhibit circadian oscillations. This review aims to provide an update on the molecular mechanisms underlying circadian rhythms in the kidney, and to discuss how dysregulation of circadian rhythms can interfere with kidney function. RECENT FINDINGS: The molecular mechanism responsible for generating and maintaining circadian rhythms has been unraveled in great detail. This mechanism, known as the circadian clock, drives circadian oscillation in expression levels of a large number of renal mRNA transcripts. Several proteins critically involved in renal homeostatic functions have been shown to exhibit significant circadian oscillation in their expression levels or in their posttranslational modifications. In transgenic mouse models, disruption of circadian clock activity results in dramatic changes in the circadian pattern of urinary sodium and potassium excretion and causes significant changes in arterial blood pressure. A growing amount of evidence suggests that dysregulation of circadian rhythms is associated with the development of hypertension and accelerated progression of chronic kidney disease and cardiovascular disease in humans. Chronotherapy studies have shown that the efficacy of antihypertensive medication is greatly dependent on the circadian time of drug administration. SUMMARY: Recent research points to the major role of circadian rhythms in renal function and in control of blood pressure. PMID- 23666415 TI - FGF23 and Klotho in chronic kidney disease. AB - PURPOSE OF REVIEW: The wealth of data regarding fibroblast growth factor-23 (FGF23) and Klotho in chronic kidney disease (CKD) has risen exponentially over the past decade. This review is an attempt to summarize pivotal aspects of previous research, provide an update of recent findings and define important areas for future investigation. RECENT FINDINGS: The phosphaturic hormone FGF23 increases dramatically as renal function declines. Identification of contributing stimuli to the rise in FGF23 is fundamental and recent evidence suggest a multifactorial cause which entails perturbed osteocyte function and renal mechanisms such as Klotho deficiency and, somewhat paradoxically, systemic Klotho excess. Circulating FGF23 predicts adverse outcomes, particularly cardiovascular disease, in CKD as well as in the general population. The concept of FGF23 merely as a biomarker and regulator of mineral metabolism is currently challenged by data linking FGF23 to pathological processes such as cardiac hypertrophy. Conversely, tissue level of the FGF23 coreceptor Klotho declines in early CKD and this deficiency is linked to accelerated ageing, cellular senescence, vascular calcification, oxidative stress and renal fibrosis. At present, methodological difficulties limit the utility of soluble Klotho measurements. Animal proof-of concept studies have demonstrated beneficial effects of Klotho delivery in CKD, whereas anti-FGF23 therapy using neutralizing antibodies improved biochemical and bone parameters at the expense of increased vascular calcification and mortality. SUMMARY: Pathological alterations of FGF23-Klotho in CKD are implicated as clinical biomarkers and may provide novel therapeutic strategies to alleviate the cardiovascular risk and slow CKD progression. PMID- 23666416 TI - Impact of new vitamin D data on future studies and treatment. AB - PURPOSE OF REVIEW: This review evaluates recently published data on clinical effects of vitamin D supplementation, focusing on randomized, placebo-controlled trials and nontraditional actions on the cardiovascular and immune systems. RECENT FINDINGS: Several randomized trials evaluating vitamin D therapy have recently emerged, in both the general population and in individuals with chronic kidney disease (CKD). In the former, measurable effects on cardiovascular risk factors have not been detected, with the possible exception of a modest reduction in blood pressure. Studies aimed at boosting immunity have demonstrated efficacy only in specific, high-risk populations. In CKD, the benefits of nutritional vitamin D appear largely limited to earlier stages of disease. Benefits of active vitamin D agents, outside of their known effects on mineral metabolism, have also thus far eluded detection. One possible exception that has accumulated supportive evidence is the link between active vitamin D analogs and decreased proteinuria. Large-scale clinical trials, now underway, will be critical to understanding of the potential benefits and hazards of vitamin D treatment. SUMMARY: New trials evaluating the effects of vitamin D supplementation have failed to reveal any robust clinical benefits beyond its known actions on mineral and bone disease. PMID- 23666417 TI - Update on cystinuria. AB - PURPOSE OF REVIEW: Cystinuria is a rare genetic disease with increased urinary excretion of the poorly soluble amino acid cystine. It can lead to significant morbidity in affected patients due to the often large and recurrent resulting kidney stones. Treatment is focused on the prevention of stone formation. There have been few advances in the available therapeutic options for the disorder in the last 15-20 years. RECENT FINDINGS: Although no new treatments have emerged in the prevention of cystinuria in recent years, several developments hold promise for advancing the field of caring for affected patients. A new method of measuring urinary cystine and estimating potential for stone formation, called cystine capacity, may prove to be a useful tool in monitoring the disease. The discoveries of the mutations that cause cystinuria have led to a new classification system based on genotype that is more accurate than the prior phenotypic one. The finding of new compounds that inhibit cystine crystal growth in vitro, now being tested in animal models, may lead to new potential therapies in years to come. The Rare Kidney Stone Consortium has developed a registry and hopes to lead further efforts in dealing with cystinuria. SUMMARY: With several recent advances in the monitoring and treatment of cystinuria, and the gathering of clinical patient data, there are now opportunities for new management protocols and therapies. PMID- 23666418 TI - Innovations in bones and stones. PMID- 23666419 TI - Effect of depression onset on adherence to medication among hypertensive patients: a longitudinal modelling study. AB - OBJECTIVES: Although a link between depression and poor adherence to antihypertensive medication (AHM) has been found, it is not known whether depression actually leads to poorer adherence or whether poor adherence only is a marker of depression. In this study we aimed to determine the time order between hypertension, depression and changes in adherence to AHM. METHODS: The analyses were based on data gathered from a longitudinal cohort of Finnish employees (The Finnish Public Sector Study). A total of 852 chronically hypertensive men and women at baseline with a recorded onset of depression during the 9-year observation window and 2359 hypertensive control participants matched for age, sex, socio-economic status, time of study entry, employer and geographic area were included in the study. Individuals with any sign of depression during 4 years before the beginning of the study were excluded. To describe long-term trajectories (4 years before and 4 years after the recorded depression) of AHM adherence in relation to the onset of depression, annual data on reimbursed AHM prescriptions were gathered from the national Drug Prescription Register. Annual nonadherence rates (i.e. number of 'days-not-treated') were based on filled prescriptions. RESULTS: Among male cases, the rate of 'days-not-treated' was 1.52 times higher (95% confidence interval 1.08-2.14) in the years after the onset of depression compared to preonset levels. In women and in male controls, no change in adherence to AHM was observed between these time periods. CONCLUSION: In hypertensive men, the onset of recorded depression increases the risk of nonadherence to AHM. PMID- 23666420 TI - Sex differences in noninvasive vascular function in the community. AB - OBJECTIVE: The relation of noninvasive vascular function to sex, sex hormones, and reproductive history in the general population is little understood. METHODS: We simultaneously assessed flow-mediated dilation (FMD) and peripheral arterial tonometry in 454 women (mean age 40.4+/-16.1 years, age range 19-78 years) and 100 men (mean age 44.7+/-15.3 years) in a community-based cohort. Plasma estradiol, progesterone, luteinizing hormone, and follicle stimulating hormones were measured, and menstrual cycle and reproductive history were recorded. RESULTS: Vascular function was blunted in men as compared to women irrespective of menopausal status and adjustment for classical cardiovascular risk factors and hormones. Vascular reactivity changed during the menstrual cycle and correlated with estradiol concentrations for FMD, r=0.13 and inversely with progesterone for pulse amplitude, r=-0.14, and brachial artery diameter, r=-0.10. Multivariable adjusted regressions showed a relation of estradiol with FMD, beta 0.658, 95% confidence interval (CI) 0.084/1.232, P=0.025 in women. Age at menarche (beta 0.070, 95% CI 0.039/0.101, P<0.0001) and breastfeeding duration (beta -0.006, 95% CI -0.011/-0.001, P=0.036) were related to brachial artery diameter, age at menarche also to FMD (beta -0.455, 95% CI -0.886/-0.023, P=0.039). CONCLUSION: Sex differences in noninvasive conduit and peripheral arterial function with better vascular reactivity in women were not fully explained by female sex hormones and menopausal status. Age at menarche and duration of breastfeeding were also related to vascular function and need further investigation. PMID- 23666421 TI - Silencing of Atp2b1 increases blood pressure through vasoconstriction. AB - BACKGROUND: Recent genome-wide association studies (GWASs) have identified 30 genetic loci that regulate blood pressure, increasing our understanding of the cause of hypertension. However, it has been difficult to define the causative genes at these loci due to a lack of functional analyses. METHOD: In this study, we aimed to validate the candidate gene ATP2B1 in 12q21, variants near which have the strongest association with blood pressure in Asians and Europeans. ATP2B1 functions as a calcium pump to fine-tune calcium concentrations - necessary for repolarization following muscular contractions. We silenced Atp2b1 using an siRNA complex, injected into mouse tail veins. RESULTS: In treated mice, blood pressure rose and the mesenteric arteries increased in wall : lumen ratio. Moreover, the arteries showed enhanced myogenic responses to pressure, and contractile responses to phenylephrine increased compared with the control, suggesting that blood pressure is regulated by ATP2B1 through the contraction and dilation of the vessel, likely by controlling calcium concentrations in the resting state. CONCLUSION: These results support that ATP2B1 is the causative gene in the blood pressure-associated 12q21 locus and demonstrate that ATP2B1 expression in the vessel influences blood pressure. PMID- 23666422 TI - Vascular and parenchymal lesions along with enhanced neurogenesis characterize the brain of asymptomatic stroke-prone spontaneous hypertensive rats. AB - BACKGROUND AND OBJECTIVES: Spontaneously hypertensive stroke-prone rats (SHRSPs) develop hypertension, cerebrovascular abnormalities and a stroke phenotype in association with higher levels of proteinuria. Here, we focus on cerebral abnormalities preceding lesions detectable by MRI. METHODS: Longitudinal assessment of brain histology was performed in salt-loaded male SHRSPs (n = 26) and Wistar-Kyoto (WKY) normotensive control animals (n = 27). Groups of rats were sacrificed at different time points: Time 0, before the salt diet administration; Time 1, when proteinuria achieved 40 mg/day; Time 2, when proteinuria exceeded 100 mg/day. RESULTS: At Time 0, no brain lesions were observed. At Time 1, changes of the cortical penetrating arteries, vasogenic oedema, lacunae and focal cell loss appeared in SHRSPs and worsened at Time 2, although no lesions were yet detected by MRI. Staining for proliferation markers revealed a significant boost of cellular mitosis in the subventricular zone (SVZ) of SHRSPs. Moreover, we observed higher immunopositivity for nestin, glial fibrillary acidic protein and doublecortin (markers for neural stem cells, astrocytes and immature neurons, respectively). At Time 2, apoptotic caspase-3 as well as 4-hydroxynonenal positive neurons were associated to decreased nestin and doublecortin staining. High expression levels of glial fibrillary acidic protein were maintained in the SVZ. No comparative alterations and SVZ activation were recorded in WKYs. CONCLUSION: Appearance of vascular changes in SHRSPs, before any MRI-detectable brain lesion, is coupled to active neural proliferation in the SVZ. With disease progression, only newborn astrocytes can survive, likely because of the neurotoxicity triggered by brain oedema and oxidative stress. PMID- 23666423 TI - Prevalence, awareness, and control of hypertension among Asian Indians living in urban Singapore and rural India. AB - BACKGROUND: Hypertension is a major modifiable risk factor associated with cardiovascular morbidity and mortality. We compared the epidemiology of hypertension in South Asian Indians living in two geographic regions with vastly different socioeconomic settings (urban Singapore and rural India). METHODS: We analyzed data from two large population-based studies: the Singapore Indian Eye Study (SINDI, n = 3228, aged 40-80 years, 49.2% women) and the Central India Eye and Medical Study (CIEMS, n = 3591, aged >=40 years, 52.6% women). Hypertension was defined as SBP at least 140 or DBP at least 90 mmHg or self-reported history/treatment for hypertension. RESULTS: The age-adjusted prevalence of hypertension in SINDI and CIEMS were 58.6 and 25.3%. After adjusting for potential confounders, increasing age, overweight/obese, and diabetes status showed a positive association and 'never drinking alcohol' showed a protective association with hypertension in both populations. Current smoking and being female showed a protective association and no formal education showed a positive association with hypertension in SINDI. Among those with hypertension in SINDI and CIEMS, 72.4 and 25.3% were aware of their condition of whom 85 and 31.6% were on treatment for hypertension. The blood pressure control was similar between the two populations (48.7% in SINDI and 46.9% in CIEMS). CONCLUSION: The prevalence of hypertension, the level of awareness, and treatment for hypertension was higher in Indians living in Singapore than in rural Indians. Socioeconomic and metabolic factors explain some of the observed differences between the two populations, which may provide insights to develop public health strategies. PMID- 23666424 TI - Relationship between serum infliximab trough levels and endoscopic activities in patients with Crohn's disease under scheduled maintenance treatment. AB - BACKGROUND AND AIMS: Few data are available to support the clinical relevance of infliximab (IFX) trough levels for prediction of endoscopic disease activity in Crohn's disease (CD). This study evaluated the endoscopic disease activities in relation to clinical outcome using several laboratory markers including serum IFX trough levels in patients with CD undergoing scheduled IFX maintenance treatment. MATERIALS AND METHODS: A total of 78 sessions of endoscopy were performed on 45 patients with CD. Endoscopic activity was assessed using the modified Rutgeerts scoring system. IFX trough levels and anti-IFX antibodies (ATIs) were determined by immunoassays. RESULTS: Endoscopic activity negatively correlated with serum IFX trough levels (Spearman's rank correlation coefficient (rho) = -0.54, P < 0.0001) and serum albumin levels (rho = -0.46, P < 0.0001), and positively correlated with CRP (C-reactive protein) levels (rho = 0.55, P < 0.0001), ESR (erythrocyte sedimentation rate) (rho = 0.47, P < 0.0001) and fecal calprotectin levels. IFX trough levels and serum albumin levels were significantly elevated in the mucosal healing (MH) group, but ATIs, CRP, ESR and fecal calprotectin levels were significantly elevated in the nonmucosal healing group. Receiver operation curve revealed that the optimal cutoff value of IFX trough levels for identifying normal laboratory markers was 0.6 MUg/ml for CRP, 1.0 MUg/ml for serum albumin and 1.1 MUg/ml for fecal calprotectin. Identification of mucosal healing needed a higher cutoff value of 4.0 MUg/ml. Thiopurine treatment did not affect IFX trough and ATI levels. CONCLUSION: Mucosal healing requires higher IFX trough levels, compared to those to achieve normalization of routine clinical markers. PMID- 23666425 TI - Nitric oxide and zinc-mediated protein assemblies involved in mu opioid receptor signaling. AB - Opioids are among the most effective analgesics in controlling the perception of intense pain, although their continuous use decreases their potency due to the development of tolerance. The glutamate N-methyl-D-aspartate (NMDA) receptor system is currently considered to be the most relevant functional antagonist of morphine analgesia. In the postsynapse of different brain regions the C terminus of the mu-opioid receptor (MOR) associates with NR1 subunits of NMDARs, as well as with a series of signaling proteins, such as neural nitric oxide synthase (nNOS)/nitric oxide (NO), protein kinase C (PKC), calcium and calmodulin dependent kinase II (CaMKII) and the mitogen-activated protein kinases (MAPKs). NO is implicated in redox signaling and PKC falls under the regulation of zinc metabolism, suggesting that these signaling elements might participate in the regulation of MOR activity by the NMDAR. In this review, we discuss the influence of redox signaling in the mechanisms whose plasticity triggers opioid tolerance. Thus, the MOR C terminus assembles a series of signaling proteins around the homodimeric histidine triad nucleotide-binding protein 1 (HINT1). The NMDAR NR1 subunit and the regulator of G protein signaling RGSZ2 bind HINT1 in a zinc independent manner, with RGSZ2 associating with nNOS and regulating MOR-induced production of NO. This NO acts on the RGSZ2 zinc finger, providing the zinc ions that are required for PKC/Raf-1 cysteine-rich domains to simultaneously bind to the histidines present in the HINT1 homodimer. The MOR-induced activation of phospholipase beta (PLCbeta) regulates PKC, which increases the reactive oxygen species (ROS) by acting on NOX/NADPH, consolidating the long-term PKC activation required to regulate the Raf-1/MAPK cascade and enhancing NMDAR function. Thus, RGSZ2 serves as a Redox Zinc Switch that converts NO signals into Zinc signals, thereby modulating Redox Sensor Proteins like PKCgamma and Raf-1. Accordingly, redox-dependent and independent processes weave together to situate the MOR under the negative control of the NMDAR. PMID- 23666426 TI - A combination of epitope prediction and molecular docking allows for good identification of MHC class I restricted T-cell epitopes. AB - In silico identification of T-cell epitopes is emerging as a new methodology for the study of epitope-based vaccines against viruses and cancer. In order to improve accuracy of prediction, we designed a novel approach, using epitope prediction methods in combination with molecular docking techniques, to identify MHC class I restricted T-cell epitopes. Analysis of the HIV-1 p24 protein and influenza virus matrix protein revealed that the present approach is effective, yielding prediction accuracy of over 80% with respect to experimental data. Subsequently, we applied such a method for prediction of T-cell epitopes in SARS coronavirus (SARS-CoV) S, N and M proteins. Based on available experimental data, the prediction accuracy is up to 90% for S protein. We suggest the use of epitope prediction methods in combination with 3D structural modelling of peptide-MHC-TCR complex to identify MHC class I restricted T-cell epitopes for use in epitope based vaccines like HIV and human cancers, which should provide a valuable step forward for the design of better vaccines and may provide in depth understanding about activation of T-cell epitopes by MHC binding peptides. PMID- 23666427 TI - Morphology and growth of mammalian cells in a liquid/liquid culture system supported with oxygenated perfluorodecalin. AB - Adherent A431, BHK-21, and C2C12 cells were cultured on a flexible interface formed between two immiscible liquid phases: (i) hydrophobic perfluorodecalin (PFD) and (ii) aqueous culture medium (DMEM). BHK-21 cells formed multicellular aggregates characterized by irregular shapes. A431, as well as C2C12 cells, grew as tight multicellular sheets of 3-D cells. Enhanced mass transfer and facilitated access of the cells to the O2 dissolved in PFD/DMEM by approx. 250 % and thereby increased the density of BHK-21 cells. Thus the liquid/liquid system is a simple, ready-to-use, and fully scalable (independent of vessel shapes); consequently it is a method for 3-D cultures of adherent animal cells in which the growth of anchorage-dependent cells is not limited by confluence effect. PMID- 23666428 TI - Acceleration effect of amino acid supplementation on glycerol assimilation by Escherichia coli in minimal medium. AB - Growth of Escherichia coli BL21 in a glycerol minimal medium was accelerated following supplementation with trace amounts of amino acid (0.35 mM). Of 12 amino acids tested, Arg and Ser gave the highest response, increasing cell growth by 63 and 53 %, respectively, compared to control cells. The ability of amino acids to accelerate cell growth was "switch-like" and was achieved by promoting glycerol utilization, which may be applied to shorten the long lag-phase when glycerol is used as carbon source. Acceleration of cell growth following amino acid supplementation was also observed using lactose minimal medium. PMID- 23666429 TI - easyHealthApps: e-Health Apps dynamic generation for smartphones & tablets. AB - Mobile phones and especially smartphones have been embraced by a rapidly increasing number of people worldwide and this trend is expected to evolve even more in the years to come. There are numerous smartphone Apps that record critical medical data in an effort to solve a particular health issue each time. We studied such applications and not surprisingly, we have found that development and design effort is often repeated. Software patterns have been detected to exist, however re-usability has not been enforced. This leads to lost programming manpower and to increased probability of repeating bugs in Apps. Moreover, at the moment smartphone e-Health Apps demand time, effort and costs for development. Unfortunately even simple data recording Apps are practically impossible to be produced by multiple health domain users who are not developers. In this work, we propose, design and implement a simple and integrated solution which gives healthcare professionals and researchers the ability to create their own data intensive smartphone applications, independent of the desired healthcare domain. The proposed approach applies efficient software techniques that hide development from the users and enable App creation through a simple Web User Interface. The Apps produced are in native format and it is possible to dynamically receive m Health business logic and the chosen UI. Evaluation of the proposed solution has shown that the generated Apps are functionally and UI equivalent to human-coded Apps according to a number of comparison parameters. Furthermore, e-Health professionals show particular interest in developing Apps on their own for a particular domain they focus on. PMID- 23666430 TI - Resolution of hypertension and secondary aldosteronism after surgical treatment of primary hyperparathyroidism. PMID- 23666431 TI - Brain stem tumors in children and adolescents: single institutional experience. AB - PURPOSE: Pediatric brain stem tumors (BsT) are a heterogeneous group of diseases. Our aim was to analyze our experience to find out prognostic factors. METHOD: A retrospective study with BsT patients was performed. Imaging characteristics, extension of surgery, pathology, and adjuvant therapy were analyzed and correlated with overall survival (OS) and progression-free survival (PFS) as outcome measures. RESULT: Since 1980 to 2010, we analyzed 65 BsT patients, 41 of them girls (63%), median age of 8 years (range 13.9 months to 17.6 years). Twenty two patients (33.8%) had diffuse intrinsic pontine gliomas (DIPG) and 43 (66.2%) presented with focal BsT. Histology was available in 42 patients; the most frequent is low-grade glioma in 24/42 patients (57%). DIPG's histology (obtained usually at necropsy) confirmed five high-grade gliomas. After median follow-up of 49.3 months (0.5-175 months), 20/22 DIPG patients have died (90.9%), while 27/43 with focal tumors were alive (62.8%). Variables related to outcome were histology (better for low-grade glioma (LGG) OS p < 0.001), surgery (better if operated OS p < 0.001), and adjuvant therapy (worse if given, PFS p = 0.001, OS p = 0.024). The outcome for DIPG was dismal, median OS/EFS of 14.2/9.4 months, significantly worse than focal BsT (p = 0.000), while OS/EFS was 122.8/87.2 months for focal intrinsic, 88.2/47.1 months for exophytic, and 124.4/54 months for cervico medullary tumors: no differences were found among them, except the histology (OS p < 0.001 for low-grade vs high-grade tumors). CONCLUSION: BsT in children comprised two different groups: diffuse (DIPG) and focal gliomas. The DIPGs continue having a dismal prognosis, needing new approaches, while focal tumors including LGG have better prognosis. PMID- 23666432 TI - A new technique to facilitate optimal directions for cranial distractor implantation. AB - INTRODUCTION: We describe a new technique in distraction cranioplasty procedure to facilitate the placement of cranial distractors in a correct position. CONCLUSION: Avoiding conflict of the vectors when placing several distractors allows later attainment of the planned amount of distraction. PMID- 23666433 TI - Epileptic encephalopathy with continuous spikes and waves during sleep. AB - Epileptic encephalopathy with continuous spikes and waves during slow sleep (EECSWSS) is an age-related childhood condition characterized by epilepsy, cognitive or behavioral impairment, and electroencephalographic abnormality of continuous spike-wave discharges during slow sleep. Continuous spikes and waves during slow sleep (or electrical status epilepticus during sleep) is an electrographic pattern characterized by nearly continuous spike-wave discharges during non-REM sleep, with a frequency of 1.5-3 Hz and usually diffuse and bilateral in distribution. Most authors consider EECSWSS as wide spectrum of epileptic conditions of different origin associated with heterogeneous clinical manifestations and neuropsychological impairment of different severity in close temporal concordance with the appearance of the electroencephalographic pattern of electrical status epilepticus during sleep. The long-term prognosis of this condition is overall poor owing to the persistence of neuropsychological impairment. Therefore, early recognition and effective therapy are necessary to improve long-term prognosis. PMID- 23666434 TI - Prioritization strategies for patient evacuations. AB - Evacuation from a health care facility is considered last resort, and in the event of a complete evacuation, a standard planning assumption is that all patients will be evacuated. A literature review of the suggested prioritization strategies for evacuation planning-as well as the transportation priorities used in actual facility evacuations-shows a lack of consensus about whether critical or non-critical care patients should be transferred first. In addition, it is implied that these policies are "greedy" in that one patient group is given priority, and patients from that group are chosen to be completely evacuated before any patients are evacuated from the other group. The purpose of this paper is to present a dynamic programming model for emergency patient evacuations and show that a greedy, "all-or-nothing" policy is not always optimal as well as discuss insights of the resulting optimal prioritization strategies for unit- or floor-level evacuations. PMID- 23666435 TI - Measuring cardiac autonomic nervous system (ANS) activity in children. AB - The autonomic nervous system (ANS) controls mainly automatic bodily functions that are engaged in homeostasis, like heart rate, digestion, respiratory rate, salivation, perspiration and renal function. The ANS has two main branches: the sympathetic nervous system, preparing the human body for action in times of danger and stress, and the parasympathetic nervous system, which regulates the resting state of the body. ANS activity can be measured invasively, for instance by radiotracer techniques or microelectrode recording from superficial nerves, or it can be measured non-invasively by using changes in an organ's response as a proxy for changes in ANS activity, for instance of the sweat glands or the heart. Invasive measurements have the highest validity but are very poorly feasible in large scale samples where non-invasive measures are the preferred approach. Autonomic effects on the heart can be reliably quantified by the recording of the electrocardiogram (ECG) in combination with the impedance cardiogram (ICG), which reflects the changes in thorax impedance in response to respiration and the ejection of blood from the ventricle into the aorta. From the respiration and ECG signals, respiratory sinus arrhythmia can be extracted as a measure of cardiac parasympathetic control. From the ECG and the left ventricular ejection signals, the preejection period can be extracted as a measure of cardiac sympathetic control. ECG and ICG recording is mostly done in laboratory settings. However, having the subjects report to a laboratory greatly reduces ecological validity, is not always doable in large scale epidemiological studies, and can be intimidating for young children. An ambulatory device for ECG and ICG simultaneously resolves these three problems. Here, we present a study design for a minimally invasive and rapid assessment of cardiac autonomic control in children, using a validated ambulatory device (1-5), the VU University Ambulatory Monitoring System (VU-AMS, Amsterdam, the Netherlands, www.vu-ams.nl). PMID- 23666437 TI - Age and gender disparities in the risk of carotid revascularization procedures. AB - The potential effect of age and gender stratification in the outcome of patients with carotid artery stenosis undergoing carotid revascularization procedures (CRP) may have important implications in clinical practice. Both European Stroke Organization and American Heart Association guidelines suggest that age and sex should be taken into account when selecting a CRP for an individual patient. We reviewed available literature data through Medline and Embase. Our search was based on the combination of terms: age, gender, sex, carotid artery stenosis, carotid artery stenting (CAS) and carotid endarterectomy (CEA). Postoperative stroke and mortality rates increased with age after any CRP (CEA or CAS), especially in patients aged over 75 years. Older patients with carotid artery stenosis undergoing CAS were found to have a nearly double risk of stroke or death compared with CEA, while CEA was found to benefit more patients aged over 70 years with symptomatic carotid artery stenosis. Male patients with symptomatic or asymptomatic carotid artery stenosis had lower stroke/mortality rates and benefited more from CEA compared with females. For the periprocedural risk of stroke or death in patients with carotid artery stenosis after CAS no sex differences were found. Therefore, CEA appears to have lower perioperative risks than CAS in patients aged over 70 years, and thus should be the treatment of choice if not contraindicated. The periprocedural risk of CEA is lower in men than in women, while there was no effect of gender on the periprocedural risk of CAS. PMID- 23666439 TI - Factors affecting frequency of patient use of Internet-based telemedicine to manage cardiovascular disease risk. AB - We examined the frequency of use by patients of a web-based reporting system to monitor and control cardiovascular disease (CVD) risk factors. A total of 192 patients with intermediate or high CVD risk were categorized into four quartiles based on their frequency of use of the telemedicine reporting system over one year. The lowest frequency users (Quartile I) averaged 17 reporting days in one year and the highest frequency users (Quartile IV) averaged 211 reporting days in one year. Factors associated with more frequent use were overall knowledge of CVD (P = 0.014), blood lipids (P = 0.017), smoking (P = 0.036), higher scores in medication self-efficacy (P = 0.016) and higher income (P = 0.002). All quartiles showed trends of decreasing systolic blood pressure from hypertensive (>=140 mm Hg) to pre-hypertensive (<140) ranges. Patients were able to lower CVD risk with as few as two transmissions per month using the telemedicine system. Telemedicine reporting coupled with self-assessment of health status can promote a strong patient-provider partnership for managing the chronic risk factors of CVD. PMID- 23666438 TI - Telerehabilitation for people with chronic obstructive pulmonary disease: feasibility of a simple, real time model of supervised exercise training. AB - We evaluated the safety and feasibility of home telerehabilitation for people with chronic obstructive pulmonary disease (COPD). Eight patients with mean age of 66 years and moderately impaired lung function took part. The telerehabilitation equipment in the participant's home included an exercise bicycle, a tablet computer with webcam for low bandwidth videoconferencing, and a pulse oximeter positioned so that the display was visible while videoconferencing. Participants undertook supervised aerobic training twice a week for eight weeks, with two participants and a physiotherapist attending each class via videoconferencing from separate locations. Primary outcomes were adverse events, sessions attended and system usability. Secondary outcomes were the 6-minute walk distance (6MWD) and Chronic Respiratory Questionnaire (CRQ). No significant adverse events occurred during the study. Participants attended 76% of possible sessions. System usability ratings were excellent when sessions were delivered via the university network (mean 94 out of 100) but lower when using the hospital network (mean 59 out of 100), with 67% of technical problems related to data network capability. Five participants completed the programme, with clinically significant improvements in 6MWD (mean 27 m, SD 40) and CRQ dyspnoea (4 units, SD 4). Simple home-based telerehabilitation using readily available equipment is safe and feasible for people with COPD. Effective delivery of telerehabilitation requires an adequate data network. PMID- 23666436 TI - Magnetic resonance spectroscopy to assess neuroinflammation and neuropathic pain. AB - Proton magnetic resonance spectroscopy ((1)H MRS) has been applied to numerous clinical studies, especially for neurological disorders. This technique can non invasively evaluate brain metabolites and neurochemicals in selected brain regions and is particularly useful for assessing neuroinflammatory disorders. Neurometabolites assessed with MRS include the neuronal markers N-acetylaspartate (NAA) and glutamate (Glu), as well as the glial marker myo-inositol (MI). Therefore, the concentrations of these metabolites typically correspond to disease severity and often correlate well with clinical variables in the various brain disorders. Neuroinflammation with activated astrocytes and microglia in brain disorders are often associated with elevated MI, and to a lesser extent elevated total creatine (tCr) and choline containing compounds (Cho), which are found in higher concentrations in glia than neurons, while neuronal injury is indicated by lower than normal levels of NAA and Glu. This review summarizes the neurometabolite abnormalities found in MRS studies performed in patients with neuroinflammatory disorders or neuropathic pain, which also may be associated with neuroinflammation. These brain disorders include multiple sclerosis, neuroviral infections (including Human Immunodeficiency virus and Hepatitis C), degenerative brain disorders (including Alzheimer's disease and Parkinson's disease), stimulant abuse (including methamphetamine and cocaine) as well as several chronic pain syndromes. PMID- 23666440 TI - Clinical course outcomes for store and forward teledermatology versus conventional consultation: a randomized trial. AB - We assessed the clinical course of patients after store and forward teledermatology in comparison with conventional consultations. Patients being referred from primary care to dermatology clinics were randomly assigned to teledermatology or a conventional consultation. A total of 392 patients were randomized; 261 patients completed the study and were included in the analysis. Their clinical course was rated on a five-point scale by a panel of three dermatologists, blinded to study assignment, who reviewed serial digital image sets. The clinical course was assessed by comparing images sets between baseline and first clinic visit (if one occurred) and between baseline and nine months. There was no evidence to suggest a difference between the two groups in either clinical course between baseline and nine months post-referral (P = 0.88) or between baseline and the first dermatology clinic visit (P = 0.65). Among teledermatology referrals, subsequent presentation for an in-person dermatology clinic visit was significantly correlated with clinical course (P = 0.023). Store and forward teledermatology did not result in a significant difference in clinical course at either of two post-referral time periods. PMID- 23666441 TI - A miniaturised electron ionisation time-of-flight mass spectrometer that uses a unique helium ion removal pulsing technique specifically for gas analysis. AB - A miniaturised reflectron time-of-flight mass spectrometer combined with an electron ionisation ion source has been developed for the analysis of gases. An entirely new helium ion removal pulsing technique in this mass spectrometer is used to achieve an improved performance for the first time. The helium carrier gas, which enters into the source along with the gaseous sample, is simultaneously ionised and then orthogonally introduced into the time-of-fight mass analyser. Once the relatively light helium ions in the ion packet become extremely close to the reflectron plate (B-plate for short in this article), a modulated pulse is instantaneously applied on the B-plate and a negative reflectron voltage is set to the B-plate and lasts for a very short period, during which all the helium ions are directly bumped into the B-plate and subsequently removed. The helium ion removal pulsing technique can efficiently avoid saturation of the micro-channel plate caused by too many helium ions. A compact and durable instrument is designed, which has a mass resolving resolution greater than 400 FWHM for online gas analysis. The technology may also be further developed to remove other ions for TOF mass spectrometry. PMID- 23666442 TI - Peculiarities and applications of galactanolytic enzymes that act on type I and II arabinogalactans. AB - Arabinogalactans (AGs) are branched galactans to which arabinose residues are bound as side chains and are widely distributed in plant cell walls. They can be grouped into two types based on the structures of their backbones. Type I AGs have beta-1,4-galactan backbones and are often covalently linked to the rhamnogalacturonan-I region of pectins. Type II AGs have beta-1,3-galactan backbones and are often covalently linked to proteins. The main enzymes involved in the degradation of AGs are endo-beta-galactanases, exo-beta-galactanases, and beta-galactosidases, although other enzymes such as alpha-L-arabinofuranosidases, beta-L-arabinopyranosidases, and beta-D-glucuronidases are required to remove the side chains for efficient degradation of the polysaccharides. Galactanolytic enzymes have a wide variety of potential uses, including the bioconversion of AGs to fermentable sugars for production of commodity chemicals like ethanol, biobleaching of cellulose pulp, modulation of pectin properties, improving animal feed, and determining the chemical structure of AGs. This review summarizes our current knowledge about the biochemical properties and potential applications of AG-degrading enzymes. PMID- 23666443 TI - Bifunctional immobilization of a hyperthermostable endo-beta-1,3-glucanase. AB - Laminarinase A (LamA) from Pyrococcus furiosus is a hyperthermostable endo-beta 1,3-glucanase (EC 3.2.1.39) belonging to the glycosyl hydrolase family GH16. Here, we report the two-step immobilization of LamA on macroporous acrylic epoxy beads, extra-functionalized with disulfide groups. To facilitate initial immobilization via thiol-disulfide exchange, we introduced, by site-directed mutagenesis, a superficial cysteine residue near the protein C-terminal end. The thus-obtained S296C variant showed similar catalytic properties as native LamA. The activity of immobilized S296C displayed an inverse relationship with particle size. Use of conventional beads (150-300 MUm in diameter) obstructed the catalytic efficiency due to pore diffusion limitation of the polysaccharide substrate. Bifunctional attachment to milled beads (20-40 MUm) resulted in high enzyme load and outstanding catalytic features. Bifunctional immobilized S296C showed extreme pH stability and could be repeatedly used at 60 degrees C without significant activity loss. PMID- 23666444 TI - Catalytic activity of the two-component flavin-dependent monooxygenase from Pseudomonas aeruginosa toward cinnamic acid derivatives. AB - 4-Hydroxyphenylacetate 3-hydroxylases (HPAHs) of the two-component flavin dependent monooxygenase family are attractive enzymes that possess the catalytic potential to synthesize valuable ortho-diphenol compounds from simple monophenol compounds. In this study, we investigated the catalytic activity of HPAH from Pseudomonas aeruginosa strain PAO1 toward cinnamic acid derivatives. We prepared Escherichia coli cells expressing the hpaB gene encoding the monooxygenase component and the hpaC gene encoding the oxidoreductase component. E. coli cells expressing HpaBC exhibited no or very low oxidation activity toward cinnamic acid, o-coumaric acid, and m-coumaric acid, whereas they rapidly oxidized p coumaric acid to caffeic acid. Interestingly, after p-coumaric acid was almost completely consumed, the resulting caffeic acid was further oxidized to 3,4,5 trihydroxycinnamic acid. In addition, HpaBC exhibited oxidation activity toward 3 (4-hydroxyphenyl)propanoic acid, ferulic acid, and coniferaldehyde to produce the corresponding ortho-diphenols. We also investigated a flask-scale production of caffeic acid from p-coumaric acid as the model reaction for HpaBC-catalyzed syntheses of hydroxycinnamic acids. Since the initial concentrations of the substrate p-coumaric acid higher than 40 mM markedly inhibited its HpaBC catalyzed oxidation, the reaction was carried out by repeatedly adding 20 mM of this substrate to the reaction mixture. Furthermore, by using the HpaBC whole cell catalyst in the presence of glycerol, our experimental setup achieved the high-yield production of caffeic acid, i.e., 56.6 mM (10.2 g/L) within 24 h. These catalytic activities of HpaBC will provide an easy and environment-friendly synthetic approach to hydroxycinnamic acids. PMID- 23666445 TI - Intravenous infusion of ascorbic acid decreases serum histamine concentrations in patients with allergic and non-allergic diseases. AB - Histamine plays an important role in the development of symptoms in allergic, infectious, neoplastic and other diseases. Empirical findings have suggested beneficial effects of ascorbic acid supplementation in those diseases, and these effects are assumed to be related to a possible decrease in systemic histamine concentration. In the present study, we systematically investigated for the first time the effect of 7.5 g of intravenously administered ascorbic acid on serum histamine levels (as detected by ELISA) in 89 patients (19 with allergic and 70 with infectious diseases). When all patients were grouped together, there was a significant decline in histamine concentration from 0.83 to 0.57 ng/ml*m2 body surface area (BSA, p<0.0001). The decrease in serum histamine concentration in patients with allergic diseases (1.36 to 0.69 ng/ml*m2 BSA, p=0.0007) was greater than that in patients with infectious diseases (0.73 to 0.56 ng/ml*m2 BSA, p=0.01). Furthermore, the decline in histamine concentration after ascorbic acid administration was positively correlated with the basal, i.e. pre-therapeutic, histamine concentration. Intravenous infusion of ascorbic acid clearly reduced histamine concentrations in serum, and may represent a therapeutic option in patients presenting with symptoms and diseases associated with pathologically increased histamine concentration. PMID- 23666446 TI - Enhanced electrochemical reactions of 1,4-benzoquinone at nanoporous electrodes. AB - We report that the proton-coupled electron transfer kinetics of 1,4-benzoquinone was significantly enhanced in electrified nanopores in aqueous media. At nanoporous Pt and Au electrodes, the voltammetric behaviour of 1,4-benzoquinone at nanoporous electrodes was clearly distinct from that at flat surfaces. Proton transfer as well as electron transfer kinetics were facilitated in the nanopores by the confinement effect, which indicates all factors originated from the geometric features of nano-scale concave space surrounded by inner walls, suggesting how to utilize nanoporous electrodes for electrocatalysis. PMID- 23666447 TI - Developing topic-specific search filters for PubMed with click-through data. AB - OBJECTIVES: Search filters have been developed and demonstrated for better information access to the immense and ever-growing body of publications in the biomedical domain. However, to date the number of filters remains quite limited because the current filter development methods require significant human efforts in manual document review and filter term selection. In this regard, we aim to investigate automatic methods for generating search filters. METHODS: We present an automated method to develop topic-specific filters on the basis of users' search logs in PubMed. Specifically, for a given topic, we first detect its relevant user queries and then include their corresponding clicked articles to serve as the topic-relevant document set accordingly. Next, we statistically identify informative terms that best represent the topic-relevant document set using a background set composed of topic irrelevant articles. Lastly, the selected representative terms are combined with Boolean operators and evaluated on benchmark datasets to derive the final filter with the best performance. RESULTS: We applied our method to develop filters for four clinical topics: nephrology, diabetes, pregnancy, and depression. For the nephrology filter, our method obtained performance comparable to the state of the art (sensitivity of 91.3%, specificity of 98.7%, precision of 94.6%, and accuracy of 97.2%). Similarly, high-performing results (over 90% in all measures) were obtained for the other three search filters. CONCLUSION: Based on PubMed click-through data, we successfully developed a high-performance method for generating topic-specific search filters that is significantly more efficient than existing manual methods. All data sets (topic-relevant and irrelevant document sets) used in this study and a demonstration system are publicly available at http://www.ncbi.nlm.nih.gov/CBBresearch/Lu/downloads/CQ_filter/ PMID- 23666448 TI - Gigahertz quantized charge pumping in graphene quantum dots. AB - Single-electron pumps are set to revolutionize electrical metrology by enabling the ampere to be redefined in terms of the elementary charge of an electron. Pumps based on lithographically fixed tunnel barriers in mesoscopic metallic systems and normal/superconducting hybrid turnstiles can reach very small error rates, but only at megahertz pumping speeds that correspond to small currents of the order of picoamperes. Tunable barrier pumps in semiconductor structures are operated at gigahertz frequencies, but the theoretical treatment of the error rate is more complex and only approximate predictions are available. Here, we present a monolithic, fixed-barrier single-electron pump made entirely from graphene that performs at frequencies up to several gigahertz. Combined with the record-high accuracy of the quantum Hall effect and proximity-induced Josephson junctions, quantized-current generation brings an all-graphene closure of the quantum metrological triangle within reach. Envisaged applications for graphene charge pumps outside quantum metrology include single-photon generation via electron-hole recombination in electrostatically doped bilayer graphene reservoirs, single Dirac fermion emission in relativistic electron quantum optics and read-out of spin-based graphene qubits in quantum information processing. PMID- 23666449 TI - Update on the prevalence of antiretroviral drug resistance in treatment-naive individuals. PMID- 23666450 TI - Controlling the HIV epidemic with antiretrovirals: IAPAC consensus statement on treatment as prevention and preexposure prophylaxis. AB - In the context of emerging evidence related to preexposure prophylaxis and HIV treatment as prevention, an evidence summit was held in mid-2012 to discuss the current state of the science and to provide a platform for consensus building around whether and how these prevention strategies might be implemented globally. Health care providers, researchers, policy makers, people living with HIV/AIDS, and representatives of government authorities, donor agencies, pharmaceutical companies, advocacy organizations, and professional associations attended from 52 countries. An international advisory committee was convened to identify key messages and recommendations based upon the data presented and discussed at the summit. The advisory committee further worked to develop this consensus statement meant to assist relevant stakeholders in taking stock and mapping out a route forward to enhance the HIV prevention armamentarium. PMID- 23666451 TI - Antiemetic effect of naloxone in combination with dexamethasone and droperidol in patients undergoing laparoscopic gynecological surgery. AB - PURPOSE: We examined the effects of dexamethasone, droperidol, naloxone, and a combination of these three agents on postoperative nausea and vomiting (PONV) in female patients. METHODS: In this randomized, controlled study, 120 female patients with ASA PS I or II undergoing laparoscopic gynecological surgery were randomly allocated into four groups. Patients received dexamethasone 8 mg (Dx group) or droperidol 1 mg (Dr group) before induction of general anesthesia. Anesthesia was induced and maintained with propofol and remifentanil. Postoperative analgesia was provided by intravenous patient-controlled analgesia using a disposable infusion pump filled with fentanyl 20 MUg/kg alone (Dx group), fentanyl 20 MUg/kg with droperidol 2 mg (Dr group), fentanyl 20 MUg/kg with naloxone 0.1 mg (Nx group), or fentanyl 20 MUg/kg with droperidol 2 mg and naloxone 0.1 mg (Cm group) in a total volume of 80 ml, with a constant infusion rate of 4 ml/h and a bolus dose 2 ml with a 30-min lockout time. RESULTS: The number of patients who developed PONV and required a rescue antiemetic was significantly less in the Cm group than in the Nx group (p < 0.001 for all). The incidence of PONV was 43, 43, 70, and 17 % in the Dx, Dr, Nx, and Cm groups, respectively. CONCLUSION: A combination of naloxone, droperidol, and dexamethasone was effective for preventing PONV in patients receiving fentanyl for postoperative analgesia after laparoscopic gynecological surgery, although further investigations are required to examine the effect of adding naloxone to other antiemetics. PMID- 23666452 TI - Early postoperative cognitive dysfunction is associated with higher cortisol levels in aged patients following hip fracture surgery. AB - This study aimed to evaluate the relationship between plasma cortisol levels and the occurrence of postoperative cognitive dysfunction (POCD) in aged patients following hip fracture surgery. A total of 175 patients, aged 65 years or older, who were scheduled for hip fracture surgery with spinal anesthesia were enrolled. Perioperative plasma levels of cortisol and neurocognitive tests were determined at 1 day preoperatively and 7 days postoperatively. Seventy-seven patients completed both blood sample collections and neurocognitive tests. POCD occurred in 29.9 % of patients at 7 days postoperatively. POCD patients presented significantly higher cortisol levels compared with non-POCD patients (P < 0.05). Furthermore, plasma cortisol levels were negatively correlated with mini-mental state examination (MMSE) scores at 7 days postoperatively (P < 0.0001). A specificity of 93 % and a sensitivity of 35 % were identified for the plasma cortisol measurement to discriminate POCD patients from non-POCD patients. The results suggest higher plasma cortisol levels are associated with POCD in aged patients following hip fracture surgery with spinal anesthesia. PMID- 23666454 TI - A review on botanical species and chemical compounds with appetite suppressing properties for body weight control. AB - As obesity has reached epidemic proportions, the management of this global disease is of clinical importance. The availability and popularity of natural dietary supplements for the treatment of obesity has risen dramatically in recent years. The purpose of this paper was to review the effect of commonly available over the counter plant-derived supplements used to suppress appetite for obesity control and management. The data were obtained from the electronic databases PubMed, SpringerLink, Google Scholar, ScienceDirect, and MEDLINE with full text (via EBSCOHost) and the databases were accessed during late 2012 - early January 2013. The botanical species discussed in this review include Camellia sinensis, Caralluma fimbriata, Citrus aurantium, Coleus forskohlii, Garcinia cambogia and Phaseolus vulgaris. This review found that many botanical species including crude extracts and isolated compounds from plants have been shown to provide potentially promising therapeutic effects including appetite control and weight loss. However, many of these crude extracts and compounds need to be further investigated to define the magnitude of the effects, optimal dosage, mechanisms of action, long term safety, and potential side effects. PMID- 23666455 TI - Comparison of ethylene glycol and propylene glycol for the vitrification of immature porcine oocytes. AB - Our aim was to optimize a cryoprotectant treatment for vitrification of immature porcine cumulus-oocyte complexes (COCs). Immature COCs were vitrified either in 35% ethylene glycol (EG), 35% propylene glycol (PG) or a combination of 17.5% EG and 17.5% PG. After warming, the COCs were in vitro matured (IVM), and surviving oocytes were in vitro fertilized (IVF) and cultured. The mean survival rate of vitrified oocytes in 35% PG (73.9%) was higher (P<0.05) than that in 35% EG (27.8%). Oocyte maturation rates did not differ among vitrified and non-vitrified control groups. Blastocyst formation in the vitrified EG group (10.8%) was higher (P<0.05) than that in the vitrified PG group (2.0%) but was lower than that in the control group (25.0%). Treatment of oocytes with 35% of each cryoprotectant without vitrification revealed a higher toxicity of PG on subsequent blastocyst development compared with EG. The combination of EG and PG resulted in 42.6% survival after vitrification. The maturation and fertilization rates of the surviving oocytes were similar in the vitrified, control and toxicity control (TC; treated with EG+PG combination without cooling) groups. Blastocyst development in the vitrified group was lower (P<0.05) than that in the control and TC groups, which in turn had similar development rates (10.7%, 18.1% and 23.3%, respectively). In conclusion, 35% PG enabled a higher oocyte survival rate after vitrification compared with 35% EG. However, PG was greatly toxic to oocytes. The combination of 17.5% EG and 17.5% PG yielded reasonable survival rates without toxic effects on embryo development. PMID- 23666456 TI - Authors' response. PMID- 23666457 TI - Another cause of hyperglyceroluria: aquaporin 7 gene mutation. PMID- 23666458 TI - Long-term outcomes for infants with intestinal atresia studied at Children's National Medical Center. AB - OBJECTIVES: Intestinal atresia is a common cause of intestinal obstruction in neonates. The predominant cause of late complications in these children is prolonged dependence on parenteral nutrition (PN). Our aims were to analyze the outcomes for patients with intestinal atresia at our institution, and to see how these changed with the implementation of an intestinal rehabilitation program (IRP). METHODS: This is a retrospective cohort study. The patient population is all children with intestinal atresias (118 patients) treated at our institution from July 2000 to June 2010, 20 of whom became PN dependent. RESULTS: Survival to hospital discharge was 95% for all patients, and 100% for those who had isolated atresia. Twenty of 118 patients (17%) were PN dependent beyond initial hospital discharge. At discharge, their median intestinal length was 22.5 cm, and they required PN for a mean of 88.5% of energy needs. Of these 20 patients, 2 died, 2 received transplants, and 2 transferred away for transplantation. The remaining 14 joined the IRP. Their mean energy requirement from PN is presently 10%, down from 87% at IRP enrollment, and 10 patients fully weaned off PN. Eleven of the 14 children had hyperbilirubinemia, with mean direct bilirubin of 7.5 mg/dL. All resolved their cholestasis during an average of 12 weeks. CONCLUSIONS: These results compare favorably with those reported in earlier periods. With programs such as the IRP, patients with short bowel secondary to intestinal atresia can show improvement in liver function and nutritional parameters, and discontinue PN, avoiding the need for transplantation. PMID- 23666459 TI - Aspartate aminotransferase to platelet ratio index correlates with hepatic cirrhosis but not with fibrosis in pediatric patients with intestinal failure. AB - BACKGROUND AND OBJECTIVES: Patients with intestinal failure (IF) require parenteral nutrition (PN) support to obtain enough nutrients to sustain growth; long-term PN use is associated with significant liver damage. The aim of this study was to analyze the use of a noninvasive test, the aspartate aminotransferase to platelet ratio index (APRI), in the diagnosis of liver disease in pediatric patients with IF. METHODS: Medical records of all Boston Children's Hospital patients who received PN and underwent a liver biopsy from January 2006 until November 2010 were reviewed. Patients with IF with a clinical diagnosis were selected. APRI was calculated as (aspartate aminotransferase [U/L]/upper normal limit) * 100/platelets (10(9) cells/L). Presence of fibrosis and cirrhosis was estimated using the METAVIR score in liver biopsies. RESULTS: Sixty-two liver biopsies from 48 patients (22 girls) were studied. Mean APRI values in the different METAVIR categories (0-1, 2-3, 4) were 1.80, 1.17, and 4.24, respectively (analysis of variance P = 0.053; Bonferroni test for cirrhosis vs fibrosis P = 0.048). APRI could significantly predict cirrhosis (odds ratio 1.2; 95% confidence interval [CI] 1.001-1.43) but not fibrosis (METAVIR 2-3, odds ratio 1.00; 95% CI 0.86-1.18). Area under the receiver operating characteristic curve for cirrhosis was 0.67 (95% CI 0.45-0.89; P = 0.13). CONCLUSIONS: APRI, a noninvasive, easy-to-obtain bedside test, significantly predicts cirrhosis but not fibrosis in pediatric patients with IFALD. Because the clinicians need a noninvasive test to differentiate among different stages of liver fibrosis rather than differentiating cirrhosis from normal, we cannot recommend the use of this test in pediatric patients with IFALD for this purpose. PMID- 23666460 TI - Effect of remote ischemic preconditioning on phosphorylated protein signaling in children undergoing tetralogy of Fallot repair: a randomized controlled trial. AB - BACKGROUND: Our previous randomized controlled trial demonstrated cardiorespiratory protection by remote ischemic preconditioning (RIPC) in children before cardiac surgery. However, the impact of RIPC on myocardial prosurvival intracellular signaling remains unknown in cyanosis. RIPC may augment phosphorylated protein signaling in myocardium and circulating leukocytes during tetralogy of Fallot (ToF) repair. METHODS AND RESULTS: Children (n=40) undergoing ToF repair were double-blind randomized to RIPC (n=11 boys, 9 girls) or control (sham RIPC: n=9 boys, 11 girls). Blood samples were taken before, immediately after, and 24 hours after cardiopulmonary bypass. Resected right ventricular outflow tract muscle and leukocytes were processed for protein expression and mitochondrial respiration. There was no difference in age (7.1 +/- 3.4 versus 7.1 +/- 3.4 months), weight (7.7 +/- 1.8 versus 7.5 +/- 1.9 kg), or bypass or aortic cross-clamp times between the groups (control versus RIPC, mean+/-SD). No differences were seen between the groups for an increase in the ratio of phosphorylated to total protein for protein kinase B, p38 mitogen activated protein kinase, signal transducer and activator of transcription 3, glycogen synthase kinase 3beta, heat shock protein 27, Connexin43, or markers associated with promotion of necrosis (serum cardiac troponin I), apoptosis (Bax, Bcl-2), and autophagy (Parkin, Beclin-1, LC3B). A high proportion of total proteins were in phosphorylated form in control and RIPC myocardium. In leukocytes, mitochondrial respiration and assessed protein levels did not differ between groups. CONCLUSIONS: In patients with cyanotic heart disease, a high proportion of proteins are in phosphorylated form. RIPC does not further enhance phosphorylated protein signaling in myocardium or circulating leukocytes in children undergoing ToF repair. CLINICAL TRIAL REGISTRATION: URL: (http://www.anzctr.org.au/trial_view.aspx?id=335613. Unique identifier: Australian New Zealand Clinical Trials Registry number ACTRN12610000496011. PMID- 23666461 TI - Angiopoietin-like 2 promotes atherogenesis in mice. AB - BACKGROUND: Angiopoietin like-2 (angptl2), a proinflammatory protein, is overexpressed in endothelial cells (ECs) from patients with coronary artery disease (CAD). Whether angptl2 contributes to atherogenesis is unknown. We tested the hypothesis that angptl2 promotes inflammation and leukocyte adhesion onto ECs, thereby accelerating atherogenesis in preatherosclerotic dyslipidemic mice. METHODS AND RESULTS: In ECs freshly isolated from the aorta, basal expression of TNF-alpha and IL-6 mRNA was higher in 3-month-old severely dyslipidemic mice (LDLr(-/-); hApoB100(+/+) [ATX]) than in control healthy wild-type (WT) mice (P<0.05) and was increased in both groups by exogenous angptl2 (100 nmol/L). Angptl2 stimulated the adhesion of leukocytes ex vivo on the native aortic endothelium of ATX, but not WT mice, in association with higher expression of ICAM-1 and P-selectin in ECs (P<0.05). Antibodies against these endothelial adhesion molecules prevented leukocyte adhesion. Intravenous administration of angptl2 for 1 month in preatherosclerotic 3-month-old ATX mice increased (P<0.05) total cholesterol and LDL-cholesterol levels, strongly induced (P<0.05) the expression of endothelial proinflammatory cytokines and adhesion molecules while accelerating atherosclerotic lesion formation by 10-fold (P<0.05). Plasma and aortic tissue levels of angptl2 increased (P<0.05) with age and were higher in 6- and 12-month-old ATX mice than in age-matched WT mice. Angptl2 accumulated to high levels in the atherosclerotic lesions (P<0.05). Finally, angptl2 was greatly expressed (P<0.05) in ECs cultured from CAD patients, and circulating angptl2 levels were 6-fold higher in CAD patients compared with age-matched healthy volunteers. CONCLUSIONS: Angptl2 contributes to the pathogenesis of atherosclerosis. PMID- 23666462 TI - Retraction note: Effect of preischemic treatment with fenofibrate, a peroxisome proliferator-activated receptor-alpha ligand, on hepatic ischemia-reperfusion injury in rats. PMID- 23666463 TI - Loss of RUNX3 expression may contribute to poor prognosis in patients with chondrosarcoma. AB - Chondrosarcoma is the second most common type of bone cancer. Loss of RUNX3 expression has been demonstrated in many other cancers. However, no studies have shown the relationship between RUNX3 expression and chondrosarcoma. In this study, we detected RUNX3 expression in the progression of chondrosarcoma. In patient samples, the levels of RUNX3 mRNA and protein were lower in cancer tissues than in normal tissues. Down-regulation of RUNX3 mRNA in tumor tissues was associated with an increase in RUNX3 promoter methylation. Loss of RUNX3 expression was significantly associated with more aggressive chondrosarcoma types and decreased survival time of patients. To examine the effects of exogenous expression of RUNX3 in vitro, chondrosarcoma cells were transfected with the pcDNA3.1-RUNX3 expression vector. Relative to control cells, RUNX3-expressing cells exhibited lower proliferation and higher apoptosis rates as assessed by colony formation and Annexin V-FITC/PI double staining, respectively. Taken together, these results suggest that RUNX3 acts a tumor suppressor in chondrosarcoma and that RUNX3 promoter methylation may be the molecular mechanism for its decreased expression. PMID- 23666464 TI - gp78 is specifically expressed in human prostate cancer rather than normal prostate tissue. AB - Elevated expression of gp78 has been observed in many types of cancers including lung, stomach, colon, liver and skin cancer. But there is no report about its expression in prostate cancers. In this study, using immunohistochemical staining we found gp78 is highly expressed in prostate cancers especially early stage tumors, but not in normal prostate tissues. gp78 protein expression is heterogeneous. In some tumors it was expressed in basal cells, while others in stromal cells. For gp78 is a ubiquitin E3 ligase, we then investigated the expression pattern of its cognate E2 (ubiquitin conjugating enzyme)-Ube2g2 in prostate cancers. We found it was expressed in both cancerous and normal tissues of prostate without significant differences in expression level. And unlike gp78, it exhibited a homogeneous expression pattern in different cell types in prostate tissues. In conclusion, our results indicate that gp78 is expressed specifically in human prostate cancer rather than normal prostate tissues, it could be a putative biomarker for prostate cancer diagnosis. PMID- 23666465 TI - Effects of age, sex, and sertraline administration on seizure-induced respiratory arrest in the DBA/1 mouse model of sudden unexpected death in epilepsy (SUDEP). AB - DBA/1 mice are susceptible to audiogenic seizure-induced respiratory arrest (S IRA), leading to death, which is a model of human sudden unexpected death in epilepsy (SUDEP). Female DBA/1 mice exhibited 71% susceptibility to S-IRA on the third daily test when seizure testing began at postnatal day (PND) 24-30, which was slightly (>10%) but not significantly lower than males. When initial seizure testing was delayed (to >7 weeks of age), DBA/1 mice of both sexes exhibited significantly reduced S-IRA susceptibility, as compared to mice tested initially at PND 24-30. These sex and age issues had not been previously evaluated and may be important for the future use of this SUDEP model. We also observed that 30 min after administering a selective serotonin reuptake inhibitor (SSRI), sertraline (40, 50, or 75 mg/kg i.p.), a significantly reduced S-IRA incidence in DBA/1 mice occurred without blocking seizures, which may be relevant to SUDEP prevention. PMID- 23666466 TI - CCN2/CTGF is required for matrix organization and to protect growth plate chondrocytes from cellular stress. AB - CCN2 (connective tissue growth factor (CTGF/CCN2)) is a matricellular protein that utilizes integrins to regulate cell proliferation, migration and survival. The loss of CCN2 leads to perinatal lethality resulting from a severe chondrodysplasia. Upon closer inspection of Ccn2 mutant mice, we observed defects in extracellular matrix (ECM) organization and hypothesized that the severe chondrodysplasia caused by loss of CCN2 might be associated with defective chondrocyte survival. Ccn2 mutant growth plate chondrocytes exhibited enlarged endoplasmic reticula (ER), suggesting cellular stress. Immunofluorescence analysis confirmed elevated stress in Ccn2 mutants, with reduced stress observed in Ccn2 overexpressing transgenic mice. In vitro studies revealed that Ccn2 is a stress responsive gene in chondrocytes. The elevated stress observed in Ccn2-/- chondrocytes is direct and mediated in part through integrin alpha5. The expression of the survival marker NFkappaB and components of the autophagy pathway were decreased in Ccn2 mutant growth plates, suggesting that CCN2 may be involved in mediating chondrocyte survival. These data demonstrate that absence of a matricellular protein can result in increased cellular stress and highlight a novel protective role for CCN2 in chondrocyte survival. The severe chondrodysplasia caused by the loss of CCN2 may be due to increased chondrocyte stress and defective activation of autophagy pathways, leading to decreased cellular survival. These effects may be mediated through nuclear factor kappaB (NFkappaB) as part of a CCN2/integrin/NFkappaB signaling cascade. PMID- 23666467 TI - Ten developments in the use of biologicals for systemic lupus erythematosus. AB - Belimumab has recently been approved, and several other types of biological therapy with different mechanisms of action are currently in phase II and III studies. This review puts these approaches in context, emphasizing mechanistic categories and clinical trial designs. Most of the promising approaches involve B cell depletion or modulation. Post-approval experience with belimumab is critically reviewed. PMID- 23666468 TI - Manipulative therapy (Feldenkrais, massage, chiropractic manipulation) for neck pain. AB - Neck pain is an extremely common symptom with many possible etiologies. A substantial number of patients are turning to complementary and alternative medicine (CAM). Low-quality evidence supports the beneficial effects of CAM. Feldenkrais, massage therapy, and spinal manipulation are discussed in detail. Complications are generally benign and self-limited, although occasional catastrophic consequences have been documented. Despite the favorable opinion many rheumatologists have of some CAM therapy, many patients are not disclosing CAM use to their medical providers. By expressing interest, asking questions, and taking a shared-decision-making approach, providers can encourage disclosure and provide valuable input. PMID- 23666469 TI - Update on oxalate crystal disease. AB - Oxalate arthropathy is a rare cause of arthritis characterized by deposition of calcium oxalate crystals within synovial fluid. This condition typically occurs in patients with underlying primary or secondary hyperoxaluria. Primary hyperoxaluria constitutes a group of genetic disorders resulting in endogenous overproduction of oxalate, whereas secondary hyperoxaluria results from gastrointestinal disorders associated with fat malabsorption and increased absorption of dietary oxalate. In both conditions, oxalate crystals can deposit in the kidney leading to renal failure. Since oxalate is primarily renally eliminated, it accumulates throughout the body in renal failure, a state termed oxalosis. Affected organs can include bones, joints, heart, eyes, and skin. Since patients can present with renal failure and oxalosis before the underlying diagnosis of hyperoxaluria has been made, it is important to consider hyperoxaluria in patients who present with unexplained soft tissue crystal deposition. The best treatment of oxalosis is prevention. If patients present with advanced disease, treatment of oxalate arthritis consists of symptom management and control of the underlying disease process. PMID- 23666471 TI - New molecular insights into osteosarcoma targeted therapy. AB - PURPOSE OF REVIEW: Recent translational studies in osteosarcoma are discussed with the purpose to shed light on the new molecular therapeutic targets. RECENT FINDINGS: The genetic aberrations of vascular endothelial growth factor (VEGF), mammalian target of rapamycin, Wnt signaling pathway, the inactivation of p53, Rb, WWOX genes, and amplification of APEX1, c-myc, RECQL4, RPL8, MDM2, VEGFA might be involved in the pathogenesis of osteosarcoma. The promising therapeutic targets for osteosarcoma patients include: integrin, ezrin, statin, NOTCH/HES1, matrix metalloproteinases (MMPs), m-calpain, and Src, which are involved in tumor cell invasion and metastasis; aldolase A, fructose-bisphosphate, sulfotransferase family 3A, member 1, BCL2-associated athanogene 3, heat shock protein 70 (HSP70), B-cell lymphoma 2-interacting mediator (BIM), polo-like kinase 1, hypoxia inducible factor 1, alpha subunit, minibrain-related kinase, Bcl-xl, caspase-3, midkine, high mobility group box 1 protein (HMGB1), and Beclin1, which are involved in tumor proliferation and apoptosis; met proto-oncogene (hepatocyte growth factor receptor), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, insulin-like growth factor (IGF)-1R, fms-related tyrosine kinase 4, platelet derived growth factor receptor, beta polypeptide, IGF-I/II, and c-kit, which are involved in tumor growth; endosialin, VEGF, thrombin, and MMPs, which are involved in tumor angiogenesis; transforming growth factor-alpha/beta, parathyroid hormone-like hormone, interleukin-6, interleukin-11, receptor activator of nuclear factor-kappaB ligand, nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1, and cathepsin, which are involved in osteoclast function; Myc, HSP90, p-Met, p-Akt, p-STAT3, and cyclin D1, which are transcriptional factors; p-GP, hydroxysteroid (17-beta) dehydrogenase 10, HMGB1, BIM, inorganic phosphate, Bcl-2, PARP, mdm2, p21, Bax, and mitogen-activated protein kinase 1, which are involved in drug sensitivity. Furthermore, microRNAs such as miR-215 are also therapeutic targets. SUMMARY: These translational studies in osteosarcoma have identified new molecular targets for osteosarcoma. PMID- 23666470 TI - Cardiac structure and functions in patients with asymptomatic primary hyperparathyroidism. AB - BACKGROUND: The data about cardiovascular (CV) changes in patients with asymptomatic primary hyperparathyroidism (PHPT) are scarce. AIM: The aim of this study is to compare cardiac structure and functions in patients with asymptomatic PHPT and controls by using tissue Doppler echocardiography. SUBJECTS AND METHODS: Thirty-eight patients with asymptomatic PHPT and 31 sex- and age-matched controls with similar cardiac risk factors were evaluated. RESULTS: There was no significant difference in ejection fraction (EF) between the patients and the controls [64+/-5.95 vs 62+/-3.25% (p=0.094)]. Left ventricular mass index (LVMI) was significantly higher in patients than controls [105.96 (66.45-167.24) vs 93.79 (64.25- 139.25) g/m2, p=0.014]. There was a significant correlation between LVMI and serum calcium (Ca) (r=0.240, p<0.005). Myocardial performance index (MPI) was significantly higher in patients than controls [0.49 (0.35-0.60) vs 0.39 (0.33-0.62), p<0.001]. There was positive correlation between theMPI and serumCa levels (r=0.505, p<0.001), parathyroid hormone (PTH) levels (r=0.464, p<0.001) and LVMI (r=0.270, p<0.005). When the normotensive patients and controls were evaluated, the difference between the groups remained statistically significant considering LVMI and MPI [109 (66.45-167.24) g/m2 vs 94.17 (64.25 75.10) g/m2, p=0.03; and 0.49 (0.35-0.60) vs 0.39 (0.33-0.62), p<0.01, respectively]. There were significant correlations between MPI and Ca (r=0.566, p<0.001), and PTH (r=0.472, p<0.001). CONCLUSIONS: Our study results showed that cardiacmorphology and diastolic functions are altered in the patients with asymptomatic PHPT. High serum PTH and Ca levels may have an impact on these CV changes. Whether these subtle CV changes would affect cardiac systolic functions and mortality in patients with asymptomatic PHPT should be investigated in further prospective studies. PMID- 23666472 TI - Palliative sedation in end-of-life care. AB - PURPOSE OF REVIEW: The aim of this review was to present and comment on recent data published on palliative sedation in palliative and end-of-life care. Palliative sedation is a medical procedure used to deal with the refractory symptoms occurring in the advanced stages of cancer. It has clinical, nursing, relational and ethical implications, making it a highly sensitive issue. RECENT FINDINGS: Over the last 12 months, a number of authors have published interesting new findings on different areas of palliative sedation, that is prevalence, indications, monitoring, duration and choice of drugs. In particular, a clear definition of palliative sedation and of its more pronounced form, deep continuous sedation (DCS), has emerged. It has been confirmed that, when performed in the correct way and with the right aims, palliative sedation does not have a detrimental impact on survival. SUMMARY: Recent findings confirm that palliative sedation is an integral part of a medical palliative care approach and is needed in certain clinical situations. It is a legitimate clinical practice from any ethical point of view. While oncologists should have a basic knowledge of the procedure, its in depth study is a core competency for palliative care physicians. PMID- 23666473 TI - Pazopanib in sarcomas: expanding the PALETTE. AB - PURPOSE OF REVIEW: After failure of standard therapy, few effective treatment options exist for adult patients with metastatic sarcomas, and median survival remains dismal at approximately 1 year. Pazopanib, a multitargeted tyrosine kinase inhibitor, has recently been approved for nonadipocytic soft tissue sarcomas refractory to chemotherapy. In this review, we will revisit the efficacy of pazopanib in sarcomas, and present a patient case that illustrates two of many unanswered questions: which sarcoma patients are most likely to benefit from pazopanib therapy, and what criteria are best suited to accurately detect benefit in clinical trials? RECENT FINDINGS: Pazopanib has been tested in sarcoma patients in a phase II and phase III study, and was shown to prolong progression free survival by 3 months relative to placebo. Although histology has been the primary stratification variable for subgroup analysis in large sarcoma trials, the PALETTE study did not demonstrate superior response within histologic cohorts. Ongoing trials seek to explore efficacy of pazopanib in previously excluded histologies, as well as include correlative studies to identify histologic and molecular biomarkers to predict patients likely to benefit. SUMMARY: Pazopanib has been proven to provide modest benefit overall to nonadipocytic soft tissue sarcoma patients, but we have yet to identify the molecular basis for those patients who derive exceptional benefit. PMID- 23666474 TI - A classification of components of workplace disability management programs: results from a systematic review. AB - PURPOSE: This paper presents results from a Campbell systematic review on the nature and effectiveness of workplace disability management programs (WPDM) promoting return to work (RTW), as implemented and practiced by employers. A classification of WPDM program components, based on the review results, is proposed. METHODS: Twelve databases were searched between 1948 to July 2010 for peer-reviewed studies of WPDM programs provided by employers to re-entering workers with occupational or non-occupational illnesses or injuries. Screening of articles, risk of bias assessment and data extraction were conducted in pairs of reviewers. Studies were clustered around various dimensions of the design and context of programs. RESULTS: 16,932 records were identified by the initial search. 599 papers were assessed for relevance. Thirteen studies met inclusion criteria. Twelve peer reviewed articles (two non-randomized studies, and ten single group experimental before and after studies), including ten different WPDM programs informed the synthesis of results. Narrative descriptions of the included program characteristics provided insight on program scope, components, procedures and human resources involved. However, there were insufficient data on the characteristics of the sample and the effect sizes were uncertain. A taxonomy classifying policies and practices around WPDM programs is proposed. CONCLUSION: There is insufficient evidence to draw conclusions on the effectiveness of employer provided WPDM programs promoting RTW. It was not possible to determine if specific program components or specific sets of components are driving effectiveness. The proposed taxonomy may guide future WPDM program evaluation and clarify the setup of programs offered to identify gaps in existing company strategies. PMID- 23666476 TI - Mepanipyrim haptens and antibodies with nanomolar affinity. AB - Mepanipyrim is an anilinopyrimidine fungicide used worldwide for crop protection. With the aim of developing useful immunoreagents for mepanipyrim immunoanalysis, two new functionalized derivatives were prepared and antibodies were generated. Affinity and specificity were assessed by direct and indirect competitive ELISA using homologous and heterologous conjugates. Although all antibodies were selective for the target analyte, the immunizing hapten structure was revealed as a determinant for high-affinity antibody production (IC(50) = 3 nM). PMID- 23666475 TI - Feasibility of feature-based indexing, clustering, and search of clinical trials. A case study of breast cancer trials from ClinicalTrials.gov. AB - BACKGROUND: When standard therapies fail, clinical trials provide experimental treatment opportunities for patients with drug-resistant illnesses or terminal diseases. Clinical Trials can also provide free treatment and education for individuals who otherwise may not have access to such care. To find relevant clinical trials, patients often search online; however, they often encounter a significant barrier due to the large number of trials and in-effective indexing methods for reducing the trial search space. OBJECTIVES: This study explores the feasibility of feature-based indexing, clustering, and search of clinical trials and informs designs to automate these processes. METHODS: We decomposed 80 randomly selected stage III breast cancer clinical trials into a vector of eligibility features, which were organized into a hierarchy. We clustered trials based on their eligibility feature similarities. In a simulated search process, manually selected features were used to generate specific eligibility questions to filter trials iteratively. RESULTS: We extracted 1,437 distinct eligibility features and achieved an inter-rater agreement of 0.73 for feature extraction for 37 frequent features occurring in more than 20 trials. Using all the 1,437 features we stratified the 80 trials into six clusters containing trials recruiting similar patients by patient-characteristic features, five clusters by disease-characteristic features, and two clusters by mixed features. Most of the features were mapped to one or more Unified Medical Language System (UMLS) concepts, demonstrating the utility of named entity recognition prior to mapping with the UMLS for automatic feature extraction. CONCLUSIONS: It is feasible to develop feature-based indexing and clustering methods for clinical trials to identify trials with similar target populations and to improve trial search efficiency. PMID- 23666477 TI - Mutasynthesis of pyrrole spiroketal compound using calcimycin 3-hydroxy anthranilic acid biosynthetic mutant. AB - The five-membered aromatic nitrogen heterocyclic pyrrole ring is a building block for a wide variety of natural products. Aiming at generating new pyrrole containing derivatives as well as to identify new candidates that may be of value in designing new anticancer, antiviral, and/or antimicrobial agents, we employed a strategy on pyrrole-containing compound mutasynthesis using the pyrrole containing calcimycin biosynthetic gene cluster. We blocked the biosynthesis of the calcimycin precursor, 3-hydroxy anthranilic acid, by deletion of calB1-3 and found that two intermediates containing the pyrrole and the spiroketal moiety were accumulated in the culture. We then fed the mutant using the structurally similar compound of 3-hydroxy anthranilic acid. At least four additional new pyrrole spiroketal derivatives were obtained. The structures of the intermediates and the new pyrrole spiroketal derivatives were identified using LC-MS and NMR. One of them shows enhanced antibacterial activity. Our work shows a new way of pyrrole derivative biosynthetic mutasynthesis. PMID- 23666478 TI - Potential and limitations of Burgundy truffle cultivation. AB - Burgundy truffles (Tuber aestivum syn. Tuber uncinatum) are the highly prized fruit bodies of subterranean fungi always occurring in ectomycorrhizal symbiosis with host plants. Successful cultivation can be achieved through artificial mycorrhization and outplanting of mostly oaks and hazel on suitable terrain. Here, we review ecological requirements, the influence of environmental factors, and the importance of molecular techniques for a successful cultivation of T. aestivum across Europe. The historical background and current knowledge of T. aestivum cultivation are discussed in light of its socioeconomic relevance. PMID- 23666479 TI - A new NAD(H)-dependent meso-2,3-butanediol dehydrogenase from an industrially potential strain Serratia marcescens H30. AB - The budC gene coding for a new meso-2,3-butanediol dehydrogenase (BDH) from Serratia marcescens H30 was cloned and expressed in Escherichia coli BL21(DE3), purified, and characterized for its properties. The recombinant BDH with a molecular weight of 27.4 kDa exhibited a reversible transformation between acetoin and 2,3-butanediol. In the presence of NADH, BDH could catalyze the reduction of diacetyl and (3R)-acetoin to (3S)-acetoin and meso-2,3-butanediol, respectively, while (3S)-acetoin as a substrate could be further transformed into (2S, 3S)-2,3-butanediol at pH 9.0. For diol oxidation reactions, (3R)-acetoin and (3S)-acetoin were obtained when meso-2,3-butanediol and (2S,3S)-2,3-butanediol were used as the substrates with BDH and NAD(+). (2R,3R)-2,3-butanediol was not a substrate for the BDH at all. The low K m value (4.1 mM) in meso-2,3-butanediol oxidation reaction and no activity for diacetyl, acetoin, and 2,3-butanediol as the substrates with NADP(+)/NADPH suggested that the budC gene product belongs to a NAD(H)-dependent meso-2,3-BDH. Maximum activities for diacetyl and (3S/3R) acetoin reduction were observed at pH 8.0 and pH 5.0 while for meso-2,3 butanediol oxidation it was pH 8.0. However, the optimum temperature for oxidation and reduction reactions was about 40 degrees C. In addition, the BDH activity for meso-2,3-butanediol oxidation was enhanced in the presence of Fe(2+) and for diacetyl and (3S/3R)-acetoin reduction in the presence of Mg(2+) and Mn(2+), while several metal ions inhibited its activity, particularly Fe(3+) for reduction of diacetyl and acetoin. Sequence analysis showed that the BDH from S. marcescens H30 possessed two conserved sequences including the coenzyme binding motif (GxxxGxG) and the active-site motif (YxxxK), which are present in the short chain dehydrogenase/reductase superfamily. PMID- 23666480 TI - Escherichia coli protein YgiD produces the structural unit of plant pigments betalains: characterization of a prokaryotic enzyme with DOPA-extradiol dioxygenase activity. AB - Betalamic acid is the structural unit of all the natural pigments betalains. These are nitrogen-containing water-soluble compounds with high colorant and bioactive properties, characteristic of plants of the order Caryophyllales. The formation of betalamic acid from the precursor amino acid 3,4-dihydroxy-L phenylalanine (L-DOPA) by the enzyme 4,5-DOPA-extradiol-dioxygenase was supposed to be restricted to plants of this order and two fungal species. Here, the first case of betalamic acid formation by an enzyme other than eukaryotes is reported with a homolog enzyme from Escherichia coli. The protein YgiD has been cloned, expressed, and purified to carry out its molecular and functional characterization. The enzyme was obtained as a monomeric active protein with a molecular mass of 32 kDa characterized by chromatography, electrophoresis, and MALDI-TOF analysis. Enzyme kinetic properties are characterized in the transformation of the relevant substrate L-DOPA. Reaction was analyzed spectrophotometrically and by HPLC-DAD, electrospray ionization mass spectrometry, and time-of-flight mass spectrometry. PMID- 23666481 TI - Effects of Clostridium butyricum and Enterococcus faecium on growth performance, lipid metabolism, and cecal microbiota of broiler chickens. AB - To investigate the effects of Clostridium butyricum and Enterococcus faecium on the growth performance, lipid metabolism, and cecal microbiota of broilers, 264 one-day-old male Ross 308 broiler chicks were randomly allocated into four treatments with six replicates in a 2 * 2 factorial arrangement and fed four diets with two levels of C. butyricum (0 or 1 * 109 cfu/kg) and two levels of E. faecium (0 or 2 * 109 cfu/kg) for 42 days. There was no significant interaction between C. butyricum and E. faecium on the growth performance, lipid metabolism, and cecal microbiota of broilers. However, broilers supplemented with E. faecium had lower (P = 0.022) serum leptin level at day 21 and higher (P < 0.001) fatty acid synthase (FAS), malic enzyme (ME), and acetyl-CoA carboxylase (ACC) mRNA levels in the liver at day 42. Supplementation of C. butyricum improved (P < 0.05) the average daily feed intake and average daily gain, increased (P = 0.016) the serum insulin level at 21 days of age, enhanced (P < 0.05) the content of intramuscular fat, activities of FAS in the liver and lipoprotein lipase (LPL) in the breast muscle, mRNA expression of FAS, ME, and ACC in the liver and LPL in the breast muscle at 42 days of age, but reduced (P = 0.030) cecal Bacteroidetes relative abundance at 21 days of age. The results of this study indicate that the increased intramuscular fat content of broilers fed C. butyricum as observed may be the result of enhanced lipogenesis. PMID- 23666482 TI - Retraction note: Further notice of formal retraction of articles by Dr. Yoshitaka Fujii. AB - Retraction to: J Anesth (1997) 11:126-129DOI 10.1007/BF02480074,J Anesth (1996) 10:22-25DOI 10.1007/BF02482063,J Anesth (1996) 10:176-180DOI 10.1007/BF02471386,J Anesth (1995) 9:58-60DOI 10.1007/BF02482037,J Anesth (1995) 9:343-347DOI 10.1007/BF02479949,J Anesth (1994) 8:301-304DOI 10.1007/BF02514655. To readers of the Journal of Anesthesia: In addition to the articles listed in a retraction note in JAnesth (2013) 27:322, the following articles published by Dr. Yoshitaka Fujii in the Journal of Anesthesia also are hereby retracted as a result of: (1) overwhelming evidence of fabrication related to the fact that the distributions of many variables reported by Dr. Fujii in these studies are exceedingly unlikely [1] and (2) the inability of Dr. Fuji's institution to attest to the integrity of the study and/or the data conducted under its auspices, as set out in the Joint Editors-in-Chief Request for Determination of April 9, 2012. *Fujii Y, Udagawa T, Toyooka H. Effects of dobutamine on the fatigued diaphragm: a comparison with dopamine. J Anesth. 1994;8:301-4. *Fujii Y, Toyooka H. The dose-response relationship of amrinone in increasing the contractility of fatigued diaphragm in dogs. J Anesth. 1995;9:343-7. *Fujii Y, Toyooka H. Effects of nicardipine on diaphragmatic fatigue in the dog: the relationship between dosage and fatigability. JA. 1995;9:58-60. *Fujii Y, Toyooka H, Amaha K. Dibutyryl cyclic AMP increases the contractility of fatigued diaphragm in dogs. J Anesth. 1996;10:176-80.*Fujii Y, Toyooka H. Dobutamine increases contractility of fatigued diaphragm in dogs: the relationship between dose and diaphragmatic contractility. J Anesth. 1996;10:22-5.*Fujii Y, Toyooka H. Nicardipine inhibits amrinone-enhanced contractility in fatigued diaphragm. J Anesth.1997;11:126-9. PMID- 23666483 TI - Probability of a disease outbreak in stochastic multipatch epidemic models. AB - Environmental heterogeneity, spatial connectivity, and movement of individuals play important roles in the spread of infectious diseases. To account for environmental differences that impact disease transmission, the spatial region is divided into patches according to risk of infection. A system of ordinary differential equations modeling spatial spread of disease among multiple patches is used to formulate two new stochastic models, a continuous-time Markov chain, and a system of stochastic differential equations. An estimate for the probability of disease extinction is computed by approximating the Markov chain model with a multitype branching process. Numerical examples illustrate some differences between the stochastic models and the deterministic model, important for prevention of disease outbreaks that depend on the location of infectious individuals, the risk of infection, and the movement of individuals. PMID- 23666484 TI - Time delay implies cost on task switching: a model to investigate the efficiency of task partitioning. AB - Task allocation, and task switching have an important effect on the efficiency of distributed, locally controlled systems such as social insect colonies. Both efficiency and workload distribution are global features of the system which are not directly accessible to workers and can only be sampled locally by an individual in a distributed system. To investigate how the cost of task switching affects global performance we use social wasp societies as a metaphor to construct a simple model system with four interconnected tasks. Our goal is not the accurate description of the behavior of a given species, but to seek general conclusions on the effect of noise and time delay on a behavior that is partitioned into subtasks. In our model a nest structure needs to be constructed by the cooperation of individuals that carry out different tasks: builders, pulp and water foragers, and individuals storing water. We report a simulation study based on a model using delay-differential equations to analyze the trade-off between task switching costs and keeping a high degree of adaptivity in a dynamic, noisy environment. Combining the methods of time-delayed equations and stochastic processes we are able to represent the influence of swarm size and task switching sensitivity. We find that the system is stable for reasonable choices of parameters but shows oscillations for extreme choices of parameters and we find that the system is resilient to perturbations. We identify a trade off between reaching equilibria of high performance and having short transients. PMID- 23666485 TI - Cloacal malformation variants in male. AB - OBJECTIVE: The published surgical literatures have referred only to females as having cloacal defects and the incidence in males is not well established. As during embryogenesis, both sexes have to pass through the stage of a cloaca, there is every chance of development of cloacal anomalies in males also. Here, we are presenting our experience of male cloacal malformations. METHODS: We identified four cases of male cloaca by reviewing medical records of all anorectal malformation (ARM) patients treated at our institution in the past 19 years. Time of presentation, clinical, radiological, cystoscopic and operative findings, and outcomes were analysed. RESULTS: Out of 1,837 patients, we identified four cases (0.2 %) of male cloacal variants. All presented after 45 days (range 46 days to 28 years). Three of them had proximal hypospadias, two had a vaginal remnant and cystoscopic evaluation showed the length of the common channel ranged from 0.5 to 8 cm. One patient died of multiple anomalies and the other patients are doing well following reconstruction. CONCLUSION: None of the male cloacal patients presented in the neonatal period, proximal hypospadias was the common external genital abnormality and half of them had a vagina. Surgical outcome was satisfactory. The scarcity of reported cases of this group is a subject of further research. PMID- 23666486 TI - Using a mobile app and mobile workforce to validate data about emergency public health resources. AB - BACKGROUND: Social media and mobile applications that allow people to work anywhere are changing the way people can contribute and collaborate. OBJECTIVE: We sought to determine the feasibility of using mobile workforce technology to validate the locations of automated external defibrillators (AEDs), an emergency public health resource. METHODS: We piloted the use of a mobile workforce application, to verify the location of 40 AEDs in Philadelphia county. AEDs were pre-identified in public locations for baseline data. The task of locating AEDs was posted online for a mobile workforce from October 2011 to January 2012. Participants were required to submit a mobile phone photo of AEDs and descriptions of the location. RESULTS: Thirty-five of the 40 AEDs were identified within the study period. Most, 91% (32/35) of the submitted AED photo information was confirmed project baseline data. Participants also provided additional data such as business hours and other nearby AEDs. CONCLUSIONS: It is feasible to engage a mobile workforce to complete health research-related tasks. Participants were able to validate information about emergency public health resources. PMID- 23666488 TI - Do serum C-reactive protein and interleukin-6 predict kidney scarring after urinary tract infection? AB - OBJECTIVE: To investigate if serum C-reactive protein (s-CRP) and interleukin 6 (s-IL6) provide information for predicting renal damage and for DMSA patient selection in children with urinary tract infection (UTI). METHODS: This observational study was carried out in children with UTI. s-CRP and s-IL6 were measured at UTI diagnosis. Patients forming renal scarring were identified by DMSA scans. The usefulness of s-CRP and s-IL6 measurements for nephropathy scarring diagnosis was evaluated using diagnostic quality and efficiency indexes. RESULTS: Thirty-two children were included in the study. Eight showed renal scarring after the follow-up. The s-CRP was 110.23 +/- 59.69 mg/L and 52.46 +/- 63.13 mg/L for patients with and without renal scarring. The s-IL6 concentration was 18.34 +/- 11.80 pg/mL and 8.07 +/- 9.51 pg/mL respectively. The cut-off points for optimum nephropathy scarring diagnosis were 115 mg/L for s-CRP and 20 pg/mL for s-IL6. The value of highest sensitivity for s-CRP was >5 mg/L (S:100 %) and greatest specificity was >150 mg/L (Sp:95.83). The highest sensitivity for s IL6 was >4 pg/mL (S:100 %) and the maximum specificity was >40 pg/mL (Sp:100 %). CONCLUSIONS: Results confirm that children who will develop renal scarring show higher levels of s-IL6 and s-CRP at UTI diagnosis. However, none of the techniques provide sufficient information for predicting renal damage in all patients and for DMSA patient selection. PMID- 23666489 TI - Polymeric microfluidic devices exhibiting sufficient capture of cancer cell line for isolation of circulating tumor cells. AB - Here, we developed polymeric microfluidic devices for the isolation of circulating tumor cells. The devices, with more than 30,000 microposts in the channel, were produced successfully by a UV light-curing process lasting 3 min. The device surface was coated with anti-epithelial cell adhesion molecule antibody by just contacting the antibody solution, and a flow system including the device was established to send a cell suspension through it. We carried out flow tests for evaluation of the device's ability to capture tumor cells using an esophageal cancer cell line, KYSE220, dispersed in phosphate-buffered saline or mononuclear cell separation from whole blood. After the suspension flowed through the chip, many cells were seen to be captured on the microposts coated with the antibody, whereas there were few cells in the device without the antibody. Owing to the transparency of the device, we could observe the intact and the stained cells captured on the microposts by transmitted light microscopy and phase contrast microscopy, in addition to fluorescent microscopy, which required fluorescence labeling. Cell capture efficiencies (i.e., recovery rates of the flowing cancer cells by capture with the microfluidic device) were measured. The resulting values were 0.88 and 0.95 for cell suspension in phosphate-buffered saline, and 0.85 for the suspension in the mononuclear cell separation, suggesting the sufficiency of this device for the isolation of circulating tumor cells. Therefore, our device may be useful for research and treatments that rely on investigation of circulating tumor cells in the blood of cancer patients. PMID- 23666490 TI - Obesity and pressure ulcers among nursing home residents. AB - OBJECTIVES: To examine the prevalence of obesity and its relationship with pressure ulcers among nursing home (NH) populations, and whether such relationship varies with certified nursing assistant (CNA) level in NHs. DATA AND STUDY POPULATION: The 1999-2009 nationwide Minimum Data Sets were linked with Online Survey of Certification and Reporting records. We identified newly admitted NH residents who became long-stayers and followed them up to 1 year. ANALYSES: The outcome variable was presence of pressure ulcers during the 1-year follow-up period. Residents were categorized as normal [18.5 <= body mass index (BMI)<30 kg/m2], mild obesity (30 <= BMI <35 kg/m2), and moderate or severe obesity (BMI >= 35 kg/m2). Pooled and stratified analyses were performed to examine the relationship between obesity and pressure ulcers, and how it varied by facility CNA level. RESULTS: The prevalence of obesity increased from 16.9% to 25.8% among newly admitted NH residents over the last decade. Obesity was associated with higher risks of pressure ulcers among long-stay residents. The relationship between obesity and pressure ulcers persisted after accounting for individual health conditions at the baseline and facility-level variations. Further, the within-facility relationship between obesity and pressure ulcers varied by facility CNA levels. The odds of pressure ulcers were 18.9% higher for residents with moderate or severe obesity than for nonobese residents within NHs with low CNA levels. The percents for medium and high CNA level facilities were 14.0% and 12.8%, respectively. CONCLUSION: To prepare for the growing obesity epidemic in NHs, policies should focus on strategies to improve care provided for obese residents. PMID- 23666491 TI - Association between physician supply, local practice norms, and outpatient visit rates. AB - BACKGROUND: There is considerable regional variation in Medicare outpatient visit rates; such variations may be the consequence of patient health, race/ethnicity differences, patient preferences, or physician supply and beliefs about the efficacy of frequently scheduled visits. OBJECTIVE: The objective of the study was to test associations between varying regional Medicare outpatient visit rates and beneficiaries' health, race/ethnicity, preferences, and physician practice norms and supply. METHODS: We used Medicare claims from 2006 and 2007 and data from national surveys of 3 different groups in 2005-Medicare beneficiaries, cardiologists, and primary care physicians. Regression analysis tested explanations for outpatient visit rates: patient health (self-reported and hierarchical condition category score), self-reported race/ethnicity, preferences for care, and local physician practice norms and supply in beneficiaries' Hospital Referral Regions (HRRs) of residence. RESULTS: Beneficiaries in the highest quintile of the hierarchical condition category scores experienced 4.99 more visits than those in the lowest. Beneficiaries who were black experienced 2.14 fewer visits than others with similar health and preferences. Higher care seeking preferences were marginally significantly associated with more visits, whereas education and poverty were insignificant. HRRs with high physician supply and high-frequency practice norms were associated with 2.04 additional visits per year, whereas HRRs with high supply but low-frequency norms were associated with 1.45 additional visits. Adjusting for all individual beneficiary covariates explained <20% of the original associations between visit rates and physician supply and practice norms. CONCLUSIONS: Medicare beneficiaries' health status, race, and preferences help explain individual office visit frequency; in particular, African-American patients appear to experience lower access to care. Yet, these factors explain a small fraction of the observed regional differences associated with physician supply and beliefs about the appropriate frequency of office visits. PMID- 23666487 TI - Pharmacological approaches to restore mitochondrial function. AB - Mitochondrial dysfunction is not only a hallmark of rare inherited mitochondrial disorders but also implicated in age-related diseases, including those that affect the metabolic and nervous system, such as type 2 diabetes and Parkinson's disease. Numerous pathways maintain and/or restore proper mitochondrial function, including mitochondrial biogenesis, mitochondrial dynamics, mitophagy and the mitochondrial unfolded protein response. New and powerful phenotypic assays in cell-based models as well as multicellular organisms have been developed to explore these different aspects of mitochondrial function. Modulating mitochondrial function has therefore emerged as an attractive therapeutic strategy for several diseases, which has spurred active drug discovery efforts in this area. PMID- 23666493 TI - Acute and subacute effects of the selective serotonin-noradrenaline reuptake inhibitor duloxetine on cardiac hERG channels. AB - Duloxetine is a selective serotonin-noradrenaline reuptake inhibitor approved for treatment of major depressive disorder. So far, duloxetine has been found to be well tolerated and reported cardiac side effects were negligible. However, pharmacological effects on cardiac hERG channels have not been properly addressed yet. hERG channels were expressed in Xenopus oocytes and a human embryonic kidney (HEK) cell line. Currents were measured using voltage clamp and patch clamp techniques. Channel surface expression was quantified using Western blot analysis. We found that duloxetine inhibits heterologously expressed hERG channels in a concentration-dependent manner, yielding an IC50 of 142.8 MUM in Xenopus oocytes. Inhibitory effects were even more pronounced when using a mammalian cell line resulting in a 34 or 59% current decrease by 10 or 30 MUM duloxetine, respectively. Duloxetine did not affect channel activation or inactivation kinetics. However, channel deactivation was accelerated by duloxetine. We further showed that inhibition occurs in the open and inactivated, but not closed, states. There was no frequency dependence of block. However, effects of duloxetine were significantly attenuated when using the hERG pore mutants Y652A and F656A. Subacute effects of duloxetine on hERG channel expression were analyzed using the Western blot technique. We found that incubation with duloxetine results in a concentration-dependent decrease of channel surface expression. Whereas inhibitory effects of duloxetine seem negligible under therapeutically relevant concentrations, hERG block should be considered in cases of duloxetine overdose and when administering duloxetine to patients susceptible to drug-induced QT prolongation. PMID- 23666494 TI - Evaluation of zona pellucida function for sperm penetration during in vitro fertilization in pigs. AB - In porcine oocytes, the function of the zona pellucida (ZP) with regard to sperm penetration or prevention of polyspermy is not well understood. In the present study, we investigated the effects of the ZP on sperm penetration during in vitro fertilization (IVF). We collected in vitro-matured oocytes with a first polar body (ZP+ oocytes). Some of them were freed from the ZP (ZP- oocytes) by two treatments (pronase and mechanical pipetting), and the effects of these treatments on sperm penetration parameters (sperm penetration rate and numbers of penetrated sperm per oocyte) were evaluated. There was no evident difference in the parameters between the two groups. Secondly, we compared the sperm penetration parameters of ZP+ and ZP- oocytes using frozen-thawed epididymal spermatozoa from four boars. Sperm penetration into ZP+ oocytes was found to be accelerated relative to ZP- oocytes. Thirdly, we evaluated the sperm penetration of ZP+ and ZP- oocytes at 1-10 h after IVF (3 h gamete co-incubation). The proportions of oocytes penetrated by sperm increased significantly with time in both groups; however, the number of penetrated sperm per oocyte did not increase in ZP- oocytes. Finally, we performed IVF using ZP- oocytes divided into control (3 h) and prolonged gamete co-incubation (5 h) groups. Greater numbers of sperm penetrated in the 5 h group than in the control group. These results suggest that the ZP and oolemma are not competent factors for prevention of polyspermy in our present porcine IVF system. However, it appears that ZP removal is one of the possibilities for reducing polyspermic penetration in vitro in pigs. PMID- 23666495 TI - Recording electrical activity from identified neurons in the intact brain of transgenic fish. AB - Understanding the cell physiology of neural circuits that regulate complex behaviors is greatly enhanced by using model systems in which this work can be performed in an intact brain preparation where the neural circuitry of the CNS remains intact. We use transgenic fish in which gonadotropin-releasing hormone (GnRH) neurons are genetically tagged with green fluorescent protein for identification in the intact brain. Fish have multiple populations of GnRH neurons, and their functions are dependent on their location in the brain and the GnRH gene that they express(1) . We have focused our demonstration on GnRH3 neurons located in the terminal nerves (TN) associated with the olfactory bulbs using the intact brain of transgenic medaka fish (Figure 1B and C). Studies suggest that medaka TN-GnRH3 neurons are neuromodulatory, acting as a transmitter of information from the external environment to the central nervous system; they do not play a direct role in regulating pituitary-gonadal functions, as do the well-known hypothalamic GnRH1 neurons(2, 3) .The tonic pattern of spontaneous action potential firing of TN-GnRH3 neurons is an intrinsic property(4-6), the frequency of which is modulated by visual cues from conspecifics(2) and the neuropeptide kisspeptin 1(5). In this video, we use a stable line of transgenic medaka in which TN-GnRH3 neurons express a transgene containing the promoter region of Gnrh3 linked to enhanced green fluorescent protein(7) to show you how to identify neurons and monitor their electrical activity in the whole brain preparation(6). PMID- 23666496 TI - Dabigatran-associated subdural hemorrhage: using thromboelastography (TEG((r))) to guide decision-making. AB - Novel oral anticoagulants present challenges and uncertainties in the management of hemorrhagic emergencies. An 84-year-old man taking dabigatran presented with a subdural hematoma requiring neurosurgical intervention. Routine coagulation assays were prolonged at admission and following administration of Factor VIII Inhibitor Bypassing Activity (FEIBA). Thromboelastography (TEG((r))) was utilized to assess clot dynamics prior to placement of a subdural drain, which was safely inserted despite a prolonged thrombin time (TT). Exclusive reliance on the TT may delay necessary interventions. TEG((r)) may be a valuable tool to investigate hemostasis in patients on dabigatran requiring emergent procedures. PMID- 23666497 TI - Expression of pro-inflammatory cytokines and the risk of intracranial aneurysm. AB - Intracranial aneurysm (IA) lingers as a potentially devastating clinical problem, in which inflammation acts as a critical contributor to the pathogenesis of this disease. Cytokines play a major role in regulating inflammation. The aim of this study was to gain insight in the inflammatory response in IA by assessing plasma cytokine profiles. Plasma levels of 10 cytokines were quantified by multiplex protein arrays in 66 patients with IA and 78 healthy controls. Results showed that plasma level of interleukin 1 beta (IL-1beta) was 2.4-fold higher in patients than in controls (p < 0.05). The level of monocyte chemoattractant protein-1 (MCP-1) was 2.8-fold higher in patient than in controls (p < 0.01). The level of tumor necrosis factor-alpha (TNF-alpha) was 2.1-fold higher in cases than in controls (p < 0.001). When comparing the expression of cytokines in IA patients with different characteristics, cases with ruptured aneurysm revealed increased level of MCP-1 than those with unruptured aneurysm (p < 0.05), whereas cases with multiple numbers of aneurysms demonstrated higher levels of MCP-1 and TNF-alpha than those with single aneurysm (p < 0.05 and p < 0.05, respectively). These data indicated that IL-1beta, MCP-1, and TNF-alpha were associated with increased risk of IA and may affect the development of this disease. PMID- 23666498 TI - An extrapolation method for the efficient calculation of molecular response properties within Born-Oppenheimer molecular dynamics. AB - The calculation of molecular response properties in dynamic molecular systems is a major challenge that requires sampling over many steps of, e.g., Born Oppenheimer molecular dynamics (BO-MD) simulations. We present an extrapolation scheme to accelerate such calculations for multiple steps within BO-MD trajectories or equivalently within other sampling methods of conformational space. The extrapolation scheme is related to the one introduced by Pulay and Fogarasi [Chem. Phys. Lett., 2004, 386, 272] for self-consistent field (SCF) energy calculations. We extend the extrapolation to the quantities within our density matrix-based Laplace-transformed coupled perturbed SCF (DL-CPSCF) method that allows for linear-scaling calculations of response properties for large molecular systems. Here, we focus on the example of calculating NMR chemical shifts for which the number of required DL-CPSCF iterations reduces by roughly 40 70%. PMID- 23666499 TI - The role of B-type natriuretic Peptide testing in guiding outpatient heart failure treatment. AB - OPINION STATEMENT: While heart failure (HF) treatment guidelines exist, there are significant gaps in their implementation owing in part to the lack of objective data to help guide clinicians in their medical decision-making. B-type natriuretic peptide (BNP) and its amino-terminal equivalent (NT-proBNP) are objective markers of HF prognosis, are useful to monitor response to treatment in outpatients with HF, and may have a role in "guiding" HF care as well. Successful BNP or NT-proBNP guided HF treatment requires regular attempts to reach and maintain target values (BNP <= 125 pg/mL or NT-proBNP <= 1000 pg/mL). This may be achieved through lifestyle modifications, exercise programs, medication adjustments, and therapeutic interventions shown to reduce morbidity and mortality in HF patients. Failure to achieve biomarker targets portends a worse prognosis, proportional to the lowest achieved natriuretic peptide concentration; in those with significant biomarker "nonresponse," prognosis is poor, and alternative therapeutic strategies should be considered. PMID- 23666500 TI - Development of diabetic nephropathy in nude mice. AB - BACKGROUND: Immune dysfunction is very common in diabetes mellitus (DM). However, there is no evidence whether such immune dysfunction can influence the development of DM, especially the development of diabetic nephropathy (DN). AIM: To investigate the influence of absence of T cells on DN. MATERIALS AND METHODS: Balb/c nude mice and Balb/c wild-type nude (WT) mice were injected with streptozotocin (STZ). Serum tumor necrosis factor alpha (TNF-alpha), blood glucose, body weight, urine albumin/creatinine ratio and rate of kidney weight to body weight (KW/BW) were measured. RESULTS: After modeling, there was no difference of blood glucose level between nude mice and WT mice except at week 2 (28.3 +/- 4.9 mmol/l vs 23.1 +/- 3.9 mmol/l, p<0.01). At week 4, the serum TNF- alpha level of nude mice got to 175.08 +/- 46.03 pg/ml (p<0.05, compared with baseline level 80.19 +/- 8.46 pg/ml), whereas the TNF- alpha levels of WT mice was stable. At week 4, the body weight of nude mice was lower than that of WT mice (14.7 +/- 3.15 g vs 17.97 +/- 2.85 g, p<0.05); the urine albumin/creatinine ratio (Alb/Cr) of nude mice was higher than that of WT mice (50.96 +/- 5.57 mg/mmol vs 41.09 +/- 5.79 mg/mmol, p<0.05); the kidney weight to body weight of nude mice was higher than that of WT mice (0.01352 +/- 0.00163 vs 0.01173 +/- 0.00131, p<0.05). Correlation analysis showed urine Alb/Cr positively correlated with serum TNF-alpha level at week 4 (r = 0.588, p<0.01). At week 4, the increase of type IV collagen in the glomeruli was more prominent in diabetic nude mice than in diabetic WT mice (p<0.05). CONCLUSIONS: Absence of T cells in DM might influence the development of DN. PMID- 23666501 TI - Student reactions to public safety reports of hate crimes. AB - This study investigated participant's reactions to hate crime versus nonbiased crime incident reports that included more or less detail about the crime using a 2 (victim race: African American, unstated)*2 (amount of information: vague, detailed) between-subjects factorial design. We hypothesized that participants would be more sympathetic, more distressed, and blame the victim less if the victim was African American (designating a hate crime) and if more detail was included in the incident report. The results generally showed greater psychological impact for a hate crime versus nonbiased crime and when more information was presented than with vague information, and these two manipulations did not interact in influencing participants' reactions. These results indicate that amount of detail provided about a crime should be considered when publishing incident reports. PMID- 23666503 TI - Role of visual integration in gaze perception and emotional intelligence in schizophrenia. AB - BACKGROUND: Individuals with schizophrenia demonstrate a wide range of social cognitive deficits that significantly compromise functioning. Early visual processing is frequently disrupted in schizophrenia, and growing evidence suggests a role of perceptual dysfunctions in socioemotional functioning in the disorder. This study examined visual integration (the ability to effectively integrate individual, local visual features into a holistic representation), a target construct of basic perception identified by the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia initiative, and its relationship with eye- contact perception and emotional intelligence in schizophrenia. METHODS: Twenty-nine participants with schizophrenia (SCZ) and 23 healthy controls (HC) completed tasks measuring visual integration (Coherent Motion Task, Contour Integration Task), an eye-contact perception task, and a measure of emotional intelligence. RESULTS: SCZ participants showed compromised visual integration as suggested by poorer performance on the Contour Integration Task relative to HC. Visual integration was a significant predictor of eye contact perception and emotional intelligence among SCZ. The amounts of variances in these 2 social cognitive areas accounted for by visual integration were comparable to and overlapped with those accounted for by the diagnosis of schizophrenia. CONCLUSIONS: Individuals with schizophrenia showed compromised visual integration, and this may play a significant role in the observed deficits in higher level processing of social information in the disorder. PMID- 23666504 TI - Enzyme-linked immunosorbent/chemiluminescence assays, recombinant immunoblot assays and nucleic acid tests in the diagnosis of HCV infection. AB - The diagnosis of hepatitis C virus (HCV) infection is defined according to the results obtained from screening assays, and confirmation made by supplemental tests, in order to exclude the possibility of false-positive and false-negative results and, therefore, a misdiagnosis. Identifying the patient's true clinical status is of crucial importance to direct an accurate course of therapy, but, often, the definition of this status is only possible after conjunctions and analysis of the results obtained from each methodology applied, considering the limitations of each assay. In this manuscript, it is discussed briefly the possible results obtained from the three methods most commonly applied in routine laboratory and their contribution in the diagnosis of HCV infection. PMID- 23666508 TI - HLA-B27 alters the response to tumor necrosis factor alpha and promotes osteoclastogenesis in bone marrow monocytes from HLA-B27-transgenic rats. AB - OBJECTIVE: To determine whether HLA-B27 expression alters the response of bone marrow monocytes from HLA-B27/human beta2 -microglobulin-transgenic (B27-Tg) rats to tumor necrosis factor alpha (TNFalpha) and, if so, whether this affects the cells involved in bone homeostasis. METHODS: Bone marrow monocytes were treated with RANKL or with TNFalpha to promote osteoclast formation. Osteoclasts were quantified by counting. Gene expression was measured using quantitative polymerase chain reaction analysis, and protein was detected by enzyme-linked immunosorbent assay, immunoblotting, or immunofluorescence. Effects of endogenously produced cytokines on osteoclast formation were determined with neutralizing antibodies. RESULTS: TNFalpha treatment enhanced osteoclast formation 2.5-fold in HLA-B27-expressing cells as compared to wild-type or to HLA B7/human beta2 -microglobulin-expressing monocytes. TNFalpha induced ~4-fold up regulation of HLA-B27, which was associated with the accumulation of misfolded heavy chains, binding of the endoplasmic reticulum (ER) chaperone BiP, and activation of an ER stress response, which was not seen with HLA-B7. No differences were seen with RANKL-induced osteoclastogenesis. Enhanced interleukin 1alpha (IL-1alpha) production from ER-stressed bone marrow monocytes from B27-Tg rats was found to be necessary and sufficient for enhanced osteoclast formation. However, bone marrow monocytes from B27-Tg rats also produced more interferon beta (IFNbeta), which attenuated the effect of IL-1alpha on osteoclast formation. CONCLUSION: HLA-B27-induced ER stress alters the response of bone marrow monocytes from B27-Tg rats to TNFalpha, which is associated with enhanced production of IL-1alpha and IFNbeta, cytokines that exhibit opposing effects on osteoclast formation. The altered response of cells expressing HLA-B27 to proinflammatory cytokines suggests that this class I major histocompatibility complex allele may contribute to the pathogenesis of spondyloarthritis and its unique phenotype through downstream effects involving alterations in bone homeostasis. PMID- 23666509 TI - The chemotherapeutic agent topotecan differentially modulates the phenotype and function of dendritic cells. AB - The camptothecin analogue topotecan (TPT) induces tumor cell apoptosis due to interference with topoisomerase I and is clinically used as a second-line chemotherapeutic in the treatment for metastasizing ovarian and small cell lung carcinoma. Based on the more recent finding of TPT-mediated inhibition of the transcription factor hypoxia-induced factor-1alpha, a hallmark of solid tumors, TPT, is currently tested in clinical trials for its suitability as a first-line chemotherapeutic for the treatment for various types of tumors. Due to the gained clinical interest in TPT and in light of its modulatory effect on signaling pathways, which are also of importance for immune cell functions, we asked for potential effects of TPT on dendritic cells (DCs), the main antigen-presenting cell population of the immune system. Here, we show that TPT at a therapeutically relevant dose partially activated monocyte-derived DCs as reflected by enhanced migratory activity, elevated expression of HLA-DR and costimulatory/maturation markers, and accordingly an increased allogenic CD4(+) T cell stimulation. In marked contrast, TPT prevented full maturation of DCs stimulated with a cocktail of proinflammatory mediators, accompanied by somewhat lower upregulation of NF kappaB factors p65 and RelB. PMID- 23666510 TI - Immune-suppressive properties of the tumor microenvironment. AB - Solid tumors are more than an accumulation of cancer cells. Indeed, cancerous cells create a permissive microenvironment by exploiting non-transformed host cells. Thus, solid tumors rather resemble abnormal organs composed of the cancerous cells itself and the stroma providing the supportive framework. The stroma can be divided into the extracellular matrix consisting of proteoglycans, hyaluronic acid, and fibrous proteins, as well as stromal cells including mesenchymal and immune cells; moreover, it contains various peptide factors and metabolites. Here, we will focus on immune-modulating capacities of the tumor microenvironment. PMID- 23666511 TI - Comparative purification and characterization of two distinct extracellular monocrotophos hydrolases secreted by Penicillium aculeatum and Fusarium pallidoroseum isolated from agricultural fields. AB - The present study aimed at a comparative characterization of two distinct extracellular monocrotophos hydrolases, from Penicillium aculeatum ITCC 7980.10 (M3) and Fusarium pallidoroseum ITCC 7785.10 (M4), isolated from agricultural fields. The MCP hydrolases were purified by Sephadex G-100 column and DEAE Sepharose CL-6B ion-exchange column followed by SDS-PAGE analysis, which showed the presence of two hydrolases, of 33 and 67 kDa respectively. Both enzymes were most active at alkaline pH and were stable over a wide range of temperatures (60 70 degrees C). Between the strains, the MCP hydrolases from M3 were 2-fold more active than that from M4. Enzyme kinetic studies showed lowest Km (33.52 mM) and highest Vmax (5.18 U/mg protein) for OPH67 of M3 in comparison to the Km and Vmax of the other hydrolases purified from M3 and M4, suggesting that M3 OPH67 was the most efficient MCP hydrolase. To the best of our knowledge, this is the first report of the purification of two distinct extracellular thermostable MCP hydrolases from fungal strains Penicillium aculeatum ITCC 7980.10 and Fusarium pallidoroseum ITCC 7785.10. Owing to its potential MCP hydrolyzing activity, M3 OPH67 can perhaps used directly or in the encapsulated form for remediation of MCP contaminated sites. PMID- 23666512 TI - Nerve-oriented mesorectal excision (NOME): autonomic nerves as landmarks for laparoscopic rectal resection. AB - PURPOSE: We have developed nerve-oriented mesorectal excision (NOME) as a novel concept in rectal cancer surgery by which autonomic pelvic nerves serve as landmarks for a standardized navigation along fascial planes. This article describes the technique step by step and presents our results from 2008 to 2012. MATERIAL AND METHODS: The key steps are: preparation of the splanchnic nerves at the mid-posterior sidewall, the hypogastric nerves at the upper sidewall, and the urogenital nerve branches (Walsh) at the caudal-anterior sidewall. The dissection of the lateral ligament is strictly performed as the last step. NOME was applied in 274 consecutive mesorectal excisions (partial 20.4%, total 79.6%); a subgroup of 42 male patients underwent a questionnaire-based interview on sexual activity. RESULTS: The conversion rate was 0.7%. High (complete) specimen quality and circumferential margin negativity were achieved in 90.1% and 95.3%, respectively. Anastomotic leaks occurred in 13 (4.7%) patients. Mortality was 1.8%. The frequency of prolonged urinary catheter was 1.8%. Of 22 sexually active males interviewed, 18 (81.8%) maintained activity postoperatively. CONCLUSIONS: NOME achieves high-quality mesorectal specimens and a high rate of preservation of autonomic nerve function. The concept of using nerves as laparoscopic landmarks may help to standardize and master laparoscopic rectal cancer surgery. PMID- 23666513 TI - Barriers to screening colonoscopy in an urban population: a study to help focus further efforts to attain full compliance. AB - BACKGROUND: Awareness of colorectal cancer and decision for colorectal cancer screening is influenced by multiple factors including ethnicity, level of education, and adherence to regular medical follow up. OBJECTIVE: Our survey aimed at assessing barriers to colorectal cancer screening among urban population. DESIGN: This study is a survey of the general population. SETTING: This study was made at a local community in the downtown area of a metropolitan city. PATIENTS/SUBJECTS: The study population for this survey included 2000 non institutionalized residents from local community of Brooklyn downtown area of City of Brooklyn, NY, USA. All participants were 50 years or older. INTERVENTION: No intervention was done. MAIN OUTCOME MEASUREMENT: The survey questionnaire collected information about demographic, socioeconomic level, awareness of various cancers and their screening methods, and awareness of screening colonoscopy. RESULTS: Colonoscopy was identified as the best screening test by 31 % of the subjects. Pain and discomfort was the major reason for not having a colonoscopy. The fear of a complication declined significantly after the first colonoscopy but fear of pain and discomfort increased. Difficulty with bowel preparation before a colonoscopy was a significant problem; it discouraged significant number of participants from having another colonoscopy. LIMITATION: This study is limited by its small sample size. CONCLUSION: Physician/family and peer influence seems important but influencing only a minority of subjects. Fear of complications should be allayed using accurate statistical information. Pain should be significantly diminished and/or eliminated during colonoscopy. Future research should focus to minimize complexity and discomfort associated with bowel preparation. PMID- 23666514 TI - Returns and determinants of technical efficiency in small-scale Malabari goat production units in Kerala, India. AB - A stochastic frontier production function was employed to measure technical efficiency and its determinants in smallholder Malabari goat production units in Kerala, India. Data were obtained from 100 goat farmers in northern Kerala, selected using multistage random sampling. The parameters of the stochastic frontier production function were estimated using the maximum likelihood method. Cost and return analysis showed that the major expenditure was feed and fodder, and veterinary expenses were secondary. The chief returns were the sale of live animals, milk and manure. Individual farm technical efficiency ranged from 0.34 to 0.97 with a mean of 0.88. The study found herd size (number of animal units) and centre (locality of farm) significantly affected technical efficiency, but sex of farmer, education, land size and family size did not. Technical efficiency decreased as herd size increased; half the units with five or more adult animals had technical efficiency below 60 %. PMID- 23666515 TI - Importance of the horse and financial impact of equine trypanosomiasis on cattle raising in Venezuela. AB - In Venezuela, horses are indispensable for extensive cattle raising, and extensive cattle raising prevails in all regions. This determines the numerical relationship between horses and cattle (r = 0.93) to be relatively constant nationwide. At regional level, the average extension of cattle ranches varies greatly. However, in relation to the area covered by pastures, the numbers of horses (r = 0.95) and cattle (r = 0.93) are relatively uniform nationwide. Water buffalo occupy small fractions of the territory; therefore, their numbers are related to the area of pastures less strongly (r = 0.56). There is no information on the numerical relationship between the numbers of horses and water buffalo. In the Llanos region of the country, equine trypanosomiasis is responsible for a high mortality in horses, causing considerable financial losses to cattle ranches. So far, such losses have not been assessed. For this region, in 2008, it can be calculated that: (1) with no treatment, losses owing to horse mortality caused by this hemoparasitosis would have amounted to US$7,486,000; (2) the diagnosis and treatment of affected horses would have required an investment of US$805,000; and (3) in terms of horses saved, this investment would have resulted in benefit of US$6,232,000. Therefore, for every monetary unit invested, there would be a benefit 7.75 times greater, this ratio being applicable to any year and all regions of the country. It follows that the profitability of investing in the diagnosis and treatment of equine trypanosomiasis is guaranteed. PMID- 23666516 TI - Development of a label-free aptasensor for monitoring the self-association of lysozyme. AB - A novel aptamer and surface plasmon resonance (SPR)-based sensor was developed for the label-free detection of lysozyme. The aptasensor is characterised by a detection limit of 1 MUg mL(-1) and a linear range of 5-50 MUg mL(-1). As an application, we examined the usefulness of the aptasensor for monitoring the early stages of the aggregation of lysozyme. It was surprisingly found that, despite a significant decrease in monomer content during aggregation, the response of the aptasensor for protein solutions aged for 12 hours was similar to that for the fresh protein. To correlate the results obtained with the aptasensor with the composition of lysozyme solutions at various time points, we examined them in detail by atomic force microscopy (AFM), thioflavin T fluorescence, size exclusion chromatography (SEC) and Matrix Assisted Laser Desorption Ionisation Time of Flight Mass Spectrometry (MALDI-TOF-MS). All methods together indicated that during the initial hours of aggregation, the protein solutions contained small lysozyme oligomers (mainly dimers) and decreasing amounts of monomers. Our results thus suggest that the aptamer also recognizes lysozyme dimers/oligomers. A higher non-specific binding was observed for the aggregated lysozyme at the surface of the aptasensor as compared to the native protein. This was attributed to the hydrophobic patches which are exposed by the unfolded lysozyme and/or oligomer species, allowing for different adsorption and organisation at the surface of the aptasensor. This hypothesis is supported by square wave voltammetry (SWV) studies using solutions of aggregated lysozyme. A higher electrochemical signal due to the direct oxidation of tyrosine/tryptophan residues was observed for aged protein solutions as compared to the fresh solution, indicative of an increased number of such exposed electroactive residues and of overall increased surface hydrophobicity of the protein. Our work presents a label-free lysozyme aptasensor that is useful not only for the detection of the protein monomer but also for observing the onset of aggregation. The approach can be extended to other proteins which are prone to aggregation. PMID- 23666517 TI - Tower microneedle minimizes vitreal reflux in intravitreal injection. AB - Intravitreal injection is widely used for easy control of drug levels in posterior segment of the eye by injecting the drug directly with hypodermic needles. Patients, however, often experience complications from intravitreal injection due to repeated injections, increased intraocular pressure, and infection. In addition, injected drug reflux after intravitreal injection makes it challenging to maintain predetermined drug dose due to the drug loss through backward effusions. Here, we described that the Tower Microneedle can reduce initial reflux and bleb formation due to its smaller outer diameter compared to a traditional hypodermic needle. Furthermore, we use phenylephrine hydrochloride for pupil expansion and demonstrated that Tower Microneedle induced similar pupil expansions using only half the drug volume, in the same period of time, compared to the 31 Gauge hypodermic needle. Consequently, Tower Microneedle achieves the same therapeutic effect in the vitreous body using fewer drugs than a traditional hypodermic needle due to the decreased backward drug effusion. Tower Microneedle described herein holds great promise for intravitreal injection with less reflux and lower drug dosage. PMID- 23666518 TI - How do rituals affect cooperation? An experimental field study comparing nine ritual types. AB - Collective rituals have long puzzled anthropologists, yet little is known about how rituals affect participants. Our study investigated the effects of nine naturally occurring rituals on prosociality. We operationalized prosociality as (1) attitudes about fellow ritual participants and (2) decisions in a public goods game. The nine rituals varied in levels of synchrony and levels of sacred attribution. We found that rituals with synchronous body movements were more likely to enhance prosocial attitudes. We also found that rituals judged to be sacred were associated with the largest contributions in the public goods game. Path analysis favored a model in which sacred values mediate the effects of synchronous movements on prosocial behaviors. Our analysis offers the first quantitative evidence for the long-standing anthropological conjecture that rituals orchestrate body motions and sacred values to support prosociality. Our analysis, moreover, adds precision to this old conjecture with evidence of a specific mechanism: ritual synchrony increases perceptions of oneness with others, which increases sacred values to intensify prosocial behaviors. PMID- 23666520 TI - Use of dysmorphology for subgroup classification on autism spectrum disorder in Chinese children. AB - Data from 1,261 Chinese Autistic Spectrum Disorder (ASD) patients were evaluated and categorized into dysmorphic (10.79 %) and non-dysmorphic groups (89.21 %) upon physical examination by the presence of dysmorphic features. Abnormal MRI/CT result, IQ scores and epilepsy were significantly associated with the dysmorphic group of ASD children. However, gender, EEG abnormality and family history and recurrence of ASD were not found to be significantly different between group statuses. It is suggested that results collected from the Chinese population generally resembles that found in the Caucasians with ethnical differences still present. Current study supports the result shown in Miles' study (Miles et al. in Am J Med Genet 135A:171-180, 2005), in which heterogeneity subtypes of autism of different genetic origins which could be distinguished by presence of dysmorphic features on the patients. PMID- 23666521 TI - The enigmatic truffle Fevansia aurantiaca is an ectomycorrhizal member of the Albatrellus lineage. AB - Fevansia aurantiaca is an orange-colored truffle that has been collected infrequently in the Pacific Northwest of the USA. This sequestrate, hypogeous fungus was originally thought to be related to the genera Rhizopogon or Alpova in the Boletales, but the large, inflated cells in the trama and the very pale spore mass easily segregated it from these genera. To date, no molecular phylogenetic studies have determined its closest relatives. F. aurantiaca was originally discovered in leaf litter beneath Pinaceae, leading Trappe and Castellano (Mycotaxon 75:153-179, 2000) to suggest that it is an ectomycorrhizal symbiont of various members of the Pinaceae. However, without direct ecological or phylogenetic data, it is impossible to confirm the trophic mode of this truffle species. In this study, we combined phylogenetic analysis of the ITS and 28S ribosomal DNA with data on microscopic morphology to determine that F. aurantiaca is a member of the Albatrellus ectomycorrhizal lineage (Albatrellaceae, Russulales). PMID- 23666523 TI - Diffusion weighted MRI in chronic viral hepatitis: correlation between ADC values and histopathological scores. AB - OBJECTIVE: To investigate the utility of apparent diffusion coefficient (ADC) measurement in the diagnosis of chronic viral hepatitis (CVH) and correlation between ADC values and histopathologic severity of CVH. MATERIALS AND METHODS: The ADC values of liver parenchyma on diffusion-weighted magnetic resonance imaging (DWMRI) were measured in 50 patients with a history of CVH and 51 healthy subjects at b 100, b 600 and b 1,000 gradients. Comparison between mean ADC values of the CVH and control groups and correlation results between ADC values and necroinflammation and fibrosis scores in CVH were obtained. RESULTS: Mean ADC values of CVH patients were significantly lower than mean ADC values of the control group at b 100 and b 600 gradients (P < 0.05). There was no significant difference between the CVH and control groups at the b 1,000 gradient (P > 0.05). No significant correlation was found between ADC values and histopathologic scores of CVH (P > 0.05). CONCLUSION: ADC values obtained at the b 100 and b 600 gradients can be used to distinguish between the liver parenchyma of CVH and healthy subjects. ADC measurement was not found to be useful for estimation of the degree of necroinflammation and fibrosis in CVH. TEACHING POINTS: * In chronic viral hepatitis apparent coefficient values are decreased in the liver * There is no correlation between ADC values and histopathologic severity of CVH * DW images obtained at low b values have more ability to demonstrate an ADC decrease in viral hepatitis. PMID- 23666524 TI - Glycerol electro-oxidation over glassy-carbon-supported Au nanoparticles: direct influence of the carbon support on the electrode catalytic activity. AB - Glycerol is at present abundantly co-produced in the biodiesel fabrication and can be used as fuel in Direct Glycerol Fuel Cells (DGFC) for cogeneration of electricity, value-added chemicals and heat. With this motivation, in the present work, we investigated at a fundamental level the oxidation of glycerol over glassy carbon (GC) supported Au nanoparticles in alkaline medium using cyclic voltammetry. By controlling the Au deposition time, we varied the GC supported Au coverage from 0.4% to 30% maintaining a regular particle size distribution with a mean particle size of about 200 nm. An influence of the carbon support on the activity of the GC-supported Au nanoparticles was evidenced. Results from studies on the oxidation of glycerol and ethylene glycol on Au and Pt nanoparticles supported on a glassy carbon, highly ordered pyrolytic graphite and dimensionally stable anode under different pH conditions indicate that the carbon support participates actively in the oxidation of glycerol and other alcohols. We propose that active oxygenated species are gradually formed on the glassy carbon by potential cycling (up to the saturation of the carbon area) and these oxygenated species are additional oxygen suppliers for the oxidation of glycerol residues adsorbed on the Au particles, following a mechanism consisting of the synergism of two active elements: gold and carbon. PMID- 23666525 TI - Three-dimensional imaging of nociceptive intraepidermal nerve fibers in human skin biopsies. AB - A punch biopsy of the skin is commonly used to quantify intraepidermal nerve fiber densities (IENFD) for the diagnosis of peripheral polyneuropathy (1,2). At present, it is common practice to collect 3 mm skin biopsies from the distal leg (DL) and the proximal thigh (PT) for the evaluation of length-dependent polyneuropathies (3). However, due to the multidirectional nature of IENFs, it is challenging to examine overlapping nerve structures through the analysis of two dimensional (2D) imaging. Alternatively, three-dimensional (3D) imaging could provide a better solution for this dilemma. In the current report, we present methods for applying 3D imaging to study painful neuropathy (PN). In order to identify IENFs, skin samples are processed for immunofluorescent analysis of protein gene product 9.5 (PGP), a pan neuronal marker. At present, it is standard practice to diagnose small fiber neuropathies using IENFD determined by PGP immunohistochemistry using brightfield microscopy (4). In the current study, we applied double immunofluorescent analysis to identify total IENFD, using PGP, and nociceptive IENF, through the use of antibodies that recognize tropomyosin receptor-kinase A (Trk A), the high affinity receptor for nerve growth factor (5). The advantages of co-staining IENF with PGP and Trk A antibodies benefits the study of PN by clearly staining PGP-positive, nociceptive fibers. These fluorescent signals can be quantified to determine nociceptive IENFD and morphological changes of IENF associated with PN. The fluorescent images are acquired by confocal microscopy and processed for 3D analysis. 3D-imaging provides rotational abilities to further analyze morphological changes associated with PN. Taken together, fluorescent co-staining, confocal imaging, and 3D analysis clearly benefit the study of PN. PMID- 23666526 TI - Phantom first metacarpal. PMID- 23666527 TI - Efficacy of N-acetylcysteine in phenotypic suppression of mouse models of Niemann Pick disease, type C1. AB - Niemann-Pick disease, type C1 (NPC1), which arises from a mutation in the NPC1 gene, is characterized by abnormal cellular storage and transport of cholesterol and other lipids that leads to hepatic disease and progressive neurological impairment. Oxidative stress has been hypothesized to contribute to the NPC1 disease pathological cascade. To determine whether treatments reducing oxidative stress could alleviate NPC1 disease phenotypes, the in vivo effects of the antioxidant N-acetylcysteine (NAC) on two mouse models for NPC1 disease were studied. NAC was able to partially suppress phenotypes in both antisense-induced (NPC1ASO) and germline (Npc1-/-) knockout genetic mouse models, confirming the presence of an oxidative stress-related mechanism in progression of NPC1 phenotypes and suggesting NAC as a potential molecule for treatment. Gene expression analyses of NAC-treated NPC1ASO mice suggested NAC affects pathways distinct from those initially altered by Npc1 knockdown, data consistent with NAC achieving partial disease phenotype suppression. In a therapeutic trial of short term NAC administration to NPC1 patients, no significant effects on oxidative stress in these patients were identified other than moderate improvement of the fraction of reduced CoQ10, suggesting limited efficacy of NAC monotherapy. However, the mouse model data suggest that the distinct antioxidant effects of NAC could provide potential treatment of NPC1 disease, possibly in concert with other therapeutic molecules at earlier stages of disease progression. These data also validated the NPC1ASO mouse as an efficient model for candidate NPC1 drug screening, and demonstrated similarities in hepatic phenotypes and genome-wide transcript expression patterns between the NPC1ASO and Npc1-/- models. PMID- 23666529 TI - Whole-exome sequencing identifies ADAM10 mutations as a cause of reticulate acropigmentation of Kitamura, a clinical entity distinct from Dowling-Degos disease. AB - Reticulate acropigmentation of Kitamura (RAK) is a rare genetic disorder of cutaneous pigmentation with an autosomal dominant pattern of inheritance and a high penetration rate. The characteristic skin lesions are reticulate, slightly depressed pigmented macules mainly affecting the dorsa of the hands and feet, which first appear before puberty and subsequently expand to the proximal limb and the trunk. To identify mutations that cause RAK, we performed exome sequencing of four family members in a pedigree with RAK. Fifty-three SNV/Indels were considered as candidate mutations after some condition narrowing. We confirmed the mutation status in each candidate gene of four other members in the same pedigree to find the gene that matched the mutation status and phenotype of each member. A mutation in ADAM10 encoding a zinc metalloprotease, a disintegrin and metalloprotease domain-containing protein 10 (ADAM10), was identified in the RAK family. ADAM10 is known to be involved in the ectodomain shedding of various substrates in the skin. Sanger sequencing of four additional unrelated RAK patients revealed four additional ADAM10 mutations. We identified a total of three truncating mutations, a splice site mutation and a missense mutation in ADAM10. We searched for mutations in the KRT5 gene, a causative gene for the similar pigmentation disorder Dowling-Degos disease (DDD), in all the patients and found no KRT5 mutation. These results reveal that mutations in ADAM10 are a cause of RAK and that RAK is an independent clinical entity distinct from DDD. PMID- 23666528 TI - Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of alpha-synuclein in Parkinson's disease models. AB - Parkinson's disease is a movement disorder characterized by death of dopaminergic substantia nigra (SN) neurons and brain accumulation of alpha-synuclein. The tyrosine kinase Abl is activated in neurodegeneration. Here, we show that lentiviral expression of alpha-synuclein in the mouse SN leads to Abl activation (phosphorylation) and lentiviral Abl expression increases alpha-synuclein levels, in agreement with Abl activation in PD brains. Administration of the tyrosine kinase inhibitor nilotinib decreases Abl activity and ameliorates autophagic clearance of alpha-synuclein in transgenic and lentiviral gene transfer models. Subcellular fractionation shows accumulation of alpha-synuclein and hyper phosphorylated Tau (p-Tau) in autophagic vacuoles in alpha-synuclein expressing brains, but nilotinib enhances protein deposition into the lysosomes. Nilotinib is used for adult leukemia treatment and it enters the brain within US Food and Drug Administration approved doses, leading to autophagic degradation of alpha synuclein, protection of SN neurons and amelioration of motor performance. These data suggest that nilotinib may be a therapeutic strategy to degrade alpha synuclein in PD and other alpha-synucleinopathies. PMID- 23666530 TI - In vitro-differentiated neural cell cultures progress towards donor-identical brain tissue. AB - Multiple research groups have observed neuropathological phenotypes and molecular symptoms in vitro using induced pluripotent stem cell (iPSC)-derived neural cell cultures (i.e. patient-specific neurons and glia). However, the global differences/similarities that may exist between in vitro neural cells and their tissue-derived counterparts remain largely unknown. In this study, we compared temporal series of iPSC-derived in vitro neural cell cultures to endogenous brain tissue from the same autopsy donor. Specifically, we utilized RNA sequencing (RNA Seq) to evaluate the transcriptional progression of in vitro-differentiated neural cells (over a timecourse of 0, 35, 70, 105 and 140 days), and compared this with donor-identical temporal lobe tissue. We observed in vitro progression towards the reference brain tissue, and the following three results support this conclusion: (i) there was a significant increasing monotonic correlation between the days of our timecourse and the number of actively transcribed protein-coding genes and long intergenic non-coding RNAs (lincRNAs) (P < 0.05), consistent with the transcriptional complexity of the brain; (ii) there was an increase in CpG methylation after neural differentiation that resembled the epigenomic signature of the endogenous tissue; and (iii) there was a significant decreasing monotonic correlation between the days of our timecourse and the percent of in vitro to brain-tissue differences (P < 0.05) for tissue-specific protein-coding genes and all putative lincRNAs. Taken together, these results are consistent with in vitro neural development and physiological progression occurring predominantly by transcriptional activation of downregulated genes rather than deactivation of upregulated genes. PMID- 23666532 TI - Influence of ABCB1 polymorphisms and docetaxel pharmacokinetics on pathological response to neoadjuvant chemotherapy in breast cancer patients. AB - We have previously reported an association between ABCB1 C3435T polymorphism and docetaxel pharmacokinetics in breast cancer patients. We therefore investigated whether these parameters could account for variations in pathological response. Five ABCB1 polymorphisms including C3435T polymorphism were analyzed in breast cancer patients receiving neoadjuvant chemotherapy with doxorubicin and docetaxel (n = 101). Pathological response was assessed using the Sataloff classification. Pharmacokinetic analysis was performed for the first course of docetaxel (n = 84). No significant association was found between ABCB1 polymorphisms or docetaxel pharmacokinetics and pathological complete response. C3435T genotype was an independent predictive factor of good response in breast (response >50 %, i.e., Sataloff T-A and T-B): OR: 4.6 (95 % CI: 1.3-16.1), p = 0.015, for TT patients versus CT and CC patients. Area under the plasma concentration-time curve (AUC) of docetaxel was the only independent predictive factor of the total absence of response in breast (Sataloff T-D): OR: 14.3, (95 % CI: 1.7-118), p = 0.015, for AUC of docetaxel <3,500 MUg h/L versus >=3,500 MUg h/L. These results suggest that C3435T polymorphism and docetaxel exposure are involved in the response to neoadjuvant chemotherapy in breast cancer patients and may be useful to optimize individualized therapy. PMID- 23666531 TI - GATA3 controls the specification of prosensory domain and neuronal survival in the mouse cochlea. AB - HDR syndrome (also known as Barakat syndrome) is a developmental disorder characterized by hypoparathyroidism, sensorineural deafness and renal disease. Although genetic mapping and subsequent functional studies indicate that GATA3 haplo-insufficiency causes human HDR syndrome, the role of Gata3 in sensorineural deafness and auditory system development is largely unknown. In this study, we show that Gata3 is continuously expressed in the developing mouse inner ear. Conditional knockout of Gata3 in the developing inner ear disrupts the morphogenesis of mouse inner ear, resulting in a disorganized and shortened cochlear duct with significant fewer hair cells and supporting cells. Loss of Gata3 function leads to the failure in the specification of prosensory domain and subsequently, to increased cell death in the cochlear duct. Moreover, though the initial generation of cochleovestibular ganglion (CVG) cells is not affected in Gata3-null mice, spiral ganglion neurons (SGNs) are nearly depleted due to apoptosis. Our results demonstrate the essential role of Gata3 in specifying the prosensory domain in the cochlea and in regulating the survival of SGNs, thus identifying a molecular mechanism underlying human HDR syndrome. PMID- 23666533 TI - The effect of diode superpulsed low-level laser therapy on experimental orthodontic pain caused by elastomeric separators: a randomized controlled clinical trial. AB - The aim of this study was to evaluate the efficacy of diode superpulsed low-level laser therapy (SLLLT) in reducing experimentally induced orthodontic pain. Overall, 120 subjects (23.01 +/- 1.39 years) were enrolled for a clinical trial. Subjects were randomly assigned to upper (U, N = 60) or lower (L, N = 60) jaw groups. All subjects received 4 elastomeric separators mesial and distal to the upper (U group) or lower (L group) right first molar and bicuspids. Each subject of the U and L groups was randomly assigned to laser (Ul, N = 20 and Ll, N = 20), placebo (Up, N = 20 and Lp, N = 20) or control (Uc, N = 20 and Lc, N = 20) sub groups. Subjects in laser groups received a single GaAs diode SLLLT application (910 nm, 160 mW, beam diameter of 8 mm, applied for 340 s) immediately after placing orthodontic separators. Placebo groups received a simulated SLLLT and controls did not receive any therapy. All participants compiled a survey on pain duration and a 100-mm visual analogue scale immediately after the separators placement and after 12, 24, 36, 48, 72, and 96 h. Pain intensity of laser groups was significantly lower compared to placebo and control groups (p = 0.0001). In the laser group, 70% of subjects felt pain, while in the placebo and control groups all subjects felt pain (p = 0.0001). The end of pain occurred earlier in laser compared to placebo and control groups (p = 0.021). A single-diode SLLLT application appeared to be effective in reducing the intensity and duration of experimentally induced orthodontic pain and could be used in daily orthodontic practice. PMID- 23666534 TI - A case of spontaneous systemic immunity to melanoma associated with cure after amputation for extensive regional recurrence. AB - PURPOSE: Survival after amputation for melanoma is short; however, rare long-term survivors are reported. The mechanism for durable systemic tumor control in patients with regional failure is not known. To explore whether systemic tumor immunity may be implicated, tumor and circulating immune responses were examined in a patient who survived disease-free 14 years after hip disarticulation. METHODS: A 71-year-old female with extensive regional metastases of melanoma in the left lower extremity underwent amputation for palliative reasons. Tumor was collected at surgery, and blood was collected during follow-up. Tumor sections were evaluated for lymphocytic infiltration and NY-ESO-1 expression by immunohistochemistry. Cellular immune responses to defined tumor antigens were evaluated by ELISPOT assay, and antibody responses to a panel of tumor antigens were assayed by ELISA. RESULTS: The patient's tumor had minimal lymphocytic infiltrate (immunotype A). NY-ESO-1 was strongly expressed by the melanoma cells. Circulating T-cell responses to NY-ESO-1 peptides were observed 6 and 12 years postoperatively, and antibodies to NY-ESO-1 were detected 2-6 years after surgery. CONCLUSION: The patient described in this report experienced relentless regional tumor progression, with intravascular metastases, and then 14-year systemic disease-free survival after palliative resection, without evidence of melanoma recurrence before death from other causes. Her immune response to NY-ESO 1 likely failed to control established regional metastases because T cells were unable to infiltrate them. It is possible, however, that among other factors, the host immune response may have contributed to systemic protection. PMID- 23666535 TI - Identification of human and animal fecal contamination after rainfall in the Han River, Korea. AB - We investigated the effect of rainfall on the levels and sources of microbial contamination in the Han River, Korea. Thirty-four samples were collected at two sampling sites located upstream and downstream in the river from July 2010 to February 2011. Various fecal indicator microorganisms, including total coliform, fecal coliform, Escherichia coli, Enterococcus spp., somatic and male-specific (F+) coliphage, and four major enteric viruses were analyzed. Rainfall was positively correlated with the levels of fecal coliform and norovirus at both sampling sites. Additionally, rainfall was positively correlated with the levels of total coliform, E. coli, Enterococcus spp., and F+ coliphage at the upstream site. To identify the source of fecal contamination, microbial source tracking (MST) was conducted using both male-specific (F+) RNA coliphage and the Enterococcus faecium esp gene as previously described. Our results clearly indicated that the majority of fecal contamination at the downstream Han River site was from a human source. At the upstream sampling site, contamination from human fecal matter was very limited; however, fecal contamination from non-point animal sources increased following rainfall. In conclusion, our data suggest that rainfall significantly affects the level and source of fecal contamination in the Han River, Korea. PMID- 23666536 TI - Influence of elevated atmospheric carbon dioxide on transcriptional responses of Bradyrhizobium japonicum in the soybean rhizoplane. AB - Elevated atmospheric CO2 can influence the structure and function of rhizoplane and rhizosphere microorganisms by altering root growth and the quality and quantity of compounds released into the rhizoplane and rhizosphere via root exudation. In these studies we investigated the transcriptional responses of Bradyrhizobium japonicum cells growing in the rhizoplane of soybean plants exposed to elevated atmospheric CO2. The results of microarray analyses indicated that elevated atmospheric CO2 concentration indirectly influenced the expression of a large number of genes in Bradyrhizobium attached to soybean roots. In addition, relative to plants and bacteria grown under ambient CO2 growth conditions, genes involved in C1 metabolism, denitrification and FixK2-associated genes, including those involved in nitrogen fixation, microaerobic respiration, respiratory nitrite reductase, and heme biosynthesis, were significantly up regulated under conditions of elevated CO2 in the rhizosphere. The expression profile of genes involved in lipochitooligosaccharide Nod factor biosynthesis and negative transcriptional regulators of nodulation genes, nolA and nodD2, were also influenced by plant growth under conditions of elevated CO2. Taken together, the results of these studies indicate that the growth of soybeans under conditions of elevated atmospheric CO2 influences gene expressions in B. japonicum in the soybean rhizoplane, resulting in changes to carbon/nitrogen metabolism, respiration, and nodulation efficiency. PMID- 23666537 TI - Isolation and characterization of a thermophilic, obligately anaerobic and heterotrophic marine Chloroflexi bacterium from a Chloroflexi-dominated microbial community associated with a Japanese shallow hydrothermal system, and proposal for Thermomarinilinea lacunofontalis gen. nov., sp. nov. AB - A novel marine thermophilic and heterotrophic Anaerolineae bacterium in the phylum Chloroflexi, strain SW7(T), was isolated from an in situ colonization system deployed in the main hydrothermal vent of the Taketomi submarine hot spring field located on the southern part of Yaeyama Archipelago, Japan. The microbial community associated with the hydrothermal vent was predominated by thermophilic heterotrophs such as Thermococcaceae and Anaerolineae, and the next dominant population was thermophilic sulfur oxidizers. Both aerobic and anaerobic hydrogenotrophs including methanogens were detected as minor populations. During the culture-dependent viable count analysis in this study, an Anaerolineae strain SW7(T) was isolated from an enrichment culture at a high dilution rate. Strain SW7(T) was an obligately anaerobic heterotroph that grew with fermentation and had non-motile thin rods 3.5-16.5 MUm in length and 0.2 MUm in width constituting multicellular filaments. Growth was observed between 37-65 degrees C (optimum 60 degrees C), pH 5.5-7.3 (optimum pH 6.0), and 0.5-3.5% (w/v) NaCl concentration (optimum 1.0%). Based on the physiological and phylogenetic features of a new isolate, we propose a new species representing a novel genus Thermomarinilinea: the type strain of Thermomarinilinea lacunofontalis sp. nov., is SW7(T) (=JCM15506(T)=KCTC5908(T)). PMID- 23666538 TI - Commonalities and differences among symbiosis islands of three Mesorhizobium loti strains. AB - To shed light on the breadth of the host range of Mesorhizobium loti strain NZP2037, we determined the sequence of the NZP2037 symbiosis island and compared it with those of strain MAFF303099 and R7A islands. The determined 533 kb sequence of NZP2037 symbiosis island, on which 504 genes were predicted, implied its integration into a phenylalanine-tRNA gene and subsequent genome rearrangement. Comparative analysis revealed that the core regions of the three symbiosis islands consisted of 165 genes. We also identified several NZP2037 specific genes with putative functions in nodulation-related events, suggesting that these genes contribute to broaden the host range of NZP2037. PMID- 23666540 TI - A novel platform for sensing an amino acid by integrating hydrogel photonic crystals with ternary complexes. AB - A novel sensing platform based on the integration of hydrogel photonic crystals and ternary tetracycline-copper(II)-amino acid complexes has been proposed. Obvious and gradual diffraction wavelength shifts and color changes can be easily monitored during the stepwise coordination reaction process. This new strategy allows label-free detection and reversible sensing of glycine with high sensitivity. PMID- 23666539 TI - Identification of antimony- and arsenic-oxidizing bacteria associated with antimony mine tailing. AB - Antimony (Sb) is a naturally occurring toxic element commonly associated with arsenic (As) in the environment and both elements have similar chemistry and toxicity. Increasing numbers of studies have focused on microbial As transformations, while microbial Sb interactions are still not well understood. To gain insight into microbial roles in the geochemical cycling of Sb and As, soils from Sb mine tailing were examined for the presence of Sb- and As-oxidizing bacteria. After aerobic enrichment culturing with As(III) (10 mM) or Sb(III) (100 MUM), pure cultures of Pseudomonas- and Stenotrophomonas-related isolates with Sb(III) oxidation activities and a Sinorhizobium-related isolate capable of As(III) oxidation were obtained. The As(III)-oxidizing Sinorhizobium isolate possessed the aerobic arsenite oxidase gene (aioA), the expression of which was induced in the presence of As(III) or Sb(III). However, no Sb(III) oxidation activity was detected from the Sinorhizobium-related isolate, suggesting the involvement of different mechanisms for Sb and As oxidation. These results demonstrate that indigenous microorganisms associated with Sb mine soils are capable of Sb and As oxidation, and potentially contribute to the speciation and mobility of Sb and As in situ. PMID- 23666541 TI - Effect of substitution of concentrate mix with Sesbania sesban on feed intake, digestibility, body weight change, and carcass parameters of Arsi-Bale sheep fed a basal diet of native grass hay. AB - An experiment was conducted to assess the effect of substitution of concentrate mix with Sesbania sesban on feed intake, digestibility, average daily gain (ADG), and carcass parameters of Arsi-Bale sheep. The experiment employed 25 male sheep with mean (+/-standard error) initial body live weight (BLW) of 19.1 +/- 0.09 kg. The experiment consisted of 7 days of digestibility and 90 days of feeding trials followed by carcass evaluation. The experiment employed a randomized complete block design with five treatments and five blocks. Treatments comprised of grass hay alone fed ad libitum (GHA; control), GHA + 100 % concentrate mix (CM) consisting of wheat bran and noug seed cake at a ratio of 2:1 (0 S. sesban), GHA + 67 % CM + 33 % S. sesban (33 S. sesban), GHA + 33 % CM + 67 % S. sesban (67 S. sesban), and GHA + 100 % S. sesban (100 S. sesban). Total dry matter intake (DMI) was higher (p < 0.001) for sheep in 0 S. sesban-100 S. sesban (800-821 g/day) compared to sheep in control (611 g/day). However, the effect of S. sesban inclusion (0 S. sesban-100 S. sesban) on total DMI was quadratic, and DMI declined after 67 S. sesban. Digestibility of DM, organic matter (p < 0.01), and crude protein were higher (p < 0.001) in supplemented group compared to the control. ADG, feed conversion efficiency (ADG/DMI), slaughter BLW, hot carcass weight, and total edible offals were higher (p < 0.05-0.001) for sheep in 0 S. sesban-100 S. sesban than those in control. Increased level of S. sesban inclusion, in general, reduced growth and carcass parameters in this study. However, there was no difference between 0 S. sesban and 33 S. sesban in most parameters studied. Thus, it can be concluded that S. sesban could substitute a concentrate when it accounted for up to 33 % of the mix. PMID- 23666542 TI - Cecotrophy behavior and use of urea as non-protein nitrogen (NPN) source for capybara (Hydrochoerus hydrochaeris). AB - Fifteen female adult capybaras, with initial average body weight (BW) of 32.7 (+/ 5.8) kg, were kept in individual pens to evaluate effect of supplementation of concentrate feed and its supply time on cecotrophy behavior frequency. The animals were allocated in a completely randomized design, with five animals per treatment, receiving three diets: grass only, grass and grain corn offered in a single meal, and grass and grain corn offered in two daily meals; all cecotrophy acts were recorded. Later, in a second experiment, five capybaras received five levels of urea in their diet: 0, 10, 20, 30, and 40 g urea/100 kg BW, replacing soybean meal as true protein source, in a 5 * 5 Latin square design. The animals were weighed and their blood was collected every 2 weeks. The frequency of cecotrophy (Ps < 0.05) was higher when the capybaras were fed grass only (0.5 +/- 0.07 acts/h) than when they received grass and corn in a single meal (0.3 +/- 0.05 acts/h) and grass and corn supplied in separate meals (0.1 +/- 0.03 acts/h). With increased urea in their diet, the capybaras showed initial signs of chronic intoxication, together with increments in serum urea (r = 0.87, P < 0.05) and a decreasing trend in daily weight gain (r = -0.38, P = 0.06). Therefore, when including concentrate feeds in capybara diet, these must be mixed with roughage in a single meal to avoid high decrease in the frequency of cecotrophy behavior and increase in dry matter intake. The replacement of soybean meal with urea in capybara diet is not recommended. PMID- 23666543 TI - Safety and efficacy of the subclavian access route for TAVI in cases of missing transfemoral access. AB - OBJECTIVE: We retrospectively analysed our experience with the subclavian access transcatheter aortic valve implantation (TAVI) with the self-expandable CoreValve prosthesis and compared the results with transfemorally treated patients. BACKGROUND: For TAVI, a subclavian access is alternatively used when the femoral arteries are diseased or very small. METHODS: Between June 2007 and February 2011, 341 patients underwent CoreValve implantation in the German Heart Center, Munich through either transfemoral (n = 301) or subclavian (n = 40) approach. The subclavian approach was chosen where transfemoral approach was not possible. RESULTS: There was no difference in baseline characteristics between the groups. There were no significant differences between groups for parameters potentially related to improved valve positioning (contrast medium, fluoroscopy time, implantation of a second valve, post-implantation balloon dilatation, valve dislocation, pacemaker implantation, aortic regurgitation), while the procedure duration was longer (105 +/- 40 vs. 82 +/- 33 min, p = 0.001). With the Kaplan Meier estimate, survival was not different among groups. Strokes, myocardial ischaemia, and access vessel complications occurred in 2.5, 0, and 7.5 % (subclavian group) vs. 4.3, 2.0, 10.6 % (transfemoral group), ns. CONCLUSIONS: Our results demonstrate the safety of the subclavian access for TAVI and comparability with the transfemoral approach. With longer duration of the procedure and no significant advantages in clinical outcome, the subclavian access will have an indication for selected patients, while transfemoral TAVI should be considered first choice. PMID- 23666544 TI - When romance and rivalry awaken : attractiveness-based social judgment biases emerge at adolescence. AB - Previous research indicates positive effects of a person's attractiveness on evaluations of opposite-sex persons, but less positive or even negative effects of attractiveness on same-sex evaluations. These biases are consistent with social motives linked to mate search and intrasexual rivalry. In line with the hypothesis that such motives should not become operative until after puberty, 6- to 12-year-old participants (i.e., children) displayed no evidence for biased social evaluations based on other people's attractiveness. In contrast, 13- to 19 year-old participants (i.e., adolescents) displayed positive and negative attractiveness biases toward opposite- and same-sex targets, respectively. Moreover, these biases increased with the age-and thus the reproductive relevance of the targets being evaluated. Findings corroborate the relevance of mating related motives for social judgment and illustrate how such biases can grow during human development. At a broader conceptual level, this research demonstrates the utility of investigating proximate social judgment processes through the lens of adaptationist thinking. PMID- 23666546 TI - Relationship between oxidative stress and clinical pregnancy in assisted reproductive technology treatment cycles. AB - PURPOSE: To examine the relationship between serum total oxidant (TOS) and antioxidant (TAS) levels and clinical pregnancy in assisted reproductive technology (ART) cycles. METHODS: Prior to and after oocyte pick-up (OPU) and embryo transfer (ET), blood samples were collected from gynecologically normal females (n = 70) who were enrolled for ART solely due to male factor infertility. TAS, TOS levels and oxidative stress indexes (OSI: TOS/TAS) in four phases of treatment cycle (pre and post OPU and ET) between clinically pregnant and non pregnant patients were compared. Critical cut-off values of significantly different TAS, TOS levels and OSIes for clinical pregnancy were established. RESULTS: The TAS levels in patients with clinical pregnancy were significantly higher in all of the four phases of the cycle. Post-OPU and pre-ET TOS levels were significantly higher in clinically pregnant patients. According to OSIes; only the pre-OPU OSI was significantly lower in clinically pregnant patients compared with non-pregnant ones. Moreover, the highest area under the ROC curve (AUC) from the seven different significant measurements [1) pre-OPU OSI, 2) pre OPU TAS, 3) post-OPU TAS, 4) pre-ET TAS, 5) post-ET TAS, 6) post-OPU TOS, 7) pre ET TOS] was related to pre-OPU OSI. CONCLUSIONS: In ART cycles, women with a higher total antioxidant status prior to and after OPU and prior to and after ET have an increased probability of clinical pregnancy. Additionally; OSI before OPU was one of the most important determinants for clinical pregnancy, so the oxidant and antioxidant balance is as important as the antioxidant concentration alone. PMID- 23666547 TI - Heat generation caused by ablation of dental hard tissues with an ultrashort pulse laser (USPL) system. AB - Heat generation during the removal of dental hard tissues may lead to a temperature increase and cause painful sensations or damage dental tissues. The aim of this study was to assess heat generation in dental hard tissues following laser ablation using an ultrashort pulse laser (USPL) system. A total of 85 specimens of dental hard tissues were used, comprising 45 specimens of human dentine evaluating a thickness of 1, 2, and 3 mm (15 samples each) and 40 specimens of human enamel with a thickness of 1 and 2 mm (20 samples each). Ablation was performed with an Nd:YVO4 laser at 1,064 nm, a pulse duration of 9 ps, and a repetition rate of 500 kHz with an average output power of 6 W. Specimens were irradiated for 0.8 s. Employing a scanner system, rectangular cavities of 1-mm edge length were generated. A temperature sensor was placed at the back of the specimens, recording the temperature during the ablation process. All measurements were made employing a heat-conductive paste without any additional cooling or spray. Heat generation during laser ablation depended on the dental hard tissue (enamel or dentine) and the thickness of the respective tissue (p < 0.05). Highest temperature increase could be observed in the 1-mm thickness group for enamel. Evaluating the 1-mm group for dentine, a significantly lower temperature increase could be measured (p < 0.05) with lowest values in the 3-mm group (p < 0.05). A time delay for temperature increase during the ablation process depending on the material thickness was observed for both hard tissues (p < 0.05). Employing the USPL system to remove dental hard tissues, heat generation has to be considered. Especially during laser ablation next to pulpal tissues, painful sensations and potential thermal injury of pulp tissue might occur. PMID- 23666548 TI - Nervous system lyme disease: diagnosis and treatment. AB - OPINION STATEMENT: The tick-borne spirochete responsible for Lyme disease is highly antibiotic-sensitive. Treatment related misconceptions can be attributed to confusion in three principal realms: (1) the appropriate approach to diagnosis (who should be treated); (2) necessary and appropriate treatment; and (3) what actually constitutes nervous system infection and to what extent this mandates different treatment. Contrary to often-repeated assertions, laboratory-based diagnosis-in the appropriate setting-is as valid as it is in most other serologically diagnosed infections. Treatment is highly effective in the vast majority of patients, including those with nervous system disease. Nervous system infection, most typically meningitis, cranial neuritis, radiculoneuritis, and other forms of mononeuropathy multiplex, is highly antibiotic responsive. The encephalopathy that can be seen in some patients with active infection represents the same phenomenon that occurs in patients with many other inflammatory disorders, is not evidence of central nervous system (CNS) infection, and does not require any different, more prolonged, or more intensive treatment. In patients with infection not involving the CNS, oral treatment with amoxicillin, cefuroxime axetil, or doxycycline for 2-4 weeks is almost always curative. Despite historic preferences for parenteral treatment with ceftriaxone, cefotaxime, or meningeal dose penicillin, patients with the forms of nervous system involvement listed above are highly responsive to oral doxycycline. Parenteral regimens can be reserved for those very rare patients with parenchymal CNS involvement, other severe forms of infection, or the approximately 5 % of patients who fail to respond to oral regimens. PMID- 23666549 TI - Biopsy-proven brain metastases from prostate cancer: a series of four cases with review of the literature. AB - AIMS: Prostate cancer is very common and is the second most common cause of cancer death in males in Australia; however, brain metastases are exceedingly rare. MATERIALS AND METHODS: We review four cases of biopsy-proven brain metastases from prostate cancer and review the relevant literature. RESULTS: Three of four patients had acinar adenocarcinoma of prostate with one patient having ductal adenocarcinoma variant on histopathology. Three patients had the brain as the only site of metastatic disease. All patients underwent surgery, and three of four patients underwent adjuvant palliative radiotherapy to the brain. CONCLUSION: Brain metastases from prostate cancer are rare, but brain metastases without other sites of metastatic disease are exceedingly rare and may be more common with ductal adenocarcinoma variant. PMID- 23666550 TI - A novel method for the culture and polarized stimulation of human intestinal mucosa explants. AB - Few models currently exist to realistically simulate the complex human intestine's micro-environment, where a variety of interactions take place. Proper homeostasis directly depends on these interactions, as they shape an entire immunological response inducing tolerance against food antigens while at the same time mounting effective immune responses against pathogenic microbes accidentally ingested with food. Intestinal homeostasis is preserved also through various complex interactions between the microbiota (including food-associated beneficial bacterial strains) and the host, that regulate the attachment/degradation of mucus, the production of antimicrobial peptides by the epithelial barrier, and the "education" of epithelial cells' that controls the tolerogenic or immunogenic phenotype of unique, gut-resident lymphoid cells' populations. These interactions have been so far very difficult to reproduce with in vitro assays using either cultured cell lines or peripheral blood mononuclear cells. In addition, mouse models differ substantially in components of the intestinal mucosa (mucus layer organization, commensal bacteria community) with respect to the human gut. Thus, studies of a variety of treatments to be brought in the clinics for important stress-related or pathological conditions such as irritable bowel syndrome, inflammatory bowel disease or colorectal cancer have been difficult to carry out. To address these issues, we developed a novel system that enables us to stimulate explants of human intestinal mucosa that retain their in situ conditioning by the host microbiota and immune response, in a polarized fashion. Polarized apical stimulation is of great importance for the outcome of the elicited immune response. It has been repeatedly shown that the same stimuli can produce completely different responses when they bypass the apical face of the intestinal epithelium, stimulating epithelial cells basolaterally or coming into direct contact with lamina propria components, switching the phenotype from tolerogenic to immunogenic and causing unnecessary and excessive inflammation in the area. We achieved polarized stimulation by gluing a cave cylinder which delimited the area of stimulation on the apical face of the mucosa as will be described in the protocol. We used this model to examine, among others, differential effects of three different Lactobacilli strains. We show that this model system is very powerful to assess the immunomodulatory properties of probiotics in healthy and disease conditions. PMID- 23666551 TI - First-principles study of O2 activation on ligand-protected Au32 clusters. AB - Poly(N-vinyl-2-pyrrolidone) (PVP) is often used to protect active Au clusters from coalescence. The influences of PVP on the O2 adsorption on Au32 clusters were investigated using density functional theory calculations. Various low-lying structures of O2:Au32 and O2:Au32:PVP complexes, in which the Au32 is either neutral or anionic and the O2 is either molecular or dissociative, were identified. The PVP influences were evaluated in terms of the changes in geometry, adsorption energy, charge redistribution, spin density, and density of states upon PVP pre-adsorption. Our calculations reveal that PVP weakly adsorbs on the cluster surface, with rather small changes in the structural, geometrical and electronic properties that are relevant to the O2 activation. The activity of neutral or anionic Au32 towards O2 is kept or slightly enhanced by PVP because of the cooperative adsorption of PVP and O2. This is the structural basis of choosing PVP as the protective ligand for Au clusters. PMID- 23666552 TI - Editorial: interleukin-7 and its receptor: the axis of evil to target in Sjogren's syndrome? PMID- 23666553 TI - Interactional expression of netrin-1 and its dependence receptor UNC5B in prostate carcinoma. AB - Acting via its receptor UNC5B, netrin-1, one of the major neuronal guidance cues, plays an important role in angiogenesis, neurogenesis, tissue morphogenesis, embryonic development, cancer, inflammation, and various pathologies. However, its role has not been reported in prostate carcinoma. To investigate the association of netrin-1 and UNC5B expression with prostate carcinoma, several human prostate carcinoma cell lines were cultured and the expression levels of netrin-1 and UNC5B were determined by real-time PCR and Western blot. Calphostin C, (the inhibitor of PKC alpha) and phorbol-12-myristate 13-acetate-PMA (the agonist of PKC alpha) were used to treat the prostate carcinoma cells, and the cell proliferation and invasion abilities were measured by CCK-8 and wound healing assays. Proliferation of DU145 cells was affected by the recruitment of PMA and calphostin C in a dose-dependent manner. By immunofluorescence, we identified the localization of netrin-1 and UNC5B in prostate carcinoma cell lines (DU145, 22RV1, PC3, PC3M, and RWEP) and found that netrin-1 was highly expressed in the nucleolus but there was no expression of UNC5B. The co localization expression of PKC alpha and UNC5B was confirmed by the confocal immunofluorescence. Higher netrin-1 and lower UNC5B expression in all prostate carcinoma cell lines indicated that netrin-1 and UNC5B could be used to predict metastasis. PMID- 23666555 TI - Best friends' discussions of social dilemmas. AB - Peer relationships, particularly friendships, have been theorized to contribute to how children and adolescents think about social and moral issues. The current study examined how young adolescent best friends (191 dyads; 53.4% female) reason together about multifaceted social dilemmas and how their reasoning is related to friendship quality. Mutually-recognized friendship dyads were videotaped discussing dilemmas entailing moral, social-conventional and prudential/pragmatic issues. Both dyad members completed a self-report measure of friendship quality. Dyadic data analyses guided by the Actor-Partner Interdependence Model indicated that adolescent and friend reports of friendship qualities were related to the forms of reasoning used during discussion. Friends who both reported that they could resolve conflicts in a constructive way were more likely to use moral reasoning than friends who reported that their conflict resolution was poor or disagreed on the quality of their conflict resolution. The findings provide evidence for the important role that friendship interaction may play in adolescents' social and moral development. PMID- 23666554 TI - Differential responses to anticipation of reward after an acute dose of the designer drugs benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) alone and in combination using functional magnetic resonance imaging (fMRI). AB - RATIONALE: Functional magnetic resonance imaging (fMRI) studies have reported increased activation of the mesolimbic system in response to anticipation of rewarding stimuli. The anticipation of uncertain outcomes evokes activation in the amygdala, orbitofrontal cortex, inferior frontal gyrus and insula. Drugs known to effect dopaminergic and serotonergic neurons also alter regional activation. OBJECTIVES: Benzylpiperazine (BZP) and/or trifluoromethylphenylpiperazine (TFMPP) have been recreationally used worldwide for more than a decade. BZP affects mainly dopaminergic neurons, while TFMPP has serotonergic effects. METHODS: We investigated the effects of an acute dose of BZP, TFMPP or a combination of BZP and TFMPP on the anticipation of reward in a double-blind, placebo-controlled, crossover study using fMRI. An event-related gambling paradigm was completed by healthy controls 90 min after taking an oral dose of either BZP (200 mg), TFMPP (either 50 or 60 mg), BZP + TFMPP (100 + 30 mg) or placebo. RESULTS: After giving BZP, the anticipation of a $4 reward decreased the activation of the inferior frontal gyrus, insula and occipital regions in comparison to placebo. TFMPP increased the activation of the putamen but decreased the activity in the insula relative to placebo. When BZP and TFMPP were given in combination, activation of the rolandic operculum occurred. The magnitude of reward also affected neural correlates. CONCLUSION: We propose that the effects of BZP and TFMPP on dopaminergic and serotonergic circuitry, respectively, reflect regional changes. The dopaminergic effects of BZP appear to increase positive arousal and subsequently reduce the response to uncertainty, while TFMPP appears to alter the response to uncertainty by increasing emotional responses. PMID- 23666556 TI - Robust cytoplasmic accumulation of phosphorylated TDP-43 in transgenic models of tauopathy. AB - Frontotemporal lobar degeneration (FTLD) has been subdivided based on the main pathology found in the brains of affected individuals. When the primary pathology is aggregated, hyperphosphorylated tau, the pathological diagnosis is FTLD-tau. When the primary pathology is cytoplasmic and/or nuclear aggregates of phosphorylated TAR-DNA-binding protein (TDP-43), the pathological diagnosis is FTLD-TDP. Notably, TDP-43 pathology can also occur in conjunction with a number of neurodegenerative disorders; however, unknown environmental and genetic factors may regulate this TDP-43 pathology. Using transgenic mouse models of several diseases of the central nervous system, we explored whether a primary proteinopathy might secondarily drive TDP-43 proteinopathy. We found abnormal, cytoplasmic accumulation of phosphorylated TDP-43 specifically in two tau transgenic models, but TDP-43 pathology was absent in mouse models of Abeta deposition, alpha-synucleinopathy or Huntington's disease. Though tau pathology showed considerable overlap with cytoplasmic, phosphorylated TDP-43, tau pathology generally preceded TDP-43 pathology. Biochemical analysis confirmed the presence of TDP-43 abnormalities in the tau mice, which showed increased levels of high molecular weight, soluble TDP-43 and insoluble full-length and ~35 kD TDP 43. These data demonstrate that the neurodegenerative cascade associated with a primary tauopathy in tau transgenic mice can also promote TDP-43 abnormalities. These findings provide the first in vivo models to understand how TDP-43 pathology may arise as a secondary consequence of a primary proteinopathy. PMID- 23666557 TI - Peptide receptor imaging in neuroendocrine tumors: comparison between diagnostic scintigraphy and post-therapy whole-body scan. AB - OBJECTIVE: Several different somatostatin analogs labeled with gamma or positron emitting radionuclides exist for diagnostic imaging of neuroendocrine tumors (NETs). Differences between standard diagnostic scintigraphy (SDS) and post therapy whole-body scan (PTWBS) at peptide receptor radionuclide therapy in lesion detection are known; such differences have been correlated with the varying degree of receptor subtype expression and the varying receptor affinity profile of the different ligands. The aim of this study is to investigate differences between SDS and PTWBS obtained using the same radiopharmaceutical. METHODS: We retrospectively reviewed clinical records of 53 patients with a diagnosis of NET, who underwent both SDS and PTWBS using (111)In-Pentetreotide. We compared the number of lesions for each body region detected by SDS and PTWBS. RESULTS: In 14/53 patients (26.4%) discrepancies between SDS and PTWBS were found. PTWBS detected 68 additional lesions with respect to SDS that were distributed as follows: head and neck, 6; mediastinum, 1; liver, 10; abdomen/pelvis, 1; bone, 44; other localizations, 6. The number of lesions detected by SDS was significantly different from that revealed by PTWBS (Wilcoxon matched pairs test, P = 0.0313). The regions that contributed significantly to reach this difference were head and neck (McNemar test, P = 0.0412), liver (McNemar test, P = 0.0044), bone (McNemar test, P < 0.0001) and other localizations (McNemar test, P = 0.0412). CONCLUSION: PTWBS shows more lesions than SDS with a significant discrepancy. We suppose that administration of higher radiopharmaceutical activity, use of larger peptide amount and the different time interval between radiopharmaceutical administration and scan execution can determine a higher sensitivity of PTWBS. PMID- 23666558 TI - Differentiation of tumor sensitivity to photodynamic therapy and early evaluation of treatment effect by nuclear medicine techniques. AB - OBJECTIVE: Our final goal is to develop an appropriate method using nuclear medicine technique for monitoring the effect and prediction of Photodynamic Therapy (PDT) on tumors. The aim of this study is to evaluate the effect of PDT on tumor cells in vitro using (18)F-FDG and (99m)Tc-MIBI as tracers. METHODS: Five tumor cell lines (A431, DU145, H1650, LS180, SHIN3) with varied characteristics were irradiated after incubating for 24 h with several doses of Photofrin (PF). Singlet oxygen was monitored by the near-IR emission detection system during irradiation and generated (1)O2 was calculated. PDT effects were rapidly evaluated by nuclear medicine techniques (uptake of (18)F-FDG and (99m)Tc MIBI) and traditional methods for cell viability (MTT and trypan blue assays) at 3 h after PDT. Intracellular PF concentration was measured by absorption spectrometer and cell protein content was measured by the Lowry method. (18)F-FDG uptake, (99m)Tc-MIBI uptake, singlet oxygen, and intracellular PF concentration were standardized by protein content. Decrease % of (18)F-FDG and (99m)Tc-MIBI, MTT, and trypan blue was normalized to the control group. RESULTS: Decrease % of (18)F-FDG was exponentially related to decrease % of MTT (R (2) = 0.650, P < 0.01) while decrease % of (99m)Tc-MIBI was linearly related to that of MTT (R (2) = 0.719, P < 0.01). The decrease % of MTT was more sensitive than that of trypan blue. However, neither (1)O2 nor PF uptake was correlated with sensitivity to PDT. In addition, (18)F-FDG uptake before PDT was linearly related to decrease % of MTT (R (2) = 0.800, P < 0.05). CONCLUSIONS: Our findings in in vitro studies suggest that (99m)Tc-MIBI is better than (18)F-FDG for early evaluation of PDT effect, but (18)F-FDG uptake may be used to predict PDT sensitivity before therapy. PMID- 23666559 TI - A thermoresponsive hydrogel formed from a star-star supramolecular architecture. PMID- 23666560 TI - Dietary arsenic intake and subsequent risk of cancer: the Japan Public Health Center-based (JPHC) Prospective Study. AB - PURPOSE: Arsenic is a known human carcinogen and has been linked to adverse health outcomes, including cancer. However, the effects of arsenic exposure from food on health are still unknown. We researched to examine the association between arsenic exposure from food and incidence of cancer in a Japanese population. METHODS: We conducted a population-based prospective study in 90,378 Japanese men and women aged 45-74 years. Participants responded to a validated questionnaire that included 138 food items. We estimated dietary arsenic intake from 12 food groups (75 items) based on the questionnaire data. During 11 years of follow-up, 7,002 cancer cases were identified. Hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer were calculated by Cox proportional hazards modeling. RESULTS: Total arsenic and inorganic arsenic showed no association with the risk of total cancer in both men and women. Total arsenic and inorganic arsenic intake tended to be associated with an increased risk of lung cancer in men. In particular, these positive associations were strengthened in currently smoking men, with HRs (95% CI) in the highest categories of arsenic and inorganic arsenic intake compared with the lowest of 1.29 (95% CI = 1.03-1.61) and 1.36 (95% CI = 1.09-1.70), respectively. We also detected an interaction between arsenic and inorganic arsenic intake and smoking status in men (p(interaction) < 0.01 and 0.07, respectively). CONCLUSION: A significant dose-response trend was seen in the association of arsenic and inorganic intake with lung cancer risk in currently smoking men. PMID- 23666561 TI - Curcumin targets the AKT-mTOR pathway for uterine leiomyosarcoma tumor growth suppression. AB - BACKGROUND: Uterine leiomyosarcomas generally do not respond well to standard chemotherapy. We previously demonstrated that curcumin, the active ingredient derived from the herb Curcuma longa, inhibits uterine leiomyosarcoma cells in vitro via the inhibition of the AKT-mammalian target of rapamycin (mTOR) pathway. As a preclinical investigation, we performed an in vivo study using female nude mice to confirm the therapeutic potential of curcumin against uterine leiomyosarcoma. METHODS: Human leiomyosarcoma cells, SK-UT-1, were inoculated in female nude mice to establish subcutaneous tumors. Either vehicle control or 250 mg/kg curcumin was administered intraperitoneally every day for 14 consecutive days, and the mice were then killed. The tumors were measured every 2-3 days. The tumors were processed for immunohistochemical analyses to detect total AKT, phosphorylated AKT, total mTOR, phosphorylated mTOR, and phosphorylated S6. To detect apoptosis, the tumors were stained for cleaved PARP and TUNEL. Ki-67 immunohistochemistry was performed to determine cell viability of the tumors. RESULTS: Compared with the control, curcumin reduced uterine leiomyosarcoma tumor volume and mass significantly with a concordant decrease in mTOR and S6 phosphorylation. However, AKT phosphorylation was not significantly altered. Cleaved PARP and TUNEL staining increased significantly with curcumin administration, indicating the induction of apoptosis. There was no difference in Ki-67 staining between the two groups. CONCLUSION: Curcumin inhibited uterine leiomyosarcoma tumor growth in vivo by targeting the AKT-mTOR pathway for inhibition. PMID- 23666562 TI - Thiol-ene/acrylate substrates for softening intracortical electrodes. AB - Neural interfaces have traditionally been fabricated on rigid and planar substrates, including silicon and engineering thermoplastics. However, the neural tissue with which these devices interact is both 3D and highly compliant. The mechanical mismatch at the biotic-abiotic interface is expected to contribute to the tissue response that limits chronic signal recording and stimulation. In this work, novel ternary thiol-ene/acrylate polymer networks are used to create softening substrates for neural recording electrodes. Thermomechanical properties of the substrates are studied through differential scanning calorimetry and dynamic mechanical analysis both before and after exposure physiological conditions. This substrate system softens from more than 1 GPa to 18 MPa on exposure to physiological conditions: reaching body temperature and taking up less than 3% fluid. The impedance of 177 um(2) gold electrodes electroplated with platinum black fabricated on these substrates is measured to be 206 kOmega at 1 kHz. Specifically, intracortical electrodes are fabricated, implanted, and used to record driven neural activity. This work describes the first substrate system that can use the full capabilities of photolithography, respond to physiological conditions by softening markedly after insertion, and record driven neural activity for 4 weeks. PMID- 23666563 TI - An in situ electrochemical detection method of cell viability. AB - An in situ electrochemical method of cell viability, which integrated cell culture, pretreatment and detection in a cell culture dish, was developed. The method significantly improved the electrochemical response of cells, simplified the operation process, reduced the experiment time, avoided the use of trypsin, and was applied in the study of the effectiveness of antitumor drugs on tumor suppression. PMID- 23666564 TI - Influence of CYP2C19 polymorphism and concomitant antiepileptic drugs on serum clobazam and N-desmethyl clobazam concentrations in patients with epilepsy. AB - OBJECTIVE: The aims of this study were to identify the factors influencing the metabolism of clobazam (CLB) and its active metabolite [N-desmethyl clobazam (NCLB)] and to evaluate the NCLB concentration as an indicator for CYP2C19 polymorphism in epileptic patients. METHODS: A total of 302 serum samples from 238 Japanese patients were evaluated. The ratios of the serum CLB and NCLB concentrations to the CLB dose (CD ratios) were calculated and compared with CYP2C19 phenotypes. RESULTS: The mean CD ratio of NCLB in extensive metabolizers (EM: *1/*1), intermediate metabolizers (IM: *1/*2 or *1/*3), and poor metabolizers (PM: *2/*2, *3/*3, or *2/*3) was 3.1, 4.9, and 21.6 (MUg/mL)/(mg/kg), respectively. In the EM and IM groups, the concomitant use of hepatic enzyme inducers (phenytoin and carbamazepine) reduced the CD ratio of CLB and increased that of NCLB. In the PM group, these inducers also decreased the CD ratio for CLB but did not elevate the CD ratio for NCLB. Using multiple regression analysis, body weight showed a positive correlation with an increased CD ratio for NCLB. The concomitant use of zonisamide and stiripentol also elevated the CD ratio for NCLB in the EM and IM groups, but that of the PM group was almost unchanged. When the cut-off value of the CD ratio for NCLB was set as 10.0 (MUg/mL)/(mg/kg) for predicting the CYP2C19 PM status, the sensitivity and specificity were 94.4% and 95.7%, respectively. CONCLUSIONS: The interaction between NCLB and other antiepileptic drugs showed marked differences among CYP2C19 phenotypes. Measurement of the serum NCLB concentration is clinically useful for identifying the PM phenotype. PMID- 23666565 TI - Therapeutic monitoring of opioids: a sensitive LC-MS/MS method for quantitation of several opioids including hydrocodone and its metabolites. AB - For pain management, opioid therapy is a mainstay for treating acute pain and relieving moderate to severe chronic pain. Quantitative measurement of opioids and their metabolites in urine is used mainly for confirmation of screened results obtained for clinical and forensic purposes. Due to limitations in interpretation of urine results for pain management testing purposes, the use of blood or serum to assess opioids and their metabolites may be of benefit. This report describes a sensitive liquid chromatography-tandem mass spectrometry method for the detection of hydrocodone and its metabolites hydromorphone, norhydrocodone, and dihydrocodeine, and other common opiates that patients may be taking, including morphine, codeine, oxycodone, and oxymorphone in a single extraction. The method uses solid-phase extraction of 500 uL of sample with quantitation by liquid chromatography-tandem mass spectrometry. The assay is linear from 1.0 to 100 ng/mL and has a between-day coefficient of variation of <10%. The major advantage of this method is that a single extraction can detect hydrocodone and its metabolites and other opiates or opioids that patients frequently use simultaneously with hydrocodone. PMID- 23666566 TI - Plasma, oral fluid, and whole-blood distribution of antipsychotics and metabolites in clinical samples. AB - BACKGROUND: Oral fluid provides a noninvasive method of sample collection. The aim of this study was to obtain oral fluid, plasma, and whole blood from patients prescribed amisulpride, aripiprazole, clozapine, quetiapine, risperidone, or sulpiride and to measure plasma:whole blood and plasma:oral fluid analyte distribution. METHODS: Matched oral fluid, plasma and whole-blood samples were analyzed by liquid chromatography-tandem mass spectrometry. RESULTS: There were 101 sets of samples from 90 (56 male, 34 female) patients (nine prescribed 2 antipsychotics, and one 3). There were <= 5 samples for aripiprazole, amisulpride, and sulpiride. There was a good relationship between the plasma and hemolyzed whole-blood concentrations (R > 0.95), with plasma:whole-blood ratios varying between 0.7 (amisulpride) and 1.8 (aripiprazole). Amisulpride plasma and oral fluid concentrations were similar, whereas aripiprazole and dehydroaripiprazole oral fluid concentrations were approximately 8% of those in the plasma, reflecting the weak and strong plasma protein binding of these compounds, respectively. For the other analytes, plasma concentrations were 2-4 times higher than oral fluid concentrations. In general, there was a poor relationship (R = 0.3-0.7) between the plasma and oral fluid concentrations, possibly due to intrapatient saliva pH variation during sample collection. CONCLUSIONS: This work shows that hemolyzed whole-blood samples can be used for therapeutic drug monitoring purposes for the analytes of interest, provided that the plasma:whole-blood ratio is taken into account when interpreting results. For aripiprazole and dehydroaripiprazole, measurements in oral fluid will probably not be feasible. However, the relationship between plasma and oral fluid concentration for amisulpride, clozapine (and norclozapine), quetiapine (and possibly quetiapine metabolites), and risperidone/9-hydroxyrisperidone shows potential for oral fluid analysis. PMID- 23666567 TI - Improved method for therapeutic drug monitoring of 6-thioguanine nucleotides and 6-methylmercaptopurine in whole-blood by LC/MSMS using isotope-labeled internal standards. AB - OBJECTIVES: Thiopurine drugs (azathioprine, 6-mercaptopurine) show wide interindividual variability and a narrow therapeutic range thus making therapeutic monitoring of their active metabolite 6-thioguanine nucleotides (6 TGN) desirable. We improved the currently available laborious and complex methodology of therapeutic drug monitoring of 6-TGN and the metabolite 6 methylmercaptopurine (6-MMP) in washed erythrocytes (ery) based on a whole-blood method. METHODS: The analytes were hydrolyzed and extracted from 25-uL ethylenediaminetetraacetic acid-anticoagulated whole-blood spiked with isotope labeled 6-TG-C2N and 6-MMP-d3 internal standards. Chromatography was performed in 5.1 minutes on a C18 reverse phase column followed by detection via electrospray interface-coupled API 4000 mass spectrometer set up in the positive multiple reaction monitoring mode. The hemoglobin concentration was measured in 20 uL of the original sample (AHD575 method), and the results were standardized to 120 g/L of hemoglobin. RESULTS: Calibration curves were linear with r > 0.999 (6-TGN and 6-MMP up to 10,000 pmol/0.2 mL). The limit of quantification was 30 pmol/0.2 mL for 6-TGN and 6-MMP. Intraassay and interassay imprecision was <7.5% at 3 tested levels for 6-TGN and 6-MMP, respectively. Method comparisons were as follows: Ery 6-TGN: y = 1.3x - 11 and ery 6-MMP y = 1.1x - 124. CONCLUSIONS: The new method compares favorably with established ones, allowing for rapid single run determination of 6-TGN and 6-MMP from <50 uL of fresh or frozen whole blood. Linearity and limits of quantification cover the clinically relevant range. Variability during sample preparation and matrix effects are compensated by the use of isotope-labeled internal standards. The whole-blood method is hemoglobin standardized to avoid falsely low results in the case of anemia. The method correlates well with 6-TGN measured in washed erythrocytes, but it requires significantly less hands-on time. Preliminary therapeutic ranges for the most common indications of azathioprine and 6-MP are provided. PMID- 23666568 TI - Testing ethylglucuronide in maternal hair and nails for the assessment of fetal exposure to alcohol: comparison with meconium testing. AB - BACKGROUND: The deleterious effects exerted by prenatal ethanol exposure include physical, mental, behavioral, and/or learning disabilities that are included in the term fetal alcohol spectrum disorder. The measurement of ethylglucuronide (EtG) in alternative biological matrices, including neonatal and maternal hair, neonatal meconium, and maternal nails, is receiving increasing interest for the accurate evaluation of the in utero exposure to alcohol. OBJECTIVE: To evaluate the correlation between EtG in maternal hair and nails with EtG in neonatal meconium to further explore the suitability of these biomarkers in disclosing prenatal exposure to ethanol. METHODS: A total of 151 maternal hair strands (0-6 cm), nail clips (2-6 mm), and corresponding neonatal meconium and nails samples were obtained from neonatal wards of 4 Mediterranean public hospitals: Rome, Florence, and Belluno in Italy and Barcelona in Spain. Hair, nails, and meconium were analyzed for the presence of EtG by validated liquid chromatography mass spectrometry assay. Meconium was also analyzed for the presence of fatty acid ethyl esters (FAEEs) as a complementary biomarker of potential in utero exposure to alcohol. RESULTS: Eighteen newborns resulted in utero exposed to maternal alcohol consumption by FAEE testing in meconium with EtG values between 0.5 and 1.5 nmol/g. Unfortunately, none of these cases were confirmed by the presence of EtG in maternal hair and nails samples, which resulted all negative to this biomarker. DISCUSSION AND CONCLUSIONS: The results confirm that FAEEs and EtG in meconium are the best biomarkers to assess in utero exposure to maternal alcohol. EtG in hair and nails are not good biomarkers to disclose alcohol consumption lower than on daily basis and lower than 1-2 alcoholic units per day. PMID- 23666569 TI - Inosine monophosphate dehydrogenase expression and activity are significantly lower in kidney transplant recipients with diabetes mellitus. AB - BACKGROUND: Inosine 5'-monophosphate dehydrogenase (IMPDH) is a target of the immunosuppressive drug, mycophenolic acid (MPA). A 12-hour clinical pharmacokinetic and pharmacodynamic study was conducted to compare IMPDH1 and IMPDH2 gene expression, IMPDHI and IMPDHII protein levels, and enzyme activity between kidney transplant recipients with respect to diabetes status. METHODS: Nondiabetic (ND, n = 11) and diabetic (D, n = 9) kidney transplant recipients and on nontransplant nondiabetic (n = 10) and diabetic (n = 10) volunteers were included in the study. RESULTS: Area under the effect curve values for gene expression: IMPDH1 [ND: 22.1 (13.8-31.3) versus D: 4.5 (2.3-6.5), P < 0.001] and IMPDH2 [ND: 15.3 (11.0-21.7) versus D: 6.1 (4.6-8.6), P < 0.001], protein level: IMPDHI [ND: 1.0 (0.5-1.3) versus 0.5 (0.4-0.7), P = 0.002] and IMPDHII [ND: 1.0 (0.6-1.6) versus D: 0.7 (0.6-0.8) P < 0.001] and enzyme activity [ND: 180 (105 245) versus D: 29.9 (15.3-35.6) umole.s(-1).mole(-1) adenosine monophosphate, P < 0.001] was significantly lower in transplant recipients with diabetes. Similar results were observed in nontransplanted volunteers. Kinetic studies of MPA mediated suppression of IMPDH activity in nontransplanted individuals revealed an approximately 2.5-fold lower half-maximum effective concentration (EC50) for diabetic as compared with nondiabetic [ND: 50.2 (49.8-50.7) versus D: 15.8 (15.6 16.3) nmole/L, P = 0.004] volunteers. This difference was not related to several IMPDH gene variants. CONCLUSIONS: This study indicates a significantly lower IMPDH gene expression, protein level, and enzyme activity in diabetic patients. Further clinical studies in a larger number of patients are warranted to verify whether MPA dosing must be optimized for kidney transplant recipients with diabetes mellitus. PMID- 23666570 TI - Quality management and accreditation in a mixed research and clinical hair testing analytical laboratory setting-a review. AB - BACKGROUND: Quality management and accreditation in the analytical laboratory setting are developing rapidly and becoming the standard worldwide. Quality management refers to all the activities used by organizations to ensure product or service consistency. Accreditation is a formal recognition by an authoritative regulatory body that a laboratory is competent to perform examinations and report results. The Motherisk Drug Testing Laboratory is licensed to operate at the Hospital for Sick Children in Toronto, Ontario. The laboratory performs toxicology tests of hair and meconium samples for research and clinical purposes. Most of the samples are involved in a chain of custody cases. OBJECTIVES: Establishing a quality management system and achieving accreditation became mandatory by legislation for all Ontario clinical laboratories since 2003. The Ontario Laboratory Accreditation program is based on International Organization for Standardization 15189-Medical laboratories-Particular requirements for quality and competence, an international standard that has been adopted as a national standard in Canada. METHODS: The implementation of a quality management system involves management commitment, planning and staff education, documentation of the system, validation of processes, and assessment against the requirements. The maintenance of a quality management system requires control and monitoring of the entire laboratory path of workflow. RESULT: The process of transformation of a research/clinical laboratory into an accredited laboratory, and the benefits of maintaining an effective quality management system, are presented in this article. PMID- 23666571 TI - Issues about axial diffusion during segmental hair analysis. AB - The detection of a single drug exposure in hair (doping offence, drug-facilitated crime) is based on the presence of the compound of interest in the segment corresponding to the period of the alleged event. However, in some cases, the drug is detected in consecutive segments. As a consequence, interpretation of the results is a challenge that deserves particular attention. Literature evaluation and data obtained from the 20-year experience in drug testing in hair of the author are used as the basis to establish a theory to validate the concept of single exposure in authentic forensic cases where the drug is detected in 2 or 3 segments. The gained experience recommends to wait for 4-5 weeks after the alleged event and then to collect strands of hair. Assuming normal hair growth rate (1 cm/mo), it is advisable to cut the strand into 3 segments of 2 cm to document eventual exposure. Administration of a single dose would be confirmed by the presence of the drug in the proximal 2-cm segment (root), whereas not detected in the 2 other segments. However, in the daily experience of the author, it was noticed that sometimes (about 1 case from 10 examinations), the drug can be detected in 2 or 3 consecutive segments. Such a disposition was even observed in volunteer experiments in the literature. As it was also described for cocaine in early 1996, there is considerable variability in the area over which incorporated drug can be distributed in the hair shaft and in the rate of axial distribution of drug along the hair shaft. This can explain why a small amount of drug, as compared with the concentration in the proximal segment, can be measured in the second segment, as a result of an irregular movement. Another explanation for broadening the band of positive hair from a single dose is that drugs and metabolites are incorporated into hair during formation of the hair shaft via diffusion from sweat and other secretions. The presence of confounding interferences in the hair matrix or changes in the hair structure due to cosmetic treatments might mislead the final result of hair analysis. To qualify for a single exposure in hair, the author proposes to consider that the highest drug concentration must be detected in the segment corresponding to the period of the alleged event (calculated with a hair growth rate at 1 cm/mo) and that the measured concentration be at least 3 times higher than those measured in the previous or the following segments. This must only be done using scalp hair after cutting the hair directly close to the scalp. PMID- 23666572 TI - Lessons from routine dose adjustment of tacrolimus in renal transplant patients based on global exposure. AB - OBJECTIVES: Since 2007, a number of transplantation centers have been routinely using an expert system for tacrolimus (TAC) dose adjustment in kidney allograft recipients, based on PK modeling and Bayesian estimation for area-under-the-curve (AUC) determination. This has allowed the setting up of a large database of TAC pharmacokinetic profiles and AUC values, a part of which was analyzed here. METHODS: We retrospectively studied 2030 requests posted by 21 different centers for routine TAC dose adjustment in 1000 different adult renal transplant patients (not enrolled in any kind of concentration-controlled clinical trial). For each request, the following information was obtained: time elapsed since transplantation, TAC daily dose, calculated AUC, and trough concentration (C0). RESULTS: The dose-standardized exposure to TAC significantly and progressively increased in the months after transplantation: from month (M) 1 to M9 C0/dose increased from 2.33 to 3.44 mcg.L(1).mg(1) and AUC/dose from 43.1 to 64.2 mcg.h(1).L(1).mg(1), respectively. On the contrary, in patients beyond the first year whose C0 or AUC was in the target range, the odds of remaining in this range were high for a long time period, suggesting a low intrapatient variability in the stable phase. Regression analyses showed that the correlation between C0 and AUC was better in the first 3-month period (r(2) = 0.76) than later on (r(2) <= 0.67). Using the regression equations obtained, AUC ranges corresponding to different applicable C0 targets were calculated. CONCLUSIONS: From a large number of kidney graft recipients, we have estimated the relationships between C0 and AUC, modeled the evolution of TAC exposure with time and defined AUC targets that could be useful to lead further controlled-concentration trials and improve routine TAC therapeutic drug monitoring. PMID- 23666573 TI - Population pharmacokinetics of theophylline in premature Korean infants. AB - OBJECTIVES: The aim of this study was to investigate the population pharmacokinetics of theophylline in premature Korean infants and to assess the influence of clinical covariates. METHODS: Blood samples were first obtained after 1 week of maintenance dosing and then acquired approximately 4 weeks after continuous dosing. The time points were just before dosing and 2, 4, or 6 hours (at randomly assigned time points) after dosing. Two single-nucleotide polymorphism markers, -3860 G>A (CYP1A2*1C) and -163C>A (CYP1A2*1F), were genotyped. Gestational age (GA), postnatal age (PNA), postconceptional age (PCA = GA + PNA), body weight (BW), height, serum AST, serum ALT, serum BUN, serum creatinine, oxygen support, sex, delivery mode, and CYP1A2 genotypes were used for covariate model building. External validation was analyzed using data from an additional 27 patients. RESULTS: A total of 334 serum concentration measurements were made in 100 patients. A one-compartment absorptive model with first-order elimination was fitted to the data in NONMEM (version 7.1.2). The final model included the following parameters: Clearance (L/h) = 0.00492 * (BW)(3.53) + 0.00646 * (PNA), and volume of distribution (L) = 1.53 * (BW). The addition of the CYP1A2*1C or CYP1A2*1F genotypes to the model did not improve the model. The external validation results confirmed the predictive performance without bias in the final model. CONCLUSIONS: The selected covariates were generally consistent with previous studies. However, the mean volume of distribution was higher than the values reported in other population pharmacokinetic studies, which may have been due to the use of 2 sampling time points. The predictive performance was reasonably acceptable. Therefore, the present model may permit more accurate selection of doses to achieve target theophylline concentrations in premature infants. PMID- 23666575 TI - Vancomycin-induced acute kidney injury detected by a prospective pharmacovigilance program from laboratory signals. AB - BACKGROUND: Retrospective studies have identified elevated vancomycin trough levels >20 mg/L as a predictor of nephrotoxicity with a high variable incidence of 12.6%-65%. However, the elevated levels may represent the effect of renal compromise rather than the cause of nephrotoxicity. The aim of this study was to report the incidence of acute kidney injury (AKI) and associated risk factors in adult patients with vancomycin trough levels >20 mg/L in a prospective Pharmacovigilance Program from Laboratory Signals at a Hospital. METHODS: This was a prospective follow-up of all cases with serum vancomycin trough levels >20 mg/L between June 2010 and May 2011. AKI was defined using the Risk, Injury, Failure, Loss, End-stage criteria. Patients with vancomycin-induced AKI (VIAKI) were compared with vancomycin-tolerant patients. RESULTS: During 12 months of study, 271 samples corresponding to 179 cases were monitored. Vancomycin did not alter the renal function in 68.2% [95% confidence interval (CI): 60.8-74.9] of cases, and 13.4% (95% CI: 8.8-19.3) of AKI cases were induced by other causes. Nephrotoxicity without AKI criteria was found in 10.1% (95% CI: 6.1-15.4) of cases, and VIAKI occurred in 8.4% (95% CI: 4.8-13.4) of cases. The VIAKI group had a significantly lower basal glomerular filtration rate at baseline and higher vancomycin trough levels at the time of the signal. The majority of the group was in the intensive care unit and received nephrotoxic agents during vancomycin therapy. The most frequent stage of VIAKI was injury (53.3%). VIAKI occurred after 7 days (range: 3-14) of treatment, and in 53.3% of cases, the daily dose was >30 mg/kg. Renal function was recovered at discharge in 73.3% of cases and 66.7% of cases had other suspected drugs. CONCLUSIONS: The Pharmacovigilance Program from Laboratory Signals at a Hospital provides early identification and early evaluation of cases. Renal function and vancomycin trough levels should be closely monitored from the second week of treatment in adults, intensive care patients, and those who receive concurrent nephrotoxic agents. PMID- 23666574 TI - Population pharmacokinetics of sirolimus in pediatric patients with neurofibromatosis type 1. AB - PURPOSE: The narrow therapeutic index and large interpatient variability in sirolimus pharmacokinetics (PK) make therapeutic drug monitoring necessary. Factors responsible for PK variability are not well understood, and published PK studies do not include pediatric patients with neurofibromatosis type 1 (NF1). The objectives of this study were to estimate sirolimus clearance in a cohort of children with NF1 using data collected in a concentration-guided trial, to evaluate the effect of treatment duration on clearance and dose requirements, and to evaluate the association of sirolimus clearance with patient-specific factors, including age, weight, body surface area (BSA), race, and sex. METHODS: Sirolimus concentration-time data were collected from an ongoing prospective trial in children with NF1. An iterative 2-stage Bayesian method was used for the PK parameter analyses. RESULTS: Data from 44 patients with NF1 were included in the analyses. Mean age was 8.4 years (SD 4.5, range 3-18), and mean weight was 29.8 kg (SD 16.7, range 12-85.8). Mean sirolimus clearance was 11.8 L/h (SD 4.6, range 2.2-24.1), and the mean dose to obtain a target trough concentration of 10-15 ng/mL was 2.0 mg/m administered twice daily (SD 0.72, range 0.77-3.85). A nonlinear relationship between age and clearance was observed. Total body weight and BSA were strong predictors of sirolimus clearance (r = 0.67 and 0.65, respectively). CONCLUSIONS: Sirolimus clearance in children with NF1 is comparable with that in pediatric transplant patients. Clearance was most associated with body size parameters (BSA and total body weight) in children with NF1. When normalized for size, an age effect on clearance was observed in the youngest patients, most likely because of the maturational changes in drug absorption and metabolism. A mean dose of 2.0 mg/m twice a day was required for attainment of target trough concentrations of 10-15 ng/mL in children greater than 3 years of age who have NF1. The updated model will allow PK-guided individualized dosing of sirolimus in patients with NF1. PMID- 23666576 TI - Contributing factors to the apparent clearance of bepridil in patients with paroxysmal or persistent atrial fibrillation: analysis using population pharmacokinetics. AB - BACKGROUND: Bepridil is used as an antiarrhythmic drug due to its class I, class III, and class IV electrophysiological properties, but it has serious adverse effects such as QT prolongation and torsade de pointes. Bepridil has complex pharmacokinetic (PK) properties with large interindividual differences in plasma concentrations. The aim of this study was to evaluate the contributing factors to changes in the dose-concentration relationship of bepridil and the risk factors for excessive QT prolongation in patients with paroxysmal or persistent atrial fibrillation (AF). METHODS: A population PK analysis was performed by using NONMEM based on 425 concentration points from 76 patients receiving bepridil. A 1 compartment model approximating an intravenous model was used to examine the interindividual variability of the apparent systematic clearance (CL/F) of bepridil. A population PK-pharmacodynamic analysis was performed using the linear regression. RESULTS: Age was a contributing factor to the CL/F of bepridil in AF patients. The QTc interval increased as the area under the plasma bepridil concentration time curve (AUC) increased. The AUC in patients without a bundle branch block, the baseline QT interval, and the existence of structural heart disease in patients with a bundle branch block were explanatory variables of excessive QTc prolongation (QTc > 500 ms) during bepridil therapy. CONCLUSIONS: Using population PK methodology, this study showed that age was a contributing factor to the apparent clearance of bepridil in Japanese patients with AF and that excessive QT prolongation might be related to a larger AUC. PMID- 23666577 TI - Severe tremor after cotrimoxazole-induced elevation of venlafaxine serum concentrations in a patient with major depressive disorder. AB - : We describe a female patient who was an extensive metabolizer of cytochrome P450 isoenzyme (CYP) 2D6 and an intermediate metabolizer of CYP2C19 (genotype: CYP2C19 *1/*2). She exhibited high serum concentrations of venlafaxine and O desmethylvenlafaxine and developed severe tremor after comedication with cotrimoxazole (sulfamethazole/trimethoprim). Venlafaxine is mainly metabolized by O- and N-demethylation. O-demethylation is catalyzed by the highly polymorphic CYP2D6 and N-demethylation by several enzymes, CYP2C19, CYP2C9, and CYP3A4. The observed overall pharmacokinetic effect was most probably the result of decreased N-demethylation of venlafaxine by (1) reduced expression of CYP2C19 due to a genetic deficit and (2) inhibition of CYP2C9 by cotrimoxazole. PMID- 23666578 TI - PETINIA total phenytoin assay on the vista 1500 analyzer is not suitable for monitoring free phenytoin concentration if ultrafiltration is performed at room temperature. AB - BACKGROUND: Phenytoin is a strongly protein-bound anticonvulsant requiring free drug monitoring for certain patients. Recently, free phenytoin assay on the TDx analyzer was discontinued by the Abbott Laboratories, but Roche Diagnostics has an assay for the determination of free phenytoin. METHODS: Because a clinical laboratory may not have an instrument for using Roche free phenytoin assay, we studied the possibility of determining free phenytoin using particle-enhanced turbidimetric inhibition immunoassay (PETINIA) total phenytoin assay on the Vista 1500 analyzer by comparing free phenytoin values obtained by Roche assay and Hitachi 917 analyzer with values obtained by using PETINIA assay. RESULTS: When protein-free ultrafiltrates were prepared at room temperature from 41 different patients taking phenytoin, using Roche assay (x axis) and PETINIA (y axis) assay, the following regression equation was observed: y = 0.8526x + 0.0661 (r = 0.85, n = 41). The regression equation indicated significant negative bias with the reference method. However, when additional 30 specimens were studied where ultrafiltration was performed at 37 degrees C, lesser negative bias was observed as revealed by the regression equation: y = 0.922x - 0.117 (r = 0.90, n = 30). CONCLUSIONS: We conclude that PETINIA assay on the Vista 1500 analyzer is not suitable for monitoring free phenytoin concentration if ultrafiltration is performed at room temperature but may be used with caution if ultrafiltration is performed at physiological temperature of 37 degrees C, which is the desirable temperature for preparation of ultrafiltrate. PMID- 23666579 TI - A screening method for 30 drugs in hair using ultrahigh-performance liquid chromatography time-of-flight mass spectrometry. AB - OBJECTIVES: The objectives of this study were to develop and to validate a qualitative screening method that met the new Society of Hair Testing (SoHT) guideline criteria for thresholds. METHODS: Extraction of 20 mg hair was performed by a previously validated procedure using overnight incubation in a mixture of methanol:acetonitrile:formiate buffer pH 3 (10:10:80). Analysis was performed on an Agilent 6540 quadrupole time-of-flight mass spectrometer in combination with an Agilent 1290 Infinity ultrahigh-performance liquid chromatography system. Separation was achieved with a 12-minute linear gradient chromatography on a high-strength silica T3 column at acidic conditions. An in house database containing 30 compounds from the groups amphetamines, opiates, opioids, cocaine, benzodiazepines, and other sedatives including 6 deuterated internal standards was built by analyzing solutions from certified standards. Data were extracted using mass accuracy of +/- 10 ppm, retention time deviation of +/- 0.15 minutes, and area of >= 30,000 counts. Identification was based on scoring of retention time, accurate mass measurement, and isotopic pattern. Validation included selectivity, repeatability of analyte area, and the scoring parameters at the proposed thresholds and a method comparison with the present liquid chromatography-mass spectrometry-mass spectrometry method using 50 authentic hair samples. A daily cutoff calibrator was used to identify positive samples. RESULTS: All cutoffs could be met with imprecisions of less than 5% for most parameters and analytes. Hair from drug-free subjects did not produce any positive results and the method comparison agreed in more than 90% of the cases. CONCLUSIONS: We conclude that the developed method meets the criteria of the new SoHT guidelines for screening cutoffs. Even though no thresholds have been suggested for benzodiazepines, we conclude that thresholds between 0.05 and 0.1 ng/mg should be sufficient to determine regular use of these substances. PMID- 23666580 TI - Maternal hair analysis for the detection of illicit drugs, medicines, and alcohol exposure during pregnancy. AB - BACKGROUND/OBJECTIVES: Drug of abuse consumption throughout pregnancy is a serious public health problem and an important economic cost to the health system. The aim of this work was to compare maternal interview and hair analysis to determine drug consumption throughout pregnancy and to study relations among maternal interview, hair results, and neonatal outcomes. METHODS: Two hundred nine mothers agreed to participate. After delivery, they were interviewed and a hair sample collected. Hair samples were segmented in trimesters and analyzed for 35 drugs [opioids, cocaine, amphetamines, Delta-tetrahydrocannabinol (THC), ketamine, methadone, antidepressants, benzodiazepines, and hypnotics; limits of quantification 5-100 pg/mg] and for ethyl glucuronide (limit of quantification 10 pg/mg) by liquid chromatography-tandem mass spectrometry. Statistical analysis was performed with chi test and t test. RESULTS: In the interview, 4.3% mothers declared using illicit drugs during pregnancy (cocaine 1.4%, THC 2.9%, and opiates 1%), 3.3% medicines (methadone 1.9%, benzodiazepines 1.9%, and antidepressants 0.5%), 21.5% tobacco, and 13.7% alcohol. Hair analysis showed 15.4% prevalence in illicit drugs (cocaine 12.4%, THC 3.8%, opiates 1%, and ketamine 1%), 22.5% in medicines (methadone 3.3%, benzodiazepines 11%, antidepressants 9.1%, zopiclone 1%, and fentanyl 1.4%), and 3.9% in alcohol. Neonatal abstinence syndrome was developed in 8.1% newborns, all of them from mothers with high methadone-positive hair results (>926.2 pg/mg). Statistically significant lower newborn weight and length were found in neonates from declared smokers compared with nonsmokers (P < 0.05). CONCLUSIONS: Maternal hair analysis showed to be more sensitive than maternal interview to detect drug use during pregnancy, except for alcohol. In this preliminary study, no statistically significant differences were found between exposed and nonexposed newborns to drugs, except for tobacco consumption. PMID- 23666581 TI - Monitoring salivary melatonin concentrations in children with sleep disorders using liquid chromatography-tandem mass spectrometry. AB - BACKGROUND: Melatonin is synthesized in the pineal gland and is an important circadian phase marker, especially in the determination of sleep patterns. Both temporary and permanent abnormal sleep patterns occur in children; therefore, it is desirable to have methods for monitoring melatonin in biological fluids in the diagnosis and treatment of such disorders. OBJECTIVE: The objective of the study is to develop a liquid chromatography-tandem mass spectrometry method for the determination of melatonin in saliva and to apply it to monitoring salivary concentrations in children with sleep disorders. METHODS: A deuterated internal standard (d7-melatonin) was added to a diluted saliva sample (20 uL) in an autosampler vial insert, and 50 uL were injected. Plasticware was strictly avoided, and all glassware was scrupulously cleaned and then baked at 120 degrees C for at least 48 hours to obtain satisfactory performance. Reverse-phase chromatography was performed on a C8 column using a linear gradient elution profile comprising mobile phases A (0.1% aqueous formic acid) and B (15% methanol in acetonitrile containing 0.1% formic acid), pumped at a total flow rate of 0.8 mL/min. The run time was 8 minutes. After atmospheric pressure chemical ionization, mass spectrometric detection was in positive ion mode. Mass detection was by selected reaction monitoring mode with the following mass transitions used for quantification: melatonin, m/z 233.0 -> 173.8 and d7-melatonin, m/z 240.0 -> 178.3. RESULTS: Linearity (r > 0.999) was established from 3.9 to 1000 pg/mL. Imprecision (coefficient of variation percent) was less than 11%, and accuracy was 100-105% (7.0-900 pg/mL). The method was selective, and the mean (range) ratio of the slopes of calibrations in water to those in daytime saliva samples collected from 10 healthy adult subjects was 0.989 (0.982-0.997), indicating negligible matrix effects. The application of the assay was demonstrated in healthy adults and in children being clinically investigated for sleep disturbances. CONCLUSIONS: A validated liquid chromatography-tandem mass spectrometry method suitable for monitoring salivary melatonin in children with circadian rhythm sleep disorders is reported. The method also has potential application to pediatric population pharmacokinetic studies using sparse sampling of saliva as the biological sample matrix. PMID- 23666582 TI - Potential cost-effectiveness of therapeutic drug monitoring for depressed patients treated with citalopram. AB - BACKGROUND: For patients treated with citalopram, it was recently shown that serum concentrations above 50 ng/mL on day 7 of treatment are associated with an improved therapeutic outcome. The aim of this post hoc analysis was to calculate a potential cost-effectiveness of therapeutic drug monitoring (TDM) considering costs for hospitalization, medication, and drug analysis. METHODS: The study included patients with major depression. Weekly measurements of serum concentrations and assessments of psychopathology were conducted. RESULTS: Fifty five patients were included in this analysis. For patients with high citalopram serum concentrations (>50 ng/mL), the mean duration of hospitalization was 49 +/- 20 days, and it was 72 +/- 37 days (P = 0.03) in the group with low drug concentrations (<50 ng/mL). Considering daily costs for hospitalization of 250?,;, the potential savings amounted to 5750?,; per patient for the 23 days. Assuming that 11% of the variation of duration of hospitalization per patient were attributed to the serum concentration of the drug, the resulting savings were 633?,; per patient. Considering the officially listed price of 21?,; per TDM assay, total costs for weekly measurements over a period of 10 weeks of hospitalization were 210?,;. In the groups with high and low serum concentrations, daily costs for citalopram medication were 3.00 +/- 0.80?,; and 2.42 +/- 0.70?,;, respectively (P = 0.002), and the mean number of comedications was nearly identical, that is, 1.87 +/- 1.74 and 1.81 +/- 1.86 drugs, respectively (P = 0.919). CONCLUSIONS: The data taken together indicate that TDM guided dosing of citalopram has the potential to be cost effective by reducing the length of hospitalization. PMID- 23666583 TI - CYP3A5 genotype had no impact on intrapatient variability of tacrolimus clearance in renal transplant recipients. AB - BACKGROUND: The risk of long-term chronic allograft nephropathy and graft loss after kidney transplantation is increased in patients with a high intrapatient variability in the clearance of tacrolimus. CYP3A5 genotype has a significant influence on the oral bioavailability of tacrolimus and is a potential influence on variability of exposure. METHODS: The study population consisted of 118 renal transplant recipients with stable renal function 12 months after transplant. The intrapatient variability of tacrolimus concentration was calculated. The patients were divided into low- and high-intraindividual variability groups using the median variability of tacrolimus clearance as the cutoff value. RESULTS: No differences in baseline characteristics were observed between the expressers (n = 37) and nonexpressers (n = 81) except for ethnicity, which is in line with previous observations. Tacrolimus dose requirement was significantly higher in patients expressing CYP3A5, confirming earlier observations (P < 0.0001). However, intraindividual variability of tacrolimus clearance was not related to CYP3A5 genotype (P = 0.3331). CONCLUSIONS: The intrapatient variability of tacrolimus clearance was not associated with CYP3A5 genotype in stable renal transplant recipients. PMID- 23666584 TI - Drugs of abuse in hair: application in pediatric patients. AB - BACKGROUND: We are describing a case of pediatric maltreatment. A 3-year-old boy was brought to the emergency room because of drowsiness that was caused by what his parents described as an 'accidental' intake of a powder contained in a plastic wrapper that was found in a park. METHODS: Urine immunochemical screening for drugs of abuse showed a positive result for opiate exposure. Despite the described 'accident,' the physician suspected abuse and ordered a hair analysis to verify possible intake of drugs of abuse. The child's hair was analyzed along its whole length for drugs of abuse using gas chromatography mass spectrometry in accordance with international guidelines. RESULTS AND DISCUSSION: Morphine and 6 acetylmorphine were identified, and the doctor informed the city's juvenile court. The boy's family was involved with social services for a period of observation to confirm suspected prolonged abuse. Hair analysis proves to be a useful tool for periodical examination of drug exposure to protect children from significant health and social risks. PMID- 23666585 TI - Sleep-related adductor laryngeal dystonia causing sleep apnea: a sleep-related breathing disorder diagnosed with sleep endoscopy and treated with botulinum toxin. AB - OBJECTIVES/HYPOTHESIS: Obstructive sleep apnea syndrome (OSAS) is a chronic condition, characterized by recurrent episodes of upper airway collapse during sleep, which affects up to 5% of adults in the Western population. The muscle tone of the human body ordinarily relaxes during sleep, thus causing airway obstruction and leading to sleep apnea. We report a case of a 68-years old male in which dystonic closure of the larynx during sleep caused OSAS. The sleep endoscopy was crucial in establishing the diagnosis of laryngeal dystonia. A botulinum toxin injection in the vocal cord improved the OSAS. These findings define a novel sleep-related breathing disorder. PMID- 23666586 TI - Re: Percutaneous nephrostomy for malignant ureteric obstruction: have we got the balance right? PMID- 23666587 TI - Percutaneous nephrostomy for ureteric obstruction due to advanced pelvic malignancy: have we got the balance right? AB - PURPOSE: The optimal management of patients with ureteric obstruction in advanced pelvic malignancy is unclear. Effective judgment is required to decide which patients would benefit most from decompression of the urinary tract. The objective of our study was to assess survival and complication rates post percutaneous nephrostomy (PCN) in patients with ureteric obstruction due to advanced pelvic malignancy. METHODS: A detailed retrospective case review of all patients who underwent PCN for ureteric obstruction due to pelvic malignancy in one calendar year was conducted to assess indication, survival time, length of stay post-procedure and complications. RESULTS: Thirty-six nephrostomies were performed on 22 patients with prostate cancer being the commonest primary (55 %). Renal failure was the commonest mode of presentation (56 %). Eight patients (36 %) presented without a prior diagnosis of cancer. All PCNs except one were initially technically successful, and 56 % of renal units were able to be antegradely stented and rendered free of nephrostomy. Median survival post nephrostomy was 78 days (range 4-1,137), with the subset of bladder cancer patients having the poorest survival. Dislodgement of the nephrostomy tube was the most common troublesome complication which led to the greatest morbidity, sometimes requiring repeat nephrostomy insertion. Patients stayed for a median of 23 (range 3-89) days in hospital, which amounted to 29 % of their remaining lifetime spent in hospital. CONCLUSIONS: Although effective in improving renal function, PCN is a procedure not without associated morbidity and does not always prolong survival. Therefore, the decision to decompress an obstructed kidney with advanced pelvic malignancy should not be taken lightly. We recommend that such cases be discussed in a multidisciplinary setting, and a decision is taken only after a full informed discussion involving patients and their relatives. PMID- 23666588 TI - The number of nodes removed as well as the template of the dissection is independently correlated to cancer-specific survival after radical cystectomy for muscle-invasive bladder cancer. AB - PURPOSE: To assess the impact of the number of lymph nodes removed and of the template of dissection during radical cystectomy for bladder cancer on patients' survival rates. MATERIALS AND METHODS: We evaluated 282 consecutive patients who underwent radical cystectomy for muscle-invasive or high-grade superficial bladder cancer between 1995 and 2011. Exclusion criteria were incomplete follow up data and neo-adjuvant or adjuvant treatments. Patients were divided into groups according to the most informative cut-point of number of lymph nodes retrieved and of the template of dissection. The cancer-specific survival rates were estimated by the Kaplan-Meier method. The univariate and multivariable forward-stepwise Cox proportional hazards regression were applied to analyze the survival outcomes. RESULTS: The mean (SD) follow-up was 59.2 +/- 44.3 months, and the mean (SD) age of the entire cohort population was 68.3 +/- 8.3 years. The cancer-specific survival rates were 58.7 and 47.7 % at 5 and 10 years, respectively. Considering both node-positive and node-negative patients, those with at least 14 LNs removed and those submitted to extended or super-extended PLND experienced significantly higher cancer-specific survival at both univariate and multivariable analysis. CONCLUSIONS: Patients undergoing a more extended pelvic lymph node dissection, both in terms of number of LN removed and in terms of template of dissection, will experience a better cancer-specific survival. Our data support a potential role of lymphadenectomy on cancer outcome. PMID- 23666589 TI - The Mark Coventry Award: Higher tissue concentrations of vancomycin with low-dose intraosseous regional versus systemic prophylaxis in TKA: a randomized trial. AB - BACKGROUND: In response to increasing antibiotic resistance, vancomycin has been proposed as an alternative prophylactic agent in TKA. However, vancomycin requires a prolonged administration time, risks promoting further antibiotic resistance, and can cause systemic toxicity. Intraosseous regional administration (IORA) is known to achieve markedly higher antibiotic concentrations than systemic administration and may allow the use of a lower vancomycin dose. QUESTIONS/PURPOSES: We assessed whether low-dose IORA vancomycin can achieve tissue concentrations equal or superior to those of systemic administration in TKA and compared complications between patients treated with IORA and intravenous vancomycin. METHODS: We randomized 30 patients undergoing primary TKA to receive 250 or 500 mg vancomycin via IORA or 1 g via systemic administration. IORA was performed as a bolus injection into a tibial intraosseous cannula below an inflated thigh tourniquet immediately before skin incision. Subcutaneous fat and bone samples were taken during the procedure and antibiotic concentrations measured. RESULTS: The overall mean tissue concentration of vancomycin in subcutaneous fat was 14 MUg/g in the 250-mg IORA group, 44 MUg/g in the 500-mg IORA group, and 3.2 MUg/g in the systemic group. Mean concentrations in bone were 16 MUg/g in the 250-mg IORA group, 38 MUg/g in the 500-mg IORA group, and 4.0 MUg/g in the systemic group. One patient in the systemic group developed red man syndrome during infusion. CONCLUSIONS: Low-dose IORA vancomycin results in tissue concentrations equal or superior to those of systemic administration. IORA optimizes timing of vancomycin administration, and the lower dose may reduce the risk of systemic side effects while providing equal or enhanced prophylaxis in TKA. PMID- 23666590 TI - Translation and cultural adaptation of the Turkish Lysholm knee scale: ease of use, validity, and reliability. AB - BACKGROUND: The Lysholm knee scale, first published in 1982, is an eight-item questionnaire designed to evaluate patients after knee ligament injury. However, as a tool developed in English, its use as a validated instrument has been limited to English-language populations. QUESTIONS/PURPOSES: The objectives of this study were to test the ease of use, reliability, and validity of a Turkish language, culturally adapted version of the Lysholm knee scale. METHODS: The Lysholm knee scale was translated into Turkish according to Guillemin's recommendations. Seventy patients (mean age, 36 years; range, 17-72 years) with different knee complaints were included, and the scale was completed twice by each participant at 3- to 14-day intervals to assess test-retest reliability based on the interrater correlation coefficient, whereas Cronbach's alpha evaluated internal consistency. External validity was evaluated with correlations between the Lysholm knee scale, Kujala Anterior Knee Pain Scale, and SF-36. The distribution of floor and ceiling effects was determined. RESULTS: Patients completed the Turkish-language Lysholm questionnaire in approximately 3 minutes. The test-retest reliability was 0.82, with a Cronbach's alpha coefficient of 0.68. The Lysholm knee score was strongly correlated with the Kujala Anterior Knee Pain Scale (r = 0.78). The Turkish Lysholm knee scale showed high correlations with the SF-36 physical component score (r = 0.61) and a low association with the mental component domain (r = 0.14). CONCLUSIONS: The Turkish version of the Lysholm knee scale is quickly administered, valid, and reliable, and can be used for patients with various knee disorders. PMID- 23666591 TI - Orthopaedic case of the month: A 62-year-old woman with neck pain and neurologic findings. PMID- 23666592 TI - Efficacy of combined osteotomy and ulnar nerve transposition for cubitus valgus with ulnar nerve palsy in adults. AB - BACKGROUND: Tardy ulnar nerve palsy is a common late complication of traumatic cubitus valgus deformity. Whether both problems can be corrected together, safely and effectively, in a single surgical procedure remains unknown. QUESTIONS/PURPOSES: We therefore reviewed a patient cohort having this combined surgery and compared preoperatively and at a minimum of 24 months postoperatively (1) active elbow ROM; (2) radiographic correction of the cubitus valgus deformity of the preoperative and postoperative humerus-elbow-wrist angles and the medial prominence index; (3) ulnar nerve function through grip strength and static two point discrimination; and (4) overall upper limb disability by the DASH score. METHODS: Between 2004 and 2009, 13 patients who had traumatic cubitus valgus deformities and tardy ulnar nerve palsy (Dellon's Grade III) were treated with simultaneous supracondylar dome osteotomy and anterior transposition of the ulnar nerve and were reviewed retrospectively. The minimum followup was 24 months (mean, 33 months; range, 24-52 months). RESULTS: The mean preoperative ROM was 16 degrees to 124 degrees and mean postoperative ROM was 10 degrees to 126 degrees . All osteotomies healed uneventfully. The mean postoperative humerus elbow-wrist angle was 11 degrees and the average correction was 24 degrees . None of the patients had recurrence of the deformity or residual prominence of the medial condyle at the last followup. The mean grip strength and static two point discrimination improved from 20 kg of force and 6.9 mm to 27 kg of force and 4.0 mm (p=0.002 and p=0.004, respectively). Subjective ulnar nerve symptoms improved in all but one patient. The mean DASH score improved from 29 points to 16 points (p=0.001). CONCLUSION: A combined supracondylar dome osteotomy and anterior transposition of the ulnar nerve is effective in correcting posttraumatic cubitus valgus deformity and its associated ulnar nerve palsy. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 23666594 TI - Periodic mesoporous organosilicas functionalized with a wide variety of amines for CO2 adsorption. AB - The adsorption of CO2 on amine modified periodic mesoporous organosilicas (PMOs) has been investigated. An ethenylene-bridged PMO is modified with a wide range of diamines and polyamines. A variety of dangling N-containing functionalities, i.e., diaminobutane, diaminohexane, diaminododecane, diethylenetriamine and tetraethylenepentamine, as nucleophiles in a substitution reaction is used. The CO2 adsorption capacity of these materials is probed and compared with amine functionalized SBA-15 material, in an effort to reach the maximal CO2/N ratio of 0.5 when using dry conditions in a chemisorption process. The materials showed good CO2 adsorption behaviour and this maximum amine efficiency value has been approximated by the PMO material modified with diaminododecane. PMID- 23666593 TI - Changes in weight and health behaviors after pregnancies complicated by gestational diabetes mellitus: the CARDIA study. AB - OBJECTIVE: Prepregnancy to postpregnancy change in weight, body mass index (BMI), waist circumference, diet, and physical activity in women with and without gestational diabetes mellitus (GDM) were compared. DESIGN AND METHODS: Using the Coronary Artery Risk Development in Young Adults study, women with at least one pregnancy during 20 years of follow-up (n = 1,488 with 3,125 pregnancies) was identified. Linear regression with generalized estimating equations to compare prepregnancy to postpregnancy changes in health behaviors and anthropometric measurements between 137 GDM pregnancies and 1,637 non-GDM pregnancies, adjusted for parity, age at delivery, outcome measure at the prepregnancy exam, race, education, mode of delivery, and interval between delivery and postpregnancy examination were used. RESULTS: When compared with women without GDM in pregnancy, women with GDM had higher prepregnancy mean weight (158.3 vs. 149.6 lb, P = 0.011) and BMI (26.7 vs. 25.1 kg/m(2) , P = 0.002), but nonsignificantly lower total daily caloric intake and similar levels of physical activity. Both GDM and non-GDM groups had higher average postpartum weight of 7-8 lbs and decreased physical activity on average 1.4 years after pregnancy. CONCLUSIONS: Both groups similarly increased total caloric intake but reduced fast food frequency. Prepregnancy to postpregnancy changes in body weight, BMI, waist circumference, physical activity, and diet did not differ between women with and without GDM in pregnancy. Following pregnancy, women with and without GDM increased caloric intake, BMI, and weight and decreased physical activity, but reduced their frequency of eating fast food. Given these trends, postpartum lifestyle interventions, particularly for women with GDM, are needed to reduce obesity and diabetes risk. PMID- 23666595 TI - Enhancement of wound closure in diabetic mice by ex vivo expanded cord blood CD34+ cells. AB - Diabetes can impair wound closure, which can give rise to major clinical problems. Most treatments for wound repair in diabetes remain ineffective. This study aimed to investigate the influence on wound closure of treatments using expanded human cord blood CD34(+) cells (CB-CD34(+) cells), freshly isolated CB CD34(+) cells and a cytokine cocktail. The test subjects were mice with streptozotocin-induced diabetes. Wounds treated with fresh CB-CD34(+) cells showed more rapid repair than mice given the PBS control. Injection of expanded CB-CD34(+) cells improved wound closure significantly, whereas the injection of the cytokine cocktail alone did not improve wound repair. The results also demonstrated a significant decrease in epithelial gaps and advanced re epithelialization over the wound bed area after treatment with either expanded CB CD34(+) cells or freshly isolated cells compared with the control. In addition, treatments with both CB-CD34(+) cells and the cytokine cocktail were shown to promote recruitment of CD31(+)-endothelial cells in the wounds. Both the CB CD34(+) cell population and the cytokine treatments also enhanced the recruitment of CD68-positive cells in the early stages (day 3) of treatment compared with PBS control, although the degree of this enhancement was found to decline in the later stages (day 9). These results demonstrated that expanded CB-CD34(+) cells or freshly isolated CB-CD34(+) cells could accelerate wound repair by increasing the recruitment of macrophages and capillaries and the reepithelialization over the wound bed area. Our data suggest an effective role in wound closure for both ex vivo expanded CB-CD34(+) cells and freshly isolated cells, and these may serve as therapeutic options for wound treatment for diabetic patients. Wound closure acceleration by expanded CB-CD34(+) cells also breaks the insufficient quantity obstacle of stem cells per unit of cord blood and other stem cell sources, which indicates a broader potential for autologous transplantation. PMID- 23666597 TI - PTPN4 negatively regulates CrkI in human cell lines. AB - PTPN4 is a widely expressed non-receptor protein tyrosine phosphatase. Although its overexpression inhibits cell growth, the proteins with which it interacts to regulate cell growth are unknown. In this study, we identified CrkI as a PTPN4 interacting protein using a yeast two-hybrid, and confirmed this interaction using in vitro GST pull-down and co-immunoprecipitation and co-localization assays. We further determined the interactional regions as the SH3 domain of CrkI and the proline-rich region between amino acids 462 and 468 of PTPN4. Notably, overexpression of PTPN4 inhibits CrkI-mediated proliferation and wound healing of HEK293T cells, while knockdown of PTPN4 by siRNA in Hep3B cells enhances CrkI mediated cell growth and motility. Moreover, our data show that ectopic expression of PTPN4 reduces the phosphorylation level of CrkI in HEK293T cells. These findings suggest that PTPN4 negatively regulates cell proliferation and motility through dephosphorylation of CrkI. PMID- 23666596 TI - Identification of a non-canonical nuclear localization signal (NLS) in BRCA1 that could mediate nuclear localization of splice variants lacking the classical NLS. AB - The breast cancer type 1 susceptibility gene (BRCA1) is a tumor suppressor gene, mutations or loss of which lead to genomic instability and breast cancer. BRCA1 protein is part of a large multi-protein complex involved in a variety of DNA repair and transcription regulatory functions. At least four splice variants have been described and these differ in their function and tissue and spatio-temporal expression patterns. Structural analysis has revealed the presence of two nuclear localization signals (NLS) located in exon 11 of BRCA1. Interestingly, a splice variant of the protein that lacks both of the known NLS still manages to gain entry to the nucleus. While there is experimental proof for the translocation of these proteins by binding to other established nuclear proteins, we examined the possibility of a hitherto unidentified NLS in this particular variant. In this paper, we present evidence for the existence of a previously unreported non canonical NLS contained within the first 39 amino acids of exon 11. A fusion protein with this 39mer and a reporter green fluorescent protein translocated into the nucleus when it was expressed in breast epithelial cells. We demonstrate the presence of a hitherto unreported noncanonical NLS in exon 11a of BRCA1. This NLS might aid proteins that were encoded by splice variants and lack the canonical NLS to localize to the nucleus. PMID- 23666598 TI - Differences in physical fitness and subjectively rated physical health in Vietnamese and German older adults. AB - This cross-sectional study aims to investigate the differences in physical fitness and subjectively rated physical health of Vietnamese and German older adults in a community dwelling. The Vietnamese sample was a random sample of 96 community-dwelling individuals aged 60 to 80 years; 50 % were women. Education is 0 % less than 5 years, 23.95 % 5 to 9 years, 47.91 % 10 to 12 years, and 28.12 % more than 12 years. The German sample was a random sample of 159 community dwelling persons aged 59 to 90 years; 79.8 % were women. Education is 1.25 % less than 5 years, 40.25 % 5 to 9 years, 38.84 % 10 to 12 years, and 21.38 % more than 12 years. Senior Fitness Test and Short Form-36 were used as outcome measures. The Vietnamese sample shows significantly higher performance levels in motor abilities, i.e., aerobic fitness, strength, and flexibility. The Vietnamese sample indicates a lower difference in performance levels between age groups than the German sample. No differences in subjectively rated physical health factors were found. The higher performance levels of the Vietnamese sample might reflect a more active lifestyle throughout the life span, especially in socially mediated domains like living arrangements or labor work. Lower performance levels in the studied age groups of the German sample might lead to higher risks of cardiovascular diseases and proneness of falls. A more active lifestyle after retirement could contribute to a healthier, more capable, and more independent individual and collective aging. Subjectively rated health stated is a culturally mitigated domain and therefore might be independent of actual physical fitness levels. PMID- 23666599 TI - RAHelp: an online intervention for individuals with rheumatoid arthritis. AB - OBJECTIVE: To test an intervention for improving self-management in rheumatoid arthritis (RA) using an online, cognitive-behavioral, self-management group program (RAHelp), with weekly telephone support. METHODS: A 2-group, randomized study design was used to compare an intervention for RA versus a waiting-list control condition. The intervention used a secure web site (RAHelp.org) to provide a 10-week program with weekly educational modules for improving self efficacy in self-management of RA, plus tools for group interaction. Weekly telephone contacts were made to encourage use of program tools and apply newly learned skills. A nationwide convenience sample of 106 adult participants (mean age 50 years, 93% women) was recruited primarily through online advertisements. Main outcome measures included the Arthritis Impact Measurement Scales 2 (affective, physical, role, social, and pain/symptom components), Arthritis Self Efficacy Scale (ASES), Center for Epidemiologic Studies Depression Scale, Quality of Life Scale (QLS), Rapid Assessment of Disease Activity in Rheumatology, Social Provisions Scale, and University of California, Los Angeles Loneliness Scale 3. RESULTS: Group differences with large and moderate effect sizes (ES) were found immediately postintervention for self-efficacy (ASES; ES 0.92, P = 0.00001) and quality of life (QLS; ES 0.66, P = 0.003), respectively. At 9 months postintervention, differences in self-efficacy (ASES; ES 0.92, P = 0.00001) and quality of life (QLS; ES 0.71, P = 0.004) remained robust. CONCLUSION: RAHelp appears to have beneficial effects in terms of self-efficacy and quality of life among individuals with RA who are willing to use an online service format. PMID- 23666600 TI - Reply: To PMID 22736048. PMID- 23666602 TI - Study of ozone-initiated limonene reaction products by low temperature plasma ionization mass spectrometry. AB - Limonene and its ozone-initiated reaction products were investigated in situ by low temperature plasma (LTP) ionization quadrupole time-of-flight (QTOF) mass spectrometry. Helium was used as discharge gas and the protruding plasma generated ~850 ppb ozone in front of the glass tube by reaction with the ambient oxygen. Limonene applied to filter paper was placed in front of the LTP afterglow and the MS inlet. Instantly, a wide range of reaction products appeared, ranging from m/z 139 to ca. 1000 in the positive mode and m/z 115 to ca. 600 in the negative mode. Key monomeric oxidation products including levulinic acid, 4 acetyl-1-methylcyclohexene, limonene oxide, 3-isopropenyl-6-oxo-heptanal, and the secondary ozonide of limonene could be identified by collision-induced dissociation. Oligomeric products ranged from the nonoxidized dimer of limonene (C20H30) and up to the hexamer with 10 oxygen atoms (C60H90O10). The use of LTP for in situ ozonolysis and ionization represents a new and versatile approach for the assessment of ozone-initiated terpene chemistry. PMID- 23666601 TI - Comparative analysis of oxy-hemoglobin and aquomet-hemoglobin by hydrogen/deuterium exchange mass spectrometry. AB - The function of hemoglobin (Hb) as oxygen transporter is mediated by reversible O2 binding to Fe(2+) heme in each of the alpha and beta subunits. X-ray crystallography revealed different subunit arrangements in oxy-Hb and deoxy-Hb. The deoxy state is stabilized by additional contacts, causing a rigidification that results in strong protection against hydrogen/deuterium exchange (HDX). Aquomet-Hb is a dysfunctional degradation product with four water-bound Fe(3+) centers. Heme release from aquomet-Hb is relatively facile, triggering oxidative damage of membrane lipids. Aquomet-Hb crystallizes in virtually the same conformation as oxy-Hb. Hence, it is commonly implied that the solution-phase properties of aquomet-Hb should resemble those of the oxy state. This work compares the structural dynamics of oxy-Hb and aquomet-Hb by HDX mass spectrometry (MS). It is found that the aquomet state exhibits a solution-phase structure that is significantly more dynamic, as manifested by elevated HDX levels. These enhanced dynamics affect the aquomet alpha and beta subunits in a different fashion. The latter undergoes global destabilization, whereas the former shows elevated HDX levels only in the heme binding region. It is proposed that these enhanced dynamics play a role in facilitating heme release from aquomet-Hb. Our findings should be of particular interest to the MS community because oxy-Hb and aquomet-Hb serve as widely used test analytes for probing the relationship between biomolecular structure in solution and in the gas phase. We are not aware of any prior comparative HDX/MS experiments on oxy-Hb and aquomet Hb. PMID- 23666603 TI - Role of initial and day 4 human chorionic gonadotropin levels in predicting the outcome of single-dose methotrexate treatment in women with tubal ectopic pregnancy. AB - PURPOSE: The purpose of this study was to evaluate the initial and day 4 beta human chorionic gonadotropin (beta-hCG) levels as a predictor of methotrexate (MTX) therapy success for ectopic pregnancy. METHODS: Retrospective study of 87 patients with tubal ectopic pregnancy treated with a single dose of 50 mg/m(2) MTX at Bursa Sevket Yilmaz Research and Education Hospital between January 2011 and July 2012 was performed. RESULTS: The overall success rate is measured as 72.4 %. The two groups of patients, successfully treated patients (n = 63) and unsuccessfully treated patients (n = 24), were compared. The mean initial beta hCG level was significantly lower in the treatment success group than in the treatment failure group (1,417 mIU/mL versus 5,995 mIU/mL, p < 0.001). The number of cases with decreasing beta-hCG level on day 4 was significantly more in the success group compared to the failure group (61.9 and 37.5 %, respectively, p = 0.04). The success rate was 90 % when beta-hCG levels were <1,000 mIU/mL, 85.7 % when the levels were between 1,000 and 1,999 mIU/mL, and 76.5 % when the levels were between 2,000 and 2,999 mIU/mL, 54.5 % when the levels were between 3,000 and 3,999 mIU/mL. CONCLUSION: Single-dose MTX therapy is a safe and effective treatment modality for tubal ectopic pregnancies with the beta-hCG serum concentration below 3,000 mIU/mL, and beta-hCG level changes between days 0 and 4 after MTX therapy are important in predicting the outcome of treatment. PMID- 23666604 TI - Emotion regulation difficulties, youth-adult relationships, and suicide attempts among high school students in underserved communities. AB - To develop and refine interventions to prevent youth suicide, knowledge is needed about specific processes that reduce risk at a population level. Using a cross sectional design, the present study tested hypotheses regarding associations between self-reported suicide attempts, emotion regulation difficulties, and positive youth-adult relationships among 7,978 high-school students (48.6% male, 49.9% female) in 30 high schools from predominantly rural, low-income communities. 683 students (8.6%) reported a past-year suicide attempt. Emotion regulation difficulties and a lack of trusted adults at home and school were associated with increased risk for making a past-year suicide attempt, above and beyond the effects of depressive symptoms and demographic factors. The association between emotion regulation difficulties and suicide attempts was modestly lower among students who perceived themselves as having higher levels of trusted adults in the family, consistent with a protective effect. Having a trusted adult in the community (outside of school and family) was associated with fewer suicide attempts in models that controlled only for demographic covariates, but not when taking symptoms of depression into account. These findings point to adolescent emotion regulation and relationships with trusted adults as complementary targets for suicide prevention that merit further intervention studies. Reaching these targets in a broad population of adolescents will require new delivery systems and "option rich" (OR) intervention designs. PMID- 23666605 TI - Chronic rhinosinusitis increased the risk of chronic periodontitis: a population based matched-cohort study. AB - OBJECTIVES/HYPOTHESIS: Although chronic periodontitis (CP) and chronic rhinosinusitis (CRS) both share immunological disturbances as pathological factors, no prior study has investigated the risk for CP among patients with CRS. This study set out to provide an estimation of risk by utilizing a cohort study design to leverage the statistical power of a population-based dataset in Taiwan. STUDY DESIGN: A retrospective cohort study. METHODS: In total, 13,782 CRS subjects were included in the study cohort and 41,346 subjects were randomly extracted for the comparison cohort. We individually tracked each subject in this study (N = 55,128) for a 5-year period following their index date to identify those subjects who received a subsequent diagnosis of CP. Cox proportional hazards regression analysis was conducted to calculate the 5-year risk of subsequent CP following a diagnosis of CRS among the sampled subjects. RESULTS: The incidence rate of CP during the 5-year follow-up period was 5.12 (95% confidence interval [CI], 4.95-5.30) per 100 person-years and 3.24 (95% CI, 3.17 3.30) per 100 person-years for the study and comparison cohort, respectively. Cox proportional hazards regression revealed that the hazard ratio for CP during the 5-year follow-up period for subjects with CRS was 1.59 times (95% CI, 1.52-1.67) that of comparison subjects after adjusting for monthly income, geographic region, hypertension, diabetes, coronary heart disease, and hyperlipidemia, and censoring for cases who died during the 5-year follow-up period. CONCLUSIONS: This study detected an increased risk for CP among patients suffering from CRS. CRS patients should be alerted to pay particular attention to their oral hygiene practices to prevent both CP and its downstream sequelae. PMID- 23666607 TI - Copper-catalyzed rearrangement of N-aryl nitrones into epoxyketimines. PMID- 23666606 TI - Improved cell therapy protocols for Parkinson's disease based on differentiation efficiency and safety of hESC-, hiPSC-, and non-human primate iPSC-derived dopaminergic neurons. AB - The main motor symptoms of Parkinson's disease are due to the loss of dopaminergic (DA) neurons in the ventral midbrain (VM). For the future treatment of Parkinson's disease with cell transplantation it is important to develop efficient differentiation methods for production of human iPSCs and hESCs-derived midbrain-type DA neurons. Here we describe an efficient differentiation and sorting strategy for DA neurons from both human ES/iPS cells and non-human primate iPSCs. The use of non-human primate iPSCs for neuronal differentiation and autologous transplantation is important for preclinical evaluation of safety and efficacy of stem cell-derived DA neurons. The aim of this study was to improve the safety of human- and non-human primate iPSC (PiPSC)-derived DA neurons. According to our results, NCAM(+) /CD29(low) sorting enriched VM DA neurons from pluripotent stem cell-derived neural cell populations. NCAM(+) /CD29(low) DA neurons were positive for FOXA2/TH and EN1/TH and this cell population had increased expression levels of FOXA2, LMX1A, TH, GIRK2, PITX3, EN1, NURR1 mRNA compared to unsorted neural cell populations. PiPSC-derived NCAM(+) /CD29(low) DA neurons were able to restore motor function of 6 hydroxydopamine (6-OHDA) lesioned rats 16 weeks after transplantation. The transplanted sorted cells also integrated in the rodent brain tissue, with robust TH+/hNCAM+ neuritic innervation of the host striatum. One year after autologous transplantation, the primate iPSC-derived neural cells survived in the striatum of one primate without any immunosuppression. These neural cell grafts contained FOXA2/TH-positive neurons in the graft site. This is an important proof of concept for the feasibility and safety of iPSC-derived cell transplantation therapies in the future. PMID- 23666609 TI - Involvement of cathepsins B and L in inflammation and cholesterol trafficking protein NPC2 secretion in macrophages. AB - OBJECTIVE: Obesity and its related chronic inflammation are the major risk factors for developing metabolic disturbances. The roles of cathepsin cysteine proteases have been tied to inflammation and atherosclerosis. Cathepsins are important functional links between inflammation, cholesterol metabolism, and atherosclerosis in obesity. NPC2, a lysosomal protein, plays an important role in cholesterol trafficking. The objective of this study was to examine the regulation of cathepsins and NPC2 in adipose tissue and macrophages in obesity and the effect of modifying cathepsin activity in cholesterol metabolism and trafficking in macrophages. DESIGN AND METHODS: Cathepsins and NPC2 mRNA expression and protein secretion were detected in obese adipose tissue as well as 3T3-L1 adipocytes and Raw 264.7 macrophages in response to inflammatory stimuli and cathepsin inhibitors. RESULTS: It was found that high-fat diet feeding altered the mRNA and protein expression levels of cathepsins B and L (CtB and CtL) and NPC2 in adipose tissue in mice; the differential regulation of these proteins was observed between adipose depots. In vitro studies showed that TNF alpha reduces intracellular protein levels of CtB, CtL, and NPC2, but increases their secretion in 3T3-L1 adipocytes. Likewise, LPS stimulated the secretion of CtB and NPC2 in Raw 264.7 macrophages. Using the inhibitors of cathepsin enzymatic activity, it was found that CtB and CtL regulate TNF-alpha production, the expression and secretion of NPC2 protein, and the mRNA levels of the genes involved in cholesterol trafficking in macrophages. CONCLUSION: These findings suggest that CtB and CtL have a significant involvement in mediating the inflammatory response, in cholesterol trafficking, and in regulating NPC2 secretion. PMID- 23666608 TI - Patient-reported outcomes and the association with clinical response in patients with active psoriatic arthritis treated with golimumab: findings through 2 years of a phase III, multicenter, randomized, double-blind, placebo-controlled trial. AB - OBJECTIVE: To evaluate the effect of golimumab on physical function, health related quality of life (HRQOL), and productivity in psoriatic arthritis (PsA). METHODS: GO-REVEAL was a multicenter, randomized, placebo-controlled study. Adult patients with active PsA (n = 405) received golimumab (50 or 100 mg) or placebo every 4 weeks, with early escape at week 16 (placebo -> 50 mg, 50 -> 100 mg) or placebo crossover to golimumab 50 mg at week 24. Patient-reported outcomes included physical function (Health Assessment Questionnaire [HAQ] disability index [DI] score), HRQOL (36-item Short Form health survey [SF-36] mental component summary [MCS] and physical component summary [PCS] scores), and productivity (home/school/work). Clinical response was assessed using the 28 joint Disease Activity Score using the C-reactive protein level (DAS28-CRP) and the Psoriasis Area and Severity Index (PASI) score for arthritis and skin symptoms, respectively. RESULTS: At week 24, golimumab-treated patients had significant mean improvements in HAQ DI (0.36), SF-36 (PCS 7.83, MCS 3.84), and productivity (2.24) scores compared with placebo (-0.01, 0.67, -0.60, and 0.08, respectively; P < 0.001 for all). Also, greater proportions of golimumab- than placebo-treated patients had clinically meaningful improvements in HAQ DI (>=0.30) and SF-36 PCS and MCS (>=5) scores at week 24 (P < 0.05). Also at week 24, improvements in DAS28-CRP scores were significantly but moderately correlated with improvements in HAQ DI, SF-36 PCS, and productivity scores. Correlations between these patient-reported outcomes and improvements in PASI, enthesitis, and dactylitis scores were very weak. Improvements in HAQ DI, SF-36, and productivity scores were similar among all groups by week 52 and week 104 when including placebo -> golimumab crossover patients. CONCLUSION: Golimumab-treated patients had significant improvements in physical function, HRQOL, and productivity through week 24; these improvements correlated with clinical improvement in signs and symptoms of peripheral arthritis and were sustained through 2 years. PMID- 23666610 TI - A microfluidic anti-Factor Xa assay device for point of care monitoring of anticoagulation therapy. AB - The development of new point of care coagulation assay devices is necessary due to the increasing number of patients requiring long-term anticoagulation in addition to the desire for appropriate, targeted anticoagulant therapy and a more rapid response to optimization of treatment. The majority of point of care devices currently available for hemostasis testing rely on clot-based endpoints which are variable, unreliable and limited to measuring only certain portions of the coagulation pathway. Here we present a novel fluorescence-based anti-Factor Xa (FXa) microfluidic assay device for monitoring the effect of anticoagulant therapy at the point of care. The device is a disposable, laminated polymer microfluidic strip fabricated from a combination of hydrophobic and hydrophilic cyclic polyolefins to allow reagent deposition in addition to effective capillary fill. Zeonor was the polymer of choice resulting in low background fluorescence (208.5 AU), suitable contact angles (17.5 degrees +/- 0.9 degrees ) and capillary fill times (20.3 +/- 2.1 s). The device was capable of measuring unfractionated heparin and tinzaparin from 0-0.8 U ml(-1) and enoxaparin from 0-0.6 U ml(-1) with average CVs < 10%. A linear correlation was observed between the device and the fluorescent assay in the plate for plasma samples spiked with UFH, with an R(2) value of 0.99, while correlations with tinzaparin and enoxaparin resulted in sigmoidal responses (R(2) = 0.99). Plasma samples containing UFH resulted in a linear correlation between the device and a standard chromogenic assay with an R(2) value of 0.98, with both LMWHs resulting in sigmoidal relationships (R(2) = 0.99). PMID- 23666612 TI - Influence of pH on the molecular weight of poly-3-hydroxybutyric acid (P3HB) produced by recombinant Escherichia coli. AB - The production of ultrahigh molecular weight poly-3-hydroxybutyric acid (P3HB) from carbohydrates by recombinant Escherichia coli harboring genes from Ralstonia eutropha was evaluated. In shaken-flask experiments, E. coli XL1 Blue harboring plasmid pSK::phaCAB produced P3HB corresponding to 40 and 27% of cell dry weight from glucose and xylose, respectively. Cultures in bioreactor using glucose as the sole carbon source at variable pH values (6.0, 6.5, or 7.0) allowed the production of P3HB with molecular weight varying between 2.0 and 2.5 MDa. These figures are significantly higher than the values often obtained by natural bacterial strains (0.5-1.0 MDa). Contrary to reports of other authors, no influence of pH was observed on the molecular weight of the polymer produced. Using xylose, P3HB with high molecular weight was also produced, indicating the possibility to produce these polymers from lignocellulosic materials. PMID- 23666613 TI - The effect of biomass immobilization support material and bed porosity on hydrogen production in an upflow anaerobic packed-bed bioreactor. AB - The aim of this study was to investigate the effect of the support material used for biomass attachment and bed porosity on the potential generation of hydrogen gas in an anaerobic bioreactor treating low-strength wastewater. For this purpose, an upflow anaerobic packed-bed (UAPB) reactor fed with sucrose-based synthetic wastewater was used. Three reactors with various support materials (expanded clay, vegetal coal, and low-density polyethylene) were operated for hydraulic retention time (HRT) of 0.5 and 2 h. Based on the results obtained, three further reactors were operated with low-density polyethylene as a material support using various bed porosities (91, 75, and 50 %) for an HRT of 0.5 h. The UAPB reactor was found to be a feasible technology for hydrogen production, reaching a maximum substrate-based hydrogen yield of 7 mol H2 mol(-1) sucrose for an HRT of 0.5 h. The type of support material used did not affect hydrogen production or the microbial population inside the reactor. Increasing the bed porosity to 91 % provided a continuous and cyclic production of hydrogen, whereas the lower bed porosities resulted in a reduced time of hydrogen production due to biomass accumulation, which resulted in a decreasing working volume. PMID- 23666611 TI - Diffuse cystic lung diseases. AB - Diffuse cystic lung diseases are uncommon but can present a diagnostic challenge because increasing number of diseases have been associated with this presentation. Cyst in the lung is defined as a round parenchymal lucency with a well-defined thin wall (< 2 mm thickness). Focal or multifocal cystic lesions include blebs, bullae, pneumatoceles, congenital cystic lesions, traumatic lesions, and several infectious processes such as coccidioidomycosis, Pneumocystis jiroveci pneumonia, and hydatid disease. "Diffuse" distribution in the lung implies involvement of all lobes. Diffuse lung involvement with cystic lesions can be seen in pulmonary lymphangioleiomyomatosis, pulmonary Langerhans' cell histiocytosis, lymphoid interstitial pneumonia, Birt-Hogg-Dube syndrome, amyloidosis, light chain deposition disease, honeycomb lung associated with advanced fibrosis, and several other rare causes including metastatic disease. High-resolution computed tomography of the chest helps define morphologic features of the lung lesions as well as their distribution and associated features such as intrathoracic lymphadenopathy. Correlating the tempo of the disease process and clinical context with chest imaging findings serve as important clues to defining the underlying nature of the cystic lung disease and guide diagnostic evaluation as well as management. PMID- 23666614 TI - Crude cellulase from oil palm empty fruit bunch by Trichoderma asperellum UPM1 and Aspergillus fumigatus UPM2 for fermentable sugars production. AB - Cellulase is an enzyme that converts the polymer structure of polysaccharides into fermentable sugars. The high market demand for this enzyme together with the variety of applications in the industry has brought the research on cellulase into focus. In this study, crude cellulase was produced from oil palm empty fruit bunch (OPEFB) pretreated with 2% NaOH with autoclave, which was composed of 59.7% cellulose, 21.6% hemicellulose, and 12.3% lignin using Trichoderma asperellum UPM1 and Aspergillus fumigatus UPM2. Approximately 0.8 U/ml of FPase, 24.7 U/ml of CMCase and 5.0 U/ml of beta-glucosidase were produced by T. asperellum UPM1 at a temperature of 35 degrees C and at an initial pH of 7.0. A 1.7 U/ml of FPase, 24.2 U/ml of CMCase, and 1.1 U/ml of beta-glucosidase were produced by A. fumigatus UPM2 at a temperature of 45 degrees C and at initial pH of 6.0. The crude cellulase was best produced at 1% of substrate concentration for both T. asperellum UPM1 and A. fumigatus UPM2. The hydrolysis percentage of pretreated OPEFB using 5% of crude cellulase concentration from T. asperellum UPM1 and A. fumigatus UPM2 were 3.33% and 19.11%, with the reducing sugars concentration of 1.47 and 8.63 g/l, respectively. PMID- 23666615 TI - Molecular characterization, expression patterns, and association analysis with carcass traits of porcine USF1 gene. AB - The upstream stimulatory factor 1 (USF1) is a transcription factor controlling expression of several genes involved in lipid and glucose homeostasis. In this study, two isoforms of the porcine USF1 gene were detected by reverse transcription polymerase chain reaction (RT-PCR), termed USF1 wild-type (wt) and USF1/CD, both of them contain a helix-loop-helix leucine zipper (HLH-LZ) conserved domain. Tissue distribution analysis showed that the two transcripts of porcine USF1 gene were ubiquitously expressed in all tested tissues, except for heart. Moreover, we found that a single nucleotide polymorphism (SNP, C/T) in intron 10 was significantly associated with ratio of lean to fat (P < 0.05), dress percentage (P < 0.05), average backfat thickness (P < 0.05), loin eye width (P < 0.05), lean meat percentage (P < 0.01), loin eye height (P < 0.01), and loin eye area (P < 0.01). This result suggests that porcine USF1 gene may be a candidate gene of meat production trait. PMID- 23666616 TI - Outcomes of the acute palliative care unit in an academic medical center. AB - BACKGROUND: The acute palliative care units (APCU) where the palliative medicine specialists are primarily in charge with medical management are being established in few academic medical centers. The purpose of this study is to review the demographics and outcomes of the APCU admissions and the economical implications to the Montefiore Medical Center, Bronx, New York. METHODS: We retrospectively examined the demographics, diagnosis related groups (DRGs), length of hospital stay (LOS), discharge status and hospital charge data using data from intcernal cost accounting databases for consecutive admissions to the palliative care unit between February 2007 and February 2010. RESULTS: A total of 1837 patients were admitted. Six hundred eighty patients transferred from other medical-surgical units. Twenty two percent of the patients were admitted under other specialties but co-managed with the palliative medicine specialists. The top three DRGs were sepsis without or with mechanical ventilation and heart failure with major co morbidities. The average length of stay was comparable to other medical surgical units. Seventy-two percent of the patients were discharged alive, 27% died in the hospital. The median charges were lower in the palliative care unit than in medical-surgical units (p<.0001). These benefits were more likely to occur if patients were managed directly by the specialists. CONCLUSION: Our data suggests that the APCU may provide cost effective, acute care for the patients with advanced chronic illness as well as the imminently dying in need of intensive symptom management. PMID- 23666617 TI - Hospice in end-of-life patients with cancer: does it lead to changes in nonhospice health care utilization after stopping cancer treatment? AB - This study assessed the patterns of nonhospice health care utilization among 207 deceased cancer patients and focused on outcomes after cancer treatment was stopped. A total of 117 (57%) were enrolled in hospice. The mean cumulative number of emergency department visits, hospitalizations, or other noncancer clinic visits (standard deviation) among those enrolled and not enrolled in hospice was 1.8 (+/- 1.8) and 3.11 (+/- 3.0), respectively (P < .0001). Among hospice enrollees, the mean cumulative visits (standard deviation) was 1.29 (+/- 1.7) and 0.5 (+/- 1.0) before and after enrollment, respectively (P < .0001). For patients who eventually enrolled, the rates of nonhospice health care visits (visits per week) yielded a trend to suggest a decline (P = .054). Hospice was associated with a drop in nonhospice-related health care utilization, thus suggesting it provides timely medical interventions and favorable continuity of care. PMID- 23666619 TI - Myelodysplastic syndromes: what do hospitalists need to know? AB - Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem cell disorders characterized by dysplasia, ineffective hematopoiesis leading to peripheral blood cytopenias, and a variable risk of leukemic progression. MDS primarily affects the elderly, and although its prevalence is increasing, MDS is frequently overlooked and underdiagnosed. MDS should be suspected in any patient with unexplained cytopenias, and a bone marrow evaluation is ultimately needed to make the diagnosis and exclude other causes of bone marrow failure. The last 15 years have witnessed significant advances in our understanding of the complex pathogenesis, classification and prognostication, and therapeutic approaches to MDS. Several prognostic models facilitate outcome prediction and risk-adapted therapy. The addition of azacitidine, decitabine, and lenalidomide to erythropoiesis-stimulating agents in our armamentarium offered new effective therapeutic options for many patients who are not candidates for intensive interventions. Improved understanding of the genetic, epigenetic, and immunologic mechanisms that operate in MDS will help develop better prognostication tools and rationally design more effective therapies. Hospitalists are likely to encounter both patients with MDS and patients in whom MDS should be suspected. In this review of MDS, we focus on the epidemiology, diagnosis, pathogenesis, classification and prognostic tools, and treatment options. PMID- 23666620 TI - Dual role of CpG-stimulated B cells in the regulation of dendritic cells: comment on the article by Berggren et al. PMID- 23666621 TI - Pressure-induced endocytic degradation of the Saccharomyces cerevisiae low affinity tryptophan permease Tat1 is mediated by Rsp5 ubiquitin ligase and functionally redundant PPxY motif proteins. AB - Cells of Saccharomyces cerevisiae express two tryptophan permeases, Tat1 and Tat2, which have different characteristics in terms of their affinity for tryptophan and intracellular localization. Although the high-affinity permease Tat2 has been well documented in terms of its ubiquitin-dependent degradation, the low-affinity permease Tat1 has not yet been characterized fully. Here we show that a high hydrostatic pressure of 25 MPa triggers a degradation of Tat1 which depends on Rsp5 ubiquitin ligase and the EH domain-containing protein End3. Tat1 was resistant to a 3-h cycloheximide treatment, suggesting that it is highly stable under normal growth conditions. The ubiquitination of Tat1 most likely occurs at N-terminal lysines 29 and 31. Simultaneous substitution of arginine for the two lysines prevented Tat1 degradation, but substitution of either of them alone did not, indicating that the roles of lysines 29 and 31 are redundant. When cells were exposed to high pressure, Tat1-GFP was completely lost from the plasma membrane, while substantial amounts of Tat1(K29R-K31R)-GFP remained. The HPG1-1 (Rsp5(P514T)) and rsp5-ww3 mutations stabilized Tat1 under high pressure, but any one of the rsp5-ww1, rsp5-ww2, and bul1Delta bul2Delta mutations or single deletions of genes encoding arrestin-related trafficking adaptors did not. However, simultaneous loss of 9-arrestins and Bul1/Bul2 prevented Tat1 degradation at 25 MPa. The results suggest that multiple PPxY motif proteins share some essential roles in regulating Tat1 ubiquitination in response to high hydrostatic pressure. PMID- 23666622 TI - The unfolded protein response in the protozoan parasite Toxoplasma gondii features translational and transcriptional control. AB - The unfolded protein response (UPR) is an important regulatory network that responds to perturbations in protein homeostasis in the endoplasmic reticulum (ER). In mammalian cells, the UPR features translational and transcriptional mechanisms of gene expression aimed at restoring proteostatic control. A central feature of the UPR is phosphorylation of the alpha subunit of eukaryotic initiation factor-2 (eIF2) by PERK (EIF2AK3/PEK), which reduces the influx of nascent proteins into the ER by lowering global protein synthesis, coincident with preferential translation of key transcription activators of genes that function to expand the processing capacity of this secretory organelle. Upon ER stress, the apicomplexan parasite Toxoplasma gondii is known to induce phosphorylation of Toxoplasma eIF2alpha and lower translation initiation. To characterize the nature of the ensuing UPR in this parasite, we carried out microarray analyses to measure the changes in the transcriptome and in translational control during ER stress. We determined that a collection of transcripts linked with the secretory process are induced in response to ER stress, supporting the idea that a transcriptional induction phase of the UPR occurs in Toxoplasma. Furthermore, we determined that about 500 gene transcripts showed enhanced association with translating ribosomes during ER stress. Many of these target genes are suggested to be involved in gene expression, including JmjC5, which continues to be actively translated during ER stress. This study indicates that Toxoplasma triggers a UPR during ER stress that features both translational and transcriptional regulatory mechanisms, which is likely to be important for parasite invasion and development. PMID- 23666623 TI - The spatial distribution of the exocyst and actin cortical patches is sufficient to organize hyphal tip growth. AB - In the hyphal tip of Candida albicans we have made detailed quantitative measurements of (i) exocyst components, (ii) Rho1, the regulatory subunit of (1,3)-beta-glucan synthase, (iii) Rom2, the specialized guanine-nucleotide exchange factor (GEF) of Rho1, and (iv) actin cortical patches, the sites of endocytosis. We use the resulting data to construct and test a quantitative 3 dimensional model of fungal hyphal growth based on the proposition that vesicles fuse with the hyphal tip at a rate determined by the local density of exocyst components. Enzymes such as (1,3)-beta-glucan synthase thus embedded in the plasma membrane continue to synthesize the cell wall until they are removed by endocytosis. The model successfully predicts the shape and dimensions of the hyphae, provided that endocytosis acts to remove cell wall-synthesizing enzymes at the subapical bands of actin patches. Moreover, a key prediction of the model is that the distribution of the synthase is substantially broader than the area occupied by the exocyst. This prediction is borne out by our quantitative measurements. Thus, although the model highlights detailed issues that require further investigation, in general terms the pattern of tip growth of fungal hyphae can be satisfactorily explained by a simple but quantitative model rooted within the known molecular processes of polarized growth. Moreover, the methodology can be readily adapted to model other forms of polarized growth, such as that which occurs in plant pollen tubes. PMID- 23666624 TI - The hnRNP F/H homologue of Trypanosoma brucei is differentially expressed in the two life cycle stages of the parasite and regulates splicing and mRNA stability. AB - Trypanosomes are protozoan parasites that cycle between a mammalian host (bloodstream form) and an insect host, the Tsetse fly (procyclic stage). In trypanosomes, all mRNAs are trans-spliced as part of their maturation. Genome wide analysis of trans-splicing indicates the existence of alternative trans splicing, but little is known regarding RNA-binding proteins that participate in such regulation. In this study, we performed functional analysis of the Trypanosoma brucei heterogeneous nuclear ribonucleoproteins (hnRNP) F/H homologue, a protein known to regulate alternative splicing in metazoa. The hnRNP F/H is highly expressed in the bloodstream form of the parasite, but is also functional in the procyclic form. Transcriptome analyses of RNAi-silenced cells were used to deduce the RNA motif recognized by this protein. A purine rich motif, AAGAA, was enriched in both the regulatory regions flanking the 3' splice site and poly (A) sites of the regulated genes. The motif was further validated using mini-genes carrying wild-type and mutated sequences in the 3' and 5' UTRs, demonstrating the role of hnRNP F/H in mRNA stability and splicing. Biochemical studies confirmed the binding of the protein to this proposed site. The differential expression of the protein and its inverse effects on mRNA level in the two lifecycle stages demonstrate the role of hnRNP F/H in developmental regulation. PMID- 23666625 TI - Polycomb recruitment attenuates retinoic acid-induced transcription of the bivalent NR2F1 gene. AB - Polycomb proteins play key roles in mediating epigenetic modifications that occur during cell differentiation. The Polycomb repressive complex 2 (PRC2) mediates the tri-methylation of histone H3 lysine 27 (H3K27me3). In this study, we identify a distinguishing feature of two classes of PRC2 target genes, represented by the Nr2F1 (Coup-TF1) and the Hoxa5 gene, respectively. Both genes are transcriptionally activated by all-trans retinoic acid (RA) and display increased levels of the permissive H3K9/K14ac and tri-methylated histone H3 lysine 4 epigenetic marks in response to RA. However, while in response to RA the PRC2 and H3K27me3 marks are greatly decreased at the Hoxa5 promoter, these marks are initially increased at the Nr2F1 promoter. Functional depletion of the essential PRC2 protein Suz12 by short hairpin RNA (shRNA) technology enhanced the RA-associated transcription of Nr2F1, Nr2F2, Meis1, Sox9 and BMP2, but had no effect on the Hoxa5, Hoxa1, Cyp26a1, Cyp26b1 and RARbeta2 transcript levels in wild-type embryonic stem cells. We propose that PRC2 recruitment attenuates the RA-associated transcriptional activation of a subset of genes. Such a mechanism would permit the fine-tuning of transcriptional networks during differentiation. PMID- 23666626 TI - Graphite Web: Web tool for gene set analysis exploiting pathway topology. AB - Graphite web is a novel web tool for pathway analyses and network visualization for gene expression data of both microarray and RNA-seq experiments. Several pathway analyses have been proposed either in the univariate or in the global and multivariate context to tackle the complexity and the interpretation of expression results. These methods can be further divided into 'topological' and 'non-topological' methods according to their ability to gain power from pathway topology. Biological pathways are, in fact, not only gene lists but can be represented through a network where genes and connections are, respectively, nodes and edges. To this day, the most used approaches are non-topological and univariate although they miss the relationship among genes. On the contrary, topological and multivariate approaches are more powerful, but difficult to be used by researchers without bioinformatic skills. Here we present Graphite web, the first public web server for pathway analysis on gene expression data that combines topological and multivariate pathway analyses with an efficient system of interactive network visualizations for easy results interpretation. Specifically, Graphite web implements five different gene set analyses on three model organisms and two pathway databases. Graphite Web is freely available at http://graphiteweb.bio.unipd.it/. PMID- 23666627 TI - Caffeine suppresses homologous recombination through interference with RAD51 mediated joint molecule formation. AB - Caffeine is a widely used inhibitor of the protein kinases that play a central role in the DNA damage response. We used chemical inhibitors and genetically deficient mouse embryonic stem cell lines to study the role of DNA damage response in stable integration of the transfected DNA and found that caffeine rapidly, efficiently and reversibly inhibited homologous integration of the transfected DNA as measured by several homologous recombination-mediated gene targeting assays. Biochemical and structural biology experiments revealed that caffeine interfered with a pivotal step in homologous recombination, homologous joint molecule formation, through increasing interactions of the RAD51 nucleoprotein filament with non-homologous DNA. Our results suggest that recombination pathways dependent on extensive homology search are caffeine sensitive and stress the importance of considering direct checkpoint-independent mechanisms in the interpretation of the effects of caffeine on DNA repair. PMID- 23666628 TI - Real-time solution measurement of RAD51- and RecA-mediated strand assimilation without background annealing. AB - RAD51 is the central strand exchange recombinase in somatic homologous recombination, providing genomic stability and promoting resistance to DNA damage. An important tool for mechanistic studies of RAD51 is the D-loop or strand assimilation assay, which measures the ability of RAD51-coated single stranded DNA (ssDNA) to search for, invade and exchange ssDNA strands with a homologous duplex DNA target. As cancer cells generally overexpress RAD51, the D loop assay has also emerged as an important tool in oncologic drug design programs for targeting RAD51. Previous studies have adapted the traditional gel based D-loop assay by using fluorescence-based substrates, which in principle allow for use in high-throughput screening platforms. However, these existing D loop methods depend on linear oligonucleotide DNA duplex targets, and these substrates enable recombinase-independent ssDNA annealing that can obscure the recombinase-dependent strand assimilation signal. This compelled us to fundamentally re-design this assay, using a fluorescent target substrate that consists of a covalently closed linear double-hairpin dsDNA. This new microplate based method represents a fast, inexpensive and non-radioactive alternative to existing D-loop assays. It provides accurate kinetic analysis of strand assimilation in high-throughput and performs well with human RAD51 and Escherichia coli RecA protein. This advance will aid in both mechanistic studies of homologous recombination and drug screening programs. PMID- 23666630 TI - Changes in trunk orientation do not induce asymmetries in covert orienting. AB - We explored the effect of trunk orientation on responses to visual targets in five experiments, following work suggesting a disengage deficit in covert orienting related to changes in the trunk orientation of healthy participants. In two experiments, participants responded to the color of a target appearing in the left or right visual field following a peripheral visual cue that was informative about target location. In three additional experiments, participants responded to the location (left/right) of a target using a spatially compatible motor response. In none of the experiments did trunk orientation interact with spatial cuing effects, suggesting that orienting behavior is not affected by the rotation of the body relative to the head. Theoretical implications are discussed. PMID- 23666629 TI - Plant nonsense-mediated mRNA decay is controlled by different autoregulatory circuits and can be induced by an EJC-like complex. AB - Nonsense-mediated mRNA decay (NMD) is a eukaryotic quality control system that recognizes and degrades transcripts containing NMD cis elements in their 3'untranslated region (UTR). In yeasts, unusually long 3'UTRs act as NMD cis elements, whereas in vertebrates, NMD is induced by introns located >50 nt downstream from the stop codon. In vertebrates, splicing leads to deposition of exon junction complex (EJC) onto the mRNA, and then 3'UTR-bound EJCs trigger NMD. It is proposed that this intron-based NMD is vertebrate specific, and it evolved to eliminate the misproducts of alternative splicing. Here, we provide evidence that similar EJC-mediated intron-based NMD functions in plants, suggesting that this type of NMD is evolutionary conserved. We demonstrate that in plants, like in vertebrates, introns located >50 nt from the stop induces NMD. We show that orthologs of all core EJC components are essential for intron-based plant NMD and that plant Partner of Y14 and mago (PYM) also acts as EJC disassembly factor. Moreover, we found that complex autoregulatory circuits control the activity of plant NMD. We demonstrate that expression of suppressor with morphogenic effect on genitalia (SMG)7, which is essential for long 3'UTR- and intron-based NMD, is regulated by both types of NMD, whereas expression of Barentsz EJC component is downregulated by intron-based NMD. PMID- 23666631 TI - Stable renal engraftment in a patient following successful tandem autologous/reduced-intensity conditioning allogeneic transplantation for treatment of multiple myeloma with del(17p) that developed as a post transplantation lymphoproliferative disease following renal transplantation. AB - Multiple myeloma (MM) developing after renal transplantation is rare. From January 1972 to December 2011, a total of 1,485 patients underwent renal transplantation in Nagoya Daini Red Cross Hospital; 14 (0.9%) of these recipients developed post-transplantation lymphoproliferative disorders (PTLDs) including two plasma cell neoplasms. Here, we report the clinical course of a 35-year-old male with immunoglobulin G k-type MM of recipient origin that developed 5 years after renal transplantation from a human leukocyte antigen (HLA)-haploidentical female sibling donor, which was performed to address dialysis-dependent chronic glomerulonephritis. Cytogenetic analysis revealed significant del(17p) abnormalities in myeloma cells. After non-response to bortezomib treatment, the patient achieved partial response with a thalidomide-containing salvage regimen and underwent successful tandem autologous/reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (HSCT) from an unrelated male donor matched for seven of eight HLAs. At the 8-month follow-up time point, the patient's performance status remained good, and the transplanted kidney remains functional without rejection. To the best of our knowledge, this is the first report of a successful use of allogeneic HSCT for a patient who developed MM as a PTLD after renal transplantation. This patient has a transplanted kidney and transplanted hematopoietic cells that currently coexist without rejection. PMID- 23666633 TI - Quantitative and qualitative characteristics of dissolved organic matter from eight dominant aquatic macrophytes in Lake Dianchi, China. AB - The aim of this research was to determine and compare the quantitative and qualitative characteristics of dissolved organic matters (DOM) from eight aquatic macrophytes in a eutrophic lake. C, H, N, and P in ground dry leaves and C, N, and P in DOM of the species were determined, and C/N, C/P, C/H, DOC/C, TDN/N, TDP/P, DOC/TDN, and DOC/TDP were calculated. Chemical structures of the DOM were characterized by the use of multiple techniques including UV-visible, FT-IR, and (13)C CP/MAS spectra. The results showed subtle differences in quantity and quality of DOM among species and life-forms. Except oriental pepper which had a C/H of 0.7, C/H of all the other species was 0.6. C/N and C/P of ground leaves was 10.5-17.3 and 79.4-225.3, respectively, which were greater in floating and submerged species than in the others. Parrot feather also had a small C/P (102.8). DOC/C, TDN/N, and TDP/P were 7.6-16.8, 5.5-22.6, and 22.9-45.6 %, respectively. Except C/N in emergent and riparian species, C/N in the other species and C/P in all the species were lower in their DOM than in the ground leaves. DOM of the macrophytes had a SUVA254 value of 0.83-1.80. The FT-IR and (13)C NMR spectra indicated that the DOM mainly contained polysaccharides and/or amino acids/proteins. Percent of carbohydrates in the DOM was 37.3-66.5 % and was highest in parrot feather (66.5 %) and crofton weed (61.5 %). DOM of water hyacinth, water lettuce, and sago pondweed may have the greatest content of proteins. Aromaticity of the DOM was from 6.9 % in water lettuce to 17.8 % in oriental pepper. DOM of the macrophytes was also different in polarity and percent of Ar-OH. Distinguished characteristics in quantity and quality of the macrophyte-derived DOM may induce unique environmental consequences in the lake systems. PMID- 23666632 TI - Computational identification and analysis of arsenate reductase protein in Cronobacter sakazakii ATCC BAA-894 suggests potential microorganism for reducing arsenate. AB - This study focuses a bioinformatics-based prediction of arsC gene product arsenate reductase (ArsC) protein in Cronobacter sakazakii BAA-894 strain. A protein structure-based study encloses three-dimensional structural modeling of target ArsC protein, was carried out by homology modeling method. Ultimately, the detection of active binding regions was carried out for characterization of functional sites in protein. The ten probable ligand binding sites were predicted for target protein structure and highlighted the common binding residues between target and template protein. It has been first time identified that modeled ArsC protein structure in C. sakazakii was structurally and functionally similar to well-characterized ArsC protein of Escherichia coli because of having same structural motifs and fold with similar protein topology and function. Investigation revealed that ArsC from C. sakazakii can play significant role during arsenic resistance and potential microorganism for bioremediation of arsenic toxicity. PMID- 23666634 TI - Chemical and bioanalytical characterisation of PAHs in risk assessment of remediated PAH-contaminated soils. AB - Polycyclic aromatic hydrocarbons (PAHs) are common contaminants in soil at former industrial areas; and in Sweden, some of the most contaminated sites are being remediated. Generic guideline values for soil use after so-called successful remediation actions of PAH-contaminated soil are based on the 16 EPA priority pollutants, which only constitute a small part of the complex cocktail of toxicants in many contaminated soils. The aim of the study was to elucidate if the actual toxicological risks of soil samples from successful remediation projects could be reflected by chemical determination of these PAHs. We compared chemical analysis (GC-MS) and bioassay analysis (H4IIE-luc) of a number of remediated PAH-contaminated soils. The H4IIE-luc bioassay is an aryl hydrocarbon (Ah) receptor-based assay that detects compounds that activate the Ah receptor, one important mechanism for PAH toxicity. Comparison of the results showed that the bioassay-determined toxicity in the remediated soil samples could only be explained to a minor extent by the concentrations of the 16 priority PAHs. The current risk assessment method for PAH-contaminated soil in use in Sweden along with other countries, based on chemical analysis of selected PAHs, is missing toxicologically relevant PAHs and other similar substances. It is therefore reasonable to include bioassays in risk assessment and in the classification of remediated PAH-contaminated soils. This could minimise environmental and human health risks and enable greater safety in subsequent reuse of remediated soils. PMID- 23666635 TI - Deep cervical lymph node hypertrophy: a new paradigm in the understanding of pediatric obstructive sleep apnea. AB - OBJECTIVES/HYPOTHESIS: To determine if adenotonsillar hypertrophy is an isolated factor in pediatric obstructive sleep apnea (OSA), or if it is part of larger spectrum of cervical lymphoid hypertrophy. STUDY DESIGN: Prospective case control study. METHODS: A total of 70 screened patients (mean age 7.47 years) underwent polysomnography to confirm OSA, and then underwent MRI of the upper airway. Seventy-six matched controls (mean age 8.00 years) who already had an MRI underwent polysomnography. Volumetric analysis of lymphoid tissue volumes was carried out. Chi-square analysis and Student's t test were used to compare demographic data and lymph node volumes between cohorts. Fisher's Exact test and Chi-square analysis were used to compare sleep data. RESULTS: Patients and controls demonstrated no significant difference in mean age (7.47 vs. 8.00 yrs), weight (44.87 vs. 38.71 kg), height (124.68 vs. 127.65 cm), or body-mass index (23.63 vs. 20.87 kg/m(2)). OSA patients demonstrated poorer sleep measures than controls (P < 0.05) in all polysomnography categories (sleep efficiency, apnea index, apnea-hypopnea index, baseline SpO2, SpO2 nadir, baseline ETCO2, peak ETCO2 , and arousal awakening index). Children with OSA had higher lymphoid tissue volumes than controls in the retropharyngeal region (3316 vs. 2403 mm(3), P < 0.001), upper jugular region (22202 vs. 16819 mm(3), P < 0.005), and adenotonsillar region (18994 vs. 12675 mm(3), P < 0.0001). CONCLUSIONS: Children with OSA have larger volumes of deep cervical lymph nodes and adenotonsillar tissue than controls. This finding suggests a new paradigm in the understanding of pediatric OSA, and has ramifications for future research and clinical care. PMID- 23666636 TI - Synthesis of new N-substituted 5-arylidene-2,4-thiazolidinediones as anti inflammatory and antimicrobial agents. AB - A novel series of 5-arylidene-2,4-thiazolidinediones (TZDs) 2a-p was synthesized from the condensation of 3-((2-phenylthiazol-4-yl)methyl)thiazolidine-2,4-dione with different benzaldehyde derivatives. All the structures were confirmed by their spectral (IR, 1H NMR, 13C NMR and mass) and elemental analytical data. The new molecules were evaluated in vivo as anti-inflammatory agents in an acute experimental inflammation, evaluating the acute phase bone marrow response and phagocyte activity. All compounds, excepting one, reduced the absolute leukocytes count due to the lower neutrophil percentage. Phagocytary index was decreased by the same molecules, while only half of them reduced the phagocytary activity. The effect was superior to meloxicam, the reference anti-inflammatory drug, for the majority of the TZD derivatives. The new molecules were also investigated for their antimicrobial properties on Gram-positive and Gram-negative bacteria and one fungal strain. Two compounds (2e and 2n) manifested growth inhibition capacity on all the tested strains. PMID- 23666637 TI - Abi3bp is a multifunctional autocrine/paracrine factor that regulates mesenchymal stem cell biology. AB - Mesenchymal stem cells (MSCs) transplanted into injured myocardium promote repair through paracrine mechanisms. We have previously shown that MSCs over-expressing AKT1 (Akt-MSCs) exhibit enhanced properties for cardiac repair. In this study, we investigated the relevance of Abi3bp toward MSC biology. Abi3bp formed extracellular deposits with expression controlled by Akt1 and ubiquitin-mediated degradation. Abi3bp knockdown/knockout stabilized focal adhesions and promoted stress-fiber formation. Furthermore, MSCs from Abi3bp knockout mice displayed severe deficiencies in osteogenic and adipogenic differentiation. Knockout or stable knockdown of Abi3bp increased MSC and Akt-MSC proliferation, promoting S phase entry via cyclin-d1, ERK1/2, and Src. Upon Abi3bp binding to integrin-beta1 Src associated with paxillin which inhibited proliferation. In vivo, Abi3bp knockout increased MSC number and proliferation in bone marrow, lung, and liver. In summary, we have identified a novel extracellular matrix protein necessary for the switch from proliferation to differentiation in MSCs. PMID- 23666638 TI - Functionalized alkenylzinc reagents bearing carbonyl groups: preparation by direct metal insertion and reaction with electrophiles. PMID- 23666639 TI - Serum leptin and adiponectin levels and risk of renal cell carcinoma. AB - OBJECTIVE: The incidence of renal cell carcinoma (RCC) has increased rapidly in the U.S., particularly among African Americans. Despite a well-established link between obesity and RCC, the mechanism through which obesity increases cancer risk has yet to be established. Adipokines, such as leptin and adiponectin, may link obesity and cancer, with different quantitative effects by race. DESIGN AND METHODS: We evaluated the association between leptin and adiponectin concentrations and RCC risk among Caucasians (581 cases, 558 controls) and African Americans (187 cases, 359 controls) in a case-control study conducted in Detroit and Chicago. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were estimated using unconditional logistic regression. RESULTS: Among controls, Caucasians had higher median adiponectin than African Americans (males: 8.2 vs. 7.0 MUg/ml, P = 0.001; females: 13.4 vs. 8.4 MUg/ml, P < 0.0001), and lower median leptin than African Americans (males: 11.8 vs. 14.1 ng/ml, P = 0.04; females: 28.3 vs. 45.9 ng/ml, P < 0.0001). Among Caucasians, the ORs for RCC comparing the highest (Q4) to the lowest (Q1) sex-specific quartile of leptin were 3.2 (95% CI: 1.9-5.2) for males and 4.7 (95% CI: 2.6-8.6) for females. Serum leptin was not significantly associated with RCC among African American males (OR 1.5, 95% CI: 0.7-3.1) or females (OR 2.1, 95% CI: 0.8-5.5). Higher adiponectin was associated with RCC risk among African American males (Q4 vs. Q1: OR 2.3, 95% CI: 1.1-4.6) and females (OR 2.1, 95% CI: 1.2-6.7), but not significantly among Caucasian males (OR 1.6, 95% CI: 0.99-2.7) and females (OR 1.6, 95% CI: 0.9-3.1). CONCLUSION: We observed an association between both leptin and adiponectin concentrations and risk of RCC, which may differ by race. Confirmation in further investigations is needed. PMID- 23666640 TI - Synergized antimicrobial activity of eugenol incorporated polyhydroxybutyrate films against food spoilage microorganisms in conjunction with pediocin. AB - Biopolymers and biopreservatives produced by microorganisms play an essential role in food technology. Polyhydroxyalkanoates and bacteriocins produced by bacteria are promising components to safeguard the environment and for food preservation applications. Polyhydroxybutyrate (PHB)-based antimicrobial films were prepared incorporating eugenol, from 10 to 200 MUg/g of PHB. The films were evaluated for antimicrobial activity against foodborne pathogens, spoilage bacteria, and fungi such as Staphylococcus aureus, Escherichia coli, Salmonella typhimurium, Bacillus cereus, Aspergillus flavus, Aspergillus niger, Penicillium sp., and Rhizopus sp. The synergistic antimicrobial activity of the films in the presence of crude pediocin was also investigated. The broth system containing pediocin (soluble form) as well as antimicrobial PHB film demonstrated an extended lag phase and a significant growth reduction at the end of 24 h against the bacteria. Crude pediocin alone could not elicit antifungal activity, while inhibition of growth and sporulation were observed in the presence of antimicrobial PHB film containing eugenol (80 MUg/g) until 7 days in the case of molds, i.e., A. niger, A. flavus, Penicillium sp., and Rhizopus sp. in potato dextrose broth. In the present study, we identified that use of pediocin containing broth in conjunction with eugenol incorporated PHB film could function in synergized form, providing effective hurdle toward food contaminating microorganisms. Furthermore, tensile strength, percent crystallinity, melting point, percent elongation to break, glass transition temperature, and seal strength of the PHB film with and without eugenol incorporation were investigated. The migration of eugenol on exposure to different liquid food simulants was also analyzed using Fourier transform infrared spectroscopy. The study is expected to provide applications for pediocin in conjunction with eugenol containing PHB film to enhance the shelf life of foods in the food industry. PMID- 23666641 TI - State of the art for the biosorption process--a review. AB - In recent years, biosorption process has become an economic and eco-friendly alternative treatment technology in the water and wastewater industry. In this light, a number of biosorbents were developed and are successfully employed for treating various pollutants including metals, dyes, phenols, fluoride, and pharmaceuticals in solutions (aqueous/oil). However, still there are few technical barriers in the biosorption process that impede its commercialization and thus to overcome these problems there has been a steadily growing interest in this research field. This resulted in large numbers of publications and patents each year. This review reports the state of the art in biosorption research. In this review, we provide a compendium of know-how in laboratory methodology, mathematical modeling of equilibrium and kinetics, identification of the biosorption mechanism. Various mathematical models of biosorption were discussed: the process in packed-bed column arrangement, as well as by suspended biomass. Particular attention was paid to patents in biosorption and pilot-scale systems. In addition, we provided future aspects in biosorption research. PMID- 23666642 TI - Antioxidant, anti-inflammatory, and hypoglycemic effects of the leaf extract from Passiflora nitida Kunth. AB - Diabetes mellitus is a metabolic disease characterized by abnormally high plasma glucose levels, leading to major complications, such as insulin resistance, obesity, hyperlipidemia, and hypertension, also with alterations in the immune and neuronal systems. Brazilian plants have been studied as important sources for new molecules with medicinal properties. The genus Passiflora known as "Maracuja" has been used as a traditional folk medicine for a long time, so an investigation was performed regarding an endemic kind of passion fruit (Passiflora nitida Kunth) from Amazonas, Brazil. Here, we aimed to determine its potential biological activity against metabolic syndrome, oxidative stress, pain, and inflammation. The hydroethanol leaf extract revealed an in vitro alpha glucosidase inhibitory activity of 50 % inhibitory concentration (IC50) = 6.78 +/ 0.31 MUg/mL and an alpha-amylase inhibition of IC50= 93.36 +/- 4.37. In vivo, experiments of different saccharide tolerance resulted in significant glycemia control and, with alloxan-diabetic mice, resulted in a decrease of total cholesterol, a hypoglycemic effect, and an antioxidant activity by thiobarbituric acid-reactive substances measurement. Also, it decreased the carrageenan-induced edema volume and the rate of writhing as a nociceptive response. These results indicate positive effects of P. nitida extract and its potential to inhibit metabolic syndrome. PMID- 23666643 TI - High relaxivities and strong vascular signal enhancement for NaGdF4 nanoparticles designed for dual MR/optical imaging. AB - Near-infrared (NIR)-to-NIR upconverting NaY(Gd)F4 :Tm(3+) ,Yb(3+) paramagnetic nanoparticles (NPs) are efficiently detected by NIR imaging techniques. As they contain Gd(3+) ions, they also provide efficient "positive" contrast in magnetic resonance imaging (MRI). Water-dispersible small (~25 nm, "S-") and ultrasmall (<5 nm diam., "US-") NaY(Gd)F4 :Tm(3+) ,Yb(3+) NPs are synthesized by thermal decomposition and capped with citrate. The surface of citrate-coated US-NPs shows sodium depletion and high Gd elemental ratios, as confirmed by a comparative X ray photoelectron spectroscopy (XPS)/neutron absorption analysis study. US NaGd0.745 F4 :Tm0.005 ,Yb0.25 NPs have hydrodynamic diameters close to that measured by TEM, with the lowest relaxometric ratios (r2 /r1 = 1.18) reported for NaGdF4 nanoparticle suspensions (r1 = 3.37 mM(-1) s(-1) at 1.4 T and 37 degrees C). Strong relaxivity peaks in the range of 20 (0.47 T) - 300 MHz (7.05 T) are revealed in nuclear magnetic resonance dispersion profiles, with high r2 /r1 ratios at increasing field strengths for S-NPs. This indicates the superiority of US-NPs over S-NPs for achieving high positive contrast at clinical MRI field strengths. I.-v. injected citrate-coated US-NPs evidence long blood retention times (>90 min) in mice. Biodistribution studies (48 h, 8 d) show elimination through the reticuloendothelial and urinary systems, similarly to other citrate capped US-NP systems. In summary, upconverting NaY(Gd)F4 :Tm(3+) ,Yb(3+) nanoparticles have promising luminescent, relaxometric and blood-retention properties for dual MRI/optical imaging. PMID- 23666644 TI - Formation of heteroepitaxy in different shapes of Au-CdSe metal-semiconductor hybrid nanostructures. AB - Formation of heteroepitaxy and designing different-shaped heterostructured nanomaterials of metal and semiconductor in solution remains a frontier area of research. However, it is evident that the synthesis of such materials is not straightforward and needs a selective approach to retain both metal and semiconductor identities in the reaction system during heterostructure formation. Herein, the epitaxial growth of semiconductor CdSe on selected facets of metal Au seeds is reported and different shapes (flower, tetrapod, and core/shell) hetero nanostructures are designed. These results are achieved by controlling the reaction parameters, and by changing the sequence and timing for introduction of different reactant precursors. Direct evidence of the formation of heteroepitaxy between {111} facets of Au and (0001) of wurtzite CdSe is observed during the formation of these three heterostructures. The mechanism of the evolution of these hetero-nanostructures and formation of their heteroepitaxy with the planes having minimum lattice mismatch are also discussed. This shape-control growth mechanism in hetero-nanostructures should be helpful to provide more information for establishing the fundamental study of heteroepitaxial growth for designing new nanomaterials. Such metal-semiconductor nanostructures may have great potential for nonlinear optical properties, in photovoltaic devices, and as chemical sensors. PMID- 23666645 TI - Internal reinstatement hides cuing effects in source memory tasks. AB - Reinstating source details at test often has no impact on source memory. We tested the proposition that participants internally reinstate source cues when such cues are not provided by the experimenter, thus making the external cues redundant. Participants studied words paired with either a male or a female face and were later asked to specify the gender of the face studied with each word. To disrupt the ability to internally reinstate sources, some participants saw eight male faces and eight female faces throughout the study list (multiple-face condition), making it difficult to determine which face should be internally reinstated for uncued test trials. Other participants saw only a single face for each gender (single-face condition), which should facilitate internal reinstatement. Across three experiments, participants in the multiple-face condition showed improved source discrimination when the studied faces were reinstated at test, as compared to uncued trials. In contrast, participants in the single-face condition showed no effect of the face cues. Moreover, the cuing effect for the multiple-face condition disappeared when the test structure facilitated internal reinstatement. Overall, the experiments support the contention that internal reinstatement is a natural part of source retrieval that can mask the effects of external cues. PMID- 23666646 TI - Metabolomics and protozoan parasites. AB - In this review, we examine the state-of-the-art technologies (gas and liquid chromatography, mass spectroscopy and nuclear magnetic resonance, etc.) in the well-established area of metabolomics especially as they relate to protozoan parasites. PMID- 23666647 TI - PCR amplification and DNA sequence analysis of parasitic intestinal protozoa in specimens stained with Chlorazol Black E. AB - Chlorazol Black E (CBE) stain has been used for the detection and identification of intestinal parasitic protozoa. In recent years, genotyping of protozoa has been performed to examine pathogenicity and for epidemiologic analysis. In this study, protozoan DNA was amplified from preserved human fecal specimens stained with CBE that were positive for Giardia intestinalis (syn. G. lamblia and G. duodenalis), Chilomastix mesnili, Pentatrichomonas hominis, and Entamoeba histolytica. DNA was amplified from 11 of the 12 (91.6%) samples examined. DNA from CBE-stained smears of G. intestinalis, E. histolytica, and P. hominis was amplified, whereas any amplification product could not be obtained from one of three smears of C. mesnili. Storage term and protozoan number had no association with results of PCR amplification. In genotyping of G. intestinalis, four out of six (66.7%) samples were of genotype AI, while the remaining two (33.3%) samples were of genotype B. The amplified DNA sequences showed high similarity (>99%) with that of G. intestinalis in the GenBank database. These results suggest that DNA remains stable in CBE-stained smears for long term. The present study demonstrates that nuclear extracts from specimens stained with CBE can be amplified by PCR and suggests that specimens stored for extended periods could be applied to genetic and prospective epidemiologic analyses. PMID- 23666648 TI - Microsatellite loci-based distribution of Trypanosoma cruzi genotypes from Chilean chronic Chagas disease patients and Triatoma infestans is concordant with a specific host-parasite association hypothesis. AB - The objective of this study was to investigate if there is specific host-parasite association in Chilean populations of Trypanosoma cruzi. For this purpose, two groups of parasites were analyzed, one from chronic chagasic patients, and the other from Triatoma infestans triatomines in three regions of the country. The first group consisted of four types of samples: parasites from peripheral blood of non-cardiopathic T. cruzi infected patients (NB); parasites from their corresponding xenodiagnosis (NX); parasites from peripheral blood of T. cruzi infected cardiopathic patients (CB) and parasites from their xenodiagnostics (CX). The T. infestans sample in turn was from three regions: III, V and M (Metropolitan). The genetic differentiation by the Fisher exact method, the lineage distribution of the samples, the molecular phylogeny and the frequency of multiclonality were analysed. The results show that not only are the groups of T. cruzi clones from Chagas disease patients and vectors genetically differentiated, but also all the sub-groups (NB, NX, CB and CX) from the III, V and M regions. The analysis of lineage distribution was concordant with the above results, because significant differences among the percentages of TcI, TcIII and hybrids (TcV or TcVI) were observed. The phylogenetic reconstruction with these Chilean T. cruzi samples was coherent with the above results because the four chagasic samples clustered together in a node with high bootstrap support, whereas the three triatomine samples (III, V and M) were located apart from that node. The topology of the tree including published T. cruzi clones and isolates was concordant with the known topology, which confirmed that the results presented here are correct and are not biased by experimental error. Taken together the results presented here are concordant with a specific host-parasite association between some Chilean T. cruzi populations. PMID- 23666649 TI - First report of Trichinella pseudospiralis in Poland, in red foxes (Vulpes vulpes). AB - Nematode worms of the genus Trichinella are one of the most widespread zoonotic pathogens. Natural transmission between hosts can only occur through the ingestion of infected meat. To date, two Trichinella species are known to be etiological agents of disease among domestic animals and wildlife in Poland: T. spiralis and T. britovi. In the last decades, since the administration of an oral vaccination against rabies, the red fox population in Poland has increased exponentially. The study area covers the Nowy Targ region: a mountainous area (585-1138 m above the sea) in southern Poland. Of 24 red foxes examined in the study, four were infected with Trichinella isolates: three were identified as T. britovi and one as T. pseudospiralis. The muscle of red foxes infected with T. britovi harboured 2.75, 3.11, 4.4 LPG and with T. pseudospiralis 0.36 LPG. Trichinella larvae were identified at species level by genomic and mitochondrial multiplex PCR, the products of which were sequenced for comparison with other sequences available in GenBank. The sequences obtained from the Polish T. pseudospiralis isolate, deposited in GenBank under the accession numbers JQ809660.1 and JQ809661.1, matched sequences already published in GenBank. Sequence comparison showed a 100% match with the large subunit ribosomal RNA gene of T. pseudospiralis isolate ISS 013, and a 96-95% match with those of T. pseudospiralis isolates ISS 141 and ISS 470. This is the first report of the identification of T. pseudospiralis larvae from red fox in Poland. PMID- 23666650 TI - Spatio-temporal variation in the prevalence of trematodes in the bivalve Perumytilus purpuratus. AB - Perumytilus purpuratus is an abundant bivalve located in the intertidal rocky zone of South America that has been considered as a key species of the ecosystem. There are few studies of the host-parasite relationship of this bivalve; thus, this research aims to analyse the spatial and temporal variation in the prevalence of trematodes in P. purpuratus. Bivalves were collected from three localities (El Tabo, Las Cruces and Montemar) of central Chile (33 degrees S, 71 degrees W) during different seasons of 2010. The bivalves were also collected every metre, from the lowest to the highest level of the intertidal rocky zone, to determine the parasite distribution within the localities. Three species of trematodes as sporocyst stages were found: Prosorhynchoides carvajali, Proctoeces sp. and an undetermined fellodistomid species. Of the 37,692 bivalve specimens collected, 2.68% were parasitised. The undetermined fellodistomid species was the most prevalent parasite observed (1.69%). There were little detected differences in the prevalence of some trematode species between seasons. The prevalence of P. carvajali varied between localities, being most prevalent at Montemar. The distribution of trematodes along the rocky zone within the localities was variable, with P. carvajali being more prevalent in the mid-lowest level of the intertidal zone and the undetermined fellodistomid species being more prevalent in the mid-highest level. Both the abundance of definitive hosts and the environmental conditions likely result in different levels of infection by trematodes in P. purpuratus between and within the localities. PMID- 23666651 TI - Phylogenetic analysis of the genus Cylicocyclus (Nematoda: Strongylidae) based on nuclear ribosomal sequence data. AB - Seven species of Cylicocyclus Ihle, 1922 (Nematoda: Strongylidae) were collected from donkeys from Henan Province, China. Five samples of each species were selected for sequencing. Sixteen different internal transcribed spacer (ITS) sequences representing the seven species of Cylicocyclus were obtained. Sequence differences in the first internal transcribed spacer (ITS-1) among species was lower than that of the second internal transcribed spacer (ITS-2). Phylogenetic analyses were conducted using the combined ITS-1 and ITS-2 data sets from the present study and using reference sequences from the GenBank database. The MP and ML trees were similar in topology. The phylogenetic trees were divided into two clades. Clade I included 8 species of Cylicocyclus; within this group, Cylicocyclus leptostomus (Kotlan, 1920) is nested between different samples of Cylicocyclus ashworthi (LeRoux, 1924), suggesting C. ashworthi may represent a species complex. Clade II included Cylicocyclus elongatus (Looss, 1900) and Cylicocyclus ultrajectinus (Ihle, 1920); however, these two species always clustered with the comparative species (Petrovinema poculatum (Looss, 1900) and Poteriostomum imparidentatum Quiel, 1919), suggesting that C. elongatus and C. ultrajectinus represent members of other genera. PMID- 23666652 TI - Prevalence, mean intensity of infestation and host specificity of Spinturnicidae mites (Acari: Mesostigmata) on bats (Mammalia: Chiroptera) in the Pantanal, Brazil. AB - Acari ectoparasites were collected from bats during 12 months in the Rio Negro farm (19 degrees 34'22"S and 56 degrees 14'36"W), Aquidauana, Mato Grosso do Sul. A total of 654 bats belonging to the families Phyllostomidae, Noctilionidae, Molossidae, Vespertilionidae and Emballonuridae were captured. Only 136 bats of nine genera and 11 species were parasitised. Periglischrus iheringi Oudemans was the most abundant mite species, and this prevalence may be related to the low degree of host specificity of this species and due to the broad geographical distribution of its hosts. The greatest mean intensity was found to Periglischrus torrealbai Machado-Allison on Phyllostomus discolor Wagner (Phyllostomidae) and Periglischrus tonatii Herrin and Tipton associated with Lophostoma silviculum d'Orbigny (Phyllostomidae), which also had the highest prevalence of infestation. PMID- 23666653 TI - Variation in ectoparasite load in the Mehely's horseshoe bat, Rhinolophus mehelyi (Chiroptera: Rhinolophidae) in a nursery colony in western Iran. AB - We studied variation of ectoparasite load in a free ranging populations of Mehely's horseshoe bat (Rhinolophus mehelyi) on five successive occasions in a nursery roost in western Iran. In total, 87 Rhinolophus mehelyi were captured. The patterns of abundance differed greatly among parasite species but total parasite load was markedly higher in pregnant females in spring and early summer and lower in solitary males. On average, 90% of bats were infested by Eyndhovenia sp. with a mean intensity of 13.79 individuals per bat. Penicillidia sp. and one species from Streblidae were found in 66.7% and 11.49% of bats with parasite load of 2.31 and 1.8 parasite per bat, respectively. Using ratio of forearm length to body mass as an indication of bat health the correlation coefficient between parasite load and the health indicator was 0.002 for males and 0.06 for females indicating that parasite load has no apparent impact on bat's health. PMID- 23666654 TI - Differential detection of Entamoeba histolytica, Entamoeba dispar and Entamoeba moshkovskii in fecal samples by nested PCR in the United Arab Emirates (UAE). AB - Amoebiasis is one of the most important infectious diseases afflicting mainly tropical and subtropical countries. This study was carried out in the Sharjah Emirate, UAE in order to accurately detect and differentiate Entamoeba histolytica, Entamoeba dispar and E. moshkovskii in fecal samples collected from the Sharjah municipality public health clinic by ELISA and nested polymerase chain reaction (PCR). One hundred and twenty specimens were examined and the PCR was positive for E. histolytica, E. dispar and E. moshkovskii (collectively referred to as Entamoeba complex) in 19.2% (23 out of 120). Of those, 10% (12/120) were mono - infection with E. histolytica; 2.5% (3/120) with E. dispar; and 2.5% (3/120) E. moshkovskii. The nested PCR also detected mixed infections by both E. histolytica and E. dispar in 3.3% (4/120) and E. dispar and E. moshkovskii in 0.8% (1/120). The TechLab ELISA kit failed to detect E. histolytica in any of the E. histolytica PCR positive samples. Overall, the percentage of E. histolytica including those found in mixed infections was 13.3% (16/120). Compared to nested PCR, microscopy was found to have an overall sensitivity of 52.2% and a specificity of 75.2% for detection of Entamoeba complex. The present study indicates that E. histolytica is present in the UAE with an average incidence rate of 13.3%. However, larger studies need to be conducted in order to confirm these findings. We propose the use of PCR in both the routine diagnosis of amoebiasis and epidemiological survey in the UAE. PMID- 23666655 TI - Parasitic infections of the African dwarf crocodile (Osteolaemus tetraspis) and the ornate Nile monitor (Varanus ornatus) from Nigeria. AB - The parasitic infections of market derived Osteolaemus tetraspis from the rainforest and Varanus ornatus from locations in the savanna-mosaic and the rainforest of southern Nigeria were investigated. Parasites recovered from O. tetraspis included members of the Pentastomida, Trematoda and Nematoda. An undescribed pentastomid belonging to the family Sebekidae was recovered from O. tetraspis. The same parasite was also found to parasitize V. ornatus from the rainforest. Other parasites found in O. tetraspis were Pseudoneodiplostomum thomasi, Dujardinascaris sp. and larva of a Camallanus sp. Varanus ornatus from the rainforest and the derived savanna had some parasites including Duthiersia fimbriata, an unidentified pseudophyllidean cestode and Tanqua tiara in common. Cosmocerca ornata and Oswaldocruzia hoepplii were restricted to hosts from the derived savanna while the unidentified trematode occurred only in lizards from the rainforest. The unidentified pseudophyllidean cestode bears a close resemblance to Probothriocephalus, a cestode previously reported only from deep water teleosts. Pseudoneodiplostomum thomasi and Duthiersia fimbriata are new locality records for Nigeria. PMID- 23666656 TI - Evaluation of the immune response of male and female rats vaccinated with cDNA encoding a cysteine proteinase of Fasciola hepatica (FhPcW1). AB - Not only do males and females of many species vary in their responses to certain parasitic infections, but also to treatments such as vaccines. However, there are very few studies investigating differences among sexes following vaccination and infection. Here we demonstrate that female Sprague-Dawley rats vaccinated with cDNA encoding a recently discovered cysteine proteinase of Fasciola hepatica (FhPcW1) develop considerably lower liver fluke burdens after F. hepatica infection than their male counterparts. This is accompanied by differences in the course of their immune responses which involve different eosinophil and monocyte responses throughout the study as well as humoral responses. It is evident that host gender influences the outcome of parasitic infections after vaccination and research on both sexes should be considered when developing new treatments against parasites. PMID- 23666657 TI - Parasitism of ectoparasitic flies on bats in the northern Brazilian cerrado. AB - In this work we record the highest number of bat flies species among those already performed in the Brazilian cerrado and discuss the associations and patterns of parasitism of these species and their hosts. A total of 1,390 ectoparasitic flies were collected, belonging to 24 species of Streblidae and one of Nycteribiidae, parasitizing 227 bats of 15 species. Among the species found, the presence of Trichobius sp. on Lonchophylla mordax and the first occurrence of Hershkovitzia sp. on Thyroptera devivoi are highlighted. Lophostoma species presented the highest proportion of individuals with infracommunities and the highest values of parasitological indexes. The high number of bat fly species and hosts, as well as the high values for rates of parasitism and infracommunities, suggests that this area of cerrado has good shelter conditions for these species. The abundance of species and high rates of parasitism detracts from the hypothesis that a higher mean intensity of ectoparasites results from lower competition among flies for hosts in areas with lower ectoparasite species richness. Biogeographical and historical factors of host populations, besides the number of host species and individuals sampled, may contribute to species number and intensity of parasitism. PMID- 23666658 TI - Excretory/secretory products of Fasciola hepatica but not recombinant phosphoglycerate kinase induce death of human hepatocyte cells. AB - The liver fluke Fasciola hepatica infects a wide range of hosts, and has a considerable impact on the agriculture industry, mainly through infections of sheep and cattle. Further, human infection is now considered of public health importance and is hyperendemic in some regions. The fluke infection causes considerable damage to the hosts' liver. However, the mechanisms of liver destruction have not yet been completely elucidated. In the present report we incubated a human liver cell line in the presence of either F. hepatica excretory/secretory material (FhES) or recombinant phosphoglycerate kinase (FhPGK). Dosedependent cytotoxicity in the presence of FhES was observed, indicating that FhES is capable of killing human hepatocytes, supporting a role for FhES in damaging host liver cells during infection; while treatment with a recombinant intracellular protein - FhPGK, had no impact on cell survival. PMID- 23666659 TI - Detection of Theileria equi in spleen and blood of asymptomatic piroplasm carrier horses. AB - This study aimed to determine whether asymptomatic horses naturally infected with Theileria equi retain infected erythrocytes in the spleen and whether the presence of the hemoparasite in this organ is associated with parasitemia. We collected samples from 25 adult horses without clinical signs of any disease. From each animal, we collected whole blood samples from the jugular vein and a splenic puncture blood sample. All samples were submited to blood cell counts and detection of Theileria or Babesia. DNA extraction and PCR were performed in all samples for identification of piroplasm infection (T. equi and B. caballi). From the 25 horses evaluated for piroplasm detection by PCR, seven horses (28%) were positive in jugular vein blood but negative in splenic blood samples, five horses (20%) were positive in splenic blood samples but negative in jugular vein blood samples, and 13 horses (52%) were positive in both jugular vein and splenic blood samples. The hematological evaluation revealed anemia in 13 of 25 (52%) infected horses, lymphopenia in five (20%), neutrophilia in two (8%), neutropenia in one (4%), and thrombocytopenia in one (4%) infected horse. The present study demonstrated that several (20%) of the asymptomatic piroplasm carrier horses did not show parasitemia, but show infected erythrocytes in the spleen. PMID- 23666660 TI - Massive parasitism by Gussevia tucunarense (Platyhelminthes: Monogenea: Dactylogyridae) in fingerlings of bujurqui-tucunare cultured in the Peruvian Amazon. AB - A high infestation of the monogenean Gussevia tucunarense in a cultivation of bujurqui-tucunare was reported. The prevalence was 100%. The mean intensity and abundance of the parasite was 164.4 of parasites per individual. This is the first report of a high infestation by G. tucunarense in C. semifasciatus cultured from the Peruvian Amazon. PMID- 23666661 TI - Molecular characterization of kudoid parasites (Myxozoa: Multivalvulida) from somatic muscles of Pacific bluefin (Thunnus orientalis) and yellowfin (T. albacores) tuna. AB - The public health importance of Kudoa infection in fish remains unclear. Recently in Japan a Kudoa species, K. septempunctata, was newly implicated as a causative agent of unidentified food poisoning related to the consumption of raw olive flounder. Other marine fishery products are also suspected as causative raw foods of unidentified food poisoning. For this study, we detected kudoid parasites from sliced raw muscle tissues of a young Pacific bluefin and an adult yellowfin tuna. No cyst or pseudocyst was evident in muscles macroscopically, but pseudocysts were detected in both samples histologically. One substitution (within 1100 bp overlap) and ten substitutions (within 753 bp overlap) were found respectively between the partial sequences of 18S and 28S rDNAs from both isolates. Nucleotide sequence similarity searching of 18S and 28S rDNAs from both isolates showed the highest identity with those of K. neothunni from tuna. Based on the spore morphology, the mode of parasitism, and the nucleotide sequence similarity, these isolates from a Pacific bluefin and a yellowfin tuna were identified as K. neothunni. Phylogenetic analysis of the 28S rDNA sequence revealed that K. neothunni is classifiable into two genotypes: one from Pacific bluefin and the other from yellowfin tuna. Recently, an unidentified kudoid parasite morphologically and genetically similar K. neothunni were detected from stocked tuna samples in unidentified food poisoning cases in Japan. The possibility exists that K. neothunni, especially from the Pacific bluefin tuna, causes food poisoning, as does K. septempunctata. PMID- 23666662 TI - Human adenovirus detection among immunocompetent and immunocompromised patients presenting acute respiratory infection. AB - INTRODUCTION: Human adenoviruses (HAdV) play an important role in the aetiology of severe acute lower respiratory infection, especially in immunocompromised individuals. The aim of the present study was to detect HAdV using two different methods, direct fluorescence assay (DFA) and nested polymerase chain reaction (nested PCR), in samples collected from patients with acute groups from 2001 to 2010: 139 adult emergency room patients (ERP); 205 health care workers (HCW); 69 renal transplant outpatients(RTO); and 230 patients in a haematopoietic stem cell transplantation program (HSCT). RESULTS: Adenovirus was detected in 13.2% of the 643 patients tested by DFA and/or PCR: 6/139 (4.3%) adults in the ERP group, 7/205 (3.4%) in the HCW group, 4/69 (5.8%) in the RTO group and 68/230 (29.5%) in the HSCT patient group. Nested PCR had a higher detection rate (10%) compared with the DFA test (3.8%) (p<0.001). HSCT patients exhibited a significantly higher rate of HAdV infection. CONCLUSIONS: The adenovirus detection rate of the nested PCR assay was higher than that of the DFA test. However, the use of molecular methods in routine diagnostic laboratory work should be evaluated based on the specific circumstances of individual health services. PMID- 23666663 TI - Human immunodeficiency virus/Leishmania infantum in the first foci of urban American visceral leishmaniasis: clinical presentation from 1994 to 2010. AB - INTRODUCTION: Human immunodeficiency virus (HIV) coinfection with Leishmania infantum or Leishmania donovani, the agents of visceral leishmaniasis (or kala azar), has become a fatal public health problem in the tropics where kala-azar is endemic. METHODS: The clinical presentation of patients with HIV and L. infantum coinfection is described using two unique databases that together produce the largest case series of patients with kala-azar infected with HIV in South America. First, a retrospective study paired the list of all patients with kala azar from 1994 to 2004 with another of all patients with HIV/AIDS from the reference hospital for both diseases in the City of Teresina, State of Piaui, Brazil. Beginning in 2005 through to 2010 this information was prospectively collected at the moment of hospitalization. RESULTS: During the study, 256 admissions related to 224 patients with HIV/L. infantum coinfection were registered and most of them were males between 20-40 years of age. Most of the 224 patients were males between 20-40 years of age. HIV contraction was principally sexual. The most common symptoms and signs were pallor, fever, asthenia and hepatosplenomegaly. 16.8% of the cohort died. The primary risk factors associated to death were kidney or respiratory failure, somnolence, hemorrhagic manifestations and a syndrome of systemic inflammation. The diagnosis of HIV and kala-azar was made simultaneously in 124 patients. CONCLUSIONS: The urban association between HIV and kala-azar coinfection in South America is worrisome due to difficulty in establishing the diagnosis and higher mortality among the coinfected then those with either disease independently. HIV/L. infantum coinfection exhibits some singular characteristics and due to its higher mortality it requires immediate assistance to patients and greater research on appropriate combination therapy. PMID- 23666664 TI - Vascular malformation as a cause of limp in a child. PMID- 23666666 TI - Development of IgG4-related disease 10 years after chemotherapy for diffuse large B cell lymphoma and longstanding bronchial asthma. AB - Reported is a rare case IgG4-related disease that developed 10 years after combination chemotherapy for non-Hodgkin lymphoma. A 59-year-old Japanese man with longstanding bronchial asthma was referred to our hospital for bilateral hilar lymph node enlargement. The initial diagnosis was diffuse large B cell lymphoma (DLBCL) by supraclavicular lymph node biopsy. Serum IgG was high (4550 mg/dL) at diagnosis. The patient achieved complete response following six cycles of combination chemotherapy. Ten years later, bilateral submaxillary gland swelling was observed. Serum IgG and IgG4 were 2909 and 1470 mg/dL, respectively. The patient was diagnosed with IgG4-related disease by submandibular lymph node biopsy. Due to the difficulty in distinguishing IgG4-related disease from DLBCL through imaging findings alone, pathological confirmation of such lesions by biopsy is mandatory before proceeding to treatment. PMID- 23666665 TI - Nanocomposite hydrogels for cartilage tissue engineering: mesoporous silica nanofibers interlinked with siloxane derived polysaccharide. AB - Injectable materials for mini-invasive surgery of cartilage are synthesized and thoroughly studied. The concept of these hybrid materials is based on providing high enough mechanical performances along with a good medium for chondrocytes proliferation. The unusual nanocomposite hydrogels presented herein are based on siloxane derived hydroxypropylmethylcellulose (Si-HPMC) interlinked with mesoporous silica nanofibers. The mandatory homogeneity of the nanocomposites is checked by fluorescent methods, which show that the silica nanofibres dispersion is realized down to nanometric scale, suggesting an efficient immobilization of the silica nanofibres onto the Si-HPMC scaffold. Such dispersion and immobilization are reached thanks to the chemical affinity between the hydrophilic silica nanofibers and the pendant silanolate groups of the Si-HPMC chains. Tuning the amount of nanocharges allows tuning the resulting mechanical features of these injectable biocompatible hybrid hydrogels. hASC stem cells and SW1353 chondrocytic cells viability is checked within the nanocomposite hydrogels up to 3 wt% of silica nanofibers. PMID- 23666667 TI - Guest editorial: efficacy of and resistance to molecularly targeted therapy for myeloid malignancies. PMID- 23666668 TI - Gestalt-binding of tropomyosin on actin during thin filament activation. AB - Our thesis is that thin filament function can only be fully understood and muscle regulation then elucidated if atomic structures of the thin filament are available to reveal the positions of tropomyosin on actin in all physiological states. After all, it is tropomyosin influenced by troponin that regulates myosin crossbridge cycling on actin and therefore controls contraction in all muscles. In addition, we maintain that a complete appreciation of thin filament activation also requires that the mechanical properties of tropomyosin itself are recognized and then related to the effect of myosin-association on actin. Taking the Gestalt binding of tropomyosin into account, coupled with our electron microscopy structures and computational chemistry, we propose a comprehensive mechanism for tropomyosin regulatory movement over the actin filament surface that explains the cooperative muscle activation process. In fact, well-known point mutations of critical amino acids on the actin-tropomyosin binding interface disrupt Gestalt binding and are associated with a number of inherited myopathies. Moreover, dysregulation of tropomyosin may also be a factor that interferes with the gatekeeping operation of non-muscle tropomyosin in the controlling interactions of a wide variety of cellular actin-binding proteins. The clinical relevance of Gestalt-binding is discussed in articles by the Marston and the Gunning groups in this special journal issue devoted to the impact of tropomyosin on biological systems. PMID- 23666669 TI - The otolaryngology hospitalist: a novel practice paradigm. AB - OBJECTIVES/HYPOTHESIS: To define a new clinical hospitalist practice paradigm originating at the University of California, San Francisco. DESIGN: Retrospective administrative database review at a tertiary referral hospital. MATERIALS AND METHODS: A consortium model of an otolaryngologist hospitalist practice was developed. Billing records, including Current Procedural Terminology (CPT) and International Classification of Disease-9 (ICD-9) codes, were reviewed to evaluate the number and type of consultations and surgeries generated during a 2 year period. RESULTS: A total of 375 new inpatient consultations generated 951 patient encounters. The most common diagnoses were respiratory failure (12%), sinusitis (10.6%), stridor (10.6%), and dysphonia (7.6%). Twenty-six percent of consultations involved a procedure or surgical intervention, the most common of which were endoscopic sinus surgery, laryngoscopy, and tracheotomy. CONCLUSIONS: To our knowledge, ours is the first full-time otolaryngology hospitalist model in the United States. The hospitalist practice is a conceptually viable and clinically beneficial paradigm that should be considered at other similar institutions. PMID- 23666670 TI - Inhibition of alpha-adrenergic tone disturbs the distribution of blood flow in the exercising human limb. AB - The role of neuronal regulation of human cardiovascular function remains incompletely elucidated, especially during exercise. Here we, by positron emission tomography, monitored tissue-specific blood flow (BF) changes in nine healthy young men during femoral arterial infusions of norepinephrine (NE) and phentolamine. At rest, the alpha-adrenoceptor agonist NE reduced BF by ~40%, similarly in muscles (from 3.2 +/- 1.9 to 1.4 +/- 0.3 ml.min(-1).100 g(-1) in quadriceps femoris muscle), bone (from 1.1 +/- 0.4 to 0.5 +/- 0.2 ml.min(-1).100 g(-1)) and adipose tissue (AT) (from 1.2 +/- 0.7 to 0.7 +/- 0.3 ml.min(-1).100 g( 1)). During exercise, NE reduced exercising muscle BF by ~16%. BF in AT was reduced similarly as rest. The alpha-adrenoceptor antagonist phentolamine increased BF similarly in the different muscles and other tissues of the limb at rest. During exercise, BF in inactive muscle was increased 3.4-fold by phentolamine compared with exercise without drug, but BF in exercising muscles was not influenced. Bone and AT (P = 0.055) BF were also increased by phentolamine in the exercise condition. NE increased and phentolamine decreased oxygen extraction in the limb during exercise. We conclude that inhibition of alpha-adrenergic tone markedly disturbs the distribution of BF and oxygen extraction in the exercising human limb by increasing BF especially around inactive muscle fibers. Moreover, although marked functional sympatholysis also occurs during exercise, the arterial NE infusion that mimics the exaggerated sympathetic nerve activity commonly seen in patients with cardiovascular disease was still capable of directly limiting BF in the exercising leg muscles. PMID- 23666671 TI - Cardiac hypertrophy associated with impaired regulation of cardiac ryanodine receptor by calmodulin and S100A1. AB - The cardiac ryanodine receptor (RyR2) is inhibited by calmodulin (CaM) and S100A1. Simultaneous substitution of three amino acid residues (W3587A, L3591D, F3603A; RyR2ADA) in the CaM binding domain of RyR2 results in loss of CaM inhibition at submicromolar (diastolic) and micromolar (systolic) Ca2+, cardiac hypertrophy, and heart failure in Ryr2ADA/ADA mice. To address whether cardiac hypertrophy results from the elimination of CaM and S100A1 inhibition at diastolic or systolic Ca2+, a mutant mouse was generated with a single RyR2 amino acid substitution (L3591D; RyR2D). Here we report that in single-channel measurements RyR2-L3591D isolated from Ryr2D/D hearts lost CaM inhibition at diastolic Ca2+ only, whereas S100A1 regulation was eliminated at both diastolic and systolic Ca2+. In contrast to the ~2-wk life span of Ryr2ADA/ADA mice, Ryr2D/D mice lived longer than 1 yr. Six-month-old Ryr2D/D mice showed a 9% increase in heart weight-to-body weight ratio, modest changes in cardiac morphology, and a twofold increase in atrial natriuretic peptide mRNA levels compared with wild type. After 4-wk pressure overload with transverse aortic constriction, heart weight-to-body weight ratio and atrial natriuretic peptide mRNA levels increased and echocardiography showed changes in heart morphology of Ryr2D/D mice compared with sham-operated mice. Collectively, the findings indicate that the single RyR2-L3591D mutation, which distinguishes the effects of diastolic and systolic Ca2+, alters heart size and cardiac function to a lesser extent in Ryr2D/D mice than the triple mutation in Ryr2ADA/ADA mice. They further suggest that CaM inhibition of RyR2 at systolic Ca2+ is important for maintaining normal cardiac function. PMID- 23666672 TI - Adaptation of mesenteric lymphatic vessels to prolonged changes in transmural pressure. AB - In vitro studies have revealed that acute increases in transmural pressure increase lymphatic vessel contractile function. However, adaptive responses to prolonged changes in transmural pressure in vivo have not been reported. Therefore, we developed a novel bovine mesenteric lymphatic partial constriction model to test the hypothesis that lymphatic vessels exposed to higher transmural pressures adapt functionally to become stronger pumps than vessels exposed to lower transmural pressures. Postnodal mesenteric lymphatic vessels were partially constricted for 3 days. On postoperative day 3, constricted vessels were isolated, and divided into upstream (UP) and downstream (DN) segment groups, and instrumented in an isolated bath. Although there were no differences between the passive diameters of the two groups, both diastolic diameter and systolic diameter were significantly larger in the UP group than in the DN group. The pump index of the UP group was also higher than that in the DN group. In conclusion, this is the first work to report how lymphatic vessels adapt to prolonged changes in transmural pressure in vivo. Our results suggest that vessel segments upstream of the constriction adapt to become both better fluid conduits and lymphatic pumps than downstream segments. PMID- 23666673 TI - Sexual dimorphism in obesity-mediated left ventricular hypertrophy. AB - In the present study we investigated the influence of sex difference on the development of left ventricular hypertrophy (LVH) during obesity. Male and female C57BL/6J mice were fed for 15 and 25 wk with a high-fat diet (HFD) or low-fat control diet (LFD). Analysis of body composition, monitoring of body weight (BW), and echocardiographic analysis were performed, as well as analysis of expression of different adipocytokines in epicardial adipose tissue. The increment in left ventricular mass (LVM) after HFD (25 wk) was significantly stronger in male mice compared with female mice [LVM: male, 116.9 +/- 2.9 (LFD) vs. 142.2 +/- 9.3 mg (HFD); female, 84.3 +/- 3.3 (LFD) vs. 93.9 +/- 1.7 mg (HFD), Psex < 0.01]. In parallel, males developed a higher BW and fat mass after 25 wk HFD than female mice [BW: male, 33 +/- 0.9 (LFD) vs. 53 +/- 0.8 g (HFD); fat mass: male, 8.8 +/- 0.9 (LFD) vs. 22.8 +/- 0.7 g (HFD); BW: female, 22.5 +/- 0.4 (LFD) vs. 33.7 +/- 1.3 g (HFD); fat mass: female, 4.0 +/- 0.2 (LFD) vs. 13.2 +/- 1.2 g (HFD)] (P < 0.01 for BW+ fat mass female vs. male). The mRNA expression of adipocytokines in epicardial fat after 25 wk of diet showed higher levels of adiponectin (2.8 fold), leptin (4.2-fold), and vaspin (11.9-fold) in male mice compared with female mice (P < 0.05). To identify new adipose-derived molecular mediators of LVH, we further elucidated the cardiac impact of vaspin. Murine primary cardiac fibroblast proliferation was significantly induced by vaspin (1.8-fold, vaspin 1 MUg/l, P < 0.05 vs. control) compared with 1.9-fold induction by angiotensin II (10 MUM). The present study demonstrates a sex-dependent regulation of diet induced LVH associated with sexual dimorphic expression of adipocytokines in epicardial adipose tissue. PMID- 23666674 TI - Impaired contractile function due to decreased cardiac myosin binding protein C content in the sarcomere. AB - Mutations in cardiac myosin binding protein C (MyBP-C) are a common cause of familial hypertrophic cardiomyopathy (FHC). The majority of MyBP-C mutations are expected to reduce MyBP-C expression; however, the consequences of MyBP-C deficiency on the regulation of myofilament function, Ca2+ homeostasis, and in vivo cardiac function are unknown. To elucidate the effects of decreased MyBP-C expression on cardiac function, we employed MyBP-C heterozygous null (MyBP-C+/-) mice presenting decreases in MyBP-C expression (32%) similar to those of FHC patients carrying MyBP-C mutations. The levels of MyBP-C phosphorylation were reduced 53% in MyBP-C+/- hearts compared with wild-type hearts. Skinned myocardium isolated from MyBP-C+/- hearts displayed decreased cross-bridge stiffness at half-maximal Ca2+ activations, increased steady-state force generation, and accelerated rates of cross-bridge recruitment at low Ca2+ activations (<15% and <25% of maximum, respectively). Protein kinase A treatment abolished basal differences in rates of cross-bridge recruitment between MyBP-C+/ and wild-type myocardium. Intact ventricular myocytes from MyBP-C+/- hearts displayed abnormal sarcomere shortening but unchanged Ca2+ transient kinetics. Despite a lack of left ventricular hypertrophy, MyBP-C+/- hearts exhibited elevated end-diastolic pressure and decreased peak rate of LV pressure rise, which was normalized following dobutamine infusion. Furthermore, electrocardiogram recordings in conscious MyBP-C+/- mice revealed prolonged QRS and QT intervals, which are known risk factors for cardiac arrhythmia. Collectively, our data show that reduced MyBP-C expression and phosphorylation in the sarcomere result in myofilament dysfunction, contributing to contractile dysfunction that precedes compensatory adaptations in Ca2+ handling, and chamber remodeling. Perturbations in mechanical and electrical activity in MyBP-C+/- mice could increase their susceptibility to cardiac dysfunction and arrhythmia. PMID- 23666676 TI - Myofiber prestretch magnitude determines regional systolic function during ectopic activation in the tachycardia-induced failing canine heart. AB - Electrical dyssynchrony leads to prestretch in late-activated regions and alters the sequence of mechanical contraction, although prestretch and its mechanisms are not well defined in the failing heart. We hypothesized that in heart failure, fiber prestretch magnitude increases with the amount of early-activated tissue and results in increased end-systolic strains, possibly due to length-dependent muscle properties. In five failing dog hearts with scars, three-dimensional strains were measured at the anterolateral left ventricle (LV). Prestretch magnitude was varied via ventricular pacing at increasing distances from the measurement site and was found to increase with activation time at various wall depths. At the subepicardium, prestretch magnitude positively correlated with the amount of early-activated tissue. At the subendocardium, local end-systolic strains (fiber shortening, radial wall thickening) increased proportionally to prestretch magnitude, resulting in greater mean strain values in late-activated compared with early-activated tissue. Increased fiber strains at end systole were accompanied by increases in preejection fiber strain, shortening duration, and the onset of fiber relengthening, which were all positively correlated with local activation time. In a dog-specific computational failing heart model, removal of length and velocity dependence on active fiber stress generation, both separately and together, alter the correlations between local electrical activation time and timing of fiber strains but do not primarily account for these relationships. PMID- 23666675 TI - Age-related telomere uncapping is associated with cellular senescence and inflammation independent of telomere shortening in human arteries. AB - Arterial telomere dysfunction may contribute to chronic arterial inflammation by inducing cellular senescence and subsequent senescence-associated inflammation. Although telomere shortening has been associated with arterial aging in humans, age-related telomere uncapping has not been described in non-cultured human tissues and may have substantial prognostic value. In skeletal muscle feed arteries from 104 younger, middle-aged, and older adults, we assessed the potential role of age-related telomere uncapping in arterial inflammation. Telomere uncapping, measured by p-histone gamma-H2A.X (ser139) localized to telomeres (chromatin immunoprecipitation; ChIP), and telomeric repeat binding factor 2 bound to telomeres (ChIP) was greater in arteries from older adults compared with those from younger adults. There was greater tumor suppressor protein p53 (P53)/cyclin-dependent kinase inhibitor 1A (P21)-induced senescence, measured by P53 bound to P21 gene promoter (ChIP), and greater expression of P21, interleukin 8, and monocyte chemotactic protein 1 mRNA (RT-PCR) in arteries from older adults compared with younger adults. Telomere uncapping was a highly influential covariate for the age-group difference in P53/P21-induced senescence. Despite progressive age-related telomere shortening in human arteries, mean telomere length was not associated with telomere uncapping or P53/P21-induced senescence. Collectively, these findings demonstrate that advancing age is associated with greater telomere uncapping in arteries, which is linked to P53/P21-induced senescence independent of telomere shortening. PMID- 23666678 TI - Pro12Ala variant of the PPARG2 gene increases body mass index: An updated meta analysis encompassing 49,092 subjects. AB - OBJECTIVE: The peroxisome proliferator-activated receptor gamma 2 (PPARG2) gene has been intensively studied with relation to obesity and metabolic disorders. Indeed, a large number of studies assessing the association between the PPARG2 polymorphism Pro12Ala (rs1801282) and body mass index (BMI) have been published with some controversial results. In this meta-analysis, the effects of Pro12Ala polymorphism of the PPARG2 gene on BMI were investigated. DESIGN AND METHODS: Externally published data were collected and we included our own novel data from a study in the elderly participants (>55 years) of a Mediterranean cohort, the SUN ("Seguimiento Universidad de Navarra") Project (n = 972). A total of 75 independent studies with 49,092 subjects (39,806 with the genotype Pro12Pro and 9,286 carrier subjects of the Ala allele) were included. RESULTS: The meta analysis revealed a higher BMI with an overall estimation of +0.065 kg/m(2) (95%CI = 0.026-0.103, P = 0.001) for homo-/heterozygous carriers of the Ala allele of the PPARG2 gene in comparison to non-carriers. The analysis also showed that there was heterogeneity (P for heterogeneity <0.001), but funnel plots did not suggest apparent publication bias. Furthermore, the association between the Pro12Ala polymorphism of the PPARG2 gene and increased BMI was stronger in Caucasian. Thus, carriers of the Ala allele had significantly higher BMI than non carriers in a subsample of 6,528 Caucasian male subjects (standardized mean difference = 0.090, 95%CI=0.032-0.148, P = 0.002, P for heterogeneity = 0.121). CONCLUSION: This updated meta-analysis showed that carriers of the Ala12 allele of the PPARG2 gene had a higher average BMI. PMID- 23666677 TI - Apolipoprotein A-1 mimetic D-4F enhances isoflurane-induced eNOS signaling and cardioprotection during acute hyperglycemia. AB - Acute hyperglycemia (AHG) decreases the availability of nitric oxide (NO) and impairs anesthetic preconditioning (APC)-elicited protection against myocardial infarction. We investigated whether D-4F, an apolipoprotein A-1 mimetic, rescues the myocardium by promoting APC-induced endothelial NO signaling during AHG. Myocardial infarct size was measured in mice in the absence or presence of APC [isoflurane (1.4%)] with or without AHG [dextrose (2 g/kg ip)] and D-4F (0.12 or 0.6 mg/kg ip). NO production, superoxide generation, protein compartmentalization, and posttranslational endothelial NO synthase (eNOS) modifications were assessed in human coronary artery endothelial cells cultured in 5.5 or 20 mM glucose with or without isoflurane (0.5 mM) in the presence or absence of D-4F (0.5 MUg/ml). Myocardial infarct size was significantly decreased by APC (36 +/- 3% of risk area) compared with control (54 +/- 3%) in the absence, but not presence, of AHG (49 +/- 4%). D-4F restored the cardioprotective effect of APC during AHG (36 +/- 3% and 30 +/- 3%, 0.12 and 0.6 mg/kg, respectively), although D-4F alone had no effect on infarct size (53 +/- 3%). Isoflurane promoted caveolin-1 and eNOS compartmentalization within endothelial cell caveolae and eNOS dimerization, concomitant with increased NO production (411 +/- 28 vs. 68 +/- 10 pmol/mg protein in control). These actions were attenuated by AHG (NO production: 264 +/- 18 pmol/mg protein). D-4F reduced superoxide generation and enhanced caveolin-1 and eNOS caveolar compartmentalization and posttranslational eNOS modifications, thus restoring NO production during isoflurane and AHG (418 +/- 36 pmol/mg protein). In conclusion, D-4F restored the cardioprotective effect of APC during AHG, possibly by decreasing superoxide generation, which promoted isoflurane-induced eNOS signaling and NO biosynthesis. PMID- 23666679 TI - Gold-catalyzed regioselective synthesis of 2- and 3-alkynyl furans. PMID- 23666680 TI - Serial measurement of galectin-3 in patients with chronic heart failure: results from the ProBNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) study. AB - AIMS: Galectin-3 is a prognostic heart failure (HF) biomarker that may mediate cardiac fibrosis. We examined the value of serial galectin-3 measurement for prognosis and response to therapy in chronic HF. METHODS AND RESULTS: A total of 151 subjects with LV systolic dysfunction (LVSD) were followed through 908 visits over 10 +/- 3 months. The amount of time spent with a galectin-3 level <= 20.0 ng/mL and changes between baseline and subsequent values were considered across visits, and used to assess risk for adverse cardiovascular (CV) events and associations with LV remodelling. Medication effects on galectin-3 were examined. Median galectin-3 values at baseline, 3 months, and 6 months were higher in patients with CV events (21.7 vs. 18.4 ng/mL, P = 0.03; 21.7 vs. 16.5 ng/mL, P = 0.03; 23.2 vs. 16.0 ng/mL, P = 0.007). Galectin-3 concentration changed in 35.2% of subjects during study procedures; time spent at <= 20.0 ng/mL was significantly associated with a lower rate of CV events, independently predicted fewer CV events even adjusted for relevant variables including study allocation, NT-proBNP, and renal function [odds ratio (OR) = 0.90; P = 0.05], and predicted increase in LV ejection fraction (OR = 1.20; P = 0.04). Serial galectin-3 measurement at 6 months added prognostic value beyond the baseline level (P = 0.02). There were no significant effects of medications on galectin-3 levels. CONCLUSION: In chronic HF due to LVSD, serial galectin-3 measurement adds incremental prognostic information and predicts LV remodelling. In this study, HF therapies had no clear effects on galectin-3 levels. PMID- 23666681 TI - Safety and tolerability of intensified, N-terminal pro brain natriuretic peptide guided compared with standard medical therapy in elderly patients with congestive heart failure: results from TIME-CHF. AB - AIMS: NT-proBNP-guided therapy results in intensification of medical heart failure (HF) therapy and is suggested to improve outcome. However, it is feared that an intensified, NT-proBNP-guided therapy carries a risk of adverse effects. Therefore, the safety and tolerability of NT-proBNP-guided therapy in the Trial of Intensified vs standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) was assessed. METHODS AND RESULTS: A total of 495 chronic HF patients, aged >=60, with an LVEF <=45%, NYHA class >=II, randomized to NT-proBNP-guided or symptom-guided therapy and >=1 month follow-up were included in the present safety analysis. All adverse events (AEs) were recorded during the 18-month trial period. A total of 5212 AEs were noted, 433 of them serious. NT-proBNP-guided therapy led to a higher up-titration of HF medication and was well tolerated, with a dropout rate (12% vs. 11%, P = 1.0) and AE profile [number of AEs/patient-year 4.7 (2.8-9.4) vs. 5.4 (2.7-11.4), P = 0.69; number of severe AEs/patient-year 0.7 (0-2.7) vs. 1.3 (0-3.9), P = 0.21] similar to that of symptom-guided therapy, although most subjects in both treatment groups (96% vs. 95%, P = 0.55) experienced at least one AE. Age and number of co-morbidities were associated with AEs and interacted with the safety profile of NT-proBNP-guided therapy: positive effects were more frequent in younger and less co-morbid patients whereas potential negative effects-although small and related to non severe AEs only-were only seen in the older and more co-morbid patients. CONCLUSIONS: NT-proBNP-guided therapy is safe in elderly and highly co-morbid HF patients. Trial registration ISRCTN43596477. PMID- 23666682 TI - Organic field-effect transistor memory devices using discrete ferritin nanoparticle-based gate dielectrics. AB - Organic field-effect transistor (OFET) memory devices made using highly stable iron-storage protein nanoparticle (NP) multilayers and pentacene semiconductor materials are introduced. These transistor memory devices have nonvolatile memory properties that cause reversible shifts in the threshold voltage (Vth ) as a result of charge trapping and detrapping in the protein NP (i.e., the ferritin NP with a ferrihydrite phosphate core) gate dielectric layers rather than the metallic NP layers employed in conventional OFET memory devices. The protein NP based OFET memory devices exhibit good programmable memory properties, namely, large memory window DeltaVth (greater than 20 V), a fast switching speed (10 MUs), high ON/OFF current ratio (above 10(4)), and good electrical reliability. The memory performance of the devices is significantly enhanced by molecular level manipulation of the protein NP layers, and various biomaterials with heme Fe(III) /Fe(II) redox couples similar to a ferrihydrite phosphate core are also employed as charge storage dielectrics. Furthermore, when these protein NP multilayers are deposited onto poly(ethylene naphthalate) substrates coated with an indium tin oxide gate electrode and a 50-nm-thick high-k Al2 O3 gate dielectric layer, the approach is effectively extended to flexible protein transistor memory devices that have good electrical performance within a range of low operating voltages (<10 V) and reliable mechanical bending stability. PMID- 23666683 TI - Evaluation of the measurement uncertainty in automated long-term sampling of PCDD/PCDFs. AB - Since the publication of the first version of European standard EN-1948 in 1996, long-term sampling equipment has been improved to a high standard for the sampling and analysis of polychlorodibenzo-p-dioxin (PCDD)/polychlorodibenzofuran (PCDF) emissions from industrial sources. The current automated PCDD/PCDF sampling systems enable to extend the measurement time from 6-8 h to 15-30 days in order to have data values better representative of the real pollutant emission of the plant in the long period. EN-1948:2006 is still the European technical reference standard for the determination of PCDD/PCDF from stationary source emissions. In this paper, a methodology to estimate the measurement uncertainty of long-term automated sampling is presented. The methodology has been tested on a set of high concentration sampling data resulting from a specific experience; it is proposed with the intent that it is to be applied on further similar studies and generalized. A comparison between short-term sampling data resulting from manual and automated parallel measurements has been considered also in order to verify the feasibility and usefulness of automated systems and to establish correlations between results of the two methods to use a manual method for calibration of automatic long-term one. The uncertainty components of the manual method are analyzed, following the requirements of EN-1948-3:2006, allowing to have a preliminary evaluation of the corresponding uncertainty components of the automated system. Then, a comparison between experimental data coming from parallel sampling campaigns carried out in short- and long-term sampling periods is realized. Long-term sampling is more reliable to monitor PCDD/PCDF emissions than occasional short-term sampling. Automated sampling systems can assure very useful emission data both in short and long sampling periods. Despite this, due to the different application of the long-term sampling systems, the automated results could not be directly compared with manual results, not even in terms of measurement uncertainty. This investigation focuses on both uncertainty and repeatability of the automated sampling method. The standard 20988, developed by Internarional Organization of Standardization (ISO) can be used to estimate the measurement uncertainty. The results confirm that the uncertainties of manual and automated methods are comparable. At the same time, it is not appropriate to consider the manual method as a reference for the evaluation of the uncertainty of the automated sampling system, due to the high variability of both systems. PMID- 23666684 TI - Stream water chemistry in the arsenic-contaminated Baccu Locci mine watershed (Sardinia, Italy) after remediation. AB - The abandoned Pb-As Baccu Locci mine represents the first and only case of mine site remediation in Sardinia, Italy. Arsenic is the most relevant environmental concern in the Baccu Locci stream watershed, with concentrations in surface waters up to and sometimes over 1 mg/L. The main remediation action consisted in creation of a "storage site", for the collection of contaminated materials from different waste-rock dumps and most of tailings piles occurring along the Baccu Locci stream. This paper reports preliminary results on the level of contamination in the Baccu Locci stream after the completion of remediation measures. Post-remediation stream water chemistry has not substantially changed compared to the pre-remediation situation. In particular, dissolved As maintains an increasing trend along the Baccu Locci stream, with a concentration of about 400 MUg/L measured at a distance of 7 km from the storage site. Future monitoring will provide fundamental information on the effectiveness of remediation actions conducted and their applicability to other mine sites in Sardinia. At the stage of mine site characterisation of future remediation plans, it is recommended to pay more attention to the understanding of mineralogical and geochemical processes responsible for pollution. Moreover, mixing of materials with different composition and reactivity in a storage site should require careful consideration and long-term leaching tests. PMID- 23666685 TI - Adsorption of Cu(2+) and methyl orange from aqueous solutions by activated carbons of corncob-derived char wastes. AB - Corncob-derived char wastes (CCW) obtained from biomass conversion to syngas production through corncob steam gasification, which were often discarded, were utilized for preparation of activated carbon by calcination, and KOH and HNO3 activation treatments, on the view of environment protection and waste recycling. Their adsorption performance in the removal of heavy metal ions and dye molecules from wastewater was evaluated by using Cu(2+) and methyl orange (MO) as the model pollutant. The surface and structure characteristics of the CCW-based activated carbons (CACs) were investigated by N2 adsorption, CO2 adsorption, FT-IR, and He TPD. The adsorption capacity varied with the activation methods of CACs and different initial solution concentrations, indicating that the adsorption behavior was influenced by not only the surface area and porosity but also the oxygen functional groups on the surface of the CACs. The equilibrium adsorption data were analyzed with the Langmuir, Freundlich, and Temkin isotherm models, and the adsorption kinetics was evaluated by the pseudo-first-order and pseudo-second order models. PMID- 23666686 TI - Altered plasma concentrations of trace elements in ulcerative colitis patients before and after surgery. AB - Ileal pouch-anal anastomosis (IPAA) is a classical surgery for ulcerative colitis patients. However, knowledge on trace element alteration in patients who had undergone this surgery is limited. This study was conducted to assess trace element alteration in patients with ulcerative colitis before and after ileal pouch-anal anastomosis. Preoperative (40) and postoperative (35) ulcerative colitis patients were studied. The dietary assessment of trace element intake was undertaken by a semiquantitative food frequency questionnaire. Patients' trace element status of zinc, copper, manganese, selenium, calcium, iron, and vitamin D3 was assessed by measuring their blood concentrations. We found that with the similar dietary intake, there was no statistical difference in the concentrations of plasma copper, iron, calcium, and vitamin D3 in the two groups (P > 0.05). Compared with preoperative patients, postoperative patients had higher concentrations of plasma zinc (14.51 +/- 4.75 MUmol/l) and manganese (0.21 +/- 0.11 MUmol/l) and lower concentrations of plasma selenium (0.86 +/- 0.58 MUmol/l). Both preoperative and postoperative mean concentrations of plasma calcium and vitamin D3 were below their reference range, respectively. We conclude that IPAA does not seem to alter patients' abnormal trace elements completely. It is important to monitor and supply some specified trace elements even in postoperative patients. PMID- 23666687 TI - Quantitative BCR-ABL1 RQ-PCR fusion transcript monitoring in chronic myelogenous leukemia. AB - The reciprocal Philadelphia translocation between chromosomes 9 and 22 [t(9;22)(q34;q11)] creates a BCR-ABL1 fusion protein that occurs in approximately 95% of cases of chronic myelogenous leukemia (CML), 15% of cases of adult acute lymphoblastic leukemia, and 5% of adult cases of acute myeloid leukemia. The BCR ABL1 protein is a constitutively activated tyrosine kinase that induces and maintains the neoplastic phenotype in these leukemias. PCR-based methods to identify and quantitate the tumor-specific BCR-ABL1 RNA have been shown to be an ultrasensitive diagnostic/prognostic tool for Philadelphia-positive leukemias. A novel tyrosine kinase inhibitor (TKI), imatinib, has been confirmed as an effective targeted treatment in most CML patients. A consensus goal for TKI treatment is to achieve a major molecular response (MMR), defined as a 3-log (1,000-fold) reduction in BCR-ABL1 transcripts. Patients who achieve an MMR have been shown to have a significantly reduced risk of disease progression. Conversely, increasing post-therapy BCR-ABL1 RNA levels convey a significantly increased risk of disease progression. The early identification of these high risk patients may allow early changes to the therapeutic strategy, before frank relapse. Thus, quantitative measurement of BCR-ABL1 transcripts in blood and bone marrow both aids in the initial diagnosis of CML and is essential for routine post-therapy minimal residual disease monitoring. We describe here a method for quantitating BCR-ABL1 transcripts in peripheral blood or bone marrow of CML patients using real-time quantitative reverse transcription PCR (RQ-PCR). PMID- 23666688 TI - Detection of BCR-ABL1 kinase domain mutations causing imatinib resistance in chronic myelogenous leukemia. AB - The reciprocal translocation between chromosomes 9 and 22 [t(9;22)(q34;q11), Philadelphia chromosome] creates a BCR-ABL1 fusion protein that occurs in approximately 95% of cases of chronic myelogenous leukemia (CML), 15% of cases of adult acute lymphoblastic leukemia, and 5% of adult cases of acute myeloid leukemia. The BCR-ABL1 protein is a constitutively activated tyrosine kinase that induces and maintains the neoplastic phenotype in these leukemias. PCR-based methods to identify and quantitate the tumor-specific BCR-ABL1 RNA have been shown to be an ultrasensitive diagnostic, prognostic, and monitoring tool for Philadelphia-positive leukemias. A novel tyrosine kinase inhibitor (TKI), imatinib, has been confirmed as an effective targeted treatment in most CML patients. However, a significant minority of patients being treated with imatinib develop resistance to the drug as evidenced by rising BCR-ABL1 levels. The most common mechanism of resistance in these patients is the development of mutations in the BCR-ABL1 kinase domain (KD) that abrogate binding of imatinib. Although KD mutations are quite heterogeneous, the identification of the exact mutation site is clinically important, as some mutations, but not others, can be effectively treated with second-generation TKIs. One mutation, T315I, for example, renders the leukemia resistant to all first- and second-line TKIs. Thus, DNA sequencing of the BCR-ABL1 kinase domain in resistant patients helps identify those who may benefit from a change in TKI agents, or those who should be considered for other therapeutic measures, such as stem cell transplantation. We describe here a method for sequencing the BCR-ABL1 kinase domain in peripheral blood or bone marrow of CML patients. PMID- 23666689 TI - Laboratory detection of JAK2V617F in human myeloproliferative neoplasms. AB - Recently, a point mutation in the JAK2 gene, JAK2 (V617F) , was discovered in several myeloid proliferative neoplasms including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Demonstration of the mutation and other similar mutations has now become one of the major criteria in the diagnosis of these neoplasms in the revised World Health Organization Classification of Tumors of Hematopoietic Tissues. In this chapter, we compared the advantages and disadvantages of five commonly used methods for the detection of JAK2 (V617F) . We explained, based on the current literature, why analytic sensitivity of the methodology is of particular importance for the detection of JAK2 (V617F) . A detailed laboratory procedure for the performance of an extensively optimized ARMS-PCR assay was presented. The assay shows distinct patterns for normal, mutant, and mixed genotypes. Diagnostically, it is highly sensitive, highly specific, and simple to perform with no need for any specialized equipment other than thermocyclers. PMID- 23666690 TI - c-kit mutational analysis in paraffin material. AB - The current WHO classification of mastocytosis defines one major and four minor diagnostic criteria for systemic mastocytosis (SM). One of the minor criteria is the detection of the "gain-of-function" mutation D816V of the c-kit proto oncogene in extracutaneous organs. The receptor molecule KIT is a potential therapeutic target for tyrosine kinase inhibitors. KIT mutations have been described in more than 80% of SM, but only in the minority of cutaneous mastocytoses (CM). Usually exon 17 amplicons generated by polymerase chain reaction are analyzed for the detection of c-kit mutations. Most frequently the method of restriction fragment length polymorphism (RFLP) analysis using the endonuclease Hinf I is used. Another well-established technique utilizes melting point analysis of amplification products with specific hybridization probes. Recently, also allele-specific PCR assays have been described. The technique used for the detection of c-kit mutations in mastocytosis is dependent on the kind of material to be analyzed and the laboratory equipment available. In this chapter the techniques of PNA-mediated PCR-clamping in combination with melting point analysis for the genotyping of amplification products are described for mutational analysis in total DNA and microdissected cells from formalin-fixed paraffin-embedded bone marrow trephine biopsies. PMID- 23666691 TI - Detection of recurrent cytogenetic abnormalities in acute lymphoblastic and myeloid leukemias using fluorescence in situ hybridization. AB - Cytogenetic identification of clonal abnormalities present in leukemia is critical for accurate diagnosis of the disease and determination of specific therapeutic interventions for the patient. Fluorescence in situ hybridization (FISH) studies complement the diagnostic karyotype by providing a higher resolution of analysis with clarification of rearrangements observed by G-banding and identification of cryptic abnormalities not observed by the light microscope. This chapter will discuss FISH methodology as practiced in the cancer cytogenetic laboratory. PMID- 23666692 TI - Liquid bead array technology in the detection of common translocations in acute and chronic leukemias. AB - Hematologic malignancies often have specific chromosomal translocations that promote cancer initiation and progression. Translocation identification is often vital in the diagnosis, prognosis, and treatment of malignancies. A variety of methods including metaphase cytogenetics, in situ hybridization, microarray techniques, Southern blotting, and many variations of PCR are used to identify translocations. While all these techniques have utility, many have drawbacks limiting their clinical usefulness: high cost, slow turnaround time, low density, large sample requirements, high complexity, and difficult validation and standardization. Multiplexed RT-PCR combined with liquid bead array detection overcomes many of these limitations, allowing simultaneous amplification and detection of multiple translocations within one patient sample. This system has high reliability, reproducibility, and flexibility; low cost and low complexity; rapid turnaround time; and appropriate analyte density. Recently, Asuragen Inc. has developed a multiplexed RT-PCR liquid bead array panel that simultaneously analyzes 12 fusion transcripts found in four major types of hematologic malignancies, allowing rapid and efficient diagnosis. In this chapter, we review liquid bead array technology in relation to the specific hematologic translocations analyzed in the Signature LTx panel. PMID- 23666693 TI - Molecular genetic tests for FLT3, NPM1, and CEBPA in acute myeloid leukemia. AB - Patients with acute myeloid leukemia (AML) and a normal karyotype constitute the single largest cytogenetic group of AML. It is important to identify prognostic markers that predict patients' outcome more precisely. The presence of mutations in FLT3 (FMS-like tyrosine kinase 3), NPM1 (Nucleophosmin), and CEBPA (CCAAT/enhancer-binding protein alpha) genes hold prognostic significance in patients with AML and normal cytogenetics. Therefore, mutation identification may help to optimize therapeutic approaches in this group of patients. Polymerase chain reaction (PCR)-based fragment length analysis for mutations in FLT3 and NPM1 has been shown to be a fast and sensitive method, while nucleotide sequencing represents a gold standard for CEBPA heterogeneous mutational screening. We describe both fragment length assay and sequencing methods for mutational analysis of these three genes. PMID- 23666694 TI - Flow cytometric monitoring of residual disease in acute leukemia. AB - Multiparameter flow cytometry offers the unique ability to simultaneously assess and correlate multiple cellular properties at the single cell level in a timely and efficient manner. Application of this technique to the detection of residual acute leukemia after therapy has been shown to be of singular importance to monitor response to therapy and provide prognostic information. Principles and methods that allow for the sensitive detection of acute leukemia following therapy are presented. The basic protocol outlines a simple and efficient method for the labeling of white cells with monoclonal antibodies directed against cell surface antigens. A second method describes a general method for the simultaneous assessment of surface and cytoplasmic antigens using a combination of fixation followed by membrane permeabilization. An illustrative panel of validated reagents currently in use for residual disease detection for acute lymphoblastic leukemia of B or T cell lineage as well as acute myeloid leukemia is provided. Principles of data analysis that allow for the reproducible detection of small populations of abnormal hematopoietic cells in peripheral blood and bone marrow are presented. PMID- 23666695 TI - Chimerism analysis following hematopoietic stem cell transplantation. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective therapeutic approach for several hematological diseases. Chimerism studies can be helpful to assess donor engraftment, detect early signs of graft rejection, and monitor minimal residual disease. Currently the most common method for monitoring chimerism following HSCT is by PCR amplification of STR loci followed by capillary electrophoresis. Prior to transplantation, multiple STR loci in both the donor and recipient are analyzed in order to identify loci that differentiate the two individuals. Informative loci are selected to calculate the percent donor and recipient present in post-transplant specimens. This is a rapid, sensitive, and cost-effective method for monitoring chimerism in patients following HSCT. PMID- 23666696 TI - Detection of clonal immunoglobulin heavy chain gene rearrangements by the polymerase chain reaction and capillary gel electrophoresis. AB - Although well-established diagnostic criteria exist for mature B-cell neoplasms, a definitive diagnosis of a B-cell lymphoproliferative disorder cannot always be obtained using more conventional techniques such as flow cytometric immunophenotyping, conventional cytogenetics, fluorescence in situ hybridization, or immunohistochemistry. However, because B-cell malignancies contain identically rearranged immunoglobulin heavy chain genes, the polymerase chain reaction (PCR) can be a fast, convenient, and dependable option to identify clonal B-cell processes. This chapter describes the use of PCR and capillary electrophoresis to identify clonal immunoglobulin heavy chain (IGH) variable and joining region (VH JH) gene rearrangements (IGH VH-JH PCR) using a commercially available method employing multiple multiplex PCR tubes that was originally developed as the result of a large European BIOMED-2 collaborative study (Invivoscribe Technologies). The core protocol involves the use of three separate master mix tubes that target the conserved framework (FR1, FR2, and FR3) and joining (J) regions of the IGH gene. Analysis of these three framework regions can detect approximately 88% of clonal IGH gene rearrangements. PMID- 23666697 TI - Detection of clonal T-cell receptor beta and gamma chain gene rearrangement by polymerase chain reaction and capillary gel electrophoresis. AB - Although established diagnostic criteria exist for mature T-cell neoplasms, a definitive diagnosis of a T-cell lymphoproliferative disorder cannot always be obtained using more conventional techniques such as flow cytometric immunophenotyping, conventional cytogenetics, fluorescence in situ hybridization, or immunohistochemistry. However, because T-cell malignancies contain identically rearranged T-cell receptor gamma (TCRG) and/or beta (TCRB) genes, the polymerase chain reaction (PCR) can be a fast, convenient, and dependable option to identify clonal T-cell processes. This chapter describes the use of PCR and capillary electrophoresis to identify clonal TCRB and TCRG gene rearrangements (TCRB and TCRG PCR) using a commercially available method employing multiple multiplex PCR tubes that was originally developed as the result of a large European BIOMED-2 collaborative study (Invivoscribe Technologies). The core protocol for the TCRB assay involves the use of three separate multiplex master mix tubes. Tubes A and B target the framework regions within the variable and joining regions of the TCRB gene, and Tube C targets the diversity and joining regions of the TCRB gene. The core protocol for the TCRG assay utilizes two multiplex master mix tubes (Tubes A and B) that target the variable and joining regions of the TCRG gene. Use of the five BIOMED-2 TCRB and TCRG PCR multiplex tubes in parallel can detect approximately 94% of clonal TCR gene rearrangements. PMID- 23666698 TI - Detection of genetic translocations in lymphoma using fluorescence in situ hybridization. AB - Certain lymphoma types are characterized by recurring genetic translocations. Detection of these translocations enables confirmation of a suspected diagnosis and provides a genetic marker which can be subsequently monitored and followed. Rapid and reliable identification of these molecular rearrangements is a key component in the workup of lymphoma. While conventional cytogenetics may be a useful tool in this regard, fluorescence in situ hybridization (FISH) offers additional advantages including the ability to use formalin-fixed tissues, no requirement for dividing cells, ability to score many cells, improved sensitivity, and faster turnaround time for results. PMID- 23666699 TI - Molecular detection of t(14;18)(q32;q21) in follicular lymphoma. AB - The t(14;18)(q32;q21) can be detected in approximately 80% of cases of follicular lymphoma (FL). This translocation juxtaposes the BCL2 oncogene at 18q21 with the IGH@ at 14q32, and leads to overexpression of BCL2 protein which protects the cells from apoptosis. The high degree of sequence homology among the 3' portion of the JH segments and the clustering of breakpoints on chromosome 18 make the IGH@/BCL2 very amenable to polymerase chain reaction (PCR) detection. We describe two multiplex TaqMan-based real-time PCR assays which can be used to detect and quantify the major and minor breatpoint cluster regions of IGH@/BCL2 fusion products in newly diagnosed FL, and to monitor minimal residual disease during treatment or early relapse. PMID- 23666700 TI - Molecular detection of t(11;14)(q13;q32) in mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is characterized by the presence of t(11;14)(q13;q32) which juxtaposes CCND-1 gene (also known as BCL-1, PRAD-1) at 11q13 with an enhancer of the IGH@ gene at 14q32. The resultant overexpression of cyclin D1 plays an essential role in the pathogenesis of MCL. The breakpoints on chromosome 14 occur 5' to one of six JH segments, whereas only 30-50% of the breakpoints on chromosome 11 are localized within a 1 kb region called the major translocation cluster (MTC) which can be easily assessed by polymerase chain reaction (PCR). The remainder of the breakpoints are widely scattered over approximately 120 kb, making PCR analysis infeasible. We describe a TaqMan-based real-time PCR assay to detect and quantify IGH@/BCL1 fusion products in newly diagnosed MCL, and to monitor minimal residual disease during treatment or early relapse in MTC positive cases. PMID- 23666701 TI - Detection of t(2;5)(p23;q35) in anaplastic large-cell lymphoma by long-range nested polymerase chain reaction assay. AB - Anaplastic large-cell lymphoma (ALCL) is characterized by molecular abnormalities involving ALK gene located at 2p23 which results in an overexpression of ALK. Nine different rearrangements of ALK gene have been reported; the t(2;5)(p23;q35) is the most common. The t(2;5) fuses the NPM gene at 5q35 with the ALK gene. NPM/ALK, as well as ALK activation via other molecular abnormalities, plays an important role in the pathogenesis of ALCL. The lack of tight clustering within the involved NPM and ALK genes precludes analysis using standard PCR methods. We describe a long-range nested PCR assay to detect NPM/ALK gene rearrangements. PMID- 23666702 TI - EBER in situ hybridization for Epstein-Barr virus. AB - Epstein-Barr encoding region (EBER) in situ hybridization is the methodology of choice for the detection of the Epstein-Barr virus (EBV) in tissue sections. Because of the large numbers of copies of EBERs present in latently infected cells, non-isotopic methods can be used. Positive studies show staining in the nuclei of the EBV-infected cells, accentuating the chromatin and often excluding the nucleolus. False-negative results are most often the result of RNA degradation in the tissues, a finding that may be detected through the use of a polyT probe as a control for RNA preservation. PMID- 23666703 TI - Epstein-Barr virus (EBV) load determination using real-time quantitative polymerase chain reaction. AB - Epstein-Barr virus (EBV) infects virtually the entire human population and infection persists throughout the lifetime of its host. EBV has been associated with the development of a wide variety of neoplasms, including lymphoma, carcinoma, and sarcoma. In addition, EBV-associated lymphoproliferative disorders are particularly prevalent in immunosuppressed individuals, including AIDS patients, transplant recipients, and patients with congenital immunodeficiencies. In recent years, EBV viral load assessment has been extensively implemented in clinical practice for the diagnosis and monitoring of EBV-associated malignancies and lymphoproliferative disorders. The real-time quantitative polymerase chain reaction (RQ-PCR) has become the method of choice for quantification of specific EBV nucleic acid sequences. This method is fast, extremely sensitive, and accurate, requires only very small amounts of input nucleic acid, and is relatively simple to perform. These characteristics have made it the method of choice for EBV viral load determination. This chapter describes the use of a laboratory-developed RQ-PCR EBV viral load assay for the detection of EBV DNA in cell-free plasma and cerebrospinal fluid samples. PMID- 23666704 TI - Molecular and immunohistochemical detection of Kaposi sarcoma herpesvirus/human herpesvirus-8. AB - Kaposi sarcoma herpesvirus/human herpesvirus-8 (KSHV/HHV-8) is etiologically related to the development of several human diseases, including Kaposi sarcoma, primary effusion lymphoma (PEL)/extra-cavitary (EC) PEL, multicentric Castleman disease (MCD), and large B-cell lymphoma arising in KSHV/HHV-8-associated multicentric Castleman disease. Although serologic studies can identify persons infected with this virus, molecular genetics, specifically PCR (polymerase chain reaction) and immunohistochemical techniques, are rapid, sensitive, and specific, and are able to more closely link KSHV/HHV-8 to a given disease process. As these KSHV/HHV-8-related diseases cause significant morbidity and mortality in affected individuals, the identification of the virus within lesional tissue will allow for more targeted therapy. PMID- 23666705 TI - Detection of cytomegalovirus infection by quantitative polymerase chain reaction. AB - Human cytomegalovirus (CMV), also known as human herpes virus-5 (HHV-5), is a common human pathogen acquired early in life in the majority of immunocompetent individuals. Primary infection establishes a state of latency and the virus can be reactivated during immunosuppression. CMV is a significant cause of morbidity and mortality in newborns and patients with impaired immune system. Prenatal infection can result in intrauterine growth retardation, hepatitis, myocarditis, pneumonitis, and neurologic abnormalities. Individuals with congenital or acquired immunosuppression can develop a primary CMV infection, infection with another CMV strain or experience reactivation of the latent virus. The hematopoietic stem cell and solid organ transplant recipients are at high risk of developing CMV infection, especially early in a post-transplant period. The definition of CMV disease includes the evidence of end-organ involvement in the presence of CMV detected by a validated laboratory assay. The selection of a laboratory method is highly dependent on the type of sample to be tested and the clinical presentation. In the clinical practice, the quantitative PCR-based assays are most helpful, since they can measure the level of CMV DNA in whole blood, plasma, cerebrospinal fluid, amniotic fluid, tissue, and urine, and follow the kinetics of infection. In this chapter we describe the PCR assay designed to quantify CMV DNA in human plasma by amplifying a 105 base-pair (bp) fragment of the CMV immediate-early DNA polymerase gene. PMID- 23666706 TI - Thiopurine S-methyltransferase pharmacogenetics in childhood acute lymphoblastic leukemia. AB - Pharmacogenetics is the growing field of study of genetic variations underlying interindividual differences in drug response. Inherited polymorphisms in genes coding for drug-metabolizing enzymes, transporters, and targets influence toxicity as well as efficacy associated with the medication. Thiopurines are agents widely used in hematologic malignancies, transplantation, and chronic inflammatory conditions. Myelosuppression is the commonly encountered dose limiting toxicity. Polymorphisms in the thiopurine S-methyltransferase gene (TPMT), the predominant inactivating enzyme for thiopurines in hematopoietic tissue, are correlated with enzymatic activity of TPMT, thiopurine metabolism, and risk of clinical toxicity. In this chapter, we present TPMT genotype assessment that allows for prescribing pharmacogenetically guided doses to enhance patient safety and drug efficacy. PMID- 23666707 TI - MicroRNA expression profiling using microarrays. AB - MicroRNAs are small noncoding RNAs which are able to regulate gene expression at both the transcriptional and translational levels. There is a growing recognition of the role of microRNAs in nearly every tissue type and cellular process. Thus there is an increasing need for accurate quantitation of microRNA expression in a variety of tissues. Microarrays provide a robust method for the examination of microRNA expression. In this chapter, we describe detailed methods for the use of microarrays to measure microRNA expression and discuss methods for the analysis of microRNA expression data. PMID- 23666708 TI - Genetic polymorphisms of HSP70 in age-related cataract. AB - Polymorphisms have been identified in several HSP70 genes, which may affect HSP70 repair efficiency. We investigated the association of the polymorphisms in HSPA1A, HSPA1B, and HSPA1L genes in the HSPs repair pathway with the risk of cataract in a Chinese population. The study included 415 cataract patients and 386 controls. Genotyping was done by the polymerase chain reaction-restriction fragment length polymorphism method. HSPA1B 1267 A/A genotype seems to have a protective role against cataract (p = 0.014, odds ratio (OR) = 0.664, 95 % confidence intervals (CI) = 0.480-0.919), and the G allele (p = 0.057, OR = 1.216, 95 % CI = 0.999-1.479) does not seem to have a deleterious role in the development of cataract. Haplotypes with frequencies of GAT were significantly different than those of controls (p = 0.005). In HSPA1A G190C and HSPA1L T2437C polymorphisms, there were no significant differences in frequencies of the variant homozygous in patients compared to controls. We conclude that the A/A genotype of HSPA1B A1267G polymorphism seem to have a protective role against age related cataract. PMID- 23666709 TI - Age-dependent expression of stress and antimicrobial genes in the hemocytes and siphon tissue of the Antarctic bivalve, Laternula elliptica, exposed to injury and starvation. AB - Increasing temperatures and glacier melting at the Western Antarctic Peninsula (WAP) are causing rapid changes in shallow coastal and shelf systems. Climate change-related rising water temperatures, enhanced ice scouring, as well as coastal sediment runoff, in combination with changing feeding conditions and microbial community composition, will affect all elements of the nearshore benthic ecosystem, a major component of which is the Antarctic soft-shelled clam Laternula elliptica. A 454-based RNA sequencing was carried out on tissues and hemocytes of L. elliptica, resulting in 42,525 contigs, of which 48 % was assigned putative functions. Changes in the expression of putative stress response genes were then investigated in hemocytes and siphon tissue of young and old animals subjected to starvation and injury experiments in order to investigate their response to sedimentation (food dilution and starvation) and iceberg scouring (injury). Analysis of antioxidant defense (Le-SOD and Le catalase), wound repair (Le-TIMP and Le-chitinase), and stress and immune response (Le-HSP70, Le-actin, and Le-theromacin) genes revealed that most transcripts were more clearly affected by injury rather than starvation. The upregulation of these genes was particularly high in the hemocytes of young, fed individuals after acute injury. Only minor changes in expression were detected in young animals under the selected starvation conditions and in older individuals. The stress response of L. elliptica thus depends on the nature of the environmental cue and on age. This has consequences for future population predictions as the environmental changes at the WAP will differentially impact L. elliptica age classes and is bound to alter population structure. PMID- 23666710 TI - Interleukin-7 enhances the Th1 response to promote the development of Sjogren's syndrome-like autoimmune exocrinopathy in mice. AB - OBJECTIVE: Although elevated interleukin-7 (IL-7) levels have been reported in patients with primary Sjogren's syndrome (SS), the role of IL-7 in this disease remains unclear. We undertook this study to characterize the previously unexplored role of IL-7 in the development and onset of primary SS using the C57BL/6.NOD-Aec1Aec2 (B6.NOD-Aec) mouse model, which recapitulates human primary SS. METHODS: For gain-of-function studies, recombinant IL-7 or control phosphate buffered saline was injected intraperitoneally (IP) into 12-week-old B6.NOD-Aec mice for 8 weeks. For loss-of-function studies, anti-IL-7 receptor alpha-chain (anti-IL-7Ralpha) antibody or its isotype control IgG was administered IP into 16 week-old B6.NOD-Aec mice. Salivary flow measurement, histologic and flow cytometric analysis of salivary glands, and serum antinuclear antibody assay were performed to assess various disease parameters. RESULTS: Administration of exogenous IL-7 accelerated the development of primary SS, whereas blockade of IL 7Ralpha signaling almost completely abolished the development of primary SS, based on salivary gland inflammation and apoptosis, autoantibody production, and secretory dysfunction. IL-7 positively regulated interferon-gamma (IFNgamma) producing Th1 and CD8+ T cells in the salivary glands without affecting IL-17. Moreover, IL-7 enhanced the expression of CXCR3 ligands in a T cell- and IFNgamma dependent manner. Accordingly, IFNgamma induced a human salivary gland epithelial cell line to produce CXCR3 ligands. IL-7 also increased the level of tumor necrosis factor alpha, another Th1-associated cytokine that can facilitate tissue destruction and inflammation. CONCLUSION: IL-7 plays a pivotal pathogenic role in SS, which is underpinned by an enhanced Th1 response and IFNgamma/CXCR3 ligand mediated lymphocyte infiltration of target organs. These results suggest that targeting the IL-7 pathway may be a potential future strategy for preventing and treating SS. PMID- 23666714 TI - Experience of excess skin and desire for body contouring surgery in post bariatric patients. AB - BACKGROUND: This study was done to analyze the problems of post-bariatric patients with excess skin and to determine their interest in body contouring surgery. The self-administered Sahlgrenska Excess Skin Questionnaire (SESQ) was used together with a study-specific questionnaire. METHODS: The patients who were operated with bariatric surgery at Sahlgrenska University Hospital between 1999 and 2008 were identified and sent the SESQ and a study-specific questionnaire. RESULTS: The response rate was 65% (23% men). The most common problem in both men and women was the feeling of having an unattractive body (91 and 67%, respectively). The most frequently reported sites of excess skin were the upper arms in women (91%) and the abdomen in men (78%). In both women and men, excess skin on the abdomen was reported to cause the most discomfort (median 7 and 3, respectively, on a scale from 0 to 10). Women reported significantly more problems, discomfort, and amount of excess skin (p < 0.05) than men. There was a strong correlation between the amount of excess skin and the degree of discomfort for all body parts. Seventeen percent of the responders had been operated with body contouring surgery of one body part and 5% of two or more. Fourteen percent desired body contouring surgery of one body part and 61% of two or more. CONCLUSIONS: Most post-bariatric patients, but women in particular, experience significant problems of excess skin and request body contouring surgery. PMID- 23666711 TI - Polycomb determines responses to smad2/3 signaling in embryonic stem cell differentiation and in reprogramming. AB - Integration of extrinsic signals, epigenetic regulators, and intrinsic transcription factors establishes pluripotent stem cell identity. Interplay between these components also underlies the capacity of stem cells to undergo differentiation, and of differentiated cells to re-establish the pluripotent state in direct reprogramming. Polycomb repressive complexes are epigenetic regulators that play key roles in stem cell identity and in differentiated cell fates. Smad2 and Smad3 (Smad2/3), the intracellular mediators of the Nodal/Activin/transforming growth factor (TGF) beta cell-cell signaling pathway also are implicated in stem cell pluripotency and in differentiation. Here, we show that Polycomb imposes responses to Smad2/3-mediated signaling to selectively regulate expression of the master pluripotency factor Oct 4 during initiation of differentiation, but not in the self-renewing pluripotent ground state. During reprogramming back to the ground state, we find that the enhancement of reprogramming efficiency stemming from blocking Nodal/Activin/TGFbeta signaling also depends on Polycomb. These context-dependent responses to Smad2/3 imposed by Polycomb action provide a mechanism for selective gene regulation that can reconcile the apparently conflicting roles of this signaling pathway in pluripotency, differentiation, and reprogramming. PMID- 23666715 TI - Development of a novel biodegradable drug-eluting ventilation tube for chronic otitis media with effusion. AB - OBJECTIVES/HYPOTHESIS: To develop a novel drug-eluting biodegradable ventilation tube (VT), to evaluate in vitro sustained release and antibacterial adherence of ofloxacin-loaded biodegradable VT on Pseudomonas aeruginosa, and to evaluate in vivo biodegradation of VT in guinea pig ears. STUDY DESIGN: A randomized animal study. METHODS: In vitro drug release and degradation of ofloxacin-loaded VT were studied in water for 3 months. Bacterial adherence was evaluated by inoculating the VT with P aeruginosa suspension for 6 days. Scanning electron microscopy (SEM) was used for morphologic analysis. Guinea pigs were assigned to three groups: commercial Mini Shah VT, biodegradable unloaded VT, and biodegradable ofloxacin-loaded VT. Myringotomy and VT insertion were performed. SEM of VTs and histology were performed at 2, 4, 10, and 18 weeks. RESULTS: A total of 81.7% of ofloxacin in VT was eluted over 3 months. Biodegradable VTs had smoother surfaces and less bacteria adherence compared to Mini Shah VTs. VTs with ofloxacin had the least bacteria adherence. VTs resulted in neither inflammation nor otorrhea 18 weeks postinsertion in guinea pigs. Histology showed the new VTs were biocompatible. The VTs were still functioning and patent after 18 weeks postinsertion but had started degrading. CONCLUSIONS: The first novel biodegradable ofloxacin-loaded VT with sustainable drug release technology and antibacterial adherence property was studied. Patency beyond 4.5 months allowed an adequate period of ventilation. The complete degradation of the VT warrants further studies to evaluate the duration of VT resorption in situ and healing of the ear drum. PMID- 23666716 TI - Expanding nurse practice in COPD: is it key to providing high quality, effective and safe patient care? AB - The prevalence of chronic obstructive pulmonary disease (COPD), a common and preventable chronic disease, is on the increase, and so are the financial and social burdens associated with it. The management of COPD is particularly challenging, as patients have complex health and social needs requiring life-long monitoring and treatment. In order to address these issues and reduce the burden imposed by COPD, the development of innovative disease management models is vital. Nurses are in a key position to assume a leading role in the management of COPD since they frequently represent the first point of contact for patients and are involved in all stages of care. Although evidence is still limited, an increasing number of studies have suggested that nurse-led consultations and interventions for the management of COPD have the potential to impact positively on the health and quality of life of patients. The role of nurses in the management of COPD around the world could be significantly expanded and strengthened. Providing adequate educational opportunities and support to nurses, as well as addressing funding issues and system barriers and recognising the importance of the expanding roles of nurses, is vital to the well-being of patients with long-term medical conditions such as COPD and to society as a whole, in order to reduce the burden of this disease. PMID- 23666717 TI - Pulmonary rehabilitation and qualitative research. PMID- 23666719 TI - Metabolic profile and genotoxicity in obese rats exposed to cigarette smoke. AB - OBJECTIVE: Experimental studies have shown that exposure to cigarette smoke has negative effects on lipid metabolism and oxidative stress status. Cigarette smoke exposure in nonpregnant and pregnant rats causes significant genotoxicity (DNA damage). However, no previous studies have directly evaluated the effects of obesity or the association between obesity and cigarette smoke exposure on genotoxicity. Therefore, the aim of the present investigation was to evaluate DNA damage levels, oxidative stress status and lipid profiles in obese Wistar rats exposed to cigarette smoke. DESIGN AND METHODS: Female rats subcutaneously (s.c.) received a monosodium glutamate solution or vehicle (control) during the neonatal period to induce obesity. The rats were randomly distributed into three experimental groups: control, obese exposed to filtered air, and obese exposed to tobacco cigarette smoke. After a 2-month exposure period, the rats were anesthetized and killed to obtain blood samples for genotoxicity, lipid profile, and oxidative stress status analyses. RESULTS: The obese rats exposed to tobacco cigarette smoke presented higher DNA damage, triglycerides, total cholesterol, free fatty acids, VLDL-c, HDL-c, and LDL-c levels compared to control and obese rats exposed to filtered air. Both obese groups showed reduced SOD activity. These results showed that cigarette smoke enhanced the effects of obesity. CONCLUSION: In conclusion, the association between obesity and cigarette smoke exposure exacerbated the genotoxicity, negatively impacted the biochemical profile and antioxidant defenses and caused early glucose intolerance. Thus, the changes caused by cigarette smoke exposure can trigger the earlier onset of metabolic disorders associated with obesity, such as diabetes and metabolic syndrome. PMID- 23666720 TI - Introduction to mass spectrometry-based proteomics. AB - Mass spectrometry has been widely applied to study biomolecules and one rapidly developing field is the global analysis of proteins, proteomics. Understanding and handling mass spectrometry data is a multifaceted task that requires many decisions to be made to get the most comprehensive information from an experiment. Later chapters in this book deal in-depth with various aspects of the process and how different tools can be applied to the many analytical challenges. This introductory chapter is intended as a basic introduction to mass spectrometry (MS)-based proteomics to set the scene for newcomers and give pointers to reference material. There are many applications of mass spectrometry in proteomics and each application is associated with some analytical choices, instrumental limitations and data processing steps that depend on the aim of the study and means of conducting it. Different aspects of the proteome can be explored by choosing the right combination of sample preparation, MS instrumentation and data processing. This chapter gives an outline for some of these commonly used setups and some of the key concepts, many of which are explored in greater depth in later chapters. PMID- 23666721 TI - LC-MS spectra processing. AB - Peak extraction from raw data is the first step in LC-MS data analysis. The quality of this procedure is important since it affects the quality and accuracy of all subsequent analysis such as database searches and peak quantitation. The most important and most accurately measured physical entity provided by mass spectrometers is m/z values which need to be extracted by state of art algorithms and scrutinized thoroughly. The aim of this chapter is to provide a discussion of peak processing methods and furthermore discuss some of the yet unresolved or neglected issues. A few novel concepts are also proposed for analysis and visualization. The final section of this chapter provides a note on possible software for spectra processing. PMID- 23666718 TI - Of inflammasomes and pathogens--sensing of microbes by the inflammasome. AB - Inflammasomes are signalling platforms that sense a diverse range of microbial products and also a number of stress and damage associated endogenous signals. Inflammasome complexes can be formed by members of the Nod-like receptor family or the PYHIN family member AIM2. Upon formation, inflammasomes trigger proteolysis of caspase-1, which subsequently leads to a potent inflammatory response through the maturation and secretion of IL-1 family cytokines, which can be accompanied by an inflammatory cell death termed pyroptosis. Here, we review the sensing mechanisms of the currently characterized inflammasome complexes and discuss how they are involved in the innate immune response against microbial pathogens. We especially highlight recent advances in the molecular understanding of how microbial patterns are detected and discriminated from endogenous compounds by inflammasome sensors. Further, we review how inflammasomes contribute to the anti microbial host defense by cytokine-dependent and cell autonomous mechanisms. PMID- 23666722 TI - Isotopic distributions. AB - Isotopic information determined by mass spectrometry can be used in a wide variety of applications. Broadly speaking these could be classified as "passive" applications, meaning that they use naturally occurring isotopic information, and "active" applications, meaning that the isotopic distributions are manipulated in some way. The classic passive application is the determination of chemical composition by comparing observed isotopic patterns of molecules to theoretically calculated isotopic patterns. Active applications include isotope exchange experiments of a variety of types, as well as isotope labeling in tracing studies and to provide references for quantitation. Regardless of the type of application considered, the problem of theoretical calculation of isotopic patterns almost invariably arises. This paper reviews a number of application examples and computational approaches for isotopic studies in mass spectrometry. PMID- 23666723 TI - Retention time prediction and protein identification. AB - In bottom-up proteomics, proteins are typically identified by enzymatic digestion into peptides, tandem mass spectrometry and comparison of the tandem mass spectra with those predicted from a sequence database for peptides within measurement uncertainty from the experimentally obtained mass. Although now decreasingly common, isolated proteins or simple protein mixtures can also be identified by measuring only the masses of the peptides resulting from the enzymatic digest, without any further fragmentation. Separation methods such as liquid chromatography and electrophoresis are often used to fractionate complex protein or peptide mixtures prior to analysis by mass spectrometry. Although the primary reason for this is to avoid ion suppression and improve data quality, these separations are based on physical and chemical properties of the peptides or proteins and therefore also provide information about them. Depending on the separation method, this could be protein molecular weight (SDS-PAGE), isoelectric point (IEF), charge at a known pH (ion exchange chromatography), or hydrophobicity (reversed phase chromatography). These separations produce approximate measurements on properties that to some extent can be predicted from amino acid sequences. In the case of molecular weight of proteins without posttranslational modifications this is straightforward: simply add the molecular weights of the amino acid residues in the protein. For IEF, charge and hydrophobicity, the order of the amino acids, and folding state of the peptide or protein also matter, but it is nevertheless possible to predict the behavior of peptides and proteins in these separation methods to a degree which renders such predictions useful. This chapter reviews the topic of using data from separation methods for identification and validation in proteomics, with special emphasis on predicting retention times of tryptic peptides in reversed-phase chromatography under acidic conditions, as this is one of the most commonly used separation methods in proteomics. PMID- 23666724 TI - Algorithms for database-dependent search of MS/MS data. AB - The frequent used bottom-up strategy for identification of proteins and their associated modifications generate nowadays typically thousands of MS/MS spectra that normally are matched automatically against a protein sequence database. Search engines that take as input MS/MS spectra and a protein sequence database are referred as database-dependent search engines. Many programs both commercial and freely available exist for database-dependent search of MS/MS spectra and most of the programs have excellent user documentation. The aim here is therefore to outline the algorithm strategy behind different search engines rather than providing software user manuals. The process of database-dependent search can be divided into search strategy, peptide scoring, protein scoring, and finally protein inference. Most efforts in the literature have been put in to comparing results from different software rather than discussing the underlining algorithms. Such practical comparisons can be cluttered by suboptimal implementation and the observed differences are frequently caused by software parameters settings which have not been set proper to allow even comparison. In other words an algorithmic idea can still be worth considering even if the software implementation has been demonstrated to be suboptimal. The aim in this chapter is therefore to split the algorithms for database-dependent searching of MS/MS data into the above steps so that the different algorithmic ideas become more transparent and comparable. Most search engines provide good implementations of the first three data analysis steps mentioned above, whereas the final step of protein inference are much less developed for most search engines and is in many cases performed by an external software. The final part of this chapter illustrates how protein inference is built into the VEMS search engine and discusses a stand-alone program SIR for protein inference that can import a Mascot search result. PMID- 23666725 TI - Interpretation of tandem mass spectra of posttranslationally modified peptides. AB - Tandem mass spectrometry provides a sensitive means of analyzing the amino acid sequence of peptides and modified peptides by providing accurate mass measurements of precursor and fragment ions. Modern mass spectrometry instrumentation is capable of rapidly generating many thousands of tandem mass spectra and protein database search engines have been developed to match the experimental data to peptide candidates. In most studies there is a schism between discarding perfectly valid data and including nonsensical peptide identifications-this is currently a major bottleneck in data-analysis and it calls for an understanding of tandem mass spectrometry data. Manual evaluation of the data and perhaps experimental cross-checking of the MS data can save many months of experimental work trying to do biological follow-ups based on erroneous identifications. Especially for posttranslationally modified peptides there is a need for manual validation of the data because search algorithms seldom have been optimized for the identification of modified peptides and because there are many pitfalls for the unwary. This chapter describes some of the issues that should be considered when interpreting and validating tandem mass spectra and gives some useful tables to aid this process. PMID- 23666726 TI - Improving Peptide identification using empirical scoring systems. AB - Peptides and proteins are routinely identified from peptide fragmentation spectra acquired in a mass spectrometer, analyzed by database search engines. The types of fragments that can be formed are known, and it is also well appreciated that certain fragment types are more common or more informative than others. However, most search engines do not use detailed knowledge of peptide fragmentation, but rather consider a limited range of fragments, giving each an equivalent weighting in their scoring system that decides which results are likely to be correct. This chapter discusses efforts to make use of information about the frequency of observation of different fragment ion types in order to produce more sophisticated and sensitive scoring systems and demonstrates how these new scoring systems are particularly powerful for analysis of electron capture or electron transfer dissociation data. PMID- 23666727 TI - Methods and algorithms for quantitative proteomics by mass spectrometry. AB - Protein quantitation by mass spectrometry (MS) is attractive since it is possible to obtain both identification and quantitative values of proteins and their posttranslational modifications in a single experiment. In contrast, protein arrays only provide quantitative values of targeted proteins and their modifications. There are an overwhelming number of quantitative MS methods for protein and peptide quantitation. The aim here is to provide an overview of the most common MS methods and algorithms used in quantitative proteomics and discuss the computational algorithms needed to reliably quantitate proteins, peptides, and their posttranslational modifications. One of the main challenges in data analysis of many experimental projects is to pipe together a number of software solutions that are either commercial or freely available. The aim of this chapter is to provide a good set of algorithms, ideas, and resources that can easily be implemented in scripting language like R, Python, or Perl. By understanding the algorithmic ideas presented here, data from any instrument or modified experimental protocol can be analyzed and is therefore in the authors' opinion more valuable than a black box concept. PMID- 23666728 TI - Computational approaches to selected reaction monitoring assay design. AB - Selected reaction monitoring (SRM) is becoming the tool of choice for targeted quantitative proteomics, with applications as diverse as clinical diagnostics and systems biology. Assay design is critical to the success of every SRM experiment. For each protein of interest it is necessary to find a set of peptides that can be monitored as surrogates for that protein. These peptides must satisfy a number of criteria, including uniqueness in the proteome, detectability by mass spectrometry, and suitability of product ion series. Finding peptides that meet all these criteria is time consuming, especially when seeking to quantify multiple proteins in a single run. In response to these challenges, a number of groups have developed freely available tools to assist in the process of SRM assay design-these include databases, online tools, and stand-alone software. This chapter introduces some of these tools and explains how they can help to facilitate reliable SRM experiments. PMID- 23666729 TI - Feature selection and machine learning with mass spectrometry data. AB - Mass spectrometry has been used in biochemical research for a long time. However, its potential of discovering proteomic biomarkers using protein mass spectra aroused tremendous interest in last few years. In spite of its potential of biomarker discovery, it is recognized that identification of meaningful proteomic features from mass spectra needs careful evaluation. Hence, extracting meaningful feature(s) and discriminating the samples based on these features is still an open area of research. Several research groups are actively involved in making the process as perfect as possible. In this chapter, we provide a review of major contributions toward feature selection and classification of proteomic mass spectra involving MALDI-TOF and SELDI-TOF technology. Moreover, in this updated version of the chapter, we advocate the use of an adaptive ensemble classifier to classify such complex data. No single classification algorithm tends to work well on all data. Also, the performance depends on the performance criteria used to judge several classifiers. Adaptive ensemble classifier which is constructed combining several good classifiers and optimized against an array of performance measures tends to have better predictive performance on the test samples. PMID- 23666730 TI - Considerations in the analysis of hydrogen exchange mass spectrometry data. AB - A major component of a hydrogen exchange mass spectrometry experiment is the analysis of protein and peptide mass spectra to yield information about deuterium incorporation. The processing of data that are produced includes the identification of each peptic peptide to create a master table/array of peptide sequence, retention time and retention time range, mass range, and undeuterated mass. The amount of deuterium incorporated into each of the peptides in this array must then be determined. Various software platforms have been developed in order to perform this specific type of data analysis. We describe the fundamental parameters to be considered at each step along the way and how data processing, either by an individual or by software, must approach the analysis. PMID- 23666732 TI - Mass spectrometry methods for studying glycosylation in cancer. AB - Protein glycosylation is a highly complex and regulated posttranslational modification. In this process several glycosyltransferase families are involved. In cancer this delicate equilibrium is disrupted leading to glycosylation changes on glycoconjugates, namely, glycoproteins. One of the major consequences is the increase of sialylated oligosaccharide chains in glycoproteins. Here we describe an experimental methodology focused in the enrichment and characterization of sialic acid containing glycopeptides by MALDI mass spectrometry and the subsequent data analysis. PMID- 23666731 TI - Permethylated N-glycan analysis with mass spectrometry. AB - Protein glycosylation plays an important role in multiple cell functions, and aberrations of protein glycosylation are associated with various malignancies including cancer. In this chapter, we provide a detailed protocol for MALDI MS analysis of permethylated N-glycans extracted from human serum proteins. The protocol includes procedures for N-glycan purification and in-solution permethylation, structural elucidation of permethylated N-glycans by MALDI-QIT TOF MS, and construction of indices to quantify levels of certain types of glycosylation, such as fucosylation, which may serve as a potential disease biomarker. PMID- 23666733 TI - Proteomics data exchange and storage: the need for common standards and public repositories. AB - Both the existence of data standards and public databases or repositories have been key factors behind the development of the existing "omics" approaches. In this book chapter we first review the main existing mass spectrometry (MS)-based proteomics resources: PRIDE, PeptideAtlas, GPMDB, and Tranche. Second, we report on the current status of the different proteomics data standards developed by the Proteomics Standards Initiative (PSI): the formats mzML, mzIdentML, mzQuantML, TraML, and PSI-MI XML are then reviewed. Finally, we present an easy way to query and access MS proteomics data in the PRIDE database, as a representative of the existing repositories, using the workflow management system (WMS) tool Taverna. Two different publicly available workflows are explained and described. PMID- 23666734 TI - Tools for protein posttranslational modifications analysis: FAK, a case study. AB - Recent advances in mass spectrometry have resulted in an exponential increase in annotation of posttranslational modifications (PTMs). Just in the Swiss-Prot Knowledgebase, there are 89,931 of a total of 27 characterized PTM types reported experimentally. A single protein can be dynamically modified during its lifetime for regulation of its function. Considering a PTM can occur at different levels and the number of different PTMs described, the number of possibilities for a single protein is unthinkable. Narrowing the study to a single PTM can be rather unmerited considering that most proteins are heavily modified. Currently crosstalk between PTMs is plentifully reported in the literature. The example of amino acids serine and threonine on one hand and lysine on the other hand, as targets of different modifications, demand a more global analysis approach of a protein. Besides the direct competition for the same amino acid, a PTM can directly or indirectly influence other PTMs in the same protein molecule by for example steric hindrance due to close proximity between the modifications or creation of a binding site such as an SH2 binding domain for protein recruitment and further modifications. Given the complexity of PTMs a number of tools have been developed to archive, analyze, and visualize modifications. VISUALPROT is presented here to demonstrate the usefulness of visualizing all annotated protein features such as amino acid content, domains, amino acid modification sites and single amino acid polymorphisms in a single image. VISUALPROT application is demonstrated for the protein focal adhesion kinase (FAK) as an example. FAK is a highly phosphorylated cytoplasmatic tyrosine kinase comprising different domains and regions. FAK is crucial for integrating signals from integrins and receptor tyrosine kinases in processes such as cell survival, proliferation, and motility. PMID- 23666735 TI - Proteomic strategies to characterize signaling pathways. AB - Cells respond to external stimuli by transducing signals through a series of intracellular molecules and eliciting an appropriate response. The cascade of events through which the signals are transduced include post-translational modifications such as phosphorylation and ubiquitylation in addition to formation of multi-protein complexes. Improvements in biological mass spectrometry and protein/peptide microarray technology have tremendously improved our ability to probe proteins, protein complexes, and signaling pathways in a high-throughput fashion. Today, a single mass spectrometry-based investigation of a signaling pathway has the potential to uncover the large majority of known signaling intermediates painstakingly characterized over decades in addition to discovering a number of novel ones. Here, we discuss various proteomic strategies to characterize signaling pathways and provide protocols for phosphoproteomic analysis. PMID- 23666736 TI - Simple proteomics data analysis in the object-oriented PowerShell. AB - Scripting languages such as Perl and Python are appreciated for solving simple, everyday tasks in bioinformatics. A more recent, object-oriented command shell and scripting language, Windows PowerShell, has many attractive features: an object-oriented interactive command line, fluent navigation and manipulation of XML files, ability to consume Web services from the command line, consistent syntax and grammar, rich regular expressions, and advanced output formatting. The key difference between classical command shells and scripting languages, such as bash, and object-oriented ones, such as PowerShell, is that in the latter the result of a command is a structured object with inherited properties and methods rather than a simple stream of characters. Conveniently, PowerShell is included in all new releases of Microsoft Windows and therefore already installed on most computers in classrooms and teaching labs. In this chapter we demonstrate how PowerShell in particular allows easy interaction with mass spectrometry data in XML formats, connection to Web services for tools such as BLAST, and presentation of results as formatted text or graphics. These features make PowerShell much more than "yet another scripting language." PMID- 23666739 TI - B-cell progenitors and precursors change their microenvironment in fetal liver during early development. AB - The microenvironments, in which B lymphocytes develop in fetal liver, are largely still unknown. Among the nonhematopoietic cells, we have identified and FACS separated two subpopulations, CD45(-) TER119(-) VCAM-1(+) cells that are either CD105(high) LYVE-1(high) or CD105(low) ALCAM(high) . Immunohistochemical analyses find three of four c-Kit(+) IL-7Ralpha(+) B220(low) CD19(-) SLC(-) B progenitors in contact with vascular endothelial-type LYVE-1(high) cells on embryonic day 13.5. One day later c-Kit(+) IL-7Ralpha(+) cells develop to CD19(- and +) , SLC expressing, DHJH-rearranged pre/pro and pro/preB-I cells. Less than 10% are still in contact with LYVE-1(high) cells, but half of them are now in contact with mesenchymally derived ALCAM(high) liver cells. All of these ALCAM(high) cells, but not the LYVE-1(high) cells produce IL-7 and CXCL12, while both produce CXCL10. Progenitors and pro/preB-I cells are chemoattracted in vitro toward CXCL10 and 12, suggesting that lymphoid progenitors with Ig gene loci in germline configuration enter the developing fetal liver at E13.5 from vascular endothelium, attracted by CXCL10, and then migrate within a day to an ALCAM(high) liver cell microenvironment, differentiating to DHJH-rearranging, surrogate light chain-expressing pre/proB and pro/preB-I cells, attracted by CXCL10 and 12. Between E15.5 and E16.5 preB-I cells expand 10-fold in continued contact with ALCAM(high) cells and begin VH- to DHJH-rearrangements in further differentiated c-Kit(-) IL-7Ralpha(-) preBII cells. STEM Cells 2013;31:2800-2812. PMID- 23666740 TI - Ginsenoside Rg1 attenuates concanavalin A-induced hepatitis in mice through inhibition of cytokine secretion and lymphocyte infiltration. AB - The effect of ginsenoside Rg1 (Rg1) on hepatic damage caused by concanavalin A (Con A) has not been fully elucidated. This study was designed to evaluate the protective effect of Rg1 on Con A-induced hepatitis in mice and explore the potential mechanisms of this effect. C57BL/6 mice were divided randomly into the following four experimental groups: phosphate-buffered saline group, Rg1 group, Con A group, Con A + Rg1 group. Mice received Rg1 (20 mg/kg) 3 h before intravenous administration of Con A (15 mg/kg). Levels of alanine transaminase, aspartate transaminase and cytokine production were measured, the amount of phosphorylated IkappaBalpha and p65 were tested, the numbers of CD4(+) and CD8(+) T lymphocytes infiltrated in the blood, spleen and liver were calculated, intercellular adhesion molecule-1 (ICAM-1) and interferon-inducible chemokine-10 (CXCL-10) levels were measured and histological examination of the livers was conducted. Pretreatment with Rg1 markedly reduced the elevated levels of serum aminotransferase, ameliorated liver damage and suppressed proinflammatory cytokines secretion via inhibition NF-kappaB activity following Con A injection of mice. Furthermore, Rg1 administration reduced ICAM-1 and CXCL-10 mRNA expression in the liver as well as the number of CD4(+) and CD8(+) T lymphocytes infiltrating in the liver. Rg1 reduced the incidence of liver damage through inhibition of the proinflammatory response and suppressed the recruitment of CD4(+) and CD8(+) T lymphocytes to the liver. These data indicate that Rg1 represents a novel agent for the treatment of T lymphocyte-dependent liver injury. PMID- 23666741 TI - Alternative splicing of human insulin receptor gene (INSR) in type I and type II skeletal muscle fibers of patients with myotonic dystrophy type 1 and type 2. AB - INSR, one of those genes aberrantly expressed in myotonic dystrophy type 1 (DM1) and type 2 (DM2) due to a toxic RNA effect, encodes for the insulin receptor (IR). Its expression is regulated by alternative splicing generating two isoforms: IR-A, which predominates in embryonic tissue, and IR-B, which is highly expressed in adult, insulin-responsive tissues (skeletal muscle, liver, and adipose tissue). The aberrant INSR expression detected in DM1 and DM2 muscles tissues, characterized by a relative increase of IR-A versus IR-B, was pathogenically related to the insulin resistance occurring in DM patients. To assess if differences in the aberrant splicing of INSR could underlie the distinct fiber type involvement observed in DM1 and DM2 muscle tissues, we have used laser capture microdissection (LCM) and RT-PCR, comparing the alternative splicing of INSR in type I and type II muscle fibers isolated from muscle biopsies of DM1, DM2 patients and controls. In the controls, the relative amounts of IR-A and IR-B showed no obvious differences between type I and type II fibers, as in the whole muscle tissue. In DM1 and DM2 patients, both fiber types showed a similar, relative increase of IR-A versus IR-B, as also evident in the whole muscle tissue. Our data suggest that the distinct fiber type involvement in DM1 and DM2 muscle tissues would not be related to qualitative differences in the expression of INSR. LCM can represent a powerful tool to give a better understanding of the pathogenesis of myotonic dystrophies, as well as other myopathies. PMID- 23666742 TI - Expression of SOCSs in human prostate cancer and their association in prognosis. AB - Suppressors of cytokine signaling (SOCS) proteins have been identified as negative feedback regulators of cytokine-mediated signaling in various tissues, and demonstrated to play critical roles in tumorigenesis and tumor development of different cancers. The involvement of SOCSs in human prostate cancer (PCa) has not been fully elucidated. Thus, the aim of this study is to investigate the expression patterns and the clinical significance of SOCSs in PCa. The expression changes of SOCSs at mRNA and protein levels in human PCa tissues compared with adjacent benign prostate tissues were, respectively, detected by using real-time quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) and immunohistochemistry analyses. The associations of SOCSs expression with clinicopathological features and clinical outcome of PCa patients were further statistically analyzed. Among SOCSs, both QRT-PCR and immunohistochemistry analyses found that SOCS2 expression was upregulated (at mRNA level: change ratio = 1.98, P = 0.031; at protein level: 5.12 +/- 0.60 vs. 2.68 +/- 0.37, P = 0.016) and SOCS6 expression was downregulated (at mRNA level: change ratio = -1.65, P = 0.008; at protein level: 3.03 +/- 0.32 vs. 4.0.72 +/- 0.39, P = 0.004) in PCa tissues compared with those in non-cancerous prostate tissues. In addition, the upregulation of SOCS2 in PCa tissues was correlated with the lower Gleason score (P < 0.001), the absence of metastasis (P < 0.001) and the negative PSA failure (P = 0.009); the downregulation of SOCS6 tended to be found in PCa tissues with the higher Gleason score (P = 0.016), the advanced pathological stage (P = 0.007), the positive metastasis (P = 0.020), and the positive PSA failure (P = 0.032). Furthermore, both univariate and multivariate analyses showed that the downregulation of SOCS2 was an independent predictor of shorter biochemical recurrence-free survival. Our data offer the convincing evidence for the first time that the dysregulation of SOCS2 and SOCS6 may be associated with the aggressive progression of PCa. SOCS2 may be potential markers for prognosis in PCa patients. PMID- 23666743 TI - Protein kinase cdelta deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is a prototype autoimmune disease that is assumed to occur via a complex interplay of environmental and genetic factors. Rare causes of monogenic SLE have been described, providing unique insights into fundamental mechanisms of immune tolerance. The aim of this study was to identify the cause of an autosomal-recessive form of SLE. METHODS: We studied 3 siblings with juvenile-onset SLE from 1 consanguineous kindred and used next-generation sequencing to identify mutations in the disease-associated gene. We performed extensive biochemical, immunologic, and functional assays to assess the impact of the identified mutations on B cell biology. RESULTS: We identified a homozygous missense mutation in PRKCD, encoding protein kinase delta (PKCdelta), in all 3 affected siblings. Mutation of PRKCD resulted in reduced expression and activity of the encoded protein PKCdelta (involved in the deletion of autoreactive B cells), leading to resistance to B cell receptor- and calcium dependent apoptosis and increased B cell proliferation. Thus, as for mice deficient in PKCdelta, which exhibit an SLE phenotype and B cell expansion, we observed an increased number of immature B cells in the affected family members and a developmental shift toward naive B cells with an immature phenotype. CONCLUSION: Our findings indicate that PKCdelta is crucial in regulating B cell tolerance and preventing self-reactivity in humans, and that PKCdelta deficiency represents a novel genetic defect of apoptosis leading to SLE. PMID- 23666745 TI - The CNGCb and CNGCd genes from Physcomitrella patens moss encode for thermosensory calcium channels responding to fluidity changes in the plasma membrane. AB - Land plants need precise thermosensors to timely establish molecular defenses in anticipation of upcoming noxious heat waves. The plasma membrane-embedded cyclic nucleotide-gated Ca(2+) channels (CNGCs) can translate mild variations of membrane fluidity into an effective heat shock response, leading to the accumulation of heat shock proteins (HSP) that prevent heat damages in labile proteins and membranes. Here, we deleted by targeted mutagenesis the CNGCd gene in two Physcomitrella patens transgenic moss lines containing either the heat inducible HSP-GUS reporter cassette or the constitutive UBI-Aequorin cassette. The stable CNGCd knockout mutation caused a hyper-thermosensitive moss phenotype, in which the heat-induced entry of apoplastic Ca(2+) and the cytosolic accumulation of GUS were triggered at lower temperatures than in wild type. The combined effects of an artificial membrane fluidizer and elevated temperatures suggested that the gene products of CNGCd and CNGCb are paralogous subunits of Ca(2+)channels acting as a sensitive proteolipid thermocouple. Depending on the rate of temperature increase, the duration and intensity of the heat priming preconditions, terrestrial plants may thus acquire an array of HSP-based thermotolerance mechanisms against upcoming, otherwise lethal, extreme heat waves. PMID- 23666744 TI - Functional genomics identifies five distinct molecular subtypes with clinical relevance and pathways for growth control in epithelial ovarian cancer. AB - Epithelial ovarian cancer (EOC) is hallmarked by a high degree of heterogeneity. To address this heterogeneity, a classification scheme was developed based on gene expression patterns of 1538 tumours. Five, biologically distinct subgroups - Epi-A, Epi-B, Mes, Stem-A and Stem-B - exhibited significantly distinct clinicopathological characteristics, deregulated pathways and patient prognoses, and were validated using independent datasets. To identify subtype-specific molecular targets, ovarian cancer cell lines representing these molecular subtypes were screened against a genome-wide shRNA library. Focusing on the poor prognosis Stem-A subtype, we found that two genes involved in tubulin processing, TUBGCP4 and NAT10, were essential for cell growth, an observation supported by a pathway analysis that also predicted involvement of microtubule-related processes. Furthermore, we observed that Stem-A cell lines were indeed more sensitive to inhibitors of tubulin polymerization, vincristine and vinorelbine, than the other subtypes. This subtyping offers new insights into the development of novel diagnostic and personalized treatment for EOC patients. PMID- 23666746 TI - High protein intake stimulates postprandial GLP1 and PYY release. AB - OBJECTIVE: Meals high in protein induce greater intermeal satiety than meals high in fat and carbohydrates. We studied the gut hormone response and subsequent food intake after breakfasts high in protein, carbohydrate or high in fat controlled for volume, calories and appearance. DESIGN AND METHODS: Eight healthy volunteers participated in this randomized three-way crossover study. Study breakfasts were calculated to provide 20% of daily energy requirements and provided either 60% of energy from protein, fat or carbohydrate. Blood was drawn half-hourly for 4 h; energy intake at a subsequent ad libitum meal was measured. RESULTS: Total ghrelin decreased after food intake equally with the three breakfasts. PYY levels were highest after the high protein breakfast (P = 0.005). Indeed, PYY at 240 min was highest after the high protein breakfast compared to the high fat breakfast and to the high carbohydrate breakfast (P = 0.011 and P = 0.012, respectively). GLP-1 levels were highest after the high protein breakfast (P = 0.041) at 120 min and remained higher throughout the study. These differences in gut hormones did not translate into differences in food intake (1023 +/- 390 kcal after high protein, 1016 +/- 388 kcal after high fat and 1158 +/- 433 kcal after high carbohydrate). CONCLUSION: We conclude that a high protein meal increases circulating concentrations of the gut hormones PYY and GLP-1, but when meals are matched for volume, appearance and caloric value, these gut hormone changes do not translate into a reduction in ad libitum food intake. PMID- 23666747 TI - Protective effects of gallium, germanium, and strontium against ovariectomized osteoporosis in rats. AB - The effects of trace elements of gallium (Ga), germanium (Ge), and strontium (Sr) on ovariectomized (OVX) osteopenic rats were studied in this paper. The urine calcium content, serum calcium, and phosphorus contents, bone mineral content, mineral dissolution, and mechanical strength of the osteopenic rats were analyzed respectively. After the rats were fed with Ga, Ge, and Sr diet for 8 weeks, respectively, the urine calcium content decreased (P < 0.01). Plasma calcium and phosphate concentrations decreased in the order of OVX group > Ge group > Sr group > Ga group > Sham group. Mineral content increased in the order of OVX group < Ge group < Sr group < Ga group < Sham group. A dramatic decrease in calcium solubility was found both in the gallium and strontium treated animals (P < 0.05). However, the same result did not occur in germanium treated groups. The data provide an important proof of concept that gallium and strontium might be a new potential therapy for the management of postmenopausal osteoporosis in humans. PMID- 23666748 TI - Parallel polymer reactions of a polyfluorene derivative by electrochemical oxidation and reduction. PMID- 23666749 TI - Sendai virus transgene in a novel gene therapy for laryngotracheal disease. AB - OBJECTIVES/HYPOTHESIS: Vocal cord scar formation and laryngotracheal stenosis (LTS) are challenging problems for otolaryngologists. Sendai virus (SeV) vectors have been shown to transduce airway epithelium efficiently, and are thus ideal for modulating airway wound-healing therapy. To assess the potential utility of SeV gene therapy for laryngotracheal diseases, we established a novel LTS model and examined the transduction efficiency of SeV vectors in normal and LTS model tissue. STUDY DESIGN: Basic science. METHODS: Fusion (F) gene-deleted, nontransmissible SeV vectors were used. First, the route dependency and transduction efficiency of SeV vectors for normal mucosa in the larynx were examined. Next, the novel LTS rat model was established and evaluated. Finally, the transduction efficiency of SeV vectors in injured mucosa of the LTS model was evaluated. RESULTS: Simple spray delivery of the SeV vector resulted in significant and persistent expression of the reporter gene in normal laryngotracheal epithelium. Transgenic SeV-mediated expression was maximal at 3 days, decreased over time, but remained detectable for 14 days after administration. No serious side effects were observed in the larynx or trachea. The model achieved an average of 60% tracheal stenosis in the cross-sectional area. Efficient SeV-mediated transgene expression was observed in the injured mucosa at the levels of the trachea, cricoid cartilage, and vocal cord. CONCLUSION: A novel animal model for LTS was established. We successfully demonstrated SeV-mediated transgene expression in normal tissue and in the injured mucosa of the LTS model. SeV might be a promising strategy for gene therapy in laryngotracheal diseases. PMID- 23666750 TI - Endogenous osteopontin promotes ozone-induced neutrophil recruitment to the lungs and airway hyperresponsiveness to methacholine. AB - Inhalation of ozone (O3), a common environmental pollutant, causes pulmonary injury, pulmonary inflammation, and airway hyperresponsiveness (AHR) in healthy individuals and exacerbates many of these same sequelae in individuals with preexisting lung disease. However, the mechanisms underlying these phenomena are poorly understood. Consequently, we sought to determine the contribution of osteopontin (OPN), a hormone and a pleiotropic cytokine, to the development of O3 induced pulmonary injury, pulmonary inflammation, and AHR. To that end, we examined indices of these aforementioned sequelae in mice genetically deficient in OPN and in wild-type, C57BL/6 mice 24 h following the cessation of an acute (3 h) exposure to filtered room air (air) or O3 (2 parts/million). In wild-type mice, O3 exposure increased bronchoalveolar lavage fluid (BALF) OPN, whereas immunohistochemical analysis demonstrated that there were no differences in the number of OPN-positive alveolar macrophages between air- and O3-exposed wild-type mice. O3 exposure also increased BALF epithelial cells, protein, and neutrophils in wild-type and OPN-deficient mice compared with genotype-matched, air-exposed controls. However, following O3 exposure, BALF neutrophils were significantly reduced in OPN-deficient compared with wild-type mice. When airway responsiveness to inhaled acetyl-beta-methylcholine chloride (methacholine) was assessed using the forced oscillation technique, O3 exposure caused hyperresponsiveness to methacholine in the airways and lung parenchyma of wild-type mice, but not OPN deficient mice. These results demonstrate that OPN is increased in the air spaces following acute exposure to O3 and functionally contributes to the development of O3-induced pulmonary inflammation and airway and lung parenchymal hyperresponsiveness to methacholine. PMID- 23666751 TI - Endothelial colony-forming cell conditioned media promote angiogenesis in vitro and prevent pulmonary hypertension in experimental bronchopulmonary dysplasia. AB - Late-outgrowth endothelial colony-forming cells (ECFCs), a type of circulating endothelial progenitor cell (EPC), may contribute to pulmonary angiogenesis during development. Cord blood ECFCs from preterm newborns proliferate more rapidly than term ECFCs but are more susceptible to the adverse effects of hyperoxia. Recent studies suggest that bone marrow-derived EPCs protect against experimental lung injury via paracrine mechanisms independent of vascular engraftment. To determine whether human umbilical cord blood ECFCs from preterm and term newborns have therapeutic benefit in experimental neonatal lung injury, we isolated cord blood ECFCs from full-term and preterm newborns and prepared ECFC-conditioned medium (CM) to test its therapeutic benefit on fetal pulmonary artery endothelial cell (PAEC) proliferation and function as well as alveolar type 2 (AT2) cell growth. PAECs and AT2 cells were isolated from late-gestation fetal sheep. Additionally, we administered both ECFCs and ECFC-CM to bleomycin exposed newborn rats, an experimental model of bronchopulmonary dysplasia (BPD). Both term ECFC-CM and preterm ECFC-CM promoted cell growth and angiogenesis in vitro. However, when ECFC-CM was collected during exposure to mild hyperoxia, the benefit of preterm ECFC-CM was no longer observed. In the bleomycin model of BPD, treatment with ECFC-CM (or CM from mature EC) effectively decreased right ventricular hypertrophy but had no effect on alveolar septation. We conclude that term ECFC-CM is beneficial both in vitro and in experimental BPD. During oxidative stress, preterm ECFC-CM, but not term ECFC-CM, loses its benefit. The inability of term ECFC-CM to promote alveolarization may limit its therapeutic potential. PMID- 23666752 TI - IVF culture medium affects human intrauterine growth as early as the second trimester of pregnancy. AB - STUDY QUESTION: When does a difference in human intrauterine growth of singletons conceived after IVF and embryo culture in two different culture media appear? SUMMARY ANSWER: Differences in fetal development after culture of embryos in one of two IVF media were apparent as early as the second trimester of pregnancy. WHAT IS KNOWN ALREADY: Abnormal fetal growth patterns are a major risk factor for the development of chronic diseases in adult life. Previously, we have shown that the medium used for culturing embryos during the first few days after fertilization significantly affects the birthweight of the resulting human singletons. The exact onset of this growth difference was unknown. STUDY DESIGN, SIZE AND DURATION: In this retrospective cohort study, all 294 singleton live births after fresh embryo transfer in the period July 2003 to December 2006 were included. These embryos originated from IVF treatments that were part of a previously described clinical trial. Embryos were allocated to culture in either Vitrolife or Cook commercially available sequential culture media. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analysed ultrasound examinations at 8 (n = 290), 12 (n = 83) and 20 weeks' (n = 206) gestation and used first trimester serum markers [pregnancy-associated plasma protein-A (PAPP-A) and free beta-hCG]. Differences between study groups were tested by the Student's t-test, chi(2) test or Fisher's exact test, and linear multivariable regression analysis to adjust for possible confounders (for example, parity, gestational age at the time of ultrasound and fetal gender). MAIN RESULTS AND THE ROLE OF CHANCE: A total of 294 singleton pregnancies (Vitrolife group nVL = 168, Cook group: nC = 126) from 294 couples were included. At 8 weeks' gestation, there was no difference between crown-rump length-based and ovum retrieval-based gestational age (DeltaGA) (nVL = 163, nC = 122, adjusted mean difference, -0.04 days, P = 0.84). A total of 83 women underwent first-trimester screening at 12 weeks' gestation (nVL = 45, nC = 38). DeltaGA, nuchal translucency (multiples of median, MoM) and PAPP-A (MoM) did not differ between the study groups. Free beta-hCG (MoM) +/- SEM differed significantly (1.55 +/- 0.19 in Vitrolife versus 1.06 +/- 0.10 in Cook; P = 0.031, Student's t-test). At 20 weeks' gestation, a more advanced GA, reflecting an increased fetal growth, was seen at ultrasound examination in the Vitrolife group (n = 115) when compared with the Cook group (n = 91). After adjustment for confounding factors, both the difference between GA based on three biparietal diameter dating formulas minus the actual (ovum retrieval based) GA (adjusted mean difference + 1.14 days (P = 0.04), +1.14 days (P = 0.04) and +1.36 days (P = 0.048)), as well as head circumference (HC) and trans-cerebellar diameter (TCD) were significantly higher in the Vitrolife group (HCvl 177.3 mm, HCc 175.9 mm, adjusted mean difference 1.8, P = 0.03; TCDvl 20.5 mm, TCDc 20.2 mm, adjusted mean difference 0.4, P = 0.008). LIMITATIONS, REASONS FOR CAUTION: A first trimester (12 weeks) fetal screening was not yet offered routinely during the study period, therefore only 28% of women in our study participated in this elective screening programme. Although all sonographers were experienced and specially trained to perform these ultrasound examinations and were unaware of the randomization procedure, we cannot totally rule out possible intra- and inter-observer variability. Despite being indispensable in daily practice, sonographic weight formulas have a limited accuracy. WIDER IMPLICATIONS OF THE FINDINGS: According to the fetal origins hypothesis, many adult diseases originate in utero owing to adaptations made by the fetus to the environment it encounters. This study indicates that the embryonic environment is already important for fetal development. Therefore, our study emphasizes the need to investigate fetal growth patterns after assisted reproduction technologies and long-term health outcomes of IVF children, especially in relation to the culture medium used during the first few days of preimplantation development. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 23666753 TI - Reply: Extended culture and the risk of preterm delivery in singletons: confounding by indication? PMID- 23666754 TI - Extended culture and the risk of preterm delivery in singletons: confounding by indication? PMID- 23666755 TI - The neural crest transcription factor Brn3a is expressed in melanoma and required for cell cycle progression and survival. AB - Pigment cells and neuronal cells both are derived from the neural crest. Here, we describe the Pit-Oct-Unc (POU) domain transcription factor Brn3a, normally involved in neuronal development, to be frequently expressed in melanoma, but not in melanocytes and nevi. RNAi-mediated silencing of Brn3a strongly reduced the viability of melanoma cell lines and decreased tumour growth in vivo. In melanoma cell lines, inhibition of Brn3a caused DNA double-strand breaks as evidenced by Mre11/Rad50-containing nuclear foci. Activated DNA damage signalling caused stabilization of the tumour suppressor p53, which resulted in cell cycle arrest and apoptosis. When Brn3a was ectopically expressed in primary melanocytes and fibroblasts, anchorage-independent growth was increased. In tumourigenic melanocytes and fibroblasts, Brn3a accelerated tumour growth in vivo. Furthermore, Brn3a cooperated with proliferation pathways such as oncogenic BRAF, by reducing oncogene-induced senescence in non-malignant melanocytes. Together, these results identify Brn3a as a new factor in melanoma that is essential for melanoma cell survival and that promotes melanocytic transformation and tumourigenesis. PMID- 23666756 TI - Kallistatin antagonizes Wnt/beta-catenin signaling and cancer cell motility via binding to low-density lipoprotein receptor-related protein 6. AB - Kallistatin, a plasma protein, exerts pleiotropic effects in inhibiting angiogenesis, inflammation and tumor growth. Canonical Wnt signaling is the primary pathway for oncogenesis in the mammary gland. In this study, we demonstrate that kallistatin bound to the Wnt coreceptor low-density lipoprotein receptor-related protein 6 (LRP6), thus, blocking Wnt/beta-catenin signaling and Wnt-mediated growth and migration in MDA-MB-231 breast cancer cells. Kallistatin inhibited Wnt3a-induced proliferation, migration, and invasion of cultured breast cancer cells. Moreover, kallistatin was bound to LRP6 in breast cancer cells, as identified by immunoprecipitation followed by western blot. Kallistatin suppressed Wnt3a-mediated phosphorylation of LRP6 and glycogen synthase kinase 3beta, and the elevation of cytosolic beta-catenin levels. Furthermore, kallistatin antagonized Wnt3a-induced expression of c-Myc, cyclin D1, and vascular endothelial growth factor. These findings indicate a novel role of kallistatin in preventing breast tumor growth and mobility by direct interaction with LRP6, leading to blockade of the canonical Wnt signaling pathway. PMID- 23666757 TI - MicroRNA-19a targets tissue factor to inhibit colon cancer cells migration and invasion. AB - The over-expression of tissue factor (TF) and its roles in colon cancer progression have attracted much attention. However, the mechanisms regulating TF expression have not yet been shown in detail. In this study, we over-expressed miR-19a, miR20a and miR-106b in colon cancer cells, and evaluated their impact on TF expression and cellular function. We provide evidence demonstrating that miR 19a inhibited TF expression in vitro. Luciferase reporter assay confirmed that TF was a direct target of miR-19a because the miR-19a mediated repression of luciferase activity was abolished by mutation of the putative binding site. Moreover, miR-19a suppressed colon cancer cell migration and invasion. This effect was due to the indirect down-regulation of matrix metalloproteinase 9. Finally, we investigated the relevance of TF and miR-19a expression in a total of 48 paired colon cancer samples and revealed that miR-19a was inversely correlated with TF expression in stages I and II cases. Therefore, our results suggested that miR-19a was capable of suppressing TF expression in vitro and inhibiting cell migration and invasion. Although it was not the unique mechanism responsible for the expression of TF in vivo, miR-19a was inversely correlated with TF expression in early stage colon cancer patients. PMID- 23666758 TI - Manipulation of kynurenine pathway for enhanced daptomycin production in Streptomyces roseosporus. AB - Daptomycin is a cyclic lipopeptide natural product produced by Stretptomyces roseosporus, displaying good bactericidal activity against a wide range of gram positive pathogens. Daptomycin contains a 13 amino acid and kynurenine (Kyn) is essential for optimal activity of daptomycin. In this study, we characterized the Kyn pathway in S. roseosporus and investigated its role in supplying precursor for daptomycin biosynthesis. Two genes (dptJ and tdo) coding for tryptophan-2,3 dioxgenase existed in the chromosome. dptJ is located in the daptomycin biosynthetic gene cluster, while tdo is in other locus. Disruption of dptJ or tdo resulted in reduced yield by ~50%. The introduction of an additional copy of dptJ but not tdo led to enhanced production of daptomycin by 110%. Furthermore, disruption of kyn encoding kynureninase showed improved daptomycin productivity by 30%. Our results demonstrated that the enhancement of Kyn supply through metabolic engineering approach is an efficient way to increase daptomycin production. PMID- 23666759 TI - Brain morphometric changes associated with childhood-onset systemic lupus erythematosus and neurocognitive deficit. AB - OBJECTIVE: To use structural magnetic resonance imaging (MRI) to characterize changes in gray matter and white matter volumes between patients with childhood onset systemic lupus erythematosus (SLE) and matched controls, between patients with childhood-onset SLE with and those without neurocognitive deficit, and in relation to disease duration and treatment with steroids. METHODS: Twenty-two patients with childhood-onset SLE and 19 healthy controls underwent high resolution structural MRI. Probability density maps for gray matter and white matter were compared between groups. RESULTS: Neuropsychological testing confirmed the presence of neurocognitive deficit in 8 patients with childhood onset SLE. Multiple brain regions had reduced gray matter volume in the patients with childhood- onset SLE with neurocognitive deficit versus controls or patients with childhood-onset SLE without neurocognitive deficit. Neither disease duration nor cumulative oral or intravenous steroid doses accounted for decreases in gray matter. White matter volume was also reduced in patients with childhood-onset SLE with neurocognitive deficit, and the reduction was positively associated with both disease duration and cumulative oral steroid dose. Conversely, higher cumulative intravenous steroid doses were associated with higher white matter volumes. CONCLUSION: Neurocognitive deficit in patients with childhood-onset SLE is associated with multifocal decreases in both gray and white matter volumes. Since only white matter volume changes are related to disease duration and cumulative oral steroid use, this may suggest that gray and white matter alterations relate to different underlying mechanisms. Further work is needed to understand the relationship between gray and white matter alterations in childhood-onset SLE, whether the underlying mechanisms relate to immunologic, vascular, or other causes, and whether the changes are reversible or preventable. Likewise, the protective properties of intravenous steroids in maintaining white matter volumes require confirmation in larger cohorts. PMID- 23666761 TI - Facial artery musculomucosal flap for reconstruction of skull base defects: a cadaveric study. AB - OBJECTIVES/HYPOTHESIS: Failure in skull base defects reconstruction following tumor resection can have serious consequences such as ascending meningitis and pneumocephaly. The nasoseptal flap showed a very low incidence of cerebrospinal fluid leak but is not always available. The superiorly pedicled facial artery musculomucosal (FAMM) flap has been successfully used for reconstruction of head and neck defects. Our objective is to show that the FAMM flap can be used as a new alternative in skull base reconstruction. STUDY DESIGN: Cadaveric study. Feasibility. METHODS: Thirteen specimens underwent bilateral FAMM flap dissection. Two new modifications of the traditional FAMM flap have been developed. Feasibility in FAMM flap transfer to the skull base was investigated through endoscopic skull base dissection and maxillectomy in four specimens. Measurements were recorded for each harvested flap. RESULTS: The mean surface area of the modified FAMM flap efficient for reconstruction was 15.90 cm(2) . The flaps easily covered the simulated defects of the frontal sinus and the fovea ethmoidalis areas. Modifications of the traditional FAMM flap were necessary for a tension-free coverage of the planum sphenoidale and sella turcica. CONCLUSION: The FAMM flap holds high potential as a new alternative vascular flap in skull base reconstruction. However, it has not been used in patients yet and should be considered only when other options are not available. New modifications developed in this article can elongate the traditional FAMM flap, potentially contributing to a tighter seal of the skull base defect than FAMM flap alone. PMID- 23666760 TI - Fetal deficiency of lin28 programs life-long aberrations in growth and glucose metabolism. AB - LIN28A/B are RNA binding proteins implicated by genetic association studies in human growth and glucose metabolism. Mice with ectopic over-expression of Lin28a have shown related phenotypes. Here, we describe the first comprehensive analysis of the physiologic consequences of Lin28a and Lin28b deficiency in knockout (KO) mice. Lin28a/b-deficiency led to dwarfism starting at different ages, and compound gene deletions showed a cumulative dosage effect on organismal growth. Conditional gene deletion at specific developmental stages revealed that fetal but neither neonatal nor adult deficiency resulted in growth defects and aberrations in glucose metabolism. Tissue-specific KO mice implicated skeletal muscle-deficiency in the abnormal programming of adult growth and metabolism. The effects of Lin28b KO could be rescued by Tsc1 haplo-insufficiency in skeletal muscles. Our data implicate fetal expression of Lin28a/b in the regulation of life-long effects on metabolism and growth, and demonstrate that fetal Lin28b acts at least in part via mTORC1 signaling. PMID- 23666762 TI - Role of individual MARK isoforms in phosphorylation of tau at Ser262 in Alzheimer's disease. AB - The microtubule-affinity regulating kinase (MARK) family consists of four highly conserved members that have been implicated in phosphorylation of tau protein, causing formation of neurofibrillary tangles in Alzheimer's disease (AD). Understanding of roles by individual MARK isoform in phosphorylating tau has been limited due to lack of antibodies selective for each MARK isoform. In this study, we first applied the proximity ligation assay on cells to select antibodies specific for each MARK isoform. In cells, a CagA peptide specifically and significantly inhibited tau phosphorylation at Ser262 mediated by MARK4 but not other MARK isoforms. We then used these antibodies to study expression levels of MARK isoforms and interactions between tau and individual MARK isoforms in postmortem human brains. We found a strong and significant elevation of MARK4 expression and MARK4-tau interactions in AD brains, correlating with the Braak stages of the disease. These results suggest the MARK4-tau interactions are of functional importance in the progression of AD and the results also identify MARK4 as a promising target for AD therapy. PMID- 23666763 TI - Musculoskeletal function following bariatric surgery. AB - OBJECTIVE: Bariatric surgery is an effective method for acute weight loss. While the impact of bariatric surgery on general medical conditions (e.g., type 2 diabetes) is well documented, few studies focus on physical functional outcomes following weight-loss induced by bariatric surgery. DESIGN AND METHODS: We report on 50 women aged 20-74 scheduled for Roux-en-Y gastric bypass (RYGB) procedure who were enrolled for a prospective 1-year study. Height, weight, and waist circumference were recorded preoperatively and at 6 and 12 months, postoperatively. To track musculoskeletal/physical function changes, the timed get-up-and-go (TGUG) and short-form health survey-36 (SF-36) and short musculoskeletal function assessment (SFMA) questionnaires were administered. RESULTS: Patients had significant weight loss and functional improvement. At 1 year mean weight loss was 48.5 kg and mean TGUG improvement was 3.1 s. SMFA and SF-36 also showed improvement in functional components with weight loss at 6 months and 1-year post surgery. Significant associations were observed between TGUG and SMFA measures at all time points. Final weight at 1 year post bariatric surgery was also significantly correlated with most functional outcomes and changes in these outcomes. Partial correlations controlling for age revealed additional associations between body weight and functional outcomes, especially at the 6-month visit. CONCLUSION: Our results suggest that significant rapid weight loss, such as that attained by bariatric surgery, acutely improves musculoskeletal function in morbidly obese patients. Additionally, for patients with musculoskeletal disease or injury, weight loss resulting from bariatric surgery may serve as an adjunct for improving global functional outcome, and enhancing the rehabilitation potential. PMID- 23666764 TI - Lipotropes promote immunobiochemical plasticity and protect fish against low-dose pesticide-induced oxidative stress. AB - An experiment was conducted to evaluate the role of different lipotropes in modulating immunity and biochemical plasticity under conditions of sublethal low dose pesticide-induced stress in fish. Labeo rohita fish fingerlings were divided in two sets with one set of fish continuously exposed to low-dose endosulfan (1/10th of 96-h LC50) for 21 days, the other was unexposed, and both sets of fish were fed with practical diets supplemented with either 2 % lecithin, 0.5 % betaine, or 0.1 % choline and compared against unsupplemented diet. Low-dose endosulfan exposure had adverse effects (P < 0.05/P < 0.01) on hematological profile (erythrocyte count, hemoglobin, and hematocrit), serum protein (total protein, albumin, and globulin) and lipid profile (cholesterol and triglyceride), anti-oxidative status (ascorbic acid content of muscle, liver, brain, and kidney and activity of anti-oxidative enzymes: catalase and superoxide dismutase), neurotransmission (acetylcholinesterase activity in muscle and brain), immunological attributes (WBC count, albumin to globulin ratio, phagocytic activity, and serum cortisol), and metabolic plasticity as revealed from enzyme activities (muscle lactate dehydrogenase, liver and kidney glucose-6-phosphatase dehydrogenase-G6PDH activity). Dietary lipotropes prevented these effects completely or partially and the effects were lipotrope dependent. Kinetics (maximum velocity value V max, catalytic efficiency and Michaelis constant K m) of G6PDH enzyme from crude extracts of liver and kidney indicated inhibition due to endosulfan but lipotropes could protect enzyme and showed a stabilizing effect. The supplements also helped maintain integrity of histoarchitecture of the hepatocytes in endosulfan-exposed fish to a great extent. Feeding lipotropes to fish reared in endosulfan-free water also improved hematological and serum protein and lipid profiles and were immunostimulatory. In conclusion, dietary lipotropes, especially betaine and lecithin at the levels used, improve erythropoiesis, serum protein and lipid profile, anti-oxidant status, immunocompetence, neurotransmission, and protect the livers of L. rohita fingerlings even when continuously exposed to low-dose endosulfan. PMID- 23666765 TI - DNASE1L3 mutations in hypocomplementemic urticarial vasculitis syndrome. AB - OBJECTIVE: Hypocomplementemic urticarial vasculitis syndrome (HUVS) is characterized by recurrent urticaria along with dermal vasculitis, arthritis, and glomerulonephritis. Systemic lupus erythematosus (SLE) develops in >50% of patients with HUVS, although the pathogenesis is unknown. The aim of this study was to identify the causative DNA mutations in 2 families with autosomal recessive HUVS, in order to reveal the pathogenesis and facilitate the laboratory diagnosis. METHODS: Autozygosity mapping was combined with whole-exome sequencing. RESULTS: In a family with 3 affected children, we identified a homozygous frameshift mutation, c.289_290delAC, in DNASE1L3. We subsequently identified another homozygous DNASE1L3 mutation leading to exon skipping, c.320+4delAGTA, in an unrelated family. The detected mutations led to loss of function, via either nonsense-mediated messenger RNA decay or abolished endonuclease activity, as demonstrated by a plasmid nicking assay. CONCLUSION: These results show that HUVS is caused by mutations in DNASE1L3, encoding an endonuclease that previously has been associated with SLE. PMID- 23666766 TI - Rapid estimation of cartilage T2 with reduced T1 sensitivity using double echo steady state imaging. AB - PURPOSE: In principle, double echo steady state (DESS) offers morphological and quantitative T2 imaging of cartilage within one single scan. However, accurate T2 estimation is hampered by its prominent T1 dependency in the limit of low flip angles, generally used to image cartilage morphology, as for the osteoarthritis initiative. A new postprocessing approach is introduced to overcome this T1 related bias for rapid DESS-based T2 quantification in the low flip angle regime. METHODS: Based on a rough global T1 estimator and a golden section search, T2 is extracted from the ratio of the two echoes acquired with DESS. The new relaxometry method is evaluated from simulations and in vivo 3D measurements of the knee joint at 3T. RESULTS: A pronounced reduction in the T1-related bias of DESS-T2 estimation and increased zonal variation in T2 between deep and superficial cartilage layers are observed. The improvement becomes particularly evident in the range of low flip angles (alpha < 45 degrees ), commonly used for morphological DESS imaging. CONCLUSION: Using a simple global T1 estimate, the reliability of DESS-T2 quantification can be considerably increased. The results emphasize the potential of DESS to fuse accurate quantitative T2 and morphological imaging of the musculoskeletal system within one single scan. PMID- 23666767 TI - The critical flux method for reduced filter membrane fouling when monitoring high solids digesters. AB - Membrane fouling currently makes filtration of high-solids anaerobic sludges difficult and this is discouraging online monitoring of volatile fatty acids and control of high-solids digesters. The present study tests the critical flux approach to reduce membrane fouling. Filtration tests are performed on two sludges, filtered via a side-stream off two full-scale digesters. Sub-critical flux operating conditions (for minimal cake layer formation) are identified for each of the sludges and the filtration units are operated at these conditions to assess longer term performance. Results for one of the sludges (co-digested primary and secondary sludge) is found to be encouraging, showing that sufficient flux rates (up to 40 L m(-2) h(-1)) can be readily sustained to allow longer term digester monitoring and control. Filtration performance for this sludge did not deteriorate significantly over the test period. Results for the other test sludge (digested thermally hydrolyzed waste activated sludge) were not as favorable and indicated that application may be limited for very high solids digesters (>5% total solids concentration). Differences in filtration behavior for the two test sludges were ascribed to the presence of complex soluble organics, the concentration of sludge solids and their particle size. PMID- 23666768 TI - Multipotential differentiation of human urine-derived stem cells: potential for therapeutic applications in urology. AB - We sought to biologically characterize and identify a subpopulation of urine derived stem cells (USCs) with the capacity for multipotent differentiation. We demonstrated that single USCs can expand to a large population with 60-70 population doublings. Nine of 15 individual USC clones expressed detectable levels of telomerase and have long telomeres. These cells expressed pericyte and mesenchymal stem cell markers. Upon induction with appropriate media in vitro, USCs differentiated into bladder-associated cell types, including functional urothelial and smooth muscle cell lineages. When the differentiated USCs were seeded onto a scaffold and subcutaneously implanted into nude mice, multilayered tissue-like structures formed consisting of urothelium and smooth muscle. Additionally, USCs were able to differentiate into endothelial, osteogenic, chondrogenic, adipogenic, skeletal myogenic, and neurogenic lineages but did not form teratomas during the 1-month study despite telomerase activity. USCs may be useful in cell-based therapies and tissue engineering applications, including urogenital reconstruction. PMID- 23666770 TI - Anatomical reconstructions of pediatric airways from endoscopic images: a pilot study of the accuracy of quantitative endoscopy. AB - OBJECTIVES/HYPOTHESIS: To evaluate the accuracy of three-dimensional (3D) airway reconstructions obtained using quantitative endoscopy (QE). We developed this novel technique to reconstruct precise 3D representations of airway geometries from endoscopic video streams. This method, based on machine vision methodologies, uses a post-processing step of the standard videos obtained during routine laryngoscopy and bronchoscopy. We hypothesize that this method is precise and will generate assessment of airway size and shape similar to those obtained using computed tomography (CT). STUDY DESIGN: This study was approved by the institutional review board (IRB). We analyzed video sequences from pediatric patients receiving rigid bronchoscopy. METHODS: We generated 3D scaled airway models of the subglottis, trachea, and carina using QE. These models were compared to 3D airway models generated from CT. We used the CT data as the gold standard measure of airway size, and used a mixed linear model to estimate the average error in cross-sectional area and effective diameter for QE. RESULTS: The average error in cross sectional area (area sliced perpendicular to the long axis of the airway) was 7.7 mm(2) (variance 33.447 mm(4)). The average error in effective diameter was 0.38775 mm (variance 2.45 mm(2)), approximately 9% error. CONCLUSION: Our pilot study suggests that QE can be used to generate precise 3D reconstructions of airways. This technique is atraumatic, does not require ionizing radiation, and integrates easily into standard airway assessment protocols. We conjecture that this technology will be useful for staging airway disease and assessing surgical outcomes. PMID- 23666769 TI - Effects of alkali supplementation and vitamin D insufficiency on rat skeletal muscle. AB - Data on the independent and potential combined effects of acid-base balance and vitamin D status on muscle mass and metabolism are lacking. We investigated whether alkali supplementation with potassium bicarbonate (KHCO3), with or without vitamin D3 (+/- VD3), alters urinary nitrogen (indicator of muscle proteolysis), muscle fiber cross-sectional area (FCSA), fiber number (FN), and anabolic (IGF-1, Akt, p70s6k) and catabolic (FOXO3a, MURF1, MAFbx) signaling pathways regulating muscle mass. Thirty-six, 20-month-old, Fischer 344/Brown Norway rats were randomly assigned in a 2 * 2 factorial design to one of two KHCO3-supplemented diets (+/- VD3) or diets without KHCO3 (+/- VD3) for 12 weeks. Soleus, extensor digitorum longus (EDL), and plantaris muscles were harvested at 12 weeks. Independent of VD3 group, KHCO3 supplementation resulted in 35 % lower mean urinary nitrogen to creatinine ratio, 10 % higher mean type I FCSA (adjusted to muscle weight), but no statistically different mean type II FCSA (adjusted to muscle weight) or FN compared to no KHCO3. Among VD3-replete rats, phosphorylated Akt protein expression was twofold higher in the KHCO3 compared to no KHCO3 groups, but this effect was blunted in rats on VD3-deficient diets. Neither intervention significantly affected serum or intramuscular IGF-1 expression, p70s6k or FOXO3a activation, or MURF1 and MAFbx gene expression. These findings provide support for alkali supplementation as a promising intervention to promote preservation of skeletal muscle mass, particularly in the setting of higher vitamin D status. Additional research is needed in defining the muscle biological pathways that are being targeted by alkali and vitamin D supplementation. PMID- 23666771 TI - Farber disease: understanding a fatal childhood disorder and dissecting ceramide biology. PMID- 23666772 TI - The mind your health project: a randomized controlled trial of an innovative behavioral treatment for obesity. AB - OBJECTIVE: To determine whether acceptance-based behavioral treatment (ABT) would result in greater weight loss than standard behavioral treatment (SBT), and whether treatment effects were moderated by interventionist expertise or participants' susceptibility to eating cues. Recent research suggests that poor long-term weight-control outcomes are due to lapses in adherence to weight control behaviors and that adherence might be improved by enhancing SBT with acceptance-based behavioral strategies. DESIGN AND METHODS: Overweight participants (n = 128) were randomly assigned to 40 weeks of SBT or ABT. RESULTS: Both groups produced significant weight loss, and when administered by experts, weight loss was significantly higher in ABT than SBT at post-treatment (13.17% vs. 7.54%) and 6-month follow-up (10.98% vs. 4.83%). Moreover, 64% of those receiving ABT from experts (vs. 46% for SBT) maintained at least a 10% weight loss by follow-up. Moderation analyses revealed a powerful advantage, at follow up, of ABT over SBT in those potentially more susceptible to eating cues. For participants with greater baseline depression symptomology, weight loss at follow up was 11.18% in ABT versus 4.63% in SBT; other comparisons were 10.51% versus 6.00% (emotional eating), 8.29% versus 6.35% (disinhibition), and 9.70% versus 4.46% (responsivity to food cues). Mediation analyses produced partial support for theorized food-related psychological acceptance as a mechanism of action. CONCLUSIONS: Results offer strong support for the incorporation of acceptance based skills into behavioral weight loss treatments, particularly among those with greater levels of depression, responsivity to the food environment, disinhibition, and emotional eating, and especially when interventions are provided by weight-control experts. PMID- 23666773 TI - Synthesis of (+)-schisanwilsonene A by tandem gold-catalyzed cyclization/1,5 migration/cyclopropanation. PMID- 23666774 TI - Squamous cell carcinomas confined to the bronchial wall: the effect of growth patterns. AB - BACKGROUND: Squamous cell carcinomas confined to the bronchial wall (SCC-CBW) exhibit two distinct patterns of growth: superficially spreading and endobronchial mass lesions. We examined whether differences exist in the histopathological features and prognosis of SCC-CBW exhibiting different growth patterns. MATERIALS AND METHODS: In this study, 37 cases with SCC-CBW were included. Tumors were classified into two groups: superficially spreading squamous cell carcinoma (s-SCC) and nodular squamous cell carcinoma (n-SCC). For each case, the growth pattern, T and N status, lymphovascular and perineural invasions, immunohistochemical expressions of p53 and Ki-67, and survival rates were analyzed. RESULTS: Twenty cases were classified as s-SCC, and 17 cases were classified as n-SCC. There was a significant relationship and correlation between the length of s-SCC in the longitudinal axis and the depth of invasion (p = 0.01, R = 0.557). There was a statistically significant positive relationship between the depth of invasion and the nodal status (N1 involvement) (p < 0.0001, R = 0.71). CONCLUSIONS: SCC-CBW exhibits variable growth patterns. However, despite this variability, there are no biological or histological differences between tumors of different growth patterns, and this variability has very little, if any, effect on survival. PMID- 23666775 TI - What are the obstacles to training in surgery for congenital heart disease in Germany? AB - In recent years, several publications from German institutions have highlighted the need for quality assessment, complexity and risk interpretation, and assurance of sustainable structures in congenital heart surgery. In addition, there is a severe shortage of congenital cardiac surgeons in Germany. To provide quality assurance, the German Society for Thoracic and Cardiovascular Surgery (DGTHG, Deutsche Gesellschaft fur Thorax-, Herz- und Gefabetachirurgie) offers a Certificate for Congenital Cardiac Surgery, which is awarded with proof of a minimal number of congenital procedures. We outline that there are too many low volume centers in Germany putting the cardiac surgeon into the role of a "soloist." In this situation, adequate training cannot be provided in the majority of the centers in Germany. Furthermore, a considerable reduction of the specifically required operations in the "Weiterbildungsordnung fur die Arzte" (WBO) will be paramount for the future. There should be a stronger consideration for the specific requirements for congenital heart surgeons, to make their training shorter and less cumbersome. Also, the DGTHG's Certificate for Congenital Cardiac Surgery should be tailored to realistic needs in the field of congenital surgery. An adjustment of both the WBO and the Certificate would be in line with the justified claim made in the recommendations of the DGTHG. PMID- 23666777 TI - Using statistical text classification to identify health information technology incidents. AB - OBJECTIVE: To examine the feasibility of using statistical text classification to automatically identify health information technology (HIT) incidents in the USA Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database. DESIGN: We used a subset of 570 272 incidents including 1534 HIT incidents reported to MAUDE between 1 January 2008 and 1 July 2010. Text classifiers using regularized logistic regression were evaluated with both 'balanced' (50% HIT) and 'stratified' (0.297% HIT) datasets for training, validation, and testing. Dataset preparation, feature extraction, feature selection, cross-validation, classification, performance evaluation, and error analysis were performed iteratively to further improve the classifiers. Feature selection techniques such as removing short words and stop words, stemming, lemmatization, and principal component analysis were examined. MEASUREMENTS: kappa statistic, F1 score, precision and recall. RESULTS: Classification performance was similar on both the stratified (0.954 F1 score) and balanced (0.995 F1 score) datasets. Stemming was the most effective technique, reducing the feature set size to 79% while maintaining comparable performance. Training with balanced datasets improved recall (0.989) but reduced precision (0.165). CONCLUSIONS: Statistical text classification appears to be a feasible method for identifying HIT reports within large databases of incidents. Automated identification should enable more HIT problems to be detected, analyzed, and addressed in a timely manner. Semi-supervised learning may be necessary when applying machine learning to big data analysis of patient safety incidents and requires further investigation. PMID- 23666776 TI - Health information technologies in geriatrics and gerontology: a mixed systematic review. AB - OBJECTIVE: To review, categorize, and synthesize findings from the literature about the application of health information technologies in geriatrics and gerontology (GGHIT). MATERIALS AND METHODS: This mixed-method systematic review is based on a comprehensive search of Medline, Embase, PsychInfo and ABI/Inform Global. Study selection and coding were performed independently by two researchers and were followed by a narrative synthesis. To move beyond a simple description of the technologies, we employed and adapted the diffusion of innovation theory (DOI). RESULTS: 112 papers were included. Analysis revealed five main types of GGHIT: (1) telecare technologies (representing half of the studies); (2) electronic health records; (3) decision support systems; (4) web based packages for patients and/or family caregivers; and (5) assistive information technologies. On aggregate, the most consistent finding proves to be the positive outcomes of GGHIT in terms of clinical processes. Although less frequently studied, positive impacts were found on patients' health, productivity, efficiency and costs, clinicians' satisfaction, patients' satisfaction and patients' empowerment. DISCUSSION: Further efforts should focus on improving the characteristics of such technologies in terms of compatibility and simplicity. Implementation strategies also should be improved as trialability and observability are insufficient. CONCLUSIONS: Our results will help organizations in making decisions regarding the choice, planning and diffusion of GGHIT implemented for the care of older adults. PMID- 23666778 TI - Indexed distribution analysis for improved significance testing of spatially heterogeneous parameter maps: application to dynamic contrast-enhanced MRI biomarkers. AB - PURPOSE: To develop significance testing methodology applicable to spatially heterogeneous parametric maps of biophysical and physiological measurements arising from imaging studies. THEORY: Heterogeneity can confound statistical analyses. Indexed distribution analysis (IDA) transforms a reference distribution, establishing correspondences across parameter maps to which significance tests are applied. METHODS: Well-controlled simulated and clinical K(trans) data from a dynamic contrast-enhanced magnetic resonance imaging study of bevacizumab were analyzed using conventional significance tests of parameter averages, histogram analysis, and IDA. Repeated pretreatment scans provided negative control; a post treatment scan provided positive control. RESULTS: Histogram analysis was insensitive to simulated and known effects. Simulation: conventional analysis identified treatment effect (P ~ 5 * 10(-4)) and direction, but underestimated magnitude (relative error 67-81%); IDA identified treatment effect (P = 0.001), magnitude, direction, and spatial extent (100% accuracy). Bevacizumab: conventional analysis was sensitive to treatment effect (P = 0.01; 95% confidence interval on K(trans) decrease: 23-37%); IDA was sensitive to treatment effect (P < 0.05; K(trans) decrease approximately 25%), inferred its spatial extent to be 94-96%, and inferred that K(trans) decrease is independent of baseline value, an inference that conventional and histogram analyses cannot make. CONCLUSIONS: In the presence of heterogeneity, IDA can accurately infer the magnitude, direction, and spatial extent of between samples of parametric maps, which can be visualized spatially with respect to the original parameter maps. PMID- 23666779 TI - Expression of a metagenome-derived fumarate reductase from marine microorganisms and its characterization. AB - A potential novel fumarate reductase gene designated frd1A was isolated by screening a marine metagenomic library through a sequence-based strategy. Sequence analyses indicated that Frd1A and other putative fumarate reductases were closely related. The putative fumarate reductase gene was subcloned into a pETBlue-2 vector and expressed in Escherichia coli Tuner(DE3)pLacI cells. The recombinant protein was purified to homogeneity. Functional characterization by high-performance liquid chromatography demonstrated that the recombinant Frd1A protein could catalyze the hydrogenation of fumarate to succinate acid. The Frd1A protein displayed an optimal activity at pH 7.0 and 28 degrees C, which could be stimulated by adding metal ions such as Zn(2+) and Mg(2+). The Frd1A enzyme showed a comparable affinity and catalytic efficiency under optimal reaction conditions: k m =0.227 mmol/L, v max= 29.9 U/mg, and k cat/k m=5.44 * 10(4) per mol/s. The identification of Frd1A protein underscores the potential of marine metagenome screening for novel biomolecules. PMID- 23666782 TI - Editorial: entering the age of whole-exome sequencing in rheumatic diseases: novel insights into disease pathogenicity. PMID- 23666780 TI - In vivo protection of activated Tyr22-dihydrofolate reductase gene-modified canine T lymphocytes from methotrexate. AB - BACKGROUND: Nonmyeloablative allogeneic hematopoietic stem cell (HSC) transplantation can cure malignant and nonmalignant diseases affecting the hematopoietic system, such as severe combined immunodeficiencies, aplastic anemia and hemoglobinopathies. Although nonmyeloablative is favored over myeloablative transplantation for many patients, graft rejection remains problematic. One strategy for decreasing rejection is to protect donor activated T cells in the graft from methotrexate (MTX) by genetically modifying the cells to express MTX resistant dihydrofolate reductase (Tyr22-DHFR), leaving the immunosuppressive effects of MTX to act solely on activated host T lymphocytes, shifting the balance to favor allogeneic engraftment. METHODS: To evaluate MTX resistance of Tyr22-DHFR(+) T lymphocytes in vivo, we transplanted dogs with autologous CD34(+) cells modified with yellow fluorescent protein (YFP) and DHFR-green fluorescent protein (GFP) lentivirus vectors. Dogs were then treated with a standard MTX regimen days 1, 3, 6 and 11) following immune activation with a foreign antigen as a surrogate assay to mimic early transplantation. RESULTS: DHFR-GFP(+) gene marking was maintained in CD3(+) CD25(+) and CD4(+) T lymphocytes after MTX treatment, whereas the level of T lymphocytes that expressed only a fluorescent reporter (YFP(+) ) decreased. These data show that Tyr22-DHFR expression protects T lymphocytes from MTX toxicity in dogs, highlighting a clinically relevant application for preserving donor T lymphocytes during post-transplantation immunosuppression. CONCLUSIONS: The findings of the present study have implications for the clinical translation of MTX-resistant T cells to facilitate engraftment of allogeneic cells following nonmyeloablative conditioning and to minimize the risk of rejection. In summary, Tyr22-DHFR expression in T lymphocytes provides chemoprotection from MTX-mediated elimination in the context of immune activation in vivo. PMID- 23666781 TI - Enzymatic digestion of alkaline-sulfite pretreated sugar cane bagasse and its correlation with the chemical and structural changes occurring during the pretreatment step. AB - Sugar cane bagasse is recalcitrant to enzymatic digestion, which hinders the efficient conversion of its polysaccharides into fermentable sugars. Alkaline sulfite pretreatment was used to overcome the sugar cane bagasse recalcitrance. Chemical and structural changes that occurred during the pretreatment were correlated with the efficiency of the enzymatic digestion of the polysaccharides. The first 30 min of pretreatment, which removed approximately half of the initial lignin and 30% of hemicellulose seemed responsible for a significant enhancement of the cellulose conversion level, which reached 64%. After the first 30 min of pretreatment, delignification increased slightly, and hemicellulose removal was not enhanced; however, acid groups continued to be introduced into the residual lignin. Water retention values were 145% to the untreated bagasse and 210% to the bagasse pretreated for 120 min and fiber widths increased from 10.4 to 30 MUm, respectively. These changes were responsible for an additional increase in the efficiency of enzymatic hydrolysis of the cellulose, which reached 92% with the 120 min pretreated sample. PMID- 23666783 TI - Growth-associated protein-43 expression in cocultures of dorsal root ganglion neurons and skeletal muscle cells with different neurotrophins. AB - INTRODUCTION: Both target skeletal muscle (SKM) cells and neurotrophins (NTs) are essential for the maintenance of neuronal function and nerve-muscle communication. The effects of different NTs and SKM cells on growth-associated protein-43 (GAP-43) expression in dorsal root ganglion (DRG) neurons have not been clarified. METHODS: The morphological relationship between DRG neurons and SKM cells in neuromuscular cocultures was observed by scanning electron microscopy. The levels of GAP-43 and its mRNA were determined after administration of different NTs. RESULTS: DRG neurons demonstrated dense neurite outgrowth in the presence of NTs. Distinct NTs promoted GAP-43 and its mRNA expression in neuromuscular cocultures of DRG neurons and SKM cells. CONCLUSIONS: These results offer new clues for a better understanding of the effects of distinct NTs on GAP-43 expression in DRG sensory neurons in the presence of target SKM cells and implicate NTs and target SKM cells in DRG neuronal regeneration. PMID- 23666784 TI - Obesity prevention programs and policies: practitioner and policy-maker perceptions of feasibility and effectiveness. AB - OBJECTIVES: The aims of this study were to map obesity prevention activity being implemented by government, non-government, and community-based organizations; to determine practitioner and policy-maker perceptions of the feasibility and effectiveness of a range of evidence-based obesity prevention strategies; and to determine practitioner and policy-maker perceptions of preferred settings for obesity prevention strategies. DESIGN AND METHODS: This study involved a cross sectional survey of 304 public health practitioners and policy-makers from government, non-government, and community organizations across Victoria, Australia. Participants reported their organizations' current obesity prevention programs and policies, their own perceptions of the feasibility and effectiveness of strategies to prevent obesity and their preferred settings for obesity prevention. RESULTS: Thirty-nine percent had an obesity prevention policy, and 92% were implementing obesity prevention programs. The most common programs focused on education, skill-building, and increasing access to healthy eating/physical activity opportunities. School curriculum-based initiatives, social support for physical activity, and family-based programs were considered the most effective strategies, whereas curriculum-based initiatives, active after school programs, and providing access to and information about physical activity facilities were deemed the most feasible strategies. Schools were generally perceived as the most preferred setting for obesity prevention. CONCLUSION: Many organizations had obesity prevention programs, but far fewer had obesity prevention policies. Current strategies and those considered feasible and effective are often mismatched with the empirical literature. Systems to ensure better alignment between researchers, practitioners, and policy-makers, and identifying effective methods of translating empirical evidence into practice and policy are required. PMID- 23666785 TI - Brede tools and federating online neuroinformatics databases. AB - As open science neuroinformatics databases the Brede Database and Brede Wiki seek to make distribution and federation of their content as easy and transparent as possible. The databases rely on simple formats and allow other online tools to reuse their content. This paper describes the possible interconnections on different levels between the Brede tools and other databases. PMID- 23666786 TI - A highly step-economical synthesis of dictyostatin. PMID- 23666787 TI - Review: evidence that systemic sclerosis is a vascular disease. PMID- 23666788 TI - Background field removal using spherical mean value filtering and Tikhonov regularization. AB - PURPOSE: To introduce a new method for removing background artifacts in field maps and apply it to enhance the accuracy of susceptibility mapping. METHODS: A field artifact removal method is introduced that is based on the sophisticated harmonic artifact reduction for phase data (SHARP) method exploiting the harmonic mean value property. The new method uses Tikhonov regularization at the deconvolution stage and is referred to as regularization enabled SHARP (RESHARP). RESHARP was compared with SHARP in a field-forward susceptibility simulation and in human brain experiments, considering effects on both field maps and the resulting susceptibility maps. RESULTS: From the simulation, RESHARP was able to reduce error in the field map by 17.4% as compared with SHARP, resulting in a more accurate single-angle susceptibility map with 6.5% relative error (compared with 48.5% using SHARP). Using RESHARP in vivo, field and susceptibility maps of the brain displayed fewer artifacts particularly at the brain boundaries, and susceptibility measurements of iron-rich deep gray matter were also more consistent than SHARP across healthy subjects of similar age. CONCLUSION: Compared with SHARP, RESHARP removes background field artifact more effectively, leading to more accurate susceptibility measurements in iron-rich deep gray matter. PMID- 23666790 TI - Gender specific patterns of carbon uptake and water use in a dominant riparian tree species exposed to a warming climate. AB - Air temperatures in the arid western United States are predicted to increase over the next century. These increases will likely impact the distribution of plant species, particularly dioecious species that show a spatial segregation of the sexes across broad resource gradients. On the basis of spatial segregation patterns, we hypothesized that temperature increases will have a greater negative impact on female plants compared with co-occurring male plants of dioecious species. This hypothesis was tested by examining the whole-plant carbon and water relations of 10-year-old female (n = 18) and male (n = 13) Acer negundo Sarg. trees grown in a common garden in Salt Lake City, UT. The trees were established from cuttings collected where the growing season temperature averaged about 6.5 degrees C cooler than at the common garden. During May and June, stem sap flux (Js ) was similar between genders, but averaged 25% higher in males during the warmer months of July and August. Daytime canopy stomatal conductance (gs ) per unit leaf area was 12% higher in females in May : June, but was 11% higher in males in July : August. We combined measurements of sap flux-scaled transpiration with measurements of tree allometry and delta(13) C of leaf soluble sugars to estimate whole-tree carbon assimilation (Atree ) and water use efficiency (WUE) (Atree : Etree ). Atree was similar between genders until late August when Atree was 32% higher in male trees. Atree : Etree was on average 7% higher in females than in males during the growing season. Patterns of Js , gs , Atree and Atree : Etree in the present study were in contrast to those previously reported for A. negundo genders under native growing season temperatures. Results suggest that the spatial segregation of the sexes could shift under global warming such that female plants lose their dominance in high-resource habitats, and males increase their dominance in relatively lower-resource habitats. PMID- 23666789 TI - Development and evaluation of sustained-release etoposide-loaded poly(epsilon caprolactone) implants. AB - Poly(epsilon-caprolactone) implants containing etoposide, an important chemotherapeutic agent and topoisomerase II inhibitor, were fabricated by a melt method and characterized in terms of content uniformity, morphology, drug physical state, and sterility. In vitro and in vivo drug release from the implants was also evaluated. The cytotoxic activity of implants against HeLa cells was studied. The short-term tolerance of the implants was investigated after subcutaneous implantation in mice. The original chemical structure of etoposide was preserved after incorporation into the polymeric matrix, in which the drug was dispersed uniformly. Etoposide was present in crystalline form in the polymeric implant. In vitro release study showed prolonged and controlled release of etoposide, which showed cytotoxicity activity against HeLa cells. After implantation, good correlation between in vitro and in vivo drug release was found. The implants demonstrated good short-term tolerance in mice. These results tend to show that etoposide-loaded implants could be potentially applied as a local etoposide delivery system. PMID- 23666791 TI - Assessment of endothelial dysfunction by flow-mediated dilatation in men on long term androgen deprivation therapy for prostate cancer. AB - NEW FINDINGS: What is the central question of this study? Androgen deprivation therapy (ADT) for prostate cancer has been linked with increased cardiovascular risk, but the mechanisms are unclear. Is there evidence that endothelial dysfunction, as evidenced by reduced flow-mediated dilatation (FMD), is associated with ADT? What is the main finding and its importance? Reduction in FMD with preservation of glyceryl trinitrate-mediated dilatation indicates endothelial dysfunction in men with prostate cancer on long-term ADT compared with well-matched control subjects. Vascular endothelial dysfunction associated with long-term ADT for prostate cancer might explain the observed epidemiological increases in adverse cardiovascular events. Assessment of FMD may be useful in the monitoring of cardiovascular risk in men with prostate cancer on ADT. Androgen deprivation therapy (ADT) in men with prostate cancer has been linked to an increased incidence of cardiovascular events and mortality, but the underpinning mechanisms are unclear. Endothelial dysfunction is considered a precursor for cardiovascular disease. Previous studies have reported variably on the association between ADT and endothelial function. This blinded case-control study examined endothelial function, using high-resolution ultrasound to measure flow-mediated dilatation (FMD) and glyceryl trinitrate (GTN)-mediated-dilatation in the brachial artery, in 20 men with prostate cancer (69 +/- 7 years old) treated by ADT (median duration 22 months, range 6-133 months) and 20 men without prostate cancer (69 +/- 5 years old) matched for age, physical activity, coexistent cardiovascular disease and body mass index. The magnitude of dilatation was calculated traditionally and allometrically scaled, adjusting for baseline diameter. There were no differences between groups for resting vascular measures (means +/- SD). Flow-mediated dilatation was lower in men on ADT than in control subjects (3.9 +/- 2.1 versus 5.9 +/- 3.8% for traditional, P = 0.047; 3.7 +/- 2.7 versus 6.0 +/- 2.7% for allometrically scaled, P = 0.023). Response to GTN was similar in both groups (12.2 +/- 4.2 versus 14.8 +/- 5.7% for traditional, P = 0.113; 12.3 +/- 4.6 versus 14.4 +/- 4.6% for allometrically scaled, P = 0.163). The magnitude of difference in mean FMD between groups was marginally altered to 2.4% (95% confidence interval 0.3-4.5) after adjustment for the difference in body fat mass and concomitant cardiovascular medication, with the difference in FMD remaining significant (P = 0.029). There is evidence of endothelial dysfunction in men with prostate cancer on long-term ADT. Although a causal relationship is unproven, the findings are consistent with observational reports of adverse cardiovascular outcomes associated with long-term ADT for prostate cancer. PMID- 23666792 TI - Pulmonary vascular mechanics: important contributors to the increased right ventricular afterload of pulmonary hypertension. AB - Chronic hypoxia causes pulmonary vasoconstriction and vascular remodelling, which lead to hypoxic pulmonary hypertension (HPH). Hypoxic pulmonary hypertension is associated with living at high altitudes and is a complication of many lung diseases, including chronic obstructive pulmonary disease, cystic fibrosis and obstructive sleep apnoea. Pulmonary vascular changes that occur with HPH include stiffening and narrowing of the pulmonary arteries that appear to involve all vascular cell types and sublayers of the arterial wall. Right ventricular (RV) changes that occur with HPH include RV hypertrophy and RV fibrosis, often with preserved systolic and diastolic function and ventricular-vascular coupling efficiency. Both vascular stiffening and vascular narrowing are important contributors to RV afterload via increases in oscillatory and steady ventricular work, respectively. The increased blood viscosity that occurs in HPH can be dramatic and is another important contributor to RV afterload. However, the viscosity, vascular mechanics and ventricular changes that occur with HPH are all reversible. Furthermore, even with continued hypoxia the vascular remodelling does not progress to the obliterative, plexiform lesions that are seen clinically in severe pulmonary hypertension. In animal models, the RV changes appear adaptive, not maladaptive. In summary, HPH-induced vascular mechanical changes affect ventricular function, but both are adaptive and reversible, which differentiates HPH from severe pulmonary hypertension. The mechanisms of adaptation and reversibility may provide useful insight into therapeutic targets for the clinical disease state. PMID- 23666793 TI - Exacerbation of myasthenia gravis with voriconazole. AB - INTRODUCTION: We describe a patient with stable generalized myasthenia gravis who presented with new onset severe ophthalmoplegia and ptosis after initiation of voriconazole for aspergillosis. METHODS: Ligand-protein docking software was used to simulate the interaction of voriconazole with the acetylcholine receptor (AChR). We tested voriconazole binding to AChR in comparison to high affinity and neutral compounds. RESULTS: There was no clinical improvement after intravenous immunoglobulin infusion and plasmapheresis. However, the patient improved slowly after withdrawal of voriconazole. Based on our results, voriconazole binds favorably to AChR and may putatively block muscle nicotinic AChRs. Other theoretical explanations include blocking potassium channels and reducing their intracellular trafficking. CONCLUSIONS: The mechanisms involved in ocular exacerbation may be multi-factorial, reflecting the intricate dynamics of the neuromuscular junction. It is important to consider medications that harbor pyridine or pyrimidine moieties as potential causes of exacerbation in myasthenic patients, especially those who present with ocular symptoms. PMID- 23666794 TI - From health search to healthcare: explorations of intention and utilization via query logs and user surveys. AB - OBJECTIVE: To better understand the relationship between online health-seeking behaviors and in-world healthcare utilization (HU) by studies of online search and access activities before and after queries that pursue medical professionals and facilities. MATERIALS AND METHODS: We analyzed data collected from logs of online searches gathered from consenting users of a browser toolbar from Microsoft (N=9740). We employed a complementary survey (N=489) to seek a deeper understanding of information-gathering, reflection, and action on the pursuit of professional healthcare. RESULTS: We provide insights about HU through the survey, breaking out its findings by different respondent marginalizations as appropriate. Observations made from search logs may be explained by trends observed in our survey responses, even though the user populations differ. DISCUSSION: The results provide insights about how users decide if and when to utilize healthcare resources, and how online health information seeking transitions to in-world HU. The findings from both the survey and the logs reveal behavioral patterns and suggest a strong relationship between search behavior and HU. Although the diversity of our survey respondents is limited and we cannot be certain that users visited medical facilities, we demonstrate that it may be possible to infer HU from long-term search behavior by the apparent influence that health concerns and professional advice have on search activity. CONCLUSIONS: Our findings highlight different phases of online activities around queries pursuing professional healthcare facilities and services. We also show that it may be possible to infer HU from logs without tracking people's physical location, based on the effect of HU on pre- and post-HU search behavior. This allows search providers and others to develop more robust models of interests and preferences by modeling utilization rather than simply the intention to utilize that is expressed in search queries. PMID- 23666795 TI - Geometrical constraints limiting the poly(ADP-ribose) conformation investigated by molecular dynamics simulation. AB - Poly(ADP-ribosylation) is a post-transductional modification that regulates protein's function. Most of the proteins subjected to this control mechanism belong to machineries involved in DNA damage repair, or DNA interacting proteins. Poly(ADP-ribose) polymers are long chains of even 100 monomer length that can be branched at several positions but, not withstanding its importance, nothing is known concerning its structure. To understand, which are the geometrical parameters that confer to the polymer the structural constraints that determine its interaction with the target proteins, we have performed molecular dynamics of three chains of different length, made by 5, 25, and 30 units, the last one being branched. Analysis of the simulations allowed us to identify the main intra- and inter-monomer dihedral angles that govern the structure of the polymer that however, does not reach a unique definite conformation. PMID- 23666796 TI - "Recombinant protein of the day": using daily student presentations to add real world aspects to a biotechnology course. PMID- 23666797 TI - Merlin, the NF2 gene product. AB - Merlin, the protein product of NF2 gene, is one of the most versatile tumor suppressors capable of integrating different mechanisms that regulate cell proliferation, motility, survival and signaling pathways underlying and governing those mechanisms. Merlin is considered a member of the band 4.1 families of cytoskeleton-associated proteins also called ERM family and acts as tumor suppressor. The main cause for transformation of Schwann cells into schwannomas is credited to the inactivation of the neurofibromin 2 (NF2) gene and the consecutive loss of its protein merlin. Recent scientific advances improved our understanding of pathogenic mechanisms involving NF2 gene. The present review brings genetic properties of NF2 gene, molecular characteristics of merlin, summarizes mutational spectra and explains merlin's multifunctional roles regarding its involvement in neurofibromatosis associated tumorigenesis. PMID- 23666798 TI - Undifferentiated (anaplastic) thyroid carcinoma and iodine intake in Salta, Argentina. AB - This study was conducted to investigate the natural history of undifferentiated thyroid carcinoma (UTC) in the iodine-deficient province of Salta, Argentina, in relation to salt iodization and health care standards. Five hundred ninety-three thyroid cancers diagnosed from 1958 to2012 were reviewed based mainly on the WHO classification and grouped into three periods, one before and two after iodine prophylaxis. The incidence of UTC was analyzed in relation to changing concentrations of potassium iodide (KI) in salt during the prophylaxis period (from 40 to 33.3 mg KI/kg salt), establishment of primary health care centers throughout the region, and use of fine needle aspiration (FNA) cytology. Twenty nine UTCs were found in the whole series. The frequency of UTC decreased from 15.2 % (9/59 cases) in the first period to 2.6 % (10/381 cases) well after salt iodination (x (2) Fisher's test, p < 0.0002), and the incidence from 1.4/10(6)/year to 0.1/10(6)/year (Student's t test, p < 0.06), respectively. The decline of UTC after iodine prophylaxis occurred even after decreasing concentrations of KI in salt and timely coincided with the establishment of primary health care centers throughout the region and routine use of FNA. The lower rate of UTC after iodine prophylaxis in the province of Salta is mostly related to earlier detection of more differentiated thyroid tumors rather than higher salt iodization. PMID- 23666799 TI - Rhodium(III)-catalyzed synthesis of cyclopenta[b]pyrroles from 1,2-diketones, 2 aminopyridine, and alkynes. AB - Pyrrole victory: Cyclopenta[b]pyrroles have been synthesized by the rhodium(III) catalyzed oxidative annulative coupling of 1,2-diketones, 2-aminopyridine, and alkynes. This transformation can also be carried out in a one-pot sequence, thereby providing a quick and straightforward access to synthetically and pharmaceutically important cyclopenta[b]pyrroles. PMID- 23666800 TI - Predicting shifts in parasite distribution with climate change: a multitrophic level approach. AB - Climate change likely will lead to increasingly favourable environmental conditions for many parasites. However, predictions regarding parasitism's impacts often fail to account for the likely variability in host distribution and how this may alter parasite occurrence. Here, we investigate potential distributional shifts in the meningeal worm, Parelaphostrongylosis tenuis, a protostrongylid nematode commonly found in white-tailed deer in North America, whose life cycle also involves a free-living stage and a gastropod intermediate host. We modelled the distribution of the hosts and free-living larva as a complete assemblage to assess whether a complex trophic system will lead to an overall increase in parasite distribution with climate change, or whether divergent environmental niches may promote an ecological mismatch. Using an ensemble approach to climate modelling under two different carbon emission scenarios, we show that whereas the overall trend is for an increase in niche breadth for each species, mismatches arise in habitat suitability of the free living larva vs. the definitive and intermediate hosts. By incorporating these projected mismatches into a combined model, we project a shift in parasite distribution accounting for all steps in the transmission cycle, and identify that overall habitat suitability of the parasite will decline in the Great Plains and southeastern USA, but will increase in the Boreal Forest ecoregion, particularly in Alberta. These results have important implications for wildlife conservation and management due to the known pathogenicity of parelaphostrongylosis to alternate hosts including moose, caribou and elk. Our results suggest that disease risk forecasts which fail to consider biotic interactions may be overly simplistic, and that accounting for each of the parasite's life stages is key to refining predicted responses to climate change. PMID- 23666801 TI - Surgical behaviour. PMID- 23666802 TI - Increased acylation stimulating protein levels in young obese males is correlated with systemic markers of oxidative stress. AB - OBJECTIVE: As little is known about relationship between acylation stimulating protein (ASP) and oxidative stress, whether there is any link between ASP and oxidative stress in young obese males were investigated. DESIGN AND METHODS: Forty-five obese (median body mass index (BMI) = 36.99 (IQR = 3.65) kg m(-2)) male subjects (median age = 22 (IQR = 6) years) and 24 age-matched (median age = 22.5 (IQR = 4.8) years) healthy male volunteers (median body mass index (BMI) = 23.67 (IQR = 2.45) kg m(-2)) were recruited into the study. All obese subjects have BMI > 30 kg m(-2), while all controls have BMI < 25 kg m(-2). RESULTS: Fasting plasma ASP, lipid hydroperoxide, high sensitivity C-reactive protein (hs CRP), fasting insulin, triglyceride, LDL-cholesterol levels and HOMA-IR were higher, whereas the mean HDL-cholesterol levels and glutathione peroxidase (GPx) enzyme activity were significantly lower in obese subjects than controls. The linear regression analysis showed that lipid hydroperoxide was independently associated with only BMI, while ASP was independently associated with BMI and triglyceride. CONCLUSIONS: The present data support the concept that obesity occurs under condition of compex interactions by adipokines, insulin, inflammation, and oxidative stress. PMID- 23666803 TI - Sphingosine 1-phosphate counteracts the effects of interleukin-1beta in human chondrocytes. AB - OBJECTIVE: The lipid mediator sphingosine 1-phosphate (S1P) is found in the synovial fluid of osteoarthritis (OA) patients. S1P protects bovine cartilage by counteracting the effects of interleukin-1beta (IL-1beta). This study was undertaken to examine the interaction of S1P and IL-1beta in human OA chondrocytes. METHODS: Human cartilage was obtained from patients undergoing total knee joint replacement. Chondrocytes were cultured in monolayer and treated with IL-1beta and S1P. Expression of S1P receptor subtypes and genes involved in cartilage degradation was evaluated using real-time polymerase chain reaction, immunohistochemistry, and Western blotting. S1P signaling was evaluated using inhibitors of S1P receptors and small interfering RNA (siRNA) knockdown of the S1P2 receptor. Phosphorylation of MAP kinases and NF-kappaB in response to IL 1beta and S1P was detected by Western blotting. RESULTS: S1P2 was identified as the most prevalent S1P receptor subtype in human OA cartilage and chondrocytes in vitro. S1P reduced expression of inducible nitric oxide synthase (iNOS) in IL 1beta-treated chondrocytes. Reduction of ADAMTS-4 and matrix metalloproteinase 13 expression by S1P correlated with S1P2 expression. Pharmacologic inhibition of the S1P2 receptor, but not the S1P1 and S1P3 receptors, abrogated the inhibition of iNOS expression. Similar results were observed using siRNA knockdown. S1P signaling inhibited IL-1beta-induced phosphorylation of p38 MAPK. CONCLUSION: In human chondrocytes, S1P reduces the induction of catabolic genes in the presence of IL-1beta. Activation of the S1P2 receptor counteracts the detrimental phosphorylation of p38 MAPK by IL-1beta. PMID- 23666804 TI - Ancestral founder mutations in calpain-3 in the Indian Agarwal community: historical, clinical, and molecular perspective. AB - INTRODUCTION: Clinical heterogeneity of limb-girdle muscular dystrophies (LGMDs, 24 known subtypes), which includes overlapping phenotypes and varying ages of onset and morbidity, adds complexity to clinical and molecular diagnoses. METHODS: To diagnose LGMD subtype, protein analysis, using immunohistochemistry (IHC) and immunoblotting, was followed by gene sequencing through a panel approach (simultaneous sequencing of known LGMD genes) in 9 patients from unrelated families of the Indian Agarwal community. Haplotype studies were performed by targeted SNP genotyping to establish mutation segregation. RESULTS: We identified 2 founder mutations in CAPN3, a missense (c.2338G>C; p.D780H) and a splice-site (c.2099-1G>T) mutation, on 2 different haplotype backgrounds. The patients were either heterozygous for both or homozygous for either of these mutations. CONCLUSIONS: Founder mutations have immediate clinical application, at least in selected population groups. Clinically available gene panels may provide a definitive molecular diagnosis for heterogeneous disorders such as LGMD. PMID- 23666805 TI - Comparisons of multi-morbidity in family practice--issues and biases. AB - BACKGROUND: As the population ages, practice and policy need to be guided by accurate estimates of chronic disease burden in primary care. OBJECTIVE: To produce a preliminary set of methodological considerations for cross-sectional and retrospective cohort studies of multi-morbidity in primary care using three studies as examples. Prevalence rate results from the three studies were re estimated using identical age-sex groups. METHODS: We compared the methods and results of three separate studies in primary care: (i) patients in the Saguenay region of Quebec, Canada (2005); (ii) a substudy of the BEACH (Bettering the Evaluation and Care of Health) programme in Australia (2008); and (iii) the DELPHI (Deliver Primary Health Care Information) project in South-western Ontario, Canada (2009). Areas where the methods of multi-morbidity studies may differ were identified. The percentage of patients with two or more chronic conditions was compared by age-sex groups. RESULTS: Multi-morbidity prevalence varied by as much as 61%, where reported prevalence was 95% among females aged 45 64 in the Saguenay study, 46% in the BEACH substudy and 34% in the DELPHI study. Several aspects of the methods and study designs were identified as differing among the studies, including the sampling of frequent attenders, sampling period, source of data, and both the definition and count of chronic conditions. CONCLUSIONS: Understanding the differences among the methods used to produce prevalence data on multi-morbidity in primary care can help explain the varying results. Standardization of methods would allow for more valid inter-study comparisons. PMID- 23666806 TI - Are prescribed benzodiazepines likely to affect the availability of the 18 kDa translocator protein (TSPO) in PET studies? PMID- 23666807 TI - Vector control and foliar nutrition to maintain economic sustainability of bearing citrus in Florida groves affected by huanglongbing. AB - BACKGROUND: Huanglongbing (HLB) or citrus greening is a bacterial disease vectored by the Asian citrus psyllid (ACP) causing tree decline, and yield loss. Vector control and foliar nutrition are used in Florida to slow the spread of HLB and mitigate debilitating effects of the disease. A four year replicated field study was initiated February 2008 in a 5.2-ha commercial block of young 'Valencia' orange trees employing a factorial design to evaluate individual and compound effects of vector management and foliar nutrition. Insecticides were sprayed during tree dormancy and when psyllid populations exceeded a nominal threshold. A mixture consisting primarily of micro- and macro-nutrients was applied three times a year corresponding to the principal foliar flushes. RESULTS: Differences in ACP numbers from five- to 13-fold were maintained in insecticide treated and untreated plots. Incidence of HLB estimated by polymerase chain reaction (PCR), rose from 30% at the beginning of the study to 95% in only 18 months. Highest yields all four years were seen from trees receiving both foliar nutrition and vector control. Production for these trees in the fourth year was close to the pre-HLB regional average for 10 year old 'Valencia' on 'Swingle'. Nevertheless, at current juice prices, the extra revenue generated from the combined insecticide and nutritional treatment did not cover the added treatment costs. CONCLUSIONS: This experiment demonstrated that vector control, especially when combined with enhanced foliar nutrition, could significantly increase yields in a citrus orchard with high incidence of HLB. Economic thresholds for both insecticide and nutrient applications are needed under different market and environmental conditions. PMID- 23666808 TI - Positioning of inflammatory biomarkers in the heart failure landscape. AB - The clinical syndrome of heart failure is characterized by a systemic inflammatory response that contributes to end organ damage in the heart and circulation and can thus lead to worsening heart failure. The ensemble of inflammatory mediators that have been detected in heart failure patients include pro-inflammatory cytokines and their cognate receptors, as well as molecules secreted/released by macrophages (galectin-3 and pentraxin-3). Inflammatory biomarkers correlate with disease severity and prognosis across the broad spectrum of heart failure syndromes. Given the proliferation of new biomarkers that predict disease severity and prognosis in heart failure, it is reasonable to ask whether there is a current role for measuring inflammatory mediators in heart failure. This review will attempt to address this question, as well as review several novel approaches that have utilized inflammatory biomarkers to enhance risk stratification and prognosis in heart failure patients. PMID- 23666809 TI - Minimally invasive pulmonary surgery for lung cancer, up to date. AB - Recently, the minimally invasive surgical approach is an important issue in the pulmonary surgery. In this review, we present the current fashion of video assisted thoracic surgery (VATS) and new approach including robotic lobectomy. There is no clear definition or standard for this surgical procedure regarding VATS lobectomy. Therefore, no randomized controlled trial of VATS and conventional lobectomy can be set up. Although the definition of VATS lobectomy is not straightforward, VATS lobectomy showed the technical feasibility of conventional lobectomy in mortality and postoperative complication as well as lymph node dissection. VATS procedure for advanced lung cancer is unclear whether such observations can be developed into a standardized approach. There are no reports to evaluate the advantages of robotic lobectomy in terms of treatment outcomes for lung cancer compared with VATS lobectomy. However, we believe that robotic lobectomy has clear potential to improve the quality of minimally invasive surgery. PMID- 23666810 TI - Rapid and label-free identification of normal spermatozoa based on image analysis and micro-Raman spectroscopy. AB - Semen analysis is performed for evaluation of fertility disorders, however it is susceptible to subjectivity of investigators, and lacking of objective criterion for sperm cell quality remains a problem. There is an ongoing debate on which criteria should be employed to define normal spermatozoa. Here, the aim of our study is to evaluate the possibility of label-free and rapid identification of normal sperm cell through the use of image analysis combined with micro-Raman spectroscopy. By using a smooth-surfaced and hydrophobic substrate, spermatozoa smear was rapidly prepared for microscopic imaging and acrosome area can be clearly visualized without any extra stains; then a self-written image analysis program was utilized to segment sperm head and acrosome area and automatically calculates morphological indices. Most important, intensity ratio of 1055 cm(-1) to 1095 cm(-1) from the obtained Raman spectra is found to indicate a potential biomarker for assessing the sperm DNA integrity. Our preliminary study demonstrates that micro-Raman spectroscopy combined with image analysis can be a potentially useful tool for rapid and label-free identification of normal sperm cell by providing both morphological and biochemical information. PMID- 23666812 TI - Tidal downwelling and implications for the carbon biogeochemistry of cold-water corals in relation to future ocean acidification and warming. AB - Cold-water coral (CWC) reefs are recognized as ecologically and biologically significant areas that generate habitats and diversity. The interaction between hydrodynamics and CWCs has been well studied at the Mingulay Reef Complex, a relatively shallow area of reefs found on the continental shelf off Scotland, UK. Within 'Mingulay Area 01' a rapid tidal downwelling of surface waters, brought about as an internal wave, is known to supply warmer, phytoplankton-rich waters to corals growing on the northern flank of an east-west trending seabed ridge. This study shows that this tidal downwelling also causes short-term perturbations in the inorganic carbon (CT ) and nutrient dynamics through the water column and immediately above the reef. Over a 14 h period, corresponding to one semi-diurnal tidal cycle, seawater pH overlying the reef varied by ca. 0.1 pH unit, while pCO2 shifted by >60 MUatm, a shift equivalent to a ca. 25 year jump into the future, with respect to atmospheric pCO2 . During the summer stratified period, these downwelling events result in the reef being washed over with surface water that has higher pH, is warmer, nutrient depleted, but rich in phytoplankton-derived particles compared to the deeper waters in which the corals sit. Empirical observations, together with outputs from the European Regional Shelf Sea Ecosystem Model, demonstrate that the variability that the CWC reefs experience changes through the seasons and into the future. Hence, as ocean acidification and warming increase into the future, the downwelling event specific to this site could provide short-term amelioration of corrosive conditions at certain times of the year; however, it could additionally result in enhanced detrimental impacts of warming on CWCs. Natural variability in the CT and nutrient conditions, as well as local hydrodynamic regimes, must be accounted for in any future predictions concerning the responses of marine ecosystems to climate change. PMID- 23666811 TI - Nasal delivery of PLG microparticle encapsulated defensin peptides adjuvanted gp41 antigen confers strong and long-lasting immunoprotective response against HIV-1. AB - Defensins display immunostimulatory activities including a chemotactic effect for T lymphocytes/immature dendritic cells and secretion of pro-inflammatory cytokines suggest their role in bridging innate and adaptive immunity. We hypothesized whether defensins with separately emulsified HIV-1 immunogen would elicit peptide-specific systemic and mucosal antibody response in mice. The HIV-1 peptide alone in microsphere showed low peptide-specific antibody response in sera and different washes, while the presence of defensins markedly increased the antibody peak titre both in sera (102,400-409,600) (p < 0.05) and in washes (800 25,600) (p < 0.001). Defensins with HIV-1 peptide were showing 43.0-83.2% and 38.7-72.3% in vitro neutralization against laboratory isolates in serum and lavage samples, respectively, higher than HIV-1 peptide alone. Our findings may have implications in the development of new mucosal adjuvant for AIDS vaccination. PMID- 23666813 TI - Review: the role of microRNAs in osteoarthritis and chondrogenesis. PMID- 23666814 TI - Neighborhood amenities and mobility in older adults. AB - Diversity of neighborhood amenities may promote the mobility of older adults. A 2010 community-based sample of 510 adults aged >=65 years in Philadelphia, Pennsylvania, and geospatial data from the Esri Business Analyst database (Esri, Inc., Redlands, California) were used to assess associations of neighborhood amenity diversity with mobility. Neighborhoods were defined by census tract, and diversity of amenities was derived by using the Leadership in Energy and Environmental Design's neighborhood development index (US Green Building Council, Washington, DC). Generalized estimating equations adjusted for demographic, socioeconomic, and neighborhood characteristics were used to estimate differences in mobility score by tertile of amenity diversity. Analyses were stratified by participants' routine travel habits (stayed at home, stayed in home zip code, or traveled beyond home zip code). We found that for those who spent most of their time in their home neighborhoods, mobility scores (from the Life-Space Assessment, which ranges from 0 to 104 points) were 8.3 points higher (95% confidence interval: 0.1, 16.6) among those who lived in neighborhoods with the most amenity diversity compared with those who lived in neighborhoods with the least amenity diversity. No significant associations between amenity diversity and mobility were observed for those who did not leave home or who regularly traveled outside their neighborhoods. Neighborhoods with a high diversity of amenities may be important promoters of mobility in older adults who do not routinely travel outside their neighborhoods. PMID- 23666815 TI - Neonatal outcomes and birth weight in pregnancies complicated by maternal thyroid disease. AB - Maternal hypothyroidism has previously been shown to increase risk for neonatal intensive care treatment, but otherwise the association between thyroid diseases and neonatal morbidity is understudied. The Consortium on Safe Labor, a retrospective cohort (2002-2008), included 223,512 singleton deliveries of which 0.2% had hyperthyroidism, 1.4% primary and 0.1% iatrogenic hypothyroidism, and 1.3% other/unspecified thyroid disease. Logistic regression with generalized estimating equations estimated adjusted odds ratios of adverse outcomes. Intensive care treatment was more common for neonates of women with thyroid disease. Hyperthyroidism and primary hypothyroidism were associated with sepsis, respiratory distress syndrome, transient tachypnea, and apnea. Iatrogenic hypothyroidism was associated with sepsis and neonatal anemia. Hyperthyroidism was also associated with rare outcomes (prevalence, <1%) including cardiomyopathy, retinopathy of prematurity, and neonatal thyroid diseases. Hyperthyroid non-Hispanic black women had higher odds of term infants that weighed <2,500 g, and hypothyroid non-Hispanic white women had higher odds of large-for-gestational-age infants. These analyses were stratified by race/ethnicity due to interaction. Associations were similar in analyses restricted to term infants. In conclusion, thyroid diseases were associated with increased neonatal morbidity. Although we lacked data on treatment during pregnancy, these nationwide data suggest a need for better thyroid disease management to reduce neonatal morbidity. PMID- 23666816 TI - A simple but effective modeling strategy for structural properties of non-heme Fe(II) sites in proteins: test of force field models and application to proteins in the AlkB family. AB - To facilitate computational study of proteins in the AlkB family and related alpha-ketoglutarate/Fe(II)-dependent dioxygenases, we have tested a simple modeling strategy for the non-heme Fe(II) site in which the iron is represented by a simple +2 point charge with Lennard-Jones parameters. Calculations for an AlkB active site model in the gas phase and ~150 ns molecular dynamics (MD) simulations for two enzyme-dsDNA complexes (E. coli AlkB-dsDNA and ABH2-dsDNA) suggest that this simple modeling strategy provides a satisfactory description of structural properties of the Fe(II) site in AlkB enzymes, provided that care is exercised to control the binding mode of carboxylate (Asp) to the iron. MD simulations using the model for AlkB-dsDNA and ABH2-dsDNA systems find that although the structural features for the latter are overall in good agreement with the crystal structure, the dsDNA, and AlkB-dsDNA interface undergo substantial changes during the MD simulations from the crystal structure. Even for ABH2, new interactions form between a long loop region and dsDNA upon structural relaxation of the loop, supporting the role of this loop in DNA binding despite the lack of interactions between them in the crystal structure. Analysis of DNA backbone torsional distributions helps identify regions that adopt strained conformations. Collectively, the results highlight that crystal packing may have a significant impact on the structure of protein-DNA complexes; the simulations also provide additional insights regarding why AlkB and ABH2 prefer single-strand and double-strand DNA, respectively, as substrate. PMID- 23666817 TI - College expectations in high school mitigate weight gain over early adulthood: Findings from a national study of American youth. AB - OBJECTIVE: Research conducted on school-based interventions suggests that school connectedness protects against a variety of risk behaviors, including substance abuse, delinquency and sedentary behavior. The line of research is extended by examining the link between college expectations and early adult weight gain using nationally representative panel data from thirty cohorts of American high school seniors followed prospectively to age 30 in the Monitoring the Future Study (1986 2009). DESIGN AND METHODS: Growth mixture models identified two latent classes of trajectories of body mass index (BMI) from age 19 to 30: a persistently overweight class (BMI >= 25) and a second class exhibiting more moderate growth in BMI to age 30. RESULTS: Compared to those who did not expect to graduate from college, students fully expecting to graduate from college had 34% lower odds of being in the persistently overweight class (adjusted odds ratio = 0.66, 95% confidence interval = 0.54, 0.81), controlling for academic performance and socioeconomic status. CONCLUSIONS: Successful prevention of obesity early in the life course is based on a multifactorial approach incorporating strategies that address the contexts in which adolescents are embedded. The school setting may be one avenue where successful educational attachment could have positive consequences for subsequent weight gain in early adulthood. PMID- 23666818 TI - Cognitive-behavioral group treatment for driving-related anger, aggression, and risky driving in combat veterans: a pilot study. AB - The present study examined the preliminary effects of an 8-session group cognitive-behavioral treatment (CBT) designed to reduce driving-related anger, aggression, and risky driving behaviors in veterans. Participants (N = 9) with self-reported aggressive and risky driving problems completed self-report measures at pretreatment, posttreatment, and 1-month follow-up. Of those completing the treatment, 89% demonstrated reliable change in driving-related aggression and 67% evidenced reliable change in driving-related anger. Similar changes were found for secondary treatment targets. PMID- 23666819 TI - Tuning scaffold mechanics by laminating native extracellular matrix membranes and effects on early cellular remodeling. AB - At approximately 50 um thin, the human amniotic membrane (hAM) has been shown to be a versatile biomaterial with applications ranging from ocular transplants to skin and nerve regeneration. These investigations describe laminating layers of the hAM into a multilayered, conformation creating a thicker, more robust biomaterial for applications requiring more supportive structures. Amniotic membranes were decellularized using 4 M NaCl and prepared as either flat single layered sheets or rolled into concentric five-layered configurations. Constructs were seeded with human vascular smooth muscle cells and cultured over 40 days to quantify biological and mechanical changes that occurred during early remodeling events. By day 40 single-layered constructs displayed a decreasing trend in cellular densities and glycosaminoglycan (GAG) concentration, comparative to multilayered constructs with increasing cell densities (from 9.1 to 32 * 10(6) cells/g) and GAG concentrations (from 6.07 to 17.4 mg/g). Oxygen diffusion was calculated and found to be sufficient to maintain cell populations through the constructs full thickness. Although an overall decrease in the modulus of elasticity was noted, the modulus in the failure range of rolled constructs stabilized at values 25 times higher than single-layered constructs. Rolled constructs typically displayed an upregulation of contractile and matrix remodeling markers (alpha-actin, SM22 and type 1 collagen, MMP-2 respectively) indicating biological adaptation. Considerable design flexibility can be achieved by varying the number of scaffold layers, allowing the possibility of tuning the constructs physical dimensions, shape and tensile properties to suit specific targeted vascular locations. PMID- 23666820 TI - The location of knee pain and pathology in patients with a presumed meniscus tear: preoperative symptoms compared to arthroscopic findings. AB - BACKGROUND: Pain is one of the primary motivations for patients to seek medical advice. Pain location is one element in the process of formulating a diagnosis. AIMS: The purpose of the study is to determine if there is a correlation between the location of pain and the location of pathology in the knees of patients with a suspected meniscus tear. METHODS: From a possible 856 patients referred for arthroscopy, 213 patients consented to be included in the study and 193 (90 %) completed the study. The participating subjects located area of their symptoms on a diagram showing the four aspects of the knee joint. For analysis purposes symptoms were grouped into medial, lateral, posterior, or a combination of these areas. Pathology identified at arthroscopy was recorded on the International Knee Documentation Committee (IKDC) surgical form. The location of knee pathology was divided into medial compartment, lateral compartment or combinations of pathologies. Locations of pain were analysed for an association with the location of pathology found at arthroscopy. RESULTS: Of the 193 subjects who completed the study, 69 (35.7 %) of the subjects presented with one location of pain i.e. medial, lateral or posterior pain and the remaining 124 (64.3 %) had multiple areas. In correlating locations of reported pain with pathology, there was no significant correlation found (p = 0.98). CONCLUSIONS: This study found no direct correlation between the location of pain and the location of pathology in the knee in patients with a suspected meniscus tear. PMID- 23666821 TI - Quantitative analysis of betaine in Lycii Fructus by HILIC-ELSD. AB - A rapid and simple high-performance liquid chromatography (HPLC) method with evaporative light scattering detection (ELSD) was developed for the determination of betaine from Lycii Fructus. Betaine was separated with an Atlantis hydrophilic interaction liquid chromatography silica column (4.6 * 150 mm, 5 MUm, 100 A) by isocratic elution using 30 mM ammonium acetate buffer and acetonitrile (20:80, v/v %) as the mobile phase. The flow rate was 1.0 mL/min, and the temperature for the spray chamber and drift tube was set at 30 and 50 degrees C, respectively. The method was fully validated with respect to linearity, precision, accuracy, stability and robustness. The HPLC/ELSD method was applied successfully to the quantification of betaine in the extract of Lycii Fructus. The HPLC analytical method for pattern recognition analysis was validated by repeated analysis of twenty-six L. barbarum L. from China (BC01-BC26), 3 L. barbarum L. (BJ27-BJ29) from Japan, 12 L. chinense Miller from China (CC30-CC41) and 51 L. chinense Miller samples (CK42-CK92) from Korea. The results indicate that the established HPLC/ELSD method is suitable for quality evaluation of Lycii Fructus. PMID- 23666822 TI - Do tardive dyskinesia and L-dopa induced dyskinesia share common genetic risk factors? An exploratory study. AB - Tardive dyskinesia (TD) in schizophrenia patients treated with antipsychotic medications and L-dopa induced dyskinesia (LID) among Parkinson's disease (PD) affected individuals share similar clinical features. Both conditions are induced by chronic exposure to drugs that target dopaminergic receptors (antagonists in TD and agonists in LID) and cause pulsatile and nonphysiological stimulation of these receptors. We hypothesized that the two motor adverse effects partially share genetic risk factors such that certain genetic variants exert a pleiotropic effect, influencing susceptibility to TD as well as to LID. In this pilot study, we focused on 21 TD-associated SNPs, previously reported in TD genome-wide association studies or in candidate gene studies. By applying logistic regression and controlling for relevant clinical risk factors, we studied the association of the SNPs with LID vulnerability in two independent pharmacogenetic samples. We included a Jewish Israeli sample of 203 PD patients treated with L-dopa for a minimum of 3 years and evaluated the existence or absence of LID (LID+ = 128; LID = 75). An Italian sample was composed of early LID developers (within the first 3 years of treatment, N = 187) contrasted with non-early LID developers (after 7 years or more of treatment, N = 203). None of the studied SNPs were significantly associated with LID susceptibility in the two samples. Therefore, we were unable to obtain proof of concept for our initial hypothesis of an overlapping contribution of genetic risk factors to TD and LID. Further studies in larger samples are required to reach definitive conclusions. PMID- 23666823 TI - Genetic variants on chromosome 10q11.21 are associated with ischemic stroke in the northern Chinese Han population. AB - Genome-wide association studies have revealed two loci (rs1746048 and rs501120) on chromosome 10q11.21 associated with atherosclerosis. The genetic variants are related to chemokine (C-X-C motif) ligand 12, which has been shown to affect atherosclerosis. This study aims to explore the associations between these loci and risk of ischemic stroke in the northern Chinese Han population. A total of 368 patients with ischemic stroke and 381 healthy controls were included in the study. The single-nucleotide polymorphisms rs501120 and rs1746048 were analyzed by polymerase chain reaction-ligation detection reaction methods. Increased risk of ischemic stroke was associated with rs1746048 in a dominant mode. The CT + TT genotype of rs1746048 was represented at an increased frequency among patients with ischemic stroke. The genotype and allele frequencies of rs501120 were similar between patients with ischemic stroke and controls. However, the rs501120 CT + CC genotype and C allele were associated with an increased risk of ischemic stroke in the male subgroup. These correlations still remained after adjusting for confounding risk factors of stroke. Here, we present a study indicating that genetic variation on chromosome 10q11.21 might contribute to stroke susceptibility. PMID- 23666824 TI - Cuprizone-induced demyelination as a tool to study remyelination and axonal protection. AB - In the brain of multiple sclerosis (MS) patients, the conduction block of axons due to demyelination and inflammation underlies early neurological symptoms, whereas axonal transection accounts for permanent deficits occurring during later disease stages. The beneficial function of myelin for the protection of the axonal compartment and network stability between neurons has been shown in numerous studies. Thus, rapid and adequate remyelination is an important factor for axonal patronage during neuroinflammatory conditions. In this review article, we discuss frequently used experimental in vivo and in vitro animal models to examine remyelination and repair in MS. The focus of the discussion is the relevance of the toxin model 'cuprizone' to study the pathology of demyelination and the physiology of remyelination. This also includes recent findings in this animal model which implicate that axonal damage is an ongoing process independent of the initiation of endogenous remyelination. PMID- 23666825 TI - Towards in vivo intradermal surface enhanced Raman scattering (SERS) measurements: silver coated microneedle based SERS probe. AB - We propose a microneedle coated with silver (Ag) to detect analytes at low concentrations positioned at a depth of more than 700 MUm below the surface of a skin phantom with absorbers and scatterers for mimicking the intradermal surface enhanced Raman scattering (SERS) measurements. The Ag layer in the Ag-coated microneedle-based probe is found to be the key to the effective detection of analytes buried inside the aforesaid phantom. Glucose concentrations ranging from 5 to 150 mM inside phantoms can be estimated with a root mean square error (RMSE) of 3.3 mM. This work shows the potential of using microneedles for simple in vivo intradermal SERS measurements of analytes with clinical relevance. PMID- 23666826 TI - Drug adsorption on bovine and porcine sclera studied with streaming potential. AB - The affinity of a drug to a biological membrane can affect the distribution and the availability of the active compound to its target. Adsorption is usually determined with in vitro distribution studies based on partitioning of the drug between buffer and tissue, which have limitations such as the high variability of the uptake data and the need for high accuracy in the measurement of drug concentration. Furthermore, distribution studies yield solute concentrations in the bulk of the tissue, whereas electrokinetic phenomena such as streaming potential and electroosmosis reflect the electric charge density on a membrane surface. Streaming potential thus can be used in studying the conditions, by which the charge sign and density can be regulated. That, in turn, has significance to electroosmotic transport mechanism during iontophoresis. In this communication, the adsorption of model compounds methylprednisolone sodium succinate, propranolol, and cytochrome C on bovine and porcine sclera is determined as a function of their concentration by measuring streaming potential. Both membranes had negative streaming potential, proving that they carry negative charge, but had different values at negative and positive pressure differences, which is addressed to the structural asymmetry of these membranes. Bovine sclera had a clearly higher value of streaming potential, ca. -26 nV/Pa, than porcine sclera, ca. -7 nV/Pa (10 mM NaCl solution). All the model compounds were adsorbed on bovine and porcine sclera already in the millimolar concentration range and can have an impact to electroosmosis during transscleral iontophoresis. The results obtained help to better elucidate the phenomena involved in transscleral transport, both in passive diffusion and in iontophoresis, supporting the future application of iontophoresis to the noninvasive delivery of drugs to the posterior segment of the human eye. PMID- 23666827 TI - Necessity of lysophosphatidic acid receptor 1 for development of arthritis. AB - OBJECTIVE: Lysophosphatidic acid (LPA) is a bioactive lipid that binds to a group of cell surface G protein-coupled receptors (LPA receptors 1-6 [LPA1-6 ]) and has been implicated as an important mediator of angiogenesis, inflammation, and cancer growth. This study was undertaken to analyze the effects of LPA1 on the development of arthritis. METHODS: Expression of LPA receptors on synovial tissue was analyzed by immunohistochemistry and quantitative reverse transcription polymerase chain reaction. The effects of abrogation of LPA1 on collagen-induced arthritis (CIA) were evaluated using LPA1 -deficient mice or LPA1 antagonist. Migrating fluorescence-labeled CD11b+ splenocytes, which were transferred into the synovium of mice with CIA, were counted. CD4+ naive T cells were incubated under Th1-, Th2-, or Th17-polarizing conditions, and T helper cell differentiation was assessed. Osteoclast formation from bone marrow cells was examined. RESULTS: LPA1 was highly expressed in the synovium of patients with rheumatoid arthritis (RA) compared with that of patients with osteoarthritis. LPA1 -deficient mice did not develop arthritis following immunization with type II collagen (CII). LPA1 antagonist also ameliorated murine CIA. Abrogation of LPA1 was associated with reductions in cell infiltration, bone destruction in the joints, and interleukin-17 production from CII-stimulated splenocytes. Infiltration of transferred CD11b+ macrophages from LPA1 -deficient mice into the synovium was suppressed compared with infiltration of macrophages from wild-type mice. LPA1 antagonist inhibited the infiltration of macrophages from wild-type mice. Differentiation into Th17, but not Th1 or Th2, and osteoclast formation were also suppressed under conditions of LPA1 deficiency or LPA1 inhibition in vitro. CONCLUSION: Collectively, these results indicate that LPA/LPA1 signaling contributes to the development of arthritis via cellular infiltration, Th17 differentiation, and osteoclastogenesis. Thus, LPA1 may be a promising target molecule for RA therapy. PMID- 23666828 TI - Partial sleep deprivation by environmental noise increases food intake and body weight in obesity-resistant rats. AB - OBJECTIVE: Sleep restriction in humans increases risk for obesity, but previous rodent studies show weight loss following sleep deprivation, possibly due to stressful methods used to prevent sleep. Obesity-resistant (OR) rats exhibit consolidated-sleep and resistance to weight gain. It was hypothesized that sleep disruption by a less-stressful method would increase body weight, and the effect of partial sleep deprivation (PSD) on body weight in OR and Sprague-Dawley (SD) rats was examined. DESIGN AND METHODS: OR and SD rats (n = 12/group) were implanted with transmitters to record sleep/wake. After baseline recording, six SD and six OR rats underwent 8 h PSD during light phase for 9 days. Sleep was reduced using recordings of random noise. Sleep/wake states were scored as wakefulness (W), slow-wave-sleep (SWS), and rapid-eye-movement-sleep (REMS). Total number of transitions between stages, SWS-delta-power, food intake, and body weight were documented. RESULTS: Exposure to noise decreased SWS and REMS time, while increasing W time. Sleep-deprivation increased the number of transitions between stages and SWS-delta-power. Further, PSD during the rest phase increased recovery sleep during the active phase. The PSD SD and OR rats had greater food intake and body weight compared to controls CONCLUSIONS: PSD by less-stressful means increases body weight in rats. Also, PSD during the rest phase increases active period sleep. PMID- 23666829 TI - Depression and posttraumatic stress disorder in temporary settlement residents 1 year after the Sichuan earthquake. AB - The authors sought to determine the prevalence and risk factors for major depressive disorder and posttraumatic stress disorder (PTSD) among survivors living in temporary accommodation in the Yongxing settlement in Mianyang city 1 year after the Sichuan earthquake for further interventions. They interviewed 182 residents, using the Structured Clinical Interview for DSM-IV Axis I Disorders and a self-report questionnaire. The 12-month prevalence of depressive disorder and PTSD were 48.9% and 39.6%, respectively. Multivariate analysis indicated that bereaved survivors were 5.51 times (adjusted odds ratio [AOR] = 5.51; 95% confidence interval [CI] =2.14-14.22) more likely to report PTSD and 2.42 times (AOR = 2.42; 95%CI =1.00-5.48) more likely to report depressive disorder than nonbereaved survivors. Older age and receipt of government financial support were significantly associated with 12-month PTSD. Depressive disorder 12 months after the earthquake was associated with receipt of government financial support, pre earthquake physical illness, single marital status, being currently employed, and Han ethnicity. PMID- 23666830 TI - Differences in selected lifestyle risk factors for cardiovascular disease between Sri Lankans in Oslo, Norway, and in Kandy, Sri Lanka. AB - Sri Lankans in Oslo have previously been shown to have lower risk of cardiovascular disease compared with those in Kandy, Sri Lanka. Here we present lifestyle risk factors for cardiovascular diseases: frequency and type of fat consumed, frequency of fruit and vegetable intake, alcohol consumption, and leisure time physical activity between 1145 Sri Lankans living in Oslo and 678 Tamils and Sinhalese Sri Lankans living in Kandy as possible explanatory factors for the differences observed. Those in Oslo were consuming healthier fats and reported higher levels of physical activity but frequency of vegetable and fruit consumption was lower. Alcohol consumption among women was negligible. Type of fats consumed might be protective for Oslo group compared with predominantly saturated fat diet in Kandy. Higher leisure time physical activity may also be protective for the Oslo group. Higher frequency of consumption of vegetables and fruits may be beneficial in Kandy. PMID- 23666831 TI - Omega-3 fatty acids from fish, other nutrient intake, and lifestyle factors: exploring the relationship in children. AB - The omega-3 fatty acids found mostly in seafood are essential nutrients that may help prevent or control a number of diseases; however, the evidence for this is not conclusive. The positive effects may be because of other dietary and lifestyle factors. Therefore, we investigated the association between fish intake and other nutrition indicators and lifestyle and demographic factors among children. The study employed grade-4 student data of the 2000-2004 Hawaii Nutrition Education Needs Assessment Survey. In a sample 666 children (mean age = 9.57 +/- 0.06 years, 55.6% female, 62.4% Asian/Pacific Islander), analysis indicated that fish consumption is positively associated with healthy lifestyle indicators, such as physical activity and a healthy body mass index. Fish consumption is also positively associated with protein and kilocalories intake but not with fruits and vegetables consumption. Findings suggest that the positive health behaviors linked to fish consumption may lie more in physical activity than in diet behaviors. Given that fish consumption is important for children, interventions promoting fish consumption in a balanced diet with fruit and vegetable, as well as other positive lifestyle behaviors are warranted. PMID- 23666832 TI - A community-based cluster randomized controlled trial of "directly observed home based daily iron therapy" in lowering prevalence of anemia in rural women and adolescent girls. AB - In a community-based cluster randomized controlled trial, we randomly assigned clusters of anemic women and adolescent girls to either "directly observed home based daily iron therapy" (DOHBIT; n = 524 in 16 villages) or unsupervised self treatment at home (n = 535 in 16 villages) for a period of 90 days. Those in the DOHBIT group, when compared with those in the unsupervised self-treatment group, had significantly lower relative risk (RR) of anemia (16.8% vs 35.3%, RR = 0.47 [95% confidence interval (CI) = 0.33-0.65]; P < .0001), higher hemoglobin (Hb) rise of >=2 g/dL (70.2% vs 42.2%, RR = 1.56 [95% CI = 1.31-1.87]; P <.0001), and nonsignificant trend for lower side effects (3.5% vs 6.7%, RR = 0.49 [95% CI = 0.22-1.08; P < .08) on intention-to-treat analyses. On linear mixed model analysis, the subjects in the intervention group demonstrated higher mean Hb levels (13.01 vs 12.32 g/dL; P < .0001) and higher adherence to iron therapy (93% vs 60%; P < .0001). DOHBIT is effective in lowering the prevalence of anemia in rural women and adolescent girls. PMID- 23666833 TI - Barriers to immunization among children of HIV-infected mothers in Kolkata, India: a qualitative study. AB - More than one fourth of children of HIV-infected mothers living in Kolkata city are not completely immunized by 12 months of age. This qualitative study aims to explore the barriers to immunization of these children as perceived by their caregivers and the local health care service providers. In-depth interviews were conducted after obtaining written informed consent. Audio recording and hand recorded notes were used with permission. The transcripts were coded and analyzed using grounded theory. Deteriorating socioeconomic status, tightening of time schedule of caregivers due to illness in the family, stigma, discrimination, and lack of awareness about immunization prove to be major barriers for immunization of the HIV-exposed children. Interplay of these factors coupled with harassment and negative attitudes of service providers toward HIV-affected/HIV-infected people also impede immunization. The intervention efforts need to address these social barriers and adverse life events to improve immunization coverage. PMID- 23666834 TI - Influence of feeding practices and associated factors on the nutritional status of infants in rural areas of Madhya Pradesh state, India. AB - A community based cross-sectional study was undertaken in rural Madhya Pradesh (MP). The nutritional status of infants was assessed using WHO Child Growth Standards. Only 26% of infants received breast-feeding within 1 hour of birth. About 57% of children 6 to 11 months old received complementary feeding (CF). The prevalence of underweight, stunting, and wasting was 41%, 29%, and 33%, respectively. Multivariate analysis showed that the risk of underweight and stunting was 1.4 times higher among children belonging to scheduled castes and scheduled tribes compared with others, 1.4 to 1.6 times among children from households with the lowest wealth index, and 1.5 times among children of illiterate mothers. Hygienic practices, birth weight, home delivery, and CF practices were also significantly (P < .01) associated with undernutrition in multivariate analysis. Undernutrition is an important health problem in MP, and urgent steps are required to formulate policies and strategies to improve infant and young child feeding practices, socioeconomic conditions, and literacy and encouraging institutional delivery and personal hygiene. PMID- 23666835 TI - Determinants of institutional delivery among women in Bangladesh. AB - This study examines the factors that influence institutional delivery among women in Bangladesh extracting data from 2007 Bangladesh Demographic and Health Survey. We employed both bivariate and multivariate statistical analyses in this study. Findings revealed that, only 14.7% of the women went for institutional delivery and 28.8% births were delivered by trained birth attendance. The multivariate logistic regression analysis yielded quantitatively important and reliable estimates of facility delivery. The likelihood of institutional delivery was significantly higher for first-order pregnancy, couples' higher education, the richest, higher autonomy, TV ownership, non-Muslims, who received antenatal care services, pregnancy complications, and urban residents. Government should ensure quality of care, easy accessibility, and availability of all facilities free of cost in the public medical institutions. Women should be informed regarding the long-term benefit of institutional delivery through information, education, and communication program. PMID- 23666836 TI - Incidence of tobacco use among adults (15-64 years) in rural Kerala. AB - We analyzed data from a cohort study in rural Kerala, India, to study the incidence of current smoking and current smokeless tobacco use. At baseline, of 452 individuals aged 15 to 64 years, 385 were current nonsmokers and 402 were current nonusers of smokeless tobacco. Over a mean follow-up of 7.1 +/- 0.2 years, 5.5% became current smokers and 9.0% became current smokeless tobacco users. Among men, 21.1% (95% confidence interval [CI] = 11.1-36.4) of younger individuals (15-24 years) became current smokers and 22.2% (CI = 10.6-40.8) of older individuals (55-64 years) became current smokeless tobacco users. No women smoked both at baseline and at follow-up, but 9.7% (CI = 3.4-24.9) of older women (55-64 years) became current smokeless tobacco users. These findings call for effective implementation of India's Cigarettes and Other Tobacco Products Act, 2003. PMID- 23666837 TI - Effect of life skills training on dietary behavior of school adolescents in Delhi: a nonrandomized interventional study. AB - Skill-based education has been shown to reduce high-risk behavior among adolescents, but in India, life skills have often been looked at only from the reproductive health perspective. Therefore, the current study was undertaken to assess the effect of life skills training on dietary behavior of adolescents studying in grades 9 and 11 of 2 schools in Delhi. This was a nonrandomized interventional study with a control group. A self-administered questionnaire was used for assessment of dietary behavior at baseline, 15 days, and 3 months after the life skills training. Two life skills training sessions were imparted to the intervention group, focusing on the use of life skills in making healthy choices. Participants in the intervention group (n = 180) showed significant improvement in knowledge (P < .001), attitude (P = .007), and practices (P < .001) following the life skills training. To conclude, a skills-based approach does help improve the dietary behavior in adolescents. PMID- 23666838 TI - Risk factors of future smoking among Thai youth: a secondary analysis of the Thai Global Youth Tobacco Survey. AB - The study aimed to identify the risk factors for future smoking among Thai youth aged 13 to 15 years (seventh to ninth grade). Data from the nationally representative 2005 Thai Global Youth Tobacco Survey (n = 15 774) were analyzed using descriptive statistics and logistic regression. Among nonsmoking Thai youth, boys were much more likely to have intention of future smoking (odds ratio [OR] = 0.56, 95% confidence interval [CI] = 0.37-0.84). Younger youth were more likely to be cigarette smokers in the future (OR = 0.70, 95% CI = 0.56-0.88). Youth having the intention of smoking from a friend's cigarette offer were 5.29 times more likely to have intention of future smoking, compared with those who did not (95% CI = 3.75-7.46). Understanding and targeting youth at higher risk for future smoking can provide for a lowering of the youth smoking rate in Thailand and contribute to the country's continued efforts in effective youth tobacco control. PMID- 23666839 TI - World Cup's impact on mental health and lifestyle behaviors in the general population: comparing results of 2 serial population-based surveys. AB - OBJECTIVES: This study compares the prevalence of health-related behaviors and mental health well-being in the Hong Kong general male population before and after the 2006 World Cup finals. STUDY DESIGN: Two anonymous, serial, comparable cross-sectional surveys. METHODS: A total of 500 and 530 adult Chinese men, respectively, were interviewed in 2 telephone surveys before and after the finals. RESULTS: Those interviewed after the World Cup were more likely to eat snacks more than 3 d/wk, to be binge drinkers, or to spend more than 2 h/d communicating with family members. They were less likely to have higher General Health Questionnaire or lower Short Form-36 Health Survey Vitality scores (odds ratio [OR] = 0.684 and 0.765), to perceive family-related or work-related stress (OR = 0.327 and 0.345), or to self-report being sick or have visited a doctor (OR = 0.645 and 0.722). All variables between watchers versus nonwatchers of World Cup games were significant or marginally significant. CONCLUSIONS: Public health education should be incorporated into global sport events. PMID- 23666840 TI - Regional differences of maternal health care utilization in China. AB - OBJECTIVE: To describe regional differences in maternal health care (MHC) utilization in China. STUDY DESIGN: Cross-sectional comparisons of 4 MHC utilization indicators, namely, early (13 weeks within pregnancy) examinations rate (EER), prenatal examination (>4 times) rate (PER), hospital delivery rate (HDR), and postnatal visit (>1 time) rate (PVR), using index of dissimilarity (ID), linear correlation analysis, and geographical mapping. RESULTS: Significant differences existed across regions in all the indicators (P < .01). All the IDs for rural areas were higher than that for urban areas. The IDs for major regions ranged from 0.01 to 0.27. Linear correlation coefficients between MHC utilization indicators by regions varied from 0.007 to 0.889 (in absolute value, P < .05). Characteristic formats of geographical distribution were found with PER, EER, HDR, and PVR being in "high-plateau," "low-plateau," and "shifting" patterns, respectively. CONCLUSIONS: There exist substantial regional discrepancies in MHC utilization in China and future MHC-related policies should take account regional context. PMID- 23666841 TI - Betel quid chewing without tobacco: a meta-analysis of carcinogenic and precarcinogenic effects. AB - Betel quid without tobacco is an important factor influencing the incidences of oral cancer and precancer. This study systematically evaluated the associations between betel quid containing no tobacco and oral cancer and precancer, with implications for the prevention of oral cancer. We searched MEDLINE, ISI Web of Science, and EMBASE (to April 2011) and retrieved studies that investigated the relationship between chewing betel quid and oral cancer (or precancer). We performed a meta-analysis to summarize the published data and describe the prevalence of betel quid use with regard to cancerous diseases. In all, 19 eligible studies that reported odds ratios and 95% confidence intervals for oral cancer with respect to betel quid were included. The analysis identified an association suggesting that betel quid might be an important risk factor for oral cancer and precancer. The results of this review suggest that betel-chewing cessation programs should be developed to help prevent oral diseases. PMID- 23666842 TI - Patterns of maternal tobacco use among Cambodian women: findings from a nationwide sample. AB - Although current trends indicate that the rate of cigarette smoking tends to be low among women in the Western Pacific Region (<10%), recent epidemiologic data from South Asia (India, Bangladesh) and Southeast Asia (Cambodia, Vietnam, Indonesia, Malaysia) identify that a large proportion of women of reproductive age and older chew tobacco--often as part of a betel quid mixture that includes other potentially harmful ingredients (eg, areca nut). Our findings from currently pregnant women identified during a nationwide survey of adult tobacco use in Cambodia indicate that 13.0% (95% confidence interval [CI] = 8% to 17%) were current users of smoked or smokeless (in the form of a betel quid) tobacco. Most pregnant women who used tobacco indicated that their habit was either initiated (29.1%; 95% CI = 16.3-46.3) or increased (33.7%; 95% CI = 18.3-53.5) during pregnancy. Pregnancy-related symptoms such as morning sickness were reported as the reason for more than half (54.9%; 95% CI = 34.8-73.4) of the currently pregnant users to have started a tobacco habit during their lifetime. Among those pregnant women who did not use tobacco, we found strong associations (odds ratios from 2 to 14) with beliefs about the harmful effects of tobacco on adult health, faith-based beliefs in addictive substances, and beliefs that influential members of the community, health professionals, and children should not use tobacco. Our findings indicate that tobacco cessation and prevention programs in Cambodia should specifically target pregnant and reproductive-age women. PMID- 23666843 TI - Poverty does not limit tobacco consumption in Cambodia: quantitative estimate of tobacco use under conditions of no income and adult malnutrition. AB - Current data indicate that under conditions of poverty, tobacco is consumed at the expense of basic needs. In a large national sample from Cambodia, we sought to determine whether tobacco consumption declines under extreme conditions of no income and malnutrition. Our major findings are as follows: (1) Among men, there was no significant difference in the number of cigarettes smoked for no income (425, 95% confidence interval [CI] = 395-456) versus >US$2 per day (442, 95% CI = 407-477); (2) among women, there was no significant difference in the amount of loose tobacco (ie, betel quid) consumed for no income (539 g, 95% CI = 441-637) versus >US$2 per day (558 g, 95% CI = 143-973); (3) for the contrast of no income + malnutrition versus >US$2 per day + no malnutrition in a linear model, there was no significant difference for men who smoked (462 vs 517 cigarettes/month, P = .82) or women who chewed (316 vs 404 g tobacco/month, P = .34), adjusting for confounders. Among the poorest and malnourished Cambodian adults, lack of resources did not appear to prevent them from obtaining smoked or smokeless tobacco. PMID- 23666844 TI - Investigation of residents' health literacy status and its risk factors in Jiangsu Province of China. AB - Health literacy has become an important public health concern. Multistage cluster random sampling was used to select 12 450 individuals. Using the 2009 Chinese Health Literacy questionnaire, participants were divided into groups with poor or not poor health literacy status. The knowledge rates for 6 areas of health literacy were determined with the following results: science concept of health (60.0%), literacy for preventing acute infectious disease (66.8%), literacy for preventing noncommunicable chronic disease (51.9%), safety and first aid (66.8%), obtaining and making use of basic medical care (55.3%), and comprehensive health literacy (52.5%). Multiple logistic regression showed that living in a rural area, fewer individuals in a household, younger age, low education, agricultural or rural migrant occupation workers, and low family income were associated with a poor health literacy status. Our results support the use of health education and promotion interventions to improve health literacy in this high-risk population in China. PMID- 23666846 TI - Optically anisotropic thin films by shear-oriented assembly of colloidal nanorods. AB - Device-scale thin films of highly oriented (in-plane) colloidal nanorods are made available by using a simple coating process involving thixotropic rod gel suspensions. Application of this process to LaPO4 nanorods leads to films exhibiting outstanding anisotropic optical properties, such as a remarkably large birefringence (Deltan = 0.13) associated with high transparency, and sharply polarized fluorescence spectra when doped with europium. PMID- 23666845 TI - Association of subjective and objective socioeconomic status with subjective mental health and mental disorders among Japanese men and women. AB - BACKGROUND: An inverse association between socioeconomic status (SES) and mental health has been previously well reported, but the evidence is limited in Asian populations. PURPOSE: We therefore investigated the association of SES and subjective mental health and prevalence of any mental disorders in the general population of Japan. METHOD: We used data from the World Mental Health Japan Survey of 1,496 randomly selected people aged 20 years and older in Japan. Information on education level and household income were used as objective SES indicators, and subjective social status (SSS) was measured by responses to a question regarding social position. We calculated odds ratios of SES indicators for poor subjective mental health and 12-month prevalence of any mental disorders. RESULTS: The adjusted odds ratio (OR) (95 % confidence interval (CI)) of respondents who rated themselves as lower than middle status in the country (low SSS group) for poor subjective mental health was 2.24 (95 % CI: 1.41, 3.57) with reference to those who rated themselves as higher than middle status (high SSS group). Similarly, inverse associations of education level and household income with poor subjective mental health were identified. A J-shaped association was confirmed between SSS and 12-month prevalence of any mental disorders. The adjusted OR (95 % CI) of SSS for any mental diseases was 0.53 (95 % CI: 0.32, 0.86) for the middle SSS group and 1.61 (95 % CI: 0.96, 2.72) for the low SSS group, compared with the high SSS group. Those associations were not attenuated when objective SES indicators were adjusted. CONCLUSION: We found inversely linear associations between subjective and objective SES and poor subjective mental health among Japanese men and women. SSS was not significantly associated with 12-month prevalence of any mental disorders. Substantial social inequalities in mental health were identified in Japan, which has been considered an egalitarian society with relatively few inequalities in health. PMID- 23666847 TI - I-CAN: the classification and prediction of support needs. AB - BACKGROUND: Since 1992, the diagnosis and classification of intellectual disability has been dependent upon three constructs: intelligence, adaptive behaviour and support needs (Luckasson et al. 1992. Mental Retardation: Definition, Classification and Systems of Support. American Association on Intellectual and Developmental Disability, Washington, DC). While the methods and instruments to measure intelligence and adaptive behaviour are well established and generally accepted, the measurement and classification of support needs is still in its infancy. This article explores the measurement and classification of support needs. METHOD: A study is presented comparing scores on the ICF (WHO, 2001) based I-CAN v4.2 support needs assessment and planning tool with expert clinical judgment using a proposed classification of support needs. A logical classification algorithm was developed and validated on a separate sample. RESULTS: Good internal consistency (range 0.73-0.91, N = 186) and criterion validity (kappa = 0.94, n = 49) were found. CONCLUSIONS: Further advances in our understanding and measurement of support needs could change the way we assess, describe and classify disability. PMID- 23666848 TI - Accurate double many-body expansion potential energy surface by extrapolation to the complete basis set limit and dynamics calculations for ground state of NH2. AB - An accurate single-sheeted double many-body expansion potential energy surface is reported for the title system. A switching function formalism has been used to warrant the correct behavior at the H2(X1Sigmag+)+N(2D) and NH (X3Sigma-)+H(2S) dissociation channels involving nitrogen in the ground N(4S) and first excited N(2D) states. The topographical features of the novel global potential energy surface are examined in detail, and found to be in good agreement with those calculated directly from the raw ab initio energies, as well as previous calculations available in the literature. The novel surface can be using to treat well the Renner-Teller degeneracy of the 12A" and 12A' states of NH 2. Such a work can both be recommended for dynamics studies of the N(2D)+H2 reaction and as building blocks for constructing the double many-body expansion potential energy surface of larger nitrogen/hydrogen-containing systems. In turn, a test theoretical study of the reaction N(2D)+H2(X1Sigmag+)(nu=0,j=0)->NH (X3Sigma )+H(2S) has been carried out with the method of quantum wave packet on the new potential energy surface. Reaction probabilities, integral cross sections, and differential cross sections have been calculated. Threshold exists because of the energy barrier (68.5 meV) along the minimum energy path. On the curve of reaction probability for total angular momentum J = 0, there are two sharp peaks just above threshold. The value of integral cross section increases quickly from zero to maximum with the increase of collision energy, and then stays stable with small oscillations. The differential cross section result shows that the reaction is a typical forward and backward scatter in agreement with experimental measurement result. PMID- 23666849 TI - Are poor Chinese text comprehenders also poor in written composition? AB - We studied the performance in three genres of Chinese written composition (narration, exposition, and argumentation) of 158 grade 4, 5, and 6 poor Chinese text comprehenders compared with 156 good Chinese text comprehenders. We examined text comprehension and written composition relationship. Verbal working memory (verbal span working memory and operation span working memory) and different levels of linguistic tasks-morphological sensitivity (morphological compounding and morphological chain), sentence processing (syntax construction and syntax integrity), and text comprehension (narrative and expository texts)-were used to predict separately narrative, expository, and argumentation written compositions in these students. Grade for grade, the good text comprehenders outperformed the poor text comprehenders in all tasks, except for morphological chain. Hierarchical multiple regression analyses showed differential contribution of the tasks to different genres of writing. In particular, text comprehension made unique contribution to argumentation writing in the poor text comprehenders. Future studies should ask students to read and write parallel passages in the same genre for better comparison and incorporate both instructional and motivational variables. PMID- 23666850 TI - Treatment of partial ulnar collateral ligament tears in the elbow with platelet rich plasma. AB - BACKGROUND: Studies have demonstrated the potential of platelet-rich plasma (PRP) to heal damaged tissue. To date, there are no published reports of clinical outcomes of partial ulnar collateral ligament (UCL) tears of the elbow treated with PRP. HYPOTHESIS: Platelet-rich plasma will promote the healing of partial UCL tears and allow a return to play. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Thirty-four athletes with a partial-thickness UCL tear confirmed on magnetic resonance imaging were prospectively followed. All patients had failed at least 2 months of nonoperative treatment and an attempt to return to play. Baseline questionnaires, including the Kerlan-Jobe Orthopaedic Clinic Shoulder and Elbow (KJOC) and Disabilities of the Arm, Shoulder and Hand (DASH) measures, were completed by each patient before injection. Baseline ultrasound measurement of the humeral-ulnar joint space was assessed with 10 lb of valgus stress on the elbow. Each patient received a single type 1A PRP injection at the UCL under ultrasound guidance. The same treating physician at a single institution performed all injections with the same PRP preparation used. Patients completed a course of guided physical therapy and were allowed to return to play based on their symptoms and physical examination findings. Outcome scores, including KJOC and DASH scores, were collected after return to play and were compared with baseline scores. Ultrasound measurements were collected at final follow-up and compared with preinjection values. RESULTS: At an average follow-up of 70 weeks (range, 11-117 weeks), 30 of 34 athletes (88%) had returned to the same level of play without any complaints. The average time to return to play was 12 weeks (range, 10-15 weeks). The average KJOC score improved from 46 to 93 (P < .0001). The average DASH score improved from 21 to 1 (P < .0001). The sports module of the DASH questionnaire improved from 69 to 3 (P < .0001). Medial elbow joint space opening with valgus stress decreased from 28 to 20 mm at final follow up (P < .0001). The difference in medial elbow joint space opening (stressed vs nonstressed) decreased from 7 to 2.5 mm at final follow-up (P < .0001). One player had persistent UCL insufficiency and underwent ligament reconstruction at 31 weeks after injection. CONCLUSION: The results of this study indicate that PRP is an effective option to successfully treat partial UCL tears of the elbow in athletes. PMID- 23666851 TI - Preparation and properties of cellulose nanocrystals reinforced collagen composite films. AB - Collagen films have been widely used in the field of biomedical engineering. However, the poor mechanical properties of collagen have limited its application. Here, rod-like cellulose nanocrystals (CNCs) were fabricated and used to reinforce collagen films. A series of collagen/CNCs films were prepared by collagen solution with CNCs suspensions homogeneously dispersed at CNCs: collagen weight ratios of 1, 3, 5, 7, and 10. The morphology of the resulting films was analyzed by scanning electron microscopy (SEM), the enhancement of the thermomechanical properties of the collagen/CNCs composites were demonstrated by thermal gravimetric analysis (TGA) and mechanical testing. Among the CNCs contents used, a loading of 7 wt % led to the maximum mechanical properties for the collagen/CNCs composite films. In addition, in vitro cell culture studies revealed that the CNCs have no negative effect on the cell morphology, viability, and proliferation and possess good biocompatibility. We conclude that the incorporation of CNCs is a simple and promising way to reinforce collagen films without impairing biocompatibility. This study demonstrates that the composite films show good potential for use in the field of skin tissue engineering. PMID- 23666852 TI - IRF4 promotes cell proliferation by JNK pathway in multiple myeloma. AB - Interferon regulatory factor 4 (IRF4) is a member of the interferon regulatory family, which plays an important role in many lymphoid and myeloid malignancies. In the current study, using immunohistochemical staining, we found that IRF4 only expressed in plasma cells in bone marrow biopsy samples of multiple myeloma. IRF4 positive patients displayed increased disease stage (Durie-Salmon stage, p = 0.026; and International Staging System, p = 0.005). Silencing IRF4 in myeloma cell lines could inhibit myeloma cells proliferation and induce myeloma cell apoptosis, partly by JNK/Jun pathway. These results demonstrate that IRF4 plays important roles in myelomagenesis and disease progression. PMID- 23666853 TI - "Combined" small cell and "pure" small cell lung cancer: is there a clinical difference? PMID- 23666854 TI - Dark nights reverse metabolic disruption caused by dim light at night. AB - OBJECTIVE: The increasing prevalence of obesity and related metabolic disorders coincides with increasing exposure to light at night. Previous studies report that mice exposed to dim light at night (dLAN) develop symptoms of metabolic syndrome. This study investigated whether mice returned to dark nights after dLAN exposure recover metabolic function. DESIGN AND METHODS: Male Swiss-Webster mice were assigned to either: standard light-dark (LD) conditions for 8 weeks (LD/LD), dLAN for 8 weeks (dLAN/dLAN), LD for 4 weeks followed by 4 weeks of dLAN (LD/dLAN), and dLAN for 4 weeks followed by 4 weeks of LD (dLAN/LD). RESULTS: After 4 weeks in their respective lighting conditions both groups initially placed in dLAN increased body mass gain compared to LD mice. Half of the dLAN mice (dLAN/LD) were then transferred to LD and vice versa (LD/dLAN). Following the transfer dLAN/dLAN and LD/dLAN mice gained more weight than LD/LD and dLAN/LD mice. At the conclusion of the study dLAN/LD mice did not differ from LD/LD mice with respect to weight gain and had lower fat pad mass compared to dLAN/dLAN mice. Compared to all other groups dLAN/dLAN mice decreased glucose tolerance as indicated by an intraperitoneal glucose tolerance test at week 7, indicating that dLAN/LD mice recovered glucose metabolism. dLAN/dLAN mice also increased MAC1 mRNA expression in peripheral fat as compared to both LD/LD and dLAN/LD mice, suggesting peripheral inflammation is induced by dLAN, but not sustained after return to LD. CONCLUSION: These results suggest that re-exposure to dark nights ameliorates metabolic disruption caused by dLAN exposure. PMID- 23666855 TI - Inhibitory effects of hesperetin derivatives on guinea pig phosphodiesterases and their ratios between high- and low-affinity rolipram binding. AB - The phosphodiesterase (PDE)4 molecule exists as two distinct conformers, PDE4H and PDE4L , which have high and low affinities, respectively, for the selective PDE4 inhibitor, rolipram. The inhibition of PDE4H and PDE4L is associated with adverse responses, such as nausea, vomiting, and gastric hypersecretion, and with anti-inflammatory and bronchodilator effects, respectively. We determined the therapeutic (PDE4H/PDE4L) ratios of hesperetin-7-O-methylether, hesperetin-5,7,3' O-trimethylether (HTME), hesperetin-7-O-acetate, hesperetin-7,3'-O-diacetate, hesperetin-5,7,3'-O-triacetate (HTA), hesperetin-5,7,3'-O-tripropionate, hesperetin-5,7,3'-O-tributyrate, hesperetin-5,7,3'-O-triisobutyrate, and hesperetin-5,7,3'-O-tripivatate, and compared these ratios to those of hesperetin, hesperetin-7,3'-O-dimethylether, hesperidin, and hesperidin-3'-O methylether to identify derivatives with therapeutic ratios and to characterize the structure-activity relationships among these compounds. The activities of PDE isozymes 1 through 5 were measured using a two-step procedure using [(3)H]adenosine 3',5'-cyclic monophosphate or [(3)H]guanosine 3',5'-cyclic monophosphate as substrates. The inhibitory concentration (IC50) for 50% of PDE4 inhibition and effective concentration (EC50) for replacing 50% of [(3)H]rolipram binding on high-affinity rolipram-binding sites was taken as the PDE4L and PDE4H value, respectively. The HTME and the HTA dually inhibited PDE3 and PDE4, and displayed PDE4H/PDE4L ratios of 18.3 and 20.8, respectively, suggesting that they may be candidate drugs for treating asthma and chronic obstructive pulmonary disease (COPD) because the combined inhibition of PDE3 and PDE4 has synergistically anti-inflammatory and bronchodilator effects in COPD patients. PMID- 23666856 TI - Associations among SPARC mRNA expression in adipose tissue, serum SPARC concentration and metabolic parameters in Korean women. AB - OBJECTIVE: Secreted protein acidic and rich in cysteine (SPARC) is expressed in most tissues and is also secreted by adipocytes. The associations of SPARC mRNA expression in visceral adipose tissue (VAT), subcutaneous abdominal adipose tissue (SAT), serum SPARC concentration, and metabolic parameters in Korean women are investigated. DESIGN AND METHODS: This is a cross-sectional study. Fifty eight women were recruited, of whom 15 women who underwent bariatric surgery for morbid obesity (BMI mean +/- SD: 40.2+/-5.7 kg/m(2) ), 16 who underwent metabolic surgery for type 2 diabetes (BMI: 28.9+/-4.5 kg/m(2) ), and, as a control group, 27 who underwent gynecological surgery (BMI: 22.7+/-2.4 kg/m(2) ). Anthropometric variables, metabolic parameters, SPARC mRNA expression in adipose tissue, and serum SPARC concentration were measured. RESULTS: In all subjects, SPARC mRNA expression was significantly higher in SAT than in VAT. Serum SPARC concentrations (mean +/- SE) in morbidly obese subjects, subjects with type 2 diabetes, and normal weight subjects were 267.3+/-40.2 ng/mL, 130.4+/-33.0 ng/mL, and 53.1+/-2.8 ng/mL, respectively. SPARC mRNA in SAT was significantly correlated with BMI, whereas SPARC mRNA in VAT was significantly correlated with BMI and VAT area. Serum SPARC concentration was significantly correlated with BMI, waist circumference, total adipose tissue area, and SAT area. After BMI adjustment, serum SPARC concentration was significantly correlated with fasting insulin concentration and HOMA-IR score. Multivariate regression analysis showed that BMI and HOMA-IR were independently associated with serum SPARC concentration. CONCLUSIONS: Serum SPARC concentration is significantly correlated with obesity indices and might be influenced by insulin resistance. These findings suggest that SPARC may contribute to the metabolic dysregulation associated with obesity in humans. PMID- 23666858 TI - Morphological and functional changes in colon after coloplasty for management of corrosive esophageal strictures. AB - BACKGROUND: The etiology of corrosive esophageal strictures is different from that reported in Western literature, with acid ingestion being a major cause. This study evaluated functional and morphological changes in the colon used as neoesophagus. METHODS: Functional changes in the neoesophagus were evaluated by symptom score of dysphagia and manometry. Barium study and fluoroscopy were done to evaluate the flow patterns and endoscopy with histopathological examination to study the adaptive changes in the colon. RESULTS: Thirty-five patients with corrosive injury presented between 2007 and 2010. Isolated esophageal involvement was seen in 22 patients; 11 of them underwent colonic replacement. The passage of barium was smooth, without any hold up at the upper or lower anastomotic line. Endoscopic biopsy at 6 months and 1 year did not show any change in the mucosal pattern or in the muscularis layer of the transposed colon. Functional evaluation showed relief of dysphagia in all 11 patients after surgery. The mean preoperative dysphagia score was 7.81 (range 5-10), at 1 month was 0.73 (range 0 2), and at 3 months post-surgery was 0.45 (range 0-2). Manometric study at 3 months after the surgery in all 11 patients and in five patients at the end of 6 months showed no evidence of peristalsis in the neoesophagus. Three of the latter five patients demonstrated a 4-5-cm zone with a high pressure in the intraabdominal part of the transposed colon compared with that in the intrathoracic part of the colon. On barium studies, reflux from the stomach into the neoesophagus was not seen in any of the 11 patients. CONCLUSIONS: Esophagocoloplasty was associated with symptom relief, and the reflux of gastric content was low because of 4-5 cm of the colon being intraabdominal in a positive pressure environment. PMID- 23666857 TI - Angiogenesis in rheumatoid arthritis is fostered directly by toll-like receptor 5 ligation and indirectly through interleukin-17 induction. AB - OBJECTIVE: To examine the impact of Toll-like receptor 5 (TLR-5) on endothelial cell function in rheumatoid arthritis (RA) and vascularization in collagen induced arthritis (CIA). METHODS: Endothelial cell migration and tube formation assays were used to demonstrate the direct role of TLR-5 ligation in angiogenesis. Mice with CIA were treated with the TLR-5 agonist flagellin to document the effect of TLR-5 ligation in RA pathology. Vascularization in CIA was determined by immunohistochemical analysis and determination of cytokine levels in ankle joints. Spleen Th17 cells and joint interleukin-17 (IL-17) were quantified by fluorescence-activated cell sorting analysis and enzyme-linked immunosorbent assay. The development of Th17 cells induced by TLR-5 ligation was validated in RA peripheral blood mononuclear cells. RESULTS: Ligation of TLR-5 to endogenous ligands expressed in RA synovial fluid contributed to endothelial cell infiltration and tube formation. Furthermore, treatment with flagellin after the onset of CIA exacerbated joint inflammation; in contrast, inflammation in control mice remained at a plateau phase. We showed that TLR-5-enhanced disease severity was attributable to Th17 cell differentiation and joint vascularization in CIA. Examination of the underlying mechanism using RA peripheral blood mononuclear cells documented that ligation of TLR-5 in myeloid cells and production of Th17 promoting cytokines were necessary for Th17 cell polarization. Additionally, we demonstrated that blockade of the IL-17 cascade markedly reduced endothelial cell migration activated by flagellin-conditioned medium, suggesting that TLR-5 ligation can mediate RA angiogenesis either directly by attracting endothelial cells or indirectly by fostering Th17 cell development. CONCLUSION: Our data demonstrate a novel role for TLR-5 in RA angiogenesis; thus, TLR-5 may be a promising new target for RA treatment. PMID- 23666861 TI - Stroke and obstructive sleep apnea: a review. AB - Obstructive sleep apnea (OSA) has been found to be an independent risk factor for stroke in large epidemiological studies. The mechanisms underlying this relationship have been investigated over the past 2-3 decades, with a particular focus on identifying pathophysiological pathways and risk modification strategies. Despite the advancements made, the specific understanding of the implicated mechanisms is still limited. This brief review focuses on presenting some of the epidemiological evidence of the linkage between OSA and stroke, discussing mechanistic pathways and the potential effect of OSA treatment in modulating the risk for stroke in these patients. Future directions for research in this field are also discussed. PMID- 23666862 TI - Spinal dural arteriovenous fistulas: a review. AB - Spinal dural arteriovenous fistulas (SDAVF) are a rare pathologic entity with a diverse and often misleading clinical presentation. While digital subtraction spinal angiography remains the gold standard, recent advances in noninvasive vascular imaging have improved the diagnosis of SDAVF. As this condition can result in permanent spinal cord injury, all patients require treatment, which consists of surgical or endovascular occlusion of the fistula. Failure to recognize and treat SDAVF in a timely fashion can result in irreversible neurologic disability, including myelopathy, lower extremity weakness and bowel, bladder and sexual dysfunction. This article reviews the clinical features, pathogenesis, radiographic features and current treatment strategies for these complex lesions. PMID- 23666863 TI - The electrocaloric efficiency of ceramic and polymer films. AB - Efficiency is defined as eta = |Q|/|W| in order to investigate the electrical work |W| associated with electrocaloric heat |Q|. This materials parameter indicates that polymer films are slightly more energy efficient than ceramic films, and therefore both species of material remain candidates for future cooling applications. PMID- 23666865 TI - A large pseudoautosomal region on the sex chromosomes of the frog Silurana tropicalis. AB - Sex chromosome divergence has been documented across phylogenetically diverse species, with amphibians typically having cytologically nondiverged ("homomorphic") sex chromosomes. With an aim of further characterizing sex chromosome divergence of an amphibian, we used "RAD-tags" and Sanger sequencing to examine sex specificity and heterozygosity in the Western clawed frog Silurana tropicalis (also known as Xenopus tropicalis). Our findings based on approximately 20 million genotype calls and approximately 200 polymerase chain reaction-amplified regions across multiple male and female genomes failed to identify a substantially sized genomic region with genotypic hallmarks of sex chromosome divergence, including in regions known to be tightly linked to the sex determining region. We also found that expression and molecular evolution of genes linked to the sex-determining region did not differ substantially from genes in other parts of the genome. This suggests that the pseudoautosomal region, where recombination occurs, comprises a large portion of the sex chromosomes of S. tropicalis. These results may in part explain why African clawed frogs have such a high incidence of polyploidization, shed light on why amphibians have a high rate of sex chromosome turnover, and raise questions about why homomorphic sex chromosomes are so prevalent in amphibians. PMID- 23666867 TI - Multiobjective evolutionary algorithm with many tables for purely ab initio protein structure prediction. AB - This article focuses on the development of an approach for ab initio protein structure prediction (PSP) without using any earlier knowledge from similar protein structures, as fragment-based statistics or inference of secondary structures. Such an approach is called purely ab initio prediction. The article shows that well-designed multiobjective evolutionary algorithms can predict relevant protein structures in a purely ab initio way. One challenge for purely ab initio PSP is the prediction of structures with beta-sheets. To work with such proteins, this research has also developed procedures to efficiently estimate hydrogen bond and solvation contribution energies. Considering van der Waals, electrostatic, hydrogen bond, and solvation contribution energies, the PSP is a problem with four energetic terms to be minimized. Each interaction energy term can be considered an objective of an optimization method. Combinatorial problems with four objectives have been considered too complex for the available multiobjective optimization (MOO) methods. The proposed approach, called "Multiobjective evolutionary algorithms with many tables" (MEAMT), can efficiently deal with four objectives through the combination thereof, performing a more adequate sampling of the objective space. Therefore, this method can better map the promising regions in this space, predicting structures in a purely ab initio way. In other words, MEAMT is an efficient optimization method for MOO, which explores simultaneously the search space as well as the objective space. MEAMT can predict structures with one or two domains with RMSDs comparable to values obtained by recently developed ab initio methods (GAPFCG , I-PAES, and Quark) that use different levels of earlier knowledge. PMID- 23666866 TI - Associations of pericardial and intrathoracic fat with coronary calcium presence and progression in a multiethnic study. AB - OBJECTIVE: Body mass index (BMI) may not accurately or adequately reflect body composition or its role in the development of cardiovascular disease (CVD). Ectopic adipose depots may provide a more refined representation of the role of adiposity in CVD. Thus, the association of pericardial and intra-thoracic fat with coronary artery calcium (CAC) was examined. DESIGN AND METHODS: Nearly 600 white men and women, as well as Filipina women and African-American women, all without known CVD, had abdominal and chest computed tomography (CT) scans at two time points about 4 years apart from which CAC presence, severity and progression, as well as pericardial and intrathoracic fat volumes were obtained. Logistic and linear regression models with staged adjustment were used to assess associations of pericardial and intra-thoracic fat with CAC presence, severity, and progression. RESULTS: After adjustment for age, BMI, sex/ethnic group, ever smoking, and lipids, each standard deviation higher increment of intra-thoracic fat, but not pericardial fat, was significantly associated with 3.84-fold higher odds of prevalent CAC (95% CI (1.54, 9.58), P = 0.004) and a 38.4% higher CAC score (95% CI (3.5%, 90.0%), P = 0.03). Neither pericardial nor intrathoracic fat were associated with CAC progression. CONCLUSIONS: Contrary to previous reports, pericardial fat was not associated with the presence, severity or progression of CAC. However, a significant association between intrathoracic fat and both the presence and severity of CAC was demonstrated. Studies measuring fat in the thoracic cavity may consider defining intrathoracic fat as a separate entity from pericardial fat. PMID- 23666864 TI - The GenoChip: a new tool for genetic anthropology. AB - The Genographic Project is an international effort aimed at charting human migratory history. The project is nonprofit and nonmedical, and, through its Legacy Fund, supports locally led efforts to preserve indigenous and traditional cultures. Although the first phase of the project was focused on uniparentally inherited markers on the Y-chromosome and mitochondrial DNA (mtDNA), the current phase focuses on markers from across the entire genome to obtain a more complete understanding of human genetic variation. Although many commercial arrays exist for genome-wide single-nucleotide polymorphism (SNP) genotyping, they were designed for medical genetic studies and contain medically related markers that are inappropriate for global population genetic studies. GenoChip, the Genographic Project's new genotyping array, was designed to resolve these issues and enable higher resolution research into outstanding questions in genetic anthropology. The GenoChip includes ancestry informative markers obtained for over 450 human populations, an ancient human (Saqqaq), and two archaic hominins (Neanderthal and Denisovan) and was designed to identify all known Y-chromosome and mtDNA haplogroups. The chip was carefully vetted to avoid inclusion of medically relevant markers. To demonstrate its capabilities, we compared the FST distributions of GenoChip SNPs to those of two commercial arrays. Although all arrays yielded similarly shaped (inverse J) FST distributions, the GenoChip autosomal and X-chromosomal distributions had the highest mean FST, attesting to its ability to discern subpopulations. The chip performances are illustrated in a principal component analysis for 14 worldwide populations. In summary, the GenoChip is a dedicated genotyping platform for genetic anthropology. With an unprecedented number of approximately 12,000 Y-chromosomal and approximately 3,300 mtDNA SNPs and over 130,000 autosomal and X-chromosomal SNPs without any known health, medical, or phenotypic relevance, the GenoChip is a useful tool for genetic anthropology and population genetics. PMID- 23666868 TI - In vivo biocompatibility and biodegradation of a novel thin and mechanically stable collagen scaffold. AB - The demand for scaffolds comprised of natural materials such as collagen has increased in recent years. However, many scaffolds rely on chemical or physical modifications in order to comply with the necessary requirements for biomedical engineering. We evaluated the in vivo biocompatibility and biodegradation of a novel, thin, mechanically stable, and chemically non-crosslinked collagen cell carrier (CCC). CCC was implanted subcutaneously into 25 adult Lewis rats and biopsies were taken on days 7, 14, 21, 42, and 84 after surgery. For histological analysis, paraffin sections of implanted skin were immunolabeled for CD68 and stained by hematoxylin-eosin and Masson-Goldner's trichrome method. Macroscopic analysis of skin surface during wound healing process showed a normal physiological reaction. Biodegradation of CCC was completed 42 days after subcutaneous implantation. Histological evaluation revealed no evidence of encapsulation, scar formation, or long-term vascularization and inflammation. The collagen type I based biomaterial demonstrated a high in vivo biocompatibility, low irritability, complete resorption, and replacement by autologous tissue. The in vivo biocompatibility and degradation behavior encourage for further evaluation of CCC in surgical applications and regenerative medicine. PMID- 23666869 TI - Stimulation of fibrotic processes by the infrapatellar fat pad in cultured synoviocytes from patients with osteoarthritis: a possible role for prostaglandin f2alpha. AB - OBJECTIVE: Stiffening of the joint is a feature of knee osteoarthritis (OA) that can be caused by fibrosis of the synovium. The infrapatellar fat pad (IPFP) present in the knee joint produces immune-modulatory and angiogenic factors. The goal of the present study was to investigate whether the IPFP can influence fibrotic processes in synovial fibroblasts, and to determine the role of transforming growth factor beta (TGFbeta) and prostaglandin F2alpha (PGF2alpha ) in these processes. METHODS: Batches of fat-conditioned medium (FCM) were made by culturing pieces of IPFP obtained from the knees of 13 patients with OA. Human OA fibroblast-like synoviocytes (FLS) (from passage 3) were cultured in FCM with or without inhibitors of TGFbeta/activin receptor-like kinase 5 or PGF2alpha for 4 days. The FLS were analyzed for production of collagen and expression of the gene for procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2; encoding lysyl hydroxylase 2b, an enzyme involved in collagen crosslinking) as well as the genes encoding alpha-smooth muscle actin and type I collagen alpha1 chain. In parallel, proliferation and migration of the synoviocytes were analyzed. RESULTS: Collagen production and PLOD2 gene expression by the FLS were increased 1.8-fold (P < 0.05) and 6.0-fold (P < 0.01), respectively, in the presence of FCM, relative to control cultures without FCM. Moreover, the migration and proliferation of synoviocytes were stimulated by FCM. Collagen production was positively associated with PGF2alpha levels in the FCM (R = 0.89, P < 0.05), and inhibition of PGF2alpha levels reduced the extent of FCM-induced collagen production and PLOD2 expression. Inhibition of TGFbeta signaling had no effect on the profibrotic changes. CONCLUSION: These results indicate that the IPFP can contribute to the development of synovial fibrosis in the knee joint by increasing collagen production, PLOD2 expression, cell proliferation, and cell migration. In addition, whereas the findings showed that TGFbeta is not involved, the more recently discovered profibrotic factor PGF2alpha appears to be partially involved in the regulation of profibrotic changes. PMID- 23666870 TI - Potential cause of delayed strokes following carotid artery stenting. AB - Carotid artery stenting (CAS) has been developed as an alternative therapeutic strategy of carotid endarterectomy (CEA) both for symptomatic and asymptomatic extra-cranial carotid artery stenosis. Some randomized clinical trial has been successfully proven the non-inferiority of CAS compared to CEA in terms of efficacy and safety regarding freedom from major adverse event (MAE). One of the remaining problems in CAS is a non-significant but relatively higher incidence of ipsi-lateral minor stroke related to the procedure, both during and soon after the procedure. We routinely examine intravascular ultrasound (IVUS) imaging during the CAS procedure, and found some informative findings. We hereby report the representative IVUS finding, which might suggest the possible cause for delayed stroke after CAS. PMID- 23666871 TI - Subcutaneous adipose cell size and distribution: relationship to insulin resistance and body fat. AB - OBJECTIVE: Metabolic heterogeneity among obese individuals may be attributable to differences in adipose cell size. We sought to clarify this by quantifying adipose cell size distribution, body fat, and insulin-mediated glucose uptake in overweight to moderately-obese individuals. METHODS: A total of 148 healthy nondiabetic subjects with BMI 25-38 kg/m2 underwent subcutaneous adipose tissue biopsies and quantification of insulin-mediated glucose uptake with steady-state plasma glucose (SSPG) concentrations during the modified insulin suppression test. Cell size distributions were obtained with Beckman Coulter Multisizer. Primary endpoints included % small adipose cells and diameter of large adipose cells. Cell-size and metabolic parameters were compared by regression for the whole group, according to insulin-resistant (IR) and insulin-sensitive (IS) subgroups, and by body fat quintile. RESULTS: Both large and small adipose cells were present in nearly equal proportions. Percent small cells was associated with SSPG (r = 0.26, P = 0.003). Compared to BMI-matched IS individuals, IR counterparts demonstrated fewer, but larger large adipose cells, and a greater proportion of small-to-large adipose cells. Diameter of the large adipose cells was associated with % body fat (r = 0.26, P = 0.014), female sex (r = 0.21, P = 0.036), and SSPG (r = 0.20, P = 0.012). In the highest versus lowest % body fat quintile, adipose cell size increased by only 7%, whereas adipose cell number increased by 74%. CONCLUSIONS: Recruitment of adipose cells is required for expansion of body fat mass beyond BMI of 25 kg/m2 . Insulin resistance is associated with accumulation of small adipose cells and enlargement of large adipose cells. These data support the notion that impaired adipogenesis may underlie insulin resistance. PMID- 23666872 TI - Involvement of carnitine/organic cation transporter OCTN1/SLC22A4 in gastrointestinal absorption of metformin. AB - Metformin is a widely used oral anti-diabetic, but the molecular mechanism(s) of its gastrointestinal membrane permeation remains unclear. Here, we examined the role of carnitine/organic cation transporter OCTN1/SLC22A4, which is localized on apical membranes of small intestine in mice and humans, in metformin absorption. The maximum plasma concentration (Cmax ) after oral administration of metformin (50 mg/kg) in octn1 gene knockout mice (octn1 (-/-) ) was higher than that in wild-type mice, with only a minimal difference in terminal half-life, but Cmax in octn1(-/-) mice given a higher dose (175 mg/kg) was lower than that in wild-type mice. Systemic elimination of metformin after intravenous administration was similar in the two strains, suggesting the possible involvement of OCTN1 in the gastrointestinal absorption. OCTN1-mediated uptake of metformin was observed in human embryonic kidney 293 cells transfected with mouse OCTN1 gene, but much lower than the uptake of the typical substrate [(3) H]ergothioneine (ERGO). In particular, the distribution volume for OCTN1-mediated uptake increased markedly and then tended to decrease as the metformin concentration was increased. Efflux of metformin preloaded in intestinal epithelial cell line Caco-2 was inhibited by ERGO. Overall, the present findings suggest that OCTN1 transports metformin and may be involved in its oral absorption in small intestine. PMID- 23666874 TI - In vivo neutralization of botulinum neurotoxins serotype E with heavy-chain camelid antibodies (VHH). AB - Ingestion of botulinum neurotoxin (BoNT) results in botulism, a severe and frequent fatal disease known in the world. Current treatments rely on antitoxins, such as equine antitoxin and human botulism immunoglobulin. In some cases, side effects have been reported, including early anaphylactic shock and late serum sickness. Thus, diagnosis and treatment measure of BoNT are necessary and crucial. In the present study, a single-domain variable heavy-chain (VHH) antibody fragment was obtained from an immune dromedary phage display library against the putative binding domain of botulinum neurotoxin E (BoNT/E), a non toxic 50-kDa fragment. The characteristics of nanobody VHH include excellent production, superior heat stability and specific binding capacity to soluble antigen without cross-reaction to other relevant or irrelevant antigens. A total of 150 ng/Kg of nanobody entirely neutralized 3LD50 of the BoNT/E in an in vivo challenge of the mice. This phenomenon indicates BoNT/E toxin neutralizing capacity of the produced nanobody. These results also suggest possession of unique properties by the nanobody applicable in diagnostics or therapeutic purposes. PMID- 23666876 TI - In situ homeotropic alignment of nematic liquid crystals based on photoisomerization of azo-dye, physical adsorption of aggregates, and consequent topographical modification. AB - In situ homeotropic alignment is achieved by photochromic trans- to cis isomerization of an azo-dye doped in a nematic host. The augmented dipole moment of the cis-isomer formed under UV-irradiation expedites molecular assembly into crystalline aggregates. Subsequent deposition of the aggregates creates a roughened surface and induces an anchoring transition from the initial planar to a homeotropic alignment of the LCs. PMID- 23666877 TI - Small and large size for gestational age at birth, infant growth, and childhood overweight. AB - OBJECTIVE: The associations of size at birth, with infant growth of head circumference, length and weight, and fat mass and body mass index in preschool children were examined. DESIGN AND METHODS: In a population-based prospective cohort study among 3,941 children, head circumference, length and weight until the age of 4 years were repeatedly measured. Catch-up and catch-down growth were defined as a change in standard deviation scores of >0.67 from birth to 2 years of age. RESULTS: Although most children born small and large size for gestational age showed infant catch-up and catch-down growth, respectively, their mean head circumference, length and weight remained smaller and larger respectively, until the age of 4 years. Catch-up growth in children with a small and appropriate weight for gestational age and lack of catch-down growth in children born with a large weight for gestational age were associated with higher body mass index in preschool children. Children born with an appropriate weight for gestational age with catch-up growth and children born with a large weight for gestational without catch-down growth had increased risks of childhood overweight {odds ratios: 3.11 (95% confidence interval[95% CI] 2.37, 4.08) and 12.46 (95% CI: 6.07, 25.58) respectively}. CONCLUSIONS: Children born small, appropriate and large size for gestational age have different growth patterns in early childhood and persistent differences in their head circumference, length, and weight until the age of 4 years. Children born with an appropriate weight for gestational age with catch-up growth and large weight for gestational children without catch-down growth have an increased risk of overweight. PMID- 23666875 TI - Use of perfusion imaging and other imaging techniques to assess risks/benefits of acute stroke interventions. AB - The advent of multimodal neuroimaging has provided acute stroke care providers with an armamentarium of sophisticated imaging options to utilize for guidance in clinical decision-making and management of acute ischemic stroke patients. Here, we propose a framework and potential algorithm-based methodology for imaging modality selection and utilization for the purpose of achieving optimal stroke clinical care. We first review imaging options that may best inform decision making regarding revascularization eligibility, with a focus on the imaging modalities that best identify critical inclusion and exclusion criteria. Next, we review imaging methods that may guide the successful achievement of revascularization once it has been deemed desirable and feasible. Further, we review imaging modalities that may best assist in both the noninterventional care of acute stroke as well as the identification of stroke-mimics. Finally, we review imaging techniques under current investigation that show promise to improve future acute stroke management. PMID- 23666878 TI - Osteoprotegerin causes apoptosis of endothelial progenitor cells by induction of oxidative stress. AB - OBJECTIVE: Elevated serum osteoprotegerin (OPG) levels represent an independent risk factor for atherosclerotic disease, although the underlying mechanism is not clear. The aim of this study was to investigate the association of serum OPG levels and circulating endothelial progenitor cell (EPC) numbers, and to explore the effect of OPG on EPC apoptosis and its underlying mechanisms. METHODS: Flow cytometry was used to enumerate EPCs in the peripheral blood of 91 patients with systemic lupus erythematosus (SLE). Cultured EPCs, isolated from peripheral blood, were challenged with OPG, and apoptosis was evaluated by TUNEL staining. Expression of apoptosis-related proteins was measured by real-time quantitative polymerase chain reaction (qPCR) and Western blotting. Reactive oxygen species (ROS) were detected by flow cytometry, and the expression of NADPH oxidase (NOX) and MAP kinases (MAPK) was measured by qPCR and Western blotting. RESULTS: The serum OPG level was independently associated with reduced numbers of EPCs in patients with SLE. In vitro treatment with OPG significantly induced apoptosis of EPCs; this effect was mediated by syndecan 4. OPG-induced apoptosis was abolished by the ROS scavenger N-acetylcysteine and the NOX inhibitor diphenyleniodonium. OPG increased ROS production through activation of NOX-2 and NOX-4 and triggered phosphorylation of ERK-1/2 and p38 MAPK. Quenching of ROS by knockdown of NOX-2 or NOX-4 transcripts inhibited phosphorylation of ERK-1/2 and p38 MAPK. Moreover, inhibitors of ERK-1/2 and p38 MAPK decreased ROS production and subsequent EPC apoptosis, indicating a feed-forward loop between NOX and MAPK to amplify ROS production related to apoptosis. CONCLUSION: Elevated OPG levels increase apoptosis of EPCs by induction of oxidative stress. PMID- 23666879 TI - A toxicity risk index, an index for warning idiosyncratic drug toxicity. AB - Drug toxicity impedes drug development and its clinical use. In the present study, a toxicity risk index (TRI), which is an index for warning idiosyncratic drug toxicity (IDT), was proposed. The TRI of drugs was defined as a function of dose, pharmacokinetic parameters, and toxicokinetic data from covalent binding experiment. Twenty drugs, which were classified into three categories by a report (Nakayama S, Atsumi R, Takakusa H, Kobayashi Y, Kurihara A, Nagai Y, Nakai D, Okazaki O. 2009. Drug Metab Dispos 37:1970-1977), were studied with TRI. The three categories were BBW (drugs with a block box warning for IDT), WNG (drugs without a black box warning but with a warning for IDT), and SAFE (drugs without any warning). The TRIs of drugs classified as SAFE were distinctly different from those classified as BBW. The TRI of the SAFE drugs were lower than 0.456 (nmol/mg protein). In contrast, the TRI of the BBW drugs were higher than 1.10 (nmol/mg protein). These results warned us that a drug candidate, where the TRI is higher than 1.0 nmol/mg protein, should be categorized as a BBW drug. Further study with more data of TRI will give a cutoff value with a statistical meaning. Thus, TRI may be useful for decision making in drug development and its clinical use. PMID- 23666880 TI - Gold-nanorod-photosensitized titanium dioxide with wide-range visible-light harvesting based on localized surface plasmon resonance. PMID- 23666881 TI - Fabrication of polystyrene microscale porous substrate and its effects on HL-7702 cells behaviors. AB - A novel polystyrene (PS) substrate with microscale porous structure was facilely fabricated by crystalline-controlled casting method using mixed solvent [N,N dimethylformamide and ethyl alcohol (v/v)] based on the nonsolvent induced phase separation process. The substrate surfaces exhibited a bi-continuous microscale porous morphology with high porosity, large pore size and pore-pore connection structure. Moreover, behaviors of the normal human liver cell line (HL-7702) seeded on this substrate surface were carefully investigated. The results indicated that the cell adhesion, spread and cell-cell connection on the surface with subcellular pore size (~ 10 MUm) were similar to the cells proliferated on the flat PS surface. However, the number of HL-7702 cells proliferated on the PS microscale porous surface was higher than cells on the conventional PS flat surface, suggesting that the pore-pore structure was conducive to HL-7702 cell proliferation. Furthermore, hematoxylin and eosin staining and micronucleus test were performed. The results showed that fewer damages for nuclear and cytoplasm and less cell genotoxicity were caused by the microscale porous structure within the scope of pore size (~ 10 MUm) than that of the flat surface. PMID- 23666882 TI - Serotonin in testes of bat Myotis velifer during annual reproductive cycle: expression, localization, and content variations. AB - The mechanism of reproduction in mammals is very complex and in some cases is quite particular. For example in some bat species, the male presents a reproductive mechanism characterized by an annual testicular cycle that goes from recrudescence to regression (spermatogenesis to inactivity period, respectively). After recrudescence, the spermatozoa arrive at epididymis and wait to be expelled at the time of ejaculation during the mating period, which occurs some months later. Because serotonin (5-HT) has gained reproductive importance in the last years, the aim of the present study was to analyze the expression of this indolamine and both tryptophan hydroxylase and monoamine oxidase isoform A enzymes involved in its metabolism-in Myotis velifer testes, a seasonal reproductive bat species that shows temporal asynchrony in its sexual cycle, across the principal periods of their reproductive cycle. By using both Falck Hillarp histochemistry and immunofluorescence techniques, we found serotonin in vesicles of Leydig cells and probably Sertoli cells too; interestingly, both intracellular localization and concentration was variable across the different stages of the reproductive cycle, being lower during spermatogenesis phase and increasing during the mating phase. These results suggest that 5-HT is present in bat testes and it could play an important role in testicular function during their reproductive cycle. PMID- 23666883 TI - Stem cell therapy for pediatric dilated cardiomyopathy. AB - Dilated cardiomyopathy is a serious and life-threatening disorder in children. It is the most common form of pediatric cardiomyopathy. Therapy for this condition has varied little over the last several decades and mortality continues to be high. Currently, children with dilated cardiomyopathy are treated with pharmacological agents and mechanical support, but most require heart transplantation and survival rates are not optimal. The lack of common treatment guidelines and inadequate survival rates after transplantation necessitates more therapeutic clinical trials. Stem cell and cell-based therapies offer an innovative approach to restore cardiac structure and function towards normal, possibly reducing the need for aggressive therapies and cardiac transplantation. Mesenchymal stem cells and cardiac stem cells may be the most promising cell types for treating children with dilated cardiomyopathy. The medical community must begin a systematic investigation of the benefits of current and novel treatments such as stem cell therapies for treating pediatric dilated cardiomyopathy. PMID- 23666885 TI - Ferroelectric control of the conduction at the LaAlO3/SrTiO3 heterointerface. AB - Modulation of band bending at a complex oxide heterointerface by a ferroelectric layer is demonstrated. The as-grown polarization (Pup ) leads to charge depletion and consequently low conduction. Switching the polarization direction (Pdown ) results in charge accumulation and enhances the conduction at the interface. The metal-insulator transition at a conducting polar/nonpolar oxide heterointerface can be controlled by ferroelectric doping. PMID- 23666884 TI - Diagnosis and management of familial dyslipoproteinemias. AB - The three major pathways of lipoprotein metabolism provide a superb paradigm to delineate systematically the familial dyslipoproteinemias. Such understanding leads to improved diagnosis and treatment of patients. In the exogenous (intestinal) pathway, defects in LPL, apoC-II, APOA-V, and GPIHBP1 disrupt the catabolism of chylomicrons and hepatic uptake of their remnants, producing very high TG. In the endogenous (hepatic) pathway, six disorders affect the activity of the LDLR and markedly increase LDL. These include FH, FDB, ARH, PCSK9 gain-of function mutations, sitosterolemia and loss of 7 alpha hydroxylase. Hepatic overproduction of VLDL occurs in FCHL, hyperapoB, LDL subclass pattern B, FDH and syndrome X, often due to insulin resistance and resulting in high TG, elevated small LDL particles and low HDL-C. Defects in APOB-100 and loss-of-function mutations in PCSK9 are associated with low LDL-C, decreased CVD and longevity. An absence of MTP leads to marked reduction in chylomicrons and VLDL, causing abetalipoproteinemia. In the reverse cholesterol pathway, deletions or nonsense mutations in apoA-I or ABCA1 transporter disrupt the formation of the nascent HDL particle. Mutations in LCAT disrupt esterification of cholesterol in nascent HDL by LCAT and apoA-1, and formation of spherical HDL. Mutations in either CETP or SR-B1 and familial high HDL lead to increased large HDL particles, the effect of which on CVD is not resolved. The major goal is to prevent or ameliorate the major complications of many familial dyslipoproteinemias, namely, premature CVD or pancreatitis. Dietary and drug treatment specific for each inherited disorder is reviewed. PMID- 23666886 TI - Dietary modification dampens liver inflammation and fibrosis in obesity-related fatty liver disease. AB - BACKGROUND: Alms1 mutant (foz/foz) mice develop hyperphagic obesity, diabetes, metabolic syndrome, and fatty liver (steatosis). High-fat (HF) feeding converts pathology from bland steatosis to nonalcoholic steatohepatitis (NASH) with fibrosis, which leads to cirrhosis in humans. OBJECTIVE: We sought to establish how dietary composition contributes to NASH pathogenesis. DESIGN AND METHODS: foz/foz mice were fed HF diet or chow 24 weeks, or switched HF to chow after 12 weeks. Serum ALT, NAFLD activity score (NAS), fibrosis severity, neutrophil, macrophage and apoptosis immunohistochemistry, uncoupling protein (UCP)2, ATP, NF kappaB activation/expression of chemokines/adhesion molecules/fibrogenic pathways were determined. RESULT: HF intake upregulated liver fatty acid and cholesterol transporter, CD36. Dietary switch expanded adipose tissue and decreased hepatomegaly by lowering triglyceride, cholesterol ester, free cholesterol and diacylglyceride content of liver. There was no change in lipogenesis or fatty acid oxidation pathways; instead, CD36 was suppressed. These diet-induced changes in hepatic lipids improved NAS, reduced neutrophil infiltration, normalized UCP2 and increased ATP; this facilitated apoptosis with a change in macrophage phenotype favoring M2 cells. Dietary switch also abrogated NF-kappaB activation and chemokine/adhesion molecule expression, and arrested fibrosis by dampening stellate cell activation. CONCLUSION: Reversion to a physiological dietary composition after HF feeding in foz/foz mice alters body weight distribution but not obesity. This attenuates NASH severity and fibrotic progression by suppressing NF-kappaB activation and reducing neutrophil and macrophage activation. However, adipose inflammation persists and is associated with continuing apoptosis in the residual fatty liver disease. Taken together, these findings indicate that other measures, such as weight reduction, may be required to fully reverse obesity-related NASH. PMID- 23666887 TI - Determinate primary root growth as an adaptation to aridity in Cactaceae: towards an understanding of the evolution and genetic control of the trait. AB - BACKGROUND AND AIMS: Species of Cactaceae are well adapted to arid habitats. Determinate growth of the primary root, which involves early and complete root apical meristem (RAM) exhaustion and differentiation of cells at the root tip, has been reported for some Cactoideae species as a root adaptation to aridity. In this study, the primary root growth patterns of Cactaceae taxa from diverse habitats are classified as being determinate or indeterminate, and the molecular mechanisms underlying RAM maintenance in Cactaceae are explored. Genes that were induced in the primary root of Stenocereus gummosus before RAM exhaustion are identified. METHODS: Primary root growth was analysed in Cactaceae seedlings cultivated in vertically oriented Petri dishes. Differentially expressed transcripts were identified after reverse northern blots of clones from a suppression subtractive hybridization cDNA library. KEY RESULTS: All species analysed from six tribes of the Cactoideae subfamily that inhabit arid and semi arid regions exhibited determinate primary root growth. However, species from the Hylocereeae tribe, which inhabit mesic regions, exhibited mostly indeterminate primary root growth. Preliminary results suggest that seedlings of members of the Opuntioideae subfamily have mostly determinate primary root growth, whereas those of the Maihuenioideae and Pereskioideae subfamilies have mostly indeterminate primary root growth. Seven selected transcripts encoding homologues of heat stress transcription factor B4, histone deacetylase, fibrillarin, phosphoethanolamine methyltransferase, cytochrome P450 and gibberellin-regulated protein were upregulated in S. gummosus root tips during the initial growth phase. CONCLUSIONS: Primary root growth in Cactoideae species matches their environment. The data imply that determinate growth of the primary root became fixed after separation of the Cactiodeae/Opuntioideae and Maihuenioideae/Pereskioideae lineages, and that the genetic regulation of RAM maintenance and its loss in Cactaceae is orchestrated by genes involved in the regulation of gene expression, signalling, and redox and hormonal responses. PMID- 23666888 TI - Comparative molecular cytogenetic analyses of a major tandemly repeated DNA family and retrotransposon sequences in cultivated jute Corchorus species (Malvaceae). AB - BACKGROUND AND AIMS: The cultivated jute species Corchorus olitorius and Corchorus capsularis are important fibre crops. The analysis of repetitive DNA sequences, comprising a major part of plant genomes, has not been carried out in jute but is useful to investigate the long-range organization of chromosomes. The aim of this study was the identification of repetitive DNA sequences to facilitate comparative molecular and cytogenetic studies of two jute cultivars and to develop a fluorescent in situ hybridization (FISH) karyotype for chromosome identification. METHODS: A plasmid library was generated from C. olitorius and C. capsularis with genomic restriction fragments of 100-500 bp, which was complemented by targeted cloning of satellite DNA by PCR. The diversity of the repetitive DNA families was analysed comparatively. The genomic abundance and chromosomal localization of different repeat classes were investigated by Southern analysis and FISH, respectively. The cytosine methylation of satellite arrays was studied by immunolabelling. KEY RESULTS: Major satellite repeats and retrotransposons have been identified from C. olitorius and C. capsularis. The satellite family CoSat I forms two undermethylated species-specific subfamilies, while the long terminal repeat (LTR) retrotransposons CoRetro I and CoRetro II show similarity to the Metaviridea of plant retroelements. FISH karyotypes were developed by multicolour FISH using these repetitive DNA sequences in combination with 5S and 18S-5.8S-25S rRNA genes which enable the unequivocal chromosome discrimination in both jute species. CONCLUSIONS: The analysis of the structure and diversity of the repeated DNA is crucial for genome sequence annotation. The reference karyotypes will be useful for breeding of jute and provide the basis for karyotyping homeologous chromosomes of wild jute species to reveal the genetic and evolutionary relationship between cultivated and wild Corchorus species. PMID- 23666889 TI - Variation of microsporogenesis in monocots producing monosulcate pollen grains. AB - BACKGROUND AND AIMS: Microsporogenesis leading to monosulcate pollen grains has already been described for a wide range of monocot species. However, a detailed study of additional callose deposition after the completion of the cleavage walls has been neglected so far. The study of additional callose deposition in monosulcate pollen grain has gained importance since a correlation between additional callose deposition and aperture location has recently been revealed. METHODS: Microsporogenesis is described for 30 species belonging to eight families of the monocots: Acoraceae, Amaryllidaceae, Alstroemeriaceae, Asparagaceae, Butomaceae, Commelinaceae, Liliaceae and Xanthorrhoeaceae. KEY RESULTS: Five different microsporogenesis pathways are associated with monosulcate pollen grain. They differ in the type of cytokinesis, tetrad shape, and the presence and shape of additional callose deposition. Four of them present additional callose deposition. CONCLUSIONS: In all these different microsporogenesis pathways, aperture location seems to be linked to the last point of callose deposition. PMID- 23666890 TI - IgG4-related pharyngitis-an addition to the nomenclature of IgG4-related disease: comment on the article by Stone et al. PMID- 23666891 TI - Pegylated IL-10 induces cancer immunity: the surprising role of IL-10 as a potent inducer of IFN-gamma-mediated CD8(+) T cell cytotoxicity. AB - Recently, the development of several strategies based on immunotherapy has raised hopes for a more promising way to treat cancer patients. Here, we describe how interleukin (IL)-10, a seemingly unlikely candidate, stimulates the immune system in a particularly efficacious way. IL-10, an omnipotent anti-inflammatory cytokine, delivers an equally potent immune stimulation in the context of CD8(+) T cells and tumor immunity. By activation of tumor-resident, tumor-specific CD8(+) T cells, pegylated IL-10 can induce rejection of large and metastasizing tumors in mice. Here, we summarize the mechanisms of action of IL-10, the reasons why the mechanisms may be crucial for the treatment of cancer patients, and the rationale for applying pegylated IL-10 in the clinic. PMID- 23666892 TI - Emerging roles for miRNAs in the development, diagnosis, and treatment of diabetic nephropathy. AB - Although the causes of diabetic nephropathy are not yet fully known, emerging evidence suggests a role for epigenetic factors in the development of the disease. In particular, microRNAs (miRNAs) are becoming recognized as important mediators of biological processes relevant to diabetic nephropathy. Until recently, investigations of miRNAs in the development of diabetic nephropathy have remained relatively limited; however, the number of reports identifying potential new candidates and mechanisms of impact is presently expanding at a rapid pace. This review seeks to summarize these recent findings, focusing on new candidates and/or novel mechanisms, including the intersection between genetic variation and miRNA function in modulating disease expression, emerging in the field. We also review the latest advances in the diagnostic and therapeutic potential of miRNAs in the treatment of diabetic nephropathy. PMID- 23666893 TI - Corneal confocal microscopy: a new technique for early detection of diabetic neuropathy. AB - Corneal confocal microscopy (CCM) is a noninvasive method for the study of human cornea in vivo. It has increasingly been used to assess the morphology of the sub basal corneal nerve plexus. CCM has good reproducibility and may contribute to the early diagnosis of diabetic polyneuropathy. It may also be useful to document favorable changes in nerve fiber structure early after therapeutic intervention. Corneal nerve pathology is more pronounced in patients with diabetic polyneuropathy and is associated with its clinical severity. The sensitivity and specificity of CCM for the diagnosis of polyneuropathy is moderate to high. CCM now merits further use in large longitudinal studies to provide more information on the natural history of diabetic neuropathy and effects of treatment. Moreover, there is a need for a larger normative database. Finally, technical progress is expected to enable visualization of larger corneal areas and improve nerve fiber quantification, increasing diagnostic accuracy. PMID- 23666895 TI - The stoichiometry of electroless silicon etching in solutions of V2O5 and HF. PMID- 23666894 TI - Comparison of degradation behavior and the associated bone response of ZK60 and PLLA in vivo. AB - The aim of this study was to investigate whether ZK60, an extruded magnesium alloy, reacts in vivo with an appropriate host response, and to investigate how microarc oxidation treatment influences this in vivo corrosion behavior. Twelve cylinders were machined from as-extruded ZK60, with six cylinders treated with MAO and six left untreated; poly-l-lactic acid pins were used as a control to compare biocompatibility. These cylinders were implanted into the right distal femur of mice along the transepicondylar axis from the medial condyle. Microcomputerized tomography was used to quantitatively analyze corrosion in a nondestructive manner in vivo and the corrosion rate was calculated based on the volume measurements of the residual implants. The physiological response of the rats postimplantation was obtained by clinical observation and blood biochemical analysis. Histological analyses of the soft tissue around the implants were used to assess bone response in relation to the implants. The results obtained clearly indicate that the untreated ZK60 alloy showed high degradation rates in vivo, and that MAO treatment had a significant but unsatisfying effect on protecting the implant from further corrosion. Compared with PLLA, the ZK60 alloy showed good osteoconductivity and osteoinductivity, and, according to biochemical indicators, had good biocompatibility in vivo. PMID- 23666896 TI - UPLC-PDA-TOF/MS coupled with multivariate statistical analysis to rapidly analyze and evaluate Ginkgo biloba leaves from different origin. AB - In the present study, an ultra performance liquid chromatography coupled with photodiode array detector and time-of-flight mass spectrometry (UPLC-PDA-TOF/MS) was proposed and validated for rapidly analyzing and evaluating Ginkgo biloba leaves from different origins by using multivariate statistical analysis. Batches of these kinds of G. biloba leaves were subjected to UPLC-PDA-TOF/MS analysis, the datasets of retention time (RT)-m/z pairs, ion intensities and sample codes were further processed with orthogonal partial least squared discriminant analysis (OPLS-DA) to holistically compare the difference between these G. biloba leaves, and to generate an S-plot. Those compounds correlated to the points at the two ends of S were regarded as the most differentiating components. By comparing the mass/UV spectra and retention times with those of reference compounds and/or tentatively assigned by matching empirical molecular formulae with those of the known compounds published in the literatures, these differentiating components were finally characterized as kaempferol 3-O-[2-O-(6-O p-hydroxy-trans-cinnamoyl)-beta-D-glucosyl)-alpha-L-rhamnoside], kaempferol 3-O [2-O,6-O-bis(alpha-L-rhamnosyl)-beta-D-glucoside], ginkgolide C, kaempferol 3-O [2-O-(beta-D-glucosyl)-alpha-L-rhamnoside], and bilobetin. These compounds would be the potential chemical markers for the two kinds of leaves. The results suggested that this newly established approach could be used to rapidly evaluate the quality of herbs from different origin, and to provide good strategy for further rectify and standardize the herb market. PMID- 23666897 TI - Solvent-assisted directed self-assembly of spherical microdomain block copolymers to high areal density arrays. AB - The fabrication process for 5 Tb/in(2) bit patterns using solvent-assisted directed self-assembly is investigated. The N-methyl-2-pyrrolidone solvent vapor annealing method was used to achieve good long-range lateral ordering of low molecular-weight polystyrene-block-polydimethylsiloxane with a lattice spacing of 11 nm on flat Si substrates, PS modified substrates and lithographically patterned substrates, respectively. PMID- 23666899 TI - Nanoscale friction mechanisms at solid-liquid interfaces. PMID- 23666898 TI - Simple anthropometrics are more correlated with health variables than are estimates of body composition in Yup'ik people. AB - OBJECTIVES: To (1) evaluate the relationships between several indices of obesity with obesity-related risk factors; (2) compare the accuracy of body composition estimates derived from anthropometry and bioimpedance analysis (BIA) to estimates of body composition assessed by doubly-labeled water (DLW); and (3) establish equations for estimating fat mass (FM), fat-free mass (FFM), and percent body fat (PBF) in Yup'ik people. DESIGN AND METHODS: Participants included 1,056 adult Yup'ik people from 11 communities in Southwestern Alaska. In a sub-study of 30 participants, we developed population-specific linear regression models for estimating FM, FFM, and PBF from anthropometrics, age, sex, and BIA against criterion measures derived from total body water assessed with DLW. These models were then used with the population cohort and we analyzed the relationships between obesity indices and several health-related and disease status variables: (1) fasting plasma lipids, (2) glucose, (3) HbA1c, (4) adiponectin, (5) blood pressure, (6) diabetes (DM), and (7) cerebrocoronary vascular disease (CCVD) which includes stroke and heart disease. RESULTS: The best model for estimating FM in the sub-study used only three variables-sex, waist circumference (WC), and hip circumference and had multiple R(2) = 0.9730. FFM and PBF were calculated from FM and body weight. CONCLUSION: WC and other anthropometrics were more highly correlated with a number of obesity-related risk factors than were direct estimates of body composition. Body composition in Yup'ik people can be accurately estimated from simple anthropometrics. PMID- 23666900 TI - How can heart failure patients and their partners be counseled on sexual activity? AB - Sexual intimacy is part of a healthy relationship and is often reflected in overall quality of life and satisfaction. There are many psychological, physical, and medical components that influence sexual activity in heart failure (HF), and patients and partners alike often have sexual concerns and misconceptions. This article addresses what is known about sexual concerns and sexual dysfunction from a variety of perspectives, and provides guidance for health care providers on the essential elements of sexual counseling for those with HF. PMID- 23666901 TI - Implementing telemonitoring in heart failure care: barriers from the perspectives of patients, healthcare professionals and healthcare organizations. AB - The increasing prevalence of chronic diseases, such as heart failure, presents a substantial challenge to healthcare systems. Telemonitoring is believed to be a useful instrument in the delivery of heart failure care. However, a widespread use of telemonitoring is currently failing for various reasons. This article provides an overview of the barriers for the implementation of telemonitoring in heart failure patients from the perspectives of its users: patients, healthcare professionals and healthcare organisations. In doing so, identified barriers are grouped according to the perceived attributes of innovation by Rogers. Recommendations are provided as to how research can improve the implementation of telemonitoring in heart failure. PMID- 23666903 TI - Stopped in its tracks: negative regulation of the dynein motor by the yeast protein She1. AB - How do cells direct the microtubule motor protein dynein to move cellular components to the right place at the right time? Recent studies in budding yeast shed light on a new mechanism for directing dynein, involving the protein She1. She1 restricts where and when dynein moves the nucleus and mitotic spindle. Experiments with purified proteins show that She1 binds to microtubules and inhibits dynein by stalling the motor on its track. Here I describe what we have learned so far about She1, based on a combination of genetic, cell biology, and biophysical approaches. These findings set the stage for further interrogation of the She1 mechanism, and raise the question of whether similar mechanisms exist in other species. PMID- 23666904 TI - Hsp90 inhibition protects against biomechanically induced osteoarthritis in rats. AB - OBJECTIVE: Although articular cartilage has evolved to facilitate joint mobilization, severe loading can induce chondrocyte apoptosis, which is related to the progression of osteoarthritis (OA). To avoid apoptosis, chondrocytes synthesize heat-shock proteins (HSPs). This study was undertaken to examine the roles of Hsp70 and Hsp90 in biomechanically induced OA, and the possibility of using Hsp90 inhibition as an intervention strategy for OA management. METHODS: OA was biomechanically induced in rats by means of strenuous running. Disease progression was compared between running rats treated with Hsp90 inhibitor and untreated running controls. Hsp70 and Hsp90 protein levels in articular cartilage were determined by Western blotting. OA progression was monitored using contrast enhanced micro-computed tomography to measure cartilage degradation and subchondral bone changes and single-photon-emission computed tomography to examine synovial macrophage activation and histologic features. RESULTS: Chronic cartilage loading led to early OA development, characterized by degeneration of cartilage extracellular matrix. In vivo Hsp90 inhibition resulted in increased Hsp70 synthesis, which suggests that Hsp90 activity limits Hsp70 production. Hsp90 inhibitor treatment increased cartilage sulfated glycosaminoglycan levels to concentrations even beyond baseline and protected against cartilage degradation, stimulated subchondral bone thickness, and suppressed macrophage activation. CONCLUSION: Our findings indicate that Hsp90 plays a pivotal role in biomechanically induced chondrocyte stress responses. Intervention strategies that inhibit Hsp90 can potentially protect or improve cartilage health and might prevent OA development. PMID- 23666905 TI - Kombucha-synthesized bacterial cellulose: preparation, characterization, and biocompatibility evaluation. AB - Bacterial cellulose (BC) is a natural biomaterial with unique properties suitable for tissue engineering applications, but it has not yet been used for preparing nerve conduits to repair peripheral nerve injuries. The objectives of this study were to prepare and characterize the Kampuchea-synthesized bacterial cellulose (KBC) and further evaluate the biocompatibility of KBC with peripheral nerve cells and tissues in vitro and in vivo. KBC membranes were composed of interwoven ribbons of about 20-100 nm in width, and had a high purity and the same crystallinity as that of cellulose Ialpha. The results from light and scanning electron microscopy, MTT assay, flow cytometry, and RT-PCR indicated that no significant differences in the morphology and cell function were observed between Schwann cells (SCs) cultured on KBC membranes and glass slips. We also fabricated a nerve conduit using KBC, which was implanted into the spatium intermusculare of rats. At 1, 3, and 6 weeks post-implantation, clinical chemistry and histochemistry showed that there were no significant differences in blood counts, serum biochemical parameters, and tissue reactions between implanted rats and sham-operated rats. Collectively, our data indicated that KBC possessed good biocompatibility with primary cultured SCs and KBC did not exert hematological and histological toxic effects on nerve tissues in vivo. PMID- 23666906 TI - Depressive symptoms are associated with visceral adiposity in a community-based sample of middle-aged women and men. AB - OBJECTIVE: To examine the relation between measures of adiposity and depressive symptoms in a large well characterized community-based sample, we examined the relations of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) to depressive symptoms in 1,581 women (mean age 52.2 years) and 1,718 men (mean age 49.8 years) in the Framingham Heart Study. DESIGN AND METHODS: Depressive symptoms were measured using the Center for Epidemiologic Studies Depression (CES D) scale. Regression models were created to examine the association between each fat depot (exposure) and depressive symptoms (outcome). Sex-specific models were adjusted for age, body mass index, smoking, alcohol consumption, diabetes, hypertension, total and HDL cholesterol, lipid lowering treatment, CVD, menopause, C-reactive protein, and physical activity. RESULTS: Mean CES-D scores were 6.8 and 5.6 in women and men. High levels of depressive symptoms were present in 22.5% of women and 12.3% of men. In women, one standard deviation increase in VAT was associated with a 1.3 point higher CES-D score after adjusting for age and BMI (P < 0.01) and remained significant in the fully adjusted model (P = 0.03). The odds ratio of depressive symptoms per 1 standard deviation increase in VAT in women was 1.33 (P = 0.015); results were attenuated in fully adjusted models (OR 1.29, P = 0.055). In men, the association between VAT and CES-D score and depressive symptoms was not significant. SAT was not associated with CES-D score or depressive symptoms. CONCLUSIONS: This study supports an association between VAT and depressive symptoms in women. Further work is needed to uncover the complex biologic mechanisms mediating the association. PMID- 23666907 TI - Rhodium-catalyzed ortho acylation of aromatic carboxylic acids. PMID- 23666909 TI - Enhanced peroxisomal beta-oxidation is associated with prevention of obesity and glucose intolerance by fish oil-enriched diets. AB - OBJECTIVE: The effects of different amounts of omega 3-polyunsaturated fatty acids in diets with normal or high content of fat on lipid and carbohydrate metabolism were investigated. DESIGN AND METHODS: Mice were fed for 8 weeks on diets enriched with fish oil or lard at 10% or 60% of energy. Energy balance and energy expenditure were analyzed. Fatty acid (FA) oxidative capacity of the liver and the activity of enzymes involved in this pathway were assessed. RESULTS: Fish oil-fed mice had lower body weight and adiposity compared with lard-fed animals, despite having lower rates of oxygen consumption. Mice fed diets containing fish oil also displayed lower glycemia, reduced fat content in the liver, and improved glucose tolerance compared with lard-fed animals. The fish oil-containing diets increased markers of hepatic peroxisomal content and increased the generation of metabolites derived from FA beta-oxidation in liver homogenates. In contrast, no changes were observed in the content of mitochondrial electron transport chain proteins or carnitine palmitoyl transferase-1 in the liver, indicating little direct effect of fish oil on mitochondrial metabolism. CONCLUSION: Collectively, our findings suggest that the energy inefficient oxidation of FAs in peroxisomes may be an important mechanism underlying the protection against obesity and glucose intolerance of fish oil administration. PMID- 23666910 TI - Magnetic-directed patterning of cell spheroids. AB - We have described an approach to fabricate three-dimensional (3D) cell-based structures using functionalized super paramagnetic iron oxide nanoparticles (SPIONs) as patterning agents to guide the assembly of endothelial cell spheroids into 3D patterns using the magnetic forces generated by a prefabricated magnetic template. SPIONs were first uptaken by endothelial cells before they were assembled into uniform-sized spheroids through a home-made robotic spheroid maker. To guide the magnetic spheroids, a unique magnetic template was fabricated using computer-aided design and cut from a magnetic sheet. The spheroids were then guided to the prefabricated magnetic template through the attractive magnetic forces between the SPIONs inside the endothelial cells and the magnetic template. Fusion of endothelial cell spheroids over time while adhered to the magnetic template allowed for the formation of 3D cell-based structures. Subsequent removal of the prefabricated magnetic template left 3-D endothelial cell sheets, which may be stacked to fabricate complicated 3D multicellular tissue structures. To enhance the cytocompatibility, SPIONs were silica-coated before use. At low concentrations, the SPIONs did not adversely affect cell viability, proliferation, and phenotype stability. Light and confocal microscopy showed that endothelial cell spheroids could be reproducibly created with high uniformity. The endothelial cells were able to remain viable and maintain the 3D structure in vitro. We have proved the concept to use SPIONs as a patterning agent to direct the attachment and self assembly of SPION-loaded endothelial cell spheroids on a prefabricated magnetic template for the formation of 3D cell based structures. A magnetic-directed technique allows quick patterning of cell spheroids in accordance with desirable magnetic patterns, therefore, holding promise for scalable fabrication of complicated 3D multicellular tissue structures. By varying the cell types and the prefabricated magnetic patterns, this magnetic-directed patterning strategy may find use in bioprinting and multicellular tissue graft fabrication. PMID- 23666908 TI - Ribosomally synthesized and post-translationally modified peptide natural products: new insights into the role of leader and core peptides during biosynthesis. AB - Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a major class of natural products with a high degree of structural diversity and a wide variety of bioactivities. Understanding the biosynthetic machinery of these RiPPs will benefit the discovery and development of new molecules with potential pharmaceutical applications. In this Concept article, we discuss the features of the biosynthetic pathways to different RiPP classes, and propose mechanisms regarding recognition of the precursor peptide by the post-translational modification enzymes. We propose that the leader peptides function as allosteric regulators that bind the active form of the biosynthetic enzymes in a conformational selection process. We also speculate how enzymes that generate polycyclic products of defined topologies may have been selected for during evolution. PMID- 23666911 TI - Multiphysics computational models for cardiac flow and virtual cardiography. AB - A multiphysics simulation approach is developed for predicting cardiac flows as well as for conducting virtual echocardiography (ECHO) and phonocardiography (PC) of those flows. Intraventricular blood flow in pathological heart conditions is simulated by solving the three-dimensional incompressible Navier-Stokes equations with an immersed boundary method, and using this computational hemodynamic data, echocardiographic and phonocardiographic signals are synthesized by separate simulations that model the physics of ultrasound wave scattering and flow-induced sound, respectively. For virtual ECHO, a Doppler ultrasound image is reproduced through Lagrangian particle tracking of blood cell particles and application of sound wave scattering theory. For virtual PC, the generation and propagation of blood flow-induced sounds ('hemoacoustics') is directly simulated by a computational acoustics model. The virtual ECHO is applied to reproduce a color M mode Doppler image for the left ventricle as well as continuous Doppler image for the outflow tract of the left ventricle, which can be verified directly against clinically acquired data. The potential of the virtual PC approach for providing new insights between disease and heart sounds is demonstrated by applying it to modeling systolic murmurs caused by hypertrophic cardiomyopathy. PMID- 23666912 TI - Colloidal clusters by using emulsions and dumbbell-shaped particles: experiments and simulations. PMID- 23666913 TI - Passive films on metallic biomaterials under simulated physiological conditions. AB - The metallic materials used for implantable medical devices are predominantly stainless steels, Ti and its alloys, and Co-Cr alloys. The corrosion resistance of each of these materials is associated with a passive oxide film on its surface. Since corrosion resistance is crucial to implant performance, considerable effort has been focused on understanding the nature of the passive film present under physiological conditions. Surface analytical techniques and electrochemical impedance spectroscopy have been used in a number of studies to investigate the passive film formed on metallic biomaterials in simulated physiological solutions. This review focuses on the surface characteristics of these materials with regard to composition, thickness, and impedance of the passive films. Of particular interest are changes in the films with surface treatment and the nature of the films developed over time in the simulated solutions. PMID- 23666914 TI - Therapeutic efficacy of metronomic chemotherapy with cyclophosphamide and doxorubicin on murine mammary adenocarcinomas. AB - BACKGROUND: Metronomic chemotherapy (MCT) refers to the chronic and equally spaced administration of low doses of different chemotherapy drugs, without extended rest periods. Herein, we investigated the therapeutic efficacy of metronomic cyclophosphamide (Cy) combined with doxorubicin (Dox) in two mouse mammary adenocarcinoma models. MATERIALS AND METHODS: Mice were s.c. challenged with M-234p or M-406 mammary tumors, and when the tumors reached ~150 mm(3), they were treated with: (I) no treatment (controls); (II) Cy in the drinking water (30 mg/kg body weight/day); (III) Dox (0.5 mg/kg body weight i.p. three times/week); (IV) treated as (II) + (III). Mice challenged i.v. with M-234p or M-406 tumor cells received, on day 3, the same treatments. RESULTS: We found that MCT with Cy plus Dox inhibited tumor growth, decreased lung metastases, and increased the median survival time, while having low toxic effect. Combined MCT was more effective than each monotherapy causing decrease in VEGF serum concentration and tumor proliferation rate plus increase in tumor apoptosis. CONCLUSION(S): The therapeutic benefits of combined MCT with Cy and Dox on mammary adenocarcinomas together with its low toxic effect profile suggest the possibility of future translation into the clinic. PMID- 23666915 TI - Four-year survival rates for patients with metastatic melanoma who received ipilimumab in phase II clinical trials. AB - BACKGROUND: This analysis was carried out to evaluate the long-term survival of patients with metastatic melanoma who received ipilimumab, a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte antigen-4, in clinical trials. PATIENTS AND METHODS: Patients received ipilimumab in one of three completed phase II clinical trials (CA184-008, CA184-022, and CA184-007). Previously treated patients were enrolled in all studies, and treatment-naive patients were also included in study CA184-007. Patients received ipilimumab at a dose of 10 mg/kg in studies CA184-008 and CA184-007, and at doses of 0.3, 3, or 10 mg/kg in study CA184-022. Ipilimumab was given every 3 weeks for four doses, and eligible patients could receive ipilimumab maintenance therapy every 12 weeks. In study CA184-022, patients could cross over to be retreated with ipilimumab at 10 mg/kg upon disease progression. Ongoing survival follow-up is conducted in a companion study, CA184-025. RESULTS: Four-year survival rates [95% confidence interval (95% CI)] for previously treated patients who received ipilimumab at 0.3, 3, or 10 mg/kg were 13.8% [6.1-22.5], 18.2% [9.5-27.6], and 19.7% [13.4-26.5] to 28.4% [13.9-44.2], respectively. In treatment-naive patients who received ipilimumab at 10 mg/kg, 4-year survival rates were 37.7% [18.6-57.4] to 49.5% [23.8-75.4]. CONCLUSIONS: These results demonstrate durable survival in a significant proportion of patients with metastatic melanoma who received ipilimumab therapy. PMID- 23666916 TI - FOLFOXIRI in combination with panitumumab as first-line treatment in quadruple wild-type (KRAS, NRAS, HRAS, BRAF) metastatic colorectal cancer patients: a phase II trial by the Gruppo Oncologico Nord Ovest (GONO). AB - BACKGROUND: The FOLFOXIRI regimen developed by the Gruppo Oncologico Nord Ovest (GONO) demonstrated higher activity and efficacy compared with FOLFIRI in metastatic colorectal cancer (mCRC). Panitumumab is effective in some patients with KRAS codon 12-13 wild-type mCRC. KRAS codon 61, HRAS, NRAS, and BRAF V600E mutations might predict resistance to anti-epidermal growth factor receptor antibodies. PATIENTS AND METHODS: We conducted a phase II study evaluating the combination of panitumumab (6 mg/kg on day 1) with a slightly modified GONO FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, and folinate 200 mg/m2 on day 1, followed by fluorouracil 3000 mg/m2 as a 48-h continuous infusion starting on day 1) repeated every 2 weeks as first-line treatment of wild-type KRAS, HRAS, NRAS (codon 12-13-61), and BRAF unresectable mCRC patients. Fluorouracil dose was reduced to 2400 mg/m2 after two of the first three patients reported grade 3-4 diarrhoea (in one case with febrile neutropenia). Induction treatment was scheduled for a maximum of 12 cycles, followed by panitumumab +/- fluorouracil/folinate maintenance until progression. Primary end point was overall response rate (ORR). RESULTS: Eighty-seven patients were screened and 37 were enrolled. Thirty-three patients achieved an objective response (ORR: 89%; 95% CI 75% to 96%). Sixteen patients (43%) underwent secondary surgery of metastases, and R0 resection was achieved in 13 cases (35%). At a median follow up of 17.7 months, median progression-free survival was 11.3 months (95% CI 9.7 12.9 months). After amendment, most common grade 3-4 adverse events reported during induction treatment were neutropenia (48%; febrile neutropenia: 5%), diarrhoea (35%), asthenia (27%), stomatitis (14%), and skin toxic effect (14%). One treatment-related death was registered. CONCLUSIONS: Adding panitumumab to FOLFOXIRI is feasible decreasing the dose of fluorouracil and irinotecan to reduce the risk of diarrhoea. Activity and secondary resectability of metastases among Ras-BRAF wild-type patients are promising. PMID- 23666917 TI - Risk of venous thromboembolism in patients with rheumatoid arthritis. AB - OBJECTIVE: Rheumatoid arthritis (RA) is associated with cardiovascular disease (CVD), but little is known about its association with another form of vascular disorder, venous thromboembolism (VTE). METHODS: A retrospective cohort study was conducted using US insurance claims. RA and non-RA patients were matched on age, sex, and index date. Incidence rates (IRs) and rate ratios (RRs) of VTE, defined as the composite of deep vein thrombosis (DVT) or pulmonary embolism (PE), were calculated. Cox proportional hazards models compared VTE risks between RA and non RA patients, adjusting for VTE risk factors such as CVD, surgery, hospitalization, medications, and acute-phase reactants. RESULTS: Over the mean followup of 2 years, the IR for VTE among RA patients was 6.1 per 1,000 person years, 2.4 times higher (95% confidence interval [95% CI] 2.1-2.8) than the rate of non-RA patients. The IRs for both DVT (RR 2.2, 95% CI 1.9-2.6) and PE (RR 2.7, 95% CI 2.2-3.5) were higher in RA patients compared with non-RA patients. After adjusting for risk factors of VTE, the VTE risk remained elevated in RA patients (hazard ratio 1.4, 95% CI 1.1-1.7) compared to non-RA patients. The result was similar after further adjustment for elevated acute-phase reactants (hazard ratio 1.5, 95% CI 0.3-6.5). One-third of patients who developed VTE had at least 1 major VTE risk factor 90 days before and after the VTE event. CONCLUSION: Our results showed an increased risk of developing VTE for RA patients compared with non-RA patients. The risk was attenuated but remained elevated even after adjusting for various risk factors for VTE. PMID- 23666918 TI - One-pot synthesis of CeO2-supported Pd-Cu-alloy nanocubes with high catalytic activity. AB - Cerium and nanocubes: CeO2-supported Pd-Cu-alloy nanocubes (Pd-Cu NCs/CeO2) with high content and good dispersion of the Pd-Cu NCs were prepared in high yields by heating a solution containing Pd, Cu, and Ce precursors. The prepared Pd-Cu NCs/CeO2 have excellent catalytic activity and stability toward formic acid electro-oxidation due to the synergism between the Pd-Cu-alloy catalysts and the CeO2 support. PMID- 23666919 TI - Host response to microgel coatings on neural electrodes implanted in the brain. AB - The performance of neural electrodes implanted in the brain is often limited by host response in the surrounding brain tissue, including astrocytic scar formation, neuronal cell death, and inflammation around the implant. We applied conformal microgel coatings to silicon neural electrodes and examined host responses to microgel-coated and uncoated electrodes following implantation in the rat brain. In vitro analyses demonstrated significantly reduced astrocyte and microglia adhesion to microgel-coated electrodes compared to uncoated controls. Microgel-coated and uncoated electrodes were implanted in the rat brain cortex and the extent of activated microglia and astrocytes as well as neuron density around the implant were evaluated at 1, 4, and 24 weeks postimplantation. Microgel coatings reduced astrocytic recruitment around the implant at later time points. However, microglial response indicated persistence of inflammation in the area around the electrode. Neuronal density around the implanted electrodes was also lower for both implant groups compared to the uninjured control. These results demonstrate that microgel coatings do not significantly improve host responses to implanted neural electrodes and underscore the need for further improvements in implantable materials. PMID- 23666920 TI - LMNA-associated cardiocutaneous progeria: an inherited autosomal dominant premature aging syndrome with late onset. AB - Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder caused by mutations in LMNA, which encodes the nuclear scaffold proteins lamin A and C. In HGPS and related progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. LMNA-linked progerias can be grouped into two classes: (1) the processing-deficient, early onset "typical" progerias (e.g., HGPS), and (2) the processing-proficient "atypical" progeria syndromes (APS) that are later in onset. Here we describe a previously unrecognized progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA based progeria disorders. The LMNA mutation that caused LCPS in this family is a heterozygous c.899A>G (p.D300G) mutation predicted to alter the coiled-coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors, as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA progeria syndromes, and raise the possibility that typical and atypical progerias may converge upon a common mechanism to cause premature aging disease. PMID- 23666921 TI - Dual function of the McaS small RNA in controlling biofilm formation. AB - Many bacterial small RNAs (sRNAs) regulate gene expression through base-pairing with mRNAs, and it has been assumed that these sRNAs act solely by this one mechanism. Here we report that the multicellular adhesive (McaS) sRNA of Escherichia coli uniquely acts by two different mechanisms: base-pairing and protein titration. Previous work established that McaS base pairs with the mRNAs encoding master transcription regulators of curli and flagella synthesis, respectively, resulting in down-regulation and up-regulation of these important cell surface structures. In this study, we demonstrate that McaS activates synthesis of the exopolysaccharide beta-1,6 N-acetyl-D-glucosamine (PGA) by binding the global RNA-binding protein CsrA, a negative regulator of pgaA translation. The McaS RNA bears at least two CsrA-binding sequences, and inactivation of these sites compromises CsrA binding, PGA regulation, and biofilm formation. Moreover, ectopic McaS expression leads to induction of two additional CsrA-repressed genes encoding diguanylate cyclases. Collectively, our study shows that McaS is a dual-function sRNA with roles in the two major post transcriptional regulons controlled by the RNA-binding proteins Hfq and CsrA. PMID- 23666924 TI - Identifying intermediates of sequential electron and hydrogen loss from a dicarbonylcobalt hydride complex. PMID- 23666922 TI - Molecular antagonism between X-chromosome and autosome signals determines nematode sex. AB - Sex is determined in Caenorhabditis elegans by the ratio of X chromosomes to the sets of autosomes, the X:A signal. A set of genes called X signal elements (XSEs) communicates X-chromosome dose by repressing the masculinizing sex determination switch gene xol-1 (XO lethal) in a dose-dependent manner. xol-1 is active in 1X:2A embryos (males) but repressed in 2X:2A embryos (hermaphrodites). Here we showed that the autosome dose is communicated by a set of autosomal signal elements (ASEs) that act in a cumulative, dose-dependent manner to counter XSEs by stimulating xol-1 transcription. We identified new ASEs and explored the biochemical basis by which ASEs antagonize XSEs to determine sex. Multiple antagonistic molecular interactions carried out on a single promoter explain how different X:A values elicit different sexual fates. XSEs (nuclear receptors and homeodomain proteins) and ASEs (T-box and zinc finger proteins) bind directly to several sites on xol-1 to counteract each other's activities and thereby regulate xol-1 transcription. Disrupting ASE- and XSE-binding sites in vivo recapitulated the misregulation of xol-1 transcription caused by disrupting cognate signal element genes. XSE- and ASE-binding sites are distinct and nonoverlapping, suggesting that direct competition for xol-1 binding is not how XSEs counter ASEs. Instead, XSEs likely antagonize ASEs by recruiting cofactors with reciprocal activities that induce opposite transcriptional states. Most ASE- and XSE-binding sites overlap xol-1's -1 nucleosome, which carries activating chromatin marks only when xol-1 is turned on. Coactivators and corepressors tethered by proteins similar to ASEs and XSEs are known to deposit and remove such marks. The concept of a sex signal comprising competing XSEs and ASEs arose as a theory for fruit flies a century ago. Ironically, while the recent work of others showed that the fly sex signal does not fit this simple paradigm, our work shows that the worm signal does. PMID- 23666923 TI - Human ALKBH7 is required for alkylation and oxidation-induced programmed necrosis. AB - Programmed necrosis has emerged as a crucial modulator of cell death in response to several forms of cellular stress. In one form of programmed necrotic cell death, induced by cytotoxic alkylating agents, hyperactivation of poly-ADP-ribose polymerase (PARP) leads to cellular NAD and ATP depletion, mitochondrial dysfunction, reactive oxygen species formation, and ensuing cell death. Here, we show that the protein encoded by the human AlkB homolog 7 (ALKBH7) gene plays a pivotal role in DNA-damaging agent-induced programmed necrosis by triggering the collapse of mitochondrial membrane potential and large-scale loss of mitochondrial function that lead to energy depletion and cellular demise. Depletion of ALKBH7 suppresses necrotic cell death induced by numerous alkylating and oxidizing agents while having no effect on apoptotic cell death. Like wild type cells, ALKBH7-depleted cells undergo PARP hyperactivation and NAD depletion after severe DNA damage but, unlike wild-type cells, exhibit rapid recovery of intracellular NAD and ATP levels. Consistent with the recovery of cellular bioenergetics, ALKBH7-depleted cells maintain their mitochondrial membrane potential, plasma membrane integrity, and viability. Our results uncover a novel role for a mammalian AlkB homolog in programmed necrosis, presenting a new target for therapeutic intervention in cancer cells that are resistant to apoptotic cell death. PMID- 23666925 TI - Lack of achievement of a full score on the childhood myositis assessment scale by healthy four-year-olds and those recovering from juvenile dermatomyositis. AB - OBJECTIVE: To test 4-year-olds, using 14 maneuvers of the Childhood Myositis Assessment Scale (CMAS), comparing healthy children with those with juvenile dermatomyositis (DM). METHODS: Healthy 4-year-olds (n = 28) completed the CMAS. Their scores were compared with children with juvenile DM (n = 18) who had a muscle Disease Activity Score (DAS-M) of 0. RESULTS: The healthy children achieved a mean +/- SD CMAS score of 46.6 +/- 2.3 (interquartile range 46-47). There were no significant differences between boys and girls, and the scores were not significantly associated with height or weight. The greatest variation involved items that assessed endurance. Item 1, neck raise, yielded a mean +/- SD score of 28.2 +/- 19.3 seconds, with a mean +/- SD CMAS score of 2.5 +/- 0.9 (maximum score 5). Item 3, leg lift, yielded a mean +/- SD score of 55.5 +/- 37.3 seconds, with a mean +/- SD CMAS score of 3.1 +/- 1.1 (maximum score 5). Item 5, sit-ups maneuver, yielded a mean +/- SD score of 5.3 +/- 1.1 sit-ups. Almost identical data were obtained for the 18 treated children with juvenile DM who had normal strength on the DAS-M. CONCLUSION: Healthy children ages 4 years do not achieve the total CMAS score of 52 attained by older children. Both boys and girls were remarkably consistent, with a mean CMAS score of 46.6. Children ages 4 years with juvenile DM with a DAS-M of 0 also achieved a CMAS score of 46.6. We conclude that half of 4-year-old children achieve a mean CMAS score of 46 or 47, not a total CMAS score of 52, suggesting that weakness may be overdiagnosed in 4 year-olds with an inflammatory myopathy. PMID- 23666926 TI - Implications of the oxygenated electrospun poly(E-caprolactone) nanofiber for the astrocytes activities. AB - Astrocytes support structure of central nervous system (CNS) and provide nutrients to neurons. When CNS is injured, astrocytes are activated and produce glia scar. There are debates if the reactive astrocytes give beneficial or harmful effects on neuronal regeneration. In vitro tissue culture systems successfully have been used to investigate how the astrocytes activity is regulated in response to environmental conditions. Physicochemical characteristics of supporting materials for tissue culture are one of the most important environmental conditions. Electrospun nanofiber has physical uniqueness such as high surface area to volume ratio and high porosity, which is favorable to tissue culture. However, cellular activities can also be regulated in response to surface chemistry, which can be modified easily and diversely. Poly(epsilon caprolactone) (PCL) is widely used for a scaffold for tissue culture. In this research, oxygen plasma-treated PCL nanofiber was assessed to ascertain whether it can have such potentials to regulate astrocytes activity. As a result, oxygen plasma treatment increased the hydrophilicity of the PCL nanofiber which made adhesion and viability of astrocytes enhanced without cytotoxicity Activation of astrocytes in the plasma treated scaffolds was confirmed by the fact of upregulation of glial fibrillary acidic protein. Above all, oxygenated nanofiber provides an initial culture environment which makes astrocytes activated. PMID- 23666928 TI - Sclerostin inhibition reverses systemic, periarticular and local bone loss in arthritis. AB - OBJECTIVE: To test whether inhibition of sclerostin by a targeted monoclonal antibody (Scl-Ab) protects from bone and cartilage damage in inflammatory arthritis. Sclerostin is a potent inhibitor of bone formation and may be responsible for the low level of bone repair in patients with rheumatoid arthritis. METHODS: Human tumour necrosis factor transgenic mice (hTNFtg mice) developing inflammatory arthritis and local and bone loss were administered either vehicle, anti-TNF antibody, Scl-Ab, or a combination of both agents. Inflammation, systemic and periarticular bone loss, bone erosion and cartilage damage were evaluated at baseline (week 8) and after 3 weeks of treatment by clinical assessment, micro-CT and histology. RESULTS: Scl-Ab did not affect joint swelling or synovitis. Systemic bone loss in the spine and periarticular bone loss in the proximal tibia were completely blocked and partially reversed by inhibition of sclerostin but not by inhibition of TNF. Moreover, Scl-Ab completely arrested the progression of bone erosion in hTNFtg mice and in combination with TNF inhibition even led to significant regression of cortical bone erosions. Protective effects of Scl-Ab were also observed for the articular cartilage. CONCLUSIONS: These data suggest that sclerostin inhibition is a powerful tool to enhance bone repair in inflammatory arthritis. PMID- 23666929 TI - Regulatory B cells in ANCA-associated vasculitis. AB - OBJECTIVES: B cells have immunoregulatory function acting as antigen-presenting cells. A separate subset of interleukin (IL)-10 producing B cells (Breg) regulating T cell mediated immunity has been identified. In the present study, we investigated the role of Breg in antineutrophil cytoplasmic antibodies-associated vasculitis (AAV). METHODS: 17 healthy controls (HCs) and 41 patients with AAV were enrolled. 30 patients with AAV were in remission. Furthermore, 11 patients with AAV with active disease were studied. Breg were defined as IL-10(+)CD19(+) B cells upon culture with cytosine-phosphate-guanosine oligodeoxynucleotide (CpG ODN) 2006. Next to Breg, CD4(+)CD127(low)CD25(hi)CD39(neg)/CD39(+) regulatory T cells (Treg), interferon (IFN)gamma(+), IL-4(+) and Il-17A(+)T helper cell subsets were determined via flow cytometry. RESULTS: Patients with active or quiescent disease showed a diminished fraction of Breg as compared with HCs. The frequency of IFNgamma(+) T helper cells was negatively associated with Breg in untreated AAV in remission but not in active vasculitis or in HCs. Interestingly, the total Treg population and the CD39(+) Treg subpopulation correlated positively with Breg in inactive patients with AAV. CONCLUSIONS: IL-10 producing B cells are diminished in AAV. Furthermore, Breg might regulate Th1 cells and are associated with Treg in quiescent AAV. Suppression of Th1 cells by Breg may be insufficient in active AAV. PMID- 23666930 TI - A chronic animal model of migraine, induced by repeated meningeal nociception, characterized by a behavioral and pharmacological approach. AB - BACKGROUND: Migraine is a chronic neurovascular disease characterized by recurrent unilateral headache, which induces incapacity. Despite all the progress that migraine research has provided, the neural mechanisms underlying the onset and maintenance of migraine attacks are poorly understood. Due to the complex characteristics of the disorder, it is difficult to develop a proper animal model that mimics all the clinical manifestations in humans. OBJECTIVE: Taking into account the principal characteristics of the disease, the aim of this study is to develop a chronic animal model of migraine in which we can reproduce behavioral and pharmacological phenomena similar to those displayed by migraineurs. RESULTS: Our animal model displayed behavioral and pharmacological results similar to those experienced by migraineurs. Specifically, there was a decrease in routine physical activity and an increase in resting behavior. Also, the animals exhibited a novel behavior that we called ipsilateral facial grooming behavior provoked by the meningeal nociception. Moreover, one of the drugs used as treatment for migraine reduced the manifestations previously described. Our results determine that the model mimics many of the clinical features that patients exhibit during migraine attacks. This model can contribute to further understanding of the pathophysiology and the study of novel therapeutic approaches. PMID- 23666931 TI - The effect of cardiac education on knowledge and adherence to healthy lifestyle. AB - The purpose of this study was to test the effect of cardiac educational program on the level of knowledge and adherence to healthy lifestyle among patients with coronary artery disease in the north of Jordan. Pretest-posttest design was used. Eighty-four patients completed the posttest questionnaire. Knowledge and adherence to healthy lifestyle were measured at baseline and at 1 month after the application of the program. Paired t-test was used to analyze the data. The results showed that the change in the mean knowledge scores (10.50), p < .01 was statistically significant 1 month after the application of the program. In addition, the change in the mean adherence to healthy lifestyle scores (33.30), p < .01 was statistically significant 1 month after the application of the cardiac educational program. Implementing cardiac educational programs help enhance knowledge and adherence to healthy lifestyle among patients with coronary artery disease in north of Jordan. PMID- 23666932 TI - A preliminary algorithm introducing immunogenicity assessment in the management of patients with RA receiving tumour necrosis factor inhibitor therapies. AB - INTRODUCTION: Clinical remission is today the treatment goal for rheumatoid arthritis (RA), which requires fast and assertive therapeutic decisions for a tight control of disease activity. Few objective parameters are available to guide clinical decisions, particularly in switcher patients. We designed a preliminary algorithm introducing immunogenicity assessment in the current approach to patients with RA receiving tumour necrosis factor inhibitors (TNFi). OBJECTIVE: To evaluate the concordance between the new algorithm and current clinical practice, comparing the effectiveness of 'immunogenicity-based' versus 'empirical-based' switches in a cohort of patients with established RA receiving biologics. METHODS: EULAR therapeutic response was evaluated in 105 patients with RA (naive or switchers) over one year, through generalised estimation equation (GEE) analyses. Serum drug trough levels were assessed by ELISA and antidrug antibodies (ADAb) by Bridging ELISA. RESULTS: During follow-up, 48.6% of patients had therapeutic decisions concordant with the proposed algorithm (Group A), and 51.4% had discordant decisions (Group B). One year after the therapeutic decision, patients from Group A had a higher probability of achieving response (OR=7.91, p<0.001, 95% CI 3.27 to 19.13) and low disease activity (OR=9.77, p<0.001, 95% CI 4.69 to 20.37) than patients in Group B. CONCLUSIONS: Immunogenicity assessment might help to optimise therapeutic decisions, leading to a better control of disease activity with significantly better clinical outcomes in patients with RA receiving TNFi. PMID- 23666933 TI - Effect of bariatric surgery on the inflammatory response to monosodium urate crystals: a prospective study. PMID- 23666935 TI - Assessing genome-wide statistical significance for large p small n problems. AB - Assessing genome-wide statistical significance is an important issue in genetic studies. We describe a new resampling approach for determining the appropriate thresholds for statistical significance. Our simulation results demonstrate that the proposed approach accurately controls the genome-wide type I error rate even under the large p small n situations. PMID- 23666934 TI - Pigment pattern formation in the guppy, Poecilia reticulata, involves the Kita and Csf1ra receptor tyrosine kinases. AB - Males of the guppy (Poecilia reticulata) vary tremendously in their ornamental patterns, which are thought to have evolved in response to a complex interplay between natural and sexual selection. Although the selection pressures acting on the color patterns of the guppy have been extensively studied, little is known about the genes that control their ontogeny. Over 50 years ago, two autosomal color loci, blue and golden, were described, both of which play a decisive role in the formation of the guppy color pattern. Orange pigmentation is absent in the skin of guppies with a lesion in blue, suggesting a defect in xanthophore development. In golden mutants, the development of the melanophore pattern during embryogenesis and after birth is affected. Here, we show that blue and golden correspond to guppy orthologs of colony-stimulating factor 1 receptor a (csf1ra; previously called fms) and kita. Most excitingly, we found that both genes are required for the development of the black ornaments of guppy males, which in the case of csf1ra might be mediated by xanthophore-melanophore interactions. Furthermore, we provide evidence that two temporally and genetically distinct melanophore populations contribute to the adult camouflage pattern expressed in both sexes: one early appearing and kita-dependent and the other late-developing and kita-independent. The identification of csf1ra and kita mutants provides the first molecular insights into pigment pattern formation in this important model species for ecological and evolutionary genetics. PMID- 23666936 TI - Competition between the sperm of a single male can increase the evolutionary rate of haploid expressed genes. AB - The population genetic behavior of mutations in sperm genes is theoretically investigated. We modeled the processes at two levels. One is the standard population genetic process, in which the population allele frequencies change generation by generation, depending on the difference in selective advantages. The other is the sperm competition during each genetic transmission from one generation to the next generation. For the sperm competition process, we formulate the situation where a huge number of sperm with alleles A and B, produced by a single heterozygous male, compete to fertilize a single egg. This "minimal model" demonstrates that a very slight difference in sperm performance amounts to quite a large difference between the alleles' winning probabilities. By incorporating this effect of paternity-sharing sperm competition into the standard population genetic process, we show that fierce sperm competition can enhance the fixation probability of a mutation with a very small phenotypic effect at the single-sperm level, suggesting a contribution of sperm competition to rapid amino acid substitutions in haploid-expressed sperm genes. Considering recent genome-wide demonstrations that a substantial fraction of the mammalian sperm genes are haploid expressed, our model could provide a potential explanation of rapid evolution of sperm genes with a wide variety of functions (as long as they are expressed in the haploid phase). Another advantage of our model is that it is applicable to a wide range of species, irrespective of whether the species is externally fertilizing, polygamous, or monogamous. The theoretical result was applied to mammalian data to estimate the selection intensity on nonsynonymous mutations in sperm genes. PMID- 23666937 TI - A continuous method for gene flow. AB - Most modern population genetics inference methods are based on the coalescence framework. Methods that allow estimating parameters of structured populations commonly insert migration events into the genealogies. For these methods the calculation of the coalescence probability density of a genealogy requires a product over all time periods between events. Data sets that contain populations with high rates of gene flow among them require an enormous number of calculations. A new method, transition probability-structured coalescence (TPSC), replaces the discrete migration events with probability statements. Because the speed of calculation is independent of the amount of gene flow, this method allows calculating the coalescence densities efficiently. The current implementation of TPSC uses an approximation simplifying the interaction among lineages. Simulations and coverage comparisons of TPSC vs. MIGRATE show that TPSC allows estimation of high migration rates more precisely, but because of the approximation the estimation of low migration rates is biased. The implementation of TPSC into programs that calculate quantities on phylogenetic tree structures is straightforward, so the TPSC approach will facilitate more general inferences in many computer programs. PMID- 23666938 TI - Investigating incipient speciation in Arabidopsis lyrata from patterns of transmission ratio distortion. AB - Our understanding of the development of intrinsic reproductive isolation is still largely based on theoretical models and thorough empirical studies on a small number of species. Theory suggests that reproductive isolation develops through accumulation of epistatic genic incompatibilities, also known as Bateson Dobzhansky-Muller (BDM) incompatibilities. We can detect these from marker transmission ratio distortion (TRD) in hybrid progenies of crosses between species or populations, where TRD is expected to result from selection against heterospecific allele combinations in hybrids. TRD may also manifest itself because of intragenomic conflicts or competition between gametes or zygotes. We studied early stage speciation in Arabidopsis lyrata by investigating patterns of TRD across the genome in F2 progenies of three reciprocal crosses between four natural populations. We found that the degree of TRD increases with genetic distance between crossed populations, but also that reciprocal progenies may differ substantially in their degree of TRD. Chromosomes AL6 and especially AL1 appear to be involved in many single- and two-locus distortions, but the location and source of TRD vary between crosses and between reciprocal progenies. We also found that the majority of single- and two-locus TRD appears to have a gametic, as opposed to zygotic, origin. Thus, while theory on BDM incompatibilities is typically illustrated with derived nuclear alleles proving incompatible in hybrid zygotes, our results suggest a prominent role for distortions emerging before zygote formation. PMID- 23666940 TI - Computational inference methods for selective sweeps arising in acute HIV infection. AB - During the first weeks of human immunodeficiency virus-1 (HIV-1) infection, cytotoxic T-lymphocytes (CTLs) select for multiple escape mutations in the infecting HIV population. In recent years, methods that use escape mutation data to estimate rates of HIV escape have been developed, thereby providing a quantitative framework for exploring HIV escape from CTL response. Current methods for escape-rate inference focus on a specific HIV mutant selected by a single CTL response. However, recent studies have shown that during the first weeks of infection, CTL responses occur at one to three epitopes and HIV escape occurs through complex mutation pathways. Consequently, HIV escape from CTL response forms a complex, selective sweep that is difficult to analyze. In this work, we develop a model of initial infection, based on the well-known standard model, that allows for a description of multi-epitope response and the complex mutation pathways of HIV escape. Under this model, we develop Bayesian and hypothesis-test inference methods that allow us to analyze and estimate HIV escape rates. The methods are applied to two HIV patient data sets, concretely demonstrating the utility of our approach. PMID- 23666939 TI - Asymptotic distributions of coalescence times and ancestral lineage numbers for populations with temporally varying size. AB - The distributions of coalescence times and ancestral lineage numbers play an essential role in coalescent modeling and ancestral inference. Both exact distributions of coalescence times and ancestral lineage numbers are expressed as the sum of alternating series, and the terms in the series become numerically intractable for large samples. More computationally attractive are their asymptotic distributions, which were derived in Griffiths (1984) for populations with constant size. In this article, we derive the asymptotic distributions of coalescence times and ancestral lineage numbers for populations with temporally varying size. For a sample of size n, denote by Tm the mth coalescent time, when m + 1 lineages coalesce into m lineages, and An(t) the number of ancestral lineages at time t back from the current generation. Similar to the results in Griffiths (1984), the number of ancestral lineages, An(t), and the coalescence times, Tm, are asymptotically normal, with the mean and variance of these distributions depending on the population size function, N(t). At the very early stage of the coalescent, when t -> 0, the number of coalesced lineages n - An(t) follows a Poisson distribution, and as m -> n, $$n?left(n 1?right){T}_{m}/2N?left(0?right)$$ follows a gamma distribution. We demonstrate the accuracy of the asymptotic approximations by comparing to both exact distributions and coalescent simulations. Several applications of the theoretical results are also shown: deriving statistics related to the properties of gene genealogies, such as the time to the most recent common ancestor (TMRCA) and the total branch length (TBL) of the genealogy, and deriving the allele frequency spectrum for large genealogies. With the advent of genomic-level sequencing data for large samples, the asymptotic distributions are expected to have wide applications in theoretical and methodological development for population genetic inference. PMID- 23666941 TI - Factors influencing mental health providers' intention to use telepsychotherapy in First Nations communities. AB - Telemental health is the use of information and communications technologies and broadband networks to deliver mental health services and support wellness. Although numerous studies have demonstrated the efficiency and utility of telemental health, certain barriers may impede its implementation, including the attitudes of mental health service providers. The current study draws on the technology acceptance model (TAM) to understand the role of mental health service providers' attitudes and perceptions of telemental health (psychotherapy delivered via videoconferencing) on their intention to use this technology with their patients. A sample of 205 broadly defined mental health service providers working on 32 First Nations reserves in the province of Quebec completed the questionnaire adapted to assess TAM for telepsychotherapy. Confirmatory factor analysis and structural equation modeling provided evidence for the factor validity and reliability of the TAM in this sample. The key predictor of the intention to use telepsychotherapy was not mental health providers' attitude toward telepsychotherapy, nor how much they expected this service to be complicated to use, but essentially how useful they expect it to be for their First Nations patients. If telemental health via videoconferencing is to be implemented in First Nations communities, it is essential to thoroughly demonstrate its utility to mental health providers. Perceived usefulness will have a positive impact on attitudes toward this technology, and perceived ease of use will positively influence perceived usefulness. Cultural issues specific to the populations receiving telemental health services may be more efficiently addressed from the angle of perceived usefulness. PMID- 23666942 TI - Internet suicide in Japan: a qualitative content analysis of a suicide bulletin board. AB - Netto shinju, or Internet group suicide, is a contemporary form of Japanese suicide where strangers connect on the Internet and make plans to commit suicide together. In the past decade, numerous incidents have occurred whereby young Japanese make contact on the Internet, exchange tips on suicide methods, and make plans to meet offline for group/individual suicide. A systematic qualitative content/thematic analysis of online communications posted on a popular Japanese suicide bulletin board yielded a textured, thematic understanding of this phenomenon. Themes identified reflected Shneidman's theory of suicide but with an emphasis on interpersonal concerns that are embedded in Japanese culture. PMID- 23666943 TI - Insomnia and health services utilization in middle-aged and older adults: results from the Health and Retirement Study. AB - BACKGROUND: Complaints of poor sleep are common among older adults. We investigated the prospective association between insomnia symptoms and hospitalization, use of home health care services, use of nursing homes, and use of any of these services in a population-based study of middle-aged and older adults. METHODS: We studied 14,355 adults aged 55 and older enrolled in the 2006 and 2008 waves of the Health and Retirement Study. Logistic regression was used to study the association between insomnia symptoms (0, 1, or >= 2) in 2006 and reports of health service utilization in 2008, after adjustment for demographic and clinical characteristics. RESULTS: Compared with respondents reporting no insomnia symptoms, those reporting one symptom had a greater odds of hospitalization (adjusted odds ratio [AOR] = 1.28, 95% confidence interval [CI] = 1.15-1.43, p < .001), use of home health care services (AOR = 1.29, 95% CI = 1.09 1.52, p = .004), and any health service use (AOR = 1.28, 95% CI = 1.15-1.41, p < .001). Those reporting greater than or equal to two insomnia symptoms had a greater odds of hospitalization (AOR = 1.71, 95% CI = 1.50-1.96, p < .001), use of home health care services (AOR = 1.64, 95% CI = 1.32-2.04, p < .001), nursing home use (AOR = 1.45, 95% CI = 1.10-1.90, p = .009), and any health service use (AOR = 1.72, 95% CI = 1.51-1.95, p < .001) after controlling for demographics. These associations weakened, and in some cases were no longer statistically significant, after adjustment for clinical covariates. CONCLUSIONS: In this study, insomnia symptoms experienced by middle-aged and older adults were associated with greater future use of costly health services. Our findings raise the question of whether treating or preventing insomnia in older adults may reduce use of and spending on health services among this population. PMID- 23666944 TI - Decline in health for older adults: five-year change in 13 key measures of standardized health. AB - BACKGROUND: The health of older adults declines over time, but there are many ways of measuring health. It is unclear whether all health measures decline at the same rate or whether some aspects of health are less sensitive to aging than others. METHODS: We compared the decline in 13 measures of physical, mental, and functional health from the Cardiovascular Health Study: hospitalization, bed days, cognition, extremity strength, feelings about life as a whole, satisfaction with the purpose of life, self-rated health, depression, digit symbol substitution test, grip strength, activities of daily living, instrumental activities of daily living, and gait speed. Each measure was standardized against self-rated health. We compared the 5-year change to see which of the 13 measures declined the fastest and the slowest. RESULTS: The 5-year change in standardized health varied from a decline of 12 points (out of 100) for hospitalization to a decline of 17 points for gait speed. In most comparisons, standardized health from hospitalization and bed days declined the least, whereas health measured by activities of daily living, instrumental activities of daily living, and gait speed declined the most. These rankings were independent of age, sex, mortality patterns, and the method of standardization. CONCLUSIONS: All of the health variables declined, on average, with advancing age, but at significantly different rates. Standardized measures of mental health, cognition, quality of life, and hospital utilization did not decline as fast as gait speed, activities of daily living, and instrumental activities of daily living. Public health interventions to address problems with gait speed, activities of daily living, and instrumental activities of daily living may help older adults to remain healthier in all dimensions. PMID- 23666947 TI - A review of developmental research on resilience in maltreated children. AB - Research demonstrates that child maltreatment can negatively impact the psychosocial functioning of individuals well beyond the point at which the trauma occurs. Fortunately, there is evidence that many children who are maltreated succeed in overcoming some of the possible consequences that can follow exposure to this particular form of adversity. Those who do are thought to be resilient. What it means to be resilient is an issue that researchers sometimes disagree on, as is reflected by the different definitions they apply to the term and the methods they use to study the phenomenon. In this literature review, we synthesize current findings on resilience and identify areas of congruence, as well as inconsistency in research methods across the reviewed studies. We focus the review exclusively on longitudinal studies to understand the dynamic qualities of resilience. Findings of the review suggest that, while studies appear to conceptualize and measure common domains of resilience (e.g., social, emotional, behavioral functioning), the measures themselves are in some cases notably different, limiting the extent to which results can be systemically compared across studies. The review also shows that few studies, although longitudinal by design, examine resilience over extended periods of development. Consequently, little has actually been learned about how patterns of resilience unfold and are sustained. Of those studies that do examine resilience as a developmental process, the rate of stability in resilience across time is notably low. Implications for future research are discussed. PMID- 23666948 TI - Counting (green) jobs in Queensland's waste and recycling sector. AB - The waste and recycling sector has been identified as a green industry and, as such, jobs within this sector may be classed as 'green jobs'. Many governments have seen green jobs as a way of increasing employment, particularly during the global financial crisis. However, the methods used to define and quantify green jobs directly affect the quantification of these green jobs. In December 2010, Queensland introduced a waste strategy that stated intent to increase green jobs within the waste sector. This article discusses the milieu and existing issues associated with quantifying green jobs within Queensland's waste and recycling sector, and provides a review of the survey that has sought to quantify the true size of the Queensland industry sector. This research has identified nearly 5500 jobs in Queensland's private waste management and recycling sector, which indicates that official data do not accurately reflect the true size of the sector. PMID- 23666949 TI - Unravelling the role of sense of coherence: more research is needed to empirically underpin the construct. PMID- 23666950 TI - Multicenter italian experience in liver transplantation for hepatocellular carcinoma in HIV-infected patients. AB - BACKGROUND: The aim of our work is to assess the clinical outcomes of liver transplantation (LT) for hepatocellular carcinoma (HCC) in HIV-coinfected patients. This is a multicenter study involving three Italian transplant centers in northern Italy: University of Modena, University of Bologna, and University of Udine. PATIENTS AND METHODS: We compared 30 HIV-positive patients affected by HCC who underwent LT with 125 HIV-uninfected patients who received the same treatment from September 2004 to June 2009. At listing, there were no differences between HIV-infected and -uninfected patients regarding HCC features. Patients outside the University of California, San Francisco criteria (UCSF) were considered eligible for LT if a down-staging program permitted a reduction of tumor burden. RESULTS: HIV-infected patients were younger, they were more frequently anti-HCV positive, and a higher number of HIV-infected patients presented a coinfection HBV-HCV. Pre-LT treatments (liver resection and or locoregional treatments) were similar between the two groups. Histological characteristics of the tumor were similar in patients with and without HIV infection. No differences were observed in terms of overall survival and HCC recurrence rates. CONCLUSION: LT for HCC is a feasible procedure and the presence of HIV does not particularly affect the post-LT outcome. PMID- 23666951 TI - Use of central institutional review boards for multicenter clinical trials in the United States: a review of the literature. AB - BACKGROUND: To improve the efficiency of conducting multicenter clinical trials, the Food and Drug Administration, the Office of Human Research Protections, and the Department of Health and Human Services have expressed support for using a centralized institutional review board (IRB) process. However, research institutions differ in their willingness to defer to central IRBs. PURPOSE: We aimed to review and describe peer-reviewed journal articles on the use of central IRBs for multicenter clinical trials in the United States in an effort to inform the policy discussion about central IRBs. METHODS: We used a PubMed search and consulted IRB experts and the bibliographies of other reviews to identify relevant commentaries and empirical studies. RESULTS: Our search identified 33 articles related to the use of central IRBs for multicenter trials in the United States. Of these, 22 were commentary pieces and 11 were empirical studies. LIMITATIONS: Our review was restricted to journal articles about the use of central IRBs for multicenter clinical trials in the United States. CONCLUSIONS: There is limited empirical work on the use of central IRBs for multicenter trials in the United States. Most published studies focused on problems in efficiency associated with redundant local reviews of multicenter studies and the potential benefits of a centralized system. Because the absence of studies on the use of central IRBs may be due to their infrequent use, additional work is needed to generate data on the use of central IRBs and to elucidate and address the concerns that research institutions have about deferring ethical review to a central IRB. PMID- 23666952 TI - Placental weight: relation to maternal weight and growth parameters of full-term babies at birth and during childhood. AB - OBJECTIVE: Human growth is a continuous process. Studies defining placental effect on prenatal and postnatal human growth are few. We studied the anthropometric data of hundred mothers who gave birth at term after an uncomplicated singleton pregnancy, and their infants in relation to their placental weight using linear regression analysis. Mother weight, placental weight, and infant length (BL), weight (BW), and head circumference (HC) were obtained at birth and during childhood period (4.5 +/- 2 years) of age. At birth, placental weights were correlated significantly with maternal weights (r = 0.21, P = 0.031). Placental weights were significantly correlated with growth parameters of the child at birth and during childhood. Infant BW (r = 0.71, r < 0.001), body mass index SDS (BMI SDS) (r = 0.589, P < 0.001), length SDS (LSDS) (0.567, P < 0.001) and HC (r = 0.699, P < 0.001). During childhood, placental weights were correlated with BMI SDS (r = 0.296, P = 0.002) and HtSDS = (r = 0.254, P = 0.009). LSDS at birth was correlated significantly with HtSDS during childhood (r = 0.445, P < 0.001). Placental weight represents a good marker of fetal growth (at birth) and significantly correlates with early childhood growth in full-term infants. PMID- 23666953 TI - Phototherapy device effectiveness in Nigeria: irradiance assessment and potential for improvement. AB - This study investigated the effectiveness of simple-to-implement adjustments of phototherapy devices on irradiance levels in a cross-section of Nigerian hospitals. A total of 76 phototherapy devices were evaluated in 16 hospitals while adjustments were implemented for a subset of 25 devices for which consent was obtained. The mean irradiance level was 7.6 +/- 5.9 uW/cm(2)/nm for all devices prior to adjustments. The average irradiance level improved from 9.0 uW/cm(2)/nm to 27.3 uW/cm(2)/nm for the adjusted group (n = 25) compared with 6.8 +/- 5.4 uW/cm(2)/nm for the unadjusted group (n = 51). Simple, inexpensive adjustments to phototherapy devices with sub-optimal irradiance levels can significantly improve their effectiveness to acceptable international standards and should be widely promoted in resource-constrained settings. PMID- 23666954 TI - Automated artifact removal from the electroencephalogram: a comparative study. AB - Contamination of the electroencephalogram (EEG) by artifacts greatly reduces the quality of the recorded signals. There is a need for automated artifact removal methods. However, such methods are rarely evaluated against one another via rigorous criteria, with results often presented based upon visual inspection alone. This work presents a comparative study of automatic methods for removing blink, electrocardiographic, and electromyographic artifacts from the EEG. Three methods are considered; wavelet, blind source separation (BSS), and multivariate singular spectrum analysis (MSSA)-based correction. These are applied to data sets containing mixtures of artifacts. Metrics are devised to measure the performance of each method. The BSS method is seen to be the best approach for artifacts of high signal to noise ratio (SNR). By contrast, MSSA performs well at low SNRs but at the expense of a large number of false positive corrections. PMID- 23666955 TI - Kernel earth mover's distance for EEG classification. AB - Here, we propose a new kernel approach based on the earth mover's distance (EMD) for electroencephalography (EEG) signal classification. The EEG time series are first transformed into histograms in this approach. The distance between these histograms is then computed using the EMD in a pair-wise manner. We bring the distances into a kernel form called kernel EMD. The support vector classifier can then be used for the classification of EEG signals. The experimental results on the real EEG data show that the new kernel method is very effective, and can classify the data with higher accuracy than traditional methods. PMID- 23666957 TI - The role of cervical and ocular vestibular-evoked myogenic potentials in the follow-up of vestibular neuritis. AB - This study evaluates the recovery of vestibular nerve function after vestibular neuritis (VN) by vestibular-evoked myogenic potentials (VEMPs). Twenty-six patients with the diagnosis of VN were included. All patients underwent ocular VEMP (oVEMP) and cervical VEMP (cVEMP) recordings, at 6 days and 6 months from the onset of the symptoms. Of the 26 patients, 14 showed improvement on oVEMP at month 6 (group 1), and 12 showed no change or worsening on oVEMP at 6 months (group 2). At the same time, there was no change in the amplitudes of the cVEMP on either healthy or affected sides in both groups. Inability to perform the Fukuda test, and chronic white matter supratentorial lesions present on brain magnetic resonance imaging (MRI) were more frequent in patients with worse outcome on oVEMP (P = 0.044 and 0.045, respectively). Although involvement of the inferior branch of the vestibular nerve was not associated with oVEMP outcome, oVEMP latencies (N10 and P13) were associated with improvement or worsening in oVEMP amplitudes, showing that prolonged latencies correlate with 6-month improvement in oVEMP amplitudes (Pearson correlation -0.472, P = 0.041 and 0.580, P = 0.009, respectively). This study identified clinical, MRI and neurophysiological predictors of recovery in patients with superior VN, and offers additional insight into, and better understanding of, the role of VEMP in diagnosis and prognosis of patients with VN. Further studies are needed to validate this diagnostic procedure and to assess its clinical usefulness in VN management. PMID- 23666956 TI - Dissociation of vegetative and minimally conscious patients based on brain operational architectonics: factor of etiology. AB - Discrimination between patients in vegetative (VS) and minimally conscious state (MCS) is currently based upon the behavioral gold standard. Behavioral assessment remains equivocal and difficult to interpret as evidence for the presence or absence of consciousness, resulting in possible clinical misdiagnosis in such patients. Application of an operational architectonics (OA) strategy to electroencephalogram (EEG) analysis reveals that absence of consciousness in patients in VS is paralleled by significant impairment in overall EEG operational architecture compared to patients in MCS: neuronal assemblies become smaller, their life span shortened, and they became highly unstable and functionally disconnected (desynchronized). However, in a previous study, patients with different brain damage etiologies were intermixed. Therefore, the goal of the present study was to investigate whether the application of OA methodology to EEG could reliably dissociate patients in VS and MCS independent of brain damage etiology. We conclude that the observed EEG OA structure impairment in patients in VS and partial preservation in patients in MCS is a marker of consciousness/unconsciousness rather than physiological damage. Results of this study may have neuroscientific, clinical, and ethical implications. PMID- 23666958 TI - Rasamsonia argillacea mycosis in a dog: first case in Europe. PMID- 23666959 TI - Corticotropin-releasing hormone interacts with interleukin-1beta to regulate prostaglandin H synthase-2 expression in human myometrium during pregnancy and labor. AB - CONTEXT: The onset of labor appears to involve the activation of myometrial inflammatory pathways, and transcription factors such as nuclear factor-kappaB (NF-kappaB) control expression of the contraction-associated proteins required to induce a procontractile phenotype. These responses might involve CRH, which integrates immune and neuroendocrine systems. OBJECTIVES: In human myometrium we investigated cyclooxygenase 2 (PGHS2) expression and regulation by CRH and the proinflammatory cytokine IL-1beta before and after labor. DESIGN: Myometrial tissues obtained from pregnant women at term before (n = 12) or during labor (n = 10) and pathological cases of choriamnionitis-associated term labor (n = 5) were used to isolate primary myocytes and investigate in vitro, CRH effects on basal and IL-1beta regulated p65 activation and PGHS2 expression. RESULTS: In nonlaboring myometrial cells, CRH was unable to induce NF-kappaB nuclear translocation; however, it altered the temporal dynamics of IL-1beta-driven NF kappaB nuclear entry by initially delaying entry and subsequently prolonging retention. These CRH-R1-driven effects were associated with a modest inhibitory action in the early phase (within 2 hours) of IL-1beta stimulated PGHS2 mRNA expression, whereas prolonged stimulation for 6-18 hours augmented the IL-1beta effects. The early-phase effect required intact protein kinase A activity and was diminished after the onset of labor. The presence of chorioamnionitis led to exaggerated PGHS2 mRNA responses to IL-1beta but diminished effects of CRH. CONCLUSIONS: CRH is involved in the inflammatory regulation of PGHS2 expression before and during labor; these actions might be important in priming and preparing the myometrium for labor and cellular adaptive responses to inflammatory mediators. PMID- 23666960 TI - Plasmacytoid dendritic cells in patients with autoimmune thyroid disease. AB - BACKGROUND: Patients with autoimmune thyroid diseases (AITD) show defects in immunoregulatory mechanisms. Herein we assessed the expression of different regulatory receptors in circulating and thyroid dendritic cells (DCs). DESIGN: Peripheral blood samples from 49 patients with Hashimoto's thyroiditis, 35 with Graves' disease, and 34 healthy subjects were studied. Clinical parameters included grades of goiter and ophthalmopathy, thyroid function, and antibody tests. Thyroid tissue samples from 10 AITD patients were also analyzed. Levels of DCs and their expression of different regulatory molecules (IDO, ILT2, ILT3, PSGL 1, PD-L1) were studied. In vitro interferon-alpha response by plasmacytoid DCs (pDCs) and tryptophan (Trp) metabolites were determined. RESULTS: Significant low levels of pDCs, but not conventional DCs, were detected in the peripheral blood from AITD patients, mainly in those with severe disease. Furthermore, a diminished expression of ILT3, PSGL-1, and CD69 by peripheral blood pDCs from AITD patients was observed. An increased number of pDCs was found in thyroid tissue, showing a diminished expression of ILT3 and PSGL-1. A lower proportion of IDO+ pDCs, a significant increase in Trp levels, a decrease in the kyneruine/Trp ratio, and an increased in vitro interferon-alpha response were present in AITD patients. Finally, a significant correlation was found between the in vitro synthesis of IL-10 by stimulated T cells and expression of IDO by pDCs. CONCLUSIONS: The diminished number of pDCs in the peripheral blood from AITD patients as well as their abnormal phenotype could contribute significantly to the pathogenesis. PMID- 23666962 TI - Bone size and bone strength are increased in obese male adolescents. AB - CONTEXT: Controversy exists on the effect of obesity on bone development during puberty. OBJECTIVE: Our objective was to determine differences in volumetric bone mineral density (vBMD) and bone geometry in male obese adolescents (ObAs) in overlap with changes in bone maturation, muscle mass and force development, and circulating sex steroids and IGF-I. We hypothesized that changes in bone parameters are more evident at the weight-bearing site and that changes in serum estradiol are most prominent. DESIGN, SETTING, AND PARTICIPANTS: We recruited 51 male ObAs (10-19 years) at the entry of a residential weight-loss program and 51 healthy age-matched and 51 bone-age-matched controls. MAIN OUTCOME MEASURES: vBMD and geometric bone parameters, as well as muscle and fat area were studied at the forearm and lower leg by peripheral quantitative computed tomography. Muscle force was studied by jumping mechanography. RESULTS: In addition to an advanced bone maturation, differences in trabecular bone parameters (higher vBMD and larger trabecular area) and cortical bone geometry (larger cortical area and periosteal and endosteal circumference) were observed in ObAs both at the radius and tibia at different pubertal stages. After matching for bone age, all differences at the tibia, but only the difference in trabecular vBMD at the radius, remained significant. Larger muscle area and higher maximal force were found in ObAs compared with controls, as well as higher circulating free estrogen, but similar free testosterone and IGF-I levels. CONCLUSIONS: ObAs have larger and stronger bones at both the forearm and lower leg. The observed differences in bone parameters can be explained by a combination of advanced bone maturation, higher estrogen exposure, and greater mechanical loading resulting from a higher muscle mass and strength. PMID- 23666961 TI - Changes in bone resorption across the menopause transition: effects of reproductive hormones, body size, and ethnicity. AB - OBJECTIVE: Our objective was to characterize changes in bone resorption in relation to the final menstrual period (FMP), reproductive hormones, body mass index (BMI), and ethnicity. METHODS: Urinary type I collagen N-telopeptide (NTX), estradiol, and FSH levels were measured annually for up to 8 years spanning the menopause transition in 918 African American, Chinese, Japanese, or Caucasian women. RESULTS: Urinary NTX began to increase sharply about 2 years before the FMP, reaching its peak level about 1 to 1.5 years after the FMP. NTX levels declined modestly from 2 to 6 years after the FMP but remained about 20% higher than before the menopause transition. The sharp rise in FSH occurred in conjunction with a sharp decline in estradiol and shortly after FSH levels began increasing rapidly. The mean increase in urinary NTX across the menopause transition was greatest in women with BMI <25 kg/m2 and smallest in women with BMI >30 kg/m2. Increases in NTX were greatest in Japanese women and smallest in African Americans. These differences were attenuated, but not eliminated, when analyses were adjusted for covariates, particularly BMI. SUMMARY: During the menopause transition, a decline in ovarian function beginning about 2 years before the FMP is followed by an increase in bone resorption and subsequently by bone loss. The magnitude of the increase in bone resorption is inversely associated with BMI. Ethnic differences in changes in bone resorption are attenuated, but not eliminated, by adjustment for BMI. Ethnic differences in BMI, and corresponding ethnic differences in bone resorption, appear to account for much of the ethnic variation in perimenopausal bone loss. PMID- 23666963 TI - Multiple functional parathyroid cysts. PMID- 23666964 TI - A comprehensive next generation sequencing-based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma. AB - CONTEXT: Pheochromocytomas and paragangliomas are notable for a high frequency of inherited cases, many of which present as apparently sporadic tumors. OBJECTIVE: The objective of this study was to establish a comprehensive next generation sequencing (NGS)-based strategy for the diagnosis of patients with pheochromocytoma and paraganglioma by testing simultaneously for mutations in MAX, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL. DESIGN: After the methodology for the assay was designed and established, it was validated on DNA samples with known genotype and then patients were studied prospectively. SETTING: The study was performed in a diagnostic genetics laboratory. PATIENTS: DNA samples from 205 individuals affected with adrenal or extraadrenal pheochromocytoma/head and neck paraganglioma (PPGL/HNPGL) were analyzed. A proof of-principle study was performed using 85 samples known to contain a variant in 1 or more of the genes to be tested, followed by prospective analysis of an additional 120 samples. MAIN OUTCOME MEASURES: We assessed the ability to use an NGS-based method to perform comprehensive analysis of genes implicated in inherited PPGL/HNPGL. RESULTS: The proof-of-principle study showed that the NGS assay and analysis gave a sensitivity of 98.7%. A pathogenic mutation was identified in 16.6% of the prospective analysis cohort of 120 patients. CONCLUSIONS: A comprehensive NGS-based strategy for the analysis of genes associated with predisposition to PPGL and HNPGL was established, validated, and introduced into diagnostic service. The new assay provides simultaneous analysis of 9 genes and allows more rapid and cost-effective mutation detection than the previously used conventional Sanger sequencing-based methodology. PMID- 23666966 TI - Tumor suppressor role of the CL2/DRO1/CCDC80 gene in thyroid carcinogenesis. AB - CONTEXT: Thyroid carcinoma is one of the most common malignancies of the endocrine system, and, despite the high frequency of oncogene activation in thyroid neoplastic lesions, the tumor suppressor genes involved in thyroid carcinogenesis remain unidentified. Our previous data implicated a link between the CL2/CCDC80 gene and thyroid cancer. OBJECTIVE: The objective of the study was to examine the expression of the CL2/CCDC80 gene in human thyroid carcinomas in the attempt to determine whether it plays a role in thyroid carcinogenesis. DESIGN: We evaluated the expression of CL2/CCDC80 in a large number of thyroid neoplastic tissue samples differing in degree of malignancy. We also investigated the effects of its restoration in 2 human thyroid carcinoma cell lines characterized by very low levels of CL2/CCDC80 expression. RESULTS: CL2/CCDC80 expression was much lower in almost all the thyroid carcinomas analyzed than in normal thyroid tissues and was lowest in follicular variants of papillary carcinomas. Loss of heterozygosity partially accounted for CL2/CCDC80 down regulation in thyroid carcinoma samples. Restoration of CL2/CCDC80 expression in the 2 human thyroid anaplastic carcinoma cell lines resulted in a higher susceptibility to apoptosis and suppression of the malignant phenotype. CL2/CCDC80 expression positively regulated the expression of E-cadherin, thereby halting cancer progression. CONCLUSIONS: These results indicate that CL2/CCDC80 is a putative tumor suppressor gene in thyroid carcinogenesis. PMID- 23666965 TI - Expression and function of the progesterone receptor in human prostate stroma provide novel insights to cell proliferation control. AB - CONTEXT: Like other tissues, the prostate is an admixture of many different cell types that can be segregated into components of the epithelium or stroma. Reciprocal interactions between these 2 types of cells are critical for maintaining prostate homeostasis, whereas aberrant stromal cell proliferation can disrupt this balance and result in diseases such as benign prostatic hyperplasia. Although the androgen and estrogen receptors are relatively well studied for their functions in controlling stromal cell proliferation and differentiation, the role of the progesterone receptor (PR) remains unclear. OBJECTIVE: The aim of the study was to investigate the expression and function of the PR in the prostate. DESIGN AND SETTING: Human prostate biopsies, renal capsule xenografts, and prostate stromal cells were used. Immunohistochemistry, Western blotting, real-time quantitative PCR, cell proliferation, flow cytometry, and gene microarray analyses were performed. RESULTS: Two PR isoforms, PRA and PRB, are expressed in prostate stromal fibroblasts and smooth muscle cells, but not in epithelial cells. Both PR isoforms suppress prostate stromal cell proliferation through inhibition of the expression of cyclinA, cyclinB, and cdc25c, thus delaying cell cycling through S and M phases. Gene microarray analyses further demonstrated that PRA and PRB regulated different transcriptomes. However, one of the major gene groups commonly regulated by both PR isoforms was the one associated with regulation of cell proliferation. CONCLUSION: PR plays an inhibitory role in prostate stromal cell proliferation. PMID- 23666967 TI - Prepubertal girls with Turner syndrome and children with isolated SHOX deficiency have similar bone geometry at the radius. AB - CONTEXT: The low bone mineral density (BMD) and alterations in bone geometry observed in patients with Turner syndrome (TS) are likely caused by hypergonadotropic hypogonadism and/or by haploinsufficiency of the SHOX gene. OBJECTIVE: Our objective was to compare BMD, bone geometry, and strength at the radius between prepubertal girls with TS and children with isolated SHOX deficiency (SHOX-D) to test the hypothesis that the TS radial bone phenotype may be caused by SHOX-D. DESIGN AND SETTING: This comparative cross-sectional study was performed between March 2008 and May 2011 in 5 large centers for pediatric endocrinology. PATIENTS: Twenty-two girls with TS (mean age 10.3 years) and 10 children with SHOX-D (mean age 10.3 years) were assessed using peripheral quantitative computed tomography of the forearm. MAIN OUTCOMES: BMD, bone geometry, and strength at 4% and 65% sites of the radius were evaluated. RESULTS: Trabecular BMD was normal in TS (mean Z-score = -0.2 +/- 1.1, P = .5) as well as SHOX-D patients (mean Z-score = 0.5 +/- 1.5, P = .3). At the proximal radius, we observed increased total bone area (Z-scores = 0.9 +/- 1.5, P = .013, and 1.5 +/- 1.4, P = .001, for TS and SHOX-D patients, respectively) and thin cortex (Z scores = -0.7 +/- 1.2, P = 0.013, and -2.0 +/- 1.2, P < .001, respectively) in both groups. Bone strength index was normal in TS as well as SHOX-D patients (Z scores = 0.3 +/- 1.0, P = .2, and 0.1 +/- 1.3, P = .8, respectively). CONCLUSIONS: The similar bone geometry changes of the radius in TS and SHOX-D patients support the hypothesis that loss of 1 copy of SHOX is responsible for the radial bone phenotype associated with TS. PMID- 23666968 TI - Hormonal response to a mixed-meal challenge after reversal of gastric bypass for hypoglycemia. AB - CONTEXT: Severe hypoglycemia is a rare and challenging complication of Roux-en-Y gastric bypass (RYGB), which is characterized by hypersecretion of insulin and incretin hormones in the postprandial state. OBJECTIVE: The objective of the study was to determine the clinical and hormonal responses to a mixed-meal challenge after the reversal of RYGB in 2 patients with post-RYGB hypoglycemia. We hypothesized that the reversal of RYGB would lead to clinical improvement in hypoglycemia through the attenuation of incretin hormone secretion. DESIGN/SETTING/SUBJECTS/OUTCOME MEASURES: Two patients with post-RYGB hypoglycemia underwent a standardized meal tolerance test prior to and 8 and 18 months after RYGB reversal, respectively, with the measurement of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), insulin, and glucose levels. Gastric bypass was reversed by reattaching the small gastric pouch to the bypassed distal stomach and resecting the Roux limb to restore the normal flow of food bolus. RESULTS: Both subjects showed persistent evidence of hypoglycemia with marked hyperinsulinemia after the RYGB reversal. GLP-1 levels after the RYGB reversal decreased by 76% and 70%, respectively, from their prereversal levels and to the level of nonhypoglycemic post-RYGB controls. In contrast, GIP levels after the RYGB reversal increased by 3-10 times the level before the reversal and 8-26 times that of the nonhypoglycemic post-RYGB controls. CONCLUSIONS: Reversal of RYGB did not alleviate hyperinsulinemic hypoglycemia upon a mixed-meal challenge in our patients, thus suggesting its limited clinical benefit as treatment of post-RYGB hypoglycemia. The marked increase in GIP levels and concurrent decrease in GLP-1 levels in our patients suggest a possible role of GIP in persistent hyperinsulinemic hypoglycemia after the reversal of RYGB. PMID- 23666969 TI - Percutaneous laser ablation of metastatic lymph nodes in the neck from papillary thyroid carcinoma: preliminary results. AB - CONTEXT: Percutaneous laser ablation (PLA) may be useful in treating patients with metachronous metastatic lymph nodes in the neck. OBJECTIVE: Our objective was to assess PLA as a treatment of difficult-to-treat metachronous cervical lymph node metastases from papillary thyroid carcinoma. DESIGN AND SETTING: We conducted a retrospective analysis of prospectively collected data at a public hospital. PATIENTS: Fifteen patients with previous resection of papillary thyroid carcinoma with elevated serum levels of thyroglobulin (Tg) or anti-Tg antibodies (TgAbs) and 24 metachronous nodal metastases treated between September 2010 and April 2012 were followed with [18F]fluorodeoxyglucose (18FDG) positron emission tomography (PET)/computed tomography (CT) and contrast-enhanced ultrasound (CEUS). INTERVENTION: Intervention was PLA. OUTCOME MEASURES: Technique feasibility and technical success were evaluated. Tg/TgAb serum levels and 18FDG PET/CT, and CEUS appearance were assessed at 6 and 12 months and compared with baseline. Complications were recorded. RESULTS: PLA was always feasible, and technical success was achieved in all patients. At 6 months, local control was achieved in 11 of 15 patients (73%), with 6 (40%) having serum Tg/TgAb normalized (P = .017 vs baseline). Whereas 20 of 24 (83%) nodes were negative at 18FDG PET/CT and CEUS (P < .001 vs baseline), 4 were 18FDG-PET/CT-positive (3 also CEUS positive). At the 12-month follow-up, local control was achieved in 10 of 14 patients (71.4%). Sixteen of 20 nodes (80%) were negative at 18FDG-PET/CT and CEUS (P < .001 vs baseline), 4 were 18FDG-PET/CT-positive (2 also CEUS-positive). Four of 10 (40%) patients had normalization of serum Tg/TgAb (P = .098 vs baseline). No major complications occurred. CONCLUSIONS: PLA is potentially feasible, safe, and effective for the treatment of metachronous cervical nodal metastases from papillary thyroid carcinoma. This procedure may reduce or delay a large number of highly invasive repeat neck dissections. PMID- 23666970 TI - DNA methylation signatures identify biologically distinct thyroid cancer subtypes. AB - OBJECTIVE: The purpose of this study was to determine the global patterns of aberrant DNA methylation in thyroid cancer. RESEARCH DESIGN AND METHODS: We have used DNA methylation arrays to determine, for the first time, the genome-wide promoter methylation status of papillary, follicular, medullary, and anaplastic thyroid tumors. RESULTS: We identified 262 and 352 hypermethylated and 13 and 21 hypomethylated genes in differentiated papillary and follicular tumors, respectively. Interestingly, the other tumor types analyzed displayed more hypomethylated genes (280 in anaplastic and 393 in medullary tumors) than aberrantly hypermethylated genes (86 in anaplastic and 131 in medullary tumors). Among the genes indentified, we show that 4 potential tumor suppressor genes (ADAMTS8, HOXB4, ZIC1, and KISS1R) and 4 potential oncogenes (INSL4, DPPA2, TCL1B, and NOTCH4) are frequently regulated by aberrant methylation in primary thyroid tumors. In addition, we show that aberrant promoter hypomethylation associated overexpression of MAP17 might promote tumor growth in thyroid cancer. CONCLUSIONS: Thyroid cancer subtypes present differential promoter methylation signatures, and nondifferentiated subtypes are characterized by aberrant promoter hypomethylation rather than hypermethylation. Additional studies are needed to determine the potential clinical interest of the tumor subtype-specific DNA methylation signatures described herein and the role of aberrant promoter hypomethylation in nondifferentiated thyroid tumors. PMID- 23666971 TI - Identification of microRNAs in human follicular fluid: characterization of microRNAs that govern steroidogenesis in vitro and are associated with polycystic ovary syndrome in vivo. AB - CONTEXT: Human follicular fluid is a combination of proteins, metabolites, and ionic compounds that is indicative of the general state of follicular metabolism and is associated with maturation and quality of oocytes. Deviations in these components are often associated with reproductive diseases. There has been no report of microRNAs (miRNAs) in human follicular fluids. OBJECTIVE: We hypothesized that human follicular fluid may contain miRNAs. We sought to identify cell-free miRNAs in human follicular fluid and to investigate the function of these miRNAs in vitro and any roles they play in polycystic ovary syndrome (PCOS). DESIGN: Genome-wide deep sequencing and TaqMan miRNA arrays were used to identify miRNAs, and the roles of the highly expressed miRNAs in steroidogenesis were investigated in KGN cells. Quantification of candidate miRNAs in follicular fluids of PCOS and controls was performed using TaqMan miRNA assays. RESULTS: We identified miRNAs in microvesicles and the supernatant of human follicular fluid. Bioinformatics analysis showed that the most highly expressed miRNAs targeted genes associated with reproductive, endocrine, and metabolic processes. We found that miR-132, miR-320, miR-520c-3p, miR-24, and miR 222 regulate estradiol concentrations and that miR-24, miR-193b, and miR-483-5p regulate progesterone concentrations. Finally, we showed that miR-132 and miR-320 are expressed at significantly lower levels in the follicular fluid of polycystic ovary patients than in healthy controls (P = .005 and P = .0098, respectively). CONCLUSION: These results demonstrate that there are numerous miRNAs in human follicular fluids, some of which play important roles in steroidogenesis and PCOS. This study substantially revises our understanding of the content of human follicular fluid and lays the foundation for the future investigation of the role of miRNAs in PCOS. PMID- 23666972 TI - Biliopancreatic diversion in nonobese patients with type 2 diabetes: impact and mechanisms. AB - CONTEXT: Diabetes remission is frequent after biliopancreatic diversion (BPD) in morbidly obese patients with type 2 diabetes (T2D). Data, mechanisms, and clinical indications in nonobese T2D patients are scanty. OBJECTIVE: The objective of the study was to assess remission and investigate insulin sensitivity and beta-cell function after BPD in nonobese patients with long standing T2D. DESIGN, SETTING, AND PATIENTS: This was a clinical research study comparing 15 T2D patients (aged 55 +/- 1 years, duration of 16 +/- 2 years, body mass index of 28.3 +/- 0.6 kg/m2, glycosylated hemoglobin 8.6% +/- 1.3%) with 15 gender-, age-, and body mass index-matched nondiabetic controls. Before surgery and 2 months and 1 year later, a 3-hour oral glucose tolerance test, a 5-hour mixed-meal test, and a 3-hour euglycemic clamp were performed. INTERVENTION: The intervention included a BPD (distal gastrectomy, proximal ileum anastomosed to remaining stomach, biliopancreatic limb anastomosed to ileum 50 cm from the ileocecal valve). RESULTS: Glycemia improved in all patients, but remission (glycosylated hemoglobin < 6.5% and normal oral glucose tolerance test) occurred in 6 of 15 patients. Insulin resistance (19.8 +/- 0.8 MUmol . min-1 . kg(ffm)-1, P < .001 vs 40.9 +/- 5.3 of controls) resolved already at 2 months (34.2 +/- 2.8) and was sustained at 1 year (34.7 +/- 1.6), although insulin-mediated suppression of endogenous glucose production remained impaired. In contrast, beta-cell glucose sensitivity (19 [12] pmol . min-1 . m-2 . mM-1 vs 96 [73] of controls, P < .0001) rose (P = .02) only to 31 [26] at 1 year and was lower in nonremitters (16 [18]) than remitters (46 [33]). CONCLUSIONS: In nonobese patients with long standing T2D, BPD improves metabolic control but induces remission in only approximately 40% of patients. Peripheral insulin sensitivity is restored early after surgery and similarly in remitters and nonremitters, indicating a weight independent effect of the operation. The initial extent of beta-cell incompetence is the main predictor of the metabolic outcome. PMID- 23666973 TI - Changes in estradiol and testosterone levels in postmenopausal women after changes in body mass index. AB - CONTEXT: Endogenous sex hormones are risk factors for postmenopausal breast cancer. A potential route for favorable hormonal modification is weight loss. OBJECTIVE: The objective of the study was to measure change in plasma estradiol and testosterone levels in postmenopausal women in relation to change in body mass index (BMI) and plasma leptin. SETTING: The setting was a cohort study of over 100,000 female volunteers from the general population, United Kingdom. PARTICIPANTS: The participants were a sample of 177 postmenopausal women aged over 45 years who provided blood samples during 2004-2005 and again during 2010 2011. MAIN OUTCOME MEASURE: Outcomes were percentage change in plasma estradiol and testosterone levels per 1 kg/m2 change in BMI and per 1 ng/mL change in plasma leptin. RESULTS: Among women with reduction in BMI, estradiol decreased 12.7% (95% confidence interval: [6.4%, 19.5%]; P < .0001) per kg/m2 and among women with increased BMI estradiol increased 6.4% [0.2%, 12.9%] (P = .042). The corresponding figures for testosterone were 10.7% [3.0%, 19.0%] (P = .006) and 1.9% [-5.4%, 9.7%] (P = .61) per kg/m2. For women with decreases and increases in leptin, estradiol decreased by 3.6% [1.3%, 6.0%] (P = .003) per ng/mL and increased by 1.7% [-0.3%, 3.6%] (P = .094), respectively. The corresponding figures for testosterone were 4.8% [2.0%, 7.8%] (P = .009) and 0.3% [-2.0%, 2.6%] (P = .82) per ng/mL. CONCLUSIONS: In postmenopausal women, changes in BMI and plasma leptin occurring over several years are associated with changes in estradiol and testosterone levels. The results suggest that fat loss by an individual can result in substantial decreases in postmenopausal estradiol and testosterone levels and provides support for weight management to lessen breast cancer risk. PMID- 23666974 TI - Specific bone mass acquisition in elite female athletes. AB - CONTEXT: Cross-sectional studies have demonstrated that physical activity can improve bone mass acquisition. However, this design is not adequate to describe the specific kinetics of bone mass gain during pubertal development. OBJECTIVE: To compare the kinetics of bone mass acquisition in female adolescent athletes of sports that impose different mechanical loads and untrained controls throughout puberty. STUDY PARTICIPANTS: A total of 72 girls with ages ranging from 10.8 to 18.0 years were recruited: 24 rhythmic gymnasts (RG, impact activity group), 24 swimmers (SW, no-impact activity), and 24 age-matched controls (CON). MAIN OUTCOME MEASURES: Areal bone mineral density (aBMD) was determined using dual energy x-ray absorptiometry and bone turnover markers were analyzed. All the investigations were performed at baseline and after 1 year. RESULTS: At baseline and after 1 year of follow-up, RG presented significantly greater aBMD adjusted for age, fat-free soft tissue, and fat mass compared with CON and SW, only at the femoral region. When aBMD variation throughout the pubertal period was modeled for each group from individual values, the aBMD at the femoral region was significantly higher in RG compared with the other 2 groups from 12.5 to 14 years, and this difference lasted up to 18 years. Moreover, the mean annual aBMD gain tended to be higher in RG compared with SW and CON only at the femoral region and this gain lasted longer in RG. Bone remodeling markers decreased similarly with age in the 3 groups. CONCLUSIONS: This study, which was based on linear mixed models for longitudinal data, demonstrated that the osteogenic effect of gymnastics is characterized by greater bone mass gain localized at mechanically loaded bone (ie, the proximal femur) principally around the menarcheal period. Moreover, the bone mass gain lasts longer in gymnasts, which may be explained by the delay in sexual maturation. PMID- 23666975 TI - Is there a reverse J-shaped association between 25-hydroxyvitamin D and all-cause mortality? Results from the U.S. nationally representative NHANES. AB - CONTEXT: A reverse J-shaped association between serum 25-hydroxyvitamin D (25[OH]D) concentration and all-cause mortality was suggested in a 9-year follow up (1991-2000) analysis of the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994). OBJECTIVE: Our objective was to repeat the analyses with 6 years additional follow-up to evaluate whether the association persists through 15 years of follow-up. PARTICIPANTS: The study included 15 099 participants aged >= 20 years with 3784 deaths. MAIN OUTCOME MEASURE: Relative risk (RR) of death from all causes was adjusted for age, sex, race/ethnicity, and season using 2 Poisson regression approaches: traditional categorical and cubic splines. Results were given for 9 25(OH)D levels: <20, 20 to 29, 30 to 39, 40 to 49, 50 to 59, 60 to 74, 75 to 99 (reference), 100 to 119, and >= 120 nmol/L. RESULTS: The reverse J-shaped association became stronger with longer follow-up and was not affected by excluding deaths within the first 3 years of follow-up. Similar results were found from both statistical approaches for levels <20 through 119 nmol/L. Adjusted RR (95% confidence interval [CI]) estimates for all levels <60 nmol/L were significantly >1 compared with the reference group. The nadir of risk was 81 nmol/L (95% CI, 73-90 nmol/L). For 25(OH)D >= 120 nmol/L, results (RR, 95% CI) were slightly different using traditional categorical (1.5, 1.02-2.3) and cubic splines approaches (1.2, 0.9-1.4). The association appeared in men, women, adults ages 20 to 64 years, and non-Hispanic whites but was weaker in older adults. The study was too small to evaluate the association in non Hispanic black and Mexican-American adults. CONCLUSIONS: A reverse J-shaped association between serum 25(OH)D and all-cause mortality appears to be real. It is uncertain whether the association is causal. PMID- 23666977 TI - Comparative analysis of the thyrocytes and T cells: responses to H2O2 and radiation reveals an H2O2-induced antioxidant transcriptional program in thyrocytes. AB - CONTEXT: Radiation is an established cause of thyroid cancer, and growing evidence supports a role for hydrogen peroxide (H2O2) in spontaneous thyroid carcinogenesis. Little is known about the molecular programs activated by these agents in thyrocytes. OBJECTIVE: The purpose of this study was to compare the responses of thyrocytes and T cells to H2O2 and radiation. METHODS: We profiled the DNA damage and cell death induced by gamma-radiation (0.1-5 Gy) and H2O2 (0.0025-0.3 mM) in primary human thyrocytes and T cells. We next prepared thyroid and T-cell primary cultures from 8 donors operated for noncancerous thyroid pathological conditions and profiled their genome-wide transcriptional response 4 hours after (1) exposure to 1-Gy radiation, (2) treatment with H2O2 and (3) no treatment. Two H2O2 concentrations were investigated, calibrated in each cell type to elicit levels of single- and double-strand breaks equivalent to 1-Gy gamma-radiation. RESULTS: Although thyrocytes and T cells had comparable radiation responses, 3- to 10-fold more H2O2 was needed to induce detectable DNA damage in thyrocytes. At H2O2 and radiation doses inducing double-strand breaks, cell death occurred after 24 hours in T cells but not in thyrocytes. The transcriptional responses of thyrocytes and T cells to radiation were similar, involving DNA repair and cell death genes. In addition to this transcriptional program, H2O2 also up-regulated antioxidant genes in thyrocytes, including glutathione peroxidases and heme oxygenase at the double-strand breaks-inducing concentration. In contrast, a transcriptional storm involving thousands of genes was raised in T cells. Finally, we showed that inhibiting glutathione peroxidases activity increased the DNA damaging effect of H2O2 in thyrocytes. CONCLUSION: We propose that high H2O2 production in thyrocytes is matched with specific transcriptionally regulated antioxidant protection. PMID- 23666976 TI - Extent and determinants of thermogenic responses to 24 hours of fasting, energy balance, and five different overfeeding diets in humans. AB - CONTEXT: Individual variation in the ability to convert excess calories to heat and the effects of dietary macronutrient composition are unclear. OBJECTIVE: Stability and determinants of the energy expenditure (EE) response to overconsumption were assessed. DESIGN, SETTING, AND PARTICIPANTS: Twenty subjects (75% male) with normal glucose regulation were evaluated during 24 hours each of energy balance, fasting, and 5 different diets with 200% energy requirements in a clinical research unit. INTERVENTIONS: Five 1-day overfeeding diets were given in random order: high carbohydrate (75%) and low protein (3%); high carbohydrate and normal protein (20%); high fat (46%) and low protein; high fat (60%) and normal protein; and balanced (50% carbohydrates, 20% protein). MAIN OUTCOME MEASURES: The 24-hour EE, sleeping EE, and thermic effect of food (TEF) during each diet were measured with a metabolic chamber. Appetitive hormones were measured before and after the diets. RESULTS: The EE response to overfeeding exhibited good intraindividual reproducibility. Similar increases above eucaloric feeding in 24 hour EE (mean 10.7 +/- 5.7%, P < .001; range 2.9-18.8%) and sleeping EE (14.4 +/- 11.3%, P < .001; range 1.0-45.1%) occurred when overfeeding diets containing 20% protein, despite differences in fat and carbohydrate content, but the EE response during overfeeding diets containing 3% protein was attenuated. The percent body fat negatively correlated with TEF during normal protein overfeeding (r = -0.53, P < .01). Fasting peptide YY negatively correlated with TEF (r = -0.56, P < .01) and the increase in sleeping EE (r = -0.54, P < .01) during overfeeding. CONCLUSIONS: There is an intrinsic EE response to overfeeding that negatively associates with adiposity, although it represents a small percentage of consumed calories. PMID- 23666980 TI - The genetic basis for elite running performance. AB - The dominance of East African distance runners and sprinters of West African origin invites discussion around the contribution of genetic and lifestyle factors to performance. In this review, we focus on the genetic basis for performance. Previous research associating candidate genes such as ACE and ACTN3 to endurance and sprint performance in Caucasian populations has not been replicated in African populations. This may be influenced by numerous factors, including small sample sizes, comparisons across different ethnic populations and problems identifying appropriate control groups. Conceptually, these failures reveal the complex polygenic nature of physiology and performance, and the erroneous application of a candidate gene approach to more genetically diverse African populations. We argue that research has in fact established a role for genes in performance, and that the frequency, rather than the prevalence, of favourable genetic variants within certain populations may account for the performance dominance in these populations. PMID- 23666981 TI - Republished editorial: Physical activity for cancer survivors: beneficial in the short term, but longer term outcomes are lacking. PMID- 23667042 TI - Acceleration of flowering in Arabidopsis thaliana by Cape Verde Islands alleles of FLOWERING H is dependent on the floral promoter FD. AB - Flowering time in the model plant Arabidopsis thaliana is regulated by both external environmental signals and internal developmental pathways. Natural variation at the FLOWERING H (FLH) locus has previously been described, with alleles present in the Cape Verde Islands accession causing early flowering, particularly after vernalization. The mechanism of FLH-induced early flowering is not understood. Here, the integration of FLH activity into the known flowering time pathways is described using molecular and genetic approaches. The identification of molecular markers that co-segregated with the FLH locus allowed the generation of multiple combinations of FLH alleles with mutations in flowering time genes in different flowering pathways. Combining an early flowering FLH allele with mutations in vernalization pathway genes that regulate FLC expression revealed that FLH appears to act in parallel to FLC. Surprisingly, the early flowering allele of FLH requires the floral integrator FD, but not FT, to accelerate flowering. This suggests a model in which some alleles of FLH are able to affect the FD-dependent activity of the floral activator complex. PMID- 23667043 TI - Introduction of the rice CYP714D1 gene into Populus inhibits expression of its homologous genes and promotes growth, biomass production and xylem fibre length in transgenic trees. AB - The rice (Oryza sativa) OsCYP714D1 gene (also known as EUI) encodes a cytochrome P450 monooxygenase which functions as a gibberellin (GA)-deactivating enzyme, catalysing 16alpha, 17-epoxidation of non-13-hydroxylated GAs. To understand whether it would also reduce the production of active GAs and depress the growth rate in transgenic trees, we constitutively expressed OsCYP714D1 in the aspen hybrid clone Populus alba*P. berolinensis. Unexpectedly, ectopic expression of OsCYP714D1 in aspen positively regulated the biosynthesis of GAs, including the active GA1 and GA4, leading to promotion of the growth rate and biomass production in transgenic plants. Transgenic lines which showed significant expression of the introduced OsCYP714D1 gene accumulated a higher GA level and produced more numerous and longer xylem fibres than did the wild-type plants. Quantitative real-time PCR indicated that transcription of most homologous PtCYP714 genes was suppressed in these transgenic lines. Therefore, the promoted GA and biomass production in transgenic trees constitutively expressing OsCYP714D1 is probably attributed to the down-regulated expression of the native PtCYP714 homologues involved in the GA biosynthesis pathway, although their precise functions are yet to be further elucidated. PMID- 23667044 TI - C-opsin expressing photoreceptors in echinoderms. AB - Today's progress in molecular analysis and, in particular, the increased availability of genome sequences have enabled us to investigate photoreceptor cells (PRCs) in organisms that were formerly inaccessible to experimental manipulation. Our studies of marine non-chordate deuterostomes thus aim to bridge a gap of knowledge regarding the evolution of deuterostome PRCs prior to the emergence of vertebrates' eyes. In this contribution, we will show evidence for expression of a c-opsin photopigment, which, according to our phylogenetic analysis, is closely related to an assemblage of chordate visual c-opsins. An antibody raised against sea urchins' c-opsin protein (Sp-Opsin1) recognizes epitopes in a variety of tissues of different echinoderms. While in sea urchins this c-opsin is expressed in locomotory and buccal tube feet, spines, pedicellaria, and epidermis, in brittlestars and starfish we found the immuno reaction to be located exclusively in cells within the animals' spines. Structural characteristics of these c-opsin+ PRC types include the close vicinity/connection to nerve strands and a, so far unexplored, conspicuous association with the animals' calcite skeleton, which previously has been hypothesized to play a role in echinoderm photobiology. These features are discussed within the context of the evolution of photoreceptors in echinoderms and in deuterostomes generally. PMID- 23667045 TI - Expression dynamics and protein localization of rhabdomeric opsins in Platynereis larvae. AB - The larval stages of polychaete annelids are often responsive to light and can possess one to six eyes. The early trochophore larvae of the errant annelid Platynereis dumerilii have a single pair of ventral eyespots, whereas older nectochaete larvae have an additional two pairs of dorsal eyes that will develop into the adult eyes. Early Platynereis trochophores show robust positive phototaxis starting on the first day of development. Even though the mechanism of phototaxis in Platynereis early trochophore larvae is well understood, no photopigment (opsin) expression has yet been described in this stage. In late trochophore larvae, a rhabdomeric-type opsin, r-opsin1, expressed in both the eyespots and the adult eyes has already been reported. Here, we identify another Platynereis rhabdomeric opsin, r-opsin3, that is expressed in a single photoreceptor in the eyespots in early trochophores, suggesting that it mediates early larval phototaxis. We also show that r-opsin1 and r-opsin3 are expressed in adjacent photoreceptor cells in the eyespots in later stages, indicating that a second eyespot-photoreceptor differentiates in late trochophore larvae. Using serial transmission electron microscopy (TEM), we identified and reconstructed both photoreceptors and a pigment cell in the late larval eyespot. We also characterized opsin expression in the adult eyes and found that the two opsins co express there in several photoreceptor cells. Using antibodies recognizing r opsin1 and r-opsin3 proteins, we demonstrate that both opsins localize to the rhabdomere in all six eyes. In addition, we found that r-opsin1 mRNA is localized to, and translated in, the projections of the adult eyes. The specific changes we describe in opsin transcription and translation and in the cellular complement suggest that the six larval eyes undergo spectral and functional maturation during the early planktonic phase of the Platynereis life cycle. PMID- 23667046 TI - Propulsive forces of mudskipper fins and salamander limbs during terrestrial locomotion: implications for the invasion of land. AB - The invasion of land was a pivotal event in vertebrate evolution that was associated with major appendicular modifications. Although fossils indicate that the evolution of fundamentally limb-like appendages likely occurred in aquatic environments, the functional consequences of using early digited limbs, rather than fins, for terrestrial propulsion have had little empirical investigation. Paleontological and experimental analyses both have led to the proposal of an early origin of "hind limb-driven" locomotion among tetrapods or their ancestors. However, the retention of a pectoral appendage that had already developed terrestrial adaptations has been proposed for some taxa, and few data are available from extant functional models that can provide a foundation for evaluating the relative contributions of pectoral and pelvic appendages to terrestrial support among early stem tetrapods. To examine these aspects of vertebrate locomotor evolution during the invasion of land, we measured three dimensional ground reaction forces (GRFs) produced by isolated pectoral fins of mudskipper fishes (Periophthalmus barbarus) during terrestrial crutching, and compared these to isolated walking footfalls by the forelimbs and hind limbs of tiger salamanders (Ambystoma tigrinum), a species with subequally-sized limbs that facilitate comparisons to early tetrapods. Pectoral appendages of salamanders and mudskippers exhibited numerous differences in GRFs. Compared with salamander forelimbs, isolated fins of mudskippers bear lower vertical magnitudes of GRFs (as a proportion of body weight), and had GRFs that were oriented more medially. Comparing the salamanders' forelimbs and hind limbs, although the peak net GRF occurs later in stance for the forelimb, both limbs experience nearly identical mediolateral and vertical components of GRF, suggesting comparable contributions to support. Thus, forelimbs could also have played a significant locomotor role among basal tetrapods that had limbs of sub-equal size. However, the salamander hind limb and mudskipper pectoral fin had a greater acceleratory role than did the salamander forelimb. Together, data from these extant taxa help to clarify how structural change may have influenced locomotor function through the evolutionary invasion of land by vertebrates. PMID- 23667047 TI - Nuclear magnetic resonance spectroscopy of the circadian clock of cyanobacteria. AB - The most well-understood circadian clock at the level of molecular mechanisms is that of cyanobacteria. This overview is on how solution-state nuclear magnetic resonance (NMR) spectroscopy has contributed to this understanding. By exciting atomic spin-½ nuclei in a strong magnetic field, NMR obtains information on their chemical environments, inter-nuclear distances, orientations, and motions. NMR protein samples are typically aqueous, often at near-physiological pH, ionic strength, and temperature. The level of information obtainable by NMR depends on the quality of the NMR sample, by which we mean the solubility and stability of proteins. Here, we use examples from our laboratory to illustrate the advantages and limitations of the technique. PMID- 23667048 TI - Long-term functional outcomes of resected tarsal coalitions. AB - BACKGROUND: There are few long-term studies evaluating tarsal coalition resections. The purpose of this study was to compare patient outcomes following resection of calcaneonavicular (CN) and talocalcaneal (TC) bars and to determine the relationship between the extent of a coalition and the outcome of resection. METHODS: Patients younger than 18 years receiving resection for symptomatic tarsal coalition (1991-2004 inclusive) were eligible to participate. Follow-up evaluation included clinical examination to assess range of motion and self reported functional outcome questionnaires. Two validated functional scales were used: the American Academy of Orthopaedic Surgeons (AAOS) Foot and Ankle Module, and the Foot Function Index (FFI). Twenty-four patients with 32 tarsal coalition resections (19 CN and 13 TC feet) were included in this study. For CN and TC patients, the mean age at the time of surgery was 11.8 +/- 1.1 and 11.9 +/- 2.5 years, and the mean age at follow-up was 27.1 +/- 1.1 and 25.0 +/- 2.5 years, respectively. RESULTS: Inversion and eversion were significantly less for TC feet when compared with CN (P = .03 and P = .01, respectively). No difference was noted between the CN and TC groups with respect to outcome scores. Furthermore, no association was noted between the size of TC coalition or hindfoot valgus angle with respect to outcome scores. CONCLUSION: Resected CN and TC bars behaved similarly in the long term in terms of function and patient satisfaction. Favorable results were attained when resections were performed on TC coalitions that were greater than 50% of the posterior facet and hindfoot valgus angles greater than 16 degrees. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 23667049 TI - Rotational malreduction of the syndesmosis: reliability and accuracy of computed tomography measurement methods. AB - BACKGROUND: Computed tomography (CT)-based indices may be superior to plain radiographs in determining the adequacy of reduction following operative fixation of the syndesmosis in unstable ankle fractures. This study assessed the reliability and accuracy of four CT-based methods for measurement of rotational malreduction of the fibula. METHODS: A simulated Weber C ankle fracture was created by performing an osteotomy in 9 cadaver ankles. The fibula was rotated and fixed in neutral (0 degrees) and 10 to 30 degrees of internal and external rotation. Fifty-two CT images at the level of the syndesmosis were obtained in neutral and rotated positions and presented in random order to 3 independent observers. Measurements were made using commercial imaging software and 4 methods for interpreting CT scans. Interobserver reliability and accuracy were assessed and compared. RESULTS: Methods 1 and 4 showed high anatomic variability. Methods 1, 2, and 4 had a test-retest repeatability of about 15 degrees. Method 1 varied erratically with direction and degree of malrotation (R (2) = 0.15) and did not permit specification of a neutral range. Method 2 varied consistently and systematically with direction and degree of malrotation (R (2) = 0.88). Receiver operating characteristic curve analysis indicated that method 2 identified malrotation better than did the other methods. Methods 3 and 4 were somewhat more difficult to perform. CONCLUSIONS: Method 2, the angle between the tangent of the anterior tibial surface and the bisection of the vertical midline of the fibula at the level of the incisura, was fairly reliable and accurate and had greater ease of measurement compared with the other methods that were tested. CLINICAL RELEVANCE: This study demonstrated that assessment of malrotation of fibular fractures by CT scan can be difficult. We believe that of the 4 methods tested in this study, method 2, the angle between the tangent of the anterior tibial surface and the bisection of the vertical midline of the fibula at the level of the incisura, was the most useful. PMID- 23667050 TI - Conservation genetics in action: protecting diversity through innovative education programs in Madagascar, one of the world's environmental hotspots. PMID- 23667051 TI - Genetic diversity of fluorescent proteins in Caribbean agariciid corals. AB - The fluorescent protein (FP) gene family is a highly diverse group of proteins whose expression govern color diversity in corals. Here, we examine the genetic diversity of FPs and the extent to which it can be used to assess phylogenetic relationships within the coral genus Agaricia. Tissue samples were collected throughout the Florida Keys from a wide range of phenotypes within the genus Agaricia (A. agaricites [n = 7], A. fragilis [n = 13], and A. lamarcki [n = 2]), as well as the confamilial species Helioseris cucullata (n = 3). Primers were developed from published cDNA sequences to amplify a region of coding and noncoding sequences of FPs. Cloning reactions were performed to capture the multiple copies of FPs and allele diversity. In the resulting 116 cloned sequences, we identified a 179-bp coding region for phylogenetic analysis. Three distinct clades were found in all 3 species of Agaricia, potentially representing 3 copies of the FP gene. Of the 3 gene copies, 2 contain distinct subclades that display reciprocal monophyly between A. agaricites and A. fragilis, whereas A. lamarcki is polyphyletic. Further resolution of the species phylogeny is necessary to fully understand how genetic diversity within this gene family is distributed among taxa and habitats. PMID- 23667052 TI - Genetic variation and differentiation of bison (Bison bison) subspecies and cattle (Bos taurus) breeds and subspecies. AB - The genetic relationship of American plains bison (Bison bison bison) and wood bison (Bison bison athabascae) was quantified and compared with that among breeds and subspecies of cattle. Plains bison from 9 herds (N = 136), wood bison from 3 herds (N = 65), taurine cattle (Bos taurus taurus) from 14 breeds (N = 244), and indicine cattle (Bos taurus indicus) from 2 breeds (N = 53) were genotyped for 29 polymorphic microsatellite loci. Bayesian cluster analyses indicate 3 groups, 2 of which are plains bison and 1 of which is wood bison with some admixture, and genetic distances do not show plains bison and wood bison as distinct groups. Differentiation of wood bison and plains bison is also significantly less than that of cattle breeds and subspecies. These and other genetic data and historical interbreeding of bison do not support recognition of extant plains bison and wood bison as phylogenetically distinct subspecies. PMID- 23667053 TI - HIF prolyl hydroxylase 2 (PHD2) is a critical regulator of hematopoietic stem cell maintenance during steady-state and stress. AB - Hypoxia is a prominent feature in the maintenance of hematopoietic stem cell (HSC) quiescence and multipotency. Hypoxia-inducible factor (HIF) prolyl hydroxylase domain proteins (PHDs) serve as oxygen sensors and may therefore regulate this system. Here, we describe a mouse line with conditional loss of HIF prolyl hydroxylase 2 (PHD2) in very early hematopoietic precursors that results in self-renewal of multipotent progenitors under steady-state conditions in a HIF1alpha- and SMAD7-dependent manner. Competitive bone marrow (BM) transplantations show decreased peripheral and central chimerism of PHD2 deficient cells but not of the most primitive progenitors. Conversely, in whole BM transfer, PHD2-deficient HSCs replenish the entire hematopoietic system and display an enhanced self-renewal capacity reliant on HIF1alpha. Taken together, our results demonstrate that loss of PHD2 controls the maintenance of the HSC compartment under physiological conditions and causes the outcompetition of PHD2 deficient hematopoietic cells by their wild-type counterparts during stress while promoting the self-renewal of very early hematopoietic progenitors. PMID- 23667054 TI - PEAR1 attenuates megakaryopoiesis via control of the PI3K/PTEN pathway. AB - Platelet endothelial aggregation receptor-1 (PEAR1) participates in platelet aggregation via sustaining alphaIIbbeta3 activation. To investigate the role of PEAR1 in platelet formation, we monitored and manipulated PEAR1 expression in vitro in differentiating human CD34(+) hematopoietic stem cells and in vivo in zebrafish embryos. PEAR1 expression rose during CD34(+) cell differentiation up to megakaryocyte (MK) maturation. Two different lentiviral short hairpin knockdowns of PEAR1 did not affect erythropoiesis in CD34(+) cells, but increased colony-forming unit MK cell numbers twofold vs control in clonogenic assays, without substantially modifying MK maturation. The PEAR1 knockdown resulted in a twofold reduction of the phosphatase and TENsin homolog (PTEN) phosphatase expression and modulated gene expression of several phosphatidylinositol 3-kinase (PI3K)-Akt and Notch pathway genes. In zebrafish, Pear1 expression increased progressively during the first 3 days of embryo development. Both ATG and splice blocking PEAR1 morpholinos enhanced thrombopoiesis, without affecting erythropoiesis. Western blots of 3-day-old Pear1 knockdown zebrafish revealed elevated Akt phosphorylation, coupled to transcriptional downregulation of the PTEN isoform Ptena. Neutralization by morpholinos of Ptena, but not of Ptenb, phenocopied the Pear1 zebrafish knockdown and triggered enhanced Akt phosphorylation and thrombocyte formation. In summary, this is the first demonstration that PEAR1 influences the PI3K/PTEN pathway, a critical determinant of Akt phosphorylation, itself controlling megakaryopoiesis and thrombopoiesis. PMID- 23667055 TI - Megakaryocytes promote murine osteoblastic HSC niche expansion and stem cell engraftment after radioablative conditioning. AB - Successful hematopoietic stem cell (HSC) transplantation requires donor HSC engraftment within specialized bone marrow microenvironments known as HSC niches. We have previously reported a profound remodeling of the endosteal osteoblastic HSC niche after total body irradiation (TBI), defined as relocalization of surviving megakaryocytes to the niche site and marked expansion of endosteal osteoblasts. We now demonstrate that host megakaryocytes function critically in expansion of the endosteal niche after preparative radioablation and in the engraftment of donor HSC. We show that TBI-induced migration of megakaryocytes to the endosteal niche depends on thrombopoietin signaling through the c-MPL receptor on megakaryocytes, as well as CD41 integrin-mediated adhesion. Moreover, niche osteoblast proliferation post-TBI required megakaryocyte-secreted platelet derived growth factor-BB. Furthermore, blockade of c-MPL-dependent megakaryocyte migration and function after TBI resulted in a significant decrease in donor HSC engraftment in primary and competitive secondary transplantation assays. Finally, we administered thrombopoietin to mice beginning 5 days before marrow radioablation and ending 24 hours before transplant to enhance megakaryocyte function post-TBI, and found that this strategy significantly enhanced donor HSC engraftment, providing a rationale for improving hematopoietic recovery and perhaps overall outcome after clinical HSC transplantation. PMID- 23667056 TI - Smoking cessation counseling for Asian immigrants with serious mental illness: using RE-AIM to understand challenges and lessons learned in primary care behavioral health integration. AB - Engagement in modifiable risk behaviors, such as tobacco use, substantially contributes to early mortality rates in individuals with serious mental illness (SMI). There is an alarmingly high prevalence of tobacco use among subgroups of Asian Americans, such as immigrants and individuals with SMI, yet there are no empirically supported effective smoking cessation interventions that have been tailored to meet the unique cultural, cognitive, and psychological needs of Asian immigrants with SMI. In this article, we share the experiences of clinicians in the delivery of smoking cessation counseling to Asian American immigrants with SMI, in the context of an Asian-focused integrated primary care and behavioral health setting. Through a qualitative analysis of clinician perspectives organized with the RE-AIM framework, we outline challenges, lessons learned, and promising directions for delivering smoking cessation counseling to Asian American immigrant clients with SMI. PMID- 23667057 TI - Smoking among Asian Americans: acculturation and gender in the context of tobacco control policies in New York City. AB - New York City (NYC) has experienced significant decline in smoking prevalence since its antismoking campaign; however, the rates among NYC's Asian communities have persisted since 2002. Using combined data from the REACH US Risk Factor Survey (2009-2011), this article examined ethnic- and gender-specific smoking behaviors and the effects of acculturation and location of residence on cigarette smoking behavior among Chinese, Korean, Asian Indians, and other Asian Americans. Results indicated that current smoking prevalence was higher for men than women among all four groups. Korean men and women had the highest current smoking rates whereas Indians had the lowest among the four subgroups. Asian American women reporting speaking only English at home had higher current smoking prevalence, but this was not observed for men. Living in Sunset Park, an emerging Asian ethnic enclave, was associated with higher odds of smoking than living in other locations in NYC. In conclusion, smoking prevalence varied across gender and ethnic subgroups among Asian Americans in NYC. A "one-size-fits-all" type of intervention strategy for "pan-Asians" could not be effective. Community-based culturally appropriate and gender-specific interventions for smoking cessation might be an option for Asian Americans residing in linguistically isolated ethnic enclaves. PMID- 23667058 TI - Eliminating tobacco disparities among native Hawaiian Pacific Islanders through policy change: the role of community-based organizations. AB - Although cigarette smoking in the general U.S. population has decreased considerably over the past several decades, prevalence rates among Native Hawaiian Pacific Islanders (NHPI) have remained elevated by comparison with other groups. The aggregation of NHPI smoking data with that of Asians has drawn attention away from the serious smoking problems that NHPIs experience, thus, limiting funding, programs, and policies to reduce tobacco-related health disparities in their communities. In California, community-based organizations (CBOs) have played a major role in supporting the state's comprehensive tobacco control program, which is arguably one of the most successful in the nation. In this commentary, we describe the tobacco control activities of five NHPI-serving CBOs in Southern California and how they have provided anti-tobacco education for thousands of Native Hawaiians, Chamorros, Marshallese, Samoans, Tongans, and other Pacific Islander subgroups, and used advocacy and coalition building to promote smoke-free environment policies in their communities. The concerted efforts of the CBOs and their community members have made vital contributions to the reduction of tobacco-related disparities for NHPI populations in California. PMID- 23667059 TI - Offering acupuncture as an adjunct for tobacco cessation: a community clinic experience. AB - Disparities in smoking rates remain prominent within Asian Americans. Medical pluralism and cultural tailoring may enhance Asian Americans engaging with tobacco cessation assistance. We conducted a retrospective analysis of a community clinic's smoking cessation program targeting a Chinese population that offered acupuncture, nicotine replacement therapy (NRT), and counseling from 2007 to 2010. Most participants used acupuncture, with about half choosing acupuncture and NRT, followed by more than 40% choosing acupuncture only; few chose NRT only. Tobacco cessation rates at 6 months were relatively high for the acupuncture + NRT group and only acupuncture group (37.7% vs. 28.9%). In comparing tobacco reduction >50% from baseline with an expanded only NRT group, the acupuncture + NRT group had a higher odds ratio than the only acupuncture group, which had a lower odds ratio. Our evaluation of this real-world community program offering acupuncture as a cultural adjunct to a tobacco cessation program suggests that acupuncture might help with engagement by Chinese American male smokers into a tobacco cessation program that offers counseling and NRT. Future larger studies should further evaluate the efficacy of offering acupuncture in combination with NRT on the outcomes of cessation and reduction. PMID- 23667061 TI - Comment: Functional neuroimaging may quantify spinal cord demyelinating disease. PMID- 23667060 TI - Spinal cord tract diffusion tensor imaging reveals disability substrate in demyelinating disease. AB - OBJECTIVE: This study assessed the tissue integrity of major cervical cord tracts by using diffusion tensor imaging (DTI) to determine the relationship with specific clinical functions carried by those tracts. METHODS: This was a cross sectional study of 37 patients with multiple sclerosis or neuromyelitis optica with remote cervical cord disease. Finger vibratory thresholds, 25-foot timed walk (25FTW), 9-hole peg test (9HPT), and Expanded Disability Status Scale were determined. DTI covered cervical regions C1 through C6 with 17 5-mm slices (0.9 * 0.9 mm in-plane resolution). Regions of interest included posterior columns (PCs) and lateral corticospinal tracts (CSTs). Hierarchical linear mixed-effect modeling included covariates of disease subtype (multiple sclerosis vs neuromyelitis optica), disease duration, and sex. RESULTS: Vibration thresholds were associated with radial diffusivity (RD) and fractional anisotropy (FA) in the PCs (both p < 0.01), but not CSTs (RD, p = 0.29; FA, p = 0.14). RD and FA in PCs, and RD in CSTs were related to 9HPT (each p < 0.0001). 25FTW was associated with RD and FA in PCs (p < 0.0001) and RD in CSTs (p = 0.008). Expanded Disability Status Scale was related to RD and FA in PCs and CSTs (p < 0.0001). Moderate/severe impairments in 9HPT (p = 0.006) and 25FTW (p = 0.017) were more likely to show combined moderate/severe tissue injury within both PCs and CSTs by DTI. CONCLUSIONS: DTI can serve as an imaging biomarker of spinal cord tissue injury at the tract level. RD and FA demonstrate strong and consistent relationships with clinical outcomes, specific to the clinical modality. PMID- 23667062 TI - Brain reserve and cognitive reserve in multiple sclerosis: what you've got and how you use it. AB - OBJECTIVE: We first tested the brain reserve (BR) hypothesis in multiple sclerosis (MS) by examining whether larger maximal lifetime brain volume (MLBV; determined by genetics) protects against disease-related cognitive impairment, and then investigated whether cognitive reserve (CR) gained through life experience (intellectually enriching leisure activities) protects against cognitive decline independently of MLBV (BR). METHODS: Sixty-two patients with MS (41 relapsing-remitting MS, 21 secondary progressive MS) received MRIs to estimate BR (MLBV, estimated with intracranial volume [ICV]) and disease burden (T2 lesion load; atrophy of gray matter, white matter, thalamus, and hippocampus). Early-life cognitive leisure was measured as a source of CR. We assessed cognitive status with tasks of cognitive efficiency and memory. Hierarchical regressions were used to investigate whether higher BR (ICV) protects against cognitive impairment, and whether higher CR (leisure) independently protects against cognitive impairment over and above BR. RESULTS: Cognitive status was positively associated with ICV (R(2) = 0.066, p = 0.017). An ICV * disease burden interaction (R(2) = 0.050, p = 0.030) revealed that larger ICV attenuated the impact of disease burden on cognition. Controlling for BR, higher education (R(2) = 0.047, p = 0.030) and leisure (R(2) = 0.090, p = 0.001) predicted better cognition. A leisure * disease burden interaction (R(2) = 0.037, p = 0.030) showed that leisure independently attenuated the impact of disease burden on cognition. Follow-up analyses revealed that BR protected against cognitive inefficiency, not memory deficits, whereas CR was more protective against memory deficits than cognitive inefficiency. CONCLUSION: We provide evidence of BR in MS, and show that CR independently protects against disease related cognitive decline over and above BR. Lifestyle choices protect against cognitive impairment independently of genetic factors outside of one's control. PMID- 23667064 TI - One-stage repair of aberrant left brachiocephalic artery and coarctation of the aorta in right aortic arch. AB - The combination of right aortic arch with aberrant left brachiocephalic artery and aortic coarctation is very rare. Here, we report the case of a 3.1-kg neonate with multiple malformations who received detailed preoperative anatomical definition by chest computed tomography (CT) scan and eventually underwent one stage repair at the age of 17 days. The surgical technique included left brachiocephalic artery detachment and its end-to-end anastomosis to the branch of a monofurcated pulmonary homograft used to treat the aortic arch coarctation simultaneously. Postoperative control chest CT scan performed 3 months postoperatively revealed optimal repair. Considerations on imaging and surgical technique are reported. PMID- 23667065 TI - Heart transplantation in a patient with recurrent early extensive endocarditis. AB - Active valvular endocarditis could be considered a contraindication to heart transplantation. Nevertheless, there have been some reports of success with this form of treatment, despite the characteristics of the infection and its aggressive nature. Here, we describe the case of a patient with acute bicuspid aortic valvular endocarditis caused by Staphylococcus aureus and with a periannular abscess. Cryopreserved aortic homograft replacement of the aortic root was initially carried out, in addition to debridement and reconstruction of the interventricular septum with a pericardial patch. Early recurrence occurred, however, with extensive tissue destruction, a periaortic abscess and involvement of multiple valves, associated with severe sepsis. In view of the failure of 'conventional' surgery, an emergency heart transplantation was decided on after discussing the case with the Spanish National Transplant Organization (ONT), because of the theoretical contraindication of transplantation in this case. Transplantation was finally carried out after a waiting period of 3 days, in emergency code conditions, and the postoperative course proved uneventful, with no reinfection during the follow-up period. The present case suggests that heart transplantation may be an alternative option in patients suffering aggressive endocarditis with extensive involvement of the heart structures. PMID- 23667063 TI - Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein neuropathy. AB - OBJECTIVE: To determine whether rituximab 375 mg/m(2) was efficacious in patients with immunoglobulin M (IgM) anti-myelin-associated glycoprotein antibody demyelinating neuropathy (IgM anti-MAG demyelinating neuropathy). METHODS: Fifty four patients with IgM anti-MAG demyelinating neuropathy were enrolled in this randomized, double-blind, placebo-controlled trial. The inclusion criteria were inflammatory neuropathy cause and treatment (INCAT) sensory score (ISS) >=4 and visual analog pain scale >4 or ataxia score >=2. The primary outcome was mean change in ISS at 12 months. RESULTS: Twenty-six patients were randomized to a group receiving 4 weekly infusions of 375 mg/m(2) rituximab, and 28 patients to placebo. Intention-to-treat analysis, with imputation of missing ISS values by the last observation carried forward method, showed a lack of mean change in ISS at 12 months, 1.0 +/- 2.7 in the rituximab group, and 1.0 +/- 2.8 in the placebo group. However, changes were observed, in per protocol analysis at 12 months, for the number of patients with an improvement of at least 2 points in the INCAT disability scale (p = 0.027), the self-evaluation scale (p = 0.016), and 2 subscores of the Short Form-36 questionnaire. CONCLUSIONS: Although primary outcome measures provide no evidence to support the use of rituximab in IgM anti MAG demyelinating neuropathy, there were improvements in several secondary outcomes in per protocol analysis. LEVEL OF EVIDENCE: This study provides Class I evidence that rituximab is ineffective in improving ISS in patients with IgM anti MAG demyelinating neuropathy. PMID- 23667066 TI - Impact of major non-cardiac complications on outcome following cardiac surgery procedures: logistic regression analysis in a very recent patient cohort. AB - OBJECTIVES: In this study, we sought to analyse the incidence of major non cardiac complications and their impact on survival following cardiac surgery procedures in a contemporary patient cohort. We further determined independent predictors of perioperative mortality and created a logistic regression model for prediction of outcome after the occurrence of these complications. METHODS: Prospectively collected data of 5318 consecutive adult patients (mean age 68.9+/ 11.0 years; 29.3% [n=1559] female) undergoing cardiac surgery from January 2009 to May 2012 were retrospectively analysed. Outcome measures were six major non cardiac complications including respiratory failure, dialysis-dependent renal failure, deep sternal wound infection (DSWI), cerebrovascular accident (CVA), gastrointestinal complications (GIC) and sepsis and their impact on perioperative mortality and hospital length of stay using multivariate regression models. The discriminatory power was evaluated by calculating the area under the receiver operating characteristic curves (C statistic). RESULTS: A total of 1321 complications were observed in 846 (15.9%) patients: respiratory failure (n=432; 8.1%), dialysis-dependent renal failure (n=295; 5.5%), GIC (n=154; 2.9%), CVA (n=151; 2.8%), DSWI (n=146; 2.7%) and sepsis (n=143; 2.7%). Perioperative mortality was 17.0% in patients with at least one major non-cardiac complication and correlated with the number of complications (single, 9.7%; n=53/549; double, 24.0%; n=44/183; >=3, 41.2%; n=47/114, P<0.001). Six preoperative and four postoperative independent predictors of operative mortality were identified (age (odds ratio [OR] 1.8; 95% confidence interval [CI] 1.3-2.4), peripheral vascular disease (OR 2.6; 95% CI 1.6-4.2), pulmonary hypertension (OR 2.7; 95% CI 1.5 4.9), atrial fibrillation (OR 1.5; 95% CI 1.0-2.3), emergency (OR 5.0; 95% CI 3.4 7.2), other procedures than CABG (OR 1.5; 95% CI 1.0-2.1), postoperative dialysis (OR 4.0; 95% CI 2.6-6.1), sepsis (OR 3.4; 95% CI 2.0-5.6), respiratory failure (OR 3.2; 95% CI 2.2-4.9), GIC (OR 3.2; 95% CI 1.9-5.3)) and included in the logistic model, which accurately predicted outcome (C statistic, 0.892; 95% CI 0.868-0.916). Length of hospital stay was significantly increased according to the number of complications (single: median 15 (IQR 10-24) days, double: 16 (IQR 8-28) days, >=3: 20 (IQR 13-39) days, P<0.001). CONCLUSIONS: With a worsening in the risk profile of patients undergoing cardiac surgery, an increasing number of patients develop major complications leading to increased length of stay and mortality, which is correlated to the number and severity of these complications. Our predictive model based on preoperative and postoperative variables allowed us to determine with accuracy the perioperative mortality in critically ill patients after cardiac surgery. PMID- 23667067 TI - Prothrombin complex concentrate for warfarin-induced bleeding in a patient with a mechanical aortic valve. AB - Reversal of anticoagulation-induced bleeding in the perioperative period can be challenging, particularly with an unstable patient with a mechanical valve. We present a case of life-threatening bleeding successfully managed with a prothrombin complex concentrate as an alternative to fresh frozen plasma. PMID- 23667068 TI - What is the utility of preoperative frailty assessment for risk stratification in cardiac surgery? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether frailty scoring can be used either separately or combined with conventional risk scores to predict survival and complications. Five hundred and thirty-five papers were found using the reported search, of which nine cohort studies represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. There is a paucity of evidence, as advanced age is a criterion for exclusion in most randomized controlled trials. Conventional models of risk following cardiac surgery are not calibrated to accurately predict the outcomes in the elderly and do not currently include frailty parameters. There is no universally accepted definition for frailty, but it is described as a physiological decline in multiple organ systems, decreasing a patient's capacity to withstand the stresses of surgery and disease. Frailty is manifest clinically as deficits in functional capacity, such as slow ambulation and impairments in the activities of daily living (ADL). Analysis of predictive models using area under receiver operating curves (AUC) suggested only a modest benefit by adding gait speed to a Society of Thoracic Surgeons (STS score)-Predicted Risk of Mortality or Major Morbidity (PROM) risk score (AUC 0.04 mean difference). However, a specialist frailty assessment tool named FORECAST was found to be superior at predicting adverse outcomes at 1 year compared with either EuroSCORE or STS score (AUC 0.09 mean difference). However, risk models incorporating frailty parameters require further validation and have not been widely adopted. Routine collection of objective frailty measures such as 5-metre walk time and ADL assessment will help to provide data to develop new risk-assessment models to facilitate risk stratification and clinical decision-making in elderly patients. Based on the best evidence currently available, we conclude that frailty is an independent predictor of adverse outcome following cardiac surgery or transcatheter aortic valve implantation, increasing the risk of mortality 2- to 4 fold compared with non-frail patients. PMID- 23667069 TI - Immediate rescue operations after failed diagnostic or therapeutic cardiac catheterization procedures. AB - OBJECTIVES: Although rare, life-threatening complications requiring emergency cardiac surgery do occur after diagnostic and therapeutic cardiac catheterization procedures. The operative mortality has been persistently reported to remain high. The purpose of this observational study was to evaluate and report the outcomes, with particular emphasis on early mortality, of these risky operations that were performed in a single highly specialized cardiac centre. METHODS: Between June 1997 and August 2007, 100 consecutive patients, 13 after diagnostic complicated cardiac catheterization (0.038% of 34,193 angiographies) and 87 after crashed percutaneous coronary intervention (PCI; 0.56% of 15,544 PCIs), received emergency operations at the Feiring Heart Center. In the same period, 10,192 other patients underwent open cardiac surgery. Early outcome data were analysed and compared between the cohorts. Follow-up was 100% complete. RESULTS: The preoperative status of the 100 patients was that 4 had ongoing external cardiac massage, 24 were in cardiogenic shock, 32 had frank enduring ST-segment infarction but without shock and 40 had threatened acute myocardial infarction. There was 1% (1 patient) 30-day mortality in the study group, which is equal (0.9%, P=0.60) to that of all other operations. Postoperative myocardial infarction and prolonged ventilator use were significantly higher in the crash group, whereas the rate of stroke, renal failure, reopening for bleeding and mediastinitis were similar between the groups. CONCLUSIONS: With rapid transfer to an operation room, minimizing the time of warm myocardial ischaemia, and by performing complete coronary revascularization, it is possible to obtain equally low operative mortality in patients with life-threatening cardiac catheterization associated complications, as is the case with open cardiac operations in general. PMID- 23667070 TI - Adult acute rhinosinusitis. PMID- 23667071 TI - Associations between the organisation of stroke services, process of care, and mortality in England: prospective cohort study. AB - OBJECTIVE: To estimate the relations between the organisation of stroke services, process measures of care quality, and 30 day mortality in patients admitted with acute ischaemic stroke. DESIGN: Prospective cohort study. SETTING: Hospitals (n=106) admitting patients with acute stroke in England and participating in the Stroke Improvement National Audit Programme and 2010 Sentinel Stroke Audit. PARTICIPANTS: 36,197 adults admitted with acute ischaemic stroke to a participating hospital from 1 April 2010 to 30 November 2011. MAIN OUTCOME MEASURE: Associations between process of care (the assessments, interventions, and treatments that patients receive) and 30 day all cause mortality, adjusting for patient level characteristics. Process of care was measured using six individual measures of stroke care and summarised into an overall quality score. RESULTS: Of 36,197 patients admitted with acute ischaemic stroke, 25,904 (71.6%) were eligible to receive all six care processes. Patients admitted to stroke services with high organisational scores were more likely to receive most (5 or 6) of the six care processes. Three of the individual processes were associated with reduced mortality, including two care bundles: review by a stroke consultant within 24 hours of admission (adjusted odds ratio 0.86, 95%confidence interval 0.78 to 0.96), nutrition screening and formal swallow assessment within 72 hours (0.83, 0.72 to 0.96), and antiplatelet therapy and adequate fluid and nutrition for first the 72 hours (0.55, 0.49 to 0.61). Receipt of five or six care processes was associated with lower mortality compared with receipt of 0-4 in both multilevel (0.74, 0.66 to 0.83) and instrumental variable analyses (0.62, 0.46 to 0.83). CONCLUSIONS: Patients admitted to stroke services with higher levels of organisation are more likely to receive high quality care as measured by audited process measures of acute stroke care. Those patients receiving high quality care have a reduced risk of death in the 30 days after stroke, adjusting for patient characteristics and controlling for selection bias. PMID- 23667072 TI - Problems of creating bone marrow donor registries in emerging economies. PMID- 23667073 TI - Autologous blood products in musculoskeletal medicine. PMID- 23667074 TI - Rescue boards are set up in England to deal with "significant deterioration" in A&E departments. PMID- 23667075 TI - Dynamic endoscopy of the equine upper airway--what is significant? PMID- 23667076 TI - Welsh Government stops work on its draft dog control Bill. PMID- 23667079 TI - Control of bovine TB: report puts risk-based trading on the agenda. PMID- 23667080 TI - Cloned calf offers hope for the future control of trypanosomosis. PMID- 23667081 TI - AHVLA censured for health and safety failings in handling samples. PMID- 23667082 TI - A third of pet owners find it 'nearly impossible' to combat fleas. PMID- 23667083 TI - Celebrating exceptional care to pets and owners. PMID- 23667084 TI - Firefighters get to grips with farm and other animals. PMID- 23667085 TI - Protecting farmed fish against disease. PMID- 23667086 TI - Rewarding contributions to animal welfare. PMID- 23667088 TI - High calf mortality due to idiopathic necrotising enteritis. PMID- 23667089 TI - Enteric nematodes and Sarcina-like bacteria in a brown long-eared bat. PMID- 23667090 TI - Serosurveillance of orbiviruses in wild cervids from Spain. PMID- 23667091 TI - SBV transmission. PMID- 23667092 TI - Help needed to stamp out sheep scab. PMID- 23667093 TI - Transcriptional expression of selected genes associated with excretion of carboxylic acids from aci mutants of Saccharomyces cerevisiae. AB - INTRODUCTION: Saccharomyces cerevisiae is an excellent model organism for studies of transcriptional regulation of metabolic processes in other eukaryotic cells including human cells. Cellular acid-base balance can be disturbed in pathologic situations such as renal acidosis or cancer. The extracellular pH of malignant solid tumors is acidic in the range of 6.5-6.9. EG07 and EG37 aci mutants of Saccharomyces cerevisiae excessively excrete carboxylic acids to glucose containing media or distilled water. The excreted acids are Krebs and/or glyoxylate cycle intermediates. The genes restoring the wild-type phenotype have function that does not easily explain theAci+ phenotype. MATERIAL/METHODS: In this study, using real-time PCR we measured relative mRNA expression, in the mutants compared to the wild-type strain, of selected genes associated with both carboxylic acid cycles and two cell transporters, Pma1 and Pdr12, of organic acids. RESULTS: Unexpectedly, we found that the relative expression of the selected Krebs cycle and glyoxylate cycle genes did not change significantly. However, the expression of the two transporter genes was strongly elevated in EG37 and moderately increased in EG07. CONCLUSION: These results indicate that the induction of the two cell transporterg enes plays an important role in acid excretion by the aci mutants. PMID- 23667094 TI - The inhibitory effects of polyphenols on skin UV immunosuppression . AB - Long-term exposure to UV radiation leads to skin ageing and may initiate carcinogenesis. In both cases immunosuppressive activity of UV radiation plays an important role. The aim of the study is to present polyphenols commonly seen in flora and their properties protecting the skin from the damaging influence of UV rays. Polyphenols are a group of compounds which are present in plants. Their common features are: the ring structure of a molecule, hydroxyl groups in the rings and a conjugated double bond system. Such structure makes polyphenols active antioxidants. They also demonstrate anti-immunosuppressive properties. PMID- 23667095 TI - [Autophagy and BNIP3 protein in tumorogenesis]. AB - Autophagy is a process necessary for maintaining cell homeostasis in physiological conditions, as well as during certain stresses like nutrients or oxygen deprivation. Autophagy also plays an essential role in tumorigenesis. It prevents cell transformation, but on the other hand, autophagy enables existing cancer cells to adapt to harmful conditions and increased glucose demand, supports maintaining of cellular metabolism and accelerates tumor growth. Among others, it refers to Ras-transformed cells. Recent research unveiled BNIP3 protein as one of the key players involved in autophagy. Although BNIP3 is classified as proapoptotic member of BH3-only subfamily, its proapoptotic activity is questionable. However, BNIP3 demonstrates ability to induce or stimulate autophagy and its specific variant--mitophagy. This paper aims to summarize the existing body of knowledge related to the role of BNIP3 in autophagy, as well as the importance of this process in tumorigenesis. In particular, we emphasize the relation between autophagy and BNIP3 expression induced by Ras oncogene. PMID- 23667096 TI - [Characteristics of T lymphocyte subpopulations]. AB - The paper describes the characteristics, receptor profile and functions of T lymphocyte subpopulations (helper, cytotoxic, regulatory, memory and others). Among T helper cells one can enumerate Th0, Th1, Th2, Th9, Th17, Th22, T(FH) and nTh2, while T cytotoxic cells include Tc, NKT, Tgammadelta, and T CD8alphaalpha (IEL). Among regulatory cells there are nTreg, iTreg, T(R)1, and iT(R)35, as well as T lymphocytes with CD8, such as CD8+CD122+, CD8+CD28-, and CD11c+CD8+. And among memory T cells there are Tcm and Tem. Moreover, there are some so-called other T cells, such as Tn (T alphabeta CD4+ and T alphabeta CD8+), T exhausted and T anergic. PMID- 23667097 TI - [Dermoscopy on subungual melanoma]. AB - Subungual melanoma is a rare, but one of the diagnostically most difficult variants of melanoma. Unfortunately, due to its late detection, lack of an early reaction from the patient and diagnosis in advanced stages, subungual melanoma is deemed as a prognostically unfavorable variant of this malignancy. Diagnosis of subungual melanoma is very difficult to establish merely on the basis of clinical examination due to the resemblance of subungual hematoma to melanocytic nevus, fungal or bacterial infections. Dermoscopy seems to be the ideal diagnostic tool in the differential diagnosis of this life-threatening disease. AIMS: To describe the basic aspects of dermoscopy of subungual melanoma and other conditions involving the nails. METHODS: Review of medical database PubMed for the literature of the last 10 years on the dermoscopic patterns of subungual melanoma and other subungual diseases. RESULTS: We collate the fundamental rules of performing dermoscopy in subungual melanoma, as well as basic dermoscopic features and diagnostic algorithms of selected subungual lesions requiring differentiation from melanoma. CONCLUSIONS: Dermoscopy is a safe, easily repeatable diagnostic method, and the knowledge of basic dermoscopic patterns of developing melanoma in subungual localization, along with the differential diagnosis of other diseases within the nail plate, will help not only dermatologists, but also the professionals of other specialties, such as surgeons, oncologists, orthopedists, and also general practitioners. PMID- 23667098 TI - [Innate immunity to infection in the lower female genital tract]. AB - Due to the contact with the external environment, the lower female genital tract is non-sterile. The innate immune system has evolved many mechanisms to protect vaginal tissues from pathogens at the same time allowing for survival of the comensal flora. Innate immunity in the lower female genital tract undergoes hormonal regulation. Estrogen and progesterone levels also influence the vaginal mucosal epithelium remodeling with the neutrophlis playing a crucial role, as the most numerous leukocytes in the vaginal tissue. Being exposed to the environment, the vaginal epithelium consists a physical barrier for pathogens, but it also shows the presence of MHC class I and pattern recognition receptors. By production of cytokines and chemokines, the vaginal epithelium attracts innate immune cells such as neutrophiles, macrophages, dendritic cells or NK cells. Vaginal comensal flora is another important mechanism of innate immunity by production of lactic acid and hydrogen peroxide, inhibiting pathogen's growth. Disturbances of vaginal microflora can result in pathogenic infections such as bacterial vaginosis or candidosis. Together with herpes genitalis, HPV infection, chlamydiosis, trichomatosis and gonorrhoea, vaginal infections increase the risk of acquiring another sexually transmitted disease, includig HIV due to the impaired mucosal integrity, facilitating for tissue penetration by pathogens and development of local inflammation. PMID- 23667099 TI - Tissue and swab culture in diabetic foot infections: neuropathic versus neuroischemic ulcers. AB - We evaluated the diagnostic performance of swabs versus tissue cultures in 28 diabetic patients with neuropathic (group A) and 22 diabetic patients with neuroischemic foot ulcer (group B) and the differences in bacterial isolates between the 2 groups. In group A, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of swab cultures for the diagnosis of infection were 100%, 40%, 88.5%, and 100%, respectively. In group B, the corresponding values were 100%, 22.2%, 65%, and 100%. In group A, sensitivity, specificity, PPV, and NPV of swab cultures for the identification of pathogens were 100%, 14.3%, 53.8%, and 100%, respectively. In group B, the corresponding values were 100%, 18.2%, 55%, and 100%. In each group, Staphylococcus aureus and Pseudomonas aeruginosa were the most common isolates. The number of isolates was significantly higher on swab versus tissue cultures only in group A (P = .033). No differences were observed between groups in number of isolates and colony forming units. In conclusion, swab cultures are highly sensitive but less specific and have an excellent NPV both in diabetic patients with neuropathic and in those with neuroischemic foot ulcer. There are no differences between the groups in microbial load. PMID- 23667100 TI - Training to measure ankle-brachial index at the undergraduate level: can it be successful? AB - We examined the effectiveness of teaching ankle-brachial index (ABI) measurement to medical students. ABI was estimated in 28 lower limbs by an experienced vascular surgeon. After a 2-week training course, 5 fourth-year students repeated the estimations and their results were compared with that of the trainer's. There was no difference in ABI values between trainees and trainer for subjects with mild-to-moderate peripheral arterial disease (PAD; 0.77 +/- 0.22 vs 0.77 +/- 0.19, respectively, P = .95). In the 4 normal limbs, ABI was 1.37 +/- 0.12 and 1.16 +/- 0.11, as measured by the trainer and the trainees, respectively (P < .00001). In subjects with severe PAD, trainees tended to overestimate ABI (P = .0002) in the beginning of the educational process, but this was no longer the case at a later stage of the training with no difference in ABI values between the 2 examiner groups (P = .09). In conclusion, training of medical students in ABI measurement can be helpful toward accurate estimation of PAD and merits further practice. PMID- 23667101 TI - Managing diabetic foot infection in India. AB - The burden of diabetic foot complications, in terms of both physical and socioeconomical constraints, poses a heavy challenge both to the patient and the physician, especially in developing countries, where the number of people living with diabetes is increasing at an alarming rate compared with the developed world. In developing countries like India, there are specific causes and risk factors that increase the burden of diabetic foot infections (DFIs), for example, sociocultural risk factors such as barefoot walking, using improper footwear, poor knowledge of foot care practices, lack of adequate and timely access to podiatry services, and poor health care resources. Management of DFI in light of these limitations is quite a challenge to health care professionals. Several techniques and strategies are required to address this problem and should be combined with a multidisciplinary team effort to reduce the burgeoning epidemic of diabetic foot disease. This review is intended to address some of the major aspects of management of DFI in India. PMID- 23667102 TI - The performance of serum inflammatory markers for the diagnosis and follow-up of patients with osteomyelitis. AB - Serum inflammatory markers, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), white blood cells (WBC), and procalcitonin (PCT), have been used for the diagnosis of foot infections in patients with diabetes. However, little is known about their changes during treatment of patients with foot infections. The aim of this prospective study was to examine the performance of serum inflammatory markers for the diagnosis and follow-up of patients with osteomyelitis. A total of 61 patients (age 63.1 +/- 7.0 years, 45 men and 16 women, 7 with type 1 and 54 with type 2 diabetes) with untreated foot infection (34 with soft-tissue infection and 27 with osteomyelitis) were recruited. Diagnosis of osteomyelitis was based on clinical examination and was confirmed by imaging studies (X-ray, scintigraphy, magnetic resonance imaging). Determination of the inflammatory markers was performed at baseline, after 1 week, after 3 weeks, and after 3 months of treatment. At baseline, the values of CRP, ESR, WBC, and PCT were significantly higher in patients with osteomyelitis than in those with soft-tissue infections. The sensitivity and specificity for the diagnosis of osteomyelitis of CRP (cutoff value >14 mg/L) were 0.85 and 0.83, of ESR (cutoff value >67 mm/h) 0.84 and 0.75, of WBC (cutoff value >14 * 10(9)/L) 0.75 and 0.79, and of PCT (cutoff value >0.30 ng/mL) 0.81 and 0.71, respectively. All values declined after initiation of treatment with antibiotics; the WBC, CRP, and PCT values returned to near-normal levels at day 7, whereas the values of ESR remained high until month 3 only in patients with bone infection. From the inflammatory markers, ESR is recommended to be used for the follow-up of patients with osteomyelitis. PMID- 23667103 TI - Hyperbaric oxygen therapy as adjunctive treatment for diabetic foot ulcers. AB - Hyperbaric oxygen therapy (HBOT) has been suggested to improve healing of hard-to heal diabetic foot ulcers. Although the wide use of HBOT as a treatment for diabetic foot ulcers has been founded on weak scientific ground, 2 well-designed randomized, double-blind, placebo-controlled studies have in recent years put HBOT on firmer ground as treatment for diabetic patients with chronic foot ulcers. The recognition of inclusion criteria in these studies may help identify a select group of diabetic patients with hard-to-heal ulcers who might benefit from HBOT. In this review, we discuss the rationale behind the use of HBOT, its clinical application, and possible treatment complications. PMID- 23667104 TI - Current achievements with topical negative pressure to improve wound healing in dehiscent ischemic stumps of diabetic patients: a case series. AB - Negative pressure wound therapy has been increasingly used either as a primary or as an adjunctive therapeutic measure to treat a variety of recalcitrant wounds during the past years. It is thought to act by creating a local environment that promotes cell proliferation, angiogenesis, and granulation tissue formation, leading to accelerated wound healing to the point of spontaneous closure or reducing the wound size to facilitate significantly further surgical reconstruction. This case series presents our preliminary experience with the use of a Topical Negative Pressure system in the treatment of challenging ischemic wounds of diabetic patients. It aims to underscore its beneficial effects and explore its potential role in the management of ischemic amputated stumps to avoid ipsilateral re-amputation at a higher level. PMID- 23667105 TI - Secondary prevention of diabetic foot infections in a Caribbean nation: a call for improved patient education. AB - Most countries have instituted measures to limit the complications of diabetes. We evaluate secondary prevention strategies for diabetic foot infections in a Caribbean country. We performed a prospective questionnaire study evaluating all patients admitted to tertiary care hospitals across Trinidad and Tobago from July 2011 to June 2012. Primary study end points were the number of patient-detected injuries and the time interval between injury and presentation. Secondary end points included the practice of regular foot inspection (>=2 foot examinations per week) for early detection and the use of self-directed nonmedical therapies to treat foot infections. There were 446 patients admitted with diabetic foot infections at an average age of 56.9 +/- 12.4 years. Three hundred and fifty-six (80%) were previously hospitalized with foot infections and 226 (51%) had already sustained end organ injury from diabetes. There were 163 (36.6%) patients walking barefoot at the time of injury and 189 (42.4%) had footwear-related injuries. In 257 (57.6%) cases, patients identified their foot injury shortly after the event. Despite early detection, they presented to hospital after a mean interval of 6.2 +/- 5.03 days, with 78 (30.4%) having tried some form of home therapy first. Overall, 190 (42.6%) patients did not practice regular foot examinations. There is room for improvement in secondary preventative measures for diabetic foot infections in this setting. Educational campaigns may be beneficial to educate diabetics on the dangers of walking barefoot, the importance of appropriate footwear, regular foot inspection, and the importance of seeking immediate medical attention instead of experimenting with home remedies. PMID- 23667107 TI - Early inhibition of IL-1beta expression by IFN-gamma is mediated by impaired binding of NF-kappaB to the IL-1beta promoter but is independent of nitric oxide. AB - The significance of bacterial RNA recognition for initiating innate immune responses against invading pathogens has only recently started to be elucidated. Bacterial RNA is an important trigger of inflammasome activation, resulting in caspase-1-dependent cleavage of pro-IL-1beta into the active form. It was reported previously that prolonged treatment with IFN-gamma can inhibit IL-1beta production at the level of both transcription and Nlrp3 inflammasome activation in an NO-dependent manner. As a result of the delayed kinetics of NO generation after IFN-gamma stimulation, these effects were only observed at later time points. We report that IFN-gamma suppressed bacterial RNA and LPS induced IL 1beta transcription in primary murine macrophages and dendritic cells by an additional, very rapid mechanism that was independent of NO. Costimulation with IFN-gamma selectively attenuated binding of NF-kappaB p65 to the IL-1beta promoter, thus representing a novel mechanism of IL-1beta inhibition by IFN gamma. Transcriptional silencing was specific for IL-1beta because expression of other proinflammatory cytokines, such as TNF, IL-6, and IL-12p40, was not affected. Furthermore, by suppressing IL-1beta production, IFN-gamma impaired differentiation of Th17 cells and production of neutrophil chemotactic factor CXCL1 in vitro. The findings provide evidence for a rapid immune-modulating effect of IFN-gamma independent of NO. PMID- 23667106 TI - Total parenteral nutrition-associated lamina propria inflammation in mice is mediated by a MyD88-dependent mechanism. AB - Enteral nutrient deprivation via total parenteral nutrition (TPN) administration leads to local mucosal inflammatory responses, but the underlying mechanisms are unknown. Wild-type (WT) and MyD88(-/-) mice underwent jugular vein cannulation. One group received TPN without chow, and controls received standard chow. After 7 d, we harvested intestinal mucosally associated bacteria and isolated small-bowel lamina propria (LP) cells. Bacterial populations were analyzed using 454 pyrosequencing. LP cells were analyzed using quantitative PCR and multicolor flow cytometry. WT, control mucosally associated microbiota were Firmicutes-dominant, whereas WT TPN mice were Proteobacteria-domiant. Similar changes were observed in MyD88(-/-) mice with TPN administration. UniFrac analysis showed divergent small bowel and colonic bacterial communities in controls, merging toward similar microbiota (but distinct from controls) with TPN. The percentage of LP T regulatory cells significantly decreased with TPN in WT mice. F4/80(+)CD11b(+)CD11c(dull/-) macrophage-derived proinflammatory cytokines significantly increased with TPN. These proinflammatory immunologic changes were significantly abrogated in MyD88(-/-) TPN mice. Thus, TPN administration is associated with significant expansion of Proteobacteria within the intestinal microbiota and increased proinflammatory LP cytokines. Additionally, MyD88 signaling blockade abrogated decline in epithelial cell proliferation and epithelial barrier function loss. PMID- 23667108 TI - Separation of function between isotype switching and affinity maturation in vivo during acute immune responses and circulating autoantibodies in UNG-deficient mice. AB - Activation-induced deaminase converts deoxycytidine to deoxyuridine at the Ig loci. Complementary pathways, initiated by the uracil-DNA glycosylase (UNG) or the mismatch repair factor MSH2/MSH6, must process the deoxyuridine to initiate class-switch recombination (CSR) and somatic hypermutation. UNG deficiency most severely reduces CSR efficiency and only modestly affects the somatic hypermutation spectrum in vitro. This would predict isotype-switching deficiency but normal affinity maturation in Ung(-/-) mice in vivo, but this has not been tested. Moreover, puzzling differences in the amount of circulating Ig between UNG-deficient humans and mice make it unclear to what extent MSH2/MSH6 can complement for UNG in vivo. We find that Ab affinity maturation is indeed unaffected in Ung(-/-) mice, even allowing IgM responses with higher than normal affinity. Ung(-/-) mice display normal to only moderately reduced basal levels of most circulating Ig subclasses and gut-associated IgA, which are elicited in response to chronically available environmental Ag. In contrast, their ability to produce switched Ig in response to immunization or vesicular stomatitis virus infection is strongly impaired. Our results uncover a specific need for UNG in CSR for timely and efficient acute Ab responses in vivo. Furthermore, Ung(-/-) mice provide a novel model for separating isotype switching and affinity maturation during acute (but not chronic) Ab responses, which could be useful for dissecting their relative contribution to some infections. Interestingly, Ung(-/ ) mice present with circulating autoantibodies, suggesting that UNG may impinge on tolerance. PMID- 23667109 TI - Immunization with biodegradable nanoparticles efficiently induces cellular immunity and protects against influenza virus infection. AB - The ability of vaccines to induce T cell responses is crucial for preventing diseases caused by viruses or bacteria. Nanoparticles (NPs) are considered an efficient tool for inducing potent immune responses. In this study, we describe a novel vaccination approach with biodegradable calcium phosphate (CaP) NPs that serve as carrier of immunoactive TLR9 ligand (CpG) combined with a viral Ag from the influenza A virus hemagglutinin. Functionalized CaP NPs were efficiently taken up by dendritic cells in vivo and elicited a potent T cell-mediated immune response in immunized mice with high numbers of IFN-gamma-producing CD4(+) and CD8(+) effector T cells. Most importantly, both i.p. and intranasal immunization with these NPs offered protection in a mouse model of influenza virus infection. This study demonstrates the great potential of CaP NPs as a novel vaccination tool that offers substantial flexibility for several infection models. PMID- 23667110 TI - Role of macrophage receptor with collagenous structure in innate immune tolerance. AB - Macrophages play a key role in host defense against microbes, in part, through phagocytosis. Macrophage receptor with collagenous structure (MARCO) is a scavenger receptor on the cell surface of macrophages that mediates opsonin independent phagocytosis. The goal of our study is to investigate the role of MARCO in LPS or lipotechoic acid-induced macrophage tolerance. Although it has been established that expression of MARCO and phagocytosis is increased in tolerant macrophages, the transcriptional regulation and biological role of MARCO in tolerant macrophages have not been investigated. In this study, we confirm that tolerized mouse bone marrow-derived macrophages (BMDM) selectively increase expression of MARCO (both transcript and cell surface receptor) and increase phagocytosis. We found that H3K4me3 dynamic modification of a promoter site of MARCO was increased in tolerized BMDM. Blocking methylation by treatment with 5 aza-2'-deoxycytidine resulted in reduced H3K4me3 binding in the promoter of MARCO, decreased expression of MARCO, and impaired phagocytosis in tolerized BMDM. However, 5-aza-2'-deoxycytidine had no effect on the inflammatory component of innate immune tolerance. In aggregate, we found that histone methylation was critical to MARCO expression and phagocytosis in tolerized macrophages, but did not affect the inflammatory component of innate immune tolerance. PMID- 23667111 TI - Looped host defense peptide CLP-19 binds to microtubules and inhibits surface expression of TLR4 on mouse macrophages. AB - The looped host defense peptide CLP-19 is derived from a highly functional core region of the Limulus anti-LPS factor and exerts robust anti-LPS activity by directly interacting with LPS in the extracellular space. We previously showed that prophylactic administration of CLP-19 even 20 h prior to LPS challenge might significantly increase the survival rate in a lethal endotoxin shock mouse model. Such an effect may be associated with immune regulation of CLP-19. To investigate the underlying mechanisms, peptide affinity chromatography, immunofluorescence, and Western blotting procedures were used to identify alpha- and beta-tubulin as direct and specific binding partners of CLP-19 in the mouse macrophage cell line RAW 264.7. Bioinformatic analysis using the AutoDock Vina molecular docking and PyMOL molecular graphics system predicted that CLP-19 would bind to the functional residues of both alpha- and beta-tubulin and would be located within the groove of microtubules. Tubulin polymerization assay revealed that CLP-19 might induce polymerization of microtubules and prevent depolymerization. The immunoregulatory effect of CLP-19 involving microtubules was investigated by flow cytometry, immunofluorescence, and Western blotting, which showed that CLP-19 prophylactic treatment of RAW 264.7 cells significantly inhibited LPS-induced surface expression of TLR4. Taken together, these results suggest that CLP-19 binding to microtubules disrupts the dynamic equilibrium of microtubules, reducing the efficacy of microtubule-dependent vesicular transport that would otherwise translocate TLR4 from the endoplasmic reticulum to the cell surface. PMID- 23667112 TI - CD4+ T cells provide intermolecular help to generate robust antibody responses in vaccinia virus-vaccinated humans. AB - Immunization with vaccinia virus elicits a protective Ab response that is almost completely CD4(+) T cell dependent. A recent study in a rodent model observed a deterministic linkage between Ab and CD4(+) T cell responses to particular vaccinia virus proteins suggesting that CD4(+) T cell help is preferentially provided to B cells with the same protein specificity (Sette et al. 2008. Immunity 28: 847-858). However, a causal linkage between Ab and CD4(+) T cell responses to vaccinia or any other large pathogen in humans has yet to be done. In this study, we measured the Ab and CD4(+) T cell responses against four vaccinia viral proteins (A27L, A33R, B5R, and L1R) known to be strongly targeted by humoral and cellular responses induced by vaccinia virus vaccination in 90 recently vaccinated and 7 long-term vaccinia-immunized human donors. Our data indicate that there is no direct linkage between Ab and CD4(+) T cell responses against each individual protein in both short-term and long-term immunized donors. Together with the observation that the presence of immune responses to these four proteins is linked together within donors, our data suggest that in vaccinia-immunized humans, individual viral proteins are not the primary recognition unit of CD4(+) T cell help for B cells. Therefore, we have for the first time, to our knowledge, shown evidence that CD4(+) T cells provide intermolecular (also known as noncognate or heterotypic) help to generate robust Ab responses against four vaccinia viral proteins in humans. PMID- 23667113 TI - Viral antigen induces differentiation of Foxp3+ natural regulatory T cells in influenza virus-infected mice. AB - We examined the formation, participation, and functional specialization of virus reactive Foxp3(+) regulatory T cells (Tregs) in a mouse model of influenza virus infection. "Natural" Tregs generated intrathymically, based on interactions with a self-peptide, proliferated in response to a homologous viral Ag in the lungs and, to a lesser extent, in the lung-draining mediastinal lymph nodes (medLNs) of virus-infected mice. In contrast, conventional CD4(+) T cells with identical TCR specificity underwent little or no conversion to become "adaptive" Tregs. The virus-reactive Tregs in the medLNs and the lungs of infected mice upregulated a variety of molecules associated with Treg activation, as well as acquired expression of molecules (T-bet, Blimp-1, and IL-10) that confer functional specialization to Tregs. Notably, however, the phenotypes of the T-bet(+) Tregs obtained from these sites were distinct, because Tregs isolated from the lungs expressed significantly higher levels of T-bet, Blimp-1, and IL-10 than did Tregs from the medLNs. Adoptive transfer of Ag-reactive Tregs led to decreased proliferation of antiviral CD4(+) and CD8(+) effector T cells in the lungs of infected hosts, whereas depletion of Tregs had a reciprocal effect. These studies demonstrate that thymically generated Tregs can become activated by a pathogen derived peptide and acquire discrete T-bet(+) Treg phenotypes while participating in and modulating an antiviral immune response. PMID- 23667115 TI - Comparative analysis of monocyte subsets in the pig. AB - Human and mouse monocyte can be divided into two different subpopulations based on surface marker expression: CD14/16 and Ly6C/CX3CR1, respectively. Monocyte subpopulations in the pig were identified based on reciprocal expression of CD14 and the scavenger receptor CD163. The two populations, CD14(hi)-CD163(low) and CD14(low)-CD163(hi), show approximately equal abundance in the steady-state. Culture of pig PBMCs in CSF1 indicates that the two populations are a maturation series controlled by this growth factor. Gene expression in pig monocyte subpopulations was profiled using the newly developed and annotated pig whole genome snowball microarray. Previous studies have suggested a functional equivalence between human and mouse subsets, but certain genes such as CD36, CLEC4E, or TREM-1 showed human-specific expression. The same genes were expressed selectively in pig monocyte subsets. However, the profiles suggest that the pig CD14(low)-CD163(high) cells are actually equivalent to intermediate human monocytes, and there is no CD14(-) CD16(+) "nonclassical" population. The results are discussed in terms of the relevance of the pig as a model for understanding human monocyte function. PMID- 23667114 TI - MicroRNA let-7c regulates macrophage polarization. AB - Macrophages demonstrate a high level of plasticity, with the ability to undergo dynamic transition between M1 and M2 polarized phenotypes. The role of microRNAs (miRNAs) in regulating macrophage polarization has been largely undefined. In this study, we found that miRNA let-7c is expressed at a higher level in M-BMM (M2 macrophages) than in GM-BMM (M1 macrophages). let-7c levels are also greater in alveolar macrophages from fibrotic lungs as compared with those from normal lungs. let-7c expression was decreased when M-BMM converted to GM-BMM, whereas it increased when GM-BMM converted to M-BMM. LPS stimulation reduced let-7c expression in M-BMM. We found that overexpression of let-7c in GM-BMM diminished M1 phenotype expression while promoting polarization to the M2 phenotype. In contrast, knockdown of let-7c in M-BMM promoted M1 polarization and diminished M2 phenotype expression. We found that let-7c targets C/EBP-delta, a transcriptional factor that plays an important role in inflammatory response. Furthermore, we found that let-7c regulates bactericidal and phagocytic activities of macrophages, two functional phenotypes implicated in macrophage polarization. Our data suggest that the miRNA let-7c plays an important role in regulating macrophage polarization. PMID- 23667116 TI - [An overview of epilepsy: its history, classification, pathophysiology and management]. AB - Epilepsy, a common chronic set of neurological disorders characterized by seizures, affects more than 50 million people worldwide. In fact, it is estimated that the annual incidence of new onset epilepsy in the general population is more than 80 per 100,000, occurring mostly in children and the elderly. Epilepsy is not a single specific disease, or even a single syndrome, but rather a broad category of symptom complexes arising from any number of disordered brain functions. The history of epilepsy dates back to a time when it was associated with religious experiences and even demonic possession; textbooks from the Babylonian Era (718-612 BC) emphasize the supernatural nature of epilepsy, while in ancient Greece, Hippocrates described it as the "Sacred Disease". Our modern understanding of epilepsy as a neurological disorder associated with seizures only originated in the mid-19th century through the research of John Hughlings Jackson. Classification of epilepsies, epileptic syndromes, and related seizure disorders first appeared 1981 and later in 1989, as described by the International League Against Epilepsy (ILAE). Newer classifications have since been proposed by the same organization; however, these are still rather controversial and have not yet been accepted worldwide. The pathophysiology of epilepsy, including the pharmacological and neurophysiological aspects, has been studied extensively. Epileptogenicity is induced by abnormal cellular excitability that arises from depolarization and hyperpolarization events, as well as from aberrant neuronal networks that develop abnormal synchronization. These events can be studied using mutant epileptogenic animals, such as the GAERS rat model of absence epilepsy. The past 15 years has seen the development of many new drugs for the treatment of epilepsy, thus providing a diverse choice for epileptologists and their patients. However, a better understanding of these drugs is required to improve the therapeutic management of patients suffering with the chronic burden of epilepsy. PMID- 23667117 TI - [Neurophysiological observations in patients with epilepsy]. AB - In this paper, I briefly summarize what have been shown by physiological studies in human epileptic patients. My main message is that "epilepsy is simple and clear" based on our knowledge of cell physiology. The pathophysiological mechanisms, genetic abnormalities and mechanisms of action of used antiepileptic drugs are all consistent with our basic medical knowledge. I summarize three points as follows. UNDERLYING PATHOPHYSIOLOGY OF EPILEPSY: Epilepsy is produced by synchronous, abnormal excessive discharges of some human brain structure. Such discharges are induced by abnormalities in ion channels, neurotransmitters, transmitter receptors or gap junctions; related genetic abnormalities have been reported in some familial epilepsy disorders. WHAT PHYSIOLOGICAL ABNORMALITIES HAVE BEEN SHOWN IN EPILEPTIC PATIENTS? Epileptic spikes in electroencephalography may be one kind of synchronous excessive discharges. Giant SEP reflects hyperexcitability of the sensory cortex (S1) to a single stimulus, and paired stimulation SEP showed inhibitory control reduction of S1. TMS of the primary motor cortex (M1) also revealed hyperexcitability and GABAergic inhibitory reduction of M1. PHYSIOLOGICAL MECHANISMS OF ACTION OF EPILEPTIC DRUGS: TMS studies have been performed in normal subjects taking a certain antiepileptic drug. Some drugs function as sodium or calcium channel blockers, others enhance GABAergic function or modulate neuro-plastic functions. I hope that this article give you an impression of "epilepsy is easy and clear". PMID- 23667118 TI - [Classification of epileptogenic cerebral malformations: guide to understand the present conditions]. AB - For dozens of years, a variety of pathological findings have been revealed through previous observations on surgically resected lesions from patients with intractable epilepsy, including excessive number of neurons in the molecular layer of cortices, unexpected existence of white matter neurons, and persistent columnar structure. These findings have sometimes been referred to as microdysgenesis (MD) or mild malformation of cortical development (mMCD), which is defined as microscopic abnormalities of brain formations with no macroscopical and neuroradiological findings. Taylor et al. (1971) described surgical cases with giant neurons and bizarre, grotesque cells as "focal dysplasia of the cerebral cortices with epilepsy." Since 1997, such malformations have subsequently been referred to as focal cortical dysplasia (FCD), in Greenfield's Neuropathology. Since early 2000, the definition of FCD has gradually been given a broader interpretation than the case described by Taylor et al., as shown in Palmini's classification (2004) or the newest classification (2011) proposed by the Neuropathology Task Force of the International League Against Epilepsy (ILAE). The ILAE classification describes 3 types of disease: Type I, Type II, and Type III. Type I is equivalent to some, but not all, pathological phenotypes of MD or mMCD. Type II is Taylor's FCD alone. Type III, which was not included in Palmini's classification, merges brain malformation and other pathological findings. However, the reproducibility of pathological diagnosis by using the ILAE classification was low, except for Type IIb. Hence, future studies are necessary to provide further reliable criteria for the pathological diagnosis of epilepsy patients. PMID- 23667119 TI - [Epilepsy and cognitive dysfunction]. AB - Higher brain dysfunction is a major problems of epileptic patients. Epilepsy may cause transient epileptic higher brain dysfunctions like transient epileptic amnesia (TEA), or persistent epileptic higher brain dysfunction with or without findings of non-convulsive status epilepticus (NCSE). These are all defined as epilepsy with higher brain dysfunction (E-HBD). Amnesia, aphasia, or personality/behavior change are well known symptoms of E-HBD. Geshwind syndrome including personality changes seen in temporal epileptic patients, and Kluver Bucy syndrome have also reported as a symptom of epilepsy. Anti-epileptic drugs (AEDs) are used to prevent convulsive or non-convulsive attacks, but it may cause higher brain dysfunction. Sedation, impairment of concentration or memory, and dizziness are frequently seen as cognitive side effects of AEDs. We review these higher brain dysfunctions in epileptic patients, and report a case of limbic encephalitis. PMID- 23667120 TI - [Cognitive function related to temporal lobe epilepsy: advances in research on new cognitive function]. AB - The importance of neuropsychological examinations in epilepsy care and, especially, in epilepsy surgery is centered on the following roles: they offer a means to confirm the epileptic focus by multi-modal preoperative assessments and they help to assess postoperative functional changes based on preoperative cognitive functions. Furthermore, assessments of the cognitive functions of patients with epilepsy using various tests aid in providing comprehensive medical care. Thus far, research on cognitive functions related to temporal lobe epilepsy has focused on memory, language, and general intelligence. However, the concept of social cognitive function has been recently proposed in the field of neuropsychology. This cognitive function, proposed by Brothers in 1990, is a collective term for functions needed in social life; these include functions required to interpret the expressions, feelings, and intentions of others and to form and maintain smooth human relationships while making decisions necessary for self-survival. These functions mainly involve facial expression recognition and decision-making. Findings of research on neural mechanisms underlying social cognitive functions have emphasized the roles of the cerebral limbic system, such as the amygdalo-hippocampal complexes, and the emotional system in the ventromedial prefrontal area. Studies on social cognitive functions in mesial temporal lobe epilepsy are being pursued currently. Early-onset right mesial temporal lobe epilepsy with hippocampal sclerosis is the key substrate determining a severe deficit in recognizing emotional facial expressions and decision-making. In the future, neuropsychological examinations of social cognition, in addition to those of global intelligence, memory, and verbal function, will contribute to the provision of comprehensive medical care to patients with epilepsy. PMID- 23667121 TI - [Nonconvulsive status epilepticus: clinical practice and pathophysiology]. AB - The clinical spectrum of nonconvulsive status epilepticus (NCSE) is rapidly expanding from classical manifestations, such as staring, repetitive blinking, chewing, swallowing, and automatism to novel manifestations, such as acute and protracted coma, apnea, cognitive impairment, higher brain dysfunction, and cardiac arrest. It is only in the last decade that these novel NCSE manifestations have been revealed, which is certainly reflective of modern advances in critical care neurology, such as the introduction and spread of continuous electroencephalography (cEEG) monitoring. Although NCSE is a relatively frequent, treatable condition but with a high mortality rate, physicians are still unfamiliar with its clinical manifestations, thus leading to underdiagnosis. In this review, the clinical manifestations, epidemiology, diagnosis, and management of NCSE are critically described using the best available evidence and perspectives, including my hypothesis on epileptic organ dysfunction; in particular, the possible causal relationship between NCSE and cardiac arrhythmia, such as atrial fibrillation is also discussed. PMID- 23667122 TI - [Neuroimaging in epilepsy]. AB - It is now recommended that magnetic resonance imaging (MRI) or computed tomography (CT) be carried out in all patients with at least partial- and hopefully also generalized epilepsy to help identify intracranial lesions, such as hippocampal sclerosis, focal cortical dysplasia, brain tumor, cavernous malformation, and arteriovenous malformation. In order to identify epileptic focus, other neuroimaging tools, such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and magnetoencephalography (MEG), are also useful, because an epileptogenic area is not necessarily located within these intracranial lesions. With regard to epilepsy surgery, neuroimaging is also required for the identification of functionally essential cortices, such as motor and language areas. MEG and functional MRI are noninvasively, and tractography with diffusion-weighted imaging (DWI) is also useful for visualizing relevant white matter tracts. Recently, it has been reported that the cortico cortical network plays an important role in preservation of brain function. Thus, cortico-cortical evoked potentials (CCEP) and resting state fMRI are candidate methods to help clarify brain network. While good seizure control is an important treatment outcome for patients with intractable partial epilepsy, the preservation of brain function is equally important. For this reason, further development and clinical application of sophisticated imaging technique are required. PMID- 23667123 TI - [An autopsied case of argyrophilic grain dementia with parkinsonism due to multiple lacunar infarctions]. AB - A 77-year-old Japanese woman developed parkinsonism and showed tremor in the upper extremities, bradykinesia, and gait disturbance. She was diagnosed with Parkinson's disease. Treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) was ineffective. Two years later, dementia symptoms such as memory disturbance and disorientation gradually manifested and abnormal behaviors including egocentric behavior were observed. No apparent pyramidal tract signs, focal cerebral signs, or cerebellar dysfunction was observed. The patient died at the age of 90 years, and the clinical diagnosis was Parkinson's disease with dementia. The brain weight was 1,110 g. Multiple infarctions were observed in the basal ganglia and thalamus with etat crible. Argyrophilic grains corresponding to Saito's stage III were observed mainly in the limbic system. Neuronal loss with gliosis and tissue rarefaction was detected in the subiculum, parahippocampal gyrus, and amygdala. Oligodendroglial coiled bodies and argyrophilic threads were also observed in the areas in which the grains were abundant. Neurofibrillary tangles and senile plaques corresponding to Braak stage III and Consortium to Establish a Registry for Alzheimer's Disease (CERAD) stage B, respectively, were detected. The number of neurons of the substantia nigra and locus coeruleus was found to be unchanged. Pathological features of Parkinson's disease, including Lewy bodies and alpha synuclein-positive abnormal structures, were not observed. On the basis of the pathological features, we made a diagnosis of argyrophilic grain dementia (AGD) with multiple infarctions. The patient's dementia was thought to be due to AGD, and parkinsonism was suspected to be due to multiple infarctions of the basal ganglia. The clinical findings of the patient described in this case study include important findings that will help in clinically discriminating between different dementias such as Alzheimer's disease and AGD. PMID- 23667125 TI - Deciphering the role of CGI-58 in lipid metabolism in Arabidopsis. PMID- 23667124 TI - Advanced proteomic analyses yield a deep catalog of ubiquitylation targets in Arabidopsis. AB - The posttranslational addition of ubiquitin (Ub) profoundly controls the half life, interactions, and/or trafficking of numerous intracellular proteins. Using stringent two-step affinity methods to purify Ub-protein conjugates followed by high-sensitivity mass spectrometry, we identified almost 950 ubiquitylation substrates in whole Arabidopsis thaliana seedlings. The list includes key factors regulating a wide range of biological processes, including metabolism, cellular transport, signal transduction, transcription, RNA biology, translation, and proteolysis. The ubiquitylation state of more than half of the targets increased after treating seedlings with the proteasome inhibitor MG132 (carbobenzoxy-Leu Leu-Leu-al), strongly suggesting that Ub addition commits many to degradation by the 26S proteasome. Ub-attachment sites were resolved for a number of targets, including six of the seven Lys residues on Ub itself with a Lys-48>Lys-63>Lys 11>>>Lys-33/Lys-29/Lys-6 preference. However, little sequence consensus was detected among conjugation sites, indicating that the local environment has little influence on global ubiquitylation. Intriguingly, the level of Lys-11 linked Ub polymers increased substantially upon MG132 treatment, revealing that they might be important signals for proteasomal breakdown. Taken together, this proteomic analysis illustrates the breadth of plant processes affected by ubiquitylation and provides a deep data set of individual targets from which to explore the roles of Ub in various physiological and developmental pathways. PMID- 23667127 TI - A tale of two physicians: reflections on the Boston Marathon bombing. PMID- 23667126 TI - The alpha/beta hydrolase CGI-58 and peroxisomal transport protein PXA1 coregulate lipid homeostasis and signaling in Arabidopsis. AB - COMPARATIVE GENE IDENTIFICATION-58 (CGI-58) is a key regulator of lipid metabolism and signaling in mammals, but its underlying mechanisms are unclear. Disruption of CGI-58 in either mammals or plants results in a significant increase in triacylglycerol (TAG), suggesting that CGI-58 activity is evolutionarily conserved. However, plants lack proteins that are important for CGI-58 activity in mammals. Here, we demonstrate that CGI-58 functions by interacting with the PEROXISOMAL ABC-TRANSPORTER1 (PXA1), a protein that transports a variety of substrates into peroxisomes for their subsequent metabolism by beta-oxidation, including fatty acids and lipophilic hormone precursors of the jasmonate and auxin biosynthetic pathways. We also show that mutant cgi-58 plants display changes in jasmonate biosynthesis, auxin signaling, and lipid metabolism consistent with reduced PXA1 activity in planta and that, based on the double mutant cgi-58 pxa1, PXA1 is epistatic to CGI-58 in all of these processes. However, CGI-58 was not required for the PXA1-dependent breakdown of TAG in germinated seeds. Collectively, the results reveal that CGI 58 positively regulates many aspects of PXA1 activity in plants and that these two proteins function to coregulate lipid metabolism and signaling, particularly in nonseed vegetative tissues. Similarities and differences of CGI-58 activity in plants versus animals are discussed. PMID- 23667128 TI - Drug companies agree to cut price of HPV vaccine to developing countries to increase accessibility. PMID- 23667129 TI - Hospitals are invited to contribute to testing checklist for safer births. PMID- 23667130 TI - Ontario excludes thousands of children from schools for lack of vaccination. PMID- 23667131 TI - Cameron's cave-in on plain packaging is a boost to industry. PMID- 23667132 TI - Flipping the tanycyte switch: how circulating signals gain direct access to the metabolic brain. PMID- 23667133 TI - "Apologies" from pathologists: why, when, and how to say "sorry" after committing a medical error. AB - How pathologists communicate an error is complicated by the absence of a direct physician-patient relationship. Using 2 examples, we elaborate on how other physician colleagues routinely play an intermediary role in our day-to-day transactions and in the communication of a pathologist error to the patient. The concept of a "dual-hybrid" mind-set in the intermediary physician and its role in representing the pathologists' viewpoint adequately is considered. In a dual hybrid mind-set, the intermediary physician can align with the patients' philosophy and like the patient, consider the smallest deviation from norm to be an error. Alternatively, they might embrace the traditional physician philosophy and communicate only those errors that resulted in a clinically inappropriate outcome. Neither may effectively reflect the pathologists' interests. We propose that pathologists develop strategies to communicate errors that include considerations of meeting with the patients directly. Such interactions promote healing for the patient and are relieving to the well-intentioned pathologist. PMID- 23667134 TI - Acute myeloid leukemia with t(9;11) (p22;q23) and synchronous Langerhans cell histiocytosis. AB - We present here the first report of an adult patient with simultaneous LCH and AML with t(9;11).5. PMID- 23667135 TI - Cytotoxicity and genotoxicity of copper oxide nanoparticles in human skin keratinocytes cells. AB - The wide scale use of copper oxide nanoparticles (CuONPs) due to their unique properties and important applications in magnetic, thermal, electrical, sensor devices, and cosmetics makes human beings more prone to the exposure of CuONPs and its potential adverse effects. Exposure to such nanoparticles is mainly through skin and inhalation. Therefore, the aim of the present study was to assess the apoptotic and genotoxic potential of CuONPs (50 nm) in the human skin epidermal (HaCaT) cells and its underlying mechanism of cellular toxicity. Significant decreases in cell viability were observed with CuONPs exposure in a dose- and time-dependent manner and also induced significant reduction in glutathione and induction in lipid peroxidation, catalase, and superoxide dismutase in HaCaT cells. A significant increase in caspase-3 activity was observed with CuONPs exposure in HaCaT cells indicating apoptosis. Apoptosis or necrosis was confirmed with fluorescent staining (acridine orange and propidium iodide). The CuONPs also induced DNA damage that was mediated by oxidative stress. This study investigating the effects of CuONPs in human skin cells has provided valuable insights into the mechanism of potential toxicity induced by CuONPs. PMID- 23667136 TI - Reply to Mounzer and DiNubile. PMID- 23667137 TI - Seminal human immunodeficiency virus blips and structured natural conception in serodiscordant couples. PMID- 23667138 TI - Hyphomicrobium nitrativorans sp. nov., isolated from the biofilm of a methanol fed denitrification system treating seawater at the Montreal Biodome. AB - A budding prosthecate bacterial strain, designated NL23(T), was isolated from a methanol-fed denitrification system treating seawater at the Montreal Biodome, Canada. Phylogenetic analysis based on 16S rRNA (rRNA) gene sequences showed that the strain was affiliated with the genus Hyphomicrobium of the Alphaproteobacteria and was most closely related to Hyphomicrobium zavarzinii with 99.4 % sequence similarity. Despite this high level of 16S rRNA gene sequence similarity, DNA-DNA hybridization assays showed that strain NL23(T) was only distantly related to H. zavarzinii ZV-622(T) (12 %). Strain NL23(T) grew aerobically, but also had the capacity to grow under denitrifying conditions in the presence of nitrate without nitrite accumulation. Growth occurred at pH 7.0 9.5, with 0-1 % NaCl and at temperatures of 15-35 degrees C. Major fatty acids were C18 : 1omega7c or omega6c (84.6 %) and C18 : 0 (8.5 %), and major quinones were Q8 (5 %) and Q9 (95 %). The complete genome of the strain was sequenced and showed a DNA G+C content of 63.8 mol%. Genome analysis predicted open reading frames (ORF) encoding the key enzymes of the serine pathway as well as enzymes involved in methylotrophy. Also, ORF encoding a periplasmic nitrate reductase (Nap), a nitrite reductase (Nir), a nitric oxide reductase (Nor) and a nitrous oxide reductase (Nos) were identified. Our results support that strain NL23(T) represents a novel species within the genus Hyphomicrobium, for which the name Hyphomicrobium nitrativorans sp. nov. is proposed. The type strain is NL23(T) ( = ATCC BAA-2476(T) = LMG 27277(T)). PMID- 23667139 TI - Saccharomonospora amisosensis sp. nov., isolated from deep marine sediment. AB - A novel actinomycete, strain DS3030(T), was isolated from a deep sediment sample, collected from the southern Black Sea coast, Turkey, and was examined using a polyphasic approach. On the basis of 16S rRNA gene sequence analysis, strain DS3030(T) was shown to belong to the genus Saccharomonospora and to be related most closely to Saccharomonospora marina XMU15(T) (99.6 % similarity). Sequence similarities with other strains of the genus Saccharomonospora were lower than 97.0 %. The organism had chemical and morphological features typical of the genus Saccharomonospora. The cell wall of the novel strain contained meso diaminopimelic acid, arabinose and galactose as diagnostic sugars. The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and phosphatidylinositol mannoside. The predominant menaquinone was MK-9(H4). Major fatty acids were iso-C16 : 0, iso-C16 : 0 2-OH and C16 : 1cis 9. Phenotypic data clearly distinguished the new isolate from its closest relative, S. marina XMU15(T). The combined genotypic and phenotypic data and low DNA-DNA relatedness with its closest related strain reveal that strain DS3030(T) represents a novel species of the genus, for which the name Saccharomonospora amisosensis sp. nov. is proposed. The type strain is DS3030(T) ( = DSM 45685(T) = KCTC 29069(T) = NRRL B-24885(T)). PMID- 23667140 TI - Heliimonas saccharivorans gen. nov., sp. nov., a member of the family Chitinophagaceae isolated from a mineral water aquifer, and emended description of Filimonas lacunae. AB - Two isolates, with optimum growth temperature and pH of about 30 degrees C and 6.0-7.0, were recovered from a borehole head of a mineral water aquifer in Portugal. The closest relatives based on 16S rRNA gene sequence analysis were species of genera of the family Chitinophagaceae. Strains L2-4(T) and L2-109 formed translucent colonies and non-motile pleomorphic cells. Strains were strictly aerobic, and oxidase- and catalase-positive. The major fatty acids of strains L2-4(T) and L2-109 were 17 : 0 iso 3-OH, 15 : 0 iso and 15 : 1 iso G. The major polar lipids were phosphatidylethanolamine, one unidentified phospholipid, four unidentified aminophospholipids, four unidentified aminolipids and three unidentified polar lipids. Menaquinone 7 was the only respiratory quinone. The G+C content of the DNA of strains L2-4(T) and L2-109 was 42.0 and 41.4 mol%, respectively. Based on 16S rRNA gene sequence analysis, physiological and biochemical characteristics, strains L2-4(T) ( = CECT 8122(T) = LMG 26919(T)) and L2-109 ( = CECT 8121 = LMG 26920) are considered to represent a novel species of a new genus, for which the name Heliimonas saccharivorans gen. nov., sp. nov. is proposed. The type strain of Heliimonas saccharivorans is L2-4(T). Due to additional results obtained in this study an emended description of Filimonas lacunae is provided. PMID- 23667141 TI - Micromonospora schwarzwaldensis sp. nov., a producer of telomycin, isolated from soil. AB - A Gram-stain-positive, spore-forming actinomycete strain (HKI0641(T)) was isolated from a soil sample collected in the Black Forest, Germany. During screening for antimicrobial natural products this bacterium was identified as a producer of the antibiotic telomycin. Morphological characteristics and chemotaxonomic data indicated that the strain belonged to the genus Micromonospora. The peptidoglycan of strain HKI0641(T) contained meso diaminopimelic acid, and the fatty acid profile consisted predominantly of anteiso-C15 : 0, iso-C15 : 0, iso-C16 : 0 and C16 : 0. MK-10(H4), MK-10(H2) and MK-10 were identified as the major menaquinones. To determine the taxonomic positioning of strain HKI0641(T), we computed a binary tanglegram of two rooted phylogenetic trees that were based upon 16S rRNA and gyrB gene sequences. The comparative analysis of the two common classification methods strongly supported the phylogenetic affiliation with the genus Micromonospora, but it also revealed discrepancies in the assignment at the level of the genomic species. 16S rRNA gene sequence analysis identified Micromonospora coxensis DSM 45161(T) (99.1 % sequence similarity) and Micromonospora marina DSM 45555(T) (99.0 %) as the nearest taxonomic neighbours, whereas the gyrB sequence of strain HKI0641(T) indicated a closer relationship to Micromonospora aurantiaca DSM 43813(T) (95.1 %). By means of DNA-DNA hybridization experiments, it was possible to resolve this issue and to clearly differentiate strain HKI0641(T) from other species of the genus Micromonospora. The type strains of the aforementioned species of the genus Micromonospora could be further distinguished from strain HKI0641(T) by several phenotypic properties, such as colony colour, NaCl tolerance and the utilization of carbon sources. The isolate was therefore assigned to a novel species of the genus Micromonospora, for which the name Micromonospora schwarzwaldensis sp. nov. is proposed. The type strain is HKI0641(T) ( = DSM 45708(T) = CIP 110415(T)). PMID- 23667142 TI - Proposal of Motilibacteraceae fam. nov., with the description of Motilibacter rhizosphaerae sp. nov. AB - A rod-shaped actinobacterium, designated strain RS-16(T), was isolated from a rhizosphere soil and its taxonomic position was determined by a polyphasic taxonomic approach. Comparative 16S rRNA gene sequence analysis indicated that strain RS-16(T) was most closely related to the type strain of Motilibacter peucedani (98.3 % sequence similarity). The cell-wall peptidoglycan contained LL diaminopimelic acid as the diagnostic diamino acid and N-glycolylated murein. The major whole-cell sugars were glucose, galactose and mannose. The predominant menaquinone was MK-9(H4). The major fatty acids were C18 : 1omega9c and C16 : 0. The DNA G+C content was 73.1 mol%. The phenotypic and DNA-DNA hybridization data showed that strain RS-16(T) ( = KACC 16209(T) = DSM 45622(T)) represents a novel species of the genus Motilibacter, for which Motilibacter rhizosphaerae sp. nov. is proposed. Based on the phylogenetic position determined by 16S rRNA gene analysis and the signature nucleotide set of the 16S rRNA sequence, the genus Motilibacter represents a novel family of the suborder Frankineae, for which the name Motilibacteraceae fam. nov. is proposed. PMID- 23667143 TI - Code of Conduct on Biosecurity for Biological Resource Centres: procedural implementation. AB - A globally applicable code of conduct specifically dedicated to biosecurity has been developed together with guidance for its procedural implementation. This is to address the regulations governing potential dual-use of biological materials, associated information and technologies, and reduce the potential for their malicious use. Scientists researching and exchanging micro-organisms have a responsibility to prevent misuse of the inherently dangerous ones, that is, those possessing characters such as pathogenicity or toxin production. The code of conduct presented here is based on best practice principles for scientists and their institutions working with biological resources with a specific focus on micro-organisms. It aims to raise awareness of regulatory needs and to protect researchers, their facilities and stakeholders. It reflects global activities in this area in response to legislation such as that in the USA, the PATRIOT Act of 2001, Uniting and Strengthening America by Providing Appropriate Tools Required to Intercept and Obstruct Terrorism Act of 2001; the Anti-Terrorism Crime and Security Act 2001 and subsequent amendments in the UK; the EU Dual-Use Regulation; and the recommendations of the Organization for Economic Co-operation and Development (OECD), under their Biological Resource Centre (BRC) Initiative at the beginning of the millennium (OECD, 2001). Two project consortia with international partners came together with experts in the field to draw up a Code of Conduct on Biosecurity for BRCs to ensure that culture collections and microbiologists in general worked in a way that met the requirements of such legislation. A BRC is the modern day culture collection that adds value to its holdings and implements common best practice in the collection and supply of strains for research and development. This code of conduct specifically addresses the work of public service culture collections and describes the issues of importance and the controls or practices that should be in place. However, these best practices are equally applicable to all other microbiology laboratories holding, using and sharing microbial resources. The code was introduced to the Seventh Review Conference to the Biological and Toxin Weapons Convention (BTWC), United Nations, Geneva, 2011; the delegates to the States' parties recommended that this code of conduct be broadly applied in the life sciences and disseminated amongst microbiologists, hence the publishing of it here along with practical implementation guidance. This paper considers the regulatory and working environment for microbiology, defines responsibilities and provides practical advice on the implementation of best practice in handling the organism itself, associated data and technical know-how. PMID- 23667144 TI - Two novel ascomycetous yeast species, Wickerhamomyces scolytoplatypi sp. nov. and Cyberlindnera xylebori sp. nov., isolated from ambrosia beetle galleries. AB - Thirteen strains of yeasts were isolated from ambrosia beetle galleries at several sites in Japan. Based on the morphological and biochemical characteristics and phylogenetic analysis of the D1/D2 domain of the large subunit (LSU) rRNA gene of the yeasts, 10 strains were shown to represent a novel species of the genus Wickerhamomyces, described as Wickerhamomyces scolytoplatypi sp. nov. (type strain NBRC 11029(T) = CBS 12186(T)), and were closely related to Wickerhamomyces hampshirensis. The three other strains represented a novel species of the genus Cyberlindnera, described as Cyberlindnera xylebori sp. nov. (type strain NBRC 11048(T) = CBS 12187(T)), and were closely related to Cyberlindnera euphorbiiphila. It is suggested that these species are associated with ambrosia beetles and we consider ambrosia beetle galleries as good sources of novel yeasts. PMID- 23667145 TI - Nocardioides salsibiostraticola sp. nov., isolated from biofilm formed in coastal seawater. AB - A Gram-staining-positive, non-motile, aerobic, non-spore-forming and short rod shaped bacterial strain, PAMC 26527(T), was isolated from biofilm formed in coastal seawater of the Norwegian Sea. Analysis of the 16S rRNA gene sequence of strain PAMC 26527(T) revealed a clear affiliation with the genus Nocardioides. Based on phylogenetic analysis, strain PAMC 26527(T) showed the closest phylogenetic relationship with Nocardioides caricicola YC6903(T) with 16S rRNA gene sequence similarity of 96.3 %. Strain PAMC 26527(T) grew in the presence of 0-5.0 % sea salts. The optimum temperature and pH for growth were 20 degrees C and pH 7.5. The major cellular fatty acids of strain PAMC 26527(T) were iso-C16 : 0, C17 : 1omega8c and C18 : 1omega9c and the major isoprenoid quinone was MK 8(H4). Cell-wall analysis showed that strain PAMC 26527(T) contained LL diaminopimelic acid. The genomic DNA G+C content was 69.3 mol%. The combined phenotypic, chemotaxonomic and phylogenetic data showed that strain PAMC 26527(T) could be clearly distinguished from recognized members of the genus Nocardioides. Thus, strain PAMC 26527(T) should be classified as representing a novel species in the genus Nocardioides, for which the name Nocardioides salsibiostraticola sp. nov. is proposed. The type strain is PAMC 26527(T) ( = KCTC 29158(T) = JCM 18743(T)). PMID- 23667146 TI - Actinopolyspora mzabensis sp. nov., a halophilic actinomycete isolated from an Algerian Saharan soil. AB - A halophilic actinomycete strain, designated H55(T), was isolated from Saharan soil sampled in the Mzab region (Ghardaia, southern Algeria) and was characterized in a taxonomic study using a polyphasic approach. The cell wall was determined to contain meso-diaminopimelic acid and the characteristic whole-cell sugars were arabinose and galactose. The predominant menaquinones were found to be MK-10(H4) and MK-9(H4). The predominant cellular fatty acids were determined to be anteiso-C17 : 0, iso-C16 : 0 and iso-C15 : 0. The diagnostic phospholipid detected was phosphatidylcholine. The morphological and chemotaxonomic characteristics of the strain were consistent with those of members of the genus Actinopolyspora, and 16S rRNA gene sequence analysis confirmed that strain H55(T) was a member of this genus. DNA-DNA hybridization values between strain H55(T) and the type strains of the nearest species of the genus Actinopolyspora, Actinopolyspora erythraea and A. alba, were clearly below the 70 % threshold. The genotypic and phenotypic data showed that the organism represents a novel species of the genus Actinopolyspora, for which the name Actinopolyspora mzabensis sp. nov. is proposed, with the type strain H55(T) ( = DSM 45460(T) = CCUG 62965(T)). PMID- 23667147 TI - Dyella kyungheensis sp. nov., isolated from soil of a cornus fruit field. AB - A Gram-reaction-negative, aerobic, motile by one polar flagellum, yellow pigmented, rod-shaped bacterium, designated strain THG-B117(T), was isolated from soil of a cornus fruit field of Hoengseong province in South Korea and its taxonomic position was investigated by a polyphasic study. Strain THG-B117(T) grew well at 25-30 degrees C and at pH 6.0-8.0 in the absence of NaCl on nutrient agar. On the basis of 16S rRNA gene sequence similarity, strain THG B117(T) was shown to belong to the family Xanthomonadaceae and be related to Dyella japonica XD53(T) (98.7 % similarity), Dyella terrae JS14-6(T) (98.0 %), Dyella koreensis BB4(T) (96.9 %), Dyella soli JS12-10(T) (96.9 %) and Dyella thiooxydans ATSB10(T) (96.7 %). DNA-DNA hybridization experiments showed that DNA relatedness between strain THG-B117(T) and its phylogenetically closest neighbours was below 45.1 %. The G+C content of the genomic DNA of strain THG B117(T) was 64.8 mol%. The major polar lipids were phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, unidentified aminolipids, unidentified aminophospholipids and unidentified phospholipids. Phenotypic and chemotaxonomic data (major ubiquinone was Q-8, and major fatty acids were iso-C15 : 0, iso-C16 : 0, iso-C17 : 0 and iso-C17 : 1omega9c) supported the affiliation of strain THG-B117(T) with the genus Dyella. The results of physiological and biochemical tests suggested that strain THG-B117(T) was different genotypically and phenotypically from recognized species of the genus Dyella, and represents a novel species of this genus. The name Dyella kyungheensis sp. nov. is proposed, with the type strain THG-B117(T) ( = KACC 16981(T) = JCM 18747(T)). PMID- 23667148 TI - Natural regulatory T cells are resistant to calcium release-activated calcium (CRAC/ORAI) channel inhibition. AB - Organ transplant patients are often treated with immunosuppressants, such as the calcineurin phosphatase inhibitor, cyclosporin A, to block T cell-mediated graft rejection. The calcium release-activated calcium (CRAC/ORAI) channels, which act upstream of calcineurin, are essential for calcium entry and CD4(+) T-cell activation. Although cyclosporine A has also been shown to inhibit FoxP3(+) Tregs both in vitro and in vivo, the role of ORAI channel inhibition in natural Tregs (nTregs) or inducible Tregs (iTregs) has not been investigated. We found that, despite inhibition of calcium influx through the ORAI channels, ORAI channel inhibitors were unable to repress FoxP3 expression in mouse and human nTregs, whereas FoxP3 expression was inhibited in iTregs. In contrast, cyclosporin A inhibited FoxP3 expression in both nTregs and iTregs. We also generated mice with a T cell-specific, conditional knockout of ORAI1 and found that the mice have normal nTreg development and suppressive activity. Moreover, iTregs derived from ORAI1 conditional knockout mice develop normally and are still susceptible to ORAI channel inhibition. Our data indicate that unlike CD4(+) T cells and iTregs, nTregs are resistant to ORAI-mediated inhibition. Targeting ORAI channels potentially offers a novel way to inhibit pathologic T cells, while sparing nTreg mediated tolerance. PMID- 23667149 TI - Energetic basis of catalytic activity of layered nanophase calcium manganese oxides for water oxidation. AB - Previous measurements show that calcium manganese oxide nanoparticles are better water oxidation catalysts than binary manganese oxides (Mn3O4, Mn2O3, and MnO2). The probable reasons for such enhancement involve a combination of factors: The calcium manganese oxide materials have a layered structure with considerable thermodynamic stability and a high surface area, their low surface energy suggests relatively loose binding of H2O on the internal and external surfaces, and they possess mixed-valent manganese with internal oxidation enthalpy independent of the Mn(3+)/Mn(4+) ratio and much smaller in magnitude than the Mn2O3-MnO2 couple. These factors enhance catalytic ability by providing easy access for solutes and water to active sites and facile electron transfer between manganese in different oxidation states. PMID- 23667150 TI - Single-agent combinatorial cancer therapy. PMID- 23667152 TI - More mixotrophy in the marine microbial mix. PMID- 23667151 TI - Using natural variation in Drosophila to discover previously unknown endoplasmic reticulum stress genes. AB - Natural genetic variation is a rich resource for identifying novel elements of cellular pathways such as endoplasmic reticulum (ER) stress. ER stress occurs when misfolded proteins accumulate in the ER and cells respond with the conserved unfolded protein response (UPR), which includes large-scale gene expression changes. Although ER stress can be a cause or a modifying factor of human disease, little is known of the amount of variation in the response to ER stress and the genes contributing to such variation. To study natural variation in ER stress response in a model system, we measured the survival time in response to tunicamycin-induced ER stress in flies from 114 lines from the sequenced Drosophila Genetic Reference Panel of wild-derived inbred strains. These lines showed high heterogeneity in survival time under ER stress conditions. To identify the genes that may be driving this phenotypic variation, we profiled ER stress-induced gene expression and performed an association study. Microarray analysis identified variation in transcript levels of numerous known and previously unknown ER stress-responsive genes. Survival time was significantly associated with polymorphisms in candidate genes with known (i.e., Xbp1) and unknown roles in ER stress. Functional testing found that 17 of 25 tested candidate genes from the association study have putative roles in ER stress. In both approaches, one-third of ER stress genes had human orthologs that contribute to human disease. This study establishes Drosophila as a useful model for studying variation in ER stress and identifying ER stress genes that may contribute to human disease. PMID- 23667153 TI - Clinical outcome and patterns of recurrence of head and neck squamous cell carcinoma with a limited field of postoperative radiotherapy. AB - BACKGROUND: Postoperative radiotherapy is the standard treatment for head and neck squamous cell carcinoma having high-risk features in surgical specimens. However, its severe toxicity can be a significant problem. This study was undertaken to evaluate the efficacy of our limited-field postoperative radiotherapy with the aim of reducing morbidity by minimizing the radiation field. METHODS: Between 2000 and 2009, 154 patients with head and neck squamous cell carcinoma received limited-field postoperative radiotherapy. The reason for postoperative radiotherapy was close/positive margins in 33 patients and extracapsular extension in 91. The median radiation dose was 50 Gy (30-66.4). The radiation field covered the tumor bed without lymph node regions for close/positive margins and only involved sites of the neck region were irradiated for multiple nodes or extracapsular extension. RESULTS: With a median follow-up of 43 months for surviving patients, the 3-year overall survival and progression free survival rates were 53.7 and 42.1%, respectively. The 3-year rates of progression-free survival of the group having major risks (i.e. close/positive margins and/or extracapsular extension) and the group with other risks were 34.7 and 62.8%, respectively (P < 0.01). Thirty-one local recurrences (20%), of which 22 were located out-of-field, and 44 regional recurrences (29%), of which 16 were located out-of-field, developed. Late toxicity of grade 3 or greater developed in only six patients (3.8%). CONCLUSIONS: Although the toxicities associated with limited-field postoperative radiotherapy could be kept to lower levels, the locoregional control rate did not seem to be sufficient. We should arrange the radiation field depending on risk factors. PMID- 23667154 TI - Axitinib controlled metastatic renal cell carcinoma for 5 years. AB - We present two patients with a long-term response to axitinib for cytokine refractory metastatic renal cell carcinoma. One patient has had a continuing partial response for 58 months with cytokine-intolerant metastatic renal cell carcinoma and the other patient has had continuing stable disease accompanied by a mixed response for 57 months with cytokine-refractory and intolerant metastatic renal cell carcinoma. The condition of hypertension as an adverse event markedly depended on whether or not axitinib was administered. The patients responded to axitinib with an elevation of diastolic blood pressure to 90 mmHg or higher until 2 weeks after starting axitinib. To get a long-term response to axitinib, it may be important to control well the balance between treatment effect and adverse events while using drug withdrawal. PMID- 23667155 TI - Safety climate and its association with office type and team involvement in primary care. AB - OBJECTIVE: To assess differences in safety climate perceptions between occupational groups and types of office organization in primary care. METHODS: Primary care physicians and nurses working in outpatient offices were surveyed about safety climate. Explorative factor analysis was performed to determine the factorial structure. Differences in mean climate scores between staff groups and types of office were tested. Logistic regression analysis was conducted to determine predictors for a 'favorable' safety climate. RESULTS: 630 individuals returned the survey (response rate, 50%). Differences between occupational groups were observed in the means of the 'team-based error prevention'-scale (physician 4.0 vs. nurse 3.8, P < 0.001). Medical centers scored higher compared with single handed offices and joint practices on the 'team-based error prevention'-scale (4.3 vs. 3.8 vs. 3.9, P < 0.001) but less favorable on the 'rules and risks' scale (3.5 vs. 3.9 vs. 3.7, P < 0.001). Characteristics on the individual and office level predicted favorable 'team-based error prevention'-scores. Physicians (OR = 0.4, P = 0.01) and less experienced staff (OR 0.52, P = 0.04) were less likely to provide favorable scores. Individuals working at medical centers were more likely to provide positive scores compared with single-handed offices (OR 3.33, P = 0.001). The largest positive effect was associated with at least monthly team meetings (OR 6.2, P < 0.001) and participation in quality circles (OR 4.49, P < 0.001). CONCLUSIONS: Results indicate that frequent quality circle participation and team meetings involving all team members are effective ways to strengthen safety climate in terms of team-based strategies and activities in error prevention. PMID- 23667156 TI - How to recognise and treat peripheral nervous system vasculitis. AB - Peripheral neuropathy can be the first and only manifestation of necrotising primary immune-mediated vasculitis which, carries a high mortality. A clear idea of how to both recognise and treat peripheral nervous system vasculitis is important. We provide a practical approach to immediate and longer term treatment protocols. PMID- 23667157 TI - Correction. PMID- 23667158 TI - Cognitive and motor skills in school-aged children following maternal vitamin A supplementation during pregnancy in rural Nepal: a follow-up of a placebo controlled, randomised cohort. AB - OBJECTIVE: To determine the effects of maternal vitamin A supplementation from preconception through postpartum on cognitive and motor development of children at 10-13 years of age in rural Nepal. DESIGN: Follow-up assessment of children born to women randomly assigned by a village to receive either supplemental vitamin A (7000 ug retinol equivalents) or placebo weekly during a continuous 3.5 year period from 1994-1997. The participants came from 12 wards, a subset of 270 wards in the original trial. Trained staff tested children for cognition by the Universal Nonverbal Intelligence Test (UNIT) and motor ability using four subtests from the Movement Assessment Battery for Children (MABC). Data on schooling, home environment and nutritional and socioeconomic status were also collected. SETTING: Southern plains district of Sarlahi, Nepal. PARTICIPANTS: 390 Nepalese children 10-13 years of age. MAIN OUTCOME MEASURES: Raw scores on UNIT and square-root transformed scores on an abridged version of the MABC tests, expressed as cluster-summarised (mean+/-SD) values to account for the design of the original trial. RESULTS: There were no differences in UNIT (79.61+/-5.99 vs 80.69+/-6.71) or MABC (2.64+/-0.07 vs 2.49+/-0.09) test scores in children whose mothers were exposed to vitamin A vs placebo (mean differences: -1.07, 95% CI 7.10 to 9.26, p=0.78; 0.15, 95% CI 0.43 to -0.08, p=0.15), respectively. More children in the placebo group had repeated a grade in school (28% of placebo vs 16.7% of vitamin A, p=0.01). CONCLUSIONS: Preconceptional to postpartum maternal vitamin A supplementation, in an undernourished setting, does not improve cognition or motor development at ages 10-13 years. PMID- 23667159 TI - Correction. PMID- 23667160 TI - Involving patient research partners has a significant impact on outcomes research: a responsive evaluation of the international OMERACT conferences. AB - OBJECTIVE: To assess the inclusion of patients as international research partners in Outcome Measures in Rheumatology (OMERACT) conferences and how this has influenced the scope and conduct of outcomes research in rheumatology. DESIGN: A thematic content analysis of OMERACT internal documents, publications and conference proceedings, followed by a responsive evaluation including 32 qualitative semistructured interviews. SETTING: The international, biannual research conference OMERACT 10 (Malaysia, 2010). PARTICIPANTS: Senior researchers (n=10), junior researchers (n=2), representatives of the pharmaceutical industry and regulators (n=2), conference staff (n=2), new patient delegates (n=8) and experienced patient delegates (n=8). RESULTS: The role of patients evolved over 10 years from a single patient focus group to full participation in all areas of the meeting and inclusion in research group meetings between conferences. Five main categories of impact emerged: widening the research agenda; including patient relevant outcomes in core sets; enhancing patient reported instruments; changing the culture of OMERACT and consequences outside OMERACT. Patient participants identified previously neglected outcome domains such as fatigue, sleep disturbances and flares which prompted collaborative working on new programmes of research. Specific benefits and challenges for patients and professionals were identified, such as personal fulfilment, widening of research interests, difficulties in establishing equal partnerships and concerns about loss of research rigour. CONCLUSIONS: Including patients as partners in OMERACT conferences has widened its focus and adjusted the way of working. It has resulted in new developments in the research agenda and the use of more patient relevant outcomes in clinical trials. These collaborations have influenced perceptions and beliefs among many patients and researchers, and led to wider patient involvement as partners in research. PMID- 23667161 TI - Quality of newborn care: a health facility assessment in rural Ghana using survey, vignette and surveillance data. AB - OBJECTIVE: To assess the structural capacity for, and quality of, immediate and essential newborn care (ENC) in health facilities in rural Ghana, and to link this with demand for facility deliveries and admissions. DESIGN: Health facility assessment survey and population-based surveillance data. SETTING: Seven districts in Brong Ahafo Region, Ghana. PARTICIPANTS: Heads of maternal/neonatal wards in all 64 facilities performing deliveries. MAIN OUTCOME MEASURES: Indicators include: the availability of essential infrastructure, newborn equipment and drugs, and personnel; vignette scores and adequacy of reasons given for delayed discharge of newborn babies; and prevalence of key immediate ENC practices that facilities should promote. These are matched to the percentage of babies delivered in and admitted to each type of facility. RESULTS: 70% of babies were delivered in health facilities; 56% of these and 87% of neonatal admissions were in four referral level hospitals. These had adequate infrastructure, but all lacked staff trained in ENC and some essential equipment (including incubators and bag and masks) and/or drugs. Vignette scores for care of very low-birth weight babies were generally moderate-to-high, but only three hospitals achieved high overall scores for quality of ENC. We estimate that only 33% of babies were born in facilities capable of providing high quality, basic resuscitation as assessed by a vignette plus the presence of a bag and mask. Promotion of immediate ENC practices in facilities was also inadequate, with coverage of early initiation of breastfeeding and delayed bathing both below 50% for babies born in facilities; this represents a lost opportunity. CONCLUSIONS: Unless major gaps in ENC equipment, drugs, staff, practices and skills are addressed, strategies to increase facility utilisation will not achieve their potential to save newborn lives. TRIAL REGISTRATION: http://clinicaltrials.gov NCT00623337. PMID- 23667162 TI - Life-course pathways to psychological distress: a cohort study. AB - OBJECTIVES: Early life factors, like intelligence and socioeconomic status (SES), are associated with health outcomes in adulthood. Fitting comprehensive life course models, we tested (1) the effect of childhood intelligence and SES, education and adulthood SES on psychological distress at midlife, and (2) compared alternative measurement specifications (reflective and formative) of SES. DESIGN: Prospective cohort study (the Aberdeen Children of the 1950s). SETTING: Aberdeen, Scotland. PARTICIPANTS: 12 500 live-births (6282 boys) between 1950 and 1956, who were followed up in the years 2001-2003 at age 46-51 with a postal questionnaire achieving a response rate of 64% (7183). OUTCOME MEASURES: Psychological distress at age 46-51 (questionnaire). RESULTS: Childhood intelligence and SES and education had indirect effects on psychological distress at midlife, mediated by adult SES. Adult SES was the only variable to have a significant direct effect on psychological distress at midlife; the effect was stronger in men than in women. Alternative measurement specifications of SES (reflective and formative) resulted in greatly different model parameters and fits. CONCLUSIONS: Even though formative operationalisations of SES are theoretically appropriate, SES is better specified as reflective than as a formative latent variable in the context of life-course modelling. PMID- 23667163 TI - Social media use among patients and caregivers: a scoping review. AB - OBJECTIVE: To map the state of the existing literature evaluating the use of social media in patient and caregiver populations. DESIGN: Scoping review. DATA SOURCES: Medline, CENTRAL, ERIC, PubMed, CINAHL Plus Full Text, Academic Search Complete, Alt Health Watch, Health Source, Communication and Mass Media Complete, Web of Knowledge and ProQuest (2000-2012). STUDY SELECTION: Studies reporting primary research on the use of social media (collaborative projects, blogs/microblogs, content communities, social networking sites, virtual worlds) by patients or caregivers. DATA EXTRACTION: Two reviewers screened studies for eligibility; one reviewer extracted data from relevant studies and a second performed verification for accuracy and completeness on a 10% sample. Data were analysed to describe which social media tools are being used, by whom, for what purpose and how they are being evaluated. RESULTS: Two hundred eighty-four studies were included. Discussion forums were highly prevalent and constitute 66.6% of the sample. Social networking sites (14.8%) and blogs/microblogs (14.1%) were the next most commonly used tools. The intended purpose of the tool was to facilitate self-care in 77.1% of studies. While there were clusters of studies that focused on similar conditions (eg, lifestyle/weight loss (12.7%), cancer (11.3%)), there were no patterns in the objectives or tools used. A large proportion of the studies were descriptive (42.3%); however, there were also 48 (16.9%) randomised controlled trials (RCTs). Among the RCTs, 35.4% reported statistically significant results favouring the social media intervention being evaluated; however, 72.9% presented positive conclusions regarding the use of social media. CONCLUSIONS: There is an extensive body of literature examining the use of social media in patient and caregiver populations. Much of this work is descriptive; however, with such widespread use, evaluations of effectiveness are required. In studies that have examined effectiveness, positive conclusions are often reported, despite non-significant findings. PMID- 23667164 TI - Compartmentalization of destabilized enzyme-mRNA-ribosome complexes generated by ribosome display: a novel tool for the directed evolution of enzymes. AB - We have developed an in vitro evolution method for the selection for catalytic activity under the conditions of free intermolecular interaction between the enzyme and a substrate. The destabilized ternary enzyme-mRNA-ribosome complexes generated by a ribosome display of the mutant library are compartmentalized in vitro by forming a water-in-oil emulsion in such a way, that every droplet would on average contain no more than a single complex. After the complex dissociates within the droplet, the released enzyme molecule is free to interact with a substrate under the selection pressure on all its enzymatic properties (substrate binding, product formation, rate acceleration and turnover) simultaneously-an opportunity for the most efficient selection for catalytic activity. By using the M-MuLV reverse transcriptase as a model, we demonstrated the high efficiency of the method selecting for mutants synthesizing cDNA at increased temperature. A slightly modified compartmentalized ribosome display (CRD) could be used for the selection of other enzymes activities (e.g. DNA polymerase, RNA or DNA ligase terminal nucleotidyl transferase activity). Employment of microfluidics technique could broaden the scope of CRD technique furthermore providing an opportunity to select almost any enzyme at single molecule level under desired conditions. PMID- 23667166 TI - Molecular players in neutrophil chemotaxis--focus on PI3K and small GTPases. AB - Neutrophil chemotaxis is a process by which individual cells sense a gradient of chemoattractant, polarize, and then migrate toward the chemoattractant. Many features of chemotaxis are shared with other forms of cell migration. We continue to expand our understanding of the mechanisms governing these features. The rapid process through which neutrophils polarize when placed into a gradient of chemoattractant remains least well-understood. Several key molecular players involved in the regulation of polarization have been identified. However, crosstalk among the different molecular players is required to polarize the cell and to maintain cell polarity during directional migration. The mechanism(s) by which this occurs are the subject of current investigations using experimental and computational approaches. Here, we review progress in the field, putting recent observations into context with established findings. We concentrate on the signaling processes regulated by PI3Ks, their lipid products, the role of Rho family small GTPases, and crosstalk between these important families of regulators. PMID- 23667165 TI - At the bedside: CTLA-4- and PD-1-blocking antibodies in cancer immunotherapy. AB - It is increasingly appreciated that cancers are recognized by the immune system, and under some circumstances, the immune system may control or even eliminate tumors. The modulation of signaling via coinhibitory or costimulatory receptors expressed on T cells has proven to be a potent way to amplify antitumor immune responses. This approach has been exploited successfully for the generation of a new class of anticancer therapies, "checkpoint-blocking" antibodies, exemplified by the recently FDA-approved agent, ipilimumab, an antibody that blocks the coinhibitory receptor CTLA-4. Capitalizing on the success of ipilimumab, agents that target a second coinhibitory receptor, PD-1, or its ligand, PD-L1, are in clinical development. Lessons learned from treating patients with CTLA-4 and PD-1 pathway-blocking antibodies will be reviewed, with a focus on concepts likely to inform the clinical development and application of agents in earlier stages of development. See related review At the bench: Preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. PMID- 23667168 TI - Treatment of non-radiographic axial spondyloarthritis: it is only the beginning. PMID- 23667167 TI - Technical advance: autofluorescence-based sorting: rapid and nonperturbing isolation of ultrapure neutrophils to determine cytokine production. AB - The technical limitations of isolating neutrophils without contaminating leukocytes, while concurrently minimizing neutrophil activation, is a barrier to determining specific neutrophil functions. We aimed to assess the use of FACS for generating highly pure quiescent neutrophil populations in an antibody-free environment. Peripheral blood human granulocytes and murine bone marrow-derived neutrophils were isolated by discontinuous Percoll gradient and flow-sorted using FSC/SSC profiles and differences in autofluorescence. Postsort purity was assessed by morphological analysis and flow cytometry. Neutrophil activation was measured in unstimulated-unsorted and sorted cells and in response to fMLF, LTB4, and PAF by measuring shape change, CD62L, and CD11b expression; intracellular calcium flux; and chemotaxis. Cytokine production by human neutrophils was also determined. Postsort human neutrophil purity was 99.95% (sem=0.03; n=11; morphological analysis), and 99.68% were CD16(+ve) (sem=0.06; n=11), with similar results achieved for murine neutrophils. Flow sorting did not alter neutrophil activation or chemotaxis, relative to presorted cells, and no differences in response to agonists were observed. Stimulated neutrophils produced IL-1beta, although to a lesser degree than CXCL8/IL-8. The exploitation of the difference in autofluorescence between neutrophils and eosinophils by FACS is a quick and effective method for generating highly purified populations for subsequent in vitro study. PMID- 23667169 TI - Managing gout needs more than drugs: 'Il faut le savoir-faire, l'Art et la maniere'. PMID- 23667170 TI - Patients' needs and expectations with regard to rheumatology nursing care: results of multicentre focus group interviews. AB - OBJECTIVE: The contribution of rheumatology nurses to improved patient outcomes is increasingly recognised but more research is needed about the effects of interventions. The patient's role in deciding about healthcare quality is considered pivotal and therefore patients' opinions and expectations should be directional in defining priorities for a research agenda. The objective of this study was to explore needs and expectations with regard to rheumatology nursing care in patients with chronic inflammatory arthritis (CIA). METHODS: Patients aged 18-90 years from three medical clinics in different regions in The Netherlands were invited to participate in focus group interviews. The interviews were transcribed verbatim and independently analysed by the authors. In a consensus meeting the emerging subjects were categorised into themes which were verified in a fourth interview. RESULTS: In total, 20 patients, mean age 57 years old, participated in the focus group interviews. The majority had rheumatoid arthritis and mean disease duration was 15 years. The focus group interviews revealed 12 subthemes that were organised into four main themes: education, self management support, emotional support and well organised care. Additionally, patients considered opinions about 'the personality of the nurse' (eg, easy to talk to) to be important. CONCLUSIONS: Patients with CIA mentioned that many problems have to be addressed when one is faced with having a rheumatic disease. The focus group interviews yielded valuable information about the care these patients need and expect. This information will direct future research with regard to rheumatology nursing care. PMID- 23667171 TI - Ankylosing spondylitis patients with and without psoriasis do not differ in disease phenotype. PMID- 23667172 TI - Emergence of an extensively drug-resistant ArmA- and KPC-2-producing ST101 Klebsiella pneumoniae clone in Italy. PMID- 23667173 TI - miR-214 coordinates melanoma progression by upregulating ALCAM through TFAP2 and miR-148b downmodulation. AB - Malignant melanoma is one of the most aggressive human cancers, but the mechanisms governing its metastatic dissemination are not fully understood. Upregulation of miR-214 and ALCAM and the loss of TFAP2 expression have been implicated in this process, with TFAP2 a direct target of miR-214. Here, we link miR-214 and ALCAM as well as identify a core role for miR-214 in organizing melanoma metastasis. miR-214 upregulated ALCAM, acting transcriptionally through TFAP2 and also posttranscriptionally through miR-148b (itself controlled by TFAP2), both negative regulators of ALCAM. We also identified several miR-214 mediated prometastatic functions directly promoted by ALCAM. Silencing ALCAM in miR-214-overexpressing melanoma cells reduced cell migration and invasion without affecting growth or anoikis in vitro, and it also impaired extravasation and metastasis formation in vivo. Conversely, cell migration and extravasation was reduced in miR-214-overexpressing cells by upregulation of either miR-148b or TFAP2. These findings were consistent with patterns of expression of miR-214, ALCAM, and miR-148b in human melanoma specimens. Overall, our results define a pathway involving miR-214, miR-148b, TFAP2, and ALCAM that is critical for establishing distant metastases in melanoma. PMID- 23667174 TI - Stress-response protein RBM3 attenuates the stem-like properties of prostate cancer cells by interfering with CD44 variant splicing. AB - Stress-response pathways play an important role in cancer. The cold-inducible RNA binding protein RBM3 is upregulated in several types of cancer, including prostate cancer, but its pathogenic contributions are undetermined. RBM3 is expressed at low basal levels in human fetal prostate or in CD133(+) prostate epithelial cells (PrEC), compared with the adult prostate or CD133-PrEC, and RBM3 is downregulated in cells cultured in soft agar or exposed to stress. Notably, RBM3 overexpression in prostate cancer cells attenuated their stem cell-like properties in vitro as well as their tumorigenic potential in vivo. Interestingly, either overexpressing RBM3 or culturing cells at 32 degrees C suppressed RNA splicing of the CD44 variant v8-v10 and increased expression of the standard CD44 (CD44s) isoform. Conversely, silencing RBM3 or culturing cells in soft agar (under conditions that enrich for stem cell-like cells) increased the ratio of CD44v8-v10 to CD44s mRNA. Mechanistic investigations showed that elevating CD44v8-v10 interfered with MMP9-mediated cleavage of CD44s and suppressed expression of cyclin D1, whereas siRNA-mediated silencing of CD44v8 v10 impaired the ability of prostate cancer cells to form colonies in soft agar. Together, these findings suggested that RBM3 contributed to stem cell-like character in prostate cancer by inhibiting CD44v8-v10 splicing. Our work uncovers a hitherto unappreciated role of RBM3 in linking stress-regulated RNA splicing to tumorigenesis, with potential prognostic and therapeutic implications in prostate cancer. PMID- 23667175 TI - Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity. AB - Tumors with mutant RAS are often dependent on extracellular signal-regulated kinase (ERK) signaling for growth; however, MEK inhibitors have only marginal antitumor activity in these tumors. MEK inhibitors relieve ERK-dependent feedback inhibition of RAF and cause induction of MEK phosphorylation. We have now identified a MEK inhibitor, CH5126766 (RO5126766), that has the unique property of inhibiting RAF kinase as well. CH5126766 binding causes MEK to adopt a conformation in which it cannot be phosphorylated by and released from RAF. This results in formation of a stable MEK/RAF complex and inhibition of RAF kinase. Consistent with this mechanism, this drug does not induce MEK phosphorylation. CH5126766 inhibits ERK signaling output more effectively than a standard MEK inhibitor that induces MEK phosphorylation and has potent antitumor activity as well. These results suggest that relief of RAF feedback limits pathway inhibition by standard MEK inhibitors. CH5126766 represents a new type of MEK inhibitor that causes MEK to become a dominant-negative inhibitor of RAF and that, in doing so, may have enhanced therapeutic activity in ERK-dependent tumors with mutant RAS. PMID- 23667176 TI - Inhibition of tumor cell migration by LD22-4, an N-terminal fragment of 24-kDa FGF2, is mediated by Neuropilin 1. AB - LD22-4, an 86-amino acid fragment of the basic fibroblast growth factor, is an inhibitor of cell migration. LD22-4 inhibits the migration of various tumor cells, endothelial cells, and fibroblasts in vitro and suppresses tumor growth and angiogenesis in vivo. LD22-4 is effective in the presence of multiple growth factors, either alone or in combination, as well as haptotactic factors. LD22-4 inhibits the rate of malignant gliomas prepared from U87MG cells in an orthotopic mouse model by 90% compared with untreated mice. Using U87MG cells, we identified the LD22-4 membrane receptor as neuropilin 1 (NRP1). The identification of NRP1 as the LD22-4 receptor was based upon mass spectrometric analysis of proteins that bind to LD22-4, immunoprecipitation of an NRP1-LD22-4 complex formed during incubation of LD22-4 with U87MG cells, LD22-4-NRP1 coimmunoprecipitation studies, and binding of LD22-4 to HEK293 cells expressing NRP1. In contrast, NRP1 binding of an inactive mutant of LD22-4 was substantially reduced. As is typical of NRP1 binding proteins, LD22-4 itself binds to heparin and requires heparan sulfate for binding to cells. The addition of heparin to migration assays increased the inhibitory activity of LD22-4. In addition to a heparin-binding region, LD22-4 contains a 5-amino acid C-terminus that matches an NRP1 consensus binding sequence. Thus, direct binding experiments, dependence on heparan sulfate, and the presence of a NRP1 consensus binding sequence indicate that NRP1 is the binding site of LD22-4 and mediates inhibition of cell migration. PMID- 23667177 TI - MCP-1 binds to oxidized LDL and is carried by lipoprotein(a) in human plasma. AB - Lipoprotein oxidation plays an important role in pathogenesis of atherosclerosis. Oxidized low density lipoprotein (OxLDL) induces profound inflammatory responses in vascular cells, such as production of monocyte chemoattractant protein-1 (MCP 1) [chemokine (C-C motif) ligand 2], a key chemokine in the initiation and progression of vascular inflammation. Here we demonstrate that OxLDL also binds MCP-1 and that the OxLDL-bound MCP-1 retains its ability to recruit monocytes. A human MCP-1 mutant in which basic amino acids Arg-18 and Lys-19 were replaced with Ala did not bind to OxLDL. The MCP-1 binding to OxLDL was inhibited by the monoclonal antibody E06, which binds oxidized phospholipids (OxPLs) in OxLDL. Because OxPLs are carried by lipoprotein(a) [Lp(a)] in human plasma, we tested to determine whether Lp(a) binds MCP-1. Recombinant wild-type but not mutant MCP-1 added to human plasma bound to Lp(a), and its binding was inhibited by E06. Lp(a) captured from human plasma contained MCP-1 and the Lp(a)-associated endogenous MCP-1 induced monocyte migration. These results demonstrate that OxLDL and Lp(a) bind MCP-1 in vitro and in vivo and that OxPLs are major determinants of the MCP 1 binding. The association of MCP-1 with OxLDL and Lp(a) may play a role in modulating monocyte trafficking during atherogenesis. PMID- 23667178 TI - Carotenoid metabolism in mammals, including man: formation, occurrence, and function of apocarotenoids. AB - Vitamin A was recognized as an essential nutrient 100 years ago. In the 1930s, it became clear that dietary beta-carotene was cleaved at its central double to yield vitamin A (retinal or beta-apo-15'-carotenal). Thus a great deal of research has focused on the central cleavage of provitamin A carotenoids to form vitamin A (retinoids). The mechanisms of formation and the physiological role(s) of noncentral (eccentric) cleavage of both provitamin A carotenoids and nonprovitamin A carotenoids has been less clear. It is becoming apparent that the apocarotenoids exert unique biological activities themselves. These compounds are found in the diet and thus may be absorbed in the intestine, or they may form from enzymatic or nonenzymatic cleavage of the parent carotenoids. The mechanism of action of apocarotenoids in mammals is not fully worked out. However, as detailed in this review, they have profound effects on gene expression and work, at least in part, through the modulation of ligand-activated nuclear receptors. Understanding the interactions of apocarotenoids with other lipid-binding proteins, chaperones, and metabolizing enzymes will undoubtedly increase our understanding of the biological roles of these carotenoid metabolites. PMID- 23667179 TI - Identification of CAD candidate genes in GWAS loci and their expression in vascular cells. AB - Recent genome-wide association studies (GWAS) have identified 35 loci that significantly associate with coronary artery disease (CAD) susceptibility. The majority of the genes represented in these loci have not previously been studied in the context of atherosclerosis. To characterize the roles of these candidate genes in the vessel wall, we determined their expression levels in endothelial, smooth muscle, and macrophage cells isolated from healthy, prelesioned, and lesioned mouse aortas. We also performed expression quantitative locus (eQTL) mapping of these genes in human endothelial cells under control and proatherogenic conditions. Of the 57 genes studied, 31 were differentially expressed in one or more cell types in disease state in mice, and the expression levels of 8 were significantly associated with the CAD SNPs in human cells, 7 of which were also differentially expressed in mice. By integrating human and mouse results, we predict that PPAP2B, GALNT4, MAPKAPK5, TCTN1, SRR, SNF8, and ICAM1 play a causal role in the susceptibility to atherosclerosis through a role in the vasculature. Additionally, we highlight the genetic complexity of a subset of CAD loci through the differential expression of multiple candidate genes per locus and the involvement of genes that lie outside linkage disequilibrium blocks. PMID- 23667181 TI - No evidence for locus heterogeneity in Knobloch syndrome. PMID- 23667180 TI - An X chromosome-wide association analysis identifies variants in GPR174 as a risk factor for Graves' disease. AB - BACKGROUND: Graves' disease is a female preponderant autoimmune illness and the contribution of the X chromosome to its risk has long been appreciated. However, no X-linked susceptibility loci have been indentified from recent genome-wide association studies (GWAS). METHODS: We re-examined the X chromosome data from our recent GWAS for Graves' disease by including males that were previously excluded from the X chromosome analyses. The data were analysed using logistic regression analysis including sex as a covariate, and an additive method assuming X chromosome inactivation, implemented in snpMatrix. RESULTS: A cluster of single nucleotide polymorphism (SNPs) at Xq21.1 was found showing association with genome-wide significance, among which rs3827440 was a non-synonymous SNP of GPR174 (P(logistic regression)= 9.52*10(-8); P(snpMatrix)=4.60*10(-9); OR=1.76, 95% CI 1.45 to 2.13). The association was reproduced in an independent sample collection set including 4564 Graves' disease cases and 3968 sex matched controls (combined P(logistic regression)=5.53*10(-21); combined P(snpMatrix)=4.26*10( 22); OR=1.69, 95% CI 1.53 to 1.86). Notably, GPR174 was widely expressed in immune related tissues and rs3827440 genotypes were associated with distinct mRNA levels (p=0.002). GPR174 did not show sex biased gene expression in our expression analysis. Resequencing study suggested the contribution of some rare variants in the GPR174 gene region to disease risk with a collapsing p value of 1.16*10(-3). CONCLUSIONS: The finding of an X-linked risk locus for Graves' disease expands our understanding of the role of the X chromosome in disease susceptibility. PMID- 23667182 TI - Incomplete border sign. PMID- 23667183 TI - Pseudotumours: an atypical presentation of renal sarcoidosis. PMID- 23667184 TI - Benchmarking biomedical publications worldwide. PMID- 23667185 TI - Transcription factor Kruppel-like factor 2 plays a vital role in endothelial colony forming cells differentiation. AB - AIMS: Endothelial colony forming cells (ECFCs) participate in post-natal vasculogenesis. We previously reported that vascular endothelial growth factor (VEGF) promotes human ECFC differentiation through AMP-activated protein kinase (AMPK) activation. However, the mechanisms underlying transcriptional regulation of ECFC differentiation still remain largely elusive. Here, we investigated the role of transcription factor Kruppel-like factor 2 (KLF2) in the regulation of ECFC function. METHODS AND RESULTS: Human ECFCs were isolated from cord blood and cultured. Treatment with VEGF significantly increased endothelial markers in ECFCs and their capacity for migration and tube formation. The mRNA and protein levels of KLF2 were also significantly up-regulated. This up-regulation was abrogated by AMPK inhibition or by knockdown of KLF2 with siRNA. Furthermore, adenovirus-mediated overexpression of KLF2 promoted ECFC differentiation by enhancing expression of endothelial cell markers, reducing expression of progenitor cell markers, and increasing the capacity for tube formation in vitro, indicating the important role of KLF2 in ECFC-mediated angiogenesis. Histone deacetylase 5 (HDAC5) was phosphorylated by AMPK activity induced by VEGF and the AMPK agonist AICAR (5-amino-1-beta-D-ribofuranosyl-imidazole-4-carboxamide). In vivo angiogenesis assay revealed that overexpression of KLF2 in bone-marrow derived pro-angiogenic progenitor cells promoted vessel formation when the cells were implanted in C57BL/6 mice. CONCLUSION: Up-regulation of KLF2 by AMPK activation constitutes a novel mechanism of ECFC differentiation, and may have therapeutic value in the treatment of ischaemic heart disease. PMID- 23667186 TI - The effects of arterial flow on platelet activation, thrombus growth, and stabilization. AB - Injury of an arterial vessel wall acutely triggers a multifaceted process of thrombus formation, which is dictated by the high-shear flow conditions in the artery. In this overview, we describe how the classical concept of arterial thrombus formation and vascular occlusion, driven by platelet activation and fibrin formation, can be extended and fine-tuned. This has become possible because of recent insight into the mechanisms of: (i) platelet-vessel wall and platelet-platelet communication, (ii) autocrine platelet activation, and (iii) platelet-coagulation interactions, in relation to blood flow dynamics. We list over 40 studies with genetically modified mice showing a role of platelet and plasma proteins in the control of thrombus stability after vascular injury. These include multiple platelet adhesive receptors and other junctional molecules, components of the ADP receptor signalling cascade to integrin activation, proteins controlling platelet shape, and autocrine activation processes, as well as multiple plasma proteins binding to platelets and proteins of the intrinsic coagulation cascade. Regulatory roles herein of the endothelium and other blood cells are recapitulated as well. Patient studies support the contribution of platelet- and coagulation activation in the regulation of thrombus stability. Analysis of the factors determining flow-dependent thrombus stabilization and embolus formation in mice will help to understand the regulation of this process in human arterial disease. PMID- 23667187 TI - Biological responses in stented arteries. AB - Vascular walls change their dimension and mechanical properties in response to injury such as balloon angioplasty and endovascular stent implantation. Placement of bare metal stents induces neointimal proliferation/restenosis which progresses through different phases of repair with time involving a cascade of cellular reactions. These phases just like wound healing comprise distinct steps consisting of thrombosis, inflammation, proliferation, and migration followed by remodelling. It is noteworthy that animals show a rapid progression of healing after stent deployment compared with man. During stenting, endothelial cells are partially to completely destroyed or crushed along with medial wall injury and stretching promoting activation of platelets, and thrombus formation accompanied by inflammatory reaction. Macrophages and platelets play a central role through the release of cytokines and growth factors that induce vascular smooth muscle cell accumulation within the intima. Smooth muscle cells undergo complex phenotypic changes including migration and proliferation from the media towards the intima, and transition from a contractile to a synthetic phenotype; the molecular mechanisms responsible for this change are highlighted in this review. Since studies in animals and man show that smooth muscle cells play a dominant role in restenosis, drugs like rapamycin and paclitaxel have been coated on stent with polymers to allow local slow release of drugs, which have resulted in dramatic reduction of restenosis that was once the Achilles' heel of interventional cardiologists. PMID- 23667189 TI - He walked with confidence into the wilderness of life: a tribute to Philip E. Greenman, DO (1928-2013). PMID- 23667188 TI - Marginal dietary zinc deficiency in vivo induces vascular smooth muscle cell apoptosis in large arteries. AB - AIMS: Dietary zinc deficiency has been associated with the development of atherosclerosis although the effects on vascular smooth muscle cells (VSMCs), important in maintaining atherosclerotic plaque integrity, are unknown. The main aim of this study was to elucidate the effect of a zinc-deficient environment on VSMCs using an in vivo model. METHODS AND RESULTS: Rats were maintained for 2 weeks on a marginally zinc-deficient diet which resulted in a significant reduction in plasma zinc levels. Large arteries from zinc-deficient rats had significantly increased apoptosis within the VSMC layers compared with arteries from rats on a zinc-adequate diet. This apoptosis occurred in parallel with a known apoptotic pathway, namely dephosphorylation of the pro-apoptotic protein Bcl-2-associated death promoter protein (BAD). Activation of extracellular signal regulated kinase (ERK)1/2, which maintains BAD phosphorylation as a pro-survival mechanism, was decreased in arteries from zinc-deficient rats. The mechanisms of this in vivo effect were investigated in vitro. Cultured rat VSMCs incubated with plasma from zinc-deficient rats similarly resulted in increased apoptosis in parallel with BAD dephosphorylation and decreased ERK1/2 activation. Further related apoptotic mechanisms induced by plasma from zinc-deficient rats involved a prolonged rise in [Ca2+]i leading to subsequent activation of the phosphatase calcineurin. Calcineurin activation was required to dephosphorylate BAD. In addition, an increase in oxidative stress contributed to the apoptotic effect induced by plasma from zinc-deficient rats. CONCLUSION: In conclusion, a marginally zinc-deficient diet is pro-apoptotic for VSMCs and this may contribute to cardiovascular disease. PMID- 23667192 TI - The effect of osteopathic manipulative treatment on postoperative medical and functional recovery of coronary artery bypass graft patients. AB - CONTEXT: Several studies have investigated the use of osteopathic manipulative treatment (OMT) after coronary artery bypass graft (CABG) operations; however, there is little information regarding the effect of OMT in the postoperative recovery of patients undergoing CABG operations. METHODS: Patients scheduled to undergo a CABG operation were voluntarily enrolled and randomly assigned to receive 1 of 3 treatment protocols after their surgical procedure: standardized daily OMT and conventional postoperative care (the OMT group), daily time-matched placebo OMT and conventional postoperative care (the placebo group), or conventional postoperative care only (the control group). Specific OMT techniques used were thoracic inlet myofascial release, standard rib raising (with paraspinal muscle stretch to the L2 vertebral level), and soft tissue cervical paraspinal muscle stretch (with suboccipital muscle release). Primary outcome measures included time to discharge, time to postoperative bowel movement, and FIM functional assessment scores. RESULTS: Fifty-three patients completed the study protocol: 17 in the OMT group, 18 in the placebo group, and 18 in the control group. After surgical procedures, patients were discharged to home at a mean (standard deviation [SD]) rate of 6.1 (1.4), 6.3 (1.5), and 6.7 (3.0) days for the OMT group, placebo group, and control group, respectively. Patients in the OMT group were discharged 0.55 days earlier than those in the control group and 0.16 days earlier than those in the placebo group. The mean (SD) number of days to first postoperative bowel movement was 3.5 (0.9), 4.0 (0.8), and 4.0 (0.9) for the OMT group, the placebo group, and the control group, respectively. On day 3 after surgery, the mean (SD) total score on the FIM was 19.3 (6.7), 15.4 (7.3), and 18.6 (6.5) for the OMT, the placebo, and the control group, respectively; total score for the OMT group was 0.81 greater than that of the control group and 3.87 greater than that of the placebo group. None of the differences achieved statistical significance (P<.05) CONCLUSION: A daily postoperative OMT protocol improved functional recovery of patients who underwent a CABG operation. PMID- 23667193 TI - Use of the SMART Balance Master to quantify the effects of osteopathic manipulative treatment in patients with dizziness. AB - CONTEXT: Dizziness is the third most common complaint among outpatients and the most common complaint in patients aged 75 years or older. It can be incapacitating for patients, affecting both productivity and quality of life. OBJECTIVE: To evaluate the effect of osteopathic manipulative treatment (OMT) for spinal somatic dysfunction in patients with dizziness lasting longer than 3 months. DESIGN: A prospective clinical cohort study that took place in 2011. SETTING: Department of Physical Therapy laboratory at the Western University of Health Sciences College of Osteopathic Medicine in Pomona, California. PATIENTS: Sixteen participants (2 male, 14 female; mean [range] age, 49 [13-75] years) with dizziness lasting at least 3 months (mean duration of symptoms, 84 months) and spinal somatic dysfunction, but no history of known stroke or brain disease, were recruited from the local community and evaluated for postural balance control before, immediately after, and 1 week after OMT. INTERVENTION: Four osteopathic physicians board certified in neuromusculoskeletal medicine/osteopathic manipulative medicine provided OMT, including muscle energy; high-velocity, low amplitude; counterstrain; myofascial release; balanced ligamentous release; and cranial OMT techniques. MAIN OUTCOME MEASURES: Outcomes were assessed with the SMART Balance Master (NeuroCom), a validated instrument that provides graphic and quantitative analyses of sway and balance, and the Dizziness Handicap Inventory (DHI), a self-assessment inventory designed to assess precipitating physical factors associated with dizziness and functional and emotional consequences of vestibular disease. RESULTS: Paired t tests, performed to assess changes in mean composite scores for all challenge tests, revealed that balance was significantly improved both immediately and 1 week after OMT (both P<.001), with no significant difference between immediate and 1-week post-OMT scores (P=.20). The DHI scores, both total and subscale, improved significantly after OMT (P<.001), and changes in composite and DHI scores were correlated with each other (P=.047). CONCLUSION: Osteopathic manipulative treatment for spinal somatic dysfunction improved balance in patients with dizziness lasting at least 3 months. PMID- 23667194 TI - An osteopathic approach to gastrointestinal disease: somatic clues for diagnosis and clinical challenges associated with Helicobacter pylori antibiotic resistance. AB - The estimated prevalence of gastritis in the general US population is approximately 50%. Patients with gastrointestinal disease often present to the primary care practitioner with dyspepsia and abdominal pain. Osteopathic palpatory evaluation suggests that there is an association among gastrointestinal disease, the presence of posterior midthoracic pain, and chronic headache. On the basis of findings from a review of the literature, the author assesses the potential etiologic mechanisms of this clinical association. Possible mechanisms include the physiologic function of the vagus nerve, a neural convergence model, and the inherent properties of Helicobacter pylori. To demonstrate the clinical significance of these mechanisms, the author presents the case of a 30-year-old woman with headache, thoracic discomfort, and gastritis associated with H pylori infection. The author suggests that successful treatment of patients with gastrointestinal disease includes osteopathic manipulative treatment, behavioral modification, and pharmacotherapy, even when challenged by antibiotic resistance. PMID- 23667195 TI - Metastatic brain tumors: current therapeutic options and historical perspective. AB - Metastatic brain tumors affect more than 150,000 patients annually in the United States. The therapeutic paradigms for these tumors have evolved over the years and currently encompass numerous modalities implemented by treating physicians across several medical disciplines. The armamentarium of brain tumor treatment involves neurosurgical intervention, whole-brain and focused radiation modalities, chemotherapy, and immunotherapy. Patient selection, however, remains critical to achieve maximal therapeutic benefit and depends on functional status, number and location of lesions, and tissue histologic findings. Best outcomes can be expected with a multidisciplinary approach to patient care where state-of-the art treatment options are readily available. PMID- 23667196 TI - Enhancing your manuscript with graphic elements, part 2: figures. PMID- 23667197 TI - Isolated colonic polypoid ganglioneuroma. PMID- 23667198 TI - Seeing with native eyes. PMID- 23667199 TI - An HPLC-HR-MS-MS method for identification of anticoagulant rodenticides in blood. AB - This paper presents a fully validated method for the qualitative identification of bromadiolone, brodifacoum, coumachlor, coumatetralyl, difenacoum and warfarin in whole blood specimens. Samples are protein precipitated with acetonitrile, processed via solid-phase extraction and analyzed by high-performance liquid chromatography with high resolution tandem mass spectrometric detection. Limits of detection were 10 ng/mL or better for all analytes. PMID- 23667200 TI - Off-label use of oncology drugs: too much, too little, or just right? PMID- 23667201 TI - Appreciating the role of advanced practice providers in oncology. PMID- 23667202 TI - A young woman with bilateral breast cancer: identifying a genetic cause and implications for management. AB - Breast cancer is a common manifestation of an underlying genetic susceptibility to cancer, and 5% to 10% of all breast cancers are associated with a germline mutation in a known risk allele. Detection of mutations has implications for targeted screening and prevention strategies for probands, and for genetic counseling and testing of their family members. This report presents a case involving a 35-year-old woman with no family history of breast or ovarian cancer who presented with a palpable right breast lump. Imaging revealed multiple bilateral breast masses and right axillary adenopathy, and core needle biopsies showed invasive ductal carcinoma in both the right and left breast. This report discusses the appropriate genetics evaluation for a patient with bilateral breast cancer at a young age, including testing for mutations in BRCA1 and BRCA2, followed, if negative, by consideration of testing for mutations in TP53 (Li Fraumeni syndrome). Given the specialized counseling and testing needs of patients with Li-Fraumeni syndrome, and the implications for targeted screening strategies if a mutation is found, referral to a cancer genetics expert is strongly recommended. PMID- 23667203 TI - Localized colon cancer, version 3.2013: featured updates to the NCCN Guidelines. AB - The NCCN Clinical Practice Guidelines in Oncology for Colon Cancer begin with the clinical presentation of the patient to the primary care physician or gastroenterologist and address diagnosis, pathologic staging, surgical management, perioperative treatment, patient surveillance, management of recurrent and metastatic disease, and survivorship. The NCCN Colon Cancer Panel meets annually to review comments from reviewers within their institutions and to reevaluate and update their recommendations. In addition, the panel has interim conferences as new data necessitate. These NCCN Guidelines Insights summarize the NCCN Colon Cancer Panel's discussions regarding the treatment of localized disease for the 2013 update of the guidelines. PMID- 23667204 TI - Gastric cancer, version 2.2013: featured updates to the NCCN Guidelines. AB - The NCCN Clinical Practice Guidelines in Oncology for Gastric Cancer provide evidence- and consensus-based recommendations for a multidisciplinary approach for the management of patients with gastric cancer. For patients with resectable locoregional cancer, the guidelines recommend gastrectomy with a D1+ or a modified D2 lymph node dissection (performed by experienced surgeons in high volume centers). Postoperative chemoradiation is the preferred option after complete gastric resection for patients with T3-T4 tumors and node-positive T1-T2 tumors. Postoperative chemotherapy is included as an option after a modified D2 lymph node dissection for this group of patients. Trastuzumab with chemotherapy is recommended as first-line therapy for patients with HER2-positive advanced or metastatic cancer, confirmed by immunohistochemistry and, if needed, by fluorescence in situ hybridization for IHC 2+. PMID- 23667205 TI - Multidisciplinary management of locally advanced rectal cancer: neoadjuvant approaches. AB - Although tumor biology and genomics of colon and rectal cancer are no different, patients with locally advanced rectal cancer (LARC) require neoadjuvant fluoropyrimidine-based chemoradiation and total mesorectal excision. In addition to known clinical risk factors, improved algorithms integrating molecular tools are needed to stratify patients with LARC to improve treatment outcomes and reduce acute and long-term toxicities. Simply combining newer systemic or targeted agents with standard treatment in all patients yielded little success but added toxicities. This article reviews the historical data, current standards of care, and ongoing research efforts regarding biomarkers, molecular imaging, and personalized genomic information. PMID- 23667206 TI - Thymomas and thymic carcinomas: Clinical Practice Guidelines in Oncology. AB - Masses in the anterior mediastinum can be neoplasms (eg, thymomas, thymic carcinomas, or lung metastases) or non-neoplastic conditions (eg, intrathoracic goiter). Thymomas are the most common primary tumor in the anterior mediastinum, although they are rare. Thymic carcinomas are very rare. Thymomas and thymic carcinomas originate in the thymus. Although thymomas can spread locally, they are much less invasive than thymic carcinomas. Patients with thymomas have 5-year survival rates of approximately 78%. However, 5-year survival rates for thymic carcinomas are only approximately 40%. These guidelines outline the evaluation, treatment, and management of these mediastinal tumors. PMID- 23667207 TI - Thymoma versus thymic carcinoma: differences in biology impacting treatment. AB - A better understanding of the biology of both thymomas and thymic carcinomas has occurred in recent years thanks to advanced technologies such as comparative genomic hybridization, expression array analysis, and next-generation sequencing. Gene expression profiling and genomic clustering studies have shown that thymic tumors as classified by the 2004 WHO system do have different molecular features. Because of the rarity of these tumors, there is a paucity of high-quality clinical research data, and treatment decisions are often guided by the small amount of prospective trial data, retrospective series, and individual case reports. The literature does report on several advanced thymic tumors that have responded to new targeted agents, indicating that across the spectrum of thymic malignancies there may be clinically relevant molecular subsets. Genomic profiling distinguishes type B3 thymoma and thymic carcinoma from type A and B2 thymomas. Furthermore, type B2 thymomas can be separated from other subgroups in that it has a more distinctly lymphocytic component than the other groups in which epithelial cells predominate. The presence of KIT mutations in thymic carcinomas rather than in thymomas further adds to a growing body of evidence showing that underlying tumor biology may in the future lead to molecular classifications, which may enhance therapies for these rare tumors. PMID- 23667208 TI - The international thymic malignancy interest group. AB - Thymic tumors are considered an orphan disease, and therefore treatment recommendations have been largely empiric, based on small, retrospective, often poorly characterized series of patients. The International Thymic Malignancy Interest Group (ITMIG) has organized individual efforts, making collation of individual experiences and global collaboration possible. This article summarizes the development of ITMIG and accomplishments achieved since its inception in 2010. A great deal of infrastructure has been built, paving the way for scientifically robust progress in the future. Guidelines such as the NCCN Clinical Practice Guidelines in Oncology are of significant clinical value despite being, of necessity, largely consensus-based. The ITMIG provides the foundation for development of more evidence-based guidelines in the future. PMID- 23667210 TI - Current concepts in penile cancer. AB - This review highlights the significant advances made in the diagnosis and management of penile cancer. This often-aggressive tumor phenotype has been characterized by its poor prognosis, mostly attributable to its late presentation and heterogeneity of surgical care because of the paucity of cases treated at most centers. Recent advances in understanding of the risk factors predisposing to penile cancer, including its association with the human papilloma virus (HPV), have brought forth the socioepidemiologic concept of HPV vaccination in certain high-risk populations and countries, which remains highly debated. The management of penile cancer has evolved in recent years with the adoption of penile-sparing and minimally invasive surgical approaches to the inguinal lymph nodes, which are a frequent site of regional spread for this malignancy. Lastly, this review highlights the importance of adopting a multimodal approach consisting of neoadjuvant systemic chemotherapy followed by consolidative surgical resection in patients presenting with bulky/locally advanced nodal metastases from penile cancer. PMID- 23667211 TI - Double-crossed: why crossover in clinical trials may be distorting medical science. PMID- 23667209 TI - Penile cancer: Clinical Practice Guidelines in Oncology. AB - Squamous cell carcinoma of the penis represents approximately 0.5% of all cancers among men in the United States and other developed countries. Although rare, it is associated with significant disfigurement, and only half of the patients survive beyond 5 years. Proper evaluation of both the primary lesion and lymph nodes is critical, because nodal involvement is the most important factor of survival. The NCCN Clinical Practice Guidelines in Oncology for Penile Cancer provide recommendations on the diagnosis and management of this devastating disease based on evidence and expert consensus. PMID- 23667214 TI - Suicide ideation and behaviours after STN and GPi DBS surgery for Parkinson's disease: results from a randomised, controlled trial. AB - BACKGROUND: The risk of suicide behaviours post-deep brain stimulation (DBS) surgery in Parkinson's disease (PD) remains controversial. We assessed if suicide ideation and behaviours are more common in PD patients (1) randomised to DBS surgery versus best medical therapy (BMT); and (2) randomised to subthalamic nucleus (STN) versus globus pallidus interna (GPi) DBS surgery. METHODS: In Phase 1 of the Veterans Affairs CSP 468 study, 255 PD patients were randomised to DBS surgery (n=121) or 6 months of BMT (n=134). For Phase 2, a total of 299 patients were randomised to STN (n=147) or GPi (n=152) DBS surgery. Patients were assessed serially with the Unified Parkinson's Disease Rating Scale Part I depression item, which queries for suicide ideation; additionally, both suicide behaviour adverse event data and proxy symptoms of increased suicide risk from the Parkinson's Disease Questionnaire (PDQ-39) and the Short Form Health Survey (SF 36) were collected. RESULTS: In Phase 1, no suicide behaviours were reported, and new-onset suicide ideation was rare (1.9% for DBS vs 0.9% for BMT; Fisher's exact p=0.61). Proxy symptoms of relevance to suicide ideation were similar in the two groups. Rates of suicide ideation at 6 months were similar for patients randomised to STN versus GPi DBS (1.5% vs 0.7%; Fisher's exact p=0.61), but several proxy symptoms were worse in the STN group. CONCLUSIONS: Results from the randomised, controlled phase of a DBS surgery study in PD patients do not support a direct association between DBS surgery and an increased risk for suicide ideation and behaviours. PMID- 23667215 TI - Clinical characterisation of Becker muscular dystrophy patients predicts favourable outcome in exon-skipping therapy. AB - OBJECTIVE: Duchenne and Becker muscular dystrophy (DMD/BMD) are both caused by mutations in the DMD gene. Out-of-frame mutations in DMD lead to absence of the dystrophin protein, while in-frame BMD mutations cause production of internally deleted dystrophin. Clinically, patients with DMD loose ambulance around the age of 12, need ventilatory support at their late teens and die in their third or fourth decade due to pulmonary or cardiac failure. BMD has a more variable disease course. The disease course of patients with BMD with specific mutations could be very informative to predict the outcome of the exon-skipping therapy, aiming to restore the reading-frame in patients with DMD. METHODS: Patients with BMD with a mutation equalling a DMD mutation after successful exon skipping were selected from the Dutch Dystrophinopathy Database. Information about disease course was gathered through a standardised questionnaire. Cardiac data were collected from medical correspondence and a previous study on cardiac function in BMD. RESULTS: Forty-eight patients were included, representing 11 different mutations. Median age of patients was 43 years (range 6-67). Nine patients were wheelchair users (26-56 years). Dilated cardiomyopathy was present in 7/36 patients. Only one patient used ventilatory support. Three patients had died at the age of 45, 50 and 76 years, respectively. CONCLUSIONS: This study provides mutation specific data on the course of disease in patients with BMD. It shows that the disease course of patients with BMD, with a mutation equalling a 'skipped' DMD mutation is relatively mild. This finding strongly supports the potential benefit of exon skipping in patients with DMD. PMID- 23667216 TI - Type B aortic dissection after standard endovascular repair of abdominal aortic aneurysm. AB - Dissection of the aorta is a rare yet potentially serious complication following endovascular abdominal aortic aneurysm (EVAR). These can lead to visceral branch hypoperfusion, compromise of aneurysm exclusion, arterial dilation or rupture. Intimal injury and dissection in the context of EVAR may be associated with a number of risk factors that include adverse infrarenal neck morphology, device oversizing, barbed fixation and wire manipulation in the proximal aorta. Herein, we describe three cases of type B aortic dissection following EVAR and discuss possible causes. As the applicability of endovascular technology widens, clinicians are reminded of the importance of early recognition and detection of unusual sequelae following EVAR. PMID- 23667217 TI - Concomitant herpes simplex virus and cytomegalovirus endotheliitis in immunocompetent patient. AB - A case of an immunocompetent 51-year-old healthy man with chronic recurrent disciform corneal oedema and hypertensive anterior uveitis in the right eye for 2 years was unresponsive to topical corticosteroid and systemic acyclovir. Diagnostic anterior chamber tapping was performed and viral DNA PCR was positive for both cytomegalovirus and herpes simplex virus. The patient was treated with both oral valganciclovir for 3 months and long-term oral acyclovir. His condition improved significantly after the treatment; intraocular pressure and anterior chamber inflammation were controlled and the remaining keratic precipitates in the cornea started to clear up. PMID- 23667218 TI - Lactococcus lactis cremoris infection: not rare anymore? AB - A middle-aged female patient with diabetes was admitted with a right neck abscess. Ultrasound scan revealed a necrotic abscess suspicious of malignancy and biopsy showed evidence of chronic inflammation. In order to isolate the primary source of malignancy, we performed MRI and positron emission tomography scans but neither had conclusive results. Subsequently, we performed an incision and drainage of the mass in order to alleviate pressure symptoms. The ensuing histological examination revealed that the mass was caused by Lactococcus lactis cremoris. As such, the patient was treated with antibiotics and made a complete recovery. This report reinforces the scarce existing evidence that L lactis cremoris is a potential pathogen in adults. The case shows that atypical organisms should always be considered in the working diagnosis of an atypical neck abscess especially due to the rise in popularity of organic farming. PMID- 23667219 TI - Cholangiocarcinoma and brain lesions: an extremely rare finding. PMID- 23667220 TI - Panic-related hyperventilation resulting in hypophosphataemia and a high lactate. AB - A 22-year-old lady presented to the emergency department with dyspnoea and pleuritic chest pain. Life-threatening asthma, pulmonary embolus and pneumothorax were all excluded. However, investigations did show an unexplained hypophosphataemia and raised lactate, both of which were subsequently attributed to hyperventilation with a component of panic. Here we explore the mechanism of these findings and the management of hypophosphataemia. PMID- 23667221 TI - Triceps tendon avulsion and associated injuries of the elbow. AB - A rupture or avulsion of the triceps tendon is very rare but concomitant elbow injuries with avulsion of the triceps tendon are even rarer. In this study, an extraordinary and unusual injury combination (radial head and trochlear fracture associated with triceps tendon avulsion), which happened during a fall onto the elbow with outstretched hand, was identified and has been discussed in the literature. PMID- 23667222 TI - Dementia complicated with Takotsubo cardiomyopathy associated with unconsciousness induced by Wernicke's encephalopathy. AB - An 85-year-old woman who had been living alone and eating an unbalanced diet suddenly entered a neighbour's house. Her house was hot and humid due to lack of air conditioning caused by a loss of electrical power. After arrival, the patient exhibited disorientation, paresis of the right upper extremity, a tendency towards right conjugated deviation and perseveration. Electrocardiogram showed ST segment elevation and prolongation of the QT interval. Echocardiography suggested Takotsubo cardiomyopathy. The cardiac wall motion and neurological abnormalities improved after admission. The serum thiamine level was found to be low, which was compatible with a diagnosis of Wernicke's encephalopathy. Hasegawa dementia score was 10 points and the patient was suspected to have frontotemporal dementia. She was transferred to a nursing home with continuing dementia. In this case, psychological stress trigged by poor living circumstances induced by dementia and Wernicke's encephalopathy may result in the occurrence of Takotsubo cardiomyopathy. PMID- 23667223 TI - Dangers of neglect: partially embedded ring upon a finger. AB - Digital swelling is a common presentation in clinical practice. Patients presenting with swollen fingers to the emergency department will often have rings on their finger, which can be removed using a variety of simple non-operative techniques or by cutting the ring off and thus avoiding any long-term consequences. Very rarely, when there is a delay in presentation of these patients, serious consequences may proceed, including finger ischaemia, infection, tendon attrition or ultimately the need for surgical amputation. We present an unusual case of patient with psychiatric illness who presented late with a ring that had embedded upon the volar aspect of the index finger. The difficulties faced by the emergency care practitioners in such circumstances, the consequences of rings acting as a tourniquet and strategies for removal of rings on swollen fingers are highlighted. PMID- 23667224 TI - Indacaterol-induced severe constipation and abdominal pain: is there a role for colonic beta3-adrenoceptors? AB - Indacaterol is an ultra-long-acting beta2-adrenoceptor agonist that is indicated for the maintenance treatment of chronic obstructive pulmonary disease. We present a patient with severe chronic constipation and abdominal pain most probably induced by this medicament. Symptoms rapidly disappeared within 2 days after the drug withdrawal. As far as we know, no reports describing severe chronic constipation associated with indacaterol have been published. The Naranjo algorithm score and the Edwards and Aronson scale for causality assessment of suspected adverse drug reactions indicated a probable relationship between indacaterol use and constipation. Indacaterol-induced constipation is an unusual event that could be accounted for the high intrinsic activity of the drug on colonic beta3-adrenoreceptors, resulting in an inhibitory control of smooth muscle function and intestinal secretion. Clinicians should monitor such a possibility when prescribing this drug and maybe avoid its use in patients with a history of difficult bowel evacuation. PMID- 23667225 TI - Epidermoid cyst of the spleen. AB - We report the case of a patient with a palpable mass and abdominal pain in the left upper quadrant. A physical examination revealed tenderness in this region. An ultrasound performed initially showed a large cystic structure. A CT examination revealed a large cyst originating in the spleen with loculations in its upper part and focal calcification in the wall. On MRI, the cystic mass showed high signal on T1-weighted and T2-weighted images. The carbohydrate antigen 19-9 (CA 19-9) was measured at 88 U/ml (standard <37.1 mUI/l). According to the imaging examinations and laboratory tests performed, it was impossible to determine if the splenic cyst was parasitic or non-parasitic. Given the most important risks of complications encountered in parasitic cysts, it was decided to treat this splenic cyst as a parasitic cyst. For this reason, an elective laparoscopic splenectomy with preoperative embolisation of the splenic artery was performed. The histological diagnosis was a primary epidermoid splenic cyst with inner lining epithelial cells. PMID- 23667226 TI - Acute encephalomyelitis with multiple herpes viral reactivations during abatacept therapy. AB - To describe the case of a patient who had been receiving abatacept, a T-cell costimulatory molecule blocker for rheumatoid arthritis, and developed an acute encephalomyelitis associated with reactivation of the varicella zoster virus (VZV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV). A 61-year-old woman receiving abatacept therapy for rheumatoid arthritis developed a disturbance of consciousness. MRI indicated multifocal parenchymal lesions in the brainstem, supratentorial areas and cervical spinal cord. Although steroid therapy significantly improved the neurological symptoms and MRI findings, the patient died of sepsis aggravated by coinfection with a fungal infection. Retrospectively, a PCR assay revealed continued systemic reactivation of VZV, EBV and CMV. Acute encephalomyelitis may be associated with VZV EBV and CMV reactivation during abatacept therapy. Clinicians must be aware of the possibility of acute encephalomyelitis associated with herpes virus reactivation during abatacept therapy for rheumatoid arthritis. PMID- 23667227 TI - Recurrent seizures, progressive cognitive decline, Parkinsonism and a calcified brain: is it Fahr's disease? PMID- 23667228 TI - Laparoscopically assisted repair of vaginal evisceration after hysterectomy. AB - Vaginal evisceration is a rare condition most commonly associated with previous vaginal surgery. It usually presents with vaginal bleeding, lower abdominal pain and a protruding mass, and requires immediate assessment and surgical management to salvage the prolapsed bowel. Any delay in the treatment may result in bowel ischaemia and perforation which is associated with higher morbidity and mortality. We report a case of spontaneous vaginal evisceration during defaecation in a 56-year-old postmenopausal women 11 months post hysterectomy. This case highlights the benefits of a combined laparoscopic and transvaginal approach in the successful management of this surgical emergency. PMID- 23667229 TI - Noma neonatorum. PMID- 23667231 TI - Characterization of McuB, a periplasmic chaperone-like protein involved in the assembly of Myxococcus spore coat. AB - The MXAN3885 to -3882 gene locus cluster (designated here mcuABCD) of Myxococcus xanthus encodes a member of the archaic chaperone-usher (CU) systems that functions in spore coat formation. We show here that McuD, a putative spore coat protein, affects cellular accumulation and cell surface localization of the spore coat protein McuA. We previously reported that genetic disruption of the putative usher McuC nearly eliminates surface display of McuA and show here that lack of the periplasmic chaperone-like protein McuB, which forms a complex with McuA, has a similar effect. Deletion mutation confirms that the G1 beta strand of McuB is absolutely essential for the stability and secretion of McuA. Site-directed mutagenesis identified two additional alternating hydrophobic residues Ile113 and Val115, together with the highly conserved proline within the G1 strand, as critical residues for chaperone function. These findings suggest that the assembly proteins McuB and McuC mediate the transport of McuA onto the cell surface and that McuA may interact with another spore coat protein, McuD, for its secretion. Importantly, although our data argue that the M. xanthus CU system is likely to use the basic principle of donor strand complementation (DSC), as in the cases of classical CU pathways, to promote folding and stabilization of the structural subunit(s), the periplasmic chaperone McuB appears to exhibit structural variation in mediating chaperone-subunit interaction. PMID- 23667230 TI - Anr and its activation by PlcH activity in Pseudomonas aeruginosa host colonization and virulence. AB - Pseudomonas aeruginosa hemolytic phospholipase C (PlcH) degrades phosphatidylcholine (PC), an abundant lipid in cell membranes and lung surfactant. A DeltaplcHR mutant, known to be defective in virulence in animal models, was less able to colonize epithelial cell monolayers and was defective in biofilm formation on plastic when grown in lung surfactant. Microarray analyses found that strains defective in PlcH production had lower levels of Anr-regulated transcripts than the wild type. PC degradation stimulated the Anr regulon in an Anr-dependent manner under conditions where Anr activity was submaximal because of the presence of oxygen. Two PC catabolites, choline and glycine betaine (GB), were sufficient to stimulate Anr activity, and their catabolism was required for Anr activation. The addition of choline or GB to glucose-containing medium did not alter Anr protein levels, growth rates, or respiratory activity, and Anr activation could not be attributed to the osmoprotectant functions of GB. The Deltaanr mutant was defective in virulence in a mouse pneumonia model. Several lines of evidence indicate that Anr is important for the colonization of biotic and abiotic surfaces in both P. aeruginosa PAO1 and PA14 and that increases in Anr activity resulted in enhanced biofilm formation. Our data suggest that PlcH activity promotes Anr activity in oxic environments and that Anr activity contributes to virulence, even in the acute infection phase, where low oxygen tensions are not expected. This finding highlights the relationships among in vivo bacterial metabolism, the activity of the oxygen-sensitive regulator Anr, and virulence. PMID- 23667232 TI - Mutational analysis of hemoglobin binding and heme utilization by a bacterial hemoglobin receptor. AB - Iron is an essential nutrient for most living organisms. To acquire iron from their environment, Gram-negative bacteria use TonB-dependent transporters that bind host proteins at the bacterial surface and transport iron or heme to the periplasm via the Ton machinery. TonB-dependent transporters are barrel-shaped outer membrane proteins with 22 transmembrane domains, 11 surface-exposed loops, and a plug domain that occludes the pore. To identify key residues of TonB dependent transporters involved in hemoglobin binding and heme transport and thereby locate putative protective epitopes, the hemoglobin receptor of Haemophilus ducreyi HgbA was used as a model of iron/heme acquisition from hemoglobin. Although all extracellular loops of HgbA are required by H. ducreyi to use hemoglobin as a source of iron/heme, we previously demonstrated that hemoglobin binding by HgbA only involves loops 5 and 7. Using deletion, substitution, and site-directed mutagenesis, we were able to differentiate hemoglobin binding and heme acquisition by HgbA. Deletion or substitution of the GYEAYNRQWWA region of loop 5 and alanine replacement of selected histidines affected hemoglobin binding by HgbA. Conversely, mutation of the phenylalanine in the loop 7 FRAP domain or substitution of the NRQWWA motif of loop 5 significantly abrogated utilization of heme from hemoglobin. Our findings show that hemoglobin binding and heme utilization by a bacterial hemoglobin receptor involve specific motifs of HgbA. PMID- 23667233 TI - The endosymbiont Amoebophilus asiaticus encodes an S-adenosylmethionine carrier that compensates for its missing methylation cycle. AB - All organisms require S-adenosylmethionine (SAM) as a methyl group donor and cofactor for various biologically important processes. However, certain obligate intracellular parasitic bacteria and also the amoeba symbiont Amoebophilus asiaticus have lost the capacity to synthesize this cofactor and hence rely on its uptake from host cells. Genome analyses revealed that A. asiaticus encodes a putative SAM transporter. The corresponding protein was functionally characterized in Escherichia coli: import studies demonstrated that it is specific for SAM and S-adenosylhomocysteine (SAH), the end product of methylation. SAM transport activity was shown to be highly dependent on the presence of a membrane potential, and by targeted analyses, we obtained direct evidence for a proton-driven SAM/SAH antiport mechanism. Sequence analyses suggest that SAM carriers from Rickettsiales might operate in a similar way, in contrast to chlamydial SAM transporters. SAM/SAH antiport is of high physiological importance, as it allows for compensation for the missing methylation cycle. The identification of a SAM transporter in A. asiaticus belonging to the Bacteroidetes phylum demonstrates that SAM transport is more widely spread than previously assumed and occurs in bacteria belonging to three different phyla (Proteobacteria, Chlamydiae, and Bacteroidetes). PMID- 23667234 TI - Identification and characterization of type II toxin-antitoxin systems in the opportunistic pathogen Acinetobacter baumannii. AB - Acinetobacter baumannii is an opportunistic pathogen that causes nosocomial infections. Due to the ability to persist in the clinical environment and rapidly acquire antibiotic resistance, multidrug-resistant A. baumannii clones have spread in medical units in many countries in the last decade. The molecular basis of the emergence and spread of the successful multidrug-resistant A. baumannii clones is not understood. Bacterial toxin-antitoxin (TA) systems are abundant genetic loci harbored in low-copy-number plasmids and chromosomes and have been proposed to fulfill numerous functions, from plasmid stabilization to regulation of growth and death under stress conditions. In this study, we have performed a thorough bioinformatic search for type II TA systems in genomes of A. baumannii strains and estimated at least 15 possible TA gene pairs, 5 of which have been shown to be functional TA systems. Three of them were orthologs of bacterial and archaeal RelB/RelE, HicA/HicB, and HigB/HigA systems, and others were the unique SplT/SplA and CheT/CheA TA modules. The toxins of all five TA systems, when expressed in Escherichia coli, inhibited translation, causing RNA degradation. The HigB/HigA and SplT/SplA TA pairs of plasmid origin were highly prevalent in clinical multidrug-resistant A. baumannii isolates from Lithuanian hospitals belonging to the international clonal lineages known as European clone I (ECI) and ECII. PMID- 23667235 TI - HipA-triggered growth arrest and beta-lactam tolerance in Escherichia coli are mediated by RelA-dependent ppGpp synthesis. AB - Persistence is a phenomenon whereby a subpopulation of bacterial cells enters a transient growth-arrested state that confers antibiotic tolerance. While entrance into persistence has been linked to the activities of toxin proteins, the molecular mechanisms by which toxins induce growth arrest and the persistent state remain unclear. Here, we show that overexpression of the protein kinase HipA in Escherichia coli triggers growth arrest by activating synthesis of the alarmone guanosine tetraphosphate (ppGpp) by the enzyme RelA, a signal typically associated with amino acid starvation. We further demonstrate that chemically suppressing ppGpp synthesis with chloramphenicol relieves inhibition of DNA replication initiation and RNA synthesis in HipA-arrested cells and restores vulnerability to beta-lactam antibiotics. HipA-arrested cells maintain glucose uptake and oxygen consumption and accumulate amino acids as a consequence of translational inhibition. We harness the active metabolism of HipA-arrested cells to provide a bacteriophage-resistant platform for the production of biotechnologically relevant compounds, which may represent an innovative solution to the costly problem of phage contamination in industrial fermentations. PMID- 23667236 TI - Analysis of two polyhydroxyalkanoate synthases in Bradyrhizobium japonicum USDA 110. AB - Bradyrhizobium japonicum USDA 110 has five polyhydroxyalkanoate (PHA) synthases (PhaC) annotated in its genome: bll4360 (phaC1), bll6073 (phaC2), blr3732 (phaC3), blr2885 (phaC4), and bll4548 (phaC5). All these proteins possess the catalytic triad and conserved amino acid residues of polyester synthases and are distributed into four different PhaC classes. We obtained mutants in each of these paralogs and analyzed phaC gene expression and PHA production in liquid cultures. Despite the genetic redundancy, only phaC1 and phaC2 were expressed at significant rates, while PHA accumulation in stationary-phase cultures was impaired only in the DeltaphaC1 mutant. Meanwhile, the DeltaphaC2 mutant produced more PHA than the wild type under this condition, and surprisingly, the phaC3 transcript increased in the DeltaphaC2 background. A double mutant, the DeltaphaC2 DeltaphaC3 mutant, consistently accumulated less PHA than the DeltaphaC2 mutant. PHA accumulation in nodule bacteroids followed a pattern similar to that seen in liquid cultures, being prevented in the DeltaphaC1 mutant and increased in the DeltaphaC2 mutant in relation to the level in the wild type. Therefore, we used these mutants, together with a DeltaphaC1 DeltaphaC2 double mutant, to study the B. japonicum PHA requirements for survival, competition for nodulation, and plant growth promotion. All mutants, as well as the wild type, survived for 60 days in a carbon-free medium, regardless of their initial PHA contents. When competing for nodulation against the wild type in a 1:1 proportion, the DeltaphaC1 and DeltaphaC1 DeltaphaC2 mutants occupied only 13 to 15% of the nodules, while the DeltaphaC2 mutant occupied 81%, suggesting that the PHA polymer is required for successful competitiveness. However, the bacteroid content of PHA did not affect the shoot dry weight accumulation. PMID- 23667237 TI - Poly(3-hydroxybutyrate) degradation in Ralstonia eutropha H16 is mediated stereoselectively to (S)-3-hydroxybutyryl coenzyme A (CoA) via crotonyl-CoA. AB - Degradation of poly(3-hydroxybutyrate) (PHB) by the thiolytic activity of the PHB depolymerase PhaZ1 from Ralstonia eutropha H16 was analyzed in the presence of different phasins. An Escherichia coli strain was constructed that harbored the genes for PHB synthesis (phaCAB), the phasin PhaP1, and the PHB depolymerase PhaZ1. PHB was isolated in the native form (nPHB) from this recombinant E. coli strain, and the in vitro degradation of the polyester was examined. Degradation resulted in the formation of the expected 3-hydroxybutyryl coenzyme A (3HB-CoA) and in the formation of a second product, which occurred in significantly higher concentrations than 3HB-CoA. This second product was identified by liquid chromatography mass spectrometry (LC-MS) as crotonyl-CoA. Replacement of PhaP1 by PhaP2 or PhaP4 resulted in a lower degradation rate, whereas the absence of the phasins prevented the degradation of nPHB by the PHB depolymerase PhaZ1 almost completely. In addition, the in vitro degradation of nPHB granules isolated from R. eutropha H16 (wild type) and from the R. eutropha DeltaphaP1 and DeltaphaP1-4 deletion mutants was examined. In contrast to the results obtained with nPHB granules isolated from E. coli, degradation of nPHB granules isolated from the wild type of R. eutropha yielded high concentrations of 3HB-CoA and low concentrations of crotonyl-CoA. The degradation of nPHB granules isolated from the DeltaphaP1 and DeltaphaP1-4 deletion mutants of R. eutropha was significantly reduced in comparison to that of nPHB granules isolated from wild-type R. eutropha. Stereochemical analyses of 3HB-CoA revealed that the (R) stereoisomer was collected after degradation of granules isolated from E. coli, whereas the (S) stereoisomer was collected after degradation of granules isolated from R. eutropha. Based on these results, a newly observed mechanism in the degradation pathway for PHB in R. eutropha is proposed which is connected by crotonyl-CoA to the beta-oxidation cycle. According to this model, the NADPH-dependent synthesis of PHB with (R)-3HB-CoA as the intermediate and the PHB degradation yielding (S) 3HB-CoA, which is further converted in an NAD-dependent reaction, are separated. PMID- 23667238 TI - The multifunctional protein YdiV represses P fimbria-mediated adherence in uropathogenic Escherichia coli. AB - YdiV, a degenerate EAL domain protein, represses motility by interacting with FlhD to abolish FlhDC interaction with DNA. Here, we demonstrate that deletion of ydiV dysregulates coordinate control of motility and adherence by increasing adherence of Escherichia coli CFT073 to a bladder epithelial cell line by specifically increasing production of P fimbriae. Interestingly, only one of the two P fimbrial operons, pap_2, present in the genome of E. coli CFT073 was upregulated. This derepression of the pap_2 operon is abolished following deletion of either cya or crp, demonstrating cyclic AMP (cAMP)-dependent activation of the P fimbrial operon. However, the absence of YdiV does not affect the gene expression of cya and crp, and loss of SdiA in the ydiV mutant does not affect the derepression of the pap_2 operon, suggesting that YdiV control of adherence acts in response to cAMP levels. Deletion of ydiV increases motility by increasing expression of fliA, suggesting that in E. coli CFT073, YdiV regulates motility by the same mechanism as that described previously for commensal E. coli strains. Furthermore, analysis of site-directed mutations found two putative Mg(2+)-binding residues of four conserved YdiV residues (E29 and Q219) that were involved in regulation of motility and FliC production, while two conserved c-di GMP-binding residues (D156 and D165) only affected motility. None of the four conserved YdiV residues appeared to affect regulation of adherence. Therefore, we propose a model in which a degenerate EAL, YdiV, utilizes different domains to regulate motility through interaction with FlhD and adherence to epithelial cells through cAMP-dependent effects on the pap_2 promoter. PMID- 23667239 TI - Cyclohexanecarboxyl-coenzyme A (CoA) and cyclohex-1-ene-1-carboxyl-CoA dehydrogenases, two enzymes involved in the fermentation of benzoate and crotonate in Syntrophus aciditrophicus. AB - The strictly anaerobic Syntrophus aciditrophicus is a fermenting deltaproteobacterium that is able to degrade benzoate or crotonate in the presence and in the absence of a hydrogen-consuming partner. During growth in pure culture, both substrates are dismutated to acetate and cyclohexane carboxylate. In this work, the unknown enzymes involved in the late steps of cyclohexane carboxylate formation were studied. Using enzyme assays monitoring the oxidative direction, a cyclohex-1-ene-1-carboxyl-CoA (Ch1CoA)-forming cyclohexanecarboxyl-CoA (ChCoA) dehydrogenase was purified and characterized from S. aciditrophicus and after heterologous expression of its gene in Escherichia coli. In addition, a cyclohexa-1,5-diene-1-carboxyl-CoA (Ch1,5CoA)-forming Ch1CoA dehydrogenase was characterized after purification of the heterologously expressed gene. Both enzymes had a native molecular mass of 150 kDa and were composed of a single, 40- to 45-kDa subunit; both contained flavin adenine dinucleotide (FAD) as a cofactor. While the ChCoA dehydrogenase was competitively inhibited by Ch1CoA in the oxidative direction, Ch1CoA dehydrogenase further converted the product Ch1,5CoA to benzoyl-CoA. The results obtained suggest that Ch1,5CoA is a common intermediate in benzoate and crotonate fermentation that serves as an electron-accepting substrate for the two consecutively operating acyl-CoA dehydrogenases characterized in this work. In the case of benzoate fermentation, Ch1,5CoA is formed by a class II benzoyl-CoA reductase; in the case of crotonate fermentation, Ch1,5CoA is formed by reversing the reactions of the benzoyl-CoA degradation pathway that are also employed during the oxidative (degradative) branch of benzoate fermentation. PMID- 23667240 TI - Flavobacterium johnsoniae GldK, GldL, GldM, and SprA are required for secretion of the cell surface gliding motility adhesins SprB and RemA. AB - Flavobacterium johnsoniae cells move rapidly over surfaces by gliding motility. Gliding results from the movement of adhesins such as SprB and RemA along the cell surface. These adhesins are delivered to the cell surface by a Bacteroidetes specific secretion system referred to as the type IX secretion system (T9SS). GldN, SprE, SprF, and SprT are involved in secretion by this system. Here we demonstrate that GldK, GldL, GldM, and SprA are each also involved in secretion. Nonpolar deletions of gldK, gldL, or gldM resulted in the absence of gliding motility and in T9SS defects. The mutant cells produced SprB and RemA proteins but failed to secrete them to the cell surface. The mutants were resistant to phages that use SprB or RemA as a receptor, and they failed to attach to glass, presumably because of the absence of cell surface adhesins. Deletion of sprA resulted in similar but slightly less dramatic phenotypes. sprA mutant cells failed to secrete SprB and RemA, but cells remained susceptible to some phages and retained some limited ability to glide. The phenotype of the sprA mutant was similar to those previously described for sprE and sprT mutants. SprA, SprE, and SprT are needed for secretion of SprB and RemA but may not be needed for secretion of other proteins targeted to the T9SS. Genetic and molecular experiments demonstrate that gldK, gldL, gldM, and gldN form an operon and suggest that the proteins encoded by these genes may interact to form part of the F. johnsoniae T9SS. PMID- 23667241 TI - PET imaging of colorectal and breast cancer by targeting EphB4 receptor with 64Cu labeled hAb47 and hAb131 antibodies. AB - Accumulating evidence suggests that ephrin type B receptor 4 (EphB4) plays a key role in the progression of numerous cancer types. In this study, we developed a series of (64)Cu-labeled antibodies for PET imaging of tumor EphB4 expression. METHODS: Anti-EphB4 antibodies (hAb47 and hAb131) were conjugated with the (64)Cu chelator DOTA through lysine, cysteine, or oligosaccharide on the antibody. DOTA human IgG (hIgG) was also prepared as a control, which did not bind to EphB4. The EphB4 binding activity of these probes was evaluated through the bead-based binding assay with EphB4-alkaline phosphatase. The resulting PET probes were further evaluated in both HT29 (colorectal cancer) and MDA-MB-231 (breast cancer) xenografts. RESULTS: All 3 conjugation methods retained most of the EphB4 binding activity of the antibodies (83.85% +/- 3.82%, 76.25% +/- 5.90%, 98.93% +/- 3.75%, and 82.09% +/- 4.14% for DOTA-Lys-hAb47, DOTA-Cys-hAb47, DOTA-Sug-hAb47, and DOTA Lys-hAb131, respectively). Although DOTA-Sug-hAb47 demonstrated the highest receptor binding activity based on a EphB4 binding assay, the corresponding PET probe was trapped in the liver quickly in vivo. In HT29 xenografts, both (64)Cu DOTA-Lys-hAb47 and (64)Cu-DOTA-Cys-hAb47 demonstrated prominent tumor accumulation, which reached a maximum at 48 h after injection (18.13 +/- 1.73 percentage injected dose [%ID]/g and 11.81 +/- 2.05 %ID/g, respectively). In contrast, (64)Cu-DOTA-Lys-hIgG had a low tumor accumulation, thus demonstrating the target specificity of EphB4-antibody-based probes. Moreover, (64)Cu-DOTA-Lys hAb131 (29.48 +/- 2.60 %ID/g) demonstrated significantly higher HT29 tumor accumulation than (64)Cu-DOTA-Lys-hAb47. (64)Cu-DOTA-Lys-hAb131 was also found to specifically accumulate in the MDA-MB-231 tumor model (12.96 +/- 2.31 %ID/g). CONCLUSION: We have demonstrated that EphB4 can serve as a valid target for colorectal and breast cancer imaging. This approach would be valuable for evaluating disease course and therapeutic efficacy at the earliest stages of anti EphB4 treatment. Moreover, these newly developed probes may have important applications in other cancer types overexpressing EphB4. PMID- 23667242 TI - The eyes like their targets on a stable background. AB - In normal human visual behavior, our visual system is continuously exposed to abrupt changes in the local contrast and mean luminance in various parts of the visual field, as caused by actual changes in the environment, as well as by movements of our body, head, and eyes. Previous research has shown that both threshold and suprathreshold contrast percepts are attenuated by a co-occurring change in the mean luminance at the location of the target stimulus. In the current study, we tested the hypothesis that contrast targets presented with a co occurring change in local mean luminance receive fewer fixations than targets presented in a region with a steady mean luminance. To that end we performed an eye-tracking experiment involving eight observers. On each trial, after a 4 s adaptation period, an observer's task was to make a saccade to one of two target gratings, presented simultaneously at 7 degrees eccentricity, separated by 30 degrees in polar angle. When both targets were presented with a steady mean luminance, saccades landed mostly in the area between the two targets, signifying the classic global effect. However, when one of the targets was presented with a change in luminance, the saccade distribution was biased towards the target with the steady luminance. The results show that the attenuation of contrast signals by co-occurring, ecologically typical changes in mean luminance affects fixation selection and is therefore likely to affect eye movements in natural visual behavior. PMID- 23667243 TI - Dyadic confirmatory factor analysis of the inflammatory bowel disease family responsibility questionnaire. AB - OBJECTIVES: Evaluate the factor structure of youth and maternal involvement ratings on the Inflammatory Bowel Disease Family Responsibility Questionnaire, a measure of family allocation of condition management responsibilities in pediatric inflammatory bowel disease. METHODS: Participants included 251 youth aged 11-18 years with inflammatory bowel disease and their mothers. Item-level descriptive analyses, subscale internal consistency estimates, and confirmatory factor analyses of youth and maternal involvement were conducted using a dyadic data-analytic approach. RESULTS: Results supported the validity of 4 conceptually derived subscales including general health maintenance, social aspects, condition management tasks, and nutrition domains. Additionally, results indicated adequate support for the factor structure of a 21-item youth involvement measure and strong support for a 16-item maternal involvement measure. CONCLUSIONS: Additional empirical support for the validity of the Inflammatory Bowel Disease Family Responsibility Questionnaire was provided. Future research to replicate current findings and to examine the measure's clinical utility is warranted. PMID- 23667244 TI - Lacrimal gland pleomorphic adenoma: an inconceivable diagnosis in a child. AB - Pleomorphic adenoma is the most common epithelial tumour of the lacrimal gland in adults. It is rare in children less than 10 years. The low incidence in children can lead to low index of suspicion and increased likelihood of misdiagnosis. Incomplete treatment can lead to malignant transformation or recurrence. High index of suspicion is necessary for prompt diagnosis in children younger than 10 years. We describe a rare case of lacrimal gland pleomorphic adenoma (LGPA) in a 7-year-old child. Only four cases have so far been reported in the literature in children younger than 10 years. We emphasise the importance of CT scan and ultrasound-guided fine needle in the diagnosis of LGPA in children. PMID- 23667245 TI - The dental management of troublesome twos: renal tubular acidosis and rampant caries. AB - Renal tubular acidosis is a group of disorders in which there is metabolic acidosis due to defect in renal tubular acidification mechanism to maintain normal plasma bicarbonate and blood pH. Irrespective of organ system involved, oral cavity often reflects the disease occurring anywhere in the body. Thus congenital chronic renal diseases, causing acid-base disturbances affects development and structure of the teeth. Chronic renal tubular acidosis causes enamel defects, dental caries, oral candidiasis, angular cheilitis, etc. We hereby present an unusual case report of a 4-year-old boy suffering from renal tubular acidosis associated with rampant caries, whose full mouth rehabilitation has been done. PMID- 23667246 TI - Bilateral lateral periodontal cyst. AB - The bilateral lateral periodontal cyst is a rare nasological entity, which despite clinical and radiological presentation is being diagnosed by histological characteristics. It is asymptomatic in nature and is observed in routine radiography. The aim and objective of this article is to present a rare case of bilateral lateral periodontal cyst in a 14-year-old child. The clinical and radiographical findings, along with its management have been discussed. Enucleation of bilateral cyst without extraction of the adjacent tooth was performed. Lesion samples were sent for histopathological analysis. The histopathological analysis revealed a thin, non keratinised stratified squamous epithelium resembling reduced enamel epithelium. Epithelial plaques were also seen. A clinicopathological correlation incorporating the surgical, radiographical and gold standard histopathological findings was obtained to suggest the final diagnosis of the bilateral lateral periodontal cyst. PMID- 23667247 TI - Successful autologous simple limbal epithelial transplantation (SLET) in previously failed paediatric limbal transplantation for ocular surface burns. AB - A 3-year-old child sustained severe ocular surface burns in her left eye after accidental lime injury. Despite appropriate management in the acute stage, she developed limbal stem cell deficiency (LSCD) in that eye. This was initially treated with autologous ex vivo cultivated limbal epithelial transplantation (CLET), which unfortunately failed after 6 months resulting in recurrence of LSCD. One year following CLET, she underwent simple limbal epithelial transplantation (SLET) using autologous donor tissue from the healthy fellow eye. Successful restoration of the ocular surface following SLET combined with amblyopia therapy led to significant cosmetic and functional improvement. One year following SLET her vision in the left eye was 20/80 and she continues to maintain a stable, avascular and completely epithelised corneal surface. This case illustrates that SLET is effective in treating LSCD even in cases that are conventionally considered to be at high risk for failure of limbal stem cell transplantation. PMID- 23667249 TI - A Toolkit to assess health needs for congenital disorders in low- and middle income countries: an instrument for public health action. AB - BACKGROUND: In 2010 the World Health Assembly called for action to improve the care and prevention of congenital disorders, noting that technical guidance would be required for this task, especially in low- and middle-income countries. Responding to this call, we have developed a freely available web-accessible Toolkit for assessing health needs for congenital disorders. METHODS: Materials for the Toolkit website (http://toolkit.phgfoundation.org) were prepared by an iterative process of writing, discussion and modification by the project team, with advice from external experts. A customized database was developed using epidemiological, demographic, socio-economic and health-services data from a range of validated sources. Document-processing and data integration software combines data from the database with a template to generate topic- and country specific Calculator documents for quantitative analysis. RESULTS: The Toolkit guides users through selection of topics (including both clinical conditions and relevant health services), assembly and evaluation of qualitative and quantitative information, assessment of the potential effects of selected interventions, and planning and prioritization of actions to reduce the risk or prevalence of congenital disorders. CONCLUSIONS: The Toolkit enables users without epidemiological or public health expertise to undertake health needs assessment as a prerequisite for strategic planning in relation to congenital disorders in their country or region. PMID- 23667248 TI - Estrous cycle regulation of extrasynaptic delta-containing GABA(A) receptor mediated tonic inhibition and limbic epileptogenesis. AB - The ovarian cycle affects susceptibility to behavioral and neurologic conditions. The molecular mechanisms underlying these changes are poorly understood. Deficits in cyclical fluctuations in steroid hormones and receptor plasticity play a central role in physiologic and pathophysiologic menstrual conditions. It has been suggested that synaptic GABA(A) receptors mediate phasic inhibition in the hippocampus and extrasynaptic receptors mediate tonic inhibition in the dentate gyrus. Here we report a novel role of extrasynaptic delta-containing GABA(A) receptors as crucial mediators of the estrous cycle-related changes in neuronal excitability in mice, with hippocampus subfield specificity. In molecular and immunofluorescence studies, a significant increase occurred in delta-subunit, but not alpha4- and gamma2-subunits, in the dentate gyrus during diestrus. However, delta-subunit upregulation was not evident in the CA1 region. The delta-subunit expression was undiminished by age and ovariectomy and in mice lacking progesterone receptors, but it was significantly reduced by finasteride, a neurosteroid synthesis inhibitor. Electrophysiologic studies confirmed greater potentiation of GABA currents by progesterone-derived neurosteroid allopregnanolone in dissociated dentate gyrus granule cells in diestrus than in CA1 pyramidal cells. The baseline conductance and allopregnanolone potentiation of tonic currents in dentate granule cells from hippocampal slices were higher than in CA1 pyramidal cells. In behavioral studies, susceptibility to hippocampus kindling epileptogenesis was lower in mice during diestrus. These results demonstrate the estrous cycle-related plasticity of neurosteroid-sensitive, delta containing GABA(A) receptors that mediate tonic inhibition and seizure susceptibility. These findings may provide novel insight on molecular cascades of menstrual disorders like catamenial epilepsy, premenstrual syndrome, and migraine. PMID- 23667250 TI - Reduced taste sensitivity in congenital blindness. AB - Sight is undoubtedly not only important for food identification and selection but also for the modulation of gustatory sensitivity. We can, therefore, assume that taste sensitivity and eating habits are affected by visual deprivation from birth. We measured taste detection and identification thresholds of the 5 basic tastants in 13 congenitally blind and 13 sighted control subjects. Participants also answered several eating habits questionnaires, including the Food Neophobia Scale, the Food Variety Seeking Tendency Scale, the Intuitive Eating Scale, and the Body Awareness Questionnaire. Our behavioral results showed that compared with the normal sighted, blind subjects have increased thresholds for taste detection and taste identification. This finding is at odds with the superior performance of congenitally blind subjects in several tactile, auditory and olfactory tasks. Our psychometric data further indicate that blind subjects more strongly rely on internal hunger and satiety cues, instead of external contextual or emotional cues, to decide when and what to eat. We suggest that the lower taste sensitivity observed in congenitally blind individuals is due to various blindness-related obstacles when shopping for food, cooking and eating out, all of which contribute to underexpose the gustatory system to a larger variety of taste stimuli. PMID- 23667251 TI - Hypoxia-inducible factor-1alpha (HIF-1alpha) promotes cap-dependent translation of selective mRNAs through up-regulating initiation factor eIF4E1 in breast cancer cells under hypoxia conditions. AB - Hypoxia promotes tumor evolution and metastasis, and hypoxia-inducible factor 1alpha (HIF-1alpha) is a key regulator of hypoxia-related cellular processes in cancer. The eIF4E translation initiation factors, eIF4E1, eIF4E2, and eIF4E3, are essential for translation initiation. However, whether and how HIF-1alpha affects cap-dependent translation through eIF4Es in hypoxic cancer cells has been unknown. Here, we report that HIF-1alpha promoted cap-dependent translation of selective mRNAs through up-regulation of eIF4E1 in hypoxic breast cancer cells. Hypoxia-promoted breast cancer tumorsphere growth was HIF-1alpha-dependent. We found that eIF4E1, not eIF4E2 or eIF4E3, is the dominant eIF4E family member in breast cancer cells under both normoxia and hypoxia conditions. eIF4E3 expression was largely sequestered in breast cancer cells at normoxia and hypoxia. Hypoxia up-regulated the expression of eIF4E1 and eIF4E2, but only eIF4E1 expression was HIF-1alpha-dependent. In hypoxic cancer cells, HIF-1alpha-up-regulated eIF4E1 enhanced cap-dependent translation of a subset of mRNAs encoding proteins important for breast cancer cell mammosphere growth. In searching for correlations, we discovered that human eIF4E1 promoter harbors multiple potential hypoxia response elements. Furthermore, using chromatin immunoprecipitation (ChIP) and luciferase and point mutation assays, we found that HIF-1alpha utilized hypoxia response elements in the human eIF4E1 proximal promoter region to activate eIF4E1 expression. Our study suggests that HIF-1alpha promotes cap dependent translation of selective mRNAs through up-regulating eIF4E1, which contributes to tumorsphere growth of breast cancer cells at hypoxia. The data shown provide new insights into protein synthesis mechanisms in cancer cells at low oxygen levels. PMID- 23667252 TI - Yes-associated protein (YAP) promotes cell survival by inhibiting proapoptotic dendrin signaling. AB - Kidney podocytes are highly specialized terminally differentiated cells that form the final barrier to urinary protein loss. Podocytes are a target for injury by metabolic, autoimmune, hereditary, inflammatory, and other stressors. Persistence of podocyte injury leads to podocyte death and loss, which results in progressive kidney damage and ultimately kidney failure. Dendrin is a dual compartment protein with proapoptotic signaling properties. Nuclear relocation of dendrin in response to glomerular injury promotes podocyte apoptosis. Here we show that Yes associated protein (YAP), a downstream target of Hippo kinases and an inhibitor of apoptosis, is expressed in the nucleus of podocytes. The WW domains of YAP mediate the interaction with the PPXY motifs of dendrin. This interaction is functionally relevant because YAP binding to dendrin reduces dendrin-dependent, staurosporine-induced apoptosis in co-transfected HEK293 cells. Moreover gene silencing of YAP in podocytes increases adriamycin-induced podocyte apoptosis. It also increases staurosporine-induced caspase-3/7 activity, which is rescued by dendrin depletion in YAP knockdown cells. Our findings elucidate YAP binding to dendrin as a prosurvival mechanism. The antiapoptotic signaling properties of YAP in podocytes could hold significance in the quest for targeted therapeutics aimed at preventing podocyte loss. PMID- 23667253 TI - The Hbs1-Dom34 protein complex functions in non-stop mRNA decay in mammalian cells. AB - In yeast, aberrant mRNAs lacking in-frame termination codons are recognized and degraded by the non-stop decay (NSD) pathway. The recognition of non-stop mRNAs involves a member of the eRF3 family of GTP-binding proteins, Ski7. Ski7 is thought to bind the ribosome stalled at the 3'-end of the mRNA poly(A) tail and recruit the exosome to degrade the aberrant message. However, Ski7 is not found in mammalian cells, and even the presence of the NSD mechanism itself has remained enigmatic. Here, we show that unstable non-stop mRNA is degraded in a translation-dependent manner in mammalian cells. The decay requires another eRF3 family member (Hbs1), its binding partner Dom34, and components of the exosome Ski complex (Ski2/Mtr4 and Dis3). Hbs1-Dom34 binds to form a complex with the exosome-Ski complex. Also, the elimination of aberrant proteins produced from non stop transcripts requires the RING finger protein listerin. These findings demonstrate that the NSD mechanism exists in mammalian cells and involves Hbs1, Dom34, and the exosome-Ski complex. PMID- 23667254 TI - Structural characteristics of the redox-sensing coiled coil in the voltage-gated H+ channel. AB - Oxidation is an important biochemical defense mechanism, but it also elicits toxicity; therefore, oxidation must be under strict control. In phagocytotic events in neutrophils, the voltage-gated H(+) (Hv) channel is a key regulator of the production of reactive oxygen species against invading bacteria. The cytoplasmic domain of the Hv channel forms a dimeric coiled coil underpinning a dimerized functional unit. Importantly, in the alignment of the coiled-coil core, a conserved cysteine residue forms a potential intersubunit disulfide bond. In this study, we solved the crystal structures of the coiled-coil domain in reduced, oxidized, and mutated (Cys -> Ser) states. The crystal structures indicate that a pair of Cys residues forms an intersubunit disulfide bond dependent on the redox conditions. CD spectroscopy revealed that the disulfide bond increases the thermal stability of the coiled-coil protein. We also reveal that two thiol modifier molecules are able to bind to Cys in a redox-dependent manner without disruption of the dimeric coiled-coil assembly. Thus, the biochemical properties of the cytoplasmic coiled-coil domain in the Hv channel depend on the redox condition, which may play a role in redox sensing in the phagosome. PMID- 23667255 TI - The nuclear import of oncoprotein hepatitis B X-interacting protein depends on interacting with c-Fos and phosphorylation of both proteins in breast cancer cells. AB - Aberrant nuclear localization of oncogenic transcription factors and coactivators always leads to the development of cancer. We have reported that the oncoprotein hepatitis B X-interacting protein (HBXIP) acts as a novel transcriptional coactivator to promote proliferation and migration of breast cancer cells. However, the mechanism of regulating the nuclear import of HBXIP remains unclear. In the present study, we found that HBXIP interacted with c-Fos through their leucine zipper domains in vitro and in vivo. Interestingly, the leucine zipper mutant of HBXIP (or c-Fos) was unavailable to bind to c-Fos (or HBXIP), resulting in the disappearance of nuclear localization of HBXIP. Moreover, we revealed that the nuclear import of HBXIP was required for phosphorylation of c-Fos at Thr(232), Thr(325), Thr(331), and Ser(374) by ERK1/2. In addition, the mutant of HBXIP at the Ser(108) phosphorylation site failed to import into the nucleus. Strikingly, we found that the kinase ataxia telangiectasia mutated (ATM) phosphorylated HBXIP at Ser(108). The knockdown of ATM by siRNA remarkably decreased the levels of serine phosphorylation and blocked the nuclear import of HBXIP. Then, we identified that ATM could bind to HBXIP. Moreover, we validated that the nuclear import of HBXIP contributed to its nuclear function. Therefore, we conclude that the nuclear import of the oncoprotein HBXIP requires interaction with c-Fos through their leucine zipper domains and phosphorylation of both proteins in breast cancer cells. Thus, our findings provide new insights into the mechanism of the nuclear import of HBXIP. Therapeutically, the block of the nuclear import of HBXIP is significant in breast cancer. PMID- 23667256 TI - Zeb1 regulates E-cadherin and Epcam (epithelial cell adhesion molecule) expression to control cell behavior in early zebrafish development. AB - The ZEB1 transcription factor is best known as an inducer of epithelial mesenchymal transitions (EMT) in cancer metastasis, acting through transcriptional repression of CDH1 (encoding E-cadherin) and the EMT-suppressing microRNA-200s (miR-200s). Here we analyze roles of the ZEB1 zebrafish orthologs, Zeb1a and Zeb1b, and of miR-200s in control of cell adhesion and morphogenesis during gastrulation and segmentation stages. Loss and gain of function analyses revealed that Zeb1 represses cdh1 expression to fine-tune adhesiveness of migrating deep blastodermal cells. Furthermore, Zeb1 acts as a repressor of epcam in the deep cells of the blastoderm and may contribute to control of epithelial integrity of enveloping layer cells, the outermost cells of the blastoderm. We found a similar ZEB1-dependent repression of EPCAM expression in human pancreatic and breast cancer cell lines, mediated through direct binding of ZEB1 to the EPCAM promoter. Thus, Zeb1 proteins employ several evolutionary conserved mechanisms to regulate cell-cell adhesion during development and cancer. PMID- 23667257 TI - Direct expression and validation of phage-selected peptide variants in mammalian cells. AB - Phage display is a key technology for the identification and maturation of high affinity peptides, antibodies, and other proteins. However, limitations of bacterial expression restrict the range and sensitivity of assays that can be used to evaluate phage-selected variants. To address this problem, selected genes are typically transferred to mammalian expression vectors, a major rate-limiting step in the iterative improvement of peptides and proteins. Here we describe a system that combines phage display and efficient mammalian expression in a single vector, pDQ1. This system permits immediate expression of phage-selected genes as IgG1-Fc fusions in mammalian cells, facilitating the rapid, sensitive characterization of a large number of library outputs for their biochemical and functional properties. We demonstrate the utility of this system by improving the ability of a CD4-mimetic peptide to bind the HIV-1 envelope glycoprotein and neutralize HIV-1 entry. We further improved the potency of the resulting peptide, CD4mim6, by limiting its ability to induce the CD4-bound conformation of the envelope glycoprotein. Thus, CD4mim6 and its variants can be used to investigate the properties of the HIV-1 envelope glycoprotein, and pDQ1 can accelerate the discovery of new peptides and proteins through phage display. PMID- 23667259 TI - Suspected early Lyme neuroborreliosis in patients with erythema migrans. AB - BACKGROUND: Our objective was to obtain data on patients with erythema migrans (EM) who have symptoms/signs suggesting nervous system involvement and to compare epidemiologic, clinical, and microbiologic findings in patients with and without cerebrospinal fluid (CSF) pleocytosis. METHODS: Adult patients with EM and suspected early Lyme neuroborreliosis were included in this study. RESULTS: Of 161 patients, 31 (19%) had elevated and 130 (81%) had normal CSF cell counts. In contrast to patients with normal CSF cell counts, those with pleocytosis (1) more often reported radicular pain and more often presented with meningeal signs but less frequently complained of malaise; (2) had larger EM skin lesions despite similar duration; (3) more commonly had Borrelia garinii isolated from EM skin lesions (odds ratio for pleocytosis was 31 times higher in patients with established B. garinii skin infection compared to patients with other Borrelia species isolated from their EM skin lesion) and from CSF; and (4) more frequently fulfilled microbiologic criteria for established borrelial infection of the central nervous system. The positive predictive value of pleocytosis for microbiologically proven borrelial infection of the central nervous system (defined by isolation of Borrelia from CSF and/or demonstration of intrathecal synthesis of borrelial antibodies) was 67.9%, whereas normal CSF white cell counts ruled out Lyme neuroborreliosis with a predictive value of 91.9%. CONCLUSIONS: Comparison of European patients with EM who had symptoms/signs suggesting early Lyme neuroborreliosis revealed several differences in the clinical presentation and in microbiologic test results according to CSF findings. PMID- 23667258 TI - Structure-based discovery of antagonists of nuclear receptor LRH-1. AB - Liver receptor homolog 1 (nuclear receptor LRH-1, NR5A2) is an essential regulator of gene transcription, critical for maintenance of cell pluripotency in early development and imperative for the proper functions of the liver, pancreas, and intestines during the adult life. Although physiological hormones of LRH-1 have not yet been identified, crystallographic and biochemical studies demonstrated that LRH-1 could bind regulatory ligands and suggested phosphatidylinositols as potential hormone candidates for this receptor. No synthetic antagonists of LRH-1 are known to date. Here, we identify the first small molecule antagonists of LRH-1 activity. Our search for LRH-1 modulators was empowered by screening of 5.2 million commercially available compounds via molecular docking followed by verification of the top-ranked molecules using in vitro direct binding and transcriptional assays. Experimental evaluation of the predicted ligands identified two compounds that inhibit the transcriptional activity of LRH-1 and diminish the expression of the receptor's target genes. Among the affected transcriptional targets are co-repressor SHP (small heterodimer partner) as well as cyclin E1 (CCNE1) and G0S2 genes that are known to regulate cell growth and proliferation. Treatments of human pancreatic (AsPC 1), colon (HT29), and breast adenocarcinoma cells T47D and MDA-MB-468 with the LRH-1 antagonists resulted in the receptor-mediated inhibition of cancer cell proliferation. Our data suggest that specific antagonists of LRH-1 could be used as specific molecular probes for elucidating the roles of the receptor in different types of malignancies. PMID- 23667260 TI - The "epic" challenge of optimizing antimicrobial stewardship: the role of electronic medical records and technology. AB - Antimicrobial stewardship programs (ASPs) are established means for institutions to improve patient outcomes while reducing the emergence of resistant bacteria. With the increased adoption and evolution of electronic medical records (EMRs), there is a need to assimilate the tools of ASPs into EMRs, using decision support and feedback. Third-party software vendors provide the mainstay for integration of individual institutional EMR and ASP efforts. Epic is the leading implementer of EMR technology in the United States. A collaboration of physicians and pharmacists are working closely with Epic to provide a more comprehensive platform of ASP tools that may be institutionally individualized. We review the historical relationship between ASPs and the EMR, cite examples of Epic stewardship tools from 3 academic medical centers' ASPs, discuss limitations of these Epic tools, and conclude with the current process in evolution to integrate ASP tools and decision support capacities directly into Epic's EMR. PMID- 23667261 TI - Toward a better understanding of European lyme neuroborreliosis. PMID- 23667262 TI - Genotype 4 hepatitis e virus in france: an autochthonous infection with a more severe presentation. AB - Among hepatitis E virus (HEV) infections diagnosed in 2011 by the French Reference Centre for HEV, 9 were due to genotype 4, which until recently was limited to Asia. Sequences from autochthonous cases formed a single cluster very similar to Belgian swine sequences. Clinical presentation differed from genotype 3 infections. PMID- 23667263 TI - Aspergillosis due to voriconazole highly resistant Aspergillus fumigatus and recovery of genetically related resistant isolates from domiciles. AB - BACKGROUND: Azole resistance is an emerging problem in Aspergillus fumigatus and complicates the management of patients with Aspergillus-related diseases. Selection of azole resistance may occur through exposure to azole fungicides in the environment. In the Netherlands a surveillance network was used to investigate the epidemiology of resistance selection in A. fumigatus. METHODS: Clinical A. fumigatus isolates were screened for azole resistance in 8 university hospitals using azole agar dilution plates. Patient information was collected using an online questionnaire and azole-resistant A. fumigatus isolates were analyzed using gene sequencing, susceptibility testing, and genotyping. Air sampling was performed to investigate the presence of resistant isolates in hospitals and domiciles. RESULTS: Between December 2009 and January 2011, 1315 A. fumigatus isolates from 921 patients were screened. A new cyp51A-mediated resistance mechanism (TR46/Y121F/T289A) was observed in 21 azole-resistant isolates from 15 patients in 6 hospitals. TR46/Y121F/T289A isolates were highly resistant to voriconazole (minimum inhibitory concentration >=16 mg/L). Eight patients presented with invasive aspergillosis due to TR46/Y121F/T289A, and treatment failed in all 5 patients receiving primary therapy with voriconazole. TR46/Y121F/T289A Aspergillus fumigatus was recovered from 6 of 10 sampled environmental sites. CONCLUSIONS: We describe the emergence and geographical migration of a voriconazole highly resistant A. fumigatus that was associated with voriconazole treatment failure in patients with invasive aspergillosis. Recovery of TR46/Y121F/T289A from the environment suggests an environmental route of resistance selection. Exposure of A. fumigatus to azole fungicides may facilitate the emergence of new resistance mechanisms over time, thereby compromising the use of azoles in the management of Aspergillus-related diseases. PMID- 23667265 TI - Voriconazole resistance in Aspergillus fumigatus: should we be concerned? PMID- 23667264 TI - Prediction of HIV drug resistance based on virologic, immunologic, clinical, and/or adherence criteria in the Stratall ANRS 12110/ESTHER trial in Cameroon. AB - Our study in Cameroonian rural district hospitals showed that the immunologic and clinical failure criteria had poor performance to identify human immunodeficiency virus drug resistance in a timely manner. Switching to second-line antiretroviral therapy after 2 consecutive viral loads >=5000 copies/mL, as recommended by the World Health Organization, appeared to be the most appropriate strategy. PMID- 23667266 TI - Immunogenicity and safety of the human papillomavirus 6, 11, 16, 18 vaccine in HIV-infected young women. AB - BACKGROUND: The objective of this study was to determine whether the 3-dose quadrivalent human papillomavirus (HPV) vaccine series (HPV-6, -11, -16, -18) is immunogenic and safe in young women infected with human immunodeficiency virus (HIV). METHODS: We enrolled 99 women aged 16-23 years in a phase 2, open-label, multicenter trial, conducted from 2008 to 2011 by the Adolescent Medicine Trials Network for HIV/AIDS Interventions. Outcome measures were immunogenicity 4 weeks after dose 3, measured by (1) geometric mean titers (GMTs) and (2) seroconversion rates for HPV-6, -11, -16, and -18, among those seronegative and HPV DNA negative for each type. Immune responses were compared to those of a historical comparison group of HIV-negative women (n = 267) using univariate methods. Clinical and laboratory adverse events were assessed after each dose. RESULTS: The mean age of subjects was 21.4 years; 80% were non-Hispanic black, 69 were not taking antiretroviral therapy (ART), and 30 were taking ART. No differences in GMTs were noted among participants taking ART vs the comparison group, but GMTs were lower in participants not taking ART vs the comparison group for HPV-16 (2393 vs 3892 milli-Merck units per milliliter [mMU/mL], P = .012) and HPV-18 (463 vs 801 mMU/mL, P = .003). Seroconversion rates were 100% for HPV-6, -11, -16, and -18 among participants taking ART. Rates ranged from 92.3% (for HPV-18) to 100.0% (for HPV-6) among participants not taking ART. One severe adverse event (fatigue) was noted. CONCLUSIONS: In a sample of HIV-infected women who were HPV DNA and HPV seronegative, immune responses to HPV vaccination were generally robust and the vaccine was well tolerated. PMID- 23667267 TI - Laboratory diagnosis of HIV in adults: a review of current methods. AB - Of the estimated 1.2 million people infected with human immunodeficiency virus (HIV) in the United States, 20% are unaware of their diagnosis. Improved methods of HIV testing could decrease this number, as well as identify those who have recently acquired HIV infection and are at the most critical stage of infectivity. People with acute HIV infection have demonstrated enhanced transmission of HIV in multiple epidemiologic and pathogenetic studies. More than 50 000 HIV infections occur annually in the United States, and 30%-50% have been attributed to persons with recent infection. The original HIV diagnostic testing algorithm was developed by the Centers for Disease Control and Prevention in 1989. Recently proposed alterations to the algorithm would incorporate advancements made in HIV diagnostic testing, thereby increasing sensitivity while reducing turnaround time and cost. Improved diagnosis of acute HIV, and HIV type 2 in particular, would be expected. Knowledge of the available laboratory methods for HIV diagnosis is essential in the fight against the spread of HIV. PMID- 23667268 TI - Efficacy of implantable cardioverter defibrillators in young patients with catecholaminergic polymorphic ventricular tachycardia: success depends on substrate. AB - BACKGROUND: The effectiveness of implantable cardioverter-defibrillator (ICD) therapy for the management of catecholaminergic polymorphic ventricular tachycardia (VT) in young patients is not known. ICD discharges are not always effective and inappropriate discharges are common, both resulting in morbidity and mortality. METHODS AND RESULTS: This is a multicenter, retrospective review of young patients with catecholaminergic polymorphic VT and ICDs from 5 centers. ICD discharges were evaluated to determine arrhythmia mechanism, appropriateness, efficacy of therapy, and complications. A total of 24 patients were included. Median (interquartile range) ages at onset of catecholaminergic polymorphic VT symptoms and ICD implant were 10.6 (5.0-13.8) years and 13.7 (10.7-16.3) years, respectively. Fourteen patients received 140 shocks. Ten patients (42%) experienced 75 appropriate shocks and 11 patients (46%) received 65 inappropriate shocks. On actuarial analysis, freedom from appropriate shock at 1 year after ICD implant was 75%. Of appropriate shocks, only 43 (57%) demonstrated successful primary termination. All successful appropriate ICD discharges were for ventricular fibrillation. No episodes of polymorphic VT or bidirectional VT demonstrated successful primary termination. The adjusted mean (95% confidence interval) cycle length of successful discharges was significantly shorter than unsuccessful discharges (168 [152-184] ms versus 245 [229-262] ms; adjusted P=0.002). Electrical storm occurred in 29% (4/14) and induction of more malignant ventricular arrhythmias in 36% (5/14). There were no deaths. CONCLUSIONS: ICD efficacy in catecholaminergic polymorphic VT depends on arrhythmia mechanism. Episodes of ventricular fibrillation were uniformly successfully treated, whereas polymorphic and bidirectional VT did not demonstrate successful primary termination. Inappropriate shocks, electrical storm, and ICD complications were common. PMID- 23667269 TI - Postoperative troponin screening: a cardiac Cassandra? PMID- 23667271 TI - A COMPUTATIONAL MEASURE THEORETIC APPROACH TO INVERSE SENSITIVITY PROBLEMS II: A POSTERIORI ERROR ANALYSIS. AB - In part one of this paper [T. Butler and D. Estep, SIAM J. Numer. Anal., to appear], we develop and analyze a numerical method to solve a probabilistic inverse sensitivity analysis problem for a smooth deterministic map assuming that the map can be evaluated exactly. In this paper, we treat the situation in which the output of the map is determined implicitly and is difficult and/or expensive to evaluate, e.g., requiring the solution of a differential equation, and hence the output of the map is approximated numerically. The main goal is an a posteriori error estimate that can be used to evaluate the accuracy of the computed distribution solving the inverse problem, taking into account all sources of statistical and numerical deterministic errors. We present a general analysis for the method and then apply the analysis to the case of a map determined by the solution of an initial value problem. PMID- 23667270 TI - Myocardial injury after noncardiac surgery and its association with short-term mortality. AB - BACKGROUND: To identify patients at risk for postoperative myocardial injury and death, measuring cardiac troponin routinely after noncardiac surgery has been suggested. Such monitoring was implemented in our hospital. The aim of this study was to determine the predictive value of postoperative myocardial injury, as measured by troponin elevation, on 30-day mortality after noncardiac surgery. METHODS AND RESULTS: This observational, single-center cohort study included 2232 consecutive intermediate- to high-risk noncardiac surgery patients aged >=60 years who underwent surgery in 2011. Troponin was measured on the first 3 postoperative days. Log binomial regression analysis was used to estimate the association between postoperative myocardial injury (troponin I level >0.06 MUg/L) and all-cause 30-day mortality. Myocardial injury was found in 315 of 1627 patients in whom troponin I was measured (19%). All-cause death occurred in 56 patients (3%). The relative risk of a minor increase in troponin (0.07-0.59 MUg/L) was 2.4 (95% confidence interval, 1.3-4.2; P<0.01), and the relative risk of a 10- to 100-fold increase in troponin (>=0.60 MUg/L) was 4.2 (95% confidence interval, 2.1-8.6; P<0.01). A myocardial infarction according to the universal definition was diagnosed in 10 patients (0.6%), of whom 1 (0.06%) had ST-segment elevation myocardial infarction. CONCLUSIONS: Postoperative myocardial injury is an independent predictor of 30-day mortality after noncardiac surgery. Implementation of postoperative troponin monitoring as standard of care is feasible and may be helpful in improving the prognosis of patients undergoing noncardiac surgery. PMID- 23667272 TI - A Multiphysics Modeling Approach to Develop Right Ventricle Pulmonary Valve Replacement Surgical Procedures with a Contracting Band to Improve Ventricle Ejection Fraction. AB - Patients with repaired tetralogy of Fallot account for the majority of cases with late onset right ventricle (RV) failure. A new surgical procedure placing an elastic band in the right ventricle is proposed to improve RV function measured by ejection fraction. A multiphysics modeling approach is developed to combine cardiac magnetic resonance imaging, modeling, tissue engineering and mechanical testing to demonstrate feasibility of the new surgical procedure. Our modeling results indicated that the new surgical procedure has the potential to improve right ventricle ejection fraction by 2-7% which compared favorably with recently published drug trials to treat LV heart failure. PMID- 23667273 TI - Pharmacotherapy of PTSD: Current Status and Controversies. PMID- 23667274 TI - STAYING AT THE TABLE: BUILDING SUSTAINABLE COMMUNITY-RESEARCH PARTNERSHIPS. AB - In this study, the authors identify three guiding principles or relational strategies for developing successful community partnerships and building an alliance for systemic change. These principles were derived from their work over 4 years with an urban public school system, which was focused on generating a series of interventions for improving the behavioral and academic functioning of immigrant students. In their process, they developed an analysis and monitoring system of students' progress, which allowed for earlier targeted effective support. PMID- 23667275 TI - Intergenerational Transfers, the Biological Life Cycle, and Human Society. PMID- 23667276 TI - A citation-analysis of economic research institutes. AB - The citation analysis of the research output of the German economic research institutes presented here is based on publications in peer-reviewed journals listed in the Social Science Citation Index for the 2000-2009 period. The novel feature of the paper is that a count data model quantifies the determinants of citation success and simulates their citation potential. Among the determinants of the number of cites the quality of the publication outlet exhibits a strong positive effect. The same effect has the number of the published pages, but journals with size limits also yield more cites. Field journals get less citations in comparison to general journals. Controlling for journal quality, the number of co-authors of a paper has no effect, but it is positive when co-authors are located outside the own institution. We find that the potential citations predicted by our best model lead to different rankings across the institutes than current citations indicating structural change. PMID- 23667277 TI - Organizational Life and Political Incorporation of Two Asian Immigrant Groups: A Case Study. AB - Civil society is the foundation of a healthy democracy but its immigrant element has received little attention. This paper is a case study of immigrant organizations of highly-skilled Asian Indians and Chinese immigrants in a suburban town of Edison, New Jersey. I find that civic participation of Asian Indian immigrants spills over into political incorporation while Chinese immigrant organizations remain marginalized. I argue the local processes of racialization are central in explaining differences in political incorporation of immigrants. In the local context, the Chinese are seen as successful but conformist model minorities and Asian Indians as invaders and troublemakers. The racialization of Asian Indians has resulted in more political activity and higher levels of political visibility of their organizations. The results highlight shortcomings of current assimilation theories, which give little space to civic and political incorporation and view human capital in an unqualifiedly positive light. PMID- 23667278 TI - Population-Adjusted Street Connectivity, Urbanicity and Risk of Obesity in the U.S. AB - Street connectivity, defined as the number of (3-way or more) intersections per area unit, is an important index of built environments as a proxy for walkability in a neighborhood. This paper examines its geographic variations across the rural urban continuum (urbanicity), major racial-ethnic groups and various poverty levels. The population-adjusted street connectivity index is proposed as a better measure than the regular index for a large area such as county due to likely concentration of population in limited space within the large area. Based on the data from the Behavioral Risk Factor Surveillance System (BRFSS), this paper uses multilevel modeling to analyze its association with physical activity and obesity while controlling for various individual and county-level variables. Analysis of data subsets indicates that the influences of individual and county-level variables on obesity risk vary across areas of different urbanization levels. The positive influence of street connectivity on obesity control is limited to the more but not the mostly urbanized areas. This demonstrates the value of obesogenic environment research in different geographic settings, helps us reconcile and synthesize some seemingly contradictory results reported in different studies, and also promotes that effective policies need to be highly sensitive to the diversity of demographic groups and geographically adaptable. PMID- 23667279 TI - Partially hidden Markov model for time-varying principal stratification in HIV prevention trials. AB - It is frequently of interest to estimate the intervention effect that adjusts for post-randomization variables in clinical trials. In the recently completed HPTN 035 trial, there is differential condom use between the three microbicide gel arms and the No Gel control arm, so that intention to treat (ITT) analyses only assess the net treatment effect that includes the indirect treatment effect mediated through differential condom use. Various statistical methods in causal inference have been developed to adjust for post-randomization variables. We extend the principal stratification framework to time-varying behavioral variables in HIV prevention trials with a time-to-event endpoint, using a partially hidden Markov model (pHMM). We formulate the causal estimand of interest, establish assumptions that enable identifiability of the causal parameters, and develop maximum likelihood methods for estimation. Application of our model on the HPTN 035 trial reveals an interesting pattern of prevention effectiveness among different condom-use principal strata. PMID- 23667280 TI - A Unified Approach to Semiparametric Transformation Models under General Biased Sampling Schemes. AB - We propose a unified estimation method for semiparametric linear transformation models under general biased sampling schemes. The new estimator is obtained from a set of counting process-based unbiased estimating equations, developed through introducing a general weighting scheme that offsets the sampling bias. The usual asymptotic properties, including consistency and asymptotic normality, are established under suitable regularity conditions. A closed-form formula is derived for the limiting variance and the plug-in estimator is shown to be consistent. We demonstrate the unified approach through the special cases of left truncation, length-bias, the case-cohort design and variants thereof. Simulation studies and applications to real data sets are presented. PMID- 23667282 TI - The Role of Social Relationships in the Association between Adolescents' Depressive Symptoms and Academic Achievement. AB - While research has established that depression interferes with academic achievement, less is understood about the processes by which social relationships may buffer the relationship between depression and academic outcomes. In this study we examined the role of positive relationships in the school, family and peer contexts in the association between depressive symptoms and academic achievement among 894 adolescents aged 12-17 years living in Santiago, Chile. Depressive symptoms were associated with lower levels of academic achievement; parental monitoring, school belonging, positive mother relationships, and having academically inclined peers moderated this relationship, though some interactions differed by sex and age. Implications for promoting the academic success of adolescents experiencing depressive symptoms are discussed. PMID- 23667281 TI - The DIVA model: A neural theory of speech acquisition and production. AB - The DIVA model of speech production provides a computationally and neuroanatomically explicit account of the network of brain regions involved in speech acquisition and production. An overview of the model is provided along with descriptions of the computations performed in the different brain regions represented in the model. The latest version of the model, which contains a new right-lateralized feedback control map in ventral premotor cortex, will be described, and experimental results that motivated this new model component will be discussed. Application of the model to the study and treatment of communication disorders will also be briefly described. PMID- 23667283 TI - Case Study of the Development of an Infant with Autism from Birth to Two Years of Age. AB - This report describes a case study of the development of an infant with autism who was observed closely by professionals from birth and to whom a comprehensive psychological evaluation was administered at approximately 1 and 2 years of age. During the first 6 months of life, this infant displayed difficulties in oral motor coordination and muscle tone that fluctuated between hypotonia and hypertonia. He startled easily, had poor state regulation, and was hypersensitive to touch. Notably, however, during the first 6 months, this infant vocalized and responded socially to others by smiling and cooing. During the second half of the first year, he continued to demonstrate diffuse sensorimotor difficulties and diminished oral motor control. Hypersensitivity now extended to a wider range of stimuli. He had problems in sleep regulation. Motor stereotypies, including rocking, head banging, and toe walking, were observed. Difficulties in the domain of social interaction began to emerge during the second 6 months, including poor eye contact, failure to engage in imitative games, and lack of imitative vocal responses. By a little over 1 year of age, this infant met diagnostic criteria for autism based on the Autism Diagnostic Interview. There were several domains in which this toddler with autism did not show impairments. In the areas of immediate memory for actions, working memory, response inhibition, and speech perception, this 1-year old with autism displayed no evidence of significant impairment on the tests administered. This case study offers clues regarding the nature of autism at its earliest stages. Understanding early development in autism will be important for developing early screening and diagnostic tools. PMID- 23667284 TI - Marital Happiness and Psychological Well-Being Across the Life Course. AB - Using data from six waves of the Study of Marital Instability over the Life Course (N = 1,998), we conducted a latent class analysis to test for distinct marital happiness trajectories. We found three distinct marital happiness trajectories: low, middle, and high happiness. Initial levels of life happiness were strongly associated with membership in the marital happiness trajectories and with various demographic and attitude-related control variables. Using fixed effects regression with time-varying covariates, we also found that marital happiness trajectory membership was associated with subsequent changes in both life happiness and depressive symptoms. All respondents experienced a decrease in life happiness between Wave 1 and the end of their observed time in their marriage, but respondents in the high marital happiness trajectory experienced the smallest decline. Respondents in both the high and middle marital happiness trajectories also experienced a decline in depressive symptoms across time. Intervention and policy implications are discussed. PMID- 23667285 TI - A note on statistical method for genotype calling of high-throughput SNP arrays. AB - We study the genotype calling algorithms for the high-throughput single nucleotide polymorphism (SNP) arrays. Building upon the novel SNP-RMA preprocessing approach and the state-of-the-art CRLMM approach for genotype calling, we propose a simple modification to better model and combine the information across multiple SNPs with empirical Bayes modeling, which could often significantly improve the genotype calling of CRLMM. Through applications to the HapMap Trio data set and a non-HapMap test set of high quality SNP chips, we illustrate the competitive performance of the proposed method. PMID- 23667286 TI - Immigration, Wealth and the 'Mortality Plateau' in Emergent Urban-Industrial Towns of Nineteenth-Century Massachusetts. AB - The mortality transition in Western Europe and the U.S. encompassed a much more complex set of conditions and experiences than earlier thought. Our research addresses the complex set of relationships among growing urban communities, family wealth, immigration and mortality in New England by examining individual level, socio-demographic mortality correlates during the nineteenth-century mortality plateau and its early twentieth-century decline. In contrast to earlier theories that proposed a more uniform mortality transition, we offer an alternative hypothesis that focuses on the impact of family wealth and immigration on individual-level mortality during the early stages of the mortality transition in Northampton and Holyoke, Massachusetts. PMID- 23667288 TI - Extremely Electron-Rich, Boron-Functionalized, Icosahedral Carborane-Based Phosphinoboranes. AB - We have prepared the first examples of B9-connected trivalent aryl and alkyl phosphinoborane species via Pd-catalyzed phosphination of 9-iodo-meta-carborane. Our studies highlight the unique electronic features of the B9-connected meta carboranyl moiety as compared to its C1-based analogue. This work suggests that the B9-functionalized meta-carboranyl substituent in these ligands exhibits more electron-releasing character than any other known carbon-based substituent, ultimately laying the foundation for a new class of phosphine ligands with extremely electron-rich character. PMID- 23667287 TI - Epidural cortical stimulation and aphasia therapy. AB - BACKGROUND: There are several methods of delivering cortical brain stimulation to modulate cortical excitability and interest in their application as an adjuvant strategy in aphasia rehabilitation after stroke is growing. Epidural cortical stimulation, although more invasive than other methods, permits high frequency stimulation of high spatial specificity to targeted neuronal populations. AIMS: First, we review evidence supporting the use of epidural cortical stimulation for upper limb recovery after focal cortical injury in both animal models and human stroke survivors. These data provide the empirical and theoretical platform underlying the use of epidural cortical stimulation in aphasia. Second, we summarize evidence for the application of epidural cortical stimulation in aphasia. We describe the procedures and primary outcomes of a safety and feasibility study (Cherney, Erickson & Small, 2010), and provide previously unpublished data regarding secondary behavioral outcomes from that study. MAIN CONTRIBUTION: In a controlled study comparing epidural cortical stimulation plus language treatment (CS/LT) to language treatment alone (LT), eight stroke survivors with nonfluent aphasia received intensive language therapy for 6 weeks. Four of these participants also underwent surgical implantation of an epidural stimulation device which was activated only during therapy sessions. Behavioral data were collected before treatment, immediately after treatment, and at 6 and 12 weeks following the end of treatment. The effect size for the primary outcome measure, the Western Aphasia Battery Aphasia Quotient, was benchmarked as moderate from baseline to immediately post-treatment, and large from baseline to the 12-week follow-up. Similarly, effect sizes obtained at the 12-week follow-up for the Boston Naming Test, the Communicative Effectiveness Index, and for correct information units on a picture description task were greater than those obtained immediately post treatment. When effect sizes were compared for individual subject pairs on discourse measures of content and rate, effects were typically larger for the investigational subjects receiving CS/LT than for the control subjects receiving LT alone. These analyses support previous findings regarding therapeutic efficacy of CS/LT compared to LT i.e. epidural stimulation of ipsilesional premotor cortex may augment behavioral speech-language therapy, with the largest effects after completion of therapy. CONCLUSIONS: Continued investigation of epidural cortical stimulation in combination with language training in post-stroke aphasia should proceed cautiously. Carefully planned studies that customize procedures to individual profiles are warranted. Information from research on non-invasive methods of CS/LT may also inform future studies of epidural cortical stimulation. PMID- 23667289 TI - Practical Research Strategies for Reducing Social and Racial/Ethnic Disparities in Obesity. AB - Adult and childhood obesity and related adverse outcomes are most common among racial/ethnic minorities and socio-economically disadvantaged populations in the United States . Research approaches to obesity developed in mainstream populations and deploying new information technologies may exacerbate existing disparities in obesity. Current obesity management and prevention research priorities will not maximally impact this critical problem unless investigators explicitly focus on discovering innovative strategies for preventing and managing obesity in the disadvantaged populations that are most affected. On the basis of our research experience, four key research approaches are needed: (1) elucidating the underlying social forces that lead to disparities; (2) directly involving community members in the development of research questions and research methods; (3) developing flexible strategies that allow tailoring to multiple disadvantaged populations; and (4) building culturally and socio-economically tailored strategies specifically for populations most affected by obesity. Our experience with a community-based longitudinal cohort study and two health center-based clinical trials illustrate these principles as a contrast to traditional research priorities that can inadvertently worsen existing social inequities. If obesity research does not directly address healthcare and health-outcome disparities, it will contribute to their perpetuation. PMID- 23667290 TI - FACIAL ASYMMETRY IS NEGATIVELY RELATED TO CONDITION IN FEMALE MACAQUE MONKEYS. AB - The face is an important visual trait in social communication across many species. In evolutionary terms there are large and obvious selective advantages in detecting healthy partners, both in terms of avoiding individuals with poor health to minimise contagion and in mating with individuals with high health to help ensure healthy offspring. Many models of sexual selection suggest that an individual's phenotype provides cues to their quality. Fluctuating asymmetry is a trait that is proposed to be an honest indicator of quality and previous studies have demonstrated that rhesus monkeys gaze longer at symmetric faces, suggesting preferences for such faces. The current study examined the relationship between measured facial symmetry and measures of health in a captive population of female rhesus macaque monkeys. We measured asymmetry from landmarks marked on front-on facial photographs and computed measures of health based on veterinary health and condition ratings, number of minor and major wounds sustained, and gain in weight over the first four years of life. Analysis revealed that facial asymmetry was negatively related to condition related health measures, with symmetric individuals being healthier than more asymmetric individuals. Facial asymmetry appears to be an honest indicator of health in rhesus macaques and asymmetry may then be used by conspecifics in mate-choice situations. More broadly, our data support the notion that faces are valuable sources of information in non-human primates and that sexual selection based on facial information is potentially important across the primate lineage. PMID- 23667291 TI - Age Differences in Goal Concordance, Time Use, and Well-Being. AB - The primary purpose of the present study was to investigate age differences in goal concordance, time use, and Well-Being. Past research has found that despite age-related decline in life circumstances (e.g., health), the Well-Being of older adults is as high as young adults. The present study used a novel approach to explore the Paradox of Well-Being. One hundred and seventy-seven adults participated in the study. They first generated their three most important personal strivings and rated levels of goal concordance for external, introjected, identified, and intrinsic reasons. Then, they reported their actual and ideal time use in 10 categories of activities in the past 24 hours. Finally, Well-Being was assessed by the Flourishing Scale and the Scale of Positive and Negative Experience (Diener, Wirtz, et al., 2010). Older adults did not differ from young adults in overall Well-Being. However, they held higher levels of goal concordance and were more likely to spend time in spirituality and religion related activities than young adults. The relationships between goal concordance, time use, and Well-Being were examined separately for young and older adults. Implications were discussed to improve Well-Being for young and older adults. PMID- 23667292 TI - SYNTHETIC STUDIES ON MPC1001: A DIPOLAR CYCLOADDITION APPROACH TO THE PYRROLIDINE RING SYSTEM. AB - A novel [1,3]-dipolar azomethine ylide cycloaddition has been developed in an approach to the synthesis of the MPC1001 family of natural products. PMID- 23667294 TI - Cognitive Behavioral Therapy for Adherence and Depression (CBT-AD) in Type 2 Diabetes. AB - Depression is one of the most common psychological problems among individuals diabetes, and it is associated with worse treatment adherence and clinical outcomes. As part of a program of treatment research aimed at integrating interventions for depression and treatment nonadherence, five depressed patients with suboptimally controlled type 2 diabetes were treated with 10-12 sessions of individual cognitive behavioral therapy for adherence and depression (CBT-AD) in a case-series design. The intervention was delivered in a hospital setting by a collaborative team consisting of a psychologist, a nurse educator, and a dietitian. Post-treatment, all participants demonstrated a decrease in depression severity and demonstrated improvements in diabetes self-care. Four of the five demonstrated improved glycemic control. These preliminary results provide evidence for the acceptability, feasibility, and potential utility of CBT-AD for patients with type 2 diabetes and depression. PMID- 23667295 TI - 'A drop of water in the pool': information and engagement of linguistic communities around a municipal pesticide bylaw to protect the public's health. AB - The Multicultural Yard Health and Environment Project (MYHEP) used Toronto's Pesticide Bylaw roll-out process to examine how culturally specific perceptions and practices might influence the relevance of municipal public health information and community engagement strategies and the effectiveness of health protection initiatives. In Canada, and particularly in Toronto, such information is needed for governments to effectively engage with increasingly diverse populations. Focus groups and individual interviews were conducted with Spanish- and Cantonese-speaking participants to document opinions about pesticide use and regulation and views on municipal information and engagement strategies. MYHEP participants reported a need for more accessible environmental health messaging. There was confusion over the safety and legality of pesticide products available for sale in Toronto stores. Most participants indicated they were unwilling to make formal complaints about neighbours who were not complying with the bylaw (an important mechanism for enforcement). Results indicate that environmental health communication and engagement strategies need to be more carefully tailored to address local sociocultural and linguistic contexts in order to provide more equitable environmental health protection and promotion for all residents. These findings led Toronto Public Health to adapt its efforts so as to better engage communities regarding environmental health. PMID- 23667296 TI - The impact of cuts in legal aid funding on charities. AB - This article focusses on the specific impact of the cuts in legal aid funding on the charitable sector. The sector plays a significant role in advice giving. Some charities have the provision of legal advice as their sole purpose, whilst the work of other charities includes the giving of legal advice. Funding comes via a number of sources including legal aid, local authorities and charitable trusts. Whilst this volume highlights the legal aid reforms that will lead to significant cuts in funding, this article notes that charitable providers of legal advice have also suffered major cuts from their other traditional funding sources. Against this background, the article considers the serious and often unforeseen consequences for charities of the legal aid reforms, which go far beyond the impact on the high street law firm and access to justice for claimants. PMID- 23667297 TI - KERNEL-SMOOTHED CONDITIONAL QUANTILES OF CORRELATED BIVARIATE DISCRETE DATA. AB - Socio-economic variables are often measured on a discrete scale or rounded to protect confidentiality. Nevertheless, when exploring the effect of a relevant covariate on the outcome distribution of a discrete response variable, virtually all common quantile regression methods require the distribution of the covariate to be continuous. This paper departs from this basic requirement by presenting an algorithm for nonparametric estimation of conditional quantiles when both the response variable and the covariate are discrete. Moreover, we allow the variables of interest to be pairwise correlated. For computational efficiency, we aggregate the data into smaller subsets by a binning operation, and make inference on the resulting prebinned data. Specifically, we propose two kernel based binned conditional quantile estimators, one for untransformed discrete response data and one for rank-transformed response data. We establish asymptotic properties of both estimators. A practical procedure for jointly selecting band- and binwidth parameters is also presented. Simulation results show excellent estimation accuracy in terms of bias, mean squared error, and confidence interval coverage. Typically prebinning the data leads to considerable computational savings when large datasets are under study, as compared to direct (un)conditional quantile kernel estimation of multivariate data. With this in mind, we illustrate the proposed methodology with an application to a large dataset concerning US hospital patients with congestive heart failure. PMID- 23667298 TI - FAST APPROACH TO THE TRACY-WIDOM LAW AT THE EDGE OF GOE AND GUE. AB - We study the rate of convergence for the largest eigenvalue distributions in the Gaussian unitary and orthogonal ensembles to their Tracy-Widom limits. We show that one can achieve an O(N-2/3) rate with particular choices of the centering and scaling constants. The arguments here also shed light on more complicated cases of Laguerre and Jacobi ensembles, in both unitary and orthogonal versions. Numerical work shows that the suggested constants yield reasonable approximations even for suprisingly small values of N. PMID- 23667299 TI - The Drift toward Problem Behavior during the Transition to Adolescence: The Contributions of Youth Disclosure, Parenting, and Older Siblings. AB - Prospective associations of mothers' parenting processes, youth disclosure and youth problem behavior were examined in a longitudinal design following 244 adolescent sibling dyads over a three year period. For both siblings, authoritative parenting was positively associated with youth disclosure and negatively related to problem behavior, and coercive parenting was negatively associated with youth disclosure and positively related to problem behavior. When the influence of older sibling problem behavior on younger sibling problem behavior was modeled, younger sibling disclosure accounted for the relationship of maternal parenting processes to problem behavior. Findings indicate the important role of sibling influence in the development of problem behavior, contextualizing the relative roles of maternal parenting and youth disclosure in the transmission of risk. PMID- 23667300 TI - Safety Versus Passenger Service: The Flight Attendants' Dilemma. AB - After 9/11, new security duties were instituted at many U.S. air carriers and existing safety and security duties received increased emphasis. Concurrently, in flight services were changed and in many cases, cabin crews were reduced. This article examines the post-9/11 conflict between passenger service and the timely performance of safety and security duties at 1 major U.S. air carrier. In-flight data were obtained on both international and domestic flights. The data suggest that the prompt performance of the safety and security duties is adversely affected by the number of service duties occurring in the later part of both international and domestic flights. PMID- 23667301 TI - Changes in Scoliosis Patient and Parental Assessment of Mental Health in the Course of Cheneau Brace Treatment Based on the Strengths and Difficulties Questionnaire. AB - In the presented study we aimed to investigate the influence of bracing time on perception of mental health by both parents and children with Adolescent Idiopathic Scoliosis (AIS) longitudinally, in relation to socio-demographic and scoliosis-related data. The study design was comprised of three questionnaire assessments, with the second and the third evaluation taking place 6 and 12 months after the beginning of the study, respectively. Thirty-six AIS females treated conservatively and their parents completed the Polish versions of The Strengths and Difficulties Questionnaire-25 (SDQ-25). The results indicated psychiatric disorder was unlikely, but concern all SDQ-25 parent and patient domains and general results. Patient results do not differ significantly in regards to the total score and the particular domains of the SDQ-25. Parents SDQ 25 results differ significantly in regards to the emotional symptoms domain only (p = .023, after Bonferroni correction, the difference is insignificant). The study groups differ significantly within the 2nd evaluation in regards to hyperactivity/inattention domain (p = .026) and within the last evaluation in regards to emotional symptoms domain (p = .009). After Bonferroni correction the differences are insignificant. In general, parents and their children with AIS perceived patients' mental health in a similar way. Patient and parent assessment of mental health was unchanged after a 12-month brace treatment period. Poor psychological outcome was associated with more severe spinal deformity, brace wearing duration and age of patient. PMID- 23667302 TI - Recent clinical and translational research on pediatric myocarditis. AB - Myocarditis is one of the most common causes of a pediatric dilated cardiomyopathy phenotype. While pediatric myocarditis is generally associated with resolution of myocardial dysfunction, approximately 30% of pediatric myocarditis patients will die or undergo heart transplantation. Cardiac magnetic resonance imaging is increasingly being utilized as the primary diagnositic modality in adult myocarditis. Animal studies and adult experience suggest that autoimmunity may contribute to cardiac dysfunction in myocarditis. These adult findings have yet to be evaluated fully in children, but may have an impact on the diagnosis and treatment of pediatric myocarditis in the future. The recent availability of pediatric specific ventricular assist devices may offer the potential for long-term support to allow for a greater chance for myocardial recovery. PMID- 23667303 TI - Associations between Marijuana Use During Emerging Adulthood and Aspects of the Significant Other Relationship in Young Adulthood. AB - A prospective design was used to examine the association of marijuana use during the transition from late adolescence to early adulthood with reported relationship quality with significant other in the mid- to late twenties. The community-based sample consisted of 534 young adults (mean age = 27) from upstate New York. The participants were interviewed at four points in time at mean ages 14, 16, 22, and 27 years. Marijuana use during the transition from late adolescence to early adulthood was associated with less relationship cohesion and harmony, and with more relationship conflict with control on variables reflecting the participants' early interpersonal adjustment and the quality of the relationships with their parents. Findings suggest that marijuana use during emerging adulthood predicts diminished relationship quality with a partner in the mid- to late twenties. PMID- 23667304 TI - The Association of Externalizing Behavior and Parent-Child Relationships: An Intergenerational Study. AB - We investigated the influence of the child's behavior on the quality of the mutual parent-child attachment relationships across three generations. We did so using a prospective longitudinal study which spanned 20 years from adolescence through adulthood. Study participants completed in-class questionnaires as students in the East Harlem area of New York City at the first wave and provided follow-up data at 4 additional points in time. 390 participants were included in these analyses; 59% female, 45% African American, and 55% Puerto Rican. Using structural equation modeling, we determined that externalizing behavior in the child was negatively related to the mutual parent-child attachment relationship for two generations of children. We also found continuity in externalizing behavior for the participant over time and from the participant to his/her child. Additionally, we found continuity in the quality of the mutual attachment relationship from the participant's relationship with his/her parents to the participant's relationship with his/her child. Finally, the mutual attachment relationship of the participant with his/her parents had a negative association with the participant's externalizing behavior in adulthood. Based on these results, we propose that family interventions should focus on the role of the child's externalizing behavior in the context of the parent-child attachment relationship. Furthermore, we suggest that prevention programs should address externalizing behavior as early as possible, as the effects of externalizing behavior in adolescence can persist into adulthood and extend to the next generation. PMID- 23667305 TI - The Chinese Life-Steps Program: A Cultural Adaptation of a Cognitive-Behavioral Intervention to Enhance HIV Medication Adherence. AB - China is considered to be the new frontier of the global AIDS pandemic. Although effective treatment for HIV is becoming widely available in China, adherence to treatment remains a challenge. This study aimed to adapt an intervention promoting HIV-medication adherence-favorably evaluated in the West-for Chinese HIV-positive patients. The adaptation process was theory-driven and covered several key issues of cultural adaptation. We considered the importance of interpersonal relationships and family in China and cultural notions of health. Using an evidence-based treatment protocol originally designed for Western HIV positive patients, we developed an 11-step Chinese Life-Steps program with an additional culture-specific intervention option. We describe in detail how the cultural elements were incorporated into the intervention and put into practice at each stage. Clinical considerations are also outlined and followed by two case examples that are provided to illustrate our application of the intervention. Finally, we discuss practical and research issues and limitations emerging from our field experiments in a HIV clinic in Beijing. The intervention was tailored to address both universal and culturally specific barriers to adherence and is readily applicable to generalized clinical settings. This evidence-based intervention provides a case example of the process of adapting behavioral interventions to culturally diverse communities with limited resources. PMID- 23667306 TI - TYPE III EXCITABILITY, SLOPE SENSITIVITY AND COINCIDENCE DETECTION. AB - Some neurons in the nervous system do not show repetitive firing for steady currents. For time-varying inputs, they fire once if the input rise is fast enough. This property of phasic firing is known as Type III excitability. Type III excitability has been observed in neurons in the auditory brainstem (MSO), which show strong phase-locking and accurate coincidence detection. In this paper, we consider a Hodgkin-Huxley type model (RM03) that is widely-used for phasic MSO neurons and we compare it with a modification of it, showing tonic behavior. We provide insight into the temporal processing of these neuron models by means of developing and analyzing two reduced models that reproduce qualitatively the properties of the exemplar ones. The geometric and mathematical analysis of the reduced models allows us to detect and quantify relevant features for the temporal computation such as nearness to threshold and a temporal integration window. Our results underscore the importance of Type III excitability for precise coincidence detection. PMID- 23667307 TI - Examining the Relationship Between Word Reading Efficiency and Oral Reading Rate in Predicting Comprehension Among Different Types of Readers. AB - To further explore contextual reading rate, an important aspect of reading fluency, we examined the relationship between word reading efficiency (WRE) and contextual oral reading rate (ORR), the degree to which they overlap across different comprehension measures, whether oral language (semantics and syntax) predicts ORR beyond contributions of word-level skills, and whether the WRE-ORR relationship varies based on different reader profiles. Assessing reading and language of average readers, poor decoders, and poor comprehenders, ages 10 to 14, ORR was the strongest predictor of comprehension across various formats; WRE contributed no unique variance after taking ORR into account. Findings indicated that semantics, not syntax, contributed to ORR. Poor comprehenders performed below average on measures of ORR, despite average WRE, expanding previous findings suggesting specific weaknesses in ORR for this group. Together, findings suggest that ORR draws upon skills beyond those captured by WRE and suggests a role for oral language (semantics) in ORR. PMID- 23667308 TI - Very rapid effect of pitavastatin on microvascular function in comparison to rosuvastatin: reactive hyperemia peripheral arterial tonometric study. AB - BACKGROUND: It has been reported that pitavastatin improves endothelial function faster than other statins. Recently introduced reactive hyperemia peripheral arterial tonometry (RH-PAT) provides objective and quantitative assessment of peripheral microvascular function. PURPOSE: This study aimed to investigate whether peripheral microvascular function improved 2 hours after pitavastatin in subjects with coronary artery disease (CAD) using RH-PAT, and the results were compared with those of rosuvastatin. METHODS: This study included 94 subjects with CAD, assigned to a group given 2 mg of pitavastatin (n = 36), a group given 2.5 mg of rosuvastatin (n = 38), and a control group (n = 20). RH-PAT examinations were performed before and 2 hours after statin administration. RESULTS: The RH-PAT index increased 2 hours after pitavastatin administration from 1.82 +/- 0.45 to 2.16 +/- 0.62 (P = 0.02), whereas there were no differences in the RH-PAT index in the rosuvastatin group (1.79 +/- 0.71 to 1.91 +/- 0.53, P = 0.09) and the control group (1.68 +/- 0.36 to 1.84 +/- 0.58, P = 0.4). No significant changes were observed at 2 hours in serum cholesterol levels in each group. CONCLUSION: The present study demonstrated that peripheral microvascular function improved 2 hours after a single clinical dose of pitavastatin, but not after rosuvastatin. PMID- 23667309 TI - Microbubble-mediated ultrasound therapy: a review of its potential in cancer treatment. AB - The inherently toxic nature of chemotherapy drugs is essential for them to kill cancer cells but is also the source of the detrimental side effects experienced by patients. One strategy to reduce these side effects is to limit the healthy tissue exposure by encapsulating the drugs in a vehicle that demonstrates a very low leak rate in circulation while simultaneously having the potential for rapid release once inside the tumor. Designing a vehicle with these two opposing properties is the major challenge in the field of drug delivery. A triggering event is required to change the vehicle from its stable circulating state to its unstable release state. A unique mechanical actuation type trigger is possible by harnessing the size changes that occur when microbubbles interact with ultrasound. These mechanical actuations can burst liposomes and cell membranes alike allowing for rapid drug release and facilitating delivery into nearby cells. The tight focusing ability of the ultrasound to just a few cubic millimeters allows for precise control over the tissue location where the microbubbles destabilize the vehicles. This allows the ultrasound to highlight the tumor tissue and cause rapid drug release from any carrier present. Different vehicle designs have been demonstrated from carrying drug on just the surface of the microbubble itself to encapsulating the microbubble along with the drug within a liposome. In the future, nanoparticles may extend the circulation half life of these ultrasound triggerable drug-delivery vehicles by acting as nucleation sites of ultrasound-induced mechanical actuation. In addition to the drug delivery capability, the microbubble size changes can also be used to create imaging contrast agents that could allow the internal chemical environment of a tumor to be studied to help improve the diagnosis and detection of cancer. The ability to attain truly tumor-specific release from circulating drug-delivery vehicles is an exciting future prospect to reduce chemotherapy side effects while increasing drug effectiveness. PMID- 23667310 TI - Patient education for phosphorus management in chronic kidney disease. AB - OBJECTIVES: This review explores the challenges and solutions in educating patients with chronic kidney disease (CKD) to lower serum phosphorus while avoiding protein insufficiency and hypercalcemia. METHODS: A literature search including terms "hyperphosphatemia," "patient education," "food fatigue," "hypercalcemia," and "phosphorus-protein ratio" was undertaken using PubMed. RESULTS: Hyperphosphatemia is a strong predictor of mortality in advanced CKD and is remediated via diet, phosphorus binders, and dialysis. Dietary counseling should encourage the consumption of foods with the least amount of inorganic or absorbable phosphorus, low phosphorus-to-protein ratios, and adequate protein content, and discourage excessive calcium intake in high-risk patients. Emerging educational initiatives include food labeling using a "traffic light" scheme, motivational interviewing techniques, and the Phosphate Education Program - whereby patients no longer have to memorize the phosphorus content of each individual food component, but only a "phosphorus unit" value for a limited number of food groups. Phosphorus binders are associated with a clear survival advantage in CKD patients, overcome the limitations associated with dietary phosphorus restriction, and permit a more flexible approach to achieving normalization of phosphorus levels. CONCLUSION: Patient education on phosphorus and calcium management can improve concordance and adherence and empower patients to collaborate actively for optimal control of mineral metabolism. PMID- 23667311 TI - Vitamin D and depression in geriatric primary care patients. AB - PURPOSE: Vitamin D deficiency is common in the elderly. Vitamin D deficiency may affect the mood of people who are deficient. We investigated vitamin D status in older primary care patients and explored associations with depression. PATIENTS AND METHODS: A cross-sectional study was conducted and association analyses were performed. Primary care patients at a single academic medical center who were >=60 years with serum total 25-hydroxyvitamin D (25[OH]D) levels were included in the analysis. The primary outcome was a diagnosis of depression. Frailty scores and medical comorbidity burden scores were collected as predictors. RESULTS: There were 1618 patients with a mean age of 73.8 years (+/-8.48). The majority (81%) had optimal (>=25 ng/mL) 25(OH)D range, but 17% met mild-moderate (10-24 ng/mL) and 3% met severe (<10 ng/mL) deficiencies. Those with severe deficiency were older (P < 0.001), more frail (P < 0.001), had higher medical comorbidity burden (P < 0.001), and more frequent depression (P = 0.013). The 694 (43%) with depression had a lower 25(OH)D than the nondepressed group (32.7 vs 35.0, P = 0.002). 25(OH)D was negatively correlated with age (r = -0.070, P = 0.005), frailty (r = -0.113, P < 0.001), and medical comorbidity burden (r = -0.101, P < 0.001). A 25(OH)D level was correlated with depression (odds ratio = 0.990 and 95% confidence interval [CI] = 0.983-0.998, P = 0.012). Those with severe vitamin D deficiency were twice as likely to have depression (odds ratio = 2.093 with 95% CI 1.092-4.011, P = 0.026). CONCLUSION: Vitamin D deficiency was present in a fifth of this older primary care population. Lower vitamin D levels were associated with depression. Those with severe deficiency were older and more likely had depression. PMID- 23667312 TI - Critical appraisal of bilastine for the treatment of allergic rhinoconjunctivitis and urticaria. AB - Bilastine is a second generation antihistamine indicated for the treatment of seasonal or perennial allergic rhinoconjunctivitis and chronic urticaria with a daily dose of 20 mg, in adults and children over 12 years of age. The efficacy of bilastine has been shown to be similar to that of the comparator drugs for the control of the nasal and nonnasal symptoms of allergic rhinoconjunctivitis, while also showing a subjective improvement in the quality of life and in overall clinical impression. For chronic urticaria the symptoms (itching and the development of papules) lessens from the second day of treatment onwards, in a similar way to other antihistamines used as comparators. Bilastine should not be administered at meal times to avoid interference with the absorption process. It is not distributed to the central nervous system, is scarcely metabolized, and elimination is through the kidneys and feces, with a 14-hour elimination half life. It has no effect on cytochrome P450. During clinical development, bilastine was shown to be a drug that is adequately tolerated, with a similar effect to placebo with regard to drowsiness and changes in heart rate. In relation to its use, headaches were the most frequent adverse effect to be reported. No cardiotoxic effects have been observed, and the therapeutic dose does not alter the state of alertness. PMID- 23667313 TI - Updates on the diagnosis and treatment of intracranial nerve malignant peripheral nerve sheath tumors. AB - BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are rare entities and MPNSTs of intracranial nerves are even more sporadic. MPNSTs present diagnosis and treatment challenges since there are no defined diagnosis criteria and no established therapeutic strategies. METHODS: We reviewed literature for MPNST-related articles. We found 45 relevant studies in which 60 cases were described. RESULTS: We identified 60 cases of intracranial nerve MPNSTs. The age ranged from 3 to 75 years old. Male to female ratio was 1.5:1. The most involved cranial nerves (CNs) were CN VIII (60%), CN V (27%), and CN VII (10%). Most of the MPNSTs reported (47%) arose sporadically, 40% arose from a schwannoma, 8% arose from a neurofibroma, and 6% arose from an unspecified nerve tumor. Twenty patients had a history of radiation exposure, four patients had neurofibromatosis type 1 (NF1), four patients had neurofibromatosis type 2 (NF2), and NF2 was suspected in two other patients. Twenty-two patients were treated with radiotherapy and presented a higher survival rate. Seventy-two percent of patients died of their disease while 28% of patients survived. One-year survival rate was 33%. Forty-five percent of tumors recurred and 19% of patients had metastases. CONCLUSION: MPNSTs involving CNs are very rare. Diagnosis is made in regards to the histological and pathological findings. Imaging may help orient the diagnosis. A preexisting knowledge of the clinical situation is more likely to lead to a correct diagnosis. The mainstay of treatment is radical surgical resection with adjuvant radiotherapy. Since these tumors are associated with a poor prognosis, a close follow-up is mandatory. PMID- 23667314 TI - A review of the use of somatostatin analogs in oncology. AB - Somatostatin is a neuropeptide produced by paracrine cells that are located throughout the gastrointestinal tract, lung, and pancreas, and is also found in various locations of the nervous system. It exerts neural control over many physiological functions including inhibition of gastrointestinal endocrine secretion through its receptors. Potent and biologically stable analogs of somatostatin have been developed. These somatostatin analogs show different efficacy on different receptors, and receptors are varyingly concentrated in specific tissues. Antitumor and antisecretory effects of somatostatin analogs in cancer have been shown in several in vivo and in vitro studies. However, these activities have not always yielded into clinically relevant patient outcome benefit. Somatostatin analogs are of clinical benefit in treating symptoms of ectopic hormone secretion (adrenocorticotropic hormone, growth hormone-releasing hormone) in lung cancer, without inducing a significant tumor response. They have also been shown to induce a statistically significant decrease in bone pain and increase in Karnofsky performance status in patients with metastatic prostate cancer. Somatostatin analogs alone or in combination with other agents have only limited antitumoral effect in breast cancer. In gastrointestinal cancers, studies have not shown an objective tumor response to somatostatin analogs except in endocrine tumors of the liver with symptomatic and biochemical improvement. In neuroendocrine tumors of the gastrointestinal system and pancreas, very high symptomatic and biochemical response rates have been achieved with somatostatin analogs. Antiproliferative activity has been clearly shown in metastatic midgut neuroendocrine tumors. PMID- 23667315 TI - Treatment outcomes after initiation of exenatide twice daily or insulin in clinical practice: 12-month results from CHOICE in six European countries. AB - OBJECTIVE: The CHanges to treatment and Outcomes in patients with type 2 diabetes initiating InjeCtablE therapy (CHOICE) study assessed time to, and reasons for, significant treatment change after patients with type 2 diabetes (T2DM) initiated their first injectable glucose-lowering therapy (exenatide twice daily [BID] or insulin) in routine clinical practice, and these patients' clinical outcomes, in six European countries. This paper reports interim data from the first 12 months of the study. RESEARCH DESIGN AND METHODS: CHOICE (NCT00635492) is a prospective, noninterventional, observational study. Clinical data were collected at initiation of first injectable therapy and after approximately 3, 6, and 12 months. RESULTS: Of 2497 patients enrolled in CHOICE, 1096 in the exenatide BID and 1239 in the insulin cohorts had >=1 post-baseline assessment and were included in this analysis. Overall, 32.2% of the exenatide BID cohort and 29.1% of the insulin cohort (Kaplan-Meier estimates) had significant treatment change during the first 12 months, most commonly discontinuing injectable therapy or adding new T2DM therapy, respectively. Glycemic control improved in both cohorts, but weight loss occurred only in the exenatide BID cohort (mean change -3.3 kg). Hypoglycemia occurred in 13.2% of the exenatide BID cohort and 28.6% of the insulin cohort (82.8% and 55.6% of these patients, respectively, received sulfonylureas). The post hoc endpoint of glycated hemoglobin < 7%, no weight gain, and no hypoglycemia was attained at 12 months by 24.3% and 10.3% of patients who had data at 12 months and who were receiving exenatide BID and insulin, respectively. CONCLUSION: About 30% of patients in CHOICE changed treatment in the first 12 months after initiation of first injectable therapy (exenatide BID or insulin). Overall, both cohorts achieved improved glycemic control, which was accompanied by a mean weight loss in the exenatide BID cohort. PMID- 23667316 TI - The impact of JNK inhibitor D-JNKI-1 in a murine model of chronic colitis induced by dextran sulfate sodium. AB - PURPOSE: The c-Jun N-terminal kinases (JNK) are involved in the activation of T cells and the synthesis of proinflammatory cytokines. Several studies have established the relevance of the JNK pathway in inflammatory bowel diseases. The present study analyzed the therapeutic effect of D-JNKI-1, a specific JNK inhibiting peptide, in a low-dose dextran sulfate sodium (DSS) model of chronic colitis. METHODS: DSS colitis was induced in female C57/BL6 mice by cyclic administration using different concentrations of DSS (1.0% and 1.5%). Mice in the intervention groups received subcutaneous administration of 1 MUg/kg D-JNKI-1 on days 2, 12, and 22. They were monitored daily to assess the severity of colitis, body weight, stool consistency, and the occurrence of occult blood or gross rectal bleeding using evaluation of the disease activity index. The animals were sacrificed after 30 days, and the inflamed intestine was histologically evaluated using a crypt damage score. Immunohistochemical quantification of CD4(+) and CD8(+) cells was also carried out. RESULTS: Administration of 1 MUg/kg D-JNKI-1 resulted in a significant decrease in the disease activity index (P = 0.013 for 1.0% DSS; P = 0.007 for 1.5% DSS). As a mild form of colitis was induced, histological examination did not show any distinct damage to the mucosa and crypts. However, expression of CD4(+) and CD8(+) cells was reduced in mice treated with D-JNKI-1 (not significant). CONCLUSION: Administration of D-JNKI-1 resulted in a clinical attenuation of chronic DSS colitis, and a therapeutic effect of D-JNKI-1 must therefore be assumed. The decrease in CD4(+) and CD8(+) cells may reflect the influence of D-JNKI-1 on T-cell activation, differentiation, and migration. PMID- 23667318 TI - Naturalization Ceremonies and the Role of Immigrants in the American Nation. AB - Although immigration is an essential element in the American national story, it presents difficulties for constructing national membership and national identity in terms of shared intrinsic values. In this paper, I analyze speeches made at naturalization ceremonies during two time periods (1950-1970 and 2003-present) in order to examine the evolving roles of immigrants, as articulated to immigrants themselves. Naturalization ceremonies are a unique research site because the usually implied nationalist content is made explicit to brand new members of the nation. I find a shift in the framing from immigrants as potential liabilities and weak links in the earlier period to immigrants as morally superior redeemers of the American nation in the later period. I discuss the significance of this shift and the relationship between the roles presented at naturalization ceremonies and the discourse found elsewhere in the public sphere. PMID- 23667317 TI - Cardio-ankle vascular index (CAVI) as an indicator of arterial stiffness. AB - Arterial stiffness has been identified as an independent predictor of prognostic outcomes for patients with cardiovascular disease. Although measurement of pulse wave velocity has been a widely accepted noninvasive approach to the assessment of arterial stiffness, its accuracy is hampered by changes in blood pressure. Taking the exponential relation between intravascular pressure and arterial diameter into consideration, a stiffness parameter can be obtained by plotting the natural logarithm of systolic-diastolic pressure ratio against the arterial wall extensibility. Cardio-ankle vascular index (CAVI), which is calculated based on the stiffness parameter thus obtained, is theoretically independent of changes in blood pressure. With this distinct advantage, CAVI has been widely applied clinically to assess arterial stiffness in subjects with known cardiovascular diseases including those with diagnosed atherosclerosis, coronary heart disease, and stroke as well as those at risk, including those with hypertension, diabetes, the elderly, and the obese. Because of its enhanced sensitivity, not only has the index been used to discern subtle changes in the disease process, it has also been utilized in studying normal individuals to assess their potential risks of developing cardiovascular diseases. The primary aims of assessing arterial stiffness using CAVI are not only to aid in early detection of arteriosclerosis to allow timely treatment and change in lifestyle, but also to quantitatively evaluate the progression of disease and the effectiveness of treatment. Despite its merit of being unaffected by blood pressure, discretion in data interpretation is suggested because an elevated CAVI represents not just vascular stiffness caused by pathological changes in the arterial wall, but can also be attributed to an increased vascular tone brought about by smooth muscle contraction. Moreover, certain patient populations, such as those with an ankle brachial index < 0.9, may give falsely low CAVI and are suggested to be excluded from study. PMID- 23667319 TI - The influence glutamic acid in protonated b3 -> b2 formation from VGEIG and related analogs. AB - A direct pathway for the fragmentation of peptide b3 fragment ions to b2 ions has, until now, not been identified. Experimental evidence for the formation of a b3 anhydride structure and isomerization to an extended macrocycle is demonstrated here by comparison of the completely different fragmentation patterns of the b3 ions generated from protonated VGEIG and its methyl ester. In particular, the absence of a b2 ion in the fragmentation spectrum of the methyl ester b3 indicates that facile fragmentation of an anhydride-type b3 is responsible for virtually all b2 ions formed. The stability of this b3 structure and the ease with which it fragments to the b2 may be responsible for the relatively high abundance of the b3 and b2 ions. IRMPD action spectroscopy measurements indicate the presence of a ring protonated oxazolone in the b2 population. VGEIG and three related analogs, VALEIG, VADEIG, and V(Aib)EIG were studied by QCID-HDX-SORI experiments in an FT-ICR instrument, and provide significant evidence for extensive alpha proton scrambling in an ion-molecule complex formed between the b2 and neutral loss fragment following formation of the b2. MS3 and HDX of VG(2,2-d2)EIG indicate that the scrambled b2 ions have the same structure as the unscrambled b2. Based on these data and with the support of molecular modeling, we propose a new mechanism for this scrambling, in which the alpha protons are transferred in a multistep pathway during an ion-molecule complex formed between the b2 and amino-terminated anhydride ring neutral loss component. PMID- 23667321 TI - Chemical-shift water-fat MRI of white adipose depots: inability to resolve cell size differences. AB - PURPOSE: Adipocyte cell size varies among individuals and importantly, is inversely correlated with insulin sensitivity, and modifiable by weight loss or pharmaceutical agents. However, there are no non-invasive, in vivo methods for adipocyte cell size determination. Here we apply Chemical-Shift Water-Fat MRI to in vivo measures of subcutaneous (inguinal) and visceral (gonadal) white adipose tissue (WAT) to determine whether the fat-signal fraction (FF) is a sensitive indicator of adipocyte cell size. MATERIALS AND METHODS: C57BL/6J male mice (8 weeks old) were singly housed and fed a low-fat diet, high-fat diet or very high fat diet (n = 16 or 15/group) for 8 weeks. Food intake, body weight and composition were measured; CS-MRI was performed on a 9.4 Tesla Bruker magnet with respiratory gating and anesthesia. Histology was acquired for gonadal WAT; both gonadal and inguinal WAT were fixed with osmium tetroxide and then measured through Image J for cell size. RESULTS: Mice fed with higher fat content diets gained significantly more body weight, fat and lean mass while maintaining higher energy intakes over the 8 weeks. There was no significant difference in fat fraction for either gonadal (P = 0.1295) or inguinal (P = 0.4704) WAT among the three groups, despite significantly larger adipocytes (P <0.0001) in mice on high fat diets. CONCLUSION: Although diet-induced obesity significantly increased the amount of fat mass, as well as mean and overall white adipocyte cell size, the CS MRI measured fat fraction between groups were not significantly different. These results do not support the utility of CS-MRI measured FF for in vivo determination of adipocyte cell size. PMID- 23667320 TI - Nanoparticle-Based Delivery of RNAi Therapeutics: Progress and Challenges. AB - RNA interference (RNAi) is an evolutionarily conserved, endogenous process for post-transcriptional regulation of gene expression. Although RNAi therapeutics have recently progressed through the pipeline toward clinical trials, the application of these as ideal, clinical therapeutics requires the development of safe and effective delivery systems. Inspired by the immense progress with nanotechnology in drug delivery, efforts have been dedicated to the development of nanoparticle-based RNAi delivery systems. For example, a precisely engineered, multifunctional nanocarrier with combined passive and active targeting capabilities may address the delivery challenges for the widespread use of RNAi as a therapy. Therefore, in this review, we introduce the major hurdles in achieving efficient RNAi delivery and discuss the current advances in applying nanotechnology-based delivery systems to overcome the delivery hurdles of RNAi therapeutics. In particular, some representative examples of nanoparticle-based delivery formulations for targeted RNAi therapeutics are highlighted. PMID- 23667322 TI - Reinvigorating the role of science in democracy. AB - Private and political interests routinely conspire to sideline and misrepresent science and evidence in the public policy process. The Center for Science and Democracy, a new initiative at the Union of Concerned Scientists, endeavors to change this dynamic to strengthen the role of science in decision making. PMID- 23667324 TI - The geography of recent genetic ancestry across Europe. AB - The recent genealogical history of human populations is a complex mosaic formed by individual migration, large-scale population movements, and other demographic events. Population genomics datasets can provide a window into this recent history, as rare traces of recent shared genetic ancestry are detectable due to long segments of shared genomic material. We make use of genomic data for 2,257 Europeans (in the Population Reference Sample [POPRES] dataset) to conduct one of the first surveys of recent genealogical ancestry over the past 3,000 years at a continental scale. We detected 1.9 million shared long genomic segments, and used the lengths of these to infer the distribution of shared ancestors across time and geography. We find that a pair of modern Europeans living in neighboring populations share around 2-12 genetic common ancestors from the last 1,500 years, and upwards of 100 genetic ancestors from the previous 1,000 years. These numbers drop off exponentially with geographic distance, but since these genetic ancestors are a tiny fraction of common genealogical ancestors, individuals from opposite ends of Europe are still expected to share millions of common genealogical ancestors over the last 1,000 years. There is also substantial regional variation in the number of shared genetic ancestors. For example, there are especially high numbers of common ancestors shared between many eastern populations that date roughly to the migration period (which includes the Slavic and Hunnic expansions into that region). Some of the lowest levels of common ancestry are seen in the Italian and Iberian peninsulas, which may indicate different effects of historical population expansions in these areas and/or more stably structured populations. Population genomic datasets have considerable power to uncover recent demographic history, and will allow a much fuller picture of the close genealogical kinship of individuals across the world. PMID- 23667323 TI - Dampening the signals transduced through hedgehog via microRNA miR-7 facilitates notch-induced tumourigenesis. AB - Fine-tuned Notch and Hedgehog signalling pathways via attenuators and dampers have long been recognized as important mechanisms to ensure the proper size and differentiation of many organs and tissues. This notion is further supported by identification of mutations in these pathways in human cancer cells. However, although it is common that the Notch and Hedgehog pathways influence growth and patterning within the same organ through the establishment of organizing regions, the cross-talk between these two pathways and how the distinct organizing activities are integrated during growth is poorly understood. Here, in an unbiased genetic screen in the Drosophila melanogaster eye, we found that tumour like growth was provoked by cooperation between the microRNA miR-7 and the Notch pathway. Surprisingly, the molecular basis of this cooperation between miR-7 and Notch converged on the silencing of Hedgehog signalling. In mechanistic terms, miR-7 silenced the interference hedgehog (ihog) Hedgehog receptor, while Notch repressed expression of the brother of ihog (boi) Hedgehog receptor. Tumourigenesis was induced co-operatively following Notch activation and reduced Hedgehog signalling, either via overexpression of the microRNA or through specific down-regulation of ihog, hedgehog, smoothened, or cubitus interruptus or via overexpression of the cubitus interruptus repressor form. Conversely, increasing Hedgehog signalling prevented eye overgrowth induced by the microRNA and Notch pathway. Further, we show that blocking Hh signal transduction in clones of cells mutant for smoothened also enhance the organizing activity and growth by Delta-Notch signalling in the wing primordium. Together, these findings uncover a hitherto unsuspected tumour suppressor role for the Hedgehog signalling and reveal an unanticipated cooperative antagonism between two pathways extensively used in growth control and cancer. PMID- 23667325 TI - Genomics recapitulates history in Europe. PMID- 23667326 TI - Recruitment, assembly, and molecular architecture of the SpoIIIE DNA pump revealed by superresolution microscopy. AB - ATP-fuelled molecular motors are responsible for rapid and specific transfer of double-stranded DNA during several fundamental processes, such as cell division, sporulation, bacterial conjugation, and viral DNA transport. A dramatic example of intercompartmental DNA transfer occurs during sporulation in Bacillus subtilis, in which two-thirds of a chromosome is transported across a division septum by the SpoIIIE ATPase. Here, we use photo-activated localization microscopy, structured illumination microscopy, and fluorescence fluctuation microscopy to investigate the mechanism of recruitment and assembly of the SpoIIIE pump and the molecular architecture of the DNA translocation complex. We find that SpoIIIE assembles into ~45 nm complexes that are recruited to nascent sites of septation, and are subsequently escorted by the constriction machinery to the center of sporulation and division septa. SpoIIIE complexes contain 47+/ 20 SpoIIIE molecules, a majority of which are assembled into hexamers. Finally, we show that directional DNA translocation leads to the establishment of a compartment-specific, asymmetric complex that exports DNA. Our data are inconsistent with the notion that SpoIIIE forms paired DNA conducting channels across fused membranes. Rather, our results support a model in which DNA translocation occurs through an aqueous DNA-conducting pore that could be structurally maintained by the divisional machinery, with SpoIIIE acting as a checkpoint preventing membrane fusion until completion of chromosome segregation. Our findings and proposed mechanism, and our unique combination of innovating methodologies, are relevant to the understanding of bacterial cell division, and may illuminate the mechanisms of other complex machineries involved in DNA conjugation and protein transport across membranes. PMID- 23667327 TI - Multiplexing stimulus information through rate and temporal codes in primate somatosensory cortex. AB - Our ability to perceive and discriminate textures relies on the transduction and processing of complex, high-frequency vibrations elicited in the fingertip as it is scanned across a surface. How naturalistic vibrations, and by extension texture, are encoded in the responses of neurons in primary somatosensory cortex (S1) is unknown. Combining single unit recordings in awake macaques and perceptual judgments obtained from human subjects, we show that vibratory amplitude is encoded in the strength of the response evoked in S1 neurons. In contrast, the frequency composition of the vibrations, up to 800 Hz, is not encoded in neuronal firing rates, but rather in the phase-locked responses of a subpopulation of neurons. Moreover, analysis of perceptual judgments suggests that spike timing not only conveys stimulus information but also shapes tactile perception. We conclude that information about the amplitude and frequency of natural vibrations is multiplexed at different time scales in S1, and encoded in the rate and temporal patterning of the response, respectively. PMID- 23667328 TI - The Influence of Prosodic Stress Patterns and Semantic Depth on Novel Word Learning in Typically Developing Children. AB - The goal of this study was to investigate the effects of prosodic stress patterns and semantic depth on word learning. Twelve preschool-aged children with typically developing speech and language skills participated in a word learning task. Novel words with either a trochaic or iambic prosodic pattern were embedded in one of two learning conditions, either in children's stories (semantically rich) or picture matching games (semantically sparse). Three main analyses were used to measure word learning: comprehension and production probes, phonetic accuracy, and speech motor stability. Results revealed that prosodic frequency and density influence the learnability of novel words, or that there are prosodic neighborhood density effects. The impact of semantic depth on word learning was minimal and likely depends on the amount of experience with the novel words. PMID- 23667329 TI - Measuring coverage in MNCH: evaluation of community-based treatment of childhood illnesses through household surveys. AB - Community case management (CCM) is a strategy for training and supporting workers at the community level to provide treatment for the three major childhood diseases--diarrhea, fever (indicative of malaria), and pneumonia--as a complement to facility-based care. Many low- and middle-income countries are now implementing CCM and need to evaluate whether adoption of the strategy is associated with increases in treatment coverage. In this review, we assess the extent to which large-scale, national household surveys can serve as sources of baseline data for evaluating trends in community-based treatment coverage for childhood illnesses. Our examination of the questionnaires used in Demographic and Health Surveys (DHS) and Multiple Indicator Cluster Surveys (MICS) conducted between 2005 and 2010 in five sub-Saharan African countries shows that questions on care seeking that included a locally adapted option for a community-based provider were present in all the DHS surveys and in some MICS surveys. Most of the surveys also assessed whether appropriate treatments were available, but only one survey collected information on the place of treatment for all three illnesses. This absence of baseline data on treatment source in household surveys will limit efforts to evaluate the effects of the introduction of CCM strategies in the study countries. We recommend alternative analysis plans for assessing CCM programs using household survey data that depend on baseline data availability and on the timing of CCM policy implementation. PMID- 23667330 TI - Measuring coverage in MNCH: current indicators for measuring coverage of diarrhea treatment interventions and opportunities for improvement. AB - Diarrhea morbidity and mortality remain important child health problems in low- and middle-income countries. The treatment of diarrhea and accurate measurement of treatment coverage are critical if child mortality is going to continue to decline. In this review, we examine diarrhea treatment coverage indicators collected in two large-scale community-based household surveys--the Demographic and Health Surveys (DHS) and Multiple Indicator Cluster Surveys (MICS). Current surveys do not distinguish between children with mild diarrhea episodes and those at risk for dehydration. Additional disease severity questions may improve the identification of cases of severe diarrhea but research is needed to identify indicators with the highest sensitivity and specificity. We also review the current treatment indicators in these surveys and highlight three areas for improvement and research. First, specific questions on fluids other than oral rehydration salts (ORS) should be eliminated to refocus the treatment of dehydration on ORS and to prevent confusion between prevention and treatment of dehydration. Second, consistency across surveys and throughout translations is needed for questions about the caregiver behavior of "offering" the sick child fluid and food. Third, breastfeeding should be separated from other fluid and food questions to capture the frequency and duration of nursing sessions offered during the illness. Research is also needed to assess the accuracy of the current zinc indicator to determine if caregivers are correctly recalling zinc treatment for current and recent diarrhea episodes. PMID- 23667331 TI - Measuring coverage in MNCH: total survey error and the interpretation of intervention coverage estimates from household surveys. AB - Nationally representative household surveys are increasingly relied upon to measure maternal, newborn, and child health (MNCH) intervention coverage at the population level in low- and middle-income countries. Surveys are the best tool we have for this purpose and are central to national and global decision making. However, all survey point estimates have a certain level of error (total survey error) comprising sampling and non-sampling error, both of which must be considered when interpreting survey results for decision making. In this review, we discuss the importance of considering these errors when interpreting MNCH intervention coverage estimates derived from household surveys, using relevant examples from national surveys to provide context. Sampling error is usually thought of as the precision of a point estimate and is represented by 95% confidence intervals, which are measurable. Confidence intervals can inform judgments about whether estimated parameters are likely to be different from the real value of a parameter. We recommend, therefore, that confidence intervals for key coverage indicators should always be provided in survey reports. By contrast, the direction and magnitude of non-sampling error is almost always unmeasurable, and therefore unknown. Information error and bias are the most common sources of non-sampling error in household survey estimates and we recommend that they should always be carefully considered when interpreting MNCH intervention coverage based on survey data. Overall, we recommend that future research on measuring MNCH intervention coverage should focus on refining and improving survey-based coverage estimates to develop a better understanding of how results should be interpreted and used. PMID- 23667332 TI - Measuring coverage in MNCH: determining and interpreting inequalities in coverage of maternal, newborn, and child health interventions. AB - To monitor progress towards the Millennium Development Goals, it is essential to monitor the coverage of health interventions in subgroups of the population, because national averages can hide important inequalities. In this review, we provide a practical guide to measuring and interpreting inequalities based on surveys carried out in low- and middle-income countries, with a focus on the health of mothers and children. Relevant stratification variables include urban/rural residence, geographic region, and educational level, but breakdowns by wealth status are increasingly popular. For the latter, a classification based on an asset index is the most appropriate for national surveys. The measurement of intervention coverage can be made by single indicators, but the use of combined measures has important advantages, and we advocate two summary measures (the composite coverage index and the co-coverage indicator) for the study of time trends and for cross-country comparisons. We highlight the need for inequality measures that take the whole socioeconomic distribution into account, such as the relative concentration index and the slope index of inequality, although simpler measures such as the ratio and difference between the richest and poorest groups may also be presented for non-technical audiences. Finally, we present a framework for the analysis of time trends in inequalities, arguing that it is essential to study both absolute and relative indicators, and we provide guidance to the joint interpretation of these results. PMID- 23667333 TI - Measuring coverage in MNCH: tracking progress in health for women and children using DHS and MICS household surveys. AB - Household surveys are the primary data source of coverage indicators for children and women for most developing countries. Most of this information is generated by two global household survey programmes-the USAID-supported Demographic and Health Surveys (DHS) and the UNICEF-supported Multiple Indicator Cluster Surveys (MICS). In this review, we provide an overview of these two programmes, which cover a wide range of child and maternal health topics and provide estimates of many Millennium Development Goal indicators, as well as estimates of the indicators for the Countdown to 2015 initiative and the Commission on Information and Accountability for Women's and Children's Health. MICS and DHS collaborate closely and work through interagency processes to ensure that survey tools are harmonized and comparable as far as possible, but we highlight differences between DHS and MICS in the population covered and the reference periods used to measure coverage. These differences need to be considered when comparing estimates of reproductive, maternal, newborn, and child health indicators across countries and over time and we discuss the implications of these differences for coverage measurement. Finally, we discuss the need for survey planners and consumers of survey results to understand the strengths, limitations, and constraints of coverage measurements generated through household surveys, and address some technical issues surrounding sampling and quality control. We conclude that, although much effort has been made to improve coverage measurement in household surveys, continuing efforts are needed, including further research to improve and refine survey methods and analytical techniques. PMID- 23667334 TI - Measuring coverage in MNCH: design, implementation, and interpretation challenges associated with tracking vaccination coverage using household surveys. AB - Vaccination coverage is an important public health indicator that is measured using administrative reports and/or surveys. The measurement of vaccination coverage in low- and middle-income countries using surveys is susceptible to numerous challenges. These challenges include selection bias and information bias, which cannot be solved by increasing the sample size, and the precision of the coverage estimate, which is determined by the survey sample size and sampling method. Selection bias can result from an inaccurate sampling frame or inappropriate field procedures and, since populations likely to be missed in a vaccination coverage survey are also likely to be missed by vaccination teams, most often inflates coverage estimates. Importantly, the large multi-purpose household surveys that are often used to measure vaccination coverage have invested substantial effort to reduce selection bias. Information bias occurs when a child's vaccination status is misclassified due to mistakes on his or her vaccination record, in data transcription, in the way survey questions are presented, or in the guardian's recall of vaccination for children without a written record. There has been substantial reliance on the guardian's recall in recent surveys, and, worryingly, information bias may become more likely in the future as immunization schedules become more complex and variable. Finally, some surveys assess immunity directly using serological assays. Sero-surveys are important for assessing public health risk, but currently are unable to validate coverage estimates directly. To improve vaccination coverage estimates based on surveys, we recommend that recording tools and practices should be improved and that surveys should incorporate best practices for design, implementation, and analysis. PMID- 23667335 TI - Measuring coverage in MNCH: indicators for global tracking of newborn care. AB - Neonatal mortality accounts for 43% of under-five mortality. Consequently, improving newborn survival is a global priority. However, although there is increasing consensus on the packages and specific interventions that need to be scaled up to reduce neonatal mortality, there is a lack of clarity on the indicators needed to measure progress. In 2008, in an effort to improve newborn survival, the Newborn Indicators Technical Working Group (TWG) was convened by the Saving Newborn Lives program at Save the Children to provide a forum to develop the indicators and standard measurement tools that are needed to measure coverage of key newborn interventions. The TWG, which included evaluation and measurement experts, researchers, individuals from United Nations agencies and non-governmental organizations, and donors, prioritized improved consistency of measurement of postnatal care for women and newborns and of immediate care behaviors and practices for newborns. In addition, the TWG promoted increased data availability through inclusion of additional questions in nationally representative surveys, such as the United States Agency for International Development-supported Demographic and Health Surveys and the United Nations Children's Fund-supported Multiple Indicator Cluster Surveys. Several studies have been undertaken that have informed revisions of indicators and survey tools, and global postnatal care coverage indicators have been finalized. Consensus has been achieved on three additional indicators for care of the newborn after birth (drying, delayed bathing, and cutting the cord with a clean instrument), and on testing two further indicators (immediate skin-to-skin care and applications to the umbilical cord). Finally, important measurement gaps have been identified regarding coverage data for evidence-based interventions, such as Kangaroo Mother Care and care seeking for newborn infection. PMID- 23667336 TI - Measuring coverage in MNCH: challenges and opportunities in the selection of coverage indicators for global monitoring. AB - Global monitoring of intervention coverage is a cornerstone of international efforts to improve reproductive, maternal, newborn, and child health. In this review, we examine the process and implications of selecting a core set of coverage indicators for global monitoring, using as examples the processes used by the Countdown to 2015 for Maternal, Newborn and Child Survival and the Commission on Accountability for Women's and Children's Health. We describe how the generation of data for global monitoring involves five iterative steps: development of standard indicator definitions and measurement approaches to ensure comparability across countries; collection of high-quality data at the country level; compilation of country data at the global level; organization of global databases; and rounds of data quality checking. Regular and rigorous technical review processes that involve high-level decision makers and experts familiar with indicator measurement are needed to maximize uptake and to ensure that indicators used for global monitoring are selected on the basis of available evidence of intervention effectiveness, feasibility of measurement, and data availability as well as programmatic relevance. Experience from recent initiatives illustrates the challenges of striking this balance as well as strategies for reducing the tensions inherent in the indicator selection process. We conclude that more attention and continued investment need to be directed to global monitoring, to support both the process of global database development and the selection of sets of coverage indicators to promote accountability. The stakes are high, because these indicators can drive policy and program development at the country and global level, and ultimately impact the health of women and children and the communities where they live. PMID- 23667337 TI - Measuring coverage in MNCH: accuracy of measuring diagnosis and treatment of childhood malaria from household surveys in Zambia. AB - BACKGROUND: To assess progress in the scale-up of rapid diagnostic tests and artemisinin-based combination therapies (ACTs) across Africa, malaria control programs have increasingly relied on standardized national household surveys to determine the proportion of children with a fever in the past 2 wk who received an effective antimalarial within 1-2 d of the onset of fever. Here, the validity of caregiver recall for measuring the primary coverage indicators for malaria diagnosis and treatment of children <5 y old is assessed. METHODS AND FINDINGS: A cross-sectional study was conducted in five public clinics in Kaoma District, Western Provence, Zambia, to estimate the sensitivity, specificity, and accuracy of caregivers' recall of malaria testing, diagnosis, and treatment, compared to a gold standard of direct observation at the health clinics. Compared to the gold standard of clinic observation, for recall for children with fever in the past 2 wk, the sensitivity for recalling that a finger/heel stick was done was 61.9%, with a specificity of 90.0%. The sensitivity and specificity of caregivers' recalling a positive malaria test result were 62.4% and 90.7%, respectively. The sensitivity and specificity of recalling that the child was given a malaria diagnosis, irrespective of whether a laboratory test was actually done, were 76.8% and 75.9%, respectively. The sensitivity and specificity for recalling that an ACT was given were 81.0% and 91.5%, respectively. CONCLUSIONS: Based on these findings, results from household surveys should continue to be used for ascertaining the coverage of children with a fever in the past 2 wk that received an ACT. However, as recall of a malaria diagnosis remains suboptimal, its use in defining malaria treatment coverage is not recommended. PMID- 23667338 TI - Measuring coverage in MNCH: challenges in monitoring the proportion of young children with pneumonia who receive antibiotic treatment. AB - Pneumonia remains a major cause of child death globally, and improving antibiotic treatment rates is a key control strategy. Progress in improving the global coverage of antibiotic treatment is monitored through large household surveys such as the Demographic and Health Surveys (DHS) and the Multiple Indicator Cluster Surveys (MICS), which estimate antibiotic treatment rates of pneumonia based on two-week recall of pneumonia by caregivers. However, these survey tools identify children with reported symptoms of pneumonia, and because the prevalence of pneumonia over a two-week period in community settings is low, the majority of these children do not have true pneumonia and so do not provide an accurate denominator of pneumonia cases for monitoring antibiotic treatment rates. In this review, we show that the performance of survey tools could be improved by increasing the survey recall period or by improving either overall discriminative power or specificity. However, even at a test specificity of 95% (and a test sensitivity of 80%), the proportion of children with reported symptoms of pneumonia who truly have pneumonia is only 22% (the positive predictive value of the survey tool). Thus, although DHS and MICS survey data on rates of care seeking for children with reported symptoms of pneumonia and other childhood illnesses remain valid and important, DHS and MICS data are not able to give valid estimates of antibiotic treatment rates in children with pneumonia. PMID- 23667339 TI - Measuring coverage in MNCH: a prospective validation study in Pakistan and Bangladesh on measuring correct treatment of childhood pneumonia. AB - BACKGROUND: Antibiotic treatment for pneumonia as measured by Demographic and Health Surveys (DHS) and Multiple Indicator Cluster Surveys (MICS) is a key indicator for tracking progress in achieving Millennium Development Goal 4. Concerns about the validity of this indicator led us to perform an evaluation in urban and rural settings in Pakistan and Bangladesh. METHODS AND FINDINGS: Caregivers of 950 children under 5 y with pneumonia and 980 with "no pneumonia" were identified in urban and rural settings and allocated for DHS/MICS questions 2 or 4 wk later. Study physicians assigned a diagnosis of pneumonia as reference standard; the predictive ability of DHS/MICS questions and additional measurement tools to identify pneumonia versus non-pneumonia cases was evaluated. Results at both sites showed suboptimal discriminative power, with no difference between 2- or 4-wk recall. Individual patterns of sensitivity and specificity varied substantially across study sites (sensitivity 66.9% and 45.5%, and specificity 68.8% and 69.5%, for DHS in Pakistan and Bangladesh, respectively). Prescribed antibiotics for pneumonia were correctly recalled by about two-thirds of caregivers using DHS questions, increasing to 72% and 82% in Pakistan and Bangladesh, respectively, using a drug chart and detailed enquiry. CONCLUSIONS: Monitoring antibiotic treatment of pneumonia is essential for national and global programs. Current (DHS/MICS questions) and proposed new (video and pneumonia score) methods of identifying pneumonia based on maternal recall discriminate poorly between pneumonia and children with cough. Furthermore, these methods have a low yield to identify children who have true pneumonia. Reported antibiotic treatment rates among these children are therefore not a valid proxy indicator of pneumonia treatment rates. These results have important implications for program monitoring and suggest that data in its current format from DHS/MICS surveys should not be used for the purpose of monitoring antibiotic treatment rates in children with pneumonia at the present time. PMID- 23667340 TI - Measuring coverage in MNCH: new findings, new strategies, and recommendations for action. AB - Considerable progress has been made in reducing maternal, newborn, and child mortality worldwide, but many more deaths could be prevented if effective interventions were available to all who could benefit from them. Timely, high quality measurements of intervention coverage--the proportion of a population in need of a health intervention that actually receives it--are essential to support sound decisions about progress and investments in women's and children's health. The PLOS Medicine "Measuring Coverage in MNCH" Collection of research studies and reviews presents systematic assessments of the validity of health intervention coverage measurement based on household surveys, the primary method for estimating population-level intervention coverage in low- and middle-income countries. In this overview of the Collection, we discuss how and why some of the indicators now being used to track intervention coverage may not provide fully reliable coverage measurements, and how a better understanding of the systematic and random error inherent in these coverage indicators can help in their interpretation and use. We draw together strategies proposed across the Collection for improving coverage measurement, and recommend continued support for high-quality household surveys at national and sub-national levels, supplemented by surveys with lighter tools that can be implemented every 1-2 years and by complementary health-facility-based assessments of service quality. Finally, we stress the importance of learning more about coverage measurement to strengthen the foundation for assessing and improving the progress of maternal, newborn, and child health programs. PMID- 23667341 TI - Measuring coverage in MNCH: population HIV-free survival among children under two years of age in four African countries. AB - BACKGROUND: Population-based evaluations of programs for prevention of mother-to child HIV transmission (PMTCT) are scarce. We measured PMTCT service coverage, regimen use, and HIV-free survival among children <=24 mo of age in Cameroon, Cote D'Ivoire, South Africa, and Zambia. METHODS AND FINDINGS: We randomly sampled households in 26 communities and offered participation if a child had been born to a woman living there during the prior 24 mo. We tested consenting mothers with rapid HIV antibody tests and tested the children of seropositive mothers with HIV DNA PCR or rapid antibody tests. Our primary outcome was 24-mo HIV-free survival, estimated with survival analysis. In an individual-level analysis, we evaluated the effectiveness of various PMTCT regimens. In a community-level analysis, we evaluated the relationship between HIV-free survival and community PMTCT coverage (the proportion of HIV-exposed infants in each community that received any PMTCT intervention during gestation or breastfeeding). We also compared our community coverage results to those of a contemporaneous study conducted in the facilities serving each sampled community. Of 7,985 surveyed children under 2 y of age, 1,014 (12.7%) were HIV-exposed. Of these, 110 (10.9%) were HIV-infected, 851 (83.9%) were HIV-uninfected, and 53 (5.2%) were dead. HIV-free survival at 24 mo of age among all HIV-exposed children was 79.7% (95% CI: 76.4, 82.6) overall, with the following country-level estimates: Cameroon (72.6%; 95% CI: 62.3, 80.5), South Africa (77.7%; 95% CI: 72.5, 82.1), Zambia (83.1%; 95% CI: 78.4, 86.8), and Cote D'Ivoire (84.4%; 95% CI: 70.0, 92.2). In adjusted analyses, the risk of death or HIV infection was non significantly lower in children whose mothers received a more complex regimen of either two or three antiretroviral drugs compared to those receiving no prophylaxis (adjusted hazard ratio: 0.60; 95% CI: 0.34, 1.06). Risk of death was not different for children whose mothers received a more complex regimen compared to those given single-dose nevirapine (adjusted hazard ratio: 0.88; 95% CI: 0.45, 1.72). Community PMTCT coverage was highest in Cameroon, where 75 of 114 HIV exposed infants met criteria for coverage (66%; 95% CI: 56, 74), followed by Zambia (219 of 444, 49%; 95% CI: 45, 54), then South Africa (152 of 365, 42%; 95% CI: 37, 47), and then Cote D'Ivoire (3 of 53, 5.7%; 95% CI: 1.2, 16). In a cluster-level analysis, community PMTCT coverage was highly correlated with facility PMTCT coverage (Pearson's r = 0.85), and moderately correlated with 24 mo HIV-free survival (Pearson's r = 0.29). In 14 of 16 instances where both the facility and community samples were large enough for comparison, the facility based coverage measure exceeded that observed in the community. CONCLUSIONS: HIV free survival can be estimated with community surveys and should be incorporated into ongoing country monitoring. Facility-based coverage measures correlate with those derived from community sampling, but may overestimate population coverage. The more complex regimens recommended by the World Health Organization seem to have measurable public health benefit at the population level, but power was limited and additional field validation is needed. PMID- 23667342 TI - Providing impetus, tools, and guidance to strengthen national capacity for antimicrobial stewardship in Viet Nam. PMID- 23667343 TI - Disability transitions and health expectancies among adults 45 years and older in Malawi: a cohort-based model. AB - BACKGROUND: Falling fertility and increasing life expectancy contribute to a growing elderly population in sub-Saharan Africa (SSA); by 2060, persons aged 45 y and older are projected to be 25% of SSA's population, up from 10% in 2010. Aging in SSA is associated with unique challenges because of poverty and inadequate social supports. However, despite its importance for understanding the consequences of population aging, the evidence about the prevalence of disabilities and functional limitations due to poor physical health among older adults in SSA continues to be very limited. METHODS AND FINDINGS: Participants came from 2006, 2008, and 2010 waves of the Malawi Longitudinal Survey of Families and Health, a study of the rural population in Malawi. We investigate how poor physical health results in functional limitations that limit the day-to day activities of individuals in domains relevant to this subsistence-agriculture context. These disabilities were parameterized based on questions from the SF-12 questionnaire about limitations in daily living activities. We estimated age specific patterns of functional limitations and the transitions over time between different disability states using a discrete-time hazard model. The estimated transition rates were then used to calculate the first (to our knowledge) microdata-based health expectancies calculated for SSA. The risks of experiencing functional limitations due to poor physical health are high in this population, and the onset of disabilities happens early in life. Our analyses show that 45-y old women can expect to spend 58% (95% CI, 55%-64%) of their remaining 28 y of life (95% CI, 25.7-33.5) with functional limitations; 45-y-old men can expect to live 41% (95% CI, 35%-46%) of their remaining 25.4 y (95% CI, 23.3-28.8) with such limitations. Disabilities related to functional limitations are shown to have a substantial negative effect on individuals' labor activities, and are negatively related to subjective well-being. CONCLUSIONS: Individuals in this population experience a lengthy struggle with disabling conditions in adulthood, with high probabilities of remitting and relapsing between states of functional limitation. Given the strong association of disabilities with work efforts and subjective well-being, this research suggests that current national health policies and international donor-funded health programs in SSA inadequately target the physical health of mature and older adults. PMID- 23667344 TI - Intimate partner violence and population mental health: why poverty and gender inequities matter. PMID- 23667345 TI - Grand challenges: integrating maternal mental health into maternal and child health programmes. PMID- 23667346 TI - Stress Reactivity, Social Anxiety, and Alcohol Consumption in People With Alcoholism: A Laboratory Study. AB - OBJECTIVE: Social anxiety may maintain alcohol dependence through increased reactivity to stressful events, a propensity to drink to cope with stressful events, or both. The current study is a secondary analysis of an existing dataset that examined differences between individuals with alcohol dependence and concurrent high and low social anxiety in objective and subjective stress reactivity to a laboratory stressor (Trier Social Stress Test; TSST), as well as consumption of alcohol following the stressor. METHODS: Forty participants with alcohol dependence (20 women) were randomly assigned to the TSST condition as part of the parent study. Post-hoc analysis of social anxiety measures yielded high (n = 19) and low (n = 21) social anxiety groups. Participants completed the TSST, followed by a small dose of their favorite alcoholic beverage (target blood alcohol concentration 0.03g/dl) to prime subsequent laboratory drinking. Participants received a sham beer taste test of two glasses (710ml total) of beer. Differences between high and low social anxiety groups was assessed via subjective and objective (mean arterial pressure, serum cortisol) reactivity to the TSST and consumption of alcohol during the taste test (total mls consumed, mls/kg of body weight, and likelihood of consuming all the beer available). RESULTS: No differences emerged in either objective or subjective measures of stress reactivity between high and low socially anxious groups. There were also no differences between social anxiety groups in amount of alcohol consumed during the taste test. CONCLUSIONS: No differences were observed between high and low socially anxious participants with concurrent alcohol dependence on stress reactivity or alcohol consumption following a stressor. Given that all participants in this study had alcohol dependence, negative results may suggest that heightened stress reactivity and drinking to cope are more relevant to the development of alcohol dependence and that other factors may maintain alcohol use once dependence has developed. PMID- 23667347 TI - Modern Prejudice and Same-Sex Parenting: Shifting Judgments in Positive and Negative Parenting Situations. AB - The current study compares the effects of traditional and modern anti-homosexual prejudice on evaluations of parenting practices of same-sex and opposite-sex couples. Undergraduate university student participants (N = 436) completed measures of traditional and modern anti-homosexual prejudice and responded to a vignette describing a restaurant scene in which parents react to their child's undesirable behavior. The parents' sexual orientation and the quality of their parenting (positive or negative quality) were varied randomly. It was predicted that participants who score higher in modern prejudice would rate the negative parenting behaviors of same-sex parents more negatively than similar behaviors in opposite-sex parents. It was also predicted that this modern prejudice effect would be most pronounced for male participants. Both hypotheses were supported. PMID- 23667348 TI - The Impact of an Innovative Mindfulness-Based Stress Reduction Program on the Health and Well-Being of Nurses Employed in a Corporate Setting. AB - This study implemented an innovative new model of delivering a Mindfulness-Based Stress Reduction (MBSR) program that replaces six of the eight traditional in person sessions with group telephonic sessions (tMBSR) and measured the program's impact on the health and well-being of nurses employed within a large health care organization. As part of a nonrandomized pre-post intervention study, 36 nurses completed measures of health, stress, burnout, self-compassion, serenity, and empathy at three points in time. Between baseline (Time 1) and the end of the 8 week tMBSR intervention (Time 2), participants showed improvement in general health, t(37) = 2.8, p < .01, decreased stress, t(37) = 6.8, p < .001, decreased work burnout, t(37) = 4.0, p < .001, and improvement in several other areas. Improvements were sustained 4 months later (Time 3), and individuals who continued their MBSR practice after the program demonstrated better outcomes than those that did not. Findings suggest that the tMBSR program can be a low cost, feasible, and scalable intervention that shows positive impact on health and well being, and could allow MBSR to be delivered to employees who are otherwise unable to access traditional, on-site programs. PMID- 23667349 TI - The Emergence of the Trigger Tool as the Premier Measurement Strategy for Patient Safety. PMID- 23667350 TI - A Stiff Injectable Biodegradable Elastomer. AB - Injectable materials often have shortcomings in mechanical and drug-eluting properties that are attributable to their high water contents. A water-free, liquid four-armed PEG modified with dopamine end groups is described which changed from liquid to elastic solid by reaction with a small volume of Fe3+ solution. The elastic modulus and degradation times increased with increasing Fe3+ concentrations. Both the free base and the water-soluble form of lidocaine could be dissolved in the PEG4-dopamine and released in a sustained manner from the cross-linked matrix. PEG4-dopamine was retained in the subcutaneous space in vivo for up to 3 weeks with minimal inflammation. This material's tailorable mechanical properties, biocompatibility, ability to incorporate hydrophilic and hydrophobic drugs and release them slowly are desirable traits for drug delivery and other biomedical applications. PMID- 23667352 TI - Festschrift editorial--for whom the bell tolls. PMID- 23667351 TI - An ethnoveterinary study of medicinal plants in treatment of diseases and syndromes of herd dog in southern regions of Ilam province, Iran. AB - This paper describes a selection of the ethnoveterinary medicines used for herd dogs in the southern regions of Ilam province, Iran. Traditional botanical medicine is the primary mode of healthcare for most of the rural population in Ilam province. In this study, a questionnaire was distributed among 45 residential areas in 22 rural zones of the southern areas of Ilam province. The objective of this study was the recognition of natural medicinal methods using medicinal plants, and the classification of ethnoveterinary applications and collection of domestic science. Twenty-two medicinal plants from 16 families were identified. The main application of these plants was for the detection and treatment of digestive disorders using Citrullus colocynthis, Aristolochia clematis, Scrophularia deserti, Quercus brantii, Ceracus microcarpa, Echium strigosa, Pistacia atlantica, and Pistacia khinjuk which have been applied using Euphurbia graminifolius, Peganum harmala, Salsola rigida, Artemisia herba-alba, Amygdalus arabica, jolbak of salt water, Peganum harmala L., and Nicotina tabacum for external and internal parasite disorders. S. deserti for ophthalmic disorders, and P. atlantica, P. khinjuk, and Q. brantii for respiratory disorders were applied. The present study confirmed the traditional medical effects of some plants and revealed the unique medical effects of other plants, which if recognized could be useful in the creation of new ideas and increasing knowledge for the modern pharmaceutical industry. Since very few clinical trials have been conducted on plants native to Ilam province, it is necessary that more research be conducted to ensure that labeled and standardized products are introduced for human consumption. PMID- 23667353 TI - Childhood and adolescence: challenges in mental health. AB - Mental health is an integral and essential component of health. The World Health Organization (WHO) constitution states: "Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity." More than 450 million people suffer from mental disorders worldwide. In India, mental health services, especially for children and adolescents, are limited both in terms of number of facilities as well as trained professionals. The majority of mental health services are restricted to urban areas, that is, medical colleges or regional mental health institutes. Mere presence of a treatment facility does not guarantee that all children/adolescents suffering from mental illness will utilize such services. In fact, most of the time there is a significant delay from the patient side in accessing mental health services either because of lack of awareness or associated stigma. It is high time to promote positive mental health in children, adolescents and their parents through health education. Parental counseling is of utmost importance in order to avoid the delay in treatment seeking. PMID- 23667354 TI - Interview with Dr. Charley Zeanah: (interviewed by Normand Carrey MD, Tulane University, New Orleans, January 9, 2013). AB - Dr. Charles Zeanah is the Mary K. Sellars-Polchow Chair in Psychiatry, Professor of Clinical Pediatrics and Vice Chair for Child and Adolescent Psychiatry in the Department of Psychiatry and Behavioral Sciences at Tulane University School of Medicine in New Orleans. He is also Executive Director of the Institute for Infant and Early Childhood Mental Health at Tulane. He is the recipient of multiple awards including the Irving Phillips Award for Prevention, (AACAP), the Presidential Citation for Distinguished Research and Leadership in Infant Mental Health (American Orthopsychiatric Association), the Sarah Haley Memorial Award for Clinical Excellence (International Society for Traumatic Stress Studies), the Blanche F. Ittelson Award for Research in Child Psychiatry (APA), and the Serge Lebovici Award for International Contributions in Infant Mental Health (World Association for Infant Mental Health). Dr. Zeanah is a Distinguished Fellow of AACAP, a Distinguished Fellow of the APA and a Board Member of Zero to Three. He is the Editor of Handbook of Infant Mental Health (3(rd) edition) considered as the state of the art textbook and standard reference in the field of Infant Mental Health. PMID- 23667355 TI - Heterogeneity of Depressive Symptom Trajectories through Adolescence: Predicting Outcomes in Young Adulthood. AB - OBJECTIVE: This study describes developmental trajectories of depressive symptoms in adolescents and examines the association between trajectory group and mental health outcomes in young adulthood. METHODS: Depressive symptoms were self reported every three months from grade seven through grade 11 by 1293 adolescents in the Nicotine Dependence in Teens (NDIT) study and followed in young adulthood (average age 20.4, SD=0.7, n=865). Semi-parametric growth modeling was used to identify sex-specific trajectories of depressive symptoms. RESULTS: THREE DISTINCT TRAJECTORY GROUPS WERE IDENTIFIED: 50% of boys and 29% of girls exhibited low, decreasing levels of depressive symptoms; 14% of boys and 28% of girls exhibited high and increasing levels; and 36% of boys and 43% of girls exhibited moderate levels with linear increase. Trajectory group was a statistically significant independent predictor of depression, stress, and self rated mental health in young adulthood in boys and girls. Boys, but not girls, in the high trajectory group had a statistically significant increase in the likelihood of seeking psychiatric care. CONCLUSIONS: Substantial heterogeneity in changes in depressive symptoms over time was found. Because early depressive symptoms predict mental health problems in young adulthood, monitoring adolescents for depressive symptoms may help identify those most at risk and in need of intervention. PMID- 23667356 TI - Randomized Clinical Trial of a Primary Care Internet-based Intervention to Prevent Adolescent Depression: One-year Outcomes. AB - OBJECTIVE: We developed a primary care/Internet-based intervention for adolescents at risk for depression (CATCH-IT, Competent Adulthood Transition with Cognitive-behavioral, Humanistic and Interpersonal Training). This phase II clinical trial compares two forms of primary care provider (PCP) engagement (motivational interview [MI] and brief advice [BA]) for adolescents using the Internet program. METHOD: ADOLESCENTS SCREENING POSITIVE FOR DEPRESSION WERE RECRUITED FROM PRIMARY CARE PRACTICES AND RANDOMLY ASSIGNED TO A VERSION OF THE INTERVENTION: PCP MI + Internet program or PCP BA + Internet program. Between group and within-group comparisons were conducted on depressive disorder outcome measures at baseline and one-year post-enrollment. Regression analyses examined factors predicting declines in depressed mood. RESULTS: Both groups demonstrated significant within-group decreases in depressed mood, loneliness, and self-harm ideation. While no between-group differences were noted in depressed mood or depressive disorder measures at one-year, fewer participants in the MI group had experienced a depressive episode. Greater participant automatic negative thoughts and more favorable ratings of a component of the Internet-based training experience predicted declines in depressed mood at one-year. CONCLUSIONS: A primary care/Internet-based intervention for depression prevention demonstrated sustained reductions in depressed mood, and, when coupled with motivational interviewing, reduction in the likelihood of being diagnosed with a depressive episode. This tool may help extend the services at the disposal of a primary care provider and can provide a bridge for adolescents at risk for depression prior to referral to mental health specialists. PMID- 23667357 TI - Suicide and Deliberate Self-injurious Behavior in Juvenile Correctional Facilities: A Review. AB - OBJECTIVE: Describe the rates of suicidal ideation, self-injury, and suicide among detained youth as well as risk factors and preventive measures that have been attempted. METHOD: Literature searches in PubMed, PsycINFO, and the Social Science Citation Index were undertaken to identify published studies written in English. Governmental data was also included from English-speaking nations. RESULTS: The adjusted risk of suicide was 3 to 18 times higher than age-matched controls. The prevalence of lifetime suicidal ideation ranged from 16.9% to 59% while lifetime self-injury ranged from 6.2% to 44%. Affective disorders, borderline personality traits, substance use disorders, impulse control disorders, and anxiety disorders were associated with suicidal thoughts and self injury. Screening for suicidal ideation upon entry was associated with a decreased rate of suicide. CONCLUSIONS: All youth should be screened upon admission. Identified co-morbid disorders should also be treated. PMID- 23667358 TI - Promoting Resilience in High-risk Children in Jamaica: A Pilot Study of a Multimodal Intervention. AB - OBJECTIVE: To assess the effectiveness of a multimodal afterschool and summer intervention called the Dream-A-World (DAW) Project for a cohort of school-aged Jamaican children from an impoverished, disadvantaged inner-city community in Kingston, Jamaica. Children were selected by their teachers based on severe disruptive disorders and academic underachievement and compared with a matched control group. The pilot was a child focused therapeutic modality without parental intervention for disruptive conduct and academic failure. METHOD: A group psychotherapeutic intervention of creative arts therapies and remedial academic support adapted for the Jamaican context was implemented with 30 children from an inner-city primary school. The intervention was implemented over 21/2 years spanning grade three to six with evaluation of outcomes using the ASEBA Teacher Report Form (TRF) and end of term grades for the intervention group versus matched controls who were offered usual school supports. RESULTS: The intervention group made significant improvements in school social and behavior adjustment measured by the TRF, with more successful outcome amongst boys for behavioral gains. No significant improvements were made by the girls. Limitations of cohort size, lack of parent data and questions of gender disparities in outcome were unresolved interpretative issues. CONCLUSION: This multi-modal mental health and academic intervention for high-risk children living in an impoverished, violent neighbourhood, improved global functioning of boys more than girls, and raised questions for design of further preventive planning. PMID- 23667359 TI - Immigrant Children with Autism Spectrum Disorder: The Relationship between the Perspective of the Professionals and the Parents' Point of View. AB - BACKGROUND: The purpose of this study was to compare a medical diagnosis of autism spectrum disorder (ASD) with the perceptions of immigrant parents regarding their child's difficulties. METHODS: Semistructured interviews were conducted with parents. The children were assessed using the ADOS, and a multiaxial diagnosis was reached using the DSM-IV. RESULTS: The majority of parents recognized symptoms in their child that were related to autism. Less often, however, parents believed their children had a developmental delay or communication problem rather than an ASD. There were also parents who failed to see any problem at all in their child although the child was, nonetheless, diagnosed as having an ASD. CONCLUSIONS: The failure of immigrant mothers to acknowledge a diagnosis of ASD in their younger children may represent an attempt to preserve hope for their child's future. Mothers of older children may not, however, agree with the psychiatric diagnosis. Community services need to balance the need to convey accurate medical information with the need to protect parents' investment in their children. This may be particularly true for immigrant parents who are living outside their cultural framework. PMID- 23667360 TI - Children with Autism and Attention Difficulties: A Pilot Study of the Association between Sensory, Motor, and Adaptive Behaviors. AB - OBJECTIVES: This pilot study aimed to compare sensory processing, motor skills and adaptive behaviors in children with a double diagnosis of Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD) (ASD+ADHD) with children with ADHD alone and to examine the association of sensory processing and motor skills with adaptive behaviors (self-care). METHOD: Thirty children aged 5-14 years diagnosed with ASD+ADHD (n = 13) or ADHD (n = 17) were evaluated on their sensory processing and motor skills and adaptive behaviors. Analysis of covariance compared the groups on these dimensions. Correlation analyses examined the association between sensory processing and motor skills and adaptive behaviors. RESULTS: Compared to children with ADHD alone, children with ASD+ADHD had poorer skills in sensory processing (p < 0.001), motor (p = 0.001) and adaptive behaviors (p < 0.001). For all children, increased autonomy in self care was correlated with better sensory processing (p < 0.001) and motor skills (p = 0.002). CONCLUSION: Children with ASD+ADHD have poorer sensory processing, motor and adaptive skills than those with ADHD alone. Sensory processing and motor deficits were negatively associated with autonomy in self-care. Interventions aiming to improve sensory processing and motor skills and autonomy in self-care should become important targets for these children. PMID- 23667361 TI - BCFPI Validation for a High-risk High-needs Sample of Children and Youth Admitted to Tertiary Care. AB - OBJECTIVE: This study examined the validity and reliability of the Brief Child and Family Phone Interview (BCFPI) in a sample of high-risk, high-need children and youth admitted to a tertiary residential psychiatric facility. This is the first validation study of the BCFPI with children and youth functioning at the extreme clinical range. METHOD: Participants consisted of children and youth in a southwestern Ontario tertiary residential mental health facility. Two hundred twenty seven children and youth aged 6.28 to 16.74 (M = 12.06 years, SD = 2.46) were evaluated. Internal consistencies of each scale were tested using Cronbach's alpha, and subsequently confirmed with unidimensional principal components analyses. Concurrent validity was evaluated through Pearson product-moment correlations between each subscale and the empirically validated subscales in the Conners' Rating Scales. RESULTS: With exception of the conduct subscale (alpha =.68), all Cronbach's alpha estimates were in the acceptable range. Each scale demonstrated acceptable factor loadings on a single-factor principal components extraction derived from the pool of items within each scale. Concurrent validity was evidenced by moderate to strong correlations identified with selected measures of the Conners' Parent Rating Scale. CONCLUSIONS: Considered together, the results of this study indicate that the BCFPI is a reliable and valid indicator of child functioning within this client population, and is recommended in the assessment of tertiary populations. PMID- 23667362 TI - Sensitivity of scales to evaluate change in symptomatology with psychostimulants in different ADHD subtypes. AB - OBJECTIVE: To assess the sensitivity of scales (Conners' Global Index Parent and Teacher form [CGI-P, CGI-T], Clinical Global Impression Scale [CGI], Continuous Performance Test [CPT], and Restricted Academic Situation Scale [RASS]) in evaluating improvement in symptomatology with methylphenidate in different Attention Deficit Hyperactivity Disorder (ADHD) subtypes. METHOD: Four hundred and ninety children (309 with ADHD Combined/Hyperactive [ADHD-CH] and 181 with ADHD Inattentive subtype [ADHD-I]) participated in a two week double-blind placebo-controlled crossover methylphenidate trial. RESULTS: CGI-P showed small effect size for ADHD-I and medium effect size for the ADHD-CH subtype. CGI-T showed medium effect size for ADHD-I and large effect size for ADHD-CH subtype. CGI and RASS showed large effect size while CPT showed medium effect size for both subtypes. CONCLUSION: Acute behavioural assessments by clinicians (CGI, RASS) are better at detecting improvement with medication in all subtypes than parent or teacher reports (CGI-P, CGI-T). CGI-T is better than CGI-P for ADHD-I in detecting change in symptomatology as there is a greater demand for attention at school. PMID- 23667363 TI - Child and Adolescent Mental Health Service Management Strategies that may Influence Wait Times. AB - OBJECTIVES: (1) To describe the strategies employed by child mental health agencies to manage service demands; (2) to determine whether the types of strategies used are related to meeting Canadian Psychiatric Association (CPA) benchmarks and wait times; and, (3) to determine whether the types of strategies used are related to agency characteristics. METHODS: An online questionnaire was distributed to 379 agencies providing child mental health services in Canada. The survey inquired about agency characteristics, wait times, ability to meet benchmarks and a series of strategies which may impact wait times. Spearman's rank correlations were used to determine relationships between variables. RESULTS: One hundred thirteen agencies returned adequately completed surveys (29.8%). Collaborating with other agencies/providers and referring families to self-help resources were the most commonly endorsed strategies. The use of more upstream/ pre-waitlist strategies was related to the ability to meet CPA benchmarks for urgent cases. No cluster of strategies was related to estimated wait times. Restriction strategies were most consistently related to agency size. CONCLUSIONS: Multiple strategies were endorsed by many agencies, but very few demonstrated relationships to wait time variables. Rigorous evaluation of commonly used service strategies are required to determine whether any positive impacts are being obtained by such efforts. PMID- 23667365 TI - Letters from ainsworth: contesting the 'organization' of attachment. AB - As Main (1999) noted in her obituary for Mary Ainsworth, 'she was interacting weekly by letter and manuscript with her mentor and friend, John Bowlby, and their academic correspondence formed an important part of her, and implicitly our, life.' These letters of Ainsworth to John Bowlby during the 1980s, available in the Wellcome Trust Library in London, contain valuable reflections on the work of her pupils to extend her system of classifying infant behaviour in the Strange Situation Procedure. Mary Main proposed a D classification and interpreted such behaviour as a breakdown in an ABC strategy caused by a conflict between a disposition to approach and flee from the caregiver. Patricia Crittenden extended the subtypes of A and C, using a developmental model of information processing, and observed that they could be used together in A/C combinations. These letters offer insight into Ainsworth's intellectual rationale for encouraging both Main and Crittenden in their conflicting endeavours. PMID- 23667364 TI - Memantine: a review of possible uses in child and adolescent psychiatry. AB - OBJECTIVE: To provide a review of published literature regarding the pharmacology of memantine and potential benefits for use in child and adolescent psychiatry. METHOD: A LITERATURE SEARCH OF SEVERAL DATABASES (MEDLINE, PSYCHINFO, CINAHL, PSYCARTICLES) WAS CONDUCTED WITH THE SEARCH TERMS: 'memantine' with limits: English language, Human trials, all child (aged 0-18 years). The search was later expanded to include 'Adults' and relevant articles were also selected from reference lists. RESULT: The search did not find any well-controlled studies in children and adolescents except for open label trials, as monotherapy in autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), as well as an augmenting agent in obsessive compulsive disorder (OCD). No study was found in anxiety disorders (AD), the most common psychiatric disorder in children or in mood disorders, both major depressive disorder (MDD) and bipolar disorder (BD). Studies in adults for those disorders with onset in childhood or adolescence, were also mostly open-label and as an add-on therapy. All the studies reported that memantine is a safe drug with minimal drug interactions and a very acceptable adverse effect profile comparable to placebo. CONCLUSION: Memantine has demonstrated beneficial effects in some childhood disorders but the evidence is too limited at present and does not provide enough support of its efficacy to advocate for its regular use in those conditions. Such use remains off-label until further validation of efficacy comes from blinded, randomized, placebo controlled studies. PMID- 23667366 TI - Commentary on "letters from ainsworth: contesting the 'organization' of attachment". PMID- 23667367 TI - Acinar cell carcinoma of the pancreas: clinical and cytomorphologic characteristics. AB - Acinar cell carcinoma is a rare malignant epithelial neoplasm with predominantly exocrine acinar differentiation and is seen primarily in older men (mean age, 62 years). The presenting symptoms are usually non-specific, and jaundice is often not present. Symptoms relating to the overproduction and release of lipase into the circulation are present in 10-15% of patients. Characteristic cytomorphologic features include a population of cells with minimal pleomorphism, eccentrically placed nuclei with a single prominent nucleoli and moderate hyperchromasia. The cytoplasm is finely granular, and the background may contain granular debris secondary to cytolysis. A significant proportion of the cases also have a minor neuroendocrine component or scattered neuroendocrine cells. Approximately 50% of patients have metastatic disease at presentation, often restricted to the regional lymph nodes and liver. The prognosis is poor, only slightly better than that of pancreatic ductal adenocarcinoma. PMID- 23667368 TI - Guideline Recommendations for EGFR Mutation Testing in Lung Cancer: Proposal of the Korean Cardiopulmonary Pathology Study Group. AB - Mutations of the epidermal growth factor receptor (EGFR) are the strongest predictive factor for response to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. EGFR TKIs are approved in Korea as a first-line treatment for lung cancer patients with mutated EGFR. Rapid and accurate EGFR mutation testing is essential for patient selection and establishing targeted therapies with EGFR TKIs. Thus, a standard set of guideline recommendations for EGFR mutation testing suitable for the Korean medical community is necessary. In this article, we propose a set of guideline recommendations for EGFR mutation testing that was discussed and approved by the Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists. PMID- 23667369 TI - EGFR Gene Amplification and Protein Expression in Invasive Ductal Carcinoma of the Breast. AB - BACKGROUND: The epidermal growth factor receptor (EGFR) is a surrogate marker for basal-like breast cancer. A recent study suggested that EGFR may be used as a target for breast cancer treatment. METHODS: A total of 706 invasive ductal carcinomas (IDC) of the breast were immunophenotyped, and 82 cases with EGFR protein expression were studied for EGFR gene amplification. RESULTS: EGFR protein was expressed in 121 of 706 IDCs (17.1%); 5.9% were of luminal type, 25.3% of epidermal growth factor receptor 2 (HER-2) type, and 79.3% of basal-like tumors. EGFR gene amplification and high polysomy (fluorescent in situ hybridization [FISH]-positive) were found in 18 of 82 cases (22.0%); 41.2% of the HER-2(+), EGFR(+), cytokeratin 5/6(-) (CK5/6(-)) group, 11.2% of the HER-2(-), EGFR(+), CK5/6(-) group, and 19.1% of the HER-2(-), EGFR(+), CK5/6(+) group. FISH positive cases were detected in 8.3% of the EGFR protein 1(+) expression cases, 15.9% of 2(+) expression cases, and 38.5% of 3(+) expression cases. In group 2, the tumors had a high Ki-67 labeling (>60%), but the patients showed better disease-free survival than those with tumors that co-expressed HER-2 or CK5/6. CONCLUSIONS: EGFR-directed therapy can be considered in breast cancer patients with EGFR protein overexpression and gene amplification, and its therapeutic implication should be determined in HER-2 type breast cancer patients. PMID- 23667370 TI - Hedgehog related protein expression in breast cancer: gli-2 is associated with poor overall survival. AB - BACKGROUND: The hedgehog (Hh) signaling pathway is known to play a critical role in various malignancies, but its clinicopathologic role in breast cancer is yet to be established. METHODS: Tissue microarray blocks from 334 cases of breast cancer were prepared. The expression of six Hh signaling proteins including sonic hedgehog (Shh), patched (Ptch), smoothened (Smo), and the glioma-associated oncogene (Gli)-1, Gli-2, and Gli-3 were analyzed immunohistochemically. RESULTS: The expression of Hh signaling proteins was significantly correlated with some prognostic factors including the correlation of lymph node metastasis with the expression of Shh (p=0.001) and Ptch (p=0.064), the correlation of the stages with Shh and Gli-3 expression (p=0.007 and p=0.024, respectively), the correlation of the nuclear grade with the Smo (p=0.004) and Gli-3 (p=0.000), and the correlation of the histologic grade with the Ptch (p=0.016), Smo (p=0.007), and Gli-3 (p=0.000). The Shh, Ptch, Smo, Gli-1, and Gli-2 expression was significantly different between the phenotypes (p=0.000, p=0.001, p=0.004, p=0.039, and p=0.031, respectively). Gli-2 expression was correlated with a worse overall survival outcome (p=0.012). CONCLUSIONS: Hh pathway activation is correlated with a more aggressive clinical behavior in breast carcinomas. The comparison of phenotypes suggested that the Hh pathway may be a useful therapeutic target for breast carcinoma. Patients with Gli-2 expression had a significantly lower overall survival rate and, therefore, it showed promise as a prognostic marker. PMID- 23667371 TI - No detection of simian virus 40 in malignant mesothelioma in Korea. AB - BACKGROUND: Simian virus 40 (SV40), a polyomavirus, was discovered as a contaminant of a human polio vaccine in the 1960s. It is known that malignant mesothelioma (MM) is associated with SV40, and that the virus works as a cofactor to the carcinogenetic effects of asbestos. However, the reports about the correlation between SV40 and MM have not been consistent. The purpose of this study is to identify SV40 in MM tissue in Korea through detection of SV40 protein and DNA. METHODS: We analyzed 62 cases of available paraffin-blocks enrolled through the Korean Malignant Mesothelioma Surveillance System and performed immunohistochemistry for SV40 protein and real-time polymerase chain reaction (PCR) for SV40 DNA. RESULTS: Of 62 total cases, 40 had disease involving the pleura (64.5%), and 29 (46.8%) were found to be of the epithelioid subtype. Immunostaining demonstrated that all examined tissues were negative for SV40 protein. Sufficient DNA was extracted for real-time PCR analysis from 36 cases. Quantitative PCR of these samples showed no increase in SV40 transcript compared to the negative controls. CONCLUSIONS: SV40 is not associated with the development of MM in Korea. PMID- 23667372 TI - Prognostic Significance of BCL9 Expression in Hepatocellular Carcinoma. AB - BACKGROUND: BCL9 enhances beta-catenin-mediated transcriptional activity regardless of the mutational status of the Wnt signaling components and increases the cell proliferation, migration, invasion, and metastatic potential of tumor cells. The goal of this study was to elucidate the prognostic significance of BCL9 protein expression in hepatocellular carcinoma (HCC) patients. METHODS: We evaluated BCL9 protein expression by immunohistochemistry in tumor tissue from 288 primary HCC patients who underwent curative hepatectomy. The impact of BCL9 expression on the survival of the patients was analyzed. The median follow-up period was 97.1 months. RESULTS: Nuclear BCL9 protein expression was observed in 74 (25.7%) of the 288 HCCs. BCL9 expression was significantly associated with younger age (p=0.038), higher Edmondson grade (p=0.001), microvascular invasion (p=0.013), and intrahepatic metastasis (p=0.017). Based on univariate analyses, BCL9 expression showed an unfavorable influence on both disease-free survival (DFS, p=0.012) and disease-specific survival (DSS, p=0.032). Multivariate analyses revealed that higher Barcelona Clinic Liver Cancer stage was an independent predictor of both shorter DFS (p<0.001) and shorter DSS (p<0.001). BCL9 expression tended to be an independent predictor of shorter DFS (p=0.078). CONCLUSIONS: BCL9 protein expression might be a marker of shorter DFS in HCC patients after curative hepatectomy. PMID- 23667373 TI - EBV-Positive T/NK-Cell Lymphoproliferative Disease of Childhood. AB - BACKGROUND: Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH), EBV-positive systemic T-cell lymphoproliferative disease (STLPD) of childhood, and chronic active EBV (CAEBV) infection may develop after primary EBV infection. This study reviewed the clinicopathological spectrum of EBV-associated T- and natural killer (NK)-cell LPD, including STLPD and CAEBV infection, with an analysis of T-cell clonality. METHODS: Clinicopathological features of seven patients with EBV-associated HLH or STLPD and 12 patients with CAEBV infection were reviewed. Immunohistochemical staining and a T-cell receptor (TCR) gene rearrangement study were performed. RESULTS: STLPD and EBV-positive HLH showed significantly overlapping clinicopathological findings. One patient with STLPD and one patient with EBV-positive HLH demonstrated moderate to severe atypia of the infiltrating lymphocytes, whereas the remaining patients lacked significant atypia. Twelve patients had CAEBV infection, four of whom suffered mosquito-bite hypersensitivity, five showed NK lymphocytosis, and one suffered hydroa vacciniforme. Infiltrating lymphocytes were predominantly small and devoid of atypia. Hemophagocytic histiocytosis was found in seven of 11 patients. Monoclonality was detected in three (50%) of the six patients with successful TCR gene analysis. CONCLUSIONS: EBV-positive HLH and STLPD share similar clinicopathological findings and may constitute a continuous spectrum of acute EBV-associated T- or NK-cell proliferative disorders. The distinction of EBV-positive T-cell LPD from EBV-positive HLH may be difficult during routine diagnoses because of the technical limitations of clonality assessment. PMID- 23667374 TI - Human papillomavirus prevalence and cell cycle related protein expression in tonsillar squamous cell carcinomas of korean patients with clinicopathologic analysis. AB - BACKGROUND: Human papillomavirus (HPV)-related tonsillar squamous cell carcinoma (TSCC) has recently been characterized as a distinct subset with a favorable prognosis. The prevalence and clinicopathologic significance of HPV-related TSCC in Koreans are not well known. METHODS: HPV in situ hybridization (ISH) accompanied by p53, p16, pRb, and cyclin D1 immunohistochemical staining were performed on 89 resection cases of TSCC from 2000 through 2010. RESULTS: HPV was detected by ISH in 59 of 89 cases (66.3%). HPV-positive TSCCs were more common in younger ages (p=0.005), and tumor sizes were smaller in the HPV-positive compared to the HPV-negative group (p=0.040). Positive HPV staining was significantly correlated with p16 expression (p<0.001), pRb inactivation (p=0.003), and cyclin D1 down-regulation (p<0.001) but not with p53 expression (p=0.334). Seventeen cases that showed p16-immunopositivity with HPV-negativity by ISH were retested by HPV typing; HPV DNA was not detected in all cases. There was no significant difference between HPV-positive and HPV-negative patients either in the disease specific survival (DSS, p=0.857) or overall survival (p=0.910). Furthermore, pRb inactivated cases showed better DSS (p=0.023), and p53-positive cases showed worse DSS (p=0.001). CONCLUSIONS: Although high HPV prevalence was noted, it was not correlated with histopathologic findings or survival benefit. In addition to p53 expression, pRb inactivation along with p16 overexpression and down regulation of cyclin D1 are thought to be important pathogenetic steps for developing TSCCs. PMID- 23667375 TI - A solitary fibrous tumor with giant cells in the lacrimal gland: a case study. AB - Orbital solitary fibrous tumor (SFT) has recently been proposed as the encompassing terminology for hemangiopericytoma, giant cell angiofibroma (GCAF), and fibrous histiocytoma of the orbit. The lacrimal gland is a very rare location for both SFT and GCAF. A 39-year-old man presented with a painless left upper eyelid mass. An orbital computed tomography scan identified a 1.1 cm-sized well defined nodule located in the left lacrimal gland. He underwent a mass excision. Histopathologic examination showed a proliferation of relatively uniform spindle cells with a patternless or focally storiform pattern. Dilated vessels were prominent, but angiectoid spaces lined with giant cells were absent. Floret-type giant cells were mostly scattered in the periphery. The tumor was immunoreactive for CD34 and CD99, but negative for smooth muscle actin and S-100 protein. This is the first Korean case of SFT of the lacrimal gland with overlapping features of GCAF, suggesting a close relationship between the two entities. PMID- 23667376 TI - Silent Colonic Malakoplakia in a Living-Donor Kidney Transplant Recipient Diagnosed during Annual Medical Examination. AB - Malakoplakia is a characteristic inflammatory condition, which is usually seen in the urogenital tract, and less frequently in the gastrointestinal tract. We present a case of colonic malakoplakia in an immunocompromised patient. A 55-year old female visited the outpatient clinic for routine cancer surveillance. Her past medical history was significant for kidney transplantation 11 years ago, and she had been taking immunosuppressants. A colonoscopy revealed several depressed flat lesions and elevated polyps, which were 0.3 to 0.4 cm in size and accompanied by whitish exudates. A biopsy revealed an infiltration of histiocytes with ample granular eosinophilic cytoplasm, with some lymphocytes and plasma cells. Many histiocytes had the characteristic morphology, described as Michaelis Gutmann bodies: one or several round basophilic structures of approximately 1 to 10 um in size with some being laminated, some appearing homogeneous, and others having a dense central core with a targetoid appearance. These Michaelis-Gutmann bodies were positively stained on von Kossa stain, and were diagnostic for malakoplakia. PMID- 23667377 TI - Papillary Carcinoma of the Thyroid Gland with Nodular Fasciitis-like Stroma. AB - Papillary thyroid carcinoma with nodular fasciitis-like stroma (PTC-NFS) is a rare variant of PTC. The term 'PTC with fibromatosis-like stroma' has been used as a synonym to describe this variant. It is characterized by extensive proliferation of fibroblasts and myofibroblasts in the tumor stroma, which occurs in up to 80% of the tumors. We herein describe a case of PTC-NFS which developed in a 49-year-old woman with the demonstration of findings of ultrasonography, fine needle aspiration cytology and histological examination of the lesion. To characterize the stromal components, we investigated the expression of several immunohistochemical markers which have been shown to be expressed differently in nodular fasciitis (NF) and fibromatosis (FM). The immunostaining results demonstrated nuclear and cytoplasmic accumulation of beta-catenin, cytoplasmic transforming growth factor-beta expression and nuclear Smad expression in the stromal cells, suggesting that the stromal cells in this case have similar molecular profiles to those of FM rather than NF. PMID- 23667378 TI - Congenital peribronchial myofibroblastic tumor: a case study and literature review. AB - Congenital peribronchial myofibroblastic tumor (CPMT) is a benign pulmonary spindle cell neoplasm of intrauterine and perinatal period, which is thought to arise from primitive peribronchial mesenchyme. We present a case detected incidentally in a one-month-old infant. The solid and partially necrotic tumor involved the right middle and lower lobes of the lung with extension to the diaphragm. Histologically, the tumor was composed of fasciculated monotonous spindle cells, proliferating peribronchiolar cartilage and round cells with rich vasculature, and high mitotic activity was identified in the round cell area. Immunohistochemical and electron microscopic studies showed that the spindle cells were myofibroblastic in phenotype. Although the tumor showed several malignant pathological features, recurrence was not observed in the two-year follow-up period, consistent with the benign clinical behavior of CPMT. PMID- 23667379 TI - Extrapelvic Uterus-like Masses Presenting as Colonic Submucosal Tumor: A Case Study and Review of Literature. AB - A uterus-like mass (ULM) is a central cavity lined by endometrial glands and stroma and surrounded by thick-walled smooth muscles. To date, 31 cases of ULM have been reported in the English literature. ULM typically presents as a single mass and is located in the pelvic cavity. We report here a very rare case of multiple extrapelvic ULMs involving the cecum, descending colon, and mesocolon. After extensive literature research, our case appears to be the first case of multiple ULMs found in extrapelvic sites and the first case of ULM in the colon. The present case suggests that ULM should be included in the differential diagnosis of colonic submucosal tumors in female patients with chronic abdominal pain or menstruation-associated symptoms. PMID- 23667380 TI - ThinPrep Cytological Findings of Desmoplastic Small Round Cell Tumor with Extensive Glandular Differentiation: A Case Study. AB - Desmoplastic small round cell tumor (DSRCT) is a rare and highly aggressive neoplasm. The cytological diagnosis of this tumor has only been reported in a few cases. In most of these cases, the diagnosis was made using fine-needle aspiration cytology. Most DSRCTs resemble disseminated carcinomatoses in their clinical manifestation as well as cytomorphologically, even in young-adult patients. These authors report a case of using peritoneal-washing and pleural effusion ThinPrep cytology to diagnose DSRCT, with extensive glandular differentiation and mucin vacuoles. We found that fibrillary stromal fragment, clinical setting, and adjunctive immunocytochemical staining were most helpful for avoiding misdiagnosis. PMID- 23667381 TI - Mucinous Non-neoplastic Cyst of the Pancreas. PMID- 23667382 TI - Do Different Depression Phenotypes Have Different Risks for Recurrent Coronary Heart Disease? AB - Although research has consistently established that depression and elevated depressive symptoms are associated with an increased risk of acute coronary syndrome (ACS) recurrence and mortality, clinical trials have failed to show that conventional depression interventions offset this risk. As depression is a complex and heterogeneous syndrome, we believe that using simpler, or intermediary, phenotypes rather than one complex phenotype may allow better identification of those at particular risk of ACS recurrence and mortality and may contribute to the development of specific depression treatments that would improve medical outcomes. Although there are many possible intermediary phenotypes, specifiers, and dimensions of depression, we will focus on only two when considering the relation between depression and risk of ACS recurrence and mortality: Inflammation-Induced Incident Depression and Anhedonic Depression. Future research on intermediary phenotypes of depression is needed to clarify which are associated with the greatest risk for ACS recurrence and mortality and which, if any, are benign. Theoretical advances in depression phenotyping may also help elucidate the behavioral and biological mechanisms underlying the increased risk of ACS among patients with specific depression phenotypes. Finally, tests of depression interventions may be guided by this new theoretical approach. PMID- 23667384 TI - Lipid Phase Separation and Protein-Ganglioside Clustering in Supported Bilayers Are Induced by Photorelease of Ceramide. AB - Photolysis of 6-bromo-7-hydroxycoumarinyl-caged ceramide was used to generate ceramide with spatial and temporal control in supported lipid bilayers prepared from mixtures of caged ceramide and phospholipids. The caged ceramide molecules are randomly distributed in fluid 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine (POPC) bilayers, and upon photolysis with long wavelength UV light small ordered ceramide domains are formed that phase separate from the bulk fluid membrane. Irradiation of a spatially restricted area leads to the transient formation of ceramide-enriched gel phase domains that equilibrate via lipid diffusion with the surrounding unirradiated membrane. Photorelease of C16 ceramide in supported bilayers prepared from POPC, caged ceramide and the ganglioside GM1 (90:10:1 molar ratio) results in partitioning of a ganglioside protein complex into the ceramide-enriched domains, modeling some aspects of ceramide's behavior in cells. The photo-uncaging strategy used here for delivery of ceramide in bilayers provides a novel and useful alternative to the enzymatic generation of ceramide in sphingomyelin-containing membranes. The ability to control membrane phase separation behavior and the clustering of membrane anchored proteins illustrates the potential of photo-uncaging for studying the compartmentalization of ceramide in cellular membranes. PMID- 23667383 TI - Androgen regulation of epithelial-mesenchymal transition in prostate tumorigenesis. AB - Prostate cancer patient mortality is ascribed to the spread of cancerous cells to areas outside the prostate gland and the inability of current treatment strategies to effectively block progression to metastasis. Understanding the cellular mechanisms contributing to the dissemination of malignant cells and metastasis is critically significant to the generation of effective therapeutic modalities for improved patient survival while combating therapeutic resistance. In recent years, the phenomenon of epithelial-mesenchymal transitions (EMTs) has received considerable attention due to accumulating evidence indicating a role for this developmentally conserved process in tumorigenesis. Cancer cells at the invasive edges of tumors undergo EMT under the influence of contextual signals that they receive from the microenvironment, such as TGF-beta. Also derived from developmental studies is the fact that EMT induction is reversible; thus, upon removal of EMT-inducing signals, cells occasionally revert to the epithelial state of their cellular ancestors via the process of mesenchymal-epithelial transition. This article discusses the current evidence supporting a central role for EMT and its reverse process, mesenchymal-epithelial transition, in the metastatic progression of prostate cancer to advanced disease and the involvement of androgen signaling in its regulation towards the development of castration resistant prostate cancer. PMID- 23667385 TI - Fatigue and non-fatigue mathematical muscle models during functional electrical stimulation of paralyzed muscle. AB - Electrical muscle stimulation demonstrates potential for preventing muscle atrophy and for restoring functional movement after spinal cord injury (SCI). Control systems used to optimize delivery of electrical stimulation protocols depend upon the algorithms generated using computational models of paralyzed muscle force output. The Hill-Huxley-type model, while being highly accurate, is also very complex, making it difficult for real-time implementation. In this paper, we propose a Wiener-Hammerstein system to model the paralyzed skeletal muscle under electrical stimulus conditions. The proposed model has substantial advantages in identification algorithm analysis and implementation including computational complexity and convergence, which enable it to be used in real-time model implementation. Experimental data sets from the soleus muscles of fourteen subjects with SCI were collected and tested. The simulation results show that the proposed model outperforms the Hill-Huxley-type model not only in peak force prediction, but also in fitting performance for force output of each individual stimulation train. PMID- 23667386 TI - AIDS Exceptionalism: On the Social Psychology of HIV Prevention Research. AB - The current analysis considers the HIV prevention research record in the social sciences. We do so with special reference to what has been termed "AIDS Exceptionalism"- departures from standard public health practice and prevention research priorities in favor of alternative approaches to prevention that, it has been argued, emphasize individual rights at the expense of public health protection. In considering this issue, we review the historical context of the HIV epidemic; empirically demonstrate a pattern of prevention research characterized by systematic neglect of prevention interventions for HIV-infected persons; and articulate a rationale for "Prevention for Positives," supportive prevention efforts tailored to the needs of HIV+ individuals. We then propose a social psychological conceptualization of processes that appear to have influenced developments in HIV prevention research and directed its focus to particular target populations. Our concluding section considers whether there are social and research policy lessons to be learned from the record of HIV prevention research that might improve our ability to addresses effectively, equitably, and in timely fashion future epidemics that play out, as HIV does, at the junction of biology and behavior. At the first quarter century of the AIDS epidemic, it is important to weigh our accomplishments against our failures in the fight against AIDS...Future historians will conclude that we cannot escape responsibility for our failure to use effective, scientifically proven strategies to control the AIDS epidemic...They will also likely regard as tragic those instances when we allowed scarce resources to be used to support ideologically driven "prevention" that only served a particular political agenda.Editorial: A Quarter Century of AIDS. American Journal of Public Health. (Stall & Mills, 2006, p. 961). PMID- 23667388 TI - An enzyme-linked immunosorbent assay for detecting 3-phenoxybenzoic acid in plasma and its application in farmers and consumers. AB - The aim of this study was to identify a plasma biomarker of exposure to pyrethroid insecticides. A major metabolite, 3-phenoxybenzoic acid (3-PBA), can be detected in urine but urinary 3-PBA cannot be used to assess the active dose. The 3-PBA-adduct represents a much more persistent class of biomarkers than metabolites excreted into urine, having half lives up to several weeks or months. We developed an enzyme-linked immunosorbent assay (ELISA) for total 3-PBA including adduct formed after alkaline hydrolysis, liquid-liquid extraction (LLE) and solid phase extraction (SPE) of the sample. The developed ELISA had an IC50 value of 26.7 ng/mL. The intra- and inter-assay coefficients of variation (%CV) were lower than 5% and were within the optimum condition variance (OCV) range. The LLE cleanup technique satisfactorily eliminated the matrix effect from plasma samples before SPE and ELISA analysis yielding good recoveries (85.9-99.4%) with a limit of quantitation (LOQ, 5 ng/mL) that was 30- to 47-fold more sensitive than previous studies. Moreover, the developed method could separate more than 80% of 3-PBA from adduct form. The method was successfully applied to the detection of the target in real samples obtained from consumers (n=50) and farmers (n=50). To our knowledge, this is the first ELISA method for detecting 3 PBA in human plasma and applied to a field study. PMID- 23667387 TI - STimulant Reduction Intervention using Dosed Exercise (STRIDE) - Description of the Exercise Intervention and Behavioral Program to Ensure Adherence. PMID- 23667389 TI - Reconstruction of Thermographic Signals to Map Perforator Vessels in Humans. AB - Thermal representations on the surface of a human forearm of underlying perforator vessels have previously been mapped via recovery-enhanced infrared imaging, which is performed as skin blood flow recovers to baseline levels following cooling of the forearm. We noted that the same vessels could also be observed during reactive hyperaemia tests after complete 5-min occlusion of the forearm by an inflatable cuff. However, not all subjects showed vessels with acceptable contrast. Therefore, we applied a thermographic signal reconstruction algorithm to reactive hyperaemia testing, which substantially enhanced signal-to noise ratios between perforator vessels and their surroundings, thereby enabling their mapping with higher accuracy and a shorter occlusion period. PMID- 23667391 TI - Spectroscopic investigations on the interactions of potent platinum(II) anticancer agents with bovine serum albumin. AB - The interactions of three platinum(II)-based anticancer complexes [(5,6-dimethyl 1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)](2+), [(5,6-dimethyl 1,10-phenanthroline)(1R,2R-diaminocyclohexane)platinum(II)](2+), and [(5,6 dimethyl-1,10-phenanthroline)(1,2-diaminoethane)platinum(II)](2+) (56MEEN) with BSA have been examined by circular dichroism (CD), fluorescence and (1)H pulsed gradient spin-echo (PGSE) diffusion NMR spectroscopy. The number of association constants and sites differed depending upon the spectroscopic method. This may be because each technique monitors different types of interaction/s and/or as a consequence of the different concentration ranges required for each technique. The titration of BSA with the achiral 56MEEN as monitored by CD indicates a reduction in the alpha-helical nature of the albumin, with the association constant calculated to be ~5 * 10(6) M(-1) for one site. Due to the chiral nature of the other two complexes, their association with albumin was not monitored using CD but was examined using fluorescence and PGSE diffusion NMR. Titration of BSA with any of the three metal complexes resulted in quenching of fluorescence, with the number of association sites calculated to be ~1.1, with an association constant of ~2 * 10(5) M(-1). PGSE diffusion NMR provided insights into interactions occurring with the BSA in its entirety, rather than with individual regions. Metal complex binding sites were estimated (~10 equivalent) from the diffusion data, with the average association constant for all sites ~10(2) 10(3)M(-1). These experiments highlight the information that can be elucidated from complementary spectroscopic techniques and demonstrate the usefulness of PGSE diffusion NMR in monitoring multiple weak binding sites, which is of great importance in studying drug-biomolecule interactions. PMID- 23667390 TI - Effects of adult onset mild calorie restriction on weight of reproductive organs, plasma parameters and gene expression in male mice. AB - Calorie restriction (CR) extends lifespan and delays onset of age-related diseases in various organisms, even when started later in life. Despite benefits for health and lifespan, CR's negative impact on reproduction is documented in some animals. Studies employing approximately 40% CR detected a delay in sexual maturation and impairment of fertility, which were combined with extension of the reproductive period. In contrast, mild CR (10-20%) is apparently not deleterious to reproduction. Hence, we hypothesized that mild CR started at 8 months of age would prolong reproductive capabilities and improve health parameters of male mice. To test this hypothesis, we assessed the effects of 10 and 20% CR on reproductive organ weights, selected plasma parameters and hepatic/testicular gene expression in normal male mice of heterogeneous genetic background. Starting at 8 months of age (adult), mice were assigned to 3 regimen groups: 10% CR (n = 8), 20% CR (n = 9) or ad libitum (AL; n = 8). Four months of CR were sufficient to reduce glycemia in a non-fasted protocol. Mild CR initiated in adulthood did not significantly impact final body weight, most of the analyzed plasma parameters or weight of androgen-dependent organs. Moreover, CR did not interfere with expression of the assessed testicular genes, or most of the hepatic genes, but it did cause an increase in the levels of peroxisome proliferator-activated receptor gamma (Pparg) and mouse sulfotransferase (mSTa); and a decrease in glucose-6-phosphatase-alpha (G6pc) mRNA, which might signify improvement of body condition. The important finding of our study was that a mild CR regimen, as low as 10 and 20%, was sufficient to impair glycemia in a non-fasted state, and also the levels of plasma IGF-1, corroborating the concept that mild CR has the potential for improving health and longevity, even when started later in life. PMID- 23667392 TI - Early orthogeriatric treatment of trauma in the elderly: a systematic review and metaanalysis. AB - BACKGROUND: More than 125,000 hip fractures occur in Germany every year, with a one-year mortality of about 25%. To improve treatment outcomes, models of cooperation between trauma surgery and geriatrics have been developed. Their benefit has not yet been unequivocally demonstrated. METHODS: We systematically searched the Medline database and the Cochrane Library for prospective randomized controlled trials in which the treatment of elderly patients with fractures by the trauma surgery service alone was compared with preoperatively initiated collaborative treatment by the trauma surgery and geriatric services ("orthogeriatric" treatment). We investigated three treatment outcome variables- length of hospital stay, in-hospital mortality, and one-year mortality--in a metaanalysis. RESULTS: The five trials of hip fracture treatment that met the selection criteria all had relatively small study populations and a high risk of bias. The outcomes with respect to hospital stay differed greatly among trials (I(2): 88.5%), and geriatric intervention was not found to have any statistically significant effect (0.06 days, 95% confidence interval [CI]: -3.74 to 3.62 days). The relative risk of dying in the hospital was 0.66 for orthogeriatric treatment (95% CI: 0.28-1.55, p = 0.34), and the hazard ratio for one-year mortality was 0.79 in favor of orthogeriatric treatment (95% CI: 0.57 to 1.10, p = 0.17). A metaanalysis of functional outcomes was not possible. CONCLUSION: Only a few randomized controlled trials of early orthogeriatric treatment have been performed, and these trials are of limited quality. Due to low case numbers, a benefit from interdisciplinary orthogeriatric treatment could not clearly be demonstrated. Further trials are needed. PMID- 23667394 TI - Additional important aspects. PMID- 23667393 TI - Dissociative seizures: a challenge for neurologists and psychotherapists. AB - BACKGROUND: The prevalence of dissociative seizures is between 2 and 33 sufferers per 100,000 persons. 70% of sufferers are women. Dissociative seizures markedly impair quality of life. Their close superficial resemblance to epileptic seizures makes them hard to diagnose. METHODS: Selective literature search in PubMed and PsycINFO. RESULTS: Persons with dissociative seizures constitute a mixed group with a wide variety of predisposing, precipitating, and maintaining factors. Some 90% have comorbid psychiatric disorders such as depression, anxiety, somatoform disorders, personality disorders, or post-traumatic stress disorder. Video-EEG monitoring enables highly reliable diagnosis. Psychotherapy is considered the treatment of first choice; in prospective studies, it has been found to lower the frequency of dissociative seizures by at least 50%, or to eliminate them completely, in 50% to 80% of patients. An individually tailored combination of behavioral therapeutic, imagery-based, and psychodynamic approaches seems reasonable. For the treatment of psychiatric comorbidities, psychotherapy is indicated, in combination with psychoactive drugs if necessary. Before any treatment is provided, the diagnosis should be communicated to the patient in an appropriate way, ideally by both the neurologist and the psychotherapist, so that the patient can develop an alternative disease model. CONCLUSION: When the diagnosis of dissociative seizures has been made, psychotherapy is indicated, possibly in combination with psychoactive medication, in the setting of long-term treatment provided in collaboration by the neurologist, psychiatrist, psychotherapist, and family physician. Further randomized trials are needed to determine which treatments are best for which subgroups of patients. PMID- 23667395 TI - In reply. PMID- 23667396 TI - Iatrogenic chronification as a result of pseudo diagnosis. PMID- 23667397 TI - In reply. PMID- 23667398 TI - Cross-Sectional Study of Unmet Mental Health Need in 5- to 7-Year Old Latino Children in the United States: Do Teachers and Parents Make a Difference in Service Utilization? AB - The aim of the study is to examine the rates of mental health service utilization in young Latino children of immigrants in relation to maternal and teacher reports of child mental health need. Specific knowledge is lacking about gaps in service utilization among young Latino children, the fastest growing and possibly the most underserved segment of the US child population. The associations of mental health service utilization (Service Assessment for Children and Adolescents) and mental health need (clinical levels of internalizing, externalizing, or total problems reported by mothers [Child Behavior Checklist] and teachers [Teacher's Report Form]) were examined in a community sample of young Latino children of immigrants (n = 228; mean age = 6) and compared across mothers' and teachers' responses. Mother-teacher agreement was also studied. Sixty-five children (28.5 %) had a mental health need; most (76.9 %) of these received no services. For all types of mental health need, service utilization was more likely when need was reported by mothers rather than teachers (p = .03). Teachers' reports were not associated with service utilization. Mother-teacher agreement was low for externalizing (r = .23; p <= 0.01) and total problems (r = .21; p <= 0.05), and nonsignificant for internalizing problems. This study is the first in the United States to document, in such a young Latino group, high rates of unmet need comparable to those among older Latino youth; low or no mother teacher agreement on which children had a mental health need; low utilization of school-based services; and a lack of association between service utilization and teacher-reported mental health need-both for externalizing and internalizing problems. These findings suggest that schools are not effectively leveraging mental health services for young Latino children. Potential factors responsible for the findings are discussed. PMID- 23667399 TI - eQTL Mapping Using RNA-seq Data. AB - As RNA-seq is replacing gene expression microarrays to assess genome-wide transcription abundance, gene expression Quantitative Trait Locus (eQTL) studies using RNA-seq have emerged. RNA-seq delivers two novel features that are important for eQTL studies. First, it provides information on allele-specific expression (ASE), which is not available from gene expression microarrays. Second, it generates unprecedentedly rich data to study RNA-isoform expression. In this paper, we review current methods for eQTL mapping using ASE and discuss some future directions. We also review existing works that use RNA-seq data to study RNA-isoform expression and we discuss the gaps between these works and isoform-specific eQTL mapping. PMID- 23667400 TI - Periprosthetic fractures around the knee-the best way of treatment. AB - BACKGROUND: A variety of methods has been described to stabilise periprosthetic fractures around total knee arthroplasty (TKA). Our report offers a review of the actual strategies in the reduction and fixation of these fractures. Surgical treatment should be based on the following four steps:Diagnostics: By taking the patients' history together with an X-ray of the knee and femur, the fracture is analysed. It is crucial to define whether any losening of the prosthesis had occurred. In selected cases, CT-scan may add important information on the stability of the implant.Classification and planning: For most fractures around the distal femur, the Rorabeck classification is used while fractures around the proximal tibia are best classified according to the Felix classification. Additionally the Orthopaedic Trauma Association (OTA) may be helpful in the planning process for reduction and fixation.Surgigal technique: In fractures around a stable implant (Rorabeck type I and II; Felix type A and C), it is favourable to use plates and retrograde nails (in Rorabeck I or II with an open box of a TKA). For reduction, three methods are available: (a) the open technique (with direct or indirect reduction); (b) the mini open technique (direct reduction of the fracture by cerclage or lag screw and percutaneous plate fixation in OTA type 32 or 33-A1) and (c) the minimally invasive technique (indirect reduction and percutaneous fixation in all other OTA types). Fractures with a loose prosthesis (Rorabeck III and Felix B) are best stabilised by hinged revision arthroplasty.Rehabilitation: It is of great importance for the aged patient to be mobilised out of bed early. In most of the cases, partial weight bearing has to be performed by the aid of frames during the first 6 weeks after surgery. In a well-fixed revision prosthesis with a cemented stem, early full weight bearing might be allowed. CONCLUSION: Standardised less invasive procedures to treat periprosthetic fractures present a valuable alternative to open techniques. The main advantages are lower rates of oft tissue complications and implant failures following less invasive techniques of long plate application. Polyaxial locking systems allow for stable plate fixation around intramedullary implants. PMID- 23667401 TI - High Pulsatility Flow Induces Acute Endothelial Inflammation through Overpolarizing Cells to Activate NF-kappaB. AB - Large artery stiffening and small artery inflammation are both well-known pathological features of pulmonary and systemic hypertension, but the relationship between them has been seldom explored. We previously demonstrated that stiffening-induced high pulsatility flow stimulated a pro-inflammatory response in distal pulmonary artery endothelial cells (PAEC). Herein, we hypothesized that high pulsatility flow activated PAEC pro-inflammatory responses are mediated through cell structural remodeling and cytoskeletal regulation of NF kappaB translocation. To test this hypothesis, cells were exposed to low and high pulsatility flows with the same mean physiological flow shear stress. Results showed that unidirectional, high pulsatility flow led to continuous, high-level NF-kappaB activation, whereas low pulsatility flow induced only transient, minor NF-kappaB activation. Compared to cell shape under the static condition, low pulsatility flow induced cell elongation with a polarity index of 1.7, while high pulsatility flow further increased the cell polarity index to a value greater than 3. To explore the roles of cytoskeletal proteins in transducing high flow pulsatility into NF-kappaB activation, PAECs were treated with drugs that reduce the synthesis-breakdown dynamics of F-actin or microtubules (cytochalasin D, phalloidin, nocodazole, and taxol) prior to flow. Results showed that these pre treatments suppressed NF-kappaB activation induced by high pulsatility flow, but drugs changing dynamics of F-actin enhanced NF-kappaB activation even under low pulsatility flow. Taxol was further circulated in the flow to examine its effect on cells. Results showed that circulating taxol (10nM) reduced PAEC polarity, NF kappaB activation, gene expression of pro-inflammatory molecules (ICAM-1 and VCAM 1), and monocyte adhesion on the PAECs under high pulsatility flow. Therefore, taxol effectively reduced high pulsatility flow-induced PAEC overpolarization and pro-inflammatory responses via inhibiting cytoskeletal remodeling. This study suggests that stabilizing microtubule dynamics might bea potential therapeutic means of reducing endothelial inflammation caused by high pulsatility flow. PMID- 23667402 TI - Reach of a kiosk-based pediatric injury prevention program. AB - While controlled trials are important for determining the efficacy of public health programs, implementation studies are critical to guide the translation of efficacious programs to general practice. To implement an evidence-based injury prevention program and examine program use and completion rates in two implementation phases, Safe N' Sound, an evidence-based program, was implemented in five pediatric clinics. Data on program use were collected from program files and patient census data. Program use averaged 12.1% of eligible patients during implementation and 9.5% during the continuation phase. Program completion averaged 9.7% and 6.5%, respectively. Findings from this study can inform the dissemination of evidence-based public health programs, particularly in practice based clinical settings. PMID- 23667404 TI - The reality of aging viewed from the arterial wall. PMID- 23667403 TI - NUTORC-a transdisciplinary health services and outcomes research team in transplantation. AB - The field of solid organ transplantation has historically concentrated research efforts on basic science and translational studies. However, there has been increasing interest in health services and outcomes research. The aim was to build an effective and sustainable, inter- and transdisciplinary health services and outcomes research team (NUTORC), that leveraged institutional strengths in social science, engineering, and management disciplines, coupled with an international recognized transplant program. In 2008, leading methodological experts across the university were identified and intramural funding was obtained for the NUTORC initiative. Inter- and transdisciplinary collaborative teams were created across departments and schools within the university. Within 3 years, NUTORC became fiscally sustainable, yielding more than tenfold return of the initial investment. Academic productivity included funding for 39 grants, publication of 60 manuscripts, and 166 national presentations. Sustainable educational opportunities for students were created. Inter- and transdisciplinary health services and outcomes research in transplant can be innovative and sustainable. PMID- 23667405 TI - Multiple congenital bilateral trigger digits in a 2-year-old child: case report. AB - Trigger finger is a rare condition in children. In this paper, we report on a 2 year-old boy with multiple congenital bilateral trigger digits. The patient had no history of perinatal trauma, viral or bacterial infections, or metabolic disorders. The patient was treated with physiotherapy for one year. At the one year follow-up, the boy presented with six trigger fingers (3 on the right hand, 3 on the left hand). Neither thumb was involved. The six trigger fingers were treated surgically: first, the right-hand trigger fingers and, six months later, those of the left hand. After each operation, a 4-week brace in extension was applied to the operated hand. The symptoms were completely resolved after surgical treatment. Many authors have recommended surgical release for the treatment of trigger finger in children; empirical treatment with physiotherapy may be an option when symptoms present or appear at an older age. PMID- 23667406 TI - A physiological dynamic testing machine for the elbow joint. AB - BACKGROUND: The aim of our study was to develop a test setup combining realistic force transmission with physiological movement patterns at a frequency that mimicked daily use of the elbow, to assess implants in orthopedic joint reconstruction and trauma surgery. METHODS: In a multidisciplinary approach, an in vitro biomechanical testing machine was developed and manufactured that could simulate the repetitive forceful movement of the human elbow joint. The construction involved pneumatic actuators. An aluminum forearm module enabled movements in 3 degrees of freedom, while motions and forces were replicated via force and angular sensors that were similar to in vivo measurements. RESULTS: In the initial testing, 16 human elbow joint specimens were tested at 35 Nm in up to 5000 cycles at a range of 10 degrees extension to 110 degrees flexion. The transmitted forces led to failure in 9 out of the 16 tested specimens, significantly more often in females and small specimens. CONCLUSIONS: It is possible to construct a testing machine to simulate nearly physiological repetitive elbow motions. The prototype has a number of technical deficiencies that could be modified. When testing implants for the human elbow with cadaver specimens, the specimen has to be chosen according to the intended use of the implant under investigation. PMID- 23667407 TI - Midterm Results of 58 Fractures of the Coronoid Process of the Ulna and their Concomitant Injuries. AB - BACKGROUND: In general, fractures of the coronoid process are rare and usually occur in combination with additional elbow joint injuries. The treatment of these injuries aims to regain a stable as well as a flexible and loadable joint. Although there is currently little evidence, therapy recommendations remain controversial. Therefore, the aim of this study was to prognostically determine relevant factors for therapy recommendation by analysing a representative patient population of two trans-regional trauma centres. MATERIAL AND METHODS: Seventy seven patients with a fracture of the coronoid process were treated within an 8 year period (2001 to 2009). After an average of 48 months (SD 31), treatment outcome of 58 patients (75%) was acquired. The results were statistically analysed. RESULTS: The average age of the patient was 51.8 years (SD 13.6); 36 were male and 34 had a fracture on the right arm. Applying the fracture types of the coronoid process in accordance with Regan/Morrey, the result was: Type I (19), II (17) and III (22). Further injuries were also detected: 40 radial head fractures, 17 proximal ulnar fractures and 2 fractures of the olecranon. A luxation was detected in 44 of the 58 patients (76%). The patients' average MEPS (Mayo Elbow Performance Score) was 80.6 points (SD 18), with significant differences between the various therapy strategies. Fifteen% of the coronoid process fractures were reconstructable to a limited extent only by means of osteosynthesis. In 33% of the patients, instabilities remained. The average extension/flexion came to 107 degrees (SD 28), and pronation and supination 153 degrees (SD 38). CONCLUSION: At present, a surgical therapy of ligamentary injuries cannot be statistically justified. A stable osseous reconstruction appears to make more sense. The strongest negative prognostic parameters in our patient population were: therapy with an external fixator, immobilisation for more than 21 days, the occurrence of complications and unstable osteosyntheses on the coronoid process. PMID- 23667408 TI - Hepatitis C Virus Envelope Protein E1 Binds PERK and Represses the Unfolded Protein Response. AB - Unfolded protein response (UPR) is a cellular adaptive response which functions to reduce stress caused by misfolded proteins in the endoplasmic reticulum (ER). We and others have previously shown that infection with hepatitis C virus (HCV) or expression of the viral proteins can trigger the UPR. HCV is a single-stranded positive-sense RNA virus causing chronic diseases in humans. Its genome encodes two envelope proteins E1 and E2 that mature in the ER to form non-covalently bound native complex and disulphide-bonded aggregates. Apart from the ER targeting proteins, cytosolic forms have been documented. We have previously shown that the ER-targeting E1 and E2 are capable of eliciting the UPR whereas others have shown that the cytosolic-targeting E2 can bind to the ER stress kinase PERK to dampen the UPR. In this report, we further show that the other envelope protein E1, in its cytosolic form, can also bind PERK and dampen the UPR. Using GST-pulldown assay, we show that E1 binds to the cytoplasmic domain of PERK, suggesting interaction of E1 and PERK takes place in the cytoplasm. Using reporter gene assay and Western blotting, we show that cytosolic E1 can repress UPR-induced BiP and CHOP promoter activity and reduce UPR-induced CHOP expression level. Altogether these results suggest opposing functions of ER- and cytosolic forms of HCV envelope proteins depending on their subcellular localization. PMID- 23667409 TI - Role of Filopodia in HSV-1 Entry into Zebrafish 3-O-Sulfotransferase-3-Expressing Cells. AB - BACKGROUND: Heparan sulfate proteoglycans (HSPGs) modified by zebrafish (ZF) encoded glucosaminyl 3-O sulfotransferase-3 (3-OST-3) generate a receptor for herpes simplex virus type-1 (HSV-1) entry and spread. In order to elucidate the mechanism by which HSV-1 enters into ZF-3-OST-3 cells, we investigated the mode of viral entry. RESULTS: Under high resolution scanning electron microscopy (SEM), actin cytoskeleton changes were observed by a dramatic increase in the number of filopodia formed during early interactions of HSV-1 with the target cells. While the increase in number was common among all the infected cells, the highest numbers of filopodia was observed in cells expressing the 3-OST-3 modified form of heparan sulfate (HS) encoded either by human or ZF. The levels of viral infection and filopodia induction were reduced with the actin polymerization inhibitors, Cytochalasin-D and Lantriculin B, suggesting an important role for actin reorganization during ZF-3-OST-3 mediated HSV-1 entry. Supporting an interesting possibility of filopodia usage during HSV-1 spread, pre treatment of cytochalasin D in ZF-3-OST-3 cells drastically reduced virus glycoprotein induced cell fusion. CONCLUSIONS: Taken together, our results provide new evidence on the involvement of filopodia during HSV-1 infection of ZF 3-OST-3 cells and confirm a role for modified heparan sulfate in cytoskeleton rearrangement during HSV-1 entry. PMID- 23667410 TI - Helicobacter pylori and Gastric Inflammation: Role of MUC1 Mucin. AB - More than half of the world's population is infected with Helicobacter pylori, which is strongly linked to the development of chronic gastric inflammation (gastritis), peptic ulcer disease, and stomach cancer. However, for unknown reasons, the vast majority of infected individuals are asymptomatic beyond histologic inflammation. This review article will summarize current knowledge on the molecular mechanisms of H. pylori colonization of the gastric mucosa, with a particular focus on the biochemistry of MUC1 mucin in the host response to bacterial infection. PMID- 23667411 TI - The effect of red blood cell aggregation on velocity and cell-depleted layer characteristics of blood in a bifurcating microchannel. AB - Red blood cell (RBC) aggregation is a multifaceted phenomenon, and whether it is generally beneficial or deleterious remains unclear. In order to better understand its effect on microvascular blood flow, the phenomenon must be studied in complex geometries, as it is strongly dependent on time, flow, and geometry. The cell-depleted layer (CDL) which forms at the walls of microvessels has been observed to be enhanced by aggregation; however, details of the characteristics of the CDL in complex regions, such as bifurcations, require further investigation. In the present study, a microchannel with a T-junction was used to analyze the influence of aggregation on the flow field and the CDL. Micro-PIV using RBCs as tracers provided high resolution cell velocity data. CDL characteristics were measured from the same data using a newly developed technique based on motion detection. Skewed and sharpened velocity profiles in the daughter branches were observed, contrary to the behavior of a continuous Newtonian fluid. RBC aggregation was observed to increase the skewness, but decrease the sharpening, of the velocity profiles in the daughter branches. The CDL width was found to be significantly greater, with a wider distribution, in the presence of aggregation and the mean width increased proportionally with the reciprocal of the fraction of flow entering the daughter branch. Aggregation also significantly increased the roughness of the interface between the CDL and the RBC core. The present results provide further insight into how RBC aggregation may affect the flow in complex geometries, which is of importance in both understanding its functions invivo, and utilizing it as a tool in microfluidic devices. PMID- 23667412 TI - INCORPORATING BIOLOGICAL INFORMATION INTO LINEAR MODELS: A BAYESIAN APPROACH TO THE SELECTION OF PATHWAYS AND GENES. AB - The vast amount of biological knowledge accumulated over the years has allowed researchers to identify various biochemical interactions and define different families of pathways. There is an increased interest in identifying pathways and pathway elements involved in particular biological processes. Drug discovery efforts, for example, are focused on identifying biomarkers as well as pathways related to a disease. We propose a Bayesian model that addresses this question by incorporating information on pathways and gene networks in the analysis of DNA microarray data. Such information is used to define pathway summaries, specify prior distributions, and structure the MCMC moves to fit the model. We illustrate the method with an application to gene expression data with censored survival outcomes. In addition to identifying markers that would have been missed otherwise and improving prediction accuracy, the integration of existing biological knowledge into the analysis provides a better understanding of underlying molecular processes. PMID- 23667413 TI - Truffle brules have an impact on the diversity of soil bacterial communities. AB - BACKGROUND: The development of Tuber melanosporum mycorrhizal symbiosis is associated with the production of an area devoid of vegetation (commonly referred to by the French word 'brule') around the symbiotic plants and where the fruiting bodies of T. melanosporum are usually collected. The extent of the ecological impact of such an area is still being discovered. While the relationship between T. melanosporum and the other fungi present in the brule has been assessed, no data are available on the relationship between this fungus and the bacteria inhabiting the brule. METHODOLOGY/PRINCIPAL FINDINGS: We used DGGE and DNA microarrays of 16S rRNA gene fragments to compare the bacterial and archaeal communities inside and outside of truffle brules. Soil samples were collected in 2008 from four productive T. melanosporum/Quercus pubescens truffle-grounds located in Cahors, France, showing characteristic truffle brule. All the samples were analyzed by DGGE and one truffle-ground was analyzed also using phylogenetic microarrays. DGGE profiles showed differences in the bacterial community composition, and the microarrays revealed a few differences in relative richness between the brule interior and exterior zones, as well as differences in the relative abundance of several taxa. CONCLUSIONS/SIGNIFICANCE: The different signal intensities we have measured for members of bacteria and archaea inside versus outside the brule are the first demonstration, to our knowledge, that not only fungal communities, but also other microorganisms are affected by T. melanosporum. Firmicutes (e.g., Bacillus), several genera of Actinobacteria, and a few Cyanobacteria had greater representation inside the brule compared with outside, whereas Pseudomonas and several genera within the class Flavobacteriaceae had higher relative abundances outside the brule. The findings from this study may contribute to future searches for microbial bio-indicators of brules. PMID- 23667417 TI - Remote dynamic three-dimensional scene reconstruction. AB - Remote dynamic three-dimensional (3D) scene reconstruction renders the motion structure of a 3D scene remotely by means of both the color video and the corresponding depth maps. It has shown a great potential for telepresence applications like remote monitoring and remote medical imaging. Under this circumstance, video-rate and high resolution are two crucial characteristics for building a good depth map, which however mutually contradict during the depth sensor capturing. Therefore, recent works prefer to only transmit the high resolution color video to the terminal side, and subsequently the scene depth is reconstructed by estimating the motion vectors from the video, typically using the propagation based methods towards a video-rate depth reconstruction. However, in most of the remote transmission systems, only the compressed color video stream is available. As a result, color video restored from the streams has quality losses, and thus the extracted motion vectors are inaccurate for depth reconstruction. In this paper, we propose a precise and robust scheme for dynamic 3D scene reconstruction by using the compressed color video stream and their inaccurate motion vectors. Our method rectifies the inaccurate motion vectors by analyzing and compensating their quality losses, motion vector absence in spatial prediction, and dislocation in near-boundary region. This rectification ensures the depth maps can be compensated in both video-rate and high resolution at the terminal side towards reducing the system consumption on both the compression and transmission. Our experiments validate that the proposed scheme is robust for depth map and dynamic scene reconstruction on long propagation distance, even with high compression ratio, outperforming the benchmark approaches with at least 3.3950 dB quality gains for remote applications. PMID- 23667418 TI - Modelling food and population dynamics in honey bee colonies. AB - Honey bees (Apis mellifera) are increasingly in demand as pollinators for various key agricultural food crops, but globally honey bee populations are in decline, and honey bee colony failure rates have increased. This scenario highlights a need to understand the conditions in which colonies flourish and in which colonies fail. To aid this investigation we present a compartment model of bee population dynamics to explore how food availability and bee death rates interact to determine colony growth and development. Our model uses simple differential equations to represent the transitions of eggs laid by the queen to brood, then hive bees and finally forager bees, and the process of social inhibition that regulates the rate at which hive bees begin to forage. We assume that food availability can influence both the number of brood successfully reared to adulthood and the rate at which bees transition from hive duties to foraging. The model predicts complex interactions between food availability and forager death rates in shaping colony fate. Low death rates and high food availability results in stable bee populations at equilibrium (with population size strongly determined by forager death rate) but consistently increasing food reserves. At higher death rates food stores in a colony settle at a finite equilibrium reflecting the balance of food collection and food use. When forager death rates exceed a critical threshold the colony fails but residual food remains. Our model presents a simple mathematical framework for exploring the interactions of food and forager mortality on colony fate, and provides the mathematical basis for more involved simulation models of hive performance. PMID- 23667419 TI - In vivo intracellular oxygen dynamics in murine brain glioma and immunotherapeutic response of cytotoxic T cells observed by fluorine-19 magnetic resonance imaging. AB - Noninvasive biomarkers of anti-tumoral efficacy are of great importance to the development of therapeutic agents. Tumor oxygenation has been shown to be an important indicator of therapeutic response. We report the use of intracellular labeling of tumor cells with perfluorocarbon (PFC) molecules, combined with quantitative 19F spin-lattice relaxation rate (R1) measurements, to assay tumor cell oxygen dynamics in situ. In a murine central nervous system (CNS) GL261 glioma model, we visualized the impact of Pmel-1 cytotoxic T cell immunotherapy, delivered intravenously, on intracellular tumor oxygen levels. GL261 glioma cells were labeled ex vivo with PFC and inoculated into the mouse striatum. The R1 of 19F labeled cells was measured using localized single-voxel magnetic resonance spectroscopy, and the absolute intracellular partial pressure of oxygen (pO2) was ascertained. Three days after tumor implantation, mice were treated with 2*107 cytotoxic T cells intravenously. At day five, a transient spike in pO2 was observed indicating an influx of T cells into the CNS and putative tumor cell apoptosis. Immunohistochemistry and quantitative flow cytometry analysis confirmed that the pO2 was causally related to the T cells infiltration. Surprisingly, the pO2 spike was detected even though few (~4*104) T cells actually ingress into the CNS and with minimal tumor shrinkage. These results indicate the high sensitivity of this approach and its utility as a non-invasive surrogate biomarker of anti-cancer immunotherapeutic response in preclinical models. PMID- 23667420 TI - Honokiol dimers and magnolol derivatives with new carbon skeletons from the roots of Magnolia officinalis and their inhibitory effects on superoxide anion generation and elastase release. AB - Two honokiol dimers, houpulins A and B (1 and 2), and two magnolol derivatives, houpulins C and D (3 and 4), were isolated and characterized from an ethanol extract obtained from the roots of Magnolia officinalis. The chemical structures were determined based on spectroscopic and physicochemical analyses, which included 1D and 2D NMR, as well as mass spectrometry data. These four oligomers possess new carbon skeletons postulated to be biosynthesized from the coupling of three or four C6-C3 subunits. In addition, the new oligomers were evaluated for inhibition of superoxide anion generation and elastase release, and houpulin B (2) was identified as a new anti-inflammatory lead compound. PMID- 23667421 TI - The role of diatom nanostructures in biasing diffusion to improve uptake in a patchy nutrient environment. AB - BACKGROUND: Diatoms are important single-celled autotrophs that dominate most lit aquatic environments and are distinguished by surficial frustules with intricate designs of unknown function. PRINCIPAL FINDINGS: We show that some frustule designs constrain diffusion to positively alter nutrient uptake. In nutrient gradients of 4 to 160 times over <5 cm, the screened-chambered morphology of Coscincodiscus sp. biases the nutrient diffusion towards the cell by at least 3.8 times the diffusion to the seawater. In contrast, the open-chambers of Thalassiosira eccentrica produce at least a 1.3 times diffusion advantage to the membrane over Coscincodiscus sp. when nutrients are homogeneous. SIGNIFICANCE: Diffusion constraint explains the success of particular diatom species at given times and the overall success of diatoms. The results help answer the unresolved question of how adjacent microplankton compete. Furthermore, diffusion constraint by supramembrane nanostructures to alter molecular diffusion suggests that microbes compete via supramembrane topology, a competitive mechanism not considered by the standard smooth-surface equations used for nutrient uptake nor in microbial ecology and cell physiology. PMID- 23667422 TI - Porcine neonatal blood dendritic cells, but not monocytes, are more responsive to TLRs stimulation than their adult counterparts. AB - The neonatal immune system is often considered as immature or impaired compared to the adult immune system. This higher susceptibility to infections is partly due to the skewing of the neonatal immune response towards a Th2 response. Activation and maturation of dendritic cells (DCs) play an important role in shaping the immune response, therefore, DCs are a target of choice for the development of efficient and protective vaccine formulations able to redirect the neonatal immune response to a protective Th1 response. As pigs are becoming more important for vaccine development studies due to their similarity to the human immune system, we decided to compare the activation and maturation of a subpopulation of porcine DCs in adult and neonatal pigs following stimulation with different TLR ligands, which are promising candidates for adjuvants in vaccine formulations. Porcine blood derived DCs (BDCs) were directly isolated from blood and consisted of a mix of conventional and plasmacytoid DCs. Following CpG ODN (TLR9 ligand) and imiquimod (TLR7 ligand) stimulation, neonatal BDCs showed higher levels of expression of costimulatory molecules and similar (CpG ODN) or higher (imiquimod) levels of IL-12 compared to adult BDCs. Another interesting feature was that only neonatal BDCs produced IFN-alpha after TLR7 or TLR9 ligand stimulation. Stimulation with CpG ODN and imiquimod also induced enhanced expression of several chemokines. Moreover, in a mixed leukocyte reaction assay, neonatal BDCs displayed a greater ability to induce lymphoproliferation. These findings suggest that when stimulated via TLR7 or TLR9 porcine DCs display similar if not better response than adult porcine DCs. PMID- 23667424 TI - Structures of coxsackievirus, rhinovirus, and poliovirus polymerase elongation complexes solved by engineering RNA mediated crystal contacts. AB - RNA-dependent RNA polymerases play a vital role in the growth of RNA viruses where they are responsible for genome replication, but do so with rather low fidelity that allows for the rapid adaptation to different host cell environments. These polymerases are also a target for antiviral drug development. However, both drug discovery efforts and our understanding of fidelity determinants have been hampered by a lack of detailed structural information about functional polymerase-RNA complexes and the structural changes that take place during the elongation cycle. Many of the molecular details associated with nucleotide selection and catalysis were revealed in our recent structure of the poliovirus polymerase-RNA complex solved by first purifying and then crystallizing stalled elongation complexes. In the work presented here we extend that basic methodology to determine nine new structures of poliovirus, coxsackievirus, and rhinovirus elongation complexes at 2.2-2.9 A resolution. The structures highlight conserved features of picornaviral polymerases and the interactions they make with the template and product RNA strands, including a tight grip on eight basepairs of the nascent duplex, a fully pre-positioned templating nucleotide, and a conserved binding pocket for the +2 position template strand base. At the active site we see a pre-bound magnesium ion and there is conservation of a non-standard backbone conformation of the template strand in an interaction that may aid in triggering RNA translocation via contact with the conserved polymerase motif B. Moreover, by engineering plasticity into RNA-RNA contacts, we obtain crystal forms that are capable of multiple rounds of in-crystal catalysis and RNA translocation. Together, the data demonstrate that engineering flexible RNA contacts to promote crystal lattice formation is a versatile platform that can be used to solve the structures of viral RdRP elongation complexes and their catalytic cycle intermediates. PMID- 23667423 TI - Modeling stem cell induction processes. AB - Technology for converting human cells to pluripotent stem cell using induction processes has the potential to revolutionize regenerative medicine. However, the production of these so called iPS cells is still quite inefficient and may be dominated by stochastic effects. In this work we build mass-action models of the core regulatory elements controlling stem cell induction and maintenance. The models include not only the network of transcription factors NANOG, OCT4, SOX2, but also important epigenetic regulatory features of DNA methylation and histone modification. We show that the network topology reported in the literature is consistent with the observed experimental behavior of bistability and inducibility. Based on simulations of stem cell generation protocols, and in particular focusing on changes in epigenetic cellular states, we show that cooperative and independent reaction mechanisms have experimentally identifiable differences in the dynamics of reprogramming, and we analyze such differences and their biological basis. It had been argued that stochastic and elite models of stem cell generation represent distinct fundamental mechanisms. Work presented here suggests an alternative possibility that they represent differences in the amount of information we have about the distribution of cellular states before and during reprogramming protocols. We show further that unpredictability and variation in reprogramming decreases as the cell progresses along the induction process, and that identifiable groups of cells with elite-seeming behavior can come about by a stochastic process. Finally we show how different mechanisms and kinetic properties impact the prospects of improving the efficiency of iPS cell generation protocols. PMID- 23667425 TI - Construction and applications of rabbit hemorrhagic disease virus replicon. AB - The study of rabbit hemorrhagic disease virus (RHDV) has long been hindered by the absence of an in vitro culture system. In this study, using RHDV as a model, a series of DNA-based reporter replicons were constructed in which the firefly luciferase (Fluc) gene was fused in-frame with the open reading frame of the replicon. In this construct, the Fluc gene was inserted where the coding region of viral structural protein was deleted and was under the control of a minimal cytomegalovirus (CMV) immediate-early promoter. Fluc activity analysis showed that these reporter replicons replicate efficiently in mammalian cells. On the basis of the replicon, 5'non-coding regions (5'NCR) and genome-linked protein (VPg) were deleted, and the effect on the expression of replicon was analyzed. The results showed that the expression level of Fluc was reduced in the absence of 5'NCR and VPg, suggesting that the 5'NCR and VPg may play an important role in replication and/or translation of RHDV. To further verify the speculation, we also constructed a replication deficient mutant (pRHDV-luc/Delta3D), and the impact of 5'NCR and VPg deletion on viral translation efficiency was analyzed, our results indicated that both VPg and 5'NCR were involved in RHDV translation. PMID- 23667427 TI - Measuring coverage in MNCH: testing the validity of women's self-report of key maternal and newborn health interventions during the peripartum period in Mozambique. AB - BACKGROUND: As low-income countries strive to meet targets for Millennium Development Goals 4 and 5, there is growing need to track coverage and quality of high-impact peripartum interventions. At present, nationally representative household surveys conducted in low-income settings primarily measure contact with the health system, shedding little light on content or quality of care. The objective of this study is to validate the ability of women in Mozambique to report on facility-based care they and their newborns received during labor and one hour postpartum. METHODS AND FINDINGS: The study involved household interviews with women in Mozambique whose births were observed eight to ten months previously as part of a survey of the quality of maternal and newborn care at government health facilities. Of 487 women whose births were observed and who agreed to a follow-up interview, 304 were interviewed (62.4%). The validity of 34 indicators was tested using two measures: area under receiver operator characteristic curve (AUC) and inflation factor (IF); 27 indicators had sufficient numbers for robust analysis, of which four met acceptability criteria for both (AUC >0.6 and 0.75lambda2/4. AB - The present work is concerned with exact solutions of Stokes second problem for magnetohydrodynamics (MHD) flow of a Burgers' fluid. The fluid over a flat plate is assumed to be electrically conducting in the presence of a uniform magnetic field applied in outward transverse direction to the flow. The equations governing the flow are modeled and then solved using the Laplace transform technique. The expressions of velocity field and tangential stress are developed when the relaxation time satisfies the condition gamma = lambda2/4 or gamma> lambda2/4. The obtained closed form solutions are presented in the form of simple or multiple integrals in terms of Bessel functions and terms with only Bessel functions. The numerical integration is performed and the graphical results are displayed for the involved flow parameters. It is found that the velocity decreases whereas the shear stress increases when the Hartmann number is increased. The solutions corresponding to the Stokes' first problem for hydrodynamic Burgers' fluids are obtained as limiting cases of the present solutions. Similar solutions for Stokes' second problem of hydrodynamic Burgers' fluids and those for Newtonian and Oldroyd-B fluids can also be obtained as limiting cases of these solutions. PMID- 23667443 TI - Identification of commensal Escherichia coli genes involved in biofilm resistance to pathogen colonization. AB - Protection provided by host bacterial microbiota against microbial pathogens is a well known but ill-understood property referred to as the barrier effect, or colonization resistance. Despite recent genome-wide analyses of host microbiota and increasing therapeutic interest, molecular analysis of colonization resistance is hampered by the complexity of direct in vivo experiments. Here we developed an in vitro-to-in vivo approach to identification of genes involved in resistance of commensal bacteria to exogenous pathogens. We analyzed genetic responses induced in commensal Escherichia coli upon entry of a diarrheagenic enteroaggregative E. coli or an unrelated Klebsiella pneumoniae pathogen into a biofilm community. We showed that pathogens trigger specific responses in commensal bacteria and we identified genes involved in limiting colonization of incoming pathogens within commensal biofilm. We tested the in vivo relevance of our findings by comparing the extent of intestinal colonization by enteroaggregative E. coli and K. pneumoniae pathogens in mice pre-colonized with E. coli wild type commensal strain, or mutants corresponding to identified colonization resistance genes. We demonstrated that the absence of yiaF and bssS (yceP) differentially alters pathogen colonization in the mouse gut. This study therefore identifies previously uncharacterized colonization resistance genes and provides new approaches to unravelling molecular aspects of commensal/pathogen competitive interactions. PMID- 23667444 TI - Genetic variation in FADS genes and plasma cholesterol levels in 2-year-old infants: KOALA Birth Cohort Study. AB - OBJECTIVE: Single nucleotide polymorphisms (SNPs) in genes involved in fatty acid metabolism (FADS1 FADS2 gene cluster) are associated with plasma lipid levels. We aimed to investigate whether these associations are already present early in life and compare the relative contribution of FADS SNPs vs traditional (non-genetic) factors as determinants of plasma lipid levels. METHODS: Information on infants' plasma total cholesterol levels, genotypes of five FADS SNPs (rs174545, rs174546, rs174556, rs174561, and rs3834458), anthropometric data, maternal characteristics, and breastfeeding history was available for 521 2-year-old children from the KOALA Birth Cohort Study. For 295 of these 521 children, plasma HDLc and non-HDLc levels were also known. Multivariable linear regression analysis was used to study the associations of genetic and non-genetic determinants with cholesterol levels. RESULTS: All FADS SNPs were significantly associated with total cholesterol levels. Heterozygous and homozygous for the minor allele children had about 4% and 8% lower total cholesterol levels than major allele homozygotes. In addition, homozygous for the minor allele children had about 7% lower HDLc levels. This difference reached significance for the SNPs rs174546 and rs3834458. The associations went in the same direction for non-HDLc, but statistical significance was not reached. The percentage of total variance of total cholesterol levels explained by FADS SNPs was relatively low (lower than 3%) but of the same order as that explained by gender and the non-genetic determinants together. CONCLUSIONS: FADS SNPs are associated with plasma total cholesterol and HDLc levels in preschool children. This brings a new piece of evidence to explain how blood lipid levels may track from childhood to adulthood. Moreover, the finding that these SNPs explain a similar amount of variance in total cholesterol levels as the non-genetic determinants studied reveals the potential importance of investigating the effects of genetic variations in early life. PMID- 23667445 TI - 4-Deoxyaurone formation in Bidens ferulifolia (Jacq.) DC. AB - The formation of 4-deoxyaurones, which serve as UV nectar guides in Bidens ferulifolia (Jacq.) DC., was established by combination of UV photography, mass spectrometry, and biochemical assays and the key step in aurone formation was studied. The yellow flowering ornamental plant accumulates deoxy type anthochlor pigments (6'-deoxychalcones and the corresponding 4-deoxyaurones) in the basal part of the flower surface whilst the apex contains only yellow carotenoids. For UV sensitive pollinating insects, this appears as a bicoloured floral pattern which can be visualized in situ by specific ammonia staining of the anthochlor pigments. The petal back side, in contrast, shows a faintly UV absorbing centre and UV absorbing rays along the otherwise UV reflecting petal apex. Matrix-free UV laser desorption/ionisation mass spectrometric imaging (LDI-MSI) indicated the presence of 9 anthochlors in the UV absorbing areas. The prevalent pigments were derivatives of okanin and maritimetin. Enzyme preparations from flowers, leaves, stems and roots of B. ferulifolia and from plants, which do not accumulate aurones e.g. Arabidopsis thaliana, were able to convert chalcones to aurones. Thus, aurone formation could be catalyzed by a widespread enzyme and seems to depend mainly on a specific biochemical background, which favours the formation of aurones at the expense of flavonoids. In contrast to 4-hydroxyaurone formation, hydroxylation and oxidative cyclization to the 4-deoxyaurones does not occur in one single step but is catalyzed by two separate enzymes, chalcone 3 hydroxylase and aurone synthase (catechol oxidase reaction). Aurone formation shows an optimum at pH 7.5 or above, which is another striking contrast to 4 hydroxyaurone formation in Antirrhinum majus L. This is the first example of a plant catechol oxidase type enzyme being involved in the flavonoid pathway and in an anabolic reaction in general. PMID- 23667446 TI - Expression of VEGF and semaphorin genes define subgroups of triple negative breast cancer. AB - Triple negative breast cancers (TNBC) are difficult to treat due to a lack of targets and heterogeneity. Inhibition of angiogenesis is a promising therapeutic strategy, but has had limited effectiveness so far in breast cancer. To quantify heterogeneity in angiogenesis-related gene expression in breast cancer, we focused on two families--VEGFs and semaphorins--that compete for neuropilin co receptors on endothelial cells. We compiled microarray data for over 2,600 patient tumor samples and analyzed the expression of VEGF- and semaphorin-related ligands and receptors. We used principal component analysis to identify patterns of gene expression, and clustering to group samples according to these patterns. We used available survival data to determine whether these clusters had prognostic as well as therapeutic relevance. TNBC was highly associated with dysregulation of VEGF- and semaphorin-related genes; in particular, it appeared that expression of both VEGF and semaphorin genes were altered in a pro angiogenesis direction. A pattern of high VEGFA expression with low expression of secreted semaphorins was associated with 60% of triple-negative breast tumors. While all TNBC groups demonstrated poor prognosis, this signature also correlated with lower 5-year survival rates in non-TNBC samples. A second TNBC pattern, including high VEGFC expression, was also identified. These pro-angiogenesis signatures may identify cancers that are more susceptible to VEGF inhibition. PMID- 23667447 TI - Trends in citations to books on epidemiological and statistical methods in the biomedical literature. AB - BACKGROUND: There are no analyses of citations to books on epidemiological and statistical methods in the biomedical literature. Such analyses may shed light on how concepts and methods changed while biomedical research evolved. Our aim was to analyze the number and time trends of citations received from biomedical articles by books on epidemiological and statistical methods, and related disciplines. METHODS AND FINDINGS: The data source was the Web of Science. The study books were published between 1957 and 2010. The first year of publication of the citing articles was 1945. We identified 125 books that received at least 25 citations. Books first published in 1980-1989 had the highest total and median number of citations per year. Nine of the 10 most cited texts focused on statistical methods. Hosmer & Lemeshow's Applied logistic regression received the highest number of citations and highest average annual rate. It was followed by books by Fleiss, Armitage, et al., Rothman, et al., and Kalbfleisch and Prentice. Fifth in citations per year was Sackett, et al., Evidence-based medicine. The rise of multivariate methods, clinical epidemiology, or nutritional epidemiology was reflected in the citation trends. Educational textbooks, practice-oriented books, books on epidemiological substantive knowledge, and on theory and health policies were much less cited. None of the 25 top-cited books had the theoretical or sociopolitical scope of works by Cochrane, McKeown, Rose, or Morris. CONCLUSIONS: Books were mainly cited to reference methods. Books first published in the 1980s continue to be most influential. Older books on theory and policies were rooted in societal and general medical concerns, while the most modern books are almost purely on methods. PMID- 23667448 TI - Managing hytrosavirus infections in Glossina pallidipes colonies: feeding regime affects the prevalence of salivary gland hypertrophy syndrome. AB - Many species of tsetse flies are infected by a virus that causes salivary gland hypertrophy (SGH) syndrome and the virus isolated from Glossina pallidipes (GpSGHV) has recently been sequenced. Flies with SGH have a reduced fecundity and fertility. Due to the deleterious impact of SGHV on G. pallidipes colonies, several approaches were investigated to develop a virus management strategy. Horizontal virus transmission is the major cause of the high prevalence of the GpSGHV in tsetse colonies. Implementation of a "clean feeding" regime (fresh blood offered to each set of flies so that there is only one feed per membrane), instead of the regular feeding regime (several successive feeds per membrane), was among the proposed approaches to reduce GpSGHV infections. However, due to the absence of disposable feeding equipment (feeding trays and silicone membranes), the implementation of a clean feeding approach remains economically difficult. We developed a new clean feeding approach applicable to large-scale tsetse production facilities using existing resources. The results indicate that implementing this approach is feasible and leads to a significant reduction in virus load from 10(9) virus copies in regular colonies to an average of 10(2.5) and eliminates the SGH syndrome from clean feeding colonies by28 months post implementation of this approach. The clean feeding approach also reduced the virus load from an average of 10(8) virus copy numbers to an average of 10(3) virus copies and SGH prevalence of 10% to 4% in flies fed after the clean fed colony. Taken together, these data indicate that the clean feeding approach is applicable in large-scale G. pallidipes production facilities and eliminates the deleterious effects of the virus and the SGH syndrome in these colonies. PMID- 23667449 TI - Lead tolerance and accumulation in Hirschfeldia incana, a Mediterranean Brassicaceae from metalliferous mine spoils. AB - Lead is a heavy metal of particular concern with respect to environmental quality and health. The lack of plant species that accumulate and tolerate Pb is a limiting factor to understand the molecular mechanisms involved in Pb tolerance. In this study we identified Hirschfeldia incana, a Brassicaceae collected from metalliferous mine spoils in Morocco, as a Pb accumulator plant. H. incana exhibited high Pb accumulation in mine soils and in hydroponic cultures. Major Pb accumulation occurred in the roots and a part of Pb translocated from the roots to the shoots, even to the siliques. These findings demonstrated that H. incana is a Pb accumulator species. The expression of several candidate genes after Pb exposure was measured by quantitative PCR and two of them, HiHMA4 and HiMT2a, coding respectively for a P1B-type ATPase and a metallothionein, were particularly induced by Pb-exposure in both roots and leaves. The functional characterization of HiHMA4 and HiMT2a was achieved using Arabidopsis T-DNA insertional mutants. Pb content and primary root growth analysis confirmed the role of these two genes in Pb tolerance and accumulation. H. incana could be considered as a good experimental model to identify genes involved in lead tolerance and accumulation in plants. PMID- 23667450 TI - LipidHome: a database of theoretical lipids optimized for high throughput mass spectrometry lipidomics. AB - Protein sequence databases are the pillar upon which modern proteomics is supported, representing a stable reference space of predicted and validated proteins. One example of such resources is UniProt, enriched with both expertly curated and automatic annotations. Taken largely for granted, similar mature resources such as UniProt are not available yet in some other "omics" fields, lipidomics being one of them. While having a seasoned community of wet lab scientists, lipidomics lies significantly behind proteomics in the adoption of data standards and other core bioinformatics concepts. This work aims to reduce the gap by developing an equivalent resource to UniProt called 'LipidHome', providing theoretically generated lipid molecules and useful metadata. Using the 'FASTLipid' Java library, a database was populated with theoretical lipids, generated from a set of community agreed upon chemical bounds. In parallel, a web application was developed to present the information and provide computational access via a web service. Designed specifically to accommodate high throughput mass spectrometry based approaches, lipids are organised into a hierarchy that reflects the variety in the structural resolution of lipid identifications. Additionally, cross-references to other lipid related resources and papers that cite specific lipids were used to annotate lipid records. The web application encompasses a browser for viewing lipid records and a 'tools' section where an MS1 search engine is currently implemented. LipidHome can be accessed at http://www.ebi.ac.uk/apweiler-srv/lipidhome. PMID- 23667451 TI - MRI enhancement in stromal tissue surrounding breast tumors: association with recurrence free survival following neoadjuvant chemotherapy. AB - RATIONALE AND OBJECTIVES: Normal-appearing stromal tissues surrounding breast tumors can harbor abnormalities that lead to increased risk of local recurrence. The objective of this study was to develop a new imaging methodology to characterize the signal patterns of stromal tissue and to investigate their association with recurrence-free survival following neoadjuvant chemotherapy. MATERIALS AND METHODS: Fifty patients with locally-advanced breast cancer were imaged with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) before (V1) and after one cycle (V2) of adriamycin-cytoxan therapy. Contrast enhancement in normal-appearing stroma around the tumor was characterized by the mean percent enhancement (PE) and mean signal enhancement ratio (SER) in distance bands of 5 mm from the tumor edge. Global PE and SER were calculated by averaging all stromal bands 5 to 40 mm from tumor. Proximity-dependent PE and SER were analyzed using a linear mixed effects model and Cox proportional hazards model for recurrence-free survival. RESULTS: The mixed effects model displayed a decreasing radial trend in PE at both V1 and V2. An increasing trend was less pronounced in SER. Survival analysis showed that the hazard ratio estimates for each unit decrease in global SER was statistically significant at V1 [estimated hazard ratio = 0.058, 95% Wald CI (0.003, 1.01), likelihood ratio p = 0.03]; but was not so for V2. CONCLUSIONS: These findings show that stromal tissue outside the tumor can be quantitatively characterized by DCE-MRI, and suggest that stromal enhancement measurements may be further developed for use as a potential predictor of recurrence/disease-free survival following therapy. PMID- 23667452 TI - An international comparison of the effect of policy shifts to organ donation following cardiocirculatory death (DCD) on donation rates after brain death (DBD) and transplantation rates. AB - During the past decade an increasing number of countries have adopted policies that emphasize donation after cardiocirculatory death (DCD) in an attempt to address the widening gap between the demand for transplantable organs and the availability of organs from donation after brain death (DBD) donors. In order to examine how these policy shifts have affected overall deceased organ donor (DD) and DBD rates, we analyzed deceased donation rates from 82 countries from 2000 2010. On average, overall DD, DBD and DCD rates have increased over time, with the proportion of DCD increasing 0.3% per year (p = 0.01). Countries with higher DCD rates have, on average, lower DBD rates. For every one-per million population (pmp) increase in the DCD rate, the average DBD rate decreased by 1.02 pmp (95% CI: 0.73, 1.32; p<0.0001). We also found that the number of organs transplanted per donor was significantly lower in DCD when compared to DBD donors with 1.51 less transplants per DCD compared to DBD (95% CI: 1.23, 1.79; p<0.001). Whilst the results do not infer a causal relationship between increased DCD and decreased DBD rates, the significant correlation between higher DCD and lower DBD rates coupled with the reduced number of organs transplanted per DCD donor suggests that a national policy focus on DCD may lead to an overall reduction in the number of transplants performed. PMID- 23667453 TI - A hierarchical network approach for modeling Rift Valley fever epidemics with applications in North America. AB - Rift Valley fever is a vector-borne zoonotic disease which causes high morbidity and mortality in livestock. In the event Rift Valley fever virus is introduced to the United States or other non-endemic areas, understanding the potential patterns of spread and the areas at risk based on disease vectors and hosts will be vital for developing mitigation strategies. Presented here is a general network-based mathematical model of Rift Valley fever. Given a lack of empirical data on disease vector species and their vector competence, this discrete time epidemic model uses stochastic parameters following several PERT distributions to model the dynamic interactions between hosts and likely North American mosquito vectors in dispersed geographic areas. Spatial effects and climate factors are also addressed in the model. The model is applied to a large directed asymmetric network of 3,621 nodes based on actual farms to examine a hypothetical introduction to some counties of Texas, an important ranching area in the United States of America. The nodes of the networks represent livestock farms, livestock markets, and feedlots, and the links represent cattle movements and mosquito diffusion between different nodes. Cattle and mosquito (Aedes and Culex) populations are treated with different contact networks to assess virus propagation. Rift Valley fever virus spread is assessed under various initial infection conditions (infected mosquito eggs, adults or cattle). A surprising trend is fewer initial infectious organisms result in a longer delay before a larger and more prolonged outbreak. The delay is likely caused by a lack of herd immunity while the infection expands geographically before becoming an epidemic involving many dispersed farms and animals almost simultaneously. Cattle movement between farms is a large driver of virus expansion, thus quarantines can be efficient mitigation strategy to prevent further geographic spread. PMID- 23667454 TI - Scientific foundations for an IUCN Red List of ecosystems. AB - An understanding of risks to biodiversity is needed for planning action to slow current rates of decline and secure ecosystem services for future human use. Although the IUCN Red List criteria provide an effective assessment protocol for species, a standard global assessment of risks to higher levels of biodiversity is currently limited. In 2008, IUCN initiated development of risk assessment criteria to support a global Red List of ecosystems. We present a new conceptual model for ecosystem risk assessment founded on a synthesis of relevant ecological theories. To support the model, we review key elements of ecosystem definition and introduce the concept of ecosystem collapse, an analogue of species extinction. The model identifies four distributional and functional symptoms of ecosystem risk as a basis for assessment criteria: A) rates of decline in ecosystem distribution; B) restricted distributions with continuing declines or threats; C) rates of environmental (abiotic) degradation; and D) rates of disruption to biotic processes. A fifth criterion, E) quantitative estimates of the risk of ecosystem collapse, enables integrated assessment of multiple processes and provides a conceptual anchor for the other criteria. We present the theoretical rationale for the construction and interpretation of each criterion. The assessment protocol and threat categories mirror those of the IUCN Red List of species. A trial of the protocol on terrestrial, subterranean, freshwater and marine ecosystems from around the world shows that its concepts are workable and its outcomes are robust, that required data are available, and that results are consistent with assessments carried out by local experts and authorities. The new protocol provides a consistent, practical and theoretically grounded framework for establishing a systematic Red List of the world's ecosystems. This will complement the Red List of species and strengthen global capacity to report on and monitor the status of biodiversity. PMID- 23667455 TI - Age and sex pattern of cardiovascular mortality, hospitalisation and associated cost in India. AB - CONTEXT: Though the cardiovascular diseases are the leading cause of mortality in India, little is known about the human and economic loss attributed to the disease. The aim of this paper is to account the age and sex pattern of mortality, hospitalisation and the cost of hospitalisation for cardiovascular diseases in India. DATA AND METHODS: Data for the present study has been drawn from multiple sources; 52(nd) and 60(th) rounds of the National Sample Survey, Special Survey of Death, 2001-03 and the Sample Registration System 2004-2010. Under the changing demographics and constant assumptions of mortality, hospitalisation and cost of hospitalisation, we have estimated the deaths, hospitalisation and cost of hospitalisation for cardiovascular diseases in India during 2004 to 2021. Descriptive analyses and multivariate techniques were used to understand the socio-economic differentials in cost of hospitalisation for cardiovascular diseases in India. FINDINGS: In India, the cardiovascular diseases accounted for an estimated 1.4 million deaths in 2004 and it is likely to be 2.1 million in 2021. An estimated 6.7 million people were hospitalised for cardiovascular diseases in 2004, and projected to be 10.9 million by 2021. Unlike mortality, majority of the hospitalisation due to cardiovascular diseases will be in the prime working age group (25-59). The estimated cost of hospitalisation for cardiovascular diseases was 94/- billion rupees in 2004 and expected to be 152/- billion rupees by 2021, at 2004 prices. The cost of hospitalisation for cardiovascular diseases was significantly high in private health centres, high fertility states and among high socio-economic groups. CONCLUSION: The cardiovascular mortality and hospitalisation will be largely concentrated in the prime working age group and the cost of hospitalisation is expected to increase substantially in coming years. This calls for mobilising resources, increasing access to health insurance and devising strategies for the prevention, control and treatment of cardiovascular diseases in India. PMID- 23667456 TI - Increased Tc22 and Treg/CD8 ratio contribute to aggressive growth of transplant associated squamous cell carcinoma. AB - Immune suppressed organ transplant recipients suffer increased morbidity and mortality from primary cutaneous SCC. We studied tumor microenvironment in transplant-associated SCC (TSCC), immune-competent SCC and normal skin by IHC, IF and RT-PCR on surgical discard. We determined T cell polarization in TSCC and SCC by intracellular cytokine staining of T cell crawl outs from human skin explants. We studied the effects of IL-22, an inducer of keratinocyte proliferation, on SCC proliferation in vitro. SCC and TSCC are both associated with significantly higher numbers of CD3(+) and CD8(+) T cells compared to normal skin. TSCC showed a higher proportion of Foxp3(+) T regs to CD8(+) T cells compared to SCC and a lower percentage of IFN-gamma producing CD4(+) T cells. TSCC, however, had a higher percentage of IL-22 producing CD8(+) T cells compared to SCC. TSCC showed more diffuse Ki67 and IL-22 receptor (IL-22R) expression by IHC. IL-22 induced SCC proliferation in vitro despite serum starvation. Diminished cytotoxic T cell function in TSCC due to decreased CD8/T-reg ratio may permit tumor progression. Increased IL-22 and IL-22R expression could accelerate tumor growth in transplant patients. IL-22 may be an attractive candidate for targeted therapy of SCC without endangering allograft survival. PMID- 23667457 TI - Analysis of the transcriptional differences between indigenous and invasive whiteflies reveals possible mechanisms of whitefly invasion. AB - BACKGROUND: The whitefly Bemisa tabaci is a species complex of more than 31 cryptic species which include some of the most destructive invasive pests of crops worldwide. Among them, Middle East-Asia Minor 1 (MEAM1) and Mediterranean have invaded many countries and displaced the native whitefly species. The successful invasion of the two species is largely due to their wide range of host plants, high resistance to insecticides and remarkable tolerance to environmental stresses. However, the molecular differences between invasive and indigenous whiteflies remain largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here the global transcriptional difference between the two invasive whitefly species (MEAM1, MED) and one indigenous whitefly species (Asia II 3) were analyzed using the Illumina sequencing. Our analysis indicated that 2,422 genes between MEAM1 and MED; 3,073 genes between MEAM1 and Asia II 3; and 3,644 genes between MED and Asia II 3 were differentially expressed. Gene Ontology enrichment analysis revealed that the differently expressed genes between the invasive and indigenous whiteflies were significantly enriched in the term of 'oxidoreductase activity'. Pathway enrichment analysis showed that carbohydrate, amino acid and glycerolipid metabolisms were more active in MEAM1 and MED than in Asia II 3, which may contribute to their differences in biological characteristics. Our analysis also illustrated that the majority of genes involved in 'drug metabolic pathway' were expressed at a higher level in MEAM1 and MED than in Asia II 3. Taken together, these results revealed that the genes related to basic metabolism and detoxification were expressed at an elevated level in the invasive whiteflies, which might be responsible for their higher resistance to insecticides and environmental stresses. CONCLUSIONS/SIGNIFICANCE: The extensive comparison of MEAM1, MED and Asia II 3 gene expression may serve as an invaluable resource for revealing the molecular mechanisms underlying their biological differences and the whitefly invasion. PMID- 23667458 TI - Improved method for linear B-cell epitope prediction using antigen's primary sequence. AB - One of the major challenges in designing a peptide-based vaccine is the identification of antigenic regions in an antigen that can stimulate B-cell's response, also called B-cell epitopes. In the past, several methods have been developed for the prediction of conformational and linear (or continuous) B-cell epitopes. However, the existing methods for predicting linear B-cell epitopes are far from perfection. In this study, an attempt has been made to develop an improved method for predicting linear B-cell epitopes. We have retrieved experimentally validated B-cell epitopes as well as non B-cell epitopes from Immune Epitope Database and derived two types of datasets called Lbtope_Variable and Lbtope_Fixed length datasets. The Lbtope_Variable dataset contains 14876 B cell epitope and 23321 non-epitopes of variable length where as Lbtope_Fixed length dataset contains 12063 B-cell epitopes and 20589 non-epitopes of fixed length. We also evaluated the performance of models on above datasets after removing highly identical peptides from the datasets. In addition, we have derived third dataset Lbtope_Confirm having 1042 epitopes and 1795 non-epitopes where each epitope or non-epitope has been experimentally validated in at least two studies. A number of models have been developed to discriminate epitopes and non-epitopes using different machine-learning techniques like Support Vector Machine, and K-Nearest Neighbor. We achieved accuracy from ~54% to 86% using diverse s features like binary profile, dipeptide composition, AAP (amino acid pair) profile. In this study, for the first time experimentally validated non B cell epitopes have been used for developing method for predicting linear B-cell epitopes. In previous studies, random peptides have been used as non B-cell epitopes. In order to provide service to scientific community, a web server LBtope has been developed for predicting and designing B-cell epitopes (http://crdd.osdd.net/raghava/lbtope/). PMID- 23667459 TI - The PARIGA server for real time filtering and analysis of reciprocal BLAST results. AB - BLAST-based similarity searches are commonly used in several applications involving both nucleotide and protein sequences. These applications span from simple tasks such as mapping sequences over a database to more complex procedures as clustering or annotation processes. When the amount of analysed data increases, manual inspection of BLAST results become a tedious procedure. Tools for parsing or filtering BLAST results for different purposes are then required. We describe here PARIGA (http://resources.bioinformatica.crs4.it/pariga/), a server that enables users to perform all-against-all BLAST searches on two sets of sequences selected by the user. Moreover, since it stores the two BLAST output in a python-serialized-objects database, results can be filtered according to several parameters in real-time fashion, without re-running the process and avoiding additional programming efforts. Results can be interrogated by the user using logical operations, for example to retrieve cases where two queries match same targets, or when sequences from the two datasets are reciprocal best hits, or when a query matches a target in multiple regions. The Pariga web server is designed to be a helpful tool for managing the results of sequence similarity searches. The design and implementation of the server renders all operations very fast and easy to use. PMID- 23667460 TI - Productive infection of bovine papillomavirus type 2 in the urothelial cells of naturally occurring urinary bladder tumors in cattle and water buffaloes. AB - BACKGROUND: Papillomaviruses (PVs) are highly epitheliotropic as they usually establish productive infections within squamous epithelia of the skin, the anogenital tract and the oral cavity. In this study, early (E) and late (L) protein expression of bovine papillomavirus type 2 (BPV-2) in the urothelium of the urinary bladder is described in cows and water buffaloes suffering from naturally occurring papillomavirus-associated urothelial bladder tumors. METHODS AND FINDINGS: E5 protein, the major oncoprotein of the BPV-2, was detected in all tumors. L1 DNA was amplified by PCR, cloned and sequenced and confirmed to be L1 DNA. The major capsid protein, L1, believed to be only expressed in productive papillomavirus infection was detected by Western blot analysis. Immunohistochemical investigations confirmed the presence of L1 protein both in the cytoplasm and nuclei of cells of the neoplastic urothelium. Finally, the early protein E2, required for viral DNA replication and known to be a pivotal factor for both productive and persistent infection, was detected by Western blot and immunohistochemically. Electron microscopic investigations detected electron dense particles, the shape and size of which are consistent with submicroscopic features of viral particles, in nuclei of neoplastic urothelium. CONCLUSION: This study shows that both active and productive infections by BPV-2 in the urothelium of the bovine and bubaline urinary bladder can occur in vivo. PMID- 23667461 TI - A phenylalanine to serine substitution within an O-protein mannosyltransferase led to strong resistance to PMT-inhibitors in Pichia pastoris. AB - Protein O-mannosyltransferases (PMTs) catalyze the initial reaction of protein O mannosylation by transferring the first mannose unit onto serine and threonine residues of a nascent polypeptide being synthesized in the endoplasmic reticulum (ER). The PMTs are well conserved in eukaryotic organisms, and in vivo defects of these enzymes result in cell death in yeast and congenital diseases in humans. A group of rhodanine-3-acetic acid derivatives (PMTi) specifically inhibits PMT activity both in vitro and in vivo. As such, these chemical compounds have been effectively used to minimize the extent of O-mannosylation on heterologously produced proteins from different yeast expression hosts. However, very little is known about how these PMT-inhibitors interact with the PMT enzyme, or what structural features of the PMTs are required for inhibitor-protein interactions. To better understand the inhibitor-enzyme interactions, and to gain potential insights for developing more effective PMT-inhibitors, we isolated PMTi-resistant mutants in Pichia pastoris. In this study, we report the identification and characterization of a point mutation within the PpPMT2 gene. We demonstrate that this F664S point mutation resulted in a near complete loss of PMTi sensitivity, both in terms of growth-inhibition and reduction in O-mannosylglycan site occupancy. Our results provide genetic evidence demonstrating that the F664 residue plays a critical role in mediating the inhibitory effects of these PMTi compounds. Our data also indicate that the main target of these PMT-inhibitors in P. pastoris is Pmt2p, and that the F664 residue most likely interacts directly with the PMTi-compounds. PMID- 23667462 TI - A highly productive, whole-cell DERA chemoenzymatic process for production of key lactonized side-chain intermediates in statin synthesis. AB - Employing DERA (2-deoxyribose-5-phosphate aldolase), we developed the first whole cell biotransformation process for production of chiral lactol intermediates useful for synthesis of optically pure super-statins such as rosuvastatin and pitavastatin. Herein, we report the development of a fed-batch, high-density fermentation with Escherichia coli BL21 (DE3) overexpressing the native E. coli deoC gene. High activity of this biomass allows direct utilization of the fermentation broth as a whole-cell DERA biocatalyst. We further show a highly productive bioconversion processes with this biocatalyst for conversion of 2 substituted acetaldehydes to the corresponding lactols. The process is evaluated in detail for conversion of acetyloxy-acetaldehyde with the first insight into the dynamics of reaction intermediates, side products and enzyme activity, allowing optimization of the feeding strategy of the aldehyde substrates for improved productivities, yields and purities. The resulting process for production of ((2S,4R)-4,6-dihydroxytetrahydro-2H-pyran-2-yl)methyl acetate (acetyloxymethylene-lactol) has a volumetric productivity exceeding 40 g L(-1) h( 1) (up to 50 g L(-1) h(-1)) with >80% yield and >80% chromatographic purity with titers reaching 100 g L(-1). Stereochemical selectivity of DERA allows excellent enantiomeric purities (ee >99.9%), which were demonstrated on downstream advanced intermediates. The presented process is highly cost effective and environmentally friendly. To our knowledge, this is the first asymmetric aldol condensation process achieved with whole-cell DERA catalysis and it simplifies and extends previously developed DERA-catalyzed approaches based on the isolated enzyme. Finally, applicability of the presented process is demonstrated by efficient preparation of a key lactol precursor, which fits directly into the lactone pathway to optically pure super-statins. PMID- 23667463 TI - Common and cluster-specific simultaneous component analysis. AB - In many fields of research, so-called 'multiblock' data are collected, i.e., data containing multivariate observations that are nested within higher-level research units (e.g., inhabitants of different countries). Each higher-level unit (e.g., country) then corresponds to a 'data block'. For such data, it may be interesting to investigate the extent to which the correlation structure of the variables differs between the data blocks. More specifically, when capturing the correlation structure by means of component analysis, one may want to explore which components are common across all data blocks and which components differ across the data blocks. This paper presents a common and cluster-specific simultaneous component method which clusters the data blocks according to their correlation structure and allows for common and cluster-specific components. Model estimation and model selection procedures are described and simulation results validate their performance. Also, the method is applied to data from cross-cultural values research to illustrate its empirical value. PMID- 23667464 TI - Prenatal intestinal obstruction affects the myenteric plexus and causes functional bowel impairment in fetal rat experimental model of intestinal atresia. AB - BACKGROUND: Intestinal atresia is a rare congenital disorder with an incidence of 3/10,000 birth. About one-third of patients have severe intestinal dysfunction after surgical repair. We examined whether prenatal gastrointestinal obstruction might effect on the myenteric plexus and account for subsequent functional disorders. METHODOLOGY/PRINCIPAL FINDINGS: We studied a rat model of surgically induced antenatal atresia, comparing intestinal samples from both sides of the obstruction and with healthy rat pups controls. Whole-mount preparations of the myenteric plexus were stained for choline acetyltransferase (ChAT) and nitric oxide synthase (nNOS). Quantitative reverse transcription PCR was used to analyze mRNAs for inflammatory markers. Functional motility and permeability analyses were performed in vitro. Phenotypic studies were also performed in 8 newborns with intestinal atresia. In the experimental model, the proportion of nNOS immunoreactive neurons was similar in proximal and distal segments (6.7+/-4.6% vs 5.6+/-4.2%, p = 0.25), but proximal segments contained a higher proportion of ChAT-immunoreactive neurons (13.2+/-6.2% vs 7.5+/-4.3%, p = 0.005). Phenotypic changes were associated with a 100-fold lower concentration-dependent contractile response to carbachol and a 1.6-fold higher EFS-induced contractile response in proximal compared to distal segments. Transcellular (p = 0.002) but not paracellular permeability was increased. Comparison with controls showed that modifications involved not only proximal but also distal segments. Phenotypic studies in human atresia confirmed the changes in ChAT expression. CONCLUSION: Experimental atresia in fetal rat induces differential myenteric plexus phenotypical as well as functional changes (motility and permeability) between the two sides of the obstruction. Delineating these changes might help to identify markers predictive of motility dysfunction and to define guidelines for post-surgical care. PMID- 23667465 TI - Expression patterns of GmAP2/EREB-like transcription factors involved in soybean responses to water deficit. AB - Soybean farming has faced several losses in productivity due to drought events in the last few decades. However, plants have molecular mechanisms to prevent and protect against water deficit injuries, and transcription factors play an important role in triggering different defense mechanisms. Understanding the expression patterns of transcription factors in response to water deficit and to environmental diurnal changes is very important for unveiling water deficit stress tolerance mechanisms. Here, we analyzed the expression patterns of ten APETALA2/Ethylene Responsive Element Binding-like (AP2/EREB-like) transcription factors in two soybean genotypes (BR16: drought-sensitive; and Embrapa 48: drought-tolerant). According to phylogenetic and domain analyses, these genes can be included in the DREB and ERF subfamilies. We also analyzed a GmDRIP-like gene that encodes a DREB negative regulator. We detected the up-regulation of 9 GmAP2/EREB-like genes and identified transcriptional differences that were dependent on the levels of the stress applied and the tissue type analyzed (the expression of the GmDREB1F-like gene, for example, was four times higher in roots than in leaves). The GmDRIP-like gene was not induced by water deficit in BR16 during the longest periods of stress, but was significantly induced in Embrapa 48; this suggests a possible genetic/molecular difference between the responses of these cultivars to water deficit stress. Additionally, RNAseq gene expression analysis over a 24-h time course indicates that the expression patterns of several GmDREB-like genes are subject to oscillation over the course of the day, indicating a possible circadian regulation. PMID- 23667466 TI - Akt1 enhances CA916798 expression through mTOR pathway. AB - Multi-drug resistance leads to the failure of chemotherapy for cancers. Our previous study showed that overexpression of CA916798 led to multi-drug resistance. However, the underlying mechanisms remain unknown. In the current study, we observed that the levels of phosphorylated AKT, phosphorylated mTOR and CA916798 all increased in the drug resistant human adenocarcinoma samples and paralleled with the change of drug resistance. The results of immunofluorescence and Co-IP indicated that the positive correlation of CA916798 expression with AKT1 activation might be associated with drug resistance of lung adenocarcinoma. Furthermore, AKT1 stimulated CA916798 expression through mTOR pathway in both A549 and A549/CDDP cell lines, which was also observed in the xenografted tumor in nude mice. The results showed that CA916798 located in the downstream of PI3K/AKT/mTOR pathway. Inhibition of PI3K by LY294002 could efficiently reduce CA916798 expression and tumor size in vivo as well. Additionally, LY294002 combined with rapamycin inhibited CA916798 expression and tumor size stronger than LY294002 alone. Our findings may also provide a new explanation for synergistic anti-tumor effects of PI3K and mTORC1 inhibitors. PMID- 23667467 TI - Effect of hormone replacement therapy on cardiovascular outcomes: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Hormone replacement therapy (HRT) is widely used to controlling menopausal symptoms and prevent adverse cardiovascular events. However, the benefit and risk of HRT on cardiovascular outcomes remains controversial. METHODOLOGY AND PRINCIPAL FINDINGS: We systematically searched the PubMed, EmBase, and Cochrane Central Register of Controlled Trials databases for obtaining relevant literature. All eligible trials reported on the effects of HRT on cardiovascular outcomes. We did a random effects meta-analysis to obtain summary effect estimates for the clinical outcomes with use of relative risks calculated from the raw data of included trials. Of 1903 identified studies, we included 10 trials reporting data on 38908 postmenopausal women. Overall, we noted that estrogen combined with medroxyprogesterone acetate therapy as compared to placebo had no effect on coronary events (RR, 1.07; 95%CI: 0.91-1.26; P = 0.41), myocardial infarction (RR, 1.09; 95%CI: 0.85-1.41; P = 0.48), stroke (RR, 1.21; 95%CI: 1.00-1.46; P = 0.06), cardiac death (RR, 1.19; 95%CI: 0.91-1.56; P = 0.21), total death (RR, 1.06; 95%CI: 0.81-1.39; P = 0.66), and revascularization (RR, 0.95; 95%CI: 0.83-1.08; P = 0.43). In addition, estrogen therapy alone had no effect on coronary events (RR, 0.93; 95%CI: 0.80-1.08; P = 0.33), myocardial infarction (RR, 0.95; 95%CI: 0.78-1.15; P = 0.57), cardiac death (RR, 0.86; 95%CI: 0.65-1.13; P = 0.27), total mortality (RR, 1.02; 95%CI: 0.89-1.18; P = 0.73), and revascularization (RR, 0.77; 95%CI: 0.45-1.31; P = 0.34), but associated with a 27% increased risk for incident stroke (RR, 1.27; 95%CI: 1.06 1.53; P = 0.01). CONCLUSION/SIGNIFICANCE: Hormone replacement therapy does not effect on the incidence of coronary events, myocardial infarction, cardiac death, total mortality or revascularization. However, it might contributed an important role on the risk of incident stroke. PMID- 23667468 TI - Fli-1 overexpression in hematopoietic progenitors deregulates T cell development and induces pre-T cell lymphoblastic leukaemia/lymphoma. AB - The Ets transcription factor Fli-1 is preferentially expressed in hematopoietic tissues and cells, including immature T cells, but the role of Fli-1 in T cell development has not been closely examined. To address this we retrovirally overexpressed Fli-1 in various in vitro and in vivo settings and analysed its effect on T cell development. We found that Fli-1 overexpression perturbed the DN to DP transition and inhibited CD4 development whilst enhancing CD8 development both in vitro and in vivo. Surprisingly, Fli-1 overexpression in vivo eventuated in development of pre-T cell lymphoblastic leukaemia/lymphoma (pre-T LBL). Known Fli-1 target genes such as the pro-survival Bcl-2 family members were not found to be upregulated. In contrast, we found increased NOTCH1 expression in all Fli-1 T cells and detected Notch1 mutations in all tumours. These data show a novel function for Fli-1 in T cell development and leukaemogenesis and provide a new mouse model of pre-T LBL to identify treatment options that target the Fli-1 and Notch1 signalling pathways. PMID- 23667469 TI - Early Chk1 phosphorylation is driven by temozolomide-induced, DNA double strand break- and mismatch repair-independent DNA damage. AB - Temozolomide (TMZ) is a DNA methylating agent used to treat brain cancer. TMZ induced O6-methylguanine adducts, in the absence of repair by O6-methylguanine DNA methyltransferase (MGMT), mispair during DNA replication and trigger cycles of futile mismatch repair (MMR). Futile MMR in turn leads to the formation of DNA single and double strand breaks, Chk1 and Chk2 phosphorylation/activation, cell cycle arrest, and ultimately cell death. Although both pChk1 and pChk2 are considered to be biomarkers of TMZ-induced DNA damage, cell-cycle arrest, and TMZ induced cytotoxicity, we found that levels of pChk1 (ser345), its downstream target pCdc25C (ser216), and the activity of its upstream activator ATR, were elevated within 3 hours of TMZ exposure, long before the onset of TMZ-induced DNA double strand breaks, Chk2 phosphorylation/activation, and cell cycle arrest. Furthermore, TMZ-induced early phosphorylation of Chk1 was noted in glioma cells regardless of whether they were MGMT-proficient or MGMT-deficient, and regardless of their MMR status. Early Chk1 phosphorylation was not associated with TMZ induced reactive oxygen species, but was temporally associated with TMZ-induced alkalai-labile DNA damage produced by the non-O6-methylguanine DNA adducts and which, like Chk1 phosphorylation, was transient in MGMT-proficient cells but persistent in MGMT-deficient cells. These results re-define the TMZ-induced DNA damage response, and show that Chk1 phosphorylation is driven by TMZ-induced mismatch repair-independent DNA damage independently of DNA double strand breaks, Chk2 activation, and cell cycle arrest, and as such is a suboptimal biomarker of TMZ-induced drug action. PMID- 23667470 TI - A next-generation sequencing method for genotyping-by-sequencing of highly heterozygous autotetraploid potato. AB - Assessment of genomic DNA sequence variation and genotype calling in autotetraploids implies the ability to distinguish among five possible alternative allele copy number states. This study demonstrates the accuracy of genotyping-by-sequencing (GBS) of a large collection of autotetraploid potato cultivars using next-generation sequencing. It is still costly to reach sufficient read depths on a genome wide scale, across the cultivated gene pool. Therefore, we enriched cultivar-specific DNA sequencing libraries using an in solution hybridisation method (SureSelect). This complexity reduction allowed to confine our study to 807 target genes distributed across the genomes of 83 tetraploid cultivars and one reference (DM 1-3 511). Indexed sequencing libraries were paired-end sequenced in 7 pools of 12 samples using Illumina HiSeq2000. After filtering and processing the raw sequence data, 12.4 Gigabases of high quality sequence data was obtained, which mapped to 2.1 Mb of the potato reference genome, with a median average read depth of 63* per cultivar. We detected 129,156 sequence variants and genotyped the allele copy number of each variant for every cultivar. In this cultivar panel a variant density of 1 SNP/24 bp in exons and 1 SNP/15 bp in introns was obtained. The average minor allele frequency (MAF) of a variant was 0.14. Potato germplasm displayed a large number of relatively rare variants and/or haplotypes, with 61% of the variants having a MAF below 0.05. A very high average nucleotide diversity (pi = 0.0107) was observed. Nucleotide diversity varied among potato chromosomes. Several genes under selection were identified. Genotyping-by-sequencing results, with allele copy number estimates, were validated with a KASP genotyping assay. This validation showed that read depths of ~60-80* can be used as a lower boundary for reliable assessment of allele copy number of sequence variants in autotetraploids. Genotypic data were associated with traits, and alleles strongly influencing maturity and flesh colour were identified. PMID- 23667471 TI - A behavioral paradigm to evaluate hippocampal performance in aged rodents for pharmacological and genetic target validation. AB - Aged-related cognitive ability is highly variable, ranging from unimpaired to severe impairments. The Morris water maze (a reliable tool for assessing memory) has been used to distinguish aged rodents that are superior learners from those that are learning impaired. This task, however, is not practical for pre- and post-pharmacological treatment, as the memory of the task is long lasting. In contrast, the object location memory task, also a spatial learning paradigm, results in a less robust memory that decays quickly. We demonstrate for the first time how these two paradigms can be used together to assess hippocampal cognitive impairments before and after pharmacological or genetic manipulations in rodents. Rats were first segregated into superior learning and learning impaired groups using the object location memory task, and their performance was correlated with future outcome on this task and on the Morris water maze. This method provides a tool to evaluate the effect of treatments on cognitive impairment associated with aging and neurodegenerative disorders. PMID- 23667472 TI - Historical zoonoses and other changes in host tropism of Staphylococcus aureus, identified by phylogenetic analysis of a population dataset. AB - BACKGROUND: Staphylococcus aureus exhibits tropisms to many distinct animal hosts. While spillover events can occur wherever there is an interface between host species, changes in host tropism only occur with the establishment of sustained transmission in the new host species, leading to clonal expansion. Although the genomic variation underpinning adaptation in S. aureus genotypes infecting bovids and poultry has been well characterized the frequency of switches from one host to another remains obscure. We sought to identify sustained switches in host tropism in the S. aureus population, both anthroponotic and zoonotic, and their distribution over the species phylogeny. METHODOLOGIES/RESULTS: We have used a sample of 3042 isolates, representing 696 distinct MLST genotypes, from a well-established database (www.mlst.net). Using an empirical parsimony approach (AdaptML) we have investigated the distribution of switches in host association between both human and non-human (henceforth referred to as animal) hosts. We reconstructed a credible description of past events in the form of a phylogenetic tree; the nodes and leaves of which are statistically associated with either human or animal habitats, estimated from extant host-association and the degree of sequence divergence between genotypes. We identified 15 likely historical switching events; 13 anthroponoses and two zoonoses. Importantly, we identified two human-associated clade candidates (CC25 and CC59) that have arisen from animal-associated ancestors; this demonstrates that a human-specific lineage can emerge from an animal host. We also highlight novel rabbit-associated genotypes arising from a human ancestor. CONCLUSIONS: S. aureus is an organism with the capacity to switch into and adapt to novel hosts, even after long periods of isolation in a single host species. Based on this evidence, animal-adapted S. aureus lineages exhibiting resistance to antibiotics must be considered a major threat to public health, as they can adapt to the human population. PMID- 23667473 TI - Association study confirmed susceptibility loci with keloid in the Chinese Han population. AB - Keloid is benign fibroproliferative dermal tumors with unknown etiology. Recently, a genome-wide association study (GWAS) in Japanese population has identified 3 susceptibility loci (rs873549 at 1q41, rs940187 and rs1511412 at 3q22.3, rs8032158 at 15p21.3) for keloid. In order to examine whether these susceptibility loci are associated with keloid in the Chinese Han population, twelve previously reported SNPs were selected for replication in 714 cases and 2,944 controls by using Sequenom MassArray system. We found three SNPs in two regions showed significant association with keloid in the Chinese Han population: 1q41 (rs873549, P = 3.03*10(-33), OR = 2.05, 95% CI: 1.82-2.31 and rs1442440, P = 9.85*10(-18), OR = 0.56, 95% CI: 0.49-0.64, respectively) and 15q21.3 (rs2271289 located in NEDD4, P = 1.02*10(-11), OR = 0.66, 95% CI: 0.58-0.74). We also detected one risk haplotype AG (P = 1.36*10(-31), OR = 2.02) and two protective haplotypes of GA and AA (GA, P = 1.94*10(-19), OR = 0.53, AA, P = 0.00043, OR = 0.78, respectively) from the two SNPs (rs873549 and rs1442440). Our study confirmed two previously reported loci 1q41 and 15q21.3 for keloid in the Chinese Han population, which suggested the common genetic factor predisposing to the development of keloid shared by the Chinese Han and Japanese populations. PMID- 23667474 TI - Can long-range PCR be used to amplify genetically divergent mitochondrial genomes for comparative phylogenetics? A case study within spiders (Arthropoda: Araneae). AB - The development of second generation sequencing technology has resulted in the rapid production of large volumes of sequence data for relatively little cost, thereby substantially increasing the quantity of data available for phylogenetic studies. Despite these technological advances, assembling longer sequences, such as that of entire mitochondrial genomes, has not been straightforward. Existing studies have been limited to using only incomplete or nominally intra-specific datasets resulting in a bottleneck between mitogenome amplification and downstream high-throughput sequencing. Here we assess the effectiveness of a wide range of targeted long-range PCR strategies, encapsulating single and dual fragment primer design approaches to provide full mitogenomic coverage within the Araneae (Spiders). Despite extensive rounds of optimisation, full mitochondrial genome PCR amplifications were stochastic in most taxa, although 454 Roche sequencing confirmed the successful amplification of 10 mitochondrial genomes out of the 33 trialled species. The low success rates of amplification using long Range PCR highlights the difficulties in consistently obtaining genomic amplifications using currently available DNA polymerases optimised for large genomic amplifications and suggests that there may be opportunities for the use of alternative amplification methods. PMID- 23667476 TI - Diversity of T cell epitopes in Plasmodium falciparum circumsporozoite protein likely due to protein-protein interactions. AB - Circumsporozoite protein (CS) is a leading vaccine antigen for falciparum malaria, but is highly polymorphic in natural parasite populations. The factors driving this diversity are unclear, but non-random assortment of the T cell epitopes TH2 and TH3 has been observed in a Kenyan parasite population. The recent publication of the crystal structure of the variable C terminal region of the protein allows the assessment of the impact of diversity on protein structure and T cell epitope assortment. Using data from the Gambia (55 isolates) and Malawi (235 isolates), we evaluated the patterns of diversity within and between epitopes in these two distantly-separated populations. Only non-synonymous mutations were observed with the vast majority in both populations at similar frequencies suggesting strong selection on this region. A non-random pattern of T cell epitope assortment was seen in Malawi and in the Gambia, but structural analysis indicates no intramolecular spatial interactions. Using the information from these parasite populations, structural analysis reveals that polymorphic amino acids within TH2 and TH3 colocalize to one side of the protein, surround, but do not involve, the hydrophobic pocket in CS, and predominately involve charge switches. In addition, free energy analysis suggests residues forming and behind the novel pocket within CS are tightly constrained and well conserved in all alleles. In addition, free energy analysis shows polymorphic residues tend to be populated by energetically unfavorable amino acids. In combination, these findings suggest the diversity of T cell epitopes in CS may be primarily an evolutionary response to intermolecular interactions at the surface of the protein potentially counteracting antibody-mediated immune recognition or evolving host receptor diversity. PMID- 23667475 TI - A multi-platform draft de novo genome assembly and comparative analysis for the Scarlet Macaw (Ara macao). AB - Data deposition to NCBI Genomes: This Whole Genome Shotgun project has been deposited at DDBJ/EMBL/GenBank under the accession AMXX00000000 (SMACv1.0, unscaffolded genome assembly). The version described in this paper is the first version (AMXX01000000). The scaffolded assembly (SMACv1.1) has been deposited at DDBJ/EMBL/GenBank under the accession AOUJ00000000, and is also the first version (AOUJ01000000). Strong biological interest in traits such as the acquisition and utilization of speech, cognitive abilities, and longevity catalyzed the utilization of two next-generation sequencing platforms to provide the first draft de novo genome assembly for the large, new world parrot Ara macao (Scarlet Macaw). Despite the challenges associated with genome assembly for an outbred avian species, including 951,507 high-quality putative single nucleotide polymorphisms, the final genome assembly (>1.035 Gb) includes more than 997 Mb of unambiguous sequence data (excluding N's). Cytogenetic analyses including ZooFISH revealed complex rearrangements associated with two scarlet macaw macrochromosomes (AMA6, AMA7), which supports the hypothesis that translocations, fusions, and intragenomic rearrangements are key factors associated with karyotype evolution among parrots. In silico annotation of the scarlet macaw genome provided robust evidence for 14,405 nuclear gene annotation models, their predicted transcripts and proteins, and a complete mitochondrial genome. Comparative analyses involving the scarlet macaw, chicken, and zebra finch genomes revealed high levels of nucleotide-based conservation as well as evidence for overall genome stability among the three highly divergent species. Application of a new whole-genome analysis of divergence involving all three species yielded prioritized candidate genes and noncoding regions for parrot traits of interest (i.e., speech, intelligence, longevity) which were independently supported by the results of previous human GWAS studies. We also observed evidence for genes and noncoding loci that displayed extreme conservation across the three avian lineages, thereby reflecting their likely biological and developmental importance among birds. PMID- 23667477 TI - Protective role of Helicobacter pylori infection in prognosis of gastric cancer: evidence from 2,454 patients with gastric cancer. AB - BACKGROUND: A number of studies have investigated the association between Helicobacter pylori (H. pylori) infection and the prognosis of gastric cancer (GC), with inconsistent and inconclusive results. We performed a meta-analysis to derive a more precise estimation of the association. METHODOLOGY/PRINCIPAL FINDINGS: A systematic search of PubMed, EMBASE, Cochrane and Chinese wanfang databases was performed with the last search updated on February 19, 2013. The hazard ratio (HR) and its 95% confidence interval (95%CI) were used to assess the strength of association. A total of 12 studies including 2454 patients with GC were involved in this meta-analysis. The pooled HR was 0.71 (95%CI: 0.57-0.87; P = 0.001) for OS and 0.60 (95%CI: 0.30-1.18; P = 0.139) for DFS in GC patients, respectively. The protective role of H. pylori infection in the prognosis of GC was also observed among different subgroups stratified by ethnicity, statistical methodology, H. pylori evaluation method and quality assessment. There was no evidence of publication bias. CONCLUSIONS/SIGNIFICANCE: This meta-analysis suggests a protective role for H. pylori infection in the prognosis of GC. The underlying mechanisms need to be further elucidated, which could provide new therapeutic approaches for GC. PMID- 23667478 TI - Tetramerization reinforces the dimer interface of MnSOD. AB - Two yeast manganese superoxide dismutases (MnSOD), one from Saccharomyces cerevisiae mitochondria (ScMnSOD) and the other from Candida albicans cytosol (CaMnSODc), have most biochemical and biophysical properties in common, yet ScMnSOD is a tetramer and CaMnSODc is a dimer or "loose tetramer" in solution. Although CaMnSODc was found to crystallize as a tetramer, there is no indication from the solution properties that the functionality of CaMnSODc in vivo depends upon the formation of the tetrameric structure. To elucidate further the functional significance of MnSOD quaternary structure, wild-type and mutant forms of ScMnSOD (K182R, A183P mutant) and CaMnSODc (K184R, L185P mutant) with the substitutions at dimer interfaces were analyzed with respect to their oligomeric states and resistance to pH, heat, and denaturant. Dimeric CaMnSODc was found to be significantly more subject to thermal or denaturant-induced unfolding than tetrameric ScMnSOD. The residue substitutions at dimer interfaces caused dimeric CaMnSODc but not tetrameric ScMnSOD to dissociate into monomers. We conclude that the tetrameric assembly strongly reinforces the dimer interface, which is critical for MnSOD activity. PMID- 23667479 TI - Aggregate-reactivation activity of the molecular chaperone ClpB from Ehrlichia chaffeensis. AB - Rickettsiale diseases, including human monocytic ehrlichiosis caused by Ehrlichia chaffeensis, are the second leading cause of the tick-borne infections in the USA and a growing health concern. Little is known about how E. chaffeensis survives the host-induced stress in vertebrate and tick hosts. A molecular chaperone ClpB from several microorganisms has been reported to reactivate aggregated proteins in cooperation with the co-chaperones DnaK/DnaJ/GrpE (KJE). In this study, we performed the first biochemical characterization of ClpB from E. chaffeensis. The transcript of E. chaffeensis ClpB (EhClpB) is strongly upregulated after infection of cultured macrophages and its level remains high during the Ehrlichia replicative stage. EhClpB forms ATP-dependent oligomers and catalyzes the ATP hydrolysis, similar to E. coli ClpB (EcClpB), but its ATPase activity is insensitive to the EcClpB activators, casein and poly-lysine. EhClpB in the presence of E. coli KJE efficiently reactivates the aggregated glucose-6 phosphate dehydrogenase (G6PDH) and firefly luciferase. Unlike EcClpB, which requires the co-chaperones for aggregate reactivation, EhClpB reactivates G6PDH even in the absence of KJE. Moreover, EhClpB is functionally distinct from EcClpB as evidenced by its failure to rescue a temperature-sensitive phenotype of the clpB-null E. coli. The clpB expression pattern during the E. chaffeensis infection progression correlates with the pathogen's replicating stage inside host cells and suggests an essential role of the disaggregase activity of ClpB in the pathogen's response to the host-induced stress. This study sets the stage for assessing the importance of the chaperone activity of ClpB for E. chaffeensis growth within the mammalian and tick hosts. PMID- 23667480 TI - Rapamycin attenuates the progression of tau pathology in P301S tau transgenic mice. AB - Altered autophagy contributes to the pathogenesis of Alzheimer's disease and other tauopathies, for which curative treatment options are still lacking. We have recently shown that trehalose reduces tau pathology in a tauopathy mouse model by stimulation of autophagy. Here, we studied the effect of the autophagy inducing drug rapamycin on the progression of tau pathology in P301S mutant tau transgenic mice. Rapamycin treatment resulted in a significant reduction in cortical tau tangles, less tau hyperphosphorylation, and lowered levels of insoluble tau in the forebrain. The favourable effect of rapamycin on tau pathology was paralleled by a qualitative reduction in astrogliosis. These effects were visible with early preventive or late treatment. We further noted an accumulation of the autophagy associated proteins p62 and LC3 in aged tangle bearing P301S mice that was lowered upon rapamycin treatment. Thus, rapamycin treatment defers the progression of tau pathology in a tauopathy animal model and autophagy stimulation may constitute a therapeutic approach for patients suffering from tauopathies. PMID- 23667481 TI - Dependence of micelle size and shape on detergent alkyl chain length and head group. AB - Micelle-forming detergents provide an amphipathic environment that can mimic lipid bilayers and are important tools for solubilizing membrane proteins for functional and structural investigations in vitro. However, the formation of a soluble protein-detergent complex (PDC) currently relies on empirical screening of detergents, and a stable and functional PDC is often not obtained. To provide a foundation for systematic comparisons between the properties of the detergent micelle and the resulting PDC, a comprehensive set of detergents commonly used for membrane protein studies are systematically investigated. Using small-angle X ray scattering (SAXS), micelle shapes and sizes are determined for phosphocholines with 10, 12, and 14 alkyl carbons, glucosides with 8, 9, and 10 alkyl carbons, maltosides with 8, 10, and 12 alkyl carbons, and lysophosphatidyl glycerols with 14 and 16 alkyl carbons. The SAXS profiles are well described by two-component ellipsoid models, with an electron rich outer shell corresponding to the detergent head groups and a less electron dense hydrophobic core composed of the alkyl chains. The minor axis of the elliptical micelle core from these models is constrained by the length of the alkyl chain, and increases by 1.2-1.5 A per carbon addition to the alkyl chain. The major elliptical axis also increases with chain length; however, the ellipticity remains approximately constant for each detergent series. In addition, the aggregation number of these detergents increases by ~16 monomers per micelle for each alkyl carbon added. The data provide a comprehensive view of the determinants of micelle shape and size and provide a baseline for correlating micelle properties with protein-detergent interactions. PMID- 23667482 TI - Contribution of bone marrow-derived hematopoietic stem/progenitor cells to the generation of donor-marker+ cardiomyocytes in vivo. AB - BACKGROUND: Definite identification of the cell types and the mechanism relevant to cardiomyogenesis is essential for effective cardiac regenerative medicine. We aimed to identify the cell populations that can generate cardiomyocytes and to clarify whether generation of donor-marker(+) cardiomyocytes requires cell fusion between BM-derived cells and recipient cardiomyocytes. METHODOLOGY/PRINCIPAL FINDINGS: Purified BM stem/progenitor cells from green fluorescence protein (GFP) mice were transplanted into C57BL/6 mice or cyan fluorescence protein (CFP) transgenic mice. Purified human hematopoietic stem cells (HSCs) from cord blood were transplanted into immune-compromised NOD/SCID/IL2rgamma(null) mice. GFP(+) cells in the cardiac tissue were analyzed for the antigenecity of a cardiomyocyte by confocal microscopy following immunofluorescence staining. GFP(+) donor derived cells, GFP(+)CFP(+) fused cells, and CFP(+) recipient-derived cells were distinguished by linear unmixing analysis. Hearts of xenogeneic recipients were evaluated for the expression of human cardiomyocyte genes by real-time quantitative polymerase chain reaction. In C57BL/6 recipients, Lin(-/low)CD45(+) hematopoietic cells generated greater number of GFP(+) cardiomyocytes than Lin( /low)CD45(-) mesenchymal cells (37.0+/-23.9 vs 0.00+/-0.00 GFP(+) cardiomyocytes per a recipient, P = 0.0095). The number of transplanted purified HSCs (Lin( /low)Sca-1(+) or Lin(-)Sca-1(+)c-Kit(+) or CD34(-)Lin(-)Sca-1(+)c-Kit(+)) showed correlation to the number of GFP(+) cardiomyocytes (P<0.05 in each cell fraction), and the incidence of GFP(+) cardiomyocytes per injected cell dose was greatest in CD34(-)Lin(-)Sca-1(+)c-Kit(+) recipients. Of the hematopoietic progenitors, total myeloid progenitors generated greater number of GFP(+) cardiomyocytes than common lymphoid progenitors (12.8+/-10.7 vs 0.67+/-1.00 GFP(+) cardiomyocytes per a recipient, P = 0.0021). In CFP recipients, all GFP(+) cardiomyocytes examined coexpressed CFP. Human troponin C and myosin heavy chain 6 transcripts were detected in the cardiac tissue of some of the xenogeneic recipients. CONCLUSIONS/SIGNIFICANCE: Our results indicate that HSCs resulted in the generation of cardiomyocytes via myeloid intermediates by fusion-dependent mechanism. The use of myeloid derivatives as donor cells could potentially allow more effective cell-based therapy for cardiac repair. PMID- 23667483 TI - Design and validation of a method to determine the position of the fovea by using the nerve-head to fovea distance of the fellow eye. AB - PURPOSE: To measure the nerve-head to fovea distance (NFD) on fundus photographs in fellow eyes, and to compare the NFD between fellow eyes. METHODS: Diabetic patients without retinopathy, (n = 183) who were screened by fundus photography at the University Medical Center Groningen, the Netherlands from January 1(st) 2005 until January 1(st) 2006 were included. The NFD was measured in left and right eyes both from the center and from the rim of the nerve-head. To determine inter- and intra-observer agreement, repeated measurements by one observer (n = 3) were performed on all photographs and by two observers on 60 photographs (30 paired eyes). The effect of age, gender, and refractive error on NFD was analysed. RESULTS: The correlation of NFDs between the left and the right eye was 0.958 when measured from the center of the nerve head (mean difference 0.0078 mm. +/-SD 0.079 (95% limits of agreement -0.147-0.163)) and 0.963 when measured from the rim (mean difference 0.0056+/-SD 0.073 (95% limits of agreement -0.137 0.149)). Using the NFD between fellow eyes interchangeably, resulted in a standard error of 0.153 mm. Intra- and inter-observer variability was small. We found a significant effect of age (center of the nerve-head (P = 0.006) and rim of the nerve head (P = 0.003)) and refractive error (center of nerve-head (P<0.001) and rim of nerve head (P<0.001)) on NFD. CONCLUSIONS: The NFD in one eye provides a confident, reproducible, and valid method to address the position of the fovea in the fellow eye. We recommend using the NFD measured from the center of the nerve-head since the standard error by this method was smallest. Age and refractive error have an effect on NFD. PMID- 23667484 TI - Exposure levels of environmental endocrine disruptors in mother-newborn pairs in China and their placental transfer characteristics. AB - There is a growing concern about the potential health effects of exposure to various environmental chemicals during pregnancy and infancy. The placenta is expected to be an effective barrier protecting the developing embryo against some endocrine disruptors (EDs) circulating in maternal blood. The current study was designed to assess in utero exposure levels of non-persistent organic pollutants (non-POPs) and persistent organic pollutants (POPs) in Chinese newborns and potential role of placenta barrier against fetal exposure to these commonly-used environmental endocrine disruptors. A total of 230 newborn-mother pairs were enrolled during 2010-2011, 201 pairs of which were recruited from Shanghai, and the other 29 pairs came from Wenzhou. Maternal blood, cord blood, and meconium specimens were collected in the subject population from Shanghai and analyzed for non-POPs, including mono-2-ethylhexyl phthalate (MEHP), octylphenol (OP) and 4 nonylphenol (4-NP). A total of 19 polybrominated diphenyl ethers (PBDEs) congeners, which belong to POPs, were detected in maternal and cord blood specimens from the other 29 pairs. Fetal-maternal ratios (F-M ratios) and regression coefficients were presented to assess potential function of placenta on barricading the mother/fetal transfer of these EDs. Concentrations of the detected non-POPs in cord blood samples were approximately 20% lower than those in maternal blood, and regression coefficients of which were all over 0.80. In contrast, PBDEs levels in cord blood samples were significantly higher than those in maternal blood. MEHP levels in meconium were much higher than those in cord blood samples, and highly correlated. Therefore, observations demonstrated that the placental barrier slightly decreased the fetal exposure to most non-POPs, while PBDEs seemed to be totally transferred across the placenta and finally reached the fetus. For in utero exposure assessment of Di-2-ethylhexyl phthalate (DEHP), MEHP level in meconium may be a useful biomarker. PMID- 23667485 TI - Identification of 5-Iodotubercidin as a genotoxic drug with anti-cancer potential. AB - Tumor suppressor p53, which is activated by various stress and oncogene activation, is a target for anti-cancer drug development. In this study, by screening panels of protein kinase inhibitors and protein phosphatase inhibitors, we identified 5-Iodotubercidin as a strong p53 activator. 5-Iodotubercidin is purine derivative and is used as an inhibitor for various kinases including adenosine kinase. We found that 5-Iodotubercidin could cause DNA damage, verified by induction of DNA breaks and nuclear foci positive for gammaH2AX and TopBP1, activation of Atm and Chk2, and S15 phosphorylation and up-regulation of p53. As such, 5-Iodotubercidin induces G2 cell cycle arrest in a p53-dependent manner. Itu also induces cell death in p53-dependent and -independent manners. DNA breaks were likely generated by incorporation of 5-Iodotubercidin metabolite into DNA. Moreover, 5-Iodotubercidin showed anti-tumor activity as it could reduce the tumor size in carcinoma xenograft mouse models in p53-dependent and -independent manners. These findings reveal 5-Iodotubercidin as a novel genotoxic drug that has chemotherapeutic potential. PMID- 23667486 TI - C5a receptor deficiency alters energy utilization and fat storage. AB - OBJECTIVE: To investigate the impact of whole body C5a receptor (C5aR) deficiency on energy metabolism and fat storage. DESIGN: Male wildtype (WT) and C5aR knockout (C5aRKO) mice were fed a low fat (CHOW) or a high fat high sucrose diet induced obesity (DIO) diet for 14 weeks. Body weight and food intake were measured weekly. Indirect calorimetry, dietary fatload clearance, insulin and glucose tolerance tests were also evaluated. Liver, muscle and adipose tissue mRNA gene expression were measured by RT-PCR. RESULTS: At week one and 12, C5aRKO mice on DIO had increased oxygen consumption. After 12 weeks, although food intake was comparable, C5aRKO mice had lower body weight (-7% CHOW, -12% DIO) as well as smaller gonadal (-38% CHOW, -36% DIO) and inguinal (-29% CHOW, -30% DIO) fat pads than their WT counterparts. Conversely, in WT mice, C5aR was upregulated in DIO vs CHOW diets in gonadal adipose tissue, muscle and liver, while C5L2 mRNA expression was lower in C5aRKO on both diet. Furthermore, blood analysis showed lower plasma triglyceride and non-esterified fatty acid levels in both C5aRKO groups, with faster postprandial triglyceride clearance after a fatload. Additionally, C5aRKO mice showed lower CD36 expression in gonadal and muscle on both diets, while DGAT1 expression was higher in gonadal (CHOW) and liver (CHOW and DIO) and PPARgamma was increased in muscle and liver. CONCLUSION: These observations point towards a role (either direct or indirect) for C5aR in energy expenditure and fat storage, suggesting a dual role for C5aR in metabolism as well as in immunity. PMID- 23667487 TI - The efficacy of lapatinib in metastatic breast cancer with HER2 non-amplified primary tumors and EGFR positive circulating tumor cells: a proof-of-concept study. AB - BACKGROUND: Analysis of circulating tumor cells (CTCs) provides real-time measures of cancer sub-populations with potential for CTC-directed therapeutics. We examined whether lapatinib which binds both HER2 and EGFR could induce depletion of the EGFR-positive pool of CTCs, which may in turn lead to clinical benefits. PATIENTS AND METHODS: Patients with metastatic breast cancer and HER2 non-amplified primary tumors with EGFR-positive CTCs were recruited and lapatinib 1500 mg daily was administered, in a standard two step phase 2 trial. RESULTS: There were no responses leading to termination at the first analysis with 16 patients recruited out of 43 screened. In 6 out of 14 (43%) individuals eligible for the efficacy analysis, a decrease in CTCs was observed with most of these having a greater decrease in their EGFR-positive CTC pool. CONCLUSIONS: This is one of the first studies of CTC-directed therapeutics and suggests that lapatinib monotherapy is not having any demonstrable clinical effects by reducing the EGFR positive pool of CTCs in HER2 non-amplified primary tumors. Our attempt to expand the pool of patients eligible for a targeted therapy was unsuccessful; the role of clonal populations in cancer biology and therapeutic strategies to control them will require extensive evaluation in years to come. TRIAL REGISTRATION: Clinical trials.gov NCT00820924. PMID- 23667489 TI - Zooplankton feeding on the nuisance flagellate Gonyostomum semen. AB - The large bloom-forming flagellate Gonyostomum semen has been hypothesized to be inedible to naturally occurring zooplankton due to its large cell size and ejection of long slimy threads (trichocysts) induced by physical stimulation. In a grazing experiment using radiolabelled algae and zooplankton collected from lakes with recurring blooms of G. semen and lakes that rarely experience blooms, we found that Eudiaptomus gracilis and Holopedium gibberum fed on G. semen at high rates, whereas Daphnia cristata and Ceriodaphnia spp. did not. Grazing rates of E. gracilis were similar between bloom-lakes and lakes with low biomass of G. semen, indicating that the ability to feed on G. semen was not a result of local adaptation. The high grazing rates of two of the taxa in our experiment imply that some of the nutrients and energy taken up by G. semen can be transferred directly to higher trophic levels, although the predominance of small cladocerans during blooms may limit the importance of G. semen as a food resource. Based on grazing rates and previous observations on abundances of E. gracilis and H. gibberum, we conclude that there is a potential for grazer control of G. semen and discuss why blooms of G. semen still occur. PMID- 23667488 TI - Variability of HIV-1 genomes among children and adolescents from Sao Paulo, Brazil. AB - BACKGROUND: Genetic variability is a major feature of the human immunodeficiency virus type 1 (HIV-1) and considered the key factor to frustrating efforts to halt the virus epidemic. In this study, we aimed to investigate the genetic variability of HIV-1 strains among children and adolescents born from 1992 to 2009 in the state of Sao Paulo, Brazil. METHODOLOGY: Plasma and peripheral blood mononuclear cells (PBMC) were collected from 51 HIV-1-positive children and adolescents on ART followed between September 1992 and July 2009. After extraction, the genetic materials were used in a polymerase chain reaction (PCR) to amplify the viral near full length genomes (NFLGs) from 5 overlapped fragments. NFLGs and partial amplicons were directly sequenced and data were phylogenetically inferred. RESULTS: Of the 51 samples studied, the NFLGs and partial fragments of HIV-1 from 42 PBMCs and 25 plasma were successfully subtyped. Results based on proviral DNA revealed that 22 (52.4%) patients were infected with subtype B, 16 (38.1%) were infected with BF1 mosaic variants and 4 (9.5%) were infected with sub-subtype F1. All the BF1 recombinants were unique and distinct from any previously identified unique or circulating recombinant forms in South America. Evidence of dual infections was detected in 3 patients coinfected with the same or distinct HIV-1 subtypes. Ten of the 31 (32.2%) and 12 of the 21 (57.1%) subjects with recovered proviral and plasma, respectively, protease sequences were infected with major mutants resistant to protease inhibitors. The V3 sequences of 14 patients with available sequences from PBMC/or plasma were predicted to be R5-tropic virus except for two patients who harbored an X4 strain. CONCLUSIONS: The high proportion of HIV-1 BF1 recombinant, coinfection rate and vertical transmission in Brazil merits urgent attention and effective measures to reduce the transmission of HIV among spouses and sex partners. PMID- 23667490 TI - Molecular diversity of HIV-1 among people who inject drugs in Kuala Lumpur, Malaysia: massive expansion of circulating recombinant form (CRF) 33_01B and emergence of multiple unique recombinant clusters. AB - Since the discovery of HIV-1 circulating recombinant form (CRF) 33_01B in Malaysia in the early 2000 s, continuous genetic diversification and active recombination involving CRF33_01B and other circulating genotypes in the region including CRF01_AE and subtype B' of Thai origin, have led to the emergence of novel CRFs and unique recombinant forms. The history and magnitude of CRF33_01B transmission among various risk groups including people who inject drugs (PWID) however have not been investigated despite the high epidemiological impact of CRF33_01B in the region. We update the most recent molecular epidemiology of HIV 1 among PWIDs recruited in Malaysia between 2010 and 2011 by population sequencing and phylogenetic analysis of 128 gag-pol sequences. HIV-1 CRF33_01B was circulating among 71% of PWIDs whilst a lower prevalence of other previously dominant HIV-1 genotypes [subtype B' (11%) and CRF01_AE (5%)] and CRF01_AE/B' unique recombinants (13%) were detected, indicating a significant shift in genotype replacement in this population. Three clusters of CRF01_AE/B' recombinants displaying divergent yet phylogenetically-related mosaic genomes to CRF33_01B were identified and characterized, suggestive of an abrupt emergence of multiple novel CRF clades. Using rigorous maximum likelihood approach and the Bayesian Markov chain Monte Carlo (MCMC) sampling of CRF33_01Bpol sequences to elucidate the past population dynamics, we found that the founder lineages of CRF33_01B were likely to have first emerged among PWIDs in the early 1990 s before spreading exponentially to various high and low-risk populations (including children who acquired infections from their mothers) and later on became endemic around the early 2000 s. Taken together, our findings provide notable genetic evidence indicating the widespread expansion of CRF33_01B among PWIDs and into the general population. The emergence of numerous previously unknown recombinant clades highlights the escalating genetic complexity of HIV-1 in the Southeast Asian region. PMID- 23667491 TI - Characterizing the crucial components of iron homeostasis in the maize mutants ys1 and ys3. AB - To acquire iron (Fe), graminaceous plants secrete mugineic acid family phytosiderophores through the phytosiderophore efflux transporter TOM1 and take up Fe in the form of Fe(III)-phytosiderophore complexes. Yellow stripe 1 (ys1) and ys3 are recessive mutants of maize (Zea mays L.) that show typical symptoms of Fe deficiency, i.e., interveinal chlorosis of the leaves. The ys1 mutant is defective in the Fe(III)-phytosiderophore transporter YS1 and is therefore unable to take up Fe(III)-phytosiderophore complexes. While the ys3 mutant has been shown to be defective in phytosiderophores release, the causative gene has not been identified. The present study was performed to characterize the expression profiles of the genes in ys1 and ys3 mutants to extend our understanding of Fe homeostasis in maize. Using quantitative real-time polymerase chain reaction, we assessed changes in the levels of gene expression in response to Fe deficiency of genes involved in Fe homeostasis, such as those related to phytosiderophore biosynthesis and Fe transport. As with other crops, these Fe deficiency-inducible genes were also upregulated in maize. In addition, these Fe deficiency-inducible genes were upregulated in both the ys1 and ys3 mutants, even under Fe-sufficient conditions. Indeed, the Fe concentrations in the roots of ys1 and ys3 plants were lower than that of wild-type controls. These results suggest that ys1 and ys3 are Fe-deficient during growth in the presence of Fe. In agreement with previous reports, the level of YS1 expression decreased in the ys1 mutant. Moreover, the expression level of a homolog of TOM1 in maize decreased significantly in the ys3 mutant. Unspliced introns of ZmTOM1 were detected only in ys3, and not in YS1YS3 or ys1, suggesting that ZmTOM1 may be involved in the ys3 phenotype. PMID- 23667492 TI - Sponge communities on Caribbean coral reefs are structured by factors that are top-down, not bottom-up. AB - Caribbean coral reefs have been transformed in the past few decades with the demise of reef-building corals, and sponges are now the dominant habitat-forming organisms on most reefs. Competing hypotheses propose that sponge communities are controlled primarily by predatory fishes (top-down) or by the availability of picoplankton to suspension-feeding sponges (bottom-up). We tested these hypotheses on Conch Reef, off Key Largo, Florida, by placing sponges inside and outside predator-excluding cages at sites with less and more planktonic food availability (15 m vs. 30 m depth). There was no evidence of a bottom-up effect on the growth of any of 5 sponge species, and 2 of 5 species grew more when caged at the shallow site with lower food abundance. There was, however, a strong effect of predation by fishes on sponge species that lacked chemical defenses. Sponges with chemical defenses grew slower than undefended species, demonstrating a resource trade-off between growth and the production of secondary metabolites. Surveys of the benthic community on Conch Reef similarly did not support a bottom up effect, with higher sponge cover at the shallower depth. We conclude that the structure of sponge communities on Caribbean coral reefs is primarily top-down, and predict that removal of sponge predators by overfishing will shift communities toward faster-growing, undefended species that better compete for space with threatened reef-building corals. PMID- 23667493 TI - Loss of the Arabidopsis thaliana P4-ATPase ALA3 reduces adaptability to temperature stresses and impairs vegetative, pollen, and ovule development. AB - Members of the P4 subfamily of P-type ATPases are thought to help create asymmetry in lipid bilayers by flipping specific lipids between the leaflets of a membrane. This asymmetry is believed to be central to the formation of vesicles in the secretory and endocytic pathways. In Arabidopsis thaliana, a P4-ATPase associated with the trans-Golgi network (ALA3) was previously reported to be important for vegetative growth and reproductive success. Here we show that multiple phenotypes for ala3 knockouts are sensitive to growth conditions. For example, ala3 rosette size was observed to be dependent upon both temperature and soil, and varied between 40% and 80% that of wild-type under different conditions. We also demonstrate that ala3 mutants have reduced fecundity resulting from a combination of decreased ovule production and pollen tube growth defects. In-vitro pollen tube growth assays showed that ala3 pollen germinated ~2 h slower than wild-type and had approximately 2-fold reductions in both maximal growth rate and overall length. In genetic crosses under conditions of hot days and cold nights, pollen fitness was reduced by at least 90-fold; from ~18% transmission efficiency (unstressed) to less than 0.2% (stressed). Together, these results support a model in which ALA3 functions to modify endomembranes in multiple cell types, enabling structural changes, or signaling functions that are critical in plants for normal development and adaptation to varied growth environments. PMID- 23667494 TI - Two-gene phylogeny of bright-spored Myxomycetes (slime moulds, superorder Lucisporidia). AB - Myxomycetes, or plasmodial slime-moulds, are one of the largest groups in phylum Amoebozoa. Nonetheless, only ~10% are in the database for the small subunit (SSU) ribosomal RNA gene, the most widely used gene for phylogenetics and barcoding. Most sequences belong to dark-spored Myxomycetes (order Fuscisporida); the 318 species of superorder Lucisporidia (bright-spored) are represented by only eleven genuine sequences. To compensate for this, we provide 66 new sequences, 37 SSU rRNA and 29 elongation factor 1-alpha (EF-1alpha), for 82% of the genera of Lucisporidia. Phylogenetic analyses of single- and two-gene alignments produce congruent topologies and reveal both morphological characters that have been overemphasised and those that have been overlooked in past classifications. Both classical orders, Liceida and Trichiida, and several families and genera are para/polyphyletic; some previously unrecognised clades emerge. We discuss possible evolutionary pathways. Our study fills a gap in the phylogeny of Amoebozoa and provides an extensive SSU rRNA sequence reference database for environmental sampling and barcoding. We report a new group I intron insertion site for Myxomycetes in one Licea. PMID- 23667495 TI - Multiple-to-multiple relationships between microRNAs and target genes in gastric cancer. AB - MicroRNAs (miRNAs) act as transcriptional regulators and play pivotal roles in carcinogenesis. According to miRNA target databases, one miRNA may regulate many genes as its targets, while one gene may be targeted by many miRNAs. These findings indicate that relationships between miRNAs and their targets may not be one-to-one. However, many reports have described only a one-to-one, one-to multiple or multiple-to-one relationship between miRNA and its target gene in human cancers. Thus, it is necessary to determine whether or not a combination of some miRNAs would regulate multiple targets and be involved in carcinogenesis. To find some groups of miRNAs that may synergistically regulate their targets in human gastric cancer (GC), we re-analyzed our previous miRNA expression array data and found that 50 miRNAs were up-regulated on treatment with 5-aza-2' deoxycytidine in a GC cell line. The "TargetScan" miRNA target database predicted that some of these miRNAs have common target genes. We also referred to the GEO database for expression of these common target genes in human GCs, which might be related to gastric carcinogenesis. In this study, we analyzed two miRNA combinations, miR-224 and -452, and miR-181c and -340. Over-expression of both miRNA combinations dramatically down-regulated their target genes, DPYSL2 and KRAS, and KRAS and MECP2, respectively. These miRNA combinations synergistically decreased cell proliferation upon transfection. Furthermore, we revealed that these miRNAs were down-regulated through promoter hypermethylation in GC cells. Thus, it is likely that the relationships between miRNAs and their targets are not one-to-one but multiple-to-multiple in GCs, and that these complex relationships may be related to gastric carcinogenesis. PMID- 23667496 TI - A role for programmed cell death in the microbial loop. AB - The microbial loop is the conventional model by which nutrients and minerals are recycled in aquatic eco-systems. Biochemical pathways in different organisms become metabolically inter-connected such that nutrients are utilized, processed, released and re-utilized by others. The result is that unrelated individuals end up impacting each others' fitness directly through their metabolic activities. This study focused on the impact of programmed cell death (PCD) on a population's growth as well as its role in the exchange of carbon between two naturally co occurring halophilic organisms. Flow cytometric, biochemical, 14C radioisotope tracing assays, and global transcriptomic analyses show that organic algal photosynthate released by Dunalliela salina cells undergoing PCD complements the nutritional needs of other non-PCD D. salina cells. This occurs in vitro in a carbon limited environment and enhances the growth of the population. In addition, a co-occurring heterotroph Halobacterium salinarum re-mineralizes the carbon providing elemental nutrients for the mixoheterotrophic chlorophyte. The significance of this is uncertain and the archaeon can also subsist entirely on the lysate of apoptotic algae. PCD is now well established in unicellular organisms; however its ecological relevance has been difficult to decipher. In this study we found that PCD in D. salina causes the release of organic nutrients such as glycerol, which can be used by others in the population as well as a co occurring halophilic archaeon. H. salinarum also re-mineralizes the dissolved material promoting algal growth. PCD in D. salina was the mechanism for the flow of dissolved photosynthate between unrelated organisms. Ironically, programmed death plays a central role in an organism's own population growth and in the exchange of nutrients in the microbial loop. PMID- 23667497 TI - Impact of Scotland's comprehensive, smoke-free legislation on stroke. AB - BACKGROUND: Previous studies have reported a reduction in acute coronary events following smoke-free legislation. Evidence is lacking on whether stroke is also reduced. The aim was to determine whether the incidence of stroke, overall and by sub-type, fell following introduction of smoke-free legislation across Scotland on 26 March 2006. METHODS AND FINDINGS: A negative binomial regression model was used to determine whether the introduction of smoke-free legislation resulted in a step and/or slope change in stroke incidence. The model was adjusted for age group, sex, socioeconomic deprivation quintile, urban/rural residence and month. Interaction tests were also performed. Routine hospital administrative data and death certificates were used to identify all hospital admissions and pre-hospital deaths due to stroke (ICD10 codes I61, I63 and I64) in Scotland between 2000 and 2010 inclusive. Prior to the legislation, rates of all stroke, intracerebral haemorrhage and unspecified stroke were decreasing, whilst cerebral infarction was increasing at 0.97% per annum. Following the legislation, there was a dramatic fall in cerebral infarctions that persisted for around 20 months. No visible effect was observed for other types of stroke. The model confirmed an 8.90% (95% CI 4.85, 12.77, p<0.001) stepwise reduction in cerebral infarction at the time the legislation was implemented, after adjustment for potential confounders. CONCLUSIONS: Following introduction of national, comprehensive smoke free legislation there was a selective reduction in cerebral infarction that was not apparent in other types of stroke. PMID- 23667498 TI - Tourism revenue as a conservation tool for threatened birds in protected areas. AB - Many bird populations worldwide are at risk of extinction, and rely heavily on protected area networks for their continued conservation. Tourism to these areas contributes to conservation by generating revenue for management. Here we quantify the contribution of tourism revenue for bird species in the IUCN Red List, using a simple accounting method. Relevant data are available for 90 (16%) of the 562 critically endangered and endangered species. Contributions of tourism to bird conservation are highest, 10-64%, in South America, Africa, and their neighbouring islands. Critically endangered bird species rely on tourism more heavily than endangered species (p<0.02). Many protected areas could also enhance their management budgets by promoting birdwatching tourism specifically. PMID- 23667499 TI - Could sensory mechanisms be a core factor that underlies freezing of gait in Parkinson's disease? AB - The main objective of this study was to determine how manipulating the amount of sensory information available about the body and surrounding environment influenced freezing of gait (FOG), while walking through a doorway. It was hypothesized that the more limited the sensory information, the greater the occurrence of freezing of gait. Nineteen patients with Parkinsons disease who experience freezing of gait (PD-FOG) walked through a doorway or into open space in complete darkness. The three doorway conditions included: (i) FRAME (DARK)- walking through the remembered door frame; (ii) FRAME--walking through the door with the door frame illuminated; (iii) FRAME+BODY--walking through the door (both the door and the limbs illuminated). Additionally, two conditions of walking away from the doorway included: (iv) NO FRAME (DARK)--walking into open space; (v) NO FRAME+BODY--walking into open space with the limbs illuminated, to evaluate whether perception (or fear) of the doorway might account for FOG behaviour. Key outcome measures included: the number of freezing of gait episodes recorded, total duration of freezing of gait, and the percentage of time spent frozen. Significantly more freezing of gait episodes occurred when participants walked toward the doorway in complete darkness compared to walking into open space (p<0.05). Similar to previous studies, velocity (p<0.001) and step length (p<0.0001) significantly decreased when walking through the door in complete darkness, compared to all other conditions. Significant increases in step width variability were also identified but only when walking into open space (p<0.005). These results support the notion that sensory deficits may have a profound impact on freezing of gait that need to be carefully considered. PMID- 23667500 TI - Biomarkers of cardiac dysfunction and mortality from community-acquired pneumonia in adults. AB - BACKGROUND: Cardiac dysfunction is common in acute respiratory diseases and may influence prognosis. We hypothesised that blood levels of N-terminal B-type natriuretic peptide (NT-proBNP) and high-sensitivity Troponin T would predict mortality in adults with community-acquired pneumonia. METHODS AND FINDINGS: A prospective cohort of 474 consecutive patients admitted with community-acquired pneumonia to two New Zealand hospitals over one year. Blood taken on admission was available for 453 patients and was analysed for NT-proBNP and Troponin T. Elevated levels of NT-proBNP (>220 pmol/L) were present in 148 (33%) and 86 (19%) of these patients respectively. Among the 26 patients who died within 30 days of admission, 23 (89%) had a raised NT-proBNP and 14 (53%) had a raised Troponin T level on admission compared to 125 (29%) and 72 (17%) of the 427 who survived (p values<0.001). Both NT-proBNP and Troponin T predicted 30-day mortality in age adjusted analysis but after mutual adjustment for the other cardiac biomarker and the Pneumonia Severity Index, a raised N-terminal pro-brain natriuretic peptide remained a predictor of 30-day mortality (OR = 5.3, 95% CI 1.4-19.8, p = 0.013) but Troponin T did not (OR = 1.3, 95% CI 0.5-3.2, p = 0.630). The areas under the receiver-operating curves to predict 30-day mortality were similar for NT-proBNP (0.88) and the Pneumonia Severity Index (0.87). CONCLUSIONS: Elevated N-terminal B-type natriuretic peptide is a strong predictor of mortality from community acquired pneumonia independent of clinical prognostic indicators. The pathophysiological basis for this is unknown but suggests that cardiac involvement may be an under-recognised determinant of outcome in pneumonia and may require a different approach to treatment. In the meantime, measurement of B type natriuretic peptides may help to assess prognosis. PMID- 23667501 TI - Membrane transporters for sulfated steroids in the human testis--cellular localization, expression pattern and functional analysis. AB - Sulfated steroid hormones are commonly considered to be biologically inactive metabolites, but may be reactivated by the steroid sulfatase into biologically active free steroids, thereby having regulatory function via nuclear androgen and estrogen receptors which are widespread in the testis. However, a prerequisite for this mode of action would be a carrier-mediated import of the hydrophilic steroid sulfate molecules into specific target cells in reproductive tissues such as the testis. In the present study we detected predominant expression of the Sodium-dependent Organic Anion Transporter (SOAT), the Organic Anion Transporting Polypeptide 6A1, and the Organic Solute Carrier Partner 1 in human testis biopsies. All of these showed significantly lower or even absent mRNA expression in severe disorders of spermatogenesis (arrest at the level of spermatocytes or spermatogonia, Sertoli cell only syndrome). Only SOAT was significantly lower expressed in biopsies showing hypospermatogenesis. By use of immunohistochemistry SOAT was localized to germ cells at various stages in human testis biopsies showing normal spermatogenesis. SOAT immunoreactivity was detected in zygotene primary spermatocytes of stage V, pachytene spermatocytes of all stages (I-V), secondary spermatocytes of stage VI, and round spermatids (step 1 and step 2) in stages I and II. Furthermore, SOAT transport function for steroid sulfates was analyzed with a novel liquid chromatography tandem mass spectrometry procedure capable of profiling steroid sulfate molecules from cell lysates. With this technique, the cellular inward-directed SOAT transport was verified for the established substrates dehydroepiandrosterone sulfate and estrone-3-sulfate. Additionally, beta-estradiol-3-sulfate and androstenediol-3-sulfate were identified as novel SOAT substrates. PMID- 23667502 TI - Plant ontogeny, spatial distance, and soil type influence patterns of relatedness in a common Amazonian tree. AB - The formation of spatial genetic structure (SGS) may originate from different patterns of seed deposition in the landscape, and is mostly determined by seed dispersal limitation. After dispersal, mechanisms such as filtering by environmental factors or attack by herbivores/pathogens throughout plant development stages, and potentially either disrupt or intensify SGS patterns. We investigated how the genotype of Protium subserratum (Burseraceae), a common tree species in the Ducke Reserve, Brazil, is distributed across the landscape. We used seven microsatellite markers to assess the SGS among plants at different life stages and in different environments. By quantifying the patterns of relatedness among plants of different sizes, we inferred the ontogenetic stage in which SGS changes occurred, and compared these effects across soil types. Relatedness among seedlings decreased when distance between seedlings increased, especially for the youngest seedlings. However, this trend was not continued by older plants, as relatedness values were higher among neighboring individuals of the juvenile and adult size class. Contrasting relatedness patterns between seedlings and larger individuals suggests a trade-off between the negative effects of being near closely-related adults (e.g. due to herbivore and pathogen attack) and the advantage of being in a site favorable to establishment. We also found that soil texture strongly influenced density-dependence patterns, as young seedlings in clay soils were more related to each other than were seedlings in bottomland sandy soils, suggesting that the mechanisms that create and maintain patterns of SGS within a population may interact with environmental heterogeneity. PMID- 23667503 TI - Imaging of VSOP labeled stem cells in agarose phantoms with susceptibility weighted and T2* weighted MR Imaging at 3T: determination of the detection limit. AB - OBJECTIVES: This study aimed to evaluate the detectability of stem cells labeled with very small iron oxide particles (VSOP) at 3T with susceptibility weighted (SWI) and T2* weighted imaging as a methodological basis for subsequent examinations in a large animal stroke model (sheep). MATERIALS AND METHODS: We examined ovine mesenchymal stem cells labeled with VSOP in agarose layer phantoms. The experiments were performed in 2 different groups, with quantities of 0-100,000 labeled cells per layer. 15 different SWI- and T2*-weighted sequences and 3 RF coils were used. All measurements were carried out on a clinical 3T MRI. Images of Group A were analyzed by four radiologists blinded for the number of cells, and rated for detectability according to a four-step scale. Images of Group B were subject to a ROI-based analysis of signal intensities. Signal deviations of more than the 0.95 confidence interval in cell containing layers as compared to the mean of the signal intensity of non cell bearing layers were considered significant. RESULTS: GROUP A: 500 or more labeled cells were judged as confidently visible when examined with a SWI-sequence with 0.15 mm slice thickness. Group B: 500 or more labeled cells showed a significant signal reduction in SWI sequences with a slice thickness of 0.25 mm. Slice thickness and cell number per layer had a significant influence on the amount of detected signal reduction. CONCLUSION: 500 VSOP labeled stem cells could be detected with SWI imaging at 3 Tesla using an experimental design suitable for large animal models. PMID- 23667504 TI - Effect of small molecules modulating androgen receptor (SARMs) in human prostate cancer models. AB - The management of hormone-refractory prostate cancer represents a major challenge in the therapy of this tumor, and identification of novel androgen receptor antagonists is needed to render treatment more effective. We analyzed the activity of two novel androgen receptor antagonists, (S)-11 and (R)-9, in in vitro and in vivo experimental models of hormone-sensitive or castration resistant prostate cancer (CRPC). In vitro experiments were performed on LNCaP, LNCaP-AR, LNCaP-Rbic and VCaP human prostate cancer cells. Cytotoxic activity was assessed by SRB and BrdU uptake, AR transactivation by luciferase reporter assay and PSA levels by Real Time RT-PCR and ELISA assays. Cell cycle progression related markers were evaluated by western blot. In vivo experiments were performed on SCID mice xenografted with cells with different sensitivity to hormonal treatment. In hormone-sensitive LNCaP and LNCaP-AR cells, the latter expressing high androgen receptor levels, (R)-9 and (S)-11 exhibited a higher cytotoxic effect compared to that of the reference compound ((R)-bicalutamide), also in the presence of the synthetic androgen R1881. Furthermore, the cytotoxic effect produced by (R)-9 was higher than that of (S)-11 in the two hormone resistant LNCaP-AR and VCaP cells. A significant reduction in PSA levels was observed after exposure to both molecules. Moreover, (S)-11 and (R)-9 inhibited DNA synthesis by blocking the androgen-induced increase in cyclin D1 protein levels. In vivo studies on the toxicological profile of (R)-9 did not reveal the presence of adverse events. Furthermore, (R)-9 inhibited tumor growth in various in vivo models, especially LNCaP-Rbic xenografts, representative of recurrent disease. Our in vitro results highlight the antitumor activity of the two novel molecules (R)-9 and (S)-11, making them a potentially attractive option for the treatment of CRPC. PMID- 23667505 TI - The chromatin remodeling factor CSB recruits histone acetyltransferase PCAF to rRNA gene promoters in active state for transcription initiation. AB - The promoters of poised rRNA genes (rDNA) are marked by both euchromatic and heterochromatic histone modifications and are associated with two transcription factors, UBF and SL1 that nucleate transcription complex formation. Active rRNA genes contain only euchromatic histone modifications and are loaded with all components of transcriptional initiation complex including RNA polymerase I. Coupled with histone acetylation and RNA polymerase I targeting, poised promoters can be converted to active ones by ATP-dependent chromatin remodeling factor CSB for initiation of rDNA transcription. However, it is not clear how dynamic histone modifications induce the assembly of polymerase I transcription initiation complex to active promoters during such conversion. Here we show that a complex consisting of CSB, RNA polymerase I and histone acetyltransferase PCAF is present at the rDNA promoters in active state. CSB is required for the association of PCAF with rDNA, which induces acetylation of histone H4 and histone H3K9. Overexpression of CSB promotes the association of PCAF with rDNA. Knockdown of PCAF leads to decreased levels of H4ac and H3K9ac at rDNA promoters, prevents the association of RNA polymerase I and inhibits pre-rRNA synthesis. The results demonstrate that CSB recruits PCAF to rDNA, which allows histone acetylation that is required for the assembly of polymerase I transcription initiation complex during the transition from poised to active state of rRNA genes, suggesting that CSB and PCAF play cooperative roles to establish the active state of rRNA genes by histone acetylation. PMID- 23667506 TI - Neutralizing antibodies in patients with chronic hepatitis C, genotype 1, against a panel of genotype 1 culture viruses: lack of correlation to treatment outcome. AB - The correlation of neutralizing antibodies to treatment outcome in patients with chronic hepatitis C virus (HCV) infection has not been established. The aim of this study was to determine whether neutralizing antibodies could be used as an outcome predictor in patients with chronic HCV, genotype 1, infection treated with pegylated interferon-alpha and ribavirin. Thirty-nine patients with chronic hepatitis C, genotype 1a or 1b, with either sustained virologic response (n = 23) or non-sustained virologic response (n = 16) were enrolled. Samples taken prior to treatment were tested for their ability to neutralize 6 different HCV genotype 1 cell culture recombinants (1a: H77/JFH1, TN/JFH1, DH6/JFH1; 1b: J4/JFH1, DH1/JFH1, DH5/JFH1). The results were expressed as the highest dilution yielding 50% neutralization (NAb50-titer). We observed no genotype or subtype specific differences in NAb50-titers between patients with chronic HCV infection with and without sustained virologic response when tested against any of the included culture viruses. However, NAb50-titers varied significantly with a mean reciprocal NAb50-titer of 800 (range: 100-6400) against DH6/JFH1 compared to a mean NAb50-titer of 50 (range: <50-400) against all other included isolates. Subsequent studies demonstrated that the efficient neutralization of DH6/JFH1 could be linked to engineered adaptive mutations in the envelope-2 protein. In analysis of envelope 1 and 2 sequences of HCV, recovered from a subset of patients, we observed no apparent link between relatedness of patient sequences with culture viruses used and the corresponding neutralization results. In conclusion, pre-treatment levels of neutralizing antibodies against HCV genotype 1 isolates could not predict treatment outcome in patients with chronic HCV infection. High neutralization susceptibility of DH6/JFH1 could be correlated with adaptive envelope mutations previously highlighted as important for neutralization. Our study emphasizes the importance of using multiple culture viruses for neutralization studies and contributes to the current knowledge about neutralizing epitopes, important for future therapeutic- and vaccine-studies. PMID- 23667507 TI - Sexual dimorphism floral microRNA profiling and target gene expression in andromonoecious poplar (Populus tomentosa). AB - Although the molecular basis of poplar sex-specific flower development remains largely unknown, increasing evidence indicates an essential role for microRNAs (miRNAs). The specific miRNA types and precise miRNA expression patterns in dioecious plant flower development remain unclear. Here, we used andromonoecious poplar, an exceptional model system, to eliminate the confounding effects of genetic background of dioecious plants. This system, combined with high throughput sequencing and computational analysis, allowed us to characterize sex specific miRNAomes from female and male flowers. Comparative miRNAome analysis combined with quantitative real-time PCR revealed the expression patterns of 27 miRNAs in poplar flower and showed that the targets of these miRNAs are involved in flower organogenesis, Ca(2+) transport, phytohormone synthesis and metabolism, and DNA methylation. This paper describes a complex regulatory network consisting of these miRNAs expressed in sex-specific flower development in a dioecious plant. The conserved and novel miRNA locations were annotated in the Populus trichocarpa genome. Among these, miRNA Pto-F70 and 4 targets are located in the sex-determination regions of chromosome XIX. Furthermore, two novel miRNAs, Pto F47 and Pto-F68, were shown for the first time to be regulatory factors in phytohormone interactions. To our knowledge, this report is the first systematic investigation of sex-specific flower-related miRNAs and their targets in poplar, and it deepens our understanding of the important regulatory functions of miRNAs in female and male flower development in this dioecious plant. PMID- 23667508 TI - Evidence that Doublecortin is dispensable for the development of adult born neurons in mice. AB - In mammals, adult neural stem cells give rise to new hippocampal dentate granule neurons and interneurons of the olfactory bulb throughout life. The microtubule associated protein Doublecortin (DCX) is expressed by migrating neuroblasts and immature neurons, and is widely used as a stage-specific marker of adult neurogenesis and as a marker to identify neurogenic activity in the adult brain per se. Mutations in the DCX gene have been causally linked to human lissencephalic syndromes. Moreover, embryonic loss of DCX function interferes with neuronal migration and dendritic patterning in a species- and region specific manner. A putative function of DCX in adult neurogenesis has not been directly explored. Here we show that overexpression of DCX in newly generated dentate granule neurons of the adult mouse brain has no effect on morphological maturation or migration. We also show that micro (mi) RNA-mediated retroviral knockdown of DCX does not alter morphological maturation of adult born dentate granule cells or migration of new neurons in either adult neurogenic niche. Thus, the present data indicate that DCX is dispensable for the development of new neurons in adult mice. PMID- 23667509 TI - Crystal structure of human TWEAK in complex with the Fab fragment of a neutralizing antibody reveals insights into receptor binding. AB - The tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine playing a key role in tissue regeneration and remodeling. Dysregulation of TWEAK signaling is involved in various pathological processes like autoimmune diseases and cancer. The unique interaction with its cognate receptor Fn14 makes both ligand and receptor promising targets for novel therapeutics. To gain insights into this important signaling pathway, we determined the structure of soluble human TWEAK in complex with the Fab fragment of an antibody selected for inhibition of receptor binding. In the crystallized complex TWEAK is bound by three Fab fragments of the neutralizing antibody. Homology modeling shows that Fab binding overlaps with the putative Fn14 binding site of TWEAK. Docking of the Fn14 cysteine rich domain (CRD) to that site generates a highly complementary interface with perfectly opposing charged and hydrophobic residues. Taken together the presented structure provides new insights into the biology of TWEAK and the TWEAK/Fn14 pathway, which will help to optimize the therapeutic strategy for treatment of related cancer types and autoimmune diseases. PMID- 23667510 TI - Mycoplasma pneumoniae CARDS toxin is internalized via clathrin-mediated endocytosis. AB - Bacterial toxins possess specific mechanisms of binding and uptake by mammalian cells. Mycoplasma pneumoniae CARDS (Community Acquired Respiratory Distress Syndrome) toxin is a 68 kDa protein, which demonstrates high binding affinity to human surfactant protein-A and exhibits specific biological activities including mono-ADP ribosylation and vacuolization. These properties lead to inflammatory processes in the airway and a range of cytopathologies including ciliostasis, loss of tissue integrity and injury, and cell death. However, the process by which CARDS toxin enters target cells is unknown. In this study, we show that CARDS toxin binds to mammalian cell surfaces and is internalized rapidly in a dose and time-dependent manner using a clathrin-mediated pathway, as indicated by inhibition of toxin internalization by monodansylcadaverine but not by methyl beta-cyclodextrin or filipin. Furthermore, the internalization of CARDS toxin was markedly inhibited in clathrin-depleted cells. PMID- 23667511 TI - De novo assembly, functional annotation and comparative analysis of Withania somnifera leaf and root transcriptomes to identify putative genes involved in the withanolides biosynthesis. AB - Withania somnifera is one of the most valuable medicinal plants used in Ayurvedic and other indigenous medicine systems due to bioactive molecules known as withanolides. As genomic information regarding this plant is very limited, little information is available about biosynthesis of withanolides. To facilitate the basic understanding about the withanolide biosynthesis pathways, we performed transcriptome sequencing for Withania leaf (101L) and root (101R) which specifically synthesize withaferin A and withanolide A, respectively. Pyrosequencing yielded 8,34,068 and 7,21,755 reads which got assembled into 89,548 and 1,14,814 unique sequences from 101L and 101R, respectively. A total of 47,885 (101L) and 54,123 (101R) could be annotated using TAIR10, NR, tomato and potato databases. Gene Ontology and KEGG analyses provided a detailed view of all the enzymes involved in withanolide backbone synthesis. Our analysis identified members of cytochrome P450, glycosyltransferase and methyltransferase gene families with unique presence or differential expression in leaf and root and might be involved in synthesis of tissue-specific withanolides. We also detected simple sequence repeats (SSRs) in transcriptome data for use in future genetic studies. Comprehensive sequence resource developed for Withania, in this study, will help to elucidate biosynthetic pathway for tissue-specific synthesis of secondary plant products in non-model plant organisms as well as will be helpful in developing strategies for enhanced biosynthesis of withanolides through biotechnological approaches. PMID- 23667512 TI - The Mediterranean benthic herbivores show diverse responses to extreme storm disturbances. AB - Catastrophic storms have been observed to be one of the major elements in shaping the standing structure of marine benthic ecosystems. Yet, little is known about the effect of catastrophic storms on ecosystem processes. Specifically, herbivory is the main control mechanism of macrophyte communities in the Mediterranean, with two main key herbivores: the sea urchin Paracentrotus lividus and the fish Sarpa salpa. Consequently, the effects of extreme storm events on these two herbivores (at the population level and on their behaviour) may be critical for the functioning of the ecosystem. With the aim of filling this gap, we took advantage of two parallel studies that were conducted before, during and after an unexpected catastrophic storm event. Specifically, fish and sea urchin abundance were assessed before and after the storm in monitored fixed areas (one site for sea urchin assessment and 3 sites for fish visual transects). Additionally, we investigated the behavioural response to the disturbance of S. salpa fishes that had been tagged with acoustic transmitters. Given their low mobility, sea urchins were severely affected by the storm (ca. 50% losses) with higher losses in those patches with a higher density of sea urchins. This may be due to a limited availability of refuges within each patch. In contrast, fish abundance was not affected, as fish were able to move to protected areas (i.e. deeper) as a result of the high mobility of this species. Our results highlight that catastrophic storms differentially affect the two dominant macroherbivores of rocky macroalgal and seagrass systems due to differences in mobility and escaping strategies. This study emphasises that under catastrophic disturbances, the presence of different responses among the key herbivores of the system may be critical for the maintenance of the herbivory function. PMID- 23667513 TI - Consensus HIV-1 FSU-A integrase gene variants electroporated into mice induce polyfunctional antigen-specific CD4+ and CD8+ T cells. AB - Our objective is to create gene immunogens targeted against drug-resistant HIV-1, focusing on HIV-1 enzymes as critical components in viral replication and drug resistance. Consensus-based gene vaccines are specifically fit for variable pathogens such as HIV-1 and have many advantages over viral genes and their expression-optimized variants. With this in mind, we designed the consensus integrase (IN) of the HIV-1 clade A strain predominant in the territory of the former Soviet Union and its inactivated derivative with and without mutations conferring resistance to elvitegravir. Humanized IN gene was synthesized; and inactivated derivatives (with 64D in the active site mutated to V) with and without elvitegravir-resistance mutations were generated by site-mutagenesis. Activity tests of IN variants expressed in E coli showed the consensus IN to be active, while both D64V-variants were devoid of specific activities. IN genes cloned in the DNA-immunization vector pVax1 (pVaxIN plasmids) were highly expressed in human and murine cell lines (>0.7 ng/cell). Injection of BALB/c mice with pVaxIN plasmids followed by electroporation generated potent IFN-gamma and IL-2 responses registered in PBMC by day 15 and in splenocytes by day 23 after immunization. Multiparametric FACS demonstrated that CD8+ and CD4+ T cells of gene-immunized mice stimulated with IN-derived peptides secreted IFN-gamma, IL-2, and TNF-alpha. The multi-cytokine responses of CD8+ and CD4+ T-cells correlated with the loss of in vivo activity of the luciferase reporter gene co-delivered with pVaxIN plasmids. This indicated the capacity of IN-specific CD4+ and CD8+ T cells to clear IN/reporter co-expressing cells from the injection sites. Thus, the synthetic HIV-1 clade A integrase genes acted as potent immunogens generating polyfunctional Th1-type CD4+ and CD8+ T cells. Generation of such response is highly desirable for an effective HIV-1 vaccine as it offers a possibility to attack virus-infected cells via both MHC class I and II pathways. PMID- 23667514 TI - Knockdown of regulator of cullins-1 (ROC1) expression induces bladder cancer cell cycle arrest at the G2 phase and senescence. AB - Regulator of Cullins-1 (ROC1) is a key subunit in the Cullin-RING ligase (CRL) protein complex. Overexpression of ROC1 protein is associated with tumor progression and poor prognosis of non-muscle invasive bladder transitional cell carcinoma (NMIBC). This study was designed to assess the effects of ROC1 knockdown in bladder cancer cells and to determine the potential mechanisms involved. A total of 112 bladder cancer tissue specimens were recruited for immunohistochemical analyses of ROC1 overexpression. Bladder cancer cell lines were used to knockdown ROC1 expression using ROC1 siRNA. Our data showed that ROC1 knockdown remarkably inhibited bladder cancer cell growth, arrested cells at the G2 phase of the cell cycle, and induced the p53-dependent cell senescence. Molecularly, G2 arrest was associated with upregulation of p21, p27, cyclin B1, and Cdc2 proteins. ROC1 knockdown induced-senescence functioned through p53/p21 pathway. Knockdown of p21 expression partially rescued ROC1 knockdown-induced growth inhibition in cancer cells. Furthermore, nude mouse xenograft analyses confirmed these in vitro data. In conclusion, data from the current study indicate that ROC1 plays an essential role in bladder cancer progression and could serve as a novel anticancer target for bladder transitional cell carcinoma (BTCC). PMID- 23667515 TI - Time-resolved FRET -based approach for antibody detection - a new serodiagnostic concept. AB - Forster resonance energy transfer (FRET) is a phenomenon widely utilized in biomedical research of macromolecular interactions. In FRET energy is transferred between two fluorophores, the donor and the acceptor. Herein we describe a novel approach utilizing time-resolved FRET (TR-FRET) for the detection of antibodies not only in a solution-phase homogenous assay but also in single- and two-step solid-phase assays. Our method is based on the principle that the Y-shaped immunoglobulin G molecule is able to simultaneously bind two identical antigen molecules. Hence, if a specific IgG is mixed with donor- and acceptor-labeled antigens, the binding of antigens can be measured by TR-FRET. Using donor- and acceptor-labeled streptavidins (SAs) in conjunction with a polyclonal and a monoclonal anti-SA antibody we demonstrate that this approach is fully functional. In addition we characterize the immune complexes responsible for the TR-FRET signal using density gradient ultracentrifugation and solid-phase immunoassays. The homogenous TR-FRET assay described provides a rapid and robust tool for antibody detection, with a wide potential in medical diagnostics. PMID- 23667516 TI - Plasma concentrations of endocannabinoids and related primary fatty acid amides in patients with post-traumatic stress disorder. AB - BACKGROUND: Endocannabinoids (ECs) and related N-acyl-ethanolamides (NAEs) play important roles in stress response regulation, anxiety and traumatic memories. In view of the evidence that circulating EC levels are elevated under acute mild stressful conditions in humans, we hypothesized that individuals with traumatic stress exposure and post-traumatic stress disorder (PTSD), an anxiety disorder characterized by the inappropriate persistence and uncontrolled retrieval of traumatic memories, show measurable alterations in plasma EC and NAE concentrations. METHODS: We determined plasma concentrations of the ECs anandamide (ANA) and 2-arachidonoylglycerol (2-AG) and the NAEs palmitoylethanolamide (PEA), oleoylethanolamide (OEA), stearoylethanolamine (SEA), and N-oleoyldopamine (OLDA) by HPLC-MS-MS in patients with PTSD (n = 10), trauma-exposed individuals without evidence of PTSD (n = 9) and in healthy control subjects (n = 29). PTSD was diagnosed according to DSM-IV criteria by administering the Clinician Administered PTSD Scale (CAPS), which also assesses traumatic events. RESULTS: Individuals with PTSD showed significantly higher plasma concentrations of ANA (0.48 +/- 0.11 vs. 0.36 +/- 0.14 ng/ml, p = 0.01), 2 AG (8.93 +/- 3.20 vs. 6.26+/-2.10 ng/ml, p<0.01), OEA (5.90 +/- 2.10 vs. 3.88 +/- 1.85 ng/ml, p<0.01), SEA (2.70 +/- 3.37 vs. 0.83 +/- 0.47, ng/ml, p<0.05) and significantly lower plasma levels of OLDA (0.12 +/- 0.05 vs. 0.45 +/- 0.59 ng/ml, p<0.05) than healthy controls. Moreover, PTSD patients had higher 2-AG plasma levels (8.93 +/- 3.20 vs. 6.01 +/- 1.32 ng/ml, p = 0.03) and also higher plasma concentrations of PEA (4.06 +/- 1.87 vs. 2.63+/-1.34 ng/ml, p<0.05) than trauma exposed individuals without evidence of PTSD. CAPS scores in trauma-exposed individuals with and without PTSD (n = 19) correlated positively with PEA (r = 0.55, p = 0.02) and negatively with OLDA plasma levels (r = -0.68, p<0.01). CAPS subscores for intrusions (r = -0.65, p<0.01), avoidance (r = -0.60, p<0.01) and hyperarousal (r = -0.66, p<0.01) were all negatively related to OLDA plasma concentrations. CONCLUSIONS: PTSD appears to be associated with changes in plasma EC/NAE concentrations. This may have pathophysiological and diagnostic consequences but will need to be reproduced in larger cohorts. PMID- 23667517 TI - Ammonium transport proteins with changes in one of the conserved pore histidines have different performance in ammonia and methylamine conduction. AB - Two conserved histidine residues are located near the mid-point of the conduction channel of ammonium transport proteins. The role of these histidines in ammonia and methylamine transport was evaluated by using a combination of in vivo studies, molecular dynamics (MD) simulation, and potential of mean force (PMF) calculations. Our in vivo results showed that a single change of either of the conserved histidines to alanine leads to the failure to transport methylamine but still facilitates good growth on ammonia, whereas double histidine variants completely lose their ability to transport both methylamine and ammonia. Molecular dynamics simulations indicated the molecular basis of the in vivo observations. They clearly showed that a single histidine variant (H168A or H318A) of AmtB confines the rather hydrophobic methylamine more strongly than ammonia around the mutated sites, resulting in dysfunction in conducting the former but not the latter molecule. PMF calculations further revealed that the single histidine variants form a potential energy well of up to 6 kcal/mol for methylamine, impairing conduction of this substrate. Unlike the single histidine variants, the double histidine variant, H168A/H318A, of AmtB was found to lose its unidirectional property of transporting both ammonia and methylamine. This could be attributed to a greatly increased frequency of opening of the entrance gate formed by F215 and F107, in this variant compared to wild-type, with a resultant lowering of the energy barrier for substrate to return to the periplasm. PMID- 23667518 TI - Detection of novel polyomaviruses, TSPyV, HPyV6, HPyV7, HPyV9 and MWPyV in feces, urine, blood, respiratory swabs and cerebrospinal fluid. AB - Eight novel human polyomaviruses have been discovered since 2007. Prevalence rates and tissue tropism for the most recent members HPyV 6, 7, 9, TSPyV and MWPyV are largely unknown. We used real-time PCR to determine the presence of HPyV 6, 7, 9, TSPyV and MWPyV in feces (n = 263), urine (n = 189), blood (n = 161), respiratory swabs (n = 1385) and cerebrospinal fluid (n = 171) from both healthy control children and children and adults undergoing diagnostic testing. Whole genome sequencing was able to be performed on 9 MWPyV positive specimens. Novel polyomaviruses were only detected in respiratory swabs and feces, with no detections of HPyV 9 in any sample type. MWPyV was found to be the most prevalent novel polyomavirus, being detected in 18 (1.5%) respiratory specimens from symptomatic patients, 16 (9.8%) respiratory sample from healthy control children, 11 (5.9%) fecal specimens from patient suffering gastrointestinal illness, and in 13 (15.3%) of feces from healthy control children. MWPyV was found only in respiratory and fecal specimens from children, the oldest being 9 years old. HPyV 6, 7, 9 and TSPyV were also detected in respiratory specimens and fecal specimens at low prevalence (<1.3%). The majority of these detections were found in immunocompromised patients. Our findings suggest that MWPyV can result in a subclinical infection, persistent or intermittent shedding, particularly in young children. The other novel polyomaviruses were also found in respiratory and fecal specimens, but at lower prevalence and most commonly in immunocompromised individuals. PMID- 23667519 TI - Lycopene and beta-carotene induce growth inhibition and proapoptotic effects on ACTH-secreting pituitary adenoma cells. AB - Pituitary adenomas comprise approximately 10-15% of intracranial tumors and result in morbidity associated with altered hormonal patterns, therapy and compression of adjacent sella turcica structures. The use of functional foods containing carotenoids contributes to reduce the risk of chronic diseases such as cancer and vascular disorders. In this study, we evaluated the influence of different concentrations of beta-carotene and lycopene on cell viability, colony formation, cell cycle, apoptosis, hormone secretion, intercellular communication and expression of connexin 43, Skp2 and p27(kip1) in ACTH-secreting pituitary adenoma cells, the AtT20 cells, incubated for 48 and 96 h with these carotenoids. We observed a decrease in cell viability caused by the lycopene and beta-carotene treatments; in these conditions, the clonogenic ability of the cells was also significantly decreased. Cell cycle analysis revealed that beta-carotene induced an increase of the cells in S and G2/M phases; furthermore, lycopene increased the proportion of these cells in G0/G1 while decreasing the S and G2/M phases. Also, carotenoids induced apoptosis after 96 h. Lycopene and beta-carotene decreased the secretion of ACTH in AtT20 cells in a dose-dependent manner. Carotenoids blocked the gap junction intercellular communication. In addition, the treatments increased the expression of phosphorylated connexin43. Finally, we also demonstrate decreased expression of S-phase kinase-associated protein 2 (Skp2) and increased expression of p27(kip1) in carotenoid-treated cells. These results show that lycopene and beta-carotene were able to negatively modulate events related to the malignant phenotype of AtT-20 cells, through a mechanism that could involve changes in the expression of connexin 43, Skp2 and p27(kip1); and suggest that these compounds might provide a novel pharmacological approach to the treatment of Cushing's disease. PMID- 23667520 TI - Interaction of gamma-herpesvirus genome maintenance proteins with cellular chromatin. AB - The capacity of gamma-herpesviruses to establish lifelong infections is dependent on the expression of genome maintenance proteins (GMPs) that tether the viral episomes to cellular chromatin and allow their persistence in latently infected proliferating cells. Here we have characterized the chromatin interaction of GMPs encoded by viruses belonging to the genera Lymphocryptovirus (LCV) and Rhadinovirus (RHV). We found that, in addition to a similar diffuse nuclear localization and comparable detergent resistant interaction with chromatin in transfected cells, all GMPs shared the capacity to promote the decondensation of heterochromatin in the A03-1 reporter cell line. They differed, however, in their mobility measured by fluorescence recovery after photobleaching (FRAP), and in the capacity to recruit accessory molecules required for the chromatin remodeling function. While the AT-hook containing GMPs of LCVs were highly mobile, a great variability was observed among GMPs encoded by RHV, ranging from virtually immobile to significantly reduced mobility compared to LCV GMPs. Only the RHV GMPs recruited the bromo- and extra terminal domain (BET) proteins BRD2 and BRD4 to the site of chromatin remodeling. These findings suggest that differences in the mode of interaction with cellular chromatin may underlie different strategies adopted by these viruses for reprogramming of the host cells during latency. PMID- 23667521 TI - Genetic, physiological, and gene expression analyses reveal that multiple QTL enhance yield of rice mega-variety IR64 under drought. AB - BACKGROUND: Rice (Oryza sativa L.) is a highly drought sensitive crop, and most semi dwarf rice varieties suffer severe yield losses from reproductive stage drought stress. The genetic complexity of drought tolerance has deterred the identification of agronomically relevant quantitative trait loci (QTL) that can be deployed to improve rice yield under drought in rice. Convergent evidence from physiological characterization, genetic mapping, and multi-location field evaluation was used to address this challenge. METHODOLOGY/PRINCIPAL FINDINGS: Two pairs of backcross inbred lines (BILs) from a cross between drought-tolerant donor Aday Sel and high-yielding but drought-susceptible rice variety IR64 were produced. From six BC4F3 mapping populations produced by crossing the +QTL BILs with the -QTL BILs and IR64, four major-effect QTL--one each on chromosomes 2, 4, 9, and 10--were identified. Meta-analysis of transcriptome data from the +QTL/ QTL BILs identified differentially expressed genes (DEGs) significantly associated with QTL on chromosomes 2, 4, 9, and 10. Physiological characterization of BILs showed increased water uptake ability under drought. The enrichment of DEGs associated with root traits points to differential regulation of root development and function as contributing to drought tolerance in these BILs. BC4F3-derived lines with the QTL conferred yield advantages of 528 to 1875 kg ha-1 over IR64 under reproductive-stage drought stress in the targeted ecosystems of South Asia. CONCLUSIONS/SIGNIFICANCE: Given the importance of rice in daily food consumption and the popularity of IR64, the BC4F3 lines with multiple QTL could provide higher livelihood security to farmers in drought-prone environments. Candidate genes were shortlisted for further characterization to confirm their role in drought tolerance. Differential yield advantages of different combinations of the four QTL reported here indicate that future research should include optimizing QTL combinations in different genetic backgrounds to maximize yield advantage under drought. PMID- 23667523 TI - Adenosine monophosphate forms ordered arrays in multilamellar lipid matrices: insights into assembly of nucleic acid for primitive life. AB - A fundamental question of biology is how nucleic acids first assembled and then were incorporated into the earliest forms of cellular life 4 billion years ago. The polymerization of nucleotides is a condensation reaction in which phosphodiester bonds are formed. This reaction cannot occur in aqueous solutions, but guided polymerization in an anhydrous lipid environment could promote a non enzymatic condensation reaction in which oligomers of single stranded nucleic acids are synthesized. We used X-ray scattering to investigate 5'-adenosine monophosphate (AMP) molecules captured in a multilamellar phospholipid matrix composed of dimyristoylphosphatidylcholine. Bragg peaks corresponding to the lateral organization of the confined AMP molecules were observed. Instead of forming a random array, the AMP molecules are highly entangled, with the phosphate and ribose groups in close proximity. This structure may facilitate polymerization of the nucleotides into RNA-like polymers. PMID- 23667522 TI - Cross talk between peritoneal macrophages and B-1 cells in vitro. AB - B-1 cells constitute a distinct B cell population with unique phenotypic and functional characteristics. They represent the main B cell population found in mouse peritoneal and pleural cavities. The communication between B-1 cells and peritoneal macrophages has been previously studied, and the effect this interaction has on macrophages has been previously described. Using an in vitro co-culture model, herein we demonstrated that peritoneal macrophages were able to increase survival rates and to stimulate proliferation of B-1 cells. IL-6 was also found to be important in B-1 cell survival; recombinant IL-6 increases the percentage of viable B-1 cells in culture. Furthermore, molecules involved in the IL-6 signaling pathway, such as STAT-3 and Bcl-2, were highly expressed in B-1 cells after co-culture with peritoneal macrophages. IL-6-deficient peritoneal macrophages were not able to increase B-1 cell survival, confirming the importance of this cytokine. Altogether, our results indicate a novel mechanism in which peritoneal macrophages are able to regulate the B-1 population via IL-6 secretion. PMID- 23667524 TI - Presenilin promotes dietary copper uptake. AB - Dietary copper is essential for multicellular organisms. Copper is redox active and required as a cofactor for enzymes such as the antioxidant Superoxide Dismutase 1 (SOD1). Copper dyshomeostasis has been implicated in Alzheimer's disease. Mutations in the presenilin genes encoding PS1 and PS2 are major causes of early-onset familial Alzheimer's disease. PS1 and PS2 are required for efficient copper uptake in mammalian systems. Here we demonstrate a conserved role for presenilin in dietary copper uptake in the fly Drosophila melanogaster. Ubiquitous RNA interference-mediated knockdown of the single Drosophila presenilin (PSN) gene is lethal. However, PSN knockdown in the midgut produces viable flies. These flies have reduced copper levels and are more tolerant to excess dietary copper. Expression of a copper-responsive EYFP construct was also lower in the midgut of these larvae, indicative of reduced dietary copper uptake. SOD activity was reduced by midgut PSN knockdown, and these flies were sensitive to the superoxide-inducing chemical paraquat. These data support presenilin being needed for dietary copper uptake in the gut and so impacting on SOD activity and tolerance to oxidative stress. These results are consistent with previous studies of mammalian presenilins, supporting a conserved role for these proteins in mediating copper uptake. PMID- 23667525 TI - Immunomodulation and T helper TH1/TH2 response polarization by CeO2 and TiO2 nanoparticles. AB - Immunomodulation by nanoparticles, especially as related to the biochemical properties of these unique materials, has scarcely been explored. In an in vitro model of human immunity, we demonstrate two catalytic nanoparticles, TiO2 (oxidant) and CeO2 (antioxidant), have nearly opposite effects on human dendritic cells and T helper (T(H)) cells. For example, whereas TiO2 nanoparticles potentiated DC maturation that led towards T(H)1-biased responses, treatment with antioxidant CeO2 nanoparticles induced APCs to secrete the anti-inflammatory cytokine, IL-10, and induce a T(H)2-dominated T cell profile. In subsequent studies, we demonstrate these results are likely explained by the disparate capacities of the nanoparticles to modulate ROS, since TiO2, but not CeO2 NPs, induced inflammatory responses through an ROS/inflammasome/IL-1beta pathway. This novel capacity of metallic NPs to regulate innate and adaptive immunity in profoundly different directions via their ability to modulate dendritic cell function has strong implications for human health since unintentional exposure to these materials is common in modern societies. PMID- 23667526 TI - Mithramycin exerts an anti-myeloma effect and displays anti-angiogenic effects through up-regulation of anti-angiogenic factors. AB - Mithramycin (MTM), a cytotoxic compound, is currently being investigated for its anti-angiogenic activity that seems to be mediated through an inhibition of the transcription factor SP1. In this study we evaluated its anti-myeloma effects in the syngenic 5TGM1 model in vitro as well as in vivo. In vitro, MTM inhibited DNA synthesis of 5TGM1 cells with an IC50 of 400 nM and induced an arrest in cell cycle progression at the G1/S transition point. Western-blot revealed an up regulation of p53, p21 and p27 and an inhibition of c-Myc, while SP1 remained unaffected. In rat aortic ring assays, a strong anti-angiogenic effect was seen, which could be explained by a decrease of VEGF production and an up-regulation of anti-angiogenic proteins such as IP10 after MTM treatment. The administration of MTM to mice injected with 5TGM1 decreased 5TGM1 cell invasion into bone marrow and myeloma neovascularisation. These data suggest that MTM displays anti-myeloma and anti-angiogenic effects that are not mediated by an inhibition of SP1 but rather through c-Myc inhibition and p53 activation. PMID- 23667528 TI - Cumulative signal transmission in nonlinear reaction-diffusion networks. AB - Quantifying signal transmission in biochemical systems is key to uncover the mechanisms that cells use to control their responses to environmental stimuli. In this work we use the time-integral of chemical species as a measure of a network's ability to cumulatively transmit signals encoded in spatiotemporal concentrations. We identify a class of nonlinear reaction-diffusion networks in which the time-integrals of some species can be computed analytically. The derived time-integrals do not require knowledge of the solution of the reaction diffusion equation, and we provide a simple graphical test to check if a given network belongs to the proposed class. The formulae for the time-integrals reveal how the kinetic parameters shape signal transmission in a network under spatiotemporal stimuli. We use these to show that a canonical complex-formation mechanism behaves as a spatial low-pass filter, the bandwidth of which is inversely proportional to the diffusion length of the ligand. PMID- 23667527 TI - The sensitivity of diffuse large B-cell lymphoma cell lines to histone deacetylase inhibitor-induced apoptosis is modulated by BCL-2 family protein activity. AB - BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease and this variation can often be used to explain the response of individual patients to chemotherapy. One cancer therapeutic approach currently in clinical trials uses histone deacetylase inhibitors (HDACi's) as monotherapy or in combination with other agents. METHODOLOGY/PRINCIPAL FINDINGS: We have used a variety of cell-based and molecular/biochemical assays to show that two pan-HDAC inhibitors, trichostatin A and vorinostat, induce apoptosis in seven of eight human DLBCL cell lines. Consistent with previous reports implicating the BCL-2 family in regulating HDACi-induced apoptosis, ectopic over-expression of anti apoptotic proteins BCL-2 and BCL-XL or pro-apoptotic protein BIM in these cell lines conferred further resistance or sensitivity, respectively, to HDACi treatment. Additionally, BCL-2 family antgonist ABT-737 increased the sensitivity of several DLBCL cell lines to vorinostat-induced apoptosis, including one cell line (SUDHL6) that is resistant to vorinostat alone. Moreover, two variants of the HDACi-sensitive SUDHL4 cell line that have decreased sensitivity to vorinostat showed up-regulation of BCL-2 family anti-apoptotic proteins such as BCL-XL and MCL-1, as well as decreased sensitivity to ABT-737. These results suggest that the regulation and overall balance of anti- to pro-apoptotic BCL-2 family protein expression is important in defining the sensitivity of DLBCL to HDACi-induced apoptosis. However, the sensitivity of DLBCL cell lines to HDACi treatment does not correlate with expression of any individual BCL-2 family member. CONCLUSIONS/SIGNIFICANCE: These studies indicate that the sensitivity of DLBCL to treatment with HDACi's is dependent on the complex regulation of BCL-2 family members and that BCL-2 antagonists may enhance the response of a subset of DLBCL patients to HDACi treatment. PMID- 23667529 TI - Monitoring of single-cell responses in the optic tectum of adult zebrafish with dextran-coupled calcium dyes delivered via local electroporation. AB - The zebrafish (Danio rerio) has become one of the major animal models for in vivo examination of sensory and neuronal computation. Similar to Xenopus tadpoles neural activity in the optic tectum, the major region controlling visually guided behavior, can be examined in zebrafish larvae by optical imaging. Prerequisites of these approaches are usually the transparency of larvae up to a certain age and the use of two-photon microscopy. This principle of fluorescence excitation was necessary to suppress crosstalk between signals from individual neurons, which is a critical issue when using membrane-permeant dyes. This makes the equipment to study neuronal processing costly and limits the approach to the study of larvae. Thus there is lack of knowledge about the properties of neurons in the optic tectum of adult animals. We established a procedure to circumvent these problems, enabling in vivo calcium imaging in the optic tectum of adult zebrafish. Following local application of dextran-coupled dyes single-neuron activity of adult zebrafish can be monitored with conventional widefield microscopy, because dye labeling remains restricted to tens of neurons or less. Among the neurons characterized with our technique we found neurons that were selective for a certain pattern orientation as well as neurons that responded in a direction-selective way to visual motion. These findings are consistent with previous studies and indicate that the functional integrity of neuronal circuits in the optic tectum of adult zebrafish is preserved with our staining technique. Overall, our protocol for in vivo calcium imaging provides a useful approach to monitor visual responses of individual neurons in the optic tectum of adult zebrafish even when only widefield microscopy is available. This approach will help to obtain valuable insight into the principles of visual computation in adult vertebrates and thus complement previous work on developing visual circuits. PMID- 23667530 TI - Adoptive cellular immunotherapy in metastatic renal cell carcinoma: a systematic review and meta-analysis. AB - PURPOSE: Metastatic renal cell carcinoma (mRCC), as one of the most immunogenic tumors has been the focus of adoptive cellular immunotherapy (ACI), but the effects of ACI on objective response and survival in patients with mRCC are still controversial. Therefore, a systematic review and meta-analysis was performed to address this issue. METHODS: A search was conducted in the PubMed database for randomized clinical trials (RCTs) with ACI in mRCC. All included articles in this study were assessed according to the selection criteria and were divided into two groups: ACI versus no ACI. Outcomes were toxicity, objective response, 1-, 3- and 5-year survival. Risk ratio (RR) and 95% confidence intervals (CI) were calculated using a fixed-effects meta-analysis. Heterogeneity was measured by value of I(2) or P. RESULTS: 4 studies (469 patients) were included. Most of ACI related adverse reactions were grade 1 or 2 and reversible. ACI provided significant benefit in terms of objective response (RR = 1.65; 95% CI, 1.15 to 2.38; P = 0.007, I(2) = 49%), 1-year survival (RR = 1.30; 95% CI, 1.12 to 1.52; P = 0.0008, I(2) = 0%), 3-year survival (RR = 2.76; 95% CI, 1.85 to 4.14; P<0.00001, I(2) = 46%) and 5-year survival (RR = 2.42; 95% CI, 1.21 to 4.83; P = 0.01, I(2) = 28%). CONCLUSIONS: ACI may be a safe and effective treatment for improving objective response, 1-, 3- and 5-year survival in patients with mRCC. Besides, five obstacles for ACI, including high degree of personalization, unsuitable WHO/RECIST response criteria, inadequate identification of tumor associated antigens (TAAs), lack of effective combination treatments and less attention paid to the quality of ACI products, should be overcome during the successful development of more potent ACI for cancer in the future. PMID- 23667531 TI - The SOX2-interactome in brain cancer cells identifies the requirement of MSI2 and USP9X for the growth of brain tumor cells. AB - Medulloblastomas and glioblastomas, the most common primary brain tumors in children and adults, respectively, are extremely difficult to treat. Efforts to identify novel proteins essential for the growth of these tumors may help to further our understanding of the biology of these tumors, as well as, identify targets for future therapies. The recent identification of multiple transcription factor-centric protein interaction landscapes in embryonic stem cells has identified numerous understudied proteins that are essential for the self-renewal of these stem cells. To identify novel proteins essential for the fate of brain tumor cells, we examined the protein interaction network of the transcription factor, SOX2, in medulloblastoma cells. For this purpose, Multidimensional Protein Identification Technology (MudPIT) identified >280 SOX2-associated proteins in the medulloblastoma cell line DAOY. To begin to understand the roles of SOX2-associated proteins in brain cancer, we focused on two SOX2-associated proteins, Musashi 2 (MSI2) and Ubiquitin Specific Protease 9x (USP9X). Recent studies have implicated MSI2, a putative RNA binding protein, and USP9X, a deubiquitinating enzyme, in several cancers, but not brain tumors. We demonstrate that knockdown of MSI2 significantly reduces the growth of DAOY cells as well as U87 and U118 glioblastoma cells. We also demonstrate that the knockdown of USP9X in DAOY, U87 and U118 brain tumor cells strongly reduces their growth. Together, our studies identify a large set of SOX2-associated proteins in DAOY medulloblastoma cells and identify two proteins, MSI2 and USP9X, that warrant further investigation to determine whether they are potential therapeutic targets for brain cancer. PMID- 23667532 TI - Evaluation of treatment thresholds for unconjugated hyperbilirubinemia in preterm infants: effects on serum bilirubin and on hearing loss? AB - BACKGROUND: Severe unconjugated hyperbilirubinemia may cause deafness. In the Netherlands, 25% lower total serum bilirubin (TSB) treatment thresholds were recently implemented for preterm infants. OBJECTIVE: To determine the rate of hearing loss in jaundiced preterms treated at high or at low TSB thresholds. DESIGN/METHODS: In this retrospective study conducted at two neonatal intensive care units in the Netherlands, we included preterms (gestational age <32 weeks) treated for unconjugated hyperbilirubinemia at high or low TSB thresholds. Infants with major congenital malformations, syndromes, chromosomal abnormalities or toxoplasmosis, rubella, cytomegalovirus, herpes, syphilis, and human immunodeficiency infections were excluded. We analyzed clinical characteristics and TSB levels during the first ten postnatal days. After two failed automated Auditory Brainstem Response (ABR) tests we used the results of the diagnostic ABR examination to define normal, unilateral, and bilateral hearing loss (>35 dB). RESULTS: There were 479 patients in the high and 144 in the low threshold group. Both groups had similar gestational ages (29.5 weeks) and birth weights (1300 g). Mean and mean peak TSB levels were significantly lower after the implementation of the novel thresholds: 152 +/- 43 umol/L and 212 +/- 52 umol/L versus 131 +/- 37 umol/L and 188 +/- 46 umol/L for the high versus low thresholds, respectively (P<0.001). The incidence of hearing loss was 2.7% (13/479) in the high and 0.7% (1/144) in the low TSB threshold group (NNT = 50, 95% CI, 25-3302). CONCLUSIONS: Implementation of lower treatment thresholds resulted in reduced mean and peak TSB levels. The incidence of hearing impairment in preterms with a gestational age <32 weeks treated at low TSB thresholds was substantially lower compared to preterms treated at high TSB thresholds. Further research with larger sample sizes and power is needed to determine if this effect is statistically significant. PMID- 23667533 TI - A novel approach of preventing Japanese cedar pollen dispersal that is the cause of Japanese cedar pollinosis (JCP) using pollen-specific fungal infection. AB - In Japan, Japanese cedar pollen dispersal is one of the major causes of pollinosis. Sydowia japonica is an ascomycetous fungus that grows exclusively on the male strobili of Japanese cedar, suggesting a possible mechanism for controlling pollen dispersal. To evaluate this possibility, eleven isolates of S. japonica were collected from around Japan and used as an inoculum to male strobili of Japanese cedar. The treatment demonstrated that the fungus infected only the pollen and prevented pollen dispersal. The fungus did not cause any additional symptoms to other parts of Japanese cedar, such as needles, stems, and buds. All S. japonica isolates collected around Japan could serve to control pollen dispersal. Periodic observation of the fungal pathogenesis with stereomicroscope and scanning electron microscope showed that hyphal fragments and conidia of S. japonica germinated on the surface of male strobili, and the germ tube entered pollen sacs through opening microsporophylls. Within the pollen sacs, the hyphae penetrated pollen gradually, such that all pollen was infected by the fungus by approximately one month before the pollen dispersal season. The infected pollen was destroyed due to the fungal infection and was never released. Our data suggests a novel approach of preventing pollen dispersal using pollen specific fungal infection. PMID- 23667534 TI - Spatial transmission of Swine Vesicular Disease virus in the 2006-2007 epidemic in Lombardy. AB - In 2006 and 2007 pig farming in the region of Lombardy, in the north of Italy, was struck by an epidemic of Swine Vesicular Disease virus (SVDV). In fact this epidemic could be viewed as consisting of two sub-epidemics, as the reported outbreaks occurred in two separate time periods. These periods differed in terms of the provinces or municipalities that were affected and also in terms of the timing of implementation of movement restrictions. Here we use a simple mathematical model to analyse the epidemic data, quantifying between-farm transmission probability as a function of between-farm distance. The results show that the distance dependence of between-farm transmission differs between the two periods. In the first period transmission over relatively long distances occurred with higher probability than in the second period, reflecting the effect of movement restrictions in the second period. In the second period however, more intensive transmission occurred over relatively short distances. Our model analysis explains this in terms of the relatively high density of pig farms in the area most affected in this period, which exceeds a critical farm density for between-farm transmission. This latter result supports the rationale for the additional control measure taken in 2007 of pre-emptively culling farms in that area. PMID- 23667535 TI - LIN9, a subunit of the DREAM complex, regulates mitotic gene expression and proliferation of embryonic stem cells. AB - The DREAM complex plays an important role in regulation of gene expression during the cell cycle. We have previously shown that the DREAM subunit LIN9 is required for early embryonic development and for the maintenance of the inner cell mass in vitro. In this study we examined the effect of knocking down LIN9 on ESCs. We demonstrate that depletion of LIN9 alters the cell cycle distribution of ESCs and results in an accumulation of cells in G2 and M and in an increase of polyploid cells. Genome-wide expression studies showed that the depletion of LIN9 results in downregulation of mitotic genes and in upregulation of differentiation specific genes. ChIP-on chip experiments showed that mitotic genes are direct targets of LIN9 while lineage specific markers are regulated indirectly. Importantly, depletion of LIN9 does not alter the expression of pluripotency markers SOX2, OCT4 and Nanog and LIN9 depleted ESCs retain alkaline phosphatase activity. We conclude that LIN9 is essential for proliferation and genome stability of ESCs by activating genes with important functions in mitosis and cytokinesis. PMID- 23667536 TI - IL-21 is required for optimal antibody production and T cell responses during chronic Toxoplasma gondii infection. AB - Previous studies have indicated that Il21r (-/-) mice chronically infected with Toxoplasma gondii display a defect in serum IgG; however, the basis for this antibody defect was not defined and questions remain about the role of IL-21 in promoting the production of IL-10, which is required to limit infection-induced pathology during toxoplasmosis. Therefore, Il21 (-/-) mice were challenged with T. gondii to determine whether IL-21 impacts the parasite-specific CD8(+) T cell response, its contribution to thymus-dependent antibody production after infection, and balance between protective and pathogenic responses. Whereas IL-21 has been implicated in the differentiation of IL-10 producing CD4(+) T cells no immune-mediated pathology was evident in Il21 (-/-) mice during the acute response, nor was there a defect in the development of this population in chronically infected Il21 (-/-) mice. However, Il21 (-/-) mice displayed a defect in IgG production after infection that correlated with a decrease in GC B cell numbers, the CD4(+) and CD8(+) T cell numbers in the brain were reduced over the course of the chronic infection leading to a decrease in total IFN-gamma production and an increase in parasite numbers associated with susceptibility to toxoplasmic encephalitis. Together, these results identify a key role for IL-21 in shaping the humoral and cellular response to T. gondii, but indicate that IL 21 has a limited role in regulating immunopathology. PMID- 23667537 TI - The impact of paralogy on phylogenomic studies - a case study on annelid relationships. AB - Phylogenomic studies based on hundreds of genes derived from expressed sequence tags libraries are increasingly used to reveal the phylogeny of taxa. A prerequisite for these studies is the assignment of genes into clusters of orthologous sequences. Sophisticated methods of orthology prediction are used in such analyses, but it is rarely assessed whether paralogous sequences have been erroneously grouped together as orthologous sequences after the prediction, and whether this had an impact on the phylogenetic reconstruction using a super matrix approach. Herein, I tested the impact of paralogous sequences on the reconstruction of annelid relationships based on phylogenomic datasets. Using single-partition analyses, screening for bootstrap support, blast searches and pruning of sequences in the supermatrix, wrongly assigned paralogous sequences were found in eight partitions and the placement of five taxa (the annelids Owenia, Scoloplos, Sthenelais and Eurythoe and the nemertean Cerebratulus) including the robust bootstrap support could be attributed to the presence of paralogous sequences in two partitions. Excluding these sequences resulted in a different, weaker supported placement for these taxa. Moreover, the analyses revealed that paralogous sequences impacted the reconstruction when only a single taxon represented a previously supported higher taxon such as a polychaete family. One possibility of a priori detection of wrongly assigned paralogous sequences could combine 1) a screening of single-partition analyses based on criteria such as nodal support or internal branch length with 2) blast searches of suspicious cases as presented herein. Also possible are a posteriori approaches in which support for specific clades is investigated by comparing alternative hypotheses based on differences in per-site likelihoods. Increasing the sizes of EST libraries will also decrease the likelihood of wrongly assigned paralogous sequences, and in the case of orthology prediction methods like HaMStR it is likewise decreased by using more than one reference taxon. PMID- 23667538 TI - Control of temperature on microbial community structure in hot springs of the Tibetan Plateau. AB - The Tibetan Plateau in Northwest China hosts a number of hot springs that represent a biodiversity hotspot for thermophiles, yet their diversity and relationship to environmental conditions are poorly explored in these habitats. In this study we investigated microbial diversity and community composition in 13 Tibetan hot springs with a wide range of temperatures (22.1-75 degrees C) and other geochemical conditions by using the 16S rRNA gene pyrosequencing approach. Bacteria (10(8)-10(11) copy/g; 42 bacterial phyla) in Tibetan hot springs were more abundant and far more diverse than Archaea (10(7)-10(10) copy/g; 5 archaeal phyla). The dominant bacterial phyla systematically varied with temperature. Moderate temperatures (75-66 degrees C) favored Aquificae, GAL35, and novel Bacteria, whereas low temperatures (60-22.1 degrees C) selected for Deinococcus Thermus, Cyanobacteria, and Chloroflexi. The relative abundance of Aquificae was correlated positively with temperature, but the abundances of Deinococcus Thermus, Cyanobacteria, and Chloroflexi were negatively correlated with temperature. Cyanobacteria and Chloroflexi were abundant in Tibetan hot springs and their abundances were positively correlated at low temperatures (55-43 degrees C) but negatively correlated at moderate temperatures (75-55 degrees C). These correlation patterns suggest a complex physiological relationship between these two phyla. Most archaeal sequences were related to Crenarchaeota with only a few related to Euryarchaeota and Thaumarchaeota. Despite the fact that microbial composition in Tibetan hot springs was strongly shaped by temperature, microbial diversity (richness, evenness and Shannon diversity) was not significantly correlated with temperature change. The results of this study expand our current understanding of microbial ecology in Tibetan hot springs and provide a basis for a global comparison. PMID- 23667539 TI - Preparation of organic light-emitting diode using coal tar pitch, a low-cost material, for printable devices. AB - We have identified coal tar pitch, a very cheap organic material made from coal during the iron-making process, as a source from which could be obtained emissive molecules for organic light-emitting diodes. Coal tar pitch was separated by simple dissolution in organic solvent, and subsequent separation by preparative thin-layer chromatography was used to obtain emissive organic molecules. The retardation factor of preparative thin-layer chromatography played a major role in deciding the emission characteristics of the solution as photoluminescence spectra and emission-excitation matrix spectra could be controlled by modifying the solution preparation method. In addition, the device characteristics could be improved by modifying the solution preparation method. Two rounds of preparative thin-layer chromatography separation could improve the luminance of organic light emitting diodes with coal tar pitch, indicating that less polar components are favorable for enhancing the luminance and device performance. By appropriate choice of the solvent, the photoluminescence peak wavelength of separated coal tar pitch could be shifted from 429 nm (cyclohexane) to 550 nm (chloroform), and consequently, the optical properties of the coal tar pitch solution could be easily tuned. Hence, the use of such multicomponent materials is advantageous for fine-tuning the net properties at a low cost. Furthermore, an indium tin oxide/poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate)/coal tar pitch/LiF/Al system, in which the emissive layer was formed by spin-coating a tetrahydrofuran solution of coal tar pitch on the substrate, showed a luminance of 176 cd/m(2). In addition, the emission spectrum of coal tar pitch was narrowed after the preparative thin-layer chromatography process by removing the excess emissive molecules. PMID- 23667540 TI - N,N'-dinitrosopiperazine--mediated heat-shock protein 70-2 expression is involved in metastasis of nasopharyngeal carcinoma. AB - N,N'-Dinitrosopiperazine (DNP) is invovled in nasopharyngeal carcinoma (NPC) development and metastasis, and it shows organ specificity to the nasopharyngeal epithelium. Herein, we demonstrate that DNP induces heat-shock protein (HSP) 70-2 expression in NPC cells (6-10B) at a non-cytotoxic concentration. DNP induced HSP70-2 expression in a dose- and time- dependent manner, but showed no effect on other HSP70 family members. Furthermore, DNP also increased HSP70-2 RNA transcription through directly binding to the hypoxia-responsive elements (HRE) and heat shock elements (HSE) located in the HSP70-2 promoter. DNP-mediated HSP70 2 expression might act through enhancing the transcription of HSP70-2 RNA. Importantly, DNP induced motility and invasion of 6-10B cells dose- and time dependently, and DNP-mediated NPC metastasis was confirmed in nude mice, which showed high HSP70-2 expression in the metastatic tumor tissue. However, the motility and invasion of NPC cells that were stably transfected using short interfering RNA against HSP70-2 could not effectively induce DNP. These results indicate that DNP induces HSP70-2 expression through increasing HSP70-2 transcription, increases the motility and invasion of cells, and promotes NPC tumor metastasis. Therefore, DNP mediated HSP70-2 expression may be an important factor of NPC-high metastasis. PMID- 23667541 TI - Assessing cue-induced brain response as a function of abstinence duration in heroin-dependent individuals: an event-related fMRI study. AB - The brain activity induced by heroin-related cues may play a role in the maintenance of heroin dependence. Whether the reinforcement or processing biases construct an everlasting feature of heroin addiction remains to be resolved. We used an event-related fMRI paradigm to measure brain activation in response to heroin cue-related pictures versus neutral pictures as the control condition in heroin-dependent patients undergoing short-term and long-term abstinence. The self-reported craving scores were significantly increased after cue exposure in the short-term abstinent patients (t = 3.000, P = 0.008), but no increase was found in the long-term abstinent patients (t = 1.510, P = 0.149). However, no significant differences in cue-induced craving changes were found between the two groups (t = 1.193, P = 0.850). Comparing between the long-term abstinence and short-term abstinence groups, significant decreases in brain activation were detected in the bilateral anterior cingulated cortex, left medial prefrontal cortex, caudate, middle occipital gyrus, inferior parietal lobule and right precuneus. Among all of the heroin dependent patients, the abstinence duration was negatively correlated with brain activation in the left medial prefrontal cortex and left inferior parietal lobule. These findings suggest that long-term abstinence may be useful for heroin-dependent patients to diminish their saliency value of heroin-related cues and possibly lower the relapse vulnerability to some extent. PMID- 23667542 TI - The overnight effect of dietary energy balance on postprandial plasma free amino acid (PFAA) profiles in Japanese adult men. AB - The plasma free amino acid (PFAA) profile is affected by various nutritional conditions, such as the dietary energy balance. Regarding the clinical use of PFAA profiling, it is of concern that differences in food ingestion patterns may generate systematic errors in a plasma amino acid profile and constitute a confounding factor in assessment. In this study, the overnight impact of the dietary energy balance on the postprandial plasma amino acid profile was investigated to elucidate in particular the effects of high protein meals typical in Japanese cuisine. We conducted diet-controlled, crossover trials in eleven healthy male volunteers aged 40-61 y. They consumed either a normal meal (meal N) or high protein meal (meal H) at dinner. Forearm venous blood was collected, and plasma amino acid concentrations were measured before dinner and the next morning. We found that a high protein meal in the evening that contained 40% energy would significantly increase the PFAA concentration the next morning, even more than 12 hours after the meal. Among amino acids, the most significant difference was observed in the branched-chain amino acids (BCAAs) and in some urea-cycle related compounds. If the subject consumed the high protein diet at dinner, the PFAA profile after overnight fasting might be still affected by the meal even 12 hours after the meal, suggesting that the PFAA profile does not reflect the subject's health condition, but rather the acute effect of high protein ingestion. PMID- 23667543 TI - Selective role of mevalonate pathway in regulating perforin but not FasL and TNFalpha release in human Natural Killer cells. AB - We have analyzed the effects of fluvastatin, an inhibitor of the enzyme 3-hydroxy 3-methylglutaryl-coenzyme A (HMG-CoA) reductase involved in mevalonate synthesis, on human NK cell-mediated anti-tumor cytolysis. Fluvastatin inhibited the activation of the small guanosin triphosphate binding protein (GTP) RhoA and the consequent actin redistribution induced by ligation of LFA1 involved in NK-tumor target cell adhesion. Also, fluvastatin reduced ganglioside M1 rafts formation triggered through the engagement of NK cell activating receptors as FcgammaRIIIA (CD16), NKG2D and DNAM1. Cytolysis of tumor targets was inhibited up to 90% when NK cells were cultured with fluvastatin by affecting i) receptor-mediated increase of the intracellular free calcium concentration, ii) activation of akt1/PKB and iii) perforin and granzyme release. Fluvastatin displayed a stronger inhibiting effect on NKG2D, DNAM1, 2B4, NKp30, NKp44 and NKp46 than on CD16 mediated NK cell triggering. This was in line with the impairment of surface expression of all these receptors but not of CD16. Remarkably, fluvastatin did not affect the expression of the inhibiting receptors CD94, KIR2D and LAIR1. FasL release elicited by either NK-tumor cell interaction or CD16 or NKG2D engagement, as well as FasL-mediated killing, were not sensitive to fluvastatin. Moreover, TNFalpha secretion triggered in NK cells upon incubation with tumor target cells or engagement of NKG2D receptor was not impaired in fluvastatin-treated NK cells. Likewise, antibody dependent cellular cytotoxicity (ADCC) triggered through FcgammaRIIIA engagement with the humanized monoclonal antibody rituximab or trastuzumab was only marginally affected in fluvastatin-treated NK cells. Altogether these findings suggest that interference with mevalonate synthesis impairs activation and assembly of cytoskeleton, degranulation and cytotoxic effect of perforins and granzyme but not FasL- and TNFalpha-mediated cytotoxicity. PMID- 23667544 TI - BSP gene silencing inhibits migration, invasion, and bone metastasis of MDA-MB 231BO human breast cancer cells. AB - Bone sialoprotein (BSP) has been implicated in a variety of physiological and pathophysiological events, including tumor cell invasion, bone homing, adhesion, and matrix degradation. To explore the potential involvement of BSP in human breast cancer cell invasion and metastasis, we used retrovirus-mediated RNAi to deplete BSP levels in the human bone-seeking breast cancer cell line MDA-MB-231BO (231BO) and established the 231BO-BSP27 and 231BO-BSP81 cell clones. Cell proliferation, colony formation, wound healing, and the ability to invade into matrigel of these BSP-depleted clones were all decreased. Both 231BO-BSP27 cells and 231BO-BSP81 cells showed a significant (15.4% and 28.6% respectively) reduction of bone metastatic potential following intracardiac injection as determined by X-ray detection and by hematoxylin and eosin staining. Moreover, the expression of integrins alphavbeta3 and beta3 was decreased in the BSP silenced cells whereas ectopic BSP expression increased the integrins alphavbeta3 and beta3 levels. These results together suggest that BSP silencing decreased the integrin alphavbeta3 and beta3 levels, in turn inhibiting cell migration and invasion and decreasing the ability of the cells to metastasize to bone. PMID- 23667545 TI - Immunophenotyping of inflammatory cells associated with Schmallenberg virus infection of the central nervous system of ruminants. AB - Schmallenberg virus (SBV) is a recently discovered Bunyavirus associated mainly with abortions, stillbirths and malformations of the skeletal and central nervous system (CNS) in newborn ruminants. In this study, a detailed immunophenotyping of the inflammatory cells of the CNS of affected animals was carried out in order to increase our understanding of SBV pathogenesis. A total of 82 SBV-polymerase chain reaction (PCR) positive neonatal ruminants (46 sheep lambs, 34 calves and 2 goat kids) were investigated for the presence of inflammation in the brain and spinal cord. The study focused on 15 out of 82 animals (18.3%) showing inflammation in the CNS. All 15 neonates displayed lymphohistiocytic meningoencephalomyelitis affecting most frequently the mesencephalon and the parietal and temporal lobes. The majority of infiltrating cells were CD3-positive T cells, followed by CD79alpha-positive B cells and CD68-positive microglia/macrophages. Malformations like por- and hydranencephaly, frequently found in the temporal lobe, showed associated demyelination and axonal loss. SBV antigen was detected in 37 out of 82 (45.1%) neonatal brains by immunohistochemistry. In particular, SBV antigen was found in 93.3% (14 out of 15 ruminants) and 32.8% (22 out of 67 ruminants) of animals with and without encephalitis, respectively. Highest amounts of virus-protein expression levels were found in the temporal lobe. Our findings suggest that: (i) different brain regions display differential susceptibility to SBV infection; (ii) inflammatory cells in the CNS are found only in a minority of virus infected animals; (iii) malformations occur in association with and without inflammation in the CNS; and (iv) viral antigen is strongly associated with the presence of inflammation in naturally infected animals. Further studies are required to explore the cell tropism and pathogenesis of SBV infection in ruminants. PMID- 23667546 TI - Enhanced accumulation of copper and lead in amaranth (Amaranthus paniculatus), Indian mustard (Brassica juncea) and sunflower (Helianthus annuus). AB - BACKGROUND: Soil contamination by copper (Cu) and lead (Pb) is a widespread environmental problem. For phytoextraction to be successful and viable in environmental remediation, strategies that can improve plant uptake must be identified. In the present study we investigated the use of nitrogen (N) fertilizer as an efficient way to enhance accumulation of Cu and Pb from contaminated industrial soils into amaranth, Indian mustard and sunflower. METHODS/PRINCIPAL FINDINGS: Plants were grown in a greenhouse and fertilized with N fertilizer at rates of 0, 190 and 380 mg kg-1 soil. Shoots, roots and total accumulation of Cu and Pb, transfer factor (TF), translocation index were assessed to evaluate the transport and translocation ability of tested plants. Addition of N fertilizer acidified the industrial soil and caused the pH to decrease to 5.5 from an initial pH of 6.9. Industrial soil amended with N fertilizer resulted in the highest accumulation of Pb and Cu (for Pb 10.1-15.5 mg kg-1, for Cu 11.6-16.8 mg kg-1) in the shoots, which was two to four folds higher relative to the concentration in roots in all the three plants used. Sunflower removed significantly higher Pb (50-54%) and Cu (34-38%) followed by amaranth and Indian mustard from industrial soils with the application of N fertilizer. The TF was <1 while the shoot and root concentration (SC/RC) ratios of Pb and Cu were between 1.3-4.3 and 1.8-3.8, respectively, regardless of plant species. CONCLUSIONS: Sunflower is the best plant species to carry out phytoextraction of Pb and Cu. In contrast, Pb and Cu removal by Indian mustard and amaranth shows great potential as quick and short duration vegetable crops. The results suggest that the application of N fertilizer in contaminated industrial soil is an effective amendment for the phytoextraction of Pb and Cu from contaminated industrial soils. PMID- 23667547 TI - The bacterial pathogen Xylella fastidiosa affects the leaf ionome of plant hosts during infection. AB - Xylella fastidiosa is a plant pathogenic bacterium that lives inside the host xylem vessels, where it forms biofilm believed to be responsible for disrupting the passage of water and nutrients. Here, Nicotiana tabacum was infected with X. fastidiosa, and the spatial and temporal changes in the whole-leaf ionome (i.e. the mineral and trace element composition) were measured as the host plant transitioned from healthy to diseased physiological status. The elemental composition of leaves was used as an indicator of the physiological changes in the host at a specific time and relative position during plant development. Bacterial infection was found to cause significant increases in concentrations of calcium prior to the appearance of symptoms and decreases in concentrations of phosphorous after symptoms appeared. Field-collected leaves from multiple varieties of grape, blueberry, and pecan plants grown in different locations over a four-year period in the Southeastern US showed the same alterations in Ca and P. This descriptive ionomics approach characterizes the existence of a mineral element-based response to X. fastidiosa using a model system suitable for further manipulation to uncover additional details of the role of mineral elements during plant-pathogen interactions. This is the first report on the dynamics of changes in the ionome of the host plant throughout the process of infection by a pathogen. PMID- 23667548 TI - Highly efficient NMR assignment of intrinsically disordered proteins: application to B- and T cell receptor domains. AB - We present an integrated approach for efficient characterization of intrinsically disordered proteins. Batch cell-free expression, fast data acquisition, automated analysis, and statistical validation with data resampling have been combined for achieving cost-effective protein expression, and rapid automated backbone assignment. The new methodology is applied for characterization of five cytosolic domains from T- and B-cell receptors in solution. PMID- 23667549 TI - Stem cells derived from neonatal mouse kidney generate functional proximal tubule like cells and integrate into developing nephrons in vitro. AB - We have recently shown that kidney-derived stem cells (KSCs) isolated from the mouse newborn kidney differentiate into a range of kidney-specific cell types. However, the functionality and integration capacity of these mouse KSCs remain unknown. Therefore, the main objectives of this study were (1) to determine if proximal tubule-like cells, generated in vitro from KSCs, displayed absorptive function typical of proximal tubule cells in vivo, and (2) to establish whether the ability of KSCs to integrate into developing nephrons was comparable with that of metanephric mesenchyme (MM), a transient population of progenitor cells that gives rise to the nephrons during kidney organogenesis. We found that proximal tubule-like cells generated in vitro from mouse KSCs displayed megalin dependent absorptive function. Subsequently, we used a chimeric kidney rudiment culture system to show that the KSCs could generate proximal tubule cells and podocytes that were appropriately located within the developing nephrons. Finally, we compared the ability of KSCs to integrate into developing kidneys ex vivo with that of metanephric mesenchyme cells. We found that KSCs integrated into nascent nephrons to a similar extent as metanephric mesenchyme cells while both were excluded from ureteric bud branches. Our analysis of the behavior of the two cell types shows that some, but not all KSC characteristics are similar to those of the MM. PMID- 23667550 TI - Drug resistant clinical isolates of Mycobacterium tuberculosis from different genotypes exhibit differential host responses in THP-1 cells. AB - Mycobacterium tuberculosis (MTB) persistently infects and survives within the host macrophages. Substantial genotypic variation exists among MTB strains which correlate with their interactions with the host. The present study was designed to establish a correlation, if any, between infection and induction of innate immune response by genetically diverse drug resistant MTB isolates from India. For this purpose, three clinical isolates from ancient and modern lineages, along with H37Ra and H37Rv were evaluated for intracellular growth, phagocytic index, induction of proinflammatory cytokines and apoptosis following infection in THP-1 cell line. A wide variation in the induction of cytokines was revealed subsequent to infection with different strains. EAI-5 strain from ancient lineage 1, induced higher proinflammatory responses, higher apoptosis and moderate intracellular growth compared to other strains, in contrast, for Beijing strain of modern lineage 2, all three parameters were lowest among the clinical isolates. Further, the responses induced by LAM-6 from modern lineage 4 were at a moderate level, similar to the laboratory strain H37Rv which also belongs to lineage 4. Thus, these profiles were specific to their respective lineages and/or genotypes and independent of their drug resistance status. Further, a positive correlation, among TNF-alpha, IL-1beta, IL-6 and IL-12 induced in infected THP-1 cells was demonstrated. In addition, induction of all pro-inflammatory cytokines correlated well with the host cell apoptosis. A positive correlation was observed between phagocytic index in the category of '>10 bacilli/cell' and induction of apoptosis, only for virulent strains, indicating that initial accumulation of MTB strains inside the host cell may be an important determining factor for different innate responses. PMID- 23667552 TI - Network-based segmentation of biological multivariate time series. AB - Molecular phenotyping technologies (e.g., transcriptomics, proteomics, and metabolomics) offer the possibility to simultaneously obtain multivariate time series (MTS) data from different levels of information processing and metabolic conversions in biological systems. As a result, MTS data capture the dynamics of biochemical processes and components whose couplings may involve different scales and exhibit temporal changes. Therefore, it is important to develop methods for determining the time segments in MTS data, which may correspond to critical biochemical events reflected in the coupling of the system's components. Here we provide a novel network-based formalization of the MTS segmentation problem based on temporal dependencies and the covariance structure of the data. We demonstrate that the problem of partitioning MTS data into [Formula: see text] segments to maximize a distance function, operating on polynomially computable network properties, often used in analysis of biological network, can be efficiently solved. To enable biological interpretation, we also propose a breakpoint-penalty (BP-penalty) formulation for determining MTS segmentation which combines a distance function with the number/length of segments. Our empirical analyses of synthetic benchmark data as well as time-resolved transcriptomics data from the metabolic and cell cycles of Saccharomyces cerevisiae demonstrate that the proposed method accurately infers the phases in the temporal compartmentalization of biological processes. In addition, through comparison on the same data sets, we show that the results from the proposed formalization of the MTS segmentation problem match biological knowledge and provide more rigorous statistical support in comparison to the contending state-of-the-art methods. PMID- 23667551 TI - Early onset pre-eclampsia is associated with altered DNA methylation of cortisol signalling and steroidogenic genes in the placenta. AB - Placental cortisol is inactivated in normotensive pregnancies, but is frequently present in pre-eclampsia associated placentae. Since glucocorticoids are strongly associated with the programming of long-term health, we assessed DNA methylation of genes involved in cortisol signalling and bioavailability, and hormonal signalling in the placenta of normotensive and hypertensive pregnancies. Candidate genes/CpG sites were selected through analysis of Illumina Infinium HumanMethylation450 BeadChip array data on control (n = 19) and early onset pre eclampsia (EOPET; n = 19) placental samples. DNA methylation was further quantified by bisulfite pyrosequencing in a larger cohort of control (n = 111) cases, in addition to EOPET (n = 19), late onset pre-eclampsia (LOPET; n = 18) and normotensive intrauterine growth restriction (nIUGR; n = 13) cases. DNA methylation (percentage points) was increased at CpG sites within genes encoding the glucocorticoid receptor (NR3C1 exon 1D promoter; +8.46%; P<0.01) and corticotropin releasing hormone (CRH) binding protein (CRHBP intron 3; +9.14%; P<0.05), and decreased within CRH (5' UTR; -4.30%; P = 0.11) in EOPET-associated placentae, but not in LOPET nor nIUGR cases, compared to controls. Differential DNA methylation was not observed among groups at the 11beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) gene promoter. Significant hypomethylation was observed in pre-eclampsia but not nIUGR placentae for steroidogenic genes, including CYP11A1 (exon1; EOPET; -9.66%; P<0.00001, and LOPET; -5.77%; P<0.001), 3beta-hydroxy-delta-5-steroid dehydrogenase type 1 (HSD3B1 exon 2; EOPET; 12.49%; P<0.00001, and LOPET; -6.88%; P<0.001), TEA domain family member 3 (TEAD3 intron 1; EOPET; -12.56%; P<0.00001) and CYP19 (placental-specific exon 1.1 promoter; EOPET; -10.62%, P<0.0001). These data represent dysregulation of the placental epigenome in pre-eclampsia related to genes involved in maintaining the hormonal environment during pregnancy and highlights particular susceptibility in the early onset syndrome. PMID- 23667553 TI - A semi-supervised method for drug-target interaction prediction with consistency in networks. AB - Computational prediction of interactions between drugs and their target proteins is of great importance for drug discovery and design. The difficulties of developing computational methods for the prediction of such potential interactions lie in the rarity of known drug-protein interactions and no experimentally verified negative drug-target interaction sample. Furthermore, target proteins need also to be predicted for some new drugs without any known target interaction information. In this paper, a semi-supervised learning method NetCBP is presented to address this problem by using labeled and unlabeled interaction information. Assuming coherent interactions between the drugs ranked by their relevance to a query drug, and the target proteins ranked by their relevance to the hidden target proteins of the query drug, we formulate a learning framework maximizing the rank coherence with respect to the known drug target interactions. When applied to four classes of important drug-target interaction networks, our method improves previous methods in terms of cross validation and some strongly predicted interactions are confirmed by the publicly accessible drug target databases, which indicates the usefulness of our method. Finally, a comprehensive prediction of drug-target interactions enables us to suggest many new potential drug-target interactions for further studies. PMID- 23667554 TI - An analysis of the benefit of using HEV genotype 3 antigens in detecting anti-HEV IgG in a European population. AB - BACKGROUND: The benefit of using serological assays based on HEV genotype 3 in industrialised settings is unclear. We compared the performance of serological kits based on antigens from different HEV genotypes. METHODS: Taking 20 serum samples from patients in southwest France with acute HEV infection (positive PCR for HEV genotype 3) and 550 anonymised samples from blood donors in southwest Switzerland, we tested for anti-HEV IgG using three enzyme immunoassays (EIAs) (MP Diagnostics, Dia.Pro and Fortress) based on genotype 1 and 2 antigens, and one immunodot assay (Mikrogen Diagnostik recomLine HEV IgG/IgM) based on genotype 1 and 3 antigens. RESULTS: All acute HEV samples and 124/550 blood donor samples were positive with >=1 assay. Of PCR-confirmed patient samples, 45%, 65%, 95% and 55% were positive with MP Diagnostics, Dia.Pro, Fortress and recomLine, respectively. Of blood donor samples positive with >=1 assay, 120/124 (97%), were positive with Fortress, 19/124 (15%) were positive with all EIAs and 51/124 (41%) were positive with recomLine. Of 11/20 patient samples positive with recomLine, stronger reactivity for HEV genotype 3 was observed in 1/11(9%), and equal reactivity for both genotypes in 5/11 (45.5%). CONCLUSIONS: Although recomLine contains HEV genotype 3, it has lower sensitivity than Fortress in acute HEV infection and fails to identify infection as being due to this genotype in approximately 45% of patients. In our single blood donor population, we observe wide variations in measured seroprevalence, from 4.2% to 21.8%, depending on the assay used. PMID- 23667555 TI - Solution structure and Rpn1 interaction of the UBL domain of human RNA polymerase II C-terminal domain phosphatase. AB - The ubiquitin-like modifier (UBL) domain of ubiquitin-like domain proteins (UDPs) interacts specifically with subunits of the 26 S proteasome. A novel UDP, ubiquitin-like domain-containing C-terminal domain phosphatase (UBLCP1), has been identified as an interacting partner of the 26 S proteasome. We determined the high-resolution solution structure of the UBL domain of human UBLCP1 by nuclear magnetic resonance spectroscopy. The UBL domain of hUBLCP1 has a unique beta strand (beta3) and beta3-alpha2 loop, instead of the canonical beta4 observed in other UBL domains. The molecular topology and secondary structures are different from those of known UBL domains including that of fly UBLCP1. Data from backbone dynamics shows that the beta3-alpha2 loop is relatively rigid although it might have intrinsic dynamic profile. The positively charged residues of the beta3 alpha2 loop are involved in interacting with the C-terminal leucine-rich repeat like domain of Rpn1. PMID- 23667556 TI - Testing insecticidal activity of novel chemically synthesized siRNA against Plutella xylostella under laboratory and field conditions. AB - BACKGROUND: Over the last 60 years, synthetic chemical pesticides have served as a main tactic in the field of crop protection, but their availability is now declining as a result of the development of insect resistance. Therefore, alternative pest management agents are needed. However, the demonstration of RNAi gene silencing in insects and its successful usage in disrupting the expression of vital genes opened a door to the development of a variety of novel, environmentally sound approaches for insect pest management. METHODOLOGY/PRINCIPAL FINDINGS: Six small interfering RNAs (siRNAs) were chemically synthesized and modified according to the cDNA sequence of P. xylostella acetylcholine esterase genes AChE1 and AChE2. All of them were formulated and used in insecticide activity screening against P. xylostella. Bioassay data suggested that Si-ace1_003 and Si-ace2_001 at a concentration of 3 ug cm(-2) displayed the best insecticidal activity with 73.7% and 89.0%, mortality, respectively. Additional bioassays were used to obtain the acute lethal concentrations of LC50 and LC90 for Si-ace2_001, which were 53.66 ug/ml and 759.71 ug/ml, respectively. Quantitative Real-time PCR was used to confirm silencing and detected that the transcript levels of P. xylostella AChE2 (PxAChE2) were reduced by 5.7-fold compared to the control group. Consequently, AChE activity was also reduced by 1.7-fold. Finally, effects of the siRNAs on treated plants of Brassica oleracea and Brassica alboglabra were investigated with different siRNA doses. Our results showed that Si-ace2_001 had no negative effects on plant morphology, color and growth of vein under our experimental conditions. CONCLUSIONS: The most important finding of this study is the discovery that chemically synthesized and modified siRNA corresponding to P. xylostella AChE genes cause significant mortality of the insect both under laboratory and field conditions, which provides a novel strategy to control P. xylostella and to develop bio-pesticides based on the RNA interference technology. PMID- 23667557 TI - Screening for diabetic retinopathy and nephropathy in patients with diabetes: a nationwide survey in Korea. AB - This study was performed to identify factors associated with screening for diabetic retinopathy and nephropathy. Data from the Korean National Health and Nutrition Examination Survey between 2007 and 2009 were analyzed. Of 24,871 participants, 1,288 patients diagnosed with diabetes at >=30 years of age were included. 36.3% received screening for diabetic retinopathy, and 40.5% received screening for diabetic nephropathy during the previous year. Patients living in rural areas, those with less education, those who had not received education about diabetes care, and those who did not receive medical care for diabetes were screened less often for retinopathy or nephropathy. Patients with poorer self reported health status were screened more often. Occupation, smoking status, and diabetes duration were associated with retinopathy screening. Lower family income was associated with decreased nephropathy screening. Receiving education about diabetes care and receiving medical care for diabetes were significant factors in patients with a shorter duration of diabetes (the significant odds ratio [OR] of not receiving education varied between 0.27 and 0.51, and that of not receiving medical care varied between 0.34 and 0.42). Sociodemographic factors and health related factors as well as education and medical care influenced screening for diabetic complications among those with a longer duration of diabetes (for retinopathy and nephropathy, the significant OR of living in a rural area varied between 0.56 and 0.61; for retinopathy, the significant OR of current smokers was 0.55, and the p-trend of subjective health status was <0.001; for nephropathy, the significant OR of a monthly household income of <3000 dollars was 0.61 and the p-trends of education and subjective health status were 0.030 and 0.007, respectively). Efforts to decrease sociodemographic disparities should be combined with education about diabetes care to increase the screening, especially for those with a longer duration of diabetes. PMID- 23667558 TI - The confounding effect of population structure on Bayesian skyline plot inferences of demographic history. AB - Many coalescent-based methods aiming to infer the demographic history of populations assume a single, isolated and panmictic population (i.e. a Wright Fisher model). While this assumption may be reasonable under many conditions, several recent studies have shown that the results can be misleading when it is violated. Among the most widely applied demographic inference methods are Bayesian skyline plots (BSPs), which are used across a range of biological fields. Violations of the panmixia assumption are to be expected in many biological systems, but the consequences for skyline plot inferences have so far not been addressed and quantified. We simulated DNA sequence data under a variety of scenarios involving structured populations with variable levels of gene flow and analysed them using BSPs as implemented in the software package BEAST. Results revealed that BSPs can show false signals of population decline under biologically plausible combinations of population structure and sampling strategy, suggesting that the interpretation of several previous studies may need to be re-evaluated. We found that a balanced sampling strategy whereby samples are distributed on several populations provides the best scheme for inferring demographic change over a typical time scale. Analyses of data from a structured African buffalo population demonstrate how BSP results can be strengthened by simulations. We recommend that sample selection should be carefully considered in relation to population structure previous to BSP analyses, and that alternative scenarios should be evaluated when interpreting signals of population size change. PMID- 23667559 TI - The Drosophila Cadherin Fat regulates tissue size and planar cell polarity through different domains. AB - The Drosophila Cadherin Fat (Ft) has been identified as a crucial regulator of tissue size and Planar Cell Polarity (PCP). However, the precise mechanism by which Ft regulates these processes remains unclear. In order to advance our understanding of the action of Ft, we have sought to identify the crucial Ft effector domains. Here we report that a small region of the Ft cytoplasmic domain (H2 region) is both necessary and sufficient, when membrane localized, to support viability and prevent tissue overgrowth. Interestingly, the H2 region is dispensable for regulating PCP signaling, whereas the mutant Ft lacking the H2 region is fully capable of directing PCP. This result suggests that Ft's roles in PCP signaling and tissue size control are separable, and each can be carried out independently. Surprisingly, the crucial regions of Ft identified in our structure-function study do not overlap with the previously reported interaction regions with Atrophin, Dco, or Lowfat. PMID- 23667560 TI - Host growth can cause invasive spread of crops by soilborne pathogens. AB - Invasive soilborne plant pathogens cause substantial damage to crops and natural populations, but our understanding of how to prevent their epidemics or reduce their damage is limited. A key and experimentally-tested concept in the epidemiology of soilborne plant diseases is that of a threshold spacing between hosts below which epidemics (invasive spread) can occur. We extend this paradigm by examining how plant-root growth may alter the conditions for occurrence of soilborne pathogen epidemics in plant populations. We hypothesise that host-root growth can 1) increase the probability of pathogen transmission between neighbouring plants and, consequently, 2) decrease the threshold spacing for epidemics to occur. We predict that, in systems initially below their threshold conditions, root growth can trigger soilborne pathogen epidemics through a switch from non-invasive to invasive behaviour, while in systems above threshold conditions root growth can enhance epidemic development. As an example pathosystem, we studied the fungus Rhizoctonia solani on sugar beet in field experiments. To address hypothesis 1, we recorded infections within inoculum donor and host-recipient pairs of plants with differing spacing. We translated these observations into the individual-level concept of pathozone, a host-centred form of dispersal kernel. To test hypothesis 2 and our prediction, we used the pathozone to parameterise a stochastic model of pathogen spread in a host population, contrasting scenarios of spread with and without host growth. Our results support our hypotheses and prediction. We suggest that practitioners of agriculture and arboriculture account for root system expansion in order to reduce the risk of soilborne-disease epidemics. We discuss changes in crop design, including increasing plant spacing and using crop mixtures, for boosting crop resilience to invasion and damage by soilborne pathogens. We speculate that the disease-induced root growth observed in some pathosystems could be a pathogen strategy to increase its population through host manipulation. PMID- 23667561 TI - Coronin 1B regulates S1P-induced human lung endothelial cell chemotaxis: role of PLD2, protein kinase C and Rac1 signal transduction. AB - Coronins are a highly conserved family of actin binding proteins that regulate actin-dependent processes such as cell motility and endocytosis. We found that treatment of human pulmonary artery endothelial cells (HPAECs) with the bioactive lipid, sphingosine-1-phosphate (S1P) rapidly stimulates coronin 1B translocation to lamellipodia at the cell leading edge, which is required for S1P-induced chemotaxis. Further, S1P-induced chemotaxis of HPAECs was attenuated by pretreatment with small interfering RNA (siRNA) targeting coronin 1B (~36%), PLD2 (~45%) or Rac1 (~50%) compared to scrambled siRNA controls. Down regulation PLD2 expression by siRNA also attenuated S1P-induced coronin 1B translocation to the leading edge of the cell periphery while PLD1 silencing had no effect. Also, S1P induced coronin 1B redistribution to cell periphery and chemotaxis was attenuated by inhibition of Rac1 and over-expression of dominant negative PKC delta, epsilon and zeta isoforms in HPAECs. These results demonstrate that S1P activation of PLD2, PKC and Rac1 is part of the signaling cascade that regulates coronin 1B translocation to the cell periphery and the ensuing cell chemotaxis. PMID- 23667562 TI - The carboxy-terminal alphaN helix of the archaeal XerA tyrosine recombinase is a molecular switch to control site-specific recombination. AB - Tyrosine recombinases are conserved in the three kingdoms of life. Here we present the first crystal structure of a full-length archaeal tyrosine recombinase, XerA from Pyrococcus abyssi, at 3.0 A resolution. In the absence of DNA substrate XerA crystallizes as a dimer where each monomer displays a tertiary structure similar to that of DNA-bound Tyr-recombinases. Active sites are assembled in the absence of dif except for the catalytic Tyr, which is extruded and located equidistant from each active site within the dimer. Using XerA active site mutants we demonstrate that XerA follows the classical cis-cleavage reaction, suggesting rearrangements of the C-terminal domain upon DNA binding. Surprisingly, XerA C-terminal alphaN helices dock in cis in a groove that, in bacterial tyrosine recombinases, accommodates in trans alphaN helices of neighbour monomers in the Holliday junction intermediates. Deletion of the XerA C terminal alphaN helix does not impair cleavage of suicide substrates but prevents recombination catalysis. We propose that the enzymatic cycle of XerA involves the switch of the alphaN helix from cis to trans packing, leading to (i) repositioning of the catalytic Tyr in the active site in cis and (ii) dimer stabilisation via alphaN contacts in trans between monomers. PMID- 23667563 TI - Common interactions between S100A4 and S100A9 defined by a novel chemical probe. AB - S100A4 and S100A9 proteins have been described as playing roles in the control of tumor growth and metastasis. We show here that a chemical probe, oxyclozanide (OX), selected for inhibiting the interaction between S100A9 and the receptor for advanced glycation end-products (RAGE) interacts with both S100A9 and S100A4. Furthermore, we show that S100A9 and S100A4 interact with RAGE and TLR4; interactions that can be inhibited by OX. Hence, S100A4 and S100A9 display similar functional elements despite their primary sequence diversity. This was further confirmed by showing that S100A4 and S100A9 dimerize both in vitro and in vivo. All of these interactions required levels of Zn++ that are found in the extracellular space but not intracellularly. Interestingly, S100A4 and S100A9 are expressed by distinct CD11b+ subpopulations both in healthy animals and in animals with either inflammatory disease or tumor burden. The functions of S100A9 and S100A4 described in this paper, including heterodimerization, may therefore reflect S100A9 and S100A4 that are released into the extra-cellular milieu. PMID- 23667564 TI - Effect of oxidative stress induced by Brevibacterium sp. BS01 on a HAB causing species--Alexandrium tamarense. AB - Harmful algal blooms occur all over the world, destroying aquatic ecosystems and threatening other organisms. The culture supernatant of the marine algicidal actinomycete BS01 was able to lysis dinoflagellate Alexandrium tamarense ATGD98 006. Physiological and biochemical responses to oxidative stress in A. tamarense were investigated to elucidate the mechanism involved in BS01 inhibition of algal growth. Transmission electron microscope analysis revealed that there were some chloroplast abnormalities in response to BS01 supernatant. The decrease in cellular-soluble protein content suggested that cell growth was greatly inhibited at high concentration of BS01 supernatant. The increase in the levels of reactive oxygen species (ROS) and malondialdehyde contents following exposure to BS01 supernatant indicated that algal cells suffered from oxidative damage. The content of pigment was significantly decreased after 12 h treatment, which indicated that the accumulation of ROS destroyed pigment synthesis. Moreover, the decrease of Fv/Fm ratio suggested that in the photosynthetic system, the dominant sites producing ROS were destroyed by the supernatant of the BS01 culture. The activities of the antioxidant enzymes including superoxide dismutase and peroxidase increased in a short time and decreased slightly with increasing exposure time. A real-time PCR assay showed changes in the transcript abundances of two photosynthetic genes, psbA and psbD. The results showed that BS01 supernatant reduced the expression of the psbA gene after 2 h exposure, but the expression of the psbD gene was increased at concentrations of 1.0 and 1.5%. Our results demonstrated that the expression of the psbA gene was inhibited by the BS01 supernatant, which might block the electron transport chain, significantly enhancing ROS level and excess activity of the antioxidant system. The accumulation of ROS destoryed pigment synthesis and membrane integrity, and inhibited or ultimately killed the algal cells. PMID- 23667565 TI - The use of amino sugars by Bacillus subtilis: presence of a unique operon for the catabolism of glucosamine. AB - B. subtilis grows more rapidly using the amino sugar glucosamine as carbon source, than with N-acetylglucosamine. Genes for the transport and metabolism of N-acetylglucosamine (nagP and nagAB) are found in all the sequenced Bacilli (except Anoxybacillus flavithermus). In B. subtilis there is an additional operon (gamAP) encoding second copies of genes for the transport and catabolism of glucosamine. We have developed a method to make multiple deletion mutations in B. subtilis employing an excisable spectinomycin resistance cassette. Using this method we have analysed the contribution of the different genes of the nag and gam operons for their role in utilization of glucosamine and N-acetylglucosamine. Faster growth on glucosamine is due to the presence of the gamAP operon, which is strongly induced by glucosamine. Although the gamA and nagB genes encode isozymes of GlcN6P deaminase, catabolism of N-acetylglucosamine relies mostly upon the gamA gene product. The genes for use of N-acetylglucosamine, nagAB and nagP, are repressed by YvoA (NagR), a GntR family regulator, whose gene is part of the nagAB yvoA(nagR) operon. The gamAP operon is repressed by YbgA, another GntR family repressor, whose gene is expressed divergently from gamAP. The nagAB yvoA synton is found throughout the Bacilli and most firmicutes. On the other hand the ybgA-gamAP synton, which includes the ybgB gene for a small protein of unknown provenance, is only found in B. subtilis (and a few very close relatives). The origin of ybgBA-gamAP grouping is unknown but synteny analysis suggests lateral transfer from an unidentified donor. The presence of gamAP has enabled B. subtilis to efficiently use glucosamine as carbon source. PMID- 23667566 TI - TRAM-34, a putatively selective blocker of intermediate-conductance, calcium activated potassium channels, inhibits cytochrome P450 activity. AB - TRAM-34, a clotrimazole analog characterized as a potent and selective inhibitor of intermediate-conductance, calcium-activated K(+) (IKCa) channels, has been used extensively in vitro and in vivo to study the biological roles of these channels. The major advantage of TRAM-34 over clotrimazole is the reported lack of inhibition of the former drug on cytochrome P450 (CYP) activity. CYPs, a large family of heme-containing oxidases, play essential roles in endogenous signaling and metabolic pathways, as well as in xenobiotic metabolism. However, previously published work has only characterized the effects of TRAM-34 on a single CYP isoform. To test the hypothesis that TRAM-34 may inhibit some CYP isoforms, the effects of this compound were presently studied on the activities of four rat and five human CYP isoforms. TRAM-34 inhibited recombinant rat CYP2B1, CYP2C6 and CYP2C11 and human CYP2B6, CYP2C19 and CYP3A4 with IC50 values ranging from 0.9 uM to 12.6 uM, but had no inhibitory effects (up to 80 uM) on recombinant rat CYP1A2, human CYP1A2, or human CYP19A1. TRAM-34 also had both stimulatory and inhibitory effects on human CYP3A4 activity, depending on the substrate used. These results show that low micromolar concentrations of TRAM-34 can inhibit several rat and human CYP isoforms, and suggest caution in the use of high concentrations of this drug as a selective IKCa channel blocker. In addition, in vivo use of TRAM-34 could lead to CYP-related drug-drug interactions. PMID- 23667567 TI - Generation of mRx-Cre transgenic mouse line for efficient conditional gene deletion in early retinal progenitors. AB - During mouse eye development, all retinal cell types are generated from the population of retina-committed progenitors originating from the neuroepithelium of the optic vesicle. Conditional gene inactivation provides an efficient tool for studying the genetic basis of the developing retina; however, the number of retina-specific Cre lines is limited. Here we report generation of the mRx-Cre BAC transgenic mouse line in which the expression of Cre recombinase is controlled by regulatory sequences of the mouse Rx gene, one of the earliest determinants of retinal development. When mRx-Cre transgenic mice were crossbred with the ROSA26R or ROSA26R-EYFP reporter lines, the Cre activity was observed in the optic sulcus from embryonic day 8.5 onwards and later in all progenitors residing in the neuroepithelium of the optic cup. Our results suggest that mRx Cre provides a unique tool for functional genetic studies in very early stages of retinal development. Moreover, since eye organogenesis is dependent on the inductive signals between the optic vesicle and head surface ectoderm, the inductive ability of the optic vesicle can be analyzed using mRx-Cre transgenic mice. PMID- 23667568 TI - Selection and phylogenetics of salmonid MHC class I: wild brown trout (Salmo trutta) differ from a non-native introduced strain. AB - We tested how variation at a gene of adaptive importance, MHC class I (UBA), in a wild, endemic Salmo trutta population compared to that in both a previously studied non-native S. trutta population and a co-habiting Salmo salar population (a sister species). High allelic diversity is observed and allelic divergence is much higher than that noted previously for co-habiting S. salar. Recombination was found to be important to population-level divergence. The alpha1 and alpha2 domains of UBA demonstrate ancient lineages but novel lineages are also identified at both domains in this work. We also find examples of recombination between UBA and the non-classical locus, ULA. Evidence for strong diversifying selection was found at a discrete suite of S. trutta UBA amino acid sites. The pattern was found to contrast with that found in re-analysed UBA data from an artificially stocked S. trutta population. PMID- 23667569 TI - Engineering T cell function using chimeric antigen receptors identified using a DNA library approach. AB - Genetic engineering of cellular function holds much promise for the treatment of a variety of diseases including gene deficiencies and cancer. However, engineering the full complement of cellular functions can be a daunting genetic exercise since many molecular triggers need to be activated to achieve complete function. In the case of T cells, genes encoding chimeric antigen receptors (CARs) covalently linking antibodies to cytoplasmic signaling domains can trigger some, but not all, cellular functions against cancer cells. To date, relatively few CAR formats have been investigated using a candidate molecule approach, in which rationally chosen molecules were trialed one by one. Therefore, to expedite this arduous process we developed an innovative screening method to screen many thousands of CAR formats to identify genes able to enhance the anticancer ability of T cells. We used a directional in-frame library of randomly assembled signaling domains in a CAR specific for the tumor associated antigen erbB2. Several new and original CARs were identified, one of which had an enhanced ability to lyse cancer cells and inhibit tumor growth in mice. This study highlights novel technology that could be used to screen a variety of molecules for their capacity to induce diverse functions in cells. PMID- 23667570 TI - Long-lived bright red emitting azaoxa-triangulenium fluorophores. AB - The fluorescence lifetimes of most red emitting organic probes are under 4 nanoseconds, which is a limiting factor in studying interactions and conformational dynamics of macromolecules. In addition, the nanosecond background autofluorescence is a significant interference during fluorescence measurements in cellular environment. Therefore, red fluorophores with longer lifetimes will be immensely helpful. Azaoxa-triangulenium fluorophores ADOTA and DAOTA are red emitting small organic molecules with high quantum yield, long fluorescence lifetime and high limiting anisotropy. In aqueous environment, ADOTA and DAOTA absorption and emission maxima are respectively 540 nm and 556 nm, and 556 nm and 589 nm. Their emission extends beyond 700 nm. Both probes have the limiting anisotropy between 0.36-0.38 at their absorption peak. In both protic and aprotic solvents, their lifetimes are around 20 ns, making them among the longest-lived red emitting organic fluorophores. Upon labeling of avidin, streptavidin and immunoglobulin their absorption and fluorescence are red-shifted. Unlike in free form, the protein-conjugated probes have heterogeneous fluorescence decays, with the presence of both significantly quenched and unquenched populations. Despite the presence of significant local motions due to a flexible trimethylene linker, we successfully measured both intermediate nanosecond intra-protein motions and slower rotational correlation times approaching 100 ns. Their long lifetimes are unaffected by the cell membrane (hexadecyl-ADOTA) and the intra-cellular (DAOTA Arginine) localization. Their long lifetimes also enabled successful time-gating of the cellular autofluorescence resulting in background-free fluorescence lifetime based images. ADOTA and DAOTA retain a long fluorescence lifetime when free, as protein conjugate, in membranes and inside the cell. Our successful measurements of intermediate nanosecond internal motions and long correlations times of large proteins suggest that these probes will be highly useful to study slower intra-molecular motions and interactions among macromolecules. The fluorescence lifetime facilitated gating of cellular nanosecond autofluorescence should be of considerable help in in vitro and in vivo applications. PMID- 23667571 TI - Increased mammogram-induced DNA damage in mammary epithelial cells aged in vitro. AB - Concerned about the risks of mammography screening in the adult population, we analyzed the ability of human mammary epithelial cells to cope with mammogram induced DNA damage. Our study shows that an X-ray dose of 20 mGy, which is the standard dose received by the breast surface per two-view mammogram X-ray exploration, induces increased frequencies of DNA double-strand breaks to in vitro aged-but not to young-human mammary epithelial cells. We provide evidence that aged epithelial breast cells are more radiosensitive than younger ones. Our studies point to an inefficient damage response of aged cells to low-dose radiation, this being due to both delayed and incomplete mobilization of repair proteins to DNA strand breaks. This inefficient damage response is translated into an important delay in double-strand break disappearance and consequent accumulation of unrepaired DNA breaks. The result of this is a significant increase in micronuclei frequency in the in vitro aged mammary epithelial cells exposed to doses equivalent to a single mammogram X-ray exploration. Since our experiments were carried out in primary epithelial cell cultures in which cells age at the same time as they undergo replication-dependent telomere shortening, we needed to determine the contribution of these two factors to their phenotype. In this paper, we report that the exogenous expression of human telomerase retrotranscriptase in late population doubling epithelial cells does not rescue its delayed repair phenotype. Therefore, retarded DNA break repair is a direct consequence of cellular aging itself, rather than a consequence of the presence of dysfunctional telomeres. Our findings of long-lasting double strand breaks and incomplete DNA break repair in the in vitro aged epithelial cells are in line with the increased carcinogenic risks of radiation exposures at older ages revealed by epidemiologic studies. PMID- 23667572 TI - Drug-associated adverse events and their relationship with outcomes in patients receiving treatment for extensively drug-resistant tuberculosis in South Africa. AB - BACKGROUND: Treatment-related outcomes in patients with extensively drug resistant tuberculosis (XDR-TB) are poor. However, data about the type, frequency and severity of presumed drug-associated adverse events (AEs) and their association with treatment-related outcomes in patients with XDR-TB are scarce. METHODS: Case records of 115 South-African XDR-TB patients were retrospectively reviewed by a trained researcher. AEs were estimated and graded according to severity [grade 0 = none; grade 1-2 = mild to moderate; and grade 3-5 = severe (drug stopped, life-threatening or death)]. FINDINGS: 161 AEs were experienced by 67/115(58%) patients: 23/67(34%) required modification of treatment, the offending drug was discontinued in 19/67(28%), reactions were life-threatening in 2/67(3.0%), and 6/67(9.0%) died. ~50% of the patients were still on treatment at the time of data capture. Sputum culture-conversion was less likely in those with severe (grade 3-5) vs. grade 0-2 AEs [2/27(7%) vs. 24/88(27%); p = 0.02]. The type, frequency and severity of AEs was similar in HIV-infected and uninfected patients. Capreomycin, which was empirically administered in most cases, was withdrawn in 14/104(14%) patients, implicated in (14/34) 41% of the total drug withdrawals, and was associated with all 6 deaths in the severe AE group (renal failure in five patients and hypokalemia in one patient). CONCLUSION: Drug associated AEs occur commonly with XDR-TB treatment, are often severe, frequently interrupt therapy, and negatively impact on culture conversion outcomes. These preliminary data inform on the need for standardised strategies (including pre treatment counselling, early detection, monitoring, and follow-up) and less toxic drugs to optimally manage patients with XDR-TB. PMID- 23667573 TI - Analysis of nitrification efficiency and microbial community in a membrane bioreactor fed with low COD/N-ratio wastewater. AB - In this study, an approach using influent COD/N ratio reduction was employed to improve process performance and nitrification efficiency in a membrane bioreactor (MBR). Besides sludge reduction, membrane fouling alleviation was observed during 330 d operation, which was attributed to the decreased production of soluble microbial products (SMP) and efficient carbon metabolism in the autotrophic nitrifying community. 454 high-throughput 16S rRNA gene pyrosequencing revealed that the diversity of microbial sequences was mainly determined by the feed characteristics, and that microbes could derive energy by switching to a more autotrophic metabolism to resist the environmental stress. The enrichment of nitrifiers in an MBR with a low COD/N-ratio demonstrated that this condition stimulated nitrification, and that the community distribution of ammonia oxidizing bacteria (AOB) and nitrite oxidizing bacteria (NOB) resulted in faster nitrite uptake rates. Further, ammonia oxidation was the rate-limiting step during the full nitrification. PMID- 23667574 TI - Excitability of motor cortices as a function of emotional sounds. AB - We used transcranial magnetic stimulation (TMS) to clarify how non-verbal emotionally-characterized sounds modulate the excitability of the corticospinal motor tract (CST). While subjects were listening to sounds (monaurally and binaurally), single TMS pulses were delivered to either left or right primary motor cortex (M1), and electromyographic activities were recorded from the contralateral abductor pollicis brevis muscle. We found a significant increase in CST excitability in response to unpleasant as compared to neutral sounds. The increased excitability was lateralized as a function of stimulus valence: Unpleasant stimuli resulted in a significantly higher facilitation of motor potentials evoked in the left hemisphere, while pleasant stimuli yielded a greater CST excitability in the right one. Furthermore, TMS induced higher motor evoked potentials when listening to unpleasant sounds with the left than with the right ear. Taken together, our findings provide compelling evidence for an asymmetric modulation of CST excitability as a function of emotional sounds along with ear laterality. PMID- 23667575 TI - Growth kinetics of bacterial pili from pairwise pilin association rates. AB - Bacterial pilogenesis is a remarkable example of biological non-templated self assembly where a small number of different building blocks are arranged in a specific order resulting in a macroscopic hair-like fiber containing up to thousands copies of protein subunits. A number of advanced experimental techniques have been used to understand pilus growth. While details such as the conformation of the protein building blocks before and after the elementary polymerization step have enhanced our understanding of this mechanism, such information does not explain the high efficiency of this growth process. In this study, we focused on the growth of the Escherichia coli P-pilus, which is formed by the assembly of six subunits, structurally similar incomplete Ig-like domains. These subunits undergo polymerization through fold complementation by the donation of a beta-sheet strand in a specific conserved order. All pairwise rates of association of the individual subunits with the corresponding beta-sheet donor strand peptides have been previously determined through non-covalent mass spectrometry. Here we use computational simulations to determine donor-strand exchange rates and subunit concentrations necessary to warrant the growth of pili showing similar lengths and subunit orders to those observed in vivo. Our findings confirm that additional factors must be involved in the modulation of the donor-strand exchange rate and/or pilin subunit concentration at the usher must be important for the precise ordering and rapid polymerization rates observed in vivo. PMID- 23667576 TI - Automatic ability attribution after failure: a dual process view of achievement attribution. AB - Causal attribution has been one of the most influential frameworks in the literature of achievement motivation, but previous studies considered achievement attribution as relatively deliberate and effortful processes. In the current study, we tested the hypothesis that people automatically attribute their achievement failure to their ability, but reduce the ability attribution in a controlled manner. To address this hypothesis, we measured participants' causal attribution belief for their task failure either under the cognitive load (load condition) or with full attention (no-load condition). Across two studies, participants attributed task performance to their ability more in the load than in the no-load condition. The increased ability attribution under cognitive load further affected intrinsic motivation. These results indicate that cognitive resources available after feedback play crucial roles in determining causal attribution belief, as well as achievement motivations. PMID- 23667577 TI - Targeting human microRNA genes using engineered Tal-effector nucleases (TALENs). AB - MicroRNAs (miRNAs) have quickly emerged as important regulators of mammalian physiology owing to their precise control over the expression of critical protein coding genes. Despite significant progress in our understanding of how miRNAs function in mice, there remains a fundamental need to be able to target and edit miRNA genes in the human genome. Here, we report a novel approach to disrupting human miRNA genes ex vivo using engineered TAL-effector (TALE) proteins to function as nucleases (TALENs) that specifically target and disrupt human miRNA genes. We demonstrate that functional TALEN pairs can be designed to enable disruption of miRNA seed regions, or removal of entire hairpin sequences, and use this approach to successfully target several physiologically relevant human miRNAs including miR-155*, miR-155, miR-146a and miR-125b. This technology will allow for a substantially improved capacity to study the regulation and function of miRNAs in human cells, and could be developed into a strategic means by which miRNAs can be targeted therapeutically during human disease. PMID- 23667578 TI - Cellular development associated with induced mycotoxin synthesis in the filamentous fungus Fusarium graminearum. AB - Several species of the filamentous fungus Fusarium colonize plants and produce toxic small molecules that contaminate agricultural products, rendering them unsuitable for consumption. Among the most destructive of these species is F. graminearum, which causes disease in wheat and barley and often infests the grain with harmful trichothecene mycotoxins. Synthesis of these secondary metabolites is induced during plant infection or in culture in response to chemical signals. Our results show that trichothecene biosynthesis involves a complex developmental process that includes dynamic changes in cell morphology and the biogenesis of novel subcellular structures. Two cytochrome P-450 oxygenases (Tri4p and Tri1p) involved in early and late steps in trichothecene biosynthesis were tagged with fluorescent proteins and shown to co-localize to vesicles we provisionally call "toxisomes." Toxisomes, the inferred site of trichothecene biosynthesis, dynamically interact with motile vesicles containing a predicted major facilitator superfamily protein (Tri12p) previously implicated in trichothecene export and tolerance. The immediate isoprenoid precursor of trichothecenes is the primary metabolite farnesyl pyrophosphate. Changes occur in the cellular localization of the isoprenoid biosynthetic enzyme HMG CoA reductase when cultures non-induced for trichothecene biosynthesis are transferred to trichothecene biosynthesis inducing medium. Initially localized in the cellular endomembrane system, HMG CoA reductase, upon induction of trichothecene biosynthesis, increasingly is targeted to toxisomes. Metabolic pathways of primary and secondary metabolism thus may be coordinated and co-localized under conditions when trichothecene biosynthesis occurs. PMID- 23667579 TI - Conservation of avian diversity in the Sierra Nevada: moving beyond a single species management focus. AB - BACKGROUND: As a result of past practices, many of the dry coniferous forests of the western United States contain dense, even-aged stands with uncharacteristically high levels of litter and downed woody debris. These changes to the forest have received considerable attention as they elevate concerns regarding the outcome of wildland fire. However, attempts to reduce biomass through fuel reduction (i.e., thinning of trees) are often opposed by public interest groups whose objectives include maintaining habitat for species of concern such as the spotted owl, Strix occidentalis, the northern goshawk, Accipiter gentilis, and the Pacific fisher, Martes pennanti. Whether protection of these upper-trophic level species confers adequate conservation of avian forest diversity is unknown. METHODOLOGY AND PRINCIPAL FINDINGS: We use a multi species occurrence model to estimate the habitat associations of 47 avian species detected at 742 sampling locations within an 880-km(2) area in the Sierra Nevada. Our approach, which accounts for variations in detectability of species, estimates occurrence probabilities of all species in a community by linking species occurrence models into one hierarchical community model, thus improving inferences on all species, especially those that are rare or observed infrequently. We address how the avian community is influenced by covariates related to canopy cover, tree size and shrub cover while accounting for the impacts of abiotic variables known to affect species distributions. CONCLUSIONS AND SIGNIFICANCE: Environmental parameters estimated through our approach emphasize the importance of within and between stand-level heterogeneity in meeting biodiversity objectives and suggests that many avian species would increase under more open canopy habitat conditions than those favored by umbrella species of high conservation concern. Our results suggest that a more integrated approach that emphasizes maintaining a diversity of habitats across environmental gradients and minimizing urbanization may have a greater benefit to ecosystem functioning then a single-species management focus. PMID- 23667580 TI - Protein clustering and RNA phylogenetic reconstruction of the influenza A [corrected] virus NS1 protein allow an update in classification and identification of motif conservation. AB - The non-structural protein 1 (NS1) of influenza A virus (IAV), coded by its third most diverse gene, interacts with multiple molecules within infected cells. NS1 is involved in host immune response regulation and is a potential contributor to the virus host range. Early phylogenetic analyses using 50 sequences led to the classification of NS1 gene variants into groups (alleles) A and B. We reanalyzed NS1 diversity using 14,716 complete NS IAV sequences, downloaded from public databases, without host bias. Removal of sequence redundancy and further structured clustering at 96.8% amino acid similarity produced 415 clusters that enhanced our capability to detect distinct subgroups and lineages, which were assigned a numerical nomenclature. Maximum likelihood phylogenetic reconstruction using RNA sequences indicated the previously identified deep branching separating group A from group B, with five distinct subgroups within A as well as two and five lineages within the A4 and A5 subgroups, respectively. Our classification model proposes that sequence patterns in thirteen amino acid positions are sufficient to fit >99.9% of all currently available NS1 sequences into the A subgroups/lineages or the B group. This classification reduces host and virus bias through the prioritization of NS1 RNA phylogenetics over host or virus phenetics. We found significant sequence conservation within the subgroups and lineages with characteristic patterns of functional motifs, such as the differential binding of CPSF30 and crk/crkL or the availability of a C-terminal PDZ-binding motif. To understand selection pressures and evolution acting on NS1, it is necessary to organize the available data. This updated classification may help to clarify and organize the study of NS1 interactions and pathogenic differences and allow the drawing of further functional inferences on sequences in each group, subgroup and lineage rather than on a strain-by-strain basis. PMID- 23667581 TI - The FIGS (focused identification of germplasm strategy) approach identifies traits related to drought adaptation in Vicia faba genetic resources. AB - Efficient methods to explore plant agro-biodiversity for climate change adaptive traits are urgently required. The focused identification of germplasm strategy (FIGS) is one such approach. FIGS works on the premise that germplasm is likely to reflect the selection pressures of the environment in which it developed. Environmental parameters describing plant germplasm collection sites are used as selection criteria to improve the probability of uncovering useful variation. This study was designed to test the effectiveness of FIGS to search a large faba bean (Vicia faba L.) collection for traits related to drought adaptation. Two sets of faba bean accessions were created, one from moisture-limited environments, and the other from wetter sites. The two sets were grown under well watered conditions and leaf morpho-physiological traits related to plant water use were measured. Machine-learning algorithms split the accessions into two groups based on the evaluation data and the groups created by this process were compared to the original climate-based FIGS sets. The sets defined by trait data were in almost perfect agreement to the FIGS sets, demonstrating that ecotypic differentiation driven by moisture availability has occurred within the faba bean genepool. Leaflet and canopy temperature as well as relative water content contributed more than other traits to the discrimination between sets, indicating that their utility as drought-tolerance selection criteria for faba bean germplasm. This study supports the assertion that FIGS could be an effective tool to enhance the discovery of new genes for abiotic stress adaptation. PMID- 23667582 TI - Cerebrospinal fluid melanin-concentrating hormone (MCH) and hypocretin-1 (HCRT-1, orexin-A) in Alzheimer's disease. AB - Ancillary to decline in cognitive abilities, patients with Alzheimer's disease (AD) frequently suffer from behavioural and psychological symptoms of dementia (BPSD). Hypothalamic polypeptides such as melanin-concentrating hormone (MCH) and hypocretin-1 (HCRT-1, orexin-A) are promoters of sleep-wake regulation and energy homeostasis and are found to impact on cognitive performance. To investigate the role of MCH and HCRT-1 in AD, cerebrospinal fluid (CSF) levels were measured in 33 patients with AD and 33 healthy subjects (HS) using a fluorescence immunoassay (FIA). A significant main effect of diagnosis (F(1,62) = 8.490, p<0.01) on MCH levels was found between AD (93.76+/-13.47 pg/mL) and HS (84.65+/-11.40 pg/mL). MCH correlated with T-tau (r = 0.47; p<0.01) and P-tau (r = 0.404; p<0.05) in the AD but not in the HS. CSF-MCH correlated negatively with MMSE scores in the AD (r = -0.362, p<0.05) and was increased in more severely affected patients (MMSE<=20) compared to HS (p<0.001) and BPSD-positive patients compared to HS (p<0.05). In CSF-HCRT-1, a significant main effect of sex (F(1,31) = 4.400, p<0.05) with elevated levels in females (90.93+/-17.37 pg/mL vs. 82.73+/-15.39 pg/mL) was found whereas diagnosis and the sex*diagnosis interaction were not significant. Elevated levels of MCH in patients suffering from AD and correlation with Tau and severity of cognitive impairment point towards an impact of MCH in AD. Gender differences of CSF-HCRT-1 controversially portend a previously reported gender dependence of HCRT-1-regulation. Histochemical and actigraphic explorations are warranted to further elucidate alterations of hypothalamic transmitter regulation in AD. PMID- 23667583 TI - Optimal monochromatic energy levels in spectral CT pulmonary angiography for the evaluation of pulmonary embolism. AB - BACKGROUND: The aim of this study was to determine the optimal monochromatic spectral CT pulmonary angiography (sCTPA) levels to obtain the highest image quality and diagnostic confidence for pulmonary embolism detection. METHODS: The Institutional Review Board of the Shanghai Jiao Tong University School of Medicine approved this study, and written informed consent was obtained from all participating patients. Seventy-two patients with pulmonary embolism were scanned with spectral CT mode in the arterial phase. One hundred and one sets of virtual monochromatic spectral (VMS) images were generated ranging from 40 keV to 140 keV. Image noise, clot diameter and clot to artery contrast-to-noise ratio (CNR) from seven sets of VMS images at selected monochromatic levels in sCTPA were measured and compared. Subjective image quality and diagnostic confidence for these images were also assessed and compared. Data were analyzed by paired t test and Wilcoxon rank sum test. RESULTS: The lowest noise and the highest image quality score for the VMS images were obtained at 65 keV. The VMS images at 65 keV also had the second highest CNR value behind that of 50 keV VMS images. There was no difference in the mean noise and CNR between the 65 keV and 70 keV VMS images. The apparent clot diameter correlated with the keV levels. CONCLUSIONS: The optimal energy level for detecting pulmonary embolism using dual-energy spectral CT pulmonary angiography was 65-70 keV. Virtual monochromatic spectral images at approximately 65-70 keV yielded the lowest image noise, high CNR and highest diagnostic confidence for the detection of pulmonary embolism. PMID- 23667584 TI - Sago-type palms were an important plant food prior to rice in southern subtropical China. AB - Poor preservation of plant macroremains in the acid soils of southern subtropical China has hampered understanding of prehistoric diets in the region and of the spread of domesticated rice southwards from the Yangtze River region. According to records in ancient books and archaeological discoveries from historical sites, it is presumed that roots and tubers were the staple plant foods in this region before rice agriculture was widely practiced. But no direct evidences provided to test the hypothesis. Here we present evidence from starch and phytolith analyses of samples obtained during systematic excavations at the site of Xincun on the southern coast of China, demonstrating that during 3,350-2,470 aBC humans exploited sago palms, bananas, freshwater roots and tubers, fern roots, acorns, Job's-tears as well as wild rice. A dominance of starches and phytoliths from palms suggest that the sago-type palms were an important plant food prior to the rice in south subtropical China. We also believe that because of their reliance on a wide range of starch-rich plant foods, the transition towards labour intensive rice agriculture was a slow process. PMID- 23667585 TI - Intense inflammation and nerve damage in early multiple sclerosis subsides at older age: a reflection by cerebrospinal fluid biomarkers. AB - Inflammatory mediators have crucial roles in leukocyte recruitment and subsequent central nervous system (CNS) neuroinflammation. The extent of neuronal injury and axonal loss are associated with the degree of CNS inflammation and determine physical disability in multiple sclerosis (MS). The aim of this study was to explore possible associations between a panel of selected cerebrospinal fluid biomarkers and robust clinical and demographic parameters in a large cohort of patients with MS and controls (n = 1066) using data-driven multivariate analysis. Levels of matrix metalloproteinase 9 (MMP9), chemokine (C-X-C motif) ligand 13 (CXCL13), osteopontin (OPN) and neurofilament-light chain (NFL) were measured by ELISA in 548 subjects comprising different MS subtypes (relapsing-remitting, secondary progressive and primary progressive), clinically isolated syndrome and persons with other neurological diseases with or without signs of inflammation/infection. Principal component analyses and orthogonal partial least squares methods were used for unsupervised and supervised interrogation of the data. Models were validated using data from a further 518 subjects in which one or more of the four selected markers were measured. There was a significant association between increased patient age and lower levels of CXCL13, MMP9 and NFL. CXCL13 levels correlated well with MMP9 in the younger age groups, but less so in older patients, and after approximately 54 years of age the levels of CXCL13 and MMP9 were consistently low. CXCL13 and MMP9 levels also correlated well with both NFL and OPN in younger patients. We demonstrate a strong effect of age on both inflammatory and neurodegenerative biomarkers in a large cohort of MS patients. The findings support an early use of adequate immunomodulatory disease modifying drugs, especially in younger patients, and may provide a biological explanation for the relative inefficacy of such treatments in older patients at later disease stages. PMID- 23667586 TI - Extensive variation in cadmium tolerance and accumulation among populations of Chamaecrista fasciculata. AB - Plant populations may vary substantially in their tolerance for and accumulation of heavy metals, and assessment of this variability is important when selecting species to use in restoration or phytoremediation projects. We examined the population variation in cadmium tolerance and accumulation in a leguminous pioneer species native to the eastern United States, the partridge pea (Chamaecrista fasciculata). We assayed growth, reproduction and patterns of cadmium accumulation in six populations of C. fasciculata grown on a range of cadmium-contaminated soils. In general, C. fasciculata exhibited tolerance in low to moderate soil cadmium concentrations. Both tolerance and accumulation patterns varied across populations. C. fasciculata exhibited many characteristics of a hyperaccumulator species, with high cadmium uptake in shoots and roots. However, cadmium was excluded from extrafloral nectar. As a legume with tolerance for moderate cadmium contamination, C. fasciculata has potential for phytoremediation. However, our findings also indicate the importance of considering the effects of genetic variation on plant performance when screening plant populations for utilization in remediation and restoration activities. Also, there is potential for cadmium contamination to affect other species through contamination of leaves, fruits, flowers, pollen and root nodules. PMID- 23667587 TI - Impact of rheumatoid arthritis disease activity test on clinical practice. AB - BACKGROUND: Variability exists in the assessment of disease activity in rheumatoid arthritis (RA) patients that may affect quality of care. OBJECTIVES: To measure the impact on quality of care of a Multi-Biomarker Disease Activity (MBDA) test that quantitatively assesses RA disease activity. METHODS: Board certified rheumatologists without prior experience with the MBDA test (N = 81) were randomized into an intervention or control group as part of a longitudinal randomized-control study. All physicians were asked to care for three simulated RA patients, using Clinical Performance and Value (CPVTM) vignettes, in a before and after design. CPVTM vignettes have been validated to assess the quality of clinical practice and identify variation in care. The vignettes covered all domains of a regular patient visit; scores were determined as a percentage of explicit predefined criteria completed. Three vignettes, representing typical RA cases, were administered each round. In the first round, no physician received information about the MBDA test. In the second round, only physicians in the intervention group were given educational materials about the test and hypothetical test results for each of the simulated patients. The outcome measures were the overall quality of care, disease assessment and treatment. RESULTS: The overall quality scores in the intervention group improved by 3 percent (p = 0.02) post-intervention compared with baseline, versus no change in the control group. The greatest benefit in the intervention group was to the quality of disease activity assessment and treatment decisions, which improved by 12 percent (p<0.01) compared with no significant change in the control group. The intervention was associated with more appropriate use of biologic and/or combination DMARDs in the co-morbidity case type (p<0.01). CONCLUSIONS: Based on these results, use of the MBDA test improved the assessment and treatment decisions for simulated cases of RA and may prove useful for rheumatologists in clinical practice. PMID- 23667588 TI - Distinct functional and temporal requirements for zebrafish Hdac1 during neural crest-derived craniofacial and peripheral neuron development. AB - The regulation of gene expression is accomplished by both genetic and epigenetic means and is required for the precise control of the development of the neural crest. In hdac1(b382) mutants, craniofacial cartilage development is defective in two distinct ways. First, fewer hoxb3a, dlx2 and dlx3-expressing posterior branchial arch precursors are specified and many of those that are consequently undergo apoptosis. Second, in contrast, normal numbers of progenitors are present in the anterior mandibular and hyoid arches, but chondrocyte precursors fail to terminally differentiate. In the peripheral nervous system, there is a disruption of enteric, DRG and sympathetic neuron differentiation in hdac1(b382) mutants compared to wildtype embryos. Specifically, enteric and DRG-precursors differentiate into neurons in the anterior gut and trunk respectively, while enteric and DRG neurons are rarely present in the posterior gut and tail. Sympathetic neuron precursors are specified in hdac1(b382) mutants and they undergo generic neuronal differentiation but fail to undergo noradrenergic differentiation. Using the HDAC inhibitor TSA, we isolated enzyme activity and temporal requirements for HDAC function that reproduce hdac1(b382) defects in craniofacial and sympathetic neuron development. Our study reveals distinct functional and temporal requirements for zebrafish hdac1 during neural crest derived craniofacial and peripheral neuron development. PMID- 23667589 TI - Gli1 mediates lung cancer cell proliferation and Sonic Hedgehog-dependent mesenchymal cell activation. AB - Non-Small-Cell-Lung-Cancer (NSCLC) represents approximately 85% of all lung cancers and remains poorly understood. While signaling pathways operative during organ development, including Sonic Hedgehog (Shh) and associated Gli transcription factors (Gli1-3), have recently been found to be reactivated in NSCLC, their functional role remains unclear. Here, we hypothesized that Shh/Gli1 3 could mediate NSCLC autonomous proliferation and epithelial/stromal signaling in the tumoral tissue. In this context, we have investigated the activity of Shh/Gli1-3 signaling in NSCLC in both, cancer and stromal cells. We report here that inhibition of Shh signaling induces a significant decrease in the proliferation of NSCLC cells. This effect is mediated by Gli1 and Gli2, but not Gli3, through regulation of cyclin D1 and cyclin D2 expression. While exogenous Shh was unable to induce signaling in either A549 lung adenocarcinoma or H520 lung squamous carcinoma cells, both cells were found to secrete Shh ligand, which induced fibroblast proliferation, survival, migration, invasion, and collagen synthesis. Furthermore, Shh secreted by NSCLC mediates the production of proangiogenic and metastatic factors in lung fibroblasts. Our results thus provide evidence that Shh plays an important role in mediating epithelial/mesenchymal crosstalk in NSCLC. While autonomous Gli activity controls NSCLC proliferation, increased Shh expression by NSCLC is associated with fibroblast activation in tumor-associated stroma. Our study highlights the relevance of studying stromal-associated cells in the context of NSCLC regarding new prognosis and therapeutic options. PMID- 23667590 TI - Beyond the binding site: in vivo identification of tbx2, smarca5 and wnt5b as molecular targets of CNBP during embryonic development. AB - CNBP is a nucleic acid chaperone implicated in vertebrate craniofacial development, as well as in myotonic dystrophy type 2 (DM2) and sporadic inclusion body myositis (sIBM) human muscle diseases. CNBP is highly conserved among vertebrates and has been implicated in transcriptional regulation; however, its DNA binding sites and molecular targets remain elusive. The main goal of this work was to identify CNBP DNA binding sites that might reveal target genes involved in vertebrate embryonic development. To accomplish this, we used a recently described yeast one-hybrid assay to identify DNA sequences bound in vivo by CNBP. Bioinformatic analyses revealed that these sequences are G-enriched and show high frequency of putative G-quadruplex DNA secondary structure. Moreover, an in silico approach enabled us to establish the CNBP DNA-binding site and to predict CNBP putative targets based on gene ontology terms and synexpression with CNBP. The direct interaction between CNBP and candidate genes was proved by EMSA and ChIP assays. Besides, the role of CNBP upon the identified genes was validated in loss-of-function experiments in developing zebrafish. We successfully confirmed that CNBP up-regulates tbx2b and smarca5, and down regulates wnt5b gene expression. The highly stringent strategy used in this work allowed us to identify new CNBP target genes functionally important in different contexts of vertebrate embryonic development. Furthermore, it represents a novel approach toward understanding the biological function and regulatory networks involving CNBP in the biology of vertebrates. PMID- 23667591 TI - Engineered monoclonal antibody with novel antigen-sweeping activity in vivo. AB - Monoclonal antibodies are widely used to target disease-related antigens. However, because conventional antibody binds to the antigen but cannot eliminate the antigen from plasma, and rather increases the plasma antigen concentration by reducing the clearance of the antigen, some clinically important antigens are still difficult to target with monoclonal antibodies because of the huge dosages required. While conventional antibody can only bind to the antigen, some natural endocytic receptors not only bind to the ligands but also continuously eliminate them from plasma by pH-dependent dissociation of the ligands within the acidic endosome and subsequent receptor recycling to the cell surface. Here, we demonstrate that an engineered antibody, named sweeping antibody, having both pH dependent antigen binding (to mimic the receptor-ligand interaction) and increased binding to cell surface neonatal Fc receptor (FcRn) at neutral pH (to mimic the cell-bound form of the receptor), selectively eliminated the antigen from plasma. With this novel antigen-sweeping activity, antibody without in vitro neutralizing activity exerted in vivo efficacy by directly eliminating the antigen from plasma. Moreover, conversion of conventional antibody with in vitro neutralizing activity into sweeping antibody further potentiated the in vivo efficacy. Depending on the binding affinity to FcRn at neutral pH, sweeping antibody reduced antigen concentration 50- to 1000-fold compared to conventional antibody. Thereby, sweeping antibody antagonized excess amounts of antigen in plasma against which conventional antibody was completely ineffective, and could afford marked reduction of dosage to a level that conventional antibody can never achieve. Thus, the novel mode of action of sweeping antibody provides potential advantages over conventional antibody and may allow access to the target antigens which were previously undruggable by conventional antibody. PMID- 23667592 TI - Enhancing hit identification in Mycobacterium tuberculosis drug discovery using validated dual-event Bayesian models. AB - High-throughput screening (HTS) in whole cells is widely pursued to find compounds active against Mycobacterium tuberculosis (Mtb) for further development towards new tuberculosis (TB) drugs. Hit rates from these screens, usually conducted at 10 to 25 uM concentrations, typically range from less than 1% to the low single digits. New approaches to increase the efficiency of hit identification are urgently needed to learn from past screening data. The pharmaceutical industry has for many years taken advantage of computational approaches to optimize compound libraries for in vitro testing, a practice not fully embraced by academic laboratories in the search for new TB drugs. Adapting these proven approaches, we have recently built and validated Bayesian machine learning models for predicting compounds with activity against Mtb based on publicly available large-scale HTS data from the Tuberculosis Antimicrobial Acquisition Coordinating Facility. We now demonstrate the largest prospective validation to date in which we computationally screened 82,403 molecules with these Bayesian models, assayed a total of 550 molecules in vitro, and identified 124 actives against Mtb. Individual hit rates for the different datasets varied from 15-28%. We have identified several FDA approved and late stage clinical candidate kinase inhibitors with activity against Mtb which may represent starting points for further optimization. The computational models developed herein and the commercially available molecules derived from them are now available to any group pursuing Mtb drug discovery. PMID- 23667593 TI - Cancer-associated fibroblasts from hepatocellular carcinoma promote malignant cell proliferation by HGF secretion. AB - Cancer-associated fibroblasts (CAFs) are reported to support tumorigenesis by stimulating angiogenesis, cancer cell proliferation, and invasion in most solid tumors. However, the roles of CAFs in the liver cancer microenvironment have not been thoroughly studied. In our previous study, we successfully isolated CAFs from hepatocellular carcinoma (HCC) (H-CAFs) and proved that H-CAFs suppressed the activation of NK cells and thereby created favorable conditions for HCC progression. In our present study, we found that the proliferation of MHCC97L and Hep3B cells was significantly promoted by treatment with conditioned medium from H-CAFs. Pathological analysis also revealed that H-CAFs increased the proportion of Ki-67 (+) malignant cells and prevented them from undergoing necrosis. Moreover, the concentration of hepatocyte growth factor (HGF) cytokine in the conditioned medium of H-CAFs was higher than conditioned medium from normal skin fibroblasts (NSFs). Anti-HGF significantly reduced the proliferation-promoting capability of H-CAFs. In addition, we found that the abundance of H-CAFs correlated positively with tumor size. These results indicate that H-CAFs are an important factor for promoting the growth of HCC in vitro and in vivo, and that HGF plays a key role in HCC proliferation induced by H-CAFs. PMID- 23667594 TI - Phenotypic divergence among west European populations of Reed Bunting Emberiza schoeniclus: the effects of migratory and foraging behaviours. AB - Divergent selection and local adaptation are responsible for many phenotypic differences between populations, potentially leading to speciation through the evolution of reproductive barriers. Here we evaluated the morphometric divergence among west European populations of Reed Bunting in order to determine the extent of local adaptation relative to two important selection pressures often associated with speciation in birds: migration and diet. We show that, as expected by theory, migratory E. s. schoeniclus had longer and more pointed wings and a slightly smaller body mass than the resident subspecies, with the exception of E. s. lusitanica, which despite having rounder wings was the smallest of all subspecies. Tail length, however, did not vary according to the expectation (shorter tails in migrants) probably because it is strongly correlated with wing length and might take longer to evolve. E. s. witherbyi, which feed on insects hiding inside reed stems during the winter, had a very thick, stubby bill. In contrast, northern populations, which feed on seeds, had thinner bills. Despite being much smaller, the southern E. s. lusitanica had a significantly thicker, longer bill than migratory E. s. schoeniclus, whereas birds from the UK population had significantly shorter, thinner bills. Geometric morphometric analyses revealed that the southern subspecies have a more convex culmen than E. s. schoeniclus, and E. s. lusitanica differs from the nominate subspecies in bill shape to a greater extent than in linear bill measurements, especially in males. Birds with a more convex culmen are thought to exert a greater strength at the bill tip, which is in agreement with their feeding technique. Overall, the three subspecies occurring in Western Europe differ in a variety of traits following the patterns predicted from their migratory and foraging behaviours, strongly suggesting that these birds have became locally adapted through natural selection. PMID- 23667595 TI - Cellular and molecular characterization of multipolar Map5-expressing cells: a subset of newly generated, stage-specific parenchymal cells in the mammalian central nervous system. AB - Although extremely interesting in adult neuro-glio-genesis and promising as an endogenous source for repair, parenchymal progenitors remain largely obscure in their identity and physiology, due to a scarce availability of stage-specific markers. What appears difficult is the distinction between real cell populations and various differentiation stages of the same population. Here we focused on a subset of multipolar, polydendrocyte-like cells (mMap5 cells) expressing the microtubule associated protein 5 (Map5), which is known to be present in most neurons. We characterized the morphology, phenotype, regional distribution, proliferative dynamics, and stage-specific marker expression of these cells in the rabbit and mouse CNS, also assessing their existence in other mammalian species. mMap5 cells were never found to co-express the Ng2 antigen. They appear to be a population of glial cells sharing features but also differences with Ng2+progenitor cells. We show that mMap5 cells are newly generated, postmitotic parenchymal elements of the oligodendroglial lineage, thus being a stage-specific population of polydendrocytes. Finally, we report that the number of mMap5 cells, although reduced within the brain of adult/old animals, can increase in neurodegenerative and traumatic conditions. PMID- 23667596 TI - Motor recovery and synaptic preservation after ventral root avulsion and repair with a fibrin sealant derived from snake venom. AB - BACKGROUND: Ventral root avulsion is an experimental model of proximal axonal injury at the central/peripheral nervous system interface that results in paralysis and poor clinical outcome after restorative surgery. Root reimplantation may decrease neuronal degeneration in such cases. We describe the use of a snake venom-derived fibrin sealant during surgical reconnection of avulsed roots at the spinal cord surface. The present work investigates the effects of this fibrin sealant on functional recovery, neuronal survival, synaptic plasticity, and glial reaction in the spinal motoneuron microenvironment after ventral root reimplantation. METHODOLOGY/PRINCIPAL FINDINGS: Female Lewis rats (7 weeks old) were subjected to VRA and root replantation. The animals were divided into two groups: 1) avulsion only and 2) replanted roots with fibrin sealant derived from snake venom. Post-surgical motor performance was evaluated using the CatWalk system twice a week for 12 weeks. The rats were sacrificed 12 weeks after surgery, and their lumbar intumescences were processed for motoneuron counting and immunohistochemistry (GFAP, Iba-1 and synaptophysin antisera). Array based qRT-PCR was used to evaluate gene regulation of several neurotrophic factors and receptors as well as inflammatory related molecules. The results indicated that the root reimplantation with fibrin sealant enhanced motor recovery, preserved the synaptic covering of the motoneurons and improved neuronal survival. The replanted group did not show significant changes in microglial response compared to VRA-only. However, the astroglial reaction was significantly reduced in this group. CONCLUSIONS/SIGNIFICANCE: In conclusion, the present data suggest that the repair of avulsed roots with snake venom fibrin glue at the exact point of detachment results in neuroprotection and preservation of the synaptic network at the microenvironment of the lesioned motoneurons. Also such procedure reduced the astroglial reaction and increased mRNA levels to neurotrophins and anti-inflammatory cytokines that may in turn, contribute to improving recovery of motor function. PMID- 23667598 TI - Contrasting selective pressures on seed traits of two congeneric species by their main native guilds of dispersers on islands. AB - Many fleshy-fruited plants from the Mediterranean and Macaronesian islands are dispersed through endozoochory. In mainland Mediterranean areas, reciprocal adaptations have been found between plants and animals, although evidence is scarce. On small isolated oceanic islands, such reciprocal adaptations might well be more prevalent due to intrinsic island traits. Here we evaluate the existence of selective pressures exerted by two different disperser guilds (lizards and birds) on two seed traits (seed coat thickness and seed germination pattern) of two congeneric species present on Mediterranean and Macaronesian islands. In the continental Balearic Islands, Rubia peregrina has evolved mostly with birds, although frugivorous lizards are present in some of these islands and are known to eventually consume its fruits. By contrast, R. fruticosa, endemic to the Macaronesian archipelago, has evolved mostly interacting with lizards and only recently with birds. We hypothesized that R. fruticosa would be especially adapted to saurochory, with thicker seed coats and higher germination proportion, whereas R. peregrina would be more adapted to ornithocory, with thinner seed coats and showing a lower germination percentage after being ingested by lizards. Captivity experiments of seed ingestions by natural and non-natural dispersers (i.e., frugivores that have not evolved with those plants) were conducted. Results suggest that dispersers did not exert any strong enough selective pressure to induce changes in germination patterns. We attribute this to the fact that the Rubiaceae is an ancestral family in the Mediterranean (both on continent and islands) and thus probably interacted with lizards in the past. Lastly, although we hold that the seed coat structure of R. fruticosa is probably associated with its evolutionary success after a long interaction with insular lizards, our findings support the idea that the relationship between endozoochorous plants and the guild of dispersers with whom they evolved is rather unspecific. PMID- 23667597 TI - The second intracellular loop of the human cannabinoid CB2 receptor governs G protein coupling in coordination with the carboxyl terminal domain. AB - The major effects of cannabinoids and endocannabinoids are mediated via two G protein-coupled receptors, CB1 and CB2, elucidation of the mechanism and structural determinants of the CB2 receptor coupling with G proteins will have a significant impact on drug discovery. In the present study, we systematically investigated the role of the intracellular loops in the interaction of the CB2 receptor with G proteins using chimeric receptors alongside the characterization of cAMP accumulation and ERK1/2 phosphorylation. We provided evidence that ICL2 was significantly involved in G protein coupling in coordination with the C terminal end. Moreover, a single alanine substitution of the Pro-139 in the CB2 receptor that corresponds to Leu-222 in the CB1 receptor resulted in a moderate impairment in the inhibition of cAMP accumulation, whereas mutants P139F, P139M and P139L were able to couple to the Gs protein in a CRE-driven luciferase assay. With the ERK activation experiments, we further found that P139L has the ability to activate ERK through both Gi- and Gs-mediated pathways. Our findings defined an essential role of the second intracellular loop of the CB2 receptor in coordination with the C-terminal tail in G protein coupling and receptor activation. PMID- 23667599 TI - Factors associated with coverage of cotrimoxazole prophylaxis in HIV-exposed children in South Africa. AB - BACKGROUND: The World Health Organisation and the Joint United Nations Programme in 2006 reaffirmed the earlier recommendation of 2000 that all HIV-exposed infants in resource-poor countries should commence cotrimoxazole (CTX) prophylaxis at 6-weeks of life. CTX prophylaxis should be continued until the child is confirmed HIV-uninfected and there is no further exposure to breastmilk transmission. We determined CTX coverage and explored factors associated with CTX administration in HIV-exposed infants at a primary health clinic in South Africa. METHODS: In a cross-sectional study of HIV-exposed infants 6-18 months of age attending a child immunisation clinic, data from the current visit and previous visits related to CTX prophylaxis, feeding practice and infant HIV testing were extracted from the child's immunisation record. Further information related to the administration of CTX prophylaxis was obtained from an interview with the child's mother. RESULTS: One-third (33.0%) HIV-exposed infants had not initiated CTX at all and breastfed infants were more likely to have commenced CTX prophylaxis as compared to their non-breastfed counterparts (78.7% vs 63.4%) (p = 0.008). Availability of infant's HIV status was strongly associated with continuation or discontinuation of CTX after 6 months of age or after breastfeeding cessation. Maternal self-reports indicated that only 52.5% (95%CI 47.5-57.5) understood the reason for CTX prophylaxis, 126 (47%) did not dose during weekends; 55 (21%) dosed their infants 3 times a day and 70 (26%) dosed their infants twice daily. CONCLUSION: A third of HIV-exposed children attending a primary health care facility in this South African setting did not receive CTX prophylaxis. Not commencing CTX prophylaxis was strongly associated with infants not breastfeeding and unnecessary continued exposure to CTX in this paediatric population was due to limited availability of early infant diagnosis. Attendance at immunization clinics can be seen as missed opportunities for early infant diagnosis of HIV and related care. PMID- 23667600 TI - Crayfish impact desert river ecosystem function and litter-dwelling invertebrate communities through association with novel detrital resources. AB - Shifts in plant species distributions due to global change are increasing the availability of novel resources in a variety of ecosystems worldwide. In semiarid riparian areas, hydric pioneer tree species are being replaced by drought tolerant plant species as water availability decreases. Additionally, introduced omnivorous crayfish, which feed upon primary producers, allochthonous detritus, and benthic invertebrates, can impact communities at multiple levels through both direct and indirect effects mediated by drought-tolerant plants. We tested the impact of both virile crayfish (Orconectes virilis) and litter type on benthic invertebrates and the effect of crayfish on detrital resources across a gradient of riparian vegetation drought-tolerance using field cages with leaf litter bags in the San Pedro River in Southeastern Arizona. Virile crayfish increased breakdown rate of novel drought-tolerant saltcedar (Tamarix ramosissima), but did not impact breakdown of drought-tolerant seepwillow (Baccharis salicifolia) or hydric Fremont cottonwood (Populus fremontii) and Gooding's willow (Salix goodingii). Effects on invertebrate diversity were observed at the litter bag scale, but no effects were found at the cage scale. Crayfish decreased alpha diversity of colonizing macroinvertebrates, but did not affect beta diversity. In contrast, the drought-tolerant litter treatment decreased beta diversity relative to hydric litter. As drought-tolerant species become more abundant in riparian zones, their litter will become a larger component of the organic matter budget of desert streams which may serve to homogenize the litter-dwelling community and support elevated populations of virile crayfish. Through impacts at multiple trophic levels, crayfish have a significant effect on desert stream ecosystems. PMID- 23667601 TI - Genome-scale modeling of the protein secretory machinery in yeast. AB - The protein secretory machinery in Eukarya is involved in post-translational modification (PTMs) and sorting of the secretory and many transmembrane proteins. While the secretory machinery has been well-studied using classic reductionist approaches, a holistic view of its complex nature is lacking. Here, we present the first genome-scale model for the yeast secretory machinery which captures the knowledge generated through more than 50 years of research. The model is based on the concept of a Protein Specific Information Matrix (PSIM: characterized by seven PTMs features). An algorithm was developed which mimics secretory machinery and assigns each secretory protein to a particular secretory class that determines the set of PTMs and transport steps specific to each protein. Protein abundances were integrated with the model in order to gain system level estimation of the metabolic demands associated with the processing of each specific protein as well as a quantitative estimation of the activity of each component of the secretory machinery. PMID- 23667602 TI - Serial foodborne norovirus outbreaks associated with multiple genotypes. AB - Noroviruses (NoV) have been recognized as an important pathogen associated with acute gastroenteritis worldwide during the past three decades. In the spring of 2012, a series of foodborne outbreaks in tourist groups were reported to Xiamen Center for Disease Control and Prevention, Xiamen, Fujian province, China. Among a total of 268 tourists in 7 groups, the prevalence rate of acute gastroenteritis was 16.0% (43/268). Twenty-three feces or anal swabs were collected for laboratory tests of causative agents, no bacterial pathogen was identified, while 22 of them were positive for NoV RNA. In addition, thirteen NoV fragments were recovered from positive specimens and sequenced, belonging to five genotypes such as GI.3, GI.4, GII.4, GII.6, and GII.14, respectively. However, NoV fragments obtained from locally infected patients showed distinct genotypes. Therefore, epidemiological investigation and laboratory analyses demonstrated that the serial foodborne NoV outbreaks in tourists were co-infection of multiple genotypes induced acute gastroenteritis linked to a restaurant. PMID- 23667603 TI - Widespread occurrence of Batrachochytrium dendrobatidis in contemporary and historical samples of the endangered Bombina pachypus along the Italian peninsula. AB - Batrachochytrium dendrobatidis is considered a main driver of the worldwide declines and extinctions of amphibian populations. Nonetheless, fundamental questions about its epidemiology, including whether it acts mainly as a "lone killer" or in conjunction with other factors, remain largely open. In this paper we analysed contemporary and historical samples of the endangered Apennine yellow bellied toad (Bombina pachypus) along the Italian peninsula, in order to assess the presence of the pathogen and its spreading dynamics. Once common throughout its range, B. pachypus started to decline after the mid-1990s in the northern and central regions, whereas no declines have been observed so far in the southern region. We show that Batrachochytrium dendrobatidis is currently widespread along the entire peninsula, and that this was already so at least as early as the late 1970s, that is, well before the beginning of the observed declines. This temporal mismatch between pathogen occurrence and host decline, as well as the spatial pattern of the declines, suggests that the pathogen has not acted as a "lone killer", but in conjunction with other factors. Among the potentially interacting factors, we identified two as the most probable, genetic diversity of host populations and recent climate changes. We discuss the plausibility of this scenario and its implications on the conservation of B. pachypus populations. PMID- 23667604 TI - Malaria control and the intensity of Plasmodium falciparum transmission in Namibia 1969-1992. AB - BACKGROUND: Historical evidence of the levels of intervention scale up and its relationships to changing malaria risks provides important contextual information for current ambitions to eliminate malaria in various regions of Africa today. METHODS: Community-based Plasmodium falciparum prevalence data from 3,260 geo coded time-space locations between 1969 and 1992 were assembled from archives covering an examination of 230,174 individuals located in northern Namibia. These data were standardized the age-range 2 to less than 10 years and used within a Bayesian model-based geo-statistical framework to examine the changes of malaria risk in the years 1969, 1974, 1979, 1984 and 1989 at 5*5 km spatial resolution. This changing risk was described against rainfall seasons and the wide-scale use of indoor-residual house-spraying and mass drug administration. RESULTS: Most areas of Northern Namibia experienced low intensity transmission during a ten year period of wide-scale control activities between 1969 and 1979. As control efforts waned, flooding occurred, drug resistance emerged and the war for independence intensified the spatial extent of moderate-to-high malaria transmission expanded reaching a peak in the late 1980s. CONCLUSIONS: Targeting vectors and parasite in northern Namibia was likely to have successfully sustained a situation of low intensity transmission, but unraveled quickly to a peak of transmission intensity following a sequence of events by the early 1990s. PMID- 23667605 TI - Comparative physiology of oleaginous species from the Yarrowia clade. AB - Yarrowia lipolytica is a genetically tractable yeast species that has become an attractive model for analyses of lipid metabolism, due to its oleaginous nature. We investigated the regulation and evolution of lipid metabolism in non Saccharomycetaceae yeasts, by carrying out a comparative physiological analysis of eight species recently assigned to the Yarrowia clade: Candida alimentaria, Y. deformans, C. galli, C. hispaniensis, C. hollandica, C. oslonensis, C. phangngensis and Y. yakushimensis. We compared the abilities of type strains of these species to grow on 31 non hydrophobic (sugars and other carbohydrate compounds) and 13 hydrophobic (triglycerides, alkanes and free fatty acids) carbon sources. Limited phenotypic diversity was observed in terms of the range of substrates used and, in the case of short-chain fatty acids, their toxicity. We assessed the oleaginous nature of these species, by evaluating their ability to store and to synthesize lipids. The mean lipid content of cells grown on oleic acid differed considerably between species, ranging from 30% of cell dry weight in C. oslonensis to 67% in C. hispaniensis. Lipid synthesis in cells grown on glucose resulted in the accumulation of C18:1 (n-9) as the major compound in most species, except for C. alimentaria and Y. yakushimensis, which accumulated principally C18:2(n-6), and C. hispaniensis, which accumulated both C16:0 and C18:1(n-9). Thus, all species of the clade were oleaginous, but they presented specific patterns of growth, lipid synthesis and storage, and therefore constitute good models for the comparative analysis of lipid metabolism in this basal yeast clade. PMID- 23667606 TI - Comprehensive investigation of the caveolin 2 gene: resequencing and association for kidney transplant outcomes. AB - Caveolae are plasma membrane structures formed from a complex of the proteins caveolin-1 and caveolin-2. Caveolae interact with pro-inflammatory cytokines and are dysregulated in fibrotic disease. Although caveolae are present infrequently in healthy kidneys, they are abundant during kidney injury. An association has been identified between a CAV1 gene variant and long term kidney transplant survival. Chronic, gradual decline in transplant function is a persistent problem in kidney transplantation. The aetiology of this is diverse but fibrosis within the transplanted organ is the common end point. This study is the first to investigate the association of CAV2 gene variants with kidney transplant outcomes. Genomic DNA from donors and recipients of 575 kidney transplants performed in Belfast was investigated for common variation in CAV2 using a tag SNP approach. The CAV2 SNP rs13221869 was nominally significant for kidney transplant failure. Validation was sought in an independent group of kidney transplant donors and recipients from Dublin, Ireland using a second genotyping technology. Due to the unexpected absence of rs13221869 from this cohort, the CAV2 gene was resequenced. One novel SNP and a novel insertion/deletion in CAV2 were identified; rs13221869 is located in a repetitive region and was not a true variant in resequenced populations. CAV2 is a plausible candidate gene for association with kidney transplant outcomes given its proximity to CAV1 and its role in attenuating fibrosis. This study does not support an association between CAV2 variation and kidney transplant survival. Further analysis of CAV2 should be undertaken with an awareness of the sequence complexities and genetic variants highlighted by this study. PMID- 23667607 TI - Anandamide reduces intracellular Ca2+ concentration through suppression of Na+/Ca2+ exchanger current in rat cardiac myocytes. AB - PURPOSE: Anandamide, one of the endocannabinoids, has been reported to exhibit cardioprotective properties, particularly in its ability to limit the damage produced by ischemia reperfusion injury. However, the mechanisms underlying the effect are not well known. This study is to investigate whether anandamide alter Na(+)/Ca(2+) exchanger and the intracellular free Ca(2+) concentration ([Ca(2+)]i). METHODS: Na(+)/Ca(2+) exchanger current (I(NCX)) was recorded and analysed by using whole-cell patch-clamp technique and [Ca(2+)]i was measured by loading myocytes with the fluorescent Ca(2+) indicator Fura-2/AM. RESULTS: We found that I(NCX) was enhanced significantly after perfusion with simulated ischemic external solution; [Ca(2+)]i was also significantly increased by simulated ischemic solution. The reversal potential of I(NCX) was shifted to negative potentials in simulated ischemic external solution. Anandamide (1-100 nM) failed to affect I(NCX) and [Ca(2+)]i in normal solution. However, anandamide (1-100 nM) suppressed the increase in INCX in simulated ischemic external solution concentration-dependently and normalized INCX reversal potential. Furthermore, anandamide (100 nM) significantly attenuated the increase in [Ca(2+)]i in simulated ischemic solution. Blocking CB1 receptors with the specific antagonist AM251 (500 nM) failed to affect the effects of anandamide on I(NCX) and [Ca(2+)]i in simulated ischemic solution. CB2 receptor antagonist AM630 (100 nM) eliminated the effects of anandamide on I(NCX) and [Ca(2+)]i in simulated ischemic solution, and CB2 receptor agonist JWH133 (100 nM) simulated the effects of anandamide that suppressed the increase in I(NCX) and [Ca(2+)]i in simulated ischemic solution. In addition, pretreatment with the Gi/o-specific inhibitor pertussis toxin (PTX, 500 ng/ml) eliminated the effects of anandamide and JWH133 on I(NCX) in simulated ischemic solution. CONCLUSIONS: Collectively, these findings suggest that anandamide suppresses calcium overload through inhibition of I(NCX) during perfusion with simulated ischemic solution; the effects may be mediated by CB2 receptor via PTX-sensitive Gi/o proteins. This mechanism is importantly involved in the anti-ischemia injury caused by endocannabinoids. PMID- 23667608 TI - Prevalence, mass, and glucose-uptake activity of 18F-FDG-detected brown adipose tissue in humans living in a temperate zone of Italy. AB - BACKGROUND: The 18F-fluorodeoxyglucose (18F-FDG)-detected brown adipose tissue (BAT), is enhanced by cold stimulus and modulated by other factors that still have to be disentangled. We investigated the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in a population of adults living in the temperate climatic zone of the Rome area. METHODS AND FINDINGS: We retrospectively analyzed 6454 patients who underwent 18F-FDG positron emission tomography/computed tomography (PET/CT) examinations. We found 18F-FDG BAT in 217 of the 6454 patients (3.36%). Some of them underwent more than one scan and the positive scans were 278 among 8004 (3.47%). The prevalence of patients with at least one positive scan was lower in men (1.77%; 56 of 3161) compared with women (4.88%; 161 of 3293). The BAT positive patients were most frequently younger, thinner and with lower plasma glucose levels compared with BAT negative patients. The amount of BAT in the defined region of interest, the activity of BAT and the number of positive sites of active BAT were similar in both sexes. The prevalence of patients with 18F-FDG positive PET/CT was highest in December-February, lower in March-May and September-November, and lowest in June-August and was positively correlated with night length and negatively correlated with ambient temperature. Changes in day length and variations of temperature, associated with the prevalence of positive BAT patients. Among the patients who had multiple scans, outdoor temperature was significantly lower and day length was shorter on the occasion when BAT was detected. CONCLUSIONS: This study identifies day length, outdoor temperature, age, sex, BMI, and plasma glucose levels as major determinants of the prevalence, mass, and activity of 18F-FDG-detected BAT. PMID- 23667609 TI - Nrf2 pathway regulates multidrug-resistance-associated protein 1 in small cell lung cancer. AB - Although multidrug-resistance-associated protein-1 (MRP1) is a major contributor to multi-drug resistance (MDR), the regulatory mechanism of Mrp1 still remains unclear. Nrf2 is a transcription factor that regulates cellular defense response through antioxidant response elements (AREs) in normal tissues. Recently, Nrf2 has emerged as an important contributor to chemo-resistance in tumor tissues. In the present study, the role of Nrf2-ARE pathway on regulation of Mrp1 was investigated. Compared with H69 lung cancer cells, H69AR cells with MDR showed significantly higher Nrf2-ARE pathway activity and expression of Mrp1 as well. When Nrf2 was knocked down in H69AR cells, MRP1's expression decreased accordingly. Moreover, those H69AR cells with reduced Nrf2 level restored sensitivity to chemo-drugs. To explore how Nrf2-ARE pathway regulates Mrp1, the promoter of Mrp1 gene was searched, and two putative AREs--ARE1 and ARE2--were found. Using reporter gene and ChIP assay, both ARE1 and ARE2 showed response to and interaction with Nrf2. In 40 cases of cancer tissues, the expression of Nrf2 and MRP1 was measured by immunohistochemistry (IHC). As the quantitive data of IHC indicated, both Nrf2 and MRP1 showed significantly higher expression in tumor tissue than adjacent non-tumor tissue. And more important, the correlation analysis of the two genes proved that their expression was correlative. Taken together, theses data suggested that Nrf2-ARE pathway is required for the regulatory expression of Mrp1 and implicated Nrf2 as a new therapeutic target for MDR. PMID- 23667610 TI - 3C3R modified PBL pediatric teaching of Chinese medical students. AB - A Content, Context, Connection and Researching, Reasoning, Reflecting (3C3R) model is a conceptual framework for problem-based learning (PBL) problem design. We introduced the 3C3R-PBL method into a pediatric teaching plan, and evaluated its effectiveness and feasibility. The 3C3R model was applied in a pediatric problem design teaching plan "why the lips turn purple when a baby is crying". All students were assigned either into a traditional PBL course or into a 9-step 3C3R model PBL course (3C3R-PBL). The performance outcomes of both groups were compared. For the PBL group, the proportion of students scoring >=4 for content, context, and problem design connection, was 90.8%, 80.3%, and 64.5% respectively, while for tutors, it was 71.4%, 71.4%, and 28.6%; for researching, reasoning, and reflecting, the proportion of students scoring >=4 was 81.6%, 55.3%, and 40.8%, while for tutors, it was 71.4%, 100%, and 57.1%. The learning difficulty was not considered high with only 31.6% of students and 42.9% of tutors rating the task as difficult. For the 3C3R-PBL group, the proportion of students scoring content, context, and connection, >=4 was 100%, 98.4%, and 90.5%, while for tutors it was 100%, 100%, 83.3%; for researching, reasoning, and reflecting, the proportion of students scoring >=4 was 95.2%, 88.9%, and 76.2%, while for tutors it was 100% for all 3 R components. Students and tutors were convinced by the content, case context, research process and reasoning process of both teaching plans, while scores for connection and reflecting were significantly improved when the PBL plan was amended by a 3C3R model (p<0.05) and the case learning difficulty was statistically increased (p<0.05). The 3C3R model, evaluated for the first time in China, was helpful for effective and reliable problem design in a pediatric PBL teaching plan for Chinese students. PMID- 23667611 TI - Prevalence and antimicrobial susceptibility patterns of bacteria from milkmen and cows with clinical mastitis in and around Kampala, Uganda. AB - BACKGROUND: Identification of pathogens associated with bovine mastitis is helpful in treatment and management decisions. However, such data from sub Saharan Africa is scarce. Here we describe the distribution and antimicrobial susceptibility patterns of bacteria from cows with clinical mastitis in Kampala, Uganda. Due to high concern of zoonotic infections, isolates from milkmen are also described. METHODOLOGY/PRINCIPAL FINDINGS: Ninety seven milk samples from cows with clinical mastitis and 31 nasal swabs from milkmen were collected (one sample per cow/human). Fifty eight (60%) Gram-positive isolates namely Staphylococci (21), Enterococci (16), Streptococci (13), Lactococci (5), Micrococci (2) and Arcanobacteria (1) were detected in cows; only one grew Staphylococcus aureus. Furthermore, 24 (25%) coliforms namely Escherichia coli (12), Klebsiella oxytoca (5), Proteus vulgaris (2), Serratia (2), Citrobacter (1), Cedecea (1) and Leclercia (1) were identified. From humans, 24 Gram-positive bacteria grew, of which 11 were Staphylococci (35%) including four Staphylococcus aureus. Upon susceptibility testing, methicillin-resistant coagulase-negative staphylococci (CoNS) were prevalent; 57%, 12/21 in cows and 64%, 7/11 in humans. However, methicillin-resistant Staphylococcus aureus was not detected. Furthermore, methicillin and vancomycin resistant CoNS were detected in cows (Staphylococcus hominis, Staphylococcus lugdunensis) and humans (Staphylococcus scuiri). Also, vancomycin and daptomycin resistant Enterococci (Enterococcus faecalis and Enterococcus faecium, respectively) were detected in cows. Coliforms were less resistant with three pan-susceptible isolates. However, multidrug resistant Klebsiella, Proteus, Serratia, Cedecea, and Citrobacter were detected. Lastly, similar species grew from human and bovine samples but on genotyping, the isolates were found to be different. Interestingly, human and bovine Staphylococcus aureus were genetically similar (spa-CC435, spa-type t645 corresponding to ST121) but with different susceptibility patterns. CONCLUSIONS/SIGNIFICANCE: CoNS, Enterococci, Streptococci, and Escherichia coli are the predominant pathogens associated with clinical bovine-mastitis in Kampala, Uganda. Multidrug resistant bacteria are also prevalent. While similar species occurred in humans and cows, transmission was not detected. PMID- 23667612 TI - The natural human IgM antibody PAT-SM6 induces apoptosis in primary human multiple myeloma cells by targeting heat shock protein GRP78. AB - In contrast to other haematological malignancies, targeted immunotherapy has not entered standard treatment regimens for de novo or relapsed multiple myeloma (MM) yet. While a number of IgG-formatted monoclonal antibodies are currently being evaluated in clinical trials in MM, our study aimed to investigate whether the fully human IgM monoclonal antibody PAT-SM6 that targets a tumour-specific variant of the heat shock protein GRP78 might be an attractive candidate for future immunotherapeutic approaches. We here show that GRP78 is stably and consistently expressed on the surface on tumour cells from patients with de novo, but also relapsed MM and that binding of PAT-SM6 to MM cells can specifically exert cytotoxic effects on malignant plasma cells, whereas non-malignant cells are not targeted. We demonstrate that the induction of apoptosis and, to a lesser extent, complement dependent cytotoxicity is the main mode of action of PAT-SM6, whereas antibody dependent cellular cytotoxicity does not appear to contribute to the cytotoxic properties of this antibody. Given the favourable safety profile of PAT-SM6 in monkeys, but also in a recent phase I trial in patients with malignant melanoma, our results form the basis for a planned phase I study in patients with relapsed MM. PMID- 23667613 TI - Early and unintentional release of planned motor actions during motor cortical preparation. AB - Voluntary movements are often preceded by a movement-related potential beginning as much as two seconds prior to the onset of movement. In light of evidence that motor actions can be prepared and initiated in less than 200 ms, the function of this early activity has remained enigmatic. We hypothesized that the movement related potential reflects the state of preparation of the planned movement. This was tested by delivering a startling acoustic stimulus during the preparation phase of a load-release task. The cue to release the load was presented either 3.5 seconds after a warning cue (PREDICT condition) or randomly between 4-12 seconds (REACT condition). Electroencephalographic, electromyographic and limb and load kinematic signals were recorded. In a subset of trials, a startle stimulus was delivered at -1500, -1000, -500, -250, -100 or 0 ms before the release cue. A contingent-negative variation (CNV) waveform, with a late phase of slow-rising negativity beginning an average of 1459 ms prior to movement, was observed for the PREDICT condition but not the REACT condition. For both conditions, the startle stimulus frequently evoked the early and unintentional release of the load-release sequence. The incidence of release was significantly (p<0.001) correlated with the late phase of the CNV for the PREDICT condition but not the REACT condition. For the REACT condition, the incidence of movement release was subject-specific, constant across the preparation interval, and uncorrelated with cortical activity. The onset of movement release by the startle stimulus was significantly shorter (p<0.001) for the PREDICT compared to the REACT condition. These findings provide evidence that the late phase of the CNV reflects cortical activity mediating the progressive preparation and storage of the forthcoming movement and that during this phase an intense sensory stimulus can evoke early and unintentional release of the planned action. PMID- 23667614 TI - Questioning the causal link between maternal smoking during pregnancy and offspring use of psychotropic medication: a sibling design analysis. AB - A recent population-based, longitudinal study from Finland observed a dose response association between smoking during pregnancy (SDP) and use of psychotropic medications in exposed children and young adults. However, this association may be confounded by unmeasured familial characteristics related to both SDP and offspring mental health. Consequently, we aim to investigate the effect of SDP by means of a sibling design that to some extent allows controlling for unknown environmental and genetic confounders. Using the Swedish Medical Birth Register (1987-1993), which was linked to the Swedish Prescribed Drugs Register (July 2005-December 2008), we investigated 579,543 children and among them 39, 007 were discordant for use of psychotropic medication and 4,021 siblings discordant for both use of psychotropic medication and for smoking exposure. Replicating the Finnish study using traditional logistic regression methods we found an association between exposure to >=10 cigarettes per day during pregnancy and psychotropic drug use (odds ratio = 1.61, 95% confidence interval 1.56, 1.66). Similar in size to the association reported from Finland (odds ratio = 1.63; 95% confidence interval 1.53, 1.74). However, in the adjusted sibling analysis using conditional logistic regression, the association was considerably reduced (odds ratio 1.22; 95% confidence interval 1.08, 1.38). Preventing smoking is of major public health importance. However, SDP per se appears to have less influence on offspring psychotropic drug use than previously suggested. PMID- 23667615 TI - Inhaled steroids modulate extracellular matrix composition in bronchial biopsies of COPD patients: a randomized, controlled trial. AB - RATIONALE: Smoking and inflammation contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD), which involves changes in extracellular matrix. This is thought to contribute to airway remodeling and airflow obstruction. We have previously observed that long-term treatment with inhaled corticosteroids can not only reduce bronchial inflammation, but can also attenuate lung function decline in moderate-severe COPD. We hypothesized that inhaled corticosteroids and current smoking modulate bronchial extracellular matrix components in COPD. OBJECTIVE: To compare major extracellular matrix components (elastic fibers; proteoglycans [versican, decorin]; collagens type I and III) in bronchial biopsies 1) after 30-months inhaled steroids treatment or placebo; and 2) between current and ex-smokers with COPD. METHODS: We included 64 moderate-severe, steroid-naive COPD patients (24/40 (ex)-smokers, 62+/-7 years, 46 (31-54) packyears, post-bronchodilator forced expiratory volume in one second (FEV1) 62+/-9% predicted) at baseline in this randomized, controlled trial. 19 and 13 patients received 30-months treatment with fluticasone or placebo, respectively. Bronchial biopsies collected at baseline and after 30 months were studied using (immuno)histochemistry to evaluate extracellular matrix content. Percentage and density of stained area were calculated by digital image analysis. RESULTS: 30-Months inhaled steroids increased the percentage stained area of versican (9.6% [CI 0.9 to 18.3%]; p = 0.03) and collagen III (20.6% [CI 3.8 to 37.4%]; p = 0.02) compared to placebo. Increased collagen I staining density correlated with increased post-bronchodilator FEV1 after inhaled steroids treatment (Rs = 0.45, p = 0.04). There were no differences between smokers and ex smokers with COPD in percentages and densities for all extracellular matrix proteins. CONCLUSIONS: These data show that long-term inhaled corticosteroids treatment partially changes the composition of extracellular matrix in moderate severe COPD. This is associated with increased lung function, suggesting that long-term inhaled steroids modulate airway remodeling thereby potentially preventing airway collapse in COPD. Smoking status is not associated with bronchial extracellular matrix proteins. TRIAL REGISTRATION: ClinicalTrials.gov NCT00158847. PMID- 23667616 TI - Administration of bleomycin via the oropharyngeal aspiration route leads to sustained lung fibrosis in mice and rats as quantified by UTE-MRI and histology. AB - Pulmonary fibrosis can be experimentally induced in small rodents by bleomycin. The antibiotic is usually administered via the intratracheal or intranasal routes. In the present study, we investigated the oropharyngeal aspiration of bleomycin as an alternative route for the induction of lung fibrosis in rats and mice. The development of lung injury was followed in vivo by ultrashort echo time magnetic resonance imaging (UTE-MRI) and by post-mortem analyses (histology of collagen, hydroxyproline determination, and qRT-PCR). In C57BL/6 mice, oropharyngeal aspiration of bleomycin led to more prominent lung fibrosis as compared to intranasal administration. Consequently, the oropharyngeal aspiration route allowed a dose reduction of bleomycin and, therewith, a model refinement. Moreover, the distribution of collagen after oropharyngeal aspiration of bleomycin was more homogenous than after intranasal administration: for the oropharyngeal aspiration route, fibrotic areas appeared all over the lung lobes, while for the intranasal route fibrotic lesions appeared mainly around the largest superior airways. Thus, oropharyngeal aspiration of bleomycin induced morphological changes that were more comparable to the human disease than the intranasal administration route did. Oropharyngeal aspiration of bleomycin led to a homogeneous fibrotic injury also in rat lungs. The present data suggest oropharyngeal aspiration of bleomycin as a less invasive means to induce homogeneous and sustained fibrosis in the lungs of mice and rats. PMID- 23667617 TI - Uptake of preventive treatment for intestinal schistosomiasis among school children in Jinja district, Uganda: a cross sectional study. AB - BACKGROUND: In Uganda, the current national health sector strategic and investment plan underscores schistosomiasis as one of the diseases targeted for elimination by the year 2015. However, uptake of treatment among school children is unknown but suspected to be low. We estimated the uptake and predictors of preventive treatment with praziquantel. METHODS: In a cross sectional study carried out in Jinja district of Uganda, a random sample of 1,010 children in 12 primary schools was questioned about their uptake of praziquantel, knowledge and perceptions about schistosomiasis, support for taking preventive treatment and the dangers of taking praziquantel. The prevalence and mean intensity of infection with Schistosoma mansoni were determined. RESULTS: Self reported uptake of praziquantel at last mass treatment was 28.2% (95% confidence interval (CI): 22.9%-33.6%). Overall prevalence and mean intensity of S. mansoni infection was 35% (95% CI: 25.4%-37.9%) and 116.1 eggs per gram (epg) of stool (95% CI: 98.3 137.1) respectively. Uptake of praziquantel was more likely if a child was from a school with high prevalence of infection, had knowledge about schistosomiasis transmission and prevention, and reported teachers' support to take praziquantel. Of the 285 children who took praziquantel, 142 (49.8%) developed side effects. Of the 725 children who did not take the drug, 522 (72.0%) reported fear of side effects as a major reason for non-uptake. CONCLUSIONS: Uptake of praziquantel in this population is very low. Fear of side effects of praziquantel, lack of knowledge about schistosomiasis transmission and prevention and lack of teacher support are some of the major factors associated with low uptake. PMID- 23667618 TI - Independent and supra-additive effects of alcohol consumption, cigarette smoking, and metabolic syndrome on the elevation of serum liver enzyme levels. AB - We investigated the independent and combined effects of alcohol consumption, cigarette smoking and metabolic syndrome on abnormal liver function, i.e., the elevation of serum liver enzyme levels. Participants of a Korean population-based prospective cohort aged >=30 years without liver disease, diabetes, or cardiovascular diseases were included. Information on alcohol consumption, smoking status, and metabolic syndrome, defined as per the criteria of the Adult Treatment Panel III, were applied to evaluate their impact on serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma glutamyl transferase (GGT). Alcohol consumption, cigarette smoking and metabolic syndrome were the significant individual factors that elevated serum liver enzyme levels. Supra-additive effects of metabolic syndrome and either alcohol consumption or cigarette smoking were also identified. The combination of heavy drinking (>=24 g/day) and metabolic syndrome conferred an effect that was higher than the sum of the two individual effects (Synergic Index (SI): AST, 2.37 [1.20 4.67]; GGT, 1.91 [1.17-3.13]). Only GGT level (odds ratio 6.04 [3.68-9.94], SI 2.33 [1.24-4.41]) was significantly elevated when the effect of moderate drinking (<24 g/day) and metabolic syndrome was combined. The combined effect of any level of alcohol consumption and cigarette smoking was also supra-additive on the elevation of GGT level with SIs of 5.57 for drinking <24 g/day and smoking <=20 pack years, 5.12 for <24 g/day and >20 pack years, 1.80 for >=24 g/day and <=20 pack years, 2.03 for >=24 g/day and >20 pack years, while only the combined effect of drinking >=24 g/day and smoking >20 pack years elevated the AST level (SI 4.55 [3.12-6.61]). The combined effect of cigarette smoking and metabolic syndrome was not supra-additive. To prevent fatty liver disease and other related diseases, a multifactorial prevention strategy that includes limited alcohol consumption, smoking cessation and rectification of adverse metabolic profiles is required. PMID- 23667619 TI - Different types of laughter modulate connectivity within distinct parts of the laughter perception network. AB - Laughter is an ancient signal of social communication among humans and non-human primates. Laughter types with complex social functions (e.g., taunt and joy) presumably evolved from the unequivocal and reflex-like social bonding signal of tickling laughter already present in non-human primates. Here, we investigated the modulations of cerebral connectivity associated with different laughter types as well as the effects of attention shifts between implicit and explicit processing of social information conveyed by laughter using functional magnetic resonance imaging (fMRI). Complex social laughter types and tickling laughter were found to modulate connectivity in two distinguishable but partially overlapping parts of the laughter perception network irrespective of task instructions. Connectivity changes, presumably related to the higher acoustic complexity of tickling laughter, occurred between areas in the prefrontal cortex and the auditory association cortex, potentially reflecting higher demands on acoustic analysis associated with increased information load on auditory attention, working memory, evaluation and response selection processes. In contrast, the higher degree of socio-relational information in complex social laughter types was linked to increases of connectivity between auditory association cortices, the right dorsolateral prefrontal cortex and brain areas associated with mentalizing as well as areas in the visual associative cortex. These modulations might reflect automatic analysis of acoustic features, attention direction to informative aspects of the laughter signal and the retention of those in working memory during evaluation processes. These processes may be associated with visual imagery supporting the formation of inferences on the intentions of our social counterparts. Here, the right dorsolateral precentral cortex appears as a network node potentially linking the functions of auditory and visual associative sensory cortices with those of the mentalizing associated anterior mediofrontal cortex during the decoding of social information in laughter. PMID- 23667620 TI - Effect of signal peptide on stability and folding of Escherichia coli thioredoxin. AB - The signal peptide plays a key role in targeting and membrane insertion of secretory and membrane proteins in both prokaryotes and eukaryotes. In E. coli, recombinant proteins can be targeted to the periplasmic space by fusing naturally occurring signal sequences to their N-terminus. The model protein thioredoxin was fused at its N-terminus with malE and pelB signal sequences. While WT and the pelB fusion are soluble when expressed, the malE fusion was targeted to inclusion bodies and was refolded in vitro to yield a monomeric product with identical secondary structure to WT thioredoxin. The purified recombinant proteins were studied with respect to their thermodynamic stability, aggregation propensity and activity, and compared with wild type thioredoxin, without a signal sequence. The presence of signal sequences leads to thermodynamic destabilization, reduces the activity and increases the aggregation propensity, with malE having much larger effects than pelB. These studies show that besides acting as address labels, signal sequences can modulate protein stability and aggregation in a sequence dependent manner. PMID- 23667621 TI - Raised intraocular pressure as a potential risk factor for visual loss in Leber Hereditary Optic Neuropathy. AB - Leber Hereditary Optic Neuropathy (LHON) is an important cause of inherited mitochondrial blindness among young adults. The majority of patients carry one of three mitochondrial DNA (mtDNA) point mutations: m.3460G>A, m.11778G>A and m.14484T>C, all of which affect critical complex I subunits of the mitochondrial respiratory chain. LHON is characterised by marked incomplete penetrance, clearly implying that the mtDNA mutation is insufficient on its own to trigger retinal ganglion cell dysfunction and visual loss. In this case series of three affected patients harbouring the m.11778G>A mutation, we provide evidence suggesting that raised intraocular pressure could be a risk factor triggering visual loss in at risk LHON carriers. PMID- 23667622 TI - Reduced endothelium-dependent relaxation to anandamide in mesenteric arteries from young obese Zucker rats. AB - Impaired vascular function, manifested by an altered ability of the endothelium to release endothelium-derived relaxing factors and endothelium-derived contracting factors, is consistently reported in obesity. Considering that the endothelium plays a major role in the relaxant response to the cannabinoid agonist anandamide, the present study tested the hypothesis that vascular relaxation to anandamide is decreased in obese rats. Mechanisms contributing to decreased anandamide-induced vasodilation were determined. Resistance mesenteric arteries from young obese Zucker rats (OZRs) and their lean counterparts (LZRs) were used. Vascular reactivity was evaluated in a myograph for isometric tension recording. Protein expression and localization were analyzed by Western blotting and immunofluorescence, respectively. Vasorelaxation to anandamide, acetylcholine, and sodium nitroprusside, as well as to CB1, CB2, and TRPV1 agonists was decreased in endothelium-intact mesenteric arteries from OZRs. Incubation with an AMP-dependent protein kinase (AMPK) activator or a fatty acid amide hydrolase inhibitor restored anandamide-induced vascular relaxation in OZRs. CB1 and CB2 receptors protein expression was decreased in arteries from OZRs. Incubation of mesenteric arteries with anandamide evoked endothelial nitric oxide synthase (eNOS), AMPK and acetyl CoA carboxylase phosphorylation in LZRs, whereas it decreased phosphorylation of these proteins in OZRs. In conclusion, obesity decreases anandamide-induced relaxation in resistance arteries. Decreased cannabinoid receptors expression, increased anandamide degradation, decreased AMPK/eNOS activity as well as impairment of the response mediated by TRPV1 activation seem to contribute to reduce responses to cannabinoid agonists in obesity. PMID- 23667623 TI - Cyclooxygenase-2 inhibition blocks M2 macrophage differentiation and suppresses metastasis in murine breast cancer model. AB - Tumor cells are often associated with abundant macrophages that resemble the alternatively activated M2 subset. Tumor-associated macrophages (TAMs) inhibit anti-tumor immune responses and promote metastasis. Cyclooxygenase-2 (COX-2) inhibition is known to prevent breast cancer metastasis. This study hypothesized that COX-2 inhibition affects TAM characteristics potentially relevant to tumor cell metastasis. We found that the specific COX-2 inhibitor, etodolac, inhibited human M2 macrophage differentiation, as determined by decreased CD14 and CD163 expressions and increased TNFalpha production. Several key metastasis-related mediators, such as vascular endothelial growth factor-A, vascular endothelial growth factor-C, and matrix metalloproteinase-9, were inhibited in the presence of etodolac as compared to untreated M2 macrophages. Murine bone marrow derived M2 macrophages also showed enhanced surface MHCII IA/IE and CD80, CD86 expressions together with enhanced TNFalpha expressions with etodolac treatment during differentiation. Using a BALB/c breast cancer model, we found that etodolac significantly reduced lung metastasis, possibly due to macrophages expressing increased IA/IE and TNFalpha, but decreased M2 macrophage-related genes expressions (Ym1, TGFbeta). In conclusion, COX-2 inhibition caused loss of the M2 macrophage characteristics of TAMs and may assist prevention of breast cancer metastasis. PMID- 23667625 TI - Bird migration advances more strongly in urban environments. AB - Urbanization has a marked effect on the reproduction and other ecological and behavioural traits of many living organisms, including birds. In migrant birds, survival and reproductive output is influenced by the (mis)synchronization of arrival with the availability of resources. Many recent studies have shown that arrival timing is related to temperatures en-route and at destination. Because urban areas are "heat islands", with higher temperatures that influence earlier vegetation and invertebrate development, this should favour earlier arrival of migrant birds to cities rather than to rural areas. In this paper, we analysed differences between urban and rural habitats in mean dates and trends of first arrival dates of 18 species of migratory bird species in western Poland during 1983-2010. For many individual species, and overall, mean first arrival date was significantly earlier in rural areas than in urban areas (significant for 11 species). However, the trend towards earlier first arrival dates was stronger in urban areas for 15 of the 18 species (significantly stronger in four species). Consequently, arrival dates in urban areas are fast approaching, or have now matched or passed those in rural areas. These findings suggest that recent environmental changes may have more rapidly changed the migratory habits of birds occupying urban habitats than those occupying rural habitats. PMID- 23667624 TI - Cortical hypoexcitation defines neuronal responses in the immediate aftermath of traumatic brain injury. AB - Traumatic brain injury (TBI) from a blow to the head is often associated with complex patterns of brain abnormalities that accompany deficits in cognitive and motor function. Previously we reported that a long-term consequence of TBI, induced with a closed-head injury method modelling human car and sporting accidents, is neuronal hyper-excitation in the rat sensory barrel cortex that receives tactile input from the face whiskers. Hyper-excitation occurred only in supra-granular layers and was stronger to complex than simple stimuli. We now examine changes in the immediate aftermath of TBI induced with same injury method. At 24 hours post-trauma significant sensorimotor deficits were observed and characterisation of the cortical population neuronal responses at that time revealed a depth-dependent suppression of neuronal responses, with reduced responses from supragranular layers through to input layer IV, but not in infragranular layers. In addition, increased spontaneous firing rate was recorded in cortical layers IV and V. We postulate that this early post-injury suppression of cortical processing of sensory input accounts for immediate post-trauma sensory morbidity and sets into train events that resolve into long-term cortical hyper-excitability in upper sensory cortex layers that may account for long-term sensory hyper-sensitivity in humans with TBI. PMID- 23667626 TI - Dengue virus type 3 adaptive changes during epidemics in Sao Jose de Rio Preto, Brazil, 2006-2007. AB - Global dengue virus spread in tropical and sub-tropical regions has become a major international public health concern. It is evident that DENV genetic diversity plays a significant role in the immunopathology of the disease and that the identification of polymorphisms associated with adaptive responses is important for vaccine development. The investigation of naturally occurring genomic variants may play an important role in the comprehension of different adaptive strategies used by these mutants to evade the human immune system. In order to elucidate this role we sequenced the complete polyprotein-coding region of thirty-three DENV-3 isolates to characterize variants circulating under high endemicity in the city of Sao Jose de Rio Preto, Brazil, during the onset of the 2006-07 epidemic. By inferring the evolutionary history on a local-scale and estimating rates of synonymous (dS) and nonsynonimous (dN) substitutions, we have documented at least two different introductions of DENV-3 into the city and detected 10 polymorphic codon sites under significant positive selection (dN/dS > 1) and 8 under significant purifying selection (dN/dS < 1). We found several polymorphic amino acid coding sites in the envelope (15), NS1 (17), NS2A (11), and NS5 (24) genes, which suggests that these genes may be experiencing relatively recent adaptive changes. Furthermore, some polymorphisms correlated with changes in the immunogenicity of several epitopes. Our study highlights the existence of significant and informative DENV variability at the spatio-temporal scale of an urban outbreak. PMID- 23667627 TI - A mixture approach to vagueness and ambiguity. AB - When asked to indicate which items from a set of candidates belong to a particular natural language category inter-individual differences occur: Individuals disagree which items should be considered category members. The premise of this paper is that these inter-individual differences in semantic categorization reflect both ambiguity and vagueness. Categorization differences are said to be due to ambiguity when individuals employ different criteria for categorization. For instance, individuals may disagree whether hiking or darts is the better example of sports because they emphasize respectively whether an activity is strenuous and whether rules apply. Categorization differences are said to be due to vagueness when individuals employ different cut-offs for separating members from non-members. For instance, the decision to include hiking in the sports category or not, may hinge on how strenuous different individuals require sports to be. This claim is supported by the application of a mixture model to categorization data for eight natural language categories. The mixture model can identify latent groups of categorizers who regard different items likely category members (i.e., ambiguity) with categorizers within each of the groups differing in their propensity to provide membership responses (i.e., vagueness). The identified subgroups are shown to emphasize different sets of category attributes when making their categorization decisions. PMID- 23667628 TI - Combining inferential and deductive approaches to estimate the potential geographical range of the invasive plant pathogen, Phytophthora ramorum. AB - Phytophthora ramorum, an invasive plant pathogen of unknown origin, causes considerable and widespread damage in plant industries and natural ecosystems of the USA and Europe. Estimating the potential geographical range of P. ramorum has been complicated by a lack of biological and geographical data with which to calibrate climatic models. Previous attempts to do so, using either invaded range data or surrogate species approaches, have delivered varying results. A simulation model was developed using CLIMEX to estimate the global climate suitability patterns for establishment of P. ramorum. Growth requirements and stress response parameters were derived from ecophysiological laboratory observations and site-level transmission and disease factors related to climate data in the field. Geographical distribution data from the USA (California and Oregon) and Norway were reserved from model-fitting and used to validate the models. The model suggests that the invasion of P. ramorum in both North America and Europe is still in its infancy and that it is presently occupying a small fraction of its potential range. Phytophthora ramorum appears to be climatically suited to large areas of Africa, Australasia and South America, where it could cause biodiversity and economic losses in plant industries and natural ecosystems with susceptible hosts if introduced. PMID- 23667629 TI - Acute exercise induces FGF21 expression in mice and in healthy humans. AB - Fibroblast growth factor 21 (FGF21) plays an important role in the regulation of energy homeostasis during starvation and has an excellent therapeutic potential for the treatment of type 2 diabetes in rodents and monkeys. Acute exercise affects glucose and lipid metabolism by increasing glucose uptake and lipolysis. However, it is not known whether acute exercise affects FGF21 expression. Here, we showed that serum FGF21 level is increased in mice after a single bout of acute exercise, and that this is accompanied by increased serum levels of free fatty acid, glycerol and ketone body. FGF21 gene expression was induced in the liver but not in skeletal muscle and white adipose tissue of mice after acute exercise, and further, the gene expression levels of hepatic peroxisome proliferator-activated receptor alpha (PPARalpha) and activating transcription factor 4 (ATF4) were also increased. In addition, we observed increased FGF21 level in serum of healthy male volunteers performing a treadmill run at 50 or 80% VO2max. These results suggest that FGF21 may also be associated with exercise induced lipolysis in addition to increased catecholamines and reduced insulin. PMID- 23667631 TI - A semi-quantitative method to denote generic physical activity phenotypes from long-term accelerometer data--the ATLAS index. AB - BACKGROUND: Physical activity is inversely correlated to morbidity and mortality risk. Large cohort studies use wearable accelerometer devices to measure physical activity objectively, providing data potentially relevant to identify different activity patterns and to correlate these to health-related outcome measures. A method to compute relevant characteristics of such data not only with regard to duration and intensity, but also to regularity of activity events, is necessary. The aims of this paper are to propose a new method--the ATLAS index (Activity Types from Long-term Accelerometric Sensor data)--to derive generic measures for distinguishing different characteristic activity phenotypes from accelerometer data, to propose a comprehensive graphical representation, and to conduct a proof of-concept with long-term measurements from different devices and cohorts. METHODS: The ATLAS index consists of the three dimensions regularity (reg), duration (dur) and intensity (int) of relevant activity events identified in long term accelerometer data. It can be regarded as a 3D vector and represented in a 3D cube graph. 12 exemplary data sets of three different cohort studies with 99,467 minutes of data were chosen for concept validation. RESULTS: Five archetypical activity types are proposed along with their dimensional characteristics (insufficiently active: low reg, int and dur; busy bee: low dur and int, high reg; cardio-active: medium reg, int and dur, endurance athlete: high reg, int and dur; and weekend warrior: high int and dur, low reg). The data sets are displayed in one common graph, indicating characteristic differences in activity patterns. CONCLUSION: The ATLAS index incorporates the relevant regularity dimension apart from the widely-used measures of duration and intensity. Along with the 3D representation, it allows to compare different activity types in cohort study populations, both visually and computationally using vector distance measures. Further research is necessary to validate the ATLAS index in order to find normative values and group centroids. PMID- 23667630 TI - Role of corticosterone on sleep homeostasis induced by REM sleep deprivation in rats. AB - Sleep is regulated by humoral and homeostatic processes. If on one hand chronic elevation of stress hormones impair sleep, on the other hand, rapid eye movement (REM) sleep deprivation induces elevation of glucocorticoids and time of REM sleep during the recovery period. In the present study we sought to examine whether manipulations of corticosterone levels during REM sleep deprivation would alter the subsequent sleep rebound. Adult male Wistar rats were fit with electrodes for sleep monitoring and submitted to four days of REM sleep deprivation under repeated corticosterone or metyrapone (an inhibitor of corticosterone synthesis) administration. Sleep parameters were continuously recorded throughout the sleep deprivation period and during 3 days of sleep recovery. Plasma levels of adrenocorticotropic hormone and corticosterone were also evaluated. Metyrapone treatment prevented the elevation of corticosterone plasma levels induced by REM sleep deprivation, whereas corticosterone administration to REM sleep-deprived rats resulted in lower corticosterone levels than in non-sleep deprived rats. Nonetheless, both corticosterone and metyrapone administration led to several alterations on sleep homeostasis, including reductions in the amount of non-REM and REM sleep during the recovery period, although corticosterone increased delta activity (1.0-4.0 Hz) during REM sleep deprivation. Metyrapone treatment of REM sleep-deprived rats reduced the number of REM sleep episodes. In conclusion, reduction of corticosterone levels during REM sleep deprivation resulted in impairment of sleep rebound, suggesting that physiological elevation of corticosterone levels resulting from REM sleep deprivation is necessary for plentiful recovery of sleep after this stressful event. PMID- 23667632 TI - Glioma cell death induced by irradiation or alkylating agent chemotherapy is independent of the intrinsic ceramide pathway. AB - BACKGROUND/AIMS: Resistance to genotoxic therapy is a characteristic feature of glioma cells. Acid sphingomyelinase (ASM) hydrolyzes sphingomyelin to ceramide and glucosylceramide synthase (GCS) catalyzes ceramide metabolism. Increased ceramide levels have been suggested to enhance chemotherapy-induced death of cancer cells. METHODS: Microarray and clinical data for ASM and GCS in astrocytomas WHO grade II-IV were acquired from the Rembrandt database. Moreover, the glioblastoma database of the Cancer Genome Atlas network (TCGA) was used for survival data of glioblastoma patients. For in vitro studies, increases in ceramide levels were achieved either by ASM overexpression or by the GCS inhibitor DL-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) in human glioma cell lines. Combinations of alkylating chemotherapy or irradiation and ASM overexpression, PPMP or exogenous ceramide were applied in parental cells. The anti-glioma effects were investigated by assessing proliferation, metabolic activity, viability and clonogenicity. Finally, viability and clonogenicity were assessed in temozolomide (TMZ)-resistant cells upon treatment with PPMP, exogenous ceramide, alkylating chemotherapy, irradiation or their combinations. RESULTS: Interrogations from the Rembrandt and TCGA database showed a better survival of glioblastoma patients with low expression of ASM or GCS. ASM overexpression or PPMP treatment alone led to ceramide accumulation but did not enhance the anti-glioma activity of alkylating chemotherapy or irradiation. PPMP or exogenous ceramide induced acute cytotoxicity in glioblastoma cells. Combined treatments with chemotherapy or irradiation led to additive, but not synergistic effects. Finally, no synergy was found when TMZ-resistant cells were treated with exogenous ceramide or PPMP alone or in combination with TMZ or irradiation. CONCLUSION: Modulation of intrinsic glioma cell ceramide levels by ASM overexpression or GCS inhibition does not enhance the anti-glioma activity of alkylating chemotherapy or irradiation. PMID- 23667634 TI - Effects of rootstocks on cryotolerance and overwintering survivorship of genic male sterile lines in upland cotton (Gossypium hirsutum L.). AB - Grafting desirable scion on stress-tolerant rootstocks provides an opportunity to improve the cryotolerance of scion. Genic male sterile (GMS) lines of plant could be used as sterile line and maintainer in breeding, and they have the conspicuous characteristics that the fertility of which is easy to regain but hard to maintain by sexual reproduction. In order to maintain the fertility of GMS cotton by means of its perennial growth on the basis of frostless winters in Nanning, Guangxi autonomous region, GMS line A4 was grafted onto 7 cryotolerant rootstocks (F118, F697, F098, F112, F113, P098 and P113), and the cryotolerance and the overwintering survivorship of scions were investigated. In consequence, when compared with control (self-grafted A4), the relative conductivity of the grafted plants in shoot bark was reduced (8.80%), the content of soluble sugar, soluble protein and free proline were higher, 25.00, 1.55, 3.46%, respectively; the overwintering survival rate and the height of regeneration bud under field condition of grafted plants were higher, 10.44, 15.75%, respectively; the order of the grafted plants based on the average subordinate function value of overwintering survivorship was A4/F113>A4/F118>A4/F098>A4/F697>A4/F112>A4/P098>A4/P113>A4/A4(CK); the correlation analyses indicated that the physiological parameters of cryotolerance could be used for forecasting the overwintering survivorship, and the relative conductivity could be chosen as the first physiological parameter for forecasting cryotolerance or overwintering survivorship. The results indicate that the cryotolerance and the overwintering survivorship of GMS cotton could be improved by grafting, and F113 appeared to be a valuable rootstock. PMID- 23667633 TI - Regulatable in vivo biotinylation expression system in mouse embryonic stem cells. AB - Embryonic stem (ES) cells have several unique attributes, the two most important of which are they can differentiate into all cell types in the body and they can proliferate indefinitely. To study the regulation of these phenomena, we developed a regulatable in vivo biotinylation expression system in mouse ES cells. The E. coli biotin ligase gene BirA, whose protein product can biotinylate a 15-aa peptide sequence, called the AviTag, was cloned downstream of an IRES. The primary vector containing the doxycycline controlled transactivator gene tTA and IRES-BirA was knocked into the ROSA26 locus by homologous recombination. The secondary vector containing the AviTag tagged hKlf4 gene was exchanged into the ROSA26 locus using Cre recombinase. Western blot analysis showed that the doxycycline induced BirA protein can biotinylate the doxycycline induced AviTag tagged hKlf4 protein. The induction of hKlf4 repressed cell growth in the presence or absence of LIF. Chromatin immunoprecipitation assays using streptavidin beads showed that the AviTag tagged hKlf4 protein could enrich the Nanog enhancer. Our results suggested that the regulatable biotinylation system is promising for the gene function studies in mouse ES cells. PMID- 23667635 TI - Next-generation sequencing identifies transportin 3 as the causative gene for LGMD1F. AB - Limb-girdle muscular dystrophies (LGMD) are genetically and clinically heterogeneous conditions. We investigated a large family with autosomal dominant transmission pattern, previously classified as LGMD1F and mapped to chromosome 7q32. Affected members are characterized by muscle weakness affecting earlier the pelvic girdle and the ileopsoas muscles. We sequenced the whole exome of four family members and identified a shared heterozygous frame-shift variant in the Transportin 3 (TNPO3) gene, encoding a member of the importin-beta super-family. The TNPO3 gene is mapped within the LGMD1F critical interval and its 923-amino acid human gene product is also expressed in skeletal muscle. In addition, we identified an isolated case of LGMD with a new missense mutation in the same gene. We localized the mutant TNPO3 around the nucleus, but not inside. The involvement of gene related to the nuclear transport suggests a novel disease mechanism leading to muscular dystrophy. PMID- 23667636 TI - The impact of epidemic violence on the prevalence of psychiatric disorders in Sao Paulo and Rio de Janeiro, Brazil. AB - BACKGROUND: Violence and other traumatic events, as well as psychiatric disorders are frequent in developing countries, but there are few population studies to show the actual impact of traumatic events in the psychiatric morbidity in low and middle-income countries (LMIC). AIMS: To study the relationship between traumatic events and prevalence of mental disorders in Sao Paulo and Rio de Janeiro, Brazil. METHODS: Cross-sectional survey carried out in 2007-2008 with a probabilistic representative sample of 15- to 75-year-old residents in Sao Paulo and Rio de Janeiro, Brazil, using the Composite International Diagnostic Interview. RESULTS: The sample comprised 3744 interviews. Nearly 90% of participants faced lifetime traumatic events. Lifetime prevalence of any disorders was 44% in Sao Paulo and 42.1% in Rio de Janeiro. One-year estimates were 32.5% and 31.2%. One-year prevalence of traumatic events was higher in Rio de Janeiro than Sao Paulo (35.1 vs. 21.7; p<0.001). Participants from Rio de Janeiro were less likely to have alcohol dependence (OR = 0.55; p = 0.027), depression (OR = 0.6; p = 0.006) generalized anxiety (OR = 0.59; p = 0.021) and post-traumatic stress disorder (OR = 0.62; p = 0.027). Traumatic events correlated with all diagnoses--e.g. assaultive violence with alcohol dependence (OR = 5.7; p<0.001) and with depression (OR = 1.7; p = 0.001). CONCLUSION: Our findings show that psychiatric disorders and traumatic events, especially violence, are extremely common in Sao Paulo and Rio de Janeiro, supporting the idea that neuropsychiatric disorders and external causes have become a major public health priority, as they are amongst the leading causes of burden of disease in low and middle-income countries. The comparison between the two cities regarding patterns of violence and psychiatric morbidity suggests that environmental factors may buffer the negative impacts of traumatic events. Identifying such factors might guide the implementation of interventions to improve mental health and quality of life in LMIC urban centers. PMID- 23667637 TI - Impairment of mitochondria in adult mouse brain overexpressing predominantly full length, N-terminally acetylated human alpha-synuclein. AB - While most forms of Parkinson's Disease (PD) are sporadic in nature, a small percentage of PD have genetic causes as first described for dominant, single base pair changes as well as duplication and triplication in the alpha-synuclein gene. The alpha-synuclein gene encodes a 140 amino acid residue protein that interacts with a variety of organelles including synaptic vesicles, lysosomes, endoplasmic reticulum/Golgi vesicles and, reported more recently, mitochondria. Here we examined the structural and functional interactions of human alpha-synuclein with brain mitochondria obtained from an early, pre-manifest mouse model for PD over expressing human alpha-synuclein (ASOTg). The membrane potential in ASOTg brain mitochondria was decreased relative to wildtype (WT) mitochondria, while reactive oxygen species (ROS) were elevated in ASOTg brain mitochondria. No selective interaction of human alpha-synuclein with mitochondrial electron transport complexes cI-cV was detected. Monomeric human alpha-synuclein plus carboxyl terminally truncated forms were the predominant isoforms detected in ASOTg brain mitochondria by 2-dimensional PAGE (Native/SDS) and immunoblotting. Oligomers or fibrils were not detected with amyloid conformational antibodies. Mass spectrometry of human alpha-synuclein in both ASOTg brain mitochondria and homogenates from surgically resected human cortex demonstrated that the protein was full-length and postranslationally modified by N-terminal acetylation. Overall the study showed that accumulation of full-length, N-terminally acetylated human alpha-synuclein was sufficient to disrupt brain mitochondrial function in adult mice. PMID- 23667638 TI - Apoptosis of bone marrow mesenchymal stem cells caused by homocysteine via activating JNK signal. AB - Bone marrow mesenchymal stem cells (BMSCs) are capable of homing to and repair damaged myocardial tissues. Apoptosis of BMSCs in response to various pathological stimuli leads to the attenuation of healing ability of BMSCs. Plenty of evidence has shown that elevated homocysteine level is a novel independent risk factor of cardiovascular diseases. The present study was aimed to investigate whether homocysteine may induce apoptosis of BMSCs and its underlying mechanisms. Here we uncovered that homocysteine significantly inhibited the cellular viability of BMSCs. Furthermore, TUNEL, AO/EB, Hoechst 333342 and Live/Death staining demonstrated the apoptotic morphological appearance of BMSCs after homocysteine treatment. A distinct increase of ROS level was also observed in homocysteine-treated BMSCs. The blockage of ROS by DMTU and NAC prevented the apoptosis of BMSCs induced by homocysteine, indicating ROS was involved in the apoptosis of BMSCs. Moreover, homocysteine also caused the depolarization of mitochondrial membrane potential of BMSCs. Furthermore, apoptotic appearance and mitochondrial membrane potential depolarization in homocysteine-treated BMSCs was significantly reversed by JNK inhibitor but not p38 MAPK and ERK inhibitors. Western blot also confirmed that p-JNK was significantly activated after exposing BMSCs to homocysteine. Homocysteine treatment caused a significant reduction of BMSCs-secreted VEGF and IGF-1 in the culture medium. Collectively, elevated homocysteine induced the apoptosis of BMSCs via ROS-induced the activation of JNK signal, which provides more insight into the molecular mechanisms of hyperhomocysteinemia-related cardiovascular diseases. PMID- 23667639 TI - Salinity tolerance of Picochlorum atomus and the use of salinity for contamination control by the freshwater cyanobacterium Pseudanabaena limnetica. AB - Microalgae are ideal candidates for waste-gas and -water remediation. However, salinity often varies between different sites. A cosmopolitan microalga with large salinity tolerance and consistent biochemical profiles would be ideal for standardised cultivation across various remediation sites. The aims of this study were to determine the effects of salinity on Picochlorum atomus growth, biomass productivity, nutrient uptake and biochemical profiles. To determine if target end-products could be manipulated, the effects of 4-day nutrient limitation were also determined. Culture salinity had no effect on growth, biomass productivity, phosphate, nitrate and total nitrogen uptake at 2, 8, 18, 28 and 36 ppt. 11 ppt, however, initiated a significantly higher total nitrogen uptake. While salinity had only minor effects on biochemical composition, nutrient depletion was a major driver for changes in biomass quality, leading to significant increases in total lipid, fatty acid and carbohydrate quantities. Fatty acid composition was also significantly affected by nutrient depletion, with an increased proportion of saturated and mono-unsaturated fatty acids. Having established that P. atomus is a euryhaline microalga, the effects of culture salinity on the development of the freshwater cyanobacterial contaminant Pseudanabaena limnetica were determined. Salinity at 28 and 36 ppt significantly inhibited establishment of P. limnetica in P. atomus cultures. In conclusion, P. atomus can be deployed for bioremediation at sites with highly variable salinities without effects on end product potential. Nutrient status critically affected biochemical profiles--an important consideration for end-product development by microalgal industries. 28 and 36 ppt slow the establishment of the freshwater cyanobacterium P. limnetica, allowing for harvest of low contaminant containing biomass. PMID- 23667640 TI - Acridone derivative 8a induces oxidative stress-mediated apoptosis in CCRF-CEM leukemia cells: application of metabolomics in mechanistic studies of antitumor agents. AB - A new acridone derivative, 2-aminoacetamido-10-(3, 5-dimethoxy)-benzyl-9(10H) acridone hydrochloride (named 8a) synthesized in our lab shows potent antitumor activity, but the mechanism of action remains unclear. Herein, we report the use of an UPLC/Q-TOF MS metabolomic approach to study the effects of three compounds with structures optimized step-by-step, 9(10H)-acridone (A), 10-(3,5 dimethoxy)benzyl-9(10H)-acridone (I), and 8a, on CCRF-CEM leukemia cells and to shed new light on the probable antitumor mechanism of 8a. Acquired data were processed by principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) to identify potential biomarkers. Comparing 8a-treated CCRF-CEM leukemia cells with vehicle control (DMSO), 23 distinct metabolites involved in five metabolic pathways were identified. Metabolites from glutathione (GSH) and glycerophospholipid metabolism were investigated in detail, and results showed that GSH level and the reduced/oxidized glutathione (GSH/GSSG) ratio were significantly decreased in 8a treated cells, while L-cysteinyl-glycine (L-Cys-Gly) and glutamate were greatly increased. In glycerophospholipid metabolism, cell membrane components phosphatidylcholines (PCs) were decreased in 8a-treated cells, while the oxidative products lysophosphatidylcholines (LPCs) were significantly increased. We further found that in 8a-treated cells, the reactive oxygen species (ROS) and lipid peroxidation product malondialdehyde (MDA) were notably increased, accompanied with decrease of mitochondrial transmembrane potential, release of cytochrome C and activation of caspase-3. Taken together our results suggest that the acridone derivative 8a induces oxidative stress-mediated apoptosis in CCRF CEM leukemia cells. The UPLC/Q-TOF MS based metabolomic approach provides novel insights into the mechanistic studies of antitumor drugs from a point distinct from traditional biological investigations. PMID- 23667641 TI - Non-invasive magnetic resonance imaging in rats for prediction of the fate of grafted kidneys from cardiac death donors. AB - The main objective of this study was to assess cardiac death (CD) kidney grafts before transplantation to determine whether blood oxygen level-dependent (BOLD) and diffusion MRI techniques can predict damage to these grafts after transplantation. We assessed CD kidney tissue by BOLD and diffusion MRI. We also examined pathological and gene expression changes in CD kidney grafts before and after transplantation. Although there was significantly more red cell congestion (RCC) in the inner stripe of the outer medulla (IS) in both 1 h after cardiac death (CD1h) and CD2h kidneys destined for grafts before transplantation compared with CD0h (p<0.05), CD2h, but not CD1h, kidney grafts had significantly different RCC in the IS 2 days after transplantation (p<0.05). Consistent with these pathological findings, tissue plasminogen activator (tPA) gene expression was increased only in the cortex and medulla of CD2h kidney grafts after transplantation. BOLD MRI successfully and non-invasively imaged and quantified RCC in the IS in both CD1h and CD2h kidney grafts (p<0.05). Diffusion MRI also non-invasively assessed increased the apparent diffusion coefficient in the IS and decreased it in the outer stripe (OS) of CD2h grafts, in concordance with interstitial edema in the IS and tubule cellular edema in the OS. These two types of edema in the outer medulla could explain the prolonged RCC in the IS only of CD2h kidney grafts, creating part of a vicious cycle inhibiting red cells coming out of capillary vessels in the IS. Perfusion with University of Wisconsin solution before MRI measurements did not diminish the difference in tissue damage between CD1h and CD2h kidney grafts. BOLD and diffusion MRI, which are readily available non-invasive tools for evaluating CD kidney grafts tissue damage, can predict prolonged organ damage, and therefore the outcome, of transplanted CD kidney grafts. PMID- 23667642 TI - Developing a vulnerability mapping methodology: applying the water-associated disease index to dengue in Malaysia. AB - The Water-associated Disease Index (WADI) was developed to identify and visualize vulnerability to different water-associated diseases by integrating a range of social and biophysical determinants in map format. In this study vulnerability is used to encompass conditions of exposure, susceptibility, and differential coping capacity to a water-associated health hazard. By assessing these conditions, the tool is designed to provide stakeholders with an integrated and long-term understanding of subnational vulnerabilities to water-associated disease and contribute to intervention strategies to reduce the burden of illness. The objective of this paper is to describe and validate the WADI tool by applying it to dengue. A systemic ecohealth framework that considers links between people, the environment and health was applied to identify secondary datasets, populating the index with components including climate conditions, land cover, education status and water use practices. Data were aggregated to create composite indicators of exposure and of susceptibility in a Geographic Information System (GIS). These indicators were weighted by their contribution to dengue vulnerability, and the output consisted of an overall index visualized in map format. The WADI was validated in this Malaysia case study, demonstrating a significant association with dengue rates at a sub-national level, and illustrating a range of factors that drive vulnerability to the disease within the country. The index output indicated high vulnerability to dengue in urban areas, especially in the capital Kuala Lumpur and surrounding region. However, in other regions, vulnerability to dengue varied throughout the year due to the influence of seasonal climate conditions, such as monsoon patterns. The WADI tool complements early warning models for water-associated disease by providing upstream information for planning prevention and control approaches, which increasingly require a comprehensive and geographically broad understanding of vulnerability for implementation. PMID- 23667643 TI - Viral infection increases glucocorticoid-induced interleukin-10 production through ERK-mediated phosphorylation of the glucocorticoid receptor in dendritic cells: potential clinical implications. AB - The hypothalamic-pituitary-adrenal axis plays a central role in the adaptive response to stress including infection of pathogens through glucocorticoids. Physical and/or mental stress alter susceptibility to viral infection possibly by affecting this regulatory system, thus we explored potential cellular targets and mechanisms that underlie this phenomenon in key immune components dendritic cells (DCs). Dexamethasone (DEX) treatment and subsequent Newcastle disease virus (NDV) infection most significantly and cooperatively stimulated mRNA expression of the interleukin (IL)-10 in murine bone marrow-derived DCs among 89 genes involved in the Toll-like receptor signaling pathways. NDV increased DEX-induced IL-10 mRNA and protein expression by 7- and 3-fold, respectively, which was observed from 3 hours after infection. Conventional DCs (cDCs), but not plasmacytoid DCs (pDCs) were major sources of IL-10 in bone marrow-derived DCs treated with DEX and/or infected with NDV. Murine cytomegalovirus and DEX increased serum IL-10 cooperatively in female mice. Pre-treatment of DCs with the extracellular signal regulated kinase (ERK) inhibitor U0126 abolished cooperative induction of IL-10 by DEX and NDV. Further, ERK overexpression increased IL-10 promoter activity stimulated by wild-type human GR but not by its mutant defective in serine 203, whereas ERK knockdown abolished NDV/DEX cooperation on IL-10 mRNA and phosphorylation of the mouse GR at serine 213. NDV also increased DEX-induced mRNA expression of three known glucocorticoid-responsive genes unrelated to the Toll-like receptor signaling pathways in DCs. These results indicate that virus and glucocorticoids cooperatively increase production of anti-inflammatory cytokine IL-10 by potentiating the transcriptional activity of GR in DCs, through which virus appears to facilitate its own propagation in infected hosts. The results may further underlie in part known exacerbation of IL-10/T helper-2 related allergic disorders by stress and viral infection. PMID- 23667644 TI - Changes in heart rate variability are associated with expression of short-term and long-term contextual and cued fear memories. AB - Heart physiology is a highly useful indicator for measuring not only physical states, but also emotional changes in animals. Yet changes of heart rate variability during fear conditioning have not been systematically studied in mice. Here, we investigated changes in heart rate and heart rate variability in both short-term and long-term contextual and cued fear conditioning. We found that while fear conditioning could increase heart rate, the most significant change was the reduction in heart rate variability which could be further divided into two distinct stages: a highly rhythmic phase (stage-I) and a more variable phase (stage-II). We showed that the time duration of the stage-I rhythmic phase were sensitive enough to reflect the transition from short-term to long-term fear memories. Moreover, it could also detect fear extinction effect during the repeated tone recall. These results suggest that heart rate variability is a valuable physiological indicator for sensitively measuring the consolidation and expression of fear memories in mice. PMID- 23667645 TI - Dickkopf homolog 3 (DKK3) plays a crucial role upstream of WNT/beta-CATENIN signaling for Sertoli cell mediated regulation of spermatogenesis. AB - Testicular Sertoli cells (Sc) are main somatic component of seminiferous tubules that govern the differentiation of germ cells (Gc) and provide them physical support. Sc are the target of follicle stimulating hormone (FSH) and testosterone (T) which are known to regulate spermatogenesis. FSH and T levels in human and sub-human male primates remain high during infancy (4-6 months post birth), similar to those during puberty. Subsequently, juvenile phase is marked with low levels of these hormones. In spite of prolonged hormonal exposure, spermatogenesis is not discerned during infancy unlike that during puberty. Situation during infancy is similar to certain idiopathic male infertility, where prolonged hormone supplementation fails to initiate spermatogenesis. In our quest to determine non hormonal causes of idiopathic infertility which may reside within the Sc, we investigated the association between spermatogenesis and Sc specific gene(s) expressed differentially during puberty and infancy. Although products of several genes may be necessary for quantitatively normal spermatogenesis, one needs to investigate their roles one by one. Differential display and real time PCR analysis revealed higher expression of a known tumor suppressor, Dickkopf homolog 3 (DKK3), by pubertal monkey Sc as compared to infant Sc. To evaluate role of DKK3 in spermatogenesis, we generated DKK3 knock down mice (DKDM) using shRNA construct targeted to DKK3. In testis of adult DKDM, expression of DKK3 mRNA and protein were significantly (p<0.05) low and was associated with elevated WNT-4/beta-CATENIN activity. Elevated beta-CATENIN activity is known to restrict Sc maturation. Abundant expression of infant Sc marker, Mullerian inhibiting substance (MIS), in the testes of adult DKDM confirmed lack of Sc maturation in DKDM. Gc differentiation and fertility was severely compromised in DKDM. This is the first report of role of DKK3 in the testis and DKK3 mediated regulation of spermatogenesis via WNT-4/beta-CATENIN modulation. PMID- 23667646 TI - Effects of biliverdin administration on acute lung injury induced by hemorrhagic shock and resuscitation in rats. AB - Hemorrhagic shock and resuscitation induces pulmonary inflammation that leads to acute lung injury. Biliverdin, a metabolite of heme catabolism, has been shown to have potent cytoprotective, anti-inflammatory, and anti-oxidant effects. This study aimed to examine the effects of intravenous biliverdin administration on lung injury induced by hemorrhagic shock and resuscitation in rats. Biliverdin or vehicle was administered to the rats 1 h before sham or hemorrhagic shock inducing surgery. The sham-operated rats underwent all surgical procedures except bleeding. To induce hemorrhagic shock, rats were bled to achieve a mean arterial pressure of 30 mmHg that was maintained for 60 min, followed by resuscitation with shed blood. Histopathological changes in the lungs were evaluated by histopathological scoring analysis. Inflammatory gene expression was determined by Northern blot analysis, and oxidative DNA damage was assessed by measuring 8 hydroxy-2' deoxyguanosine levels in the lungs. Hemorrhagic shock and resuscitation resulted in prominent histopathological damage, including congestion, edema, cellular infiltration, and hemorrhage. Biliverdin administration prior to hemorrhagic shock and resuscitation significantly ameliorated these lung injuries as judged by histopathological improvement. After hemorrhagic shock and resuscitation, inflammatory gene expression of tumor necrosis factor-alpha and inducible nitric oxide synthase were increased by 18- and 8-fold, respectively. Inflammatory gene expression significantly decreased when biliverdin was administered prior to hemorrhagic shock and resuscitation. Moreover, after hemorrhagic shock and resuscitation, lung 8-hydroxy-2' deoxyguanosine levels in mitochondrial DNA expressed in the pulmonary interstitium increased by 1.5-fold. Biliverdin administration prior to hemorrhagic shock and resuscitation decreased mitochondrial 8-hydroxy-2' deoxyguanosine levels to almost the same level as that in the control animals. We also confirmed that biliverdin administration after hemorrhagic shock and resuscitation had protective effects on lung injury. Our findings suggest that biliverdin has a protective role, at least in part, against hemorrhagic shock and resuscitation-induced lung injury through anti-inflammatory and anti-oxidant mechanisms. PMID- 23667648 TI - Galectin-9-mediated protection from allo-specific T cells as a mechanism of immune privilege of corneal allografts. AB - The eye is an immune-privileged organ, and corneal transplantation is therefore one of the most successful organ transplantation. The immunosuppressive intraocular microenvironment is known as one of the mechanisms underlying immune privilege in the eye. T-cell immunoglobulin and mucin domain (Tim)-3 is a regulatory molecule for T-cell function, and galectin (Gal)-9 is a Tim-3 ligand. We investigated the role of this pathway in establishing the immune-privileged status of corneal allografts in mice. Gal-9 is constitutively expressed on the corneal epithelium, endothelium and iris-ciliary body in normal mouse eyes and eyes bearing surviving allografts, and Tim-3 was expressed on CD8 T cells infiltrating the allografts. Allograft survival in recipients treated with anti Tim-3 monoclonal antibody (mAb) or anti-Gal-9 mAb was significantly shorter than that in control recipients. In vitro, destruction of corneal endothelial cells by allo-reactive T cells was enhanced when the cornea was pretreated with anti-Gal-9 mAb. Blockade of Tim-3 or Gal-9 did not abolish anterior chamber-associated immune deviation. We propose that constitutive expression of Gal-9 plays an immunosuppressive role in corneal allografts. Gal-9 expressed on corneal endothelial cells protects them from destruction by allo-reactive T cells within the cornea. PMID- 23667647 TI - Tauroursodeoxycholic acid mitigates high fat diet-induced cardiomyocyte contractile and intracellular Ca2+ anomalies. AB - OBJECTIVES: The endoplasmic reticulum (ER) chaperone tauroursodeoxycholic acid (TUDCA) has exhibited promises in the treatment of obesity, although its impact on obesity-induced cardiac dysfunction is unknown. This study examined the effect of TUDCA on cardiomyocyte function in high-fat diet-induced obesity. METHODS: Adult mice were fed low or high fat diet for 5 months prior to treatment of TUDCA (300 mg/kg. i.p., for 15d). Intraperitoneal glucose tolerance test (IPGTT), cardiomyocyte mechanical and intracellular Ca(2+) property, insulin signaling molecules including IRS-1, Akt, AMPK, ACC, GSK-3beta, c-Jun, ERK and c-Jun N terminal kinase (JNK) as well as ER stress and intracellular Ca(2+) regulatory proteins were examined. Myocardial ultrastructure was evaluated using transmission electron microscopy (TEM). RESULTS: High-fat diet depressed peak shortening (PS) and maximal velocity of shortening/relengthenin as well as prolonged relengthening duration. TUDCA reversed or overtly ameliorated high fat diet-induced cardiomyocyte dysfunction including prolongation in relengthening. TUDCA alleviated high-fat diet-induced decrease in SERCA2a and phosphorylation of phospholamban, increase in ER stress (GRP78/BiP, CHOP, phosphorylation of PERK, IRE1alpha and eIF2alpha), ultrastructural changes and mitochondrial permeation pore opening. High-fat diet feeding inhibited phosphorylation of AMPK and promoted phosphorylation of GSK-3beta. TUDCA prevented high fat-induced dephosphorylation of AMPK but not GSK-3beta. High fat diet promoted phosphorylation of IRS-1 (Ser(307)), JNK, and ERK without affecting c-Jun phosphorylation, the effect of which with the exception of ERK phosphorylation was attenuated by TUDCA. CONCLUSIONS: These data depict that TUDCA may ameliorate high fat diet feeding-induced cardiomyocyte contractile and intracellular Ca(2+) defects through mechanisms associated with mitochondrial integrity, AMPK, JNK and IRS-1 serine phosphorylation. PMID- 23667649 TI - Metabolic risk profile among overweight and obese lactating women in Sweden. AB - BACKGROUND: Obesity and cardiovascular diseases are increasing globally and any association between reproduction and these conditions is of concern. Unfortunately, little is known about normal levels of metabolic risk factors in women of different body mass index throughout the reproductive cycle. This study is one of the first to describe the metabolic risk profile of lactating overweight or obese women at 8-12 weeks postpartum. METHODS: During 2007-2009, 66 overweight or obese Swedish lactating women without known diseases underwent detailed measurements of their metabolic profiles, dietary intake and general health before entering a lifestyle intervention trial. Baseline measurements took place between 8-12 wk postpartum. Almost all women were exclusively breastfeeding their term infants. RESULTS: The women were regarded as healthy, as reflected in the absence of diagnosed diseases, their own perceptions and in normal hemoglobin, albumin and fasting plasma glucose values. Four women were diagnosed with metabolic syndrome. In these cases, underlying conditions included large waist circumference, low HDL cholesterol values, high triglyceride values and relatively high blood pressure. The metabolic profile differed between overweight and obese women; obese women had significantly higher levels of fasting insulin (p = 0.017), borderline higher HOMA values (p = 0.057) and significantly higher triglyceride values (p = 0.029), as well as larger waist and hip circumferences (p<0.001 and p<0.001). However, no significant differences between overweight and obese women were detected for LDL or total cholesterol levels. Overweight and obese women reported similar total energy and macronutrient intakes, but obese women tended to be less physically active (p = 0.081). CONCLUSIONS: Among generally healthy lactating women, obesity as compared to overweight is associated with increased metabolic risk. This cut-off is thus important also in the early postpartum period, and obesity among these women should warrant proper health investigation. Macronutrient intake did not differ between the groups and, hence, cannot explain these differences. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01343238. PMID- 23667651 TI - Diverging responses of tropical Andean biomes under future climate conditions. AB - Observations and projections for mountain regions show a strong tendency towards upslope displacement of their biomes under future climate conditions. Because of their climatic and topographic heterogeneity, a more complex response is expected for biodiversity hotspots such as tropical mountain regions. This study analyzes potential changes in the distribution of biomes in the Tropical Andes and identifies target areas for conservation. Biome distribution models were developed using logistic regressions. These models were then coupled to an ensemble of 8 global climate models to project future distribution of the Andean biomes and their uncertainties. We analysed projected changes in extent and elevational range and identified regions most prone to change. Our results show a heterogeneous response to climate change. Although the wetter biomes exhibit an upslope displacement of both the upper and the lower boundaries as expected, most dry biomes tend to show downslope expansion. Despite important losses being projected for several biomes, projections suggest that between 74.8% and 83.1% of the current total Tropical Andes will remain stable, depending on the emission scenario and time horizon. Between 3.3% and 7.6% of the study area is projected to change, mostly towards an increase in vertical structure. For the remaining area (13.1%-17.4%), there is no agreement between model projections. These results challenge the common believe that climate change will lead to an upslope displacement of biome boundaries in mountain regions. Instead, our models project diverging responses, including downslope expansion and large areas projected to remain stable. Lastly, a significant part of the area expected to change is already affected by land use changes, which has important implications for management. This, and the inclusion of a comprehensive uncertainty analysis, will help to inform conservation strategies in the Tropical Andes, and to guide similar assessments for other tropical mountains. PMID- 23667650 TI - Asymmetric multisensory interactions of visual and somatosensory responses in a region of the rat parietal cortex. AB - Perception greatly benefits from integrating multiple sensory cues into a unified percept. To study the neural mechanisms of sensory integration, model systems are required that allow the simultaneous assessment of activity and the use of techniques to affect individual neural processes in behaving animals. While rodents qualify for these requirements, little is known about multisensory integration and areas involved for this purpose in the rodent. Using optical imaging combined with laminar electrophysiological recordings, the rat parietal cortex was identified as an area where visual and somatosensory inputs converge and interact. Our results reveal similar response patterns to visual and somatosensory stimuli at the level of current source density (CSD) responses and multi-unit responses within a strip in parietal cortex. Surprisingly, a selective asymmetry was observed in multisensory interactions: when the somatosensory response preceded the visual response, supra-linear summation of CSD was observed, but the reverse stimulus order resulted in sub-linear effects in the CSD. This asymmetry was not present in multi-unit activity however, which showed consistently sub-linear interactions. These interactions were restricted to a specific temporal window, and pharmacological tests revealed significant local intra-cortical contributions to this phenomenon. Our results highlight the rodent parietal cortex as a system to model the neural underpinnings of multisensory processing in behaving animals and at the cellular level. PMID- 23667652 TI - Regulation of immune responsiveness in vivo by disrupting an early T-cell signaling event using a cell-permeable peptide. AB - The inducible T cell kinase (ITK) regulates type 2 (Th2) cytokines that provide defense against certain parasitic and bacterial infections and are involved in the pathogenesis of lung inflammation such as allergic asthma. Activation of ITK requires the interaction of its SH3 domain with the poly-proline region of its signaling partner, the SH2 domain containing leukocyte phosphoprotein of 76 kilodaltons (SLP-76). The specific disruption of the ITK-SH3/SLP-76 poly-proline interaction in vitro by a cell-permeable competitive inhibitor peptide (R9-QQP) interferes with the activation of ITK and the transduction of its cellular functions in T lymphocytes. In the present investigation, we assessed the effects of R9-QQP treatment on the induction of an in vivo immune response as represented by lung inflammation in a murine model of allergic asthma. We found that mice treated with R9-QQP and sensitized and challenged with the surrogate allergen ovalbumin (OVA) display significant inhibition of lung inflammation in a peptide specific manner. Thus, parameters of the allergic response, such as airway hyper responsiveness, suppression of inflammatory cell infiltration, reduction of bronchial mucus accumulation, and production of relevant cytokines from draining lymph nodes were significantly suppressed. These findings represent the first demonstration of the biological significance of the interaction between ITK and SLP-76 in the induction of an immune response in a whole animal model and specifically underscore the significance of the ITK-SH3 domain interaction with the poly-proline region of SLP-76 in the development of an inflammatory response. Furthermore, the experimental approach of intracellular peptide-mediated inhibition might be applicable to the study of other important intracellular interactions thus providing a paradigm for dissecting signal transduction pathways. PMID- 23667653 TI - CBARA1 plays a role in stemness and proliferation of human embryonic stem cells. AB - Human embryonic stem cells (hESCs) are capable of unlimited self-renewal and can generate almost all of the cells in the body. Although some pluripotency factors have been identified, much remains unclear regarding the molecules and mechanisms that regulate hESC self-renewal and pluripotency. In this study, we identified a mitochondrial gene, CBARA1, that is expressed in undifferentiated hESCs and that is down-regulated rapidly after cellular differentiation. To study its role in hESCs, endogenous CBARA1 expression was knocked down using shRNA. CBARA1 knockdown in hESCs resulted in down-regulation of Oct4 and Nanog expression, attenuated cell growth, and G0/G1 phase cell cycle arrest; however, knockdown did not noticeably affect apoptosis. Taken together, these results suggest that CBARA1 is a marker for undifferentiated hESCs that plays a role in maintaining stemness, cell cycle progression, and proliferation. PMID- 23667654 TI - Fusion of ZMYND8 and RELA genes in acute erythroid leukemia. AB - Acute erythroid leukemia was diagnosed in a 4-month-old boy. Cytogenetic analysis of bone marrow (BM) cells showed a t(11;20)(p11;q11) translocation. RNA extracted from the BM was sequenced and analyzed for fusion transcripts using the software FusionMap. A ZMYND8-RELA fusion was ranked first. RT-PCR and direct sequencing verified the presence of an in frame ZMYND8-RELA chimeric transcript. Fluorescence in situ hybridization showed that the ZMYND8-RELA was located on the p12 band of der(11); therefore a cytogenetically invisible pericentric inversion in chromosome 11 must have taken place besides the translocation. The putative ZMYND8-RELA fusion protein contains the Zinc-PHD finger domain, a bromodomain, a PWWP domain, a MYND type of zinc finger of ZMYND8, and the entire RELA protein, indicating that it might act leukemogenically by influencing several cellular processes including the NF-kappa-B pathway. PMID- 23667655 TI - Fine de novo sequencing of a fungal genome using only SOLiD short read data: verification on Aspergillus oryzae RIB40. AB - The development of next-generation sequencing (NGS) technologies has dramatically increased the throughput, speed, and efficiency of genome sequencing. The short read data generated from NGS platforms, such as SOLiD and Illumina, are quite useful for mapping analysis. However, the SOLiD read data with lengths of <60 bp have been considered to be too short for de novo genome sequencing. Here, to investigate whether de novo sequencing of fungal genomes is possible using only SOLiD short read sequence data, we performed de novo assembly of the Aspergillus oryzae RIB40 genome using only SOLiD read data of 50 bp generated from mate paired libraries with 2.8- or 1.9-kb insert sizes. The assembled scaffolds showed an N50 value of 1.6 Mb, a 22-fold increase than those obtained using only SOLiD short read in other published reports. In addition, almost 99% of the reference genome was accurately aligned by the assembled scaffold fragments in long lengths. The sequences of secondary metabolite biosynthetic genes and clusters, whose products are of considerable interest in fungal studies due to their potential medicinal, agricultural, and cosmetic properties, were also highly reconstructed in the assembled scaffolds. Based on these findings, we concluded that de novo genome sequencing using only SOLiD short reads is feasible and practical for molecular biological study of fungi. We also investigated the effect of filtering low quality data, library insert size, and k-mer size on the assembly performance, and recommend for the assembly use of mild filtered read data where the N50 was not so degraded and the library has an insert size of ~2.0 kb, and k-mer size 33. PMID- 23667656 TI - Junctional adhesion molecule-A regulates vascular endothelial growth factor receptor-2 signaling-dependent mouse corneal wound healing. AB - Inflammation and angiogenesis are integral parts of wound healing. However, excessive and persistent wound-induced inflammation and angiogenesis in an avascular tissue such as the cornea may be associated with scarring and visual impairment. Junctional adhesion molecule A (Jam-A) is a tight junction protein that regulates leukocyte transmigration as well as fibroblast growth factor-2 (FGF-2)-induced angiogenesis. However its function in wound-induced inflammation and angiogenesis is still unknown. In this study, we report spontaneous corneal opacity in Jam-A deficient mice associated with inflammation, angiogenesis and the presence of myofibroblasts. Since wounds and/or corneal infections cause corneal opacities, we tested the role of Jam-A in wound-induced inflammation, angiogenesis and scarring by subjecting Jam-A deficient mice to full thickness corneal wounding. Analysis of these wounds demonstrated increased inflammation, angiogenesis, and increased number of myofibroblasts thereby indicating that Jam A regulates the wound-healing response by controlling wound-induced inflammation, angiogenesis and scarring in the cornea. These effects were not due to inflammation alone since the inflammation-induced wound-healing response in Jam-A deficient mice was similar to wild type mice. In order to determine the molecular mechanism associated with the observed aberrant corneal wound healing in Jam-A deficient mice, we assessed the expression of the components of vascular endothelial growth factor A (VEGF-A)/vascular endothelial growth factor receptor- 2(VEGFR-2) signaling pathway. Interestingly, we observed increased levels of VEGF A mRNA in Jam-A deficient eyes. We also observed nuclear localization of phosphorylated SMAD3 (pSMAD3) indicative of TGFbeta pathway activation in the Jam A deficient eyes. Furthermore the increased wound-induced corneal inflammation, angiogenesis, and scarring in Jam-A deficient mice was attenuated by treatment with DC101, an anti-vascular endothelial growth factor receptor-2 (VEGFR-2) antibody. Our results suggest that in the absence of Jam-A, the VEGF-A/VEGFR-2 pathway is upregulated, thereby augmenting wound induced corneal inflammation, angiogenesis, and myofibroblast accumulation leading to scarring. PMID- 23667657 TI - The second face of blindness: processing speed deficits in the intact visual field after pre- and post-chiasmatic lesions. AB - PURPOSE: Damage along the visual pathway results in a visual field defect (scotoma), which retinotopically corresponds to the damaged neural tissue. Other parts of the visual field, processed by the uninjured tissue, are considered to be intact. However, perceptual deficits have been observed in the "intact" visual field, but these functional impairments are poorly understood. We now studied temporal processing deficits in the intact visual field of patients with either pre- or post-chiasmatic lesions to better understand the functional consequences of partial blindness. METHODS: Patients with pre- (n = 53) or post-chiasmatic lesions (n = 98) were tested with high resolution perimetry--a method used to map visual fields with supra-threshold light stimuli. Reaction time of detections in the intact visual field was then analyzed as an indicator of processing speed and correlated with features of the visual field defect. RESULTS: Patients from both groups exhibited processing speed deficits in their presumably "intact" field as indicated by comparison to a normative sample. Further, in both groups processing speed was found to be a function of two factors. Firstly, a spatially restricted (retinotopic) influence of the scotoma was seen in longer reaction times when stimuli were presented in intact field sectors close to the defect. Secondly, patients with larger scotomata had on average longer reaction times in their intact field indicating a more general (non-retinotopic) influence of the scotoma. CONCLUSIONS: Processing speed deficits in the "intact" visual field of patients with visual system damage demonstrate that visual system lesions have more widespread consequences on perception than previously thought. Because dysfunctions of the seeing field are expected to contribute to subjective vision, including visual tests of the presumed "intact" field may help to better understand vision loss and to improve methods of vision restoration and rehabilitation. PMID- 23667658 TI - The relationship between P3 amplitude and working memory performance differs in young and older adults. AB - While some elderly show deteriorations in cognitive performance, others achieve performance levels comparable to young adults. To examine whether age-related changes in brain activity varied with working memory performance efficiency, we recorded electroencephalography (EEG) from young and older healthy adults during performance on an n-back task with two loads (0- and 1-back) and two versions (identity and integrated). Young adults showed a typical P3 amplitude pattern with a parietal-maximum. Compared to young adults, the P3 amplitude of older adults was characterized by frontal hyperactivity coupled with posterior hypoactivity. Moreover, P3 amplitude in young and older adults varied with working memory performance efficiency. Among young adults, more efficient performance correlated with a larger P3 amplitude at parietal sites. In contrast, a higher P3 amplitude at midline electrode sites in older adults correlated with less efficient performance. Particularly, the enhanced frontal midline EEG activity in older adults during working memory performance seems to reflect inefficient use of neural resources due to frontal lobe dysfunction. PMID- 23667659 TI - Methicillin-resistant Staphylococcus aureus in pigs and farm workers on conventional and antibiotic-free swine farms in the USA. AB - Much uncertainty remains about the origin and public health implications of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA). This study aimed to investigate the occurrence and prevalence of MRSA in general and LA-MRSA in particular in pigs and farm workers in five states. We collected nasal swabs from pigs and farm workers at 45 swine herds (21 antibiotic-free herds; 24 conventional herds) in Illinois, Iowa, Minnesota, North Carolina and Ohio. MRSA was isolated from 50 of 1085 pigs (4.6%) and 31 of 148 (20.9%) of farm workers. MRSA-positive pigs and people were clustered in four conventional swine farms in Iowa and Illinois. Based on genotyping, spa type t034, a common livestock associated variant, was predominant among both human and swine isolates. These results confirm the presence of LA-MRSA in pigs and swine farm workers in the USA, but the prevalence found is relatively low compared with European studies. PMID- 23667660 TI - Fusion of CCL21 non-migratory active breast epithelial and breast cancer cells give rise to CCL21 migratory active tumor hybrid cell lines. AB - The biological phenomenon of cell fusion has been linked to tumor progression because several data provided evidence that fusion of tumor cells and normal cells gave rise to hybrid cell lines exhibiting novel properties, such as increased metastatogenic capacity and an enhanced drug resistance. Here we investigated M13HS hybrid cell lines, derived from spontaneous fusion events between M13SV1-EGFP-Neo breast epithelial cells exhibiting stem cell characteristics and HS578T-Hyg breast cancer cells, concerning CCL21/CCR7 signaling. Western Blot analysis showed that all cell lines varied in their CCR7 expression levels as well as differed in the induction and kinetics of CCR7 specific signal transduction cascades. Flow cytometry-based calcium measurements revealed that a CCL21 induced calcium influx was solely detected in M13HS hybrid cell lines. Cell migration demonstrated that only M13HS hybrid cell lines, but not parental derivatives, responded to CCL21 stimulation with an increased migratory activity. Knockdown of CCR7 expression by siRNA completely abrogated the CCL21 induced migration of hybrid cell lines indicating the necessity of CCL21/CCR7 signaling. Because the CCL21/CCR7 axis has been linked to metastatic spreading of breast cancer to lymph nodes we conclude from our data that cell fusion could be a mechanism explaining the origin of metastatic cancer (hybrid) cells. PMID- 23667661 TI - Obesity and Staphylococcus aureus nasal colonization among women and men in a general population. AB - BACKGROUND: Obesity and diabetes mellitus (DM) have been linked to increased risk of infections, and Staphylococcus aureus nasal colonization is a major risk factor for developing infections with the microbe. We therefore sought to find whether body mass index (BMI) and waist circumference (WC) could be associated with S. aureus colonization independent of DM. METHODOLOGY: S. aureus colonization was assessed by nasal swab cultures among 2,169 women and 1,709 men, aged 30-87 years, in the population-based Tromso Staph and Skin Study in 2007-08. Height (cm), weight (kg), WC (cm), and glycated haemoglobin (HbA1c,%) were measured. Multivariable logistic regression analyses including information on DM, HbA1c, hormonal contraceptive use and other potential confounders were used. RESULTS: In the female population, each 2.5 kg/m(2) increase in BMI was associated with a 7% higher odds of S. aureus nasal colonization (P = 0.01). When comparing obese and lean women aged 30-43 years, we observed that BMI >=32.5 versus <22.5 kg/m(2) and WC >=101 versus <80 cm was associated with a 2.60 and 2.12 times higher odds of S. aureus colonization, respectively (95% confidence intervals 1.35-4.98 and 1.17-3.85). Among men, high WC was also associated with S. aureus nasal colonization. The associations did not change significantly when the analysis was restricted to participants without signs of pre-diabetes (HbA1c <6.0%) among women and men, and to non-users of hormonal contraceptives among women. CONCLUSION: Our results support that obesity is a possible determinant for S. aureus nasal colonization independent of DM, in particular for premenopausal women. The role of obesity at different ages and by sex should be addressed in future prospective studies of S. aureus colonization. PMID- 23667662 TI - Sources of variability in musculo-articular stiffness measurement. AB - The assessment of musculo-articular stiffness (MAS) with the free-oscillation technique is a popular method with a variety of applications. This study examined the sources of variability (load applied and frequency of oscillation) when MAS is assessed. Over two testing occasions, 14 healthy men (27.7+/-5.2 yr, 1.82+/ 0.04 m, 79.5+/-8.4 kg) were measured for isometric maximum voluntary contraction and MAS of the knee flexors using submaximal loads relative to the individual's maximum voluntary contraction (MAS%MVC) and a single absolute load (MASABS). As assessment load increased, MAS%MVC (coefficient of variation (CV) = 8.1-12.1%; standard error of measurement (SEM) = 51.6-98.8 Nm-1) and frequency (CV = 4.8 7.0%; SEM = 0.060-0.075 s-1) variability increased consequently. Further, similar levels of variability arising from load (CV = 6.7%) and frequency (CV = 4.8-7.0%) contributed to the overall MAS%MVC variability. The single absolute load condition yielded better reliability scores for MASABS (CV = 6.5%; SEM = 40.2 Nm-1) and frequency (CV = 3.3%; SEM = 0.039 s-1). Low and constant loads for MAS assessment, which are particularly relevant in the clinical setting, exhibited superior reliability compared to higher loads expressed as a percentage of maximum voluntary contraction, which are more suitable for sporting situations. Appropriate sample size and minimum detectable change can therefore be determined when prospective studies are carried out. PMID- 23667663 TI - Habitat-mediated dive behavior in free-ranging grey seals. AB - Understanding the links between foraging behaviour and habitat use of key species is essential to addressing fundamental questions about trophic interactions and ecosystem functioning. Eight female grey seals (Halichoerus grypus) were equipped with time-depth recorders linked to Fastloc GPS tags following the annual moult in southwest Ireland. Individual dives were coupled with environmental correlates to investigate the habitat use and dive behaviour of free-ranging seals. Dives were characterised as either pelagic, benthic, or shallow (where errors in location and charted water depth made differentiating between pelagic and benthic dives unreliable). Sixty-nine percent of dives occurring in water >50 m were benthic. Pelagic dives were more common at night than during the day. Seals performed more pelagic dives over fine sediments (mud/sand), and more benthic dives when foraging over more three-dimensionally complex rock substrates. We used Markov chain analysis to determine the probability of transiting between dive states. A low probability of repeat pelagic dives suggests that pelagic prey were encountered en route to the seabed. This approach could be applied to make more accurate predictions of habitat use in data-poor areas, and investigate contentious issues such as resource overlap and competition between top predators and fisheries, essential for the effective conservation of these key marine species. PMID- 23667664 TI - Serum peptidome variations in a healthy population: reference to identify cancer specific peptides. AB - The emergence of mass spectrometry (MS)-based signatures as biomarkers has generated considerable enthusiasm among oncologists. However, variations in normal individuals also exist, and a better understanding of serum peptide patterns of healthy individuals will be important for further exploring disease specific serum peptide patterns. Following development of a serum peptide pattern platform, we analyzed 500 serum samples obtained from healthy individuals. Samples from breast (n = 84), lung (n = 70), and rectal (n = 30) cancer patients were also examined. Extensive data analysis revealed negligible contributions of age to serum peptide patterns except in healthy individuals between 20-30 and 60+ years of age. Gender-related variations in the serum patterns of healthy individuals were only observed in 20-30 year-old individuals. Our results revealed substantial variation in individual peptide profiles, but 65 peptides were detected at a 20% higher frequency in the healthy population. A peptide profile was developed for each type of cancer, containing 10 discriminating peptides not prevalent in healthy individuals. Sequence identification of 111 signature peptides revealed that they fell into several tight clusters and most were exopeptidase products of serum resident proteins. We have obtained a MS based serum peptide profile for healthy individuals, providing a reference for observing the occurrence of cancer-specific peptides. PMID- 23667665 TI - Aberrant functional organization within and between resting-state networks in AD. AB - Altered functional characteristics have been reported in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD); nonetheless, comprehensive analyses of the resting-state networks (RSNs) are rare. This study combined multiple imaging modalities to investigate the functional and structural changes within each RSN and between RSNs in aMCI/AD patients. Eight RSNs were identified from functional MRI data from 35 AD, 18 aMCI and 21 normal control subjects using independent component analysis. We compared functional connectivity (FC) within each RSN and found decreased FC in the several cognitive-related RSNs in AD, including the bilateral precuneus of the precuneus network, the posterior cingulate cortex and left precuneus of the posterior default mode network (DMN), and the left superior parietal lobule of the left frontoparietal network (LFP). We further compared the grey matter volumes and amplitudes of low-frequency fluctuations of these regions and found decreases in these measures in AD. Importantly, we found decreased inter-network connectivity between the visual network and the LFP and between the anterior and posterior DMNs in AD. All indices in aMCI patients were numerically between those of controls and AD patients. These results suggest that the brain networks supporting complex cognitive processes are specifically and progressively impaired over the course of AD, and the FC impairments are present not only within networks but also between networks. PMID- 23667666 TI - Are auditory percepts determined by experience? AB - Audition--what listeners hear--is generally studied in terms of the physical properties of sound stimuli and physiological properties of the auditory system. Based on recent work in vision, we here consider an alternative perspective that sensory percepts are based on past experience. In this framework, basic auditory qualities (e.g., loudness and pitch) are based on the frequency of occurrence of stimulus patterns in natural acoustic stimuli. To explore this concept of audition, we examined five well-documented psychophysical functions. The frequency of occurrence of acoustic patterns in a database of natural sound stimuli (speech) predicts some qualitative aspects of these functions, but with substantial quantitative discrepancies. This approach may offer a rationale for auditory phenomena that are difficult to explain in terms of the physical attributes of the stimuli as such. PMID- 23667667 TI - Huaier aqueous extract inhibits ovarian cancer cell motility via the AKT/GSK3beta/beta-catenin pathway. AB - Traditional Chinese medicine has gained popularity due to its ability to kill tumor cells. Recently, the apoptotic and anti-angiogenic effects of Trametes robiniophila murr (Huaier) have been investigated. The aim of this study was to investigate its effect on cell mobility and tumor growth in ovarian cancer. Cell viability and motility were measured using SRB, scratch and migration assays. Cell apoptosis was analysed by annexin V/PI staining. Using a reverse-phase protein array (RPPA) assay, we analyzed the levels of 153 proteins and/or phosphorylations in Huaier-treated and untreated cells. Huaier inhibited cell viability and induced both early and late apoptosis in SKOV3, SKOV3.ip1 and Hey cells in a time- and dose-dependent manner. Cell invasiveness and migration were also suppressed significantly. The RPPA results showed significant differences (of at least 30%; P <0.05) in the levels of 7 molecules in SKOV3 cells and 10 in SKOV3.ip1 cells between the untreated and treated cells. Most of the molecules identified play roles in cell proliferation, apoptosis or cell adhesion/invasion. Western blot analysis further validated that Huaier treatment resulted in decreased AKT phosphorylation, enhanced expression of total GSK3beta, inhibition of the phosphorylation of GSK3beta on S9, reduction of both cytoplasmic beta catenin expression and nuclear beta-catenin translocation, and transcriptional repression of several Wnt/beta-catenin target genes (DIXDC1, LRP6, WNT5A, and cyclin D1). After knocking down GSK3beta, beta-catenin expression could not be inhibited by Huaier. Finally, Huaier inhibited the growth of ovarian tumor xenografts in vivo. These studies indicate that Huaier inhibits tumor cell mobility in ovarian cancer via the AKT/GSK3beta/beta-catenin signaling pathway. PMID- 23667668 TI - Interclonal variations in the molecular karyotype of Trypanosoma cruzi: chromosome rearrangements in a single cell-derived clone of the G strain. AB - Trypanosoma cruzi comprises a pool of populations which are genetically diverse in terms of DNA content, growth and infectivity. Inter- and intra-strain karyotype heterogeneities have been reported, suggesting that chromosomal rearrangements occurred during the evolution of this parasite. Clone D11 is a single-cell-derived clone of the T. cruzi G strain selected by the minimal dilution method and by infecting Vero cells with metacyclic trypomastigotes. Here we report that the karyotype of clone D11 differs from that of the G strain in both number and size of chromosomal bands. Large chromosomal rearrangement was observed in the chromosomes carrying the tubulin loci. However, most of the chromosome length polymorphisms were of small amplitude, and the absence of one band in clone D11 in relation to its reference position in the G strain could be correlated to the presence of a novel band migrating above or below this position. Despite the presence of chromosomal polymorphism, large syntenic groups were conserved between the isolates. The appearance of new chromosomal bands in clone D11 could be explained by chromosome fusion followed by a chromosome break or interchromosomal exchange of large DNA segments. Our results also suggest that telomeric regions are involved in this process. The variant represented by clone D11 could have been induced by the stress of the cloning procedure or could, as has been suggested for Leishmania infantum, have emerged from a multiclonal, mosaic parasite population submitted to frequent DNA amplification/deletion events, leading to a 'mosaic' structure with different individuals having differently sized versions of the same chromosomes. If this is the case, the variant represented by clone D11 would be better adapted to survive the stress induced by cloning, which includes intracellular development in the mammalian cell. Karyotype polymorphism could be part of the T. cruzi arsenal for responding to environmental pressure. PMID- 23667669 TI - Stanniocalcin-1 protects retinal ganglion cells by inhibiting apoptosis and oxidative damage. AB - Optic neuropathy including glaucoma is one of the leading causes of irreversible vision loss, and there are currently no effective therapies. The hallmark of pathophysiology of optic neuropathy is oxidative stress and apoptotic death of retinal ganglion cells (RGCs), a population of neurons in the central nervous system with their soma in the inner retina and axons in the optic nerve. We here tested that an anti-apoptotic protein stanniocalcin-1 (STC-1) can prevent loss of RGCs in the rat retina with optic nerve transection (ONT) and in cultures of RGC 5 cells with CoCl2 injury. We found that intravitreal injection of STC-1 increased the number of RGCs in the retina at days 7 and 14 after ONT, and decreased apoptosis and oxidative damage. In cultures, treatment with STC-1 dose dependently increased cell viability, and decreased apoptosis and levels of reactive oxygen species in RGC-5 cells that were exposed to CoCl2. The expression of HIF-1alpha that was up-regulated by injury was significantly suppressed in the retina and in RGC-5 cells by STC-1 treatment. The results suggested that intravitreal injection of STC-1 might be a useful therapy for optic nerve diseases in which RGCs undergo apoptosis through oxidative stress. PMID- 23667670 TI - Anaplastic lymphoma kinase is required for neurogenesis in the developing central nervous system of zebrafish. AB - Anaplastic Lymphoma Kinase (ALK) was initially discovered as an oncogene in human lymphoma and other cancers, including neuroblastoma. However, little is known about the physiological function of ALK. We identified the alk ortholog in zebrafish (Danio rerio) and found that it is highly expressed in the developing central nervous system (CNS). Heat-shock inducible transgenic zebrafish lines were generated to over-express alk during early neurogenesis. Its ectopic expression resulted in activation of the MEK/ERK pathway, increased cell proliferation, and aberrant neurogenesis leading to mis-positioning of differentiated neurons. Thus, overexpressed alk is capable of promoting cell proliferation in the nervous system, similar to the situation in ALK-related cancers. Next, we used Morpholino mediated gene knock-down and a pharmacological inhibitor to interfere with expression and function of endogenous Alk. Alk inhibition did not affect neuron progenitor formation but severely compromised neuronal differentiation and neuron survival in the CNS. These data indicate that tightly controlled alk expression is critical for the balance between neural progenitor proliferation, differentiation and survival during embryonic neurogenesis. PMID- 23667672 TI - Intrinsic constraints on sympodial growth morphologies of azooxanthellate scleractinian coral Dendrophyllia. AB - BACKGROUND: Asexual increase occurs in virtually all colonial organisms. However, little is known about the intrinsic mechanisms that control asexual reproduction and the resultant morphologies of colonies. Scleractinian corals, both symbiotic (zoaxanthellate) and non-symbiotic (azooxanthellate) corals are known to form elaborate colonies. To better understand the growth mechanisms that control species-specific type of colony in azooxanthellate dendrophyllid scleractinian corals, we have studied details of the budding pattern in the sympodial colonies of Dendrophyllia boschmai and Dendrophyllia cribrosa. PRINCIPAL FINDINGS: Budding exhibits the following regularities: (1) the two directive septa of offset corallites are oriented almost perpendicular to the growth direction of parent corallites; (2) offsets generally occur in either of the lateral primary septa that occur on one side of a corallite; the individuals thus show a definite polarity with respect to the directive septa, and only when branching dichotomously offsets occur in both primary septa; (3) the lateral corallites grow more-or-less diagonally upwards; and (4) the regularities and polarities are maintained throughout growth. Given these regularities, D. boschmai grows in a zigzag fashion by alternately budding on the right and left sites. In contrast, D. cribrosa grows helically by budding at a particular site. CONCLUSIONS/SIGNIFICANCE: The strict constraints on budding regularities and shifts in budding sites observed in the sympodial growth forms of corals greatly affect resulting morphologies in azooxanthellate coral colonies. A precise understanding of these intrinsic constraints leads to a fundamental comprehension of colony-forming mechanisms in modular organisms. PMID- 23667671 TI - Functional characterization of a novel KCNJ11 in frame mutation-deletion associated with infancy-onset diabetes and a mild form of intermediate DEND: a battle between K(ATP) gain of channel activity and loss of channel expression. AB - ATP-sensitive potassium (K(ATP)) channels are widely distributed in various tissues and cell types where they couple cell metabolism to cell excitability. Gain of channel function (GOF) mutations in the genes encoding Kir6.2 (KCNJ11) or the associated regulatory ssulfonylurea receptor 1 subunit (ABCC8), cause developmental delay, epilepsy and neonatal diabetes (DEND) due to suppressed cell excitability in pancreatic beta-cells and neurons. The objective of this study was to determine the molecular basis of infancy-onset diabetes and a mild form of intermediate DEND, resulting from a novel KCNJ11 in frame mutation plus deletion. The naturally occurring Kir6.2 mutation plus deletion (Ser225Thr, Pro226_Pro232del) as well as the isolated S225T mutation or isolated del226-232 deletion were coexpressed with SUR1 in COS cells in homozygous or heterozygous states. The protein expression and gating effects of the resulting channels were assessed biochemically and electrophysiologically. For both the deletion and point mutations, simulated heterozygous expression resulted in overall increased conductance in intact cells in basal conditions and rightward shifted ATP dose response curves in excised patches, due to increased intrinsic open probability. Interestingly, homomeric channels for the combined deletion/mutation, or for the deletion alone, showed dramatically reduced channel expression at the cell membrane, which would underlie a reduced function in vivo. These results demonstrate that both the mis-sense mutation and the deleted region in the Kir6.2 subunit are important for control of the intrinsic channel gating and suggest that the clinical presentation could be affected by the competition between loss of-function by reduced trafficking and enhanced channel gating. PMID- 23667673 TI - Alcohol-related dysfunction in working-age men in Izhevsk, Russia: an application of structural equation models to study the association with education. AB - BACKGROUND: Acute alcohol-related dysfunctional behaviours, such as hangover, are predictive of poor health and mortality. Although much is known about the association of education with alcohol consumption, little is known about its association with these dysfunctional behaviours. METHODS: The study population was 1,705 male drinkers aged 25-54 years resident in the city of Izhevsk, Russia who participated in a cross-sectional survey (2003-6). Structural equation modelling was used to examine the relationships between education, beverage and non-beverage alcohol intake, drinking patterns, and acute alcohol-related dysfunction score among these drinkers. RESULTS: Dysfunction was related to all other drinking variables, with the strongest predictors being spirit intake, non beverage alcohol consumption and drinking patterns. There was a strong relationship between education and acute dysfunction which was not explained by adjusting for alcohol intake and drinking patterns (mean adjusted dysfunction score 0.35 SD (95% CI 0.10, 0.61) lower in men with higher versus secondary education). CONCLUSIONS: Although by definition one or more aspects of alcohol consumption should explain the educational differences in alcohol-related dysfunction, detailed information on drinking only partly accounted for the observed patterns. Thus beyond their intrinsic interest, these results illustrate the challenges in constructing statistical models that convincingly identify the pathways that link educational differences to health-related outcomes. PMID- 23667674 TI - Rapamycin upregulates autophagy by inhibiting the mTOR-ULK1 pathway, resulting in reduced podocyte injury. AB - The podocyte functions as a glomerular filtration barrier. Autophagy of postmitotic cells is an important protective mechanism that is essential for maintaining the homeostasis of podocytes. Exploring an in vivo rat model of passive Heymann nephritis and an in vitro model of puromycin amino nucleotide (PAN)-cultured podocytes, we examined the specific mechanisms underlying changing autophagy levels and podocyte injury. In the passive Heymann nephritis model rats, the mammalian target-of-rapamycin (mTOR) levels were upregulated in injured podocytes while autophagy was inhibited. In PAN-treated podocytes, mTOR lowered the level of autophagy through the mTOR-ULK1 pathway resulting in damaged podocytes. Rapamycin treatment of these cells reduced podocyte injury by raising the levels of autophagy. These in vivo and in vitro experiments demonstrate that podocyte injury is associated with changes in autophagy levels, and that rapamycin can reduce podocyte injury by increasing autophagy levels via inhibition of the mTOR-ULK1 pathway. These results provide an important theoretical basis for future treatment of diseases involving podocyte injury. PMID- 23667676 TI - Metabolic states following accumulation of intracellular aggregates: implications for neurodegenerative diseases. AB - The formation of intracellular aggregates is a common etiology of several neurodegenerative diseases. Mitochondrial defects and oxidative stress has been pointed as the major mechanistic links between the accumulation of intracellular aggregates and cell death. In this work we propose a "metabolic cell death by overcrowding" as an alternative hypothesis. Using a model of neuron metabolism, we predict that as the concentration of protein aggregates increases the neurons transit through three different metabolic phases. The first phase (0-6 mM) corresponds with the normal neuron state, where the neuronal activity is sustained by the oxidative phosphorylation of lactate. The second phase (6-8.6 mM) is characterized by a mixed utilization of lactate and glucose as energy substrates and a switch from ammonia uptake to ammonia release by neurons. In the third phase (8.6-9.3 mM) neurons are predicted to support their energy demands from glycolysis and an alternative pathway for energy generation, involving reactions from serine synthesis, one carbon metabolism and the glycine cleavage system. The model also predicts a decrease in the maximum neuronal capacity for energy generation with increasing the concentration of protein aggregates. Ultimately this maximum capacity becomes zero when the protein aggregates reach a concentration of about 9.3 mM, predicting the cessation of neuronal activity. PMID- 23667675 TI - Genome wide association study of age at menarche in the Japanese population. AB - Age at menarche (AAM) is a complex trait involving both genetic and environmental factors. To identify the genetic factors associated with AAM, we conducted a large-scale meta-analysis of genome-wide association studies using more than 15,000 Japanese female samples. Here, we identified an association between SNP (single nucleotide polymorphism) rs364663 at the LIN28B locus and AAM, with a P value of 5.49*10(-7) and an effect size of 0.089 (year). We also evaluated 33 SNPs that were previously reported to be associated with AAM in women of European ancestry. Among them, two SNPs rs4452860 and rs7028916 in TMEM38B indicated significant association with AAM in the same directions as reported in previous studies (P = 0.0013 with an effect size of 0.051) even after Bonferroni correction for the 33 SNPs. In addition, six loci in or near CCDC85A, LOC100421670, CA10, ZNF483, ARNTL, and RXRG exhibited suggestive association with AAM (P<0.05). Our findings elucidated the impact of genetic variations on AAM in the Japanese population. PMID- 23667677 TI - An evaluation of culture results during treatment for tuberculosis as surrogate endpoints for treatment failure and relapse. AB - It is widely acknowledged that new regimens are urgently needed for the treatment of tuberculosis. The primary endpoint in the Phase III trials is a composite outcome of failure at the end of treatment or relapse after stopping treatment. Such trials are usually both long and expensive. Valid surrogate endpoints measured during or at the end of treatment could dramatically reduce both the time and cost of assessing the effectiveness of new regimens. The objective of this study was to evaluate sputum culture results on solid media during treatment as surrogate endpoints for poor outcome. Data were obtained from twelve randomised controlled trials conducted by the British Medical Research Council in the 1970s and 80s in East Africa and East Asia, consisting of 6974 participants and 49 different treatment regimens. The month two culture result was shown to be a poor surrogate in East Africa but a good surrogate in Hong Kong. In contrast, the month three culture was a good surrogate in trials conducted in East Africa but not in Hong Kong. As well as differences in location, ethnicity and probable strain of Mycobacteria tuberculosis, Hong Kong trials more often evaluated regimens with rifampicin throughout and intermittent regimens, and patients in East African trials more often presented with extensive cavitation and were slower to convert to culture negative during treatment. An endpoint that is a summary measure of the longitudinal profile of culture results over time or that is able to detect the presence of M. tuberculosis later in treatment is more likely to be a better endpoint for a phase II trial than a culture result at a single time point and may prove to be an acceptable surrogate. More data are needed before any endpoint can be used as a surrogate in a confirmatory phase III trial. PMID- 23667678 TI - Roaring high and low: composition and possible functions of the Iberian stag's vocal repertoire. AB - We provide a detailed description of the rutting vocalisations of free-ranging male Iberian deer (Cervus elaphus hispanicus, Hilzheimer 1909), a geographically isolated and morphologically differentiated subspecies of red deer Cervus elaphus. We combine spectrographic examinations, spectral analyses and automated classifications to identify different call types, and compare the composition of the vocal repertoire with that of other red deer subspecies. Iberian stags give bouts of roars (and more rarely, short series of barks) that are typically composed of two different types of calls. Long Common Roars are mostly given at the beginning or at the end of the bout, and are characterised by a high fundamental frequency (F0) resulting in poorly defined formant frequencies but a relatively high amplitude. In contrast, Short Common Roars are typically given in the middle or at the end of the bout, and are characterised by a lower F0 resulting in relatively well defined vocal tract resonances, but low amplitude. While we did not identify entirely Harsh Roars (as described in the Scottish red deer subspecies (Cervus elaphus scoticus)), a small percentage of Long Common Roars contained segments of deterministic chaos. We suggest that the evolution of two clearly distinct types of Common Roars may reflect divergent selection pressures favouring either vocal efficiency in high pitched roars or the communication of body size in low-pitched, high spectral density roars highlighting vocal tract resonances. The clear divergence of the Iberian red deer vocal repertoire from those of other documented European red deer populations reinforces the status of this geographical variant as a distinct subspecies. PMID- 23667679 TI - Telomere shortening in the esophagus of Japanese alcoholics: relationships with chromoendoscopic findings, ALDH2 and ADH1B genotypes and smoking history. AB - Chromoendoscopy with Lugol iodine staining provides important information on the development of squamous cell carcinoma (SCC). In particular, distinct iodine unstained lesions (DIULs) larger than 10 mm show a high prevalence in high-grade intraepithelial neoplasia. It has also been reported that inactive ALDH2*1/*2 and less-active ADH1B*1/*1, and smoking, are risk factors for esophageal SCC. We previously examined telomere shortening in the esophageal epithelium of alcoholics, and suggested a high prevalence of chromosomal instability in such individuals. In the present study, we attempted to analyze telomere lengths in 52 DIULs with reference to both their size and multiplicity, ALDH2 and ADH1B genotypes, and smoking history. Patients with DIULs <10 mm (n = 42) had significantly longer telomeres than those with DIULs >=10 mm (n = 10, p = 0.008). No significant differences in telomere length were recognized between the ALDH2 and ADH1B genotypes (ALDH2 active/inactive = 35/17, ADH1B active/inactive = 32/20; p = 0.563, 0.784, respectively) or among four groups of patients divided according to smoking history (never-, ex-, light, and heavy smokers = 3, 6, 21, and 22 patients, respectively; p = 0.956). Patients without multiple DIULs (n = 17) had significantly longer telomeres than patients with multiple DIULs (n = 35, p = 0.040). It is suggested that alcoholism reduces telomere length in the esophagus, irrespective of genotype or smoking habit. Telomere shortening may not generate cancer directly, but may create conditions under which SCC can develop more easily, depending on subsequent exposure to carcinogens. PMID- 23667680 TI - Production of recombinant disulfide-rich venom peptides for structural and functional analysis via expression in the periplasm of E. coli. AB - Disulfide-rich peptides are the dominant component of most animal venoms. These peptides have received much attention as leads for the development of novel therapeutic agents and bioinsecticides because they target a wide range of neuronal receptors and ion channels with a high degree of potency and selectivity. In addition, their rigid disulfide framework makes them particularly well suited for addressing the crucial issue of in vivo stability. Structural and functional characterization of these peptides necessitates the development of a robust, reliable expression system that maintains their native disulfide framework. The bacterium Escherichia coli has long been used for economical production of recombinant proteins. However, the expression of functional disulfide-rich proteins in the reducing environment of the E. coli cytoplasm presents a significant challenge. Thus, we present here an optimised protocol for the expression of disulfide-rich venom peptides in the periplasm of E. coli, which is where the endogenous machinery for production of disulfide-bonds is located. The parameters that have been investigated include choice of media, induction conditions, lysis methods, methods of fusion protein and peptide purification, and sample preparation for NMR studies. After each section a recommendation is made for conditions to use. We demonstrate the use of this method for the production of venom peptides ranging in size from 2 to 8 kDa and containing 2-6 disulfide bonds. PMID- 23667682 TI - Predictive equations using regression analysis of pulmonary function for healthy children in Northeast China. AB - BACKGROUND: There have been few published studies on spirometric reference values for healthy children in China. We hypothesize that there would have been changes in lung function that would not have been precisely predicted by the existing spirometric reference equations. The objective of the study was to develop more accurate predictive equations for spirometric reference values for children aged 9 to 15 years in Northeast China. METHODOLOGY/PRINCIPAL FINDINGS: Spirometric measurements were obtained from 3,922 children, including 1,974 boys and 1,948 girls, who were randomly selected from five cities of Liaoning province, Northeast China, using the ATS (American Thoracic Society) and ERS (European Respiratory Society) standards. The data was then randomly split into a training subset containing 2078 cases and a validation subset containing 1844 cases. Predictive equations used multiple linear regression techniques with three predictor variables: height, age and weight. Model goodness of fit was examined using the coefficient of determination or the R(2) and adjusted R(2). The predicted values were compared with those obtained from the existing spirometric reference equations. The results showed the prediction equations using linear regression analysis performed well for most spirometric parameters. Paired t tests were used to compare the predicted values obtained from the developed and existing spirometric reference equations based on the validation subset. The t test for males was not statistically significant (p>0.01). The predictive accuracy of the developed equations was higher than the existing equations and the predictive ability of the model was also validated. CONCLUSION/SIGNIFICANCE: We developed prediction equations using linear regression analysis of spirometric parameters for children aged 9-15 years in Northeast China. These equations represent the first attempt at predicting lung function for Chinese children following the ATS/ERS Task Force 2005 guidelines on spirometry standardization. PMID- 23667681 TI - VBP15, a glucocorticoid analogue, is effective at reducing allergic lung inflammation in mice. AB - Asthma is a chronic inflammatory condition of the lower respiratory tract associated with airway hyperreactivity and mucus obstruction in which a majority of cases are due to an allergic response to environmental allergens. Glucocorticoids such as prednisone have been standard treatment for many inflammatory diseases for the past 60 years. However, despite their effectiveness, long-term treatment is often limited by adverse side effects believed to be caused by glucocorticoid receptor-mediated gene transcription. This has led to the pursuit of compounds that retain the anti-inflammatory properties yet lack the adverse side effects associated with traditional glucocorticoids. We have developed a novel series of steroidal analogues (VBP compounds) that have been previously shown to maintain anti-inflammatory properties such as NFkappaB-inhibition without inducing glucocorticoid receptor mediated gene transcription. This study was undertaken to determine the effectiveness of the lead compound, VBP15, in a mouse model of allergic lung inflammation. We show that VBP15 is as effective as the traditional glucocorticoid, prednisolone, at reducing three major hallmarks of lung inflammation--NFkappaB activity, leukocyte degranulation, and pro-inflammatory cytokine release from human bronchial epithelial cells obtained from patients with asthma. Moreover, we found that VBP15 is capable of reducing inflammation of the lung in vivo to an extent similar to that of prednisone. We found that prednisolone--but not VBP15 shortens the tibia in mice upon a 5 week treatment regimen suggesting effective dissociation of side effects from efficacy. These findings suggest that VBP15 may represent a potent and safer alternative to traditional glucocorticoids in the treatment of asthma and other inflammatory diseases. PMID- 23667683 TI - Pre-immunization with an intramuscular injection of AAV9-human erythropoietin vectors reduces the vector-mediated transduction following re-administration in rat brain. AB - We have recently demonstrated that adeno-associated virus serotype 9 (AAV9) mediated human erythropoietin (hEPO) gene delivery into the brain protects dopaminergic (DA) neurons in the substantia nigra in a rat model of Parkinson's disease. In the present study, we examined whether pre-exposure to AAV9-hEPO vectors with an intramuscular or intrastriatal injection would reduce AAV9 mediated hEPO transduction in rat brain. We first characterized transgene expression and immune responses against AAV9-hEPO vectors in rat striatum at 4 days, 3 weeks and 6 months, and with doses ranging from 10(11) to 10(13) viral genomes. To sensitize immune system, rats received an injection of AAV9-hEPO into either the muscle or the left striatum, and then sequentially an injection of AAV9-hEPO into the right striatum 3 weeks later. We observed that transgene expression exhibited in a time course and dose dependent manner, and inflammatory and immune responses displayed in a time course manner. Intramuscular, but not intrastriatal injections of AAV9-hEPO resulted in reduced levels of hEPO transduction and increased levels of the major histocompatibility complex (MHC) class I and class II antigen expression in the striatum following AAV9-hEPO re administration. There were infiltration of the cluster of differentiation 4 (CD4) and CD8-lymphacytes, and accumulation of activated microglial cells and astrocytes in the virally injected striatum. In addition, the sera from the rats with intramuscular injections of AAV9-hEPO contained greater levels of antibodies against both AAV9 capsid protein and hEPO protein than the other treatment groups. hEPO gene expression was negatively correlated with the levels of circulating antibodies against AAV9 capsid protein. Intramuscular and intrastriatal re-administration of AAV9-hEPO led to increased numbers of red blood cells in peripheral blood. Our results suggest that pre-immunization with an intramuscular injection can lead to the reduction of transgene expression in the striatal re-administration. PMID- 23667684 TI - Adiponectin increases secretion of rat submandibular gland via adiponectin receptors-mediated AMPK signaling. AB - Adiponectin and adiponectin receptors (AdipoR1/2) are expressed in various tissues and are involved in the regulation of multiple functions such as energy metabolism and inflammatory responses. However, the effect of adiponectin and AdipoRs in submandibular glands has not been fully evaluated. In the present study, we found that mRNA and protein of both adiponectin and AdipoR1/2 were expressed in rat submandibular glands and in the SMG-C6 cell line, as evidenced by RT-PCR and Western blot analysis. Immunofluorescence staining showed that adiponectin was diffused in the cytoplasm, while AdipoR1/2 was concentrated in the membrane of acinar cells. Saliva flow was significantly increased by full length adiponectin (fAd) or globular adiponectin (gAd) perfusion in isolated rat submandibular glands. 5-Aminoimidazole-4-carboxamide-1-4-ribofuranoside (AICAR), an adenosine monophosphate activated protein kinase (AMPK) activator, also increased saliva secretion. fAd, gAd, and AICAR all increased the average width of apical tight junctions in perfused submandibular glands, and decreased transepithelial electrical resistance (TER) in SMG-C6 cells, suggesting that adiponectin promoted secretion by modulating paracellular permeability. fAd and gAd increased p-AMPK levels, while AraA, an AMPK antagonist, abolished fAd- and gAd-induced changes in secretion, tight junction ultrastructure, and TER. Moreover, both AdipoR1 and AdipoR2 were required for fAd- or gAd-induced p-AMPK and TER responses, suggesting from their inhibition following AdipoR1 or AdipoR2 knockdown, and co-knockdown of AdipoRs by RNA interference. Our results suggest that adiponectin functions as a promoter of salivary secretion in rat submandibular glands via activation of AdipoRs, AMPK, and paracellular permeability. PMID- 23667685 TI - Analysis of URI nuclear interaction with RPB5 and components of the R2TP/prefoldin-like complex. AB - Unconventional prefoldin RPB5 Interactor (URI) was identified as a transcriptional repressor that binds RNA polymerase II (pol II) through interaction with the RPB5/POLR2E subunit. Despite the fact that many other proteins involved in transcription regulation have been shown to interact with URI, its nuclear function still remains elusive. Previous mass spectrometry analyses reported that URI is part of a novel protein complex called R2TP/prefoldin-like complex responsible for the cytoplasmic assembly of RNA polymerase II. We performed a mass spectrometry (MS)-based proteomic analysis to identify nuclear proteins interacting with URI in prostate cells. We identified all the components of the R2TP/prefoldin-like complex as nuclear URI interactors and we showed that URI binds and regulates RPB5 protein stability and transcription. Moreover, we validated the interaction of URI to the P53 and DNA damage-Regulated Gene 1 (PDRG1) and show that PDRG1 protein is also stabilized by URI binding. We present data demonstrating that URI nuclear/cytoplasmic shuttling is affected by compounds that stall pol II on the DNA (alpha-amanitin and actinomycin-D) and by leptomycin B, an inhibitor of the CRM1 exportin that mediates the nuclear export of pol II subunits. These data suggest that URI, and probably the entire R2TP/prefoldin-like complex is exported from the nucleus through CRM1. Finally we identified putative URI sites of phosphorylation and acetylation and confirmed URI sites of post-transcriptional modification identified in previous large-scale analyses the importance of which is largely unknown. However URI post-transcriptional modification was shown to be essential for URI function and therefore characterization of novel sites of URI modification will be important to the understanding of URI function. PMID- 23667686 TI - Withaferin A effectively targets soluble vimentin in the glaucoma filtration surgical model of fibrosis. AB - Withaferin A (WFA) is a natural product that binds to soluble forms of the type III intermediate filament (IF) vimentin. Currently, it is unknown under what pathophysiological contexts vimentin is druggable, as cytoskeltal vimentin-IFs are abundantly expressed. To investigate druggability of vimentin, we exploited rabbit Tenon's capsule fibroblast (RbTCF) cell cultures and the rabbit glaucoma filtration surgical (GFS) model of fibrosis. WFA potently caused G0/G1 cell cycle inhibition (IC50 25 nM) in RbTCFs, downregulating ubiquitin E3 ligase skp2 and inducing p27(Kip1) expression. Transforming growth factor (TGF)-beta-induced myofibroblast transformation caused development of cell spheroids with numerous elongated invadopodia, which WFA blocked potently by downregulating soluble vimentin and alpha-smooth muscle actin (SMA) expression. In the pilot proof-of concept study using the GFS model, subconjunctival injections of a low WFA dose reduced skp2 expression in Tenon's capsule and increased p27(Kip1) expression without significant alteration to vimentin-IFs. This treatment maintains significant nanomolar WFA concentrations in anterior segment tissues that correspond to WFA's cell cycle targeting activity. A ten-fold higher WFA dose caused potent downregulation of soluble vimentin and skp2 expression, but as found in cell cultures, no further increase in p27(Kip1) expression was observed. Instead, this high WFA dose potently induced vimentin-IF disruption and downregulated alpha-SMA expression that mimicked WFA activity in TGF-beta-treated RbTCFs that blocked cell contractile activity at submicromolar concentrations. These findings illuminate that localized WFA injection to ocular tissues exerts pharmacological control over the skp2-p27(Kip1) pathway by targeting of soluble vimentin in a model of surgical fibrosis. PMID- 23667687 TI - Expression of SLP-2 was associated with invasion of esophageal squamous cell carcinoma. AB - INTRODUCTION: Stomatin-like protein 2 (SLP-2), a member of the Stomatin superfamily, has been identified as an oncogenic-related protein and found to be up-regulated in multi-cancers. Nonetheless, the expression pattern and regulation of SLP-2 in human esophageal squamous cell carcinoma (ESCC) remain unexplored. METHODS: Immunohistochemistry and immunofluorescence staining analysis were performed to show SLP-2 expression and location. RNAi method was used to inhibit specific protein expression. Transwell assay was done to investigate cells invasive capability. RT-PCR and Western blot analysis were used to detect mRNA and protein expression levels. RESULTS: Immunohistochemical analysis showed that up-regulation of SLP-2 was found in invasive front compared with cancer central tissue in ESCC. Inhibition of SLP-2 by SLP-2 siRNA can decrease ESCC cells invasive capability through MMP-2 dependent manner. Up-regulation of SLP-2 was effectively abrogated by the ERK1/2 inhibitors either PD98059 or U0126, but no effect was showed by the treatment of AKT inhibitors either LY294002 or MK-2206. So the regulation of SLP-2 was involved in activation of the MAPK/ERK pathway. CONCLUSIONS: We found that PMA/EGF could induce the up-regulated expression of SLP-2 probably through activating ERK signalling. The current study suggests that SLP-2 may represent an important molecular hallmark that is clinically relevant to the invasion of ESCC. PMID- 23667688 TI - Structural and population-based evaluations of TBC1D1 p.Arg125Trp. AB - Obesity is now a leading cause of preventable death in the industrialised world. Understanding its genetic influences can enhance insight into molecular pathogenesis and potential therapeutic targets. A non-synonymous polymorphism (rs35859249, p.Arg125Trp) in the N-terminal TBC1D1 phosphotyrosine-binding (PTB) domain has shown a replicated association with familial obesity in women. We investigated these findings in the Avon Longitudinal Study of Parents and Children (ALSPAC), a large European birth cohort of mothers and offspring, and by generating a predicted model of the structure of this domain. Structural prediction involved the use of three separate algorithms; Robetta, HHpred/MODELLER and I-TASSER. We used the transmission disequilibrium test (TDT) to investigate familial association in the ALSPAC study cohort (N = 2,292 mother offspring pairs). Linear regression models were used to examine the association of genotype with mean measurements of adiposity (Body Mass Index (BMI), waist circumference and Dual-energy X-ray absorptiometry (DXA) assessed fat mass), and logistic regression was used to examine the association with odds of obesity. Modelling showed that the R125W mutation occurs in a location of the TBC1D1 PTB domain that is predicted to have a function in a putative protein:protein interaction. We did not detect an association between R125W and BMI (mean per allele difference 0.27 kg/m(2) (95% Confidence Interval: 0.00, 0.53) P = 0.05) or obesity (odds ratio 1.01 (95% Confidence Interval: 0.77, 1.31, P = 0.96) in offspring after adjusting for multiple comparisons. Furthermore, there was no evidence to suggest that there was familial association between R125W and obesity (chi(2) = 0.06, P = 0.80). Our analysis suggests that R125W in TBC1D1 plays a role in the binding of an effector protein, but we find no evidence that the R125W variant is related to mean BMI or odds of obesity in a general population sample. PMID- 23667689 TI - Colour constancy across the life span: evidence for compensatory mechanisms. AB - It is well known that the peripheral visual system declines with age: the yellowing of the lens causes a selective reduction of short-wavelength light and sensitivity losses occur in the cone receptor mechanisms. At the same time, our subjective experience of colour does not change with age. The main purpose of this large-scale study (n = 185) covering a wide age range of colour-normal observers (18-75 years of age) was to assess the extent to which the human visual system is able to compensate for the changes in the optical media and at which level of processing this compensation is likely to occur. We report two main results: (1) Supra-threshold parafoveal colour perception remains largely unaffected by the age-related changes in the optical media (yellowing of the lens) whereas our ability to discriminate between small colour differences is compromised with an increase in age. (2) Significant changes in colour appearance are only found for unique green settings under daylight viewing condition which is consistent with the idea that the yellow-blue mechanism is most affected by an increase in age due to selective attenuation of short-wavelength light. The data on the invariance of hue perception, in conjunction with the age-related decline in chromatic sensitivity, provides evidence for compensatory mechanisms that enable colour-normal human observers a large degree of colour constancy across the life span. These compensatory mechanisms are likely to originate at cortical sites. PMID- 23667690 TI - Transcriptome sequencing of Zhikong scallop (Chlamys farreri) and comparative transcriptomic analysis with Yesso scallop (Patinopecten yessoensis). AB - BACKGROUND: Bivalves play an important role in the ecosystems they inhabit and represent an important food source all over the world. So far limited genetic research has focused on this group of animals largely due to the lack of sufficient genetic or genomic resources. Here, we performed de novo transcriptome sequencing to produce the most comprehensive expressed sequence tag resource for Zhikong scallop (Chlamys farreri), and conducted the first transcriptome comparison for scallops. RESULTS: In a single 454 sequencing run, 1,033,636 reads were produced and then assembled into 26,165 contigs. These contigs were then clustered into 24,437 isotigs and further grouped into 20,056 isogroups. About 47% of the isogroups showed significant matches to known proteins based on sequence similarity. Transcripts putatively involved in growth, reproduction and stress/immune-response were identified through Gene ontology (GO) and KEGG pathway analyses. Transcriptome comparison with Yesso scallop (Patinopecten yessoensis) revealed similar patterns of GO representation. Moreover, 38 putative fast-evolving genes were identified through analyzing the orthologous gene pairs between the two scallop species. More than 46,000 single nucleotide polymorphisms (SNPs) and 350 simple sequence repeats (SSRs) were also detected. CONCLUSION: Our study provides the most comprehensive transcriptomic resource currently available for C. farreri. Based on this resource, we performed the first large-scale transcriptome comparison between the two scallop species, C. farreri and P. yessoensis, and identified a number of putative fast-evolving genes, which may play an important role in scallop speciation and/or local adaptation. A large set of single nucleotide polymorphisms and simple sequence repeats were identified, which are ready for downstream marker development. This transcriptomic resource should lay an important foundation for future genetic or genomic studies on C. farreri. PMID- 23667691 TI - Prolactin expression in the cochlea of aged BALB/c mice is gender biased and correlates to loss of bone mineral density and hearing loss. AB - Prolactin is a versatile hormone with over 300 known functions and predominantly expressed in the pituitary. However, its expression has additionally been found in a number of extrapituitary organs. Recently, we described the expression of prolactin in the inner ear of mice, where it was correlated to age. Previous research has shown prolactin to be linked to abnormal bone metabolism and hearing loss due to changes in morphology of the bony otic capsule. Here we further investigated the relationship between prolactin, hearing loss and cochlea bone metabolism. BALB/c mice were tested for hearing using ABR at 6 and 12 months of age. Bone mineral density of the cochlea was evaluated using microCT scanning. Prolactin expression was calculated using quantitative real time PCR. Expression of the key regulators of bone metabolism, osteoprotegerin and receptor activator of nuclear factor-kappaB ligand were also determined. We found that prolactin expression was exclusive to the female mice. This also correlated to a greater threshold shift in hearing for the females between 6 and 12 months of age. Analyses of the cochlea also show that the bone mineral density was lower in females compared to males. However, no gender differences in expression of osteoprotegerin or receptor activator of nuclear factor-kappaB ligand could be found. Further analysis of cochlea histological sections revealed larger ostocyte lacunae in the females. These results provide a possible mechanism for an age related hearing loss sub-type that is associated with gender and provides clues as to how this gender bias in hearing loss develops. In addition, it has the potential to lead to treatment for this specific type of hearing loss. PMID- 23667692 TI - Low concentrations of metformin selectively inhibit CD133+ cell proliferation in pancreatic cancer and have anticancer action. AB - Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States. The prognosis remains dismal with little advance in treatment. Metformin is a drug widely used for the treatment of type II diabetes. Recent epidemiologic data revealed that oral administration of metformin is associated with a reduced risk of pancreatic cancer, suggesting its potential as a novel drug for this disease. Many studies have demonstrated the in vitro anticancer action of metformin, but the typically used concentrations were much higher than the in vivo plasma and tissue concentrations achieved with recommended therapeutic doses of metformin, and low concentrations of metformin had little effect on the proliferation of pancreatic cancer cells. We examined the effect of low concentrations of metformin on different subpopulations of pancreatic cancer cells and found that these selectively inhibited the proliferation of CD133+ but not CD24+CD44+ESA+ cells. We also examined the effect of low concentrations of metformin on cell invasion and in vivo tumor formation, demonstrating in vitro and in vivo anticancer action. Metformin was associated with a reduction of phospho-Erk and phospho-mTOR independent of Akt and AMPK phosphorylation. CD133+ pancreatic cancer cells are considered to be cancer stem cells that contribute to recurrence, metastasis and resistance to adjuvant therapies in pancreatic cancer. Our results provide a basis for combination of metformin with current therapies to improve the prognosis of this disease. PMID- 23667693 TI - Propensity score estimation to address calendar time-specific channeling in comparative effectiveness research of second generation antipsychotics. AB - BACKGROUND: Channeling occurs when a medication and its potential comparators are selectively prescribed based on differences in underlying patient characteristics. Drug safety advisories can provide new information regarding the relative safety or effectiveness of a drug product which might increase selective prescribing. In particular, when reported adverse effects vary among drugs within a therapeutic class, clinicians may channel patients toward or away from a drug based on the patient's underlying risk for an adverse outcome. If channeling is not identified and appropriately managed it might lead to confounding in observational comparative effectiveness studies. OBJECTIVE: To demonstrate channeling among new users of second generation antipsychotics following a Food and Drug Administration safety advisory and to evaluate the impact of channeling on cardiovascular risk estimates over time. DATA SOURCE: Florida Medicaid data from 2001-2006. STUDY DESIGN: Retrospective cohort of adults initiating second generation antipsychotics. We used propensity scores to match olanzapine initiators with other second generation antipsychotic initiators. To evaluate channeling away from olanzapine following an FDA safety advisory, we estimated calendar time-specific propensity scores. We compare the performance of these calendar time-specific propensity scores with conventionally-estimated propensity scores on estimates of cardiovascular risk. PRINCIPAL FINDINGS: Increased channeling away from olanzapine was evident for some, but not all, cardiovascular risk factors and corresponded with the timing of the FDA advisory. Covariate balance was optimized within period and across all periods when using the calendar time-specific propensity score. Hazard ratio estimates for cardiovascular outcomes did not differ across models (Conventional PS: 0.97, 95%CI: 0.81-3.18 versus calendar time-specific PS: 0.93, 95%CI: 0.77-3.04). CONCLUSIONS: Changes in channeling over time was evident for several covariates but had limited impact on cardiovascular risk estimates, possibly due to unmeasured confounding. Although calendar time-specific propensity scores appear to improve covariate balance, the impact on comparative effectiveness results is limited in this setting. PMID- 23667694 TI - Usutu virus persistence and West Nile virus inactivity in the Emilia-Romagna region (Italy) in 2011. AB - BACKGROUND: The circulation of West Nile virus and Usutu virus was detected in the Emilia-Romagna region in 2008 and 2009. To evaluate the extent of circulation of both viruses, environmental surveillance, based on bird and mosquito testing, was conducted in 2008 and gradually improved over the years. METHODS: In February March 2009-2011, 5,993 hibernating mosquitoes were manually sampled, out of which 80.1% were Culex pipiens; none tested positive for the viruses. From 2008 to 2011, 946,213 mosquitoes, sampled between May and October, were tested; 86.5% were Cx. pipiens. West Nile virus was detected in 32 Cx. pipiens pools, and Usutu virus was detected in 229 mosquito pools (217 Cx. pipiens, 10 Aedes albopictus, one Anopheles maculipennis s.l., and one Aedes caspius). From 2009 to 2011, of 4,546 birds collected, 42 tested positive for West Nile virus and 48 for Usutu virus. West Nile virus and Usutu virus showed different patterns of activity during the 2008-2011 surveillance period. West Nile virus was detected in 2008, 2009, and 2010, but not in 2011. Usutu virus, however, was continuously active throughout 2009, 2010, and 2011. CONCLUSIONS: The data strongly suggest that both viruses overwinter in the surveyed area rather than being continually reintroduced every season. The lack of hibernating mosquitoes testing positive for the viruses and the presence of positive birds sampled early in the season support the hypothesis that the viruses overwinter in birds rather than in mosquitoes. Herd immunity in key bird species could explain the decline of West Nile virus observed in 2011, while the persistence of Usutu virus may be explained by not yet identified reservoirs. Reported results are comparable with a peri-Mediterranean circulation of the West Nile virus lineage 1 related strain, which became undetectable in the environment after two to three years of obvious circulation. PMID- 23667695 TI - Decrease in irisin in patients with chronic kidney disease. AB - Patients with chronic kidney disease have abnormal energy expenditure and metabolism. The mechanisms underlying altered energy expenditure in uremia are unknown and remain to be elucidated. Irisin is a peroxisome proliferator activated receptor gamma coactivator 1-alpha-dependent myokine, and it increases energy expenditure in the absence of changes in food intake or activity. We hypothesize that chronic kidney disease patients have altered irisin levels. We measured resting irisin levels in 38 patients with stage 5 chronic kidney disease and in 19 age- and sex-matched normal subjects. Plasma irisin levels were significantly decreased in chronic kidney disease patients (58.59%; 95% CI 47.9% 69.2%, p<0.0001). The decrease in irisin levels was inversely correlated with the levels of blood urea nitrogen and creatinine. Further association analysis revealed that irisin level is independently associated with high-density lipoprotein cholesterol level. Our results suggest that chronic kidney disease patients have lower than normal irisin levels at rest. Furthermore, irisin may play a major role in affecting high-density lipoprotein cholesterol levels and abnormal energy expenditure in chronic kidney disease patients. PMID- 23667696 TI - The 53BP1 homolog in C. elegans influences DNA repair and promotes apoptosis in response to ionizing radiation. AB - 53BP1 contributes to activation of the G2/M checkpoint downstream of ATM and MDC1 in response to ionizing radiation and promotes nonhomologous end-joining (NHEJ) in mammalian cells. In order to determine whether the cellular activities of 53BP1 are conserved in the model organism C. elegans, we analyzed the function of its homolog, HSR-9 in response to DNA damage. Deletion or Mos1-insertion in hsr-9 did not affect the sensitivity of worms to double strand DNA breaks (DSBs), as reflected in embryonic survival and larval development. Nevertheless, the hsr-9 mutations, as well as a lig-4 deletion, reversed the hypersensitivity of rad-54 deficient worms to DSBs. In addition, oocyte chromosomal aberrations, which were increased by rad-54 knockdown in response to DSBs, were also reduced by the hsr-9 mutations. The hsr-9 mutations did not prevent the cell cycle arrest induced by DSBs in mitotically proliferating germ cells. However, they attenuated apoptosis induced by DSBs, but not when CEP-1 (a p53 ortholog) was absent, suggesting that HSR-9 functions in the same pathway as CEP-1. We concluded that the 53BP1 homolog in C. elegans is not directly involved in cell cycle arrest in response to DSBs, but that it promotes apoptosis and also a form of NHEJ that occurs only when rad 54 is deficient. PMID- 23667697 TI - Poly-Ub-substrate-degradative activity of 26S proteasome is not impaired in the aging rat brain. AB - Proteostasis is critical for the maintenance of life. In neuronal cells an imbalance between protein synthesis and degradation is thought to be involved in the pathogenesis of neurodegenerative diseases during aging. Partly, this seems to be due to a decrease in the activity of the ubiquitin-proteasome system, wherein the 20S/26S proteasome complexes catalyse the proteolytic step. We have characterised 20S and 26S proteasomes from cerebrum, cerebellum and hippocampus of 3 weeks old (young) and 24 month old (aged) rats. Our data reveal that the absolute amount of the proteasome is not dfferent between both age groups. Within the majority of standard proteasomes in brain the minute amounts of immuno subunits are slightly increased in aged rat brain. While this goes along with a decrease in the activities of 20S and 26S proteasomes to hydrolyse synthetic fluorogenic tripeptide substrates from young to aged rats, the capacity of 26S proteasomes for degradation of poly-Ub-model substrates and its activation by poly-Ub-substrates is not impaired or even slightly increased in brain of aged rats. We conclude that these alterations in proteasome properties are important for maintaining proteostasis in the brain during an uncomplicated aging process. PMID- 23667699 TI - Foraging ranges of insectivorous bats shift relative to changes in mosquito abundance. AB - The need to develop effective management strategies for insectivorous bat populations requires an understanding of factors influencing habitat use. Availability of pest prey, such as mosquitoes is likely to be one such factor. To assess whether this is the case, we radio-tracked Vespadelus vulturnus Thomas (little forest bat), a predator of Aedes vigilax Skuse (saltmarsh mosquito), in saltmarsh and adjacent coastal swamp forest during periods of high and low Ae. vigilax abundance. When mosquito abundance in structurally-open saltmarsh was similar to the more cluttered coastal swamp forest, use of saltmarsh by V. vulturnus was disproportionately greater than its availability, with saltmarsh selected preferentially for foraging. However, at times of low Ae. vigilax abundance in saltmarsh, use of saltmarsh by V. vulturnus was reduced and all habitats were used in proportion to availability in the study area. This is the first radio-tracking study to demonstrate a shift in foraging range by an insectivorous bat species correlated with fluctuations in the distribution and abundance of a particular prey resource. The shift in foraging range by V. vulturnus, corresponding with a spatio-temporal variation in abundance of Ae. vigilax highlights the importance of mosquitoes as a dietary item. Broadscale pest control of Ae. vigilax may have ecological implications for the diet and habitat use of V. vulturnus. An adaptive management approach is proposed, whereby careful monitoring of insectivorous bat populations is recommended before and after any application of broadscale mosquito control measures. We also suggest a precautionary approach is taken such that broadscale control of mosquitoes avoids the lactation period of bats, a time when their energetic demands are greatest and when there is reduced risk of contracting mosquito-borne diseases transmitted by Ae. vigilax. PMID- 23667698 TI - FTY720/fingolimod, a sphingosine analogue, reduces amyloid-beta production in neurons. AB - Sphingosine-1-phosphate (S1P) is a pluripotent lipophilic mediator working as a ligand for G-protein coupled S1P receptors (S1PR), which is currently highlighted as a therapeutic target for autoimmune diseases including relapsing forms of multiple sclerosis. Sphingosine related compounds, FTY720 and KRP203 known as S1PR modulators, are phosphorylated by sphingosine kinase 2 (SphK2) to yield the active metabolites FTY720-P and KRP203-P, which work as functional antagonists for S1PRs. Here we report that FTY720 and KRP203 decreased production of Amyloid beta peptide (Abeta), a pathogenic proteins causative for Alzheimer disease (AD), in cultured neuronal cells. Pharmacological analyses suggested that the mechanism of FTY720-mediated Abeta decrease in cells was independent of known downstream signaling pathways of S1PRs. Unexpectedly, 6-days treatment of APP transgenic mice with FTY720 resulted in a decrease in Abeta40, but an increase in Abeta42 levels in brains. These results suggest that S1PR modulators are novel type of regulators for Abeta metabolisms that are active in vitro and in vivo. PMID- 23667700 TI - Embryos of the viviparous dermapteran, Arixenia esau develop sequentially in two compartments: terminal ovarian follicles and the uterus. AB - Three main reproductive strategies have been described among insects: most common oviparity, ovoviviparity and viviparity. In the latter strategy, the embryonic development takes place within the body of the mother which provides gas exchange and nutrients for embryos. Here we present the results of histological and EM analyses of the female reproductive system of the viviparous earwig, Arixenia esau, focusing on all the modifications related to the viviparity. We show that in the studied species the embryonic development consists of two "physiological phases" that take place in two clearly disparate compartments, i.e. the terminal ovarian follicle and the uterus. In both compartments the embryos are associated with synthetically active epithelial cells. We suggest that these cells are involved in the nourishment of the embryo. Our results indicate that viviparity in arixeniids is more complex than previously considered. We propose the new term "pseudoplacento-uterotrophic viviparity" for this unique two-phase reproductive strategy. PMID- 23667701 TI - The transient nature of Bunyamwera orthobunyavirus NSs protein expression: effects of increased stability of NSs protein on virus replication. AB - The NSs proteins of bunyaviruses are the viral interferon antagonists, counteracting the host's antiviral response to infection. During high multiplicity infection of cultured mammalian cells with Bunyamwera orthobunyavirus (BUNV), NSs is rapidly degraded after reaching peak levels of expression at 12hpi. Through the use of inhibitors this was shown to be the result of proteasomal degradation. A recombinant virus (rBUN4KR), in which all four lysine residues in NSs were replaced by arginine residues, expresses an NSs protein (NSs4KR) that is resistant to degradation, confirming that degradation is lysine-dependent. However, despite repeated attempts, no direct ubiquitylation of NSs in infected cells could be demonstrated. This suggests that degradation of NSs, although lysine-dependent, may be achieved through an indirect mechanism. Infection of cultured mammalian cells or mice indicated no disadvantage for the virus in having a non-degradable NSs protein: in fact rBUN4KR had a slight growth advantage over wtBUNV in interferon-competent cells, presumably due to the increased and prolonged presence of NSs. In cultured mosquito cells there was no difference in growth between wild-type BUNV and rBUN4KR, but surprisingly NSs4KR was not stabilised compared to the wild-type NSs protein. PMID- 23667702 TI - Processing technology investigation of loquat (Eriobotrya japonica) leaf by ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry combined with chemometrics. AB - Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) and multivariate statistical analysis were used to investigate the processing technology of Loquat (Eriobotrya japonica) leaf (pipaye, PPY). The differences in samples processed using different methods were revealed by unsupervised principal component analysis (PCA). In the scores plot of PCA, honey-processed PPY (PPPY), crude PPY (CPPY), and heated PPY (HPPY) were clearly discriminated. Furthermore, samples processed at different temperatures could also be distinguished; indeed, our PCA results demonstrated the importance of temperature during processing. Two unique marker ions were found to discriminate between PPPY and CPPY by orthogonal partial least squares discriminant analysis (OPLS-DA), which could be used as potential chemical markers. The method was further confirmed by a verification test with commercial PPY. The orthogonal array experiment revealed an optimized processing condition with 50% honey at 140 degrees C for 20 min after 4 h of moistening time, a process that provides significant information for standardized production. PMID- 23667703 TI - Evolution of and horizontal gene transfer in the Endornavirus genus. AB - The transfer of genetic information between unrelated species is referred to as horizontal gene transfer. Previous studies have demonstrated that both retroviral and non-retroviral sequences have been integrated into eukaryotic genomes. Recently, we identified many non-retroviral sequences in plant genomes. In this study, we investigated the evolutionary origin and gene transfer of domains present in endornaviruses which are double-stranded RNA viruses. Using the available sequences for endornaviruses, we found that Bell pepper endornavirus like sequences homologous to the glycosyltransferase 28 domain are present in plants, fungi, and bacteria. The phylogenetic analysis revealed the glycosyltransferase 28 domain of Bell pepper endornavirus may have originated from bacteria. In addition, two domains of Oryza sativa endornavirus, a glycosyltransferase sugar-binding domain and a capsular polysaccharide synthesis protein, also exhibited high similarity to those of bacteria. We found evidence that at least four independent horizontal gene transfer events for the glycosyltransferase 28 domain have occurred among plants, fungi, and bacteria. The glycosyltransferase sugar-binding domains of two proteobacteria may have been horizontally transferred to the genome of Thalassiosira pseudonana. Our study is the first to show that three glycome-related viral genes in the genus Endornavirus have been acquired from marine bacteria by horizontal gene transfer. PMID- 23667705 TI - Humans strengthen bottom-up effects and weaken trophic cascades in a terrestrial food web. AB - Ongoing debate about whether food webs are primarily regulated by predators or by primary plant productivity, cast as top-down and bottom-up effects, respectively, may becoming superfluous. Given that most of the world's ecosystems are human dominated we broadened this dichotomy by considering human effects in a terrestrial food-web. We studied a multiple human-use landscape in southwest Alberta, Canada, as opposed to protected areas where previous terrestrial food web studies have been conducted. We used structural equation models (SEMs) to assess the strength and direction of relationships between the density and distribution of: (1) humans, measured using a density index; (2) wolves (Canis lupus), elk (Cervus elapahus) and domestic cattle (Bos taurus), measured using resource selection functions, and; (3) forage quality, quantity and utilization (measured at vegetation sampling plots). Relationships were evaluated by taking advantage of temporal and spatial variation in human density, including day versus night, and two landscapes with the highest and lowest human density in the study area. Here we show that forage-mediated effects of humans had primacy over predator-mediated effects in the food web. In our parsimonious SEM, occurrence of humans was most correlated with occurrence of forage (beta = 0.637, p<0.0001). Elk and cattle distribution were correlated with forage (elk day: beta = 0.400, p<0.0001; elk night: beta = 0.369, p<0.0001; cattle day: beta = 0.403, p<0.0001; cattle, night: beta = 0.436, p<0.0001), and the distribution of elk or cattle and wolves were positively correlated during daytime (elk: beta = 0.293, p <0.0001, cattle: beta = 0.303, p<0.0001) and nighttime (elk: beta = 0.460, p<0.0001, cattle: beta = 0.482, p<0.0001). Our results contrast with research conducted in protected areas that suggested human effects in the food web are primarily predator-mediated. Instead, human influence on vegetation may strengthen bottom up predominance and weaken top-down trophic cascades in ecosystems. We suggest that human influences on ecosystems may usurp top-down and bottom-up effects. PMID- 23667704 TI - Characterization of the complete uric acid degradation pathway in the fungal pathogen Cryptococcus neoformans. AB - Degradation of purines to uric acid is generally conserved among organisms, however, the end product of uric acid degradation varies from species to species depending on the presence of active catabolic enzymes. In humans, most higher primates and birds, the urate oxidase gene is non-functional and hence uric acid is not further broken down. Uric acid in human blood plasma serves as an antioxidant and an immune enhancer; conversely, excessive amounts cause the common affliction gout. In contrast, uric acid is completely degraded to ammonia in most fungi. Currently, relatively little is known about uric acid catabolism in the fungal pathogen Cryptococcus neoformans even though this yeast is commonly isolated from uric acid-rich pigeon guano. In addition, uric acid utilization enhances the production of the cryptococcal virulence factors capsule and urease, and may potentially modulate the host immune response during infection. Based on these important observations, we employed both Agrobacterium-mediated insertional mutagenesis and bioinformatics to predict all the uric acid catabolic enzyme encoding genes in the H99 genome. The candidate C. neoformans uric acid catabolic genes identified were named: URO1 (urate oxidase), URO2 (HIU hydrolase), URO3 (OHCU decarboxylase), DAL1 (allantoinase), DAL2,3,3 (allantoicase-ureidoglycolate hydrolase fusion protein), and URE1 (urease). All six ORFs were then deleted via homologous recombination; assaying of the deletion mutants' ability to assimilate uric acid and its pathway intermediates as the sole nitrogen source validated their enzymatic functions. While Uro1, Uro2, Uro3, Dal1 and Dal2,3,3 were demonstrated to be dispensable for virulence, the significance of using a modified animal model system of cryptococcosis for improved mimicking of human pathogenicity is discussed. PMID- 23667706 TI - Secondhand smoke exposure and health services use among adolescent current smokers. AB - BACKGROUND: To investigate the associations of secondhand smoke (SHS) exposure with medical consultation and hospitalisation among adolescents in Hong Kong. METHODS: A total of 35827 secondary 1 (US grade 7) to secondary 5 students from 85 randomly selected schools completed an anonymous questionnaire on smoking, SHS at home, SHS outside home, medical consultation in the past 14 days, hospitalisation in the past 12 months, and socio-demographic characteristics. Current smoking was defined as any smoking in the past 30 days. SHS exposure was classified as none (reference), 1-4 and 5-7 days/week. Logistic regression yielded adjusted odds ratios (AORs) for medical consultation and hospitalisation in relation to SHS exposure at home and outside home in current smokers. Analyses were also done among never-smokers for comparison. RESULTS: Among all students, 15.9% had medical consultation and 5.2% had been hospitalised. Any SHS exposure at home was associated with AORs (95% CI) for medical consultation and hospitalisation of 1.69 (1.14-2.51) and 2.85 (1.47-5.52) in current smokers, and 1.03 (0.91-1.15) and 1.25 (1.02-1.54) in never-smokers, respectively, (P<0.01 for interaction between smoking status and SHS exposure at home). SHS exposure outside home was generally not associated with medical consultation and hospitalisation in smokers and never-smokers. CONCLUSIONS: SHS exposure at home was associated with health services use among adolescent current smokers. Adolescent smokers should be aware of the harm of SHS in addition to that from their own smoking. The evidence helps health care professionals to advise adolescent smokers to avoid SHS exposure and stop smoking. PMID- 23667707 TI - Signal transduction pathways in the pentameric ligand-gated ion channels. AB - The mechanisms of allosteric action within pentameric ligand-gated ion channels (pLGICs) remain to be determined. Using crystallography, site-directed mutagenesis, and two-electrode voltage clamp measurements, we identified two functionally relevant sites in the extracellular (EC) domain of the bacterial pLGIC from Gloeobacter violaceus (GLIC). One site is at the C-loop region, where the NQN mutation (D91N, E177Q, and D178N) eliminated inter-subunit salt bridges in the open-channel GLIC structure and thereby shifted the channel activation to a higher agonist concentration. The other site is below the C-loop, where binding of the anesthetic ketamine inhibited GLIC currents in a concentration dependent manner. To understand how a perturbation signal in the EC domain, either resulting from the NQN mutation or ketamine binding, is transduced to the channel gate, we have used the Perturbation-based Markovian Transmission (PMT) model to determine dynamic responses of the GLIC channel and signaling pathways upon initial perturbations in the EC domain of GLIC. Despite the existence of many possible routes for the initial perturbation signal to reach the channel gate, the PMT model in combination with Yen's algorithm revealed that perturbation signals with the highest probability flow travel either via the beta1-beta2 loop or through pre-TM1. The beta1-beta2 loop occurs in either intra- or inter-subunit pathways, while pre-TM1 occurs exclusively in inter-subunit pathways. Residues involved in both types of pathways are well supported by previous experimental data on nAChR. The direct coupling between pre-TM1 and TM2 of the adjacent subunit adds new insight into the allosteric signaling mechanism in pLGICs. PMID- 23667708 TI - The small molecule triclabendazole decreases the intracellular level of cyclic AMP and increases resistance to stress in Saccharomyces cerevisiae. AB - The Ras-adenylyl cyclase-protein kinase A nutrient-sensing pathway controls metabolism, proliferation and resistance to stress in Saccharomyces cerevisiae. The genetic disruption of this pathway increases resistance to a variety of stresses. We show here that the pharmacological inhibition of this pathway by the drug triclabendazole increases resistance to oxidants, heat stress and extends the chronological life. Evidence is presented that triclabendazole decreases the intracellular level of cyclic AMP by inhibiting adenylyl cyclase and triggers the parallel rapid translocation of the stress-resistance transcription factor Msn2 from the cytosol into the nucleus, as deduced from experiments employing a strain in which MSN2 is replaced with MSN2-GFP (GFP, green fluorescent protein). Msn2 and Msn4 are responsible for activating the transcription of numerous genes that encode proteins that protect cells from stress. The results are consistent with triclabendazole either inhibiting the association of Ras with adenylyl cyclase or directly inhibiting adenylyl cyclase, which in turn triggers Msn2/4 to enter the nucleus and activate stress-responsible element gene expression. PMID- 23667709 TI - The role of the N-D1 linker of the N-ethylmaleimide-sensitive factor in the SNARE disassembly. AB - N-ethylmaleimide-sensitive factor (NSF) is a member of the type II AAA+ (ATPase associated with various cellular activities) family. It plays a critical role in intracellular membrane trafficking by disassembling soluble NSF attachment protein receptor (SNARE) complexes. Each NSF protomer consists of an N-terminal domain (N domain) followed by two AAA ATPase domains (D1 and D2) in tandem. The N domain is required for SNARE/alpha-SNAP binding and the D1 domain accounts for the majority of ATP hydrolysis. Little is known about the role of the N-D1 linker in the NSF function. This study presents detailed mutagenesis analyses of NSF N D1 linker, dissecting its role in the SNARE disassembly, the SNARE/alpha-SNAP complex binding, the basal ATPase activity and the SNARE/alpha-SNAP stimulated ATPase activity. Our results show that the N-terminal region of the N-D1 linker associated mutants cause severe defect in SNARE complex disassembly, but little effects on the SNARE/alpha-SNAP complex binding, the basal and the SNARE/alpha SNAP stimulated ATPase activity, suggesting this region may be involved in the motion transmission from D1 to N domain. Mutating the residues in middle and C terminal region of the N-D1 linker increases the basal ATPase activity, indicating it may play a role in autoinhibiting NSF activity until it encounters SNARE/alpha-SNAP complex substrate. Moreover, mutations at the C-terminal sequence GIGG exhibit completely abolished or severely reduced activities of the substrate binding, suggesting that the flexibility of N-D1 linker is critical for the movement of the N domain that is required for the substrate binding. Taken together, these data suggest that the whole N-D1 linker is critical for the biological function of NSF to disassemble SNARE complex substrate with different regions responsible for different roles. PMID- 23667710 TI - Comparison of rapid diagnostic tests for the detection of Plasmodium vivax malaria in South Korea. AB - South Korea is one of many countries with endemic Plasmodium vivax malaria. Here we report the evaluation of four rapid diagnostic tests (RDTs) for diagnosis of this disease. A total of 253 subjects were enrolled in the study. The sensitivities, specificities and agreement frequencies were estimated by comparing the four RDTs against the standard of nested-PCR and microscopic examination. The CareStart(TM) and SD Bioline had higher test sensitivities (99.4 and 98.8%, respectively) compared with the NanoSign and Asan Easy tests (93.0 and 94.7%, respectively). The CareStart(TM) and SD Bioline tests could detect P. vivax in samples with parasite densities <150/MUl, which was a slightly better performance than the other two RDTs. The quantitative accuracy of the four RDTs was also estimated by comparing results with P. vivax counts from blood samples. Lower test price would result in increased use of these RDTs in the field. The results of this study contribute valuable information that will aid in the selection of a diagnostic method for the detection of malaria. PMID- 23667711 TI - The response of the Mediterranean gorgonian Eunicella singularis to thermal stress is independent of its nutritional regime. AB - Over the last few decades, sessile benthic organisms from the Mediterranean Sea have suffered from the global warming of the world's oceans, and several mass mortality events were observed during warm summers. It has been hypothesized that mortality could have been due to a nutrient (food) shortage following the stratification of the water column. However, the symbiotic gorgonian Eunicella singularis has also presented a locally exceptional mortality, despite its autotrophic capacities through the photosynthesis of its dinoflagellate symbionts. Thus, this study has experimentally investigated the response of E. singularis to a thermal stress (temperature increase from 18 to 26 degrees C), with colonies maintained more than 2 months under four nutritional diets: autotrophy only (AO), autotrophy and inorganic nitrogen addition (AN), autotrophy and heterotrophy (AH), heterotrophy only (HO). At 18 degrees C, and contrary to many other anthozoans, supplementation of autotrophy with either inorganic nitrogen or food (heterotrophy) had no effect on the rates of respiration, photosynthesis, as well as in the chlorophyll, lipid and protein content. In the dark, heterotrophy maintained the gorgonian's metabolism, except a bleaching (loss of pigments), which did not affect the rates of photosynthesis. At 24 degrees C, rates of respiration, and photosynthesis significantly decreased in all treatments. At 26 degrees C, in addition to a decrease in the lipid content of all treatments, a bleaching was observed after 1 week in the AO treatment, while the AH and AN treatments resisted three weeks before bleaching. These last results suggest that, temperatures above 24 degrees C impair the energetic reserves of this species and might explain the mortality events in the Mediterranean. PMID- 23667712 TI - Effects of resveratrol in pregnancy using murine models with reduced blood supply to the uterus. AB - Preeclampsia (PE) and fetal growth restriction (FGR) contribute significantly to fetal and maternal morbidity and mortality. Although the causes of PE and FGR are not fully understood, both conditions are known to be associated with impaired uterine artery blood flow. Resveratrol, a polyphenol found in a number of plants, has been shown to induce relaxation of uterine arteries in vitro as well as improve many pathological conditions associated with PE and FGR. We hypothesized that treatment of endothelial nitric oxide synthase knockout mice (eNOS-/-) and catechol-O-methyltransferase knockout mice (COMT-/-) with resveratrol during pregnancy would improve uterine artery blood flow and therefore ameliorate the PE like phenotype and FGR in these murine models. Pregnant C57BL/6J, eNOS-/- and COMT-/- mice received either resveratrol supplemented diet (4 g/kg diet) or control diet between gestational day (GD) 0.5 and GD 18.5. Resveratrol supplementation significantly increased uterine artery blood flow velocity and fetal weight in COMT-/- but not in eNOS-/- mice. There were no effects of resveratrol on litter size and placental weight among the groups. In conclusion, resveratrol increased uterine artery blood flow velocity and fetal weight in COMT /- mice, suggesting potential as a therapeutic strategy for PE and FGR. PMID- 23667713 TI - Measurement of Uptake and Release Capacities of Mesoporous Silica Nanoparticles Enabled by Nanovalve Gates. AB - The uptake and release capacities of mesoporous silica particles are measured on nanovalve-gated stimulated release systems, using a water soluble biological stain, Hoechst 33342, as the cargo model. Five different types of mesoporous silica nanoparticles: 2D-hexagonal MCM-41, swollen pore MCM-41, rod-like MCM-41, hollow mesoporous nanoparticles and radial mesoporous nanoparticles are studied and compared. Solid silica nanoparticles are used as the control. Because of the presence of the nanovalves, the loaded and capped particles can be washed thoroughly without losing the content of the mesopores. The quantity of Hoechst 33342 molecules trapped within the nanoparticles and released upon opening the nanovalves are systematically studied for the first time. The loading conditions are optimized by varying the Hoechst concentration in the loading solutions. Surprisingly, increasing the Hoechst concentration in the loading solution does not always result in a larger amount of Hoechst being trapped and released. Among the five types of mesoporous silica nanoparticles, the radial mesoporous nanoparticles and the swollen pore MCM-41 particles show the highest and lowest release capacity, respectively. The uptake capacities is correlated with the specific surface area of the materials rather than their internal volume. The uptake and release behaviors are also affected by charge and spatial factors. PMID- 23667714 TI - Type 2 diabetes in older people; the importance of blood pressure control. AB - Diabetes and hypertension often coexist and their coexistence substantially promote cardiovascular disease (CVD) and chronic kidney disease. Control of blood pressure to a level of 140/90 mm Hg in people with diabetes can prevent or at least delay CVD and chronic kidney disease.. In the past many society treatment guidelines have stressed tight blood pressure control (=< 130/80) for people with diabetes. But recommendations for such tight blood pressure control have not been supported by recent large randomized control trials, especially in in elderly. Here we review the recent literature regarding the benefits of blood pressure control in elderly patients with diabetics. We further focus on evidence for specific levels of blood pressure treatment goals, in this population subset.. PMID- 23667715 TI - Accurate preterm labor diagnosis using a CD55-TLR4 combination biomarker model. AB - We previously demonstrated immune activation in the maternal peripheral circulation associated with preterm labor (PTL). There was an elevation in WBC mRNA of anti-inflammatory complement decay-accelerating factor (CD55) and the innate-immune response activating toll-like receptor 4 (TLR4). These findings suggested that collectively, these two molecules might serve as useful biomolecules to aid in the diagnosis of PTL. In this study, we used a combined marker approach to determine whether a dual marker model utilizing both CD55 and TLR4 mRNA levels to classify PTL would increase diagnostic accuracy compared to either molecule alone. Two methods were evaluated; a linear discriminant (LD) method and a distribution free (DF) method, in order to find the optimal linear combination of TLR4 and CD55 data to diagnose PTL accurately. Our results indicated that a combined CD55-TLR4 dual marker model could provide statistically significant improvements compared to CD55 or TLR4 single marker models for PTL classification performance. PMID- 23667716 TI - Structure-Based Design and Synthesis of an HIV-1 Entry Inhibitor Exploiting X-Ray and Thermodynamic Characterization. AB - The design, synthesis, thermodynamic and crystallographic characterization of a potent, broad spectrum, second-generation HIV-1 entry inhibitor that engages conserved carbonyl hydrogen bonds within gp120 has been achieved. The optimized antagonist exhibits a sub-micromolar binding affinity (110 nM) and inhibits viral entry of clade B and C viruses (IC50 geometric mean titer of 1.7 and 14.0 MUM, respectively), without promoting CD4-independent viral entry. thermodynamic signatures indicate a binding preference for the (R,R)-over the (S,S)-enantiomer. The crystal structure of the small molecule-gp120 complex reveals the displacement of crystallographic water and the formation of a hydrogen bond with a backbone carbonyl of the bridging sheet. Thus, structure-based design and synthesis targeting the highly conserved and structurally characterized CD4:gp120 interface is an effective tactic to enhance the neutralization potency of small molecule HIV-1 entry inhibitors. PMID- 23667718 TI - Error Analysis and Propagation in Metabolomics Data Analysis. AB - Error analysis plays a fundamental role in describing the uncertainty in experimental results. It has several fundamental uses in metabolomics including experimental design, quality control of experiments, the selection of appropriate statistical methods, and the determination of uncertainty in results. Furthermore, the importance of error analysis has grown with the increasing number, complexity, and heterogeneity of measurements characteristic of 'omics research. The increase in data complexity is particularly problematic for metabolomics, which has more heterogeneity than other omics technologies due to the much wider range of molecular entities detected and measured. This review introduces the fundamental concepts of error analysis as they apply to a wide range of metabolomics experimental designs and it discusses current methodologies for determining the propagation of uncertainty in appropriate metabolomics data analysis. These methodologies include analytical derivation and approximation techniques, Monte Carlo error analysis, and error analysis in metabolic inverse problems. Current limitations of each methodology with respect to metabolomics data analysis are also discussed. PMID- 23667719 TI - Lung Clear "Sugar" Cell Tumor and JAK V617F Positive Essential Thrombocythemia: a Simple Coincidence? AB - The primary clear cell tumor of the lung is an extremely rare benign tumor. This tumor is called "sugar tumor" since clear cell tumor of the lung contains abundant glycogen. We here present a case of lung clear cell tumor of the lung associated to essential thrombocythemia. To the best of our knowledge, there is no report about this association. A 44-Year-Old Woman admitted to our clinic with a 2-month history of fatigue. On physical examination, the spleen was 3 cm palpable below the left costal margin on the mid axillary line. The laboratory tests revealed an elevated platelet counts (1,014,000/mm(3)). A pulmonary nodule (3,5 cm) was detected in the upper right lobe on the chest X-ray. Then, thoracic computed tomography (CT) was planned. The nodule looked like benign pattern on CT scan and total excision was performed for curative and diagnostic treatment. Microscopically, the tumor was composed of nests of rounded or oval cells with distinct cell borders, optically clear cytoplasm and small nucleus. By immunohistochemistry, tumor cells were positive for HMB-45, NSE and focal S100 antigen. And, it was diagnosed as clear "sugar" cell tumor. After tumor excision the lasting thrombocytosis induced us to perform bone marrow biopsy and JAK2 mutation research. Diagnosis of Essential Thrombocythemia was made. In conclusion, it is important to make an evaluation for myeloproliferative diseases in clear "sugar" cell tumor in adults if thrombocytosis was lasting after treatment. PMID- 23667720 TI - A rare case of rosai-dorfman disease in an adult male associated with auto-immune hemolytic anemia. AB - Rosai-Dorfman disease (RDD) is a rare benign histiocytic proliferative disorder predominantly of the lymph nodes, which mostly occurs in children and young adults typically presenting with lymphadenopathy. Our case is of a 63 year-old African-American male who presented with subjective fever, weight loss, bilateral axillary and inguinal lymphadenopathy as well as auto-immune hemolytic anemia. The histological analysis showed emperipolesis and histiocytes that were positive for S-100 and CD-68 consistent with RDD. After steroid treatment and splenectomy, patient's symptoms and hemolytic anemia had resolved. Our case is the first case of RDD reported to be associated with auto-immune hemolytic anemia in an adult. PMID- 23667717 TI - Porphyromonas gingivalis fimbriae. AB - Marginal periodontitis is not a homogeneous disease but is rather influenced by an intricate set of host susceptibility differences as well as diversities in virulence among the harbored organisms. It is likely that clonal heterogeneity of subpopulations with both high and low levels of pathogenicity exists among organisms harbored by individuals with negligible, slight, or even severe periodontal destruction. Therefore, specific virulent clones of periodontal pathogens may cause advanced and/or aggressive periodontitis. Porphyromonas gingivalis is a predominant periodontal pathogen that expresses a number of potential virulence factors involved in the pathogenesis of periodontitis, and accumulated evidence shows that its expression of heterogenic virulence properties is dependent on clonal diversity. Fimbriae are considered to be critical factors that mediate bacterial interactions with and invasion of host tissues, with P. gingivalis shown to express two distinct fimbria-molecules, long and short fimbriae, on the cell surface, both of which seem to be involved in development of periodontitis. Long fimbriae are classified into six types (I to V and Ib) based on the diversity of fimA genes encoding FimA (a subunit of long fimbriae). Studies of clones with type II fimA have revealed their significantly greater adhesive and invasive capabilities as compared to other fimA type clones. Long and short fimbriae induce various cytokine expressions such as IL-1alpha, IL beta, IL-6, and TNF-alpha, which result in alveolar bone resorption. Although the clonal diversity of short fimbriae is unclear, distinct short fimbria-molecules have been found in different strains. These fimbriae variations likely influence the development of periodontal disease. PMID- 23667721 TI - Interest in Determining the CD34+ CD38- Phenotype in the Diagnosis and Prognosis of Acute Leukemia in Abidjan - Cote d'Ivoire. AB - BACKGROUND: In Cote d'Ivoire, acute leukemias account for 12.5% of hematological malignancies. Acute leukemias are due to an anomaly of the stem cell characterized among other things by the expression of CD34(+) CD38(-) surface markers. This CD34(+) CD38(-) phenotype as well as other factors such as tumor syndrome, high leukocytosis and blasts are considered as important factors of poor prognosis. We therefore proposed to investigate the prognostic value of the expression of CD34(+) CD38(-) markers in acute leukemias in Abidjan. METHODS: We selected 23 patients aged 33 years on whom we performed Complete Blood Count, bone marrow aspiration and immunophenotyping. To search for myeloperoxydase, smears of blood or bone marrow were stained with benzidine and revealed by the use of Hydrogen peroxide. Acute leukemias were then identified and distributed using the score proposed by the European Group for the Immunological characterization of Leukemias. The definitive diagnosis was made by combining morphological characters that serve as the basis for the French-American-British classification as well as cytochemical and immunophenotypic characters. RESULTS: According to the cytological and immunophenotypic classifications, the acute lymphoid leukemia 2 and B IV predominated. 52.2% (12/33) of patients were CD34(+) CD38(-). This phenotype was found in almost all cytological immunophenotypic types. The medullary invasion by blasts (reflection of the tumor mass) of the total sample of CD34(+), CD34(+) CD38(-) patients and those not expressing CD34(+) was respectively 79.4%, 81.25%, 83.3% and 74.8%. CONCLUSION: There was therefore no correlation between medullary blasts and the expression of CD34(+) CD38(-). To the factors we selected it would have been necessary to associate the study of cytogenetic and molecular anomalies to better understand the role of CD34(+) CD38(-) phenotype, concerning prognosis. PMID- 23667722 TI - Acute lymphoblastic leukemia experience: epidemiology and outcome of two different regimens. AB - OBJECTIVES: Accurate data about adult acute lymphoblastic leukemia (ALL) are lacking. We aim to assess demographics, prognostic factors, and outcome of ALL therapy at King Hussein Cancer Center (KHCC) in Jordan, and to compare the efficacy of two protocols. METHODS: We reviewed medical records of adults diagnosed and treated for ALL at KHCC from January, 2007 to December, 2011. RESULTS: Over a 5-year period, 108 patients with ALL were treated (66 with the Hyper-CVAD regimen, and 42 with the CALGB 8811 regimen). Median age at diagnosis was 33 years, with 63% males. The most common immunophenotype was CD10-positive common ALL, and 16% have BCR-ABL translocation. Complete response (CR) rate was 88%. After a median follow-up of 32 months (range, 10-72 months), the median survival (MS) was 30 months, and CR duration (CRD) was 28 months. In the multivariate analysis, the presence of BCR-ABL translocation was the only poor prognostic factor with lower MS of 23 months (p<0.01). There was no difference in MS or CRD between the two used regimens. CONCLUSION: International protocols for adult ALL were successfully applied to our patients. There is no difference in efficacy between Hyper-CVAD and CALGB 8811 regimens. Future protocols for adult ALL should incorporate new targeted agents and minimal residual disease monitoring to improve outcome. PMID- 23667723 TI - Physician's Attitude Towards Treatment of Older Patients and the Choice of Therapy. AB - The treatment of acute myeloid leukemia in older patients is still object of controversies, because of considerable heterogeneity among patients and different characteristics in the disease. Reluctance in administering conventional intensive chemotherapy relies on life-threatening complications induced by treatment in an often frail patient population. Nonetheless, while there is general consensus on the management of frail patients with supportive care only, a wide area of uncertainty remains for a considerable proportion of patients in whom treatment beyond support is feasible, with the aim of altering the natural history of the disease. Several predictive score have been proposed in order to prevent toxicity in absence of survival advantage; however in the daily practice patients' and physician attitude does still play a major role in the final therapeutic decision. PMID- 23667724 TI - Impact of pretransplant donor and recipient cytomegalovirus serostatus on outcome for multiple myeloma patients undergoing reduced intensity conditioning allogeneic stem cell transplantation. AB - Scope of the study was to investigate the impact of pre-transplant CMV serostatus of the donor and/or recipient on the outcome of patients undergoing allogeneic hematopoietic stem cell transplantation (Allo-SCT) for Multiple Myeloma (MM). To our knowledge no data are available in the literature about this issue. We retrospectively followed 99 consecutive patients who underwent reduced-intensity conditioning (RIC) Allo-SCT for MM in our cancer center at Marseille between January 2000 and January 2012. Based upon CMV serostatus, patients were classified as low risk (donor [D]-/recipient [R] -) 17 patients (17.1%), intermediate risk (D+/R) 14 patients (14.1%), or high risk - either (D-/R+) 31 patients (31.3%) or (D+/R+), 37 patients (37.3%). Cumulative incidence of CMV reactivation was 39% with a median time of 61 days (26-318). Three patients (3%) developed CMV disease. Two factors were associated with CMV reactivation: CMV serostatus group (low: 0% vs. intermediate: 29% vs. high: 50%; p=0.001) and the presence of grade II-IV acute GvHD (Hazard Ratio: HR=2.1 [1.1-3.9]). Thirty-six of the 39 patients (92%) with CMV reactivation did not present positive detection of CMV after a 21-day median duration preemptive treatment with ganciclovir. Cumulative incidence of day 100 grade II-IV acute GvHD, 1-year chronic GvHD and day 100 transplantation related mortality (TRM) were 37%, 36% and 9%, respectively. CMV reactivation and serostatus were not associated with increased GvHD and TRM or short survival. Only the presence of acute GvHD as a time dependent variable was significantly associated with increased TRM (p=0.005). Two year overall and progression free survival were 56% and 34%, respectively. Donor and recipient CMV serostatus and acute GvHD are independent factors for increased CMV reactivation in high-risk MM patients undergoing RIC Allo-SCT. However, we did not find any influence of CMV reactivation on post transplantation outcome. CMV monitoring and pre-emptive treatment strategy could in part explain these results. Novel prophylactic measures such as immunotherapy and drug prophylaxis need to be considered in this group of patients, warranting further prospective studies. PMID- 23667726 TI - Recurrent/Persistent Pneumonia among Children in Upper Egypt. AB - OBJECTIVES: Recurrent/persistent pneumonia in children continues to be a major challenge for the pediatricians. The aim of our study was to establish the prevalence and underlying causes of recurrent/persistent pneumonia in children in Upper Egypt. SETTINGS: Assiut University Children Hospital, Assiut, Egypt. PATIENTS AND METHODS: Patients, admitted for pneumonia to the hospital during 2 years, were investigated with microbiological, biochemical, immunological and radiological tests in order to establish the prevalence of recurrent/persistent pneumonia and to find out its underlying causes. RESULTS: 113 out of 1228 patients (9.2%) met the diagnosis of recurrent/persistent pneumonia. Identified causes were; aspiration syndrome (17.7%), pulmonary TB (14.0%), congenital heart disease (11.5%), bronchial asthma (9.7%), immune deficiency disorders (8.8%) and vitamin D deficiency rickets (7.0%). Other causes included; congenital anomalies of the respiratory tract, interstitial lung diseases, bronchiectasis, and sickle cell anemia. No predisposing factors could be identified in 15% of cases. CONCLUSION: Approximately 1 out of 10 children with diagnosis of pneumonia in Assiut University Children Hospital had recurrent/persistent pneumonia. The most frequent underlying cause for recurrent/persistent pneumonia was aspiration syndrome, followed by pulmonary TB. PMID- 23667725 TI - The use of monoclonal antibodies in the treatment of autoimmune complications of chronic lymphocytic leukemia. AB - Autoimmune cytopenias are a frequent complication in CLL, occurring in approximately 5-10% of the patients. The most common manifestation is autoimmune haemolytic anaemia, followed by immune thrombocytopenia and only rarely pure red blood cell aplasia or autoimmune granulocytopenia. Initial treatment is as for the idiopathic autoimmune cytopenias, with most patients responding to conventional corticosteroid therapy. Patients, who do not respond to conventional therapy after 4-6 weeks, should be considered for alternative immunosuppression, monoclonal antibody therapy or splenectomy. While randomized trials demonstrating the benefit of rituximab in CLL-related autoimmune diseases are still lacking, there are considerable data in the literature that provide evidence for its effectiveness. The monoclonal antibody alemtuzumab also displays considerable activity against both the malignant disease and the autoimmune complication in patients with CLL, although at the expense of greater toxicity. A number of new monoclonal antibodies, such as ofatumumab, GA-101, lumiliximab, TRU-016, epratuzumab, and galiximab, are currently investigated in CLL and their activity in CLL-related autoimmune cytopenias should be evaluated in future studies. PMID- 23667727 TI - Third party cord blood transplant boosts autologous hematopoiesis in a case of persistent bone marrow aplasia after double transplant failure for B-thalassemia major. AB - A 9-year-old female received an allogeneic stem cell transplant (SCT) from an ABO incompatible HLA-matched sibling for beta-thalassemia major, without achieving a complete donor chimerism. Subsequently, the patient received five donor lymphocyte infusions, without increasing donor chimerism, and autologous SCT. Due to the persistent bone marrow aplasia, the patient received a second allogeneic SCT from the same donor without obtaining any engrafment. After the double transplant failure, we performed an unrelated transplant from a full-matched umbilical cord blood (UCBT) without administering any neither conditioning regimen nor GVHD prophylaxis. Forty days after UCBT, trilinear engraftment was documented. Surprisingly, the hematopoietic reconstitution was related to the re expansion of the autologous (beta-thalassemic) hematopoietic stem cell, as documented by chimerism studies. At present, 30 months after UCBT, there is stable hematopoietic autologous reconstitution. This is the first description of the restoration of autologous hematopoiesis obtained with UCBT in a thalassemia major patient after a double transplant failure. PMID- 23667728 TI - Complex and multifaceted therapy-related myeloid neoplasm following laryngeal cancer treated with Cisplatin and radiotherapy. PMID- 23667729 TI - Chlorambucil plus Rituximab as Front-Line Therapy in Elderly/Unfit Patients Affected by B-Cell Chronic Lymphocytic Leukemia: Results of a Single-Centre Experience. AB - The current standard first line therapy for fit patients with B-CLL/SLL is based on combination of fludarabine-cyclophosphamide and rituximab. However, elderly patients or patients with comorbidities poorly tolerate purine analogue-based chemotherapy and they are often treated with Chlorambucil (Chl) only. However, complete response (CR) and overall response (OR) rates with Chl are relatively low. We now investigated whether the addition of Rituximab to Chl will improve the efficacy without impairing the tolerability in elderly and unfit patients. We included in our study 27 elderly or unfit patients that had not received prior therapy. All patients were treated with Chl (1mg/Kg per 28-day cycle for 8 cycles) plus Rituximab (375 mg/m(2) for the first course and 500 mg/m(2) for subsequent cycles until the 6(th) cycle). We obtained an OR rate of 74%. The most frequent adverse effect was grade 3-4 neutropenia, which occurred in 18.5% of the patients. Infections or grade 3-4 extra-hematological side effects were not recorded. None of the patients required reduction of dose, delay of therapy or hospitalization. Overall, these data suggest that Chl-R is an effective and well tolerated regimen in elderly/unfit patients with CLL. PMID- 23667730 TI - Self-representation of children suffering from congenital heart disease and maternal competence. AB - Child development may be subject to forms of motor, physical, cognitive and self representation impairments when complex congenital heart disease (CHD) occurs. In some cases, inadequacy of both self-representation as well as the family system are displayed. It seems to be important to search the likely internal and external resources of the CHD child, and the possible connections among such resources, which may help him/her to manage his/her own risk condition. The research project inquires the possible resources related to the self representation and self-esteem levels of the CHD child, and those related to maternal self-perception as competent mothers. A group of 25 children (mean age = 10.2; SD=1.8) suffering from specific forms of CHD, and a group made up of their relative mothers (mean age = 38.2; SD=5) were studied. The tools used were the Human Figure Drawing, to investigate child body-related self-representation; the TMA scale (Self-esteem Multidimensional Test), to investigate the child's self esteem; and the Q-sort questionnaire, to assess how mothers perceived their maternal competence. Data concerning the likely correlations between the child's self-representation and the maternal role competence show [that] positive correlations between some indicators of maternal competence, specific aspects of CHD children's self-representation (mothers' emotional coping and children's self image adequacy) and self-esteem (mothers' emotional scaffolding and children's self-esteem at an emotional level). By detecting the occurrence of specific correlations among resources of both child and mother, the study provides cardiologists with information that is useful for building a relationship with the families concerned, which would seem to enhance the quality of the process of the cure itself. PMID- 23667731 TI - Update on complications in pediatric anesthesia. AB - Complications in pediatric anesthesia can happen, even in our modern hospitals with the most advanced equipment and skilled anesthesiologists. It is important, albeit in a tranquil and reassuring way, to inform parents of the possibility of complications and, in general, of the anesthetic risks. This is especially imperative when speaking to the parents of children who will be operated on for minor procedures: in our experience, they tend to think that the anesthesia will be a light anesthesia without risks. Often the surgeons tell them that the operation is very simple without stressing the fact that it will be done under general anesthesia which is identical to the one we give for major operations. Different is the scenario for the parents of children who are affected by malignant neoplasms: in these cases they already know that the illness is serious. They have this tremendous burden and we choose not to add another one by discussing anesthetic risks, so we usually go along with the examination of the child without bringing up the possibility of complications, unless there is some specific problem such as a mediastinal mass. PMID- 23667732 TI - Helicobacter pylori infection has no impact on manometric and pH-metric findings in adolescents and young adults with gastroesophageal reflux and antral gastritis: eradication results to no significant clinical improvement. AB - The relationship between Helicobacter pylori (Hp) gastritis and gastroesophageal reflux disease (GERD) remains controversial. The aim was to investigate the association between Hp infection and gastroesophageal reflux (GER) and the impact of Hp eradication on esophageal acid exposure and motility in adolescents and young adults with Hp gastritis and GERD. Sixty-four patients with symptoms suggestive for GERD, of which 40 Hp-positive (group A) and 24 Hp-negative (group B), underwent endoscopy-biopsy, esophageal manometry and 24-hour pH-metry. All group A patients received eradication treatment and were re-evaluated six months later again with 24-hour pH-metry, esophageal manometry, endoscopy-biopsy and clinical assessment. At inclusion, there were no significant differences between the two groups regarding sex, age, grade of endoscopic esophagitis, manometric and pH-metry findings. All Hp-positive patients had an antral predominant gastritis. Eradication of Hp was successful in all patients, and gastritis and esophagitis were healed in all patients. The mean lower esophageal sphincter pressure (LESP) increased significantly from 11.25 mmHg before to 11.71 mmHg after eradication (P<0.05). A significant decrease in reflux index was observed (mean RI 6.02% before versus 4.96% after eradication (P<0.05). However clinical symptoms of GER improved not significantly after 6 months follow up. Conclusively, in children and young adults with GER symptoms and GERD, the presence or absence of Hp has no impact on manometric and pH-metric findings. Eradication of Hp infection results in increase in LESP with a consequent decrease in esophageal acid exposure but not significant clinical improvement. PMID- 23667733 TI - Video-assisted thoracoscopic extended thymectomy in myasthenic children. AB - Myasthenia gravis (MG) is an autoimmune disease marked by weakness of voluntary musculature. Medical and surgical therapy of adult myasthenia is well documented. There is little pediatric surgical evidence, only a few case reports being available. The aim of this paper is to verify whether the surgical and anesthesiological techniques can warrant an early and safe discharge from the operating room. The secondary aim is to assess the presence of perioperative indicators that can eventually be used as predictors of postoperative care. During the years 2006-2009, 10 pediatric patients were treated according to a surgical approach based on video assisted thoracoscopic extended thymectomy (VATET). Standard preoperative evaluation is integrated with functional respiratory tests. Anesthetic induction was made with propofol and fentanyl/remifentanyl and maintenance was obtained with sevoflurane/desflurane/propofol +/- remifentanyl. A muscle relaxant was used in only one patient. Right or left double-lumen bronchial tube (Rusch Bronchopart(r) Carlens) placement was performed. Six patients were transferred directly to the surgical ward while 4 were discharged to the intensive care unit (ICU); ICU stay was no longer than 24 h. Length of hospital stay was 4.4+/-0.51 days. No patient was readmitted to the hospital and no surgical complications were reported. Volatile and intravenous anesthetics do not affect ventilator weaning, extubation or the postoperative course. Paralyzing agents are not totally contraindicated, especially if short-lasting agents are used with neuromuscular monitoring devices and new reversal drugs. Perioperative evaluation of the myasthenic patient is mandatory to assess the need for postoperative respiratory support and also predict timely extubation with early transfer to the surgical department. Availability of new drugs and of reversal drugs, the current practice of mini invasive surgical techniques, and the availability of post anesthesia care units are the keys to the safety and successful prognosis of patients affected by MG who undergo thymectomy. PMID- 23667734 TI - Pattern of congenital anomalies in newborn: a hospital-based study. AB - Birth defects, encountered frequently by pediatricians, are important causes of childhood morbidity and mortality. Birth defects can be classified according to their severity, pathogenic mechanism, or whether they are involving a single system or multiple systems. This hospital-based prospective descriptive study highlights the prevalence of Congenital Anomalies (CAs) in one year among live born neonates delivered in Zagazig University Hospital (Egypt). All women giving birth to viable babies were included. Demographic details, associated risk factors and the type of CAs in all babies were recorded. Diagnosis of CAs was based on clinical evaluation, radiographic examination, ultrasonography, echocardiography and chromosomal analysis of the newborn whenever recommended. The overall incidence of CAs among live born neonates was 2.5%, as most of the cases were referred to Zagazig University Hospital (Egypt) for delivery. The musculoskeletal system (23%) was the most commonly involved followed by the central nervous system (20.3%). Involvement of more than one system was observed in (28.6%) cases. Among maternal and fetal risk factors; parental consanguinity, maternal under nutrition and obesity, positive history of an anomaly in the family, low birth weight, and prematurity were significantly associated with higher frequency of CAs (P<0.05), with non-significant differences for maternal age and the sex of the neonates. The current study highlights the prevalence of congenital anomalies in one year in Zagazig University Hospital. It revealed a high prevalence of congenital anomalies in our locality and stressed the importance of carrying out a thorough clinical examination of all neonates at birth. PMID- 23667735 TI - Impact of maternal vitamin D status during pregnancy on the prevalence of neonatal vitamin D deficiency. AB - Maternal vitamin D deficiency is not uncommon. The lack of vitamin D during pregnancy may result in poor fetal growth and altered neonatal development that may persist into later life. Recognition of risk factors and early detection of vitamin D deficiency during pregnancy is important in order to prevent neonatal vitamin D deficiency and related complications. The aim of the current study is to assess the effect of maternal vitamin D status on the neonatal vitamin D stores. A total of 92 pregnant women at the end of the 3(rd) trimester and their newborns were recruited from Al Khafji Joint Operation Hospital, Saudi Arabia, during the year 2011. Maternal and cord blood samples were taken for determination of serum levels of circulating 25-hydroxyvitamin D3 [25(OH)D3] concentration, serum calcium (Ca(++)), phosphorus (PO4) and alkaline phosphatase (ALP). Compared with pregnant women with adequate vitamin D levels, women deficient in vitamin D had infants with vitamin D deficiency (X+/-SD 33.44+/ 18.33 nmol/L vs 55.39+/-17.37 nmol/L, P=0.01). Maternal and neonatal serum 25(OH)D3 levels showed a positive correlation with serum Ca(++) and negative correlation with serum PO4 and ALP. Neonatal 25(OH)D was related to maternal 3(rd) trimester levels (r=0.89, P=0.01). The newborn serum 25(OH)D3 concentrations rely on maternal vitamin D status. Poor maternal vitamin D status may adversely affect neonatal vitamin D status and, consequently, calcium homeostasis. PMID- 23667736 TI - A Mast Cell Degranulation Screening Assay for the Identification of Novel Mast Cell Activating Agents. AB - The development and use of vaccines and their ability to prevent infection/disease is a shining example of the benefit of biomedical research. Modern vaccines often utilize subunit immunogens that exhibit minimal immunogenicity and require the use of adjuvants to maximize the induction of protective immune responses. We recently described a novel class of vaccine adjuvants, mast cell (MC) activators, that exhibit safe and effective vaccine adjuvant activity when administered by intranasal or intradermal routes. A compound library containing 580 functionalized benzopyrans, a structural motif found in a diverse array of natural and designed bioactive compounds, was screened using a MC degranulation assay to identify novel MC activating compounds for future evaluation as novel vaccine adjuvants. This approach identified 12 novel MC degranulating compounds. Therefore, MC degranulation can be used to reliably detect novel compounds for evaluation as adjuvants for use in mucosal vaccine strategies. PMID- 23667737 TI - Design and Preparation of New Palladium Precatalysts for C-C and C-N Cross Coupling Reactions. AB - A series of easily prepared, phosphine-ligated palladium precatalysts based on the 2-aminobiphenyl scaffold have been prepared. The role of the precatalyst associated labile halide (or pseudohalide) in the formation and stability of the palladacycle has been examined. It was found that replacing the chloride in the previous version of the precatalyst with a mesylate leads to a new class of precatalysts with improved solution stability and that are readily prepared from a wider range of phosphine ligands. The differences between the previous version of precatalyst and that reported here are explored. In addition, the reactivity of the latter is examined in a range of C-C and C-N bond forming reactions. PMID- 23667738 TI - Real-time Polymerase Chain Reaction Analysis of Sewage Samples to Determine Oral Polio Vaccine Circulation Duration and Mutation After Mexican National Immunization Weeks. AB - BACKGROUND: Oral polio vaccine (OPV) can mutate and cause outbreaks of paralytic poliomyelitis with prolonged replication. After poliovirus eradication, global use of inactivated polio vaccine (IPV) may be needed until all OPV stops circulating. Mexico, where children receive routine IPV but where OPV is given only during biannual national immunization weeks (NIWs), provides a natural setting to study duration of OPV circulation in a community primarily vaccinated with IPV. METHODS: One-liter sewage samples from four separate arroyos (creeks) near Orizaba, Mexico, were collected monthly for 12 months. Concentrated sewage underwent RNA extraction, reverse transcription, and real-time polymerase chain reaction (PCR) to detect OPV serotypes 1, 2, and 3 and their variants containing the serotype-specific point mutation in the 5' untranslated region associated with neurovirulence. RESULTS: OPV was detected 3, 4, 5, and 7 months after the May 2010 NIW, but was not detected at 6 or 8 months. A second and third NIW occurred in February 2011 and May 2011, and OPV was detected in the sewage monthly after both of these NIW through July 2011 when collection stopped. The OPV detected was primarily serotype 2 and predominantly contained the point mutations in the 5' untranslated region associated with increased neurovirulence. CONCLUSIONS: OPV was detected in sewage as late as 7 months after an NIW in a Mexican community primarily vaccinated with IPV, but was not detected at 8 months, suggesting that OPV circulation may have ceased. These data suggest that in communities with high vaccination rates, 1 or 2 years of IPV administration after OPV cessation could be sufficient to prevent outbreaks of paralytic poliomyelitis from vaccine-derived strains. PMID- 23667739 TI - Identification of a novel deletion mutant strain in Saccharomyces cerevisiae that results in a microsatellite instability phenotype. AB - The DNA mismatch repair (MMR) pathway corrects specific types of DNA replication errors that affect microsatellites and thus is critical for maintaining genomic integrity. The genes of the MMR pathway are highly conserved across different organisms. Likewise, defective MMR function universally results in microsatellite instability (MSI) which is a hallmark of certain types of cancer associated with the Mendelian disorder hereditary nonpolyposis colorectal cancer. (Lynch syndrome). To identify previously unrecognized deleted genes or loci that can lead to MSI, we developed a functional genomics screen utilizing a plasmid containing a microsatellite sequence that is a host spot for MSI mutations and the comprehensive homozygous diploid deletion mutant resource for Saccharomyces cerevisiae. This pool represents a collection of non-essential homozygous yeast diploid (2N) mutants in which there are deletions for over four thousand yeast open reading frames (ORFs). From our screen, we identified a deletion mutant strain of the PAU24 gene that leads to MSI. In a series of validation experiments, we determined that this PAU24 mutant strain had an increased MSI specific mutation rate in comparison to the original background wildtype strain, other deletion mutants and comparable to a MMR mutant involving the MLH1 gene. Likewise, in yeast strains with a deletion of PAU24, we identified specific de novo indel mutations that occurred within the targeted microsatellite used for this screen. PMID- 23667740 TI - The expression of embryonic liver development genes in hepatitis C induced cirrhosis and hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) remains a difficult disease to study even after a decade of genomic analysis. Patient and disease heterogeneity, differences in statistical methods and multiple testing issues have resulted in a fragmented understanding of the molecular basis of tumor biology. Some researchers have suggested that HCC appears to share pathways with embryonic development. Therefore we generated targeted hypotheses regarding changes in developmental genes specific to the liver in HCV-cirrhosis and HCV-HCC. We obtained microarray studies from 30 patients with HCV-cirrhosis and 49 patients with HCV-HCC and compared to 12 normal livers. Genes specific to non-liver development have known associations with other cancer types but none were expressed in either adult liver or tumor tissue, while 98 of 179 (55%) genes specific to liver development had differential expression between normal and cirrhotic or HCC samples. We found genes from each developmental stage dysregulated in tumors compared to normal and cirrhotic samples. Although there was no single tumor marker, we identified a set of genes (Bone Morphogenetic Protein inhibitors GPC3, GREM1, FSTL3, and FST) in which at least one gene was over-expressed in 100% of the tumor samples. Only five genes were differentially expressed exclusively in late-stage tumors, indicating that while developmental genes appear to play a profound role in cirrhosis and malignant transformation, they play a limited role in late-stage HCC. PMID- 23667742 TI - Impact of myenteric plexus alterations on diabetes related gastrointestinal dysmotility. PMID- 23667743 TI - When will my esophagus be fixed? PMID- 23667741 TI - The protective effect of glibenclamide in a model of hemorrhagic encephalopathy of prematurity. AB - We studied a model of hemorrhagic encephalopathy of prematurity (EP) that closely recapitulates findings in humans with hemorrhagic EP. This model involves tandem insults of 20 min intrauterine ischemia (IUI) plus an episode of elevated venous pressure induced by intraperitoneal glycerol on post-natal day (P) 0. We examined Sur1 expression, which is upregulated after focal ischemia but has not been studied after brief global ischemia including IUI. We found that 20 min IUI resulted in robust upregulation of Sur1 in periventricular microvessels and tissues. We studied tandem insult pups from untreated or vehicle-treated dams (TI CTR), and tandem insult pups from dams administered a low-dose, non hypoglycemogenic infusion of the Sur1 blocker, glibenclamide, for 1 week after IUI (TI-GLIB). Compared to pups from the TI-CTR group, pups from the TI-GLIB group had significantly fewer and less severe hemorrhages on P1, performed significantly better on the beam walk and accelerating Rotarod on P35 and in tests of thigmotaxis and rapid learning on P35-49, and had significantly greater body and brain weights at P52. We conclude that low-dose glibenclamide administered to the mother at the end of pregnancy protects pups subjected to IUI from post-natal events of elevated venous pressure and its consequences. PMID- 23667744 TI - Longitudinal muscle dysfunction in achalasia esophagus and its relevance. AB - Muscularis propria of the esophagus is organized into circular and longitudinal muscle layers. Goal of this review is to summarize the role of longitudinal muscle in physiology and pathophysiology of esophageal sensory and motor function. Simultaneous manometry and ultrasound imaging that measure circular and longitudinal muscle contraction respectively reveal that during peristalsis 2 layers of the esophagus contract in perfect synchrony. On the other hand, during transient relaxation of the lower esophageal sphincter (LES), longitudinal muscle contracts independently of circular muscle. Recent studies provide novel insights, i.e., longitudinal muscle contraction of the esophagus induces LES relaxation and possibly descending relaxation of the esophagus. In achalasia esophagus and other motility disorders there is discoordination between the 2 muscle layers. Longitudinal muscle contraction patterns are different in the recently described three types of achalasia identified by high-resolution manometry. Robust contraction of the longitudinal muscle in type II achalasia causes pan-esophageal pressurization and is the mechanism of whatever little esophageal emptying that take place in the absence of peristalsis and impaired LES relaxation. It may be that preserved longitudinal muscle contraction is also the reason for superior outcome to medical/surgical therapy in type II achalasia esophagus. Prolonged contractions of longitudinal muscles of the esophagus is a possible mechanism of heartburn and "angina like" pain seen in esophageal motility disorders and possibly achalasia esophagus. Novel techniques to record longitudinal muscle contraction are on the horizon. Neuro-pharmacologic control of circular and longitudinal muscles is different, which provides an important opportunity for the development of novel pharmacological therapies to treat sensory and motor disorders of the esophagus. PMID- 23667745 TI - Patient-reported outcomes in gastroenterology: clinical and research applications. AB - Patient-generated reports, also known as Patient-Reported Outcomes (PROs), capture the patients' illness experience in a structured format and may help bridge the gap between patients and providers. PROs measure any aspect of patient reported health (e.g., physical, emotional or social symptoms) and can help to direct care and improve clinical outcomes. When clinicians systematically collect patient-reported data in the right place at the right time, PRO measurement can effectively aid in detection and management of conditions, improve satisfaction with care and enhance the patient-provider relationship. This review article summarizes the latest approaches to PRO measuring for clinical trials and clinical practice, with a focus on use of PROs in gastroenterology. PMID- 23667747 TI - Gastrointestinal motility changes and myenteric plexus alterations in spontaneously diabetic biobreeding rats. AB - BACKGROUND/AIMS: Type 1 diabetes is often accompanied by gastrointestinal motility disturbances. Vagal neuropathy, hyperglycemia, and alterations in the myenteric plexus have been proposed as underlying mechanism. We therefore studied the relationship between vagal function, gastrointestinal motiliy and characteristics of the enteric nervous system in the biobreeding (BB) rat known as model for spontaneous type 1 diabetes. METHODS: Gastric emptying breath test, small intestinal electromyography, relative risk-interval variability, histology and immunohistochemistry on antral and jejunal segments were performed at 1, 8 and 16 weeks after diabetes onset and on age-matched controls. RESULTS: We observed no consistent changes in relative risk-interval variability and gastric emptying rate. There was however, a loss of phases 3 with longer duration of diabetes on small intestinal electromyography. We found a progressive decrease of nitrergic neurons in the myenteric plexus of antrum and jejunum, while numbers of cholinergic nerve were not altered. In addition, a transient inflammatory infiltrate in jejunal wall was found in spontaneous diabetic BB rats at 8 weeks of diabetes. CONCLUSIONS: In diabetic BB rats, altered small intestinal motor control associated with a loss of myenteric nitric oxide synthase expression occurs, which does not depend on hyperglycemia or vagal dysfunction, and which is preceded by transient intestinal inflammation. PMID- 23667746 TI - Primary Care Management of Chronic Constipation in Asia: The ANMA Chronic Constipation Tool. AB - Chronic constipation (CC) may impact on quality of life. There is substantial patient dissatisfaction; possible reasons are failure to recognize underlying constipation, inappropriate dietary advice and inadequate treatment. The aim of these practical guidelines intended for primary care physicians, and which are based on Asian perspectives, is to provide an approach to CC that is relevant to the existing health-care infrastructure. Physicians should not rely on infrequent bowel movements to diagnose CC as many patients have one or more bowel movement a day. More commonly, patients present with hard stool, straining, incomplete feeling, bloating and other dyspeptic symptoms. Physicians should consider CC in these situations and when patients are found to use laxative containing supplements. In the absence of alarm features physicians may start with a 2-4 week therapeutic trial of available pharmacological agents including osmotic, stimulant and enterokinetic agents. Where safe to do so, physicians should consider regular (as opposed to on demand dosing), combination treatment and continuous treatment for at least 4 weeks. If patients do not achieve satisfactory response, they should be referred to tertiary centers for physiological evaluation of colonic transit and pelvic floor function. Surgical referral is a last resort, which should be considered only after a thorough physiological and psychological evaluation. PMID- 23667748 TI - Validation of octanoate breath test for measuring gastric emptying in rats. AB - BACKGROUND/AIMS: Lack of simple and repeatable tests hampers gastric emptying studies in rats. The aim of this study was to adapt the (14)C-octanoate solid gastric emptying breath test for application in rats, and to validate it against radioscintigraphic method. METHODS: After ingestion of a meal containing 3 mCi (99m)Tc and 2 uCi (14)C-octanoate, 23 male Wistar rats were placed on a gamma camera in a airflow container. Scintigraphic images were taken at regular intervals. The amount of (14)CO2 in a regularly replaced hyamine hydroxide solution, capturing CO2 in the outflow air, was counted using liquid scintillation spectrometry. (99m)Tc gastric retention curves and (14)CO2 excretion curves were fitted to their respective data. Three rats underwent the same procedures after administration of atropine. RESULTS: Overall Tr10% (time at which 10% of the original amount of (99m)Tc remained in the stomach) was 355 +/- 64 minutes; Te90% (time at which 90% of total amount of (14)CO2 was excreted) was 325 +/- 106 minutes. Their correlation coefficient was 0.71, R-square 0.50 and P < 0.005. Tr1/2 (50% of original amount of (99m)Tc remained) was 124 +/- 28 minutes; Te1/2 (50% of total amount of (14)CO2 excreted) 114 +/- 32 minutes. Their correlation coefficient was 0.83 with R-square of 0.69 and P < 0.00005. In 12 immobilized animals correlation was even better: correlation coefficient 0.84; R-square 0.71 and P < 0.001 (Tr10% was 388 +/- 117 minutes; Te90% 532 +/- 219 minutes; Tr1/2 of 165 +/- 54 minutes; Te1/2 of 175 +/- 67 minutes). Atropine significantly lengthened all emptying times: 904 +/- 307 and 1461 +/- 684 minutes for Tr10% and Te90%, respectively; and 432 +/- 117 minutes for Tr1/2 and 473 +/- 190 minutes for Te1/2. CONCLUSIONS: We adapted and validated the (14)C-octanoate gastric emptying breath test for application in rats. PMID- 23667749 TI - Experimental and Automated Analysis Techniques for High-resolution Electrical Mapping of Small Intestine Slow Wave Activity. AB - BACKGROUND/AIMS: Small intestine motility is governed by an electrical slow wave activity, and abnormal slow wave events have been associated with intestinal dysmotility. High-resolution (HR) techniques are necessary to analyze slow wave propagation, but progress has been limited by few available electrode options and laborious manual analysis. This study presents novel methods for in vivo HR mapping of small intestine slow wave activity. METHODS: Recordings were obtained from along the porcine small intestine using flexible printed circuit board arrays (256 electrodes; 4 mm spacing). Filtering options were compared, and analysis was automated through adaptations of the falling-edge variable-threshold (FEVT) algorithm and graphical visualization tools. RESULTS: A Savitzky-Golay filter was chosen with polynomial-order 9 and window size 1.7 seconds, which maintained 94% of slow wave amplitude, 57% of gradient and achieved a noise correction ratio of 0.083. Optimized FEVT parameters achieved 87% sensitivity and 90% positive-predictive value. Automated activation mapping and animation successfully revealed slow wave propagation patterns, and frequency, velocity, and amplitude were calculated and compared at 5 locations along the intestine (16.4 +/- 0.3 cpm, 13.4 +/- 1.7 mm/sec, and 43 +/- 6 uV, respectively, in the proximal jejunum). CONCLUSIONS: The methods developed and validated here will greatly assist small intestine HR mapping, and will enable experimental and translational work to evaluate small intestine motility in health and disease. PMID- 23667750 TI - Regional difference in colonic motility response to electrical field stimulation in Guinea pig. AB - BACKGROUND/AIMS: In isolated guinea-pig colon, we investigated regional differences in peristalsis evoked by intrinsic electrical nerve stimulation. METHODS: Four colonic segments from mid and distal colon of Hartley guinea pigs, were mounted horizontally in an organ bath. Measurement of pellet propulsion time, intraluminal pressure, electrical field stimulation (EFS; 0.5 ms, 60 V, 10 Hz), and response of pharmacological antagonists, were performed to isolated segments of colon to determine the mechanisms underlying peristaltic reflexes evoked by focal electrical nerve stimuli. RESULTS: In fecal pellet propulsion study, the velocity of pellet propulsion was significantly faster in the distal colon and decreased gradually to the proximal part of the mid colon. Intraluminal pressure recording studies showed that luminal infusion initiated normal peristaltic contractions (PCs) in 82% trials of the distal colon, compared to that of mid colon. In response to EFS, the incidence of PCs was significantly increased in the distal colon in contrast, the incidence of non-peristaltic contractions (NPCs) was significantly higher in the middle-mid colon, distal-mid colon and distal colon, compared to that of proximal-mid colon. Addition of L NAME into the bath increased the frequency of NPCs. EFS failed to cause any PCs or NPCs contractions in the presence of hexamethonium, atropine or tetrodotoxin. CONCLUSIONS: This study has revealed that electrical nerve stimulation of distal colon is the most likely region to elicit a peristaltic wave, compared with the mid or proximal colon. Our findings suggest that EFS-evoked PCs can be modulated by endogenous nitric oxide. PMID- 23667751 TI - Clinical analysis of primary eosinophilic esophagitis. AB - BACKGROUND/AIMS: Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder of the esophagus. Similar to asthma, EoE can induce irreversible structural changes in the esophagus as a result of chronic and persistent eosinophilic inflammation. The aim of this study was to analyse changes in symptoms, eosinophil counts and endoscopic findings after treatment. METHODS: Nine patients with EoE (6 men and 3 women; mean age, 36.44 years) were diagnosed with EoE based on typical symptoms, endoscopic abnormalities and infiltration of the esophageal epithelium with >= 15 eosinophils/high-power field. The average endoscopic follow-up period was 10 months, ranging from 1 to 25 months. Symptoms and endoscopic and pathological findings at initial observation and follow-up were evaluated. RESULTS: Seven of the 9 patients had dysphagia symptoms, which improved in 4 of 6 patients who were treated with proton pump inhibitor. Two patients were unresponsive to proton pump inhibitor and another 2 patients were treated with corticosteroid, which led to symptomatic relief. In 8 patients, esophageal eosinophilia was improved histologically at follow-up after treatment. Six of the 9 patients had typical endoscopic findings of EoE at initial examination. Despite treatment, these findings remained in 5 of the 6 patients at follow-up endoscopy. CONCLUSIONS: After treatment, the symptoms and eosinophil counts were temporarily improved, but the endoscopic findings of EoE were generally not improved. This indicates that deformity of esophageal structure due to eosinophilic inflammation might be irreversible despite proper management. PMID- 23667752 TI - Predictable Marker for Regression of Barrett's Esophagus by Proton Pump Inhibitor Treatment in Korea. AB - BACKGROUND/AIMS: There has been no report regarding the regression of Barrett's esophagus (BE) by continuous treatment of proton pump inhibitor (PPI). The aim of this study was to determine the regression rate of BE by PPI and predictable markers related to regression. METHODS: Thirty-five patients diagnosed as BE were consecutively enrolled and most of them took continuous PPI. The 25 patients underwent endoscopic surveillance and received biopsy. If the specialized intestinal metaplasia (SIM) was lost at any point of surveillance and did not recur, the case was regarded as the regression group. The proportion of SIM was graded and the mucin phenotype was decided using immunohistochemistry for MUC2, MUC5AC and MUC6. To assess the cell proliferation indexes and the degree of intestinal maturation, immunohistochemistry for Ki67 and CDX2 were performed. RESULTS: The regression of BE occurred in the 11 (44%) patients. The clinical and demographic factors showed no difference between the regression (n = 11) and persistence group (n = 14). The lower grade of SIM (P < 0.001) and gastric predominant mucin phenotype (P = 0.018) were more frequent, and the number of Ki67 positive cell per gland (P = 0.008) and the mean extent of CDX2 (P = 0.022) were lower in the regression group than in the persistence group. CONCLUSIONS: The regression of BE by PPI treatment was frequent in Korea. The immunohistochemical detection of mucin phenotype, grade of SIM, Ki67 and CDX2 expression in Barrett's mucosa could be useful as a predictable marker for regression of SIM in BE. PMID- 23667753 TI - A randomized, double blinded, clinical trial to assess the efficacy and cost effectiveness of omeprazole compared to rabeprazole in the maintenance therapy of patients with gastroesophageal reflux disease. AB - BACKGROUND/AIMS: The aim of this study was to evaluate the efficacy and cost efficiency of omeprazole 10 mg and rabeprazole 10 mg once daily for 24 weeks in the maintenance therapy. METHODS: This was a randomized, open-label study enrolling 279 patients with erosive esophagitis A or B (Los Angeles classification) and typical gastroesophageal reflux disease symptoms. Patients who showed complete endoscopic and symptomatic healing after 8 weeks of proton pump inhibitor treatment were randomly allocated to maintenance treatment with omeprazole 10 mg once daily or rabeprazole 10 mg once daily for 42 weeks. The primary efficacy endpoint was the proportion of patients with symptomatic remission at 42 weeks. RESULTS: At the end of 42 weeks of maintenance therapy, 96.4% of omeprazole and 95.1% of rabeprazole treated patients remained symptom free (P > 0.05). Two drugs were also comparable with regard to the severity and frequency of reflux symptoms during the maintenance phase (P > 0.05). By the cost minimization analysis, the mean total costs per patient for remaining symptom free for 6 months were 241,775 won for omeprazole and 287,115 won for rabeprazole, respectively. CONCLUSIONS: Omeprazole 10 mg appeared to have similar efficacy in maintaining symptomatic remission as rabeprazole 10 mg, but was superior to rabeprazole 10 mg in terms of cost efficiency in the maintenance therapy of gastroesophageal reflux disease symptoms. PMID- 23667754 TI - Early Effect of Single-dose Sitagliptin Administration on Gastric Emptying: Crossover Study Using the (13)C Breath Test. AB - BACKGROUND/AIMS: The gastrointestinal motility effects of endogenous incretin hormones enhanced by dipeptidyl peptidase-IV (DPP-IV) inhibitors have not yet been sufficiently investigated. The aim of this study was to determine whether single pre-prandial sitagliptin, the DPP-IV inhibitor, administration might have an effect on the rate of liquid gastric emptying using the (13)C-acetic acid breath test. METHODS: Ten healthy male volunteers participated in this randomized, two-way crossover study. The subjects fasted for overnight and were randomly assigned to receive 50 mg sitagliptin 2 hours before ingestion of the liquid test meal (200 kcal per 200 mL, containing 100 mg (13)C-acetate) or the test meal alone. Under both conditions, breath samples were collected for 150 minutes following the meal. Liquid gastric emptying was estimated by the values of the following parameters: the time required for 50% emptying of the labeled meal (T1/2), the analog to the scintigraphy lag time for 10% emptying of the labeled meal (Tlag), the gastric emptying coefficient and the regression estimated constants (beta and kappa), calculated by using the (13)CO2 breath excretion curve using the conventional formulae. The parameters between the 2 test conditions were compared statistically. RESULTS: No significant differences in the calculated parameters, including T1/2, Tlag, gastric emptying coefficient or beta and kappa, were observed between the 2 test conditions. CONCLUSIONS: The present study revealed that single-dose sitagliptin intake had no significant influence on the rate of liquid gastric emptying in asymptomatic volunteers. PMID- 23667755 TI - Effect of Helicobacter pylori Eradication on Functional Dyspepsia. AB - BACKGROUND/AIMS: This study evaluated the effect of Helicobacter pylori eradication on functional dyspepsia (FD), and the relationship between the changes of histological gastritis and FD symptom responses. METHODS: A total of 213 FD patients diagnosed by Rome III criteria were consecutively enrolled. H. pylori tests and gastritis grade by the Sydney system were performed before and 1 year after the proton pump based-eradication therapy for 7 days. Serum levels of pepsinogen, and genetic polymorphisms IL-6, IL-8 and IL-10 were investigated. RESULTS: Total of 91 patients completed the 1 year follow-up. When the response rate of dyspepsia was compared at 1 year between the non-eradicated group (n = 24) and eradicated group (n = 67), each group showed complete response of 62.5% and 62.7%; satisfactory response (>= 50%) of 0.0% and 19.4%; partial response (< 50%) of 12.5% and 11.9%; and refractory response of 25.0% and 6.0%, respectively (P = 0.015). In addition, the responder group (complete + satisfactory response) at 1 year showed improvement of activity and chronic inflammation in both the antrum and corpus (all P < 0.001). Multivariate analysis showed that H. pylori eradication (OR, 5.81; 95% CI, 1.07-31.59) and symptom improvement at 3 month (OR, 28.90; 95% CI, 5.29-157.82) were associated with the improvement of dyspepsia at 1 year. Among the successfully eradicated FD patients (n = 67), male (P = 0.013) and higher initial BMI (P = 0.016) were associated with the improvement of dyspepsia at 1 year. CONCLUSIONS: H. pylori eradication improved FD symptoms, as well as gastritis at 1 year, suggesting that inflammation mediates FD. PMID- 23667756 TI - Mucosal mast cell count is associated with intestinal permeability in patients with diarrhea predominant irritable bowel syndrome. AB - BACKGROUND/AIMS: Although mucosal mast cell tryptase is known to significantly increase intestinal permeability, the relationship between mucosal mast cells and intestinal permeability remains unclear. The objective of this study was to evaluate the correlation among intestinal permeability, tryptase activity and mucosal mast cell count. METHODS: Rectal biopsies from 16 patients with diarrhea predominant irritable bowel syndrome (IBS-D) and 7 normal subjects were assessed for tryptase activity and macromolecular permeability using horseradish peroxidase in Ussing chambers. In addition, mucosal mast cell levels were immunohistochemically quantified via image analysis. RESULTS: Rectal biopsy of tissues from IBS-D patients showed significantly increased permeability compared with those from normal controls (0.644 +/- 0.08 and 0.06 +/- 0.00 ng/2 hr/mm(2), P < 0.01). Tryptase activity was also substantially higher in rectal biopsy samples from IBS-D patients than those from normal controls (0.86 +/- 0.18 and 0.28 +/- 0.04 mU/mg protein, P < 0.05). Mucosal mast cell counts were not significantly different between the 2 groups (P > 0.05). However, correlation analysis revealed that only mucosal mast cell count was significantly correlated with intestinal permeability in IBS-D patients (r = 0.558, P < 0.05). CONCLUSIONS: This study demonstrated a positive correlation between the number of mucosal mast cells and intestinal permeability, suggesting that mucosal mast cells play an important role for increased intestinal permeability in patients with IBS-D. PMID- 23667757 TI - How to perform and interpret timed barium esophagogram. AB - Timed barium esophagogram (TBE) is a simple and objective method for assessing the esophageal emptying. The technique of TBE is similar to usual barium swallow with some modifications, which include taking multiple sequential films at pre decided time interval after a single swallow of a fixed volume of a specific density barium solution. While many authors have used height and width of the barium column to assess the esophageal emptying, others have used the area of the barium column. TBE is being used in patients with suspected or confirmed achalasia and to follow-up those who have been treated with pneumatic dilation or myotomy. This review discusses technique of performing TBE, interpretation and its utility in clinical practice. PMID- 23667758 TI - Three-dimension High-resolution Anorectal Manometry Can Precisely Measure Perineal Descent. PMID- 23667759 TI - A Case of Rumination Documented by Using High-resolution Impedance Manometry. PMID- 23667760 TI - Columnar-lined Esophagus: Its Prevalence and Predictors in Patients With Gastroesophageal Reflux Disease (Am J Gastroenterol 2012;107:1655-1661). PMID- 23667761 TI - Accumulation of Alpha-synuclein Causes Colonic Dysmotility Independently of Enteric Nervous Damage in the Early Stage of Parkinson's Disease (Neurogastroenterol Motil 2012;24:e425-e436). PMID- 23667762 TI - Is the completion time of a questionnaire a pivotal factor when proving feasibility? PMID- 23667763 TI - Is the Completion Time of a Questionnaire a Pivotal Factor When Proving Feasibility?: Author's Reply. PMID- 23667764 TI - Is ramosetron really useful to treat diabetic diarrhea with rapid small bowel transit? PMID- 23667765 TI - Is Ramosetron Really Useful to Treat Diabetic Diarrhea With Rapid Small Bowel Transit?: Author's Reply. PMID- 23667766 TI - Narcotic bowel syndrome: is it more common than before? PMID- 23667769 TI - Management practices of hepatitis C virus infected alcoholic hepatitis patients: A survey of physicians. AB - AIM: To survey gastroenterologists and hepatologists regarding their current views on treating hepatitis C virus (HCV) infected alcoholic hepatitis (AH) patients. METHODS: A sixteen item questionnaire was electronically mailed to gastroenterologists and hepatologists. A reminder was sent after 2 mo to increase the response rate. Participation of respondents was confidential. Accessing secured web site to respond to the questionnaire was considered as informed consent. Responses received on the secured website were downloaded in an excel sheet for data analysis. RESULTS: Analyzing 416 responses to 1556 (27% response rate) emails, 57% respondents (56% gastroenterologists) reported HCV prevalence > 20% amongst AH patients. Sixty nine percent often treated AH and 46% preferred corticosteroids (CS). Proportion of respondents with consensus (75% or more respondents agreeing on question) on specific management of HCV infected AH were: routine HCV testing (94%), HCV not changing response to CS (80%) or pentoxifylline (91%), no change in approach to treating HCV infected AH (75%). None of respondent variables: age, specialty, annual number of patients seen, and HCV prevalence could predict respondent to be in consensus on any of or all 4 questions. Further, only 4% would choose CS for treating HCV infected AH as opposed to 47% while treating HCV negative AH. CONCLUSION: Gastroenterologists and hepatologists believe that AH patients be routinely checked for HCV. However, there is lack of consensus on choice of drug for treatment and outcome of HCV positive AH patients. Studies are needed to develop guidelines for management of HCV infected AH patients. PMID- 23667770 TI - Standard triple versus levofloxacin based regimen for eradication of Helicobacter pylori. AB - AIM: To compare the eradication rates for Helicobacter pylori (H. pylori) and ulcer recurrence of standard triple therapy (STT) and levofloxacin based therapy (LBT). METHODS: Seventy-four patients with perforated duodenal ulcer treated with simple closure and found to be H. pylori infected on 3 mo follow up were randomized to receive either the STT group comprising of amoxicillin 1 g bid, clarithromycin 500 mg bid and omeprazole 20 mg bid or the LBT group comprising of amoxicillin 1 g bid, levofloxacin 500 mg bid and omeprazole 20 mg bid for 10 d each. The H. pylori eradication rates, side effects, compliance and the recurrence of ulcer were assessed in the two groups at 3 mo follow up. RESULTS: Thirty-four patients in the STT group and 32 patients in the levofloxacin group presented at 3 mo follow up. H. pylori eradication rates were similar with STT and the LBT groups on intention-to-treat (ITT) analysis (69% vs 80%, P = 0.425) and (79% vs 87%, P = 0.513) by per-protocol (PP) analysis respectively. Ulcer recurrence in the STT and LBT groups on ITT analysis was (20% vs 14%, P = 0.551) and (9% vs 6%, P = 1.00) by PP analysis. Compliance and side effects were also comparable between the groups. A complete course of STT costs Indian Rupees (INR) 1060.00, while LBT costs only INR 360.00. CONCLUSION: H. pylori eradication rates and the rate of ulcer recurrence were similar between the STT and LBT. The LBT is a more economical option compared to STT. PMID- 23667771 TI - Interaction of insulin with prokinetic drugs in STZ-induced diabetic mice. AB - AIM: To study the possible interactions of metoclopramide, domperidone and erythromycin in streptozotocin-induced diabetic mice treated with insulin by various parameters. METHODS: Effects of the individual as well as combined drugs were studied in diabetic mice via estimation of the blood glucose and serum insulin levels, small intestinal transit (SIT), gastric emptying (GE), xylose absorption and glucose tolerance tests. Groups were given insulin 2 IU/kg s.c., metoclopramide 20 mg/kg p.o., domperidone 20 mg/kg p.o. and erythromycin 6 mg/kg p.o. individually and in combination. There were also normal and diabetic control groups. The first set of experiments was carried out to investigate the subchronic effect on blood glucose and serum insulin levels in diabetic mice of one week of daily dose administration of the tested drugs individually as well as the combination of insulin with each prokinetic drug. The other five sets of experiments were carried out to investigate the acute effect of a single dose of each drug individually and in combination on blood glucose and serum insulin levels, SIT, GE, oral xylose absorption and glucose tolerance tests. RESULTS: The study included the prokinetic drugs metoclopramide (20 mg/kg), domperidone (20 mg/kg) and erythromycin (6 mg/kg), as well as insulin (2 IU/kg), which was individually effective in decreasing SIT, enhancing GE and increasing xylose absorption significantly in diabetic mice. Erythromycin tended to decrease blood glucose level and increase serum insulin level after 1 wk of daily administration in diabetic mice. Erythromycin potentiated the effect of insulin on blood glucose level and serum insulin level whereas other prokinetic agents failed to do so after repeated dose administration in diabetic mice. Metoclopramide or erythromycin in combination with insulin significantly decreased SIT, in diabetic mice, to lower levels than with insulin alone. Administration of prokinetic drugs along with insulin antagonized the action of insulin on xylose absorption. These combinations also increased the rate of glucose absorption from the gut. CONCLUSION: The present study suggests that prokinetic drugs could potentially improve glycemic control in diabetic gastroparesis by allowing a more predictable absorption of nutrients, matched to the action of exogenous insulin. The use of prokinetics, such as erythromycin, may be interesting in the clinic in decreasing the need for insulin in diabetic patients. The dose of insulin may be safely decreased with erythromycin in chronic treatments. PMID- 23667772 TI - Protracted Tyrosine Phosphorylation of the Glutamate Receptor Subunit NR2 in the Rat Hippocampus Following Transient Cerebral Ischemia is Prevented by Intra Ischemic Hypothermia. AB - Changes in the dynamic interactions of macromolecules in cell membranes appear to underlie the robust neuroprotective effect of hypothermia against selective neuronal degeneration in the CA1 region of the rat hippocampus after transient cerebral ischemia, but the detailed mechanisms are still elusive. Using the two vessel occlusion model of transient normothermic cerebral ischemia of 15 min duration, we investigated the tyrosine phosphorylation of synaptic proteins in general and that of the NMDA receptor subunits in particular, at different times of recirculation. Specifically, the effect of intra-ischemic hypothermia (33 degrees C), which provides neuroprotection to the CA1 region of the hippocampus, was studied. Phosphorylation of tyrosine residues on the NMDA receptor (NR) 2, but not of the NR1 or the AMPA receptor subunit 1 (GluR1) proteins, was markedly enhanced following cerebral ischemia. Protein tyrosine phosphorylation was persistently increased in the postsynaptic densities of the vulnerable CA1 region, but was transient in the CA3/dentate gyrus (DG) neurons where cell death was not evident. The phospho-tyrosine phosphatase activity decreased during reperfusion in the CA1 region but not in CA3/DG. Importantly, decreasing body temperature to 33 degrees C during ischemia modified the dynamics of the protein tyrosine phosphorylation of NR2 in the CA1 region, which was transient and similar in time course to that seen in the CA3/DG region after normothermic ischemia. We conclude that the protracted tyrosine phosphorylation of the NR2 subunit in the hippocampus CA1 region following normothermic ischemia is attenuated by hypothermia and therefore constitutes an important target for hypothermic neuroprotection. PMID- 23667773 TI - Effects of different fluid regimes and desmopressin on uncontrolled hemorrhage during hypothermia in the rat. AB - Resuscitation with large volumes of crystalloids during traumatic hemorrhagic shock might increase the mortality by inducing rebleeding. However, few studies have addressed this problem during hypothermic conditions. Sixty-eight Sprague Dawley rats were exposed to a standardized femoral artery injury and resuscitated with low (LRe), medium (MRe), or high (HRe) intensity using lactated Ringer's solution after being cooled to 30 degrees C. An additional MRe group was also given desmopressin since this drug might reverse hypothermic-induced impairment of the primary hemostasis. The rats were rewarmed after 90 minutes and observed for 3 hours. The incidence, on-set time, duration, and volume of bleedings and hemodynamic changes were recorded. Rebleedings occurred in 60% of all animals and were more voluminous in the HRe group than in the LRe group (p=0.01). The total rebleeding volume per animal increased with the rate of fluid administration (r=0.50, p=0.01) and the duration of each rebleeding episode was longer in the HRe group than in the LRe group (p<0.001). However, the mortality tended to be higher in the LRe group (LRe=6/15, MRe=1/15, HRe=2/15, p=0.07). Desmopressin did not change the bled volume or the mortality. Overall, the mortality increased if rebleeding occurred (10/35 rebleeders died vs. 1/25 nonrebleeders, p=0.015). Liberal fluid administration increased the rebleeding volume while a trend toward higher mortality was seen with the restrictive fluid program. Desmopressin had no effect on the studied parameters. PMID- 23667774 TI - Induction of a prolonged hypothermic state by drug-induced reduction in the thermoregulatory set-point. AB - BACKGROUND: The marked improvement in outcome following induction of hypothermia after cardiac arrest has spurred the search for better methods to induce cooling. A regulated decrease in core temperature mediated by a drug-induced reduction in the set point for thermoregulation may be an ideal means of inducing hypothermia. To this end, the exploratory drug HBN-1 was assessed as a means to induce mild and prolonged hypothermia. METHODS: Free moving rats were infused i.v. for 12 hours with: a vehicle at room temperature (normothermia), a vehicle chilled to 4 degrees C (forced hypothermia), or HBN-1 (mixture of ethanol, lidocaine, and vasopressin) at room temperature. Core (intra-abdominal) temperature (Tc) was measured telemetrically, tail skin temperature (Ttail) by infrared thermography, metabolic rate (MR) was estimated with indirect calorimetery, and shivering was scored visually. RESULTS: HBN-1 elicited a reduction in Tc from 37.5 degrees C to 34 degrees C within 80 minutes after initiation of the infusion; Tc was maintained between 33 degrees C and 34 degrees C for more than 13 hours. HBN-1 infusion was associated with a reduction in MR (p=0.0006), a slight reduction in Ttail, and no evidence of shivering (p<0.001). The forced hypothermia group displayed shivering (p<0.001), a significant increase in MR, and a decrease in Ttail, indicative of peripheral vasoconstriction to reduce heat loss. CONCLUSION: HBN-1 infusion induced a mild and prolonged hypothermia in free moving, unanesthetized rats characterized by modulation of thermoeffectors to reduce heat gain and increase heat loss. HBN-1 thus appears to elicit regulated hypothermia and may provide a new method for achieving a prolonged state of therapeutic hypothermia. PMID- 23667775 TI - Implication for long-term hypothermia on degradation of interleukin-8 mRNA in endothelial cells stimulated with lipopolysaccharides. AB - This experimental study investigated the effects of long-term hypothermia on the production of interleukin (IL)-8 protein and its mRNA expression in endothelial cells stimulated by lipopolysaccharides (LPS). Human umbilical vein endothelial cells were separated into a non-cooling group (N group: 37 degrees C) and a cooling group (C group: 30 degrees C). These groups were incubated with LPS (1 MUg/mL) for 0, 2, 6, 24, 48, 72, and 96 hours. Production of the IL-8 protein secreted into the supernatant and mRNA expression in the cells were measured using enzyme-linked immunoabsorbent assay (ELISA) and real-time reverse transcription polymerase chain reaction (RT-PCR) analysis. To evaluate mRNA stability, both groups were incubated with actinomycin D at 6 hours after incubation with LPS for 24 hours. The degradation ratio was calculated by comparing the total expression of mRNA at 6 hours versus 0 hours. The protein levels in the C group were significantly lower than the N group between 6 and 96 hours. The mRNA expression in the C group was also significantly lower than in the N group up to 48 hours, but at 72 hours it was significantly higher than N group. IL-8 mRNA was less degraded in the C group compared to the N group. Under long-term hypothermia, IL-8 protein production was suppressed, while IL-8 mRNA was stabilized after LPS treatment. The potential of IL-8 to produce an inflammatory response in endothelial cells may persist even during long-term hypothermia. PMID- 23667776 TI - Post-cardiac arrest therapeutic hypothermia in New Jersey hospitals: analysis of adoption and implementation. AB - BACKGROUND: While national guidelines recommend the use of therapeutic hypothermia (TH) for the treatment of out-of-hospital cardiac arrest (OHCA), adoption of the technique has been slow. In addition, little is known about how TH is applied in practice. This study sought to characterize the adoption and implementation of TH by acute care hospitals in the state of New Jersey. METHODS: A survey of all 73 acute care hospitals in New Jersey was conducted to solicit information about TH adoption, application, and methods. Additional information was gained through a review of 18 written TH protocols (covering 21 hospitals). RESULTS: After growing slowly from 2004 to 2008, TH use among New Jersey hospitals accelerated between 2009 and 2011. By 2011, 68.4% of New Jersey hospitals had a TH program in place, with an additional 13.6% indicating plans to begin one. Most hospitals indicated low volumes of OHCA patients (e.g., <=10 per month). There was no relationship between OHCA volume and development of a TH program. The per hospital volume of OHCA patients receiving TH is even lower given the extensive patient exclusion criteria used by many facilities. TH hospitals vary widely in their TH exclusion criteria and cooling equipment and methods. DISCUSSION: The vast majority of New Jersey hospitals are now organized to implement national TH guidelines for initial survivors of OHCA. However, limited volumes of OHCA cases per hospital and lack of uniformity on how the guidelines are implemented raise new questions about the effectiveness of current practice in postarrest care. More detailed analysis of TH volumes versus outcomes and comparative studies of TH techniques are required to optimize postarrest care. PMID- 23667777 TI - Temperature affects thrombolytic efficacy using rt-PA and eptifibatide, an in vitro study. AB - The potential for hypothermia as a neuroprotectant during stroke has led to its increase in clinical use. At the same time, combination pharmaceutical therapies for ischemic stroke using recombinant tissue plasminogen activator (rt-PA), and GP IIb-IIIa inhibitors, such as Eptifibatide (Epf ), are under study. However, there is little data on how the reactions triggered by these agents are impacted by temperature. Here, clot lysis during exposure to the combination of rt-PA and Epf is measured in an in vitro human clot model at hypothermic temperatures. The hypothesis is that lytic efficacy of rt-PA and Epf decreases with decreasing temperature. Whole blood clots from 31 volunteers were exposed to rt-PA (0.5 MUg/mL) and Epf (0.63 MUg/mL) in human fresh-frozen plasma (rt-PA+Epf ), rt-PA alone in plasma (rt-PA Alone), or to plasma alone (Control), at temperatures from 30 degrees C to 37 degrees C, for 30 minutes. Clot lysis was measured using a microscopic imaging technique; the mean fractional clot loss (FCL) at 30 minutes was used to determine lytic efficacy. Temperature had a significant impact on FCL in clots exposed to rt-PA+Epf, with the FCL being lower at 30 degrees C to 36 degrees C than at 37 degrees C. The FCL remained significantly higher for rt PA+Epf-treated clots than Controls regardless of temperature, with the exception of measurements made at 30 degrees C when no significant differences in the FCL were observed between groups. The use of hypothermia as a neuroprotectant may negatively impact the therapeutic benefit of thrombolytic agents. PMID- 23667778 TI - Therapeutic hypothermia for refractory status epilepticus in a child with malignant migrating partial seizures of infancy and SCN1A mutation: a case report. AB - Status epilepticus (SE) is a common indication for neurocritical care and can be refractory to standard measures. Refractory SE (RSE) is associated with high morbidity and mortality. Unconventional therapies may be utilized in certain cases, including therapeutic hypothermia (TH), bumetanide, and the ketogenic diet. However, the literature describing the use of such therapies in RSE is limited. Details of a case of TH for RSE in an infant with malignant migrating partial seizures of infancy were obtained from the medical record. A 4-month-old child developed SE that was refractory to treatment with concurrent midazolam, phenobarbital, fosphenytoin, topiramate, levetiracetam, folinic acid, and pyridoxal-5-phosphate. This led to progressive implementation of three unconventional therapies: TH, bumetanide, and the ketogentic diet. Electrographic seizures ceased for the entirety of a 43-hour period of TH with a target rectal temperature of 33.0 degrees C-34.0 degrees C. No adverse effects of hypothermia were noted other than a single episode of asymptomatic hypokalemia. Seizures recurred 10 hours after rewarming was begun and did not abate with reinstitution of hypothermia. No effect was seen with administration of bumetanide. Seizures were controlled long-term within 48 hours of institution of the ketogenic diet. TH and the ketogenic diet may be effective for treating RSE in children. PMID- 23667779 TI - Temperature affects thrombolytic efficacy using rt-Pa and eptifibatide, an in vitro study: editorial commentary on Meunier et al., 2012. PMID- 23667781 TI - Determinants of Pneumonia Risk During Endovascular Hypothermia. AB - Therapeutic hypothermia is a promising neuroprotective therapy with multiple mechanisms of action. Previously, we demonstrated the feasibility of thrombolysis combined with endovascular hypothermia and an antishivering regimen, but pneumonia occurred more often in cooled patients. We sought to identify whether any factors could be identified that increased pneumonia risk. We examined 26 patients who underwent endovascular hypothermia. Pneumonia was assessed and scored as present by the treating physician without prespecified definitions or surveillance protocols. Using logistic regression, we examined the risk of pneumonia; the effects of age, weight, body mass index (BMI), body surface area, respiration rate, heart rate, blood pressure, baseline National Institutes of Health Stroke Scale (NIHSS), gender, shivering, and area under the curve below 34 degrees C; and total meperidine dose, individually and in a multivariable model. Pneumonia was reported by site investigators in 13 subjects (50%). In univariate analyses, BMI and baseline NIHSS emerged as the baseline variables that were independently associated with risk of pneumonia. Multivariable logistic regression analysis identified baseline NIHSS as marginally associated with risk of pneumonia, after adjustment for BMI (OR: 1.19, 95% CI: 0.98, 1.43; p=0.0740). In a group of hypothermia patients suffering a 50% reported incidence of pneumonia, we found no variables that explained risk other than baseline NIHSS. Future trials should include rigorous definitions of pneumonia and prespecified surveillance methods to minimize case ascertainment bias. Measures to prevent pneumonia are needed in all patients treated with hypothermia. PMID- 23667780 TI - Temporal profile of cerebrospinal fluid, plasma, and brain interleukin-6 after normothermic fluid-percussion brain injury: effect of secondary hypoxia. AB - Interleukin-6 (IL-6) is a proinflammatory cytokine that may play multiple roles in the pathogenesis of traumatic brain injury (TBI). The present study determined time-dependent changes in IL-6 concentrations in vulnerable brain regions, cerebrospinal fluid (CSF) samples, and plasma after normothermic TBI. Because secondary insults are common in head injured patients, we also assessed the consequences of a post-traumatic secondary hypoxic insult on this pleiotropic cytokine. Male Sprague-Dawley rats were intubated, anesthetized, and underwent a moderate parasagittal fluid-percussion brain injury (1.8-2.1 atm, 37 degrees C) followed by either 30 minutes of normoxic or hypoxic (pO2 = 30-40 mmHg) gas levels. Rats were sacrificed 3, 6, or 24 hours after TBI or shamoperated procedures. Brain samples, including the ipsilateral cerebral cortex and hippocampus were dissected and analyzed. Plasma and CSF samples were collected at similar times and stored at -80 degrees C until analysis. IL-6 levels were significantly increased ( p < 0.05) at 3, 6, and 24 hours in the cerebral cortex and at 6 hours in the hippocampus after TBI. IL-6 levels in the TBI normoxic group for both structures returned to control levels by 24 hours. Plasma levels of IL-6 were elevated at all time points, while CSF levels were high at 3 and 6 hours, but normalized by 24 hours. Post-traumatic hypoxia led to significantly elevated ( p < 0.05) IL-6 protein levels in the cerebral cortex at 24 hours compared to sham-operated controls. These findings demonstrate that moderate TBI leads to an early increase in IL-6 brain, plasma, and CSF protein levels. Secondary post-traumatic hypoxia, a common secondary injury mechanism, led to prolonged elevations in plasma IL-6 levels that may participate in the pathophysiology of this complicated TBI model. PMID- 23667782 TI - Three-photon excited fluorescence imaging of unstained tissue using a GRIN lens endoscope. AB - We present a compact and portable three-photon gradient index (GRIN) lens endoscope system suitable for imaging of unstained tissues, potentially deep within the body, using a GRIN lens system of 1 mm diameter and 8 cm length. The lateral and axial resolution in water is 1.0 MUm and 9.5 MUm, respectively. The ~200 MUm diameter field of view is imaged at 2 frames/s using a fiber-based excitation source at 1040 nm. Ex vivo imaging is demonstrated with unstained mouse lung at 5.9 mW average power. These results demonstrate the feasibility of three-photon GRIN lens endoscopy for optical biopsy. PMID- 23667783 TI - Silicon photomultipliers for improved detection of low light levels in miniature near-infrared spectroscopy instruments. AB - Silicon photomultipliers are novel solid state photodetectors that recently became commercially available. The goal of this paper was to investigate their suitability for low light level detection in miniaturized functional near infrared spectroscopy instruments. Two measurement modules with a footprint of 26*26 mm(2) were built, and the signal-to-noise ratio was assessed for variable source-detector separations between 25 and 65 mm on phantoms with similar optical properties to those of a human head. These measurements revealed that the signal to-noise ratio of the raw signal was superior to an empirically derived design requirement for source-detector separations up to 50 mm. An arterial arm occlusion was also performed on one of the authors in vivo, to induce reproducible hemodynamic changes which confirmed the validity of the measured signals. The proposed use of silicon photomultipliers in functional near-infrared spectroscopy bears large potential for future development of precise, yet compact and modular instruments, and affords improvements of the source-detector separation by 67% compared to the commonly used 30 mm. PMID- 23667784 TI - Study on chromatic aberration in a population of Chinese myopic eyes by means of optical design. AB - Two kinds of individual eye models, involving and without involving the angle between visual axis and optical axis, are established by means of optical design. We use them to study the properties of the transverse chromatic aberration (TCA) and longitudinal chromatic aberration (LCA) over the visible spectrum. Then the effects of the LCA and TCA on the visual quality of human eyes are evaluated. The statistical averages of TCA and LCA over the visible spectrum for Chinese myopic eyes are obtained. Results show that both TCA and LCA restrict the visual performance, and LCA is more detrimental than TCA. PMID- 23667785 TI - Combined reflectance confocal microscopy/optical coherence tomography imaging for skin burn assessment. AB - A combined high-resolution reflectance confocal microscopy (RCM)/optical coherence tomography (OCT) instrument for assessing skin burn gravity has been built and tested. This instruments allows for visualizing skin intracellular details with submicron resolution in the RCM mode and morphological and birefringence modifications to depths on the order of 1.2 mm in the OCT mode. Preliminary testing of the dual modality imaging approach has been performed on the skin of volunteers with some burn scars and on normal and thermally-injured Epiderm FTTM skin constructs. The initial results show that these two optical technologies have complementary capabilities that can offer the clinician a set of clinically comprehensive parameters: OCT helps to visualize deeper burn injuries and possibly quantify collagen destruction by measuring skin birefringence, while RCM provides submicron details of the integrity of the epidermal layer and identifies the presence of the superficial blood flow in the upper dermis. Therefore, the combination of these two technologies within the same instrument may provide a more comprehensive set of parameters that may help clinicians to more objectively and nonivasively assess burn injury gravity by determining tissue structural integrity and viability. PMID- 23667786 TI - In vivo quantification of the scattering properties of tissue using multi diameter single fiber reflectance spectroscopy. AB - Multi diameter single fiber reflectance (MDSFR) spectroscopy is a non-invasive optical technique based on using multiple fibers of different diameters to determine both the reduced scattering coefficient (MUs') and a parameter gamma that is related to the angular distribution of scattering, where gamma = (1 g2)/(1-g1) and g1 and g2 the first and second moment of the phase function, respectively. Here we present the first in vivo MDSFR measurements of MUs'(lambda) and gamma(lambda) and their wavelength dependence. MDSFR is performed on nineteen mice in four tissue types including skin, liver, normal tongue and in an orthotopic oral squamous cell carcinoma. The wavelength dependent slope of MUs'(lambda) (scattering power) is significantly higher for tongue and skin than for oral cancer and liver. The reduced scattering coefficient at 800 nm of oral cancer is significantly higher than of normal tongue and liver. Gamma generally increases with increasing wavelength; for tumor it increases monotonically with wavelength, while for skin, liver and tongue gamma(lambda) reaches a plateau or even decreases for longer wavelengths. The mean gamma(lambda) in the wavelength range 400-850 nm is highest for liver (1.87 +/- 0.07) and lowest for skin (1.37 +/- 0.14). Gamma of tumor and normal tongue falls in between these values where tumor exhibits a higher average gamma(lambda) (1.72 +/- 0.09) than normal tongue (1.58 +/- 0.07). This study shows the potential of using light scattering spectroscopy to optically characterize tissue in vivo. PMID- 23667787 TI - A generalized hybrid algorithm for bioluminescence tomography. AB - Bioluminescence tomography (BLT) is a promising optical molecular imaging technique on the frontier of biomedical optics. In this paper, a generalized hybrid algorithm has been proposed based on the graph cuts algorithm and gradient based algorithms. The graph cuts algorithm is adopted to estimate a reliable source support without prior knowledge, and different gradient-based algorithms are sequentially used to acquire an accurate and fine source distribution according to the reconstruction status. Furthermore, multilevel meshes for the internal sources are used to speed up the computation and improve the accuracy of reconstruction. Numerical simulations have been performed to validate this proposed algorithm and demonstrate its high performance in the multi-source situation even if the detection noises, optical property errors and phantom structure errors are involved in the forward imaging. PMID- 23667788 TI - Zirconia dental implants degradation by confocal Raman microspectroscopy: analytical simulation and experiments. AB - Subsurface hydrothermal degradation of yttria stabilized tetragonal zirconia polycrystals (3Y-TZP) is presented. Evaluation of low temperature degradation (LTD) phase transformation induced by aging in 3Y-TZP is experimentally studied by Raman confocal microspectroscopy. A non-linear distribution of monoclinic volume fraction is determined in depth by using different pinhole sizes. A theoretical simulation is proposed based on the convolution of the excitation intensity profile and the Beer-Lambert law (optical properties of zirconia) to compare between experiment and theory. The calculated theoretical degradation curves matche closely to the experimental ones. Surface transformation (V0) and transformation factor in depth (T) are obtained by comparing simulation and experience for each sample with nondestructive optical sectioning. PMID- 23667789 TI - Chromatic confocal microscopy for multi-depth imaging of epithelial tissue. AB - We present a novel chromatic confocal microscope capable of volumetric reflectance imaging of microstructure in non-transparent tissue. Our design takes advantage of the chromatic aberration of aspheric lenses that are otherwise well corrected. Strong chromatic aberration, generated by multiple aspheres, longitudinally disperses supercontinuum light onto the sample. The backscattered light detected with a spectrometer is therefore wavelength encoded and each spectrum corresponds to a line image. This approach obviates the need for traditional axial mechanical scanning techniques that are difficult to implement for endoscopy and susceptible to motion artifact. A wavelength range of 590-775 nm yielded a >150 um imaging depth with ~3 um axial resolution. The system was further demonstrated by capturing volumetric images of buccal mucosa. We believe these represent the first microstructural images in non-transparent biological tissue using chromatic confocal microscopy that exhibit long imaging depth while maintaining acceptable resolution for resolving cell morphology. Miniaturization of this optical system could bring enhanced speed and accuracy to endomicroscopic in vivo volumetric imaging of epithelial tissue. PMID- 23667790 TI - A GAMOS plug-in for GEANT4 based Monte Carlo simulation of radiation-induced light transport in biological media. AB - We describe a tissue optics plug-in that interfaces with the GEANT4/GAMOS Monte Carlo (MC) architecture, providing a means of simulating radiation-induced light transport in biological media for the first time. Specifically, we focus on the simulation of light transport due to the Cerenkov effect (light emission from charged particle's traveling faster than the local speed of light in a given medium), a phenomenon which requires accurate modeling of both the high energy particle and subsequent optical photon transport, a dynamic coupled process that is not well-described by any current MC framework. The results of validation simulations show excellent agreement with currently employed biomedical optics MC codes, [i.e., Monte Carlo for Multi-Layered media (MCML), Mesh-based Monte Carlo (MMC), and diffusion theory], and examples relevant to recent studies into detection of Cerenkov light from an external radiation beam or radionuclide are presented. While the work presented within this paper focuses on radiation induced light transport, the core features and robust flexibility of the plug-in modified package make it also extensible to more conventional biomedical optics simulations. The plug-in, user guide, example files, as well as the necessary files to reproduce the validation simulations described within this paper are available online at http://www.dartmouth.edu/optmed/research-projects/monte-carlo software. PMID- 23667791 TI - Coherence-gated Doppler: a fiber sensor for precise localization of blood flow. AB - Miniature optical sensors that can detect blood vessels in front of advancing instruments will significantly benefit many interventional procedures. Towards this end, we developed a thin and flexible coherence-gated Doppler (CGD) fiber probe (O.D. = 0.125 mm) that can be integrated with minimally-invasive tools to provide real-time audio feedback of blood flow at precise locations in front of the probe. Coherence-gated Doppler (CGD) is a hybrid technology with features of laser Doppler flowmetry (LDF) and Doppler optical coherence tomography (DOCT). Because of its confocal optical design and coherence-gating capabilities, CGD provides higher spatial resolution than LDF. And compared to DOCT imaging systems, CGD is simpler and less costly to produce. In vivo studies of rat femoral vessels using CGD demonstrate its ability to distinguish between artery, vein and bulk movement of the surrounding soft tissue. Finally, by placing the CGD probe inside a 30-gauge needle and advancing it into the brain of an anesthetized sheep, we demonstrate that it is capable of detecting vessels in front of advancing probes during simulated stereotactic neurosurgical procedures. Using simultaneous ultrasound (US) monitoring from the surface of the brain we show that CGD can detect at-risk blood vessels up to 3 mm in front of the advancing probe. The improved spatial resolution afforded by coherence gating combined with the simplicity, minute size and robustness of the CGD probe suggest it may benefit many minimally invasive procedures and enable it to be embedded into a variety of surgical instruments. PMID- 23667792 TI - A three-parameter logistic model to characterize ovarian tissue using polarization-sensitive optical coherence tomography. AB - In this paper, a logistic prediction model is introduced to characterize the ovarian tissue. A new parameter, the phase retardation rate, was extracted from phase images of polarization-sensitive optical coherence tomography (PS-OCT). Statistical significance of this parameter between normal and malignant ovarian tissues was demonstrated (p<0.0001). Linear regression analysis showed that this parameter was positively correlated (R = 0.74) with collagen content, which was associated with the development of ovarian tissue malignancy. When this parameter and the optical scattering coefficient and the phase retardation estimated from the 33 ovaries were used as input predictors to the logistic model, 100% sensitivity and specificity in classifying malignant and normal ovaries were achieved. Ten additional ovaries were imaged and used to validate the prediction model and 100% sensitivity and 83.3% specificity were achieved. These results showed that the three-parameter prediction model based on quantitative parameters estimated from PS-OCT images could be a powerful tool to detect and diagnose ovarian cancer. PMID- 23667793 TI - Target Identification by Diazirine Photo-Cross-linking and Click Chemistry. AB - Target identification of biologically active small-molecules is often the rate determining step in forward chemical genetics. Photo-affinity labeling (PAL) represents a useful biochemical strategy for target identification in complex protein mixtures. This unit describes the use of alkyl diazirine-based photo affinity probes and Cu(I)-catalyzed click chemistry to covalently label and visualize the targets of biologically active small-molecules. A general method for affinity purification of probe-modified proteins, useful for identification of protein targets, is also described. PMID- 23667795 TI - Overtraining, Exercise, and Adrenal Insufficiency. AB - Running, or any aerobic training in moderation, has a positive effect on health. There is a point of diminishing returns, where chronic stress from overtraining, which is common in runners, may be linked to problems in the adrenal gland. Overtraining Syndrome (OS) has been linked with adrenal insufficiency. There is a direct link between stress and the adrenal glands, and the physical stress of overtraining may cause the hormones produced in these glands to become depleted. Overtraining Syndrome (OS) has been described as chronic fatigue, burnout and staleness, where an imbalance between training/competition, versus recovery occurs. Training alone is seldom the primary cause. In most cases, the total amount of stress on the athlete exceeds their capacity to cope. A triggering stressful event, along with the chronic overtraining, pushes the athlete to start developing symptoms of overtraining syndrome, which is far worse than classic overtraining. Overtraining can be a part of healthy training, if only done for a short period of time. Chronic overtraining is what leads to serious health problems, including adrenal insufficiency. Severe overtraining over an extended period can result in adrenal depletion. An Addison-Type overtraining syndrome, where the adrenal glands are no longer able to maintain proper hormone levels and athletic performance is severely compromised has been described by researchers. The purpose of this review is to describe the relationship between overtraining, chronic fatigue, and adrenal insufficiency and to address the overlap in these conditions, as well as examine critical research on the relationship between the dysfunction of the adrenal axis in over trained and stressed athletes. PMID- 23667794 TI - Bioorthogonal profiling of protein methylation (BPPM) using an azido analog of S adenosyl-L-methionine. AB - Protein methyltransferases (PMTs) utilize S-adenosyl-L-methionine (SAM) as a cofactor and transfer its sulfonium methyl moiety to diverse substrates. These methylation events can lead to meaningful biological outcomes, from transcriptional activation/silencing to cell cycle regulation. This article describes recently developed technology based on protein engineering in tandem with SAM analog cofactors and bioorthogonal click chemistry to unambiguously profile the substrates of a specific PMT. The protocols encapsulate the logic and methods of selectively profiling the substrates of a candidate PMT by (1) engineering the selected PMT to accommodate a bulky SAM analog; (2) generating a proteome containing the engineered PMT; (3) visualizing the proteome-wide substrates of the designated PMT via bioorthogonal labeling with a fluorescent tag; and finally (4) pulling down the proteome-wide substrates for mass spectrometric analysis. PMID- 23667796 TI - Seasonality patterns of mood and behavior in the Old Order Amish. AB - BACKGROUND: Although humans have become partially isolated from physical seasonal environmental changes through artificial lighting and temperature control, seasonal changes in mood and behavior have been described across hemispheres, continents, ethnicities and occupations. The Old Order Amish are more exposed than the general population to environmental seasonal changes both occupationally as well as through their limited use of electric light in the winter and air conditioning in the summer; yet, their seasonal changes in mood and behavior have not been previously studied. METHODS: The aim of this study was to analyze seasonal patterns in mood and behavior in the Old Order Amish of Lancaster County, Pennsylvania, who returned completed Seasonal Pattern Assessment Questionnaires (SPAQ). Monthly seasonal patterns were analyzed with repeated measures ANOVAs, followed by a post hoc t-test if significant. The chi2 was used for presence or absence of seasonal patterns for each item. RESULTS: More than 75% of the participants reported at least one seasonal change. More than 75 % endorsed seasonality in "feeling best" but only <25% did so for "feeling worst". Mood-wise, the best month was May, and the worst months were January and February. CONCLUSIONS: There were significant seasonal patterns for all mood and behavior items reported by the majority of participants. The results were consistent with an overall winter pattern of seasonality previously consistently reported in predominantly Caucasian populations. PMID- 23667797 TI - Macroporous polymer supported azide and nanocopper (I): efficient and reusable reagent and catalyst for multicomponent click synthesis of 1,4-disubstituted-1H 1,2,3-triazoles from benzyl halides. AB - Macroporous polymer supported nanoparticles of copper(I) iodide catalyst and macroporous polymer supported azide reagent were used to simplify the synthesis of 1,4-disubstituted-1H-1,2,3-triazoles from various benzyl halides following the green chemistry principles. This new one-pot protocol facilitates the workup of the reaction and provides the products in short times and at high yields. Heterogeneous catalyst and reagent can be reloaded and reused at least for 5 runs without significant decrease in the yields. PMID- 23667798 TI - Protective role of adjuvant and potassium permanganate on oxidative stress response of Nile tilapia (Oreochromis niloticus) challenged with Saprolegnia ferax. AB - Saprolegniosis are one of the most important oomycetes affecting freshwater fish worldwide. It leads to huge losses in fish farms due to their massive destruction to the fish epidermis leading to sever heamodilution and death, yet little literature studied the oxidative stress response regarding the saprolegniosis. Nile tilapia fish were subcutaneously abraded and divided into four groups: control group, abraded but not challenged, infected group, challenged with Saprolegnia. ferax (S. ferax) zoospores 2 * 10(4) for one week, potassium permanganate (KMnO4) group, challenged with S. ferax zoospores 2 * 10(4) for one week then treated with KMnO4 and lasted for 2 weeks after, Freund's complete adjuvant (FCA) group challenged with S. ferax zoospores 2 * 10(4) for one week then treated with FCA and lasted for 2 weeks after and control positive group, challenged with S. ferax zoospores 2 * 10(4) for 3 weeks. Higher mortalities were recovered from the challenged group, which declined upon treatment compared to the continued increased rate in the control positive group. Oxidative stress indicators Nitric Oxide (NO), glutathione (GSH) and superoxide dismutase (SOD) were measured; biochemical parameters: total protein, albumin, globulin, aspartate aminotranseferase (AST), and alanine aminoranferase (ALT) were also measured. Sodium (Na(+)) and potassium (K(+)) levels were measured as indicators of Plasma osmolality. Almost of the measured parameters showed varying reduction significant levels in treatment groups compared with the infected and the control ones. Thus, this study revealed that KMnO4 have a protective role against oxidative stress response, furthermore our data provide evidence for the role of FCA in modulating the oxidative stress response and enhancing fish immune response against infections. PMID- 23667799 TI - Web accessibility support for visually impaired users using link content analysis. AB - Web pages are used for a variety of purposes. End users must understand dynamically changing content and sequentially follow page links to find desired material, requiring significant time and effort. However, for visually impaired users using screen readers, it can be difficult to find links to web pages when link text and alternative text descriptions are inappropriate. Our method supports the discovery of content by analyzing 8 categories of link types, and allows visually impaired users to be aware of the content represented by links in advance. This facilitates end users access to necessary information on web pages. Our method of classifying web page links is therefore effective as a means of evaluating accessibility. PMID- 23667800 TI - Antibiotic prescription preferences in paediatric outpatient setting in Estonia and Sweden. AB - Aims of the study were to compare the paediatric outpatient antibiotic use in two countries with low overall antibiotic consumption and antibacterial resistance levels - Sweden and Estonia - and to describe the adherence to Estonian treatment guideline. All prescriptions for systemic antibiotics for children less than 18 years during 2007 from the Swedish Prescribed Drug Register and Estonian Health Insurance Fund database were identified to conduct a descriptive drug utilisation study. The total paediatric antibiotic use was 616 and 353 per 1000 in Estonia and Sweden, respectively. The greatest between country differences occurred in the age group 2 to 6 years -Estonian children received 1184 and Swedish children 528 prescriptions per 1000. Extended spectrum penicillin amoxicillin (189 per 1000) or its combination with beta-lactamase inhibitor (81 per 1000) and a newer macrolide clarithromycin (127 per 1000) were prescribed most often in Estonia whereas narrow spectrum penicillin phenoxymethylpenicillin (169 per 1000) and older generation macrolide erythromycin (21 per 1000) predominated in Sweden. For acute bronchitis, 17 different antibiotics (most commonly clarithromycin) were prescribed in Estonia despite the guideline recommendation not to use antibiotics. The higher rate of antibiotic use especially of extended spectrum antibiotics in Estonia compared to Sweden emphasizes the need for national activities to promote appropriate use of antibiotics while treating children, even when the overall antibiotic consumption is low. PMID- 23667801 TI - Gamma radiation mediated green synthesis of gold nanoparticles using fermented soybean-garlic aqueous extract and their antimicrobial activity. AB - Aspergillus oryzae was used to enhance the mobilization of antioxidants of soybean matrix along with garlic as a co-substrate by modulating polyphenolic substances during solid-state fermentation. Mobilized polyphenols were used as a green tool for synthesis and stabilization of gold nanoparticles (AuNPs). The radiation-induced AuNPs synthesis is a simple, clean and inexpensive process which involves radiolysis of aqueous solution that provides an efficient method to reduce metal ions. Gamma irradiated aqueous extract of fermented soybean and garlic was used for rapid preparation of AuNPs combining both effects of radiolytic reactions by radiation and stabilization by bioactive components of fermented extract. The synthesized AuNPs were confirmed by UV-Visible spectrophotometry, dynamic light scattering (DLS), Fourier Transform infra red (FT-IR) spectrophotometry, and transmission electron microscope (TEM) analysis which revealed morphology of spherical AuNPs with size ranging from 7-12 nm. The synthesized AuNPs exhibited antimicrobial activity against both Gram positive and Gram negative bacteria, as measured by well diffusion assay. PMID- 23667802 TI - International student mobility and highly skilled migration: a comparative study of Canada, the United States, and the United Kingdom. AB - Against the backdrop of demographic change and economic reconfiguration, recruiting international students, especially those at tertiary level, has drawn growing attention from advanced economies as part of a broad strategy to manage highly skilled migration. This comparative study focuses on three English speaking countries receiving international students: Canada, the United States, and the United Kingdom. International student policies, in particular entry and immigration regulations, and the trends in student mobility since the late 1990s are examined drawing on secondary data. By exploring the issue from the political economy perspectives, this study identifies distinct national strategies for managing student mobility, determines key factors shaping the environment of student migration in each nation, and addresses the deficiency of human capital theory in the analysis of global competition for high skills. PMID- 23667803 TI - Clinical implication of Time To Brain Metastasis (TTBM) according to breast cancer subtypes. AB - The aims of the present study were to investigate how breast cancer (BC) subtypes and treatment affect time to brain metastasis (TTBM). We retrospectively investigated 189 consecutive patients who were diagnosed with brain metastasis (BM) from BC between 2000 and 2009 at Samsung Medical Center. We analyzed TTBM from initial diagnosis of metastatic BC according to subtypes and trastzumab (T) administration before BM diagnosis. The median age of 189 BM patients from BC was 48 years. We divided TTBM into four groups considering BC subtypes and treatment; HR-positive/HER2-negative (n=45), HER2-positive with T before BM development (n=47), HER2-positive without T before BM development (n=39), and TNBC (n=58). The median TTBMs for each group were 17.5 months, 13.7 months, 5.8 months, and 2.9 months, respectively (p<0.001). HER2-positive without T (HR 1.892, p=0.008) and TNBC (HR 1.652, p=0.023) were independently associated with shorter TTBM. In multivariate analysis, HER2-positive without T (hazard ratio 1.725, p=0.002) and TNBC (hazard ratio 1.579, p=0.022) were independent risk factors for worse metastatic OS compared with HR-positive/HER2-negative subtype. TTBMs were shorter in patients with HER2-positive without T and TNBC among BC subtypes. Prospective clinical study for high risk patients for early BM is warranted. PMID- 23667804 TI - Plasmablastic lymphoma of the maxillary sinus in an HIV-negative patient: a case report and literature review. AB - Plasmablastic lymphoma (PBL) is a rare and aggressive variant of diffuse large B cell lymphoma. The prognosis of PBL patients is poor. The majority of patients succumb to a fulminant disease course, with most dying in the first year after diagnosis. The small number of HIV-negative PBL cases reported in the literature to date is composed of single case reports and small case series. Consequently, the natural history of the disease in HIV-negative individuals and the optimum treatment are not well characterized. Intensive induction chemotherapy has been associated with marked improved overall survival. However the optimal regimen has not been defined. We describe the third case of PBL of the maxillary sinus which occurred in a 24-year old HIV-negative man. We outline the clinicopathological features and report success using a hyper-CVAD regimen with 6 cycles and consolidation radiation therapy yielding a complete remission of four years. PMID- 23667805 TI - Effect of Melia azedarach (Sapindales: Meliaceae) fruit extracts on Citrus Leafminer Phyllocnistis citrella (Lepidoptera: Gracillariidae). AB - Melia azedarach L. extracts were studied in comparison with selected biorational insecticides against the citrus leafminer Phyllocnistis citrella Stainton under field conditions. Citrus limon (L.) Burm. F. trees were exposed to: Melia extracts of green and mature fruits, Neem oil (30% a.i.), abamectin (1.8% a.i.) and control. Two sprays of each treatment (except for Melia mature fruit extract) were executed at 10-d intervals. The live number of the 1(st) and later (2(nd) & 3(rd)) larval instars per leaf were recorded at initial sampling date and at 10-d intervals after each spray application. Results indicated that there were significant differences in the number of live larval instars among treatments. Melia extracts and the two biorationals, neem oil and abamectin, decreased the larvae population significantly to lower numbers than that of the control at 10 days after each spray application. However, the decrease caused by neem oil and abamectin was significantly higher than that of Melia extracts. Thus, these extracts might be considered as potential alternative with other biorational control methods in management of the leafminer. Further research including bioassays is needed to determine the factors responsible for reducing larvae population and whether these Melia extracts can be utilized in future citrus IPM programs as a tool for citrus leafminer management. PMID- 23667806 TI - Protein co-migration database (PCoM -DB) for Arabidopsis thylakoids and Synechocystis cells. AB - Protein-protein interactions are critical for most cellular processes; however, many remain to be identified. Here, to comprehensively identify protein complexes in photosynthetic organisms, we applied the recently developed approach of blue native PAGE (BN-PAGE) coupled with LC-MS/MS to the thylakoid proteins of Arabidopsis thaliana and the whole cell proteins of whole cell proteins of Synechocystis sp. PCC 6803. We identified 245 proteins from the purified Arabidopsis thylakoid membranes and 1,458 proteins from the whole cells of Synechocystis using the method. Next, we generated protein migration profiles that were assessed by plotting the label-free estimations of protein abundances versus migration distance in BN-PAGE. Comparisons between the migration profiles of the major photosynthetic complexes and their band patterns showed that the protein migration profiles were well correlated. Thus, the protein migration profiles allowed us to estimate the molecular size of each protein complex and to identify co-migrated proteins with the proteins of interest by determining the protein pairs that contained peaks in the same gel slice. Finally, we built the protein co-migration database for photosynthetic organisms (PCoM-DB: http://pcomdb.lowtem.hokudai.ac.jp/proteins/top) to make our data publicly accessible online, which stores the analyzed data with a user-friendly interface to compare the migration profiles of proteins of interest. It helps users to find unidentified protein complexes in Arabidopsis thylakoids and Synechocystis cells. The accumulation of the data from the BN-PAGE coupled with LC-MS/MS should reveal unidentified protein complexes and should aid in understanding the adaptation and the evolution of photosynthetic organisms. PMID- 23667808 TI - A review on electronic and optical properties of silicon nanowire and its different growth techniques. AB - Electronic and optical properties of Silicon Nanowire (SiNW) obtained from theoretical studies and experimental approaches have been reviewed. The diameter dependency of bandgap and effective mass of SiNW for various terminations have been presented. Optical absorption of SiNW and nanocone has been compared for different angle of incidences. SiNW shows greater absorption with large range of wavelength and higher range of angle of incidence. Reflectance of SiNW is less than 5% over majority of the spectrum from the UV to near IR region. Thereafter, a brief description of the different growth techniques of SiNW is given. The advantages and disadvantages of the different catalyst materials for SiNW growth are discussed at length. Furthermore, three thermodynamic aspects of SiNW growth via the vapor-liquid-solid mechanism are presented and discussed. PMID- 23667807 TI - Halomonas sp. BS4, A biosurfactant producing halophilic bacterium isolated from solar salt works in India and their biomedical importance. AB - Halophilic bacteria were isolated from Thamaraikulam solar salt works in India. After routine biosurfactant screening by various methods, the biosurfactant producing bacteria, Halomonas sp BS4 was confirmed by 16 S rRNA sequencing. The growth optimization of Halomonas sp BS4 revealed their optimum growth at 8% NaCl and 6-8 pH in the growth medium. Further the partially purified biosurfactants were characterized by TLC, FTIR and GC-MS analysis. GC-MS results revealed that, the partial purified biosurfactants contain 1, 2-Ethanediamine N, N, N', N' tetra, 8-Methyl-6-nonenamide, (Z)-9-octadecenamide and a fatty acid derivative. Pharmacological screening of antibacterial, antifungal, antiviral and anticancer assays revealed that, the biosurfactant extracted from Halomonas sp BS4 effectively controlled the human pathogenic bacteria and fungi an aquaculturally important virus, WSSV. The biosurfactant also suppressed the proliferation of mammary epithelial carcinoma cell by 46.77% at 2.5 MUg concentration. Based on these findings, the present study concluded that, there is a possibility to develop eco-friendly antimicrobial and anticancer drugs from the extremophilic origin. PMID- 23667809 TI - High-dose intravenous methylprednisolone for the prophylactic treatment of cluster headache. AB - BACKGROUND: Triptans are effective for immediate relief of episodic cluster headache (CH) but do not reduce the frequency of attacks. Intravenous bolus injection of corticosteroids like methylprednisolone (MP) has been reported to decrease the frequency of CH attacks. We validated the prophylactic efficacy of MP pulse therapy by monitoring CH recurrence over several years following treatment of six consecutive male patients (mean age: 38.8 years, range: 26-54 years) afflicted by frequent (often daily) CH attacks. FINDINGS: Total MP dose per infusion was 250-500 mg for five patients and 125 mg for the sixth (a diabetic). High-dose MP was administered for 2 or 3 consecutive days in hospital for the first two patients treated. The next four patients received a single bolus injection at presentation, and in some cases a second injection days later at an outpatient clinic. The first two cases treated were also prescribed daily oral prednisolone for at most 6 months while the latter four cases were not. The frequency of CH attacks was markedly reduced in all patients, with intervals between attacks ranging from 4 to 23 months. We noted no apparent adverse events following MP administration. CONCLUSIONS: High-dose MP therapy reduced CH attack frequency and improved patient quality of life. PMID- 23667811 TI - Wicked problems: a value chain approach from Vietnam's dairy product. AB - ABSTRACT: In the past few years, dairy industry has become one of the fastest growing sectors in the packaged food industry of Vietnam. However, the value added creation among different activities in the value chain of Vietnam dairy sector is distributed unequally. In the production activities, the dairy farmers gain low value-added rate due to high input cost. Whereas the processing activities, which managed by big companies, generates high profitability and Vietnamese consumers seem to have few choices due to the lack of dairy companies in the market. These wicked problems caused an unsustainable development to the dairy value chain of Vietnam. This paper, therefore, will map and analyze the value chain of the dairy industry in Vietnam. It will also assess the value created in each activity in order to imply solutions for a sustainable development of Vietnam's dairy industry. JEL CODES: M10, M11. PMID- 23667810 TI - Gene expression profiling of the anti-glioma effect of Cilengitide. AB - Cilengitide (EMD121974), an inhibitor of the adhesive function of integrins, demonstrated preclinical efficacy against malignant glioma. It is speculated that cilengitide can inhibit tumor growth, invasion, and angiogenesis. However, the effects of cilengitide on these processes have not been sufficiently examined. In this study, we investigated the anti-glioma effect of cilengitide using DNA microarray analysis. U87DeltaEGFR cells (human malignant glioma cell line) were used for this experiment. The cells were harvested after 16 h of cilengitide treatment, and mRNA was extracted. Gene expression and pathway analyses were performed using a DNA microarray (CodeLinkTMHuman Whole Genome Bioarray). The expression of 265 genes was changed with cilengitide treatment. The expression of 214 genes was up-regulated by more than 4-fold and the expression of 51 genes was down-regulated by more than 4-fold compared to the controls. In pathway analysis, "apoptotic cleavage of cellular proteins" and "TNF receptor signaling pathway" were over-represented. Apoptotic-associated genes such as caspase 8 were up regulated. Gene expression profiling revealed more detailed mechanism of the anti glioma effect of cilengitide. Genes associated with apoptosis were over represented following cilengitide treatment. PMID- 23667812 TI - The dairy chains in North Africa (Algeria, Morocco and Tunisia): from self sufficiency options to food dependency? AB - The Maghreb countries (Algeria, Morocco and Tunisia) have experienced since the early 1950s a rapid demographic growth coupled to a significant rhythm of urbanization. This has led to a marked increase in the demand of dairy products. In order to secure the supply, specific policies have been implemented. They mainly consisted in the establishment of a dairy industry, based on the processing of either raw milk produced locally (in Morocco and Tunisia) or imported milk powder (in Algeria). These divergent options have had significant consequences on the whole organization of the dairy chains in these countries, from cattle rearing practices, to milk collection and processing. They have also implied differences in milk and its derivatives' prices and levels of consumption. The paper draws a comparative analysis of milk chains within the three countries: a supply mainly based on imports in Algeria, whereas in Morocco and Tunisia, the demand is satisfied by a chain relying on locally produced cattle milk. The paper also emphasizes on the future challenges that will have to be addressed: a rising volatility of milk and other strategic inputs' prices (feed, machinery, cattle, etc.) in global markets, an improvement in consumers' awareness about milk quality, a further pressure on natural resources (mainly soils and water) to get more raw milk, in countries already suffering an acute water stress. The article also establishes recommendations about specific issues related to the development of the dairy chains in the context of North Africa. These are mainly linked to the fragmented offer induced by numerous smallholder farms, which implies obvious difficulties to assess the hygienic and the chemical quality of milk batches delivered daily. Moreover, this fragmented offer also means that specific support programs will have to be designed, as the vast majority of farms are not dairy specialized, expecting both milk and calf crop from their herds. PMID- 23667813 TI - Giant lipoma of the third finger of the hand. AB - We report a case of a 50-year old female presenting with a giant tumor on the volar aspect of the third finger of the left hand, a thorough clinical and paraclinical evaluation followed by surgical resection resulted in a benign lipoma with an uneventful postoperative course. We present this case due to its rare location and repercussion in the decision making process when other more common similar pathologies with varying prognosis are conceived. PMID- 23667814 TI - Effect of dietary fat type on anxiety-like and depression-like behavior in mice. AB - Dietary fat plays an important role in higher brain functions. We aimed to assess the short and long term intake of three different types of dietary fat (soybean oil, lard, and fish oil) on anxiety-like and depression-like behavior in mice. For the short term intake assessment, a behavioral test battery for anxiety and depression was carried out for a 3-day feeding period. For the long term intake assessment, a behavioral test battery began after the 4-week feeding period. During the short term intake, the time spent in the open arms of the elevated plus-maze was the longest in the fish oil fed group, followed by the soybean oil and lard-fed groups. The elevated plus-maze is a common animal model to assess anxiety, in which an increased time spent in the open arms indicates an anxiolytic effect. The difference between the fish oil-fed group and lard-fed group was statistically significant (p < 0.01), but there was no significant difference between the soybean oil-fed group and the other two groups. Similar results were observed after a 4-week feeding period. On the other hand, there was no significant difference among the three groups in behavior tests to evaluate depression. Thus, the dietary fat types appeared to influence anxiety but not depression in mice, both in short term (3 days) and long term (4 weeks) feeding. PMID- 23667815 TI - The instantiation of values. AB - The paper argues that values are universals, either properties or relations. For the latter, instantiation is a matter of the content of the relation, the relata, and the context (the instantiation of further relations). This moderate realist conception helps us solve some notorious problems in axiology, i.e. malicious pleasure, compassion, envy, and perverted love. Another other important implication of this conception is that there is a further property, the one of being a value. It is a higher-order property which can be instantiated by relation (and property) values to various degrees. Finally, the questions of whether particularity is a value and how rarity can be a value are also addressed. The underlying ontological conception provides a sound way of finding a answer to these questions as well. PMID- 23667816 TI - The effect of tea fermentation on rosmarinic acid and antioxidant properties using selected in vitro sprout culture of Orthosiphon aristatus as a model study. AB - Orthosiphon aristatus, an Indonesian medicinal plant, is normally used as a traditional herbal tea. Recently, this plant has begun to attract attention due to its antioxidant properties. However, little is known about tea fermentation effect on antioxidant properties of this plant. Thus, to extend the tea fermentation study, in vitro sprout culture of this plant was established as a new feature model. This model plant was selected based on three reasons. Firstly, as a native tropical plant, to grow this plant in sub-tropic area is considered difficult. Secondly, the in vitro sprout culture is more genetically stable compared to other types of in vitro cultures. Thirdly, results showed that this in vitro sprout culture grew faster and produced higher biomass than in vitro tissue culture. Both characteristics are important in producing tea leaves. Accordingly, the aim of the current study was twofold. First was to establish high rosmarinic acid line of in vitro sprout culture of Orthosiphon aristatus by elicitation. Second was to evaluate the effect of tea fermentation on antioxidant properties of this plant. Results showed that yeast extract (5 g/L) elicitation resulted in the highest production of rosmarinic acid. This elicited plant was subjected to partial and full tea fermentation. Results revealed that both tea fermentations decreased the level of rosmarinic acid, total phenolic compounds, flavonoids, and flavonols. These decreases were concomitant with reduced antioxidant activities as measured by 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging activity, Trolox equivalent antioxidant capacity (TEAC), and Superoxide dismutase (SOD)-like activity assays. HPLC results showed that the longer the tea fermentation was, the greater reduction rosmarinic acid was found. High correlation value of 0.922 between rosmarinic acid and antioxidant activities was also observed. These results indicated that rosmarinic acid is the major contributor to the antioxidant activities of Orthosiphon aristatus. These results may provide useful information, in particular, for the food and pharmaceutical industries in the development of functional foods desiring maximum potential health benefits from Orthosiphon aristatus. PMID- 23667817 TI - Molecular Characterization of camphor utilizing bacterial isolates from refinery sludge and detection of target loci-Cytochrome P-450 cam mono oxygenase (cam C gene) by PCR and gene probe. AB - This study presents the isolation and molecular characterization of bacterial strains utilizing 1, 7, 7-Trimethylbicyclo (2.2.1) heptane-2-one (camphor) as a sole source of carbon, isolated from the biomass sludge sample collected from an effluent treatment plant of Mathura Refinery Limited (MRL), India. Initial screening was carried out where the 16S rDNA PCR was performed using reported eubacterial primer set followed by Amplified Ribosomal DNA Restriction Analysis (ARDRA). About 47% of the isolates have shown unique ARDRA pattern based on which, 15 distinct isolates were selected and tested for the presence of cam C gene that was successfully demonstrated by PCR using gene specific primers. A Dot Blot experiment was designed to detect the cam C loci in the plasmid DNA of all camphor isolates based on non-radioactive "Biotin-Streptavidin" detection system. The bacterial identity with respect to partial 16S rDNA gene sequences of all camphor isolates placed them in 9 major genera viz., Pseudomonas sp., Staphylococcus sp., Alcaligenes sp., Agromyces sp., Stenotrophomonas sp., Reichenowia sp., Achromobacter sp., Brevibacterium sp. and Pseudaminobacter sp. A detailed phylogentic tree was also constructed to establish their evolutionary status from the gene sequence data. PMID- 23667818 TI - Cost of comprehensive patient assistance program in early breast cancer patients. AB - Existing comprehensive patient assistance programs can help cancer patients overcome needs and barriers to care: yet the costs of such programs and who utilizes them is not well described. 333 women with primary early stage breast cancer in New York City either chose to attend or abstain from attending one of these programs. We obtained the operating costs of the most utilized patient assistance program. Patients who utilized patient assistance programs were significantly more likely to be English speaking (p=0.04) and have 1.5 years more advanced schooling than non-utilizers (p=0.008). At the cost of 73 dollars per hour encounters, patients reported benefiting the most from information resources (71% of patients) followed by emotional support (52% of patients); 5% of patients reported getting help with insurance, 5% with financial assistance, 4% with help obtaining medication, 2% with transportation. Existing comprehensive patient assistance programs offer informational, psychological and financial support at low cost. Patients who currently use these programs are English speakers with more education. PMID- 23667820 TI - Inhibition of Flavobacterium psychrophilum biofilm formation using a biofilm of the antagonist Pseudomonas fluorescens FF48. AB - The most important bacterial pathology currently occurring in Chilean freshwater salmon farming is the cold-water disease produced by the psychrotrophic bacteria Flavobacterium psychrophilum. The main aim of this study was to characterize the inhibitory activity of an antagonist strain on the formation of biofilms of a F. psychrophilum strain. The antagonistic strain Pseudomonas fluorescens FF48 was isolated from the sediment beneath the salmon cages of a freshwater Chilean salmon farm and was identified by using the 16S rRNA gene sequence analysis. The production of siderophores, mainly during the stationary phase of growth of the antagonist strain was demonstrated using the Chrome Azurol S method and through F. psychrophilum inhibition under iron saturation conditions. Subsequently, the effect of the antagonist supernatant on the formation of F. psychrophilum biofilm was tested using the crystal violet staining method observing an inhibition of the growth of F. psychrophilum, but no effect was observed when iron saturation concentrations were used. Furthermore, when the antagonist strain was previously deposited on the support, it completely inhibited the formation of F. psychrophilum biofilms, but when both bacteria were inoculated simultaneously no inhibitory effect was detected. In conclusion, it was demonstrated that FF48 strain is able to inhibit the formation of F. psychrophilum biofilms in vitro probably mediated by the siderophore production, suggesting its potential use as a biocontrol biofilm in freshwater fish rearing systems to prevent the persistence of biofilms of the fish pathogenic species F. psychrophilum. PMID- 23667819 TI - Male reproductive traits of full-sibs of different age classes in three-spined sticklebacks (Gasterosteus aculeatus). AB - The process of ageing is associated with negative effects of mutations acting late in life, which range from those affecting cells to those affecting the whole organism. In many animal taxa, the deterioration of the phenotype with age also affects traits such as males' primary and secondary sexual characteristics. In three-spined sticklebacks (Gasterosteus aculeatus), males usually reproduce at one or two years of age. To see whether sexual selection has the potential to differ between young and old males, full-sib brothers of different age classes were compared, which were bred and raised under standardised laboratory conditions. During two simulated, successive breeding seasons males were allowed to build their nest in single tanks either in the first ("young males") or in the second ("old males") breeding season. A comparison of reproductively active brothers of the first and second breeding season showed that older males produce more but smaller sperm, which might be of lower quality. The fact that older males stored more sperm is size dependent as the results show that larger males possess a greater absolute testis mass, which is inextricably linked to sperm number. However, independent of body size, old males had a lower intensity of red/orange and UV breeding coloration as well as a reduced testis melanisation, which might have consequences in female mate choice and sperm competition. PMID- 23667821 TI - How intermittent presentation affects conscious perceptual reversals of ambiguous figures. AB - Continually observing an ambiguous figure, we can perceive reversals between different interpretations. How perceptual reversals change when an ambiguous stimulus is presented intermittently? Since no reversal can be consciously perceived during off-periods, we use net Average Reversal Interval (netARI) but not usual average reversal interval to measure the perceptual reversal rate. NetARI is calculated by dividing accumulated time of on-periods by the number of reversals. The results are: (1) presenting an ambiguous figure intermittently increased the perceptual reversal rate; (2) the longer the exposure of Necker cube, the slower the perceptual reversal rate was, and when on-periods were longer as 15 s, the perceptual reversal rate was slowed down and was almost same to that in the continuous case; (3) the length of off-periods (which ranged from 1 s to 5 s in the present study) did not affect the reversal rate. PMID- 23667822 TI - Life history and assessment of grapevine phylloxera leaf galling incidence on Vitis species in Uruguay. AB - Grapevine phylloxera, Daktulosphaira vitifoliae (Fitch) (Hemiptera: Phylloxeridae) is a worldwide pest of Vitis species. It has forms that feed on leaves and roots. Root forms predominate on Vitis vinifera (L.) cultivars, while leaf forms predominate on Vitis species from its native American range. Recently, high densities of D. vitifoliae infestations in leaves of V. vinifera in Brazil, Peru, and Uruguay have been reported. The aims of this study were to determine the seasonal development of grape phylloxera, quantify infestation levels on V. vinifera leaves, and compare them with infestation levels on leaves of a rootstock of American origin. Studies were conducted in two vineyards in Uruguay from 2004-2007. Terminal shoots of 3309 C and Cabernet Sauvignon, Chardonnay, Tannat, Viognier, grafted onto resistant rootstock, were sampled weekly and leaves examined for gall presence and insect life stage. First galls were detected in early October; eggs began to appear within two weeks. Two oviposition peaks occurred by the end of December, and they coincided with bursts of shoot growth. On 3309C rootstock, oviposition peaks were more frequent than on the European cultivars. Based on thermal accumulation, D. vitifoliae could complete eight generations a year in Uruguay. Rootstock 3309C suffered the greatest damage but in some cases was similar to the European cultivars. Damage to Chardonnay, Cabernet Sauvignon and Viognier were also high. There were no galls on Tannat. The 2005-2006 season was characterized by low infestation rates caused by a prolonged drought that affected vegetative growth. There were also differences between vineyards, where the vigorous plants suffering more damage. Leaf galling phylloxera incidence and damage were mainly associated to the cultivar but plant vigor and environmental factors also contributed to increase the incidence. PMID- 23667823 TI - Abundance and diversity of zooplankton in semi intensive prawn (Macrobrachium rosenbergii) farm. AB - The present study was carried out on the seasonal abundance and diversity of zooplankton in a semi- intensive prawn farm of Bagerhat district from July to December, 2008. Plankton samples were collected by conical shaped monofilament nylon net (Plankton net) and Lugol's solution was used for preservation. The zooplankton abundance was influenced by physico-chemical factors. During the study period 11 genera of zooplankton under 5 orders were recorded from the study ponds namely Copepoda, Rotifera, Cladocera, Ostracoda and Crustacean Larvae. Among all groups copepod was the dominant order. The percentages of Copepoda, Rotifera, Cladocera, Ostracoda and Crustacean Larvae in semi-intensive culture system were 54%, 28%, 12%, 4% and 2% respectively. But the genera Brachionus under the order of Rotifer was dominant among all other genera. Cyclops and Helidiaptomus under the order of Copepod were the 2nd dominant genera. Numbers of zooplankton species were recorded to be the highest in summer season and minimum at early winter season. Highest number of zooplankton found at the month of October. Total zooplankton shows significant positive relationship with water temperature ((r = +0.384), Dissolve Oxygen(r = +0.113), pH(r = +0.320), Free CO2 (r = +0.319), Alkalinity(r = +0.269), Hardness (r = +0.402) and negative relationship with Salinity(r = -0.486), Transparency(r = -0.693). The findings of the present study will help to improve the management strategies of shrimp culture system. PMID- 23667824 TI - Changing monoclonal antibody keeping unaltered the chemotherapy regimen in metastatic colorectal cancer patients: is efficacy maintained? AB - Monoclonal antibodies bevacizumab and cetuximab both improve overall survival (OS), progression free survival (PFS) and overall response rate (ORR) when combined with irinotecan-containing regimens. The optimal sequence of these monoclonal antibodies in combination with chemotherapy is controversial. This study analysed the efficacy of cetuximab plus Folfiri after progression with the same regimen plus bevacizumab in patients with metastatic colorectal cancer (mCRC). Patients are eligible if progressive disease (PD) after Folfiri bevacizumab; ECOG PS 0-1. Primary endpoint is the disease control rate (DCR:ORR plus stable disease > 6 months); secondary endpoints: ORR, PFS, duration of response, OS and toxicity. ORR and DCR were reported with their confidence interval at 95%. Kaplan-Meier method was used for PFS and OS evaluation. RESULTS: 54 patients were enrolled to receive Folfiri-cetuximab after PD to Folfiri bevacizumab treatment. Median age was 65 (43-80), M/F 31/23, ECOG PS 0/1 was 36/ 18, WT Kras 33(61%). The DCR was 64.8% (CI 95% 52.1-77.5). Among the group of patients with stable or progressive disease at first line treatment, 13.3% of them obtained a response at second line. For second line treatment median duration of response was 6 months and clinical benefit 7 months. The ORR was 22.2% (CI 95% 11.1-33.3). The median progression-free survival was 7 months (CI 95% 6-8). The median overall survival for second line treatment was 14 months (CI 95% 11-17). No grade 4 toxicity was observed. Data suggest that this sequential combination therapy is active and well tolerated. At disease progression to first line chemotherapy treatment the maintenance of the same chemotherapy regimen and the change of the monoclonal antibody showed efficacy in response and survival in patients with mCRC. PMID- 23667825 TI - Effects of acidic water in combination with aluminum on swimming behavior and survival of yolk-sac larval in Goldfish (Carassius auratus gibelio). AB - Yolk-sac fry of Goldfish (Carassius auratus gibelio) were exposed to various concentrations of Al and pH for 3, 7 and 10 days. In this study number of dead fish, total length of larvae, yolk sac length, swimming activity, the number of gill cover movements and the number of heart beat was measured. The lowest and highest number of gill cover movements belong to the waters containing 50 mg L-1 of aluminum, pH 5.25 and acidic waters with pH 6.7 respectively. There was no significant difference in the number of heartbeat between control group and larvae exposure to acidic waters with pH 6.7 and waters containing 150 mgL-1 of aluminum and the highest number of heartbeat belong to these larvae than other experiment doses. The larval of Goldfish in the all experiment doses lost their swimming ability after 3 days. The highest number of swimming larvae and also lowest number of non-swimming larvae significantly belong to control group compared to other experiment doses (p < 0.05). The larval in the control group only were maintained their swimming activity after 7 and 10 days and in the all experiment treatments lost their swimming ability. There was significant difference in the number of dead larvae and the number of non-swimming larvae between control group and larvae exposure to acidic waters and waters containing 300 mgL-1 of aluminum and pH 4.75 (p < 0.05) and lowest number of non-swimming larvae was observed in the control group. Also the highest of yolk sac length belong to the waters containing 600 mgL-1 of aluminum and pH 4.75. The larvae of Goldfish were not survived in the waters containing 300 and 600 mgL-1 of aluminum and waters with low acidity after 7 days. PMID- 23667826 TI - Bacterial biosensors for screening isoform-selective ligands for human thyroid receptors alpha-1 and beta-1. AB - Subtype-selective thyromimetics have potential as new pharmaceuticals for the prevention or treatment of heart disease, high LDL cholesterol and obesity, but there are only a few methods that can detect agonistic behavior of TR-active compounds. Among these are the rat pituitary GH3 cell assay and transcriptional activation assays in engineered yeast and mammalian cells. We report the construction and validation of a newly designed TRalpha-1 bacterial biosensor, which indicates the presence of thyroid active compounds through their impacts on the growth of an engineered Escherichia coli strain in a simple defined medium. This biosensor couples the configuration of a hormone receptor ligand-binding domain to the activity of a thymidylate synthase reporter enzyme through an engineered allosteric fusion protein. The result is a hormone-dependent growth phenotype in the expressing E. coli cells. This sensor can be combined with our previously published TRbeta-1 biosensor to detect potentially therapeutic subtype selective compounds such as GC-1 and KB-141. To demonstrate this capability, we determined the half-maximal effective concentration (EC50) for the compounds T3, Triac, GC-1 and KB-141 using our biosensors, and determined their relative potency in each biosensor strain. Our results are similar to those reported by mammalian cell reporter gene assays, confirming the utility of our assay in identifying TR subtype-selective therapeutics. This biosensor thus provides a high-throughput, receptor-specific, and economical method (less than US$ 0.10 per well at laboratory scale) for identifying important therapeutics against these targets. PMID- 23667827 TI - Brain morphological abnormalities in 49,XXXXY syndrome: A pediatric magnetic resonance imaging study. AB - As a group, people with the sex chromosome aneuploidy 49,XXXXY have characteristic physical and cognitive/behavioral tendencies, although there is high individual variation. In this study we use magnetic resonance imaging (MRI) to examine brain morphometry in 14 youth with 49,XXXXY compared to 42 age-matched healthy controls. Total brain size was significantly smaller (t=9.0, p<.001), and rates of brain abnormalities such as colpocephaly, plagiocephaly, periventricular cysts, and minor craniofacial abnormalities were significantly increased. White matter lesions were identified in 50% of subjects, supporting the inclusion of 49,XXXXY in the differential diagnosis of small multifocal white matter lesions. Further evidence of abnormal development of white matter was provided by the smaller cross sectional area of the corpus callosum. These results suggest that increased dosage of genes on the X chromosome has adverse effects on white matter development. PMID- 23667828 TI - Mitochondrially targeted compounds and their impact on cellular bioenergetics. AB - Mitochondria are recognized as critical sites of localized injury in a number of chronic pathologies which has led to the development of organelle directed therapeutics. One of the approaches employed to target molecules to the mitochondrion is to conjugate a delocalized cation such as triphenylphosphonium (TPP+) to various redox active compounds. Mitochondrially targeted antioxidants have also been used in numerous cell culture based studies as probes of the contribution of the mitochondrial generation of reactive oxygen species on cell signaling events. However, concentrations used in vitro are typically 10-100 times greater than those generated from oral dosing in a wide range of animal models and in humans. In the present study, we determined the effects of mitochondrial targeted antioxidants, MitoQ, MitoTempol, and MitoE on cellular bioenergetics of mesangial cells in culture and compared these to TPP+ conjugated compounds which lack the antioxidant functional group. We found that all TPP+ compounds inhibited oxidative phosphorylation to different extents independent of the antioxidant functional groups. These findings show that the TPP+ moiety can disrupt mitochondrial function at concentrations frequently observed in cell culture and this behavior is dependent on the linker group and independent of antioxidant properties. Moreover, TPP+ moiety alone is unlikely to achieve the concentrations needed to contribute to the protective mechanisms of the mitochondrially targeted compounds that have been reported in vivo. PMID- 23667829 TI - Think globally, act locally. PMID- 23667830 TI - Overview of atopic dermatitis. AB - Atopic dermatitis (AD) is a very common chronic disease that reportedly affects 10%-20% of the general population. The prevalence of AD appears to be steadily increasing, at least in developing countries. Two pathogenetic mechanisms have been mentioned. Traditionally immunological aberrations are thought to be a primary event in the initial development of AD ("inside-to-outside hypothesis"). Another hypothesis assumes that there is an intrinsic defect in epidermal barrier. Due to this barrier defect, allergens or irritants can easily penetrate the epidermal barrier, and induce immunologic reaction secondarily ("outside-to inside hypothesis"). These days the epidermal barrier defect seems to gain more support as a primary event than immunological aberrations in the early changes of AD since the filaggrin mutation was reported in AD patients. Clinically AD initially affects face, and with age, flexural areas are typically involved. AD has many different clinical features. Diagnostic criteria for AD in each country may be a little different, although based on the criteria proposed by Hanifin and Rajka. AD can be controlled effectively with topical and/or systemic treatments and fortunately spontaneously disappears with age. However, in some cases very resistant to conventional therapies, additional treatments such as immunosuppressive agents are needed. PMID- 23667831 TI - What's new in the diagnosis and management of food allergy in children? AB - This article reviews the recent advances in the diagnosis and management of IgE mediated food allergy in children. It will encompass the emerging technology of component testing; moves to standardization of the allergy food challenge; permissive diets which allow for inclusion of extensively heated food allergens with allergen avoidance; and strategies for accelerating tolerance and food desensitization including the use of adjuvants for specific tolerance induction. PMID- 23667832 TI - Prevalence of latex allergy in spina bifida patients in Singapore. AB - BACKGROUND: Latex allergy and its clinical presentation are rising in prevalence across the globe, especially amongst patients with spina bifida (SB). While studies have been well-established in Europe and America, data from Asia are limited. OBJECTIVE: The aim of this study is to investigate the scenario in Singapore. METHODS: 35 subjects with SB, aged 5 to 32 years answered a questionnaire and underwent skin prick test (SPT) using a latex solution, 3 common house dust mites and 3 commonly cross-reacting food allergens (banana, kiwi and avocado). We also noted the relation between latex sensitization with atopy and doctor-diagnosed allergy. The prevalence of cross-reactivity with fruits was also studied. RESULTS: Sensitization to latex (i.e. a positive SPT) was found in 16 (46%, 95% confidence interval 29%-63%) of the subjects. Only 5 (31%) of the subjects who were sensitized to latex had clinical manifestations. Atopy (i.e. positive SPT to house dust mites) was present in 23 (66%) of the subjects and 13 (57%) of them was also sensitized to latex. There was a positive trend between latex sensitization and atopy (81.2% vs. 52.6%, p = 0.076), as well as latex sensitization with those having both atopy and doctor-diagnosed allergy (i.e. asthma, allergic rhinitis, eczema, drug allergy) (93.8% vs. 63.2%, p = 0.032). Only 6 (38%) subjects had allergy to the food allergens tested. CONCLUSION: Almost half of the SB patients in Singapore are sensitized to latex. This number is comparable to that in Europe and America. Positive trend between latex sensitization and those with both atopy and doctor-diagnosed allergy (p = 0.032) is suggestive of a possible cause-effect relationship. PMID- 23667833 TI - Correlation between plasma D-dimer levels and the severity of patients with chronic urticaria. AB - BACKGROUND: Beside autoimmunity, coagulation pathway is also involved in the pathogenesis of chronic urticaria (CU). Previous studies showed that plasma D dimer levels paralleled the severity of the disease. To date, there are no data concerning D-dimer level in Thai patients with CU. OBJECTIVE: This study aimed to find the relationship between plasma D-dimer levels and the disease severity of Thai CU patients. The secondary objective is to analyze plasma D-dimer level in each group of patients who performed autologous plasma skin testing (APST) and autologous serum skin testing (ASST). METHODS: We retrospectively reviewed case record forms of chronic idiopathic urticaria (CIU) patients aged at least 18 years in Skin Allergy Clinic, Siriraj Hospital Mahidol University, Bangkok, during June 2008 to June 2011. RESULTS: Of 120 patients, plasma D-dimer level was abnormal in 58 patients (48.3%). The study showed statistically significant positive correlation between disease severity and plasma D-dimer level (p < 0.05, r = 0.537). There was no statistically significant difference in plasma D-dimer level between APST positive and negative groups, and also between ASST positive and negative groups. In APST negative group, plasma D-dimer level was elevated in 29 patients (47.5%) and correlated with disease severity. CONCLUSION: This study showed elevated plasma D-dimer levels in nearly half of Thai patients with CIU. There was a positive correlation between plasma D-dimer levels and the severity of disease activity. Investigation for plasma D-dimer level may be an alternative way to evaluate disease severity in patients with CIU. PMID- 23667834 TI - Clinical evaluation of pediatric anaphylaxis and the necessity for multiple doses of epinephrine. AB - BACKGROUND: Epinephrine administered intramuscularly is the treatment of choice for anaphylaxis, and more than 1 dose is occasionally required. OBJECTIVE: To determine clinical background of anaphylaxis for improving the treatment, management, and prognosis of anaphylaxis. METHODS: Children who had satisfied the diagnostic criteria for anaphylaxis according to the National Institute of Allergy and Infectious Disease Food Allergy and Anaphylaxis Network were selected from our hospital from April 1, 2009 to March 31, 2012. RESULTS: We analyzed 61 patients from the ages of 2 months to 14 years who satisfied the diagnostic criteria for anaphylaxis. Parents of 32 children (52.5%) reported that they had been administered single dose of epinephrine, and 3 children (4.9%) reported receiving multiple doses of epinephrine. The latter group experienced syncope more often (p = 0.049) than the former and suffered more often from comorbid allergic diseases (p = 0.043) that included either bronchial asthma, allergic rhinitis, or atopic dermatitis. Two (3.3%) children experienced biphasic reactions. Patients who experienced a biphasic reaction were more likely to have experienced syncope (p = 0.033), vomiting (p = 0.02), and administration of multiple doses of epinephrine (p = 0.0016). CONCLUSION: Our findings lead us to recommend that children receiving more than 1 injection of epinephrine should be observed for 24 hours, because it seems that children with requiring more than 1 injection of epinephrine might be have biphasic reactions. PMID- 23667835 TI - Utility of penicillin allergy testing in patients presenting with a history of penicillin allergy. AB - BACKGROUND: Current statistics show that approximately 10% of patients claim to be allergic to penicillin yet only 10% of these have demonstrable allergy. The most appropriate and cost-effective antibiotics are sometimes withheld on the basis of patient history of drug allergy. OBJECTIVE: Investigation of IgE hypersensitivity and delayed hypersensitivity in patients with a history of penicillin allergy to a teaching hospital allergy clinic. METHODS: Patients underwent skin prick and intradermal testing (IDT) with major and minor penicillin determinants. Those with negative skin tests were administered a three day oral challenge. Demographic and clinical details about the reactions were noted. RESULTS: One hundred twenty eight patients underwent testing, of these, one hundred and ten had self-reported histories of penicillin allergy and eighteen were referred because of other antibiotic allergies. Seventeen patients with self-reported penicillin allergy had either positive skin tests or oral challenge results, corresponding to 15% of patients having proven allergy. None reacted on skin prick testing, four reacted to IDT, thirteen reacted to oral challenge (five immediate and eight delayed). Analysis of clinical histories showed that patients with a well-defined history of allergy and a history of anaphylaxis were more likely to have a positive test compared to patients with vague histories. Skin testing proved to be less sensitive than oral challenge. CONCLUSION: A minority of patients presenting with a history of penicillin allergy have evidence of immune-mediated hypersensitivity (17/110, 15%) in this study. Of these, eight out of seventeen (47%) had delayed reactions, demonstrating the usefulness and discriminating power of objective testing, which must include three-day oral challenge. Discriminating factors for immune-mediated allergy from patient history were a clear description of the original reaction and a history of anaphylaxis. Negative allergy testing enables the use of penicillin as first-line treatment when necessary and this can significantly reduce costs of antibiotics. PMID- 23667836 TI - Staphylococcal enterotoxin specific IgE and asthma: a systematic review and meta analysis. AB - BACKGROUND: Recent literature suggests that Staphylococcal enterotoxin specific IgE may be a risk factor for asthma. OBJECTIVE: To investigate the associations between Staphylococcal enterotoxin sensitization and asthma. METHODS: A systematic review and meta-analysis was performed for relevant case-control or population-based studies, published in the peer-reviewed journals until February 2013. Data were extracted on study designs, subjects, definitions and the prevalence of Staphylococcal enterotoxin sensitization. RESULTS: A total of 683 studies were initially identified, of which 7 studies finally met the inclusion criteria (5 case-control and 2 population-based studies). All the included studies reported higher prevalence of the sensitization in asthmatics than in controls, despite clinical and methodological heterogeneity. In a meta-analysis, the pooled odds ratio of the sensitization for asthma was 2.95 (95% confidence intervals 2.28-3.82). CONCLUSION: Staphylococcal enterotoxin sensitization was significantly associated with asthma. The mechanisms of associations warrant further elucidation. PMID- 23667837 TI - Chronic cough in subjects with upper airway diseases - analysis of mechanisms and clinical applications. AB - Cough is the commonest respiratory symptom leading to a medical consultation. Although acute cough which is usually associated with respiratory viral infection is not a problem to manage, chronic cough is frequently a diagnostic and therapeutic challenge as it does not respond to usual treatments. Specific group of chronic coughers are considered to have upper airway diseases, lately categorized as having upper airway cough syndrome. There is an increasing pool of evidence that upper airway diseases have significant involvements in the regulation of cough reflex, indicating that they must be taken into considerations as major triggers of coughing in the patients. Here we summarize current literature and experiences on the pathogenesis of upper airway cough syndrome, and discuss further clinical applications. PMID- 23667838 TI - Acute eosinophilic pneumonia related to a mesalazine suppository. AB - It has been well known that mesalazine can cause the interstitial lung disease, such as Bronchiolitis obliterans with organizing pneumonia (BOOP), Non-Specific Interstitial Pneumonia (NSIP), or eosinophilic pneumonia. 5-Aminosalicylic acid (5-ASA), mesalazine, and sulfasalazine are important drugs for treating inflammatory bowel disease. Topical products of these limited systemic absorption and have less frequent side effects, therefore suppository form of these drugs have been used more than systemic drug. Most cases of measalzine-induced lung toxicity develop from systemic use of the drug. A 30-year-old woman had an interstitial lung disease after using mesalazine suppository because of ulcerative colitis. The lung biopsy demonstrated eosinophilic pneumonia combined with BOOP. She was recovered after stopping of mesalazine suppository and treatment with systemic steroid. PMID- 23667839 TI - Passive smoking could still represent a risk factor in Mexican children with asthma. PMID- 23667840 TI - Lack of association between passive smoking and asthma prevalence in Mexican children. PMID- 23667841 TI - N-ras mutation detection by pyrosequencing in adult patients with acute myeloid leukemia at a single institution. AB - BACKGROUND: N-ras mutations are one of the most commonly detected abnormalities of myeloid origin. N-ras mutations result in a constitutively active N-ras protein that induces uncontrolled cell proliferation and inhibits apoptosis. We analyzed N-ras mutations in adult patients with AML at a particular institution and compared pyrosequencing analysis with a direct sequencing method for the detection of N-ras mutations. METHODS: We analyzed 90 bone marrow samples from 83 AML patients. We detected N-ras mutations in codons 12, 13, and 61 using the pyrosequencing method and subsequently confirmed all data by direct sequencing. Using these methods, we screened the N-ras mutation quantitatively and determined the incidence and characteristic of N-ras mutation. RESULTS: The incidence of N ras mutation was 7.2% in adult AML patients. The patients with N-ras mutations showed significant higher hemoglobin levels (P=0.022) and an increased incidence of FLT3 mutations (P=0.003). We observed 3 cases with N-ras mutations in codon 12 (3.6%), 2 cases in codon 13 (2.4%), and 1 case in codon 61 (1.2%). All the mutations disappeared during chemotherapy. CONCLUSIONS: There is a low incidence (7.2%) of N-ras mutations in AML patients compared with other populations. Similar data is obtained by both pyrosequencing and direct sequencing. This study showed the correlation between the N-ras mutation and the therapeutic response. However, pyrosequencing provides quantitative data and is useful for monitoring therapeutic responses. PMID- 23667842 TI - In vitro fluconazole and voriconazole susceptibilities of Candida bloodstream isolates in Korea: use of the CLSI and EUCAST epidemiological cutoff values. AB - BACKGROUND: At present, the clinical breakpoints (CBPs) of both fluconazole and voriconazole are available only for 3 common Candida species in the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) methods. Epidemiological cutoff values (ECVs) were recently applied to both methods to detect the emergence of acquired resistance (i.e., non-wild-type isolates) among 5 common Candida species. METHODS: We performed a nationwide study to determine the fluconazole and voriconazole susceptibility of Candida bloodstream isolates (BSIs) using both the CLSI and EUCAST methods. A total of 423 BSIs of 5 Candida species were collected from 8 hospitals. The azole susceptibilities were assessed on the basis of the species-specific CBPs and ECVs. RESULTS: Of the 341 BSIs of 3 common Candida species (i.e., C. albicans, C. tropicalis, and C. parapsilosis), 0.3% and 0.9%, 0.0% and 1.5% of isolates were categorized as fluconazole and voriconazole resistant according to the CLSI and EUCAST CBPs, respectively. Of 423 total BSIs, 1.4% and 2.6% had fluconazole minimum inhibitory concentrations (MICs) exceeding the ECVs according to the CLSI and EUCAST, respectively; 1.0% and 2.1% had voriconazole MICs exceeding the ECVs according to the CLSI and EUCAST, respectively. Categorical agreement between the methods using ECVs was 98.3% for fluconazole and 98.3% for voriconazole. CONCLUSIONS: The EUCAST and CLSI methods using ECVs provide highly concordant results. Moreover, non-wild-type isolates with possibly acquired azole resistance were rare among the BSIs of 5 common Candida species in Korea. PMID- 23667843 TI - Flow cytometric human leukocyte antigen-B27 typing with stored samples for batch testing. AB - BACKGROUND: Flow cytometry (FC) HLA-B27 typing is still used extensively for the diagnosis of spondyloarthropathies. If patient blood samples are stored for a prolonged duration, this testing can be performed in a batch manner, and in-house cellular controls could easily be procured. In this study, we investigated various methods of storing patient blood samples. METHODS: WE COMPARED FOUR STORAGE METHODS: three methods of analyzing lymphocytes (whole blood stored at room temperature, frozen mononuclear cells, and frozen white blood cells [WBCs] after lysing red blood cells [RBCs]), and one method using frozen platelets (FPLT). We used three ratios associated with mean fluorescence intensities (MFI) for HLAB27 assignment: the B27 MFI ratio (sample/control) for HLA-B27 fluorescein 5-isothiocyanate (FITC); the B7 MFI ratio for HLA-B7 phycoerythrin (PE); and the ratio of these two ratios, B7/B27 ratio. RESULTS: Comparing the B27 MFI ratios of each storage method for the HLA-B27+ samples and the B7/B27 ratios for the HLA B7+ samples revealed that FPLT was the best of the four methods. FPLT had a sensitivity of 100% and a specificity of 99.3% for HLA-B27 assignment in DNA typed samples (N=164) when the two criteria, namely, B27 MFI ratio >4.0 and B7/B27 ratio <1.5, were used. CONCLUSIONS: The FPLT method was found to offer a simple, economical, and accurate method of FC HLA-B27 typing by using stored patient samples. If stored samples are used, this method has the potential to replace the standard FC typing method when used in combination with a complementary DNA-based method. PMID- 23667844 TI - Performance evaluation of the OraQuick hepatitis C virus rapid antibody test. AB - BACKGROUND: A reliable rapid assay for hepatitis C virus (HCV) may be helpful in various clinical settings. We evaluated the performance of the OraQuick HCV Rapid Antibody Test (OraSure Technologies Inc., Bethlehem, PA, USA). METHODS: Clinical sensitivity and specificity were evaluated with oral fluids and sera from 137 patients diagnosed with hepatitis C and 300 healthy blood donors in a multi center collaborative study. The stored sera of 200 proven HCV-infected patients and 200 healthy subjects were also evaluated. Analytical sensitivity was estimated with 4 commercial seroconversion panels and 7 Korean reference panels. The performance of 4 laboratory-based tests (3 chemiluminescence assays and 1 enzyme immunoassay) and 4 rapid test kits was compared. We also assessed the interference due to bilirubin, hemoglobin, lipid, rheumatoid factor, multipara, and several viral infections. RESULTS: The clinical sensitivity and specificity of the OraQuick HCV test using oral fluid were 97.8% (95% confidence interval [CI], 93.2-99.4%) and 100% (95% CI, 98.4-100%), respectively. The clinical sensitivity using serum samples was 100%. Using the 4 seroconversion panels, the OraQuick HCV test showed results comparable to those of the laboratory-based assays; its analytical sensitivity was higher than that of the other rapid test kits. There was no cross-reactivity with common interfering factors. CONCLUSIONS: The clinical performance of the OraQuick HCV Test is comparable to that of laboratory-based tests with both serum and oral fluid. This supports the supplementary use of rapid HCV testing using oral fluid in various medical and non-medical settings. PMID- 23667845 TI - Analysis of the stability of urea in dried blood spots collected and stored on filter paper. AB - The ability to use dry blood spots (DBSs) on filter paper for the analysis of urea levels could be an important diagnostic tool for areas that have limited access to laboratory facilities. We developed a method for the extraction and quantification of urea from DBSs that were stored on 3M Whatman filter paper and investigated the effect of long-term storage on the level of urea in DBSs. DBSs of 4.5 mm in diameter were used for our assay, and we determined the urea levels in blood using a commercially available enzymatic kit (UV GLDH-method; Randox laboratories Ltd., UK). The DBSs on filter discs were stored at 4C or at 37C for 120 days. The mean intra- and inter-assay coefficient of variance for our method of urea extraction from dried blood was 4.2% and 6.3%, respectively. We collected 75 fresh blood samples and compared the urea content of each fresh sample with the urea content of DBSs taken from corresponding fresh blood samples. Regression analysis reported a regression coefficient (r) value of 0.97 and a recovery of urea from dried spots was 102.2%. Urea concentrations in DBSs were stable for up to 120 and 90 days when stored at 4C and 37C, respectively. Our results show that urea can be stored and quantitatively recovered from small volumes of blood that was collected on filter paper. PMID- 23667846 TI - Modified CHROMagar Acinetobacter medium for direct detection of multidrug resistant Acinetobacter strains in nasal and rectal swab samples. AB - This study aimed to investigate whether CHROMagar Acinetobacter medium (CHROMagar, France) in combination with an antimicrobial supplement (modified CHROMagar Acinetobacter; CHROMagar, France) can be used for detecting and isolating multidrug-resistant Acinetobacter species (MRA) in nasal and rectal surveillance cultures. Nasal and rectal swab samples were collected from patients in an intensive care unit at a teaching hospital. The samples were used to inoculate modified CHROMagar Acinetobacter plates, which were examined after 24 and 48 hr of incubation at 37C. Their susceptibility against the antimicrobial agents meropenem, imipenem, ciprofloxacin, and amikacin was analyzed using the Etest (bioMerieux, France). A total of 406 paired samples (406 nasal swabs and 406 rectal swabs) were obtained from 226 patients, and 120 samples (28 nasal and 28 rectal cultures, 47 nasal cultures only, and 17 rectal cultures only) yielded MRA. Seventy-five MRA isolates (18.5%) were recovered from the 406 nasal samples, and 45 MRA isolates (11.1%) were recovered from the 406 rectal samples. Of the 120 MRA isolates, 3 (2.5%) were detected only after 48 hr of incubation. The use of modified CHROMagar Acinetobacter together with nasal and rectal swabs and 1 day incubation is an effective surveillance tool for detecting MRA colonization. PMID- 23667847 TI - A case of CD4(+)T-cell large granular lymphocytic leukemia. AB - We report here a case of a 59-yr-old man with CD4(+) T-cell large granular lymphocytic leukemia (T-LGL). Peripheral blood examination indicated leukocytosis (45*10(9) cells/L) that consisted of 34% neoplastic lymphoid cells. Other laboratory results indicated no specific abnormalities except for serum antinuclear antibody titer (1:640), glucose (1.39 g/L), and hemoglobin A1c (7.7%) levels. Computed tomography indicated multiple small enlarged lymph nodes (<1 cm in diameter) in both the axillary and inguinal areas, a cutaneous nodule (1.5 cm in diameter) in the left suboccipital area, and mild hepatosplenomegaly. Bone marrow examination revealed hypercellular marrow that consisted of 2.4% neoplastic lymphoid cells. The neoplastic lymphoid cells exhibited a medium size, irregularly shaped nuclei, a moderate amount of cytoplasm, and large granules in the cytoplasm. Immunohistochemical analysis indicated CD3(+), CD4(+), T-cell receptor betaF1(+), granzyme B(+), and TIA1(+). Flow cytometric analysis of the neoplastic lymphoid cells revealed CD3+, cytoplasmic CD3(+), CD4(+), and CD7(+). Cytogenetic analysis indicated an abnormal karyotype of 46,XY,inv(3)(p21q27),t(12;17)(q24.1;q21),del(13)(q14q22)[2]/46,XY[28]. The patient was diagnosed with CD4(+) T-LGL and received chemotherapy (10.0 mg methotrexate). This is the second case of CD4(+) T-LGL that has been reported in Korea. PMID- 23667848 TI - A case of Clostridium difficile bacteremia in a patient with loop ileostomy. AB - Clostridium difficile, an anaerobic, spore-forming, gram-positive, rod-shaped bacterium, is the most common nosocomial pathogen causing pseudomembranous colitis. C. difficile is not intrinsically invasive and rarely infects extraintestinal sites. The bacterium, therefore, is not commonly detected in blood cultures. Here, we report a case of C. difficile bacteremia in a patient who had underwent loop ileostomy because of rectal obstruction following metastatic colon cancer originated from prostate cancer. PMID- 23667850 TI - A case of IgM deficiency with B cell deficiency detected by ABO discrepancy in a patient with acute osteomyelitis. AB - ABO discrepancy refers to an inconsistency between red cell and serum typings and has various causes, including hypogammaglobulinemia. IgM deficiency is a rare disorder that may accompany several conditions such as infection and autoimmune disorders. Here, we describe a case of IgM deficiency discovered during the evaluation of an ABO discrepancy in a 16-yr-old Korean boy. ABO blood grouping showed that while his cell type was O+, serum typing detected only anti-A (3+). Anti-B was not detectable at room temperature but was graded at 1+ at 4C. ABO genotyping revealed an O/O genotype. His serum IgG, IgA, and IgM concentrations were 770 mg/dL (reference range: 800-1,700 mg/dL), 244 mg/dL (reference range: 100-490 mg/dL), and 13.5 mg/dL (reference range: 50-320 mg/dL), respectively. He was diagnosed with acute osteomyelitis on the basis of clinical presentation and imaging studies. The symptoms gradually improved within 3 weeks of treatment. However, the ABO discrepancy and IgM deficiency persisted even 6 months after recovery and lymphocyte subset analysis revealed CD19+ B cell deficiency. To the best of our knowledge, IgM deficiency detected by ABO discrepancy in a patient with acute osteomyelitis has not been reported before. PMID- 23667849 TI - The first Korean case of disseminated mycetoma caused by Nocardia pseudobrasiliensis in a patient on long-term corticosteroid therapy for the treatment of microscopic polyangiitis. AB - Nocardia pseudobrasiliensis is predominantly associated with invasive infections in immunocompromised patients. We report a case of disseminated mycetoma caused by N. pseudobrasiliensis in a 57-yr-old woman with microscopic polyangiitis, who was treated for 3 months with corticosteroids. The same organism was isolated from mycetoma cultures on the patient's scalp, right arm, and right leg. The phenotypic characteristics of the isolate were consistent with both Nocardia brasiliensis and N. pseudobrasiliensis, i.e., catalase and urease positivity, hydrolysis of esculin, gelatin, casein, hypoxanthine, and tyrosine, but no hydrolysis of xanthine. The isolate was identified as N. pseudobrasiliensis based on 16S rRNA and hsp65 gene sequencing. The patient was treated for 5 days with intravenous ampicillin/sulbactam, at which time both the mycetomas and fever had subsided and discharged on amoxicillin/clavulanate. This case highlights a very rare presentation of mainly cutaneous mycetoma caused by N. pseudobrasiliensis. This is the first reported case of N. pseudobrasiliensis infection in Korea. PMID- 23667851 TI - A case of late-onset Li-Fraumeni-like syndrome with unilateral breast cancer. AB - Li-Fraumeni syndrome (LFS) is a rare, inherited syndrome associated with increased risk of various early-onset tumors. Since the introduction of classic LFS criteria, various criteria have been proposed to include patients with incomplete LFS features, which make up Li-Fraumeni-like syndromes (LFL). Germline missense mutations of TP53 are the primary cause of LFS and LFL. Mutations mostly reside in the DNA-binding domain of the gene and have a dominant-negative effect (DNE) over alternate wild-type alleles. Germline TP53 mutation c.566C>T results in the missense mutation GCC (Ala) to GTC (Val) at codon 189 (A189V) and has been reported in a case of multiple primary colon tumors. Herein we report a second case of the same mutation in a breast cancer patient, who has familial history of late-onset malignancies. Due to the relatively late onset of malignancies, neither case fulfils previously defined criteria for the syndrome. Mutational analysis for breast tissue in this patient showed a loss of heterozygosity. These clinical features may suggest a relatively weak DNE of A189V compared to other TP53 mutations, and in silico predictions and in vitro findings of the function of A189V mutant protein are conflicting. Considering the increased risk of malignancies and the therapeutic implications for patients who have a TP53 mutation, care must be taken when treating those who are suspected of possessing cancer-prone traits due to TP53 mutation, especially when there is a family history of late-onset cancer with low penetrance. PMID- 23667852 TI - Identification of ATM mutations in Korean siblings with ataxia-telangiectasia. AB - Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder. It is characterized by early-onset, progressive cerebellar ataxia, oculomotor apraxia, choreoathetosis, conjunctival telangiectasias, immunodeficiency, and an increased risk of malignancy. Although A-T is known to be the most common cause of progressive cerebellar ataxia in childhood, there have been no confirmed cases in Korea. We report the clinical and genetic findings of Korean siblings who presented with limb and truncal ataxia, oculomotor apraxia, choreoathetosis, and telangiectasias of the eyes. Sequence analysis of the ataxia-telangiectasia mutated (ATM) gene revealed a known missense mutation (c.8546G>C; p.Arg2849Pro) and a novel intronic variant of intron 17 (c.2639-19_2639-7del13). Reverse-transcription PCR and sequencing analysis revealed that the c.2639-19_2639-7del13 variant causes a splicing aberration that potentiates skipping exon 18. Because A-T is quite rare in Korea, the diagnosis of A-T in Korean patients can be delayed. We recommend that a diagnosis of A-T should be suspected in Korean patients exhibiting the clinical features of A-T. PMID- 23667853 TI - A novel mutation (c.200T>C) in the NAGLU gene of a Korean patient with mucopolysaccharidosis IIIB. AB - Mucopolysaccharidosis (MPS) IIIB is a lysosomal storage disorder (LSD) caused by abnormalities of the enzyme alpha-N-acetylglucosaminidase (NAGLU) that is required for degradation of heparan sulfate. The patient in this study was a 4-yr old boy. He presented with normal height and weight, pectus carinatum, and multiple persistent Mongolian spots on his back. He had mild dysmorphic features with prominent speech developmental delays and, to a lesser extent, motor developmental delays. The cetylpyridinium chloride precipitation test revealed excessive mucopolysacchariduria (657.2 mg glycosaminoglycan/g creatinine; reference range, <175 mg glycosaminoglycan/g creatinine). Thin layer chromatography showed urinary heparan sulfate excretion. NAGLU enzyme activity was significantly decreased in leukocytes (not detected; reference range, 0.9 1.51 nmol/hr/mg protein) as well as in plasma (0.14 nmol/hr/mg protein; reference range, 22.3-60.9 nmol/hr/mg protein). PCR and direct sequencing analysis of the NAGLU gene showed that the patient was a compound heterozygote for 2 mutations: c.200T>C (p.L67P) and c.1444C>T (p.R482W). The c.200T>C mutation was a novel finding. This is the first report of a Korean patient with MPS IIIB who was confirmed by molecular genetic analyses and biochemical investigation. PMID- 23667854 TI - Plasma cell myeloma initially presenting as lung cancer. PMID- 23667855 TI - Two cases of myeloproliferative neoplasm with a concurrent JAK2 (V617F) mutation and BCR/ABL translocation without chronic myelogenous leukemia phenotype acquisition during hydroxyurea treatment. PMID- 23667856 TI - Analysis of Retinal Development and Diseases Using RNA-Seq. PMID- 23667858 TI - Functions of the hemodynamic response during hypercapnia. Functional MRI study. AB - Functional MRI was applied for studying the dynamics of brain hemodynamic response evoked by involuntary (visual) and voluntary (motor) excitations under condition of interdependent sensorimotor and visual paradigm (hand clenching in response to a light flash). Activation of the corresponding areas of the visual and sensorimotor cortex (Brodmann areas 18-4, respectively) was observed and quantitative data characterizing the response signal maximum delay were obtained. It was found that breath holding-induced hypercapnia disorders neuronal networks created during visual-motor stimulation. PMID- 23667859 TI - Peculiarities of amnesia development during memory reconsolidation impairment induced by isolated or combined treatment with neurotransmitter receptor antagonists. AB - The effects of serotonin and glutamate receptor antagonists on conditioned food aversion memory reconsolidation were studied in experiments on edible snails. Injections of NMDA and AMPA glutamate receptor antagonists to trained snails before the reminder were found to induce the development of "irreversible" amnesia: repeated training of these animals was not followed by memory formation. Administration of serotonin receptor antagonist before the reminder led to the development of "reversible" amnesia, repeated training was followed by memory formation. The combined administration of serotonin receptor antagonist with NMDA and AMPA receptor antagonists partially or completely abolished amnesia development. We hypothesized that both memory reconsolidation and amnesia induction require integration of specific patterns converging to neurons and involving certain types of neuro-transmitter receptors. PMID- 23667860 TI - Role of ryanodine receptors in the effects of hydrogen sulfide on transmitter release from the frog motor nerve ending. AB - We studied the role of ryanodine receptors in the effects of hydrogen sulfide on transmitter release from frog motor nerve ending. Sodium hydrosulfide (300 MUM), a donor of hydrogen sulfide, reversibly increased the frequency of miniature endplate current without changes in its amplitude-time parameters. These effects were associated with reversible increase in endplate current amplitude, which was abolished by activation of ryanodine receptors of intracellular Ca(2+)stores with caffeine (3 mM) and ryanodine (0.5 MUM). Under conditions of ryanodine receptors blockade with ryanodine (10 MUM), sodium hydrosulfide had no effect on induced transmitter release, but its effects remained unchanged during ryanodine receptors blockade with dantrolene (25 MUM). We concluded that an enhanced acetylcholine release induced by hydrogen sulfide is related to an increase of intracellular Ca(2+)concentration due to activation of ryanodine receptors for intracellular Ca(2+)-pool. PMID- 23667857 TI - Exercise Recommendations for Cancer-Related Fatigue, Cognitive Impairment, Sleep problems, Depression, Pain, Anxiety, and Physical Dysfunction: A Review. AB - Cancer and its treatments produce a myriad of burdensome side effects and significantly impair quality of life (QOL). Exercise reduces side effects and improves QOL for cancer patients during treatment and recovery. Exercise prior to, during, and after completion of cancer treatments provides numerous beneficial outcomes. Exercise represents an effective therapeutic intervention for preparing patients to successfully complete treatments, for reducing acute, chronic and late side effects, and for improving QOL during and after treatments. This overview of exercise oncology and side-effect management summarizes existing evidence-based exercise guidelines for cancer patients and survivors. PMID- 23667861 TI - Activity of succinate dehydrogenase in the neocortex and hippocampus of Mongolian gerbils with ischemic and reperfusion brain injury. AB - We analyzed changes in activity of SDH, one of the most important enzymes of the Krebs cycle, in the cytoplasm of hippocampal and cortical neurons of Mongolian gerbils (Meriones unguiculatus) at the early and delayed reperfusion period after global brain ischemia. The data indicate that SDH activity in pyramidal neurons of various hippocampal areas and in neurons of II, III and V layers of cerebral cortex after 7-min forebrain ischemia depends on both the localization of these neurons and duration of the postischemic reperfusion. SDH activity in neurons significantly increased on days 2 and 7 after reperfusion. PMID- 23667862 TI - Influence of space flight factors on the ultrastructure of rat diaphragm muscle. AB - Analysis of ultrastructural changes in diaphragm muscle and synaptic apparatus after 7- and 14-day biosatellite spaceflight showed destructive and atrophic changes that developed starting from in the early terms of exposure. Structural alterations of different severity were revealed in all elements of the muscle (muscle fibers, neuromuscular junctions, intramuscular nerves, and blood vessels) and were paralleled by activation of regeneration processes. PMID- 23667863 TI - Lymph flow and contractile activity of mesenteric lymph nodes in rats with toxic hepatitis effects of antioxidants. AB - We studied contractile function of isolated mesenteric lymph nodes in rats with toxic hepatitis. We observed suppression of spontaneous and stimulated contractile activity of mesenteric lymph nodes and changes in biochemical composition of the lymph. We propose a method of correction of these dysfunctions with antioxidant alpha-tocopherol and Selen-Active. PMID- 23667864 TI - Dynamics of lipid peroxidation-antioxidant defense system during alloxan diabetes in rats. AB - We studied the dynamics of lipid peroxidation-antioxidant defense system in rat model of alloxan diabetes and compared it with disorders of carbohydrate and lipid metabolism. It was found that rats not treated with insulin developed hyperglycemia, hypertriglyceridemia, hypocholesterolemia, and hypotocoferolemia with simultaneous accumulation of circulating LPO products 96 h after the administration of alloxan. The severity of hyperglycemia and hypertriglyceridemia decreased, hypercholesterolemia developed, hypotocoferolemia returned to normal, and the tendency to LPO inhibition was observed in rats 10 days after alloxan administration against the background of previous one-week treatment with insulin. In 17 days after the induction of alloxan diabetes preceded by two-week insulin therapy, the content of lipoperoxides reduced below the normal values with simultaneous progression of hypercholesterolemia, hypertriglyceridemia and the increase in serum fructosamine. PMID- 23667865 TI - Dynamics of neurotransmitters in the structures of the rat jejunum during chronic alcohol intoxication. AB - We studied the effects of ethanol on bioamine-containing structures in the jejunum at different stages of alcohol intoxication. The content of catecholamines, serotonin, and histamine in enterocytes of the villus epithelium, submucosa mast cells, crypt enterocytes, and muscular layer was measured by luminescent microscopy and cytospectrofluorometry. Uneven increase of biogenic amine content was found in rats in the initial period of chronic alcohol intoxication (60 days). Further alcohol intake (up to 180 days) impaired the balance of biogenic amines; catecholamines started to prevail. PMID- 23667866 TI - Activity of matrix metalloproteinases during antimycobacterial therapy in mice with simulated tuberculous inflammation. AB - Matrix metalloproteinases are shown to be involved in the pathogenesis of tuberculosis inflammation. In the early stages of BCG-granuloma formation in mouse liver and lungs, the serum levels of matrix metalloproteinases 2 and 7 increased by 4.5 times and remained unchanged while the pathology developed. Antimycobacterial therapy with isoniazid reduced enzyme activity almost to the level of intact control. The decrease in activity of matrix metalloproteinases 2 and 7 that play the most prominent role in the development of destructive forms of tuberculosis is of great therapeutic importance. PMID- 23667867 TI - The study of the proteome of healthy human blood plasma under conditions of long term confinement in an isolation chamber. AB - We identified changes in the proteome of healthy human blood plasma caused by exposure to 105-day confinement in an isolation chamber. After removal of major proteins and concentration of minor proteins, plasma fractions were analyzed by two-dimensional electrophoresis followed by identification of significantly different protein spots by mass spectrometric analysis of the peptide fragments. The levels of alpha- and beta-chains of fibrinogen, a fragment of complement factor C4, apolipoproteins AI and E, plasminogen factor C1 complement, and immunoglobulin M changed in participants during the isolation period. These changes probably reflect the adaptive response to altered conditions of life. PMID- 23667868 TI - Effects of selective inhibitors of neuronal and inducible NO-synthase on ATP content and survival of cultured rat cerebellar neurons during hyperstimulation of glutamate receptors. AB - We studied the effects of selective inhibitors of neuronal and inducible NO synthase (7-nitroindazole and aminoguanidine) and non-selective NO-synthase inhibitor L-NAME on ATP content and survival of cultured rat cerebellar neurons during hyperstimulation of glutamate receptors with toxic doses of glutamate. Application of 100 MUM glutamate reduced ATP content in the primary culture of 7 8- and 14-15-day-old cerebellar granule cells by 66 and 49%, respectively, in comparison with the control. Inhibition of nitric oxide synthesis with 7 nitroindazole during glutamate exposure in the culture of 7-8-day-old neurons and with 7-nitroindazole and aminoguanidine in the culture of 14-15-day-old neurons ensured better protection of cells from ATP level decrease than non-specific inhibition with L-NAME. In addition, inhibition of neuronal and inducible NO synthase during glutamate exposure decreased death of "young" neurons, whereas death of "old" neurons remained high under these conditions. PMID- 23667869 TI - Alpha-tocopherol prevents ERK1/2 activation in PC12 cells under conditions of oxidative stress and its contribution to the protective effect. AB - Preincubation with 100 nM and 100 MUM alpha-tocopherol for 18 h prevented long term activation of extracellular signal-activated kinase (ERK1/2), induced by H2O2in PC12 cells. alpha-Tocopherol significantly reduced H2O2-induced death of PC12 cell, but its protective effect was significantly lower in the presence of ERK1/2 inhibitor. These data show that prevention of long-term activation of ERK1/2 by alpha-tocopherol contributes to the increase in viability of PC12 cells exposed to H2O2. This fact suggests that inhibition of ERK1/2 activity by alpha tocopherol reduces neuronal cell death in the brain under conditions of oxidative stress in vivo. PMID- 23667870 TI - Autoantibodies to neuron-specific proteins S100, GFAP, MBP and NGF in the serum of rats with streptozotocin-induced diabetes. AB - The appearance of autoantibodies to neuronal proteins (S100, GFAP, MBP, and NGF) in rat serum was analyzed by ELISA on days 5, 10, 17, 25, and 32 after streptozotocin injection. Simultaneously, blood glucose and insulin autoantibodies were assayed. Serum glucose level increased on the next day after streptozotocin injection and the level of autoantibodies to insulin significantly increased on day 5 indicating the development of diabetes. The levels of antibodies to specific neuronal proteins (S100, GFAP, MBP, and NGF) also increased at this term. It is concluded that diabetes with streptozotocin is associated with damage to the blood-brain barrier. PMID- 23667871 TI - Effect of IKK-2 inhibitor on local Th1 and Th2 type inflammation. AB - We studied the capacity of IKK-2 inhibitor ([5-(p-fluorophenyl)-2-ureido] thiophene-3-carboxamide) and non-steroidal anti-inflammatory drug voltaren to reduce the severity of local inflammation in Th1- and Th2-type immune response. The test substances (inhibitor in concentrations from 2*10(-13)to 2*10(-16)M and 9.8*10(-4)M voltaren) were shown to reduce edema caused by sheep erythrocytes (Th1-type immune response) and local immediate-type hypersensitivity response (Th2-type immune response). The anti-inflammatory effects of IKK-2 inhibitor in Th1-type immune response were similar to those of voltaren. PMID- 23667872 TI - Cerebroprotective effects of emoxipin, reamberin, and mexidol in alloxan diabetes. AB - The effects of original Russian preparations, derivatives of 3-hydroxypyridine and succinic acid (emoxipin, reamberin, mexidol), on the cellular composition of the cerebrocortical and diencephalic structures were studied and correlations of shifts in the cellular composition with changes in the severity of hyperglycemia in rats with alloxan diabetes were analyzed. The efficiency of 3-hydroxypyridine and succinic acid derivatives was evaluated in comparison with alpha-lipoic acid. Seven injections of the optimal doses of all the studied drugs prevented the neuron loss in layers I-III of the primary somatosensory cortex. In addition, emoxipin, reamberin, and alpha-lipoic acid prevented astrocyte loss in the neocortical surface layers and of neurons in the hypothalamic paraventricular nucleus. Reamberin limited microglial infiltration of the hippocampal field CA1. Injection of alpha-lipoic acid augmented the increase in astrocyte count in the paraventricular nucleus and potentiated the reduction of tigroid granularity of CA1 field neurons. Emoxipin and mexidol caused an increase in the counts of neurons and oligodendrocytes in CA1 field. By contrast, reamberin and alpha lipoic acid reduced the counts of neurons and oligodendrocytes, respectively, in this hippocampal zone. More favorable effects of emoxipin and mexidol vs. reamberin and alpha-lipoic acid on the cellular composition of the hippocampus of rats with alloxan diabetes were explained by more effective correction of hyperglycemia under the effect of 3-hydroxypyridine derivatives. PMID- 23667873 TI - Effect of dihydroquercetin on the tone of isolated rat veins. AB - Dihydroquercetin effects on the tone of isolated segments of the portal vein of rats were studied. Dihydroquercetin did not modify the basal venous tone, but reduced the amplitude of contractions induced by KCl and norepinephrine hydrotartrate. PMID- 23667874 TI - Comparative evaluation of the efficiency of prostatotropic agents of natural origin in experimental benign prostatic hyperplasia. AB - Comparative evaluation of the efficiency of prostatotropic agents was carried out in rat experiments. Serenoa repens plant preparation and polypeptides isolated from the cattle prostate were used for the treatment of benign hyperplasia. Drugs in parallel with sulpiride similarly led to shrinkage of the acinar epithelial area and to emergence of a trend to an increase of the stromal/epithelial proportion, more so after Serenoa repens treatment. PMID- 23667875 TI - Enthalpy of chemical substances as a criterion of their hygienic standardization. AB - The data on toxicity estimation and hygienic regulation for chemical substances are presented. Toxicological studies were performed under conditions of acute experiment. We established the relationship between enthalpy and toxicity of chemical substances. A correlation between thermodynamic properties and toxicity parameters of chemical substances was found. The obtained data were used for evaluation of toxicity and hygienic standardization of chemical substances. PMID- 23667876 TI - Effects of neuroprotector cortexin on the dynamics of neuroendocrine system parameters in patients with organic emotionally labile (asthenic) disorders. AB - Addition of neuroprotector Cortexin to standard drug therapy of patients with organic emotionally labile (asthenic) disorders had a great influence on the neuroendocrine system and neurosteroid content: normalization of blood concentration of cortisol, dehydroepiandrosterone sulphate, and thyroid hormones was observed. Clinical improvement was associated with the recovery of organism homeostatic systems. PMID- 23667877 TI - Clastogenic and anticlastogenic activity of glucocorticoid hormones hydrocortisone and its synthetic analogs prednisolone and dexamethasone. AB - Clastogenic and anticlastogenic activity of glucocorticoid hormones hydrocortisone, prednisolone, and dexamethasone was studied by counting chromosome aberrations in Crepis capillaris test system. Hydrocortisone in a concentration of 12.5 mg/ml produced a clastogenic effect and increased the number of chromosome aberrations in comparison with spontaneous level. Hydrocortisone (6.25 and 3.13 mg/ml), prednisolone (15, 7.5, and 3.75 mg/ml), and dexamethasone (1, 0.5, 0.25, and 0.125 mg/ml) exhibited an anticlastogenic effect and reduced ethyl methanesulfonate-induced mutagenesis. PMID- 23667878 TI - Effects of polymorphisms of NOS3 and GNB3 genes on skin microvascular reactivity in normal pregnancy. AB - We studied the relationship between endothelial NO-synthase gene (NOS3) and G protein beta3 subunit gene (GNB3) polymorphisms and reactivity of skin microvessels during physiological gestation. T-786C NOS3 polymorphism influenced the maximum blood flow rate in skin microvessels and the severity of postocclusive reactive hyperemia during the third trimester of pregnancy. The relationship between G894T NOS3 polymorphism and the duration of postocclusive reactive hyperemia was revealed. C825T GNB3 polymorphism affects the duration and severity of postocclusive reactive hyperemia during the first and third trimesters of pregnancy. Thus, NOS3 and GNB3 polymorphisms affect blood flow in the skin microvessels during physiological gestation. PMID- 23667879 TI - Detection and genotyping of Helicobacter pylori gene vacA in children with gastroduodenal diseases and in adults with gastric cancer in Vladivostok. AB - Geographical distribution of individual genotypes of Helicobacter pylori, predominance of virulent types in various regions of Russia, particularly in the Prymorye Territory, remains unclear. We examined 115 children with various gastroduodenal pathology and 33 patients with gastric cancer, of which 57.39 and 60% respectively were infected with H. pylori. All samples positive for H. pylori were further analyzed for gene vacA mosaicism. In all clinical subgroups, variants s1 and m1 predominated; the frequency of genotype s1 was significantly increased (1.3-fold) in the group of cancer patients in comparison with the group of children with gastroduodenal pathology. Three variants of allele combination of signaling and middle regions of the vacA gene (s1m1, s1m2, and s2m2) were revealed; s1m1 was the most frequent in both groups. We suggest that this genotype is a marker of complicated course of gastroduodenitis and a factor of gastric cancer development in local population. PMID- 23667880 TI - Spontaneous platelet aggregation in patients with acute coronary syndrome. AB - Spontaneous platelet aggregation was evaluated in patients with acute coronary syndrome on days 1, 3-5, and 8-12 of the disease. On day 1, aggregation was analyzed after aspirin, but before clopidogrel administration; during other periods after both antiaggregants. The mean levels of spontaneous aggregation after antithrombotic therapy did not change during different periods after the onset of acute coronary syndrome, in contrast to ADP-induced aggregation that decreased after the development of clopidogrel effects (days 3-5 and 8-12). Spontaneous aggregation during different periods directly correlated (r>0.4, p<0.01) with spontaneous and ADP-induced aggregation during different periods (r=0.372, r=0.447, and r=0.543 on days 1, 3-5, and 8-12, respectively; p<0.01). No relationship between spontaneous aggregation and plasma concentration of von Willebrand's factor was detected. Spontaneous aggregation was completely suppressed after in vitro addition of prostaglandin E1 (platelet activation inhibitor), slightly (by ~20%) decreased in the presence of antibodies to glycoprotein Ib, blocking its reactions with von Willebrand's factor, and did not change in the presence of aptamer inhibiting thrombin activity. PMID- 23667881 TI - Coordination of the stomatognathic and postural system activities and their functional status. AB - Analysis of correlations of the functional parameters of the stomatognathic and postural systems with sub-, decompensated, and compensated status was carried out. Disorders in the masticatory muscle activity and interactions between the postural and stomatognathic systems were detected in patients with sub- and decompensated functional status. A significant correlation between the studied functional parameters was detected in the patients with the compensated functional status. PMID- 23667882 TI - Structure and function of immunocompetent organs in broilers. AB - Treatment of broilers by mainite and shatrashanite natural zeolites led to establishment and development of the morphophysiological status of the thymus, bursa of Fabricius, and spleen. PMID- 23667883 TI - Vibration-induced pulmonary disease: transformation of the bronchial mucosal epithelium and endothelium. AB - Long-term vibration exposure of humans leads to development of manifest atrophy and structural mosaicism of the bronchial epithelium in the mucosa of the large bronchi (diffuse degeneration of multilamellar cylindrical epithelium, focal hyperplasia, and squamous cell metaplasia). The mucosal subepithelial stroma is characterized by sclerosis, hypoelastosis, and reduction of microvessels. Radioautography confirms the reduction of protein-producing activity of bronchial epitheliocytes and endotheliocytes. PMID- 23667884 TI - Contribution of maternal chronic experimental hepatic disease to the development of nonspecific cell resistance in the progeny. AB - Morphofunctional pecularities of the bone marrow neutrophil maturation were studied in the progeny of female rats with chronic experimental toxic hepatitis, similar to hepatitis B by morphological, biochemical, and physiological characteristics. The lysosomal, phagocytic, and killing activities of cells were reduced during the morphologically identifiable stages of neutrophilopoiesis (myeloblasts, promyelocytes, myelocytes, metamyelocytes, stab and segmented neutrophils). PMID- 23667885 TI - Effects of placental tissue secretory products on the formation of vascular tubules by EA.Hy926 endothelial cells. AB - The formation of vascular tubules by EA.Hy926 endothelial cells was studied in the presence of placental secretory products from women with normal gestation at early and late periods and with gestosis. The factors secreted by placental tissues at the early stages of placental development stimulated the branching angiogenesis, while the products of the end of pregnancy stimulated nonbranching angiogenesis. In gestosis the placental tissue secreted products stimulating even more intense nonbranching angiogenesis, which manifested by a lesser number of branchings of vascular tubes formed by EA.Hy926 endothelial cells. PMID- 23667886 TI - 3beta-hydroxysteroid dehydrogenase in the brain ependymocytes. AB - We studied activity of 3beta-hydroxysteroid dehydrogenase in rat brain ependymocytes. Enzyme activity was found in the cytoplasm of cells lining the villi in the vascular plexuses in the lateral ventricles and cells lining the ventricles. These data suggest that ependymocyte can synthesize neurosteroids. PMID- 23667887 TI - The morphology of the microcirculatory bed in burn shock and its correction with perfluorothane infusion. AB - The use of perflurothane for correction of burn shock is justified, because it effectively normalizes the microcirculatory bed values and protects the ischemic tissues. PMID- 23667888 TI - Measurement of plasma hemoglobin peroxidase activity. AB - We described a spectrophotometric method for measuring hemoglobin peroxidase activity in human plasma using o-dianisidine (o-DA) as the substrate and myeloperoxidase specific inhibitor 4-aminobensoic acid hydrazide (ruling out the probable contribution of myeloperoxidase to the measured parameter value). The optimal conditions (pH 5.5; 2 mM H2O2) have been determined, at which hemoglobin makes the main contribution to plasma oxidation of o-DA. A significant positive correlation between hemoglobin peroxidase activity measured by the spectrophotometric method and hemoglobin level measured by the pyridine hemochromogenic method has been detected (r=0.624; p<0.01) in plasma specimens from 16 donors. Plasma hemoglobin peroxidase activities were measured in healthy individuals and patients with type 2 diabetes mellitus and coronary heart disease. High plasma hemoglobin peroxidase activities in both groups of patients indicates disorders in the mechanisms of clearance of hemoglobin and its highly reactive derivatives and can serve as specific markers of diseases associated with oxidative stress. PMID- 23667889 TI - Characteristics of induced human pluripotent stem cells using DNA microarray technology. AB - We performed transcriptome analysis of some human induced pluripotent stem cells, embryonic stem cells, and human somatic cells using DNA microarrays. PluriTest bioinformatic system was used for evaluation of cell pluripotency. Changes in the genome structure and status of X-chromosome gene expression was analyzed using microarray technology. PMID- 23667890 TI - Age-related differences in rat multipotent mesenchymal stromal bone marrow cells. AB - We studied multipotent mesenchymal stromal cells isolated from the bone marrow of young (1 month) and old (>12 months) rats. The cell cultures derived from old rats were characterized by lower cell yield in the primary culture, lower number of doublings, and reduced colony-forming capacity of precursor cells. PMID- 23667891 TI - Effect of intracerebral transplantation of mesenchymal stem cells on pial microcirculation in rats. AB - We studied the effect of intracerebral transplantation of bone marrow mesenchymal stem cells on microcirculation (density of microvascular network and reactivity of arterioles) in the pia mater of 2-3-month-old rats. It was found that after transplantation of mesenchymal stem cells, the density of pial microcirculatory network in the contralateral hemisphere significantly increased (by 1.7 times; p<0.05) in comparison with both intact animals and controls. The number of arterioles in the studied area increased most markedly (by ~2.5 times; p<0.05) in comparison with other groups. Intracerebral transplantation of mesenchymal stem cells or conditioned culture medium (alpha-MEM) had no effect on reactivity of pial arterioles. PMID- 23667892 TI - Effect of calcium phosphate materials on multipotent mesenchymal cells from exfoliated deciduous teeth (SHED cells) in vitro. AB - Various calcium phosphate ceramic materials were created and their effect on cultured mesenchymal cells from exfoliated deciduous tooth pulp was evaluated. Tricalcium phosphate ceramics provides best cell survival and is an optimal material for bone tissue engineering. Analysis of the effects of tricalcium phosphate ceramics on osteogenic differentiation of SHED cells suggests that this material potentiated dexamethasone-induced osteogenic differentiation, which manifested in the increased number of ossification foci and enhanced extracellular matrix production by cells. Thus, the tricalcium phosphate ceramics created by us is a promising biomedical material that can be used for tissue engineered bone analogs. PMID- 23667893 TI - Induction of osteogenic differentiation of multipotent mesenchymal stromal cells from human adipose tissue. AB - We studied of osteogenic differentiation of multipotent mesenchymal stromal cells from human adipose tissue. Experiments showed that 1alpha,25-dihydroxycalciferol is a more effective inductor of osteogenesis than dexamethasone. Comparative analysis revealed activation of gene expression for the major osteogenic markers on day 7 of culturing in a medium containing 1alpha,25-dihydroxycalciferol. It was found that transcription of genes encoding type 1 collagen proteins, osteopontin, osteocalcin, and bone sialoprotein peaked on day 14 in culture, while the expression of alkaline phosphatase and bone morphogenetic protein-2 genes increased over 21 days. Intensive mineralization of the extracellular matrix was observed starting from day 14 in culture. On the basis of the analysis of these data, optimal terms for osteogenic induction (day 14) and an optimal inductor (1alpha,25-dihydroxycalciferol) were chosen and the protocol of effective osteogenic differentiation of multipotent mesenchymal stromal cells from human adipose tissue was developed for creation of tissue-engineered bone equivalents. PMID- 23667894 TI - Effect of type 1 herpes simplex infection of phenotypic peculiarities of human vascular endothelial cells in culture. AB - We studied the effect of type 1 herpes simplex infection on the production of innate immunity mediators in human vascular endothelial cells in culture. It was found that production of anti-inflammatory cytokines IL-1beta, IL.6, and TNF alpha in infected cultures depended on the level of their spontaneous production, while IL-8 production was suppressed irrespective of its spontaneous level. Shedding of cell adhesion molecules of early (P-selectin and E-selectin) and late (PECAM-1 and VE-cadherin) phases of leukocyte recruitment depended on individual capacity of human vascular endothelial cell cultures to maintain reproduction of type 1 herpes simples virus. The production of vasodilator NO and vasoconstrictor endothelin-1 by infected cultures also depended on spontaneous synthesis of this transmitter by non-infected cultures. PMID- 23667895 TI - Effect of hydrocortisone on multipotent human mesenchymal stromal cells. AB - We studied the effect of natural glucocorticosteroid hydrocortisone on total cell production, cloning efficiency, and expression of genes important for the function of mesenchymal stromal cells. Addition of hydrocortisone to the culture medium reduces the total cell yield by 2 times and significantly increased cloning efficiency by 2-3 times; this effect was more pronounced in multipotent mesenchymal stromal cells obtained from female donors. Hydrocortisone had no effect on the expression of immunomodulatory factors produced by multipotent mesenchymal stromal cells. Hydrocortisone inhibits the expression of bone differentiation markers, increases the expression of the early adipocyte differentiation marker at the beginning of culturing, and dramatically stimulates the expression of the late adipocyte differentiation marker throughout the culturing period. The findings suggest that hydrocortisone activates multipotent mesenchymal stromal cells. PMID- 23667896 TI - Modern principles of classification and development of nutrient media for culturing of human and animal cells. AB - Analysis of the main principles of classification and development of nutrient media used for culturing of human and animal cells in biology and medicine is presented. The key moments of induction and regulation of mitogenic cascades and their differences in cells of continuous lines, diploid cells, and primary cultures are discussed. Some variants of classification of nutrient media for various cell culture types are described. Peculiarities of composition and the prospects of using serum-free media are discussed. Practical results obtained by the authors in the development of diverse purpose nutrient media are presented. PMID- 23667897 TI - Peptidegic regulation of differentiation of embryonic retinal cells. AB - We studied Molecular mechanisms of the retinoprotective effect of short peptides AEDG and KE. The peptides stimulate differentiation of neurons and retinal pigment epithelium cells and therefore can be considered as potential retinoprotective preparations for the treatment of age-related degenerative changes in the retina. PMID- 23667898 TI - Highlight: 29 th Winter School on Proteinases and Their Inhibitors. PMID- 23667899 TI - Genetic polymorphisms in the human tissue kallikrein (KLK) locus and their implication in various malignant and non-malignant diseases. AB - The Kallikrein ( KLK ) gene locus encodes a family of serine proteases and is the largest contiguous cluster of protease-encoding genes attributed an evolutionary age of 330 million years. The KLK locus has been implicated asa high susceptibility risk loci in numerous cancer studies through the last decade. The KLK3 gene already has established clinical relevance as a biomarker in prostate cancer prognosis through its encoded protein, prostate-specific antigen. Data mined through genome-wide association studies (GWAS) and next-generation sequencing point to many important candidate single nucleotide polymorphisms(SNPs) in KLK3 and other KLK genes. SNPs in the KLK locus have been found to be associated with several diseases including cancer, hypertension, cardiovascular disease and atopic dermatitis. Moreover, introducing a model incorporating SNPs to improve the efficiency of prostate-specific antigen in detecting malignant states of prostate cancer has been recently suggested. Establishing the functional relevance of these newly-discovered SNPs, and their interactions with each other, through in silico investigations followed by experimental validation,can accelerate the discovery of diagnostic and prognostic biomarkers. In this review, we discuss the various genetic association studies on the KLK loci identified either through candidate gene association studies or at the GWAS and post-GWAS front to aid researchers in streamlining their search for the most significant, relevant and therapeutically promising candidate KLK gene and/or SNP for future investigations. PMID- 23667901 TI - Cysteine cathepsins are not critical for TRAIL- and CD95-induced apoptosis in several human cancer cell lines. AB - The potential role of cysteine cathepsins in tumor necrosis factor-related apoptosis-inducing ligand(TRAIL/Apo2L)- and CD95 (Fas/APO-1)-induced apoptosis was investigated using four different cell lines (HeLa, HuH-7, Jurkat, and U 937). All four cell lines exhibited different levels of cathepsins and responded differently to apoptosis triggering, with Jurkat cells being the most sensitive and the only ones that were sensitive to the agonistic anti-APO-1 antibody. Apoptosis was accompanied by caspase activation, loss of the mitochondria and lysosome integrity, and the release of cysteine cathepsins into the cytosol, as judged based on the hydrolysis of the cysteine cathepsin substrate benzyloxycarbonyl-Phe-Arg-7-amino-4-methylcoumarin and by the immunological detection of cathepsin B. The inhibition of caspases by the broad-spectrum inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone prevented apoptosis,including the mitochondrial and lysosomal membrane permeabilization, as well as cathepsin release into the cytosol, consistent with caspases playing a crucial role in the process. Conversely, however, although the broad-spectrum cysteine cathepsin inhibitor (2 S ,3 S )-trans -epoxysuccinyl-leucyl amido-3 methyl-butane ethyl ester and the more cathepsin B-selective inhibitor[(2 S ,3 S )-3-propylcarbamoyloxirane-2-carbonyl]-l-isoleucyl-l-proline methyl ester completely blocked cathepsin activity, these inhibitors neither prevented apoptosis including the mitochondrial and lysosomal membrane permeabilization, as well as cathepsin release into the cytosol, consistent with caspases playing a crucial role in the process. Conversely, however, although the broad-spectrum cysteine cathepsin inhibitor (2 S ,3 S )-trans -epoxysuccinyl-leucylamido-3 methyl-butane ethyl ester and the more cathepsin B-selective inhibitor[(2 S ,3 S )-3-propylcarbamoyloxirane-2-carbonyl]-l-isoleucyl-l-proline methyl ester completely blocked cathepsin activity, these inhibitors neither prevented apoptosis and its progression nor the mitochondrial and lysosomal membrane permeabilization associated with this type of cell death. Consequently, cathepsin release into the cytosol was also not prevented. Together, these data indicate that cysteine cathepsins are not required for the TRAIL- and CD95-mediated apoptosis in various human cancer cell lines. This does not, however, rule out that lysosomes and cysteine cathepsins are involved in the amplification, but not in the initiation, of death receptor-mediated apoptosis in certain cell lines or under different stimulation conditions than the ones employed here. PMID- 23667900 TI - Three-dimensional cultures modeling premalignant progression of human breast epithelial cells: role of cysteine cathepsins. AB - The expression of the cysteine protease cathepsin B is increased in early stages of human breast cancer.To assess the potential role of cathepsin B in premalignant progression of breast epithelial cells, we employed a 3D reconstituted basement membrane overlay culture model of MCF10A human breast epithelial cells and isogenic variants that replicate the in vivo phenotypes of hyper plasia(MCF10AneoT) and atypical hyperplasia (MCF10AT1). MCF10A cells developed into polarized acinar structures with central lumens. In contrast, MCF10AneoT and MCF10AT1 cells form larger structures in which the lumens are filled with cells. CA074Me, a cell-permeable inhibitor selective for the cysteine cathepsins B and L,reduced proliferation and increased apoptosis of MCF10A, MCF10AneoT and MCF10AT1 cells in 3D culture. We detected active cysteine cathepsins in the isogenic MCF10 variants in 3D culture with GB111, a cell permeable activity based probe, and established differential inhibition of cathepsin B in our 3D cultures. We conclude that cathepsin B promotes proliferation and premalignant progression of breast epithelial cells. These findings are consistent with studies by others showing that deletion of cathepsin B in the transgenic MMTV-PyMT mice, a murine model that is predisposed to development of mammary cancer, reduces malignant progression. PMID- 23667902 TI - Overexpression of the urokinase receptor splice variant uPAR-del4/5 in breast cancer cells affects cell adhesion and invasion in a dose-dependent manner and modulates transcription of tumor-associated genes. AB - mRNA levels of the urokinase receptor splice variant uPAR-del4/5 are associated with prognosis in breast cancer. Its overexpression in cancer cells affects tumor biologically relevant processes. In the present study, individual breast cancer cell clones displaying low vs. high uPAR-del4/5 expression were analyzed demonstrating that uPAR-del4/5 leads to reduced cell adhesion and invasion in a dose-dependent manner. Additionally,matrix metalloproteinase-9 (MMP-9) was found to be strongly upregulated in uPAR-del4/5 overexpressing compared to vector control cells. uPAR-del4/5 may thus play an important role in the regulation of the extracellular proteolytic network and, by this, influence the metastatic potential of breast cancer cells. PMID- 23667903 TI - Cell surface engineering of renal cell carcinoma with glycosylphosphatidylinositol-anchored TIMP-1 blocks TGF- beta 1 activation and reduces regulatory ID gene expression. AB - Tissue inhibitor of metalloproteinase 1 (TIMP-1) controls matrix metalloproteinase activity through 1:1stoichiometric binding. Human TIMP-1 fused to a glycosylphosphatidylinositol(GPI) anchor (TIMP-1 - GPI) shifts the activity of TIMP-1 from the extracellular matrix to the cell surface. TIMP-1 - GPI treated renal cell carcinoma cells show increased apoptosis and reduced proliferation.Transcriptomic profiling and regulatory pathway mapping were used to identify the potential mechanisms driving these effects. Significant changes in the DNA binding inhibitors, TGF- beta 1/SMAD and BMP pathways resulted from TIMP-1 - GPI treatment. These events were linked to reduced TGF- beta 1 signaling mediated by inhibition of proteolytic processing of latent TGF- beta 1 by TIMP-1 GPI. PMID- 23667905 TI - CLIPPER: an add-on to the Trans-Proteomic Pipeline for the automated analysis of TAILS N-terminomics data. AB - Data analysis in proteomics is complex and with the extra challenges involved in the interpretation of data from N-terminomics experiments, this can be daunting.Therefore, we have devised a rational pipeline of steps to approach N terminomics data analysis in a statistically based and valid manner. We have automated these steps in CLIPPER, an add-on to the Trans-Proteomic Pipeline(TPP). Applying CLIPPER to the analysis of N- terminomics data generated by terminal amine isotopic labeling of substrates (TAILS) enables high confidence peptide to protein assignment, protein N-terminal characterization and annotation, and for protease analysis readily allows protease substrate discovery with high confidence. PMID- 23667904 TI - Gingipain aminopeptidase activities in Porphyromonas gingivalis. AB - Bestatin, a specific inhibitor of metalloaminopeptidases,inhibits the growth of Porphyromonas gingivalis. To identify its target enzyme, a library of fluorescent substrates was used but no metalloaminopeptidase activity was found. The aminopeptidase activity of P. gingivalis was bestatin-insensitive and directed exclusively toward N-terminal arginine and lysine substrates. Class-specific inhibitors and gingipain-null mutants showed that gingipains were the only enzymes responsible for this activity.The kinetic constants obtained for Rgps were comparable to those of human aminopeptidases but Kgp aminopeptidase activity was weaker. This finding reveals a new role for gingipains as aminopeptidases in the degradation of proteins and peptides in P. gingivalis. PMID- 23667906 TI - A conformational switch is responsible for the reversal of the 6S RNA-dependent RNA polymerase inhibition in Escherichia coli. AB - 6S RNA is a bacterial transcriptional regulator,which accumulates during stationary phase and inhibits transcription from many promoters due to stable association with sigma 70 -containing RNA polymerase. This inhibitory RNA polymerase ~ 6S RNA complex dissociates during nutritional upshift, when cells undergo outgrowth from stationary phase, releasing active RNA polymerase ready for transcription. The release reaction depends on a characteristic property of 6S RNAs, namely to act as template for the de novo synthesis of small RNAs, termed pRNAs.Here, we used limited hydrolysis with structure-specific RNases and in-line probing of isolated 6S RNA and 6SRNA ~ pRNA complexes to investigate the molecular details leading to the release reaction. Our results indicate that pRNA transcription induces the refolding of the 6S RNA secondary structure by disrupting part of the closing stem(conserved sequence regions CRI and CRIV) and formation of a new hairpin (conserved sequence regions CRIII and CRIV). Comparison of the dimethylsulfate modification pattern of 6S RNA in living cells at stationary growth and during outgrowth confirmed the conformational change observed in vitro. Based on our results, a model describing the individual steps of the release reaction is presented. PMID- 23667907 TI - Molecular determinants of human dipeptidyl peptidase III sensitivity to thiol modifying reagents. AB - Human dipeptidyl peptidase III (DPP III) is a member of the metallopeptidase family M49, involved in protein metabolism and oxidative stress response. DPPIII crystal structure shows the two lobe-like domains separated by a wide cleft. The human enzyme has a total of six cysteines, three in the lower (Cys19, Cys147,and Cys176) and three in the upper (Cys509, Cys519,and Cys654), catalytic, domain containing the active site zinc ion. To elucidate the molecular basis of this enzyme ' s susceptibility to sulfhydryl reagents, biochemical analysis of a set of Cys to Ala mutants was used, supported by mass spectrometry. Cys176, a residue 44 A apart from the catalytic center of the ligand-free enzyme, was found responsible for the inactivation with the submicromolar concentration of an organomercurial compound, and three additional cysteines contributed to sensitivity to aromatic disulfides. Upon treatment with oxidized glutathione [glutathione disulfide(GSSG)], cysteine residues at positions 147, 176, and 654 were found glutathionylated. The mutational analysis confirmed the involvement of Cys176 and Cys654 inhuman DPP III inactivation by GSSG. Observation that Cys176, a residue quite distant from the active center,contributes to enzyme inactivation, indicates that the substrate-binding site of human DPP III comprises both lower and upper protein domain. PMID- 23667908 TI - Characterization of angiotensin I-converting enzyme N-domain selectivity using positional-scanning combinatorial libraries of fluorescence resonance energy transfer peptides. AB - Somatic angiotensin I-converting enzyme (ACE)has two homologous active sites (N and C domains) that show differences in various biochemical properties.In a previous study, we described the use of positionals canning synthetic combinatorial (PS-SC) libraries of fluorescence resonance energy transfer (FRET) peptides to define the ACE C-domain versus N-domain substrate specificity and developed selective substrates for the C-domain(Bersanetti et al., 2004). In the present work, we used the results from the PS-SC libraries to define the N-domain preferences and designed selective substrates for this domain. The peptide Abz GDDVAK(Dnp)-OH presented the most favorable residues for N-domain selectivity in the P 3 to P 1 ' positions. The fluorogenic analog Abz-DVAK(Dnp)-OH (Abz = ortho aminobenzoic acid; Dnp = 2,4-dinitrophenyl)showed the highest selectivity for ACE N-domain( k cat /K m = 1.76 MU m -1 . s -1) . Systematic reduction of the peptide length resulted in a tripeptide that was preferentially hydrolyzed by the C domain. The binding of Abz-DVAK(Dnp)-OH to the active site of ACE N-domain was examined using a combination of conformational analysis and molecular docking. Our results indicated that the binding energies for the N-domain-substrate complexes were lower than those for the C-domain-substrate, suggesting that the former complexes are more stable. PMID- 23667909 TI - Mast cells limit extracellular levels of IL-13 via a serglycin proteoglycan serine protease axis. AB - Mast cell (MC) granules contain large amounts of proteases of the chymase, tryptase and carboxypeptidase A (MC-CPA) type that are stored in complex with serglycin,a proteoglycan with heparin side chains. Hence, serglycinprotease complexes are released upon MC degranulation and may influence local inflammation. Here we explored the possibility that a serglycin-protease axis may regulate levels of IL-13, a cytokine involved in allergic asthma. Indeed, we found that wild-type MCs efficiently degraded exogenous or endogenously produced IL-13 upon degranulation,whereas serglycin -/- MCs completely lacked this ability.Moreover, MC-mediated IL-13 degradation was blocked both by a serine protease inhibitor and by a heparin antagonist,which suggests that IL-13 degradation is catalyzed by serglycin-dependent serine proteases and that optimal IL-13 degradation is dependent on both the serglycin and the protease component of the serglycin-protease complex.Moreover, IL-13 degradation was abrogated in MC CPA -/-MC cultures, but was normal in cultures of MCs with an inactivating mutation of MC-CPA, which suggests that the IL-13-degrading serine proteases rely on MC-CPA protein.Together, our data implicate a serglycin-serine protease axis in the regulation of extracellular levels of IL-13. Reduction of IL-13 levels through this mechanism possibly can provide a protective function in the context of allergic inflammation. PMID- 23667910 TI - Filum terminale. PMID- 23667911 TI - Cribriform neuroepithelial tumor or atypical teratoid/rhabdoid tumor? PMID- 23667912 TI - Supraventricular arrhythmias in patients with cardiac sarcoidosis prevalence, predictors, and clinical implications. AB - BACKGROUND: Cardiac sarcoidosis (CS) is known to be associated with congestive heart failure, conduction disorders, and tachyarrhythmias. Ventricular arrhythmias are the most feared cardiac manifestation because they often are unpredictable, may be the fi rst manifestation of the disease, and may be fatal. The propensity for the development of supraventricular arrhythmias (SVAs) in patients with CS has not been described. The aim of this study was to assess the prevalence as well as the predictors of SVA. METHODS: We retrospectively investigated 100 patients with biopsy specimen-proven systemic sarcoidosis and evidence of cardiac involvement (defi ned by cardiac biopsy specimen, PET scan, or cardiac MRI). The mean follow-up was 5.8 3.6 years. ECG, Holter monitoring, implantable cardioverter defibrillator interrogations, or electrophysiology studies were used to document SVA. Echocardiographic data, demographics, and extracardiac involvement were recorded, and univariate and Poisson regressions were performed to compare characteristics of patients with and without documented SVA. RESULTS: The prevalence of SVA was 32%, and atrial fibrillation was the most common arrhythmia, comprising 18% of the total burden, followed by atrial tachycardias (7%), atrial fl utter (5%), and other supraventricular tachycardias (2%). Of the patients with SVA, 96% were symptomatic. Left atrial enlargement (LAE) was more frequent in the group with SVA, with an incidence of 267.8 per 1,000 person-years, and it significantly increased the likelihood of SVA on multivariate analysis (risk ratio, 6.12; 95% CI, 2.19-17.11). Diastolic dysfunction, systemic hypertension, and right atrial enlargement were predictors of SVA on univariate analysis. Left ventricular hypertrophy, right ventricular dysfunction, tricuspid valve disease, pulmonary hypertension, and pulmonary sarcoidosis were not associated with SVA on univariate analysis. CONCLUSIONS: The study systematically evaluated the frequency of SVA in a large number of patients with CS. SVA in patients with CS is frequent and associated with symptoms. LAE was clearly associated with the development of SVA in this patient population. The extent to which LAE predicts the occurrence of SVA in larger, more diverse CS populations should be evaluated prospectively. PMID- 23667913 TI - Author response. PMID- 23667914 TI - Author response. PMID- 23667915 TI - [Neuroimmune mechanisms in the development of post -stroke depression]. PMID- 23667916 TI - [The role of magnesium in neuroprotection and neuroplasticity]. PMID- 23667917 TI - [The necessity of the revision of a family of words of the Alphabet Index with the tribal name meningitis in the ICD-11]. PMID- 23667918 TI - [The research and practical conference "Actual issues of psychiatric care: diagnosis, rehabilitation, forms of social support, Moscow Oct 25, 2012]. PMID- 23667919 TI - [International Congresses on later Amyotrophic sclerosis]. PMID- 23667920 TI - Reply: cadmium-zinc-telluride SPECT in very morbidly obese patients routinely provides high-diagnostic-quality myocardial perfusion imaging. PMID- 23667921 TI - Dr. de Rotte, et al reply. PMID- 23667922 TI - Response. PMID- 23667923 TI - Response. PMID- 23667924 TI - Response. PMID- 23667925 TI - Response. PMID- 23667926 TI - Response. PMID- 23667927 TI - Reply to Suderman et al.: Importance of accounting for blood cell composition in epigenetic studies. PMID- 23667928 TI - Deformity surgery. Response. PMID- 23667929 TI - Critical illness polyneuropathy/critical illness myopathy and acute motor-sensory axonal neuropathy. Response. PMID- 23667930 TI - Accessory articulation. Response. PMID- 23667931 TI - Curve progression. Response. PMID- 23667932 TI - Author's response. PMID- 23667933 TI - Author's response. PMID- 23667934 TI - Author's response. PMID- 23667936 TI - From the archives. PMID- 23667935 TI - Author's response. PMID- 23667937 TI - Bibliography. Genitourinary system. Current world literature. PMID- 23667938 TI - Bibliography. Innovative early clinical trials methodology and new therapeutics in cancer. Current world literature. PMID- 23667939 TI - Variations in four genes may lead to an increase in colorectal cancer. PMID- 23667940 TI - New research provides hope for personalized treatment of asthma. PMID- 23667941 TI - Melanoma resistance gene identified. PMID- 23667942 TI - Identification of chemosensitive pancreatic cancer with gene profiling. PMID- 23667943 TI - Lactate dehydrogenase B: new metabolic marker in carcinogenesis. PMID- 23667944 TI - Evaluating lymphatic biomarkers in primary cutaneous melanomas. PMID- 23667945 TI - Elevated cyclin B2 expression in invasive breast carcinoma is associated with unfavorable clinical outcome. PMID- 23667946 TI - TGF-beta upregulates miR-181a expression to promote breast cancer metastasis. PMID- 23667947 TI - Focus on value-based purchasing to help your hospital succeed. AB - Case managers are in a position to help their hospitals score well and not lose reimbursement as the Centers for Medicare & Medicaid Services shifts from paying hospitals for quantity and moves toward basing reimbursement on quality. Be aware of the metrics included in value-based purchasing, analyze your metrics, and make improvements. Make the case for technology to help case managers analyze all the data needed to identify areas for improvement. Keep in mind that CMS is adding new components every year and that the measurement period starts long before the payment year. PMID- 23667948 TI - Patient-centered care helps hospital succeed. PMID- 23667949 TI - Care coordination cuts admissions, ED visits, LOS. AB - Gundersen Health in La Crosse, WI, has decreased the length of stay by 46% and unplanned admissions or emergency department visits by 64% through an integrated care coordination program that focuses on the most complex patients. Care coordinators who are nurses or social workers follow at-risk patients through the continuum, interacting with them face-to-face in the clinic or hospital and following up by telephone. Patients are identified for the program using a two pronged tool that assesses both healthcare and psycho-social needs. Care coordinators follow the patients for as long as a year. PMID- 23667950 TI - Hospital's proactive approach to RAs pays off. AB - Alamance Regional Medical Center in Burlington, NC, appeals all Recovery Auditor denials, up to administrative law judge level, and works to avoid denials by carefully scrutinizing admissions for medical necessity. The utilization review department reviews all admissions for medical necessity, regardless of where they come in to the hospital. Care coordinators staff the emergency department seven days a week and work with physicians on medical necessity and patient status. Computer software tracks every record request and denial and appeals quickly. PMID- 23667951 TI - Take advantage of opportunities to reduce ED violence, recidivism among children and young adults. AB - There is evidence that ED-based interventions can make a difference in short circuiting the cycle of violence that often impacts children and young adults. Since the Violence Intervention Advocacy Program was launched at Boston Medical Center in 2006, recidivism to the ED among gunshot victims is down by 30% and recidivism among stabbing victims is down by about one-half. At Denver Health Medical Center, the At Risk Intervention and Monitoring (AIM) project just launched in June, but thus far, none of the patients being followed in the program have reappeared in the ED with a violent injury. The U.S. Centers for Disease Control and Prevention reports that 700,000 people between the ages of 10 and 24 were treated in EDs for injuries caused by violence in 2009. To effectively intervene with victims of violence, experts recommend that EDs partner with community groups that have deep ties to the neighborhoods most impacted by violence. To avoid re-traumatizing victims of violence, health care personnel need to be trained in how to provide"trauma-informed care," a method of speaking to patients so that they feel empowered and safe. With young victims of violence, the biggest issues requiring attention are mental health, safety, and housing. PMID- 23667952 TI - Use split-flow approach to speed patients to needed care, eliminate inefficiencies and duplication. AB - To address time and space challenges in the midst of surging demand, the ED at St. Mary Medical Center in Langhorne, PA, turned to the split-flow model, an evidence-based practice that relies heavily on the queuing theory to improve patient throughput. In less than one year, the approach has enabled administrators to reduce door-to-physician times from an average of 47 minutes to 23.5 minutes, and overall length-of-stay in the ED for discharged patients has been slashed by 21 minutes. Under the split-flow system implemented at St. Mary, an expedited triage/assessment process directs patients to prompt care, pediatric care, acute care, or an expedited treatment area (ETA) where patients will undergo further testing or procedures. This initial assessment typically takes about three minutes. Patients sent to the ETA remain there for no longer than 30 minutes.They may then be moved to a holding area while awaiting test results. Patients are constantly moving in the split-flow model, so it is important to pay close attention to handoffs. Patients will begin the process with one nurse and finish with another. PMID- 23667953 TI - For success with frequent ED utilizers, take steps to understand patient needs, connect them with appropriate resources. AB - Through its newly created Consistent Care Program, St. Luke's Hospital in Cedar Rapids, IA, has been able to significantly reduce ED utilization among patients who have been identified as having used the ED at least 12 times in the past year. Patients who meet program criteria are automatically identified once per month. A committee of social workers, nurses, and providers then creates care plans for these individuals, so that when they present to the ED, emergency providers will have a consistent road map to follow. In one year, the program has reduced the number ED visits among frequent utilizers by one-third, saving the hospital close to $1 million. Of the original 103 patients who were first identified for the program in January of 2012, only 10 patients still meet the criteria of visiting the ED 12 times in 12 months. Administrators say that key elements of the program are case manager who can interact with the patients and their providers, a mechanism for flagging these patients when they present to the ED, and engaged providers. PMID- 23667954 TI - Computational optical sensing and imaging: introduction to feature issue. AB - The 2012 Computational Optical Sensing and Imaging (COSI) conference of the Optical Society of America was one of six colocated meetings composing the Imaging and Applied Optics Congress held in Monterey, California, 24-28 June. COSI, together with the Imaging Systems and Applications, Optical Sensors, Applied Industrial Optics, and Optical Remote Sensing of the Environment conferences, brought together a diverse group of scientists and engineers sharing a common interest in measuring and processing of information carried by optical fields. This special feature includes several papers based on presentations given at the 2012 COSI conference as well as independent contributions, which together highlight several important trends. PMID- 23667955 TI - The plasma small dense LDL-cholesterol calculation formula proposed by Srisawasdi et al is not applicable to Koreans who are healthy or have metabolic syndrome. PMID- 23667956 TI - APTT reagents for different coagulation tests: one size does not fit all. PMID- 23667957 TI - Comments on homeopathy resolution. PMID- 23667958 TI - Opposition to reducing preveterinary education requirements. PMID- 23667959 TI - Importance of reducing pain during routine procedures. PMID- 23667960 TI - Buying organic. PMID- 23667961 TI - Veterinary workforce concerns. PMID- 23667962 TI - In memoriam: Clinton Hartmann. PMID- 23667963 TI - We can work it out. PMID- 23667964 TI - The rebound effect. PMID- 23667966 TI - [Letter of retraction]. PMID- 23667965 TI - Adverse drug reactions. PMID- 23667967 TI - [The bureaucratic jungle of off-list and off-label patients]. PMID- 23667968 TI - [Sulfonamide allergy and cross-reactivity]. AB - Beside beta-lactams, sulfonamide antibiotics are among the most common causes of drug allergy. Hypersensitivity to sulfonamides including IgE-mediated immediate, delayed cell-mediated mechanisms, and severe life-threatening reactions are still incompletely understood. Unfounded concerns of cross-reactivity between sulfonamide antibiotics and a variety of non-antibiotic-containing sulfonamide drugs render pharmacotherapy unnecessarily difficult. Here, the history, clinical manifestations, diagnosis and treatment of sulfonamide allergy are briefly reviewed. PMID- 23667969 TI - [Severe delayed drug hypersensitivity reactions]. AB - Although most delayed drug hypersensitivity reactions are mild and show rapid improvement after drug discontinuation, there are severe systemic and/or cutaneous drug reactions which may be life-threatening. These entities are discussed here, namely DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms), acute generalized exanthematous pustulosis (AGEP), Stevens Johnson syndrome and toxic epidermal necrolysis (TEN). Early detection of warning signs and symptoms may help to take appropriate measures precociously. PMID- 23667970 TI - [Allergy to radiographic contrast media]. AB - Allergy to radiographic contrast media Hypersensitivity reactions to radio contrast media are common in the daily practice. These products are responsible for immediate (< or = 1 hour after administration) and non immediate (> 1 hour after administration) hypersensitivity reactions. A diagnostic work-up by an allergologist with skin tests and in some cases provocation tests is of value in reducing the risk of recurrent hypersensitivity reactions to iodinated contrast media. A careful selection of the patients is required because the incidence of breakthrough reactions is still concerning, even with proper premedication. Practical recommendations are presented in this article. For gadolinium-based contrast agents, data in the literature is not sufficient for suggesting guidelines. PMID- 23667971 TI - [Peripheral blood eosinophilia: diagnostic value and further assessment]. AB - Although not specific, an increased in peripheral blood eosinophils may contribute substantially to the diagnosis of numerous infectious, allergic and inflammatory diseases. The scope of this article is to detail pathologies associated with peripheral eosinophilia by order of frequency and to guide further investigations. PMID- 23667972 TI - [Allergic asthma in adults: diagnosis and clinical management]. AB - Asthma is one of the most common chronic diseases in Switzerland. Its prevalence is between 7% and 10% in Western countries and almost half of all asthma patients are sensitized to one or more allergens. It is important to identify this particular group of allergic patients in order to be able to propose a targeted treatment. Due to recent scientific advances, allergologists have gained novel tests to precisely diagnose sensitizations to allergens as well as new treatment options beside allergen avoidance, bronchodilators, topical steroids and desensitization. Here, we summarize the current diagnostic and treatment guidelines for the general practitioner. PMID- 23667973 TI - [Autoimmune hepatitis]. AB - Autoimmune hepatitis is a systemic disease, difficult to diagnose due the high variability of the clinical presentation and some non specific histological features. The recent identification of additional autoantibodies used as serological markers, as well as simplified diagnostic criteria should help the primary care physician to advance with the diagnostic process. These progresses are crucial as undiagnosed and therefore untreated autoimmune hepatitis has a poor prognosis, whereas immunosuppressive therapy leads to remission in a majority of cases. PMID- 23667974 TI - [Consensus 2012--diagnosis and treatment of patients with dementia in Switzerland]. AB - The 2012 Swiss consensus paper on diagnosis and management of patients suffering from dementia resulted from the work of an expert panel who met on March 23d to 25th in Luzem. Based on a literature review, panel members wrote a first draft that was subsequently circulated among multiple dementia experts in Switzerland. After adaptation and revisions according to comments, all consulted dementia specialists and panel members fully endorse the consensus content. The conference was financed by the Swiss Alzheimer Forum. PMID- 23667975 TI - [Practical problems with ECG in elderly. Case No. 22]. PMID- 23667976 TI - [Labyrinth]. PMID- 23667977 TI - [The age-linked dependence can be prevented (1)]. PMID- 23667978 TI - [Domperidone, diclofenac: the time has come for drug alerts]. PMID- 23667980 TI - [Why so many physicians in Geneva?]. PMID- 23667981 TI - [Trend in proteomics analysis of phosphorylation and glycosylation]. PMID- 23667982 TI - [Applications of multi-micro-volume pressure-assisted derivatization reaction device for analysis of polar heterocyclic aromatic amines by gas chromatography mass spectrometry]. AB - A multi-micro-volume pressure-assisted derivatization reaction device has been designed and made for the silylation derivatization of polar heterocyclic aromatic amines by N-(tert-butyldimethylsilyl )-N-methyl-trifluoroacetamide (MTBSTFA) with 1% catalyst tert-butyldimethylchlorosilane (TBDMCS) at a high temperature. The tert-butyldimethylsilyl derivatives then could be automatically analyzed by gas chromatography-mass spectrometry. Using the pressure-assisted device, the silylation reaction may occur at a temperature higher than the boiling points of the reagents, and several micro-volume samples can be simultaneously pretreated in the same device to shorten the sample-preparation time and to improve the repeatability. The derivatization conditions including the headspace volume of the vial, the evaporative surface area of the reagent, derivatization temperature and time have been discussed for the use of the pressure-assisted device. The experimental results proved that the device is an effective way for the simultaneous derivatization of several micro-volume samples at a high temperature. Compared with a common device, the derivative amounts were obviously increased when using the pressure-assisted device at 90 degrees C. Quantitative derivatization can be achieved even at 150 degrees C while there was no common device could be applied at such a high temperature due to the heavy losses of reagents by evaporation. However, no obviously higher reaction speed has been observed in such a circumstance with a higher temperature and a higher pressure using the pressure-assisted device. PMID- 23667983 TI - [Application of molecularly imprinted polymer particles in capillary electrochromatography]. AB - Molecularly imprinted polymer (MIP) particles prepared by molecular imprinting technique (MIT) possess the ability of specific identification and selective affinity towards template molecules and their structural analogues. They also have a large specific surface area and rapid mass transfer kinetics, thus they have been widely used as stationary phases in liquid chromatography and matrixes in solid phase extraction. Using MIP particles as capillary electrochromatography (CEC) stationary phase, which combines the high speed and efficiency of CEC with the high affinity and selectivity of MIP, has become one of the most promising separation technique in analytical science. There are several different strategies of MIP particles applied in CEC: as packing materials packed into a capillary column; as entrapping materials entrapped into different matrix frameworks inside a capillary column; as pseudostationary phases (PSPs) added into the running buffer of CEC. This review focuses on the recent developments of MIP particles in CEC and prospects the future developments in this field. PMID- 23667984 TI - [Simultaneous determination of 18 pharmaceuticals and personal care products in surface water by ultra-high performance liquid chromatography-tandem mass spectrometry]. AB - An analytical method has been developed and validated for the simultaneous determination of 18 pharmaceuticals and personal care products (PPCPs), including antibiotics (trimethoprim, erythromycin x 2H2O, norfloxacin, ofloxacin, pencilline G, penicillin V potassium salt, cephalexin and sulfamethoxazole), beta bloker (atenolol), anophelifuge (N, N-diethyl-3-methylbenzoylamide, DEET), antiepileptics (carbamazepine), central nervous system stimulant (caffeine), lipid modifying agent (clofibric acid), non-steroidal anti-inflammatory drugs (ibuprofen, naproxen and diclofenac sodium salt) and antimicrobial agents (triclosan and triclocarban). The detection and qualification of the target compounds were performed by ultra-high performance liquid chromatography-tandem mass spectrometry. The optimized mobile phases were methanol as organic phase, 0. 3% (v/v) formic acid-5 mmol/L ammonium acetate for positive electrospray ionization (ESI+) and 5 mmol/L ammonium acetate for ESI- as inorganic phase. Water samples were concentrated by solid phase extraction at 2 mL/min, and all the target PPCPs were efficiently extracted at pH 7. The extracted PPCPs were eluted by the mixture of methanol and acetonitrile (1 : 1, v/v). The average recoveries of the target compounds in the spiked pure water samples ranged from 53.9% - 112%. The average recoveries of the target compounds ranged from 45.1% - 156.6% with the relative standard deviations ranged from 2.4% - 15.7%, in the surface water samples spiked at 100 ng/L. The surface water samples collected from Yu Hangtang River in Hangzhou were detected. The results showed that nine PPCPs were detected including caffeine that reached a maximum concentration of 550.7 ng/L. It proved that this analytical method is reliable and acceptable. PMID- 23667985 TI - [Determination of four kinds of illegal additive residues in sprouts and source beans by high performance liquid chromatography-tandem mass spectrometry]. AB - A reversed-phase high performance liquid chromatography coupled with tandem mass spectrometric (LC-MS/MS) method was developed for the determination of 4 chlorophenoxyacetic acid, 6-benzylaminopurine, enrofloxacin and norfloxacin residues in sprouts and source beans. The sample was extracted by acetonitrile containing 0.1% acetic acid and concentrated. The chromatographic analysis was carried out on a C18 column with methanol and 0.1% formic acid solution as the mobile phases in gradient elution program. The MS analysis was set in electrospray ionization mode and separated to two segments of positive and negative modes. The precursor ions were m/z 189.9, 226.1, 359.9 and 320.1, while the product ions for quantification were m/z 127.0, 91.2, 315.9 and 276.2 for 4 chlorophenoxyacetic acid, 6-benzylaminopurine, enrofloxacin and norfloxacin, respectively. The calibration curves showed good linearity in the range of 5 - 200 microg/L with correlation coefficients more than 0.995. The limits of detection (LODs) were 1 microg/kg and the limits of quantification (LOQs) were 5 microg/kg for the four compounds spiked in mung bean sprouts and mung beans. The recoveries of the four compounds spiked at three levels of 5.0, 10.0 and 20.0 microg/kg ranged from 70% to 91%, with the relative standard deviations (RSDs) less than 14%. The method established is accurate, sensitive, simple, and has considerable advantages in the analysis of the four kinds of illegal additive residues in sprouts and beans simultaneously. PMID- 23667986 TI - [Determination of inabenfide residue in food by high performance liquid chromatography-tandem mass spectrometry]. AB - A high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/ MS) method was established for the determination of inabenfide in fruits, vegetables, tea, honey, cereals and animal-derived foods. The food samples were extracted with acetonitrile, then purified by dispersion solid phase extraction using primary secondary amine (PSA) and C18 as solid phase. The residue was determined and confirmed by HPLC-MS/MS and quantified by external standard method. The mass spectrometric detection was operated with electrospray in positive ionization mode and inabenfide was identified in multiple reaction monitoring (MRM) mode. The interference of matrix was reduced by the matrix-matched calibration standard curves. The linear range of the method was 1 - 100 microg/kg, with the correlation coefficients (r2) of 0.998 - 0.999. The recoveries of inabenfide spiked in food samples were 85.2% - 112.4% at the spiked levels of 5, 10, 50 microg/kg. The relative standard deviations (RSDs) were less than 8.5%. The limits of detection (LODs) were 0.08 - 1.64 microg/kg, and the limits of quantification (LOQs) were 0.30 - 5.48 microg/kg. The results showed that the proposed method is sensitive and accurate for the determination of inabenfide in foodstuffs. PMID- 23667987 TI - [Determination of acetyl coenzyme A in grape berries by high performance liquid chromatography-tandem mass spectrometry]. AB - A high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/ MS) method was developed for the determination of acetyl coenzyme A in grape berries using n-propionyl coenzyme A as an internal standard (IS). The sample was extracted with water and then centrifuged for 5 min at 10 000 r/min on a centrifuge at 4 degrees C, and cleaned-up with a C18 solid phase extraction cartridge. The identification and quantification were carried out by using electrospray ionization in positive ion mode (ESI +) with multiple reaction monitoring (MRM). The total run time was 1 min and the elution of both acetyl coenzyme A and n-propionyl coenzyme A occurred at about 0.45 min. This was achieved with a mobile phase consisting of 5 mmol/L ammonium formate-acetonitrile (20: 80, v/v) at a flow rate of 0.4 mL/min on a C18 column. A linear response function was established for the concentration range of 1 - 2 000 microg/L for acetyl coenzyme A and the correlation coefficient was more than 0.99. The limit of detection of acetyl coenzyme A was 0.1 microg/L. The spiked recoveries at 50, 500, 1 000 microg/L ranged from 82.87% - 89.67% with the relative standard deviations less than 10%. This method is simple, rapid, sensitive and can significantly reduce the loss of acetyl coenzyme A during the experiment. It is suitable for the determination of acetyl coenzyme A in grape berries. PMID- 23667988 TI - [Rapid analysis of 28 primary aromatic amines in aqueous food simulants by high performance liquid chromatography-tandem mass spectrometry]. AB - A novel method for rapid analysis of the migration amounts of 28 primary aromatic amines (PAAs) in aqueous food simulants (10% ethanol, 30 g/L acetic acid and 20% ethanol aqueous solution) was developed using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). After the migration test, the soaking solution was cooled down from 100 degrees C, vortexed, filtered through a hydrophilic polytetrafluoroethylene filter with a disposable syringe, and then the filtrate was analyzed by HPLC-MS/MS. A Zorbax SB-Phenyl column (250 mm x 4.6 mm, 5 microm) was selected for chromatography. The mobile phase consisted of water and 0.1% formic acid-25% acetonitrile-methanol solution with gradient elution. The 28 PAAs in aqueous food simulants were detected by tandem mass spectrometer operated in positive electrospray ionization (ESI+) and multiple reaction monitoring (MRM) mode. The limits of quantification for the 28 PAAs were between 0.002 microg/L and 10 microg/L. The linearity of the method was good with correlation coefficients (r2) greater than 0.995 over the concentration range from 5 microg/L or 10 microg/L to 100 microg/L. The average recoveries of the 28 PAAs were between 76.6% and 114% with the relative standard deviations between 1.53% and 8.97% at the levels of 10, 20, and 40 microg/L. The method shows rapid pretreatment, the lower limits of quantification, good recoveries and accuracies, and meets the requirement of European Union (EU) No 10/2011 regulation for the specific migration of PAAs. The method has been applied to analyze the 28 PAAs in different aqueous food simulants from the migration test of 30 batches of food contact material samples exported to EU. PMID- 23667989 TI - [Determination of migration of 25 primary aromatic amines from food contact plastic materials by gas chromatography-mass spectrometry]. AB - A solid phase extraction (SPE) combination with gas chromatography-mass spectrometry (GC-MS) was developed for the determination of the migration of 25 primary aromatic amines (PAAs) from food contact plastic materials and articles. The samples were extracted by deionized water and 30 g/L acetic acid, and the pH value of the solution was adjusted to 8 - 10 with ammonia. The extracts were cleaned up and concentrated on an SPE column, then eluted by equal volume of methyl-tert-butyl ether and ethanol. The analysis of the target compounds was performed by GC-MS. The results indicated that the limits of detection were in the range of 0.4 -2.0 microg/kg for different PAAs. The recoveries and relative standard deviations (n = 7) of 10 microg/kg PAAs ranged from 51.6% -118.4% and 0.5% -9.8%, respectively, except the 2,4-diaminoanisole in the acid simulant. The effects of different experimental conditions such as the pH value and volume ratio of methyl-tert-butyl ether and ethanol were studied. The results showed that the method is accurate and stable, and could meet the requirement of the European Commission Regulation (EU) No 10/2011 for the determination of primary aromatic amines. It can be applied in the analysis of the primary aromatic amines in real food contact plastic material and article samples. PMID- 23667990 TI - [Simultaneous determination of neutral sugars and uronic acid constituents in a novel bacterial polysaccharide using gas chromatography-mass spectrometry]. AB - The purified novel bacterial polysaccharide was acid-hydrolyzed, followed by the subsequent derivatization using ethanethiol-trifluoroacetic acid and acetic anhydride-pyridine systems sequentially. Our findings differ from the previous reports in that the glucuronic acid was obtained through effective derivatization. The neutral sugars and glucuronic acid were analyzed using gas chromatography-mass spectrometry (GC-MS) with xyloses as an internal standard. The polysaccharide was found to be composed of fucose, glucose, glucuronic acid and galactose, with the relative molar ratio of 1.50: 1.0: 0.79: 2.06. The neutral sugars ratio was similar to the relative molar ratio for fucose, glucose and galactose of 1.76: 1.0: 1.98 through alditol acetates determined by GC. The percentages of glucuronic acid analyzed using either the carbazole and sulfuric acid method or the above method were 16.19% and 14.85%, respectively. These results indicate that it is practicable to use the derivatization method and GC MS to quantitatively analyze neutral sugars and glucuronic acid simultaneously in polysaccharide. For GC-MS analysis, the procedure was developed for the simultaneous determination of the derivatives in 25 min, and was performed using an HP-5MS column. Molecular ion peaks were observed in the electron ionization (EI) mass spectra. The fragmentation mechanism for glucuronic acid derivative is discussed in detail. PMID- 23667991 TI - [Application of capillary zone electrophoresis in the interaction analysis of protein C with protein C activator from Agkistrodon acutus venom]. AB - A new capillary zone electrophoresis method (CZE) has been established for the interaction analysis of protein C (PC) with a protein C activator (PCA) from Agkistrodon acutus venom. The analysis was performed on an uncoated fused-silica capillary with 75 microm i.d. and a total length of 60.2 cm (50 cm to the detector) with a buffer solution of 50 mmol/L Tris-HCl (pH 7.4) and 198 nm of wavelength. The factors which influence the separation of the PCA, such as buffer solution and ion concentration, and the interaction between the PCA and PC incubated for different times at 37.5 degrees C were studied. The linear range was from 10 to 300 mg/L. The limit of detection was 3 mg/L (S/N = 3). The relative standard deviation (RSD) for the migration time of the PCA was 0.56%. The RSD for the peak area was 3.8% (n = 6). The equal volumes of the PCA (200 mg/L) and PC (60 mg/L) were incubated for five minutes, at which their binding rate reached the maximum. And no hydrolyzed peptide chain from PC was found in the electropherogram. The PCA from Agkistrodon acutus venom could activate PC directly through changing the space conformation of PC. The method is simple, and highly sensitive with high resolution, and will provide important theoretical basis for the rapid detection of venom proteins and their activities in the future. PMID- 23667992 TI - [Simultaneous determination of o-phthalaldehyde, p-chloro-m-xylenol and triclosan in compound chemical disinfectants and daily chemicals by micellar electrokinetic chromatography]. AB - A novel method for the separation and determination of o-phthalaldehyde (OPA), p chloro-m-xylenol (PCMX) and triclosan in daily chemicals and compound chemical disinfectants in a single run by micellar electrokinetic chromatography (MEKC) was established. The factors such as the buffer concentration and pH, the concentration of sodium dodecyl sulfate (SDS), and the sample buffer, were investigated in detail. The analysis was carried out using a 50 microm uncoated capillary of 40.2 cm in total length (effective length: 30 cm). The running buffer was 20 mmol/L Na2B4O7, and 80 mmol/L SDS. The sample buffer was 2 mmol/L Na2B4O7-8 mmol/L SDS (without pH adjustment) containing 10% (v/v) methanol. The detection wavelength was 214 nm. The relative standard deviations (RSDs) of the corrected peak areas of the three components were in the range of 1.1% - 3.8%, and the RSDs of migration times were less than 0.9%. The limits of detection (LODs, S/N = 3) were 4.0, 0.4 and 0.4 mg/L, and the limits of quantification (LOQs, S/N = 10) were 12, 1.2, and 1.2 mg/L for OPA, PCMX and triclosan, respectively. The corrected peak areas and the concentrations of the three components showed good linear relationship within the ranges of 12 - 2 000 mg/L, 1.2 - 200 mg/L and 1.2 - 200 mg/L with the correlation coefficients of 0.999 4, 0.999 3 and 0.999 5 for OPA, PCMX and triclosan, respectively. The method was used for the determination of the three components in compound chemical disinfectants, hand washing liquids, soaps and a toothpaste. The results showed that the three components could be assayed in a single run with simple sample pretreatment, rapidity, accuracy and low cost, and the method is convenient for routine analysis. PMID- 23667993 TI - [Rapid screening of 176 pesticide residues in vegetables by ultra fast liquid chromatography-tandem mass spectrometry]. AB - A multiresidue analytical method for rapid screening of 176 pesticide residues in vegetables was developed by using ultra fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS). The vegetable samples were extracted by acetonitrile. It is not necessary for the extract to make a further purification after salting out. Multiple reaction monitoring with information-dependent acquisition of enhanced product ion (MRM-IDA-EPI) was used for the analysis. Based on EPI spectra and chromatographic peak area, identification and quantification of the 176 pesticide residues in vegetables were carried out by using library search technique. All the pesticides had the good linearity within their respective linear ranges (r > 0.99). The average recoveries of the 174 pesticides except for carbosulfan and cyromazine were in the range of 72.4% to 126.4% with the relative standard deviations (RSDs) from 1.0% to 18.7%. The limits of detection and quantification of the method were 0.005 - 2.0 microg/kg and 0.1 - 10 microg/kg, respectively. The results demonstrated that the method has distinct advantages of rapid speed, high sensitivity and good accuracy. Therefore, this method is suitable for the rapid screening of pesticide residues in vegetables. PMID- 23667994 TI - [Determination of Huperzine A in the extract of Huperzia serrata by high performance liquid chromatography]. AB - A high performance liquid chromatographic (HPLC) method was established to determine the Huperzine A in the extract of Huperzia serrata. After extracted by methanol/ water/formic acid (10/90/0.2, v/v/v), the sample was filtered for HPLC analysis. The separation was performed on an XCharge C18 column (150 mm x 4.6 mm, 5 microm) by gradient elution with water (containing 0.1% (v/v) trifluoroacetic acid) and acetonitrile (containing 0.09% (v/v) trifluoroacetic acid) as the mobile phases. Rapid separation was achieved within 10 min at a flow rate of 2 mL/min with ultraviolet absorption detection at a wavelength of 310 nm. Under the optimized conditions, good linearity was obtained in the range of 2. 12 - 106 mg/L with the correlation coefficient (R2) of about 0.999 9. The average recovery was 102.34% with the relative standard deviation (RSD) of 0.46%. The intraday and interday precisions were all below 2%. The results demonstrate that this method is simple, rapid and accurate with good reproducibility, and can be used to evaluate the quality of Huperzia serrata. PMID- 23667995 TI - [Determination of fluorescent whitening agents in plastic food contact materials by high performance liquid chromatography with fluorescence detector]. AB - A method for the determination of fluorescent whitening agents in plastic food contact materials by high performance liquid chromatography (HPLC) with fluorescence detector was developed. The samples were extracted with trichloromethane by sonication for 30 min at 40 degrees C. The HPLC method was performed on a column of Eclipse XDB-C18 (250 mm x 4.6 mm, 5 microm) by gradient elution using 5 mmol/L ammonium acetate and acetonitrile as the mobile phases, and detected by the fluorescence detector at an excitation wavelength of 350 nm and an emission wavelength of 430 nm. The experimental results indicated that the four fluorescent whitening agents were separated well. The limits of detection (LOD) (S/N = 3) were 0.3, 0.1, 0.05, 0.14 mg/L, and the limits of quantification (LOQ) (S/N = 10) were 1.0, 0.4, 0.2, 0.5 mg/L for 1,4-bis (4-cyanostyryl) benzene (C. I. 199), 1,4-bis (2-benzoxazolyl) naphthalene (C. I. 367), 4,4'-bis(2 methoxystyryl) biphenyl (C. I. 378) and 2,5-thiophenediylbis (5-tert-butyl-1,3 benzoxazole) (C. I. 184), respectively. Good linearities with correlation coefficients (r2) not less than 0.991 were obtained. The proposed method is simple, accurate, sensitive and can meet the requirements of the routine determination of fluorescent whitening agents in entry-exit products. PMID- 23667996 TI - [Determination of trace chloride in sodium sulfate of analytical reagent-grade by valve-switching ion chromatography]. AB - A valve-switching ion chromatography system was developed for the determination of trace chloride in sodium sulfate using a single pump, a suppressor, two valves and three columns. Using this technique, the trace chloride was eluted from the concentrator column (IonPac TAC-ULP1, 23 mm x 5 mm) to the analytical column (IonPac AS18, 250 mm x 4 mm), and the sulfate flowed to the waste. Under the optimized separation conditions, the method showed good linearity (r2 > 0.999) in the range of 0.03 - 1 mg/L and the average recoveries of chloride were 98.0% - 103.0% with the relative standard deviation less than 2%. The limit of detection was 0.01 mg/L (S/N = 3). The results demonstrated that this system has the advantages of high sensitivity, facile automation and simple sample pretreatment, which might be a promising approach for the determination of trace chloride in high-purity reagents. PMID- 23667997 TI - [Advance in studies on effect of paeoniflorin on nervous system]. AB - Paeoniflorin (PF) is the chief active component of paeonia, with diverse pharmacological actions and wide application. Recently, the effect of PF on nervous system has attracted increasingly more attention. According to current study findings, PF can ameliorate the decline of memory and learning capacities in many dementia model animals, and have effect in protecting the cerebral ischemia injury, treating Parkinson's disease, reliving pain and improving neural synapse plasticity. Thought its mechanism has not been clarified, current findings show that adenosine A1 receptor plays an important role, while M cholinergic receptor, opiate receptor, calcium ion channel and NF-KB may also play a part in paeoniflorin's effect on nervous system. PMID- 23667998 TI - [Historical records and modern studies on agarwood production method and overall agarwood production method]. AB - Agarwood is a precious traditional Chinese medicine with the efficacy of promoting qi circulation and relieving pain, warming middle-jiao, controlling nausea and vomiting, governing inspiration and relieving asthma, therefore it is widely applied in the clinic. Meanwhile, agarwood is also a precious spice. Aquilaria sinensis is the only source of agarwood production in China. Under natural conditions, a healthy A. sinensis tree produces no agarwood. Only if being wounded or infected with fungus can it synthetize and accumulate agarwood. It takes a decade or even several decades to produce agarwood, thus natural agarwood can not meet market demands. The essay summarizes historical records of agarwood production method and modern agarwood production method, in order to provide basis and reference for large-scale production of agarwood. PMID- 23667999 TI - [Discussion on correlation between preparation, in vivo conversion process and potential structure-activity relationship of ginsenoside]. AB - Ginseng is one of traditional Chinese medicines widely used worldwide according to the theory that "food and medicine share the same origin". Its main active ingredients are believed to be ginsenoside. In the past decades, studies on their chemical structure and pharmacological activity have made significant progress. So far, however, there is not a specific describtion on ginseng preparation and in vivo conversion process as well as an explanation on why rare ginsenoside can enhance anticancer activity. Therefore, this essay first describes the diversity of ginsenoside contained in ginseng, including natural ginsenoside, special ginsenoside generated from preparation and bioconversion processes. Subsequently, it summarizes the preparation and in vitro conversion processes, and discusses the potential structure-activity relationship between rare ginsenoside and its pharmacological activity. The study on the correlation between these chemical changes and their pharmacological activity help bring forth new ideas to the enhancement of anticancer activity of ginsenoside, and facilitate the development of new anticancer drugs. PMID- 23668000 TI - [Application and advance of artificial antigens in studies on allergic reaction of traditional Chinese medicine injections]. AB - There are some small molecules with potential allergenicity in traditional Chinese medicine injections. They are lack of immunogenicity due to their small molecular weight, but they can lead to allergic reactions when they were coupled with appropriate vectors. Therefore, how to couple small molecule semi-antigens with vectors to prepare complete antigens with immunogenicity and reactogenicity is the key for screening small molecular allergenic substances out of traditional Chinese medicine injections. In terms of semi-antigen characteristics of traditional Chinese medicine injections, vector selection and application, coupling method and complete antigen purification and identification, the author introduces the latest research situations of artificial antigen and antibody preparation technology, the advance in experimental studies on screening of allergenic substances in traditional Chinese medicine injections, as well as the application prospect of immuno-chip technology in studies on allergenic substances in traditional Chinese medicine injections, with the aim of providing new experimental thoughts and methods for safety control of traditional Chinese medicine injections. PMID- 23668001 TI - [Numerical analysis of morphological variation of germplasm resources of dioscorea]. AB - OBJECTIVE: Botanical characters of germplasm resources of Dioscorea were observed and compared, which could to offer reference for its genetic improvement, germplasm resource identification and classification. METHOD: Based on field cultivation, twenty-four morphological traits of ninety-four Dioscorea germplasm resources were observed or determined. And the morphological differences among germplasm resources were compared by principal component analysis and cluster analysis. RESULT: There were ample morphological diversity in the twenty-four traits, in especially in leaf size and tuber characters of the ninety-four Dioscorea germplasm resources. The first seven principal components which accounted for 80. 957% of total variance were extracted from the principal component analysis. The ninety-four germplasm resources could be divided into four clusters, which belonging to Dioscorea opposite, D. persimili, D. fordii and D. alata respectively. CONCLUSION: There were large morphological variation among germplasm resources on Dioscorea. Identification of germplasm resources of Dioscorea should focus on leaf size and tuber characters. PMID- 23668002 TI - [Separation and identification of endophytic fungi from desert plant Cynanchum komarovii]. AB - OBJECTIVE: The research aimed to investigate the entophytic fungal community of Cynanchum Komarrovii, including the biodiversity in different organs and the correlations with ecological environment. Endophytic fungi with patent bioactivity were also rapidly screened. METHOD: PDA medium was used to isolate and purify the endophytic fungi from C. komarovii living in Shaanxi and Ningxia district, respectively. The strains were identified based on the morphological characteristics of the fungi and similarity of 5.8S gene and internal transcribed spacer (ITS) sequence. Pyriculaia oryzae model was applied to preliminarily screen the active fungi. RESULT: Ninety-four strains of endophytic fungi were isolated and identified to 9 species, 13 genera, 9 families and 6 orders, among them, 47 strains were from the plants living in Ningxia. And then, 5 of them were isolated from roots, 14 from branches, and 28 from leaves. They were identified belonging to 8 species, 9 genera, 5 families and 4 orders. Additionally, 47 strains were from the plants living in Shaanxi. 16 were isolated from the roots, 18 from branches, 13 from leaves. They were identified belonging to 5 species, 8 genera, 6 families and 4 orders. By preliminary screening, 18 strains of endophytes completely inhibited the germination of conidium, which showed a potential bioactivity for these fungi. Both N4 and S17 strains had stronger growth inhibition effect. CONCLUSION: Endophytic fungi from desert plant C. komarovii have the feature of diversity. Different geographical environment and type of organizations lead to the significant difference on the quantity and the species composition. Most of fungi in Ningxia C. komarovii distribute in leaves. However, most of those in Shaanxi C. komarovii distribute in stems and leaves. It also indicated that endophytes from C. komarovii had a strong antifungal activity. PMID- 23668003 TI - [Micro-macroscopical identification of Siegesbeckiae herba]. AB - OBJECTIVE: To comprehend the connections and differences of the three sources of Siegesbeckiae Herba. METHOD: Using traditional Chinese medicine micro macroscopical identification to identify these three sources of Siegesbeckiae Herba. RESULT: Three sources of Siegesbeckiae Herba are obviously different when using micro-macroscopical identification. CONCLUSION: Micro-macroscopical identification can distinguish three sources of Siegesbeckiae Herba veritably and directly. PMID- 23668004 TI - [Effect of particle design on micromeritic property of dental ulcer powder]. AB - OBJECTIVE: To prepare dental ulcer powder by using particle design technology, and compare the effect on the micromeritic property of dental ulcer powder with regular grinding and ultrafine grinding methods. METHOD: Above three methods were respectively used to make dental ulcer powder, in order to evaluate their difference in appearance character, grain size distribution, specific surface area and porosity, contact angle, micro-morphological character and borneol's stability. RESULT: Compared with normal powder, ultrafine powder and particle design showed increase in color uniformity and decrease in sour taste, and the particle design powder smells almost no borneol. Their grain size distributions were significantly less that of normal powder (P < 0.01), with the same grain size distribution in ultrafine powder and particle design powder. Their specific surface areas and porosities were significantly more than that of normal powder (P < 0.01), with the highest figures in ultrafine powder. Their contact angles were significantly more than that of normal powder (P < 0.01), with the highest figure in particle design powder. The surface of normal powder was smooth, with a few of small particle adhered. The surface of ultrafine powder was partially coated with small particles, where as the surface of particle design powder was mostly coated with particles. There was difference in micro-morphological character and surface attachment among the three. The 10-day accelerate stability experiment showed that normal power, ultrafine powder and particle design powder lost borneol by 90. 13% , 66. 48% and 40.57%, respectively. Particle design powder showed the highest stability, followed by ultrafine powder and normal powder. CONCLUSION: The preparation process can affect the micromeritic properties, by changing microscopic structure of the powders. We can design the macroscopic property of powder by regulating the formation of the microscopic structure with particle design technology. PMID- 23668005 TI - [Study on andrographolide solid dispersion vectored by hydroxyapatite]. AB - OBJECTIVE: To prepare andrographolide solid dispersion, with hydroxyapatite as vector, in order to increase drug dissolution. METHOD: Andrographolide and hydroxyapatite were dispersed in 95% ethanol. The solvent evaporation method was adopted to prepare andrographolide solid dispersion, in order to study its dissolution behavior, stability and physical characteristics. RESULT: The solid dispersion prepared with andrographolide and hydroxyapatite with the proportion of 1:8 existed in the vector in an amorphous form, according to differential scanning calorimetry, scanning electron microscopy and X-ray powder diffraction. The in vitro dissolution of andrographolide solid dispersions was up to 93% at 45 min. After the accelerated stability test for three months, the drug dissolution and content in andrographolide solid dispersion showed no significant change. CONCLUSION: The prepared solid dispersions with hydroxyapatite as the vector can effectively improve the stability and dissolution of water-insoluble drug andrographolide. PMID- 23668006 TI - [Optimization of preparation of salt-processed psoraleae fructus medicines with multi-index orthogonal method]. AB - OBJECTIVE: To optimize the preparation of salt-processed Psoraleae Fructus by the orthogonal test method. METHOD: With the 12 components such as coumarin, flavone and phenolics as study indexes, a L9 (3(4)) orthogonal test was adopted to compare the effect of different factors on salt-processed Psoraleae Fructus. RESULT: According to the finalized optimal process, 100 g Psoraleae Fructus was added with 2 g salt, moistened for 2 hours, and then fried for 10 min at 150 degrees. CONCLUSION: The orthogonal test is so reasonable and reliable that it can provide basis for the preparation of salt-processed Psoraleae Fructus. PMID- 23668007 TI - [Chemical constituents from Pachysandra terminalis]. AB - To study chemical constituents from Pachysandra terminalis. By repeated column chromatography, including silica gel, Toyopearl HW-40, and preparative HPLC, four new (14) and one known (5) compounds were isolated and purified. On the basis of spectral data analysis, the structure of isolated compounds were elucidated as follow: 2-methyl-3-methylenepentane-1, 2, 5-triol (1), 4-methyl-3 methylenepentane-1, 2, 5-triol (2), 4-methyl-3-methylenepentane-1, 2, 5-triol-5-O beta-D-glucopyranoside (3), 4-methyl-3-methylenep- entane-1, 2, 5-triol-1-O-beta D-glucopyranoside (4), (7S, 8R, 8' R)-(+)-lariciresinol-9-O-beta-D-glucopyrano side (5). Compound 5 was isolated from this genus for the first time. PMID- 23668008 TI - [Chemical constituents and their antitumor cytotoxic activity in leaves of Ilex centrochinensis]. AB - OBJECTIVE: To investigate the chemical constituents in leaves of Ilex centrochinensis and their antitumor bioactivity. METHOD: Various chromatography techniques such as column chromatography on silica gel, Sephadex LH-20 and preparative HPLC were used to isolate and purify the compounds and their structures were identified by spectral data and physicochemical properties. Their antitumor effect was tested by MTT method. RESULT: Ten compounds were isolated and identified as 1,4-benzenediol (1), (2S)-5,4'-dihydroxy-7,3' dimethoxyflavan(2), (2S)-5,4'-dihydroxy-7-methoxyflavan (3), kaempferol (4), quercetin (5), naringenin (6), ursolic acid (7), uvaol (8), oleanolic acid (9) and beta-sitosterols (10). CONCLUSION: Compounds 1-5, 7, 8 were isolated from the species for the first time, among which compounds 1-3 were isolated from the Ilex genus for the first time. Compounds 2 and 3 showed strong cytotoxic activity against Huh7 cell lines with IC50 values of 8.98, 13.04 mg x L(-1), respectively. Compounds 7-9 exhibited weak cytotoxic activity against Caco-2 cell lines with IC50 values of 28.52, 38.28, 33.04 mg x L(-1), respectively. PMID- 23668009 TI - [Triterpenes from aerial parts of Clematoclethra scandens subsp. actinidioides]. AB - To study the chemical constituents of Clematoclethra scandens subsp. actinidioides, chromatographic methods such as silica gel and MCI column chromatographic technology, and preparative HPLC were used and sixteen compounds were isolated from the aerial parts of this plant. By using spectroscopic techniques including 1H, 13C-NMR, HMBC and ESI-MS, these compounds were identified as betulinic acid (1), ursolic acid (2), oleanic acid (3), corosolic acid (4), 3beta-(trans-p-coumaroyloxy)-2alpha, 23-dihydroxyurs-12-en-28-oic acid (5), 3beta-(trans-p-coumaroyloxy)-2alpha, 23-dihydroxyurs-12, 20 (30)-dien-28-oic acid (6), 2alpha, 3alpha, 23-trihydroxyurs-12, 20 (30)-dien-28-oic acid (7), 2alpha, 3alpha, 23-trihydroxyurs-12-en-28-oic acid (8), asiatic acid (9), 2alpha, 3alpha, 24-tri-hydroxyurs-12-en-28-oic acid (10), 2alpha, 3beta, 23-trihydroxyurs 12, 20 (30)-dien-28-oic acid (11), 2alpha, 3beta, 19alpha, 24-tetrahydroxyurs-12 en-28-oic acid (12), 2alpha, 3alpha, 19alpha, 24-tetrahydroxyurs-12-en-28-oic acid (13), 2alpha, 3beta, 23, 24-tetrahydroxyurs-12-en-28-oic acid (14), 2alpha, 3alpha, 19alpha, 23, 24-pentahydroxyurs-12-en-28-oic acid (15) and daucosterol (16). Among them, compounds 3-6, 11-12, 14 and 15 were isolated from this endemic plant for the first time. PMID- 23668010 TI - [Chemical constituents of Gentiana rhodantha]. AB - OBJECTIVE: To determine the chemical constituents of Gentiana rhodantha. METHOD: To isolate the constituents, column chromatography over silica gel, MCI, Sephadex LH-20 and C18 reverse-phased silica gel were used. Spectroscopic methods were used to elucidate the structures of the isolated compounds. RESULT: Sixteen compounds were isolated and elucidated as ten phonemic compounds, namely 1,3,7,8 tetrahydroxylxanthone (1), rhodanthenone D (2), 1,3,6,7-tetrahydroxylxanthone (3), 1,3,7-trihydroxy-4,8-dimethoxyxanthone (4), quercetin (5), isoorientin (6), mangiferin (7), norswertianolin (8), gallic acid ethyl ester (9) and salicylic acid (10), and six triterpenes including alpha-amyrin (11), erythrodiol 3-O palmitate (12), ursolic aldehyde (13), uvaol 3-O-acetyl (14), ursolic acid (15) and 2alpha-hydroxyursolic acid (16). CONCLUSION: Compounds 4-6, 8, 10-12, 15 and 16 were isolated from this plant for the first time. Compounds 1 and 3 were obtained firstly from the genus Gentiana and compounds 9, 13-14 were firstly from the family Gentianaceae. PMID- 23668011 TI - [Chemical constituents of Rhododendron seniavinii]. AB - OBJECTIVE: To study the chemical constituents of Rhododendron seniavinii. METHOD: Compounds were isolated from the aqueous extract of the leaves of R. seniavinii by using Sephadex LH-20, ODS open column chromatography and other means. Their structures were elucidated according to spectral data and physiochemical properties. RESULT: Thirteen compounds were isolated from R. seniavinii and identified as 5-methoxydehydroconiferyl alcohol (1), dehydroconiferyl alcohol (2), (-)-syringaresinol (3), (-)-lyoniresinol (4), (+)-lyoniresinol 3alpha-O-beta D-glucopyranoside (5), (-)-lyoniresinol 3alpha-O-beta-D-glucopyranoside (6), 3,4,5-trimethoxyphenyl-1-O-beta-D-glucopyranoside (7), nikoenoside (8), 3,5,7 trihydroxychromone-3-0-alpha-L-rhamnopyranoside (9), 3,4,5-trimethoxyphenol (10), scopoletin (11), scopolin (12) and quercitrin (13). CONCLUSION: Compounds 1-12 were obtained from this plant for the first time. PMID- 23668012 TI - [Multi-component of Cibotium baronetz decoction pieces via 1H-NMR spectroscopic analysis]. AB - OBJECTIVE: 1H-NMR technology was carried out to investigate the chemical difference between 30 batches of Cibotium baronetz decoction pieces and look for new method for quality control of C. baronetz decoction pieces. METHOD: Six hundreds MHz H-NMR spectroscopy and principle component analysis (PCA) were used to discriminate between 30 batches of commercially available cibotium samples based on multi-component metabolite profiles. RESULT: Saccharide is the principle component of C. baronetz decoction pieces, and steroid and triterpene were the discriminately chemical component. Protocatechuic acid, protocatechuic aldehyde, cibotiumbaroside A, cibotiumbaroside B and 4-O-caffeoyl-D-glucoside could be used as the marker for controlling the quality of commercial C. baronetz decoction pieces. CONCLUSION: Pattern-recognition techniques applied to proton nuclear magnetic resonance (1H-NMR) spectra of 80% methanol extraction of C. baronetz could correctly discriminate not only the quality, but also the chemical component for batches of commercial C. baronetz decoction pieces. PMID- 23668013 TI - [Determination of terpene lactones in Ginkgo biloba leaves in different ages by UPLC-TQ-MS]. AB - OBJECTIVE: To establish an ultra-high performance liquid chromatography coupled with triple quadrupole mass (UPLC-TQ-MS) for determination of four terpene lactones. METHOD: Chromatographic separation was carried out on a ACQUITY UPLC BEH C18 column (2.1 mm x 100 mm, 1.7 microm) with isocratic elution of 70% methanol at a flow rate of 0.4 mL x min(-1), the column temperature was set at 30 degrees C; Waters Xevo TQ worked in multiple reaction monitoring mode. RESULT: All calibration curves were linear (r > 0.990 3) over the tested ranges. The average recoveries ranged from 98.83% to 103.9% with RSD value below 3.0%. The contents of total terpene lactones in Ginkgo biloba leaves were significantly different in different ages. The contents in the leaves of young ginkgo tree were higher than that in old tree. CONCLUSION: The method was simple and fast with high precision, sensitivity and repeatability, which can be used for qualitative and quantitative analysis of terpene lactones in G. biloba leaves. PMID- 23668014 TI - [Effect of puerarin combined with felodipine on mRNA and protein expression of apelin and APJ in renovascular hypertensive rat]. AB - OBJECTIVE: To explore the effect of puerarin combined with felodipine on the mRNA and protein expression of apelin and APJ in renal tissue of renovascular hypertensive rat. METHOD: Sixty-two Sprague-Dawley rats were used, of which 8 rats were randomly chosen as sham-operation group. The remaining rats were made for the rat model with renovascular hypertension. The renovascular hypertensive rats were randomly divided into 5 groups as follows: 4 groups which were treated with felodipine (0.8 mg x kg(-1) x d(-1)), puerarin (50 mg x kg(-1) x d(-1)), puerarin combined with felodipine (puerarin 25 mg x kg(-1) x d(-1) + felodipine 0.4 mg x kg(-1) x d(-1)) or captopril combined with felodipine (captopril 15 mg x kg(-1) x d(-1) x felodipine 0.4 mg x kg(-1) x d(-1)), and 1 group which was treated with distilled water. Drugs or distilled water were administered for 8 weeks. The expression of apelin and APJ mRNA and protein in ischemic and non ischemic kidneys was assessed by RT-PCR or Western blot. RESULT: Compared with sham-operation group, the expression of apelin mRNA and protein in ischemic and non-ischemic kidneys in model group was increased significantly (P < 0.01); the expression of APJ mRNA and protein in ischemic kidneys had no significance, while that in non-ischemic kidneys was decreased (P < 0. 01). Compared with model group, the expression of apelin mRNA and protein in ischemic and non-ischemic kidneys was decreased significantly in all drug-treated groups (P < 0.01); while that of APJ mRNA and protein in non-ischemic kidneys was upregulated (P < 0.01). Compared with felodipine group, the expression of apelin mRNA and protein in ischemic and non-ischemic kidneys was decreased (P < 0.01 or P < 0.05) in the group treated with both puerarin and felodipine; and the expression of APJ mRNA and protein in ischemic kidneys did not reach significant level, however, that was upregulated in non-ischemic kidneys (P < 0.01 or P < 0.05). CONCLUSION: Puerarin downregulates the expression of apelin mRNA and protein in ischemic and non-ischemic kidneys, and upregulates that of APJ mRNA and protein in non ischemic kidneys. Combination of puerarin and felodipine enhances the above mentioned effects and shows no significant difference versus the combination of felodipine and captopril. The results suggest that puerarin regulates blood pressure and protects target organ through apelin/APJ pathway and that puerarin has synergetic effects with CCB. PMID- 23668015 TI - [Experimental study on therapeutic effect of Dabuyin Wan on true precocious puberty in female rats]. AB - OBJECTIVE: To study the therapeutic effect of Dabuyin Wan on true precocious puberty of female rats and its possible mechanism. METHOD: Twenty-two-day-old female SD rats were subcutaneously injected with 40 mg x kg(-1) N-methyl-DL aspartic acid (NMA) at 14:00 and 16:00 every day; meanwhile, the rats were given Dabuyin Wan for intervention. Visual inspection was conducted for the time of vaginal opening. The first estrus was observed by yaginal smear test. Their ovaries and uterus were weighed to calculate organ coefficients. Conventional pathological slices were made to observe morphological changes in ovaries and uterus and calculate the thickness of uterine walls and the number of corpus luteums. The level of E2 in serum was detected to assess the therapeutic effect of Dabuyin Wan on NMA precocious puberty in rats. expressions of GnRH, GPR54 and Kiss-1 mRNA in hypothalamus were measured by semi-quantitative RT-PCR to investigate the possible mechanism of Dabuyin Wan. RESULT: Dabuyin Wan at 3.24 g x kg(-1) and 1.62 g x kg(-1) significantly decreased the organ coefficients in rats with precocious puberty (P < 0.05), decrease the number of vaginal openings in rats (P < 0.01) and the thickness of uterine walls and the number of corpus luteums (P < 0.05), and notably down-regulated expressions of GnRH, GPR54 and Kiss-1 mRNA in hypothalamus (P < 0.05), without significant impact on E2 in serum. CONCLUSION: Dabuyin Wan may inhibit GnRH synthesis and release as well as startup of hypothalamic-pituitary-gonadal axis by down-regulating Kiss-1/GPR54 mRNA expression in hypothalamus, in order to realize the therapeutic effect on true precocious puberty. PMID- 23668016 TI - [Effect of cordyceps polysaccharide on lipid peroxidation of rats with dimethylnitrosamine-induced liver fibrosis]. AB - OBJECTIVE: To observe the pharmacological effect of Cordyceps polysaccharide on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. METHOD: DMN rat liver fibrosis model was established and divided into the normal group (N, n = 6), the model group (M, n = 11), the Cordyceps polysaccharide group (C, n = 8) and the colchicine group (Q, n = 9). During the modeling for four weeks, Cordyceps polysaccharide (60 mg x kg(-1)) and colchicine (0.1 mg x kg(-1)) were orally administered for three weeks, while the model and normal groups were given disinfected water of the same amount. OBSERVATION: serum ALT, AST, GGT and Alb, TBil content; content of hydroxyproline (Hyp) in liver tissues; liver pathology and collagen staining; SOD activity and MDA, GSH, GSH-Px in liver tissues; protein expression of proliferating cell nuclear antigen (PCNA) in liver tissues. RESULT: Serum ALT, AST, GGT, TBil significantly increased, and A1b decreased significantly in the model group. Hepatic Hyp significantly increased in the model group, whereas the index remarkably decreased in the Cordyceps polysaccharide group and the colchicine group. HE staining: the structure of normal hepatic lobules was damaged, with hepatocytes tumefaction and proliferation of connective tissues in portal tracts in the model group, while the Cordyceps polysaccharide group and the colchicine group recorded notable reduction in above pathological changes. Collagen staining: the model group showed hepatic lobule fibrous septum and many intact pseudolobules; while the Cordyceps polysaccharide group and the colchicine group witnessed decrease in collagen deposition. The model group showed significant decrease in SOD, GSH-Px and GSH and increase in MDA, whereas the Cordyceps polysaccharide group and the colchicine group recorded notable growth in GSH and GSH-Px. The model group showed significant decrease in protein expression of PCNA in liver tissues, while the Cordyceps polysaccharide group and the colchicine group showed significant reduction. CONCLUSION: Cordyceps polysaccharide can significantly inhibit DMN induced liver fibrosis and lipid peroxidation in rats. PMID- 23668017 TI - [Synthesis and identification of rutin complete antigen and analysis its immunogenicity]. AB - OBJECTIVE: Synthesis and identification of complete antigen of rutin, the traditional Chinese medicine active ingredient, and develop rapid detection of rutin using enzyme-linked immunoassay method (ELISA). Immunogenicity of the complete antigen was also studied. METHOD: Prepare the complete antigen by sodium periodate solution and identified by UV scanning and SDS-PAGE test. Male New Zealand white rabbits were immunized by the antigen to obtain the antiserum. RESULT: The results of UV analysis showed that the coupling ratio of complete antigen is 13: 1. SDS-PAGE display of the artificial antigen was delayed compared with bovine serum protein. The titer of rutin antibody is 1:4 000. The sensitivity of IC50 was 5.37 mg x L(-1), the lowest detection limit was 1 mg x L( 1), the average recovery was 102%, the intra and interspecific RSD were less than 10%, cross-reactivity rate of antibodies and other analogs were less than 1%. CONCLUSION: Rutin complete antigen was synthesized successfully, and the rapid detection of rutin by ELISA method was successfully established. PMID- 23668018 TI - [Protective effect of medicated serum prepared with taohong siwu tang on hydrogen peroxide-induced human umbilical vein endothelial cells]. AB - OBJECTIVE: To study the protective effect of medicated serum prepared with Taohong Siwu Tang on hydrogen peroxide-injured human umbilical vein endothelial cells (HUVECs). METHOD: Sprague Dawley rats were orally administered with 10 mL x kg(-1) extracts from Taohong Siwu Tang (1.75 g crude drug), twice a day for three days, in order to prepare medicated serum of Taohong Siwu Tang. The effect of medicated serum pre-treated with Taohong Siwu Tang (with concentrations of 5%, 10%, 15%) on reduction of H2O2-induced cell activity was detected MTT. Cell morphological changes were observed under microscope. The effect of medicated serum prepared with Taohong Siwu Tang on the apoptosis and antioxidant capacity of HUVECs was detected with the content of malondialdehyde (MDA) and dehydrogenase (LDH), the activity of superoxide dismutase (SOD) and AO/EB staining. The expression of Caspase-3 was determined by western blot. RESULT: Compared with the blank serum control group, cell were significantly less active after being damaged by H2O2 (400 micromol x L(-1)). Medicated serum could significantly improve the SOD activity, reduce the levels of LDH and MDA, and inhibite the expression of Caspase-3. AO/EB staining and inverted microscope also showed that medicated serum prepared with Taohong Siwu Tang could reduce cell apoptosis induced by H2O2. CONCLUSION: Medicated serum prepared with Taohong Siwu Tang has significant protective effect on HUVECs injured by H2O2. PMID- 23668020 TI - [Effect of prescriptions replenishing vital essence, tonifying Qi and activating blood on TNF-alpha, IL-1beta expressions in serum and submaxillary gland of NOD mice with Sjogren's syndrome]. AB - OBJECTIVE: To observe effect of prescriptions replenishing vital essence, tonifying Qi and activating blood on expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-IP (IL-1beta) in serum and submaxillary gland of non obese diabetic (NOD) mice with Sjogren's syndrome. METHOD: Thirty-two NOD mice were divided into four groups at random: the model group, the traditional Chinese medicine (TCM) group, the hydroxychloroquine group, the TCM and western medicine (WM) group, with 8 mice in each group. Eight Balb/C mice were taken as the normal normal control group. The TCM group was orally administered with 0.4 mL decoction replenishing vital essence, tonifying Qi and activating blood (100 g x kg(-1)) everyday; the hydroxychloroquine group were given 0.4 mL hydroxychloroquine (60 mg x kg(-1)) everyday; the TCM WM group were given 0.4 mL decoction, replenishing vital essence tonifying Qi and activating blood (50 g x kg(-1)) and hydroxychloroquine (60 mg x kg(-1)) everyday. Mice were sacrificed after eight weeks, and their arterial blood and tissues of submaxillary gland were collected. The levels of TNF-alpha, IL-1beta in serum were detected by ELISA. Expressions of TNF-alpha, IL-1beta protein in submaxillary gland were detected by immunohisto chemistry. RESULT: Compared with other groups, TNF-alpha, IL-1beta in serum and submaxillary gland in the model group were higher (P < 0.05). The normal group showed lower serum TNF-alpha level than other groups (P < 0.05), but without statistical significance compared with the TCM group. IL-1beta in serum in the TCM group and the TCM WM group were lower than that of the hydroxychloroquine group (P < 0.05), but without statistical significance compared with the normal group. TNF-alpha protein expression in the TCM group and the TCM WM group showed no significant difference compared with the normal group, whereas the TCM WM group were notably lower than that of the hydroxychloroquine group (P < 0.05). IL 1beta expression in the TCM WM group showed no significant difference compared with the normal group. CONCLUSION: The decoction replenishing vital essence, tonifying Qi and activating blood can decrease the levels of TNF-alpha, IL-1beta in serum and submaxillary gland of NOD mice with Sjogren's syndrome. It may improve pathological damage of submaxillary gland by regulating Th1/Th2 cell factors, in order to achieve the therapeutic effect on SS. PMID- 23668019 TI - [Angelica sinensis polysaccharides delay aging of hematopoietic stem cells through inhibitting oxidative damge]. AB - OBJECTIVE: The effect of angelica sinensis polysaccharides (ASP) on the production of reactive oxygen specie (ROS), the capability of total anti-oxidant (T-AOC), and the expression of p16 in mRNA level in mice hematopoietic stem cells (HSCs) were observed to explore the underlying mechanism that ASP delay aging of HSCs in vivo. METHOD: C57BL/6J mice were randomly divided into normal group, aging group, and the above groups treated with ASP. Mice were uniformly explored in X-ray (3.0 Gy/8 F) to erect model of aging. Normal and aging ASP intervention groups mice were treated with ASP by intragastric administration, while normal and aging groups were treated with equal-volume NS during X-ray irradiation. Mice HSCs were isolated by magnetic cell sorting and cultured in vitro. Senescence associated beta-galactosidase (SA-beta-Gal) staining was used to detect aging HSCs. Cell cycles analysis and CFU-Mix cultivation were used to evaluate the capability of self-renewing and colony forming in HSCs. The production of ROS in HSCs was evaluated by flow cytometry analysis and immunofluorescence assess, respectively. T-AOC was detected by chemical colorimetric method. The expression of p16 was determined by real-time quantitative PCR (qRT-PCR). RESULT: Exogenous X-ray irradiation induced HSCs aging was compared with normal group without irradiation. Biological feature of HSCs in aging group with X-ray irradiation as follows: The percentage of SA-beta-Gal positive cells, the ratio of G1 stages and the production of ROS were significantly increased , the expression of p16 in mRNA level was also upregulated. The capacility of colony forming and T-AOC in HSCs were decreased. ASP could significantly decrease the percentage of SA-beta Gal positive cells, the ratio of G1 stages and the production of ROS in HSCs, and downregulate the expression of p16 in mRNA level in HSCs contrast to aging group without ASP treatment. In addition, ASP could remarkably increase T-AOC and the capacility of colony forming in HSCs compared with aging group without ASP treatment. CONCLUSION: X-ray (3.0 Gy/8 F) could induce mice HSCs aging. ASP could delay senescence HSCs aging which maybe partly ascribed to the inhibition of oxidative damage and the downregulation of p16 mRNA expression. PMID- 23668021 TI - [Study on metabolism of Coptis chinensis alkaloids from different compatibility of Wuji Wan in human intestinal flora]. AB - OBJECTIVE: To study the metabolism of berberine and palmatine in prescription compatibility of Wuji Wan in human intestinal flora. METHOD: The L9 (3(4)) orthogonal design was adopted to compare prescription compatibility of nine groups of Wuji Wan composed of Coptis chinensis, Evodiae and fried Radix paeoniae alba into and single ingredient of C. chinensis. They were cultivated with fresh human excrements under anaerobic conditions for 24 h. A HPLC-UV method was adopted for determining berberine and palmatine in bacteria culture medium, in order to compare the metabolism of the two components in different prescription compatibility. RESULT: Metabolism of berberine was positively correlated with doses, whereas metabolism of palmatine was negatively correlated with doses in extracts from C. chinensis. Compound compatibility speeded up the metabolism of berberine in low dose, which was positively related to the doses of Evodiae and fried Paeoniae Alba Radix; meanwhile Compound compatibility slowed down the metabolism of berberine in high dose, which was negatively related to the dose of Evodiae. Compound compatibility speeded up the metabolism of palmatine in high dose, which was negatively related to the doses of Evodiae and fried Paeoniae Alba Radix. CONCLUSION: The metabolism of the compatibility of Wuji Wan speeds up, when Coptis chinensis components metabolite rapidly in intestinal flora; while the metabolism of the compatibility of Wuji Wan slows down, when C. chinensis components metabolite slowly in intestinal flora. Therefore, they show a balanced effect. Additionally, different proportion of C. chinensis, Evodiae and fried Paeoniae Alba Radix cause difference in metabolism speed of berberine and palmatine to some extent. PMID- 23668022 TI - [Study on in vitro/in vivo correlation of extracts from Ligusticum chuanxiong after transdermal administration]. AB - OBJECTIVE: To study the transdermal permeation and in vivo pharmacokinetics of effective constituent ferulic acid from Ligusticum chuanxiong, in order to establish the in vitro/in vivo correlation in transdermal permeation. METHOD: Franz diffusion cell was adopted in the in vitro transdermal permeation, with CD 1 nude rat abdominal skin as the permeation medium. Linear probes were implanted in CD-1 nude rats. With PBS as perfusate, microdialysis was employed to study the pharmacokinetics. Ferulic acid concentrations in the receptor solution and dialysate were assessed by high performance liquid chromatography (HPLC). The study on correlation between in vitro and in vivo data was conducted by deconvolution methods. RESULT: The transdermal permeation rate of ferulic acid from Ligusticum chuanxiong was (0.094 4 +/- 0.049 4) microg x cm2 x min, with Cmax of ferulic acid being 808.91 microg x L(-1), and Tmax being 183 min after dermal administration. The in vitro/in vivo correlation was 93.61. CONCLUSION: Ferulic acid in extracts from L. chuanxiong can quickly penetrate skins. By using the in vitro/in vivo correlation in transdermal permeation, simple in vitro transdermal permeation method can be adopted to study the changes in its pharmacokinetics. PMID- 23668023 TI - [Comparative study on pharmacokinetics of senkyunolide I after administration of simple recipe and compound recipe in rats]. AB - OBJECTIVE: To develop a LC-MS method for the determination of senkyunolide I (SI) in rat plasma, in order to observe whether there is significant change in the pharmacokinetics parameters of complex prescriptions of Huoluoxiaolingdan (HLXL) and single herbal extracts from Ligusticum chuanxiong Hort. in rats, and assess the effect of other components in HLXL on the pharmacokinetics of SI. METHOD: Twelve male Sprague-Dawley (SD) rats were randomly divided into two groups, and orally administered with extract from HLXL and L. chuanxiong (both equal to SI 4.53 mg x kg(-1)). Their blood was collected at different time points for LC-MS, in order to detect the plasma concentration of SI. The pharmacokinetic parameters of SI were calculated by DAS 2.0 software. SPSS 16.0 software was used for independent-sample T-test and Nonparametric T-test. RESULT: A linear relationship of SI ranged from 6.750 to 675.0 microg x L(-1), and with the lowest limit of detection being 6.750 microg L(-1). Both of the plasma concentration-time curves of SI were fitted with the two-compartment model for extract of HLXL and L. chuanxiong. The detected AUC and Cmax of SI showed significant difference, with no significant difference in other parameters. CONCLUSION: The LC-MS determination method established in this experiment was so exclusive, accurate and sensitive that it is suitable for pharmacokinetic studies on extracts of HLXL and SI from L. chuanxion. The experiment results show that other ingredients of HLXL have noticeable effect on the absorption of SI in rat plasma. PMID- 23668024 TI - [Determination of plasma protein binding rate of arctiin and arctigenin with ultrafiltration]. AB - OBJECTIVE: To determine the plasma protein binding rate of arctiin and arctigenin. METHOD: The ultrafiltration combined with HPLC was employed to determine the plasma protein binding rate of arctiin and arctigenin as well as rat plasma and healthy human plasma proteins. RESULT: The plasma protein binding rate of arctiin with rat plasma at the concentrations of 64. 29, 32.14, 16.07 mg x L(-1) were (71.2 +/- 2.0)%, (73.4 +/- 0.61)%, (78.2 +/- 1.9)%, respectively; while the plasma protein binding rate of arctiin with healthy human plasma at the above concentrations were (64.8 +/- 3.1)%, (64.5 +/- 2.5)%, (77.5 +/- 1.7)%, respectively. The plasma protein binding rate of arctigenin with rat plasma at the concentrations of 77.42, 38.71, 19.36 mg x L(-1) were (96.7 +/- 0.41)%, (96.8 +/- 1.6)%, (97.3 +/- 0.46)%, respectively; while the plasma protein binding rate of arctigenin with normal human plasma at the above concentrations were (94.7 +/- 3.1)%, (96.8 +/- 1.6)%, (97.9 +/- 1.3)%, respectively. CONCLUSION: The binding rate of arctiin with rat plasma protein was moderate, which is slightly higher than the binding rate of arctiin with healthy human plasma protein. The plasma protein binding rates of arctigenin with both rat plasma and healthy human plasma are very high. PMID- 23668025 TI - [Systematic review of diagnosis criteria on drug induced liver injury in China from 2005 to 2012]. AB - OBJECTIVE: To summarize the application of diagnosis criteria on drug induced liver injury in China from 2005 to 2012 in China. METHOD: We systematically searched the journals included in four commonly accepted Chinese electronic databases for medical research, i.e. CNKI, CBM, VIP and Wanfang database, for articles published from 2005 to 2012. The articles meeting the inclusion criteria were considered eligible for our analysis. Relevant information was extracted using a standardized form in Excel 2007. RESULT: Overall,273 studies were included for the present review. 199 Case Series and 74 Case Report. There are 15 various standard of diagnosis using in 199 Case Series for DILI. Chinese general standard, 1997 Maria Criteria, and Medical records are generally used. The use of the three standard has no trend with time and various journals in 199 Case Series. 74 Case Report all use medical records as criteria on DILI diagnosis. CONCLUSION: We don't have the consolidate criteria on DILI diagnosis at present, so when we choose the standard of diagnosis, we should consider many factors in order to avoid missed diagnosis and misdiagnosis. PMID- 23668026 TI - [Clinical study of decoction of invigorating Qi and clearing lung combined standardized myrtol on acute exacerbation of chronic obstructive pulmonary disease (AECOPD)]. AB - OBJECTIVE: To investigate the clinical effect of decoction of invigorating Qi and clearing lung combined standardized myrtol on acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHOD: Ninety and eight patients with AECOPD patients were randomly divided into the treatment group and the control group, with 50 cases and 48 cases respectively. All the patients were given the conventional treatment. The control group was treated by standardized myrtol with 3 times a day, 300 mg each time taken orally. The treatment group was given decoction of invigorating Qi and clearing lung with 2 times a day, one dose per day taken orally, combined standardized myrtol (usage as above). After Two weeks, the scores of clinical symptom, blood gas analysis and pulmonary function were observed. RESULT: Both FEV1 and FEV1% were raised in the two groups after treating. And the treatment group was significantly higher than control group (P < 0.01). PaO2 and PaO2/FiO2 rose, with PaCO2 decreased in the two groups (P < 0.01). PaO2 and PaO2/FiO2 were significantly improved, and PaCO2 was significantly decreased in the treatment group compared to the control group (P < 0.01). In the clinical curative effect comparison aspects, clinical control rates were 42.0% in treatment group and 20.83% in control group respectively, with significant difference between the two groups (P < 0.05). Significant efficiency is 86.0% in treatment group and 52.08% in control group respectively, with significant difference between the two groups (P < 0.01). CONCLUSION: Decoction of invigorating Qi and clearing lung combined with standardized myrtol can obviously improve clinical symptom, blood gas an analysis and pulmonary function in patients with AECOPD. PMID- 23668027 TI - [Research advances of Tasmayi]. AB - Tasmayi (mumie, shilajit) is a pale brown to black substance which leaks from the layers of rocks in many mountain ranges during the warm summer months. In traditional Kazakh medicine, it is used for the treatment of bone fracture and many inflammatory ailments. It is also used as a remedy in the traditional medical systems of many countries such as India, Russia and Kazakhstan. According to the literatures, Tasmayi possesses anti-inflammatory, antiulcerogenic, antibacterial, free radical scavenging, antioxidative, memory enhancing, antidiabetic, antistress, antiallergic, immunomodulative, anti AIDS, anabolic and regeneration stimulating activities. The major physiological action of Tasmayi could be belonging to the presence of dibenzo-alpha-pyrones along with humic and fulvic acids. PMID- 23668028 TI - [Relationship between chemical constituents and herbs properties of relative plant herbs]. AB - The material fundament of Chinese herbs is chemical constituents which represented the properties of herbs, including five fundamental natures (cold, cool, neutral, warm and hot), seven flavors (sour, bitter, sweet, salty, acerbity, mild and pungent) and twelve meridians (liver, heart, spleen, lung, kidney, Xin Bao, Gall bladder, small intestine, stomach, large intestine, bladder and San Jiao). In this article, authors study the relationship between chemical constituents of plant herbs and their properties. First, authors build a relationship network where the herbs with similar chemical compositions are connected each other. The particular difference of our work is to filter the common chemical constituents that many plants from different families contained. As a result, considering relative plants have similar chemical constituents, the relative plant herbs are clustering closely and the herbs of different family are connected loosely in our network. The results indicates that the method of building the herbs network is correct. The characteristics of herbs' properties in the network are that the same properties are usually connected regardless the plant families. There is "properties hole" phenomenon, that is, the majority of adjacent drugs of a herb have a certain properties, while the drug does not have the properties. PMID- 23668029 TI - [Present and future of traditional Chinese medicine clinical pharmacy]. AB - Traditional Chinese medicine clinical pharmacy is the contact theory of traditional Chinese medicine and herbal application on the bridge, this paper systematically reviews the clinical pharmacy of traditional Chinese medicine the history, current situation of clinical pharmacy to conduct a comprehensive review, put forward the development of Chinese clinical pharmacy path, in order to strengthen the traditional Chinese medicine clinical pharmacy discipline construction and research. PMID- 23668030 TI - [Application of reference extracts in quality control of traditional Chinese medicines]. AB - The essay summarizes the current development and application of reference extracts from traditional Chinese medicines (TCMs). Through the analysis on problems in the quality control of TCMs, and on the basis of the current application of reference extracts in Chinese Pharmacopoeia, it investigates reference extracts from TCMs and forecasts the study orientation on TCM quality standards. Despite a wide prospect for the application of reference extracts in quality control of TCMs, there remain problems in varieties and standards. It is of great significance for the TCM understanding to further promote the development of reference extracts. PMID- 23668031 TI - [Study on generation cause of genuine medical herbs]. AB - Chinese herbal medicine are the main means to prevent and treat diseases in traditional Chinese medicine, thus the quality of traditional Chinese medicinal herbs decides the clinical efficacy. Though the producing areas of genuine medical herbs had been recorded in the Qing and Han Dynasties, genuine medical herbs had not been finally established and thrived until the Ming and Qing Dynasties. Their development in more than 1 000 years was affected by many factors. Thepractice examination and theoretical direction of TCM were the theoretical basis for the generation of genuine medical herbs, while the differences in the ecological environment and herbal germplasm indicated their essential causes. The social development in the Ming and Qing Dynasties was also an intangible impetus driving force that could not be neglected. PMID- 23668032 TI - [Applying graphics processing unit in real-time signal processing and visualization of ophthalmic Fourier-domain OCT system]. AB - This investigation introduces GPU (Graphics Processing Unit)- based CUDA (Compute Unified Device Architecture) technology into signal processing of ophthalmic FD OCT (Fourier-Domain Optical Coherence Tomography) imaging system, can realize parallel data processing, using CUDA to optimize relevant operations and algorithms, in order to solve the technical bottlenecks that currently affect ophthalmic real-time imaging in OCT system. Laboratory results showed that with GPU as a general parallel computing processor, the speed of imaging data processing using GPU+CPU mode is more than dozens times faster than traditional CPU platform based serial computing and imaging mode when executing the same data processing, which reaches the clinical requirements for two dimensional real-time imaging. PMID- 23668033 TI - [In-vitro electrochemical stability evaluation of a flexible MEMS microelectrode]. AB - Three-electrode testing method was used to investigate the effect of temperature on electrode impedance, and the pH shifts in saline solution resulting from the electrical stimulation were also determined. Experiments in PBS (phosphate buffered solution) solution showed that the electrode impedance was almost invariable at the human body temperature range (35 degrees C-40 degrees C). And the experiments in unbuffered saline solution showed that pH shifts decreased from 0.03 to 0.005 when the frequency of biphasic charged-balanced pulses increased from 1 Hz to 100 Hz. Even stimulated by monophasic pulses (frequency is 15 Hz, amplitude is 50 microA), the stimulus-induced pH shift of electrode only varies 0.15 (anodic pulse current increased 0.15 and cathodic pulse current decreased 0.15). PMID- 23668034 TI - [Quantitative comparison study on the SNR method of phased-array coil in 3.0 T MRI]. AB - In this paper, ACR single image method and NEMA dual-image method were measured SNR using two types of phased-array coils. The correlation equation of the two methods was obtained and substitutability of two methods was analyzed. The results showed that the two methods are replaceable in the evaluation of coils, but the later method gets higher SNR than the first method because structure noise is eliminated. PMID- 23668035 TI - [Comparative analysis of calculation methods of coil sensitivity in parallel MRI]. AB - Calculation methods of coil sensitivity in parallel MRI were elaborated, compared and analyzed. PMID- 23668036 TI - [Mobile phone based data acquisition and evaluation system for the alternative four diagnostic methods of traditional Chinese medicine]. AB - This study is dedicated to integrate the theories of the four diagnostic methods of TCM and the methods of mobile healthcare so as to achieve the goal of the four diagnostic functions of TCM on mobile phone. An Android smartphone based data acquisition system has been developed and experimentally demonstrated. It was shown that the prototype could successfully achieve the fundamental function of the four diagnostic methods of TCM and thus help preliminarily interpret the symptoms of human diseases. PMID- 23668037 TI - [Research on multifunctional fitness monitor based on FFT and photoelectric sensor]. AB - This paper proposes a multifunctional fitness monitor based on FFT and photoelectric sensor, which uses pulse-type and non-invasive detection method to complete the analysis of the human blood oxygen saturation and heart rate. The system collects the absorption of red and infrared light absorbed by fingertip, then by programmable gain amplifier and the Fast Fourier analysis, it extracts the amplitude, frequency of the AC signal. PIC24FJ128GA010 is used to complete the collection, automatic gain judgment and signal processing. Finally, the result is calibrated by pulse blood oxygen emulator. Furthermore, it realizes the pedometer function based on three axles acceleration sensors MMA7260, which enhances fitness monitor's usability and allows people to obtain dynamic physiological signs when exercising. PMID- 23668038 TI - [A novel serial port auto trigger system for MOSFET dose acquisition]. AB - To synchronize the radiation of microSelectron-HDR (Nucletron afterloading machine) and measurement of MOSFET dose system, a trigger system based on interface circuit was designed and corresponding monitor and trigger program were developed on Qt platform. This interface and control system was tested and showed stable operate and reliable work. This adopted serial port detect technique may expand to trigger application of other medical devices. PMID- 23668039 TI - [Reproducibility of a portable spirometer based on differential pressure sensor]. AB - OBJECTIVE: Assessing the reproducibility of a portable spirometer, including reproducibility of inter-observer and day-today. METHODS: Lung ventilation function was performed in 22 healthy volunteers by two observers on the same day and repeated by the first observer after 24h. RESULTS: The inter-observer and day to-day intra-class correlation coefficients are all higher than 0.75. There are no significant difference between each other. Bland-Altman chart shows good limits of agreement between inter-observer and day-to-day, only scattered data are outside of the limits of agreement. CONCLUSIONS: The portable spirometer shows good inter-observer and day-to-day reproducibility, and can be used for testing lung function in clinical. PMID- 23668040 TI - [Optimum design and performance evaluation of down-sampling algorithm for visual prosthesis imaging processing]. AB - According to analyses of the real-time performance of the visual prosthesis image processing system, down-sampling is a key factor which influences the processing speed. Based on these analyses, the algorithm of grid sampled averaging was proposed for down-sampling. Then the effect of grid parameters on the result and algorithm complexity was evaluated by using the regional-averaging algorithm as a reference. Our research shows that the grid-averaging algorithm could reduce the computation burden by 90% or more, with no significant difference from the regional-averaging algorithm. PMID- 23668041 TI - [Design and realization of the communication system for the mobile medical terminal]. AB - OBJECTIVE: Realizing wireless communication based on handset devices for medical staff; providing an instant messaging method. METHODS: Constructing a set of communication protocols and standards; developing software both on server and client. RESULTS: Building an instant messaging system which follows the customized specification; based on Android the client provides functions like address book, message, voice service etc. CONCLUSION: As an independent module of the mobile medical terminal, the system can provide convenient communication for medical service with other mobile business. PMID- 23668042 TI - [Great significance of accelerating publishing medical equipment supervision and management regulations (amendment)]. AB - Since medical equipment supervision and management regulations (Amendment) started modification in 2005, 7 years have passed. A few days ago, the Legal Affairs Office of the State Council issued Amendment Third Draft. After studied the draft, we feel it suits the medical device regulatory practice, has a new look, and introduces many new regulatory concepts, with innovative administrative license and regulatory design, of course, the new regulatory regime will inevitably initiate many new problems, explore some new system design. Therefore, based on preliminary interpretation, we publish some experiences, throw away a brick in order to get a gem. PMID- 23668043 TI - [Key technologies and implementation of the medical equipment road transportation simulation platform based on 6-DOF parallel robots]. AB - In view of the shortage of medical equipment road transportation simulation platform, we put forward a road transportation simulation method based on 6-DOF parallel robots. A 3D road spectrum model was built by the improvement of the harmonic superposition method. The simulation model was then compared with the standard model to verify its performance. Taking the road spectrum as the excitation, we could get the robot motion data to control the parallel robot through the S-shaped linear interpolation of the absolute position. It can simulate the movement of vehicles with different speed under various road conditions efficiently and accurately. PMID- 23668044 TI - [Study on holes testing methods of natural latex rubber condoms]. AB - Designed a contrast pinhole detect testing including water leak method, electrical method and improved electrical method, and concluded that the water leak method is most suitable as the arbitration method, and recommended the national standard add the requirement on electrolytic liquid filling volume of electrical test in order to improve detection accuracy. PMID- 23668045 TI - [Safety analysis and test advices of superconductive magnet]. AB - Based on the current GB standard and IEC standard, some unique security risk points of the superconductive magnet were discussed and pointed, some security eigenvalue of widely used MRI were calculated, method and technology of the quench risk & protection were focused. Currently during the type test of superconductive MRI, the national standards and industry standards have not included items focus on superconductive magnet particularly, so this paper gives some recommended discussing and hopes to improve and enhance the future standard. Because superconductive MRI uses a large number of helium gas which is very short in China and if quenching, helium will evaporate quickly, so the helium recycling are also discussed. PMID- 23668046 TI - [Comparison of ablation effect of Nd:YAG laser with different power and energy based on ultrasound guidance]. AB - To explore the optimum laser power and energy in porcine thyroid ablation in vitro with 1 064 nm Nd:YAG laser of different power and energy guided by ultrasound after comparison of size and pathology of ablation lesions. The experimental results showed that Laser ablation effect of porcine thyroid in vitro is definite, the size of ablation lesions increases as the laser power and energy increases, when the laser power and energy are 3 W and 1 800 J, the ablation lesion effect reaches ideal level. PMID- 23668047 TI - [Research and application of supply catalog and encoding identification technology applied to medical consumable materials management]. AB - In this article, medical consumable materials supply catalog technology was introduced through the principle, method and application of topic studies, at the same time bar code tags to tag and identify medical consumable materials were introduced. These two techniques established the correspondence between the real supplies logistics and information flow system, provided foundation for medical supplies all process tracking and traceability management. Supply catalog and encoding identification technology provide a new solution for the effective management of medical consumable materials. PMID- 23668048 TI - [2011 after-service customer satisfaction survey of monitoring devices in Shanghai area]. AB - In 2011, Shanghai Medical Equipment Management Quality Control Center launched the fifth after-sale service satisfaction survey for medical devices in Shanghai area. There are 8 classes medical devices involving in the survey. This paper demonstrates the investigation results of monitoring devices which are from different manufacturers. PMID- 23668049 TI - [Exploration and practice of the medical equipment maintenance management based on HRP]. AB - Based on HRP (Hospital Resource Planning) system's device management module, A new online information management system is proposed and realized to meet the new challenge of medical devices' repairing and maintenance. the traditional telephone report or online report can all be deal. the repair progress can be visualized in real time PM planning and it's early warning are added. PMID- 23668050 TI - [Application effect of meticulous management of operation room's endoscopic instruments]. AB - OBJECTIVE: Discussion meticulous management of operation room's endoscopic instruments for operation safety and efficiency. METHOD: Establishing an endoscopic management team, to strengthen the details of management, to establish and regulate a series processes of the endoscopic instruments. RESULTS: Endoscopic instruments' damage rate was decreased after its meticulous management, the missing parts number was reduced, the cleaning and sterilization effect were satisfied, physicians' satisfaction were increased. CONCLUSIONS: Endoscopic instruments meticulous management can maximize the utilization of endoscopic equipment, decrease hospital infection rate, safeguard the operation smoothly. PMID- 23668051 TI - [A method of medical device power supply maintenance]. AB - Based on the circuit board, we draw its circuit diagram. By analyzing the circuit diagram, we maintain medical device power supply and achieve the troubleshooting goal quickly. PMID- 23668052 TI - [Gambro hemodialysis reverse osmosis water treatment system troubleshooting]. AB - Described gambro hemodialysis reverse osmosis water treatment system can not supply water due to PC PLC failure, the reasons of failure were analysed, troubleshooting methods and procedures were introduced. PMID- 23668053 TI - Aberrant claudin-4 transcript levels in eutopic endometrium of women with idiopathic infertility and minimal endometriosis. AB - INTRODUCTION: Claudin-4 (CLDN4) is a transmembrane protein, responsible for cellular contact and organization. A different expression of claudin 4 in the endometrium, depending on the menstrual cycle and with peak at the aim of the 'implantation window', has been observed. CLDN4 is believed to play an important role in embryo implantation. THE AIM: The aim of the study was to compare the mRNA CLDN4 expression levels in two subgroups of infertile women (idiopathic infertility or minimal endometriosis) and compare them to fertile controls. METHOD: The study included 36 women with idiopathic infertility and 24 with minimal endometriosis. The control group comprised 26 women. Eutopic endometrium samples were collected with a Pipelle device during the implantation window. Firstly mRNA was extracted from the endometrium and reverse transcribed into cDNA. Real time PCR was used for the assessment of relative expression levels. RESULTS: The observed transcription level of CLDN4 did not differ statistically between the studied groups, but was significantly higher when compared to controls. CONCLUSIONS: Exceedingly high levels of CLDN4 might negatively influence fertility rates. PMID- 23668054 TI - [The value of progesterone and estrogen receptors expression in tissue microarray method in prognosis of patients with endometrioid endometrial cancer]. AB - OBJECTIVES: To assess prognostic significance of progesterone receptors (PR) and estrogen receptors (ER) expression in the tissue microarray (TMA) technique for disease free survival (DFS) and overall survival (OS) in endometrioid endometrial cancer (EEC). MATERIAL AND METHODS: The study included 151 consecutive patients, aged 37-86 years (62.80 +/- 9.99), with the EEC in stages I-III (FIGO), treated surgically at the Pirogow Memorial Hospital of Lodz between 2000 and 2007. Afterwards, they were subsequently treated and examined at the Regional Cancer Center, Copernicus Memorial Hospital of Lodz. Tissue cores 2 mm in size, in duplicate, were taken from the formalin-fixed and paraffin-embedded tissue donor blocks from surgery and constructed into the TMA recipient blocks. Using TMAs, the expression of PR and ER was examined and presented as Total Score (TS). The TS was determined by adding the intensity and marker distribution scores in a given case. The relationship between PR and ER expression, DFS and OS was examined. DFS was defined as the period from primary surgery until relapse. OS was defined as the period from primary surgery until the end of the follow-up (60 months) or until the death of the patient. The study was approved by the Ethics Committee of the Medical University of Lodz (RNN/82/11/KE). RESULTS: Lack of the PR and ER expression was found in 46 cases (30.46%) and 67 cases (44.37%), respectively. The expression of the PR and ER was weak in 24 cases (15.89%) and 22 cases (14.57%), respectively. Strong PR and ER expression was found in 81 patients (53.65%) and 62 patients (41.06%), respectively. Follow-up after surgery varied from 3 to 60 months (50.95 +/- 16.36). In 30 patients (19.87%) relapse was diagnosed 1-54 months (22.17 +/- 15.59) after surgery. During follow-ups, 29 patients (19.21%) died. In univariate analysis better DFS was related to the presence of PR (p = 0.010), higher TS of PR (HR = 0.81; 95% CI 0.71-0.94), the presence of ER (p = 0.001) and higher TS of ER (HR = 0.88; 95% CI 0.78-0.99). DFS differed significantly between the groups: without PR and ER expression (A), with presence of the PR but not ER expression (B), with the ER but not PR expression (C) and with the PR and ER expression (D) (p = 0.004). In univariate analysis OS was not related to PR expression (p = 0.110), TS of PR (HR = 0.89; 95% CI 0.80 1.02) and ER expression (p = 0.070). TS of ER was connected to better OS (HR = 0.83; 95% CI 0.72-0.96). The OS differed between groups A, B, C and D (p = 0.006). In multivariate analysis variants of PR/ER expression influenced the DFS (p = 0.039) and OS (p = 0.016). CONCLUSIONS: The expression of the PR and ER can significantly affect therapeutic decisions in selected patients with EEC. In EEC, common assessment of PR and ER expression is of higher prognostic value, than compared to single evaluation of PR and ER receptors. PMID- 23668055 TI - Analysis of false negative results of subjective ultrasonography assessment of adnexal masses. AB - OBJECTIVES: Currently transvaginal ultrasonography is the most effective method for ovarian tumor malignancy prediction. The aim of the study was to estimate the risk of false negative results in subjective interpretation of the ultrasound examination of ovarian tumors according to menopausal status. MATERIAL AND METHODS: 318 women (210 pre and 108 post menopause) with adnexal masses were diagnosed preoperatively between 2004 and 2010. Subjective assessment of tumor characteristics was conducted by experienced ultrasound examiner. Tumors were divided into groups of: "certainly benign" (n = 84), "probably benign" (n = 116), "uncertain" (n = 61), "probably malignant" (n = 47), and "certainly malignant" (n = 10). The percentage of false negative results was calculated among the first two groups according to menopausal status. RESULTS: There were 91 malignant and 227 benign adnexal masses diagnosed in histopathological evaluation. There was one false negative result of subjective interpretation of ultrasound findings in postmenopausal women - 1.6% (1/64). She was a 63-year-old woman with bilateral solid ovaries sized: 4.2 x 3.1 cm and 4.6 x 2.5 cm in ultrasound evaluation, where serous adenocarcinoma was diagnosed. There were three false negative results in premenopausal women - 2.2% (3/136). The first was a 34-year-old woman with a cyst with the appearance of ground glass of 19 x 11 cm in size where endometrioid ovarian adenocarcinoma was diagnosed. The second woman was a 32-year old with a bilocular cyst 8 x 4.5 cm diagnosed with borderline mucinous tumor. The third patient was a 21-year-old woman with unilocular-solid cyst 4.2 x 3.2 cm where histopathological examination revealed borderline serous tumor. CONCLUSIONS: Subjective ultrasound evaluation of adnexal masses has high specificity but even in the group of tumors considered benign in premenopausal as well as postmenopausal women malignancy can be found. This occurs slightly more often before menopause. PMID- 23668056 TI - A clinico-pathological evaluation of 194 patients with ovarian teratoma: 7-year experience in a single center. AB - OBJECTIVES: To evaluate patients diagnosed with teratoma over a period of seven years with regard to their general characteristics and treatment methods. MATERIAL AND METHODS: A total of 194 patients histologically diagnosed with ovarian teratoma (mature or immature) in the years 2005-2012 at the Ege University Gynecology and Obstetrics Department were evaluated. RESULTS: Average patient age was 34.3 +/- 2.16 years. Of these, 169 (86.3%) were premenopausal and 27 (13.7%) postmenopausal; average cyst diameter, measured during the surgery was 6.9 +/- 0.63 cm. While the teratoma had been an asymptomatic finding in 148 (75.5%) patients, 48 (24.5%) were symptomatic. In 107 patients (54.5%) a laparotomy and in 89 (45.5%) a laparoscopy were performed. The presence of torsion was observed during surgery in 9 (4.5%) patients. The 49 (55%) patients who underwent laparoscopic cystectomy experienced a rupture during the intervention, with no cases of clinical chemical peritonitis following the surgery CONCLUSION: Caution must be exercised with regard to possible cyst rupture in elderly patients and those with large dermoids; an laparoscopic approach may be reserved for younger patients. In case a rupture occurs during the operation, abundant peritoneal lavage is indicated; in order to limit risks during the controlled excision of the cyst an Endobag should be used if possible. PMID- 23668057 TI - Incidence and prevalence of multiple types of genital human papillomavirus (HPV) infection in men: a study in Poland. AB - OBJECTIVES: Infections with human papillomavirus (HPV) are sexually transmitted. Their prevalence in males is comparable to females, but infection in men is largely unknown. Since such information is needed to establish prevention strategies, the goal of our study was to estimate the incidence of type-specific genital HPV infection among men in Poland. MATERIAL AND METHODS: Within a multi center clinical preventive trial, penile sampling of 826 (100%) uncircumcised and sexually active males (aged 25-69 yrs.) was studied. Peniscopy was performed in addition to routine clinical examination. DNA HPV in smears was detected by hybrid capture (HC2) and in the biopsy material by means of polymerase chain reaction (PCR). RESULTS: Twenty-three HPV types were detected, including 11 high risk oncogenic (53-6.4% men) and in 65 (7.87%) individuals both oncogenic and nononcogenic simultaneously--altogether 118 (14.3%) and also 12 low-risk multiple nononcogenic types (248-30% men). Penile HPV prevalence was approximately 26.8%. In 53 (6.4%) cases we detected multiple oncogenic types (single HPV16 in only 17 cases--2.1%). Penile HPV DNA was detection did not appear to be associated with age. Our analyses also suggested a lower prevalence of HPV infection among male participants who reported consistent condom use and fewer sexual partners. In men with history of having more than 10 sexual partners over their lifetime increased the likelihood of detecting HPV DNA. CONCLUSIONS: Data from our study showing a high prevalence of HPV infection in the Polish population of men will be helpful for future studies on HPV transmission dynamics. PMID- 23668058 TI - [Knowledge of women and men about breast cancer prevention]. AB - OBJECTIVES: To assess the level of knowledge of men and women about the importance of mammography in preventing breast cancer. MATERIAL AND METHODS: The study group comprised 100 men and 100 women of the Provincial Hospital in Biala Podlaska. We used original questionnaires designed by the authors of the present study. RESULTS: Only 14% of women and 20% of men knew that over 4,000 women in Poland die of breast cancer annually. The respondents declared cervical cancer (88% of women and 76% men) and breast cancer (84% of the women and men) to be the major threat and health issue for women. Forty-eight percent of women reported that they had a check-up at their gynecologist in the past six months. Sixty-four percent of women declared that they performed breast self-examination, and 44% of women had examined the breasts more than a year ago. Thirty-eight percent of men did not know when their wife/partner had their breasts examined. Respondents from both groups knew most of the symptoms of suspected cancer. Ninety-seven percent of woman and 78% of man were able to indicate genetic factors that increase the risk of breast cancer. Fifty-two percent of women had a mammogram and 56% had a breast ultrasound. According to the men - 51% and 54% of women (wives/partners) had a mammogram and ultrasound, respectively. Only 47% of women received an invitation for a mammogram and 68% did not respond to it. According to men, 39% of their wives/partners received such as invitation and 68% of them did not use it. Seventy-four percent of the surveyed woman did not have a mammogram and 64% did not undergo a breast ultrasound in the last year. Seventy-six percent of women and 83% of men did not know the contraindications to mammography. Seventy percent of women and 68% of men argued that in order to perform a mammogram, one should consult a doctor for a referral. Sixty-six percent of women and 72% of men thought mammogram was the most effective method of detecting breast cancer. Thirty-two percent of women declared that they possessed knowledge about mammography. According to 65% of women and 66% of men, fear and fear of disease are the factors preventing patients from having a mammogram. Sixty-seven percent of women and 53% of men were of the opinion that the awareness of Polish women about breast cancer is average. Ninety percent of respondents supported the idea of bus mammography. The most well-known organizations involved in prevention of breast cancer proved to be the Amazons (86% of women and 84% men) and the AVON pink ribbon campaign (71% of women and 46% of men). Forty-six percent of women and 65% of men derived their knowledge about cancer from television and 47% of women and 46% of men from newspapers. Half of women and men thought that education about cancer should be initiated as early as middle school. According to the surveyed women the arguments that might convince women to participate in the exam were: the chance to take care of one's health (63%), possibility to have the test performed close to home (44%), no charge for the test (32%), or other unspecified factors (5%). According to respondents, men and women often would benefit from mammography if they could perform it in their neighborhood (62%) or if the mammogram could be performed free of charge (51%). CONCLUSIONS: Only half of the women ever had a mammogram, and only one-third of the surveyed females received invitations. As the most important barriers to preventive action, they reported lack of knowledge, lack of financial resources and limited access to mammography. Knowledge of men and women about mammography as a breast cancer prevention method is unsatisfactory. We should make an effort to increase the awareness of women and men about the importance of breast self-exam and participation in organized screening programs. PMID- 23668059 TI - [Relaxin 2--a pregnancy hormone involved in the process of carcinogenesis]. AB - Relaxin 2 is a polypeptide hormone structurally related to insulin and insulin like growth factors (IGFs). However it does not interact with insulin receptors and has a decidedly different biological properties. Relaxin 2 activates LGR 7 and LGR 8 relaxin receptors, that belong to the leucine-rich repeat-containing (LRR), G protein-coupled receptors. The characteristic functions of relaxin are associated with female reproductive system, especially during pregnancy. However recent studies have shown that polypeptides with relaxin-like factor family (RLF) are involved in cell proliferation and differentiation, as well as invasion and angiogenesis of female and male reproductive cancers. This review provides information on the structure and function of relaxin and its receptors. Furthermore, we present evidence of the involvement of these elements in the process of cancerogenesis. PMID- 23668060 TI - [Legal aspects in pediatric and adolescent gynecology]. AB - Childhood and adolescent gynecology is an emerging specialty at the intersection of pediatrics, pediatric endocrinology gynecology pediatric surgery dermatology psychiatry, public health medicine and genetics, and in fact addresses many legal issues. Poland lacks a uniform standing of medical and legal environments on how to deal with a juvenile patient who has become sexually active and seeks the advice of a gynecologist, gynecologic examination and requests to be prescribed contraceptives. It needs to be taken into account that in Poland a parent or a legal guardian has legal guardianship, custody and control of a child until 18 years of age but once a juvenile reaches the chronological age of 16 years, and is given full rights of a patient, both parties need to consent to medical care. According to the Act on Health Care Institutions, a patient has the right to self determination, respect for physical and mental integrity as well as privacy whereas, after the patient reaches the age of 16 years, the legal representative becomes in practice a mere co-decision maker to have medical services performed. Therefore, information obtained from a juvenile patient during physical test and medical interview does not have to be revealed to a legal representative, if the patient requests confidentiality and on condition it does not affect patient health and/or the planned medical procedures (e.g. the need to perform an operation). Knowledge about procedures for juvenile patients shall enable doctors to make conscious choices about conduct and care or in most cases, only advice, without the risk of breaching the Polish law. PMID- 23668061 TI - [Intestinal obstruction during pregnancy]. AB - This is a review of literature concerning intestinal obstruction in pregnant women. Approximately 50-90% and 30% of pregnant women, respectively suffer from nausea and vomiting, mostly during the first trimester. There is also increased risk of constipation. During the perioperative period, the administration of tocolytics should be considered only in women showing symptoms of a threatening premature delivery. Intensive hydration should be ordered to sustain uterine blood flow. The incidence of intestinal obstruction during pregnancy is estimated at 1:1500-1:66431 pregnancies and is diagnosed in II and III trimester in most cases. However, it can also occur in the I trimester (6%) or puerperium. Symptoms of intestinal obstruction in pregnancy include: abdominal pains (98%), vomiting (82%), constipation (30%). Abdominal tenderness on palpation is found in 71% and abnormal peristalsis in 55% of cases. The most common imaging examination in the diagnosis of intestinal obstruction is the abdominal X-ray. However ionizing radiation may have a harmful effect on the fetus, especially during the first trimester. X-ray is positive for intestinal obstruction in 82% of pregnant women. Ultrasonography and magnetic resonance imaging are considered safe and applicable during pregnancy. Intestinal obstruction in pregnant women is mostly caused by: adhesions (54.6%), intestinal torsion (25%), colorectal carcinoma (3.7%), hernia (1.4%), appendicitis (0.5%) and others (10%). Adhesive obstruction occurs more frequently in advanced pregnancy (6% - I trimester 28% - II trimester; 45% - III trimester 21% - puerperium). Treatment should begin with conservative procedures. Surgical treatment may be necessary in cases where the pain turns from recurrent into continuous, with tachycardia, pyrexia and a positive Blumberg sign. If symptoms of fetal anoxia are observed, a C-section should be carried out before surgical intervention. The extent of surgical intervention depends on the intraoperative evaluation. Intestinal torsion during pregnancy mostly occurs in the sigmoid colon and cecum. Small bowel torsion secondary to adhesions is diagnosed in 42% of pregnant women with intestinal obstruction. The risk of intestinal torsion is higher in the 16-20 and 32-36 weeks of pregnancy and during puerperium. Intestinal torsion results in vessel occlusion which induces more severe symptoms and makes urgent surgical intervention necessary. The overall prognosis is poor--during II and III trimester the fetal mortality rate reaches 36% and 64%, respectively while the risk of maternal death is 6%. Acute intestinal pseudoobstruction can be diagnosed during puerperium, especially following a C-section. Diagnosis is made on the basis of radiological confirmation of colon distension at the cecum as > 9cm, lack of air in the sigmoid colon and rectum, exclusion of mechanical obstruction. In most cases, the treatment is based on easing intestine gas evacuation and administering neostigmine. The authors point out the need for multi-specialty cooperation in the diagnostic-therapeutic process of pregnant women suspected with intestinal obstruction, since any delay in making a correct diagnosis increases the risk of severe complications, both for the woman and the fetus. PMID- 23668062 TI - [Total pelvic exenteration in vaginal cancer--case report]. AB - Vaginal cancer is a rare neoplasm and in about 65% to 90% of cases it is a metastatic one. It is diagnosed in women aged from 60 to 70 years, but it can also appear in younger patients. Squamous cell carcinoma is the most frequently found histopathological type. Risk factors for the development of vaginal cancer are thought to be similar to those of cervical cancer. We present a case of a 52 year old woman with vaginal cancer treated with brachytherapy. Due to neoplasm recurrence, additional examinations were performed in the course of one year. The patient was qualified for total pelvic exenteration. A leakage from the abdominal wound was observed post operatively. It was successfully noninvasively treated. In 3 months time she was hospitalized because of the superficial abdominal abscess which was located next to the left ureterostomy. The patient undergoes regular gynecological, surgical and urological control examinations. So far the results do not show any recurrence of the neoplastic process. Total pelvic exenteration should be considered in selected groups of patients. PMID- 23668063 TI - [Huge uterine leiomyoma with degenerative changes mimicking ovarian carcinoma--a case report]. AB - Leiomyomas are the most common benign uterine tumors. Although 20-40% of all women in reproductive age may have uterine leiomyomas, they are not very common in pregnancy. Only 0.3-2.6% af all pregnant women are diagnosed with leiomyomas. The leiomyomas are symptomatic in 20-50% of all cases. Clinical symptoms are usually excessive or irregular menstrual bleeding, problems resulting from adjacent organs pressure, sterility miscarriage or problems during the labour. Leiomyomas are known to have estrogen receptors and can demonstrate an extensive growth in high estrogens concentration environment. During the pregnancy they can grow, stay the same size or as well decrease. Rapid leiomyoma's growth, caused by its transformation into sarcoma, takes place in about 0.1-0.8% of all cases. In this article we present a case of patient with leiomyoma, which rapid growth, which imitated ovarian tumor. A 40-year old patient was admitted to the 1st Department of Obstretrics and Gynecology Medical University of Warsaw, in May 2012 because of a large abdominal tumor. She had four vaginal deliveries and one cesarean section. The patients delivered three months before admission. Since the labour she had suffered from dysuria and noticed a quick waits enlargement. On admission the patient was in good general condition, without any stomachache. A giant tumor in her lower and middle abdomen was found. The tumor reached three fingers above the navel. In the ultrasound scan a large solid-cystic the tumor with moderate vascularization was described. It looked like the ovarian neoplasm. The CA-125 plasma concentration was 389,5 IU/ml. After giving a written informed consent the patient had an operation. During the operation a solid-cystic peducled uterine tumor was diagnosed. The diameter of the tumor was about 25 cm. The uterine and uterine appendages had no pathological macroscopic changes. Intraoperative histopathological examination was carried out and revealed mesenchymal tumor without evident polymorphism or mitosis. Because of lack of any signs of malignancy during the operation only the tumor with its peduncle was removed. The patient was discharged in good general condition after three day of postoperative hospitalization. The final histopathological examination revealed leiomyoma with cystic degeneration changes. A small focus of necrosis and extravasation was found. 4 weeks after the operation there were no abnormalities in the gynecological examination and the CA-125 concentration was 27 IU/ml. The presented case illustrates diagnostic difficulties, which may occur when atypical rapid tumor enlargement and its ultrasound image and laboratory tests results imitate ovarian tumor. PMID- 23668064 TI - [Regression of cystic lesions on brain MRI in a child with hypoxic-ischemic encephalopathy treated with selective head cooling]. AB - The authors present the first case of regression of cystic lesions on brain MRI in a newborn after therapeutic hypothermia in Poland. Multicystic encephalopathy is the most severe form of hypoxic-ischemic encephalopathy and its regression is described very rarely in the literature. Magnetic resonance imaging is an accepted, optimal method of evaluation of the brain and establishing prognosis in children with HIE. After normal pregnancy an emergency cesarean section was performed at 37 weeks gestation due to the markers of intrauterine hypoxia on CTG. The condition of the newborn was serious: 3, 5, 7, 8 points according to Apgar score in 1st, 3nd, 5th and 10th minute of life, respectively. The infant required resuscitation. The cooling procedure lasted 72 hours. The first MRI study was performed at the age of 3 weeks and revealed cavities in the frontal and parietal lobed. The Evans index was 0.33. The second MRI investigation was carried out at the age of 5 weeks. The cavitary appearance did not change, the Evans index decreased to 0.32. The child underwent third MRI at the age of 2 years 4 months. No cystic lesions were found. There were signs of gliosis in their place and focal cortical-subcortical atrophy. The Evans index was 0.28 (within the normal limits). The neuropsychological status of the child at the age of 2.5 years is normal and brain MRI reveals strikingly mild lesions as compared to cavitary injury reported at the age of 3 and 5 weeks. The presented case shows that severe hypoxic-ischemic lesions such as cavities in an infant after cooling procedure do not necessarily mean poor prognosis, as with time even such lesions may regress. Therefore, even after the MRI diagnosis of multicystic encephalopathy the prognosis should be made with care. PMID- 23668065 TI - [Recommendation of the Polish Gynaecologic Society Experts concerning application of Mastodynon in gynaecology?]. PMID- 23668066 TI - [Stereotaxis for human neurosurgery]. AB - The article is devoted to main principles of acad. N.P. Bechtereva the scientific school such as the complex method to study the human brain, the method of intracerebral long-term electrodes, the stereotactic method (computerized stereotaxy) and their development combined with the modern method of intrascopy (tomography). The connection between multitude electrodes methods and investigations of pathophysiological mechanisms of Parkinson disease, temporal epilepsy, various forms of obsessive-compulsive syndromes is studied. PMID- 23668067 TI - [Functional biomarkers in the diagnostics of mental disorders: cognitive event related potentials]. AB - The article is devoted to recent researches in the field of fundamental knowledge about the mechanisms of information processing in human brain for the diagnosis of mental disorders performed in the laboratory of neurobiology for action programming of the Bechtereva Institute of Human Brain, RAS. These researches were connected with analysis of functional components for cognitive ERPs obtained in diverse behavioral conditions. The main goal of this fundamental approach is the decomposition of multi-channel ERPs into functionally different components. These components are generated in various cortical areas have different temporal dynamics and reflect a variety of mental operations. The main methodology we used is the independent component analysis, applied to a large set of ERPs (from hundreds of people) obtained by varying of functional conditions in one psychological test. In particular, components related to psychological processes such as the comparison of sensory signals with the trace in working memory, inhibition of current activity, monitoring of the conflict were identified in the GO/NOGO test. In the framework of European project normative database was constructed for the components described above and this allowed comparing the data obtained from large groups of patients (including patients with attention deficit disorder, schizophrenia, obsessive disorders, depression, autism, dyslexia, brain trauma and dementia) with the healthy subjects. This article presents data from patients with a diagnosis of attention deficit disorder and schizophrenia. PMID- 23668068 TI - [Polyfunctionality of neurons: blocking of the extreme pathological afferentation leads to an improvement of the higher functions of the brain (on the example of patients in a vegetative state)]. AB - In this paper possible mechanism of improvement of the functional state of the brain areas, maintaining movement, visual, auditory, and higher functions of the brain during correction of generalized spastic syndrome (botulinotherapy with Xeomin) in patients in a vegetative state (VS) is discussed. If to consider the vegetative state as stable pathological condition (SPC) of the brain, then from the perspective of the theory of structural and functional organization of the brain with systems with rigid and flexible elements (N.P. Behtereva), the therapy led to an unbalance of SPC, "functional release" of neurons and redistribution of their functions to provide other activities, the formation of new interneuronal connections. Taking into account the functional variability of neurons (S.V. Medvedev), blocking neuromuscular transmission in spastic muscles leads to a reduction of abnormal afferent and efferent hyperactivity of motor and sensory neuronal circuits, which releases the brain for other activities. This allows to consider botulinotherapy of pharmacoresistant muscle spasticity in patients in VS and minimal consciousness, not only as a symptomatic treatment, but also as a "indirect neuroprotection". PMID- 23668069 TI - [Power spectra of the main EEG rhythms in children with different types of attention deficit hyperactivity disorder]. AB - We investigated a group of children aged 9-12 years with attention deficit hyperactivity disorder (ADHD) combined type, have divided into two variants of the clinical picture of ADHD: residual-organic variant (ADH D RO) and idiopathic variant (ADHD RI). We studied the power spectral analysis in the main frequency bands in background EEG eyes closed and are open. The significant differences between both groups observed in the theta frequency band in the fronto-central and occipital leads. In the fronto-central leads of the cortex were the maximum values in the group of children ADHD RO, whereas in children with ADHD IR, the largest values of power spectra were in the occipital leads. Statistically significant differences in spectral power in the alpha range between healthy subjects and groups children with ADHD had not been received. Thus, our studies have shown that these two variants of ADHD have some neurophysiological differences that must be considered when choosing a treatment. PMID- 23668070 TI - [Improving source localization of ERPs in the GO/NOGO task by modeling of their cross-covariance structure]. AB - We studied 19-channel event-related potentials (ERPs) during the GO/NOGO task in 517 healthy subjects. Decomposition of multi-channel ERP into independent components was performed with a method based on modeling the cross-covariance structure of the transient response. The results show that this method allows us to obtain low-correlated components with acceptable reliability. The identified components have been associated with psychological processes such as the attended sensory mismatch operation, the decision-making on the subsequent action, the action inhibition operation, the conflict monitoring operation and others. In conclusion, the separation of the ERP recording into independent components and the use of the sLORETA helps localizing sources of ERPs more accurately than the conventional analysis of the ERP. PMID- 23668071 TI - [Neuroimmunology: theoretical and clinical aspects]. AB - The aspects of neuroimmune interactions (during cerebral ischemia and stroke- experimental and clinical data, demyelinating process in patients with multiple sclerosis,secondary immunodeficiency) are discussed in this article. Literature overview and authors' experience are presented as well. PMID- 23668072 TI - [Factor structure of regional CBF and CMRglu values as a tool for the study of default mode of the brain]. AB - In the present article it was shown that the functional connectivity of brain structures, revealed by factor analysis of resting PET CBF and rCMRglu data, is an adequate tool to study the default mode of the human brain. The identification of neuroanatomic systems of default mode (default mode network) during routine clinical PET investigations is important for further studying the functional organization of the normal brain and its reorganizations in pathological conditions. PMID- 23668073 TI - [Pathology of the anterior cingulate cortex in obsessive compulsive disorder]. AB - In the present article the features of the functional activity of the anterior cingulate cortex (ACC), a key element of neuroanatomical brain system of an error detection, in drug-resistant forms of obsessive-compulsive disorder (OCD) are discussed on a basis of both original and literature data. Available data indicate the presence of functional deficit in the ACC during OCD. This allows to suggest that functions of the ACC in OCD patient are partially redistributed between other brain areas. Thus in contrast to the previously accepted notion, the ACC as the target ofstereotactic surgery for OCD is pathologically altered brain region. Probably this is the reason why stereotactic destruction of ACC does not lead to significant changes in the patient's psyche. The essence of the pathological reorganisation of the functional activity of the brain in OCD remains unclear and requires further investigation. PMID- 23668074 TI - [Frontal bilateral synchronous theta-waves and the resting EEG coherence in children aged 7-8 and 9-10 with learning difficulties]. AB - The resting state cortical functional connectivity was studied in children of 7-8 (N = 29) and 9-10 (N = 23) years with learning difficulties whose EEG showed the frontal bilateral synchronous theta waves (FTW) and in the control children of 7 8 (N = 32) and 9-10 (N = 16) years who did not experience school difficulties and whose EEG did not show signs of abnormality. The functional connectivity was estimated in the theta, alpha1, alpha2, and beta1 frequency bands via measuring the coherence for the resting EEG that was free from any abnormal patterns. Compared to control children, there was a reduction in the strength of the functional coupling between the frontal and anterior temporal cortices found predominantly in the left hemisphere of FTW children. The relative weakness of the coupling between the frontal cortex and the other cortical areas was more pronounced in children of 7-8 than in children of 9-10 years. These between-group differences were unaffected by the frequency band or gender factors. PMID- 23668075 TI - [Eye movements during reading as an indicator of development of reading skill]. AB - In this issue the parametres of oculomotor activity were investigated by the eye movements videoregistration's method at reading of texts of different complexity by pupils with various reading skill level. The parametres of eye movements and their determination is described. It is shown that the general time of reading, average fixations duration and total regressions count decreases, average amplitude progressive and regressive saccades increases in process of development reading skill. That testifies to perfection of mechanisms of implementation cognitive processes that form the basis of reading. PMID- 23668076 TI - [The autonomic correlates of individual differences in the time parameters and effectiveness of intellectual activity of the person]. AB - The individual differences of autonomic support of intellectual activity (simple and complex sensorimotor reaction, storing and reproduction to the screen of the monitor of the visual information) were studied. Intellectual computer tests passing speed is a relatively steady individual characteristic, revealed in different kinds of activity. Students who reached high speed and accuracy in performance of intellectual visually-motor tasks were characterized high lability of autonomic indices, which manifests itself in a change in the absolute values and relationship of the characteristics of heart and respiration rate in accordance with activity stages. These changes were specific for each form of activity and were connected with the results of the tests. In an initial condition these students differed high values of TP and power of LF and HF ranges of heart rate variability at a LF/HF ratio close to unity. PMID- 23668077 TI - [Voluntary alpha-power increasing training impact on the heart rate variability]. AB - In order to study the effect of the alpha EEG power increasing training at heart rate variability (HRV) as the index of the autonomic regulation of cognitive functions there were follow tasks: (1) to figure out the impact of biofeedback in the voluntary increasing the power in the individual high-frequency alpha-band effect on heart rate variability and related characteristics of cognitive and emotional spheres, (2) to determine the nature of the relationship between alpha activity indices and heart rate variability, depending on the alpha-frequency EEG pattern at rest (3) to examine how the individual alpha frequency EEG pattern is reflected in changes HRV as a result of biofeedback training. Psychometric indicators of cognitive performance, the characteristics of the alpha-EEG activity and heart rate variability (HRV) as LF/HF and pNN50 were recorded in 27 healthy men aged 18-34 years, before, during, and after 10 sessions of training of voluntary increase in alpha power in the individual high-frequency alpha band with eyes closed. To determine the biofeedback effect on the alpha power increasing training, data subjects are compared in 2 groups: experimental (14) with the real and the control group (13 people)--with mock biofeedback. The follow up effect of trainings was studied through month over the 10 training sessions. Results showed that alpha biofeedback training enhanced the fluency and accuracy in cognitive performance, decreased anxiety and frontal EMG, increased resting frequency, width and power in individual upper alpha range only in participants with low baseline alpha frequency. While mock biofeedback increased resting alpha power only in participants with high baseline resting alpha frequency and did change neither cognitive performance, nor HRV indices. Biofeedback training eliminated the alpha power decrease in response to arithmetic task in both with high and low alpha frequency participants and this effect was followed up over the month. Mock biofeedback training has no such effect. The positive correlation between the alpha-peak frequency and pNN50 in patients with initially low, but negative--those with high baseline alpha frequency explains the multidirectional biofeedback effects on HRV in low and high alpha frequency subjects. The individual alpha-frequency EEG pattern determines the effectiveness of the alpha EEG biofeedback training in changing heart rate variability, which provides a basis for predicting the results and develop individual approaches to the biofeedback technology implementation that can be used in clinical practice for treatment and rehabilitation of psychosomatic syndromes and in educational training. PMID- 23668078 TI - [Comparative analysis of gas exchange and cardiorespiratory systems reactions to increasing normobaric hypoxia and physical load of swimmers and skiers]. AB - Qualification comparable groups of young men engaged in cyclic kinds of sports were tested with stepwise accruing loads on bicycle ergometer and 25-minute exponential increasing normobaric hypoxia to final concentration of 10% oxygen. Group of skiers, having the greatest values of the maximal oxygen consumption at muscular work, show the relaxed cardiorespiratory reactions and more falling of blood oxygen in the hypoxia. The swimmers, having restrictions of ventilatory function in the course of trainings, form preadaptation to hypoxia with changes of external respiration and gas exchange functions that allows at hypoxia to better oxygen sate the blood in lungs. The joint assessment of aerobic capacity at physical work and physiological reactions to hypoxia shows the direct relation between individual maximal oxygen consumption and the descent rate of blood oxygen saturation at accruing hypoxia that can be useful at an assessment of a sportsman functional state and its correction at training processes. PMID- 23668079 TI - [Estimation of the forced expiration tracheal sounds intensity]. AB - The investigation of tracheal sounds of forced expiration is realized on the basis of the mathematical model of forced expiration. It is demonstrated that a separation flow in the region of a dynamical contraction trachea during forced expiration may to cause tracheal sounds generation. PMID- 23668080 TI - [Genetic regulation of plant shoot stem cells]. AB - This article describes the main features of plant stem cells and summarizes the results of studies of the genetic control of stem cell maintenance in the apical meristem of the shoot. It is demonstrated that the WUS-CLV gene system plays a key role in the maintenance of shoot apical stem cells and the formation of adventitious buds and somatic embryos. Unconventional concepts of plant stem cells are considered. PMID- 23668081 TI - [Parental effects of conditional mutations and their explanations]. AB - A study of the properties of conditional dominant and recessive lethals in Drosophila melanogaster has demonstrated parental effects in the inheritance and manifestation of these mutations. Maternal and paternal effects are present when conditional mutations interact with (1) one another, (2) the Y chromosome, or (3) chromosomal rearrangements, as well as (4) when the visual expression of a conditional mutation is inherited or (5) during the formation ofmorphoses (monstrosities) in mutant offspring. The maternal and paternal effects do not exclude one another: the same mutation can display both patterns. The characters manifesting themselves at late developmental stages (morphoses) are inherited according to a parental effect pattern. A general concept of the parental effect is proposed and its types are classified. PMID- 23668082 TI - [Microevolutionary changes in populations of Chironomus nuditarsis Str. (Keyl, 1962) (Chironomidae, Diptera) from central Caucasus]. AB - Karyotypes of the Chironomus nuditarsis Str. (Chironomidae, Diptera) (Keyl, 1962) chironomids from central Caucasian populations located at different altitudes above the sea level (a.s.l.) were examined. Specific features of the inversion polymorphism of the high-mountain (more than 1000 m a.s.l.), foothill (500-1000 m a.s.l.), and plain (up to 500 m a.s.l.) populations were identified. A new chromosome banding sequence, ndt F2 (lg-e 7a-8c), which was endemic to Caucasian populations, was described. With the increase in the altitude of the reservoir a.s.l., the decrease in the frequency ofndt G1.2 and ndt B2.2 inversions and the number of inversions per individual and per arm was observed. In the high mountain population, only the ndt G2.2 homozygotes were detected. The plain population is an interstitial population, while foothill and high-mountain populations are terminal. Cytogenetic distances between the high-mountain and other samples range from 0.174 to 0.223, which is higher than the mean interpopulation value for this species (0.138). The allochrony of the life cycle in aborigines from the foothill population and aborigines from the high-mountain population can be caused by factors such as low high-mountain reservoir temperature. This factor increases the duration of the stages of larvae developmental, which leads to a reduced number of generations and results in a shift in the imago flight and mating timing. PMID- 23668083 TI - [Interspecies variability of number of bristles on dorsal surface of aedeagus in D. virilis species group and its genetic mapping with interspecies hybrids of D. virilis and D. lummei]. AB - The results of morphologic and hybrid analyses of the feature of the male reproductive system of sibling species in the virilis group were presented. Bristles appeared on the surfaces of male genitals (aedeagus). The occurrence of a specific expression of the examined feature in the phyllades of D. virilis group, the correspondence of both the number and distribution pattern of the bristles on surfaces ofthe aedeagus and developmental temperature in D. virilis and D. lummei, as well as the link between feature and sexual behavior, have been shown. Dominance of D. lummei phenotype in the interspecies D. virilis x D. lummei was found. The interspecies hybrids D. virilis and D. lummei were used for a genetic analysis of the variability of the examined feature. The significant influence of chromosomes 2 and 6 on the number of bristles on the aedeagus in hybrid males was shown. Furthermore, the correspondence between the effects of the autosomes 2 and 6 on the variability of the examined feature and the genetic status of the other chromosomes (the effect of interaction between genetic factors, chromosomes here) was revealed. The adaptive value of the examined feature related to the involvement in the formation of isolating barriers at the copulation stage is under discussion. PMID- 23668084 TI - [Selection of initiation replication mutants of IncP-9 plasmid pBS267]. AB - A minireplicon containing the rep gene and oriV site of the gamma subgroup of the IncP-9 caprolactam pBS267 biodegradation plasmid was cloned for the first time. It was established that a minimized variant of pBS267 plasmid cannot be sustained in E. coli and is inherited in an unstable way in bacteria Pseudomonas. Using in vitro mutagenesis, mutant variants of the minireplicon were produced, characterized by an increased number of copies in cells, the ability to replicate in E. coli, and relatively stable inheritance in P. putida cells. The obtained constructs are the basis for a study of the replication mechanisms of IncP-9 group plasmids, as well as use as vectors for molecular cloning in a wide range of gram-negative bacteria. PMID- 23668085 TI - [Selective elimination of alleles in rice anther cultures]. AB - The nature of heterosis is discussed and selective elimination of alleles (introduced in the hybrid genotype by the parental forms) in anther culture is shown. This supports the possibility of removing viability-reducing alleles (lethal, semilethal, and less effective alleles) from the genotypes of heterotic hybrids in anther culture. PMID- 23668086 TI - [Genetic diversity, population structure, and differentiation of Siberian larch, Gmelin larch and Cajander larch on SSR-markers data]. AB - The genetic diversity of SSR markers was studied in six populations of Siberian larch, two populations of Gmelin larch, and four populations of Cajander larch. Seven pairs of nuclear microsatellite loci were used for this analysis. 103 allelic variants were detected in 365 individuals of three species of larch. According to the AMOVA results, the variability proportion that characterizes the differences between three Larix species was twice as higher (15%) than the proportion that accounts for among-population differences within the species (6%). The differentiation of the populations of three species of larch based on SSR markers exceeded 12% (FsT = 0.121). A significant correlation of the genetic distances with the geographic distances between populations was found (r = 0.835, P = 0.01). PMID- 23668087 TI - R-ISSR - for fingerprinting, mapping and identification of new genomic loci in rye (secale cereale l.). AB - The results of the research confirming the possibility of applying various combinations of RAPD and ISSR primers in one multiplex PCR and the generation of a new type of R-ISSR products for the rye genome were presented in this work. The following was applied in the research: five rye genotypes including two inbred lines (153/79-1 and Otl-3), hybrid F1 and two bulks (tolerant and susceptible) formed from recombinant inbred lines - RILs (F9) varying in the response to abiotic stress caused by nutrient deficiencies at the seedling stage. While evaluating the possibility of applying R-ISSR to the assessment of the rye variability, five of its genotypes were amplified separately with the RAPD and ISSR primers in each PCR reaction. These primers were combined in R-ISSR amplifications. The products of RAPD, ISSR and R-ISSR amplification were separated in 1.5% agarose gel. 32 R-ISSR combinations were examined, combining 20 and 8 selected RAPD and ISSR primers, respectively. 658 loci were amplified, including 230 RAPD, 180 ISSR and 271 R-ISSR, including 157 new loci. Over 91 loci were found, with an identical electrophoretic mobility for three methods. It was shown that R-ISSR products with electrophoretic mobility on agarose gels, identical to the co-migrating RAPD or ISSR, are not products of RAPD or ISSR, but they possess sequences of heteroamplicons - R-ISSR. The occurrence of sequences of primers used to R-ISSR was demonstrated while sequencing seven selected products of the above type. The ISSR primers with a low Tm were proven to generate repeatable fingerprints in the thermal profile of the reaction specific for RAPD and combined with the RAPD primer - repeatable R-ISSR profiles. A similar range of variability as described in RAPD or ISSR was observed in the R ISSR profiles. The correlation coefficient between genetic similarity matrices for five rye genotypes, calculated with the Mantel test, amounted to rABC = 0.870. PMID- 23668088 TI - Genotype x environment interaction patterns for grain yield of spring barley in different regions of Kazakhstan. AB - Barley plays an important role in agricultural sector of Kazakhstan and it is grown in many different climate zones over 1.5 min hectares annually. Therefore development of optimal cultivars for specific environments is a major challenge for barley breeding community in Kazakhstan. One of the approaches to address this question is to test large collection of commercial cultivars and advanced lines over a number of environmental sites that reflect major spatial and temporal climate variations in the country. In this work 103 cultivars and advanced lines of spring barley bred in six different breeding stations of Kazakhstan were grown in different testing sites in seven regions over 2009-2011 years. The major tasks of this research were to evaluate genotype x x environment interactions and assess grain yield in associations with developmental stages of barley, such as heading date and seed maturation date. The results suggest that (i) heading and seed maturation dates are significantly correlated with grain yield in specific regions and may have opposite correlation indexes in response to environmental conditions; (ii) accessions of different bred origin vary in their ability to exhibit environmentally-dependent plastic responses; (iii) spatial variation was more important than temporal variation in GxE interactions; (iv) biplot analysis is effective approach in identification of best suitable and stable accessions for both broad and narrow environments. The obtained results are further contribution to understanding of complex mechanisms of genotype x environment interactions. PMID- 23668089 TI - [Molecular genetic identification and phylogeny of Daphnia species (Crustacea, Cladocera) from water bodies of Lake Chany basin]. AB - The data on the molecular genetic identification of Daphnia species from the water bodies of Lake Chany basin are presented. Phylogenetic relationships between these species have been established. The fragments of the mitochondrial DNA 16S and 12S genes were used as genetic markers. According to the data obtained, the water bodies examined were inhabited by five Daphnia species, including Daphnia (Daphnia) galeata Sars, D. (D) longispina O. E Muller, D. (D) curvirostris Eylmann, D. (D) pulex Leydig, and D. (Ctenodaphnia) magna Straus. In addition, a group of longispina-like individuals that form a separate phylogenetic cluster was identified. PMID- 23668090 TI - [The pleiotropic effect of selection for behavior on coat color in grey rats (Rattus norvegicus)]. AB - The effects of selection for a type of behavior relative to humans (tame and aggressive) on the intensity of coat color in agouti rats with the AAHH genotype were studied. Animals that were not under selection for behavior (wild animals) were used as the control. Morphometric analysis of the hair parameters that influence the intensity of coat color demonstrated that, on the one hand, polymorphism in the main coat color exists in the population of wild agouti rats, that is, both light and dark agouti animals exist. On the other hand, it was demonstrated that selection for a type of behavior in rats is accompanied by selection of animals that differ in the intensity of the main genetically identical coat color. Dark-colored animals are more prevelent among the aggressive animals, while light-colored animals prevail among tame animals. The association of the effects of selection for behavior with the modification of coat color is probably caused by the presence of common neurohormonal mechanisms for the regulation of these processes. PMID- 23668091 TI - [Genetic structure of sable (Martes zibellina L.) from Eurasia based on distribution of mitochondrial lineages]. AB - The phylogeography of the sable, which is a commercially valuable species, is extremely complicated and poorly investigated. Specifically, the effects of factors such as the range dynamics of the sable during the Pleistocene Epoch, the localization of glacial refugia, species distribution pattern in Holocene, and recent dramatic population decline, along with massive reacclimatization measures, on the species phylogeography remain unclear. Based on the sequence analysis of the control region of mitochondrial DNA from sables that inhabit different parts of the species range, a suggestion was made of the considerably high Pleistocene genetic diversity in sable, which was subsequently lost. The initial diversity of mitochondrial lineages is mostly preserved in the Urals, while in the eastern part of the range, it seems to have been depleted as early as before the last glacial maximum. On the other hand, the even greater depletion of the mitochondrial lineages observed in some populations of central Siberia can be associated with the dramatic population decline at the turn of the 20th century. PMID- 23668092 TI - [Increased risk of tisomy 21 in offspring of carriers of balanced non contributing autosomal rearrangements is not explained by interchromosomal effect]. AB - Only relatively recently the suggestion that interchromosomal effect (ICE) may be present in man had stopped to be argued. At once it became evident that this phenomenon is inherent to a proportion of balanced chromosome rearrangement carriers, predominantly to patients with fertility problems. It is important to establish whether ICE operates in genome of fertile rearrangement carriers and to determine what kind of rearrangement and how far increases a risk of aneuploidy offspring. Using own and literature data 1) we have assessed rates of inherited non-contributing balanced rearrangements in patients with trisomy 21 (T21) and rates of both mutant and inherited non-contributing balanced rearrangements in parents of offspring with T21 and 2) we have analyzed a parental origin of T21 in affected offspring of carriers of balanced rearrangement. We have found that carriers of balanced reciprocal translocation or inversion, but not robertsonian translocation, are at increased risk of T21 offspring. However these data do not support the existence of ICE in its common sense, i.e. as an effect of rearrangement on other chromosome's segregation at the carrier's meiosis. Probably the data obtained suggest an effect of paternal rearrangements on maternal chromosomes segregation after fertilization. PMID- 23668093 TI - [Analysis of H63D mutation in hemochromatosis (HFE) gene in populations of central Eurasia]. AB - An analysis of the frequency of H63D (c. 187C>G) mutations in the HFEgene in 19 populations from Central Eurasia demonstrated that the distribution of the mutation in the region of interest was not uniform and that there were the areas of H63D accumulation. The investigation of three polymorphic variants, c.340+4T>C (rs2071303, IVS2(+4)T>C), c.893-44T>C (rs1800708, IVS4(-44)T>C), and c.1007-47G>A (rs1572982, IVS5(-47)A>G), in the HFE gene in individuals homozygous for H63D mutations in the HFE gene revealed the linkage of H63D with three haplotypes, *CTA, *TG, and *TTA. These findings indicated the partial spread of the mutation in Central Eurasia from Western Europe, as well as the possible repeated appearance of the mutation on the territory on interest. PMID- 23668094 TI - The 5q31 region in two African populations as a facet of natural selection by infectious diseases. AB - Cases of extreme natural selection could lead either to rapid fixation or extinction of alleles depending on the population structure and size. It may also manifest in excess of heterozygosity and the locus concerned will be displaying such drastic features of allele change. We suspect the 5q31 in chromosome 5 to mirror situation of such extreme natural selection particularly that the region encompasses genes of type 2 cytokine known to associate with a number of infectious and non-infectious diseases. We typed two sets of single nucleotide polymorphisms (SNPS) in two populations: an initial limited set of only 4 SNP within the genes of IL-4, IL-13, IL-5 and IL-9 in 108 unrelated individuals and a replicating set of 14 SN P in 924 individuals from the same populations with disregard to relatedness. The results suggest the 5q31 area to be under intense selective pressure as indicated by marked heterozygosity independent of Linkage Disequilibrium (LD); difference in heterozygosity, allele, and haplotype frequencies between generations and departure from Hardy-Weinberg expectations (DHWE). The study area is endemic for several infectious diseases including malaria and visceral leishmaniasis (VL). Malaria caused by Plasmodiumfalciparum, however, occurs mostly with mild clinical symptoms in all ages, which makes it unlikely to account for these indices. The strong selection signals seems to emanate from recent outbreaks of VL which affected both populations to varying extent. PMID- 23668095 TI - Medicine and law as model professions: the heart of the matter (and how we have missed it). AB - This article has two coordinate goals: to undergird the functionalist understanding of professionalism with classical normative theory and to advance the classical theory of civic virtue with the insights of modern social science. More specifically, this article seeks to connect classical theories about the care of the body and the soul with modern theories of market and government failure. The first step is to distinguish two kinds of professions, caring professions like medicine and public professions like law, by identifying the distinctive virtue of each. The distinctive virtue of the caring professions is single-minded commitment to those in their care, their principals, to the virtual exclusion of all other concerns; the distinctive virtue of the public professions is commitment to the common good, sometimes even at the expense of their principals' self-defined interest. The next step is to show how these two distinctive professional virtues, the one principal-protecting, the other public protecting, branch from the same root, the common function of all proper professions: guaranteeing the delivery of socially essential but necessarily esoteric knowledge when the usual protections of both private contracts and government regulation systematically fail. The third and final step is to map out the implications of this neo-classical understanding of professionalism, beginning at its core in the paradigmatic caring and public professions of medicine and law, through putative professions that take these as their models, to the kind of republican society that places care of individuals and concern for the public welfare at the center of its value system. The result of this analysis should be not only a fuller theoretical appreciation of professionalism's proper function, but also a practical guide to professionals themselves for better service to both the individuals in their care and the common good of all humankind. PMID- 23668096 TI - The goals of FDA regulation and the challenges of meeting them. PMID- 23668097 TI - Special topic introduction: Minerva at the departure gate. PMID- 23668098 TI - Asking the right questions: body scanners, is salus populi supreme lex the answer? PMID- 23668099 TI - Security scanners in comparative perspective. PMID- 23668100 TI - Protection for psychotherapy notes under the HIPAA Privacy Rule: as private as a hospital gown. PMID- 23668101 TI - When oil attacks: litigation options for Nigerian plaintiffs in U.S. federal courts. PMID- 23668102 TI - The patent eligibility of diagnostic methods after Prometheus: a redefined test for transformation. PMID- 23668103 TI - [Characterization of chemical compositions in PM2.5 and its impact on hazy weather during 16th Asian Games in Guangzhou]. AB - Aerosol samples for PM2.5 were collected days and nights from 4 to 30 November 2010 in Guangzhou. The concentrations of organic carbon, element carbon, and water-solubility ions of all particle samples were determined by thermal/optical carbon analyzer and ion chromatography, respectively. In-situ online PM,, mass concentrations, light extinction coefficients (bext), and selected meteorological parameters for this period were also measured. Temporal variation of PM,, mass concentrations and its relationship with bext were discussed, and bext was reconstructed by revised IMPROVE formula. The results showed that the average mass concentration ol PM2.5 was (77.0 +/- 24.4) microg.m-3 during the Asian Games period, which was 27.8% lower than that of the period before Asian Games. PM2.5 and relative humidity were the dominant factors contributing to hazy weather. The average value of bx, was 418 Mm-1 during the Asian Games period, which was 28.3% lower than that of the period before Asian Games. The major contributors to bext included (NH4) 2SO4, POM, and LAC, which accounted for 87.0% of bext during the Asian Games period. A series of stringent air quality control measures were implemented by the Guangzhou Municipal Government and other cooperative cities, which greatly alleviated the hazy weathers in Guangzhou urban area during the Asian Games period. PMID- 23668104 TI - [PM2.5 pollution and aerosol optical properties in fog and haze days during autumn and winter in Beijing area]. AB - A study on the PM2.5 pollution and aerosol optical properties in haze-fog days was carried out from Sep. 1st to Dec. 7th, 2011 in Beijing area by using PM2.5 concentration, aerosol scattering coefficient (sigma sca) and absorption coefficient (sigma abs) measured under urban and rural environment. The effect of weather condition on the PM25 pollution and aerosol optical properties was discussed as well. The results showed that the PM2.5 concentration, sigma sca and sigma abs, were evidently higher in haze-fog days than those in non-haze-fog days. The average PM2.5 concentrations in haze-fog days with values of 97.6 microg m-3 and 64.4 microg.m-3 were as 3.3 and 4.8 times as those in non-haze-fog days at urban and rural stations, respectively. The higher PM2.5 concentration in urban area resulted in the more frequent fog and haze phenomena than that in rural area. The PM25 concentration, sigma sca, and sigma abs were significantly higher in urban area than that in rural area in mist days, while relatively close in mist-haze days. This difference suggested that the effect of regional transport of pollution was relatively evident in mist-haze days but weak in mist day. In fog days the sigma sca showed no evident difference between urban and rural area, and was the highest in all types of fog and haze weather. The scattering property of aerosol was the strongest in fog days. The different weather conditions resulted in various characteristics of spatial distribution of PM2.5 concentration, sigma sca and sigma abs, as well as the strength of PM2,5 pollution and aerosol extinction. The pollutants transported by the strong southwest wind above the boundary layer and subsided in the boundary layer companying with the local accumulation of pollutants due to the weak diffusion resulted in the most serious haze-fog episode with the strongest PM2.5 pollution and aerosol extinction. PMID- 23668105 TI - [Forming potential of secondary organic aerosols and sources apportionment of VOCs in autumn of Shanghai, China]. AB - A continuous measurement was conducted in urban area of Shanghai from 1stSeptember to 21st November, 2011. The mass concentration of PM2.5 and the mixing ratio of VOCs were obtained during the period. Four pollution episodes were observed: PD1 (20th-23th September), PD2 (5th-9th October), PD3 (13rd - 18th October), PD4 (10th - 14th November). The average mass concentrations of PM2.5 were (45+/-16), (76+/-46), (57+/-36) and (122+/-92) microg.m-3, respectively. The mixing ratio of VOCs were (30.87+/-30.77) x10(-9), (32.09+/-30.69) x10(-)9, (34.04+/-28.13) x10(-9) and (44.27+/-31.58) x10(-9). Alkane, alkene and aromatic hydrocarbons accounted for 53. 58% , 27. 89% , and 10. 96% of the total VOCs, respectively. The OH radical loss rate (LOH) and the ozone formation potential (OFP) were applied to assess the chemical reactivity of VOCs, the results showed that the alkenes and aromatics were the most important contributors to LOH and OFP in the atmosphere in the urban area of Shanghai, in autumn. Fractional aerosol coefficients (FAC) and the ratio of organic carbon to element carbon (OC/EC) were used to estimate the potential formation of secondary organic aerosols (SOA) in Shanghai, the SOA concentration values obtained by the two methods were 1.43 microg.m-3 and 4.54 microg.m-3, respectively. The value predicted by OC/EC was significantly higher, which was mainly due to the low amount of SOA precursors measured in this study. The aromatics were not only the most important contributors to OFP, but also important SOA precursors. By applying the positive matrix factorization (PMF) model, six major sources were extracted to identify the sources of VOCs in autumn in Shanghai, including vehicle exhaust (24.30%), incomplete combustion (17.39%), fuel evaporation (16.01%) , LPG/NG leakage (15.21%) , petrochemical industry (14.00% ), and paint/solvent usage (13.09%). Vehicle exhaust and paint/solvent usage contain abundant aromatics species which are the most important contributors to OFP and important SOA precursors. The above two sources contributed 37.39% of the total VOCs concentration. Hence, these sources should be listed as priority of air pollution control strategy for Shanghai in future. PMID- 23668106 TI - [Study on number concentration distribution of atmospheric ultrafine particles in Hangzhou]. AB - Atmospheric ultrafine particles (UFPs) were measured with fast mobility particle sizer(FMPS) in Hangzhou, during March 2011 to February 2012. The number concentration and size distribution of UFPs associated with meteorology were studied. The results showed that the number concentration of UFPs was logarithmic bi-modal distribution, and the seasonal levels presented winter > summer > spring> autumn. The highest monthly average concentration was 3.56 x 10(4) cm-3 in December and the lowest was 2.51 x 10(4) cm-3 in October. The seasonal values of count medium diameter(CMD) were spring > winter > autumn > summer. The highest monthly average CMD was 53. 51 nm in April and the lowest was 16.68 nm in June. Meteorological factors had effects on concentration of UFPs. PMID- 23668107 TI - [Pollution characteristics and source identification of atmospheric particulate matters n-alkanes in Baoding City]. AB - Organic matter has been a very important component in the ambient particulate matter of big cities in China. In order to investigate the mass concentrations and sources of the organic matter which are adsorbed in ambient particulate matters in the industry cities of Hebei province, aerosol samples were collected with Anderson sampler during Sep. 2009 to Aug. 2010, in Baoding city, Hebei province. The concentration of n-alkanes was determined via GC-MS. About 66.7% of the daily average concentrations of fine particulate matters were higher than the 24-hour average threshold value of class II standard of the ambient air quality standard (GB 3095-2012, 75 microg.m-3). About 96% of the daily average concentrations of inhalable particles were higher than 150 microg.m-3)(GB 3095 2012). The total concentration of n-alkanes was in the range of 111.23-979.81 ng.m-3 with an average of 264.2 ng.m-3. The n-alkene homologues from C14 to C32 were detected with different peak carbon numbers ranging from 20 to 27 in different seasons. In summer, the peak carbon number was 27, while it was C20, C21 or C22 in winter and spring. The CPI values were 0. 97, 1. 24, 0. 92 and 0. 86 in spring,summer, autumn and winter, respectively, with an average of 1.01. These results indicated that the incomplete combustion of fossil fuel and vehicle emissions was the main resource of n-alkanes in winter and spring, and the high plant waxes were playing a major role in summer and autumn. The primary sources were anthropogenic activities all year round. PMID- 23668108 TI - [Study on pollution characteristics of carbonaceous aerosols in Xi'an City during the spring festival]. AB - The samples of PM2.5 with 8 times periods were collected using Automated Cartridge Collection Unit (ACCU) of Rupprecht& Patashnick (R&P)Corporation, and monitored by R&P1400a instrument of TEOM series online during 2011 Spring Festival in Xi'an city. The organic carbon (OC), elemental carbon (EC), water soluble organic carbon (WSOC) and water-insoluble organic carbon (WIOC) contents of 3 h integrated PM2.5 were analyzed to evaluate the influence of firework display on the carbonaceous components in urban air. The mass concentration of PM2.5 was found increased significantly from 00:00 A. M. to 02:59 A. M. at the Chinese Lunar New Year's Eve than the non-firework periods, reaching 1514.8 microg.m-3 at 01:00 A. M. The mass concentrations of OC, EC, WSOC, and WIOC during the same time period were 123.3 microg.m-3, 18.6 microg.m-3, 66.7 microg.m 3, and 56.6 microg.m-3, about 1.7, 1.2, 1.4, and 2.2 times higher than the average in normal days, respectively. Correlation analysis among WSOC, OC, and EC contents in PM25 showed that firework emission was an obvious source of carbonaceous aerosol in the Spring Festival vacation. However, it only contributes to 9. 4% for aerosol in fireworks emission. PMID- 23668109 TI - [Characteristics of PM10 and PM2.5 concentrations in mountain background region of East China]. AB - The online PM10 and PM2.5 concentrations were measured from March 2011 'to February 2012 at the national atmospheric background monitoring station in Wuyishan of Fujian Province to discuss the characteristic of PM10 and PM2.5 concentrations and the impact factors in forest and mountain background region of East China. HYSPLIT (Hybrid Single Particle Lagrangian Integrated Trajectory) Model was used to investigate the potential sources of particulates during the pollution episodes. The results showed that the background concentrations of PM10 and PM2.5 were (23 +/- 16) microg.m-3 and (18 +/- 12) microg.m-3, respectively. Seasonal variations of PMl0 and PM2.5 loadings were observed, and loadings decreased in the same order: spring > autumn > winter > summer. PM10 and PM2.5 concentrations were obviously higher in spring than in other seasons because of the transportation of dust storm. The fine particles were the dominant pollutant which accounted for 76% of PM10. The good correlation between PM10/PM2.5 and gas pollutants suggested that regional transportation and secondary aerosol were the major sources in the background station. One episode occurring in April 2011 was related with the transportation of dust storm. However, another episode occurring in September 2011 had close relationship with the transportation of higher pollutant loadings in East China. PMID- 23668110 TI - [Assessment of TVOC and odor in the remediation site of contaminated soil and groundwater using electronic nose]. AB - According to the conditions of a contaminated soil and groundwater remediation site in Shanghai, the self-built electronic nose was applied to detect VOCs and odor of previously remedied soil and groundwater, remedying soil and groundwater, and the air above and around the site. Combining the formula of TPI and OPI, the value of each point was got and was shown in figures. Results showed: 1. Comparing the determination results of previously remedied with remedying contaminated soil and groundwater, the concentration of TVOC and odor was overall declined. The result was consistent with the fact. The detection result of electronic nose was proved to be right; 2. In the remediation process of soil and groundwater, the volatilization of VOCs and odor was inflected by temperature and works of crushing, adding medicine and turning the soil on time. The concentration showed a trend of overall decline with stage rising, so the electronic noses can be used for dynamic monitoring of the whole remediation process; 3. Combined with the GIS, the electronic noses can preliminary assess space pollution situation caused by the remediation of contaminated soil and groundwater and the influence on the residence in the surrounding region. However, further study on the refined classification of the impact degree is needed. PMID- 23668111 TI - [Characteristics of mercury exchange flux between soil and atmosphere under the snow retention and snow melting control]. AB - Jiapigou gold mine, located in the upper Songhua River, was once the largest mine in China due to gold output, where gold extraction with algamation was widely applied to extract gold resulting in severe mercury pollution to ambient environmental medium. In order to study the characteristics of mercury exchange flux between soil (snow) and atmosphere under the snow retention and snow melting control, sampling sites were selected in equal distances along the slope which is situated in the typical hill-valley terrain unit. Mercury exchange flux between soil (snow) and atmosphere was determined with the method of dynamic flux chamber and in all sampling sites the atmosphere concentration from 0 to 150 cm near to the earth in the vertical direction was measured. Furthermore, the impact factors including synchronous meteorology, the surface characteristics under the snow retention and snow melting control and the mercury concentration in vertical direction were also investigated. The results are as follows: During the period of snow retention and melting the air mercury tends to gather towards valley bottom along the slope and an obvious deposit tendency process was found from air to the earth's surface under the control of thermal inversion due to the underlying surface of cold source (snow surface). However, during the period of snow melting, mercury exchange flux between the soil and atmosphere on the surface of the earth with the snow being melted demonstrates alternative deposit and release processes. As for the earth with snow covered, the deposit level of mercury exchange flux between soil and atmosphere is lower than that during the period of snow retention. The relationship between mercury exchange flux and impact factors shows that in snow retention there is a remarkable negative linear correlation between mercury exchange flux and air mercury concentration as well as between the former and the air temperature. In addition, in snow melting mercury exchange flux is remarkably negatively linearly correlated to air mercury concentration and positively linearly correlated to air temperature. Furthermore, there is a general positive linear correlation between mercury exchange flux and soil temperature on the surface of earth after snow melting. PMID- 23668112 TI - [Study on heavy metal contaminations and the sources of Pb pollution in Jinghai Bay using the stable isotope technique]. AB - The concentrations of typical heavy metals including Cu, Hg, Pb, Zn, Mn, Cd, Cr and As in the surface sediment and suspended particulate matter (SPM) in Jinghai Bay, Rongcheng city were tested. The degree of heavy metal pollution in the surface sediment was assessed according to the national standard of marine sediment quality. The potential ecological risk (PER) of heavy metals to marine ecosystem in Jinghai Bay was assessed using PER coefficient and risk index. The results showed that the levels of heavy metals and PER in the surface sediments were low enough to meet the requirement of the first class of the sediment quality standards except the levels of Cu and Zn in the sampling site S2 and Cd in S3, S4, S5 and S6 which met the requirements of the second class of the sediment quality standards. The PER coefficients of heavy metals increased following the sequence of Zn < Cr < Pb < Cu < As residential-culture-education district > square of park > suburban farmland. the input way of PGEs in snow cover was found a remarkable difference with the amount of input within different function areas, which was the main reason caused that PGEs content of snow cover in each function area varied and had a certain regularity. PMID- 23668115 TI - [Effect of dust deposition collection methods on collection efficiency]. AB - There are lots of dust deposition collection methods on dust deposition, but there is no standard field observation method. At present, researchers have studied dust deposition using different methods in this issue, but due to the different observation method and collection efficiency, the research results are incomparable. The efficiency of the standard dust deposition gauge including dry, wet, net, net and glass ball and slowing speed methods was studied in the Tengger Desert. The amount of the dry method collected material was only about 5% to 62% of the wet method, the net method was only about 43% to 89% of the wet method, the net and glass ball method was only about 40% to 80% of the wet method. Wind speed obviously affected the dust deposition efficiency in all observation methods, the dust deposition efficiency decreased with increasing wind speed when the wind speed was smaller than 2.5 m.s-1, but the dust deposition efficiency had no clear trend with wind speed when the wind speed was larger than 2.5 m.s-1. The particle size of collected material by wet method was the smallest, followed by the slowing speed method, the net and glass ball method, the wet method and the dry method. There are relationships between the averaged wind speed, the averaged larger than 5 m.s-1 wind speed and the amount of dust deposition collected by the wet and the slowing speed methods, which can be expressed as exponential function. There are also linear relationships between the amount of collected material by the wet and dry, net, net and glass ball and slowing speed methods. The wet method is the best dust deposition collecting method, followed by the slow wind speed method. Therefore, in the arid and semi-arid regions, the slowing wind speed method can be used to replace the wet method to collect dust deposition. PMID- 23668116 TI - [Regionalization of the freshwater eco-regions in the Haihe River Basin of China]. AB - There is a growing concern about the ecological conditions in the Haihe River which have been profoundly impacted by the growing human population and intensifying development over the past several decades. By identifying the spatial characteristics of terrestrial and fluvial landscapes, we propose the guidelines and criterions for regionalizing the freshwater ecosystems in the Haihe River basin. The first-level and second-level zones reflect the spatial patterns of the natural backgrounds which could impact the surface water quantity and quality. The 6 first-level zones are regionalized according to topographic characteristics, runoff depth, annual precipitation and evaporation. They represent the spatial pattern of water resource quantity. The 16 second-level zones are regionalized according to the vegetation and soil types overlaid by the first-level zones. They represent the spatial patterns of eco-hydrological processes and water purifying functions of terrestrial landscapes. Finally, the eco-regions are evaluated by the field survey data including water quality, aquatic vegetation and zoobenthos communities. This study could potentially be used to guide the decision-making process for the management of water resources and local ecological projects in the Haihe River basin. The methods formulated in this research can possibly provide important references for other watersheds in China. PMID- 23668117 TI - [Characteristics of diffuse attenuation coefficient of underwater irradiance in the lakes in the middle and lower reaches of Yangtze river ]. AB - Based on the underwater irradiance profile measurement and water samples collection in September, October 2007 in Lake Donghu, Lake Liangzi and Lake Honghu, and in April in 2010 in Lake Kuileihu, the diffuse attenuation coefficient and the dominant attenuation factors were analyzed. The ranges of diffuse attenuation coefficient and total suspended solid (TSS), organic suspended solid (OSS), inorganic suspended solid (ISS), chlorophyll a (Chla), and dissolved organic carbon (DOC) concentration varied less in Lake Donghu and Lake Kuileihu than in Lake liangzi and Lake Honghu. The regression analysis showed that ISS was the dominant affecting factor of transparency in Lake Donghu and Lake Kuileihu, but ISS and OSS jointly controlled the transparency in Lake Liangzi and Lake Honghu. The diffuse attenuation coefficient minimum occurred near 580 nm. At around 675 nm, the diffuse attenuation coefficient peak was due to phytoplankton absorption, especially at sites with high pigment concentration. The euphotic depth was less than the mean water depth in Lake Donghu, suggesting that the submerged aquatic vegetation (SAV) can not grow in the present underwater light climate. However, the euphotic depth was larger than the mean water depth in other three lakes showing that the underwater light climate can meet the light requirements for the growth of SAV. The regression analysis showed that ISS was the dominant affecting factor of PAR attenuation in Lake Donghu and Lake Kuileihu, but ISS, OSS and Chla jointly controlled PAR attenuation in lake Liangzi and lake Honghu. The significant correlation between the beam attenuatin coefficient at 750 nm and PAR difffuse attenuation coefficient showed that the particles scattering significantly contributed to underwater irradiance attenuation. PMID- 23668118 TI - [Study on influencing factors and universality of chlorophyll-a retrieval model in inland water body]. AB - The semi-analytical three-and four-band model and bio-optical analytical model of chlorophyll-a were checked by the 'mh, constituents and optical properties with high spatio-temporal variation. The influencing factors and universality of the retrieval model were studied by the modeling checking results. The study results indicate that the unjversality of bio-optical analytical model is much higher than the three-and four-band model, and the accuracy of the retrieval model is acceptable, but the accuracy of the retrieval model was highly affected by the specific absorption coefficient of chlorophyll-a. The accuracy of the three-and four-band model higher than the bio-optical analytical model. However, the universality of the three-and four-band model is not very high, because of the optimal wavelength position of the retrieval factors and the greater variability of the retrieval model parameters. The spectral shape of particle backscattering coefficient and chlorophyll-a specific absorption coefficient are the dominant influencing factors of the three and four-band retrieval model. PMID- 23668119 TI - [Effect of dissolved oxygen on diversity of ammonia-oxidizing microorganisms in enrichment culture from estuarine wetland surface sediments and ammonia-oxidizing rate]. AB - Dissolved oxygen (DO) is one of the important environmental factors influencing the ammonia oxidation process. In order to examine the effects of DO on ammonia oxidation process and its potential mechanisms, surface sediments from Jiulong River Estuarine Wetland were collected and cultured to obtain enrichment cultures. Then the enrichment cultures were inoculated under different levels of DO, and the diversity of ammonia-oxidizing microorganisms was analyzed using PCR DGGE technique to determine the effect of DO on the ammonia oxidation rate and the ammonia-oxidizing microorganism diversity. Results showed that the Shannon index was 2. 00 and 2.05 for ammonia-oxidizing bacteria (AOB) under saturated and aerobic conditions, respectively, and the values were 2.49 (saturated) and 2.03 (aerobic) for ammonia-oxidizing archaea (AOA). However, this index was 1.76 and 1.80 for AOB under hypoxia and anaerobic condition, and 1.27 and 2. 21 for AOA. Under saturated and aerobic conditions ( higher DO level), the ammonia-oxidizing rates were 14.20 mg.(L.d)-1 and 13.36 mg.(L.d)-1 and the related conversation rates of NH+4 -N were 93.8% and 88. 2% , respectively. In comparison, under hypoxia and anaerobic conditions (lower DO level), the ammonia-oxidizing rates were 7.82 mg.(L.d) -1 and 5.66 mg.(L.d)-1 and the related conversation rates of NH+4 -N were 51.7% and 37.4% , respectively. The correlation analysis showed that DO concentration was highly significantly positively correlated with the ammonia oxidation rate, and was significantly positively correlated with the AOB diversity index; DO and ammonia oxidation rate had no correlation with indices of AOA community. PMID- 23668120 TI - [Spatial variation of soil moisture/salinity and the relationship with vegetation under natural conditions in Yancheng coastal wetland]. AB - Taking the core part of Yancheng national nature reserve as the study area, according to soil sampling analysis of coastal wetlands in April and May 2011 land the 2011 ETM + remote sensing image, the spatial difference characteristic of coastal wetlands soil moisture and salinity, and the relationship with vegetation under natural conditions, were investigated with the model of correspondence analysis (CCA), linear regression simulation and geo-statistical method. The results showed: Firstly, the average level of the soil moisture was fluctuating between 36.820% and 46.333% , and the soil salinity was between 0.347% and 1.328% , in a more detailed sense, the Spartina swamp was the highest, followed by the mudflats swamp, the Suaeda salsa swamp, and the Reed marsh. Secondly, the spatial variation of soil moisture was consistent with that of the salinity, and the degree of variation in the east-west direction was greater than that in the north-south. The maximum soil moisture and salinity were found in the southwest Spartina swamp. The minimum was in the Reed swamp. The soil moisture and salinity were divided into 5 levels, from I to V. Level IV occupied the highest proportion, which were 36.156% and 28.531% , respectively. Finally, different landscape types with the combination of soil moisture and salinity showed a common feature that the moisture and salinity were from both high to low. The soil moisture value of Reed marshes was lower than 40.116% and the salinity value was lower than 0. 676% . The soil moisture value of Suaeda salsa marshes was between 38. 162% and 46. 403% and the salinity value was between 0.417% and 1.295%. The soil moisture value of Spartina swamp was higher than 43.214% and the salinity was higher than 1.090%. The soil moisture value of beach was higher than 43.214% and the salinity was higher than 0.677%. PMID- 23668121 TI - [Spatial heterogeneity and classified control of agricultural non-point source pollution in Huaihe River Basin]. AB - Agricultural non-point source pollution is of importance in river deterioration. Thus identifying and concentrated controlling the key source-areas are the most effective approaches for non-point source pollution control. This study adopts inventory method to analysis four kinds of pollution sources and their emissions intensity of the chemical oxygen demand (COD), total nitrogen (TN), and total phosphorus (TP) in 173 counties (cities, districts) in Huaihe River Basin. The four pollution sources include livestock breeding, rural life, farmland cultivation, aquacultures. The paper mainly addresses identification of non-point polluted sensitivity areas, key pollution sources and its spatial distribution characteristics through cluster, sensitivity evaluation and spatial analysis. A geographic information system (GIS) and SPSS were used to carry out this study. The results show that: the COD, TN and TP emissions of agricultural non-point sources were 206.74 x 10(4) t, 66.49 x 10(4) t, 8.74 x 10(4) t separately in Huaihe River Basin in 2009; the emission intensity were 7.69, 2.47, 0.32 t.hm-2; the proportions of COD, TN, TP emissions were 73%, 24%, 3%. The paper achieves that: the major pollution source of COD, TN and TP was livestock breeding and rural life; the sensitivity areas and priority pollution control areas among the river basin of non-point source pollution are some sub-basins of the upper branches in Huaihe River, such as Shahe River, Yinghe River, Beiru River, Jialu River and Qingyi River; livestock breeding is the key pollution source in the priority pollution control areas. Finally, the paper concludes that pollution type of rural life has the highest pollution contribution rate, while comprehensive pollution is one type which is hard to control. PMID- 23668122 TI - [Phosphorus output characteristics under different rainfall-runoffs in Gaolan River]. AB - Through capturing the dynamics of water quantity and quality during varied intensities of rainfall, the variation characteristics of different forms of phosphorus and flux during the producing of runoff were studied systematically in Gaolan River watershed (a secondary tributary of Three Gorges Reservoir). Meanwhile, the phosphoric loadings from point and non-point sour,-were identified, respectively. The results show that: the variation of rainfall-runoff under " squat" rain was relatively slow, while un,c "pointed thin" rain it presented quickly both during rising and recession. Total phosphorus concentration increased quickly because soil carried particulate phosphorus into water under the heavy rainfall, while the relative variations of dissolved total phosphorus and orthophosphate concentration were slightly elevated. Compared with "squat" rain, the maximum value of total phosphorus concentration and flux were both higher in "pointed thin" rain, which led to the more heavily soil erosion. The dynamics of flux and concentratiorn of phosphorus were generally consistent with that of the flow rate between the two different types of rain. Phosphorus from non-point source accounts for 90% during the whole heavy rain. Because of the long lasted time during " squat" rain, the contribution of the "squat" rain outweighs the "pointed thin" rain. PMID- 23668123 TI - [Monitoring and analysis on evolution process of rainfall runoff water quality in urban area]. AB - In order to find the water quality evolution law and pollution characteristics of the rainfall runoff from undisturbed to the neighborhood exit, 6 times evolution process of rainfall runoff water quality were monitored and analyzed from July to October in 2011, and contrasted the clarification efficiency of the grassland to the roof runoff rudimentarily at the same time. The research showed: 1. the results of the comparison from "undisturbed, rainfall-roof, rainfall runoff-road, rainfall-runoff the neighborhood exit runoff " showed that the water quality of the undisturbed rain was better than that from the roof and the neighborhood exist, but the road rainfall runoff water quality was the worst; 2. the average concentrations of the parameters such as COD, ammonia nitrogen and total nitrogen all exceeded the Fifth Class of the Surface Water Quality Standard except for the soluble total phosphorus from undisturbed rainfall to the neighborhood exit; 3. the runoff water quality of the short early fine days was better than that of long early fine days, and the last runoff water quality was better than that of the initial runoff in the same rainfall process; 4. the concentration reduction of the grassland was notable, and the reduction rate of the grassland which is 1.0 meter wide of the roof runoff pollutants such as COD and nitrogen reached 30%. PMID- 23668124 TI - [Characteristics and contribution of the strengthening units of composite constructed wetland for treating urban sewage]. AB - There are some defects in constructed wetland, including the uneven distribution of flow, easily blocked, lack of oxygen supply systems and the unsatisfactory phosphorus adsorption capacity of the substrates, etc. The research mainly studied the function and contribution of the pool of hydrolysis acidification, the natural reoxygenation/sinking device and strengthen slot for reducing nitrogen and phosphorus. The results showed the removal efficiency of COD and SS in hydrolysis-acidification pool accounted for 38.05% and 34.82% of the total removal efficiency of system. The SS removal efficiency of the natural reoxygenation/sinking device accounted for 22.01% of the total removal efficiency of system, and the concentration of DO kept above 2.5 mg.L-1. The two strengthen slots can ensure the TP, TN, COD up to the standard of the level 1 of GB 18918 2002. PMID- 23668125 TI - [Inactivation of Mycobacteria mucogenicum in drinking water: chlorine resistance and mechanism analysis]. AB - In recent years, chlorine-resistant bacteria were detected in drinking water distribution systems which threatened the drinking water safety. Our group detected one strain named Mycobacteria mucogenicum from the drinking water distribution system of a city in south China. This paper studied chlorine resistance and mechanism of Mycobacteria mucogenicum. Inactivation experiments of one strain Mycobacteria mucogenicum were conducted with free chlorine, monochloramind and chlorine dioxide. The CT values of 99.9% inactivation by free chlorine, monochloramine and chlorine dioxide were detected as (76.25 +/- 47.55)mg.min.L-1, (1396 +/-382)mg.min.L-1, (13.5 +/- 4.9) mg.min L-1. Using transmission electronmicroscopy (TEM) observed the inactivation process of Mycobacteria mucogenicum. The bacteria surface hydrophobic of Mycobacteria mucogenicum was 37.2%. Mycobacteria mucogenicum has a higher hydrophobicity than other bacteria which prevented the diffusion of chlorine into cells. Mycobacteria mucogenicum is more resistant to chorine than other bacteria. PMID- 23668126 TI - [Partial biological characteristics and algicidal activity of an algicidal bacterium]. AB - An algicidal bacterium was isolated from freshwater (Lake Donghu in Wuhan) and coded as A01. The morphology of the algicidal bacterium was observed using optical microscope and electron microscopes, the results showed that A01 was rod shaped, approximately 1.5 microm in length and 0.45 microm in width and with no flagella structure. A01 was Gram-negative and belongs to the family Acinetobacter sp. though identification by Gram's staining and 16S rDNA gene analysis. A01 exhibited strong algicidal activity on the bloom-forming cyanobacterium Anabaena eucompacta under laboratory conditions. The removal rate of chlorophyll a after 7 day incubation with the culture supernatant of A01 and thalli were 77% and 61%, respectively. Microscopic observation showed that almost all cyanobacterial cells were destroyed within 3 d of co-incubation with the supernatant of algicidal bacterium, but a mass of the cyanobacterial cell lysis was observed only after 5 d of co-incubation with the thalli of algicidal bacterium. These results indicated that the main algicidal component of A01 was in its culture supernatant. In other words, the strain A01 could secrete algicidal component against Anabaena eucompacta. PMID- 23668127 TI - [Effects of macrophytes pyrolysis bio-oil on Skeletonema costatum antioxidant enzyme activities]. AB - In order to reveal the preliminary inhibition mechanisms of aquatic plants bio oils on Skeletonema costatum, effects of Arundo donax L. 300 degees C, Ph. australis Trin. 400 degrees C and Typha orientalis Pres1 400 degrees C bio-oils on the concentration change of malondialdehyde (MDA) and the activity of antioxidant enzymes system (SOD, POD and CAT) were evaluated. The results showed that the higher Ihe Bio-oil concentrations, the higher the MDA contents in Skeletonema costatum was, and when the Bio-oil concentration was 10 mg.L-1 the MDA concentration increased with the reaction time. Superoxide dismutase (SOD) activity also increased with the increase of bio-oil concentration. For Arundo donax L 300 degrees C and Typha orientalis Presl 400 degrees C bio-oil, when the reaction time was longer, the S0D activity of Skeletonema costatum first increased and then decreased, and in both cases the maximum SOD activity was measured at 24 h. reaching 93.6 U (10(7) cells)-1 and 8.23 U (10(7) cells)-1, respectively. For Ph. australis Trin 400 degrees C bio-oil, the SOD activity kept increasing within 72 h. The peroxidase ( POD) activity of Skeletonema costatum also increased with the increase of bio-il concentrations. In the presence of Arundo donax L. 300 degrees C and Ph. australis Trin 400 degrees C bio-oil, the POD activity of Skeletonma, costatum first increased and then decreased, while with Typha orientalis Presl 400 degrees C bio-oil the POD activity increased with fluctuations. For all the three bio-oils, the catalase (CAT) activities increased first and then decreased when the reaction time was prolonged, and the higher the bio-oils concentration, the greater the CAT activity was. Pyrolysis bio-oils enhance the activity of antioxidant enzymes, leading to intracellular oxidative stress in the algae, which seems to be the main inhibitory mechanism for algae PMID- 23668128 TI - [Mechanism and kinetics of phenol degradation by TiO2 photocatalytic combined technologies]. AB - The combination H2O2, or electrical catalytic (EC) system with TiO2 photbcatalytic system for phenol degradation was investigated. The catalytic systems of TiO2/UV, H2O2/UV, TiO2/UV/H2O2 and TiO2/UV/EC were compared to investigate the phenol degradation mechanism and kinetic model. The degradation of phenol in TiO2/UV/H2O2 and TiO2/UV/EC system is more effective than that in TiO2/UV system. With the solution pH of 6, TiO, concentration of 0.2 g.L-1, UV illumination of 2 h, the photocatalysis removal efficiency of phenol reaches to 86%, if the current density of 12 mA.cm-2 is added, the removal efficiency of phenol could reach to 100%. The energy utilization in different catalytic systems was also compared. When phenol is degraded in 15 min, in TiO2/UV/EC system the energy utilization is the highest of 0.0306 g.(kW. h)-1 with the energy consumption of 0.0640 kW.h-1. It indicates that much more energy is used in TiO2/UV/EC system for phenol degradation. During the analysis of intermediate products in different catalysis systems, the first-order kinetic model of phenol degradation and intermediate products such as hydroquinone, catechol and benzoquinone formation were established. The kinetic model is validated the phenol degradation pathway in different catalysis systems, and also indicates the TiO2/UV/EC system could enhance phenol and intermediate products degradation. PMID- 23668129 TI - [Biodegradation characteristics of organic pollutants contained in tannery wastewater]. AB - In the batch experiments inoculated with activated sludge from tannery wastewater treatment plant, biodegradation characteristics and kinetics of three tanning agents, naphthalene-2-sulfonic sodium, tannic acid and bayberry tannin, were studied under aerobic and anaerobic conditions. And the aerobic/anaerobic biodegradation laws of real tannery wastewater with respect to COD change were also investigated using the same batch experiments. The results showed aerobic degradation was superior to anaerobic degradation for tanning agent removal and mineralization. The removal rates of naphthalene-2-sulfonic sodium, tannic acid and bayberry tannin by aerobic biodegradation were >90% , >90% and 50% -75% , respectively whereas 10%-40%, >95% and 20% -30%, respectively by anaerobic degradation. In terms of COD removal about tannic acid biodegradation, the removal rates under aerobic and anaerobic conditions were >75% and < 75% ,respectively. The first-order kinetic constants during aerobic biodegradation of tannic acid and bayberry tannin were slightly influenced by initial concentrations while initial concentration had a significant effect on the first order kinetics rate in the case of naphthalene-2-sulfonic sodium aerobic biodegradation because naphthalene- 2-sulfonic sodium with initial concentration >or= 70 mg.L-1 was toxic to microorganism leading to a significant decline of kinetic constants. Biodegradation of real tannery wastewater under aerobic and anaerobic conditions represented obvious stage characteristics and the COD concentration had a good linear correlation with reaction time in the phases of fast degradation and slow degradation. The aerobic maximum specific degradation rate wqas 11.6 times higher of anaerobic degradation. PMID- 23668130 TI - [Microbial degradation mechanism of disperse azo dye Red 30 by Streptomyces sp. FX645]. AB - One strain, identified as Streptomyces sp. FX645 which was isolated from the sludge collected in a printing and dyeing mill, had high potency of degradation and decolourisation of azo dye Red 30 (AR30). The microbial degradation mechanism on AR30 by strain FX645 was proposed through analyzing the UV-vis spectra and LC MS spectra of the degradation products and investigating the variations in the concentrations of the degradation products in the culture. It is suggested that the azo bond of AR30 was iniially cracked by azo reductase to produce 2,6 dichloro- 4-nitrobenzenamine and 2-[(4-aminophenyl)-(2-cyanoethyl) amino] ethylacetate, which then generated several aromatic amine compounds under the actions of nitror4duction, aminoacylation and cyano hydrolysis, respectively. PMID- 23668131 TI - [Study on preparation and performance of a biological carrier with tourmaline]. AB - In order to strengthen the activity of biofilm on the carrier surface, the tourmpaline on polyurethane (TPU) carrier was prepared using waterborne polyurethane as medium. The physical properties of TPU carrier were characterized by scanning electron microscope(SEM) and water absorbency, and its effect on biofilm biomass and nitrifying ability was studied. The results showed that the tourmaline loading amount of TPU carrier can be affected by waterborne polyurethane. Tourmaline can optimize the number of polar groups of the TPU carrier and the pH of the nitrification condition. The amount of nitrobacteria and nitrate bacteria irreversibly adsorbed on the TPU carrier was increased by 74.82% and 71.89% , respectively. Correspondingly, the removing rate of NH+4 -N and NO-2 -N has risen by 8.12% and 9.08%, respectively, compared to the control without carrier. The TPU carrier was indicated to promote the nitrification. PMID- 23668132 TI - [Study on the Chlorella pyrenoidosa cultivation technology based on the excess sludge utilization]. AB - Microalgae cultivation based on the waste water or other reused waste can not only make rational use of the waste, but also provide cheap materials for microalgae production. In the present study, Chlorella pyrenoidosa was used to develop a new way for microalgae cultivation based on the mix culture media with different ratio of sludge extracts and SE (selenite enrichment). Results showed that after 14 d cultivation under the same cultivating condition, the absorbency of C. pyrenoidosa at 680 nm was 0. 858 and 0. 845, respectively, when the ratio between culture medium of SE and sludge extracts was 1:9 and 2:8, and the absorbency at 680 nm was 0.247 and 0.571, respectively, when the ratio between culture medium of SE and sludge extracts was 0:10 and 10:0. Our results also demonstrated that highest content of chlororphyll, beta-carotene and protein was achieved in C. pyrenoidosa cultivated in the mix medium between SE and sludge extracts with the ratio of 2: 8. Therefore, sludge extracts can be used as a good medium to cultivate C. pyrenoidosa, and the C. pyrenoidosa grew much better in this mix medium than in SE medium. In this study, the best condition for C. pyrenoidosa cultivation was achieved in the mix medium with 80% sludge extracts, and C. pyrenoidosa grew very well and the content of chlororphyll and protein was also high in the microalgae cell in this mixture medium. PMID- 23668133 TI - [Effects of mild thermal pretreatment on anaerobic digestibility of sludge with low organic content]. AB - The effects of mild pretreatment at temperature of 100 degrees C on the solubilization anP anaerobic digestibility of high solid sludge with low organic content were studied with the variation of heating times. Experimental results show soluble organic concentrations in supernatant increase with the prolonging of thermal pretreatment time rapidly, and slowly after 30 min. The dissolution rates of COD, protein and carbohydrate with 30 min of thermal pretreatment at 100 degrees C were 10.5%, 11.6% and 8.2%, respectively. Mild thermal pretreatment not only enhanced total methane yield, but also advanced the peak time of methane production. The methane production ratio with 30 min of thermal hydrolysis was 136 mL.g-1 (VS) at day 10 of anaerobic digestion, with an 86% increase over the control group. VS reduction ratio after 30 days anaerobic digestion o also increased to 33.3% with 30 min of thermal pretreatment at 100 degrees C compared with 19.1% in control group. In addition, studies on enzymatic activity indicated the activities of four key enzymes (protease, acetokinase, phosphotransacetylase and coenzyme F420) involved in anaerobic digestion were all enhanced by mild thermal pretreatment. PMID- 23668134 TI - [Effect of natural and hydrothermal synthetic goethite on the release of methane in the anaerobic decomposition process of organic matter]. AB - The effects of natural goethite (NGt) and synthetic goethite (SGt) on the release of methane in the anaerobic biochemical system consisted of dissimilatory iron reducing bacteria (DIRB) and methane-producing bacteria (MPB) were investigated through batch tests with sodium acetate as the carbon source. To explore the effects and mechanisms of both mineral materials on the release of methane in the anaerobic decomposition process of organic matter in the presence of DIRB, the main gas components and total organic carbon (TOC) , total inorganic carbon (TIC), and Fe2+ in the aqueous phase of the experimental process were determined and XRD analyses were conducted for the solid-phase product. Moreover, the minerals were analyzed by specific surface area (BET), X-ray diffraction (XRD), X ray fluorescence (XRF). Modified Gompertz equation was used to fit the cumulative methane and carbon dioxide. Results showed that the maximum cumulative production of methane was brought forward by 60-78 days by the addition of goethite and CO2 was effectively reduced by 30% - 67% compared with the control samples. SGt was more effective than NGt in promoting the release of CH4 and reducing the CO, emission. Furthermore, the analysis of the solid product showed that the addition of goethite can fix part of CO2 by the formation of siderite. PMID- 23668135 TI - [Concentrations and distribution characteristics of PCDD/Fs in spent etching solution and its copper salt recycling products]. AB - Concentrations of 17 PCDD/Fs congeners in spent etching solution and its copper salt recycling products were determined by the high resolution gas chromatography high resolution mass spectrometry (HRGC-HRMS). The PCDD/F concentrations and corresponding WHO-TEQ (toxic equivalent quantity) values were in the range of 0-3 460 pg.L (mean= 616 pg.L-1) and 0-246 pg.L-1 (mean = 42.9 pg.L-1) , respectively, in the spent etching solution, and 1.08-24.6 ng.kg-1 (mean = 8.83 ng.kg-1) and 0.112-0.715 ng.kg-1 (mean = 0.338 ng.kg-1), respectively, in the copper salt products. The established purification treatment technique could remove most of the PCDD/Fs in the etching solution. Of the copper products, higher PCDD/F concentrations were detected in industrial products than in feed grade and plating grade products. Similar distribution characteristics were found for PCDD/ Fs in all copper salt products as the followings: 1. PCDFs were more abundant than PCDDs, 2. high chlorinated congeners were more abundant than low chlorinated congeners, except for 2,3,7,8-TCDF in the copper sulfate products. PMID- 23668136 TI - [Case study on health risk assessment based on site-specific conceptual model]. AB - Site investigation was carried out on an area to be redeveloped as a subway station, which is right downstream of the groundwater of a former chemical plant. The results indicate the subsurface soil and groundwater in the area are both polluted heavily by 1,2-dichloroethane, which was caused by the chemical plant upstream with the highest concentration was 104.08 mg.kg-1 for soil sample at 8.6 m below ground and the highest concentration was 18500 microg.L-1 for groundwater. Further, a site-specific contamination conceptual model, giving consideration to the specific structure configuration of the station, was developed, and the corresponding risk calculation equation was derived. The carcinogenic risks calculated with models developed on the generic site conceptual model and derived herein on the site-specific conceptual model were compared. Both models indicate that the carcinogenic risk is significantly higher than the acceptable level which is 1 x 10(-6). The comparison result reveals that the risk calculated with the former models for soil and groundwater are higher than the one calculated with the latter models by 2 times and 1.5 times, respectively. The finding in this paper indicates that the generic risk assessment model may underestimate the risk if specific site conditions and structure configuration are not considered. PMID- 23668137 TI - [Study on the risk assessment method of regional groundwater pollution]. AB - Based on the boundary elements of system risk assessment, the regional groundwater pollution risk assessment index system was preliminarily established, which included: regional groundwater specific vulnerability assessment, the regional pollution sources characteristics assessment and the health risk assessment of regional featured pollutants. The three sub-evaluation systems were coupled with the multi-index comprehensive method, the risk was characterized with the Spatial Analysis of ArcMap, and a new method to evaluate regional groundwater pollution risk that suitable for different parts of natural conditions, different types of pollution was established. Take Changzhou as an example, the risk of shallow groundwater pollution was studied with the new method, and found that the vulnerability index of groundwater in Changzhou is high and distributes unevenly; The distribution of pollution sources is concentrated and has a great impact on groundwater pollution risks; Influenced by the pollutants and pollution sources, the values of health risks are high in the urban area of Changzhou. The pollution risk of shallow groundwater is high and distributes unevenly, and distributes in the north of the line of Anjia-Xuejia Zhenglu, the center of the city and the southeast, where the human activities are more intense and the pollution sources are intensive. PMID- 23668138 TI - [Groundwater organic pollution source identification technology system research and application]. AB - Groundwater organic pollutions are found in large amount of locations, and the pollutions are widely spread once onset; which is hard to identify and control. The key process to control and govern groundwater pollution is how to control the sources of pollution and reduce the danger to groundwater. This paper introduced typical contaminated sites as an example; then carried out the source identification studies and established groundwater organic pollution source identification system, finally applied the system to the identification of typical contaminated sites. First, grasp the basis of the contaminated sites of geological and hydrogeological conditions; determine the contaminated sites characteristics of pollutants as carbon tetrachloride, from the large numbers of groundwater analysis and test data; then find the solute transport model of contaminated sites and compound-specific isotope techniques. At last, through groundwater solute transport model and compound-specific isotope technology, determine the distribution of the typical site of organic sources of pollution and pollution status; invest identified potential sources of pollution and sample the soil to analysis. It turns out that the results of two identified historical pollution sources and pollutant concentration distribution are reliable. The results provided the basis for treatment of groundwater pollution. PMID- 23668139 TI - [Study on soil organic carbon pools and turnover characteristics along an elevation gradient in Qilian Mountain]. AB - On the basis of the first order dynamic model combining with the laboratory soil incubation experiment, characteristics of soil organic carbon pools(Csoc), active carbon pools(Ca), slow carbon pools(Cs), passive carbon pools(Cr) and their turnover in Qilian Mountain were studied. It has been showed that the size of Csoc in horizon A and B ranges from 7.606- 89.026 g.kg - and 5.804-84.267 g.kg-1, which shows tendency of "increase-decrease-increase-decrease" with elevation. The size of Cs, Cs, and Cr in horizon A and B under different elevations respectively ranges from 0.180-1.328 g.kg-1, 0.159-1.273 g.kg-1; 3.650-35.173 g.kg-1, 3.703 43. 623 g.kg-1; 3.776-65.298 g.kg-1, 1.942-48. 121 g.kg-1, which incarnates no obvious variation law with elevation. The contents of Csoc, Cr and Cs significantly differ with different elevation gradients. There is no significant difference in the C, content between different elevation gradients. Decomposition rate of Csoc also has no evident change law in elevation. The peak of daily carbon release rate varies with carbon release rate in the whole incubation process, which could be used to present character of SOC turnover rate. It has been also showed that Caand peak of daily carbon release rate have a significant relationship, and they follow the linear relationship. The incubation reveals that Csoc turns over in sequence of Ca, Cs, and Cr,. Polynomial equation presents relation between total SOC release amount and time, of which cubic polynomial has achieved preferable precision(R2 >0.99). PMID- 23668140 TI - [Response of black soil organic carbon, nitrogen and its availability to longterm fertilization]. AB - Based on the long-term fertilization experiments, effects of various fertilization practices on the soil organic carbon (SOC) and total nitrogen (TN) in the surface (0-20 cm) and subsurface (20-40 cm) black soil in northeast China were studied. Results showed that, compared with the CK, long-term application of organic manure, especially the combination of mineral fertilizers and organic manure significantly increased the organic SOC and TN in the surface soil. Application of mineral fertilizers plus organic manure with conventional (NPM) and high application (N2P2M2) rate increased SOC significantly by 24. 6% and 25.1% , and TN by 29.5% and 32.8%, respectively. However, there was no significant difference among the treatments for SOC and TN at the subsurface. Compared with the CK (CKh), mineral fertilizer plus organic manure (NPM and N2P2M2) did not only increase the soil microbial biomass carbon (SMBC) and nitrogen (SMBN) , dissolved organic carbon (DOC) and nitrogen (DN), but also significantly increased the ratio of SMBC and DOC to SOC, SMBN and TN to TN. Application of the NPM and N2P2M2 increased the value of SMBC/SOC by 0.36 to 0.59 and SMBN/TN by 1.21 to 1.95 percentage points, respectively. The value of DOC/SOC and DN/TN ranged from 0.53% to 0.72% and 1.41% to 1.78%, respectively. This result indicated that SMBC, SMBN, DOC, DN and SMBC/ SOC, SMBN/TN, DOC/SOC, DN/TN were more sensitive than SOC and TN to long-term fertilization in the soil profile, and were better indicators for the impact of long-term fertilization soil fertility. The concluded that the application of manure especially manure plus mineral fertilizers can increase soil nutrients activity in the surface and subsurface black soil, acting as a helpful practice to improve soil fertility and the ability of nutrient supply, while it may cause potential environment pollution on carbon and nitrogen loss in the agroecosystem. PMID- 23668141 TI - [Phytoavailability and chemical speciation of cadmium in different Cd contaminated soils with crop root return]. AB - Pot experiments were conducted under greenhouse condition to investigate the effects of crop root return on succeeding crops growth, Cd uptake and soil Cd speciation in Cd-contaminated soil and artificial Cd-contaminated soil. The results showed that the amount of root residue returned to soil by corn and kidney bean growth successive for 3 times was 0.4%-1.1%. The Cd returned to soil by root residue was 1.3%-3.5% to the total soil Cd. There was no significant difference in the shoot dry weights of winter wheat and Chinese cabbage grown on the 2 Cd-contaminated soils with and without root return. While Cd concentration of Chinese cabbage increased significantly in the Cd-contaminated soil with corn or kidney bean root return. Light fraction of soil organic matter increased with root return in both of the Cd-contaminated soils. The percentage of Cd in the light fraction of soil organic matter increased with root return in the artificial Cd-contaminated soil. Soil carbonates-bound Cd concentration decreased significantly with corn root return in the Cd-contaminated soil. Soil exchangeable Cd concentration decreased and soil Fe-Mn oxide-bound Cd concentration increased significantly with kidney bean root return in the artificial Cd-contaminated soil. PMID- 23668142 TI - [Study on mechanism of SOM stabilization of paddy soils under long-term fertilizations]. AB - Fourier transform infrared spectroscopy (FTIR) was applied to study the structure of soil organic matter (SOM) of paddy soils under long-term different fertilization treatments. The aim was to clarify the different distribution of SOM between different fertilization methods and between topsoil and subsoil, and to explore the stability mechanism of SOM under different fertilization treatments. The results showed that the content of topsoil organic carbon (SOC) was the highest under organic-inorganic fertilizations, with the increment of SOC by 18.5%, 12.9% and 18.4% under high organic manure (HOM), low organic manure (LOM) and straw returning (STW) respectively compared with no fertilization treatment (CK). The long-term fertilizations also changed the chemical structure of SOM. As compared with CK, different fertilization treatments increased the functional group absorbing intensity of chemical resistance compounds (aliphatic, aromaticity), carbohydrate and organo-silicon compounds, which was the most distinctive under treatments of HOM, LOM and STW. For example, the absorbing intensity of alkyl was 0.30, 0.25 and 0.29 under HOM, LOM and STW, respectively. These values were increased by 87% , 56% and 81% as compared with that under CK treatment. The functional group absorbing intensity of SOM in the topsoil was stronger than that in the subsoil, with the most distinctive difference under HOM, LOM and STW treatments. The present research indicated that the enhanced chemical resistance of functional group of SOM may contribute to the high contents of SOC in the paddy soils under long-term organic-inorganic fertilizations, which also suggested a chemical stabilization mechanism of SOM in the paddy soils. PMID- 23668143 TI - [Aging process of Cr(III) in 22 typical soils of China and influence factors Analysis]. AB - Aging process is a key factor influencing the availability and toxicity of heavy metals in soil. However, the aging of chromium (Cr) in soils and its influence factors are still unclear, as a result of complexity of soils in China. This study was conducted to investigate the aging process of Cr(Ill) in 22 typical soils of China by using 0.01 mol.L-1 CaCl2 as the extractant for available Cr. The results manifested that Cr spiked in the soil was time-dependently transferred from the available fraction into less labile fractions. Two regions could be distinguished: the first one for short extraction time (t <21 days), corresponding to a faster transformation of metals and the second for longer extraction time (t >21 days) where the transformation was relatively slower. The decrease of Cr in available fraction during the incubation could be simulated by the Elovich equation, and decrease rates were applied to reflect the transformation rates of aging process among various soils. Multiple regression analysis showed that decrease rates might be related to the organic matter, pH and amorphous Fe oxides of soil, and organic matter was the key factor to the aging process. PMID- 23668144 TI - [Residual characteristics of HCHs in soils of a former lindane production enterprise]. AB - In order to study the soil pollution status of the fields left by organochlorine pesticide manufacturing enterprises, soils from a former lindane production enterprise of Xinxiang were investigated in November, 2010. A soxhlet extraction gas chromatography-electron capture detector (SE-GC-ECD) method was used to detect the HCH residues in the contaminated soil samples. Results showed that the detection rate of the four HCHs isomers in each sampling site was 100%. In the 0 20 cm topsoil, concentrations of HCH residues (Sig;ma HCH ) changed with volatility, ranging from 0.0343 to 19.5608 mg.kg-1. In the soil layer at 0-80 cm depth and around the center point, concentrations of HCH residues (Sigma HCH ) first increased and then reduced while the soil depth increased, varying from 0.031 3 to 0.2947 mg.kg-1. Analysis of HCH composition showed that concentrations of the four isomers were in the order of beta-HCH > delta-HCH > alpha-HCH > alpha HCH. The average percentage of p-HCH isomer was approximately 50%, which was obviously higher than those of the other isomers, indicating that there was no recent input of HCH. The results showed that over the recent decades, the HCH level in most of the soil samples (67.9%) were below the residue criterion of 0.5 mg.kg-1 of the China Soil Environmental Quality Standard (GB 15618-1995), indicating that they were safe. However, soil samples in western and eastern parts of backyard near the production plant were still seriously contaminated, the HCH concentrations in which were 1.5-20 times higher than the residue criterion of 1.0 mg.kg-1 of the China Soil Environmental Quality Standard, causing great potential safety hazard to human and environment. PMID- 23668145 TI - [Evaluation and source analysis of the mercury pollution in soils and vegetables around a large-scale zinc smelting plant]. AB - The farming soil and vegetable samples around a large-scale zinc smelter were collected for mercury content analyses, and the single pollution index method with relevant regulations was used to evaluate the pollution status of sampled soils and vegetables. The results indicated that the surface soil and vegetables were polluted with mercury to different extent. Of the soil samples, 78% exceeded the national standard. The mercury concentration in the most severely contaminated area was 29 times higher than the background concentration, reaching the severe pollution degree. The mercury concentration in all vegetable samples exceeded the standard of non-pollution vegetables. Mercury concentration, in the most severely polluted vegetables were 64.5 times of the standard, and averagely the mercury concentration in the vegetable samples was 25.4 times of the standard. For 85% of the vegetable samples, the mercury concentration, of leaves were significantly higher than that of roots, which implies that the mercury in leaves mainly came from the atmosphere. The mercury concentrations in vegetable roots were significantly correlated with that in soils, indicating the mercury in roots was mainly from soil. The mercury emissions from the zinc smelter have obvious impacts on the surrounding soils and vegetables. Key words:zinc smelting; mercury pollution; soil; vegetable; mercury content PMID- 23668146 TI - [Residue of organic fluorine pollutants in hair and nails collected from Tianjin]. AB - In order to explore the residue and distributions of organic fluorine pollutants in hair and nails, the residue levels of total fluorine (TF), extractable organic fluorine (EOF) and perfluorinated chemicals (PFCs) in hair and nails collected from Tianjin adults were measured by the cyclic neutron activation analysis (CNAA) combined with the high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The results showed that inorganic fluorine (mean: 2.0 mg.kg-1, 4.5 mg.kg-1) was the primary fluorine in TF while EOF(mean: 0.7 mg.kg-1, 1.8 mg.kg-1) was minor. The average amount of identified fluorine (IF) was 0.038 mg.kg-1 in hair and 0.047 mg.kg-1 in nails, accounting or 7.1% (2.6%-16%) and 3.5% (1.1%-11%) of EOF, respectively, which indicated that more than 84% of EOF was unknown. The major residue in hair and nails were medium-and short-chain PFCs,in which perfluorooctane sulfonate, perfluorooctanoic acid and perfluorononanoic acid were the main species. TF, EOF and IF levels in dyed and permed hair were significantly higher than untreated hair (P <0.05), and the concentrations of Sigma PFCs in hair and nails showed no difference between genders. With significantly higher levels of sigma PFCs and PFOS residues than hair (P <0.01), nails could potentially become a more sensitive bioindicator for the exposure level of PFCs in human. PMID- 23668147 TI - [Analysis of estrogens, nonylphenol, 4-tert-octylphenol and bisphenol A in the sediments]. AB - Estrogens and alkylphenols have received much attention because of its endocrine disrupting effects to aquatic ecosystem in recent years. The fate of these compounds in sediments which is a repository of many organic pollutants has an important significance on the study of behaviors of target compounds in the environment. It is difficult to separate trace estrogens from sediments with complex matrices. Alkali extraction, liquid-liquid extraction and LC-MS/MS were used to analyze estrogens, nonylphenol, 4-tert-octylphenol and bisphenol A in sediments based on their physicochemical properties. The results showed that recoveries of the seven target compounds were 61.3%-93.7%. The established pretreatment method can effectively remove pollutants that cannot dissolve in alkali solution or that cannot dissolve in both acid and alkali solution. It can widely be used to analyze sediments and soil samples because of its low cost and simple operation but with high recoveries and low detection limit. PMID- 23668148 TI - [Investigation of As, Cu and Zn species and concentrations in animal feeds]. AB - Seventy chicken and seventy-six pig feeds were collected from the feed stores in Guangdong province, and the species and concentrations of As, Cu and Zn were determined. We also examined the stability of roxarsone (ROX), one of the most widely used organoarsenical additives, either in the additive or in the feed at room temperature. The results showed that, averagely, the chicken and pig feeds contained 3.6 and 6.5 mg.kg-1 (As), 18.2 and 119.4 mg.kg-1 (Cu),and 124.6 and 486.2 mg.kg-1 (Zn), respectively. The excessive dosages of As, Cu and As in animal feeds will lead to higher residue of As, Cu and Zn in animal manures. Based on the national limit criteria for feed or feed additive, it was supposed that organoarsenicals had been used, only few feed samples exceeded the As limit, however, the excessive Cu and Zn in pig feeds were much more common. Organoarsenicals were found in 25.4% of the total feed samples, and As(Ill) and As(V) were the two most commonly detected As impurities in feeds bearing organoarsenicals. The mean detectable ROX and arsenilic acid were 7.0 and 21.2 mg.kg-1, respectively. Organoarsenicals were detectable in 24. 3% of the chicken feed samples and 26. 3% of the pig feed samples. Moreover, ROX was commonly used in chicken feeds, while p-ASA in pig feeds. ROX and the inorganic As impurities, either in the commercial additive or in the feed, remained stable for at least 30 days at room temperature, indicating the higher As impurities in feeds probably originated from the As impurities in organoarsenical additives. This is a new As exposure pathway for the producer and user of organoarsenicals and feeds amending organoarsenicals. PMID- 23668149 TI - [Residue dynamics of flubendiamide in paddy field]. AB - Residue dynamics and terminal residue of flubendiamide 19.8% suspension concentrate (SC) in rice and field environment were measured by ultra performance liquid chromatography (UPLC). As flubendiamide and its metabolite were applied at a range of concentrations from 0.05 to 1.0 mg.kg-1, average recoveries of them in soil, water, rice straw, rice grain and rice hull samples ranged from 78.2% to 104.8%, with variation coefficients of 1.1% -4.4%. One-year and three-area results showed that the half-life of gradation for flubendiamide was 9. 8 to 17.3 d in water, 10. 8 to 22.4 d in soil, and 7.6 to 17.3 d in rice plants, respectively. Residues of metabolite NNI-des-iodo in water were detected, but not in soil or rice plants. When flubendiamide was applied at the recommended dose, its residue in rice grain on the 10th day after application was lower than 0.5 mg.kg-1, the maximum residue limit allowed by US for agricultural chemical residues in rice. PMID- 23668151 TI - [Biodegradation of nitrobenzene by a halophilic Myroides odoratimimus strain Y6]. AB - Aimed at efficient remediation of nitrobenzene-contaminated saline wastewater, the nitrobenzene-degrading characteristics of a Myroides odoratimimus strain Y6 were studied and analyzed. The effects of temperature, pH, initial concentration of nitrobenzene, inoculum concentration and culture type on the biodegradation of nitrobenzene by strain Y6 under saline conditions were studied. Strain Y6 showed the highest efficiency of nitrobenzene degradation in 7% NaC1 (mass fraction). The optimal conditions for the biodegradation of nitrobenzene by strain Y6 were at pH 6.0, 28 degrees C and D600 = 1. With initial concentrations of 100 and 200 mg.L-1, 97.5% and 65.7% of nitrobenzene were transformed after 168 h in 7% NaCL, respectively. Three kinds of additional compounds, glucose, starch and glycerin were tested to choose a favorite carbon source for the co-metabolism of strain Y6. The results showed that all these three compounds could promote nitrobenzene biodegradation and cell growth. And the rate of degradation could increase to 93.3% ,with 800 mg.L-1 glucose as the primary substrate. These results suggest that strain Y6 could be a potential candidate for treating nitrobenzene contaminated saline wastewater. To date, this is the only study on the degradation of nitrobenzene by M. odoratimimus. PMID- 23668150 TI - [Isolation of two endophytic phenanthrene-degrading strains and their degradation capacity]. AB - Two endophytic bacterial strains, which could degrade high concentration (up to 200 mg.L-1) of phenanthrene in liquid, were isolated from plants grown in PAHs contaminated soils by the selective. enrichment culture. According to the results of morphology, physiology and the phylogenetic analyses of 16S rDNA sequence, stain P1 was identified as Stenotrophomonas sp. , and strain P3 was identified as Pseudomonas sp.. Two strains were aerobic bacteria, the degradation rates of phenanthrene (100 mg.L-1) by strain P1 and strain P3 were all greater than 90% at 28 degrees C on the rotation shaker at 150 r.min-1 for 7 days. The degradation rates of phenanthrene by two strains were greater than 70% when cultivated under the conditions as: 20-30 degrees C , pH 6-8, 0%-4% NaCl, 10-30 mL/100 mL inventory. It suggested that the optimum culture condition was: 30 degrees C, pH 7.0, NaCl< or =4% , inventory < or = 30 mL/100 mL flask. Through comprehensive comparison analyses on the degradation capacity of two strains, it showed that the tolerance of strain P1 to high temperature was higher than that of str ain P3, while the tolerance of strain P3 to pH change and anoxic condition was higher than that of strain P1. PMID- 23668152 TI - [Effect of immobilization on biosensor for benzene derivates detection]. AB - A whole cell sensor, Pseudomonas fluorescens A506 (pTS), was immobilized by sodium alginate and the factors of cell density, immobilization time and beads usage were optimized. The performance of the immobilized cells was compared with that of the free cells. After 2 h immobilization,the increasing speed of fluorescent signal of immobilized cells was 2.26 times as high as that of the free cells,and the peak value was 2.23 times as high during the detection time ranging from 1.5 to 6.0 h. The constantly lower growth and density of the immobilized cell implied the enhanced signal intensity of single cells after immobilization. Meanwhile, the cell density decreased as the immobilization time prolonged. Cell density and immobilization time were the dominant factors affecting the detection signal. For benzene at higher concentrations, the immobilized biosensor showed more rapid signal response at the early period of detection. PMID- 23668153 TI - [Investigation of bacterial diversity in the biological desulfurization reactor for treating high salinity wastewater by the 16S rDNA cloning method]. AB - The bacterial diversity in the biological desulfurization reactor operated continuously for 1 year was studied by the 16S rDNA cloning and sequencing method. Forty clones were randomly selected and their partial 16S rDNA genes (ca. 1,400 bp) were sequenced and blasted. The results indicated that there were dominant bacterias in the biological desulfurization reactor, where 33 clones belonged to 3 different published phyla, while 1 clone belonged to unknown phylum. The dominant bacterial community in the system was Proteobacteria, which accounted for 85.3%. The bacterial community succession was as follows: the gamma Proteobacteria(55.9%), beta-Proteobacteria(17.6%), Actinobacteridae (8.8%), delta Proteobacteria (5.9%) , alpha-Proteobacteria(5.9%), and Sphingobacteria (2.9%). Halothiobacillus sp. ST15 and Thiobacillus sp. UAM-I were the major desulfurization strains. PMID- 23668154 TI - [Assessment of the effect of influent NH+4-N concentration on the abundance and community structure of functional bacteria in CANON process]. AB - To investigate macroscopic performance and microcosmic ecosystem of CANON process in low ammonium concentration at room temprature, a steady-operation CANON reactor was achieved in different ammonium concentrations by adjusting aeration and hydraulic retention time (HRT), and the effect of ammonium concentration on the abundance and community structure of functional bacteria was analyzed using PCR-DGGE and real-time PCR. The results indicated a high TN removal loading of over 1.0 g.(L.d)-1 in relatively high ammonium which was significantly reduced with the ammonium concentration of 100 mg.L-1. The community structure of ammonium oxidizing bacteria (AOB) changed sharply with the decrease of ammonium concentraion, which was not the same as anaerobic ammonium oxidizing bacteria (ANAMMOX bacteria). Besides, the abundance of the two functional groups of bacteria reduced while the population of nitrite oxidizing bacteria (NOB) rose with the decrease of ammonium, which might be the main reason for the reduction of nitrogen removal efficiency. Consequently, some strategies are needed to reduce the loss of AOB and ANAMMOX bacteria and inhibit the growth of NOB so as to maintain the nitrogen removal performance in low ammonium concentration. PMID- 23668155 TI - [Biodegradation of lignocellulose by Penicillium simplicissimum and characters of lignocellulolytic enzymes]. AB - Penicillium simplicissimum(Oudem.) Thomrn BGA can secrete lignocellulolytic enzymes, among these enzymes the highest activities of hemicellulase, cellulase, lignin peroxidase (Lip), manganese peroxidase (Mnp) and laccase are 146.82 Iu.g 1, 2.78 U.g-1, 47.97 U.g-1, 34.56 U.g-1 and 17.94 U.g-1 respectively. According to the results and the statistical analysis of SPSS, the ability of secreting lignocellulolytic enzymes by Penicillium simplicissimum significantly correlated with the structure of lignocellulose, and the biodegradation of lignocellulose was probably a kind of synergistic effect of several lignocellulolytic enzymes. In the solid-state fermentation of 30 days, the hemicellulose content has a significantly negative correlation with the fermentation days(r = -0.946, P < 0.01), there was also a significantly negative correlation between the cellulose biodegradation and the lignin-biodegradation (r = -0.818, P<0.05). As unselected enzymes, Lip and Mnp can degrade hemicellulose and cellulose corporately when biodegrades lignin. The significant correlation is showed between Lip, Mnp and cellulose (correlation parameters are r = 0. 922, P <0.01; r = 0.807, P<0.05 respectively). In addition, the biosorption is found to have a very important effect in the removal of liquid alkali lignin by Penicillium simplicissimum. Key words:Penicillium simplicissimum; lignocellulolytic enzymes; biodegradation; biosorption; synergistic effect PMID- 23668156 TI - [Microbial community structure and distribution characteristics in oil contaminated soil]. AB - Molecular biology methods such as PCR-DGGE combined with phylogenetic analysis were used for the soil microbial community structure and distribution profiling. Relationship of microbial community structure and distribution differed in a typical oil contaminated field was studied. Results showed that soil oil content was the main factor to the difference of microbial community structure similarity. The similarity index of microbial community structure and oil content had a significantly negative correlation. The contaminated soil microorganism genus had an uneven distribution. Thus, soil pollution had obvious stress and differentiation for microbial community structure and species relationship. Dominant species in oil contaminated soil were identified as Gulosibacter, Halomonas, Petrobacter, Methylocystis, and Pseudoalteromonas. The findings provide a basis for understanding the microbial characteristics of oil contaminated soil. PMID- 23668157 TI - [Degradation of oxytetracycline in chicken feces aerobic-composting and its effects on their related parameters]. AB - In order to illustrate the degradation of tetracyclines (TCs) and their influences on process parameters during the period of chicken feces aerobic composting, the degradation of oxytetracycline (OTC), a kind of TCs and its effects on parameters during the period of chick feces aerobic-composting including temperature, pH, and germination index were investigated using the method of aerobic-composting. The contents of OTC decreased gradually with composting time. The degradation rate was high before 10 d, and then decreased gradually. The differences in OTC degradation among the OTC treatments were also found. The degradation rate of OTC was higher at the level of 25 mg.kg-1, than that of other levels. The degradation curve of OTC could be described by the first-order kinetic model, and the correlation coefficients ranged from 0. 911 1 to 0. 9913. The impacts of OTC on chick feces composting were found. OTC could decrease the rising rate of composting temperature and make the high temperature (> or =50 degrees C) period shorter than that of the control. The values of pH, TN, WSC, and the content of NH: -N of composting were 4.58%, 12.62%, 49.06%, and 35.30% higher than those of the control. The impacts of OTC on maturity of chicken feces composting was not found when the OTC addition contents were lower than 50 mg.kg-1. However, the strong impacts of OTC on maturity of chicken feces composting were found when the OTC addition contents were higher than 50 mg.kg-1. The rates of NH+4 -N to NO-3 -N, and GI were much higher than 0. 5 and lower than 80% , respectively. Theses results suggest that OTC have strong impacts on chicken feces composting when the contents of TOC was higher than 50 mg.kg-1, although OTC have the short half-life period ranged from 1.79-4.88 d. PMID- 23668158 TI - [Research of moisture content variation in MSW landfill]. AB - Using time domain reflectometry (TDR) technology, waste moisture content variation in aerobic and anaerobic landfill of MSW was monitored, in order to study its disciplinarian. The results showed that volume moisture content of waste increased with landfill time and water holding capacity of waste improved continuously. The correlation of water quantity and moisture content was positive in early aerobic landfill, but it became negative later. In anaerobic landfill, moisture content variation was caused by settlement and compression of MSW. TDR readings and waste material-based volume moisture content had a good correlation. The maximum error between them is about +/- 5% in aerobic landfill and +/- 2% in anaerobic landfill. TDR technology is applicable to measure moisture content in practical landfill engineering. PMID- 23668159 TI - [Anaerobic digestion of lignocellulosic biomass with animal digestion mechanisms]. AB - Lignocellulosic material is the most abundant renewable resource in the earth. Herbivores and wood-eating insects are highly effective in the digestion of plant cellulose, while anaerobic digestion process simulating animal alimentary tract still remains inefficient. The digestion mechanisms of herbivores and wood-eating insects and the development of anaerobic digestion processes of lignocellulose were reviewed for better understanding of animal digestion mechanisms and their application in design and operation of the anaerobic digestion reactor. Highly effective digestion of lignocellulosic materials in animal digestive system results from the synergistic effect of various digestive enzymes and a series of physical and biochemical reactions. Microbial fermentation system is strongly supported by powerful pretreatment, such as rumination of ruminants, cellulase catalysis and alkali treatment in digestive tract of wood-eating insects. Oxygen concentration gradient along the digestive tract may stimulate the hydrolytic activity of some microorganisms. In addition, the excellent arrangement of solid retention time, digesta flow and end product discharge enhance the animal digestion of wood cellulose. Although anaerobic digestion processes inoculated with rumen microorganisms based rumen digestion mechanisms were developed to treat lignocellulose, the fermentation was more greatly limited by the environmental conditions in the anaerobic digestion reactors than that in rumen or hindgut. Therefore, the anaerobic digestion processes simulating animal digestion mechanisms can effectively enhance the degradation of wood cellulose and other organic solid wastes. PMID- 23668160 TI - [Where do you suspect is the source of the bleeding?]. PMID- 23668161 TI - [The new general practice EBM 2 (uniform rating scale)]. PMID- 23668162 TI - [A message for the general election campaign]. PMID- 23668163 TI - [Interview with the Daiichi-Sankyo managing director Ralf Goddertz (interview by Dirk Einecke and Cornelius Heyer)]. PMID- 23668164 TI - [Baby with injuries: was violence the cause?]. PMID- 23668165 TI - [Skin problems after 50]. PMID- 23668166 TI - [Bach, but not heavy metal is good for heart patients]. PMID- 23668167 TI - [What is the cause?]. PMID- 23668168 TI - ["Doctor, am I allowed to fly?"]. PMID- 23668169 TI - [Was that not unhealthy?]. PMID- 23668170 TI - [With proton scanning multiple exposures are safe]. PMID- 23668171 TI - [At what age and what intervals is it sensible?]. PMID- 23668172 TI - [A poisonous argument]. PMID- 23668173 TI - [Sometimes only magic helps]. PMID- 23668174 TI - [Reducing blood sugar at the cost of increasing weight must be avoided]. PMID- 23668175 TI - [Antidiabetic drug therapy in overweight and obese adults with type 2 diabetes]. PMID- 23668176 TI - [Bariatric surgery--significance, risks and long term consequences]. PMID- 23668177 TI - [Snoring and sleep disorders]. PMID- 23668178 TI - [Painful swelling of a joint: arthrosis gout, infection or rheumatism?]. PMID- 23668179 TI - [Clostridium difficile infections - still a major challenge]. PMID- 23668180 TI - [Two patients with palpitations. Always benign?]. PMID- 23668181 TI - [Pain therapy in cancer patients]. PMID- 23668182 TI - [Acute rhinosinusitis. Effective therapy with a 5 plant combination]. PMID- 23668183 TI - Effects of pH on the hierarchical structures and photocatalytic performance of BiVO4 powders prepared via the microwave hydrothermal method. AB - BiVO4 powders with hierarchical structures were prepared by the microwave hydrothermal method at different pHs, using Bi(NO3)3.5H2O and NH4VO3 as raw materials. The results show that, when the pH value of the precursor is 0.59, the as-prepared powders are monoclinic BiVO4 crystals with octahedron and decahedron morphologies. Spherical and polyhedral BiVO4 with particle sizes in the range of 2-4 MUm can be prepared under the strong acid condition (pH = 0.70-1.21) and possess a mixed crystal consisting of tetragonal and monoclinic phases, whereas rodlike and dendritic BiVO4 with a pure monoclinic phase can be obtained within a very wide pH range (pH = 4.26-9.76). The phase transformation from tetragonal phase to monoclinic phase occurs at pH 3.65. At pH >9.76, the powders are the nonstoichiometric crystals between the mixed-phase BiVO4 and non-BiVO4. The photocatalytic efficiencies were evaluated by the degradation of Rhodamine B (RhB) under UV and simulated sunlight irradiation. The corresponding relationship among pH values of the precursor, crystalline phase, morphology, and photocatalytic performance of the powders was also discussed. PMID- 23668184 TI - Asymmetry in the discrimination of length during spatial learning. AB - The ability of rats to solve a discrimination between two objects that differ in length was investigated in five experiments. Using a rectangular swimming pool, Experiment 1 revealed it is easier to locate a submerged platform when it is near the center of a long rather than a short wall. For Experiments 2-4, the objects were black or white panels pasted onto the gray walls of a square pool, with two long panels pasted to two opposing walls and two short panels pasted to the remaining walls. The platform was easier to locate when it was placed near the middle of a long rather than a short panel. This effect was found when the long panels were twice (Experiments 2-4) or four times the length of the short panels (Experiment 4). Experiment 5 demonstrated that rats can solve a discrimination between panels of length 15 and 45 cm more readily than when they are 70 and 100 cm. The results are consistent with the claim that generalization gradients based on stimulus magnitude are steeper for stimuli that are weaker rather than stronger than the stimulus used for the original training. PMID- 23668185 TI - Blocking and associability change. AB - Blocking of learning about a conditioned stimulus (the "blocked" cue) occurs when it is trained alongside an additional stimulus (the "blocking" cue) that has been previously presented with the outcome. A number of theories (e.g., N. J. Mackintosh. 1975a. A Theory of Attention: Variations in the Associability of Stimuli With Reinforcement. Psychological Review, 82, 276-298; J. M. Pearce & G. Hall. 1980. A Model for Pavlovian Learning: Variation in the Effectiveness of Conditioned But Not Unconditioned Stimuli. Psychological Review, 87, 532-552) account for this attenuation in learning by proposing that attention paid to the blocked cue is restricted. In three experiments, we examined the associability of both blocked and blocking cues. In Experiment 1, rats were trained with a blocking protocol before being given a test discrimination composed of two components; one of these components required the use of the previously blocked cue as a discriminative stimulus, and the other component was soluble by using the blocking cue. To our surprise, the component that depended on the blocked cue was more readily solved than the component dependent on the blocking cue. The results of Experiments 2 and 3 suggest that this is due to the quantity of exposure that each stimulus received during initial training. Implications for theories of blocking, and more widely associative learning, are discussed. PMID- 23668186 TI - Extinction of reinstated or ABC renewed fear responses renders them resistant to subsequent ABA renewal. AB - Three experiments used an ABA renewal paradigm to study deepening of response loss produced by extinction of reinstated or ABC renewed fear responses. In Experiment 1, rats were trained with two stimuli, S1 and S2, in context A and extinguished to S1 in context B and S2 in context C, shocked in B but not in C, and subjected to additional extinction of S1 in B and S2 in C. Rats froze less to S1 than S2 when subsequently tested in A. In Experiments 2 and 3, following training of S1 and S2 in A, one group received extinction of S1 in B and S2 in C followed by extinction of S1 in C and S2 in B. This group froze less to S1 in A or to S2 in a novel context, D, than a group always extinguished to S1 in B and S2 in C or a group extinguished to both S1 and S2 in B and C. These results show that additional extinction of a conditioned stimulus (conditional stimulus [CS]) exhibiting either reinstatement or ABC renewal renders that CS resistant to ABA renewal. They are consistent with theories that allow a role for context in extinction learning and that use error-correction mechanisms to update this learning. PMID- 23668187 TI - Multiple loci and genetic interactions involving flowering time genes regulate stem branching among natural variants of Arabidopsis. AB - Shoot branching is a major determinant of plant architecture. Genetic variants for reduced stem branching in the axils of cauline leaves of Arabidopsis were found in some natural accessions and also at low frequency in the progeny of multiparent crosses. Detailed genetic analysis using segregating populations derived from backcrosses with the parental lines and bulked segregant analysis was used to identify the allelic variation controlling reduced stem branching. Eight quantitative trait loci (QTLs) contributing to natural variation for reduced stem branching were identified (REDUCED STEM BRANCHING 1-8 (RSB1-8)). Genetic analysis showed that RSB6 and RSB7, corresponding to flowering time genes FLOWERING LOCUS C (FLC) and FRIGIDA (FRI), epistatically regulate stem branching. Furthermore, FLOWERING LOCUS T (FT), which corresponds to RSB8 as demonstrated by fine-mapping, transgenic complementation and expression analysis, caused pleiotropic effects not only on flowering time, but, in the specific background of active FRI and FLC alleles, also on the RSB trait. The consequence of allelic variation only expressed in late-flowering genotypes revealed novel and thus far unsuspected roles of several genes well characterized for their roles in flowering time control. PMID- 23668188 TI - STIM1 negatively regulates Ca2+ release from the sarcoplasmic reticulum in skeletal myotubes. AB - STIM1 (stromal interaction molecule 1) mediates SOCE (store-operated Ca2+ entry) in skeletal muscle. However, the direct role(s) of STIM1 in skeletal muscle, such as Ca2+ release from the SR (sarcoplasmic reticulum) for muscle contraction, have not been identified. The times required for the maximal expression of endogenous STIM1 or Orai1, or for the appearance of puncta during the differentiation of mouse primary skeletal myoblasts to myotubes, were all different, and the formation of puncta was detected with no stimulus during differentiation, suggesting that, in skeletal muscle, the formation of puncta is a part of the differentiation. Wild-type STIM1 and two STIM1 mutants (Triple mutant, missing Ca2+-sensing residues but possessing the intact C-terminus; and E136X, missing the C-terminus) were overexpressed in the myotubes. The wild-type STIM1 increased SOCE, whereas neither mutant had an effect on SOCE. It was interesting that increases in the formation of puncta were observed in the Triple mutant as well as in wild-type STIM1, suggesting that SOCE-irrelevant puncta could exist in skeletal muscle. On the other hand, overexpression of wild-type or Triple mutant, but not E136X, attenuated Ca2+ releases from the SR in response to KCl [evoking ECC (excitation-contraction coupling) via activating DHPR (dihydropyridine receptor)] in a dominant-negative manner. The attenuation was removed by STIM1 knockdown, and STIM1 was co-immunoprecipitated with DHRP in a Ca2+-independent manner. These results suggest that STIM1 negatively regulates Ca2+ release from the SR through the direct interaction of the STIM1 C-terminus with DHPR, and that STIM1 is involved in both ECC and SOCE in skeletal muscle. PMID- 23668189 TI - Honey bee promoter sequences for targeted gene expression. AB - The honey bee, Apis mellifera, displays a rich behavioural repertoire, social organization and caste differentiation, and has an interesting mode of sex determination, but we still know little about its underlying genetic programs. We lack stable transgenic tools in honey bees that would allow genetic control of gene activity in stable transgenic lines. As an initial step towards a transgenic method, we identified promoter sequences in the honey bee that can drive constitutive, tissue-specific and cold shock-induced gene expression. We identified the promoter sequences of Am-actin5c, elp2l, Am-hsp83 and Am-hsp70 and showed that, except for the elp2l sequence, the identified sequences were able to drive reporter gene expression in Sf21 cells. We further demonstrated through electroporation experiments that the putative neuron-specific elp2l promoter sequence can direct gene expression in the honey bee brain. The identification of these promoter sequences is an important initial step in studying the function of genes with transgenic experiments in the honey bee, an organism with a rich set of interesting phenotypes. PMID- 23668190 TI - [Current status and challenges in the treatment of multiple myeloma in China]. PMID- 23668191 TI - [To attach importance to standardized diagnosis and treatment, basic and translational study on multiple myeloma in our country]. PMID- 23668192 TI - [Treatment strategy of multiple myeloma based on prognostic stratification]. PMID- 23668193 TI - [Biology study and novel drugs for targeting therapy of multiple myeloma]. PMID- 23668194 TI - [Clinical consideration of relapsed and refractory multiple myeloma]. PMID- 23668195 TI - [To promote the process of standardized molecular cytogenetic testing for multiple myeloma]. PMID- 23668196 TI - [Prevention and treatment of multiple myeloma bone disease]. PMID- 23668197 TI - [Multiple myeloma and second tumors]. PMID- 23668198 TI - [Selection of maintenance therapy for multiple myeloma and its significance]. PMID- 23668199 TI - [Clinical benefit and regimen selection for patients with newly-diagnosed multiple myeloma in the era of novel agents]. PMID- 23668200 TI - [Analysis of the efficacy and prognosis on first-line autologous hematopoietic stem cell transplantation of patients with multiple myeloma]. AB - OBJECTIVE: To explore the efficacy and prognosis of first-line autologous hematopoietic stem cell transplantation (ASCT) for newly diagnosed patients with multiple myeloma(MM). METHODS: From January 2005 to December 31, 2012, 60 patients with MM were enrolled. All patients received thalidomide or/and bortezomib-based induction therapy, then received high-dose melphalan (200 mg/m2) and autologous stem cell support to get a >= partial response (PR), and followed by thalidomide-dexamethasone (TD) +/-bortezomib as consolidation or maintenance treatment. With the follow up to December 31, 2012, the overall survival (OS), progression free survival (PFS) and the prognostic factors, including ISS stage, response and fluorescent in situ hybridization (FISH) data of cytogenetics were analyzed. RESULTS: With a median follow up of 36.8 (12.0-102.5) months, the median OS and PFS estimate were not reached and 86.5 months, respectively. After transplantation, all (100%) patients received very good partial response (VGPR), and 34 (56.7%) patients achieved complete response (CR) after consolidation or maintenance treatment. The patients that achieved CR resulted in long term PFS (P=0.030), with no difference in OS (P=0.942). The univariate analysis showed that the abnormalities, including 13q14 deletion, 1q21 gain, IgH location and p53 deletion had the prognostic impacts. If the t(4;14) or p53 deletion was excluded, there would be no correlation between 13q14 deletion or 1q21 gain with PFS and OS. The patients with p53 deletion had a worst survival. CONCLUSION: There has been significant improvement in the outcome for young MM patients by using ASCT and novel drugs. Cytogenetic abnormalities and response to therapy are the main factors affecting the survival of patients. PMID- 23668201 TI - [Clinical feature and efficacy of patients with multiple myeloma and renal impairment treated with bortezomib based chemotherapy]. AB - OBJECTIVE: To explore the efficacy and safety of bortezomib (btz) based chemotherapy in multiple myeloma (MM) patients with renal-function impairment (RI). METHODS: Fifty-six MM patients with impaired renal function treated with bortazomib based regimens in our single center were retrospectively analyzed. RESULTS: The median age was 59 (ranged 30-77) years. 39.3% were kappa-restricted MM, while 57.1% were lambda-restricted MM. Nine patients were IgD-MM, and 14 were light chain MM. Median creatinine clearance (CrCl) was 25.33 (7.23-59.55) ml/min. The number of patients with mild, moderate and severe RI was 6, 35 and 15, respectively. Overall response rate of MM was 82.4% (>=MR), including 32.4% complete response (CR), 17.6% very good partial response (VGPR) and 26.5% partial response (PR). The rate of renal response was 89.3%, including 62.5% CR, 14.3% PR and 12.5% minor response (MR). A median time of optimal response was 25.5 (ranged 5-240) days. There was no significant difference in the median overall survival and the time to progress in different RI groups. Adverse events observed were similar to those patients with normal renal function previously reported. Most adverse events were manageable, 55.6% patients developed peripheral neuropathy and 10 patients discontinued bortezomib. CONCLUSION: The incidence of RI is higher in patients with IgD-MM and lambda restricted MM. Bortezomib based treatment is a highly effective and safe option in MM patients with impaired renal function. In this analysis, renal function was improved in a substantial proportion of patients. Peripheral neuropathy is the major adverse events which limit its use in MM patients. PMID- 23668202 TI - [The efficacy and safety analysis of bortezomib retreatment in 76 patients with relapsed/refractory multiple myeloma]. AB - OBJECTIVE: To evaluate the efficacy and safety of bortezomib retreatment in 76 patients with relapsed/refractory multiple myeloma (MM), who previously responded to bortezomib. METHODS: Retrospective analysis of 76 MM patients, who had achieved at least a partial response (PR) on initial bortezomib therapy in our hospital from May 2006 to August 2011, received bortezomib retreatment when they relapsed or progressed. RESULTS: The overall response rate (ORR) was 60.5%, among them 6.5% patients achieved CR, 5.8% patients achieved very good partial response (VGPR), 38.2% patients achieved PR. Then we further stratified all patients into 3 groups according to the response of initial bortezomib therapy, including CR group, VGPR group and PR group. After bortezomib retreatment, the ORR of the 3 groups was 84.6%, 73.1% and 43.2%, respectively. According to the response of bortezomib retreatment, the patients were divided into 2 groups: group 1 who at least achieved PR, group 2 who showed no response. The median progression-free survival (PFS) after bortezomib retreatment for group 1 and 2 was 7(1-39) and 5(1 14) months, respectively (P>0.05), while the median overall survival (OS) after bortezomib retreatment was 16(2-64) and 8(1-28) months, respectively (P<0.05). Adverse events (AE) were identified in 88% patients during bortezomib retreatment, including neutropenia, diarrhea and thrombocytopenia, only 9.2%(7 patients) reached III-IV grade of AE. Severe peripheral neuropathy occurred in only one patient. CONCLUSION: Bortezomib retreatment regimen is demonstrated a higher response rate in patients who achieved deeper response in initial treatment, with no more adverse events. PMID- 23668203 TI - [Busulfan, cyclophosphamide and etoposide as conditioning for autologous stem cell transplantation in multiple myeloma]. AB - OBJECTIVE: To evaluate the efficacy and safety of dose-reduced intravenous busulfan, cyclophosphamide and etoposide (BCV) as conditioning for autologous stem cell transplantation (ASCT) in multiple myeloma (MM). METHODS: From September 2007 to September 2010, thirty-two ASCT-eligible patients with MM received high dose melphalan (HDM) as conditioning in our center. Median age was 53.5 (30-63) years. From October 2010 to October 2012, thirty-eight patients conditioned by BCV regimen (intravenous busulfan, total doses 9.6 mg/kg), whose median age was 54(35-64) years. RESULTS: There were no statistical differences in clinical characteristics between the two groups, including myeloma isotype, Durie Salmon staging, international staging system(ISS), and patients received the first line, second line or more than third line therapy. The median time to neutrophil and platelet engraftment were 10.5 vs 11 days (P=0.057) and 11 vs 12 days (P=0.100) in the BCV and HDM groups, respectively. The toxicity of two conditioning regimens had no significant difference. None of hepatic veno occlusive disease and early transplant related mortality was observed. Although overall response rates showed no significant difference between two groups (P>0.05), the CR rates increased from 44.74% pre-ASCT to 63.18% post-ASCT in the BCV group, while 37.50% to 59.38% in the HDM group. During the median follow-up of 16 months (range 2-27) in BCV group, ten patients (26.32%) developed progressive disease and PFS at 12 months were 71.37%. CONCLUSIONS: In this study, the dose-reduced intravenous busulfan, cyclophosphamide and etoposide (BCV) conditioning was demonstrated an effective and safety regimen for ASCT-eligible patients with MM. However, the long term observation is needed. PMID- 23668204 TI - [Observation of humoral immunity reconstitution and its relationship with infection after autologous hematopoietic stem cell transplantation for patients with multiple myeloma]. AB - OBJECTIVE: To study the humoral immunity reconstitution and its relationship with infection in patients with multiple myeloma (MM) after undergoing autologous hematopoietic stem cell transplantation (auto-HSCT). METHODS: Forty-two MM patients undergoing auto-HSCT were included in this study. Peripheral blood were obtained for immunoglobulin detection, including IgG, IgA and IgM before transplantation and 1, 3, 6, 12, 18 and 24 months after transplantation. The time, type, pathogen of infection between 1 and 24 month after transplantation were analyzed. RESULTS: The level of IgA at 6 month [(0.75+/-0.59) g/L] after auto-HSCT was lower than that of pre-auto-HSCT [(1.04+/-0.70) g/L], and reached the level of pre-auto-HSCT at 9 months [(0.99+/-0.52) g/L] after auto-HSCT. The level of IgM reached the level of pre-auto-HSCT [(0.45+/-0.26) g/L] at 3 months after auto-ASCT [(0.50+/-0.26) g/L]. The level of IgG reached the level of pre auto-HSCT [(9.80+/-2.98) g/L] at 1 month after auto-HSCT [(11.09+/-2.69) g/L], and higher than that of pre-auto-HSCT at 9 months after auto-HSCT [(12.07+/-3.57) g/L]. The level of IgG with IgG-type MM was higher than that of patients with light-chain type and IgD-type MM at 6, 9 and 12 months after auto-HSCT. The IgA level of patients who obtained complete remission (CR) is much higher than that of patients who obtained nCR in IgG-type patients. The incidence of infection in 6 month after auto-HSCT was higher than that of (6-12) month and >12 month after auto-HSCT. The incidence of infection was strongly negative correlated with IgA (r =-0.943, P=0.005) and IgG (r=-0.943, P=0.005) level. The frequency of viral infection was also negatively correlated with IgA and IgG. CONCLUSION: The reconstitution time of IgG, IgA and IgM was different in MM patients after auto HSCT. IgG recovered first, then IgM, and IgM the last. The incidence of infection was negatively correlated with IgA and IgG. With the recovery of IgG and IgA, the incidence of infection was decreased accordingly. PMID- 23668205 TI - [Effect of nuclear receptor inhibitor importazole on the proliferation and apoptosis of multiple myeloma cells]. AB - OBJECTIVE: To investigate the effect of nuclear receptor inhibitor importazole (IPZ) on cell cycle and apoptosis of multiple myeloma (MM) cells and its regulatory mechanisms. METHODS: MM cell lines RPMI 8226 and NCI-H929 cells were treated with different concentrations of IPZ. Cell viability was detected through MTT method. Cell cycle and apoptosis were measured by flow cytometry (FCM). Nuclear NF-kappaBprotein expression was tested by Western blot. Electrophoretic mobility shift assay (EMSA) was used to analyze the DNA binding activity. RESULTS: IPZ induced a dose- and time- dependent inhibition of myeloma cells growth. And the IC50 values of IPZ on RPMI 8226 and NCI-H929 after 48 hours incubation were (4.43+/-0.41) and (4.78+/-0.35) MUmol/L, respectively, and the percentages of S phase cells decreased from (54.95+/-4.34)% and (51.38+/-2.43)% to (42.77+/-3.19)% and (40.98+/-6.46)%, respectively. After treatment with IPZ at 8, 12 and 16 MUmol/L, the apoptosis rate significantly increased from (2.47+/ 0.60)% of the control group to (14.53+/-0.90)%, (32.57+/-1.80)% and (58.3+/-1.9)% (P<0.05) in RPMI 8226 and from (2.37+/-0.70)% of the control group to (19.46+/ 0.70) %, (46.02+/-1.10) % and (60.63+/-1.60)% in NCI-H929, respectively. Treatment of RPMI 8226 and NCI-H929 cells with 8 MUmol/L IPZ for 24 h could inhibit NF-kappaB import to nucleus and reduce its DNA binding activity. CONCLUSION: The nuclear receptor inhibitor importazole inhibits proliferation and induces apoptosis of multiple myeloma cells by blocking the NF-kappaB signal pathway in vitro. PMID- 23668206 TI - [Clinical significance of abnormal protein bands in multiple myeloma treated with bortezomib-based induction regimen and autologous stem cell transplantation]. AB - OBJECTIVE: To study the clinical significance of abnormal protein bands (APB) in multiple myeloma (MM) patients treated with bortezomib-based induction regimen and autologous stem cell transplantation (ASCT). METHODS: Sixty-eight MM patients submitted to bortezomib-based induction therapy and ASCT from January 2007 to July 2012 were retrospectively studied. Monoclonal protein was detected by immunofixation electrophoresis (IFE). RESULTS: Of all 68 patients, 33 (48.5%) patients had APB. At the first emergence of an APB, two patients with light chain type achieved CR and before transplantation, and thirty-one patients were after transplantation with median time of 104 (ranged 33-404) days. The median duration of APB appearance was 105 (ranged 35-801) days. Patients who developed APB compared with those without APB, had a significantly higher CR plus very good partial response (VGPR) rates (100.0% vs 85.7%%, P=0.017) and CR rates (87.9% vs 62.9%) (P=0.03). There were no significant differences in gender, age, HGB, ALB, beta2-microglobulin, M protein type, Durie-Salmon and ISS stages, the case number of first line or second line treatment, induction courses of bortezomib-based regimen, and the mode of ASCT. With a median follow-up of 33.4 (ranged 7.0-71.7) months, patients with APB tended to have a longer overall survival (OS) versus non-APB patients, although no significant difference obtained (P>0.05). Among APB patients, OS was longer in patients whose appearance of APB occurred <6 months after transplantation than those >= 6 months, but the significant difference was not obtained yet (P>0.05). CONCLUSIONS: Patients who developed APB had a significantly better response to bortezomib-based induction regimen followed ASCT. APB emergence has a good prognostic significance. PMID- 23668207 TI - [Expression level of microRNA-92a and its clinical significance in multiple myeloma patients]. AB - OBJECTIVE: To investigate the relationship between the expression level of microRNA 92a (miR-92a) and del(13q14) and the prognosis of MM patients, and to explore the pathway that miR-92a involved. METHODS: Bone marrow samples from 53 newly diagnosed MM patients were collected, del(13q14) was analyzed by interphase fluorescence in situ hybridization in sorted CD138 positive plasma cell. The expression of miR-92a in plasma cells was measured by quantitative real-time PCR. The expression of c-jun was detected by Western blot in miR-92a transfected MM cell lines (LP-1, U266 and JJN3). RESULTS: Of the 53 MM patients, del(13q14) was detected in 31 (58.4%) patients. The median levels of miR-92a in MM patients with or without del(13q14) were 27.36+/-2.61 and 21.87+/-15.98, respectively (P>0.05). With the median follow-up of 13.5 (0.5-72.5) months, the median duration of progression-free survival of patients with high expression level of miR-92a was significantly shorter than those with low expression level of miR-92a (4.5 months vs 14.0 months, P=0.006). Overexpression of miR-92a in MM cell lines induces time dependent down-regulation of c-jun. CONCLUSIONS: High expression of miR-92a was associated with poor prognosis in MM patients. The expression level of miR-92a was not associated with del(13q14), and the effect of miR-92a on the progress of MM might be involved in c-jun pathway. PMID- 23668208 TI - [Apoptosis of multiple myeloid cells induced by polysaccharides extracts from Hedyotis diffusa and its mechanism]. AB - OBJECTIVE: To explore the proliferation inhibition and apoptosis effects of polysaccharides extracts from Hedyotis diffusa (PEHD) on multiple myeloma (MM) cell line RPMI 8226 cells in vitro, so as to provide experimental theory for the clinical application in the treatment of MM. METHODS: MTT assay was used to examine the effects of PEHD on cell growth. The apoptotic cells were analyzed by flow cytometry with AnnexinV/PI staining. Hoechst staining was used to observe the morphological changes of RPMI 8226 cell apoptosis. The expression levels of caspase-3,-8,-9, PARP, nucleoprotein NF-kappaB protein and other channel protein were assayed by Western blotting method. RESULTS: The growth of RPMI 8226 cells were suppressed after treatment with PEHD, the highest inhibition rate reached to 92.3%, the results in the doses from 1 to 4 mg/ml showed a dose-and-time dependent manner. The proportion of apoptotic cells in 1, 2 and 3 mg/ml PEHD treatment groups for 24 h were 22.52%, 62.31% and 69.94%, respectively, and significantly higher than that of control 8.93%. After treated with PEHD, apoptotic body appeared in RPMI 8226 cells nucleus and the number of apoptotic body increased in a dose-dependent manner. With the increasing of PEHD concentration, the expression of caspase-8,-9,-3 and PARP protein increased. The expression of Mcl-1, Bcl-xl, Bid and Bim protein decreased gradually, but the expression of Bax, Bak and Bad protein increased, and the expression of p-AKT protein (60 kDa) and NF-kappaB obviously decreased. CONCLUSION: PEHD could inhibited the growth of RPMI 8226 cells and displayed a dose-and-time-dependent manner, its mechanism may involve cell apoptosis induction, which was associated with the activation of caspase-8, caspase-9, and caspase-3 protein and the down regulation of p-AKT and NF-kappaB protein expression. PMID- 23668209 TI - [Clinical and laboratory features of four cases with IgM multiple myeloma]. AB - OBJECTIVE: To improve the understanding of the clinical and laboratory features of the IgM multiple myeloma (MM). METHODS: The clinical data of four cases of IgM MM patients were collected, their clinical and laboratory features were summarized and analyzed. RESULTS: Four patients met the criteria of IgM MM. They were all male. The age at the diagnosis ranged from 54 to 69 years. The primary symptoms included bone pain, hyperviscosity and bleeding. Three cases had kappa chain and only one case had lambda-chain. They were all staged IIIA according to the Durie-Salmon staging system (DSS). One case stagedIand three cases staged II according to the international staging system (ISS). The average value of IgM, hemoglobin, serum calcium, creatinine and the proportion of bone marrow plasma cells were 83.6 (52.9-111.0) g/L, 79.5 (61.0-105.0) g/L, 3.20(2.11-6.00) mmol/L, 104.3 (56.0-171.0) MUmol/L and 0.558 (0.290-0.775), respectively. Bone destruction was found in 3 cases. Immunophenotypes of bone marrow plasma cells were analyzed in 3 patients. Results showed that these cells expressed CD38 and CD138, and did not express CD19, CD20 and CD117. Chromosome and fluorescence in situ hybridization (FISH) analysis were carried out in 4 cases and found that all of them had IgH translocations and 1q21 amplification, 2 cases had 13q and 17p deletion, and 3 cases had t(11;14). Three patients received bortezomib-based regimens as induction therapy and reached partial response (PR) - very good partial response (VGPR). Followed up to November 30, 2012, the median progress free survival (PFS) and overall survival (OS) of the 4 cases were only 6.0 (2.5 7.0) months and 17.5 (2.5-27.0) months, respectively. CONCLUSIONS: IgM MM is very rare and is no more than 0.5% in all types of MM. IgM MM have frequent t(11;14) and amp(1q21). Bortezomib-based regimens are effective for it, however, the disease progresses rapidly and has poor prognosis. PMID- 23668210 TI - [Curative effect observation of patients with primary systemic amyloidosis treated by the combination of bortezomib with dexamethasone and cyclophosphamide]. AB - OBJECTIVE: To analyze the efficacy and side effects of the combination regimen containing bortezomib, cyclophosphamide and dexamethasone(BCD) in the treatment of primary systemic amyloidosis (PSA). METHODS: The clinical manifestation, efficacy and side effects of 22 PSA patients after treatment were retrospectively analyzed. RESULTS: Of the 22 PSA patients, 9 were newly diagnosed cases and 13 relapsed cases, 20(90.9%) had symptomatic cardiac involvement and 20 (90.9%) had 2 or more organs involved. The median free light chain were 140 mg/L. There were no specific abnormality was found by G-banding and FISH. RQ-PCR-MAGE C1/CT7/ABL had high positive incidence in amyloidosis and can be observed ahead of the flow cytometry and morphology examination. Hematological response occurred in 88.9% in newly diagnosed patients, with 55.6% organ response, 2 patients occured sudden death during BCD interval. For relapsed patients, the hematological response was 46.2%, with 30.7% organ response. Ten of the 22 PSA patients developed peripheral neurophathy, 1 liver dysfunction, 1 severe infection after intra-tracheal stent. CONCLUSIONS: BCD produces rapid and high hematological responses in the PSA patients especially in newly diagnosed patients. It is well tolerated with few side effects. MAGE C1/CT7 might be helpful in the early detection of the clonal plasma cell. PMID- 23668211 TI - [Analysis of the therapeutic effect and safety of diagnosis and treatment regimen in Chinese adult patients with acute lymphoblastic leukemia--the comparative study of one single centre]. PMID- 23668212 TI - [Clinical analysis of therapeutic impact and prognosis of autologous peripheral blood stem cell transplantation in multiple myeloma]. PMID- 23668213 TI - [Analysis of peripheral blood lymphocyte subsets and relevant prognostic factors of 34 newly diagnosed multiple myeloma patients]. PMID- 23668214 TI - [Role of imaging examination for the diagnosis and treatment of multiple myeloma]. PMID- 23668215 TI - [Current progress in multiple myeloma and tumor vascular targeting therapy]. PMID- 23668216 TI - [Pathogenesis, prevention and treatment of multiple myeloma with peripheral neuritis and renal impairment]. PMID- 23668217 TI - [Technical requirements for the certificate application of detection reagents used for flow cytometry]. PMID- 23668218 TI - [Hotspot report of the 54th American Society of Hematology Annual Meeting Drug resistance of multiple myeloma]. PMID- 23668219 TI - [Hepatitis B virus carrier couples with diffuse large B cell lymphoma]. PMID- 23668220 TI - Cutaneous clear cell sarcoma in a 12-year-old boy. PMID- 23668221 TI - Taste and olfactory status in a gourmand with a right amygdala lesion. AB - In a patient with a lesion of the right amygdala and temporal pole who had the characteristics of the gourmand syndrome, sensory and hedonic testing was performed to examine the processing of taste, olfactory, and some emotional stimuli. The gourmand syndrome describes a preoccupation with food and a preference for fine eating and is associated with right anterior lesions. It was found that the taste thresholds for sweet, salt, bitter, and sour were normal; that the patient did not dislike the taste of salt (NaCl) at low and moderate concentrations as much as age-matched controls; that this also occurred for monosodium glutamate (MSG); that there were some olfactory differences from normal controls; and that there was a marked reduction in the ability to detect face expressions of disgust. PMID- 23668222 TI - Amide bond formation through iron-catalyzed oxidative amidation of tertiary amines with anhydrides. AB - A general and efficient method for amide bond synthesis has been developed. The method allows for synthesis of tertiary amides from readily available tertiary amines and anhydrides in the presence of FeCl2 as catalyst and tert-butyl hydroperoxide in water (T-Hydro) as oxidant. Mechanistic studies indicated that the in situ-generated alpha-amino peroxide of tertiary amine and iminium ion act as key intermediates in this oxidative transformation. PMID- 23668223 TI - Hydraulic tuning of vein cell microstructure in the evolution of angiosperm venation networks. AB - High vein density (D(V)) evolution in angiosperms represented a key functional transition. Yet, a mechanistic account on how this hydraulic transformation evolved remains lacking. We demonstrate that a consequence of producing high D(V is that veins must become very small to fit inside the leaf, and that angiosperms are the only clade that evolved the specific type of vessel required to yield sufficiently conductive miniature leaf veins. From 111 species spanning key divergences in vascular plant evolution, we show, using analyses of vein conduit evolution in relation to vein packing, that a key xylem innovation associated with high D(V) evolution is a strong reduction in vein thickness and simplification of the perforation plates of primary xylem vessels. Simple perforation plates in the leaf xylem occurred only in derived angiosperm clades exhibiting high D(V) (> 12 mm mm(-2)). Perforation plates in the vessels of other species, including extant basal angiosperms, consisted of resistive scalariform types that were associated with thicker veins and much lower D(V). We conclude that a reduction in within-vein conduit resistance allowed vein size to decrease. We suggest that this adaptation may have been a critical evolutionary step that enabled dramatic D(V) elaboration in angiosperms. PMID- 23668224 TI - Influence of periodic vs continuous daily bright light exposure on development of experimental myopia in the chick. AB - PURPOSE: In children, time spent outdoors has a protective effect against myopia development. In animal models, bright light reduces the development of experimental myopia. This study investigates how an increase in daily light exposure, presented either continuously during the day or periodically at different times of day, influences the development of experimental myopia in the chick. METHODS: Myopia was induced in Cobb Chicks (Gallus domesticus) by monocular deprivation (MD) of form vision with a translucent diffuser for 3 days (from 4 days of age) under a 12:12 light: dark cycle. MD control chicks were exposed to constant 300 lux (n = 11) during the light period. MD treatment groups received either constant 2000 lux (n = 11) during the light period or 300 lux for 10 h with a 2 h period of bright light (10 000 lux), either in the morning (n = 10), midday (n = 10) or evening (n = 10), giving the same total daily light exposure as the 2000 lux group. After 3 days of MD, refractive status, corneal curvature and axial eye dimensions were measured for all eyes under anaesthesia. RESULTS: Myopia in the constant 2000 lux group (-4.94 +/- 1.21 D) was significantly less than in the 300 lux control group (-9.73 +/- 0.96 D; p = 0.022). However, compared to the 300 lux control group, 2 h periods of 10 000 lux did not produce significant effects on refraction when presented either in the morning (-9.98 +/- 0.85; p = 1.00), midday (-8.00 +/- 1.26; p = 0.80), or evening (-13.14 +/- 1.16 D; p = 0.20), although significantly less myopia was induced in the midday group compared to the evening group (p = 0.018). Orthogonal regression showed that myopia development was matched by changes in vitreous chamber depth (R(2) = 0.69; p < 0.0001). CONCLUSIONS: In chicks, an increase in daily light exposure continuously during the day is more effective at inhibiting myopia than adding an equivalent dose within a 2 h period of bright light. A weak time-of-day effect also appears to be present in the response to bright light exposure. Our results suggest that future light-based myopia therapies in humans may be more effective if light levels are increased over the whole day, rather than through short periods of bright light exposure. PMID- 23668225 TI - The impact of discrete modes of spinal cord injury on bladder muscle contractility. AB - BACKGROUND: Prior studies have compared the effect of spinal cord injury elicited using distinct approaches on motor and visceral function. However, the impact of such discrete modes of injury specifically on bladder muscle contractility has not been explored in detail. The goal of this study is to compare the impact of complete spinal cord transection versus clip compression at thoracic vertebra eight (T8) on bladder muscle contractility. METHODS: Rats underwent no treatment (Control), laminectomy (Sham, SH); complete extradural transection (TX); or cord compression with an aneurysm clip (CX). Bladders and spinal cords were harvested at 6 wk for contractility studies or histological analysis. RESULTS: Detrusor strips from TX and CX rats showed higher spontaneous activity than those from SH rats. Furthermore, the duration of the neurally-mediated contractile response was longer in TX and CX rats compared to controls and showed attenuated relaxation. No significant differences were observed between muscle strips from SH, TX or CX rats in response to KCl, ATP or phenylephrine. However, tissues from TX and CX rats showed a higher sensitivity to carbachol compared to that from SH animals. CONCLUSIONS: Complete SCI in rats either by cord transection or compression elicits qualitatively similar changes in bladder muscle contractility. Whereas cord transection is arguably easier to perform experimentally, cord compression better models the situation observed clinically, such that each approach has clear advantages and limitations. PMID- 23668226 TI - Neuropsychiatric symptoms in Parkinson disease and dementia with Lewy bodies: what geriatric psychiatry can learn. PMID- 23668227 TI - QSAR methods for the discovery of new inflammatory bowel disease drugs. AB - INTRODUCTION: Inflammatory bowel disease (IBD) represents an important class of chronic gastrointestinal tract disease. And although there are already several useful treatments to reduce and control the symptoms, there is still no cure. One drug discovery technique used is the computer-aided (in silico) discovery approach which has largely demonstrated efficacy. Computational techniques, when used in combination with traditional drug discovery methodology, greatly increase the chance of drug discovery in a sustainable and economical fashion. AREAS COVERED: This review aims to provide the most recent and important advances of in silico IBD drug discovery. While this review is mainly focused on QSAR methods, especially those based on molecular topology (MT), additional topics, such as docking or comparative field analysis are also addressed. EXPERT OPINION: IBD is a worldwide growing health concern that can only be currently treated in symptomatic and palliative way; thus, the search for new drugs is imperative. Computer-aided methods, which focus on the drug-receptor interaction, are essential tool in this regard. It is noted, however that a major problem is that although there are many known receptors associated with IBD, none of these have yet been found essential. The use of other approaches, including QSAR methodology, is certainly a complementary and attractive alternative; especially QSAR methods based on MT, which has proven successful in other drug discovery. PMID- 23668228 TI - A multicenter, prospective trial to assess the safety and performance of the spinal modulation dorsal root ganglion neurostimulator system in the treatment of chronic pain. AB - OBJECTIVES: This multicenter prospective trial was conducted to evaluate the clinical performance of a new neurostimulation system designed to treat chronic pain through the electrical neuromodulation of the dorsal root ganglia (DRG) neurophysiologically associated with painful regions of the limbs and/or trunk. MATERIALS AND METHODS: Thirty-two subjects were implanted with a novel neuromodulation device. Pain ratings during stimulation were followed up to six months and compared with baseline ratings. Subjects also completed two separate reversal periods in which stimulation was briefly stopped in order to establish the effects of the intervention. RESULTS: At all assessments, more than half of subjects reported pain relief of 50% or better. At six months postimplant, average overall pain ratings were 58% lower than baseline (p < 0.001), and the proportions of subjects experiencing 50% or more reduction in pain specific to back, leg, and foot regions were 57%, 70%, and 89%, respectively. When stimulation was discontinued for a short time, pain returned to baseline levels. Discrete coverage of hard-to-treat areas was obtained across a variety of anatomical pain distributions. Paresthesia intensity remained stable over time and there was no significant difference in the paresthesia intensity perceived during different body postures/positions (standing up vs. lying down). CONCLUSIONS: Results of this clinical trial demonstrate that neurostimulation of the DRG is a viable neuromodulatory technique for the treatment of chronic pain. Additionally, the capture of discrete painful areas such as the feet combined with stable paresthesia intensities across body positions suggest that this stimulation modality may allow more selective targeting of painful areas and reduce unwanted side-effects observed in traditional spinal cord stimulation (SCS). PMID- 23668229 TI - Immunological aspects of atherosclerosis. AB - Cardiovascular disease is the leading cause of death in several countries. The underlying process is atherosclerosis, a slowly progressing chronic disorder that can lead to intravascular thrombosis. There is overwhelming evidence for the underlying importance of our immune system in atherosclerosis. Monocytes, which comprise part of the innate immune system, can be recruited to inflamed endothelium and this recruitment has been shown to be proportional to the extent of atherosclerotic disease. Monocytes undergo migration into the vasculature, they differentiate into macrophage phenotypes, which are highly phagocytic and can scavenge modified lipids, leading to foam cell formation and development of the lipid-rich atheroma core. This increased influx leads to a highly inflammatory environment and along with other immune cells can increase the risk in the development of the unstable atherosclerotic plaque phenotype. The present review provides an overview and description of the immunological aspect of innate and adaptive immune cell subsets in atherosclerosis, by defining their interaction with the vascular environment, modified lipids and other cellular exchanges. There is a particular focus on monocytes and macrophages, but shorter descriptions of dendritic cells, lymphocyte populations, neutrophils, mast cells and platelets are also included. PMID- 23668230 TI - Surface morphology-dependent photoelectrochemical properties of one-dimensional Si nanostructure arrays prepared by chemical etching. AB - Maximizing the optical absorption of one-dimensional Si nanostructure arrays (1DSiNSAs) is desirable for excellent performance of 1DSiNSA-based optoelectronic devices. However, a quite large surface-to-volume ratio and enhanced surface roughness are usually produced by modulation of the morphology of the 1DSiNSAs prepared in a top-down method to improve their optical absorption. Surface recombination is mainly determined by the surface characteristics and significantly affects the photogenerated carrier collection. In this paper, we systematically investigated the photoelectrochemical characteristics of 1DSiNSAs with various morphologies prepared by the metal-assisted chemical etching of Si wafers. Our results show that the saturation photocurrent density and photoresponsivity of 1DSiNSAs first increased and then gradually decreased with an increasing etching time, while the reflection spectrum was gradually suppressed to the measurable minimum. To identify the behaviors of the photoresponsivity and optical absorption of the various 1DSiNSAs, we analyzed the morphology, structure, and minority-carrier lifetime. Additionally, device physics simulations were used to confirm the significance of surface recombination. We proposed that future directions for the design of nanostructure based optoelectronic devices should include not only strong optical absorption but also low surface carrier recombination. High-performance devices could be obtained only by balancing the requirements for light absorption and photogenerated carrier collection. PMID- 23668231 TI - Slow growth of hair and nails, craniofacial abnormalities and brachyphalangy. PMID- 23668232 TI - Anomaly of pretransitional behavior at the nematic-smectic-A phase transition of amphiphilic liquid crystals with a hydrophilic group. AB - In order to clarify the origin of the X-ray diffraction peak corresponding to the smectic-like layer ordering appearing even in the nematic phase over a wide temperature range above the nematic-smectic A (NA) phase transition in liquid crystal (LC) molecules with a hydroxy group, we investigated the critical behavior of bend elastic constants and the correlation length of the smectic-like ordering in the N phase. It is found that cybotactic clusters with the transient layer ordering grow up extremely even far above the NA phase transition, and the critical exponent of the correlation length of the cybotactic clusters is estimated anomalously larger than that of conventional LC materials. Furthermore, we measured diffusion constants parallel and perpendicular to the director in the N phase, and concluded that cybotactic clusters with the smectic layer ordering create a finite potential barrier to prevent diffusion of the molecules parallel to the director as well as the true smectic A layer structure. PMID- 23668234 TI - When does playing hard to get increase romantic attraction? AB - Folk wisdom suggests playing hard to get is an effective strategy in romantic attraction. However, prior research has yielded little support for this belief. This article seeks to reconcile these contrasting views by investigating how 2 hitherto unconsidered factors, (a) the asymmetry between wanting (motivational) and liking (affective) responses and (b) the degree of psychological commitment, can determine the efficacy of playing hard to get. We propose that person B playing hard to get with person A will simultaneously increase A's wanting but decrease A's liking of B. However, such a result will only occur if A is psychologically committed to pursuing further relations with B; otherwise, playing hard to get will decrease both wanting and liking. Two studies confirm these propositions. We discuss implications for interpersonal attraction and the interplay between emotion and motivation in determining preferences. PMID- 23668233 TI - Automatic detection of modal spacing (Yellott's ring) in adaptive optics scanning light ophthalmoscope images. AB - PURPOSE: An impediment for the clinical utilisation of ophthalmic adaptive optics imaging systems is the automated assessment of photoreceptor mosaic integrity. Here we propose a fully automated algorithm for estimating photoreceptor density based on the radius of Yellott's ring. METHODS: The discrete Fourier transform (DFT) was used to obtain the power spectrum for a series of images of the human photoreceptor mosaic. Cell spacing is estimated by least-square fitting an annular pattern with a Gaussian cross section to the power spectrum; the radius of the resulting annulus provides an estimate of the modal spacing of the photoreceptors in the retinal image. The intrasession repeatability of the cone density estimates from the algorithm was evaluated, and the accuracy of the algorithm was validated against direct count estimates from a previous study. Accuracy in the presence of multiple cell types and disruptions in the mosaic was examined using images from four patients with retinal pathology and perifoveal images from two subjects with normal vision. RESULTS: Intrasession repeatability of the power spectrum method was comparable to a fully automated direct counting algorithm, but worse than that for the manually adjusted direct count values. In images of the normal parafoveal cone mosaic, we find good agreement between the power-spectrum derived density and that from the direct counting algorithm. In diseased eyes, the power spectrum method is insensitive to photoreceptor loss, with cone density estimates overestimating the density determined with direct counting. The automated power spectrum method also produced unreliable estimates of rod and cone density in perifoveal images of the photoreceptor mosaic, though manual correction of the initial algorithm output results in density estimates in better agreement with direct count values. CONCLUSIONS: We developed and validated an automated algorithm based on the power spectrum for extracting estimates of cone spacing, from which estimates of density can be derived. This approach may be used to estimate cone density in images where not every single cone is visible, though caution is needed, as this robustness becomes a weakness when dealing with images from patients with some retinal diseases. This study represents an important first step in carefully assessing the relative utility of metrics for analysing the photoreceptor mosaic, and similar analyses of other metrics/algorithms are needed. PMID- 23668235 TI - The control-freak mind: stereotypical biases are eliminated following conflict activated cognitive control. AB - Numerous daily situations require control for successful goal attainment. An important question is whether control can adjust across situations, to create control readiness from one situation to the next. Using trial to trial control adjustment paradigms, previous research generally suggested that control adjustments are domain specific. However, this research typically used neutral stimuli (e.g., single letters) devoid of personally and socially relevant goals. We propose that personal relevance may be an important modulator of control adjustment and, hence, that personally relevant control tasks can benefit from control readiness, even if it is produced by a different task. In 2 experiments we test whether control over the expression of stereotypes, a highly meaningful and desirable goal for many, can benefit from control readiness evoked by a neutral unrelated Flanker task. Results suggest that stereotype-driven behavior is modulated by independently activated control and that personal relevance may facilitate control adjustments across domains. PMID- 23668236 TI - A stepwise alpha-thalassemia screening strategy in high-prevalence areas. AB - INTRODUCTION: Coinheritance of alpha-thalassemia influences the clinical and hematological phenotypes of beta-hemoglobinopathies (beta-thalassemia and sickle cell disease) and when present together in significant frequency within a population, a spectrum of clinical forms is observed. Precise molecular characterization of alpha-thalassemia is important in understanding their disease modifying role in beta-hemoglobinopathies and for diagnostic purposes. PATIENTS AND METHODS: Because currently used approaches are labor/cost-intensive, time consuming, error-prone in certain genotype combinations and not applicable for large epidemiological screening, we developed a systematic stepwise strategy to overcome these difficulties. We successfully applied this to characterize the alpha-globin gene status in 150 Omani cord blood samples with Hb Barts and 32 patients with HbH disease. RESULTS: We observed a good correlation between alpha globin genotypes and level of Hb Bart's with the Hb Bart's levels significantly higher in both deletional and non-deletional alpha-globin genotypes. The most common alpha-globin genotype in HbH cases was alpha(TSaudi) alpha/alpha(TSaudi) alpha (n = 16; 50%) followed by -alpha(3.7) /-(MED) (n = 10; 31%). This approach detects also the alpha-globin gene triplication as exemplified by the study of a family where the beta-globin gene defect failed to explain the beta-thalassemia intermedia phenotype. CONCLUSION: Molecular characterization of alpha-thalassemia is complex due to high sequence homology between the duplicated alpha-globin genes and to the existence of a variety of gene rearrangements (small and large deletions of various sizes) and punctual substitutions (non-deletional alleles). The novelty of our strategy resides, not in the individual technical steps per se but in the reasoned sequential order of their use taking into consideration the hematological phenotype as well. PMID- 23668237 TI - Increasing atmospheric [CO2] from glacial to future concentrations affects drought tolerance via impacts on leaves, xylem and their integrated function. AB - Changes in atmospheric carbon dioxide concentration ([CO2]) affect plant carbon/water tradeoffs, with implications for drought tolerance. Leaf-level studies often indicate that drought tolerance may increase with rising [CO2], but integrated leaf and xylem responses are not well understood in this respect. In addition, the influence of the low [CO2] of the last glacial period on drought tolerance and xylem properties is not well understood. We investigated the interactive effects of a broad range of [CO2] and plant water potentials on leaf function, xylem structure and function and the integration of leaf and xylem function in Phaseolus vulgaris. Elevated [CO2] decreased vessel implosion strength, reduced conduit-specific hydraulic conductance, and compromised leaf specific xylem hydraulic conductance under moderate drought. By contrast, at glacial [CO2], transpiration was maintained under moderate drought via greater conduit-specific and leaf-specific hydraulic conductance in association with increased vessel implosion strength. Our study involving the integration of leaf and xylem responses suggests that increasing [CO2] does not improve drought tolerance. We show that, under glacial conditions, changes in leaf and xylem properties could increase drought tolerance, while under future conditions, greater productivity may only occur when higher water use can be accommodated. PMID- 23668238 TI - Autonomic cardio-respiratory reflex reactions and superselective ophthalmic arterial chemotherapy for retinoblastoma. AB - OBJECTIVE: To describe our experience with superselective ophthalmic artery chemotherapy (SOAC) in retinoblastoma and to report the serious adverse cardio respiratory reactions we have observed. METHODS: SOAC was performed using a standardized protocol for general anesthesia, ophthalmic artery catheterization, and pulsed infusion of melphalan. Adverse reactions were defined as those in which the patient required active treatment to maintain cardio-respiratory stability. RESULTS: Between December 2008 and May 2012, 54 eyes in 52 patients were treated. 143 catheterization procedures were performed, with a technical success rate of 93% (n = 133). There were no deaths or major complications. Adverse cardio-respiratory reactions developed during 35 procedures (24%; 95% CI, 18-32%). All reactions occurred during second or subsequent catheterization procedures (39%; 95% CI, .29-49%) and were characterized by hypoxia, reduced lung compliance, systemic hypotension and bradycardia. Adverse events were successfully treated in all patients. One procedure was abandoned due to prolonged hemodynamic instability. CONCLUSION: Adverse cardio-respiratory reactions are commonly observed in SOAC for retinoblastoma. We believe that the adverse clinical signs represent an autonomic reflex response, akin to the trigemino-cardiac or oculo-respiratory reflexes, and all patients should be considered at-risk. Reactions occur only during second or subsequent procedures and can be life-threatening. The routine use of intravenous atropine does not seem to have altered the incidence or severity of these reactions. Anesthetists and interventional neuroradiologists involved in SOAC must be vigilant to ensure adverse reactions, when they develop, are treated quickly and effectively. PMID- 23668239 TI - Herbivory of an invasive slug is affected by earthworms and the composition of plant communities. AB - BACKGROUND: Biodiversity loss and species invasions are among the most important human-induced global changes. Moreover, these two processes are interlinked as ecosystem invasibility is considered to increase with decreasing biodiversity. In temperate grasslands, earthworms serve as important ecosystem engineers making up the majority of soil faunal biomass. Herbivore behaviour has been shown to be affected by earthworms, however it is unclear whether these effects differ with the composition of plant communities. To test this we conducted a mesocosm experiment where we added earthworms (Annelida: Lumbricidae) to planted grassland communities with different plant species composition (3 vs. 12 plant spp.). Plant communities had equal plant densities and ratios of the functional groups grasses, non-leguminous forbs and legumes. Later, Arion vulgaris slugs (formerly known as A. lusitanicus; Gastropoda: Arionidae) were added and allowed to freely choose among the available plant species. This slug species is listed among the 100 worst alien species in Europe. We hypothesized that (i) the food choice of slugs would be altered by earthworms' specific effects on the growth and nutrient content of plant species, (ii) slug herbivory will be less affected by earthworms in plant communities containing more plant species than in those with fewer plant species because of a more readily utilization of plant resources making the impacts of earthworms less pronounced. RESULTS: Slug herbivory was significantly affected by both earthworms and plant species composition. Slugs damaged 60% less leaves when earthworms were present, regardless of the species composition of the plant communities. Percent leaf area consumed by slugs was 40% lower in communities containing 12 plant species; in communities containing only three species earthworms increased slug leaf area consumption. Grasses were generally avoided by slugs. Leaf length and number of tillers was increased in mesocosms containing more plant species but little influenced by earthworms. Overall shoot biomass was decreased, root biomass increased in plant communities with more plant species. Earthworms decreased total shoot biomass in mesocosms with more plant species but did not affect biomass production of individual functional groups. Plant nitrogen concentrations across three focus species were 18% higher when earthworms were present; composition of plant communities did not affect plant quality. CONCLUSIONS: Given the important role that both herbivores and earthworms play in structuring plant communities the implications of belowground aboveground linkages should more broadly be considered when investigating global change effects on ecosystems. PMID- 23668240 TI - Reactions of o-quinone methides with pyridinium methylides: a diastereoselective synthesis of 1,2-dihydronaphtho[2,1-b]furans and 2,3-dihydrobenzofurans. AB - A simple, general route to the 1,2-dihydronaphtho[2,1-b]furans and 2,3 dihydrobenzofurans substituted at C-2 by an acyl or aryl group, starting from phenolic Mannich bases and pyridinium ylides, has been developed. The mechanism of the reaction is believed to involve the formation of the o-quinone methide intermediate, Michael-type addition of the ylide to the o-quinone methide, followed by intramolecular nucleophilic substitution. PMID- 23668242 TI - Addressable carbene anchors for gold surfaces. AB - New strategies to access functional monolayers could augment current surface modification methods. Here we present addressable N-heterocyclic carbene (ANHC) anchors for gold surfaces. A suite of experimental and theoretical methods was used to characterize ANHC monolayers. We demonstrate grafting of highly fluorinated polymers from surface-bound ANHCs. This work establishes ANHCs as viable anchors for gold surfaces. PMID- 23668243 TI - Furthering the design and the discovery of small molecule ATP-competitive mTOR inhibitors as an effective cancer treatment. AB - INTRODUCTION: The mammalian target of rapamycin (mTOR) is a serine/threonine kinase, which is the key component of two distinct signaling complexes in cells; these complexes are the mTOR complex 1 (mTORC1) and the mTOR complex 2 (mTORC2). Given the importance of these complexes in cellular growth, survival, motility, proliferation, protein synthesis and transcription, it is not surprising that they are impacted in multiple types of cancer. Studies on a number of ATP competitive mTOR inhibitors have suggested that these inhibitors have a therapeutic superiority to rapalogs (rapamycin analogs) in a number of cancers. AREAS COVERED: This review provides insight into the binding of mTOR inhibitors with the ATP-binding site, for the benefit of future mTOR inhibitor design and discovery. The authors, furthermore, deduce that a hypothetical binding mode is from docking studies, co-crystal structures and the structure-activity relationships (SARs). The authors also highlight the preclinical and clinical development of hit/lead compounds, and the selectivity for representative mTOR inhibitors. EXPERT OPINION: The structural analysis of mTOR is hampered by its large size and complexity. Further exploration of mTOR inhibitors may therefore require the combination of structure-based drug design (SBDD, based on the mTOR homology models), fragment-based drug design (FBDD) and analog synthesis. Recent studies suggested that the global inhibition of PI3Ks may be harmful to organisms. Therefore, the future discovery of dual mTOR/PI3K inhibitors needs to ensure that inhibitors are both efficacious and have reduced adverse effects. PMID- 23668241 TI - 'All things considered': transcriptional regulation of T helper type 2 cell differentiation from precursor to effector activation. AB - T helper type 2 (Th2) cells are critical to host defence against helminth infection and the pathogenesis of allergic diseases. The differentiation of Th2 cells from naive CD4 T cells is controlled by intricate transcriptional mechanisms. At the precursor stage of naive CD4 T cells, transcriptional mechanisms maintain the potential and in the meantime prevent spontaneous differentiation to Th2 fate. In addition, intrachromosomal interactions important for co-ordinated expression of Th2 cytokines pre-exist in naive CD4 T cells. Upon T-cell receptor (TCR) engagement, naive CD4 T cells are induced by polarizing signals of the interleukin-4/Stat6 and Jagged/Notch pathways to up-regulate the expression of GATA-3. Once up-regulated, GATA-3 drives Th2 and suppresses Th1 differentiation in a cell autonomous fashion. In this stage of differentiation, the Th2 cytokine locus, as well as the interferon-gamma locus, undergoes chromatin remodelling and epigenetic modifications that contribute to the somatic memory of Th2 cytokine gene expression pattern. Once differentiated, Th2 effector cells promptly produce Th2 cytokines upon TCR stimulation, which is regulated by concerted actions of GATA-3, TCR signalling, enhancers and the Th2 locus control region. This review provides a detailed account of the transcriptional regulatory events at these different stages of Th2 differentiation. PMID- 23668244 TI - Effect of heat treatment on cyclic fatigue resistance, thermal behavior and microstructures of K3 NiTi rotary instruments. AB - OBJECTIVE: The aim of this study was to investigate the effect of heat treatment on the cyclic fatigue resistance, thermal behavior and microstructural changes of K3 NiTi rotary instruments. MATERIALS AND METHODS: Twelve control (as-received) and 12 experimental (heat-treated) K3 NiTi rotary instruments were compared in this study. Those experimental K3 instruments were heated in a furnace for 30 min at 450 degrees C and then quenched in water. The cyclic fatigue resistance was measured with a fatigue tester. The thermal characteristic and the microstructures of both instruments were investigated by differential scanning calorimetry (DSC) and transmission electron microscopy (TEM), respectively. RESULTS: There was a significant increase in the cyclic fatigue resistance between the heat-treated instruments and the as-received instruments (T-test, p < 0.05). DSC showed that the as-received and heat-treated samples were different, with an increased Af (austenite-finish temperature) for the latter. TEM analysis revealed that both as-received and heat-treated instruments were composed mainly of an austenite phase. However, the heat-treated samples had an increased appearance of larger grains, twinning martensite, TiO2 surface layer and a Ni rich inner layer. CONCLUSIONS: Heat treatment increased the cyclic fatigue resistance of NiTi files and changed the thermal behavior of the instruments without marked changes in the constituting phases of NiTi alloy. PMID- 23668245 TI - Alcohol, still the forgotten drug. PMID- 23668246 TI - Parallel copper catalysis: diastereoselective synthesis of polyfunctionalized azetidin-2-imines. AB - An efficient and diastereoselective synthesis of highly functionalized azetidin-2 imines has been achieved through a parallel catalysis strategy, including a copper-catalyzed azide-alkyne cycloaddition, a copper-catalyzed Csp-Csp(2) cross coupling reaction, and an intermolecular [2 + 2] cycloaddition. The products could be conveniently converted into the structurally interesting dihydroazeto[1,2-a]benzo[e]azepin-2(4H)-imines. PMID- 23668247 TI - Lack of Epstein-Barr virus infection in Chinese myasthenia gravis patients. AB - OBJECTIVE: There are three recent contradictory reports on the incidence of Epstein-Barr virus in the pathogenesis of myasthenia gravis, with all studies carried out in Caucasian patients. The current study evaluated whether Epstein Barr virus infection had a role in the pathogenesis of myasthenia gravis in a cohort of 30 Chinese patients. MATERIALS AND METHODS: Serial paraffin sections of thymic hyperplasia obtained from myasthenia gravis patients were analyzed for the presence of Epstein-Barr virus-encoded small RNA -1 and Epstein-Barr virus latent membrane protein 1 by in situ hybridization and immunohistochemistry, respectively. Epstein-Barr virus(+) cervical lymph nodes from lymphoma patients and Epstein-Barr virus(-) thymus specimens obtained during cardiac surgery served as the positive and negative control groups, respectively. RESULTS: All the 30 myasthenia gravis specimens were negative for both Epstein-Barr virus-encoded small RNA -1 and Epstein-Barr virus latent membrane protein 1 tests. However, we obtained well-characterized membrane and cytoplasmic immunohistochemical and in situ hybridization staining for both Epstein-Barr virus latent membrane protein 1 and Epstein-Barr virus-encoded small RNA -1, respectively, in the positive control samples. CONCLUSIONS: Our results therefore do not support a role of thymic Epstein-Barr virus infection in myasthenia gravis pathogenesis and calls for an integration of methodological and interpretation issues in detecting Epstein-Barr virus incidence in myasthenia gravis patients. PMID- 23668248 TI - Peer instruction of first-year nurse anesthetist students: a pilot study of a strategy to use limited faculty resources and promote learning. AB - A peer-instruction model was used to introduce the fundamental concepts and skills in an introductory nurse anesthetist course as an innovative teaching strategy to efficiently use simulation and faculty resources and promote learning. However, no studies have evaluated whether a peer-instruction model compared with faculty instruction facilitates learning in first-year nurse anesthetist students. The purpose of this prospective, posttest-only, true experimental pilot study was to determine whether a difference was noted in learning outcomes between first-year nurse anesthetist students who received peer instruction and those who received faculty instruction. Perceptions of peer learners and peer instructors about the benefits, limitations, and overall level of satisfaction of a peer-instruction teaching model were also examined. No statistically significant difference in learning outcomes was found between groups, which supports the use of the model. Perceptions of nurse anesthetist students were generally positive regarding the use of a peer-instruction model. PMID- 23668249 TI - Oh, the things you will learn: taking undergraduate research to the homeless shelter. AB - Teaching research to undergraduate students has been described as a challenge. This article describes how a small group of students participated in a service learning research project that culminated in the development of an educational intervention for volunteers who staff homeless shelters in the local community. By interacting with the homeless population and the volunteer staff who provide their care, students developed a greater understanding of the needs of the homeless, recognized some mental health disorders, and interacted with volunteer staff to assess their educational needs. Students were able to learn the research process through their participation in this collaborative project. The students' learning exceeded typical outcomes, as they displayed leadership skills and advocacy in areas of social justice and made compassionate connections with this vulnerable population. These students also forged new territory for future students who will be working with homeless populations and those who minister to them. PMID- 23668250 TI - Glutaraldehyde vapor cross-linked nanofibrous PVA mat with in situ formed silver nanoparticles. AB - Polyvinyl alcohol (PVA) nanofibrous mat can be easily prepared via electrospinning its aqueous solution. However, the obtained nanofibrous mat is instantaneously dissolved in water. Therefore, rendering the environmentally friendly nanofibrous mat water insoluble by cross-linking mechanism is of great interest. The electrospun PVA nanofibrous mat with an average fiber diameter of ca. 400 nm could be effectively cross-linked by glutaraldehyde vapor at room temperature. The cross-linking not only resulted in a water-insoluble nanofibrous mat but also generated an excess amount of unreacted aldehyde functional groups that could reduce silver salts into silver nanoparticles. The in situ formed silver nanoparticles along the fibrous surface showed excellent antimicrobial activity against Escherichia coli. The vapor cross-linked nanofibrous mat shows a high potential to be used for efficiently capturing and killing pathogenic bacteria. PMID- 23668251 TI - Patient perceptions of buccal gingival recessions and requests for treatment. AB - AIMS: The aims of this study were to verify patients' perception of buccal recessions and their requests for treatment. METHODS: The patients filled out a questionnaire dealing with demographic variables and perception of buccal gingival recessions. A calibrated examiner checked for recessions and recorded the clinical variables. Then, the patients were asked to explain what they believed to be the causes of the recessions and whether they were interested in obtaining treatment of their lesions. Descriptive statistics and multilevel logistic models were used. RESULTS: Of 120 enrolled patients, 96 presented 783 gingival recessions, of which 565 were unperceived. Of 218 perceived recessions, 160 were asymptomatic, 36 showed dental hypersensitivity, 13 aesthetics, 9 aesthetic + hypersensitivity issues. Only 11 patients requested treatment for their 57 recessions. Younger individuals (p = 0.0077), deeper recessions (p < 0.0001), incisors and canines (p < 0.0001) and non-carious cervical lesions (p = 0.0441) were significantly associated with patient perception of own recessions. Younger subjects (p = 0.0118), deeper recessions (p = 0.0387) and incisors (p = 0.0232) were significantly associated with patient request of treatment. Four hundred and sixty-eight recessions (60%) were not ascribed to exact causes by the patients. CONCLUSION: This study shows that perception of gingival recessions and the patients' requests for treatment should be evaluated carefully before proceeding with decision making. PMID- 23668252 TI - Contrast negation and the importance of the eye region for holistic representations of facial identity. AB - Reversing the luminance values of a face (contrast negation) is known to disrupt recognition. However, the effects of contrast negation are attenuated in chimeric images, in which the eye region is returned to positive contrast (S. Gilad, M. Meng, & P. Sinha, 2009, Role of ordinal contrast relationships in face encoding, Proceedings of the National Academy of Sciences, USA, Vol. 106, pp. 5353-5358). Here, we probe further the importance of the eye region for the representation of facial identity. In the first experiment, we asked to what extent the chimeric benefit is specific to the eye region. Our results showed a benefit for including a positive eye region in a contrast negated face, whereas chimeric faces in which only the forehead, nose, or mouth regions were returned to positive contrast did not significantly improve recognition. In Experiment 2, we confirmed that the presence of positive contrast eyes alone does not account for the improved recognition of chimeric face images. Rather, it is the integration of information from the positive contrast eye region and the surrounding negative contrast face that is essential for the chimeric benefit. In Experiment 3, we demonstrated that the chimeric benefit is dependent on a holistic representation of the face. Finally, in Experiment 4, we showed that the positive contrast eye region needs to match the identity of the contrast negated part of the image for the chimera benefit to occur. Together, these results show the importance of the eye region for holistic representations of facial identity. PMID- 23668253 TI - Stop before you leap: changing eye and hand movements requires stopping. AB - The search-step paradigm addresses the processes involved in changing movement plans, usually saccadic eye-movements. Subjects move their eyes to a target (T1) among distractors, but when the target steps to a new location (T2), subjects are instructed to move their eyes directly from fixation to the new location. We ask whether moving to T2 requires a separate stop process that inhibits the movement to T1. It need not. The movement plan for the second response may inhibit the first response. To distinguish these hypotheses, we decoupled the offset of T1 from the onset of T2. If the second movement is sufficient to inhibit the first, then the probability of responding to T1 should depend only on T2 onset. If a separate stop process is required, then the probability of responding to T1 should depend only on T1 offset, which acts as a stop signal. We tested these hypotheses in manual and saccadic search-step tasks and found that the probability of responding to T1 depended most strongly on T1 offset, supporting the hypothesis that changing from one movement plan to another involves a separate stop process that inhibits the first plan. PMID- 23668254 TI - The attraction of yellow corn: reduced attentional constraints on coding learned conjunctive relations. AB - Physiological evidence indicates that different visual features are computed quasi-independently. The subsequent step of binding features, to generate coherent perception, is typically considered a major rate-limiting process, confined to one location at a time and taking 25 ms per item or longer (A. Treisman & S. Gormican, 1988, Feature analysis in early vision: Evidence from search asymmetries, Psychological Review, Vol. 95, pp. 15-48). We examined whether these processing limitations remain once bindings are learned for familiar objects. Participants searched for objects that could appear either in familiar or unfamiliar colors. Objects in familiar colors were detected efficiently at rates consistent with simultaneous binding across multiple stimuli. Processing limitations were evident for objects in unfamiliar colors. The advantage for the learned color for known targets was eliminated when participants searched for geometric shapes carrying the object colors and when the colors fell in local background areas around the shapes. The effect occurred irrespective of whether the nontargets had familiar colors, but was largest when nontargets had incorrect colors. The efficient search for targets in familiar colors held, even when the search was biased to favor objects in unfamiliar colors. The data indicate that learned bindings can be computed with minimal attentional limitations, consistent with the direct activation of learned conjunctive representations in vision. PMID- 23668255 TI - Entanglement and polyradical character of polycyclic aromatic hydrocarbons predicted by projected Hartree-Fock theory. AB - We study strong correlation effects in a series of fused benzene rings (acenes) of varying length and width using our recently developed projected Hartree-Fock (PHF) method. These molecules, commonly known as polycyclic aromatic hydrocarbons or nanographenes, are very challenging for electronic structure theory because of their strong multireference character. This challenge is here met by PHF at moderate computational cost optimizing a spin eigenfunction obtained by projection of an unrestricted Hartree-Fock (UHF) trial determinant. The resulting method, known as SUHF, predicts that polyradical behavior and orbital entanglement are enhanced with molecular size, especially in systems whose structural motifs are dominated by zigzag edges, like oligoacenes. PMID- 23668256 TI - Bioengineering of plant (tri)terpenoids: from metabolic engineering of plants to synthetic biology in vivo and in vitro. AB - Terpenoids constitute a large and diverse class of natural products that serve many functions in nature. Most of the tens of thousands of the discovered terpenoids are synthesized by plants, where they function as primary metabolites involved in growth and development, or as secondary metabolites that optimize the interaction between the plant and its environment. Several plant terpenoids are economically important molecules that serve many applications as pharmaceuticals, pesticides, etc. Major challenges for the commercialization of plant-derived terpenoids include their low production levels in planta and the continuous demand of industry for novel molecules with new or superior biological activities. Here, we highlight several synthetic biology methods to enhance and diversify the production of plant terpenoids, with a foresight towards triterpenoid engineering, the least engineered class of bioactive terpenoids. Increased or cheaper production of valuable triterpenoids may be obtained by 'classic' metabolic engineering of plants or by heterologous production of the compounds in other plants or microbes. Novel triterpenoid structures can be generated through combinatorial biosynthesis or directed enzyme evolution approaches. In its ultimate form, synthetic biology may lead to the production of large amounts of plant triterpenoids in in vitro systems or custom-designed artificial biological systems. PMID- 23668257 TI - UV-induced occupational skin cancer: possibilities of secondary individual prevention in the "Dermatologist's Procedure". AB - Invasive squamous cell carcinoma (SCC) as a "quasi occupational disease" according to S9 Section 2 of the German Social Code Book (SGB) VII typically develops on chronically UV-damaged skin from actinic keratoses. After the Medical Scientific Committee of the Federal Ministry of Labor and Social Affairs has confirmed the legal criteria for acknowledging UV-induced SCC as an occupational disease, it is expected that the condition will be added to the official list of occupational diseases issued by the Federal Government in the near future. The Social Accident Insurance is required by law (S3 Occupational Disease Regulation) to prevent these tumors by "all appropriate means". There are excellent therapeutic and preventive measures for the management of actinic keratoses to avoid the development of SCC. The "Dermatologist's Procedure" according to SS 41 43 of the agreement between the Social Accident Insurance and the Federal Medical Association was established in Germany in 1972 to take preventive measures in insured persons with skin lesions possibly developing into an occupational disease, or worsening it, or leading to a recurrence of it This procedure proved to be very successful in the prevention of severe and/or recurring skin diseases forcing a worker to leave his job. On the basis of this agreement, the Social Accident Insurance has the instruments to independently provide preventive measures for the new occupational skin disease SCC induced by natural UV light according to S9 Section 2 of the German Social Code Book (SGB) VII. PMID- 23668258 TI - Postoperative pain, nausea and vomiting following adeno-tonsillectomy - a long term follow-up. AB - BACKGROUND: Adenotonsillectomy is a common pediatric surgical procedure. Our knowledge of the recovery profile, parental understanding, and expectations is limited. We aimed to assess the incidence of pain, nausea, and vomiting in children undergoing adenotonsillectomy on postoperative day 3 and 7. We also wished to evaluate parental understanding regarding discharge instructions as well as parental expectations and experience of their child's recovery. METHODS: We enrolled 100 children (0-16 years) undergoing elective adenotonsillectomy. On day 3 and 7, parents were questioned about their child's level of pain, nausea/vomiting and their understanding regarding postoperative instructions. RESULTS: Hundred children (median, 6.68 years) were recruited. 52% of parents rated their child's pain as VAS >= 5 on day 3, dropping to 30% by day 7. Almost 33% of patients experienced nausea on day 3, dropping to 11.6% by day 7. A similar trend was observed for postoperative vomiting. Most parents, 89%, agreed that postoperative instructions were clear. However, knowledge regarding when to seek emergency medical advice was found to be lacking. On day 7, only 44% of parents reported that their child's recovery met their expectations. CONCLUSION: Adenotonsillectomy is associated with significant pain and PONV, persisting into the seventh postoperative day. Parental education and information seems inadequate and needs to be improved. PMID- 23668259 TI - All is not lost--the improving outcome of patients with chronic lymphocytic leukaemia failing frontline therapy with fludarabine, cyclophosphamide and rituximab. PMID- 23668261 TI - "Relaxed" reference formatting: a digital dividend for authors. PMID- 23668262 TI - Studying quantum dot blinking through the addition of an engineered inorganic hole trap. AB - An all-inorganic compound colloidal quantum dot incorporating a highly emissive CdSe core, which is linked by a CdS tunneling barrier to an engineered charge carrier trap composed of PbS, is designed, and its optical properties are studied in detail at the single-particle level. Study of this structure enables a deeper understanding of the link between photoinduced charging and surface trapping of charge carriers and the phenomenon of quantum dot blinking. In the presence of the hole trap, a "gray" emissive state appears, associated with charging of the core. Rapid switching is observed between the "on" and the "gray" state, although the switching dynamics in and out of the dark "off" state remain unaffected. This result completes the links in the causality chain connecting charge carrier trapping, charging of QDs, and the appearance of a "gray" emission state. PMID- 23668263 TI - A comparative study on the bulk adhesive strength of the recombinant mussel adhesive protein fp-3. AB - Mussel adhesive protein (MAP) type 3 (fp-3) is considered one of the key components for mussel adhesion. However, its bulk adhesive strength has not been characterized due to its availability in limited quantities. In the present work, a feasible production (~47 mg l(-1)) of recombinant fp-3 was achieved, and its bulk adhesive strength was measured for the first time; ~0.57 MPa for the unmodified form and ~0.94 and ~2.28 MPa for the 3,4-dihydroxy-L-phenylalanine (DOPA)-modified form, having a 9.6% yield without and with oxidant treatment, respectively. Furthermore, values for the bulk adhesive strength of several DOPA modified recombinant MAPs were compared. The maximum adhesive strength of DOPA modified fp-3 after oxidant treatment was stronger than that of type 5 (fp-5), which has a 6.2% modification yield, and was comparable to that of hybrid types fp-131 and fp-151, which have similar yields (~5%). The strong bulk adhesive property of recombinant fp-3 demonstrates its potential use as a promising bioadhesive. PMID- 23668260 TI - Acute infection of mice with Clostridium difficile leads to eIF2alpha phosphorylation and pro-survival signalling as part of the mucosal inflammatory response. AB - The current study sought to delineate the gene expression profile of the host response in the caecum and colon during acute infection with Clostridium difficile in a mouse model of infection, and to investigate the nature of the unfolded protein response in this process. The infected mice displayed a significant up-regulation in the expression of chemokines (Cxcl1, Cxcl2 and Ccl2), numerous pro-inflammatory cytokines (Ifng, Il1b, Il6, and Il17f), as well as Il22 and a number of anti-microbial peptides (Defa1, Defa28, Defb1, Slpi and Reg3g) at the site(s) of infection. This was accompanied by a significant influx of neutrophils, dendritic cells, cells of the monocyte/macrophage lineage and all major subsets of lymphocytes to these site(s). However, CD4 T cells of the untreated and C. difficile-infected mice expressed similar levels of CD69 and CD25. Neither tissue had up-regulated levels of Tbx21, Gata3 or Rorc. The caeca and colons of the infected mice showed a significant increase in eukaryotic initiation factor 2alpha (eIF2alpha) phosphorylation, but neither the splicing of Xbp1 nor the up-regulation of endoplasmic reticulum chaperones, casting doubt on the full-fledged induction of the unfolded protein response by C. difficile. They also displayed significantly higher phosphorylation of AKT and signal transducer and activator of transcription 3 (STAT3), an indication of pro-survival signalling. These data underscore the local, innate, pro-inflammatory nature of the response to C. difficile and highlight eIF2alpha phosphorylation and the interleukin-22-pSTAT3-RegIIIgamma axis as two of the pathways that could be used to contain and counteract the damage inflicted on the intestinal epithelium. PMID- 23668264 TI - Detecting fixation on a target using time-frequency distributions of a retinal birefringence scanning signal. AB - BACKGROUND: The fovea, which is the most sensitive part of the retina, is known to have birefringent properties, i.e. it changes the polarization state of light upon reflection. Existing devices use this property to obtain information on the orientation of the fovea and the direction of gaze. Such devices employ specific frequency components that appear during moments of fixation on a target. To detect them, previous methods have used solely the power spectrum of the Fast Fourier Transform (FFT), which, unfortunately, is an integral method, and does not give information as to where exactly the events of interest occur. With very young patients who are not cooperative enough, this presents a problem, because central fixation may be present only during very short-lasting episodes, and can easily be missed by the FFT. METHOD: This paper presents a method for detecting short-lasting moments of central fixation in existing devices for retinal birefringence scanning, with the goal of a reliable detection of eye alignment. Signal analysis is based on the Continuous Wavelet Transform (CWT), which reliably localizes such events in the time-frequency plane. Even though the characteristic frequencies are not always strongly expressed due to possible artifacts, simple topological analysis of the time-frequency distribution can detect fixation reliably. RESULTS: In all six subjects tested, the CWT allowed precise identification of both frequency components. Moreover, in four of these subjects, episodes of intermittent but definitely present central fixation were detectable, similar to those in Figure 4. A simple FFT is likely to treat them as borderline cases, or entirely miss them, depending on the thresholds used. CONCLUSION: Joint time-frequency analysis is a powerful tool in the detection of eye alignment, even in a noisy environment. The method is applicable to similar situations, where short-lasting diagnostic events need to be detected in time series acquired by means of scanning some substrate along a specific path. PMID- 23668265 TI - Malnutrition: why should we care? PMID- 23668266 TI - Leukaemias into the 21st century. Part 2: the chronic leukaemias. AB - Like the acute leukaemias, the chronic leukaemias are broadly classified according to their cell lineage of origin. Chronic myeloid leukaemia and chronic lymphocytic leukaemia are the most common disease entities within the myeloid and lymphoid lineages, although several less common entities are well recognised within each broad subgroup. In common with the dramatic progress in the acute leukaemias, there has been considerable progress in our understanding of the biology and molecular genetics of the chronic leukaemias that is now being translated into significant therapeutic advances. PMID- 23668267 TI - Telehealth series. Editor's note. PMID- 23668268 TI - Practical aspects of telehealth: are my patients suited to telehealth? AB - The first in a series of articles that demonstrate the practical aspects of telehealth, this paper provides three case studies that examine the suitability of telehealth for patients living in rural and remote areas who require ongoing specialist care. PMID- 23668269 TI - Large vessel calcification in Takayasu arteritis. AB - We report the novel case of a young woman with Takayasu arteritis, with extensive large vessel disease. The case demonstrates that while mechanisms of vascular calcification are poorly understood, inflammation per se might be sufficient to mediate increased mineral stress leading to vessel calcification, even in the absence of renal impairment. PMID- 23668270 TI - Outcomes of concurrent Caesarean delivery and pheochromocytoma resection in late pregnancy. AB - Undiagnosed pheochromocytoma in pregnancy is associated with significant maternal and foetal mortality. Herein we reviewed five cases of pheochromocytoma in pregnancy occurring during late pregnancy. The mean age at presentation was 30.6 years, and the gestational age ranged from 26 to 36 weeks. All patients had elevated levels of urinary catecholamines. In three patients, the lesion was located in the adrenal gland, in one patient the urinary bladder, and there was one case of recurrent malignant pheochromocytoma with metastases. Tumour resections were performed at the time of Caesarean section in four patients, two through laparoscopy. When pheochromocytoma is diagnosed in pregnancy after the second trimester, concurrent tumour resection with Caesarean section is feasible and in our series was achieved in four cases without adverse maternal or foetal consequences. PMID- 23668271 TI - Early discharge and ambulatory care of low-risk patients with neutropenic fever in Australia. AB - Neutropenic fever commonly necessitates hospital admission following chemotherapy, contributing significantly to the economic cost of cancer management. Strategies utilising early discharge and ambulatory management with oral antibiotics have been demonstrated safe and effective internationally and included in recently published Australian guidelines. Here, we sought to evaluate this strategy for the first time in a controlled series in the Australian setting to allow ambulatory management for low-risk patients to become the new standard of care at our institution. PMID- 23668272 TI - Cardiac dysfunction and N-terminal pro-B-type natriuretic peptide in exacerbations of chronic obstructive pulmonary disease. AB - Elevated levels of B-type natriuretic peptides among patients with exacerbations of chronic obstructive pulmonary disease (COPD) are associated with higher mortality. The pathophysiology is unclear. To establish if elevated levels of N terminal pro-B-type natriuretic peptide (NT-proBNP) are due to right or left heart dysfunction, we performed echocardiograms in 18 patients admitted to hospital with COPD. Elevated levels of NT-proBNP were associated with both right and left heart dysfunction and indicate that these patients have biventricular dysfunction rather than isolated right ventricular compromise. PMID- 23668273 TI - Should patients with systemic sclerosis-related pulmonary arterial hypertension be anticoagulated? AB - Pulmonary arterial hypertension (PAH) is a major cause of mortality in scleroderma and despite 'advanced' therapies confers a median survival of less than 5 years. Anticoagulation in systemic sclerosis-related PAH (SSc-PAH) is currently one of the most contentious issues in the management of patients with connective tissue disease. While some studies have shown a survival benefit with warfarin therapy in this disease, others have not. Accordingly, a state of clinical equipoise exists in relation to anticoagulation in SSc-PAH. With an over fivefold reduction in mortality demonstrated in some observational studies, the issue of anticoagulation in SSc-PAH demands resolution through a well-designed randomised controlled trial. PMID- 23668274 TI - Pathological polydipsia from a brain lesion. PMID- 23668275 TI - Anti-Ri antibody-associated paraneoplastic brainstem encephalitis successfully treated after treating the underlying malignancy with letrozole. PMID- 23668276 TI - Terlipressin and hyponatraemia: the cause or the treatment? PMID- 23668277 TI - Author reply: To PMID 23176166. PMID- 23668278 TI - Contraception advice in women with pulmonary arterial hypertension. PMID- 23668279 TI - Author reply: To PMID 22032309. PMID- 23668280 TI - Endothelin receptor antagonists-induced hepatotoxicity. PMID- 23668281 TI - Does cardiac testing before trastuzumab therapy actually make a difference? PMID- 23668282 TI - Author reply: To PMID 21981464. PMID- 23668283 TI - Statistical issues in the interpretation of diabetes as a risk factor for dementia. PMID- 23668284 TI - Ludicrous use of acronyms. PMID- 23668285 TI - Editor's note. PMID- 23668286 TI - When is an acronym sufficiently sanctioned by long usage to be accepted? PMID- 23668287 TI - Carbon and chlorine isotope fractionation during microbial degradation of tetra- and trichloroethene. AB - Two-dimensional compound-specific isotope analysis (2D-CSIA), combining stable carbon and chlorine isotopes, holds potential for monitoring of natural attenuation of chlorinated ethenes (CEs) in contaminated soil and groundwater. However, interpretation of 2D-CSIA data sets is challenged by a shortage of experimental Cl isotope enrichment factors. Here, isotope enrichments factors for C and Cl (i.e., epsilonC and epsilonCl) were determined for biodegradation of tetrachloroethene (PCE) and trichloroethene (TCE) using microbial enrichment cultures from a heavily CE-contaminated aquifer. The obtained values were epsilonC = -5.6 +/- 0.70/00 (95% CI) and epsilonCl = -2.0 +/- 0.50/00 for PCE degradation and epsilonC = -8.8 +/- 0.20/00 and epsilonCl = -3.5 +/- 0.50/00 for TCE degradation. Combining the values for both epsilonC and epsilonCl yielded mechanism-diagnostic epsilonCl/epsilonC ratios of 0.35 +/- 0.11 and 0.37 +/- 0.11 for the degradation of PCE and TCE, respectively. Application of the obtained epsilonC and epsilonCl values to a previously investigated field site gave similar estimates for the fraction of degraded contaminant as in the previous study, but with a reduced uncertainty in assessment of the natural attenuation. Furthermore, 16S rRNA gene clone library analyses were performed on three samples from the PCE degradation experiments. A species closely related to Desulfitobacterium aromaticivorans UKTL dominated the reductive dechlorination process. This study contributes to the development of 2D-CSIA as a tool for evaluating remediation strategies of CEs at contaminated sites. PMID- 23668288 TI - Twisted benign ovarian teratoma presenting with pain and generalized pruritus: a case report. AB - INTRODUCTION: Cystic ovarian teratomas comprise 20% of all ovarian neoplasms, and are commonly encountered in patients between 20 and 40 years of age. Although these cysts are usually asymptomatic, we present the case of a patient whose cyst resulted in pruritus and abdominal pain. Based on a MEDLINE search of the literature, we believe this is the first case report of a twisted ovarian cyst presenting with generalized pruritus. CASE PRESENTATION: A 35-year-old Sri Lankan woman presented with lower abdominal pain of one day's duration with vomiting and generalized pruritus. She had no history of allergies and was not on medication. Upon a physical examination, our patient was found to have an acute abdomen, localized peritonism in her lower abdomen and tachycardia of 100 beats per minute. Computed tomography showed that the cyst, which contained calcified structures, originated from her left ovary. After laparoscopy-assisted removal of the twisted ovarian cyst, her symptoms resolved completely. Histological examination confirmed a benign ovarian teratoma. CONCLUSIONS: An unusual case of torsion of an ovarian teratoma presenting with abdominal pain and generalized pruritus, believed to be due to an antibody-mediated response, was resolved after surgical removal of the cyst. PMID- 23668289 TI - Bodipy derivatives as organic triplet photosensitizers for aerobic photoorganocatalytic oxidative coupling of amines and photooxidation of dihydroxylnaphthalenes. AB - We used iodo-Bodipy derivatives that show strong absorption of visible light and long-lived triplet excited states as organic catalysts for photoredox catalytic organic reactions. Conventionally most of the photocatalysts are based on the off the-shelf compounds, usually showing weak absorption in the visible region and short triplet excited state lifetimes. Herein, the organic catalysts are used for two photocatalyzed reactions mediated by singlet oxygen ((1)O2), that is, the aerobic oxidative coupling of amines and the photooxidation of dihydroxylnaphthalenes, which is coupled to the subsequent addition of amines to the naphthoquinones, via C-H functionalization of 1,4-naphthoquinone, to produce N-aryl-2-amino-1,4-naphthoquinones (one-pot reaction), which are anticancer and antibiotic reagents. The photoreactions were substantially accelerated with these new iodo-Bodipy organic photocatalysts compared to that catalyzed with the conventional Ru(II)/Ir(III) complexes, which show weak absorption in the visible region and short-lived triplet excited states. Our results will inspire the design and application of new organic triplet photosensitizers that show strong absorption of visible light and long-lived triplet excited state and the application of these catalysts in photoredox catalytic organic reactions. PMID- 23668290 TI - Advances in the role of microRNAs in lipid metabolism-related anti atherosclerotic drug discovery. AB - INTRODUCTION: Atherosclerosis is one of the leading causes of mortality in industrialized and developing nations and there remains a large unmet medical need for new therapeutic approaches. Therefore, efforts are continuing needed to discover and develop novel drugs based on the advances in the understanding of molecular basis in lipid metabolism, especially a critical role of miRNAs in regulating lipid metabolism. miRNAs are endogeneous non-coding small RNAs that regulate gene expression on the post-transcriptional level. Some miRNAs have been proposed as potential targets in anti-atherosclerotic drug discovery. AREAS COVERED: This review provides a summary of recently reported miRNAs which are functioning in various pathways of lipid metabolism. Furthermore, this review describes the strategies currently employed for the miRNA-based drug discovery, including: the development of antisense oligonucleotides targeting the specific miRNAs directly and the discovery of small molecules targeting the miRNA activity or biogenesis by application of biochemical or cell-based screening assays. EXPERT OPINION: miRNAs play a prominent role in lipid metabolism and provide intriguing therapeutic targets, which add a new dimension for anti atherosclerotic drug discovery. Translation of these targets and strategies for drug discovery, although still challenging, has shown a promising potential for a more effective reduction in atherosclerotic risk in the future. PMID- 23668291 TI - Commentary to Manfredini et al. J Oral Rehabil. 2012;39:463-71. PMID- 23668293 TI - Dysphagia in amyotrophic lateral sclerosis: prevalence and clinical findings. AB - OBJECTIVES: To characterize swallowing deficits in amyotrophic lateral sclerosis (ALS); investigate the delay in dysphagia onset; estimate correlations between dysphagia severity and patients' functional status; identify the symptom(s) most likely to predict dysphagia. MATERIALS AND METHODS: A group of 49 consecutive patients with ALS, 14 with bulbar onset and 35 with spinal onset, underwent swallowing evaluation including bedside and fiberoptic endoscopic examination to detect dysphagia. RESULTS: Patients with dysphagia were more likely than those without to have bulbar onset ALS (P = 0.02); more severely impaired chewing (P = 0.01); and tongue muscle deficits (P = 0.001). The only variable measured at first examination significantly associated with dysphagia was a more than mild tongue muscle deficit. The only variable useful in predicting dysphagia was a chewing deficit. In 10 of the 49 patients studied, swallowing evaluation disclosed an impaired cough reflex. CONCLUSIONS: Dysphagia in patients with ALS correlates significantly with bulbar onset and with oral swallowing impairment. Fiberoptic swallowing evaluation is a useful tool for detecting swallowing deficits and laryngeal sensitivity in patients with ALS. An impaired cough reflex is an unexpected finding in many patients with ALS. PMID- 23668292 TI - Attachable solvatochromic fluorophores and bioconjugation studies. AB - The synthesis and utility of attachable cyclopenta[b]naphthalene solvatochromic fluorophores related to Prodan are described. Two fluorophores were selected for functionalization and bioconjugation studies. The skeletons were chemically modified to include reactive functional groups and showed minimal alteration of the optical properties when compared to the parent dyes. The functionalized fluorophores were covalently attached to the carboxyl group of a fatty acid, and azido- and thiol-containing amino acids, demonstrating their potential for labeling biomolecules. PMID- 23668294 TI - Antibacterial and hemocompatibility switchable polypropylene nonwoven fabric membrane surface. AB - In this article, a facile approach to fabricate a biofunctional polypropylene nonwoven fabric membrane (PP NWF) with a switchable surface from antibacterial property to hemocompatibility is presented. In the first step, a cationic carboxybetaine ester monomer, [(2-(methacryboxy) ethyl)]-N,N-dimethylamino ethylammonium bromide, methyl ester (CABA-1-ester) was synthesized. Subsequently, this monomer was introduced on the PP NWF surface via plasma pretreatment and a UV-induced graft polymerization technique. Finally, a switchable surface from antibacterial property to hemocompatibility was easily realized by hydrolysis of poly(CABA-1-ester) moieties on the PP NWF surface under mild conditions. Surface hydrolysis behaviors under different pH conditions were investigated. These PP NWFs grafted with poly(CABA-1-ester) segments can cause significant suppression of S. aureus proliferation; after hydrolysis, these surfaces covered by poly[(2 (methacryloxy) ethyl)] carboxybetaine (poly(CABA)) chains exhibited obvious reduction in protein adsorption and platelet adhesion, and remarkably enhanced antithrombotic properties. This strategy demonstrated that a switchable PP NWF surface from antibacterial property to hemocompatibility was easily developed by plasma pretreatment and UV-induced surface graft polymerization and that this surface may become an attractive platform for a range of biomedical applications. PMID- 23668295 TI - Problematic alcohol use in clients recovering from drug dependence--time to adjust our focus. PMID- 23668296 TI - Palladium-catalyzed addition of potassium aryltrifluoroborates to aliphatic nitriles: synthesis of alkyl aryl ketones, diketone compounds, and 2 arylbenzo[b]furans. AB - A palladium-catalyzed addition of potassium aryltrifluoroborates to aliphatic nitriles has been developed, leading to a wide range of alkyl aryl ketones with moderate to excellent yields. Moreover, several dinitriles (e.g., malononitrile, glutaronitrile, and adiponitrile) were applicable to this process for the construction of 1,3-, 1,5-, or 1,6-dicarbonyl compounds. The scope of the developed approach is successfully explored toward the one-step synthesis of 2 arylbenzo[b]furans via sequential addition and intramolecular annulation reactions. The methodology accepted a wide range of substrates and is applicable to library synthesis. PMID- 23668297 TI - Balancing the risk of eye irritation from UV-C with infection from bioaerosols. AB - The very aspect (phototoxicity) that makes short-wavelength ultraviolet (UV) radiation an effective germicidal agent also is responsible for the unwanted side effects of erythema (reddening of the skin) and photokeratitis ("welder's flash" or "snow-blindness"). Overexposure to this short-wavelength UV radiation can produce these unwanted side effects from a very mild irritation of the skin and eyes to a rather painful case of photokeratitis. These effects are fortunately transient, as only superficial cells of the eye-the corneal epithelium-and the most superficial layer of the skin-the superficial epidermis-are significantly affected. Normal turnover of these cells soon erase the signs and symptoms of these effects. Radiant energy in the UV-C band has very shallow penetration depths which account for the very superficial nature of any injury to the skin and eyes from excessive exposure, minimum risk of delayed effects and at the same time the strong absorption by bioaerosols. Guidelines for human exposure to UV-C must be applied intelligently so as not to limit germicidal efficacy in upper room ultraviolet germicidal irradiation. PMID- 23668298 TI - beta-Lactam antibiotics form distinct haptenic structures on albumin and activate drug-specific T-lymphocyte responses in multiallergic patients with cystic fibrosis. AB - beta-Lactam antibiotics provide the cornerstone of treatment for respiratory exacerbations in patients with cystic fibrosis. Unfortunately, approximately 20% of patients develop multiple nonimmediate allergic reactions that restrict therapeutic options. The purpose of this study was to explore the chemical and immunological basis of multiple beta-lactam allergy through the analysis of human serum albumin (HSA) covalent binding profiles and T-cell responses against 3 commonly prescribed drugs; piperacillin, meropenem, and aztreonam. The chemical structures of the drug haptens were defined by mass spectrometry. Peripheral blood mononuclear cells (PBMC) were isolated from 4 patients with multiple allergic reactions and cultured with piperacillin, meropenem, and aztreonam. PBMC responses were characterized using the lymphocyte transformation test and IFN gamma /IL-13 ELIspot. T-cell clones were generated from drug-stimulated T-cell lines and characterized in terms of phenotype, function, and cross-reactivity. Piperacillin, meropenem, and aztreonam formed complex and structurally distinct haptenic structures with lysine residues on HSA. Each drug modified Lys190 and at least 6 additional lysine residues in a time- and concentration-dependent manner. PBMC proliferative responses and cytokine release were detected with cells from the allergic patients, but not tolerant controls, following exposure to the drugs. 122 CD4+, CD8+, or CD4+CD8+ T-cell clones isolated from the allergic patients were found to proliferate and release cytokines following stimulation with piperacillin, meropenem, or aztreonam. Cross-reactivity with the different drugs was not observed. In conclusion, our data show that piperacillin-, meropenem-, and aztreonam-specific T-cell responses are readily detectable in allergic patients with cystic fibrosis, which indicates that multiple beta-lactam allergies are instigated through priming of naive T-cells against the different drug antigens. Characterization of complex haptenic structures on distinct HSA lysine residues provides a chemical basis for the drug-specific T-cell response. PMID- 23668299 TI - Use of the Bonfils intubating fibrescope in a baby with a severely compromised airway. AB - We report the successful use of a 2-mm rigid Bonfils intubation endoscope as a rescue device in a 5-week-old baby presenting with an unstable airway due to massive macroglossia and multiple hemorrhagic lymphangiomata compressing the airway and resulting in a Cormack and Lehane grade 4 view. The limited intraoral space rendered it impossible to visualize the laryngeal inlet or insert a laryngeal mask, Glidescope or Airtraq blade into the patient's mouth. A 2-mm Bonfils fibrescope passed easily into the patient's mouth and facilitated a grade 1 view of the laryngeal inlet with subsequent successful intubation at first attempt with a 3.5-mm uncuffed endotracheal tube. There are very few alternatives to rescue such an airway in this age group with this type of pathology and surgical intervention would have been difficult due to the vascular nature of the lesion. Bonfils intubation endoscopes (Karl Storz Endoscopy, Tuttlingen, Germany) are a series of reusable devices consisting of a rigid metal tube with a fixed 40 degrees anterior tip curvature containing a fibreoptic bundle. They are available in three sizes with outside diameters of 2, 3.5, or 5 mm. The advantage of the pediatric 2-mm Bonfils fibrescope is that it allows intubation with a 2.5 mm endotracheal tube. There is a paucity of the literature pertaining to the use of the Bonfils endoscope as a rescue device for intubation of small infants and neonates. In our case, the infant's airway was compromised as a result of a receding mandible, large protruding tongue, glottic distortion, and limited intraoral space. This prevented the use of bulkier rescue airway devices with the potential for traumatic manipulation, which could have lead to rapid deterioration of an already unstable airway. We feel that many clinicians are unaware of the benefits of the Bonfils fibrescope and suggest further studies to increase its use in elective and emergency situations. PMID- 23668300 TI - Abstracts of the RACP (Royal Australasian College of Physicians) Future Directions in Health Congress 2013. May 26-29, 2013. Perth, Western Australia, Australia. PMID- 23668301 TI - Enhancing the efficiency of solution-processed polymer:colloidal nanocrystal hybrid photovoltaic cells using ethanedithiol treatment. AB - Advances in colloidal inorganic nanocrystal synthesis and processing have led to the demonstration of organic-inorganic hybrid photovoltaic (PV) cells using low cost solution processes from blends of conjugated polymer and colloidal nanocrystals. However, the performance of such hybrid PV cells has been limited due to the lack of control at the complex interfaces between the organic and inorganic hybrid active materials. Here we show that the efficiency of hybrid PV devices can be significantly enhanced by engineering the polymer-nanocrystal interface with proper chemical treatment. Using two different conjugated polymers, poly(3-hexylthiophene) (P3HT) and poly[2,6-(4,4-bis(2-ethylhexyl)-4H cyclopenta[2,1-b;3,4-b']-dithiophene)-alt-4,7-(2,1,3-benzothiadiazole)] (PCPDTBT), we show that treating the polymer:nanocrystal hybrid film in an ethanedithiol-containing acetonitrile solution can increase the efficiency of the hybrid PV devices by 30-90%, and a maximum power conversion efficiency of 5.2 +/- 0.3% was obtained in the PCPDTBT:CdSe devices at 0.2 sun (AM 1.5G), which was slightly reduced to 4.7 +/- 0.3% at 1 sun. The ethanedithiol treatment did not result in significant changes in the morphology and UV-vis optical absorption of the hybrid thin films; however, infrared absorption, NMR, and X-ray photoelectron spectroscopies revealed the effective removal of organic ligands, especially the charged phosphonic acid ligands, from the CdSe nanorod surface after the treatment, accompanied by the possible monolayer passivation of nanorod surfaces with Cd-thiolates. We attribute the hybrid PV cell efficiency increase upon the ethanedithiol treatment to the reduction in charge and exciton recombination sites on the nanocrystal surface and the simultaneous increase in electron transport through the hybrid film. PMID- 23668302 TI - Selective oxidation of alcohols to esters using heterogeneous Co3O4-N@C catalysts under mild conditions. AB - Novel cobalt-based heterogeneous catalysts have been developed for the direct oxidative esterification of alcohols using molecular oxygen as benign oxidant. Pyrolysis of nitrogen-ligated cobalt(II) acetate supported on commercial carbon transforms typical homogeneous complexes to highly active and selective heterogeneous Co3O4-N@C materials. By applying these catalysts in the presence of oxygen, the cross and self-esterification of alcohols to esters proceeds in good to excellent yields. PMID- 23668304 TI - Novel therapies for oral lichen planus. AB - Oral lichen planus (OLP) is a chronic mucocutaneous disorder commonly found in middle-aged women. Despite the progress in research and advance in knowledge on OLP, a successful management is still difficult to achieve. The main aim of OLP treatment is to control the symptoms of the affected patients. Steroids and other immunosuppressive drugs have been recommended and widely used in the treatment of OLP. Topical corticosteroids are the mainstay of OLP treatment, but strong evidence on their effectiveness is lacking. The effectiveness of alternative ways of managing OLP has been recently reported. Topical aloe vera, topical pimecrolimus and oral curcuminoids are the most promising of the new treatment modalities. Other interesting modalities are topically applied thalidomide and amlexanox. Nevertheless, the careful assessment between the risks and benefits of these drugs is crucial and larger and well-conducted trials need to confirm the above encouraging results. PMID- 23668303 TI - The secondary structure of apolipoprotein A-I on 9.6-nm reconstituted high density lipoprotein determined by EPR spectroscopy. AB - Apolipoprotein A-I (ApoA-I) is the major protein component of high-density lipoprotein (HDL), and is critical for maintenance of cholesterol homeostasis. During reverse cholesterol transport, HDL transitions between an array of subclasses, differing in size and composition. This process requires ApoA-I to adapt to changes in the shape of the HDL particle, transiting from an apolipoprotein to a myriad of HDL subclass-specific conformations. Changes in ApoA-I structure cause alterations in HDL-specific enzyme and receptor-binding properties, and thereby direct the HDL particle through the reverse cholesterol transport pathway. In this study, we used site-directed spin label spectroscopy to examine the conformational details of the ApoA-I central domain on HDL. The motional dynamics and accessibility to hydrophobic/hydrophilic relaxation agents of ApoA-I residues 99-163 on 9.6-nm reconstituted HDL was analyzed by EPR. In previous analyses, we examined residues 6-98 and 164-238 (of ApoA-I's 243 residues), and combining these findings with the current results, we have generated a full-length map of the backbone structure of reconstituted HDL associated ApoA-I. Remarkably, given that the majority of ApoA-I's length is composed of amphipathic helices, we have identified nonhelical residues, specifically the presence of a beta-strand (residues 149-157). The significance of these nonhelical residues is discussed, along with the other features, in the context of ApoA-I function in contrast to recent models derived by other methods. PMID- 23668305 TI - Evidence for mixed feelings of happiness and sadness from brief moments in time. AB - Theorists disagree about whether valence is a basic building block of affective experience or whether the positive and negative substrates underlying valence are separable in experience. If positivity and negativity are separable in experience, people should be able to feel happy and sad at the same time. We addressed limitations of earlier evidence for mixed feelings by collecting moment to-moment measures of happiness and sadness that required participants to monitor their feelings only occasionally. In Study 1, participants were occasionally cued to press one button if they felt happy and another if they felt sad. Participants spent more time reporting mixed feelings (i.e., simultaneously pressing both buttons) during bittersweet scenes than non-bittersweet scenes. In Study 2, participants reported their feelings only once. Participants spent more time reporting mixed feelings when cued during a bittersweet, as opposed to non bittersweet, scene. These results extend earlier evidence that happiness and sadness can co-occur. PMID- 23668306 TI - Alcohol use following drug treatment: more than just a risk factor? PMID- 23668307 TI - Letter to the editor. One-tailed tests are rarely appropriate in either basic or applied research. PMID- 23668308 TI - Preoperative factors predicting the surgical response of bilateral lateral rectus recession surgery in patients with infantile exotropia. AB - PURPOSE: To determine the preoperative factors affecting the efficacy in bilateral lateral rectus recession surgery for infantile exotropia. METHODS: This was a retrospective study of 50 patients with infantile exotropia who had bilateral lateral rectus recession surgery correction with more than 1 year of follow-up. Preoperative parameters influencing the response of the surgery were obtained and evaluated using multiple regression analysis including age at onset, age at surgery, interval between onset and surgery, preoperative deviation, refractive error, anisometropia, amount of surgery performed, presence of A- or V pattern, and preoperative phase of exotropia. The response to surgery was defined as the change in deviation divided by the amount of the surgery. RESULTS: Thirty two (64%) and 24 (48%) patients had successful outcome at 6 weeks and 1 year postoperatively, respectively. The mean response to surgery was 1.79 +/- 0.63 prism diopters (PD)/mm recession at 6 weeks and 1.58 +/- 0.75 PD/mm recession at 1 year postoperatively. Exotropic drift was 5.12 +/- 7.27 PD at 6 weeks and 8.02 +/- 6.81 PD at 1 year postoperatively. Pre-operative deviation was correlated with the response of surgery at 6 weeks (beta = 0.342, P = .020) and 1 year (beta = 0.391, P = .007) postoperatively. CONCLUSIONS: Surgical response decreases over time due to the exotropic drift. Larger preoperative distance deviation was associated with larger surgical response. Both the exotropic drift and the preoperative deviation should be considered in applying the surgical dose in infantile exotropia. PMID- 23668309 TI - Decreased solar radiation and increased temperature combine to facilitate fouling by marine non-indigenous species. AB - Studies of the effects of climate changes on marine biofouling have mainly focused on the effects of temperature increase, but a decrease in the level of solar radiation could also influence the establishment and persistence of fouling species. To test if decreased solar radiation and/or increased temperature influenced marine fouling communities, solar radiation, and temperature were manipulated by deploying shading devices in the intertidal zone of a central California estuary. Non-indigenous species (NIS) recruiting to artificial substrata had greater coverage under the shading treatments than under transparent plates, indicating that low radiation facilitates recruitment and growth of NIS. In contrast, the coverage of NIS underneath warmer black plates was higher than that on white plates. Furthermore, spatial comparisons of recruitment showed that NIS had a tendency to grow better in the warmer region of the estuary whereas native species showed the opposing trend. The results suggest that both lower radiation and higher temperature may facilitate the spread of marine NIS. PMID- 23668311 TI - Physicochemical characteristics of polymer-coated metal-oxide nanoparticles and their toxicological effects on zebrafish (Danio rerio) development. AB - Coated nanoparticles (NPs) will end up in the environment due to their proposed use in agricultural applications and may potentially cause toxic effects due to their unique properties. To determine the effects of coated NPs on zebrafish (Danio rerio) development, we tested aqueous poly(acrylic acid) (PAA)-coated metal-oxide NPs including TiO2, ZnO, Fe2O3, and CeO2, as well as the polymer coating alone (nanocapsule). Zebrafish embryos were exposed to NPs over a 72 h period at 1, 10, 50, 100, 200, 400, 800, 1200, 1600, and 2000 mg/L to measure various end points. We also ran free metal controls. Time-dependent changes in physicochemical properties of NPs were characterized using dynamic light scattering. Dissolution experiments over 72 h showed minimal free metals were present in stock suspensions and released from the NPs. Interestingly, nanocapsules (>= 800 mg/L) cause inhibition of hatch, and we suggest that a low pH environment may explain this effect. This study has also demonstrated that CeO2 NPs and nanocapsules containing Nile red are able to traverse the chorion. Overall, our findings indicate that each NP type is stable and neither the NP or encapsulating PAA coating causes apparent toxicity to developing zebrafish. PMID- 23668310 TI - Thymoquinone attenuates tumor growth in ApcMin mice by interference with Wnt signaling. AB - BACKGROUND: Patients with familial adenomatous polyposis (FAP) are at increased risk for the development of colorectal cancer. Surgery and chemoprevention are the most effective means to prevent cancer development. Thymoquinone (TQ) is considered the main compound of the volatile Nigella sativa seed oil and has been reported to possess anticarcinogenic properties. In this study we evaluated the chemopreventive properties of TQ in a mouse model of FAP. METHODS: APCMin mice were fed with chow containing 37.5 mg/kg or 375 mg/kg TQ for 12 weeks. H&E stained intestine tissue sections were assessed for tumor number, localization, size, and grade. Immunohistochemistry for beta-catenin, c-myc, Ki-67 and TUNEL staining was performed to investigate TQ's effect on major colorectal cancer pathways. TQ's impact on GSK-3beta and beta-catenin were studied in RKO cells. RESULTS: 375 mg/kg but not 37.5 mg/kg TQ decreased the number of large polyps in the small intestine of APCMin mice. TQ induced apoptosis in the neoplastic tissue but not in the normal mucosa. Furthermore, upon TQ treatment, beta-catenin was retained at the membrane and c-myc decreased in the nucleus, which was associated with a reduced cell proliferation in the villi. In vitro, TQ activated GSK-3beta, which induced membranous localization of beta-catenin and reduced nuclear c-myc expression. CONCLUSIONS: In summary, TQ interferes with polyp progression in ApcMin mice through induction of tumor-cell specific apoptosis and by modulating Wnt signaling through activation of GSK-3beta. Nigella sativa oil (or TQ) might be useful as nutritional supplement to complement surgery and chemoprevention in FAP. PMID- 23668312 TI - A thioethylalkylamido (TEA) thioester surrogate in the synthesis of a cyclic peptide via a tandem acyl shift. AB - The cyclic cystine-knot peptide, kalata B1, was synthesized by employing a novel Fmoc-compatible thioethylalkylamido (TEA) thioester surrogate via an N-S acyl shift followed by a thiol-thioester exchange reaction. TEA thioester surrogate is cost-effective, conveniently prepared in one-step with starting materials, readily available from commercial sources, and highly efficient in preparing peptide thioesters. PMID- 23668313 TI - Repigmentation of cutaneous scars depends on original wound type. AB - Cutaneous scarring is currently an inevitable outcome following skin injury. Abnormal pigmentation within scars makes them more noticeable, causing distress for patients, particularly as there is no reliable and effective treatment available to date. The Duroc pig, known to scar badly, was used to investigate repigmentation of scars resulting from three different wound types: incisional, partial thickness excisional and full thickness excisional. Wounds were created on the backs of Duroc pigs and the resulting scars harvested at days 35, 56, 70 and 90 days post-injury. Scars were processed for histology and immunohistochemistry, quantitatively analysed using image analysis software and subjected to statistical analysis. Photographs of the macroscopic appearance of scars were scored for pigmentation using a visual analogue scale. Results demonstrated temporal and spatial differences in melanocyte repopulation and function within scars from different wound types. The microscopic pigment deposition did not correlate with macroscopic appearances in mature scars. Pigmentation of scars is dependent on the width and depth of wounds. This study has provided important information on which we can base future studies to investigate factors controlling the repigmentation of scars. PMID- 23668314 TI - Drug-releasing shape-memory polymers - the role of morphology, processing effects, and matrix degradation. AB - INTRODUCTION: Shape-memory polymers (SMPs) have gained interest for temporary drug-release systems that should be anchored in the body by self-sufficient active movements of the polymeric matrix. AREAS COVERED: Based on the so far published scientific literature, this review highlights three aspects that require particular attention when combining SMPs with drug molecules: i) the defined polymer morphology as required for the shape-memory function, ii) the strong effects that processing conditions such as drug-loading methodologies can have on the drug-release pattern from SMPs, and iii) the independent control of drug release and degradation by their timely separation. EXPERT OPINION: The combination of SMPs with a drug-release functionality leads to multifunctional carriers that are an interesting technology for pharmaceutical sciences and can be further expanded by new materials such as thermoplastic SMPs or temperature memory polymers. Experimental studies should include relevant molecules as (model) drugs and provide a thermomechanical characterization also in an aqueous environment, report on the potential effect of drug type and loading levels on the shape-memory functionality, and explore the potential correlation of polymer degradation and drug release. PMID- 23668315 TI - Validation of reference genes aiming accurate normalization of qPCR data in soybean upon nematode parasitism and insect attack. AB - BACKGROUND: Soybean pathogens and pests reduce grain production worldwide. Biotic interaction cause extensive changes in plant gene expression profile and the data produced by functional genomics studies need validation, usually done by quantitative PCR. Nevertheless, this technique relies on accurate normalization which, in turn, depends upon the proper selection of stable reference genes for each experimental condition. To date, only a few studies were performed to validate reference genes in soybean subjected to biotic stress. Here, we report reference genes validation in soybean during root-knot nematode (Meloidogyne incognita) parasitism and velvetbean caterpillar (Anticarsia gemmatalis) attack. FINDINGS: The expression stability of nine classical reference genes (GmCYP2, GmELF1A, GmELF1B, GmACT11, GmTUB, GmTUA5, GmG6PD, GmUBC2 and GmUBC4) was evaluated using twenty-four experimental samples including different organs, developmental stages, roots infected with M. incognita and leaves attacked by A. gemmatalis. Two different algorithms (geNorm and NormFinder) were used to determine expression stability. GmCYP2 and GmUBC4 are the most stable in different organs. Considering the developmental stages, GmELF1A and GmELF1B genes are the most stable. For spatial and temporal gene expression studies, normalization may be performed using GmUBC4, GmUBC2, GmCYP2 and GmACT11 as reference genes. Our data indicate that both GmELF1A and GmTUA5 are the most stable reference genes for data normalization obtained from soybean roots infected with M. incognita, and GmCYP2 and GmELF1A are the most stable in soybean leaves infested with A. gemmatalis. CONCLUSIONS: Future expression studies using nematode infection and caterpilar infestation in soybean plant may utilize the reference gene sets reported here. PMID- 23668316 TI - CERAD test performance and cognitive impairment in Parkinson's disease. AB - OBJECTIVES: Many patients with Parkinson's disease (PD) develop mild cognitive impairment (PD-MCI) and dementia (PDD). The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neurocognitive test battery was originally developed to identify early Alzheimer's disease, but it has become a widely used screening instrument also for other types of dementia. The aim of the study was to examine differences in CERAD test performances between cognitively intact and impaired PD patients. MATERIALS AND METHODS: Eighty-eight PD patients participating in a rehabilitation course were studied. The Clinical Dementia Rating (CDR) was used to assess cognitive impairment. Sixty-six patients were cognitively intact and 22 had cognitive impairment (>=1 in two or more domains or a sum of boxes score of >=3). The Finnish CERAD test battery was used to measure cognitive functions in seven different domains (language functions, verbal learning, visuospatial functions, delayed recall, memory consolidation, recognition memory, and executive functions). RESULTS: There were significant differences between the cognitively intact and impaired patients in six CERAD subtests (wordlist learning sum, wordlist delayed recall, constructional praxis recall, clock drawing, verbal fluency and constructional praxis copy) when controlling for covariates (disease duration, motor symptoms, age, and education). No differences were observed in memory consolidation scores. CONCLUSIONS: The results indicate that mild cognitive impairment in PD is related to deficits in memory, executive functions, and visuospatial functions. The memory deficit is non-amnestic and does not entail accelerated forgetting. CERAD shows promise in identifying PD patients with cognitive impairment and increased risk of dementia. PMID- 23668317 TI - Visual field staging systems in glaucoma and the activities of daily living. PMID- 23668318 TI - Reply: To PMID 22633358. PMID- 23668319 TI - Fluence measurements employing iodide/iodate chemical actinometry as applied to upper-room germicidal radiation. AB - To measure the fluence distribution in the upper room of a facility equipped with germicidal UV lamps a method has been developed utilizing iodide/iodate chemical actinometry together with spherical (1 cm) quartz irradiation chambers. The use of spherical vessels allows radiation from essentially all directions to be measured. Such a measurement allows an estimate of the radiation flux at a given point in space, i.e. the fluence rate. When a battery of spheres located at various points in a room are simultaneously irradiated, a measure of the fluence distribution can be obtained. The use of the iodide/iodate chemical actinometer is uniquely qualified to measure germicidal UV radiation. The purpose of this report is to provide details on how this system can be used to measure fluence rates. In particular, it describes how a hand-held colorimeter can be used to measure the absorbance changes in irradiated spheres. PMID- 23668320 TI - Multifunctional structural supercapacitor composites based on carbon aerogel modified high performance carbon fiber fabric. AB - A novel multifunctional material has been designed to provide excellent mechanical properties while possessing a high electrochemical surface area suitable for electrochemical energy storage: structural carbon fiber fabrics are embedded in a continuous network of carbon aerogel (CAG) to form a coherent but porous monolith. The CAG-modification process was found to be scalable and to be compatible with a range of carbon fiber fabrics with different surface properties. The incorporation of CAG significantly increased the surface area of carbon fiber fabrics, and hence the electrochemical performance, by around 100 fold, resulting in a CAG-normalized specific electrode capacitance of around 62 F g(-1), determined by cyclic voltammetry in an aqueous electrolyte. Using an ionic liquid (IL) electrolyte, the estimated energy density increased from 0.003 to 1 Wh kg(-1), after introducing the CAG into the carbon fiber fabric. 'Proof-of concept' multifunctional structural supercapacitor devices were fabricated using an IL-modified solid-state polymer electrolyte as a multifunctional matrix to provide both ionic transport and physical support for the primary fibers. Two CAG impregnated carbon fabrics were sandwiched around an insulating separator to form a functioning structural electrochemical double layer capacitor composite. The CAG-modification not only improved the electrochemical surface area, but also reinforced the polymer matrix surrounding the primary fibers, leading to dramatic improvements in the matrix-dominated composite properties. Increases in in-plane shear strength and modulus, of up to 4.5-fold, were observed, demonstrating that CAG-modified structural carbon fiber fabrics have promise in both pure structural and multifunctional energy storage applications. PMID- 23668321 TI - Solvent-manipulated guest binding and signaling of a fluorescent resorcin[4]arene cavitand with 1,3,2-benzodiazaboryl D-pi-A conjugation flaps. AB - The conformation of resorcin[4]arene cavitand system 1 was controlled by DMSO through a hydrogen bonding network between benzodiazaborole NHs of the cavitand flaps and DMSO molecules to stabilize the vase form. Subsequently, a guest binding cavity of 1 was formed to accommodate tetraalkylammonium guest 3, permitting the monitoring of the guest by the unaided eye as a result of a CH-pi interaction between the benzodiazaborole pi-donor group and the guest. PMID- 23668323 TI - Syndapin--a membrane remodelling and endocytic F-BAR protein. AB - Syndapin [also called PACSIN (protein kinase C and casein kinase II interacting protein)] is an Fes-CIP4 homology Bin-amphiphysin-Rvs161/167 (F-BAR) and Src homology 3 domain-containing protein. Three genes give rise to three main isoforms in mammalian cells. They each function in different endocytic and vesicle trafficking pathways and provide critical links between the cytoskeletal network in different cellular processes, such as neuronal morphogenesis and cell migration. The membrane remodelling activity of syndapin via its F-BAR domain and its interaction partners, such as dynamin and neural Wiskott-Aldrich syndrome protein binding to its Src-homology 3 domain, are important with respect to its function. Its various partner proteins provide insights into its mechanism of action, as well as its differential roles in these cellular processes. Signalling pathways leading to the regulation of syndapin function by phosphorylation are now contributing to our understanding of the broader functions of this family of proteins. PMID- 23668322 TI - Cellular interaction and toxicity depend on physicochemical properties and surface modification of redox-active nanomaterials. AB - The study of the chemical and biological properties of CeO2 nanoparticles (CNPs) has expanded recently due to its therapeutic potential, and the methods used to synthesize these materials are diverse. Moreover, conflicting reports exist regarding the toxicity of CNPs. To help resolve these discrepancies, we must first determine whether CNPs made by different methods are similar or different in their physicochemical and catalytic properties. In this paper, we have synthesized several forms of CNPs using identical precursors through a wet chemical process but using different oxidizer/reducer; H2O2 (CNP1), NH4OH (CNP2), or hexamethylenetetramine (HMT-CNP1). Physicochemical properties of these CNPs were extensively studied and found to be different depending on the preparation methods. Unlike CNP1 and CNP2, HMT-CNP1 was readily taken into endothelial cells and the aggregation can be visualized using light microscopy. Exposure to HMT CNP1 also reduced cell viability at a 10-fold lower concentration than CNP1 or CNP2. Surprisingly, exposure to HMT-CNP1 led to substantial decreases in ATP levels. Mechanistic studies revealed that HMT-CNP1 exhibited substantial ATPase (phosphatase) activity. Though CNP2 also exhibits ATPase activity, CNP1 lacked ATPase activity. The difference in catalytic (ATPase) activity of different CNPs preparation may be due to differences in their morphology and oxygen extraction energy. These results suggest that the combination of increased uptake and ATPase activity of HMT-CNP1 may underlie the biomechanism of the toxicity of this preparation of CNPs and may suggest that ATPase activity should be considered when synthesizing CNPs for use in biomedical applications. PMID- 23668324 TI - Central granular cell odontogenic tumor: a systematic review. AB - Central granular cell odontogenic tumor (CGCOT) is a rare benign odontogenic neoplasm reported with various terms and is not included in the 2005 WHO classification of odontogenic tumors. It shows a predilection for middle-aged women, usually presenting as an asymptomatic swelling of the mandibular premolar molar region. Radiographic manifestations include unilocular or multilocular radiolucent lesion, but mixed density lesions can also occur. Histopathology shows sheets and lobules of round to polygonal cells with abundant eosinophilic, granular cytoplasm and eccentrically placed nuclei. Immunohistochemical and ultrastructural features suggest the histiocytic origin of granular cells. The neoplasm does not exhibit an aggressive biological behavior and hence enucleation or curettage ensuring complete removal remains the treatment of choice. We present a systematic review on clinical, radiological, histopathological, immunohistochemical and treatment aspect of CGCOT. Published articles were identified through a literature search using online databases (PubMed, MEDLINE, Scopus) and cross-references for papers published from the year 1950 to March 2013. From a total of 37 papers, 26 (38 cases) were extracted from the database for systematic review. PMID- 23668326 TI - Carbon monoxide induced reductive elimination of disulfide in an N-heterocyclic carbene (NHC)/thiolate dinitrosyl iron complex (DNIC). AB - Dinitrosyliron complexes (DNICs) are organometallic-like compounds of biological significance in that they appear in vivo as products of NO degradation of iron sulfur clusters; synthetic analogues have potential as NO storage and releasing agents. Their reactivity is expected to depend on ancillary ligands and the redox level of the distinctive Fe(NO)2 unit: paramagnetic {Fe(NO)2}(9), diamagnetic dimerized forms of {Fe(NO)2}(9) and diamagnetic {Fe(NO)2}(10) DNICs (Enemark Feltham notation). The typical biological ligands cysteine and glutathione themselves are subject to thiolate-disulfide redox processes, which when coupled to DNICs may lead to intricate redox processes involving iron, NO, and RS(-)/RS*. Making use of an N-heterocyclic carbene-stabilized DNIC, (NHC)(RS)Fe(NO)2, we have explored the DNIC-promoted RS(-)/RS* oxidation in the presence of added CO wherein oxidized {Fe(NO)2}(9) is reduced to {Fe(NO)2}(10) through carbon monoxide (CO)/RS* ligand substitution. Kinetic studies indicate a bimolecular process, rate = k [Fe(NO)2](1)[CO](1), and activation parameters derived from kobs dependence on temperature similarly indicate an associative mechanism. This mechanism is further defined by density functional theory computations. Computational results indicate a unique role for the delocalized frontier molecular orbitals of the Fe(NO)2 unit, permitting ligand exchange of RS* and CO through an initial side-on approach of CO to the electron-rich N-Fe-N site, ultimately resulting in a 5-coordinate, 19-electron intermediate with elongated Fe-SR bond and with the NO ligands accommodating the excess charge. PMID- 23668325 TI - Demonstration of HNE-related aldehyde formation via lipoxygenase-catalyzed synthesis of a bis-allylic dihydroperoxide intermediate. AB - One of the proposed pathways to the synthesis of 4-hydroxy-nonenal (HNE) and related aldehydes entails formation of an intermediate bis-allylic fatty acid dihydroperoxide. As a first direct demonstration of such a pathway and proof of principle, herein we show that 8R-lipoxygenase (8R-LOX) catalyzes the enzymatic production of the HNE-like product (11-oxo-8-hydroperoxy-undeca-5,9-dienoic acid) via synthesis of 8,11-dihydroperoxy-eicosa-5,9,12,14-tetraenoic acid intermediate. Incubation of arachidonic acid with 8R-LOX formed initially 8R hydroperoxy-eicosatetraenoic acid (8R-HPETE), which was further converted to a mixture of products including a prominent HPNE-like enone. A new bis-allylic dihydroperoxide was trapped when the incubation was repeated on ice. Reincubation of this intermediate with 8R-LOX successfully demonstrated its conversion to the enone products, and this reaction was greatly accelerated by coincubation with NDGA, a reductant of the LOX iron. These findings identify a plausible mechanism that could contribute to the production of 4-hydroxy-alkenals in vivo. PMID- 23668327 TI - Managing relapses: encouraging the engagement of alternative rewarding activities. PMID- 23668328 TI - The snake in the grass revisited: an experimental comparison of threat detection paradigms. AB - The current investigation compares the results of two commonly used visual detection paradigms-the standard adult button-press detection paradigm used in Ohman, Flykt, and Esteves (2001), and the new child-friendly touch-screen detection paradigm used in LoBue and DeLoache (2008)-within the same samples of adult participants. Results suggest that both paradigms produce the same pattern of findings with regard to detection latency for threat-relevant versus threat irrelevant stimuli: Adults detected threat-relevant targets more quickly than threat-irrelevant targets across the varying procedures. However, results with respect to automaticity of detection as suggested by Ohman et al. (2001) were only replicated with the classic button-press paradigm. The findings validate the touch-screen visual search procedure and have important implications for choosing an appropriate methodology for studying threat detection. PMID- 23668329 TI - Letter to the editor. One, two, or lots of sides to a problem? PMID- 23668330 TI - Cardioprotective effect of remote ischemic postconditioning on children undergoing cardiac surgery: a randomized controlled trial. AB - BACKGROUND: Remote ischemic postconditioning (RPostC) is a noninvasive intervention that has demonstrated cardioprotection and neuroprotection in animal studies. OBJECTIVE: Our goal was to investigate the cardio-cerebral protective effects of RPostC on children undergoing open-heart surgery for repair of congenital heart defects (CHD). METHODS: Children undergoing open-heart repair of CHD were randomly assigned to a RPostC or control group. RPostC was induced by three 5-min cycles of lower limb ischemia and reperfusion using a blood pressure cuff (200 mmHg) at the onset of aortic unclamping. Serum cardiac troponin I (cTnI), creatine kinase-MB (CK-MB), neuron-specific enolase (NSE), S100beta, cytokines, and clinical outcomes were assessed. RESULTS: There were 35 children in the control group and 34 in the RPostC group. The mean age (3.64 +/- 1.95 years vs. 3.45 +/- 3.02 years, P = 0.80), weight (15.11 +/- 6.91 kg vs. 13.40 +/- 6.33 kg, P = 0.37), surgical time (144.82 +/- 38.51 min vs. 129.92 +/- 30.76 min, P = 0.15), and bypass time (78.01 +/- 27.22 min vs. 72.52 +/- 26.05 min, P = 0.49) were not different. Compared with the control group, the postoperative levels of cTnI (P = 0.037) and CK-MB (P = 0.046) were significantly reduced in the RPostC group. Furthermore, the MAP was higher (P = 0.008), and ICU stay (36.87 +/- 3.30 h vs. 60.57 +/- 7.35 h, P = 0.006) and postoperative hospital stay (8.56 +/- 1.50 days vs. 10.06 +/- 2.41 days, P = 0.048) were shorter in the RPostC group than in the control group. However, the postoperative CVP and the concentrations of NSE, S100beta, CRP, TNF-alpha, IL-1beta, IL-6, and IL-10 were not significantly different. CONCLUSION: RPostC significantly alleviates cardiac injury in children undergoing open-heart repair of CHD and may also reduce cerebral injury. PMID- 23668332 TI - Safety evaluation of leflunomide in rheumatoid arthritis. AB - INTRODUCTION: Leflunomide is a prodrug which is rapidly converted following oral administration and absorption to an active metabolite with anti-proliferative effects (A77 1726/teriflunomide). Leflunomide was developed as an immunomodulatory agent and subsequently developed as a disease-modifying anti rheumatic drug (DMARD) for the management of rheumatoid arthritis (RA). AREAS COVERED: This review article covers the mechanism of action of the drug, clinical indications, including efficacy data from clinical trials, safety data from clinical trials, post marketing studies and surveillance databases and safety in special populations. Additionally, the review discusses the current place of leflunomide in the management of RA, and its likely future as an anti-rheumatic drug. EXPERT OPINION: Leflunomide is a relatively safe drug, with proven efficacy in RA management. Its clinical use is limited by the historic parallel development of other agents, including methotrexate, which has become the synthetic DMARD of choice and biological DMARDs that have superior efficacy. PMID- 23668331 TI - Optimization of benzoxazole-based inhibitors of Cryptosporidium parvum inosine 5' monophosphate dehydrogenase. AB - Cryptosporidium parvum is an enteric protozoan parasite that has emerged as a major cause of diarrhea, malnutrition, and gastroenteritis and poses a potential bioterrorism threat. C. parvum synthesizes guanine nucleotides from host adenosine in a streamlined pathway that relies on inosine 5'-monophosphate dehydrogenase (IMPDH). We have previously identified several parasite-selective C. parvum IMPDH (CpIMPDH) inhibitors by high-throughput screening. In this paper, we report the structure-activity relationship (SAR) for a series of benzoxazole derivatives with many compounds demonstrating CpIMPDH IC50 values in the nanomolar range and >500-fold selectivity over human IMPDH (hIMPDH). Unlike previously reported CpIMPDH inhibitors, these compounds are competitive inhibitors versus NAD(+). The SAR study reveals that pyridine and other small heteroaromatic substituents are required at the 2-position of the benzoxazole for potent inhibitory activity. In addition, several other SAR conclusions are highlighted with regard to the benzoxazole and the amide portion of the inhibitor, including preferred stereochemistry. An X-ray crystal structure of a representative E.IMP.inhibitor complex is also presented. Overall, the secondary amine derivative 15a demonstrated excellent CpIMPDH inhibitory activity (IC50 = 0.5 +/- 0.1 nM) and moderate stability (t1/2 = 44 min) in mouse liver microsomes. Compound 73, the racemic version of 15a, also displayed superb antiparasitic activity in a Toxoplasma gondii strain that relies on CpIMPDH (EC50 = 20 +/- 20 nM), and selectivity versus a wild-type T. gondii strain (200-fold). No toxicity was observed (LD50 > 50 MUM) against a panel of four mammalian cells lines. PMID- 23668333 TI - Synthesis of [2]rotaxanes by the copper-mediated threading reactions of aryl iodides with alkynes. AB - The catalytic activity of the macrocyclic phenanthroline-copper(I) complex is utilized for the Sonogashira-type reaction to synthesize [2]rotaxanes. Thus, [2]rotaxanes were prepared by reactions between terminal alkynes and aryl iodides in the presence of the macrocyclic copper complex. Bulky substituents were introduced to the substrates to stabilize the rotaxane. The bond-forming reaction proceeded selectively inside the macrocyclic complex so that the rotaxanes could be synthesized. PMID- 23668335 TI - Life-cycle energy and greenhouse gas emission benefits of lightweighting in automobiles: review and harmonization. AB - Replacing conventional materials (steel and iron) with lighter alternatives (e.g., aluminum, magnesium, and composites) decreases energy consumption and greenhouse gas (GHG) emissions during vehicle use but may increase energy consumption and GHG emissions during vehicle production. There have been many life cycle assessment (LCA) studies on the benefits of vehicle lightweighting, but the wide variety of assumptions used makes it difficult to compare results from the studies. To clarify the benefits of vehicle lightweighting we have reviewed the available literature (43 studies). The GHG emissions and primary energy results from 33 studies that passed a screening process were harmonized using a common set of assumptions (lifetime distance traveled, fuel-mass coefficient, secondary weight reduction factor, fuel consumption allocation, recycling rate, and energy intensity of materials). After harmonization, all studies indicate that using aluminum, glass-fiber reinforced plastic, and high strength steel to replace conventional steel decreases the vehicle life cycle energy use and GHG emissions. Given the flexibility in options implied by the variety of materials available and consensus that these materials have substantial energy and emissions benefits, it seems likely that lightweighting will be used increasingly to improve fuel economy and reduce life cycle GHG emissions from vehicles. PMID- 23668334 TI - Genome scan study of prostate cancer in Arabs: identification of three genomic regions with multiple prostate cancer susceptibility loci in Tunisians. AB - BACKGROUND: Large databases focused on genetic susceptibility to prostate cancer have been accumulated from population studies of different ancestries, including Europeans and African-Americans. Arab populations, however, have been only rarely studied. METHODS: Using Affymetrix Genome-Wide Human SNP Array 6, we conducted a genome-wide association study (GWAS) in which 534,781 single nucleotide polymorphisms (SNPs) were genotyped in 221 Tunisians (90 prostate cancer patients and 131 age-matched healthy controls). TaqMan SNP Genotyping Assays on 11 prostate cancer associated SNPs were performed in a distinct cohort of 337 individuals from Arab ancestry living in Qatar and Saudi Arabia (155 prostate cancer patients and 182 age-matched controls). In-silico expression quantitative trait locus (eQTL) analysis along with mRNA quantification of nearby genes was performed to identify loci potentially cis-regulated by the identified SNPs. RESULTS: Three chromosomal regions, encompassing 14 SNPs, are significantly associated with prostate cancer risk in the Tunisian population (P = 1 * 10-4 to P = 1 * 10-5). In addition to SNPs located on chromosome 17q21, previously found associated with prostate cancer in Western populations, two novel chromosomal regions are revealed on chromosome 9p24 and 22q13. eQTL analysis and mRNA quantification indicate that the prostate cancer associated SNPs of chromosome 17 could enhance the expression of STAT5B gene. CONCLUSION: Our findings, identifying novel GWAS prostate cancer susceptibility loci, indicate that prostate cancer genetic risk factors could be ethnic specific. PMID- 23668337 TI - Optimum heart sound signal selection based on the cyclostationary property. AB - Noise often appears in parts of heart sound recordings, which may be much longer than those necessary for subsequent automated analysis. Thus, human intervention is needed to select the heart sound signal with the best quality or the least noise. This paper presents an automatic scheme for optimum sequence selection to avoid such human intervention. A quality index, which is based on finding that sequences with less random noise contamination have a greater degree of periodicity, is defined on the basis of the cyclostationary property of heart beat events. The quality score indicates the overall quality of a sequence. No manual intervention is needed in the process of subsequence selection, thereby making this scheme useful in automatic analysis of heart sound signals. PMID- 23668336 TI - Identification of the origin of adrenergic and cholinergic nerve fibers within the superior hypogastric plexus of the human fetus. AB - Nerve fibers contributing to the superior hypogastric plexus (SHP) and the hypogastric nerves (HN) are currently considered to comprise an adrenergic part of the autonomic nervous system located between vertebrae (T1 and L2), with cholinergic aspects originating from the second to fourth sacral spinal segments (S2, S3 and S4). The aim of this study was to identify the origin and the nature of the nerve fibers within the SHP and the HN, especially the cholinergic fibers, using computer-assisted anatomic dissection (CAAD). Serial histological sections were performed at the level of the lumbar spine and pelvis in five human fetuses between 14 and 30 weeks of gestation. Sections were treated with histological staining [hematoxylin-eosin (HE) and Masson's trichrome (TriM)] and with immunohistochemical methods to detect nerve fibers (anti-S100), adrenergic fibers (anti-TH), cholinergic fibers (anti-VAChT) and nitrergic fibers (anti-nNOS). The sections were then digitalized using a high-resolution scanner and the 3D images were reconstructed using winsurf software. These experiments revealed the coexistence of adrenergic and cholinergic fibers within the SHP and the HNs. One third of these cholinergic fibers were nitrergic fibers [anti-VACHT (+)/anti-NOS (+)] and potentially pro-erectile, while the others were non-nitrergic [anti VACHT (+)/anti-NOS (-)]. We found these cholinergic fibers arose from the lumbar nerve roots. This study described the nature of the SHP nerve fibers which gives a better understanding of the urinary and sexual dysfunctions after surgical injuries. PMID- 23668338 TI - Intelligent ensemble T-S fuzzy neural networks with RCDPSO_DM optimization for effective handling of complex clinical pathway variances. AB - Takagi-Sugeno (T-S) fuzzy neural networks (FNNs) can be used to handle complex, fuzzy, uncertain clinical pathway (CP) variances. However, there are many drawbacks, such as slow training rate, propensity to become trapped in a local minimum and poor ability to perform a global search. In order to improve overall performance of variance handling by T-S FNNs, a new CP variance handling method is proposed in this study. It is based on random cooperative decomposing particle swarm optimization with double mutation mechanism (RCDPSO_DM) for T-S FNNs. Moreover, the proposed integrated learning algorithm, combining the RCDPSO_DM algorithm with a Kalman filtering algorithm, is applied to optimize antecedent and consequent parameters of constructed T-S FNNs. Then, a multi-swarm cooperative immigrating particle swarm algorithm ensemble method is used for intelligent ensemble T-S FNNs with RCDPSO_DM optimization to further improve stability and accuracy of CP variance handling. Finally, two case studies on liver and kidney poisoning variances in osteosarcoma preoperative chemotherapy are used to validate the proposed method. The result demonstrates that intelligent ensemble T-S FNNs based on the RCDPSO_DM achieves superior performances, in terms of stability, efficiency, precision and generalizability, over PSO ensemble of all T-S FNNs with RCDPSO_DM optimization, single T-S FNNs with RCDPSO_DM optimization, standard T-S FNNs, standard Mamdani FNNs and T-S FNNs based on other algorithms (cooperative particle swarm optimization and particle swarm optimization) for CP variance handling. Therefore, it makes CP variance handling more effective. PMID- 23668339 TI - Serial slice image segmentation of digital human based on adaptive geometric active contour tracking. AB - Segmentation is one of the crucial problems for the digital human research, as currently digital human datasets are manually segmented by experts with anatomy knowledge. Due to the thin slice thickness of digital human data, the static slices can be regarded as a sequence of temporal deformation of the same slice. This gives light to the method of object contour tracking for the segmentation task for the digital human data. In this paper, we present an adaptive geometric active contour tracking method, based on a feature image of object contour, to segment tissues in digital human data. The feature image is constructed according to the matching degree of object contour points, image variance and gradient, and statistical models of the object and background colors. Utilizing the characteristics of the feature image, the traditional edge-based geometric active contour model is improved to adaptively evolve curve in any direction instead of the single direction. Experimental results demonstrate that the proposed method is robust to automatically handle the topological changes, and is effective for the segmentation of digital human data. PMID- 23668340 TI - ECG signal enhancement using S-Transform. AB - Electrocardiogram (ECG), which is a noninvasive technique, is used generally as a primary diagnostic tool for cardiovascular diseases. In real-time scenario, noises like channel noise, muscle artifacts, electrode motion and baseline wander are often embedded with ECG signals during acquisition and transmission. In this paper, an automatic ECG signal enhancement technique is proposed to remove noise components from time-frequency domain represented noisy ECG signal. Stockwell transform (S-Transform) is used in this work to represent the noisy ECG signal in time-frequency domain. Next, masking and filtering technique is applied to remove unwanted noise components from time-frequency domain. The proposed technique does not require any prior information like R-peak position or reference signal as auxiliary signal. This method is evaluated on ECG signals which are available in MIT-BIH Arrhythmia database. The experimental results demonstrate that the proposed method shows better signal to noise ratio (SNR) and lower root means square error (RMSE) compared to earlier reported wavelet transform with soft thresholding (WT-Soft) and wavelet transform with subband dependent threshold (WT Subband) based technique. To quantify the significant difference among all methods, the performances of different ECG enhancement techniques at 1.25dB input SNR level are compared using analysis of variance (ANOVA) based statistical evaluation technique and it is seen that the proposed method yields superior performance compared to other methods. R-peak detection test is also conducted on enhanced ECG signal in addition to SNR and RMSE to evaluate the quality of biology-related information preserved in the enhanced ECG signal. The performance of R-peak detection for denoised ECG signals, in terms of sensitivity and positive predictivity using proposed enhancement method, is also better than WT Soft, WT-Subband methods, and validates the superiority of the proposed method. PMID- 23668341 TI - An evaluation of the effects of wavelet coefficient quantisation in transform based EEG compression. AB - In recent years, there has been a growing interest in the compression of electroencephalographic (EEG) signals for telemedical and ambulatory EEG applications. Data compression is an important factor in these applications as a means of reducing the amount of data required for transmission. Allowing for a carefully controlled level of loss in the compression method can provide significant gains in data compression. Quantisation is easy to implement method of data reduction that requires little power expenditure. However, it is a relatively simple, non-invertible operation, and reducing the bit-level too far can result in the loss of too much information to reproduce the original signal to an appropriate fidelity. Other lossy compression methods allow for finer control over compression parameters, generally relying on discarding signal components the coder deems insignificant. SPIHT is a state of the art signal compression method based on the Discrete Wavelet Transform (DWT), originally designed for images but highly regarded as a general means of data compression. This paper compares the approaches of compression by changing the quantisation level of the DWT coefficients in SPIHT, with the standard thresholding method used in SPIHT, to evaluate the effects of each on EEG signals. The combination of increasing quantisation and the use of SPIHT as an entropy encoder has been shown to provide significantly improved results over using the standard SPIHT algorithm alone. PMID- 23668342 TI - Reducing redundancy in wireless capsule endoscopy videos. AB - We eliminate similar frames from a wireless capsule endoscopy video of the human intestines to maximize spatial coverage and minimize the redundancy in images. We combine an intensity correction method with a method based an optical flow and features to detect and reduce near-duplicate images acquired during the repetitive backward and forward egomotions due to peristalsis. In experiments, this technique reduced duplicate image of 52.3% from images of the small intestine. PMID- 23668343 TI - Fuzzy logic based anaesthesia monitoring systems for the detection of absolute hypovolaemia. AB - Anaesthesia monitoring involves critical diagnostic tasks carried out amongst lots of distractions. Computers are capable of handling large amounts of data at high speed and therefore decision support systems and expert systems are now capable of processing many signals simultaneously in real time. We have developed two fuzzy logic based anaesthesia monitoring systems; a real time smart anaesthesia alarm system (RT-SAAM) and fuzzy logic monitoring system-2 (FLMS-2), an updated version of FLMS for the detection of absolute hypovolaemia. This paper presents the design aspects of these two systems which employ fuzzy logic techniques to detect absolute hypovolaemia, and compares their performances in terms of usability and acceptability. The interpretation of these two systems of absolute hypovolaemia was compared with clinicians' assessments using Kappa analysis, RT-SAAM K=0.62, FLMS-2 K=0.75; an improvement in performance by FLMS-2. PMID- 23668344 TI - A mathematical based calculation of a myelinated segment in axons. AB - The brain is a complicated system that controls all of the body's actions and reactions by receiving and processing different stimuli and producing the proper responses. The brain accomplishes this task using various sensory elements such as neurons. The axon is the most important element of the neuron in terms of signal generation and propagation. Although much effort has been made studying the characteristics of the axon, there is no research that focuses on measuring the length of this element from a mathematical point of view. In this paper, we propose for the first time a new mathematical model of the generation of action potentials in the axon. Using this model and the diffusion phenomenon in axons, we propose a characteristic length for the myelinated segments in axons. This mathematically calculated value is corroborated by comparison with values measured by biologists. PMID- 23668345 TI - Wavelet adaptation for automatic voice disorders sorting. AB - Early diagnosis of voice disorders and abnormalities by means of digital speech processing is a subject of interest for many researchers. Various methods are introduced in the literature, some of which are able to extensively discriminate pathological voices from normal ones. Voice disorders sorting, on the other hand, has received less attention due to the complexity of the problem. Although, previous publications show satisfactory results in classifying one type of disordered voice from normal cases, or two different types of abnormalities from each other, no comprehensive approach for automatic sorting of vocal abnormalities has been offered yet. In this paper, a solution for this problem is suggested. We create a powerful wavelet feature extraction approach, in which, instead of standard wavelets, adaptive wavelets are generated and applied to the voice signals. Orthogonal wavelets are parameterized via lattice structure and then, the optimal parameters are investigated through an iterative process, using the genetic algorithm (GA). GA is guided by the classifier results. Based on the generated wavelet, a wavelet-filterbank is constructed and the voice signals are decomposed to compute eight energy-based features. A support vector machine (SVM) then classifies the signals using the extracted features. Experimental results show that six various types of vocal disorders: paralysis, nodules, polyps, edema, spasmodic dysphonia and keratosis are fully sorted via the proposed method. This could be a successful step toward sorting a larger number of abnormalities associated with the vocal system. PMID- 23668346 TI - Segmentation of microarray images using pixel classification-comparison with clustering-based methods. AB - OBJECTIVE: DNA microarray technology yields expression profiles for thousands of genes, in a single hybridization experiment. The quantification of the expression level is performed using image analysis. In this paper we introduce a supervised method for the segmentation of microarray images using classification techniques. The method is able to characterize the pixels of the image as signal, background and artefact. METHODS AND MATERIAL: The proposed method includes five steps: (a) an automated gridding method which provides a cell of the image for each spot. (b) Three multichannel vector filters are employed to preprocess the raw image. (c) Features are extracted from each pixel of the image. (d) The dimension of the feature set is reduced. (e) Support vector machines are used for the classification of pixels as signal, background, artefacts. The proposed method is evaluated using both real images from the Stanford microarray database and simulated images generated by a microarray data simulator. The signal and the background pixels, which are responsible for the quantification of the expression levels, are efficiently detected. RESULTS: A quality measure (qindex) and the pixel-by-pixel accuracy are used for the evaluation of the proposed method. The obtained qindex varies from 0.742 to 0.836. The obtained accuracy for the real images is about 98%, while the accuracies for the good, normal and bad quality simulated images are 96, 93 and 71%, respectively. The proposed classification method is compared to clustering-based techniques, which have been proposed for microarray image segmentation. This comparison shows that the classification based method reports better results, improving the performance by up to 20%. CONCLUSIONS: The proposed method can be used for segmentation of microarray images with high accuracy, indicating that segmentation can be improved using classification instead of clustering. The proposed method is supervised and it can only be used when training data are available. PMID- 23668347 TI - Analysis of the effects of different pulsatile inlet profiles on the hemodynamical properties of blood flow in patient specific carotid artery with stenosis. AB - In this study the biomechanical characteristics of a realistic carotid artery [3] are studied numerically using different inlet velocity profiles. Several experimental data measured [32] at the common carotid artery are used as inlet boundary conditions. Computation domain is generated using computed tomography (CT) data of a real patient. Three dimensional (3D) transient NS equations are solved, in this actual domain, using the proposed boundary conditions. Effects of different input conditions on the results of simulation are discussed. Main parameters such as velocity profiles, wall shear stress (WSS) and pressure distributions are investigated at the critical parts of the carotid artery such as bifurcation and sinusoidal enlargement regions. Results show that the input boundary conditions and slope/curvature discontinuities in the realistic geometry have strong relationship with the velocity, pressure and WSS distributions as expected. The most important conclusion obtained from our model is the existence of negative relation between velocity at several inner points of the internal carotid artery and velocity at the inlet of the common carotid artery. PMID- 23668348 TI - An ensemble of SVM classifiers based on gene pairs. AB - In this paper, a genetic algorithm (GA) based ensemble support vector machine (SVM) classifier built on gene pairs (GA-ESP) is proposed. The SVMs (base classifiers of the ensemble system) are trained on different informative gene pairs. These gene pairs are selected by the top scoring pair (TSP) criterion. Each of these pairs projects the original microarray expression onto a 2-D space. Extensive permutation of gene pairs may reveal more useful information and potentially lead to an ensemble classifier with satisfactory accuracy and interpretability. GA is further applied to select an optimized combination of base classifiers. The effectiveness of the GA-ESP classifier is evaluated on both binary-class and multi-class datasets. PMID- 23668349 TI - Computational identification of operon-like transcriptional loci in eukaryotes. AB - Operons are primarily a bacterial phenomenon, not commonly observed in eukaryotes. However, new research indicates that operons are found in higher organisms as well. There are instances of operons found in C. elegans, Drosophila melanogaster and other eukaryotic species. We developed a prototype using positional, structural and gene expression information to identify candidate operons. We focused our efforts on "trans-spliced" operons in which the pre-mRNA is trans-spliced into individual transcripts and subsequently translated, as widely observed in C. elegans and some instances in Drosophila. We identify several candidate operons in Drosophila melanogaster of which two have been subsequently molecularly validated. PMID- 23668350 TI - Structural modeling and simulation studies of human cyclooxygenase (COX) isozymes with selected terpenes: implications in drug designing and development. AB - In view of recently implicated role of COX-1 in human health and diseases, including cancer, development of safe and selective drugs, as COX-1 inhibitor is desirable. Human COX-1 and COX-2 isozymes have been modeled using in silico tools and relative efficacies of terpenoids as their inhibitors have been investigated by docking. The docking analyses of 10 selected terpenoids along with drugs revealed that all of the terpenoids were more potent inhibitors of COX-1 rather than COX-2 with the oleanolic acid as the most potent inhibitor of COX in general (binding energy [-18.68Kcal/mol and -18.25Kcal/mol] and estimated Ki [5.57*10( 8)uM and 11.4*10(-8)uM] for COX-1 and COX-2, respectively) and beta-carotene as most selective inhibitor of COX-1. Furthermore, ibuprofen and aspirin were found to be preferential inhibitor of COX-1 and COX-2, respectively. PMID- 23668351 TI - A primary estimation of the cardiometabolic risk by using artificial neural networks. AB - Estimation of the cardiometabolic risk (CMR) has a leading role in the early prevention of atherosclerosis and cardiovascular diseases. The CMR estimation can be separated into two parts: primary estimation (PE-CMR) that includes easily obtained, non-invasive and low-cost diagnostic methods and secondary estimation (SE-CMR) involving complex, invasive and/or expensive diagnostic methods. This paper presents a PE-CMR solution based on artificial neural networks (ANN) as it would be of great interest to develop a procedure for PE-CMR that would save time and money by extracting the persons with potentially higher CMR and conducting complete SE-CMR tests only on them. ANN inputs are values obtained by using PE CMR methods, i.e. primary risk factors: gender, age, waist-to-height ratio, body mass index, systolic and diastolic blood pressures. ANN output is cmr-coefficient obtained from the number of disturbances in biochemical indicators, i.e. secondary risk factors: HDL-, LDL- and total cholesterol, triglycerides, glycemia, fibrinogen and uric acid. ANN training and testing are done by dataset that includes 1281 persons. The accuracy of our solution is 82.76%. PMID- 23668352 TI - Protein transport in the connecting cilium of a photoreceptor cell: modeling the effects of bidirectional protein transitions between the diffusion-driven and motor-driven kinetic states. AB - Physics of protein transport through the connecting cilium (CC) of a photoreceptor cell is a long-standing question in cellular biology. There is evidence implicating both molecular motor-driven and diffusion-driven modes of intracellular transport. Based on available experimental clues, this paper develops a new model for intraflagellar transport (IFT) of proteins synthesized in the inner segment and transported through the CC to the outer segment of a photoreceptor cell. The model accounts for the competition between two modes of protein transport: molecular motor-driven transport and diffusion. The obtained solutions made it possible to calculate how the number of protein molecules transported through the CC at a given time depends on their diffusivity. Modeling results were compared with published experimental estimates, and conclusions about possible contributions of diffusion to IFT were made. PMID- 23668353 TI - Mammographical mass detection and classification using local seed region growing spherical wavelet transform (LSRG-SWT) hybrid scheme. AB - The purpose of this study is to implement accurate methods of detection and classification of benign and malignant breast masses in mammograms. Our new proposed method, which can be used as a diagnostic tool, is denoted Local Seed Region Growing-Spherical Wavelet Transform (LSRG-SWT), and consists of four steps. The first step is homomorphic filtering for enhancement, and the second is detection of the region of interests (ROIs) using a Local Seed Region Growing (LSRG) algorithm, which we developed. The third step incoporates Spherical Wavelet Transform (SWT) and feature extraction. Finally the fourth step is classification, which consists of two sequential components: the 1st classification distinguishes the ROIs as either mass or non-mass and the 2nd classification distinguishes the masses as either benign or malignant using a Support Vector Machine (SVM). The mammograms used in this study were acquired from the hospital of Istanbul University (I.U.) in Turkey and the Mammographic Image Analysis Society (MIAS). The results demonstrate that the proposed scheme LSRG-SWT achieves 96% and 93.59% accuracy in mass/non-mass classification (1st component) and benign/malignant classification (2nd component) respectively when using the I.U. database with k-fold cross validation. The system achieves 94% and 91.67% accuracy in mass/non-mass classification and benign/malignant classification respectively when using the I.U. database as a training set and the MIAS database as a test set with external validation. PMID- 23668354 TI - Functional performance of aCGH design for clinical cytogenetics. AB - Array-comparative genomic hybridization (aCGH) technology enables rapid, high resolution analysis of genomic rearrangements. With the use of it, genome copy number changes and rearrangement breakpoints can be detected and analyzed at resolutions down to a few kilobases. An exon array CGH approach proposed recently accurately measures copy-number changes of individual exons in the human genome. The crucial and highly non-trivial starting task is the design of an array, i.e. the choice of appropriate (multi)set of oligos. The success of the whole high level analysis depends on the quality of the design. Also, the comparison of several alternative designs of array CGH constitutes an important step in development of new diagnostic chip. In this paper, we deal with these two often neglected issues. We propose a new approach to measure the quality of array CGH designs. Our measures reflect the robustness of rearrangements detection to the noise (mostly experimental measurement error). The method is parametrized by the segmentation algorithm used to identify aberrations. We implemented the efficient Monte Carlo method for testing noise robustness within DNAcopy procedure. Developed framework has been applied to evaluation of functional quality of several optimized array designs. PMID- 23668355 TI - Computer-aided identification of EGFR tyrosine kinase inhibitors using ginsenosides from Panax ginseng. AB - Natural products have served as structural resources in the history of drug discovery for cancer therapy. Among these natural products, Korean Panax ginseng serves as a potential anti-cancer medicinal plant. To determine the anti-cancer activities of Korean P. ginseng active compounds, we performed pharmacophore based virtual screening and molecular docking studies on EGFR (epidermal growth factor receptor) tyrosine kinase domain. The EGFR family tyrosine kinase receptor is a cell surface receptor that regulates diverse biological processes including cell proliferation, differentiation, survival, and apoptosis. Over expression of EGFR tyrosine kinase domain associated with the development and progression of numerous human cancers. In our study, we developed the best pharmacophore model (Hypo1) using a diverse training set and validated by Fischer's randomization, a test set, and a decoy set. The best validated model was employed in the virtual screening of P. ginseng compound database. Further, chosen molecules were evaluated by applying ADMET screening and molecular docking studies. Finally, 14 compounds were obtained based on binding affinity scores and interactions with protein active site residues. These final lead compounds from P. ginseng can be used in the designing of new EGFR tyrosine kinase inhibitors. PMID- 23668356 TI - A modular approach to computer-aided auscultation: analysis and parametric characterization of murmur acoustic qualities. AB - In the present work, a modularized approach to computer-aided auscultation based on the traditional cardiac auscultation of murmur is proposed. Under such an approach, the present paper concerns the task of evaluating murmur acoustic quality character. The murmurs were analyzed in their time-series representation, frequency representation as well as time-frequency representation, allowing extraction of interpretable features based on their signal structural and spectral characters. The features were evaluated using scatter plots, receiver operating characteristic curves (ROC), and numerical experiments using a KNN classifier. The possible physiological and hemodynamical associations with the feature set are made. The implication and advantage of the modular approach are discussed. PMID- 23668357 TI - Triple therapy with deferiprone, idebenone and riboflavin in Friedreich's ataxia open-label trial. AB - OBJECTIVES: The objective of the study was to test the efficacy, safety and tolerability of triple therapy with deferiprone, idebenone and riboflavin in Friedreich's ataxia (FRDA) patients in a clinical pilot study. PATIENTS AND METHODS: Patients included in this study were 10 males and three females, 14-61 years of age (average 30.2 +/- 12.1), diagnosed with FRDA with normal ventricular function. Patients were treated with triple therapy with deferiprone at 5-25 mg/kg/day, idebenone at 10-20 mg/kg/day and riboflavin at 10-15 mg/kg/day for 15 45 months. The efficacy of this triple therapy was assessed by change from baseline on the scale for the assessment and rating of ataxia (SARA) and by the change from baseline in echocardiogram parameters. RESULTS: Four patients discontinued due to adverse events (AEs) related with deferiprone. The annual worsening rate (AWR) was estimated in this series as 0.96 (CI 95%: 0.462-1.608) SARA score, whereas AWR for our FRDA cohort was estimated as 2.05 +/- 1.23 SARA score. LVMI only decreased by 6.5 g/m(2) (6.2%) at the end of the first year of therapy. LVEF remained stable, except in case of three patients. CONCLUSION: Our results seem to indicate some uncertain benefit on the neurological and heart functions of this triple therapy in FRDA. PMID- 23668358 TI - Experimental investigation of interactions between the temperature field and biofouling in a synthetic treated sewage stream. AB - Biofouling causes significant losses in efficiency in heat exchangers recovering waste heat from treated sewage. The influence of the temperature field on biofouling was investigated using a flat plate heat exchanger which simulated the channels in a plate and frame unit. The test surface was a 316 stainless steel plate, and a solution of Bacillus sp. and Aeromonas sp. was used as a model process liquid. The test cell was operated under co-current, counter-current, and constant wall temperature configurations, which gave different temperature distributions. Biofouling was monitored via changes in heat transfer and biofilm thickness. The effect of uniform temperature on biofouling formation was similar to the effect of uniform temperature on planktonic growth of the organisms. Further results showed that the temperature field, and particularly the wall temperature, influenced the rate of biofouling strongly. The importance of wall temperature suggests that fouling could be mitigated by using different configurations in summer and winter. PMID- 23668359 TI - Endothelium-independent relaxant effect of Rubus coreanus extracts in corpus cavernosum smooth muscle. AB - INTRODUCTION: Rubus coreanus is a perennial shrub native to the southern part of the Korean peninsula. Although it is known that R. coreanus has a dose-dependent relaxation effect on rabbit corpus cavernosum (CC), the exact mechanism of action by which R. coreanus work is not fully known. AIMS: To elucidate the direct effects of unripe R. coreanus extract (RCE) on CC smooth muscle cells. METHODS: Dried unripe R. coreanus fruits were pulverized and extracted with 95% ethanol. Isolated rabbit CC strips were mounted in an organ-bath system, and the effects of RCE were evaluated. To estimate [Ca(2+)]i , we used a Fura-2 fluorescent technique. MAIN OUTCOME MEASURES: The effects of unripe RCE on ion channels and the intracellular Ca(2+) concentration ([Ca(2+)]i ) of CC. RESULTS: RCE effectively relaxed phenylephrine (PE)-induced tone in rabbit CC, and removal of the endothelium did not completely abolish the relaxation effect of RCE. Tetraethylammonium (1 mM) did not inhibit RCE-induced relaxation in strips precontracted by PE in the organ bath. However, CaCl2 -induced constriction of CC strips, bathed in Ca(2+)-free buffer and primed with PE, was abolished by RCE. In addition, RCE decreased basal [Ca(2+)]i in corporal smooth muscle cells. The increases of [Ca(2+)]i evoked by 60 mM K(+)-containing solution in A7r5 cells were suppressed by RCE, and RCE relaxed KCl-induced tone in endothelium-free CC, which indicated that RCE blocked the voltage-dependent Ca(2+) channels (VDCCs). RCE decreased basal [Ca(2+)]i and the [Arg8]-vasopressin-induced [Ca(2+)]i increases in A7r5 cells, and RCE inhibited the contraction of endothelium-free CC induced by PE in Ca(2+)-free solution, which suggested that RCE might act as a modulator of corporal smooth muscle cell tone by inhibiting Ca(2+) release from sarcoplasmic reticulum. CONCLUSION: RCE acts through endothelium-independent and endothelium-dependent pathways to relax CC. RCE may inhibit VDCCs and Ca(2+) release from sarcoplasmic reticulum. PMID- 23668360 TI - Natural variation in Early flowering1 contributes to early flowering in japonica rice under long days. AB - Natural variation in heading-date genes enables rice, a short-day (SD) plant, to flower early under long-day (LD) conditions at high latitudes. Through analysis of heading-date quantitative trait loci (QTL) with F7 recombinant inbred lines from the cross of early heading 'H143' and late heading 'Milyang23 (M23)', we found a minor-effect Early Heading3 (EH3) QTL in the Hd16 region on chromosome 3. We found that Early flowering1 (EL1), encoding casein kinase I (CKI), is likely to be responsible for the EH3/Hd16 QTL, because a missense mutation occurred in the highly conserved serine/threonine kinase domain of EL1 in H143. A different missense mutation was found in the EL1 kinase domain in Koshihikari. In vitro kinase assays revealed that EL1/CKI in H143 and Koshihikari are non-functional. In F7:9 heterogeneous inbred family-near isogenic lines (HNILs), HNIL(H143) flowered 13 days earlier than HNIL(M23) in LD, but not in SD, in which EL1 mainly acts as a LD-dependent flowering repressor, down-regulating Ehd1 expression. In the world rice collection, two types of non-functional EL1 variants were found in japonica rice generally cultivated at high latitudes. These results indicate that natural variation in EL1 contributes to early heading for rice adaptation to LD in temperate and cooler regions. PMID- 23668361 TI - Utilisation of the healthcare system for authentic early experience placements. AB - INTRODUCTION: Authentic early experience in clinical contexts adds interest and relevance to basic medical education, and is regarded positively by both learners and teachers. However, with the recent expansion of medical education, the healthcare system appears close to reaching its capacity for student supervision. This study explores the utilisation of the healthcare system for early clinical placements. METHODS: A secondary analysis was conducted of data from the Medical Schools Outcomes Database, collected from the 2010 annual questionnaire, focusing on the timing, duration and location of clinical placements during 2009 within the first half of basic medical education programs in Australia. RESULTS: Data was received for 67% of Australian medical students, reporting a total of 16 812 early clinical placements that occupied 97 319 days of supervised time in a wide variety of hospital, general practice and Indigenous health contexts, both urban and rural, across the Australian healthcare system. These early placements occupied about 16% of total clinical placement time for all students in all training years during 2009. The majority of these placements were for only a few hours or days; exceptions were longitudinal placements in regional and rural communities at a minority of schools. CONCLUSION: Early clinical placements may pose significant resource costs for placement providers, particularly supervision time and expertise. As medical education expands and the teaching capacity of the Australian healthcare system appears to reach its limits, it may be necessary to allocate placements according to their specific learning outcomes, prioritise more acute settings for more senior students, and increase capacity in less acute health and social care settings. PMID- 23668362 TI - Cancer immunotherapies, their safety and toxicity. AB - INTRODUCTION: Cancer immunotherapy encompasses a wide range of treatment modalities that harness the anti-tumor effects of the immune system. Some immunotherapies broadly activate the immune system while others precisely target distinct tumor antigens. Because of this heterogeneity, the side effects associated with immunotherapy can be mild and localized or more severe and systemic. AREAS COVERED: Cytokines, adoptive cellular therapies and vaccines are the most commonly used immunotherapies for the treatment of a number of malignancies and have been used for many decades. Checkpoint blockade has recently emerged as a promising immunotherapy. The biggest benefits of immunotherapy have been demonstrated in melanoma, renal cell carcinoma and hematologic malignancies. Emerging data are highlighting the potential for broad applicability of immunotherapy in a number of solid and hematologic malignancies. EXPERT OPINION: Immunotherapies are slowly becoming integrated into the standard of care in cancer treatment. Promising results using immunotherapy have been reported demonstrating complete remissions and cures in many patients with aggressive malignancies. The complexity and cost of engineering and administering of some forms of immunotherapy limit their use to distinct patient populations. High-throughput and cost-effective techniques are being used to broaden the applications of immunotherapy to treat cancer patients. PMID- 23668363 TI - Induction of long intergenic non-coding RNA HOTAIR in lung cancer cells by type I collagen. AB - BACKGROUND: The tumor microenvironment is a crucial determinant in tumor progression. Interstitial extracellular matrix (ECM), such as type I collagen (Col-1), is aberrantly enriched in the tumor microenvironment and promotes tumor progression. Long intergenic non-coding RNAs (lincRNA) are a new family of regulatory RNAs that modulate fundamental cellular processes via diverse mechanisms. FINDINGS: We investigated whether the expression of lincRNAs was regulated by the tumor promoting Col-1. In a three-dimensional organotypic culture model using the reconstituted basement membrane ECM Matrigel (rBM 3-D), supplementation of Col-1 disrupted acini, a differentiation feature of well differentiated lung adenocarcinoma cells, and concurrently induced the expression of a tumor-promoting lincRNA, HOX transcript antisense RNA (HOTAIR). Induction of HOTAIR by Col-1 was diminished by a neutralizing antibody against the Col-1 receptor alpha2beta1 integrin. Col-1 activates the expression of a reporter gene controlled by the human HOTAIR promoter. Moreover the expression of HOTAIR and Col-1 was concurrently up-regulated in human non-small cell lung cancer. CONCLUSIONS: Our findings indicate that tumor-promoting Col-1 up-regulates the expression of HOTAIR in NSCLC cells. These initial results warrant further investigation of HOTAIR and other lincRNA genes in lung tumorigenesis. PMID- 23668364 TI - Peptide nucleic acid (PNA)-DNA duplexes: comparison of hybridization affinity between vertically and horizontally tethered PNA probes. AB - We compare the PNA-DNA duplex hybridization characteristics of vertically tethered and new horizontally tethered PNA probes on solid surfaces. The horizontal 15-mer PNA probe has been synthesized with linker molecules attached at three locations (gamma-points) positioned along the PNA backbone that provides covalent attachment of the probe with the backbone aligned parallel to the surface, which is important for DNA hybridization assays that use electric field effect sensors for detection. A radioactive labeled assay and real-time surface plasmon resonance (SPR) biosensor are used to assess the probe surface density, nonspecific binding, and DNA hybridization affinity, respectively, of the new PNA probe configuration. The estimated equilibrium dissociation constants of the horizontally tethered duplex and the vertically tethered duplex are of the same order of magnitude (KD ~ 5 nM), which indicates a sufficient hybridization affinity for many electronic biosensors that benefit from the horizontal alignment, which minimizes the effects of counterion screening. PMID- 23668365 TI - Scanning-Raman-microscopy for the statistical analysis of covalently functionalized graphene. AB - We report on the introduction of a systematic method for the quantitative and reliable characterization of covalently functionalized graphene based on Scanning Raman-Microscopy (SRM). This allows for recording and analyzing several thousands of Raman spectra per sample and straightforward display of various Raman properties and their correlations with each other in histograms or coded 2D plots. In this way, information about the functionalization efficiency of a given reaction, the reproducibility of the statistical analysis, and the sample homogeneity can be easily deduced. Based on geometric considerations, we were also able to provide, for the first time, a correlation between the mean defect distance of densely packed point defects and the Raman ID/IG ratio directly obtained from the statistical analysis. This proved to be the prerequisite for determining the degree of functionalization, termed theta. As model compounds, we have studied a series of arylated graphenes (GPh) for which we have developed new synthetic procedures. Both graphite and graphene grown by chemical vapor deposition (CVD) were used as starting materials. The best route toward GPh consisted of the initial reduction of graphite with a Na/K alloy in 1,2 dimethoxyethane (DME) as it yields the highest overall homogeneity of products reflected in the widths of the Raman ID/IG histograms. The Raman results correlate nicely with parallel thermogravimetric analysis (TGA) coupled with mass spectrometry (MS) studies. PMID- 23668366 TI - Stepwise pore size reduction of ordered nanoporous silica materials at angstrom precision. AB - A facile vacuum-assisted vapor deposition process has been developed to control the pore size of ordered mesoporous silica materials in a stepwise manner with angstrom precision, providing an unprecedented paradigm for screening a designer hydrophobic drug nanocarrier with optimized pore diameter to maximize drug solubility. PMID- 23668367 TI - Effect of lipid and fatty acid composition of phospholipid vesicles on long-term stability and their response to Staphylococcus aureus and Pseudomonas aeruginosa supernatants. AB - Phospholipid vesicles have been the focus of attention as potential vehicles for drug delivery, as they are biomimetic, easy to produce, and contain an aqueous compartment which can be used to carry hydrophilic material, such as drugs or dyes. Lipid vesicles used for this purpose present a particular challenge, as they are not especially stable and can rapidly break down and release their contents away from the target area, especially at physiological temperatures/environments. This study aims to investigate optimum methods for vesicle stabilization where the vesicles are employed as part of a system or technology that signals the presence of pathogenic bacteria via the effect of secreted cytolytic virulence factors on a sensor interface. A number of approaches have been investigated and are presented here as a systematic study of the long-term (14 day) stability at 37 degrees C, and at various pHs. The response of vesicles, both in suspension and within hydrogels, to Staphylococcus aureus (RN 4282) and Pseudomonas aeruginosa (PAO1) whole bacteria, and supernatants from overnight cultures of both (containing secreted proteins but free of cells), was measured via a sensitive encapsulated carboxyfluorescein release assay. The results showed that lipid chain length, cholesterol concentration, and stabilization via photopolymer stable components were critical in achieving stability. Finally, dispersion of the optimum vesicle formulation in hydrogel matrixes was investigated, culminating in the in vivo demonstration of a simple prototype wound dressing. PMID- 23668368 TI - Regiospecific 6-endo-annulation of in situ generated 3,4-dienamides/acids: synthesis of delta-lactams and delta-lactones. AB - A novel and efficient method for the construction of alpha-(1,3-dithiolan-2 ylidene) delta-lactam and delta-lactone rings has been developed. It involves the regiospecific 6-endo-annulation of in situ generated 2-(1,3-dithiolan-2-ylidene) 3,4-dienamides/acids from the dehydrative coupling of alpha-oxo ketene dithioacetals with tertiary propargyl alcohols promoted by BF3.Et2O. A range of alpha-(1,3-dithiolan-2-ylidene) delta-lactams and delta-lactones are obtained in good to high yields. In addition, indenes are prepared by using alpha-acetyl ketene dithioacetal as the precursor. PMID- 23668369 TI - Mathematical model for cyclodextrin alteration of bioavailability of organic pollutants. AB - While many cyclodextrin-based applications have been developed to assess or enhance bioavailability of organic pollutants, the choice of cyclodextrin (CD) is largely empirical, with little consideration of pollutant diversity and environmental matrix effects. This study aimed at developing a mathematical model for quantifying CD alteration of bioavailability of organic pollutants. Cyclodextrin appears to have multiple effects, together contributing to its bioavailability-enhancing property. Cyclodextrin is adsorbed onto the adsorbent matrix to different extents. The adsorbed CD is capable of sequestrating organic pollutants, highlighting the role of a pseudophase similar to solid environmental matrix. Aqueous CD can reduce adsorption of organic pollutants via inclusion complexation. The two effects cancel each other to a certain degree, which determines the levels of organic pollutants dissolved (comprising freely dissolved and CD-included forms). Additionally, the CD-included form is nearly identical in biological activity to the free form. A mathematical model of one variable (i.e., CD concentration) was derived to quantify effects of CD on the bioavailability of organic pollutants. Model analysis indicates that alteration of bioavailability of organic pollutants by CD depends on both CD (type and level) and environmental matrix. The selection of CD type and amendment level for a given application may be predicted by the model. PMID- 23668370 TI - Robust closed-loop control of induction and maintenance of propofol anesthesia in children. AB - BACKGROUND: During closed-loop control, a drug infusion is continually adjusted according to a measure of clinical effect (e.g., an electroencephalographic depth of hypnosis (DoH) index). Inconsistency in population-derived pediatric pharmacokinetic/pharmacodynamic models and the large interpatient variability observed in children suggest a role for closed-loop control in optimizing the administration of intravenous anesthesia. OBJECTIVE: To clinically evaluate a robustly tuned system for closed-loop control of the induction and maintenance of propofol anesthesia in children undergoing gastrointestinal endoscopy. METHODS: One hundred and eight children, aged 6-17, ASA I-II, were enrolled. Prior to induction of anesthesia, NeuroSENSETM sensors were applied to obtain the WAVCNS DoH index. An intravenous cannula was inserted and lidocaine (0.5 mg.kg(-1) ) administered. Remifentanil was administered as a bolus (0.5 MUg.kg(-1) ), followed by continuous infusion (0.03 MUg.kg(-1) .min(-1) ). The propofol infusion was closed-loop controlled throughout induction and maintenance of anesthesia, using WAVCNS as feedback. RESULTS: Anesthesia was closed-loop controlled in 102 cases. The system achieved and maintained an adequate DoH without manual adjustment in 87/102 (85%) cases. Induction of anesthesia (to WAVCNS <= 60) was completed in median 3.8 min (interquartile range (IQR) 3.1 5.0), culminating in a propofol effect-site concentration (Ce ) of median 3.5 MUg.ml(-1) (IQR 2.7-4.5). During maintenance of anesthesia, WAVCNS was measured within 10 units of the target for median 89% (IQR 79-96) of the time. Spontaneous breathing required no manual intervention in 91/102 (89%) cases. CONCLUSIONS: A robust closed-loop system can provide effective propofol administration during induction and maintenance of anesthesia in children. Wide variation in the calculated Ce highlights the limitation of open-loop regimes based on pharmacokinetic/pharmacodynamic models. PMID- 23668371 TI - Effect of non-phospholipid-based cationic and phospholipid-based anionic nanosized emulsions on skin retention and anti-inflammatory activity of celecoxib. AB - CONTEXT: Celecoxib (CXB, 0.2 g)-loaded anionic and cationic nanosized emulsions were prepared by a well-established combined emulsification method. OBJECTIVES: To investigate the effect of non-phospholipid-based cationic and phospholipid based anionic emulsions on skin retention and anti-inflammatory activity of CXB. METHODS: Using Keshary-Chien diffusion cells with cellulose acetate membrane or excised rat skin, in vitro release and skin retention of CXB from solution and emulsions were studied. The anti-inflammatory activity was evaluated by the carrageenan-induced hind paw edema method in Wistar rats. RESULTS: The amount of drug released through artificial membrane has decreased from 122.00 +/- 0.70 MUg/cm(2) for the CXB solution to 55.80 +/- 0.70 MUg/cm(2) for anionic emulsion, and then further decreased to 24.79 +/- 0.90 MUg/cm(2) for cationic emulsion. The JSS value obtained with solution, anionic, and cationic emulsions were 6825.79 +/ 920.86, 2513.15 +/- 382.71, and 1925.67 +/- 147.42, respectively. Cationic emulsion showed a significantly higher level (P <= 0.05) of drug accumulation in full-thickness rat skin than anionic emulsion, and a substantially lesser percentage inhibition of edema values compared with both solution and anionic emulsion. DISCUSSION AND CONCLUSION: Sustained drug release together with increased skin accumulation and simultaneously decreased skin permeation as observed with cationic emulsion should substantiate its suitability as a topical delivery vehicle for CXB. PMID- 23668372 TI - Modification of pharmacological activity of nebivolol due to Maillard reaction. AB - Lactose is used as an excipient in solid dosage forms of nebivolol. Ultraviolet spectroscopy, Fourier-transform infrared spectroscopy and differential scanning calorimetry were used to study the interaction between nebivolol and lactose. The formation of a Maillard product was noted in aqueous mixtures of nebivolol and lactose heated at 60 degrees C at unbuffered and buffered alkaline pH. A similar Maillard adduct formation was evident within 15 days in a dry physical mixture of nebivolol and lactose maintained at 40 degrees C and 75% relative humidity in the dark. High-performance liquid chromatography and liquid chromatography-mass spectrometry analyses of the reaction mixtures confirmed the formation of a nebivolol-lactose adduct. The effects of intravenously administered nebivolol and the nebivolol-lactose adduct on the blood pressure and heart rate of anesthetized normotensive rats were investigated. The bradycardic effect of the adduct was significantly less than that of nebivolol. The present investigation reveals an incompatibility between nebivolol and lactose, leading to the loss of the pharmacological activity of nebivolol. Hence, the use of lactose as an excipient in dosage forms of nebivolol, a secondary amine, needs reconsideration. PMID- 23668373 TI - Growth characteristics of human parechovirus 1 to 6 on different cell lines and cross- neutralization of human parechovirus antibodies: a comparison of the cytopathic effect and real time PCR. AB - BACKGROUND: Human parechoviruses (HPeVs) are among the most frequently detected picornaviruses in humans. HPeVs are usually associated with mild gastrointestinal and respiratory symptoms with the exception of HPeV3 which causes neonatal sepsis and CNS infection. Previous studies showed various results in culturing different HPeV genotypes, inducing only a low cytopathic effect (CPE). METHODS: In vitro growth characteristics of the different HPeV genotypes in a range of 10 different cell lines are scored with CPE and measured in the supernatant by real time PCR. In the optimal cell line for each genotype a standard neutralization assay with the available HPeV antibodies (Abs) was performed and scored by CPE and measured by real time PCR. RESULTS: All six HPeV types were able to replicate on the RD99, A549, and Vero cell lines. HPeV1 was the only genotype able to replicate on all cell lines. Most efficient growth of HPeV1, 2, 4, 5, and 6 was shown on the HT29 cell line, while HPeV3 was unable to replicate on HT29. In all cases viral replication could be measured by real time PCR before CPE appeared. The polyclonal Abs available against HPeV1, 2, 4 and 5 all showed neutralization of their respective genotype after 7 days with inhibition of >60% in real time PCR and full inhibition of CPE, although cross-neutralization is shown. Replication of HPeV3 could only be inhibited by 12% by the anti-HPeV3 (aHPeV3) Ab and no inhibition of CPE was shown after 7 days. CONCLUSION: When replication is monitored by PCR, growth of HPeV genotypes 1 to 6 is supported by most of the cell lines tested, where viral replication is measured before appearance of CPE. A combination of HT29 and Vero cells would therefore support replication of all culturable HPeV types, so viral replication could be detected by PCR within 3 days for all genotypes.In addition, we showed efficient neutralization for HPeV1, 2, 4, 5, while cross- neutralization was shown between these types, indicating possible common neutralizing epitopes. For HPeV3 no efficient (cross-) neutralization was shown, indicating different neutralizing epitopes for HPeV3 compared to the other HPeV genotypes. PMID- 23668374 TI - Papules on the hands and feet. PMID- 23668375 TI - The chemokine receptor CCR5 Delta32 allele in natalizumab-treated multiple sclerosis. AB - OBJECTIVE: The chemokine receptor CCR5 may be important for the recruitment of pathogenic T cells to the CNS in multiple sclerosis (MS). We hypothesized that this chemokine receptor might still be important for T-cell migration during treatment with anti-very late antigen (VLA)-4 antibody. We therefore analysed whether natalizumab-treated MS patients carrying the CCR5 Delta32 deletion allele, which results in reduced expression of CCR5 on the cell surface, had lower disease activity. METHODS: CCR5 Delta32 was analysed in 212 natalizumab treated MS patients. RESULTS: CCR5 Delta32 status had no significant impact on the frequency of relapses 1 year prior to natalizumab treatment or during the first 48 weeks of treatment. The multiple sclerosis severity score (MSSS) was significantly lower at baseline in patients carrying CCR5 Delta32 (P = 0.031). CONCLUSIONS: CCR5 Delta32 is not associated with lower disease activity in MS patients treated with natalizumab. We found lower MSSS scores in patients carrying CCR5 Delta32 compared with the remaining patients, which is consistent with previous studies reporting an association with a more favourable disease course. Further studies are, however, needed before the relationship between CCR5 Delta32 and disease activity in MS can be definitely established. PMID- 23668376 TI - The importance of pharmacokinetic studies in drug development. PMID- 23668377 TI - Reconciling theories for metabolic scaling. AB - Metabolic theory specifies constraints on the metabolic organisation of individual organisms. These constraints have important implications for biological processes ranging from the scale of molecules all the way to the level of populations, communities and ecosystems, with their application to the latter emerging as the field of metabolic ecology. While ecologists continue to use individual metabolism to identify constraints in ecological processes, the topic of metabolic scaling remains controversial. Much of the current interest and controversy in metabolic theory relates to recent ideas about the role of supply networks in constraining energy supply to cells. We show that an alternative explanation for physicochemical constraints on individual metabolism, as formalised by dynamic energy budget (DEB) theory, can contribute to the theoretical underpinning of metabolic ecology, while increasing coherence between intra- and interspecific scaling relationships. In particular, we emphasise how the DEB theory considers constraints on the storage and use of assimilated nutrients and derive an equation for the scaling of metabolic rate for adult heterotrophs without relying on optimisation arguments or implying cellular nutrient supply limitation. Using realistic data on growth and reproduction from the literature, we parameterise the curve for respiration and compare the a priori prediction against a mammalian data set for respiration. Because the DEB theory mechanism for metabolic scaling is based on the universal process of acquiring and using pools of stored metabolites (a basal feature of life), it applies to all organisms irrespective of the nature of metabolic transport to cells. Although the DEB mechanism does not necessarily contradict insight from transport-based models, the mechanism offers an explanation for differences between the intra- and interspecific scaling of biological rates with mass, suggesting novel tests of the respective hypotheses. PMID- 23668378 TI - 2012 Annual Meeting of the Safety Pharmacology Society: spotlight on targeted oncology medicines. AB - INTRODUCTION: The 12th Annual Meeting of the Safety Pharmacology (SP) Society (SPS) covered various subjects among which safety issues concerning oncolytic drugs are reviewed and discussed in details. AREAS COVERED: The challenges faced by a medical oncologist during the development of new anticancer medicines were the focus of the keynote address. Romidepsin, a drug initially abandoned because of serious cardiotoxicity in dogs, was successfully rescued for clinical evaluation by tailoring the dose regimen to mitigate cardiac toxicity risks. The integration of SP endpoints into long-term toxicology offers the advantage of determining safety on organ function during chronic exposures, whilst also supporting the principal goals of the 3Rs framework. State-of-the-art imaging technologies can provide valuable, interpretable and translational (human to mouse to human) data for the detection of myocardial function impairment. The future growth of SP was discussed in terms of areas in need of innovative approaches as identified, in particular, in a worldwide sharing of SP data and methodologies. EXPERT OPINION: The need for epochal changes to ensure a bright future for SP should be promoted by the SPS. These comprise chiefly the expansion of the SP birth charter from primarily a regulatory discipline to include an efficiently organized experimental discovery science for which the name Exploratory SP (ESP) is proposed. Its mission would be the early and cost effective assessment of the safety of clinical drug candidates on organ function based on mechanistic grounds and conducted outside of current expensive and time consuming regulatory frontiers and constraints. The implementation of a high standard ESP discipline could also promote the gradual replacement of standalone safety investigations with SP assays performed within long-term toxicity studies. PMID- 23668379 TI - The global online sexuality survey (GOSS): The United States of America in 2011 Chapter III--Premature ejaculation among English-speaking male Internet users. AB - INTRODUCTION: The Global Online Sexuality Survey (GOSS) is a worldwide epidemiologic study of sexuality and sexual disorders. In 2010, the first report of GOSS came from the Middle East. AIM: This report studies the prevalence rate of premature ejaculation (PE) in the U.S. as of 2011-2012 and evaluates risk factors for PE. METHODS: GOSS was randomly deployed to English-speaking male web surfers in the USA via paid advertising on Facebook(r), comprising 146 questions. MAIN OUTCOME MEASURES: Prevalence of PE as per the International Society of Sexual Medicine's (ISSM) definition. RESULTS: With a mean age of 52.38 years +/- 14.5, 1,133 participants reported on sexual function. As per the ISSM definition of PE, the prevalence rate of PE in the USA as of 2011 was 6.3%. This is in contrast to 49.6% as per the Premature Ejaculation Diagnostic Tool (PEDT), 77.6% as per unfiltered subjective reports, and 14.4% as per subjective reporting on more consistent basis. 56.3% of the latter reported lifelong PE. 63.2% could be classified as having natural variable PE. Erectile dysfunction is a possible predisposing factor for acquired PE, while genital size concerns may predispose to lifelong PE. Age, irregular coitus, circumcision, and the practice of masturbation did not pose a risk for PE, among other risk factors. Oral treatment for PE was more frequently used and reported to be more effective than local anesthetics, particularly in those with lifelong PE. CONCLUSION: Applying the ISSM definition, prevalence of PE is far less than diagnosed by other methods, 6.3% among Internet users in USA as of the year 2011. PEDT measures both lifelong and acquired PE, in addition to 35% men with premature-like ejaculatory dysfunction, making it inaccurate for isolating lifelong and acquired PE cases. PMID- 23668380 TI - Anti-biofilm activities of quercetin and tannic acid against Staphylococcus aureus. AB - Staphylococcus aureus is a leading cause of nosocomial infections because of its resistance to diverse antibiotics. The formation of a biofilm is one of the mechanisms of drug resistance in S. aureus. The anti-biofilm abilities of 498 plant extracts against S. aureus were examined. Seventy-two plant extracts belonging to 59 genera and 38 families were found to significantly inhibit the formation of biofilms of S. aureus without affecting the growth of planktonic cells. The most active extract, from Alnus japonica, inhibited the formation of biofilms by three S. aureus strains by >70% at 20 MUg ml(-1). Transcriptional analyses showed that extract of A. japonica repressed the intercellular adhesion genes icaA and icaD most markedly. Quercetin and tannic acid are major anti biofilm compounds in the extract of A. japonica. Additionally, the extract of A. japonica and its component compound quercetin, reduced hemolysis by S. aureus. This phenomenon was not observed in the treatment with tannic acid. This study suggests that various plant extracts, such as quercetin and tannic acid, could be used to inhibit the formation of recalcitrant biofilms of S. aureus. PMID- 23668381 TI - Use of seclusion: finding the voice of the patient to influence practice. AB - Seclusion for escalating behavior in psychiatric patients has been a controversial intervention over the past 3 decades. The current study investigated the experience of seclusion from the perspective of inpatient psychiatric patients in the mid-western United States. Twelve patients were interviewed about their experiences; the interviews were transcribed into a written text. A phenomenological method was used to analyze the text, and themes were generated. Three themes emerged: (a) Patient Hope for Respect and Open Communication described patients' desires for discussion about their individual problems before their behavior escalated; (b) Patient Emotional Response to the Seclusion Process described accelerating emotions such as anxiety and anger. Patients perceived disrespect from staff prior to and during seclusion; and (c) Patient Insight into Behavior and the Importance of Positive Coping Skills described the importance of debriefing with staff and learning positive coping skills. Further improved education for nurses is needed to help manage psychiatric patients, for it is the goal of the mental health profession to understand the reasons these seclusion episodes occur and to directly take the steps to eliminate the need for the seclusion process entirely. PMID- 23668382 TI - Sexting: serious problems for youth. AB - Youth engaging in sexting (texting plus sex) includes behaviors such as sending, receiving, or forwarding of nude or partially nude images via cell phones. The true prevalence of tweens and teens engaging in sexting is unclear. This might be because of the general secrecy of the behavior, the rapid advances in technology, and the lack of a clear definition that accounts for the added developmental factors (e.g., peak sexual development, impulsivity). Additionally, there is a lack of recognition of the consequences and increased risks of sexting (e.g., shame and guilt, earlier sexual behavior, bullying, incarceration, substance abuse, depression, suicide) for youth as a vulnerable population. The purpose of this article is to examine sexting behaviors among youth by exploring factors specific to today's adolescent population that may influence the prevalence and outcomes of sexting behavior. Implications for nursing practice, including the assessment, intervention, and evaluation that is needed to treat adolescents affected by sexting, are discussed. PMID- 23668383 TI - Educating law enforcement officers about mental illness: nurses as teachers. AB - With the advent of new psychotherapeutic agents, many individuals with mental illness are living successfully in communities. However, they may become involved in situations with law enforcement officers, which may lead to potentially negative experiences. During police academy training, new officers may receive training focused on optimizing interactions with people with physical/mental disabilities; however, this may be inadequate to enable effective communication between officers and individuals with mental illness. Given the growing prevalence of mental illness, it is increasingly likely that officers will encounter such individuals. An exemplar educational program geared to staff police officers in the city of Orange, California is described. This program provides law enforcement officers with training about psychiatric disorders and affected individuals, effective communication skills, and interventions that may assist in management of field contacts with individuals with mental illness. PMID- 23668384 TI - In vitro evaluation of anti-infective activity of a Lactobacillus plantarum strain against Salmonella enterica serovar Enteritidis. AB - BACKGROUND: Salmonella enterica serovar Enteritidis infections are known to exhibit worldwide prevalence with increased morbidity and mortality. The conventional strategies like antibiotic therapy and vaccination have not only proved to be of sub-optimal efficacy but also led to the development of multidrug resistant strains of Salmonella. Antimicrobial activities of probiotics against various enteropathogens and other health promoting effects have assumed greater significance in recent years. The present study aims to evaluate the efficacy of a Lactobacillus plantarum strain (KSBT 56, isolated from a traditional food product of India), in preventing Salmonella enterica serovar Enteritidis growth and pathogenicity in vitro. METHODS AND RESULTS: The cell free culture supernatant (CFCS) of KSBT 56 strain notably inhibited the growth of Salmonella Enteritidis without affecting the growth of other gram-positive lactic acid bacteria. The isolated KSBT 56 strain produces lactic acid similar to other standard probiotic strains like Lactobacillus plantarum MTCC 1407. The free radical production by KSBT 56 strain was studied by using sodC mutant of S. Enteritidis, which exhibited reduced growth in the presence of CFCS of the KSBT 56 strain, indicating the inhibitory activity of free radicals on the growth of S. Enteritidis. Our results also showed a significant reduction in the biofilm forming ability of Salmonella Enteritidis in the presence of the KSBT 56 strain (2 log cfu/ml, p = 0.01). Further, the anti-infective characteristics of KSBT 56 strain was validated by gentamicin protection assay which revealed 80% reduction in the invasion of Salmonella Enteritidis to HCT-116 cell line (Salmonella Enteritidis and KSBT 56 in a 1:1 ratio) and delayed addition of Salmonella Enteritidis by 1 h. Similarly, the reduced adhesion of Salmonella to the HCT-116 cells was observed along with the down regulation of hilA gene of Salmonella Pathogenicity Island 1 (SPI1) indicating that they might have acted synergistically to decrease the invasion of the pathogen into the cell line. CONCLUSIONS: KSBT 56 strain effectively inhibited the growth, invasion and the biofilm forming ability of Salmonella Enteritidis without inhibiting the growth of other Lactobacillus strains. Overall, our result suggested that KSBT 56 can be used as a potential probiotic strain with considerable beneficial effects on the host. PMID- 23668385 TI - The Arabidopsis gibberellin methyl transferase 1 suppresses gibberellin activity, reduces whole-plant transpiration and promotes drought tolerance in transgenic tomato. AB - Previous studies have shown that reduced gibberellin (GA) level or signal promotes plant tolerance to environmental stresses, including drought, but the underlying mechanism is not yet clear. Here we studied the effects of reduced levels of active GAs on tomato (Solanum lycopersicum) plant tolerance to drought as well as the mechanism responsible for these effects. To reduce the levels of active GAs, we generated transgenic tomato overexpressing the Arabidopsis thaliana GA METHYL TRANSFERASE 1 (AtGAMT1) gene. AtGAMT1 encodes an enzyme that catalyses the methylation of active GAs to generate inactive GA methyl esters. Tomato plants overexpressing AtGAMT1 exhibited typical GA-deficiency phenotypes and increased tolerance to drought stress. GA application to the transgenic plants restored normal growth and sensitivity to drought. The transgenic plants maintained high leaf water status under drought conditions, because of reduced whole-plant transpiration. The reduced transpiration can be attributed to reduced stomatal conductance. GAMT1 overexpression inhibited the expansion of leaf epidermal cells, leading to the formation of smaller stomata with reduced stomatal pores. It is possible that under drought conditions, plants with reduced GA activity and therefore, reduced transpiration, will suffer less from leaf desiccation, thereby maintaining higher capabilities and recovery rates. PMID- 23668386 TI - High-performance, highly bendable MoS2 transistors with high-k dielectrics for flexible low-power systems. AB - While there has been increasing studies of MoS2 and other two-dimensional (2D) semiconducting dichalcogenides on hard conventional substrates, experimental or analytical studies on flexible substrates has been very limited so far, even though these 2D crystals are understood to have greater prospects for flexible smart systems. In this article, we report detailed studies of MoS2 transistors on industrial plastic sheets. Transistor characteristics afford more than 100x improvement in the ON/OFF current ratio and 4x enhancement in mobility compared to previous flexible MoS2 devices. Mechanical studies reveal robust electronic properties down to a bending radius of 1 mm which is comparable to previous reports for flexible graphene transistors. Experimental investigation identifies that crack formation in the dielectric is the responsible failure mechanism demonstrating that the mechanical properties of the dielectric layer is critical for realizing flexible electronics that can accommodate high strain. Our uniaxial tensile tests have revealed that atomic-layer-deposited HfO2 and Al2O3 films have very similar crack onset strain. However, crack propagation is slower in HfO2 dielectric compared to Al2O3 dielectric, suggesting a subcritical fracture mechanism in the thin oxide films. Rigorous mechanics modeling provides guidance for achieving flexible MoS2 transistors that are reliable at sub-mm bending radius. PMID- 23668387 TI - Long-term fluorescent cellular tracing by the aggregates of AIE bioconjugates. AB - There is a great demand for long-term cellular tracers because of their great importance in monitoring biological processes, pathological pathways, therapeutic effects, etc. Herein we report a new type of fluorescence "turn-on" probe for tracing live cells over a long period of time. We synthesized the fluorogenic probe by attaching a large number of tetraphenylethene (TPE) labels to a chitosan (CS) chain. The resultant TPE-CS bioconjugate shows a unique aggregation-induced emission (AIE) behavior. It is nonfluorescent when dissolved but becomes highly emissive when its molecules are aggregated. The AIE aggregates can be readily internalized by HeLa cells. The cellular staining by the TPE-CS aggregates is so indelible that it enables cell tracing for as long as 15 passages. The internalized AIE aggregates are kept inside the cellular compartments and do not contaminate other cell lines in the coculture systems, permitting the differentiation of specific cancerous cells from normal healthy cells. PMID- 23668388 TI - Factors controlling the export of nitrogen from agricultural land in a large central European catchment during 1900-2010. AB - Using an empirical model, we quantified the nitrogen (N) export from agricultural land in a large central European catchment (upper Vltava river, Czech Republic, about 13,000 km(2)) over the 1959-2010 period. The catchment witnessed a rapid socio-economic shift from a planned to a market economy in the 1990s, resulting in an abrupt (~50%) reduction in N fertilization rates at otherwise relatively stable land-use practices. This large-scale "experiment" enabled disentangling and quantification of individual effects of N fertilization and drainage on N leaching. The model is based on a two-step regression between annual N export and three independent variables: (i) annual average discharge in the first step and (ii) net anthropogenic nitrogen inputs (NANI) and proportion of drained agricultural land in the second step. Results show that N export was more related to mineralization of soil organic N pools due to drainage and tillage than to external N sources (NANI). The model, together with other reconstructed N sources in the catchment (leaching from forests, waste waters, and atmospheric deposition) and extrapolated back to 1900, explained 77% of the observed variability in N concentrations in the Vltava river during the 1900-2010 period. PMID- 23668389 TI - Internet gaming disorder and the DSM-5. PMID- 23668390 TI - Wither codeine? PMID- 23668391 TI - Synthesis of nucleoside tetraphosphates and dinucleoside pentaphosphates via activation of cyclic trimetaphosphate. AB - A procedure for the synthesis of dinucleoside 5'-pentaphosphates (Np5N) and nucleoside 5'-tetraphosphates (Np4) is described. The procedure relies on the activation of cyclic trimetaphosphate followed by a reaction with a nucleoside 5' monophosphate (NMP) to give intermediates of type 3. Reaction of 3 with water or an NMP gives the desired products in yields ranging from 77 to 86%. PMID- 23668392 TI - TGF-beta1 sensitizes TRPV1 through Cdk5 signaling in odontoblast-like cells. AB - BACKGROUND: Odontoblasts are specialized cells that form dentin and they are believed to be sensors for tooth pain. Transforming growth factor-beta1 (TGF beta1), a pro-inflammatory cytokine expressed early in odontoblasts, plays an important role in the immune response during tooth inflammation and infection. TGF-beta1 is also known to participate in pain signaling by regulating cyclin dependent kinase 5 (Cdk5) in nociceptive neurons of the trigeminal and dorsal root ganglia. However, the precise role of TGF-beta1 in tooth pain signaling is not well characterized. The aim of our present study was to determine whether or not in odontoblasts Cdk5 is functionally active, if it is regulated by TGF-beta1, and if it affects the downstream pain receptor, transient receptor potential vanilloid-1 (TRPV1). RESULTS: We first determined that Cdk5 and p35 are indeed expressed in an odontoblast-enriched primary preparation from murine teeth. For the subsequent analysis, we used an odontoblast-like cell line (MDPC-23) and found that Cdk5 is functionally active in these cells and its kinase activity is upregulated during cell differentiation. We found that TGF-beta1 treatment potentiated Cdk5 kinase activity in undifferentiated MDPC-23 cells. SB431542, a specific inhibitor of TGF-beta1 receptor 1 (Tgfbr1), when co-administered with TGF-beta1, blocked the induction of Cdk5 activity. TGF-beta1 treatment also activated the ERK1/2 signaling pathway, causing an increase in early growth response-1 (Egr-1), a transcription factor that induces p35 expression. In MDPC 23 cells transfected with TRPV1, Cdk5-mediated phosphorylation of TRPV1 at threonine-407 was significantly increased after TGF-beta1 treatment. In contrast, SB431542 co-treatment blocked TRPV1 phosphorylation. Moreover, TGF-beta1 treatment enhanced both proton- and capsaicin-induced Ca2+ influx in TRPV1 expressing MDPC-23 cells, while co-treatment with either SB431542 or roscovitine blocked this effect. CONCLUSIONS: Cdk5 and p35 are expressed in a murine odontoblast-enriched primary preparation of cells from teeth. Cdk5 is also functionally active in odontoblast-like MDPC-23 cells. TGF-beta1 sensitizes TRPV1 through Cdk5 signaling in MDPC-23 cells, suggesting the direct involvement of odontoblasts and Cdk5 in dental nociceptive pain transduction. PMID- 23668393 TI - Stroke-associated differences in rates of activity of daily living loss emerge years before stroke onset. AB - OBJECTIVES: To compare typical age-related changes in activities of daily living (ADLs) independence in stroke-free adults with long-term ADL trajectories before and after stroke. DESIGN: Prospective, observational study. SETTING: Community dwelling Health and Retirement Study (HRS) cohort. PARTICIPANTS: HRS participants who were stroke free in 1998 and were followed through 2008 (average follow-up 7.9 years) (N = 18,441). MEASUREMENTS: Strokes were assessed using self- or proxy report of a doctor's diagnosis and month and year of event. Logistic regression was used to compare within-person changes in odds of self-reported independence in five ADLs in those who remained stroke free throughout follow-up (n = 16,816), those who survived a stroke (n = 1,208), and those who had a stroke and did not survive to participate in another interview (n = 417). Models were adjusted for demographic and socioeconomic covariates. RESULTS: Even before stroke, those who later developed stroke had significantly lower ADL independence and were experiencing faster independence losses than similar-aged individuals who remained stroke free. Of those who developed a stroke, survivors experienced slower pre-stroke loss of ADL independence than those who died. ADL independence declined at the time of stroke and decline continued afterwards. CONCLUSION: In adults at risk of stroke, disproportionate ADL limitations emerge well before stroke onset. Excess disability in stroke survivors should not be entirely attributed to effects of acute stroke or quality of acute stroke care. Although there are many possible causal pathways between ADL and stroke, the association may be noncausal. For example, ADL limitations may be a consequence of stroke risk factors (e.g., diabetes mellitus) or early cerebrovascular ischemia. PMID- 23668394 TI - Regulation of osteoblast proliferation and differentiation by interrod spacing of Sr-HA nanorods on microporous titania coatings. AB - Strontium-doped hydroxyapatite (Ca9Sr1(PO4)6(OH)2, Sr1-HA) nanorods with different lateral spacing (e.g., interrod spacing) values (67.3 +/- 3.8, 95.7 +/- 4.2, and 136.8 +/- 8.7 nm) and nanogranulates were grown on microarc-oxidized microporous TiO2, respectively, to form multilayer coatings. The coatings reveal two kinds of micro/nanoscaled hierarchical surfaces with a similar microscale roughness, e.g., nanogranulated 2D pattern and nanorod-shaped 3D pattern in nanotopography. When hFOB1.19 cells are employed, the proliferation and differentiation of osteoblasts on the coatings were evaluated by examining MTT assay, expressions of osteogenesis-related genes [alkaline phosphatase (ALP), runt-related transcription factor 2, osterix, osteopontin (OPN), osteocalcin (OCN), and collagen I (Col-I)], ALP activity, contents of intracellular Ca(2+), Col-I, OPN, and OCN, extracellular collagen secretion, and extracellular matrix mineralization. The results reveal that the proliferation and differentiation of osteoblasts can be directly regulated by the interrod spacing of the Sr1-HA nanorods, which are significantly enhanced on the nanorod-shaped 3D patterns with interrod spacing smaller than 96 nm and more pronounced with decreasing the interrod spacing but inhibited on the nanorods with spacing larger than 96 nm compared to the nanogranulated 2D pattern. The difference in the cellular activity is found to be related with the intracellular Ca(2+) concentrations, which are regulated by variation of the surface topology of Sr1-HA crystals. Our work provides insight to the surface structural design of a biomedical implant favoring osteointegration. PMID- 23668395 TI - The sexual functioning profile of a nonforensic sample of individuals reporting sexual aggression against women. AB - INTRODUCTION: Sexual offenders are believed to present marked sexual difficulties. However, most of the studies characterizing sex offenders' sexual functioning were conducted with samples of documented/incarcerated sexual aggressors. At the present state of the knowledge there is limited information on the sexual functioning profile of individuals reporting some form of sexual violence but who were not documented/apprehended by the judicial system. AIM: The aim of this preliminary study was to characterize a sample of community sexual aggressors (college students) according to their sexual functioning. Results were expected to add information about the relationship between sexual functioning and sexual violence, and to impact strategies aimed at preventing sexual aggression on college campus. METHODS: One hundred sixty-one male college students participated in a cross-sectional study. Students were recruited at a Portuguese university using nonrandom methods. Among these students, 35 reported sexual aggression against women. The measures were completed individually and anonymously. MAIN OUTCOME MEASURES: Participants completed a modified version of the International Index of Erectile Function, the Sexual Inhibition and Sexual Excitation Scales, the Sexual Self-Consciousness Scale, the Questionnaire of Cognitive Schema Activation in Sexual Context, and the Sexual-Esteem Scale. RESULTS: Results indicated that students reporting sexual aggression against women presented significantly more erectile and orgasmic difficulties, and more sexual inhibition due to the threat of performance failure than the control peers. Additionally, students reporting sexual aggression presented more sexual embarrassment, and more schemas of undesirability and incompetence. CONCLUSIONS: Results pointed toward a possible relationship between sexual violence as reported by college students and sexual performance anxiety. These findings are expected to impact conceptual models on sexual aggression perpetrated by nonforensic individuals. PMID- 23668397 TI - Cogmed Working Memory Training for youth with ADHD: a closer examination of efficacy utilizing evidence-based criteria. AB - The current review applied the evidence-based treatment criteria espoused by the Society for Clinical Child and Adolescent Psychology (Silverman & Hinshaw, 2008 ) to specifically evaluate the short-term and longer term efficacy of Cogmed Working Memory Training (CWMT) as a treatment for youth with Attention Deficit/Hyperactivity Disorder (ADHD). Utilizing a systematic literature search, 7 studies that employed the school-age version of CWMT were identified for this review. The data reviewed herein suggest mixed findings regarding the benefit of CWMT for youth with ADHD. Two randomized controlled studies have demonstrated that CWMT led to improvements in neuropsychological outcomes and parent-rated ADHD symptoms relative to wait-list control and placebo treatment conditions. Another study demonstrated effects of CWMT relative to a placebo condition on an analog observation of behavior during an academic task, although this study did not find an effect of CWMT on parent-rated ADHD. Finally, an additional study utilizing an active comparison control condition did not find incremental benefits of CWMT on parent- or teacher-rated ADHD. Critical issues in interpreting existing studies include lack of alignment between demonstrated outcomes and the hypothesized model of therapeutic benefit of CWMT, issues with equivalence of control conditions, and individual differences that may moderate treatment response. Collectively, the strengths and limitations of the studies reviewed suggest that CWMT is best defined as a Possibly Efficacious Treatment for youth with ADHD. We suggest future directions for research and conclude with clinical implications of our findings for the treatment of youth with ADHD. PMID- 23668398 TI - Comparison of p40 (DeltaNp63) and p63 expression in prostate tissues--which one is the superior diagnostic marker for basal cells? AB - AIMS: p63 is one of the standard markers for basal cells of the prostate gland. Recently, it has been suggested that the p63 isoform p40 might be more specific as a basal cell marker. In this study we compare the staining characteristics of p63 and p40 in normal and malignant prostate tissues. METHODS AND RESULTS: A prostatectomy cohort (n = 640) in tissue microarray format was evaluated for p63 (clone 4A4) and for p40 (rabbit polyclonal) immunoreactivity in malignant and normal tissues. Immunoreactivity of basal and secretory cells was evaluated in a semiquantitative manner and compared case-wise. In normal tissues, p40 showed highly similar immunoreactivity compared to p63. The staining patterns were absolutely identical in 88% of cases. Additional cytoplasmic p40 staining in tumour cells occurred in 59.6% of cancer cases. Differences were seen in nuclear staining of carcinomas: 1.4% of carcinomas were p63-positive, whereas 0.6% were p40-positive. CONCLUSIONS: In most cases, p40 stains prostatic basal cells as reliably as p63, with only minor differences. Aberrant staining of tumour cells is seen more rarely than with p63 (clone 4A4), establishing its higher specificity. However, additional cytoplasmic immunoreactivity narrows its eligibility for antibody cocktails (e.g. with alpha-methylacyl-CoA racemase). PMID- 23668399 TI - Spectroscopic evidence for neutral and anionic adsorption of (S)-glutamic acid on Ag(111). AB - We report here on a combined photoemission and vibrational spectroscopy investigation of (S)-glutamic acid adsorption on Ag(111). We show that, in the temperature range 250 K <= T <= 400 K, non-zwitterionic adsorption takes place and the anionic form prevails at nonvanishing coverage. Significant conformational changes of the self-assembled layer must occur above 300 K, corresponding to a substantial reduction of the sticking probability and a modification of the vibrational spectrum. The similarity of behavior with respect to glutamic acid adsorption on the previously investigated Ag(100) and Ag(110) surfaces is also discussed. PMID- 23668400 TI - Investigational drugs for coagulation disorders. AB - INTRODUCTION: The current standard treatment in persons with hemophilia (PWH) is prophylaxis, given intravenously twice or thrice weekly, which is associated with a non negligible burden on patients' quality of life. Therefore the main attempts aiming to improve the management of PWH are targeted towards the development of a new generation of coagulation factors endowed with properties facilitating prophylaxis and/or a better control of bleeding. AREAS COVERED: This article summarizes the main results obtained so far in the development of new antihemophilic products, and emphasizes the formidable requirements imposed upon by regulatory agencies to get marketing authorization for new drugs, which make progress in this field difficult. Published literature on new molecules for replacement treatment in hemophilia A and B has been retrieved by using PubMed search and all ongoing clinical trials have been looked for online. EXPERT OPINION: New molecules are usually engineered to have a longer plasma half-life but also in some instances a higher potency. The prolongation of half-life may be obtained by using sustained release delivery vehicles, by chemical modification or by creating fusion proteins. Factors VIII, IX and VII have been variably modified in order to obtain improved coagulation products and results from Phase I/II studies are encouraging, particularly for factor IX. However, Phase III studies that should provide evidence on efficacy and effectiveness more cogent for clinical use are still ongoing and results are not yet available. PMID- 23668401 TI - Alendronate sodium. AB - This chapter is a review on physical and chemical properties, methods of preparation, analysis, as well as pharmacodynamics and pharmacokinetics of Alendronate sodium (4-amino-1-hydroxybutane-1,1-diphosphonic acid sodium salt), a bone metabolism regulator, indicated for the treatment of excessive bone resorption and osteoporosis. PMID- 23668396 TI - Diabetes and cancer: two diseases with obesity as a common risk factor. AB - There is a growing body of evidence to support a connection between diabetes (predominantly type 2), obesity and cancer. Multiple meta-analyses of epidemiological data show that people with diabetes are at increased risk of developing many different types of cancers, along with an increased risk of cancer mortality. Several pathophysiological mechanisms for this relationship have been postulated, including insulin resistance and hyperinsulinaemia, enhanced inflammatory processes, dysregulation of sex hormone production and hyperglycaemia. In addition to these potential mechanisms, a number of common risk factors, including obesity, may be behind the association between diabetes and cancer. Indeed, obesity is associated with an increased risk of cancer and diabetes. Abdominal adiposity has been shown to play a role in creating a systemic pro-inflammatory environment, which could result in the development of both diabetes and cancer. Here, we examine the relationship between diabetes, obesity and cancer, and investigate the potential underlying causes of increased cancer risk in individuals with diabetes. Current treatment recommendations for reducing the overall disease burden are also explored and possible areas for future research are considered. PMID- 23668402 TI - Aripiprazole. AB - Aripiprazole is an atypical antipsychotic drug which belongs to the benzisoxazole derivatives. Aripiprazole is available in many salts and polymorphs forms. X-ray diffraction, IR spectroscopy, and DSC could be used for differentiating the polymorphs of aripiprazole. Some instrumental methods of analysis such as UV spectrophotometer, HPTLC, HPLC, and CE can be applied for analyzing aripiprazole and its impurities. Chromatography methods that have an MS/MS detector is the method of choice for analyzing aripiprazole and its metabolites. Bioavailability studies of the polymorphs of aripiprazole and their pharmaceutical preparations are very important to optimize the formulations of the dosage forms. PMID- 23668403 TI - Butyl methoxy dibenzoylmethane. AB - A comprehensive profile on Butyl methoxy dibenzoylmethane, one of the most commonly used ultraviolet (UV) filters in topical sunscreen products, is prepared. This UV filter, often referred to as Avobenzone, has its main absorbance in the UVA I region of the spectrum and is susceptible to photodegradation. The profile contains the following sections: general information, use and mechanism of action, method of preparation, physical characteristics, methods of analysis, stability, and toxicity. The physical characteristics section includes the melting range, differential scanning calorimetry, partition coefficient, ionization constant, solubility, and UV, infrared, nuclear magnetic resonance ((1)H NMR and (13)C NMR) and mass spectrometry and X-ray powder diffractometry. The method of analysis section in addition to compendial identification and purity and assay methods includes thin layer gas and high-performance liquid chromatography. The photostability and photostabilization of Butyl methoxy dibenzoylmethane, in addition to its toxicity, are also documented. PMID- 23668404 TI - Carvedilol. AB - Carvedilol ((2RS)-1-(9H-carbazol-4-yloxy)-3-[[2-(2 methoxyphenoxy)ethyl]amino]propan-2-ol), a beta1-, beta2-, and alpha1 adrenoreceptor blocker drug with antioxidant and antiproliferative effects, is indicated for treatment of hypertension, stable angina pectoris, and congestive heart failure. A profile of this drug substance is provided in this chapter and includes physical characteristics of Carvedilol (e.g., UV-vis, IR, NMR, and mass spectra). Details regarding the stability of Carvedilol in the solid state and solution phase are presented and methods of analysis (compendial and literature) are summarized. Furthermore, an account of the pharmacokinetics (ADME) and synthesis of Carvedilol are presented. PMID- 23668405 TI - Melatonin: comprehensive profile. AB - This chapter includes the aspects of melatonin. The drug is synthesized in the pineal gland starting from tryptophane or synthetically by using indole as starting material. Melatonin has been used as an adjunct to interleukin-2 therapy for malignant neoplasms, as contraceptive, in the management of various forms of insomnia, to alleviate jet lag following long flights, and finally as free radical scavenger and hence as an antioxidant and an anti-inflammatory. The chapter discusses the drug metabolism and pharmacokinetics and presents various method of analysis of this drug such as biological analysis, spectroscopic analysis, and chromatographic techniques of separation. It also discusses its physical properties such as solubility characteristics, X-ray powder diffraction pattern, and thermal methods of analysis. The chapter is concluded with a discussion on its biological properties such as activity, toxicity, and safety. PMID- 23668406 TI - Menadione. AB - This chapter includes the aspects of Menadione (vitamin K). The drug is synthesized by the use of itaconic acid obtained through Friedel-Craft condensation or by direct oxidation of the 2-methyl-1,4-naphthquinone. Vitamin K generally maintains healthy blood clotting and prevents excessive bleeding and hemorrhage, it is also important for maintaining healthy bone structure and for carbohydrate storage in the body. In addition, it is given to newborn babies born in hospitals to prevent the development of life-threatening bleeding caused by low prothrombin levels. The chapter discusses the drug metabolism and pharmacokinetics and presents various method of analysis of this drug such as compendial tests, electrochemical analysis, spectroscopic analysis, and chromatographic techniques of separation. It also discusses its physical properties such as solubility characteristics, X-ray powder diffraction pattern, and thermal methods of analysis. The chapter is concluded with a discussion on its biological properties such as activity, toxicity, and safety. PMID- 23668407 TI - Analytical profile of moxidectin. AB - Moxidectin or F28249alpha is a potent endectocide and semisynthetic methoxime derivative of naturally occurring nemadectin. It is well known for the novel mode of action against a broad range of nematode and anthropod animal parasites. In this work, physicochemical and pharmaceutical aspects of moxidectin are described including stability, semisynthesis, purification processes, formulation compositions, impurities, and degradation pathways. Additional experiments such as DSC, XRD, and CHN analysis were carried out to complete the profile of moxidectin. The importance of safety and quality of drug substances was highlighted by chronological developments involving moxidectin and its analogues. The information gathered from the literature was used to trace the origins of moxidectin-related substances presented in the European Pharmacopeia (EP) compendial monograph. During the review, it was noticed that majority of impurities presented in the EP does not have any potential to increase with time in drug substance or formulated products; therefore, they do not require monitoring during stability studies. This also showed the requirement for further characterization of the impurities observed during long-term storage and development of stability indicating methods distinguishing between process impurities and the true degradation products. Furthermore, the stability of moxidectin in formulations is also reviewed in conjunction with known degradation routes and innovative ways to formulate products that are stable and effective at intended shelf life. PMID- 23668408 TI - Paroxetine hydrochloride. AB - Paroxetine hydrochloride (3S-trans)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4 fluorophenyl)-piperidine hydrochloride (or (-)-(3S,4R)-(4-(p-fluorophenyl)-3 [[3,4-(methylenedioxy)-phenoxy]methyl]piperidine hydrochloride), a phenylpiperidine derivative, is a selective serotonin reuptake inhibitor. Paroxetine is indicated for the treatment of depression, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, and social anxiety disorder. The physicochemical properties, spectroscopic data (1D and 2D NMR, UV, FT-IR, MS, PXRD), stability, methods of preparation and chromatographic methods of analysis of pharmaceutical, and biological samples of paroxetine are documented in this review. Pharmacokinetics, metabolism, and pharmacological effects are also discussed. PMID- 23668409 TI - Paroxetine hydrochloride: polymorphs and solvatomorphs. AB - The polymorphic (crystal systems for which a substance can exist in structures defined by different unit cells, and where each of the forms has the same elemental composition) and solvatomorphic (systems where the crystal structures of the substance are defined by different unit cells, but where these unit cells differ in their elemental composition through the inclusion of one or molecules of solvent) landscape of paroxetine hydrochloride have been critically evaluated in order to learn how many authentic crystal forms have actually been discovered. After a survey of the patent and open literature, it was determined that paroxetine hydrochloride has been crystallized in four genuine nonsolvated polymorphic forms and in four fully characterized solvatomorphic forms. PMID- 23668410 TI - Sucralose. AB - Sucralose is a nonnutritive, zero-calorie artificial sweetener. It is a chlorinated sugar substitute that is about 600 times as sweet as sucrose. It is produced from sucrose when three chlorine atoms replace three hydroxyl groups. It is consumed as tablets (Blendy) by diabetic and obese patients. It is also used as an excipient in drug manufacturing. Unlike other artificial sweeteners, it is stable when heated and can, therefore, be used in baked and fried foods. The FDA approved sucralose in 1998. This review presents a comprehensive profile for sucralose including physical, analytical, and ADME profiles and methods of its synthesis. Spectral data for X-ray powder diffraction and DSC of sucralose are recorded and presented. The authors also recorded FT-IR, (1)H- and (13)C NMR, and ESI-MS spectra. Interpretation with detailed spectral assignments is provided. The analytical profile of sucralose covered the compendial methods, spectroscopic, and different chromatographic analytical techniques. The ADME profile covered all absorption, distribution, metabolism, and elimination data in addition to pharmacokinetics and pharmacological effects of sucralose. Some nutritional aspects for sucralose in obesity and diabetes are also presented. Both chemical and microbiological synthesis schemes for sucralose are reviewed and included. PMID- 23668411 TI - Tramadol hydrochloride. AB - A profile of the analgesic tramadol hydrochloride ((1RS,2RS)-2 [(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloride) is provided in this chapter and includes a summary of the physical characteristics known for this drug substance (e.g., UV/vis, IR, NMR, and mass spectra). Details regarding the stability of tramadol hydrochloride in the solid state and solution phase are presented and methods of analysis (compendial and literature) are summarized. Furthermore, an account of biological properties and a description of the chemical synthesis of tramadol hydrochloride are given. PMID- 23668412 TI - The comprehensive profiling of drug substances and pharmaceutical excipients. Preface. PMID- 23668413 TI - Control of postharvest blue mold of Nanfeng mandarin by application of strain YS 1 Paenibacillus brasilensis. AB - In order to study its commercial value, antagonistic spectrum and storage application of YS-1 Paenibacillus brasilensis were investigated in this paper. YS 1 P. brasilensis showed obvious antifungal activity to 5 different fruit pathogens, which was of broad antagonistic spectrum. Effect and application of YS 1 P. brasilensis fermentation liquid on Nanfeng mandarin at different storage temperatures were also investigated with the puncture inoculation method. Results showed that lesion diameter and disease incidence at 25 degrees C were higher than those at 5 degrees C after end of the storage, and there was significant difference between them. P. brasilensis fermentation liquid was effective for control of Penicillium italicum on Nanfeng mandarin stored at 5 degrees C for 25 d or 25 degrees C for 20 d. Preharvest treatment combined with postharvest treatment significantly reduced the decay rate of Nanfeng mandarin by 5.8% more than the control, particularly in the 1st 2 mo of storage. Fruits treated with P. brasilensis fermentation liquid in preharvest and postharvest period tended to have higher total sugar content, titratable acidity, ascorbic acid (AsA) content, and soluble solids content than those in the control group, and there was significant difference between the 2 groups. A delay was observed in the drop in AsA content. In this article, strain YS-1 is reported for the 1st time as a biocontrol agent against blue mold of Nanfeng mandarin. The research will provide an application reference for preservation of citrus. PMID- 23668414 TI - The polygenetically inherited metabolic syndrome of male WOKW rats is associated with enhanced autophagy in adipose tissue. AB - BACKGROUND: Recent studies revealed that autophagy is up-regulated in obese individuals, as evidenced by increased expression of autophagy related genes. As argued elsewhere, it is possible that initially insulin resistance functions as an adaptive mechanism to increase autophagy in order to protect cells against death. We have shown that Wistar Ottawa Karlsburg W (RT1(u)) rats (WOKW) develop a metabolic syndrome with insulin resistance in adipose tissue, closely resembling the human disease. Therefore, the aim of this study was to characterize the autophagy phenotype in WOKW rats to clarify the interrelation between insulin resistance and autophagy in adipose tissue. METHODS: Subcutaneous and epidydimal adipose tissue samples of 5-months-old WOKW and healthy LEW.1 W male rats were investigated and protein levels (Western blot and immunhistochemistry) of key autophagy genes, including Atg5, Atg7, LC3-II/LC3-I and apoptosis marker cleaved caspase-3 were analyzed. RESULTS: WOKW rats displayed a significant increase of autophagy related proteins (Atg5, Atg7) in adipose tissue compared with LEW.1 W. This increase was predominantly found in epididymal adipose tissue. Furthermore, the LC3-II/LC3-I ratio as a marker of autophagosomes was significantly up-regulated in subcutaneous adipose tissue of WOKW rats. Cleaved caspase-3 was just slightly detectable in visceral adipose tissue and not detected in subcutaneous fat. CONCLUSION: Insulin resistance in adipose tissue of obese WOKW rats is associated with up-regulation of differing autophagy markers in visceral and subcutaneous fat depots. This fact not only qualifies the WOKW rat for further detailed analysis of genetic determinants of metabolic syndrome but also highlights its suitability for autophagy research. PMID- 23668415 TI - The interactions and essential effects of intrinsic insulin-like growth factor-I on Leishmania (Leishmania) major growth within macrophages. AB - Previously, we showed in Leishmania infections that extrinsic insulin-like growth factor (IGF)-I favored Leishmania proliferation and leishmaniasis development. In this study, the interaction of intrinsically expressed IGF-I and Leishmania (Leishmania) major in macrophages was addressed, and a key finding was the observation, using confocal microscopy, of the co-localization of IGF-I and parasites within macrophages. Following stimulation with interferon-gamma (IFN gamma), which is known to inhibit IGF-I production in macrophages, we observed a reduction in the expression of both IGF-I mRNA and protein. This reduced expression was accompanied by a reduction in the cellular parasite load that was completely recovered with the addition of extrinsic IGF-I, which suggests an essential role for IGF-I in Leishmania growth. PMID- 23668416 TI - The role of self-transcendence: a missing variable in the pursuit of successful aging? AB - While successful aging is often defined as the absence of disease and disability or as life satisfaction, self-transcendence may also play an important role. The objective of this research was to test a nursing theory of successful aging proposing that transcendence and adaptation predict successful aging. In this cross-sectional exploratory study, a convenience sample of older adults (N = 152) were surveyed about self-transcendence, proactive coping, and successful aging. Using hierarchical multiple regression, self-transcendence, proactive coping, and all control variables (i.e., sex, race, perceived health, place of residence) together explained 50% of the variance in successful aging (p < 0.001). However, proactive coping alone was not a significant predictor of successful aging. Thus, this study did not support the theory that both self-transcendence and proactive coping predict successful aging. Self-transcendence was the only significant contributor to this multidimensional view of successful aging. Self-transcendence is an important variable in the pursuit of successful aging, which merits further investigation. PMID- 23668417 TI - Bispyrimidines as potent histamine H(4) receptor ligands: delineation of structure-activity relationships and detailed H(4) receptor binding mode. AB - The basic methylpiperazine moiety is considered a necessary substructure for high histamine H4 receptor (H4R) affinity. This moiety is however also the metabolic hot spot for various classes of H4R ligands (e.g., indolcarboxamides and pyrimidines). We set out to investigate whether mildly basic 2-aminopyrimidines in combination with the appropriate linker can serve as a replacement for the methylpiperazine moiety. In the series of 2-aminopyrimidines, the introduction of an additional 2-aminopyrimidine moiety in combination with the appropriate linker lead to bispyrimidines displaying pKi values for binding the human H4R up to 8.2. Furthermore, the methylpiperazine replacement results in compounds with improved metabolic properties. The attempt to transfer the knowledge generated in the class of bispyrimidines to the indolecarboxamides failed. Combining the derived structure-activity relationships with homology modeling leads to new detailed insights in the molecular aspects of ligand-H4R binding in general and the binding mode of the described bispyrimidines in specific. PMID- 23668418 TI - Foamy virus in the tree shrew Tupaia belangeri is highly related to simian foamy virus in Macaca mulatta. AB - Foamy viruses (FVs) are ancient retrovirus that infect most nonhuman primates and several animals, but are rarely reported in tree shrew Tupaia belangeri. In the present study, foamy virus was detected in tree shrew. Phylogenetic analysis indicated that FVtup shared the highest homology with SFVmac (99.3%) in China. The discovery of FVtup indicated that the tree shrew is a new host of foamy virus. FVtup is highly prevalent in Tupaia in China and there is the possibility of cross-species transmission from nonhuman primate to Tupaia. PMID- 23668419 TI - Variation in rice cadmium related to human exposure. AB - Cereal grains are the dominant source of cadmium in the human diet, with rice being to the fore. Here we explore the effect of geographic, genetic, and processing (milling) factors on rice grain cadmium and rice consumption rates that lead to dietary variance in cadmium intake. From a survey of 12 countries on four continents, cadmium levels in rice grain were the highest in Bangladesh and Sri Lanka, with both these countries also having high per capita rice intakes. For Bangladesh and Sri Lanka, there was high weekly intake of cadmium from rice, leading to intakes deemed unsafe by international and national regulators. While genetic variance, and to a lesser extent milling, provide strategies for reducing cadmium in rice, caution has to be used, as there is environmental regulation as well as genetic regulation of cadmium accumulation within rice grains. For countries that import rice, grain cadmium can be controlled by where that rice is sourced, but for countries with subsistence rice economies that have high levels of cadmium in rice grain, agronomic and breeding strategies are required to lower grain cadmium. PMID- 23668420 TI - Asymmetric synthesis of tetrahydro-beta-carbolines via chiral phosphoric acid catalyzed transfer hydrogenation reaction. AB - Chiral phosphoric acid catalyzed enantioselective transfer hydrogenation of hydroxylactams has been realized to provide enantioenriched tetrahydro-beta carbolines in dioxane at room temperature (up to 94% yield, 90% ee). PMID- 23668421 TI - How can we develop a more precise examination of the role of alcohol in recovery from drug dependence? PMID- 23668422 TI - Alkaline post-treatment of Cd(II)-glutathione coordination polymers: toward green synthesis of water-soluble and cytocompatible CdS quantum dots with tunable optical properties. AB - In this study, we demonstrate a facile and environmentally friendly method for the synthesis of glutathione (GSH)-capped water-soluble CdS quantum dots (QDs) with a high cytocompatibility and a tunable optical property based on alkaline post-treatment of Cd-GSH coordination polymers (CPs). Cd-GSH CPs are synthesized with the coordination reaction of Cd(2+) with GSH at different pH values, and the CdS QDs are then formed by adding NaOH to the aqueous dispersion of the Cd-GSH CPs to break the coordination interaction between Cd(2+) and GSH with the release of sulfur. The particle size and optical property of the as-formed CdS QDs are found to be easily tailored by simply adjusting the starting pH values of GSH solutions used for the formation of Cd-GSH CPs, in which the wavelengths of trap state emission of the QDs red-shift with an increase in the sizes of the QDs that is caused by an increase in the starting pH values of GSH solutions. In addition, the use of GSH as the capping reagent eventually endows the as-formed CdS QDs with enhanced water solubility and good cytocompatibility, as demonstrated with HeLa cells. The method demonstrated here is advantageous in that the cadmium precursor and the sulfur source are nontoxic and easily available, and the size, optical properties, water solubility, and cytocompatibilty of the as-formed CdS QDs are simply achieved and experimentally regulated. This study offers a new and green synthetic route to water-soluble and cytocompatible CdS QDs with tunable optical properties. PMID- 23668424 TI - The perioperative course of factor XIII and associated chest tube drainage in newborn and infants undergoing cardiac surgery. AB - BACKGROUND: Perioperative acquired factor XIII deficiency has been looked upon as a potential cause of postoperative bleeding in adult cardiac surgery. METHODS: Forty-four infants were prospectively studied for the time course of factor XIII in plasma and the effect on chest tube drainage (CTD) and transfusion requirements in the first 24 h after surgery. A reconstituted blood prime (RBP) with fresh-frozen plasma (FFP) and packed red blood cells (PRBC) was used. Samples were taken at baseline, after cardiopulmonary bypass and upon arrival in the ICU. Differences in blood loss and transfusion requirements based on a cutoff value of 70% factor XIII activity at the time of ICU admission were also calculated. RESULTS: Baseline factor XIII activity was 79%, decreased to 71% after CPB (P = 0.102) and increased back up to 77% at ICU arrival (P = 0.708). There was no significant correlation between factor XIII, CTD, age, cyanosis, platelet count, and transfusion requirements at any time point. Only preoperative fibrinogen levels correlated significantly with factor XIII activity. Perioperative blood transfusions (PRBC P = 0.712, FFP P = 0.909, platelets P = 0.807) and chest tube losses (P = 0.424 at 6 h and P = 0.215 at 24 h) were not significantly different above or below a 70% factor XIII activity at ICU arrival. CONCLUSION: Factor XIII activity in infants with congenital heart defects is within the lower range of normal adults, independent of patient's age and the presence of cyanosis. Reconstituted blood prime maintains factor XIII activity at sufficient levels during pediatric cardiac surgery. We could not detect a correlation between FXIII and CTD. PMID- 23668425 TI - Are users of sulphonylureas at the time of an acute coronary syndrome at risk of poorer outcomes? AB - AIMS: Adenosine triphosphate sensitive potassium (K(ATP)) channel activity is cardioprotective during ischaemia. One of the purported mechanisms for sulphonylurea adverse effects is through inhibition of these channels. The purpose of this study is to examine whether patients using K(ATP) channel inhibitors at the time of an acute coronary syndrome are at greater risk of death or heart failure (HF) than those not exposed. METHODS: Using linked administrative databases we identified all adults who had an acute coronary syndrome between April 2002 and October 2006 (n = 21 023). RESULTS: Within 30 days of acute coronary syndrome, 5.3% of our cohort died and 15.6% were diagnosed with HF. Individuals with diabetes exhibited significantly higher risk of death (adjusted OR: 1.20, 95% CI: 1.03-1.40) and death or HF (aOR: 1.73, 95% CI: 1.59 1.89) than individuals without diabetes. However, there was no significantly increased risk of death (aOR: 1.00, 95% CI: 0.76-1.33) or death/HF (aOR: 1.06, 95% CI: 0.89-1.26) in patients exposed to K(ATP) channel inhibitors versus patients not exposed to K(ATP) channel inhibitors prior to their acute coronary syndrome. CONCLUSIONS: Diabetes is associated with an increased risk of death or HF within 30 days of an acute coronary syndrome. However, we did not find any excess risk of death or HF associated with use of K(ATP) channel inhibitors at the time of an acute coronary syndrome, raising doubts about the hypothesis that sulphonylureas inhibit the cardioprotective effects of myocardial K(ATP) channels. PMID- 23668426 TI - The challenge of water sustainability. PMID- 23668423 TI - Intensive weight loss intervention in older individuals: results from the Action for Health in Diabetes Type 2 diabetes mellitus trial. AB - OBJECTIVES: To compare the effects of 4 years of intensive lifestyle intervention on weight, fitness, and cardiovascular disease risk factors in older and younger individuals. DESIGN: Randomized controlled clinical trial. SETTING: Sixteen U.S. clinical sites. PARTICIPANTS: Individuals with type 2 diabetes mellitus: 1,053 aged 65 to 76 and 4,092 aged 45 to 64. INTERVENTIONS: An intensive behavioral intervention designed to promote and maintain weight loss through caloric restriction and increased physical activity was compared with diabetes mellitus support and education. MEASUREMENTS: Standardized assessments of weight, fitness (based on graded exercise testing), and cardiovascular disease risk factors. RESULTS: Over 4 years, older individuals had greater intervention-related mean weight losses (6.2%) than younger participants (5.1%; interaction P = .006) and comparable relative mean increases in fitness (0.56 vs 0.53 metabolic equivalents; interaction P = .72). These benefits were seen consistently across subgroups of older adults formed according to many demographic and health factors. Of a panel of age-related health conditions, only self-reported worsening vision was associated with poorer intervention-related weight loss in older individuals. The intensive lifestyle intervention produced mean increases in high-density lipoprotein cholesterol (2.03 mg/dL; P < .001) and decreases in glycated hemoglobin (0.21%; P < .001) and waist circumference (3.52 cm; P < .001) over 4 years that were at least as large in older as in younger individuals. CONCLUSION: Intensive lifestyle intervention targeting weight loss and increased physical activity is effective in overweight and obese older individuals to produce sustained weight loss and improvements in fitness and cardiovascular risk factors. PMID- 23668427 TI - Chronic cough hypersensitivity syndrome. AB - Chronic cough has been suggested to be due to three conditions, asthma, post nasal drip, and reflux disease. A different paradigm has evolved in which cough is viewed as the primary condition characterised by afferent neuronal hypersensitivity and different aspects of this syndrome are manifest in the different phenotypes of cough. There are several advantages to viewing cough hypersensitivity as the unifying diagnosis; Communication with patients is aided, aetiology is not restricted and therapeutic avenues opened. Cough Hypersensitivity Syndrome is a more applicable label to embrace the clinical manifestations of this disabling disease. PMID- 23668428 TI - Subxiphoid approach to epicardial implantation of implantable cardioverter defibrillators in children. AB - BACKGROUND: Epicardial implantation of implantable cardioverter defibrillators (ICDs) is considered in the presence of intracardiac shunt, venous access issue, or small body size. We report our experience with epicardial ICD coil implantation using a minimally invasive method. METHODS: Nine patients who underwent epicardial ICD implantation were included. The median age was 7.4 years (3.9-9.6 years) and the median weight was 15 kg (12-24 kg). Diagnosis at the time of implantation included long QT syndrome (n = 5), catecholaminergic polymorphic ventricular tachycardia (n = 2), hypertrophic cardiomyopathy (n = 1), and fast monomorphic ventricular tachycardia (n = 1). The minimally invasive method involved a subxiphoid incision to place the epicardial pacing leads. The ICD coil was placed in the transverse sinus in four patients using an access path posterior to the heart. The second approach involved a path anterior to the heart to reach the epicardial location posterior to the left atrial appendage in the five remaining patients. No fluoroscopy was used in either approach. The median defibrillation threshold (DFT) at implantation was 7.5 J. RESULTS: Lower DFTs were observed in the anterior approach (10 J vs 5 J). Appropriate ICD shocks were observed in three patients during the median 18-month follow-up period (0.3-28 months). No inappropriate shocks were noted. One patient developed pericardial tamponade 39 days after the procedure and was surgically drained. CONCLUSIONS: Minimally invasive epicardial ICD coil implantation in children with low DFT values is possible. The anterior implantation approach appears superior to the posterior approach. PMID- 23668430 TI - Assessment of MUC4 expression in primary bone tumours. PMID- 23668439 TI - Vibrational excitation and product branching ratios in dissociation of the isotopologs of H3O: experiment and theory. AB - The dissociation dynamics of the Rydberg radical H3O and the deuterated isotopologs have been studied by dissociative charge exchange of H3O(+) with Cs. Center-of-mass kinetic energy release distributions were measured with a fast beam translational spectrometer and compared with direct dynamics quasiclassical trajectory calculations with initial conditions from an ab initio potential energy surface for H3O(+). The experimental branching fractions for dissociation of each isotopolog were obtained and compared with the calculated branching fractions. The dominant dissociation channel for all species is elimination of an H/D atom, and the water product was formed with a significant vibrational inversion in stretching vibrations that varies with the mass of the leaving atom in the dissociation. Branching fractions for the mixed isotopologs show that H atom elimination is favored over D atom elimination. Given the importance of H3O(+) in plasmas, astrochemistry, and in condensed phases, the striking energy partitioning found in this neutralization process is notable. PMID- 23668440 TI - Improvement of dysphagia in a child affected by Pompe disease treated with enzyme replacement therapy. AB - AIM: Dysphagia is a known complication in Pompe Disease (PD), a severe metabolic myopathy due to alpha-glucosidase deficiency. Enzyme replacement therapy (ERT) with alglucosidase alfa is the only approved therapy for PD. Presently no data are available on the effects of ERT on dysphagia in PD patients. The aim of this work is to evaluate the course of this complication in a 6 years old boy affected by PD after treatment with ERT. METHODS: Dysphagia was assessed by Videofluoroscopic Swallowing Study (VFSS) at baseline, before the start of ERT and after 36 months of therapy. We used the Dysphagia Severity Rating Scale (DSS) to define the severity grade of dysphagia. RESULTS: VFSS performed at baseline revealed complete incoordination of oral stage swallowing which was classified as a grade 1 dysphagia according to DSS. After 36 months of treatment VFSS revealed normal swallowing, classified as grade 0 by DSS. CONCLUSION: Our results suggest that ERT is effective in improving dysphagia. VFSS may be a useful tool to investigate and monitor swallowing disorders in patients affected by PD. PMID- 23668441 TI - Novel hybrids of (phenylsulfonyl)furoxan and anilinopyrimidine as potent and selective epidermal growth factor receptor inhibitors for intervention of non small-cell lung cancer. AB - A series of hybrids (12a-k) from (phenylsulfonyl)furoxan and anilinopyrimidine were synthesized and biologically evaluated as epidermal growth factor receptor (EGFR) inhibitors for intervention of non-small-cell lung cancer (NSCLC). Compound 12k exhibited strong and selective EGFR L858R/T790M inhibitory activity (IC50 = 0.047 MUM) and displayed antiproliferative effects on EGFR mutation NSCLC cell lines HCC827 (del E746_A750) and H1975 (L858R/T790M) with IC50 values of 0.007 and 0.029 MUM, respectively. Additionally, 12k released high levels of NO in H1975 cells but not in normal human cells, and its activity was diminished by pretreatment with a NO scavenger. Furthermore, 12k induced apoptosis of H1975 and HCC827 cells more strongly than WZ4002 (1), inhibited EGFR downstream signaling in H1975 cells, and suppressed the nuclear factor-kappaB activation in H1975 cells, while 1 had no significant effects under the same conditions. Finally, 12k substantially inhibited tumor growth in an H1975 xenograft mouse model. Overall, 12k might be a promising candidate for the treatment of NSCLC. PMID- 23668442 TI - Additional techniques for diagnosing scabies. PMID- 23668444 TI - Diagnosis of urinary incontinence. AB - Urinary incontinence is common, increases in prevalence with age, and affects quality of life for men and women. The initial evaluation occurs in the family physician's office and generally does not require urologic or gynecologic evaluation. The basic workup is aimed at identifying possible reversible causes. If no reversible cause is identified, then the incontinence is considered chronic. The next step is to determine the type of incontinence (urge, stress, overflow, mixed, or functional) and the urgency with which it should be treated. These determinations are made using a patient questionnaire, such as the 3 Incontinence Questions, an assessment of other medical problems that may contribute to incontinence, a discussion of the effect of symptoms on the patient's quality of life, a review of the patient's completed voiding diary, a physical examination, and, if stress incontinence is suspected, a cough stress test. Other components of the evaluation include laboratory tests and measurement of postvoid residual urine volume. If the type of urinary incontinence is still not clear, or if red flags such as hematuria, obstructive symptoms, or recurrent urinary tract infections are present, referral to a urologist or urogynecologist should be considered. PMID- 23668445 TI - Updated guidelines on outpatient anticoagulation. AB - The American College of Chest Physicians provides recommendations for the use of anticoagulant medications for several indications that are important in the primary care setting. Warfarin, a vitamin K antagonist, is recommended for the treatment of venous thromboembolism and for the prevention of stroke in persons with atrial fibrillation, atrial flutter, or valvular heart disease. When warfarin therapy is initiated for venous thromboembolism, it should be given the first day, along with a heparin product or fondaparinux. The heparin product or fondaparinux should be continued for at least five days and until the patient's international normalized ratio is at least 2.0 for two consecutive days. The international normalized ratio goal and duration of treatment with warfarin vary depending on indication and risk. Warfarin therapy should be stopped five days before major surgery and restarted 12 to 24 hours postoperatively. Bridging with low-molecular-weight heparin or other agents is based on balancing the risk of thromboembolism with the risk of bleeding. Increasingly, self-testing is an option for selected patients on warfarin therapy. The ninth edition of the American College of Chest Physicians guidelines, published in 2012, includes a discussion of anticoagulants that have gained approval from the U.S. Food and Drug Administration since publication of the eighth edition in 2008. Dabigatran and apixaban are indicated for the prevention of systemic embolism and stroke in persons with nonvalvular atrial fibrillation. Rivaroxaban is indicated for the prevention of deep venous thrombosis in patients undergoing knee or hip replacement surgery, for treatment of deep venous thrombosis and pulmonary embolism, for reducing the risk of recurrent deep venous thrombosis and pulmonary embolism after initial treatment, and for prevention of systemic embolism in patients with nonvalvular atrial fibrillation. PMID- 23668446 TI - Evaluation and diagnosis of wrist pain: a case-based approach. AB - Patients with wrist pain commonly present with an acute injury or spontaneous onset of pain without a definite traumatic event. A fall onto an outstretched hand can lead to a scaphoid fracture, which is the most commonly fractured carpal bone. Conventional radiography alone can miss up to 30 percent of scaphoid fractures. Specialized views (e.g., posteroanterior in ulnar deviation, pronated oblique) and repeat radiography in 10 to 14 days can improve sensitivity for scaphoid fractures. If a suspected scaphoid fracture cannot be confirmed with plain radiography, a bone scan or magnetic resonance imaging can be used. Subacute or chronic wrist pain usually develops gradually with or without a prior traumatic event. In these cases, the differential diagnosis is wide and includes tendinopathy and nerve entrapment. Overuse of the muscles of the forearm and wrist may lead to tendinopathy. Radial pain involving mostly the first extensor compartment is commonly de Quervain tenosynovitis. The diagnosis is based on history and examination findings of a positive Finkelstein test and a negative grind test. Nerve entrapment at the wrist presents with pain and also with sensory and sometimes motor symptoms. In ulnar neuropathies of the wrist, the typical presentation is wrist discomfort with sensory changes in the fourth and fifth digits. Activities that involve repetitive or prolonged wrist extension, such as cycling, karate, and baseball (specifically catchers), may increase the risk of ulnar neuropathy. Electrodiagnostic tests identify the area of nerve entrapment and the extent of the pathology. PMID- 23668447 TI - Diabetes: treating hypertension. PMID- 23668448 TI - Screening for intimate partner violence and abuse of elderly and vulnerable adults. PMID- 23668449 TI - A persistent facial rash. PMID- 23668450 TI - AAN/AHS update recommendations for migraine prevention in adults. PMID- 23668451 TI - Screening for intimate partner violence and abuse of elderly and vulnerable adults: recommendation statement. PMID- 23668452 TI - Metformin use in adolescents. PMID- 23668453 TI - Should family physicians routinely screen for vitamin D deficiency? No: screening is unnecessary, and routine supplementation makes more sense. PMID- 23668454 TI - Should family physicians routinely screen for vitamin D deficiency? Yes: targeted screening in at-risk populations is prudent. PMID- 23668456 TI - Health conditions for travellers to Saudi Arabia for the pilgrimage to Mecca (Hajj & Umra) for 1434 (2013). PMID- 23668455 TI - Effects of allergic phenotype on respiratory symptoms and exacerbations in patients with chronic obstructive pulmonary disease. AB - RATIONALE: Chronic obstructive pulmonary disease (COPD) guidelines make no recommendations for allergy diagnosis or treatment. OBJECTIVES: To determine whether an allergic phenotype contributes to respiratory symptoms and exacerbations in patients with COPD. METHODS: Two separate cohorts were analyzed: National Health and Nutrition Survey III (NHANES III) and the COPD and domestic endotoxin (CODE) cohort. Subjects from NHANES III with COPD (n = 1,381) defined as age > 40 years, history of smoking, FEV1/FVC < 0.70, and no diagnosis of asthma were identified. The presence of an allergic phenotype (n = 296) was defined as self-reported doctor diagnosed hay fever or allergic upper respiratory symptoms. In CODE, former smokers with COPD (n = 77) were evaluated for allergic sensitization defined as a detectable specific IgE to perennial allergens. Bivariate and multivariate models were used to determine whether an allergic phenotype was associated with respiratory symptoms and exacerbations. MEASUREMENTS AND MAIN RESULTS: In NHANES III, multivariate analysis revealed that individuals with allergic phenotype were more likely to wheeze (odds ratio [OR], 2.1; P < 0.01), to have chronic cough (OR, 1.9; P = 0.01) and chronic phlegm (OR, 1.5; P < 0.05), and to have increased risk of COPD exacerbation requiring an acute doctor visit (OR, 1.7; P = 0.04). In the CODE cohort, multivariate analysis revealed that sensitized subjects reported more wheeze (OR, 5.91; P < 0.01), more nighttime awakening due to cough (OR, 4.20; P = 0.03), increased risk of COPD exacerbations requiring treatment with antibiotics (OR, 3.79; P = 0.02), and acute health visits (OR, 11.05; P < 0.01). An increasing number of sensitizations was associated with a higher risk for adverse health outcomes. CONCLUSIONS: Among individuals with COPD, evidence of an allergic phenotype is associated with increased respiratory symptoms and risk of COPD exacerbations. PMID- 23668457 TI - Necrotizing pneumonia following cardiac surgery in a neonate. AB - In this report, we discuss the case of a male neonate who underwent surgical correction for coarctation of the aorta. The recovery of this patient was complicated by postsurgical necrotizing pneumonitis that resolved completely after a prolonged hospital stay with recurrent deterioration. PMID- 23668458 TI - Nocardia abscessus brain abscess in an immunocompetent host. AB - Nocardia brain abscesses typically occur in immunocompromised patients. Most cases of nocardiosis are caused by the Nocardia asteroides complex and Nocardia brasiliensis. Here, we present a patient with a Nocardia abscessus brain abscess. The diagnosis was confirmed by DNA sequencing, and the organism was susceptible to linezolid, clarithromycin, ceftriaxone, imipenem, tobramycin, amikacin, minocycline and sulfamethoxazole. The patient was successfully treated medically in combination with surgical excision. PMID- 23668459 TI - Antimicrobial resistance in the food chain and the AGISAR initiative. PMID- 23668460 TI - Comparison of the tuberculin skin test and Quanti-FERON-TB Gold In-Tube (QFT-G) test for the diagnosis of latent tuberculosis infection in dialysis patients. AB - Dialysis patients are more likely than the general population to develop active tuberculosis (TB). In these patients, the availability of a highly sensitive and specific test to diagnose latent TB will ensure earlier treatment and decreased progression to active disease. In the current study, the Quanti-FERON-TB Gold In Tube (QFT-G) test was compared with the tuberculin skin test (TST) for the diagnosis of latent tuberculosis infection (LTBI) among 200 hemodialysis patients and 15 confirmed TB disease cases in a tertiary care center in Saudi Arabia. Among the LTBI cases, 26 (13%) were TST positive, and 65 (32.5%) were positive by the QTF-G test, with an overall agreement between the 2 tests of 75.5% (k=0.34) being observed. Among the confirmed tuberculosis disease cases, none were positive by TST, and 10 (66.7%) were positive by the QTF-G test, resulting in an overall agreement of 33.3% (k=0). A comparison between the TST and the QTF-G test was performed based on the sensitivity, specificity, and area under the curve (AUC) obtained for the tests. The QTF-G test was more sensitive and less specific than the TST in predicting the confirmed TB disease cases. When we tested the correspondence of the AUC values between the 2 diagnostic modalities, the obtained p-value was 0.0003. In conclusion, the AUCs of the examined diagnostic modalities are significantly different in predicting LTBI and tuberculosis. PMID- 23668461 TI - Impact of a new vaccine clinic on hepatitis B vaccine completion and immunological response rates in an HIV-positive cohort. AB - INTRODUCTION: Hepatitis B virus vaccination (HBVV) in the HIV-infected population has poor reported completion rates and immunological response rates. At our HIV clinic, we established a vaccine clinic to improve HBVV outcomes using interventions such as SMS text reminders and double-dose (DD) HBVV for standard dose non-responders (SD NRs). METHODS: A five-year (2003-2008) retrospective review of the completion rates and immunological response rates for HBVV after the establishment of the dedicated vaccine clinic was conducted. Statistical significance was assumed at p<0.05, and the analysis was performed using SPSS (v16). RESULTS: A total of 354 HIV-infected patients were included. Seventy-five percent (268/354) of patients completed the SD HBVV, an 84% (226/268) returned for the hepatitis B surface antibody evaluation. Only 47.3% (107/226) responded to standard-dose hepatitis B vaccination. Responders had higher absolute numbers (p=0.017) and percentages of CD4 cells (p<0.001) and were more likely to be receiving HAART (p=0.001). There was a 70% (48/69) response rate to DD HBVV among SD NRs. On-treatment analysis showed an 88% (155/176) overall immunological response to SD HBVV and DD HBVV, if required. CONCLUSION: High HBVV completion and response rates in this HIV cohort were enabled through the use of multiple interventions, including the use of SMS text message reminders and routine referral for DD vaccination. PMID- 23668462 TI - Prevalence of multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa in an Italian hospital. AB - The severity and extent of disease caused by multidrug-resistant organisms (MDROs) varies by the population(s) affected and the institution(s) at which these organisms are found; therefore, preventing and controlling MDROs are extremely important. A retrospective study of patients who were infected with Acinetobacter baumannii or Pseudomonas aeruginosa was performed at the Spedali Civili Hospital in Brescia, Italy, from 2007 to 2010. A total of 167 (0.52%) A. baumannii isolates and 2797 P. aeruginosa (8.7%) isolates were identified among 31,850 isolates. Amikacin and colistin were the most active agents against A. baumannii strains. Multidrug resistance (MDR) was observed in 57 isolates (54%). Most MDR isolates (42 out of 57, 73%) were resistant to four classes of antibiotics. P. aeruginosa was recovered more frequently from the respiratory tract, followed by the skin/soft tissue, urine and blood. Colistin, amikacin and piperacillin/tazobactam were active against 100%, 86% and 75% of P. aeruginosa isolates, respectively. A total of 20% (n=316) of P. aeruginosa isolates were MDR. In summary, A. baumannii was more rare than P. aeruginosa but was more commonly MDR. Epidemiological data will help to implement better infection control strategies, and developing a local antibiogram database will improve the knowledge of antimicrobial resistance patterns in our region. PMID- 23668463 TI - Hepatitis C, hepatitis B and HIV infection among Egyptian prisoners: seroprevalence, risk factors and related chronic liver diseases. AB - BACKGROUND AND AIM: Prisons in Egypt do not currently screen for blood-borne viruses, and there are no statistics concerning the prevalence of hepatitis C virus, hepatitis B virus or human immunodeficiency virus among prisoners. This study was performed to detect the prevalence of antibodies against hepatitis C, hepatitis B core and human immunodeficiency virus among Egyptian prisoners. METHODS: The study was conducted in an Egyptian prison. The prisoners voluntarily completed a risk factor questionnaire and provided blood specimens for testing for antibodies against hepatitis C virus, hepatitis B virus core antigen and human immunodeficiency virus. Positive results were confirmed by the detecting HCV RNA via polymerase chain reaction. Multivariate regression analysis was performed to determine the factors that were independently associated with positive HCV serology. RESULTS: Five hundred resident prisoners were screened. The prevalence of hepatitis C virus antibodies was 15.8% (79/500), and viremia was confirmed by PCR in 77.2% (61/79) of the antibody-positive prisoners. The prevalence of antibodies to hepatitis B core antigen was 9.8% (49/500), and 1.2% (6/500) of prisoners were dually infected with HBV and HCV. Antibodies to human immunodeficiency virus were not detected in any of the prisoners. The best predictor for hepatitis C and hepatitis B infection was a history of intravenous drug use (P<0.011 for HBV and P<0.001 for HCV), a period of >10 years spent in prison (P<0.052 for HBV and P<0.021 for HCV) and shared toiletries (P<0.059 for HBV and P<0.002 for HCV). CONCLUSION: Hepatitis C and hepatitis B virus infections constitute an important public health problem in prisons. Public health strategies to prevent morbidity and mortality from these infections should include hepatitis B vaccination, HCV testing, counseling and medical management of infected prisoners. PMID- 23668464 TI - Nasal carriage and antimicrobial susceptibility of Staphylococcus aureus among medical students at the HRH Princess Maha Chakri Sirindhorn Medical Center, Thailand: a cross sectional study. AB - OBJECTIVE: To determine the epidemiology of the nasal carriage of Staphylococcus aureus and its susceptibility pattern among preclinical medical students at the HRH Princess Maha Chakri Sirindhorn Medical Center, Srinakharinwirot University. METHODS: Nasal swabs were taken from 128 preclinical medical students prior to working at the hospital. Susceptibility testing of S. aureus was performed using Kirby Bauer's disc diffusion method. RESULTS: Of the 128 participants, 38/128 (29.7%; 95% confidence interval [CI]=21.8%, 37.6%) were carriers of S. aureus. No methicillin-resistant S. aureus was detected by the cefoxitin disk diffusion test. Resistance of S. aureus to erythromycin, clindamycin, tetracycline, chloramphenicol and fusidic acid was observed at the following rates: 63.2% (95% CI; 47.8%, 78.5%), 63.2% (95% CI; 47.8%, 78.5%), 34.2% (95% CI; 19.1%, 49.3%), 2.6% (95% CI; -2.5%, 7.7%) and 2.6% (95% CI; -2.5%, 7.7%), respectively. There was no statistically significant correlation between nasal carriage of S. aureus and possible risk factors. CONCLUSIONS: The prevalence of asymptomatic nasal carriage of S. aureus was higher than reported by previous literature in Thailand, and S. aureus isolates exhibited relatively high resistance to erythromycin and clindamycin. PMID- 23668465 TI - High level of gentamicin resistance (HLGR) among enterococcus strains isolated from clinical specimens. AB - BACKGROUND: Enterococci are pathogens that can cause nosocomial infections and acquire resistance properties via several molecular mechanisms. The aac (6')Ie aph(2")Ia gene plays a significant role in the emergence of high-level gentamicin resistant (HLGR) strains. The screening of resistant strains and the provision of appropriate antibiotic therapy can decide the outcome of serious nosocomial infections. METHODS: In the present study, 142 enterococci were isolated from patients, and the species were identified using standard methods. An antimicrobial susceptibility test was performed using the disc diffusion method, and the minimum inhibition concentration (MIC) of gentamicin was determined according to the broth micro-dilution method. Additionally, PCR was utilized to detect the aac(6')Ie-aph(2")Ia gene, the presence of which was confirmed by digestion with Sca1 and sequencing. RESULTS: Of the 142 isolates, 62 (43.7%) were found to exhibit the HLGR phenotype. All except one of the HLGR isolates contained the aac(6')Ie-aph(2")Ia gene. The prevalence of resistance to other antibiotics and multi-drug resistance (MDR) was higher among the HLGR isolates compared to the non-HLGR isolates. CONCLUSIONS: Our results indicate that high prevalence rates of MDR and HLGR enterococci are an important problem associated with medical treatment. Furthermore, the presence of the aac(6')Ie-aph(2")Ia gene was shown to correspond to the presence of the HLGR phenotype among enterococci. PMID- 23668466 TI - Screening employees of services for homeless individuals in Montreal for tuberculosis infection. AB - The results of a tuberculin skin test (TST) screening program offered to employees of services for homeless people in Montreal from 1998 to 2005 were analyzed to assess the occupational risk of tuberculosis (TB) infection. Employees with no known contact with TB were selected among volunteer participants. They were followed in two dynamic cohorts: individuals with a negative two-step baseline TST (cohort A) and individuals with a negative single baseline TST (cohort B). We estimated the prevalences of initial positive TST, boosting effect, and conversion rate. The average age of the workers was 38.9 years. The prevalence of an initial positive TST was 12.9%. A booster effect was observed in 5.1% of workers who completed a two-step TST. The incidence of conversion was 2.3/100 person-years for cohort A (n=93) and 3.5/100 person-years for cohort B (n=221). The incidence of conversion was not significantly associated with any of the demographics or workplace factors investigated. Our findings are comparable to the rates reported among community workers, whose risk is higher than the average health worker. This suggests that there are occasional unidentified contagious cases among the homeless individuals of participating institutions. PMID- 23668467 TI - Antimicrobial agent prescription patterns for chemotherapy-induced febrile neutropenia in patients with hematological malignancies at Sultan Qaboos University Hospital, Oman. AB - OBJECTIVES: The aim of this study was to describe the antimicrobial prescription patterns of patients with hematological malignancies who developed febrile neutropenia (FN) at Sultan Qaboos University Hospital (SQUH) in Oman. METHODS: This was a retrospective observational study covering a period of 3 years (January 2007-February 2010). FN episodes were studied in patients with hematological malignancies in three different wards at SQUH. RESULTS: A total of 176 FN episodes were analyzed. Overall, 64% of the 107 patients studied experienced at least 2 episodes during the analysis period. Approximately, 69% of the febrile neutropenia episodes had severe neutropenia. The duration of neutropenia was less than 1 week in the majority of the episodes (57%). The mean duration of treatment was approximately 7 days, with no significant difference between specialties or different types of malignancies. Only 34 (19%) episodes had positive cultures, and most of these were from blood samples (30 episodes, 88%). The majority of isolates were gram-negative organisms (63%). The initial empirical treatment included monotherapy (37%), dual therapy (60%) and triple therapy (3%). CONCLUSIONS: This study demonstrates that there is a large variation in the antimicrobial treatment of FN episodes in patients with hematological malignancies at SQUH. All chosen drugs were within international guideline recommendations. PMID- 23668468 TI - Provider-initiated HIV testing and counseling among tuberculosis patients in a hospital in the Oromia region of Ethiopia. AB - BACKGROUND: Routine testing for human immunodeficiency virus (HIV) in settings with generalized HIV epidemics affords the benefit of diagnosing the infection early and thereby preventing morbidity, mortality and sustained transmission; early detection hastens the initiation of cotrimoxazole prophylaxis and anti retroviral treatment (ART). Therefore, the objective of this study was to assess HIV counseling and testing among tuberculosis patients under routine care conditions in the Bishoftu hospital within the Oromia region of Ethiopia. METHODS: A retrospective study was conducted from a tuberculosis (TB) registry, which included data from all adult patients who were diagnosed and treated at Bishoftu Hospital in Oromia from 2009 through 2011. The data were reviewed, coded and entered into the computer software, SPSS version 16.0, for analysis. We used a descriptive and multi-variable logistic regression model to predict HIV positive status. RESULTS: Among the 682 patients recorded on the TB registry, the required variables for this study were completed for 681 adult tuberculosis patients. Out of all the TB patients for whom the variables were collected, 98% (669/681) were offered HIV counseling and testing, and nearly all of them (668/669) accepted and were tested for HIV. Among those patients who accepted for testing and were tested for HIV, 32.2% (215/668) tested positive. Pulmonary TB, among all types of all forms of TB, urban residence and the 25-64 age group were more generally associated with an HIV-positive status; however, male sex and pulmonary-positive types of TB were less likely to be HIV-positive. CONCLUSION: The acceptance rate for HIV counseling and testing services among TB patients was very high. However, there were missed cases in which the test was not offered. The prevalence of HIV was very high, and the infection was more prevalent among urban residents, females, young people and pulmonary-negative TB patients; thus, these patients need attention from all concerned parties. PMID- 23668469 TI - Rift Valley fever among children and adolescents in southwestern Saudi Arabia. AB - PURPOSE: Rift Valley fever (RVF) virus has expanded its geographical range, reaching Asia in 2000. This work investigated RVF seroprevalence among children born after the 2000-2001 outbreak in Saudi Arabia and compared it with the seroprevalence of adolescents born before the outbreak. DESIGN: In a seroepidemiological study in southwestern Saudi Arabia (Jazan, Aseer, and Al Qunfuda), a random sample of 389 children and adolescents was investigated. Data were collected regarding the subjects' sociodemographic status, housing conditions, and animal contact. Blood samples were collected and tested for RVF specific IgG and IgM. RESULTS: None of the study samples were found to be seropositive for anti-RVF virus IgM. None of the study subjects aged 1-8 years (born after the outbreak) were positive for RVF-specific IgG. In contrast, 14 subjects (4.8%) aged 9-19 years (born before the outbreak) were positive for RVF specific IgG. Among adolescents in our study, 4.9% were positive for anti-RVF IgG. This study showed that among adolescents, a history of contact with aborted animals (aOR=13.361, 95% CI=5.091-35.072) and transporting aborted animals (aOR=18.861, 95% CI=11.125-31.622) were significant risk factors. CONCLUSIONS: Despite the low virus activity recently reported among animals, neither clinically apparent RVF infections nor outbreaks among humans have been documented, indicating that the control measures taken by the Ministry of Agriculture and Ministry of Health are effective. PMID- 23668470 TI - Alcohol-selling outlets and mortality in Switzerland--the Swiss National Cohort. AB - AIM: To examine the association of alcohol-related mortality and other causes of death with neighbourhood density of alcohol-selling outlets for on-site consumption. DESIGN, SETTING AND PARTICIPANTS: Longitudinal study of the adult Swiss population (n = 4 376 873) based on census records linked to mortality data from 2001 to 2008. MEASUREMENTS: Sex-specific hazard ratios (HR) for death and 95% confidence intervals (95%CI) were calculated using Cox models adjusting for age, educational level, occupational attainment, marital status and other potential confounders. The density of alcohol-selling outlets within 1000 m of the residence was calculated using geocodes of outlets and residences. FINDINGS: Compared with >17 outlets within 1000 m the HR for alcohol-related mortality in men was 0.95 (95%CI: 0.89-1.02) for 8-17 outlets, 0.84 (95%CI: 0.77-0.90) for 3-7 outlets, 0.76 (95%CI: 0.68-0.83) for 1-2 outlets and 0.60 (95%CI: 0.51-0.72) for 0 outlets. The gradient in women was somewhat steeper, with a HR comparing 0 with >17 outlets of 0.39 (95%CI: 0.26-0.60). Mortality from mental and behavioural causes and lung cancer were also associated with density of alcohol-selling outlets: HRs comparing 0 outlets with >17 outlets were 0.64 (95%CI: 0.52-0.79) and 0.79 (95%CI: 0.72-0.88), respectively, in men and 0.46 (95%CI: 0.27-0.78) and 0.63 (95%CI: 0.52-0.77), respectively, in women. There were weak associations in the same direction with all-cause mortality in men but not in women. CONCLUSIONS: In Switzerland, alcohol-related mortality is associated with the density of outlets around the place of residence. Community-level interventions to reduce alcohol outlet density may usefully complement existing interventions. PMID- 23668471 TI - Century-long source apportionment of PAHs in Athabasca oil sands region lakes using diagnostic ratios and compound-specific carbon isotope signatures. AB - Evaluating the impact that airborne contamination associated with Athabasca oil sands (AOS) mining operations has on the surrounding boreal forest ecosystem requires a rigorous approach to source discrimination. This study presents a century-long historical record of source apportionment of polycyclic aromatic hydrocarbons (PAHs) in dated sediments from two headwater lakes located approximately 40 and 55 km east from the main area of open pit mining activities. Concentrations of the 16 Environmental Protection Agency (EPA) priority PAHs in addition to retene, dibenzothiophene (DBT), and six alkylated groups were measured, and both PAH molecular diagnostic ratios and carbon isotopic signatures (delta(13)C) of individual PAHs were used to differentiate natural from anthropogenic inputs. Although concentrations of PAHs in these lakes were low and below the Canadian Council of Ministers of the Environment (CCME) guidelines, diagnostic ratios pointed to an increasingly larger input of petroleum-derived (i.e., petrogenic) PAHs over the past 30 years concomitant with delta(13)C values progressively shifting to the value of unprocessed AOS bitumen. This petrogenic source is attributed to the deposition of bitumen in dust particles associated with wind erosion from open pit mines. PMID- 23668472 TI - Interface architecture for superthick carbon-based films toward low internal stress and ultrahigh load-bearing capacity. AB - Superthick diamond-like carbon (DLC) films [(Six-DLC/Siy-DLC)n/DLC] were deposited on 304 stainless steel substrates by using a plane hollow cathode plasma-enhanced chemical vapor deposition method. The structure was investigated by scanning electron microscopy and transmission electron microscopy. Chemical bonding was examined by Raman, Auger electron, and X-ray photoelectron spectroscopy techniques. Mechanical and tribological properties were evaluated using nanoindentation, scratch, interferometry, and reciprocating-sliding friction testing. The results showed that implantation of a silicon ion into the substrate and the architecture of the tensile stress/compressive stress structure decreased the residual stress to almost 0, resulting in deposition of (Six DLC/Siy-DLC)n/DLC films with a thickness of more than 50 MUm. The hardness of the film ranged from 9 to 23 GPa, and the adhesion strength ranged from 4.6 to 57 N depending on the thickness of the film. Friction coefficients were determined in three tested environments, namely, air, water, and oil. Friction coefficients were typically below 0.24 and as low as 0.02 in a water environment. The as prepared superthick films also showed an ultrahigh load-bearing capacity, and no failure was detected in the reciprocating wear test with contact pressure higher than 3.2 GPa. Reasons for the ultrahigh load-bearing capacity are proposed in combination with the finite-element method. PMID- 23668473 TI - Nonlinear eddy viscosity modeling and experimental study of jet spreading rates. AB - Indoor airflow pattern is strongly influenced by turbulent shear and turbulent normal stresses that are responsible for entrainment effects and turbulence driven secondary motion. Therefore, an accurate prediction of room airflows requires reliable modeling of these turbulent quantities. The most widely used turbulence models include RANS-based models that provide quick solutions but are known to fail in turbulent free shear and wall-affected flows. In order to cope with this deficiency, this study presents a nonlinear k-epsilon turbulence model and evaluates it along with linear k-epsilon models for an indoor isothermal linear diffuser jet flow measured in two model rooms using PIV. The results show that the flow contains a free jet near the inlet region and a wall-affected region downstream where the jet is pushed toward the ceiling by entrainment through the well-known Coanda effect. The CFD results show that an accurate prediction of the entrainment process is very important and that the nonlinear eddy viscosity model is able to predict the turbulence-driven secondary motions. Furthermore, turbulence models that are calibrated for high Reynolds free shear layer flows were not able to reproduce the measured velocity distributions, and it is suggested that the model constants of turbulence models should be adjusted before they are used for room airflow simulations. PMID- 23668475 TI - Emergence of Klebsiella pneumoniae co-producing NDM-type and OXA-181 carbapenemases. AB - The emergence of carbapenemase-producing Enterobacteriaceae is a rapidly evolving threat worldwide. Here, we report the molecular characterization of two Klebsiella pneumoniae isolates carrying both bla(OXA -181) and bla(NDM -1) or bla(NDM -5) isolated from epidemiologically unrelated patients in Singapore. The bla(OXA -181) genes were found existing in different genetic environments. PMID- 23668474 TI - Pathogenesis of infantile haemangioma. AB - Haemangioma is a vascular tumour of infancy that is well known for its rapid growth during the first weeks to months of a child's life, followed by a spontaneous but slow involution. During the proliferative phase, the vessels are disorganized and composed of immature endothelial cells. When the tumour involutes, the vessels mature and enlarge but are reduced in number. Fat, fibroblasts and connective tissue replace the vascular tissue, with few, large, feeding and draining vessels evident. Both angiogenesis and vasculogenesis have been proposed as mechanisms contributing to the neovascularization in haemangioma tumours. In recent years, several of the 'building blocks', the cells comprising the haemangioma, have been isolated. Among them are haemangioma progenitor/stem cells, endothelial cells and pericytes. This review focuses on these cell types, and the molecular pathways within these cells that have been implicated in driving the pathogenesis of infantile haemangioma. PMID- 23668476 TI - Direct catalytic asymmetric Mannich-type reaction of alpha-sulfanyl lactones. AB - Catalytic asymmetric Mannich-type reactions of alpha-sulfanyl lactones to aldimines were promoted by a chiral Ag complex/DBU binary catalyst. The reaction proceeded in a syn-selective manner in high enantioselectivity. Alkylative activation of the sulfide of the Mannich adduct allowed for the formation of trisubstituted aziridines. PMID- 23668477 TI - Regional variation in mortality impact of the 2009 A(H1N1) influenza pandemic in China. AB - BACKGROUND: Laboratory-confirmed deaths grossly underestimate influenza mortality burden, so that reliable burden estimates are derived from indirect statistical studies, which are scarce in low- and middle-income settings. OBJECTIVES: Here, we used statistical excess mortality models to estimate the burden of seasonal and pandemic influenza in China. METHODS: We modeled data from a nationally representative population-based death registration system, combined with influenza virological surveillance data, to estimate influenza-associated excess mortality for the 2004-2005 through 2009-2010 seasons, by age and region. RESULTS: The A(H1N1) pandemic was associated with 11.4-12.1 excess respiratory and circulatory (R&C) deaths per 100,000 population in rural sites of northern and southern China during 2009-2010; these rates were 2.2-2.8 times higher than those of urban sites (P<0.01). Influenza B accounted for a larger proportion of deaths than pandemic A(H1N1) in 2009-2010 in some regions. Nationally, we attribute 126,200 (95% CI, 61,000-248,400) excess R&C deaths (rate of 9.4/100,000) and 2,323,000 (1,166,000-4,533,000) years of life lost (YLL) to the first year of A(H1N1)pdm circulation. CONCLUSIONS: The A(H1N1) pandemic posed a mortality and YLL burden comparable to that of interpandemic influenza in China. Our high burden estimates in rural areas highlight the need to enhance epidemiological surveillance and healthcare services, in underdeveloped and remote areas. PMID- 23668479 TI - Magnetic resonance imaging (MRI) anatomy of the ovine lumbar spine. AB - Although the ovine spine is a useful research model for intervertebral disc pathology and vertebral surgery, there is little peer-reviewed information regarding the MRI anatomy of the ovine spine. To describe the lumbar spine MRI anatomy, 10 lumbar segments of cadaver ewes were imaged by 1.5-Tesla MR. Sagittal and transverse sequences were performed in T1 and T2 weighting (T1W, T2W), and the images were compared to gross anatomic sagittal and transverse sections performed through frozen spines. MRI was able to define most anatomic structures of the ovine spine in a similar way as can be imaged in humans. In both T1W and T2W, the signals of ovine IVDs were similar to those observed in humans. Salient anatomic features were identified: (1) a 2- to 3-mm linear zone of hypersignal was noticed on both extremities of the vertebral body parallel to the vertebral plates in sagittal planes; (2) the tendon of the crura of the diaphragm appeared as a hypointense circular structure between hypaxial muscles and the aorta and caudal vena cava; (3) dorsal and ventral longitudinal ligaments and ligamentum flavum were poorly imaged; (4) no ilio-lumbar ligament was present; (5) the spinal cord ended between S1-S2 level, and the peripheral white matter and central grey matter were easily distinguished on T1W and T2W images. This study provides useful reference images to researchers working with ovine models. PMID- 23668478 TI - Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. AB - AIMS: Sodium-glucose co-transporter 2 (SGLT2) reabsorbs glucose and sodium in the renal proximal tubule. Dapagliflozin, an SGLT2 inhibitor, targets hyperglycaemia in type 2 diabetes by increasing renal glucose excretion. To investigate whether the parallel occurring sodium loss would have diuretic-like physiologic effects, we compared dapagliflozin and hydrochlorothiazide (HCTZ) effects on 24-h blood pressure (BP), body weight, plasma volume and glomerular filtration rate (GFR). METHODS: In this randomized, placebo-controlled, double-blind trial, 75 subjects with type 2 diabetes were assigned placebo, dapagliflozin 10 mg/day, or HCTZ 25 mg/day. Changes from baseline BP, body weight, plasma volume and GFR were assessed after 12 weeks of treatment. RESULTS: Subjects' mean age was 56 years, type 2 diabetes mellitus (T2DM) duration 6.3 years, and haemoglobin A1c (HbA1c) 7.5%. Treatment with placebo, dapagliflozin or HCTZ resulted in changes from baseline in 24-h ambulatory mean systolic blood pressure (SBP) of -0.9 (95%CI 4.2, +2.4), -3.3 (95%CI -6.8, +0.2), and -6.6 (95%CI -9.9, -3.2) mmHg, respectively at week 12, adjusted for baseline SBP. Body weight decreased with dapagliflozin and HCTZ. In a sub-study plasma volume appeared to decrease with dapagliflozin but did not change with placebo or HCTZ treatment. Dapagliflozin induced a greater reduction in GFR (-10.8%; 95%CI -14.6, -6.7) relative to placebo (-2.9%; 95% CI -6.9, +1.2) or HCTZ (-3.4%; 95%CI -7.3, +0.6). CONCLUSIONS: Dapagliflozin-induced SGLT2 inhibition for 12 weeks is associated with reductions in 24-h BP, body weight, GFR and possibly plasma volume. Cumulatively, these effects suggest that dapagliflozin may have a diuretic-like capacity to lower BP in addition to beneficial effects on glycaemic control. PMID- 23668480 TI - Vocal cord paralysis secondary to spontaneous internal carotid dissection: case report and systematic review of the literature. AB - OBJECTIVES: To present a rare case of unilateral vocal cord paralysis (VCP) secondary to spontaneous internal carotid artery dissection and to perform a literature review. CASE REPORT: A 35-year-old male presented to the emergency department with acute onset hoarseness and dysphagia. History, physical exam and laryngoscopy revealed left sided VCP without obvious cause. Magnetic Resonance Imaging (MRI) demonstrated a left internal carotid artery dissection of unknown etiology. Neurovascular surgery was consulted and treatment with aspirin was initiated. The dysphagia and hoarseness resolved in 12 weeks with long-term neurosurgery follow-up as the management plan. METHODS: Systematic literature review was conducted by 3 independent reviewers. Since 1988 only 9 cases of VCP due to internal carotid artery dissection have been reported. These were reviewed for: demographics, diagnostic method, treatment and vocal cord function. RESULTS: 7 patients had unilateral while 2 had bilateral VCP. MRI was used for diagnosis in 7 cases and 5 cases utilized a type of angiography. All received antithrombotic treatment with 5 out of the 9 patients experiencing vocal cord recovery in an average of 7.2 weeks. CONCLUSION: MRI is crucial in the work-up of idiopathic VCP. If an ipsilateral internal carotid artery dissection is found, antithrombotic treatment is initiated with an expectation that vocal cord mobility is likely to return. PMID- 23668481 TI - Spectrum and frequency of GJB2 mutations in a cohort of 264 Portuguese nonsyndromic sensorineural hearing loss patients. AB - OBJECTIVE: To assess the spectrum and prevalence of mutations in the GJB2 gene in Portuguese nonsyndromic sensorineural hearing loss (NSSHL) patients. DESIGN: Sequencing of the coding region, basal promoter, exon 1, and donor splice site of the GJB2 gene; screening for the presence of the two common GJB6 deletions. STUDY SAMPLE: A cohort of 264 Portuguese NSSHL patients. RESULTS: At least one out of 21 different GJB2 variants was identified in 80 (30.2%) of the 264 patients analysed. Two mutant alleles were found in 53 (20%) of these probands, of which 83% (44/53) harboured at least one c.35delG allele. Twenty-seven (10.2%) of the probands harboured only one mutant allele. Subsequent analysis revealed that the GJB6 deletion del(GJB6-D13S1854) was present in at least 7.4% (2/27) of the patients carrying only one mutant GJB2 allele. Overall, one in five (55/264) of the patients were diagnosed as having DFNB1-related NSSHL, of which the vast majority (53/55) harboured only GJB2 mutations. CONCLUSIONS: This study provides clear demonstration that mutations in the GJB2 gene are an important cause of NSSHL in Portugal, thus representing a valuable indicator as regards therapeutical and rehabilitation options, as well as genetic counseling of these patients and their families. PMID- 23668482 TI - Necrotizing sarcoid granulomatosis with hemoptysis: a case report and literature review. AB - We present a case of 39-year-old male with the symptoms of fever, cough, chest pain and bloody phlegm, whose chest CT showed multiple subpleural nodules and inflammatory infiltration. Video-Assisted Thoracic Surgery ( VATS ) for right subplural nodule was performed and confirmed the diagnosis of necrotizing sarcoid granulomatosis. Prednisolone was administered and the symptoms were under control untill the occurrence of intermittent hemoptysis after 10 months. Chest CT and bronchoscope revealed the right lower lobe nodule with intraluminal necrotic tissue in the right lower lobe posterior basal segment respectively. Fatal hemoptysis happened during endobronchial biopsy by flexible bronchoscope forcep. Based on this case, we reviewed the relevant literature and discussed the clinical features, pathological changes and prognosis of the disease. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1955868163936338. PMID- 23668483 TI - Predictors of pacemaker dependence and pacemaker dependence as a predictor of mortality in patients with implantable cardioverter defibrillator. AB - BACKGROUND: The prevalence, predictors, and survival for the development of pacemaker dependence (PD) in patients implanted with an implantable cardioverter defibrillator (ICD) are unknown. METHODS: This was a retrospective analysis of 1,550 consecutive patients with ICD implantation at a single center from 1996 to 2008 with a mean of 4.2 +/- 3.4 years. Patients with implant intrinsic heart rates less than 40 beats/min (n = 48) and cardiac resynchronization therapy (n = 444) were excluded leaving 1,058 patients in this study. PD was defined as an intrinsic rhythm <40 beats/min after inhibiting the pacemaker, <50 beats/min with transient symptoms of dizziness relieved by resumption of pacing and right ventricle pacing despite algorithms to promote intrinsic conduction at the 3 monthly follow-up ICD clinic visits. Multivariate regression and Cox proportional hazard models were used for analysis. RESULTS: The mean age was 64 +/- 13 years; 79% were male with a primary indication for the ICD in 57%. PD occurred in 142 (13.4%) of patients, with a mean time to PD of 2.6 +/- 1.9 years. PD was associated with a 48% increased odds for mortality versus non-PD ICD patients during the mean follow-up time of 4.2 +/- 3.4 years (adjusted odds ratio = 1.48 [95% confidence interval 1.080-2.042]; P = 0.015). Older age, a history of atrial fibrillation, amiodarone use, and secondary prevention were the strongest predictors for the development of PD. CONCLUSIONS: In this single-center ICD cohort, the development of PD was not uncommon and was associated with decreased survival. PMID- 23668484 TI - Lead optimization of a 4-aminopyridine benzamide scaffold to identify potent, selective, and orally bioavailable TYK2 inhibitors. AB - Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2 fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL 12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon gamma (IFNgamma), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo. PMID- 23668485 TI - Chlorine induces the unfolded protein response in murine lungs and skin. AB - Chlorine (Cl2) is an important industrial chemical. Accidental full body exposure to Cl2 poses an environmental, occupational, and public health hazard characterized mainly by injury to the lung, skin, and ocular epithelia. The cellular mechanisms underlying its acute toxicity are incompletely understood. This study examined whether whole body exposure of BALB/c mice to Cl2 in environmental chambers leads to the up-regulation of the unfolded protein response (UPR) in their lungs and skin. Shaved BALB/c mice were exposed to a sublethal concentration of Cl2 (400 ppm for 30 min) and returned to room air for 1 or 6 hours and killed. IL-6 and TNF-alpha were increased significantly at 1 and 6 hours after Cl2 exposure in the lungs and at 6 hours in the skin. These changes were accompanied by increased UPR signaling (i.e., activation of protein kinase RNA-like endoplasmic reticulum kinase, inositol-requiring enzyme 1 alpha, and activating transcription factor 6alpha) at these time points. The expression of hepcidin, which regulates tissue accumulation and mobilization of iron, was increased in the skin and lungs of Cl2-exposed mice. The data shown herein indicate for the first time the up-regulation of UPR signaling and hepcidin in the skin and lungs of Cl2-exposed mice, which persisted when the mice were returned to room air for 6 hours. PMID- 23668486 TI - Fifty-two-week continuous abstinence rates of smokers being treated with varenicline versus nicotine replacement therapy. AB - BACKGROUND AND AIMS: Cross-study comparisons of effect sizes suggest that varenicline is more effective than nicotine replacement therapy (NRT) in aiding smoking cessation, but evidence from direct comparisons is limited. This study compared biochemically verified 52-week sustained abstinence rates in smokers attending the same clinical service according to whether they used varenicline or NRT in their quit attempt. METHODS: This was a prospective cohort study of 855 smokers attending a large smoking cessation clinic who used their choice of NRT product or varenicline in their quit attempt. All received the same behavioural support programme and chose their medication option (n = 519 varenicline; n = 336 NRT). The primary outcome measure was self-report of 52 weeks' abstinence following the target quit date confirmed by expired air carbon monoxide concentration. Baseline measures included socio-demographic variables, mental health diagnoses, measures of smoking, cigarette dependence and past use of NRT or varenicline. RESULTS: The 52-week abstinence rates were 42.8% versus 31.0% in those using varenicline versus NRT, respectively (P < 0.001). After adjusting for all baseline variables, the odds of remaining abstinent for 52 weeks were 2.03 (95% CI 1.46-2.82), P < 0.001 times higher in those using varenicline than those using NRT. CONCLUSIONS: Smokers in the same behavioural support programme who use varenicline appear to have a greater probability of achieving long-term abstinence than those using their choice of nicotine replacement therapy options, even after adjusting for potentially confounding smoker characteristics. PMID- 23668487 TI - From cradle-to-grave at the nanoscale: gaps in U.S. regulatory oversight along the nanomaterial life cycle. AB - Engineered nanomaterials (ENMs) promise great benefits for society, yet our knowledge of potential risks and best practices for regulation are still in their infancy. Toward the end of better practices, this paper analyzes U.S. federal environmental, health, and safety (EHS) regulations using a life cycle framework. It evaluates their adequacy as applied to ENMs to identify gaps through which emerging nanomaterials may escape regulation from initial production to end-of life. High scientific uncertainty, a lack of EHS and product data, inappropriately designed exemptions and thresholds, and limited agency resources are a challenge to both the applicability and adequacy of current regulations. The result is that some forms of engineered nanomaterials may escape federal oversight and rigorous risk review at one or more stages along their life cycle, with the largest gaps occurring at the postmarket stages, and at points of ENM release to the environment. Oversight can be improved through pending regulatory reforms, increased research and development for the monitoring, control, and analysis of environmental and end-of-life releases, introduction of periodic re evaluation of ENM risks, and fostering a "bottom-up" stewardship approach to the responsible management of risks from engineered nanomaterials. PMID- 23668488 TI - Weak frustration regulates sliding and binding kinetics on rugged protein-DNA landscapes. AB - A fundamental step in gene-regulatory activities, such as repression, transcription, and recombination, is the binding of regulatory DNA-binding proteins (DBPs) to specific targets in the genome. To rapidly localize their regulatory genomic sites, DBPs reduce the dimensionality of the search space by combining three-dimensional (3D) diffusion in solution with one-dimensional (1D) sliding along DNA. However, the requirement to form a thermodynamically stable protein-DNA complex at the cognate genomic target sequence imposes a challenge on the protein because, as it navigates one-dimensionally along the genome, it may come in close contact with sites that share partial or even complete sequence similarity with the functional DNA sequence. This puzzling issue creates a conflict between two basic requirements: finding the cognate site quickly and stably binding it. Here, we structurally assessed the interface adopted by a variety of DBPs to bind DNA specifically and nonspecifically, and found that many DBPs utilize one interface to specifically recognize a DNA sequence and another to assist in propagating along the DNA through nonspecific associations. While these two interfaces overlap each other in some proteins, they present partial overlap in others and frustrate the protein-DNA interface. Using coarse-grained molecular dynamics simulations, we demonstrate that the existence of frustration in DBPs is a compromise between rapid 1D diffusion along other regions in the genome (high frustration smoothens the landscape for sliding) and rapid formation of a stable and essentially active protein-DNA complex (low frustration reduces the free energy barrier for switching between the two binding modes). PMID- 23668489 TI - Update on bevacizumab and other angiogenesis inhibitors for brain cancer. AB - INTRODUCTION: Primary and metastatic brain tumors remain a major challenge. The most common primary adult malignant brain tumor, glioblastoma (GBM), confers a dismal prognosis as does the development of CNS metastases for most systemic malignancies. Anti-angiogenic therapy has been a major clinical research focus in neuro-oncology over the past 5 years. AREAS COVERED: Culmination of this work includes US FDA accelerated approval of bevacizumab for recurrent GBM and the completion of two placebo-controlled Phase III studies of bevacizumab for newly diagnosed GBM. A multitude of anti-angiogenics are in evaluation for neuro oncology patients but none has thus far surpassed the therapeutic benefit of bevacizumab. EXPERT OPINION: These agents demonstrate adequate safety and the majority of GBM patients derive benefit. Furthermore, their anti-permeability effect can substantially decrease tumor-associated edema leading to stable or improved neurologic function and quality of life. In particular, anti-angiogenics significantly prolong progression-free survival - a noteworthy achievement in the context of infiltrative and destructive brain tumors like GBM; however, in a manner analogous to other cancers, their impact on overall survival for GBM patients is modest at best. Despite substantial clinical research efforts, many fundamental questions regarding anti-angiogenic agents in brain tumor patients remain unanswered. PMID- 23668490 TI - Women's health--broadening the remit. PMID- 23668491 TI - Homelessness, health, and inclusion. PMID- 23668492 TI - Promoting healthy hearing. PMID- 23668493 TI - SARS legacy: outbreak reporting is expected and respected. PMID- 23668496 TI - Fukushima residents still struggling 2 years after disaster. PMID- 23668497 TI - Backlash against new NHS competition regulations. PMID- 23668498 TI - Israeli doctors accused of collusion in torture. PMID- 23668501 TI - Joseph Sung: marking the tenth anniversary of SARS. PMID- 23668503 TI - The benefits and harms of breast cancer screening. PMID- 23668504 TI - The benefits and harms of breast cancer screening. PMID- 23668505 TI - The benefits and harms of breast cancer screening. PMID- 23668506 TI - The benefits and harms of breast cancer screening. PMID- 23668507 TI - The benefits and harms of breast cancer screening. PMID- 23668508 TI - The benefits and harms of breast cancer screening. PMID- 23668509 TI - The benefits and harms of breast cancer screening. PMID- 23668510 TI - The benefits and harms of breast cancer screening. PMID- 23668511 TI - The benefits and harms of breast cancer screening. PMID- 23668512 TI - The benefits and harms of breast cancer screening. PMID- 23668513 TI - The benefits and harms of breast cancer screening - Authors' reply. PMID- 23668516 TI - Traumatic brain injury and fracture. PMID- 23668517 TI - India launches programme for child-health screening. PMID- 23668519 TI - Onychomycosis in close quarter living review of the literature. AB - Onychomycosis is defined as a fungal infection of the nail bed and/or nail plate. The prevalence of onychomycosis has increased dramatically as a worldwide condition in the twentieth century due to occlusive footwear, global wars and natural migration. Risk factors generally leading to onychomycosis development include bodily spread of dermatophyte and non-dermatophyte tinea pedis, peripheral vascular disease, damaged nails via sports and trauma, older age, genetics, immunodeficiency and diabetes. Many publications discuss prevalence, symptoms and treatment of the disease in individual cases, hospitals or specific locations, but few strongly link the cause of onychomycosis to living environments. This is a review of the current literature on the prevalence of onychomycosis and its relationship to surrounding living environments of those infected. A Pubmed search was performed with 'onychomycosis'. Articles were selected based on the relevance to close quarter living environments. All ages can be affected with onychomycosis, ranging from children in boarding schools to elderly in nursing homes. Although not directly linking living environments to transmission and infection in all articles reviewed, onychomycosis was very prevalent in many different close quarter living settings, including within families, boarding schools, military quarters and nursing homes. This review demonstrates that various close quarter living environments are highly associated with increased transmission and infection with onychomycosis. PMID- 23668520 TI - Molecular weight effects upon the adhesive bonding of a mussel mimetic polymer. AB - Characterization of marine biological adhesives are teaching us how nature makes materials and providing new ideas for synthetic systems. One of the most widely studied adhering animals is the marine mussel. This mollusk bonds to wet rocks by producing an adhesive from cross-linked proteins. Several laboratories are now making synthetic mimics of mussel adhesive proteins, with 3,4 dihydroxyphenylalanine (DOPA) or similar molecules pendant from polymer chains. In select cases, appreciable bulk bonding results, with strengths as high as commercial glues. Polymer molecular weight is amongst several parameters that need to be examined in order to both understand biomimetic adhesion as well as to maximize performance. Experiments presented here explore how the bulk adhesion of a mussel mimetic polymer varies as a function of molecular weight. Systematic structure-function studies were carried out both with and without the presence of an oxidative cross-linker. Without cross-linking, higher molecular weights generally afforded higher adhesion. When a [N(C4H9)4](IO4) cross-linker was added, adhesion peaked at molecular weights of ~50,000-65,000 g/mol. These data help to illustrate how changes to the balance of cohesion versus adhesion influence bulk bonding. Mussel adhesive plaques achieve this balance by incorporating several proteins with molecular weights ranging from 6000 to 110,000 g/mol. To mimic these varied proteins we made a blend of polymers containing a range of molecular weights. Interestingly, this blend adhered more strongly than any of the individual polymers when cross-linked with [N(C4H9)4](IO4). These results are helping us to both understand the origins of biological materials as well as design high performance polymers. PMID- 23668522 TI - Obesity in pregnancy. PMID- 23668523 TI - Dietary fat modification and the risk of future cardiovascular events and mortality. PMID- 23668524 TI - Diagnosis and management of acute diverticulitis. AB - Uncomplicated diverticulitis is localized diverticular inflammation, whereas complicated diverticulitis is diverticular inflammation associated with an abscess, phlegmon, fistula, obstruction, bleeding, or perforation. Patients with acute diverticulitis may present with left lower quadrant pain, tenderness, abdominal distention, and fever. Other symptoms may include anorexia, constipation, nausea, diarrhea, and dysuria. Initial laboratory studies include a complete blood count, basic metabolic panel, urinalysis, and measurement of C reactive protein. Computed tomography, the most commonly performed imaging test, is useful to establish the diagnosis and the extent and severity of disease, and to exclude complications in selected patients. Colonoscopy is recommended four to six weeks after resolution of symptoms for patients with complicated disease or for another indication, such as age-appropriate screening. In mild, uncomplicated diverticulitis, antibiotics do not accelerate recovery, or prevent complications or recurrences. Hospitalization should be considered if patients have signs of peritonitis or there is suspicion of complicated diverticulitis. Inpatient management includes intravenous fluid resuscitation and intravenous antibiotics. Patients with a localized abscess may be candidates for computed tomography guided percutaneous drainage. Fifteen to 30 percent of patients admitted with acute diverticulitis require surgical intervention during that admission. Laparoscopic surgery results in a shorter length of stay, fewer complications, and lower in-hospital mortality compared with open colectomy. The decision to proceed to surgery in patients with recurrent diverticulitis should be individualized and based on patient preference, comorbidities, and lifestyle. Interventions to prevent recurrences of diverticulitis include increased intake of dietary fiber, exercise, cessation of smoking, and, in persons with a body mass index of 30 kg per m(2) or higher, weight loss. PMID- 23668525 TI - Psoriasis. AB - Psoriasis is a chronic inflammatory skin condition that is often associated with systemic manifestations. It affects about 2 percent of U.S. adults, and can significantly impact quality of life. The etiology includes genetic and environmental factors. Diagnosis is based on the typical erythematous, scaly skin lesions, often with additional manifestations in the nails and joints. Plaque psoriasis is the most common form. Atypical forms include guttate, pustular, erythrodermic, and inverse psoriasis. Psoriasis is associated with several comorbidities, including cardiovascular disease, lymphoma, and depression. Topical therapies such as corticosteroids, vitamin D analogs, and tazarotene are useful for treating mild to moderate psoriasis. More severe psoriasis may be treated with phototherapy, or may require systemic therapy. Biologic therapies, including tumor necrosis factor inhibitors, can be effective for severe psoriasis and psoriatic arthritis, but have significant adverse effect profiles and require regular monitoring. Management of psoriasis must be individualized and may involve combinations of different medications and phototherapy. PMID- 23668526 TI - Clinical management of urinary incontinence in women. AB - Most cases of urinary incontinence in women fall under one of three major subtypes: urge, stress, or mixed. A stepped-care approach that advances from least invasive (behavioral modification) to more invasive (surgery) interventions is recommended. Bladder retraining and pelvic floor muscle exercises are first line treatments for persons without cognitive impairment who present with urge incontinence. Neuromodulation devices, such as posterior tibial nerve stimulators, are an option for urge incontinence that does not respond to behavioral therapy. Pharmacologic therapy with anticholinergic medications is another option for treating urge incontinence if behavioral therapy is unsuccessful; however, because of adverse effects, these agents are not recommended in older adults. Other medication options for urge incontinence include mirabegron and onabotulinumtoxinA. Sacral nerve stimulators, which are surgically implanted, have also been shown to improve symptoms of urge incontinence. Pelvic floor muscle exercises are considered first-line treatment for stress incontinence. Noninvasive electrical and magnetic stimulation devices are also available. Alternatives for treating stress incontinence include vaginal inserts, such as pessaries, and urethral plugs. Limited or conflicting evidence exists for the use of medications for stress incontinence; no medications are approved by the U.S. Food and Drug Administration for this condition. Minimally invasive procedures, including radiofrequency denaturation of the urethra and injection of periurethral bulking agents, can be used if stress incontinence does not respond to less invasive treatments. Surgical interventions, such as sling and urethropexy procedures, should be reserved for stress incontinence that has not responded to other treatments. PMID- 23668528 TI - Multiple vesicles and bullae on the scrotum. PMID- 23668529 TI - AUA guideline addresses diagnosis, evaluation, and follow-up of asymptomatic microhematuria. PMID- 23668531 TI - Psoriasis. PMID- 23668530 TI - Diverticulitis. PMID- 23668532 TI - Asymptomatic brucellosis infection in humans: implications for diagnosis and prevention. AB - Human brucellosis is mainly caused by contact with Brucella-infected animals and their secretions and carcasses. Individuals who are continuously in contact with animals are considered to be at a high risk but only some show symptoms and are diagnosed as cases of brucellosis. Here, we showed that asymptomatic brucellosis infections occur among humans. Asymptomatic infections mainly result from less frequent contact with Brucella and/or contact with low-virulence Brucella. In our study, patients with asymptomatic infection had low antibody titres and different contact patterns. Awareness of asymptomatic infection is important for early diagnosis of brucellosis and prevention of chronic infection. PMID- 23668533 TI - Syntheses of 3,4-benzotropolones by ring-closing metatheses. AB - Ortho-lithiated styrenes or ortho-lithiated benzaldehyde dimethyl acetals were added to 2,2-dimethoxypent-4-enals 7. The resulting alcohols were carried on to the aromatic dienones 10. These were ring-closed by olefin metathesis. Hydrolysis of the dimethyl ketal moiety and enolization provided the 3,4-benzotropolones 5. Overall, this access comprises 4-6 steps and totaled a 22-81% yield. PMID- 23668534 TI - Combination therapy of dipeptidyl peptidase-4 inhibitors and metformin in type 2 diabetes: rationale and evidence. AB - The main pathogenesis of type 2 diabetes mellitus (T2DM) includes insulin resistance and pancreatic islet dysfunction. Metformin, which attenuates insulin resistance, has been recommended as the first-line antidiabetic medication. Dipeptidyl peptidase-4 (DPP-4) inhibitors are novel oral hypoglycaemic agents that protect glucagon-like peptide-1 (GLP-1) from degradation, maintain the bioactivity of endogenous GLP-1, and thus improve islet dysfunction. Results from clinical trials have shown that the combination therapy of DPP-4 inhibitors and metformin [as an add-on, an initial combination or a fixed-dose combination (FDC)] provides excellent efficacy and safety in patients with T2DM. Moreover, recent studies have suggested that metformin enhances the biological effect of GLP-1 by increasing GLP-1 secretion, suppressing activity of DPP-4 and upregulating the expression of GLP-1 receptor in pancreatic beta-cells. Conversely, DPP-4 inhibitors have a favourable effect on insulin sensitivity in patients with T2DM. Therefore, the combination of DPP-4 inhibitors and metformin provides an additive or even synergistic effect on metabolic control in patients with T2DM. This article provides an overview of clinical evidence and discusses the rationale for the combination therapy of DPP-4 inhibitors and metformin. PMID- 23668537 TI - Genetics of hypopigmentary disorders. PMID- 23668536 TI - Economic empowerment and AIDS-related stigma in rural Kenya: a double-edged sword? AB - Economic empowerment, HIV risk and AIDS-related stigma appear intricately intertwined for women in Kenya. Their interaction must be understood in order to implement effective economic interventions that also decrease HIV risk and stigma. We conducted a qualitative study amongst women in a rural Kamba-speaking community of southeastern Kenya to pursue whether engagement in an economic empowerment initiative (a basket weaving cooperative) influences women's perspectives and experiences with HIV risk and AIDS-related stigma. We conducted seven women's focus groups: participants in the local basket-weaving cooperative comprised four focus groups and non-participants comprised the remaining three groups. The HIV status of the women was not known. Three dominant themes emerged from the focus groups: empowerment, pervasive vulnerability and unanticipated social paradoxes. Contradictions found in these themes suggest that economic empowerment can become a double-edged sword. Economic empowerment enhanced perceived individual, domestic and social community status. However, this enhancement was not protective of domestic violence and perceived HIV risk. Social perceptions may have paradoxically contributed barriers to HIV testing and treatment putting women at greater HIV risk. In conclusion, economic empowerment initiatives for women in developing countries in the context of the HIV epidemic should be coupled with peer mediated support and HIV-risk education. PMID- 23668539 TI - Albinism in Europe. AB - Albinism is a rare genetic condition associated with a variable hypopigmentation phenotype, which can affect the pigmentation of only the eyes or both the eyes and the skin/hair, resulting in ocular (OA) or oculocutaneous albinism (OCA), respectively. At least four forms of OCA and one of OA are known, associated with TYR (OCA1), OCA2 (OCA2), TYRP1 (OCA3), SLC45A2 (OCA4) and GPR143 (OA1) loci, respectively. Additionally, the rarest syndromic forms of albinism, affecting the normal function of other organs, can be grouped in Hermansky-Pudlak syndrome (HPS1-9) and the Chediak-Higashi syndrome (CHS1). In summary, a total of 15 genes are currently associated with various types of albinism. However, new genes have been recently described, associated with autosomal recessive oculocutaneous albinism with highly similar phenotypes but diverse molecular origin, indicating that there are likely to be more than 15 genes whose mutations will be associated with albinism. In this review, we will describe the different types of albinism and comment on its prevalence in European countries. Some preclinical attempts for innovative therapeutic approaches of different types of albinism will be also discussed. PMID- 23668540 TI - Hypopigmentation in Hermansky-Pudlak syndrome. AB - Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, bleeding tendency, and ceroid deposition which often leads to death in midlife. Currently, nine genes have been identified as causative for HPS in humans. Hypopigmentation is the prominent feature of HPS, attributable to the disrupted biogenesis of melanosome, a member of the lysosome-related organelle (LRO) family. Current understanding of the cargo transporting mechanisms into the melanosomes expands our knowledge of the pathogenesis of hypopigmentation in HPS patients. PMID- 23668538 TI - Modern vitiligo genetics sheds new light on an ancient disease. AB - Vitiligo is a complex disorder in which autoimmune destruction of melanocytes results in white patches of skin and overlying hair. Over the past several years, extensive genetic studies have outlined a biological framework of vitiligo pathobiology that underscores its relationship to other autoimmune diseases. This biological framework offers insight into both vitiligo pathogenesis and perhaps avenues towards more effective approaches to treatment and even disease prevention. PMID- 23668541 TI - Alopecia areata possibly induced by autoimmune reaction in a patient with human T cell lymphotropic virus-1-associated myelopathy. AB - A 38-year-old female patient suffered from alopecia areata totalis followed by human T-cell lymphotropic virus-1-associated myelopathy (HAM). These two diseases have recently been considered to be related to cell-mediated autoimmune reactions. Immunohistochemistry revealed accumulation of CXCR3+ CD8+ T cells around hair bulbs in alopecic lesions. Furthermore, flow cytometric analysis showed the elevated frequency of CD8+ human leukocyte antigen DR+ -activated T cells at the initial time and declined at the hair regrowth phase with HAM. CD4+ CD25+ adult T-cell leukemia/lymphoma cells were elevated at hair loss phase and decreased after improvement of hair loss. These results suggest that autoreactive and cytotoxic CD8(+) T cells induce not only alopecia areata but also HAM in ATL patients. This case highlights that the autoimmune reactions may play an important role in the pathogenesis of alopecia areata and HAM. PMID- 23668535 TI - DNA barcoding commercially important fish species of Turkey. AB - DNA barcoding was used in the identification of 89 commercially important freshwater and marine fish species found in Turkish ichthyofauna. A total of 1765 DNA barcodes using a 654-bp-long fragment of the mitochondrial cytochrome c oxidase subunit I gene were generated for 89 commercially important freshwater and marine fish species found in Turkish ichthyofauna. These species belong to 70 genera, 40 families and 19 orders from class Actinopterygii, and all were associated with a distinct DNA barcode. Nine and 12 of the COI barcode clusters represent the first species records submitted to the BOLD and GenBank databases, respectively. All COI barcodes (except sequences of first species records) were matched with reference sequences of expected species, according to morphological identification. Average nucleotide frequencies of the data set were calculated as T = 29.7%, C = 28.2%, A = 23.6% and G = 18.6%. Average pairwise genetic distance among individuals were estimated as 0.32%, 9.62%, 17,90% and 22.40% for conspecific, congeneric, confamilial and within order, respectively. Kimura 2 parameter genetic distance values were found to increase with taxonomic level. For most of the species analysed in our data set, there is a barcoding gap, and an overlap in the barcoding gap exists for only two genera. Neighbour-joining trees were drawn based on DNA barcodes and all the specimens clustered in agreement with their taxonomic classification at species level. Results of this study supported DNA barcoding as an efficient molecular tool for a better monitoring, conservation and management of fisheries. PMID- 23668542 TI - Development and analysis of alpha 1-antitrypsin neoglycoproteins: the impact of additional N-glycosylation sites on serum half-life. AB - Therapeutic efficacy of glycoproteins is affected by many factors, including molecular size and net charge; both are influenced by the presence and composition of glycan structures. Human alpha 1-antitrypsin (A1AT) was cloned and expressed in human embryonic kidney cells (HEK293) that are capable of mammalian glycosylation. Utilizing PCR-based site-directed mutagenesis, new A1AT variants were created with single, double, or triple additional N-glycosylation sites to the three naturally occurring N-glycosylation sites. Because of the supplementary N-glycans, the A1AT variants exhibited an increased molecular weight. Retention of inhibitory activity was shown via trypsin inhibitory assay. The A1AT variants were treated with PNGase F, and the resulting N-glycans were analyzed by MALDI TOF mass spectrometry. The N-glycan profile of the recombinant A1AT variants was mostly composed of monofucosylated bi-, tri-, and tetraantennary complex-type N glycans, with a tendency toward higher antennary structures compared to the wild type. The relevance of N-glycosylation in A1AT for the circulatory serum half life was demonstrated in CD1 mice. The A1AT neoglycoprotein with an additional N glycosylation site at position N123 exhibited a 62% increase in serum half-life. Additionally, using a two-compartment model, the A1AT variants exhibited increased alpha-phase values, especially N123 (223%) and N201 (255%). The results suggest the recombinant A1AT neoglycoprotein as a serious alternative to A1AT derived from human plasma. PMID- 23668543 TI - Oncostatin M modulates fibroblast function via signal transducers and activators of transcription proteins-3. AB - Oncostatin M (OSM), an inflammatory cytokine of the interleukin-6 (IL-6) superfamily, plays a key role in various biological processes such as modulation of extracellular matrix (ECM), cell proliferation, cell survival, and induction of inflammation. It has been reported that OSM was increased in asthma and pulmonary fibrosis, and thus OSM may play a role in airway remodeling and the development of lung parenchymal fibrosis. Recruitment of lung fibroblasts to the sites of airway injury and subsequent differentiation into myofibroblasts is believed to contribute to excess ECM deposition. In the current study, we assessed the ability of OSM to modulate fibroblast collagen gel contraction, migration toward fibronectin, and expression of alpha-smooth muscle actin (alpha SMA). We demonstrated that OSM augments gel contraction, chemotaxis, and alpha SMA expression. OSM-augmented fibroblast chemotaxis was mediated by the signal transducer and activator of transcription (STAT3) and p38 mitogen-activated protein kinase, while augmentation on gel contraction and alpha-SMA expression was mediated by STAT3. Neither transforming growth factor-beta1 nor PGE2 was involved in mediating OSM effect on the cells. The Th2 cytokines IL-4 and IL-13, which also are believed to play an important role in promoting lung fibrosis and airway remodeling, act through STAT3, and we demonstrated the potential for additive effects of OSM with IL-4 and IL-13. The present study supports the concept that OSM may contribute to tissue remodeling, which may be additive with IL-4 or IL-13. Blockade of OSM or OSM-mediated STAT3 signaling could be a therapeutic target to regulate lung fibrotic mechanisms. PMID- 23668544 TI - Pet ownership, dog types and attachment to pets in 9-10 year old children in Liverpool, UK. AB - BACKGROUND: Little is known about ethnic, cultural and socioeconomic differences in childhood ownership and attitudes to pets. The objective of this study was to describe the factors associated with living with different pet types, as well as factors that may influence the intensity of relationship or 'attachment' that children have to their pet. Data were collected using a survey of 1021 9-10 year old primary school children in a deprived area of the city of Liverpool, UK. RESULTS: Dogs were the most common pet owned, most common 'favourite' pet, and species most attached to. Twenty-seven percent of dog-owning children (10% of all children surveyed) reported living with a 'Bull Breed' dog (which includes Pit Bulls and Staffordshire Bull Terriers), and the most popular dog breed owned was the Staffordshire Bull Terrier. Multivariable regression modelling identified a number of variables associated with ownership of different pets and the strength of attachment to the child's favourite pet. Girls were more likely to own most pet types, but were no more or less attached to their favourite pet than boys. Children of white ethnicity were more likely to own dogs, rodents and 'other' pets but were no more or less attached to their pets than children of non-white ethnicity. Single and youngest children were no more or less likely to own pets than those with younger brothers and sisters, but they showed greater attachment to their pets. Children that owned dogs lived in more deprived areas than those without dogs, and deprivation increased with number of dogs owned. 'Pit Bull or cross' and 'Bull Breed' dogs were more likely to be found in more deprived areas than other dog types. Non-whites were also more likely to report owning a 'Pit Bull or cross' than Whites. CONCLUSIONS: Gender, ethnicity and socioeconomic status were associated with pet ownership, and sibling status with level of attachment to the pet. These are important to consider when conducting research into the health benefits and risks of the common childhood phenomenon of growing up with pets. PMID- 23668545 TI - In vitro delivery of aerosolized treprostinil via modern mechanical ventilation. AB - BACKGROUND: The Tyvaso Inhalation System is a hand-held nebulizer system used to administer treprostinil, an approved therapy for pulmonary arterial hypertension. Our goal was to establish an in vitro method for delivering a standard dose of treprostinil through a ventilator circuit and artificial airway. METHODS: An AeroTech II jet nebulizer (continuous air flow at 10 L/min; Biodex Medical Systems) was placed in the ventilator circuit with a test lung. Two ventilators were tested, the Drager Evita 2 Dura (Drager Medical GmbH) and Avea (CareFusion), without humidity. Delivered dose was defined by capturing radiolabeled particles exiting the endotracheal tube with a filter (Pari) and measuring radioactivity. Particle distributions were measured distal to the endotracheal tube by cascade impaction. We hypothesized that drug delivery would be determined by the number of breaths needed, such that the complete time of inspiration totaled 29 sec (e.g., number of breaths needed=29 sec/TI, where TI is the inspiratory time of an average breath read from the ventilator display). RESULTS: Nebulizer output was linear for 6 min, and the standard prescribed target dose of 54 MUg (3.1% of full ampule) was delivered in 29 sec. Using our TI algorithm to control delivery, the mean inhaled dose+/-SD was 72.2+/-16.5 MUg (range 47.2-98.6; n=23). Drager delivered higher doses than Avea. Effects of mode, breathing pattern, and positive-end expiratory pressures were not significant. The mass median aerodynamic diameter and fine particle fraction were 0.71+/-0.015 and 0.997+/ 0.0006, respectively. CONCLUSIONS: Using the algorithm, it was possible to deliver aerosolized treprostinil, at controlled doses, via mechanical ventilation over a wide range of controlled breathing patterns. The conditions of nebulization must be precisely followed (one full ampule per treatment, use of the AeroTech II nebulizer, continuous nebulization using an external flow of 10 L/min, bypass of the humidifier or removal of in-line heat and moisture exchanger, and treatment completed in 6 min or less). PMID- 23668546 TI - Influence of exhalation valve and nebulizer position on albuterol delivery during noninvasive positive pressure ventilation. AB - BACKGROUND: Early studies have found better clinical efficiency when a nebulizer was used with noninvasive positive pressure ventilation (NPPV), compared with spontaneous breathing without NPPV. However, very limited research addressed factors that might affect aerosol delivery. This study aimed to investigate the influence of exhalation valves and nebulizer positions on aerosol delivery during NPPV. METHODS: We determined the efficiency of aerosol delivery in patients receiving NPPV with a lung model that simulates spontaneous breathing. Single arch exhalation port, plateau exhalation valve, and whisper swivel were chosen as exhalation valves under different levels of inspiratory and expiratory pressures. A nebulizer was filled with 1 mL of 0.5% albuterol solution in 3 mL of normal saline, driven with 8 L/min oxygen, and placed at either a proximal position in the ventilator circuit (near the ventilator outlet, where humidifiers are usually connected) or a distal position in the ventilator circuit (between exhalation valve and lung model connection). Albuterol was collected by filters and then measured by ultraviolet spectrophotometry. The velocities of gas flow were also measured at different nebulizer positions. RESULTS: Significant differences in the gas flow velocity were shown between proximal and distal positions of the breathing circuit under four combinations of inspiratory and expiratory pressure levels (15/5, 15/10, 25/5, and 25/10 cmH2O) (p<0.05). When the nebulizer was positioned distally, the single-arch exhalation port had the highest aerosol delivery, and the whisper swivel had the lowest aerosol delivery (p<0.05). When the nebulizer was placed proximally, the single-arch exhalation port had lower efficiency of aerosol delivery than the whisper swivel and plateau exhalation valve (p<0.05). In addition, higher inspiratory pressure was associated with increased aerosol delivery (p<0.05). The influence of expiratory pressure on aerosol delivery appeared too complex to predict. CONCLUSIONS: The type of exhalation valve and the position of the nebulizer in the ventilator circuit have a significant influence on the efficiency of aerosol delivery during NPPV. As a result, with different exhalation valves, an appropriate nebulizer position should be carefully chosen, and the inhaled dose should be adjusted after accurate prediction of aerosol delivery to ensure optimal clinical efficacy. PMID- 23668547 TI - Comparison of laser diffraction measurements by Mastersizer X and Spraytec to characterize droplet size distribution of medical liquid aerosols. AB - BACKGROUND: The Mastersizer X (Malvern Instruments) used to be the reference device for assessing droplet size distribution of aerosols by laser diffraction, but it has not been updated and has gradually been replaced by the Spraytec (Malvern Instruments), which is considered to provide greater accuracy and higher acquisition speed. METHODS: The aim of this study was to compare the use of the two diffractometers to characterize medical liquid aerosols in a wide range of droplet sizes, using four nasal sprays to produce large droplets (10-180 MUm) and 10 nebulizers to produce smaller droplets (0.5-20 MUm). The influence of the inhalation cell provided with the Spraytec on the measurements was also determined. RESULTS: Correlation between the devices was low for large droplets (R(2)=0.37) and high for smaller droplets (R(2)=0.97). The Spraytec overestimated the median diameter of small droplets by 14%, and Bland-Altman tests showed no equivalence (limits of agreement over 20%). An artifact peak in the large size range was observed with the Spraytec, which could be due to difficulty for the multiple scattering algorithm to process high-density aerosol clouds. The difference was reduced to 5% by using the inhalation cell provided by the Spraytec with a 15 L/min aspiration. CONCLUSION: The Mastersizer X and the Spraytec cannot be considered as equivalent laser diffraction devices, but the difference can be reduced with the Spraytec inhalation cell. PMID- 23668548 TI - Lung deposition and pharmacokinetics of nebulized cyclosporine in lung transplant patients. AB - BACKGROUND: Inhaled cyclosporine (CsA) is being investigated as a prophylaxis for lung transplant rejection. Lung deposition and systemic exposure of nebulized CsA in lung transplant patients was evaluated as part of the Phase 3 cyclosporine inhalation solution (CIS) trial (CYCLIST). METHODS: Ten patients received 300 mg of CIS (62.5 mg/mL CsA in propylene glycol) admixed with 148 MBq of Tc-DTPA (technetium-99m bound to diethylenetriaminepentaacetic acid) administered using a Sidestream((r)) disposable jet nebulizer. Deposition was assessed using a dual headed gamma camera. Blood samples were collected over a 24-hr time period after aerosol dosing and analyzed for CsA levels. A pharmacokinetic analysis of the resulting blood concentration versus time profiles was performed. RESULTS: The average total deposited dose was 53.7 +/- 12.7 mg. Average pulmonary dose was 31.8 +/- 16.3 mg, and stomach dose averaged 15.5 +/- 11.1 mg. Device performance was consistent, with breathing maneuvers influencing dose variation. Predose coaching with five of 10 patients reduced stomach deposition (22.6 +/- 11.2 vs. 8.3 +/- 5.2 mg; p=0.03). Blood concentrations declined quickly from a maximum of 372 +/- 140 ng/mL to 15.3 +/- 9.7 ng/mL at 24 hr post dose. Levels of AUC(0-24) [area under the concentration vs. time curve from 0 to 24 hr] averaged 1,493 +/- 746 ng hr/mL. On a three times per week dose regimen, this represents <5% of the weekly systemic exposure of twice per day oral administration. CONCLUSIONS: Substantial doses of CsA can be delivered to the lungs of lung transplant patients by inhaled aerosol. Systemic levels are small relative to typical oral CsA administration. PMID- 23668549 TI - Anti-Vascular endothelial growth factor therapy impairs endothelial function of retinal microcirculation in colon cancer patients - an observational study. AB - BACKGROUND: To assess acute effects of bevacizumab (anti-VEGF therapy) on cerebral microvessels and systemic cardiovascular regulation. DESIGN AND SUBJECTS: 20 consecutive patients with colorectal cancer (median age: 60.4 years, range 45.5-73.9 years) received bevacizumab intravenously (5 mg/kg) uncoupled of chemotherapy. Prior to and within the first 24 hours after bevacizumab infusion, patients were investigated for retinal endothelial function. A series of a triple 24-hour ambulatory blood pressure measurement was conducted. Retinal endothelial function was determined as flicker light-induced vasodilation. The integrity of baroreflex arc and autonomic cardiovascular control was examined by stimulatory manoeuvres. RESULTS: Bevacizumab therapy significantly reduced the vasodilatory capacity of retinal arterioles in response to flicker light. A slight decrease in diastolic pressure and heart rate was observed after bevacizumab infusion but this was unrelated to changes in retinal function. The pressure response upon nitroglycerin was largely preserved after bevacizumab infusion. The proportion of patients with abnormal nocturnal blood pressure regulation increased under anti angiogenic therapy. Autonomic blood pressure control was not affected by bevacizumab treatment. CONCLUSIONS: Bevacizumab acutely impairs microvascular function independent of blood pressure changes. Imaging of the retinal microcirculation seems a valuable tool for monitoring pharmacodynamic effects of bevacizumab. TRIAL REGISTRATION: NCT ID: NCT00740168. PMID- 23668550 TI - Boron as a surrogate for N-nitrosodimethylamine rejection by reverse osmosis membranes in potable water reuse applications. AB - The results of this study reveal a strong linear correlation (R(2) = 0.95) between the rejections of boron and N-nitrosodimethylamine (NDMA) by six different reverse osmosis (RO) membranes, suggesting that boron can be used as a surrogate for NDMA rejection. This proposal is based on the premise that the rejection of both boric acid and NDMA is governed by steric hindrance and that they have similar molecular dimensions. The concept proposed here is shown to be valid at pH 8 or below where boron exists as the neutral boric acid species and NDMA is also a neutral solute. Observed changes in the rejections of these two species, as a function of permeate fluxes and feed solution temperatures, were also almost identical. Boron rejection increased from 21 to 79%, and the correlation coefficient of the linear regression between boron and NDMA rejections was 0.99 as the permeate flux increased from 5 to 60 L m(-2)h(-1). Similarly, a linear correlation between boron and NDMA rejections was observed as the feed solution temperature increased from 10 to 40 degrees C. This linear correlation was also validated in a tertiary treated effluent matrix. PMID- 23668551 TI - The challenge of atrial tachycardia management in rheumatic heart disease. PMID- 23668553 TI - Roles of viscosity, polarity, and hydrogen-bonding ability of a pyrrolidinium ionic liquid and its binary mixtures in the photophysics and rotational dynamics of the potent excited-state intramolecular proton-transfer probe 2,2'-bipyridine 3,3'-diol. AB - The room-temperature ionic liquid [C3mpyr][Tf2N] and its binary mixtures with methanol and acetonitrile provide microenvironments of varying viscosity, polarity, and hydrogen-bonding ability. The present work highlights their effects on the photophysics and rotational dynamics of a potent excited-state intramolecular double-proton-transfer (ESIDPT) probe, 2,2'-bipyridine-3,3'-diol [BP(OH)2]. The rotational diffusion of the proton-transferred diketo (DK) tautomer in [C3mpyr][Tf2N] ionic liquid was analyzed for the first time from the experimentally obtained temperature-dependent fluorescence anisotropy data using Stokes-Einstein-Debye (SED) hydrodynamic theory and Gierer-Wirtz quasihydrodynamic theory (GW-QHT). It was found that the rotation of the DK tautomer in neat ionic liquid is governed solely by the viscosity of the medium, as the experimentally observed boundary-condition parameter, Cobs, was very close to the GW boundary-condition parameter (CGW). On the basis of photophysical studies of BP(OH)2 in IL-cosolvent binary mixtures, we suggest that methanol molecules form hydrogen bonds with the cationic counterpart of the DK tautomers, as evidenced by the greater extent of the decrease in the fluorescence lifetime of BP(OH)2 upon addition of methanol compared to acetonitrile. It is also possible for the methanol molecules to form hydrogen bonds with the constituents of the RTIL, which is supported by the lesser extent of the decrease in the viscosity of the medium upon addition of methanol, leading to a less effective decrease in the rotational relaxation time compared to that observed upon acetonitrile addition. PMID- 23668554 TI - The collectivity of drinking cultures: is the theory applicable to African settings? AB - AIMS: Skog's theory of collective drinking behaviour implies that countries with a strict informal social control of drinking alcohol would not exhibit 'collective displacement' of consumption (a linear association between population mean consumption and percentile values across the full range of the distribution), as do countries with less informal social control. This paper aimed to test this hypothesis by examining the alcohol consumption distributions in African countries with a strong informal control of alcohol. DESIGN SETTING, PARTICIPANTS AND MEASUREMENTS: Data on alcohol consumption from the World Health Organization's general population surveys in 15 African countries were aggregated and analysed with respect to skewedness and collective displacement of the distribution. FINDINGS: The distribution of consumption was strongly positively skewed, with 10-15% of the drinkers consuming more than twice the mean consumption. There was also clear evidence of a collective displacement of the consumption distribution, and the consumption mean was a strong predictor of the distribution percentile values across the full range of the distribution. Correspondingly, consumption mean predicted the prevalence of heavy drinkers. CONCLUSION: The distribution patterns of alcohol consumption in African countries are consistent with those observed previously in industrialized countries. These findings seem to counter Skog's theory of collective drinking behaviour and support the universality of the observation that the prevalence of problem drinking is linked closely to mean consumption. PMID- 23668555 TI - Controversies in primary treatment of low-risk papillary thyroid cancer. AB - In many parts of the world, incidence of papillary thyroid cancer is increasing faster than any other malignancy. Most papillary thyroid cancers that are diagnosed are small and are generally regarded as being low risk, with little or no effect on mortality. Papillary thyroid cancer is a clinical challenge because it is difficult to prove benefit from the traditional therapeutic triad for this disorder (ie, total thyroidectomy with or without prophylactic central neck dissection, radioiodine remnant ablation, and suppression of serum thyroid stimulating hormone with levothyroxine). However, risk of disease recurrence might be reduced by these therapies in a subset of patients with more aggressive disease. In the past decade, professional societies and other groups have established evidence-based clinical practice guidelines for management of papillary thyroid cancer, but these efforts have been made difficult by a paucity of randomised controlled trials. In this review, we summarise epidemiological data for disease incidence, discuss some controversies in disease management, and outline a therapeutic framework founded in the best available medical evidence and existing recommendations from clinical practice guidelines. PMID- 23668557 TI - UK hantavirus, renal failure, and pet rats. PMID- 23668558 TI - Taking on big soda. PMID- 23668556 TI - Progress in molecular-based management of differentiated thyroid cancer. AB - Substantial developments have occurred in the past 5-10 years in clinical translational research of thyroid cancer. Diagnostic molecular markers, such as RET-PTC, RAS, and BRAF(V600E) mutations; galectin 3; and a new gene expression classifier, are outstanding examples that have improved diagnosis of thyroid nodules. BRAF mutation is a prognostic genetic marker that has improved risk stratification and hence tailored management of patients with thyroid cancer, including those with conventionally low risks. Novel molecular-targeted treatments hold great promise for radioiodine-refractory and surgically inoperable thyroid cancers as shown in clinical trials; such treatments are likely to become a component of the standard treatment regimen for patients with thyroid cancer in the near future. These novel molecular-based management strategies for thyroid nodules and thyroid cancer are the most exciting developments in this unprecedented era of molecular thyroid-cancer medicine. PMID- 23668559 TI - Differentiated thyroid cancer: getting the complete picture. PMID- 23668560 TI - A new report card on the UK's health. PMID- 23668561 TI - GBD 2010 country results: a global public good. PMID- 23668562 TI - Health in the UK: could do even better? PMID- 23668563 TI - Enterovirus 71 encephalitis: a new vaccine on the horizon? PMID- 23668565 TI - 2013 Gairdner Global Health Award goes to King Holmes. PMID- 23668566 TI - The 2013 Gairdner Foundation International Award winners. PMID- 23668567 TI - China's new leaders cut off one-child policy at the root. PMID- 23668568 TI - Profile: SATVI--a leading light in tuberculosis vaccine research. PMID- 23668570 TI - David Nutt: making the medical case for addiction. PMID- 23668571 TI - "An inexpressible dread": psychoses of influenza at fin-de-siecle. PMID- 23668573 TI - Mortality from HIV in the Global Burden of Disease study - authors' reply. PMID- 23668574 TI - Mortality from HIV in the Global Burden of Disease study. PMID- 23668575 TI - Annual deaths attributable to physical inactivity: whither the missing 2 million? PMID- 23668576 TI - Time-critical mortality conditions in low-income and middle-income countries. PMID- 23668577 TI - Annual deaths attributable to physical inactivity: whither the missing 2 million? - Authors' reply. PMID- 23668578 TI - Integration not competition: surgical care in low-income and middle-income settings. PMID- 23668579 TI - Life expectancy in the Occupied Palestinian Territory. PMID- 23668580 TI - Can pregnant women in Blackpool wait for further research? PMID- 23668582 TI - Myth of falling productivity in the UK NHS confirmed. PMID- 23668583 TI - Loss of reason. PMID- 23668586 TI - Systematics and position of Nephrops among the lobsters. AB - This chapter presents and explains the position of Nephrops norvegicus in the classification of lobsters. Covered, in order, are systematic classification of Nephrops, taxonomic history of Nephrops, and analysis of Nephrops in nephropid phylogeny. The genus Nephrops was erected by Leach in 1814 and has a long and interesting taxonomic history. Prior to 1972, Nephrops was known by 14 Recent species. All but one of these, N. norvegicus, were removed to a new genus, Metanephrops, by Jenkins (1972). Today, N. norvegicus is still the only known living representative of the genus. Similarly, Nephrops is known by only one fossil species, the Miocene Nephrops kvistgaardae, although several other fossil species have been previously referred to this genus. Nephrops, along with the other familiar and commercially important marine clawed lobsters, is referred to Family Nephropidae, one of 17 marine clawed lobster families arrayed in 3 infraorders, 6 families each in the Astacidea and Glypheidea and 5 in the Polychelida. Infraorder Astacidea includes the Superfamily Nephropoidea, as well as the lesser known 'reef lobsters' of the Superfamily Enoplometopoidea, and the freshwater crayfish, Superfamily Astacoidea. In phylogenetic analyses, the freshwater crayfish form a sister group to the Nephropoidea. It is interpreted that freshwater crayfish evolved from nephropoid lobsters, but from which lobster group is uncertain. The taxonomic placement of N. norvegicus is stable at all levels, from species on up. Despite that, the phylogenetic relationships of Nephrops to other nephropid genera are unsettled due to conflicting results in morphological and molecular analyses. Currently, new morphological characters and new genes are being analysed in the hope of elucidating nephropid phylogeny. PMID- 23668584 TI - UK health performance: findings of the Global Burden of Disease Study 2010. AB - BACKGROUND: The UK has had universal free health care and public health programmes for more than six decades. Several policy initiatives and structural reforms of the health system have been undertaken. Health expenditure has increased substantially since 1990, albeit from relatively low levels compared with other countries. We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) to examine the patterns of health loss in the UK, the leading preventable risks that explain some of these patterns, and how UK outcomes compare with a set of comparable countries in the European Union and elsewhere in 1990 and 2010. METHODS: We used results of GBD 2010 for 1990 and 2010 for the UK and 18 other comparator nations (the original 15 members of the European Union, Australia, Canada, Norway, and the USA; henceforth EU15+). We present analyses of trends and relative performance for mortality, causes of death, years of life lost (YLLs), years lived with disability (YLDs), disability adjusted life-years (DALYs), and healthy life expectancy (HALE). We present results for 259 diseases and injuries and for 67 risk factors or clusters of risk factors relevant to the UK. We assessed the UK's rank for age-standardised YLLs and DALYs for their leading causes compared with EU15+ in 1990 and 2010. We estimated 95% uncertainty intervals (UIs) for all measures. FINDINGS: For both mortality and disability, overall health has improved substantially in absolute terms in the UK from 1990 to 2010. Life expectancy in the UK increased by 4.2 years (95% UI 4.2-4.3) from 1990 to 2010. However, the UK performed significantly worse than the EU15+ for age-standardised death rates, age-standardised YLL rates, and life expectancy in 1990, and its relative position had worsened by 2010. Although in most age groups, there have been reductions in age-specific mortality, for men aged 30-34 years, mortality rates have hardly changed (reduction of 3.7%, 95% UI 2.7-4.9). In terms of premature mortality, worsening ranks are most notable for men and women aged 20-54 years. For all age groups, the contributions of Alzheimer's disease (increase of 137%, 16-277), cirrhosis (65%, ?15 to 107), and drug use disorders (577%, 71-942) to premature mortality rose from 1990 to 2010. In 2010, compared with EU15+, the UK had significantly lower rates of age-standardised YLLs for road injury, diabetes, liver cancer, and chronic kidney disease, but significantly greater rates for ischaemic heart disease, chronic obstructive pulmonary disease, lower respiratory infections, breast cancer, other cardiovascular and circulatory disorders, oesophageal cancer, preterm birth complications, congenital anomalies, and aortic aneurysm. Because YLDs per person by age and sex have not changed substantially from 1990 to 2010 but age-specific mortality has been falling, the importance of chronic disability is rising. The major causes of YLDs in 2010 were mental and behavioural disorders (including substance abuse; 21.5% [95 UI 17.2-26.3] of YLDs), and musculoskeletal disorders (30.5% [25.5-35.7]). The leading risk factor in the UK was tobacco (11.8% [10.5-13.3] of DALYs), followed by increased blood pressure (9.0 % [7.5-10.5]), and high body-mass index (8.6% [7.4-9.8]). Diet and physical inactivity accounted for 14.3% (95% UI 12.8-15.9) of UK DALYs in 2010. INTERPRETATION: The performance of the UK in terms of premature mortality is persistently and significantly below the mean of EU15+ and requires additional concerted action. Further progress in premature mortality from several major causes, such as cardiovascular diseases and cancers, will probably require improved public health, prevention, early intervention, and treatment activities. The growing burden of disability, particularly from mental disorders, substance use, musculoskeletal disorders, and falls deserves an integrated and strategic response. FUNDING: Bill & Melinda Gates Foundation. PMID- 23668587 TI - Habitat and ecology of Nephrops norvegicus. AB - This review summarizes the data on habitat, population ecology and ecosystem roles of Nephrops norvegicus. The species has a broad range in the northeast Atlantic and Mediterranean, although it is possible that small or isolated patches of suitable habitat may not be occupied due to restrictions on larval supply. Nephrops densities are related to the silt-clay content of sediments, with interactions between habitat quality and density indicating competition for resources. An analysis of density-size interactions across fishery functional management units (FUs) suggests that growth is suppressed at high densities due to competition (e.g. in the western Irish Sea), although recruitment dynamics or size-selective mortality may also shape the size structure of populations. Nephrops biomass available across FUs may be similar, reflecting a constant yield due to the inverse relationship between individual size and population density. Gaps in the understanding of Nephrops' ecology reflect uncertain ageing criteria, reliance on fisheries-dependent data and few if any undisturbed habitats in which to examine fisheries-independent interactions. PMID- 23668589 TI - The reniform reflecting superposition compound eyes of Nephrops norvegicus: optics, susceptibility to light-induced damage, electrophysiology and a ray tracing model. AB - The large reniform eyes of the reptant, tube-dwelling decapod Nephrops norvegicus are described in detail. Optically these reflecting superposition compound eyes are a little unusual in that they are laterally flattened, a feature that may enhance their sensitivity in that region, albeit at the expense of resolution. Electrophysiological and anatomical investigations suggest that the eyes are tuned to appropriate spectral and temporal sensitivities in the long and short term through movement of proximal pigments and possibly rhabdom adaptation. Although exposure to ambient surface light intensities is shown to cause damage to the retinal layer, especially in deeper living animals, there is no evidence yet that demonstrates an impact of eye damage on their survival. It is suggested that experimentation on marine decapods, with sensitive eyes, requires that particular attention is paid to their light environment. PMID- 23668588 TI - Sensory biology and behaviour of Nephrops norvegicus. AB - The Norway lobster is one of the most important commercial crustaceans in Europe. A detailed knowledge of the behaviour of this species is crucial in order to optimize fishery yields, improve sustainability of fisheries, and identify man made environmental threats. Due to the cryptic life-style in burrows, the great depth and low-light condition of their habitat, studies of the behaviour of this species in its natural environment are challenging. Here, we first provide an overview of the sensory modalities (vision, chemoreception, and mechanoreception) of Nephrops norvegicus. We focus particularly on the role of the chemical and mechanical senses in eliciting and steering spatial orientation behaviours. We then concentrate on recent research in social behaviour and biological rhythms of Nephrops. A combination of laboratory approaches and newly developed tracking technologies has led to a better understanding of aggressive interactions, reproductive behaviours, activity cycles, and burrow-related behaviours. Gaps in our knowledge are identified and suggestions for future research are provided. PMID- 23668590 TI - Stress biology and immunology in Nephrops norvegicus. AB - The Norway lobster Nephrops norvegicus lives at low-light depths, in muddy substrata of high organic content where water salinities are high and fluctuations in temperature are moderate. In this environment, the lobsters are naturally exposed to a number of potential stressors, many of them as a result of the surficial breakdown of organic material in the sediment. This process (early diagenesis) creates a heterogeneous environment with temporal and spatial fluctuations in a number of compounds such as oxygen, ammonia, metals, and hydrogen sulphide. In addition to this, there are anthropogenically generated stressors, such as human-induced climate change (resulting in elevated temperature and ocean acidification), pollution and fishing. The lobsters are thus exposed to several stressors, which are strongly linked to the habitat in which the animals live. Here, the capacity of Nephrops to deal with these stressors is summarised. Eutrophication-induced hypoxia and subsequent metal remobilisation from the sediment is a well-documented effect found in some wild Nephrops populations. Compared to many other crustacean species, Nephrops is well adapted to tolerate periods of hypoxia, but prolonged or severe hypoxia, beyond their tolerance level, is common in some areas. When the oxygen concentration in the environment decreases, the bioavailability of redox-sensitive metals such as manganese increases. Manganese is an essential metal, which, taken up in excess, has a toxic effect on several internal systems such as chemosensitivity, nerve transmission and immune defence. Since sediment contains high concentrations of metals in comparison to sea water, lobsters may accumulate both essential and non essential metals. Different metals have different target tissues, though the hepatopancreas, in general, accumulates high concentrations of most metals. The future scenario of increasing anthropogenic influences on Nephrops habitats may have adverse effects on the fitness of the animals. PMID- 23668591 TI - Reproduction: life cycle, larvae and larviculture. AB - Nephrops norvegicus represents a very valuable fishery across Europe, and the species possesses a relatively complex life cycle and reproductive biology across spatial and temporal scales. Insights into embryonic and larval biology, and associated abiotic and biotic factors that influence recruitment, are important since this will affect population and species success. Much of the fishery, and indeed scientific sampling, is reliant on trawling, which is likely to cause direct and indirect stresses on adults and developing embryos. We have collated evidence, including that garnered from laboratory studies, to assess the likely effects on reproduction and population. Using know-how from hatchery operations in similar species such as Homarus sp., we also seek to optimise larviculture that could be commercialised to create a hatchery and thus assist stock remediation. This review chapter is therefore divided into three sections: (1) general N. norvegicus reproductive biology, (2) life cycle and larval biology and (3) a comprehensive review of all rearing attempts for this species to date, including a likely way forward for pilot scale and hence commercial restocking operations. PMID- 23668592 TI - Nephrops fisheries in European waters. AB - This review focuses on the Norway lobster (Nephrops norvegicus) as a resource, describing how the fishery has developed from the 1960s to the present day to become one of the most economically important fisheries in Europe. In 2010, the total landings were 66,500 tonnes, of which UK fishers landed a significant part (58.1%). The Nephrops fishery is also important for countries such as Ireland (11.7% of the total) and Sweden (1.9%) where it is of regional importance. Some are also taken in the Mediterranean, where Italian, Spanish and Greek fishers together take approximately 7% of the total landing. More than 95% of Nephrops are taken using single- or multi-rig trawlers targeting Nephrops or in mixed species fisheries. In regions such as Western Scotland and the Swedish West Coast, creel fisheries account for up to a quarter of the total landings. Across the range, a small proportion (<5%) is taken using traps in a fishery characterised by larger sized animals that gain a higher price and have lower discard and by-catches of ground fish with low mortalities. The trawling sector, however, is reducing the by-catches of ground fish with the aid of technical measures, such as square-mesh panels and grids and national systems of incentives. Assessments for Nephrops are operated via the 34 functional units (FUs) regarded as stocks. Changes in management procedures have arisen as a result of the advisory input from underwater TV fishery-independent stock surveys. The total allowable catch does not follow FUs but is agreed upon per management area. PMID- 23668593 TI - Nephrops norvegicus: introduction to the Issue. PMID- 23668594 TI - Environmental study of azole-resistant Aspergillus fumigatus with TR34/L98H mutations in the cyp51A gene in Iran. AB - Azole resistance in Aspergillus is emerging in European and Asian countries. As azoles are mainstay of therapy in the management of aspergillosis, azole resistance has serious implications in patient management. We report the emergence of resistance to triazoles in environmental Aspergillus fumigatus isolates in Iran. The TR34/L98H mutation was the only resistance mechanism. Overall 3.3% of the A. fumigatus isolates from hospital surroundings in Sari and Tehran had the same TR34/L98H STRAf genotype and were related to some resistant clinical and environmental TR34/L98H isolates from the Netherlands and India. It is emphasised that routine resistance surveillance studies focusing on environmental and clinical samples are warranted to yield the true prevalence of azole resistance in A. fumigatus in Iran. PMID- 23668596 TI - Coping with unfair events constructively or destructively: the effects of overall justice and self-other orientation. AB - Drawing on fairness heuristic theory (Lind, 2001, 2002), it was predicted that how employees cope with an unfair event-whether they are more or less forgiving, and whether they are more or less vengeful-will depend jointly on (a) their perceptions of overall organizational justice and (b) the degree to which they focus on their own interests or on the interests of others. Data were collected in a 2-part field survey of 153 employees who reported their responses to a recent unfair event. Hierarchical regression analyses (controlling possible 3rd variable explanations) revealed the 2 predicted 2-way interactions. Perceptions of overall organizational justice (a) facilitated forgiveness among those with strong other-orientation, and (b) suppressed revenge among those with strong self concern. Together, the data suggest that perceiving one's organization as a fair entity can shape proximal responses to unfair events, simultaneously facilitating constructive responses in some employees, and suppressing destructive responses in other employees. Theoretically, the findings are consistent with the idea that overall justice fulfills psychological needs that are differentially relevant to employees as a function of their chronic attention to others or to themselves, which in turn enables them to cope with unfair events more beneficially. The data have implications for the study of workplace forgiveness and revenge, as well as more broadly for the literatures on organizational justice and workplace mistreatment. PMID- 23668595 TI - Impact of carbapenem resistance on clinical and economic outcomes among patients with Acinetobacter baumannii infection in Colombia. AB - Acinetobacter baumannii is a major cause of healthcare-associated infection, often affecting critically ill patients. The purpose of the study was to examine the associations of carbapenem resistance with mortality, length of hospital stay and hospital costs among patients infected with A. baumannii in intensive-care units (ICUs) in Colombia. A prospective, multicentre cohort study was conducted among 165 patients with A. baumannii infection admitted to ICUs between April 2006 and April 2010. Patients with carbapenem-resistant A. baumannii had higher risk of 30-day mortality than patients with carbapenem-susceptible A. baumannii in the univariate analysis (unadjusted hazard ratio = 2.12; 95% CI 1.14-3.95; p 0.018). However, carbapenem resistance was not significantly associated with risk of mortality (adjusted hazard ratio = 1.45; 95% CI 0.74-2.87; p 0.28) after adjusting for APACHE II score and other confounding factors. We did not find a significant difference in length of stay in ICU after the onset of infection between the two groups in the multivariate analysis (adjusted mean = 13.1 days versus 10.5 days; p 0.14). The average total cost of hospitalization among patients with carbapenem-resistant A. baumannii was significantly higher than that among patients with carbapenem-susceptible A. baumannii in the multivariate analysis (adjusted cost; US$ 11 359 versus US$ 7049; p <0.001). Carbapenem resistance was not significantly associated with mortality, though we are unable to rule out an increased risk due to the limited sample size. Carbapenem resistance was associated with an additional cost of hospitalization. PMID- 23668597 TI - Causes and consequences of collective turnover: a meta-analytic review. AB - Given growing interest in collective turnover (i.e., employee turnover at unit and organizational levels), the authors propose an organizing framework for its antecedents and consequences and test it using meta-analysis. Based on analysis of 694 effect sizes drawn from 82 studies, results generally support expected relationships across the 6 categories of collective turnover antecedents, with somewhat stronger and more consistent results for 2 categories: human resource management inducements/investments and job embeddedness signals. Turnover was negatively related to numerous performance outcomes, more strongly so for proximal rather than distal outcomes. Several theoretically grounded moderators help to explain average effect-size heterogeneity for both antecedents and consequences of turnover. Relationships generally did not vary according to turnover type (e.g., total or voluntary), although the relative absence of collective-level involuntary turnover studies is noted and remains an important avenue for future research. PMID- 23668598 TI - Treat-to-target trials: uses, interpretation and review of concepts. AB - Treat-to-target trial designs compare investigational insulins with a standard insulin. Treat-to-target trials force-titrate insulin dosages to achieve a prespecified treatment goal. With comparable glycaemic control, comparisons of safety endpoints such as hypoglycaemia can be made to establish the risk-benefit profile of the new insulin. Glargine versus NPH showed comparable A1C reductions; however, A1C <7% without associated nocturnal hypoglycaemia was reached in more patients on glargine and overall hypoglycaemia was lower. Detemir versus glargine showed non-inferiority between the groups; however, with less weight gain and more injection site reactions with detemir. Detemir/aspart versus glargine/aspart showed non-inferiority between the treatments, however, with less weight gain in the detemir group but comparable risk of hypoglycaemia. Degludec in combination with aspart versus glargine/aspart showed comparable A1C reductions. However, degludec-treated patients had less overall hypoglycaemia and less nocturnal hypoglycaemia. Because insulin titrations are guided by goal attainment with each treatment, treat-to-target trials enable clinicians to determine differences in non-glycaemic treatment effects, such as rates of hypoglycaemia and weight gain, at the same level of glycaemic control. PMID- 23668599 TI - rs2072135, a low-penetrance variant for chronic lymphocytic leukaemia? AB - Recent multi-stage genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) that are robustly associated with chronic lymphocytic leukaemia (CLL) risk. Given that most of these SNPs map to non-coding regions of the genome, it suggests that the functional basis of many GWAS signals will be through differential gene expression. By referencing publically accessible expression quantitative trait loci (eQTL) data on lymphoblastoid cells lines (LCLs) we have globally demonstrated an association between GWAS P-values and eQTLs, consistent with much of the variation in CLL risk being defined by variants impacting on gene expression. To explore using eQTL data to select GWAS SNPs for replication, we genotyped rs2072135 (GWAS P-value = 0.0024, eQTL P-value = 1.510(-19)) in five independent case-control series totalling 1968 cases and 3538 controls. While not attaining statistical significance (combined P-value = 1 * 10(-4)), rs2072135 defines a promising risk locus for CLL. Incorporating eQTL information offers an attractive strategy for selecting SNPs from GWAS for validation. PMID- 23668600 TI - Liquid chromatography with diode array detection and tandem mass spectrometry for the determination of neonicotinoid insecticides in honey samples using dispersive liquid-liquid microextraction. AB - The combination of solid-phase extraction with dispersive liquid-liquid microextraction (SPE-DLLME) is proposed for the determination of five neonicotinoid insecticides in honey. After a cleanup stage, the analytes were eluted using acetonitrile. DLLME was performed by injecting rapidly the acetonitrile extract into 10 mL of water containing a 10% (w/v) NaCl and 100 MUL of CHCl3. The settled organic phase obtained after centrifugation was evaporated, reconstituted in acetonitrile (ACN), and submitted to liquid chromatography (LC) with photodiode array detection (DAD) and atmospheric pressure chemical ionization-ion trap-tandem mass spectrometry (APCI-IT-MS/MS). The matrix effect was evaluated, and quantification was carried out using external aqueous calibrations when using DAD, the matrix-matched calibration method was applied for MS/MS. Detection limits in the 0.2-1.0 and 0.02-0.13 ng/g ranges were obtained when using DAD and MS/MS, respectively. The SPE-DLLME-LC-APCI-IT-MS/MS method was applied for the analysis of different honey samples, and none was found to contain residues. PMID- 23668602 TI - Experiences of female partners of masculine-identifying trans persons. AB - This paper explores the intimate relationship experiences of the cisgender (i.e., not transgender) female partners of masculine-identifying transgender persons, with a particular focus on these partners' self-understanding of their sexual orientation. Limited research about this topic has been conducted to date. Semi structured interviews were conducted with eight South African women who are or have been cisgender female partners of masculine-identifying trans persons. Although the interviews showed that the relationship experiences of female partners of masculine-identifying trans persons are diverse, several common themes emerged in the narratives. The way that participants labelled their sexual orientation did not change from before to after their relationship with a transgender partner. The participants reported varied family and community responses to their relationships. Specific emotional and informational support needs for women with transgender partners were identified. PMID- 23668601 TI - Both flagella and F4 fimbriae from F4ac+ enterotoxigenic Escherichia coli contribute to attachment to IPEC-J2 cells in vitro. AB - The role of flagella in the pathogenesis of F4ac+ Enterotoxigenic Escherichia coli (ETEC) mediated neonatal and post-weaning diarrhea (PWD) is not currently understood. We targeted the reference C83902 ETEC strain (O8:H19:F4ac+ LT+ STa+ STb+), to construct isogenic mutants in the fliC (encoding the major flagellin protein), motA (encoding the flagella motor), and faeG (encoding the major subunit of F4 fimbriae) genes. Both the DeltafliC and DeltafaeG mutants had a reduced ability to adhere to porcine intestinal epithelial IPEC-J2 cells. F4 fimbriae expression was significantly down-regulated after deleting fliC, which revealed that co-regulation exists between flagella and F4 fimbriae. However, there was no difference in adhesion between the DeltamotA mutant and its parent strain. These data demonstrate that both flagella and F4 fimbriae are required for efficient F4ac+ ETEC adhesion in vitro. PMID- 23668603 TI - An alternative receptor to poly I:C on cell surfaces for interferon induction. AB - Not-self or denatured nucleic acids are recognized by pattern recognition receptors localized mainly in endosomes and cytoplasm, such as Toll-like receptor (TLR) 3, TLR7, TLR9, retinoic acid-inducible gene-I, DNA-dependent activator of IFN-regulatory factors and other receptors. The binding of polyriboinosinic:polyribocytidylic acid (poly I:C), a synthetic dsRNA that robustly induces type I interferon, to a putative cell-surface receptor on a rabbit kidney cell line, RK13, has been analyzed by the authors and RK13 cells found to capture poly I:C in a specific fashion with sufficient affinity. These findings suggest that an alternative receptor to poly I:C participates in the induction of type 1 interferon, which localizes on cell surfaces. Although the nature of this molecule has not yet been identified, accumulating evidence has led the present authors to speculate that there are undefined classes of RNA recognition molecules on cell surfaces and that these are unlikely to be categorized as previously reported dsRNA receptors. Although many years have passed since this possibility was first reported by the present authors, it remains attractive. In this article, previously reported cell-surface dsRNA receptors are reviewed in comparison with other receptors reported to date that are firmly involved in the innate immune-sensing of nucleic acids. PMID- 23668604 TI - Horizontal gene transfer of a genetic island encoding a type III secretion system distributed in Vibrio cholerae. AB - Twelve Vibrio cholerae isolates with genes for a type III secretion system (T3SS) were detected among 110 environmental and 14 clinical isolates. T3SS-related genes were distributed among the various serogroups and pulsed-field gel electrophoresis of NotI-digested genomes showed genetic diversity in these strains. However, the restriction fragment length polymorphism profiles of the T3SS-related genes had similar patterns. Additionally, naturally competent T3SS negative V. cholerae incorporated the ca. 47 kb gene cluster of T3SS, which had been integrated into a site on the chromosome by recombination. Therefore, it is suggested that horizontal gene transfer of T3SS-related genes occurs among V. cholerae in natural ecosystems. PMID- 23668605 TI - A recombinant carboxy-terminal domain of alpha-toxin protects mice against Clostridium perfringens. AB - Clostridium perfringens alpha-toxin (CP, 370 residues) is one of the main agents involved in the development of gas gangrene. In this study, the immunogenicity and protective efficacy of the C-terminal domain (CP251-370) of the toxin and phospholipase C (PLC; CB, 372 residues) of Clostridum bifermentans isolated from cases of clostridium necrosis were examined. The recombinant proteins were expressed as glutathione S-transferase (GST) fusion proteins. Antibodies that cross-reacted with alpha-toxin were produced after immunization with recombinant proteins including GST-CP251-370, GST-CP281-370, GST-CP311-370, CB1-372 and GST CB251-372. Anti-GST-CP251-370, anti-GST-CP281-370 and anti-GST-CP311-370 sera neutralized both the PLC and hemolytic activities of alpha-toxin, whereas anti CB1-372 and anti-GST-CB251-372 weakly neutralized these activities. Immunization with GST-CP251-370 and GST-CP281-370 provided protection against the lethal effects of the toxin and C. perfringens type A NCTC8237. Partial protection from the toxin and C. perfringens was elicited by immunization with GST-CP311-370 and CB1-372. GST-CP251-370 and GST-CP281-370 are promising candidates for vaccines for clostridial-induced gas gangrene. PMID- 23668606 TI - Evaluation of the double-disk synergy test for New Delhi metallo-beta-lactamase-1 and other metallo-beta-lactamase producing gram-negative bacteria by using metal ethylenediaminetetraacetic acid complexes. AB - New Delhi metallo-beta-lactamase-1 (NDM-1), one of the metallo-beta-lactamases (MBLs), has been identified from clinical isolates worldwide. Rapid detection of NDM-1 producers is necessary to prevent their dissemination. Seven types of EDTA complexes were evaluated as MBL inhibitors in double-disk synergy tests (DDSTs), resulting in detection of the first isolate of NDM-1-producing Escherichia coli (NDM-1 Dok01) in Japan. NDM-1 Dok01 was detected when EDTA magnesium disodium salt tetrahydrate (Mg-EDTA), EDTA calcium disodium salt dihydrate, EDTA cobalt disodium salt tetrahydrate and EDTA copper disodium salt tetrahydrate were used as MBL inhibitors. The sensitivity and specificity of DDSTs using Mg-EDTA for 75 MBL producers and 25 non-MBL producers were 96.0% and 100%, respectively. These findings indicate that the DDST method using Mg-EDTA can detect MBL-producing strains, including NDM-1 producers. PMID- 23668607 TI - Comparative evaluation of agar dilution and broth microdilution methods for antibiotic susceptibility testing of Helicobacter cinaedi. AB - The aim of this study was to establish a broth microdilution method for antimicrobial susceptibility testing of Helicobacter cinaedi and to assess the prevalence and mechanisms of fluoroquinolone resistance in Japanese clinical isolates. A broth microdilution method using modified Levinthal broth was developed and compared with the agar dilution method for testing susceptibility to ampicillin, gentamicin, tetracycline and ciprofloxacin. The minimum inhibitory concentrations obtained by these two methods were almost the same for all the antibiotics tested, demonstrating the broth microdilution method to be a suitable and reliable technique for antimicrobial susceptibility testing. A broth microdilution method for antimicrobial susceptibility test for H. cinaedi was established. This method is expected to help improve treatment. PMID- 23668608 TI - Distribution of Streptococcus troglodytae and Streptococcus dentirousetti in chimpanzee oral cavities. AB - The aim of this study was to analyze the distribution and phenotypic properties of the indigenous streptococci in chimpanzee (Pan troglodytes) oral cavities. Eleven chimpanzees (aged from 9 to 44 years, mean +/- SD, 26.9 +/- 12.6 years) in the Primate Research Institute of Kyoto University were enrolled in this research and brushing bacterial samples collected from them. Streptococci were isolated from the oral cavities of all chimpanzees. The isolates (n = 46) were identified as thirteen species by 16S rRNA genes analysis. The predominant species was Streptococcus sanguinis of mitis streptococci from five chimpanzees (45%). Mutans streptococci were isolated from six chimpanzees (55%). The predominant species in the mutans streptococci were Streptococcus troglodytae from four chimpanzees (36%), this species having been proposed as a novel species by us, and Streptococcus dentirousetti from three chimpanzees (27%). Streptococcus mutans was isolated from one chimpanzee (9%). However, Streptococcus sobrinus, Streptococcus macacae and Streptococcus downei, which are indigenous to human and monkey (Macaca fasciclaris) oral habitats, were not isolated. Of the mutans streptococci, S. troglodytae, S. dentirousetti, and S. mutans possessed strong adherence activity to glass surface. PMID- 23668609 TI - Anthocyanins from black soybean inhibit Helicobacter pylori-induced inflammation in human gastric epithelial AGS cells. AB - Infection with Helicobacter pylori leads to gastritis, peptic ulcers and gastric cancer. Moreover, when the gastric mucosa is exposed to H. pylori, gastric mucosal inflammatory cytokine interleukin-8 (Il-8) and reactive oxygen species increase. Anthocyanins have anti-oxidative, antibacterial and anti-inflammatory properties. However, the effect of anthocyanins in H. pylori-infected cells is not yet clear. In this study, therefore, the effect of anthocyanins on H. pylori infected human gastric epithelial cells was examined. AGS cells were pretreated with anthocyanins for 24 hrs followed by H. pylori 26695 infection for up to 24 hrs. Cell viability and ROS production were examined by 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide and 2',7'-dichlorofluorescein diacetate assay, respectively. Western blot analyses and RT-PCR were performed to assess gene and protein expression, respectively. IL-8 secretion in AGS cells was measured by ELISA. It was found that anthocyanins decrease H. pylori-induced ROS enhancement. Anthocyanins also inhibited phosphorylation of mitogen-activated protein kinases, translocation of nuclear factor-kappa B and Ikappabetaalpha degradation. Furthermore anthocyanins inhibited H. pylori-induced inducible nitric oxide synthases and cyclooxygenase-2 mRNA expression and inhibited IL-8 production by 45.8%. Based on the above findings, anthocyanins might have an anti inflammatory effect in H. pylori-infected gastric epithelial cells. PMID- 23668610 TI - Expression and immunological characterization of cardamom mosaic virus coat protein displaying HIV gp41 epitopes. AB - The coat protein of cardamom mosaic virus (CdMV), a member of the genus Macluravirus, assembles into virus-like particles when expressed in an Escherichia coli expression system. The N and C-termini of the coat protein were engineered with the Kennedy peptide and the 2F5 and 4E10 epitopes of gp41 of HIV. The chimeric proteins reacted with sera from HIV positive persons and also stimulated secretion of cytokines by peripheral blood mononuclear cells from these persons. Thus, a system based on the coat protein of CdMV can be used to display HIV-1 antigens. PMID- 23668611 TI - Sequence and phylogenetic analyses of the water-soluble glucan synthesizing glucosyltransferase genes of Streptococcus dentirousetti. AB - Two tandemly aligned glucosyltransferase (GTF) genes whose gene products are responsible for water-soluble glucan synthesis were isolated from Streptococcus dentirousetti NUM1303 and sequenced. One of the GTF genes of S. dentirousetti consisted of a 4110 bp open reading frame (ORF) that encoded for a 1369 amino acid protein and was revealed to be a S. sobrinus gtfS homolog. The percent similarity of amino acid sequences of the GTF-S from S. dentirousetti compared to those from S. sobrinus was 99%. In addition, a putative gtfT was found in tandem in the downstream region of the S. dentirousetti gtfS. The gtfT of S. dentirousetti consisted of a 4527 bp ORF encoding for 1508 amino acids. The similarity of amino acid sequences of the GTF-T from S. dentirousetti and S. sobrinus was 94%. Phylogenetic analysis based on amino acid sequences from other related streptococcal GTFs suggested that both GTF-S and GTF-T of S. dentirousetti are closely related to S. sobrinus. PMID- 23668612 TI - Cephalosporin resistant Escherichia coli from cancer patients in Cairo, Egypt. AB - Cephalosporin-resistant Escherichia coli has been increasingly reported worldwide. In this study, 32 cephalosporin resistant E. coli isolates identified from cancer patients in Cairo, Egypt in 2009-2010 were analyzed. Twenty-three were of phylogenetic group D, seven A and one each B1 and B2. By rep-PCR 15 phylogroup D isolates were grouped in four clusters, one with sequence type (ST) 405 and three ST68. Seventeen isolates showed single patterns. blaCTX-M-15 and aac(6')-Ib-cr were the most common resistance determinants. blaOXA-48 and blaVIM were also detected. Multidrug resistant E. coli seriously affects healthcare, especially in immunocompromised hosts, such as cancer patients. PMID- 23668613 TI - Rapid detection of human cytomegalovirus UL97 and UL54 mutations for antiviral resistance in clinical specimens. AB - Drug-resistant cytomegalovirus appears during prolonged anti-cytomegalovirus therapy. Assays for human cytomegalovirus viral protein kinase (UL97) and viral DNA polymerase (UL54) gene mutations conferring drug resistance have been used rather than susceptibility assays to assess clinical specimens. In this study a sensitive system for genotype assay of UL97 and UL54 in clinical specimens with as few as six copies/ug of DNA was developed. PMID- 23668614 TI - Molecular epidemiology of Coxsackievirus A16 strains isolated from children in Yamagata, Japan between 1988 and 2011. AB - To clarify the longitudinal molecular epidemiology of coxsackievirus A16, phylogenetic analysis based on the VP1 region of 220 isolates in Yamagata, Japan was performed. The resultant phylogenetic tree indicates that the Yamagata isolates and reference strains can be readily genotyped into three genogroups, and 0, 12 and 208 isolates belonged to the first, second, and third genogroups, respectively. The first genogroup includes only the prototype strain, the second strains that had disappeared by the end of the 20th century and the third comprises those that have been circulating since then in local communities, such as Yamagata. PMID- 23668616 TI - Retraction: Soft braces in the treatment of Adolescent Idiopathic Scoliosis (AIS) - Review of the literature and description of a new approach. PMID- 23668615 TI - Adenosine monophosphate-activated protein kinase is required for pulmonary artery smooth muscle cell survival and the development of hypoxic pulmonary hypertension. AB - Human pulmonary artery smooth muscle cells (HPASMCs) express both adenosine monophosphate-activated protein kinase (AMPK) alpha1 and alpha2. We investigated the distinct roles of AMPK alpha1 and alpha2 in the survival of HPASMCs during hypoxia and hypoxia-induced pulmonary hypertension (PH). The exposure of HPASMCs to hypoxia (3% O2) increased AMPK activation and phosphorylation, and the inhibition of AMPK with Compound C during hypoxia decreased their viability and increased lactate dehydrogenase activity and apoptosis. Although the suppression of either AMPK alpha1 or alpha2 expression led to increased cell death, the suppression of AMPK alpha2 alone increased caspase-3 activity and apoptosis in HPASMCs exposed to hypoxia. It also resulted in the decreased expression of myeloid cell leukemia sequence 1 (MCL-1). The knockdown of MCL-1 or MCL-1 inhibitors increased caspase-3 activity and apoptosis in HPASMCs exposed to hypoxia. On the other hand, the suppression of AMPK alpha1 expression alone prevented hypoxia-mediated autophagy. The inhibition of autophagy induced cell death in HPASMCs. Our results suggest that AMPK alpha1 and AMPK alpha2 play differential roles in the survival of HPASMCs during hypoxia. The activation of AMPK alpha2 maintains the expression of MCL-1 and prevents apoptosis, whereas the activation of AMPK alpha1 stimulates autophagy, promoting HPASMC survival. Moreover, treatment with Compound C, which inhibits both isoforms of AMPK, prevented and partly reversed hypoxia-induced PH in mice. Taking these results together, our study suggests that AMPK plays a key role in the pathogenesis of pulmonary arterial hypertension, and AMPK may represent a novel therapeutic target for the treatment of pulmonary arterial hypertension. PMID- 23668617 TI - Microstructure of an immiscible polymer blend and its stabilization effect on amorphous solid dispersions. AB - This study proposes use of the phase separation of immiscible polymer blends as a formulation approach to improve the stabilization and solubilization of amorphous molecular dispersions of poorly soluble drugs. This approach uses the phase separation and different drug solubilization properties of the two immiscible polymers in the blend to optimize drug loading and stabilization. The model system tested in this study is a EUDRAGIT E PO-PVP-VA 50/50 (w/w) blend loaded with felodipine via hot melt extrusion. The phase separation behavior of the polymer blend and drug loaded polymer blend formulations were characterized using a range of thermal (MTDSC), spectroscopic (ATR-FTIR), and imaging (AFM and thermal transition mapping) techniques. The polymer blend formulations demonstrated superior performance in drug release as well as stabilization against stressed temperature, stressed humidity, and mechanical milling in comparison to the drug-polymer binary systems. This is attributed to the configuration of the phase separated microstructure of the polymer blend formulations where the hydrophilic polymer domains host high concentrations of molecularly dispersed drug which are protected from moisture induced recrystallization on aging by the hydrophobic polymer domains. Additionally drug incorporation as a molecular dispersion in different polymer phases reduces the drug recrystallization tendency on aging under high temperatures and during milling. PMID- 23668618 TI - Genetics of serum and muscle lipids in pigs. AB - Pork meat is one of the most important sources of animal protein in the human diet. Its nutritional properties are partly determined by intramuscular fat content and composition, with existing general consensus about the detrimental effects of cholesterol and saturated fat on cardiovascular health in humans. Because of their physiological resemblance, pigs can be also used as a valuable animal model to study the genetics of human diseases such as atherosclerosis, obesity and dyslipidaemias. Heritability estimates and QTL maps of porcine muscle and serum lipid traits evidence that a considerable amount of genetic variance determining these phenotypes exists, but its molecular basis remains mostly unknown. The recent advent of high-throughput genotyping and sequencing technologies has revolutionised the field of animal genomics. With these powerful tools, finding needles in the genomic haystack has become increasingly feasible. However, these methodological advances should not be deemed as magic bullets. The goal of identifying the many polymorphisms that shape the variability of lipid phenotypes is so challenging that success can be achieved only under the scope of large international consortia. PMID- 23668619 TI - Response to imatinib in villonodular pigmented synovitis (PVNS) resistant to nilotinib. AB - BACKGROUND: Pigmented villonodular synovitis (PVNS) is a rare locally aggressive tumor. PVNS is characterized in most cases by a specific t(1;2) translocation, which fuses the colony stimulating factor-1 (CSF1) gene to the collagen type VIa3 (COL6A3) promoter thus leading through a paracrine effect to the attraction of non-neoplastic inflammatory cells expressing CSF1-receptor. Imatinib is a tirosin kinase inhibitors (TKI) active against CSF1-receptor whose activity in naive PVNS was already described. We report on two PVNS patients who responded to imatinib after failure to nilotinib, another CSF1-receptor inhibitor. METHODS: Since August 2012, 2 patients with progressive, locally advanced PVNS resistant to nilotinib (Patient 1: man, 34 years; Patient 2: woman, 24 years) have been treated with second-line imatinib 400 mg/day. Both patients are evaluable for response. RESULTS: Both patients are still on treatment (7 and 4 months). Patient 1 had a dimensional response by MRI after 2 months from starting imatinib, together with symptomatic improvement. In Patient 2 a metabolic response was detected by [18F]fluorodeoxyglucose-positron emission tomography (PET) at 6 weeks coupled with tumor shrinkage by MRI, and symptomatic improvement. CONCLUSIONS: Imatinib showed antitumor activity in 2 patients with nilotinib-resistant PVNS. This observation strengthen the idea that targeted agent with similar profile can give a different clinical result, as already described for gastrointestinal stromal tumor (GIST) patients treated with the same agents. Molecular studies are needed to clarify the biologic mechanism(s) underlying the response. PMID- 23668620 TI - Self-assembly of patterned nanoparticles on cellular membranes: effect of charge distribution. AB - Nanoparticle-assisted drug delivery has been emerging as an active research area. Achieving high drug loading is only one facet of drug delivery issues; it is also important to investigate the effect of surface charge distribution on self assembly of nanoparticles on cellular membranes. By considering the electrostatic distribution of patterned nanoparticles, we used dissipative particle dynamics simulations to investigate the self-assembly of pattern charged nanoparticles with five different surface charged patterns. It is found that both surface charged pattern and nanoparticle size significantly affect the self-assembly of nanoparticles on cellular membranes. Results indicate that 1/2 pattern charged small nanoparticles can self-assemble into dendritic structures, while those with a 1/4 pattern self-assemble into clusters. As the nanoparticle size increases, 1/2 pattern charged medium nanoparticles can self-assemble into linear structures, while those with a 1/4 pattern self-assemble into clusters. For very large nanoparticles, both 1/2 pattern and 1/4 pattern charged nanoparticles self assemble into flaky structures with different connections. By considering the effects of surface charged pattern and nanoparticle size on self-assembly, we found that nanoparticle self-assembly requires a minimum effective charged area. When the local charged area of nanoparticles is less than the threshold, surface charge cannot induce nanoparticle self-assembly; that is, the surface charged pattern of a nanoparticle would determine effectively the self-assembly structure. It is expected that this work will provide guidance for nanoparticle assisted drug delivery. PMID- 23668621 TI - Arsenic dissolution from Japanese paddy soil by a dissimilatory arsenate-reducing bacterium Geobacter sp. OR-1. AB - Dissimilatory As(V) (arsenate)-reducing bacteria may play an important role in arsenic release from anoxic sediments in the form of As(III) (arsenite). Although respiratory arsenate reductase genes (arrA) closely related to Geobacter species have been frequently detected in arsenic-rich sediments, it is still unclear whether they directly participate in arsenic release, mainly due to lack of pure cultures capable of arsenate reduction. In this study, we isolated a novel dissimilatory arsenate-reducing bacterium, strain OR-1, from Japanese paddy soil, and found that it was phylogenetically closely related to Geobacter pelophilus. OR-1 also utilized soluble Fe(III), ferrihydrite, nitrate, and fumarate as electron acceptors. OR-1 catalyzed dissolution of arsenic from arsenate-adsorbed ferrihydrite, while Geobacter metallireducens GS-15 did not. Furthermore, inoculation of washed cells of OR-1 into sterilized paddy soil successfully restored arsenic release. Arsenic K-edge X-ray absorption near-edge structure analysis revealed that strain OR-1 reduced arsenate directly on the soil solid phase. Analysis of putative ArrA sequences from paddy soils suggested that Geobacter-related bacteria, including those closely related to OR-1, play an important role in arsenic release from paddy soils. Our results provide direct evidence for arsenic dissolution by Geobacter species and support the hypothesis that Geobacter species play a significant role in reduction and mobilization of arsenic in flooded soils and anoxic sediments. PMID- 23668622 TI - Lichenoid chronic graft-vs-host disease following Blaschko lines. PMID- 23668623 TI - Cumulative life course impairment: the imprint of psoriasis on the patient's life. AB - We now realize that moderate to severe psoriasis takes a toll on the patient's overall health beyond the effects on the skin itself, and so we use quality of life (QOL) measures to assess how the individual perceives both the impact of disease and the response to treatment. However, available instruments give us a cross-sectional assessment of QOL at a specific moment, and we lack longitudinal studies of how a disease affects each and every aspect of a patient's life over time-including physical and psychological wellbeing, social and emotional relationships, vocational and employment decisions, and how they change the individual's outlook. A new concept, cumulative life course impairment (CLCI), captures the notion of the ongoing effect of a disease, providing us with a new paradigm for assessing the impact of psoriasis on QOL. Unlike conventional measurement tools and scales, which focus on a specific moment in the patient's life, a CLCI tool investigates the repercussions of disease that accumulate over a lifetime, interfering with the individual's full potential development and altering perspectives that might have been different had psoriasis not been present. The accumulated impact will vary from patient to patient depending on circumstances that interact differently over time as the burden of stigmatization, concomitant physical and psychological conditions associated with psoriasis, coping mechanisms, and external factors come into play and are modulated by the individual's personality. PMID- 23668624 TI - Cravings as a mediator and moderator of drinking outcomes in the COMBINE study. AB - AIMS: Investigators of the COMBINE (Combining Medications and Behavioral Interventions for Alcoholism) study examined whether combining medications with a behavioral intervention would improve outcomes over monotherapies. Unexpectedly, the combination did not offer any advantage over either treatment alone. This study aimed to explain the lack of incremental benefit offered by the combination over either monotherapy by assessing the role of cravings as a treatment mediator and moderator. DESIGN: Secondary mediation and moderation analyses of COMBINE study data. SETTING: Eleven United States academic sites. PARTICIPANTS: A total of 863 patients randomized to one of four treatment groups: naltrexone (100 mg/day; n = 209), the combined behavioral intervention (CBI, n = 236), naltrexone and CBI combined (n = 213) and placebo naltrexone (n = 205). MEASUREMENTS: Percentage of days abstinent (PDA) measured between 13 and 16 weeks post baseline. Cravings, the potential mediator/moderator, were measured at baseline, weeks 4 and 12 using the Obsessive-Compulsive Drinking Scale. FINDINGS: Compared with placebo, naltrexone, CBI and the combination all increased PDA by an additional 6-10 percentage points for those with high cravings (P < 0.05 for all three treatment groups). None had significant effects on PDA for those with low cravings. The effects of all three treatments were mediated at least partially by cravings; craving reduction explained 48-53% of treatment effects (P < 0.05 for all three treatment groups). Furthermore, naltrexone appeared to reduce cravings at 4 weeks, while CBI did not reduce cravings until 12 weeks. CONCLUSIONS: The Combining Medications and Behavioral Interventions for Alcoholism (COMBINE) naltrexone + CBI combination may not be more beneficial than either monotherapy because craving reduction is a common mechanism of both. PMID- 23668625 TI - Evaluation of domino liver transplantations in Germany. AB - A retrospective multicenter study has been conducted to evaluate domino liver transplantations (DLTs) in Germany. The study provides insight into survival and features having an impact on the assessment of neuropathy after DLT. In addition, a neurologic follow-up program with a scheme to estimate the likelihood of de novo amyloidosis is presented. A series of 61 DLTs at seven transplant centers in Germany was enrolled. The mean age of domino recipients at the time of transplantation was 58 years, 46 of them being men, and 15 being women. The median follow-up was 46 months. The overall 1-, 3-, and 5-year survival of domino recipients was 81.6%, 70.8% and 68.8%, respectively. Causes of death were primarily not related to familial amyloidosis. The main indication of DLT was hepatocellular carcinoma. Two of the reported domino recipients developed symptoms and signs of de novo amyloidosis within 10 years after transplantation. A total of 30 domino graft recipients (49.18%) presented with diabetes post transplantation. In conclusion, an advanced follow-up program is crucial to evaluate the risk of transmitting familial amyloidosis by DLT and to establish more strict selection criteria for domino recipients. PMID- 23668626 TI - Phase II study of concomitant chemoradiotherapy with local hyperthermia and metronidazole for locally advanced fixed rectal cancer. AB - AIM: Locally advanced fixed T4 rectal cancer has a poor prognosis and no standard treatment strategy. The aim of this study was to investigate the safety and efficacy of neoadjuvant chemoradiotherapy using hypofractionated radiotherapy combined with local hyperthermia, capecitabine, oxaliplatin and metronidazole. METHOD: Radiotherapy was given to a total dose of 40 Gy in 10 fractions. Capecitabine 650 mg/m(2) twice a day was given on days 1-22 and intravenous oxaliplatin 50 mg/m(2) was administered on days 3, 10 and 17. Local hyperthermia, 41-45 degrees C for 60 min, was performed on days 8, 10, 15 and 17. Metronidazole 10 g/m(2) was administered per rectum on days 8 and 15. Surgery was carried out within 6-8 weeks after neoadjuvant treatment. The primary end-point was R0 resection rate. Secondary end-points included 2-year disease-free survival, 2 year overall survival, local recurrence rate, grade III-IV tumour regression (Dworak) and treatment toxicity. RESULTS: From July 2006 to February 2011, 64 previously untreated patients were enrolled. R0 resection was carried out in 59 (92.2%). Five (7.8%) remained inoperable. Seven (10.9%) patients had grade IV and 30 (46.9%) had grade III regression. The main grade III toxic events included diarrhoea (15.6%, n = 10), vomiting (3.1%, n = 2), proctitis (3.1%, n = 2) and skin reaction (1.6%, n = 1). Only one (1.6%) patient had grade IV diarrhoea and vomiting. The median follow-up was 24.9 months. Two-year overall survival was 91% and 2-year disease-free survival was 83%. CONCLUSION: Hyperthermia combined with chemotherapy to produce radiosensitization for locally advanced fixed primary rectal cancer is followed by a high R0 resection rate, with toxicity comparable with standard regimens. PMID- 23668627 TI - Localized surface plasmon resonance detection of biological toxins using cell surface oligosaccharides on glyco chips. AB - We have detected biological toxins using localized surface plasmon resonance (LSPR) and synthetic glycosyl ceramides (beta-lactoside, globosyl trisaccharide (Gb3), or GM1 pentasaccharide) attached to gold (Au) nanoparticles. The particle diameters ranged from 5-100 nm. The detection sensitivity for three toxins (ricin, Shiga toxin, and cholera toxin) was found to depend not only on the attached glycoside but also on the diameter of the Au nanoparticles. For the detection of ricin, the 20-nm beta-lactoside-coated Au nanoparticle exhibited the highest LSPR response, whereas 40-nm Gb3- and GM1-coated Au nanoparticles gave the best results for Shiga toxin and cholera toxin, respectively. In addition, a blocking process on the nanoparticle surface greatly improved the detection sensitivity for cholera toxin. The LSPR system enabled us to detect ricin at 30 ng/mL, Shiga toxin at 10 ng/mL, and the cholera toxin at 20 ng/mL. PMID- 23668628 TI - Longer follow-up confirms major improvement in outcome in children and adolescents with Philadelphia chromosome acute lymphoblastic leukaemia treated with continuous imatinib and haematopoietic stem cell transplantation. Results from the Spanish Cooperative Study SHOP/ALL-2005. PMID- 23668629 TI - Use of culture geometry to control hypoxia-induced vascular endothelial growth factor secretion from adipose-derived stem cells: optimizing a cell-based approach to drive vascular growth. AB - Adipose-derived stem cells (ADSCs) possess potent angiogenic properties and represent a source for cell-based approaches to delivery of bioactive factors to drive vascularization of tissues. Hypoxic signaling appears to be largely responsible for triggering release of these angiogenic cytokines, including vascular endothelial growth factor (VEGF). Three-dimensional (3D) culture may promote activation of hypoxia-induced pathways, and has furthermore been shown to enhance cell survival by promoting cell-cell interactions while increasing angiogenic potential. However, the development of hypoxia within ADSC spheroids is difficult to characterize. In the present study, we investigated the impact of spheroid size on hypoxia-inducible transcription factor (HIF)-1 activity in spheroid cultures under atmospheric and physiological oxygen conditions using a fluorescent marker. Hypoxia could be induced and modulated by controlling the size of the spheroid; HIF-1 activity increased with spheroid size and with decreasing external oxygen concentration. Furthermore, VEGF secretion was impacted by the hypoxic status of the culture, increasing with elevated HIF-1 activity, up to the point at which viability was compromised. Together, these results suggest the ability to use 3D culture geometry as a means to control output of angiogenic factors from ADSCs, and imply that at a particular environmental oxygen concentration an optimal culture size for cytokine production exists. Consideration of culture geometry and microenvironmental conditions at the implantation site will be important for successful realization of ADSCs as a pro-angiogenic therapy. PMID- 23668630 TI - Phylotastic! Making tree-of-life knowledge accessible, reusable and convenient. AB - BACKGROUND: Scientists rarely reuse expert knowledge of phylogeny, in spite of years of effort to assemble a great "Tree of Life" (ToL). A notable exception involves the use of Phylomatic, which provides tools to generate custom phylogenies from a large, pre-computed, expert phylogeny of plant taxa. This suggests great potential for a more generalized system that, starting with a query consisting of a list of any known species, would rectify non-standard names, identify expert phylogenies containing the implicated taxa, prune away unneeded parts, and supply branch lengths and annotations, resulting in a custom phylogeny suited to the user's needs. Such a system could become a sustainable community resource if implemented as a distributed system of loosely coupled parts that interact through clearly defined interfaces. RESULTS: With the aim of building such a "phylotastic" system, the NESCent Hackathons, Interoperability, Phylogenies (HIP) working group recruited 2 dozen scientist-programmers to a weeklong programming hackathon in June 2012. During the hackathon (and a three month follow-up period), 5 teams produced designs, implementations, documentation, presentations, and tests including: (1) a generalized scheme for integrating components; (2) proof-of-concept pruners and controllers; (3) a meta API for taxonomic name resolution services; (4) a system for storing, finding, and retrieving phylogenies using semantic web technologies for data exchange, storage, and querying; (5) an innovative new service, DateLife.org, which synthesizes pre-computed, time-calibrated phylogenies to assign ages to nodes; and (6) demonstration projects. These outcomes are accessible via a public code repository (GitHub.com), a website (http://www.phylotastic.org), and a server image. CONCLUSIONS: Approximately 9 person-months of effort (centered on a software development hackathon) resulted in the design and implementation of proof-of-concept software for 4 core phylotastic components, 3 controllers, and 3 end-user demonstration tools. While these products have substantial limitations, they suggest considerable potential for a distributed system that makes phylogenetic knowledge readily accessible in computable form. Widespread use of phylotastic systems will create an electronic marketplace for sharing phylogenetic knowledge that will spur innovation in other areas of the ToL enterprise, such as annotation of sources and methods and third-party methods of quality assessment. PMID- 23668631 TI - Thiol-ene enabled detection of thiophosphorylated kinase substrates. AB - Protein phosphorylation is a ubiquitous posttranslational modification that regulates cell signaling in both prokaryotes and eukaryotes. Although the study of phosphorylation has made great progress, several major hurdles remain, including the difficulty of the assignment of endogenous substrates to a discrete kinase and of global phosphoproteomics investigations. We have developed a novel chemical strategy for detecting phosphorylated proteins. This method utilizes adenosine 5'-O-(3-thiotriphosphate) (ATPgammaS), which results in the transfer of a thiophosphate moiety by a kinase to its substrate(s). This group can subsequently be employed as a nucleophilic handle to promote protein detection. To selectively label thiophosphorylated proteins, cellular thiols (e.g., cysteine containing proteins) must first be blocked. Most common cysteine-capping strategies rely upon the nucleophilicity of the sulfur group and would therefore also modify the thiophosphate moiety. We hypothesized that the radical-mediated thiol-ene reaction, however, would be selective for cysteine over thiophosphorylated amino acids due to the differences in the electronics and pKa values between these groups. Here, we report rapid and specific tagging of thiophosphorylated proteins in vitro following chemoselective thiol capping using the thiol-ene reaction. PMID- 23668633 TI - Abdominal computed tomography--a new tool for predicting recurrent stone disease. AB - PURPOSE: To evaluate whether CT-identified Randall plaques can be used to foresee the recurrence of stone disease (SD); to define a cut point that could identify a high-risk population. MATERIALS AND METHODS: A retrospective study of patients attended for SD from January 2004 to December 2009 was conducted. Study population was patients with a first episode of calcium SD that was diagnosed by abdominal CT. Papillae tip attenuation was measured in Hounsfield units (HU) on unenhanced abdominal CT images. Patients with recurrent SD were identified; t test, Pearson correlation, and receiver operating characteristic (ROC) curve analysis were used. RESULTS: A total of 543 patients were evaluated; 187 fulfilled the criteria and were included, and 49 (26.2%) had recurrent SD. Mean follow-up: 5 years (3-7 years). Papillae tip attenuation was significantly higher in the recurrent group (46.2 HU vs 40.1 HU, P=0.01) and correlated well with the possibility of developing SD (R=0.83). Attenuation >43 HU showed a ROC curve area under the curve=0.87 with sensitivity=77% and specificity=84% separating patients with a RR=8.7 of development of recurrent SD. The number of papillae >43 HU correlated with recurrent SD (RR=11.2 for >=3 papillae vs <3 papillae with density >43 HU). CONCLUSIONS: The presence of the Randall plaques can be used as a marker for predicting SD recurrence. A cut point of 43 HU could be used to identify a high-risk population. PMID- 23668632 TI - Stereotactic body radiotherapy for localized prostate cancer: disease control and quality of life at 6 years. AB - BACKGROUND: Stereotactic body radiotherapy (SBRT) may yield disease control for prostate cancer in a brief, hypofractionated treatment regimen without increasing treatment toxicity. Our report presents a 6-year update from 304 low- (n = 211), intermediate- (n = 81), and high-risk (n = 12) prostate cancer patients who received CyberKnife SBRT. METHODS: The median PSA at presentation was 5.8 ng/ml. Fifty-seven patients received neoadjuvant hormonal therapy for up to one year. The first 50 patients received a total dose of 35 Gy in 5 fractions of 7 Gy. The subsequent 254 patients received a total dose of 36.25 Gy in 5 fractions of 7.25 Gy. Toxicity was assessed with the Expanded Prostate Cancer Index Composite questionnaire and the Radiation Therapy Oncology Group urinary and rectal toxicity scale. Biochemical failure was assessed using the nadir + 2 definition. RESULTS: No patients experienced Grade III or IV acute complications. Fewer than 5% of patients experienced any acute Grade II urinary or rectal toxicities. Late urinary Grade II complications were observed in 4% of patients treated to 35 Gy and 9% of patients treated to 36.25 Gy. Five (2%) late Grade III urinary toxicities occurred in patients who were treated with 36.25 Gy. Late Grade II rectal complications were observed in 2% of patients treated to 35 Gy and 5% of patients treated to 36.25 Gy. Bowel and urinary quality of life (QOL) scores initially decreased, but later returned to baseline values. An overall decrease of 20% in the sexual QOL score was observed. QOL in each domain was not differentially affected by dose. For patients that were potent prior to treatment, 75% stated that they remained sexually potent. Actuarial 5-year biochemical recurrence-free survival was 97% for low-risk, 90.7% for intermediate risk, and 74.1% for high-risk patients. PSA fell to a median of 0.12 ng/ml at 5 years; dose did not influence median PSA levels. CONCLUSIONS: In this large series with long-term follow-up, we found excellent biochemical control rates and low and acceptable toxicity, outcomes consistent with those reported for from high dose rate brachytherapy (HDR BT). Provided that measures are taken to account for prostate motion, SBRT's distinct advantages over HDR BT include its noninvasiveness and delivery to patients without anesthesia or hospitalization. PMID- 23668634 TI - First human dose-escalation study with remogliflozin etabonate, a selective inhibitor of the sodium-glucose transporter 2 (SGLT2), in healthy subjects and in subjects with type 2 diabetes mellitus. AB - BACKGROUND: Remogliflozin etabonate (RE) is the prodrug of remogliflozin, a selective inhibitor of the renal sodium-dependent glucose transporter 2 (SGLT2), which could increase urine glucose excretion (UGE) and lower plasma glucose in humans. METHODS: This double-blind, randomized, placebo-controlled, single-dose, dose-escalation, crossover study is the first human trial designed to evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of RE. All subjects received single oral doses of either RE or placebo separated by approximately 2 week intervals. In Part A, 10 healthy subjects participated in 5 dosing periods where they received RE (20 mg, 50 mg, 150 mg, 500 mg, or 1000 mg) or placebo (4:1 active to placebo ratio per treatment period). In Part B, 6 subjects with type 2 diabetes mellitus (T2DM) participated in 3 dose periods where they received RE (50 mg and 500 mg) or placebo (2:1 active to placebo per treatment period). The study protocol was registered with the NIH clinical trials data base with identifier NCT01571661. RESULTS: RE was generally well-tolerated; there were no serious adverse events. In both populations, RE was rapidly absorbed and converted to remogliflozin (time to maximum plasma concentration [Cmax;Tmax] approximately 1 h). Generally, exposure to remogliflozin was proportional to the administered dose. RE was rapidly eliminated (mean T1/2 of ~25 min; mean plasma T1/2 for remogliflozin was 120 min) and was independent of dose. All subjects showed dose-dependent increases in 24-hour UGE, which plateaued at approximately 200 to 250 mmol glucose with RE doses >=150 mg. In T2DM subjects, increased plasma glucose following OGTT was attenuated by RE in a drug-dependent fashion, but there were no clear trends in plasma insulin. There were no apparent effects of treatment on plasma or urine electrolytes. CONCLUSIONS: The results support progression of RE as a potential treatment for T2DM. TRIAL REGISTRATION: ClinicalTrials.gov NCT01571661. PMID- 23668635 TI - Improving peptide identification sensitivity in shotgun proteomics by stratification of search space. AB - Because of its high specificity, trypsin is the enzyme of choice in shotgun proteomics. Nonetheless, several publications do report the identification of semitryptic and nontryptic peptides. Many of these peptides are thought to be signaling peptides or to have formed during sample preparation. It is known that only a small fraction of tandem mass spectra from a trypsin-digested protein mixture can be confidently matched to tryptic peptides. If other possibilities such as post-translational modifications and single-amino acid polymorphisms are ignored, this suggests that many unidentified spectra originate from semitryptic and nontryptic peptides. To include them in database searches, however, may not improve overall peptide identification because of the possible sensitivity reduction from search space expansion. To circumvent this issue for E-value-based search methods, we have designed a scheme that categorizes qualified peptides (i.e., peptides whose differences in molecular weight from the parent ion are within a specified error tolerance) into three tiers: tryptic, semitryptic, and nontryptic. This classification allows peptides that belong to different tiers to have different Bonferroni correction factors. Our results show that this scheme can significantly improve retrieval performance compared to those of search strategies that assign equal Bonferroni correction factors to all qualified peptides. PMID- 23668636 TI - Bystander effect between zebrafish embryos in vivo induced by high-dose X-rays. AB - We employed embryos of the zebrafish, Danio rerio, for our studies on the in vivo bystander effect between embryos irradiated with high-dose X-rays and naive unirradiated embryos. The effects on the naive whole embryos were studied through quantification of apoptotic signals at 25 h post fertilization (hpf) through the terminal dUTP transferase-mediated nick end-labeling (TUNEL) assay followed by counting the stained cells under a microscope. We report data showing that embryos at 5 hpf subjected to a 4-Gy X-ray irradiation could release a stress signal into the medium, which could induce a bystander effect in partnered naive embryos sharing the same medium. We further demonstrated that this bystander effect (induced through partnering) could be successfully suppressed through the addition of the nitric oxide (NO) scavenger 2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) into the medium but not through the addition of the CO liberator tricarbonylchloro(glycinato)ruthenium(II) (CORM-3). This shows that NO was involved in the bystander response between zebrafish embryos induced through X-ray irradiation. We also report data showing that the bystander effect could be successfully induced in naive embryos by introducing them into the irradiated embryo conditioned medium (IECM) alone, i.e., without partnering with the irradiated embryos. The IECM was harvested from the medium that had conditioned the zebrafish embryos irradiated at 5 hpf with 4-Gy X-ray until the irradiated embryos developed into 29 hpf. NO released from the irradiated embryos was unlikely to be involved in the bystander effect induced through the IECM because of the short life of NO. We further revealed that this bystander effect (induced through IECM) was rapidly abolished through diluting the IECM by a factor of 2* or greater, which agreed with the proposal that the bystander effect was an on/off response with a threshold. PMID- 23668637 TI - Investigating gene expression differences in two chicken groups with variable propensity to feather pecking. AB - Feather pecking is a major welfare problem in egg production. It may be caused by genetic, physiological and environmental factors. The main aim of this study was to uncover gene expression variability in brain tissue between individuals from high feather pecking and low feather pecking groups using the Chicken Gene Expression Microarray. In total, 313 signals were initially identified as significant (P <= 0.05) for the fold change higher than two. A subset of functional candidate genes including downregulated (GLUL, TSPO, MAOA) and upregulated (HTR1B, SIP1, PSEN1) transcripts was subjected to quantitative PCR validation. The significance level and direction of the fold change in gene expression observed by the microarray analysis were confirmed for four genes (HTR1B, SIP1, PSEN1 and GLUL). Newly identified candidate genes play an important role in neurotransmission and psychopathological disorders and can be considered as potential genetic components involved in complex feather pecking behavior. It can be concluded that this study has revealed some interesting differences in gene expression between high and low feather pecking groups and helped to approach elucidation of the genetic foundations of feather pecking. PMID- 23668638 TI - Adverse events after coronary revascularization procedures in California 2000 to 2010. AB - Public reporting of coronary artery bypass grafting (CABG) mortality in California was initiated in 2003. Drug-eluting stents were widely introduced in the same year. Adverse events after percutaneous coronary intervention (PCI) and CABG were analyzed to study the impact of these events. Annual California hospital discharge data were collected from 2000 through 2010. In-hospital mortality and hospital readmission for adverse events <1 year were determined for patients undergoing isolated CABG, PCI for acute coronary syndrome (PCI-ACS), and all other PCIs (PCI-noACS). CABG volume peaked in 2000 and subsequently decreased by 58%; PCI volume peaked in 2005 and subsequently decreased by 20%. After 2003, in-hospital mortality and 1-year mortality for CABG decreased whereas mortality after PCI remained unchanged. Event rates for acute myocardial infarction and stroke varied little over the decade; acute myocardial infarction at 1 year was 2.5% to 2.8% (CABG), 4.5% to 5.4% (PCI-ACS), and 4.6% to 5.8% (PCI-noACS); stroke rate was 1.4% to 1.7% (CABG), 1.2% to 1.6% (PCI-ACS), and 1.0% to 1.2% (PCI noACS). Reintervention for PCI decreased markedly, from 18.8% to 12.8% (PCI-ACS) and 22.5% to 13.3% (PCI-noACS). Multiple adverse cardiovascular and cerebral events rate at 1 year decreased from 10.8% to 9.4% (CABG), 26.5% to 21.2% (PCI ACS), and 26.8% to 18.4% (PCI-noACS). Excluding reinterventions, multiple adverse cardiovascular and cerebral events rate at 1 year was 8.3% (CABG), 14.6% (PCI ACS), and 10.1% (PCI-noACS) in 2010. In conclusion, the volume of coronary interventions in California decreased whereas adverse event rates decreased after the introduction of public reporting and drug-eluting stents. Lower procedure volume combined with improved outcomes resulted in an annual decrease of >6,000 adverse events by the end of the decade. PMID- 23668639 TI - Transfer of patients with suspected acute aortic syndrome. AB - Patients with acute aortic syndrome (AAS) often require emergent transfer for definitive therapy. The aim of this study was to evaluate the safety of transfer and the ability to optimize hemodynamics in subjects with AAS transported by an aortic network. A total of 263 consecutive patients with suspected AAS transferred to a coronary care unit from March 2010 to June 2012 were included. Transfers were accomplished by the institutional critical care transfer system using ground ambulance (n = 47), helicopter (n = 196), or fixed-wing jet (n = 20) from referring centers directly to the coronary care unit, bypassing the emergency department. The transfer mortality rate was 0%, and the in-hospital mortality rate was 9% (n = 23). Initial systolic blood pressure and heart rate at the time of arrival of the transfer team to the referring hospital were compared with those on arrival to the coronary care unit. The median transfer distance was 66 km (interquartile range 24 to 119), and the median transfer time was 87 minutes (interquartile range 67 to 114). The transfer team achieved significant reductions in systolic blood pressure (from 142 +/- 29 to 132 +/- 23 mm Hg) (mean difference in systolic blood pressure 10 mm Hg, 95% confidence interval 7 to 14, p <0.0001) and heart rate (from 78 +/- 16 to 75 +/- 16 beats/min) (mean difference in heart rate 3 beats/min, 95% confidence interval 1 to 4, p <0.0001). In conclusion, these results indicate that patients with AAS can be safely transferred to specialized centers for definitive treatment, and a well-trained critical care transfer team can actively continue to optimize medical management during transit. PMID- 23668640 TI - Agr function is upregulated by photodynamic therapy for Staphylococcus aureus and is related to resistance to photodynamic therapy. AB - Photodynamic therapy (PDT) has been considered a feasible alternative for antimicrobial therapy of multidrug-resistant pathogens. However, bacterial response mechanisms against PDT-generated photo-oxidative stress remain largely unknown. Herein, it is shown that the accessory gene regulator Agr is involved in Staphylococcus aureus response to photo-oxidative stress generated by laser induced PDT with the photosensitizer chlorin e6 . Transcriptional profiling revealed that sublethal PDT induces a general stress response and also activates Agr-dependent gene regulation. Moreover, mutant S. aureus lacking Agr function showed hypersusceptibility to two independent PDT conditions with higher energy densities, demonstrating Agr-dependent S. aureus resistance against PDT. PMID- 23668641 TI - Young adults' recreational social environment as a predictor of ecstasy use initiation: findings of a population-based prospective study. AB - AIMS: To examine prospectively the contribution of the recreational social environment to ecstasy initiation. DESIGN: Population-based retrospective/prospective cohort study. SETTING: Data from screening an Australian young adult population to obtain samples of users and non-users of ecstasy. PARTICIPANTS: A sample of 204 ecstasy-naive participants aged 19-23 years was obtained, and a 6-month follow-up identified those who initiated ecstasy use. MEASUREMENTS: We assessed a range of predictors of ecstasy initiation, including elements of participants' social environment, such as ecstasy-using social contacts and involvement in recreational settings. FINDINGS: More than 40% of ecstasy-naive young adults reported ever receiving ecstasy offers. Ecstasy initiation after 6 months was predicted independently by having, at recruitment, many ecstasy-using social contacts [adjusted relative risk (ARR) 3.15, 95% confidence interval (CI): 1.57, 6.34], attending electronic/dance music events (ARR 6.97, 95% CI: 1.99, 24.37), receiving an ecstasy offer (ARR 4.02, 95% CI: 1.23, 13.10), early cannabis use (ARR 4.04, 95% CI: 1.78, 9.17) and psychological distress (ARR 5.34, 95% CI: 2.31, 12.33). Adjusted population attributable fractions were highest for ecstasy-using social contacts (17.7%) and event attendance (15.1%). CONCLUSIONS: In Australia, ecstasy initiation in early adulthood is associated predominantly with social environmental factors, including ecstasy-using social contacts and attendance at dance music events, and is associated less commonly with psychological distress and early cannabis use, respectively. A combination of universal and targeted education programmes may be appropriate for reducing rates of ecstasy initiation and associated harms. PMID- 23668642 TI - Validation of noninvasive morphological and diffusion imaging in mouse emphysema by micro-computed tomography and hyperpolarized (129)Xe magnetic resonance imaging. AB - Animal disease models are pivotal in investigating the pathogenesis of emphysema and developing novel drugs, but the modalities to evaluate murine emphysema models have been of limited validity and sensitivity. In this study, we evaluated hyperpolarized (129)Xe magnetic resonance imaging (MRI) and micro-computed tomography (micro-CT) compared with traditional methods, such as plethysmography and histology. Elastase-treated mice and adiponectin knockout mice were used as murine emphysema models to evaluate these modalities. Three weeks after elastase administration, significant and heterogeneous emphysema was evaluated according to the mean linear intercept and plethysmography parameters. Notably, the distribution of low-density areas, as examined by micro-CT, correlated with the mean linear intercept and plethysmography parameters in whole lungs. These correlations were also observed in regional areas. Furthermore, we introduced hyperpolarized (129)Xe MRI, which can evaluate gas exchange between the alveoli and blood during spontaneous breathing. Parameters of gas exchange (fD) and alveolar size (Vs/Va) were significantly decreased in elastase-treated mice, and moderately correlated with the plethysmography parameters. Of importance, we could detect a decrease of the fD value in low-density areas with micro-CT, suggesting that gas exchange decreased in emphysematous lesions. Likewise, these parameters (fD and Vs/Va) were also decreased in adiponectin knockout mice, which exhibit emphysema with a homogeneous distribution. We demonstrated the feasibility of (129)Xe MRI and micro-CT in combination with traditional modalities. These noninvasive modalities provide complementary data that can be used for repeated estimations of regional gas exchange and lung morphology. PMID- 23668643 TI - Treatment of head injuries. AB - Sports-related brain injuries are increasing in incidence and may affect athletes from many different sports. Concussion is the most common form of sports-related head injury and is a form of mild traumatic brain injury. Evaluations of concussed athletes should include careful history, focused neurologic examination, balance testing, and cognitive testing. Postinjury management consists of avoiding aggravating factors until symptoms resolve. Return to play should not begin until all symptoms resolve, and then this should be done in a graduated fashion that avoids recreating symptoms. Research is ongoing concerning the maximum safe number of concussive injuries and any possible long-term sequelae. PMID- 23668644 TI - Treatment of neck injuries. AB - Spinal cord injuries are uncommon in sports. Planning and practice for their occurrence, however, remains an essential component of Sideline Medical Team preparedness. Evaluation of cervical nerve injury, cervical cord injury, and cervical disc disease can be complex. Medical management, diagnostic imaging techniques and surgical recommendations in this setting continue to evolve. Most published guidance offers occasionally opposed expert opinion with sport participation after Cervical Cord Neuropraxia in the setting of Cervical Spinal Stenosis appearing particularly polarizing. Such conflicts can present challenges to clinicians in forming management and Return to Play decisions for the health of their athletes. PMID- 23668646 TI - Lumbar injuries of the pediatric population. AB - Primary musculoskeletal etiologies, such as stress fractures, strains, facet arthropathy, and sacroiliac joint dysfunction, are more common causes of pediatric pain than systemic diseases, both in the office setting and the emergency room. Systemic features, young age, and atypical pain should clue physicians to causes other than a primary musculoskeletal cause and prompt an intensive search for other conditions. PMID- 23668645 TI - Back pain in adults. AB - This article provides a summary of the many causes of back pain in adults. There is an overview of the history and physical examination with attention paid to red flags that alert the clinician to more worrisome causes of low back pain. An extensive differential diagnosis for back pain in adults is provided along with key historical and physical examination findings. The various therapeutic options are summarized with an emphasis on evidence-based findings. These reviewed treatments include medication, physical therapy, topical treatments, injections, and complementary and alternative medicine. The indications for surgery and specialty referral are also discussed. PMID- 23668647 TI - The athlete's hip and groin. AB - Groin and hip injuries are seen in athletes who perform quick directional changes and cutting movements. Because forces generated through athletic performance are transferred through the hip, injuries to these areas may limit athletes with mild pain or lead to career-ending injuries. The anatomy of the hip and groin is complex and symptoms often overlap. This article discusses some athletic causes, but other medical conditions may be associated with hip and groin pain as well. Updates in evaluation and treatment are discussed for adductor strains, hip osteoarthritis, femoroacetabular impingement, sports hernia, osteitis pubis, and obturator nerve entrapment. PMID- 23668648 TI - Ligamentous injuries of the knee: anterior cruciate, medial collateral, posterior cruciate, and posterolateral corner injuries. AB - This article discusses athletic injuries of the anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), medial collateral ligament (MCL), and posterolateral corner. Best evidence to date validates that conservative management of ACL ruptures is a reasonable strategy. Current data also seem to advocate nonoperative management of PCL injuries. All isolated MCL injuries, regardless of grade, are usually treated with a brief period of immobilization and symptomatic management. Although the surgical literature often advocates surgical treatment of posterolateral corner injuries, there have been no randomized trials substantiating that these injuries are best treated surgically. PMID- 23668649 TI - Meniscal, plica, patellar, and patellofemoral injuries of the knee: updates, controversies and advancements. AB - In athletes, meniscus tears and cysts, patellar tendonitis, patellofemoral pain syndrome (PFPS), and plica are common injuries. Meniscus tears are usually best treated by partial meniscectomy. Up to 90% of patients with patellar tendonitis can be successfully treated conservatively with expectation of good results. Nonoperative treatment of PFPS, properly focused on the causative factors, can be expected to be successful in most cases. For plica, most physicians recommend a trial of conservative therapy for at least 6 to 8 weeks, followed perhaps by a steroid injection, and ultimately, if symptoms persist, surgery. PMID- 23668650 TI - Foot and ankle update. AB - The purpose of this foot and ankle update is to educate the reader on important foot and ankle topics including current controversies, physical examination, diagnostics, and management. Quick-view lists are used to give easy access to the most significant knowledge points for providing patient care for these entities. These topics were chosen either because they are very common or because of the high morbidity involved should there be a misdiagnosis or mismanagement. PMID- 23668651 TI - The evaluation and treatment of elbow injuries. AB - This article reviews elbow injuries that occur at the medial, lateral, anterior, and posterior aspects, including pediatric elbow injuries. A description, imaging, anatomy (where appropriate), mechanism of injury, physical examination, diagnostics, differential diagnosis, management, cause for referral to an orthopedic surgeon, controversies, and advancements in management for each type of injury are included. PMID- 23668652 TI - Treatment of hand and wrist injuries. AB - Evaluation of the hand and wrist requires a thorough understanding of the anatomic alignment of various bones, tendons, and ligaments along with the physiologic function in order to make an accurate diagnosis that portends appropriate healing and function while minimizing future disability. This article provides the latest research-based evidence of important trends in the treatment and rehabilitation of hand and wrist injuries. PMID- 23668653 TI - Overuse injuries. AB - Tendinopathy and chronic tendon issues related to tendinosis are conditions difficult to treat. These conditions often lead to patients' quality of life declining because of the inability to participate in exercise, occupation-related activities, and activities of daily living. By better understanding the pathophysiology related to the development of tendinosis, clinicians will be better able to understand the treatment options available and their limitations while allowing novel therapies to be developed. Conservative treatment of tendinosis starting with a sound rehabilitation program seems to be the best place to start while reserving surgical approaches for cases that have failed conservative management. PMID- 23668654 TI - Sports nutrition needs: before, during, and after exercise. AB - This article discusses how athletes should properly fuel their bodies before, during, and after exercise to maximize athletic performance. Emphasis is placed on hydration status and glycogen stores being maintained above deficits that negatively affect sport performance. Timing of nutrient intake is as important as composition. PMID- 23668655 TI - Nutritional supplements and ergogenic AIDS. AB - Performance enhancing drugs, ergogenic aids, and supplements come in many forms. The financial, personal, social, and health-related impact of these substances has wide and varied consequences. This article reviews common substances and practices used by athletes. It discusses the history, use, effects, and adverse effects of androgenic anabolic steroids, peptide hormones, growth factors, masking agents, diuretics, volume expanders, beta-blockers, amphetamines, caffeine, other stimulants, and creatine. The evidence base behind the use, safety, and efficacy of these items as well as testing for these substances is discussed. PMID- 23668656 TI - The potential role of sports psychology in the obesity epidemic. AB - Sports psychologists play an important role in enhancing performance among athletes. In conjunction with team physicians, they can also shed light on psychological disorders common in athletes, such as mood and eating disorders, and overtraining syndrome. Sports psychologists can also lend their expertise to assist with injury prevention and recovery and compliance issues. Sports psychology has a role in helping to reverse the growing obesity epidemic among school-aged children. These professionals, working with coaches, can increase children's levels of physical activity. Cognitive-behavioral techniques could lead to enhanced enjoyment, increased participation, improved school performance, and a reduction in obesity. PMID- 23668657 TI - Medicolegal aspects of sports medicine. AB - Legal issues in sports medicine are rapidly developing and establishing an important body of jurisprudence that defines the legal rights and duties of all those involved with protecting the health and safety of athletes. The law makes important distinctions between the relevant duty of care owed to high-school, college, and professional athletes because of the differing legal relationships that arise out of athletic participation at different levels of competition. PMID- 23668658 TI - Common injuries, weekend warriors, and dedicated athletes. PMID- 23668659 TI - As exercise has, over the last decades, become more and more a part of our daily lives. Introduction. PMID- 23668661 TI - Flush at room temperature followed by storage on ice creates the best lung graft preservation in rats. AB - Current clinical lung preservation techniques have not eliminated ischaemia reperfusion (I/R) injury, despite many improvements. The optimal combination of flush and storage temperatures remain unclear in lung preservation. This is the first study to investigate a range of temperatures with 24-h inflated storage using consistent state-of-the-art preservation techniques. A rat lung transplant model was used to investigate the optimal combination of flush and storage temperatures. In six groups, rat lungs were flushed at 4 degrees C, 10 degrees C or room temperature (F(4) /F(10) /F(Rt)) with Perfadex and stored inflated for 24 h in Perfadex on melting ice or at 10 degrees C (S(ice) /S(10)). Left donor lungs were transplanted for analysis. During 2-h reperfusion, the lung graft function was measured (blood gases, maximum ventilation pressure and static compliance) and lung graft injury was also assessed (W/D ratio, total lung protein, Tryptase, Myeloperoxidase). Right donor lungs were assessed for W/D ratio only after flush and storage. For baseline measurements, left lungs without intervention were used. The combination of F(Rt) -S(ice) showed a significantly higher pO(2), lower P(max), low W/D ratios and total protein levels of left lungs after reperfusion when compared with F(4) -S(ice) and baseline. Storage at 10 degrees C did not improve preservation. We conclude that F(Rt) -S(ice) creates the best lung graft preservation. PMID- 23668662 TI - Optimizing stream water mercury sampling for calculation of fish bioaccumulation factors. AB - Mercury (Hg) bioaccumulation factors (BAFs) for game fishes are widely employed for monitoring, assessment, and regulatory purposes. Mercury BAFs are calculated as the fish Hg concentration (Hg(fish)) divided by the water Hg concentration (Hg(water)) and, consequently, are sensitive to sampling and analysis artifacts for fish and water. We evaluated the influence of water sample timing, filtration, and mercury species on the modeled relation between game fish and water mercury concentrations across 11 streams and rivers in five states in order to identify optimum Hg(water) sampling approaches. Each model included fish trophic position, to account for a wide range of species collected among sites, and flow-weighted Hg(water) estimates. Models were evaluated for parsimony, using Akaike's Information Criterion. Better models included filtered water methylmercury (FMeHg) or unfiltered water methylmercury (UMeHg), whereas filtered total mercury did not meet parsimony requirements. Models including mean annual FMeHg were superior to those with mean FMeHg calculated over shorter time periods throughout the year. FMeHg models including metrics of high concentrations (80th percentile and above) observed during the year performed better, in general. These higher concentrations occurred most often during the growing season at all sites. Streamflow was significantly related to the probability of achieving higher concentrations during the growing season at six sites, but the direction of influence varied among sites. These findings indicate that streamwater Hg collection can be optimized by evaluating site-specific FMeHg-UMeHg relations, intra-annual temporal variation in their concentrations, and streamflow-Hg dynamics. PMID- 23668660 TI - Drug-resistance development differs between HIV-1-infected patients failing first line antiretroviral therapy containing nonnucleoside reverse transcriptase inhibitors with and without thymidine analogues. AB - OBJECTIVES: We evaluated the emergence of drug resistance in patients failing first-line regimens containing one nonnucleoside reverse transcriptase inhibitor (NNRTI) administered with zidovudine (ZDV) + lamivudine (the ZDV group) or non thymidine analogues (non-TAs) (tenofovir or abacavir, + lamivudine or emtricitabine; the non-TA group). METHODS: Three hundred HIV-1-infected patients failing a first-line NNRTI-containing regimen (nevirapine, n = 148; efavirenz, n = 152) were included in the analysis. Virological failure was defined as viraemia >= 400 HIV-1 RNA copies/mL for the first time at least 6 months after starting the NNRTI-based regimen. For each patient, a genotypic resistance test at failure was available. The presence of drug-resistance mutations in HIV-1 reverse transcriptase was evaluated by comparing patients treated with NNRTI + zidovudine + lamivudine vs. those treated with NNRTI + non-TA. RESULTS: A total of 208 patients were failing with NNRTI + zidovudine + lamivudine and 92 with NNRTI + non-TA. No significant differences were observed between the non-TA group and the ZDV group regarding the time of virological failure [median (interquartile range): 12 (8-25) vs. 13 (9-32) months, respectively; P = 0.119] and viraemia [median (interquartile range): 4.0 (3.2-4.9) vs. 4.0 (3.3-4.7) log10 copies/mL, respectively; P = 0.894]. Resistance to reverse transcriptase inhibitors (RTIs) occurred at a significant lower frequency in the non-TA group than in the ZDV group (54.3 vs. 75.5%, respectively; P = 0.001). This difference was mainly attributable to a significantly lower prevalence of NNRTI resistance (54.3 vs. 74.0%, respectively; P = 0.002) and of the nucleoside reverse transcriptase inhibitor (NRTI) mutation M184V (23.9 vs. 63.5%, respectively; P < 0.001) in the non-TA group compared with the ZDV group. As expected, the mutation K65R was found only in the non-TA group (18.5%; P < 0.001). CONCLUSIONS: At first-line regimen failure, a lower prevalence of RTI resistance was found in patients treated with NNRTI + non-TA compared with those treated with NNRTI + zidovudine + lamivudine. These results confirm that the choice of backbone may influence the prevalence of drug resistance at virological failure. PMID- 23668663 TI - Deregulation of excitatory neurotransmission underlying synapse failure in Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia in the elderly. Memory loss in AD is increasingly attributed to soluble oligomers of the amyloid beta peptide (AbetaOs), toxins that accumulate in AD brains and target particular synapses. Glutamate receptors appear to be centrally involved in synaptic targeting by AbetaOs. Once bound to neurons, AbetaOs dysregulate the activity and reduce the surface expression of both N-methyl-D-aspartate (NMDA) and 2-amino-3 (3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) types of glutamate receptors, impairing signaling pathways involved in synaptic plasticity. In the extracellular milieu, AbetaOs promote accumulation of the excitatory amino acids, glutamate and D-serine. This leads to overactivation of glutamate receptors, triggering abnormal calcium signals with noxious impacts on neurons. Here, we review key findings linking AbetaOs to deregulated glutamate neurotransmission and implicating this as a primary mechanism of synapse failure in AD. We also discuss strategies to counteract the impact of AbetaOs on excitatory neurotransmission. In particular, we review evidence showing that inducing neuronal hyperpolarization via activation of inhibitory GABA(A) receptors prevents AbetaO-induced excitotoxicity, suggesting that this could comprise a possible therapeutic approach in AD. PMID- 23668664 TI - Taken for granted: normalizing nurses' work in hospitals. AB - The aim of this article is to add to the research surrounding nurses' work in hospitals. Throughout history, nurses have faced adverse working conditions, an aspect of their work that remains remarkably unchanged today. Prevailing historical ideologies and sociopolitical conditions influences the context of nurses' work in contemporary hospitals. This research revealed how ruling patriarchal power and nurses' altruistic ways normalize the conditions in hospitals as nurses' work. Moving discourses further add to the work of nurses in hospitals. For example, cost containment strategies, overcapacity and short staffing have resulted in practices to accommodate these problems. While contemporary hospitals may look different, clearly, inside, little has changed since the early days; hospital issues have clearly become an ordinary part of nurses' work. This article discusses how the conditions in hospitals have become an ordinary part of nurses' work. The research in this article emphasizes how prevailing ideologies and institutional discourses make invisible and taken-for granted, how this normalizing of nurses' work contributes to sustaining the hospital's power. PMID- 23668666 TI - Pharmacological management of essential thrombocythemia. AB - INTRODUCTION: Two factors have deeply influenced the area of essential thrombocythemia (ET). A gain-of-function mutation in the pseudokinase region of the JAK2 gene, which partly explains the pathophysiology of myeloproliferative neoplasms (MPNs), was discovered in 2005 and is present in 50 - 60% of ET patients. Furthermore, the 2008 WHO MPN classification outlined criteria for the separation of ET and early or prefibrotic primary myelofibrosis (PMF). However, these and other new findings have not yet changed the pharmacotherapy of ET, which is based on risk stratification for thrombohemorrhagic risk and aims to reduce thrombosis and bleeding. AREAS COVERED: Studies on the basis for and the validation of the WHO classification as well as studies on possible new risk factors are covered. The most important drugs for ET treatment and consensus recommendations for management of ET are also presented. EXPERT OPINION: The new WHO classification should be used for both ET studies and clinical practice, since true ET has a different prognosis than early PMF. The management of patients should be based on risk stratification. Age > 60 years or previous throbosis (high risk) and platelet counts > 1500 * 10(9)/l warrant cytoreductive treatment, and high risk patients and selected low risk patients should be given anti-aggregation therapy. PMID- 23668665 TI - Identification of a novel indoline derivative for in vivo fluorescent imaging of blood-brain barrier disruption in animal models. AB - Disruption of the blood-brain barrier (BBB) can occur in various pathophysiological conditions. Administration of extraneous tracers that can pass the disrupted, but not the intact, BBB and detection of the extravasation have been widely used to assess BBB disruption in animal models. Although several fluorescent tracers have been successfully used, the administration of these tracers basically requires intravascular injection, which can be laborious when using small animals such as zebrafish. To identify fluorescent tracers that could be easily administered into various animal models and visualize the BBB disruption in vivo, we prepared nine structurally related indoline derivatives (IDs) as a minimum set of diverse fluorescent compounds. We found that one ID, ZMB741, had the highest affinity for serum albumin and emitted the strongest fluorescence in the presence of serum albumin of the nine IDs tested. The affinity to serum albumin and the fluorescence intensity was superior to those of Evans blue and indocyanine green that have been conventionally used to assess the BBB disruption. We showed that ZMB741 could be administered into zebrafish by static immersion or mice by intraperitoneal injection and visualizes the active disruption of their BBB. These results suggest that ZMB741 can be a convenient and versatile tool for in vivo fluorescent imaging of BBB disruption in various animal models. The strategy used in this study can also be applied to diversity oriented libraries to identify novel fluorescent tracers that may be superior to ZMB741. PMID- 23668667 TI - Efficacy of an experiential, dissonance-based smoking intervention for college students delivered via the internet. AB - OBJECTIVE: College represents a window of opportunity to reach the sizeable number of cigarette smokers who are vulnerable to lifelong smoking. The underutilization of typical cessation programs suggests the need for novel and more engaging approaches for reaching college smokers. The aim of the present study was to test the efficacy of a dissonance-enhancing, Web-based experiential intervention for increasing smoking cessation motivation and behavior. METHOD: We used a 4-arm, randomized design to examine the efficacy of a Web-based, experiential smoking intervention (Web-Smoke). The control conditions included a didactic smoking intervention (Didactic), a group-based experiential intervention (Group), and a Web-based nutrition experiential intervention (Web-Nutrition). We recruited 341 college smokers. Primary outcomes were motivation to quit, assessed immediately postintervention, and smoking abstinence at 1 and 6 months following the intervention. RESULTS: As hypothesized, the Web-Smoke intervention was more effective than control groups in increasing motivation to quit. At 6-month follow up, the Web-Smoke intervention produced higher rates of smoking cessation than the Web-Nutrition control intervention. Daily smoking moderated intervention outcomes. Among daily smokers, the Web-Smoke intervention produced greater abstinence rates than both the Web-Nutrition and Didactic control conditions. CONCLUSION: Findings demonstrate the efficacy of a theory-based intervention delivered over the Internet for increasing motivation to quit and smoking abstinence among college smokers. The intervention has potential for translation and implementation as a secondary prevention strategy for college-aged smokers. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23668668 TI - Comparison of youth, caregiver, therapist, trained, and treatment expert raters of therapist adherence to a substance abuse treatment protocol. AB - OBJECTIVE: This study evaluated the accuracy of youth, caregiver, therapist, and trained raters relative to treatment experts on ratings of therapist adherence to a substance abuse treatment protocol for adolescents. METHOD: Adherence ratings were provided by youth and caregivers in an ongoing trial evaluating a Contingency Management (CM) intervention for youth in juvenile drug court. These ratings were compared to those provided by therapists and trained raters, and each rater type was compared to ratings provided by CM treatment experts. Data were analyzed using item-response-theory-based Many-Facet Rasch Models. RESULTS: Relative to treatment experts, youth and caregivers were significantly more likely to endorse the occurrence of CM components. In contrast, therapists and trained raters were much more consistent with treatment experts. In terms of practical significance, youth and caregivers each had a 97% estimated probability of indicating that a typical treatment component had occurred. By comparison, the probability was 31%, 19%, and 26% for therapists, trained raters, and treatment experts, respectively. CONCLUSIONS: Youth and caregivers were highly inaccurate relative to treatment experts, whereas, therapists and trained raters were generally consistent with treatment experts. The implications of these findings for therapist adherence measurement are considered. PMID- 23668669 TI - Epidural analgesia is not superior to systemic postoperative analgesia with regard to preventing chronic or neuropathic pain after thoracotomy. AB - BACKGROUND: To assess prospectively the incidence of chronic and neuropathic pain in patients undergoing anteroaxillary thoracotomy with postoperative epidural analgesia or controlled-release oxycodone pain regimen. METHODS: 77 patients who underwent anteroaxillary thoracotomy were enrolled in our observational study. 40 patients received postoperatively a standardized oral analgesic protocol with controlled-release oxycodone and IV non opioid (CRO Group), and 37 patients received epidural analgesia with ropivacaine 0.1% + 1 MUg/ml sufentanil (EDA Group) and IV non opioid. The painDETECT questionnaire was completed from the patients with one of the authors (JL) on the 7th postoperative day and six months postoperatively. RESULTS: The data of 60 patients were eligible for statistical analysis, 28 patients in the CRO Group and 32 patients in the EDA Group. 17 patients did not reach the 6-months follow-up interval (12 drop outs in the CRO Group and 5 drop outs in the EDA Group). 79% percent of patients in the CRO Group and 74% percent of patients in the EDA Group had a numeric rating scale score (NRS) = 0 after 6 months. 22% percent of patients in the CRO Group and 16% percent of patients in the EDA Group experienced a NRS 1-3 6-months postoperatively. No patient in the CRO Group and 9% percent of patients in the EDA Group had 6-months postoperatively a NRS 4-6. Neither in the CRO Group nor in the EDA Group we could detect a neuropathic pain 6 months postoperatively corresponding to a painDETECT score > 18. Overall, with regard to NRS, there was no statistical difference between the two groups (p = 0.13). 90% percent of patients in the CRO Group and 90% percent of patients in the EDA Group showed 6 months postoperatively a painDETECT score < 13 (definitely no neuropathic pain), and 9% percent in the EDA Group and 11% in the CRO Group had a 6-months painDETECt score 13-18 (p = not significant). CONCLUSION: These pilot data indicate that epidural analgesia is not superior to systemic postoperative analgesia with regard to preventing chronic or neuropathic pain after thoracotomy. PMID- 23668670 TI - Single nucleotide polymorphism discovery in albacore and Atlantic bluefin tuna provides insights into worldwide population structure. AB - The optimal management of the commercially important, but mostly over-exploited, pelagic tunas, albacore (Thunnus alalunga Bonn., 1788) and Atlantic bluefin tuna (BFT; Thunnus thynnus L., 1758), requires a better understanding of population structure than has been provided by previous molecular methods. Despite numerous studies of both species, their population structures remain controversial. This study reports the development of single nucleotide polymorphisms (SNPs) in albacore and BFT and the application of these SNPs to survey genetic variability across the geographic ranges of these tunas. A total of 616 SNPs were discovered in 35 albacore tuna by comparing sequences of 54 nuclear DNA fragments. A panel of 53 SNPs yielded FST values ranging from 0.0 to 0.050 between samples after genotyping 460 albacore collected throughout the distribution of this species. No significant heterogeneity was detected within oceans, but between-ocean comparisons (Atlantic, Pacific and Indian oceans along with Mediterranean Sea) were significant. Additionally, a 17-SNP panel was developed in Atlantic BFT by cross-species amplification in 107 fish. This limited number of SNPs discriminated between samples from the two major spawning areas of Atlantic BFT (FST = 0.116). The SNP markers developed in this study can be used to genotype large numbers of fish without the need for standardizing alleles among laboratories. PMID- 23668671 TI - Genetic predisposition to obesity and lifestyle factors--the combined analyses of twenty-six known BMI- and fourteen known waist:hip ratio (WHR)-associated variants in the Finnish Diabetes Prevention Study. AB - Recent genome-wide association studies have identified multiple loci associated with BMI or the waist:hip ratio (WHR). However, evidence on gene-lifestyle interactions is still scarce, and investigation of the effects of well-documented dietary and other lifestyle data is warranted to assess whether genetic risk can be modified by lifestyle. We assessed whether previously established BMI and WHR genetic variants associate with obesity and weight change in the Finnish Diabetes Prevention Study, and whether the associations are modified by dietary factors or physical activity. Individuals (n 459) completed a 3 d food record and were genotyped for twenty-six BMI- and fourteen WHR-related variants. The effects of the variants individually and in combination were investigated in relation to obesity and to 1- and 3-year weight change by calculating genetic risk scores (GRS). The GRS were separately calculated for BMI and the WHR by summing the increasing alleles weighted by their published effect sizes. At baseline, the GRS were not associated with total intakes of energy, macronutrients or fibre. The mean 1- and 3-year weight changes were not affected by the BMI or WHR GRS. During the 3-year follow-up, a trend for higher BMI by the GRS was detected especially in those who reported a diet low in fibre (P for interaction=0.065). Based on the present findings, it appears unlikely that obesity-predisposing variants substantially modify the effect of lifestyle modification on the success of weight reduction in the long term. In addition, these findings suggest that the association between the BMI-related genetic variants and obesity could be modulated by the diet. PMID- 23668672 TI - High correlations in gene expression between paired umbilical cord blood and neonatal blood of healthy newborns on Guthrie cards. AB - OBJECTIVE: To examine the correlation in genes expressed in paired umbilical cord blood (UCB) and newborn blood (NB). METHOD: Total mRNA and mRNA of three gene sets (inflammatory, hypoxia, and thyroidal response) was assessed using microarray in UCB and NB spotted on Guthrie cards from 7 mother/infant pairs. RESULTS: The average gene expression correlation between paired UCB and NB samples was 0.941 when all expressed genes were considered, and 0.949 for three selected gene sets. CONCLUSION: The high correlation of UCB and NB gene expression suggest that either source may be useful for examining gene expression in the perinatal period. PMID- 23668674 TI - Metabolite-dependent regulation of gene expression in Trypanosoma brucei. AB - Mechanisms regulating gene expression in trypanosomatid protozoa differ significantly from those in other eukaryotes. Transcription of the genome appears to be more or less constitutive with the polyadenylation and trans-splicing of large polycistronic RNAs producing monocistronic RNAs whose translation may then depend upon information within their 3' untranslated regions (3'UTRs). Various 3'UTR sequences involved in life-cycle stage-dependent differential gene expression have been described. Moreover, several RNA-binding proteins have been implicated in regulating expression of these transcripts through altering either their stability or their ability to interact with ribosomes. In this issue of Molecular Microbiology Xiao et al. report on a regulatory element within the 3'UTR of the transcript that encodes the polyamine pathway regulatory protein called prozyme. It appears that the RNA element controls translation of the prozyme RNA causing expression to be upregulated when levels of decarboxylated S adenosylmethionine (dcAdoMet) are depleted. Since prozyme activates the enzyme S adenosylmethionine decarboxylase (AdoMetDC), which is responsible for the production of dcAdoMet, losing this metabolite leads to upregulation of prozyme, activation of AdoMetDC and restoration of optimal levels of dcAdomet. The system thus represents a novel metabolite-sensing regulatory circuit that maintains polyamine homeostasis in these cells. PMID- 23668673 TI - Expression of Toll-like receptors 2 and 9 in cells of dog jejunum and colon naturally infected with Leishmania infantum. AB - BACKGROUND: Infection with parasite protozoa is a long-term health issue in tropical and subtropical regions throughout the world. The Toll-like receptor (TLR) signaling pathway is one of the first-responding defense systems against Leishmania. The aim of this study was to investigate the expression of TLR2 and TLR9 in jejunum and colon and its correlation with CD11c, CD11b, and CD14 receptors used as markers for dendritic cells and macrophages. METHODS: Twenty four dogs infected with Leishmania infantum were used in this study. Cytometry was carried out in lamina propria cells from jejunum and colon using markers for TLR2, TLR9, CD11b, CD11c and CD14. RESULTS: Cellular inflammatory exudate was diffuse in the mucosa and submucosa, predominately comprising mononuclear cells: plasma cells, macrophages, and lymphocytes. Despite the parasite load, microscopy showed no erosion was evident in the epithelial mucosa layers. The colon harbored more parasites than the jejunum. Flow cytometry revealed higher frequency of TLR2+ and CD11c+ dendritic cells in the colon than in the jejunum. Conversely, TLR9-expressing cells were more frequent in jejunum. Moreover, frequency of macrophages (CD11b+ and CD14+) expressing simultaneity TLR9 were lower in the colon than in jejunum, while CD11c+ cells predominated in the colon. Despite of the negative ELISA serum results, IL-10 and TNF-alpha were higher in jejunum than colon of infected animals. However, IL-4 was higher in colon than jejunum of infected animals. A higher expression these cytokines were demonstrated in infected dogs compared to uninfected dogs. CONCLUSIONS: There was no correlation between clinical signs and pathological changes and immunological and parasitological findings in the gastrointestinal tract in canine visceral leishmaniasis. However, jejunum showed a lower parasite load with increased frequency and expression of CD11b, TLR9, CD14/CD11b/TLR9 receptors and IL-10 and TNF-alpha cytokines. Conversely, the colon showed a higher parasite load along with increased frequency and expression of TLR2, CD11c receptors, and IL-4 cytokine. Thus, Leishmania infantum is able to interfere in jejunum increased expression of TLR2, TLR9, CD11b, CD14, CD14/CD11b/TLR9 receptors, IL-10, and TNF alpha; and in colon increased expression of CD11c, TLR2, TLR9, CD11b, CD14 e, CD14/CD11b/TLR9 receptors, IL-10, and TNF-alpha. PMID- 23668675 TI - A randomized crossover study to assess the effect of an oat-rich diet on glycaemic control, plasma lipids and postprandial glycaemia, inflammation and oxidative stress in Type 2 diabetes. AB - AIMS: In the UK, lifestyle intervention is first-line management in Type 2 diabetes. It is unclear what type of diet is most efficacious for improving glycaemic control. This study investigated the effects of an oat-enriched diet on glycaemic control, postprandial glycaemia, inflammation and oxidative stress compared with standard dietary advice. METHODS: In a randomized crossover design, 27 volunteers with Type 2 diabetes, managed on diet and lifestyle only, were observed for two consecutive 8-week periods following either the oat-enriched diet or re-enforced standard dietary advice. Volunteers attended at baseline (habitual intake) and 8 and 16 weeks. Measurements included basic clinical measurements and fasted and postprandial (3-h) glucose and insulin in response to a healthy test meal. Markers of inflammation and oxidative stress, including high sensitivity C-reactive protein, interleukin 6, interleukin 18, tumour necrosis factor-alpha, adiponectin, thiobarbituric acid reactive substances, oxygen radical antioxidant capacity, oxidized LDL and urinary isoprostanes, were also measured at fasting and in the postprandial period. RESULTS: There were no diet related effects on glycaemic control or glycaemic or insulinaemic responses to the test meal. Total cholesterol (5.1 +/- 1.0 vs. 4.9 +/- 0.8 mmol/l, P = 0.019) concentrations declined following the oat-enriched diet compared with standard dietary advice. There was a postprandial decline in adiponectin concentration (P = 0.009), but no effect of dietary intervention. None of the measures of oxidative stress or inflammation were altered by the oat-enriched diet compared with standard dietary advice. CONCLUSION: The oat-enriched diet had a modest impact on lipid lowering, but did not impact on oxidative stress or inflammation in these volunteers with Type 2 diabetes. PMID- 23668676 TI - Effectiveness of metronidazole as an adjunct to scaling and root planing in the treatment of chronic periodontitis: a systematic review and meta-analysis. AB - BACKGROUND: Metronidazole (MET) has been suggested as an adjunct to scaling and root planing (SRP) in the treatment of chronic periodontitis. However, its clinical effectiveness and effects on periodontal pathogens remain to be defined. The present meta-analysis assessed the scientific evidence concerning the effect of MET adjunctive to SRP as compared to SRP alone. METHODS: A literature search of electronic databases was performed for articles published through December 16, 2012, followed by a manual search of several dental journals. A meta-analysis was conducted according to recommendations of the Cochrane Collaboration and PRISMA. Weighted mean differences (MDs) and 95% confidence intervals (CIs) were calculated for probing depth reduction, clinical attachment level gain, bleeding on probing index and suppuration. All outcomes were evaluated as changes from baseline to the end of follow-up. Heterogeneity was assessed with the chi-squared based Cochran Q test and I(2) statistic. The level of significance was set at p < 0.05. RESULTS: After the study selection process, six randomized clinical trials were included in the meta-analysis. The results of the meta-analysis indicated that SRP + MET provided additional benefits when compared to SRP alone in terms of probing depth reduction (MD, 0.18; 95% CI, 0.09-0.28; p < 0.05) and clinical attachment level gain (MD, 0.10; 95% CI, 0.08-0.12; p < 0.05). No evidence of heterogeneity was detected. CONCLUSION: The meta-analysis results seem to support the effectiveness of adjunctive MET with SRP compared to SRP alone. However, given the low number of included studies and limitations of meta-analysis, future studies are needed to confirm these results. PMID- 23668677 TI - Overexpression of alphavbeta6 integrin alters the colorectal cancer cell proteome in favor of elevated proliferation and a switching in cellular adhesion that increases invasion. AB - Many proteins enhance cancer progression toward life-threatening metastases. These include linking proteins called integrins that mediate cell adhesion to the extracellular matrix (ECM), consequently altering both function and phenotype. Specific neoexpression of the beta6 integrin subunit correlates with the epithelial-to-mesenchymal transition, metastasis, and poor overall patient survival. While beta6 is implicated in these processes, exactly how it affects signaling and/or proteolytic pathways in metastasis remains unclear. A membrane enriched peptide immobilized pH gradient isoelectric focusing (IPG-IEF) shotgun proteomics study was undertaken in which subclones of the SW480 colorectal cancer cell line transfected with a vector inducing unregulated beta6 integrin overexpression were compared with the "empty" mock vector control cell line. beta6 overexpression induced a significant change in 708 proteins and was found to be localized across most intracellular locations, some involving cellular processes and pathways underpinning cancer progression. Proteomics data have been deposited to the ProteomeXchange with identifier PXD000230. beta6 expression increased cell proliferation 4-fold while decreasing cell adhesion to many integrin ECM substrates. beta6 expression also enhanced cell invasion and promoted the expression/repression of many established cancer-related pathways. PMID- 23668678 TI - A 10-year study of membrane filter system versus blood culture bottles in culturing vitrectomy cassette vitreous in infectious endophthalmitis. AB - PURPOSE: To compare the microbiological outcomes of membrane filter system and blood culture bottle techniques in culturing diluted vitrectomy cassette vitreous. DESIGN: Retrospective comparative case series. METHODS: Diluted vitrectomy cassette vitreous specimens from March 25, 2002 to July 11, 2012 were cultured using both membrane filter system and blood culture bottles. The isolates were divided into 3 groups: ones that had positive cultures with (1) both membrane filter system and blood culture bottles, (2) membrane filter system only, and (3) blood culture bottles only. The 48-hour as well as 2-week results were documented. RESULTS: A total of 447 patients with 168 positive cultures were studied. At the 48-hour time point, 126 isolates were documented. Of those, 104 (82%) were culture positive with both membrane filter system and blood culture bottles, 15 (12%) were culture positive only with membrane filter system, and 7 (6%) were culture positive only with blood culture bottles. At the 2-week time point, an additional 42 organisms were isolated. Of those, 19 (45%) were culture positive with both membrane filter system and blood culture bottles, 11 (26%) with membrane filter system only, and 12 (29%) with blood culture bottles only. Out of 168 total isolates, 123 (73%) were culture positive with both membrane filter system and blood culture bottles, 26 (16%) with membrane filter system only, and 19 (11%) with blood culture bottles only. Among all microbiological outcomes, there was no significant difference between membrane filter system and blood culture bottle (P = .37). Of those organisms that were culture positive only with either membrane filter system or blood culture bottle, mold and Mycobacterium species were culture positive more commonly with membrane filter system (P = .034 and P = .016, respectively), and gram-positive organisms were culture positive more commonly with blood culture bottles (P = .021). CONCLUSIONS: In the current study, a combination of membrane filter system and blood culture bottles for culture of diluted vitrectomy cassette vitreous provides the highest number of positive culture outcomes. The blood culture bottle method is technically easier and represents a viable alternative to the more complex membrane filter system technique. PMID- 23668679 TI - Conversion to aflibercept for chronic refractory or recurrent neovascular age related macular degeneration. AB - PURPOSE: To explore the visual and anatomic outcomes of patients with refractory or recurrent neovascular age-related macular degeneration (AMD) who were converted from bevacizumab and/or ranibizumab to aflibercept. DESIGN: Two-center, retrospective chart review. METHODS: Treatment history, visual acuity (VA), and central macular thickness (CMT) on spectral-domain optical coherence tomography were collected. Patients were divided into "refractory" (persistent exudation despite monthly injections) or "recurrent" (exudation suppressed, but requiring frequent injections). RESULTS: One hundred and two eyes of 94 patients were included; 68 were refractory and 34 were recurrent. Eyes received a mean of 20.4 prior bevacizumab/ranibizumab injections and a mean of 3.8 aflibercept injections. Mean follow-up was 18 weeks. Mean VA was 20/50-1 before conversion, 20/50-2 after 1 aflibercept injection (P = .723), and 20/50+2 after the final injection (P = .253). Subgroup analysis of refractory and recurrent cases also showed stable VA. Of the refractory cases, mean CMT had improved after 1 injection (P < .001) and the final injection (P < .001). Intraretinal (P < .001) and subretinal (P < .001) fluid decreased after 1 injection, and the mean injection interval was extended from 5.2 to 6.2 weeks (P = .003). Of the recurrent cases, mean CMT improved after 1 injection (P < .001) and the final injection (P < .001). Intraretinal (P = .003) and subretinal (P = .046) fluid decreased after 1 injection, and the mean injection interval was extended from 7.2 to 9.5 weeks (P = .001). CONCLUSIONS: Converting patients with chronic neovascular AMD to aflibercept results in stabilized vision and improved anatomic outcomes, while allowing injection intervals to be extended. PMID- 23668680 TI - Epiretinal membrane surgery outcomes in highly myopic eyes without traction maculopathy: long-term results of a case-control study. AB - PURPOSE: To evaluate the outcomes of epiretinal membrane (ERM) surgery in highly myopic eyes without traction maculopathy, and to compare them with those from non highly myopic eyes. DESIGN: Retrospective nested case-control study from a cohort of 509 consecutive patients (509 eyes) who underwent pars plana vitrectomy with ERM removal. METHODS: Thirty-two highly myopic eyes (with a refractive error of more than -6.00 diopters [D]), which underwent surgery for isolated ERM, were included in the study. For each case studied, we selected from the same cohort 2 age-matched controls who had ERM surgery (n = 64 non-highly myopic eyes). The best-corrected visual acuity (BCVA), the central macular thickness (CMT), and the surgical complications were analyzed. RESULTS: The mean follow-up duration was 3.2 +/- 1.5 years for the study cases and 3.4 +/- 1.6 years for the control group (P = .608). At the final follow-up examination, the mean logMAR BCVA had improved significantly, from 0.56 to 0.26 (P < .001) for the case group and from 0.54 to 0.22 (P < .001) for the control group. At the final optical coherence tomography (OCT), the mean CMT had improved significantly, from 433 to 314 MUm (P < .001) for the case group and from 428 to 303 MUm (P < .001) for the control group. There was no significant difference between the 2 groups as regards visual or CMT improvement (P = .526 and P = .483, respectively). The incidence of surgical complications was not significant between the 2 groups. CONCLUSIONS: The results of ERM surgery were not different in terms of anatomic and visual outcomes and surgical complication between highly myopic and non-highly myopic eyes. PMID- 23668681 TI - Randomized trial of ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for retinitis pigmentosa. AB - PURPOSE: To evaluate the safety and effect on visual function of ciliary neurotrophic factor delivered via an intraocular encapsulated cell implant for the treatment of retinitis pigmentosa (RP). DESIGN: Ciliary neurotrophic factor for late-stage retinitis pigmentosa study 3 (CNTF3; n = 65) and ciliary neurotrophic factor for early-stage retinitis pigmentosa study 4 (CNTF4; n = 68) were multicenter, sham-controlled dose-ranging studies. METHODS: Patients were randomly assigned to receive a high- or low-dose implant in 1 eye and sham surgery in the fellow eye. The primary endpoints were change in best-corrected visual acuity (BCVA) at 12 months for CNTF3 and change in visual field sensitivity at 12 months for CNTF4. Patients had the choice of retaining or removing the implant at 12 months for CNTF3 and 24 months for CNTF4. RESULTS: There were no serious adverse events related to either the encapsulated cell implant or the surgical procedure. In CNTF3, there was no change in acuity in either ciliary neurotrophic factor- or sham-treated eyes at 1 year. In CNTF4, eyes treated with the high-dose implant showed a significant decrease in sensitivity while no change was seen in sham- and low dose-treated eyes at 12 months. The decrease in sensitivity was reversible upon implant removal. In both studies, ciliary neurotrophic factor treatment resulted in a dose-dependent increase in retinal thickness. CONCLUSIONS: Long-term intraocular delivery of ciliary neurotrophic factor is achieved by the encapsulated cell implant. Neither study showed therapeutic benefit in the primary outcome variable. PMID- 23668682 TI - Approach to the diagnosis of the uveitides. AB - PURPOSE: To describe an approach to diagnosing the uveitides, a collection of about 30 separate diseases characterized by intraocular inflammation. DESIGN: Perspective. METHODS: Integration of clinical approach with a more formal, informatics-derived approach to characterization and a Bayesian approach to laboratory testing. RESULTS: The patient's uveitis is characterized along several dimensions: course, laterality, anatomic location of the inflammation, morphology, presence of active infection, and the host (age, presence of a systemic disease). Posterior uveitis can be characterized further by whether it is primarily a retinitis, choroiditis, or retinal vasculitis; by whether it is paucifocal or multifocal; and by the morphology of the lesions. This characterization narrows the differential diagnosis to 1 or, at most, a few diseases. Laboratory screening (ie, testing all patients) should be reserved for those diseases that can present as any type of uveitis, whereas targeted testing (ie, testing a subset with specific features) is used selectively. Laboratory testing should be used to identify an infection (which will alter therapy) or a systemic disease that will affect the patient's health. A uveitis that is not one of the established diagnoses is designated as "undifferentiated" with the course, laterality, and anatomic location (eg, undifferentiated bilateral chronic anterior uveitis). We avoid the term "idiopathic" uveitis as most identified noninfectious uveitic diseases are idiopathic, and most systemic diseases associated with uveitis also are idiopathic (eg, juvenile idiopathic arthritis). CONCLUSION: This approach should lead to the correct diagnosis of the specific uveitic disease in the large majority of cases without overuse of laboratory testing. PMID- 23668683 TI - Factorial experimental design for the culture of human embryonic stem cells as aggregates in stirred suspension bioreactors reveals the potential for interaction effects between bioprocess parameters. AB - Traditional optimization of culture parameters for the large-scale culture of human embryonic stem cells (ESCs) as aggregates is carried out in a stepwise manner whereby the effect of varying each culture parameter is investigated individually. However, as evidenced by the wide range of published protocols and culture performance indicators (growth rates, pluripotency marker expression, etc.), there is a lack of systematic investigation into the true effect of varying culture parameters especially with respect to potential interactions between culture variables. Here we describe the design and execution of a two parameter, three-level (3(2)) factorial experiment resulting in nine conditions that were run in duplicate 125-mL stirred suspension bioreactors. The two parameters investigated here were inoculation density and agitation rate, which are easily controlled, but currently, poorly characterized. Cell readouts analyzed included fold expansion, maximum density, and exponential growth rate. Our results reveal that the choice of best case culture parameters was dependent on which cell property was chosen as the primary output variable. Subsequent statistical analyses via two-way analysis of variance indicated significant interaction effects between inoculation density and agitation rate specifically in the case of exponential growth rates. Results indicate that stepwise optimization has the potential to miss out on the true optimal case. In addition, choosing an optimum condition for a culture output of interest from the factorial design yielded similar results when repeated with the same cell line indicating reproducibility. We finally validated that human ESCs remain pluripotent in suspension culture as aggregates under our optimal conditions and maintain their differentiation capabilities as well as a stable karyotype and strong expression levels of specific human ESC markers over several passages in suspension bioreactors. PMID- 23668684 TI - How does rate of smoking cessation vary by age, gender and social grade? Findings from a population survey in England. AB - AIMS: To assess the incidence of long-term smoking cessation as a function of age, gender, social grade and their interactions. DESIGN AND SETTING: Cross sectional surveys of population representative samples of smokers in England. PARTICIPANTS: A total of 24 094 ever smokers (>=21 and <=60 years of age) participating in household surveys between November 2006 and February 2011. MEASUREMENTS: The ratio of long-term (>1 year) ex-smokers to ever-smokers was calculated for each age. Regression analyses were used to model the association between age and quit ratio, with the change in quit ratio by year of age n years versus all years up to n-1 years, yielding an estimate of the quitting incidence at that age. Analyses were conducted for the entire sample and then for the sample stratified by gender and social grade, and interactions assessed between these variables. FINDINGS: A cubic trend was needed to fit the data. The estimated quitting incidence between ages 21 and 30 was 1.5% (95% CI: 1.0%-2.0%), between 31 and 50 it was 0.3% (95% CI: 0.2%-0.5%) and between 51 and 60 it was 1.2% (95% CI: 0.7%-1.7%). Age interacted with gender and social grade: women and smokers from higher social grades had a higher incidence of quitting than men and those from lower social grades specifically in young adulthood. CONCLUSIONS : The incidence of smoking cessation in England appears to be greater in young and old adults compared with those in middle age. Women and higher social grade smokers show a greater incidence of quitting than men and those from lower social grades specifically in young adulthood. PMID- 23668685 TI - A moderated mediation model: racial discrimination, coping strategies, and racial identity among Black adolescents. AB - This study examined a moderated mediation model among 314 Black adolescents aged 13-18. The model included general coping strategies (e.g., active, distracting, avoidant, and support-seeking strategies) as mediators and racial identity dimensions (racial centrality, private regard, public regard, minority, assimilationist, and humanist ideologies) as moderators of the relation between perceived racial discrimination and depressive symptoms. Moderated mediation examined if the relation between perceived racial discrimination and depressive symptoms varied by the mediators and moderators. Results revealed that avoidant coping strategies mediated the relation between perceptions of racial discrimination and depressive symptoms. The results indicated that avoidant coping strategies mediated the relation between perceived racial discrimination and depressive symptoms among youth with high levels of the minority/oppressive ideology. PMID- 23668686 TI - Dissolved organic matter and inorganic ions in a central Himalayan glacier- insights into chemical composition and atmospheric sources. AB - Melting of Himalayan glaciers can be accelerated by the deposition of airborne black carbon and mineral dust as it leads to significant reductions of the surface albedo of snow and ice. Whereas South Asia has been shown a primary source region to these particles, detailed sources of these aerosol pollutants remain poorly understood. In this study, the chemical compositions of snow pit samples collected from Jima Yangzong glacier in the central Himalayas were analyzed to obtain information of atmospheric aerosols deposited from summer 2009 to spring 2010. Especially, an Aerodyne high resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS) was used for the first time to chemically characterize the dissolved organic and inorganic matter (DOM and DIM) in snow samples. The concentrations of these species varied seasonally, with high levels observed during the winter-spring period and low levels during the summer monsoon period. On average, the dissolved substances was dominated by organics (58%) with important contributions from inorganic species, NO3(-) (12.5%), Ca(2+) (9.1%), NH4(+) (8.7%), and SO(4)(2-) (8.1%). DOM was found more oxidized with an average (+/- 1sigma) atomic oxygen-to-carbon ratio (nO/nC) of 0.64 (+/- 0.14) and organic mass-to-carbon ratio (OM/OC) of 2.01 (+/- 0.19) during the winter-spring periods compared to the summer season (nO/nC = 0.31 +/- 0.09 and OM/OC = 1.58 +/- 0.12). In addition, biomass burning particles were found significantly enhanced in snow during the winter-spring periods, consistent with HYSPLIT back trajectory analysis of air mass history, which indicates prevailing atmospheric transport from northwest India and Nepal. PMID- 23668687 TI - Respirology Case Reports-new and filling a gap. PMID- 23668688 TI - Inhibition of the mTOR pathway: a possible protective role in coronary artery disease. AB - The main approach to obesity and type-II diabetes is to unravel the mechanisms involved in nutrient absorption and fuel allocation. In conditions of over nutrition, cells must cope with a multitude of extracellular signals generated by changes in nutrient load, hormonal milieu, adverse cytokine/adipokine profile, and apoptosis/anti-apoptosis processes. To date studies have demonstrate that among all nutrients, lipids and carbohydrates play a major regulatory role in the gene transcription of glycolytic and lipogenic enzymes, insulin, and adipokines. These nutrients mainly exert their effects through the gene expression of sterol responsive binding protein 1 and 2 (SREBP) and the mammalian target of rapamycin (mTOR). Excess of adipose tissue is known to confer a significantly higher risk of coronary artery disease. Administration of rapamycin effectively attenuated inflammation, inhibited progression, and enhanced stability of atherosclerotic plaques in animal models. Herein we discuss the mTOR pathway and the molecular mechanisms of mTOR inhibitors, hypothesizing a possible protective role in atherosclerosis, taking into account also previous clinical studies emphasizing their opposite role. PMID- 23668690 TI - Treating myoclonic epilepsy in children: state-of-the-art. AB - INTRODUCTION: Myoclonic seizures can be observed in various clinical settings and different epileptic conditions, including some forms of both diopathic and symptomatic epilepsies. Relatively little has been written on treatment of myoclonic seizures. Some old antiepileptic drugs, such as valproate and some benzodiazepines, are widely used but more treatment options exist today for some newer antiepileptic drugs. Nevertheless, patients can be refractory to drug treatment and some drugs may exacerbate or even induce myoclonus. AREAS COVERED: Key safety, tolerability, and efficacy data are presented for different antiepileptic drugs with antimyoclonic effect, alone and/or in combination. EXPERT OPINION: Treatment of myoclonic seizures in children is mainly based on prospective and retrospective studies, with little evidence from randomized clinical trials. Valproate is commonly the first choice alone or in combination with some benzodiazepines or levetiracetam. There is still insufficient evidence for the use of topiramate and zonisamide as monotherapy. Of major importance remains avoidance of medication that may aggravate the seizures. Better understanding of pathophysiologic mechanisms of myoclonic seizures and myoclonic epilepsies could yield great improvement in the treatment and quality of life of patients. PMID- 23668689 TI - High mammographic density in women of Ashkenazi Jewish descent. AB - INTRODUCTION: Percent mammographic density (PMD) adjusted for age and body mass index is one of the strongest risk factors for breast cancer and is known to be approximately 60% heritable. Here we report a finding of an association between genetic ancestry and adjusted PMD. METHODS: We selected self-identified Caucasian women in the California Pacific Medical Center Research Institute Cohort whose screening mammograms placed them in the top or bottom quintiles of age-adjusted and body mass index-adjusted PMD. Our final dataset included 474 women with the highest adjusted PMD and 469 with the lowest genotyped on the Illumina 1 M platform. Principal component analysis (PCA) and identity-by-descent analyses allowed us to infer the women's genetic ancestry and correlate it with adjusted PMD. RESULTS: Women of Ashkenazi Jewish ancestry, as defined by the first principal component of PCA and identity-by-descent analyses, represented approximately 15% of the sample. Ashkenazi Jewish ancestry, defined by the first principal component of PCA, was associated with higher adjusted PMD (P = 0.004). Using multivariate regression to adjust for epidemiologic factors associated with PMD, including age at parity and use of postmenopausal hormone therapy, did not attenuate the association. CONCLUSIONS: Women of Ashkenazi Jewish ancestry, based on genetic analysis, are more likely to have high age-adjusted and body mass index-adjusted PMD. Ashkenazi Jews may have a unique set of genetic variants or environmental risk factors that increase mammographic density. PMID- 23668691 TI - n-3 fatty acids, inflammation and immunity: new mechanisms to explain old actions. AB - Numerous effects of n-3 fatty acids EPA and DHA on functional responses of cells involved in inflammation and immunity have been described. Fatty acid-induced modifications in membrane order and in the availability of substrates for eicosanoid synthesis are long-standing mechanisms that are considered important in explaining the effects observed. More recently, effects on signal transduction pathways and on gene expression profiles have been identified. Over the last 10 years or so, significant advances in understanding the mechanisms of action of n 3 fatty acids have been made. These include the identification of new actions of lipid mediators that were already described and of novel interactions among those mediators and the description of an entirely new family of lipid mediators, resolvins and protectins that have anti-inflammatory actions and are critical to the resolution of inflammation. It is also recognised that EPA and DHA can inhibit activation of the prototypical inflammatory transcription factor NF kappaB. Recent studies suggest three alternative mechanisms by which n-3 fatty acids might have this effect. Within T-cells, as well as other cells of relevance to immune and inflammatory responses, EPA and DHA act to disrupt very early events involving formation of the structures termed lipid rafts which bring together various proteins to form an effective signalling platform. In summary, recent research has identified a number of new mechanisms of action that help to explain previously identified effects of n-3 fatty acids on inflammation and immunity. PMID- 23668692 TI - First and second trimester screening for large for gestational age infants. AB - OBJECTIVES: To find the best early predictor model for fetal growth and large for gestational age (LGA) infants considering clinical, ultrasonographic and biochemical variables. METHOD: In 2097 singleton pregnancies at first trimester, we evaluated maternal characteristics, PAPP-A and beta-HCG proteins, fetal nuchal translucency thickness and uterine artery pulsatility index (UtA-PI). At second trimester fetal ultrasound biometry and UtA-PI were then measured. The relationships between birth weight and LGA and maternal characteristics, first and second trimester variables, and all variables combined, were studied. The performance of screening was determined by receiver operating characteristic curves analysis. RESULTS: Stepwise regression analysis showed that in the prediction of birthweight percentile there were significant contributions from all maternal factors, PAPP-A and Ut-A PI in the first trimester, and fetal biometric variables in the second trimester. Maternal charateristics combined with PAPP-A, beta-hCG, fetal NT and uterine artery PI identified 30.2 % LGA (FPR 10%). The combined model reached a sensitivity of 41.2% (FPR 10%) and 56.2% (FPR 20%). CONCLUSIONS: Sensitivity of the screening for LGA improves significantly after addition of second trimester ultrasound measurements to first trimester variables and maternal characteristics. PMID- 23668693 TI - Corticotropin-releasing factor infusion into nucleus incertus suppresses medial prefrontal cortical activity and hippocampo-medial prefrontal cortical long-term potentiation. AB - The medial prefrontal cortex (mPFC) in the rat has been implicated in a variety of cognitive processes, including working memory and expression of fear memory. We investigated the inputs from a brain stem nucleus, the nucleus incertus (NI), to the prelimbic area of the mPFC. This nucleus strongly expresses corticotropin releasing factor type 1 (CRF1 ) receptors and responds to stress. A retrograde tracer was used to verify connections from the NI to the mPFC. Retrogradely labelled cells in the NI expressed CRF receptors. Electrophysiological manipulation of the NI revealed that stimulation of the NI inhibited spontaneous neuronal firing in the mPFC. Similarly, CRF infusion into the NI, in order to mimic a stressful condition, inhibited neuronal firing and burst firing in the mPFC. The effect of concurrent high-frequency stimulation of the NI on plasticity in the hippocampo-prelimbic medial prefrontal cortical (HP-mPFC) pathway was studied. It was found that electrical stimulation of the NI impaired long-term potentiation in the HP-mPFC pathway. Furthermore, CRF infusion into the NI produced similar results. These findings might account for some of the extra pituitary functions of CRF and indicate that the NI may play a role in stress driven modulation of working memory and possibly other cognitive processes subserved by the mPFC. PMID- 23668694 TI - Modification of a prey catching response and the development of behavioral persistence in the fire-bellied toad (Bombina orientalis). AB - The present report investigated how fire-bellied toads (Bombina orientalis) modified their response in a prey catching task in which the attribution of food reward was contingent on snapping toward a visual stimulus of moving prey displayed on a computer screen. Two experiments investigated modification of the snapping response, with different intervals between the opportunity to snap at the visual stimulus and reward administration. The snapping response of unpaired controls was decreased compared with the conditioned toads when hour or day intervals were used, but intervals of 5 min produced only minimal change in snapping. The determinants of extinction of the response toward the visual stimulus were then investigated in 3 experiments. The results of the first experiment suggested that increased resistance to extinction depended mostly on the number of training trials, not on partial reinforcement or the magnitude of reinforcement during training. This was confirmed in a second experiment showing that overtraining resulted in resistance to extinction, and that the pairing of the reward with a response toward the stimulus was necessary for that effect, as opposed to pairing reward solely with the experimental context. The last experiment showed that the time elapsed between training trials also influenced extinction, but only in toads that received few training trials. Overall, the results suggest that toads learning about a prey stimulus progress from an early flexible phase, when an action can be modified by its consequences, to an acquired habit characterized by an increasingly inflexible and automatic response. PMID- 23668696 TI - Exclusion in corvids: the performance of food-caching Eurasian jays (Garrulus glandarius). AB - Choice by exclusion involves selecting a rewarded stimulus by rejecting alternatives that are unlikely to be rewarded. It has been proposed that in corvids, exclusion is an adaptive specialization for caching that, together with object permanence and observational spatial memory, enhances a bird's ability to keep track of the contents of caches. Thus, caching species are predicted to perform well in tasks requiring exclusion. We tested this prediction by assessing the performance of Eurasian jays (Garrulus glandarius), a highly specialized cacher, in a two-way object choice task in which food was hidden in 1 of 2 cups. Consistent with the corvids' capacity for observational spatial memory, jays were highly accurate when shown the location of the food reward. However, the jays failed to exclude the empty cup when shown its contents. This failure to select the baited cup when shown the empty cup was possibly due to jays attending to the experimenter's movements and erroneously selecting the empty cup by responding to these local enhancement cues. To date, no corvids have been tested in an auditory two-way object choice task. Testing exclusion in the auditory domain requires that a bird use the noise produced when the baited cup is shaken to locate the reward. Although jays chose the baited cup more frequently than predicted by chance, their performance did not differ from trials controlling for the use of conflicting cues provided by the experimenter. Overall, our results provide little support for the hypothesis that caching has shaped exclusion abilities in corvids. PMID- 23668695 TI - Personality structure in brown capuchin monkeys (Sapajus apella): comparisons with chimpanzees (Pan troglodytes), orangutans (Pongo spp.), and rhesus macaques (Macaca mulatta). AB - Species comparisons of personality structure (i.e., how many personality dimensions and the characteristics of those dimensions) can facilitate questions about the adaptive function of personality in nonhuman primates. Here we investigate personality structure in the brown capuchin monkey (Sapajus apella), a New World primate species, and compare this structure to those of chimpanzees (Pan troglodytes), orangutans (Pongo spp.), and rhesus macaques (Macaca mulatta). Brown capuchins evolved behavioral and cognitive traits that are qualitatively similar to those of great apes, and individual differences in behavior and cognition often reflect differences in personality. Thus, we hypothesized that brown capuchin personality structure would overlap more with great apes than with rhesus macaques. We obtained personality ratings from seven sites, including 127 brown capuchin monkeys. Principal-components analysis identified five personality dimensions (Assertiveness, Openness, Neuroticism, Sociability, and Attentiveness), which were reliable across raters and, in a subset of subjects, significantly correlated with relevant behaviors up to a year later. Comparisons between species revealed that brown capuchins and great apes overlapped in personality structure, particularly chimpanzees in the case of Neuroticism. However, in some respects (i.e., capuchin Sociability and Openness) the similarities between capuchins and great apes were not significantly greater than those between capuchins and rhesus macaques. We discuss the relevance of our results to brown capuchin behavior and the evolution of personality structure in primates. PMID- 23668697 TI - Anti tumor necrosis factor - alpha adalimumab for complex regional pain syndrome type 1 (CRPS-I): a case series. AB - BACKGROUND AND AIMS: Evidence suggests tumor necrosis factor-alpha (TNF-alpha) mediates, at least in part, symptoms and signs in complex regional pain syndrome (CRPS). Here, we present a case series of patients with CRPS type 1, in whom the response to the anti-TNF-alpha adalimumab was assessed. METHODS: Ten patients with CRPS type 1 were recruited. Assessments were performed before treatment, at 1 week, and 1, 3, and 6 months following 3 biweekly subcutaneous injections (40 mg/0.8 mL) adalimumab (Humira((r)) ) and included the followings: Pain intensity using a 0-10 cm visual analog scale; the Short Form of the McGill Pain Questionnaire; the Beck Depression Inventory; the SF-36 questionnaire and mechanical and thermal thresholds (Von frey hair and Thermal Sensory Analyzer, respectively). In addition to the description of individual patient responses, both intention to treat (ITT) and per-protocol (PP) analyses were performed for the entire group. RESULTS: Three subgroups of patients were identified (3 patients in each): "nonresponders", "partial responders", and "robust responders" in whom improvement in almost all parameters was noted. Both the ITT and PP analyses demonstrated only a trend toward improvement in mechanical pain thresholds following treatment (ITT chi2 = 13.83, P = 0.008; PP chi2 = 10.29, P = 0.036). CONCLUSION: These results suggest adalimumab, and possibly other anti-TNF alpha, can be potentially useful in some (although not in all) patients with CRPS type 1. These preliminary results along with the growing body of evidence which points to the involvement of TNF-alpha in the pathogenesis of CRPS justify further studies in this area. PMID- 23668698 TI - Symptoms of irritable bowel syndrome in patients with inflammatory bowel disease: examining the role of sub-clinical inflammation and the impact on clinical assessment of disease activity. AB - BACKGROUND: Symptoms compatible with irritable bowel syndrome (IBS) are frequently present in patients with inflammatory bowel disease (IBD); however, the cause of this phenomenon is unclear. AIM: To determine the different contributions of 'true IBS' and sub-clinical inflammation in producing IBS-type symptoms in IBD patients, and to ascertain the impact these symptoms have on the clinical assessment of IBD activity. METHODS: In this cross-sectional study, 169 IBD patients completed questionnaires to assess disease activity, presence of IBS type symptoms, and levels of anxiety and depression. Stool samples were collected for analysis of faecal calprotectin (FC). RESULTS: IBS-type symptoms were significantly more common in female patients (OR = 4.64, 1.55-13.88) and were associated with higher levels of anxiety (OR = 1.11, 1.01-1.21). There was no statistical difference between the FC levels of patients in clinical remission with IBS-type symptoms compared with those without (median values = 111 MUg/g vs. 45.5 MUg/g respectively, P = 0.171). The prevalence of IBS-type symptoms in patients with a normal FC level was 31%. CONCLUSIONS: A substantial number of IBD patients with normal faecal calprotectin level experience IBS-type symptoms. These patients exhibit similar features to people diagnosed with IBS in the general community, suggesting that the conditions are not mutually exclusive and may coexist in a considerable number of IBD patients. A systematic diagnostic approach is required to assess IBD patients with IBS-type symptoms as sub clinical inflammation may play a role in a proportion of cases. PMID- 23668699 TI - Direct brow lift after Mohs-induced temporal nerve transection. PMID- 23668700 TI - Improving implantable cardioverter defibrillator therapy through better programming. PMID- 23668701 TI - Rise of robotics in urologic surgery: current status and future directions. PMID- 23668703 TI - MarginProbe: intraoperative margin assessment during breast conserving surgery by using radiofrequency spectroscopy. AB - In breast conserving surgery, the tumor should be removed with a clean margin, a rim of healthy tissue surrounding. Failure to achieve clean margins in the initial surgery results in a re-excision procedure. Re-excision rates are reported as being 11-46% for invasive carcinoma and ductal carcinoma in situ (DCIS). Re-excisions can have negative consequences such as increased postoperative infections, negative impact on cosmesis, patient anxiety and increased medical costs. Therefore, the surgical margin of invasive and intraductal (DCIS) breast tissue is a subject of intense discussion. Different options for intraoperative assessment are available, but all in all, they are unsatisfying. Frozen section margin examination is possible but is time consuming and restricted to the assessment of invasive carcinoma. In the case of DCIS, there is no procedure for intraoperative margin assessment. Thus, a solution for efficient intraoperative surgical margin assessment is needed. For this purpose, an innovative, real-time, intraoperative margin-assessment device (MarginProbe, Dune Medical Devices, Caesarea, Israel) was designed, and recent published clinical data reported a reduction of re-excisions by more than 50%. PMID- 23668704 TI - Randomized trial evaluating intraoperative ultrasound guidance for palpable breast cancer excision. AB - Breast-conserving surgery with lumpectomy and adjuvant radiation is the treatment of choice for the majority of early-stage breast cancers. The goals of surgery are to remove the tumor with adequate margins while maintaining an excellent cosmetic outcome. Multiple factors have been associated with higher local recurrence rates, including positive surgical margins. For most nonpalpable breast cancers, needle localization is considered the gold standard for tumor localization when performing lumpectomies. By contrast, palpable breast cancers have historically been excised to grossly negative margins based on palpation alone, which may lead to higher positive margin rates. As a result, ultrasound has been proposed as a tool for intraoperative guidance in the surgical excision of palpable masses. The trial under discussion is a randomized study demonstrating that the use of ultrasound intraoperatively to guide breast conservation surgery decreases the rate of positive margins and the volume of excised tissue, potentially allowing for a better cosmetic outcome. PMID- 23668705 TI - Renal sympathetic denervation: hypertension therapy and beyond. AB - Hypertension is one of the most important treatable causes of mortality and morbidity in the world, but despite the wide availability of pharamacological therapy, blood pressure is poorly controlled in many patients. Renal sympathetic denervation (RSD) is a novel therapeutic option whereby the renal sympathetic nerves, which lie within and around the wall of the renal arteries, are ablated using a catheter placed within the arterial lumen. The Symplicity HTN-2 trial has shown that RSD reduces blood pressure to a clinically relevant degree; this finding has resulted in an explosion in interest in the procedure and RSD has the potential to become a standard therapy for many hypertensive patients. Many new devices are in development that will simplify the procedure, and several novel indications for RSD are currently being investigated in clinical trials. PMID- 23668706 TI - Therapeutic time window of noninvasive brain stimulation for pain treatment: inhibition of maladaptive plasticity with early intervention. AB - Neuromodulatory effects of noninvasive brain stimulation (NIBS) have been extensively studied in chronic disorders such as major depression, chronic pain and stroke. However, few studies have explored the use of these techniques in acute conditions. A possible use of NIBS in acute disorders is to prevent or reverse ongoing maladaptive plastic alterations, seemingly responsible for treatment refractoriness and detrimental behavioral changes. In this review, the authors discuss the potential role of NIBS in blocking maladaptive plasticity using the transition of acute to chronic pain in conditions such as postsurgical pain, central poststroke pain, pain after spinal cord injury and pain after traumatic brain injury as a model. The authors also present suggestions for clinical trial design using NIBS in the acute stage of illnesses. PMID- 23668707 TI - Long-term outcomes of penile prostheses for the treatment of erectile dysfunction. AB - Since their introduction 60 years ago, penile prostheses have remained the standard therapy for the management of refractory erectile dysfunction, with multiple long-term series reporting outcomes. A PubMed search was performed from 1990 to present, and outcomes of penile prosthetics were reviewed. Studies with <12 months follow-up were excluded. Overall mechanical survival of three-piece prostheses range from 81-94, 68-89 and 57-76% at 5, 10 and 15 years, respectively. Contemporary infection rates following recent device modifications are 1-2% (low risk) to 2-3% (high risk). Patient satisfaction ranges from 75-100% and varies by prosthetic device. Outcomes are further reviewed among specialized populations (revision surgery, Peyronie's disease, priapism, corporal fibrosis and neurologic impairments). Penile prostheses remain a viable surgical treatment option with excellent mechanical reliability, low infection rates and significant patient/partner satisfaction. PMID- 23668708 TI - Cold atmospheric plasma devices for medical issues. AB - Cold atmospheric plasma science is an innovative upcoming technology for the medical sector. The plasma composition and subsequent effects on cells, tissues and pathogens can vary enormously depending on the plasma source, the plasma settings and the ambient conditions. Cold atmospheric plasmas consist of a highly reactive mix of ions and electrons, reactive molecules, excited species, electric fields and to some extent also UV radiation. In the last year, this partly ionized gas has been demonstrated to have a broad antimicrobial activity, while resistance and resistance development are unlikely. Furthermore, recent research has indicated that plasmas also have a strong influence on various cell lines and cell functions, including anticancer properties. This review summarizes the major plasma designs available and their main benefits, as well as assessing possible risks of this new technology. PMID- 23668709 TI - General surgical complications associated with the use of long-term mechanical circulatory support devices: are we 'under-reporting' problems? AB - Multiple complications are associated with use of ventricular assist devices (VADs). Cardiac-related complications and infections are most frequently reported. VADs, however, can also lead to a number of general surgical complications equally significant in terms of morbidity and mortality. The authors performed a systematic literature search to review current data that specifically relate general surgical complications to patients who undergo left VAD implantation. The review provides a relatively clear understanding of the spectrum of general surgical complications and shows that they contribute significantly to morbidity and mortality in these patients. PMID- 23668710 TI - Electrothermal bipolar vessel sealing system (LigaSure) for hemostasis during thyroid surgery: a comprehensive review. AB - Conventional hemostatic technologies utilized in thyroid surgery include clamp and-tie, clips and monopolar and bipolar diathermy. Over the last decade, there has been a major shift towards utilizing newer hemostatic technologies, most notably the electrothermal bipolar vessel sealing systems (EBVS) and the Harmonic Scalpel (Ethicon Endosurgery, OH, USA), for thyroid surgery. Since the first report of EBVS thyroidectomy in 2003, more than 50 studies have been published evaluating EBVS utilization for thyroid surgery. In addition to providing a historical perspective and exploring the principles of EBVS technology, this review aims to evaluate the current published data regarding EBVS utilization for thyroid surgery. In particular, a focus is given to LigaSure (Covidien, Dublin, Ireland) technology because it has been studied most thoroughly in the literature. This review will also evaluate studies comparing the EBVS with Harmonic Scalpel technology for thyroid surgery. PMID- 23668711 TI - Additional peculiarities of medical devices that should be considered in their development process. AB - Medical devices are peculiar products: their definition varies from country to country, they are used to treat diseases and they are different from pharmaceuticals. In 2012, the authors began to describe the complex and demanding environment of the medical device industry. In this article, the authors' previous research is extended with additional peculiarities of medical devices such as recall, pricing and adoption factors. PMID- 23668713 TI - Effortful control moderates bidirectional effects between children's externalizing behavior and their mothers' depressive symptoms. AB - This study examined bidirectional associations between mothers' depressive symptoms and children's externalizing behavior and whether they were moderated by preschool-age effortful control and gender. Mothers and teachers reported on 224 primarily White, middle-class children at ages 3, 5, and 10. Effortful control was assessed via behavioral battery and mother ratings. Structural equation modeling indicated that maternal depressive symptoms at child age 3 predicted more externalizing behavior at age 10 among children with low effortful control and among boys. Externalizing behavior at age 3 predicted fewer depressive symptoms at the age 10 assessments among mothers of children with high effortful control. Boys with suboptimal self-regulation exposed to high levels of maternal depressive symptoms were at greatest risk for school-age behavioral problems. PMID- 23668714 TI - Optimized fragmentation conditions for iTRAQ-labeled phosphopeptides. AB - Protein phosphorylation is an important post-translational modification that plays a regulatory role within numerous biological processes. The simultaneous identification, localization, and quantification of phosphorylated proteins is vital for understanding this dynamic control mechanism. The application of isobaric labeling strategies, for example, iTRAQ, for quantitative phosphopeptide analysis requires simultaneous monitoring of peptide backbone fragmentation, loss of phosphoryl moieties, and the cleavage of isobaric labeling reporter ions. In the present study, we have examined MS/MS fragmentation modes available in the Orbitrap Velos MS (collision induced dissociation (CID), CID plus multistage activation, and higher energy collision dissociation (HCD)), for their ability to generate ions required for simultaneous quantification and identification of iTRAQ labeled phosphopeptides in a semicomplex (12) and a complex (131) phosphopeptide mix. The required normalized collision energies for quantification and identification of iTRAQ-labeled phosphopeptides require a compromise between the optimal parameters for each aspect. Here, we were able to determine an optimized MS/MS measurement protocol that involves CID measurement in ion trap for identification followed by HCD measurement for parallel identification and quantification that satisfies the time requirements for LC-MS/MS experiments. PMID- 23668715 TI - Use of [13C18] oleic acid and mass isotopomer distribution analysis to study synthesis of plasma triglycerides in vivo: analytical and experimental considerations. AB - We have previously reported on a liquid chromatography-mass spectrometry method to determine the disposition of [(13)C18]-oleic acid following intravenous and oral administration in vivo. This approach has enabled us to study a variety of aspects of lipid metabolism including a quantitative assessment of triglyceride synthesis. Here we present a more rigorous evaluation of the constraints imposed upon the analytical method in order to generate accurate data using this stable isotope tracer approach along with more detail on relevant analytical figures of merit including limits of quantitation, precision, and accuracy. The use of mass isotopomer distribution analysis (MIDA) to quantify plasma triglyceride synthesis is specifically highlighted, and a re-evaluation of the underlying mathematics has enabled us to present a simplified series of equations. The derivation of this MIDA model and the significance of all underlying assumptions are explored in detail, and examples are given of how it can successfully be applied to detect differences in plasma triglyceride synthesis in lean and high-fat diet fed mouse models. More work is necessary to evaluate the applicability of this approach to triglyceride stores with slower rates of turnover such as in adipose or muscle tissue; however, the present report provides investigators with the tools necessary to conduct such studies. PMID- 23668716 TI - Antifeedant, larvicidal and growth inhibitory bioactivities of novel polyketide metabolite isolated from Streptomyces sp. AP-123 against Helicoverpa armigera and Spodoptera litura. AB - BACKGROUND: Considerable attention has been paid to actinomycetes, especially the secondary metabolites obtained from Streptomyces species, as the best alternatives to chemicals as biological control agents for polyphagous pests such as Helicoverpa armigera and Spodoptera litura. On the basis of their novel biocontrol attributes, novel polyketide metabolite isolated from marine Streptomyces sp. AP-123 exhibited significant antifeedant, larvicidal and growth inhibitory activities against polyphagous pests. RESULTS: Leaf disc no-choice method was used for the insect bioassay. The polyketide metabolite presented significant antifeedant activities against H. armigera (78.51%) and S. litura (70.75%) at 1000 ppm concentration. The metabolite also exhibited high larvicidal activities against H. armigera (63.11%) and S. litura (58.22%) and the LC50 values were 645.25 ppm for H. armigera and 806.54 ppm for S. litura. The metabolite also prolonged the larval-pupal duration of the insects at all the tested concentrations. CONCLUSIONS: The activities of the polyketide metabolite were concentration dependent for both the insects therefore it could be used as an agent to prepare new pesticidal formulations. PMID- 23668717 TI - Early-pregnancy maternal vitamin D status and maternal hyperglycaemia. AB - AIMS: To estimate the association between serum 25-hydroxyvitamin D concentrations and maternal hyperglycaemia (post-load glucose concentration >= 7.5 mmol/l). METHODS: Pregnant women (n = 429; 61% black, 36% obese, 45% smokers) enrolled in a cohort study at <16 weeks gestation. Non-fasting blood samples were assayed for serum 25-hydroxyvitamin D at enrolment. At 24-28 weeks gestation, maternal hyperglycaemia was determined using a 50-g 1-h oral glucose challenge test. RESULTS: A total of 67% of women had 25-hydroxyvitamin D concentrations < 50 nmol/l and 11% had maternal hyperglycaemia. Among smokers, each 23-nmol/l increase in serum 25-hydroxyvitamin D was associated with a reduction in the odds of maternal hyperglycaemia [odds ratio: 0.30 (95% CI: 0.13, 0.68)] after adjustment for parity, race/ethnicity, age, pre-pregnancy BMI, marital status, income, family history of diabetes, and gestational age of gestational diabetes mellitus screening. Among non-smokers, we found no association between early pregnancy vitamin D status and maternal hyperglycaemia. CONCLUSIONS: Smoking status may modify the relationship between poor maternal vitamin D status and maternal hyperglycaemia. PMID- 23668718 TI - Laugh-induced seizure: a case report. AB - INTRODUCTION: A laugh-induced seizure is an unrecognized condition and to the best of our knowledge no case has been reported in the medical literature until now. We present an interesting and extremely rare case in which laughing generated the seizure activity that was recorded and confirmed by video electroencephalography. CASE PRESENTATION: A 43-year-old obese Caucasian man with history of bipolar disorder and chronic headache presented with multiple episodes of seizures, all induced by laughter while watching comedy shows. Each episode lasted approximately five seconds. In each instance, he started laughing, then his arms started shaking and he felt like 'his consciousness was being vacuumed away'. A physical examination revealed normal findings. He had been maintained on valproic acid for bipolar disorder and topiramate for his chronic headache, but this did not control his symptoms. His sleep-deprived electroencephalography and brain magnetic resonance imaging were normal except for an arachnoid cyst measuring 4.2 * 2.1cm in the anterior right middle cranial fossa. His video electroencephalography demonstrated laugh-induced seizure activities. He was then placed on carbamazepine. Following treatment, he had two episodes of mild staring but no frank seizures, and his seizures have remained well controlled on this regimen for more than a year. CONCLUSIONS: Laugh-induced seizure is a most unusual clinical entity without any previous case report. Confirmatory diagnosis can be made by video electroencephalography recording of seizure activities provoked by laughing. As in gelastic seizure without hypothalamic hamartoma, our case responded well to polytherapy with topiramate and carbamazepine on top of laugh-provocation avoidance. Further study is required to establish the standard treatment of this condition. PMID- 23668720 TI - Respirology case reports-birth of a new online journal. PMID- 23668719 TI - The geographical pattern of thyroid cancer mortality between 1980 and 2009 in Italy. AB - BACKGROUND: Mortality for thyroid cancer (TC) is low and has been decreasing worldwide; yet few population studies based on mortality have been conducted. Several nonradiation risk factors have been associated with TC, including residence in goiter-endemic areas (as an indicator of iodine deficiency). We used mortality data to perform a spatial-temporal analysis regarding TC in Italy and investigated the association between mortality and socioeconomic status and geographical features (residing in a mountainous area is a proxy for iodine deficiency). METHODS: We analyzed data from Italy's National Mortality Database (1980-2009). To evaluate temporal trends in mortality the age-standardized death rate (ASR) was used; to identify geographic areas with excess deaths due to TC standardized mortality rates (SMR) were calculated. We also calculated the rate ratios (RR) of the ASR and the 95% CI by sex. We performed a cluster analysis to identify municipalities with major departures from expected mortality, both in the entire study period and in two separate periods to evaluate the spatial temporal variability. Finally, we evaluated the association between mortality and index of deprivation and altitude. RESULTS: There were 16,473 deaths due to TC (10,690 females, 5783 males). The mean ASR was unsurprisingly low (0.58/100.000). There was a trend of decrease in mortality throughout Italy (-42% for 2007-2009 vs. 1980-1984), more pronounced among women. The decrease was greater in the north. Four geographic clusters were identified when considering the entire study period, two in the north and two in the south; however, the clusters in northern Italy refer to the earlier period (1980-1994) and those in southern Italy to the later period (1995-2009). Mortality was associated with residing in a mountainous area. A slight association with high socioeconomic status was found. CONCLUSIONS: This study reveals space-time differences in TC mortality in Italy. It shows an association between mortality and residing in mountainous areas, which is a proxy of iodine deficiency. The observed temporal north-south shift cannot be explained by socioeconomic differences, whereas the efficient prophylaxis program implemented in the 1980s in some areas of northern Italy can help to explain the disappearance of the clusters in those areas in the period 1995-2009. PMID- 23668721 TI - Pseudo-symmetry analysis of the d-block molecular orbitals in four-coordinate complexes. AB - A rigorous definition of the concept of pseudo-symmetry, which is as important to chemistry as the concepts of symmetry implemented through group theory, should allow us to apply those group theoretical tools to molecules that are significantly distorted from those ideal symmetries best known and understood by the chemical community. In this paper, we consider four-coordinate transition metal complexes with geometries along the interconversion path between the square and the tetrahedron and show how their molecular orbitals can be expressed in terms of either the tetrahedral or tetragonal symmetry groups. Furthermore, we analyze how the intensity of a d-d absorption band can be related to the degree of symmetry loss of the d-block molecular orbitals by means of their decomposition in terms of contributions from different pseudo-symmetry representations. As a final example, we also show how the substitution of a single ligand in a square planar complex affects the symmetry of the molecular orbitals and the absorption intensity associated to an electronic transition. PMID- 23668722 TI - Mitotic rate in melanoma should be recorded as the number of mitoses per mm2 (not per high power field): surgeons tell your pathologists! PMID- 23668723 TI - Ectopic fat, insulin resistance and non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease (NAFLD) is now recognised as the hepatic component of metabolic syndrome (MetS). NAFLD is an example of ectopic fat accumulation in a visceral organ that causes organ-specific disease, and affects risk of other related diseases such as type 2 diabetes and CVD. NAFLD is a spectrum of fat-associated liver conditions that can culminate in end stage liver disease, hepatocellular carcinoma and the need for liver transplantation. Simple steatosis, or fatty liver, occurs early in NAFLD and may progress to non alcoholic steatohepatitis, fibrosis and cirrhosis with increased risk of hepatocellular carcinoma. Prevalence estimates for NAFLD range from 2 to 44% in the general population and it has been estimated that NAFLD exists in up to 70% of people with type 2 diabetes. Although many obese people have NAFLD, there are many obese people who do not develop ectopic liver fat. The aim of this review which is based on a presentation at the Royal Society of Medicine, UK in December 2012 is to discuss development of NAFLD, ectopic fat accumulation and insulin resistance. The review will also describe the relationships between NAFLD, type 2 diabetes and CVD. PMID- 23668724 TI - Iron sulfide (FeS) nanotubes using sulfurization of hematite nanowires. AB - We report the phase transformation of hematite (alpha-Fe2O3) single crystal nanowires to crystalline FeS nanotubes using sulfurization with H2S gas at relatively low temperatures. Characterization indicates that phase pure hexagonal FeS nanotubes were formed. Time-series sulfurization experiments suggest epitaxial growth of FeS as a shell layer on hematite. This is the first report of hollow, crystalline FeS nanotubes with NiAs structure and also on the Kirkendall effect in solid-gas reactions with nanowires involving sulfurization. PMID- 23668725 TI - Assessment of the quality of reporting in abstracts of systematic reviews with meta-analyses in periodontology and implant dentistry. AB - BACKGROUND: Proper scientific reporting is necessary to ensure the correct interpretation of study results by readers. The main objective of this study was to assess the quality of reporting in abstracts of systematic reviews (SRs) with meta-analyses in periodontology and implant dentistry. Differences in reporting of abstracts in Cochrane and paper-based reviews were also assessed. METHODS: The PubMed electronic database and the Cochrane database for SRs were searched on November 11, 2012, independently and in duplicate, for SRs with meta-analyses related to interventions in periodontology and implant dentistry. Assessment of the quality of reporting was performed independently and in duplicate, taking into account items related to the effect direction, numerical estimates of effect size, measures of precision, probability and consistency. RESULTS: We initially screened 433 papers and included 146 (127 paper-based and 19 Cochrane reviews, respectively). The direction of evidence was reported in two-thirds of the abstracts while strength of evidence and measure of precision (i.e., confidence interval) were reported in less than half the selected abstracts. Measures of consistency such as I(2) statistics were reported in only 5% of the selected sample of abstracts. Cochrane abstracts reported the limitations of evidence and precision better than paper-based ones. Two items ("meta-analysis" in title and abstract, respectively), were nevertheless better reported in paper-based abstracts. CONCLUSION: Abstracts of SRs with meta-analyses in periodontology and implant dentistry currently have no uniform standard of reporting, which may hinder readers' understanding of study outcomes. PMID- 23668726 TI - NMDA receptors in the lateral hypothalamus have an inhibitory influence on the tachycardiac response to acute restraint stress in rats. AB - The aim of the present study was to investigate the role of the lateral hypothalamus (LH) and its local glutamatergic neurotransmission in the cardiovascular adjustments observed when rats are submitted to acute restraint stress. Bilateral microinjection of the nonspecific synaptic inhibitor CoCl2 (0.1 nmol in 100 nL) into the LH enhanced the heart rate (HR) increase evoked by restraint stress without affecting the blood pressure increase. Local microinjection of the selective N-methyl-d-aspartate (NMDA) glutamate receptor antagonist LY235959 (2 nmol in 100 nL) into the LH caused effects that were similar to those of CoCl2 . No changes were observed in the restraint-related cardiovascular response after a local microinjection of the selective non-NMDA glutamatergic receptor antagonist NBQX (2 nmol in 100 nL) into the LH. Intravenous administration of the muscarinic cholinergic receptor antagonist homatropine methyl bromide (0.2 mg/kg), a quaternary ammonium drug that does not cross the blood-brain barrier, abolished the changes in cardiovascular responses to restraint stress following LH treatment with LY235959. In summary, our findings show that the LH plays an inhibitory role on the HR increase evoked by restraint stress. Present results also indicate that local NMDA glutamate receptors, through facilitation of cardiac parasympathetic activity, mediate the LH inhibitory influence on the cardiac response to acute restraint stress. PMID- 23668727 TI - Comparative effects of empathic verbal responses: reflection versus validation. AB - The comparative effects of different types of empathic verbal responses were identified through a quantitative, experimental study. In particular, the study explored how reflection and validation interacted with negative emotions among 80 university student participants (29 men, 51 women). Participants were manipulated to experience social exclusion through a game and were randomly assigned to 1 of 3 groups (control/reflection/validation). Findings indicated varied levels of affects among groups. Both reflection and validation as an empathic verbal response increased sense of belonging, whereas validation increased self-esteem more than reflection did. Moreover, validation was more effective than reflection in lowering both negative mood and aggression toward the people who excluded the participant. Implications and future directions for research and training are discussed. PMID- 23668728 TI - Moderated path analysis of the relationships between masculinity and men's attitudes toward seeking psychological help. AB - This study tested a theoretical model of one mediator and 4 moderators of the relationships between 2 masculinity variables (Traditional Masculinity Ideology and Gender Role Conflict) and Attitudes Toward Seeking Professional Psychological Services (Attitudes). Self-stigma was the hypothesized mediator, and the hypothesized moderators were (a) Depression, (b) General Self-efficacy, (c) Precontemplation, and (d) Barriers to Help-seeking. A sample of 654 men responded to an online survey of 9 questionnaires. After evaluating mediation in the absence of moderation, moderated path analyses were conducted for each moderator. The relationship between Traditional Masculinity Ideology and Attitudes was partially mediated by Self-stigma, whereas that between Gender Role Conflict and Attitudes was completely mediated. No indirect or direct paths involving Gender Role Conflict were moderated by any moderators. Both Depression and Barriers to Help-seeking demonstrated mediated moderation by moderating both Stage 1 (the path from Traditional Masculinity Ideology to Self-stigma) of the mediated relationships and the direct effects between Traditional Masculinity Ideology and Attitudes. Precontemplation moderated the direct effect between Traditional Masculinity Ideology and Attitudes. The findings suggest that the relationships between masculinity variables and men's negative help-seeking attitudes may be better understood through their relationships with other variables that serve as mediators and moderators. Findings from the present study may offer some direction in the design of interventions to remediate men's negative help-seeking attitudes. PMID- 23668729 TI - Development and initial validation of The Sexual Orientation Beliefs Scale (SOBS). AB - The purpose of these studies was to develop and validate a measure of beliefs about sexual orientation (SO) that incorporates essentialist, social constructionist, and constructivist themes. The Sexual Orientation Beliefs Scale (SOBS) is offered as a multidimensional instrument with which to assess a broad range of beliefs about SO, which evidence suggests are highly correlated with positive and negative attitudes about sexual minorities. An initial exploratory factor analysis (EFA) was conducted in the general population with a lesbian, gay, bisexual, and transgender-identified (LGBT) sample (n = 323) and suggested a 4-factor structure of naturalness (alpha = .86), discreetness (alpha = .82), entitativity (alpha = .75), and personal and social importance (alpha = .68); this 4-factor structure was supported by confirmatory factor analysis (CFA) with an independent LGBT sample (n = 330; "Form 1"). Additional EFA (n = 183) and CFA (n = 201) in a college student, mostly heterosexual-identified population suggest a slightly different factor structure, whereby group homogeneity (alpha = .84) and informativeness (alpha = .77) are salient themes ("Form 2"), and this structure was replicated across SO groups. Finally, a study of test-retest reliability in an undergraduate, mostly heterosexual-identified sample (n = 45) demonstrated strong temporal stability for the SOBS. PMID- 23668730 TI - New approach to repair of expanded earlobe. PMID- 23668731 TI - Premature birth: implications for cardiovascular health. PMID- 23668732 TI - The potential role of natriuretic peptides in acute coronary syndrome stratification. PMID- 23668734 TI - Million HeartsTM: preventing a million heart attacks and strokes through public private collaboration. Interview by Caroline Telfer. AB - Janet S Wright speaks to Caroline Telfer, Assistant Commissioning Editor. Janet S Wright is the Executive Director of Million HeartsTM, a US Department of Health and Human Services initiative with the explicit goal of preventing a million heart attacks and strokes by 2017. From May 2008-September 2011, Dr Wright served as Senior Vice President for Science and Quality at the American College of Cardiology (ACC). The division she led at the ACC encompasses the clinical guidelines, performance measures, health policy statements and appropriate-use criteria; quality improvement projects such as Door-to-Balloon and Hospital-to Home; and the National Cardiovascular Data Registry, a suite of databases containing over 12 million patient records in both inpatient and outpatient care settings. Prior to joining the ACC, Dr Wright spent many years in practice in Chico, CA, USA. Dr Wright served on the ACC's Board of Trustees and chaired the Task Force on Performance Assessment, Recognition, Reinforcement, Reward and Reporting. She was a member of National Committee for Quality Assurance's Clinical Programs Committee and of the Quality Alliance Steering Committee. She served on the board of the Center for Information Therapy, a nonprofit organization committed to the provision of personalized health information during each healthcare encounter. From 2003 until moving to Washington (USA), Dr Wright served as a founding member of the Independent Citizens' Oversight Committee, the 29-person board charged with administering the California Institute for Regenerative Medicine. Her primary interests are the design and implementation of systems of care to achieve optimal outcomes for patients and the full deployment of hooks, tricks and cues that help people get and stay healthy. PMID- 23668735 TI - Highlights of the 6th World Congress in Paediatric Cardiology and Cardiac Surgery. AB - The 6th World Congress in Paediatric Cardiology and Cardiac Surgery took place in Cape Town, South Africa, in February 2013. The congress is the largest meeting in the field of congenital and paediatric heart disease and attracts a global audience of specialists with the aim of sharing the latest multidisciplinary developments in research and clinical practice. The congress was commended as a huge success and this article aims to give a general flavor of the diverse meeting through detailing a few specific highlights from the various tracks. PMID- 23668736 TI - The benefits of ivabradine are independent of resting heart rate. AB - Evaluation of: Tardif JC, Ponikowski P, Kahan T; on behalf of the ASSOCIATE investigators. Effects of ivabradine in patients with stable angina receiving beta-blockers according to baseline heart rate: an analysis of the ASSOCIATE study. Int. J. Cardiol. pii:S0167-5273(12)01385-X (2012). Chronic stable angina pectoris is the most common manifestation of coronary artery disease. A large body of evidence points to high resting heart rate (HR) as a risk factor for mortality in various populations, including patients with cardiovascular disease. Elevated HR is an important pathophysiological variable that increases myocardial oxygen demand and also limits tissue perfusion by reducing the duration of diastole, during which most myocardial perfusion occurs. Large epidemiological trials have established that elevated resting HR is a prognostic factor for cardiovascular events and mortality in healthy individuals and in patients with myocardial infarction, stable coronary artery disease and heart failure. The classical treatments for HR reduction show such negative aspects. beta-blocker therapy exerts negative effects on regional myocardial blood flow and function when HR reduction is eliminated by atrial pacing. Calcium channel antagonists functionally antagonize coronary vasoconstriction mediated through alpha adrenoreceptors and are thus devoid of this undesired effect, but the compounds are nevertheless negative inotrope. Ivabradine (IVA), a pure HR-lowering drug, reduces the myocardial oxygen demand of exercise and contributes to the restoration of oxygen balance, which has demonstrated a benefit in chronic cardiovascular disease. No relevant negative effects are evidenced on cardiac conduction, contractility, relaxation or repolarization, or blood pressure. In this post-hoc analysis, the authors show that IVA treatment, compared with the placebo group, had no significant impact on systolic or diastolic blood pressure at rest or during exercise and reduces HR in all stages of physical exercise and during the treatment period. These benefits are independent of baseline HR, both at rest and during physical exercise, confirming that HR reduction with IVA is beneficial in all patients, even with beta-blocker therapy, if their resting HR is above 60 bpm. PMID- 23668737 TI - Changes in BNP and QTc for prediction of sudden death in heart failure. AB - Evaluation of: Vrtovec B, Knezevic I, Poglajen G, Sebesjen M, Okrajsek R, Haddad F. Relation of B-type natriuretic peptide level in heart failure to sudden cardiac death in patients with and without QT interval prolongation. Am. J. Cardiol. 111(6), 886-890 (2013). Guidelines recommend an implantable cardioverter defibrillator (ICD) for patients with chronic heart failure (HF) and left ventricular ejection fraction (LVEF) <35%, and New York Heart Association (NYHA) class II/III, despite optimal medical treatment. However, by this mode of patient selection, many patients receive an ICD but never use it. Therefore, additional clinical and laboratory parameters, including estimated glomerular filtration rate and B-type natriuretic petide (BNP), and ECG parameters such as the corrected QT-interval (QTc), have been suggested for a more refined assessment of the risk of sudden cardiac death (SCD). However, changes in these parameters over time may be even more informative for SCD prediction than single measures, but this had not been investigated so far. In the present paper, the authors assessed the association between changes in BNP and QTc during a 3-month period in 398 patients with advanced chronic HF (NYHA III/IV) and LVEF <40%. After a follow-up of 1 year, 20 patients had suffered SCD. Patients with a significant (>=10%) increase in BNP were more likely to have a significant (>=10%) increase in QTc and had a longer QTc at 3 months than those without. The risk of SCD did not differ between patients with and without a significant increase in BNP, but was higher in patients with a significant increase in QTc compared with those without. Among patients with an increase in BNP of >=10%, those with an increase in QTc of >=10% were several-fold more likely to experience SCD compared with those without, whereas there was no such association between the change in QTc and SCD among patients without an increase in BNP of >=10%. Thus, this study showed that changes in QTc better predicted SCD than changes in BNP, and that a strategy using both a marker of heart failure severity and a marker of the propensity of the left ventricle for arrhythmia better predicted SCD than a single-marker strategy. Further studies are required to evaluate whether novel markers besides LVEF and NYHA class alone (e.g., biomarkers and cardiac MRI) will allow a more accurate selection of patients with chronic HF who need an ICD. PMID- 23668738 TI - Can dabigatran improve blood pressure control? AB - Hypertension is the most frequent condition associated with atrial fibrillation (AF) and stroke, the most terrible complication of AF. Achieving blood pressure (BP) goals as well as an adequate antithrombotic treatment are critical to reduce the incidence of stroke. But are interactions between anticoagulants and antihypertensive agents relevant for achieving BP targets? We present the case of a patient with hypertension and AF in which the interaction between losartan and acenocoumarol was associated with an irregular systolic BP control, but after switching to dabigatran, BP control improved. In this report, the possible mechanisms that may explain this change are discussed. PMID- 23668739 TI - A novel patch for heart rhythm monitoring: is the Holter monitor obsolete? AB - A number of substantial improvements to the 60-year-old concept of the Holter monitor have recently been developed. One promising advance is the Zio((r)) Patch (iRhythm Technologies, Inc., CA, USA), a small 2 * 5-inch patch, which can continuously record up to 14 days of a single ECG channel of cardiac rhythm without the need for removal during exercise, sleeping or bathing. Its ease-of use, which enables optimal long-term monitoring, has been established in the ambulatory setting, although some insurance carriers have been reluctant to reimburse appropriately for this advance, an issue characteristic of other heart monitors, treated as 'loss-leaders.' In this article, in addition to discussing possible reasons for this reluctance, a novel model for direct-to-consumer marketing of heart monitoring, outside of the traditional health insurance reimbursement model, is also presented. Additional current and future advances in heart rhythm recording are also discussed. Such potentially revolutionary opportunities have only recently become possible as a result of technologic advances. PMID- 23668741 TI - Cardiac MRI of acute coronary syndrome. AB - Acute coronary syndrome (ACS) is a major cause of morbidity and mortality worldwide. New serological biomarkers, such as troponins, have improved the diagnosis of ACS; however, the diagnosis of ACS can still be difficult as there is marked heterogeneity in its presentation and significant overlap with other disorders presenting with chest pain. Evidence is accumulating that cardiac MRI provides information that can aid the detection and differential diagnosis of ACS, guide clinical decision-making and improve risk-stratification after an event. In this review, we present the relevant cardiac MRI techniques that can be used to detect ACS accurately, provide differential diagnosis, identify the sequelae of ACS, and determine prognostication after ACS. PMID- 23668742 TI - Antiplatelet and anticoagulant strategies in acute coronary syndrome: where we are in 2013. AB - Multiple antiplatelet and anticoagulant therapies are available for the treatment of acute coronary syndromes. The combination of agents should be tailored to the individual patient carefully considering the balance between ischemic and bleeding risk, as well as the planned revascularization strategy. Despite multiple large-scale, rigorously designed and conducted randomized controlled trials, it can be difficult to select the correct pharmacotherapy for each patient and many unanswered questions remain, such as the safety and optimal doses of differing combinations of antiplatelet/anticoagulant therapy, as well as the timing and duration of therapies. In addition, the headline results of many trials report improved efficacy outcomes at the cost of increased bleeding risk; however, very few show a clear mortality benefit. It is therefore difficult to weigh up the risk-benefit profile of emerging therapies. PMID- 23668743 TI - Management of the patient with diabetes and coronary artery disease: a contemporary review. AB - Diabetes mellitus is a metabolic disease with microvascular and macrovascular complications, and is well known to increase the risk of coronary atherosclerosis. Despite recent reductions in the prevalence of coronary artery disease and cardiovascular events in the USA, persons with diabetes remain up to four-times as likely to die of cardiovascular disease than the general population. Diabetes is associated with an atherogenic lipid profile, induces a hypercoagulable state, and increases coronary plaque volume, progression and instability. Medicinal and procedural treatments in the patient with diabetes should be multifactorial, targeting and managing the many coexisting risk factors that contribute to atherosclerosis. This type of treatment is complex and should be individualized, and guided by a careful review of recent literature. Here we discuss important clinical data and their impact on up-to-date recommendations for the management of coronary artery disease in the patient with Type 2 diabetes mellitus. PMID- 23668740 TI - Pharmacologic treatments for pulmonary hypertension: exploring pharmacogenomics. AB - Pulmonary hypertension (PH) is a disease with multiple etiologies and is categorized into five broad groups. Of these groups, pulmonary arterial hypertension (PAH) is the most studied and, therefore, all of the currently available drug classes (prostacyclin analogs, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors) were developed to treat PAH. Thus, limited treatment data exist for the less-studied non-PAH forms of PH. Pharmacogenomics can be a tool to better understand the pathways involved in PH, as well as to improve personalization of therapy. However, little pharmacogenomic research has been carried out on this disease. New treatments for PH are on the horizon, deriving from both repurposed currently available drugs and novel therapeutics. PMID- 23668745 TI - Menopausal hormone therapy: examining cardiovascular and clinical impacts of treatment. AB - Postmenopausal women have reduced levels of female sex hormones and this may play a significant role in the onset of cardiovascular disease. Menopausal hormone therapy (MHT), which is primarily prescribed for the treatment of perimenopausal symptoms, has been associated with risk of coronary heart disease, hypertension and stroke in women. This review will summarize the outcomes of observational studies and randomized clinical trials that have investigated the influence of MHT use on the cardiovascular system. In addition, it will explore how the timing of MHT prescription relative to menopause, dosage and route of administration may alter the impact of MHT on cardiovascular health. PMID- 23668744 TI - Plasmonic photothermal therapy for atheroregression below Glagov threshold. AB - The advent of nanomedicine allowed for the development and design of tools that enhance detailed diagnosis and target treatment of atherosclerosis. Given the rapid progress in nanoagent synthesis and utility, clinical application of these technologies can be anticipated in the near future. This review article focuses on the development of these technologies in interventional cardiology, with the main goal of achieving atheroregression below a Glagov threshold of 40%. Special attention is given to plasmonic photothermal therapy. Vascular remodeling maintains the lumen dimension as long as the external elastic membrane can accommodate an increase in plaque burden that does not surpass a certain threshold. We propose that this threshold becomes the target for the development of strategies that reverse atherosclerosis, especially for the generation of devices and tools of nanomedicine. PMID- 23668746 TI - Heart failure and iron deficiency anemia in Italy: results from CARMES-1 registry. AB - AIMS: To assess the prevalence of anemia and iron deficiency anemia in heart failure (HF) patients, to evaluate the effectiveness of current iron deficiency treatment strategies after discharge, and to analyze hospital readmissions and mortality rates in patients with and without anemia. PATIENTS & METHODS: A patient registry-based, multicenter, retrospective, observational, cohort study of 418 hospitalized HF patients in Italy, monitored from 1 March 2010 to 30 March 2011. RESULTS: Among patients with HF, 35.9% had anemia at admission; only 51.3% were treated with current iron deficiency treatment strategies during hospitalization and then only 29% of patients who were anemic at discharge were treated with iron at home. After a 4-week follow-up, only 11% of these patients reached the hemoglobin target value (study primary end point). However, current iron deficiency treatment strategies were not significantly associated with reduced risk of rehospitalization, but with a significantly reduced mortality rate after a 6-month follow-up (study secondary end points: 11.7 vs 51.7%; p < 0.0001). CONCLUSION: In HF patients, there is poor attention paid to anemia, its causes and treatment. Current iron deficiency treatment strategies are mismanaged and CARMES-1 demonstrated that they appear to be insufficient at improving patient outcome in terms of rehospitalization rate reduction, generating high costs, which could be avoided through an optimized treatment strategy. Therefore, more efficacious, efficient and cost-effective treatment strategies are required in Italy for HF patients with iron deficiency anemia to meet this unmet medical need. PMID- 23668748 TI - Fenitrothion: an alternative insecticide for the control of deltamethrin resistant populations of Triatoma infestans in northern Argentina. AB - Deltamethrin-based campaigns to control Triatoma infestans (Klug) (Hemiptera: Reduviidae) have decreased in success as a result of the development of insecticide resistance. We compared the in vitro effects of the pyrethroid deltamethrin and two doses of the organophosphate fenitrothion, presented on different materials, on T. infestans from La Esperanza, Argentina. Laboratory tests demonstrated a decrease in susceptibility to deltamethrin in the field population [LD50 : 30.32 nanograms per insect (ng/i)] compared with the reference population (LD50 : 0.13 ng/i), giving a high resistance ratio of 233.42. By contrast, similar susceptibility to fenitrothion was assessed in both the field and reference populations (LD50 : 21.65 ng/i and 21.38 ng/i, respectively). The effectiveness of the formulated insecticides varied according to the surfaces to which they were applied. The application of fenitrothion formulations to glass or brick resulted in mortality of 90-100%. The application of fenitrothion formulations to wood or mud caused mortality in the range of 6.7-56.7%. Resistant insects presented low mortality when exposed to the deltamethrin formulation and high mortality when exposed to fenitrothion formulations. Moreover, the insecticides demonstrated residual activity only when applied to glass. The present work demonstrates that fenitrothion is an alternative to pyrethroids for the management of deltamethrin-resistant insects in La Esperanza. However, this effectiveness is not sustained over time. PMID- 23668749 TI - Hericium erinaceus (Lion's Mane) mushroom extracts inhibit metastasis of cancer cells to the lung in CT-26 colon cancer-tansplanted mice. AB - This study investigated the antimetastatic activity of four Hericium erinaceus edible mushroom extracts using CT-26 murine colon carcinoma cells as an indicator of inhibition of cell migration to the lung. Hot water (HWE) and microwaved 50% ethanol (MWE) extracts of H. erinaceus strongly elicited cancer cell death through apoptosis and inhibited metastasis of cancer cells to the lungs by 66% and 69%, respectively. HWE and MWE reduced the expression of matrix metalloproteinases MMP-2 and MMP-9 in cells and their activities in culture media. Urokinase-type plasminogen activator (u-PA), another extracellular matrix (ECM)-degrading proteinase, also showed decreased protein expression. In CT-26 cells, HWE and MWE down-regulated extracellular signal-regulated kinase (ERK), c Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) phosphorylations. The reduced phosphorylations seem to cause reduction of activity of the MMPs, thereby blocking migration and invasion of cells. Dietary administration of HWE and MWE reduced the formation of tumor nodules in the lung by about 50% and 55%, respectively, and prevented increases in lung weight caused by cancer cell metastasis. These results demonstrate the effectiveness of HWE and MWE as beneficial antimetastatic agents, targeting their upstream signaling molecules for mediating the expression of the ECM-degrading proteinases. Acidic and alkaline extracts were not bioactive. Bioactivity seems to be related to composition. H. erinaceus edible mushrooms have the potential to serve as a health-promoting functional food. PMID- 23668750 TI - Record mobility in transparent p-type tin monoxide films and devices by phase engineering. AB - Here, we report the fabrication of nanoscale (15 nm) fully transparent p-type SnO thin film transistors (TFT) at temperatures as low as 180 degrees C with record device performance. Specifically, by carefully controlling the process conditions, we have developed SnO thin films with a Hall mobility of 18.71 cm(2) V(-1) s(-1) and fabricated TFT devices with a linear field-effect mobility of 6.75 cm(2) V(-1) s(-1) and 5.87 cm(2) V(-1) s(-1) on transparent rigid and translucent flexible substrates, respectively. These values of mobility are the highest reported to date for any p-type oxide processed at this low temperature. We further demonstrate that this high mobility is realized by careful phase engineering. Specifically, we show that phase-pure SnO is not necessarily the highest mobility phase; instead, well-controlled amounts of residual metallic tin are shown to substantially increase the hole mobility. A detailed phase stability map for physical vapor deposition of nanoscale SnO is constructed for the first time for this p-type oxide. PMID- 23668751 TI - Startle myoclonus induced by Lyme neuroborreliosis: a case report. AB - INTRODUCTION: The normal startle response is a form of physiological myoclonus. Its anatomic origin is probably the brain stem. Pathologic startles are defined as reproducible exaggerated startle responses to trivial and not surprising stimuli. Symptomatic forms of an exaggerated startle response can be due to a variety of brain stem disorders. We have, however, found scant data about an exaggerated startle reflex induced by Lyme neuroborreliosis. We therefore report the case of a patient with this unusual presentation. CASE PRESENTATION: A 69 year old Caucasian man presented with a two-week history of a pronounced startle myoclonus, as well as a four-week history of double vision, gait disturbance and severe lancinating pain in his upper thoracic region. Neurological examination showed an excessive startle reaction of his upper trunk evoked by visual and tactile stimulation, a positive sign of Lhermitte, mild right-sided palsy of his sixth and seventh cranial nerve, moderate dysarthria, very brisk deep tendon reflexes, pallhypesthesia of his legs, and an atactic gait disturbance. A diagnosis of a Lyme neuroborreliosis was confirmed by cerebrospinal fluid examination. Under intravenous treatment with ceftriaxone, our patient improved considerably with complete remission in a follow-up at two months. CONCLUSIONS: This case illustrates the chameleon role that neuroborreliosis likes to play: although the wide spectrum of different symptoms that neuroborreliosis can present with has been described, to the best of our knowledge this is the first case report about a symptomatic form of a pathologic startle response as the predominating sign of Lyme neuroborreliosis. PMID- 23668752 TI - Effect of polymer-graft modification on the order formation in particle assembly structures. AB - The propensity of particle brush materials to form long-ranged ordered assembly structures is shown to sensitively depend on the brush architecture (i.e., the particle radius as well as molecular weight and grafting density of surface-bound chains). In the limit of stretched chain conformations of surface-grafted chains the formation of regular particle array structures is observed and interpreted as a consequence of hard-sphere-type interactions between polymer-grafted particles. As the degree of polymerization of surface-grafted chains increases beyond a threshold value, a reduction of the structural regularity is observed that is rationalized with the increased volume occupied by relaxed polymer segments. The capacity of polymer grafts to increase or decrease order in particle brush assembly structures is interpreted on the basis of a mean-field scaling model, and "design criteria" are developed to help guide the future synthesis of colloidal systems that are capable of forming mechanically robust yet ordered assembly structures. PMID- 23668753 TI - Combined associations between moderate to vigorous physical activity and sedentary behaviour with cardiometabolic risk factors in children. AB - The objective of this study was to examine the combined associations between time spent in moderate- to vigorous-intensity physical activity (MVPA) and time spent sedentary in relation to cardiometabolic risk factors in a cohort of Canadian children. A cross-sectional study was conducted on 536 white children aged 8-10 years with at least 1 obese biological parent. Time spent in MVPA and sedentary behaviour over 7 days was measured using accelerometry and participants were stratified by tertiles. Daily screen time over 7 days was also self-reported by the child. Outcomes included waist circumference, systolic and diastolic blood pressure, fasting triglycerides, high-density lipoprotein cholesterol, and glucose concentrations. Analyses of covariance comparing tertiles of sedentary time/MVPA showed that higher levels of MVPA were associated with lower waist circumference, fasting triglycerides and diastolic blood pressure, and higher high-density lipoprotein (HDL) cholesterol, irrespective of sedentary time. In linear regression, MVPA was inversely associated with waist circumference and diastolic blood pressure and positively associated with HDL cholesterol, independent of covariates including sedentary time. In contrast, sedentary time was positively associated with diastolic blood pressure but after adjustment for MVPA the association was no longer statistically significant. Self-reported screen time was positively associated with waist circumference and negatively associated with HDL cholesterol independent of covariates including MVPA. Overall, a high level of MVPA was associated with reduced cardiometabolic risk in this sample of children, regardless of their amount of sedentary behaviour. The type of sedentary behaviour (i.e., screen time) might be more important than overall sedentary time in relation to cardiometabolic risk. PMID- 23668754 TI - Acute glycemic and blood lipid response to the ingestion of a candy bar-like protein supplement compared with its candy bar counterpart. AB - Candy bar-like protein supplements are sometimes consumed for their sugar alcohol content, which lowers the glycemic response. The purpose of this study was to determine the acute glycemic and blood lipid response to the ingestion of a candy bar-like protein supplement compared with its candy bar counterpart. In a crossover design, 5 males and 5 females (N = 10; age, 24 +/- 5.5 years; height, 174 +/- 8.3 cm; weight, 80 +/- 21.9 kg) consumed a candy bar (CBR) or a similar protein bar (PBR) after a 10-h fast. Blood draws occurred at baseline and at 15, 30, 45, and 60 min after consumption and were analyzed for blood glucose, insulin, and lipid profiles. A 2*5 ANOVA was used, with Student's t tests for significant interactions. A significant (p < 0.05) blood glucose time effect occurred in both groups, with a more profound glucose response from the CBR at 15 min (CBR: 6.2 +/- 0.8 mmol.L(-1); PBR: 4.9 +/- 0.5 mmol.L(-1)). Triglycerides increased significantly (p < 0.05), independent of group, peaking at 60 min (Delta CBR: 0.8 +/- 0.3 mmol.L(-1); Delta PBR: 1.3 +/- 0.3 mmol.L(-1)). Insulin increased significantly (p < 0.05), independent of group, peaking at 15 min (Delta CBR: 42 +/- 27 MUIU.mL(-1); Delta PBR: 25 +/- 11 MUIU.mL(-1)). No significant change (p > 0.05) was observed in total cholesterol. Blood glucose, triglycerides, and insulin all increased significantly in response to both CBR and PBR consumption. The CBR elicited a greater effect on blood glucose; however, the PBR had a strong impact on serum triglycerides and insulin. PMID- 23668755 TI - Factors contributing to the fatigue-related reduction in active dorsiflexion joint range of motion. AB - Reductions in active joint range of motion (ROM) are responsible for decreased work-generating capacity during fatiguing repetitive isotonic shortening contractions. Factors responsible for impairing the joint-angle-specific net torque developed during muscle shortening could include fatigue-induced torque loss, shortening-induced torque depression in the agonist muscle, and opposing passive tension of the antagonists, but these have not been systematically explored. Nine men (aged 25.8 +/- 2.0 years) performed a maximal-effort fatiguing task that consisted of repetitive loaded shortening dorsiflexions through a 40 degrees ankle joint ROM until active ROM decreased by 50%. Torque developed during contractile shortening, as well as passive opposing tension, was quantified before and after the reduction in active ROM. Before fatigue, and compared with maximum voluntary isometric contraction torque at the terminal ROM, shortening-induced torque depression in the agonist muscle and passive tension from the antagonists reduced net torque developed at the end of contractile shortening by ~42% and ~19%, respectively. After fatigue, a steepened ascending joint torque-angle relationship remained during contractile shortening, but neither muscle coactivation nor contractile slowing contributed to the fatigue induced torque loss. Fatigue-induced torque loss, shortening-induced torque depression in the agonist, and passive tension in the antagonist greatly depressed net torque developed at the end of contractile shortening. These contributed to the fatigue-induced reduction in active ROM by impairing the ability of the dorsiflexors to generate sufficient torque to overcome the imposed load at the end of contractile shortening. PMID- 23668756 TI - The impact of acute mental stress on brachial artery flow-mediated dilation differs when shear stress is elevated by reactive hyperemia versus handgrip exercise. AB - Acute mental stress can impair brachial artery (BA) flow-mediated dilation (FMD) in response to reactive hyperemia (RH) induced increases in shear stress. Handgrip exercise (HGEX) is emerging as a useful tool to increase shear stress for FMD assessment; however, the impact of acute mental stress on HGEX-FMD is unknown. The purpose of this study was to determine whether acute mental stress attenuates RH- and HGEX-induced BA-FMD to a similar extent. In 2 counterbalanced visits, 16 healthy males (19-27 years of age) performed RH-FMD or HGEX-FMD tests after a counting control task (prestress FMD) and a speech and arithmetic stress task (poststress FMD). BA diameter and mean blood velocity were assessed with echo and Doppler ultrasound, respectively. Shear stress was estimated using shear rate (SR = BA blood velocity/BA diameter). Mean arterial pressure (MAP), heart rate (HR), and salivary cortisol were used to assess stress reactivity. Results are expressed as mean +/- SE. The stress task elevated MAP (Delta24.0 +/- 2.6 mm Hg) and HR (Delta15.5 +/- 1.9 beats.min(-1)), but not cortisol (prestress vs. poststress: 4.4 +/- 0.7 nmol.L(-1) vs. 4.7 +/- 0.7 nmol.L(-1); p = 0.625). There was no difference between the pre- and poststress SR stimulus for RH (p = 0.115) or HGEX (p = 0.664). RH-FMD decreased from 5.2% +/- 0.6% prestress to 4.1% +/- 0.5% poststress (p = 0.071); however, stress did not attenuate HGEX-FMD (prestress vs. poststress: 4.1% +/- 0.6% vs. 5.3% +/- 0.6%; p = 0.154). The pre- to poststress change in FMD was significantly different in the RH-FMD vs. the HGEX-FMD test (-1.1% +/- 0.6% vs. +1.1% +/- 0.8%; p = 0.015). In conclusion, acute mental stress appears to have a disparate impact on FMD stimulated by RH vs. HGEX induced increases in shear stress. PMID- 23668757 TI - Biomarkers of oxidative stress and tissue damage released by muscle and liver after a single bout of swimming exercise. AB - Both acute exercise and excessive training can cause oxidative stress. The resulting increase in free radicals and the inadequate response from antioxidant systems can lead to a framework of cellular damage. An association between affected tissue and the biomarkers of oxidative stress that appear in plasma has not been clearly established. The aim of this study was to evaluate the source of oxidative stress biomarkers found in the plasma of untrained rats after a single bout of swimming exercise at 2 different intensities: low intensity (SBLIE) or high intensity (SBHIE). Immediately after the exercise, aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyltransferase (GGT), and lactate dehydrogenase (LDH) were measured in plasma to characterize cell damage. Oxidative stress was assessed using protein carbonylation (PC), total antioxidant capacity (TAC), and thiobarbituric acid reactive substances (TBARS) quantified by malondialdehyde concentration. SBHIE raised levels of plasma AST (93%) and ALT (17%), and both exercise regimens produced an increase in GGT (7%) and LDH (~55%). Plasma levels of PC and TBARS were greater in the SBHIE group; there were no changes in TAC. SBLIE caused only a modest increase in TBARS. In muscle, there were no changes in TAC, PC, or TBARS, regardless of exercise intensity, In the liver, TAC and TBARS increased significantly in both the SBLIE and SBHIE groups. This indicates that the oxidative stress biomarkers measured in the plasma immediately after a single bout of swimming exercise were generated primarily in the liver, not in muscle. PMID- 23668758 TI - Rapid development of systemic insulin resistance with overeating is not accompanied by robust changes in skeletal muscle glucose and lipid metabolism. AB - Prolonged overeating and the resultant weight gain are clearly linked with the development of insulin resistance and other cardiometabolic abnormalities, but adaptations that occur after relatively short periods of overeating are not completely understood. The purpose of this study was to characterize metabolic adaptations that may accompany the development of insulin resistance after 2 weeks of overeating. Healthy, nonobese subjects (n = 9) were admitted to the hospital for 2 weeks, during which time they ate ~4000 kcals.day(-1) (70 kcal.kg( 1) fat free mass.day(-1)). Insulin sensitivity was estimated during a meal tolerance test, and a muscle biopsy was obtained to assess muscle lipid accumulation and protein markers associated with insulin resistance, inflammation, and the regulation of lipid metabolism. Whole-body insulin sensitivity declined markedly after 2 weeks of overeating (Matsuda composite index: 8.3 +/- 1.3 vs. 4.6 +/- 0.7, p < 0.05). However, muscle markers of insulin resistance and inflammation (i.e., phosphorylation of IRS-1-Ser(312), Akt Ser(473), and c-Jun N-terminal kinase) were not altered by overeating. Intramyocellular lipids tended to increase after 2 weeks of overeating (triacylglyceride: 7.6 +/- 1.6 vs. 10.0 +/- 1.8 nmol.mg(-1) wet weight; diacylglyceride: 104 +/- 10 vs. 142 +/- 23 pmol.mg(-1) wet weight) but these changes did not reach statistical significance. Overeating induced a 2-fold increase in 24-h insulin response (area under the curve (AUC); p < 0.05), with a resultant ~35% reduction in 24-h plasma fatty acid AUC (p < 0.05). This chronic reduction in circulating fatty acids may help explain the lack of a robust increase in muscle lipid accumulation. In summary, our findings suggest alterations in skeletal muscle metabolism may not contribute meaningfully to the marked whole-body insulin resistance observed after 2 weeks of overeating. PMID- 23668759 TI - Validity of the SC-StepMX pedometer during treadmill walking and running. AB - The purpose of this study was to examine the validity of the SC-StepMX pedometer for measuring step counts. A convenience sample of 40 participants wore 4 SC StepMX pedometers, 2 Yamax DigiWalker pedometers, and 2 Actical accelerometers around their waist on a treadmill at 4 speeds based on each participant's self paced walking speed (50%, 100%, 180%, and 250%; range: 1.4-14.1 km.h(-1)). The SC StepMX demonstrated lower mean absolute percent error (-0.2%) compared with the Yamax DigiWalker (-20.5%) and the Actical (-26.1%). Mean measurement bias was lower for the SC-StepMX (0.1 +/- 9.1; 95% confidence interval = -17.8 to 18.0 steps.min(-1)) when compared with both the Yamax DigiWalker (-15.9 +/- 23.3; 95% confidence interval = -61.6 to 29.7 steps.min(-1)) and the Actical (-22.0 +/- 36.3; 95% CI = -93.1 to 49.1 steps.min(-1)). This study demonstrates that the SC StepMX pedometer is a valid tool for the measurement of step counts. The SC StepMX accurately measures step counts at slower walking speeds when compared with 2 other commercially available activity monitors. This makes the SC-StepMX useful in measuring step counts in populations that are active at lower intensities (e.g., sedentary individuals, the elderly). PMID- 23668760 TI - The ergogenic effect of beta-alanine combined with sodium bicarbonate on high intensity swimming performance. AB - We investigated the effect of beta-alanine (BA) alone (study A) and in combination with sodium bicarbonate (SB) (study B) on 100- and 200-m swimming performance. In study A, 16 swimmers were assigned to receive either BA (3.2 g.day(-1) for 1 week and 6.4 g.day(-1) for 4 weeks) or placebo (PL; dextrose). At baseline and after 5 weeks of supplementation, 100- and 200-m races were completed. In study B, 14 were assigned to receive either BA (3.2 g.day(-1) for 1 week and 6.4 g.day(-1) for 3 weeks) or PL. Time trials were performed once before and twice after supplementation (with PL and SB), in a crossover fashion, providing 4 conditions: PL-PL, PL-SB, BA-PL, and BA-SB. In study A, BA supplementation improved 100- and 200-m time-trial performance by 2.1% (p = 0.029) and 2.0% (p = 0.0008), respectively. In study B, 200-m time-trial performance improved in all conditions, compared with presupplementation, except the PL-PL condition (PL-SB, +2.3%; BA-PL, +1.5%; BA-SB, +2.13% (p < 0.05)). BA-SB was not different from BA-PL (p = 0.21), but the probability of a positive effect was 78.5%. In the 100-m time-trial, only a within-group effect for SB was observed in the PL-SB (p = 0.022) and BA-SB (p = 0.051) conditions. However, 6 of 7 athletes swam faster after BA supplementation. The probability of BA having a positive effect was 65.2%; when SB was added to BA, the probability was 71.8%. BA and SB supplementation improved 100- and 200-m swimming performance. The coingestion of BA and SB induced a further nonsignificant improvement in performance. PMID- 23668761 TI - A study of DNA protective effect of orange juice supplementation. AB - The potential acute genoprotective effect of orange juice supplementation was investigated. Six healthy subjects (aged 33 to 60 years; 3 women and 3 men) were asked to drink 400 mL of commercial orange juice, which contained 100 mg vitamin C and 40.8 g sugar. Venous blood (2 mL) was taken before and 2 h after ingestion (test trial). A week later, the subjects were asked to repeat the trial by drinking 400 mL water with 100 mg vitamin C and 40.8 g glucose (control trial). Lymphocytes isolated from blood samples underwent comet assay on the day of collection. Pre- and postingestion DNA damage scores were measured in both the test and control trials. Results showed that there was a significant decrease in DNA damage induced by hydrogen peroxide after 2 h of supplementation with orange juice, and no change in baseline DNA damage. There was no significant decrease in the DNA damage in lymphocytes in the control trial. PMID- 23668762 TI - Comparison of intra-arterial and manual auscultation of blood pressure during submaximal exercise in humans. AB - Blood pressure (BP) is a key measure of cardiovascular function, and accurate measurement is important to ensure proper clinical evaluation, diagnosis, and treatment. We compared intra-arterial (direct) and cuff auscultation (manual) measurement techniques at rest and during 2 levels of submaximal constant-load exercise (9 min at 40% and 75% maximum watts). Sixty-four adults (aged 29.0 +/- 0.7 years; 48% male; height, 173.7 +/- 1.2 cm; mass, 73.0 +/- 1.7 kg; body mass index, 24.1 +/- 0.4 kg.m(-2); body surface area, 1.87 +/- 0.03 m(2)) participated in the study. At rest, low, and moderate intensity, direct measurement demonstrated higher systolic BP (SBP) and diastolic BP (DBP) (bias for SBP: 22, 31, and 27 mm Hg and for DBP: 5, 7, and 17 mm Hg; rest, low-, and moderate intensity, respectively; p < 0.01). At rest, the correlation and agreement between the 2 methods was modest (SBP: r = 0.56, bias = +22.1 mm Hg; DBP: r = 0.53, bias = +4.9 mm Hg; p < 0.001). There was good correlation and agreement with SBP at low and moderate intensity; however, DBP demonstrated a weaker relationship (SBP: r = 0.74 and 0.74, bias = +30.2 and +26.8 mm Hg; DBP: r = 0.39 and 0.28, bias = +7.1 and +13.4 mm Hg; for low and moderate intensity, respectively; p < 0.001). Further, manual measurement demonstrated a greater slope from rest to moderate exercise for the relationship between pulse pressure (PP) and cardiac output (13.6 +/- 0.4 vs 12.3 +/- 0.4, p = 0.03). As exercise intensity increases, manual DBP tends to bias low compared with direct DBP, which, when combined with parallel increases in SBP, leads to no differences in PP between methods at moderate exercise. Because PP is used to calculate other cardiovascular parameters (mean arterial pressure, systemic vascular resistance), measurement technique and exercise intensity should be considered when using cardiovascular variables as outcome measures. PMID- 23668763 TI - Effect of exercise training on diastolic function in metabolic syndrome. AB - It has been reported that metabolic syndrome (MetS) impairs left ventricular (LV) diastolic function. The objective of this study was to determine whether exercise training can improve LV diastolic function in individuals with MetS. Twenty-eight individuals with MetS (9 males, aged 60 +/- 5 years) underwent a 1-year combined endurance and resistance exercise training program; maximal aerobic capacity (VO2max), blood pressure, blood markers, and LV diastolic function were measured at weeks 0, 12, 24, and 52 throughout the training. Pulsed wave Doppler echocardiography across the mitral valve was used to assess peak early flow velocity (E) and peak atrial flow velocity (A) to determine the E/A ratio. Individuals with MetS had a reversed E/A ratio, suggesting impaired LV relaxation, the first stage of LV diastolic dysfunction. Exercise training reduced systolic blood pressure (SBP) (129 +/- 14 to 120 +/- 12 mm Hg; p < 0.01) and increased VO2max (29.2 +/- 6.3 to 33.4 +/- 6.5 mL.kg(-1).min(-1); p < 0.01) and high-density lipoprotein cholesterol (1.04 +/- 0.21 to 1.12 +/- 0.25 mmol.L( 1); p = 0.02), but did not improve LV diastolic function. Individuals with an E/A ratio <1 at the start of training had a tendency toward an increased E/A ratio (p = 0.12) accompanied by significant decreases in SBP and increases in VO2max with exercise training. Combined resistance and aerobic exercise training improved cardiometabolic health but did not improve the impaired LV diastolic function of individuals with MetS. PMID- 23668764 TI - Effect of plasma donation and blood donation on aerobic and anaerobic responses in exhaustive, severe-intensity exercise. AB - The purpose of this study was to investigate the immediate and delayed effects of plasma donation and blood donation on responses in exhaustive, severe-intensity exercise. Nineteen young men and women performed exhaustive cycle ergometer tests at ~3.3 W.kg(-1) before and then 2 h, 2 days, and 7 days after withdrawal of either 8-10 mL.kg(-1) (~700 mL) of plasma (n = 10) or 1 unit (450 mL) of whole blood (n = 9). Time to exhaustion was significantly (p < 0.05) decreased after the removal of plasma (-11% after 2 h) and after the removal of blood (-19% after 2 h and -7% after 2 days). Maximal oxygen uptake (.VO(2max)) was not affected by plasma donation, but .VO(2max) was reduced following blood withdrawal (-15% after 2 h, -10% after 2 days, and -7% after 7 days) presumably because of effects on blood volume, total haemoglobin content, and haemoglobin concentration. The kinetics of the oxygen uptake (.VO2) response was not affected by either intervention. Two measures of anaerobic capacity, postexercise blood lactate concentration, and maximal accumulated oxygen deficit were reduced (-14%, -15%, respectively) 2 h after plasma donation, but neither was affected by blood donation. Removal of plasma and removal of blood have different effects on blood constituency, on the .VO2 response, and on performance. Plasma donation appears to affect exercise performance because of reduced anaerobic capacity, whereas blood donation affects performance because of lowered .VO(2max). PMID- 23668765 TI - Antioxidant effect of organic purple grape juice on exhaustive exercise. AB - This study aimed to assess the potential protective effect of organic purple grape juice (PGJ) on oxidative stress produced by an exhaustive exercise bout in rats. To test this hypothesis, rats were acutely treated with organic PGJ (Vitis labrusca) and subsequently submitted to an exhaustive exercise bout. Parameters of oxidative stress, such as thiobarbituric acid reactive species (TBARS) levels, 2',7',-dichlorofluorescein diacetate (DCFH-DA) oxidation, and nonprotein sulfhydryl levels (NP-SH) in the brain, skeletal muscle, and blood, were evaluated. Enzyme activity of Na(+),K(+)-ATPase, Ca(2+)-ATPase, and delta aminolevulinate dehydratase (delta-ALA-D) in the brain, skeletal muscle, and blood were also assayed. Statistical analysis showed that the exhaustive exercise bout increased TBARS levels and DCFH-DA oxidation, and decreased NP-SH levels in rat tissue. Ca(2+)-ATPase activity was increased in groups exposed to both exercise and PGJ treatment. The results indicate that organic PGJ intake was able to protect against the oxidative damage caused by an exhaustive exercise bout in different rat tissues. PMID- 23668766 TI - Prolonged moderate-intensity exercise oxygen uptake response following heavy intensity priming exercise with short- and longer-term recovery. AB - This study examines the effects of recovery duration following heavy-intensity "priming" exercise (Hvy) on pulmonary oxygen (O2) uptake (VO2p) during subsequent prolonged moderate-intensity exercise (Mod). Nine participants (6 men and 3 women) (27 +/- 7 years) each completed 3 repetitions of 2 continuous Mod 1-Hvy Mod 2 leg-cycling protocols in which Mod 2 lasted 30 min, but was preceded by a recovery duration of either 6 (R6) or 20 (R20) min at 20 W following Hvy; in each case, Mod 1 and Hvy lasted 6 min and were preceded by 6 min at 20 W. VO2p, heart rate (HR), and near-infrared spectroscopy (NIRS)-derived muscle deoxygenation ([HHb]) responses were modeled as a monoexponential; additionally, 60-s averages were computed every 6 min in Mod 1 and Mod 2. VO2p was elevated (p < 0.05) throughout Mod 2 compared with Mod 1 in both R6 and R20 (by -82 mL.min(-1) or ~5.0%); this occurred despite a complete recovery of baseline VO2p (VO2pBsln) following R20. HR and minute ventilation (VE), but not [HHb], were also elevated throughout Mod 2. The phase II time constant for VO2p (tauVO2p) was reduced in Mod 2 (22 s (Mod 1), 19 s (Mod 2); p < 0.05), as was the "overshoot" in the normalized [HHb]/O2 uptake ratio (p < 0.05). This study shows that VO2p was elevated during Mod following Hvy, regardless of recovery duration; however, a determining role for VO2pBsln is precluded. Furthermore, neither VO2p, HR, nor VE showed any evidence of a readjustment back to no-Hvy conditions during prolonged Mod (p > 0.05). Lastly, regardless of recovery duration, tauVO2p was reduced to a similar extent with Hvy, likely resulting from an improved matching of local muscle O2 delivery to O2 utilization. PMID- 23668767 TI - Open-ended time durations for stationary start intense cycle ergometer exercise testing. AB - The study involved application of different applied loads to measure altered test durations, time to peak power, peak power, and peak cadence during intense cycle ergometry exercise. Healthy, physically active male (n = 11) and female (n = 11) subjects (18-45 years) performed the following 3 bouts of intense cycle ergometry at peak cadence to volitional exhaustion on 3 separate days, 48 h to 1 week apart: (i) 85 g.kg(-1) body mass load; (ii) 75 g.kg(-1) body mass load; and (iii) 100 g.kg(-1) body mass load. Trials (ii) and (iii) were performed in random order after trial (i). Exercise consisted of a stationary start, where test termination occurred when cadence decreased to <35 r.min(-1). Mean (+/-SD) for gender main effects for time to peak power were 7.64 +/- 2.76 vs. 9.49 +/- 2.76 s (p < 0.001) for males and females, respectively. Relative peak power data for males vs. females for 75, 85, and 100 g.kg(-1) were 10.01 +/- 1.371 vs. 7.81 +/- 1.25, 10.16 +/- 1.61 vs. 7.67 +/- 1.35, and 10.91 +/- 2.03 vs. 7.31 +/- 1.37 W.kg(-1), respectively. The means for test duration for the GENDER * LOAD interaction (p = 0.09) were 68.25 +/- 17.80 vs. 56.5 +/- 11.56, 63.70 +/- 17.21 vs.57.95 +/- 10.45, and 51.99 +/- 14.59 vs. 49.54 +/- 12.45 s for males vs. females for each of 75, 85, and 100 g.kg(-1), respectively. Stepwise multiple regression involving load and gender resulted in an explanation of variance (R(2)) of only 31.2%. Open ended testing should be performed at a load of 100 g.kg(-1) body mass for males and 85 g.kg(-1) body mass females, causing volitional exhaustion in approximately 60 s and should allow test duration to be another measured variable. PMID- 23668768 TI - Effects of an acute bout of resistance exercise on fiber-type specific to GLUT4 and IGF-1R expression. AB - The effects of resistance exercise on fiber-type-specific expression of insulin like growth factor I receptor (IGF-1R) and glucose transporter 4 (GLUT4) was determined in 6 healthy males. The expression of both genes increased in Type I fibers (p < 0.05), but only GLUT4 increased (p < 0.05) in Type II fibers. These data demonstrates that an acute bout of resistance exercise can up-regulate mechanisms of glucose uptake in slow and fast-twitch fibers, but the IGF signaling axis may not be as effective in fast-twitch fibers. PMID- 23668770 TI - Molecular modeling of the green leaf volatile methyl salicylate on atmospheric air/water interfaces. AB - Methyl salicylate (MeSA) is a green leaf volatile (GLV) compound that is emitted in significant amounts by plants, especially when they are under stress conditions. GLVs can then undergo chemical reactions with atmospheric oxidants, yielding compounds that contribute to the formation of secondary organic aerosols (SOAs). We investigated the adsorption of MeSA on atmospheric air/water interfaces at 298 K using thermodynamic integration (TI), potential of mean force (PMF) calculations, and classical molecular dynamics (MD) simulations. Our molecular models can reproduce experimental results of the 1-octanol/water partition coefficient of MeSA. A deep free energy minimum was found for MeSA at the air/water interface, which is mainly driven by energetic interactions between MeSA and water. At the interface, the oxygenated groups in MeSA tend to point toward the water side of the interface, with the aromatic group of MeSA lying farther away from water. Increases in the concentrations of MeSA lead to reductions in the height of the peaks in the MeSA-MeSA g(r) functions, a slowing down of the dynamics of both MeSA and water at the interface, and a reduction in the interfacial surface tension. Our results indicate that MeSA has a strong thermodynamic preference to remain at the air/water interface, and thus chemical reactions with atmospheric oxidants are more likely to take place at this interface, rather than in the water phase of atmospheric water droplets or in the gas phase. PMID- 23668771 TI - Architectural spiroligomers designed for binuclear metal complex templating. AB - The first structurally, spectroscopically, and electronically characterized metal spiroligomer complexes are reported. The binuclear [M2L2](4+) ions (M = Mn, Zn) are macrocyclic "squares" and are characterized by X-ray diffraction, (1)H and (13)C NMR, electronic absorption, emission, and mass spectroscopies. The manganese complex contains two spin-independent Mn(II) ions and is additionally characterized using EPR and CD spectroscopies and CV. PMID- 23668772 TI - Clinical, metabolic and psychological outcomes and treatment costs of a prospective randomized trial based on different educational strategies to improve diabetes care (PRODIACOR). AB - AIM: To evaluate the effect of system interventions (formalized data collection and 100% coverage of medications and supplies) combined with physician and/or patient education on therapeutic indicators and costs in Type 2 diabetes. METHODS: This was a randomized 2 * 2 design in public health, social security or private prepaid primary care clinics in Corrientes, Argentina. Thirty-six general practitioners and 468 adults with Type 2 diabetes participated. Patients of nine participating physicians were selected randomly and assigned to one of four structured group education programmes (117 patients each): control (group 1), physician education (group 2), patient education (group 3), and both physician education and patient education (group 4), with identical system interventions in all four groups. Outcome measures included HbA(1c), BMI, blood pressure, fasting glucose, lipid profile, drug consumption, resource use and patient well-being at baseline and every 6 months up to 42 months. RESULTS: HbA(1c) decreased significantly from 4 mmol/mol to 10 mmol/mol by 42 months (P < 0.05); the largest and more consistent decrease was in the groups where patients and physicians were educated. Blood pressure and triglycerides decreased significantly in all groups; the largest changes were recorded in the combined education group. The World Health Organization-5 Lowe score showed significant improvements, without differences among groups. The lowest treatment cost was seen in the combined education group. CONCLUSIONS: In a primary care setting, educational interventions combined with comprehensive care coverage resulted in long-term improvement in clinical, metabolic and psychological outcomes at the best cost effectiveness ratio. PMID- 23668773 TI - Swiss children's moral and psychological judgments about inclusion and exclusion of children with disabilities. AB - Children's judgments about inclusion and exclusion of children with disabilities were investigated in a Swiss sample of 6-, 9-, and 12-year-old children from inclusive and noninclusive classrooms (N = 422). Overall, the majority of children judged it as morally wrong to exclude children with disabilities. Yet, participants were less likely to expect the inclusion of children with mental or physical disabilities in academic and athletic contexts compared to social contexts. Moreover, older children more consistently coordinated disability type with context of exclusion. There were also significant differences depending on the type of classroom. The findings extend existing research on exclusion by investigating exclusion based on disability across different age groups and educational settings. PMID- 23668775 TI - Normothermic acellular ex vivo liver perfusion reduces liver and bile duct injury of pig livers retrieved after cardiac death. AB - We compared cold static with acellular normothermic ex vivo liver perfusion (NEVLP) as a novel preservation technique in a pig model of DCD liver injury. DCD livers (60 min warm ischemia) were cold stored for 4 h, or treated with 4 h cold storage plus 8 h NEVLP. First, the livers were reperfused with diluted blood as a model of transplantation. Liver injury was determined by ALT, oxygen extraction, histology, bile content analysis and hepatic artery (HA) angiography. Second, AST levels and bile production were assessed after DCD liver transplantation. Cold stored versus NEVLP grafts had higher ALT levels (350 +/- 125 vs. 55 +/- 35 U/L; p < 0.0001), decreased oxygen extraction (250 +/- 65 mmHg vs. 410 +/- 58 mmHg, p < 0.01) and increased hepatocyte necrosis (45% vs. 10%, p = 0.01). Levels of bilirubin, phospholipids and bile salts were fivefold decreased, while LDH was sixfold higher in cold stored versus NEVLP grafts. HA perfusion was decreased (twofold), and bile duct necrosis was increased (100% vs. 5%, p < 0.0001) in cold stored versus NEVLP livers. Following transplantation, mean serum AST level was higher in the cold stored versus NEVLP group (1809 +/- 205 U/L vs. 524 +/- 187 U/L, p < 0.05), with similar bile production (2.5 +/- 1.2 cc/h vs. 2.8 +/- 1.4 cc/h; p = 0.2). NEVLP improved HA perfusion and decreased markers of liver duct injury in DCD grafts. PMID- 23668774 TI - Evaluation of the Hepa Wash(r) treatment in pigs with acute liver failure. AB - BACKGROUND: Mortality of patients with acute liver failure (ALF) is still unacceptably high. Available liver support systems are still of limited success at improving survival. A new type of albumin dialysis, the Hepa Wash(r) system, was newly introduced. We evaluated the new liver support system as well as the Molecular Adsorbent Recycling System (MARS) in an ischemic porcine model of ALF. METHODS: In the first study animals were randomly allocated to control (n=5) and Hepa Wash (n=6) groups. In a further pilot study, two animals were treated with the MARS-system. All animals received the same medical and surgical procedures. An intraparenchymal intracranial pressure was inserted. Hemodynamic monitoring and goal-directed fluid therapy using the PiCCO system was done. Animals underwent functional end-to-side portacaval shunt and ligation of hepatic arteries. Treatment with albumin dialysis was started after fall of cerebral perfusion pressure to 45 mmHg and continued for 8 h. RESULTS: All animals in the Hepa Wash group survived the 13-hour observation period, except for one that died after stopping treatment. Four of the control animals died within this period (p=0.03). Hepa Wash significantly reduced impairment of cerebral perfusion pressure (23+/-2 vs. 10+/-3 mmHg, p=0.006) and mean arterial pressure (37+/-1 vs. 24+/-2 mmHg, p=0.006) but had no effect on intracranial pressure (14+/-1 vs. 15+/ 1 mmHg, p=0.72). Hepa Wash also enhanced cardiac index (4.94+/-0.32 vs. 3.36+/ 0.25 l/min/m2, p=0.006) and renal function (urine production, 1850 +/- 570 vs. 420 +/- 180 ml, p=0.045) and eliminated water soluble (creatinine, 1.3+/-0.2 vs. 3.2+/-0.3 mg/dl, p=0.01; ammonia 562+/-124 vs. 1382+/-92 MUg/dl, p=0.006) and protein-bound toxins (nitrate/nitrite 5.54+/-1.57 vs. 49.82+/-13.27 MUmol/l, p=0.01). No adverse events that could be attributed to the Hepa Wash treatment were observed. CONCLUSIONS: Hepa Wash was a safe procedure and improved multiorgan system failure in pigs with ALF. The survival benefit could be the result of ameliorating different organ functions in association with the detoxification capacity of water soluble and protein-bound toxins. PMID- 23668776 TI - Evaluation of scaling and root planing effect in generalized chronic periodontitis by fractal and multifractal analysis. AB - BACKGROUND AND OBJECTIVE: Fractal and multifractal analysis are useful additional non-invasive methods for quantitative description of complex morphological features. However, the quantitative and qualitative assessment of morphologic changes within human gingival cells and tissues are still unexplored. The aim of this work is to assess the structural gingival changes in patients with generalized chronic periodontitis (GCP), before and after scaling and root planing (SRP) by using fractal and multifractal analysis. MATERIAL AND METHODS: Twelve adults with untreated chronic periodontitis were treated only by SRP. At baseline and after SRP, gingivomucosal biopsies were collected for histopathological examination. Fractal and multifractal analysis of digital images of the granular, spinous and basal and conjunctive layers structure, using the standard box-counting method was performed. The fractal dimension was determined for cell membrane, nuclear membrane of cell and nucleolus membrane of cell. RESULTS: In GCP a higher fractal dimension corresponds to a higher geometric complexity of cells contour, as its values increase when the contour irregularities increase. The generalized fractal dimensions were determined for the conjunctive layer structure of patients with GCP and patients with GCP and SRP. The fractal and multifractal analysis of gingival biopsies confirmed earlier findings that SRP reduces gingival injury in patients with GCP. CONCLUSION: It has been shown that fractal and multifractal analysis of tissue images as a non invasive technique could be used to measure contrasting morphologic changes within human gingival cells and tissues and can provide detailed information for investigation of healthy and diseased gingival mucosa from patients with GCP. PMID- 23668777 TI - Seebeck coefficient of nanowires interconnected into large area networks. AB - We measured the macroscopic Seebeck coefficient of silicon nanowires (SiNWs), organized in a highly interconnected networks on large areas (order of mm(2)). The fabricated networks are very reliable with respect to random nanowire failure and are electrically and thermally equivalent to many SiNWs placed in parallel between the electrical contacts. The equivalent SiNWs have a macroscopic length of the order of millimeters and are very narrow (width smaller than 100 nm) so that they can be used to exploit thermoelectric properties at nanoscale for macroscopic electrical power generation and/or cooling. The measurement of the Seebeck coefficient S, facilitated by the macroscopic dimensions of the network, gives an insight into two questions, nanowire effective doping and carrier mobility, which are widely discussed in the literature. We found that the measured value of S is compatible with an effective doping that is higher than that of the original wafer. This higher doping is consistent with the value estimated from the measured electrical conductivity of the SiNWs with the assumption that the electron mobility inside the nanowire is equal to that of bulk silicon. PMID- 23668779 TI - The effects of protoype medium on usability testing. AB - Inconsistencies among testing methods and results in previous research prompted this study that builds upon a systematic usability testing research framework to better understand how interface medium influences users' abilities to detect usability flaws in applications. Interface medium was tested to identify its effects on users' perceptions of usability and abilities to detect usability problems and severe usability problems. Results indicated that medium has no effect on users' abilities to detect usability problems or perceptions of usability. However, results did indicate an interaction between the medium and the tested application in which users were able to identify significantly more usability problems on a higher fidelity medium using a particular application. Results also indicated that as users' perceptions of an application's usability increases, the users are less able to detect usability problems in that application. Usability testing should begin early in the design process, even if low fidelity mediums will be used. PMID- 23668778 TI - A redundant role of human thyroid peroxidase propeptide for cellular, enzymatic, and immunological activity. AB - BACKGROUND: Thyroid peroxidase (TPO) is a dimeric membrane-bound enzyme of thyroid follicular cells, responsible for thyroid hormone biosynthesis. TPO is also a common target antigen in autoimmune thyroid disease (AITD). With two active sites, TPO is an unusual enzyme, and thus there is much interest in understanding its structure and role in AITD. Homology modeling has shown TPO to be composed of different structural modules, as well as a propeptide sequence. During the course of studies to obtain homogeneous preparations of recombinant TPO for structural studies, we investigated the role of the large propeptide sequence in TPO. METHODS: An engineered recombinant human TPO preparation expressed in Chinese hamster ovary (CHO) cells lacking the propeptide (TPODeltapro; amino acid residues 21-108) was characterized and its properties compared to wild-type TPO. Plasma membrane localization was determined by cell surface protein biotinylation, and biochemical studies were performed to evaluate enzymatic activity and the effect of deglycosylation. Immunological investigations using autoantibodies from AITD patients and other epitope-specific antibodies that recognize conformational determinants on TPO were evaluated for binding to TPODeltapro by flow cytometry, immunocytochemistry, and capture enzyme linked immunosorbent assay. Molecular modeling and dynamics simulation of TPODeltapro comprising a dimer of myeloperoxidase-like domains was performed in order to investigate the impact of propeptide removal and the role of glycosylation. RESULTS: The TPODeltapro was expressed on the cell surface at comparable levels to wild-type TPO. The TPODeltapro was enzymatically active and recognized by patients' autoantibodies and a panel of epitope-specific antibodies, confirming structural integrity of the two major conformational determinants recognized by autoantibodies. Faithful intracellular trafficking and N-glycosylation of TPODeltapro was also maintained. Molecular modeling and dynamics simulations were consistent with these observations. CONCLUSIONS: Our results point to a redundant role for the propeptide sequence in TPO. The successful expression of TPODeltapro in a membrane-anchored, enzymatically active form that is insensitive to intramolecular proteolysis, and importantly is recognized by patients' autoantibodies, is a key advance for purification of substantial quantities of homogeneous preparation of TPO for crystallization, structural, and immunological studies. PMID- 23668780 TI - Impact of police body armour and equipment on mobility. AB - Body armour is used widely by law enforcement and other agencies but has received mixed reviews. This study examined the influence of stab resistant body armour (SRBA) and mandated accessories on physiological responses to, and the performance of, simulated mobility tasks. Fifty-two males (37 +/- 9.2 yr, 180.7 +/- 6.1 cm, 90.2 +/- 11.6 kg, VO2max 50 +/- 8.5 ml kg(-1) min(-1), BMI 27.6 +/- 3.1, mean +/- SD) completed a running VO2max test and task familiarisation. Two experimental sessions were completed (>=4 days in between) in a randomised counterbalanced order, one while wearing SRBA and appointments (loaded) and one without additional load (unloaded). During each session participants performed five mobility tasks: a balance task, an acceleration task that simulated exiting a vehicle, chin-ups, a grappling task, and a manoeuvrability task. A 5-min treadmill run (zero-incline at 13 km.h(-1), running start) was then completed. One min after the run the five mobility tasks were repeated. There was a significant decrease in performance during all tasks with loading (p < 0.001). Participants were off-balance longer; slower to complete the acceleration, grapple and mobility tasks; completed fewer chin-ups; and had greater physiological cost (? %HRmax, ? %VO2max, ? RER) and perceptual effort (? RPE) during the 5-min run. Mean performance decreases ranged from 13 to 42% while loaded, with further decreases of 6-16% noted after the 5-min run. Unloaded task performance was no different between phases. Wearing SRBA and appointments significantly reduced mobility during key task elements and resulted in greater physiological effort. These findings could have consequences for optimal function in the working environment and therefore officer and public safety. PMID- 23668781 TI - Cognitive regulation of saccadic velocity by reward prospect. AB - It is known that expectation of reward speeds up saccades. Past studies have also shown the presence of a saccadic velocity bias in the orbit, resulting from a biomechanical regulation over varying eccentricities. Nevertheless, whether and how reward expectation interacts with the biomechanical regulation of saccadic velocities over varying eccentricities remains unknown. We addressed this question by conducting a visually guided double-step saccade task. The role of reward expectation was tested in monkeys performing two consecutive horizontal saccades, one associated with reward prospect and the other not. To adequately assess saccadic velocity and avoid adaptation, we systematically varied initial eye positions, saccadic directions and amplitudes. Our results confirmed the existence of a velocity bias in the orbit, i.e., saccadic peak velocity decreased linearly as the initial eye position deviated in the direction of the saccade. The slope of this bias increased as saccadic amplitudes increased. Nevertheless, reward prospect facilitated velocity to a greater extent for saccades away from than for saccades toward the orbital centre, rendering an overall reduction in the velocity bias. The rate (slope) and magnitude (intercept) of reward modulation over this velocity bias were linearly correlated with amplitudes, similar to the amplitude-modulated velocity bias without reward prospect, which presumably resulted from a biomechanical regulation. Small-amplitude (<= 5 degrees ) saccades received little modulation. These findings together suggest that reward expectation modulated saccadic velocity not as an additive signal but as a facilitating mechanism that interacted with the biomechanical regulation. PMID- 23668782 TI - Clinical usefulness of a guideline-based screening tool for the diagnosis of allergic rhinitis in asthmatics: the Self Assessment of Allergic Rhinitis and Asthma questionnaire. AB - BACKGROUND AND OBJECTIVE: Allergic rhinitis (AR) is common in asthmatic patients and may impair asthma control. However, this comorbidity is frequently missed. A simple test is needed to enable physicians to diagnose and evaluate the severity of both diseases. The Self Assessment of Allergic Rhinitis and Asthma (SACRA) questionnaire, which GINA and ARIA Japan committees developed in 2011, consist of questionnaires based on GINA and ARIA guidelines for the diagnosis and severity of AR and asthma, and a visual analogue scale (VAS) to evaluate the severity of both diseases. Our objective was to investigate the clinical usefulness of SACRA as a patient-based screening tool for identifying asthmatic patients with AR. METHODS: SACRA, ACT (Asthma Control Test) and serum IgE RAST were performed in asthmatic patients. The correlation between SACRA and other parameters were analyzed. RESULTS: Four hundred twenty asthmatic patients were enrolled. Among 168 subjects who self-reported no concomitant AR, 76 asthmatics scored one or more symptoms on SACRA. Eventually, 32 of these 76 subjects were diagnosed with AR by physicians based on laboratory data or physical examinations by ear, nose and throat specialists. The sensitivity and specificity of SACRA for the diagnosis of AR were 92% and 66%, respectively. The estimated prevalence of AR among asthmatics was 66%, almost identical to that of the previous nationwide study in Japan. The level of asthma control assessed by the VAS on SACRA and the ACT score showed a strong correlation (r = -0.700, P < 0.001). CONCLUSIONS: SACRA may be a clinically useful tool for identifying bronchial asthma patients with AR. PMID- 23668783 TI - A look at product development with genetically modified crops: examples from maize. AB - Plant breeding for crop genetic improvement involves the cycle of creating genetic diversity and exploiting that diversity to derive an improved cultivar with outstanding performance for specific traits of interest. Genetic modification through transformation essentially expands the genepool to facilitate access to genes otherwise not available through crossing. Transgenic events are defined by the DNA sequence that has been incorporated into the target genome and the specific point(s) of insertion. In the development of a new transgenic trait, typically many events are generated and evaluated with the aim of identifying one exhibiting consistent trait expression at or above specified thresholds, stable inheritance, and the absence of any negative effects. With transgenic traits for maize, once commercial candidates have been identified, these events are introgressed into elite lines, often through the use of molecular markers that can accelerate the breeding process and aid in producing a quality conversion. Converted elite lines are yield-tested to ensure performance equivalency with their unconverted counterparts. Finally, before commercial sale of seed, quality control monitoring is conducted to ensure event identity and purity and the absence of any unintended events. This monitoring complements other quality control measures to confirm seed viability and line/hybrid purity and uniformity in seed treatments, all in an effort to ensure customer satisfaction and to comply with governmental regulations. Thus, genetically modified (GM) cultivars are subject to significant testing and auditing prior to seed sale and distribution to farmers, more testing and auditing than with non-GM cultivars. PMID- 23668784 TI - A functional autophagy pathway is required for rapamycin-induced degradation of the Sgs1 helicase in Saccharomyces cerevisiae. AB - In yeast Saccharomyces cerevisiae, the immunosuppressant rapamycin mimics starvation by inhibiting the kinase Tor1. We recently documented that this treatment triggers a rapid degradation of Sgs1, a helicase involved in several biological processes such as the prevention of genomic instability. Herein, we show that yeast strains deleted for genes ATG2, ATG9, and PEP4, encoding components of the autophagy pathway, prevent rapamycin-induced degradation of Sgs1. We propose that defects in the autophagy pathway prevent degradation of key proteins in the rapamycin response pathway and as a consequence cause resistance to the drug. PMID- 23668785 TI - Transcriptional and posttranscriptional inhibition of HMGCR and PC biosynthesis by geraniol in 2 Hep-G2 cell proliferation linked pathways. AB - Geraniol, present in the essential oils of many aromatic plants, has in vitro and in vivo antitumor activity against several cell lines. We investigated the effects of geraniol on lipid metabolic pathways involved in Hep-G2 cell proliferation and found that geraniol inhibits the mevalonate pathway, phosphatidylcholine biosynthesis, cell growth, and cell cycle progression (with an arrest occurring at the G0/G1 interphase) and increases apoptosis. The expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate limiting step in cholesterol synthesis, was inhibited at the transcriptional and posttranscriptional levels, as assessed by real-time RT-PCR, Western blots, and [(14)C]HMG-CoA-conversion radioactivity assays. That geraniol decreased cholesterogenesis but increased the incorporation of [(14)C]acetate into other nonsaponifiable metabolites indicated the existence of a second control point between squalene and cholesterol involved in redirecting the flow of cholesterol derived carbon toward other metabolites of the mevalonate pathway. That exogenous mevalonate failed to restore growth in geraniol-inhibited cells suggests that, in addition to the inhibition of HMGCR, other dose-dependent actions exist through which geraniol can impact the mevalonate pathway and consequently inhibit cell proliferation. These results suggest that geraniol, a nontoxic compound found in many fruits and herbs, exhibits notable potential as a natural agent for combatting cancer and (or) cardiovascular diseases. PMID- 23668786 TI - The effects of human umbilical cord perivascular cells on rat hepatocyte structure and functional polarity. AB - Hepatocyte culture is a useful tool for the study of their biology and the development of bioartificial livers. However, many challenges have to be overcome since hepatocytes rapidly lose their normal phenotype in vitro. We have recently demonstrated that human umbilical cord perivascular cells (HUCPVCs) are able to provide support to hepatocytes. In the present study we go further into exploring the effects that HUCPVCs have in the functional polarization, and both the internal and external organization, of hepatocytes. Also, we investigate HUCPVC hepatocyte crosstalk by tracking both the effects of HUCPVCs on hepatocyte transcription factors and those of hepatocytes on the expression of hepatotrophic factors in HUCPVCs. Our results show that HUCPVCs maintain the functional polarity of hepatocytes ex vivo, as judged by the secretion of fluorescein into bile canaliculi, for at least 40 days. Transmission electron microscopy revealed that hepatocytes in coculture organize in an organoid-like structure embedded in extracellular matrix surrounded by HUCPVCs. In coculture, hepatocytes displayed a higher expression of C/EBPalpha, implicated in maintenance of the mature hepatocyte phenotype, and HUCPVCs upregulated hepatocyte growth factor and Jagged1 indicating that these genes may play important roles in HUCPVC-hepatocyte interactions. PMID- 23668787 TI - Mechanism of cardiomyocyte PGC-1alpha gene regulation by ERRalpha. AB - Peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1alpha (PGC 1alpha) regulates critical genes involved in cardiac mitochondrial biogenesis and fatty acid oxidation, and its loss is associated with impaired metabolism and various cardiac pathologies. Estrogen-related receptor alpha (ERRalpha) targets many of the same genes as PGC-1alpha, and extensive cross talk exists between these 2 regulators. Here we report the identification of an evolutionarily conserved ERRalpha binding site within the PGC-1alpha promoter. Using luciferase reporter assays and overexpression, inhibition, or knockdown of ERRalpha, we show that PGC-1alpha expression is critically dependent upon ERRalpha in primary cardiomyocytes. We demonstrate that short-term hypoxia results in reduced ERRalpha mRNA expression, which precedes a similar loss of PGC-1alpha mRNA. However, chromatin immunoprecipitation reveals that despite a key role for ERRalpha in regulating PGC-1alpha in normoxic cardiomyocytes, ERRalpha loss is not responsible for PGC-1alpha loss in hypoxia. Histone deacetylase 5 (HDAC5) has previously been demonstrated to strongly inhibit expression of PGC-1alpha, and we show that overexpression of ERRalpha is sufficient to overcome this repressive effect. Our data elucidates the mechanism by which ERRalpha regulates cardiac PGC 1alpha gene expression, and suggests that ERRalpha may provide a means to normalize PGC-1alpha expression that could be useful in the development of strategies aimed at improving cardiac metabolism in disease. PMID- 23668788 TI - Identification of amino acids responsible for stop codon recognition for polypeptide chain release factor. AB - One factor involved in eukaryotic translation termination is class 1 release factor in eukaryotes (eRF1), which functions to decode stop codons. Variant code species, such as ciliates, frequently exhibit altered stop codon recognition. Studies revealed that some class-specific residues in the eRF1 N-terminal domain are responsible for stop codon reassignment in ciliates. Here, we investigated the effects on stop codon recognition of chimeric eRF1s containing the N-terminal domain of Euplotes octocarinatus and Blepharisma japonicum eRF1 fused to Saccharomyces cerevisiae M and C domains using dual luciferase read-through assays. Mutation of class-specific residues in different eRF1 classes was also studied to identify key residues and motifs involved in stop codon decoding. As expected, our results demonstrate that 3 pockets within the eRF1 N-terminal domain were involved in decoding stop codon nucleotides. However, allocation of residues to each pocket was revalued. Our data suggest that hydrophobic and class specific surface residues participate in different functions: modulation of pocket conformation and interaction with stop codon nucleotides, respectively. Residues conserved across all eRF1s determine the relative orientation of the 3 pockets according to stop codon nucleotides. However, quantitative analysis of variant ciliate and yeast eRF1 point mutants did not reveal any correlation between evolutionary conservation of class-specific residues and termination related functional specificity and was limited in elucidating a detailed mechanism for ciliate stop codon reassignment. Thus, based on isolation of suppressor tRNAs from Euplotes and Tetrahymena, we propose that stop codon reassignment in ciliates may be controlled by cooperation between eRF1 and suppressor tRNAs. PMID- 23668789 TI - Phenotypic alteration of limbal niche-associated limbal epithelial stem cell deficiency by ultraviolet-B exposure-induced phototoxicity in mice. AB - Good vision requires a healthy cornea, and a healthy cornea needs healthy stem cells. Limbal epithelial stem cells (LESCs) are a traditional source of corneal epithelial cells and are recruited for the continuous production of epithelium without seizing throughout an animal's life, which maintains corneal transparency. Like the maintenance of other adult somatic stem cells, the maintenance of LESCs depends on the specific microenvironmental niche in which they reside. The purpose of this study was to determine the microenvironmental damage associated with LESCs fate due to ultraviolet (UV)-B exposure in a mouse model. Structural alteration and deregulation of the stem cell and its neighboring niche components were observed by using clinical, morphological, explant culture study, and flowcytometric analysis, which demonstrated that the limbal microenvironment plays an important role in cornea-related disease development. In UV-exposed mice, overexpression of vascular endothelial growth factor receptor 2 indicated neovascularization, decreased CD38 expression signified the alteration of limbal epithelial superficial cells, and the loss of limbal stem cell marker p63 indicated limbal stem cell deficiency in the limbal vicinity. We concluded that LESC deficiency diseases (LESCDDs) are associated with pathophysiological changes in the LESC niche, with some inhibitory interception such as UV-B irradiation, which results in corneal defects. PMID- 23668790 TI - Nucleotides metabolizing ectoenzymes as possible markers of mesenchymal stem cell osteogenic differentiation. AB - Growing murine mesenchymal stem cells (mMSCs) from mouse bone marrow decreased their rate of proliferation in the presence of benzoylbenzoyl-ATP persistently, but the inhibitory effect of ATP was strong only in a concentration of 50 MUmol.L(-1) and lasted for 48 h in culture. These results hinted at ATP hydrolysis by the cell surface enzymes at the lower concentrations and thus it may be not able to inhibit MSCs. By using ATP, ADP, or AMP as substrates, we tested the ectonucleotidase activity on the surface of undifferentiated MSCs and MSC-derived osteoblasts. Here, we report that although nucleoside triphosphate diphosphohydrolase (NTPDase)1 and NTPDase8 are engaged in the metabolism of ATP in MSC-derived osteoblasts, NTPDase3 is responsible for its metabolism in undifferentiated MSCs. In this study, we also realized that osteoblasts effectively metabolize ADP to ATP and AMP. The enzymatic activity of adenylate kinase (AK) is consistent with the high expression level of the AK gene. Therefore, it was tempting to suggest that this enzyme, together with NTPDase1 and NTPDase8, assume the role of specific markers that allowed distinction between differentiated osteoblasts and early undifferentiated MSCs. Additionally, unlike osteoblasts, undifferentiated MSCs demonstrated the activity of 5' nucleotidase (CD73). However, the expression analysis of CD73 mRNA did not show any differences; CD73 mRNA was expressed in both kinds of cells to the same extent. PMID- 23668791 TI - Raman microspectroscopy as a diagnostic tool to study single living nasopharyngeal carcinoma cell lines. AB - Raman spectroscopy can provide molecular-level fingerprint information about the biochemical composition and structure of cells and tissues with excellent spatial resolution. In this study, Raman spectroscopy of 3 different nasopharyngeal carcinoma cell lines C666-1, CNE1, and CNE2 and 1 nasopharyngeal normal cell line NP69 acquired on a piece of silica glass slide are presented to investigate the differences among them. The results show the ratio of I1657/I1449 (= 0.7) could provide good distinction between tumor and normal cell lines very easily, which coincides with existing reports about the study of different cell lines and bronchial tissue. In addition, several statistical analytical methods were used to classify these 4 different cell lines and then achieved an exciting result with great sensitivity and specificity of >90%, respectively. The findings of this work further support former work where cells' Raman spectra were acquired on a different substrate. All of these results indicate Raman spectroscopy has the potential to discriminate between normal and tumor cells and have potential use in early diagnosis of nasopharyngeal carcinoma. PMID- 23668792 TI - Regulation of transforming growth factor beta 1 gene expression by dihydropteridine reductase in kidney 293T cells. AB - Quinoid dihydropteridine reductase (QDPR) is an enzyme involved in the metabolic pathway of tetrahydrobiopterin (BH4). BH4 is an essential cofactor of nitric oxide synthase (NOS) and can catalyze arginine to citrulline to release nitric oxide. Point mutations of QDPR have been found in the renal cortex of spontaneous Otsuka Long Evans Tokushima Fatty (OLETF) diabetic rats. However, the role of QDPR in DN is not clear. This study investigates the effects of QDPR overexpression and knockdown on gene expression in the kidney. Rat QDPR cDNA was cloned into pcDNA3.1 vector and transfected in human kidney cells (293T). The expression of NOS, transforming growth factor beta 1 (TGF-beta1), Smad3, and NADPH oxidase were examined by RT-PCR and Western blot analyses. BH4 was assayed by using ELISA. Expression of QDPR was significantly decreased and TGF-beta1 and Smad3 were increased in the renal cortex of diabetic rats. Transfection of QDPR into 293T cells increased the abundance of QDPR in cytoplasm and significantly reduced the expression of TGF-beta1, Smad3, and the NADPH oxidases NOX1 and NOX4. Moreover, abundance of neuronal NOS (nNOS) mRNA and BH4 content were significantly increased. Furthermore, inhibition of QDPR resulted in a significant increase in TGF-beta1 expression. In conclusion, QDPR might be an important factor mediating diabetic nephropathy through its regulation of TGF beta1/Smad3 signaling and NADPH oxidase. PMID- 23668793 TI - Congenital asymptomatic diaphragmatic hernias in adults: a case series. AB - INTRODUCTION: Congenital diaphragmatic hernia is a major malformation occasionally found in newborns and babies. Congenital diaphragmatic hernia is defined by the presence of an orifice in the diaphragm, more often to the left and posterolateral, that permits the herniation of abdominal contents into the thorax. The aim of this case series is to provide information on the presentation, diagnosis and outcome of three patients with late-presenting congenital diaphragmatic hernias. The diagnosis of congenital diaphragmatic hernia is based on clinical investigation and is confirmed by plain X-ray films and computed tomography scans. CASE PRESENTATIONS: In the present report three cases of asymptomatic abdominal viscera herniation within the thorax are described. The first case concerns herniation of some loops of the large intestine into the left hemi-thorax in a 75-year-old Caucasian Italian woman. The second case concerns a rare type of herniation in the right side of the thorax of the right kidney with a part of the liver parenchyma in a 57-year-old Caucasian Italian woman. The third case concerns herniation of the stomach and bowel into the left side of the chest with compression of the left lung in a 32-year-old Caucasian Italian man. This type of hernia may appear later in life, because of concomitant respiratory or gastrointestinal disease, or it may be an incidental finding in asymptomatic adults, such as in the three cases featured here. CONCLUSIONS: Patients who present with late diaphragmatic hernias complain of a wide variety of symptoms, and diagnosis may be difficult. Additional investigation and research appear necessary to better explain the development and progression of this type of disease. PMID- 23668794 TI - Oxidative stress and APO E polymorphisms in Alzheimer's disease and in mild cognitive impairment. AB - A number of evidences indicates oxidative stress as a relevant pathogenic factor in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Considering its recognized major genetic risk factors in AD, apolipoprotein (APO E) has been investigated in several experimental settings regarding its role in the process of reactive oxygen species (ROS) generation. The aim of this work has been to evaluate possible relationships between APO E genotype and plasma levels of selected oxidative stress markers in both AD and MCI patients. APO E genotypes were determined using restriction enzyme analysis. Plasma levels of oxidative markers, advanced oxidation protein products, iron-reducing ability of plasma and, in MCI, activity of superoxide dismutases were evaluated using spectrophotometric analysis. We found, compared to controls, increased levels of oxidized proteins and decreased values of plasma-reducing capacity in both AD patients (p < 0.0001) and MCI patients (p < 0.001); the difference between AD and MCI patients was significant only for plasma-reducing capacity (p < 0.0001), the former showing the lowest values. Superoxide dismutase activity was reduced, although not at statistical level, in MCI compared with that in controls. E4 allele was statistically associated (p < 0.05) with AD patients. When comparing different APO E genotype subgroups, no difference was present, as far as advanced oxidation protein products and iron-reducing ability of plasma levels were concerned, between E4 and non-E4 carriers, in both AD and MCI; on the contrary, E4 carriers MCI patients showed significantly decreased (p < 0.05) superoxide dismutase activity with respect to non-E4 carriers. This study, in confirming the occurrence of oxidative stress in AD and MCI patients, shows how it can be related, at least for superoxide dismutase activity in MCI, to APO E4 allele risk factor. PMID- 23668795 TI - The relationship between root concavities in first premolars and chronic periodontitis. AB - OBJECTIVE: To evaluate the significance of first premolar root concavity on clinical indices of chronic periodontal disease and alveolar bone defects. METHODS: Three-dimensional reconstruction by cone beam computed tomography was used to observe root surface anatomy and the type of alveolar bone defect seen in the mesial and distal sites of 272 first premolars from 99 patients who had presented with chronic periodontitis. Periodontal clinical indicators at each site were measured using a Florida Probe Corporation (Gainesville, FL, USA). RESULTS: The incidence of mesial and distal root concavities of the maxillary first premolars was 100% and 39.3% respectively, and in the mandibular, the incidence was 42.5% and 31.3% respectively. The distributions of the different types of concavities in terms of both age and gender of the patients were not statistically significant. The mean probing depth and clinical attachment loss of the first premolars with root concavities were significantly higher than those without concavity (p < 0.05). Plaque accumulation was significantly different in the premolars with/without root concavities (p < 0.001). The type of alveolar bone defects with concavities was significantly different from those without concavities (p < 0.05). Ramp shape bone defects were dominant for teeth without concavities, while crater shape was seen for teeth with concavities. CONCLUSION: Root concavities of the first premolars were associated with periodontal disease, and the type of interproximal alveolar bone defect. Root concavities may be important in contributing to local periodontal disease of the first premolars. PMID- 23668796 TI - Dynamics behind the long-lived coherences of I2 in solid Xe. AB - The absorption spectrum of I2 in solid Xe shows resolved zero-phonon lines and phonon side bands near the origin of the B<-X transition (550-625 nm). The long lived |B??X| coherence in this energy range (T2 = 600 fs on average) emerges as vibrationally unrelaxed fluorescence in resonance Raman (RR) spectra. Upon excitation in the structureless continuum at 532 nm, the oscillatory RR progression exhibits electronic dephasing time of T2 = 150 fs. Two RR progressions with markedly different vibrational coherence on the X-state are observed. The main progression of sharp overtones (T2 > 21 ps) is assigned to molecules trapped in double-substitution sites. The minor progression, which shows dephasing times T2 = 6-0.6 ps for v = 1-8, is assigned to molecules in triple-substitution sites. The line progressions allow a detailed characterization of the solvated B- and X-state potentials. Time-resolved coherent anti-Stokes Raman scattering is used to probe selected vibrational coherences on the X-state. Assignments are obtained through molecular dynamics simulations, which reproduce the relative dephasing rates between the two sites, clarify the role of rotation-translation dynamics, and enable quantum dynamics simulations of the spectra by the potentials of mean force that accurately describe the molecule-surrounding interactions. PMID- 23668797 TI - Effect of cross-linkers in fabrication of carrageenan-alginate matrices for tissue engineering application. AB - The three-dimensional (3D) scaffold serves as a structural substrate and as a niche for cell proliferation to ensure tissue regeneration. Ideal scaffolds should have porous structures with high pore interconnectivity to allow cell adherence, differentiation, and proliferation while ensuring suitable mechanical strength and biodegradability without inflicting any immune response. Cross linker is one of the major factors that affect the mechanical and biological properties of scaffolds. In this study, different chemical cross-linker effects on scaffold architecture were examined. Porous 3D scaffolds based on carrageenan and alginate (CA) were successfully fabricated by a freeze-drying technique and using various cross-linkers like glutaraldehyde (GA), genipin, and ethyl (dimethylamino propyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS). The chemical cross-linker effects on the CA scaffold were characterized by scanning electron microscopy, differential scanning calorimetry, and thermogravimetry. A human fibroblast cell line (L929) was seeded into the fabricated scaffold, and cell proliferation was assessed by MTT and live/dead assay. Overall results suggested the potential cross-linkers for ideal CA biomaterial could be EDC/NHS among other agents tested as the scaffold CAEN was found to be porous, interconnected, and physically and mechanically stable. When compared to matrices with other cross linkers, higher cell attachment, better cellular response, and higher metabolic activity could be observed in the scaffold synthesized using EDC/NHS as cross linker. PMID- 23668798 TI - Inelastic X-ray scattering of a transition-metal complex (FeCl4(-)): vibrational spectroscopy for all normal modes. AB - The tetraethylammonium salt of the transition-metal complex FeCl4(-) has been examined using inelastic X-ray scattering (IXS) with 1.5 meV resolution (12 cm( 1)) at 21.747 keV. This sample serves as a feasibility test for more elaborate transition-metal complexes. The IXS spectra were compared with previously recorded IR, Raman, and nuclear resonant vibrational spectroscopy (NRVS) spectra, revealing the same normal modes but with less strict selection rules. Calculations with a previously derived Urey-Bradley force field were used to simulate the expected Q and orientation dependence of the IXS intensities. The relative merits of IXS, compared to other photon-based vibrational spectroscopies such as NRVS, Raman, and IR, are discussed. PMID- 23668799 TI - Longitudinal associations between adolescent perceived degree and style of parental prohibition and internalization and defiance. AB - This study examined associations between perceived degree and style of parental prohibition and adolescents' internalization of and oppositional defiance against parental rules in the friendship and moral domain. Relations were investigated in 2 longitudinal adolescent samples (total N = 532). Results indicated that perceived style but not degree of prohibition related to overtime changes in internalization and oppositional defiance. Specifically, in line with self determination theory, autonomy-supportive and controlling styles of prohibiting were found to relate differentially to quality of internalization and oppositional defiance. Cross-lagged analyses indicated that several of these associations were reciprocal. The discussion focuses on the critical role of perceived parental style for communicating prohibitions. PMID- 23668800 TI - Preference for point-light human biological motion in newborns: contribution of translational displacement. AB - In human newborns, spontaneous visual preference for biological motion is reported to occur at birth, but the factors underpinning this preference are still in debate. Using a standard visual preferential looking paradigm, 4 experiments were carried out in 3-day-old human newborns to assess the influence of translational displacement on perception of human locomotion. Experiment 1 shows that human newborns prefer a point-light walker display representing human locomotion as if on a treadmill over random motion. However, no preference for biological movement is observed in Experiment 2 when both biological and random motion displays are presented with translational displacement. Experiments 3 and 4 show that newborns exhibit preference for translated biological motion (Experiment 3) and random motion (Experiment 4) displays over the same configurations moving without translation. These findings reveal that human newborns have a preference for the translational component of movement independently of the presence of biological kinematics. The outcome suggests that translation constitutes the first step in development of visual preference for biological motion. PMID- 23668801 TI - Spatially resolved correlation of active and total doping concentrations in VLS grown nanowires. AB - Controlling axial and radial dopant profiles in nanowires is of utmost importance for NW-based devices, as the formation of tightly controlled electrical junctions is crucial for optimization of device performance. Recently, inhomogeneous dopant profiles have been observed in vapor-liquid-solid grown nanowires, but the underlying mechanisms that produce these inhomogeneities have not been completely characterized. In this work, P-doping profiles of axially modulation-doped Si nanowires were studied using nanoprobe scanning Auger microscopy and Kelvin probe force microscopy in order to distinguish between vapor-liquid-solid doping and the vapor-solid doping. We find that both mechanisms result in radially inhomogeneous doping, specifically, a lightly doped core surrounded by a heavily doped shell structure. Careful design of dopant modulation enables the contributions of the two mechanisms to be distinguished, revealing a surprisingly strong reservoir effect that significantly broadens the axial doping junctions. PMID- 23668802 TI - Expression of Toll-like receptor-3 is enhanced in active inflammatory bowel disease and mediates the excessive release of lipocalin 2. AB - Anti-microbial peptides might influence the pathogenesis and course of inflammatory bowel disease (IBD). We sought to clarify the role of the anti microbial glycoprotein lipocalin 2 (LCN2) in the colon by determining its localization and regulation in IBD. Following a microarray gene expression study of colonic biopsies from a large IBD population (n = 133), LCN2 was localized using immunohistochemistry and in-situ hybridization. Moreover, we examined the regulation of LCN2 in HT-29 cells with a panel of pattern recognition receptors (PRRs) and sought evidence by immunohistochemistry that the most relevant PRR, the Toll-like receptor (TLR)-3, was indeed expressed in colonic epithelium in IBD. LCN2 was among the 10 most up-regulated genes in both active ulcerative colitis (UCa) and active Crohn's disease (CDa) versus healthy controls. LCN2 protein was found in both epithelial cells and infiltrating neutrophils, while mRNA synthesis was located solely to epithelial cells, indicating that de-novo synthesis and thus regulation of LCN2 as measured in the gene expression analysis takes place in the mucosal epithelial cells. LCN2 is a putative biomarker in faeces for intestinal inflammation, different from calprotectin due to its epithelial site of synthesis. LCN2 release from the colonic epithelial cell line HT-29 was enhanced by both interleukin (IL)-1beta and the TLR-3 ligand poly(I:C), and TLR-3 was shown to be expressed constitutively in colonic epithelial cells and markedly increased during inflammation. PMID- 23668803 TI - Jervell and Lange-Nielsen syndrome in a father and daughter from a large highly inbred family: a 16-year follow-up of 59 living members. AB - OBJECTIVE: To report the autosomal dominant inheritance of the Jervell and Lange Nielsen syndrome in a highly inbred family, the initiation of Torsades de Pointes, and the natural history of the syndrome based on a 16-year follow-up of the kindred. METHOD: A family tree was constructed that included 66 blood relatives from three successive generations. Electrocardiograms were obtained from 59 living members including the proband, four members from a nuclear family, and 54 from the extended family. Evoked response audiometry was recorded for the proband and the nuclear family. All 59 family members were followed up regularly for 16 years. RESULTS: A total of 24 living members were affected--QTc: 480-680 ms. The proband had long QTc, bilateral high-tone sensorineural deafness, recurrent syncope, and Torsades de Pointes. The asymptomatic father had long QTc and unilateral high-tone sensorineural deafness that involved specifically the left ear. One asymptomatic sibling of the proband had long QTc and normal hearing. The mother and another sibling were asymptomatic; QTc and hearing were normal in both. A total of 21 affected members from the extended family had only long QTc, and all were asymptomatic. There were three congenitally deaf first cousins who had recurrent syncope and adrenergic-triggered sudden death. In all, seven of 10 parents had consanguineous marriage to a first cousin. Each affected offspring had at least one affected parent. The severely symptomatic proband who received only beta-blocker therapy and the 23 affected members without antiadrenergic therapy, all remained asymptomatic throughout the 16-year follow up period. CONCLUSION: Jervell and Lange-Nielsen syndrome was inherited as autosomal dominant in this kindred. The majority of the affected members had a mild phenotype. The severity of auditory and cardiac phenotypes corresponded. PMID- 23668804 TI - Possible usefulness of tianeptine in treatment-resistant depression. AB - OBJECTIVE: Tianeptine is an atypical antidepressant drug, augmenting serotonin reuptake and preventing stress-associated changes in the brain. In this paper, we present the use of tianeptine in eight American treatment-resistant patients with major depressive disorder. METHODS: Two male and six female patients with major depressive disorder, aged 44-72 years with duration of the illness 3-40 years, were studied. All met criteria for treatment-resistant depression (TRD) as they failed four or more trials of medication, and two failed both ECT and Vagal Nerve Stimulation trials. In three patients, the drug was used as monotherapy, and in five, it was added to ongoing antidepressant treatment. RESULTS: The remission (<= 7 points on the 17-item Hamilton Depression Rating Scale) after 8 weeks of treatment was obtained in four female patients (50%). Of them, three still require other psychotropic medications to remain in remission and all four responders have been in remission with ongoing treatment with tianeptine for > 2 years. In two patients, the drug was terminated due to the incidence of delirium, and in one, it was due to severe agitation. CONCLUSION: The results may suggest a possible usefulness of tianeptine in selected patients with TRD. They also point to a possible serious side effect of this drug not hitherto reported. PMID- 23668805 TI - Fatal hypersensitivity reaction to an oral spray of flurbiprofen: a case report. AB - WHAT IS KNOWN AND OBJECTIVE: Safety of the anti-inflammatory drug flurbiprofen is comparable with that of other non-steroidal anti-inflammatory drugs of the propionic acid class, which are commonly associated with gastrointestinal and renal side effects. Here we report a case of a fatal hypersensitivity reaction to an oral spray of flurbiprofen taken for sore throat. CASE SUMMARY: A 29-year-old man came to the emergency care unit reporting sore throat with an intense burning sensation associated with fever. Pharyngotonsillitis was diagnosed, and local treatment with oral flurbiprofen spray was prescribed. Immediately after using the spray, the patient experienced a severe reaction characterized by serious dyspnoea, followed by death. The cause of death was heart failure with acute asphyxia from oedema of the glottis. The cause of death was concluded to be hypersensitivity to flurbiprofen spray. WHAT IS NEW AND CONCLUSION: Oral propionic acid derivatives have been associated with a relatively high frequency of allergic reactions. However, allergy to flurbiprofen has rarely been documented. Scientific literature reports two relevant cases of hypersensitivity reaction to flurbiprofen: in one case, a patient presented with a maculopapular rash 48 h after having taken oral flurbiprofen followed by angio-oedema and hypotension. In another case, a single oral dose of flurbiprofen caused itching and swelling around the eyes, redness and increased lacrimation. We describe, for the first time, a fatal case of hypersensitivity reaction to flurbiprofen oral spray. Hypersensitivity reactions to flurbiprofen are infrequent; however, health professionals should be aware of potential adverse reactions, even during topical administration as oral spray. PMID- 23668807 TI - Underlying protective mechanism of alpha1-adrenoceptor activation against irradiation-induced damage in rat submandibular gland. AB - OBJECTIVES: Damage to salivary gland after radiotherapy for head and neck malignant tumours can lead to irreversible oral complaints, which severely impair quality of life. The protective effect of alpha1-adrenoceptor activation on the salivary glands after irradiation has previously been demonstrated. However, the exact mechanism remains unclear. In this study, we investigated the underlying cytoprotective mechanism of alpha1-adrenoceptor activation in rat submandibular glands after irradiation. STUDY DESIGN: Rats were locally irradiated using a linear accelerator in the head and neck region with a dose of 20Gy. After irradiation, phenylephrine (5mg/kg) was injected intraperitoneally for 7 successive days and the submandibular glands were then collected. The antiapoptotic effect of phenylephrine on the gland was examined by TUNEL, the proliferative cellular nuclei antigen (PCNA) was determined by immunohistochemistry, and the activation of c-Jun N-terminal kinase (JNK) was detected by Western blot. RESULTS: The irradiation only group showed severe atrophy, increased apoptosis, enhanced cell proliferation, and the phosphorylation of JNK was markedly increased by 26.89% (P<0.05), compared to the control. The phenylephrine-treated group, however, showed remarkably alleviated atrophy, decreased apoptosis, and further increased cell proliferation, and the phosphorylation of JNK was markedly decreased by 36.00% (P<0.05), compared to the irradiation only group. CONCLUSIONS: The data showed that the underlying protective mechanism of alpha1-adrenoceptor activation in irradiated gland might be related to improved cell proliferation, inhibited cell apoptosis, and depressed activation of JNK. It could be helpful in protecting salivary glands against irradiation damage. PMID- 23668808 TI - Re-categorisation of male lower urinary tract symptoms based on the international prostate symptom score questionnaire. AB - AIMS: The purpose of this study was to develop a new sub-classification system for male lower urinary tract symptoms (LUTS)-mild, moderate and severe-using the conventional International Prostate Symptoms Score (I-PSS). METHODS: From October 2007 to March 2012, a total of 2234 male patients (>= 50 years old) presenting with LUTS were enrolled in this study. Patients were sorted according to their I PSS (ranging from 1 to 35 points) and divided into three groups based on their quality of life (QoL) score. A chi-square automatic interaction detection (CHAID) algorithm, based on adjusted significance testing, was used. The Kappa coefficient was calculated for the agreement of original and new categorisation. RESULTS: Mean total I-PSS and QoL scores were 11.0 and 2.9 respectively. According to the original classification, 838 patients (38.6%) had mild, 1053 (48.5%) had moderate and 282 (13.0%) had severe symptoms. After the CHAID algorithm was applied, the scores were re-categorised as 'mild' (1-6 points), 'moderate' (7-21 points) and 'severe' (22-35 points). The overall model was able to correctly predict whether an I-PSS was associated with mild, moderate or severe symptoms, with 70.1% accuracy. According to this new classification, 704 patients (32.4%) were shown to have mild, 1255 (57.8%) to have moderate and 214 (9.8%) to have severe LUTS. The agreement of conventional and new categorisation is very strong (Kappa coefficient = 0.84). CONCLUSIONS: Conventional categorisation of LUTS by I-PSS needs to be updated and the category of moderate LUTS should be broadened. PMID- 23668806 TI - Association of IL-4 and IL-10 maternal haplotypes with immune responses to P. falciparum in mothers and newborns. AB - BACKGROUND: Particular cytokine gene polymorphisms are involved in the regulation of the antibody production. The consequences of already described IL-4, IL-10 and IL-13 gene polymorphisms on biological parameters and antibody levels were investigated among 576 mothers at delivery and their newborns in the context of P. falciparum placental malaria infection. METHODS: The study took place in the semi-rural area of Tori-Bossito, in south-west Benin, where malaria is meso endemic. Six biallelic polymorphisms were determined by quantitative PCR using TaqMan(r) Pre-Designed SNP Genotyping Assays, in IL-4 (rs2243250, rs2070874), IL 10 (rs1800896, rs1800871, rs1800872) and IL-13 (rs1800925) genes. Antibody responses directed to P. falciparum MSP-1, MSP-2, MSP-3, GLURP-R0, GLURP-R2 and AMA-1 recombinant proteins were determined by ELISA. RESULTS: The maternal IL-4( 590)*T/IL-4(+33)*T haplotype (one or two copies) was associated with favorable maternal condition at delivery (high haemoglobin levels, absence of placental parasites) and one of its component, the IL-4(-590)TT genotype, was related to low IgG levels to MSP-1, MSP-2/3D7 and MSP-2/FC27. Inversely, the maternal IL-10( 1082)AA was positively associated with P. falciparum placenta infection at delivery. As a consequence, the IL-10(-819)*T allele (in CT and TT genotypes) as well as the IL-10(-1082)*A/IL-10(-819)*T/IL-10(-592)*A haplotype (one or two copies) in which it is included, were related to an increased risk for anaemia in newborns. The maternal IL-10(-1082)AA genotype was related to high IgG levels to MSP-2/3D7 and AMA-1 in mothers and newborns, respectively. The IL-13 gene polymorphism was only involved in the newborn's antibody response to AMA-1. CONCLUSION: These data revealed that IL-4 and IL-10 maternal gene polymorphisms are likely to play a role in the regulation of biological parameters in pregnant women at delivery (anaemia, P. falciparum placenta infection) and in newborns (anaemia). Moreover, IL-4, IL-10 and IL-13 maternal gene polymorphisms were related to IgG responses to MSP-1, MSP-2/3D7 and MSP-2/FC27 in mothers as well as to AMA-1 in newborns. PMID- 23668809 TI - HIV/AIDS stigma: measurement and relationships to psycho-behavioral factors in Latino gay/bisexual men and transgender women. AB - Despite the increased interest in HIV/AIDS stigma and its negative effects on the health and social support of people living with HIV/AIDS (PLWHA), little attention has been given to its assessment among Latino gay/ bisexual men and transgender women (GBT) living with HIV/AIDS. The purpose of this paper is twofold: to develop a multidimensional assessment of HIV/AIDS stigma for Latino GBT living with HIV/AIDS, and to test whether such stigma is related to self esteem, safe sex self-efficacy, social support, and alcohol, and drug use. The sample included 170 HIV+ Latino GBT persons. The results revealed three dimensions of stigma: internalized, perceived, and enacted HIV/AIDS stigma. Enacted HIV/AIDS stigma comprised two domains: generalized and romantic and sexual. Generalized enacted HIV/AIDS stigma was related to most outcomes. Internalized HIV/AIDS stigma mediated the associations between generalized enacted HIV/AIDS stigma and self-esteem and safe sex self-efficacy. In addition, romantic and sexual enacted HIV/AIDS stigma significantly predicted drug use. Perceived HIV/AIDS stigma was not associated with any outcome. These findings expand the understanding of the multidimensionality of stigma and the manner in which various features impact marginalized PLWHA. PMID- 23668810 TI - Antineoplastic drug contamination of surfaces throughout the hospital medication system in Canadian hospitals. AB - We previously reported that there is a potential for antineoplastic drug contamination throughout the hospital medication system (process flow of drug within a facility from delivery to waste disposal) due to the various surfaces contacted by health care workers. This article describes the contamination of these frequently contacted surfaces as well as identifies factors that may be associated with surface contamination. Surfaces which health care workers frequently contact were wiped and the concentration of cyclophosphamide (CP) was determined using high-performance liquid chromatography-tandem mass spectrometry. Descriptive and inferential statistical analyses were performed. A backward stepwise multiple linear regression was conducted to identify determinants associated with surface contamination. Overall, 229 surfaces were sampled, most on two occasions, for a total of 438 surface wipes. The mean CP concentration was 0.201 ng/cm(2), the geometric mean 0.019 ng/cm(2), and the geometric standard deviation 2.54, with a range of less than detection (LOD) to 26.1 ng/cm(2). (Method LOD was 0.356 ng/wipe; factoring in the surface area of the wiped surface, results in a sample LOD ranging from 0.00 to 0.049 ng/cm(2)). Our study found that frequently contacted surfaces at every stage of the hospital medication system had measureable levels of antineoplastic drug contamination. Two factors were statistically significant with respect to their association with surface contamination: (1) the stage of the hospital medication system, and (2) the number of job categories responsible for drug transport. The drug preparation stage had the highest average contamination. Those hospitals that had two or more drug transport job categories had higher levels of surface contamination. Neither the reported handling of CP prior to wipe sampling nor the cleaning of surfaces appeared to be associated with contamination. PMID- 23668811 TI - Non-thermal plasma treatment is associated with changes in transcriptome of human epithelial skin cells. AB - Non-thermal atmospheric pressure plasma has recently gained attention in the field of biomedical and clinical applications. In the area of plasma medicine research, one promising approach is to promote wound healing by stimulation of cells involved. To understand basic molecular and cellular mechanisms triggered by plasma treatment, we investigated biological effects of an argon plasma jet kinpen on human epithelial skin cells. For assessment of transcriptome changes cell culture medium was plasma treated and applied to the HaCaT keratinocyte cell culture (indirect treatment). Consequently, whole-genome microarrays were used to analyze this interaction in detail and identified a statistically significant modification of 3,274 genes including 1,828 up- and 1,446 downregulated genes. Particularly, cells after indirect plasma treatment are characterized by differential expression of a considerable number of genes involved in the response to stress. In this regard, we found a plasma-dependent regulation of oxidative stress answer and increased expression of enzymes of the antioxidative defense system (e.g. 91 oxidoreductases). Our results demonstrate that plasma not only induces cell reactions of stress-sensing but also of proliferative nature. Consistent with gene expression changes as well as Ingenuity Pathway Analysis prediction, we propose that stimulating doses of plasma may protect epithelial skin cells in wound healing by promoting proliferation and differentiation. In conclusion, gene expression profiling may become an important tool in identifying plasma-related changes of gene expression. Our results underline the enormous clinical potential of plasma as a biomedical tool for stimulation of epithelial skin cells. PMID- 23668813 TI - Successful treatment of an unintentional tattoo on the ala after the removal of nose piercings. PMID- 23668812 TI - Successful heart transplantation from a donor with Ullrich congenital muscular dystrophy. AB - Heart transplantation is the most effective therapy for children with end-stage heart disease; however, its use is limited by the number of donor organs available. This shortage may be further compounded by concerns about organ quality, leading to refusal of potential donor organ offers. We report on the successful transplantation and 5-year follow-up of a heart from a donor with Ullrich congenital muscular dystrophy (UCMD). The candidate was critically ill at the time of the transplant and the donor organ was declined repeatedly on the match run list due to concerns about organ quality, despite having normal cardiac function by echocardiography on minimal inotropic support. We believe the diagnosis of "muscular dystrophy" in the donor combined with a lack of understanding about the specifics of the diagnosis of UCMD enabled our candidate to receive a primary offer for this organ. We are unaware of any previous reports of the use of a heart from a donor with UCMD for orthotopic heart transplantation in adults or children. PMID- 23668814 TI - Model complexity needed for quantitative analysis of high resolution isotope and concentration data from a toluene-pulse experiment. AB - Separating microbial- and physical-induced effects on the isotope signals of contaminants has been identified as a challenge in interpreting compound-specific isotope data. In contrast to simple analytical tools, such as the Rayleigh equation, reactive-transport models can account for complex interactions of different fractionating processes. The question arises how complex such models must be to reproduce the data while the model parameters remain identifiable. In this study, we reanalyze the high-resolution data set of toluene concentration and toluene-specific delta(13)C from the toluene-pulse experiment performed by Qiu et al. (this issue). We apply five reactive-transport models, differing in their degree of complexity. We uniquely quantify degradation and sorption properties of the system for each model, estimate the contributions of biodegradation-induced, sorption-induced, and transverse-dispersion-induced isotope fractionation to the overall isotope signal, and investigate the error introduced in the interpretation of the data when individual processes are neglected. Our results show that highly resolved data of both concentration and isotope ratios are needed for unique process identification facilitating reliable model calibration. Combined analysis of these highly resolved data demands reactive transport models accounting for nonlinear degradation kinetics and isotope fractionation by both reactive and physical processes such as sorption and transverse dispersion. PMID- 23668815 TI - Attachment of alginate microcapsules onto plasma-treated PDMS sheet for retrieval after transplantation. AB - Although transplantation of microencapsulated islets has been proposed as a therapy for the treatment of diabetes mellitus, limited retrievability of the cells has impeded its medical usage. To achieve retrieval of microencapsulated islets, capsules were attached to polydimethylsiloxane (PDMS) with a biocompatible adhesive. Because the hydrophobic nature of the PDMS surface prevents attachment, surface modification is essential. Alginate microcapsules were attached to modified PDMS sheets, and the mechanical stability of the resulting constructs was determined. Acrylic acid (AA) and acrylamide (AM) mixtures were grafted on the surfaces of PDMS sheets using a two-step oxygen plasma treatment (TSPT). TSPT-PDMS was characterized according to water contact angle and zeta-potential measurements. The contact angle was altered by changing the ratio of AM to AA to generate hydrophilic surface. Evaluation of the surface charge at pH 2, 7, and 12 confirmed the presence of polar groups on the modified surface. Microcapsules were attached to TSPT-PDMS using Histoacryl(r) and shown to be in a monolayered and half-exposed state. The shear stress resistance of alginate capsules attached to the PDMS sheet indicates the possibility of transplantation of encapsulated cells without scattering in vivo. This method is applicable to retrieve microencapsulated porcine islets when required. PMID- 23668816 TI - Ensuring that blood transfusion sets administer an effective dose of functional blood components. AB - BACKGROUND: Proposed changes to ISO 1135-4 will require that blood transfusion administration sets are demonstrated by the manufacturers to be suitable for the range of cellular and plasma blood components for which they are designated. AIMS: To design a test protocol to asses the depletion of the blood components by transfusion sets and damage and activation of blood components during their passage through the set. METHODS: Transfusion giving sets (CareFusion Ref no. 60895 180311 and Fresenius Ref no. 2900032) were assessed by comparing samples of the blood component taken prior to and after passage through the transfusion set in strict accordance with the manufacturer's instructions. As well as depletion of red cells, platelets and FVIIIc, the following markers of damage/activation were assessed: red cells-supernatant haemolysis and potassium; FFP-prothrombin fragments 1 and 2 and fibrinopeptide A and platelets-pH, CD62P, CD63 and sP selectin. RESULTS: The CareFusion and the Fresenius transfusion sets gave less than 5% depletion of blood components and caused negligible and clinically insignificant effects on red cells, platelet concentrates and FFP. CONCLUSION: A practical test protocol has been established to assess the depletion, damage to and activation of the key constituents of commonly requested blood components. This protocol would provide a valuable addition to ISO 1135-4 in assuring the suitability of transfusion sets. PMID- 23668817 TI - Reappraisal and suppression mediate the contribution of regulatory focus to anxiety in healthy adults. AB - Theory and research link regulatory focus (RF) in the form of promotion and prevention goal orientation with internalizing symptoms (e.g., anxiety), but the relevant mechanisms are not well understood. This study investigated the role of two emotion regulation (ER) strategies (cognitive reappraisal and expressive suppression) as possible mediators. Path analysis using data from 179 healthy young participants (110 women, 69 men) revealed that stronger promotion orientation was significantly associated with less anxiety, and that the use of reappraisal and suppression partially mediated this association. Prevention was associated with more suppression but was not directly associated with anxiety. There were no gender differences in these effects. Collectively, these findings suggest that effective ER, through heightened use of reappraisal and dampened use of suppression, serves as a mechanism through which promotion confers protection against anxiety. This research provides empirical support to initiatives aimed at promoting healthy psychological adjustment and preventing anxiety, by optimizing ER strategies with respect to RF goal orientations. PMID- 23668818 TI - Do people essentialize emotions? Individual differences in emotion essentialism and emotional experience. AB - Many scientific models of emotion assume that emotion categories are natural kinds that carve nature at its joints. These beliefs remain strong, despite the fact that the empirical record on the issue has remained equivocal for over a century. In this research, the authors examined one reason for this situation: People essentialize emotion categories by assuming that members of the same category (e.g., fear) have a shared metaphysical essence (i.e., a common causal mechanism). In Study 1, the authors found that lay people essentialize emotions by assuming that instances of the same emotion category have a shared essence that defines them, even when their surface features differ. Study 2 extended these findings, demonstrating that lay people tend to essentialize categories the more a category is of the body (vs. the mind). In Study 3, we examined the links between emotion essentialism and the complexity of actual emotional experiences. In particular, we predicted and found that individuals who hold essentialist beliefs about emotions describe themselves as experiencing highly differentiated emotional experiences but do not show evidence of stronger emotional differentiation in their momentary ratings of experience in everyday life. Implications for the science of emotion are discussed. PMID- 23668819 TI - Involvement of oxidative stress associated with glutathione depletion and p38 mitogen-activated protein kinase activation in arsenic disulfide-induced differentiation in HL-60 cells. AB - Arsenic disulfide (As2S2) has been traditionally used to treat certain types of leukemia. However, a detailed mechanism of action of As2S2 is not sufficiently documented. The effects of As2S2 on HL-60 cells were therefore investigated by focusing on proliferation, differentiation, generation of reactive oxygen species (ROS), intracellular glutathione (GSH) depletion and activation of p38 mitogen activated protein kinase (MAPK). As2S2 at 0.5-8 MUM induced cell differentiation based on an increment in CD11b expression, nitroblue tetrazolium (NBT)-positive cells and cell size change. A transient increase in ROS level along with intracellular GSH level was also observed. p38 MAPK activation gradually increased after ROS generation and was sustained during cell differentiation. Decreased CD11b expression was accompanied by p38 MAPK activation, and a p38 MAPK inhibitor restored CD11b expression. The results suggest that moderate levels of oxidative stress induced by As2S2 correlate with HL-60 cell differentiation. Suppression of p38 MAPK can augment the efficacy of As2S2 to induce HL-60 cell differentiation. PMID- 23668820 TI - CD1d expression as a prognostic marker for chronic lymphocytic leukemia. AB - We analyzed the expression of CD1d, an antigen-presenting molecule, on peripheral blood leukemic cells of cases of chronic lymphocytic leukemia (CLL) by flow cytometry. We demonstrated variable expression of CD1d on leukemic lymphocytes and an association between high expression of CD1d with shorter time to treatment and overall survival of patients. CD1d was positively associated with CD38 expression, but not with unmutated heavy chain variable (VH) mutational status or adverse cytogenetics of leukemic lymphocytes. Our findings support that CD1d expression is a prognostic marker for CLL. PMID- 23668821 TI - Impaired removal of Vbeta8(+) lymphocytes aggravates colitis in mice deficient for B cell lymphoma-2-interacting mediator of cell death (Bim). AB - We investigated the role of B cell lymphoma (BCL)-2-interacting mediator of cell death (Bim) for lymphocyte homeostasis in intestinal mucosa. Lymphocytes lacking Bim are refractory to apoptosis. Chronic colitis was induced in Bim-deficient mice (Bim(-/-) ) with dextran sulphate sodium (DSS). Weight loss and colonoscopic score were increased significantly in Bim(-/-) mice compared to wild-type mice. As Bim is induced for the killing of autoreactive cells we determined the role of Bim in the regulation of lymphocyte survival at mucosal sites. Upon chronic dextran sulphate sodium (DSS)-induced colitis, Bim(-/-) animals exhibited an increased infiltrate of lymphocytes into the mucosa compared to wild-type mice. The number of autoreactive T cell receptor (TCR) Vbeta8(+) lymphocytes was significantly higher in Bim(-/-) mice compared to wild-type controls. Impaired removal of autoreactive lymphocytes in Bim(-/-) mice upon chronic DSS-induced colitis may therefore contribute to aggravated mucosal inflammation. PMID- 23668822 TI - Self-discrepancy monitoring and its impact on negative mood: an experimental investigation. AB - BACKGROUND: The perception of self-discrepancies between the actual self and the ideal self has been defined as a cognitive risk factor for depression (Higgins, 1987). In this view, self-discrepancy monitoring (SDM) refers to the voluntary re orientation of attention towards detecting discrepancies between ideal and actual selves, even in a positive situation. AIMS: The goal of this study was to explore the impact of SDM on levels of mood in the face of positive stimuli. METHOD: Two clinical and two non-clinical samples were recruited from two different European countries (Italy and Romania). All participants were asked to focus on a past positive experience, and were then randomly allocated to one of two induction tasks. The experimental condition consisted of monitoring discrepancies between personal goals and the recalled positive experience, while the control condition consisted of observing what the participant was feeling. RESULTS: The findings show that, after recalling a positive memory, SDM leads to a significant decrease in mood over a short period independent of the severity of depressive symptoms. This effect is partially mediated by the concurrent change in levels of brooding. CONCLUSIONS: Self-discrepancy monitoring in response to positive stimuli tends to lower current mood independent of the initial level of depressive symptoms, and seems to be a global trigger of emotional distress that does not refer only to a depressed cognitive style. PMID- 23668823 TI - "Struggling with daily life and enduring pain": a qualitative study of the experiences of pregnant women living with pelvic girdle pain. AB - BACKGROUND: Few studies have investigated the experiences of living with pelvic girdle pain (PGP) and its impact on pregnant women's lives. To address this gap in knowledge, this study investigates the experiences of women living with PGP during pregnancy. METHODS: A purposive sample, of nine pregnant women with diagnosed PGP, were interviewed about their experiences. Interviews were recorded, transcribed to text and analysed using a Grounded Theory approach. RESULTS: The core category that evolved from the analysis of experiences of living with PGP in pregnancy was "struggling with daily life and enduring pain". Three properties addressing the actions caused by PGP were identified: i) grasping the incomprehensible; ii) balancing support and dependence and iii) managing the losses. These experiences expressed by the informants constitute a basis for the consequences of PGP: iv) enduring pain; v) being a burden; vi) calculating the risks and the experiences of the informants as vii) abdicating as a mother. Finally, the informants' experiences of the consequences regarding the current pregnancy and any potential future pregnancies is presented in viii) paying the price and reconsidering the future. A conceptual model of the actions and consequences experienced by the pregnant informants living with PGP is presented. CONCLUSIONS: PGP during pregnancy greatly affects the informant's experiences of her pregnancy, her roles in relationships, and her social context. For informants with young children, PGP negatively affects the role of being a mother, a situation that further strains the experience. As the constant pain disturbs most aspects of the lives of the informants, improvements in the treatment of PGP is of importance as to increase the quality of life. This pregnancy-related condition is prevalent and must be considered a major public health concern during pregnancy. PMID- 23668824 TI - No evidence of triclosan-resistant bacteria following long-term use of triclosan containing toothpaste. AB - BACKGROUND AND OBJECTIVE: There is a paucity of data in relation to the possible emergence of triclosan (TCS)-resistant bacteria following long-term exposure to TCS toothpaste. Therefore, this study investigated whether long-term continuous exposure to TCS in toothpaste selects for TCS-resistant bacteria within the oral biofilm. MATERIAL AND METHODS: Dental plaque samples were collected from 40 individuals during year 5 of a randomised controlled trial. Participants had been randomly assigned to use TCS (3000 MUg/mL TCS) (n = 18) or placebo toothpaste (n = 22). Diluted plaque samples were plated on to Wilkins-Chalgren agar plates containing 5% (v/v) laked sheep red blood cells and TCS (concentrations ranging from 25 to 150 MUg/mL) and incubated at 37 degrees C under microaerophilic and anaerobic conditions for 2-10 d. Selected bacterial isolates were identified by partial 16S rDNA sequencing and TCS minimum inhibitory concentration (MIC) determined for each isolate. RESULTS: At 3000 MUg/mL TCS no growth was observed under microaerophilic or anaerobic conditions in either group. The MICs of TCS for all isolates ranged from 125 to 1000 MUg/mL in both groups. Species common to both groups had similar MICs. Veillonella parvula and Campylobacter gracilis were the most frequent isolates from both groups, with similar MICs in both groups. CONCLUSION: The use of TCS-containing toothpaste did not appear to lead to an increase in MIC of TCS of oral bacterial isolates. PMID- 23668825 TI - Prostatic paracoccidioidomycosis with a fatal outcome: a case report. AB - INTRODUCTION: Paracoccidioidomycosis is a systemic mycosis in Latin America that can affect various organs. Few case reports of paracoccidioidomycosis affecting the prostate are found in the literature. CASE PRESENTATION: We present the case of a 79-year-old Caucasian man with a six-month history of irritative symptoms of the prostate (urgency, frequency and nocturia) and difficulty initiating urination that progressed to urinary retention and the use of a urinary catheter. The anatomopathological analysis of the transurethral resection of the prostate revealed chronic granulomatous prostatitis of fungal etiology (paracoccidioidomycosis) with extensive necrosis. The patient began treatment with itraconazole at a dose of 100mg/day for six months. Radiography of the thorax revealed bilaterally diffuse nodular reticular interstitial lesions. The patient progressed to respiratory failure and was sent to the intensive care unit, but suffered a cardiopulmonary arrest and was pronounced dead. CONCLUSIONS: Due to the high incidence of paracoccidioidomycosis in countries like Brazil, urologists should suspect blastomycosis in all patients with symptoms of lower urinary obstruction with chronic abacterial prostatitis. Considering that paracoccidioidomycosis has the potential to affect various organs, following diagnosis, the treatment must be initiated as soon as possible. PMID- 23668826 TI - Shape-directed binary assembly of anisotropic nanoplates: a nanocrystal puzzle with shape-complementary building blocks. AB - We present the binary self-assembly of two anisotropic nanoplate building blocks mediated by shape complementarity. We use rhombic GdF3 and tripodal Gd2O3 nanoplates as building blocks in which the size and shape are designed to be optimal for complementary organization. A liquid interfacial assembly technique allows the formation of self-assembled binary superlattices from two anisotropic nanoplates over a micrometer length scale. Shape-directed self-assembly guides the position of each anisotropic nanoplate in the binary superlattices, allowing for long-range orientational and positional order of each building block. The design of shape complementary anisotropic building blocks offers the possibility to self-assemble binary superlattices with predictable and designable structures. PMID- 23668827 TI - Bullet point ethics as policy advice? PMID- 23668828 TI - Infrared spectroscopy and phase behavior of n-butane aerosols and thin films at cryogenic temperatures. AB - Spectroscopic studies of two phase transitions of solid n-butane aerosol droplets performed under conditions representative of those in the lower atmosphere of Titan are presented. Pure n-butane aerosols and mixed ensembles of n butane/acetylene, n-butane/carbon dioxide and n-butane/water aerosols were generated in a bath gas cooling cell at 78 K and their phase transition dynamics monitored using infrared extinction spectroscopy. For pure n-butane aerosols the volume and surface nucleation constants were found to range from JV = 10(12) 10(14) cm(-3) s(-1) and JS = 10(13) -10(15) cm(-2) s(-1), respectively, for the first observed transition, and JV = 10(9) -10(11) cm(-3) s(-1) and JS = 10(11) 10(13) cm(-2) s(-1) for the second observed transition. The phases of the n butane aerosols were determined by comparing their spectroscopic signatures with spectra collected from thin films of liquid and solid n-butane. The first observed transition was from an amorphous-annealed phase into the metastable crystalline phase II of n-butane. The second transition was from the metastable crystalline phase II into the crystalline phase III. The effect of the presence of a second aerosol substance (acetylene, carbon dioxide or water) was examined; while this accelerated the first phase transition, it did not directly influence the rate of the second phase transition. The kinetic studies might be important for the understanding of cloud formation on Titan, while the spectral data provided, which include the first reported spectrum of liquid n-butane close to the melting point, are expected to be of use for remote sensing applications. PMID- 23668829 TI - Determinants of respirable silica exposure in stone countertop fabrication: a preliminary study. AB - A preliminary study of personal exposure to respirable quartz was conducted in four shops that used a variety of wet and dry methods to fabricate countertops from granite and quartz-containing synthetic stone-like materials. Full-shift time-weighted average (TWA) exposures exceeded the ACGIH threshold limit value of 0.025 mg/m(3) for all workers who used dry fabrication methods, even for very limited time, during any part of the work shift (n = 15 person-days). The geometric mean of exposures for workers who used dry methods extensively was about 1 mg/m(3) (n = 12 person-days). Workers who operated only automated or remotely controlled stone cutting or shaping equipment had calculated TWA exposures of approximately 0.02 mg/m(3) (n = 3 person-days). Task-specific geometric mean exposures for various wet and dry manual operations were ranked based on estimated concentrations extracted from multi-task partial-shift sample results using a linear algebra procedure. Limited use of dry methods was observed in shops that had previously reported using only wet methods. These results suggest that even shops that report using only wet methods might, in fact, resort to brief use of dry methods for specific operations. Therefore, there may be reason for concern over potential overexposure to respirable quartz in all stone countertop shops. PMID- 23668830 TI - Antioxidant activity of selected stilbenoids and their bioproduction in hairy root cultures of muscadine grape (Vitis rotundifolia Michx.). AB - Stilbenoids are polyphenolic phytoalexins with health-related properties in humans. Muscadine grape ( Vitis rotundifolia ) hairy root cultures were established via Agrobacterium rhizogenes -mediated transformation, and the effects of growth regulators (3-indolebutyric acid and 6-benzylaminopurine) and methyl jasmonate (MeJA) on stilbenoid production were studied. Twenty-one-day-old hairy root cultures were treated with 100 MUM MeJA for 24 h, and then the stilbenoids were extracted from the medium and tissue with ethyl acetate and analyzed by HPLC. Resveratrol, piceid, and epsilon-viniferin were observed preferentially in tissue, whereas piceatannol was observed only in medium. Growth regulators did not affect the yield of stilbenoids, whereas higher levels were found upon treatment with MeJA. Stilbenoids identified in the hairy root cultures were analyzed for their radical scavenging capacity showing piceatannol and epsilon-viniferin as the strongest antioxidants. Muscadine grape hairy root cultures were demonstrated to be amenable systems to study stilbenoid biosynthesis and a sustainable source of these bioactive compounds. PMID- 23668831 TI - Role of the aerosol phase state in ammonia/amines exchange reactions. AB - The exchange reaction of ammonia in (NH4)2SO4 with an amine and the corresponding reverse reaction of amines in aminium sulfates with ammonia were investigated using an electrodynamic balance coupled with a Raman spectrometer. The temporal changes in particle mass, chemical composition, and phase state were simultaneously monitored. When the salt particles were in an aqueous state at elevated relative humidities (RHs), the exchange of ammonia/amine vapors in the particle phase was reversible. The exchange rates of aqueous particles were in general higher than those of their corresponding solid counterparts. An aqueous phase was essential for the effective displacement of ammonia and amines. Aminium salts in different phase states and with different evaporation characteristics showed remarkably different reaction behaviors in ammonia vapor. The less compact amorphous aminium sulfate solids were more susceptible to ammonia exchange than the crystalline solids. The aminium salts in a liquid state exhibited substantial amine evaporation at <3% RH and formed acidic bisulfate. Under ammonia exposure, these acidic aminium droplets underwent both neutralization and displacement reactions. Stable solid salts containing ammonium, aminium, sulfate, and bisulfate were formed and hindered further reactions. The result suggests that ambient aminium sulfates may be acidic. Overall, the phase states of the ammonium and aminium salt particles crucially determine the heterogeneous reaction rates and final product properties and identities. PMID- 23668832 TI - Chronic pancreatitis: role of oxidative stress and antioxidants. AB - Chronic pancreatitis (CP) is characterized by pain, and exocrine and endocrine insufficiency of pancreas. Several hypotheses have been put forward to explain the hitherto partially understood pathophysiology of CP. In the past decade, animal and clinical studies have suggested that an increased chronic oxidative stress (OS) plays a key role in pathophysiology of CP and perpetuates its clinical and histological symptoms (pain and fibrosis-necrosis, respectively). Mounting OS in pancreatic acinar cells is a result of overproduction of free radicals (FR) during xenobiotic metabolism. It has been shown that Phase I cytochrome P450 enzymes of xenobiotic pathway are induced when exposed to a xenobiotic overload including alcohol, tobacco, smoke and other dietary toxins, which exceeds the capacity of Phase II conjugation due to limited glutathione availability. Consequently, there is an overload of toxic metabolites as well as FR. Additionally, bioactivation of subsequently entering compounds may occur increasing their toxicity. Such an imbalance overwhelms the antioxidant capacity of the body resulting in undefended chronic OS that derails the normal physiology of pancreatic acinar cells since FR act as second messengers controlling the cellular signaling. OS hypothesis is further supported by the studies that demonstrated that antioxidant supplementation ameliorated pain. Moreover, animal studies have demonstrated a cessation of fibrotic cascade with antioxidant supplementation. In a recent large randomized controlled trial, it was demonstrated that antioxidant supplementation led to a significant reduction in pain, and also lowered the OS in patients with alcoholic or idiopathic CP. PMID- 23668833 TI - Frequency and correlates of anxiety and mood disorders among TB- and HIV-infected Zambians. AB - We determined the frequency and correlates of current common mental disorders (CMDs) in a consecutive series of 649 adult patients with human immunodeficiency virus (HIV), tuberculosis (TB) or both receiving treatment at 16 primary health care centres across Zambia. Data on socio-demographic variables, clinical disease features, anxiety and mood disorders were collected. The frequency of any anxiety disorder (AD) was 30.8% and major depressive disorder (MDD) 11.3%. Although differences by disease group did not reach statistical significance, rates of suicidality (34.8%) and panic disorder (4.1%) were highest for the TB-HIV group (n = 269), while rates of generalised AD (13.3%), obsessive compulsive disorder (7.6%), posttraumatic stress disorder (7.4%) and any AD (37.8%) were highest for the HIV group (n = 149). Female gender (p = 0.004) predicted any current AD as well as current suicidality (p = 0.009), while lower education status (p < 0.001) predicted current MDD. World Health Organisation (WHO) clinical staging and antiretroviral treatment status were not significantly associated with MDD or anxiety in the HIV and co-infected groups. This study indicates the importance of early identification of CMDs in TB, HIV and co-infected patients, especially women and uneducated patients, newly initiated on treatment in primary care settings. PMID- 23668834 TI - Effect of an educational intervention in primary care physicians on the compliance of indicators of good clinical practice in the treatment of type 2 diabetes mellitus [OBTEDIGA project]. AB - AIM: To evaluate the effect of an educational intervention among primary care physicians on several indicators of good clinical practice in diabetes care. METHODS: Two groups of physicians were randomly assigned to the intervention or control group (IG and CG). Every physician randomly selected two samples of patients from all type 2 diabetic patients aged 40 years and above and diagnosed more than a year ago. Baseline and final information were collected cross sectionally 12 months apart, in two independent samples of 30 patients per physician. The educational intervention comprised: distribution of educational materials and physicians' specific bench-marking information, an on-line course and three on-site educational workshops on diabetes. External observers collected information directly from the physicians and from the medical records of the patients on personal and family history of disease and on the evolution and treatment of their disease. Baseline information was collected retrospectively in the control group. RESULTS: Intervention group comprised 53 physicians who included a total of 3018 patients in the baseline and final evaluations. CG comprised 50 physicians who included 2868 patients in the same evaluations. Measurement of micro-albuminuria in the last 12 months (OR = 1.6, 95% CI: 1.1 2.4) and foot examination in the last year (OR = 2.0, 95% CI: 1.1-3.6) were the indicators for which greater improvement was found in the IG. No other indicator considered showed statistically significant improvement between groups. CONCLUSIONS: The identification of indicators with very low level of compliance and the implementation of a simple intervention in physicians to correct them is effective in improving the quality of care of diabetic patients. PMID- 23668835 TI - Technical considerations for follicular unit extraction in African-American hair. PMID- 23668836 TI - Primary leptomeningeal histiocytic sarcoma in a patient with a good outcome: a case report and review of the literature. AB - INTRODUCTION: Histiocytic sarcoma is a rare neoplasm with few cases reported in the literature of which some were diagnosed in animals. This neoplasm arises from abnormal reticuloendothelial system cell proliferation of histiocytes and has an aggressive behavior especially if located in the central nervous system. We present the first case of a patient with histiocytic sarcoma that involved the meninges and had a good course after multidisciplinary treatment. CASE PRESENTATION: Our patient was a 41-year-old Caucasian woman with no previous history of disease who started with systemic symptoms such as headache and chills. Magnetic resonance imaging with gadolinium contrast of the brain suggested a mass 1.5*2cm in diameter in the temporal lobe with a non-uniform vasogenic edema. This lesion was implanted in the meninges and surgery was the first treatment. The histological findings revealed a histiocytic sarcoma. The patient received concomitant chemoradiotherapy after surgery with good tolerance and currently lives without disease. CONCLUSION: Although histiocytic sarcomas in the brain present an unusual location and have a poorer prognosis, we have identified the first primary leptomeningeal histiocytic sarcoma with a disease free survival greater than 3 years following multidisciplinary treatment with surgery and chemotherapy and radiotherapy. PMID- 23668837 TI - Atomic-scale tomography: a 2020 vision. AB - Atomic-scale tomography (AST) is defined and its place in microscopy is considered. Arguments are made that AST, as defined, would be the ultimate microscopy. The available pathways for achieving AST are examined and we conclude that atom probe tomography (APT) may be a viable basis for AST on its own and that APT in conjunction with transmission electron microscopy is a likely path as well. Some possible configurations of instrumentation for achieving AST are described. The concept of metaimages is introduced where data from multiple techniques are melded to create synergies in a multidimensional data structure. When coupled with integrated computational materials engineering, structure properties microscopy is envisioned. The implications of AST for science and technology are explored. PMID- 23668838 TI - Establishment of experimental models for Alzheimer's disease research. AB - Alzheimer's disease (AD) is a severe neurodegenerative disease in brain. It leads to a progressive and irreversible decline in memory and cognition. There is no curing method for AD now. AD patients will eventually die. The typical neuropathological changes of AD brain include extracellular senile plaques (deposition of beta-amyloid) and intracellular neurofibrillary tangles. It is predicted that 1 in 85 people in the world will be diagnosed as AD in 2050. In AD research, experimental models are very important. In the past decades, many experimental models of AD were established. In this review, the experimental models that commonly used in AD research are concisely summarized. These models make great contributions to AD research. However, they do have their limitations due to incomplete reflection of AD pathology. Therefore, new experimental models of AD are needed to be established in the future. PMID- 23668839 TI - Growth of vertical GaAs nanowires on an amorphous substrate via a fiber-textured Si platform. AB - We demonstrate the vertical self-catalyzed molecular beam epitaxy (MBE) growth of GaAs nanowires on an amorphous SiO2 substrate by using a smooth [111] fiber textured silicon thin film with very large grains, fabricated by aluminum-induced crystallization. This generic platform paves the way to the use of inexpensive substrates for the fabrication of dense ensembles of vertically standing nanowires (NWs) with promising perspectives for the integration of NWs in devices. PMID- 23668841 TI - Nuclear spin symmetry conservation and relaxation in water ((1)H2(16)O) studied by cavity ring-down (CRD) spectroscopy of supersonic jets. AB - We report high resolution near-infrared laser spectra of water seeded in a supersonic jet expansion of argon probed by cavity ring-down spectroscopy (CRDS) in the R branch of the 2nu3 band (above 7500 cm(-1)) at several effective temperatures T < 30 K. Our goal is to study nuclear spin symmetry conservation and relaxation. For low mole fractions of water in the gas mixture, we obtained the lowest rotational temperatures and observed nuclear spin symmetry conservation, in agreement with theoretical expectation for inelastic collisions of isolated H2O molecules with Ar and similar to a previous series of experiments with other small molecules in supersonic jet expansions. However, for the highest mole fractions of water, which we used (xH2O < 1.6%), we obtained slightly higher rotational temperatures and observed nuclear spin symmetry relaxation, which cannot be explained by the intramolecular quantum relaxation mechanism in the monomer H2O. The nuclear spin symmetry relaxation observed is, indeed, seen to be related to the formation of water clusters at the early stage of the supersonic jet expansion. Under these conditions, two mechanisms can contribute to nuclear spin symmetry relaxation. The results are discussed in relation to claims of the stability of nuclear spin isomers of H2O in the condensed phase and briefly also to astrophysical spectroscopy. PMID- 23668840 TI - Disordered Toll-like receptor 2 responses in the pathogenesis of pulmonary sarcoidosis. AB - In this study, we hypothesized that the granulomatous disorder sarcoidosis is not caused by a single pathogen, but rather results from abnormal responses of Toll like receptors (TLRs) to conserved bacterial elements. Unsorted bronchoalveolar lavage (BAL) cells from patients with suspected pulmonary sarcoidosis and healthy non-smoking control subjects were stimulated with representative ligands of TLR-2 (in both TLR-2/1 and TLR-2/6 heterodimers) and TLR-4. Responses were determined by assessing resulting production of tumour necrosis factor (TNF)-alpha and interleukin (IL)-6. BAL cells from patients in whom sarcoidosis was confirmed displayed increased cytokine responses to the TLR-2/1 ligand 19-kDa lipoprotein of Mycobacterium tuberculosis (LpqH) and decreased responses to the TLR-2/6 agonist fibroblast stimulating ligand-1 (FSL)-1. Subsequently, we evaluated the impact of TLR-2 gene deletion in a recently described murine model of T helper type 1 (Th1)-associated lung disease induced by heat-killed Propionibacterium acnes. As quantified by blinded scoring of lung pathology, P. acnes-induced granulomatous pulmonary inflammation was markedly attenuated in TLR-2(-/-) mice compared to wild-type C57BL/6 animals. The findings support a potential role for disordered TLR-2 responses in the pathogenesis of pulmonary sarcoidosis. PMID- 23668842 TI - Enhanced preservation of pig cardiac allografts by combining erythropoietin with glyceryl trinitrate and zoniporide. AB - Erythropoietin has a tissue-protective effect independent of its erythropoietic effect that may be enhanced by combining it with the nitric oxide donor glyceryl trinitrate (GTN) and the sodium-hydrogen exchange inhibitor zoniporide in rat hearts stored with an extracellular-based preservation solution (EBPS). We thus sought to test this combination of agents in a porcine model of orthotopic heart transplantation incorporating donor brain death and total ischaemic time of approximately 260 min. Pig hearts were stored in one of four storage solutions: unmodified EBPS (CON), EBPS supplemented with GTN and zoniporide (GZ), EBPS supplemented with erythropoietin and zoniporide (EZ), or EBPS supplemented with all three agents (EGZ). A total of 4/5 EGZ hearts were successfully weaned from cardiopulmonary bypass compared with only 2/5 GZ hearts, 0/5 CON hearts and 0/5 EG hearts (p = 0.017). Following weaning from bypass EGZ hearts demonstrated superior contractility and haemodynamics than GZ hearts. All weaned hearts displayed impaired diastolic function. Release of troponin I from EGZ hearts was lower than all other groups. In conclusion, supplementation of EBPS with erythropoietin, glyceryl trinitrate and zoniporide provided superior donor heart preservation than all other strategies tested. PMID- 23668843 TI - Trajectories of illness intrusiveness domains following a diagnosis of breast cancer. AB - OBJECTIVE: To identify trajectories of illness intrusiveness over the first 2 years after a breast cancer diagnosis and describe associated patient and treatment characteristics. Illness intrusiveness, or how much an illness disrupts life domains, has been shown to be highly related to quality of life. METHODS: Women recruited within 8 months of a breast cancer diagnosis (n = 653) completed questionnaires at baseline and 6, 12, and 18 months postbaseline. Group-based trajectory modeling was used to identify trajectories in three established domains of illness intrusiveness: instrumental, intimacy, and relationships and personal development. Bivariate analyses identified contextual, disease/treatment, psychological, and social characteristics of women in trajectory groups. RESULTS: Forty-one percent of women fell into a trajectory of consistently low illness intrusiveness (Low) across all three domains. Other women varied such that some reported illness intrusiveness that decreased over time on at least one domain (9-34%), and others reported consistently high intrusiveness on at least one domain (11-17%). A fourth trajectory of increased illness intrusiveness emerged in the relationship and personal development domain (9%). Characteristics of women in the Low group were being older; being less likely to have children at home; and having stage I cancer, fewer symptoms, and better psychosocial status. CONCLUSIONS: Women experienced different patterns of illness intrusiveness in the first 2 years after a diagnosis of breast cancer with a high percentage reporting Low intrusiveness. However, women differentially followed the other trajectory patterns by domain, suggesting that the effect of breast cancer on some women's lives may be specific to certain areas. PMID- 23668844 TI - Multiethnic differences in responses to laboratory pain stimuli among children. AB - OBJECTIVE: A growing body of literature suggests ethnic differences in experimental pain. However, these studies largely focus on adults and the comparison between Caucasians and African Americans. The primary aim of this study is to determine ethnic differences in laboratory-induced pain in a multiethnic child sample. METHOD: Participants were 214 healthy children (mean age = 12.7, SD = 3.0 years). Ninety-eight Caucasian, 58 Hispanic, 34 African American, and 24 Asian children were exposed to four trials of pressure and radiant heat pain stimuli. Pain responses were assessed with self-report measures (i.e., pain intensity and unpleasantness) and behavioral observation (i.e., pain tolerance). RESULTS: Asians demonstrated more pain sensitivity than Caucasians, who evidenced more pain sensitivity than African Americans and Hispanics. The results hold even after controlling for age, sex, SES, and experimenter's ethnicity. Asians also showed higher anticipatory anxiety compared with other ethnic groups. Anticipatory anxiety accounted for some ethnic differences in pain between Asians, Hispanics, and African Americans. CONCLUSIONS: By examining response to laboratory pain stimuli in children representing multiple ethnicities, an understudied sample, the study reveals unique findings compared to the existing literature. These findings have implications for clinicians who manage acute pain in children from diverse ethnic backgrounds. Future investigations should examine mechanisms that account for ethnic differences in pain during various developmental stages. PMID- 23668845 TI - Testing a dissonance body image intervention among young girls. AB - OBJECTIVE: Body image and eating disorder interventions based on cognitive dissonance have been shown to be effective among girls and women aged 14 and above. This article reports a preliminary examination of whether a dissonance intervention is also effective when delivered in a school setting to 12- and 13 year-old girls in the United Kingdom. METHOD: Girls (N = 106, mean age = 12.07 years, SD = .27) were allocated to the intervention condition or a waitlist control. RESULTS: In contrast to the control group, girls in the intervention condition reported significant reductions in body dissatisfaction and internalization of a thin body ideal post-intervention. There was no significant change in self-reported dietary restraint for either condition. In addition, compared with the control group, girls in the intervention condition showed increased resilience to negative media effects 1-month post-intervention. CONCLUSIONS: Results suggests that dissonance based programs can reduce body dissatisfaction, internalization and negative media effects among a younger group of girls than previously examined and in a United Kingdom school setting. PMID- 23668846 TI - Momentary assessment of affect, physical feeling states, and physical activity in children. AB - OBJECTIVE: Most research on the interplay of affective and physical feelings states with physical activity in children has been conducted under laboratory conditions and fails to capture intraindividual covariation. The current study used Ecological Momentary Assessment (EMA) to bidirectionally examine how affective and physical feeling states are related to objectively measured physical activity taking place in naturalistic settings during the course of children's everyday lives. METHODS: Children (N = 119, ages 9-13 years, 52% male, 32% Hispanic) completed 8 days of EMA monitoring, which measured positive affect (PA), negative affect (NA), feeling tired, and feeling energetic up to 7 times per day. EMA responses were time-matched to accelerometer assessed moderate-to vigorous physical activity (MVPA) in the 30 min before and after each EMA survey. RESULTS: Higher ratings of feeling energetic and lower ratings of feeling tired were associated with more MVPA in the 30 min after the EMA prompt. More MVPA in the 30 min before the EMA prompt was associated with higher ratings of PA and feeling energetic and lower ratings of NA. Between-subjects analyses indicated that mean hourly leisure-time MVPA was associated with less intraindividual variability in PA and NA. CONCLUSIONS: Physical feeling states predict subsequent physical activity levels, which in turn, predict subsequent affective states in children. Active children demonstrated higher positive and negative emotional stability. Although the strength of these associations were of modest magnitude and their clinical relevance is unclear, understanding the antecedents to and consequences of physical activity may have theoretical and practical implications for the maintenance and promotion of physical activity and psychological well being in children. PMID- 23668848 TI - Does physical activity change over 24 months in persons with relapsing-remitting multiple sclerosis? AB - OBJECTIVE: There is strong evidence for prevalent physical inactivity among persons with multiple sclerosis (MS). By comparison, very little is known about natural occurring change in physical activity over time. Such inquiry is important for identifying the rate, patterns, and predictors of change for the design and delivery of behavioral interventions in this population. The present study conducted latent growth modeling (LGM) and latent class growth analysis (LCGA) for understanding the rate, patterns, and predictors of change in physical activity over a 24-month period among persons with MS. METHODS: On three occasions each separated by 12 months, persons (n = 269) with relapsing-remitting MS (RRMS) completed a battery of questionnaires that included assessment of physical activity behavior. Data were analyzed using Mplus 3.0. RESULTS: The LGM indicated that a linear model provided a good fit to the data (chi2 = 3.94, p = .05, CFI = .987, SRMR = .025), but the slope (Ms = 0.8) was nonsignificant (p > .05) and indicated no change in physical activity over time. LCGA identified a 2 class solution, and, based on the Lo-Mendell-Rubin likelihood ratio test, this model fit the data better than the 1-class solution. The 2-class solution consisted of low-active (~80%) and high-active (~20%) persons, but there was no change in physical activity over time per group. Sex and disability, but not age and disease duration, were predictors of being in the low active class. CONCLUSIONS: There was prevalent physical inactivity, but little interindividual and intraindividual change over 24 months in this cohort of persons with RRMS. Such results identify the importance of behavior interventions, perhaps early in the disease process wherein physical inactivity originates. PMID- 23668847 TI - Physical activity as a mediator linking neighborhood environmental supports and obesity in African Americans in the path trial. AB - OBJECTIVE: African Americans have the highest rates of obesity in the United States. Engaging in recommended levels of physical activity (PA) reduces risk for obesity. Social and environmental supports for PA may be important to increase PA. This study hypothesized that PA would mediate the effects of neighborhood and social supports for PA on body mass index (BMI). METHOD: Baseline data were collected from 434 underserved African American adults in the Positive Action for Today's Health (PATH) trial. Features of the neighborhood environment (i.e., infrastructure for walking, access to services, and crime) and peer social support were measured with validated surveys. Moderate-to-vigorous PA (MVPA) was assessed based on 7-day accelerometry estimates (in minutes per day), and self reported walking and exercise were obtained using the Four-Week Physical Activity History questionnaire. RESULTS: The sample was predominantly female (63%) and obese (MBMI = 30.88 kg/m2, SD = 8.43). Neither crime nor social support was significantly associated with either PA or BMI; thus, they were excluded from the final models. Infrastructure for walking predicted MVPA (B = 4.06, p = .01) and self-reported walking (B = 7.39, p = .03). A positive association between access to services and MVPA approached significance (B = 2.27, p = .06). MVPA (B = 0.07, p < .001) and self-reported walking (B = -0.02, p = .01) predicted BMI, but only MVPA mediated the effect of infrastructure for walking on BMI (B = -0.03, p = .04). No significant direct or indirect effects of predictors were found for self-reported exercise. CONCLUSION: Findings suggest that MVPA is a mediator linking infrastructure for walking and BMI in underserved communities. PMID- 23668849 TI - Self-regulating smoking and snacking through physical activity. AB - OBJECTIVE: Emotional snacking contributes to weight gain after smoking cessation. Exercise acutely reduces cravings for cigarettes and snack food. This study examined if different exercise intensities acutely reduces snack and cigarette cravings and attentional bias (AB) to video clips of snacks and cigarettes among abstinent smokers. METHODS: Abstinent smokers (and snackers; N = 23) randomly did 15 mins of moderate and vigorous cycling and a passive control in a cross-over design. Visual initial AB (IAB) and maintained AB (MAB) were assessed pre- and after treatment while watching paired snacking/neutral or smoking/neutral video clips. Desire to snack and smoke were assessed throughout. RESULTS: ANOVAs revealed significant condition * time interactions for initial and maintained AB for smoking [IAB: F(1.58, 34.75) = 3.58, MAB: F(2, 44) = 4.52, p < .05] and snacking [IAB: F(2, 44) = 8.13, MAB: F(2, 44) = 5.08, p < .01]. IAB for both smoking and snacking were lower after moderate and vigorous exercise than the control. MAB was lower only after vigorous exercise. Fully repeated ANOVAs revealed a condition * time interaction for desire to smoke, F(3.31, 72.75) = 12.62, and snack F(4.34, 95.52) = 9.51, p < .001. Cravings were lower after moderate and vigorous exercise, compared with control. CONCLUSIONS: Exercise acutely reduces both AB and cravings for cigarettes and snacks and may help self regulation of smoking and snacking. Vigorous exercise was only more advantageous for reducing MAB. PMID- 23668850 TI - Do media portrayals of obesity influence support for weight-related medical policy? AB - OBJECTIVE: The purpose of this research was to examine the impact of nonstigmatizing visual portrayals of obesity on support for a discriminatory weight-based medical policy. METHOD: Participants read an online news story about a policy to deny fertility treatment to obese women that was accompanied by a nonstigmatizing, stigmatizing, or no image of an obese couple. A balanced discussion of the policy was presented, with information both questioning the policy as discriminatory and supporting the policy because of weight-related medical complications. RESULTS: Results revealed that participants who viewed the nonstigmatizing image were less supportive of the policy to deny obese women fertility treatment and recommended the policy less strongly than participants who viewed the stigmatizing image. Furthermore, weaker perceptions of medical risk mediated the effect of the nonstigmatizing image on policy ratings. CONCLUSION: The findings indicate that simply eliminating stigmatizing media portrayals of obesity may help reduce bias. PMID- 23668851 TI - Sleep disturbances predict later trauma-related distress: cross-panel investigation amidst violent turmoil. AB - OBJECTIVE: Sleep disturbances, including trouble falling and remaining asleep and recurrent nightmares, are symptoms of posttraumatic stress. A growing body of literature indicates that sleep disturbance may also convey vulnerability for the continuation of other symptoms of posttraumatic stress, including fear, anxiety, and heightened arousal. However, longitudinal research, which could help understand how these relationships unfold over time, has been limited. METHOD: The longitudinal relationships between sleep disturbance and posttraumatic stress were investigated in 779 Palestinian adults randomly selected and interviewed twice during the period from April 2008 to November 2008, amid ongoing violent political turmoil. The recruitment method produced a representative sample and excellent retention. Cross-panel structural equation modeling was used to examine relationships between sleep and distress across two study periods. RESULTS: Results indicated that initial sleep problems were associated with increased posttraumatic stress disorder (PTSD), depression, and intrapersonal resource loss at follow-up 6 months later, but initial PTSD, depression, and intrapersonal resource loss were not associated with increased sleep problems at follow-up. CONCLUSIONS: Sleep problems may confer vulnerability to longer-term distress in the presence of ongoing political violence. Future research should examine whether interventions targeting trauma-related sleep problems may improve prevention and treatment for PTSD and related disorders. PMID- 23668852 TI - Harsh parenting and adolescent health: a longitudinal analysis with genetic moderation. AB - OBJECTIVE: This study was designed to examine the prospective relations of harsh parenting during preadolescence, anger across adolescence, and a health phenotype at late adolescence among African American youths living in the rural South. A second purpose was to determine whether, for genetic reasons, some youths will be more sensitive than others to a harsh parenting to anger to poor health pathway. METHOD: Participants were 368 youths (age 11.2 at the first assessment) who provided data on receipt of harsh parenting during preadolescence (ages 11 to 13), anger across adolescence (ages 16 to 18), and a health phenotype consisting of C Reactive Protein, depressive symptoms, and health problems at age 19. Youths were genotyped at the 5-HTTLPR at age 16. RESULTS: The data analysis revealed that (a) harsher parenting was associated positively across time with anger and poor health, (b) anger across adolescence also was associated positively across time with poor health, (c) anger served as a mediator connecting harsh parenting and poor health, and (d) the harsh parenting to anger to poor health pathway was significant only for youths carrying one or two copies of a short allele at the 5 HTTLPR. CONCLUSIONS: These findings are consistent with the hypothesis that harsh parent-child interactions presage health through effects on emotion regulation, particularly anger. This mediational pathway pertained only to youths carrying a gene that confers sensitivity and reactivity to harsh family processes and the negative emotional states they occasion. PMID- 23668853 TI - Associations between dispositional optimism and diurnal cortisol in a community sample: when stress is perceived as higher than normal. AB - OBJECTIVES: This study examined whether dispositional optimism would be associated with reduced levels of cortisol secretion among individuals who perceive stress levels that are either higher than their normal average (i.e., within-person associations) or higher than the stress levels of other individuals (i.e., between-person associations). METHODS: Stress perceptions and four indicators of diurnal cortisol (area-under-the-curve, awakening, afternoon/evening, and cortisol awakening response [CAR] levels) were assessed on 12 different days over 6 years in a sample of 135 community-dwelling older adults. RESULTS: Hierarchical linear models showed that although pessimists secreted relatively elevated area-under-the-curve, awakening, and afternoon/evening levels of cortisol (but not CAR) on days they perceived stress levels that were higher than their normal average, optimists were protected from these stress-related elevations in cortisol. However, when absolute stress levels were compared across participants, there was only a significant effect for predicting CAR (but not the other cortisol measures), indicating that optimism was associated particularly strongly with a reduced CAR among participants who experienced high levels of stress. CONCLUSIONS: Dispositional optimism can buffer the association between stress perceptions and elevated levels of diurnal cortisol when individuals perceive higher-than-normal levels of stress, and it may predict a reduced CAR among individuals who generally perceive high stress levels. Research should examine relative, in addition to absolute, levels of stress to identify the personality factors that help individuals adjust to psychological perceptions of stress. PMID- 23668854 TI - The impact of firefighter personal protective equipment and treadmill protocol on maximal oxygen uptake. AB - This study investigated the effects of firefighter personal protective equipment (PPE) on the determination of maximal oxygen uptake (VO(2max)) while using two different treadmill protocols: a progressive incline protocol (PIP) and a progressive speed protocol (PSP), with three clothing conditions (Light-light clothing; Boots-PPE with rubber boots; Shoes-PPE with running shoes). Bruce protocol with Light was performed for a reference test. Results showed there was no difference in VO(2max) between Bruce Light, PIP Light, and PSP Light. However, VO(2max) was reduced in Boots and Shoes with shortened maximal performance time (7 and 6 min reduced for PIP Boots and Shoes, respectively; 11 and 9 min reduced for PSP Boots and Shoes, respectively), whereas the increasing rate of VO(2) in Boots and Shoes during submaximal exercise was greater compared with Light. Wearing firefighter boots compared with wearing running shoes also significantly affected submaximal VO(2) but not VO(2max). These results suggest that firefighters' maximal performance determined from a typical VO(2max) test without wearing PPE may overestimate the actual performance capability of firefighters wearing PPE. PMID- 23668855 TI - alpha-Monoacylated and alpha,alpha'- and alpha,beta'-diacylated dipyrrins as highly sensitive fluorescence "turn-on" Zn2+ probes. AB - With the purpose of developing readily synthesized CHEF (chelation-enhanced fluorescence) type Zn(2+) probes with relatively simple molecular structures and excellent sensing behavior, p-anisoyl chloride was used for the acylation of 5 (pentafluorophenyl)dipyrromethane. Interestingly, the alpha,beta'-diacylated product PS2 with a unique substitution mode was obtained in high yield in addition to the normal alpha-substituted mono- and diacylated products PS1 and PS3. Further oxidation of PS1-PS3 afforded dipyrrins S1-S3. Crystal structure and (1)H NMR measurements of S2 demonstrate the existence of a pure tautomer, which is consistent with DFT calculations. S1-S3 show highly Zn(2+) selective "turn-on" fluorescence based on a CHEF mechanism by the formation of 2:1 (probe:metal) Zn(2+) complexes. The emission colors can be easily tuned from green to red by changing the dipyrrin substitution modes. Furthermore, these probes demonstrate fast responses and wide applicable pH ranges. Among them, S2 shows the highest Zn(2+) sensitivity, with a detection limit of 4.4 * 10(-8) M. PMID- 23668856 TI - Polyphenols protect the epithelial barrier function of Caco-2 cells exposed to indomethacin through the modulation of occludin and zonula occludens-1 expression. AB - The aim of this study was to determine the protective effect of quercetin, epigallocatechingallate, resveratrol, and rutin against the disruption of epithelial integrity induced by indomethacin in Caco-2 cell monolayers. Indomethacin decreased the transepithelial electrical resistance and increased the permeability of the monolayers to fluorescein-dextran. These alterations were abolished by all the tested polyphenols but rutin, with quercetin being the most efficient. The protective effect of quercetin was associated with its capacity to inhibit the redistribution of ZO-1 protein induced in the tight junction by indomethacin or rotenone, a mitochondrial complex-I inhibitor, and to prevent the decrease of ZO-1 and occludin expression induced by indomethacin. The fact that the antioxidant polyphenols assayed in this study differ in their protective capacity against the epithelial damage induced by indomethacin suggests that this damage is due to the ability of this agent to induce not only oxidative stress but also mitochondrial dysfunction. PMID- 23668858 TI - Altered mRNA and protein expression of filaggrin in the skin of a canine animal model for atopic dermatitis. AB - BACKGROUND: Filaggrin is a structural protein that has attracted increasing interest over the past decade for its role in the pathogenesis of human atopic dermatitis (AD). Null mutations in its sequence are considered risk factors in the development of AD. HYPOTHESIS/OBJECTIVES: To investigate canine filaggrin mRNA and protein expression in the skin of atopic beagles with experimentally induced AD compared with breed-matched healthy control dogs. METHODS: All dogs were environmentally challenged for 3 days consecutively with allergens to which the atopic dogs had been sensitized. Skin biopsy specimens were taken from six healthy and seven atopic beagles before and after allergen challenge. Canine filaggrin mRNA was measured using quantitative real-time PCR. Indirect immunofluorescence was used to localize the filaggrin protein in canine skin. Analysis of variance with Tukey's multiple comparison test (over-time effect) and unpaired Student's t-test (treatment effect) were used. Values of P <= 0.05 were considered significant. RESULTS: Analysis of variance showed a significantly higher expression of filaggrin mRNA in atopic dogs compared with healthy control dogs (P = 0.004 on day 3 and P = 0.01 on day 10) and a decreased mRNA expression on day 3 in healthy control dogs (effect of time, P = 0.006). On blinded evaluation, filaggrin immunofluorescence was distributed homogeneously in the stratum granulosum and the stratum corneum in healthy dogs. Atopic dogs showed a patchy immunofluorescence pattern, which was exacerbated after environmental challenge. CONCLUSIONS AND CLINICAL IMPORTANCE: Altered epidermal filaggrin mRNA expression and protein distribution was detected in this experimental model. PMID- 23668859 TI - Evaluation of azithromycin in systemic and toothpaste forms for the treatment of ciclosporin-associated gingival overgrowth in dogs. AB - BACKGROUND: Gingival overgrowth is an adverse effect of ciclosporin therapy. Azithromycin (AZI) in capsule and toothpaste form is an effective treatment for ciclosporin-associated gingival overgrowth (CsAGO) in humans. HYPOTHESIS/OBJECTIVES: To evaluate AZI in a systemic and a toothpaste form for the treatment of CsAGO in dogs. The secondary objective was to determine which treatment is more effective. ANIMALS: Thirty-six client-owned dogs with CsAGO. METHODS: Dogs were randomly assigned to the following four groups: AZI capsule; AZI toothpaste; placebo capsule; and placebo toothpaste. Treatments were for 4 weeks, and measurements of gingival sulcus depth, tooth length and subjective global scores were taken at weeks 0, 2, 4 and 8. The AZI dose was 10 mg/kg daily, and brushing (8.5% AZI) was once daily. RESULTS: There was a significant decrease in gingival sulcus depth for the AZI capsule group at week 8 and for the AZI toothpaste group at weeks 2, 4 and 8. The mean decrease in gingival sulcus depth was significantly greater in active versus placebo groups (P = 0.0356). The tooth length and subjective global scores were not significantly different for any groups. Gastrointestinal adverse events occurred in all groups, but more frequently in the AZI capsule group. CONCLUSIONS AND CLINICAL IMPORTANCE: Azithromycin improved CsAGO in only one measured parameter, gingival sulcus depth. Only one dog in the AZI capsule group had complete resolution of CsAGO. Further studies are warranted. Azithromycin capsules were associated with the most gastrointestinal adverse effects. PMID- 23668860 TI - Synthesis, anticancer, and antibacterial activities of piplartine derivatives on cell cycle regulation and growth inhibition. AB - A series of piplartine derivatives were synthesized via Baylis-Hillman reaction and evaluated for anticancer and antibacterial activities. The cytotoxicity of these compounds was examined in two different human tumor cell lines, IMR-32 and HeLa. The antibacterial activity was examined in Staphylococcus aureus and Pseudomonas aeruginosa. The results showed that compounds 2b, 2e, and 2j were found to be the most active compounds, which displayed line no cytotoxicity, but G2-M cell cycle arrest in tumor cells, and showed cytostatic effects in bacteria. PMID- 23668861 TI - Isolation and characterization of SSEA3(+) stem cells derived from goat skin fibroblasts. AB - Novel stem cells expressing stage-specific embryonic antigen 3 (SSEA-3) reside among human dermal fibroblasts and are known as multilineage-differentiating stress-enduring (Muse) cells. They enhance the generation efficiency of induced pluripotent stem cells. However, Muse cells have only been found in humans. We aimed to isolate SSEA3-positive cells from terminally differentiated skin fibroblasts of adult goat and determine their pluripotency. Cell clusters from SSEA3(+) populations possessed stem cell-like morphological features and normal karyotypes, were consistently positive for alkaline phosphatase, and expressed stem cell pluripotency markers. These SSEA3(+) cells remained undifferentiated over eight passages in suspension culture and were able to differentiate into cells of all three germ layers in vitro and in vivo. Our combined findings suggest that a subset of adult stem cells expressing SSEA3 also exist among adult goat skin fibroblasts. We are the first to report that multipotent adult goat cells exist among terminally differentiated goat skin in suspension culture. Our results also provide a promising platform for generation of a transgenic goat, because the undifferentiated state of stem cells was thought to be more efficient as donor cells for somatic cell nuclear transfer. PMID- 23668863 TI - Exploration of plasma-enhanced chemical vapor deposition as a method for thin film fabrication with biological applications. AB - Chemical vapor deposition (CVD) has been used historically for the fabrication of thin films composed of inorganic materials. But the advent of specialized techniques such as plasma-enhanced chemical vapor deposition (PECVD) has extended this deposition technique to various monomers. More specifically, the deposition of polymers of responsive materials, biocompatible polymers, and biomaterials has made PECVD attractive for the integration of biotic and abiotic systems. This review focuses on the mechanisms of thin-film growth using low-pressure PECVD and current applications of classic PECVD thin films of organic and inorganic materials in biological environments. The last part of the review explores the novel application of low-pressure PECVD in the deposition of biological materials. PMID- 23668862 TI - Cloning changes the response to obesity of innate immune factors in blood, liver, and adipose tissues in domestic pigs. AB - The objective of this study was to evaluate the usefulness of cloned pigs as porcine obesity models reflecting obesity-associated changes in innate immune factor gene expression profiles. Liver and adipose tissue expression of 43 innate immune genes as well as serum concentrations of six immune factors were analyzed in lean and diet-induced obese cloned domestic pigs and compared to normal domestic pigs (obese and lean). The number of genes affected by obesity was lower in cloned animals than in control animals. All genes affected by obesity in adipose tissues of clones were downregulated; both upregulation and downregulation were observed in the controls. Cloning resulted in a less differentiated adipose tissue expression pattern. Finally, the serum concentrations of two acute-phase proteins (APPs), haptoglobin (HP) and orosomucoid (ORM), were increased in obese clones as compared to obese controls as well as lean clones and controls. Generally, the variation in phenotype between individual pigs was not reduced in cloned siblings as compared to normal siblings. Therefore, we conclude that cloning limits both the number of genes responding to obesity as well as the degree of tissue-differentiated gene expression, concomitantly with an increase in APP serum concentrations only seen in cloned, obese pigs. This may suggest that the APP response seen in obese, cloned pigs is a consequence of the characteristic skewed gene response to obesity in cloned pigs, as described in this work. This should be taken into consideration when using cloned animals as models for innate responses to obesity. PMID- 23668865 TI - Rehabilitation of children with traumatic brain injury: a critical review. AB - The purpose of this critical review of the English literature published between 1975 and 2009 was to assess the quality of the evidence for the efficacy of rehabilitation intervention after traumatic brain injury in children. "Evidence for intervention studies" was used to classify the research strength of design and report. Only a minority (16/439) of the published studies has been related to traumatic brain injury in children and has used a scientific or quasiscientific design. Only one study met the criteria of class I "evidence for intervention" studies. However, this study included adults, as well as children. The other 15 studies, although reporting positive results, had many methodologic deficiencies, and consequently their validity is questionable. Although the methodologic and ethical difficulties involved are acknowleged, a multicenter approach is required to achieve valid conclusions. Use of designs such as comparative effectiveness research might prove to be a practical solution. High-quality intervention research would facilitate stronger evidence-based counseling for children and families requiring posttraumatic brain injury intervention and to policy makers. PMID- 23668866 TI - Neurocysticercosis in infants and toddlers: report of seven cases and review of published patients. AB - Neurocysticercosis in infants and toddlers has received little attention in the literature, and little is known about the mechanisms of disease acquisition and clinical forms of presentation of the disease in this age group. All patients aged <=3 years with neurocysticercosis evaluated at Hospital-Clinica Kennedy, Guayaquil, over a 22-year period were included in this study. Their household contacts were screened to detect Taenia solium carriers, which may represent the source of infection. A literature search on neurocysticercosis in infants and toddlers was also performed to compare personal cases with those described elsewhere. A total of 25 infants and toddlers with neurocysticercosis were included (seven from our institution and 18 from the literature). All patients had seizures as the primary manifestation of the disease, and neuroimaging studies showed one or two parenchymal brain cysticerci in the colloidal stage in 88% of patients. The source of infection was investigated in 11 houses, including the seven households of the present series, and only four of the 18 reported in the literature. A Taenia carrier was found in five (45%) of these households, including three from the present series and two from the literature. A sizable proportion of infants and toddlers with neurocysticercosis have been infected at home. Compulsory search of Taenia carriers among household contacts will allow the detection of the potential source of infection and will reduce further spread of the disease. The search must not be limited to family members, but also extended to domestic employees who are in daily contact with the children. PMID- 23668867 TI - Valproate and lamotrigine in pediatric patients with refractory epilepsy: after the first year. AB - The combination of lamotrigine and valproate/divalproex sodium has been shown to be effective in the treatment of refractory epilepsy. This study aims to evaluate the pharmacologic properties of using this combination in a pediatric population refractory to antiepileptic drugs, with an extended follow-up. We studied a group of 51 patients, ranging from 4 to 16 years of age. Sixteen patients (31.4%) had generalized epilepsy and 35 (69.6%) had focal epilepsy. The combination was effective in 39 patients (76.5%) in the first year of follow-up and in 36 patients (70.6%) in the second year, with a reduction in drop attacks observed in 22 (88.5%). Adverse effects included rash, leading to discontinuation in four patients (7.8%). Slower introduction of lamotrigine minimizes adverse effects, thereby improving quality of life and adherence to treatment. In addition, therapeutic efficacy is maintained with lower doses of lamotrigine, even after the first year of treatment. PMID- 23668868 TI - The maintenance of wakefulness test in pediatric narcolepsy. AB - Objective tools are needed to assess the response to treatment in pediatric narcolepsy. This article presents a single-center experience documenting the use of the maintenance of wakefulness test (MWT) in a pediatric series. This study reviewed the charts of children with narcolepsy who had an MWT performed between January 2008 and June 2012. A cutoff was used for mean sleep latency: <8 minutes for inadequate control of hypersomnia, and >20 minutes to indicate adequate control on medications. Thirteen tests were performed on 10 children (median age 15.8 years, range 8.7-20.3 years) with narcolepsy, of which six had cataplexy and three were boys. Comorbid conditions included Prader-Willi syndrome, bipolar affective disorder, and epilepsy (n = 1 each). The median mean sleep latency for all studies was 16 minutes (range 5.8-40 minutes). Sleep-onset rapid eye movement sleep events were seen in three of 13 studies. In seven patients, findings from the MWT resulted in changes in management. These data suggest that the MWT may be a useful and feasible test for assessing response to treatment in children with narcolepsy. Future research is needed to obtain normative MWT data on children with and without narcolepsy. PMID- 23668869 TI - Mutation spectrum of NF1 and clinical characteristics in 78 Korean patients with neurofibromatosis type 1. AB - Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant disorders in humans. NF1 is caused by mutations of the NF1 gene. Mutation detection is complex owing to the large size of the NF1 gene, the presence of pseudogenes, and the great variety of mutations. Also, few probable genotype phenotype correlations have been found in NF1. In this study 78 Korean patients from 60 families were screened for NF1 mutations. Mutation analysis of the entire coding region and flanking splice sites was carried out and included the use of a combination of reverse transcription polymerase chain reaction, multiplex ligation probe amplification, or fluorescence in situ hybridization. Mutation spectrum and genotype-phenotype relationship were assessed. Fifty-two distinct NF1 mutations were identified in 60 families. The mutations included 30 single base substitutions (12 missense and 18 nonsense), 11 missplicing mutations, seven small insertion or deletions, and four gross deletions. Sixteen (30.8%) mutations were novel; c.1A>G, c.2033_2034insC, c.2540T>C, c.4537C>T, c.5546G>A, c.6792C>A, and c.6792C>G were recurrently identified. The mutations were evenly distributed across exon 1 through intron 47 of NF1, and no mutational hot spots were found. A genotype-phenotype analysis suggests that there is no clear relationship between specific mutations and clinical features. This analysis revealed a wide spectrum of NF1 mutations in Korean patients. As technologies advance in molecular genetics, the mutation detection rate will increase. Considering that 30.8% of detected mutations were novel, exhaustive mutation analysis of NF1 may be an important tool in early diagnosis and genetic counseling. PMID- 23668870 TI - A proposed new method for electroencephalography trace recording in children younger than two years: an observational study. AB - Epilepsy is a common disorder in pediatric neurology, and electroencephalography (EEG) continues to play an important role in its diagnosis. However, the small size of a child's head and immaturity of the brain make EEG interpretation more difficult in children than in adults. This article presents a new method of EEG recording for children younger than 2 years designed to improve recording accuracy in children with small heads. This novel method of EEG recording, in which an increase in distance between recording electrodes is achieved without decreasing the number of electrodes or channels, compares with the traditional 10 20 system in terms of pathologic waves, artifacts, sleep spindles, and wave frequencies. Increased wave amplitude was noted with the new montages in 90 of 105 (85.7%) individuals. The calculation of wave frequency was easier and more reliable in the new montages in comparison with the prevailing recordings. More numerous sleep spindles were detected in 49 of 105 (47.6%) children. The number of detected pathological waves increased in 49 of 105 (47.6%) children on the new montages versus the 10-20 electrode system. The incidence of artifact waves in the traces was similar between the two methods in 94 (89.5%) patients and diminished in 11 of 105 (10.5%) patients. These preliminary studies suggest that the new recording system might be a suitable substitute for the routine 10-20 system, especially in young infants and neonates. Further evaluation and multicenter clinical trials will contribute to the reliability of this proposed method. PMID- 23668871 TI - GABA(A) receptor imaging with positron emission tomography in the human newborn: a unique binding pattern. AB - Flumazenil is a specific, reversibly bound antagonist at benzodiazepine binding sites of gamma-aminobutyric acid A receptors; these sites can be imaged using positron emission tomography with 11C-flumazenil. We reported an exponential decline of flumazenil volume of distribution (proportional to receptor binding) of gamma-aminobutyric acid A receptors in children 2 to 17 years. Six newborns (33.3-46.7 weeks' postconception) were studied. All had experienced epileptic seizures and undergone 60-minute dynamic 11C-flumazenil-positron emission tomography imaging after injection of 0.4 mCi/kg of 11C-flumazenil. All newborns were scanned during their natural sleep. Binding potential (indicating flumazenil receptor binding) was calculated using Logan-plot analysis. Visual and quantitative analyses showed highest receptor binding in the amygdala-hippocampus region, sensory-motor cortex, thalamus, brainstem and basal ganglia, in that order. Cerebellum and most of the cerebral cortex showed relatively low binding. This is the first demonstration of gamma-aminobutyric acid A receptor binding in human neonates and is strikingly different from that in older children/adults, showing a programmed pattern of expression. The ontogeny data of flumazenil receptor binding from children may contribute to understanding regional differences in synaptic plasticity and improve rational therapeutic use of drugs acting at the gamma-aminobutyric acid A receptor in the pediatric population. PMID- 23668872 TI - Herpes simplex encephalitis with occipital localization in an infant: a different route of entry in the brain system? AB - Herpes simplex encephalitis classically involves the periventricular white matter in infants and the mesial temporal lobes, inferior frontal lobes, and insula in older children and adults. However, the increasing use of polymerase chain reaction to detect viral DNA in the cerebrospinal fluid has allowed the expansion of the spectrum of radiologic findings possibly associated with herpes simplex encephalitis. This study presents a rare case of a previously healthy infant with herpes simplex encephalitis with occipital involvement and permanent visual impairment. Possible pathogenic mechanisms are discussed. PMID- 23668873 TI - In utero oxcarbazepine and a withdrawal syndrome, anomalies, and hyponatremia. AB - Oxcarbazepine is an antiepileptic agent that has been used during pregnancy, although its safety during pregnancy has not been sufficiently established. This article presents an infant born with renal and cardiac malformations who developed a withdrawal syndrome and hyponatremia following in utero exposure to oxcarbazepine. The infant was born at 35 weeks' gestation by urgent cesarean section to a mother in status epilepticus who had been treated with oxcarbazepine throughout her pregnancy. Evaluation for congenital anomalies identified mild aortic stenosis, a bicuspid aortic valve, patent foramen ovale, patent ductus arteriosus, and severe left hydronephrosis due to left ureteropelvic junction stenosis. On the third day of life the infant developed clinical signs of a withdrawal syndrome, which peaked on day 7 and resolved by day 12. Transient hyponatremia resolved by day 8 of life. Follow-up showed normal development at 15 months. The association of a withdrawal syndrome with oxcarbazepine exposure has not been previously reported. The hyponatremia is consistent with adult reports. The possible association of oxcarbazepine with renal and cardiac malformations requires further confirmation. PMID- 23668874 TI - Neonatal hypocalcemic seizures due to excessive maternal calcium ingestion. AB - Hypocalcemia is a common, treatable cause of neonatal seizures. A term girl neonate with no apparent risk factors developed seizures on day 5 of life, consisting of rhythmic twitching of all extremities in a migrating pattern. Physical examination was normal except for jitteriness. Laboratory evaluation was unremarkable except for decreased total and ionized serum calcium levels and an elevated serum phosphorus level. The mother had ingested 3-6 g of calcium carbonate daily during the final 4 months of pregnancy to control morning sickness. The baby's electroencephalogram showed multifocal interictal sharp waves and intermittent electrographic seizures consisting of focal spikes in the left hemisphere accompanied by rhythmic jerking of the right arm and leg. Treatment with intravenous calcium gluconate over several days resulted in cessation of seizures and normalization of serum calcium. The child has remained seizure free and is normal developmentally at 9 years of age. Hypocalcemic seizures in this newborn were likely secondary to excessive maternal calcium ingestion, which led to transient neonatal hypoparathyroidism and hypocalcemia. Inquiry about perinatal maternal medication use should include a search for over the-counter agents that might not be thought of as "drugs," as in this case, antacids. PMID- 23668875 TI - Intraparenchymal schwannoma involving the brainstem in a young woman. AB - Schwannomas are tumors derived from the Schwann cells, which form the myelin sheath of the peripheral nerves. Fewer than 1% of these tumors occur within the brain parenchyma without arising from the cranial nerves. Only 55 cases have been published after the first recorded case. We report a 17-year-old girl with a 3 month history of unspecific dizziness, unsteadiness, and headache. Magnetic resonance imaging showed a heterogeneous cystic lesion involving midbrain, pons, and left cerebellar peduncle. The patient underwent a retromastoid craniotomy with complete resection of the tumor. Pathologic examination was compatible with intraparenchymal schwannoma. Since the first case of intraparenchymal schwannoma involving the brainstem was described in 1980, only seven others have been reported. Diagnosis of intraparenchymal schwannoma is almost never made preoperatively. Immunohistochemical staining is crucial in distinguishing a Schwannoma from a meningioma, glial tumor, or metastatic tumor. Pathologic findings are those typical of acoustic neurinomas. Histogenesis of intraparenchymal schwannoma remains unclear, and several theories have been proposed to explain their origin. The recognition of this curable tumor and its differentiation from brainstem glioma, which generally has a less favorable outcome, is of obvious importance. PMID- 23668876 TI - Cerebritis arising from acute sinusitis evolving into a large brain abscess. PMID- 23668877 TI - Spontaneous bowel perforation from distal catheter leading to meningitis: a rare but frequently overlooked complication of ventriculoperitoneal shunts. PMID- 23668878 TI - Asymmetric drug-induced tremor: rare feature of a common event. PMID- 23668879 TI - Prenatal diagnosis and management of a huge infratentorial/supratentorial multiloculated arachnoid cystic malformation in an infant. PMID- 23668880 TI - HIV/AIDS stigma and utilization of voluntary counselling and testing in Nigeria. AB - BACKGROUND: Despite the recognition of stigma as a hindrance to public health treatment and prevention there are gaps in evidence on the relationship between HIV stigma and VCT services utilization in Nigeria. The purpose of this study was to examine a community's perceptions, feelings and attitudes towards people living with HIV/AIDS and how this is associated with access to utilization of voluntary counselling and treatment in Nigeria. METHODS: A cross-sectional random study of Nigerians, using a mixed-method approach was carried out in two distinct ethnic areas of the country. Both quantitative and qualitative methods (mixed methods) were used to collect data in Osun State (Yoruba ethnic group) in the South-West and Imo State (Igbo ethnic group) in the South East. Multivariate logistic regression was the model used to examine the association of interest. RESULTS: It is shown that Nigerian public attitudes to HIV/AIDS and those infected with the disease are negative. The markers for stigma on the overall stigma index are significant predictors of utilization of voluntary counselling and testing. As the sum of negative feelings increases, there is less likelihood to using voluntary counselling and testing (VCT) and vice versa. CONCLUSIONS: Current national efforts at addressing the AIDS pandemic can only be successful when the issue of AIDS is de-stigmatized and is made a critical part of those efforts. One way to do this is through well-designed messages that should be posted in the media, community halls, health centers and other public places aimed at humanizing the disease and those affected and infected by it. PMID- 23668881 TI - Colloidal properties and stability of graphene oxide nanomaterials in the aquatic environment. AB - While graphene oxide (GO) has been found to be the most toxic graphene-based nanomaterial, its environmental fate is still unexplored. In this study, the aggregation kinetics and stability of GO were investigated using time-resolved dynamic light scattering over a wide range of aquatic chemistries (pH, salt types (NaCl, MgCl2, CaCl2), ionic strength) relevant to natural and engineered systems. Although pH did not have a notable influence on GO stability from pH 4 to 10, salt type and ionic strength had significant effects on GO stability due to electrical double layer compression, similar to other colloidal particles. The critical coagulation concentration (CCC) values of GO were determined to be 44 mM NaCl, 0.9 mM CaCl2, and 1.3 mM MgCl2. Aggregation and stability of GO in the aquatic environment followed colloidal theory (DLVO and Schulze-Hardy rule), even though GO's shape is not spherical. CCC values of GO were lower than reported fullerene CCC values and higher than reported carbon nanotube CCC values. CaCl2 destabilized GO more aggressively than MgCl2 and NaCl due to the binding capacity of Ca(2+) ions with hydroxyl and carbonyl functional groups of GO. Natural organic matter significantly improved the stability of GO in water primarily due to steric repulsion. Long-term stability studies demonstrated that GO was highly stable in both natural and synthetic surface waters, although it settled quickly in synthetic groundwater. While GO remained stable in synthetic influent wastewater, effluent wastewater collected from a treatment plant rapidly destabilized GO, indicating GO will settle out during the wastewater treatment process and likely accumulate in biosolids and sludge. Overall, our findings indicate that GO nanomaterials will be stable in the natural aquatic environment and that significant aqueous transport of GO is possible. PMID- 23668883 TI - TRO19622 promotes myelin repair in a rat model of demyelination. AB - BACKGROUND/AIMS: Multiple sclerosis is a neurodegenerative autoimmune disease characterized by diffuse oligodendrocyte injury, axonal loss and multifocal demyelination of myelin sheaths in the central nervous system. TRO19622 is a small cholesterol-like compound, which displays remarkable neuroprotective and neuroregenerative properties in neural cell culture and rodent models of nerve trauma. Therefore, the aim of the present study is to evaluate the pharmacological action of TRO19622 on the demyelination/remyelination processes by using a rat model of cuprizone-induced demyelination. METHODS: Using Female Sprague-Dawley rats models of demyelination, we morphologically and functionally assessed the effect of TRO19622 on myelination in vivo. RESULTS: In this study, we first provided in vivo proof that cuprizone intoxication contributed to spatial learning and memory ability injury and that TRO19622 restored neurological function. The structure of myelin injury and repair in cuprizone intoxication rats was then measured by T2-weighted magnetic resonance imaging. These magnetic resonance imaging-based results and trends were confirmed by histological, immunohistochemistry and electron microscopy analyses. CONCLUSIONS: The results clearly showed that TRO19622 promoted myelin formation with consequent functional improvement. PMID- 23668882 TI - Defining a key receptor-CheA kinase contact and elucidating its function in the membrane-bound bacterial chemosensory array: a disulfide mapping and TAM-IDS Study. AB - The three core components of the ubiquitous bacterial chemosensory array - the transmembrane chemoreceptor, the histidine kinase CheA, and the adaptor protein CheW - assemble to form a membrane-bound, hexagonal lattice in which receptor transmembrane signals regulate kinase activity. Both the regulatory domain of the kinase and the adaptor protein bind to overlapping sites on the cytoplasmic tip of the receptor (termed the protein interaction region). Notably, the kinase regulatory domain and the adaptor protein share the same fold constructed of two SH3-like domains. The present study focuses on the structural interface between the receptor and the kinase regulatory domain. Two models have been proposed for this interface: Model 1 is based on the crystal structure of a homologous Thermotoga complex between a receptor fragment and the CheW adaptor protein. This model has been used in current models of chemosensory array architecture to build the receptor-CheA kinase interface. Model 2 is based on a newly determined crystal structure of a homologous Thermotoga complex between a receptor fragment and the CheA kinase regulatory domain. Both models present unique strengths and weaknesses, and current evidence is unable to resolve which model best describes contacts in the native chemosensory arrays of Escherichia coli, Salmonella typhimurium, and other bacteria. Here we employ disulfide mapping and tryptophan and alanine mutation to identify docking sites (TAM-IDS) to test Models 1 and 2 in well-characterized membrane-bound arrays formed from E. coli and S. typhimurium components. The results reveal that the native array interface between the receptor protein interaction region and the kinase regulatory domain is accurately described by Model 2, but not by Model 1. In addition, the results show that the interface possesses both a structural function that contributes to stable CheA kinase binding in the array and a regulatory function central to transmission of the activation signal from receptor to CheA kinase. On-off switching alters the disulfide formation rates of specific Cys pairs at the interface, but not most Cys pairs, indicating that signaling perturbs localized regions of the interface. The findings suggest a simple model for the rearrangement of the interface triggered by the attractant signal and for longer range transmission of the signal in the chemosensory array. PMID- 23668884 TI - The professional legacy of Michael Metz. PMID- 23668885 TI - Nanoscale obstacle arrays frustrate transport of EphA2-Ephrin-A1 clusters in cancer cell lines. AB - Juxtacrine signaling interactions between the EphA2 receptor tyrosine kinase and its ephrin-A1 ligand contribute to healthy tissue maintenance and misregulation of this system is observed in at least 40% of human breast cancer. Hybrid live cell-supported membrane experiments in which membrane-linked ephrin-A1 displayed in supported membranes interacts with EphA2 in living cells have revealed large scale clustering of EphA2/ephrin-A1 complexes as well as their lateral transport across the cell surface during triggering. Here, we utilize 100 nm spaced hexagonally ordered arrays of gold nanodots embedded within supported membranes to present defined obstacles to the movement and assembly of EphA2 clusters. By functionalizing both the supported membrane and the nanodots with ephrin-A1, we perform a type of affinity chromatography on EphA2 signaling clusters in live cell membranes. Analysis of 10 different breast cancer cell lines reveals that EphA2 transport is most frustrated by nanodot arrays in the most diseased cell lines. These observations suggest that strong physical association among EphA2 receptors, as well as their assembly into larger clusters, correlates with and may contribute to the pathological misregulation of the EphA2/ephrin-A1 pathway in breast cancer. PMID- 23668886 TI - Neutrophil gelatinase-associated lipocalin (NGAL) for the early detection of cardiac surgery associated acute kidney injury. AB - BACKGROUND: Acute kidney injury (AKI) is a common complication after cardiac surgery. Neutrophil gelatinase-associated lipocalin (NGAL) may be an early biomarker for cardiac surgery-associated (CSA) AKI. We investigated whether increased urinary NGAL concentrations were predictive of AKI within 4 days after surgery and of mortality within 9 months. METHODS: Consecutive patients (n = 141) undergoing major cardiac surgery were included. Creatinine, blood urea nitrogen, cystatin C and urinary NGAL were measured before, 4 hours and 4 days after extracorporeal circulation. RESULTS: AKI was observed in 47 (33.3%) patients. The 4-hour urinary NGAL measurement was an independent predictor of stage 2 and 3 AKI (AUC 0.901; 95% CI 0.81-0.99). Patients with AKI had a higher 9-month mortality rate (19.1% vs. 3.2%; logrank 10.9; P = 0.001; HR 19.8; 95% CI 3.7-107.1). Urinary NGAL was not predictive of mortality within 9 months after surgery. CONCLUSION: Urinary NGAL is a biomarker for very early risk stratification of AKI after cardiac surgery and may be useful as a basis for early interventional strategies to prevent CSA-AKI. PMID- 23668887 TI - Leukocyte transcript alterations in West-African girls following a booster vaccination with diphtheria-tetanus-pertussis vaccine. AB - BACKGROUND: Observational studies from low-income countries have shown that the vaccination against diphtheria, tetanus and pertussis (DTP) is associated with excess female mortality due to infectious diseases. METHODS: To investigate possible changes in gene expression after DTP vaccination, we identified a group of nine comparable West African girls, from a biobank of 356 children, who were due to receive DTP booster vaccine at age 18 months. As a pilot experiment we extracted RNA from blood samples before, and 6 weeks after, vaccination to analyze the coding transcriptome in leukocytes using expression microarrays, and ended up with information from eight girls. The data was further analyzed using dedicated array pathway and network software. We aimed to study whether DTP vaccination introduced a systematic alteration in the immune system in girls. RESULTS: We found very few transcripts to alter systematically. Those that did mainly belonged to the Interferon (IFN) signalling pathway. We scrutinized this pathway as well as the Interleukin (IL) pathways. Two out of eight showed a down regulated IFN pathway and two showed an up-regulated IFN pathway. The two with down-regulated IFN pathway had also down-regulated IL-6 pathway. In the study of networks, two of the girls stood out as not having the inflammatory response as top altered network. CONCLUSION: The transcriptome changes following DTP booster vaccination were subtle, but although the material was small, it was possible to identify sub groups that deviate from each other, mainly in the IFN response. PMID- 23668888 TI - Peptide hormones in infants with feeding disorders. AB - The prevalence of eating problems in otherwise healthy infants is a common problem in Western countries. Peptide hormones such as adiponectin, ghrelin and resistin have been shown to play an important role in the regulation of satiety and hunger in several diseases and states. The aim of this study was to evaluate the peptide hormone levels in children with eating problems. In this study, 12 otherwise healthy infants (mean age 10.4 months) with eating problems and 12 healthy controls were studied. At their first hospital visit samples for analysis of adiponectin, ghrelin and resistin were obtained and a careful physical examination was carried out. To exclude any possible anatomic or metabolic reason for eating problems necessary investigations were also performed. Adiponectin levels were significantly higher in the cases than in the controls (p = 0.033), and the difference was still significant after adjustment for weight (p < 0.05). Resistin and ghrelin concentrations showed no significant differences. Conclusions. For the first time we were able to show in this pilot study that adiponectin concentrations were elevated in the infants with eating problems. Cross-sectional association does not necessarily imply causal relationship. Thus, further studies with larger number of cases will be needed to clarify the role of adiponectin in the eating problems in infants. PMID- 23668891 TI - Palliative treatment of presacral recurrence of endometrial cancer using irreversible electroporation: a case report. AB - INTRODUCTION: Irreversible electroporation (IRE) is a new minimally invasive tumor ablation technique which induces irreversible disruption of cell membrane integrity by changing the transmembrane potential resulting in cell death. Irreversible electroporation is currently undergoing clinical investigation as local tumor therapy for malignant liver and lung lesions. This is the first case report to describe the successful palliative ablation of a presacral recurrence of an endometrial cancer to achieve locoregional tumor control and pain relief. CASE PRESENTATION: A 56-year-old Caucasian woman was referred for interventional treatment of an advanced local recurrence of endometrial cancer (11.9 * 11.6 * 14.9cm) with infiltration of the sacral bone and nerve plexus. Due to the immediate proximity to the sacral plexus, the patient could neither undergo surgical therapy nor a second radiation therapy. Due to its ablation mechanism irreversible electroporation was deemed to be the best therapy option. CONCLUSION: We showed in this case that a large tumor mass adjacent to a bundle of neural structures, the sacral plexus, can be widely ablated by irreversible electroporation with only minor temporary impairment of the neural function, even though a large infiltrating tissue volume (941cm3) was ablated. PMID- 23668890 TI - Multicenter Australian trial of islet transplantation: improving accessibility and outcomes. AB - Whilst initial rates of insulin independence following islet transplantation are encouraging, long-term function using the Edmonton Protocol remains a concern. The aim of this single-arm, multicenter study was to evaluate an immunosuppressive protocol of initial antithymocyte globulin (ATG), tacrolimus and mycophenolate mofetil (MMF) followed by switching to sirolimus and MMF. Islets were cultured for 24 h prior to transplantation. The primary end-point was an HbA1c of <7% and cessation of severe hypoglycemia. Seventeen recipients were followed for >= 12 months. Nine islet preparations were transported interstate for transplantation. Similar outcomes were achieved at all three centers. Fourteen of the 17 (82%) recipients achieved the primary end-point. Nine (53%) recipients achieved insulin independence for a median of 26 months (range 7-39 months) and 6 (35%) remain insulin independent. All recipients were C-peptide positive for at least 3 months. All subjects with unstimulated C-peptide >0.2 nmol/L had cessation of severe hypoglycemia. Nine of the 17 recipients tolerated switching from tacrolimus to sirolimus with similar graft outcomes. There was a small but significant reduction in renal function in the first 12 months. The combination of islet culture, ATG, tacrolimus and MMF is a viable alternative for islet transplantation. PMID- 23668893 TI - Mapping the pharyngeal and intestinal pH of Caenorhabditis elegans and real-time luminal pH oscillations using extended dynamic range pH-sensitive nanosensors. AB - Extended dynamic range pH-sensitive ratiometric nanosensors, capable of accurately mapping the full physiological pH range, have been developed and used to characterize the pH of the pharyngeal and intestinal lumen of Caenorhabditis elegans in real-time. Nanosensors, 40 nm in diameter, were prepared by conjugating pH-sensitive fluorophores, carboxyfluorescein (FAM) and Oregon Green (OG) in a 1:1 ratio, and a reference fluorophore, 5-(and-6) carboxytetramethylrhodamine (TAMRA) to an inert polyacrylamide matrix. Accurate ratiometric pH measurements were calculated through determination of the fluorescence ratio between the pH-sensitive and reference fluorophores. Nanosensors were calibrated with an automated image analysis system and validated to demonstrate a pH measurement resolution of +/-0.17 pH units. The motility of C. elegans populations, as an indicator for viability, showed nematodes treated with nanosensors, for concentrations ranging from 50.00 to 3.13 mg/mL, were not statistically different to nematodes not challenged with nanosensors up to a period of 4 days (p < 0.05). The nanosensors were also found to remain in the C. elegans lumen >24 h after nanosensor challenge was removed. The pH of viable C. elegans lumen was found to range from 5.96 +/- 0.31 in the anterior pharynx to 3.59 +/- 0.09 in the posterior intestine. The pharyngeal pumping rate, which dictates the transfer of ingested material from the pharynx to the intestine, was found to be temperature dependent. Imaging C. elegans at 4 degrees C reduced the pharyngeal pumping rate to 7 contractions/min and enabled the reconstruction of rhythmic pH oscillations in the intestinal lumen in real-time with fluorescence microscopy. PMID- 23668892 TI - Utilization of nondentist providers and attitudes toward new provider models: findings from the National Dental Practice-Based Research Network. AB - OBJECTIVES: The purpose of this study was to quantify, within the National Dental Practice-Based Research Network, current utilization of dental hygienists and assistants with expanded functions and quantify network dentists' attitudes toward a new nondentist provider model - the dental therapist. METHODS: National Dental Practice-Based Research Network practitioner-investigators participated in a single, cross-sectional administration of a questionnaire. RESULTS: Current nondentist providers are not being utilized by network practitioner-investigators to the fullest extent allowed by law. Minnesota practitioners, practitioners in large group practices, and those with prior experience with expanded-function nondentist providers delegate at a higher rate and had more-positive perceptions of the new dental therapist model. CONCLUSIONS: Expanding scopes of practice for dental hygienists and assistants has not translated to the maximal delegation allowed by law among network practices. This finding may provide insight into dentists' acceptance of newer nondentist provider models. PMID- 23668894 TI - Late-onset Pneumocystis jirovecii pneumonia post-fludarabine, cyclophosphamide and rituximab: implications for prophylaxis. AB - OBJECTIVE: Fludarabine, cyclophosphamide and rituximab (FCR) therapy for lymphoid malignancies has historically been associated with a low reported incidence of Pneumocystis jirovecii pneumonia (PJP). However, prophylaxis was routinely used in early studies, and molecular diagnostic tools were not employed. The objective of this study was to review the incidence of PJP during and post-FCR in the era of highly sensitive molecular diagnostics and (18) F-fluorodeoxyglucose (FDG) positron emission tomography (PET)-computerised tomography (CT). METHODS: All patients treated with standard FCR at the Peter MacCallum Cancer Centre (March 2009 to June 2012) were identified from a medications management database. Laboratory-confirmed PJP cases during this time were identified from an electronic database. RESULTS: Overall, 66 patients were treated with a median of 5.5 FCR cycles. Eight PJP cases were identified, 6 of whom had received chemotherapy prior to FCR. In 5 cases, (18) F-FDG PET demonstrated bilateral ground-glass infiltrates. Median CD4(+) lymphocyte counts at time of PJP diagnosis and 9-12 months following FCR were 123 and 400 cells/MUL, respectively. In patients receiving no prophylaxis, 9.1% developed PJP during FCR. The rate following FCR was 18.4%, with median onset at 6 months (2.4-24 months). CONCLUSION: Given the high rate of late-onset PJP, consideration should be given for extended PJP prophylaxis for up to 12 months post-FCR, particularly in pretreated patients. Further evaluation of the role of CD4(+) monitoring is warranted to quantify risk of disease development and to guide duration of prophylaxis. PMID- 23668895 TI - Ultra-HPLC-MS(n) (Poly)phenolic profiling and chemometric analysis of juices from ancient Punica granatum L. Cultivars: a nontargeted approach. AB - This study deals with the qualitative characterization of the phenolic profile of pomegranate juices obtained from ancient accessions. Composition data, together with genetic, morphological, and agronomical parameters, may lead to a full characterization of such germplasm, with the aim of its retrieval and biodiversity valorization. Environmental adaptation, indeed, may contribute to an enrichment of the phenolic content in pomegranate, with important effects on its nutritional properties. More than 65 punicalagins, ellagic acid derivatives, flavonoids, anthocyanins, and phenylpropanoids were simultaneously detected from four centuries old Punica granatum L. ecotypes from northern Italy and compared with those of P. granatum cv. Dente di Cavallo, a widely cultivated Italian cultivar, using a simple ultra-HPLC (uHPLC) separation and MS(n) linear ion trap mass spectrometric characterization. Fingerprinting phytochemical discrimination of the accessions was obtained by chemometric analysis despite their limited geographical distribution, confirming the great intraspecific variability in pomegranate secondary metabolism. The combined recourse to uHPLC-MS(n) qualitative fingerprinting and multivariate analysis may represent a useful tool for the discrimination and selection of pomegranate germplasm with specific properties related to polyphenolic content. PMID- 23668896 TI - ShopSmart 4 Health - protocol of a skills-based randomised controlled trial promoting fruit and vegetable consumption among socioeconomically disadvantaged women. AB - BACKGROUND: There is a need for evidence on the most effective and cost-effective approaches for promoting healthy eating among groups that do not meet dietary recommendations for good health, such as those with low incomes or experiencing socioeconomic disadvantage. This paper describes the ShopSmart 4 Health study, a randomised controlled trial conducted by Deakin University, Coles Supermarkets and the Heart Foundation, to investigate the effectiveness and cost-effectiveness of a skill-building intervention for promoting increased purchasing and consumption of fruits and vegetables amongst women of low socioeconomic position (SEP). METHODS/DESIGN: ShopSmart 4 Health employed a randomised controlled trial design. Women aged 18-60 years, holding a Coles store loyalty card, who shopped at Coles stores within socioeconomically disadvantaged neighbourhoods and met low income eligibility criteria were invited to participate. Consenting women completed a baseline survey assessing food shopping and eating habits and food related behaviours and attitudes. On receipt of their completed survey, women were randomised to either a skill-building intervention or a wait-list control condition. Intervention effects will be evaluated via self-completion surveys and using supermarket transaction sales data, collected at pre- and post-intervention and 6-month follow-up. An economic evaluation from a societal perspective using a cost-consequences approach will compare the costs and outcomes between intervention and control groups. Process evaluation will be undertaken to identify perceived value and effects of intervention components. DISCUSSION: This study will provide data to address the currently limited evidence base regarding the effectiveness and cost-effectiveness of skill-building intervention strategies aimed at increasing fruit and vegetable consumption among socioeconomically disadvantaged women, a target group at high risk of poor diets. TRIAL REGISTRATION: Current Controlled Trials ISRCTN48771770. PMID- 23668897 TI - Zernike vs. Bessel circular functions in visual optics. AB - PURPOSE: We propose the Bessel Circular Functions as alternatives of the Zernike Circle Polynomials to represent relevant circular ophthalmic surfaces. METHODS: We assess the fitting capabilities of the orthogonal Bessel Circular Functions by comparing them to Zernike Circle Polynomials for approximating a variety of computationally generated surfaces which can represent ophthalmic surfaces. RESULTS: The Bessel Circular Functions showed better modelling capabilities for surfaces with abrupt variations such as the anterior eye surface at the limbus region, and influence functions. From our studies we find that the Bessel Circular Functions can be more suitable for studying particular features of post surgical corneal surfaces. CONCLUSIONS: We show that given their boundary conditions and free oscillating properties, the Bessel Circular Functions are an alternative for representing specific wavefronts and can be better than the Zernike Circle Polynomials for some important cases of corneal surfaces, influence functions and the complete anterior corneal surface. PMID- 23668898 TI - Protease expression in giant cell tumour of bone: a comparative study on feline and human samples. AB - Human giant cell tumour of bone (GCTB) is a rare low grade of malignancy tumour with tendency to recur. During tumourigenesis the bone remodeling balance is subverted by the tumour cellular components that interacting with bone matrix induce release of growth factors and cytokines, promoting cell proliferation and bone resorption. The master regulators of this positive feed-back are acid and neutral proteases that destroying extracellular matrix increase osteolysis. In contrast, in cats, very few data are reported on GCTB biological activity. In this study, histological features and metalloproteinase (MMPs) and urokinase plasminogen activator system (uPA) expression were compared in human and feline GCTB and differences in distribution and intensity related to histological pattern and clinical behaviour were determined. In both species, the overexpression of these molecules suggested a strong and complex cross-talk between tumour and microenvironment. PMID- 23668899 TI - The relationship between interpersonal problems, negative cognitions, and outcomes from cognitive behavioral group therapy for depression. AB - BACKGROUND: Interpersonal functioning is a key determinant of psychological well being, and interpersonal problems (IPs) are common among individuals with psychiatric disorders. However, IPs are rarely formally assessed in clinical practice or within cognitive behavior therapy research trials as predictors of treatment attrition and outcome. The main aim of this study was to investigate the relationship between IPs, depressogenic cognitions, and treatment outcome in a large clinical sample receiving cognitive behavioral group therapy (CBGT) for depression in a community clinic. METHODS: Patients (N=144) referred for treatment completed measures of IPs, negative cognitions, depression symptoms, and quality of life (QoL) before and at the completion of a 12-week manualized CBGT protocol. RESULTS: Two IPs at pre-treatment, 'finding it hard to be supportive of others' and 'not being open about problems,' were associated with higher attrition. Pre-treatment IPs also predicted higher post-treatment depression symptoms (but not QoL) after controlling for pre-treatment symptoms, negative cognitions, demographics, and comorbidity. In particular, 'difficulty being assertive' and a 'tendency to subjugate one's needs' were associated with higher post-treatment depression symptoms. Changes in IPs did not predict post treatment depression symptoms or QoL when controlling for changes in negative cognitions, pre-treatment symptoms, demographics, and comorbidity. In contrast, changes in negative cognitions predicted both post-treatment depression and QoL, even after controlling for changes in IPs and the other covariates. LIMITATIONS: Correlational design, potential attrition bias, generalizability to other disorders and treatments needs to be evaluated. CONCLUSIONS: Pre-treatment IPs may increase risk of dropout and predict poorer outcomes, but changes in negative cognitions during treatment were most strongly associated with improvement in symptoms and QoL during CBGT. PMID- 23668900 TI - Empathy in adults with clinical or subclinical depressive symptoms. AB - BACKGROUND: Depression is associated with problems in social functioning. Impaired empathic abilities might underlie this association. Empathy is a multidimensional construct and involves both affective and cognitive processes. We reviewed the literature to find out to what extent depression may be associated with abnormal levels of affective and cognitive empathy. We also explored potential gender differences in these associations. METHODS: We used PsycInfo and Medline to conduct a systematic review of all studies on empathy and depression conducted in individuals with a primary diagnosis of major depressive disorder (MDD; patient samples) or in individuals with primarily subclinical depressive symptoms (analog samples). RESULTS: Thirty-seven studies met the inclusion criteria. The results indicated that depression was related to one type of affective empathy. Specifically, depression was related to high levels of empathic stress but not to abnormal empathic concern. Further, depression was related to limited cognitive empathy, as indicated by poor perspective taking, theory of mind, and empathic accuracy. LIMITATIONS: Few studies have considered the variable gender in their design and analyses. Between and within study variation in demographic and clinical variables limits the interpretation of results. Self-report measures of empathy are subjective and vulnerable to bias. Poor performance on the more objective laboratory tasks might partially be explained by the broader cognitive deficits commonly observed in depression. Lastly, because all studies used a cross-sectional design, causality is difficult to establish. CONCLUSIONS: Empathic abilities may be impaired in depression. The relation between empathy, depression, and gender is unclear. Future studies could use implicit and more ecologically valid measures of empathy. Insight into impaired empathy in depression may not only help explain poor social functioning in MDD but also benefit clinician-patient interactions. PMID- 23668901 TI - Which symptoms are indicative of depression in epilepsy settings? An analysis of the diagnostic significance of somatic and non-somatic symptoms. AB - BACKGROUND: Depression is a common psychiatric co-morbidity in epilepsy. However, there have been no previous studies which have investigated the validity of individual symptoms for comorbid depression in epilepsy, in particular the diagnostic value of somatic and non-somatic symptoms. METHODS: Patients with epilepsy diagnosed in a specialist epilepsy clinic were approached and completed several self-reported mood scales, prior to or immediately after their neurology outpatient consultations. Symptoms of depression were elicited using PHQ-9, BDI II and HADS scales, comprising a total of 44 self report questions. 266 patients returned complete questionnaires of whom 18.0% met criteria for DSM-IV major depression according to the WHO Major Depression Inventory. RESULTS: Against DSM IV major depressive disorder (MDD), both somatic and non-somatic symptoms were valuable. The top five most useful questions relating to a diagnosis of MDD in epilepsy were "Moving or speaking so slowly that other people could have noticed" "Little interest or pleasure in doing things" "Feeling down depressed or hopeless" "Trouble concentrating on things such as reading" and "Feeling tired or having little energy." Four of these symptoms were rated as excellent initial screening questions for depression namely, "Moving or speaking so slowly that other people could have noticed" "Little interest or pleasure in doing things" "Feeling down depressed or hopeless" "Trouble concentrating on things such as reading." The item "Moving or speaking so slowly that other people could have noticed" from the PHQ9 was endorsed in about 90% of depressed patients with epilepsy but only about 6% of non-depressed patients. CONCLUSION: These findings suggest that both somatic and non-somatic symptoms can be valuable when diagnosing depression in epilepsy and should be considered when designing scales for depression in epilepsy. Specific psychological symptoms and specific somatic symptoms are indicative of depression in epilepsy. PMID- 23668902 TI - The clinical utility of different quantitative methods for measuring treatment resistance in major depression. AB - BACKGROUND: Despite the acknowledged healthcare and economic burdens of chronic major depression, there is no agreed method to rate the degree to which patients are conceptualised as being refractory to treatment. There are a variety of tools which can be used to describe treatment resistance but their utility in clinical practice is uncertain. METHODS: We used a range of contemporary tools to rate the treatment histories of patients in a variety of care settings which included: primary care; affective disorders specialist clinics; patients receiving ECT; referrals to a tertiary affective disorders service; and patients undergoing neurosurgical treatment (vagus nerve stimulation or anterior cingulotomy) for chronic, refractory major depression. RESULTS: All tools demonstrated statistically significant differences in scores between care settings, as well as between tiers of service, although differences between some groups were small and confidence intervals were wide. The Massachusetts General Hospital staging method appeared to perform as well as more complex scoring methods and represents a reasonable compromise between time to complete and its ability to inform management decisions. LIMITATIONS: Numbers in some groups were low, but are likely to be representative. The ability of such tools to predict outcome was not examined and the proposed cut-offs require validation. CONCLUSIONS: Currently available staging methods appear to have the ability to differentiate between clinically-relevant sub-groups of patients with major depression. Further development of such tools is warranted due to their ability to not only describe characteristics of patients in different care settings, but also meet the need to have meaningful cut-offs which might guide referral to specialist treatment. PMID- 23668903 TI - Do benzodiazepines moderate the effectiveness of bitemporal electroconvulsive therapy in major depression? AB - BACKGROUND: Electroconvulsive therapy (ECT) is the most effective treatment for depression. However, the use of concomitant medications during ECT is controversial, especially benzodiazepines, as some past evidence suggests these may reduce the efficacy of ECT. This study analysed the effect of benzodiazepines on treatment outcomes in a group of depressed patients treated with bitemporal (BT) ECT. METHODS: 90 patients with major depression who received BT ECT were analysed. Clinical, demographic and ECT data were extracted from clinical records. Mood improvement was rated by trained psychiatrists using the Hamilton Depression Rating Scale (HDRS-21) at baseline and after the final ECT treatment. The association between benzodiazepine dose and mood outcomes over the ECT course was examined with regression analyses, controlling for variables that may affect ECT efficacy. RESULTS: Hierarchical multiple regression analysis found only current episode duration (t=-4.77, p<0.001) was a significant predictor of change in HDRS. Benzodiazepine dose was not associated with a change in HDRS (p>0.05, R(2)=0.39). LIMITATIONS: This was a retrospective study. The use of the half-age dosing method for ECT did not permit examination of the effects of benzodiazepines on seizure threshold. CONCLUSIONS: Benzodiazepines did not affect the efficacy of BT ECT with the dosing method used. However, these results may not generalise to other forms of ECT, ECT given with other methods of dose determination or to other populations less responsive to ECT. PMID- 23668904 TI - Correlative gene expression pattern linking RNF123 to cellular stress-senescence genes in patients with depressive disorder: implication of DRD1 in the cerebral cortex. AB - BACKGROUND: The expression level of the RNF1213 gene in blood cells has been identified as a disease risk marker, more than ten years before the diagnosis of depression (Glahn et al., 2012). To explore the status of this gene in the acute depressive state we have quantified the expression of RNF123 in the blood leukocytes (N=17), dorsolateral prefrontal and cingulate cortex (N=24) of patients with diagnosed depression and of matched controls. We have measured the expression of the DRD1 gene as a "neuronal probe". We have also quantified the mRNA of six genes previously identified as markers of the biopsychological stress associated with major depression: FOS, DUSP1, OGG1, STMN1, p16(INK4a) and TERT. METHODS: The steady state of mRNA has been quantified by the real-time quantitative PCR technique. RESULTS: RNF123 was overexpressed by 45% in the cingulate cortex of patients with psychotic depression. There were distinct co expression patterns of RNF123 and stress-related genes in the blood cells and brain cortex of patients, demonstrating a transcriptional regulatory shift. In both the prefrontal and cingulate cortex of these patients a strong correlation interlinked STMN1, TERT and DRD1 pointing to a role of these genes in dopamine signaling. LIMITATIONS: The two groups of patients were clinically heterogeneous. All the patients had received antidepressant treatment, details of which were not available. CONCLUSION: We did not identify RNF123 as a clinically relevant, peripheral state marker of depression, but our study probably lacked statistical power to detect small effect size. It is likely to be involved in distinct pleiotropic molecular pathways at peripheral (blood) and central (brain) level. PMID- 23668905 TI - Differentiating Army suicide attempters from psychologically treated and untreated soldiers: a demographic, psychological and stress-reaction characterization. AB - BACKGROUND: Suicide is the leading cause of death in most armies during peace time. The recent dramatic rise in suicides in the US Army further focuses attention on the causes of suicidal behavior in the military. METHODS: This study investigated demographic characteristics, psychological profile and stress related risk factors associated with suicide attempts in Israelis aged 18-21 years, who served in the Army in 2009. Soldiers who attempted suicide (N=60) were compared to soldiers treated by a mental health professional, but reported no suicidal behavior (N=58), and to controls (N=50). RESULTS: Suicide attempters had lower socioeconomic status and less cognitive ability compared with treated soldiers and untreated control soldiers. Only 25% of the suicide attempters had received mental healthcare prior to the attempt. The majority of the attempts were non-lethal (86.2%), and only 5.2% used firearms. Attempters had more previous suicide attempts (37.9%) and deliberate selfharm incidents (19.3%), compared to almost no such behaviors in the other two groups. Following the suicide attempt, 77% were diagnosed with moderate to severe mental disorders, 44.8% personality disorders and 8.6% mood disorders. Attempters reported higher levels of general stress compared to their peers in the other two groups. Being away from home and obeying authority were especially more stressful in attempters. CONCLUSIONS: Young soldiers are less prone to seek mental health assistance, despite suffering from higher levels of stress. Screening is required to detect soldiers at risk for suicidal behavior and preventive intervention will require active outreach. PMID- 23668906 TI - Comment on "Prediction of soil sorption coefficients using model molecular structures for organic matter and the quantum mechanical COSMO-SAC model". PMID- 23668908 TI - Association between low-activity allele of cathecolamine-O-methyl-transferase (COMT) and Borderline Personality Disorder in an Italian population. AB - The objective of the present study was to test the association between Borderline Personality Disorder (BPD) and the cathecolamine-O-methyl-transferase (COMT) low activity (Met158) single nucleotide polymorphism (SNP). In this case-control study, DNA was obtained from venous blood of 19 BPD patients and 36 healthy subjects. COMT-Val158Met single-nucleotide polymorphism was genotyped by predesigned SNP assay. The COMT Met158 allele was over-represented in patients with BPD in comparison to normal subjects (68.4% vs 44.4%, respectively; Fisher exact test, p = .02). In terms of genotype, the Met158Met subjects were more frequent in patients versus controls (47.4% vs 22.2%, respectively), whereas the high-activity genotype Val158Val was under-represented (10.5% vs 33.3%, respectively). The allele encoding for the COMT with low enzymatic efficiency was found to be over-represented in BPD, possibly resulting in excessive synaptic dopaminergic activity and ultimately affecting externalizing behaviours, such as impulsivity and aggressiveness. PMID- 23668909 TI - The association of cancer patients' emotional suppression and their self-rating of psychological distress on short screening tools. AB - Emotional suppression of negative emotions was previously reported to be related to higher psychological distress in cancer patients. The possible effect of elevated levels of emotional suppression on the use of instruments for screening for distress in cancer patients has not been studied. To assess the relation of cancer patients' emotional suppression to their self-rating on the Distress Thermometer (DT) and Hospital Anxiety and Depression Scale (HADS). Two hundred forty one cancer patients, aged 21-87 years, completed the DT, the HADS and the Courtauld Emotional Control scale (CEC). Participants reported moderated levels of psychological distress but high mean levels of emotional suppression. Older age and higher levels of education and income predicted lower score on the DT and the HADS. Higher emotional suppression predicted lower self-reported psychological distress on the DT, the total HADS score and the HADS depression subscale, but not on the anxiety subscale. Emotion-regulation style may affect cancer patients' self-rating on the screening instruments, hence, reduce their accurate identification of distressed patients. PMID- 23668907 TI - The 3.2 A resolution structure of a receptor: CheA:CheW signaling complex defines overlapping binding sites and key residue interactions within bacterial chemosensory arrays. AB - Bacterial chemosensory arrays are composed of extended networks of chemoreceptors (also known as methyl-accepting chemotaxis proteins, MCPs), the histidine kinase CheA, and the adaptor protein CheW. Models of these arrays have been developed from cryoelectron microscopy, crystal structures of binary and ternary complexes, NMR spectroscopy, mutational, data and biochemical studies. A new 3.2 A resolution crystal structure of a Thermotoga maritima MCP protein interaction region in complex with the CheA kinase-regulatory module (P4-P5) and adaptor protein CheW provides sufficient detail to define residue contacts at the interfaces formed among the three proteins. As in a previous 4.5 A resolution structure, CheA-P5 and CheW interact through conserved hydrophobic surfaces at the ends of their beta-barrels to form pseudo 6-fold symmetric rings in which the two proteins alternate around the circumference. The interface between P5 subdomain 1 and CheW subdomain 2 was anticipated from previous studies, whereas the related interface between CheW subdomain 1 and P5 subdomain 2 has only been observed in these ring assemblies. The receptor forms an unexpected structure in that the helical hairpin tip of each subunit has "unzipped" into a continuous alpha-helix; four such helices associate into a bundle, and the tetramers bridge adjacent P5-CheW rings in the lattice through interactions with both P5 and CheW. P5 and CheW each bind a receptor helix with a groove of conserved hydrophobic residues between subdomains 1 and 2. P5 binds the receptor helix N-terminal to the tip region (lower site), whereas CheW binds the same helix with inverted polarity near the bundle end (upper site). Sequence comparisons among different evolutionary classes of chemotaxis proteins show that the binding partners undergo correlated changes at key residue positions that involve the lower site. Such evolutionary analyses argue that both CheW and P5 bind to the receptor tip at overlapping positions. Computational genomics further reveal that two distinct CheW proteins in Thermotogae utilize the analogous recognition motifs to couple different receptor classes to the same CheA kinase. Important residues for function previously identified by mutagenesis, chemical modification and biophysical approaches also map to these same interfaces. Thus, although the native CheW-receptor interaction is not observed in the present crystal structure, the bioinformatics and previous data predict key features of this interface. The companion study of the P5-receptor interface in native arrays (accompanying paper Piasta et al. (2013) Biochemistry, DOI: 10.1021/bi400385c) shows that, despite the non-native receptor fold in the present crystal structure, the local helix-in-groove contacts of the crystallographic P5-receptor interaction are present in native arrays and are essential for receptor regulation of kinase activity. PMID- 23668910 TI - Determinants of uptake of whole-body skin self-examination in older men. AB - Early detection through whole-body Skin Self-Examination (wbSSE) may decrease mortality from melanoma. Using the Health Action Process Approach (HAPA) or Health Belief Model (HBM) we aimed to assess determinants of uptake of wbSSE in 410 men 50 years of older who participated in the control group of a randomized trial. Overall, the HAPA was a significantly better predictor of wbSSE compared to the HBM (p < .001). The construct of self-efficacy in the HBM was a significant predictor of future wbSSE (p = .001), while neither perceived threat (p = .584) nor outcome expectations (p = .220) were. In contrast, self-efficacy, perceived threat, and outcome expectations predicted intention to perform SSE, which predicted behavior (p = .015). The HAPA construct volitional self-efficacy was also associated with wbSSE (p = .046). The use of the HAPA model for future SSE interventions for this population is warranted. PMID- 23668911 TI - Effects of a structured physical-activity counseling and referral scheme in long term unemployed individuals: a pilot accelerometer study. AB - Unemployment is associated with health risks. Physical activity produces health benefits. This study examined the effects of a physical activity counseling and exercise referral scheme on physical-activity behavior in long-term unemployed individuals. In this study, 51 long-term unemployed persons received physical activity counseling and exercise referral. Further, 21 unemployed and 17 employed persons with no intervention were included. Physical activity was measured over 7 consecutive days prior to and 12 weeks after counseling by accelerometer. Participants who started exercising increased their amount of moderate physical activity from 26 +/- 14 to 35 +/- 25 minutes/day and total physical activity from 207 +/- 86 to 288 +/- 126 counts/minute. Generally, unemployed persons were less active and less healthy compared to employed persons. Persons who are willing and motivated benefit from structured physical activity counseling and exercise referral and increase physical activity to a health promoting level. Physical activity inequalities could be reduced. PMID- 23668912 TI - Left atrial appendage occlusion: single center experience with PLAATO LAA Occlusion System((r)) and AMPLATZERTM Cardiac Plug. AB - OBJECTIVES: To evaluate patient selection, safety, feasibility, and midterm results of percutaneous left atrial appendage (LAA) occlusion. BACKGROUND: Oral anticoagulants (OAC) are the gold standard for stroke prevention in most patients with atrial fibrillation (AF). As the LAA is the main source of AF-related thrombi, LAA occlusion might reduce the thromboembolic (TE) risk. Recently, LAA closure was implemented in the European Society of Cardiology guidelines for the management of AF. METHODS: This retrospective single center study examined all LAA percutaneous closures (September 2003-September 2011). RESULTS: Twenty-five patients were included in the study; median age at closure was 73 years (minimum maximum range 49-85 years), 68% men. Median CHA2DS2-VASc score and HAS-BLED score were 5 (IQR 4-6) and 4 (IQR 4-5), respectively. Most frequent reason for LAA closure was intracranial hemorrhage during OAC treatment (52%). Successful device implantation was achieved in 96%. During a follow-up of 60.6 patient years, the TE stroke event rate was 4.95 per 100 patient years, versus an expected rate of 8.78 and 2.90 without and with OAC, respectively. No peripheral embolism occurred. Major procedure-related adverse events occurred in two patients. CONCLUSIONS: Percutaneous closure of the LAA is feasible and safe. Intracranial hemorrhage was the most important indication for LAA closure. A low number of TE stroke events occurred during follow-up. LAA closure might be a good alternative in patients with a firm contraindication for OAC. PMID- 23668913 TI - Effects of puerarin on cholinergic enzymes in the brain of ovariectomized guinea pigs. AB - Estrogen has beneficial effects on neurodegenerative disorders and cognitive function of postmenopausal women. Puerarin, isolated from Pueraria lobota, has been classified as a phytoestrogen, which can be highly effective against cerebrovascular diseases. In this study, the effects of puerarin on neural cholinergic system in the brain of ovariectomized guinea pigs were studied. The puerarin at the doses used (15 mg/kg body weight (bw)/day and 30 mg/kg bw/day) for 10 days had the estrogenic activity indicated by the attenuation of the reduction of uterine weight induced by ovariectomy. In brain, puerarin treatment increased choline acetyltransferase (ChAT) activity and expression in hippocampus, and increased ChAT immnuopositive signals in septal diagonal region. Puerarin treatment could suppress the increase of acetylcholinesterase expression and activity to the levels of the intact group, although they were not significantly different from those of the ovariectomized animals. Moreover, puerarin decreased the beta-amyloid immunopositive staining in hippocampus. In brief, the present study suggests that puerarin prevents the dysfunction of the neuronal cholinergic system and ameliorates the increase of beta-amyloid caused by estrogen deficiency. PMID- 23668915 TI - It may be possible to delay the onset of neurodegenerative diseases with an immunosuppressive drug (rapamycin). AB - Rapamycin might have beneficial effects, some of them acting via autophagy, in several cellular, fly and mouse models of degenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and dominant spinocerebellar atrophy (SCA). Other more sophisticated mechanisms have been described such as intervention in cell signaling and cell transcription particularly related to PD. Yet AD, PD, HD and SCA3 are chronic degenerative diseases, and chronic administration of rapamycin at advanced clinical stages may result in deleterious systemic effects due to chronic inhibition of mammalian target of rapamycin (mTOR). Studies are needed to uncover more specific inhibitors of particular mTOR signaling pathways, and to establish realistic guidelines for treatment at early stages of neurodegenerative processes. PMID- 23668914 TI - Arv1 regulates PM and ER membrane structure and homeostasis but is dispensable for intracellular sterol transport. AB - The pan-eukaryotic endoplasmic reticulum (ER) membrane protein Arv1 has been suggested to play a role in intracellular sterol transport. We tested this proposal by comparing sterol traffic in wild-type and Arv1-deficient Saccharomyces cerevisiae. We used fluorescence microscopy to track the retrograde movement of exogenously supplied dehydroergosterol (DHE) from the plasma membrane (PM) to the ER and lipid droplets and high performance liquid chromatography to quantify, in parallel, the transport-coupled formation of DHE esters. Metabolic labeling and subcellular fractionation were used to assay anterograde transport of ergosterol from the ER to the PM. We report that sterol transport between the ER and PM is unaffected by Arv1 deficiency. Instead, our results indicate differences in ER morphology and the organization of the PM lipid bilayer between wild-type and arv1Delta cells suggesting a distinct role for Arv1 in membrane homeostasis. In arv1Delta cells, specific defects affecting single C-terminal transmembrane domain proteins suggest that Arv1 might regulate membrane insertion of tail-anchored proteins involved in membrane homoeostasis. PMID- 23668916 TI - Epitaxial GaN microdisk lasers grown on graphene microdots. AB - Direct epitaxial growth of inorganic compound semiconductors on lattice-matched single-crystal substrates has provided an important way to fabricate light sources for various applications including lighting, displays and optical communications. Nevertheless, unconventional substrates such as silicon, amorphous glass, plastics, and metals must be used for emerging optoelectronic applications, such as high-speed photonic circuitry and flexible displays. However, high-quality film growth requires good matching of lattice constants and thermal expansion coefficients between the film and the supporting substrate. This restricts monolithic fabrication of optoelectronic devices on unconventional substrates. Here, we describe methods to grow high-quality gallium nitride (GaN) microdisks on amorphous silicon oxide layers formed on silicon using micropatterned graphene films as a nucleation layer. Highly crystalline GaN microdisks having hexagonal facets were grown on graphene dots with intermediate ZnO nanowalls via epitaxial lateral overgrowth. Furthermore, whispering-gallery mode lasing from the GaN microdisk with a Q-factor of 1200 was observed at room temperature. PMID- 23668919 TI - Italian psychology under protection: Agostino Gemelli between Catholicism and fascism. AB - Between the 1930s and 1940s, Agostino Gemelli (1878-1959) was the main Italian psychologist; he accepted and promoted an empirical conception of psychology influenced by neo-Thomism. The views of Gemelli were a landmark for many psychologists and psychological models in Catholic universities. Gemelli, moreover, throughout his scientific activity, continued ongoing work of expertise in matters concerning science, morality, and psychology. He was a Franciscan monk but also an officer of the Italian air force, a psychologist, and a rector. During the period of fascist rule in Italy, Gemelli sought compromise solutions to foster the survival of psychological institutions. Around his story, contrasting interpretations have emerged. The aim of this article is to look at Agostino Gemelli as an important historical subject to understand the ways in which scientific enterprises and institutions are likely to be influenced by political regimes and by the dogmatic and intolerant milieu. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23668917 TI - Rasch-built Overall Disability Scale for patients with chemotherapy-induced peripheral neuropathy (CIPN-R-ODS). AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a common neurological side effect of cancer treatment and may lead to declines in patients' daily functioning and quality of life. To date, there are no modern clinimetrically well-evaluated outcome measures available to assess disability in CIPN patients. The objective of the study was to develop an interval-weighted scale to capture activity limitations and participation restrictions in CIPN patients using the Rasch methodology and to determine its validity and reliability properties. A preliminary Rasch-built Overall Disability Scale (pre-R-ODS) comprising 146 items was assessed twice (interval: 2-3 weeks; test-retest reliability) in 281 CIPN patients with a stable clinical condition. The obtained data were subjected to Rasch analyses to determine whether model expectations would be met, and if necessarily, adaptations were made to obtain proper model fit (internal validity). External validity was obtained by correlating the CIPN-R-ODS with the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) neuropathy scales and the Pain-Intensity Numeric-Rating-Scale (PI-NRS). The preliminary R-ODS did not meet Rasch model's expectations. Items displaying misfit statistics, disordered thresholds, item bias or local dependency were systematically removed. The final CIPN-R-ODS consisting of 28 items fulfilled all the model's expectations with proper validity and reliability, and was unidimensional. The final CIPN-R-ODS is a Rasch-built disease-specific, interval measure suitable to detect disability in CIPN patients and bypasses the shortcomings of classical test theory ordinal-based measures. Its use is recommended in future clinical trials in CIPN. PMID- 23668918 TI - Clinically suspected acute myopericarditis with cardiac tamponade associated with peripheral blood eosinophilia presenting in early pregnancy: a case report. AB - INTRODUCTION: The clinical presentation of eosinophilic myocarditis may vary from asymptomatic to the manifestation of severe symptoms, including cardiac tamponade and arrhythmias. In pregnant patients with this condition, drugs must be used cautiously up to approximately the 4th month of pregnancy because drug use should be limited during the period of fetal organogenesis. CASE PRESENTATION: A 30-year old Asian woman at 14 weeks of pregnancy with progressive malaise was hospitalized. The electrocardiogram revealed ST elevation and low QRS voltage. Echocardiography revealed massive pericardial effusion and myocardial swelling. A laboratory examination revealed an increase in her white blood cell count, with a predominance of neutrophils. Pericardial drainage was performed for relief of the cardiac tamponade. The pericardial effusion revealed an abundance of eosinophils. Subsequently, the peripheral blood eosinophil count began to rise, and the patient was clinically diagnosed with eosinophilic myopericarditis. The patient's condition improved rapidly following the initiation of prednisolone treatment, and she finally delivered a full-term normal infant. CONCLUSIONS: A patient with clinically suspected myopericarditis in the early stage of pregnancy who improved rapidly with pericardial drainage and prednisolone therapy, and successfully delivered a normal full-term infant; the diagnosis was made in the early stage of the disease, based on the detection of an abundance of eosinophils in the pericardial effusion preceding the subsequent development of peripheral blood eosinophilia. PMID- 23668920 TI - The effect of stem surface treatment and material on pistoning of ulnar components in linked cemented elbow prostheses. AB - BACKGROUND: The ulnar component of a total elbow replacement can fail by "pistoning." Stem surface treatments have improved stability at the stem-cement interface but with varied success. This study investigated the role of surface treatment and stem substrate material on implant stability under axial loading. MATERIALS AND METHODS: Sixty circular stems (diameter, 8 mm) made of cobalt chrome (n = 30) or titanium (n = 30) had different surfaces: smooth, sintered beads, and plasma spray. The surface treatment length was either 10 mm or 20 mm. Stems were potted in bone cement, allowed to cure for 24 hours, and tested in a materials testing machine under a compressive staircase loading protocol. Failure was defined as 2 mm of push-out or completion of the protocol. Two-way analyses of variance compared the effects of surface treatment and substrate material on interface strength and motion. RESULTS: Significant interactions were found between surface treatment and substrate material for both interface strength and motion (P < .05). For titanium, the 20-mm beaded stems had greater interface strength than all other stems (P < .05) and had less motion than the 10-mm plasma spray and smooth stems (P < .05). For cobalt chrome, the 20-mm beaded stems showed greater interface strength (P < .05) and similar motion (P > .05) to the 20-mm plasma-spray stems (P < .05), which outperformed all other stems (P < .05). Mechanisms of catastrophic failure varied: smooth stems debonded at the stem cement interface, beaded stems experienced debonding of the beads from the stem, and plasma-spray stems showed loss of frictional force between the surface treatment and cement. DISCUSSION AND CONCLUSION: Stem surface treatment can enhance ulnar component stability but is dependent on substrate material. PMID- 23668921 TI - Efficacy of continuous subacromial bupivacaine infusion for pain control after arthroscopic rotator cuff repair. AB - BACKGROUND AND HYPOTHESIS: Arthroscopic rotator cuff repair can be a painful outpatient procedure. The purpose of this study was to evaluate the efficacy of continuous subacromial bupivacaine infusion to relieve pain after arthroscopic rotator cuff repair. We hypothesized that patients receiving continuous subacromial bupivacaine infusions after arthroscopic rotator cuff repair will have less postoperative pain in the early postoperative period than placebo and control groups. MATERIALS AND METHODS: Eighty-eight patients undergoing arthroscopic rotator cuff repair were randomized in a blinded fashion into 1 of 3 groups. Group 1 received no postoperative subacromial infusion catheter. Group 2 received a postoperative subacromial infusion catheter filled with saline solution. Group 3 received a postoperative subacromial infusion catheter filled with 0.5% bupivacaine without epinephrine. Infusion catheters were scheduled to infuse at 4 mL/h for 50 hours. Postoperative pain levels were assessed with visual analog scale scores hourly for the first 6 postoperative hours, every 6 hours for the next 2 days, and then every 12 hours for the next 3 days. Patients recorded daily oxycodone consumption for the first 5 postoperative days. RESULTS: Immediately postoperative, the group with no catheter had significantly lower visual analog scale scores (P = .04). There were no significant differences in visual analog scale scores among the groups at any other time point. There were no differences found among the groups regarding mean daily oxycodone consumption. CONCLUSION: The use of continuous bupivacaine subacromial infusion catheters resulted in no detectable pain reduction after arthroscopic rotator cuff repair based on visual analog scale scores and narcotic medication consumption. PMID- 23668922 TI - Surface modification of silicon oxide with trialkoxysilanes toward close-packed monolayer formation. AB - In order to scrutinize potential of trialkoxysilanes to form close-packed monolayer, surface modification of silicon oxide was carried out with the trialkoxysilanes bearing a ferrocene moiety for analysis by electrochemical methods. As it was found that hydrogen-terminated silicon reacts with trialkoxysilane through natural oxidation in organic solvents, where the silicon oxide layer is thin enough to afford conductivity for electrochemical analysis, hydrogen-terminated silicon wafer was immersed in trialkoxysilane solution for surface modification without oxidation treatment. Cyclic voltammetry measurements to determine surface concentrations of the immobilized ferrocene-silane on silicon surface were carried out with various temperature, concentration, solvent, and molecular structure, while the blocking effect in the cyclic voltammogram was investigated to obtain insight into density leading to the close packed layer. The results suggested that a monolayer modification tended to occur under milder conditions when the ferrocene-silane had a longer alkyl chain, and formation of a close-packed layer to show significant blocking effect was observed. However, the surface modification proceeded even when surface concentration of the immobilized ferrocene-silane was greater than that expected for the monolayer. On the basis of these tendencies, the surface of silicon oxide modified with trialkoxysilane is considered to be a partial multilayer rather than monolayer although a close-packed layer is formed. This result is supported by the comparison with carbon surface modified with ferrocene-diazonium, in which a significant blocking effect was observed when surface concentrations of the immobilized ferrocene moiety are lower than that for silicon oxide modified with ferrocene-silane. PMID- 23668923 TI - Sperm viral infection and male infertility: focus on HBV, HCV, HIV, HPV, HSV, HCMV, and AAV. AB - Chronic viral infections can infect sperm and are considered a risk factor in male infertility. Recent studies have shown that the presence of HIV, HBV or HCV in semen impairs sperm parameters, DNA integrity, and in particular reduces forward motility. In contrast, very little is known about semen infection with human papillomaviruses (HPV), herpesviruses (HSV), cytomegalovirus (HCMV), and adeno-associated virus (AAV). At present, EU directives for the viral screening of couples undergoing assisted reproduction techniques require only the evaluation of HIV, HBV, and HCV. However, growing evidence suggests that HPV, HSV, and HCMV might play a major role in male infertility and it has been demonstrated that HPV semen infection has a negative influence on sperm parameters, fertilization, and the abortion rate. Besides the risk of horizontal or vertical transmission, the negative impact of any viral sperm infection on male reproductive function seems to be dramatic. In addition, treatment with antiviral and antiretroviral therapies may further affect sperm parameters. In this review we attempted to focus on the interactions between defined sperm viral infections and their association with male fertility disorders. All viruses considered in this article have a potentially negative effect on male reproductive function and dangerous infections can be transmitted to partners and newborns. In light of this evidence, we suggest performing targeted sperm washing procedures for each sperm infection and to strongly consider screening male patients seeking fertility for HPV, HSV, and HCMV, both to avoid viral transmission and to improve assisted or even spontaneous fertility outcome. PMID- 23668924 TI - Effectiveness and tolerability of rotigotine transdermal patch for the treatment of restless legs syndrome in a routine clinical practice setting in Germany. AB - OBJECTIVE: We aimed to assess effectiveness and tolerability of rotigotine in patients with moderate to severe idiopathic restless legs syndrome (RLS) under daily practice conditions in Germany. METHODS: In this 3-month noninterventional study, effectiveness was assessed using RLS-6 (primary variables were symptom severity when falling asleep [item 2] and during the night [item 3]). Data were collected at baseline and at the end of treatment. Safety assessments included adverse events (AEs). RESULTS: Six hundred and eighty-four patients were treated with rotigotine and 418 (61%) completed the study. The full analysis set (FAS) comprised 564 patients (106 de novo; 458 pretreated [454 had complete rotigotine dosing data]). Mean rotigotine dose of longest duration was 2.4+/-1.4 mg/24 h. Rotigotine improved all RLS-6 items (mean change from baseline [item 2], -2.4+/ 3.6; [item 3], -2.7+/-3.4), with the most pronounced improvement observed in daytime symptoms while at rest (item 4, -2.9+/-3.2). AEs were typical of dopaminergic treatment and transdermal administration. De novo patients generally started rotigotine on 1 mg/24 h (85% [90/106]) and pretreated patients on 1 (50% [227/454]) or 2 mg/24 h (40% [183/454]). Most patients who were pretreated with levodopa (57%), pramipexole (84%), or ropinirole (78%) monotherapy discontinued these medications on initiation of rotigotine. CONCLUSIONS: Rotigotine was effective and well-tolerated when used in routine clinical practice. PMID- 23668925 TI - Response to comment on "Prediction of soil sorption coefficients using model molecular structures for organic matter and the quantum mechanical COSMO-SAC model". PMID- 23668927 TI - Urinary bladder malignant paraganglioma with vertebral metastasis: a case report with literature review. AB - Paraganglioma is a rare neuroendocrine neoplasm observed in patients of all ages, with an estimated incidence of 3/1,000,000 population. It has long been recognized that some cases are familial. The majority of these tumors are benign, and the only absolute criterion for malignancy is the presence of metastases at sites where chromaffin tissue is not usually found. Some tumors show gross local invasion and recurrence, which may indeed kill the patient, but this does not necessarily associate with metastatic potential. Here, we report a case of vertebral metastatic paraganglioma that occurred 19 months after the patient had undergone partial cystectomy for urinary bladder paraganglioma. We believe this to be a rarely reported bone metastasis of paraganglioma arising originally within the urinary bladder. In this report, we also provide a summary of the general characteristics of this disease, together with progress in diagnosis, treatment, and prognosis. PMID- 23668926 TI - Dysregulation of mTOR activity through LKB1 inactivation. AB - Mammalian target of rapamycin (mTOR) is aberrantly activated in many cancer types, and two rapamycin derivatives are currently approved by the Food and Drug Administration (FDA) of the United States for treating renal cell carcinoma. Mechanistically, mTOR is hyperactivated in human cancers either due to the genetic activation of its upstream activating signaling pathways or the genetic inactivation of its negative regulators. The tumor suppressor liver kinase B1 (LKB1), also known as serine/threonine kinase 11 (STK11), is involved in cell polarity, cell detachment and adhesion, tumor metastasis, and energetic stress response. A key role of LKB1 is to negatively regulate the activity of mTOR complex 1 (mTORC1). This review summarizes the molecular basis of this negative interaction and recent research progress in this area. PMID- 23668928 TI - Molecular mechanisms of tumor resistance to PI3K-mTOR-targeted therapy. AB - Deregulation of the phosphatidylinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) signaling pathway occurs frequently in a wide range of human cancers and is a major driving force in tumorigenesis. Thus, small molecules targeting this pathway are under active development as anticancer therapeutics. Although small-molecule inhibitors of the PI3K-mTOR pathway have shown promising clinical efficacy against human cancers, the emergence of drug resistance may limit their success in the clinic. To date, several resistance mechanisms, including both PI3K-dependent and -independent mechanisms, have been described. Here, we summarize the current understanding of resistance mechanisms to PI3K mTOR inhibitors and discuss potential strategies for overcoming resistance for potential clinical application. PMID- 23668929 TI - Intraarterial chemotherapy with gemcitabine and cisplatin in locally advanced or recurrent penile squamous cell carcinoma. AB - The prognosis of locally advanced or recurrent squamous cell carcinoma (SCC) of the penis after conventional treatment is dismal. This study aimed to evaluate the therapeutic effects of intraarterial chemotherapy with gemcitabine and cisplatin on locally advanced or recurrent SCC of the penis. Between April 1999 and May 2011, we treated 5 patients with locally advanced penile SCC and 7 patients with recurrent disease with intraarterial chemotherapy. The response rate and toxicity data were analyzed, and survival rates were calculated. After 2 to 6 cycles of intraarterial chemotherapy with gemcitabine and cisplatin, 1 patients with locoregionally advanced disease achieved a complete response, and 4 achieved partial response. Of the 7 patients with recurrent disease, 2 achieved complete response, 3 achieved partial response, 3 had stable disease, and 1 developed progressive disease. An objective tumor response was therefore achieved in 10 of the 12 patients. The median overall survival for the patients was 24 months (range, 10-50 months). Three out of 10 patients who responded were long term survivors after intraarterial chemotherapy. Intraarterial chemotherapy with gemcitabine and cisplatin may be effective and potentially curative in locoregionally advanced or recurrent penile SCC. The contribution of this therapy in the primary management of advanced or recurrent penile SCC should be prospectively investigated. PMID- 23668930 TI - Clinical implications of microRNAs in liver cancer stem cells. AB - The prognosis of patients diagnosed with hepatocellular carcinoma (HCC) is often dismal, mainly due to late presentation, high recurrence rate, and frequent resistance to chemotherapy and radiotherapy. Accumulating evidence on the differential microRNA (miRNA) expression patterns between non-tumor and HCC tissues or between liver cancer stem cells (CSCs) and non-CSC subsets and the significant clinical implications of these differences suggest that miRNAs are a promising, non-invasive marker for the prognosis and diagnosis of the disease. This perspective article summarizes the current knowledge of miRNAs in liver CSCs and highlights the need for further investigations of the role of miRNAs in regulating liver CSC subsets for possible future clinical applications. PMID- 23668932 TI - The zebrafish CreZoo: an easy-to-handle database for novel CreER(T2)-driver lines. AB - We report a new open access database, the zebrafish CreZoo ( http://crezoo.crt dresden.de ), which contains novel CreER(T2)-driver lines that express Cre fused to the mutated human ligand-binding domain of the estrogen receptor (CreER(T2)) in several tissues. Recently, the conditional Cre/loxP technology has been added to the toolbox for the precise manipulation of the zebrafish genome, but currently the number of CreER(T2)-driver lines is limited. To enlarge the pool of existing CreER(T2)-driver lines, we conducted a genome-wide screen using a gene trap cassette comprising a splice acceptor and an mCherry-tagged variant of CreER(T2). All molecular and expression data obtained in this screen are summarized in the CreZoo database, which currently comprises an inventory of about 47 Cre-driver lines expressing CreER(T2) in a cell- and tissue-specific manner during development and adulthood. Combined with other Cre-dependent effector lines, the CreZoo will be a great tool to manipulate the zebrafish genome. PMID- 23668931 TI - Efficacy of sotrastaurin plus tacrolimus after de novo kidney transplantation: randomized, phase II trial results. AB - Sotrastaurin, a novel immunosuppressant, blocks early T cell activation through protein kinase C inhibition. Efficacy and safety of sotrastaurin with tacrolimus were assessed in a dose-ranging non-inferiority study in renal transplant recipients. A total of 298 patients were randomized 1:1:1:1 to receive sotrastaurin 100 (n = 77; discontinued in December 2011) or 200 mg (n = 73) b.i.d. plus standard tacrolimus (sTAC; 5-12 ng/mL), sotrastaurin 300 mg (n = 75) b.i.d. plus reduced tacrolimus (rTAC; 2-5 ng/mL) or enteric-coated mycophenolic acid (MPA) plus sTAC (n = 73); all patients received basiliximab and corticosteroids. Composite efficacy failure (treated biopsy-proven acute rejection >= grade IA, graft loss, death or loss to follow up) rates at Month 12 were 18.8%, 12.4%, 10.9% and 14.0% for the sotrastaurin 100, 200 and 300 mg, and MPA groups, respectively. The median estimated glomerular filtration rates were 55.7, 53.3, 64.9 and 59.2 mL/min, respectively. Mean heart rates were faster with higher sotrastaurin doses and discontinuations due to adverse events and gastrointestinal adverse events were more common. Fewer patients in the sotrastaurin groups experienced leukopenia than in the MPA group (1.3-5.5% vs. 16.5%). Sotrastaurin 200 and 300 mg had comparable efficacy to MPA in prevention of rejection with no significant difference in renal function between the groups. PMID- 23668933 TI - A novel, reliable method for repeated blood collection from aquarium fish. AB - Collecting blood from laboratory animals is necessary for a wide variety of scientific studies, but the small size of the zebrafish makes this common procedure challenging. We developed a novel, minimally invasive method to collect repeated blood samples from adult zebrafish. This method minimizes trauma to the zebrafish and yields a low mortality rate of 2.3%. The maximum volume of blood that can be collected using this technique is approximately 2% of body weight. To avoid blood loss anemia and hemorrhagic death, we recommend that the total blood sample volume collected over repeat bleeds should be <=0.4% of body weight per week, and <=1% of body weight per 2 weeks. Additionally, we applied this method to the study of zebrafish glycolipid metabolism by measuring blood glucose and plasma triacylglyceride levels weekly over a 5-week period in both control and overfed zebrafish. The overfed fish developed significantly increased fasting blood glucose levels compared with normally fed fish. This new method of blood collection is essential for zebrafish or other small aquarium fish research requiring repeated blood samples, and increases the utility of the zebrafish as a model animal in hematological studies of human diseases. PMID- 23668934 TI - The zebrafish as a model to study polycystic liver disease. AB - In the polycystic liver diseases (PLD), genetic defects initiate the formation of cysts in the liver and kidney. In rodent models of PLD (i.e., the PCK rat and Pkd2(WS25/-) mouse), we have studied hepatorenal cystic disease and therapeutic approaches. In this study, we employed zebrafish injected with morpholinos against genes involved in the PLD, including sec63, prkcsh, and pkd1a. We calculated the liver cystic area, and based on our rodent studies, we exposed the embryos to pasireotide [1 MUM] or vitamin K3 [100 MUM] and assessed the endoplasmic reticulum (ER) in cholangiocytes in embryos treated with 4 phenylbutyrate (4-PBA). Our results show that (a) morpholinos against sec63, prkcsh, and pkd1a eliminate expression of the respective proteins; (b) phenotypic body changes included curved tail and the formation of hepatic cysts in zebrafish larvae; (c) exposure of embryos to pasireotide inhibited hepatic cystogenesis in the zebrafish models; and (d) exposure of embryos to 4-PBA resulted in the ER in cholangiocytes resolving from a curved to a smooth appearance. Our results suggest that the zebrafish model of PLD may provide a means to screen drugs that could inhibit hepatic cystogenesis. PMID- 23668935 TI - Impaired exploratory eye movements in children with Asperger's syndrome. AB - OBJECTIVE: Previous eye-tracking studies using an eye mark recorder have reported that disturbances in exploratory eye movements in adult schizophrenic patients are associated with social functioning. The current study sought to determine whether exploratory eye-movement disturbances are present in children with Asperger's syndrome (AS) compared with typically developing (TD) children. MATERIALS/PARTICIPANTS: The participants were 23 children with AS and 23 age matched TD children. We measured exploratory eye movements using an EMR-8B eye mark recorder and an exploratory eye movement-measuring device. METHOD: Eye movements were recorded while participants freely observed a geometric figure (free viewing task), and while they complied with the instructions of an experimenter (repeat-comparison task). We assessed eye fixation points (EFPs) and total eye scanning length (TESL) in all tasks, and measured the responsive search score (RSS) in the repeat-comparison task. RESULTS: In the free viewing task, children with AS exhibited significantly shorter TESL compared with TD children. In the repeat-comparison task, children with AS exhibited significantly lower RSS. Autism Spectrum Screening Questionnaire scores were negatively correlated with both EFP and TESL, but not RSS. CONCLUSION: The current results revealed that children with AS exhibited dysfunction in exploratory eye movements. Thus, assessing exploratory eye movements in a repeat-comparison task may be useful for detecting social impairment among children with AS. PMID- 23668936 TI - Primary structure and characterization of a non hemorrhagic metalloproteinase with fibrinolytic activity, from the snake venom of Protobothrops tokarensis (Tokara-habu). AB - A low molecular weight metalloproteinase, named PT-H2 protease, with fibrinolytic activity, was purified from the venom of Protobothrops tokarensis (Tokara-habu) by gel-filtration using Sephadex G-100, and ion-exchange chromatographies using CM-Sepharose Fast Flow and Mono S HR 5/5. By this procedure, about 85 mg of purified protein were obtained from 1.0 g of P. tokarensis venom. The purified protein showed a single protein band with a molecular weight of about 22.5 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under reducing conditions. The pI of purified protein showed a single band of 6.8. This proteinase showed a strong fibrinolytic activity. Further, this proteinase showed fibrinogenase activity and proteolytic activity against synthetic substrates for matrix metalloproteinase, ADAM-17, and TACE (tumor necrosis factor converting enzyme). These proteolytic activities were inhibited by metalloproteinase inhibitors such as EDTA. PT-H2 protease consisted of 201 amino acid residues and had a calculated molecular weight of 22,994.7 Da. This protein showed conservation of the Zn2+-binding HEXXHXXGXXHD sequence. PT-H2 protease showed high homology from 51.7 to 99.5% with amino acid sequences of other snake venom metalloproteinases. PMID- 23668937 TI - Conotoxin truncation as a post-translational modification to increase the pharmacological diversity within the milked venom of Conus magus. AB - Milked venoms of Conus demonstrate direct lineage to US Food and Drug Administration approved and present in-trial drug leads. Yet the complexity of the milked venom has not been adequately investigated or characterized, in a sustainable manner. In this study we determine the extent of molecular mass differentiation in milked venom from captive Conus magus and confirm the expression of known conotoxin constituents. We demonstrate the presence of post translational N-terminal peptide truncation, which differentiates the milked venom constituent alpha-conotoxin MI from the novel alpha-conotoxin MIC. This truncation has a direct effect on peptide bioactivity--K(i) of 89.1 +/- 9.1 and 248.7 +/- 10.9 nM (alpha-conotoxin MI and MIC respectively) toward the muscle type nAChR (Torpedo). These milked venom conotoxins demonstrated acute lethality in fish, with a LD50 of 12.24 and 23.29 MUg kg-1 for alpha-conotoxin MI and MIC respectively. By synthesizing and investigating the synthetic intermediate variant des[Gly]1alpha-conotoxin MI, it was demonstrated that retention of the N terminal arginine residue increased affinity at the muscle-type nAChR site (binding Ki of 73.3 +/- 5.8 nM and lethal toxicity level LD50 of 8.19 MUg kg-1). This post-translational modification event within the milked venom of C. magus represents a unique mechanism by which cone snails are able to increase the chemical and pharmacological diversity of their venoms. PMID- 23668938 TI - VdTX-1, a reversible nicotinic receptor antagonist isolated from venom of the spider Vitalius dubius (Theraphosidae). AB - Theraphosid spider venoms can block neurotransmission in vertebrate nerve-muscle preparations in vitro, but few of the components involved have been characterized. In this work, we describe the neuromuscular activity of venom from the Brazilian theraphosid Vitalius dubius and report the purification and pharmacological characterization of VdTX-1, a 728 Da toxin that blocks nicotinic receptors. Neuromuscular activity was assayed in chick biventer cervicis preparations and muscle responses to exogenous ACh and KCl were determined before and after incubation with venom or toxin. Changes in membrane resting potential were studied in mouse diaphragm muscle. The toxin was purified by a combination of filtration through Amicon(r) filters, cation exchange HPLC and RP-HPLC; toxin purity and mass were confirmed by mass spectrometry. Venom caused progressive neuromuscular blockade and muscle contracture; the blockade but not the contracture was reversible by washing. Venom attenuated contractures to exogenous ACh and KCl. Filtration yielded low (LM, <5 kDa) and high (HM, >5 kDa) fractions, with the latter reproducing the contracture seen in venom but with a slight and progressive twitch blockade. The LM fraction caused reversible blockade and attenuated contractures to ACh, but had no effect on contractures to KCl. VdTX-1 (728 Da) purified from the LM fraction was photosensitive and reduced the E(max) to ACh in biventer cervicis muscle without affecting the EC50; VdTX-1 also abolished carbachol-induced depolarizations. V. dubius venom contains at least two components that affect vertebrate neurotransmission. One component, VdTX-1, blocks nicotinic receptors non-competitively to produce reversible blockade without muscle contracture. PMID- 23668939 TI - Vertical graphene-base hot-electron transistor. AB - We demonstrate vertical graphene-base hot-electron transistors (GB-HETs) with a variety of structures and material parameters. Our GB-HETs exhibit a current saturation with a high current on-off ratio (>10(5)), which results from both the vertical transport of hot electrons across the ultrathin graphene base and the filtering of hot electrons through a built-in energy barrier. The influences of the materials and their thicknesses used for the tunneling and filtering barriers on the common-base current gain alpha are studied. The optimization of the SiO2 thickness and using HfO2 as the filtering barrier significantly improves the common-base current gain alpha by more than 2 orders of magnitude. The results demonstrate that GB-HETs have a great potential for high-frequency, high-speed, and high-density integrated circuits. PMID- 23668940 TI - Comparing two methods of identifying alliance rupture events. AB - This study compared two methods of detecting ruptures in therapy sessions, a procedure based on a self-report measure, the Working Alliance Inventory (WAI), and an observational Rupture Resolution Rating System (3RS). We anticipated that the 3RS would detect more ruptures than the WAI. We examined the longitudinal data of 38 patient-therapist dyads in a cognitive-behavioral therapy condition. The sample included cases that did not complete treatment (dropped cases) as well as good-outcome and poor-outcome cases. At the end of each session, patients completed the WAI self-report questionnaire. Six judges were trained to observe and detect the occurrence of ruptures, and then rated 201 videotaped sessions. Longitudinal statistical models were applied to the data retrieved from the WAI questionnaires completed by patients. We found discrepancies in the ability of the two methods to detect rupture events with the observational 3RS detecting more ruptures than the WAI. Thus, the use of observational systems for the detection of alliance ruptures is crucial for effectively assessing the quality of the therapeutic alliance over the course of treatment. Furthermore, observational systems proven to detect ruptures can be used to improve clinical practice and training of new clinicians. PMID- 23668941 TI - Elective surgical cricothyroidotomy in oral and maxillofacial surgery. AB - Surgical Cricothyroidotomy is regarded as an emergency procedure today even though it has a good evidential record as an elective surgical airway. A misunderstanding of Jackson's landmark paper in 1921 has made the simple and safe procedure unpopular because of the fear of subglottic stenosis. We present the incidence of subglottic stenosis after surgical cricothyroidotomy, discuss evidence for elective surgical cricothyroidotomy, and suggest potential applications in oral and maxillofacial surgery. PMID- 23668942 TI - Oral cancer examinations among smokers and moderate-heavy drinkers, United States, 2008. AB - OBJECTIVES: Smoking and moderate-heavy alcohol consumption are primary risk factors for oral cancer. This report uses national data to test whether adults with these risk factors received oral cancer examinations (OCEs) at a rate consistent with their risk. METHODS: Data from the 2008 National Health Interview Survey (NHIS) were used for this analysis. The main outcome variables described lifetime receipt of extraoral or intraoral OCEs. Other variables described health care visits, as well as the timing of, reasons for, and type of practitioner providing the most recent OCE. Descriptor variables were smoking and drinking status. Covariates included several sociodemographic factors. Weighted bivariate and multivariable analyses were conducted using SUDAAN software. RESULTS: According to the 2008 NHIS, about 34 percent of adults aged 40 years or older reported receiving either an extraoral or intraoral examination during their lifetime. Current smokers were no more likely to have received an OCE than were never smokers, controlling for relevant covariates. Moderate-heavy drinkers and light drinkers were significantly more likely to have received an OCE than were lifetime abstainers. CONCLUSIONS: Current smokers did not receive OCEs at a rate consistent with their increased risk, whereas moderate-heavy drinkers did. One explanation for this finding is that medical and dental visit behaviors indirectly influenced OCE rates. Dentition status played an important role, as having teeth is strongly associated with dental visit behaviors. Health-care practitioners are encouraged to consider the smoking and drinking statuses of their patients when they conduct routine physical examinations of the head and neck. PMID- 23668943 TI - [Results after laparoscopic liver resection: an appropriate option in malignant disease]. AB - INTRODUCTION: The laparoscopic approach is not yet widely used in liver surgery, but has proven to be safe and feasible in selected patients even in malignant disease. The experience and results of a hepato-pancreato-biliary (HPB) surgery unit in the treatment of malignant liver disease by laparoscopic approach is presented. MATERIAL AND METHODS: Between February 2002 and May 2011, 71 laparoscopic liver resections were performed, 43 for malignant disease (only patients with more than one year of follow-up were included). Mean age was 63 years old and 58% of the patients were male. Forty-nine per cent of the lesions were located in segments ii-iii. Thirty segmentectomies were performed, 7 limited resections and 6 major hepatectomies. RESULTS: The median operative time was 163 min. There were 3 conversions. Five cases (11%) required blood transfusion. The oral intake began at 32 h and the median hospital stay was 6.7 days. There were no reoperations and there was one case of mortality. Nine patients (21%) had postoperative complications. The mean number of resected lesions was 1.2, with an average size of 3.5 cm. All resections were R0. The median survival after resection of colorectal liver metastases (CLM) was 69% and 43.5% at 36 and 60 months, respectively, and 89% and 68% at 36 and 60 months, respectively, in hepatocellular carcinoma (HCC). CONCLUSION: The laparoscopic liver resection in malignant disease is feasible and safe in selected patients. The same oncological rules as for open surgery should be followed. In selected patients it offers similar long-term oncological results as open surgery. PMID- 23668944 TI - Usefulness of an optical tracking system in laparoscopic surgery for motor skills assessment. AB - INTRODUCTION: The objective of this study is to assess the usefulness of an evaluation system of surgical skills based on motion analysis of laparoscopic instruments. METHOD: This system consists of a physical laparoscopic simulator and a tracking and assessment system of technical skills in laparoscopy. Six surgeons with intermediate experience (between 1 and 50 laparoscopic surgeries) and 5 experienced surgeons (more than 50 laparoscopic surgeries) took part in this study. All participants were right-handed. The subjects performed 3 repetitions of a cutting task on synthetic tissue with the right hand, dissection of a gastric serous layer, and a suturing task in the dissection previously done. Objective metrics such as time, path length, speed of movements, acceleration and motion smoothness were analyzed for the instruments of each hand. RESULTS: In the cutting task, experienced surgeons show less acceleration (P=.014) and a smoother motion (P=.023) using the scissors. Regarding the dissection activity, experienced surgeons need less time (P=.006) and less length with both instruments (P=.006 for dissector and P=.01 for scissors). In the suturing task, experienced surgeons require less time (P=.037) and distance travelled (P=.041) by the dissector. CONCLUSIONS: This study shows the usefulness of the evaluation system for the cutting, dissecting, and suturing tasks. It represents a significant step in the development of advanced systems for training and assessment of surgical skills in laparoscopic surgery. PMID- 23668945 TI - One-pot environmentally friendly approach toward highly catalytically active bimetal-nanoparticle-graphene hybrids. AB - A one-pot universal approach with simple metal sputtering onto room temperature ionic liquids has been developed to prepare bimetal-nanoparticle (NP)-graphene hybrids, and the process is environmentally friendly and completely free of additives and byproducts. The graphene-supported bimetallic NPs have an Ag-based core and an Au/Pd-rich shell, demonstrated by the scanning transmission electron microscopy. The X-ray absorption near-edge spectroscopy using synchrotron radiation reveals the occurrence of charge redistribution at both the Ag@Au and Ag@Pd core-shell interfaces. The as-prepared Ag@Au and Ag@Pd bimetal-NP-graphene hybrids are highly catalytically active for reduction of 4-nitrophenol, whose catalytic activity is superior to the corresponding monometallic hybrids. The catalytic superiority is ascribed to the electronic structure modification and morphological irregularity of the graphene-supported bimetallic NPs. PMID- 23668946 TI - Identification and characterisation of maize microRNAs involved in developing ears. AB - In maize, kernel row number trait is determined during the period when spikelet pair meristems (SPMs) give rise to spikelet meristems (SMs). Expression levels of many genes change during this period due to regulation at transcriptional and post-transcriptional levels. MicroRNAs (miRNAs) act as key regulating factors of post-transcriptional gene expression. To discover miRNAs involved in maize ear development, Solexa deep sequencing was performed on a maize inbred line, Zong3. Ears at the stage when SPMs produce SMs were harvested to extract RNA. Deep sequencing revealed 85 conserved miRNAs belonging to 17 miRNA families. miRNA families differed greatly in their abundance, from over 160,000 to only five reads. In addition, 31 novel maize miRNAs were identified using stringent criteria. The results show that miRNA-mediated regulation of gene expression is present in developing maize ears at the stage when SPMs produce SMs; both conserved and novel miRNAs are involved. PMID- 23668947 TI - Rapid onset of a kainate-induced mirror focus in rat hippocampus is mediated by contralateral AMPA receptors. AB - The development of an epileptic "mirror" focus in an area of the brain contralateral to the primary epileptic focus typically evolves over days in the experimental setting after status epilepticus or electrical kindling of the primary focal region. In contrast, we observed the rapid development of an apparent mirror focus in the contralateral hippocampus following microinjection of kainic acid (KA) in the ipsilateral hippocampus in rats. Using multisite intracranial recordings, local field potentials were recorded in anesthetized adult male rats using electrodes implanted in the CA3 region of both hippocampi and in the anteromedial nucleus of the thalamus. Epileptogenesis was induced by microinjection of KA in the ipsilateral CA3 region. Development of seizures was followed under three experimental perturbations to the contralateral hippocampus: (A) no treatment, (B) pre-treatment with microinjection of the AMPA/Kainate receptor antagonist CNQX, and (C) pre-treatment with microinjection of the selective kainate receptor antagonist UBP 301. Both control and UBP 301 groups had seizures preferentially originate in the contralateral hippocampus appearing within ten minutes of KA injection. In contrast, the CNQX group had seizures preferentially originate in the ipsilateral hippocampus. By tracking the order of seizure onset, the probability that a hippocampal seizure would propagate across commissural fibers prior to any thalamic seizure activity was significantly reduced in the CNQX group compared to control and UBP groups suggesting that the AMPA receptor mediated component responsible for mirror focus development was also necessary for the spread of ictal activity via the commissural fibers. Understanding how a complex circuit in the brain develops may be critical to uncovering ways of either disrupting its development or treating its effects. The rapid appearance of a contralateral mirror focus via AMPA receptors in a limbic epilepsy model might be the mechanism by which a putative long-term mirror focus is established in vivo and may also underlie how secondary generalization progresses in some cases. PMID- 23668948 TI - PIP implant biodurability: a post-publicity update. AB - INTRODUCTION: in the year since Poly Implant Prothese (PIP) found itself the epicentre of intense, global media attention initial studies have started to evaluate the abnormally high premature device failure rate suspected for their mammary prostheses. A cohort free from most of the usual confounding variables affords opportunities to improve upon previous estimates of rupture prevalence, assess the media effect and evaluate contemporary ultrasound scan (USS) accuracy. PATIENTS & METHODS: 460 patients who underwent cosmetic breast augmentation (BA) with PIP silicone prostheses (January 2000-August 2005) have now been followed since their withdrawal in 2010. Initial recall study generated a crude rupture rate of 15.9-33.8% over 6-11 years. Global publicity that followed the lymphoma related death of a French patient in December 2011 led to 127 patients (27.4%) of our original cohort making de novo or further contact as a direct result. To date, 283 (61.5%) have been reviewed of whom 167 (59%) have undergone breast USS. In toto, 163 (35.4%) have had their implants replaced or removed. RESULTS: Kaplan Meier analysis places 10-year PIP mammary implant survival between 60 (95% confidence interval (CI): 54-67) and 81% (95% CI: 78-85). Post-publicity evaluees were found to have occult device failure in 31.6%. Of 85 patients who had definitive confirmation of USS findings by surgical exploration, 79 (92.9%) were completely accurate. USS in our series had a sensitivity of 97.3% and specificity of 93.1%. DISCUSSION: this study not only reaffirms PIP's rupture prevalence to be higher than comparative breast prostheses, but also records the media's beneficial effect in improving recall. Importantly, there is a relatively high proportion of patients with ruptured devices of which they are otherwise unaware. Ultrasonography, at least in PIP-augmented women, seems to be a more accurate tool than previously measured, especially in the presence of rupture. Finally, 35.2% resisted all attempts at review despite repeated efforts and widespread media coverage. PMID- 23668949 TI - The importance of pre-natal diagnosis of facial congenital malformations. PMID- 23668950 TI - Reconstruction of anterior floor of mouth defects by the local mandible myofascial flap following cancer ablation: a pilot study. AB - BACKGROUND: The purpose of this study is to review our experience with the use of the local mandible myofascial (LMM) flap for anterior floor of mouth (AFOM) reconstruction following cancer ablation to assess its reliability, associated complications and functional results. METHODS: This is a retrospective analysis of 13 LMM flaps (nine patients) performed for AFOM reconstruction from March 2010 to June 2012. All patients underwent surgical resection and immediate reconstruction with LMM flaps. They were followed up for 3-30 months to evaluate the survival rate of the flaps, mobility of tongue and aesthetic outcome of the lower lip and mental region. RESULTS: All the flaps were successfully transferred. No obvious complications were found in either the AFOM or the donor region. The majority of patients resumed to a regular diet (89%, 8/9) and speech was considered as functional and/or understandable by the surgeon in all of the patients. Dental restoration was successful for 89% (8/9) of the patients. The shape and motion of the lower lip and the mental region of all patients were acceptable. CONCLUSIONS: The LMM flap is well suited for AFOM reconstruction because it is reliable, has few significant complications and allows preservation of oral function. PMID- 23668951 TI - A rare case of 'histiocytoid haemangioma' of the hand. AB - Histiocytoid haemangioma has been identified by Rosai in 1979 as a group of vascular tumour-like lesions. This lesion can occur in a wide variety of sites. Surgical excision is the treatment of choice. We present the case of a 35-year old man with a swelling in the thenar region of his right hand. Preoperative X rays, magnetic resonance imaging (MRI) and angio-computed tomography (angio-CT) demonstrated a lesion invading the radial digital artery to the index finger without any bone erosion. It was excised 'en bloc' with the artery itself. The radial digital nerve to the index finger and the main digital artery to the thumb were preserved. No local recurrence was observed at the 3-year follow-up. Histiocytoid haemangioma of the hand is a rare disease, and patients should undergo early surgical treatment to achieve complete excision of the lesion without any functional deficit. PMID- 23668952 TI - Use of the Accordion Severity Grading System for negative outcomes of carpal tunnel syndrome. AB - A universal classification of the negative outcomes of carpal tunnel release surgery does not, as yet, exist. In order to avoid the use of arbitrary factors we have applied the Accordion Severity Grading System, which uses rigorously defined qualitative terms to classify complications. It also provides a uniform manner for grading the severity of complications, enabling outcome comparisons between centres. We analysed the negative outcomes of 500 device-assisted carpal tunnel releases performed over a 2-year period in the author's department. In order to establish a standardised list of complications we used the terms employed within the guidelines of the American Academy of Orthopaedic Surgeons. Most of these terms were subsequently defined using the data variables and definitions taken from the American College of Surgeons National Surgical Quality Improvement Program or the Medical Subject Headings of the National Library of Medicine. We also adopted the quantitative severity weighting, as proposed by the Accordion system, in order to determine the postoperative morbidity index for our assisted carpal tunnel releases. The most common complications were pain and reversible damage to peripheral nerves. Other common negative events, other than complications, included hand weakness, which we classified as a sequela of the procedure, and incomplete retinaculum release, which we classified as failure to cure. The overall postoperative morbidity index for complications was 0.014. Although the Accordion system was developed for more complex procedures, it may also be adopted for carpal tunnel release surgery where it provides an objective and universal method for the classification of complications. PMID- 23668953 TI - A 'migrant' mass of the forehead: diagnosis and treatment. AB - BACKGROUND: Primary cutaneous large B-cell lymphoma, leg type, is a rare and aggressive neoplasm as defined by the World Health Organization/European Organisation for Research and Treatment of Cancer classification of cutaneous lymphomas. In some cases this disease may simulate other forms of benign or malignant solid tumours. MATERIAL: We present a case of a 74-year-old man showing a quickly 'migrant' mass on his forehead. First skin biopsy, ultrasound and magnetic resonance images were not significant. A deeper biopsy revealed a pathology consistent with a primary cutaneous diffuse large B-cell lymphoma leg type. RESULTS: The patient was successfully treated with only local radiotherapy (total dose: 32.4 Gy). At 1-year follow-up there were no recurrences. DISCUSSION: To the best of our knowledge, this is the second case of a primary cutaneous diffuse large B-cell lymphoma leg type developed as a quickly 'migrant' lesion. In contrast with the first report, our case developed in a non-leg site. From these two cases, we should bear in mind that aggressive and quickly migrant cutaneous or subcutaneous masses might mask a lymphomatous disease. PMID- 23668954 TI - Classification of contour deformities after massive weight loss: the applicability of the Pittsburgh Rating Scale in The Netherlands. AB - BACKGROUND: The Pittsburgh Rating Scale is the only validated classification system of skin deformities occurring after massive weight loss. The purpose of this study was to replicate the validation of the Pittsburgh Rating Scale classification and to evaluate its usefulness in the treatment of massive weight loss patients in The Netherlands. METHODS: Thirteen trained observers applied the Pittsburgh Rating Scale to photographs of 25 patients. These photographs showed the 10 regions of the body for which the Pittsburgh Rating Scale is designed. Six of the observers were medical specialists, three were medical interns in plastic surgery and four observers were specialised nurse practitioners. As a measure of inter-rater agreement we calculated the intraclass correlation with a threshold value of 0.6 for good validity. The observers also answered 11 questions about the scale's usefulness in daily practice. RESULTS: In two consecutive tests the photographs of 10 regions were scored, which resulted in a total of 20 observations per patient. Sixty percent of the intraclass correlation values were below the threshold of 0.6 for good validity. The mean intraclass correlation value was 0.577. CONCLUSIONS: The Pittsburgh Rating Scale could not be validated as a reliable classification system for skin deformities after massive weight loss. The scale however seems to be a good first step in a challenging task. There was no doubt among the observers that a good classification system would be beneficial for adequate treatment. A modified Pittsburgh Rating Scale should include, besides anatomical parameters, functional disability and hygienic impairment scores and perioperative risk factors. PMID- 23668955 TI - Cloning and characterization of bottlenose dolphin (Tursiops truncatus) interleukin-10. AB - The function of cytokines in cetaceans has so far only been determined for the proinflammatory cytokines. In this study, we cloned bottlenose dolphin (Tursiops truncatus) interleukin-10 (IL-10) cDNA from concanavalin A (Con A)-stimulated peripheral blood mononuclear cells (PBMC), and investigated the mRNA expression levels in various tissues and the bioactivity of recombinant dolphin (rd) IL-10. The gene encodes a polypeptide of 178 amino acids which encompasses the mature protein sequence of 158 amino acids. Quantitative expression analysis of dolphin IL-10 revealed that the highest mRNA levels are found in the spleen. To assess its function, rdIL-10 was produced in human embryonic kidney 293 cells and its bioactivity was demonstrated through IL-10-induced inhibition of proinflammatory cytokine mRNA expression IFN-gamma, TNF-alpha, and IL-2 of Con A-stimulated PBMC. These results indicated that the structure and function of bottlenose dolphin IL 10 is similar to that of other animals. This is the first report of the characterization of an anti-inflammatory cytokine in cetaceans. PMID- 23668956 TI - Substrate mapping strategies for successful ablation of ventricular tachycardia: a review. AB - Catheter ablation of ventricular tachycardia (VT) currently has an important role in the treatment of incessant ventricular tachycardia and reduction of the number of episodes of recurrent ventricular tachycardia. Conventional mapping techniques require ongoing tachycardia and haemodynamic stability during the procedure. However, in many patients with scar-related ventricular tachycardia, non inducibility of clinical tachycardia, poor induction reproducibility, haemodynamic instability, and multiple ventricular tachycardias with frequent spontaneous changes of morphology, preclude tachycardia mapping. To overcome these limitations, new strategies for mapping and ablation in sinus rhythm (SR) - substrate mapping strategies - have been developed and are currently used by many centres. This review summarizes the progresses recently achieved in the ablative treatment of ventricular tachycardia using a substrate mapping approach in patients with structural heart disease. PMID- 23668957 TI - ["Surface" capillaroscopy and trophic disorders of the lower limbs]. PMID- 23668958 TI - Endothelium-dependent epithelial-mesenchymal transition of tumor cells: exclusive roles of transforming growth factor beta1 and beta2. AB - BACKGROUND: Induction of epithelial-mesenchymal transition (EMT) is essential for the metastasis of tumor cells and maintaining their stemness. This study aimed to examine whether endothelial cells, which are most closely located to tumor cells in vivo, play a role in inducing EMT in tumor cells or not. METHODS: Concentrated culture medium of bovine aortic endothelial cells (BAECs) was applied to tumor cell lines (A549 and PANC-1) and epithelial cell line (NMuMg). Cadherin conversion, expressions of alpha-smooth muscle actin and ZO-1, actin fiber formation and cell migration were examined as hallmarks of the induction of EMT in these cell lines. Transforming growth factor beta (TGFbeta) antibodies were used to neutralize TGFbeta1, TGFbeta2 and TGFbeta3. Expression and release of TGFbeta proteins in BAECs as well as in porcine and human endothelial cells were assessed by Western blotting and ELISA, respectively. RESULTS: Conditioned medium of BAEC induced EMT in the examined cell lines. All endothelial cells from various species and locations expressed TGFbeta1 and TGFbeta2 proteins and much lower level of TGFbeta3 protein. Conditioned medium from these endothelial cells contained TGFbeta1 and TGFbeta2, but TGFbeta3 could not be detected. Neutralizing antibody against each of TGFbeta1 or TGFbeta2 did not reverse endothelium dependent EMT, but simultaneous neutralization of both TGFbeta1 and TGFbeta2 completely abolished it. CONCLUSIONS: Endothelial cells may play a role in the induction and maintenance of EMT in tumor cells by constitutively releasing TGFbeta1 and TGFbeta2. GENERAL SIGNIFICANCE: The present results provide a novel strategy of the inhibition of tumor metastasis by targeting vascular endothelium. PMID- 23668960 TI - Antimony (Sb) contaminated shooting range soil: Sb mobility and immobilization by soil amendments. AB - Antimony (Sb) in lead bullets poses a major environmental risk in shooting range soils. Here we studied the effect of iron (Fe)-based amendments on the mobility of Sb in contaminated soil from shooting ranges in Norway. Untreated soil showed high Sb concentrations in water extracts from batch tests (0.22-1.59 mg L(-1)) and soil leachate from column tests (0.3-0.7 mg L(-1)), occurring exclusively as Sb(V). Sorption of Sb to different iron-based sorbents was well described by the Freundlich equation (Fe2(SO4)3, log KF = 6.35, n = 1.51; CFH-12 (Fe oxyhydroxide), log KF = 4.16-4.32, n = 0.75-0.76); Fe(0) grit, log KF = 3.26, n = 0.47). These sorbents mixed with soil (0.5 and 2% w/w), showed significant sorption of Sb in batch tests (46-92%). However, for Fe2(SO4)3 and CFH-12 liming was also necessary to prevent mobilization of lead, copper, and zinc. Column tests showed significant retention of Sb (89-98%) in soil amended with CFH-12 (2%) mixed with limestone (1%) compared to unamended soil. The sorption capacity of soils amended with Fe(0) (2%) increased steadily up to 72% over the duration period of the column test (64 days), most likely due to the gradual oxidation of Fe(0) to Fe oxyhydroxides. Based on the experimental results, CFH-12 and oxidized Fe(0) are effective amendments for the stabilization of Sb in shooting range soils. PMID- 23668959 TI - HPLC-based monitoring of products formed from hydroethidine-based fluorogenic probes--the ultimate approach for intra- and extracellular superoxide detection. AB - BACKGROUND: Nearly ten years ago, we demonstrated that superoxide radical anion (O2?-) reacts with the hydroethidine dye (HE, also known as dihydroethidium, DHE) to form a diagnostic marker product, 2-hydroxyethidium (2-OH-E(+)). This particular product is not derived from reacting HE with other biologically relevant oxidants (hydrogen peroxide, hydroxyl radical, or peroxynitrite). This discovery negated the longstanding view that O2?- reacts with HE to form the other oxidation product, ethidium (E(+)). It became clear that due to the overlapping fluorescence spectra of E(+) and 2-OH-E(+), fluorescence-based techniques using the "red fluorescence" are not suitable for detecting and measuring O2?- in cells using HE or other structurally analogous fluorogenic probes (MitoSOX(TM) Red or hydropropidine). However, using HPLC-based assays, 2 OH-E(+) and analogous hydroxylated products can be easily detected and quickly separated from other oxidation products. SCOPE OF REVIEW: The principles discussed in this chapter are generally applicable in free radical biology and medicine, redox biology, and clinical and translational research. The assays developed here could be used to discover new and targeted inhibitors for various superoxide-producing enzymes, including NADPH oxidase (NOX) isoforms. MAJOR CONCLUSIONS: HPLC-based approaches using site-specific HE-based fluorogenic probes are eminently suitable for monitoring O2?- in intra- and extracellular compartments and in mitochondria. The use of fluorescence-microscopic methods should be avoided because of spectral overlapping characteristics of O2?--derived marker product and other, non-specific oxidized fluorescent products formed from these probes. GENERAL SIGNIFICANCE: Methodologies and site-specific fluorescent probes described in this review can be suitably employed to delineate oxy radical dependent mechanisms in cells under physiological and pathological conditions. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn. PMID- 23668961 TI - Bisphenol A degradation in water by ligninolytic enzymes. AB - Many endocrine disruptor compounds, such as bisphenol A (BPA) are used today and released into the environment at low doses but they are barely degraded in wastewater treatment plants. One of the potential alternatives to effectively degrade endocrine disruptor compounds is based on the use of the oxidative action of extracellular fungal enzymes. The aim of this work is to study the ability of free and encapsulated enzymes (manganese peroxidase, lignin peroxidase and laccase) to degrade BPA. Higher degradation of BPA (90%) by ligninolytic enzymes encapsulated on polyacrylamide hydrogel and pectin after 8h was obtained. The degradation of BPA while using the free enzyme (26%) was lower than the value obtained with encapsulated enzymes. The presence of pectin in the formulation significantly (p>0.05) enhanced the activity of enzymes. Kinetics of BPA degradation showed an increase in Vm, while Km remained constant when enzymes were encapsulated. Hence, encapsulation protected the enzymes from non competitive inhibition. PMID- 23668962 TI - A step towards the use of biomonitors as estimators of atmospheric PAHs for regulatory purposes. AB - One of the main drawbacks of using lichens to monitor atmospheric PAHs has been reported as the inexistence of studies aiming to translate PAH values in lichens into the atmospheric equivalents ones, in order to use this information for regulatory purposes. In this work, PAH concentrations in lichens were compared with PAH concentrations measured in a conventional active sampler in an outdoor environment for a 9-month span. Significant positive correlations between HMW PAHs, Sigma16 EPA-PAHs, and BaP equivalent concentrations in lichens and those in air (TSP) were found. Concentrations of Sigma16 EPA-PAHs in lichens and air showed a seasonal variation, with highest values during winter and lowest values during summer. Meteorological variables - temperature, atmospheric pressure, relative humidity, and wind speed - showed to significantly influence PAH concentrations in both lichens and air. Based on the significant linear correlations, equations for translating PAH concentrations measured in lichens into equivalent ones for air were proposed for the first time, allowing a broader use of lichens' information regarding PAHs in monitoring schemes and decision making. PMID- 23668963 TI - Evaluating the impact of recycled fiber content on effluent recycling in newsprint manufacture. AB - This paper investigates the effect of using recycled fiber (RCF) in newsprint production on the effluent quality and its treatability using membrane operations for internal and external recycling and reuse. Increased chemical usage in RCF for deinking had significant impact on the silica and sodium content of the effluent which in turn limits the membrane's operation. Increasing the RCF content from 0% to 50% is estimated to increase the silica content from 4 to 119mgL(-1) and sodium content from 135 to 500mgL(-1). A process model was developed to calculate the impact of these excess chemicals on the greenhouse gas (GHG) emission and brine disposal for an integrated membrane plant design producing 4MLday(-1) of recycled water. As the ratio of RCF increased from 0% to 50% in the mill process, the operating pressure increased for nanofiltration (NF) and reverse osmosis (RO). Additionally, organics presence in the feed increased the NF operating pressure above the simulated value and reduced the silica removal efficiency by 15%. Incorporation of lime coagulation pretreatment was found to be essential to operate RO at high recoveries with relatively GHG emissions. Without pretreatment, as RCF content increased from 0% to 50%, RO recovery decreased from 80% to 22% and the expended GHG increased from 0.9 to 3.5kgCO2m(-3). Although the excess sodium concentration limits the brine disposal for irrigation purposes, a partial blending of the treated wastewater with other process streams resulted in the reduction of sodium absorption ratio by 20%. PMID- 23668964 TI - Evaluation of a UV-light emitting diodes unit for the removal of micropollutants in water for low energy advanced oxidation processes. AB - There is growing interest in using light emitting diodes (LEDs) as alternative to traditional mercury lamps for the removal of micropollutants by advanced oxidation processes due to their low energy consumption and potential for high efficiency and long lifetime. This study investigates the penetration and coverage of the light emitted by LEDs in order to build an optimised LED collimated beam apparatus. From the experimental data, cost analysis was conducted in order to identify when LEDs will become economically viable. It was observed that if their development follows the predictions, LEDs should be a viable alternative to traditional lamps within 7yr for both UV/H2O2 and UV/TiO2 processes. However, parameters such as wall plug efficiency and input power need to improve for LEDs to become competitive. PMID- 23668965 TI - A positron emission tomography study in healthy volunteers to estimate mGluR5 receptor occupancy of AZD2066 - estimating occupancy in the absence of a reference region. AB - AZD2066 is a new chemical entity pharmacologically characterized as a selective, negative allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). Antagonism of mGluR5 has been implicated in relation to various diseases such as anxiety, depression, and pain disorders. To support translation from preclinical results and previous experiences with this target in man, a positron emission tomography study was performed to estimate the relationship between AZD2066 plasma concentrations and receptor occupancy in the human brain, using the mGluR5 radioligand [(11)C]-ABP688. The study involved PET scans on 4 occasions in 6 healthy volunteers. The radioligand was given as a tracer dose alone and following oral treatment with different doses of AZD2066. The analysis was based on the total volume of distribution derived from each PET-assessment. A non-linear mixed effects model was developed where ten delineated brain regions of interest from all PET scans were included in one simultaneous fit. For comparison the analysis was also performed according to a method described previously by Lassen et al. (1995). The results of the analysis showed that the total volume of distribution decreased with increasing drug concentrations in all regions with an estimated Kipl of 1170 nM. Variability between individuals and occasions in non-displaceable volume of distribution could explain most of the variability in the total volume of distribution. The Lassen approach provided a similar estimate for Kipl, but the variability was exaggerated and difficult to interpret. PMID- 23668966 TI - Selectively and progressively disrupted structural connectivity of functional brain networks in Alzheimer's disease - revealed by a novel framework to analyze edge distributions of networks detecting disruptions with strong statistical evidence. AB - Alzheimer's disease (AD) disrupts selectively and progressively (increasing with severity) functional connectivity of intrinsic brain networks (IBNs), most prominent in the default mode network. Given that IBNs' functional connectivity depends on structural connectivity, we hypothesize for our study selective and progressive changes of IBN based structural connectivity in AD. To achieve strong statistical evidence, we introduce a novel statistical method based on the edge frequency distributions of structural connectivity networks. Such non-Gaussian distributions are compared in a multiple testing scheme, combining a flexible nonparametric test statistic with permutation based strong control of the family wise error rate. We assessed 26 healthy elderly, 23 patients with AD-dementia, and 28 patients with mild cognitive impairment (MCI) by resting-state functional MRI, diffusion tensor imaging, and clinical-neuropsychological testing including annual follow-up assessment. After 3years, 50% of the patients with MCI converted to AD. Tractography of diffusion tensor data identifies structural connectivity networks between regions of IBNs, which are detected by an independent component analysis of resting state fMRI data. We find that IBNs' structural connectivity is selectively and progressively disrupted with primary changes in the default mode network. Correspondent results are found for IBNs' functional connectivity. In addition, structural connectivity across the nodes of all IBNs separated individual MCI patients converting to AD from non-converters. Conclusively, our study provides a new approach to analyze connectivity networks by their non Gaussian edge frequency distributions and achieves strong statistical evidence by application of the family wise error rate. Data analysis provides selective and progressive disruptions of IBN's structural connectivity in AD and demonstrates the increased power of our method compared to recent studies. PMID- 23668968 TI - Patient-specific detection of perfusion abnormalities combining within-subject and between-subject variances in Arterial Spin Labeling. AB - In this paper, patient-specific perfusion abnormalities in Arterial Spin Labeling (ASL) were identified by comparing a single patient to a group of healthy controls using a mixed-effect hierarchical General Linear Model (GLM). Two approaches are currently in use to solve hierarchical GLMs: (1) the homoscedastic approach assumes homogeneous variances across subjects and (2) the heteroscedastic approach is theoretically more efficient in the presence of heterogeneous variances but algorithmically more demanding. In practice, in functional magnetic resonance imaging studies, the superiority of the heteroscedastic approach is still under debate. Due to the low signal-to-noise ratio of ASL sequences, within-subject variances have a significant impact on the estimated perfusion maps and the heteroscedastic model might be better suited in this context. In this paper we studied how the homoscedastic and heteroscedastic approaches behave in terms of specificity and sensitivity in the detection of patient-specific ASL perfusion abnormalities. Validation was undertaken on a dataset of 25 patients diagnosed with brain tumors and 36 healthy volunteers. We showed evidence of heterogeneous within-subject variances in ASL and pointed out an increased false positive rate of the homoscedastic model. In the detection of patient-specific brain perfusion abnormalities with ASL, modeling heterogeneous variances increases the sensitivity at the same specificity level. PMID- 23668967 TI - Connectivity-based neurofeedback: dynamic causal modeling for real-time fMRI. AB - Neurofeedback based on real-time fMRI is an emerging technique that can be used to train voluntary control of brain activity. Such brain training has been shown to lead to behavioral effects that are specific to the functional role of the targeted brain area. However, real-time fMRI-based neurofeedback so far was limited to mainly training localized brain activity within a region of interest. Here, we overcome this limitation by presenting near real-time dynamic causal modeling in order to provide feedback information based on connectivity between brain areas rather than activity within a single brain area. Using a visual spatial attention paradigm, we show that participants can voluntarily control a feedback signal that is based on the Bayesian model comparison between two predefined model alternatives, i.e. the connectivity between left visual cortex and left parietal cortex vs. the connectivity between right visual cortex and right parietal cortex. Our new approach thus allows for training voluntary control over specific functional brain networks. Because most mental functions and most neurological disorders are associated with network activity rather than with activity in a single brain region, this novel approach is an important methodological innovation in order to more directly target functionally relevant brain networks. PMID- 23668969 TI - Self-regulation of human brain activity using simultaneous real-time fMRI and EEG neurofeedback. AB - Neurofeedback is a promising approach for non-invasive modulation of human brain activity with applications for treatment of mental disorders and enhancement of brain performance. Neurofeedback techniques are commonly based on either electroencephalography (EEG) or real-time functional magnetic resonance imaging (rtfMRI). Advances in simultaneous EEG-fMRI have made it possible to combine the two approaches. Here we report the first implementation of simultaneous multimodal rtfMRI and EEG neurofeedback (rtfMRI-EEG-nf). It is based on a novel system for real-time integration of simultaneous rtfMRI and EEG data streams. We applied the rtfMRI-EEG-nf to training of emotional self-regulation in healthy subjects performing a positive emotion induction task based on retrieval of happy autobiographical memories. The participants were able to simultaneously regulate their BOLD fMRI activation in the left amygdala and frontal EEG power asymmetry in the high-beta band using the rtfMRI-EEG-nf. Our proof-of-concept results demonstrate the feasibility of simultaneous self-regulation of both hemodynamic (rtfMRI) and electrophysiological (EEG) activities of the human brain. They suggest potential applications of rtfMRI-EEG-nf in the development of novel cognitive neuroscience research paradigms and enhanced cognitive therapeutic approaches for major neuropsychiatric disorders, particularly depression. PMID- 23668971 TI - Brain morphometry reproducibility in multi-center 3T MRI studies: a comparison of cross-sectional and longitudinal segmentations. AB - Large-scale longitudinal multi-site MRI brain morphometry studies are becoming increasingly crucial to characterize both normal and clinical population groups using fully automated segmentation tools. The test-retest reproducibility of morphometry data acquired across multiple scanning sessions, and for different MR vendors, is an important reliability indicator since it defines the sensitivity of a protocol to detect longitudinal effects in a consortium. There is very limited knowledge about how across-session reliability of morphometry estimates might be affected by different 3T MRI systems. Moreover, there is a need for optimal acquisition and analysis protocols in order to reduce sample sizes. A recent study has shown that the longitudinal FreeSurfer segmentation offers improved within session test-retest reproducibility relative to the cross sectional segmentation at one 3T site using a nonstandard multi-echo MPRAGE sequence. In this study we implement a multi-site 3T MRI morphometry protocol based on vendor provided T1 structural sequences from different vendors (3D MPRAGE on Siemens and Philips, 3D IR-SPGR on GE) implemented in 8 sites located in 4 European countries. The protocols used mild acceleration factors (1.5-2) when possible. We acquired across-session test-retest structural data of a group of healthy elderly subjects (5 subjects per site) and compared the across-session reproducibility of two full-brain automated segmentation methods based on either longitudinal or cross-sectional FreeSurfer processing. The segmentations include cortical thickness, intracranial, ventricle and subcortical volumes. Reproducibility is evaluated as absolute changes relative to the mean (%), Dice coefficient for volume overlap and intraclass correlation coefficients across two sessions. We found that this acquisition and analysis protocol gives comparable reproducibility results to previous studies that used longer acquisitions without acceleration. We also show that the longitudinal processing is systematically more reliable across sites regardless of MRI system differences. The reproducibility errors of the longitudinal segmentations are on average approximately half of those obtained with the cross sectional analysis for all volume segmentations and for entorhinal cortical thickness. No significant differences in reliability are found between the segmentation methods for the other cortical thickness estimates. The average of two MPRAGE volumes acquired within each test-retest session did not systematically improve the across-session reproducibility of morphometry estimates. Our results extend those from previous studies that showed improved reliability of the longitudinal analysis at single sites and/or with non-standard acquisition methods. The multi-site acquisition and analysis protocol presented here is promising for clinical applications since it allows for smaller sample sizes per MRI site or shorter trials in studies evaluating the role of potential biomarkers to predict disease progression or treatment effects. PMID- 23668970 TI - The minimal preprocessing pipelines for the Human Connectome Project. AB - The Human Connectome Project (HCP) faces the challenging task of bringing multiple magnetic resonance imaging (MRI) modalities together in a common automated preprocessing framework across a large cohort of subjects. The MRI data acquired by the HCP differ in many ways from data acquired on conventional 3 Tesla scanners and often require newly developed preprocessing methods. We describe the minimal preprocessing pipelines for structural, functional, and diffusion MRI that were developed by the HCP to accomplish many low level tasks, including spatial artifact/distortion removal, surface generation, cross-modal registration, and alignment to standard space. These pipelines are specially designed to capitalize on the high quality data offered by the HCP. The final standard space makes use of a recently introduced CIFTI file format and the associated grayordinate spatial coordinate system. This allows for combined cortical surface and subcortical volume analyses while reducing the storage and processing requirements for high spatial and temporal resolution data. Here, we provide the minimum image acquisition requirements for the HCP minimal preprocessing pipelines and additional advice for investigators interested in replicating the HCP's acquisition protocols or using these pipelines. Finally, we discuss some potential future improvements to the pipelines. PMID- 23668972 TI - Phosphorylation accelerates geldanamycin-induced Akt degradation. AB - Hsp90 (Heat shock protein-90) is a cellular buffer against erroneous gene products and also plays an essential role in facilitating proper folding, maturation, and activity of its client proteins. The phosphatidylinositol-3 kinase (PI-3K)-Akt pathway transduces a survival signal involved in tumor development. The kinase activity of Akt depends on its association with Hsp90. Hsp90 inhibition causes Akt degradation, but the mechanism remains unclear. Several reports showed that the Hsp90 inhibitor geldanamycin (GA) induces Thr308 and Ser473 phosphorylations of Akt, however, it is still unknown about the significance of GA-induced Akt activation in degradation of the kinase. We treated Hela cells with GA to observe Akt degradation and found that LY294002 delayed Akt degradation. Mutation of Thr308 or Ser473 also caused delayed Akt ubiquitination and degradation. Inhibition of Akt dephosphorylation enhanced GA mediated Akt degradation. In this report, we show that GA-mediated transient activation of Akt accelerates its association with the E3 ligase CHIP (C-terminal Hsp70-interacting protein)-mediated ubiquitination and subsequent proteasome degradation. PMID- 23668973 TI - Assessment of everyday functioning in schizophrenia: implications for treatments aimed at negative symptoms. AB - Assessment of functional impairment in schizophrenia is complicated by problems in self-assessment on the part of patients. These problems can be surmounted through the use of appropriate informants and reliable rating scales. In terms of treatment of negative symptoms, not every aspect of functional outcome is adversely impacted by negative symptoms, requiring assessment of multiple aspects of everyday functioning. Failures in the achievement of functional milestones are likely caused by complex combinations of factors, some of which may reside outside the individual. Assessment of sub-threshold milestones (looking for work vs. full time employment) may be the maximally viable strategy and this relies on the use of rating scales. In addition, there are considerable differences across informants in terms of the extent to which their ratings converge with other indices of patient functioning, such as cognitive test performance. Global scores may not adequately capture functioning in different domains, thus suggesting that rating scales with clear separation of social, vocational, and residential functioning may be preferable. PMID- 23668974 TI - Differential white blood cell counts may predict urinary tract infection in acute non-affective psychosis. PMID- 23668975 TI - The impact of prolactin-raising antipsychotics on bone mineral density in patients with schizophrenia: findings from a longitudinal observational cohort. AB - To examine the effect of prolactin-raising antipsychotics on bone mineral density (BMD), data of 164 schizophrenia patients who received >=2 dual-energy x-ray absorptiometry scans were analyzed (49.3% men; mean +/- SD age: 58.5 +/- 11.0 years; duration of treatment: 26.7 +/- 13.8 years). Patients were divided into a prolactin-raising antipsychotic (n=141) or prolactin-sparing (n=23) group, and time x group interaction was examined using mixed effect model. Although the BMD difference did not reach significance over 3.4 +/- 1.6 years, a significant antipsychotic-class vs. time interaction was found (p=0.011), indicating a negative impact of prolactin-raising antipsychotics on BMD. Large-scale, randomized-controlled data are required to replicate and extend these findings. PMID- 23668976 TI - Predicting end-stage renal disease after liver transplant. AB - Few equations have been developed to predict end-stage renal disease (ESRD) after deceased donor liver transplant. This retrospective observational cohort study analyzed all adult deceased donor liver transplant recipients in the Scientific Registry of Transplant Recipients (SRTR) database, 1995-2010. The prediction equation for ESRD was developed using candidate predictor variables available in SRTR after implementation of the allocation policy based on the model for end stage liver disease. ESRD was defined as initiation of maintenance dialysis therapy, kidney transplant or registration on the kidney transplant waiting list. We used Cox proportional hazard models to develop separate equations for assessing risk of ESRD by 6 months posttransplant and between 6 months and 5 years posttransplant. Variables in the 6-month equation included recipient age, history of diabetes, history of dialysis before liver transplant, history of malignancy, body mass index, serum creatinine and liver donor risk index. Variables in the 6-month to 5-year equation included recipient race, history of diabetes, hepatitis C status, serum albumin, serum bilirubin and serum creatinine. The prediction equations have good calibration and discrimination (C statistics 0.74-0.78). We have produced risk prediction equations that can be used to aid in understanding the risk of ESRD after liver transplant. PMID- 23668977 TI - The innate immune response during liver inflammation and metabolic disease. AB - The role of the inflammatory response is to combat tissue injury and infection. Innate immune cells recognize cell damage or pathogen invasion with intracellular or surface-expressed pattern recognition receptors (PRRs). Activated PRRs subsequently initiate signaling cascades that trigger the release of factors promoting the inflammatory response. Because the liver is a site where foreign antigens from the gastrointestinal tract encounter the immune system, it is particularly enriched with innate immune cells. These cells can modify and disrupt critical processes implicated in metabolic disease. As such, metabolic stress initiates a feedforward cycle of inflammatory responses, resulting in a state of unresolved chronic inflammation in the liver. Accordingly, the crosstalk between these innate immune cells and the resident parenchymal cells plays an important role in the development of acute and chronic liver disease. PMID- 23668978 TI - Influence of minor children and contribution to household income on work hours of female dentists. AB - OBJECTIVE: To study the association of having minor children and contribution to household income on weekly work hours of Iowa female dentists. METHODS: A 28 question survey was mailed to all active Iowa dentists. This study represents female dentists who responded to the survey (n = 192; response rate = 63 percent). The dependent variable was whether dentists currently worked full- or part-time (>= 32 versus <32 hours/week). The associations of having minor children and the percent women contributed toward their household income were then analyzed using stepwise logistic regression, controlling for covariates (alpha = 0.05). RESULTS: Of the respondents, 14.6 percent worked part-time. Females who had no minor children (40.1 percent) were 3.1 times as likely to work full-time (P = 0.0353), and those who contributed >60 percent to household income (57.8 percent) were 3.0 times as likely to work full-time (P = 0.0129). The final regression model indicated that those who contributed >60 percent to household income (P = 0.0096) and had no leave of absence longer than 45 consecutive days within the prior 2 years (P = 0.0483) were more likely to work full-time compared with their counterparts. CONCLUSION: Iowa female dentists who provided more than 60 percent to household income and had not taken a leave of absence during the past 2 years were more likely to work full-time. The inclusion of leave of absence as a predictor variable negates any additional influence of the presence or absence of minor children in the regression model, indicating that these variables are highly correlated for this population. PMID- 23668980 TI - Nimodipine nanocrystals for oral bioavailability improvement: preparation, characterization and pharmacokinetic studies. AB - This study intended to develop nimodipine (NMD) nanocrystals with different sizes for oral administration and to investigate the relationship between dissolution and pharmacokinetics for NMD nanocrystals and Nimotop((r)). NMD nanocrystals were prepared by combination of microprecipitation and high pressure homogenization and were further lyophilized. The particle size, morphology and aqueous solubility of the NMD nanocrystals were determined. With Nimotop((r)) as the control, the dissolution rate was evaluated and the pharmacokinetic study was undertaken in beagle dogs. NMD nanocrystals with mean diameters of about 159.0, 503.0 and 833.3 nm were prepared, respectively. The lyophilization didn't affect the particle sizes of the redispersed nanocrystals. The aqueous solubility was significantly improved and displayed a size-dependent manner. The nanocrystals exhibited lower dissolution patterns than Nimotop((r)) under non-sink condition, but bioavailability of the two nanocrystals (159.0 and 833.3 nm) was equivalent, about 2.6-fold higher than Nimotop((r)). In conclusion, oral nanocrystal drug delivery system was a promising strategy in improving the oral bioavailability of poorly soluble or insoluble drugs. But we could not establish a favorable in vitro in vivo correlation for NMD nanocrystals and Nimotop((r)) and thus the oral absorption mechanism of the NMD nanocrystals required further study. PMID- 23668981 TI - Molecularly imprinted poly(hydroxyethyl methacrylate) based cryogel for albumin depletion from human serum. AB - Macroporous cryogels imprinted with human serum albumin (HSA) have been prepared by copolymerization of 2-hydroxyethyl methacrylate with a functional co-monomer of N-methacryloyl-L-phenylalanine. The cryogels were used for the depletion of HSA from human serum. HSA-imprinted cryogels were prepared with gel fraction yields up to 90%, and their chemical structure, morphology and porosity were characterized by FTIR-spectroscopy, scanning electron microscopy, swelling studies and flow dynamics. Selective binding experiments were performed in the presence of competitive proteins like human transferrin and myoglobin. Albumin imprinted cryogel column was optimized for fast protein liquid chromatography. Sodium-dodecyl sulfate polyacrylamide gel electrophoresis was used to show the efficiency of albumin depletion. PMID- 23668982 TI - Trans-ferulic acid-based solid lipid nanoparticles and their antioxidant effect in rat brain microsomes. AB - In this study, stearic acid- and stearyl ferulate-based solid lipid nanoparticles containing trans-ferulic acid (SLN-FA and SLN-SF-FA, respectively), were prepared and characterized for loading efficiency, size and shape. In addition, by using rat brain microsomes, we evaluated in vitro the antioxidant activity of these formulations against three well known initiators of lipid peroxidation, such as AAPH, NADPH/ADP-Fe(3+) and SIN-1 which in turn generate the peroxyl and perferryl radicals as well as peroxynitrite, respectively. Commercially available FA and its ethyl ester (FAEE) were used as comparators. Both SLN-FA and SLN-SF-FA dose dependently reduced lipid peroxidation induced by the three oxidants. Interestingly, SLN-SF-FA displayed greater efficacy (EC50) and potency (maximal activity) against AAPH- and NADPH/ADP-Fe(3+)-induced lipid peroxidation. Our results support the idea that this new formulations could facilitate the uptake of FA by the cells because of their lipophilic structure, thus increasing FA bioavailability. Furthermore, stearyl ferulate-based nanoparticles could prevent the degradation of FA entrapped on their structure, making FA almost entirely available to explicate its antioxidant power once released. PMID- 23668983 TI - Biocomposite scaffolds containing chitosan/alginate/nano-silica for bone tissue engineering. AB - Bone tissue engineering is a promising alternative method for treating bone loss by a combination of biomaterials and cells. In this study, we fabricated biocomposite scaffolds by blending chitosan (CS), alginate (Alg) and nano-silica (nSiO2), followed by freeze drying. The prepared scaffolds (CS/Alg, CS/Alg/nSiO2) were characterized by SEM, FT-IR and XRD analyses. In vitro studies such as swelling, biodegradation, biomineralization, protein adsorption and cytotoxicity were also carried out. The scaffolds possessed a well-defined porous architecture with pore sizes varying from 20 to 100 MUm suitable for cell infiltration. The presence of nSiO2 in the scaffolds facilitated increased protein adsorption and controlled swelling ability. The scaffolds were biodegradable and the addition of nSiO2 improved apatite deposition on these scaffolds. There was no significant cytotoxicity effect of these CS/Alg/nSiO2 scaffolds towards osteolineage cells. Thus, these results indicate that CS/Alg/nSiO2 scaffolds may have potential applications for bone tissue engineering. PMID- 23668984 TI - Facile fabrication of uniform size-controlled microparticles and potentiality for tandem drug delivery system of micro/nanoparticles. AB - This article describes a rapid and facile method for manufacturing various size controlled gel particles with utilizing inkjet printing technology. Generally, the size of droplets could be controlled by changing nozzle heads of inkjet printer, from which ink solution is ejected. However, this method uses drying process before gelling microparticles, and with that, the size of microparticles was easily controlled by only altering the concentration of ejected solution. When sodium alginate solution with various concentrations was ejected from inkjet printer, we found that the concentration of alginate solution vs. the volume of dried alginate particle showed an almost linear relationship in the concentration range from 0.1 to 3.0%. After dried alginate particles were soaked into calcium chloride solution, the size of microgel beads were obtained almost without increasing their size. The microparticles including various sizes of nanoparticles were easily manufactured by ejecting nanoparticle-dispersed alginate solution. The release of 25-nm sized nanoparticles from alginate microgel beads was finished in a relatively-rapid manner, whereas 100-nm sized nanoparticles were partially released from those ones. Moreover, most of 250-nm sized nanoparticles were not released from alginate microgel beads even after 24 h soaking. This particle fabricating method would enable the tandem drug delivery system with a combination of the release from nano and microparticles, and be expected for the biological and tissue engineering application. PMID- 23668985 TI - Curcumin-containing liposomes stabilized by thin layers of chitosan derivatives. AB - Stable vesicles for efficient curcumin encapsulation, delivery and controlled release have been obtained by coating of liposomes with thin layer of newly synthesized chitosan derivatives. Three different derivatives of chitosan were obtained and studied: the cationic (by introduction of the stable, quaternary ammonium groups), the hydrophobic (by attachment of N-dodecyl groups) and cationic-hydrophobic one (containing both quaternary ammonium and N-dodecyl groups). Zeta potential measurements confirmed effective coating of liposomes with all these chitosan derivatives. The liposomes coated with cationic hydrophobic chitosan derivative are the most promising curcumin carriers; they can easily penetrate cell membrane and release curcumin in a controlled manner. Biological studies indicated that such systems are non-toxic for murine fibroblasts (NIH3T3) while toxic toward murine melanoma (B16F10) cell line. PMID- 23668986 TI - 3-Anhydro-6-hydroxy-ophiobolin A, a new sesterterpene inhibiting the growth of methicillin-resistant Staphylococcus aureus and inducing the cell death by apoptosis on K562, from the phytopathogenic fungus Bipolaris oryzae. AB - A new ophiobolin derivative, 3-anhydro-6-hydroxy-ophiobolin A (1), as well as two known ophiobolin derivatives 3-anhydro-ophiobolin A (2) and 3-anhydro-6-epi ophiobolin A (3) were isolated from the PDB culture of a phytopathogenic fungus Bipolaris oryzae. The structure of 1 was elucidated through 2D NMR and other spectroscopic techniques. Compound 1 exhibited strong antimicrobial activity against Bacille Calmette-Guerin, Bacillus subtilis, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus with MIC value of 12.5 MUg/mL, and potent antiproliferative activity against cell lines HepG2 and K562 with IC50 of 6.49 MUM and 4.06 MUM, respectively. Further studies on the cytotoxicity of compound 1 against K562 cells demonstrated that it induced apoptosis, observed by flow cytometric method. Preliminary structure-activity relationships of these ophiobolins and the mechanism of apoptosis induced by 1 were analyzed. PMID- 23668987 TI - 8-Aminoquinoline-based ratiometric zinc probe: unexpected binding mode and its application in living cells. AB - PMQA, an 8-aminoquinoline-based ratiometric fluorescent sensor, demonstrates the Zn(2+)-induced red-shift of emission (85nm), and was successfully applied to image zinc in living cells. Compared to 2:1 stoichiometry in PMQA-Zn(2+), PMQA Cu(2+) shows 1:1 composition. Both nitrogen atoms from the aminoquinoline are missing in binding of zinc, while they are critically involved in Cu(2+) chelation. The structure difference between PMQA-Zn(2+) and PMQA-Cu(2+) might shed light in designing novel zinc probes without suffering from copper interference. PMID- 23668988 TI - Discovery of potent and efficacious urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with reduced CYP2C9 inhibition properties. AB - Potent, reversible inhibition of the cytochrome P450 CYP2C9 isoform was observed in a series of urea-containing nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. This unwanted property was successfully removed from the described inhibitors through a combination of structure-based design and medicinal chemistry activities. An optimized compound which did not inhibit CYP2C9 exhibited potent anti-NAMPT activity (17; BC NAMPT IC50=3 nM; A2780 antiproliferative IC50=70 nM), good mouse PK properties, and was efficacious in an A2780 mouse xenograft model. The crystal structure of this compound in complex with the NAMPT protein is also described. PMID- 23668989 TI - New azole antagonists with high affinity for the P2Y(1) receptor. AB - Five-membered-ring heterocyclic urea mimics have been found to be potent and selective antagonists of the P2Y1 receptor. SAR of the various heterocyclic replacements is presented, as well as side-chain SAR of the more potent thiadiazole ring system which leads to thiadiazole 4c as a new antiplatelet agent. PMID- 23668990 TI - Using student and school factors to differentiate adolescent current smokers from experimental smokers in Canada: a multilevel analysis. AB - OBJECTIVE: In order to understand the factors that differentiate adolescents who have tried smoking from those who have become established smokers, this study examined which student- and school-level factors differentiated current smokers from experimental smokers among a nationally representative sample of Canadian secondary school students. METHOD: Student-level secondary data from the 2008 2009 Canadian Youth Smoking Survey was linked with school-level data from the 2006 Census and one built environment characteristic, and examined using multilevel logistic regression analyses. RESULTS: The current smoking rates varied (P<0.001) across schools. The number of tobacco retailers surrounding the schools was associated with current smoking when adjusting for student characteristics. Additionally, students were more likely to be current smokers if they were: male, in higher grades, believed that smoking can help when they are bored, reported low school connectedness, used marijuana, had a sibling or close friend who smoked, and had no smoking bans at home. CONCLUSIONS: These study findings suggest that school anti-smoking strategies need to target males, increase students' attachment to their school, address tobacco-related beliefs, and include interventions targeting smoking siblings and friends. The government should consider zoning restrictions to limit sales of tobacco products near schools. PMID- 23668991 TI - Comparative serum proteomic analysis of adenomyosis using the isobaric tags for relative and absolute quantitation technique. AB - OBJECTIVE: To identify differentially expressed proteins from the serum of women with and without adenomyosis and to explore the potential pathogenesis of adenomyosis. DESIGN: Serum samples from patients with adenomyosis were compared with samples from healthy controls. SETTING: University hospital. PATIENT(S): Twenty patients with adenomyosis and 20 healthy volunteers. INTERVENTION(S): Collection of serum samples. MAIN OUTCOME MEASURE(S): Protein expression of serum was evaluated with iTRAQ (isobaric tags for relative and absolute quantitation) technology, and the validation of protein was performed with Western blot. RESULT(S): A total of 167 proteins were identified from 1,406 distinct peptides using iTRAQ technology. Twenty-five proteins were abnormally expressed in adenomyosis patients compared with the control group; 4 of these proteins were significantly down-regulated and 21 were significantly up-regulated in women with adenomyosis. Western blotting was used to validate the relative increases in serum protein levels for three of the identified proteins. CONCLUSION(S): The differentially expressed proteins identified in our study are mainly involved in cell adhesion, the immune response, and the inflammatory response. On the basis of the results of this study, it can be concluded that these mechanisms may play an important role in the pathogenesis of adenomyosis. Additionally, these proteins may provide clues for not only a promising biomarker for the diagnosis of adenomyosis but also a potential target for therapeutic intervention. PMID- 23668992 TI - Predictors of ovarian response in women treated with corifollitropin alfa for in vitro fertilization/intracytoplasmic sperm injection. AB - OBJECTIVE: To identify predictors of ovarian response in women undergoing ovarian stimulation with corifollitropin alfa in a GnRH antagonist protocol and determine specific thresholds for the prediction of low and excessive responders. DESIGN: Retrospective cohort study. SETTING: University-based tertiary care center. PATIENT(S): Infertile women undergoing ovarian stimulation for in vitro fertilization/intracytoplasmic sperm injection. INTERVENTION(S): Controlled ovarian hyperstimulation with corifollitropin alfa in a GnRH antagonist protocol. MAIN OUTCOME MEASURE(S): Relationship between ovarian reserve tests and ovarian response. RESULT(S): Antimullerian hormone (AMH) and antral follicle count (AFC) were the only independent predictors for low and excessive ovarian response. In prediction of excessive response, the area under the receiver operating characteristic curve [AUC (95% CI)] for AMH was 0.890 (0.832-0.947) and 0.897 (0.829-0.964) for AFC. The optimal thresholds for identifying excessive responders were 3.52 ng/mL for AMH (sensitivity 89.5, specificity 83.8) and 16 for AFC (sensitivity 80.0, specificity 84.5). AMH and AFC also predicted low ovarian response: AUCs AMH 0.836 (0.783-0.889) and AFC 0.830 (0.767-0.894). The optimal thresholds for predicting low response were 1.37 ng/mL for AMH (sensitivity 74.1, specificity 77.5) and 8 for AFC (sensitivity 72.2, specificity 84.6). For both excessive and low ovarian responses, a logistic regression model combining the biomarkers was associated with improved discrimination. CONCLUSION(S): AMH and AFC are the best predictors for low and excessive response in women treated with corifollitropin alfa in an antagonist protocol. Using AMH and AFC to select suitable candidates for treatment with corifollitropin alfa may result in a safe and convenient stimulation. PMID- 23668993 TI - Uterus transplantation in nonhuman primates. PMID- 23668994 TI - The feasibility and safety of early removal of nasogastric tube after total gastrectomy for gastric cancer. AB - BACKGROUND/AIMS: To evaluate the feasibility and safety of early removal of nasogastric tube after total gastrectomy for gastric cancer. METHODOLOGY: Data of 142 gastric cancer patients who underwent total gastrectomy from January 2011 to March 2012 were retrospectively collected and analyzed. Early removal ER group n=57 of nasogastric tube was defined as removal within postoperative 48 h, and conventional placement CP group n=85 of nasogastric tube was defined as removal till flatus and less than 300 cc gastric juice drainage. Outcome measures included postoperative temperature, hospital stay length, days to passage of flatus, days to semi-liquid diet, postoperative complications and mortality. RESULTS: No statistically significant difference was found between the ER group and the CP group in postoperative highest temperature p=0,456 the incidence of temperature over 38.5C p=0,772 postoperative hospital stay length p=0,102 and time to flatus p=0,163 There was no death or reoperation in patients of both groups. There were no significant differences in postoperative complications between the two groups 22,8% vs 30,6%, p=0,309 There was no anastomotic leakage, hemorrhage or stenosis. There was a trend of decreased risk of postoperative pneumonia in the ER group 10,5% vs 21,2% despite no significance p=0,097 CONCLUSIONS: The early removal of nasogastric tube within postoperative 48 h after total gastrectomy is feasible and safe in common practice and might also have a potential benefit in preventing postoperative pneumonia. PMID- 23668995 TI - Bioinspired photoelectric conversion system based on carbon-quantum-dot-doped dye semiconductor complex. AB - Compared to nature's photoelectric conversion processes, artificial devices are still far inferior in efficiency and stability. Inspired by light absorption and resonance energy transfer processes of chlorophyll, we developed a highly efficient photoelectric conversion system by introducing Carbon quantum dots (CQDs) as an electron transfer intermediary. Compared with conventional dye sensitized semiconductor systems, the present CQD-doped system showed significantly higher photoelectric conversion efficiency, as much as 7 times that without CQDs. The CQD-doped dye/semiconductor system may provide a powerful approach to the development of highly efficient photoelectric devices. PMID- 23668996 TI - An MRI denoising method using image data redundancy and local SNR estimation. AB - This paper presents an LMMSE-based method for the three-dimensional (3D) denoising of MR images assuming a Rician noise model. Conventionally, the LMMSE method estimates the noise-less signal values using the observed MR data samples within local neighborhoods. This is not an efficient procedure to deal with this issue while the 3D MR data intrinsically includes many similar samples that can be used to improve the estimation results. To overcome this problem, we model MR data as random fields and establish a principled way which is capable of choosing the samples not only from a local neighborhood but also from a large portion of the given data. To follow the similar samples within the MR data, an effective similarity measure based on the local statistical moments of images is presented. The parameters of the proposed filter are automatically chosen from the estimated local signal-to-noise ratio. To further enhance the denoising performance, a recursive version of the introduced approach is also addressed. The proposed filter is compared with related state-of-the-art filters using both synthetic and real MR datasets. The experimental results demonstrate the superior performance of our proposal in removing the noise and preserving the anatomical structures of MR images. PMID- 23668997 TI - Leisure activity, health, and medical correlates of neurocognitive performance among monozygotic twins: the Older Australian Twins Study. AB - OBJECTIVES: We aimed to examine associations between each of three leisure activities (Cognitive, Physical, and Social) and performance in selected cognitive domains (Speed, Memory, Verbal ability, and Executive functions) and global cognition. We also aimed to explore associations between medical and health factors and late-life cognition. METHOD: Our sample comprised 119 pairs of monozygotic twins from the Older Australian Twins Study. Their mean age was 71 years and 66% were women. We used a discordant co-twin design, with cognitive performance measures as dependent variables and leisure activities as independent variables. Multiple regression analyses were performed, adjusting for potentially relevant medical and health factors. RESULTS: Discordance in Cognitive Activity and Social Activity participation was positively associated with discordance in performance on some cognitive domains. There were no associations between Physical Activity participation and cognition. Discordance in several cardiovascular, frailty, and sensory variables was associated with discordance in cognitive performance measures. DISCUSSION: This study identified lifestyle and health-related influences on late-life cognition. Our findings not only help in understanding the neurobiological mechanisms, they also have practical implications for interventions to prevent or slow age-related cognitive decline. PMID- 23668998 TI - In vivo determination of elastic properties of the human aorta based on 4D ultrasound data. AB - Computational analysis of the biomechanics of the vascular system aims at a better understanding of its physiology and pathophysiology. To be of clinical use, however, these models and thus their predictions, have to be patient specific regarding geometry, boundary conditions and material. In this paper we present an approach to determine individual material properties of human aortae based on a new type of in vivo full field displacement data acquired by dimensional time resolved three dimensional ultrasound (4D-US) imaging. We developed a nested iterative Finite Element Updating method to solve two coupled inverse problems: The prestrains that are present in the imaged diastolic configuration of the aortic wall are determined. The solution of this problem is integrated in an iterative method to identify the nonlinear hyperelastic anisotropic material response of the aorta to physiologic deformation states. The method was applied to 4D-US data sets of the abdominal aorta of five healthy volunteers and verified by a numerical experiment. This non-invasive in vivo technique can be regarded as a first step to determine patient individual material properties of the human aorta. PMID- 23668999 TI - Nuclear expression of Smad proteins and its prognostic significance in clear cell renal cell carcinoma. AB - Smad2, Smad3, and Smad4 are components of the transforming growth factor beta signaling pathway associated with tumorigenesis. The expression of these proteins is associated with tumor progression and prognosis of many cancers. This study aimed to evaluate the nuclear expression of Smad2, Smad3, and Smad4 in clear cell renal cell carcinoma and to assess the clinical significance and prognostic value of their expression patterns. The nuclear expression levels of Smads were evaluated in 637 cases of clear cell renal cell carcinomas using immunohistochemistry. To determine the statistical significance of Smad expression in clear cell renal cell carcinoma, each of the cases were divided into 2 groups (low and high expression groups) according to the extent of nuclear staining. Nuclear expressions of Smad3 and Smad4 were inversely correlated with the patient's age, the nuclear grade, the tumor size, and the pTNM stage. The Smad3-low and Smad4-low groups showed significantly shorter cancer-specific and progression-free survival times. Furthermore, multivariate analysis showed that both Smad3 and Smad4 were independent predictors for progression-free survival (P = .008 and P = .022, respectively). However, Smad2 expression was not related to clinicopathologic parameters and patients' survival. These results suggest that nuclear expressions of Smad3 and Smad4 were related to prognosis of clear cell renal cell carcinoma patients and may serve as novel prognostic markers in clear cell renal cell carcinoma patients. PMID- 23669000 TI - Topical application of tranexamic acid after adenoidectomy: a double-blind, prospective, randomized, controlled study. AB - OBJECTIVE: Is to evaluate the efficacy of tranexamic acid when applied locally in children after primary isolated adenoidectomy with respect to intra-operative blood loss and post-operative bleeding. STUDY DESIGN: Prospective, double-blind, randomized, controlled trial. SETTING: Otolaryngology department, Tanta University and Tiba Hospitals, Egypt. PATIENTS AND METHODS: Over three years, 400 children underwent primary isolated adenoidectomy followed by topical application of tranexamic acid (tranexamic acid group, 200 children) or saline (Placebo group, 200 children) with at least two weeks' follow up. Intra-operative blood loss and post-operative hemorrhage were monitored. RESULTS: Both groups were almost equivalent in age and gender. The frequency of primary post-adenoidectomy hemorrhage as well as the rate of postnasal packing and blood transfusion required to manage severe bleeding were higher in placebo group. The volume of blood loss during surgery showed significant reduction in tranexamic acid group. CONCLUSION: Topical application of tranexamic acid after adenoidectomy led to a significant reduction in blood loss during surgery and decreasing in the rate of post-operative bleeding as well as the need for postnasal packing and blood transfusion. PMID- 23669001 TI - Current status and practical use of effluent biomarkers in peritoneal dialysis patients. AB - Long-term peritoneal dialysis therapy can lead to alterations in the function and morphology of the peritoneal membrane. Assessment of the peritoneal dialysis membrane usually is done by investigating the transport of small solutes and fluid. Assessment of morphologic alterations and their development would require repetitive peritoneal biopsies that usually are not feasible. Peritoneal tissues are bathed in dialysis solutions during peritoneal dialysis and may secrete or shed substances that can be recovered in peritoneal effluent. These molecular effluent biomarkers may give insight into morphologic changes. In this review, established and emerging candidate biomarkers in peritoneal dialysis are discussed. Additionally, requirements, challenges, and clinical applications of effluent biomarkers in peritoneal dialysis are addressed. PMID- 23669002 TI - Outcomes of patients receiving maintenance dialysis admitted over weekends. AB - BACKGROUND: Hospital admissions over weekends have been associated with worse outcomes in different patient populations. The cause of this difference in outcomes remains unclear; however, different staffing patterns over weekends have been speculated to contribute. We evaluated outcomes in patients on maintenance dialysis therapy admitted over weekends using a national database. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: We included nonelective admissions of adult patients (>=18 years) on maintenance dialysis therapy (n = 3,278,572) identified using appropriate International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for 2005-2009 using the Nationwide Inpatient Sample database. PREDICTOR: Weekend versus weekday admission. OUTCOMES: The primary outcome measure was all-cause in-hospital mortality. Secondary outcomes included mortality by day 3 of admission, length of hospital stay, time to death, and discharge disposition. MEASUREMENTS: We adjusted for patient and hospital characteristics, payer, year, comorbid conditions, and primary discharge diagnosis common to maintenance dialysis patients. RESULTS: There were an estimated 704,491 admissions over weekends versus 2,574,081 over weekdays. Unadjusted all-cause in-hospital mortality was 40,666 (5.8%) for weekend admissions in comparison to 138,517 (5.4%) for weekday admissions (P < 0.001). In a multivariable model, patients admitted over weekends had higher all-cause in-hospital mortality (OR, 1.06; 95% CI, 1.01-1.10) in comparison to those admitted over weekdays and higher mortality during the first 3 days of admission (OR, 1.18; 95% CI, 1.10-1.26). Patients admitted over weekends were less likely to be discharged to home, had longer hospital stays, and had shorter times to death compared with those admitted over weekdays on adjusted analysis. LIMITATIONS: Use of ICD-9-CM codes to identify patients, defining weekend as midnight Friday to midnight Sunday. CONCLUSIONS: Maintenance dialysis patients admitted over weekends have increased mortality rates and longer lengths of stay compared with those admitted over weekdays. Further studies are needed to identify the reasons for worse outcomes for weekend admissions in this patient population. PMID- 23669003 TI - The "all inside" arthroscopic Brostrom procedure: a prospective study of 40 consecutive patients. AB - Lateral ankle sprains are the most common injury in sports. Nonoperative therapy is recommended initially, including functional rehabilitation. Surgery might be an option for those patients in whom nonoperative attempts fail. Various surgical approaches have been described in published studies for treating chronic lateral ankle instability. The procedures are typically grouped into 2 main categories: anatomic and nonanatomic repair of the lateral ligament complex. The open modified Brostrom-Gould anatomic repair technique is widely accepted as the reference standard for lateral ankle stabilization. In the present study, we used an arthroscopic approach to treat chronic anterior talofibular ligament tears without the extensive open incisions common in the traditional modified Brostrom Gould procedure. Our hypothesis was that the use of an all-inside arthroscopic Brostrom procedure would provide a minimally invasive technique with acceptable patient outcomes. We also wished to explore the complication rates and interval to return to weightbearing activity. A total of 40 ankles in 40 consecutive patients were included in the cohort. PMID- 23669004 TI - Dysplasia epiphysealis hemimelica of talus mimicking posterior ankle impingement syndrome in a young male: a case report with review of the literature. AB - Dysplasia epiphysealis hemimelica is a rare skeletal developmental disorder representing an osteocartilaginous tumor arising from 1 or more epiphyses during childhood. We report a case of a young male who presented with complaints of pain and swelling in the posteromedial aspect of the left ankle with the clinical diagnosis of posterior impingement syndrome. Imaging studies, including radiography, computed tomography, and magnetic resonance imaging, suggested the possibility of localized juxta-articular dysplasia epiphysealis hemimelica arising from the talus. The patient was successfully treated by surgical excision. The postoperative histologic findings were consistent with osteochondroma. This case report emphasizes the possibility of dysplasia epiphysealis hemimelica in the differential diagnosis of impingement syndromes around the ankle. The aim of the present study was to familiarize clinicians with this rare entity, because the number of documented cases has been increasing. PMID- 23669005 TI - Early weightbearing using Achilles suture bridge technique for insertional Achilles tendinosis: a review of 43 patients. AB - Posterior heel pain caused by insertional Achilles tendinosis can necessitate surgical intervention when recalcitrant to conservative care. Surgical treatment can necessitate near complete detachment of the Achilles tendon to fully eradicate the offending pathologic features and, consequently, result in long periods of non-weightbearing. A suture bridge technique using bone anchors is available for reattachment of the Achilles tendon. This provides restoration of the Achilles footprint on the calcaneus, including not only contact, but also actual pressure between the tendon and bone. We performed a review of 43 patients who underwent surgical treatment of insertional Achilles tendinosis with reattachment of the Achilles tendon using the suture bridge technique. The mean age was 53 (range 29 to 87) years. The mean follow-up period was 24 (range 13 to 52) months. The mean postoperative American Orthopaedic Foot and Ankle Society score was 90 (range 65 to 100). The mean preoperative visual analog scale pain score was 6.8 (range 2 to 10) and the mean postoperative visual analog scale pain score was 1.3 (range 0 to 6). The mean interval to weightbearing was 10 (range 0 to 28) days. No postoperative ruptures occurred. Of the 43 patients, 42 (97.6%) successfully performed the single heel rise test at the final postoperative visit. Concomitant procedures were performed in 35 patients, including 33 (77%) requiring open gastrocnemius recession and 2 (5%) requiring flexor hallucis longus tendon transfer. A total of 42 patients (97.6%) returned to regular shoe gear, and 42 (97.6%) returned to their activities of daily living, including running for 20 athletic patients (100%). Complications included postoperative wound dehiscense requiring surgical debridement in 2 patients (5%) and soft tissue infection requiring antibiotics and surgical debridement in 1 (2%) patient. Our findings support using the Achilles tendon suture bridge for reattachment of the Achilles tendon in the surgical treatment of insertional Achilles tendinosis. PMID- 23669006 TI - Lateral meniscal cyst causing irreversible peroneal nerve palsy. AB - We report an unusual case of irreversible foot drop occurring secondary to a large lateral meniscal cyst. We discuss the presentation and management of this rare case and highlight some of the less common causes of foot drop. PMID- 23669007 TI - Rapid plasticity of motor corticospinal system with robotic reach training. AB - Goal-directed reaching is important for the activities of daily living. Populations of neurons in the primary motor cortex that project to spinal motor circuits are known to represent the kinematics of reaching movements. We investigated whether repetitive practice of goal-directed reaching movements induces use-dependent plasticity of those kinematic characteristics, in a manner similar to finger movements, as had been shown previously. Transcranial magnetic stimulation (TMS) was used to evoke upper extremity movements while the forearm was resting in a robotic cradle. Plasticity was measured by the change in kinematics of these evoked movements following goal-directed reaching practice. Baseline direction of TMS-evoked arm movements was determined for each subject. Subjects then practiced three blocks of 160 goal-directed reaching movements in a direction opposite to the baseline direction (14 cm reach 180 degrees from baseline direction) against a 75-Nm spring field. Changes in TMS-evoked whole arm movements were assessed after each practice block and after 5 min following the end of practice. Direction and the position of the point of peak velocity of TMS evoked movements were significantly altered following training and at a 5-min interval following training, while amplitude did not show significant changes. This was accompanied by changes in the motor-evoked potentials (MEPs) of the shoulder and elbow agonist muscles that partly explained the change in direction, mainly by increase in agonist MEP, without significant changes in antagonists. These findings demonstrate that the arm representation accessible by motor cortical stimulation under goes rapid plasticity induced by goal-directed robotic reach training in healthy subjects. PMID- 23669008 TI - Effects of exercise training on fitness, mobility, fatigue, and health-related quality of life among adults with multiple sclerosis: a systematic review to inform guideline development. AB - OBJECTIVE: To conduct a systematic review of evidence surrounding the effects of exercise training on physical fitness, mobility, fatigue, and health-related quality of life in adults with multiple sclerosis (MS). DATA SOURCES: The databases included EMBASE, 1980 to 2011 (wk 12); Ovid MEDLINE and Ovid OLDMEDLINE, 1947 to March (wk 3) 2011; PsycINFO, 1967 to March (wk 4) 2011; CINAHL all-inclusive; SPORTDiscus all-inclusive; Cochrane Library all-inclusive; and Physiotherapy Evidence Database all-inclusive. STUDY SELECTION: The review was limited to English-language studies (published before December 2011) of people with MS that evaluated the effects of exercise training on outcomes of physical fitness, mobility, fatigue, and/or health-related quality of life. DATA EXTRACTION: One research assistant extracted data and rated study quality. A second research assistant verified the extraction and quality assessment. DATA SYNTHESIS: From the 4362 studies identified, 54 studies were included in the review. The extracted data were analyzed using a descriptive approach. There was strong evidence that exercise performed 2 times per week at a moderate intensity increases aerobic capacity and muscular strength. The evidence was not consistent regarding the effects of exercise training on other outcomes. CONCLUSIONS: Among those with mild to moderate disability from MS, there is sufficient evidence that exercise training is effective for improving both aerobic capacity and muscular strength. Exercise may improve mobility, fatigue, and health-related quality of life. PMID- 23669010 TI - Phylogenetic and biogeographic analyses of the Sino-Himalayan endemic genus Cyananthus (Campanulaceae) and implications for the evolution of its sexual system. AB - Cyananthus (Campanulaceae) is a small genus consisting of ca. 20 species endemic to the Sino-Himalayan region. Based on phylogenetic analysis using nuclear ribosomal ITS and four plastid markers (matK, rbcL, psbA-trnH and trnG-S), our results strongly support the monophyly of Cyananthus and its close relationship with the Codonopsis clade of the platycodonoids. Three major clades are supported, corresponding to the three sections of the genus, with sect. Cyananthus, which mainly occurs in the Himalayas, being a sister to the clade comprising the other two sections (sect. Stenolobi and sect. Annui) distributed primarily in the Hengduan Mountain region. We also observed that Cyananthus exhibits variation in its sexual system, possessing both hermaphroditic and gynodioecious species. Character evolution analyses using Mesquite suggest that gynodioecy evolved from hermaphroditism only once in sect. Stenolobi, but that there is a reversal in C. formosus. Molecular dating and biogeographic analysis with LAGRANGE support dispersal from the Himalayas to the Hengduan Mountains during the early evolution of Cyananthus. The extensive uplift of the Qinghai Tibetan Plateau and the Hengduan Mountains played an important role in the subsequent diversification of the genus. PMID- 23669009 TI - Molecular phylogeny and historical biogeography of West Indian boid snakes (Chilabothrus). AB - The evolutionary and biogeographic history of West Indian boid snakes (Epicrates), a group of nine species and 14 subspecies, was once thought to be well understood; however, new research has indicated that we are missing a clear understanding of the evolutionary relationships of this group. Here, we present the first multilocus, species-tree based analyses of the evolutionary relationships, divergence times, and historical biogeography of this clade with data from 10 genes and 6256 bp. We find evidence for a single colonization of the Caribbean from mainland South America in the Oligocene or early Miocene, followed by a radiation throughout the Greater Antilles and Bahamas. These findings support the previous suggestion that Epicrates sensu lato Wagler is paraphyletic with respect to the anacondas (Eunectes Wagler), and hence we restrict Epicrates to the mainland clade and use the available name Chilabothrus Dumeril and Bibron for the West Indian clade. Our results suggest some diversification occurred within island banks, though most species divergence events seem to have occurred in allopatry. We also find evidence for a remarkable diversification within the Bahamian archipelago suggesting that the recognition of another Bahamian endemic species C. strigilatus is warranted. PMID- 23669011 TI - Diversification and dispersal of the Hawaiian Drosophilidae: the evolution of Scaptomyza. AB - The genus Scaptomyza is emerging as a model lineage in which to study biogeography and ecological adaptation. To place future research on these species into an evolutionary framework we present the most comprehensive phylogeny of Scaptomyza to date, based on 5042 bp of DNA sequence data and representatives from 13 of 21 subgenera. We infer strong support for the monophyly of almost all subgenera with exceptions corroborating hypotheses of conflict inferred from previous taxonomic studies. We find evidence that the lineage originated in the Hawaiian Islands and subsequently dispersed to the mainland and other remote oceanic islands. We also identify that many of the unique ecological niches exploited by this lineage (e.g., herbivory, spider predation) arose singly and independently. PMID- 23669012 TI - Elongation factor-1alpha, a putative single-copy nuclear gene, has divergent sets of paralogs in an arachnid. AB - Identification of paralogy in candidate nuclear loci is an important prerequisite in phylogenetics and statistical phylogeography, but one that is often overlooked. One marker commonly assumed to be a single-copy gene and claimed to harbor great utility for inferring recent divergences is elongation factor-1alpha (EF-1alpha). To test this hypothesis, we systematically cloned EF-1alpha in three disjunct populations of the harvestman Metasiro americanus. Here we show that EF 1alpha has a large number of paralogs in this species. The paralogs do not evolve in a concerted manner, and the paralogs diverged prior to the population divergence. Moreover, the paralogs of M. americanus are not comparable to the highly divergent EF-1alpha paralogs found in bees and spiders, which are easily recognized and separated through the use of specific primers. We demonstrate statistically that our detection of paralogs cannot be attributed to amplification error. The presence of EF-1alpha paralogs in M. americanus prevents its use in statistical phylogeography, and the presence of out-paralogs argues against its use in phylogenetic inference among recently diverged clades. These data contradict the common assumption that EF-1alpha is for most or all taxa a single-copy gene, or that it has a small number of paralogs that are homogenized through gene conversion, unequal crossing over, or other processes. PMID- 23669013 TI - Phylogeny of the non-monophyletic Cayratia Juss. (Vitaceae) and implications for character evolution and biogeography. AB - Cayratia consists of ca. 60 species primarily distributed in the tropical and subtropical regions of Asia, Australia, and Africa. It is an excellent candidate for exploring the evolution of intercontinental disjunct distributions in the Old World. Previous phylogenetic work of Vitaceae with a few species of Cayratia sampled showed that Cayratia was not monophyletic and was closely related to Cyphostemma and Tetrastigma. We herein expanded taxon sampling of Cayratia (25/60 species) with its allied genera Cyphostemma (39/150 species), Tetrastigma (27/95 species), and other related genera from Vitaceae represented, employing five plastid markers (atpB-rbcL, rps16, trnC-petN, trnH-psbA, and trnL-F), to investigate the phylogeny, character evolution and biogeography of Cayratia. The phylogenetic analyses have confirmed the monophyly of the Cayratia-Cyphostemma Tetrastigma (CCT) clade and resolved Cayratia into three lineages: the African Cayratia clade, subg. Cayratia, and subg. Discypharia. The African Cayratia was supported as the first diverging lineage within the CCT clade and Tetrastigma is resolved as sister to subg. Discypharia. Character optimizations suggest that the presence/absence of a membrane enclosing the ventral infolds in seeds is an important character for the taxonomy of Cayratia. The presence of bracts on the lower part of the inflorescence axis is inferred to have arisen only once in Cayratia, but this character evolved several times in Tetrastigma. Both the branching pattern of tendrils and the leaf architecture are suggested as important infrageneric characters, but should be used cautiously because some states evolved multiple times. Ancestral area reconstruction and molecular dating suggest that the CCT clade originated from continental Africa in the late Cretaceous, and it then reached Asia twice independently in the late Cretaceous and late Oligocene, respectively. Several dispersals are inferred from Asia to Australia since the Eocene. PMID- 23669014 TI - Is fibroid heterogeneity a significant issue for clinicians and researchers? AB - The clinical and scientific literature overwhelmingly deals with fibroids as a single entity or disease. This convenient assumption of homogeneity may be an important oversight given that substantial evidence exists for heterogeneity between fibroids at many levels. Failure to recognize and accommodate fibroid heterogeneity can have significant ramifications for both clinical treatment decisions and research protocol design. The aim of this article is to review the current knowledge of fibroid heterogeneity and to identify key areas where fibroid heterogeneity should be taken into consideration both clinically and when designing research protocols. Uterine leiomyomata display significant and well documented heterogeneity in symptoms, diagnostic imaging appearance, pathology, genetic background and therapeutic requirements. Additional research is needed to better understand fibroid heterogeneity as it relates to pathogenesis, molecular targets for potential new therapies, patient symptoms and, ultimately, treatment. To this list should also be added heterogeneity of genetics, lifestyle and individual clinical characteristics of the fibroid. Increasingly, an understanding of uterine leiomyoma heterogeneity will be of importance for clinicians who see patients with this common and costly disease. PMID- 23669015 TI - Reproductive hormone concentrations in pregnancy and neonates: a systematic review. AB - Although much research focuses on hormones during gestation, little is known about the actual hormone concentrations within the fetal surroundings. The aim of this study was to combine all available oestrogen, androgen, sex hormone-binding globulin (SHBG), anti-Mullerian hormone (AMH), inhibin, gonadotrophin and dehydroepiandrosterone sulphate (DHEAS) concentrations during gestation and post partum into graphical representations reporting weighted mean hormone values. A systematic search was performed in Pubmed and Embase from inception to March 2012. Studies were evaluated by two reviewers; manuscripts were included if the actual hormone concentrations were reported together with the gestational age at time of sampling. A total of 97 articles were found eligible for this review. Maternal serum oestrogens, inhibin A, SHBG, androstenedione and testosterone rise during gestation, which is followed by a rapid decline in the post-partum period. For AMH and DHEAS, an inverse relationship is found, while gonadotrophin concentrations are negligible during gestation. For girls cord blood oestriol and post-partum FSH concentrations are higher, while for boys cord blood FSH and neonatal testosterone, inhibin B, LH and AMH concentrations are higher. In conclusion, longitudinally measured endocrine data during gestation and in the peri- and post-natal period are lacking, especially for twin pregnancies. PMID- 23669016 TI - Developmental dynamics of IMSI-derived embryos: a time-lapse prospective study. AB - Because sperm vacuoles were marked as zones without chromatin in the sperm nucleus, which may reflect underlying chromosomal or DNA defects, this study considered whether they influence the morphology and dynamics of early developmental events in preimplantation embryos. Oocytes were injected with spermatozoa of four classes, according to the number and size of vacuoles at *6000 magnification, and derived embryos were observed under time-lapse microscopy. For each embryo, the times of pronuclei appearance and disappearance and the first, second and third divisions were determined and related to its respective class of injected spermatozoa and its developmental stage. Embryos arising from normal class-I spermatozoa (without vacuoles) reached the 4-cell stage significantly earlier than embryos developed from class-IV spermatozoa (with large vacuoles and other abnormalities) (P=0.012). Blastocysts from class-I spermatozoa required the shortest mean time for all developmental events in comparison with blastocysts from spermatozoa of other classes (with vacuoles). Blastocysts also showed significantly earlier first division than arrested embryos in embryos arising from class-I spermatozoa (P=0.033). An insight into the developmental dynamics of embryo development according to morphology and head vacuoles of injected spermatozoa in morphologically selected sperm-derived embryos was observed for the first time. PMID- 23669017 TI - Fertility preservation consultation for women with cancer: are we helping patients make high-quality decisions? AB - To investigate the efficacy of the current fertility preservation consultation process in patients' decision-making and socio-demographic and cognitive factors that may affect patients' decision-making, a prospective pilot survey was conducted at university-based IVF centres and included women aged 18-43 years seen for fertility preservation between April 2009 and December 2010. Patients' views on consultation and decision-making about fertility preservation were measured. Among 52 women who completed the survey, more than half (52%) requested their consultation. All patients answered that consultation was a helpful resource of information, and 73% made their decision about treatment after consultation. Decisional conflict was lower in patients who felt strongly that they were given opportunities to ask questions during the consultation (P=0.001) and higher those who reported that cost was strongly influential in the treatment decision (P<0.001) and who did not receive treatment (P<0.001). Although consultation appeared to play a critical role in patients' decision-making about fertility preservation, the referral rate for consultation by oncologists is still poor. Decision-making appears to be significantly impaired in patients grappling with financial concerns and when the opportunity to ask questions is not felt to be sufficient. PMID- 23669018 TI - Epidermal keratinocytes form a functional skin barrier in the absence of Atg7 dependent autophagy. AB - BACKGROUND: Cornification of keratinocytes involves the degradation of intracellular constituents which has led to the hypothesis that autophagy plays a role in this process. Mice, in which essential autophagy-related genes such as Atg7 are deleted systemically, die after birth and have not been characterized for potential epidermal defects. OBJECTIVE: This study tested whether autophagy is essential for epidermal barrier formation and function. METHODS: Atg7 was inactivated in epidermal keratinocytes by the Cre-loxP system under the control of the keratin K14 promoter (Atg7Deltaepi mice). Autophagic activity was detected using the GFP-microtubule-associated protein light chain 3 (GFP-LC3) reporter construct and Western blot analysis of LC3. Epidermal morphology was examined by histological and ultrastructural analyses, and barrier functions were assessed by dye diffusion and water loss assays. RESULTS: Suprabasal epidermal cells of normal mice contained GFP-LC3-labeled autophagosomes and epidermal lysates of these mice showed an excess of lipidated over non-lipidated LC3. These features of active autophagy were efficiently suppressed in Atg7Deltaepi epidermis. Atg7Deltaepi mice survived the perinatal period and were apparently healthy. Histologically, their epidermis was inconspicuous and ultrastructural analysis revealed no significant defect in cornification. There was however, an increase in the thickness of corneocytes in the back skin of mutant mice. Nevertheless, resistance to dye penetration into the skin and transepidermal water loss were normal in Atg7Deltaepi mice. CONCLUSION: This study demonstrates that autophagy is constitutively active in the epidermis but not essential for the barrier function of the skin. PMID- 23669019 TI - Recent advances of in vitro tests for the diagnosis of food-dependent exercise induced anaphylaxis. AB - Food-dependent exercise-induced anaphylaxis (FDEIA) is a special form of IgE mediated food allergy and exhibits allergic symptoms in combination of causative food-intake and triggers such as exercise. As the causative foods and the condition of triggers vary among patients, diagnosis of FDEIA is not always easy. Serum food-specific IgE tests, which are widely used in the diagnosis of FDEIA, have rather low sensitivity, because the tests mostly utilize crude extracts of foods. Concept of using defined allergen molecules has been proposed as the term "component-resolved diagnostics" for diagnosis of IgE-mediated allergy. Use of purified allergens such as recombinant omega-5 gliadin turned out to highly improve its sensitivity and specificity of the tests in the diagnosis of wheat dependent exercise-induced anaphylaxis (WDEIA). Recently, CD203c expression-based basophil activation test (BAT) is reported to be useful in identifying adult patients with WDEIA and predicting causative allergens in WDEIA, when combined with appropriate allergens. Detection of serum allergen levels possibly gives useful information whether food challenge tests have been performed with sufficient strength. PMID- 23669020 TI - HLA-B*58:01 strongly associates with allopurinol-induced adverse drug reactions in a Japanese sample population. PMID- 23669021 TI - Racial differences in determinants of live donor kidney transplantation in the United States. AB - Few studies have compared determinants of live donor kidney transplantation (LDKT) across all major US racial-ethnic groups. We compared determinants of racial-ethnic differences in LDKT among 208 736 patients who initiated treatment for end-stage kidney disease during 2005-2008. We performed proportional hazards and bootstrap analyses to estimate differences in LDKT attributable to sociodemographic and clinical factors. Mean LDKT rates were lowest among blacks (1.19 per 100 person-years [95% CI: 1.12-1.26]), American Indians/Alaska Natives AI/ANs (1.40 [1.06-1.84]) and Pacific Islanders (1.10 [0.78-1.84]), intermediate among Hispanics (2.53 [2.39-2.67]) and Asians (3.89 [3.51-4.32]), and highest among whites (6.46 [6.31-6.61]). Compared with whites, the largest proportion of the disparity among blacks (20%) and AI/ANs (29%) was attributed to measures of predialysis care, while the largest proportion among Hispanics (14%) was attributed to health insurance coverage. Contextual poverty accounted for 16%, 4%, 18%, and 6% of the disparity among blacks, Hispanics, AI/ANs and Pacific Islanders but none of the disparity among Asians. In the United States, significant disparities in rates of LDKT persist, but determinants of these disparities vary by race-ethnicity. Efforts to expand preESKD insurance coverage, to improve access to high-quality predialysis care and to overcome socioeconomic barriers are important targets for addressing disparities in LDKT. PMID- 23669022 TI - Consistency and inconsistency in testing biomarkers in breast cancer. A GRELL study in cut-off variability in the Romance language countries. AB - PURPOSE: Biological markers are crucial factors in order to differentiate female breast cancers and to determine the right therapy. This study aims at evaluating whether testing for biomarkers for female breast cancer has similar frequency and characteristics across and within countries. METHODS: Population-based cancer registries of the Association for cancer registration and epidemiology in Romance language countries (GRELL) were asked to complete a questionnaire on biomarkers testing. The data collected referred to invasive female breast cancer cases diagnosed between 2004 and 2009. The investigation focused on 1) the overexpression and amplification of the human epidermal growth factor receptor 2 oncogene (HER2); 2) the expression of oestrogen (ER) and progesterone (PgR) receptors; and 3) the proliferation index (PI). Weighted percentages, the heterogeneity among and within countries, and the correlation between responses and calendar years were evaluated. The study was based on 19,644 breast cancers. RESULTS: Overall, 85.9% of the cases were tested for HER2, 91.8% for both ER and PgR, and 74.1% for proliferative markers. For HER2 and ER-PgR, the frequency of testing increased from 2004 to 2009. Testing varied among countries (HER2 from 82.0% to 95.9%, ER-PgR from 89.3% to 98.9%, PI from 10% to 92%) and also within the same country (e.g. HER2 in Italy from 51% to 99%) as well as within single cancer registries. The most relevant differences were in the scores for positive/negative/not clearly defined HER2 (e.g. HER2 was defined positive if IHC 3+ in 21/33 registries), and in the cut-off of positive cells for ER/PgR (from >0% to >30%) and PI positivity (from >0% to >20%). CONCLUSIONS: Biological markers are widely tested in the Romance language countries; however, the parameters defining their positivity may vary, raising concerns about homogeneity in breast cancer classification and treatment. PMID- 23669023 TI - Identification of interferon-gamma-inducible-lysosomal thiol reductase (GILT) gene from Mefugu (Takifugu obscures) and its immune response to LPS challenge. AB - Interferon-gamma-inducible-lysosomal thiol reductase (GILT) plays a key role in the processing and presentation of MHC class II-restricted antigen (Ag) by catalyzing disulfide bond reduction. In this study, a Mefugu cDNA (ToGILT) encodes a deduced protein of 242 amino acids with a putative molecular weight of 28.6 kDa. It contains typical features of GILT proteins including the signature sequence CQHGX2ECX2NX4C, CXXC motif and other five cysteines. Genomic analysis revealed that ToGILT gene exhibited a similar exon-intron organization to human and mouse GILT. Phylogenetic analysis showed that ToGILT derived from a common ancestor with other vertebrate GILT proteins. The ToGILT mRNA was expressed in a tissue-specific manner and obviously up-regulated in spleen and kidney after LPS induction. These results suggest that ToGILT may be involved in the immune response to bacteria challenge in Takifugu obscurus. PMID- 23669025 TI - Multivariate optimization of capillary electrophoresis methods: a critical review. AB - In this article a review on the recent applications of multivariate techniques for optimization of electromigration methods, is presented. Papers published in the period from August 2007 to February 2013, have been taken into consideration. Upon a brief description of each of the involved CE operative modes, the characteristics of the chemometric strategies (type of design, factors and responses) applied to face a number of analytical challenges, are presented. Finally, a critical discussion, giving some practical advices and pointing out the most common issues involved in multivariate set-up of CE methods, is provided. PMID- 23669024 TI - Diagnostic yield of EGD in children: a retrospective single-center study of 1000 cases. AB - BACKGROUND: Pediatric EGD is increasingly being used, but few studies have recently evaluated the diagnostic yield. OBJECTIVE: To assess the association between presenting clinical symptoms and the likelihood of significant endoscopic and histologic abnormalities for initial diagnostic endoscopy. DESIGN: Retrospective cohort study. SETTING: Large, tertiary care children's hospital. PATIENTS: One thousand patients, ages 1 month to 18 years, who underwent initial diagnostic EGD in 2009 and 2010. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Endoscopic and histologic abnormalities. RESULTS: The most common primary indications for endoscopy were generalized abdominal pain (28.7%), gastroesophageal reflux (11.7%), and failure to thrive (9.5%). The overall prevalence of an endoscopic abnormality was 34.7% and of a histologic abnormality, 40.4%. The highest rates of endoscopic abnormalities were found in patients with strictures on upper GI radiology (100%), foreign body (88%), and GI bleeding (57%). The highest rates of histologic abnormalities were in patients with positive celiac screening (91%), foreign body (88%), dysphagia (51%), and GI bleeding (49%), and the lowest rates of histologic abnormalities were miscellaneous indications (17%), strictures on radiology (25%), and reflux (26%). Females and patients < 1 year of age had lower rates of abnormal histologic abnormalities. LIMITATIONS: Retrospective nature of the study, limitation to a single tertiary care center, and simplification of complex patient presentations to a single indication. CONCLUSIONS: Rates of endoscopic and histologic abnormalities from EGD vary based on age and indication for endoscopy, and this should be factored into the decision to proceed with initial endoscopy along with consideration of adverse event rates and effects of anesthesia. PMID- 23669026 TI - Conjugation of dexamethasone to C60 for the design of an anti-inflammatory nanomedicine with reduced cellular apoptosis. AB - Dexamethasone (DEX) is a well-known anti-inflammatory drug, whose widespread clinical use is nevertheless restricted by its serious side effects. By conjugation of DEX with C60, we found that this nanomedicine retained the anti inflammatory activity of DEX while reducing side effects in the animal model. In mouse thymocytes, the CCK-8 assay showed that the cytotoxicity of DEX-C60 was significantly lower than that of free DEX. Flow cytometric studies revealed that incubation with DEX-C60 induced much less apoptotic thymocytes. Interestingly, such reduced cytotoxicity and apoptosis were not observed when equal moles of free C60 and free DEX were coincubated with thymocytes, suggesting that the conjugation alters the signal pathway of DEX. Indeed, we found that the binding of DEX-C60 and a glucocorticoid receptor (GR) was partially blocked in the thymocytes, which resulted in down-regulation of several apoptosis-related genes. These findings help understand the mechanism of beneficial effects of this new nanomedicine, DEX-C60, and promote its clinical applications. PMID- 23669027 TI - The emergency department "carousel": an ethnographically-derived model of the dynamics of patient flow. AB - Emergency department (ED) overcrowding reduces efficiency and increases the risk of medical error leading to adverse events. Technical solutions and models have done little to redress this. A full year's worth of ethnographic observations of patient flow were undertaken, which involved making hand-written field-notes of the communication and activities of emergency clinicians (doctors and nurses), in two EDs in Sydney, Australia. Observations were complemented by semi-structured interviews. We applied thematic analysis to account for the verbal communication and activity of emergency clinicians in moving patients through the ED. The theoretical model that emerged from the data analysis is the ED "carousel". Emergency clinicians co-construct a moving carousel which we conceptualise visually, and which accounts for the collective agency of ED staff, identified in the findings. The carousel model uniquely integrates diagnosis, treatment and transfer of individual patients with the intellectual labour of leading and coordinating the department. The latter involves managing staff skill mix and the allocation of patients to particular ED sub-departments. The model extends traditional patient flow representations and underlines the importance of valuing ethnographic methods in health services research, in order to foster organisational learning, and generate creative practical and policy alternatives that may, for example, reduce or ameliorate access block and ED overcrowding. PMID- 23669028 TI - Reducing uncertainty in triaging mental health presentations: examining triage decision-making. AB - Little is known about how emergency department (ED) nurses make decisions and even less is known about triage nurses' decision-making. There is compelling motivation to better understand the processes by which triage nurses make decisions, particularly with complex patient populations such as those with frequently emotive mental health and illness issues. While accuracy and reliability of triage decisions generally have been improved through the introduction of standardised triage scales and instruments, other factors such as lack of knowledge or confidence related to mental health issues, past experiences that may elicit transference and countertransference, judgments about individuals based on their behavioural presentations may impact on decisions made at triage. In this paper, we review the current research regarding the effectiveness of triage tools particularly with mental health presentations, present a theoretical framework that may guide research in understanding how triage nurses approach decision-making, and apply that framework to thinking about research in mental health-related triage. Developing a better understanding of how triage nurses make decisions, particularly in situations where issues related to mental health and illness may raise the levels of uncertainty, is crucial to ensure that they have the skills and tools they need to provide the most effective, sensitive, and compassionate care possible. PMID- 23669029 TI - Australian Emergency Department health professionals' reasons to invite or not invite Family Witnessed Resuscitation: a qualitative perspective. AB - BACKGROUND: Debate continues regarding the effectiveness of Family Witnessed Resuscitation and little is known about the reasons why staff invite family presence. AIM: Explore why health professionals invite or not invite Family Witnessed Resuscitation. DESIGN: Descriptive qualitative study. METHOD: Three open-ended questions enabled 114 clinicians to describe why they would or would not invite family presence. Data were analysed using qualitative data analysis. RESULTS: Four themes representing factors that influenced staff decision to invite or not invite Family Witnessed Resuscitation were identified: motivating factors, personal choice, staff judgment, and organisational factors. Motivating factors described reasons to invite family presence, and staff and organisational factors were reasons to not invite family presence. CONCLUSION: Family presence can be beneficial for staff and family and is likely to be motivated by family specific factors where this choice is appropriate for all stakeholders. Participants described factors that can impact on the appropriateness of inviting family presence and these need to be considered before an invitation is extended. RELEVANCE TO PRACTICE: To support all parties throughout the process it is imperative that a skilled support person be available to the family and that written policies and guidelines be available for staff. PMID- 23669030 TI - AMPK connects energy stress to PIK3C3/VPS34 regulation. AB - The class III phosphatidylinositol (PtdIns)-3 kinase, PIK3C3/VPS34, forms multiple complexes and regulates a variety of cellular functions, especially in intracellular vesicle trafficking and autophagy. Even though PtdIns3P, the product of PIK3C3, is thought to be a critical membrane marker for the autophagosome, it is unclear how PIK3C3 is regulated in response to autophagy inducing stimuli. A complexity of PIK3C3 biology is due in part to the existence of multiple complexes, of which the ATG14- or UVRAG-containing complexes play important roles in autophagy. We recently discovered differential regulation of distinct PIK3C3 complexes in response to energy starvation and showed a mechanism by which AMPK directly phosphorylates PIK3C3 and BECN1 to regulate non- and pro autophagic PIK3C3 complexes, respectively. PMID- 23669031 TI - A fast workflow for identification and quantification of proteomes. AB - The current in-depth proteomics makes use of long chromatography gradient to get access to more peptides for protein identification, resulting in covering of as many as 8000 mammalian gene products in 3 days of mass spectrometer running time. Here we report a fast sequencing (Fast-seq) workflow of the use of dual reverse phase high performance liquid chromatography - mass spectrometry (HPLC-MS) with a short gradient to achieve the same proteome coverage in 0.5 day. We adapted this workflow to a quantitative version (Fast quantification, Fast-quan) that was compatible to large-scale protein quantification. We subjected two identical samples to the Fast-quan workflow, which allowed us to systematically evaluate different parameters that impact the sensitivity and accuracy of the workflow. Using the statistics of significant test, we unraveled the existence of substantial falsely quantified differential proteins and estimated correlation of false quantification rate and parameters that are applied in label-free quantification. We optimized the setting of parameters that may substantially minimize the rate of falsely quantified differential proteins, and further applied them on a real biological process. With improved efficiency and throughput, we expect that the Fast-seq/Fast-quan workflow, allowing pair wise comparison of two proteomes in 1 day may make MS available to the masses and impact biomedical research in a positive way. PMID- 23669032 TI - Possible links between stress defense and the tricarboxylic acid (TCA) cycle in Francisella pathogenesis. AB - Francisella tularensis is a highly infectious bacterium causing the zoonotic disease tularemia. In vivo, this facultative intracellular bacterium survives and replicates mainly in the cytoplasm of infected cells. We have recently identified a genetic locus, designated moxR that is important for stress resistance and intramacrophage survival of F. tularensis. In the present work, we used tandem affinity purification coupled to mass spectrometry to identify in vivo interacting partners of three proteins encoded by this locus: the MoxR-like ATPase (FTL_0200), and two proteins containing motifs predicted to be involved in protein-protein interactions, bearing von Willebrand A (FTL_0201) and tetratricopeptide (FTL_0205) motifs. The three proteins were designated here for simplification, MoxR, VWA1, and TPR1, respectively. MoxR interacted with 31 proteins, including various enzymes. VWA1 interacted with fewer proteins, but these included the E2 component of 2-oxoglutarate dehydrogenase and TPR1. The protein TPR1 interacted with one hundred proteins, including the E1 and E2 subunits of both oxoglutarate and pyruvate dehydrogenase enzyme complexes, and their common E3 subunit. Remarkably, chromosomal deletion of either moxR or tpr1 impaired pyruvate dehydrogenase and oxoglutarate dehydrogenase activities, supporting the hypothesis of a functional role for the interaction of MoxR and TPR1 with these complexes. Altogether, this work highlights possible links between stress resistance and metabolism in F. tularensis virulence. PMID- 23669033 TI - Neuroprotective compounds from the bulbs of Lycoris radiata. AB - Three new alkaloids (1-3) and one new phenolic glycoside (4), together with twenty five known alkaloids (5-29), were isolated from the bulbs of Lycoris radiata collected from Huaihua county of Hunan province, China. Their structures were elucidated on the basis of comprehensive NMR and MS spectroscopic analysis. The isolated alkaloids were evaluated for their neuroprotective activities against CoCl2, H2O2 and Abeta(25-35)-induced SH-SY5Y cell injuries. Compounds 1-3 showed significant neuroprotective effects against H2O2 or CoCl2-induced SH-SY5Y cell death, while compound 3 exhibited significant neuroprotective effects against Abeta(25-35)-induced SH-SY5Y cell injury. The known alkaloids 5-29 also exhibited similar bioactivities of different degrees. These findings highlight the fact that the over 100 Amaryllidaceae alkaloids may have a big potential to neuroprotective activity. PMID- 23669034 TI - Chemical constituents of Callicarpa nudiflora and their anti-platelet aggregation activity. AB - Two new triterpenoids, 2alpha,3alpha,19alpha,23-tetrahydroxyurs-12,20(30)-dien-28 oic acid (1) and 2alpha,3alpha,19alpha-trihydroxyurs-12-en-28-oic acid-28-O-beta D-xylopyranosyl (1->2)-beta-D-glucopyranoside (2), and a new acylated flavone glycoside, luteolin 3'-O-(6"-E-caffeoyl)-beta-D-glucopyranoside (3), together with three known compounds (4-6), were isolated from the leaves of Callicarpa nudiflora Hook. Their structures were elucidated on the basis of spectroscopic data and chemical methods. Anti-platelet aggregation activities of these compounds were evaluated in vitro. Compounds 1 and 2 showed inhibitory effects on ADP-induced platelet aggregation with EC50 values of 9.48 MUM and 25.31 MUM, respectively. PMID- 23669036 TI - Proceedings of the 5th European Conference on Bloodstream Infections. Introduction. PMID- 23669035 TI - New model for adenine-induced chronic renal failure in mice, and the effect of gum acacia treatment thereon: comparison with rats. AB - INTRODUCTION: This study aimed at comparing the effects of feeding mice and rats with adenine to induce a state of chronic renal failure (CRF), and to assess the effect of treatment with gum acacia (GA) thereon. METHODS: We compared the outcome, in mice, of feeding adenine at three different doses (0.75%, 0.3%, and 0.2%, w/w). Biochemical and histopathological studies were conducted in plasma, urine and renal homogenates from both species. RESULTS: When mice and rats were fed adenine (0.75%, w/w), all treated rats survived the treatment, but all treated mice died within 1-2 days. The dosage in mice was reduced to 0.3%, w/w, for 4 weeks, but again all treated mice died within 3-4 days. A further reduction in the dosage in mice to 0.2%, w/w, for 4 weeks resulted in no mortality, and produced alterations similar to those observed in rats fed adenine at a dose of 0.75%,w/w, for 4 weeks. Plasma creatinine, urea and urinary protein were significantly increased (P<0.001) in adenine-treated mice and rats, and this action was incompletely, but significantly (P<0.05), reversed by GA. Adenine significantly (P<0.001) reduced superoxide dismutase (SOD) activity and reduced glutathione (GSH) concentration in renal homogenates from both species, and these reductions were significantly (P<0.05) ameliorated by GA. DISCUSSION: Our data suggest that mice are more sensitive to adenine than rats, and that a dose of adenine of 0.2%, w/w, for 4 weeks in mice is suggested as a model for CRF. In both models, GA (15%, w/v, in the drinking water for 4 weeks) given concomitantly with adenine ameliorated the severity of CRF to a similar extent. PMID- 23669037 TI - Preparation of quercetin and rutin-loaded ceramide liposomes and drug-releasing effect in liposome-in-hydrogel complex system. AB - In this study, we developed a 2-step delivery system to enhance transdermal permeation of quercetin and its glycoside rutin, an antioxidant. Liposome-in hydrogel complex systems were prepared by incorporating ceramide liposomes, which consist of biocompatible lipid membranes, into cellulose hydrogel. We evaluated the encapsulation efficiency, in vitro release behavior, and skin permeability of formulations that remained stable for over 3 weeks. Rutin had greater encapsulation efficiency and better in vitro release properties than quercetin. However, quercetin demonstrated greater skin permeability than rutin. We also found that liposome-in-hydrogel complex systems (quercetin, 67.42%; rutin 59.82%) improved skin permeability of quercetin and rutin compared to control (phosphate buffer, pH 7.4) (quercetin, 2.48%; rutin, 1.89%) or single systems of hydrogel (quercetin, 31.77%; rutin, 26.35%) or liposome (quercetin, 48.35%; rutin, 37.41%). These results indicate that liposome-in-hydrogel systems can function as potential drug delivery systems to enhance transdermal permeation of the water insoluble antioxidants quercetin and rutin. PMID- 23669038 TI - The CC1-FHA dimer is essential for KIF1A-mediated axonal transport of synaptic vesicles in C. elegans. AB - KIF1A, a member of kinesin-3 motors, plays a pivotal role in anterograde axonal transport of synaptic vesicles (SVs). We have shown that the CC1-FHA tandem of KIF1A forms a stable dimer that is crucial for both the dimerization and activation of the motor. However, it remains to be determined whether the CC1-FHA dimer is essential for KIF1A-mediated axonal transport in vivo. Here, we use Caenorhabditis elegans as the model organism to probe the in vivo function of the CC1-FHA dimer. Disruption of the CC1-FHA dimer severely impairs the KIF1A mediated regulation of the locomotion and pumping behavior of C. elegans and exerts a significant impact on KIF1A-mediated axonal SV transport. Thus, together with previous structural and biochemical studies, the in vivo data presented in this study firmly establish the essential role of the CC1-FHA dimer for KIF1A mediated neuronal transport. PMID- 23669039 TI - Disruption of polyubiquitin gene Ubc leads to defective proliferation of hepatocytes and bipotent fetal liver epithelial progenitor cells. AB - We have previously demonstrated that disruption of polyubiquitin gene Ubc leads to mid-gestation embryonic lethality most likely due to a defect in fetal liver development, which can be partially rescued by ectopic expression of Ub. In a previous study, we assessed the cause of embryonic lethality with respect to the fetal liver hematopoietic system. We confirmed that Ubc(-/-) embryonic lethality could not be attributed to impaired function of hematopoietic stem cells, which raises the question of whether or not FLECs such as hepatocytes and bile duct cells, the most abundant cell types in the liver, are affected by disruption of Ubc and contribute to embryonic lethality. To answer this, we isolated FLCs from E13.5 embryos and cultured them in vitro. We found that proliferation capacity of Ubc(-/-) cells was significantly reduced compared to that of control cells, especially during the early culture period, however we did not observe the increased number of apoptotic cells. Furthermore, levels of Ub conjugate, but not free Ub, decreased upon disruption of Ubc expression in FLCs, and this could not be compensated for by upregulation of other poly- or mono-ubiquitin genes. Intriguingly, the highest Ubc expression levels throughout the entire culture period were observed in bipotent FLEPCs. Hepatocytes and bipotent FLEPCs were most affected by disruption of Ubc, resulting in defective proliferation as well as reduced cell numbers in vitro. These results suggest that defective proliferation of these cell types may contribute to severe reduction of fetal liver size and potentially mid-gestation lethality of Ubc(-/-) embryos. PMID- 23669040 TI - GnRH neuron type-specific transcriptome analysis by laser captured single-cell microarray in the medaka. AB - Most vertebrates possess at least two gonadotropin-releasing hormone (GnRH) neuron types. To understand the physiological significance of the multiple GnRH systems in the brain, we examined three GnRH neuron type-specific transcriptomes using single-cell microarray analyses in the medaka (Oryzias latipes). A microarray profile of the three GnRH neuron types revealed five genes that are uniquely expressed in specific GnRH neuron types. GnRH1 neurons expressed three genes that are homologous to functionally characterised genes, GnRH2 neurons uniquely expressed one unnamed gene, and GnRH3 neurons uniquely expressed one known gene. These genes may be involved in the modulation or maintenance of each GnRH neuron type. PMID- 23669041 TI - Involvement of AAT transporters in methylmercury toxicity in Caenorhabditis elegans. AB - Methylmercury (MeHg) is a potent neurotoxin that enters mammalian cells as a conjugate with L-cysteine through L-type large neutral amino acid transporter, LAT1, by a molecular mimicry mechanism by structurally resembling L-methionine. Caenorhabditis elegans (C. elegans) has been increasingly used to study the neurotoxic effects of MeHg, but little is known about uptake and transport of MeHg in the worm. This study examined whether MeHg uptake through LAT1 is evolutionarily conserved in nematodes. MeHg toxicity in C. elegans was blocked by pre-treatment of worms with l-methionine, suggesting a role for amino acid transporters in MeHg transport. Knockdown of aat-1, aat-2, and aat-3, worm homologues to LAT1, increased the survival of C. elegans following MeHg treatment and significantly attenuated MeHg content following exposure. These results indicate that MeHg is transported in the worm by a conserved mechanism dependent on functioning amino acid transporters. PMID- 23669042 TI - Exercise training improves leptin sensitivity in peripheral tissue of obese rats. AB - The present study examined the change to the effect of the leptin sensitivity by leptin resistance-induced leptin receptor (ObRb) and leptin-related suppressor of cytokine signaling 3 (SOCS3) mRNA levels in hypothalamic, liver, muscle and leptin protein levels in blood after eight 8 weeks of exercise training and/or dietary control of high fat induced obese rats. After 2 weeks of adaptation maintenance, four-week-old male SD rats (n=42) were randomly divided into control (CO) (n=8) and high-fat diet (HF) (n=32) groups. The HF group randomly divided into HF, HF+exercise training (HFT), changed to normal diet (HFND) and changed to normal diet and exercise training (HFNDT) groups. 13 weeks of HF group average body weight significantly increased in comparison to the CO group (p<0.05). Plasma leptin levels of the HFT, HFND and HFNDT group were significantly decreased in comparison to the HF group (p<0.05). The mRNA expression of ObRb and SOCS3 in the liver and muscle of the HF group was significantly decreased comparison to that of the HFT, HFND and HFNDT group after 8 weeks intervention (p<0.05). In addition, the mRNA expression of ObRb and SOCS3 in the hypothalamus of the HF group was significantly increased comparison to that of the HFT, HFND and HFNDT group (p<0.05). HFND group also was significantly reduced comparison to of the HFT and HFNDT group (p<0.05). These findings suggest that the effect of leptin sensitivity in peripheral may primarily the more relate to combined dietary control and exercise training more than effect of dietary control. PMID- 23669043 TI - Rapid method for Mycobacterium tuberculosis identification using electrospray ionization tandem mass spectrometry analysis of mycolic acids. AB - Mycolic acids (MAs), which play a crucial role in the architecture of mycobacterial cell walls, were analyzed using electrospray ionization tandem mass spectrometry. A targeted analysis based on the 10 most abundant and characteristic multiple reaction monitoring pairs was used to profile the crude fatty acid mixtures from Mtb and several nontuberculous mycobacterial strains. Comparative analysis yielded unique profiles for MAs, enabling the reliable identification of mycobacterial species. In a case-control study of tuberculosis (TB) and non-TB Polish patients, we demonstrated the potential diagnostic utility of our approach for the rapid diagnosis of active TB with sensitivity and specificity surpassing those of existing methods. This robust method allows the identification of TB-positive patients after 2 h of sample preparation in the case of direct sputum analysis or 10 days of culturing, both of which are followed by 1 min of liquid chromatography-tandem mass spectrometry analysis. PMID- 23669044 TI - An aptamer based surface plasmon resonance biosensor for the detection of bovine catalase in milk. AB - In this research, we report the development of an aptamer based SPR biosensor for the detection of catalase in milk samples with minimal sample preparation. A biotin tagged aptamer was immobilized onto a gold surface by affinity capture. A limit of detection (LOD) in the nanomolar range (20.5 nM, RSD: 15.2%) was found and a dynamic range of 15-1000 nM was established for catalase in buffer and the aptamer showed good specificity toward catalase. This biosensor has the potential to be used in the detection of catalase in milk samples, a key indicator of mastitis disease in milk. PMID- 23669045 TI - A sensitive electrochemical DNA biosensor for specific detection of Enterobacteriaceae bacteria by Exonuclease III-assisted signal amplification. AB - A specific and sensitive methodology was developed successfully for quantitative detection of Enterobacteriaceae bacteria by integrating Exonuclease III-assisted target recycling amplification with a simple electrochemical DNA biosensor. After target DNA hybridizes with capture DNA, Exonuclease III can selectively digest the capture DNA, which releases the target to undergo a new hybridization and cleavage cycle on sensor surface, leading to a successful target recycling. Finally, the left capture DNA is recognized by detection probe to produce the detectable signal, which decreases with the increasing target DNA concentration. Under the optimal conditions, the proposed strategy could detect target DNA down to 8.7 fM with a linear range from 0.01 pM to 1 nM, showing high sensitivity. Meanwhile, the sensing strategy was successfully used for detection of Enterobacteriaceae bacteria down to 40 CFU mL-1 in milk samples. This strategy presented a simple, rapid and sensitive platform for Enterobacteriaceae bacteria detection and would become a versatile and powerful tool for food safety, biothreat detection and environmental monitoring. PMID- 23669046 TI - A sensitive and selective chemosensor for GSSG detection based on the recovered fluorescence of NDPA-Fe3O4@SiO2-Cu(II) nanomaterial. AB - A sensitive and selective sensor for oxidized glutathione (GSSG) detection based on the recovered fluorescence of naphthalimide-DPA (NDPA)-Fe3O4@SiO2-Cu(II) system is reported. NDPA-Fe3Fe3O4@SiO2 was characterized by X-ray power diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infrared spectra (FT-IR) and fluorophotometry. The fluorescence of NDPA Fe3O4@SiO2 could be quenched by Cu2+ due to the coordination of Cu2+ with the tridentate receptor DPA. This coordination process reduced the electron-donating ability of the nitrogen atom in the DPA moiety, thus suppressing the internal charge transfer (ICT) process in NDPA-Fe3O4@SiO2. In the presence of GSSG, the fluorescence of NDPA-Fe3O4@SiO2-Cu(II) was recovered because of strong coordination of Cu2+ with GSSG, which promoted the decomplexation between NDPA Fe3O4@SiO2 and Cu2+, and enhanced the ICT process. The NDPA-Fe3O4@SiO2-Cu(II) nanomaterial exhibited high sensitivity towards GSSG, and a good linear relationship was obtained from 5 nM to 60 MUM. The limit of detection, based on a signal-to-noise ratio of 3, was 50 pM. In addition, the presence of magnetic Fe3O4 nanoparticles (NPs) in NDPA-Fe3O4@SiO2 NPs would also facilitate the magnetic separation of NDPA-Fe3O4@SiO2 from the solution. Through the use of added internal standards, we successfully determined the concentration of GSSG in HEK 293 cell lysate to be 1.15 MUM by the prepared chemsensor NDPA-Fe3O4@SiO2 Cu(II). The proposed method is anticipated to fabricate other sensitive fluorescence sensors based on organic-inorganic hybrid magnetic nanoparticles. PMID- 23669048 TI - Seeing triggers acting, hearing does not trigger saying: evidence from children's weak inhibition. AB - There is evidence to suggest action imitation is automatic in adults and children. Children's weak inhibitory control means that automatic activation can have dramatic effects on behaviour. In three developmental studies, we investigated whether verbal imitation, like action imitation, is automatic. In Experiment 1 (n=96), 3-year-olds' accuracy was investigated on three well established inhibitory tasks, and on a novel task which required the suppression of verbal imitation. Experiment 2 (n=48) compared 3-year-olds' accuracy on well matched action and verbal tasks. In Experiment 3 (n=96), 5-, 7- and 11-year-olds reaction times were compared on verbal and action tasks using conditions that enabled the tasks' inhibitory demands to be assessed. Consistent support was found for verbal imitation being less automatic than action imitation. We suggest that this difference may reflect the greater complexity of speech, and has consequences for children's behaviour and learning. PMID- 23669049 TI - Perceptual categories enable pattern generalization in songbirds. AB - Since Chomsky's pioneering work on syntactic structures, comparative psychologists interested in the study of language evolution have targeted pattern complexity, using formal mathematical grammars, as the key to organizing language relevant cognitive processes across species. This focus on formal syntactic complexity, however, often disregards the close interaction in real-world signals between the structure of a pattern and its constituent elements. Whether such features of natural auditory signals shape pattern generalization is unknown. In the present paper, we train birds to recognize differently patterned strings of natural signals (song motifs). Instead of focusing on the complexity of the overtly reinforced patterns, we ask how the perceptual groupings of pattern elements influence the generalization pattern knowledge. We find that learning and perception of training patterns is agnostic to the perceptual features of underlying elements. Surprisingly, however, these same features constrain the generalization of pattern knowledge, and thus its broader use. Our results demonstrate that the restricted focus of comparative language research on formal models of syntactic complexity is, at best, insufficient to understand pattern use. PMID- 23669050 TI - [Ethnicity and vitamin D]. AB - Cohort studies, mainly US, show that vitamin D deficiency is more common in African-American population. Social and environmental factors play a role but the difference in skin color is essential. Despite low 25-hydroxyvitamin D concentrations, a lower risk of fragility or fracture exists in these populations. Vitamin D deficiency is a contributing factor in many chronic diseases. There is a relationship between vitamin D deficiencies, progression of chronic kidney disease and increased relative risk of mortality. If the ethnicity of patients is now taken into account to estimate renal function, probably specific recommendations for vitamin D deficiency are needed. PMID- 23669051 TI - A modified technique of displacement measurement of a piston made of magnetic material inside a cylinder. AB - Movement of piston inside a cylinder has many applications in industries and measurement of its displacement inside the cylinder is very much important to study its operation and control. In the present paper a non contact type displacement measurement technique of a piston made of magnetic material inside a cylinder has been proposed. In this technique, the difference of inductances of two identical coils wound outside a cylinder due to movement of piston inside it has been found to be linearly related with the displacement. A modified differential inductance measurement circuit has been designed to develop the proposed displacement transducer. The design of the circuit along with principle of operation has been described in the paper. The operation of the proposed circuit has been experimentally studied and the experimental results are reported in the paper. The proposed transducer has been found to have very good linearity and repeatability. PMID- 23669047 TI - Conflation of cocaine seeking and cocaine taking responses in IV self administration experiments in rats: methodological and interpretational considerations. AB - IV drug self-administration is a special case of an operant task. In most operant experiments, the instrumental response that completes the schedule requirement is separate and distinct from the consumptive response (e.g. eating or drinking) that follows the delivery of the reinforcing stimulus. In most IV self administration studies drug seeking and drug taking responses are conflated. The instrumental lever press or nose poke is also a consumptive response. The conflation of these two response classes has important implications for interpretation of the data as they are differentially regulated by dose and price. The types of pharmacological pretreatments that affect appetitive responses are not necessarily the same as those that affect consumptive responses suggesting that the neurobiology of the two response classes are to some extent controlled by different mechanisms. This review discusses how schedules of reinforcement and behavioral economic analyses can be used to assess the regulation of drug seeking and drug taking separately. New methods are described that allow the examination of appetitive or consumptive responding in isolation and provide subjects with greater control over the self-administered dose. These procedures provide novel insights into the regulation of drug intake. Cocaine intake patterns that result in large, intermittent spikes in cocaine levels are shown to produce increases in appetitive responding (i.e. drug seeking). The mechanisms that control drug intake should be considered distinct from appetitive and motivational processes and should be taken into consideration in future IV self-administration studies. PMID- 23669052 TI - APN-led nursing rounds: an emphasis on evidence-based nursing care. AB - In today's healthcare environment, nursing staff are challenged to care for patients with increasingly complex needs in an ever-changing environment. Nurses are expected to stay up to date on a tremendous number of institutional initiatives, best practice guidelines, and policies and procedures. These practice imperatives are often disseminated through passive means of information sharing such as staff meetings and electronic mail. In this setting, it is difficult for nurses to simultaneously focus on incorporating practice updates while continuing to value basic nursing functions such as oral care, skin care, and incontinence management. The concept of Interventional Patient Hygiene emphasises that basic nursing functions are not only tasks, but also important evidence-based interventions that contribute to improved health for the patient. Interventional Patient Hygiene facilitates the integration of science and practice. This article describes a quality improvement intervention, Advanced practice nurse-led nursing rounds, which supports Interventional Patient Hygiene and be used to help staff integrate best practices while balancing the multiple priorities inherent in nursing care. PMID- 23669053 TI - Can factors related to mortality be used to predict the follow-up health-related quality of life (HRQoL) in cardiac surgery patients? AB - BACKGROUND: Optimal selection of patients and choice of treatment methods in cardiac surgery calls for methods to predict outcome both in terms of mortality and health-related quality of life (HRQoL). Our target was to evaluate whether indicators predicting mortality can also be used to predict follow-up HRQoL. METHODS: Preoperative and intensive care-related data of 571 elective cardiac surgery patients treated in the Helsinki University Central Hospital were used to predict, in a stepwise (forward) binary logistic regression, the probability of being dead at six months after operation. Furthermore, Tobit regression models were employed to predict the follow-up HRQoL of patients using also treatment complications and patients' experiences of pain and restlessness during treatment as explanatory variables. RESULTS: The EuroSCORE, renal, respiratory and neurological complications as well as urgent sternotomy were all statistically significant predictors of mortality. By contrast, follow-up HRQoL was predicted by the baseline HRQoL, diabetes and male gender as well as experience of pain and restlessness during the ICU stay. CONCLUSION: Mortality and HRQoL after cardiac surgery appear to be explained by different factors. Pain and restlessness during ICU treatment affect follow-up HRQoL in a negative manner and as potentially modifiable factors, need attention during treatment. PMID- 23669054 TI - Combined prevalence of frailty and mild cognitive impairment in a population of elderly Japanese people. AB - OBJECTIVE: Preventive strategies for frailty and mild cognitive impairment (MCI) are important for avoiding future functional decline and dementia in older adults. The purpose of this study was to use a population-based survey to ascertain the single and combined prevalence of frailty and MCI and to identify the relationships between frailty and MCI in older Japanese adults. DESIGN: Cross sectional study. SETTING: General community. PARTICIPANTS: A total of 5104 older adults (aged 65 years or older, mean age 71 years) who were enrolled in the Obu Study of Health Promotion for the Elderly (OSHPE). MEASUREMENTS: Each participant underwent detailed physical and cognitive testing to assess frailty and MCI. We considered the frailty phenotype to be characterized by limitations in 3 or more of the following 5 domains: mobility, strength, endurance, physical activity, and nutrition. Screening for MCI included a standardized personal interview, the Mini Mental State Examination, and the National Center for Geriatrics and Gerontology Functional Assessment Tool (NCGG-FAT), which included 8 tasks used to assess logical memory (immediate and delayed recognition), word list memory (immediate and delayed recall), attention and executive function (tablet version of Trail Making Test-part A and B), processing speed (tablet version of digit symbol substitution test), and visuospatial skill (figure selection). RESULTS: The overall prevalence of frailty, MCI, and frailty and MCI combined was 11.3%, 18.8%, and 2.7%, respectively. We found significant relationships between frailty and MCI (the odds ratio adjusted for age, sex, and education was 2.0 (95% confidence interval 1.5-2.5). CONCLUSIONS: Using the OSHPE criteria, we found more participants with MCI than with frailty. The prevalence of frailty and MCI combined was 2.7% in our population. Future investigation is necessary to determine whether this population is at increased risk for disability or mortality. PMID- 23669055 TI - The Gravettian calvaria from Mollet III cave (Serinya, Northeastern Iberian Peninsula). PMID- 23669056 TI - Increasing the efficiency of thermoacoustic carbon nanotube sound projectors. AB - Carbon nanotubes (CNTs) can generate smooth-spectra sound emission over a wide frequency range (1-10(5) Hz) by means of thermoacoustics (TA). However, in the low frequencies f, where the need for large area sound projectors is high, the sound generation efficiency eta of open CNT sheets is low, since eta [proportionality] f(2). Together with this problem, the nanoscale thickness of CNT sheets, their high sensitivity to the environment and the high surface temperatures useful for TA sound generation are other drawbacks, which we address here by protective encapsulation of free-standing CNT sheets in inert gases. We provide an extensive experimental study of such closed systems for different thermodynamic regimes and rationalize our observations within a basic theoretical framework. The observed sound pressure levels for encapsulated argon filled TA transducers (130 dB in air and 200 dB underwater in the near field at 5 cm distance, and 100 and 170 dB in the far field at 1 m distance) are Q times higher than those for open systems, where Q is the resonant quality factor of the thin enclosure plates. Moreover, the sound generation efficiency of the encapsulated system increases toward low frequencies (eta [proportionality] 1/f(2)). Another method to increase eta in the low frequency region is by modulation of the applied high frequency carrier current with a low frequency resonant envelope. This approach enables sound generation at the frequency of the applied current without the need for additional energy-consuming biasing. The acoustical and geometrical parameters providing further increases in efficiency and transduction performance for resonant systems are discussed. PMID- 23669057 TI - What else is in store for autophagy? Exocytosis of autolysosomes as a mechanism of TFEB-mediated cellular clearance in Pompe disease. AB - It is hard to find an area of biology in which autophagy is not involved. In fact, the topic extends beyond scientific research to stimulate intellectual exercise and entertainment-autophagy has found its way into a crossword puzzle (Klionsky, 2013). We have found yet another function of autophagy while searching for a better treatment for Pompe disease, a devastating metabolic myopathy resulting from excessive lysosomal glycogen storage. To relieve this glycogen burden, we stimulated lysosomal exocytosis through upregulation of transcription factor EB (TFEB). Overexpression of TFEB in Pompe muscle clears the cells of enlarged lysosomes, reduces glycogen levels, and alleviates autophagic buildup, the major secondary abnormality in Pompe disease. Unexpectedly, the process of exocytosis does not seem to be a purely lysosomal event; vesicles arranged along the plasma membrane are double-labeled with the lysosomal marker LAMP1 and the autophagosomal marker LC3, indicating that TFEB induces the exocytosis of autolysosomes. Furthermore, the effects of TFEB are almost abrogated in autophagy deficient Pompe mice, suggesting a previously unrecognized role of autophagy in TFEB-mediated cellular clearance. PMID- 23669058 TI - Thirdhand smoke and exposure in California hotels: non-smoking rooms fail to protect non-smoking hotel guests from tobacco smoke exposure. AB - INTRODUCTION: This study examined tobacco smoke pollution (also known as thirdhand smoke, THS) in hotels with and without complete smoking bans and investigated whether non-smoking guests staying overnight in these hotels were exposed to tobacco smoke pollutants. METHODS: A stratified random sample of hotels with (n=10) and without (n=30) complete smoking bans was examined. Surfaces and air were analysed for tobacco smoke pollutants (ie, nicotine and 3 ethynylpyridine, 3EP). Non-smoking confederates who stayed overnight in guestrooms provided urine and finger wipe samples to determine exposure to nicotine and the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl) 1-butanone as measured by their metabolites cotinine and 4-(methylnitrosamino)-1 (3-pyridyl)-1-butanol (NNAL), respectively. FINDINGS: Compared with hotels with complete smoking bans, surface nicotine and air 3EP were elevated in non-smoking and smoking rooms of hotels that allowed smoking. Air nicotine levels in smoking rooms were significantly higher than those in non-smoking rooms of hotels with and without complete smoking bans. Hallway surfaces outside of smoking rooms also showed higher levels of nicotine than those outside of non-smoking rooms. Non smoking confederates staying in hotels without complete smoking bans showed higher levels of finger nicotine and urine cotinine than those staying in hotels with complete smoking bans. Confederates showed significant elevations in urinary NNAL after staying in the 10 most polluted rooms. CONCLUSIONS: Partial smoking bans in hotels do not protect non-smoking guests from exposure to tobacco smoke and tobacco-specific carcinogens. Non-smokers are advised to stay in hotels with complete smoking bans. Existing policies exempting hotels from complete smoking bans are ineffective. PMID- 23669059 TI - Adolescent peer-rejection persistently alters pain perception and CB1 receptor expression in female rats. AB - Peer-interactions are particularly important during adolescence and teenagers display enhanced sensitivity toward rejection by peers. Social rejection has been shown to induce alterations in pain perception in humans. However, the neurobiological consequences of adolescent social rejection have yet to be extensively characterized, and no appropriate animal model is available. Here, we propose inadequate playful interactions in adolescent rats as a novel animal model for social peer-rejection and examine potential long-term consequences into adulthood. Acute social pairing of female adolescent Wistar rats with an age matched rat from the less playful Fischer344 strain was found to alter social play and decrease pain reactivity, indicating Fischer rats as inadequate social partners for Wistar animals. Therefore, in a second experiment, adolescent female Wistar rats were either reared with another Wistar rat (adequate social rearing; control) or with a Fischer rat (inadequate social rearing; play-deprived). Beginning on day 50, all Wistar rats were group housed with same-strain partners and tested for behavioral, neurobiological and endocrine differences in adulthood. Playful peer-interactions were decreased during adolescence in play deprived animals, without affecting social contact behavior. Consequently, adult play-deprived rats showed decreased pain sensitivity and increased startle reactivity compared to controls, but did not differ in activity, anxiety-related behavior or social interaction. Both groups also differed in their endocrine stress-response, and expression levels of the cannabinoid CB1 receptor were increased in the thalamus, whereas FAAH levels were decreased in the amygdala. The present animal model therefore represents a novel approach to assess the long term consequences of peer-rejection during adolescence. PMID- 23669060 TI - Commentary on "Cognition in schizophrenia". PMID- 23669061 TI - Respiratory muscle dysfunction: a multicausal entity in the critically ill patient undergoing mechanical ventilation. AB - Respiratory muscle dysfunction, particularly of the diaphragm, may play a key role in the pathophysiological mechanisms that lead to difficulty in weaning patients from mechanical ventilation. The limited mobility of critically ill patients, and of the diaphragm in particular when prolonged mechanical ventilation support is required, promotes the early onset of respiratory muscle dysfunction, but this can also be caused or exacerbated by other factors that are common in these patients, such as sepsis, malnutrition, advanced age, duration and type of ventilation, and use of certain medications, such as steroids and neuromuscular blocking agents. In this review we will study in depth this multicausal origin, in which a common mechanism is altered protein metabolism, according to the findings reported in various models. The understanding of this multicausality produced by the same pathophysiological mechanism could facilitate the management and monitoring of patients undergoing mechanical ventilation. PMID- 23669062 TI - Clinical effects of combined olmesartan medoxomil and amlodipine on clinic and ambulatory blood pressure in elderly patients with resistant hypertension. AB - Elderly patients with resistant hypertension are at increased risk for cardiovascular events. Clinical trials suggest that resistant hypertension involves perhaps 10-15% of hypertension study participants. In this study, 157 resistant hypertension patients older than 60 years were randomized to 8 weeks double-blind treatment with placebo, AML 10 mg/day, OM 40 mg/day and AM*L (10 mg/day)+OM (40 mg/day). Research outcomes suggested that ALM+OM combination therapy had superior efficacy than ALM or OM monotherapies in terms of the clinic blood pressure and 24-h ambulatory blood pressure. In addition, more patients receiving combination therapy (62.5%) achieved BP goal than those treated with placebo (18.4%), AML (37.5) or OM (38.5%) monotherapies. The adverse events in both groups were comparable. Thus, the combination of AML+OM provides a safe and effective option for the treatment of resistant hypertension in challenging elderly patient populations. PMID- 23669063 TI - Consequences of snowy winters on male mating strategies and reproduction in a mountain ungulate. AB - Alternative mating tactics (AMTs) are intrasexual variants in mating behaviour of several species ranging from arthropods to mammals. Male AMTs coexist between and within populations. In particular, male ungulates rarely adopt just one tactic throughout their lifetime. Tactics commonly change according to internal factors (age, body size, condition) and external conditions (weather, resources, predation, animal density). However, the influence of weather has not yet been investigated in upper vertebrates. Such influence may be relevant in species whose rutting period occurs late in fall or in winter, when environmental conditions and the snow cover in particular may vary considerably. We detected two AMTs in Alpine ibex (Capra ibex) males: older and full-grown males mainly adopted the tending tactic, while younger males usually pursued an alternative one (coursing tactic). Weather was found to influence the use of AMTs by males: in snowy mating seasons, the coursing tactic was no longer used due to difficulties in moving through deep snow. In snowy rutting periods, males appeared to delay or even avoid mating activities and a decrease of births was reported in the second part of the following birth season. Snow cover may have a negative effect on population dynamics by reducing the recruitment and on population genetic variability, as a consequence of poorer mating opportunities. Studies on factors affecting mating behaviour and leading to a reduced availability of mates and a decrease in female productivity are especially relevant in species, like Alpine ibex, whose genetic variability is low. PMID- 23669064 TI - Neurotrophins play differential roles in short and long-term recognition memory. AB - The neurotrophin family of proteins are believed to mediate various forms of synaptic plasticity in the adult brain. Here we have assessed the roles of these proteins in object recognition memory in the rat, using icv infusions of function blocking antibodies or the tyrosine kinase antagonist, tyrphostin AG879, to block Trk receptors. We report that tyrphostin AG879 impairs both short-term and long term recognition memory, indicating a requirement for Trk receptor activation in both processes. The effect of inhibition of each of the neurotrophins with activity-blocking neutralising antibodies was also tested. Treatment with anti BDNF, anti-NGF or anti-NT4 had no effect on short-term memory, but blocked long term recognition memory. Treatment with anti-NT3 had no effect on either process. We also assessed changes in expression of neurotrophins and their respective receptors in the hippocampus, dentate gyrus and perirhinal cortex over a 24 h period following training in the object recognition task. We observed time dependent changes in expression of the Trk receptors and their ligands in the dentate gyrus and perirhinal cortex. The data are consistent with a pivotal role for neurotrophic factors in the expression of recognition memory. PMID- 23669066 TI - Squamous cell carcinoma of the tonsil masquerading as a peritonsillar abscess. AB - A 58-year-old man presented to the emergency department with a persistent left sided sore throat of 2-month duration. The sore throat had not responded to antibiotic therapy. Over the past week, the soreness had increased and was aggravated by opening the mouth. He denied fever but admitted to a 10-lb weight loss. His social history was significant for alcohol and tobacco use. Physical examination revealed a bulging and erythematous left soft palate with a deviated uvula. Areas of the tonsil were noted to be ulcerating through the soft palate. In the upper left neck, a 3-cm, firm, nontender, lymph node was palpated anterior to the sternocleidomastoid muscle. A computed tomography of the neck with contrast revealed an enhancing tonsillar mass as well as enlarged lymph nodes bilaterally. A transoral biopsy returned squamous cell carcinoma. PMID- 23669065 TI - Gamma band plasticity in sensory cortex is a signature of the strongest memory rather than memory of the training stimulus. AB - Gamma oscillations (~30-120Hz) are considered to be a reflection of coordinated neuronal activity, linked to processes underlying synaptic integration and plasticity. Increases in gamma power within the cerebral cortex have been found during many cognitive processes such as attention, learning, memory and problem solving in both humans and animals. However, the specificity of gamma to the detailed contents of memory remains largely unknown. We investigated the relationship between learning-induced increased gamma power in the primary auditory cortex (A1) and the strength of memory for acoustic frequency. Adult male rats (n=16) received three days (200 trials each) of pairing a tone (3.66 kHz) with stimulation of the nucleus basalis, which implanted a memory for acoustic frequency as assessed by associatively-induced disruption of ongoing behavior, viz., respiration. Post-training frequency generalization gradients (FGGs) revealed peaks at non-CS frequencies in 11/16 cases, likely reflecting normal variation in pre-training acoustic experiences. A stronger relationship was found between increased gamma power and the frequency with the strongest memory (peak of the difference between individual post- and pre-training FGGs) vs. behavioral responses to the CS training frequency. No such relationship was found for the theta/alpha band (4-15 Hz). These findings indicate that the strength of specific increased neuronal synchronization within primary sensory cortical fields can determine the specific contents of memory. PMID- 23669067 TI - FACS binding assay for analysing GDNF interactions. AB - Glial cell-line derived neurotrophic factor (GDNF) is a secreted protein with great therapeutic potential. However, in order to analyse the interactions between GDNF and its receptors, researchers have been mostly dependent of radioactive binding assays. We developed a FACS-based binding assay for GDNF as an alternative to current methods. We demonstrated that the FACS-based assay using TGW cells allowed readily detection of GDNF binding and displacement to endogenous receptors. The dissociation constant and half maximal inhibitory concentration obtained were comparable to other studies using standard binding assays. Overall, this FACS-based, simple to perform and adaptable to high throughput setup, provides a safer and reliable alternative to radioactive methods. PMID- 23669068 TI - Acute and subchronic treatments with selective serotonin reuptake inhibitors increase Nociceptin/Orphanin FQ (NOP) receptor density in the rat dorsal raphe nucleus; interactions between nociceptin/NOP system and serotonin. AB - Nociceptin/Orphanin FQ is the endogenous ligand of NOP receptor, formerly referred to as the Opioid Receptor-Like 1 receptor. We have previously shown that NOP receptors were located on serotonergic neurons in the rat dorsal raphe nucleus, suggesting possible direct interactions between nociceptin and serotonin in this region, which is a target for antidepressant action. In the present study, we investigated further the link between Selective Serotonin Reuptake Inhibitor (SSRI) antidepressant treatments and the nociceptin/NOP receptor system. Intraperitoneal administration of the SSRI citalopram induced an increase in NOP-receptor density, measured by autoradiographic [(3)H] nociceptin binding, in the rat dorsal raphe nucleus, from the first to the 21st day of treatment. This effect was also observed with other SSRIs (sertraline, fluoxetine), but not with two tricyclic antidepressants (imipramine, clomipramine) and was abolished by pre-treatment with para-chlorophenylalanine, an inhibitor of serotonin synthesis. Using microdialysis experiments, we demonstrated that NOP-receptor activation by infusion of nociceptin 10(-6) M or 10(-5) M increased the level of extracellular serotonin in the dorsal raphe nucleus. This effect was abolished by co-infusion of the NOP-receptor antagonist UFP 101. These results confirm the existence of reciprocal interactions between serotonin and nociceptin/NOP transmissions in the dorsal raphe nucleus. PMID- 23669070 TI - Pyrolysis of cassava rhizome in a counter-rotating twin screw reactor unit. AB - A counter-rotating twin screw reactor unit was investigated for its behaviour in the pyrolysis of cassava rhizome biomass. Several parameters such as pyrolysis temperature in the range of 500-700 degrees C, biomass particle size of <0.6mm, the use of sand as heat transfer medium, nitrogen flow rate of 4-10 L/min and nitrogen pressure of 1-3 bar were thoroughly examined. It was found that the pyrolysis temperature of 550 degrees C could maximise the bio-oil yield (50 wt.%). The other optimum parameters for maximising the bio-oil yield were the biomass particle size of 0.250-0.425 mm, the nitrogen flow rate of 4 L/min and the nitrogen pressure of 2 bar. The use of the heat transfer medium could increase the bio-oil yield to a certain extent. Moreover, the water content of bio-oil produced with the counter-rotating twin screw reactor was relatively low, whereas the solids content was relatively high, compared to some other reactor configurations. PMID- 23669069 TI - Somatostatin receptor subtype-4 agonist NNC 26-9100 mitigates the effect of soluble Abeta(42) oligomers via a metalloproteinase-dependent mechanism. AB - Soluble amyloid-beta peptide (Abeta) oligomers have been hypothesized to be primary mediators of Alzheimer's disease progression. In this regard, reduction of soluble Abeta-oligomers levels within the brain may provide a viable means in which to treat the disease. Somatostatin receptor subtype-4 (SSTR4) agonists have been proposed to reduce Abeta levels in the brain via enhancement of enzymatic degradation. Herein we evaluated the effect of selective SSTR4 agonist NNC 26 9100 on the changes in learning and soluble Abeta42 oligomer brain content with and without co-administration of the M13-metalloproteinase family enzyme inhibitor phosphoramidon, using the senescence-accelerated mouse prone-8 (SAMP8) model. NNC 26-9100 treatment (0.2 ug i.c.v. in 2 uL) improved learning, which was blocked by phosphoramidon (1 and 10mM, respectively). NNC 26-9100 decreased total soluble Abeta42, an effect which was blocked by phosphoramidon (10mM). Extracellular, intracellular, and membrane fractions were then isolated from cortical tissue and assessed for soluble oligomer alterations. NNC 26-9100 decreased the Abeta42 trimeric (12 kDa) form within the extracellular and intracellular fractions, and produced a band-split effect of the Abeta42 hexameric (25 kDa) form within the extracellular fraction. These effects were also blocked by phosphoramdon (1 and 10mM, respectively). Subsequent evaluation of NNC 26-9100 in APPswe Tg2576 transgenic mice showed a similar learning improvement and corresponding reduction in soluble Abeta42 oligomers within extracellular, intracellular, and membrane fractions. These data support the hypothesis that NNC 26-9100 reduces soluble Abeta42 oligomers and enhances learning through a phosphoramidon-sensitive metalloproteinase-dependent mechanism. PMID- 23669071 TI - Coupling bioelectricity generation and oil sands tailings treatment using microbial fuel cells. AB - In this study, four dual-chambered microbial fuel cells (MFC1-4) were constructed and filled with different ratios of mature fine tailings and oil sands process affected water to test the feasibility of MFCs to simultaneously generate electricity and treat oil sands tailings. After 800 h of operation, the maximum voltage was observed in MFC4 at 0.726 V with 1.2kOmega external resistance loaded. The maximum power density reached 392 +/- 15 mW/m(2) during the 1,700 h of MFC4 operation. With continuous electricity generation, MFC4 removed 27.8% of the total COD, 81.8% of the soluble COD and 32.9% of the total acid extractable organics. Moreover, effective removal of eight heavy metals, includes 97.8% of (78)Se, 96.8% of Ba, 94.7% of (88)Sr, 81.3% for (66)Zn, 77.1% of (95)Mo, 66.9% of (63)Cu, 44.9% of (53)Cr and 32.5% of Pb, was achieved. PMID- 23669072 TI - Screening of novel plants for biogas production in northern conditions. AB - The objective of this study was to screen nine annual or perennial novel plants for biogas production cultivated in years 2007-2010 in Finland. The most promising novel plants for biogas production were found to be brown knapweed, giant goldenrod and Japanese millet producing 14-27 t total solids/ha and 4000 6100 Nm(3)CH4/ha. The specific methane yields of all studied plants varied from 170 to 381 Nm(3)CH4/t volatile solids (VS), depending on harvest time and plant species. Co-digestion of brown knapweed with cow manure in continuously stirred tank reactor was investigated and the highest methane yield was 254 NL CH4/kg VS, when the share of brown knapweed was 50% in the feed VS (organic loading rate (OLR) 2 kg VS/m(3)/d). The cultivation managements and sustainability of novel plants for biogas production have to be investigated. PMID- 23669074 TI - Altered structure and resting-state functional connectivity of the basal ganglia in migraine patients without aura. AB - The aim of this study was to investigate the relevance of the basal ganglia (BG) in pathogenesis of migraine by assessing the abnormal volume and resting-state networks of the BG in migraine patients without aura (MWoA). The volume of the subsets in the BG was compared between 40 MWoA and 40 age- and gender-matched healthy controls. The resting-state functional connectivity of BG subsets with abnormal volume was also investigated. Reduced volume in the left caudate and the right nucleus accumbens (NAc) was detected in the migraine group compared with healthy controls; meanwhile, increased functional connectivity between the BG and several brain regions within nociceptive and somatosensory processing pathways was observed. Correlation analysis revealed significant correlations between the volume of the bilateral caudate and right NAc and disease duration. In addition, an increased monthly frequency of migraine attack was associated with increased functional connectivity between the bilateral caudate and left insula, and longer disease duration was correlated with increased functional connectivity between the right NAc and bilateral anterior cingulate cortex. Our results revealed abnormal volume of BG and dysfunctional dynamics during interictal resting state within pain pathways of the BG in MWoA, which validated the association between the BG and migraine. PERSPECTIVE: Our findings revealed the presence of reduced volume in NAc and caudate of the BG and interictal dysfunctional dynamics within BG networks in MWoA. The abnormal structure and function within the pain-related pathways of the BG were possibly associated with impaired pain processing and modulatory processes in MWoA. PMID- 23669073 TI - Drosophila miR-277 controls branched-chain amino acid catabolism and affects lifespan. AB - Development, growth and adult survival are coordinated with available metabolic resources, ascertaining that the organism responds appropriately to environmental conditions. MicroRNAs are short (21-23 nt) regulatory RNAs that confer specificity on the RNA-induced silencing complex (RISC) to inhibit a given set of mRNA targets. We profiled changes in miRNA expression during adult life in Drosophila melanogaster and determined that miR-277 is downregulated during adult life. Molecular analysis revealed that this miRNA controls branched-chain amino acid (BCAA) catabolism and as a result it can modulate the activity of the TOR kinase, a central growth regulator, in cultured cells. Metabolite analysis in cultured cells as well as flies suggests that the mechanistic basis may be an accumulation of branched-chain alpha-keto-acids (BCKA), rather than BCAAs, thus avoiding potentially detrimental consequences of increased branched chain amino acid levels on e.g., translational fidelity. Constitutive miR-277 expression shortens lifespan and is synthetically lethal with reduced insulin signaling, indicating that metabolic control underlies this phenotype. Transgenic inhibition with a miRNA sponge construct also shortens lifespan, in particular on protein rich food. Thus, optimal metabolic adaptation appears to require tuning of cellular BCAA catabolism by miR-277. PMID- 23669077 TI - Letter from the editor: "You will just be a year weaker, dad". PMID- 23669075 TI - Biomarkers of endothelial activation/dysfunction in infectious diseases. AB - Endothelial dysfunction contributes to the pathogenesis of a variety of potentially serious infectious diseases and syndromes, including sepsis and septic shock, hemolytic-uremic syndrome, severe malaria, and dengue hemorrhagic fever. Because endothelial activation often precedes overt endothelial dysfunction, biomarkers of the activated endothelium in serum and/or plasma may be detectable before classically recognized markers of disease, and therefore, may be clinically useful as biomarkers of disease severity or prognosis in systemic infectious diseases. In this review, the current status of mediators of endothelial cell function (angiopoietins-1 and -2), components of the coagulation pathway (von Willebrand Factor, ADAMTS13, and thrombomodulin), soluble cell surface adhesion molecules (soluble E-selectin, sICAM-1, and sVCAM-1), and regulators of vascular tone and permeability (VEGF and sFlt-1) as biomarkers in severe infectious diseases is discussed in the context of sepsis, E. coli O157:H7 infection, malaria, and dengue virus infection. PMID- 23669076 TI - Ineffective delivery of diet-derived microRNAs to recipient animal organisms. AB - Cross-kingdom delivery of specific microRNAs to recipient organisms via food ingestion has been reported recently. However, it is unclear if such delivery of microRNAs occurs frequently in animal organisms after typical dietary intake. We found substantial levels of specific microRNAs in diets commonly consumed orally by humans, mice, and honey bees. Yet, after ingestion of fruit replete with plant microRNAs (MIR156a, MIR159a, and MIR169a), a cohort of healthy athletes did not carry detectable plasma levels of those molecules. Similarly, despite consumption of a diet with animal fat replete in endogenous miR-21, negligible expression of miR-21 in plasma or organ tissue was observed in miR-21 -/- recipient mice. Correspondingly, when fed vegetarian diets containing the above plant microRNAs, wild-type recipient mice expressed insignificant levels of these microRNAs. Finally, despite oral uptake of pollen containing these plant microRNAs, negligible delivery of these molecules was observed in recipient honeybees. Therefore, we conclude that horizontal delivery of microRNAs via typical dietary ingestion is neither a robust nor a frequent mechanism to maintain steady-state microRNA levels in a variety of model animal organisms, thus defining the biological limits of these molecules in vivo. PMID- 23669078 TI - ACSM clinician profile. Steven D. Stovitz, MD, MS, FACSM. PMID- 23669079 TI - Placebos for athletes: do they exist? If not, do they work anyway? PMID- 23669081 TI - Osteoarthritis--a silent problem that needs our attention! PMID- 23669082 TI - Marathon runner prolonged normothermic cardiopulmonary arrest and neurologically intact survival. PMID- 23669083 TI - Sideline coverage of youth football. AB - Youth football is a popular sport in the United States and has been for some time. There are currently more than 3 million participants in youth football leagues according to USA Football. While the number of participants and overall injuries may be higher in other sports, football has a higher rate of injuries. Most youth sporting events do not have medical personnel on the sidelines in event of an injury or emergency. Therefore it is necessary for youth sports coaches to undergo basic medical training in order to effectively act in these situations. In addition, an argument could be made that appropriate medical personnel should be on the sideline for collision sports at all levels, from youth to professional. This article will discuss issues pertinent to sideline coverage of youth football, including coaching education, sideline personnel, emergency action plans, age and size divisions, tackle versus flag football, and injury prevention. PMID- 23669084 TI - Medical management of youth baseball and softball tournaments. AB - The medical management of youth baseball and softball tournaments requires both proper planning and a basic awareness of commonly seen sport-specific injuries. While youth sporting events are designed to be a fun experience for all, injuries and emergencies will occur. With proper planning, and supplies, the impact of these issues can be minimized. This article will outline some basic principles for the medical personnel that may be involved in youth baseball and softball events. PMID- 23669085 TI - Medical coverage of youth basketball events. AB - Basketball is among the most popular team sports for boys and girls in the United States and is continuing to grow in popularity worldwide. Increased popularity translates to an increased number of events and, unfortunately, the injuries that occur as a result. In this article, we discuss ways to be prepared in the coverage of youth basketball events, with an emphasis on the evaluation and treatment of some of the most commonly encountered injuries within the sport of basketball. We also give special consideration to injuries that are specific to the skeletally immature athlete. By having a greater knowledge and understanding of these injuries, a provider of medical coverage for basketball events hopefully will gain a higher sense of confidence in handling associated problems as they arise. PMID- 23669086 TI - Sideline management from head to toe of the skeletally immature athlete. AB - Many articles have been written on specific injury patterns and types of injuries that occur in sports, but few have addressed sideline management with a specific focus on the injuries affecting skeletally immature athletes. This article will review the most common injuries that can occur with the skeletally immature athlete from head to toe in comparison to a skeletally mature or adult athlete. It will address also how to approach these injuries from a sideline and sports medicine perspective, thus providing insight for health care professionals to evaluate and treat young athletes that could allow them to return to sports safely. PMID- 23669087 TI - Bilateral chronic exertional compartment syndrome of the forearm: a case report and review of the literature. PMID- 23669088 TI - Eccentric training for the treatment of tendinopathies. AB - Tendinopathy can result from overuse and is experienced in the affected tendon as pain with activity, focal tenderness to palpation, and decreased ability to tolerate tension, which results in decreased functional strength. While tendinopathy often occurs in those who are active, it can occur in those who are inactive. Research has shown that an eccentric exercise program can be effective in the treatment of tendinopathies. The earliest studied was the Achilles tendon, and subsequent studies have shown benefits using eccentric exercises on other body regions including the patellar tendon, proximal lateral elbow, and rotator cuff. In this article, we review the research on using an eccentric exercise program in the treatment of painful tendinopathy and proposed mechanisms for why eccentric exercises are effective in treating this and then finish by providing a general framework for prescribing an eccentric exercise program to those with a symptomatic tendinopathy. PMID- 23669089 TI - Injury and illnesses prevention for ultramarathoners. AB - The popularity of ultramarathon races continue to grow with runners participating in races throughout the world. These events offer challenges unique to an ultramarathon compared to a marathon race. These challenges require the athlete to focus on factors including race distance, race stages, race environment (temperature, humidity, and altitude), appropriate training, nutritional preparation, and equipment. Athletes ill prepared for these challenges will be at risk from injury and illness. The goal of this article is to review preventive strategies for managing commonly encountered musculoskeletal injuries and medical illnesses in ultramarathon runners. PMID- 23669090 TI - Recognition and rehabilitation of the female athlete triad/tetrad: a multidisciplinary approach. AB - While the benefits of physical activity are numerous, the female athlete triad poses a significant health risk to young athletes. Emerging research links the triad to endothelial dysfunction--a sentinel event in cardiovascular disease- suggesting that this complex interplay of metabolic and endocrine factors may be described more accurately as a tetrad. Effective treatment of the triad/tetrad requires a multidisciplinary approach. Emphasis must be placed on prevention, recognition, and treatment of triad for the promotion of healthy nutritional and activity profiles in female athletes across their lifespans. PMID- 23669091 TI - Rehabilitation and return to running after lower limb stress fractures. AB - Lower limb stress fractures are common injuries in runners. In terms of treatment, much of the medical literature has focused primarily on rest and cessation of running, but little has been written about the rehabilitation and functional progression of runners following a lower limb stress fracture. This article reviews the scientific evidence behind common rehabilitation concepts used for runners recovering from these injuries and also discusses sport-specific training modalities such as deep water running and antigravity treadmill training. Overall this article is intended to be a practical resource for clinicians to guide runners in functional rehabilitation and return to running following lower limb stress injury. PMID- 23669093 TI - Wrist actigraphy for measuring sleep in intervention studies with Alzheimer's disease patients: application, usefulness, and challenges. AB - Sleep disorders are common in patients with Alzheimer's disease (AD). An important aspect of intervention studies in patients with sleep disorders is the choice of assessment strategy. This paper presents a literature review concerning assessment strategies for measuring sleep in intervention studies with AD patients, with a focus on actigraphy. Thirty-seven articles were selected for this review, having analysis of sleep/nocturnal rhythm disturbances by actigraphy as the primary or secondary outcome. The advantages and limitations of actigraphy were discussed vis-a-vis polysomnography and subjective interventions. The following methodological aspects were addressed: impact of experimental design and patient setting, inclusion and exclusion criteria, placement of the actigraphy device, adherence to the regimen, duration of recordings and the choice of sleep parameters. Our analyses suggest that the methods used in intervention studies encompassing sleep disorders and dementia could be improved by increasing accuracy of diagnosis, categorization of sleep disturbances, adherence to actigraphy, and by clearly defining the variables and endpoints in each study. Also, controlling variables that could interfere with sleep and describing the data processing and analysis might improve interpretation of results. PMID- 23669094 TI - Supine position related obstructive sleep apnea in adults: pathogenesis and treatment. AB - The most striking feature of obstructive respiratory events is that they are at their most severe and frequent in the supine sleeping position: indeed, more than half of all obstructive sleep apnea (OSA) patients can be classified as supine related OSA. Existing evidence points to supine related OSA being attributable to unfavorable airway geometry, reduced lung volume, and an inability of airway dilator muscles to adequately compensate as the airway collapses. The role of arousal threshold and ventilatory control instability in the supine position has however yet to be defined. Crucially, few physiological studies have examined patients in the lateral and supine positions, so there is little information to elucidate how breathing stability is affected by sleep posture. The mechanisms of supine related OSA can be overcome by the use of continuous positive airway pressure. There are conflicting data on the utility of oral appliances, while the effectiveness of weight loss and nasal expiratory resistance remains unclear. Avoidance of the supine posture is efficacious, but long term compliance data and well powered randomized controlled trials are lacking. The treatment of supine related OSA remains largely ignored in major clinical guidelines. Supine OSA is the dominant phenotype of the OSA syndrome. This review explains why the supine position so favors upper airway collapse and presents the available data on the management of patients with supine related OSA. PMID- 23669095 TI - Effect of wine-based marinades on the behavior of Salmonella Typhimurium and background flora in beef fillets. AB - The aim of this study was to evaluate the wine-based marinades to control the survival of acid-adapted and non-adapted Salmonella Typhimurium and background flora of fresh beef stored aerobically or under modified atmosphere. Beef slices were inoculated with a 3-strain cocktail of acid-adapted or non-adapted Salmonella Typhimurium strains DT 193, 4/74 and DSM 554 and marinated by immersion in wine (W) or wine supplemented with 0.3% thyme essential oil (WEO), for 12h at 4 degrees C. Marinated slices were then stored under air or modified atmosphere conditions at 5 degrees C. S. Typhimurium and background flora were followed for a 19-day period of storage. S. Typhimurium individual strains were monitored by pulsed field gel electrophoresis. Marination with wine significantly (P<0.05) reduced the background flora compared to the control (non-marinated). Furthermore, immersion of fillets in W or WEO marinades for 12h significantly (P<0.05) reduced the levels of S. Typhimurium compared to the non-marinated (control) samples by 1.1 and 1.4logCFU/g or 2.0 and 1.9logCFU/g for acid-adapted and non-adapted cells, respectively. Acid-adapted cells were more susceptible (P<0.05) to the addition of thyme essential oil in the wine marinade. The epidemic multi-drug resistant DT 193, the 4/74 and DSM 554 strains survived marination (for both W and WEO) and were detected at about similar proportions as revealed by PFGE results. Present results indicate that wine-based marinades are efficient, from a safety and shelf life stand point, in reducing pathogen's levels as well as the background beef flora. PMID- 23669096 TI - A highly active SERS sensing substrate: core-satellite assembly of gold nanorods/nanoplates. AB - Regiospecific core-satellite assembly of gold nanoplates (AuNPs)/gold nanorods (AuNRs) can be fabricated via ss-DNA hybridization. SERS behavior of the DNA driven assembly has been explored from inducing transition between para-ATP and DMAB through plasmon-assisted catalysis, suggesting that the core-satellite assembly can be utilized as highly active optical substrate. Moreover, a Raman label tagged thymine-rich DNA functionalized AuNRs/AuNPs assembly can be employed as in situ SERS sensing of mercury ions at the ultrasensitive ppt level, which indicates that the core-satellite assembly is appropriate as a versatile SERS substrate for the application of optical chemical or biosensing. PMID- 23669097 TI - Surface modification of PVDF hollow fiber membrane and its application in membrane aerated biofilm reactor (MABR). AB - A novel composite hollow fiber membrane for membrane aerated biofilm rector (MABR) was prepared by coating L-3,4-dihydroxyphenylalanine (DOPA) on the surface of PVDF membrane. MABR process study was conducted to test the performances of the original and modified membranes for 166 days. The results indicate that coated membrane showed 2 times higher gas flux, lower water contact angle (declined from 86.5 degrees to 52 degrees ), and significantly improved surface roughness. The modified membrane displayed an excellent MABR performance. Its COD, NH4(+)-N and TN removal efficiencies were kept above 90%, 98.8% and 84.2% during the first 4-month experiment. By tracking experiment at 0.01 MPa, to achieve COD removal efficiency of 85.9%, half an hour is required with the modified membrane, instead of 6h using the original one. Besides, faster NH4(+)-N and TN removal at 0.01 MPa were also achieved with DOPA composite membrane. PMID- 23669098 TI - Characterization of pyrene degradation by Pseudomonas sp. strain Jpyr-1 isolated from active sewage sludge. AB - Using pyrene as a sole carbon, a new polycyclic aromatic hydrocarbons (PAHs) degrading bacterial strain was isolated from the active sewage sludge. This strain was identified as Pseudomonas sp. Jpyr-1 by 16S rRNA gene sequence analysis. The maximum degradation rate of pyrene was 3.07 mg L(-1)h(-1) in 48 h incubation with initial pyrene concentration of 200 mg L(-1). Moreover, in binary system consisting of pyrene and another PAH, the enzyme system of Jpyr-1 showed a preference toward pyrene. Furthermore, competitive inhibition of pyrene degradation by other PAH compounds occurred in the binary system. Jpyr-1 could also rapidly degrade other PAHs, such as benzanthracene, chrysene and benzo[a]pyrene. Moreover, several metabolites were detected during pyrene degradation which indicated that Jpyr-1 degraded pyrene through the o-phthalate pathway. Taken together, these results indicated that Pseudomonas sp. Jpyr-1 was a new PAHs-degrading strain that might be useful in the bioremediation of sites contaminated with PAHs. PMID- 23669099 TI - Study the catalyzing mechanism of dissolved redox mediators on bio denitrification by metabolic inhibitors. AB - The effect of dissolved redox mediators on denitrification by Paracoccus versutus sp. GW1 were studied with alpha-AQS, AQS, 1,5-AQDS, AQDS and 2,7-AQDS. AQDS presented the best catalytic effect which increased denitrification rate by 1.5 fold with 0.17 mmol L(-1). Denitrification rate was found to be pseudo-zero order with 0-0.32 mmol L(-1) AQDS (k=19.874C AQDS+10.301 (R(2)=0.9984)). The accelerating mechanism for respiratory chain was also explored by using metabolic inhibitors. Addition of AQDS eased the inhibitions of rotenone, dicumarol, sodium azide on respiratory chain, and enhanced the nitrite accumulation during bio denitrification process. AQDS exhibited slight catalytic effect on nitrite denitrification. These results allowed us to deduce the accelerating site of AQDS on the denitrification respiratory chain. Increased nitrate denitrification by AQDS might mainly attribute to the accelerated electrons transfer from NADH to nitrate reductase via complex I and ubiquinone/ubiqunol. This study provided further understanding of the mechanism of redox mediators on denitrification. PMID- 23669100 TI - The Extracellular Matrix Metalloproteinase Inducer (EMMPRIN, CD147) - a potential novel target in atherothrombosis prevention? AB - The immunoglobulin superfamily member EMMPRIN (CD147) plays an important role in a number of organ systems, including the cardiovascular system. Here we review the contemporary understanding of EMMPRIN and EMMPRIN-associated sequelae in the course of atherosclerosis. A significant body of data documents the pivotal role of EMMPRIN in the complex processes of atherogenesis, atheroprogression, and acute atherosclerothrombosis, a role that goes beyond that of a mere marker of inflammation. PMID- 23669101 TI - Antibody inhibition of human cytomegalovirus spread in epithelial cell cultures. AB - Anti-cytomegalovirus (CMV) antibodies reduce the incidence of CMV transmission and ameliorate the severity of CMV-associated disease. Neutralizing activity, measured as the ability of antibodies to prevent entry of cell-free virus, is an important component of natural immunity. However, in vivo CMV amplification may occur mainly via spread between adjacent cells within tissues. Thus, inhibition of cell-to-cell spread may be important when evaluating therapeutic antibodies or humoral responses to infection or immunization. In vitro CMV cell-to-cell spread is largely resistant to antibodies in fibroblast cultures but sensitive in endothelial cell cultures. In the present study antibodies in CMV hyperimmuneglobulin or seropositive human sera inhibited CMV cell-to-cell spread in epithelial cell cultures. Spread inhibition activity was quantitated with a GFP reporter assay employing GFP-tagged epithelialtropic variants of CMV strains Towne or AD169. Measurement of spread inhibition provides an additional parameter for the evaluation of candidate vaccines or immunotherapeutics and to further characterize the role of antibodies in controlling CMV transmission and disease. PMID- 23669102 TI - Isolation of infectious chikungunya virus and dengue virus using anionic polymer coated magnetic beads. AB - Mosquitoes-borne viruses are a major threat for human populations. Among them, chikungunya virus (CHIKV) and dengue virus (DENV) cause thousands of cases worldwide. The recent propagation of mosquito vectors competent to transmit these viruses to temperate areas increases their potential impact on susceptible human populations. The development of sensitive methods allowing the detection and isolation of infectious viruses is of crucial interest for determination of virus contamination in humans and in competent mosquito vectors. However, simple and rapid method allowing the capture of infectious CHIKV and DENV from samples with low viral titers useful for further genetic and functional characterization of circulating strains is lacking. The present study reports a fast and sensitive isolation technique based on viral particles adsorption on magnetic beads coated with anionic polymer, poly(methyl vinyl ether-maleic anhydrate) and suitable for isolation of infectious CHIKV and DENV from the four serotypes. Starting from quite reduced biological material, this method was accurate to combine with conventional detection techniques, including qRT-PCR and immunoblotting and allowed isolation of infectious particles without resorting to a step of cultivation. The use of polymer-coated magnetic beads is therefore of high interest for rapid detection and isolation of CHIKV and DENV from samples with reduced viral loads and represents an accurate approach for the surveillance of mosquito vector in area at risk for arbovirus outbreaks. PMID- 23669103 TI - Comparison of two PCR strategies for the detection of bovine papillomavirus. AB - Bovine papillomavirus (BPV) is a diverse group of double-stranded DNA oncogenic viruses, which have been detected in epithelial lesions and body fluids. Most studies of BPV infection rely on a single method for DNA detection; however the use of any single method or technique may underestimate the true prevalence of this virus. The purpose of this study was to compare two PCR strategies for the detection of BPV in skin lesions and fluids: these involve the use of BPV type specific and consensus primers. Seventy-two cutaneous lesions, 57 blood samples and 59 semen samples were collected. PCR was used with the FAP consensus primers and BPV type-specific primers (for BPVs 2, 3, 4, 5, 8, 9 and 10), along with sequencing assays, to detect the BPV types. Phylogenetic analysis was carried out by means of the maximum likelihood method. It was found that both FAP and BPV type-specific primer sets could amplify BPV types of DNA in skin lesions, blood and semen samples. However, the BPV type-specific primers were more sensitive than the consensus primers and were able to detect co-infection of BPV in the samples. The consensus primers amplified five BPV types and were more suitable for detecting new putative BPV types. Thus, account should be taken of both PCR primer systems to identify co-infection, the presence of novel viruses, and avoid false-negative results. PMID- 23669104 TI - Derivation and validation of a waist circumference optimal cutoff for diagnosing metabolic syndrome in a South African mixed ancestry population. PMID- 23669105 TI - Antidiabetic gliptins in combination with G-CSF enhances myocardial function and survival after acute myocardial infarction. AB - BACKGROUND: Medical stimulation of endogenous progenitor cell circulation may serve as a new therapeutic tool for treatment of acute myocardial infarction. We analyzed the effects of antidiabetic gliptins plus GCSF (granulocyte colony stimulating factor) on myocardial regeneration after myocardial infarction in a mouse model. METHODS AND RESULTS: After surgical LAD-ligation (left anterior descending artery), Sitagliptin/Vildagliptin was applied yielding sufficient blood levels verified by mass spectrometry and significantly reducing activity of dipeptidyl peptidase (DPP) IV. GCSF or saline was administered intraperitoneally for 6 days. We assessed stem cell mobilization and homing (flow cytometry), infarct size (histology), neovascularization and cellular proliferation (immunohistology), heart function (Millar tip catheterization) and survival (Kaplan-Meier-curves). Gliptins+/-GCSF administration increased mobilization and cardiac homing of bone-marrow derived stem cells by stabilization of cardiac SDF1 (stromal cell-derived factor). For Sitagliptin, it could be shown that resident cardiac stem cells were stimulated, neovascularization was enhanced and cardiac remodeling was reduced. These effects finally improved myocardial function and increased survival for both gliptins. Although gliptins as a mono therapy lead to remarkable effects in a dose dependent manner and were superior to G-CSF mono therapy, dual application of GCSF and gliptins revealed the best results. Since both gliptins yielded comparable effects concerning stem cell homing, cardiac function and survival, we suggest a class-effect of DPP-IV-inhibitors. CONCLUSIONS: Thus, gliptins+GCSF and in high concentrations even as mono therapy have beneficial effects on cardiac regeneration after myocardial infarction beyond its anti-diabetic potential. PMID- 23669106 TI - Modeling left atrial volume, shape, and contraction patterns in normal subjects by cardiac magnetic resonance imaging. AB - BACKGROUND: Left atrial three-dimensional shape and contraction patterns are not well described. We quantified the LA using three-dimensional cardiac MRI (CMR) in a group of normal subjects. METHODS: Three-dimensional vectors were used to quantitate atrial shape and contraction using a geometric model as a three dimensional prolate ellipsoid. Atrial area and length at end-systole and end diastole were made in the horizontal long axis (HLA) and vertical long axis (VLA) planes. Biplane area-length products and the orthogonal LA long axis vector comprised 3 orthogonal vector lengths composed of axis measures for shape and volume calculations at end-diastole and end-systole. Vector fractional shortening in 3 dimensions was calculated for each 3-space orthogonal vector. Echocardiograms were used for comparison. RESULTS: The normal LA is an oblate ellipsoid with significantly longer HLA short axis than the vertical VLA short axis (p<0.001). LA contraction in the long axis dimension is smaller than both HLA and VLA short axis dimensional changes (p<0.001). Linear correlations between LAEDV vs. LASV and LAESV vs. LAEF were highly significant. CONCLUSIONS: This dimensional analysis quantitates normal left atrial shape for the first time, modeled as a prolate 3-D ellipsoid. LA contractile functions and derives mostly from contraction in the HLA and VLA short axis directions. Though LA end diastolic volume is considered the marker of left atrial health or disease, this notion should be reconsidered in view of LA static and functional modeling in 3 dimensions. PMID- 23669107 TI - Successful closure of patent ductus arteriosus in a 66 year old patient. PMID- 23669109 TI - The pivotal roles of risk factors for incident atrial fibrillation: interweaving pieces of puzzle. PMID- 23669108 TI - Cardiac autonomic control in Brugada syndrome patients during sleep: the effects of sleep disordered breathing. AB - AIMS: Brugada syndrome is characterized by typical ECG features, ventricular arrhythmias and sudden cardiac death (SCD), more frequent during nighttime. Autonomic cardiovascular control has been implicated in triggering the ventricular arrhythmias. Sleep-disordered breathing (SDB) elicits marked autonomic changes during sleep and is also associated with an increased risk of nighttime SCD. Brugada patients may have a higher likelihood of SDB compared to controls. However, no data are available on cardiac autonomic control in Brugada patients, particularly with regard to the comorbidity of SDB. METHODS: We evaluated autonomic cardiovascular control in Brugada patients with SDB (BRU-SDB, n=9), without SDB (BRU, n=9), in controls (CON, n=8) and in non-Brugada patients with SDB (n=6), during wakefulness and sleep (N2, N3 and REM). Linear spectral and entropy-derived measures of heart rate variability (HRV) were performed during apnea-free stable breathing epochs. RESULTS: Total HRV was attenuated in BRU-SDB compared to CON and BRU. During N2 and REM, in BRU-SDB patients sympathetic modulation decreased compared to BRU and CON, while during REM, they showed an increased parasympathetic modulation, compared to the other two groups. BRU-SDB and SDB were similar in terms of spectral components. Entropy-derived indices showed preserved dynamic changes in Brugada patients compared to controls through the different sleep stages. CONCLUSION: Brugada syndrome per se does not appear associated with an altered autonomic cardiovascular control during wakefulness and sleep. The comorbidity with SDB may contribute to disrupted autonomic cardiovascular regulation during sleep, possibly predisposing to the increased likelihood of sleep-related ventricular tachyarrhythmias and SCD. PMID- 23669110 TI - Radiofrequency ablation of idiopathic ventricular arrhythmia originating from the tricuspid annulus. PMID- 23669111 TI - Drugs for attention deficit-hyperactivity disorder do not increase the mid-term risk of sudden death in children: a meta-analysis of observational studies. PMID- 23669112 TI - A case of myocardial infarction in a 17-year-old woman. PMID- 23669113 TI - The maladaptive effects of HIV protease inhibitors (lopinavir/ritonavir) on the rat heart. PMID- 23669114 TI - Prevalence of thoracic ascending aortic aneurysm in adult patients with known abdominal aortic aneurysm: an echocardiographic study. PMID- 23669115 TI - Cardioncology, oncocardiology. Are we barking up the wrong tree? PMID- 23669116 TI - Elevated heart rate is also a risk factor after cardiac transplantation: time to slow down? PMID- 23669117 TI - Future challenges in providing appropriate care for adults with congenital heart disease. PMID- 23669118 TI - Use of the Cultex(r) Radial Flow System as an in vitro exposure method to assess acute pulmonary toxicity of fine dusts and nanoparticles with special focus on the intra- and inter-laboratory reproducibility. AB - Exposure of the respiratory tract to airborne particles (including metal-dusts and nano-particles) is considered as a serious health hazard. For a wide range of substances basic knowledge about the toxic properties and the underlying pathomechanisms is lacking or even completely missing. Legislation demands the toxicological characterization of all chemicals placed on the market until 2018 (REACH). As toxicological in vivo data are rare with regard to acute lung toxicity or exhibit distinct limitations (e.g. inter-species differences) and legislation claims the reduction of animal experiments in general ("3R" principle), profound in vitro models have to be established and characterized to meet these requirements. In this paper we characterize a recently introduced advanced in vitro exposure system (Cultex(r) RFS) showing a great similarity to the physiological in vivo exposure situation for the assessment of acute pulmonary toxicity of airborne materials. Using the Cultex(r) RFS, human lung epithelial cells (A549 cells) were exposed to different concentrations of airborne metal dusts (nano- and microscale particles) at the air-liquid-interface (ALI). Cell viability (WST-1 assay) as a parameter of toxicity was assessed 24h after exposure with special focus on the intra- and inter-laboratory (three independent laboratories) reproducibility. Our results show the general applicability of the Cultex(r) RFS with regard to the requirements of the ECVAM (European Centre for the Validation of Alternative Methods) principles on test validity underlining its robustness and stability. Intra- and inter-laboratory reproducibility can be considered as sufficient if predefined quality criteria are respected. Special attention must be paid to the pure air controls that turned out to be a critical parameter for a rational interpretation of the results. Our results are encouraging and future work is planned to improve the inter-laboratory reproducibility, to consolidate the results so far and to develop a valid prediction model. PMID- 23669121 TI - Traumatic dural tears: what do we know and are they a problem? AB - BACKGROUND CONTEXT: Iatrogenic dural tears are common complications encountered in spine surgery with known ramifications. There is little information, however, with respect to the implications and complications of traumatic dural tears. PURPOSE: To describe the demographics and characteristics of traumatically acquired dural tears and evaluate the complication rate associated with traumatic dural tears in patients who have undergone surgical treatment for spine injuries. STUDY DESIGN: Retrospective review of a single Level I trauma center to identify patients with traumatic dural tears between January 1, 2003 and December 31, 2009. PATIENT SAMPLE: The sample comprises 187 patients with traumatic dural tears identified from 1,615 patients who underwent operative management of their traumatic injury. OUTCOME MEASURES: The outcome measures consisted of a description of the location and nature of dural tears and associated fracture patterns and neurologic status as well as an assessment of complications attributable to the traumatic dural tear. METHODS: No funding was received or used in this study. In total, 1,615 operatively managed spine injuries over a 7 year period were reviewed to identify 187 patients with traumatic dural tears. Operative reports were reviewed to assess location and description of injury as well as type of repair, if done. Associated spinal cord injuries as well as fracture level, patterns, and complications were recorded. Postoperative records were assessed focusing on complications related to the traumatic dural tears. RESULTS: Traumatic dural tears were identified in 9.1% (67/739) of cervical, 9.9% (45/452) of thoracic, and 17.6% (75/424) of lumbosacral spine fractures. Among the patients, 82.3% (154/187) had a formal dural repair. Fracture patterns included burst (AO Type A3) 26.2% (49/187), flexion distraction (AO Type B) 16% (30/187), and fracture dislocations (AO Type C) 36.4% (68/187). A complete neurologic injury was noted in 48.7% (91/187) of the patient population, whereas no neurologic injury was noted in 17.1% (32/187). Two patients (1%) developed a persistent cerebral spinal fluid leak that necessitated an irrigation and debridement with exploration and closure of the cerebral spinal fluid tear. Two patients (1%) developed a pseudomeningocele; one required a return to the operating room for irrigation and debridement, and the other suspected of having developed meningitis was treated with intravenous antibiotics. Among the patients, 2.1% (4/187) were noted to have a complication directly related to a traumatic dural tear. CONCLUSIONS: Traumatic dural tears occurred in 11.6% of patients with operatively managed traumatic spine injuries at a regional Level 1 trauma center. In total, 83% had a neurologic injury and 49% had complete spinal cord injuries. Patients with traumatically induced dural tears have a low likelihood of developing a complication attributable to the dural tear. PMID- 23669120 TI - Distinct, but not completely separate spatial transport routes in the nuclear pore complex. AB - The nuclear pore complex (NPC), which provides the permeable and selective transport path between the nucleus and cytoplasm of eukaryotic cells, allows both the passive diffusion of small molecules in a signal-independent manner and the transport receptor-facilitated translocation of cargo molecules in a signal dependent manner. However, the spatial and functional relationships between these two transport pathways, which represent critical information for unraveling the fundamental nucleocytoplasmic transport mechanism, remain in dispute. The direct experimental examination of passive and facilitated transport with a high spatiotemporal resolution under real-time trafficking conditions in native NPCs is still difficult. To address this issue and further define these transport mechanisms, we recently developed single-point edge-excitation sub-diffraction (SPEED) microscopy and a deconvolution algorithm to directly map both passive and facilitated transport routes in three dimensions (3D) in native NPCs. Our findings revealed that passive and facilitated transport occur through spatially distinct transport routes. Signal-independent small molecules exhibit a high probability of passively diffusing through an axial central viscous channel, while transport receptors and their cargo complexes preferentially travel through the periphery, around this central channel, after interacting with phenylalanine glycine (FG) filaments. Strikingly, these two distinct transport zones are not completely separate either spatially or functionally. Instead, their conformations are closely correlated and simultaneously regulated. In this review, we will specifically highlight a detailed procedure for 3D mapping of passive and facilitated transport routes, demonstrate the correlation between these two distinct pathways, and finally, speculate regarding the regulation of the transport pathways driven by the conformational changes of FG filaments in NPCs. PMID- 23669122 TI - Primary cervical amyloidoma: a case report and review of the literature. AB - BACKGROUND CONTEXT: Primary solitary amyloidosis or amyloidoma is a disease process characterized by the focal deposition of amyloid in the absence of a plasma cell dyscrasia with normal serum protein measurements. Solitary amyloidomas affecting the vertebrae are very uncommon but typically affect the thoracic spine. Primary cervical amyloidosis is an exceedingly rare entity with exceptionally good prognosis, but requires diligence of the treating physician to establish the diagnosis and implement the appropriate surgical intervention. PURPOSE: This study aimed to present a rare case of primary cervical amyloidosis with long-term follow-up and review the clinical presentation, characteristic imaging findings, diagnostic pathology, differential diagnosis, treatment algorithm, and prognosis of the disease entity. This case demonstrates the progressive resorption of the amyloidoma over time after surgical stabilization. Previous reported cases of primary cervical amyloidosis will also be reviewed. STUDY DESIGN: This study is a report and review of the literature. METHODS: A 77 year-old woman presented with a several-week history of gradual progressive weakness in her upper and lower extremities. Computed tomography and magnetic resonance imaging demonstrated a retro-odontoid nonenhancing soft-tissue mass, with erosive bony changes and severe mass effect on the upper cervical cord. The patient was taken to the operating room for decompression and posterior spinal stabilization. RESULTS: Intraoperative tissue specimens demonstrated amyloidosis and extensive systemic workup did not reveal any inflammatory processes, systemic amyloidosis, or plasma cell dyscrasia. Postoperatively, the patient regained full strength and ambulatory status. The patient remains asymptomatic at a 2-year follow-up. A postoperative follow-up magnetic resonance imaging demonstrated complete resorption of the residual amyloidoma. CONCLUSIONS: Primary solitary amyloidosis is a rare form of amyloidosis that is important to differentiate given its excellent prognosis with surgical management. Treatment should include surgical decompression and spinal stabilization. This is the first case report to clinically and radiographically demonstrate the progressive resorption of a primary amyloidoma over time after surgical stabilization in the upper cervical spine. It is imperative that surgeons encountering such lesions maintain a high suspicion for this rare disease entity and advise their pathologists accordingly to establish the correct diagnosis. PMID- 23669123 TI - Fullerol nanoparticles suppress inflammatory response and adipogenesis of vertebral bone marrow stromal cells--a potential novel treatment for intervertebral disc degeneration. AB - BACKGROUND CONTEXT: Intervertebral disc degeneration, leading to chronic back pain, is a major health problem in western societies. Vertebral bone marrow has been considered to play an important role in nutrition supply and metabolic exchange for discs. Vertebral bone marrow lesions, including fatty marrow replacement and inflammatory edema, noted on magnetic resonance imaging were first described in 1988. PURPOSE: To investigate the potential of a free radical scavenger, fullerol nanoparticles, to prevent vertebral bone marrow lesion and prevent disc degeneration by inhibiting inflammation and adipogenic differentiation of vertebral bone marrow stromal cells (vBMSCs). STUDY DESIGN/SETTING: Fullerol nanoparticle solutions were prepared to test their in vitro suppression effects on mouse vBMSC inflammation and adipogenic differentiation compared with non-fullerol-treated groups. METHODS: With or without fullerol treatment, vBMSCs from Swiss Webster mice were incubated with 10 ng/mL interleukin-1 beta (IL-1 beta). The intracellular reactive oxygen species (ROS) were measured with fluorescence staining and flow cytometry. In addition, vBMSCs were cultured with adipogenic medium (AM) with or without fullerol. Gene and protein expressions were evaluated by real-time polymerase chain reaction and histologic methods. RESULTS: Fluorescence staining and flow cytometry results showed that IL-1 beta markedly increased intracellular ROS level, which could be prevented by fullerol administration. Fullerol also decreased the basal ROS level to 77%. Cellular production of matrix metalloproteinase (MMP)-1, 3, and 13 and tumor necrosis factor alpha (TNF-alpha) induced by IL-1 beta was suppressed by fullerol treatment. Furthermore, adipogenic differentiation of the vBMSCs was retarded markedly by fullerol as revealed by less lipid droplets in the fullerol treatment group compared with the adipogenic group. The expression of adipogenic genes PPARgamma and aP2 was highly elevated with AM but decreased on fullerol administration. CONCLUSIONS: These results suggest that fullerol prevents the catabolic activity of vBMSCs under inflammatory stimulus by decreasing the level of ROS, MMPs, and TNF-alpha. Also, fat formation in vBMSCs is prevented by fullerol nanoparticles, and, therefore, fullerol may warrant further in vivo investigation as an effective biological therapy for disc degeneration. PMID- 23669124 TI - Triparesis caused by gas-containing extensive epidural abscess secondary to Aeromonas hydrophila infection of a thoracic vertebroplasty: a case report. AB - BACKGROUND CONTEXT: Aeromonas hydrophila is a motile gram-negative non sporeforming rod with facultative anaerobic metabolism. Except for gastrointestinal disease, skin and soft-tissue infections represent the second most common site of human Aeromonas infections. However, to our knowledge, A. hydrophila infection of the spine has not been reported to date. PURPOSE: To report the first case of A. hydrophila spinal infection of the T7 vertebra after vertebroplasty. STUDY DESIGN: Case report. METHODS: A 72-year-old man was transferred to our emergency department with chief complaints of severe midthoracic pain and triparesis. He had undergone vertebroplasty for a painful vertebral fracture at T7 5 weeks before transfer. Magnetic resonance imaging showed an infection of the T7 vertebroplasty and an extensive epidural abscess. The epidural abscess originating from the infected T7 vertebroplasty extended from the T8 to the C4 epidural space. Computed tomography demonstrated sparsely scattered gas in the epidural abscess, strongly suggestive of an anaerobic infection. RESULTS: Emergency multilevel laminectomies from C5 to T8 and a posterior instrumentation from T3 to T10 were performed. A. hydrophila was isolated from the blood cultures. The patient was treated with intravenous ampicillin/sulbactam. Posterior decompression and stabilization in combination with appropriate antibiotic treatment completely resolved the neurologic deficit and infection without the need for further anterior corpectomy of the infected T7 vertebroplasty. CONCLUSIONS: This is the first reported case of spine infection caused by A. hydrophila. The infection developed after vertebroplasty for the management of a painful vertebral fracture. Triparesis occurred rapidly due to an extensive epidural abscess containing gas. Emergency decompression and stabilization in combination with appropriate antibiotic treatment achieved a successful clinical outcome. PMID- 23669125 TI - Assessing kyphosis with SpineScan: another attempt to reduce our dependence on radiography. AB - BACKGROUND CONTEXT: Kyphosis management is mainly conservative, with annual examinations to assess angular progression. This includes physical examination and usually long spine X-rays, notorious for ionizing radiation. Several nonradiological instruments have been devised for this, but none have become popular. SpineScan, a programmed digital inclinometer, has been proved effective for screening kyphoscoliosis. PURPOSE: The aim of this study was to assess the accuracy of SpineScan in monitoring kyphosis. STUDY DESIGN/SETTING: Prospective, observational, diagnostic accuracy study. PATIENT SAMPLE: Twenty-eight subjects examined for kyphosis, with recent full-length lateral spine X-rays. METHODS: Each subject was examined by two examiners. The technique involved the subject standing with arms flexed to 90 degrees and then sliding the SpineScan from just below C7 to L2. Maximum X-ray kyphotic Cobb angle was compared with the SpineScan result. The study was institutional review board approved, and all patients signed an informed consent. RESULTS: The mean Cobb angle of the 28 subjects on radiography was 51 degrees +/- 15 degrees . The mean SpineScan angle of all trials of all examiners was 54 degrees +/- 12 degrees . The difference between the two measurements was significantly different from zero (3.2 degrees +/- 9.4 degrees , p<.0001) and not normally distributed. The difference was significantly affected by the Cobb angle, examiner, and interaction between Cobb and examiner (statistical significance for all p<.0001). Ninety-five percent confidence intervals for all examiners ranged between -16 degrees and 22 degrees and for separate examiners between -25 degrees and 32 degrees , far above the 5 degrees preplanned error level. CONCLUSIONS: The results demonstrated that there is significant error in monitoring kyphosis with SpineScan. Even for a more modest indication including replacing radiography with SpineScan on alternate visits, the measurement was not accurate enough. Future research is necessary to find a nonradiographic method of kyphosis follow-up, possibly using a digitalized modification of one of the described instruments. PMID- 23669126 TI - Factors affecting dynamic foraminal stenosis in the lumbar spine. AB - BACKGROUND CONTEXT: Lumbar foraminal stenosis is a common clinical problem and a significant cause of lower extremity radiculopathy. Minimal in vivo data exists quantifying changes in foraminal area (FA) as the spine moves from flexion to extension in the lumbar spine or on the relationship between FA and lumbar segmental angular motion, translational motion (TM), or disc bulge migration. PURPOSE: To use kinetic magnetic resonance imaging (kMRI) to evaluate changes in dimensions of lumbar neural foramina during weight bearing in neutral, flexion, and extension positions. To evaluate the relationship between foraminal stenosis and lumbar segmental angular motion, TM, and disc bulge migration. STUDY DESIGN: A retrospective radiographic study. PATIENT SAMPLE: Forty-five patients with a mean age of 44 years undergoing kMRI for symptoms of low back pain or radiculopathy. OUTCOME MEASURES: Magnetic resonance imaging measurements of FA, angular motion, TM, and disc bulge migration. METHODS: Kinetic magnetic resonance imaging of the lumbar spine was reviewed in 45 patients with low back pain or radiculopathy, and parasagittal images were evaluated for changes in neural foraminal dimensions in various degrees of motion with weight bearing. The changes in foraminal dimension were correlated to the amount of segmental angular motion, TM, and disc bulge migration at each level. Neural foramina were also assessed qualitatively by Wildermuth criteria. Only those foramina that were clearly visualized with well-defined anatomic boundaries in all three positions were taken into consideration. Patients with previous surgery, tumor, and scoliosis were excluded from the study. RESULTS: There was a significant decrease in the FA from flexion to neutral (p<.05) at all levels except L5-S1 and from neutral to extension at all levels (p<.05). The average percent decrease in FA was 30.0% with the greatest decrease from flexion to extension occurring at L2-L3 (167-107 mm(2)) and the smallest change occurring at L5-S1 (135-106 mm(2)) (p<.05). The magnitude of change in FA increased as angular motion at a segment increased. The mean change in FA was 32.3 mm(2) when angular motion was less than 5 degrees and was 75.16 mm(2) when angular motion exceeded 15 degrees . The extent of disc bulging posteriorly in the neural foramen was also correlated with the reduction in the FA from flexion to extension, but TM had no effect. CONCLUSIONS: Foraminal area decreased significantly in extension compared with flexion and neutral on MRI. Lumbar disc bulge migration and angular motion at each level contributed independently to the decrease in FA in extension, whereas TM had no effect on FA. PMID- 23669127 TI - Superior mesenteric artery pseudoaneurysm. PMID- 23669128 TI - Woman with pale fingers. PMID- 23669129 TI - Medical outcomes associated with nonmedical use of methadone and buprenorphine. AB - BACKGROUND: There exists a significant amount of misinformation regarding methadone and buprenorphine, and a belief that toxicity associated with nonmedical use of methadone and nonmedical use of buprenorphine is similar in severity and outcomes. OBJECTIVE: The objective of this study is to compare outcomes associated with nonmedical use of methadone vs. nonmedical use of buprenorphine in patients presenting to the Emergency Department (ED) and reported to poison centers. METHODS: This was a retrospective cohort study using data from the American Association of Poison Control Centers from January 1, 2003 to December 31, 2009 (7 years). Inclusion criteria were nonmedical use of methadone or buprenorphine (or buprenorphine/naloxone) as a single substance by history, age 18 years or older, ingestions only, evaluated in an ED. Outcome measures were clinical effects, treatments, disposition, and final medical outcomes. RESULTS: Of 1,920 cases, 1,594 were in the methadone group and 326 were in the buprenorphine group. Frequently reported clinical effects were lethargy, 59.2% vs. 29.4%, and respiratory depression, 28.7% vs. 2.5%, for methadone and buprenorphine groups, respectively. Hospitalization rates were 67.4% in the methadone group and 32.2% in the buprenorphine group. Half of all patients in the methadone group were admitted to the intensive care unit (ICU) vs. only 15% of all the patients in the buprenorphine group. Twenty-six patients in the methadone group died vs. no deaths in the buprenorphine group. There were significant differences in the distribution of clinical effects, disposition, and medical outcomes (p < 0.001). CONCLUSIONS: Patients who use methadone nonmedically have higher hospitalization rates, greater ICU utilization rates, and considerably worse medical outcomes when compared with patients who use buprenorphine nonmedically. PMID- 23669130 TI - Octreotide for the treatment of hypoglycemia after insulin glargine overdose. AB - BACKGROUND: Intentional insulin glargine overdose is rarely reported in the literature, but usually results in prolonged hypoglycemia requiring intensive care unit admission. OBJECTIVE: We report a case of using octreotide to treat prolonged hypoglycemia after a large insulin glargine overdose. CASE REPORT: A 56 year-old man with type 2 diabetes mellitus presented to the Emergency Department after a multidrug overdose including up to 3,300 units insulin glargine. He required admission to the intensive care unit for mechanical ventilation and blood-glucose monitoring every 30 to 60 min. He received a continuous dextrose infusion for >100 h for persistent hypoglycemia. Octreotide, a somatostatin analogue, was given on day 4 of admission in an attempt to inhibit any insulin secretion from the pancreas that might be occurring in response to the dextrose infusion and to minimize the amount of fluid being given. After three doses, improvements in the patient's blood glucoses were seen, however, this could have coincided with complete absorption of the insulin. CONCLUSIONS: Prolonged hypoglycemia often occurs after large overdoses of insulin glargine due to a depot effect at the site of injection. Octreotide is a potential adjunctive treatment to dextrose in patients with a functioning pancreas. PMID- 23669131 TI - Pediatric rash: dermatologic manifestations of incontinentia pigmenti. PMID- 23669132 TI - Validation of a real-time PCR based method for detection of Clostridium botulinum types C, D and their mosaic variants C-D and D-C in a multicenter collaborative trial. AB - Two real-time PCR arrays based on the GeneDisc((r)) cycler platform (Pall GeneDisc Technologies) were evaluated in a multicenter collaborative trial for their capacity to specifically detect and discriminate Clostridium botulinum types C, D and their mosaic variants C-D and D-C that are associated with avian and mammalian botulism. The GeneDisc((r)) arrays developed as part of the DG Home funded European project 'AnibioThreat' were highly sensitive and specific when tested on pure isolates and naturally contaminated samples (mostly clinical specimen from avian origin). Results of the multicenter collaborative trial involving eight laboratories in five European Countries (two laboratories in France, Italy and The Netherlands, one laboratory in Denmark and Sweden), using DNA extracts issued from 33 pure isolates and 48 naturally contaminated samples associated with animal botulism cases, demonstrated the robustness of these tests. Results showed a concordance among the eight laboratories of 99.4%-100% for both arrays. The reproducibility of the tests was high with a relative standard deviation ranging from 1.1% to 7.1%. Considering the high level of agreement achieved between the laboratories these PCR arrays constitute robust and suitable tools for rapid detection of C. botulinum types C, D and mosaic types C-D and D-C. These are the first tests for C. botulinum C and D that have been evaluated in a European multicenter collaborative trial. PMID- 23669134 TI - Electronic structure and transport properties of N2(AA)-doped armchair and zigzag graphene nanoribbons. AB - Substitutional doping in graphene nanoribbons (GNRs) promises to enable specific tuning of their electronic properties. Recent work by Lv et al (2012 Nature Sci. Rep. 2 586) on large sheets of nitrogen-doped graphene determined that a highly predominant amount of nitrogen dopants (80%) are present in pairs of neighbouring atoms of the same sublattice A, denoted as N2(AA) dopants, following the notation of Lv et al. Here, we explore the electronic and transport properties of armchair (aGNR) and zigzag (zGNR) graphene nanoribbons under different orientations of the N2(AA) dopants with respect to the ribbon growth direction. For all dopant configurations of zGNRs and aGNRs, we find a substantial decrease in conductance, with new conductance gaps opening in some cases, and spatially localized states induced around the dopant sites. We also provide simulated scanning tunnelling microscopy images that will aid in the experimental identification of the presence of these structures in N-doped GNR samples. PMID- 23669133 TI - Csi1 illuminates the mechanism and function of Rabl configuration. AB - The nuclear envelope not only compartmentalizes the genome but is also home to the SUN-KASH domain proteins, which play essential roles both in genome organization and in linking the nucleus to the cytoskeleton. In interphase fission yeast cells, centromeres are clustered near the nuclear periphery. A recent report demonstrates that the inner nuclear membrane SUN domain protein Sad1 and a novel protein Csi1 connect centromeres to the nuclear envelope and that centromere clustering during interphase is critical for the efficient capture of kinetochores by microtubules during mitosis. PMID- 23669135 TI - Antinociceptive activity of Rhoifoline A from the ethanol extract of Zanthoxylum nitidum in mice. AB - AIM OF THE STUDY: Antinociceptive activity of Rhoifoline A (RA), a benzophenanthridine alkaloid obtained from the ethanol extract of Zanthoxylum nitidum, was evaluated in mice using chemical and thermal models of nociception. MATERIALS AND METHODS: RA was evaluated on anti-nociceptive activity in mice using chemical and thermal models of nociception. RESULTS: RA administered intraperitoneally at doses of 10, 20, 40 and 80 mg/kg exhibited significant inhibitions on chemical nociception induced by intraperitoneal acetic acid and subplantar formalin, and on thermal nociception in the tail-flick test and the hot plate test. RA neither significantly impaired motor coordination in the rotarod test nor did spontaneous locomotion in the open-field test. RA did not enhance the pentobarbital sodium induced sleep time. These results indicated that the observed antinociceptive activity of RA was unrelated to sedation or motor abnormality. Core body temperature measurement showed that RA did not affect temperature during a 2-hour period. Furthermore, RA-induced antinociception in the hot plate test was insensitive to naloxone or glibenclamide but significantly antagonized by L-NAME, methylene blue and nimodipine. CONCLUSIONS: Therefore, it is reasonable that the analgesic mechanism of RA possibly involved the NO-cGMP signaling pathway and L-type Ca(2+) channels. PMID- 23669136 TI - White matter damage is associated with memory decline in chronic alcoholics: a quantitative diffusion tensor tractography study. AB - Neuroimaging studies have reported an association between white matter integrity and cognitive performance in normal aging and various neuropathological conditions. We compared alcoholics with controls and hypothesized that the degree of disconnection of white matter fibers would be negatively correlated with memory dysfunction scores. Diffusion tensor imaging (DTI) based tractography and PGI-memory scale (PGIMS) test was performed in 10 abstinent chronic alcoholic and 10 demographically equivalent control men. DTI measures [fractional anisotropy (FA), and mean diffusivity (MD)] from all of the major cerebral tracts were calculated and a comparison was done between patient group and controls. Spearman's rank correlation coefficient was computed between memory dysfunction score and DTI measures. Compared to controls alcoholic participants had significantly reduced FA in corpus callosum (CC), fornix (FX), and right hemispheric arcuate fasciculus (AF), anterior thalamic radiation (ATR) and inferior longitudinal fasciculus (ILF). A significant inverse correlation with memory dysfunction score was observed with right cingulum, right uncinate fasciculus, right ILF and left ILF. The inverse correlation of memory dysfunction score with FA of white matter tracts suggest that white matter deficit in these white matter fibers may contribute to underlying dysfunction in memory in alcoholism. PMID- 23669137 TI - Adolescent fluoxetine treatment decreases the effects of neonatal immune activation on anxiety-like behavior in mice. AB - Experimental studies have shown conflicting effects of neonatal infection on anxiety-like behaviors and hypothalamic-pituitary-adrenal (HPA) axis activity in adult rats. We investigated for the first time whether neonatal exposure to lipopolysaccharide (LPS) is associated with increased levels of anxiety-like behaviors in mice. Moreover, there have been several studies showing that adolescent fluoxetine (FLX) treatment can influence HPA axis development and prevent occurrence of psychiatric disorders induced by common early-life insults. In the present study, we also investigated the effects of adolescent FLX exposure following neonatal immune activation on anxiety-like behavior in mice. Neonatal mice were treated to LPS (50MUg/kg) or saline on postnatal days (PND) 3 and 5, then male and female mice of both neonatal intervention groups received oral administration of FLX (5 and 10mg/kg/day) or water via regular drinking bottles during the adolescent period (PNDs 35-65). The results showed that postnatal immune challenge increased anxiety-like behavior in the open field, elevated plus maze and light-dark box in adult mice (PND 90). Furthermore, the adolescent FLX treatment inhibited the anxiety-like behavior induced by neonatal infection in both sexes. However, this study indicates the negative effects of the FLX on normal behavioral symptoms in male control mice. Taken together, the current data provide experimental evidence that neonatal infection increases anxiety levels in male and female mice in adulthood. Additionally, the findings of this study support the hypothesis that an early pharmacological intervention with FLX may be an effective treatment for reducing the behavioral abnormalities induced by common early-life insults. PMID- 23669138 TI - Heavy metal accumulation and tolerance of energy grass (Elymus elongatus subsp. ponticus cv. Szarvasi-1) grown in hydroponic culture. AB - Phytoremediation is a plant based, cost effective technology to detoxify or stabilise contaminated soils. Fast growing, high biomass, perennial plants may be used not only in phytoremediation but also in energy production. Szarvasi-1 energy grass (Elymus elongatus subsp. ponticus cv. Szarvasi-1), a good candidate for this combined application, was grown in nutrient solution in order to assess its Cd, Cu, Ni, Pb and Zn accumulation and tolerance. Its shoot metal accumulation showed the order Pb < Ni < Cu ~ Cd < Zn. In parallel with this, Pb and Ni had no or very little influence on the growth, dry matter content, chlorophyll concentration and transpiration of the plants. Cu and Cd treatment resulted in significant decreases in all these parameters that can be attributed to Fe plaque formation in the roots suggested by markedly increased Fe and Cu accumulation. This came together with decreased shoot and root Mn concentrations in both treatments while shoot Cu and Zn concentrations decreased under Cd and Cu exposure, respectively. Zn treatment had no effect or even slightly stimulated the plants. This may be due to a slight stimulation of Fe translocation and a very efficient detoxification mechanism. Based on the average 300 mg kg-1 (dry mass) Zn concentration which is 0.03% of the shoot dry mass the variety is suggested to be classified as Zn accumulator. PMID- 23669139 TI - Treatment of posterior pelvic ring disruptions using a minimally invasive adjustable plate. AB - OBJECTIVE: Iliosacral (IS) screw fixation and posterior tension band plate (TBP) technique are two treatment alternatives for posterior pelvic ring injuries. However, IS screw fixation requires continuous fluoroscopic guidance for appropriate screw insertion and carries a risk of neurovascular injuries. TBP technique also has some disadvantages, including limited reduction potential, difficulty in precontouring the plate and a higher rate of symptomatic implants. To address these limitations, we introduced a minimally invasive adjustable plate (MIAP). This study aims to present the preliminary radiological and clinical results of posterior pelvic ring disruptions treated with MIAP. METHODS: The MIAP conforms to the irregular shape of posterior pelvic ring and can be used without prebending. This plate has a role in reducing compressed or separated fractures/dislocations. Sixteen patients, including seven males and nine females, were treated with MIAP through a minimally invasive approach. The fracture patterns consisted of six Type B and ten Type C fractures according to OTA classification of fracture. Preoperative and postoperative radiography was taken to assess the fracture displacement and reduction quality. Postoperative rehabilitation programme was individualised and early exercise was encouraged. Patients were followed up and the functional outcome was evaluated based upon the scoring system proposed by Lindahl and associates. RESULTS: All posterior pelvic ring disruptions were reduced and fixed with MIAP. The average duration of surgery was 49 min, the average radiation exposure was 6s, and the average blood loss was 80 mL for the treatment of posterior pelvic ring injuries. Overall radiological results of the reduction were excellent in eleven patients and good in five. The patients were followed up for 30 months on average. All fractures healed. The functional outcome was excellent in ten patients, good in four and fair in two. There were no iatrogenic neurovascular injuries, implant failures, irritative symptoms or pressure sores due to subcutaneous implantation. CONCLUSION: Favourable clinical and radiological outcomes can be achieved in treating posterior pelvic disruptions with MIAP. This plate is effective in view of its simplicity, less radiation exposure, safety, minimal invasion and stable fixation. PMID- 23669140 TI - Predictors of transfer to rehabilitation for trauma patients admitted to a level 1 trauma centre--a model derivation and internal validation study. AB - OBJECTIVE: Determine the predictors of transfer to rehabilitation in a cohort of trauma patients and derive a risk score based clinical prediction tool to identify such patients during the acute phase of injury management. METHODS: Trauma registry data at a single level one trauma centre were obtained for all patients aged between 15 and 65 years admitted due to injury between 2007 and 2011. Multivariable logistic regression with stepwise selection was performed to derive a prediction model for transfer to rehabilitation. The model was tested on a validation dataset using receiver operator characteristic analyses and bootstrap cross validation on the entire dataset. A clinical prediction risk score was developed based on the final model. RESULTS: There were 4900 patients included in the study. Variables found to be the strongest predictors of rehabilitation after logistic regression with stepwise selection were pelvic injuries (OR 12.6 95% CI 6.2, 25.2 p<0.001), need for intensive care unit admission (OR 7.2 95% CI 4.2, 12.3 p<0.001) and neurosurgical operation (OR 10.5 95% CI 4.7, 23.1 p<0.001). After bootstrap cross validation the mean AUC was 0.86 (95% CI 0.84, 0.89). The model had a sensitivity of 89% and specificity of 64%. CONCLUSION: Intensive unit admission, neurosurgical operation, pelvic injuries and other lower limb injuries were the most important predictors of the need for rehabilitation after trauma. The prediction model has good overall sensitivity, discrimination and could be further validated for use in clinical practice. PMID- 23669141 TI - Seeking for a way to revive erythropoietin production in chronic kidney disease. PMID- 23669142 TI - A method to investigate discrepancies between perceived and actual balance in older women. AB - Despite the established relationship between low balance confidence and poorer balance and gait performance, discrepancies may occur between an individual's perceived and actual abilities. This study determined if trunk sway measures could assist in identifying potential discrepancies between perceived and actual balance. Older women completed the Activities-specific Balance Confidence (ABC) scale and performed a series of 16 stance, gait and tandem gait tasks. Duration (or completed steps for tandem gait tasks) and trunk pitch and roll angle and angular velocity were calculated. Low (mean ABC score<=70%, n=33) and high (mean ABC score>=90%, n=99) balance confidence groups were identified from a pool of 204 participants. The low balance confidence group had greater stance trunk pitch and roll sway, shorter one leg stance durations, reduced gait trunk roll sway, longer gait durations, less tandem gait trunk roll sway and completed fewer tandem gait steps compared to the high balance confidence group. Stepwise linear discriminant analysis identified four variables that were used to achieve a classification accuracy of 75.8% for low and 90.9% for high balance confidence groups. This study reinforces the influence of low balance confidence on stance and gait control and provides direction for the identification and treatment of individuals with discrepancies between perceived and actual balance. PMID- 23669143 TI - Aerobic capacities and exercise tolerance in neuromuscular diseases: a descriptive study. AB - INTRODUCTION: Up until now, there has been little description of the test exercises carried out in patients with neuromuscular diseases. However, prescription of physical therapy by exercise requires rigorous individualized assessment of the patient's physical endurance parameters. OBJECTIVE: To describe exercise tolerance and external limitation factors in a sample group of adult patients suffering from neuromuscular diseases. MATERIALS AND METHODS: A descriptive retrospective study of exercise tests realized at the Reims university hospital for patients divided into three groups according to their pathologies: CMT hereditary neuropathies, muscular dystrophies, metabolic myopathies. RESULTS: Forty-four (44) tests were analyzed. Cessation was occasioned on 63.6% of the cases by muscular symptomatology, with no possibility of maintaining the cycling frequency in 29.5% of the overall population. Insufficient lung volume recruitment was involved in 61.4% of the patients, final oxygen pulse (VO2/heart rate) was 80% lower than the theoretical pulse in 50% of the patients, and there existed an early first ventilatory threshold in 54.5% of the cases. Peripheral deconditioning was highly severe in 18% of the population and significantly greater in the subjects suffering from dystrophies (VT1 at 31% of the maximum theoretical O2, P<0.001). DISCUSSION: The main limitation factor in exercise tests is peripheral. Ventilatory and cardiovascular limitations can nonetheless be added on; while they are absent when the patient is at rest, they are unmasked in effort situations. Exercise tests could be of great interest in screening and managing the relevant pathologies. Multicenter studies on homogeneous populations could facilitate definition of the procedures specific to exercise tests for patients suffuring from neuromuscular diseases. PMID- 23669144 TI - Long-term high-intensity interval training associated with lifestyle modifications improves QT dispersion parameters in metabolic syndrome patients. AB - BACKGROUND: QT dispersion (QTd) is a marker of myocardial electrical instability, and is increased in metabolic syndrome (MetS). Moderate intensity continuous exercise (MICE) training was shown to improve QTd in MetS patients. OBJECTIVES: To describe long-term effects of MICE and high-intensity interval exercise training (HIIT) on QTd parameters in MetS. METHODS: Sixty-five MetS patients (53 +/- 9 years) were assigned to either a MICE (60% of peak power output [PPO]), or a HIIT program (alternating phases of 15-30 s at 80% of PPO interspersed by passive recovery phases of equal duration), twice weekly during 9 months. Ventricular repolarization indices (QT dispersion=QTd, standard deviation of QT = sdQT, relative dispersion of QT = rdQT, QT corrected dispersion = QTcd), metabolic, anthropometric and exercise parameters were measured before and after the intervention. RESULTS: No adverse events were noted during exercise. QTd decreased significantly in both groups (51 vs 56 ms in MICE, P < 0.05; 34 vs 38 ms in HIIT, P < 0.05). Changes in QTd were correlated with changes in maximal heart rate (r = -0.69, P < 0.0001) and in heart rate recovery (r = -0.49, P < 0.01) in the HIIT group only. When compared to MICE, HIIT training induced a greater decrease in weight, BMI and waist circumference. Exercise capacity significantly improved by 0.82 and 1.25 METs in MICE and HIIT groups respectively (P < 0.0001). Lipid parameters also improved to the same degree in both groups. CONCLUSION: In MetS, long-term HIIT and MICE training led to comparable effects on ventricular repolarization indices, and HIIT might be associated with greater improvements in certain cardiometabolic risk factors. PMID- 23669145 TI - Transport of NaYF4:Er3+, Yb3+ up-converting nanoparticles into HeLa cells. AB - An effective, simple and practically useful method to incorporate fluorescent nanoparticles inside live biological cells was developed. The internalization time and concentration dependence of a frequently used liposomal transfection factor (Lipofectamine 2000) was studied. A user friendly, one-step technique to obtain water and organic solvent soluble Er(3+) and Yb(3+) doped NaYF4 nanoparticles coated with polyvinylpyrrolidone was obtained. Structural analysis of the nanoparticles confirmed the formation of nanocrystals of the desired sizes and spectral properties. The internalization of NaYF4 nanoparticles in HeLa cervical cancer cells was determined at different nanoparticle concentrations and for incubation periods from 3 to 24 h. The images revealed a redistribution of nanoparticles inside the cell, which increases with incubation time and concentration levels, and depends on the presence of the transfection factor. The study identifies, for the first time, factors responsible for an effective endocytosis of the up-converting nanoparticles to HeLa cells. Thus, the method could be applied to investigate a wide range of future 'smart' theranostic agents. Nanoparticles incorporated into the liposomes appear to be very promising fluorescent probes for imaging real-time cellular dynamics. PMID- 23669146 TI - DNA replicates semiconservatively. PMID- 23669147 TI - Influence of micro-mixing on the size of liposomes self-assembled from miscible liquid phases. AB - Ethanol injection and variations of it are a class of methods where two miscible phases-one of which contains dissolved lipids-are mixed together leading to the self-assembly of lipid molecules to form liposomes. This method has been suggested, among other applications, for in situ synthesis of liposomes as drug delivery capsules. However, the mechanism that leads to a specific size selection of the liposomes in solution based self-assembly in general, and in flow focussing microfluidic devices in particular, has so far not been established. Here we report two aspects of this problem. A simple and easily fabricated device for the synthesis of monodisperse unilamellar liposomes in a co-axial flow focussing microfluidic geometry is presented. We also show that the size of liposomes is dependent on the extent of micro-convective mixing of the two miscible phases. Here, a viscosity stratification induced hydrodynamic instability leads to a gentle micro-mixing which results in larger liposome size than when the streams are mixed turbulently. The results are in sharp contrast to a purely diffusive mixing in macroscopic laminar flow that was believed to occur under these conditions. Further precise quantification of the mixing characteristics should provide the insights to develop a general theory for size selection for the class of ethanol injection methods. This will also lay grounds for obtaining empirical evidence that will enable better control of liposome sizes and for designing drug encapsulation and delivery devices. PMID- 23669148 TI - A TaqMan-based multiplex real-time PCR assay for the simultaneous detection of Wuchereria bancrofti and Brugia malayi. AB - With the Global Program for the Elimination of Lymphatic Filariasis continuing to make strides towards disease eradication, many locations endemic for the causative parasites of lymphatic filariasis are realizing a substantial decrease in levels of infection and rates of disease transmission. However, with measures of disease continuing to decline, the need for time-saving and economical molecular diagnostic assays capable of detecting low levels of parasite presence is increasing. This need is greatest in locations co-endemic for both Wuchereria bancrofti and Brugia parasites because testing for both causative agents individually results in significant increases in labor and reagent costs. Here we describe a multiplex, TaqMan-based, real-time PCR assay capable of simultaneously detecting W. bancrofti and Brugia malayi DNA extracted from human bloodspots or vector mosquito pools. With comparable sensitivity to established singleplex assays, this assay provides significant cost and labor savings for disease monitoring efforts in co-endemic locations. PMID- 23669149 TI - MRI-based sector analysis enhances prostate palladium-103 brachytherapy quality assurance in a phase II prospective trial of men with intermediate-risk localized prostate cancer. AB - PURPOSE: Palladium-103 ((103)Pd) may be superior to other isotopes in brachytherapy for localized intermediate-risk prostate cancer because of its relatively short half-life, higher initial dose rate, and greater dose heterogeneity within the target volume; these properties also underscore the need for accurate target delineation and postimplant quality assurance. We assessed the use of prostate sector analysis based on MRI for quality assurance after (103)Pd monotherapy. METHODS AND MATERIALS: Fifty men with intermediate-risk prostate cancer underwent (103)Pd monotherapy in a prospective phase II trial at MD Anderson Cancer Center. Dosimetric analyses on day 30 after the implant were done using both CT and fused CT/MRI scans. Dosimetric variables were assessed for the entire prostate and for each of three or six sectors. Volumes and dosimetric variables were compared with paired t tests. RESULTS: Postimplant dosimetric variables for the entire prostate were significantly different on CT vs. CT/MRI (p = 0.019 for V100 and p < 0.01 for D90). Prostate volumes were smaller on the CT/MRI scans (p < 0.00001). The base sector contributed the greatest difference, with doses based on CT/MRI lower than those based on CT (p < 0.01 for V100 and D90). To date, these lower base doses have not affected biochemical outcomes for patients with disease in prostate base biopsy samples. CONCLUSIONS: CT/MRI is more precise than CT for prostate volume delineation and dosimetric quality assessment and thus provides superior heterogeneity control assessment after (103)Pd monotherapy implants. PMID- 23669150 TI - Impact of experience and technical changes on acute urinary and rectal morbidity in low-dose prostate brachytherapy using loose seeds real-time implantation. AB - PURPOSE: To assess the impact of experience and technical changes on morbidity during the first year after permanent prostate brachytherapy. METHODS AND MATERIALS: From July 2003 to May 2010, 150 patients with prostate cancer underwent low-dose iodine-125 prostate brachytherapy as a monotherapy by the same medical team (one urologist and one radiation oncologist). Patients were divided into three periods: P1 (n = 64), P2 (n = 45), and P3 (n = 41) according to technical changes: use of an automatic stepper from P2, use of a high-frequency ultrasound probe in P3. Urinary toxicity was analyzed according to the incidence of acute urinary retention (AUR), Delta International Prostate Symptom Score (Delta IPSS) defined as IPPS maximal - IPSS at baseline, and proportion of patients with Delta IPSS >=5 and IPSS total >15. The Radiation Therapy Oncology Group classification was used to evaluate the rectal morbidity. RESULTS: The incidence of AUR (6% overall) decreased significantly with time: 12.5% (8/64) during P1, 2.2% (1/45) in P2, and 0% in P3 (p = 0.014). Mean Delta IPSS (11.6) remained stable during the three periods. Patients with Delta IPSS >=5 and IPSS total >15 were 58.7%, 58.1%, and 56.1% for P1, P2, and P3 (p = 0.96), respectively. Grade 1 and 2 proctitis were observed in 15.3% and 9.3% of the patients without any significant difference between the three periods. CONCLUSION: The incidence of AUR decreased significantly with time. This was probably because of the experience of the practitioner and the use of an automatic stepper that allowed reducing prostatic traumatism. Experience and technical changes did not seem to affect rectal morbidity. PMID- 23669151 TI - Patient satisfaction with physician errors in detecting and identifying patient emotion cues. AB - OBJECTIVE: Previous research has examined physicians' ability to respond to or identify the type of emotion cues. Yet in physician-patient interactions, identification and response are preceded by the ability to detect whether an emotion cue has occurred. This research assesses consequences of emotion detection errors for patient satisfaction. METHODS: Participants responding to an online survey read one of six randomly assigned descriptions of a physician patient interaction varying on: whether the patient presented an emotion cue; whether the physician detected an emotion cue; and whether the physician correctly identified the cue. Participants then rated satisfaction with the physician. RESULTS: Satisfaction was highest when the physician correctly detected the patient's emotion cue and lowest when the physician failed to detect the patient's emotion. Failing to detect the emotion cue had lower satisfaction than other emotion processing errors, including falsely detecting an emotion cue that was not there or incorrectly identifying the type of emotion. CONCLUSIONS: Emotion cue detection has implications for patient satisfaction distinct from emotion identification. PRACTICE IMPLICATIONS: Results suggest it may be better for physicians to incorrectly identify than miss an emotion. Training for healthcare providers should consider incorporating emotion detection. PMID- 23669152 TI - Online support group use and psychological health for individuals living with HIV/AIDS. AB - OBJECTIVE: The Internet provides an opportunity for individuals with HIV/AIDS to obtain support and information in a timely and convenient manner. The present study examines the psychological effects of online support group use for individuals living with HIV/AIDS. METHODS: A total of 340 HIV positive online support group users completed an online survey. RESULTS: Results from structural equation modeling showed that individuals with higher levels of online support group participation had higher levels of empowering processes, which in turn, had higher levels of optimism toward life. Optimism was related to lower levels of loneliness and depression while loneliness was also related to higher levels of depression. CONCLUSION: The findings suggest that participants with higher levels of online support group participation had better psychological health than those with lower levels of participation. PRACTICE IMPLICATIONS: Findings suggest that the use of online support groups could be promoted to individuals with HIV/AIDS. Healthcare professionals should work to increase the motivation and confidence patients have in using online support groups. Health education should also be provided to patients with HIV/AIDS so to improve their skills and literacy in using online support groups. PMID- 23669153 TI - Shared decision-making to improve attention-deficit hyperactivity disorder care. AB - OBJECTIVE: To examine the effect of a shared decision-making intervention with parents of children newly diagnosed with attention-deficit/hyperactivity disorder. METHODS: Seven pediatricians participated in a pre/post open trial of decision aids for use before and during the office visit to discuss diagnosis and develop a treatment plan. Encounters pre- (n=21, control group) and post intervention implementation (n=33, intervention group) were compared. We video recorded encounters and surveyed parents. RESULTS: Compared to controls, intervention group parents were more involved in shared decision-making (31.2 vs. 43.8 on OPTION score, p<0.01), more knowledgeable (6.4 vs. 8.1 questions correct, p<0.01), and less conflicted about treatment options (16.2 vs. 10.7 on decisional conflict total score, p=0.06). Visit duration was unchanged (41.0 vs. 41.6min, p=0.75). There were no significant differences in the median number of follow-up visits (0 vs. 1 visits, p=0.08), or the proportion of children with medication titration (62% vs. 76%, p=0.28), or parent-completed behavior rating scale to assess treatment response (24% vs. 39%, p=0.36). CONCLUSIONS: Our intervention increased shared decision-making with parents. Parents were better informed about treatment options without increasing visit duration. PRACTICE IMPLICATIONS: Interventions are available to prepare parents for visits and enable physicians to elicit parent preferences and involvement in decision-making. PMID- 23669154 TI - Cartoon visual: a useful commutation tool between doctors and patients. PMID- 23669155 TI - Dramatic increase in HIV prevalence after scale-up of antiretroviral treatment. AB - OBJECTIVES: To investigate HIV prevalence trends in a rural South African community after the scale-up of antiretroviral treatment (ART) in 2004. METHODS: We estimated adult HIV prevalence (ages 15-49 years) using data from a large, longitudinal, population-based HIV surveillance in rural KwaZulu-Natal, South Africa, over the period from 2004 (the year when the public-sector ART scale-up started) to 2011. We control for selection effects due to surveillance nonparticipation using multiple imputation. We further linked the surveillance data to patient records from the local HIV treatment program to estimate ART coverage. RESULTS: ART coverage of all HIV-infected people in this community increased from 0% in 2004 to 31% in 2011. Over the same observation period adult HIV prevalence increased steadily from 21 to 29%. The change in overall HIV prevalence is nearly completely explained by an increase of HIV-infected people receiving ART, and it is largely driven by increases in HIV prevalence in women and men older than 24 years. CONCLUSION: The observed dramatic increase in adult HIV prevalence can most likely be explained by increased survival of HIV-infected people due to ART. Future studies should decompose HIV prevalence trends into HIV incidence and HIV-specific mortality changes to further improve the causal attribution of prevalence increases to treatment success rather than prevention failure. PMID- 23669157 TI - Lost or just not following up: public health effort to re-engage HIV-infected persons lost to follow-up into HIV medical care. AB - OBJECTIVE: Locate persons living with HIV (PLWH) presumed lost to follow-up (LTFU), and assist them with partner services and linkage to HIV-related care. DESIGN: Locate and facilitate re-engagement in care for PLWH-LTFU in New York City (NYC), with longitudinal follow-up using HIV surveillance registry. SETTINGS: HIV care facilities and communities in NYC. PATIENTS: PLWH, reported in the NYC HIV surveillance registry, who had a NYC care provider and residential address at last report in the registry. Presumed-LTFU was defined as having no CD4+ or viral load during the most recent 9 months during the study period July 2008-December 2010. INTERVENTION: Case-workers conducted public health investigation to locate PLWH presumed-LTFU and offered them assistance with partner and linkage-to-care services. MAIN OUTCOME MEASURES: Results of partner and linkage-to-care services, and reasons for LTFU. RESULTS: From July 2008 to December 2010, 797 PLWH presumed-LTFU were prioritized for investigation; 14% were never located. Of the 689 located, 33% were current to care, 5% had moved or were incarcerated, 2% had died, and 59% (409) were verified to be LTFU. Once located, 77% (315/409) accepted clinic appointments, and 57% (232/409) returned to care. Among the 161 who provided reasons for LTFU, the most commonly reported was 'felt well' (41%). CONCLUSIONS: Health department case-workers helped more than half PLWH-LTFU re-engage in HIV medical care. HIV prevention strategies must include efforts to re-engage PLWH-LTFU in care, for treatment consideration under current treatment guidelines to improve their clinical status and decrease transmission risk. PMID- 23669156 TI - Comparisons of creatinine and cystatin C for detection of kidney disease and prediction of all-cause mortality in HIV-infected women. AB - BACKGROUND: Cystatin C could improve chronic kidney disease (CKD) classification in HIV-infected women relative to serum creatinine. DESIGN: Retrospective cohort analysis. METHODS: Cystatin C and creatinine were measured from specimens taken and stored during the 1999-2000 examination among 908 HIV-infected participants in the Women's Interagency HIV study (WIHS). Mean follow-up was 10.2 years. Predictors of differential glomerular filtration rate (GFR) estimates were evaluated with multivariable linear regression. The associations of baseline categories (<60, 60-90, and >90 ml/min per 1.73 m) of creatinine estimated GFR (eGFRcr), cystatin C eGFR (eGFRcys), and combined creatinine-cystatin C eGFR (eGFRcr-cys) with all-cause mortality were evaluated using multivariable Cox regression. The net reclassification index (NRI) was calculated to evaluate the effect of cystatin C on reclassification of CKD staging. RESULTS: CKD risk factors were associated with lower eGFRcys and eGFRcr-cys values compared with eGFRcr. Relative to eGFR more than 90, the eGFR less than 60 category by eGFRcys (Adjusted hazard ratio: 2.56; 95% confidence interval: 1.63-4.02), eGFRcr-cys (3.11; 1.94-5.00), and eGFRcr (2.34; 1.44-3.79) was associated with increased mortality risk. However, the eGFR 60-90 category was associated with increased mortality risk for eGFRcys (1.80; 1.28-2.53) and eGFRcr-cys (1.91; 1.38-2.66) but not eGFRcr (1.20; 0.85-1.67). The overall NRI for mortality was 26% when reclassifying from eGFRcr to eGFRcys (P < 0.001) and was 20% when reclassifying from eGFRcr to eGFRcr-cys (P < 0.001). CONCLUSION: The addition of cystatin C may improve mortality risk prediction by stages of kidney function relative to creatinine. CKD risk factors are associated with an overestimate of GFR by serum creatinine relative to cystatin C. PMID- 23669159 TI - Systematic review of population-based studies on the impact of images on UV attitudes and behaviours. AB - Visual images have been shown to influence health behaviours. The effectiveness of population interventions, which use visual images to influence skin cancer prevention behaviours, has not been systematically evaluated. We, therefore, undertook a systematic review of peer-reviewed, health education and health promotion research on skin cancer and tanning to examine the outcomes of studies, which used visual images as part of their methodology. Our objective was to describe the impact of visual images on UV protection and exposure attitudes and behaviours across the studies. Twenty-three studies met the inclusion criteria. Images positively impact knowledge, attitudes and behaviours related to UV exposure and UV protection. Images also influence the perceived attractiveness of untanned or tanned skin, which in turn, influences UV exposure attitudes and behaviours. Implications for future health promotion research and practice are discussed. PMID- 23669158 TI - Influence of HIV infection on response to tenofovir in patients with chronic hepatitis B. AB - BACKGROUND: HIV worsens the natural history of chronic hepatitis B virus (HBV) infection. Suppression of HBV replication slows progression of liver damage. Information about the influence of HIV on response to tenofovir in HIV/HBV coinfected patients is scarce. METHODS: All individuals with persistent HBsAg+ at four clinics in Spain were identified. Information from the subset that initiated tenofovir therapy was examined. RESULTS: A total of 176 patients with chronic hepatitis B were evaluated, of whom 138 (78.4%) were coinfected with HIV. Prior lamivudine exposure was extensive in both groups, and nearly half of HBV viremic patients harboured drug resistance mutations. Most patients took tenofovir coformulated along with emtricitabine (Truvada). Of 101 HBV viremic patients at the time of beginning tenofovir (78 with HIV coinfection and 33 with HBV alone), a similar proportion achieved undetectable HBV-DNA at weeks 24, 48 and 96 of tenofovir therapy. Interestingly, HIV/HBV-coinfected patients with positive HBeAg showed a lower response than HBeAg-negatives. In multivariate analysis, however, baseline serum HBV-DNA was the only predictor of virological response to tenofovir. CONCLUSION: The antiviral efficacy of tenofovir is similar in HIV/HBV coinfected and HBV-monoinfected patients, achieving undetectable HBV-DNA nearly 90% of patients at week 96 of therapy. Baseline serum HBV-DNA is the major determinant of time-trends in virological response, with no significant influence of HBeAg, drug resistance mutations nor coinfection with hepatitis C or delta viruses. PMID- 23669160 TI - Will China's Cooperative Medical System fail again? Insight from farmer satisfaction survey. AB - This paper studied the sustainability of China's New Rural Cooperative Medical System (NCMS) by evaluating the satisfaction rate of its participants-the farmers. The study related the overall satisfaction of the farmers to their satisfaction with the four different aspects of the program. It also identified which personal and program attributes affect the farmers' satisfaction rate. Survey data of 1278 households from 66 counties in Shandong Province of China were collected in 2011 using a multi-stage stratified cluster-sampling method. To overcome the nepotistic barriers in rural China, field surveys in each township were conducted by university students from the same place. Data were analyzed using multiple regressions and structural equation modeling method. The results showed that 86% of the farmers were either satisfied or very satisfied with the NCMS and 82% indicated their intention to continue participating in the program. Aside from its financial benefits, both the publicity and reimbursement procedure of the program were found to be significant factors in influencing the satisfaction of the farmers. Majority of the participants held positive opinions toward the NCMS, contradicting the negative assessments made by many previous studies. Given the high proportion of farmers willing to continue with the program, it is likely to be sustainable in the near future. Greater publicity and education efforts should be made to make the farmers better informed about the program, and measures should be taken to improve its reimbursement procedure and the setting of the premium level. PMID- 23669161 TI - Alcohol injection for Morton's neuroma: a five-year follow-up. AB - BACKGROUND: Although many treatment modalities are available for Morton's neuroma (MN), studies looking at the long-term effectiveness of most forms of treatment are scarce. The injection of MN with alcohol has gained popularity over the past 10 years with widespread media coverage. Many surgeons have anecdotally questioned the long-term effectiveness of this treatment. We reviewed a cohort of patients at an average 5-year follow-up to assess the medium-term results of alcohol injection. METHODS: We used the modified Johnson score and visual analogue scales to assess 45 of the original cohort of patients with an average follow-up of 61 months (range, 33-73 months). Any complications from the procedure were also noted. RESULTS: Our results indicated that by 5 years, 16 of 45 patients had undergone surgical treatment and a further 13 patients had return of symptoms. Only 29% (13/45) remained symptom free. The visual analog scale and modified Johnson scores showed statistically significant deterioration in patients' symptoms at 5 years following alcohol injection. CONCLUSION: Injection with alcohol sclerosant for MN has been marketed as a definitive management option comparable to surgical excision. Our investigation illustrated that although short-term results are encouraging, alcohol injection does not offer permanent resolution of symptoms for most patients and can be associated with considerable morbidity. Our investigation provides the only long-term data for alcohol injection treatment of MN. LEVEL OF EVIDENCE: Level II, prospective case series. PMID- 23669162 TI - Characteristics of patients with chronic exertional compartment syndrome. AB - BACKGROUND: Chronic exertional compartment syndrome (CECS) is a condition that causes reversible ischemia and lower extremity pain during exercise. To date there are few large studies examining the characteristics of patients with CECS. This study aimed to present these characteristics by examining the largest published series of patients with a confirmed diagnosis of the disorder. METHODS: An IRB-approved, retrospective review was undertaken of patients with a suspected diagnosis of CECS undergoing pre- and postexercise compartment pressure testing between 2000 and 2012. Patients were evaluated for gender, age, duration of symptoms, pain level, specific compartments involved, compartment pressure measurements, and participation and type of athletics. RESULTS: Two-hundred twenty-six patients (393 legs) underwent compartment pressure testing. A diagnosis of CECS was made in 153 (67.7%) patients and 250 (63.6%) legs with elevated compartment measurements; average age of the patients was 24 years (range, 13-69 years). Female patients accounted for 92 (60.1%) of those with elevated pressures. Anterior and lateral compartment pressures were elevated most frequently, with 200 (42.5%) and 167 (35.5%) compartments, respectively. One hundred forty-one (92.2%) patients reported participation in sports, with running being the most common individual sport and soccer being the most common team sport. Duration of pain prior to diagnosis averaged 28 months. CONCLUSION: Although there is ample literature pertaining to the diagnostic criteria and treatment algorithm of the condition, few papers have described the type of patient most likely to develop CECS. This is the largest study to date to evaluate the type of patient likely to present with chronic exertional compartment syndrome. LEVEL OF EVIDENCE: Level III, retrospective review. PMID- 23669163 TI - Comparison of gait after total ankle arthroplasty and ankle arthrodesis. AB - BACKGROUND: Prior studies reported improved gait after total ankle arthroplasty and better parameters of gait than those reported in earlier studies of patients after ankle arthrodesis. However, there are very limited data prospectively evaluating the effects on gait after ankle arthroplasty compared with ankle arthrodesis. Controversy remains regarding the relative advantages and disadvantages of these 2 treatments and especially the differences in function between them. METHODS: We performed a prospective study involving 28 patients with posttraumatic and primary ankle osteoarthritis and a control group of 14 normal volunteers. We compared gait in 14 patients who had undergone ankle arthrodesis with the gait of 14 patients who had ankle arthroplasty preoperatively and at 1 year postoperatively. Three-dimensional gait analysis was performed with a 12-camera digital-motion capture system. Temporospatial measurements included stride length and cadence. The kinematic parameters that were measured included the sagittal plane range of motion of the ankle and the coronal plane range of motion of the ankle. Double force plates were used to collect kinetic parameters such as ankle coronal and plantar flexion-dorsiflexion moments and sagittal plane ankle power. Center of pressure (CoP) and its progression in gait cycle were calculated. RESULTS: Baseline parameters showed comparability among the treatment and control groups. Temporospatial analysis, using time as the main effect, showed that compared with ankle arthrodesis, patients with total ankle arthroplasty had higher walking velocity attributable to both increases in stride length and cadence as well as more normalized first and second rockers of the gait cycle. Kinematic analysis, using time and intervention as the main effects, showed that patients who had ankle arthroplasty had better sagittal dorsiflexion (P = .001), whereas those undergoing ankle arthrodesis had better coronal plane eversion (P = .01). Neither ankle arthrodesis nor arthroplasty altered the CoP progression during stance phase. Total ankle arthroplasty produced a more symmetrical vertical ground reaction force curve, which was closer to that of the controls than was the curve of the ankle arthrodesis group. CONCLUSIONS: Patients in both the arthrodesis and arthroplasty groups had significant improvements in various parameters of gait when compared with their own preoperative function. Neither group functioned as well as the normal control subjects. Neither group was superior in every parameter of gait at 1 year postoperatively. However, the data suggest that the major parameters of gait after ankle arthrodesis in deformed ankle arthritis are comparable to gait function after total ankle arthroplasty in nondeformed ankle arthritis. LEVEL OF EVIDENCE: Level II, prospective comparative study. PMID- 23669164 TI - Predictors and pregnancy outcomes associated with a newborn birth weight of 4000 g or more in Lusaka, Zambia. AB - OBJECTIVE: To identify predictors and outcomes associated with a birth weight of 4000g or more in Lusaka, Zambia. METHODS: Data from women who delivered between February 2006 and August 2011 were obtained from electronic perinatal records at 25 public sector facilities in Lusaka. Macrosomia was defined as a birth weight of 4000g or more and normal birth weight as 2500-3999g. Maternal and newborn characteristics were analyzed for association with macrosomia. RESULTS: There were 4717 macrosomic and 187 117 normal birth weight newborns. The strongest predictors of macrosomia were high BMI (adjusted odds ratio [AOR], 2.88; 95% confidence interval [CI], 1.95-4.24), prior macrosomic newborn (AOR, 7.60; 95% CI, 6.81-8.49), and history of diabetes (AOR, 3.09; 95% CI, 1.36-6.98). Macrosomic newborns were at increased risk for cesarean delivery (AOR, 1.63; 95% CI, 1.35-1.96), fresh stillbirth (AOR, 2.24; 95% CI, 1.56-3.21), Apgar score of under 7 at 5minutes (AOR, 2.03; 95% CI, 1.33-3.11), and neonatal intensive care admission (AOR, 2.07; 95% CI, 1.32-3.23). CONCLUSION: Screening for macrosomia should be considered for high-risk patients in Sub-Saharan Africa. Institutional delivery at facilities with operating rooms and neonatal intensive care services should be encouraged. PMID- 23669166 TI - Reversible CO2 adsorption by an activated nitrogen doped graphene/polyaniline material. AB - For effective adsorption of carbon dioxide (CO2), we investigate a porous N functionalized graphene adsorbent produced by the chemical activation of a reduced graphene oxide/polyaniline composite. The N-doped graphene composite is microporous with a maximum BET surface area of 1336 m(2) g(-1). It shows a highly reversible maximum CO2 storage capacity of 2.7 mmol g(-1) at 298 K and 1 atm (5.8 mmol g(-1) at 273 K and 1 atm). The N-doped graphene shows good stability during recycling with only an initial decrease of 10% (3-2.7 mmol g(-1)) in adsorption capacity before attaining a cycling equilibrium. The adsorbance capacity is correlated with N content * pore volume or N content * surface area. Given that there is no proper correlation parameter, these factors can be used to increase the CO2 adsorption capacity of N-doped graphene materials for practical utility. The as synthesized material also displays selectivity towards CO2 adsorption compared to H2, N2, Ar or CH4. The as formed material shows that graphene can be uniformly N-doped using the presented synthetic method. PMID- 23669165 TI - Whole-gland ablation of localized prostate cancer with high-intensity focused ultrasound: oncologic outcomes and morbidity in 1002 patients. AB - BACKGROUND: High-intensity focused ultrasound (HIFU) is a nonsurgical therapy for selected patients with localized prostate cancer (PCa). OBJECTIVE: The long-term oncologic and morbidity outcomes of primary HIFU therapy for localized PCa were evaluated in a prospective, single-arm, single-institution cohort study. DESIGN, SETTING, AND PARTICIPANTS: Participants were patients treated with HIFU for localized PCa from 1997 to 2009. Excluded were patients with local recurrence following radiotherapy. A second HIFU session was systematically performed in patients with biopsy-proven local recurrence. INTERVENTION: Whole-gland prostate ablation with transrectal HIFU. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Incontinence was assessed using the Ingelman-Sundberg score, and potency was assessed using the five-item version of the International Index of Erectile Function (IIEF-5) scores. Primary outcomes were survival rates (biochemical-free, cancer-specific, metastasis-free, and overall survival). Secondary outcomes were morbidity rates. Median follow-up was 6.4 yr (range: 0.2-13.9). The Kaplan-Meier method was used to determine survival estimates, and multivariate analysis was used to determine predictive factors of biochemical progression. RESULTS AND LIMITATIONS: A total of 1002 patients were included. The median nadir prostate specific antigen (PSA) was 0.14 ng/ml, with 63% of patients reaching a nadir PSA <=0.3 ng/ml. Sixty percent of patients received one HIFU session, 38% received two sessions, and 2% received three sessions. The 8-yr biochemical-free survival rates (Phoenix definition) were 76%, 63%, and 57% for low-, intermediate-, and high-risk patients, respectively (p < 0.001). At 10 yr, the PCa-specific survival rate and metastasis-free survival rate (MFSR) were 97% and 94%, respectively. Salvage therapies included external-beam radiation therapy (EBRT) (13.8%), EBRT plus androgen-deprivation therapy (ADT) (9.7%), and ADT alone (12.1%). Severe incontinence and bladder outlet obstruction decreased with refinement in the technology, from 6.4% and 34.9% to 3.1% and 5.9%, respectively. Limitations included the fact that the study was a single-arm study without a comparison group, technological improvements, changes in surgical protocol during the study, and the use of ADT to downsize the prostate in 39% of patients. CONCLUSIONS: HIFU is a potentially effective treatment of localized PCa, with a low PCa-specific mortality rate and a high MFSR at 10 yr as well as acceptable morbidity. PMID- 23669167 TI - Characteristics of NO cycle coupling with urea cycle in non-hyperammonemic carriers of ornithine transcarbamylase deficiency. AB - Urea cycle deficient patients with prominent hyperammonemic often exhibit abnormal production of nitric oxide (NO), which reduces vascular tone, along with amino acid abnormalities. However, information related to the metabolic changes in heterozygotes of ornithine transcarbamylase deficiency (OTCD) lacking overt hyperammonemia is quite limited. We examined vascular mediators and amino acids in non-hyperammonemic heterozygotes. Twenty-four heterozygous OTCD adult females without hyperammonemic bouts, defined as non-hyperammonemic carriers, were enrolled. We measured blood amino acids constituting urea cycle and nitric oxide (NO) cycle. Blood concentrations of nitrate/nitrite (NOx) as stable NO metabolites, asymmetric dimethylarginine (ADMA) inhibiting NO synthesis, and endothelin-1 (ET-1) raising vascular tone were also determined. NOx concentrations were significantly lower in non-hyperammonemic carriers (p < 0.01). However, ADMA and ET-1 levels in this group were comparable to those in the age-matched control group. Arginine and citrulline levels were also significantly lower in non-hyperammonemic carriers than in controls (p < 0.01). Of the 24 non-hyperammonemic carriers, 10 often developed headaches. Their daily NOx and arginine levels were significantly lower than those in headache-free carriers (p < 0.05). In three carriers receiving oral l-arginine, blood NOx concentrations were significantly higher. In two of those three, the occurrence of headaches was decreased. These results suggest that NO cycle coupling with the urea cycle is altered substantially even in non-hyperammonemic OTCD carriers, predisposing them to headaches. PMID- 23669168 TI - Acrosin activity is a suitable indicator of boar semen preservation at 17 degrees C when increasing environmental temperature and radiation. AB - The effect of increasing environmental temperature and radiation on the sperm quality and the field fertility of refrigerated seminal doses from AI boars (N = 30) was analyzed throughout four experimental months (from March through June). In each experimental month, analyses of sperm quality were performed at days 0, 1, 3, 5, 7, and 9 of refrigeration of seminal doses; pregnancy rate and litter size were evaluated using double monospermic inseminations of multiparous female animals using seminal doses at Days 1 to 2 and Days 3 to 4 of refrigeration. Sperm quality was assessed from the evaluation of conventional parameters of sperm concentration, sperm motility, sperm morphology, and sperm viability, and capacitation parameters of membrane lipid disorder, intracellular calcium content, and acrosin activity. Results showed that sperm quality of boar seminal doses was negatively affected by increasing temperature and radiation, which resulted in significantly decreased sperm motility and viability, acrosin activity, pregnancy rate, and litter size, and significantly increased intracellular calcium levels in the trials performed in June. In any experimental month, aging of refrigerated doses was associated with the progressive increase of intracellular calcium levels and inactivation of acrosin, that began from Day 5 of storage in the trials performed in March and April, from Day 3 in those of May, and from Day 0 in those of June. Among the sperm parameters analyzed, only acrosin activity exhibited a clearly differentiated pattern in association with increasing temperature and radiation, and a significant correlation with pregnancy rate and litter size. These results highlighted the potential role of acrosin activity as an indicator of boar sperm preservation at 17 degrees C in boars. PMID- 23669169 TI - Serum paraoxonase and arylesterase activity and oxidative status in patients with multiple sclerosis. AB - The aim of this study was to investigate serum paraoxonase and arylesterase activities, and to determine oxidative status via the measurement of total oxidant status (TOS), total antioxidant status (TAS) and the oxidative stress index (OSI) in patients with relapsing-remitting multiple sclerosis (RRMS). Results were compared with data from healthy controls. A total of 60 subjects, including 30 newly diagnosed and untreated patients with RRMS (20 females, 10 males, 18-40 years of age) and 30 healthy controls (20 female, 10 male 20-40 years of age) were enrolled in this study. The oxidative status of the RRMS patients was measured by TOS, TAS and estimation of the OSI was made by a new automated method. Paraoxonase (PON1) and arylesterase activities were measured spectrophotometrically. TAS levels of RRMS patients were significantly lower than that of controls (p < 0.05). TOS levels of RRMS patients were higher than that of controls (p < 0.05). PON1 and arylesterase activities of RRMS patients were lower, but not significantly, than those of controls (p > 0.05). There was no correlation between serum PON1 activity and OSI in patients with RRMS (p > 0.05). Hypercholesterolemia was not observed in multiple sclerosis patients. In conclusion, although the mechanism underlying the significant reduction of TAS levels of multiple sclerosis patients compared with those of controls is unknown, the results imply that endogenous antioxidants may have been exhausted by increased oxidative stress and we believe that additional antioxidant treatment might be beneficial for these patients. PMID- 23669170 TI - Thrombo-embolic cerebral infarction secondary to giant Lambl's excrescence. AB - Lambl's excrescences are common fibrinous strands found at the contact margin of cardiac valves. They are referred to as "giant" when multiple strands form a complex. Embolic stroke secondary to these valvular strands has rarely been described in the literature. We present a patient with recurrent thrombo-embolic cerebral infarction secondary to giant Lambl's excrescence successfully treated with anticoagulation. PMID- 23669171 TI - Prevalence of positive syphilis serology and meningovascular neurosyphilis in patients admitted with stroke and TIA from a culturally diverse population (2005 09). AB - The study aims were to determine the prevalence of positive syphilis serology and meningovascular neurosyphilis (NS) in patients admitted with transient ischaemic attack (TIA) and stroke to a tertiary hospital serving a culturally diverse community. A retrospective cohort analysis was conducted using routinely collected administrative data and medical records to identify patients admitted with TIA, stroke and other conditions, with positive syphilis serology, between 2005 and 2009. Direct medical record review confirmed diagnoses of meningovascular NS. Syphilis serology was requested in 27% (893/3270) of all patients with TIA and stroke (2005-09) of whom 4% (38/893) were positive. Thirty seven patients with positive serology had clinical characteristics consistent with meningovascular NS. Their mean age was 72+/-13 years; 65% were male and 68% had a recorded place of birth in South-East Asia or the Pacific Islands. One of 12 patients with suspected meningovascular NS with cerebrospinal fluid (CSF) analysis had a positive CSF Venereal Disease Research Laboratory (VDRL) test. Three patients (8%) met diagnostic criteria for "definite or probable" meningovascular NS. All three patients with a "definite or probable" meningovascular NS and 15 (44%) of the remainder who had positive serology without confirmation of NS were treated with intravenous or intramuscular penicillin. Lumbar puncture (LP) and penicillin were underutilised in patients with TIA and stroke with positive serology. In conclusion, syphilis testing should be considered part of the diagnostic work-up of TIA and stroke, particularly in ethnically diverse populations. In patients with TIA and stroke with positive syphilis serology, it would seem appropriate to further pursue diagnosis and treatment and in patients unable to undergo LP, empiric treatment for NS should be considered. PMID- 23669172 TI - Clinical characteristics and risk factors of chronic subdural haematoma associated with clipping of unruptured cerebral aneurysms. AB - Chronic subdural haematoma (CSDH) is an uncommon but potentially serious complication of clipping unruptured cerebral aneurysms. We conducted a study to identify the patients who are at risk of developing postoperative CSDH. The data from 713 consecutive patients who underwent clipping of unruptured anterior circulation aneurysms were reviewed, and risk factors correlated with CSDH were identified by multivariate regression analysis of demographic variables. Fifteen patients (2.1%) developed CSDH after the surgery. Advanced age (odds ratio [OR] 1.151, 95% confidence interval [CI] 1.051-1.261) and male gender (OR 3.167, 95% CI 1.028-9.751) were correlated with CSDH. Subsequently, all 713 patients were quadrichotomized on the basis of gender and age, with 70 years as the cut-off value for age. The frequency of CSDH in men <70 years of age was 1.3% and that in men >=70 years of age was 15.1%, with risk of CSDH was significantly higher in the older men (OR 13.39; 95% CI: 3.42-52.44). The frequency of CSDH in women <70 years of age was 0.6% and that in women >=70 years of age was 3.7%. As in men, the risk of CSDH was significantly higher in the older women (OR 6.69, 95% CI 1.10-40.73). The interval between the aneurysm clipping and CSDH development was 0.5-6 months, suggesting that clinical observation should be continued up to 6 months after surgery. Although prognosis for patients with a postoperative CSDH complication is generally favourable, the risk of CSDH should be taken into account when considering elective clipping of unruptured aneurysms in patients >=70 years of age. PMID- 23669173 TI - Intranasal myiasis: a rare complication of transnasal skull base surgery. AB - A 57-year-old woman with a history of atypical intracranial meningioma had undergone multiple craniotomies and endoscopic skull base procedures over several years. She presented most recently with nasal discharge consisting of intranasal larvae. Isolated organisms from the nasal cavity and maxillary sinus were identified as blow fly larvae (Calliphoridae family). The patient was treated with transnasal debridement and antibiotic therapy. The organisms were successfully eradicated and she is free from further signs of infection. Intranasal myiasis is an unusual complication of anterior skull base surgery. PMID- 23669174 TI - Improvement of the penumbra for small radiosurgical fields using flattening filter free low megavoltage beams. AB - BACKGROUND: In stereotactic radiosurgery, sharp beam edges have clear advantages to spare normal tissues. In general, the dose gradient is a limiting factor in minimizing dose to nearby critical structures for clinical cases. Therefore the penumbral width should be diminished. METHODS: A Varian Clinac 2100 linear accelerator equipped with in-house designed radiosurgical collimator was modeled using the EGSnrc/BEAMnrc Monte Carlo code and compared with the measurements. The 0.015 cm(3) PinPoint chamber was used to measure the 6 MV photon beam characteristics and to validate Monte Carlo calculations. Additional to the standard (STD) linac, a flattening filter free (FFF) linac was simulated. Percent depth doses, beam profiles and output factors were calculated for small field sizes with diameter of 5, 10, 20 and 30mm with DOSXYZnrc. The mean energy and photon fluence at the water surface were calculated with BEAMDP for both FFF linac and STD linacs. RESULTS: The penumbra width (80%-20%) was decreased by 0.5, 0.3, 0.2 and 0.2mm for field sizes of 5, 10, 20 and 30mm respectively when removing the FF. The fluence of photons at the surface increased up to 3.6 times and the mean energy decreased by a factor of 0.69 when removing the FF. The penumbra width (80%-20%) decreased by 17% when a 2 MeV monoenergetic electron pencil beam incident on the target is used instead of 6.2 MeV. CONCLUSIONS: It was found that the penumbra of small field sizes is decreased by removing the FF. Likewise using low megavoltage photons reduced the beam penumbra maintaining adequate penetration and skin sparing. PMID- 23669175 TI - CNV resolution does not cause NoGo anteriorisation of the P3: a failure to replicate Simson et al. AB - For 35 years, some researchers have argued that CNV resolution may affect or even produce the increased P3 for NoGo compared to Go trials, and thus that no 'inhibitory' NoGo P3 exists. This is based on the work of Simson et al. (1977b), the scalp topography of potentials in auditory and visual Go/NoGo tasks. Electroencephalography and Clinical Neurophysiology, 43, 864-875, which compared Go and NoGo topography after CNV was subtracted from NoGo trials only. Specifically, the NoGo P3 topography showed the distinctive frontocentral maximum, which is often linked to motor inhibition, when referenced to a pre target baseline. This NoGo topography changed to a more parietal maximum, similar to that on Go trials, when referenced to a pre-cue baseline. Many researchers have cited this study, while failing to use the delayed response design on which Simson et al. based their argument. We attempted to replicate Simson et al.'s experiment with delayed responses and also with immediate responses, as are more often used. As expected, the amplitudes of CNV and P3 to both Go and NoGo trials were increased when immediate compared to delayed responses were required, but we failed to replicate the topographic shift of NoGo P3 with different baselines for both delayed and immediate responses. That is, subtraction of the CNV from NoGo P3 did not change the distinctive frontocentral topography of this component. The results suggest that CNV may affect the amplitude and measurement of the NoGo P3, but that NoGo P3 anteriorisation is not caused by CNV resolution. PMID- 23669176 TI - Cheek metastasis from gallbladder adenocarcinoma. PMID- 23669177 TI - Automatic classification of the interferential tear film lipid layer using colour texture analysis. AB - The tear film lipid layer is heterogeneous among the population. Its classification depends on its thickness and can be done using the interference pattern categories proposed by Guillon. This papers presents an exhaustive study about the characterisation of the interference phenomena as a texture pattern, using different feature extraction methods in different colour spaces. These methods are first analysed individually and then combined to achieve the best results possible. The principal component analysis (PCA) technique has also been tested to reduce the dimensionality of the feature vectors. The proposed methodologies have been tested on a dataset composed of 105 images from healthy subjects, with a classification rate of over 95% in some cases. PMID- 23669178 TI - RDFBuilder: a tool to automatically build RDF-based interfaces for MAGE-OM microarray data sources. AB - This paper presents RDFBuilder, a tool that enables RDF-based access to MAGE-ML compliant microarray databases. We have developed a system that automatically transforms the MAGE-OM model and microarray data stored in the ArrayExpress database into RDF format. Additionally, the system automatically enables a SPARQL endpoint. This allows users to execute SPARQL queries for retrieving microarray data, either from specific experiments or from more than one experiment at a time. Our system optimizes response times by caching and reusing information from previous queries. In this paper, we describe our methods for achieving this transformation. We show that our approach is complementary to other existing initiatives, such as Bio2RDF, for accessing and retrieving data from the ArrayExpress database. PMID- 23669179 TI - A novel neural network approach to cDNA microarray image segmentation. AB - Microarray technology has become a great source of information for biologists to understand the workings of DNA which is one of the most complex codes in nature. Microarray images typically contain several thousands of small spots, each of which represents a different gene in the experiment. One of the key steps in extracting information from a microarray image is the segmentation whose aim is to identify which pixels within an image represent which gene. This task is greatly complicated by noise within the image and a wide degree of variation in the values of the pixels belonging to a typical spot. In the past there have been many methods proposed for the segmentation of microarray image. In this paper, a new method utilizing a series of artificial neural networks, which are based on multi-layer perceptron (MLP) and Kohonen networks, is proposed. The proposed method is applied to a set of real-world cDNA images. Quantitative comparisons between the proposed method and commercial software GenePix((r)) are carried out in terms of the peak signal-to-noise ratio (PSNR). This method is shown to not only deliver results comparable and even superior to existing techniques but also have a faster run time. PMID- 23669180 TI - WITHDRAWN: Neuronal cell-type specific DNA methylation patterns of the Cacna1cgene. AB - The Publisher regrets that this article is an accidental duplication of an articlethat has already been published, http://dx.doi.org/10.1016/j.ijdevneu.2012.11.007. The duplicate article has therefore been withdrawn. PMID- 23669181 TI - Perinatal undernutrition stimulates seeking food reward. AB - Experiments in animals have revealed that perinatal nutritional restriction, which manifests in adulthood, increases food intake and preference for palatable foods. Considering this, we aimed to evaluate the effects of perinatal malnutrition on hedonic control of feeding behavior. In this study, we divided Wistar rats into two groups according to the diet provided to their mothers during pregnancy and lactation: the control group (diet with 17% casein) and low protein group (diet with 8% casein). We assessed the animals' motivational behavior in adulthood by giving them a stimulus of food reward. We also assessed their neuronal activation triggered by the stimulus of palatable food using FOS protein labeling of neurons activated in the caudate putamen, paraventricular, dorsomedial, ventromedial, and lateral hypothalamic nuclei and amygdala. Evaluation of body weight in malnourished animals showed reduction from the 6th day of life until adulthood. Analysis of feeding behavior revealed that these animals were more motivated by food reward, but they had delays during learning of the task. This finding correlated with the number of c-FOS-immunoreactive neurons, which indicated that malnourished animals had an increase in the number of neurons activated in response to the palatable diet, especially in the amygdala and caudate putamen. The study therefore confirmed our hypothesis that early nutritional insults promote changes in encephalic control mechanisms, especially those related to food intake and search for reward. PMID- 23669182 TI - Incidence, predictors, and outcomes of hemodynamic instability following carotid angioplasty and stenting. AB - OBJECTIVE: To explore the incidence, predictors, and outcomes of hemodynamic instability (HI) following carotid angioplasty and stenting (CAS). METHODS: We retrospectively evaluated data on 257 CAS procedures performed in 245 patients from 2002 to 2011 at a single institution. The presence of periprocedural HI, as defined by hypertension (systolic blood pressure >160 mm Hg), hypotension (systolic blood pressure <90 mm Hg), and/or bradycardia (heart rate <60 beats per minute), was recorded. Clinically significant HI (CS-HI) was defined as periprocedural HI lasting greater than 1 hour in total duration. Logistic regression was used to analyze the role of multiple demographic, clinical, and procedural variables. RESULTS: Mean age was 70.9 +/- 9.9 years (67% male). HI occurred following 84% (n = 216) of procedures. The incidence of hypertension, hypotension, and bradycardia was 54%, 31%, and 60%, respectively. Sixty-three percent of cases involved CS-HI. Recent stroke was an independent risk factor for the development of CS-HI (odds ratio, 5.24; confidence interval, 1.28-21.51; P = .02), whereas baseline chronic obstructive pulmonary disease was protective against CS-HI (odds ratio, 0.34; confidence interval, 0.15-0.80; P = .01). Patients with CS-HI were more likely to experience periprocedural stroke compared to other patients (8% vs 1%; P = .03). There were no significant differences in the incidence of mortality or other major complications between those with and without CS-HI. CONCLUSIONS: HI represents a common occurrence following CAS. While the presence of periprocedural HI alone did not portend a worse clinical outcome, CS-HI was associated with increased risk of stroke. Expeditious intervention to prevent and manage CS-HI is of critical importance in order to minimize adverse clinical events following CAS. PMID- 23669184 TI - Patient satisfaction with point-of-care laboratory testing: report of a quality improvement program in an ambulatory practice of an academic medical center. AB - BACKGROUND: Point-of-care laboratory testing (POCT) offers reduced turnaround time and may facilitate medical decision-making and improve clinical operations. However, there is very little published data concerning the impact of POCT on patient satisfaction. METHODS: We implemented POCT for hemoglobin A1c, lipid panel and comprehensive metabolic panel in a primary care practice and monitored patient satisfaction with on-site testing using an anonymous survey. RESULTS: A total of 97 surveys (65% response rate) were reviewed. On a scale of 1 (poor) to 4 (excellent) the mean response to the question "Compared with your past experiences of physician office visits that did not have on-site testing please rank your overall level of satisfaction with today's office visit" was 3.96. In 34 surveys a free text comment was included which was uniformly very positive. CONCLUSIONS: Our study strongly indicates a high level of patient satisfaction with on-site POCT in a primary care setting. PMID- 23669183 TI - Tocopherol supplementation reduces NO production and pulmonary inflammatory response to bleomycin. AB - Bleomycin causes acute lung injury through production of reactive species and initiation of inflammation. Previous work has shown alteration to the production of reactive oxygen species results in attenuation of injury. Vitamin E, in particular, gamma-tocopherol, isoform, has the potential to scavenge reactive oxygen and nitrogen species. This study examines the utility of dietary supplementation with tocopherols in reducing bleomycin-mediated acute lung injury. Male C57BL6/J mice were intratracheally instilled with PBS or 2 units/kg bleomycin. Animals were analyzed 3 and 8 days post instillation at the cellular, tissue, and organ levels. Results showed successful delivery of tocopherols to the lung via dietary supplementation. Also, increases in reactive oxygen and nitrogen species due to bleomycin are normalized in those mice fed tocopherol diet. Injury was not prevented but inflammation progression was altered, in particular macrophage activation and function. Inflammatory scores based on histology demonstrate limited progression of inflammation in those mice treated with bleomycin and fed tocopherol diet compared to control diet. Upregulation of enzymes and cytokines involved in pro-inflammation were limited by tocopherol supplementation. Day 3 functional changes in elastance in response to bleomycin are prevented, however, 8 days post injury the effect of the tocopherol diet is lost. The effect of tocopherol supplementation upon the inflammatory process is demonstrated by a shift in the phenotype of macrophage activation. The effect of these changes on resolution and the progression of pulmonary fibrosis has yet to be elucidated. PMID- 23669185 TI - Metabolomics in noninvasive breast cancer. AB - Breast cancer remains the most leading cause of death among women worldwide. Common methods for diagnosis and surveillance include mammography, histopathology and blood tests. The major drawback of mammography is the high rate of false reports, aside from the risk from repeated exposure to harmful ionizing radiations; histopathology is time consuming and often prone to subjective interpretations; blood-based tests are attractive, but lack the sensitivity and specificity. Obviously, more sensitive biomarkers for early detection and molecular targets for better treating breast cancer are urgently needed. Fortunately, molecular level 'omics' diagnosis is becoming increasingly popular; metabolomics, diagnosis based on 'metabolic fingerprinting' may provide clinically useful biomarkers applied toward identifying metabolic alterations and has introduced new insights into the pathology of breast cancer. By applying advanced analytical and statistical tools, metabolomics involves the comprehensive profiling of the full complement of low molecular weight compounds in a biological system and could classify the basis of tumor biology of breast cancer, to identify new prognostic and predictive markers and discover new targets for future therapeutic interventions. This advanced bioanalytic methods may now open new avenues for diagnostics in cancer via discovery of biomarkers. In this review we take a closer look at the metabolomics used within the field of breast cancer diagnosis. Further, we highlight the most interesting metabolomics publications and discuss these in detail; additional studies are mentioned as a reference for the interested reader. A general trend is an increased focus on biological interpretation rather than merely the ability to classify samples. PMID- 23669187 TI - Paraneoplastic scleroderma-like tissue reactions in the setting of an underlying plasma cell dyscrasia: a report of 10 cases. AB - INTRODUCTION: Systemic plasma cell dyscrasias have diverse manifestations in the skin and include an inflammatory paraneoplastic process. We encountered cases of scleroderma and eosinophilic fasciitis in the setting of an underlying plasma cell dyscrasia. MATERIALS AND METHODS: Ten cases of scleroderma-like tissue reactions in the setting of an underlying plasma cell dyscrasia were encountered. The biopsies were stained for Transforming growth factor (Transforming growth factor) beta, IgG4, kappa, and lambda. RESULTS: Patients presented with a sclerodermoid reaction represented by eosinophilic fasciitis (5 cases), morphea (3 cases), and systemic scleroderma (2 cases). The mean age of presentation was 70 years with a striking female predominance (4:1). Acral accentuation was noted in 8 cases. In 6 of the cases, the cutaneous sclerosis antedated (4 cases) by weeks to 2 years or occurred concurrently (2 cases) with the initial diagnosis of the plasma cell. The biopsies showed changes typical of eosinophilic fasciitis and/or scleroderma. In 5 cases, light chain-restricted plasma cells were present on the biopsy. There was staining of the plasma cells for Transforming growth factor beta in 3 out of 5 cases tested. CONCLUSIONS: In any older patient presenting with a sudden onset of eosinophilic fasciitis or scleroderma especially with acral accentuation, investigations should be conducted in regards to an underlying plasma cell dyscrasia. PMID- 23669186 TI - Gene methylation in gastric cancer. AB - Gastric cancer is one of the most common malignancies and remains the second leading cause of cancer-related death worldwide. Over 70% of new cases and deaths occur in developing countries. In the early years of the molecular biology revolution, cancer research mainly focuses on genetic alterations, including gastric cancer. Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer, including DNA methylation, histone modifications, nucleosome positioning, noncoding RNAs, and microRNAs. Aberrant DNA methylation in the promoter regions of gene, which leads to inactivation of tumor suppressor and other cancer-related genes in cancer cells, is the most well-defined epigenetic hallmark in gastric cancer. The advantages of gene methylation as a target for detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as serum and gastric washes have led to many studies of application in gastric cancer. This review focuses on the most common and important phenomenon of epigenetics, DNA methylation, in gastric cancer and illustrates the impact epigenetics has had on this field. PMID- 23669188 TI - Effect of a warm footbath before bedtime on body temperature and sleep in older adults with good and poor sleep: an experimental crossover trial. AB - BACKGROUND: The decrease in core body temperature before sleep onset and during sleep is associated with dilation of peripheral blood vessels, which permits heat dissipation from the body core to the periphery. A lower core temperature coupled with a higher distal (hands and feet) temperature before sleep are associated with shorter sleep latency and better sleep quality. A warm footbath is thought to facilitate heat dissipation to improve sleep outcomes. OBJECTIVES: This study examined the effect of a warm footbath (40 degrees C water temperature, 20-min duration) on body temperature and sleep in older adults (>=55 years) with good and poor sleep. DESIGN: Two groups and an experimental crossover design was used. SETTING AND PARTICIPANTS: Forty-three adults responded to our flyer and 25 participants aged 59.8+/-3.7 years (poor sleeper with a Pittsburgh Sleep Quality Index score>=5=17; good sleepers with a Pittsburgh Sleep Quality Index score<5=8) completed this study. METHODS: All participants had body temperatures (core, abdomen, and foot) and polysomnography recorded for 3 consecutive nights. The first night was for adaptation and sleep apnea screening. Participants were then randomly assigned to either the structured foot bathing first (second night) and non-bathing second (third night) condition or the non-bathing first (second night) and foot bathing second (third night) condition. RESULTS: A footbath before sleep significantly increased and retained foot temperatures in both good and poor sleepers. The pattern of core temperatures during foot bathing was gradually elevated (poor sleepers vs. good sleepers=+0.40+/-0.58 degrees C vs. +0.66+/-0.17 degrees C). There were no significant changes in polysomnographic sleep and perceived sleep quality between non-bathing and bathing nights for both groups. CONCLUSION: A footbath of 40 degrees C water temperature and 20-min duration before sleep onset increases foot temperatures and distal-proximal skin temperature gradients to facilitate vessel dilatation and elevates core temperature to provide heat load to the body. This footbath does not alter sleep in older adults with good and poor sleep. PMID- 23669189 TI - Pseudoperoxidase investigations of hydroperoxides and inhibitors with human lipoxygenases. AB - Understanding the mode of action for lipoxygenase (LOX) inhibitors is critical to determining their efficacy in the cell. The pseudoperoxidase assay is an important tool for establishing if a LOX inhibitor is reductive in nature, however, there have been difficulties identifying the proper conditions for each of the many human LOX isozymes. In the current paper, both the 234 nM decomposition (UV) and iron-xylenol orange (XO) assays are shown to be effective methods of detecting pseudoperoxidase activity for 5-LOX, 12-LOX, 15-LOX-1 and 15 LOX-2, but only if 13-(S)-HPODE is used as the hydroperoxide substrate. The AA products, 12-(S)-HPETE and 15-(S)-HPETE, are not consistent hydroperoxide substrates since they undergo a competing transformation to the di-HETE products. Utilizing the above conditions, the selective 12-LOX and 15-LOX-1 inhibitors, probes for diabetes, stroke and asthma, are characterized for their inhibitory nature. Interestingly, ascorbic acid also supports the pseudoperoxidase assay, suggesting that it may have a role in maintaining the inactive ferrous form of LOX in the cell. In addition, it is observed that nordihydroguaiaretic acid (NDGA), a known reductive LOX inhibitor, appears to generate radical species during the pseudoperoxidase assay, which are potent inhibitors against the human LOX isozymes, producing a negative pseudoperoxidase result. Therefore, inhibitors that do not support the pseudoperoxidase assay with the human LOX isozymes, should also be investigated for rapid inactivation, to clarify the negative pseudoperoxidase result. PMID- 23669190 TI - Cyclopropane-ring formation in the acyl groups of chlorosome glycolipids is crucial for acid resistance of green bacterial antenna systems. AB - Green photosynthetic bacteria have unique light-harvesting antenna systems called chlorosomes. Chlorobaculum tepidum, a model organism of the bacteria, biosynthesized monogalactosyl- and rhamnosylgalactosyldiacylglycerides possessing a methylene-bridged palmitoleyl group characterized by a cis-substituted cyclopropane ring as the dominant glycolipids of its chlorosome surface. The formation of the cyclopropane ring was chemically inhibited by supplementation of sinefungin, an analog of S-adenosyl-L-methionine, into the bacterial cultivation. The presence of the cyclopropane ring reinforced acid resistance of the light harvesting chlorosomes and suppressed acidic demetalation (pheophytinization) of bacteriochlorophyll-c pigments constructing the core part of chlorosomes. The ring-formation would represent direct and post-synthetic modifications of chlorosome membrane properties and was tolerant of acidic environments. PMID- 23669191 TI - Structure-activity relationships for ferriprotoporphyrin IX association and beta hematin inhibition by 4-aminoquinolines using experimental and ab initio methods. AB - In order to probe structure-activity relationships of association with ferriprotoporphyrin IX (logK) and inhibition of beta-hematin formation, a series of 4-aminoquinolines with varying substituents at the 7-position (X) have been synthesized. These have been further elaborated by introduction of two different R groups on the 4-amino nitrogen atom in the form of methyl (R=Me) and ethylamine (R=EtNH2) side chains. Data for a previously investigated series containing an N,N-diethyl-ethylamine side chain were also compared with the findings of this study. Experimentally, logK values for the simple 4-aminoquinoline series (R=H) were found to correlate with the hydrophobicity constant (pi) of the group X. The logK values for the series with R=Me and EtNH2 were found to correlate with those of the series with R=H. The log of the 50% beta-hematin inhibitory activity (logBHIA50) was found to correlate with logK and either meta (sigmam) or para (sigmap) Hammett constants for the series with R=Me and EtNH2, but not the simple series with R=H. To further improve predictability, correlations with ab initio electrostatic parameters, namely Mulliken and CHelpG charges were investigated. The best correlations were found with CHelpG charges which indicated that logK values can be predicted from the charges on atom H-8 and the group X in the quinolinium species computed in vacuum, while logBHIA50 values can be predicted from the CHelpG charges on C-7, C-8 and N-1 for the neutral species in vacuum. These correlations indicate that association and inhibition of beta-hematin formation are separately determined. They also suggest that electron withdrawing groups at the 7-position, but not necessarily hydrophobic groups are required for hemozoin inhibition. The upshot is that the correlations imply that considerably more hydrophilic hemozoin inhibitors are feasible. PMID- 23669192 TI - Evaluation of intrinsic spectroscopic properties of chromophore assemblies by shielding with cyclohexyl base pairs within a DNA duplex. AB - Here, we investigated spectroscopic behaviors of tetramethylrhodamine (TMR) homo- and hetero-dimers within DNA duplex. In order to shield the chromophores from natural base pairs, we used cyclohexyl base pairs as 'insulators'; these pairs were inserted between the chromophores and nucleobases. When a single TMR moiety was sandwiched between cyclohexyl base pairs, the emission intensity increased by fivefold relative to a TMR between natural base pairs, because electron transfer from nucleobases was suppressed. Next, we inserted two TMRs between the cyclohexyl base pairs and found that they facilitated H-dimer formation of TMR; a distinct hypsochromic shift was induced only when cyclohexyl base pairs were inserted. We further examined quenching behavior of a TMR paired with a quencher dye between cyclohexyl base pairs. Interestingly, fluorescence from TMR was quenched by nitro methyl red more efficiently in the presence of cyclohexyl base pairs than in their absence. This suggests that neighboring natural base pairs disturbed electron or hole transfer between the fluorophore and the quencher. The cyclohexyl base pairs shielded the chromophore pair from the natural base pairs and allowed intrinsic electron transfer. PMID- 23669193 TI - Effect of organometallic clamp properties on the apparent diversity of tensile response of nanowires. AB - The influence of the experimental boundary conditions used for tensile testing of individual nanowires on the measured apparent mechanical response is reported. Using a microelectromechanical platform designed for in situ tensile testing, in combination with digital image correlation of sequences of scanning electron microscope images, the mechanical behavior of single crystalline Si, Pd, and Ge2Sb2Te5 nanowires was measured during load-unload cycles. In situ testing enables direct determination of the nanowire strain. Comparison of the direct strain with common metrics for apparent strain that include any compliance or slipping of the clamping materials (electron-beam induced Pt-containing deposits) highlights several different artifacts that may be manifested. Calculation of the contact stiffness is thus enabled, providing guidelines for both proper strain measurement and selection of clamping materials and geometries that facilitate elucidation of intrinsic material response. Our results suggest that the limited ability to tailor the stiffness of electron-beam induced deposits results from the predominance of the organic matrix in controlling its mechanical properties owing to relatively low Pt content and sparse morphology. PMID- 23669194 TI - Hyper-activation of foldase-dependent lipase with lipase-specific foldase. AB - The LST-03 lipase from Pseudomonas aeruginosa LST-03 requires lipase-specific foldase for activation. Abundant expression of the active lipase was successfully accomplished with individual expression of the lipase and foldase in a heterologous host and subsequent in vitro activation. Although the activity of the native lipase from culture supernatant of P. aeruginosa LST-03 was 110 kI.U./g, that after in vitro activation using individually expressed lipase and foldase was 228 kI.U./g. Furthermore, the activity after in vitro activation with afterwards adding calcium ions was 359 kI.U./g. However, the incubation of the lipase with the foldase in the presence of calcium ions resulted in a small conformational transition and low activation levels of the lipase by the foldase. The lipase showed high affinity for the foldase in the presence of calcium ions. The results indicate that in a cellular environment that contains calcium ions, the lipase would not become a hyperactive form by the foldase. PMID- 23669195 TI - Revision surgery for diabetic foot infections: giving another chance to the patient. AB - Revision surgery (RS) is frequently needed to control diabetic foot infections. It is the aim of this retrospective observational study to analyze the variables associated with undergoing RS and the variables associated with undergoing a major amputation when RS was required. We conducted a retrospective study of patients with diabetes treated in our department during 10 years (January 1, 2000 to January 1, 2010) who had foot infections identifying those who required RS. In all, 167 out of 417 patients (40%) with diabetes who underwent surgery for foot infections underwent RS for persistent infection. The predictive variables related to undergoing revision surgery were erythrocyte sedimentation rate >70 mm/h (odds ratio [OR] = 1.6, 95% confidence interval [CI] = 1.1-2.6), leukocytosis (OR = 1.6, 95% CI = 1.1-2.5), peripheral arterial disease (OR = 1.5, 95% CI = 1.0-2.4), and isolation of gram-negative rods from tissue biopsy (OR = 2.2, 95% CI = 1.5-3.4). Seventy-nine out of 167 patients (47.3) who underwent RS required a higher level of surgery achieving a limb salvage rate of 70.7%. Predictive variables related to undergoing a major amputation after RS were persistent infection located in the bone (OR = 0.08, 95% CI = 0.03-0.22), ischemic heart disease (OR = 3.4, 95% CI = 1.4-8.5), 2 or more reoperations (OR = 3.0, 95% CI = 1.2-7.1), isolation of gram-negative rods from tissue biopsy (OR = 3.3, 95% CI = 1.3-8.4), and peripheral arterial disease (OR = 6.5, 95% CI = 1.9 22.8). Despite the fact that 40% of patients underwent reoperations for diabetic foot infections and 47.3% of them required a higher level of surgery, a high rate of limb salvage could be achieved. PMID- 23669196 TI - The effectiveness of post-contact defenses in a prey with no pre-contact detection. AB - Most empirical and theoretical papers on prey-predator interactions are for animals with long-range detection, animals that can detect and react to predators long before these touch the prey. Heavy-bodied and chemically defended harvestmen (Arachnida, Opiliones) are an exception to this general pattern and rely on contact to detect arthropod predators. We examined the interactions between the Brazilian wandering spider Ctenus ornatus with harvestmen (Mischonyx cuspidatus) or control prey (Gryllus sp. and M. cuspidatus immature, both with soft integuments). Considering a prey-predator system in which fleeing from or reacting to a predator at a distance is not possible, we predicted both a high survival value of near-range defense mechanisms and that mortality would be higher in the absence of such defense mechanisms. We also expected the predator to behave differently when interacting with harvestmen or with a control prey without such defense mechanisms. Our results from laboratory experiments partially matched our predictions: First of all, histological sections showed that the integument of adult harvestmen is thicker than that of immature harvestmen and that of crickets. Adult harvestmen were less preyed upon than the control prey; the heavy armature increases the survival rate but the secretions from the scent glands do not. The predator did behave differently when attacking harvestmen compared to crickets. Despite the large size difference between predator and harvestmen, the protection provided by the armature allowed some of the harvestmen to survive encounters without pre-contact detection, thus greatly reducing the reliance on long-range detection to survive encounters with predators. Harvestmen call for theoretical and empirical work on prey-predator interactions that take into account the possibility that prey may not detect the predator before contact is established. PMID- 23669197 TI - Self-adhesive restoratives as pit and fissure sealants: a comparative laboratory study. AB - OBJECTIVES: To evaluate the properties of self-adhesive restorative materials used as sealants in comparison with sealants with hydrophobic or hydrophilic monomers. METHODS: The self-adhesive materials tested were Fusio (FS) and Vertise Flow (VF) and the sealants Embrace Wetbond (EM/hydrophilic) and Helioseal-F (HS/hydrophobic). The properties tested were: (a) degree of cure (%DC, n: 5, ATR FTIR), (b) extent of oxygen inhibition (n: 5, transmission optical microscopy), (c) flow (n: 5, ASTM D-4242 method), (d) hardness (VH0.2kp/10s dry/1w in water), (e) adaptation, microleakage and fissure penetration (n: 10, 1% fuschin dye, reflection optical microscopy and ESEM). Statistical analysis was performed by one-way ANOVA plus Tukey test (a-d), Fisher's exact and Kruskal-Wallis plus Tukey tests (e) at a 95% confidence level. RESULTS: VF showed the highest %DC(76.1) followed by HS(68.7) and EM(61.3), FS(59.2). HS demonstrated the highest extent of oxygen inhibition (23MUm vs. 13-10MUm of the rest). EM and HS exhibited the greatest flow, followed by FS and VM. The VHN(0.2kp/10s) ranking before and after 1week water exposure was FS>=VF>EM>=HS. Water storage increased VF and reduced HS values. The lowest adaptation and microleakage scores were found in HS. FS and VF after alumina sandblasting showed the worst adaptation and leakage scores, that were improved after acid-etching. Improved fissure penetration was found in HS, EM and FS, VF after acid-etching. SIGNIFICANCE: Although the self-adhesive materials presented improved setting characteristics, their low flow affected fissure penetration capacity. When combined with enamel acid-etching, adaptation and microleakage scoring were substantially improved in comparison with enamel sandblasting. The sealant with the hydrophobic monomers demonstrated the best sealing characteristics. PMID- 23669198 TI - Osteoblast and bone tissue response to surface modified zirconia and titanium implant materials. AB - OBJECTIVE: This study examined the in vitro and in vivo response of osteoblasts to a novel, acid-etched and sandblasted zirconia surface. METHODS: Osteoblastic hFOB 1.19 cells were cultured either on electrochemically anodized titanium (TiUnite((r))), machined titanium (Ti-m), sandblasted and acid-etched zirconia (TZP-proc), and machined zirconia (TZP-A-m). The surface topography of the various substrates was analyzed by 3D laserscan measurements and scanning electron microscopy. At culture days 1, 3, 7, 14, 21, and 28, cell proliferation was determined. Gene expression was analyzed using RT-PCR. Histologic analysis and biomechanical testing was performed on miniature implants placed in the rat femur. RESULTS: During the first 7 days, a retarded cell proliferation was observed on the TiUnite((r)) surface. After 28 days of cultivation, cell proliferation reached similar levels on all surfaces. An up-regulation of bone and extracellular matrix specific genes could be seen for TZP-proc at day 21. The mean bone-implant contact rate after a healing period of 14 and 28 days, respectively, was higher for TiUnite((r)) than for TZP-proc. At 28 day, the biomechanical test showed significantly higher values for TiUnite((r)) than for all other surfaces. SIGNIFICANCE: The novel, rough zirconia surface was accepted by hFOB 1.19 cells and integrates into rat bone tissue. However, osseointegration seemed to proceed more slowly and to a lesser extent compared to a moderately roughened titanium surface. PMID- 23669199 TI - Preoperative predictors of microvascular invasion in multinodular hepatocellular carcinoma. AB - BACKGROUND: The preoperative predictors of microvascular invasion (MVI) in multinodular hepatocellular carcinoma (HCC) are currently unclear. METHODS: We retrospectively analyzed 266 patients who underwent potentially curative resection of multinodular HCC. MVI was diagnosed on pathological examination in 64 patients. Preoperative risk factors for MVI were identified and survival curves were analyzed. RESULTS: Patients with MVI had significantly lower overall and recurrence-free survival rates than those without MVI (overall survival, 1 year: 86% vs. 71%, 3 years: 58% vs. 16%; recurrence-free survival, 1 year: 69% vs. 12%; 3 years: 48% vs. 12%; both P < 0.001). Multivariate analysis showed that serum alpha-fetoprotein (AFP) level >400 MUg/L (odds ratio [OR] = 3.732, P = 0.016), serum gamma-glutamyltransferase (GGT) level >130 U/L (OR = 19.779, P < 0.001), total tumor diameter >8 cm (OR = 5.545, P = 0.010), and tumor number >3 (OR = 11.566, P = 0.007) were independent predictors of MVI. A scoring system was constructed, and the MVI rate was significantly higher in patients with a score of >=3 than those with a score of <3 (64.1% vs. 10.9%, P < 0.001). Overall and recurrence-free survival rates were significantly lower in patients with a score of >=3 (both P < 0.001). CONCLUSIONS: Serum AFP level >400 MUg/L, serum GGT level >130 U/L, total tumor diameter >8 cm, and tumor number >3 were preoperative predictors of MVI in patients with multinodular HCC. In patients with a high risk of MVI and well-preserved liver function, anatomic resection may be worth considering. PMID- 23669200 TI - Anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer (NSCLC): results of a multi-centre ALK-testing. AB - BACKGROUND: The reliable identification of non-small cell lung cancers (NSCLC) with chromosomal breaks in the gene of the anaplastic lymphoma kinase (ALK) is crucial for the induction of therapy with ALK-inhibitors. In order to ensure a reliable detection of ALK-breaks by means of fluorescence in situ hybridization (FISH) testing, round robin tests are essential. In preparation of a nation (German)-wide round robin test we initiated a pre-testing phase involving 8 experts in FISH-diagnostics to identify NSCLC cases (n = 10) with a pre-tested ALK-status. In addition, ALK immunohistochemistry (IHC) was performed to assess ALK protein expression. MATERIAL AND METHODS: Sections derived from a tissue microarray, each consisting of 3 cores from 10 NSCLC cases, were independently tested for ALK protein expression by IHC and genomic ALK-breaks by FISH involving 8 institutes of pathology. Based on a pre-screening, 5 cases were identified to be clearly ALK-break negative, whereas the remaining 5 cases were ALK-break positive including one case with low percentage (20%) of positive cells. The latter had been additionally tested by RT-PCR. RESULTS: The 5 unequivocal ALK break negative NSCLC were almost consistently scored negative by means of FISH and IHC by all 8 experts. Interestingly, 4 of the 5 cases with pre-defined ALK breaks revealed homogenous FISH results whereas IHC for the detection of ALK protein expression showed heterogeneous results. The remaining case (low number of ALK-break positive cells) was scored negative by 3 experts and positive by the other 5. RT-PCR revealed the expression of an EML4-ALK fusion gene variant 1. CONCLUSION: ALK-break negative NSCLC cases revealed concordant homogeneous results by means of FISH and IHC (score 0-1) by all 8 experts. Discordant FISH results were raised in one ALK-break positive case with a low number of affected tumor cells. The remaining 4 ALK-break positive cases revealed concordant FISH data whereas the ALK-IHC revealed very diverse results. The cases with concordant FISH results provide an excellent basis for round robin ALK-FISH testing. As long as standardized ALK-IHC protocols are missing, ALK protein expression cannot by regarded as the method of choice for identification of patients eligible for treatment with ALK inhibitors. PMID- 23669201 TI - Maxillary desmoplastic fibroma with initial symptoms suggestive of sinusitis. AB - Desmoplastic fibroma (DF) is a benign intra-osseous neoplasm characterized by the formation of abundant collagen fibers. It arises most commonly in the jaws and exhibits local aggressiveness and high recurrence rates after local resection. An uncommon case of expansive DF involving the right maxilla, maxillary sinus, and inferior orbital wall of a 49-year-old man whose initial symptoms were similar to acute sinusitis is presented, and the criteria for diagnosis and clinical management are discussed. PMID- 23669202 TI - Peripheral-type ameloblastic fibrodentinoma with features of so-called "immature dentinoma". AB - We report herein a rare case of peripheral-type ameloblastic fibrodentinoma (PAFD) with features of so-called "immature dentinoma" in the gingiva. The patient was a 51-year-old woman, who presented to our hospital complaining of mild swelling in the left upper buccal gingiva. Periapical radiography of the area did not reveal obvious bone resorption and the provisional clinical diagnosis was a benign tumor. The entire mass was excised under general anesthesia, and the pathological diagnosis was PAFD according to the classification by World Health Organization. More precisely, the detail of the histological examination revealed that our case was compatible with unusual type of ameloblastic fibrodentinoma, so-called "immature dentinoma". The postoperative course was satisfactory and the excised area has remained free of recurrence for 5 years. PMID- 23669203 TI - Keratocyst of the buccal mucosa: case report and immunohistochemical comparative study with sporadic intraosseous keratocystic odontogenic tumor. AB - OBJECTIVES: Describe a new case of keratocyst of the buccal mucosa and compare its immunohistochemical features with 13 sporadic intraosseous keratocystic odontogenic tumors (KOT). CASE REPORT AND STUDY DESIGN: A male complaining about an enlargement on the left buccal mucosa was referred to the Stomatology Clinic. Clinical examination revealed a solitary nodule posterior to the parotid papilla. An excisional biopsy was performed following clinical diagnosis of epidermoid cyst. Microscopically, the lesion was characterized by a lining of five cell layers, with columnar basal cells and a corrugated parakeratinized surface. Immunohistochemical reactions for PTCH-1, Smo, Shh, mTOR, bcl-2, Ck17, and Ck19 were performed. PTCH-1 was not expressed in the keratocyst of the buccal mucosa, but was observed in suprabasal layers of eight (61.5%) cases of sporadic intraosseous KOT. Shh, mTOR, bcl-2, Ck17, and Ck19 expression was observed in all the cases investigated. CONCLUSIONS: The morphology and immunoprofile of this lesion are similar to sporadic intraosseous KOT. PMID- 23669204 TI - Hypereosinophilic syndrome - lymphocytic variant transforming into peripheral T cell lymphoma with severe oral manifestations. AB - Hypereosinophilic syndrome (HES) is a rare disease defined by organ damage directly attributable to hypereosinophilia of any type. Here, we report for the first time the case of a patient with a lymphocytic type of HES (HES-L) who had liver, skin, spleen, lung, bone marrow, digestive track, and mouth involvement. Associated T-cells displayed an aberrant CD30+ phenotype and were monoclonal. Thymus activated and regulated chemokine serum level was positive. Despite steroids (Cortancyl 20 mg [Sanofi Aventis, France], imatinib mesylate [Glivec 400 mg; Novartis Europharm], interferon alpha 2A [Roferon-A 3 MUI/0.5 ml; Roche]) and other lines of therapy including imatinib mesylate treatment, an oral necrotic lesion developed, and finally progressed into a peripheral CD30+ T-cell lymphoma. CHOP chemotherapy (cyclophosphamide, hydroxydoxorubicin, oncovin, prednisone), interferon-alpha, and mepolizumab were ineffective. Although progression into peripheral T-cell lymphoma is documented as a rare complication of HES-L, severe oral extension of HES-L is described for the first time. PMID- 23669205 TI - Metabolic characterization of cell systems used in in vitro toxicology testing: lung cell system BEAS-2B as a working example. AB - The bioactivation of pro-toxicants is the biological process through which some chemicals are metabolized into reactive metabolites. Therefore, in vitro toxicological evaluation should ideally be conducted in cell systems retaining adequate metabolic competency and relevant to the route of exposure. The respiratory tract is the primary route of exposure to inhaled pro-toxicants and lung-derived BEAS-2B cell line has been considered as a potentially suitable model for in vitro toxicology testing. However, its metabolic activity has not been characterized. We performed a gene expression analysis for 41 metabolism related genes and compared the profile with liver- and lung-derived cell lines (HepaRG, HepG2 and A549). To confirm that mRNA expression was associated with the corresponding enzyme activity, we used a series of metabolic substrates of CYPs (CYP1A1/1B1, CYP1A2, CYP2A6/2A13 and CYP2E1) known to bioactivate inhaled pro toxicants. CYP activities were compared between BEAS-2B, HepaRG, HepG2, and A549 cells and published literature on primary bronchial epithelium cells (HBEC). We found that in contrast to HBEC, BEAS-2B and A549 have limited CYP activity which was in agreement with their CYP gene expression profile. Control cell lines such as HepG2 and HepaRG were metabolically active for the tested CYPs. We recommend that similar strategies can be used to select suitable cell systems in the context of pro-toxicant assessment. PMID- 23669206 TI - Assessing sleep in adolescents through a better understanding of sleep physiology. AB - OVERVIEW: Adolescents need about nine hours of sleep per night, yet most teens get far less. Inadequate sleep has consequences not only for academic performance but also for mental and physical health; it has been linked to lowered resilience and an increased risk of cardiovascular and metabolic diseases. It's imperative that assessment of sleep become a routine part of adolescent health care. An understanding of sleep physiology is essential to helping nurses better assess and manage sleep deprivation in this population. Sleep assessment involves evaluating the three main aspects of sleep: amount, quality, and architecture. The authors provide an overview of sleep physiology, describe sleep changes that occur during adolescence, and discuss the influence of these changes on adolescent health. They also provide simple questions that nurses can use to assess sleep and risk factors for disrupted sleep, and discuss patient education and other interventions. PMID- 23669207 TI - Using evidence-based practice to reduce catheter-associated urinary tract infections. AB - OVERVIEW: In November 2009, AJN launched a 12-part series, Evidence-Based Practice, Step by Step, authored by nursing leaders from the Arizona State University College of Nursing and Health Innovation's Center for the Advancement of Evidence-Based Practice. Through hypothetical scenarios, based on the authors' collective clinical experience, the series illustrated the seven steps of evidence-based practice (EBP), defined as "a problem-solving approach to the delivery of health care that integrates the best evidence from studies and patient care data with clinician expertise and patient preferences and values." This article reports on an EBP project in which the seven-step approach to EBP described in the AJN series was used to reduce the incidence of catheter associated urinary tract infection among adult patients in a long-term acute care hospital by reducing the duration of catheterization. PMID- 23669208 TI - Reply: To PMID 23333660. PMID- 23669209 TI - [The risk of radiation in the intensive care unit]. PMID- 23669210 TI - Unilateral nephrectomy causes an early abrupt decrease in plasma arginine and simultaneous reduction in glomerular filtration rate in living kidney donors. AB - OBJECTIVES: Living donor kidney transplantation is regarded as beneficial to allograft recipients and not particularly detrimental to the donors. Recently we have documented a reduced glomerular filtration rate (GFR) in living kidney donors (LKDs). Considering kidneys as essential for l-arginine (Arg) metabolism, in the present study we analyzed plasma Arg and related compounds comparing them with the function of remaining kidney in LKDs after donation. DESIGN AND METHODS: We analyzed GFR, plasma Arg, asymmetric dimethylarginine (ADMA), citrulline (Cit), glutamine (Gln), ornithine (Orn), phenylalanine (Phe), tyrosine (Tyr), thiobarbituric acid reactive substances (TBARS), urea, creatinine, nitrite, nitrate and their sum (NOx) in blood samples taken from LKDs before, immediately after (0-time) and 1, 2, 3, 7 and 14 days following surgery. RESULTS: Gradual and moderate creatinine increase and albumin decrease were associated with decreased GFR. An abrupt decrease in Arg occurred, staying below baseline level throughout the 14 days. Also decreases in Gln, Cit, Orn, increase in Phe and TBARS, and unaltered ADMA, nitrite and NOx concentrations were obtained. Despite increased net protein catabolism (indicated by elevated Phe/Tyr ratios) lack of Arg, suggested by decreased molar Arg/Phe ratios, occurred. Decreased molar Arg/Gln suggests an early but transient decrease in Arg synthesis. CONCLUSION: Unilateral nephrectomy causes an early abrupt decrease in plasma arginine and reduction in glomerular filtration rate in LKDs that was associated with increased net protein breakdown in the peripheral tissues and elevated oxidative damage, which has to be considered in their therapy. PMID- 23669211 TI - Morphology and ultrastructure of antennal sensilla of Macrocentrus cingulum Brischke (Hymenoptera: Braconidae) and their probable functions. AB - Macrocentrus cingulum Brischke (Hymenoptera: Braconidae) is a polyembryonic endoparasitoid of the Asian corn borer, Ostrinia furnacalis and the European corn borer, Ostrinia nubilalis. To better understand the host location mechanism, we examined the external morphology and ultrastructure of the antennal sensilla of this parasitoid by using scanning and transmission electron microscopy. Antennae of male and female of the M. cingulum are filiform in shape, 5.90-6.64mm in length and consist of scape, pedicel, and flagellum with 39 and 40 flagellomeres, respectively. Cuticular pore and nine types of morphologically distinct sensilla were identified in both sexes, including two types of sensilla chaetica (nonporous), s. trichodea (nonporous), s. basiconica I (nonporous blunt tip), s. basiconica II (porous wall) and basiconica III (nonporous wall) with branched blunt tip, s. coeloconica with finger-like projections, protruded s. campaniform with central tip pore, and plate-like s. placodea (porous). We compared number, morphology, and distribution of sensilla between sexes. S. campaniform and non porous basiconica type I may play a role in gustatory functions whereas type II, and s. placodea may play a function in detecting odor stimuli due to their pores wall. The sensilla chaetica and s. trichodea may be involved in mechnosensation. S. coeloconica probably plays a role as thermo-hygro receptor, whilst cuticular pores may detect odor stimuli. No differences in antenna shape and basic structure in the males and females, but male antennae length and width were significantly greater than those of females. Furthermore, males had more placodea than females. The sensilla types, morphology, and structure of both sexes were compared to those found in other parasitic hymenoptera, especially braconid wasps. PMID- 23669212 TI - mTOR-independent autophagy counteracts apoptosis in herpes simplex virus type 1 infected U251 glioma cells. AB - We investigated the role of autophagy, a stress-inducible lysosomal self digestion of cellular components, in modulation of herpes simplex virus type 1 (HSV-1)-triggered death of U251 human glioma cells. HSV-1 caused apoptotic death in U251 cells, characterized by phosphatidylserine externalization, caspase activation and DNA fragmentation. HSV-1-induced apoptosis was associated with the induction of autophagic response, as confirmed by the conversion of cytosolic LC3 I to autophagosome-associated LC3-II, increase in intracellular acidification, presence of autophagic vesicles, and increase in proteolysis of the selective autophagic target p62. HSV-1-triggered autophagy was not associated with the significant increase in the expression of proautophagic protein beclin-1 or downregulation of the major autophagy suppressor mammalian target of rapamycin (mTOR). Moreover, the phosphorylation of mTOR and its direct substrate p70 S6 kinase was augmented by HSV-1 infection, while the mTOR stimulator Akt and inhibitor AMPK-activated protein kinase (AMPK) were accordingly activated and suppressed, respectively. An shRNA-mediated knockdown of the autophagy-essential LC3beta, as well as pharmacological inhibition of autophagy with bafilomycin A1 or 3-methyladenine, markedly accelerated apoptotic changes and ensuing cell death in HSV-1-infected glioma cells. These data indicate that AMPK/Akt/mTOR independent autophagy could prolong survival of HSV-1-infected U251 glioma cells by counteracting the coinciding apoptotic response. PMID- 23669213 TI - Third-hand smoke as a potential intervention message for promoting smoke-free homes in low-income communities. AB - Third-hand smoke (THS) is the residual tobacco smoke contaminant that remains after a cigarette is extinguished. It can react with the indoor air pollutant nitrous acid to produce a carcinogen. Understanding perceptions of THS is critical, as it may inform the development of messages for promoting smoke-free homes. Six focus groups, of smokers and non-smokers, with 39 participants were conducted. Participants were asked whether they knew about THS and its harmful effects and whether it would motivate people to make their homes smoke free. They also answered questions about THS beliefs. Participants were mostly African American, female and high-school graduate or General Educational Development (GED) recipients. Most of the participants had not heard about it and did not know what THS was. When asked about the dangers of THS, some participants made references to children indicating that they can easily inhale or ingest the residue leading to harmful effects. Almost all of the participants stated that they thought being educated about THS would motivate people to make their homes smoke free. There is a need for more scientific understanding of the potential dangers of THS and subsequent education about its exposure and harm to children and possibly adults. PMID- 23669214 TI - Description of an efficacious behavioral peer-driven intervention to reduce racial/ethnic disparities in AIDS clinical trials. AB - AIDS clinical trials (ACTs) are critical to the development of new treatments for HIV infection. However, people of color living with HIV/AIDS are involved in ACTs at disproportionally low rates, with African-Americans experiencing the greatest under-representation. In this article, we describe the core elements and key characteristics of a highly efficacious multi-component peer-driven intervention (PDI) designed to increase rates of screening for and enrollment into ACTs among African-American and Latino/Hispanic individuals, by addressing the main complex, multi-level barriers they experience to ACTs. We discuss the process of developing the intervention, the theoretical models guiding its delivery format and content, and provide an overview of the intervention's components. We then use brief case studies to illustrate a number of key issues that may arise during intervention implementation. Finally, we describe lessons learned and provide recommendations for the PDI's uptake in clinical and clinical trials settings. PMID- 23669215 TI - Breast milk fatty acid composition of women living far from the coastal area in Brazil. AB - OBJECTIVES: To evaluate the fatty acid composition of mature human milk of women living far from the coastal area of Brazil. METHODS: Mature breast milk samples were obtained from 47 lactating women aged between 18 and 35 years, who delivered their babies at term and who exclusively or predominantly breastfed. Milk collection took place after the fifth week postpartum by hand expression. The fatty acid composition of the milk was determined by gas chromatography. RESULTS: It was observed that the concentration of eicosapentaenoic acid (0.08%) was higher than that observed in previous studies in Brazil. However, the content of docosahexaenoic acid (0.09%) found in human milk was one of the lowest verified in the world. The content of trans fatty acids (2.05%) was similar to that reported in national studies previous to the mandatory declaration of this fatty acid content in food labels, suggesting that this measure had no effect on reducing the content of this fatty acid in the usual diet of women. CONCLUSIONS: Low levels of docosahexaenoic acid and high concentrations of trans fatty acids were observed in mature breast milk of women living far from the coastal area in Brazil. PMID- 23669216 TI - Alterations in the pulmonary histoarchitecture of neonatal mice exposed to hyperoxia. AB - OBJECTIVES: To analyze the effects of exposure to hyperoxia (100% oxygen) on the lung histoarchitecture of neonatal mice. METHODS: Neonatal Balb/c mice were exposed to hyperoxia (HG) (100% oxygen) (n= 10) in a chamber (15 x 20 x 30 cm) for 24 hours with a flow of 2 L/min. The control group (CG) (n = 10) was exposed to normoxia in the same type of chamber and for the same time. After exposure, the animals were euthanized by decapitation; the lungs were removed and processed for histological examination according to the laboratory routine. Three-mm thick sections were stained with hematoxylin and eosin (H&E). The morphometric analysis was performed with in order to analyze the macrophages present in the alveolar lumen, surface density (Sv) of gas exchange, volume density (Vv) of lung parenchyma, and areas of atelectasis. RESULTS: A decrease in the number of alveolar macrophages (MO) was observed in the HG (HG = 0.08 +/-0.01 MO/mm(2), CG = 0.18 +/- 0.03 MO/mm(2), p=0.0475), Sv of gas exchange in HG (HG = 8.08 +/- 0.12 mm(2)/mm(3), CG=8.65 +/- 0.20mm(2)/mm(3), p = 0.0233), Vv of lung parenchyma in HG (HG = 54.7/33.5/83.5%/mm(2); CG = 75/56.7/107.9%/mm(2), p<0.0001) when compared with the CG. However, there was an increase in areas of atelectasis in HG (HG = 17.5/11.3/38.4 atelectasis/mm(2), CG = 14/6.1/24.4 atelectasis/mm(2), p=0.0166) when compared with the CG. CONCLUSION: The present results indicate that hyperoxia caused alterations in lung histoarchitecture, increasing areas of atelectasis and diffuse alveolar hemorrhage. PMID- 23669217 TI - Specific instruments to assess quality of life in children and adolescents with asthma. AB - OBJECTIVE: To identify and describe specific instruments to assess health-related quality of life (HRQoL) in children and adolescents with asthma. DATA SOURCE: Searches were performed in the PubMed, Ovid, and LILACS databases using different combinations of key words (MeSH terms), selecting original articles on the development of specific HRQoL questionnaires, published in English, Portuguese, or Spanish, between 1990 and 2012. DATA SYNTHESIS: A total of 15 instruments that met the inclusion criteria were identified. Most studies assessed reliability through internal consistency, reproducibility, and/or sensitivity to changes. Validity was assessed by comparison with healthy controls (discordant validity) or factorial analysis. CONCLUSIONS: Of the 15 instruments, three are the most frequently used: Pediatric Asthma Quality of Life Questionnaire (PAQLQ), Pediatric Quality of Life Inventory 4.0 (PedsQL-Asthma), and Disability Kids (DISABKIDS). In general, these three tools have adequate psychometric characteristics and are practical to implement, but only PAQLQ has been culturally adapted to Brazil. PMID- 23669218 TI - A DNA-binding protein encoded by ORF008L of Singapore grouper iridovirus. AB - Singapore grouper iridovirus (SGIV) is a major viral pathogen that can cause substantial economic losses in aquaculture, but its genome replication, organization and package are largely unknown. We isolated SGIV protein-DNA core by freeze-thaw lysis of viral particles and gradient centrifugation. Twelve proteins were identified from the core by mass spectrometry. ORF008L, one of the core proteins, was identified as a collagen-like protein and its DNA binding ability was demonstrated by electrophoretic mobility shift assay (EMSA). Binding of ORF008L to DNA was neither sequence specific nor pH dependent, and it protected DNA from degradation by DNase I in vitro. These results suggest that ORF008L may play a role in protection or stabilization of the viral genome during infection. PMID- 23669219 TI - Isolated cranial mononeuropathy: an unusual initial presentation and disease progression of metastatic carcinoma of the breast. PMID- 23669220 TI - Multiple myeloma mimicking metastatic pancreas cancer. PMID- 23669221 TI - When retrospective comparative effectiveness research hinders science and patient centered care. PMID- 23669222 TI - Detection of circulating tumor cells harboring a unique ALK rearrangement in ALK positive non-small-cell lung cancer. AB - PURPOSE: The diagnostic test for ALK rearrangement in non-small-cell lung cancer (NSCLC) for crizotinib treatment is currently done on tumor biopsies or fine needle aspirations. We evaluated whether ALK rearrangement diagnosis could be performed by using circulating tumor cells (CTCs). PATIENTS AND METHODS: The presence of an ALK rearrangement was examined in CTCs of 18 ALK-positive and 14 ALK-negative patients by using a filtration enrichment technique and filter adapted fluorescent in situ hybridization (FA-FISH), a FISH method optimized for filters. ALK-rearrangement patterns were determined in CTCs and compared with those present in tumor biopsies. ALK-rearranged CTCs and tumor specimens were characterized for epithelial (cytokeratins, E-cadherin) and mesenchymal (vimentin, N-cadherin) marker expression. ALK-rearranged CTCs were monitored in five patients treated with crizotinib. RESULTS: All ALK-positive patients had four or more ALK-rearranged CTCs per 1 mL of blood (median, nine CTCs per 1 mL; range, four to 34 CTCs per 1 mL). No or only one ALK-rearranged CTC (median, one per 1 mL; range, zero to one per 1 mL) was detected in ALK-negative patients. ALK rearranged CTCs harbored a unique (3'5') split pattern, and heterogeneous patterns (3'5', only 3') of splits were present in tumors. ALK-rearranged CTCs expressed a mesenchymal phenotype contrasting with heterogeneous epithelial and mesenchymal marker expressions in tumors. Variations in ALK-rearranged CTC levels were detected in patients being treated with crizotinib. CONCLUSION: ALK rearrangement can be detected in CTCs of patients with ALK-positive NSCLC by using a filtration technique and FA-FISH, enabling both diagnostic testing and monitoring of crizotinib treatment. Our results suggest that CTCs harboring a unique ALK rearrangement and mesenchymal phenotype may arise from clonal selection of tumor cells that have acquired the potential to drive metastatic progression of ALK-positive NSCLC. PMID- 23669223 TI - Cutaneous head and neck malignancies with perineural spread to contralateral cranial nerves: an argument for extending postoperative radiotherapy volume. PMID- 23669224 TI - Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. AB - PURPOSE: To provide recommendations about prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer. Prophylaxis in the outpatient, inpatient, and perioperative settings was considered, as were treatment and use of anticoagulation as a cancer-directed therapy. METHODS: A systematic review of the literature published from December 2007 to December 2012 was completed in MEDLINE and the Cochrane Collaboration Library. An Update Committee reviewed evidence to determine which recommendations required revision. RESULTS: Forty-two publications met eligibility criteria, including 16 systematic reviews and 24 randomized controlled trials. RECOMMENDATIONS: Most hospitalized patients with cancer require thromboprophylaxis throughout hospitalization. Thromboprophylaxis is not routinely recommended for outpatients with cancer. It may be considered for selected high-risk patients. Patients with multiple myeloma receiving antiangiogenesis agents with chemotherapy and/or dexamethasone should receive prophylaxis with either low-molecular weight heparin (LMWH) or low-dose aspirin. Patients undergoing major cancer surgery should receive prophylaxis, starting before surgery and continuing for at least 7 to 10 days. Extending prophylaxis up to 4 weeks should be considered in those with high-risk features. LMWH is recommended for the initial 5 to 10 days of treatment for deep vein thrombosis and pulmonary embolism as well as for long-term (6 months) secondary prophylaxis. Use of novel oral anticoagulants is not currently recommended for patients with malignancy and VTE. Anticoagulation should not be used for cancer treatment in the absence of other indications. Patients with cancer should be periodically assessed for VTE risk. Oncology professionals should provide patient education about the signs and symptoms of VTE. PMID- 23669225 TI - Clinical trials of palliative chemotherapy in platinum-resistant or -refractory ovarian cancer: time to think differently? PMID- 23669227 TI - Benefits and adverse events in younger versus older patients receiving neoadjuvant chemotherapy for osteosarcoma: findings from a meta-analysis. AB - PURPOSE: The LIVESTRONG Young Adult Alliance has conducted a meta-analysis of individual patient data from prospective neoadjuvant chemotherapy osteosarcoma studies and registries to examine the relationships of sex, age, and toxicity on survival. PATIENTS AND METHODS: Suitable data sets were identified by a survey of published data reported in PubMed. The final pooled data set comprised 4,838 patients from five international cooperative groups. RESULTS: After accounting for important variables known at study entry such as tumor location and histology, females experienced higher overall survival rates than males (P = .005) and children fared better than adolescents and adults (P = .002). Multivariate landmark analysis following surgery indicated that a higher rate of chemotherapy-induced tumor necrosis was associated with longer survival (P < .001), as was female sex (P = .004) and the incidence of grade 3 or 4 mucositis (P = .03). Age group was not statistically significant in this landmark analysis (P = .12). Females reported higher rates of grade 3 or 4 thrombocytopenia relative to males (P < .001). Children reported the highest rates of grade 3 or 4 neutropenia (P < .001) and thrombocytopenia (P < .001). The achievement of good tumor necrosis was higher for females than for males (P = .002) and for children than for adults (P < .001). CONCLUSION: These results suggest fundamental differences in the way chemotherapy is handled by females compared with males and by children compared with older populations. These differences may influence survival in a disease in which chemotherapy is critical to overall outcomes. PMID- 23669226 TI - Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. AB - For almost four decades, my work has focused on one challenge: improving the delivery and efficacy of anticancer therapeutics. Working on the hypothesis that the abnormal tumor microenvironment-characterized by hypoxia and high interstitial fluid pressure--fuels tumor progression and treatment resistance, we developed an array of sophisticated imaging technologies and animal models as well as mathematic models to unravel the complex biology of tumors. Using these tools, we demonstrated that the blood and lymphatic vasculature, fibroblasts, immune cells, and extracellular matrix associated with tumors are abnormal, which together create a hostile tumor microenvironment. We next hypothesized that agents that induce normalization of the microenvironment can improve treatment outcome. Indeed, we demonstrated that judicious use of antiangiogenic agents- originally designed to starve tumors--could transiently normalize tumor vasculature, alleviate hypoxia, increase delivery of drugs and antitumor immune cells, and improve the outcome of various therapies. Our trials of antiangiogenics in patients with newly diagnosed and recurrent glioblastoma supported this concept. They revealed that patients whose tumor blood perfusion increased in response to cediranib survived 6 to 9 months longer than those whose blood perfusion did not increase. The normalization hypothesis also opened doors to treating various nonmalignant diseases characterized by abnormal vasculature, such as neurofibromatosis type 2. More recently, we discovered that antifibrosis drugs capable of normalizing the tumor microenvironment can improve the delivery and efficacy of nano- and molecular medicines. Our current efforts are directed at identifying predictive biomarkers and more-effective strategies to normalize the tumor microenvironment for enhancing anticancer therapies. PMID- 23669228 TI - Identification of somatic genomic alterations in circulating tumors cells: another step forward in non-small-cell lung cancer? PMID- 23669229 TI - Drug-resistant tuberculosis treatment complicated by antiretroviral resistance in HIV coinfected patients: a report of six cases in Lesotho. AB - Treating drug-resistant tuberculosis (DR-TB) is particularly challenging in high human immunodeficiency virus (HIV) prevalence settings. Neither antiretroviral resistance testing nor viral load monitoring is widely available in sub-Saharan Africa, and antiretroviral resistance can complicate the clinical management for DR-TB/HIV coinfected patients. We describe six cases of antiretroviral resistance in DR-TB patients with HIV coinfection in Lesotho. Two patients died before or immediately after antiretroviral resistance was detected by genotyping; the remaining four patients were switched to effective antiretroviral therapy (ART) regimens. Favorable DR-TB treatment outcomes in coinfected patients require successful management of their HIV infection, including treatment with an effective ART regimen. Coinfected patients undergoing DR-TB treatment may require closer monitoring of their response to ART, including routine viral load testing, to ensure that they receive an effective ART regimen concurrent with DR-TB treatment. PMID- 23669230 TI - Regulation of Aedes aegypti population dynamics in field systems: quantifying direct and delayed density dependence. AB - Transgenic strains of Aedes aegypti have been engineered to help control transmission of dengue virus. Although resources have been invested in developing the strains, we lack data on the ecology of mosquitoes that could impact the success of this approach. Although studies of intra-specific competition have been conducted using Ae. aegypti larvae, none of these studies examine mixed age cohorts at densities that occur in the field, with natural nutrient levels. Experiments were conducted in Mexico to determine the impact of direct and delayed density dependence on Ae. aegypti populations. Natural water, food, and larval densities were used to estimate the impacts of density dependence on larval survival, development, and adult body size. Direct and delayed density dependent factors had a significant impact on larval survival, larval development, and adult body size. These results indicate that control methods attempting to reduce mosquito populations may be counteracted by density dependent population regulation. PMID- 23669231 TI - Association between CD4+ T-lymphocyte counts and fecal excretion of Schistosoma mansoni eggs in patients coinfected with S. mansoni and human immunodeficiency virus before and after initiation of antiretroviral therapy. AB - Previously, we have shown that persons with human immunodeficiency virus 1 (HIV 1) infection and reduced CD4(+) T-lymphocyte counts excrete significantly fewer Schistosoma mansoni eggs than HIV-1-negative persons with similar intensities of schistosome infections. To determine how antiretroviral therapy (ART) might affect egg excretion, we conducted a study of HIV+ adults living in an area highly endemic for S. mansoni as they began an ART program. Fecal egg excretion and CD4(+) T-lymphocyte counts were evaluated at enrollment as well as 2 and 4 weeks after initiation of ART. Fourteen individuals who were Kato-Katz-negative at enrollment subsequently started excreting S. mansoni eggs accompanied by a significant increase in CD4(+) T lymphocytes (P = 0.004). Study participants who were S. mansoni egg-positive at enrollment and received both praziquantel and ART also showed significantly increased CD4(+) T-lymphocyte counts compared with baseline (P < 0.0001). Our data support a role for CD4(+) T lymphocytes in S. mansoni egg excretion. PMID- 23669232 TI - Blood stage of Plasmodium vivax in central China is still susceptible to chloroquine plus primaquine combination therapy. AB - In central China, Plasmodium vivax accounts for all of the native reported cases of malaria. Chloroquine (CQ) plus primaquine (PQ) have been used for more than 60 years as the frontline drugs, but the risk of treatment failure remains unknown. To measure the effectiveness and safety of CQ-PQ among vivax malaria patients, a total of 39 subjects with monoinfection vivax malaria was enrolled in a study from 2008 to 2009. There were no recrudescence or danger signs observed within the 28-day follow-up period, showing that blood stage of P. vivax isolates from central China is still susceptible to CQ plus PQ combination therapy. However, the antirelapse efficacy of PQ is difficult to assess because of the high rate of loss to follow-up after 28 days; also, parasites persisted in a single case at 3 days post-antimalarial drug treatment, indicating that continuous annual monitoring is needed in central China. PMID- 23669233 TI - Coverage-dependent effect of insecticide-treated curtains for dengue control in Thailand. AB - Evidence on the effectiveness of insecticide-treated curtains (ITCs) for reducing densities of Aedes mosquitoes, the principal vectors of dengue, is scarce. In Laem Chabang southeast of Bangkok, Thailand, the Breteau Index (BI) (number of positive containers/100 houses) was 45 in October 2006. In March 2007, we distributed long-lasting ITCs in 22 clusters (2,032 houses) and selected 66 control clusters (661 houses). Routine control activities continued in all clusters. Six months after distribution, the BI was 25.8 and 77.6 in intervention and control areas, respectively (P < 0.001). Eighteen months after distribution, the BI was 21.8 and 23.8, respectively (P = 0.28). The average number of ITCs/house at cluster level was associated with the BI (P < 0.01) after six months, when 70.5% of households still used ITCs, but not at 18 months, when ITC coverage had decreased to 33.2%. Deployment of ITCs can result in considerable reductions in Aedes infestation levels, but the effect is coverage dependent. PMID- 23669234 TI - Efficient attachment of carbon nanotubes to conventional and high-frequency AFM probes enhanced by electron beam processes. AB - Carbon nanotubes are considered to be an ideal imaging tip for atomic force microscopy (AFM) applications, and a number of methods for fabricating these types of probe have been developed in recent years. This work reports the attachment of carbon nanotubes to AFM probes using a micromanipulator within a scanning electron microscope. Electron beam induced deposition and etching are used to enhance the quality and attachment of the carbon nanotube tip and improve the fabrication rate of the CNT AFM probes compared to existing techniques. The attachment process is also improved by using a mat of SWCNTs (buckypaper) as a CNT source, which simultaneously improves the ease of fabrication and rate of nanotube probe production. The aim of these improvements is to simplify and improve the attachment process such that these probes can be better and more widely used in applications that benefit from their unique properties. This improved process is then used to attach CNTs to the new generation of low-mass, high-frequency probes, which are designed for rapid AFM imaging. The ability of these probes to operate with CNT tips is demonstrated, and their wear-resistance properties were found to be significantly enhanced compared to unmodified probes. These wear-resistant probes imaging at high scan rates are proposed to be effective tools for increasing throughput in metrological analysis, particularly for imaging high-modulus surfaces with high roughness and high-aspect-ratio features. PMID- 23669235 TI - Platelet-rich plasma in the pathologic processes of cartilage: review of basic science evidence. AB - PURPOSE: The purpose of this study was to systematically review the basic science evidence for the use of platelet-rich plasma (PRP) in the treatment of pathologic processes of cartilage, both as an adjunct to cartilage repair and as a conservative management strategy for osteoarthritis, with the intent of determining the effect of PRP and whether a proof of concept for its use has been established to facilitate further investigation at a clinical level. METHODS: Using the terms "platelet-rich plasma OR PRP OR autologous conditioned plasma OR ACP AND cartilage OR chondrocytes OR chondrogenesis OR osteoarthritis OR arthritis" we searched EMBASE and PubMed/Medline in April 2012. Two authors performed the search, 3 authors independently assessed the studies for inclusion, and 2 authors extracted the data. Extracted data included cytologic analysis of PRP, study design, and results. RESULTS: Twenty-one studies (12 in vitro, 8 in vivo, one in vitro and in vivo) met the inclusion criteria. The effects of PRP in these studies included increasing chondrocyte and mesenchymal stem cell proliferation, proteoglycan deposition, and type II collagen deposition. PRP was also found to increase the cell viability of chondrocytes and the migration and chondrogenic differentiation of mesenchymal stem cells (MSCs) and to inhibit the effect of catabolic cytokines. In vivo, PRP was used as an adjunct to concomitant surgical management, including microfracture surgery and implant, scaffold, and graft insertion. Not all studies concluded that PRP has a positive effect on cartilage repair. CONCLUSIONS: The current basic science evidence suggests that PRP has several potential effects on cartilage repair and osteoarthritis, and a proof of concept has been established. Well-designed randomized controlled trials (RCTs) are needed to extrapolate this evidence to the clinical setting. PMID- 23669236 TI - Modulation of glutathione intracellular levels alters the spontaneous proliferation of lymphocyte from HTLV-1 infected patients. AB - The human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus associated with neoplasias and inflammatory diseases, such as adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 infected individuals present a spontaneous T lymphocyte proliferation. This phenomenon is related to the HTLV-1-proviral load and the persistence of the infection. Viral proteins induce many cellular mediators, which can be associated with the abnormal cellular proliferation. The intracellular levels of glutathione (GSH) are important to modulate the cellular proliferation. The aim of this study was to investigate the correlation between the modulation of intracellular GSH levels and the spontaneous lymphocyte proliferation during the HTLV-1 infection. Intracellular GSH level can be modulated by using dl-buthionine-[S,R]-sulfoximine (BSO, GSH synthesis inhibitor) and N-acetylcysteine (NAC, peptide precursor). Our results demonstrated that BSO was capable of inducing a decrease in the spontaneous proliferation of PBMC derived from HTLV-1 carriers. On the other hand, the GSH precursor induces an increase in mitogen-stimulated cellular proliferation in infected and uninfected individuals. Similar results were observed by the inhibition of ABCC1/MRP1 protein, augmenting the mitogen-induced proliferation. This effect can be related with an increase in the GSH levels since ABCC1/MRP1 transports GSH to the extracellular medium. There was a significant difference on the expression of CD69 and CD25 molecules during the lymphocyte activation. We did not observe any alterations on CD25 expression induced by BSO or NAC. However, our results demonstrated that NAC treatment induced an increase in CD69 expression on unstimulated CD8(+) T lymphocytes obtained from HTLV-1 infected individuals, healthy donors and HTLV carriers. Therefore, our results suggest that the cellular proliferation promoted by the infection with HTLV-1 and the activation phenotype of CD8(+) T lymphocytes can be regulated by changing the intracellular GSH levels; suggesting the modulation of these intracellular levels as a new approach for the treatment of pathologies associated with the HTLV-1 infection. PMID- 23669237 TI - Knockdown of nucleophosmin by RNA interference reverses multidrug resistance in resistant leukemic HL-60 cells. AB - Nucleophosmin, a multifunctional nucleolar phosphoprotein, is involved in many cellular activities. However, the role of NPM in drug-resistance of leukemia has not yet been explored. We designed and selected one shRNA targeting on NPM gene transduction into HL-60 and HL-60/ADR cell lines (an adriamycin resistant cell line) by lentivirus. Cell proliferation, apoptosis and differentiation were assessed. The expressions of the related genes and proteins were detected by real time quantitative RT-PCR and Western blotting. The results showed obvious down regulation of NPM mRNA and protein levels after NPM RNAi. NPM-targeted RNAi also resulted in many cellular changes, such as, suppressing cell proliferation and inducing cell differentiation. Down-regulation of NPM gene could arrest the cell cycle progression, an increase in the proportion of G0/G1 phase in knockdown groups. NPM gene silencing could also induce pro-apoptotic genes and proteins expression, and inhibit anti-apoptotic genes/proteins expression. Furthermore, IC50 of two chemotherapeutic agents (adriamycin and ADR; daunorubicin and DNR) to HL-60 and HL-60/ADR cells decreased, especially more remarkable on HL-60/ADR cells. IC50 of ADR on HL-60/ADR cells was reduced from 12.544 +/- 0.851 MUmol/L (before NPM RNAi) to 6.331 +/- 0.522 MUmol/L (after NPM RNAi), IC50 of DNR was reduced from 2.152 +/- 0.143 MUmol/L (before NPM RNAi) to 1.116 +/- 0.093 MUmol/L (after NPM RNAi). The relative reversal rate of HL-60/ADR cells on ADR was 50.2%, and on DNR was 48.9%. In conclusion, our results demonstrated that shRNA expression vectors could effectively reduce NPM expression and restore the drug sensitivity of resistant leukemic cells to conventional chemotherapeutic agents. PMID- 23669238 TI - An interplay between scavenger receptor A and CD14 during activation of J774 cells by high concentrations of LPS. AB - Lipopolysaccharide (LPS) activates macrophages by binding to the TLR4/MD-2 complex and triggers two pro-inflammatory signaling pathways: one relies on MyD88 at the plasma membrane, and the other one depends on TRIF in endosomes. When present in high doses, LPS is internalized and undergoes detoxification. We found that the uptake of a high concentration of LPS (1000ng/ml) in macrophage-like J774 cells was upregulated upon inhibition of clathrin- and dynamin-mediated endocytosis which, on the other hand, strongly reduced the production of pro inflammatory mediators TNF-alpha and RANTES. The binding and internalization of high amounts of LPS was mediated by scavenger receptor A (SR-A) with participation of CD14 without an engagement of TLR4. Occupation of SR-A by dextran sulfate or anti-SR-A antibodies enhanced LPS-induced production of TNF alpha and RANTES by about 70%, with CD14 as a limiting factor. Dextran sulfate also elevated the cell surface levels of TLR4 and CD14, which could have contributed to the upregulation of the pro-inflammatory responses. Silencing of SR-A expression inhibited the LPS-triggered TNF-alpha production whereas RANTES release was unchanged. These data indicate that SR-A is required for maximal production of TNF-alpha in cells stimulated with LPS, possibly by modulating the cell surface levels of TLR4 and CD14. PMID- 23669239 TI - Pattern of induction of colicin E9 synthesis by sub MIC of Norfloxacin antibiotic. AB - The presence of dual SOS boxes in the regulatory region of the most of colicin operons confines synthesis of colicin to times of stress, presumably to reduce the cost of its production. However, in presence of certain inducing agents, such as antibiotics, this tight control of colicin operon is usually lost. Although synthesis of most of colicins is known to be regulated by SOS response of host cell, different patterns of induction from distinct colicins against various inducing agents have been shown in recent years. In this study, we investigated the induction pattern of enzymatic colicin E9 (ColE9) synthesis following treatment with various concentrations (sub MICs) of the Norfloxacin (NOR) using pSBM23 construct which carries transcriptional fusion of SOS inducible promoter of pColE9 (ColE9p) and a fluorescent reporter gene (gfpmut2) into kanamycin resistant pColE9-J plasmid. Flow cytomtry analysis of the Escherichia coli cells containing pSBM23, following treatment with various concentrations showed that the SOS response mediated induction of the synthesis of ColE9 happens in a dose dependent manner. In summary, our results suggest that the presence, even in a minute amount, of SOS response inducing agents such as fluoroquinolone antibiotic in natural habitat of colicinogenic population can promote such a costly antagonistic behaviour of microbes. PMID- 23669240 TI - Macrobrachium rosenbergii cathepsin L: molecular characterization and gene expression in response to viral and bacterial infections. AB - Cathepsin L (MrCathL) was identified from a constructed cDNA library of freshwater prawn Macrobrachium rosenbergii. MrCathL full-length cDNA is 1161 base pairs (bp) with an ORF of 1026bp which encodes a polypeptide of 342 amino acid (aa) long. The eukaryotic cysteine proteases, histidine and asparagine active site residues were identified in the aa sequence of MrCathL at 143-154, 286-296 and 304-323, respectively. The pair wise clustalW analysis of MrCathL showed the highest similarity (97%) with the homologous cathepsin L from Macrobrachium nipponense and the lowest similarity (70%) from human. Phylogenetic analysis revealed two distinct clusters of the invertebrates and vertebrates cathepsin L in the phylogenetic tree. MrCathL and cathepsin L from M. nipponense were clustered together, formed a sister group to cathepsin L of Penaeus monodon, and finally clustered to Lepeophtheirus salmonis. High level of (P<0.05) MrCathL gene expression was noticed in haemocyte and lowest in eyestalk. Furthermore, the MrCathL gene expression in M. rosenbergii was up-regulated in haemocyte by virus [M. rosenbergii nodovirus (MrNV) and white spot syndrome baculovirus (WSBV)] and bacteria (Vibrio harveyi and Aeromonas hydrophila). The recombinant MrCathL exhibited a wide range of activity in various pH between 3 and 10 and highest at pH 7.5. Cysteine proteinase (stefin A, stefin B and antipain) showed significant influence (100%) on recombinant MrCathL enzyme activity. The relative activity and residual activity of recombinant MrCathL against various metal ions or salts and detergent tested at different concentrations. These results indicated that the metal ions, salts and detergent had an influence on the proteinase activity of recombinant MrCathL. Conclusively, the results of this study imply that MrCathL has high pH stability and is fascinating object for further research on the function of cathepsin L in prawn innate immune system. PMID- 23669242 TI - Antiproliferative activity of the dimeric phloroglucinol and benzophenone derivatives of Hypericum spp. native to southern Brazil. AB - A large number of plants are known to possess strong antitumor properties. Previous studies have verified the antiproliferative activity of the extracts and fractions from six species of Hypericum spp. growing in southern Brazil. In the present study, the in-vitro antiproliferative effects of two dimeric phloroglucinols (japonicin A and uliginosin B, isolated from Hypericum myrianthum) and two benzophenones (cariphenone A and cariphenone B, isolated from H. carinatum) were investigated against three tumor cell lines (HT-29 - human colon carcinoma cells; U-251 - human glioma cell line, and OVCAR-3 - human ovarian carcinoma cells). In addition, different doses of these compounds were associated with cytotoxic drugs commonly used as chemotherapy in the clinic. Cariphenone A and cariphenone B showed moderate antiproliferative activity against all tumor cell lines at a dose of 100 MUg/ml. Unlike benzophenones, japonicin A and uliginosin B exerted antiproliferative effects only in the OVCAR 3 cell line. Moreover, a very strong synergistic effect was demonstrated by the association of subeffective doses of japonicin A with the chemotherapeutic drug paclitaxel, decreasing cellular proliferation of the OVCAR-3 cell line. These preliminary results provide a scientific basis to further pursue these compounds as potential combined therapy for certain tumor types. PMID- 23669241 TI - Gene discovery in the tropical scallop Nodipecten nodosus: construction and sequencing of a normalized cDNA library. AB - We report the construction and characterization of a normalized cDNA library from the digestive gland of the marine bivalve Nodipecten nodosus, a commercially valuable tropical scallop. A total of 288 clones were sequenced, and 250 unique sequences were obtained. The cDNA library showed a small sequence redundancy (2.3%) and high numbers of recombinant (99.9%) and independent clones (2.0 * 10(6) cfu), indicating that the cDNA library generated in this study is a profitable resource for efficient gene discovery for N. nodosus. EST functional annotation by Gene Ontology term assignment revealed the identification of sequences potentially involved in aquaculture and ecotoxicology relevant processes such as apoptosis, growth, lipid metabolism, reproduction, development, response to stress and immunity. PMID- 23669243 TI - Excess androgen during perinatal life alters steroid receptor expression, apoptosis, and cell proliferation in the uteri of the offspring. AB - Exposure to environmental chemicals may contribute to reproductive disorders, especially when it occurs in critical periods of development. The female reproductive system can be a target for androgens derived from environmental contaminants or pathological conditions. The purpose of this study was to assess the long-term effects of androgens on uterine tissue after maternal exposure limited to the time of gestation and lactation. Pregnant Wistar rats were treated with testosterone propionate (TP) at 0.05 mg/kg, 0.1 mg/kg, 0.2 mg/kg or corn oil (vehicle), s.c., from gestational day 12 until the end of lactation. The results show changes in the pattern of expression of receptors for estrogen, progesterone, and androgen at all doses tested, and decreases in both apoptosis and cell proliferation indices at 0.1 and 0.2 mg/kg. We conclude that early TP exposure, under these experimental conditions, causes changes in cellular and molecular parameters that are essential for normal uterine function in the adult. PMID- 23669244 TI - [Validity and reliability of the Culture of Quality Health Services questionnaire in Mexico]. AB - INTRODUCTION: Patient Safety is a major public health problem worldwide and is responsibility of all those involved in health care. Establishing a Safety Culture has proved to be a factor that favors the integration of work teams, communication and construction of clear procedures in various organizations. Promote a culture of safety depends on several factors, such as organization, work unit and staff. Objective assessment of these factors will help to identify areas for improvement and establish strategic lines of action. OBJECTIVE: [corrected] To adapt, validate and calibrate the questionnaire Culture of Quality in Health Services (CQHS) in Mexican population. MATERIAL AND METHODS: A cross with a stratified representative sample of 522 health workers. The questionnaire was translated and adapted from Singer's. Content was validated by experts, internal consistency, confirmatory factorial validity and item calibration with Samejima's Graded Response Model. RESULTS: Convergent and divergent construct validity was confirmed from the CQHS, item calibration showed that the questionnaire is able to discriminate between patients and represent different levels of the hypothesized dimensions with greater accuracy and lower standard error. CONCLUSIONS: The CQHS is a valid and reliable instrument to assess patient safety culture in hospitals in Mexico. PMID- 23669246 TI - Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic. AB - AIM: To determine the frequency and spectrum of mutations causing Familial Hypercholesterolaemia (FH) in patients attending a single UK specialist hospital lipid clinic in Oxford and to identify characteristics contributing to a high mutation detection rate. METHODS: 289 patients (272 probands) were screened sequentially over a 2-year period for mutations in LDLR, APOB and PCSK9 using standard molecular genetic techniques. The Simon Broome (SB) clinical diagnostic criteria were used to classify patients and a separate cohort of 409 FH patients was used for replication. RESULTS: An FH-causing mutation was found in 101 unrelated patients (LDLR = 54 different mutations, APOB p.(Arg3527Gln) = 10, PCSK9 p.(Asp374Tyr) = 0). In the 60 SB Definite FH patients the mutation detection rate was 73% while in the 142 with Possible FH the rate was significantly lower (27%, p < 0.0001), but similar (14%, p = 0.06) to the 70 in whom there was insufficient data to make a clinical diagnosis. The mutation detection rate varied significantly (p = 9.83 * 10(-5)) by untreated total cholesterol (TC) levels (25% in those <8.1 mmol/l and 74% in those >10.0 mmol/l), and by triglyceride levels (20% in those >2.16 mmol/l and 60% in those <1.0 mmol/l (p = 0.0005)), with both effects confirmed in the replication sample (p for trend = 0.0001 and p = 1.8 * 10(-6) respectively). There was no difference in the specificity or sensitivity of the SB criteria versus the Dutch Lipid Clinic Network score in identifying mutation carriers (AROC respectively 0.73 and 0.72, p = 0.68). CONCLUSIONS: In this genetically heterogeneous cohort of FH patients the mutation detection rate was significantly dependent on pre-treatment TC and triglyceride levels. PMID- 23669247 TI - Cigarette-smoke-induced atherogenic lipid profiles in plasma and vascular tissue of apolipoprotein E-deficient mice are attenuated by smoking cessation. AB - Tobacco smoke exerts perturbations on lipid metabolism and arterial cell function that accelerate atherosclerosis. Lipidomics has emerged as a key technology in helping to elucidate the lipid-related mechanisms of atherosclerosis. In this study, we investigated the effects of smoking cessation on plaque development and aortic arch content of various lipid molecular classes and species. Apolipoprotein E-deficient mice were exposed to fresh air (sham) or to mainstream cigarette smoke (CS) for 6 months, or to CS for 3 months followed by sham for 3 months (cessation group). Lipids from plasma and aortic arches, plasma lipoprotein profiles and plaque morphometry measurements were analyzed. We already showed that CS exposure accelerated plaque size and total cholesterol content of the aortic arch at 3 and 6 months. Marked increases were seen in the relative enrichment of cholesteryl esters, phospholipids, sphingomyelins, and glycosphingolipids. Smoking cessation slowed plaque progression and resulted in lower levels of many lipid species in plasma and aortic arch. While CS exposure promoted rapid lipid accumulation in mouse aorta, smoking cessation translated into a slow removal of lipids from the vessel wall. Despite the smoking cessation dependent metabolic changes leading to increased animal body weight, accumulation of proatherogenic lipids in the vessel was halted after exposure cessation, indicating that the clinical benefits of smoking cessation translate directly to the vessel wall and its lipid makeup. PMID- 23669248 TI - Daidzein inhibits carbohydrate digestive enzymes in vitro and alleviates postprandial hyperglycemia in diabetic mice. AB - This study was designed to investigate whether daidzein inhibits alpha glucosidase and alpha-amylase activities and alleviates postprandial hyperglycemia in streptozotocin-induced diabetic mice. Daidzein showed prominent inhibitory effects against alpha-glucosidase and alpha-amylase. The IC50 values of daidzein against alpha-glucosidase and alpha-amylase were 0.048 and 0.301 mmol, respectively, which showed that daidzein was more effective than acarbose. The increase in postprandial blood glucose levels was more significantly suppressed in the daidzein-administered group than in the water group of both streptozotocin-induced diabetic and normal mice. Moreover, the area under the curve was significantly lowered following daidzein administration (2043 versus 2475 mmol min l) in the streptozotocin-induced diabetic mice. These results indicated that daidzein may be a potent alpha-glucosidase inhibitor and suppress the postprandial hyperglycemia caused by starch. PMID- 23669249 TI - Effect of atorvastatin and methotrexate on solid Ehrlich tumor. AB - Hydroxymethyl glutaryl CoA reductase is the key enzyme in cholesterol synthesis. A relationship was found between cholesterol and the development of many types of cancer. Atorvastatin is a hypolipidemic drug that may have a role in treatment of cancer. Moreover, atorvastatin was reported to decrease the resistance of cancer cells to many chemotherapeutic agents. The aim of this work was to study the effect of each of methotrexate (MTX) and atorvastatin alone and in combination on solid Ehrlich carcinoma (SEC) in mice. Fifty BALB/c mice were divided into five equal groups: control untreated group, SEC, SEC+MTX, SEC+atorvastatin, SEC+MTX+atorvastatin. Tumor volume, tissue glutathione reductase (GR), catalase, malondialdehyde (MDA), cholesterol and tumor necrosis factor alpha (TNF-alpha) were determined. A part of the tumor was examined for histopathological and immunohistochemical study. MTX or atorvastatin alone or in combination induced significant increase in tissue catalase and GR with significant decrease in tumor volume, tissue MDA, cholesterol and TNF-alpha and alleviated the histopathological changes with significant increase in p53 expression and apoptotic index compared to SEC group. In conclusion, the combination of MTX and atorvastatin had a better effect than each of MTX or atorvastatin alone against solid Ehrlich tumor in mice. PMID- 23669245 TI - Wasting mechanisms in muscular dystrophy. AB - Muscular dystrophy is a group of more than 30 different clinical genetic disorders that are characterized by progressive skeletal muscle wasting and degeneration. Primary deficiency of specific extracellular matrix, sarcoplasmic, cytoskeletal, or nuclear membrane protein results in several secondary changes such as sarcolemmal instability, calcium influx, fiber necrosis, oxidative stress, inflammatory response, breakdown of extracellular matrix, and eventually fibrosis which leads to loss of ambulance and cardiac and respiratory failure. A number of molecular processes have now been identified which hasten disease progression in human patients and animal models of muscular dystrophy. Accumulating evidence further suggests that aberrant activation of several signaling pathways aggravate pathological cascades in dystrophic muscle. Although replacement of defective gene with wild-type is paramount to cure, management of secondary pathological changes has enormous potential to improving the quality of life and extending lifespan of muscular dystrophy patients. In this article, we have reviewed major cellular and molecular mechanisms leading to muscle wasting in muscular dystrophy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. PMID- 23669250 TI - Market dynamics of community pharmacies in Minnesota, U.S. from 1992 through 2012. AB - BACKGROUND: An understanding of community pharmacy market dynamics is important for monitoring access points for pharmacist services. OBJECTIVES: The purpose of this study was to describe (1) changes in pharmacy mix (independent versus chain) between 1992 and 2002 and between 2002 and 2012 for 87 counties in Minnesota (state in U.S.) and (2) the number (and proportion) of community pharmacies in Minnesota for the years 1992, 2002, and 2012 using a new categorization method developed specifically for this study. METHODS: Data included licensure records for 1992, 2002, and 2012 from the State of Minnesota Board of Pharmacy and county level demographics for 1990, 2000 and 2010 from the US Census Bureau. Descriptive statistics were used to summarize findings over time and to describe associations between study variables. RESULTS: The ratio of independent pharmacies to chain pharmacies changed from approximately 2:1 in 1992 to 1:2 in 2012. The primary market factors associated with changes in the number of community pharmacies per county were (1) the metropolitan designation of the county and (2) whether the population density (persons/square mile) was increasing or decreasing. The face of community pharmacy in Minnesota changed between 1992 and 2012. By 2012, pharmacies were located in traditional retail pharmacies, mass merchandiser outlets, supermarkets, and clinics/medical centers. Furthermore, specialty pharmacies grew in proportion to meet patient needs. CONCLUSIONS: Between 1992 and 2012, the market dynamics of community pharmacies in Minnesota was characterized by vigorous market entry and exit. In light of recent health reform that is exhibiting characteristics such as continuity-of-care models, performance based payment, technology advances, and the care of patients becoming more "ambulatory" (versus in-patient), we suggest that the market dynamics of community pharmacies will continue to exhibit vigorous market entry and exit in this new environment. It is proposed that the community pharmacy categories developed for this study will be useful for monitoring market dynamics in the future. PMID- 23669251 TI - Significance of obesity markers and adipocytokines in high grade and high stage prostate cancer in North Indian men - a cross-sectional study. AB - BACKGROUND: Prostate cancer (CaP) in India is the 10th most common malignancy affecting men. CaP incidence in India is low, but rising like other countries. The reasons for this racial disparity are uncertain. The foremost reasons that may underlie regional/ethnic differences are genetic polymorphisms, altered hormonal status, socioeconomic status, and obesity. This study aimed at investigating the role of adipocytokines in stimulating the promotion and progression of CaP. METHODS: A cross-sectional study on histopathologically proven prostate cancer (N=95) and benign prostatic hyperplasia (N=95) patients was undertaken. CaP patients were classified into high-grade (N=62) and low-grade (N=33), and high stage (N=31) and low stage (N=64) groups. The level of body mass index (BMI), waste to hip ratio (WHR), interleukin-6 (IL-6), leptin, and adiponectin were compared between BPH and CaP groups and between grades and stages of prostate cancer. RESULTS: The level of BMI was significantly (p<0.001) higher in CaP patients (26.58+/-4.76) in comparison to BPH (22.15+/-2.90). Similarly, WHR was significantly (p<0.0001) higher in the CaP patients (1.08+/ 0.37) in comparison to BPH (0.86+/-0.15). Leptin (BPH: 25.60, CaP: 56.00) and II 6 levels (BPH: 9.90, CaP: 32.30) were significantly higher, but adiponectin was significantly lower in CaP patients as compared to BPH. High grade CaP patients had significantly higher BMI and WHR in comparison to low grade, and WHR was also higher in high stage CaP. Leptin and IL-6 level were higher in high stage and high grade, but adiponectin was low in high stage and high grade groups in comparison to low stage and low grade groups. CONCLUSIONS: Higher BMI and WHR correlate with prostate cancer independently, suggesting obesity to be a promoter of poor prostate health. Leptin and IL-6 appear to have stimulating effect on prostate cancer cells inducing the promotion and progression of CaP, but adiponectin appears to be protective against prostate cancer. PMID- 23669252 TI - Impact of normalization strategy on cardiac expression of pro-inflammatory cytokines: evaluation of reference genes in different human myocardial regions after Left Ventricular Assist Device support. AB - OBJECTIVE: New device therapies have expanded the strategies for treating heart failure (HF) patients. Unloading of the heart with a left ventricular assist device (LVAD) can lead to the reversal of many remodeling changes whose underlying mechanisms are not yet completely known. Molecular analysis might play a role in obtaining further insight into the regulatory mechanisms of this process. A critical step in an RT-PCR study is the selection of reference genes for data normalization. This study aimed to determine an optimal combination of stably expressed reference genes in different regions of the human heart in order to study the effects of LVAD implants on cardiac remodeling, and in particular to check their reliability on the evaluation of pro-inflammatory cytokine expression. DESIGN AND METHODS: We validated nine of the most commonly used reference genes in human myocardium samples obtained at heart transplantation from patients with LVAD implant (n=30 from a total of six patients) and from heart transplant (HT from a total of seven patients) recipients as controls (n=35). Samples from both left (LV) and right (RV) ventricles were analyzed. The normalization strategy was tested by analyzing mRNA expression of IL-6, IL-8 and TNF-alpha, whose protein levels were measured by immunometric assay. RESULTS: The most stable gene combinations changed according to the experimental groups (the LVAD and HT groups and the different myocardial regions). Considering all the cardiac samples as a whole, the three most stably expressed genes were PPIA, RPL13A, and YWHAZ (M=0.70). Using the best normalization strategy, a significant increase in IL-6, IL-8 mRNA expression was observed in LVAD samples compared to HT (p<0.0001). Similar results were obtained by protein analysis. CONCLUSIONS: Our results underline the importance of always selecting reference genes for the specific system studied. The most appropriate normalization strategy is of pivotal importance for understanding the molecular mechanisms associated with the pathophysiology of HF, such as inflammation. PMID- 23669253 TI - Vitamin D3 supplementation modulates inflammatory responses from the muscle damage induced by high-intensity exercise in SD rats. AB - Vitamin D is an important factor for calcium and phosphorus homeostasis. A negative relationship has been observed between vitamin D status and diseases such as cancer, arthritis, diabetes, and muscle fiber atrophy. However, the relationship between vitamin D and prevention of skeletal muscle damage has not been clearly elucidated. The purpose of this study was to investigate the effects of vitamin D on exercise-induced muscle changes. Rats were divided into 3 groups: (1) sedentary control (C: n=10), (2) high-intensity exercise (HE: n=10), and (3) high-intensity exercise with vitamin D supplementation (HED: n=10; i.p. 1000 IU/kg body weight). Rats were trained for 30 min/day on treadmills (5 days/week for 8 weeks) with the running speed gradually increased up to 30 m/min at a 3 degrees incline. At the end of the training period, the running speed was 38 m/min at a 5 degrees incline. The high-intensity exercise significantly increased plasma creatine kinase (CK) and lactate dehydrogenase (LDH) activity. In addition, IL-6 and TNF-alpha levels as well as phosphorylation of AMPK, p38, ERK1/2, IKK, and IkappaB were significantly increased. Vitamin D-treated rats showed a significant decrease in plasma CK level, phosphorylation of AMPK, p38, ERK1/2, IKK, and IkappaB, and gene expression of IL-6 and TNF-alpha. Furthermore, the protein expression of vitamin D receptor (VDR) was highly increased in the muscles of HED-treated rats, respectively. Therefore, we concluded that vitamin D may play a pivotal role in exercise-induced muscle damage and inflammation through the modulation of MAPK and NF-kappaB involved with VDR. PMID- 23669254 TI - [The intraosseous infusion in adult]. AB - Intraosseous infusion is an old knowledge, abandoned in the 1950s in favor of the peripheral vein, and it was essentially described in pediatrics and military medicine. Since 2005, this way is experiencing a resurgence of interest in emergency medicine particularly in adults after the failure's installation of a peripheral vein in order not to waste the time of care and administration of treatment. New devices that allow intraosseous infusion are currently used in humans. We propose to review the different kind of catheters used, to know the main technical characteristics, indications, contraindications and potential complications. We propose a comparison with the peripheral vein and a comparison between the different catheters. PMID- 23669255 TI - [Pulmonary lobe torsion: an eventuality following oesophagectomy]. PMID- 23669256 TI - Continence coach: pelvic floor pain syndrome in chronic pelvic pain revisited: a case study. PMID- 23669257 TI - A cross-sectional, comparative study of pain and activity in persons with and without injection-related venous ulcers. AB - Persons with leg ulcers, including venous ulcers, often report pain. A cross sectional, comparative study was conducted among 61 patients receiving care in an urban clinic (31 with and 30 without a venous ulcer, mean age 54 years [range 40 to 65 years], 93% African American) to examine pain and its relation to activity and walking in persons with injectionrelated venous ulcers. The questionnaire included items about pain and its treatment, as well as activity and walking (ie, Brief Pain Inventory [BPI] Short Form, Self-Treatment of Pain, Pain and Narcotic Use, Difficulty with Activities, and Walking Scale questionnaires). Among those with a venous ulcer (VU+), worst pain significantly related to total interference (r = 0.65, P <0.0001) and total difficulty (r = 0.42, P = 0.02) BPI scores. The common pain sites for those VU+ involved the legs (24, 36.4%), wound sites (13, 19.7%), back (eight, 12.1%), general body (five, 7.6%), shoulder and knee (four, 6.1% each), and other (eight, 12.1%). Persons VU+ were more likely than those without a venous ulcer (VU-) to have received a prescription for narcotics in the past year (96% versus 41%, X(2) = 21.3, P <0.0001). Persons VU+ versus VU- were significantly (X(2) = 8.89, P = 0.003) more likely to resort to street drug use and relapse to addiction if pain was not adequately treated. They were also twice as likely to have decreased walking over the past 5 years (67% versus 33%, X(2) = 5.93, P <0.02). Among those VU+, venous ulcers added to chronic pain and decreased walking. These findings highlight the negative effects of injection related venous ulcers on pain, activity, and walking, as well as the propensity of this groupto resort to illicit drug use for pain control. Persons VU+ should have pain assessed and treated. PMID- 23669258 TI - Ramadan fasting in patients with a stoma: a prospective study of quality of life and nutritional status. AB - Ramadan fasting is an Islamic obligation for healthy Muslims after the age of puberty. Persons with an acute or chronic disease may be excused from this obligation; the degree of the disease is an important parameter for not fasting. Little is known about the effect of fasting on persons with a stoma. A prospective study was conducted among 56 patients with a cancer-related fecal stoma (33 [58.9%] male, mean age 55.9 +/- 13.1 years) over two periods of Ramadan to analyze the effect of fasting 15 to 16 hours on nutritional and metabolic status and quality of life. Eligible patients were divided into two groups: fasting (n = 14) and nonfasting (n = 42). Demographic and stoma information, as well as disease and treatmentrelated variables, were evaluated. Participants completed cancer patient and colorectal cancer patient quality-of-life instruments and rated their religious orientation. Laboratory tests (blood urea nitrogen, creatinin, cholesterol, prealbumin, albumin, and transferrin) were performed 1 to 3 weeks before Ramadan, and questionnaires and tests were repeated 1 to 3 weeks after Ramadan in people who fasted. Demographic parameters, including religious orientation scale scores, were similar between fasting and nonfasting groups. Patients in the fasting group had significantly higher albumin levels (4.6 +/- 0.2 versus 4.1 +/- 0.4, P = 0.001), prealbumin levels (27.6 +/- 7.4 versus 21.3 +/- 8.5, P = 0.018), and global health status scores (81.5 +/- 16.7 versus 68.3 +/- 20.1, P = 0.030) than patients in the nonfasting group. Patients who fasted also had their stoma for a longer period of time than patients in the nonfasting group (average 9 months [range 3-87 months] in the fasting versus 4.5 months [range 3-36 months] in the nonfasting group, P = 0.084), and the proportion of patients with a permanent stoma was higher in the fasting group than in the nonfasting group (P = 0.051). Ramadan fasting had almost no influence on quality of life. Fasting lowered prealbumin levels (27.6 +/- 7.4 versus 21.2 +/- 4.4; P = 0.046), but did not adversely affect other nutritional or global health status variables. Most patients in the fasting group (13, 92.9%) stated they would feel sad if they were not fasting. The results of this study suggest that although fasting may decrease prealbumin levels, persons with a stoma and good nutritional status may decide for themselves whether to fast. PMID- 23669259 TI - The effect of a cellulose dressing and topical vancomycin on methicillin resistant Staphylococcus aureus (MRSA) and Gram-positive organisms in chronic wounds: a case series. AB - High levels of persistent bacteria may contribute to wound chronicity and delayed healing. A prospective study was conducted to: 1) evaluate the effect of applying vancomycin topically on appropriately cultured chronic lower leg wounds, specifically methicillin-resistant Staphylococcus aureus (MRSA) and Gram-positive bacteria, and 2) evaluate its effect in combination with a cellulose dressing on healing. Twenty-three (23) outpatients (11 men, 12 women, average age 65 years [range 39-89 years]) with lower extremity wounds (15 venous ulcers, six chronic open wounds with a history of diabetes, and two chronic open trauma wounds) averaging 43.58 weeks' (range 5-121 weeks) duration and swab-cultured positive for MRSA or Gram-positive bacteria were provided 1 g vancomycin delivered by a cellulose dressing and changed every 72 hours. Patients served as their own control, and all wounds were debrided once a week. Wound surface area and bacterial and exudate levels were recorded weekly during the 3-week pretreatment period and compared to 3-week treatment period levels. Patients were followed until healed. Mean change in wound surface area was +14.5% (SD 71.91) per week before and -24.6% (SD 13.59) during the vancomycin treatment period (P = 0.014), average exudate levels decreased from 2.75 (range 1-4) to 1.81 (range 0-3) (P = 0.016), and the number of patients with positive wound cultures for MRSA or Gram positive bacteria decreased from 23 to four after the 3-week study period. All wounds healed after an average of 8.18 weeks (SD 4.76, range 2-17 weeks). The results of this study suggest topical vancomycin applied using a dressing that retains moisture reduces wound bacterial load and may facilitate healing. Randomized, controlled clinical studies to evaluate the effectiveness and efficacy of this treatment modality and explore the relationship between wound culture results and healing are warranted. PMID- 23669260 TI - Cell surface clustering of heparan sulfate proteoglycans by amphipathic cell penetrating peptides does not contribute to uptake. AB - For arginine-rich cell-penetrating peptides (CPPs), an association with heparan sulfate (HS) chains is considered the first step in the stimulation of uptake for many cells. Much less is known about the role of HS chains in the cell association and internalization of arginine-free amphipathic CPP such as transportan-10 (TP10). Here, we report that various TP10 analogs differ in their capacity to accumulate on HS-rich plasma membranes in an HS-dependent manner. No accumulation was observed on HS-poor plasma membranes or when HS was removed by enzymatic cleavage. The TP10 analog that strongly clustered on the cell surface, also showed a pronounced capacity to form clusters with HS chains in solution. However, aggregation occurred in a thermodynamically different way compared to the interaction of arginine-rich CPP with HS. To monitor the impact of the peptide on the aggregation of the glycocalyx by time-lapse microscopy, sialic acids were visualized by metabolic labeling using copper-free click chemistry to attach fluorophores to metabolically incorporated azido sugars. Strikingly, a highly enhanced HS-mediated accumulation on the plasma membrane of a particular TP10 analog did not correlate with a better uptake. These findings illustrate that the mode of interaction between cell-penetrating peptides and HS chains has important functional consequences regarding peptide internalization and that there is no direct coupling of interaction, accumulation and uptake. PMID- 23669261 TI - Activation of the phospholipase C signaling pathway in nerve growth factor treated neurons by carbon nanotubes. AB - Low concentrations of carbon nanotubes (CNTs) promoted the number of nerve growth factor (NGF)-treated neurons with neurite outgrowth by activating extracellular signal-regulated kinase (ERK), even when MEK inhibitor was added to the neuron culture medium. We speculated that CNTs may activate ERK through the phospholipase C (PLC) signaling pathway independent of the Ras/Raf/MEK cascade involved in the ERK signaling pathway. CNTs enhanced phosphorylation of PLC gamma1 in NGF-treated neurons but failed to increase the number and length of neurites of NGF-treated neurons with neurite outgrowth when a PLC inhibitor, an inositol triphosphate receptor (IP3R) inhibitor, or an inhibitor of protein kinase C (PKC) in the PLC signaling pathway were added to the neuron culture medium. Furthermore, intracellular Ca(++) levels of cells treated with CNTs+NGF were higher than those of cells treated with NGF alone. Although the combination of CNTs and NGF increased the concentration of phosphorylated ERK (p-ERK) in MEK inhibitor-treated neurons, CNTs did not induce phosphorylation of ERK in PLC inhibitor-treated neurons. These data suggest that PKC in the PLC signaling pathway may activate ERK independent of the Ras/Raf/MEK cascade. In summary, we identified a role of PLC signaling in mediating neurite outgrowth of NGF-treated neurons in the presence of CNTs. PMID- 23669262 TI - A prototype catheter designed for ultraviolet C disinfection. AB - BACKGROUND: Disinfection of the intraluminal space of single-lumen polymer tubes can be obtained by ultraviolet C (UVC) light exposure from an external light source. In existing catheters UVC disinfection is hampered by the design of the catheter hub and tube connector. AIM: To demonstrate that it is possible to design a single-lumen catheter with a hub, tube connector and tube parts that can be UVC-disinfected throughout its entire lumen. METHODS: Two single-lumen catheters were designed: one control and one for UVC exposure. They were contaminated with Pseudomonas aeruginosa (10(4)-10(5) cfu/mL) before UVC light exposure, sampling and plate counting. FINDINGS: Two minutes of UVC exposure was sufficient to obtain 4 log10 disinfection for the full-length prototype catheter. This exposure corresponds to ~40 mJ/cm(2) at the catheter tip and indicates that even shorter exposure times can be achieved. CONCLUSIONS: It is possible to design catheters that can be disinfected throughout the entire lumen. UVC light exposure could be useful as a decontamination method for catheters in clinical use. PMID- 23669263 TI - Quality control of the surveillance programme of ICU-acquired infection (ENVIN HELICS registry) in Spain. AB - BACKGROUND: Data validation is an essential aspect for the accuracy of a nosocomial infection surveillance registry. AIM: To report the results of the first quality control programme in the national surveillance programme of intensive care unit (ICU)-acquired infection in Spain (ENVIN-HELICS registry). METHOD: During 2008, of 13,824 records included in the database, 1500 (10.8%) registries from 20 ICUs were reviewed. These ICUs were selected at random and stratified according to the number of cases included in the registry. The proportion of infected patients, which was 9.6% [95% confidence interval (CI) 8.09-11.16], was maintained during the selection of cases for review. Two physicians were trained for the purpose of the study and undertook the review. RESULTS: Overall sensitivity, specificity and positive and negative predictive values of the ENVIN-HELICS registry for the identification of patients with any device-related infection acquired during their ICU stay were 86.0% (95% CI 80.0 92.0), 98.7% (95% CI 82.19-93.6), 87.9% (95% CI 82.19-93.6) and 98.5% (95% CI 97.8-99.2), respectively, with a kappa index of 0.85 (95% CI 0.79-0.92). Secondary bloodstream infection had the lowest sensitivity (59.3%), and intubation-associated pneumonia had the highest sensitivity (86.3%). CONCLUSION: There was good correlation between data reported by the registrars and data validated by auditors, confirming the reliability of the ENVIN-HELICS registry. PMID- 23669264 TI - Walking speed, physical activity, and breast cancer in postmenopausal women. AB - Higher self-reported physical activity is associated with lower breast cancer incidence and mortality. Objectively measured timed walking speed, predictive of longevity in older adults, has been associated with ambulatory physical activity in small studies but definitive assessment of the association is lacking. Participants were a subset of 14 719 postmenopausal women in the Women's Health Initiative study who, at entry, had 10 m, timed walking speed determined. After 12.4 years [mean (SD) (3.5)] follow-up, 762 invasive breast cancers were diagnosed in this group. In addition, 8162 of these women self-reported physical activity. Simple linear regression was used to examine the relationship between timed walking speed and self-reported physical activity. A Cox proportional hazard model was used to estimate age-adjusted hazard ratios and 95% confidence intervals for the association between timed walking speed and invasive breast cancer incidence. Although a linear regression model for self-reported physical activity [log metabolic equivalent task (MET) h/week] versus 10 m, timed walking speed had a statistically significant slope (coefficient=0.03, P<0.0001, correlation=0.20), the magnitude of the relationship was not clinically useful. Timed walking speed quintile was not associated with breast cancer incidence in age-adjusted or multivariant analyses (P for trend=0.60). Timed walking speed was not associated with self-reported physical activity in a clinically useful manner or with breast cancer incidence. Our findings do not support use of timed walking speed as an objective surrogate for self-reported physical activity. PMID- 23669265 TI - Preparation of novel antiproliferative emodin derivatives and studies on their cell cycle arrest, caspase dependent apoptosis and DNA binding interaction. AB - Emodin (1) is the major bioactive compound of several herb species, which belongs to anthraquinone class of compound. As a part of our drug discovery program, large quantities of emodin (1) was isolated from the roots of Rheum emodi and a library of novel emodin derivatives 2-15 were prepared to evaluate their antiproliferative activities against HepG2, MDA-MB-231 and NIH/3T3 cells lines. The derivatives 3 and 12 strongly inhibited the proliferation of HepG2 and MDA-MB 231 cancer cell line with an IC50 of 5.6, 13.03 and 10.44, 5.027, respectively, which is comparable to marketed drug epirubicin (III). The compounds 3 and 12 were also capable of inducing cell cycle arrest and caspase dependent apoptosis in HepG2 cell lines and exhibit DNA intercalating activity. These emodin derivatives hold promise for developing safer alternatives to the marketed epirubicin. PMID- 23669266 TI - Puerarin improves metabolic function leading to hepatoprotective effects in chronic alcohol-induced liver injury in rats. AB - Puerarin (PR), an active component extracted from the kudzu root, has been widely used as an ethno-medicine to treat hepatopathy in China. Therefore, the aim of the present study was to investigate the hepatoprotective action of PR in chronic alcohol-induced liver injury in rats. Data showed that the serum levels of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) were elevated following PR administration. In addition, the levels of endogenous CYP2E1, CYP1A2, and CYP3A proteins in liver tissue were also gradually decreased following PR treatment. Histopathological examinations suggested that alcohol induced hepatocellular lesions were mitigated by PR treatment. Collectively, these data indicate that PR contributes to cytoprotection against alcohol-induced liver lesions through improving metabolic function. PMID- 23669268 TI - Patient-satisfaction measures in anesthesia: qualitative systematic review. AB - Patient satisfaction is an important measure of the quality of health care and is used as an outcome measure in interventional and quality improvement studies. Previous studies have found that there are few appropriately developed and validated questionnaires available. The authors conducted a systematic review to identify all tools used to measure patient satisfaction with anesthesia, which have undergone a psychometric development and validation process, appraised the quality of these processes, and made recommendations of tools that may be suitable for use in different clinical and academic settings. There are a number of robustly developed and subsequently validated instruments, however, there are still many studies using nonvalidated instruments or poorly developed tools, claiming to accurately assess satisfaction with anesthesia. This can lead to biased and inaccurate results. Researchers in this field should be encouraged to use available validated tools, to ensure that patient satisfaction is measured and reported fairly and accurately. PMID- 23669269 TI - Simulation-based assessment and retraining for the anesthesiologist seeking reentry to clinical practice: a case series. AB - BACKGROUND: Established models for assessment and maintenance of competency in anesthesiology may not be adequate for anesthesiologists wishing to reenter practice. The authors describe a program developed in their institution incorporating simulator-based education, to help determine competency in licensed and previously licensed anesthesiologists before return to practice. METHODS: The authors have used simulation for assessment and retraining at their institution since 2002. Physicians evaluated by the authors' center undergo an adaptable 2 day simulation-based assessment conducted by two board-certified anesthesiologists. A minimum of three cases are presented on each day, with specific core competencies assessed, and participants complete a standard Clinical Anesthesia Year 3 level anesthesia knowledge test. Participants are debriefed extensively and retraining regimens are designed, where indicated, consisting of a combination of simulation and operating-room observership. RESULTS: Twenty anesthesiologists were referred to the authors' institution between 2002 and 2012. Fourteen participants (70%) were in active clinical practice 1 yr after participation in the authors' program, five (25%) were in supervised positions, and nine (45%) had resumed independent clinical practice. The reasons of participants not in practice were personal (1 participant) and medico-legal (3 participants); two participants were lost to follow-up. Two of 14 physicians, who were formally assessed in the authors' program, were deemed likely unfit for safe return to practice, irrespective of further training. These physicians were unavailable for contact 1 yr after assessment. CONCLUSION: Anesthesiologists seeking to return to active clinical status are a heterogeneous group. The simulated environment provides an effective means by which to assess baseline competency and also a way to retrain physicians. PMID- 23669270 TI - Perioperative systemic magnesium to minimize postoperative pain: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Systemic magnesium has been used to minimize postoperative pain with conflicting results by clinical studies. It remains unknown whether the administration of perioperative systemic magnesium can minimize postoperative pain. The objective of the current investigation was to evaluate the effect of systemic magnesium on postoperative pain outcomes. METHODS: A wide search was performed to identify randomized controlled trials that evaluated the effects of systemic magnesium on postoperative pain outcomes in surgical procedures performed under general anesthesia. Meta-analysis was performed using a random effect model. Publication bias was evaluated by examining the presence of asymmetric funnel plots using Egger regression. RESULTS: Twenty randomized clinical trials with 1,257 subjects were included. The weighted mean difference (99% CI) of the combined effects favored magnesium over control for pain at rest (<=4 h, -0.74 [-1.08 to -0.48]; 24 h, -0.36 [-0.63 to -0.09]) and with movement at 24 h, -0.73 (-1.37 to -0.1). Opioid consumption was largely decreased in the systemic magnesium group compared with control, weighted mean difference (99% CI) of -10.52 (-13.50 to -7.54) mg morphine IV equivalents. Publication bias was not present in any of the analysis. Significant heterogeneity was present in some analysis, but it could be partially explained by the sole intraoperative administration of magnesium compared with the intraoperative and postoperative administration. None of the studies reported clinical toxicity related to toxic serum levels of magnesium. CONCLUSION: Systemic administration of perioperative magnesium reduces postoperative pain and opioid consumption. Magnesium administration should be considered as a strategy to mitigate postoperative pain in surgical patients. PMID- 23669271 TI - Early signatures of regime shifts in gene expression dynamics. AB - Recently, a large number of studies have been carried out on the early signatures of sudden regime shifts in systems as diverse as ecosystems, financial markets, population biology and complex diseases. The signatures of regime shifts in gene expression dynamics are less systematically investigated. In this paper, we consider sudden regime shifts in the gene expression dynamics described by a fold bifurcation model involving bistability and hysteresis. We consider two alternative models, models 1 and 2, of competence development in the bacterial population B. subtilis and determine some early signatures of the regime shifts between competence and noncompetence. We use both deterministic and stochastic formalisms for the purpose of our study. The early signatures studied include the critical slowing down as a transition point is approached, rising variance and the lag-1 autocorrelation function, skewness and a ratio of two mean first passage times. Some of the signatures could provide the experimental basis for distinguishing between bistability and excitability as the correct mechanism for the development of competence. PMID- 23669272 TI - Detection of vascular malformation mimicking lung mass in 18F-FDG PET/CT. PMID- 23669274 TI - Comparison of perioperative outcomes in outpatient and inpatient laparoscopic hysterectomy. AB - STUDY OBJECTIVE: To compare 30-day postoperative outcomes in outpatient and inpatient laparoscopic hysterectomy procedures. DESIGN: Retrospective observational study (Canadian Task Force classification II-2). SETTING: More than 250 hospitals that participate in the American College of Surgeons National Surgical Quality Improvement Program. PATIENTS: Women undergoing laparoscopic hysterectomy between 2006 and 2010. INTERVENTION: Of 8846 patients, 3564 underwent treatment as outpatients, as defined by hospital billing. MEASUREMENTS AND MAIN RESULTS: Overall morbidity was low in both cohorts; however, significantly fewer 30-day complications were observed in outpatients (4.5%) than inpatients (7.2%) (p < .001). Individual medical and wound complications were also rare and were less common in outpatients whenever a significant difference existed. After adjusting for demographic and operative variables, multivariate regression models found outpatients to be at significantly lower risk for overall perioperative morbidity (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.53-0.78). Outpatients were less likely to experience wound complications (OR, 0.63; 95% CI, 0.46-0.87) and were at lower risk of medical complications (adjusted OR, 0.61; 95% CI, 0.49-0.77) and deep vein thrombosis (adjusted odds ratio, 0.61; 95% CI, 0.47-0.80). Outpatient designation was not a significant predictor for repeat operation (p = .09). CONCLUSIONS: Outpatient laparoscopic hysterectomy procedures are not associated with increased risk of 30-day postoperative complications. PMID- 23669273 TI - Retinal pigment epithelium (RPE) exosomes contain signaling phosphoproteins affected by oxidative stress. AB - Age-related macular degeneration (AMD) is a leading cause of vision loss and blindness among the elderly population in the industrialized world. One of the typical features of this pathology is the gradual death of retinal pigment epithelial (RPE) cells, which are essential for maintaining photoreceptor functions and survival. The etiology is multifactorial, and oxidative stress is clearly one of the key factors involved in disease pathogenesis (Plafker, Adv. Exp. Med. Biol. 664 (2010) 447-56; Qin, Drug Dev. Res. 68 (2007) 213-225). Recent work has revealed the presence of phosphorylated signaling proteins in the vitreous humour of patients affected by AMD or other retinal diseases. While the location of these signaling proteins is typically the cell membrane or intracellular compartments, vitreous samples were proven to be cell-free (Davuluri et al., Arch. Ophthalmol. 127 (2009) 613-21). To gain a better understanding of how these proteins can be shed into the vitreous, we used reverse phase protein arrays (RPMA) to analyze the protein and phosphoprotein content of exosomes shed by cultured ARPE-19 cells under oxidative stress conditions. Seventy two proteins were shown to be released by ARPE-19 cells and compartmentalized within exosomes. Forty one of them were selectively detected in their post-translationally modified form (i.e., phosphorylated or cleaved) for the first time in exosomes. Sets of these proteins were linked together reflecting activation of pathway units within exosomes. A subset of (phospho)proteins were altered in exosomes secreted by ARPE-19 cells subjected to oxidative stress, compared to that secreted by control/non stressed cells. Stress altered exosome proteins were found to be involved in pathways regulating apoptosis/survival (i.e, Bak, Smac/Diablo, PDK1 (S241), Akt (T308), Src (Y416), Elk1 (S383), ERK 1/2 (T202/Y204)) and cell metabolism (i.e., AMPKalpha1 (S485), acetyl-CoA carboxylase (S79), LDHA). Exosomes may thus represent the conduit through which membrane and intracellular signaling proteins are released into the vitreous. Changes in their (phospho)protein content upon stress conditions suggest their possible role in mediating cell-cell signaling during physio pathological events; furthermore, exosomes may represent a potential source of biomarkers. PMID- 23669275 TI - Residential proximity to major roadways and renal function. AB - BACKGROUND: Living near major roadways has been associated with increased risk of cardiovascular events, but little is known about its impact on renal function. METHODS: We calculated the estimated glomerular filtration rate (eGFR) for 1103 consecutive Boston-area patients hospitalised with confirmed acute ischaemic stroke between 1999 and 2004. We used linear regression to evaluate the association between eGFR and categories of residential distance to major roadway (0 to <=50, >50 to <=100, >100 to <=200, >200 to <=400, >400 to <=1000 and >1000 m) adjusting for age, sex, race, smoking, comorbid conditions, treatment with ACE inhibitor and neighbourhood-level socioeconomic characteristics. In a second analysis, we considered the log of distance to major roadway as a continuous variable. RESULTS: Patients living closer to a major roadway had lower eGFR than patients living farther away (Ptrend=0.01). Comparing patients living 50 m versus 1000 m from a major roadway was associated with a 3.9 ml/min/1.73 m(2) lower eGFR (95% CI 1.0 to 6.7; p=0.007): a difference comparable in magnitude to the reduction in eGFR observed for a 4-year increase in age in population-based studies. The magnitude of this association did not differ significantly across categories of age, sex, race, history of hypertension, diabetes or socioeconomic status. CONCLUSIONS: Living near a major roadway is associated with lower eGFR in a cohort of patients presenting with acute ischaemic stroke. If causal, these results imply that exposures associated with living near a major roadway contribute to reduced renal function, an important risk factor for cardiovascular events. PMID- 23669276 TI - Evaluation of hyperelastic models for the non-linear and non-uniform high strain rate mechanics of tibial cartilage. AB - Accurate modeling of the high strain-rate response of healthy human knee cartilage is critical to investigating the mechanism(s) of knee osteoarthritis and other cartilage disorders. Osteoarthritis has been suggested to originate from regional shifts in joint loading during walking and other high strain-rate physical activities. Tibial plateau cartilage under compression rates analogous to walking exhibits a non-linear and location-dependent mechanical response. A constitutive model of cartilage that efficiently predicts the non-linear and non uniform high strain-rate mechanics of tibial plateau cartilage is important for computational studies of osteoarthritis development. A transversely isotropic hyperelastic statistical chain model has been developed. The model's ability to simulate the 1-strain/s unconfined compression response of healthy human tibial plateau articular cartilage has been assessed, along with two other hyperelastic statistical chain models. The transversely isotropic model exhibited a superior fit to the non-linear stress-strain response of the cartilage. Furthermore, the model maintained its predictive capability after being reduced from four degrees of freedom to one. The remaining material constant of the model, which represented the local collagen density of the tissue, demonstrated a regional dependence in close agreement with physiological variations in collagen density and cartilage modulus in human knees. The transversely isotropic eight-chain network of freely jointed chains with a regionally-dependent material constant represents a novel and efficient approach for modeling the complex response of human tibial cartilage under high strain-rate compression. The anisotropy and microstructural variations of the cartilage matrix dictate the model's response, rendering it directly applicable to computational modeling of the human knee. PMID- 23669277 TI - Incidence and clinical and immunological characteristics of primary Toxoplasma gondii infection in HIV-infected patients. AB - OBJECTIVES: To determine the incidence and laboratory characteristics of primary Toxoplasma gondii infection in HIV-infected individuals. METHODS: This retrospective study was conducted between 1988 and 2012 on a cohort of 1130 HIV infected patients at the AIDS Center Prague. Toxoplasma serology, standard laboratory parameters, and health status were evaluated at 3-6-month intervals for all patients. RESULTS: The total person-time of follow-up of patients at risk of Toxoplasma seroconversion was 3046.3 years; there were 14 primary T. gondii infections, yielding an incidence rate of 0.0046 (95% confidence interval 0.0027 0.0078). Most of the subjects were clinically asymptomatic, but in one case seroconversion was accompanied by transient cervical lymphadenopathy. The CD4+ T lymphocyte count geometric mean increased from 418 (95% confidence interval 303 579) cells/MUl before seroconversion to 501 (95% confidence interval 363-691) cells/MUl after seroconversion (p = 0.004), while other parameters (CD8+ T lymphocytes, natural killer cells, viral load, beta2-microglobulin, total immunoglobulins) remained unchanged. As compared to the control group, patients with primary toxoplasmosis had higher initial levels of total immunoglobulins IgA and IgG and a tendency to higher CD8+ T lymphocyte counts. CONCLUSIONS: Neither the incidence nor the course of the primary Toxoplasma infection was influenced by the immune status of the patients. Immune parameters of patients with primary Toxoplasma infection did not differ from those of the controls. PMID- 23669279 TI - Grip strength dynamometry: reliability and validity for adults with upper limb burns. AB - BACKGROUND: Upper limb (UL) burns can result in significant loss of strength and physical function. The aim of this study was to establish the reliability and validity of grip strength dynamometry (GSD) for measuring burn-affected UL strength over time. METHODS: A retrospective sample of adult participants (n=89) with UL burns was obtained from Royal Perth Hospital. Data were compiled from assessments conducted at discharge, one, three, six and 12 months afer burn. Within-session reliability and validity was examined through multivariable analyses. RESULTS: GSD demonstrated within-session reliability for all investigated timepoints (ICC's>=0.87, p<0.0005.) Criterion validity was confirmed with GSD and QuickDASH being significantly associated in both right (b=0.17, p=0.002) and left (b=0.14, p=0.002) hands. Construct validity was demonstrated through significant association of GSD values with location of burn (p<0.35); time after burn (p<0.012); surgical intervention (p=0.003) and burn size (p<0.05). CONCLUSION: This study demonstrates that grip strength dynamometry is a reliable and valid outcome measure for measuring burn-affected UL strength from one month to one year after burn. PMID- 23669278 TI - Cytochrome P450 2E1 potentiates ethanol induction of hypoxia and HIF-1alpha in vivo. AB - Ethanol induces hypoxia and elevates HIF-1alpha in the liver. CYP2E1 plays a role in the mechanisms by which ethanol generates oxidative stress, fatty liver, and liver injury. This study evaluated whether CYP2E1 contributes to ethanol-induced hypoxia and activation of HIF-1alpha in vivo and whether HIF-1alpha protects against or promotes CYP2E1-dependent toxicity in vitro. Wild-type (WT), CYP2E1 knock-in (KI), and CYP2E1 knockout (KO) mice were fed ethanol chronically; pair fed controls received isocaloric dextrose. Ethanol produced liver injury in the KI mice to a much greater extent than in the WT and KO mice. Protein levels of HIF-1alpha and downstream targets of HIF-1alpha activation were elevated in the ethanol-fed KI mice compared to the WT and KO mice. Levels of HIF prolyl hydroxylase 2, which promotes HIF-1alpha degradation, were decreased in the ethanol-fed KI mice in association with the increases in HIF-1alpha. Hypoxia occurred in the ethanol-fed CYP2E1 KI mice as shown by an increased area of staining using the hypoxia-specific marker pimonidazole. Hypoxia was lower in the ethanol-fed WT mice and lowest in the ethanol-fed KO mice and all the dextrose fed mice. In situ double staining showed that pimonidazole and CYP2E1 were colocalized to the same area of injury in the hepatic centrilobule. Increased protein levels of HIF-1alpha were also found after acute ethanol treatment of KI mice. Treatment of HepG2 E47 cells, which express CYP2E1, with ethanol plus arachidonic acid (AA) or ethanol plus buthionine sulfoximine (BSO), which depletes glutathione, caused loss of cell viability to a greater extent than in HepG2 C34 cells, which do not express CYP2E1. These treatments elevated protein levels of HIF-1alpha to a greater extent in E47 cells than in C34 cells. 2 Methoxyestradiol, an inhibitor of HIF-1alpha, blunted the toxic effects of ethanol plus AA and ethanol plus BSO in the E47 cells in association with inhibition of HIF-1alpha. The HIF-1alpha inhibitor also blocked the elevated oxidative stress produced by ethanol/AA or ethanol/BSO in the E47 cells. These results suggest that CYP2E1 plays a role in ethanol-induced hypoxia, oxidative stress, and activation of HIF-1alpha and that HIF-1alpha contributes to CYP2E1 dependent ethanol-induced toxicity. Blocking HIF-1alpha activation and actions may have therapeutic implications for protection against ethanol/CYP2E1-induced oxidative stress, steatosis, and liver injury. PMID- 23669280 TI - Pharmacokinetics of a self-microemulsifying drug delivery system of tacrolimus. AB - This study evaluated the pharmacokinetics of tacrolimus (Tac) in a novel self microemulsifying drug delivery system (SMEDDS) for improved oral administration. SMEDDS Tac consisted of ethyl oleate as the oily phase, Solutol HS 15 as the surfactant and glycofurol as the co-surfactant and contained 0.5mg/mL tacrolimus. Blood and tissue concentrations of tacrolimus from two study groups (oral application of SMEDDS Tac and Prograf(r)) were determined using ELISA technique following tacrolimus administration in rats. There was no difference between area under the whole blood concentration-time curve in the SEDDM Tac group and the Prograf(r) group. Maximum concentrations of the drug were three times higher (P<0.05) in the SEDDM Tac group accompanied by a 3-fold earlier peak time. Elimination half-life was significantly lower in the SEDDM Tac group. Application of SMEDDS Tac increased tissue accumulation. Already after 15 min, Tac levels of small intestine, liver, kidney, spleen, heart and bone marrow were significantly higher in the SMEDDS Tac group than in the Prograf(r) group (P<0.05). However, the Tac concentration in the kidney was significantly lower in the SMEDDS Tac group. Formulation of SMEDDS did not affect blood-brain barrier function. The SMEDDS is a potentially useful method for a local delivery of Tac to target organs. The selection of the optimum SMEDDS Tac composition might have advantage as an alternative oral dosage form for Tac. PMID- 23669281 TI - Results of a phase III clinical trial with an HBsAg-HBIG immunogenic complex therapeutic vaccine for chronic hepatitis B patients: experiences and findings. AB - BACKGROUND & AIMS: Even though various experimental therapeutic approaches for chronic hepatitis B infection have been reported, few of them have been verified by clinical trials. We have developed an antigen-antibody (HBsAg-HBIG) immunogenic complex therapeutic vaccine candidate with alum as adjuvant (YIC), aimed at breaking immune tolerance to HBV by modulating viral antigen processing and presentation. A double-blind, placebo-controlled, phase II B clinical trial of YIC has been reported previously, and herein we present the results of the phase III clinical trial of 450 patients. METHODS: Twelve doses of either YIC or alum alone as placebo were administered randomly to 450 CHB patients and they were followed for 24weeks after the completion of immunization. The primary end point was HBeAg seroconversion, and the secondary end points were decrease in viral load, improvement of liver function, and histology. RESULTS: In contrast to the previous phase II B trial using six doses of YIC and alum as placebo, six more injections of YIC or alum resulted in a decrease of the HBeAg seroconversion rate from 21.8% to 14.0% in the YIC group, but an increase from 9% to 21.9% in the alum group. Decrease in serum HBV DNA and normalization of liver function were similar in both groups (p>0.05). CONCLUSIONS: Overstimulation with YIC did not increase but decreased its efficacy due to immune fatigue in hosts. An appropriate immunization protocol should be explored and is crucial for therapeutic vaccination. Multiple injections of alum alone could have stimulated potent inflammatory and innate immune responses contributing to its therapeutic efficacy, and needs further investigation. PMID- 23669282 TI - Reliability of the estimation of total hepatic blood flow by Doppler ultrasound in patients with cirrhotic portal hypertension. AB - BACKGROUND & AIMS: Hepatic blood flow (HBF) is best estimated by the Fick's method during indocyanine green constant infusion (ICG-HBF) on hepatic vein catheterization. We investigated the consistency and agreement of HBF measured by Doppler ultrasound (US-HBF) as compared with ICG-HBF in portal hypertensive patients with cirrhosis. METHODS: In 50 patients observed for HVPG measurement (56% compensated; Child score 7 +/- 2; HVPG 16.6 +/- 6.0 mmHg; varices in 75%) US HBF (Sequoia-512-Acuson; 4.5-7 MHz convex probe; US-HBF = hepatic artery blood flow+portal vein blood flow) and ICG-HBF (Fick's method after an equilibration period of at least 45 min of ICG bolus of 5 mg + constant rate infusion of 0.2 mg/min). Intraclass correlation coefficient (ICC) for consistency and absolute agreement between US-HBF and ICG-HBF were calculated. RESULTS: Mean ICG-HBF and US-HBF were similar, being respectively 1004 +/- 543 ml/min and 994 +/- 494 ml/min (p = 0.661 vs. ICG-HBF). However, results in individual patients disclosed marked differences between the two methods (386 +/- 415 ml/min) and showed only moderate consistency (ICC 0.456; p < 0.0001), absolute agreement (ICC 0.461; p < 0.0001) and linear correlation (R = 0.464; p < 0.0001). The discrepancy between the two methods was maximal in patients with poor liver function, high HBF by any technique and more arterialized liver circulation. Hepatic artery blood flow >=40% of US-HBF indicated, with 90% specificity, a discrepancy >=20% between US HBF and ICG-HBF. CONCLUSIONS: HBF estimations by Doppler-ultrasound and ICG are significantly correlated, but their discrepancy in individual cases is high. Estimation of HBF by Doppler-US should be considered unreliable in patients with poor hepatic function and large liver arterialization. PMID- 23669283 TI - NKT-cell subsets: promoters and protectors in inflammatory liver disease. AB - Natural killer T cells (NKT) are innate-like cells which are abundant in liver sinusoids and express the cell surface receptors of NK cells (e.g., NK1.1 (mouse) or CD161+/CD56+(human)) as well as an antigen receptor (TCR) characteristic of conventional T cells. NKT cells recognize lipid antigens in the context of CD1d, a non-polymorphic MHC class I-like molecule. Activation of NKT cells has a profound influence on the immune response against tumors and infectious organisms and in autoimmune diseases. NKT cells can be categorized into at least two distinct subsets: iNKT or type I use a semi-invariant TCR, whereas type II NKT TCRs are more diverse. Recent evidence suggests that NKT-cell subsets can play opposing roles early in non-microbial liver inflammation in that type I NKT are proinflammatory whereas type II NKT cells inhibit type I NKT-mediated liver injury. PMID- 23669284 TI - A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in cirrhosis. AB - BACKGROUND & AIMS: The Acute Kidney Injury Network (AKIN) criteria are widely used in nephrology, but information on cirrhosis is limited. We aimed at evaluating the AKIN criteria and their relationship with the cause of kidney impairment and survival. METHODS: We performed a prospective study of 375 consecutive patients hospitalized for complications of cirrhosis. One-hundred and seventy-seven (47%) patients fulfilled the criteria of Acute Kidney Injury (AKI) during hospitalization, the causes being hypovolemia, infections, hepatorenal syndrome (HRS), nephrotoxicity, and miscellaneous (62, 54, 32, 8, and 21 cases, respectively). RESULTS: At diagnosis, most patients had AKI stage 1 (77%). Both the occurrence of AKI and its stage were associated with 3-month survival. However, survival difference between stages 2 and 3 was not statistically significant. Moreover, if stage 1 patients were categorized into 2 groups according to the level of serum creatinine used in the classical definition of kidney impairment (1.5mg/dl), the two groups had a significantly different outcome. Combining AKIN criteria and maximum serum creatinine, 3 risk groups were identified: (A) patients with AKI stage 1 with peak creatinine <= 1.5mg/dl; (B) patients with stage 1 with peak creatinine >1.5mg/dl; and (C) patients with stages 2-3 (survival 84%, 68%, and 36%, respectively; p<0.001). Survival was independently related to the cause of kidney impairment, patients with HRS or infection-related having the worst prognosis. CONCLUSIONS: A classification that combines the AKIN criteria and classical criteria of kidney failure in cirrhosis provides a better risk stratification than AKIN criteria alone. The cause of impairment in kidney function is key in assessing prognosis in cirrhosis. PMID- 23669285 TI - Tuberculous sepsis during antiviral HCV triple therapy. PMID- 23669286 TI - Reply to: "portal uptake function in veno-occlusive regions evaluated by real time fluorescent imaging using indocyanine green". PMID- 23669287 TI - Autophagy in the liver. PMID- 23669288 TI - Coagulopathy in cirrhosis - the role of the platelet in hemostasis. PMID- 23669289 TI - Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890. AB - BACKGROUND & AIMS: In phase III trials, the safety profile of triple therapy (pegylated interferon/ribavirin with boceprevir or telaprevir) seems to be similar in HCV treatment-experienced cirrhotic and non-cirrhotic patients, but few cirrhotics were included. We report the week 16 safety and efficacy analysis in a cohort of compensated cirrhotics treated in the French Early Access Programme. METHODS: 674 genotype 1 patients, prospectively included, received 48 weeks of triple therapy. The analysis is restricted to 497 patients reaching week 16. RESULTS: A high incidence of serious adverse events (40.0%), and of death and severe complications (severe infection or hepatic decompensation) (6.4%), and a difficult management of anaemia (erythropoietin and transfusion use in 50.7% and 12.1%) were observed. Independent predictors of anaemia < 8 g/dl or blood transfusion were: female gender (OR 2.19, 95% CI 1.11-4.33, p=0.024), no lead-in phase (OR 2.25, 95% CI 1.15-4.39, p=0.018), age >= 65 years (OR 3.04, 95% CI 1.54 6.02, p=0.0014), haemoglobin level (<= 12 g/dl for females, <= 13 g/dl for males) (OR 5.30, 95% CI 2.49-11.5, p=0.0001). Death or severe complications were related to platelets count <= 100,000/mm(3) (OR 3.11, 95% CI 1.30-7.41, p=0.0105) and albumin <35 g/dl (OR 6.33, 95% CI 2.66-15.07, p=0.0001), with a risk of 44.1% in patients with both. However, the on-treatment virological response was high. CONCLUSIONS: The safety profile was poor and patients with platelet count <= 100,000/mm(3) and serum albumin <35 g/L should not be treated with the triple therapy. PMID- 23669290 TI - XIAP downregulation promotes caspase-dependent inhibition of proteasome activity in AML cells. AB - To further understand the role of XIAP in acute myeloid leukemia (AML), we suppressed XIAP expression by antisense oligonucleotides and determined the effect on gene expression profiles and biological pathways. XIAP inhibition upregulated expression of proteasome genes in a manner similar to the proteasome inhibitor bortezomib or MG132; decreased 20S proteasome activity, an effect which was diminished in the presence of a pan-caspase inhibitor; and increased IkappaBalpha, Mcl-1, and HSP70 in AML cells. In addition to multiple functions already described, XIAP contributes to increased proteasome activity in AML cells, and the antitumor effect of XIAP inhibition may be mediated in part through caspase-dependent proteasome inhibition. PMID- 23669291 TI - The influence of XPD, APE1, XRCC1, and NBS1 polymorphic variants on DNA repair in cells exposed to X-rays. AB - Polymorphism of genes coding for proteins which participate in DNA repair may predispose to or protect against development of cancer. Here we studied how common polymorphisms of the genes XPD (Asp312Asn and Lys751Gln), APE1 (Asp148Glu), XRCC1 (Arg399Gln), and NBS1 (Gln185Glu) influence DNA repair and other responses after X-irradiation of lymphocytes from colon carcinoma patients. Genotypes with polymorphic Asp148Glu APE1 and Asp312Asn XPD showed a significantly higher level of DNA incisions immediately after irradiation (p=0.049 and p=0.047 respectively) and Asp312Asn XPD showed a significantly increased capacity to repair of DNA strand breaks as measured 180min after irradiation by comet assays (p=0.004). In contrast, it was the wild type XRCC1 genotype which was associated with a lower level of DNA breaks after irradiation (p=0.014, at 180min after irradiation) and polymorphism of NBS1 did not correlate with any changes in DNA breaks or repair capacity. To confirm the influence of XPD polymorphism on repair, we established stably-transfected HCT116 (colon carcinoma) cells which over-expressed the wild-type or variant XPD protein. Cells over-expressing Asp312Asn XPD showed a higher level of DNA breaks shortly after irradiation and more efficient repair than cells over-expressing the wild-type gene XPD312Asp, and an earlier inhibition of cell cycle transit but faster recovery from this inhibition. Polymorphisms in DNA repair genes therefore influence not only DNA repair capacity but also cell proliferation, and may serve as markers of individual repair capacity and susceptibility to environmental and occupational carcinogens. PMID- 23669292 TI - Complex aberrations in lymphocytes exposed to mixed beams of (241)Am alpha particles and X-rays. AB - Modern radiotherapy treatment modalities are associated with undesired out-of field exposure to complex mixed beams of high and low energy transfer (LET) radiation that can give rise to secondary cancers. The biological effectiveness of mixed beams is not known. The aim of the investigation was the analysis of chromosomal damage in human peripheral blood lymphocytes (PBL) exposed to a mixed beam of X-rays and alpha particles. Using a dedicated exposure facility PBL were exposed to increasing doses of alpha particles (from (241)Am), X-rays and a mixture of both. Chromosomal aberrations were analysed in chromosomes 2, 8 and 14 using fluorescence in situ hybridisation. The found and expected frequencies of simple and complex aberrations were compared. Simple aberrations showed linear dose-response relationships with doses. A higher than expected frequency of simple aberrations was only observed after the highest mixed beam dose. A linear quadratic dose response curve for complex aberrations was observed after mixed beam exposure. Higher than expected frequencies of complex aberrations were observed for the two highest doses. Both the linear-quadratic dose-response relationship and the calculation of expected frequencies show that exposure of PBL to mixed beams of high and low LET radiation leads to a higher than expected frequency of complex-type aberrations. Because chromosomal changes are associated with cancer induction this result may imply that the cancer risk of exposure to mixed beams in radiation oncology may be higher than expected based on the additive action of the individual dose components. PMID- 23669293 TI - CYP19A1 gene polymorphisms and risk of lung cancer. AB - OBJECTIVES: To investigate the association between polymorphisms of aromatase (encoded by the CYP19A1 gene and a key enzyme in biosynthesis of oestradiol) and the risk of lung cancer, and whether there were differences stratified by sex and smoking history. METHODS: This case-control study included consecutive, nonselected and pathologically-confirmed lung cancer patients and healthy people. Participants were classed as nonsmokers or smokers by questionnaire. Peripheral blood samples from all participants were genotyped for three single-nucleotide polymorphism (SNPs; rs727479, rs730154 and rs10046); allelic frequencies were compared across genotype and clinical records. RESULTS: A total of 529 patients with lung cancer and 567 age- and sex-matched controls were included. After adjustment for age, sex and smoking history, rs727479 was significantly associated with the incidence of lung cancer (for alleles AC vs AA). There was also a significant difference between patients and controls in haplotype CCA, while haplotype ACA was only significantly associated with nonsmokers and female nonsmokers. CONCLUSIONS: Polymorphisms of CYP19A1 may be related to the increased risk of lung cancer; in particular, haplotype ACA may contribute to lung-cancer progression in nonsmokers. Further validation with larger populations is required. PMID- 23669294 TI - Randomized controlled trial of zoledronic acid for treatment of osteoporosis in women. AB - OBJECTIVE: To assess the effect of zoledronic acid (ZOL) on bone mineral density (BMD) and fracture risk at the L1-L4 vertebrae, femoral neck, hip and trochanter in Chinese women with osteoporosis. METHODS: A randomized controlled trial was conducted in female patients with osteoporosis, randomized to receive one 5-mg ZOL intravenous infusion per year or placebo equivalent. Facture risk and BMD were measured over a 2-year follow-up period. RESULTS: A statistically significant reduction in the risk of fracture was observed at the trochanter in the ZOL group (n = 242) compared with the placebo group (n = 241); (odds ratio 0.54 [95% confidence interval 0.29, 0.98]): BMD was 0.24, 0.28, 0.31 and 0.22 greater at the L1-L4 vertebrae, total hip, femoral neck and trochanter, respectively, in the ZOL group. The incidence of adverse events was comparable between treatment groups. CONCLUSIONS: This study indicated that ZOL could increase BMD and reduce fracture risk in women with osteoporosis over a 2-year follow-up period, and was not associated with any serious drug-related adverse effects. PMID- 23669295 TI - Association between cytotoxic T-lymphocyte associated protein 4 gene +49 A/G polymorphism and chronic infection with hepatitis B virus: a meta-analysis. AB - OBJECTIVE: This meta-analysis determined the relationship between polymorphisms of the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) gene and hepatitis B virus (HBV) clearance in chronic hepatitis B. METHODS: Published studies reporting associations between CTLA4 gene +49A/G polymorphisms and chronic HBV infection were reviewed. Odds ratio (OR) and 95% confidence interval (CI) were calculated to assess the risk of persistent HBV according to genotype. RESULTS: Six studies, involving 1076 chronic HBV patients and 1294 controls, were included. The risk of persistent HBV in patients with a +49 GG/AG genotype decreased significantly compared with the AA genotype (OR 0.65; 95% CI 0.52, 0.82). The variant G allele was negatively associated with chronic HBV infection versus the A allele (OR 0.77; 95% CI 0.68, 0.88). When stratifying by type of study control, a significantly decreased risk was associated with CTLA4+49 variant genotypes (AG and GG) in both spontaneous recovery control group and healthy control group. CONCLUSIONS: Findings of this meta-analysis suggest that A at position +49 of the CTLA4 gene may significantly increase the risk of persistent HBV infection, whereas G at position +49 may positively influence virus clearance. PMID- 23669296 TI - Procalcitonin as a biomarker for early sepsis in the emergency department. AB - OBJECTIVES: In the critical care setting, increasing levels of midregional proadrenomedullin (MRproADM), midregional proatrial natriuretic peptide (MRproANP), procalcitonin (PCT), copeptin, and proendothelin-1 (proET-1) have been shown to be correlated with increasing severity of sepsis. The objective of this study was to investigate the utility of sepsis biomarkers in an Emergency Department (ED) population. METHODS: Through a prospective, observational pilot study, we investigated the utility of MRproADM, MRproANP, PCT, copeptin, and proET-1 in predicting a diagnosis of early sepsis in patients presenting to the ED for suspected infection. Data were analyzed using nonparametric Mann-Whitney U tests, chi2-tests, and receiver operating characteristic curves. RESULTS: Of the 66 patients enrolled in this study, 37 (56.1%) were men, with a median age of 58 years [interquartile range (IQR) 39-69 years], and 19 (28.8%) had a final diagnosis of early sepsis. A higher percentage of sepsis patients compared with no-sepsis patients met systemic inflammatory response syndrome (SIRS) criteria at initial presentation (85.7 vs. 41.3%; P<0.0001) and were admitted to the hospital (84.2 vs. 55.6%; P=0.02). PCT was higher in sepsis patients [median 0.32 ng/ml (IQR 0.19-1.17) vs. 0.18 ng/ml (IQR 0.07-0.54); P=0.04]. There were no differences between groups for MRproADM, MRproANP, copeptin, or proET-1 (P>=0.53). The C-statistic was maximized with the combination of SIRS criteria and PCT levels (0.92+/-0.05), which was better than PCT alone (0.67+/-0.08; P=0.005) or SIRS alone (0.75+/-0.07; P=0.04). CONCLUSION: In this pilot study, we found that the combination of SIRS criteria and PCT levels is useful for the early detection of sepsis in ED patients with suspected infection. Larger studies investigating use of PCT are necessary. PMID- 23669297 TI - Risk factors for neurosurgical site infection after neurosurgery in Rennes, France: comparison of logistic and Cox models. AB - The logistic model is widely used to assess the risk factors for surgical site infections (SSIs). An alternative to the logistic model is the Cox model. The objective of this study was to compare these 2 models to identify the risk factors of SSIs in neurosurgery. The Cox model is a valid alternative for assessing the risk factors of SSIs. PMID- 23669298 TI - Improving hand hygiene compliance in the anesthesia working room work area: More than just more hand rubs. AB - BACKGROUND: The anesthesia working area represents an environment with a high density of invasive and, thus, infection-prone procedures. The 2 primary goals of this study were (1) to perform a precise analysis of anesthesia-related hand hygiene (HH) procedures and (2) to optimize HH compliance. METHODS: We conducted a prospective, triphase before/after study to determine opportunities for and compliance with hand disinfection (World Health Organization definition) in an anesthesia working area. Standard operating procedures were optimized for invasive procedures during 2 predefined intervention periods to improve work flow practices. RESULTS: Seven hundred fifty anesthesia procedures were evaluated with 12,142 indications for HH. Compliance significantly increased from 10% (465/4,636) to 30% (1,202/4,029) and finally to 55% (1,881/3,477; all P < .001) in phases I, II, and III, respectively. We identified a significant increase in the number of hand rubs performed during 1 anesthesia procedure (2 to 8, respectively; P < .001) in parallel with a significant decrease in number of opportunities needing a hand rub (24 to 14, respectively; P < .0001) because of improved work flow practices. Notably, the greatest improvement was seen before aseptic tasks (8% to 55%, respectively). CONCLUSION: Our study provides the first detailed data on anesthesia-related and indication-specific HH. Importantly, HH compliance improved significantly without a noticeable increasing workload. PMID- 23669299 TI - Vancomycin-resistant Enterococcus outbreak in a neonatal intensive care unit: epidemiology, molecular analysis and risk factors. AB - BACKGROUND: Vancomycin-resistant Enterococcus faecium (VRE) may cause outbreaks in neonatal intensive care units (NICU). We describe a biphasic VRE outbreak and identify risk factors for VRE acquisition. METHODS: After the occurrence of 2 cases of VRE infections in a 44-bed NICU, a bundle of interventions was implemented that included active surveillance cultures for VRE, enhanced infection control measures, and audits on antimicrobial use, from June to December 2008. Analysis was performed using polymerase chain reaction and pulse field gel electrophoresis techniques. A case-control study was conducted to identify risk factors. RESULTS: Among 253 neonates screened, 101 (39.9%) were found to be colonized with VRE. During the first 9 weeks of the study period, 59 new cases were detected. Molecular analysis showed 1 predominant clone. During weeks 10-12, no new cases of VRE colonization were detected; however, at week 13, just when the outbreak appeared to be over, a second wave occurred, with 42 new cases and multiple clones detected. Multivariate analysis identified administration of antimicrobial therapy for late-onset neonatal sepsis and hospitalization during the first month of this outbreak as significant risk factors for VRE colonization. CONCLUSION: Both a high prevalence of VRE colonization and antimicrobial use promoted the transmission of VRE during this biphasic outbreak. Adherence to infection control measures and antimicrobial stewardship policies are of utmost importance. PMID- 23669300 TI - Risk factors for postoperative endophthalmitis caused by Pseudomonas aeruginosa: possible role of environment. AB - This article describes an investigation to identify risk factors for postoperative endophthalmitis caused by Pseudomonas aeruginosa. A retrospective case-control study, including 8 cases and 24 controls operated from 2005 to 2009, was undertaken. The risk factors associated with P aeruginosa infection were a particular operating room (P = .003) and longer phacoemulsification duration (P = .001), suggesting that infection was not associated with patient characteristics but rather with the surgical environment and phacoemulsification duration. PMID- 23669301 TI - Interaction between two cholesterol metabolism genes influences memory: findings from the Wisconsin Registry for Alzheimer's Prevention. AB - The strongest genetic factor for late-onset Alzheimer's disease (AD) is APOE; nine additional susceptibility genes have recently been identified. The effect of these genes is often assumed to be additive and polygenic scores are formed as a summary measure of risk. However, interactions between these genes are likely to be important. We sought to examine the role of interactions between the nine recently identified AD susceptibility genes and APOE in cognitive function and decline in 1,153 participants from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of middle-aged adults enriched for a parental history of AD. Participants underwent extensive cognitive testing at baseline and up to two additional visits approximately 4 and 6 years later. The influence of the interaction between APOE and each of 14 single nucleotide polymorphisms (SNPs) in the nine recently identified genes on three cognitive factor scores (Verbal Learning and Memory, Working Memory, and Immediate Memory) was examined using linear mixed models adjusting for age, gender, and ancestry. Interactions between the APOE epsilon4 allele and both of the genotyped ABCA7 SNPs, rs3764650 and rs3752246, were associated with all three cognitive factor scores (p-values <= 0.01). Both of these genes are in the cholesterol metabolism pathway leading to AD. This research supports the importance of considering non-additive effects of AD susceptibility genes. PMID- 23669302 TI - Evaluation of multimodal imaging in carriers of X-linked retinitis pigmentosa. AB - The aim of this study was to investigate visualization of the tapetal-like reflex using current imaging modalities and evaluate SD-OCT changes in known carriers of X-linked retinitis pigmentosa (XLRP); the objective being the development of an optimal protocol for clinicians to identify carriers. Ten XLRP carriers (19 eyes) were examined using color fundus photography, 488 nm reflectance (488-R), near infrared reflectance (NIR-R), autofluorescence (AF) and spectral domain optical coherence tomography (SD-OCT) imaging (Spectralis SLO-OCT, Heidelberg). Horizontal line scans through the fovea were acquired in all subjects and in a group of 10 age-similar controls. Peripheral SD-OCT scans (extending to 27.5 degrees eccentricity) were also acquired in both eyes of 7 carriers. MP-1 microperimetery (10-2 pattern; Nidek) was performed in one eye of each carrier. For the XLRP carriers, a tapetal reflex was observed with all imaging modalities in 8 of 19 eyes. It had the same retinal location on color fundus, 488-R and NIR R imaging but a different location on AF. The tapetal reflex was most easily detected in 488-R images. The horizontal foveal SD-OCT scans were qualitatively normal, but measurements showed significant outer retinal layer thinning in all eyes. Additionally, the 14 eyes with peripheral SD-OCTs demonstrated patchy loss of the inner segment ellipsoid band. Microperimetry exhibited patchy visual sensitivity loss in 9 eyes. Full field ERGs were variable, ranging from normal to severely abnormal rod and cone responses. Our findings suggest that an optimal protocol for identifying carriers of XLRP should include 488-R imaging in a multimodal approach. Peripheral SD-OCT imaging and central retinal layer quantification revealed significant structural abnormalities. PMID- 23669304 TI - An alginate-antacid formulation localizes to the acid pocket to reduce acid reflux in patients with gastroesophageal reflux disease. AB - BACKGROUND & AIMS: Alginate rafts (polysaccharide polymers that precipitate into a low-density viscous gel when they contact gastric acid) have been reported to form at the acid pocket, an unbuffered pool of acid that floats on top of ingested food and causes postprandial acid reflux. We studied the location of an alginate formulation in relation to the acid pocket and the corresponding effects on reflux parameters and acid pocket positioning in patients with gastroesophageal reflux disease (GERD). METHODS: We randomly assigned patients with symptomatic GERD and large hiatal hernias to groups who were given either (111)In-labeled alginate-antacid (n = 8, Gaviscon Double Action Liquid) or antacid (n = 8, Antagel) after a standard meal. The relative positions of labeled alginate and acid pocket were analyzed for 2 hours by using scintigraphy; reflux episodes were detected by using high-resolution manometry and pH-impedance monitoring. RESULTS: The alginate-antacid label localized to the acid pocket. The number of acid reflux episodes was significantly reduced in patients receiving alginate-antacid (3.5; range, 0-6.5; P = .03) compared with those receiving antacid (15; range, 5-20), whereas time to acid reflux was significantly increased in patients receiving alginate-antacid (63 minutes; range, 23-92) vs those receiving antacid (14 minutes; range, 9-23; P = .01). The acid pocket was located below the diaphragm in 71% of patients given alginate-antacid vs 21% of those given antacid (P = .08). There was an inverse correlation between a subdiaphragm position of the acid pocket and acid reflux (r = -0.76, P < .001). CONCLUSIONS: In a study of 16 patients with GERD, we observed that the alginate antacid raft localizes to the postprandial acid pocket and displaces it below the diaphragm to reduce postprandial acid reflux. These findings indicate the importance of the acid pocket in GERD pathogenesis and establish alginate-antacid as an appropriate therapy for postprandial acid reflux. PMID- 23669303 TI - PI 3-kinase independent role for AKT in F-actin regulation during outer segment phagocytosis by RPE cells. AB - Daily phagocytosis of photoreceptor outer segment fragments (POS) by the retinal pigment epithelium (RPE) is essential for vision. RPE cells use an uptake machinery that is highly similar to the one macrophages use to phagocytose apoptotic cells. In both forms of phagocytosis, particle binding induces phagocyte signaling that is required for F-actin assembly and re-arrangement beneath bound particles. Macrophage binding of apoptotic cells stimulates PI3 kinases (PI3K) and AKT kinases (AKT), which may be downstream of PI3K, and PI3K inhibition decreases engulfment. Here, we used specific inhibitory agents to investigate whether and how PI3K and AKT contribute to RPE phagocytosis. Either PI3K or AKT inhibition eliminated AKT activation by RPE cells in response to POS and increased the numbers of POS bound by RPE cells. Analyzing the quality of bound POS, we found a higher fraction of POS associated with F-actin phagocytic cups and myosin II in RPE receiving AKT inhibitor. In these cells, individual POS also recruited more F-actin and myosin II than POS in control cells. In contrast, PI3K inhibition did not alter frequency of phagocytic cups but individual cups contained less F-actin (but similar levels of myosin II) compared to control cups. Annexin AII, another phagocytic cup protein of RPE cells, associated with bound POS regardless of inhibitor treatment. POS engulfment proceeded normally if cells already carried surface-bound POS when receiving inhibitors. However, PI3K inhibition during POS binding blocked subsequent POS engulfment. In striking contrast, AKT inhibition had no effect on POS engulfment. Taken together, these results suggest distinct regulatory roles of PI3K and AKT during POS phagocytosis by RPE cells. PMID- 23669305 TI - Prevalence and lifetime risk of endoscopy-related complications among patients with inflammatory bowel disease. AB - BACKGROUND & AIMS: Few studies have analyzed the safety of endoscopy in patients with inflammatory bowel disease (IBD). We aimed to determine the prevalence of procedure-related complications among these patients, compared with the general population, and estimate the lifetime risk of colonoscopy-related complications. METHODS: We collected data on complications in 685 patients with IBD and 17,000 patients without IBD (controls) using an automated system to track all emergency department visits to the Beth Israel Deaconess Medical Center within 14 days of an endoscopic procedure, from March 1, 2007, to November 30, 2007. We reviewed charts of all IBD patients to determine health care use (telephone calls or visits to a gastroenterologist or primary care physician and visits to other emergency departments or hospitals) after endoscopy. The lifetime risk of procedure-related complications was estimated using a Markov Monte Carlo model. RESULTS: Rates of complications were 1.17% among patients with IBD and 0.96% among controls (P = .55). The chart review showed that 3.8% of the IBD cohort received medical care within 14 days of the endoscopic procedure. Based on a Markov Monte Carlo simulation model, the lifetime risk of complications after a surveillance colonoscopy protocol was 12.7% among patients with IBD and 2.0% in the general population undergoing screening colonoscopy (P < .001). CONCLUSIONS: Although the risk of adverse events after each endoscopic procedure was similar for patients with IBD and the general population, IBD patients have an increased lifetime risk of complications after colonoscopies. A higher percentage of patients with IBD also seek medical care after endoscopic procedures than controls. PMID- 23669306 TI - Diverticular disease: reconsidering conventional wisdom. AB - Colonic diverticula are common in developed countries and complications of colonic diverticulosis are responsible for a significant burden of disease. Several recent publications have called into question long-held beliefs about diverticular disease. Contrary to conventional wisdom, studies have not shown that a high-fiber diet protects against asymptomatic diverticulosis. The risk of developing diverticulitis among individuals with diverticulosis is lower than the 10% to 25% proportion that commonly is quoted, and may be as low as 1% over 11 years. Nuts and seeds do not increase the risk of diverticulitis or diverticular bleeding. It is unclear whether diverticulosis, absent diverticulitis, or overt colitis is responsible for chronic gastrointestinal symptoms or worse quality of life. The role of antibiotics in acute diverticulitis has been challenged by a large randomized trial that showed no benefit in selected patients. The decision to perform elective surgery should be made on a case-by-case basis and not routinely after a second episode of diverticulitis, when there has been a complication, or in young people. A colonoscopy should be performed to exclude colon cancer after an attack of acute diverticulitis but may not alter outcomes among individuals who have had a colonoscopy before the attack. Given these surprising findings, it is time to reconsider conventional wisdom about diverticular disease. PMID- 23669307 TI - Synergistic effects of family history of hepatocellular carcinoma and hepatitis B virus infection on risk for incident hepatocellular carcinoma. AB - BACKGROUND & AIMS: Little is known about the effects of family history of hepatocellular carcinoma (HCC) on hepatitis B progression or risk of HCC. We examined how family HCC history and presence or stage of hepatitis B virus (HBV) infection affect risk for HCC. METHODS: We performed a population-based cohort study of 22,472 participants from 7 townships in Taiwan who underwent evaluation for liver disease from 1991 through 1992. Those who received a first diagnosis of HCC from January 1, 1991, to December 31, 2008, were identified from the Taiwanese cancer registry. RESULTS: There were 374 cases of incident HCC over 362,268 person-years of follow-up evaluation. The cumulative risk of HCC in hepatitis B surface antigen (HBsAg)-seronegative patients without a family history of HCC was 0.62%, in those with a family history of HCC the cumulative risk was 0.65%, in HBsAg-seropositive patients without a family history of HCC the cumulative risk was 7.5%, and in HBsAg-seropositive patients with a family history of HCC the cumulative risk was 15.8% (P < .001). The multivariate adjusted hazard ratio for HBsAg-seropositive individuals with family history, compared with HBsAg-seronegative individuals without a family history of HCC, was 32.33 (95% confidence interval, 20.8-50.3; P < .001). The relative excess risk owing to interaction was 19, the attributable proportion was 0.59, and the synergy index value was 2.54. These findings indicate synergy between family HCC history and HBsAg serostatus. The synergy between these factors remained significant in stratification analyses by HBeAg serostatus and serum level of HBV DNA. CONCLUSIONS: Family history of HCC multiplies the risk of HCC at each stage of HBV infection. Patients with a family history of HCC require more intensive management of HBV infection and surveillance for liver cancer. PMID- 23669308 TI - Uptake of genetic testing by relatives of lynch syndrome probands: a systematic review. AB - BACKGROUND & AIMS: Screening of persons with newly diagnosed colorectal cancer for Lynch syndrome can yield substantial benefits at acceptable costs, presuming sufficient uptake of genetic testing by first-degree relatives of Lynch syndrome probands. We performed a systematic review of the literature to determine the frequency of and factors associated with genetic testing of first-degree relatives of Lynch syndrome probands. METHODS: We searched 4 databases (CINAHL, PsycInfo, PUBMED, and SCOPUS) for articles published through May 2011 reporting uptake of genetic testing by relatives of Lynch syndrome probands. Two investigators independently screened articles to determine whether they met inclusion criteria; data were collected on study population, genetic counseling, and genetic testing. A narrative, qualitative systematic review was performed. RESULTS: We identified 1258 potentially relevant articles; 533 underwent full text review, and 8 were included in the final analysis. Of first-degree relatives of Lynch syndrome probands, 52% or less received genetic testing. For each proband, 3.6 or fewer relatives underwent genetic testing. Demographic factors (age <50 years, female sex, parenthood, level of education, employment, participation in medical studies), psychological factors (lack of depressive symptoms), and possibly family history (greater number of relatives with cancer) were associated with uptake of genetic testing. CONCLUSIONS: Genetic testing appears to be underutilized by first-degree relatives of patients with Lynch syndrome. The clinical benefit and economic feasibility of screening persons with colorectal cancer for Lynch syndrome depend on optimizing family-wide uptake of genetic testing. Future research and clinical efforts should focus on ways to overcome barriers to genetic testing. PMID- 23669309 TI - Transient flare of ulcerative colitis after fecal microbiota transplantation for recurrent Clostridium difficile infection. AB - Clostridium difficile infection (CDI) is a common cause of infectious diarrhea and is usually treated with metronidazole or vancomycin. CDI recurs in 15%-30% of patients after the initial episode and in up to 65% after a second episode. Recurrent infections are a challenge to treat, and patients are usually managed with prolonged pulsed or tapered vancomycin. Fecal microbiota transplantation is an alternative treatment that has a 91% rate of success worldwide, with no reported complications. We describe a patient with ulcerative colitis that had been quiescent for more than 20 years who developed a flare of ulcerative colitis after fecal microbiota transplantation, indicating the need for caution in treating CDI with fecal microbiota transplantation in patients with inflammatory bowel disease. PMID- 23669310 TI - Signaling networks of Rho GTPases in cell motility. AB - The last decades have witnessed an exponential increase in our knowledge of Rho GTPase signaling network which further highlighted the cross talk between these proteins and the complexity of their signaling pathways. In this review, we summarize the upstream and downstream players from Rho GTPases that are mainly involved in actin polymerization leading to cell motility and potentially playing a role in cancer cell metastasis. PMID- 23669311 TI - Speciation of platinum in blood plasma and urine by micelle-mediated extraction and graphite furnace atomic absorption spectrometry. AB - A highly sensitive and selective technique for the speciation of platinum by cloud point extraction prior to determination by graphite furnace atomic absorption spectrometry (GFAAS) was described. The separation of Pt(II) from Pt(IV) was performed in the presence of 4-(p-chlorophenyl)-1-(pyridin-2 yl)thiosemicarbazide (HCPTS) as chelating agent and Triton X-114 as a non-ionic surfactant. The extraction of Pt(II)-HCPTS complex needs temperature higher than the cloud point temperature of Triton X-114 and pH = 7, while Pt(IV) remains in the aqueous phase. The Pt(II) in the surfactant phase was analyzed by GFAAS, and the concentration of Pt(IV) was calculated by subtraction of Pt(II) from total platinum which was directly determined by GFAAS. The effect of pH, concentration of chelating agent, surfactant, and equilibration temperature were investigated. An enrichment factor of 42 was obtained for the preconcentration of Pt(II) with 50 mL solution. Under the optimum experimental conditions, the calibration curve was linear up to 30 MUgL(-1) with detection limit of 0.08 MUgL(-1) and the relative standard deviation was 1.8%. No considerable interference was observed due to the presence of coexisting anions and cations. The accuracy of the results was verified by analyzing different spiked samples (tap water, blood plasma and urine). The proposed method was applied to the speciation analysis of Pt in blood plasma and urine with satisfactory results. PMID- 23669312 TI - Syntheses, characterization, antimicrobial and cytotoxic activities of pyridine 2,5-dicarboxylate complexes with 1,10-phenanthroline. AB - In this study, four mononuclear M(II)-pyridine-2,5-dicarboxylate (M = Co(II), Ni(II), Cu(II) and Zn(II) complexes with pyridine-2,5-dicarboxylic acid or isocinchomeronic acid, 1,10-phenanthroline (phen), [Co(Hpydc)(2)(phen)].H(2)O (1), [Ni(pydc)(phen)(2)].6.5H(2)O (2) [Cu(pydc)(phen)(H(2)O)(2)] (3) and [Zn(pydc)(phen)(H(2)O)(2)].H(2)O (4) have been synthesized. Elemental, thermal and mass analyses, molar conductance, magnetic susceptibilities, IR and UV/vis spectroscopic studies have been performed to characterize the complexes. Subsequently, these ligands and complexes were tested for antimicrobial activity by disc diffusion method on Gram positive, negative bacteria and yeast. In addition, cytotoxic activity tests were performed on rat glioma (C6) cells by MTT viability assay for 24 and 48 h. Antimicrobial activity results demonstrated that when compared to the standard antibiotics, phen displayed the most effective antimicrobial effect. The effect of synthesized complexes was close to phen or less. Cytotoxic activity results showed that IC(50) value of phen was determined as 31 MUM for 48 h. (1) and (2) compared to the alone ligand had less toxic activity. IC(50) values of (3) for 24 and 48 h treatments were 2.5 and 0.6 MUM, respectively. IC(50) value of (4) for 48 h was 15 MUM. In conclusion, phen, (3) and (4) may be useful as antibacterial and antiproliferative agents in the future. PMID- 23669313 TI - Relevance of sonochemistry or ultrasound (US) as a proficient means for the synthesis of fused heterocycles. AB - Medicinal chemistry has been benefited by combinatorial chemistry and high throughput parallel synthesis. The use of sonochemistry under controlled conditions has been proved beneficial for medicinal chemistry and drug discovery process since it dramatically reduces reaction times, from days or hours to minutes. In addition, sonochemistry synthesis provides higher yields, lower cost, easy workups and greater purity as compared to lower yields, tedious workups, longer reaction times, lesser purity and termination of many by-products in the conventional thermal methods. PMID- 23669314 TI - Health despite frailty: exploring influences on frail older adults' experiences of health. AB - The aim of this study was to explore and identify influences on frail older adults' experience of health. A sample of older adults, 11 men and 11 women aged 67-92, with diverse ratings of self-perceived health ranging from poor to excellent were selected through a purposeful strategic sampling of frail older adults taken from a broader sample from a quantitative study on health. In total, 22 individual qualitative interviews were analyzed using qualitative content analysis in which themes were developed from raw data through a systematic reading, categorization of selected text, theme development and interpretation. To feel assured and capable was the main theme, which consisted of five subthemes: managing the unpredictable body, reinforcing a positive outlook, remaining in familiar surroundings, managing everyday life, and having a sense of belonging and connection to the whole. The importance of supporting frail older adults in subjective resilience in their context is emphasized. PMID- 23669315 TI - [Mephedrone: a new synthetic drug]. AB - Mephedrone is a synthetic psychostimulant derived from cathinone belonging to the family of phenylethylamines. Sold on the Internet, it has recently emerged in France in recreational settings, and is mostly consumed by young people from the gay community and festive environment. Identified in 2008 by the European Monitoring Centre for Drugs and Drug Addiction as a new drug on the market, the use of mephedrone has attracted media attention following the suspicious deaths of two young adults in Sweden and in England. Its legal aspect, ease of getting it on the Internet and cheap price coupled and an alternative-seeking to other psychostimulants make mephedrone a prime target for these populations and a source of abuse, with psychiatric and somatic complications. There is no curative pharmacological treatment approved by health authorities. PMID- 23669316 TI - [Senile systemic amyloidosis: definition, diagnosis, why thinking about?]. AB - Senile systemic amyloidosis (SSA) is characterized by infiltration of amyloid transthyretin fibrils in the myocardium. SSA occurs mainly (but not always) in elderly men. SSA leads to hypertrophic and/or restrictive cardiomyopathy complicated by conduction disturbances, atrial arrhythmia and systemic embolization (stroke...). That is why SSA needs a special care and to be diagnosed. Cardiac SSA diagnosis needs to exclude two other forms of cardiac amyloidosis: AL amyloidosis (light chain) and hereditary transthyretin amyloidosis (genetic testing). Scintigraphic 99mTc-DPD heart retention is observed in cardiac amyloidosis. DPD heart retention is more frequent in cardiac transthyretin amyloidosis than in cardiac AL amyloidosis. Specific treatments of cardiac TTR amyloidosis are in development. PMID- 23669317 TI - [Tabacco during pregnancy: a risk factor for addiction and psychiatric diseases?]. AB - The use of tobacco during pregnancy is a risk factor for cognitive and comportemental disorders in childhood and adolescent. TDHA, addiction and psychiatric diseases are more frequent in adolescent and adult with tobacco use during pregnancy. Strategies to quit smoking in pregnant women may improve mental health. PMID- 23669318 TI - [Juvenile spring eruption]. PMID- 23669319 TI - [Vascular rehabilitation in patients with peripheral arterial disease]. AB - Lower limb peripheral arterial disease (PAD) is a frequent debilitating disease associated with a high morbidity and mortality rate. The benefit of rehabilitation in PAD patients has been largely demonstrated, both for patients that undergo amputation, and for patients with claudication. In these latter patients, rehabilitation programs rely on a variety of additional techniques or tools, among which: stretching, specific muscle proprioception, walking and a variety of other physical activities, exercise or situations adapted to community life, lower limb and respiratory physiotherapy, patient's education, support for smoking cessation and healthy nutrition, social support, etc. Whether rehabilitation is performed in specialised integrated structures or performed on a home-based basis, various clinicians are involved. Despite evidence-based proof of efficacy, rehabilitation of PAD patients with claudication is still under used. PMID- 23669320 TI - [Leper's island: Spinalonga]. PMID- 23669321 TI - Cutaneous pigmented patches. PMID- 23669322 TI - Estrogen receptor GPR30 exerts anxiolytic effects by maintaining the balance between GABAergic and glutamatergic transmission in the basolateral amygdala of ovariectomized mice after stress. AB - G-protein-coupled receptor 30 (GPR30)/G-protein-coupled estrogen receptor is a novel estrogen membrane receptor that localizes to the cell membrane and endoplasmic reticulum. GPR30 is widely distributed and has numerous physiological functions in the central nervous system. We found that GPR30 is highly expressed in the basolateral amygdala (BLA). Additionally, GPR30 expression in the amygdala of ovariectomized (OVX) mice significantly increased after acute stress and was accompanied by anxiety-like behaviors. These effects, however, were reversed by local infusion of the GPR30 agonist (G1) in the BLA. Protein assessments revealed that G1 attenuated the up-regulation of the GluR1 subunit of the alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and NR2A-containing N methyl-d-aspartate receptors (NMDARs) in the BLA of OVX mice using an acute stress paradigm. In the same model, we found that the agonist also blocked the down-regulation of gamma-aminobutyric acid A (GABAA) receptors and NR2B containing NMDARs. Electrophysiological recording showed that the activation of GPR30 increased the inhibitory synaptic transmission in the BLA. Overall, our results indicate that estradiol reduces anxiety-like behaviors induced by acute stress at least partially through GPR30 signaling, maintaining the balance between GABAergic and glutamatergic transmission in the BLA of OVX-stressed mice. PMID- 23669323 TI - Early postnatal interference with the expression of multiple Sp1 regulated genes leads to disparate behavioral response to sub-chronic and chronic stress in rats. AB - BACKGROUND: It is currently accepted that complex behavior and mental disorder results from a combination of biological susceptibility and exposure to environmental stimuli. Most of the gene-environment interaction models focus on the interaction between the stimuli and a single candidate gene. We suggest that an alternative approach is interference with the expression of multiple genes followed by exposure to environmental insults. METHODS: Early interference with gene transcription was performed by treatment of 7 days old Wistar male rats for 4 days with the Sp1/DNA binding inhibitor, mithramycin. Environmental insult was mimicked by exposing these rats during adulthood (34 days) to sub-chronic (12 days, n=30) or chronic stress (28 days, n=48). The effects of mithramycin and stress treatment on the behavioral response and serum corticosterone concentration were assessed. RESULTS: Exposure of mithramycin treated rats to sub chronic stress led to anxious behavior in the open field test, high startle response, low sucrose preference, indifference to novel objects and high serum corticosterone concentration. However, exposure to chronic stress resulted in normal sucrose preference, startle response and serum corticosterone, novelty seeking behavior and reduced anxiety. In saline treated rats the extension of stress duration led to behavioral and hormonal adaptation to stress. CONCLUSION: Our study suggests that postnatal temporal interference with multiple gene expression can lead to hyper-responsiveness to environmental stimuli, the features of which affects the phenotypic outcomes. Such a paradigm may be used to model gene-environmental interaction in the etiology of behavioral disorders. PMID- 23669324 TI - Gut dysfunction in patients with multiple sclerosis and the role of spinal cord involvement in the disease. AB - OBJECTIVES: Bowel and bladder symptoms are highly prevalent in patients with multiple sclerosis (MS). Bladder dysfunction (affecting 75% of these patients) is caused by disease in the spinal cord, whilst the pathophysiology of bowel dysfunction is unknown. Pathways regulating both the organs lie in close proximity to the spinal cord, and coexistence of their dysfunction might be the result of a common pathophysiology. If so, the prevalence of bladder symptoms should be greater in patients with MS and bowel symptoms. This hypothesis is tested in the study. We also evaluated how patient-reported symptoms quantify bowel dysfunction. PATIENTS AND METHODS: The Neurogenic Bowel Dysfunction questionnaire and the presence of bladder symptoms were recorded in 71 patients with MS and bowel symptoms. Disability, a surrogate clinical measure of spinal cord disease, was assessed using the Expanded Disability Status Scale. Bowel and bladder symptoms were quantified by patient-reported frequency, expressed in time percentage (0, 25, 50, 75 or 100% of the time the symptom was perceived), and patient-reported severity on a visual analogue scale between 0 and 100. RESULTS: The prevalence of bladder symptoms was 85%, which is higher than that expected in an unselected population of patients with MS. Neurogenic Bowel Dysfunction score was significantly correlated with both patient-reported frequency (r=0.860, P<0.0001) and severity of bowel symptoms (r=0.659, P=<0.0001), as well as with the Expanded Disability Status Scale (r=0.526, P<0.0001). CONCLUSION: Our findings suggest that gut dysfunction in patients with MS is secondary to spinal cord disease. Patient-reported bowel symptoms quantify bowel dysfunction well. PMID- 23669325 TI - Interest of a new biodegradable stent coated with paclitaxel on anastomotic wound healing after biliary reconstruction. AB - OBJECTIVE: Benign biliary stricture of anastomotic stoma is frequent after biliary reconstruction. To prevent such a complication, a new paclitaxel-coated poly-L-lactide acid (PLLA) biodegradable biopolymer stent was designed. This original device was intended both to exert adequate mechanical support properties and to allow controlled drug delivery from the coating, with the goal of favoring wound healing after biliary reconstruction. METHODS: PLLA stents coated with three different paclitaxel concentrations were implanted in the biliary anastomosis of mongrel dogs (defining groups B, C, and D, respectively). Dogs without stent placement were included in control group A. Liver function tests and residual dosage of paclitaxel from each stent were measured. Histological data and alpha-smooth muscle actin immunohistochemical staining of biliary enteric anastomosis were examined. RESULTS: There were no significant differences in liver function among the four groups and no bile leakage was observed. The paclitaxel-coated stents could slowly release paclitaxel for 9 weeks. In groups C and D, histological examinations showed less granulation tissue and glandular hyperplasia in biliary-enteric anastomosis than in control groups A and B. Submucosal collagen deposition was reduced and alpha-smooth muscle actin-positive cells decreased significantly, indicating the inhibition of myofibroblast proliferation in groups C and D. CONCLUSION: PLLA-paclitaxel-coated stents reduced the proliferation of granulation tissue and glandular hyperplasia, and inhibited the myofibroblast proliferation and extracellular matrix overdeposition during the healing process of biliary-enteric anastomotic stoma. This original device may offer a new way for the prevention of benign biliary structure. PMID- 23669327 TI - Sensitive analysis of aminoglycoside antibiotics via hyphenation of transient moving substitution boundary with field-enhanced sample injection in capillary electrophoresis. AB - A novel field-enhanced sample injection coupled with transient moving substitution boundary method in capillary electrophoresis was developed for aminoglycoside antibiotic (AG) analysis using 18-crown-6-tetracarboxylic acid (18C6H4) as a pseudostationary phase. Results indicated that the stacking mechanism of moving substitution boundary relied on the substitution reaction between 18C6H4-bonded AG complexes and Na(+) at the substitution boundary. The stacking mechanism as well as important parameters governing pre-concentration and separation have been investigated in order to obtain maximum resolution and sensitivity. Under optimized conditions, using a sample prepared in a low conductivity matrix, the limits of detection for streptomycin, neomycin, and kanamycin were 0.62, 5.9 and 8.6 nM (S/N=3), respectively, and the detection sensitivities were improved 940-, 692-, and 415-fold, respectively. The method also gave accurate and reliable results in the analysis of AGs in river water samples. PMID- 23669326 TI - Post challenge inhibition of C3 and CD14 attenuates Escherichia coli-induced inflammation in human whole blood. AB - Combined inhibition of CD14 and complement, two main inducers of the inflammatory response, have proved particularly effective in attenuating Gram-negative bacteria-induced inflammation. Approaching possible clinical relevance, we investigated the effect of such inhibition in a post-challenge setting. Human whole blood was anti-coagulated with lepirudin. Anti-CD14, compstatin (C3 inhibitor) and the combination thereof were added 5 min prior to or 5, 15 or 30 min after adding Escherichia coli. Total incubation time with Escherichia coli was 120 min. Cytokines, myeloperoxidase (MPO) and the terminal complement complex (TCC) were measured using multiplex technology and ELISA. Delayed combined inhibition significantly attenuated the inflammatory response. IL-1beta, IL-8 and TNF-alpha were significantly inhibited in the range of 20-40%, even when adding the inhibitors with up to 30 min delay. IL-6 was significantly inhibited with 15 min delay, and MIP-1alpha and MPO with 5 min delay. Complement activation (TCC) was blocked completely at each time point compstatin was added, whereas the cytokines and MPO increased steadily between the time points. The combined regimen was significantly more effective than single inhibition in the pre challenge setting. The attenuation of Escherichia coli-induced inflammation in a post-challenge setting suggests a potential therapeutic window for this treatment in sepsis. PMID- 23669328 TI - Study of the peak variance in isocratic and gradient liquid chromatography using the transport model. AB - The expressions accounting for the peak variance in isocratic and gradient liquid chromatography is derived from the transport model. In mathematical treatments, the dwelling time is taken into account, and the type of solvent strength, gradient profile and the variation of plate height (H) with mobile phase composition (phi) is not specified. By applying a coordinate transformation, the transport model is solved by using the Laplace transform approach. A plate height equation that is suited for both isocratic and gradient elution is obtained. Based on this equation, the plate height equations for any combination of stepwise and linear gradients are derived. These equations will be algebraic when the solvent strength is linear and the H-phi plot is parabolic. The plate height equations for single stepwise, single linear and the ladder-like gradients are also given. PMID- 23669329 TI - A review of the clinical variants and the management of psoriasis. AB - PURPOSE: To enhance the learner's competence with knowledge of the clinical variants and management of psoriasis. TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. OBJECTIVES: After participating in this educational activity, the participant should be better able to:1. Demonstrate knowledge of the types, symptoms, and diagnostic testing of psoriasis.2. Apply knowledge of psoriasis treatment to patient care scenarios. ABSTRACT: Psoriasis is an inflammatory skin condition that is associated with various comorbidities. To the wound care physician, the Koebner phenomenon is of importance, as any superficial trauma can induce psoriasis. Particularly, periwound and joints are particularly susceptible to flare-ups of this condition. This review highlights the epidemiology and treatment of psoriasis. PMID- 23669330 TI - Autologous platelet-rich plasma in chronic wounds. PMID- 23669331 TI - Use of in silico systems and expert knowledge for structure-based assessment of potentially mutagenic impurities. AB - Genotoxicity hazard identification is part of the impurity qualification process for drug substances and products, the first step of which being the prediction of their potential DNA reactivity using in silico (quantitative) structure-activity relationship (Q)SAR models/systems. This white paper provides information relevant to the development of the draft harmonized tripartite guideline ICH M7 on potentially DNA-reactive/mutagenic impurities in pharmaceuticals and their application in practice. It explains relevant (Q)SAR methodologies as well as the added value of expert knowledge. Moreover, the predictive value of the different methodologies analyzed in two surveys conveyed in the US and European pharmaceutical industry is compared: most pharmaceutical companies used a rule based expert system as their primary methodology, yielding negative predictivity values of ?78% in all participating companies. A further increase (>90%) was often achieved by an additional expert review and/or a second QSAR methodology. Also in the latter case, an expert review was mandatory, especially when conflicting results were obtained. Based on the available data, we concluded that a rule-based expert system complemented by either expert knowledge or a second (Q)SAR model is appropriate. A maximal transparency of the assessment process (e.g. methods, results, arguments of weight-of-evidence approach) achieved by e.g. data sharing initiatives and the use of standards for reporting will enable regulators to fully understand the results of the analysis. Overall, the procedures presented here for structure-based assessment are considered appropriate for regulatory submissions in the scope of ICH M7. PMID- 23669332 TI - Xanthohumol, a main prenylated chalcone from hops, reduces liver damage and modulates oxidative reaction and apoptosis in hepatitis C virus infected Tupaia belangeri. AB - Hepatitis C virus (HCV) infection in Tupaia belangeri (Tupaia) represents an important model of HCV infection. Xanthohumol (XN), a major prenylated chalcone from hops, has various biological activities including hepatopreventive and anti viral activities. In this study, Tupaias infected with HCV RNA positive serum were used to evaluate the effects of XN on liver damage, oxidative reaction, apoptosis and viral protein expression in liver tissues. The Tupaias inoculated with HCV positive serum had elevated serum aminotransferase levels and inflammation, especially hepatic steatosis, and HCV core protein expression in liver tissue. In the animals inoculated with HCV positive serum, XN significantly decreased aminotransferase levels, histological activity index, hepatic steatosis score and transforming growth factor beta1 expression in liver tissue compared with the animals without XN intervention. XN reduced HCV core protein expression in liver tissue compared with those without XN intervention but the difference was not significant. XN significantly decreased malondialdehyde, potentiated superoxide dismutase and glutathione peroxidase, reduced Bax expression, promoted Bcl-xL and inhibited caspase 3 activity in liver tissues compared with the animals without XN intervention. These results indicate that XN may effectively improve hepatic inflammation, steatosis and fibrosis induced by HCV in Tupaias primarily through inhibition of oxidative reaction and regulation of apoptosis and possible suppression of hepatic stellate cell activation. The anti-HCV potential of XN needs further investigation. PMID- 23669333 TI - Intravenous immunoglobulin products contain specific antibodies to recombinant human tau protein. AB - Intravenous immunoglobulin (IVIG) products are prepared from plasma immunoglobulins from healthy donors. Pilot studies suggest that IVIG may stabilize cognitive functioning in patients with mild-to-moderate Alzheimer's disease. This study measured antibodies to recombinant human tau protein in the IVIG products Gammagard (Baxter), Gamunex (Talecris), and Flebogamma (Grifols). Anti-tau antibodies were measured by ELISA, subtracting IVIG's polyvalent binding from its binding to tau-coated wells to calculate specific anti-tau antibody levels. Because polyvalent binding of IVIG products may interfere with ELISA measurement of their specific antibody levels, the percentage of binding of each IVIG product to tau-coated wells that was specific for tau was also determined. Specific anti-tau antibodies were detected in all three IVIG products, with significant differences between these products (p<0.001) even when Flebogamma's anti-tau antibodies were doubled to account for its preparation as a 5% solution vs. 10% solutions for Gammagard and Gamunex (means: Gammagard, 3.1 MUg/ml; Gamunex, 2.5 MUg/ml; Flebogamma, 1.2 MUg/ml). The percentages of each IVIG product's specific binding to tau-coated wells also varied between the various products (p<0.001) and between all pairs of IVIG products (means: Gammagard, 73.1%; Flebogamma, 54.5%; Gamunex, 37.4%; p<0.01 for all pairwise comparisons). These findings indicate that IVIG products contain specific anti-tau antibodies. The concentrations of these antibodies and the percentages of specific binding of IVIG to tau-coated wells vary between IVIG products. Further studies are indicated to determine if IVIG also contains antibodies to pathologic forms of tau. PMID- 23669334 TI - Effect of dietary nucleotides on immune function in Balb/C mice. AB - This study investigated the effect of dietary nucleotides (NTs) on immune function in female Balb/C mice, which randomly distributed into six groups: one control group, one NF-free (NF) control group and four NT groups. NTs ranged from 0.0025% to 0.64%. Compared with the control group, the NF could significantly weaken the activity of T lymphocytes and macrophages, as well as decreased the activity of B lymphocytes and NK cell. NF significantly decreased the ratio of CD4(+)/CD8(+), whereas, it increased Tr percentage. In comparison with the NF group, the concentration of serum IL-2 and IL-4 showed an increase trend. Meanwhile, the granular cell macrophages colony stimulating factor (GM-CSF) increased significantly in the 0.04% NT group. The ratio of Th1/Th2 also showed an increasing trend after the supplements of NTs. There were no significant differences between the control and 0.04% NT group. Nevertheless, no significant differences in weight gain and lymphoid organ indices were observed in our study. These results indicate that NT supplements can prevent hypoimmunity which result from NF diet. 0.04% NTs is the healthy optimal supply proportion in mice diet. PMID- 23669335 TI - Alpinetin attenuates inflammatory responses by interfering toll-like receptor 4/nuclear factor kappa B signaling pathway in lipopolysaccharide-induced mastitis in mice. AB - Alpinetin, a novel plant flavonoid derived from Alpinia katsumadai Hayata, has been reported to exhibit anti-inflammatory properties. However, the effect of alpinetin on mastitis has not been investigated. The aim of this study was to investigate the protective effect of alpinetin against lipopolysaccharide (LPS) induced mastitis and to clarify the possible mechanism. In the present study, primary mouse mammary epithelial cells and an LPS-induced mouse mastitis model were used to investigate the effect of alpinetin on mastitis and the possible mechanism. In vivo, we observed that alpinetin significantly attenuated the infiltration of neutrophilic granulocytes, and the activation of myeloperoxidase; down-regulated the level of pro-inflammatory cytokines, including TNF-alpha, IL 1beta and IL-6; inhibited the phosphorylation of IkappaB-alpha, NF-kappaB p65 and the expression of TLR4, caused by LPS. In vitro, we also observed that alpinetin inhibited the expression of TLR4 and the production of TNF-alpha, IL-1beta and IL 6 in LPS-stimulated primary mouse mammary epithelial cells. However, alpinetin could not inhibit the production of IL-1beta and IL-6 in TNF-alpha-stimulated primary mouse mammary epithelial cells. In conclusion, our results suggest that the anti-inflammatory effects of alpinetin against LPS-induced mastitis may be due to its ability to inhibit TLR4-mediated NF-kappaB signaling pathways. Alpinetin may be a promising potential therapeutic reagent for mastitis treatment. PMID- 23669336 TI - Association of CD40--1C/T polymorphism with cerebral infarction susceptibility and its effect on sCD40L in Chinese population. AB - This study aims to determine whether functional polymorphism of CD40 is associated with the cerebral infarction (CI) susceptibility, and to investigate the effect of CD40 gene polymorphism on CD40 mRNA expression in PBMCs and plasma sCD40L concentration. A case-control study was performed in 402 CI patients and 693 controls. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The expressions of CD40 mRNA and plasma sCD40L concentration were determined. The distribution of TT genotype and the frequency of T allele in CI patients were significantly higher than those in the controls (P<0.05). The frequency of T allele was also significantly higher in the male subjects and the elder subjects (P<0.05) when stratified analysis was carried out. The PBMCs from CI patients showed significantly higher CD40 mRNA expression than controls (P<0.01), the CD40 mRNA expression from TT genotype was higher than other genotypes (P<0.05). TT genotype subjects also showed the highest plasma sCD40L concentration in the male CI patients (P<0.01). CD40 -1C/T polymorphism may interfere CI susceptibility, and the T allele may be associated with increased risk of CI. The CD40 -1C/T polymorphism is also a regulator of CD40 expression and plasma sCD40L concentration. PMID- 23669337 TI - Evaluation of an ompA-based phage-mediated DNA vaccine against Chlamydia abortus in piglets. AB - Chlamydia abortus (C. abortus) is an obligate intracellular pathogen that causes abortion in pigs and poses a zoonotic risk in pregnant women. Although attenuated and inactivated vaccines are available, they do not provide complete protection in animals underlining the need to develop new vaccines. In this study, we tested the hypothesis that intramuscular immunization with an ompA-based phage-mediated DNA chlamydial vaccine candidate will induce significant antigen-specific cellular and humoral immune responses. Thus, groups of piglets (five per group) were immunized intramuscularly with the phage-MOMP vaccine (lambda-MOMP) or a commercial live-attenuated vaccine (1B vaccine) or a GFP-expressing phage (lambda GFP) or phosphate buffered saline (PBS) (control) and antigen-specific cell mediated and humoral immune responses were evaluated. By day 63 post immunization, the lambda-MOMP vaccine elicited significantly higher (P<0.05) levels of antigen-specific serum IgG antibody responses than the 1B vaccine or control did. Also, piglets immunized with lambda-MOMP vaccine had significantly higher (P<0.05) MOMP-specific lymphocyte proliferative responses compared to those immunized with the 1B vaccine or control. Furthermore, the total T-cell numbers (CD3+) and the proportion of CD4+ and CD8+ T-cell subsets as well as the ratio of CD4+/CD8+ T cells elicited following immunization were comparable between the lambda-MOMP- and 1B-vaccinated animals on both days 63 and 70. Interestingly, although the proportion of CD3+CD4-CD8- double negative T cells on day 63 was significantly higher (P<0.05) in the 1B vaccine group compared to the lambda-MOMP-immunized group, there was a significant decrease in the proportion of this T-cell population on day 70 in the 1B compared to the lambda-MOMP vaccinated group. These results indicate that the lambda-MOMP DNA vaccine is capable of inducing antigen-specific cellular and humoral immune responses that may provide protective immunity against a live challenge infection with C. abortus. PMID- 23669338 TI - Effect of cyclosporine on lymphocytic variant hypereosinophilic syndrome. AB - Lymphocytic variant hypereosinophilic syndromes (L-HES) is thought to be caused by the over-production of interleukin (IL)-5 by type 2 helper cells, which leads to reactive eosinophil expansion and activation. Here we demonstrate the effect of cyclosporine in a patient with L-HES. In the present case, the surface markers of cells from resected lymph nodes or peripheral blood were analyzed by flow cytometry. Serum concentrations of IL-4, IL-5, and IL-8 were measured using an enzyme-linked immunosorbent assay. Methyl-prednisolone pulse therapy followed by the administration of 150 mg/day of cyclosporine combined with 15 mg/day of prednisolone ameliorated eosinophilia. However, abnormal CD3-CD4+ T cell clones remained even when the eosinophil count recovered to normal levels. An elevated IL-8 level was observed only when eosinophils increased. On the other hand, serum IL-4 and IL-5 levels were under detectable limits during the course. Cyclosporine was effective in decreasing the eosinophil count without the elimination of abnormal T cell clones in the present case. Cytotoxic agents may be necessary to cure this serious disease. Moreover, target therapy for IL-8 may be a new strategy for L-HES with high IL-8 and low IL-5 concentrations. PMID- 23669339 TI - Health risk implications from simultaneous exposure to multiple environmental contaminants. AB - Water quality has deteriorated in the upper Olifants River system, South Africa, as a result of land use activities which include mining, agriculture and industries. A health risk assessment was conducted from 2009 to 2011 in the catchment to determine the possible risks local communities face from various pollutants such as microbials, heavy metals and oestrogen in the river water and vegetation. Aluminium and manganese accumulated in plants and vanadium and aluminium concentrations found in selective water samples posed significant health risks when consumed. A quantitative microbial risk assessment revealed that the combined risk of infection ranged from 1 to 26 percent with the Norovirus posing the overall greatest health risk. The anticipated disability adjusted life years resulting from drinking untreated water from these sites are in the order of 10,000 times greater than what is considered acceptable. The oestradiol activity, caused by endocrine disrupting compounds in the water, measured above the trigger value of 0.7ngL(-1). Impoverished communities in the area, who partially depend on river water for potable and domestic use, are exposed to immune-compromising metals that increase their probability of infection from waterborne diseases caused by the excess microbial pathogens in the contaminated surface water. PMID- 23669340 TI - Methylmercury egg injections: part 1--Tissue distribution of mercury in the avian embryo and hatchling. AB - Methylmercury (MeHg) is transferred by female birds into their eggs thus leaving developing embryos exposed to MeHg from the time of fertilization through hatching. Although Hg is a developmental toxicant, little is known about how it distributes among embryonic tissues and subsequently affects neurodevelopment in birds. The main objective of the present study (Part 1 of 2) was to evaluate the distribution of Hg in tissues during different developmental stages in order to better understand potential targets of Hg in the embryo and hatchling. Eight independent, yet related, egg injection studies were conducted. In five studies, white leghorn chicken embryos were air cell injected with methylmercury chloride (MeHgCl; range injected: 0.17-6.4MUg/g egg) and Hg concentrations were assessed in seven tissues. We found that soft tissue distribution in embryos and hatchlings was similar to that seen in older birds, with higher total Hg concentrations in liver and kidney than in heart, muscle, and brain (e.g., 5.1, 3.8, 1.9, 2.3, and 1.9MUg/g wet weight, respectively, in day 19 embryos after injection with 6.4MUg/g MeHgCl). Concentrations were highest in feathers and unabsorbed yolk (e.g., 24.1 and 13.0MUg/g in day 19 embryos after injection with 6.4MUg/g MeHgCl). Tissue concentrations rose through embryonic days 11, 14, 16, and 19 but generally leveled off at days 1 and 7 post-hatch. We also report on pilot studies that demonstrated that tissue Hg accumulation after MeHgCl injection is similar in chicken and Japanese quail embryos, and that tissue Hg accumulation in chicken embryos after methylmercury cysteine, but not mercury (2) chloride, injection is similar to accumulation after MeHgCl injection. These findings suggest that embryos may accumulate kidney and brain Hg concentrations known to cause renal and neurotoxicity seen in older birds, but that sequestration of Hg into liver and excretion into rapidly growing feathers may offer some protection. This work also demonstrates that air cell injection studies are potentially a useful tool for studies of Hg toxicity in the laboratory. PMID- 23669341 TI - Methylmercury egg injections: part 2--pathology, neurochemistry, and behavior in the avian embryo and hatchling. AB - Methylmercury (MeHg) is a toxic metal that has been frequently linked to neurochemical alterations, brain lesions, neurobehavioral changes, and reproductive impairments in wild and captive birds. Much less is known about the effects of MeHg on the developing avian brain and resulting effects on hatchling behavior. The objective of this work was to use air cell injection studies to investigate the effect of in ovo MeHg exposure on brain pathology and four neurochemical biomarkers (N-methyl-d-aspartate (NMDA) receptor, gamma aminobutyric acid (GABA) receptor, glutamine synthetase (GS) and glutamic acid decarboxylase (GAD)) that have previously been studied in wild birds, and on hatchling righting response, balance, and startle response. In a series of six studies, we exposed white leghorn chicken and Japanese quail embryos to methylmercury chloride (MeHgCl) (range: 0-6.4MUg/g egg) via egg injection on embryonic day (ED) 0 and measured receptor levels and enzyme activity at different stages of embryonic (days 11, 14, and 19 in chicken; day 15 in quail) and hatchling (day 1 and day 7) development, and in whole brain or discrete brain regions (cerebrum, cerebellum, optic lobe). We assessed neurobehaviors on post hatch (PH) days 1 and 7. Despite accumulating relatively high levels of Hg in the brain, embryos and hatchlings did not consistently display neurochemical changes consistent with those seen in wild birds and laboratory mammals. Hatchlings also did not demonstrate behavioral alterations. Pathology did not indicate a difference in occurrence and types of lesions between control and dosed birds. These findings suggest that in ovo MeHg exposure alone may not be responsible for neurological impacts in bird. This work draws attention to factors, such as age and species, that may influence responses to MeHg in birds. PMID- 23669342 TI - Triggered antioxidant defense mechanism in maize grown in soil with accumulation of Cu and Zn due to intensive application of pig slurry. AB - The present study investigated changes in both the growth parameters and the enzymatic and non-enzymatic antioxidant systems of maize (Zea may L.) plants grown in Typic Hapludalf soil containing an accumulation of Cu and Zn. This accumulation developed because the soil received nineteen applications of pig slurry in no-tillage system over seven years. In this study, the maize plants were grown for fifteen and 25 days after emergence (DAE) in pots containing undisturbed and disturbed soil samples collected from a field experiment that received the rates 0, 20, 40 and 80m(3)ha(-1) of pig slurry, which totalized the amount of 0, 380, 760 and 1520m(3)ha(-1) of pig slurry in seven years, respectively, and phosphorus (P)+potassium (K) treatment (in disturbed soil samples). The maize plants grown in the undisturbed soil samples with an accumulation of Cu and Zn did not indicate an apparent decrease in growth. However, when compared to the treatment with PK fertilization, the maize plants grown in the disturbed soil with pig slurry treatments indicated higher lipid peroxidation and a number of senescent leaves, as well as a significant decrease in plant height. Additionally, when compared to the PK treatment, the leaf superoxide dismutase and ascorbate peroxidase activities decreased and increased, respectively, with the addition of pig slurry treatments in the disturbed soil at 25 DAE. In general, when compared to the treatments with 20m(3)ha(-1) of pig slurry and PK at fifteen and 25 DAE, the leaf ascorbic acid and non-protein thiol groups concentrations decreased with the addition of 40 and 80m(3)ha(-1) of pig slurry. This result suggests that the excess of Cu and Zn in the pig slurry significantly changed the antioxidant system of the maize plants. PMID- 23669343 TI - Tamoxifen elicits atheroprotection through estrogen receptor alpha AF-1 but does not accelerate reendothelialization. AB - Based on both experimental and clinical data, tamoxifen has been proposed to have cardiovascular benefits, although the mechanism(s) contributing to that protective effect are still poorly understood. In vitro experiments demonstrated that tamoxifen elicits its transcriptional effect through estrogen receptor (ER) alpha, but other targets can participate in its actions. However, although tamoxifen selectively activates the activating function (AF)-1 of ERalpha, we recently showed that this ERalpha subfunction is dispensable for the atheroprotective action of 17beta-estradiol (E2), the main ligand of ERs. The goal of the present work is to determine to which extent ERalpha and its AF-1 mediate the vasculoprotective action of tamoxifen. Our data confirm that tamoxifen exerts an atheroprotective action on low density lipoprotein receptor (LDL-r(-/-)) female mice, but, in contrast to E2, it fails to accelerate reendothelialization after carotid electric injury. Tamoxifen and E2 elicit differences in gene expression profiles in the mouse aorta. Finally, the atheroprotective action of tamoxifen is abrogated in ERalpha(-/-)LDL-r(-/-) mice and in LDL-r(-/-) mice selectively deficient in ERalphaAF-1 (ERalphaAF-1(0/0)LDL r(-/-)). Our results demonstrate, for the first time to our knowledge, that tamoxifen mediates its actions in vivo through the selective activation of ERalphaAF-1, which is sufficient to prevent atheroma, but not to accelerate endothelial healing. PMID- 23669344 TI - Absence of SERPINB6A causes sensorineural hearing loss with multiple histopathologies in the mouse inner ear. AB - A homozygous mutation of SERPINB6, a gene encoding an intracellular protease inhibitor, has recently been associated with post-lingual, autosomal-recessive, nonsyndromic hearing loss in humans (DFNB91). Herein, we describe the physiological changes underlying SERPINB6 deficiency by analyzing mutant mice in which the orthologous gene is replaced by enhanced green fluorescent protein. SERPINB6A is present in the neurosensory epithelium, lateral wall, and spiral limbus of the cochlea, with highest levels in the inner and outer hair cells of the organ of Corti, cells lining the inner sulcus, and supporting cells distributed along the epithelial gap junction layer to the outer sulcus. Measurements of hearing thresholds in these mice demonstrated age-related hearing loss in all homozygous-null, but not heterozygous, mice. Hearing impairment was first detected at 3 weeks of age, affecting only high frequencies before spreading to other frequencies as the mice aged. The defect is associated with progressive cellular degeneration within the cochlea. This begins with the hair cells, then involves the primary auditory neurons, and, finally, the fibrocytes in the lateral wall. These findings establish these mutant mice as a suitable model system to elucidate how SERPINB6 deficiency causes deafness in humans. PMID- 23669345 TI - Long-term estradiol exposure is a direct mitogen for insulin/EGF-primed endometrial cells and drives PTEN loss-induced hyperplasic growth. AB - Loss of tumor-suppressor PTEN is the most common alteration in endometrial carcinoma. However, the relationship between loss of PTEN, growth factors [eg, insulin/insulin-like growth factor (IGF)-1], epidermal growth factor (EGF), and hyperestrogenism in the development of endometrial carcinoma is still controversial. By using three-dimensional (3D) cultures of PTEN(+/+) and PTEN(+/ ) endometrial epithelial cells, we investigated the effects of EGF, insulin/IGF, and estradiol in endometrial cell proliferation. We have previously demonstrated that 3D cultures of endometrial cells require EGF and insulin/IGF to proliferate. Herein, we demonstrate that, in the presence of EGF and insulin/IGF, long-term estradiol treatment directly induces proliferation of 3D cultures. Moreover, we show that the mitogenic effects of estradiol require the presence of insulin/IGF and EGF, because withdrawal of such factors completely abolishes estradiol induced proliferation. In the presence of EGF and insulin/IGF, PTEN(+/-) and PTEN(+/+) spheroids display a similar rate of proliferation. However, the addition of estradiol causes an exaggerated proliferation of PTEN(+/-) cultures, leading to formation of complex structures, such as those observed in endometrial hyperplasia or carcinoma. In summary, we demonstrate that EGF and insulin/IGF prime endometrial epithelial cells to direct the mitogenic effects of estradiol. Furthermore, PTEN deficiency results in enhanced responsiveness to this combination, leading to the development of hyperplasia of endometrial cells in culture. PMID- 23669346 TI - Ketogenic essential amino acids replacement diet ameliorated hepatosteatosis with altering autophagy-associated molecules. AB - Ketogenic amino acid (KAA) replacement diet has been shown to cure hepatic steatosis, a serious liver disease associated with diverse metabolic defects. In this study, we investigated the effects of KAA replacement diet on nutrition sensing signaling pathway and analyzed whether induction of hepatic autophagy was involved. Mice are fed with high fat diet (HFD) or KAA replacement in high-fat diet (30% fat in food; HFD)-fed (HFD(KAAR)) and sacrificed at 8, 12, 16 weeks after initiation of experimental food. Hepatic autophagy was analyzed in protein expression of several autophagy-associated molecules and in light chain-3 green fluorescent protein (LC-3 GFP) transgenic mice. HFD(KAAR) showed increased AMP activated protein kinase (AMPK) phosphorylation and enhanced liver kinase B1 (LKB1) expression compared to control HFD-fed mice. The KAA-HFD-induced activation of AMPK was associated with an increased protein expression of sirtuin 1 (Sirt1), decreased forkhead box protein O3a (Foxo3a) level, and suppression of mammalian target of rapamycin (mTOR) phosphorylation compared with the HFD-fed mice. The intervention study revealed that a KAA-replacement diet also ameliorated all the established metabolic and autophagy defects in the HFD-fed mice, suggesting that a KAA-replacement diet can be used therapeutically in established diseases. These results indicate that KAA replacement in food could be a novel strategy to combat hepatic steatosis and metabolic abnormalities likely involvement of an induction of autophagy. PMID- 23669347 TI - The lysosomal inhibitor, chloroquine, increases cell surface BMPR-II levels and restores BMP9 signalling in endothelial cells harbouring BMPR-II mutations. AB - Pulmonary arterial hypertension (PAH) is characterized by dysregulated pulmonary artery endothelial cell (PAEC) proliferation, apoptosis and permeability. Loss-of function mutations in the bone morphogenetic protein receptor type-II (BMPR-II) are the most common cause of heritable PAH, usually resulting in haploinsufficiency. We previously showed that BMPR-II expression is regulated via a lysosomal degradative pathway. Here, we show that the antimalarial drug, chloroquine, markedly increased cell surface expression of BMPR-II protein independent of transcription in PAECs. Inhibition of protein synthesis experiments revealed a rapid turnover of cell surface BMPR-II, which was inhibited by chloroquine treatment. Chloroquine enhanced PAEC expression of BMPR II following siRNA knockdown of the BMPR-II transcript. Using blood outgrowth endothelial cells (BOECs), we confirmed that signalling in response to the endothelial BMPR-II ligand, BMP9, is compromised in BOECs from patients harbouring BMPR-II mutations, and in BMPR-II mutant PAECs. Chloroquine significantly increased gene expression of BMP9-BMPR-II signalling targets Id1, miR21 and miR27a in both mutant BMPR-II PAECs and BOECs. These findings provide support for the restoration of cell surface BMPR-II with agents such as chloroquine as a potential therapeutic approach for heritable PAH. PMID- 23669348 TI - Genome-wide loss of 5-hmC is a novel epigenetic feature of Huntington's disease. AB - 5-Hydroxymethylcytosine (5-hmC) may represent a new epigenetic modification of cytosine. While the dynamics of 5-hmC during neurodevelopment have recently been reported, little is known about its genomic distribution and function(s) in neurodegenerative diseases such as Huntington's disease (HD). We here observed a marked reduction of the 5-hmC signal in YAC128 (yeast artificial chromosome transgene with 128 CAG repeats) HD mouse brain tissues when compared with age matched wild-type (WT) mice, suggesting a deficiency of 5-hmC reconstruction in HD brains during postnatal development. Genome-wide distribution analysis of 5 hmC further confirmed the diminishment of the 5-hmC signal in striatum and cortex in YAC128 HD mice. General genomic features of 5-hmC are highly conserved, not being affected by either disease or brain regions. Intriguingly, we have identified disease-specific (YAC128 versus WT) differentially hydroxymethylated regions (DhMRs), and found that acquisition of DhmRs in gene body is a positive epigenetic regulator for gene expression. Ingenuity pathway analysis (IPA) of genotype-specific DhMR-annotated genes revealed that alternation of a number of canonical pathways involving neuronal development/differentiation (Wnt/beta catenin/Sox pathway, axonal guidance signaling pathway) and neuronal function/survival (glutamate receptor/calcium/CREB, GABA receptor signaling, dopamine-DARPP32 feedback pathway, etc.) could be important for the onset of HD. Our results indicate that loss of the 5-hmC marker is a novel epigenetic feature in HD, and that this aberrant epigenetic regulation may impair the neurogenesis, neuronal function and survival in HD brain. Our study also opens a new avenue for HD treatment; re-establishing the native 5-hmC landscape may have the potential to slow/halt the progression of HD. PMID- 23669350 TI - PGC-1alpha is a male-specific disease modifier of human and experimental amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a devastating, adult-onset neurodegenerative disorder of the upper and lower motor systems. It leads to paresis, muscle wasting and inevitably to death, typically within 3-5 years. However, disease onset and survival vary considerably ranging in extreme cases from a few months to several decades. The genetic and environmental factors underlying this variability are of great interest as potential therapeutic targets. In ALS, men are affected more often and have an earlier age of onset than women. This gender difference is recapitulated in transgenic rodent models, but no underlying mechanism has been elucidated. Here we report that SNPs in the brain-specific promoter region of the transcriptional co-activator PGC-1alpha, a master regulator of metabolism, modulate age of onset and survival in two large and independent ALS populations and this occurs in a strictly male-specific manner. In complementary animal studies, we show that deficiency of full-length (FL) Pgc-1alpha leads to a significantly earlier age of onset and a borderline shortened survival in male, but not in female ALS-transgenic mice. In the animal model, FL Pgc-1alpha-loss is associated with reduced mRNA levels of the trophic factor Vegf-A in males, but not in females. In summary, we indentify PGC-1alpha as a novel and clinically relevant disease modifier of human and experimental ALS and report a sex-dependent effect of PGC-1alpha in this neurodegenerative disorder. PMID- 23669349 TI - Bcl6a function is required during optic cup formation to prevent p53-dependent apoptosis and colobomata. AB - Mutations in BCOR (Bcl6 corepressor) are found in patients with oculo-facio cardio-dental (OFCD) syndrome, a congenital disorder affecting visual system development, and loss-of-function studies in zebrafish and Xenopus demonstrate a role for Bcor during normal optic cup development in preventing colobomata. The mechanism whereby BCOR functions during eye development to prevent colobomata is not known, but in other contexts it serves as a transcriptional corepressor that potentiates transcriptional repression by B cell leukemia/lymphoma 6 (BCL6). Here, we have explored the function of the zebrafish ortholog of Bcl6, Bcl6a, during eye development, and our results demonstrate that Bcl6a, like Bcor, is required to prevent colobomata during optic cup formation. Our data demonstrate that Bcl6a acts downstream of Vax1 and Vax2, known regulators of ventral optic cup formation and choroid fissure closure, and that bcl6a is a direct target of Vax2. Together, this regulatory network functions to repress p53 expression and thereby suppress apoptosis in the developing optic cup. Furthermore, our data demonstrate that Bcl6a functions cooperatively with Bcor, Rnf2 and Hdac1 in a common gene regulatory network that acts to repress p53 and prevent colobomata. Together, these data support a model in which p53-dependent apoptosis needs to be tightly regulated for normal optic cup formation and that Bcl6a, Bcor, Rnf2 and Hdac1 activities mediate this regulation. PMID- 23669351 TI - Enhanced optineurin E50K-TBK1 interaction evokes protein insolubility and initiates familial primary open-angle glaucoma. AB - Glaucoma is the leading cause for blindness affecting 60 million people worldwide. The optineurin (OPTN) E50K mutation was first identified in familial primary open-angle glaucoma (POAG), the onset of which is not associated with intraocular pressure (IOP) elevation, and is classified as normal-tension glaucoma (NTG). Optineurin (OPTN) is a multifunctional protein and its mutations are associated with neurodegenerative diseases such as POAG and amyotrophic lateral sclerosis (ALS). We have previously described an E50K mutation-carrying transgenic (E50K-tg) mouse that exhibited glaucomatous phenotypes of decreased retinal ganglion cells (RGCs) and surrounding cell death at normal IOP. Further phenotypic analysis of these mice revealed persistent reactive gliosis and E50K mutant protein deposits in the outer plexiform layer (OPL). Over-expression of E50K in HEK293 cells indicated accumulation of insoluble OPTN in the endoplasmic reticulum (ER). This phenomenon was consistent with the results seen in neurons derived from induced pluripotent stem cells (iPSCs) from E50K mutation-carrying NTG patients. The E50K mutant strongly interacted with TANK-binding kinase 1 (TBK1), which prohibited the proper oligomerization and solubility of OPTN, both of which are important for OPTN intracellular transition. Treatment with a TBK1 inhibitor, BX795, abrogated the aberrant insolubility of the E50K mutant. Here, we delineated the intracellular dynamics of the endogenous E50K mutant protein for the first time and demonstrated how this mutation causes OPTN insolubility, in association with TBK1, to evoke POAG. PMID- 23669354 TI - Synthesis, antibacterial activity and cytotoxicity of new fused pyrazolo[1,5 a]pyrimidine and pyrazolo[5,1-c][1,2,4]triazine derivatives from new 5 aminopyrazoles. AB - New 5-aminopyrazoles 2a-c were prepared in high yields from the reaction of known alpha,alpha-dicyanoketene-N,S-acetals 1a-c with hydrazine hydrate under reflux in ethanol. These compounds were utilized as intermediates to synthesize pyrazolo[1,5-a]-pyrimidines 3a-c, 4a-d, 5a-c, and 6a-c, as well as pyrazolo[5,1 c][1,2,4]triazines 7a-c and 8a-c, by the reaction of 2 [bis(methylthio)methylene]malononitrile, alpha,alpha-dicyanoketene-N,S-acetals 1a b, acetylacetone, acetoacetanilide as well as acetylacetone, and malononitrile, respectively. Furthermore, cyclization of 2a-c with pentan-2,5-dione yielded the corresponding 5-pyrrolylpyrazoles 9a-c. Moreover, fusion of 2a-c with acetic anhydride resulted in the corresponding 1-acetyl-1H-pyrazoles 10a-c. The antibacterial activity and cytotoxicity against Vero cells of several selected compounds are also reported. PMID- 23669353 TI - Th17 cell based vaccines in mucosal immunity. AB - Vaccination is proven to be effective in controlling many infections including small pox, influenza and hepatitis, but strain-specific factors may limit vaccine efficacy. All of these vaccines work through the generation of neutralizing antibodies but for some pathogens there may be roles for serotype-independent immunity. Recently several groups using murine vaccine models have shown that induced T helper cell responses including Th17 responses have shown the potential for CD4+ T-cell dependent vaccine responses. Th17 mediated protective responses involve the recruitment of neutrophils, release of anti-microbial peptides and IL 17-driven Th1 immunity. These effector mechanisms provide immunity against a range of pathogens including the recently described antibiotic-resistant metallo beta-lactamase 1 Klebsiella pneumoniae. Continued elucidation of the mechanism of Th17 responses and identification of effective adjuvants for inducing robust non pathogenic Th17 responses may lead to successful Th17 based vaccines. Here we summarize the recent advances in understanding the role of Th17 in vaccine induced immunity. We also discuss the current status and future challenges in Th17-based mucosal vaccine development. PMID- 23669355 TI - The Evi5 family in cellular physiology and pathology. AB - The Ecotropic viral integration site 5 (Evi5) and Evi5-like (Evi5L) belong to a small subfamily of the Tre-2/Bub2/Cdc16 (TBC) domain-containing proteins with enigmatically divergent roles as modulators of cell cycle progression, cytokinesis, and cellular membrane traffic. First recognized as a potential oncogene and a cell cycle regulator, Evi5 acts as a GTPase Activating Protein (GAP) for Rab11 in cytokinesis. On the other hand, its homologue Evi5L has Rab GAP activity towards Rab10 as well as Rab23, and has been implicated in primary cilia formation. Recent genetic susceptibility analysis points to Evi5 as an important factor in susceptibility to multiple sclerosis. We discuss below the myriad of cellular functions exhibited by the Evi5 family members, and their associations with disease conditions. PMID- 23669352 TI - Genome-wide analysis of BMI in adolescents and young adults reveals additional insight into the effects of genetic loci over the life course. AB - Genetic loci for body mass index (BMI) in adolescence and young adulthood, a period of high risk for weight gain, are understudied, yet may yield important insight into the etiology of obesity and early intervention. To identify novel genetic loci and examine the influence of known loci on BMI during this critical time period in late adolescence and early adulthood, we performed a two-stage meta-analysis using 14 genome-wide association studies in populations of European ancestry with data on BMI between ages 16 and 25 in up to 29 880 individuals. We identified seven independent loci (P < 5.0 * 10-8) near FTO (P = 3.72 * 10-23), TMEM18 (P = 3.24 * 10-17), MC4R (P = 4.41 * 10-17), TNNI3K (P = 4.32 * 10-11), SEC16B (P = 6.24 * 10-9), GNPDA2 (P = 1.11 * 10-8) and POMC (P = 4.94 * 10-8) as well as a potential secondary signal at the POMC locus (rs2118404, P = 2.4 * 10-5 after conditioning on the established single-nucleotide polymorphism at this locus) in adolescents and young adults. To evaluate the impact of the established genetic loci on BMI at these young ages, we examined differences between the effect sizes of 32 published BMI loci in European adult populations (aged 18-90) and those observed in our adolescent and young adult meta-analysis. Four loci (near PRKD1, TNNI3K, SEC16B and CADM2) had larger effects and one locus (near SH2B1) had a smaller effect on BMI during adolescence and young adulthood compared with older adults (P < 0.05). These results suggest that genetic loci for BMI can vary in their effects across the life course, underlying the importance of evaluating BMI at different ages. PMID- 23669356 TI - Cell-penetrating peptides: 20 years later, where do we stand? AB - Twenty years ago, the discovery of peptides able to cross cellular membranes launched a novel field in molecular delivery based on these non-invasive vectors, most commonly called cell-penetrating peptides (CPPs) or protein transduction domains (PTDs). These peptides were shown to efficiently transport various biologically active molecules inside living cells, and thus are considered promising devices for medical and biotechnological developments. Moreover, CPPs emerged as potential tools to study the prime mechanisms of cellular entry across the plasma membrane. This review is dedicated to CPP fundamentals, with an emphasis on the molecular requirements and mechanism of their entry into eukaryotic cells. PMID- 23669357 TI - Progranulin deficiency exaggerates, whereas progranulin-derived Atsttrin attenuates, severity of dermatitis in mice. AB - PGRN and its derived engineered protein, Atsttrin, were reported to antagonize TNFalpha and protect against inflammatory arthritis [Tang, W. et al. (2011) The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science 332 (6028) 478-484]. Here we found that PGRN level was also significantly elevated in skin inflammation. PGRN-/- mice exhibited more severe inflammation following induction of oxazolone (OXA). In contrast, recombinant Atsttrin protein effectively attenuated inflammation in mice dermatitis model. In addition, the protective role of PGRN and Atsttrin in dermatitis was probably due to their inhibition on NF-kappaB signaling. Collectively, PGRN, especially its derived engineered protein, Atsttrin, may represent a potential molecular target for prevention and treatment of inflammatory skin diseases. PMID- 23669358 TI - Minireview: pH and synaptic transmission. AB - As a general rule a rise in pH increases neuronal activity, whereas it is dampened by a fall of pH. Neuronal activity per se also challenges pH homeostasis by the increase of metabolic acid equivalents. Moreover, the negative membrane potential of neurons promotes the intracellular accumulation of protons. Synaptic key players such as glutamate receptors or voltage-gated calcium channels show strong pH dependence and effects of pH gradients on synaptic processes are well known. However, the processes and mechanisms that allow controlling the pH in synaptic structures and how these mechanisms contribute to normal synaptic function are only beginning to be resolved. PMID- 23669359 TI - Biology and trafficking of ATG9 and ATG16L1, two proteins that regulate autophagosome formation. AB - Autophagy is a highly conserved intracytoplasmic degradation pathway for proteins, oligomers, organelles and pathogens. It initiates with the formation of a cup-shaped double membrane structure called the phagophore. The membrane origin for autophagosomes has been a key question for the field. ATG9 and ATG16L1, or their yeast orthologues, are key proteins that regulate autophagosome biogenesis, and may be associated with distinct membrane sources. Here we review the biology of autophagy with a focus on ATG16L1 and ATG9, and we summarise the current knowledge of their trafficking in relation to autophagic stimuli and autophagosome formation. PMID- 23669360 TI - Physical interaction between calcineurin and Cav3.2 T-type Ca2+ channel modulates their functions. AB - Cav3.2 T-type Ca(2+) channel is required for the activation of calcineurin/NFAT signaling in cardiac hypertrophy. We aimed to investigate how Cav3.2 and calcineurin interact. We found that Ca(2+) and calmodulin modulate the Cav3.2/calcineurin interaction. Calcineurin binding to Cav3.2 decreases the enzyme's phosphatase activity and diminishes the channel's current density. Phenylephrine-induced hypertrophy in neonatal cardiac myocytes is reduced by a cell-permeable peptide with the calcineurin binding site sequence. These data suggest that Cav3.2 regulates calcineurin/NFAT pathway through both the Ca(2+) influx and calcineurin binding. Our findings unveiled a reciprocal regulation of Ca(2+) signaling which contributes to our understanding of cardiac hypertrophy. PMID- 23669361 TI - CXCL14 is a natural inhibitor of the CXCL12-CXCR4 signaling axis. AB - Activation of the CXCL12-CXCR4 pathway is crucial for the migration of hematopoietic stem cells, various immune cells, and malignant tumor cells. Here, we show that another CXC chemokine, CXCL14, specifically binds to CXCR4 with high affinity and inhibits the CXCL12-mediated chemotaxis of human leukemia-derived cell lines and CD34(+) hematopoietic progenitor cells. Thus, CXCL14 functions as a natural inhibitor of CXCL12. Our observations suggest that CXCL14 represents, along with CXCR7, molecules that co-evolved with the CXCL12-CXCR4 axis to modulate important physiological processes in development, stem cell maintenance, and immune responses. PMID- 23669363 TI - How are mammalian methionine adenosyltransferases regulated in the liver? A focus on redox stress. AB - S-adenosylmethionine synthesis is a key process for cell function, and needs to be regulated at multiple levels. In recent years, advances in the knowledge of methionine adenosyltransferases have been significant. The discovery of nuclear localization of these enzymes suggests their transport to provide the methyl donor, S-adenosylmethionine, for DNA and histone methyltransferases in epigenetic modifications, opening new regulatory possibilities. Previous hypotheses considered only the cytoplasmic regulation of these enzymes, hence the need of an update to integrate recent findings. Here, we focus mainly on the liver and redox mechanisms, and their putative effects on localization and interactions of methionine adenosyltransferases. PMID- 23669362 TI - Diabetes mellitus due to the toxic misfolding of proinsulin variants. AB - Dominant mutations in the human insulin gene can lead to pancreatic beta-cell dysfunction and diabetes mellitus due to toxic folding of a mutant proinsulin. Analogous to a classical mouse model (the Akita mouse), this monogenic syndrome highlights the susceptibility of human beta-cells to endoreticular stress due to protein misfolding and aberrant aggregation. The clinical mutations directly or indirectly perturb native disulfide pairing. Whereas the majority of mutations introduce or remove a cysteine (leading in either case to an unpaired residue), non-cysteine-related mutations identify key determinants of folding efficiency. Studies of such mutations suggest that the evolution of insulin has been constrained not only by its structure and function, but also by the susceptibility of its single-chain precursor to impaired foldability. PMID- 23669364 TI - A Trp199Glu MauG variant reveals a role for Trp199 interactions with pre methylamine dehydrogenase during tryptophan tryptophylquinone biosynthesis. AB - MauG catalyzes posttranslational modifications of a methylamine dehydrogenase precursor (preMADH) to complete the biosynthesis of its protein-derived tryptophan tryptophylquinone (TTQ) cofactor. Trp199 is present at the site of interaction between MauG and preMADH and is critical to this process as it mediates hole hopping during the inter-protein electron transfer that is required for catalysis. Trp199 was converted to Glu and the structure and reactivity of the W199E/preMADH complex were characterized. The results reveal that the nature of residue 199 is also important for productive complex formation between preMADH and MauG. PMID- 23669365 TI - Rhomboid domain containing 1 inhibits cell apoptosis by upregulating AP-1 activity and its downstream target Bcl-3. AB - We have previously reported that rhomboid domain containing 1 (RHBDD1), a new member of the Rhomboid family, is highly expressed in testis. In the present work, luciferase analyses showed that RHBDD1 enhanced the AP-1 activity in a dose and activity-dependent manner. RHBDD1 overexpression increased c-Jun activity, and the activity was visibly inhibited when RHBDD1 was knocked down. The suppression of c-Jun by inactivation of RHBDD1 was rescued by overexpressing RHBDD1. However, c-Jun overexpression did not alter the expression level of RHBDD1. Furthermore, knockdown of RHBDD1 led to increased cell apoptosis and reduced expression of Bcl-3. Our findings indicate that RHBDD1 could inhibit cell apoptosis by activating and upregulating c-Jun and its downstream target, Bcl-3. PMID- 23669366 TI - The pH sensitivity of H2O2 metabolism in skeletal muscle mitochondria. AB - Mitochondria have the capacity to produce and consume H2O2. We examined H2O2 metabolism in isolated rat skeletal muscle mitochondria and found that the substrate-dependent capacity to consume extramitochondrial H2O2 was markedly higher than the observed rate of H2O2 efflux from mitochondria under the same conditions. The substrate-dependent capacity to consume H2O2 was sensitive to the pH of the medium and we propose that pH related differences in H2O2 consumption pathways may explain inconsistencies we observed between H2O2 efflux rate and the reduction state of the matrix NADH pool. PMID- 23669367 TI - Efficient drug-delivery using magnetic nanoparticles--biodistribution and therapeutic effects in tumour bearing rabbits. AB - To treat tumours efficiently and spare normal tissues, targeted drug delivery is a promising alternative to conventional, systemic administered chemotherapy. Drug carrying magnetic nanoparticles can be concentrated in tumours by external magnetic fields, preventing the nanomaterial from being cleared by metabolic burden before reaching the tumour. Therefore in Magnetic Drug Targeting (MDT) the favoured mode of application is believed to be intra-arterial. Here, we show that a simple yet versatile magnetic carrier-system (hydrodynamic particles diameter <200nm) accumulates the chemotherapeutic drug mitoxantrone efficiently in tumours. With MDT we observed the following drug accumulations relative to the recovery from all investigated tissues: tumour region: 57.2%, liver: 14.4%, kidneys: 15.2%. Systemic intra-venous application revealed different results: tumour region: 0.7%, liver: 14.4 % and kidneys: 77.8%. The therapeutic outcome was demonstrated by complete tumour remissions and a survival probability of 26.7% (P=0.0075). These results are confirming former pilot experiments and implying a milestone towards clinical studies. FROM THE CLINICAL EDITOR: This team of investigators studied drug carrying nanoparticles for magnetic drug targeting (MDT), demonstrating the importance of intra-arterial administration resulting in improved clinical outcomes in the studied animal model compared with intra-venous. PMID- 23669368 TI - Simultaneous inhibition of aberrant cancer kinome using rationally designed polymer-protein core-shell nanomedicine. AB - Simultaneous inhibition of deregulated cancer kinome using rationally designed nanomedicine is an advanced therapeutic approach. Herein, we have developed a polymer-protein core-shell nanomedicine to inhibit critically aberrant pro survival kinases (mTOR, MAPK and STAT5) in primitive (CD34(+)/CD38(-)) Acute Myeloid Leukemia (AML) cells. The nanomedicine consists of poly-lactide-co glycolide core (~250 nm) loaded with mTOR inhibitor, everolimus, and albumin shell (~25 nm thick) loaded with MAPK/STAT5 inhibitor, sorafenib and the whole construct was surface conjugated with monoclonal antibody against CD33 receptor overexpressed in AML. Electron microscopy confirmed formation of core-shell nanostructure (~290 nm) and flow cytometry and confocal studies showed enhanced cellular uptake of targeted nanomedicine. Simultaneous inhibition of critical kinases causing synergistic lethality against leukemic cells, without affecting healthy blood cells, was demonstrated using immunoblotting, cytotoxicity and apoptosis assays. This cell receptor plus multi-kinase targeted core-shell nanomedicine was found better specific and tolerable compared to current clinical regime of cytarabine and daunorubicin. FROM THE CLINICAL EDITOR: These authors demonstrate simultaneous inhibition of critical kinases causing synergistic lethality against leukemic cells, without affecting healthy blood cells by using rationally designed polymer-protein core-shell nanomedicine, provoding an advanced method to eliminate cancer cells, with the hope of future therapeutic use. PMID- 23669369 TI - In vivo nanoneurotoxicity screening using oxidative stress and neuroinflammation paradigms. AB - Iron oxide nanoparticles (IONPs) are promising neuroimaging agents and molecular cargo across neurovascular barriers. Development of intrinsically safe IONP chemistries requires a robust in vivo nanoneurotoxicity screening model. Herein, we engineered four IONPs of different surface and core chemistries: DMSA-Fe2O3, DMSA-Fe3O4, PEG-Fe3O4 and PEG-Au-Fe3O4. Capitalizing on the ability of the peripheral nervous system to recruit potent immune cells from circulation, we characterized a spatiotemporally controlled platform for the study of in vivo nanobiointerfaces with hematogenous immune cells, neuroglial and neurovascular units after intraneural IONP delivery into rat sciatic nerve. SQUID magnetometry and histological iron stain were used for IONP tracking. Among the IONPs, DMSA Fe2O3 NPs were potent pro-apoptotic agents in nerve, with differential ability to regulate oxidative stress, inflammation and apoptotic signaling in neuroglia, macrophages, lymphocytes and endothelial cells. This platform aims to facilitate the development of predictive paradigms of nanoneurotoxicity based on mechanistic investigation of relevant in vivo bio-nanointerfaces. FROM THE CLINICAL EDITOR: This team of investigators report the development of a platform that enables screening of iron oxide nanoparticles from the standpoint of their potential neurotoxicity, utilizing rat sciatic nerves. Such screening tools are clearly needed with the potential advent of iron oxide nanoparticle-based diagnostic and therapeutic approaches. PMID- 23669370 TI - Assessment of gait sensitivity norm as a predictor of risk of falling during walking in a neuromusculoskeletal model. AB - Quantifying the risk of falling (falls risk) would be helpful in treating people with gait disorders. The gait sensitivity norm (GSN) is a stability measure that correlates well to risk of falling in passive dynamic walkers but has not been evaluated on humans or human-like walking models. We assessed the correlation of GSN to risk of falling in a neuromusculoskeletal (NMS) walking model. Specifically, we evaluated the correlation of GSN to the actual disturbance rejection (ADR) of the model and the sensitivity of this relationship to gait parameter, Poincare section selection and steady state variability correction. Statistically significant results at p<0.05 were obtained for some of the gait indicators evaluated at the point in the gait cycle where they were most variable. The correlation between GSN and ADR was sensitive to gait indicator and Poincare sections evaluated but not to steady state variability correction. The current work suggests some simple steps to reduce the sensitivity of GSN to arbitrary and subjective factors. Overall, the findings support the potential of GSN to be a clinically applicable measure of falls risk. Further study is required to identify methods to more definitively select the various factors within the GSN calculation and to confirm its ability to predict falls risk in human subjects. PMID- 23669371 TI - Biomechanical analysis of different types of pedicle screw augmentation: a cadaveric and synthetic bone sample study of instrumented vertebral specimens. AB - This study aims to determine the pull-out strength, stiffness and failure pull out energy of cement-augmented, cannulated-fenestrated pedicle screws in an osteoporotic cadaveric thoracolumbar model, and to determine, using synthetic bone samples, the extraction torques of screws pre-filled with cement and those with cement injected through perforations. Radiographs and bone mineral density measurements from 32 fresh thoracolumbar vertebrae were used to define specimen quality. Axial pull-out strength of screws was determined through mechanical testing. Mechanical pull-out strength, stiffness and energy-to-failure ratio were recorded for cement-augmented and non-cement-augmented screws. Synthetic bone simulating a human spinal bone with severe osteoporosis was used to measure the maximum extraction torque. The pull-out strength and stiffness-to-failure ratio of cement pre-filled and cement-injected screws were significantly higher than the non-cement-augmented control group. However, the cement pre-filled and cement injected groups did not differ significantly across these values (p=0.07). The cement pre-filled group had the highest failure pull-out energy, approximately 2.8 times greater than that of the cement-injected (p<0.001), and approximately 11.5 times greater than that of the control groups (p<0.001). In the axial pull out test, the cement-injected group had a greater maximum extraction torque than the cement pre-filled group, but was statistically insignificant (p=0.17). The initial fixation strength of cannulated screws pre-filled with cement is similar to that of cannulated screws injected with cement through perforations. This comparable strength, along with the heightened pull-out energy and reduced extraction torque, indicates that pedicle screws pre-filled with cement are superior for bone fixation over pedicle screws injected with cement. PMID- 23669372 TI - Could interleukin-15 potentiate histone deacetylase inhibitor effects in haematological malignancy? AB - Despite significant progress in cancer therapy, prognosis in acute leukaemia remains dismal, and the development of new therapies is urgently warranted: in acute myeloid leukaemia, the current cure rate is of 30-40% in younger and much less in older patients. Chromatin remodeling through histone acetylation is one of the major mechanisms of transcriptional control of genes, and is involved in 'gene silencing' of antioncogenes in various tumour cells. Chromatin remodeling is also involved in transcriptional control of other genes, such as NKG2D ligand genes. Histone deacetylases and acetyltransferases are involved in the epigenetic regulation of gene expression, and increased/decreased activity of histone deacetylases has been reported in several cancer types. Histone deacetylase inhibitors were reportedly active in many cancers including hematological malignancies, and have been shown in numerous experiments to reduce cancer cell growth and enhance cell differentiation, growth arrest and apoptosis. In acute myeloid leukaemia, histone deacetylase inhibitors alone had limited efficacy, but their combination with other anticancer agents yielded promising results. Interleukin (IL)-15 is regarded with great hope in the immunotherapy of cancer, and IL-15-activated cytokine-induced killer cells showed potent antileukemic activity both in vitro and in vivo. IL-15 increases expression of NKG2D and its ligands and can increase natural killer cell mediated cytotoxicity against tumour cells. The administration of IL-15 was recently shown to be safe in preclinical models, and there are ongoing clinical trials of IL-15 in patients with cancer and HIV infection. We hypothesise that IL-15 will synergise with histone deacetylase inhibitors in increasing the levels of activatory NKG2D receptors on natural killer and CD8(+) T cells and of their ligands, the MHC class I related molecule A and B, on tumor cells, and will enhance innate immune antitumour responses in acute myeloid leukaemia and other haematological malignancies. Up regulation of NKG2D-NKG2D-ligand antitumour immune response by combining histone deacetylase inhibitors with IL-15 has the potential to improve the efficacy of acute myeloid leukaemia treatment. PMID- 23669373 TI - Getting serious with retinopathy: approaching an integrated hypothesis for central serous chorioretinopathy. AB - Development of the prefrontal cortex is believed to play an important role in the maturation of higher cognitive functions such as decision making, cognition and control of part of the neural element of the stress response. The prefrontal cortex undergoes considerable maturation during childhood, including a reduction of synaptic and neural density, a growth of dendrites, and an increase in white matter volume, thereby forming distributed neural networks appropriate for complex cognitive processing, but maturation is not complete until approximately 25 years of age. Serotonin and its receptors (HTRs) play critical roles in brain development and in the regulation of cognition, mood, and anxiety. HTRs are highly expressed in the human prefrontal cortex and exert control over prefrontal excitability. Studies of post-mortem prefrontal brain tissue found distinct developmental patterns of expression of these receptors occurring in early postnatal development and also into adulthood. The general pattern of improved cognitive control and emotion regulation with maturation of the prefrontal cortex, suggests a linear increase in development from childhood to adulthood. Animal studies have shown that dopamine is crucial for communication between the accumbens, amygdala, and prefrontal cortex. Dopamine projections to the prefrontal cortex continue to develop into early adulthood. Central Serous Chorioretinopathy (CSC) is an eye disease affecting people of working age, commonly resulting in repeated unpredictable visually disabling serous retinal detachments and occasionally leading to irreversible reduction in central vision. The disease has been closely linked to the stress response. Despite a concerted effort to understand aetiopathogenesis, disease mechanisms are still largely unclear. This paper, supported by evidence in the literature, proposes a systemic approach to CSC and explains how interactions of the eye with the cerebral cortex could lead to disease. We propose that the lack of development of the neural element of the stress response and in particular the prefrontal cortex is the reason for the absence of CSC in childhood and adolescence. Additionally, we attempt to explain why excess stress hormones do not always result in CSC and why acute attacks occur only once in over half of cases. Finally, we summarise the implications that an integrated systemic hypothesis has for future CSC research and the requirement of a holistic management practice for the identification and treatment of patients with CSC. PMID- 23669374 TI - Circulating microRNA-21 as noninvasive predictive biomarker for response in cancer immunotherapy. AB - A pre-existing T cell-inflamed tumor microenvironment is predictive of clinical outcome to immunotherapy, but the mechanisms of immune effector cells infiltration of tumors are not clear. MicroRNAs are a class of small non-coding RNAs that regulate gene expression at the posttranscriptional level. Additionally, circulating miRNAs might be useful as noninvasive biomarkers of disease and therapy response. Previous studies indicate that STAT3 activity in tumor cells affects immune cells recruitment, which is prerequisite for effective T cell therapy. MiRNA-21 is one of the cell-free miRNAs that has recently been identified as a potential regulator of STAT3. Meanwhile, miRNA-21 is an oncogenic miRNA that could be detected in various tumors. Therefore, we get the hypotheses that circulating miRNA-21 is a potential predictive biomarker for response in cancer immunotherapy and so a novel therapeutic target. PMID- 23669375 TI - Why preeclampsia still exists? AB - Preeclampsia (PE) is a deadly gestational disease affecting up to 10% of women and specific of the human species. Preeclampsia is clearly multifactorial, but the existence of a genetic basis for this disease is now clearly established by the existence of familial cases, epidemiological studies and known predisposing gene polymorphisms. PE is very common despite the fact that Darwinian pressure should have rapidly eliminated or strongly minimized the frequency of predisposing alleles. Consecutive pregnancies with the same partner decrease the risk and severity of PE. Here, we show that, due to this peculiar feature, preeclampsia predisposing-alleles can be differentially maintained according to the familial structure. Thus, we suggest that an optimal frequency of PE predisposing alleles in human populations can be achieved as a result of a trade off between benefits of exogamy, importance for maintaining genetic diversity and increase of the fitness owing to a stable paternal investment. PMID- 23669376 TI - Is laterality of malignant otitis externa related to handedness? AB - Malignant otitis externa (MOE) usually affect patients with systemic diseases, especially diabetes mellitus. MOE is a mainly unilateral disease. Given that around 90% of human adults are right-handed we hypothesized that hand preference might be one of the factors involved in the development of MOE. All 38 of the patients whom we treated for MOE between August 2009 and November 2012 (28 males and 10 females, age range 43-91 years) had poorly controlled diabetes mellitus, and all of them reported itching in the involved ear. The difference in the laterality of MOE among our right- and left-handed subjects was significant: right hand dominance was associated mostly with right-sided MOE (24/34) and left hand dominance was associated with occurrence of MOE only in the left ears (4/4, p=0.006). These findings point to an unexpectedly strong relationship between the patient's handedness and laterality of his/her MOE, leading us to hypothesize that the development of MOE might be attributable to self-inflicted local trauma to the ear canal on the same side as the dominant hand. PMID- 23669377 TI - Population-based survey of filamentous fungi and antifungal resistance in Spain (FILPOP Study). AB - A population-based survey was conducted to investigate the epidemiology of and antifungal resistance in Spanish clinical strains of filamentous fungi isolated from deep tissue samples, blood cultures, and respiratory samples. The study was conducted in two different periods (October 2010 and May 2011) to analyze seasonal variations. A total of 325 strains were isolated in 29 different hospitals. The average prevalence was 0.016/1,000 inhabitants [corrected]. Strains were identified by sequencing of DNA targets and susceptibility testing by the European Committee for Antimicrobial Susceptibility Testing reference procedure. The most frequently isolated genus was Aspergillus, accounting for 86.3% of the isolates, followed by Scedosporium at 4.7%; the order Mucorales at 2.5%; Penicillium at 2.2%, and Fusarium at 1.2%. The most frequent species was Aspergillus fumigatus (48.5%), followed by A. flavus (8.4%), A. terreus (8.1%), A. tubingensis (6.8%), and A. niger (6.5%). Cryptic/sibling Aspergillus species accounted for 12% of the cases. Resistance to amphotericin B was found in 10.8% of the isolates tested, while extended-spectrum triazole resistance ranged from 10 to 12.7%, depending on the azole tested. Antifungal resistance was more common among emerging species such as those of Scedosporium and Mucorales and also among cryptic species of Aspergillus, with 40% of these isolates showing resistance to all of the antifungal compounds tested. Cryptic Aspergillus species seem to be underestimated, and their correct classification could be clinically relevant. The performance of antifungal susceptibility testing of the strains implicated in deep infections and multicentric studies is recommended to evaluate the incidence of these cryptic species in other geographic areas. PMID- 23669378 TI - Crystal structures of bifunctional penicillin-binding protein 4 from Listeria monocytogenes. AB - Penicillin-binding proteins (PBPs), which catalyze the biosynthesis of the peptidoglycan chain of the bacterial cell wall, are the major molecular target of bacterial antibiotics. Here, we present the crystal structures of the bifunctional peptidoglycan glycosyltransferase (GT)/transpeptidase (TP) PBP4 from Listeria monocytogenes in the apo-form and covalently linked to two beta-lactam antibiotics, ampicillin and carbenicillin. The orientation of the TP domain with respect to the GT domain is distinct from that observed in the previously reported structures of bifunctional PBPs, suggesting interdomain flexibility. In this structure, the active site of the GT domain is occluded by the close apposition of the linker domain, which supports the hypothesis that interdomain flexibility is related to the regulation of GT activity. The acylated structures reveal the mode of action of beta-lactam antibiotics toward the class A PBP4 from the human pathogen L. monocytogenes. Ampicillin and carbenicillin can access the active site and be acylated without requiring a structural rearrangement. In addition, the active site of the TP domain in the apo-form is occupied by the tartrate molecule via extensive hydrogen bond interactions with the catalytically important residues; thus, derivatives of the tartrate molecule may be useful in the search for new antibiotics to inhibit PBPs. PMID- 23669379 TI - Nanoscale effects of caspofungin against two yeast species, Saccharomyces cerevisiae and Candida albicans. AB - Saccharomyces cerevisiae and Candida albicans are model yeasts for biotechnology and human health, respectively. We used atomic force microscopy (AFM) to explore the effects of caspofungin, an antifungal drug used in hospitals, on these two species. Our nanoscale investigation revealed similar, but also different, behaviors of the two yeasts in response to treatment with the drug. While administration of caspofungin induced deep cell wall remodeling in both yeast species, as evidenced by a dramatic increase in chitin and decrease in beta glucan content, changes in cell wall composition were more pronounced with C. albicans cells. Notably, the increase of chitin was proportional to the increase in the caspofungin dose. In addition, the Young modulus of the cell was three times lower for C. albicans cells than for S. cerevisiae cells and increased proportionally with the increase of chitin, suggesting differences in the molecular organization of the cell wall between the two yeast species. Also, at a low dose of caspofungin (i.e., 0.5* MIC), the cell surface of C. albicans exhibited a morphology that was reminiscent of cells expressing adhesion proteins. Interestingly, this morphology was lost at high doses of the drug (i.e., 4* MIC). However, the treatment of S. cerevisiae cells with high doses of caspofungin resulted in impairment of cytokinesis. Altogether, the use of AFM for investigating the effects of antifungal drugs is relevant in nanomedicine, as it should help in understanding their mechanisms of action on fungal cells, as well as unraveling unexpected effects on cell division and fungal adhesion. PMID- 23669380 TI - Evaluation of reduced susceptibility to quaternary ammonium compounds and bisbiguanides in clinical isolates and laboratory-generated mutants of Staphylococcus aureus. AB - The MICs and minimum bactericidal concentrations (MBCs) for the biocides benzalkonium chloride and chlorhexidine were determined against 1,602 clinical isolates of Staphylococcus aureus. Both compounds showed unimodal MIC and MBC distributions (2 and 4 or 8 mg/liter, respectively) with no apparent subpopulation with reduced susceptibility. To investigate further, all isolates were screened for qac genes, and 39 of these also had the promoter region of the NorA multidrug-resistant (MDR) efflux pump sequenced. The presence of qacA, qacB, qacC, and qacG genes increased the mode MIC, but not MBC, to benzalkonium chloride, while only qacA and qacB increased the chlorhexidine mode MIC. Isolates with a wild-type norA promoter or mutations in the norA promoter had similar biocide MIC distributions; notably, not all clinical isolates with norA mutations were resistant to fluoroquinolones. In vitro efflux mutants could be readily selected with ethidium bromide and acriflavine. Multiple passages were necessary to select mutants with biocides, but these mutants showed phenotypes comparable to those of mutants selected by dyes. All mutants showed changes in the promoter region of norA, but these were distinct from this region of the clinical isolates. Still, none of the in vitro mutants displayed fitness defects in a killing assay in Galleria mellonella larvae. In conclusion, our data provide an in-depth comparative overview on efflux in S. aureus mutants and clinical isolates, showing also that plasmid-encoded efflux pumps did not affect bactericidal activity of biocides. In addition, current in vitro tests appear not to be suitable for predicting levels of resistance that are clinically relevant. PMID- 23669381 TI - Synthesis and antiviral activities of methylenecyclopropane analogs with 6-alkoxy and 6-alkylthio substitutions that exhibit broad-spectrum antiviral activity against human herpesviruses. AB - Methylenecyclopropane nucleosides have been reported to be active against many of the human herpesviruses. The most active compound of this class is cyclopropavir (CPV), which exhibits good antiviral activity against human cytomegalovirus (HCMV), Epstein-Barr virus, both variants of human herpesvirus 6, and human herpesvirus 8. CPV has two hydroxymethyl groups on the methylenecyclopropane ring, but analogs with a single hydroxymethyl group, such as the prototypical (S) synguanol, are also active and exhibit a broader spectrum of antiviral activity that also includes hepatitis B virus and human immunodeficiency virus. Here, a large set of monohydroxymethyl compounds with ether and thioether substituents at the 6 position of the purine was synthesized and evaluated for antiviral activity against a range of human herpesviruses. Some of these analogs had a broader spectrum of antiviral activity than CPV, in that they also inhibited the replication of herpes simplex viruses 1 and 2 and varicella-zoster virus. Interestingly, the antiviral activity of these compounds appeared to be dependent on the activity of the HCMV UL97 kinase but was relatively unaffected by the absence of thymidine kinase activity in HSV. These data taken together indicate that the mechanism of action of these analogs is distinct from that of CPV. They also suggest that they might be useful as broad-spectrum antiherpesvirus agents and may be effective in the treatment of resistant virus infections. PMID- 23669382 TI - cyp51A-Based mechanisms of Aspergillus fumigatus azole drug resistance present in clinical samples from Germany. AB - Since the mid-1990s, a steady increase in the occurrence of itraconazole resistant Aspergillus fumigatus isolates has been observed in clinical contexts, leading to therapeutic failure in the treatment of aspergillosis. This increase has been predominantly linked to a single allele of the cyp51A gene, termed TR/L98H, which is thought to have arisen through the use of agricultural azoles. Here, we investigated the current epidemiology of triazole-resistant A. fumigatus and underlying cyp51A mutations in clinical samples in Germany. From a total of 527 samples, 17 (3.2%) showed elevated MIC0 values (the lowest concentrations with no visible growth) for at least one of the three substances (itraconazole, voriconazole, and posaconazole) tested. The highest prevalence of resistant isolates was observed in cystic fibrosis patients (5.2%). Among resistant isolates, the TR/L98H mutation in cyp51A was the most prevalent, but isolates with the G54W and M220I substitutions and the novel F219C substitution were also found. The isolate with the G54W substitution was highly resistant to both itraconazole and posaconazole, while all others showed high-level resistance only to itraconazole. For the remaining six isolates, no mutations in cyp51A were found, indicating the presence of other mechanisms. With the exception of the strains carrying the F219C and M220I substitutions, many itraconazole-resistant strains also showed cross-resistance to voriconazole and posaconazole with moderately increased MIC0 values. In conclusion, the prevalence of azole resistant A. fumigatus in our clinical test set is lower than that previously reported for other countries. Although the TR/L98H mutation frequently occurs among triazole-resistant strains in Germany, it is not the only resistance mechanism present. PMID- 23669383 TI - Genomewide screen for modulators of evolvability under toxic antibiotic exposure. AB - Antibiotic resistance is generally selected within a window of concentrations high enough to inhibit wild-type growth but low enough for new resistant mutants to emerge. We studied de novo evolution of resistance to ciprofloxacin in an Escherichia coli knockout library. Five null mutations had little or no effect on intrinsic antibiotic susceptibility but increased the upper antibiotic dosage to which initially sensitive populations could adapt. These mutations affect mismatch repair, translation fidelity, and iron homeostasis. PMID- 23669384 TI - Population pharmacokinetics of oseltamivir: pediatrics through geriatrics. AB - Oseltamivir is a potent inhibitor of influenza virus neuraminidase enzymes essential for viral replication. This study aimed to investigate the impact of covariates on pharmacokinetic (PK) variability of oseltamivir and its active metabolite form, oseltamivir carboxylate (OC). Dosing history, plasma drug concentrations, and demographic information were pooled from 13 clinical trials providing data for 390 healthy and infected subjects ranging in age from 1 to 78 years and given oseltamivir doses of 20 to 1,000 mg. Candidate population PK models simultaneously characterizing the time course of oseltamivir and OC in plasma were evaluated by using the NONMEM software program, and subject covariates were assessed using stepwise forward selection (alpha = 0.01) and backward elimination (alpha = 0.001). A two-compartment model with first-order absorption of oseltamivir and first-order conversion of oseltamivir to OC and a one-compartment model with first-order elimination of OC were utilized. Body weight when evaluated using a power function was a significant predictor of the apparent oseltamivir clearance and both apparent OC clearance (CL(m)/F) and central volume of distribution (Vc(m)/F). Creatinine clearance was a significant predictor of CL(m)/F, while Vc(m)/F also decreased linearly with age. A visual predictive check indicated that the final model described oseltamivir and OC concentrations in plasma adequately across dose regimens and subject covariate ranges. Concordance of population mean and individual post hoc predictions of maximum concentration of drug at steady state (C(max)) and area under the plasma drug concentration-time curve from 0 to 24 h at steady state (AUC(0-24)) was high (r(2) = 0.81 and 0.71, respectively). In conclusion, a comprehensive population PK model was constructed to bridge the adult to pediatric oseltamivir PK data, allowing for reasonable estimation of the PK of OC using subject demographic data alone. PMID- 23669385 TI - Metabolism, excretion, and mass balance of the HIV-1 integrase inhibitor dolutegravir in humans. AB - The pharmacokinetics, metabolism, and excretion of dolutegravir, an unboosted, once-daily human immunodeficiency virus type 1 integrase inhibitor, were studied in healthy male subjects following single oral administration of [(14)C]dolutegravir at a dose of 20 mg (80 MUCi). Dolutegravir was well tolerated, and absorption of dolutegravir from the suspension formulation was rapid (median time to peak concentration, 0.5 h), declining in a biphasic fashion. Dolutegravir and the radioactivity had similar terminal plasma half lives (t1/2) (15.6 versus 15.7 h), indicating metabolism was formation rate limited with no long-lived metabolites. Only minimal association with blood cellular components was noted with systemic radioactivity. Recovery was essentially complete (mean, 95.6%), with 64.0% and 31.6% of the dose recovered in feces and urine, respectively. Unchanged dolutegravir was the predominant circulating radioactive component in plasma and was consistent with minimal presystemic clearance. Dolutegravir was extensively metabolized. An inactive ether glucuronide, formed primarily via UGT1A1, was the principal biotransformation product at 18.9% of the dose excreted in urine and the principal metabolite in plasma. Two minor biotransformation pathways were oxidation by CYP3A4 (7.9% of the dose) and an oxidative defluorination and glutathione substitution (1.8% of the dose). No disproportionate human metabolites were observed. PMID- 23669386 TI - Pharmacokinetic-pharmacodynamic determinants of oseltamivir efficacy using data from phase 2 inoculation studies. AB - Given the limited understanding about pharmacokinetic-pharmacodynamic (PK-PD) determinants of oseltamivir efficacy, data from two phase 2 influenza virus inoculation studies were evaluated. Healthy volunteers in studies 1 and 2 were experimentally infected with influenza A/Texas (the concentration of neuraminidase inhibitor which reduced neuraminidase activity by 50% [IC(50)] = 0.18 nM) or B/Yamagata (IC(50) = 16.76 nM), respectively. In study 1, 80 subjects received 20, 100, or 200 mg of oral oseltamivir twice daily (BID), 200 mg oseltamivir once daily, or placebo for 5 days. In study 2, 60 subjects received 75 or 150 mg of oral oseltamivir BID or placebo for 5 days. Oseltamivir carboxylate (OC) (active metabolite) PK was evaluated using individual PK data and a population PK model to derive individual values for area under the concentration-time curve from 0 to 24 h (AUC(0-24)), minimum concentration of OC in plasma (C(min)), and maximum concentration of OC in plasma (C(max)). Exposure response relationships were evaluated for continuous (area under composite symptom score curve [AUCSC], area under the viral titer curve, and peak viral titer) and time-to-event (alleviation of composite symptom scores and cessation of viral shedding) efficacy endpoints. Univariable analyses suggested the existence of intuitive and highly statistically significant relationships between OC AUC(0-24 )evaluated as a 3-group variable and AUCSC, time to alleviation of composite symptom scores, and time to cessation of viral shedding. The upper OC AUC(0-24) threshold (~14,000 ng . h/ml) was similar among these endpoints. Multivariable analyses failed to demonstrate the influence of study/strain on efficacy endpoints. These results provide the first demonstration of exposure response relationships for efficacy for oseltamivir against influenza and suggest that OC exposures beyond those achieved with the approved oseltamivir dosing regimen will provide enhanced efficacy. The clinical applicability of these observations requires further investigation. PMID- 23669387 TI - Caspofungin MICs correlate with treatment outcomes among patients with Candida glabrata invasive candidiasis and prior echinocandin exposure. AB - Mutations in Candida glabrata FKS genes, which encode the echinocandin target enzyme, are independent risk factors for treatment failures during invasive candidiasis. We retrospectively compared the ability of caspofungin susceptibility testing methods to identify C. glabrata FKS mutant isolates and predict outcomes among patients at our center. Eight percent (10/120) of sterile site C. glabrata isolates harbored FKS1 (n = 3) or FKS2 (n = 7) mutations, including 32% (10/32) recovered from patients with prior echinocandin exposure. Median echinocandin exposures for mutant and nonmutant isolates were 55 (range, 7 to 188) and 13 (3 to 84) days, respectively (P = 0.004). Sensitivity and specificity of the CLSI caspofungin resistance breakpoint MIC (>0.12 MUg/ml by broth microdilution using RPMI medium [BMD-RPMI]) were 90% (9/10) and 3% (3/110), respectively, for identifying FKS mutants. Sensitivity and specificity of receiver-operator characteristic (ROC) curve-derived breakpoints by BMD-RPMI, BMD antibiotic medium 3, Etest, and YeastOne ranged from 70 to 100% and 89 to 95%, respectively; susceptibility rates varied from 83 to 90%. The 14-day echinocandin treatment success rate was 67% (44/66); failure was more likely with prior echinocandin exposure (P = 0.002) or infection with an FKS mutant (P = 0.0001) or echinocandin-resistant isolates by BMD-AM3, Etest, and YeastOne (P <= 0.03). The failure rate among patients with prior exposure and infection with a resistant isolate was 91% (10/11); it was 22% (12/55) among others (P < 0.0001). In conclusion, ROC-derived caspofungin MIC breakpoints by several methods were sensitive and specific for identifying C. glabrata FKS mutant isolates. Mutations were seen exclusively among patients with prior echinocandin exposure. A paradigm that considers prior echinocandin exposure and caspofungin MICs accurately classified treatment outcomes for C. glabrata invasive candidiasis. PMID- 23669388 TI - Characterization of antiviral activity of benzamide derivative AH0109 against HIV 1 infection. AB - In the absence of an effective vaccine against HIV-1 infection, anti-HIV-1 strategies play a major role in disease control. However, the rapid emergence of drug resistance against all currently used anti-HIV-1 molecules necessitates the development of new antiviral molecules and/or strategies against HIV-1 infection. In this study, we have identified a benzamide derivative named AH0109 that exhibits potent anti-HIV-1 activity at an 50% effective concentration of 0.7 MUM in HIV-1-susceptible CD4(+) C8166 T cells. Mechanistic analysis revealed that AH0109 significantly inhibits both HIV-1 reverse transcription and viral cDNA nuclear import. Furthermore, our infection experiments indicated that AH0109 is capable of disrupting the replication of HIV-1 strains that are resistant to the routinely used anti-HIV-1 drugs zidovudine, lamivudine, nevirapine, and raltegravir. Together, these findings provide evidence for a newly identified antiviral molecule that can potentially be developed as an anti-HIV-1 agent. PMID- 23669389 TI - Dose responses of proveblue methylene blue in an experimental murine cerebral malaria model. PMID- 23669390 TI - Antimicrobial activity of nanoemulsion in combination with cetylpyridinium chloride in multidrug-resistant Acinetobacter baumannii. AB - Acinetobacter baumannii has emerged as a serious problematic pathogen due to the ever-increasing presence of antibiotic resistance, demonstrating a need for novel, broad-spectrum antimicrobial therapeutic options. Antimicrobial nanoemulsions are emulsified mixtures of detergent, oil, and water (droplet size, 100 to 800 nm) which have broad antimicrobial activity against bacteria, enveloped viruses, and fungi. Here, we screened the antimicrobial activities of five nanoemulsion preparations against four Acinetobacter baumannii isolates to identify the most suitable preparation for further evaluation. Among them, N5, which contains 10% (vol/vol) Triton X-100, 25% (vol/vol) soybean oil, and 1% (wt/vol) cetylpyridinium chloride (CPC), showed the best efficacy against A. baumannii in both its planktonic and biofilm forms and was selected for further study. Our data demonstrate that, while the killing of planktonic forms of A. baumannii was due to the 1% CPC component of our nanoemulsions, the breakdown of biofilms was achieved via the emulsified oil and detergent fractions. Furthermore, we documented the effect of ethanol and NaCl in combination with N5 on planktonic A. baumannii. In killing curves of N5 combined with other agents (ethanol or NaCl), a synergistic effect of a >= 2-log decrease in CFU/ml was observed. The antibiofilm activity of N5 was confirmed via a cell proliferation test and scanning electron microscopy. The effects of exposure to severe environmental conditions, which simulates the field conditions in Iraq and Afghanistan, were evaluated, and this exposure did not affect the overall antimicrobial activity of N5. These studies lay a solid foundation for the utilization of nanoemulsions against the antibiotic-resistant forms of A. baumannii. PMID- 23669391 TI - In vitro efficacies of clinically available drugs against growth and viability of an Acanthamoeba castellanii keratitis isolate belonging to the T4 genotype. AB - The effects of clinically available drugs targeting muscarinic cholinergic, adrenergic, dopaminergic, and serotonergic receptors; intracellular calcium levels and/or the function of calcium-dependent biochemical pathways; ion channels; and cellular pumps were tested against a keratitis isolate of Acanthamoeba castellanii belonging to the T4 genotype. In vitro growth inhibition (amoebistatic) assays were performed by incubating A. castellanii with various concentrations of drugs in the growth medium for 48 h at 30 degrees C. To determine amoebicidal effects, amoebae were incubated with drugs in phosphate buffered saline for 24 h, and viability was determined using trypan blue exclusion staining. For controls, amoebae were incubated with the solvent alone. Of the eight drugs tested, amlodipine, prochlorperazine, and loperamide showed potent amoebicidal effects, as no viable trophozoites were observed (>95% kill rate), while amiodarone, procyclidine, digoxin, and apomorphine exhibited up to 50% amoebicidal effects. In contrast, haloperidol did not affect viability, but all the drugs tested inhibited A. castellanii growth. Importantly, amlodipine, prochlorperazine, and loperamide showed compelling cysticidal effects. The cysticidal effects were irreversible, as cysts treated with the aforementioned drugs did not reemerge as viable amoebae upon inoculation in the growth medium. Except for apomorphine and haloperidol, all the tested drugs blocked trophozoite differentiation into cysts in encystation assays. Given the limited availability of effective drugs to treat amoebal infections, the clinically available drugs tested in this study represent potential agents for managing keratitis and granulomatous amoebic encephalitis caused by Acanthamoeba spp. and possibly against other meningoencephalitis-causing amoebae, such as Balamuthia mandrillaris and Naegleria fowleri. PMID- 23669392 TI - Ciprofloxacin-induced psychosis. PMID- 23669393 TI - Glyceryl trinitrate complements citrate and ethanol in a novel antimicrobial catheter lock solution to eradicate biofilm organisms. AB - Antimicrobial catheter lock therapy is practiced to prevent lumenal-sourced infections of central venous catheters. Citrate has been used clinically as an anticoagulant in heparin-free catheter locks. Ethanol has also been widely studied as an antimicrobial lock solution component. This study reports on the synergy of glyceryl trinitrate (GTN) with citrate and ethanol in rapidly eradicating methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis, Pseudomonas aeruginosa, and Candida albicans biofilms in an in vitro model for catheter biofilm colonization. GTN has a long history of intravenous use as a hypotensive agent. It is potentially attractive as a component of a catheter lock solution because its physiologic half-life is quite short and its metabolic pathways are known. A lock containing 7% citrate and 20% ethanol required 0.01% GTN to fully eradicate biofilms of all test organisms within 2 h in the model. This GTN concentration is below the levels where clinically significant hypotensive effects are expected. PMID- 23669394 TI - CXCR4 promotes B cell egress from Peyer's patches. AB - Peyer's patches (PPs) play a central role in supporting B cell responses against intestinal antigens, yet the factors controlling B cell passage through these mucosal lymphoid tissues are incompletely understood. We report that, in mixed chimeras, CXCR4-deficient B cells accumulate in PPs compared with their representation in other lymphoid tissues. CXCR4-deficient B cells egress from PPs more slowly than wild-type cells, whereas CXCR5-deficient cells egress more rapidly. The CXCR4 ligand, CXCL12, is expressed by cells adjacent to lymphatic endothelial cells in a zone that abuts but minimally overlaps with the CXCL13(+) follicle. CXCR4-deficient B cells show reduced localization to these CXCL12(+) perilymphatic zones, whereas CXCR5-deficient B cells preferentially localize in these regions. By photoconverting KikGR-expressing cells within surgically exposed PPs, we provide evidence that naive B cells transit PPs with an approximate residency half-life of 10 h. When CXCR4 is lacking, KikGR(+) B cells show a delay in PP egress. In summary, we identify a CXCL12(hi) perilymphatic zone in PPs that plays a role in overcoming CXCL13-mediated retention to promote B cell egress from these gut-associated lymphoid tissues. PMID- 23669395 TI - CD47 fusion protein targets CD172a+ cells in Crohn's disease and dampens the production of IL-1beta and TNF. AB - In mice, the transfer of CD172a(+) (SIRP-alpha) dendritic cells (DCs) elicits T cell-driven colitis, whereas treatment with CD47-Fc protein, a CD172a-binding agent, confers protection. The aim of this study was to elucidate the nature and functional properties of human CD172a(+) DCs in chronic intestinal inflammation. Here, we show that CD172a(+)CD11c(+) cells accumulate in the mesenteric lymph nodes (mLNs) and inflamed intestinal mucosa in patients with Crohn's disease (CD). These cells are distinct from resident DCs and may coexpress markers typically associated with monocyte-derived inflammatory DCs such as CD14 and/or DC-SIGN, E-Cadherin, and/or CX3CR1. Spontaneous IL-1beta and TNF production by HLA-DR(+) cells in CD tissues is restricted to those expressing CD172a. An avidity-improved CD47 fusion protein (CD47-Var1) suppresses the release of a wide array of inflammatory cytokines by CD172a(+) cells, which may include HLA-DR( )CD172a(+) neutrophils, in inflamed colonic explant cultures and impairs the ability of HLA-DR(+)CD172a(+) cells to activate memory Th17 but not Th1 responses in mLNs. In conclusion, targeting CD172a(+) cells may represent novel therapeutic perspectives for patients with CD. PMID- 23669398 TI - DNA repair: a changing geography? (1964-2008). AB - This article aims to explain the current state of DNA Repair studies' global geography by focusing on the genesis of the community. Bibliometric data is used to localize scientific activities related to DNA Repair at the city level. The keyword "DNA Repair" was introduced first by American scientists. It started to spread after 1964 that is to say, after P. Howard-Flanders (Yale University), P. Hanawalt (Stanford University) and R. Setlow (Oak Ridge Laboratories) found evidence for Excision Repair mechanisms. It was the first stage in the emergence of an autonomous scientific community. In this article, we will try to assess to what extent the geo-history of this scientific field is determinant in understanding its current geography. In order to do so, we will localize the places where the first "DNA Repair" publications were signed fifty years ago and the following spatial diffusion process, which led to the current geography of the field. Then, we will focus on the evolution of the research activity of "early entrants" in relation to the activity of "latecomers". This article is an opportunity to share with DNA Repair scientists some research results of a dynamic field in Science studies: spatial scientometrics. PMID- 23669396 TI - Inactivation of the RB family prevents thymus involution and promotes thymic function by direct control of Foxn1 expression. AB - Thymic involution during aging is a major cause of decreased production of T cells and reduced immunity. Here we show that inactivation of Rb family genes in young mice prevents thymic involution and results in an enlarged thymus competent for increased production of naive T cells. This phenotype originates from the expansion of functional thymic epithelial cells (TECs). In RB family mutant TECs, increased activity of E2F transcription factors drives increased expression of Foxn1, a central regulator of the thymic epithelium. Increased Foxn1 expression is required for the thymic expansion observed in Rb family mutant mice. Thus, the RB family promotes thymic involution and controls T cell production via a bone marrow-independent mechanism, identifying a novel pathway to target to increase thymic function in patients. PMID- 23669399 TI - Subclinical inflammation with increased neutrophil activity in healthy twin siblings reflect environmental influence in the pathogenesis of inflammatory bowel disease. AB - BACKGROUND: The mechanisms behind increased fecal calprotectin (FC) in healthy relatives of patients with inflammatory bowel disease (IBD) are unknown. Our aims were to explore if there is a subclinical inflammation with increased neutrophil activity in healthy twin siblings in discordant twin pairs with IBD and to assess the influence of genetics in this context. METHODS: Nuclear factor kappa B (NF kappaB) and neutrophil activity, based on myeloperoxidase (MPO) and FC, were analyzed in healthy twin siblings in discordant twin pairs with IBD and compared with healthy controls. NF-kappaB and MPO were assessed by immunohistochemistry and FC by enzyme-linked immunosorbent assay. RESULTS: In total, 33 of 34 healthy twin siblings were histologically normal. Increased NF-kappaB was more often observed in healthy twin siblings in discordant twin pairs with Crohn's disease (13/18 [73%]) and with ulcerative colitis (12/16 [75%]) than in healthy controls (8/45 [18%]). MPO was more often increased in healthy twin siblings in discordant pairs with Crohn's disease (12/18 [67%]) than in healthy controls (11/45 [24%]) and FC more often in healthy twin siblings in discordant pairs with ulcerative colitis (14/21 [67%]) than in healthy controls (6/31 [19%]). Interestingly, the observed differences remained when healthy monozygotic and dizygotic twin siblings were analyzed separately. CONCLUSIONS: We observed increased NF-kappaB, MPO, and FC in healthy twins in both monozygotic and dizygotic discordant pairs with IBD. These novel findings speak for an ongoing subclinical inflammation with increased neutrophil activity in healthy first-degree relatives. PMID- 23669397 TI - Bidirectional transcription of trinucleotide repeats: roles for excision repair. AB - Genomic instability at repetitive DNA regions in cells of the nervous system leads to a number of neurodegenerative and neuromuscular diseases, including those with an expanded trinucleotide repeat (TNR) tract at or nearby an expressed gene. Expansion causes disease when a particular base sequence is repeated beyond the normal range, interfering with the expression or properties of a gene product. Disease severity and onset depend on the number of repeats. As the length of the repeat tract grows, so does the size of the successive expansions and the likelihood of another unstable event. In fragile X syndrome, for example, CGG repeat instability and pathogenesis are not typically observed below tracts of roughly 50 repeats, but occur frequently at or above 55 repeats, and are virtually certain above 100-300 repeats. Recent evidence points to bidirectional transcription as a new aspect of TNR instability and pathophysiology. Bidirectional transcription of TNR genes produces novel proteins and/or regulatory RNAs that influence both toxicity and epigenetic changes in TNR promoters. Bidirectional transcription of the TNR tract appears to influence aspects of its stability, gene processing, splicing, gene silencing, and chemical modification of DNAs. Paradoxically, however, some of the same effects are observed on both the expanded TNR gene and on its normal gene counterpart. In this review, we discuss the possible normal and abnormal effects of bidirectional transcription on trinucleotide repeat instability, the role of DNA repair in causing, preventing, or maintaining methylation, and chromatin environment of TNR genes. PMID- 23669400 TI - The influence of depression on quality of life in patients with inflammatory bowel disease. AB - BACKGROUND: Inflammatory bowel disease is a chronic inflammatory disorder of the gastrointestinal tract that significantly impacts the health-related quality of life (HR-QOL). A decreased HR-QOL has been demonstrated in patients with active disease compared with patients in remission. In this cross-sectional study, we examined the role of depression and disease activity as independent factors in predicting patient's HR-QOL. METHODS: Hundred and five patients with either Crohn's disease (CD) or ulcerative colitis (UC) were enrolled. Disease activity was evaluated using Crohn's Disease Activity Index or Seo's Activity Index. Depressive symptoms were evaluated using Beck's Depression Inventory-II and Beck's Depression Inventory for Primary Care (BDI-PC). HR-QOL was evaluated using the Short Inflammatory Bowel Disease Questionnaire. Simple and multiple regressions were performed on quality of life score with demographic and clinical variables as predictors. RESULTS: The prevalence of depression in our study population is 25%. In patients with both CD and UC, depression is the most significant predictor to a poor HR-QOL (in CD, P = 8.22 * 10; in UC, P = 2.02 * 10). HR-QOL is weakly affected by disease activity (in CD, P = 0.110; in UC, P = 0.00492). In CD, biological use displays positive effect on HR-QOL (P = 0.00780). In total, the proportion of variance explained by all predictors is 61% for CD and 53% for UC, whereas the depression alone explains 44% and 36%. CONCLUSIONS: Our study demonstrates the importance of depression toward the quality of life in patients with inflammatory bowel disease. The diagnosis of depression should be actively sought out and treated in outpatient inflammatory bowel disease practices. PMID- 23669401 TI - Thiopurine effectiveness in patients with Crohn's disease: a study of genetic and clinical predictive factors. AB - BACKGROUND: Thiopurines are efficacious in the treatment of Crohn's disease and were recently shown to induce T-cell apoptosis by modulation of Rac1 activation. To assess whether polymorphisms in Rac1 and other apoptosis-related genes, combined with clinical parameters, can predict response to thiopurines. METHODS: A retrospective cohort of 156 thiopurine-treated patients with Crohn's disease was genotyped for 11 single-nucleotide polymorphisms (SNPs): 9 SNPs in Rac1, 1 SNP in the Fas ligand -843 T>C, and 1 SNP in the Caspase-9 93 C>T. Clinical data were extracted from the medical charts. Odds ratios (ORs) and 95% confidence intervals (CIs) of the association between demographic, clinical, and genetic variables and thiopurine response rates were calculated. RESULTS: The overall response rate to thiopurines was 74% (115/156). The Rac1 SNP rs34932801 heterozygote genotype GC was associated with a lower response rate compared with the wild-type GG genotype (46% versus 76%; OR = 0.26; 95% CI, 0.08-0.91; P = 0.036). Only wild-type homozygotes were found for 5 Rac1 SNPs. None of the other 3 Rac1 SNPs were associated with response to thiopurines. Patients with Montreal B3 behavior pattern responded worse than those with a B1 behavior pattern (59%, versus 80%; OR = 0.37; 95% CI, 0.17-0.83; P = 0.016). Sephardic Jews had a lower response rate to thiopurines compared with Jews of Ashkenazi or mixed ancestry (60% versus 82%; OR = 0.32; 95% CI, 0.15-0.69, P = 0.003). CONCLUSIONS: Rac1 SNP rs34932801carriage, Montreal B3 disease behavior, and a Sephardic Jewish origin were associated with unfavorable response to thiopurines. Corroboration of these associations in larger cohorts is warranted. PMID- 23669402 TI - High rates of metachronous colon cancer or dysplasia after segmental resection or subtotal colectomy in Crohn's colitis. AB - BACKGROUND: In ulcerative colitis, total proctocolectomy is the treatment of choice for patients with colonic dysplasia or cancer because of the high risk for metachronous neoplasia. It is unknown whether patients with Crohn's disease and colon cancer or dysplasia have a similar risk. METHODS: We retrospectively reviewed the charts of 75 patients treated at our center from 2001 to 2011 with Crohn's disease and colon cancer who underwent segmental resection or subtotal colectomy (STC). We then identified the presence or absence of subsequent colon cancer or dysplasia in these patients during the follow-up (0-19 years). RESULTS: Of the 64 patients with colon cancer, 25 had at least 1 metachronous cancer (39%). The mean time to a new cancer was 6.8 years. Eighty-five percent of patients (21/25) were undergoing annual screening colonoscopy. Of the 11 patients with dysplasia, 5 (46%) had a new dysplasia. Mean time to a new dysplastic lesion was 5.0 years. Nineteen of the 47 patients (40%) who had a segmental resection for colon cancer developed metachronous cancer and 6/17 patients (35%) with a STC had metachronous cancer. Two of the 4 patients (50%) with STC for dysplasia (50%) had a new dysplasia and 3/7 patients (43%) with segmental resection had a new dysplasia. There was no significant difference (P = 0.61) between recurrence rates in patients with segmental resection versus STC. CONCLUSIONS: The high rate of metachronous colon cancer after surgical resection suggests that total proctocolectomy should be considered. Larger studies are required to determine if the same is true for dysplasia. PMID- 23669404 TI - Crosstalk between the intestinal microbiota and the innate immune system in intestinal homeostasis and inflammatory bowel disease. AB - : Inflammatory bowel diseases are a set of complex and chronic disorders that arise in genetically predisposed individuals due to a lack of tolerance to the gut microflora. Although the intestinal microbiota is required for the proper development of the host and the maintenance of intestinal homeostasis, its dysbiosis is associated with inflammatory bowel diseases pathogenesis. In this review, we focus the discussion on the crosstalk between the innate immune system and the microbiota. We examine new findings from genetic and functional studies investigating the critical role of the intestinal epithelial cell layer and the processes that maintain its integrity in health and disease. We further explore the mechanisms of the mucosal innate immune system including dendritic cells, macrophages, and innate-like lymphocytes in mediating immunological tolerance at the steady state or pathogenic inflammatory responses in inflammatory bowel diseases. PMID- 23669403 TI - First prospective, population-based inflammatory bowel disease incidence study in mainland of China: the emergence of "western" disease. AB - BACKGROUND: Previously a disease of the West and rarely seen in China, inflammatory bowel disease (IBD) is now increasing in incidence in China. However, its true incidence is unknown. The incidence of IBD in Wuhan, a major city in central China, was investigated using population-based methods. METHODS: A prospective, population-based IBD incidence study was conducted between January 1, 2010, and December 31, 2010. New IBD cases were identified by gastroenterologists and from hospital case records in 17 central hospitals covering the health care service of central Wuhan. Cases were confirmed by follow up and assessed by a specialist IBD group every 3 months. The population at risk was 6,085,556. RESULTS: Overall, 131 new cases of IBD were identified during the 1-year period, including 97 cases of ulcerative colitis (UC) and 34 cases of Crohn's disease (CD). The age-adjusted incidence for all IBD, UC, and CD were 1.96 per 100,000 (95% confidence interval [CI], 1.62-2.30 per 100,000), 1.45 (95% CI, 1.16-1.75), and 0.51 (95% CI, 0.33-0.68), respectively. CD affected the small bowel only in 15%, colon only in 24%, and ileocolonic in 61%. CD often presented with complicated phenotype: inflammatory (44%), stricturing (29%), and penetrating (24%). Among patients with UC, complications included proctitis (34.5%), left-sided colitis (44.6%), and extensive colitis (19.5%). CONCLUSIONS: There is a substantial incidence of IBD in China. Although still lower than in the West, the emergence of IBD will necessitate specific health care planning and education and offers the possibility of identifying causative factors in a population with a rapidly increasing incidence. PMID- 23669405 TI - Hypercholesterolemia--a disease with expression from childhood. AB - INTRODUCTION: Hypercholesterolemia results from an alteration, genetic or acquired, in lipoprotein metabolism. Evidence that hypercholesterolemia is associated with the atherosclerotic process from childhood justifies the screening of high-risk children and initiation of therapy at preschool ages. OBJECTIVE: To assess children referred for pediatric consultations due to hypercholesterolemia. METHODS: Children and adolescents referred for pediatric consultations with a diagnosis of hypercholesterolemia were enrolled. Information on family history and clinical, anthropometric and biochemical parameters was recorded and, when appropriate, molecular study was performed. RESULTS: A total of 168 children were assessed. Forty-six presented a familial hypercholesterolemia phenotype and in 22 of these, a mutation in the low-density lipoprotein (LDL) receptor gene was identified. The lipid profile of the group with mutations showed significantly higher values of total and non-high-density lipoprotein (HDL) cholesterol compared to the group without mutations (total cholesterol 316.5+/-75.9 mg/dl vs. 260.9+/-42,0 mg/dl; non-HDL cholesterol 268.3+/-72.6 mg/dl vs. 203.5+/-43.9 mg/dl; p<0.05). Of the total, 55 were prescribed pharmacological therapy and the others underwent diet and exercise interventions only. A greater reduction in LDL cholesterol was observed in individuals under pharmacological therapy compared to those prescribed diet and exercise only (30.3% vs. 18.1%). Drug side effects were insignificant. CONCLUSION: It is possible to maintain a normal lipid profile in most individuals with familial hypercholesterolemia in order to reduce the risk of early onset of atherosclerosis, which is associated with serious cardiovascular complications from childhood. PMID- 23669406 TI - Infrared and NMR spectra, tautomerism, vibrational assignment, normal coordinate analysis, and quantum mechanical calculations of 4-amino-5 pyrimidinecarbonitrile. AB - The infrared (4000-200 cm(-1)) spectrum for 4-amino-5-pyrimidinecarbonitrile (APC, C5H4N4) was acquired in the solid phase. In addition, the (1)H and (13)C NMR spectra of APC were obtained in DMSO-d6 along with its mass spectrum. Initially, six isomers were hypothesized and then investigated by means of DFT/B3LYP and MP2(full) quantum mechanical calculations using a 6-31G(d) basis set. Moreover, the (1)H and (13)C NMR chemical shifts were predicted using a GIAO approximation at the 6-311+G(d,p) basis set and the B3LYP method with (and without) solvent effects using PCM method. The correlation coefficients showed good agreement between the experimental/theoretical chemical shift values of amino tautomers (1 and 2) rather than the eliminated imino tautomers (3-6), in agreement with the current quantum mechanical calculations. Structures 3-6 are less stable than the amino tautomers (1 and 2) by about 5206-8673 cm(-1) (62.3 103.7 kJ/mol). The MP2(full)/6-31G(d) computational results favor the amino structure 1 with a pyramidal NH2 moiety and calculated real vibrational frequencies, however; structure 2 is considered a transition state owing to the calculated imaginary frequency. It is worth mentioning that, the calculated structural parameters suggest a strong conjugation between the amino nitrogen and pyrimidine ring. Aided by frequency calculations, normal coordinate analysis, force constants and potential energy distributions (PEDs), a complete vibrational assignment for the observed bands is proposed herein. Finally, NH2 internal rotation barriers for the stable non-planar isomer (1) were carried out using MP2(full)/6-31G(d) optimized structural parameters. Our results are discussed herein and compared to structural parameters for similar molecules whenever appropriate. PMID- 23669407 TI - Preventive effects of p-coumaric acid on cardiac hypertrophy and alterations in electrocardiogram, lipids, and lipoproteins in experimentally induced myocardial infarcted rats. AB - The present study evaluated the preventive effects of p-coumaric acid on cardiac hypertrophy and alterations in electrocardiogram, lipids, and lipoproteins in experimentally induced myocardial infarcted rats. Rats were pretreated with p coumaric acid (8 mg/kg body weight) daily for a period of 7 days and then injected with isoproterenol (100mg/kg body weight) on 8th and 9th day to induce myocardial infarction. Myocardial infarction induced by isoproterenol was indicated by increased level of cardiac sensitive marker and elevated ST-segments in the electrocardiogram. Also, the levels/concentrations of serum and heart cholesterol, triglycerides and free fatty acids were increased in myocardial infarcted rats. Isoproterenol also increased the levels of serum low density and very low density lipoprotein cholesterol and decreased the levels of high density lipoprotein cholesterol. It also enhanced the activity of liver 3-hydroxy-3 methyl glutaryl-Coenzyme-A reductase. p-Coumaric acid pretreatment revealed preventive effects on all the biochemical parameters and electrocardiogram studied in myocardial infarcted rats. The in vitro study confirmed the free radical scavenging property of p-coumaric acid. Thus, p-coumaric acid prevented cardiac hypertrophy and alterations in lipids, lipoproteins, and electrocardiogram, by virtue of its antihypertrophic, antilipidemic, and free radical scavenging effects in isoproterenol induced myocardial infarcted rats. PMID- 23669408 TI - Inhibitory effects of astaxanthin, beta-cryptoxanthin, canthaxanthin, lutein, and zeaxanthin on cytochrome P450 enzyme activities. AB - Astaxanthin, beta-cryptoxanthin, canthaxanthin, lutein and zeaxanthin, the major xanthophylls, are widely used in food, medicine, and health care products. To date, no studies regarding the inhibitory effects of these xanthophylls on the nine CYPs isozymes have been reported. This study investigated the reversible and time-dependent inhibitory potentials of five xanthophylls on CYPs activities in vitro. The reversible inhibition results showed that the five compounds had only a weak inhibitory effect on the nine CYPs. Lutein did not inhibit the nine CYPs activities. Astaxanthin weakly inhibited CYP2C19, with an IC50 of 16.2 MUM; and beta-cryptoxanthin weakly inhibited CYP2C8, with an IC50 of 13.8 MUM. In addition, canthaxanthin weakly inhibited CYP2C19 and CYP3A4/5, with IC50 values of 10.9 and 13.9 MUM, respectively. Zeaxanthin weakly inhibited CYP3A4/5, with an IC50 of 15.5 MUM. However, these IC50 values were markedly greater than the Cmax values reported in humans. No significant IC50 shift was observed in the time dependent inhibition screening. Based on these observations, it is unlikely that these five xanthophylls from the diet or nutritional supplements alter the pharmacokinetics of drugs metabolized by CYPs. These findings provide some useful information for the safe use of these five xanthophylls in clinical practice. PMID- 23669409 TI - Life-threatening hypokalemia following rapid correction of respiratory acidosis. AB - A 56-year-old woman with a history of paraplegia and chronic pain due to neuromyelitis optica (Devic's syndrome) was admitted to a spinal cord injury unit for management of a sacral decubitus ulcer. During the hospitalization, she required emergency transfer to the intensive care unit (ICU) because of progressive deterioration of respiratory muscle function, severe respiratory acidosis, obtundation and hypotension. Upon transfer to the ICU, arterial blood gas revealed severe acute-on-chronic respiratory acidosis (pH 7.00, PCO2 120 mm Hg, PO2 211 mm Hg). The patient was immediately intubated and mechanically ventilated. Intravenous fluid boluses of normal saline (10.5 L in about 24 h) and vasopressors were started with rapid correction of hypotension. In addition, she was given hydrocortisone. Within 40 min of initiation of mechanical ventilation, there was improvement in acute respiratory acidosis. Sixteen hours later, however, the patient developed life-threatening hypokalemia (K(+) of 2.1 mEq/L) and hypomagnesemia (Mg of 1.4 mg/dL). Despite aggressive potassium supplementation, hypokalemia continued to worsen over the next several hours (K(+) of 1.7 mEq/L). Urine studies revealed renal potassium wasting. We reason that the recalcitrant life-threatening hypokalemia was caused by several mechanisms including total body potassium depletion (chronic respiratory acidosis), a shift of potassium from the extracellular to intracellular space (rapid correction of respiratory acidosis with mechanical ventilation), increased sodium delivery to the distal nephron (normal saline resuscitation), hyperaldosteronism (secondary to hypotension plus administration of hydrocortisone) and hypomagnesemia. We conclude that rapid correction of respiratory acidosis, especially in the setting of hypotension, can lead to life threatening hypokalemia. Serum potassium levels must be monitored closely in these patients, as failure to do so can lead to potentially lethal consequences. PMID- 23669410 TI - Transitions in caregiving and health dynamics of caregivers for people with AIDS: a prospective study of caregivers in Nairobi Slums, Kenya. AB - OBJECTIVE: A cohort of older people living in a low-resource setting in Nairobi is followed to understand the transitions in caregiving status and trajectories in health over a 3-year period. METHODS: Three categories of older people comprising 65 AIDS caregivers, 102 Other caregivers and 1,322 noncaregivers identified at baseline were assessed at end-line based on two self-reported health outcome measures, a functionality score and having a severe health problem. RESULTS: A majority of caregivers were still providing care at the end of the study, and or had taken on new care recipients. Compared with noncaregivers, AIDS caregivers reported poor health, with men more likely to report poor health than women. New caregivers also reported poorer health compared with noncaregivers. DISCUSSION: The results indicate improvement in health over time among male caregivers supporting the adaptation model. We recommend timely programs to support caregivers particularly at the onset of caregiving. PMID- 23669412 TI - Impaired chronotropic response to 6-min walk test and reduced survival in interstitial lung disease. AB - BACKGROUND: Reduced chronotropic response to maximal exercise has been associated with poor survival in people without respiratory disease. The contribution of chronotropic response to exercise limitation and survival in interstitial lung disease (ILD) is not well defined. This study investigated the relationships between chronotropic response during 6-min walk test, exercise capacity and survival in ILD. METHODS: Eligible participants had ILD, were ambulant and free of heart failure and beta blocker therapy. Chronotropic response during the 6-min walk test was defined as peak heart rate (HR) minus resting HR. Survival was recorded at four years. RESULTS: Sixty-two participants (40 idiopathic pulmonary fibrosis) were included, with mean (SD) TLCO 50(18)% predicted and 6-min walk distance (6MWD) 377 (127) metres. A smaller chronotropic response was associated with reduced 6MWD (r = 0.65, p < 0.001). Independent predictors of 6MWD were chronotropic response, peak oxygen uptake on cardiopulmonary exercise test; right ventricular systolic pressure on echocardiogram; and age. This model explained 83% of the variance in 6MWD, with 24% of the variance attributable to chronotropic response. A chronotropic response during 6-min walk test of less than 20 beats per minute was an independent predictor of death at four years (odds ratio 10.71, 95% confidence interval 2.67-42.94) in a model that also included oxygen desaturation and forced vital capacity. CONCLUSIONS: Impaired chronotropic response to 6-min walk test is associated with reduced 6MWD and reduced survival in ILD, independent of physical fitness and pulmonary hypertension. Investigation of the mechanisms underlying attenuated HR response to exercise in ILD is warranted. PMID- 23669413 TI - The "forgotten zone": acquired disorders of the trachea in adults. AB - The upper airway is generally defined as the air passage segment that extends between the naso- or oropharynx and the carina. The longest segment of the upper airway-the trachea-begins at the inferior portion of the larynx and extends to the branch point of the main carina. The trachea has the potential to be a "forgotten zone" in differential diagnoses, as pathological processes involving this portion may not receive prominent clinical consideration in disorders presenting with respiratory symptoms and signs. Unlike the oropharynx, this anatomical area is beyond visualization on routine inspection; unlike the mediastinum and lung fields, it is a potential "blind spot" on initial, plain radiographic examination of the chest. Nonetheless, the adult trachea is affected by a number of primary disorders and is also a target organ of a variety of systemic diseases. This review will focus on both primary and systemic diseases involving the adult trachea with specific attention to their clinical manifestations and diagnostic hallmarks. PMID- 23669411 TI - IDO1 metabolites activate beta-catenin signaling to promote cancer cell proliferation and colon tumorigenesis in mice. AB - BACKGROUND & AIMS: Indoleamine 2,3 dioxygenase-1 (IDO1) catabolizes tryptophan along the kynurenine pathway. Although IDO1 is expressed in inflamed and neoplastic epithelial cells of the colon, its role in colon tumorigenesis is not well understood. We used genetic and pharmacologic approaches to manipulate IDO1 activity in mice with colitis-associated cancer and human colon cancer cell lines. METHODS: C57Bl6 wild-type (control), IDO1-/-, Rag1-/-, and Rag1/IDO1 double-knockout mice were exposed to azoxymethane and dextran sodium sulfate to induce colitis and tumorigenesis. Colitis severity was assessed by measurements of disease activity, cytokine levels, and histologic analysis. In vitro experiments were conducted using HCT 116 and HT-29 human colon cancer cells. 1 methyl tryptophan and small interfering RNA were used to inhibit IDO1. Kynurenine pathway metabolites were used to simulate IDO1 activity. RESULTS: C57Bl6 mice given pharmacologic inhibitors of IDO1 and IDO1-/- mice had lower tumor burdens and reduced proliferation in the neoplastic epithelium after administration of dextran sodium sulfate and azoxymethane than control mice. These reductions also were observed in Rag1/IDO1 double-knockout mice compared with Rag1-/- mice (which lack mature adaptive immunity). In human colon cancer cells, blockade of IDO1 activity reduced nuclear and activated beta-catenin, transcription of its target genes (cyclin D1 and Axin2), and, ultimately, proliferation. Exogenous administration of IDO1 pathway metabolites kynurenine and quinolinic acid led to activation of beta-catenin and proliferation of human colon cancer cells, and increased tumor growth in mice. CONCLUSIONS: IDO1, which catabolizes tryptophan, promotes colitis-associated tumorigenesis in mice, independent of its ability to limit T-cell-mediated immune surveillance. The epithelial cell-autonomous survival advantage provided by IDO1 to colon epithelial cells indicate its potential as a therapeutic target. PMID- 23669414 TI - Increasing antiviral treatment through integrated hepatitis C care: a randomized multicenter trial. AB - Most individuals infected with the hepatitis C have not received antiviral treatment, with mental health and substance abuse problems being the primary barrier. Interventions have been developed to address these barriers among HCV patients considered "high-risk" for antiviral treatment. We present the design and methods of a prospective, randomized controlled multisite trial being conducted in the Veterans Affairs Healthcare System. The study employed a parallel design and the three study sites randomized a total of 364 VA patients with HCV to either Integrated Care (IC) or Usual Care (UC). The IC intervention consisted of a mental health provider (MHP) performing a) brief interventions to address risk factors; b) collaborative consultation with the HCV treatment clinicians; and c) case management prior to and during antiviral treatment. Clinical outcomes were abstracted from patient medical records and self-report questionnaires were completed at baseline, 4-months, 16-months, and 22-months after enrollment. The primary outcome of the study was sustained viral response (SVR). Secondary clinical outcomes were HCV treatment initiation and completion rates. Other secondary outcomes included substance use, depression, PTSD symptoms, quality of life, healthcare satisfaction, and healthcare utilization. The Integrated Care intervention has the potential to transform HCV antiviral treatment by increasing the number of HCV-infected individuals that can be successfully treated. PMID- 23669415 TI - Dynamics of soil gas radon concentration in a highly permeable soil based on a long-term high temporal resolution observation series. AB - This paper studies the temporal variation of soil gas radon activity concentration in a highly permeable (k = 2.0E-11 m(2)) sandy-gravelly soil in order to understand if temporal variation of soil gas radon activity concentration can affect geogenic radon potential determination. Geogenic radon potential provides information about the potential risk from radon. Its calculation takes into account the equilibrium, saturated at infinite depth, soil gas radon activity concentration (cinfinity). This concentration may vary at annual time scale due to the environmental conditions. A long-term (yearly) and high temporal resolution (15 min) observation, applied in this study, reveal various temporal features such as long-term trend, seasonality, daily periodicity and sudden events in soil gas radon time series. Results show seasonal and daily periodical variation of the measured soil gas radon activity concentration (csoilRn) in a highly permeable sandy-gravelly soil with definite seasons without obvious long transitional periods. The winter (from October 2010 to April 2011) is characterized by 2.5 times higher average soil gas radon activity concentration (median is 7.0 kBq m(-3)) than the summer (August, September 2010 and May, June, July 2011) (median is 2.8 kBq m(-3)). Daily periodicity, which is much less than the seasonal one, controls the soil gas radon activity concentration mainly in the summer season. Average (AM) value of csoilRn is higher at night than in the daytime with about 18% and 3.8% in summer and in winter, respectively. As a conclusion, in case of single csoilRn measurement on a highly permeable (k >= 2.0E-11 m(2)) soil, similar to our test site, csoilRn should be corrected according to the seasons for calculating the equilibrium activity concentration cinfinity value. PMID- 23669416 TI - [The follow up of the women vaccinated against HPV]. AB - HPV vaccine decreases significantly the risk of cervical cancer in women. However, continuing screening strategies in vaccinated women remains relevant as there is a small residual risk of cancer and pre-cancerous lesions even after prophylactic vaccination. The follow-up strategy to adopt has been the object of reflection by many experts, and especially since the vaccination catch-up population concerning women until 23 years of age will soon become the target screening population following recent guidelines. Finally, the arrival of HPV vaccines forces us to think about screening organization and optimization in a broader way so as it benefits all women concerned, whether vaccinated or not, and not only barely half of them as is the case now. The aim of this work was to clarify the issue and to make proposals for management. PMID- 23669417 TI - Is the pre-Tg DSC endotherm observed with solid state proteins associated with the protein internal dynamics? Investigation of bovine serum albumin by solid state hydrogen/deuterium exchange. AB - DSC thermograms of solid state pure proteins often show a distinct endotherm at a temperature far below the glass transition temperature of the system (Tg). We hypothesized this endotherm represents enthalpy recovery associated with an internal mobility transition of the protein molecule. Although the existence of an internal transition has been postulated, whether this endotherm is associated with such a transition has not previously been discussed. The purpose of this study was to investigate the origin of the pre-Tg endotherm in lyophilized bovine serum albumin (BSA). Due to strong glass behavior, the system Tg was determined by extrapolating Tg data of disaccharide/BSA formulations to zero saccharide. A small pre-Tg endotherm around 40-60 degrees C was observed in amorphous BSA equilibrated at 11%RH. The apparent activation energy suggested the endotherm was "alpha-mobility"-related. A solid state hydrogen/deuterium exchange study using FTIR was conducted over a temperature range spanning the endotherm. We found a fast phase, followed by essentially a plateau level which is highly temperature dependent in the 40-60 degrees C range, suggesting enhanced internal protein motion as the system passes through the temperature range of the endotherm. These results suggest the pre-Tg endotherm is associated with a protein internal mobility transition. PMID- 23669419 TI - PFS: the endpoint we love and love to hate. PMID- 23669421 TI - Missing data and measurement variability in assessing progression-free survival endpoint in randomized clinical trials. AB - Progression-free survival (PFS) is frequently used as the primary efficacy endpoint in the evaluation of cancer treatment that is considered for marketing approval. Missing or incomplete data problems become more acute with a PFS endpoint (compared with overall survival). In a given clinical trial, it is common to observe incomplete data due to premature treatment discontinuation, missed or flawed assessments, change of treatment, lack of follow-up, and unevaluable data. When incomplete data issues are substantial, interpretation of the data becomes tenuous. Plans to prevent, minimize, or properly analyze incomplete data are critical for generalizability of results from the clinical trial. Variability in progressive disease measurement between radiologists further contributes to data problems with a PFS endpoint. The repercussions of this on phase III clinical trials are complex and depend on several factors, including the magnitude of the variability and whether there is a systematic reader evaluation bias favoring one treatment arm particularly in open-label trials. PMID- 23669420 TI - Overview: progression-free survival as an endpoint in clinical trials with solid tumors. AB - Progression-free survival (PFS) is increasingly used as an important and even a primary endpoint in randomized cancer clinical trials in the evaluation of patients with solid tumors for both practical and clinical considerations. Although in its simplest form, PFS is the time from randomization to a predefined endpoint, there are many factors that can influence the exact moment of when disease progression is recorded. In this overview, we review the circumstances that can devalue the use of PFS as a primary endpoint and attempt to provide a pathway for a future desired state when PFS will become not just a secondary alternative to overall survival but rather an endpoint of choice. PMID- 23669422 TI - The imaging viewpoint: how imaging affects determination of progression-free survival. AB - Tumor measurements on computed tomgoraphic or MRI scans and/or the appearance of new lesions on any of a variety of imaging studies including positron emission tomographic scans are key determinants for assessing progression-free survival as an endpoint in many clinical trials of therapies for solid tumors. Test-retest tumor measurement reproducibility may vary considerably across serial scans on the same patient unless rigorous attention is paid to standardization of image acquisition parameters and unless measurements are made by trained, experienced observers using validated objective methods. Target lesion selection also must be done with care to choose lesions that are or will be reproducibly measurable. Likewise, new lesions will be missed or misinterpreted on follow-up imaging studies unless those imaging studies are obtained using techniques suitable for detecting early, small lesions. Reader variability is clearly a major component of the problem. The increasing availability of semiautomatic image processing algorithms will help ameliorate that issue. In addition, an array of internationally accepted guidelines, standards, and accreditation programs now exist to help address these problems. PMID- 23669423 TI - The clinical viewpoint: definitions, limitations of RECIST, practical considerations of measurement. AB - In selecting an endpoint in clinical trial design, it is important to consider that the endpoint is both reliably measured and clinically meaningful. As such, overall survival (OS) has traditionally been considered the most clinically relevant and convincing endpoint in clinical trial design as long as it is accompanied by preservation in quality of life. However, progression-free survival (PFS) is increasingly more prominent in clinical trial design because of feasibility issues (smaller sample sizes and shorter follow-up). PFS has the advantage of taking into account not only responsive disease, but stable disease as well, an issue of particular importance in the relapsed and refractory setting in which therapies are often associated with a minimal to nil response but may still confer a survival advantage. Finally, PFS has a significant advantage in molecularly selected populations, in whom OS advantages are difficult to detect due to the effects of crossover. With an understanding of the limitations and biases that are introduced with PFS as a primary endpoint, we believe that PFS is not only a viable but also a necessary alternative to OS in assessing the efficacy of selected novel-targeted therapies in molecularly defined cancer populations. Ultimately, the selection of a clinical trial endpoint should not be based on a one-size-fits all approach; rather, it should be based on the specifics of the therapeutic strategy being tested and the population under study. PMID- 23669425 TI - Plasmodium falciparum infection among neonates in the North Central region of Nigeria. AB - INTRODUCTION: This cross-sectional study investigated the rate of congenital and neonatal malaria infections in patients attending our hospital. METHODOLOGY: Thick and thin blood films of 288 neonates admitted in the Special Care Baby Unit of Jos University Teaching Hospital, Nigeria, were examined microscopically for malaria parasites. Babies' and mothers' demographic and clinical data were analyzed. RESULTS: Of 288 blood samples examined, 160 (55.6%) were from males, 115 (39.9%) were from babies 0 to 7 days old, and 173 (60.1%) were from babies 8 to 28 days old. In total, 91 (31.6%) babies had malaria parasitaemia, of whom 49 (53.8%) were males. Malaria was significantly higher in babies 8 to 28 days old (p < 0.001) and was independent of gender (p=0.692). Prevalence rates for congenital and neonatal malaria were 6.9% and 24.7% respectively. Clinical presentations on admission included fever, cough, pallor, jaundice, and inability to suck. A total of 145 (50.3%) babies had symptoms of malaria, of whom 56 (61.5%) had malaria parasitaemia. Symptoms of malaria were present in 35 (12.2%) babies of 59 (20.5%) mothers who had symptoms of malaria during pregnancy. Ten (11.0%) of these neonates had malaria parasitaemia, of whom 4 (0.4%) were 0 to -7 days old. Plasmodium falciparum was the only specie identified. No mortality was recorded against malaria-infected babies. CONCLUSION: High prevalence of malaria in these neonates calls for high index of suspicion. Inclusion of malaria parasite test in the routine battery of tests for babies presenting with clinical signs and symptoms of neonatal infections is recommended. PMID- 23669426 TI - Enterotoxigenic Escherichia coli associated with childhood diarrhoea in Colombia, South America. AB - INTRODUCTION: Intestinal Escherichia coli pathogens are major causes of diarrhoeal disease in children under five years of age worldwide. The aim of this study is to evaluate the association of E. coli pathotypes with childhood diarrhoea in Colombia. METHODOLOGY: A case-control study was conducted in 815 samples from children younger than five years of age in Cartagena, Colombia (466 cases and 349 controls). Controls were randomly selected 1:1 to cases, to obtain 349 cases and 349 controls. RESULTS: This study revealed that 27 (7.44%) cases and 12 (3.43%) controls were positives for any of the E. coli pathotypes. The difference observed was statistically significant indicating that E. coli pathotypes were associated with cases of childhood diarrhoea. Enterotoxigenic E. coli (ETEC) was the most common pathotype associated with childhood diarrhoea. Additional E. coli pathotypes were also identified. CONCLUSIONS: We conclude that after the adjustment by age, sex and socioeconomic stratum, the odds ratio obtained by logistic regression shows an association between infection with ETEC and childhood diarrhoea. PMID- 23669424 TI - Modeling the relationship between progression-free survival and overall survival: the phase II/III trial. AB - The standard phase II trial design has changed dramatically over the past decade. Randomized phase II studies have essentially become the standard phase II design in oncology for a variety of reasons. The use of these designs is motivated by concerns about the use of historical data to determine if a new agent or regimen shows promise of activity. However, randomized phase II designs come with the cost of increased study duration and patient resources. Progression-free survival (PFS) is an important endpoint used in many phase II designs. In many clinical settings, changes in PFS with the introduction of a new treatment may represent true benefit in terms of the gold standard outcome, overall survival (OS). The phase II/III design has been proposed as an approach to shorten the time of discovery of an active regimen. In this article, design considerations for a phase II/III trial are discussed and presented in terms of a model defining the relationship between OS and PFS. The design is also evaluated using 15 phase III trials completed in the Southwest Oncology Group (SWOG) between 1990 and 2005. The model provides a framework to evaluate the validity and properties of using a phase II/III design. In the evaluation of SWOG trials, three of four positive studies would have also proceeded to the final analysis and 10 of 11 negative studies would have stopped at the phase II analysis if a phase II/III design had been used. Through careful consideration and thorough evaluation of design properties, substantial gains could occur using this approach. PMID- 23669427 TI - Dissemination of IncF plasmids carrying beta-lactamase genes in Gram-negative bacteria from Nigerian hospitals. AB - INTRODUCTION: Production of beta-lactamases is the predominant cause of resistance to beta-lactam antibiotics in Gram-negative bacteria. We investigated the diversity of plasmid-borne beta-lactamase genes and replicon type of the plasmids carrying the respective genes in Gram-negative bacteria recovered from clinical infection in Nigerian hospitals. METHODOLOGY: A total of 134 Gram negative bacteria of 13 species were analyzed for antimicrobial susceptibility, phenotypic and genotypic detection of various beta-lactamases, and plasmid analysis, including replicon typing. RESULTS: Of the 134 isolates, 111 (82.8%) contained beta-lactamases, while 28 (20.9%) carried extended-spectrum beta lactamases. PCR and sequencing identified TEM-1 in 109 isolates (81.3%), SHV-1 in 33 isolates (24.6%), OXA-1 in 15 isolates (11.2%) and CTX-M enzymes (24 CTX-M-15 and 1 CTX-M-3) in 25 isolates (18.7%). Multiplex PCR showed that 6 isolates carried plasmidic AmpCs (ACT-1, DHA-1 and CMY-2); these enzymes were detected only in isolates possessing CTX-M beta-lactamases. Of 13 (76.9%) representative plasmids investigated in detail, 9 (69.2%) were self-transferable when selected by a beta-lactam and the plasmids once transferred coded for beta-lactam resistance. Replicon typing indicated IncF as the common vector encoding for beta lactamases. CONCLUSIONS: The study showed a diversity of beta-lactamase genes disseminated by conjugative IncF plasmids in Gram-negative bacteria; TEM-1, SHV 1, OXA-1, CTX-M-15, CTX-M-3 and plasmidic AmpC enzymes are in common circulation in Nigeria. PMID- 23669428 TI - A knowledge survey of obstetrics and gynecology staff on the prevention of mother to-child transmission of hepatitis B virus. AB - INTRODUCTION: This survey was designed to investigate the knowledge awareness of obstetrics and gynaecology staff (Obs/Gyn staff) on the prevention of mother-to child transmission (PMTCT) of hepatitis B virus (HBV). METHODOLOGY: Obs/Gyn staff from 21 of the 31 Chinese mainland provinces, who attended medical meetings or training classes from July to October 2011, were invited to complete a questionnaire regarding PMTCT of HBV. The questionnaire included the clinical implications of HBV serologic markers and PMTCT preventive measures for both pregnant women and infants. RESULTS: A total of 828 questionnaires were distributed, 617 (74.5%) Obs/Gyn staff participated in the survey, and 559 (90.6%) questionnaires met the inclusion criteria. Overall, 90% of participants correctly determined the positive hepatitis B surface antigen (HBsAg) as infectious, but up to 27.5% mistakenly considered the presence of anti-HBe and/or anti-HBc with negative HBsAg as infectious. In total, 96.3% respondents knew that pregnant women should be screened for HBV infection, and 95.3% realized that infants of HBsAg-positive mothers should be injected with hepatitis B immunoglobulin and vaccine. On the other hand, with the available immunoprophylaxis, 13.8% participants mistakenly believed caesarean section may prevent HBV mother-to-child transmission, and only 13% correctly answered that newborns of HBsAg positive mothers may be breastfed. CONCLUSION: Obs/Gyn staff in China have mastered the strategies of HBV PMTCT, but there is obvious insufficiency in details of the application. Intensified efforts to train the Obs/Gyn staff are required to improve the current suboptimal medical service in HBV-exposed infants and to control mother-to-infant transmission of HBV. PMID- 23669429 TI - Seroprevalence of IgM and IgG antibodies to Toxoplasma infection in healthy and HIV-positive adults from Northern Nigeria. AB - INTRODUCTION: We examined the seroprevalence of toxoplasma infection in HIV negative and -positive adults from Zaria, Northern Nigeria, and assessed its relationship with demographic, clinical, and immunological findings. METHODOLOGY: In a six-month cross-sectional study undertaken in 2008, sera of 219 adults, including 111 consecutive HIV-infected adults and 108 healthy HIV-negative adult volunteers from Zaria, Northern Nigeria, were examined for IgG and IgM antibodies to toxoplasma by ELISA. Clinical characteristics of the HIV-infected patients were documented. Differences in toxoplasma seropositivity between HIV-positive and negative adults were sought. The relationship between toxoplasma seropositivity and variables such as age, sex and antiretroviral (ART) status, as well as HIV clinical staging and CD4 cell counts were also determined. P < 0.05 was considered significant. RESULTS: The seroprevalence of toxoplasma infection (IgG positive and or IgM positive) was 32.4% in HIV-negative healthy adults and 38.7% in HIV-infected adults (P > 0.05). The rate of IgM seropositivity was 4.6% in healthy adults and 1.8% in HIV-infected patients, while the rate of IgG seropositivity (without IgM seropositivity) was 28.7% in healthy adults and 37.8% in HIV-infected patients (p > 0.05). Toxoplasma seropositivity was not associated with age, sex, ART status, CD4 cell count or HIV clinical staging. Seventy-four percent of the toxoplasma seropositive HIV-infected patients were asymptomatic and no cases of toxoplasma encephalitis were identified. CONCLUSION: Toxoplasmosis is equally prevalent in HIV-infected patients and healthy adults from similar environments in Northern Nigeria. It is imperative to develop public health policies to prevent toxoplasmosis in Nigeria, especially in HIV-infected patients. PMID- 23669430 TI - Availability and prescription practice of anti-malaria drugs in the private health sector in Yemen. AB - INTRODUCTION: Although the government of Yemen changed the national policy for treating malaria in November 2005 from chloroquine to combination drugs in the form of artesunate + sulphadoxine-pyrimethamine (SP) as first line and lumefantrine + artemether as second line treatment for uncomplicated malaria, clinicians in public and private health facilities continued to prescribe chloroquine because their knowledge about the new treatment policy was poor. METHODOLOGY: A non-randomized trial of pre- and post-evaluation of the training and reporting interventions about prescription behaviors and availability of anti malaria drugs among clinicians and pharmacists in the private sector in three governorates in Yemen was conducted. RESULTS: Adherence of clinicians in the private sector to the new national guidelines for anti-malaria drugs improved from 21% in pre-intervention period to 38% after the intervention for artesunate + SP being prescribed as the first-line treatment. Prescription of lumefantrine + artemether as the second-line anti-malaria treatment was also improved from 18% before the intervention to 22% post-intervention. Unfortunately the combination of halofantrine + SP continued to be frequently prescribed by clinicians in Sana'a city (18%). Artesunate + SP and quinine are increasing their marketing significantly from 8% in the pre-intervention period to 22% post-intervention (P value 0.001). CONCLUSIONS: The study provides evidence of usefulness of the training intervention on the national guidelines for malaria treatment. Additionally, the involvement of private health-care providers in reporting procedures will promote the rational prescription and availability of anti malaria drugs. PMID- 23669431 TI - First molecular-based detection of mucocutaneous leishmaniasis caused by Leishmania major in Iran. AB - Mucocutaneous leishmaniasis, which mostly occurs in the New World, is mainly associated with Leishmania braziliensis and to a lesser degree L. panamensis and L. amazonensis infections. Primary mucosal leishmaniasis is very rare in Iran in spite of high prevalence of cutaneous and visceral leishmanisis. A nine-year-old boy had cutaneous leishmaniaisis for five years involving the left side of his face; he then developed swelling and ulceration of the lip and left side buccal mucosa five months before hospital admission. He had severe swelling of the lower lip and there was ulceration and bleeding of the buccal mucosa. Direct smear revealed leishman bodies and nested PCR confirmed the presence of kinetoplast DNA of L. major in the oral mucosal specimen. The patient received amphotericin B deoxycholate 1 mg/kg/day for one month. The lip and face inflammatory reaction disappeared to nearly normal after one month of therapy. The patient was discharged with ketoconazole (5mg/kg/day) for six weeks. To our knowledge, this is the first report of mucocutaneous leishmaniasis caused by L. major in Iran. PMID- 23669432 TI - Sweet's syndrome: a very rare association with pulmonary tuberculosis. AB - Mycobacterium tuberculosis infection is a common infection in developing countries, including India. It can induce several cutaneous reactions such as erythema nodosum, and erythema induratum; however, association of tuberculosis with Sweet's syndrome (also known as acute febrile neutrophilic dermatosis) is extremely rare. Here we present an interesting case of sputum-positive pulmonary tuberculosis with Sweet's syndrome. A 55-year-old female who was receiving a regimen of four antitubercular drugs (isoniazid, rifampicin, pyrazinamide, ethambutol- HRZE) for six weeks for sputum-positive pulmonary tuberculosis developed new onset high-grade fever for 15 days along with multiple reddish brown plaques and nodules involving the face as well as all four limbs of the body. Histopathology of the skin lesion was suggestive of Sweet's syndrome. The patient responded well to immunosuppressive steroid therapy. PMID- 23669433 TI - Successful switch to oral therapy with doxycycline in the case of an actinomycotic hepatic abscess. AB - A 72-year-old female was admitted with the symptoms of malaise, loss of appetite, upper right quadrant pain, fever, and sweats, which had been present for last 7 days. CT-scan of the abdomen revealed a hypodense mass in the right liver lobe; histopathological examination of the biopsy specimen yielded a diagnosis of actinomycotic abscess. Treatment with intravenous ampicillin for 8 weeks followed by a course of oral doxicycline for 28 weeks resulted in the complete resolution of the abscess. PMID- 23669434 TI - Community-acquired CTX-M-15-type ESBL-producing Escherichia coli meningitis: a case report and literature review. AB - In this report, a case of community-acquired acute bacterial meningitis (CA-ABM) caused by CTX-M-15-producing Escherichia coli in an elderly male patient was presented in the light of literature. Cultures of cerebrospinal fluid, blood, ear discharge, and stool samples yielded CTX-M-15-producing E. coli in-vitro, which was resistant to the extended-spectrum cephalosporins and ciprofloxacin and susceptible to imipenem, meropenem and amikacin. Meningitis was treated with parenteral meropenem plus parenteral and intraventricular amikacin administration. Since bacterial meningitis is a life-threatening infection, empiric antibiotic therapy with carbapenem can be started before the culture results are obtained, mainly in areas where the ESBL epidemiology is well known. PMID- 23669435 TI - CTX-M-32 beta-lactamase-producing uropathogenic Escherichia coli isolated in Latin America. PMID- 23669436 TI - Non-medical prescribing by physiotherapists: issues reported in the current evidence. AB - Physiotherapists should be proactive in preparing themselves to participate in innovative models of health care, which are emerging from the healthcare workforce reforms in Australia. One challenging outcome of workforce change is physiotherapy (non-medical) prescribing (NMP), which is part of the extension of scope of physiotherapy practice. This paper summarises the current evidence base for Australian physiotherapists seeking to obtain prescribing rights. A targeted literature review was undertaken through EBSCO Host, Cochrane, Medline, SportsDiscus, Cinahl, Healthsource and Google.com using broad search terms to identify peer-reviewed and grey literature pertaining to NMP by physiotherapists, nationally and internationally. No critical appraisal was undertaken however literature was structured into the NHMRC hierarchy of evidence. Themes raised in the included literature were reported descriptively. There were six relevant peer reviewed articles, of hierarchy levels III_3 and IV. There was however, comprehensive and recent grey literature to inform Australian physiotherapy NMP initiatives. Themes included the need for standard National action in relation to legislative and regulatory/registration issues, appropriate education, credentialing and supervisory requirements for physiotherapy prescribing. Many lessons can be learnt from the literature, including the importance of planned, uniform National action (rather than piecemeal state-by-state initiatives). Essential elements include appropriate training and skills-based recognition within the discipline and the broader health team, and the need to overtly demonstrate effectiveness and safety. Regularly-evaluated service-delivery models which support NMP by physiotherapists are further required, to demonstrate efficiency, timeliness, patient centredness and equity. PMID- 23669437 TI - Differences in EMG activity during exercises targeting the scapulothoracic region: a preliminary study. AB - Surface electromyographic response of the middle, lower serratus anterior, and the upper trapezius muscles was investigated within a number of exercises. In total, 16 healthy, physically active volunteers completed three individual trials consisting of arm elevation above 120 degrees , diagonal elevation, dynamic hug, dynamic hug plus, and push-up plus while surface electromyography was used to record muscle activity in the lower and middle serratus anterior (LSA, MSA) and upper trapezius (UT) muscles. The dynamic hug plus exercise caused significant increases in the activity of the MSA compared with the other exercises (P < 0.05). The diagonal elevation, dynamic hug plus, and push up plus showed significantly higher activation in the LSA compared with the arm elevation above 120 degrees and the dynamic hug (P < 0.05). The activation of the UT and the UT/MSA and UT/LSA ratios in both the arm elevation and diagonal shoulder flexion exercises was significantly higher than that for the dynamic hug, dynamic hug plus, and push-up plus exercises (P < 0.05). The present study showed that the dynamic hug plus exercise could be used for activating MSA and LSA. Selective activation of the LSA and MSA is better achieved with exercises that include a scapular protraction component. PMID- 23669438 TI - Unusual coexistence of opportunistic lung infections in a human immunodeficiency virus positive patient suffering from persistent Pneumocystis jirovecii pneumonia: a case report. AB - It is well established that HIV patients are at high risk of opportunistic infections (OI), like the ones caused by Pneumocystis jirovecii, a worldwide pathogen implicated in interstitial pneumonia (PcP). We present a case of a newly diagnosed HIV-1 patient with multiple OI, including a persistent form of PcP, an invasive aspergillosis (IA), cytomegalovirus and Mycobacterium xenopi lung infection. We describe the combination of laboratorial screening, surgery and antimicrobial therapy that were crucial for patient recovery. PMID- 23669439 TI - Predictive factors of mortality in severe community-acquired pneumonia: a model with data on the first 24h of ICU admission. AB - OBJECTIVE: To construct a model of factors predicting mortality in severe community-acquired pneumonia (SCAP) with data on the first 24h after admission to the intensive care unit (ICU). DESIGN: A prospective, observational study was carried out. SETTING: The ICU of a university hospital. PATIENTS: ICU-admitted patients with SCAP were studied prospectively. INTERVENTIONS: Admission pneumonia scores were calculated, and clinical variables were registered during the first 24h. Relationships between predictors of mortality at 28 days were assessed by means of a multivariate logistic regression model. RESULTS: A total number of 242 SCAP patients were evaluated. The SAPS II severity score was 37.2+/-15.5 points. Bivariate analysis showed high mortality to be more frequent in elderly patients, as well as in patients with high SAPS II scores, neoplastic disease or chronic renal failure. The other prognostic factors related to increased mortality included mechanical ventilation, acute respiratory distress syndrome (ARDS), acute renal failure, bacteremia, and septic shock. Mortality at 28 days was 23.1% (56 patients). Multivariate analysis of the risk factors generated a new predictive model of mortality applicable within the first 24h after ICU admission and comprising 5 main factors: age, CURB severity score 3-4, septic shock, ARDS, and acute renal failure. CONCLUSIONS: Age in years, CURB score 3-4, septic shock, ARDS, and acute renal failure during the first 24h of ICU admission were found to be independent predictors of mortality in SCAP patients. PMID- 23669440 TI - Clinical significance of hTERC gene detection in exfoliated cervical epithelial cells for cervical lesions. AB - OBJECTIVE: To investigate the clinical significance of abnormal human telomerase RNA gene component (hTERC) gene amplification tested by fluorescence in situ hybridization in cervical lesions. METHODS: In 373 patients with cytologic abnormalities, high-risk human papilomavirus (HR-HPV) was detected by the hybrid capture II method, and abnormal amplification of the hTERC gene in exfoliated cells was detected by fluorescence in situ hybridization. RESULTS: Cell smear findings suggested atypical squamous cells in 148 patients, low-grade squamous intraepithelial lesion in 62 patients, and high-grade squamous intraepithelial lesion in 107 patients, squamous cell carcinoma in 56 patients, and cervical biopsy-revealed inflammation in 89 patients, cervical intraepithelial neoplasia (CIN) I in 36 patients, CIN II in 43 patients, CIN III in 129 patients, and infiltrating carcinoma in 76 patients. In the inflammation, CIN I, CIN II, CIN III, and infiltrating carcinoma groups, the infection rates of HR-HPV were 29.21%, 52.78%, 74.42%, 92.25%, and 93.42% (P < 0.01), respectively; the positive rates of hTERC gene amplification were 0.00%, 13.89%, 41.86%, 78.29%, and 89.47% (P < 0.01), respectively. With respect to advanced cervical lesions (>=CIN II), cytology (>= low-grade squamous intraepithelial lesion), HR-HPV testing, and hTERC testing differed insignificantly in the negative predictive value (P > 0.05), but they differed significantly in the sensitivity, specificity, and positive predictive value (P < 0.01). Among the 3 methods, hTERC testing showed the highest specificity and positive predictive value, and HR-HPV testing showed the highest sensitivity. In 41 patients with untreated CIN I and CIN II, the sensitivity of detection of hTERC gene amplification to predict lesion progression was 88.89%, and the specificity was 93.75%. CONCLUSION: Detection of abnormal amplification of the hTERC gene can assist in screening cervical lesions and identifying CIN I/II patients with a high progression risk. PMID- 23669441 TI - Simple vaginal trachelectomy in early-stage low-risk cervical cancer: a pilot study of 16 cases and review of the literature. AB - OBJECTIVE: This study aimed to evaluate the feasibility of simple vaginal trachelectomy and node assessment in patients with low-risk early-stage cervical cancer (<2 cm). METHODS: From May 2007 to November 2012, 16 women with low-risk small-volume cervical cancer underwent a simple vaginal trachelectomy preceded by laparoscopic sentinel node mapping plus or minus pelvic node dissection. Data were collected prospectively in a computerized database. Descriptive statistics and Kaplan-Meyer estimate were used for analysis. RESULTS: Patients' median age was 30 years and 12 (75%) were nulliparous. Six had a diagnostic cone, 6 had a loop electrocautery excision procedure, 3 had cervical biopsies, and 1 had polyp excision. All patients underwent a preoperative pelvic magnetic resonance imaging. Four patients had stage IA1 with lymph vascular space invasion (LSVI), 6 IA2, and 6 IB1. Ten (62.5%) had squamous lesions, 7 had adenocarcinoma. LVSI was present in 4 cases, suspicious in 2, and absent in 10. There were 2 surgical complications: a trocar site hematoma and a vaginal laceration. The median OR time was 150 minutes (range, 120-180 minutes) and median blood loss was 50 mL (range, 50-150 mL). On final pathology, lymph nodes were negative in all patients. Thirteen (81%) patients had either no residual disease (6) or residual dysplasia only (7) in the trachelectomy specimen. Margins were negative in all cases. With a median follow-up of 27 months (range, 1-65 months), there have been no recurrences. The recurrence-free survival at 24 months is 100%. Eight patients have conceived: 3 were term deliveries and 4 are ongoing. CONCLUSIONS: Simple trachelectomy and nodes seems to be a safe alternative in well-selected patients with early-stage low-risk cervical cancer. Our data will need to be confirmed in larger series. PMID- 23669442 TI - Vaginal vault dehiscence after robotic hysterectomy for gynecologic cancers: search for risk factors and literature review. AB - INTRODUCTION: Vaginal vault dehiscence following robotic-assisted hysterectomy for gynecologic cancer may be attributed to surgical techniques and postoperative therapeutic interventions. We searched for risk factors in patients with gynecologic cancers and complemented this with a literature review. METHODS: Evaluation of prospectively gathered information on all consecutive robotic surgeries for gynecologic cancers was performed in a tertiary academic cancer center between December 2007 and March 2012. The literature was reviewed for articles relevant to "gynecologic oncology" and "robotics" with "vaginal cuff dehiscence" in the English and French languages. Respective authors were contacted to complete relevant information. RESULTS: Seven dehiscences were identified of 441 cases with established gynecologic cancers. The closures in these 7 were performed using interrupted 1-Vicryl (Ethicon Inc) (3/167; 1.8%), combination of interrupted 1-Vicryl and 1-Biosyn (Covidien Inc) (3/156, 1.9%), and V-Loc (Covidien Inc) (1/118, 0.8%) sutures. Associated risk factors included adjuvant chemotherapy and/or brachytherapy, early resumption of sexual activity, and low body mass index (mean, 23 +/- 3.23 kg/m2). Dehiscences occurred regardless of suturing by staff or trainees. Review of operative videos did not reveal a detectable etiologic factor, such as excessive cautery damage to the vaginal cuff or shallow tissue sutured. All 7 colporrhexis repairs were performed through a vaginal approach without the need of laparoscopy or laparotomy. CONCLUSIONS: Postoperative chemotherapy, brachytherapy, and early resumption of sexual activities are risk factors for vaginal vault dehiscence. Surgical technique, particularly the use of delayed absorbable sutures, deserves further evaluation. PMID- 23669443 TI - CA-125 level as a prognostic indicator in type I and type II epithelial ovarian cancer. AB - OBJECTIVE: Most patients with epithelial ovarian cancer achieve a complete clinical remission (CCR) with normal CA-125 but will still relapse and die from their disease. The present study was designed to determine whether CA-125 levels before, during, and after primary treatment provide prognostic information for both type I and type II ovarian cancer. METHODS: In this retrospective study, we identified 410 patients with epithelial ovarian cancer who had achieved a CCR between 1984 and 2011. A Cox proportional hazards model and log-rank test were used to assess associations between the nadir CA-125, histotype, and prognosis. RESULTS: The baseline serum CA-125 concentration was higher in patients with type II ovarian cancer than in those with type I ovarian cancer (P < 0.001). The nadir CA-125 was an independent predictor of progression-free survival (PFS; P < 0.001) and overall survival (OS; P = 0.035) duration. The PFS and OS durations were 21.7 and 79.4 months in patients with CA-125 of 10 U/mL or less and 13.6 and 64.6 months in those with CA-125 of 11 to 35 U/mL, respectively (P = 0.01 and P = 0.002, respectively). Histotype was an independent predictor of PFS (P = 0.041): the PFS and OS durations of the patients with type I ovarian cancer were longer than those of the patients with type II ovarian cancer (P < 0.001 and P < 0.001, respectively). CONCLUSIONS: The nadir CA-125 and histotype are predictive of PFS and OS durations in patients with ovarian cancers who experienced a CCR. Progression-free survival and OS durations were shorter in the patients with CA 125 levels of 11 to 35 U/mL and type II disease than in those with CA-125 levels of 10 U/mL or less and type I ovarian cancer. PMID- 23669444 TI - Comparison of current staging systems and a novel staging system for uterine leiomyosarcoma. AB - OBJECTIVES: Uterine leiomyosarcoma (LMS) was traditionally staged by modified 1988 International Federation of Gynecology and Obstetrics (FIGO) staging criteria for endometrial adenocarcinoma. Contemporary methods of staging include the 2009 FIGO system for uterine LMS and the 2010 American Joint Committee on Cancer (AJCC) soft tissue sarcoma system. The aim of this study was to compare the accuracy of these 3 staging systems and a novel system in predicting disease specific survival for patients with uterine LMS. METHODS: Patients, evaluated at our institution with uterine LMS from 1976 to 2009, were identified. Stage was assigned retrospectively based on operative and pathology reports. Staging systems performance was compared using confidence indices. RESULTS: We identified 244 patients with uterine LMS with sufficient information to be staged by all 3 systems. For each staging method, lower stage was associated with significantly improved disease-specific survival, P < 0.001. Patients with 2010 AJCC stage IA disease (low-grade, <=5 cm) experienced no disease-specific deaths. We created a novel staging system, which used size and grade to stratify patients with disease confined to the uterus and/or cervix and combined the remaining patients with extrauterine disease as stage IV. Based on confidence index, the 2010 AJCC system and our novel system provided more accurate prognostic information than either of the 2 FIGO systems. CONCLUSIONS: Uterine LMS remains a clinically aggressive malignancy. Size and grade provided accurate prognostic information for patients with disease confined to the uterus and/or cervix. Patients with small, low-grade uterine LMS do not benefit from adjuvant therapy. PMID- 23669445 TI - Nfatc1 directs the endocardial progenitor cells to make heart valve primordium. AB - Heart valves arise from the cardiac endocardial cushions located at the atrioventricular canal (AVC) and cardiac outflow tract (OFT) during development. A subpopulation of cushion endocardial cells undergoes endocardial to mesenchymal transformation (EMT) and generates the cushion mesenchyme, which is then remodeled into the interstitial tissue of the mature valves. The cushion endocardial cells that do not undertake EMT proliferate to elongate valve leaflets. During EMT and the post-EMT valve remodeling, endocardial cells at the cushions highly express nuclear factor in activated T cell, cytoplasmic 1 (Nfatc1), a transcription factor required for valve formation in mice. In this review, we present the current knowledge of Nfatc1 roles in the ontogeny of heart valves with a focus on the fate decision of the endocardial cells in the processes of EMT and valve remodeling. PMID- 23669446 TI - Quantitative PCR analysis of genes expressed during biofilm development of methicillin resistant Staphylococcus aureus (MRSA). AB - Staphylococcus aureus biofilm associated infections remains a major clinical concern in patients with indwelling devices. Quantitative real-time PCR (qPCR) can be used to investigate the pathogenic role of such biofilms. We describe qPCRs for 12 adhesion and biofilm-related genes of four S. aureus isolates which were applied during in vitro biofilm development. An endogenous control (16S rRNA) was used for signal normalization. We compared the qPCR results with structural analysis using scanning electron microscopy (SEM). The SEM studies showed different cellular products surrounding the aggregated cells at different times of biofilm formation. Using qPCR, we found that expression levels of the gene encoding fibronectin binding protein A and B and clumping factor B (fnbA/B and clfB), which involves in primary adherence of S. aureus, were significantly increased at 24h and decreased slightly and variably at 48 h when all 4 isolates were considered. The elastin binding protein (ebps) RNA expression level was significantly enhanced more than 6-fold at 24 and 48 h compared to 12h. Similar results were obtained for the intercellular adhesion biofilm required genes type C (icaC). In addition, qPCR revealed a fluctuation in expression levels at different time points of biofilm growth of other genes, indicating that different parameter modes of growth processes are operating at different times. PMID- 23669447 TI - Odor identification deficit predicts clinical conversion from mild cognitive impairment to dementia due to Alzheimer's disease. AB - The aim of this study was to analyze the relationship between olfactory and cognitive functions in subjects affected by mild cognitive impairment (MCI) and to investigate whether olfactory deficits might reflect the likelihood of conversion from MCI to dementia. In this longitudinal study conducted on a sample of MCI outpatients, CA-SIT Smell Identification Test was administered to 88 MCI subjects and 46 healthy control subjects. MCI subjects have been divided into two groups, considering smell identification performances: 40% had normal performances (MCI olfactory-normal), whereas 60% had a moderate olfaction deficit (MCI olfactory-impaired). At 2-year follow-up, the 47% of MCI olfactory-impaired subjects and the 11% of MCI olfactory-normal subjects progressed to dementia. In a logistic regression model, a lower score in MMSE (95%, OR 1.9; IC 1.23-3.01; p = .004) and a pathological smell identification at baseline (95%, OR 5.1; IC 1.16 22.6; p = .03) were independently associated with the progression to dementia within 2 years. This study confirms that smell identification testing may be useful in high-risk settings to identify patients at risk for developing dementia. PMID- 23669448 TI - Significance of alterations in the metabolomics of sulfur-containing amino acids during liver regeneration. AB - It has been known that liver regeneration is accompanied with a profound change in the metabolomics of sulfur-containing substances in liver. However, its physiological significance in the liver regenerative process is still unclear. Our previous work showed that buthioninesulfoximine and phorone, both widely used to deplete intracellular glutathione (GSH) in biological experiments, induced contrasting changes in the sulfur-containing amino acid metabolism in liver. In this study we employed these GSH-depleting agents to evaluate the role of sulfur containing substances in the early phase of liver regeneration. Male rats treated with buthioninesulfoximine or phorone were subjected to two-thirds partial hepatectomy (PHx). At the doses used, the magnitude of GSH depletion after PHx was comparable, but buthioninesulfoximine administration inhibited the progression of liver regeneration as determined by liver weight increase, elevation of serum alanine aminotransferase activity, and cyclin D1 and proliferating cell nuclear antigen (PCNA) protein expressions, whereas liver recovery was significantly accelerated in the phorone-treated rats, suggesting that the role of GSH in this process is minimal. Hepatic concentrations of methionine, S-adenosylmethionine, cysteine, taurine and GSH were all elevated by PHx. Methionine adenosyltransferase activity was also induced in the remnant liver. Buthioninesulfoximine administration depressed the elevation of S adenosylmethionine, but increased the catabolism of cysteine to taurine. In contrast, S-adenosylmethionine elevation was augmented whereas cysteine, hypotaurine and taurine were decreased in the phorone-treated rats. PHx elevated hepatic putrescine and spermidine, but lowered spermine concentrations. Buthioninesulfoximine administration increased putrescine further, but decreased spermidine and spermine concentrations. On the contrary, both spermidine and spermine concentrations were elevated in the rats treated with phorone. The results suggest that the availability of S-adenosylmethionine plays a critical role in the progression of liver regeneration via enhancement of polyamine synthesis. These findings raise the possibility that regulating hepatic transsulfuration reactions may be capable of modifying the recovery process after liver injury. PMID- 23669449 TI - Rooted phylogeny of the three superkingdoms. AB - The traditional bacterial rooting of the three superkingdoms in sequence-based gene trees is inconsistent with new phylogenetic reconstructions based on genome content of compact protein domains. We find that protein domains at the level of the SCOP superfamily (SF) from sequenced genomes implement with maximum parsimony fully resolved rooted trees. Such genome content trees identify archaea and bacteria (akaryotes) as sister clades that diverge from an akaryote common ancestor, LACA. Several eukaryote sister clades diverge from a eukaryote common ancestor, LECA. LACA and LECA descend in parallel from the most recent universal common ancestor (MRUCA), which is not a bacterium. Rather, MRUCA presents 75% of the unique SFs encoded by extant genomes of the three superkingdoms, each encoding a proteome that partially overlaps all others. This alone implies that the common ancestor to the superkingdoms was very complex. Such ancestral complexity is confirmed by phylogenetic reconstructions. In addition, the divergence of proteomes from the complex ancestor in each superkingdom is both reductive in numbers of unique SFs as well as cumulative in the abundance of surviving SFs. These data suggest that the common ancestor was not the first cell lineage and that modern global phylogeny is the crown of a "recently" re-rooted tree. We suggest that a bottlenecked survivor of an environmental collapse, which preceded the flourishing of the modern crown, seeded the current phylogenetic tree. PMID- 23669450 TI - Bidirectional associations between pain and physical activity in adolescents. AB - OBJECTIVES: The objectives were to: (1) examine temporal relationships between pain and activity in youth, specifically, whether physical activity affects pain intensity and whether intensity of pain affects subsequent physical activity levels on a daily basis, and (2) examine clinical predictors of this relationship. METHODS: Participants were 119 adolescents (59 with chronic pain and 60 healthy) aged 12 to 18 years, 71% female. Adolescents completed 10 days of actigraphic monitoring of physical activity and daily electronic diary recordings of pain intensity, medication use, sleep quality, and mood. Linear mixed models assessed daily associations among physical activity and pain. Daily mean (average count/min) and peak (highest daily level) activity were used for analyses. Medication use, sleep quality, and mood ratings were included as covariates, and age, sex, and body mass index percentile were adjusted for. RESULTS: Higher pain intensity was associated with lower peak physical activity levels on the next day (t641=-2.25, P=0.03) and greater medication use predicted lower mean physical activity levels the same day (t641=-2.10, P=0.04). Higher mean physical activity levels predicted lower pain intensity ratings at the end of the day (t705=-2.92, P=0.004), but only in adolescents with chronic pain. DISCUSSION: Youth experiencing high pain intensity limit their physical activity level on a day-to day basis. Activity was related to subsequent pain intensity, and may represent an important focus in chronic pain treatment. Further study of the effect of medications on subsequent activity is needed. PMID- 23669451 TI - Differences in pain management between hematologists and hospitalists caring for patients with sickle cell disease hospitalized for vasoocclusive crisis. AB - OBJECTIVES: Sickle cell disease (SCD) is a chronic disease characterized by multiple vaso-occlusive complications and is increasingly cared for by hospitalists. The purpose of this study is to examine differences in pain management between hematologists and hospitalists. METHODS: We performed a single institution, retrospective review of pain management patterns and outcomes in adult SCD patients hospitalized for vaso-occlusive crisis. RESULTS: Over 26 months, we found a total of 298 patients (120 cared for by the hematologists and 178 by hospitalists), with a mean age of 32 (range 19-58). Patients cared for by hospitalists had a lower total number of hours on a patient controlled analgesia (PCA) device (171 vs. 212 hours, P=0.11). Hospitalists also were significantly more likely to utilize demand only PCA (42% vs. 23%, P=0.002) and had a significantly lower rate of using both continuous and demand PCA (54% vs. 67%, P=0.04). In addition, patients cared for by hospitalists had a significantly shorter hospitalization (8.4 days) compared to hematologists (10 days, P=0.04) with a non-significant difference in 7 and 30 day readmission rates (7.2% vs. 6.7% and 40% vs. 35% respectively). CONCLUSION: We found patients cared for by hospitalists more frequently utilized home oral pain medication during admission, had shorter lengths of hospitalization, and did not have a significant increase in readmission rates. PMID- 23669452 TI - A randomized-controlled trial of parent-led tactile stimulation to reduce pain during infant immunization injections. AB - OBJECTIVE: To determine the effectiveness of parent-led tactile stimulation for pain reduction when added to a combination of evidence-based pain-reducing interventions in infants undergoing immunization injections. METHODS: Healthy infants aged 4 to 6 months undergoing routine immunization at a primary care practice were eligible. Infants were randomized to tactile stimulation by a parent or usual care. Parents in the tactile stimulation group rubbed the ipsilateral thigh distal to the site for 15 seconds before, during, and after injections. In addition, all infants received evidence-based pain-relieving interventions including: sucrose solution, holding by a parent, and intramuscular injection without aspiration. The primary outcome was pain, measured by a validated tool, the Modified Behavioral Pain Scale (MBPS), by an observer unaware of treatment allocation using videotapes of the procedure. MBPS scores could range from 0 (no pain) to 10 (maximum pain). Parents, unaware of the study hypothesis, also rated infant pain in real time using a 100 mm visual analogue scale. RESULTS: One hundred twenty infants participated. Infant characteristics did not differ (P>0.05) between the tactile stimulation and control groups. Mean MBPS scores and parent visual analogue scale scores did not differ between groups (8.2 [1.1] vs. 8.0 [1.3]; P=0.57) and (60 [20] vs. 53 [22] mm; P=0.10), respectively. DISCUSSION: Parent-led tactile stimulation did not reduce pain in infants undergoing immunization injections when combined with other pain relieving interventions. Potential reasons for the lack of effectiveness are discussed. Investigation of the effectiveness of clinician-led tactile stimulation in this population is recommended. PMID- 23669453 TI - Continuous lesser palatine nerve block for postoperative analgesia after uvulopalatopharyngoplasty. AB - OBJECTIVES: Uvulopalatopharyngoplasty (UPPP) is a commonly performed surgical intervention used to treat obstructive sleep apnea (OSA) syndrome. Continuous peripheral nerve blocks have been shown to reduce postoperative pain and opioid requirements for other surgical procedures but have not been described previously for palate surgery. We present the use of a continuous lesser palatine nerve block catheter as a part of the multimodal postoperative pain management for UPPP. CASE REPORT: Three patients were scheduled to undergo elective UPPP and tonsillectomy for OSA with scheduled postoperative hospital admission. Each patient gave written consent to share the details of his or her case. Upon completion of the surgical procedure, but before emergence from general anesthesia, a 20-G multiorifice epidural catheter was inserted into the left nasal passage, passed into the oropharynx, and either tunneled posteriorly within the anterior portion of the soft palate with the aid of a 16-G angiocatheter or placed submucosally within the soft palate by the surgeon. Each catheter was secured using clear adhesive dressings along the cheek and anchored to the ipsilateral shoulder. A continuous infusion of ropivacaine 0.2% at 2 mL/h was delivered using a disposable infusion device postoperatively, in addition to the prescribed oral and intravenous opioids. No immediate or long-term complications due to catheter placement were identified during the patient follow-up. DISCUSSION: Continuous lesser palatine nerve block may be a useful regional anesthetic technique in the multimodal postoperative pain management of opioid sensitive OSA patients undergoing UPPP and deserves further study. PMID- 23669454 TI - Feasibility study of volumetric modulated arc therapy with constant dose rate for endometrial cancer. AB - To investigate the feasibility, efficiency, and delivery accuracy of volumetric modulated arc therapy with constant dose rate (VMAT-CDR) for whole-pelvic radiotherapy (WPRT) of endometrial cancer. The nine-field intensity-modulated radiotherapy (IMRT), VMAT with variable dose-rate (VMAT-VDR), and VMAT-CDR plans were created for 9 patients with endometrial cancer undergoing WPRT. The dose distribution of planning target volume (PTV), organs at risk (OARs), and normal tissue (NT) were compared. The monitor units (MUs) and treatment delivery time were also evaluated. For each VMAT-CDR plan, a dry run was performed to assess the dosimetric accuracy with MatriXX from IBA. Compared with IMRT, the VMAT-CDR plans delivered a slightly greater V20 of the bowel, bladder, pelvis bone, and NT, but significantly decreased the dose to the high-dose region of the rectum and pelvis bone. The MUs decreased from 1105 with IMRT to 628 with VMAT-CDR. The delivery time also decreased from 9.5 to 3.2 minutes. The average gamma pass rate was 95.6% at the 3%/3mm criteria with MatriXX pretreatment verification for 9 patients. VMAT-CDR can achieve comparable plan quality with significant shorter delivery time and smaller number of MUs compared with IMRT for patients with endometrial cancer undergoing WPRT. It can be accurately delivered and be an alternative to IMRT on the linear accelerator without VDR capability. PMID- 23669455 TI - Increased proportion of perforin-expressing CD8+T-cells indicates control of herpesvirus reactivation in children after stem cell transplantation. AB - Hematopoietic stem cell transplantation (HSCT) is frequently complicated by viral reactivations. Early diagnosis of viral reactivations and preemptive therapy relies on frequent viralload monitoring. An easy marker of effective cytotoxicity in lymphopenia is lacking and therefore we studied perforin-expression in CD8+T cells in children following HSCT. Prospectively, we weekly monitored viral loads and perforin-expression of CD8+T-cells in whole blood by FACS, until 4months after HSCT in children. 27 patients were included (median age 4,3, range 0.3 20,1years) of whom 19 developed viral reactivations. These patients showed higher percentages of perforin-expressing CD8+T-cells (17,2%, range 0-63%) than those without (6,8%; range 0-16%) (p=0.001). The increased percentage of perforin expressing CD8+T-cells coincided with a decrease in viral load with a median interval between maximum viral load and maximum level of perforin-expression of 0,4weeks (range 0.1-7.1). We conclude that perforin-expression in CD8+T-cells may be a marker for effective antiviral T-cell reconstitution early after HSCT in children. PMID- 23669456 TI - Neuroactive steroids in pregnancy: key regulatory and protective roles in the foetal brain. AB - Neuroactive steroid concentrations are remarkably high in the foetal brain during late gestation. These concentrations are maintained by placental progesterone synthesis and the interaction of enzymes in the placenta and foetal brain. 5alpha Pregnane-3alpha-ol-20-one (allopregnanolone) is a key neuroactive steroid during foetal life, although other 3alpha-hydroxy-pregnanes may make an additional contribution to neuroactive steroid action. Allopregnanolone modulates GABAergic inhibition to maintain a suppressive action on the foetal brain during late gestation. This action suppresses foetal behaviour and maintains the appropriate balance of foetal sleep-like behaviours, which in turn are important to normal neurodevelopment. Neuroactive steroid-induced suppression of excitability has a key role in protecting the foetal brain from acute hypoxia/ischaemia insults. Hypoxia-induced brain injury is markedly increased if neuroactive steroid levels are suppressed and there is increased seizure activity. There is also a rapid increase in allopregnanolone synthesis and hence levels in response to acute stress that acts as an endogenous protective mechanism. Allopregnanolone has a trophic role in regulating development, maintaining normal levels of apoptosis and increasing myelination during late gestation in the brain. In contrast, chronic foetal stressors, including intrauterine growth restriction, do not increase neuroactive steroid levels in the brain and exposure to repeated synthetic corticosteroids reduce neuroactive steroid levels. The reduced availability of neuroactive steroids may contribute to the adverse effects of chronic stressors on the foetal and newborn brain. Preterm birth also deprives the foetus of neuroactive steroid mediated protection and may increase vulnerability to brain injury and suboptimal development. These finding suggest replacement therapies should be explored. This article is part of a Special Issue entitled 'Pregnancy and steroids'. PMID- 23669457 TI - Progesterone receptor targeting with radiolabelled steroids: an approach in predicting breast cancer response to therapy. AB - Steroid receptors have demonstrated to be potentially useful biological targets for the diagnosis and therapy follow-up of hormonally responsive cancers. The over-expression of these proteins in human cancer cells as well as their binding characteristics provides a favourable mechanism for the localization of malignant tumours. The need for newer and more selective probes to non-invasively assess steroid receptor expression in hormone-responsive tumours has encouraged the synthesis and the biological evaluation of several steroidal derivatives labelled with positron and gamma emitters. The physiological effects of the steroid hormone progesterone are mediated by the progesterone receptor (PR). Since PR expression is stimulated by the oestrogen receptor (ER), PR status has been considered as a biomarker of ER activity and its value for predicting and monitoring therapeutic efficacy of hormonal therapy has been studied. Imaging of PR-expressing breast cancer patients under hormonal therapy may be advantageous, since the response to therapy can be more accurately predicted after quantification of both ER and PR status. Thus, ligands for PR targeting, although much less explored than ER ligands, have gained some importance lately as potential PET and SPECT tumour imaging agents. In this review, we present a brief survey of explored approaches for progesterone targeting using radiolabelled progestins as potential clinical probes to predict responsiveness to breast cancer therapy. This article is part of a Special Issue entitled "Synthesis and biological testing of steroid derivatives as inhibitors". PMID- 23669459 TI - Induction of seroconversion and persistence of Salmonella Typhimurium in pigs are strain dependent. AB - Foodborne salmonellosis is one of the most important bacterial zoonotic diseases worldwide. Salmonella Typhimurium is the serovar most frequently isolated from persistently infected slaughter pigs in Europe. Salmonella Typhimurium pathogenesis is host species specific. In addition, differences in in vitro behaviour of Salmonella Typhimurium strains have also been described, which may be reflected by a different course of infection within a host species. We compared the course of a Salmonella Typhimurium infection in pigs, using two Salmonella Typhimurium strains that were able to interfere with MHC II expression on porcine macrophages to a different extent in vitro. After experimental inoculation, blood and faecal samples from all pigs were collected at regular time points. At 40 days post inoculation (pi), animals were euthanized and tissue samples were bacteriologically analysed. The proportion of serologically positive piglets at 33 days pi was significantly higher in pigs that were inoculated with the strain that did not downregulate MHC II expression in vitro. Furthermore, this strain was less frequently shed and isolated in lower numbers from tonsils and ileocaecal lymph nodes than the strain that was able to markedly downregulate MHC II expression in vitro. We thus found that the delayed onset of seroconversion after oral inoculation of piglets with a particular Salmonella Typhimurium strain coincided with higher faecal shedding and increased persistence. Strain specific differences in Salmonella pathogenesis might thus have repercussions on the serological detection of Salmonella Typhimurium infections in pigs. PMID- 23669458 TI - Enhancing access and retention in substance abuse treatment: the role of Medicaid payment acceptance and cultural competence. AB - BACKGROUND: Health insurance coverage and quality of care are common factors believed to improve access for and retention of racial and ethnic minority groups in health care. However, there is little evidence that acceptance of public insurance and provision of culturally responsive care decrease wait time and retention of minority populations in community-based substance abuse treatment. METHODS: We analyzed client and program data collected in 2010-2011 from publicly funded treatment programs in Los Angeles County, CA. An analytical sample of 13,328 primarily African American and Latino clients nested within 104 treatment programs located in minority communities was analyzed using multilevel negative binomial regressions on count measures of days to initiate and days spent in treatment. RESULTS: Programs that accepted public insurance (p<.001) and in which staff reported personal involvement (p<.01) and linkages and resources with minority communities (p<.001) were negatively associated with client wait time. Similarly, programs with culturally responsive policies and assessment and treatment practices (p<.05) were positively associated with retention in treatment, after controlling for individual and program characteristics. CONCLUSIONS: These preliminary findings provide an evidentiary base for the role of community-based financial and cultural practices in improving accessibility and treatment adherence in a population at high risk of treatment dropout. Implications related to health care reform legislation, which seeks to expand public insurance and enhance culturally competent care, are discussed. PMID- 23669460 TI - Pre-exposure to nitric oxide modulates the effect of ozone on oxidative defenses and volatile emissions in lima bean. AB - The roles that ozone and nitric oxide (NO), the chief O3 precursor, play in the antioxidative balance and inducible volatile emissions of lima bean were assessed. Exposure to O3 inhibited APX, CAT, and GR, decreased GSH content and induced emissions of (E)-beta-ocimene, limonene, 1,8-cineole, linalool, (E)-4,8 dimethyl-1,3,7-nonatriene (E)-DMNT, 2-butanone and nonanal. O3 did not induce emissions of (E)-beta-caryophyllene and appeared to reduce the antioxidative capacity of plants to a greater extent than NO and NO followed by O3 (NO/O3) treatments. There were significant differences in emissions of (E)-beta-ocimene and linalool between NO/O3 treated plants and controls, but no differences in antioxidant concentrations. A model to explain the relationships between the ascorbate-glutathione cycle and O3 and NO inducible volatiles was proposed. Our findings suggest that prior exposure to NO modulates the oxidative effect of ozone by the process of cross-tolerance, which might regulate the antioxidative system and induction of volatile organic compounds. PMID- 23669461 TI - Heterogeneity of atmospheric ammonia at the landscape scale and consequences for environmental impact assessment. AB - We examined the consequences of the spatial heterogeneity of atmospheric ammonia (NH3) by measuring and modelling NH3 concentrations and deposition at 25 m grid resolution for a rural landscape containing intensive poultry farming, agricultural grassland, woodland and moorland. The emission pattern gave rise to a high spatial variability of modelled mean annual NH3 concentrations and dry deposition. Largest impacts were predicted for woodland patches located within the agricultural area, while larger moorland areas were at low risk, due to atmospheric dispersion, prevailing wind direction and low NH3 background. These high resolution spatial details are lost in national scale estimates at 1 km resolution due to less detailed emission input maps. The results demonstrate how the spatial arrangement of sources and sinks is critical to defining the NH3 risk to semi-natural ecosystems. These spatial relationships provide the foundation for local spatial planning approaches to reduce environmental impacts of atmospheric NH3. PMID- 23669462 TI - Analysis of mercury in rock varnish samples in areas impacted by coal-fired power plants. AB - Rock varnish is a manganese-iron rich coating that forms on rocks, most often in arid climates. To assess its utility as an environmental monitor of mercury contamination, cold vapor atomic absorption spectrometry (CVAAS) was used for analysis. Samples were collected in the fallout patterns of two coal-fired power plants in southern Nevada: the defunct Mohave Power Plant (MPP) and the operating Reid Gardner Power Plant (RGPP). The resultant Hg concentrations in rock varnishes were plotted as a function of the distance from each power plant. The highest concentrations of Hg occurred at locations that suggest the power plants are the main source of pollutants. In addition, past tracer plume studies carried out at MPP show that the highest tracer concentrations coincide with the highest rock varnish Hg concentrations. However, additional samples are required to further demonstrate that power plants are indeed the sources of mercury in varnishes. PMID- 23669463 TI - Height in mid childhood and psychosocial competencies in late childhood: evidence from four developing countries. AB - We use longitudinal data from children growing up in four developing countries (Peru, India, Vietnam, Ethiopia) to study the relationship between height at the age of 7-8 and a set of psychosocial competencies measured at the age of 11-12 that are known to be correlated with earnings during adulthood: self-efficacy, self-esteem and aspirations. Results show that a one standard deviation increase in height-for-age tends to increase self-efficacy, self-esteem and aspirations by 10.4%, 6.4% and 5.1%, respectively. We argue that these findings are likely to be informing of an underlying relationship between undernutrition and the formation of non-cognitive skills. PMID- 23669464 TI - Characterization of olfactory sensilla of the olive fly: behavioral and electrophysiological responses to volatile organic compounds from the host plant and bacterial filtrate. AB - The responses of olive fly (Bactrocera oleae) antennal and palpal olfactory receptors to odors emitted by Pseudomonas putida bacterial filtrate and to volatiles from a host plant were evaluated using electrophysiological and behavioral bioassays. Morphological identification of olfactory receptors was also performed. The third antennal segment (flagellum) bears four types of multiporous sensilla: trichoid, short basiconica, clavate and grooved. Maxillary palps have mechanosensory bristles and multiporous basiconica sensilla. In wind tunnel bioassays, olive fly responses to volatiles emitted by bacterial filtrate were higher than those to culture medium. Bacterial filtrate was more attractive than ammonium carbonate or a mixture of ethyl acetate and acetic acid in ethanol. GC-MS of bacterial filtrate identified some of the chemicals produced by bacterial activity, including methyl thiolacetate, ammonia, 2-pentanone, 2 heptanone, ethyl tiglate and methyl thiocyanate. Electrophysiological investigations proved that antennal sensilla are responsive to bacterial filtrate odor, methyl thiolacetate, olive leaves and olives, as well as to alpha-pinene, while acetic acid elicited an inhibitory response. Electropalpgrams recorded a specific response to bacterial filtrate by mated males and females, as well as a dose-dependent response relationship to methyl thiolacetate by mated females. The identification of new active volatile compounds in the semiochemical system of the olive fly is promising for the development of innovative control strategies in area-wide management. PMID- 23669465 TI - Complexity, adaptive complexity and the Creative View of natural selection. AB - In this paper, I respond to arguments proposed by Brunnander in this journal issue concerning my position regarding the Creative View of natural selection (Razeto-Barry & Frick, 2011). Brunnander argues that (i) the Creative View we defend does not serve to answer William Paley's question because (ii) Paley's question is "why there are complex things rather than simple ones" and (iii) natural selection cannot answer this question. Brunnander's arguments for (iii) defend a Non-creative View of natural selection (sensu Razeto-Barry & Frick, 2011). Here I claim that Brunnander's arguments for (iii) are mistaken and I also argue that even accepting (iii) we do not have to accept (i), given that statement (ii) is historically and conceptually flawed. Thus here I analyze Paley's question from a historical point of view and from a contemporary perspective in a quest for the potential conceptual relevance of Paley's question today. In this vein I argue that from a contemporary point of view statement (iii) may be correct but for different reasons than those adduced by Brunnander. PMID- 23669466 TI - Hair cuts cause cancer. PMID- 23669467 TI - Targeted investment improves access to hospice and palliative care. AB - CONTEXT: Availability of hospice and palliative care is increasing, despite lack of a clear national strategy for developing and evaluating their penetration into and impact on the target population. OBJECTIVES: To determine whether targeted investment (i.e., strategic grants made by one charitable foundation) in hospice and palliative care in one U.S. state (North Carolina [NC]) led to improved access to end-of-life care services as indicated by hospice utilization. METHODS: Access was measured by the death service ratio (DSR), defined as the proportion of people who died and were served by hospice for at least one day before death. Calculation of the DSR is based on counts of patients accessing hospice by county in a given year (numerator) and U.S. Census projected population data for that county (denominator). Multilevel modeling was the primary analytic strategy used to generate two models: 1) comparison of the DSR in counties with vs. without philanthropic funding and 2) relationship between years since receipt of a philanthropic grant and DSR. RESULTS: In NC, the average DSR increased from 20.7% in 2003 to 35.8% in 2009 (55% increase). In 2009, 82 of 100 NC counties had a DSR below the U.S. average (41.6%). In Model 1, significant associations were found between county population and DSR (P=0.03) and between receipt of philanthropic funding and DSR (P=0.01); on average, funded counties had a DSR that was 2.63 percentage points higher than unfunded counties. CONCLUSION: Receipt of philanthropic funding appeared to be associated with improved access to palliative care and hospice services in NC. PMID- 23669468 TI - Functional analysis of the RNAi response in ovary-derived silkmoth Bm5 cells. AB - Experiments of dsRNA-mediated gene silencing in lepidopteran insects in vivo are characterized by high variability although lepidopteran cell cultures have shown an efficient response to RNAi in transfection experiments. In order to identify the core RNAi factors that regulate the RNAi response of Lepidoptera, we employed the silkmoth ovary-derived Bm5 cells as a test system since this cell line is known to respond potently in silencing after dsRNA transfection. Two parallel approaches were used; involving knock-down of the core RNAi genes or over expression of the main siRNA pathway factors, in order to study possible inhibition or stimulation of the RNAi silencing response, respectively. Components from all three main small RNA pathways (BmAgo-1 for miRNA, BmAgo 2/BmDcr-2 for siRNA, and BmAgo-3 for piRNA) were found to be involved in the RNAi response that is triggered by dsRNA. Since BmAgo-3, a factor in the piRNA pathway that functions independent of Dicer in Drosophila, was identified as a limiting factor in the RNAi response, sense and antisense ssRNA was also tested to induce gene silencing but proved to be ineffective, suggesting a dsRNA-dependent role for BmAgo-3 in Bombyx mori. After efficient over-expression of the main siRNA factors, immunofluorescence staining revealed a predominant cytoplasmic localization in Bm5 cells. This is the first study in Lepidoptera to provide evidence for possible overlapping of all three known small RNA pathways in the regulation of the dsRNA-mediated silencing response using transfected B. mori derived Bm5 cells as experimental system. PMID- 23669469 TI - Poor compliance with ACG guidelines for nutrition and antibiotics in the management of acute pancreatitis: a North American survey of gastrointestinal specialists and primary care physicians. AB - CONTEXT: Despite recent updates in the treatment of acute pancreatitis emphasizing enteral nutrition over parenteral nutrition as well as minimizing antibiotic usage, mortality rates from acute pancreatitis have not improved. Data has been limited regarding physician compliance to these guidelines in the United States. METHODS: A 20 question survey regarding practice patterns in the management of acute pancreatitis was distributed to physicians at multiple internal medicine and gastroenterology conferences in North America between 2009 and 2010. Responses were analyzed using the chi-square test and multivariate logistic regression. RESULTS: Out of 406 available respondents, 43.3% of physicians utilize total parenteral nutrition/peripheral parenteral nutrition (TPN/PPN) and 36.5% utilize nasojejunal (NJ) feedings. The preferred route of nutrition was significantly related to practice type (P<0.001): academic physicians were more likely to use NJ tube feeding than private practice physicians (52.1% vs. 19.9%) while private practitioners were more likely to utilize TPN/PPN than academic physicians (70.2% vs. 20.5%). Gastroenterologists and primary care physicians were equally non-compliant as both groups favored parenteral nutrition. Multivariate logistic regression demonstrated that practice type (P<0.001) was the only independent predictor of route of nutrition. Most survey respondents appropriately do not routinely utilize antibiotics for acute pancreatitis, but when antibiotics are initiated, they are for inappropriate indications such as fever and infection prophylaxis. CONCLUSIONS: Many North American physicians are noncompliant with current ACG practice guidelines for the use of artificial nutrition in the management of acute pancreatitis, with overuse of TPN/PPN and underutilization of jejunal feedings. Antibiotics are initiated in acute pancreatitis for inappropriate indications, although there are conflicting recommendations for antibiotics in severe acute pancreatitis. Improved compliance with guidelines is needed to improve patient outcomes. PMID- 23669470 TI - Effects of fungal pancreatic enzymes on the function of islet cells in Syrian golden hamsters. AB - CONTEXT: Our previous studies showed that porcine pancreatic enzymes in Syrian golden hamsters with peripheral insulin resistance normalizes the plasma insulin level, reduces the size of enlarged islets and inhibits the increased DNA synthesis in the beta-cell of islets. OBJECTIVE: In order to exclude the possibility that these effects was attributed to some contaminants of this crude material, we tested the effect of purified fungal pancreatic enzyme (FPE) that contains primarily amylase and lipase without (FPE) and with addition of chymotrypsin (FPE+chy). MATERIAL AND METHODS: In a pilot study we tested the effect of different doses of FPE given in drinking water on insulin level, islet size and DNA synthesis of islet cells in hamsters with induced peripheral insulin resistance by a high fat diet. The most effective dose of FPE on these parameters was used in a long-term experiment with FPE and FPE+chy in hamsters fed a high fat diet for 36 or 40 weeks. RESULTS: In the pilot study a dose of 2 g/kg body weight was found to be optimal for controlling the body weight, normalizing plasma insulin level, the size of islets, the DNA synthesis and the number of insulin cells in the islets. These data were produced in the long-term study, where steatorrhea was also inhibited. Addition of chymotrypsin had no effects on these parameters. CONCLUSION: Pancreatic lipase and amylase appear to be responsible for the observed effects and offer a safe and effective natural product for the treatment of pancreatic diseases, including acute pancreatitis, chronic pancreatic, cystic fibrosis and any conditions associated with peripheral insulin resistance, including obesity and type 2 diabetes. The possible mechanism of the action is discussed. PMID- 23669471 TI - A pilot retrospective study of the relationship between estrogen use and pancreatitis/pancreatic function in women with chronic abdominal pain. AB - CONTEXT: Estrogens are thought to cause pancreatitis by raising triglyceride levels but whether there are other effects on the pancreas is debatable. OBJECTIVE: To better elucidate the relationship between estrogens and pancreatitis and pancreatic function in a pilot study. DESIGN/SETTING/PATIENTS: Our retrospectively collected database of 224 patients who had undergone secretin stimulation testing was queried for females with available medication histories, who were then divided into two groups: those taking estrogens (E) and those not on estrogens (N). Mann Whitney U and Fisher's exact tests were used. RESULTS: Seventy of the patients in the database were females with available medication histories. Thirty-five (50.0%) were taking estrogens. Twenty-nine (82.9%) of the E patients experienced any type of pancreatitis (i.e., acute pancreatitis, acute relapsing pancreatitis, chronic pancreatitis) while only 19 (54.3%) of the N patients did (P=0.019). During secretin stimulation testing, the peak bicarbonate levels for E and N patients were 80+/-18 and 90+/-23 mEq/L, respectively (P=0.058). When patients with any type of pancreatitis were excluded, E patients still displayed decreased peak bicarbonate levels in response to secretin (90+/ 18 vs. 104+/-19 mEq/L; P=0.021). Weight, age, triglyceride levels, frequency of patients with cholecystectomy and biliary stones did not significantly differ between the two groups (E and N respectively). CONCLUSIONS: These pilot data suggest exogenous estrogens may be related to the development of acute pancreatitis and acute relapsing pancreatitis, and probably to a lesser degree chronic pancreatitis, perhaps through a triglyceride independent mechanism. During secretin stimulation testing, peak bicarbonate production may be diminished in women on estrogens (even in those who have never had pancreatitis). Further study is necessary to better define the relationship between estrogen use, pancreatitis, and pancreatic function. PMID- 23669472 TI - Duration of diabetes and pancreatic cancer in a case-control study in the Midwest and the Iowa Women's Health Study (IWHS) cohort. AB - CONTEXT: Studies have shown a relationship between history of diabetes and the risk of pancreatic cancer; however, the temporal relation between diabetes and pancreatic cancer is not clearly established. OBJECTIVES: Diabetes and diabetes duration were examined in relation to pancreatic cancer in a population-based case-control study and prospective cohort. METHODS: Case-control study: pancreatic cancer cases (n=200) from the Midwest were frequency matched by age and sex to population controls (n=673). Logistic regression yielded odds ratios (ORs) and 95% confidence intervals (95% CI). Iowa Women's Health Study (IWHS) cohort: 292 incident pancreatic cancer cases occurred between 1986-2008 among 36,084 post-menopausal, initially cancer-free women. Diabetes status and diagnosis age were ascertained at baseline and follow-ups. Proportional hazards regression yielded hazard ratios (HR, 95% CI) for pancreatic cancer in relation to baseline diabetes. Time-dependent analyses accounted for diabetes diagnosed after baseline. A nested-case control analysis assessed diabetes duration as a risk factor. RESULTS: In the case-control study, compared to participants without diabetes, the multivariate ORs (95% CI) for pancreatic cancer were 2.35 (1.24 4.47) for those with diabetes and 4.00 (0.94-16.9), 2.79 (0.97-8.04), and 2.40 (0.97-5.98) for diabetes durations of 2-5 years, 5.1-10 years, and more than 10 years, respectively. In IWHS, compared to no diabetes, multivariate-adjusted HRs for pancreatic cancer were 1.86 (1.23-2.83) for baseline diabetes and 1.94 (1.40 2.69) adding diabetes during follow-up. In an IWHS nested case-control analysis, ORs were 1.70 (0.78-3.67), 2.62 (1.48-4.65), and 2.10 (1.36-3.24) for diabetes durations of 2-5 years, 5.1-10 years and more than 10 years, respectively, versus no diabetes. CONCLUSIONS: Diabetes is associated with pancreatic cancer risk and this is similar across different duration categories. PMID- 23669473 TI - Lymphoepithelial cysts of the pancreas. Can preoperative imaging distinguish this benign lesion from malignant or pre-malignant cystic pancreatic lesions? AB - CONTEXT: Lymphoepithelial cysts of the pancreas are rare true benign cystic tumors of the pancreas of uncertain etiology. Cystic neoplasms of the pancreas present a significant diagnostic dilemma in differentiating benign from premalignant or malignant variants. Since the first description of lymphoepithelial cysts in 1985, 109 cases have been reported in the literature. We describe 6 cases of this rare tumor, the preoperative imaging results, and a review the literature. PATIENTS: Five males and one female ranging in age from 47 to 76 years underwent resection for lymphoepithelial cysts. Five patients presented with abdominal pain related to the lesion and in one patient the lesion was discovered incidentally. Four patients had elevated serum CA 19-9 levels. Pre operative imaging with a CT scan and MRI of the abdomen typically revealed a well defined hypodense mass with Hounsfield units (HU) in the range of 15 to 20. One patient had papillary projections into the lesion. The mean size was 3.3 cm (ranging from 1.8 cm to 4 cm). All lesions were exophytic off the pancreatic parenchyma (1 cyst was located in the head of the pancreas, 2 were in the body, and 3 were in the tail region). Pre-operative EUS-guided/CT-guided needle aspiration, when performed, was not diagnostic. All patients underwent resection (one pancreaticoduodenectomy, five left pancreatectomies) to remove these cystic neoplasms. Pathology revealed a cyst lined by non-dysplastic squamous cells surrounded by sheets of benign lymphocytes. No evidence of malignancy was found. CONCLUSION: Lymphoepithelial cysts of the pancreas are rare and are characteristically seen in men. While a hypodense mass (less than 20 HU) with papillary projections should be considered suspicious for lymphoepithelial cyst, a definitive diagnosis cannot be made solely based on preoperative imaging. EUS guided biopsy coupled with biochemical/tumor marker studies are increasingly being used as a diagnostic tool to help differentiate between the various types of cystic pancreatic neoplasms. Imaging findings of lymphoepithelial cysts are non-specific and hence surgical resection is often required to rule out the presence of a malignant or pre-malignant cystic pancreatic lesion. In true lymphoepithelial cysts, malignant transformation is not seen and patients who have these cysts are not at increased risk of developing a pancreatic malignancy. PMID- 23669474 TI - Pancreatic tuberculosis diagnosed by EUS: one disease, many faces. AB - CONTEXT: Pancreatic/para-pancreatic tuberculosis is an extremely rare clinical entity even in endemic regions. It can present as a cystic or solid pancreatic mass mimicking pancreatic malignancy. There are no specific imaging criteria and the clinical symptoms remain vague. Therefore, most cases are diagnosed after surgical exploration for presumed pancreatic neoplasia. CASE REPORT: We report five cases of pancreatic tuberculosis each time with a different clinical presentation, in an occidental country setting where the diagnosis was done by EUS guided FNA (EUS-FNA). CONCLUSION: EUS-FNA is a safe and promising technique for the diagnosis of pancreatic/para-pancreatic tuberculosis, avoiding unnecessary surgery. PMID- 23669475 TI - Intrapancreatic accessory spleen. A case report and review of literature. AB - CONTEXT: Accessory spleen is a congenital focus of healthy splenic tissue that is separated from the main body of spleen. Although an accessory spleen usually appears as an isolated asymptomatic abnormality, it may have clinical significance in some situations. CASE REPORT: We report the case of 53-year-old woman with a 2-year history of upper abdominal discomfort after meals and weight loss. The pathologic lesion was diagnosed by the abdominal sonography and the magnetic resonance tomography in the pancreatic tail. The patient was operated with suspicion of a solid pseudopapillary neoplasm or a nonfunctioning islet cell tumor. Histopathological examination found an intrapancreatic accessory spleen, which is a congenital abnormality consisting of normal splenic tissue in ectopic sites. CONCLUSION: We present possibilities of differential diagnosis of this entity. PMID- 23669476 TI - Refractory idiopathic non-insulinoma pancreatogenous hypoglycemia in an adult: case report and review of the literature. AB - CONTEXT: Non-insulinoma pancreatogenous hypoglycemia is a rare cause of spontaneous hypoglycemia in adults. The ideal diagnostic and therapeutic approach is still controversial, not least because most reported cases lack long-term follow-up. CASE REPORT: We describe the case of a 58-year-old woman, who was diagnosed with idiopathic non-insulinoma pancreatogenous hypoglycemia in 2001. After resection of 75% of the distal pancreas, she initially experienced no additional hypoglycemic episodes and did not suffer from diabetes mellitus. However, after one month, recurrent hypoglycemia occurred. After resection of the larger part of the remaining pancreatic tissue, the patient suffered from hypoglycemic as well as hyperglycemic episodes. Octreotide and diazoxide were not successful in preventing the hypoglycemic attacks, whereas continuous insulin therapy with an insulin pump helped to stabilize the blood glucose level temporarily. Finally, all remaining pancreatic tissue had to be removed. CONCLUSION: This long-term follow-up of non-insulinoma pancreatogenous hypoglycemia treatment in an adult patient indicates that lateral pancreatectomy may not be sufficient for permanent blood glucose control and emphasizes the need of follow-up data after subtotal pancreatectomy. PMID- 23669477 TI - Massive lower gastrointestinal bleeding from Meckel's diverticulum with heterotopic pancreas: case report and a brief review of the literature. AB - CONTEXT: Heterotopic pancreas is defined as pancreatic tissue found out of the pancreas proper with no vascular or anatomical connection. It is a rare clinical entity and can be found at any portion of the alimentary system. CASE REPORT: We describe a case of Meckel's diverticulum with heterotopic pancreas who presented massive lower gastrointestinal bleeding. CONCLUSION: Lower gastrointestinal bleeding due to Meckel's diverticulum with heterotopic pancreas is extremely difficult to make a definitive diagnosis preoperatively especially when it onsets rapidly. PMID- 23669478 TI - Laparoscopic central pancreatectomy and pancreaticogastrostomy for the management of a proximally migrated pancreatic stent. AB - CONTEXT: Pancreatic stents are used for both benign and malignant pancreatic disease but can be associated with complications such as proximal migration. CASE REPORT: A 43-year-old female with benign biliary disease underwent prophylactic pancreatic stent placement after endoscopic retrograde cholangiopancreatography. This stent migrated proximally into the pancreatic duct and could not be retrieved by endoscopic measures. Therefore, she underwent surgical retrieval via a laparoscopic central pancreatectomy with pancreaticogastrostomy reconstruction. The procedure took 250 minutes with minimal blood loss. The postoperative course was uneventful and the patient was discharged on the sixth postoperative day without any evidence of pancreatic fistula. CONCLUSION: Laparoscopic central pancreatectomy is a feasible option for the unusual indication of a retained proximally migrated pancreatic duct stent. PMID- 23669479 TI - Annular pancreas in adults: a report of two cases and review of literature. AB - CONTEXT: Annular pancreas is one of the rare congenital anomalies that can manifest itself in adulthood also. No specific guidelines and protocols exist about management of such cases. We hereby discuss our experience with two such cases along with a brief review of literature about the subject. CASE REPORTS: The first patient was a male aged 27 years and presented with features of duodenal obstruction. He underwent duodenoduodenostomy . The second patient, a male aged 32 years, also presented with features of gastric outlet obstruction. He underwent Billroth type 2 reconstruction. Both patients had an uneventful recovery. CONCLUSION: Annular pancreas in adults is a rare clinical scenario. Advancements in imaging modalities have brought to forefront an even larger number of such cases. In adults it is diagnosed mainly because of the complications that arise thereof. Gastroduodenal tuberculosis can be an important differential diagnosis in endemic areas. Treatment and operative protocols have to be individualized. PMID- 23669480 TI - Recurrence of a pancreatic cystic lymphangioma after diagnosis and complete drainage by endoscopic ultrasound with fine-needle aspiration. AB - CONTEXT: Lymphangiomas are uncommon benign neoplasms that result from a blockage of the lymphatic system. Pancreatic cystic lymphangiomas are extremely rare. Pancreatic cystic lymphangiomas have been classically diagnosed on histopathologic examination following surgical excision, but recent reports have demonstrated successful diagnosis using endoscopic ultrasound with fine-needle aspiration (EUS-FNA). Data on the natural history of these lesions following drainage via EUS-FNA are lacking. We present a case of successful initial diagnosis and drainage of a pancreatic cystic lymphangioma using EUS-FNA, with unfortunate recurrence of the lesion four months later. CASE REPORT: A 50-year old female was evaluated for epigastric abdominal pain and nausea. CT scan revealed a 4 cm retroperitoneal cystic lesion. EUS-FNA was performed with complete drainage of the lesion using a 22-gauge needle. Twenty-five mL of chylous white fluid was obtained with laboratory analysis consistent with a pancreatic cystic lymphangioma. The patient was symptom-free for 4 months following drainage, but eventually had symptoms again with a CT scan confirming recurrence. CONCLUSIONS: While EUS-FNA is effective for the diagnosis of pancreatic cystic lymphangiomas, its role in the management of these lesions is questionable. Temporary relief of symptoms can be achieved after EUS-guided drainage, but recurrence is a concern. Definitive cure likely requires complete surgical excision. PMID- 23669481 TI - A first report of endoscopic ultrasound for the diagnosis of pancreatic amyloid deposition in immunoglobulin light chain (AL) amyloidosis (primary amyloidosis). AB - CONTEXT: Pancreatic involvement in systemic light chain (AL)-amyloidosis is exceedingly rare. Prior reports of endoscopic ultrasound (EUS) for the diagnosis of amyloidosis are also limited. CASE REPORT: We report the first description of EUS-guided fine needle aspiration (FNA) for the diagnosis of primary AL amyloidosis involving the pancreas. CONCLUSION: EUS-FNA can be effectively utilized for the characterization and cytologic diagnosis of pancreatic amyloidosis and potentially other accessible extraluminal amyloid deposits. PMID- 23669482 TI - Adult onset nesidioblastosis treated by subtotal pancreatectomy. AB - CONTEXT: Nesidioblastosis is a rare cause of non insulinoma pancreatogenous hypoglycemic syndrome seen in adults. It is characterized by postprandial hypoglycemia with high insulin and C-peptide levels without any detectable pancreatic lesion. The definitive diagnosis can be made only on histopathological examination of the resected specimen. CASE REPORT: We report a case of a 50-year old lady presenting with hypoglycemic attacks being misdiagnosed preoperatively as insulinoma and treated with enucleation leading to recurrence of symptoms after 6 months. Later medical therapy was tried which failed and patient needed subtotal pancreatectomy for resolution of symptoms. CONCLUSION: Nesidioblastosis should be suspected in patients with endogenous hyperinsulinemic hypoglycemia without any detectable pancreatic tumor on preoperative imaging. PMID- 23669483 TI - Multifocal anaplastic pancreatic carcinoma requiring neoadjuvant chemotherapy and total pancreatectomy: report of a case. AB - CONTEXT: Anaplastic pancreatic carcinoma is a rare tumor with poor survival. Data on surgical and medical therapies are currently limited to case reports and case series with small numbers. CASE REPORT: We describe a case of multifocal anaplastic pancreatic carcinoma treated with neoadjuvant FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil and leucovorin) and total pancreatectomy with subsequent patient disease-free survival currently at 12 months. DISCUSSION: The goal for anaplastic pancreatic carcinoma treatment should continue to be complete surgical resection. Optimum chemotherapeutic options continue to be investigated. PMID- 23669484 TI - Unusual cause of massive upper gastrointestinal bleeding: a pancreatic arteriovenous malformation. AB - CONTEXT: Upper gastrointestinal bleeding is one of the most common emergencies in gastroenterology. The common causes of the upper gastrointestinal bleeding include peptic ulcer disease, gastric erosive mucosal disease and portal hypertension. Gastrointestinal arteriovenous malformation is a less common cause of gastrointestinal bleeding and these arteriovenous malformation are most commonly located in the large and small intestine. Pancreatic arteriovenous malformation is a rare condition in which there is tumor-like formation or vascular anomaly built up via an aberrant bypass anastomosis of the arterial and venous systems in the pancreas. Splenic artery is most commonly involved (42%), followed by gastroduodenal artery (22%) and small pancreatic arteries (25%). Clinically it may present as gastrointestinal hemorrhage which is occasionally fatal. Other presentations are abdominal pain, pancreatitis, duodenal ulcer, jaundice, and portal hypertension. CASE REPORT: We present a rare case of pancreatic arteriovenous malformation presenting as massive upper gastrointestinal bleeding. CONCLUSION: Since early surgery is a life saving treatment for such cases, hence, a high index of suspicion should be maintained especially when massive bleeding is detected from the medial wall of second part of duodenum. PMID- 23669485 TI - Isolated desmoid tumor of pancreatic tail with cyst formation diagnosed by beta catenin immunostaining: a rare case report with review of literature. AB - CONTEXT: Isolated pancreatic desmoid tumors with cyst formation are uncommon benign mesenchymal soft tissue tumors, characterized by the dense fibroblastic proliferations with abundant extra-cellular collagen matrix. Intra-abdominal desmoid tumor usually involve the mesentery and retroperitoneum and mostly occur in association of familial adenomatous polyposis or Gardner's syndrome. While desmoid tumors do not metastasize, their advancement can be life threatening due to aggressive local invasion, such as mesentery involvement. Isolated, sporadic pancreatic desmoid tumors have been considered anecdotal, with only 10 cases (cystic area in three cases) described in the literature. To our best of knowledge, this patient is fourth case report displaying cyst formation in desmoid tumor of pancreatic tail. CASE REPORT: We herein report a very unusual location of sporadic desmoid tumor involving the pancreatic tail with cystic area diagnosed by beta-catenin immunostaining. A 11-year-old male presented with painless lump in left hypochondrium of abdomen. The diagnosis of pancreatic adenocarcinoma was suspected preoperatively and the patient underwent a splenopancreatectomy. Histopathological examination revealed dense fibroblastic proliferation with occasional mitosis suggestive of mesenchymal tumor. The diagnosis of desmoid tumor was confirmed by positivity of beta-catenin immunohistochemical analysis. Conservative treatment was given postoperatively. No recurrence was observed after ten months of follow-up. CONCLUSION: Desmoid tumors are very rare in the tail of pancreas with cystic area and their diagnosis can be difficult, such as in our case where it presented as a solid-cystic lesion. PMID- 23669486 TI - Papilla with separate bile and pancreatic duct orifices. PMID- 23669487 TI - A novel airway checklist for obstetric general anaesthesia. PMID- 23669488 TI - Unexpected tracheal tube blockage from a semi-dissolved misoprostol tablet. PMID- 23669489 TI - Treatment of non-traumatic out-of-hospital cardiac arrest with active compression decompression cardiopulmonary resuscitation plus an impedance threshold device. AB - BACKGROUND: A recent out-of-hospital cardiac arrest (OHCA) clinical trial showed improved survival to hospital discharge (HD) with favorable neurologic function for patients with cardiac arrest of cardiac origin treated with active compression decompression cardiopulmonary resuscitation (CPR) plus an impedance threshold device (ACD+ICD) versus standard (S) CPR. The current analysis examined whether treatment with ACD+ITD is more effective than standard (S-CPR) for all cardiac arrests of non-traumatic origin, regardless of the etiology. METHODS: This is a secondary analysis of data from a randomized, prospective, multicenter, intention-to-treat, OHCA clinical trial. Adults with presumed non-traumatic cardiac arrest were enrolled and followed for one year post arrest. The primary endpoint was survival to hospital discharge (HD) with favorable neurologic function (Modified Rankin Scale score <= 3). RESULTS: Between October 2005 and July 2009, 2738 patients were enrolled (S-CPR=1335; ACD+ITD=1403). Survival to HD with favorable neurologic function was greater with ACD+ITD compared with S-CPR: 7.9% versus 5.7%, (OR 1.42, 95% CI 1.04, 1.95, p=0.027). One-year survival was also greater: 7.9% versus 5.7%, (OR 1.43, 95% CI 1.04, 1.96, p=0.026). Nearly all survivors in both groups had returned to their baseline neurological function by one year. Major adverse event rates were similar between groups. CONCLUSIONS: Treatment of out-of-hospital non-traumatic cardiac arrest patients with ACD+ITD resulted in a significant increase in survival to hospital discharge with favorable neurological function when compared with S-CPR. A significant increase survival rates was observed up to one year after arrest in subjects treated with ACD+ITD, regardless of the etiology of the cardiac arrest. PMID- 23669490 TI - Real-time feedback during basic life support training: does it prevent skill decay? PMID- 23669491 TI - Early epinephrine in out-of-hospital cardiac arrest: is sooner better than none at all? PMID- 23669492 TI - Reply to Letter: 'Contamination of ambulance staff using the laryngeal mask airway supreme (LMAS) during cardiac arrest'. PMID- 23669493 TI - Longitudinal assessment of skill development in children with first febrile seizure. AB - To determine whether first febrile seizure (FS) has detrimental effects on development, 159 children (aged 6 months to 5 years) with FS were compared to 142 controls on measures of cognition, motor ability, and adaptive behavior. Participants were identified through the emergency department in an urban, low income community. Children were evaluated within one month of the ED visit and one year later, and difference in performance over one year was examined. Performance did not differ between cases and controls on measures of cognition (baseline: p=0.5, one year: p=0.2, change over time: p=0.1) or motor skills (baseline: p=0.9, one year: p=0.7, change over time, p=0.6). The adaptive behavior composite score did not differ by FS case status at baseline (p=0.2) or one year later (p=0.6); however, between-group differences over time approached significance (p=0.05). Findings support the idea that first FS does not pose developmental or behavioral consequences in a low socioeconomic environment. PMID- 23669494 TI - Perinatal hyperoxia exposure impairs hypoxia-induced depolarization in rat carotid body glomus cells. AB - Chronic post-natal hyperoxia reduces the hypoxic ventilatory response by reducing the carotid body sensitivity to acute hypoxia as demonstrated by a reduced afferent nerve response, reduced calcium response of carotid body glomus cells and reduced catecholamine secretion in response to acute hypoxia. The present study examined whether hyperoxia alters the electrophysiological characteristics of glomus cells. Rats were treated with hyperoxia for 1 week starting at P1 or P7 and for 2 weeks starting at P1 followed by harvesting and dissociation of their carotid bodies for whole cell, perforated-patch recording. As compared to glomus cells from normoxia animals, hyperoxia treated cells showed a significant reduction in the magnitude of depolarization in response to hypoxia and anoxia, despite little change in the depolarizing response to 20 mM K(+). Resting cell membrane potential in glomus cells from rats exposed to hyperoxia from P1 to P15 and studied at P15 was slightly depolarized compared to other treatment groups and normoxia-treated cells, but conductance normalized to cell size was not different among groups. We conclude that postnatal hyperoxia impairs carotid chemoreceptor hypoxia transduction at a step between hypoxia sensing and membrane depolarization. This occurs without a major change in baseline electrophysiological characteristics, suggesting altered signaling or alterations in the relative abundance of different leak channel isoforms. PMID- 23669495 TI - Pleural mesothelium lubrication after hyaluronidase, neuraminidase or pronase treatment. AB - Coefficient of kinetic friction (MU) of pleural mesothelium has been found to increase markedly after mesothelial blotting and rewetting. This increase disappeared after addition of a solution with hyaluronan or sialomucin, though previous morphological studies showed that only sialomucin occurs in mesothelial glycocalyx. In this research we investigated whether MU of rabbit pleural mesothelium increased after hyaluronidase, neuraminidase or pronase treatment. Hyaluronidase and neuraminidase did not increase MU, though neuraminidase cleaved sialic acid from mesothelial glycocalyx of diaphragm specimens, and removed hystochemical stain of sialic acid from glycocalyx. Sialomucin treated with neuraminidase lowered MU of blotted mesothelium, though less than untreated sialomucin; this feature plus lubrication provided by other molecules could explain why MU did not increase after neuraminidase. Short pronase treatment (in order to affect only glycocalyx proteins) increased MU; this increase was removed by hyaluronan or sialomucin. After pronase treatment MU decreased with increase in sliding velocity, indicating a regime of mixed lubrication, as in blotted mesothelium. PMID- 23669497 TI - Metaphyseal bone formation induced by a new injectable beta-TCP-based bone substitute: a controlled study in rabbits. AB - PURPOSE: Adequate filling of bone defects still poses a challenge in every day clinical work. As many bone defects are irregularly shaped the need for appropriate scaffolds reaching the complete defect surface are great. The purpose of this pre-clinical pilot study was to investigate the handling, biocompatibility, biodegradation and osteoconductivity of a new pasty bone substitute (pure phase beta-TCP, hyaluronic acid, methylcellulose) in bone tissue. METHODS: In an unilateral tibial defect model the peri-implant and bone tissue response to the new pasty bone substitute was tested in New Zealand white rabbits for up to 24 weeks compared to empty controls. Analysis included HR-pQCT scans, histomorphometric evaluation and quantification of vascularization of un decalcified histological slices. RESULTS: After 1 week the experimental group presented significantly higher new bone volume fraction (p = 0.021) primarily consisting of immature bone matrix and higher vessel density compared to controls (p = 0.013). After 4 weeks bone formation was not significantly different to controls but was distributed more evenly throughout the defect. Bone matrix was now mineralized and trabeculae were thicker than in controls (p = 0.002) indicating faster intramedullary bone maturation. Controls presented extensive periosteal bone formation, major fibrous tissue influx and high vascularization. After 12 and 24 weeks there was no new bone detectable. There were no severe signs of inflammation at all time points. CONCLUSION: The substitute showed an early induction of bone formation. It promoted accelerated intramedullary bone repair and maturation and prevented periosteal bone formation indicating its potential use for reconstructive surgery of bone defects. PMID- 23669496 TI - Chronotropic incompetence predicts mortality in severe obstructive pulmonary disease. AB - We evaluated the prevalence of chronotropic incompetence (CI), a marker of autonomic dysfunction, and its prognostic value in patients with chronic obstructive pulmonary disease (COPD). We performed a retrospective analysis of 449 patients with severe COPD who underwent a cardiopulmonary exercise test, after excluding patients with lung volume reduction surgery, left ventricular dysfunction and those not in sinus rhythm. CI was defined as percent predicted heart rate reserve (%HRR). Events were defined as death or lung transplant during a median follow-up of 68 months. Median age was 61 years; median percent predicted forced expiratory volume in one second (%FEV1) of 25% and median %HRR of 33%. The hazard ratio for an event in the lowest quartile of %HRR, taking the highest quartile as reference, was of 3.2 (95% confidence interval: 2.1-4.8; p<0.001). In a multivariate regression model, %HRR was an independent predictor of events. In conclusion, CI was an independent and powerful outcome predictor in patients with severe COPD. PMID- 23669498 TI - Persistence of both cords nine months post double cord blood transplantation for juvenile myelomonocytic leukaemia. PMID- 23669499 TI - A quantitative study of magnetic susceptibility-weighted imaging of deep cerebral veins. AB - OBJECTIVE: To evaluate the value of magnetic susceptibility-weighted imaging (SWI) for measuring deep cerebral venous diameter. METHODS: The diameters of 150 deep cerebral veins were measured by SWI and digital subtraction angiography (DSA) in 50 patients. RESULTS: SWI showed whole cerebral veins as clear soft vessels, but with a crooked hypointense linear structure along the sulcus. Venous vessel diameter as measured by SWI was greater than that by DSA, but values from the two different techniques showed significant linear correlation (r=0.905). CONCLUSION: SWI is reliable and suitable for quantitative measurements of deep cerebral veins, and more sensitive for measuring smaller vessels deep within the brain. PMID- 23669500 TI - [A new Gaceta Sanitaria guideline: basic recommendations for the publication of qualitative studies]. PMID- 23669501 TI - [Local public health networks. Apropos of an experience]. AB - Public health action on a territory is complex and requires the involvement of multiple actors, who do not always act coordinately. Networks of organizations structures including the whole of the local actors facilitate the generation of synergies and enable greater effectiveness and efficiency of the joint action from the different actors on a same landscape. We present 3 years experience of four Public Health Committees in a region of Catalonia (Spain), composed by the main actors in public health planning. Each of the committees is organized on a plenary and working groups on issues arising from the regional health diagnosis, and coincident with the Health Plan of the Region. Coordination in no case implies the loss or dilution of the firm of the actor generator of intervention initiative in public health, but their empowerment and collaboration by the other actors. In conclusion welcomes the creation of a culture of collaboration and synergies between the different organizations concerned. Lack of specificity is observed in establishing operational objectives, and the need for greater coordination and involvement of the components of the various working groups. PMID- 23669502 TI - [Prevalence of antibodies to hepatitis A virus in healthcare workers and associated variables]. AB - OBJECTIVE: Vaccination against hepatitis A is recommended in risk groups, including healthcare workers. The objective of this study was to determine the prevalence of antibodies to HAV (IgG) among workers in the healthcare setting in order to establish criteria for vaccination. METHODS: A cross-sectional, analytic, observational study of 4,864 employees was undertaken in four healthcare companies in Catalonia (Spain). The variables gathered included personal data, professional category, location of employment, and serology. RESULTS: The overall prevalence of antibodies to HAV was 52.7%. The prevalence significantly increased with greater age. The mean age of seropositive workers was 41.5 years compared with 34.3 in workers with negative serology. The highest prevalence of antibodies was found in cleaning employees (74.2%) and catering staff (75.3%). DISCUSSION: Given the high prevalence of seronegative adults susceptible to infection and the characteristics of their professional activities, vaccination of all staff working in health institutions should be considered. PMID- 23669503 TI - [Screening: a proposal for rationalization]. PMID- 23669504 TI - [Supporting the investment in screening]. PMID- 23669505 TI - Modeling and analysis of the transmission of Echinococcosis with application to Xinjiang Uygur Autonomous Region of China. AB - Echinococcosis, which is one of the zoonotic diseases, can threaten human health and hinder the development of animal husbandry seriously. Especially in Xinjiang Uygur Autonomous Region of China, Echinococcosis is regarded as one of the most serious endemic diseases.The number of human Echinococcosis has increased dramatically in the last 10 years, partially due to poor understanding of the transmission dynamics of Echinococcosis and lack of effective control measures of the disease. In this paper, in order to explore effective control and prevention measures we propose a deterministic model to study the transmission dynamics of Echinococcosis in Xinjiang. The results show that the dynamics of the model is completely determined by the basic reproductive number R0. If R0<1, the disease free equilibrium is globally asymptotically stable. When R0>1, the disease-free equilibrium is unstable, and the endemic equilibrium is globally asymptotically stable. Based on the data reported by Xinjiang Center for Disease Control and Prevention (Xinjiang CDC), the numerical simulation result matches Echinococcosis data well. The model provides an approximate estimate of the basic reproduction number R0=1.67. This indicates that Echinococcosis is endemic in Xinjiang with the current control measures. Finally, we perform some sensitivity analysis of several model parameters and give some useful comments on controlling the transmission of Echinococcosis. PMID- 23669506 TI - Critical phase shifts slow down circadian clock recovery: implications for jet lag. AB - Advancing or delaying the light-dark (LD) cycle perturbs the circadian clock, which eventually recovers its original phase with respect to the new LD cycle. Readjustment of the clock occurs by shifting its phase in the same (orthodromic re-entrainment) or opposite direction (antidromic re-entrainment) as the shift in the LD cycle. To investigate circadian clock recovery after phase shifts of the LD cycle we use a detailed computational model previously proposed for the cellular regulatory network underlying the mammalian circadian clock. The model predicts the existence of a sharp threshold separating orthodromic from antidromic re-entrainment. In the vicinity of this threshold, resynchronization of the clock after a phase shift markedly slows down. The type of re-entrainment, the position of the threshold and the time required for resynchronization depend on multiple factors such as the autonomous period of the clock, the direction and magnitude of the phase shift, the clock biochemical kinetic parameters, and light intensity. Partitioning the phase shift into a series of smaller phases shifts decreases the impact on the recovery of the circadian clock. We use the phase response curve to predict the location of the threshold separating orthodromic and antidromic re-entrainment after advanced or delayed phase shifts of the LD cycle. The marked increase in recovery times predicted near the threshold could be responsible for the most severe disturbances of the human circadian clock associated with jet lag. PMID- 23669507 TI - One- and two-photon absorption of fluorescein dianion in water: a study using S QM/MM methodology and ZINDO method. AB - One- and two-photon absorption (1PA and 2PA) of fluorescein dianion (FSD) in water were studied using a combined and sequential Quantum Mechanics/Molecular Dynamics methodology. Different sets of 250 statistically relevant (uncorrelated) configurations composed by the solute and several solvent molecules were sampled from the classical simulation. On these configurations, the electronic properties were calculated a posteriori using the Zerner's intermediate neglect of differential overlap (ZINDO) method. The linear and nonlinear absorption of FSD in water were calculated using discrete and explicit solvent models. In the largest case, the relevant configurations are composed by FSD and 47 explicit water molecules embedded in the electrostatic field of all remaining water molecules. Both INDO/CIS and INDO/CISD calculations were performed to study the absorption processes of FSD and the Sum-Over-States (SOS) model was used to describe the 2PA process. A semi-classical method for spectrum simulations was employed to simulate the 1PA and 2PA cross-section spectra of FSD in water. For comparison purposes, in the case of the 2PA process two approaches, the "full expression" and "resonant expression" methods, were employed to simulate the nonlinear spectrum. The last method assumes resonant conditions and on the computation point of view it represents an interesting option to study the 2PA process. The INDO/CI calculations give a satisfactory description of the 1PA spectrum of FSD and properly describe the unusual blue-shift of its first pi >pi(*) transition in water. In the case of 2PA, the introduction of doubly excited configuration interactions (INDO/CISD) has proven to be essential for an appropriate description of the process at the higher energy spectral region. It was observed that the solvent effects do not drastically change the cross sections of both processes. The simulated 2PA cross-section spectrum provided by the "full expression" method presents a better definition of the bands which appear along the experimental spectrum than the one provided by the "resonant expression" method. However, both approaches provide similar description for the effect of the solvent environment on the 2PA process of FSD in water. PMID- 23669508 TI - WITHDRAWN: Brain structural, neurochemical and neuroinflammatory markers of psychosis onset and relapse: Is there evidence for a psychosis relapse signature? AB - Ahead of Print article withdrawn by publisher. PMID- 23669510 TI - [Thyrotropin reference values in the first trimester of pregnancy]. PMID- 23669511 TI - Texting while driving and other risky motor vehicle behaviors among US high school students. AB - OBJECTIVE: To assess the prevalence of texting/e-mailing while driving (TWD) and association of TWD with other risky motor vehicle (MV) behaviors among US high school students. METHODS: Data were used from the Centers for Disease Control and Prevention's 2011 national Youth Risk Behavior Survey, which assessed TWD during the 30 days before the survey among 8505 students aged >=16 years from a nationally representative sample of US high school students. TWD frequency was coded into dichotomous and polychotomous variables. Logistic regression assessed the relationship between TWD and other risky driving behaviors, controlling for age, race/ethnicity, and sex. RESULTS: The prevalence of TWD on >=1 days during the 30 days before the survey was 44.5% (95% confidence interval: 40.8%-48.2%). Students who engaged in TWD were more likely than their non-TWD counterparts to not always wear their seatbelt (prevalence ratio; 95% confidence interval: 1.16; 1.07-1.26), ride with a driver who had been drinking alcohol (1.74; 1.57-1.93), and drink alcohol and drive (5.33; 4.32-6.59). These other risky MV behaviors were most likely to occur among students who frequently engaged in TWD. CONCLUSIONS: Nearly half of US high school students aged >=16 years report TWD during the past 30 days; these students are more likely to engage in additional risky MV behaviors. This suggests there is a subgroup of students who may place themselves, their passengers, and others on the road at elevated risk for a crash related injury or fatality by engaging in multiple risky MV behaviors. PMID- 23669512 TI - Early limited formula is not ready for prime time. PMID- 23669513 TI - Effect of early limited formula on duration and exclusivity of breastfeeding in at-risk infants: an RCT. AB - BACKGROUND AND OBJECTIVES: Recent public health efforts focus on reducing formula use for breastfed infants during the birth hospitalization. No previous randomized trials report the effects of brief early formula use. The objective of the study was to determine if small formula volumes before the onset of mature milk production might reduce formula use at 1 week and improve breastfeeding at 3 months for newborns at risk for breastfeeding problems. METHODS: We randomly assigned 40 exclusively breastfeeding term infants, 24 to 48 hours old, who had lost >=5% birth weight to early limited formula (ELF) intervention (10 mL formula by syringe after each breastfeeding and discontinued when mature milk production began) or control (continued exclusive breastfeeding). Our outcomes were breastfeeding and formula use at 1 week and 1, 2, and 3 months. RESULTS: Among infants randomly assigned to ELF during the birth hospitalization, 2 (10%) of 20 used formula at 1 week of age, compared with 9 (47%) of 19 control infants assigned during the birth hospitalization to continue exclusive breastfeeding (P = .01). At 3 months, 15 (79%) of 19 infants assigned to ELF during the birth hospitalization were breastfeeding exclusively, compared with 8 (42%) of 19 controls (P = .02). CONCLUSIONS: Early limited formula may reduce longer-term formula use at 1 week and increase breastfeeding at 3 months for some infants. ELF may be a successful temporary coping strategy for mothers to support breastfeeding newborns with early weight loss. ELF has the potential for increasing rates of longer-term breastfeeding without supplementation based on findings from this RCT. PMID- 23669514 TI - Elevated blood lead levels and reading readiness at the start of kindergarten. AB - OBJECTIVE: To evaluate the relationship between blood lead levels (BLLs) and reading readiness at kindergarten entry, an early marker of school performance, in a diverse urban school population. METHODS: Kindergarten reading readiness test scores for children attending public kindergarten in Providence, Rhode Island, were linked to state health department records of blood lead testing by using individual identifiers. The study population (N = 3406) was 59% Hispanic. For each child, the geometric mean BLL was estimated by using all previously reported BLLs. Analyses were adjusted for gender, age, year enrolled, race, child language, and free/reduced lunch status as a measure of socioeconomic status. RESULTS: The median geometric mean BLL was 4.2 ug/dL; 20% of children had at least 1 venous BLL >=10 ug/dL. Compared with children with BLLs <5 ug/dL, the adjusted prevalence ratios (95% confidence interval [CI]) for failing to achieve the national benchmark for reading readiness were 1.21 (1.19 to 1.23) and 1.56 (1.51 to 1.60) for children with BLLs of 5 to 9 and >=10 ug/dL, respectively. On average, reading readiness scores decreased by 4.5 (95% CI: -2.9 to -6.2) and 10.0 (95% CI: -7.0 to -13.3) points for children with BLLs of 5 to 9 and >=10 ug/dL, respectively, compared with BLLs <5 ug/dL. CONCLUSIONS: BLLs well below 10 ug/dL were associated with lower reading readiness at kindergarten entry. The high prevalence of elevated BLLs warrants additional investigation in other high risk US populations. Results suggest benefits from additional collaboration between public health, public education, and community data providers. PMID- 23669515 TI - Internet-based therapy for adolescents with chronic fatigue syndrome: long-term follow-up. AB - OBJECTIVE: Cognitive behavioral therapy (CBT) is known to be an effective treatment of adolescents with chronic fatigue syndrome (CFS), but its availability is limited. Fatigue in Teenagers on the Internet (FITNET), an Internet-based CBT program for adolescents with CFS, has been developed as an alternative to face-to-face CBT. Recently, its short-term effectiveness has been proven in a randomized clinical trial. Here we aimed to assess the long-term outcome of CFS in adolescents after FITNET treatment and after usual care. In addition, factors related to recovery at long-term follow-up (LTFU) for adolescents treated with the FITNET program were investigated. METHODS: The study was an LTFU of participants of the FITNET trial. Data were completed for 112 (88.2%) of 127 approached FITNET study participants. Primary outcomes were fatigue severity (Checklist Individual Strength-20), physical functioning (87 item Child Health Questionnaire), and school/work attendance. RESULTS: After a mean follow-up of 2.7 years, 66 (58.9%) adolescents had recovered from CFS. Most adolescents who recovered directly after treatment with FITNET were still recovered at LTFU. At LTFU there was no difference between the recovery rates for the different treatment strategies (original randomization: FITNET [64%] versus any form of usual care [52.8%]). Per additional month of "pretreatment disease duration," the odds for recovery were 4% lower (odds ratio: 0.96; 95% confidence interval: 0.93-0.99; P = .016), and per added point on "focus on bodily symptoms" (Body Consciousness Scale) of the mother (0-20 points) the odds for recovery were 11% lower (odds ratio: 0.89; 95% confidence interval: 0.80-0.99; P = .029). CONCLUSIONS: The short-term effectiveness of Internet-based CBT on adolescent CFS is maintained at LTFU. At LTFU, usual care led to similar recovery rates, although these rates were achieved at a slower pace. PMID- 23669516 TI - Dr Watson and the case of observation-level care. PMID- 23669517 TI - Prevalence of use of human milk in US advanced care neonatal units. AB - BACKGROUND AND OBJECTIVE: The American Academy of Pediatrics recommends all preterm infants receive human milk. The objective of this study was to describe the use of human milk in advanced care neonatal units of US maternity hospitals. METHODS: We used Centers for Disease Control and Prevention's national Maternity Practices in Infant Nutrition and Care survey from 2007, 2009, and 2011 to analyze 2 questions to describe the prevalence of US advanced care (special/level 2 or intensive/level 3) neonatal units routinely providing human milk to infants, and the use of any donor milk in these units. RESULTS: In 2011, 30.8% of maternity hospitals reported that most infants (>=90%) were routinely provided human milk in advanced care units, compared with 26.7% in 2009 and 21.2% in 2007 (trend P < .001). States in the Northwest and Northeast had a higher prevalence of hospitals routinely providing human milk to >=90% of infants in advanced care units. In 2011, 22.0% of maternity hospitals providing advanced care used banked donor milk, compared with 14.4% in 2009 and 11.5% in 2007 (trend P < .001). Most of this increase occurred in intensive care units (25.1% 2007 vs 45.2% 2011; trend P < .001). There was substantial geographic variation in the prevalence of advanced care units using donor milk; generally the prevalence was higher in the West and in states with a milk bank in the state or a neighboring state. CONCLUSIONS: The use of human milk in US advanced care neonatal units is increasing; however, only one-third of these units are routinely providing human milk to most infants. PMID- 23669518 TI - Current status of transition preparation among youth with special needs in the United States. AB - OBJECTIVE: To examine current US performance on transition from pediatric to adult health care and discuss strategies for improvement. METHODS: The 2009-2010 National Survey of Children with Special Health Care Needs is a nationally representative sample with 17 114 parent respondents who have youth with special health care needs (YSHCN) ages 12 and 18. They are asked about transition to an adult provider, changing health care needs, increasing responsibility for health care needs, and maintaining insurance coverage. We analyzed the association of selected characteristics with successful transition preparation. RESULTS: Overall, 40% of YSHCN meet the national transition core outcome. Several factors are associated with transition preparation, including female gender; younger age; white race; non-Hispanic ethnicity; income >=400% of poverty; little or no impact of condition on activities; having a condition other than an emotional, behavioral, or developmental condition; having a medical home; and being privately insured. CONCLUSIONS: Most YSHCN are not receiving needed transition preparation. Although most providers are encouraging YSHCN to assume responsibility for their own health, far fewer are discussing transfer to an adult provider and insurance continuity. Although changes in sample design limit trend analysis, there have been no discernible improvements since this transition outcome was measured in the 2005-2006 National Survey of Children with Special Health Care Needs. The 2011 release of the American Academy of Pediatrics/American Academy of Family Physicians/American College of Physicians clinical recommendations on transition, new transition tools, and the spread of medical home should stimulate future improvements in transition performance. PMID- 23669519 TI - Neonatal end-of-life care: a single-center NICU experience in Israel over a decade. AB - OBJECTIVES: To follow changes in the causes of neonatal deaths in the NICU at Hadassah Medical Center, Jerusalem, Israel, over a decade; to examine trends regarding types of end-of-life-care provided (primary nonintervention, maximal intensive, and redirection of intensive care, including limitation of care and withdrawal of life-sustaining treatment); and to assess the parental role in the decision-making process given that the majority of the population is religious. METHODS: All neonates who died between 2000 and 2009 were identified. The causes and circumstances of death were abstracted from the medical records. Trends in end-of-life decisions were compared between 2 time periods: 2000-2004 versus 2005 2009. RESULTS: Overall, 239 neonates died. The leading cause of death in both study periods was prematurity and its complications (76%). Among term infants, the leading cause of death was congenital anomalies (48%). Fifty-six percent of the infants received maximal intensive care; 28% had redirection of intensive care, of whom 10% had withdrawal of life-sustaining treatment; and 16% had primary nonintervention care. Over the years, maximal intensive care decreased from 65% to 46% (P < .02), whereas redirection of care increased from 19.2% to 37.5% (P < .0005). An active parental role in the end-of-life decision process increased from 38% to 84%. CONCLUSIONS: Even among religious families of extremely sick neonates, redirection of care is a feasible treatment option, suggesting that apart from survival, quality-of-life considerations emerge as an important factor in the decision-making process for the infant, parents, and caregivers. PMID- 23669520 TI - Resource utilization for observation-status stays at children's hospitals. AB - BACKGROUND AND OBJECTIVE: Observation status, in contrast to inpatient status, is a billing designation for hospital payment. Observation-status stays are presumed to be shorter and less resource-intensive, but utilization for pediatric observation-status stays has not been studied. The goal of this study was to describe resource utilization characteristics for patients in observation and inpatient status in a national cohort of hospitalized children in the Pediatric Health Information System. METHODS: This study was a retrospective cohort from 2010 of observation- and inpatient-status stays of <=2 days; all children were admitted from the emergency department. Costs were analyzed and described. Comparison between costs adjusting for age, severity, and length of stay were conducted by using random-effect mixed models to account for clustering of patients within hospitals. RESULTS: Observation status was assigned to 67 230 (33.3%) discharges, but its use varied across hospitals (2%-45%). Observation status stays had total median costs of $2559, including room costs and $678 excluding room costs. Twenty-five diagnoses accounted for 74% of stays in observation status, 4 of which were used for detailed analyses: asthma (n = 6352), viral gastroenteritis (n = 4043), bronchiolitis (n = 3537), and seizure (n = 3289). On average, after risk adjustment, observation-status stays cost $260 less than inpatient-status stays for these select 4 diagnoses. Large overlaps in costs were demonstrated for both types of stay. CONCLUSIONS: Variability in use of observation status with large overlap in costs and potential lower reimbursement compared with inpatient status calls into question the utility of segmenting patients according to billing status and highlights a financial risk for institutions with a high volume of pediatric patients in observation status. PMID- 23669521 TI - Intussusception after rotavirus vaccines reported to US VAERS, 2006-2012. AB - BACKGROUND: In 2006 and 2008, 2 new rotavirus vaccines (RotaTeq [RV5] and Rotarix [RV1]) were introduced in the United States. METHODS: We assessed intussusception events reported to the Vaccine Adverse Event Reporting System from February 2006 through April 2012 for RV5 and from April 2008 through April 2012 for RV1. For RV5, we conducted a self-controlled risk interval analysis using Poisson regression to estimate the daily reporting ratio (DRR) of intussusception comparing average daily reports 3 to 6 versus 0 to 2 days after vaccination. We calculated reporting rate differences based on DRRs and background rates of intussusception. Sensitivity analyses were conducted to assess effects of differential reporting completeness and inaccuracy of baseline rates. Few reports were submitted after RV1, allowing only a descriptive analysis. RESULTS: The Vaccine Adverse Event Reporting System received 584 confirmed intussusception reports after RV5 and 52 after RV1, with clustering 3 to 6 days after both vaccines. The DRR comparing the 3- to 6-day and the 0- to 2-day periods after RV5 dose 1 was 3.75 (95% confidence interval = 1.90 to 7.39). There was no significant increase in reporting after dose 2 or dose 3. Over all 3 doses, the excess risk of intussusception was 0.79 events (95% confidence interval = -0.04 to 1.62) per 100 000 vaccinations. From the sensitivity analyses, we conclude that under a worst-case scenario, the DRR could be 5.00 and excess risk per 100 000 doses could be 1.36. CONCLUSIONS: We observed a persistent clustering of reported intussusception events 3 to 6 days after the first dose of RV5 vaccination. This clustering could translate to a small increased risk of intussusception, which is outweighed by the benefits of rotavirus vaccination. PMID- 23669522 TI - Lyme chondritis presenting as painless ear erythema. AB - Erythema of the ear lobe in the context of Lyme disease is caused by either borrelial lymphocytoma or localized erythema migrans. Here we present a case of chondritis limited to the ear cartilage caused by Lyme disease. The patient was treated with ceftriaxone with complete resolution of symptoms. PMID- 23669523 TI - Bacteremia risk and outpatient management of febrile patients with sickle cell disease. AB - BACKGROUND AND OBJECTIVES: Previous studies have indicated that febrile children with sickle cell disease (SCD) had a 3% to 5% risk of being bacteremic due to compromised immune function. The introduction of routine penicillin prophylaxis and conjugate vaccines may have lowered the risk of bacteremia. Our goals were to determine the rate of bacteremia among children with SCD per febrile episode and to estimate the safety of outpatient management among these febrile SCD patients. METHODS: This 18-year retrospective cohort study included febrile SCD patients who presented to Boston Children's Hospital between 1993 and 2010. RESULTS: A total of 1118 febrile episodes were evaluated. Nine blood specimens had growth of a pathogen in culture (0.8%; 95% confidence interval: 0.3%-1.3%). Of the 466 febrile patients initially managed as outpatients, 3 were bacteremic (0.6%). All 3 received intravenous ceftriaxone at the initial outpatient visit and returned when contacted after growth of bacteria was detected in the blood culture. Upon return to the hospital, none were "ill appearing," required supportive care, or were admitted to an ICU. CONCLUSIONS: Our rate of bacteremia among febrile children with SCD is much lower than previous estimates, and there was no associated morbidity or mortality among the patients managed as outpatients. A well-appearing febrile child with SCD may be managed as an outpatient after blood is obtained for bacterial culture and parenteral antibiotics are administered, provided there are no other reasons for admission and the patient is able to return promptly for worsening condition or for growth of a pathogen from their blood culture. PMID- 23669524 TI - International adoption, "early" puberty, and underrecorded age. PMID- 23669525 TI - Short-term gestation, long-term risk: prematurity and chronic kidney disease. AB - Thanks to remarkable advances in neonatal intensive care, infants who once had little chance for survival can now enter adulthood. Yet the consequences of premature birth or low birth weight (LBW) on nephrogenesis, final nephron number, and long-term kidney function are unclear. This review focuses on the theory, experimental evidence, and observational data that suggest an increased risk of chronic kidney disease (CKD) for infants born prematurely. Many premature and LBW infants begin life with an incomplete complement of immature nephrons. They are then exposed to a variety of external stressors that can hinder ongoing kidney development or cause additional nephron loss such as hemodynamic alterations, nephrotoxic medications, infections, and suboptimal nutrition. Acute kidney injury, in particular, may be a significant risk factor for the development of CKD. According to Brenner's hypothesis, patients with decreased nephron number develop hyperfiltration that results in sodium retention, hypertension, nephron loss, and CKD due to secondary focal segmental glomerulosclerosis. Because the risk of CKD in premature and LBW infants has not been accurately determined, there are no evidence-based recommendations for screening or management. Yet with the first generation of infants from the surfactant era only now reaching adulthood, it is possible that there is already an unrecognized epidemic of CKD. We suggest individualized, risk-based assessments of premature and LBW infants due to the increased risk of CKD and call for additional research into the long term risk for CKD these infants face. PMID- 23669526 TI - Family-centered, evidence-based phototherapy delivery. AB - Jaundice develops in most newborn infants and is one of the most common reasons infants are rehospitalized after birth. American Academy of Pediatrics clinical practice guidelines strongly support the recommendation that clinicians promote and support breastfeeding. Recognizing that the disruptions associated with phototherapy interfere with breastfeeding, the challenge often faced by clinicians is how to provide effective phototherapy while supporting evidence based practices, such as rooming-in, skin-to-skin contact, and breastfeeding. We report here on a case that reflects a common clinical scenario in newborn medicine in order to describe a technique for providing phototherapy while maintaining evidence-based practices. This approach will assist clinicians in providing best-practices and family-centered care. PMID- 23669527 TI - Processed B-type natriuretic peptide is a biomarker of postinterventional restenosis in ischemic heart disease. AB - BACKGROUND: Restenosis, a condition in which the lesion vessel renarrows after a coronary intervention procedure, remains a limitation in management. A surrogate biomarker for risk stratification of restenosis would be welcome. B-type natriuretic peptide (BNP) is secreted in response to pathologic stress from the heart. Its use as a biomarker of heart failure is well known; however, its diagnostic potential in ischemic heart disease is less explored. Recently, it has been reported that processed forms of BNP exist in the circulation. We hypothesized that circulating processed forms of BNP might be a biomarker of ischemic heart disease. METHODS: We characterized processed forms of BNP by a newly developed mass spectrometry-based detection method combined with immunocapture using commercial anti-BNP antibodies. RESULTS: Measurements of processed forms of BNP by this assay were found to be strongly associated with presence of restenosis. Reduced concentrations of the amino-terminal processed peptide BNP(5-32) relative to BNP(3-32) [as the index parameter BNP(5-32)/BNP(3 32) ratio] were seen in patients with restenosis [median (interquartile range) 1.19 (1.11-1.34), n = 22] vs without restenosis [1.43 (1.22-1.61), n = 83; P < 0.001] in a cross-sectional study of 105 patients undergoing follow-up coronary angiography. A sensitivity of 100% to rule out the presence of restenosis was attained at a ratio of 1.52. CONCLUSIONS: Processed forms of BNP may serve as viable potential biomarkers to rule out restenosis. PMID- 23669528 TI - Comparison of bleomycin-detectable iron and labile plasma iron assays. PMID- 23669529 TI - The Onecut transcription factor HNF-6 contributes to proper reorganization of Purkinje cells during postnatal cerebellum development. AB - The Onecut (OC) family of transcription factors comprises three members in mammals, namely HNF-6 (or OC-1), OC-2 and OC-3. During embryonic development, these transcriptional activators control cell differentiation in pancreas, in liver and in the nervous system. Adult Hnf6 mutant mice exhibit locomotion defects characterized by hindlimb muscle weakness, abnormal gait and defective balance and coordination. Indeed, HNF-6 is required in spinal motor neurons for proper formation of the hindlimb neuromuscular junctions, which likely explain muscle weakness observed in corresponding mutant animals. The goal of the present study was to determine the cause of the balance and coordination defects in Hnf6 mutant mice. Coordination and balance deficits were quantified by rotarod and runway tests. Hnf6 mutant animals showed an increase in the fall frequency from the beam and were unable to stay on the rotarod even at low speed, indicating a severe balance and coordination deficit. To identify the origin of this abnormality, we assessed whether the development of the main CNS structure involved in the control of balance and coordination, namely the cerebellum, was affected by the absence of HNF-6. Firstly, we observed that Hnf6 was expressed transiently during the first week after birth in the Purkinje cells of wild type newborn mice. Secondly, we showed that, in Hnf6-/- mice, the organization of Purkinje cells became abnormal during a second phase of their development. Indeed, Purkinje cells were produced normally but part of them failed to reorganize as a regular continuous monolayer at the interface between the molecular and the granular layer of the cerebellum. Thus, the Onecut factor HNF-6 contributes to the reorganization of Purkinje cells during a late phase of cerebellar development. PMID- 23669533 TI - The topographical N170: electrophysiological evidence of a neural mechanism for human spatial navigation. AB - We recently demonstrated that the latency of a component of the event-related brain potential, the topographical N170 (NT170), is sensitive to the spatial location of reward-related stimuli in a virtual maze environment, occurring earlier for rewards found following rightward turns compared to leftward turns. We suggested that this NT170 latency effect may result from phase reset of an ongoing theta rhythm by a parahippocampal system for spatial navigation. Here we tested several predictions that follow from this proposal, namely, that the effect is observed only when the rewards are presented in a spatial environment, that it is sensitive to individual differences in spatial ability, that it is localizable to the right parahippocampal region, and that it is consistent with partial phase resetting of an ongoing theta rhythm. These results hold promise for integrating ERP measures of spatial navigation with extensive animal, human, and computational literatures on parahippocampal function. PMID- 23669534 TI - Directed attention reduces processing of emotional distracters irrespective of valence and arousal level. AB - Emotional stimuli tend to capture attention, and this so-called motivated attention is commonly measured using the early posterior negativity (EPN) and the late positive potential (LPP). We hypothesized that voluntary, directed attention reduces motivated attention more strongly for highly than moderately arousing pleasant or unpleasant pictures. Participants were instructed to direct their attention to either a picture at fixation or the letters flanking the picture. Pictures varied substantially in arousal and valence. When the pictures were attended to, EPN and LPP increased linearly with arousal. When the letters were attended to, these linear effects decreased in the EPN for pleasant and unpleasant pictures and in the LPP for pleasant pictures. Thus, directed attention decreases processing of emotional distracters more strongly for highly than moderately arousing pleasant and unpleasant pictures. These results are consistent with the view that directed attention decreases emotion effects on sensory gain. PMID- 23669535 TI - Electrocutaneous pain thresholds are higher during systole than diastole. AB - Arterial baroreceptors may modulate pain. Evidence suggests the neurophysiological correlates of pain are dampened during systole, when baroreceptors are stimulated, compared to diastole, when stimulation is minimal. However, the influence of the cardiac cycle on perception of pain remains unclear. This study examined pain thresholds in 49 healthy adults at seven intervals after the R-wave of the electrocardiogram, using an interleaved up-down staircase procedure. Electrocutaneous stimuli were delivered to the hand and participants indicated the presence or absence of pain. Pain thresholds were higher mid-cycle, indicative of pain attenuation during systole compared to diastole. Moderation analyses revealed no relationship between the magnitude of cardiac cycle-related modulation and tonic blood pressure. These findings suggest fluctuations in arterial baroreceptor activity across the cardiac cycle may influence pain in normotensive individuals; however, tonic blood pressure may not affect the magnitude of this pain modulation. PMID- 23669536 TI - A quantitative genetic model of r- and K-selection in a fluctuating population. AB - We analyze a stochastic quantitative genetic model for the joint dynamics of population size N and evolution of a multidimensional mean phenotype (z) under density-dependent selection. This generalizes our previous theories of evolution in fluctuating environments to include density-dependent (but frequency independent) selection on quantitative characters. We assume that appropriate constraints or trade-offs between fitness components exist to prevent unlimited increase of fitness. We also assume weak selection such that the expected rate of return to equilibrium is much slower for (z) than N. The mean phenotype evolves to a stationary distribution around an equilibrium point z(opt) that maximizes a simple function determined by ecological parameters governing the dynamics of population size. For any (z), the expected direction of phenotypic evolution is determined by the additive genetic covariance matrix G and the gradient of this function with respect to the mean phenotype. For the theta-logistic model of density dependence, evolution tends to maximize the expected value of N(theta). PMID- 23669537 TI - Consequences of pathogen spillover for cheatgrass-invaded grasslands: coexistence, competitive exclusion, or priority effects. AB - With the rise in species invasions and emerging infectious diseases, pathogen spillover from abundant reservoir hosts to their competitors is increasingly common. Although the potential for pathogen spillover is widespread, its consequences for host community composition remain poorly understood. To address this gap, I examine the consequences of fungal seed pathogen spillover from an exotic annual grass (cheatgrass) to a native perennial bunchgrass in the Intermountain West, United States, using a model. Integrating generalist pathogens with broader coexistence theory, the model measures the pathogen's effect on host niche differences and fitness differences, which determine the outcome of competition. The model demonstrates that the consequences of pathogen spillover depend on host differences in species-specific transmission and disease tolerance. Counterintuitively, spillover can lead to coexistence, native grass exclusion, or priority effects, in which either species can exclude the other when initially more dominant. Cheatgrass has higher tolerance for infection, which could lead to competitive dominance or to coexistence if the native grass has a fecundity or survival advantage. In sum, multihost pathogens can affect host communities in a range of ways, depending on the specific mechanism of spillover. PMID- 23669538 TI - Initiators, leaders, and recruitment mechanisms in the collective movements of damselfish. AB - Explaining how individual behavior and social interactions give rise to group level outcomes and affect issues such as leadership is fundamental to the understanding of collective behavior. Here we examined individual and collective behavioral dynamics in groups of humbug damselfish both before and during a collective movement. During the predeparture phase, group activity increased until the collective movement occurred. Although such movements were precipitated by one individual, the success or failure of any attempt to instigate a collective movement was not solely dependent on this initiator's behavior but on the behavior of the group as a whole. Specifically, groups were more active and less cohesive before a successful initiation attempt than before a failed attempt. Individuals who made the most attempts to initiate a collective movement during each trial were ultimately most likely to lead the collective movement. Leadership was not related to dominance but was consistent between trials. The probability of fish recruiting to a group movement initiative was an approximately linear function of the number of fish already recruited. Overall, these results are consistent with nonselective local mimetism, with the decision to leave based on a group's, rather than any particular individual's, readiness to leave. PMID- 23669539 TI - Thermal sensitivity of immune function: evidence against a generalist-specialist trade-off among endothermic and ectothermic vertebrates. AB - Animal body temperature (Tbody) varies over daily and annual cycles, affecting multiple aspects of biological performance in both endothermic and ectothermic animals. Yet a comprehensive comparison of thermal performance among animals varying in Tbody (mean and variance) and heat production is lacking. Thus, we examined the thermal sensitivity of immune function (a crucial fitness determinant) in Vertebrata, a group encompassing species of varying thermal biology. Specifically, we investigated temperature-related variation in two innate immune performance metrics, hemagglutination and hemolysis, for 13 species across all seven major vertebrate clades. Agglutination and lysis were temperature dependent and were more strongly related to the thermal biology of species (e.g., mean Tbody) than to the phylogenetic relatedness of species, although these relationships were complex and frequently surprising (e.g., heterotherms did not exhibit broader thermal performance curves than homeotherms). Agglutination and lysis performance were positively correlated within species, except in taxa that produce squalamine, a steroidal antibiotic that does not lyse red blood cells. Interestingly, we found the antithesis of a generalist-specialist trade-off: species with broader temperature ranges of immune performance also had higher peak performance levels. In sum, we have uncovered thermal sensitivity of immune performance in both endotherms and ectotherms, highlighting the role that temperature and life history play in immune function across Vertebrata. PMID- 23669540 TI - Sibling cooperation influences the age of nest leaving in an altricial bird. AB - In altricial birds, siblings raised within a nest usually leave the nest within hours of each other, despite often differing considerably in age. The youngest members of the brood are typically underdeveloped at this time and less likely than their older siblings to survive outside the nest, yet they risk abandonment if they do not fledge with their older siblings. Nest leaving is usually initiated by the older offspring, which may delay this process to provide more time for their younger siblings to mature, increasing the younger siblings' postfledging survival and their own inclusive fitness. We tested this hypothesis in a population of house wrens Troglodytes aedon and found that broods with broad age spans among siblings had longer nestling periods than broods with narrow age spans and that delayed fledging improves the survival and reproductive prospects of younger siblings, although at a potential cost to future siblings. We also manipulated age spans through cross-fostering and found that older foster nestlings postponed fledging when raised with younger broodmates, as predicted if the age of younger nestlings determines the time of fledging. Our results support kin-selection theory and demonstrate that the exact time of fledging is attributable, in part, to sib-sib interactions. PMID- 23669541 TI - The battle of the sexes over seed size: support for both kinship genomic imprinting and interlocus contest evolution. AB - Outcrossing creates a venue for parental conflict. When one sex provides parental care to offspring fertilized by several partners, the nonproviding sex is under selection to maximally exploit the caring sex. The caring sex may counteradapt, and a coevolutionary arms race ensues. Genetic models of this conflict include the kinship theory of genomic imprinting (parent-of-origin-specific expression of maternal-care effectors) and interlocus conflict evolution (interaction between male selfish signals and female abatement). Predictions were tested by measuring the sizes of seeds produced by within-population crosses (diallel design) and between-population crosses in outcrossing and selfing populations of Arabidopsis lyrata. Within-population diallel crosses revealed substantial maternal variance in seed size in most populations. The comparison of between- and within population crosses showed that seeds were larger when pollen came from another outcrossing population than when pollen came from a selfing or the same population, supporting interlocus contest evolution between male selfish genes and female recognition genes. Evidence for kinship genomic imprinting came from complementary trait means of seed size in reciprocal between-population crosses independent of whether populations were predominantly selfing or outcrossing. Hence, both kinship genomic imprinting and interlocus contest are supported in outcrossing Arabidopsis, whereas only kinship genomic imprinting is important in selfing populations. PMID- 23669542 TI - Separating intrinsic and environmental contributions to growth and their population consequences. AB - Among-individual heterogeneity in growth is a commonly observed phenomenon that has clear consequences for population and community dynamics yet has proved difficult to quantify in practice. In particular, observed among-individual variation in growth can be difficult to link to any given mechanism. Here, we develop a Bayesian state-space framework for modeling growth that bridges the complexity of bioenergetic models and the statistical simplicity of phenomenological growth models. The model allows for intrinsic individual variation in traits, a shared environment, process stochasticity, and measurement error. We apply the model to two populations of steelhead trout (Oncorhynchus mykiss) grown under common but temporally varying food conditions. Models allowing for individual variation match available data better than models that assume a single shared trait for all individuals. Estimated individual variation translated into a roughly twofold range in realized growth rates within populations. Comparisons between populations showed strong differences in trait means, trait variability, and responses to a shared environment. Together, individual- and population-level variation have substantial implications for variation in size and growth rates among and within populations. State-dependent life-history models predict that this variation can lead to differences in individual life-history expression, lifetime reproductive output, and population life-history diversity. PMID- 23669543 TI - Consumer interaction strength may limit the diversifying effect of intraspecific competition: a test in alewife (Alosa pseudoharengus). AB - Intraspecific competition is considered a principal driver of dietary variation, but empirical studies provide mixed support for this mechanism. Here we link comparative and experimental work testing the effects of competition and resource availability on the dietary variation of the alewife (Alosa pseudoharengus). The alewife, a consumer with extreme effects on its resources, was specifically utilized to additionally test the idea that strong interactions between a consumer and its resources can diminish the diversifying effect of competition. First, we compared the short- and long-term diet measures of wild populations across a wide range of densities. Second, in a pair of large-scale field mesocosm experiments, we explored the influence of competition and interaction strength on alewife dietary variation. Results from a whole-lake comparison and field experiments indicated that increasing competition was negatively correlated with population dietary variation. Further, altering the strength of the interaction between the alewife and its prey via prey supplementation eliminated this negative relationship. Collectively, our results suggest that competitive interactions may not drive dietary diversification in the alewife and, potentially, in other highly effective consumers. Our results also indicate that further consideration of the strength of species interactions (and the consumer traits that underlie them) would improve our understanding of the link between intraspecific competition and variation. PMID- 23669545 TI - Differences in speed and duration of bird migration between spring and autumn. AB - It has been suggested that birds migrate faster in spring than in autumn because of competition for arrival order at breeding grounds and environmental factors such as increased daylight. Investigating spring and autumn migration performances is important for understanding ecological and evolutionary constraints in the timing and speed of migration. We compiled measurements from tracking studies and found a consistent predominance of cases showing higher speeds and shorter durations during spring compared to autumn, in terms of flight speeds (airspeed, ground speed, daily travel speed), stopover duration, and total speed and duration of migration. Seasonal differences in flight speeds were generally smaller than those in stopover durations and total speed/duration of migration, indicating that rates of foraging and fuel deposition were more important than flight speed in accounting for differences in overall migration performance. Still, the seasonal differences in flight speeds provide important support for time selection in spring migration. PMID- 23669544 TI - Movement responses of caribou to human-induced habitat edges lead to their aggregation near anthropogenic features. AB - The assessment of disturbance effects on wildlife and resulting mitigation efforts are founded on edge-effect theory. According to the classical view, the abundance of animals affected by human disturbance should increase monotonically with distance from disturbed areas to reach a maximum at remote locations. Here we show that distance-dependent movement taxis can skew abundance distributions toward disturbed areas. We develop an advection-diffusion model based on basic movement behavior commonly observed in animal populations and parameterize the model from observations on radio-collared caribou in a boreal ecosystem. The model predicts maximum abundance at 3.7 km from cutovers and roads. Consistently, aerial surveys conducted over 161,920 km(2) showed that the relative probability of caribou occurrence displays nonmonotonic changes with the distance to anthropogenic features, with a peak occurring at 4.5 km away from these features. This aggregation near disturbed areas thus provides the predators of this top down-controlled, threatened herbivore species with specific locations to concentrate their search. The edge-effect theory developed here thus predicts that human activities should alter animal distribution and food web properties differently than anticipated from the current paradigm. Consideration of such nonmonotonic response to habitat edges may become essential to successful wildlife conservation. PMID- 23669546 TI - Trade-offs, geography, and limits to thermal adaptation in a tide pool copepod. AB - Antagonistic correlations among traits may slow the rate of adaptation to a changing environment. The tide pool copepod Tigriopus californicus is locally adapted to temperature, but within populations, the response to selection for increased heat tolerance plateaus rapidly, suggesting either limited variation within populations or costs of increased tolerance. To measure possible costs of thermal tolerance, we selected for increased upper lethal limits for 10 generations in 22 lines of T. californicus from six populations. Then, for each line, we measured six fitness-related traits. Selected lines showed an overall increase in male and female body sizes, fecundity, and starvation resistance, suggesting a small benefit from (rather than costs of) increased tolerance. The effect of selection on correlated traits also varied significantly by population for five traits, indicating that the genetic basis for the selection response differed among populations. Our results suggest that adaptation was limited by the presence of variation within isolated populations rather than by costs of increased tolerance. PMID- 23669547 TI - Choosy males could help explain androdioecy in a selfing fish. AB - Androdioecy (the coexistence of males and hermaphrodites) is considered a transitional state derived from pure hermaphroditism or dioecy, but the processes selecting for this rare breeding system are unclear, particularly in animals. In androdioecious species, the proportion of males in relation to hermaphrodites is usually so reduced that it is not known whether there is scope for mate choice, particularly when simultaneous hermaphrodites can self-fertilize. We investigated the potential role of male mate choice in the persistence of androdioecy in animals using a self-fertilizing androdioecious fish (Kryptolebias marmoratus) as a model. Hermaphrodites preferred to associate with males but showed no preference based on genetic similarity. In contrast, males displayed a strong preference for genetically dissimilar hermaphrodites, based, apparently, on olfactory cues. We suggest that disassortative male mate choice could be a critical factor in stabilizing androdioecy in cases where high selfing rates are associated with inbreeding depression. PMID- 23669548 TI - Assortative mating in animals. AB - Assortative mating occurs when there is a correlation (positive or negative) between male and female phenotypes or genotypes across mated pairs. To determine the typical strength and direction of assortative mating in animals, we carried out a meta-analysis of published measures of assortative mating for a variety of phenotypic and genotypic traits in a diverse set of animal taxa. We focused on the strength of assortment within populations, excluding reproductively isolated populations and species. We collected 1,116 published correlations between mated pairs from 254 species (360 unique species-trait combinations) in five phyla. The mean correlation between mates was 0.28, showing an overall tendency toward positive assortative mating within populations. Although 19% of the correlations were negative, simulations suggest that these could represent type I error and that negative assortative mating may be rare. We also find significant differences in the strength of assortment among major taxonomic groups and among trait categories. We discuss various possible reasons for the evolution of assortative mating and its implications for speciation. PMID- 23669549 TI - Adaptive dynamics with interaction structure. AB - Evolutionary dynamics depend critically on a population's interaction structure the pattern of which individuals interact with which others, depending on the state of the population and the environment. Previous research has shown, for example, that cooperative behaviors disfavored in well-mixed populations can be favored when interactions occur only between spatial neighbors or group members. Combining the adaptive dynamics approach with recent advances in evolutionary game theory, we here introduce a general mathematical framework for analyzing the long-term evolution of continuous game strategies for a broad class of evolutionary models, encompassing many varieties of interaction structure. Our main result, the canonical equation of adaptive dynamics with interaction structure, characterizes expected evolutionary trajectories resulting from any such model, thereby generalizing a central tool of adaptive dynamics theory. Interestingly, the effects of different interaction structures and update rules on evolutionary trajectories are fully captured by just two real numbers associated with each model, which are independent of the considered game. The first, a structure coefficient, quantifies the effects on selection pressures and thus on the shapes of expected evolutionary trajectories. The second, an effective population size, quantifies the effects on selection responses and thus on the expected rates of adaptation. Applying our results to two social dilemmas, we show how the range of evolutionarily stable cooperative behaviors systematically varies with a model's structure coefficient. PMID- 23669551 TI - Positive and negative regulation of developmental signaling by the endocytic pathway. AB - Multicellular organisms acquire complex architecture through highly regulated developmental processes in which cells are programmed to respond to a specific set of extracellular signals produced by themselves and others. Modulation of sensitivity or duration of response is controlled by a variety of intracellular mechanisms. The endoocytic pathway performs essential regulatory roles both for the activation as well as the inactivation of signal transduction. Early stage of endocytic pathway is required for the recruitment of cytosolic mediators for signal amplification of signaling, whereas signal termination by late endosomes/lysosomes is important for spatiotemporal regulation. Herein, we summarize recent studies showing that dysfunction in endocytic pathways causes patterning defects in early embryogenesis in mammals. PMID- 23669550 TI - Only scratching the cell surface: extracellular signals in cerebrum development. AB - Numerous roles have been identified for extracellular signals such as Fibroblast Growth Factors (FGFs), Transforming Growth Factor-betas (TGFbetas), Wingless-Int proteins (WNTs), and Sonic Hedgehog (SHH) in assigning fates to cells during development of the cerebrum. However, several fundamental questions remain largely unexplored. First, how does the same extracellular signal instruct precursor cells in different locations or at different stages to adopt distinct fates? And second, how does a precursor cell integrate multiple signals to adopt a specific fate? Answers to these questions require knowing the mechanisms that underlie each cell type's competence to respond to certain extracellular signals. This brief review provides illustrative examples of potential mechanisms that begin to bridge the gap between cell surface and cell fate during cerebrum development. PMID- 23669552 TI - Generation and interpretation of FGF morphogen gradients in vertebrates. AB - Signalling via fibroblast growth factors (FGFs) is involved in multiple aspects of vertebrate development. In several instances FGFs act as morphogens, that is secreted signalling molecules that encode positional information in their graded distribution throughout their target tissue. In recent years, work in the zebrafish model system has been instrumental in addressing the cell biological basis of FGF morphogen gradient formation and interpretation. These experiments have benefitted from the optical properties of the zebrafish embryo that render this vertebrate organism particularly suited for advanced microscopic and biophysical approaches. PMID- 23669556 TI - [Thyroid in the elderly (part 2)]. AB - Aging is associated with an increased prevalence of thyroid diseases. The diagnosis of overt hypothyroidism and hyperthyroidism may be difficult since they are often pauci- or monosymptomatic. Subclinical forms of thyroid diseases, in particular hypothyroidism, are even more frequent. Therapeutic abstention with regular follow-up is usually recommended in hypothyroidism. Radical treatment is usually preferred for subclinical hyperthyroidism since heart complications may be severe. Increased prevalence of benign and malignant nodules is observed in the elderly. The prognosis of thyroid cancer is less favorable than in adults, due to a higher proportion of histological types with a worse evolution. Whatever the thyroid disease, diagnosis and treatment modalities should be adapted to the age and general conditions of the patient. Contradictory results have been reported on the relationship between thyroid status and neuromuscular and cognitive alterations linked to aging. PMID- 23669557 TI - Characteristics of balance control in older persons who fall with injury--a prospective study. AB - OBJECTIVE: Older adults who have recently fallen demonstrate increased postural sway compared with non-fallers. However, the differences in postural control between older adults who were seriously injured (SI) as a result of a fall, compared with those who fell but were not injured (NSI) and non-fallers (NFs), has not been investigated. The objective of the present study was to investigate the underlying postural control mechanisms related to injuries resulting from a fall. METHODS: Both traditional postural sway measures of foot center-of-pressure (CoP) displacements and fractal measures, the Stabilogram-Diffusion Analysis (SDA), were used to characterize the postural control. One hundred older adults aged 65-91years were tested during narrow base upright stance in eyes closed condition; falls were monitored over a 1-year period. RESULTS: Forty-nine older adults fell during the 1-year follow-up, 13 were seriously injured as a result of a fall (SI), 36 were not injured (NSI), and 49 were non-fallers (NFs); two passed away. The SDA showed significantly higher short-term diffusion coefficients and critical displacements in SI in the anterior-posterior direction compared with both NSI and NF. However, in the medio-lateral direction there were no statistically significant differences between groups. For the traditional measures of sway, the average anterior-posterior CoP range was also larger in SI individuals. CONCLUSIONS: This work suggests that older fallers with a deterioration of anterior-posterior postural control may be at higher risk of serious injury following fall events. PMID- 23669558 TI - Development of a scale for estimating procedural distress in the newborn intensive care unit: the Procedural Load Index. AB - BACKGROUND: Infants in the newborn intensive care unit (NICU) are exposed to routine procedures that often cause distress and carry a negative burden or load on the infant's neurodevelopment. AIM: A ratio level index is introduced to estimate procedural load so as to begin to develop a system to monitor the intensity of distress associated with common NICU procedures. STUDY DESIGN: Two psychophysical methods, magnitude estimation (ME) and the general labeled magnitude scale (gLMS) were used to survey 86 clinicians via the internet to estimate the distress associated with 55 common NICU procedures. RESULTS: gLMS and ME estimations correlated highly across all procedures (r = 0.97). gLMS values were used to derive the procedural load index (PLI) as a ratio level estimation of procedural distress. CONCLUSION: The PLI ranks and differentiates distress among common NICU procedures more precisely than current tools. This methodology, if correlated with infant physiological indices and health outcomes, may be operationalized at the bedside to measure procedural distress, and help to guide the ideal timing to perform procedures and minimize their negative consequence. PMID- 23669559 TI - Parenting stress in mothers of very preterm infants -- influence of development, temperament and maternal depression. AB - OBJECTIVE: To measure levels of parenting stress and postnatal depression in mothers of very preterm infants in comparison with mothers of infants born at term is the objective of this study. The study also aimed to explore factors associated with parenting stress in the mothers of the preterm infants. METHODS: One hundred and five mothers who delivered 124 babies at <=30 weeks gestation were enrolled together with 105 term mothers who delivered 120 babies. At one year of age (corrected for prematurity for the preterm cohort), the mothers completed the Parenting Stress Index Short Form (PSI), the Edinburgh Postnatal Depression Scale (EPDS) and the Short Temperament Scale for Toddlers. The infants had neurodevelopmental assessment. The preterm and term groups were compared. RESULTS: Questionnaires were completed by 101 of the preterm mothers and 98 of the term mothers. The mean PSI Total Stress score was significantly higher for the preterm mothers (70.28 vs 64.52, p = 0.022), with 19% of the preterm group and 9% of the term group having high scores (p = 0.038).There was no group difference on the EPDS or measures of temperament, with disability being greater in the preterm infants. For the preterm group, maternal depression and infant temperament were independent predictors of Total Stress scores on multivariate analysis. CONCLUSIONS: Parenting stress in mothers of preterm infants at one year of age is significantly greater than that found in mothers of term infants. For preterm mothers, symptoms of depression and infant temperament are independent risk factors for higher levels of parenting stress. PMID- 23669560 TI - Intertidal mudflat and saltmarsh conservation and sustainable use in the UK: a review. AB - The adoption of the Convention on Wetlands of International Importance in Ramsar, Iran in 1971 committed the UK to conserve and sustainably use intertidal mudflats and saltmarshes for the benefit of present and future generations. Through consideration of their importance and value, current status, the characteristics, causes and consequences of their loss, and the associated responses to loss, this paper reviews the UK progress towards the conservation and sustainable use of intertidal mudflats and saltmarshes. Uncertainties in their current status and trends make it difficult to assess the overall net change in extent across the UK. However, it is apparent that losses due to erosion continue to exceed gains from intertidal mudflat and saltmarsh reparation (IMSR) schemes in south-east and southern England. IMSR schemes in the UK have been generally limited to relatively small-scale trials in comparison to elsewhere in Europe and in the USA. No research to date has unequivocally identified the causes of erosion. Regardless of the cause, the loss of intertidal mudflats and saltmarshes has adverse impacts on the provision of ecosystem services upon which humans and other species depend. The evidence presented in this paper suggests that alongside further science-based research, there is a need to develop a decision making process capable of accommodating complexity, uncertainty and multiple diverse perspectives, through which more informed, timely decisions and more effective, concerted actions to conserve and sustainably use intertidal mudflats and saltmarshes can be taken. PMID- 23669561 TI - Older Europeans and the European Court of Justice. AB - BACKGROUND: the European Court of Justice (ECJ) is considered by many to be the most important judicial institution of the European Union today. Despite the potential importance and relevance of the ECJ rulings to the lives and rights of older Europeans, no research has attempted to analyse or to study the ECJ rulings in this field. OBJECTIVE: to describe the ECJ case-law in the field of elder rights. METHODS: using a computerised search of the ECJ database, between the years 1994 and 2010, 123 cases directly dealing with legal rights of older persons were analysed. RESULTS: on average, only 1-2% of the annual ECJ case-load addresses rights of older persons. Unlike the clear trend in the increase of the total ECJ case load, there was no similar trend of increase in the number of cases directly involving older persons' rights. However, in the majority of the elder-rights cases, the ECJ decision was in support of the older person's rights. CONCLUSIONS: the ECJ can potentially serve as an important protector of rights of older Europeans, if and to the extent that these cases reach its jurisdiction. PMID- 23669562 TI - A pragmatic study of the predictive values of the Morse falls score. AB - BACKGROUND: inpatient falls are an important safety challenge, with around half causing physical injuries that compromise the recovery of older, frailer patients. Falls risk scores are in widespread use, but validation studies of their predictive values are few. OBJECTIVES: to assess the predictive values of the Morse falls score (MFS) in an acute general hospital. METHODS: age, admitting speciality, MFS, and any falls in the subsequent 7 days were collected in April 2011 through case note review and incident reporting systems. RESULTS: a total of 467 inpatients were included in the study; 51% were aged 75+ years; 56% had an MFS >=25; 23% had an MFS >=55; 28 fell. An MFS >=25 was not significantly better than chance in the total sample or in any subgroups considered (YI: -0.01 to 0.15). An MFS >=55 was significantly better than chance for the total sample (YI: 0.39), patients >=75 years (YI: 0.31) and geriatrician-led wards (YI 0.37), although either sensitivity or specificity fell below 70% in each of these groups. Other subgroups did not demonstrate significantly better accuracy than chance, but may have been affected by type II error. CONCLUSIONS: using MFS >=25 cannot be clinically justified, while using MFS >=55 would be contingent on an effective intervention that was ethically acceptable to withhold from the patients with an MFS < 55, despite >40% of falls occurring in that group. Given similar limitations of alternative falls risk scores, hospitals should consider directly assessing and acting on individual patients' specific modifiable risk factors for falls. PMID- 23669563 TI - Expressed prostatic secretion biomarkers improve stratification of NCCN active surveillance candidates: performance of secretion capacity and TMPRSS2:ERG models. AB - PURPOSE: Active surveillance is a viable patient option for prostate cancer provided that a clinical determination of low risk and presumably organ confined disease can be made. To standardize risk stratification schemes the NCCN (National Comprehensive Cancer Network(r)) provides guidelines for the active surveillance option. We determined the effectiveness of expressed prostatic secretion biomarkers for detecting occult risk factors in NCCN active surveillance candidates. MATERIALS AND METHODS: Expressed prostatic secretion specimens were obtained before robot-assisted radical prostatectomy. Secretion capacity biomarkers, including total RNA and expressed prostatic secretion specimen volume, were measured by standard techniques. RNA expression biomarkers, including TXNRD1 mRNA, prostate specific antigen mRNA, TMPRSS2:ERG fusion mRNA and PCA3 mRNA, were measured by quantitative reverse-transcription polymerase chain reaction. RESULTS: Of the 528 patients from whom expressed prostatic secretions were collected 216 were eligible for active surveillance under NCCN guidelines. Variable selection on logistic regression identified 2 models, including one featuring types III and VI TMPRSS2:ERG variants, and one featuring 2 secretion capacity biomarkers. Of the 2 high performing models the secretion capacity model was most effective for detecting cases in this group that were up staged or up-staged plus upgraded. It decreased the risk of up-staging in patients with a negative test almost eightfold and decreased the risk of up staging plus upgrading about fivefold while doubling the prevalence of up-staging in the positive test group. CONCLUSIONS: Noninvasive expressed prostatic secretion testing may improve patient acceptance of active surveillance by dramatically reducing the presence of occult risk factors among those eligible for active surveillance under NCCN guidelines. PMID- 23669564 TI - Technology diffusion and diagnostic testing for prostate cancer. AB - PURPOSE: While the dissemination of robotic prostatectomy and intensity modulated radiotherapy may fuel the increased use of prostatectomy and radiotherapy, these new technologies may also have spillover effects related to diagnostic testing for prostate cancer. Therefore, we examined the association of regional technology penetration with the receipt of prostate specific antigen testing and prostate biopsy. MATERIALS AND METHODS: In this retrospective cohort study we included 117,857 men 66 years old or older from the 5% sample of Medicare beneficiaries living in Surveillance, Epidemiology and End Results (SEER) areas from 2003 to 2007. Regional technology penetration was measured as the number of providers performing robotic prostatectomy or intensity modulated radiotherapy per population in a health care market, ie hospital referral region. We assessed the association of technology penetration with the prostate specific antigen testing rate and prostate biopsy using generalized estimating equations. RESULTS: High technology penetration was associated with an increased rate of prostate specific antigen testing (442 vs 425/1,000 person-years, p<0.01) and a similar rate of prostate biopsy (10.1 vs 9.9/1,000 person-years, p=0.69). The impact of technology penetration on prostate specific antigen testing and prostate biopsy was much less than the effect of age, race and comorbidity, eg the prostate specific antigen testing rate per 1,000 person-years was 485 vs 373 for men with only 1 vs 3+ comorbid conditions (p<0.01). CONCLUSIONS: Increased technology penetration is associated with a slightly higher rate of prostate specific antigen testing and no change in the prostate biopsy rate. Collectively, our findings temper concerns that adopting new technology accelerates diagnostic testing for prostate cancer. PMID- 23669565 TI - hepaCAM and p-mTOR closely correlate in bladder transitional cell carcinoma and hepaCAM expression inhibits proliferation via an AMPK/mTOR dependent pathway in human bladder cancer cells. AB - PURPOSE: We explored the correlation between hepaCAM and activated p-mTOR in bladder transitional cell carcinoma. We also determined whether the antiproliferation effect of hepaCAM is associated with the AMPK/mTOR pathway. MATERIALS AND METHODS: We performed quantitative reverse transcriptase-polymerase chain reaction to determine hepaCAM mRNA expression as well as Western blot to measure hepaCAM and p-mTOR protein levels in 25 men and 5 women. Disease was Ta T1 in 7 patients, T2-T4 in 23, grade 1 in 13, grade 2 in 9, grade 3 in 8, primary in 13 and recurrent in 17. The WST-8 assay was used to study the effect of hepaCAM on cellular proliferation. p-AMPK, p-mTOR, total AMPK, total mTOR, c-Myc and cyclin D1 were also determined by Western blot. RESULTS: hepaCAM mRNA and protein levels were significantly decreased, while p-mTOR protein was remarkably increased in bladder transitional cell carcinoma compared to adjacent tissues (each p<0.01). Spearman correlation analysis revealed that the hepaCAM decrease was associated with an increase in p-mTOR (r=-0.533, p=0.002). Also, hepaCAM inhibited the proliferation of human bladder transitional cell carcinoma cells. hepaCAM over expression activated AMPK and down-regulated p-mTOR, and its targets c-Myc and cyclin D1. Treatment with the AMPK inhibitor compound C prevented the antiproliferation effect of hepaCAM. Compound C completely blocked hepaCAM induced activation of AMPK and down-regulation of p-mTOR and its targets c-Myc and cyclin D1. CONCLUSIONS: Results suggest an important correlation between hepaCAM and p-mTOR. hepaCAM can inhibit bladder cancer cell proliferation through an AMPK/mTOR dependent pathway. PMID- 23669566 TI - Bladder and bowel dysfunction: evidence for multidisciplinary care. AB - PURPOSE: We examined the symptoms of bladder-bowel dysfunction (ie severity of voiding dysfunction and stool consistency) and psychosocial difficulties in children presenting to the pediatric urology clinic for voiding dysfunction and to the pediatric gastroenterology clinic for functional constipation. MATERIALS AND METHODS: Parents of children seen at the gastroenterology clinic were recruited during the outpatient clinic appointment, and parents of children seen at the urology clinic were randomly selected from the research database and matched to the gastroenterology sample based on age and gender of the child. All parents completed the Dysfunctional Voiding Scoring System, Bristol Stool Form Scale, Pediatric Symptom Checklist and Parenting Stress IndexTM-Short Form, which assessed severity of voiding dysfunction, stool consistency, level of psychosocial difficulties and level of parenting stress, respectively. RESULTS: Children seen at the urology and gastroenterology clinics did not differ significantly on any of the measures, indicating that the severity of their bladder-bowel dysfunction is similar. However, they had significantly more severe voiding dysfunction, more constipated stool and more psychosocial difficulties than historical healthy controls. Additionally, level of parenting stress was significantly correlated with patient level of psychosocial difficulties and severity of voiding dysfunction. CONCLUSIONS: Patients with bladder and bowel dysfunction represent a homogeneous group that would potentially benefit from a multidisciplinary treatment approach involving urology, gastroenterology and psychology professionals. PMID- 23669567 TI - Pharmacokinetics of intravesical versus oral oxybutynin in healthy adults: results of an open label, randomized, prospective clinical study. AB - PURPOSE: We investigated the pharmacokinetics of intravesical oxybutynin and discuss the clinical implications of the results. MATERIALS AND METHODS: We performed an open label, randomized, 3-period crossover clinical study in 20 healthy adults. In periods 1 and 2 subjects received a single dose of 10 mg oxybutynin HCl solution intravesically or a 5 mg tablet orally. Period 3 comprised repeat intravesical applications (7 doses) of 10 mg oxybutynin HCl. Enantioselective concentrations of oxybutynin and N-desethyloxybutynin were quantified by liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental methods, analyzed by descriptive statistics and compared using the average bioequivalence approach. RESULTS: Systemic exposure to racemic oxybutynin after intravesical administration was significantly greater, yielding 294% (90% CI 211-408) of that after oral intake of immediate release preparations, as measured by the dose normalized area under the plasma concentration time curve. In contrast, systemic exposure to racemic N desethyloxybutynin reached only 21% (90% CI 15-29). The area under the plasma concentration time curve ratio of N-desethyloxybutynin to oxybutynin was 14-fold decreased for intravesical administration. After intravesical multidose administration, the cumulation of oxybutynin (1.3-fold) and N-desethyloxybutynin (1.6-fold) was weak, absorption was prolonged and apparent elimination half-lives were longer. The study medication was well tolerated with a third of participants reporting anticholinergic adverse effects. CONCLUSIONS: Our study provides evidence of significantly higher bioavailability of intravesical vs oral administration of oxybutynin due to circumvention of the intestinal first pass metabolism. Given the high efficacy and decreased rate of adverse effects, intravesical oxybutynin should be considered in patients with neurogenic lower urinary tract dysfunction who do not tolerate oral administration or in whom oral preparations fail to improve detrusor overactivity. PMID- 23669569 TI - Prediction and characterization of cyclic proteins from sequences in three domains of life. AB - Cyclic proteins (CPs) have circular chains with a continuous cycle of peptide bonds. Their unique structural traits result in greater stability and resistance to degradation when compared to their acyclic counterparts. They are also promising targets for pharmaceutical/therapeutic applications. To date, only a few hundred CPs are known, although recent studies suggest that their numbers might be substantially higher. Here we developed a first-of-its-kind, accurate and high-throughput method called CyPred that predicts whether a given protein chain is cyclic. CyPred considers currently well-represented CP families: cyclotides, cyclic defensins, bacteriocins, and trypsin inhibitors. Empirical tests demonstrate that CyPred outperforms commonly used alignment methods. We used CyPred to estimate the incidence of CPs and found ~3500 putative CPs among 5.7+ million chains from 642 fully sequenced proteomes from archaea, bacteria, and eukaryotes. The median number of putative CPs per species ranges from three for archaea proteomes to two for eukaryotes/bacteria, with 7% of archaea, 11% of bacterial, and 16% of eukaryotic proteomes having 10+ CPs. The differences in the estimated fractions of CPs per proteome are as large as three orders of magnitude. Among eukaryotes, animals have higher ratios of CPs compared to fungi, while plants have the largest spread of the ratios. We also show that proteomes enriched in cyclic proteins evolve more slowly than proteomes with fewer cyclic chains. Our results suggest that further research is needed to fully uncover the scope and potential of cyclic proteins. A list of putative CPs and the CyPred method are available at http://biomine.ece.ualberta.ca/CyPred/. This article is part of a Special Issue entitled: Computational Proteomics, Systems Biology & Clinical Implications. Guest Editor: Yudong Cai. PMID- 23669568 TI - Risk of urinary incontinence following post-brachytherapy transurethral resection of the prostate and correlation with clinical and treatment parameters. AB - PURPOSE: We assess the risk of urinary incontinence after transurethral prostate resection in patients previously treated with prostate brachytherapy. MATERIALS AND METHODS: A total of 2,495 patients underwent brachytherapy with or without external beam radiation therapy for the diagnosis of prostate cancer between June 1990 and December 2009. Patients who underwent transurethral prostate resection before implantation were excluded from study. Overall 79 patients (3.3%) underwent channel transurethral resection of the prostate due to urinary retention or refractory obstructive urinary symptoms. Correlation analyses were performed using the chi-square (Pearson) test. Estimates for time to urinary incontinence were determined using the Kaplan-Meier method with comparisons using logistic regression and Cox proportional hazard rates. RESULTS: Median followup after implantation was 7.2 years. Median time to first transurethral prostate resection after implantation was 14.8 months. Of the 79 patients who underwent transurethral prostate resection after implantation 20 (25.3%) had urinary incontinence compared with 3.1% of those who underwent implantation only (OR 10.4, 95% CI 6-18, p<0.001). Of the 15 patients who required more than 1 transurethral prostate resection, urinary incontinence developed in 8 (53%) compared with 19% of patients who underwent only 1 resection (OR 4.9, 95% CI 1.5 16, p=0.006). Exclusion of patients who underwent multiple transurethral prostate resections still demonstrated significant differences (18.8% vs 3.1%, OR 7.1, 95% CI 3.6-13.9, p<0.001). Median time from last transurethral prostate resection to urinary incontinence was 24 months. On linear regression analysis, hormone use and transurethral prostate resection after implantation were associated with urinary incontinence (p<0.05). There was no correlation between the timing of transurethral prostate resection after implantation and the risk of incontinence. CONCLUSIONS: Urinary incontinence developed in 25.3% of patients who underwent transurethral prostate resection after prostate brachytherapy. The risk of urinary incontinence correlates with the number of transurethral prostate resections. Patients should be counseled thoroughly before undergoing transurethral prostate resection after implantation. PMID- 23669570 TI - Librational fluctuations in protein glasses. AB - Librational motions in the region of the protein "glass" (or dynamic) transition are analysed for spin-labelled haemoglobin, serum albumin and beta-lactoglobulin by EPR spectroscopy. A discontinuity in the temperature dependence of the mean square librational amplitude, , occurs in the region of 200K as found for the mean-square atomic displacement, , at the protein dynamic transition by Mossbauer spectroscopy and neutron scattering. The discontinuity in vs. T can be described by the Vogel-Tammann-Fulcher equation, implying a finite glass transition temperature. Above the dynamic transition, vs. 1/T can be approximated by the Arrhenius law with activation energies similar to those usually found for , and relaxation processes in glass-forming media and the hydration shells of proteins. Similar results are found for librational fluctuations of membranous Na,K-ATPase spin-labelled either on superficial SH groups or on those essential to activity. PMID- 23669571 TI - Auxin: simply complicated. AB - Auxin is a plant hormone involved in an extraordinarily broad variety of biological mechanisms. These range from basic cellular processes, such as endocytosis, cell polarity, and cell cycle control over localized responses such as cell elongation and differential growth, to macroscopic phenomena such as embryogenesis, tissue patterning, and de novo formation of organs. Even though the history of auxin research reaches back more than a hundred years, we are still far from a comprehensive understanding of how auxin governs such a wide range of responses. Some answers to this question may lie in the auxin molecule itself. Naturally occurring auxin-like substances have been found and they may play roles in specific developmental and cellular processes. The molecular mode of auxin action can be further explored by the utilization of synthetic auxin like molecules. A second area is the perception of auxin, where we know of three seemingly independent receptors and signalling systems, some better understood than others, but each of them probably involved in distinct physiological processes. Lastly, auxin is actively modified, metabolized, and intracellularly compartmentalized, which can have a great impact on its availability and activity. In this review, we will give an overview of these rather recent and emerging areas of auxin research and try to formulate some of the open questions. Without doubt, the manifold facets of auxin biology will not cease to amaze us for a long time to come. PMID- 23669572 TI - Phylogenetically distant barley legumains have a role in both seed and vegetative tissues. AB - Legumains or vacuolar processing enzymes are cysteine peptidases (C13 family, clan CD) with increasingly recognized physiological significance in plants. They have previously been classified as seed and vegetative legumains. In this work, the entire barley legumain family is described. The eight members of this family belong to the two phylogenetic clades in which the angiosperm legumains are distributed. An in-depth molecular and functional characterization of a barley legumain from each group, HvLeg-2 and HvLeg-4, was performed. Both legumains contained a signal peptide and were located in the endoplasmic reticulum, were expressed in seeds and vegetative tissues, and when expressed as recombinant proteins showed legumain and caspase proteolytic activities. However, the role of each protein seemed to be different in their target tissues. HvLeg-2 responded in leaves to biotic and abiotic stimuli, such as salicylic acid, jasmonic acid, nitric oxide, abscisic acid, and aphid infestation, and was induced by gibberellic acid in seeds, where the protein is able to degrade storage globulins. HvLeg-4 responded in leaves to wounding, nitric oxide, and abscisic acid treatments, and had an unknown role in the germinating seed. From these results, a multifunctional role was assumed for these two phylogenetically distant legumains, achieving different physiological functions in both seed and vegetative tissues. PMID- 23669574 TI - Is floret primordia death triggered by floret development in durum wheat? AB - Survival of floret primordia initiated seems critical for the determination of grain number and yield in wheat, and understanding what determines floret mortality would help in the development of more robust physiological models of yield determination. The growth of the juvenile spikes has been frequently considered the determinant of grain number, implying that floret development would depend on resource availability and that the onset of floret death would be related to spike growth. However, this model has been recently challenged from a study concluding that floret death started when the most advanced floret primordia reached a particular developmental stage. As the few previous studies on this relationship involved photoperiod treatments which affect both floret development and the onset of spike growth, conclusions cannot be considered mechanistic. This comprehensive study analysed in detail floret development in wheat as affected by resource availability (mainly soil nitrogen levels) and found that the onset of floret death may occur when development of the most advanced florets ranged from stages 5 to 9 and that the average and standard deviation of floret developmental stage coinciding with the onset of floret death was not related to the level of availability of resources. These results provide further support to the model relating the onset of floret death with the initiation of active growth of the juvenile spike in which florets are developing. PMID- 23669573 TI - Enhanced drought and heat stress tolerance of tobacco plants with ectopically enhanced cytokinin oxidase/dehydrogenase gene expression. AB - Responses to drought, heat, and combined stress were compared in tobacco (Nicotiana tabacum L.) plants ectopically expressing the cytokinin oxidase/dehydrogenase CKX1 gene of Arabidopsis thaliana L. under the control of either the predominantly root-expressed WRKY6 promoter or the constitutive 35S promoter, and in the wild type. WRKY6:CKX1 plants exhibited high CKX activity in the roots under control conditions. Under stress, the activity of the WRKY6 promoter was down-regulated and the concomitantly reduced cytokinin degradation coincided with raised bioactive cytokinin levels during the early phase of the stress response, which might contribute to enhanced stress tolerance of this genotype. Constitutive expression of CKX1 resulted in an enlarged root system, a stunted, dwarf shoot phenotype, and a low basal level of expression of the dehydration marker gene ERD10B. The high drought tolerance of this genotype was associated with a relatively moderate drop in leaf water potential and a significant decrease in leaf osmotic potential. Basal expression of the proline biosynthetic gene P5CSA was raised. Both wild-type and WRKY6:CKX1 plants responded to heat stress by transient elevation of stomatal conductance, which correlated with an enhanced abscisic acid catabolism. 35S:CKX1 transgenic plants exhibited a small and delayed stomatal response. Nevertheless, they maintained a lower leaf temperature than the other genotypes. Heat shock applied to drought stressed plants exaggerated the negative stress effects, probably due to the additional water loss caused by a transient stimulation of transpiration. The results indicate that modulation of cytokinin levels may positively affect plant responses to abiotic stress through a variety of physiological mechanisms. PMID- 23669575 TI - Botany meets archaeology: people and plants in the past. AB - This paper explores the close links between botany and archaeology, using case studies from the ancient Mediterranean. It explains the kinds of palaeobotanical remains that archaeologists can recover and the methods used to analyse them. The importance of iconographic and textual evidence is also underlined. Examples of key research areas that focus on ancient plants are discussed: diet and palaeoeconomy; medicines, poisons, and psychotropics; perfumes, cosmetics, and dyes; and prestige. PMID- 23669576 TI - A participatory approach for selecting cost-effective measures in the WFD context: the Mar Menor (SE Spain). AB - Achieving a good ecological status in water bodies by 2015 is one of the objectives established in the European Water Framework Directive. Cost-effective analysis (CEA) has been applied for selecting measures to achieve this goal, but this appraisal technique requires technical and economic information that is not always available. In addition, there are often local insights that can only be identified by engaging multiple stakeholders in a participatory process. This paper proposes to combine CEA with the active involvement of stakeholders for selecting cost-effective measures. This approach has been applied to the case study of one of the main coastal lagoons in the European Mediterranean Sea, the Mar Menor, which presents eutrophication problems. Firstly, face-to-face interviews were conducted to estimate relative effectiveness and relative impacts of a set of measures by means of the pairwise comparison technique. Secondly, relative effectiveness was used to estimate cost-effectiveness ratios. The most cost-effective measures were the restoration of watercourses that drain into the lagoon and the treatment of polluted groundwater. Although in general the stakeholders approved the former, most of them stated that the latter involved some uncertainties, which must be addressed before implementing it. Stakeholders pointed out that the PoM would have a positive impact not only on water quality, but also on fishing, agriculture and tourism in the area. This approach can be useful to evaluate other programmes, plans or projects related to other European environmental strategies. PMID- 23669577 TI - Faecal sludge management with the larvae of the black soldier fly (Hermetia illucens)--from a hygiene aspect. AB - Inadequate and lacking sanitation and wastewater treatment systems can lead to the spreading of diarrhoeal diseases. One contributing factor in the lack of such treatment systems is the lack of economic incentives for stakeholders throughout the service chain. However, the organic fraction of the waste is high in valuable plant nutrients and could be reused in agriculture and as animal feed. For example, grown larvae of the black soldier fly, Hermetia illucens L. (Diptera: Stratiomyidae), make an excellent protein source in animal feed, while the feeding activity of the larvae substantially reduces the dry mass of the treated material. This study examined the effect of black soldier fly larvae on the concentration of pathogenic microorganisms in human faeces and found a 6 log10 reduction in Salmonella spp. in human faeces in eight days, compared with a <2 log10 reduction in the control. No increased reduction was observed for Enterococcus spp., bacteriophage PhiX174 or Ascaris suum ova. PMID- 23669578 TI - Stabilization by hydrophobic protection as a molecular mechanism for organic carbon sequestration in maize-amended rice paddy soils. AB - The hydrophobic components of soil organic matter (SOM) are reckoned to play an important role in the stabilization of soil organic carbon (SOC). The contribution of hydrophobic substances to SOC sequestration was evaluated in four different paddy soils in the South of China, following a 6-month incubation experiment with maize straw amendments. Soil samples included: a well developed paddy soil (TP) derived from clayey lacustrine deposits in the Tai Lake plain of Jiangsu; an acid clayey paddy soil (RP) derived from red earth in the rolling red soil area of Jiangxi; a weakly developed neutral paddy soil (PP) formed on Jurassic purple shale from Chongq; and a calcic Fluvisol (MS) derived from riverine sediments from a wetland along the Yangtze valley of Anhui, China. The SOC molecular composition after 30 and 180 days of incubation, was determined by off-line thermochemolysis followed by gas chromatography-mass spectrometry analysis. Lignin, lipids and carbohydrates were the predominant thermochemolysis products released from the treated soils. A selective preservation of hydrophobic OM, including lignin and lipids, was shown in maize amended soils with prolonged incubation. The decomposition of lignin and lipids was significantly slower in the TP and RP soils characterized by a larger content of extractable iron oxyhydrates (Fed) and lower pH. The overall increase in hydrophobic substances in maize incubated samples was correlated, positively, with total content of clay and Fed, and, negatively, with soil pH. Moreover, yields of both lignin and lipid components showed a significant relationship with SOC increase after incubation. These findings showed that the larger the lipid and lignin content of SOM, the greater was the stability of SOC, thereby suggesting that OM hydrophobic components may have an essential role in controlling the processes of OC sequestration in paddy soils of South China. PMID- 23669579 TI - The passive control of air pollution exposure in Dublin, Ireland: a combined measurement and modelling case study. AB - This study investigates the potential real world application of passive control systems to reduce personal pollutant exposure in an urban street canyon in Dublin, Ireland. The implementation of parked cars and/or low boundary walls as a passive control system has been shown to minimise personal exposure to pollutants on footpaths in previous investigations. However, previous research has been limited to generic numerical modelling studies. This study combines real-time traffic data, meteorological conditions and pollution concentrations, in a real world urban street canyon before and after the implementation of a passive control system. Using a combination of field measurements and numerical modelling this study assessed the potential impact of passive controls on personal exposure to nitric oxide (NO) concentrations in the street canyon in winter conditions. A calibrated numerical model of the urban street canyon was developed, taking into account the variability in traffic and meteorological conditions. The modelling system combined the computational fluid dynamic (CFD) simulations and a semi empirical equation, and demonstrated a good agreement with measured field data collected in the street canyon. The results indicated that lane distribution, fleet composition and vehicular turbulence all affected pollutant dispersion, in addition to the canyon geometry and local meteorological conditions. The introduction of passive controls displayed mixed results for improvements in air quality on the footpaths for different wind and traffic conditions. Parked cars demonstrated the most comprehensive passive control system with average improvements in air quality of up to 15% on the footpaths. This study highlights the potential of passive controls in a real street canyon to increase dispersion and improve air quality at street level. PMID- 23669580 TI - Evaluating the fate of six common pharmaceuticals using a reactive transport model: insights from a stream tracer test. AB - Quantitative information regarding the capacity of rivers to self-purify pharmaceutical residues is limited. To bridge this knowledge gap, we present a methodology for quantifying the governing processes affecting the fate of pharmaceuticals in streaming waters and, especially, to evaluate their relative significance for tracer observations. A tracer test in Sava Brook, Sweden was evaluated using a coupled physical-biogeochemical model framework containing surface water transport together with a representation of transient storage in slow/immobile zones of the stream, which are presumably important for the retention and attenuation of pharmaceuticals. To assess the key processes affecting the environmental fate of the compounds, we linked the uncertainty estimates of the reaction rate coefficients to the relative influence of transformation and sorption that occurred in different stream environments. The hydrological and biogeochemical contributions to the fate of the pharmaceuticals were decoupled, and the results indicate a moderate hydrological retention in the hyporheic zone as well as in the densely vegetated parts of the stream. Biogeochemical reactions in these transient storage zones further affected the fate of the pharmaceuticals, and we found that sorption was the key process for bezafibrate, metoprolol, and naproxen, while primary transformation was the most important process for clofibric acid and ibuprofen. Conversely, diclofenac was not affected by sorption or transformation. PMID- 23669581 TI - Medical humanities. PMID- 23669582 TI - The relationship between the arts and medicine. AB - In this paper some of the intriguing links between the arts and medicine are explored. As a starting point I consider the notion of whole person understanding as articulated by Downie in an article entitled "Literature and medicine", published in the Journal of Medical Ethics in 1991.(1) I suggest that the arts can contribute to whole person understanding in at least three ways. The arts may stimulate: (a) insight into common patterns of response (shared human experiences); (b) insight into individual difference or uniqueness, and (c) enrichment of the language and thought of the practitioner. Much literature which explores the relationship between the arts and medicine tends to focus on the value of the arts in increasing our understanding of the particular individual, "whole person understanding" in Downie's sense of the word. This, however, assumes that "whole person understanding" should focus only on the unique in the individual. This view is, I think, mistaken. If we take the notion of "whole person" seriously then we must recognise that which is unique but also that which humans may share. I suggest that this broader view is of the greatest importance in any consideration of the relationship between the arts and medicine. PMID- 23669583 TI - Humanities special studies modules: making better doctors or just happier ones? PMID- 23669584 TI - Living with and dying from cancer: a humanities special study module. AB - We describe a humanities-based, special studies module (SSM) exploring the impact of cancer on the lives of patients, families and professionals. Literature, film, art and drama provide third year medical undergraduates with vicarious experience of all of these perspectives in a format that has proved highly acceptable to students and tutors. The development, delivery, evaluation and evolution of this humanities-based course are described and we highlight some important elements of course organisation that emerged as being integral to its success. PMID- 23669585 TI - Opening the word hoard1. PMID- 23669586 TI - A personal response to: The Woman Who Walked Into Doors by Roddy Doyle. PMID- 23669587 TI - Dynamic contrast-enhanced magnetic resonance imaging measurement of renal function in patients undergoing partial nephrectomy: preliminary experience. AB - OBJECTIVES: To evaluate changes in single-kidney glomerular filtration rate (SK GFR) using low-dose dynamic contrast-enhanced magnetic resonance (MR) renography (MRR) in patients undergoing partial nephrectomy for renal masses. MATERIALS AND METHODS: In this Health Information Patient Protection Act-compliant prospective study, 18 patients with renal masses underwent preoperative MR imaging at 1.5 T for renal mass evaluation and low-dose gadolinium-enhanced MRR. Magnetic resonance renography was repeated approximately 48 to 72 hours and 6 months after partial nephrectomy. Single-kidney glomerular filtration rate was calculated from the MRR images, and the right and left kidney values were summed for total MR GFR. Postoperative changes in SK-GFR and MR-GFR were compared with changes in estimated glomerular filtration rate calculated using modification of diet in renal disease formula, renal lesion characteristics, ischemia type (warm vs cold), and ischemia time. RESULTS: A decrease in the operated kidney SK-GFR was seen in 15 of the 18 patients, with a mean (SD) loss of 31% (23%), whereas estimated glomerular filtration rate decreased in 13 of the 18 patients with mean (SD) decrease of 19% (14%). Decrease in SK-GFR was greatest in the patients with warm ischemia time greater than 40 minutes and least in the patients with cold ischemia. In the immediate postoperative period, 6 of 7 patients (86%) with preoperative MR-GFR less than 60 mL/min per 1.73 m failed to demonstrate compensatory increase in SK-GFR in the nonoperated kidney, whereas 5 of 11 patients with baseline MR-GFR more than 60 mL/min per 1.73 m showed compensatory increase in nonoperated kidney SK-GFR. CONCLUSIONS: Magnetic resonance renography can demonstrate functional loss in the operated kidney and compensatory increase in the function of the contralateral kidney, thus enabling evaluation of various surgical techniques on kidney function. PMID- 23669588 TI - Determination of malignancy and characterization of hepatic tumor type with diffusion-weighted magnetic resonance imaging: comparison of apparent diffusion coefficient and intravoxel incoherent motion-derived measurements. AB - OBJECTIVE: The objective of this study was to compare the value of the apparent diffusion coefficient (ADC) determined with 3 b values and the intravoxel incoherent motion (IVIM)-derived parameters in the determination of malignancy and characterization of hepatic tumor type. MATERIALS AND METHODS: Seventy-six patients with 86 solid hepatic lesions, including 8 hemangiomas, 20 lesions of focal nodular hyperplasia, 9 adenomas, 30 hepatocellular carcinomas, 13 metastases, and 6 cholangiocarcinomas, were assessed in this prospective study. Diffusion-weighted images were acquired with 11 b values to measure the ADCs (with b = 0, 150, and 500 s/mm) and the IVIM-derived parameters, namely, the pure diffusion coefficient and the perfusion-related diffusion fraction and coefficient. The diffusion parameters were compared between benign and malignant tumors and between tumor types, and their diagnostic value in identifying tumor malignancy was assessed. RESULTS: The apparent and pure diffusion coefficients were significantly higher in benign than in malignant tumors (benign: 2.32 [0.87] * 10 mm/s and 1.42 [0.37] * 10 mm/s vs malignant: 1.64 [0.51] * 10 mm/s and 1.14 [0.28] * 10 mm/s, respectively; P < 0.0001 and P = 0.0005), whereas the perfusion related diffusion parameters did not differ significantly between the 2 groups. The apparent and pure diffusion coefficients provided similar accuracy in assessing tumor malignancy (areas under the receiver operating characteristic curve of 0.770 and 0.723, respectively). In the multigroup analysis, the ADC was found to be significantly higher in hemangiomas than in hepatocellular carcinomas, metastases, and cholangiocarcinomas. In the same manner, it was higher in lesions of focal nodular hyperplasia than in metastases and cholangiocarcinomas. However, the pure diffusion coefficient was significantly higher only in hemangiomas versus hepatocellular and cholangiocellular carcinomas. CONCLUSIONS: Compared with the ADC, the diffusion parameters derived from the IVIM model did not improve the determination of malignancy and characterization of hepatic tumor type. PMID- 23669590 TI - Expert report on psoriasis: Spanish dermatologists' opinions on the use of biologic agents to manage moderate to severe psoriasis in adults. AB - BACKGROUND: Although national guidelines on biologic agents for treating moderate to severe psoriasis in adults have been published in several countries, increased knowledge on the practical aspects of their implementation is required. OBJECTIVE: The objective of this study was to survey Spanish dermatologists to determine their expert opinions on practical aspects of psoriasis treatment with biologics. MATERIALS AND METHODS: An online survey was sent to 309 dermatologists who belong to the Spanish Psoriasis Group and/or the Spanish Academy of Dermatology and Venereology (AEDV). The questionnaire was designed specifically for the study and included items on various aspects of the treatment of psoriasis in clinical practice. Six coordinators in different geographic areas worked together to write the final expert report. RESULTS: The response rate was 97% (300 returned questionnaires). The biologics preferred, or considered to be the best option (median score 4 out of 4 points) by respondents, were infliximab for its short-term efficacy (74% of the respondents) and rapid onset of action (78%); ustekinumab for convenience of administration (73%); and etanercept because of its suitability for cyclic treatment (71%), safety in long-term use (72%), and the possibility of temporary interruption of treatment under certain circumstances (76%). Etanercept was assigned the highest evaluations for safety and expected survival time (scored 5 on each item by 49% and 33% of the respondents, respectively). Thirty percent of the respondents considered that clinical guidelines contain important information for therapeutic management of psoriasis. CONCLUSIONS: This study provides a unique perspective on the opinions of a large sample of dermatologists as regards current treatment of psoriasis with biologics in Spain. PMID- 23669591 TI - Nevoid basal cell carcinoma syndrome: our experience in a pediatric hospital. AB - Nevoid basal cell carcinoma (BCC) syndrome, or Gorlin syndrome, is a rare autosomal dominant disorder associated with mutations in the patched 1 gene, PTCH1. It is characterized by the presence of multiple BCCs in association with disorders affecting the bones, the skin, the eyes, and the nervous system. We describe 6 cases of nevoid BCC syndrome evaluated in our department. Palmoplantar pitting was observed in all 6 patients, multiple BCCs in 5 patients (83%), skeletal anomalies in 3 patients (50%), and odontogenic keratocysts in 1 patient (17%). We would like to stress the importance of early diagnosis and treatment in nevoid BCC syndrome and the need for continuous, long-term follow-up by a multidisciplinary team. PMID- 23669589 TI - Is there value in plasma cytokine measurements in patients with severe trauma and sepsis? AB - For the past thirty years, since IL-1beta and TNFalpha were first cloned, there have been efforts to measure plasma cytokine concentrations in patients with severe sepsis and trauma, and to use these measurements to predict clinical outcome and response to therapies. The numbers of cytokines and chemokines that have been measured in the plasma have literally exploded with the development of multiplex immune approaches. Dozens of relatively small cohort studies have shown plasma cytokine concentrations correlating with outcome in sepsis and trauma. Despite what appears to be a consensus that plasma cytokine concentrations should be useful in the clinical setting, only two cytokines, IL-6 and procalcitonin, have approached routine clinical use. IL-6 has been used as a research tool for entry into sepsis-intervention trials, while procalcitonin is being used clinically at a large number of institutions to distinguish sepsis from other inflammatory processes. For most cytokines, the relative lack of sensitivity and specificity of individual or multiplex cytokine measurements has hindered their utility to predict clinical trajectory in individual patients. The problem rests with a general misunderstanding of cytokine biology, failing to appreciate the general paracrine nature of these mediators, the presence of binding proteins, chaperones and inhibitors in the plasma, and the rapid clearance of these proteins by binding to cell receptors and clearance predominantly by the kidney. The future of using plasma cytokine measurements as an indicator of sepsis/trauma severity or predicting outcome is generally behind us, although there is optimism that procalcitonin measurements may ultimately prove to have utility in the diagnosis of severe sepsis. PMID- 23669592 TI - Variations in prison mental health services in England and Wales. AB - In responding to high levels of psychiatric morbidity amongst prisoners and recognising earlier poor quality prison mental health care, prison mental health in-reach teams have been established in England and Wales over the last decade. They are mostly provided by the National Health Service (NHS), which provides the majority of UK healthcare services. Over the same period, the prison population has grown to record levels, such that prisons in England and Wales now contain almost 90,000 of the world's overall prison population of over 10 million people (roughly the size of Paris or Istanbul). This study provides an overview of mental health in-reach services in prisons in England and Wales, including variations between them, through a telephone survey of senior staff in all prisons and young offender institutions in England and Wales. 73% of prisons took part; of them 13% had no in-reach team at all (usually low security establishments) and the majority of services were run by NHS teams, usually according to a generic community mental health team (CMHT) model rather than other specialist models. Team size was unrelated to prison size. Each nurse covered around 500 prisoners, each doctor over 3700. Many provided few or no healthcare cells and 24-h psychiatric cover (including on-call cover) was uncommon. Despite developments in recent years, mental health in-reach services still fall short of community equivalence and there is wide variation in service arrangements that cannot be explained by prison size or function. The aim of community equivalence has not yet been reached in prison healthcare and a more sophisticated measure of service improvement and standardisation would now be useful to drive and monitor future development. PMID- 23669593 TI - Cultural competence in correctional mental health. AB - Cultural competence is an essential aspect of competence as a mental health professional. In this article, the framework of cultural competence developed in general psychiatry-acquiring knowledge, attitudes, and skills necessary to understand the interaction between culture and the individual-is applied to the prison setting. Race and ethnicity, extremes of age, gender, and religion are highlighted and examined as elements of the overall culture of prisons. The model of the cultural formulation from the DSM-IV is then adapted for use by clinicians in the correctional setting, with particular emphasis on the interaction between the inmate's culture of origin and the unique culture of the prison environment. PMID- 23669594 TI - Training to be an historian of anesthesia: options at universities in the United States. AB - STUDY OBJECTIVE: To determine whether a lack of training opportunities explains the finding that few anesthesia historians have obtained formal training in history. DESIGN: Prospective study. SETTING: University hospital. MEASUREMENTS: A list of 128 medical schools within the United States (U.S.) was obtained from the Association of American Medical Colleges and information about graduate programs in history, history of science, and history of medicine was gathered. Editorial board members of journals affiliated with professional associations in history, history of science, and history of medicine were also queried. MAIN RESULTS: We were unable to identify any U.S. institution that offered graduate training in history of anesthesia, while only a handful offered such training in history of medicine. As a result, individuals wishing to pursue doctoral training in history of medicine often enroll in programs devoted to history of science, but with an emphasis on medicine. The vast majority of affiliated universities offer doctoral programs in history. We identified programs that may be considered centers of excellence based on affiliations of editorial board members. CONCLUSIONS: Graduate training in history of anesthesia is currently unavailable, and specific opportunities in history of medicine are quite limited. Individuals wishing to obtain formal training in history of anesthesia need to enroll in a history of science or history of medicine program, and choose a research topic in history of anesthesia. PMID- 23669595 TI - Impact of valvuloarterial impedance on 2-year outcome of patients undergoing transcatheter aortic valve implantation. AB - BACKGROUND: Elderly patients with severe aortic stenosis undergoing transcatheter aortic valve implantation (TAVI) often have increased calcification and fibrosis of the aorta. Indices that account for the severity of valvular obstruction and systemic vascular impedance may better assess total left ventricular afterload. The aims of the present study were to evaluate changes in valvuloarterial impedance (Zva), systemic arterial compliance, and systemic vascular resistance after TAVI and to investigate the prognostic value of these parameters. METHODS: A total of 116 patients (49% men; mean age, 81 +/- 8 years) with symptomatic severe aortic stenosis underwent TAVI. Zva, systemic arterial compliance, and systemic vascular resistance were measured at baseline and 1 and 12 months after TAVI. The primary end point was all-cause mortality. RESULTS: After TAVI, there was a significant reduction in Zva (from 5.40 +/- 1.52 mm Hg/mL/m(2) at baseline to 4.13 +/- 1.17 mm Hg/mL/m(2) at 1 month and 4.35 +/- 1.38 mm Hg/mL/m(2) at 1 year, P < .001). Systemic arterial compliance (from 0.57 +/- 0.27 to 0.57 +/- 0.28 and 0.53 +/- 0.27 mL/m(2)/mm Hg, P = .408) and systemic vascular resistance (from 1,938 +/- 669 to 1,856 +/- 888 and 1,871 +/- 767, dyne.s.cm(-5), P = .697) did not change significantly over time. During a median follow-up period of 25 months, survival rates of patients with baseline Zva >= 5 mm Hg/mL/m(2) were lower compared with those with Zva < 5 mm Hg/mL/m(2) (82% vs 91%, respectively, log-rank P = .04). On multivariate Cox proportional-hazards analysis, baseline Zva was independently associated with all-cause mortality (hazard ratio, 1.48; 95% confidence interval, 1.05-2.07; P = .025). CONCLUSIONS: In patients undergoing TAVI, there is a significant postprocedural reduction in Zva, but there is no reduction in systemic arterial compliance or vascular resistance. Baseline Zva is an independent predictor of overall mortality at 2-year follow up. PMID- 23669596 TI - Intrapulmonary shunt is a potentially unrecognized cause of ischemic stroke and transient ischemic attack. AB - BACKGROUND: Ischemic stroke is a major cause of mortality and disability. Transient ischemic attack (TIA) is a harbinger of stroke. The etiology of stroke in as many as 40% of patients remains undetermined after extensive evaluation. It was hypothesized that intrapulmonary shunt is a potential facilitator of cerebrovascular accident (CVA) or TIA. METHODS: Patients undergoing clinically indicated transesophageal echocardiography were prospectively enrolled. Comprehensive multiplane transesophageal echocardiographic imaging was performed and saline contrast done to assess for intrapulmonary shunt and patent foramen ovale. RESULTS: Three hundred twenty-one patients with either nonhemorrhagic CVA (n = 262) or TIA (n = 59) made up the stroke group. Three hundred twenty-one age matched and gender-matched patients made up the control group. Intrapulmonary shunt occurred more frequently in the stroke group (72 of 321) compared with the control group (32 of 321) (22% vs 10%, P < .0001). Intrapulmonary shunt was an independent predictor of CVA and/or TIA (odds ratio, 2.6; P < .0001). In subjects with cryptogenic CVA or TIA (n = 71), intrapulmonary shunt occurred more frequently (25 of 71) than in the control group (5 of 71) (35% vs 7%, P < .0001). Intrapulmonary shunt was an independent multivariate predictor of CVA or TIA in patients with cryptogenic CVA or TIA (odds ratio, 6.3; P < .005). CONCLUSIONS: These results suggest that intrapulmonary shunt is a potentially unrecognized facilitator of CVA and TIA, especially in patients with cryptogenic CVA and TIA. Future studies assessing the prognostic significance of intrapulmonary shunt on cerebral vascular event recurrence rates in patients after initial CVA or TIA would be of great interest. PMID- 23669597 TI - The assessment of atrial function in single ventricle hearts from birth to Fontan: a speckle-tracking study by using strain and strain rate. AB - BACKGROUND: Single ventricle (SV) exercise performance is impaired and limited by reduced ventricular preload reserve. The atrium modulates ventricular filling, and enhancement of atrial compliance can increase cardiac performance. We aimed to study atrial mechanics in SV hearts across staged surgical palliation compared with healthy children by using novel speckle-tracking echocardiography techniques. METHODS: A cross-sectional study of 81 patients with SV (1 day to 6.5 years) at 4 stages of surgical palliation (presurgery, 22; prebidirectional cavopulmonary anastomosis, 23; pre-Fontan, 22; post-Fontan, 14). The dominant atrium was assessed with speckle-tracking echocardiography for active (epsilonact), conduit (epsiloncon), and reservoir (epsilonres) strain; strain rate (SR); and epsilonact/epsilonres ratio before each stage of surgical palliation. Findings were compared with the left atrium of 51 healthy children (1 day to 5.5 years). RESULTS: Single ventricle atrial size was increased (P < .01), and atrial epsilonres was decreased (P < .01) compared with healthy controls. SV atrial epsiloncon (P < .01) and SRcon (P < .0001) was decreased, increased epsilonact persisted (P < .05), and epsilonact/epsilonres was increased (P < .001) between surgical stages. Although the expected maturational trend of increasing epsiloncon, decreasing epsilonact, and epsilonact/epsilonres occurred in SV, they lagged behind healthy maturational changes (P < .0001). CONCLUSION: Single ventricle atrium is dilated, has deceased compliance, decreased early diastolic emptying, and increased reliance on active atrial contraction for ventricular filling. This deviates from normal early childhood maturational changes and appears to parallel those of an atrium facing early ventricular diastolic dysfunction. PMID- 23669598 TI - Increasing rates of low-risk human papillomavirus infections in patients with oral cavity squamous cell carcinoma: association with clinical outcomes. AB - BACKGROUND: Although human papillomavirus (HPV) infections have been causally linked to oral cavity squamous cell carcinoma (OSCC), the potential role of low risk HPV (LR-HPV) types in the pathogenesis of this malignancy remains unclear. OBJECTIVES: We sought to investigate the distribution of HPV genotypes and their prognostic significance in OSCC patients treated by radical surgery, either with or without adjuvant therapy. STUDY DESIGN: We studied two non-overlapping OSCC cohorts for the periods 2005-2006 (2005 cohort, n = 204) and 2010-2011 (2010 cohort, n = 206). Paraffin-embedded tissue blocks were collected, and the HPV genotype was determined using PCR plus HPV blot tests. The primary study endpoint was the prevalence of HPV genotypes. The secondary endpoints were the 2-year therapeutic outcomes. RESULTS: The overall prevalence of HPV infections did not differ significantly in the two study cohorts. However, the prevalence of LR-HPV was significantly higher in the 2010 cohort than in the 2005 cohort (p = 0.002). The overall prevalence of HPV infections was not significantly associated with the 2-year outcomes. However, multivariate analysis demonstrated that LR-HPV infection was a predictor of poor 2-year disease-free survival (p = 0.036, hazard ratio [HR] = 3.1), disease-specific survival (p = 0.014, HR = 3.8), and overall survival (p = 0.016, HR = 3.2) in the subgroups of OSCC patients with poor differentiation, pN2 lymph node metastases, or extracapsular spread (n = 150). CONCLUSIONS: LR-HPV infections may have an important role in determining the clinical outcomes of certain OSCC patients bearing specific risk factors. PMID- 23669599 TI - The roles of social factor and internet self-efficacy in nurses' web-based continuing learning. AB - This study was conducted to explore the relationships among social factor, Internet self-efficacy and attitudes toward web-based continuing learning in a clinical nursing setting. The participants recruited were 244 in-service nurses from hospitals in Taiwan. Three instruments were used to assess their perceptions of social factor, Internet self-efficacy (including basic and advanced Internet self-efficacy) and attitudes toward web-based continuing learning (including perceived usefulness, perceived ease of use, affection and behavior). Structural equation modeling (SEM) was utilized to identify the hypothesized structural model. The results of this study support that social factor is a significant factor correlated to Internet self-efficacy and attitudes toward web-based continuing learning (including perceived usefulness, perceived ease of use and affection). In addition, nurses' basic Internet self-efficacy plays a key role in attitudes including perceived usefulness, perceived ease of use and affection. However, advanced self-efficacy was not correlated to any of the attitudes. The behavior dimension was not linked to social factor or Internet self-efficacy, but was linked to perceived ease of use and affection. PMID- 23669600 TI - Nursing students' perspectives of the cause of medication errors. AB - BACKGROUND: Medication errors complicate up to half of inpatient stays and some have very serious consequences. To our knowledge, this is the first qualitative study of Iranian nursing students' perspectives of medication errors. OBJECTIVES: To describe nursing students' perspectives of the causes of medication errors. DESIGN: Four focus groups were held with 24 nursing students from 4 different academic semesters in the nursing school in Tehran, between November 2011 and November 2012. Using a qualitative descriptive design, themes and subthemes were identified by content analysis. RESULTS: Two main themes emerged from the data: "under-developed caring skills in medication management" and "unfinished learning of safe medication management", which was subdivided into "drifting between being worried and being careful", and "contextualising pharmacology education". All respondents felt that their education programmes were leaving them vulnerable to "drug errors" and cited incidents where patient safety had been jeopardised. CONCLUSION: Nursing curricula need to increase investment in medicines management. If nursing students are to become competent, skilful and safe practitioners, their learning will require extensive support from their academic institutions and clinical mentors. PMID- 23669601 TI - Using radial basis function on the general form of Chou's pseudo amino acid composition and PSSM to predict subcellular locations of proteins with both single and multiple sites. AB - Prediction of protein subcellular location is a meaningful task which attracted much attention in recent years. A lot of protein subcellular location predictors which can only deal with the single-location proteins were developed. However, some proteins may belong to two or even more subcellular locations. It is important to develop predictors which will be able to deal with multiplex proteins, because these proteins have extremely useful implication in both basic biological research and drug discovery. Considering the circumstance that the number of methods dealing with multiplex proteins is limited, it is meaningful to explore some new methods which can predict subcellular location of proteins with both single and multiple sites. Different methods of feature extraction and different models of predict algorithms using on different benchmark datasets may receive some general results. In this paper, two different feature extraction methods and two different models of neural networks were performed on three benchmark datasets of different kinds of proteins, i.e. datasets constructed specially for Gram-positive bacterial proteins, plant proteins and virus proteins. These benchmark datasets have different number of location sites. The application result shows that RBF neural network has apparently superiorities against BP neural network on these datasets no matter which type of feature extraction is chosen. PMID- 23669602 TI - Rare case-series of electrocautery burn following off-pump coronary artery bypass grafting. AB - With an increasing number of off-pump coronary artery surgery procedures in high risk patients with coagulopathy, including renal failure, hepatic failure and anticoagulant drug-using patients, the frequency of related complications such as repeated exploration for bleeding is also increasing. The associated co-morbidity and repeated use of electrocautery in postoperative bleeding leaves patients susceptible to electrocautery ulcers. In this case series, rare cases of cautery burn with unique causative mechanisms are described. PMID- 23669604 TI - Thermal modelling of the completely stirred anaerobic reactor treating pig manure at low range of mesophilic conditions. AB - Most of Chinese middle size agricultural biogas plants run at the lower range of mesophilic conditions and low organic loading rates (OLRs) which result in the low biogas production. How to obtain an economically viable operation mode is a challenge for Chinese farm biogas plants. In this study, the performance of completely stirred anaerobic reactors treating pig manure was studied at 20, 28 and 38 degrees C. A thermal mathematic model was accordingly developed to decide the optimum digesting temperature and OLRs considering ambient temperature of 20, 10 and 0 degrees C. The regression surface model can fit well on the experimental data when the ambient temperature was around 10-20 degrees C, at which maximum net energy production (Np,max) can be achieved when the digesters run at OLR of 4.6-5.4 kgODM/m(3) d with temperature of above 26 degrees C. Co digestion on the pig farm was suggested in winter in order to increase the Np. PMID- 23669603 TI - Temporal variation in United States firearm injuries 1993-2008: results from a national data base. AB - BACKGROUND: There are few studies that address temporal variation in firearm associated injuries. It was the purpose of this study to analyze the temporal variation in the types and patterns of injuries associated with firearm use from a national data base. METHODS: The database used was the Inter-University Consortium for Political and Social Research Firearm Injury Surveillance Study 1993-2008. Emergency department visits associated with firearm use were analyzed for month and day of the week for various demographic variables. Statistical analyses were performed using SUDAAN 10TM software to give national estimates. Temporal variation by month or day was assessed using histograms, circular distributions, and cosinor analyses. Variation by month and day combined were analyzed using three dimensional contours. RESULTS: There were an estimated 1,841,269 injuries. Circular analyses demonstrated a non-uniform distribution for all parameters for both month and day of injury (p less than 0.001). The overall peak was September 15 with several exceptions. Injuries from BB guns had a peak on May 22, a diagnosis of a foreign body on July 11, and patients aged 10 to 14 years on April 9.The peak day was always Saturday/Sunday when significant variation existed. There were many different patterns for month and day combined. Some were "a rapidly rising high mountain starting at sea level" (hunting), or others a "series of mountain ranges starting from a high plain or steppe" (hospital admissions). CONCLUSIONS: This study provides altogether new information regarding temporal variation for injuries associated with firearms in the USA. These results can be used to assist medical resource allocation and prevention campaigns. Education campaigns can be emphasized before the peaks for which prevention is desired (eg. BB gun prevention campaigns should be concentrated in March, prior to the April/May peak). PMID- 23669605 TI - Consumer perceptions about a community pharmacy-based medication take back program. AB - The stockpiling and improper disposal of unused or expired medications has the potential to harm the environment and humans. Community-based medication take back programs have been established to ensure proper disposal of unused drugs; however, few of these programs present consumers' perceptions about the program. Therefore, the main aims of this pilot study are 1) to assess the users' and non users' perceptions about a medication take-back program and 2) to determine if perceptions differ between users and non-users. The results are based on a survey administered to 35 users and 20 non-users of a medication take-back program located at a community pharmacy in Texas. The majority of users were participating in a take-back service for the first time. Though most non-users had never participated in a take-back program, they would consider participating in the future. All users viewed the medication take-back program as a valuable service, while nearly all (90%) non-users viewed the program as a potentially valuable service. The primary reason for participating in the service was to protect the environment. Most respondents (users and non-users) were likely to choose a pharmacy that provides the take-back service more than a pharmacy that does not. More than half of respondents positively viewed paying for the service on a per weight basis. In comparison to non-users, users were significantly older, had more favorable perceptions about paying for the service, and were more likely to choose a pharmacy that provides the service. This pilot study presents overall favorable user perceptions toward medication-take back services and supports the need to establish more community-based take back programs to meet the needs of consumers. PMID- 23669606 TI - Evaluation of oxidation and glyco-oxidation of 1-palmitoyl-2-arachidonoyl phosphatidylserine by LC-MS/MS. AB - Phosphatidylserine (PS) is an aminophospholipid found mainly in the plasma membranes of all mammalians cells, playing important roles in biological processes such as apoptosis and cell signaling. Due to the presence of a free amine group, under hyperglycemic conditions, PS can undergo glycation reaction, which may increase the susceptibility to oxidation. However, far too little attention has been paid to glycation and oxidation of PS. In this work we studied the oxidation, glycation and glyco-oxidation of 1-palmitoyl-2-arachidonoyl-sn glycero-3-phospho-l-serine (PAPS). PAPS and glycated PAPS were oxidized through a Fenton reaction and the oxidation products were monitored by ESI-MS in negative mode. Also, we developed a new sensitive liquid chromatography method coupled with tandem mass spectrometry (LC-MS/MS) to provide a complete profile of oxidized and glyco-oxidized PS. We were able to separate and identify several oxidation products of PAPS and glycated PAPS with modifications in unsaturated fatty acyl chain as long chain oxidation product (hydroxy and mono to tetra hydroperoxy derivatives), and short chain products with a shortened fatty acyl chain with C5 and C8 length and aldehyde or carboxylic terminal. We have also observed oxidation products arising from structural changes in the serine polar head, which lead to oxidation products with an acetic acid terminal (glycerophosphoacetic acid derivatives) and lysoPS species. Oxidation of glycated PAPS gave rise to several products involving oxidative cleavages of the glucose moiety, mainly between C1 and C2 of the sugar unit. These oxidation products with different polar head groups have shown distinct neutral loss fragmentation patterns. Simultaneous oxidative modifications of the polar head and the fatty acyl chains were also observed. The findings from this study contribute to an ongoing effort to detect PS oxidation and glyco-oxidation products in biological systems. PMID- 23669607 TI - Scheduled multiple reaction monitoring algorithm as a way to analyse new designer drugs combined with synthetic cannabinoids in human serum with liquid chromatography-tandem mass spectrometry. AB - Here, we describe the development and application of a liquid chromatography tandem mass spectrometry method with positive electrospray ionisation and scheduled multiple reaction monitoring algorithm (s-MRM) to analyse synthetic cannabinoids (SC) combined with new designer drugs (NDD) in human serum. A Luna 5MUm C18 (2) 100A, 150mm*2mm analytical column and a mobile phase consisted of A (H2O/methanol=95/5, v/v) and B (H2O/methanol=3/97, v/v) - both with 10mM ammonium acetate and 0.1% acetic acid (pH=3.2), were used for the separation. A binary flow pumping mode with a total flow rate of 0.400mL/min was used. A single sample extraction with 1-chlorobutane for both substance groups was performed. Acceptable linearity in the validated calibration ranges of 0.05-1ng/mL for SC and 1-50ng/mL for NDD was achieved. The limit of detection was not greater than 0.02/0.40ng/mL and the limit of quantification not greater than 0.05/0.50ng/mL for SC/NDD respectively. The presented study revealed that this method is a very effective way for sensitive SC and NDD identification in human serum and has useful application in hospitals, therapy centres and forensic psychiatric centres. S-MRM ensures a method upgrade with a smaller loss of sensitivity, precision and accuracy in comparison to traditional MRM methods. Also addition of new SC and NDD can be performed in the future. PMID- 23669608 TI - Preparation and characterization of sodium dodecyl sulfate doped polypyrrole solid phase micro extraction fiber and its application to endocrine disruptor pesticide analysis. AB - A robust in house solid-phase micro extraction (SPME) surface has been developed for the headspace (HS)-SPME determination of endocrine disruptor pesticides, namely, Chlorpyrifos, Penconazole, Procymidone, Bromopropylate and Lambda Cyhalothrin in wine sample by using sodium dodecylsulfate doped polypyrrole SPME fiber. Pyrrole monomer was electrochemically polymerized on a stainless steel wire in laboratory conditions in virtue of diminishing the cost and enhancing the analyte retention on its surface to exert better selectivity and hence the developed polymerized surface could offer to analyst to exploit it as a fiber in headspace SPME analysis. The parameters, mainly, adsorption temperature and time, desorption temperature, stirring rate and salt amount were optimized to be as 70 degrees C and 45min, 200 degrees C, 600rpm and 10gL(-1), respectively. Limit of detection was estimated in the range of 0.073-1.659ngmL(-1) for the pesticides studied. The developed method was applied in to red wine sample with acceptable recovery values (92-107%) which were obtained for these selected pesticides. PMID- 23669609 TI - Determination of antazoline hydrochloride in Beagle dog plasma by HPLC-UV and its application to pharmacokinetics. AB - In order to evaluate the pharmacokinetics characteristic of antazoline hydrochloride in Beagle dogs, a sensitive and specific HPLC method was developed and validated using phenacetin as the internal standard (IS). The analyte and the IS were extracted from dog plasma by ethyl acetate under the basic condition. The analyte was separated by a C18 column and detected with a variable wavelength UV detector. The mobile phase consisted of methanol-5mmolL(-1) tetrabutyl ammonium bromide (45:55, v/v) containing 0.5% glacial acetic acid in a flow rate of 1.0mLmin(-1). Standard calibration graph for antazoline was linear over a curve range of 20-1600ngmL(-1) (R>0.99) and the lower limit of quantification was 20ngmL(-1) using a plasma sample of 500MUL. The intra- and inter-day precision values were less than 14.3% relative standard deviation (RSD). The intra-day assay accuracy was in the range of 98.1-100.6% and the inter-day assay accuracy in the range of 99.2-101.1%. The extraction recoveries were on the average of 88.4% for antazoline and 76.8% for IS. Plasma samples were stable at least for 1 month at -20 degrees C. This method was successfully applied to pharmacokinetics study of antazoline after intravenous administration to Beagle dogs. PMID- 23669610 TI - Study on urinary profile of inborn errors of metabolism by 18-crown-6 modified capillary electrophoresis with laser-induced fluorescence detection. AB - Newborn screening in urine is important for the diagnosis of many inborn errors of metabolism (IEM). Capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) is a major technological advance in screening IEM. It has the advantage of sensitive and simultaneous multiple disease screening with minimal sample requirement. The analytes were derivatized with fluorescein isothiocyanate (FITC) prior to CE-LIF analysis. In urine samples, free amino acids (AAs) were well separated from other coexisting components, exhibiting a linear calibration over the concentration range 0.01-5.0MUmol/L with the limits of detection (LODs) ranging from 0.005 to 0.010MUmol/L. The relative standard deviations (RSDs) were in the range 0.1-1.0% for peak area, and 0.2-1.0% for migration time, respectively. Under optimized conditions, the method presented here has been successfully used for the simultaneous and sensitive analysis of seven AAs in urine samples of newborn babies, and evaluating the effect of therapy as well. PMID- 23669611 TI - Quantification of urinary folate catabolites using liquid chromatography-tandem mass spectrometry. AB - Folate catabolites p-aminobenzoylglutamate (pABG) and p-acetamidobenzoylglutamate (apABG) in human urine result from break-down of endogenous folate pools and are potential biomarkers of folate status. There is growing interest in analysis of these non-invasive indicators of folate status, since widespread diseases such as cancer, arteriosclerosis and dementia may be linked to disturbed availability of folates. Determination of pABG and apABG in human urine is challenging due to their low urinary concentrations and due to interferences with other urinary compounds. To address these analytical difficulties, we developed an improved LC MS/MS method with chemical derivatization for fast, selective and sensitive quantification of pABG and apABG in human urine. Forming butyl esters of urinary folate catabolites pABG and apABG improves ionization efficiency as well as enables selective chromatographic separation on standard C18 reversed-phase column material. In contrast to some previously proposed methods for folate catabolites, the new method allows precise differentiation of apABG from pABG. Partial degradation of apABG during derivatization is exactly accounted for using a second differentially labeled stable isotope internal standard. This method is highly sensitive and covers the full range of physiologically occurring concentrations (from 2 to 1000nmol/L), with volume requirements of only 80MUL urine. Method performance has been validated according to widely accepted standard recommendations. Use of two stable isotope-labeled internal standards and qualifier ion monitoring for both analytes ensure correct identification and unbiased quantification. With run times of less than 2.5min per sample and cost efficient sample preparation, this method allows exact quantitation of urinary folate catabolites pABG and apABG for large-scale non-invasive screening of folate status in clinical and epidemiological trials. PMID- 23669612 TI - Immunocapture and LC-MS/MS for selective quantification and differentiation of the isozymes of the biomarker neuron-specific enolase in serum. AB - NSE, neuron-specific enolase, is an important biomarker for several pathological conditions including small cell lung cancer (SCLC). The current paper presents an LC-MS/MS-based approach for quantification of NSE in serum at both reference levels and elevated levels. The analytical approach utilizes selective sample preparation by immunoextraction of all forms of NSE (alphagamma, gammagamma, and gamma) followed by tryptic digestion, and separation and detection by LC-SRM-MS. The quantification of NSE is performed through a signature peptide specific for the gamma-subunit of NSE (tryptic peptide gamma16; ELPLYR). The method is validated and shows satisfactory results (linearity r(2)>0.999 (range 5 500ng/mL), intra-day precision <13% RSD, and accuracy >95%), and has a limit of quantification (of 38pg/mL; S/N=10) significantly lower than endogenous levels of healthy subjects. In addition, the method simultaneously allows determination of the alphagamma-heterodimer through a signature peptide specific for the alpha subunit (tryptic peptide alpha12; TIAPALVSK). The method was successfully applied to serum samples from healthy blood donors. In all samples from healthy blood donors both the alpha- and the gamma-subunit was detected (S/N>200 for both signature peptides), confirming the presence of the alphagamma-heterodimer in these sample. The level in one of them was determined to be (n=5) 7.3+/-0.45ng/mL of gamma-subunit of NSE. PMID- 23669613 TI - Intrauterine temporomandibular joint dislocation: prenatal sonographic evaluation. AB - Congenital temporomandibular joint (TMJ) diseases are very rare disorders and are usually diagnosed in childhood. Developmental disorders of the TMJ such as hypoplasia, hyperplasia, and aplasia of the TMJ compartments are characterized by TMJ dysfunction. In childhood, these patients experience recurrent dislocation, pain, and malocclusion. We present the case of a 25-week fetus with unilateral TMJ dislocation with fluid retention in the joint diagnosed by ultrasonography. To the best of our knowledge, this is the first case of TMJ dislocation diagnosed by ultrasonographic evaluation during the prenatal period. PMID- 23669614 TI - Breast and prostate cancer survivors in a diabetic cohort: results from the Living with Diabetes Study. AB - OBJECTIVE: Diabetes is more common in cancer survivors than in the general population. The objective of the present study was to determine cancer frequency in a cohort of patients with diabetes and to examine demographic, clinical, and quality of life differences between cancer survivors and their cancer-free peers to inform better individualized care. METHODS: Self-reported survey data from 3,466 registrants with type 2 diabetes from Australia's National Diabetes Services Scheme (NDSS) were analyzed to compare relevant variables between cancer survivors and cancer-free patients. Analyses were focused on breast and prostate cancer to reflect the most common cancers in women and men, respectively. RESULTS: Five percent of diabetic women reported a history of breast cancer and 4.2% of men reported a history of prostate cancer. Diabetic patients with a history of breast or prostate cancer were older at time of survey and diabetes diagnosis, less likely to report metformin use (women), and more likely to have two or more comorbidities than their cancer-free peers. More diabetic prostate cancer survivors also reported problems with mobility and performing usual tasks. However, cancer-free diabetic subjects reported a lower diabetes-dependent quality of life than diabetic cancer survivors. There was no association between cancer survivorship and duration of diabetes, indices of glycemic control, obesity, or diabetic complications. CONCLUSIONS: Cancer survivors comprise a significant minority of diabetic patients that are particularly vulnerable and may benefit from interventions to increase screening and treatment of other comorbidities and promote a healthy lifestyle. PMID- 23669615 TI - Culture change in infection control: applying psychological principles to improve hand hygiene. AB - Hand hygiene occurs at the intersection of habit and culture. Psychological and social principles, including operant conditioning and peer pressure of conforming social norms, facilitate behavior change. Participatory leadership and level hierarchies are needed for sustainable patient safety culture. Application of these principles progressively and significantly improved hand hygiene compared with the hospital aggregate control. Changes to hand hygiene auditing and response processes demonstrate ability to improve and sustain adherence rates within a clinical microsystem. PMID- 23669616 TI - Social and emotional neuroscience. PMID- 23669617 TI - Delayed age of gilts at first mating associated with photoperiod and number of hot days in humid subtropical areas. AB - The objective of the present study was to quantify the associations between age at first mating (AFM) in gilts and the climatic factors of photoperiod (PP; h), number of hot days (HD) and relative humidity for different herd productivity groups. This study used records of 37,362 gilts born in 2007 and 2008 in 101 Japanese herds, which were classified into high-performing and ordinary herds based on the pigs weaned per mated female per year. The climate data were obtained from 21 weather stations. The HD was defined as the number of days that achieved a maximum temperature >25 degrees C. Average values of daily PP, relative humidity and HD from day 91 to 150 after birth of a gilt were coordinated with the respective gilt performance data. Two-level mixed-effects models were applied to the data by using a herd at level 2 and a gilt at level 1. Mean AFM (ranges), PP, HD and relative humidity were 247.9 days old (152-364 days old), 12.2h (9-15h), 18.7 days (0-60 days) and 68.4% (48-87%), respectively. Delayed AFM was associated with decreased PP, more HD and being in an ordinary herd (P<0.05), but not with relative humidity. As PP rose by an hour, the AFM in high-performing herds decreased by 1.13 days rather than that in ordinary herds. It is possible that AFM in replacement gilts could be hastened by improving light control and cooling management during hot days. PMID- 23669618 TI - A modeling study on the role of fungi in removing inorganic pollutants. AB - In this paper, a non-linear mathematical model for removing an inorganic pollutant such as chromium from a water body using fungi is proposed and analyzed. It is assumed that the inorganic pollutant is discharged in a water body with a constant rate, which is depleted due to natural factors as well as by fungal absorption using dissolved oxygen in the process. The model is analyzed by using stability theory of differential equations and simulation. The analysis shows that the inorganic pollutant can be removed from the water body by fungal absorption, the rate of removal depends upon the concentration of inorganic pollutant, the density of fungal population and various interaction processes. The simulation analysis of the model confirms the analytical results. It is noted here this theoretical result is qualitatively in line with the experimental observations of one of the authors (Sanghi). PMID- 23669619 TI - pH-sensitive micelles self-assembled from multi-arm star triblock co-polymers poly(epsilon-caprolactone)-b-poly(2-(diethylamino)ethyl methacrylate)-b poly(poly(ethylene glycol) methyl ether methacrylate) for controlled anticancer drug delivery. AB - A series of amphiphilic 4- and 6-armed star triblock co-polymers poly(epsilon caprolactone)-b-poly(2-(diethylamino)ethyl methacrylate)-b-poly(poly(ethylene glycol) methyl ether methacrylate) (4/6AS-PCL-b-PDEAEMA-b-PPEGMA) were developed by a combination of ring opening polymerization and continuous activators regenerated by electron transfer atom transfer radical polymerization. The critical micelle concentration values of the star co-polymers in aqueous solution were extremely low (2.2-4.0mgl(-1)), depending on the architecture of the co polymers. The self-assembled blank and doxorubicin (DOX)-loaded three layer micelles were spherical in shape with an average size of 60-220nm determined by scanning electron microscopy and dynamic light scattering. The in vitro release behavior of DOX from the three layer micelles exhibited pH-dependent properties. The DOX release rate was significantly accelerated by decreasing the pH from 7.4 to 5.0, due to swelling of the micelles at lower pH values caused by the protonation of tertiary amine groups in DEAEMA in the middle layer of the micelles. The in vitro cytotoxicity of DOX-loaded micelles to HepG2 cells suggested that the 4/6AS-PCL-b-PDEAEMA-b-PPEGMA micelles could provide equivalent or even enhanced anticancer activity and bioavailability of DOX and thus a lower dosage is sufficient for the same therapeutic efficacy. The results demonstrate that the pH-sensitive multilayer micelles could have great potential application in delivering hydrophobic anticancer drugs for improved cancer therapy. PMID- 23669620 TI - Melt-spun shaped fibers with enhanced surface effects: fiber fabrication, characterization and application to woven scaffolds. AB - Scaffolds with a high surface-area-to-volume ratio (SA:V) are advantageous with regard to the attachment and proliferation of cells in the field of tissue engineering. This paper reports on the development of novel melt-spun fibers with a high SA:V, which enhanced the surface effects of a fiber-based scaffold while maintaining its mechanical strength. The cross-section of the fibers was altered to a non-circular shape, producing a higher SA:V for a similar cross-sectional area. To obtain fibers with non-circular cross-sectional shape, or shaped fibers, three different types of metal spinnerets were fabricated for the melt-spinning process, each with circular, triangular or cruciform capillaries, using deep X ray lithography followed by nickel electroforming. Using these spinnerets, circular and shaped fibers were manufactured with biodegradable polyester, polycaprolactone. The SA:V increase in the shaped fibers was experimentally investigated under different processing conditions. Tensile tests on the fibers and indentation tests on the woven fiber scaffolds were performed. The tested fibers and scaffolds exhibited similar mechanical characteristics, due to the similar cross-sectional area of the fibers. The degradation of the shaped fibers was notably faster than that of circular fibers, because of the enlarged surface area of the shaped fibers. The woven scaffolds composed of the shaped fibers significantly increased the proliferation of human osteosarcoma MG63 cells. This approach to increase the SA:V in shaped fibers could be useful for the fabrication of programmable, biodegradable fiber-based scaffolds in tissue engineering. PMID- 23669621 TI - Helical sub-structures in energy-storing tendons provide a possible mechanism for efficient energy storage and return. AB - The predominant function of tendons is to position the limb during locomotion. Specific tendons also act as energy stores. Energy-storing (ES) tendons are prone to injury, the incidence of which increases with age. This is likely related to their function; ES tendons are exposed to higher strains and require a greater ability to recoil than positional tendons. The specialized properties of ES tendons are thought to be achieved through structural and compositional differences. However, little is known about structure-function relationships in tendons. This study uses fascicles from the equine superficial digital flexor (SDFT) and common digital extensor (CDET) as examples of ES and positional tendons. We hypothesized that extension and recoil behaviour at the micro-level would differ between tendon types, and would alter with age in the injury-prone SDFT. Supporting this, the results show that extension in the CDET is dominated by fibre sliding. By contrast, greater rotation was observed in the SDFT, suggesting a helical component to fascicles in this tendon. This was accompanied by greater recovery and less hysteresis loss in SDFT samples. In samples from aged SDFTs, the amount of rotation and the ability to recover decreased, while hysteresis loss increased. These findings indicate that fascicles in the ES SDFT may have a helical structure, enabling the more efficient recoil observed. Further, the helix structure appears to alter with ageing; this coincides with a reduction in the ability of SDFT fascicles to recoil. This may affect tendon fatigue resistance and predispose aged tendons to injury. PMID- 23669622 TI - High density type I collagen gels for tissue engineering of whole menisci. AB - This study investigates the potential of high density type I collagen gels as an injectable scaffold for tissue engineering of whole menisci, and compares these results with previous strategies using alginate as an injectable scaffold. Bovine meniscal fibrochondrocytes were mixed with collagen and injected into micro computed tomography-based molds to create 10 and 20mgml(-1) menisci that were cultured for up to 4weeks and compared with cultured alginate menisci. Contraction, histological, confocal microscopy, biochemical and mechanical analysis were performed to determine tissue development. After 4weeks culture, collagen menisci had preserved their shape and significantly improved their biochemical and mechanical properties. Both 10 and 20mgml(-1) menisci maintained their DNA content while significantly improving the glycosaminoglycan and collagen content, at values significantly higher than the alginate controls. Collagen menisci matched the alginate control in terms of the equilibrium modulus, and developed a 3- to 6-fold higher tensile modulus than alginate by 4weeks. Further fibrochondrocytes were able to reorganize the collagen gels into a more fibrous appearance similar to native menisci. PMID- 23669624 TI - Synergistic effect of surface modification and scaffold design of bioplotted 3-D poly-epsilon-caprolactone scaffolds in osteogenic tissue engineering. AB - The hydrophobic nature and the regular scaffold architecture of bioplotted poly(epsilon-caprolactone) (PCL) scaffolds present some hurdles for homogeneous tissue formation and differentiation. The current hypothesis is that a synergistic effect of applied surface modification and scaffold design enhances colonization and osteogenic differentiation. First, PCL scaffolds with a 0/90 degrees lay-down pattern (0/90) were plotted and subjected to an oxygen plasma (O2) or multistep surface modification, including post-argon 2-amino ethylmethacrylate grafting (AEMA), followed by immobilization of gelatin type B (gelB) and physisorption of fibronectin (gelB Fn). Secondly, scaffolds of different designs were plotted (0/90 degrees shift (0/90 S), 0/45 degrees and 0/90 degrees with narrow pores (0/90 NP)) and subjected to the double protein coating. Preosteoblasts were cultured on the scaffolds and the seeding efficiency, colonization and differentiation were studied. The data revealed that a biomimetic surface modification improved colonization (gelB Fn>gelB>AEMA>O2). Compact scaffold architectures (0/90 NP, 0/45, 0/90 S>0/90) positively influenced the seeding efficiency and differentiation. Interestingly, the applied surface modification had a greater impact on colonization than the scaffold design. In conclusion, the combination of a double protein coating with a compact design enhances tissue formation in the plotted PCL scaffolds. PMID- 23669625 TI - The emergence of an unusual stiffness profile in hierarchical biological tissues. AB - Biological tissues usually exhibit complex multiscale structural architectures. In many of these, and particularly in mineralized tissues, the basic building block is a staggered array-a composite material made of soft matrix and stiff reinforcing elements. Here we study the stiffness of non-overlapping staggered arrays, a case that has not previously been considered in the literature, and introduce closed-form analytical expressions for its Young's modulus. These expressions are then used to estimate the stiffness of natural staggered biocomposites such as low-mineralized collagen fibril and mineralized tendon. We then consider a two-scale composite scheme for evaluating the modulus of a specific hierarchical structure, the compact bone tissue, which is made of mineralized collagen fibrils with weakly overlapping staggered architecture. It is found that small variations in the staggered structure induce significant differences in the macroscopic stiffness, and, in particular, provide a possible explanation for the as yet unexplained stiffening effects observed in medium mineralized tissues. PMID- 23669626 TI - Unique crystallographic pattern in the macro to atomic structure of Herdmania momus vateritic spicules. AB - Biogenic vaterite is extremely rare. The only known example of a completely vateritic mineralized structure is the spicule of the solitary ascidian, Herdmania momus. In characterizing the structure of these spicules, using state of-the-art techniques such as synchrotron X-ray diffraction and synchrotron micro and nanotomography, we observed a continuous structural pattern from the macro down to the micro, nano, and atomic scales. We show that the spicules demonstrate a unique architecture composed of micron-sized, hexagonally faceted thorns organized in partial spirals along the cylinder-like polycrystalline body of the spicule, and tilted from it at an angle of about 26 degrees . This morphological orientation coincides with the crystallographic orientation relationship between each thorn and the polycrystals within the spicule. Hence the entire spicule grows along the [011] direction of vaterite while the individual thorns grow along the [001] direction. This, together with the presence of both inter- and intra-crystalline organic phases, beautifully displays the organism's ability to achieve perfect control of mineralization biologically while employing an unstable polymorph of calcium carbonate: vaterite. PMID- 23669623 TI - Osteolysis around total knee arthroplasty: a review of pathogenetic mechanisms. AB - Aseptic loosening and other wear-related complications are some of the most frequent late reasons for revision of total knee arthroplasty (TKA). Periprosthetic osteolysis (PPOL) pre-dates aseptic loosening in many cases, indicating the clinical significance of this pathogenic mechanism. A variety of implant-, surgery- and host-related factors have been delineated to explain the development of PPOL. These factors influence the development of PPOL because of changes in mechanical stresses within the vicinity of the prosthetic device, excessive wear of the polyethylene liner, and joint fluid pressure and flow acting on the peri-implant bone. The process of aseptic loosening is initially governed by factors such as implant/limb alignment, device fixation quality and muscle coordination/strength. Later, large numbers of wear particles detached from TKA trigger and perpetuate particle disease, as highlighted by progressive growth of inflammatory/granulomatous tissue around the joint cavity. An increased accumulation of osteoclasts at the bone-implant interface, impairment of osteoblast function, mechanical stresses and increased production of joint fluid contribute to bone resorption and subsequent loosening of the implant. In addition, hypersensitivity and adverse reactions to metal debris may contribute to aseptic TKA failure, but should be determined more precisely. Patient activity level appears to be the most important factor when the long-term development of PPOL is considered. Surgical technique, implant design and material factors are the most important preventative factors, because they influence both the generation of wear debris and excessive mechanical stresses. New generations of bearing surfaces and designs for TKA should carefully address these important issues in extensive preclinical studies. Currently, there is little evidence that PPOL can be prevented by pharmacological intervention. PMID- 23669627 TI - Control of aragonite deposition in colonial corals by intra-skeletal macromolecules. AB - Scleractinian coral skeletons are composed mainly of aragonite in which a small percentage of organic matrix (OM) molecules is entrapped. It is well known that in corals the mineral deposition occurs in a biological confined nucleation site, but it is still unclear to what extent the calcification is controlled by OM molecules. Hence, the shape, size and organization of skeletal crystals from the fiber level through the colony architecture, were also attributed to factors as diverse as nucleation site mineral supersaturation and environmental factors in the habitat. In this work the OMs were extracted from the skeleton of three colonial corals, Acropora digitifera, Lophelia pertusa and Montipora caliculata. A. digitifera has a higher calcification rate than the other two species. OM molecules were characterized and their CaCO3 mineralization activity was evaluated by experiments of overgrowth on coral skeletons and of precipitation from solutions containing OM soluble and insoluble fractions and magnesium ions. The precipitates were characterized by spectroscopic and microscopic techniques. The results showed that the OM molecules of the three coral share similar features, but differ from those associated with mollusk shells. However, A. digitifera OM shows peculiarities from those from L. pertusa and M. caliculata. The CaCO3 overgrowth and precipitation experiments confirm the singularity of A. digitifera OM molecules as mineralizers. Moreover, their comparison indicates that only specific molecules are involved in the polymorphism control and suggests that when the whole extracted materials are used the OM's main effect is on the control of particles' shape and morphology. PMID- 23669628 TI - Periconceptional use of folic acid and risk of miscarriage - findings of the Oral Cleft Prevention Program in Brazil. AB - OBJECTIVE: We report on the risk of miscarriage with high- and low-dosage periconceptional folic acid (FA) supplementation from a double-blind randomized clinical trial for prevention of orofacial cleft recurrence in Brazil. METHODS: Women at risk of recurrence of orofacial clefts in their offspring were randomized into high (4 mg/day) and low (0.4 mg/day) doses of FA supplementation. The women received the study pills before pregnancy, and supplementation continued throughout the first trimester. Miscarriage rates were compared between the two FA groups and with the population rate. RESULTS: A total of 268 pregnancies completed the study protocol, with 141 in the 4.0-mg group and 127 in the 0.4-mg group. The miscarriage rate was 14.2% in the low-dose FA group (0.4 mg/day) and 11.3% for the high-dose group (4 mg/day) (P=0.4877). These miscarriage rates are not significantly different from the miscarriage rate in the Brazilian population, estimated to be around 14% (P=0.311). CONCLUSIONS: These results indicate that high-dose FA does not increase miscarriage risk in this population and add further information to the literature on the safety of high FA supplementation for prevention of birth defect recurrence. PMID- 23669630 TI - [Massive pericardial effussion after a Neisseria meningitidis infection]. PMID- 23669631 TI - Enantioselective esterification of ibuprofen under microwave irradiation. AB - Enantioselective esterification of ibuprofen has been successfully carried out in an organic solvent catalyzed by recombinant APE 1547 (a thermophilic esterase from the archaeon Aeropyrum pernix K1). Here we used microwave irradiation (MW) as the mode of heating to improve the enzyme performance. Under the optimum conditions, the enzyme activity of APE 1547 was 4.16 MUmol/mg/h and the enantioselectivity (E value) was 52.9. Compared with conventional heating, the enzyme activity and the enantioselectivity were increased about 21.9-fold and 1.4 fold, respectively. The results also indicated that APE 1547 can maintain 95% of its activity even after being used five times, suggesting that the enzyme is stable under low power MW conditions. PMID- 23669629 TI - The first 7 days of a quit attempt predicts relapse: validation of a measure for screening medications for nicotine dependence. AB - OBJECTIVES: There is a critical need for the development of novel treatments for nicotine dependence. Because the majority of smokers who make a quit attempt fail within 7 days, medication screening procedures that focus on this early cessation period may provide an indicator of treatment efficacy. To establish the clinical validity of this paradigm, it is critical to demonstrate the association of early abstinence with longer-term abstinence. We tested the number of days of abstinence during the first week after the target quit date (TQD) as a predictor of point prevalence abstinence in 3 independent pharmacotherapy trials for nicotine dependence. METHODS: This was a secondary data analysis of 3 randomized clinical trials: a placebo-controlled trial of transdermal nicotine (N = 545); an open-label nicotine replacement therapy (patch vs spray) trial (N = 566); and a bupropion placebo-controlled trial (N = 538). In separate logistic regression models, the maximum number of consecutive days of abstinence during the first week after the TQD was used to predict biochemically verified 7-day point prevalence abstinence at the end of treatment (EOT) and 6 months post-TQD. RESULTS: Across the 3 trials, the number of days of abstinence significantly predicted abstinence at EOT and 6 months (odds ratios > 1.4; Ps < 0.0001). Likewise, not having any lapse during the first week predicted abstinence at EOT and 6 months (odds ratios > 4.7; Ps < 0.0001). CONCLUSIONS: The first week of abstinence was highly predictive of EOT and long-term abstinence. Medication screening procedures that focus on this early abstinence period (ie, 6 or 7 days of consecutive abstinence) represent a valid tool for assessing the presence of a signal for medication efficacy. PMID- 23669632 TI - Synthesis, antifungal and antitumor activity of novel (Z)-5-hetarylmethylidene 1,3-thiazol-4-ones and (z)-5-ethylidene-1,3-thiazol-4-ones. AB - New hetaryl- and alkylidenerhodanine derivatives 3a-d, 3e, and 4a-d were prepared from heterocyclic aldehydes 1a-d or acetaldehyde 1e. The treatment of several rhodanine derivatives 3a-d and 3e with piperidine or morpholine in THF under reflux, afforded (Z)-5-(hetarylmethylidene)-2-(piperidin-1-yl)thiazol-4(5H)-ones and 2-morpholinothiazol-4(5H)-ones 5a-d, 6a-d, and (Z)-5-ethylidene-2 morpholinothiazol-4(5H)-one (5e), respectively, in good yields. Structures of all compounds were determined by IR, 1D and 2D NMR and mass spectrometry. Several of these compounds were screened by the U.S. National Cancer Institute (NCI) to assess their antitumor activity against 60 different human tumor cell lines. Compound 3c showed high activity against HOP-92 (Non-Small Cell Lung Cancer), which was the most sensitive cell line, with GI50 = 0.62 MUM and LC50 > 100 MUM from the in vitro assays. In vitro antifungal activity of these compounds was also determined against 10 fungal strains. Compound 3e showed activity against all fungal strains tested, but showed high activity against Saccharomyces cerevisiae (MIC 3.9 MUg/mL). PMID- 23669633 TI - Synthesis and biological evaluation of 3-benzisoxazolyl-4-indolylmaleimides as potent, selective inhibitors of glycogen synthase kinase-3beta. AB - A series of novel 3-benzisoxazolyl-4-indolyl-maleimides were synthesized and evaluated for their GSK-3beta inhibitory activity. Most compounds exhibited high inhibitory potency towards GSK-3beta. Among them, compound 7j with an IC50 value of 0.73 nM was the most promising GSK-3beta inhibitor. Preliminary structure activity relationships were examined and showed that different substituents on the indole ring and N1-position of the indole ring had varying degrees of influence on the GSK-3beta inhibitory potency. Compounds 7c, 7f, 7j-l and 7o-q could obviously reduce Abeta-induced Tau hyperphosphorylation by inhibiting GSK 3beta in a cell-based functional assay. PMID- 23669634 TI - Synthesis of a new ent-cyclozonarone angular analog, and comparison of its cytotoxicity and apoptotic effects with ent-cyclozonarone. AB - The synthesis of a newangular analog 11 of cyclozonarone was achieved via Diels Alder reaction between a sesquiterpene-1,3-diene and 1,4-benzoquinone. The cytotoxic activity of ent-cyclozonarone [(+)-10] and the angular (-) cyclozonarone analog 11 has been determined in three human cancer cell lines and in normal fibroblasts using the sulforhodamine B assay. The analyzed isomers induce cell death in different cancer cell lines by eliciting nuclear condensation and fragmentation, decreasing mitochondrial membrane permeability and increasing caspase-3 activity, all traits indicating apoptosis, with the effects of (+)-10 being stronger than those of 11 in all cases. PMID- 23669635 TI - Do vitamin A serum levels moderate outcome or the protective effect of vitamin D on outcome from malignant melanoma? AB - BACKGROUND & AIMS: Low serum vitamin D levels (25-OH-vit D2/3) are reported to be associated with thicker melanomas and poorer outcome. Vitamin A metabolites and vitamin D bind to the same heterodimeric receptor. We report a study testing the hypothesis that high vitamin A levels may reduce the protective effect of vitamin D on outcome. METHODS: Serum vitamin A levels were measured in 795 melanoma cases and assessed for association with Breslow thickness, overall (OS) and melanoma specific survival (MSS), and modification of the effect of vitamin D levels on survival. RESULTS: Higher vitamin A levels (>= 2.2 MUmol/l) conferred a non significant increased risk of melanoma-specific death (adjusted HR = 1.11, 95%CI(0.74-1.67), p = 0.60) but not for death overall (adjusted HR = 0.95, 95%CI(0.65-1.39), p = 0.79). There was reduction in the protective effect of vitamin D on OS in patients with high vitamin A levels (>= 2.2 MUmol/l)(HR = 0.99, 95%CI(0.72-1.36),p = 0.93) compared to patients with low levels (<2.2 MUmol)(HR = 0.77, 95%CI(0.64-0.93),p = 0.007), although the difference was not statistically significant (p = 0.26). CONCLUSIONS: High vitamin A levels may reduce the protective effect of vitamin D. As sub-optimal levels of vitamin D are common in temperate climates, and are usually managed by dietary supplementation, we suggest vitamin D3 supplementation alone might be preferable for melanoma patients than preparations containing vitamin D and A. PMID- 23669637 TI - Dynamic connectivity laterality of the amygdala under negative stimulus in depression: a MEG study. AB - Depression is a mental disorder characterized by emotional and cognitive dysfunction, which is related to the abnormal activity in brain regions involving emotion processing such as amygdala (AMYG). The laterality of AMYG during emotional information processing has always been a controversial issue in any depression study, however, the dynamic characteristic of laterality in the AMYG has been ignored. In this paper, we proposed to explore the time-varying functional coupling between the anterior cingulate cortex (ACC) and the bilateral AMYG in the time-frequency domain. As a result, an emotional facial expression paradigm was undertaken in this study. Using magnetoencephalogram (MEG) data acquired from 16 patients with major depression disorder and 16 matched healthy controls, we calculated the wavelet coherence. The research led to the conclusion that, after sad facial stimuli, the ACC-bilateral AMYG connectivity in depressive patients showed a significant decrease in the beta band during the first 100 ms. In addition, the ACC-left AMYG connectivity led to a significant increase in the gamma band around 400 ms and in beta band around 700 ms. Our work suggests a lack of sufficient inhibition of the ACC on the bilateral AMYG in the early period and the lateralized dysregulation of the ACC on the left AMYG in late period during the sad facial information processing task. We hypothesized that the clinical manifestations of depression may partly result from it. PMID- 23669636 TI - alpha-Synuclein mutations cluster around a putative protein loop. AB - With the recent identification of two new pathogenic mutations in alpha synuclein, we map the five known pathogenic mutations onto the best available models of the protein structure. We show that four of the five mutations map to a potential fold in the protein with the exception being the A30P mutation in which the substitution would be expected to have a profound effect on protein structure. We discuss this localisation in terms of the proposed mechanisms for mutation pathogenicity. PMID- 23669638 TI - Ectopic hair cell-like cell induction by Math1 mainly involves direct transdifferentiation in neonatal mammalian cochlea. AB - Math1, also known as Atoh1, is a basic helix-loop-helix transcription factor that plays a key role in hair cells (HCs) development. Previous studies have reported that Math1 gene transfer could induce the production of ectopic hair cell-like cells both in vitro and in vivo. Here, we focused on the mechanism of ectopic hair cell-like cellular differentiation from cells in the lateral epithelial ridge (LER) of cochlea with a human adenovirus serotype 5 (Ad5) vector encoding both Math1 and the reporter gene EGFP. Within the Ad5-EGFP-Math1 infection, hair cell like cells could be detected in the LER. 5'-Bromo-2' deoxyuridine (BrdU) incorporation test results at different time points suggested that LER cells possessed high potential to proliferation, but they could not transdifferentiate into hair cells spontaneously. Almost all of Math1 induced hair cell-like cells were BrdU negative when BrdU incorporation occurred after Math1 expression. In conclusion, Math1 induced hair cell-like cells from LER cells mainly underwent direct trans-differentiation instead of mitosis of LER cells or newly hair cell like cells. PMID- 23669639 TI - Pinocembrin protects brain against ischemia/reperfusion injury by attenuating endoplasmic reticulum stress induced apoptosis. AB - Endoplasmic reticulum stress (ER stress) is known to play a vital role in mediating ischemic reperfusion damage in brain. Our previous studies showed that pinocembrin alleviated cerebral ischemic injury in ischemia/reperfusion and vascular dementia animal models, but whether attenuation of ER stress-induced apoptosis contributes to the mechanisms remains to be elucidated. In this study, an attempt was therefore made to investigate the modulation effect of pinocembrin on ischemia/reperfusion-induced ER stress in brain. Focal cerebral ischemia/reperfusion rats were induced by middle cerebral artery occlusion (MCAO) for 2h followed by 6h reperfusion. Pinocembrin was administered in different doses (1mg/kg, 3mg/kg, and 10mg/kg, respectively) at the same time of onset of reperfusion. Neurological function and brain infarction were evaluated. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method, and flow cytometer (FCM) were used to investigate cell apoptosis in penumbra cortex. DNA fragmentation assay was also performed using electrophoresis. The expression of ER stress proteins of GRP78, CHOP/GADD153, ATF4, eIF2alpha phosphorylation was detected by western blot, and caspase-12 was evaluated by immunohistochemical analysis. Our results demonstrate that pinocembrin-treatment (3mg/kg and 10mg/kg) significantly reduced neurological deficit scores, infarct volume, and neuron apoptosis in the ischemia/reperfusion rats. It can also significantly modulate the protein levels by increasing GRP78 (10mg/kg) and attenuating CHOP/GADD153 expression along with caspase-12 activation (3mg/kg and 10mg/kg). At the same time, eIF2alpha phosphorylation was restrained and the expression of ATF4 was reduced (3mg/kg and 10mg/kg). These results suggest that the attenuation of ER stress induced apoptosis may be involved in the mechanisms of pinocembrin. PMID- 23669640 TI - Upregulated acetylcholine synthesis during early differentiation in the embryonic stem cell line CGR8. AB - Stem cells are used to generate differentiated somatic cells including neuronal cells. Synthesis and release of acetylcholine, a neurotransmitter and widely expressed signaling molecule, were investigated in the murine embryonic stem cell line CGR8 during early differentiation, i.e. in the presence of leukemia inhibitory factor (LIF) to maintain pluripotency and in the absence of LIF to induce early differentiation. CGR8 cells express choline acetyltransferase (ChAT) as demonstrated by measurement of enzyme activity and substantial inhibition by bromoacetylcholine. Pluripotent CGR8 cells showed a ChAT activity of 250 pmol acetylcholine/mg/h, contained 1.1 pmol acetylcholine/106 cells and released about 12.00 pmol acetylcholine/1 x 106 cells/6 h. Removal of LIF induced early differentiation as evidenced by reduced transcription factors Oct-4 and Nanog and a substantial slowing of the proliferation rate. Under this condition acetylcholine synthesis increased to 1640 pmol/mg/h; related to the pluripotent state the content of acetylcholine increased 10-fold and the release to about 32 pmol acetylcholine/1 x 106 cells/6 h. Enzyme kinetic analysis showed a significant increase of the K(m) for the precursor acetyl-CoA and of V(max) without a change of the K(m) for the precursor choline. In conclusion, early differentiation of the stem cell line CGR8 is associated with a substantial increase in ChAT activity and acetylcholine release. PMID- 23669641 TI - Scopolamine modulates paternal parental retrieval behavior in mice induced by the maternal mate. AB - Appropriate parental care by the father can greatly facilitate healthy human family life. Much less is known from animal studies about the factors leading to paternal parental care than those favoring maternal parent care. Recently, we have reported that sires of the ICR strain of laboratory mice can express maternal-like retrieval behavior when separated from their pups through ultrasound and pheromonal signals from the dam, i.e. mate-dependent parental care. The sire's retrieval behavior was inhibited by prior treatment of scopolamine, a muscarinic cholinergic inhibitor, and recovered by physostigmine. KCNQ K(+)-channel blocking and enhancing drugs, linopiridine and retigabine, were also examined. Linopiridine alone did not enhance care after pairing with the dam, nor change scopolamine-induced inhibition of care. Retigabine totally suppressed parental care, and this effect was partially rescued by co administration of linopiridine. These results indicate the involvement of cholinergic cellular signaling in the central nervous system in the maternal induction of paternal parental behavior in ICR mice. PMID- 23669642 TI - NF-kappaB activity is inversely correlated to RNF11 expression in Parkinson's disease. AB - RING finger protein 11 (RNF11), a negative regulator of NF-kappaB signaling pathway, colocalizes with alpha-synuclein and is sequestered in Lewy bodies in Parkinson's disease (PD). Since persistent NF-kappaB activation is reported in PD, in this report we investigated if RNF11 expression level is correlated to activated NF-kappaB in PD. We examined RNF11 expression levels in correlation to phospho-p65, a marker for activated NF-kappaB, in control and PD brain tissue from cerebral cortex. In addition we performed double immunofluorescence labeling experiments to confirm this correlation. Our investigations demonstrated that the neuronal RNF11 expression was down-regulated in PD and was usually associated with increased expression of phospho-p65. Double labeling confirmed that loss of neuronal RNF11 was linked to increased phospho-p65 expression, suggesting that persistent presence of NF-kappaB activation could be due to decreased levels of its negative regulator. Our data exemplifies the relevance of RNF11 and persistent NF-kappaB activation in PD. PMID- 23669643 TI - Curcumin promotes nerve regeneration and functional recovery in rat model of nerve crush injury. AB - BACKGROUND AND AIM: Curcumin at 100mg/kg has been shown to have a protective effect on crush nerve injury. However, it is unclear whether the protective effect of curcumin on nerve injury is dose dependent. The present study was designed to investigate such a possibility. METHODS: The rats subjected to crush nerve injury were intraperitoneally administrated daily for 4 weeks with curcumin (50 mg/kg, 100 mg/kg and 300 mg/kg), or 100 MUg/kg mecobalamin or normal saline, respectively. The axonal regeneration was investigated by retrograde labeling and morphometric analysis. The motor functional recovery was evaluated by electrophysiological studies, behavioral tests and histological appearance of the target muscles. RESULTS: Our data showed that curcumin and mecobalamin achieved better nerve regeneration and functional recovery than vehicle group. In addition, high doses of curcumin (100 mg/kg and 300 mg/kg) showed better performance in promoting nerve regeneration and functional recovery than low dose of curcumin (50 mg/kg). CONCLUSIONS: Curcumin is capable of promoting nerve regeneration after nerve injuries, highlighting the therapeutic values of curcumin as a neuroprotective drug for peripheral nerve repair applications. PMID- 23669644 TI - Copper enhances APP dimerization and promotes Abeta production. AB - Alzheimer's disease (AD) is characterized by the deposition of amyloid-beta (Abeta) plaques, senile plaque. The Abeta peptide is cleaved from amyloid precursor protein (APP) by beta-secretase and gamma-secretase. Until now, many literatures have documented that the high concentration of copper is present in Abeta plaques and enhances aggregation of. The APP copper binding domain (CuBD) is located in the N-terminal next to the growth factor-like domain that gets involved in APP homodimerization. Importantly, dimerization of APP has profound effect on Abeta production. We investigated whether copper alters the state of APP dimerization and how it affects APP metabolism. Here, we demonstrate that copper enhanced APP dimerization and increased extracellular release of Abeta. Moreover, copper chelator, D-penicillamine, suppressed APP dimerization and decreased extracellular release of Abeta. These results suggest that the action of copper may be profoundly associated with the pathway of Abeta production in AD pathogenesis. PMID- 23669645 TI - Neurobehavioral deficits of epidermal growth factor-overexpressing transgenic mice: impact on dopamine metabolism. AB - Epidermal growth factor (EGF) and its family member neuregulin-1 are implicated in the etiology of schizophrenia. Our recent pharmacological studies indicate that EGF injections to neonatal and adult rats both induce neurobehavioral deficits relevant to schizophrenia. We, however, did not evaluate the genetic impact of EGF transgene on neurobehavioral traits. Here we analyzed transgenic mice carrying the transgene of mouse EGF cDNA. As compared to control littermates, heterozygous EGF transgenic mice had an increase in EGF mRNA levels and showed significant decreases in prepulse inhibition and context-dependent fear learning, but there were no changes in locomotor behaviors and sound startle responses. In addition, these transgenic mice exhibited higher behavioral sensitivity to the repeated cocaine injections. There were neurochemical alterations in metabolic enzymes of dopamine (i.e., tyrosine hydroxylase, dopa decarboxylase, catechol-O-methyl transferase) and monoamine contents in various brain regions of the EGF transgenic mice, but there were no apparent neuropathological signs in the brain. The present findings rule out the indirect influence of anti-EGF antibody production on the reported behavioral deficits of EGF-injected mice. These results support the argument that aberrant hyper-signals of EGF have significant impact on mouse behavioral traits and dopamine metabolism. PMID- 23669646 TI - The associations of body image, anxiety, and smoking among Mexican-origin youth. AB - PURPOSE: Among Mexican-origin teenagers, anxiety is associated with cigarette experimentation, while among girls and young women from other ethnic groups the desire to be thin is associated with smoking. However, little is known about the associations of body image concerns with smoking in Mexican-origin youth, particularly when accounting for anxiety. METHODS: In 2005-2006, 1,328 Mexican origin adolescents aged 11 to 13 years enrolled in a cohort study to examine nongenetic and genetic factors associated with cigarette experimentation. In 2008 2009, 1,154 participants completed a follow-up when they reported their smoking status, anxiety, and body image. Height and weight were measured. In 2010-2011, 1,001 participants completed another follow-up when they reported their smoking status. Multivariate multinomial regression models were computed to examine associations between smoking behavior assessed in 2010-2011 and body image score, anxiety, and body mass index assessed in 2008-2009, controlling for gender, country of birth, age, and parental education. RESULTS: Of the 892 participants with complete data, 48% were boys, 74% were U.S.-born and in 2008-2009, were 14.29 years (SD = 1) old. Having smoked less than a whole cigarette was associated with being male (OR = 1.53), older age (OR = 1.42), a body mass index <85th percentile (OR = 1.93), and poor body image (OR = 1.12). Having smoked more than one cigarette was associated with being male (OR = 3.54), older age (OR = 1.86), anxiety (OR = 1.04), and poor body image (OR = 1.11). CONCLUSIONS: Poor body image and anxiety were independently associated with cigarette experimentation among Mexican-origin youth. Implications for the design of culturally appropriate smoking prevention messages are discussed. PMID- 23669647 TI - The cost of implementing a 2-1-1 call center-based cancer control navigator program. AB - OBJECTIVES: Determine the cost of implementing a call center-based cancer screening navigator program. METHODS: Social service call centers in Houston and Weslaco, TX, assessed cancer risks and implemented cancer screening promotion and navigation. Micro costing was used to estimate the program costs. Staff logs and call records tracked personnel time and material costs, including a standard 30% overhead rate. Sensitivity analysis examined the effect of varying uncertain cost parameters. Scale effects were simulated for larger population coverage. RESULTS: The total cost to recruit and navigate 732 persons, out of 2933 individuals who called the center was $215,847. The participant time cost was $19,503, and the personnel cost was $116,523. The cost per navigated participant was $295 (95% CI, $290.56-$298.07). The average cost per participant for recruitment and referral only, was $36 (95% CI, $34.9-$36.9). Average cost declines to $34 for recruitment and referral, and to $225 for recruitment, referral, and navigation when the number of participants increases to 15,000 individuals. CONCLUSIONS: Expanding 2 1-1 referral services with opportunistic cancer screening promotion takes advantage of existing infrastructure but requires substantial additional staff time, participant time, and budget. Cost estimation is the first step in a full economic evaluation and informs program planners and decision-makers on the resource and budgetary requirements of this innovative strategy for increasing cancer screening in low income communities. PMID- 23669648 TI - Femoral neck fracture after removal of the compression hip screw from healed intertrochanteric fractures. AB - OBJECTIVES: To evaluate the incidence of femoral neck fracture (FNF) after removal of a compression hip screw (CHS) without trauma and to determine the risk factors for this type of fracture. DESIGN: Retrospective study of consecutive patient series. SETTING: University teaching hospital. PATIENTS: Sixty-seven patients with a mean age of 65.3 years (45 women and 22 men). INTERVENTION: A total of 67 implants were removed in the presence of bony consolidation of the fracture site; most of them were due to hardware pain. MAIN OUTCOME MEASURES: The incidence of FNF after a CHS removal, clinical parameters (age, gender, bone mineral density, body mass index, and fracture stability), and radiologic parameters (the femoral neck-shaft angle, femoral neck width, distance between thread of lag screw, and neck cortex). Univariate analysis was performed for those parameters of the fracture group and the nonfracture group. To assess which variables were associated with FNF, a multiple logistic regression was used. RESULTS: Six (9.0%) FNFs occurred within 1 month after a CHS removal. The mean anterior and lateral neck widths were significantly smaller, and the mean anterior and inferior thread-to-cortex distances were significantly shorter in the fracture group compared with the nonfracture group. The risk factor significantly associated with FNF was the inferior thread-to-cortex distance (odds ratio, 0.462; 95% confidence interval, 0.217-0.988). CONCLUSIONS: CHS should not be removed routinely due to the risk of FNF. Furthermore, attention should be paid to at-risk patients with a hip screw positioned close to the inferior femoral neck cortex. LEVEL OF EVIDENCE: Prognostic level II. PMID- 23669649 TI - Molecular insights of the first gastropod TLR counterpart from disk abalone (Haliotis discus discus), revealing its transcriptional modulation under pathogenic stress. AB - Toll-like receptors (TLRs) are well-characterized pattern recognition receptors of innate immunity, known to induce immune responses against the pathogens by interacting with evolutionarily conserved pathogen-associated molecular patterns (PAMPs). In this study, a novel TLR homolog from disk abalone (Haliotis discus discus) was identified and characterized at molecular level. The open reading frame (ORF) of AbTLR is 3804 bp in length and encodes a 1268 amino acid peptide with a calculated molecular mass of 143.5 kDa. The deduced protein shows typical TLR domain architecture, with leucine rich repeats (LRR) and the toll-interleukin receptor (TIR) domain. Phylogenetic analysis revealed a close evolutionary relationship for AbTLR to its invertebrate counterparts, with close clustering to the molluscan homologs. Quantitative real-time PCR detected ubiquitous transcription of AbTLR in healthy tissues, but with highest levels in hemocytes. Differential transcriptional modulation of AbTLR was observed in abalone hemocytes and gills upon immune challenge, whereby Vibrio parahaemolyticus and purified lipopolysaccharide (LPS) enhanced the transcript level prominently. In addition, the viral hemorrhagic septicemia virus induced AbTLR transcription in hemocytes and gills, representing the first evidence of viral-induced immune response in mollusks to date. Collectively, our findings support a putative role for AbTLR in abalone antiviral and antibacterial defense. PMID- 23669650 TI - Comparison of different screening tools (FRAX(r), OST, ORAI, OSIRIS, SCORE and age alone) to identify women with increased risk of fracture. A population-based prospective study. AB - PURPOSE: To compare the power of FRAX(r) without bone mineral density (BMD) and simpler screening tools (OST, ORAI, OSIRIS, SCORE and age alone) in predicting fractures. METHODS: This study was a prospective, population-based study performed in Denmark comprising 3614 women aged 40-90 years, who returned a questionnaire concerning items on risk factors for osteoporosis. Fracture risk was calculated using the different screening tools (FRAX(r), OST, ORAI, OSIRIS and SCORE) for each woman. The women were followed using the Danish National Register registering new major osteoporotic fractures during 3 years, counting only the first fracture per person. Area under the receiver operating characteristic curve (ROC) and statistics and Harrell's index were calculated. Agreement between the tools was calculated by kappa statistics. RESULTS: A total of 4% of the women experienced a new major osteoporotic fracture during the follow-up period. There were no differences in the area under the curve (AUC) values between FRAX(r) and the simpler tools; AUC values between 0.703 and 0.722 (p = 0.86). Also, Harrell's C values were very similar between the tools. Agreement between the tools was modest. CONCLUSION: During 3 years follow-up FRAX(r) did not perform better in the fracture risk prediction compared with simpler tools such as OST, ORAI, OSIRIS, SCORE or age alone in a screening scenario where BMD was not measured. These findings suggest that simpler models based on fewer risk factors, which would be easier to use in clinical practice by the GP or the patient herself, could just as well as FRAX(r) be used to identify women with increased risk of fracture. SUMMARY: Comparison of FRAX(r) and simpler screening tools (OST, ORAI, OSIRIS, SCORE) in predicting fractures indicate that FRAX(r) did not perform better in fracture risk prediction compared with the simpler tools or even age alone in a screening scenario without bone mineral density assessment. PMID- 23669651 TI - Ultrasound assessment of sural nerve in Charcot-Marie-Tooth 1A neuropathy. AB - OBJECTIVE: Nerve ultrasound (US) has been used to study peripheral nerve disease, and increase of the cross-sectional area (CSA) has been described in demyelinating polyneuropathy. The objective of the current study is to characterise the US features of the sural nerve in a sample of Charcot-Marie Tooth (CMT) 1A patients. METHODS: A total of 20 CMT1A patients were enrolled. As control group we studied 37 age- and sex-matched subjects. All patients underwent clinical examination, neurophysiology and US evaluation of the bilateral sural nerve and right ulnar nerve. US results were correlated with neurophysiology and clinical data. RESULTS: Sural nerve CSA was not increased in the majority of patients (70%), whereas an increased ulnar nerve CSA was present in the whole sample. Inverse relations were found between CSA of the ulnar nerve and body mass index (BMI) (p<0.0002, R=-0.8) and CSA of the sural nerve and age (right 0.006, R=-0.6, left 0.002, R=-0.6 and left and right p=0.00003, R=-0.4). CONCLUSIONS: US showed ulnar CSA enlargement and normal sural nerve CSA. SIGNIFICANCE: The significance of normal sural nerve CSA in CMT1A patients need to be further investigated, possibly through longitudinal studies. PMID- 23669652 TI - Removal of uranyl ions in aquatic mediums by using a new material: gallocyanine grafted hydrogel. AB - A new material containing gallocyanine (GC) grafted polyacyril amide (PAA) was synthesized and its adsorption ability was examined for the removal of uranyl ions from aqueous media. The new developed adsorbent was characterized by FTIR, SEM, and PZC analysis. Adsorption of UO2(2+) ions from aqueous solution as a function of ion concentration, pH, ionic strength, temperature, and reusability of adsorbent was investigated in detail. The adsorption data were analyzed by using the Langmuir, Freundlich and Dubinin-Radushkevich (DR) models. The adsorption of UO2(2+) increased with pH and reached a plateau value in the pH range 5-6. The adsorption of UO2(2+) ions were not affected by increasing ionic strength. The adsorption mechanism followed an endothermic and spontaneous process with increased disorderliness at adsorbate/adsorbent interface. The adsorption process followed a pseudo-second-order kinetics. The new developed material is a potential adsorbent for effective removal of uranyl ions from aquatic solutions. PMID- 23669653 TI - Methysergide attenuates systemic burn edema in rats. AB - BACKGROUND: Thermal injuries of more than 20% total body surface area result in systemic shock with generalized edema. Burn shock is induced by a variety of mediators, mainly immunomodulative cytokines. Administration of methysergide (Met), a serotoninergic receptor blocking agent, reduces generalized edema in endotoxemia in rats. In this study we evaluated the systemic effects of Met after thermal injury. METHODS: Donor rats (DR [n=8]) for positive controls and study groups underwent thermal injury (100 degrees C water, 30% TBSA (Total Burn Surface Area), 12s). Shamburn plasma was harvested after a shamburn procedure ([n=4], 37 degrees C water, 30% TBSA, 12s). Plasma was harvested 4h posttrauma and was transferred to healthy individuals. Recipient animals were randomized in 3 groups (1: burnplasma, 2: shamburn, 3: burnplasma plus methysergide (Bolus of 1mg/kg body weight)). Intravital microscopy was performed in mesenteric venules (0/60/120min). Edema was assessed by FITC-albumin extravasation. Leukocyte sticking (cells/mm(2)) and microhemodynamic parameters were assessed. RESULTS: Significant systemic capillary leakage was observed after burnplasma-transfer. Edema formation was significantly lower in negative controls. Application of methysergide reduced FITC-efflux to baseline levels. Adherent leukocytes increased in all groups, at 120min the amount of adherent leukocytes in positive controls was significantly higher in comparison to shamburn, differences to MET groups were not significant. CONCLUSION: Burnplasma transfer to healthy individuals induces leukocyte activation and plasma extravasation and this effect is reduced by administration of Met. This may be attributed to leukocyte dependent as well as independent mechanisms. Evaluation of more specific serotoninergic antagonists is required to distinguish between systemic and local effects. PMID- 23669654 TI - Trends in C-reactive protein levels in US adults from 1999 to 2010. AB - C-reactive protein (CRP) is a well-known biomarker of systemic inflammation and cardiovascular disease. We investigated the trends in prevalence of elevated CRP levels (>3.0 mg/L) in a general population of US adults. Data from 27,214 subjects aged >=20 years in the 1999-2010 National Health and Nutrition Examination Survey were analyzed. After adjustment for age, sex, race/ethnicity, body mass index (weight (kg)/height (m)(2)), and medications for lowering blood pressure, glucose, and lipids, the prevalence of elevated CRP decreased significantly from 36.7% in 1999-2002 to 32.0% in 2007-2010, corresponding to a decrease in mean CRP level from 1.92 to 1.66 mg/L (both P < 0.001). The trend remained significant after additional adjustment for several traditional cardiovascular risk factors and use of different medications, including statins. However, the decreasing trends were attenuated after additional adjustment for total bilirubin (P = 0.08 and 0.02), which increased from 0.62 to 0.73 mg/dL over 12 years (P < 0.001). The decreasing trend of CRP levels is encouraging and may be related to the increase in total bilirubin levels. Such trends may be explained in part by the increasing use of medications such as statins, which can increase bilirubin levels and decrease CRP levels. PMID- 23669655 TI - Chicago Healthy Aging Study: objectives and design. AB - Investigators in the Chicago Healthy Aging Study (CHAS) reexamined 1,395 surviving participants aged 65-84 years (28% women) from the Chicago Heart Association Detection Project in Industry (CHA) 1967-1973 cohort whose cardiovascular disease (CVD) risk profiles were originally ascertained at ages 25 44 years. CHAS investigators reexamined 421 participants who were low-risk (LR) at baseline and 974 participants who were non-LR at baseline. LR was defined as having favorable levels of 4 major CVD risk factors: serum total cholesterol level <200 mg/dL and no use of cholesterol-lowering medication; blood pressure 120/<=80 mm Hg and no use of antihypertensive medication; no current smoking; and no history of diabetes or heart attack. While the potential of LR status in overcoming the CVD epidemic is being recognized, the long-term association of LR with objectively measured health in older age has not been examined. It is hypothesized that persons who were LR in 1967-1973 and have survived to older age will have less clinical and subclinical CVD, lower levels of inflammatory markers, and better physical performance/functioning and sleep quality. Here we describe the rationale, objectives, design, and implementation of this longitudinal epidemiologic study, compare baseline and follow-up characteristics of participants and nonparticipants, and highlight the feasibility of reexamining study participants after an extended period postbaseline with minimal interim contact. PMID- 23669657 TI - Analytical design of freeform optical elements generating an arbitrary-shape curve. AB - A method is proposed for designing refractive optical elements focusing a collimated incident beam into a curve with specified shape. A general relationship for the freeform surface of the optical element is derived as an envelope of a parametric family of hyperboloids of revolution that focuses the incident beam into the points on the curve. Using the thin optical element approximation, the calculation of the hyperboloid parameters providing required irradiance distribution along the curve is reduced to the solution of an explicit first order differential equation. Optical elements generating line segment focus and circular arc focus are designed. The simulation results demonstrate generation of high-quality curves. PMID- 23669658 TI - Precision absolute positional measurement of laser beams. AB - We describe an instrument which, coupled with a suitable coordinate measuring machine, facilitates the absolute measurement within the machine frame of the propagation direction of a millimeter-scale laser beam to an accuracy of around +/-4 MUm in position and +/-20 MUrad in angle. PMID- 23669659 TI - Estimating detection and identification probabilities in maritime target acquisition. AB - This work describes several approaches to the estimation of target detection and identification probabilities as a function of target range. A Bayesian approach to estimation is adopted, whereby the posterior probability distributions associated with these probabilities are analytically derived. The parameter posteriors are then used to develop credible intervals quantifying the degree of uncertainty in the parameter estimates. In our first approach we simply show how these credible intervals evolve as a function of range. A second approach, also following the Bayesian philosophy, attempts to directly estimate the parameterized performance curves. This second approach makes efficient use of the available data and yields a distribution of probability versus range curves. Finally, we demonstrate both approaches using experimental data collected from wide field-of-view imagers focused on maritime targets. PMID- 23669656 TI - MicroRNAs--mediators of myometrial contractility during pregnancy and labour. AB - The maintenance of myometrial quiescence and initiation of contractility, which lead to parturition at term and preterm, involve a shifting equilibrium between anti-inflammatory and proinflammatory signalling pathways. Progesterone (P4), acting through the progesterone receptor (PR), has an essential and multifaceted role in the maintenance of myometrial quiescence. This effect of P4-PR signalling is mediated, in part, by its anti-inflammatory actions and capacity to repress the expression of genes that encode proinflammatory cytokines, such as IL-1 and IL-6, and contraction-associated proteins, such as OXTR, GJA1 and PTGS2. By contrast, increased expression of genes that ultimately lead to parturition is mediated by enhanced inflammatory and estradiol-17beta (E2) and estrogen receptor alpha signalling, which reduce PR function, thus further intensifying the inflammatory response. To obtain a more complete understanding of the molecular events that underlie the transition of the pregnant myometrium from a refractory to a contractile state, the roles of microRNAs, their targets, and their transcriptional and hormonal regulation have been investigated. This article reviews the actions of the miR-200 family and their P4-regulated targets-the transcription factors ZEB1, ZEB2 and STAT5B-in the pregnant myometrium, as well as the role of miR-199a-3p and miR-214 and their mutual target PTGS2. The central role of ZEB1 as the mediator of the opposing actions of P4 and E2 on myometrial contractility will be highlighted. PMID- 23669660 TI - Simple and sensitive technique for alignment of the pinhole of a spatial filter of a high-energy, high-power laser system. AB - In this paper, a new method for alignment of the pinhole of a spatial filter (SF) has been proposed and demonstrated experimentally. The effect of the misalignment of the pinhole on the laser beam profiles has been calculated for circular and elliptical Gaussian laser beams. Theoretical computation has been carried out to illustrate the effect of an intensity mask, placed before the focusing lens of the SF, on the spatial beam profile after the pinhole of the SF. It is shown, both theoretically and experimentally, that a simple intensity mask, consisting of a black dot, can be used to visually align the pinhole with a high accuracy of 5% of the pinhole diameter. The accuracy may be further improved using a computer based image processing algorithm. Finally, the proposed technique has been demonstrated to align a vacuum SF of a compact 40 J Nd:phosphate glass laser system. PMID- 23669661 TI - Detailed calculation of spectral noise caused by measurement errors of Mach Zehnder interferometer optical path phases in a spatial heterodyne spectrometer with a phase shift scheme. AB - We calculate the root mean square (rms) value of the spectral noise caused by optical path phase measurement errors in a spatial heterodyne spectrometer (SHS) featuring a complex Fourier transformation. In our calculation the deviated phases of each Mach-Zehnder interferometer in the in-phase and quadrature states are treated as statistically independent random variables. We show that the rms value is proportional to the rms error of the phase measurement and that the proportionality coefficient is given analytically. The relationship enables us to estimate the potential performance of the SHS such as the sidelobe suppression ratio for a given measurement error. PMID- 23669662 TI - Influence of arrangement order ratio on the magneto-optical properties of one dimensional microcavity structures. AB - The dependence of the optical responses of microcavity-type one-dimensional (1D) photonic crystals and 1D magnetophotonic crystals (1D-MPCs) on the arrangement order ratio (AOR), which is the ratio of the first and second layers' refractive indexes of Bragg reflectors, is studied. It is demonstrated that the optical properties of two microcavity structures resulting from exchanging the order of Bragg reflector layers so that they have the same optical contrast ratios and different AORs would be different. This difference will be more noticeable in the case of microcavity type 1D-MPCs. Regarding the arrangement-dependent magneto optical properties of the structures, we can propose the efficient Bragg reflectors with high transmittance enhanced Faraday rotation. PMID- 23669663 TI - Distortion tolerant correlation filter design. AB - This paper introduces a computationally efficient algorithm for synthesis of a distortion tolerant correlation filter and associated threshold, denoted collectively as the enhanced matched filter (EMF). Application areas of EMF include imagery based automatic target detection and recognition and biometrics. The EMF is synthesized from a set of training images characterizing the target of interest within the expected distortion range. A distinguishing feature of EMF is the ascribed threshold, which is a byproduct of the filter computation process and does not rely on nontarget trainers. The EMF performance is compared to that of the synthetic discriminant function using realistic test scenarios. PMID- 23669664 TI - Fisheye lens calibration using virtual grid. AB - We present herein a technique to calibrate fisheye lenses using cross diffractive optical elements. The setup generated a robust and accurate virtual calibration grid, and the calibration was performed by rotating the camera around two axes. We propose a comparison of three fisheye mathematical models and an evaluation of the number of images in the calibration process. The comparison of our experimental data according to the 3D calibration object results showed that our technique is efficient and reliable. PMID- 23669665 TI - Modeling and simulation of the retina-like image sensor based on space-variant lens array. AB - A retina-like image sensor based on a space-variant lens array is proposed. First, the mathematical models of the proposed image sensor and its space-variant lens array are developed and verified. Second, the relationships among the parameters of the space-variant lens have been simulated and discussed. Finally, some conclusions are deduced, which will help to result in a retina-like image sensor with the characteristics of high speed, large resolution, high sensitivity, and big planar array, etc. PMID- 23669666 TI - Transmission degradation and preservation for tapered optical fibers in rubidium vapor. AB - The use of subwavelength diameter tapered optical fibers (TOFs) in warm rubidium vapor has recently been identified as a promising system for realizing ultralow power nonlinear optical effects. However, at the relatively high atomic densities needed for many of these experiments, rubidium atoms accumulating on the TOF surface can cause a significant loss of overall transmission through the fiber. Here we report direct measurements of the time scale associated with this transmission degradation for various rubidium density conditions. Transmission is affected almost immediately after the introduction of rubidium vapor into the system, and declines rapidly as the density is increased. More significantly, we show how a heating element designed to raise the TOF temperature can be used to reduce this transmission loss and dramatically extend the effective TOF transmission lifetime. PMID- 23669667 TI - Broadband mean free path of diffuse light in polydisperse ensembles of scatterers for white light-emitting diode lighting. AB - We study the diffuse transport of light through polymer slabs containing TiO(2) scattering particles. The slabs are diffuser plates typical of a commercial white light-emitting diode (LED) module (Fortimo). We have measured the diffuse transmission and reflection properties over a broad wavelength range (470-840 nm) from which we derive the transport mean free path using the theory of light diffusion. With increasing scatterer density, the mean free path becomes shorter. The mean free path increases with wavelength; hence, blue light is scattered more strongly than red light. To interpret the results, we propose an ab initio model without adjustable parameters for the mean free path by using Mie theory. We include inhomogeneous broadening as a result of the size distribution of the scattering particles as measured by dynamic light scattering. Surprisingly, the calculated mean free path decreases with wavelength, at variance with our experiments, which is caused by particles with radii R in excess of 0.25 MUm. Close inspection of the scatterers by electron microscopy reveals that large particles (R>0.4 MUm) consist of clusters of small particles (R<0.13 MUm). Therefore, we have improved our model by only taking into account the individual scatterers within the clusters. This model predicts mean free paths in good agreement with our experimental results. We discuss consequences of our results to white LED lighting modules. PMID- 23669668 TI - Spatially resolved phase-response calibration of liquid-crystal-based spatial light modulators. AB - Methods for measuring and compensating the nonlinear electro-optical effect of transmissive, parallel-aligned liquid crystal (LC)-based spatial light modulators (SLMs) are presented. Particularly, the analysis is focused on the spatial nonuniformity of the voltage versus phase modulation characteristics for an active-matrix-driven, electrically controlled birefringence type LC-SLM. A high quality reconstruction from phase-only modulating SLMs requires a well-calibrated phase addressing across the entire SLM panel. I discuss how the commonly inherent phase-response inhomogeneity of LC-SLM is characterized by purposeful localized measurement techniques. This phase-response inhomogeneity is efficiently compensated by utilizing a Legendre polynomial representation in combination with a remapping of an 8 bit gray level addressing. The calibration procedure is corroborated by measurement data. The LC-SLM's experimental demonstration finally verifies the resultant improvement in holographic imaging. PMID- 23669669 TI - Multiple-image encryption scheme based on cascaded fractional Fourier transform. AB - A multiple-image encryption scheme based on cascaded fractional Fourier transform is proposed. In the scheme, images are successively coded into the amplitude and phase of the input by cascading stages, which ends up with an encrypted image and a series of keys. The scheme takes full advantage of multikeys and the cascaded relationships of all stages, and it not only realizes image encryption but also achieves higher safety and more diverse applications. So multiuser authentication and hierarchical encryption are achieved. Numerical simulation verifies the feasibility of the method and demonstrates the security of the scheme and decryption characteristics. Finally, flexibility and variability of the scheme in application are discussed, and the simple photoelectric mixed devices to realize the scheme are proposed. PMID- 23669670 TI - Standoff photoacoustic detection of explosives using quantum cascade laser and an ultrasensitive microphone. AB - Standoff detections of explosives using quantum cascade lasers (QCLs) and the photoacoustic (PA) technique were studied. In our experiment, a mid-infrared QCL with emission wavelength near 7.35 MUm was used as a laser source. Direct standoff PA detection of trinitrotoluene (TNT) was achieved using an ultrasensitive microphone. The QCL output light was focused on explosive samples in powder form. PA signals were generated and detected directly by an ultrasensitive low-noise microphone with 1 in. diameter. A detection distance up to 8 in. was obtained using the microphone alone. With increasing detection distance, the measured PA signal not only decayed in amplitude but also presented phase delays, which clearly verified the source location. To further increase the detection distance, a parabolic sound reflector was used for effective sound collection. With the help of the sound reflector, standoff PA detection of TNT with distance of 8 ft was demonstrated. PMID- 23669671 TI - Combined laser and broadband light for measuring the tuning relation of an acousto-optic tunable filter. AB - To improve the tuning relation accuracy of an acousto-optic tunable filter, the conventional separated laser and broadband light methods were combined. The single laser test measured one accurate point and corrected the large amounts of data obtained from the broadband light method. The final tuning relation was fitted by the corrected data. A simulation and an experiment for several methods were conducted for comparison. The relative error was reduced from 0.2% to 0.05% in the 430~785 nm range. The equivalent wavelength accuracy improved from 1 to 0.2 nm. This method solved the problems associated with the use of a single laser source with few test data values and a single broadband light source with poor collimation. PMID- 23669672 TI - Preprocessed cumulative reconstructor with domain decomposition: a fast wavefront reconstruction method for pyramid wavefront sensor. AB - We present a fast method for the wavefront reconstruction from pyramid wavefront sensor (P-WFS) measurements. The method is based on an analytical relation between pyramid and Shack-Hartmann sensor (SH-WFS) data. The algorithm consists of two steps--a transformation of the P-WFS data to SH data, followed by the application of cumulative reconstructor with domain decomposition, a wavefront reconstructor from SH-WFS measurements. The closed loop simulations confirm that our method provides the same quality as the standard matrix vector multiplication method. A complexity analysis as well as speed tests confirm that the method is very fast. Thus, the method can be used on extremely large telescopes, e.g., for eXtreme adaptive optics systems. PMID- 23669673 TI - Comparing the equivalent particle number density distribution of gas and plasma flow fields. AB - In this paper, the equivalent particle number density distribution of gas and plasma flow fields is investigated. For the purpose of facilitating comparison, argon gas and argon arc plasma are chosen as practical examples for experiment. The equivalent particle number density distributions of the argon gas and argon arc plasma are reconstructed from the experimentally measured refractive index distributions obtained by moire tomography, while five cross sections, which are 7, 8.5, 10, 11.5, and 13 mm away from the jet nozzle are chosen for practical calculation and comparison. In experiment, the probe wavelength and the export pressure of argon gas and argon arc plasma are the same. The experimental results manifest that (1) the equivalent particle number density decreases with the distance away from the jet nozzle of the gas flow field, while (2) the equivalent particle number density of the plasma flow field has a different variation. Finally, the experimental results are theoretically explained and analyzed. PMID- 23669674 TI - Diffractive optical elements for mode-division multiplexing of temporal signals with the aid of Laguerre-Gaussian modes. AB - Optical aspects of space-division multiplexing with orthogonal modes of coherent light were considered in theory and experiments with the coherent optical correlator. We resorted to the mathematical tool of generating functions and technologies of diffractive optical elements to implement complex spatial filters matched to rotationally symmetrical transverse modes. Successful multiplexing and demultiplexing in free-space transmission of low-frequency temporally modulated signals through different spatial modes was demonstrated. Experimental results show low cross talk between different mode channels and feasibility of further applications in multimode fiber optical communication data links. PMID- 23669675 TI - Intrinsic fiber-optic Fabry-Perot interferometer based on arc discharge and single-mode fiber. AB - We propose a simple intrinsic Fabry-Perot interferometer (FPI) based on single mode fiber, where a thin film is formed by arc discharge to serve as one mirror of the FPI cavity. The temperature and refractive-index (RI) characteristics of the proposed device are investigated. Experimental results show that the device can provide temperature-independent measurement of RI with a fringe-contrast sensitivity of ~72.59 dB/RIU (RI units). Meanwhile, it can also be used as a temperature sensor with a wavelength sensitivity of ~8 pm/ degrees C. Therefore, the potential simultaneous measurement of RI and temperature could be realized by detecting the variations of fringe contrast and wavelength, respectively. PMID- 23669676 TI - Efficient high-energy passively Q-switched Yb:GdCa4O(BO3)3 laser. AB - A compact diode-pumped high-pulse-energy Yb:GdCa(4)O(BO(3))(3) laser passively Q switched with a Cr(4+):YAG saturable absorber is demonstrated at room temperature. An output power of 1.05 W is generated at a pulse repetition rate of 2.5 kHz when the pump power absorbed is 7.7 W, with a slope efficiency determined to be 40%. The laser pulse generated is 10.0 ns in duration, with pulse energy as high as 420 MUJ and peak power amounting to 42 kW. PMID- 23669677 TI - Single tunable laser interrogation of slab-coupled optical sensors through resonance tuning. AB - This paper describes a method for tuning the resonant wavelengths of slab-coupled optical fiber sensors (SCOSs). This method allows multiple sensors to be interrogated simultaneously with a single tunable laser. The resonances are tuned by rotating a biaxial slab waveguide relative to an optical D-fiber. As the slab waveguide rotates, its effective index of refraction changes causing the coupling wavelengths of the slab waveguide and D-fiber to shift. A SCOS fabricated with potassium titanyl phosphate crystal as the slab waveguide is shown to have resonance tuning ranges of 6.67 and 22.24 nm, respectively, for TM and TE polarized modes. PMID- 23669678 TI - Design of an LED-based compound optical system for a driving beam system. AB - This paper proposes an LED-based compound optical system, which can be involved in the design of the driving beam system in automotive headlamps with high system efficiency and low power consumption. The compound system can meet the requirements announced in the UNECE regulation "Addendum 111: Regulation No. 112 Revision 2." Also, it is composed of a nonspherical reflector, a compound lens, and a two-dimensional diverging lens. Using a single device of high-brightness LED of merely 7.6 W, the specified illumination requirements for the driving beam can be achieved. As we have expected, on the test screen at a distance of 25 m, the simulation results, as well as the testing results for the prototype, can reach the illuminance distribution requirements, including all specified regions and key points. Moreover, this compound system enjoys the features of high compactness, high energy efficiency, and feasibility of manufacturing. PMID- 23669679 TI - Numerical simulation of digital holographic microscopy through transparent samples based on pupil imaging and finite-difference time-domain methods. AB - Digital holographic microscopy (DHM) has been used to determine the morphology and shape of transparent objects. However, the obtained shape is often inaccurate depending on the object properties and the setup of the optical imaging system. To understand these effects, we developed a new DHM model on the basis of a hybrid pupil imaging and finite-difference time-domain method. To demonstrate this model, we compared the results of an experiment with those of a simulation using borosilicate glass microspheres and a mold with a linear step structure. The simulation and experimental results showed good agreement. We also showed how the curvature and refractive index of objects affect the accuracy of thickness measurements. PMID- 23669680 TI - Actively Q-switched, thulium-holmium-codoped fiber laser incorporating a silicon based, variable-optical-attenuator-based Q switch. AB - An actively Q-switched thulium-holmium-codoped fiber laser incorporating an Si based variable optical attenuator (VOA) is experimentally demonstrated. It has been shown that an Si-based VOA with a response time of hundreds of nanoseconds can be used as a cost-effective 2 MUm Q switch due to its extremely wide operating bandwidth from 1.5 to 2 MUm, and low electrical power consumption. In our study, the laser's slope efficiency was measured to be ~17% at an operating wavelength of 1.89 MUm. The repetition rate tuning range was from 20 to 80 kHz, which was limited by the optical damage threshold and the response time. The minimum temporal pulsewidth was measured to be ~184 ns at a modulation frequency of 20 kHz, and the corresponding maximum peak power was ~10 W. PMID- 23669681 TI - Optical profiles of cathode ray tube and liquid crystal display monitors: implication in cutaneous phototoxicity in photodynamic therapy. AB - Recent clinical reports suggest that overexposure to light emissions generated from cathode ray tube (CRT) and liquid crystal display (LCD) color monitors after topical or systemic administration of a photosensitizer could cause noticeable skin phototoxicity. In this study, we examined the light emission profiles (optical irradiance, spectral irradiance) of CRT and LCD monitors under simulated movie and video game modes. Results suggest that peak emissions and integrated fluence generated from monitors are clinically relevant and therefore prolonged exposure to these light sources at a close distance should be avoided after the administration of a photosensitizer or phototoxic drug. PMID- 23669682 TI - Suitability of goniospectrophotometric space curves as appearance fingerprints. AB - Goniospectrophotometric space curves were obtained by summation of spatially under-sampled bidirectional reflectance distribution function over all directions and repeating this for all wavelengths in the visible spectral region. This gives a 3D goniospectrophotometric curve called an xDNA graph. Systematic analysis applying 19 measurement geometries confirms existence of characteristic shapes of the graph for all optically similar samples. This enables distinguishing between differently rough samples, an interference effect on various transparent layers, and selective spectral absorption of light in differently thick pigmented coatings. Therefore, the considered goniospectrophotometric space curves could serve as an appearance fingerprint of such samples. PMID- 23669683 TI - Characteristics of two-wave mixing adaptive interferometer with CdTe:Ge at 1.06 and 1.55 MUm and improved temporal adaptability with temperature control. AB - We have characterized a two-wave mixing adaptive interferometer based on dc biased photorefractive CdTe:Ge crystal at 1.06 and 1.55 MUm. Excellent performance is shown at both wavelengths by demonstration of high sensitivity for measurement of small displacements and high cutoff frequency at low intensity. We have achieved a considerable reduction of the undesired low-frequency response using controlled heating of the crystal, which ensures depopulation of corresponding traps. The experimental data are used for measurement of the real and imaginary parts of the coupling constant, as well as the dielectric relaxation time of the crystal and the mobility-lifetime product of the free charge carriers. PMID- 23669684 TI - 32.5 mJ and 4.6 ns 532 nm Q-switched Nd:YAG laser at 500 Hz. AB - A laser diode side-pumped electro-optical Q-switched Nd:YAG green light laser with high repetition rates, short pulse width, and high peak power was demonstrated. We studied the performance of the oscillator at the repetition rates from 100 to 500 Hz. At 500 Hz, 61 mJ, 5 ns of 1064 nm infrared light pulses were obtained with an oscillator-amplifier system. The peak power of the pulse was 12 MW. By frequency doubling with a LiB(3)O(5)(LBO) crystal, 32.5 mJ, 4.6 ns of 532 nm green light was achieved, corresponding to a peak power of 7 MW. The frequency conversion efficiency was 53.3%. PMID- 23669685 TI - Study of the effect of mechanical pressure on determination of position and size of tumor in biological phantoms. AB - Diffuse optical tomography (DOT) is an emerging oncological imaging modality that is based on a near-infrared optical technique. DOT provides the spatial volume and depth of tumors by determination of optical properties of biological tissues, such as the absorption and scattering coefficients. During a DOT, the optical fibers are kept in contact with biological tissues that introduce a certain amount of pressure on the local biological tissue. Due to this pressure, the shape of the organ, for instance a breast, deforms. Moreover, this pressure could influence the intrinsic characteristics of the biological tissue. Therefore, pressure can be an important parameter in DOT. In this paper, the effects of pressure on the determination of the size and position of a tumor in biological phantoms are studied. To do so, tissue-like phantoms that are made of intralipid, Indian ink, and agar are constructed. Defects with optical properties similar to those of tumors are placed inside the phantoms. Then various values of pressure are applied to the phantoms. Subsequently, the optical properties of phantoms as well as the position and size of the tumor are reconstructed by inverse models based on the boundary integral method. The variations of reconstructed data induced by pressure are studied. The results demonstrate that pressure causes an increase in the scattering coefficient. PMID- 23669686 TI - Dynamic symmetrical pattern projection based laser triangulation sensor for precise surface position measurement of various material types. AB - This paper describes a custom, material-type-independent laser-triangulation based measurement system that utilizes a high-quality ultraviolet laser beam. Laser structuring applications demand material surface alignment regarding the laser focus position, where fabrication conditions are optimal. Robust alignment of various material types was solved by introducing dynamic symmetrical pattern projection, and a "double curve fitting" centroid detection algorithm with subsurface scattering compensation. Experimental results have shown that the measurement system proves robust to laser intensity variation, with measurement bias lower than 50 MUm and standard deviation lower than +/-6.3 MUm for all materials. The developed probe has been integrated into a PCB prototyping system for material referencing purposes. PMID- 23669687 TI - System design process for refractive simultaneous short and long wave infrared imaging. AB - The future of optical design is multispectral imaging. Advancements in detector technology have led to the challenge of imaging over both short wave infrared and long wave infrared spectrums. This paper discusses the technical hurdles associated with designing a refractor to image over both of these spectrums, such as minimizing chromatic focal shift while maximizing contrast. The design process is outlined on an eight element F/1, 23 degrees full field of view solution. Optomechanical design forms are evaluated by analyzing possible stresses and tolerance errors. Antireflection coating designs are discussed to complete the full system. This entire design process is highlighted as a feasibility study for the future of multispectral imaging devices. PMID- 23669688 TI - Numerical simulation of low repetition rate subnanosecond laser based on dual loss-modulation. AB - A set of coupled rate equations for diode-pumped Q-switched and mode-locked laser with electro-optic (EO) modulator and middle semiconductor saturable absorber mirror under the Gaussian spatial distribution approximation are given. The numerically simulated results of these equations show that the pulse width of the Q-switched envelope are related to the repetition rate of EO, the stimulated emission section of the gain medium, the pump power and so on. When the pulse width of the Q-switched envelope is shorter than the cavity roundtrip transmit time, i.e., the interval of two neighboring mode-locking pulses, there is only one mode-locked pulse lying in a Q-switched envelope and its repetition rate depends on that of EO. This means that single mode-locking pulses with low repetition rate, subnanosecond duration, high peak power, and high stability are generated. The simulated results are consistent with the experimental values. PMID- 23669689 TI - Phase properties of high-reflectance two-material periodic mirrors: application to oblique-incidence tunable filters. AB - Mathematical expressions are developed for the phase-shift derivative with respect to the wavelength, in the case of nonquarter-wave, two-material, high reflectance, periodic mirrors. These expressions are applied to the case of oblique incidence, and a condition relating the layer indices, which provides identical phase dispersion curves for both the P and S polarizations, is derived. The use of such mirrors in Fabry-Perot filters results in a common peak wavelength for both polarizations when the filter is used at oblique incidence, instead of the two separate spectral peaks usually observed. This property, which is illustrated by several numerical examples, is of great interest for the design of tunable filters, in which the angle of incidence is frequently used as a tuning parameter. PMID- 23669690 TI - Inversion of photon correlation spectroscopy based on truncated singular value decomposition and cascadic multigrid technology. AB - For the low accuracy of single-scale inversion method in photon correlation spectroscopy technology, a cascadic multigrid (CMG)-truncated singular value decomposition (TSVD) inversion method that combines the TSVD regularization with CMG technology is proposed. This method decomposes the original problem into several subproblems in different scale grid space. According to the particle sizes inverted from the coarsest scale to the finest scale, the solution of an original inversion problem can be obtained. For the inversion of each subproblem, TSVD method is used. The simulation and experimental data were respectively inverted by TSVD and CMG-TSVD methods. The inversion results demonstrate that the CMG-TSVD method has higher accuracy, more strong noise immunity and better smoothness than the TSVD method. PMID- 23669691 TI - Multireflection modal method for wideband fused-silica transmission gratings. AB - A multireflection modal method is proposed to give a clear physical picture for explanation of the diffraction process that takes place in a wideband fused silica transmission grating. Using rigorous coupled-wave analysis, the optimized grating exhibits diffraction efficiency greater than 93.9% for TE polarization over a bandwidth of 126 nm (from 735 to 861 nm). The designed wideband fused silica transmission grating is fabricated using holographic interference recording and inductively coupled plasma etching technology. Experimental results are in agreement with the theoretical values. PMID- 23669692 TI - Low-cost scheme for high-precision dual-wavelength laser metrology. AB - A method capable of delivering relative optical path length metrology with nanometer precision is demonstrated. Unlike conventional dual-wavelength metrology, which employs heterodyne detection, the method developed in this work utilizes direct detection of interference fringes of two He-Ne lasers as well as a less precise stepper motor open-loop position control system to perform its measurement. Although the method may be applicable to a variety of circumstances, the specific application in which this metrology is essential is in an astrometric optical long baseline stellar interferometer dedicated to precise measurement of stellar positions. In our example application of this metrology to a narrow-angle astrometric interferometer, measurement of nanometer precision could be achieved without frequency-stabilized lasers, although the use of such lasers would extend the range of optical path length the metrology can accurately measure. Implementation of the method requires very little additional optics or electronics, thus minimizing the cost and effort of implementation. Furthermore, the optical path traversed by the metrology lasers is identical to that of the starlight or science beams, even down to using the same photodetectors, thereby minimizing the noncommon path between metrology and science channels. PMID- 23669693 TI - Numerical modeling of spatial coherence using the elementary function method. AB - The elementary function method is an approximate method for propagation calculations in spatially, partially coherent light in two dimensions. In this paper, we present the numerical application of this method to a 248 nm UV excimer laser source. We present experimental results of the measurement of the degree of spatial coherence and the beam profile of this source. The elementary function method is then applied to the real beam data and used to simulate the effects of imaging an opaque edge with a source of varying degrees of spatial coherence. The effect of spatial coherence on beam homogenization is also presented. PMID- 23669694 TI - Enhanced four-wave mixing in quantum cascade semiconductor optical amplifier. AB - We designed a quantum cascade semiconductor optical amplifier (QCSOA) structure for enhanced four-wave mixing (FWM) of short optical pulses in midinfrared. To analyze FWM characteristics in a QCSOA, the evolution in the time and spectral domains of two input optical pulses with different frequencies during propagation is calculated using the finite-difference beam propagation method. Calculated third-order susceptibility responsible for FWM resonance nonlinearity of the modified structure is enhanced by two orders of magnitude. Simulation results reveal that quantum cascade structure parameters and injected pump and probe powers are extremely important in determining the amplified FWM optical pulse characteristics in both the time and frequency domains. PMID- 23669695 TI - Light turn-on transient of a whispering gallery mode resonance spectrum in different gas atmospheres. AB - We examine the resonance spectrum change after turning on the light to feed the fiber taper evanescently coupled to a silica whispering gallery mode (WGM) resonator surrounded by different gases at different pressures. The resonance shifted to a longer wavelength, indicating a temperature rise, before reaching a steady state. The increment was proportional to the power of the light and approximately reciprocally proportional to the thermal conductivity of the surrounding gas, whereas the rate of the shift was approximately proportional to the thermal conductivity. The temperature rise, caused by absorption of intense WGM in silica, was significant even when the wavelength scan range contained only a few tall resonance peaks. We then estimated the power of heat generation and the mean power of WGM during the wavelength scan. PMID- 23669696 TI - Image rotation measurement in scene matching based on holographic optical correlator. AB - Based on the stationary random properties of remote sensing images, a correlation model is proposed to resolve the effects of the image rotation and translation on the correlation value in scene matching. The rotation invariance is achieved by measuring the image rotation with the model and compensating the rotation before the 2D translation scene matching. The input image is rotated from -5 degrees to 5 degrees at an interval of 1 degrees and 11 new images are generated. The 11 new images correlate with all the template images and eleven correlation matrices are obtained. The maximum values of each correlation matrix are picked up and they could follow a fixed curve predicted by the model. Fitting the curve, the rotation corresponding to the estimated peak of the curve is considered to be the rotation of the input image. The rotation measurement of the input image can be as accurate as 0.05 degrees . With an extra 36 rotations of the input image, the measuring range of rotation can be enlarged into +/-180 degrees . This method could be very fast and accurate for scene matching in the parallel multichannel holographic optical correlator. PMID- 23669697 TI - Motion control of the wedge prisms in Risley-prism-based beam steering system for precise target tracking. AB - Two exact inverse solutions of Risley prisms have been given by previous authors, based on which we calculate the gradients of the scan field that open a way to investigate the nonlinear relationship between the slewing rate of the beam and the required angular velocities of the two wedge prisms in the Risley-prism-based beam steering system for target tracking. The limited regions and singularity point at the center and the edge of the field of regard are discussed. It is found that the maximum required rotational velocities of the two prisms for target tracking are nearly the same and are dependent on the altitude angle. The central limited region is almost independent of the prism parameters. The control singularity at the crossing center path can be avoided by switching the two solutions. PMID- 23669698 TI - Nonmechanical zoom system through pressure-controlled tunable fluidic lenses. AB - We have developed a variable-power zoom system that incorporates fluidic lenses and has no moving parts. The designed system applies two single-chamber plano convex fluid singlets, each with their own distinct design, as well as a conventional refractive lens. In this paper, we combine the two fluid elements to form a variable-power telescope, while the fixed lens enables image formation. In this configuration, the image plane location is fixed. By synchronizing the powers of the two fluidic lenses, we produce a varying magnification zoom system. The design of each lens and the coupled system is analyzed. The coupled device experimentally produced a magnification range of 0.1* to 10* zoom or a 20* zoom magnification range with no moving parts. Furthermore, we expand on optical performance and capabilities of our system with fluidic lenses relative to traditional zoom lenses. PMID- 23669699 TI - Ultrafast all-optical switching using signal flow graph for PANDA resonator. AB - In this paper, the bifurcation behavior of light in the PANDA ring resonator is investigated using the signal flow graph (SFG) method, where the optical transfer function for the through and drop ports of the PANDA Vernier system are derived. The optical nonlinear phenomena, such as bistability, Ikeda instability, and dynamics of light in the silicon-on-insulator (SOI) PANDA ring resonator with four couplers are studied. The transmission curves for bistability and instability as a function of the resonant mode numbers and coupling coefficients for the coupler are derived by the SFG method and simulated. The proposed system has an advantage as no optical pumping component is required. Simulated results show that closed-loop bistable switching can be generated and achieved by varying mode resonant numbers in the SOI-PANDA Vernier resonator, where a smooth and closed-loop bistable switching with low relative output/input power can be obtained and realized. The minimum through-port switching time of 1.1 ps for resonant mode numbers of 5;4;4 and minimum drop port switching time of 1.96 ps for resonant mode numbers of 9;7;7 of the PANDA Vernier resonator are achieved, which makes the PANDA Vernier resonator an operative component for optical applications, such as optical signal processing and a fast switching key in photonics integrated circuits. PMID- 23669700 TI - Atmospheric CO2 column measurements with an airborne intensity-modulated continuous wave 1.57 MUm fiber laser lidar. AB - The 2007 National Research Council (NRC) Decadal Survey on Earth Science and Applications from Space recommended Active Sensing of CO(2) Emissions over Nights, Days, and Seasons (ASCENDS) as a midterm, Tier II, NASA space mission. ITT Exelis, formerly ITT Corp., and NASA Langley Research Center have been working together since 2004 to develop and demonstrate a prototype laser absorption spectrometer for making high-precision, column CO(2) mixing ratio measurements needed for the ASCENDS mission. This instrument, called the multifunctional fiber laser lidar (MFLL), operates in an intensity-modulated, continuous wave mode in the 1.57 MUm CO(2) absorption band. Flight experiments have been conducted with the MFLL on a Lear-25, UC-12, and DC-8 aircraft over a variety of different surfaces and under a wide range of atmospheric conditions. Very high-precision CO(2) column measurements resulting from high signal-to-noise ratio (>1300) column optical depth (OD) measurements for a 10 s (~1 km) averaging interval have been achieved. In situ measurements of atmospheric CO(2) profiles were used to derive the expected CO(2) column values, and when compared to the MFLL measurements over desert and vegetated surfaces, the MFLL measurements were found to agree with the in situ-derived CO(2) columns to within an average of 0.17% or ~0.65 ppmv with a standard deviation of 0.44% or ~1.7 ppmv. Initial results demonstrating ranging capability using a swept modulation technique are also presented. PMID- 23669701 TI - Measurements of multiple gas parameters in a pulsed-detonation combustor using time-division-multiplexed Fourier-domain mode-locked lasers. AB - Hyperspectral absorption spectroscopy is being used to monitor gas temperature, velocity, pressure, and H(2)O mole fraction in a research-grade pulsed-detonation combustor (PDC) at the Air Force Research Laboratory. The hyperspectral source employed is termed the TDM 3-FDML because it consists of three time-division multiplexed (TDM) Fourier-domain mode-locked (FDML) lasers. This optical-fiber based source monitors sufficient spectral information in the H(2)O absorption spectrum near 1350 nm to permit measurements over the wide range of conditions encountered throughout the PDC cycle. Doppler velocimetry based on absorption features is accomplished using a counterpropagating beam approach that is designed to minimize common-mode flow noise. The PDC in this study is operated in two configurations: one in which the combustion tube exhausts directly to the ambient environment and another in which it feeds an automotive-style turbocharger to assess the performance of a detonation-driven turbine. Because the enthalpy flow [kilojoule/second] is important in assessing the performance of the PDC in various configurations, it is calculated from the measured gas properties. PMID- 23669702 TI - Fast and accurate modal decomposition of multimode fiber based on stochastic parallel gradient descent algorithm. AB - A new approach for the complete modal decomposition of the optical fields emerging from the multimode fiber is presented in this paper. Based on the stochastic parallel gradient descent algorithm, mode coefficients for all the bound modes in the multimode fiber can be exactly calculated by utilizing one intensity profile of the beam. Numerical simulation validates the feasibility, and the reconstructed error is below 0.1%. In the case of six modes within the fiber, the running time is about 2 s. PMID- 23669703 TI - Performance of a thermally deformable mirror for correction of low-order aberrations in laser beams. AB - The thermally deformable mirror is a device aiming at correcting beam-wavefront distortions for applications where classical mechanical methods are precluded by noise considerations, as in advanced gravitational wave interferometric detectors. This moderately low-cost technology can be easily implemented and controlled thanks to the good reproducibility of the actuation. By using a flexible printed circuit board technology, we demonstrate experimentally that a device of 61 actuators in thermal contact with the back surface of a high reflective mirror is able to correct the low-order aberrations of a laser beam at 1064 nm and could be used to optimize the mode matching into Fabry-Perot cavities. PMID- 23669704 TI - Experimental investigation of all-optical packet-level time slot assignment using two optical buffers cascaded. AB - We proposed and experimentally demonstrated all-optical packet-level time slot assignment scheme with two optical buffers cascaded. The function of time-slot interchange (TSI) was successfully implemented on two and three optical packets at a data rate of 10 Gb/s. Therefore, the functions of TSI on N packets should be implemented easily by the use of N-1 stage optical buffer. On the basis of the above experiment, we carried out the TSI experiment on four packets with the same two-stage experimental setup. Furthermore, packets compression on three optical packets was also carried out with the same experimental setup. The shortest guard time of the packets compression can reach to 13 ns due to the limit of FPGA's control accuracy. Due to the use of the same optical buffer, the proposed scheme has the advantages of simple and scalable configuration, modularization, and easy integration. PMID- 23669705 TI - Parallax correction for precise near-wall flow investigations using particle imaging. AB - For the basic understanding of turbulence generation in wall-bounded flows, precise measurements of the mean velocity profile and the mean velocity fluctuations very close to the wall are essential. Therefore, three techniques are established for high-resolution velocity profile measurements close to solid surfaces: (1) the nanoprobe sensor developed at Princeton University, which is a miniaturization of a classical hot-wire probe [Exp. Fluids 51, 1521 (2011)]; (2) the laser Doppler velocimetry (LDV) profile sensor, which allows measurement of the location of the particles inside the probe volume using a superposition of two fringe systems [Exp. Fluids 40, 473 (2006)]; and (3) the combination of particle image velocimetry and tracking techniques (PIV/PTV), which identify the location and velocity of submicrometer particles within the flow with digital imaging techniques [Exp. Fluids 52, 1641 (2006)]. The last technique is usually considered less accurate and precise than the other two. However, in addition to the measurement precision, the effect of the probe size, the position error, and errors due to vibrations of the model, test facility, or measurement equipment have to be considered. Taking these into account, the overall accuracy of the PTV technique can be superior, as all these effects can be compensated for. However, for very accurate PTV measurements close to walls, it is necessary to compensate the perspective error, which occurs for particles not located on the optical axis. In this paper, we outline a detailed analysis for this bias error and procedures for its compensation. To demonstrate the capability of the approach, we measured a turbulent boundary layer at Re(delta)=0.4*10(6) and applied the proposed methods. PMID- 23669706 TI - All-optical image processing and compression based on Haar wavelet transform. AB - Fast data processing and compression methods based on wavelet transform are fundamental tools in the area of real-time 2D data/image analysis, enabling high definition applications and redundant data reduction. The need for information processing at high data rates motivates the efforts on exploiting the speed and the parallelism of the light for data analysis and compression. Among several schemes for optical wavelet transform implementation, the Haar transform offers simple design and fast computation, plus it can be easily implemented by optical planar interferometry. We present an all optical scheme based on an asymmetric couplers network for achieving fast image processing and compression in the optical domain. The implementation of Haar wavelet transform through a 3D passive structure is supported by theoretical formulation and simulations results. Asymmetrical coupler 3D network design and optimization are reported and Haar wavelet transform, including compression, was achieved, thus demonstrating the feasibility of our approach. PMID- 23669707 TI - Phase aberration correction by correlation in digital holographic adaptive optics. AB - We present a phase aberration correction method based on the correlation between the complex full-field and guide-star holograms in the context of digital holographic adaptive optics (DHAO). Removal of a global quadratic phase term before the correlation operation plays an important role in the correction. Correlation operation can remove the phase aberration at the entrance pupil plane and automatically refocus the corrected optical field. Except for the assumption that most aberrations lie at or close to the entrance pupil, the presented method does not impose any other constraints on the optical systems. Thus, it greatly enhances the flexibility of the optical design for DHAO systems in vision science and microscopy. Theoretical studies show that the previously proposed Fourier transform DHAO (FTDHAO) is just a special case of this general correction method, where the global quadratic phase term and a defocus term disappear. Hence, this correction method realizes the generalization of FTDHAO into arbitrary DHAO systems. The effectiveness and robustness of this method are demonstrated by simulations and experiments. PMID- 23669708 TI - A stratified acoustic model accounting for phase shifts for underwater acoustic networks. AB - Accurate acoustic channel models are critical for the study of underwater acoustic networks. Existing models include physics-based models and empirical approximation models. The former enjoy good accuracy, but incur heavy computational load, rendering them impractical in large networks. On the other hand, the latter are computationally inexpensive but inaccurate since they do not account for the complex effects of boundary reflection losses, the multi-path phenomenon and ray bending in the stratified ocean medium. In this paper, we propose a Stratified Acoustic Model (SAM) based on frequency-independent geometrical ray tracing, accounting for each ray's phase shift during the propagation. It is a feasible channel model for large scale underwater acoustic network simulation, allowing us to predict the transmission loss with much lower computational complexity than the traditional physics-based models. The accuracy of the model is validated via comparisons with the experimental measurements in two different oceans. Satisfactory agreements with the measurements and with other computationally intensive classical physics-based models are demonstrated. PMID- 23669709 TI - A graphene-based electrochemical sensor for rapid determination of phenols in water. AB - A glassy carbon electrode (GCE) coated with a graphene/polymer film was fabricated for rapid determination of phenols in aqueous solutions. The electrochemical behavior of different phenols at the graphene/polymer-coated GCE was also investigated. In PBS buffer solution with a pH of 6.5, hydroquinone exhibits a well-defined reduction peak at the modified GCE. Based on this, an electrochemical method for the direct determination of phenols is proposed. Investigating different parameters revealed the optimized detection conditions for the electrode are a scan rate of 50 mV/s, dosage of graphene-polyaniline of 8 MUL, dosage of tyrosinase of 3 MUL, and pH of 6.5. Under the optimal conditions, the reduction peak current varies linearly with the concentration of phenols, with a linear regression equation of I (10(-6)A) = -4.887 * 10(-4)C (mol/L)-5.331 * 10(-6) with a correlation coefficient of 0.9963 and limit of detection (S/N = 3) of 2.00 * 10(-4) mol/L. The electrochemical sensor is also used to detect phenols in actual samples, where it shows great promise for rapid, simple and quantitative detection of phenols. PMID- 23669711 TI - FTT-MA: a flexible time-triggered middleware architecture for time sensitive, resource-aware AmI systems. AB - There is an increasing number of Ambient Intelligence (AmI) systems that are time sensitive and resource-aware. From healthcare to building and even home/office automation, it is now common to find systems combining interactive and sensing multimedia traffic with relatively simple sensors and actuators (door locks, presence detectors, RFIDs, HVAC, information panels, etc.). Many of these are today known as Cyber-Physical Systems (CPS). Quite frequently, these systems must be capable of (1) prioritizing different traffic flows (process data, alarms, non critical data, etc.), (2) synchronizing actions in several distributed devices and, to certain degree, (3) easing resource management (e.g., detecting faulty nodes, managing battery levels, handling overloads, etc.). This work presents FTT MA, a high-level middleware architecture aimed at easing the design, deployment and operation of such AmI systems. FTT-MA ensures that both functional and non functional aspects of the applications are met even during reconfiguration stages. The paper also proposes a methodology, together with a design tool, to create this kind of systems. Finally, a sample case study is presented that illustrates the use of the middleware and the methodology proposed in the paper. PMID- 23669710 TI - Plant-derived natural products as sources of anti-quorum sensing compounds. AB - Quorum sensing is a system of stimuli and responses in relation to bacterial cell population density that regulates gene expression, including virulence determinants. Consequently, quorum sensing has been an attractive target for the development of novel anti-infective measures that do not rely on the use of antibiotics. Anti-quorum sensing has been a promising strategy to combat bacterial infections as it is unlikely to develop multidrug resistant pathogens since it does not impose any selection pressure. A number of anti-quorum sensing approaches have been documented and plant-based natural products have been extensively studied in this context. Plant matter is one of the major sources of chemicals in use today in various industries, ranging from the pharmaceutical, cosmetic, and food biotechnology to the textile industries. Just like animals and humans, plants are constantly exposed to bacterial infections, it is therefore logical to expect that plants have developed sophisticated of chemical mechanisms to combat pathogens. In this review, we have surveyed the various types of plant based natural products that exhibit anti-quorum sensing properties and their anti quorum sensing mechanisms. PMID- 23669712 TI - Development and testing of a decision making based method to adjust automatically the harrowing intensity. AB - Harrowing is often used to reduce weed competition, generally using a constant intensity across a whole field. The efficacy of weed harrowing in wheat and barley can be optimized, if site-specific conditions of soil, weed infestation and crop growth stage are taken into account. This study aimed to develop and test an algorithm to automatically adjust the harrowing intensity by varying the tine angle and number of passes. The field variability of crop leaf cover, weed density and soil density was acquired with geo-referenced sensors to investigate the harrowing selectivity and crop recovery. Crop leaf cover and weed density were assessed using bispectral cameras through differential images analysis. The draught force of the soil opposite to the direction of travel was measured with electronic load cell sensor connected to a rigid tine mounted in front of the harrow. Optimal harrowing intensity levels were derived in previously implemented experiments, based on the weed control efficacy and yield gain. The assessments of crop leaf cover, weed density and soil density were combined via rules with the aforementioned optimal intensities, in a linguistic fuzzy inference system (LFIS). The system was evaluated in two field experiments that compared constant intensities with variable intensities inferred by the system. A higher weed density reduction could be achieved when the harrowing intensity was not kept constant along the cultivated plot. Varying the intensity tended to reduce the crop leaf cover, though slightly improving crop yield. A real-time intensity adjustment with this system is achievable, if the cameras are attached in the front and at the rear or sides of the harrow. PMID- 23669713 TI - Noise reduction in brainwaves by using both EEG signals and frontal viewing camera images. AB - Electroencephalogram (EEG)-based brain-computer interfaces (BCIs) have been used in various applications, including human-computer interfaces, diagnosis of brain diseases, and measurement of cognitive status. However, EEG signals can be contaminated with noise caused by user's head movements. Therefore, we propose a new method that combines an EEG acquisition device and a frontal viewing camera to isolate and exclude the sections of EEG data containing these noises. This method is novel in the following three ways. First, we compare the accuracies of detecting head movements based on the features of EEG signals in the frequency and time domains and on the motion features of images captured by the frontal viewing camera. Second, the features of EEG signals in the frequency domain and the motion features captured by the frontal viewing camera are selected as optimal ones. The dimension reduction of the features and feature selection are performed using linear discriminant analysis. Third, the combined features are used as inputs to support vector machine (SVM), which improves the accuracy in detecting head movements. The experimental results show that the proposed method can detect head movements with an average error rate of approximately 3.22%, which is smaller than that of other methods. PMID- 23669714 TI - WEAMR-a weighted energy aware multipath reliable routing mechanism for hotline based WSNs. AB - Reliable source to sink communication is the most important factor for an efficient routing protocol especially in domains of military, healthcare and disaster recovery applications. We present weighted energy aware multipath reliable routing (WEAMR), a novel energy aware multipath routing protocol which utilizes hotline-assisted routing to meet such requirements for mission critical applications. The protocol reduces the number of average hops from source to destination and provides unmatched reliability as compared to well known reactive ad hoc protocols i.e., AODV and AOMDV. Our protocol makes efficient use of network paths based on weighted cost calculation and intelligently selects the best possible paths for data transmissions. The path cost calculation considers end to end number of hops, latency and minimum energy node value in the path. In case of path failure path recalculation is done efficiently with minimum latency and control packets overhead. Our evaluation shows that our proposal provides better end-to-end delivery with less routing overhead and higher packet delivery success ratio compared to AODV and AOMDV. The use of multipath also increases overall life time of WSN network using optimum energy available paths between sender and receiver in WDNs. PMID- 23669715 TI - A boy with prepubertal gynecomastia, hyperprolactinemia, and hypothyroidism. AB - Non-physiologic prepubertal gynecomastia with an identifiable cause is an uncommon condition. Hyperprolactinemia due to hypothyroidism is known to result in gynecomastia in adults, but this observation has not been reported in children. We discuss here a boy who developed gynecomastia after the first year of age and was later diagnosed with congenital hypothyroidism. PMID- 23669716 TI - Pentatricopeptide repeat proteins involved in plant organellar RNA editing. AB - C-to-U RNA editing has been widely observed in organellar RNAs in terrestrial plants. Recent research has revealed the significance of a large, plant-specific family of pentatricopeptide repeat (PPR) proteins for RNA editing and other RNA processing events in plant mitochondria and chloroplasts. PPR protein is a sequence-specific RNA-binding protein that identifies specific C residues for editing. Discovery of the RNA recognition code for PPR motifs, including verification and prediction of the individual RNA editing site and its corresponding PPR protein, expanded our understanding of the molecular function of PPR proteins in plant organellar RNA editing. Using this knowledge and the co expression database, we have identified two new PPR proteins that mediate chloroplast RNA editing. Further, computational target assignment using the PPR RNA recognition codes suggests a distinct, unknown mode-of-action, by which PPR proteins serve a function beyond site recognition in RNA editing. PMID- 23669717 TI - Voltage-dependent processes in the electroneutral amino acid exchanger ASCT2. AB - Neutral amino acid exchange by the alanine serine cysteine transporter (ASCT)2 was reported to be electroneutral and coupled to the cotransport of one Na(+) ion. The cotransported sodium ion carries positive charge. Therefore, it is possible that amino acid exchange is voltage dependent. However, little information is available on the electrical properties of the ASCT2 amino acid transport process. Here, we have used a combination of experimental and computational approaches to determine the details of the amino acid exchange mechanism of ASCT2. The [Na(+)] dependence of ASCT2-associated currents indicates that the Na(+)/amino acid stoichiometry is at least 2:1, with at least one sodium ion binding to the amino acid-free apo form of the transporter. When the substrate and two Na(+) ions are bound, the valence of the transport domain is +0.81. Consistently, voltage steps applied to ASCT2 in the fully loaded configuration elicit transient currents that decay on a millisecond time scale. Alanine concentration jumps at the extracellular side of the membrane are followed by inwardly directed transient currents, indicative of translocation of net positive charge during exchange. Molecular dynamics simulations are consistent with these results and point to a sequential binding process in which one or two modulatory Na(+) ions bind with high affinity to the empty transporter, followed by binding of the amino acid substrate and the subsequent binding of a final Na(+) ion. Overall, our results are consistent with voltage dependent amino acid exchange occurring on a millisecond time scale, the kinetics of which we predict with simulations. Despite some differences, transport mechanism and interaction with Na(+) appear to be highly conserved between ASCT2 and the other members of the solute carrier 1 family, which transport acidic amino acids. PMID- 23669718 TI - Channel properties of the splicing isoforms of the olfactory calcium-activated chloride channel Anoctamin 2. AB - Anoctamin (ANO)2 (or TMEM16B) forms a cell membrane Ca(2+)-activated Cl(-) channel that is present in cilia of olfactory receptor neurons, vomeronasal microvilli, and photoreceptor synaptic terminals. Alternative splicing of Ano2 transcripts generates multiple variants with the olfactory variants skipping exon 14 and having alternative splicing of exon 4. In the present study, 5' rapid amplification of cDNA ends analysis was conducted to characterize the 5' end of olfactory Ano2 transcripts, which showed that the most abundant Ano2 transcripts in the olfactory epithelium contain a novel starting exon that encodes a translation initiation site, whereas transcripts of the publically available sequence variant, which has an alternative and longer 5' end, were present in lower abundance. With two alternative starting exons and alternative splicing of exon 4, four olfactory ANO2 isoforms are thus possible. Patch-clamp experiments in transfected HEK293T cells expressing these isoforms showed that N-terminal sequences affect Ca(2+) sensitivity and that the exon 4-encoded sequence is required to form functional channels. Coexpression of the two predominant isoforms, one with and one without the exon 4 sequence, as well as coexpression of the two rarer isoforms showed alterations in channel properties, indicating that different isoforms interact with each other. Furthermore, channel properties observed from the coexpression of the predominant isoforms better recapitulated the native channel properties, suggesting that the native channel may be composed of two or more splicing isoforms acting as subunits that together shape the channel properties. PMID- 23669719 TI - Myocardial postconditioning is lost in vascular nitrate tolerance. AB - Organic nitrates play an important role in the therapy of ischemic heart disease; however, their clinical application is limited by the development of vascular nitrate tolerance. We have previously shown attenuation of the cardioprotective effect of preconditioning in vascular nitrate tolerance. Here, we studied whether the development of vascular nitrate tolerance affects the infarct size, limiting effect of ischemic postconditioning (IPost) in the myocardium, and whether the activation of survival kinases plays a role in the molecular mechanism of postconditioning in the presence or absence of vascular nitrate tolerance. Male Wistar rats were treated with nitroglycerin/vehicle for 3 days to induce vascular nitrate tolerance. On the fourth day, isolated hearts were subjected to 30-minute coronary occlusion followed by 120-minute reperfusion with or without IPost. In nontolerant hearts, postconditioning significantly decreased infarct size as compared with ischemia/reperfusion; however, postconditioning failed to decrease infarct size in hearts of nitrate tolerant rats. Phosphorylation of ERK 1/2, Akt, or endothelial nitric oxide synthetase showed no significant differences between the groups at the 10th minute of reperfusion. Vascular nitrate tolerance interferes with the infarct size limiting effect of IPost. Activation of survival kinases is not crucial in the molecular mechanism of postconditioning, which remains unaffected in nitrate tolerance. PMID- 23669720 TI - Multimycotoxin analysis in urines to assess infant exposure: a case study in Cameroon. AB - This study was conducted to investigate mycotoxin exposure in children (n=220, aged 1.5-4.5years) from high mycotoxin contamination regions of Cameroon and to examine the association between the mycotoxin levels (in total 18 analytes) and several socio-demographic factors and anthropometric characteristics. A cross sectional study was conducted in six villages in Cameroon with 220 children. Mycotoxins and their metabolites were detected in 160/220 (73%) urine samples. There were significant differences in the mean contamination levels of ochratoxin A (p=0.01) and beta-zearalenol (p=0.017) between the two agro-ecological zones investigated. Likewise significant differences were observed in the mean levels of aflatoxin M1 (p=0.001) across the weaning categories of these children. The mean concentration of aflatoxin M1 detected in the urine of the partially breastfed children (1.43ng/mL) was significantly higher (p=0.001) than those of the fully weaned children (0.282ng/mL). Meanwhile, the mean concentrations of deoxynivalenol (3.0ng/mL) and fumonisin B1 (0.59ng/mL) detected in the urine of the male children was significantly (p value 0.021 for deoxynivalenol and 0.004 for fumonisin B1) different from the levels detected in the urine of female children; 0.71ng/mL and 0.01ng/mL for deoxynivalenol and fumonisin B1 respectively. In this study, there was no association between the different malnutrition categories (stunted, wasting and underweight) and the mycotoxin concentrations detected in the urine of these children. However, there is sufficient evidence to suggest that children in Cameroon under the age 5 are exposed to high levels of carcinogenic substances such as fumonisin B1, aflatoxin M1 and ochratoxin A through breastfeeding. To the best of our knowledge, this is the first report of its kind carried out in West Africa to determine multi mycotoxin exposure in infants. PMID- 23669721 TI - Can SLC19A1 80G>A polymorphisms predict risk of extremely delayed MTX excretion after high dose of methotrexate? PMID- 23669722 TI - Ectopic neuroblastoma in monozygotic twins with different ages of onset: possible twin-to-twin metastasis in utero with distinct genetic alterations after birth. AB - We describe neuroblastoma (NB) in monozygotic twins whose ages at the onset of the disease had a 3-year interval. The primary tumor site of twin 1 was the adrenal gland, whereas that of twin 2 was the jejunum/mesentery. MYCN amplification, DNA index, ALK mutation, and copy number alterations of DNA were different between each primary tumor. NB in ectopic sites may have resulted from twin-to-twin metastasis through vascular anastamoses in the placenta. The pathogenesis of this NB involved a premalignant stage of NB during the fetal development and subsequent molecular alterations after birth, resulting in NBs that were phenotypically similar but genetically different. PMID- 23669723 TI - Measurement of bone mineral density in children with cancer. PMID- 23669724 TI - Clear cell adenocarcinoma of the uterine cervix: a case report and review of the literature. AB - We report an extremely rare case of a patient with clear cell carcinoma of the cervix who had no history of in utero diethylstilbestrol (DES) exposure. Although clear cell adenocarcinoma is an uncommon tumor, it must be considered in the differential diagnosis in young women and children who have cervico-vaginal lesions even without in utero DES exposure history. We present the case of 2 girls, a 14-year-old and a 16-year-old, who were admitted to hospital because of intermittent vaginal bleeding and the presence of a cervical mass diagnosed as clear cell cervix carcinoma. Neither of them had a history of exposure to DES. PMID- 23669725 TI - Illness uncertainty and quality of life in children with cancer. AB - BACKGROUND: Illness uncertainty is prevalent in children with cancer and has been associated with increased psychological distress. The relationship between illness uncertainty and quality of life in pediatric cancer patients remains unclear. The aim of the present study was to examine illness uncertainty as a predictor of health-related quality of life in children diagnosed with cancer. It was hypothesized that child-reported illness uncertainty would be negatively associated with child health-related quality of life. PROCEDURE: Children aged 8 to 18 years old and receiving treatment for cancer were recruited to participate in this study. One hundred twenty children and their parent(s) completed measures of illness uncertainty, pain, anxiety, and quality of life during a routine visit to the Cancer Center at Children's Hospital of Orange County. RESULTS: Illness uncertainty was significantly associated with child age (P=0.02), overall health related (P<0.001) and cancer-related (P<0.001) quality of life, but not with treatment status (on/off chemotherapy) or demographic variables including sex and household income. Regression analyses statistically controlling for age, anxiety, and pain revealed that illness uncertainty significantly predicted child-reported cancer-related and health-related quality of life (P<0.01) as well as parent reported cancer-specific quality of life (P<0.01). CONCLUSIONS: Illness uncertainty is prevalent and associated with lower quality of life in children diagnosed with cancer. Improved communication with children regarding disease state, treatment expectations, and prognosis may alleviate uncertainty and improve functioning in this vulnerable patient population. PMID- 23669726 TI - Bacteremia due to imipenem-resistant Roseomonas mucosa in a child with acute lymphoblastic leukemia. AB - Roseomonas are described as opportunistic pathogens rarely involved in human infections. Their identification requires molecular methods and their antimicrobial susceptibility pattern varies according to the species. We report the first case of bacteremia due to Roseomonas mucosa in a child with leukemia and reviewed pediatric cases of Roseomonas infection, for which undoubted strain identification was available. Favorable outcome was observed despite resistance to numerous beta-lactams that may account for delayed effective treatment, suggesting the low virulence of Roseomonas in children. Here, the strain also displayed unusual resistance to imipenem, highlighting the possible acquisition of additional resistance by this pathogen. PMID- 23669727 TI - Transcranial Doppler in sickle cell disease. PMID- 23669728 TI - Dermatopathic lymphadenitis associated with human papilloma virus infection and verruca vulgaris. AB - Here we present a pediatric case of human papilloma virus associated with dermatopathic lymphadenitis (DL). A 5-year-old boy presented to the pediatric oncology clinic with swelling of the neck and warts on his lower jaw. His blood chemistry and complete blood count were normal, as was chest x-ray. HIV, EBV, CMV, and parvovirus serologies were negative. The patient was investigated for malignancy and lymphoma but no association was found. Histopathologic examination of the lymph node and the lesion revealed DL and verruca vulgaris, respectively. DL represents a benign form of reactive lymph node hyperplasia and described in patients with HIV and EBV infections. It is a rare entity described in patients with human papilloma virus infection. To our knowledge, this is the first report of DL in a patient with human papilloma virus infection. PMID- 23669729 TI - Children with cancer and HIV infection: what is different about them? AB - BACKGROUND: Children with HIV and cancer show an excess of non-Hodgkin lymphoma and leiomyosarcoma when compared with children with malignancy but without HIV. This study aimed at: (1) comparing the distribution of various cancers in South African children with malignancies and HIV versus children with malignancies but without HIV and (2) comparing the outcomes after therapy. PROCEDURE: This is a retrospective comparative study of 84 black children with cancer and HIV, consecutively admitted at Tygerberg Children's Hospital, Cape Town and Universitas Hospital, Bloemfontein, between 1995 and 2010, compared with 570 HIV negative black children with malignant diseases, consecutively admitted at the 2 hospitals, between 2002 and 2010. Variables studied included age, sex ratio, number of cases of each malignancy, length of follow-up, treatment abandonment, and mortality. The statistical significance was tested with the Student t test and chi test for P<=0.05. Kaplan-Meyer survival curves were constructed. RESULTS: The most frequent cancer was Kaposi sarcoma (39.3%), seen exclusively in children with HIV. Burkitt lymphoma was found more often (20.2%) in the HIV-positive group than in the HIV-negative one (2.8%, P<0.0001). Leiomyosarcoma, described as the second most frequent neoplasm encountered in HIV-positive children, was found in this series only once. The survival figures are much worse in the HIV-positive group: 26.2% versus 47.7% (P<0.0001), mainly due to drug toxicity. CONCLUSIONS: Kaposi sarcoma and Burkitt lymphoma occurred more often in children with HIV. These children have a lower tolerance of chemotherapy, even when combined with HAART. PMID- 23669730 TI - Successful treatment of recurrent pediatric inflammatory myofibroblastic tumor in a single patient with a novel chemotherapeutic regimen containing celecoxib. AB - Inflammatory myofibroblastic tumors are rare tumors characterized as low-to intermediate grade sarcomas. This is a case of a 7-year-old male with a 5-cm lung mass, which recurred 11 months after complete resection. The recurrence manifested as multifocal metastatic disease involving the ipsilateral parietal and visceral pleura. A novel chemotherapeutic regimen, which included vincristine, ifosfamide, doxorubicin, and celecoxib was utilized for the disease recurrence. The patient had complete and durable remission of the disease and has been disease-free for >4 years. This novel regimen including a cyclooxygenase 2 inhibitor may be an effective regimen for metastatic inflammatory myofibroblastic tumors. PMID- 23669731 TI - Treatment of severe human metapneumovirus (hMPV) pneumonia in an immunocompromised child with oral ribavirin and IVIG. AB - BACKGROUND: The clinical manifestations of human metapneumovirus (hMPV) infection resemble those of respiratory syncytial virus with the most severe disease occurring in infants, the elderly, chronically ill, and immunocompromised hosts. OBSERVATION: We present a case of a 2-year-old girl undergoing intensive chemotherapy for Burkitt lymphoma who developed severe hMPV pneumonia. Rapid and complete recovery was observed after treatment with oral ribavirin and intravenous immunoglobulin. CONCLUSION: As hMPV can cause severe pneumonia in immunocompromised patients and due to the reports of effective treatment with ribavirin, clinical studies to elucidate the role of ribavirin in treatment of hMPV pneumonia may be needed. PMID- 23669732 TI - Evaluation of the retinoids with cisplatin and vincristine in xenograft models of neuroblastoma. AB - Retinoids have been studied for the treatment of children with neuroblastoma for >25 years. Posttransplant administration of isotretinoin is standard of care for children with high-risk neuroblastoma, whereas fenretinide remains investigational. Previous preclinical studies have evaluated the interaction of retinoids and cytotoxic agents with conflicting results. We evaluated the schedule-dependent interaction of the cytotoxic agents, vincristine and cisplatin, with the retinoids, isotretinoin and fenretinide, in xenograft models of neuroblastoma. Concomitant administration of isotretinoin or fenretinide with the cytotoxic agents did not result in any clear potentiation of cytotoxicity. PMID- 23669733 TI - A case with sacrococcygeal primitive myxoid mesenchymal tumor of infancy: a case report and review of the literature. AB - A girl, aged 19 months, presented with a sacrococcygeal tumor that developed at 5 months after birth and gradually enlarged. Serum tumor marker levels were negative. Ultrasound imaging showed abundant blood flow in the tumor. However, neither computed tomography (CT) nor magnetic resonance imaging (MRI) showed contrast agent incorporation. The surgically resected tumor consisted of immature cells with myxoid stroma and proliferating small blood vessels. Immunostaining showed extensive vimentin expression. However, smooth muscle actin, muscle specific actin, and S-100 protein expression was negative. Neither the ETV6-NTRK3 fusion gene nor the FUS gene rearrangement was detected. Thus, the patient was diagnosed with a primitive myxoid mesenchymal tumor of infancy. This tumor primarily consisted of a mucosal stroma with a low absorption on CT, a low signal on T1-weighted MRI, and a high signal on T2-weighted MRI. A diagnosis of primitive myxoid mesenchymal tumor of infancy should be considered in cases of soft tissue tumors in infants that show prominent vascularity but little contrast enhancement on MRI or CT. PMID- 23669734 TI - Iron chelation with deferasirox for the treatment of secondary hemosiderosis in pediatric oncology patients: a single-center experience. AB - Pediatric oncology patients are often iron overloaded, due to the multiple blood transfusions necessary during the course of chemotherapy. Our aim is to report the efficacy and safety of deferasirox, an oral iron chelator, in this patient group. Deferasirox was administered to 13 children with malignancies in remission and iron overload. Ferritin, blood urea nitrogen, creatinine, transaminases, and bilirubin were recorded at 4- to 8-week intervals, and hepatic and cardiac iron overload were assessed with magnetic resonance imaging before initiation of treatment. Deferasirox was administered for an average of 6 months (SD=4.5; range, 0.3 to 18.2). Two children presented with skin rash, 1 with gastrointestinal disturbances, and 1 with fully reversible acute renal failure. The mean monthly rate of change in ferritin levels was -10.8 MUg/L before initiation of treatment (95% confidence interval [CI], -19.8 to -1.8; P=0.02) and -93.6 MUg/L during deferasirox treatment (95% CI, -118.1 to -69.1; P<0.001). The difference in the monthly rate of change in ferritin levels before and after treatment initiation was -82.8 MUg/L (95% CI, -111.6 to -53.9; P<0.001). Deferasirox was effective in reducing the iron burden. The adverse effects were easily monitored and managed. Further studies are warranted to investigate the effect of deferasirox on mortality and morbidity in this population. PMID- 23669735 TI - Familial hemophagocytic lymphohistiocytosis type 3 diagnosed at school age: a case report. AB - Familial hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition characterized by immune hyperactivation and clinical signs of extreme inflammation. We describe a 7-year-old male who presented with fever resistant to antibiotic therapy, pancytopenia, splenomegaly, hypertriglyceridemia, and hyperferritinemia. Bone marrow aspirate showed hemophagocytosis. Epstein-Barr virus genome was positive in blood. Functional screening showed reduced capacity of cytotoxic degranulation. Mutation analysis of the FHL-related genes revealed compound heterozygous for UNC13D mutations: c. 753+1G>T, and the novel c.544C>T (p.P182S). Patients with a clinical presentation of HLH, even if older than typically seen, should be screened for familial HLH by mutation analysis. PMID- 23669736 TI - An uncommon cause of anterior knee pain: patellar chondroma. AB - A 16-year-old boy presented with a patellar mass and anterior knee pain without any trauma. On physical and radiologic assessment, a mass at the superolateral edge of the patella and a hyperintense lesion on T2 sequences of magnetic resonance imaging was detected. Excisional biopsy revealed a chondroma of patella. Primary bone tumors of the patella are extremely rare and occurence of chondroma in this localization is very uncommon. Although anterior knee pain is a very frequent and usually harmless, it is essential to consider the more severe disorders such as bone tumors. PMID- 23669737 TI - Rituximab for the treatment of acute refractory ITP. AB - Most children with acute immune thrombocytopenic purpura (ITP) respond to first line therapies including intravenous immunoglobulin, corticosteroids, and Rho(D) immune globulin. However, there is no clear consensus regarding second-line therapies for the treatment of ITP, not responding to first-line therapies in the acute setting. Adapting from the chronic ITP literature, 3 patients with acute refractory ITP were treated with intravenous rituximab and showed immediate and sustained remission. Combined therapy that includes rituximab may be an effective regimen for acute refractory ITP. PMID- 23669738 TI - Retroperitoneal ganglioneuroma and reversible posterior leukoencephalopathy in a child with acute lymphoblastic leukemia. PMID- 23669739 TI - Effects of dietary fibers and their mixtures on short chain fatty acids and microbiota in mice guts. AB - Dietary fiber (DF) can be broken down into short-chain fatty acids (SCFAs) such as acetic, propionic and n-butyric acid by gut microbiota to obtain energy. Therefore, dietary fibers have effects on the balance of gut microbiota and the production of SCFAs. In the four-week feeding, mice were fed with four dietary fibers, including pectin, resistant starch (RS), fructo-oligosaccharide (FOS) and cellulose. The results showed that the mice body-weight gain was the smallest (7.0 +/- 2.3 g) when the mixture of RS-FOS-cellulose was ingested, followed by the mixture of RS-cellulose (7.2 +/- 3.5 g) and FOS-cellulose (8.3 +/- 2.5 g). Ingestion of the mixture of pectin-FOS-cellulose, RS-FOS and RS-FOS-cellulose can respectively increase the diversity of the gut microbiota with 12, 11 and 11 terminal restriction fragments (TRFs) detected (digested by Hha I). The maximum amount of total SCFAs were produced by the mixture of FOS-cellulose (5.504 +/- 0.029 MUmol mL(-1)), followed by pectin-FOS-cellulose (3.893 +/- 0.024 MUmol mL( 1)) and pectin-RS-FOS-cellulose (3.309 +/- 0.047 MUmol mL(-1)). In conclusion, the addition of DFs (pectin, RS, FOS and cellulose), in single or mixture pattern, can exert different effects. An amount of 10.7% of single DF in the diet cannot be conducive to the balance of gut microbiota after ingestion for a long time, however, it can help with body weight loss like the mixtures of DFs in this study; FOS is a very important component in the mixture of DFs for both the balance of the gut microbiota and the production of SCFAs. PMID- 23669740 TI - Evidence of oxygen vacancy induced room temperature ferromagnetism in solvothermally synthesized undoped TiO2 nanoribbons. AB - We report on the oxygen vacancy induced ferromagnetism (FM) at and above room temperature in undoped TiO2 nanoporous nanoribbons synthesized by a solvothermal route. The origin of FM in as-synthesized and vacuum annealed undoped nanoribbons grown for different reaction durations followed by calcinations was investigated by several experimental tools. X-Ray diffraction pattern and micro-Raman studies reveal the TiO2(B), TiO2(B)-anatase, and anatase-rutile mixed phases of TiO2 structure. Field emission scanning electron microscopy and transmission electron microscopy observations reveal nanoribbons with uniform pore distribution and nanopits/nanobricks formed on the surface. These samples exhibit strong visible photoluminescence associated with oxygen vacancies and a clear ferromagnetic hysteresis loop, both of which dramatically enhanced after vacuum annealing. Direct evidence of oxygen vacancies and related Ti(3+) in the as-prepared and vacuum annealed TiO2 samples are provided through X-ray photoelectron spectroscopy analysis. Micro-Raman, infrared absorption and optical absorption spectroscopic analyses further support our conclusion. The observed room temperature FM in undoped TiO2 nanoribbons is quantitatively analyzed and explained through a model involving bound magnetic polarons (BMP), which include an electron locally trapped by an oxygen vacancy with the trapped electron occupying an orbital overlapping with the unpaired electron (3d(1)) of Ti(3+) ion. Our analysis interestingly shows that the calculated BMP concentration scales linearly with concentration of oxygen vacancies and provides a stronger footing for exploiting defect engineered ferromagnetism in undoped TiO2 nanostructures. The development of such highly porous TiO2 nanoribbons constitutes an important step towards realizing improved visible light photocatalytic and photovoltaic applications of this novel material. PMID- 23669741 TI - Formulating a programme of repairs to structural home injury hazards in New Zealand. AB - Home injuries are a substantial health burden worldwide, with the home setting being at least as important as the road for injury. Focusing on common injury hazards presented by the home environment, we sought to examine the justification for significant expenditure on safety-related repairs to the housing stock. Trained inspectors assessed 961 New Zealand houses for injury hazards. Using administrative data from the Accident Compensation Corporation (the national injury insurance agency), 1328 home injuries were identified amongst the 1612 occupants of these houses over the 2006-2009 period. Telephone interviews gathered data on the location and nature of these injuries, and the attitudes of those injured to potential injury hazards in their homes. Commonly occurring injury hazards that could be repaired at modest cost were identified based on their prevalence estimated by the housing inspection, and their location with respect to the areas of the home where the injuries occurred (identified during the telephone interviews). About 38% of the home injuries studied were potentially related to a structural aspect of the home environment. Common safety hazards included the lack of working smoke detectors (65% of the sample), inadequately fenced driveways (55%), hot water temperatures measured at over 60 degrees (49%) and poorly lit access to the house (34%). A protocol for identifying and repairing important common hazards was designed. The actual safety effects of this protocol are in the process of being examined in a randomised controlled trial. PMID- 23669742 TI - Increased transcription of RPL40A and RPL40B is important for the improvement of RNA production in Saccharomyces cerevisiae. AB - Yeast (Saccharomyces cerevisiae) RNA is an important source of 5'-ribonucleotides that is used in both the food and pharmaceutical industries. Efficient transcription of rDNA is very important to construct yeast strains with high RNA content. The gene RRN10, which encodes, a component of the upstream activation factor, is essential to promote high-level transcription of rDNA. In our previous study, we isolated SupE strain as a dominant suppressor, which showed the ability to restore the severe growth defects and reduced RNA content caused by disruption of the RRN10 gene. SupE strain has multiple mutations which we designated collectively as SUPE. Further analysis on SUPE mutation indicated that RPL40A was responsible for suppression of defect caused by rrn10 disruption. However, there were no base changes in this gene as compared with the parental Deltarrn10 strain, thus suggesting that an additional copy of RPL40A suppress the defects caused by Deltarrn10 disruption, and that, in SupE strain, these defects are suppressed by increased transcription of RPL40A whose copy is doubled. When multiple copies of RPL40A were combined with SUPE mutation on an RRN10+ background, the resultant SupE strain had significantly higher RNA content than wild-type strain. In addition, increased transcription of RPL40B also showed significant effect to restore the growth defect and reduced RNA content caused by Deltarrn10 disruption. We propose a model to explain how SUPE mutation increases the transcription of ribosomal protein genes such as RPL40A and RPL40B in SupE strain, resulting in an increase in RNA content. PMID- 23669743 TI - GoldenBraid 2.0: a comprehensive DNA assembly framework for plant synthetic biology. AB - Plant synthetic biology aims to apply engineering principles to plant genetic design. One strategic requirement of plant synthetic biology is the adoption of common standardized technologies that facilitate the construction of increasingly complex multigene structures at the DNA level while enabling the exchange of genetic building blocks among plant bioengineers. Here, we describe GoldenBraid 2.0 (GB2.0), a comprehensive technological framework that aims to foster the exchange of standard DNA parts for plant synthetic biology. GB2.0 relies on the use of type IIS restriction enzymes for DNA assembly and proposes a modular cloning schema with positional notation that resembles the grammar of natural languages. Apart from providing an optimized cloning strategy that generates fully exchangeable genetic elements for multigene engineering, the GB2.0 toolkit offers an evergrowing open collection of DNA parts, including a group of functionally tested, premade genetic modules to build frequently used modules like constitutive and inducible expression cassettes, endogenous gene silencing and protein-protein interaction tools, etc. Use of the GB2.0 framework is facilitated by a number of Web resources that include a publicly available database, tutorials, and a software package that provides in silico simulations and laboratory protocols for GB2.0 part domestication and multigene engineering. In short, GB2.0 provides a framework to exchange both information and physical DNA elements among bioengineers to help implement plant synthetic biology projects. PMID- 23669744 TI - TWIN SISTER OF FT, GIGANTEA, and CONSTANS have a positive but indirect effect on blue light-induced stomatal opening in Arabidopsis. AB - FLOWERING LOCUS T (FT) is the major regulatory component controlling photoperiodic floral transition. It is expressed in guard cells and affects blue light-induced stomatal opening induced by the blue-light receptor phototropins phot1 and phot2. Roles for other flowering regulators in stomatal opening have yet to be determined. We show in Arabidopsis (Arabidopsis thaliana) that TWIN SISTER OF FT (TSF), CONSTANS (CO), and GIGANTEA (GI) provide a positive effect on stomatal opening. TSF, which is the closest homolog of FT, was transcribed in guard cells, and light-induced stomatal opening was repressed in tsf-1, a T-DNA insertion mutant of TSF. Overexpression of TSF in a phot1 phot2 mutant background gave a constitutive open-stomata phenotype. Then, we examined whether CO and GI, which are upstream regulators of FT and TSF in photoperiodic flowering, are involved in stomatal opening. Similar to TSF, light-induced stomatal opening was suppressed in the GI and CO mutants gi-1 and co-1. A constitutive open-stomata phenotype was observed in GI and CO overexpressors with accompanying changes in the transcription of both FT and TSF. In photoperiodic flowering, photoperiod is sensed by photoreceptors such as the cryptochromes cry1 and cry2. We examined stomatal phenotypes in a cry1 cry2 mutant and in CRY2 overexpressors. Light induced stomatal opening was suppressed in cry1 cry2, and the transcription of FT and TSF was down-regulated. In contrast, the stomata in CRY2 overexpressors opened even in the dark, and FT and TSF transcription was up-regulated. We conclude that the photoperiodic flowering components TSF, GI, and CO positively affect stomatal opening. PMID- 23669745 TI - The MOSS Physcomitrella patens reproductive organ development is highly organized, affected by the two SHI/STY genes and by the level of active auxin in the SHI/STY expression domain. AB - In order to establish a reference for analysis of the function of auxin and the auxin biosynthesis regulators SHORT INTERNODE/STYLISH (SHI/STY) during Physcomitrella patens reproductive development, we have described male (antheridial) and female(archegonial) development in detail, including temporal and positional information of organ initiation. This has allowed us to define discrete stages of organ morphogenesis and to show that reproductive organ development in P. patens is highly organized and that organ phyllotaxis differs between vegetative and reproductive development. Using the PpSHI1 and PpSHI2 reporter and knockout lines, the auxin reporters GmGH3(pro):GUS and PpPINA(pro):GFP-GUS, and the auxin-conjugating transgene PpSHI2(pro):IAAL, we could show that the PpSHI genes, and by inference also auxin, play important roles for reproductive organ development in moss. The PpSHI genes are required for the apical opening of the reproductive organs, the final differentiation of the egg cell, and the progression of canal cells into a cell death program. The apical cells of the archegonium, the canal cells, and the egg cell are also sites of auxin responsiveness and are affected by reduced levels of active auxin, suggesting that auxin mediates PpSHI function in the reproductive organs. PMID- 23669747 TI - New meso-substituted trans-A(2)B(2) di(4-pyridyl)porphyrins as building blocks for metal-mediated self-assembling of 4 + 4 Re(I)-porphyrin metallacycles. AB - The reaction between 5-(4-pyridyl)dipyrrylmethane and aromatic aldehydes affords meso-arylsubstituted trans-A2B2 di(4-pyridyl)porphyrins which are key building blocks in the metal-mediated self-assembling of supramolecular structures. A careful optimization of the reaction conditions allowed us to obtain 5,15 diphenyl-10,20-di(4-pyridyl)porphyrin (P1), and two analogues bearing on the meso phenyl substituents two dipropyl- (P4) or dihexyl-alkyl chains (P5), with yields ranging from 53 to 63%. Porphyrin P1 reacts with Re(CO5)Br to give the expected 4 + 4 Re(I)-porphyrin metallacycle which has been fully characterized by means of infrared, NMR and UV-Vis (absorption and emission) spectroscopies and by guest inclusion studies. Unexpectedly the addition of alkyl chains to the porphyrin fragment, which increase the solubility of the porphyrin in organic solvents, has the opposite effect on the adduct with Re(I). Indeed, the reaction between Re(CO5)Br and porphyrins P4,5 gives very insoluble materials, hampering their complete characterization. PMID- 23669746 TI - Coordination of Leaf Photosynthesis, Transpiration, and Structural Traits in Rice and Wild Relatives (Genus Oryza). AB - The genus Oryza, which includes rice (Oryza sativa and Oryza glaberrima) and wild relatives, is a useful genus to study leaf properties in order to identify structural features that control CO(2) access to chloroplasts, photosynthesis, water use efficiency, and drought tolerance. Traits, 26 structural and 17 functional, associated with photosynthesis and transpiration were quantified on 24 accessions (representatives of 17 species and eight genomes). Hypotheses of associations within, and between, structure, photosynthesis, and transpiration were tested. Two main clusters of positively interrelated leaf traits were identified: in the first cluster were structural features, leaf thickness (Thick(leaf)), mesophyll (M) cell surface area exposed to intercellular air space per unit of leaf surface area (S(mes)), and M cell size; a second group included functional traits, net photosynthetic rate, transpiration rate, M conductance to CO(2) diffusion (g(m)), stomatal conductance to gas diffusion (g(s)), and the g(m)/g(s) ratio.While net photosynthetic rate was positively correlated with gm, neither was significantly linked with any individual structural traits. The results suggest that changes in gm depend on covariations of multiple leaf (S(mes)) and M cell (including cell wall thickness) structural traits. There was an inverse relationship between Thick(leaf) and transpiration rate and a significant positive association between Thick(leaf) and leaf transpiration efficiency. Interestingly, high g(m) together with high g(m)/g(s) and a low S(mes)/g(m) ratio (M resistance to CO(2) diffusion per unit of cell surface area exposed to intercellular air space) appear to be ideal for supporting leaf photosynthesis while preserving water; in addition, thick M cell walls may be beneficial for plant drought tolerance. PMID- 23669748 TI - Toxicokinetics of alpha-thujone following intravenous and gavage administration of alpha-thujone or alpha- and beta-thujone mixture in male and female F344/N rats and B6C3F1 mice. AB - Plants containing thujone have widespread use and hence have significant human exposure. alpha-Thujone caused seizures in rodents following gavage administration. We investigated the toxicokinetics of alpha-thujone in male and female F344/N rats and B6C3F1 mice following intravenous and gavage administration of alpha-thujone or a mixture of alpha- and beta-thujone (which will be referred to as alpha,beta-thujone). Absorption of alpha-thujone following gavage administration was rapid without any dose-, species-, sex- or test article related effect. Absolute bioavailability of alpha-thujone following administration of alpha-thujone or alpha,beta-thujone was generally higher in rats than in mice. In rats, females had higher bioavailability than males following administration of either test article although a sex difference was not observed in mice. Cmax and AUCinfinity increased greater than proportional to the dose in female rats following administration of alpha-thujone and in male and female mice following administration of alpha,beta-thujone suggesting possible saturation of elimination kinetics with increasing dose. Dose-adjusted AUCinfinity for male and female rats was 5- to 15-fold and 3- to 24-fold higher than mice counterparts following administration of alpha-thujone and alpha,beta thujone, respectively (p-value<0.0001 for all comparisons). Following both intravenous and gavage administration, alpha-thujone was distributed to the brains of rats and mice with females, in general, having higher brain:plasma ratios than males. These data are in support of the observed toxicity of alpha thujone and alpha,beta-thujone where females were more sensitive than males of both species to alpha-thujone-induced neurotoxicity. In general there was no difference in toxicokinetics between test articles when normalized to alpha thujone concentration. PMID- 23669749 TI - Significance of rebounding parathyroid hormone levels during parathyroidectomy. AB - BACKGROUND: Using minimally invasive parathyroidectomy (MIP), most surgeons require a 50% decline in intraoperative parathyroid hormone (IoPTH) to determine cure, but the significance of IoPTH kinetics occurring after this drop remains unknown. The aim of this study was to determine the impact of IoPTH levels that first meet criteria for cure, but then increase again, or rebound, between 10 and 15 min postexcision. METHODS: We conducted a retrospective review of patients undergoing initial parathyroidectomy for primary hyperparathyroidism at our institution from 2001 to 2011. Rebound IoPTH was defined as an increase in parathyroid hormone >=5 pg/mL after achieving the 50% drop required for cure. Comparisons were evaluated with the Student t-test, chi-square test, or Fisher exact test where appropriate. RESULTS: Of the 1386 patients who met selection criteria, 86 (6.2%) patients exhibited rebound IoPTH. The mean magnitude of rebound was 13.8 +/- 3.6 pg/mL. Compared with those not displaying rebound, more patients with rebound IoPTH were treated with open parathyroidectomy rather than MIP (10.8% versus 4.5%, P < 0.01). The recurrence rate among those with rebound IoPTH was more than double that of the patients without rebound IoPTH (5.8% versus 2.2%, P = 0.03). Magnitude of rebound, however, did not correlate with recurrence. The rate of persistent disease was not different between those with and without rebound IoPTH. Rebound was a much better indicator of recurrence than patients whose final IoPTH levels were not within the normal range. CONCLUSIONS: Rebound IoPTH is more common in patients who develop recurrent hyperparathyroidism. Therefore, surgeons should closely monitor patients with rebound IoPTH for disease recurrence. PMID- 23669750 TI - The changing population of the United States and use of extracorporeal membrane oxygenation. AB - BACKGROUND: Neonatal extracorporeal membrane oxygenation (ECMO) has been widely used for the last 25 y. The impact of ethno-demographic changes on ECMO outcomes has not been fully examined. We evaluated the Extracorporeal Life Support Organization registry over a 21-y period to understand these trends. METHODS: A retrospective review of all neonates undergoing noncardiac ECMO in the United States between the years 1990 and 2010 was conducted based on the years of available live birth census data. Demographic, clinical, and outcome data were collated. Patient specifics, ECMO type, ECMO length, arterial blood gases, and mortality were analyzed. Univariate, bivariate, and multivariate analyses were then performed. Changes in ethnic composition of neonates on ECMO were compared with similar ethnic trend in available U.S. live birth data. RESULTS: Data were available for 18,130 neonates. Comparing ethnicity by year, the proportion of Caucasian neonates requiring ECMO dropped from 64.3% in 1990 to 49.5% in 2010, while African-American and Hispanic neonates on ECMO increased from 21.1% and 11.1% to 26.1% and 17.4%, respectively (P < 0.001). By diagnosis, congenital diaphragmatic hernia surpassed meconium aspiration syndrome as the leading indication for ECMO compared with 1990 (congenital diaphragmatic hernia, 21.5% 28.4%; meconium aspiration syndrome, 47.0%-15.7%; P < 0.05). ECMO mortality nearly doubled, from 18.5% to 34.0% over the study period. On adjusted analysis, African-Americans were 17% less likely to die on ECMO compared with Caucasian neonates. CONCLUSIONS: Neonates of ethnic minorities continue to disproportionally require ECMO support in comparison to their birth rates. Although ethnicity alone does not impact the outcome of these newborns, the increased requirement of ECMO may highlight the need for targeted education, improved prenatal care, and decision making in these groups. PMID- 23669760 TI - Empirical correction of thermal responses in the Solar Occultation for Ice Experiment nitric oxide measurements and initial data validation results. AB - The Solar Occultation for Ice Experiment (SOFIE) makes broadband transmission measurements centered at 5.32 MUm to determine the concentration profile of nitric oxide (NO). These measurements show a signal oscillation due to detector temperature variations that severely limit the accuracy of NO retrievals if corrections are not applied. An empirical correction was developed to remove this instrumental error. This paper describes the correction, its impact on the retrieval, and presents a comparison from 87 to 105 km versus coincident atmospheric chemistry experiment-Fourier transform spectrometer (ACE-FTS) measurements. The southern hemisphere (SH) shows excellent agreement between the datasets, with statistically insignificant differences. The northern hemisphere (NH) SOFIE measurements exhibit a low bias of -18.5% compared to ACE-FTS. NH measurements (sunrise observations) are still under study, and only SH NO data (sunset observations) are currently publicly available as of SOFIE data version 1.2. PMID- 23669751 TI - Descriptive epidemiology of femoroacetabular impingement: a North American cohort of patients undergoing surgery. AB - BACKGROUND: Symptomatic femoroacetabular impingement (FAI) is associated with hip pain, functional limitations, and secondary osteoarthritis. There is limited information from large patient cohorts defining the specific population affected by FAI. Establishing a large cohort will facilitate the identification of "at risk" patients and will provide a population for ongoing clinical research initiatives. The authors have therefore established a multicenter, prospective, longitudinal cohort of patients undergoing surgery for symptomatic FAI. PURPOSE: To report the clinical epidemiology, disease characteristics, and contemporary surgical treatment trends in North America for patients with symptomatic FAI. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Upon approval of the institutional review boards at 8 institutions, 12 surgeons enrolled consecutive patients undergoing surgical intervention for symptomatic FAI. Patient demographics, physical examination data, radiographic data, diagnoses, operative data, and standardized patient-reported outcome measures were collected. The first 1130 cases are summarized in this study. RESULTS: A total of 1076 consecutive patients (1130 hips) were enrolled; 55% (n = 622) were female, and 45% (n = 508) were male, with an average age of 28.4 years and average body mass index (BMI) of 25.1. Demographics revealed that 88% of patients who were predominantly treated for FAI were white, 19% reported a family history of hip surgery, 47.6% of hips had a diagnosis of cam FAI, 44.5% had combined cam/pincer FAI, and 7.9% had pincer FAI. Preoperative clinical scores (pain, function, activity level, and overall health) indicated a major dysfunction related to the hip. Surgical interventions were arthroscopic surgery (50.4%), surgical dislocation (34.4%), reverse periacetabular osteotomy (9.4%), limited open osteochondroplasty with arthroscopic surgery (5.8%), and limited open by itself (1.5%). More than 90% of the hips were noted to have labral and articular cartilage abnormalities at surgery; femoral head-neck osteochondroplasty was performed in 91.6% of the surgical procedures, acetabular rim osteoplasty in 36.7%, labral repair in 47.8%, labral debridement in 16.3%, and acetabular chondroplasty in 40.1%. CONCLUSION: This multicenter, prospective, longitudinal cohort is one of the largest FAI cohorts to date. In this cohort, FAI occurred predominantly in young, white patients with a normal BMI, and there were more female than male patients. The disease pattern of cam FAI was most common. Contemporary treatment was predominantly arthroscopic followed by surgical hip dislocation. PMID- 23669761 TI - Simple designs to correct all third- and fifth-order aberrations. AB - There have been a handful of optical designs published that correct all of the third- and fifth-order ray aberrations without aspherical elements. These published designs have a minimum of six elements. Presented here are designs with only four and five elements. The performance of the designs and their practical utility are discussed. PMID- 23669762 TI - Error analysis of the Golay3 optical imaging system. AB - We use aberration theory to derive a generalized pupil function of the Golay3 imaging system when astigmatisms exist in its submirrors. Theoretical analysis and numerical simulation using ZEMAX show that the point spread function (PSF) and the modulation transfer function (MTF) of the Golay3 sparse aperture system have a periodic change when there are piston errors. When the peak-valley value of the wavefront (PV(tilt)) due to the tilt error increases from zero to lambda, the PSF and the MTF change significantly, and the change direction is determined by the location of the submirror with the tilt error. When PV(tilt) becomes larger than lambda, the PSF and the MTF remain unvaried. We calculate the peaks of the signal-to-noise ratio (PSNR) resulting from the piston and tilt errors according to the Strehl ratio, and show that the PSNR decreases when the errors increase. PMID- 23669763 TI - Optical analysis of deviations in a concentrating photovoltaics central receiver system with a flux homogenizer. AB - The application of a kaleidoscope as a flux homogenizer to a concentrating photovoltaics system with a central receiver is investigated. The optical setup of a primary dish-type concentrator, a secondary homogenizer optics, and a photovoltaic receiver is simulated using ray tracing. The influence of various deviations from the ideal-namely sunshape (circumsolar radiation), shading, tracking error, and shape of the primary optical concentrator-on the performance of the homogenizer is analyzed quantitatively using the optical efficiency and the normalized standard deviation as a measure of inhomogeneity. Flux distributions for different progressively increasing deviations are discussed qualitatively. Experimental validation of the simulation is presented. It is demonstrated that the performance of the homogenizer is not particularly sensitive to sunshape. If sufficient length is provided, the homogenizer effectively compensates for tracking error, misalignment, and shape deviations of the primary concentrator. Yet despite the presence of the homogenizer, shading due to the holder of the receiver significantly affects the flux distribution at the receiver. PMID- 23669764 TI - Integral freeform illumination lens design of LED based pico-projector. AB - In this paper, an illumination lens design for a LED-based pico-projector is presented. Different from the traditional illumination systems composed by lens group, the integral illumination lens consists of a total internal reflector (TIR) and a freeform surface. TIR acts as collimation lens and its top surface formed by a freeform surface reshapes the nonuniform circular light pattern generated by TIR to be rectangular and uniform. Diameter and height of the lens are 16 and 10 mm, respectively. An optimization method to deal with the problem of extended light source is also presented in detail in this paper. According to the simulation results of the final optimized lens, 77% (neglecting the effect of polarization) of the power of light source is collected on liquid crystal on silicon panel with a 16?9 ratio and illumination uniformity achieves 92%. PMID- 23669765 TI - Micropulse differential absorption lidar for identification of carbon sequestration site leakage. AB - A scanning differential absorption lidar (DIAL) instrument for identification of carbon dioxide leaks at carbon sequestration sites has been developed and initial data has been collected at Montana State University. The laser transmitter uses two tunable discrete mode laser diodes operating in the continuous-wave mode with one locked to the online absorption wavelength and the other operating at the offline wavelength. Two in-line fiber optic switches are used to switch between online and offline operation. After the fiber optic switch, an acousto-optic modulator is used to generate a pulse train used to injection seed an erbium doped fiber amplifier to produce eye-safe laser pulses with maximum pulse energies of 66 MUJ, a pulse repetition frequency of 15 kHz, and an operating wavelength of 1.571 MUm. The DIAL receiver uses a 28 cm diameter Schmidt Cassegrain telescope to collect that backscattered light, which is then monitored using a photomultiplier tube module operating in the photon counting mode. The DIAL has measured carbon dioxide profiles from 1 to 2.5 km with 60 min temporal averaging. Comparisons of DIAL measurements with a Licor LI-820 gas analyzer point sensor have been made. PMID- 23669766 TI - Changes in chlorophyll a fluorescence of glyphosate-tolerant soybean plants induced by glyphosate: in vivo analysis by laser-induced fluorescence spectroscopy. AB - A significant increase in the use of the herbicide glyphosate has generated many questions about its residual accumulation in the environment and possible damage to crops. In this study, changes in chlorophyll a (chl-a) fluorescence induced by glyphosate in three varieties of glyphosate-resistant soybean plants were determined with an in vivo analysis based on a portable laser-induced fluorescence system. Strong suppression of chl-a fluorescence was observed for all plants treated with the herbicide. Moreover, the ratio of the emission bands in the red and far-red regions (685 nm/735 nm) indicates that the application of glyphosate led to chlorophyll degradation. The results also indicated that the use of glyphosate, even at concentrations recommended by the manufacturer, suppressed chl-a fluorescence. In summary, this study shows that fluorescence spectroscopy can detect, in vivo, very early changes in the photosynthetic status of transgenic soybeans treated with this herbicide. PMID- 23669767 TI - Measurement of the liquid crystal pretilt angle in cells with homogeneous and inhomogeneous liquid crystal director configuration. AB - Optical and electro-optical methods of liquid crystal (LC) director pretilt angle measurement are described for LC cells with homogeneous and inhomogeneous LC director distribution. The LC pretilt on both LC substrates can have the same or opposite direction. The phase retardation difference of both extraordinary and ordinary polarized rays passing through an LC cell with homogeneous and inhomogeneous LC director distribution has been calculated versus the LC pretilt angle theta(0) on the cell's substrates in the range 0<=theta(0)<=90 degrees . The experimental procedure for phase retardation difference determination by measurement of the LC cell transmission between crossed polarizers for cells with LC tilted alignment is described. The method developed can also be used in optical compensator design. PMID- 23669768 TI - Limitations and strategies to improve measurement accuracy in differential pulse width pair Brillouin optical time-domain analysis sensing. AB - In this work, we analyze the effects of Brillouin gain and Brillouin frequency drifts on the accuracy of the differential pulse-width pair Brillouin optical time-domain analysis (DPP-BOTDA). In particular, we demonstrate numerically that the differential gain is highly sensitive to variations in the Brillouin gain and/or Brillouin shift occurring during the acquisition process, especially when operating with a small pulse pair duration difference. We also propose and demonstrate experimentally a method to compensate for these drifts and consequently improve measurement accuracy. PMID- 23669769 TI - Detection of nitrogen dioxide using an external modulation diode laser. AB - We describe a nitrogen dioxide (NO(2)) detecting technique based on external modulation and correlation detection using a diode laser operating at 445 nm. The technique is suitable for real-time monitoring of nitrogen dioxide concentration because of its straightforward data evaluation, restraining noises, and a low degree of complexity. Measurements of concentrations of nitrogen dioxide have been carried out at room temperature and atmospheric pressure. The absorption signals have been extracted through the correlation detection technique and evaluated by a least-squares method. The results suggest a detection limit of 5 ppm using a 20 cm long gas cell with 100 ms integration time. PMID- 23669770 TI - Mitigating the effect of noise in the hybrid input-output method of phase retrieval. AB - Here a modification to the hybrid input-output (HIO) method of phase retrieval is presented which aides in mitigating the negative effects of low signal-to-noise ratios (SNRs). Various type of interferometers measure diffraction patterns which are used to determine the Fourier transform modulus of an objective. Interferometry often suffers from very low SNRs making phase retrieval difficult because of the sensitivity of most phase retrieval algorithms to local minima. Here we analyze the effect of noise on the HIO method. The result is used as a rationale for the proposed modification to the HIO method. The algorithm presented here introduces a filtering scheme which removes much of the Fourier modulus noise. Examples are shown and the results are compared to the HIO method with and without the proposed modification. Comparisons are also made to other methods of filtering the Fourier modulus noise. PMID- 23669772 TI - Generation and scanning of Airy beams array by combining multiphase patterns. AB - The method of superimposing multiple phase patterns to generate and deflect multi Airy beams is proposed in this paper. A Dammann grating and an optimized splitting grating are superimposed, respectively, with an Airy cubic phase pattern to generate an array of 4*4 equal-space Airy beams. By adding a deflection grating to the superimposed phase patterns, the transverse self accelerated Airy beams array can be deflected arbitrarily in two-dimensional plane. The impacts of superimposed phase patterns on the transverse acceleration and size of main lobe of Airy beams in array are discussed in this paper. Meanwhile, the accuracy of the steering method and the impact of the phase modulation depth on the size of the Airy beams are introduced. PMID- 23669773 TI - Femtosecond laser-induced breakdown spectroscopy of surface nitrate chemicals. AB - Ultrashort laser-induced breakdown spectroscopy was used to detect the emission radiation from the breakdown of surface contaminants by a femtosecond laser pulse. This study focused on the detection of visible to near-infrared radiation signatures from molecular fragments of the nitro (NO(x)) group present in the breakdown plasma, where target chemicals of potassium nitrate (KNO(3)) and sodium nitrate (NaNO(3)) were used. Spectral signatures at a wavelength region around 410 nm were observed for both KNO(3) and NaNO(3), and were identified as the fluorescence transitions of the NO(x)-molecular structures. The signatures obtained were systematically analyzed and studied as functions of laser parameters. It is shown that for laser parameters used in this study, laser pulse durations >=1 ps were not as effective as shorter pulses in generating these signatures. A visible wavelength NO(x) signature and the extended high-intensity propagation of a femtosecond laser could be advantageous to detecting nitro-group energetic materials at standoff distances. PMID- 23669774 TI - Generation of a uniform-square focal spot by a compound lens for solar concentration applications. AB - This paper describes a compound lens for solar photovoltaic system applications, which is composed of a front aspheric or Fresnel surface and a back array of concave surfaces. In contrast to earlier designs, the proposed method can simultaneously focus and shape sun light into a uniform-square pattern on the solar cell. For a square solar cell, this approach can maximize the solar cell's opto-electric conversion efficiency by enhancing the concentrated pattern's uniformity. In this article, the theoretical models of the beam shaping focused lens is derived and then compared with experimental data. The tolerance in assembling the component of the concentrator is also analyzed and the corresponding simulation and experimental results are discussed in detail. PMID- 23669775 TI - Gain-switched Yb-doped fiber laser for microprocessing. AB - The gain-switched fiber laser presents the simplest construction among pulsed lasers in the nanosecond region and consequently is also very robust. These properties make it potentially appropriate for industrial applications, especially in some types of microprocessing. However, careful design of such lasers is important in order to reach the required pulse parameters (peak power and pulse duration). To design and optimize a gain-switched fiber laser for microprocessing, a numerical model using time and spatial dependencies was developed and reported in this paper. The effects of pump power and laser length on the pulse duration and peak power were investigated by modeling gain-switched operation. Further, the results of modeling were compared to data from an experimental setup based on a Yb3+-doped gain-switched fiber laser, revealing good agreement. PMID- 23669776 TI - Polariton spectrum in nonlinear dielectric medium. AB - We obtain theoretically the phonon-polariton spectrum in nonlinear dielectric medium with the third-order Kerr-type nonlinearity. We investigate the dependence of number of the polariton spectrum branches on the intensity of electromagnetic field and demonstrate that the appearance of new branches located in the polariton spectrum gap is caused by the influence of dispersion of the third order dielectric susceptibility at the intensive electromagnetic field in the medium. The modulation instability of new spectrum branch waves leads to the appearance of the cnoidal waves or solitons. These new nonlinear waves one can use for designing optical devices such as the nonlinear optical filter converter. PMID- 23669777 TI - Depth resolution enhancement in double-detection optical scanning holography. AB - We propose an optical scanning holography system with enhanced axial resolution using two detections at different depths. By scanning the object twice, we can obtain two different sets of Fresnel zone plates to sample the same object, which in turn provides more information for the sectional image reconstruction process. We develop the computation algorithm that makes use of such information, solving a constrained optimization problem using the conjugate gradient method. Simulation results show that this method can achieve a depth resolution up to 1 MUm. PMID- 23669778 TI - Characteristics of photonic crystal fibers designed with an annular core using a single material. AB - We propose a kind of photonic crystal fiber (PCF) designed with an annular core and fabricated using a single material. Characteristics of such fibers, including the mode field distributions of both the core and cladding modes, the effective mode area of the fundamental core mode, and the dispersion profile, are investigated using the finite element method. The coupling between the fundamental mode and an excited core mode or cladding mode is discussed in order to apply the proposed design in mode-coupling devices. Results show that such a PCF may be suitable for both optical communications and optical sensing technologies. PMID- 23669779 TI - Filter properties of chirped fiber Bragg grating Fabry-Perot cavity: a potential wavelength stabilizer of diode laser. AB - We investigate filter properties of chirped fiber Bragg grating (CFBG) (Fabry Perot) F-P cavity through analyzing the coupled wave equation from one dimensional Helmholtz equation. We derive an approximate formula of the reflectivity of a CFBG F-P cavity, simulate the central wavelength detuning, and calculate the central wavelength shift with the increase of ambient temperature. In the experiments, we measured the spectra of a diode laser with an FBG/CFBG F-P cavity at 0 degrees C-110 degrees C. The experimental results show that the CFBG F-P cavity can help a diode laser to obtain a less central wavelength shift and a narrower 3 dB reflection bandwidth, compared with the FBG F-P cavity at 0 degrees C-110 degrees C. The research results indicate that the CFBG F-P cavity is a potential wavelength stabilizer of uncooled diode laser. PMID- 23669780 TI - Nonlinear swept frequency technique for CO2 measurements using a CW laser system. AB - A system using a nonlinear multiswept sine wave is described, which employs multichannel multiswept orthogonal waves, to separate channels and make multiple, simultaneous online/offline CO(2) measurements. An analytic expression and systematic method for determining the orthogonal frequencies for the unswept, linear swept, and nonlinear swept cases is presented. It is shown that one may reduce sidelobes of the autocorrelation function while preserving cross channel orthogonality, for thin cloud rejection. PMID- 23669781 TI - Investigation of optical fibers for high-repetition-rate, ultraviolet planar laser-induced fluorescence of OH. AB - We investigate the fundamental transmission characteristics of nanosecond duration, 10 kHz repetition rate, ultraviolet (UV) laser pulses through state-of the-art, UV-grade fused-silica fibers being used for hydroxyl radical (OH) planar laser-induced fluorescence (PLIF) imaging. Studied in particular are laser induced damage thresholds (LIDTs), nonlinear absorption, and optical transmission stability during long-term UV irradiation. Solarization (photodegradation) effects are significantly enhanced when the fiber is exposed to high-repetition rate, 283 nm UV irradiation. For 10 kHz laser pulses, two-photon absorption is strong and LIDTs are low, as compared to those of laser pulses propagating at 10 Hz. The fiber characterization results are utilized to perform single-laser-shot, OH-PLIF imaging in pulsating turbulent flames with a laser that operates at 10 kHz. The nearly spatially uniform output beam that exits a long multimode fiber becomes ideal for PLIF measurements. The proof-of-concept measurements show significant promise for extending the application of a fiber-coupled, high-speed OH-PLIF system to harsh environments such as combustor test beds, and potential system improvements are suggested. PMID- 23669782 TI - Canaglifozin (Invokana) for type 2 diabetes. PMID- 23669783 TI - Pasireoride (Signifor) for Cushing's disease. PMID- 23669784 TI - Heterogeneity of biochar properties as a function of feedstock sources and production temperatures. AB - The aim of this study was to quantify the influence of the two main categories of factors determining the yield and properties of biochar, i.e., feedstock properties and production conditions, here represented by the highest treatment temperature (HTT). To achieve this, a wide range of production temperatures (200 650 degrees C) and an extensive set of diverse feedstock (n=12) were used to calculate the sensitivity. The quantitative evaluation was based on statistical analysis of coefficients of variation, and thus derived indices representing the extent of influence of the two factors, i.e., a feedstock-depended heterogeneity (HF) and a temperature-depended heterogeneity (HT). The results showed that both feedstock properties and production conditions are important for determining the yield and properties of biochar, but their respective influence changes with the property or set of properties of interest. The biochar parameters most affected by feedstock properties were e.g., total organic carbon, fixed carbon, and mineral elements of biochar. On the other hand, biochar surface area and pH was mainly influenced by highest treatment temperature. Biochar recalcitrance was mainly determined by production temperature, while the potential total C sequestration (product of recalcitrance and pyrolysis carbon yield) depended more on feedstock. Overall, the work sheds some light on the relative importance of different biochar production process parameters on the final biochar product, which is an important step towards "designed" biochar. PMID- 23669785 TI - Effects of water vapor on flue gas conditioning in the electric fields with corona discharge. AB - Sulfur dioxide (SO2) removal via pulsed discharge nonthermal plasma in the absence of ammonia was investigated to determine how electrostatic precipitators (ESPs) can effectively collect particulate matter less than 2.5MUm in diameter from flue gas. SO2 removal increased as water vapor concentration increased. In a wet-type plasma reactor, directing a gas-phase discharge plasma toward the water film surface significantly enhanced the liquid-phase oxidation of HSO3(-) to SO4(2-). Comparisons of various absorbents revealed that the hydroxyl radical is a key factor in plasma-induced liquid-phase reactions. The resistivity, size distribution, and cohesive force of fly ash at different water vapor contents were measured using a Bahco centrifuge, which is a dust electrical resistivity test instrument, as well as a cohesive force test apparatus developed by the researchers. When water vapor content increased by 5%, fly ash resistivity in flue gas decreased by approximately two orders of magnitude, adhesive force and size increased, and specific surface area decreased. Therefore, ESP efficiency increased. PMID- 23669786 TI - Visible light photodegradation of phenanthrene catalyzed by Fe(III)-smectite: role of soil organic matter. AB - In the present study, phenanthrene is employed as a model to explore the roles played by three soil organic matter (SOM) fractions, i.e., dissolved organic matter (DOM), humic acid (HA), and fulvic acid (FA), in its photodegradation with assistance of Fe(III)-smectite under visible-light. Slight decrease in phenanthrene photodegradation rate was observed in the presence of DOM, which is explained in terms of oxidative-radical competition between DOM and target phenanthrene molecules due to the high electron-donor capacity of phenolic moieties in DOM. On the other hand, a critic content is observed with FA (0.70mg/g) and HA (0.65mg/g). Before reaching the critic content, the removal of phenanthrene is accelerated; while after that, the photodegradation rate is suppressed. The acceleration of phenanthrene degradation can be attributed to the photosensitization of FA and HA. Due to the strong interaction between phenanthrene and the phenyl rings, however, the retention of phenanthrene on SOM Fe(III)-smectite in the presence of high content of HA or FA is enhanced, thus slowing down its photodegradation. Those observations provide valuable insights into the transformation and fate of PAHs in the natural soil environment and open a window for using clay-humic substances complexes for remediation of contaminated soil. PMID- 23669787 TI - Cr(VI) reduction by a potent novel alkaliphilic halotolerant strain Pseudochrobactrum saccharolyticum LY10. AB - A novel Cr(VI)-reducing strain, Pseudochrobactrum saccharolyticum LY10, was isolated and characterized for its high Cr(VI)-reducing ability. Strain LY10 had typical characteristics of alkali-tolerance and halotolerance. Kinetic analysis indicated that the maximum reduction rate was achieved under optimum conditions with initial pH 8.3, 20gL(-1) NaCl, 55mgL(-1) Cr(VI), and 1.47*10(9)cellsmL(-1) of cell concentration. Further mechanism studies verified that the removal of Cr(VI) was mainly achieved by a metabolism-dependent bioreduction process. Strain LY10 accumulated chromium both in and around the cells, with cell walls acting as the major binding sites for chromium. X-ray absorption near-edge structure (XANES) analysis further confirmed that the chromium immobilized by the cells was in the Cr(III) state. In the present study, Pseudochrobactrum saccharolyticum was, for the first time, reported to be a Cr(VI)-reducing bacteria. Results from this research would provide a potential candidate for bioremediation of Cr(VI) contaminated environments, especially alkaline and saline milieus with Cr(VI) at low-to-mid concentrations. PMID- 23669788 TI - Investigation of acute effects of graphene oxide on wastewater microbial community: a case study. AB - The market for graphene-based products, such as graphene oxide (GO), is projected to reach nearly $675 million by 2020, hence it is expected that large quantities of graphene-based wastes will be generated by then. Wastewater treatment plants will be one of the ultimate repositories for these wastes. Efficient waste treatment relies heavily on the functions of diverse microbial communities. Therefore, systematic investigation of any potential toxic effects of GO in wastewater microbial communities is essential to determine the potential adverse effects and the fate of these nanomaterials in the environment. In the present study, we investigate the acute toxicity, i.e. short-term and high load, effect of GO on the microbial functions related to the biological wastewater treatment process. The results showed that toxic effects of GO on microbial communities were dose dependent, especially in concentrations between 50 and 300mg/L. Bacterial metabolic activity, bacterial viability, and biological removal of nutrients, such as organics, nitrogen and phosphorus, were significantly impacted by the presence of GO in the activated sludge. Furthermore, the presence of GO deteriorated the final effluent quality by increasing the water turbidity and reducing the sludge dewaterability. Microscopic techniques confirmed penetration and accumulation of GO inside the activated sludge floc matrix. Results demonstrated that the interaction of GO with wastewater produced significant amount of reactive oxygen species (ROS), which could be one of the responsible mechanisms for the toxic effect of GO. PMID- 23669789 TI - Experimental and numerical study of the dispersion of carbon dioxide plume. AB - Carbon Capture and Storage (CCS) and Enhanced Oil Recovery (EOR) technologies have been widely applied in the environmental protection and petroleum production fields. However, accidental release of carbon dioxide may cause damage and losses during oil and gas production. This paper presents a reduced-scale field experiment designed to imitate a CO2 blowout for the purpose of acquiring concentration the distribution in the flow field. Additionally, computational fluid dynamics (CFD) code was used to perform numerical simulations of the field experiment using the k-epsilon, RNG k-epsilon and SST k-omega models. The results of these models were compared with the experimental data for validation, and statistical performance indicators were introduced to verify the simulated values. According to experimental and numerical results, the interior flow structure of a CO2 plume was analyzed together with consideration of negative buoyancy effects. The concentration as a function of time was studied by comparing the observed values and simulation results. We conclude that the CFD simulation results from the k-epsilon and SST k-omega models are in acceptable agreement with the experimental data according to the Chang's criteria, and predicted values from the RNG k-epsilon model are unsatisfactory. Therefore, the CFD techniques can be satisfactorily applied in industrial risk analysis procedures with acceptable accuracy according to the Chang's criteria. PMID- 23669790 TI - Activated carbon fibers impregnated with Pd and Pt catalysts for toluene removal. AB - Few studies have investigated the use of activated carbon fibers (ACFs) impregnated with noble metals for the catalytic oxidation of volatile organic compounds (VOCs). This study determined the removal efficiency of toluene as a function of time over ACF-supported metal catalysts. Two catalysts (Pt and Pd), five reaction temperatures (120, 150, 200, 250, and 300 degrees C), and three oxygen contents (6%, 10%, and 21%) were investigated to determine the removal of toluene. To study the effects of the characteristics of the catalysts on toluene removal, the composition and morphology of the ACFs were analyzed using the BET, XPS, ICP, and FE-SEM. The results showed that the 0.42%Pd/ACFs showed greater activity for toluene removal than did 2.68%Pt/ACFs at a reaction temperature of 200 degrees C and an oxygen content of 10%. The main removal mechanism of toluene over the 2.68%Pt/ACFs at reaction temperatures less than 200 degrees C was adsorption. The long-term catalytic activity of the 2.68%Pt/ACFs for toluene removal at a reaction temperature of 250 degrees C and an oxygen content of 10% could be obtained. Furthermore, toluene removal over the 2.68%Pt/ACFs at 200 degrees C could be enhanced with increasing oxygen content. PMID- 23669791 TI - The fate of heavy metals during combustion and gasification of contaminated biomass-a brief review. AB - The literature on the presence of heavy metals in contaminated wastes is reviewed. Various categories of materials produced from domestic and industrial activities are included, but municipal solid waste, which is a more complex material, is excluded. This review considers among the most abundant the following materials - wood waste including demolition wood, phytoremediation scavengers and chromated copper arsenate (CCA) timber, sludges including de inking sludge and sewage sludge, chicken litter and spent pot liner. The partitioning of the metals in the ashes after combustion or gasification follows conventional behaviour, with most metals retained, and higher concentrations in the finer sizes due to vaporisation and recondensation. The alkali metals have been shown to catalyse the biomass conversion, particularly lithium and potassium, although other metals are active to a lesser extent. The most prevalent in biomass is potassium, which is not only inherently active, but volatilises to become finely distributed throughout the char mass. Because the metals are predominantly found in the ash, the effectiveness of their removal depends on the efficiency of the collection of particulates. The potential for disposal into soil depends on the initial concentration in the feed material. PMID- 23669792 TI - A strategy for in vitro safety testing of nanotitania-modified textile products. AB - Titanium dioxide nanomaterials are extensively used in many applications, also for modification of textile materials. Toxicological assessment of such textile materials is currently seldom performed, mainly because of lack of appropriate guidelines. The aim of the study was to assess cytotoxic and genotoxic potential of commercially available TiO2 and TiO2/Ag NMs in pristine form as well as polypropylene fibers modified with the NMs. Both titania NMs showed a cytotoxic effect on BALB/3T3 clone A31 and V79 fibroblasts after 72-h exposure. Both NMs induced a weak genotoxic effect in comet assay, with TiO2/Ag being more active. In vitro micronucleus test on human lymphocytes revealed a weak mutagenic effect of both materials after 24h of exposure. In contrast, no significant increase in micronuclei frequency was observed in the in vitro micronucleus test on V79 fibroblasts. The 24-h extracts prepared from polypropylene fibers modified with TiO2/Ag induced a cytotoxic effect on BALB/3T3 cells which strongly depended on the mode of the fibers manufacturing. The study presents a comprehensive approach to toxicity assessment of textile fibers modified with NMs. Proposed approach may form a good "starting point" for improved future testing strategies. PMID- 23669793 TI - Studying the fate of non-volatile organic compounds in a commercial plasma air purifier. AB - Degradation of non-volatile organic compounds-environmental toxins (methyltriclosane and phenanthrene), bovine serum albumin, as well as bioparticles (Legionella pneumophila, Bacillus subtilis, and Bacillus anthracis) in a commercially available plasma air purifier based on a cold plasma was studied in detail, focusing on its efficiency and on the resulting degradation products. This system is capable of handling air flow velocities of up to 3.0m s( 1) (3200Lmin(-1)), much higher than other plasma-based reactors described in the literature, which generally are limited to air flow rates below 10Lmin(-1). Mass balance studies consistently indicated a reduction in concentration of the compounds/particles after passage through the plasma air purifier, 31% for phenanthrene, 17% for methyltriclosane, and 80% for bovine serum albumin. L. pneumophila did not survive passage through the plasma air purifier, and cell counts of aerosolized spores of B. subtilis and B. anthracis were reduced by 26- and 15-fold, depending on whether it was run at 10Hz or 50Hz, respectively. However rather than chemical degradation, deposition on the inner surfaces of the plasma air purifier occured. Our interpretation is that putative "degradation" efficiencies were largely due to electrostatic precipitation rather than to decomposition into smaller molecules. PMID- 23669794 TI - Rheumatoid arthritis: preoperative evaluation for total hip and total knee replacement surgery. AB - The role of total joint replacement surgery remains significant in the contemporary management of patients with rheumatoid arthritis (RA), despite the impact of potent biologic and synthetic disease-modifying drugs. Patients with RA have a systemic polyarticular disease, with extra-articular manifestations such as anemia as well as specific comorbidities such as cardiovascular disease, which require careful preoperative assessment for optimal outcomes and fewer adverse events. This review describes the important preoperative considerations taken to prepare a patient with RA for total hip and total knee replacement surgery. PMID- 23669795 TI - A case of isolated aorta occlusion caused by Takayasu arteritis. AB - PURPOSE: We report a rare case of Takayasu arteritis causing isolated complete obliteration of the aorta. A 24-year-old woman with night sweats, weight loss, and claudication was hospitalized because of refractory hypertension. Laboratory tests showed increased inflammatory indexes. Imaging studies revealed isolated complete occlusion of thoracic and abdominal aorta. Takayasu arteritis was diagnosed. Glucosteroids and revascularization surgery were given. Clinical symptoms were relieved immediately without relapse after operation. Revascularization surgery was the effective therapy for the patient. PMID- 23669796 TI - Signal recognition antibody-positive myopathy and response to intravenous immunoglobulin G (IVIG). PMID- 23669797 TI - MDHAQ/RAPID3 to recognize improvement over 2 months in usual care of patients with osteoarthritis, systemic lupus erythematosus, spondyloarthropathy, and gout, as well as rheumatoid arthritis. AB - OBJECTIVE: To analyze whether MDHAQ (Multidimensional Health Assessment Questionnaire) scores for physical function (FN), pain, Patient Global Estimate (PATGL), and RAPID3 (Routine Assessment of Patient Index Data, a composite of these 3 measures) document improvement in patients with osteoarthritis, systemic lupus erythematosus, spondyloarthropathy, and gout, similarly to rheumatoid arthritis. METHODS: In a solo rheumatology practice, every patient completes an MDHAQ/RAPID3 and is assigned a Physician Global Estimate (DOCGL) at every visit. Mean and median FN (0-10 scale), pain (0-10), PATGL (0-10), RAPID3 (0-30), and DOCGL (0-10) were computed at first visit and 2 months later in 141 new patients with 5 diagnoses. Proportions with RAPID3 high (>12), moderate (6.1-12), and low (3.1-6) severity and remission (<=3) were computed. Differences between baseline and 2-month follow-up for each diagnosis were analyzed using paired t tests. Mean changes over 2 months across 5 diagnoses were compared using analysis of variance. RESULTS: Mean baseline scores for all measures were in narrow ranges for all 5 diagnoses: FN 1.5 to 2.5, pain 4.2 to 5.9, PATGL 4.3 to 5.6, RAPID3 10.1 to 13.7, and DOCGL 2.4 to 4.0. Improvement for FN was 9.4% to 26.8% in all diagnoses but osteoarthritis, for pain 20.2% to 35.3% in all diagnoses, PATGL 11.3% to 30.4%, RAPID3 16.8% to 27.5%, and for DOCGL 23.8% to 36.4%, similar in 5 diagnostic groups. CONCLUSIONS: MDHAQ, RAPID3, and DOCGL document similar baseline and improvement scores in patients with 5 diagnoses. These quantitative data may supplement traditional narrative, "gestalt" descriptions in usual care of patients with any rheumatic disease. PMID- 23669798 TI - Assessing process of care in rheumatoid arthritis at McGill University hospitals. AB - OBJECTIVE: In rheumatoid arthritis (RA), quality indicators (QIs) are tools used to measure process of care. This study aimed to assess performance of selected QIs from the 2004 Arthritis Foundation's QI Set at 2 major sites of a university network of teaching hospitals. METHODS: The charts and electronic hospital records of 76 RA patients were audited to determine adherence to QIs. Logistic multivariate regression analyses were performed to investigate potential determinants of nonadherence and propose measures to facilitate better QI compliance, as a potential strategy towards RA care improvement. RESULTS: We identified consistent observance of QIs mandating prescription of disease modifying antirheumatic drug therapy for all patients, drug adjustment with disease activity, prednisone tapering, and bisphosphonate therapy if indicated for patients on glucocorticoids. However, there was either lack of documentation or true inconsistent adherence to QIs dealing with radiograph performance, functional capacity assessment, and screening for hepatitis and tuberculosis before commencement of methotrexate and biologic agents, respectively. For the specific QIs analyzed, we did not find any definite independent associations with the studied variables. CONCLUSIONS: Our findings indicate that while there is frequent evidence for adherence to certain RA quality care standards at our centers, there is less compliance to others. Strategies to optimize the performance or documentation of those found most lacking, namely, functional capacity and screening for specific drug contraindications, could improve patient care. Radiographic disease monitoring, while lacking, may represent a move toward other more sensitive methods of RA progression detection, such as joint ultrasound. The inclusion of patient- and physician-derived information could help elucidate the reasons underlying nonadherence. PMID- 23669799 TI - Association between adverse reactions to allopurinol and exposures to high maintenance doses: implications for management of patients using allopurinol. AB - OBJECTIVE: The objective of this study was to estimate the association between adverse drug reactions (ADRs) and exposure to allopurinol maintenance doses higher than those in the 1984 suggested limits of Hande et al. adjusted for level of renal function. METHODS: We conducted a retrospective review of electronic health records of patients prescribed allopurinol from January 1, 2004, to June 30, 2011, to identify those who had a definite or possible ADR to allopurinol. The associations of ADRs with maintenance doses of allopurinol 1 to 1.5 times and more than 1.5 times the suggested limits of Hande et al. compared with doses within the suggested limits of Hande et al. were estimated using logistic regression models. RESULTS: Of 4755 patients prescribed allopurinol, 2946 had a serum creatinine measured within 6 months of starting allopurinol, and of these, 1268 patients' records were reviewed. Forty-eight patients had a definite ADR to allopurinol, 2 of which were allopurinol hypersensitivity syndrome. The odds ratios of definite ADRs with maintenance doses of allopurinol 1.0 to 1.5 times and more than 1.5 times suggested compared with doses within suggested limits were, respectively, 1.42 (95% confidence interval [CI], 0.66-3.04) and 2.04 (95% CI, 0.87-4.77). Among those with an allopurinol maintenance dose more than 1.5 times suggested limits, the proportion of patients with a definite ADR was 2.6% (95% CI, 1.0%-5.2%). CONCLUSIONS: There is no significant association of high maintenance doses of allopurinol with ADRs, and the absolute risk of ADRs at doses higher than 1.5 times the 1984 suggested limits of Hande et al. is low. Cautious, gradual increases in allopurinol maintenance doses above the suggested limits of Hande et al. are warranted if necessary to achieve a serum uric acid level less than 6 mg/dL. PMID- 23669800 TI - Renal amyloidosis secondary to rheumatoid arthritis: remission of proteinuria and renal function improvement with tocilizumab. PMID- 23669801 TI - Acute polyarticular gout presenting as delirium. PMID- 23669802 TI - Palmar fasciitis and polyarthritis syndrome in pancreatic carcinoma. AB - Palmar fasciitis and polyarthritis syndrome is a rare paraneoplastic condition that may portend a diagnosis of malignancy. We describe the case of a 73-year-old man who presented with progressive palmar swelling, erythema, pain, and contractures of both hands, This presentation and associated weight loss eventually led to the diagnosis of metastatic pancreatic adenocarcinoma. This case highlights the often delayed, but important diagnosis of this unusual paraneoplastic phenomenon which can mimic arthropathy, Dupuytren contracture, and scleroderma. Our case is also the first documentation of the extensive inflammatory magnetic resonance imaging changes in palmar fasciitis and polyarthritis syndrome, which affects all tissue planes including the synovium and explains its confusing clinical manifestations. PMID- 23669803 TI - A case of bilateral hemarthrosis due to pseudoaneurysms in a patient on anticoagulation therapy. AB - Hemarthrosis can occur in patients with a predisposition to hemorrhage, such as hemophiliacs or patients on anticoagulation therapy. If hemarthrosis recurs after supportive treatment, however, other etiologies such as anatomical abnormalities should be considered. Spontaneous articular pseudoaneurysm associated with anticoagulation treatment has not been reported previously. We describe a patient on anticoagulation therapy with bilateral hemarthrosis due to pseudoaneurysms. After failing to respond to the correction of over-anticoagulation, magnetic resonance imaging led to the diagnosis of articular pseudoaneurysm. The patient was treated successfully by transarterial embolization. PMID- 23669804 TI - Spider angiomata as heralding feature of a flare with alveolar hemorrhage in apparent systemic lupus erythematosus. PMID- 23669805 TI - Persistent median artery in the wrist: from a medical curiosity to a common anatomic variant with therapeutic implications. PMID- 23669806 TI - Granulomatosis with polyangiitis presenting as Henoch-Schonlein purpura in children. AB - Granulomatosis with polyangiitis (GPA), formerly known as Wegener granulomatosis, in children is an uncommon chronic organ- and life-threatening systemic vasculitis that may share at time of initial presentation a number of clinical features in common with Henoch-Schonlein purpura (HSP), a very common and comparatively benign form of childhood vasculitis. Diagnosis of GPA requires a high index of suspicion, and antineutrophil cytoplasmic antibody tests along with tissue biopsy are helpful tools for diagnosis. We report 2 patients with GPA masqueraded as HSP at time of initial presentation. Both patients presented with nonthrombocytopenic purpura on lower extremities, in addition to abdominal pain, and/or microscopic hematuria and fulfilled both the American College of Rheumatology and the Pediatric Rheumatology European Society classification criteria for HSP. Both patients eventually developed significant renal and pulmonary disease and were diagnosed with GPA. We aim to raise awareness of such atypical presentations of GPA to avoid delayed management. PMID- 23669807 TI - An unusual cause of destructive monoarthritis. PMID- 23669808 TI - Complementary and alternative medicine and conventional medicine: hand in hand. PMID- 23669809 TI - Psoriasis and psoriatic arthropathy, historical aspects: part I. AB - Psoriasis was probably described no later than the first century AD, and the term was coined in the second century. However, a clear association between descriptions recognizable as psoriasis and articular symptoms began in the 19th century. This review was from the English-language, German, and French literature. The development of the differentiation of psoriatic arthritis from clinically similar symptoms, including relevant serologic and radiologic findings and therapeutics with a focus up to the 1960s and the recognition of the efficacy of methotrexate, is reported. PMID- 23669810 TI - Are we being open enough to all approaches to therapy of rheumatoid arthritis? PMID- 23669811 TI - Immune responses of prophenoloxidase and cytosolic manganese superoxide dismutase in the freshwater crayfish Cherax quadricarinatus against a virus and bacterium. AB - Prophenoloxidase (proPO) and cytosolic manganese superoxide dismutase (cytMnSOD) play crucial roles in crustacean innate immunity. In the present study, both of the above genes were cloned from hemocytes of the red claw crayfish Cherax quadricarinatus. A phylogenetic analysis of the amino acid sequences showed that C. quadricarinatus proPO and cytMnSOD were more closely related to the proPO and cytMnSOD of other crayfish than to those of penaeids, crabs, lobsters, or freshwater prawns. A tissue distribution analysis revealed that proPO was primarily expressed in hemocytes, gills, and the heart, while cytMnSOD was detected in all tissues examined. All of the crayfish artificially infected with white spot syndrome virus (WSSV) died within 4 days. According to a non-lethal dose, there was no mortality in crayfish when infected deliberately with Aeromonas hydrophila. Total hemocyte counts (THCs) had significantly decreased in crayfish at 48 and 72 h after infection with WSSV compared to the control group. In contrast, THCs of crayfish after A. hydrophila challenge had recovered by 48 and 72 h from a lower level at 24 h. There were similar responses in enzyme activities toward WSSV and A. hydrophila infection. Phenoloxidase (PO) and superoxide dismutase (SOD) activities per hemocyte significantly increased from 48 to 72 h compared to the control group. After WSSV challenge, expressions of proPO and cytMnSOD transcripts in hemocytes significantly decreased at 12h, then had respectively recovered and increased at 24 h. At 48-72 h, transcript levels were finally downregulated. No significant differences in the expression profiles of proPO and cytMnSOD were observed between the A. hydrophila-infected and control groups, besides the significant upregulation at 24h post-infection. These results implicate proPO and cytMnSOD in the immune response, and they presented similar expression patterns, although different defense mechanisms may exist for crayfish induced by WSSV and A. hydrophila. PMID- 23669812 TI - Note on the applicability of the F-model in analysis of pollen pool heterogeneity. AB - Measuring genetic structure of pollen gametes has become the standard approach in studies on plant mating system and pollen flow. However, the popular statistical procedure, TwoGener, provides the point estimate of the pollen pool heterogeneity based on AMOVA, implying any statistical tests regarding pollen pool structure to be based on permutation procedures. In this article, the Bayesian approach was developed based on the Dirichlet-multinomial model (the so-called F-model). Computer simulations revealed the applicability of the Bayesian method in the analysis of pollen pool heterogeneity. Compared with TwoGener, the Bayesian method appeared to have better statistical properties when estimating the inverse of heterogeneity index, mostly due to the relatively high accuracy of the Bayesian estimate when the actual heterogeneity is low. Hence, the Bayesian approach may be preferred, for example, when the effective number of pollen parents is to be assessed. Other applications and potential further developments of the Bayesian method are also briefly discussed. PMID- 23669813 TI - Comparing two methods to assess power output associated with peak oxygen uptake in cyclists. AB - The aim of this study was to compare 2 methods that are frequently used to calculate the power output (MAP) that is associated with peak oxygen uptake (VO2peak) in the exercise mode of cycling. One method calculates the MAP by extrapolation of the individual VO2 to submaximal power output relationships to the measured VO2peak (MAPDaniels), whereas the other method uses the minimal power output that elicits VO2peak during a graded VO2peak test (MAPBillat). Thirteen male competitive cyclists (VO2peak = 66 +/- 5 ml.kg.min) performed 3 test sessions; first to determine MAPDaniels and MAPBillat; second and third sessions were used to measure the time to exhaustion during continuous cycling exercise to exhaustion (Tmax), time to 95% of VO2peak, and time >= 95% of VO2peak with MAPDaniels and MAPBillat. Whether it was MAPDaniels or MAPBillat that was used on the second or third test session was randomized. There was no difference between mean MAPDaniels and mean MAPBillat (380 +/- 38 vs. 383 +/- 34 W, respectively) and their associated Tmax, time to 95% of VO2peak, and time >= 95% of VO2peak during a Tmax test. In conclusion, this study did not find any difference between MAPDaniels and MAPBillat. The practical application of this study is that the choice of a method to calculate the MAP can be determined by practicality and that findings from studies using these 2 methods are comparable. PMID- 23669814 TI - Rehabilitation protocol for patellar tendinopathy applied among 16- to 19-year old volleyball players. AB - The aim of the study was to investigate the efficacy of rehabilitation protocol applied during competitive period for the treatment of patellar tendinopathy. A total of 28 male volleyball players were divided into two groups. Fifteen from experimental group (E) and 13 from control group (C) fulfilled the same tests 3 times: before the training program started (first measurement), after 12 weeks (second measurement) and after 24 weeks (third measurement). The above-mentioned protocol included the following: USG imagining with color Doppler function, clinical testing, pain intensity evaluation with VISA-P questionnaire, leg muscle strength and power and jumping ability measurements. The key element of the rehabilitation program was eccentric squat on decline board with additional unstable surface. The essential factor of the protocol was a set of preventive functional exercises, with focus on eccentric exercises of hamstrings. Patellar tendinopathy was observed in 18% of the tested young volleyball players. Implementation of the presented rehabilitation protocol with eccentric squat on decline board applied during sports season lowered the pain level of the young volleyball players. Presented rehabilitation protocol applied without interrupting the competitive period among young volleyball players together with functional exercises could be an effective method for the treatment of patellar tendinopathy. PMID- 23669815 TI - Elastic Bands as a Component of Periodized Resistance Training. AB - Joy, JM, Lowery, RP, Oliveira de Souza, E, and Wilson, JM. Elastic bands as a component of periodized resistance training. J Strength Cond Res 30(8): 2100 2106, 2016-Variable resistance training (VRT) has recently become a component of strength and conditioning programs. Prior research has demonstrated increases in power and/or strength using low loads of variable resistance. However, no study has examined using high loads of variable resistance as a part of a periodized training protocol to examine VRT within the context of a periodized training program and to examine a greater load of variable resistance than has been examined in prior research. Fourteen National Collegiate Athletic Association division II male basketball players were recruited for this study. Athletes were divided equally into either a variable resistance or control group. The variable resistance group added 30% of their 1 repetition maximum (1RM) as band tension to their prescribed weight 1 session per week. Rate of power development (RPD), peak power, strength, body composition, and vertical jump height were measured pretreatment and posttreatment. No baseline differences were observed between groups for any measurement of strength, power, or body composition. A significant group by time interaction was observed for RPD, in which RPD was greater in VRT posttraining than in the control group. Significant time effects were observed for all other variables including squat 1RM, bench press 1RM, deadlift 1RM, clean 3RM, vertical jump, and lean mass. Although there were no significant group * time interactions, the VRT group's percent changes and effect sizes indicate a larger treatment effect in the squat and bench press 1RM values and the vertical jump performed on the force plate and vertec. These results suggest that when using variable resistance as a component of a periodized training program, power and strength can be enhanced. Therefore, athletes who add variable resistance to 1 training session per week may enhance their athletic performance. PMID- 23669816 TI - Retrospective injury epidemiology of strongman athletes. AB - This study provides the first empirical evidence of strongman training and competition injury epidemiology. Strongman athletes (n = 213) (mean +/- SD: 31.7 +/- 8.8 years, 181.3 +/- 7.4 cm, 113.0 +/- 20.3 kg, 12.8 +/- 8.1 years general resistance training, and 4.4 +/- 3.4 years strongman implement training) completed a self-reported, 4-page, 1-year retrospective survey of physical injuries that caused a missed or modified training session or competition. Analysis by age (<=30 and >30 years), body mass (<=105 and >105 kg), and competitive standard (low and high level) was conducted. Eighty-two percent of strongman athletes reported injuries (1.6 +/- 1.5 training injuries per lifter per year, 0.4 +/- 0.7 competition injuries per lifter per year, and 5.5 +/- 6.5 training injuries per 1,000-hour training). Lower back (24%), shoulder (21%), bicep (11%), knee (11%), and strains and tears of muscle (38%) and tendon (23%) were frequent. The majority of injuries (68%) were acute and were of moderate severity (47%). Strongman athletes used self-treatment (54%) or medical professional treatment (41%) for their injuries. There were significantly more competition injuries for the <=30- than the >30-year athletes (0.5 +/- 0.8 vs. 0.3 +/- 0.6, p = 0.03) and >105-kg athletes compared with the <=105-kg athletes (0.5 +/- 0.8 vs. 0.3 +/- 0.6, p = 0.014). Although 54% injuries resulted from traditional training, strongman athletes were 1.9 times more likely to sustain injury when performing strongman implement training when exposure to type of training was considered. To reduce risk of injury and improve training practices, strongman athletes should monitor technique and progressions for exercises that increase risk of lower back, shoulder, bicep, and knee musculoskeletal injuries. Clinicians should advise athletes who use of strongman resistance training programs can increase injury risk over traditional exercises. PMID- 23669817 TI - Determinants, reliability, and usefulness of a bench press repeated power ability test in young basketball players. AB - The aim of the present study was to analyze the main determinants of an upper body repeated power ability (RPA) test and to examine its reliability and usefulness. Forty-five highly trained, male, young basketball players performed the RPA test (5 sets of 5 repetitions with 30 seconds of passive recovery within sets) on 2 sessions separated by 5-7 days. Power output was registered using a linear encoder attached to the barbell. Results showed no significant differences (p > 0.05) between each set in both sessions and trivial (<0.2) effect sizes in all the analyzed variables. For every set, intraclass correlation coefficient was very high (0.96-0.98) and coefficient of variation was low (3.3%-4.3%). Because the typical error of measurement values were lower or similar than the smallest worthwhile change (SWC0.2 = 0.2 * between-subject SD), the usefulness of most variables was rated as "good" or "OK" considering that small changes would be detected by this test. The percentage of power decrement could only be used to detect large effects (>1.2 * between-subject SD). An almost perfect correlation (r = 0.99; 90% confidence interval, 0.98-0.99) was found between the average power in set 1 (APbest) and the average power over 5 sets (APmean). In conclusion, the main determinant of RPA test is APbest, and because of the high reliability scores obtained, this protocol may be used to assess upper-body RPA in relatively experienced young athletes. PMID- 23669818 TI - Changes of muscle mechanics associated with anterior cruciate ligament deficiency and reconstruction. AB - Isometric and isokinetic knee strength deficits were examined on patients with anterior cruciate ligament (ACL) injury before and after ACL reconstruction. Muscle strengths of the uninjured and injured knees were measured from an ACL injured (n = 12) and a control (n = 15) group. Five isometric (10, 30, 50, 70, and 90 degrees of knee flexion) and 5 isokinetic (50, 100, 150, 200, and 250 degrees .s) strengths of quadriceps and hamstrings were measured prereconstruction and postreconstruction (3 and 6 months). Compared with the controls, the uninjured knee showed normal strength and patterns of length tension and force-velocity relationships. Compared with the uninjured knee, the injured knees showed a generally 25-30% decrease in quadriceps and hamstrings strength with normal patterns of length-tension and force-velocity relationships. By 3 months of reconstruction, weakness of quadriceps of the injured knees was exacerbated, particularly at lengthened positions (~ 40% of the uninjured knees at knee flexion 70 and 90 degrees ) and at slower velocities (~35% of the uninjured knees at the 50 and 100 degrees .s, p < 0.05), with flattened patterns of mechanical output. By 6 months of reconstruction, the quadriceps of the injured knees still showed significant weakness (~50% of the uninjured knees) in both contraction types (isometric at knee flexion 90 degrees and isokinetic at 50 degrees .s, p < 0.05). The hamstrings of the injured knees had not shown significant changes after reconstruction. A strengthening program placing emphasis on greater knee flexion angles and slower movement speed with sufficient training duration post ACL reconstruction is recommended because of long-lasting and exacerbated weakness during 3 and 6 months postreconstruction. PMID- 23669819 TI - Fluid and electrolyte balance during two different preseason training sessions in elite rugby union players. AB - The purpose of this study was to compare fluid balance between a resistance and an aerobic training sessions, in elite rugby players. It is hypothesized that resistance exercise will result in a higher prevalence of overdrinking, whereas during the aerobic session, underdrinking will be more prevalent. As with previous fluid balance studies, this was an observational study. Twenty-six players completed the resistance training session, and 20 players completed the aerobic training session. All players were members of an elite rugby union squad competing in the southern hemisphere's premier competition. For both sessions, players provided a preexercise urine sample to determine hydration status, pre- and postexercise measures of body mass, and blood sodium concentration were taken, and the weight of drink bottles were recorded to calculate sweat rates and fluid intake rates. Sweat patches were positioned on the shoulder of the players, and these remained in place throughout each training session and were later analyzed for sodium concentration. The percentage of sweat loss replaced was higher in the resistance (196 +/- 130%) than the aerobic training session (56 +/- 17%; p = 0.002). Despite this, no cases of hyponatremia were detected. The results also indicated that more than 80% of players started training in a hypohydrated state. Fluid intake seems to differ depending on the nature of the exercise session. In this group of athletes, players did not match their fluid intakes with their sweat loss, resulting in overdrinking during resistance training and underdrinking in aerobic training. Therefore, hydration strategies and education need to be tailored to the exercise session. Furthermore, given the large number of players arriving at training hypohydrated, improved hydration strategies away from the training venue are required. PMID- 23669820 TI - Optimal stimulation parameters to detect deficits in quadriceps voluntary activation. AB - The purpose of this study was to determine optimal stimulation parameters and calculation methods to estimate quadriceps voluntary activation while minimizing participant discomfort. Twelve healthy adults (8 men and 4 women; mean +/- SD, age = 36.8 +/- 15.6 years, weight = 76.1 +/- 12.9 kg, height = 170.2 +/- 8.6 cm). Repeated maximal volitional isometric contractions (MVIC) were performed while imposing 4 stimulation combinations (10 or 2 pulses; 400 or 200 V; and variable or standardized current) with the quadriceps in a relaxed state (resting twitch [RT]) and during an MVIC. Quadriceps activation was quantified by calculating the central activation ratio and the percent activation. Discomfort was quantified using the visual analog scale. When comparing calculation methods between the same stimulation parameters, the central activation ratio calculation method produced quadriceps activation values that were significantly greater (p < 0.009) than those derived using the percent activation calculation method. The doublet pulse stimulus produced less discomfort during the RT (p < 0.04) and MVIC (p < 0.001) when compared with all other combinations using a train of stimuli (10 pulses). Correlations for all estimates of quadriceps activation were strong (r = 0.85-0.99, p < 0.001). A doublet pulse stimulus produced discomfort levels that were over 50% lower than a 10-pulse train of stimuli and correlated well (r > 0.88) with activation levels obtained with a 10-pulse train of stimuli. Therefore, the use of a doublet pulse stimulus provides quadriceps activation information equivalent to other methods while minimizing participant discomfort. PMID- 23669821 TI - The combination of plyometric and balance training improves sprint and shuttle run performances more often than plyometric-only training with children. AB - Because balance is not fully developed in children and studies have shown functional improvements with balance only training studies, a combination of plyometric and balance activities might enhance static balance, dynamic balance, and power. The objective of this study was to compare the effectiveness of plyometric only (PLYO) with balance and plyometric (COMBINED) training on balance and power measures in children. Before and after an 8-week training period, testing assessed lower-body strength (1 repetition maximum leg press), power (horizontal and vertical jumps, triple hop for distance, reactive strength, and leg stiffness), running speed (10-m and 30-m sprint), static and dynamic balance (Standing Stork Test and Star Excursion Balance Test), and agility (shuttle run). Subjects were randomly divided into 2 training groups (PLYO [n = 14] and COMBINED [n = 14]) and a control group (n = 12). Results based on magnitude-based inferences and precision of estimation indicated that the COMBINED training group was considered likely to be superior to the PLYO group in leg stiffness (d = 0.69, 91% likely), 10-m sprint (d = 0.57, 84% likely), and shuttle run (d = 0.52, 80% likely). The difference between the groups was unclear in 8 of the 11 dependent variables. COMBINED training enhanced activities such as 10-m sprints and shuttle runs to a greater degree. COMBINED training could be an important consideration for reducing the high velocity impacts of PLYO training. This reduction in stretch-shortening cycle stress on neuromuscular system with the replacement of balance and landing exercises might help to alleviate the overtraining effects of excessive repetitive high load activities. PMID- 23669823 TI - Compact remote multisensing instrument for planetary surfaces and atmospheres characterization. AB - This paper describes a prototype feasibility demonstration system of a multipurpose Raman-fluorescence spectrograph and compact lidar system suitable for planetary sciences missions. The key measurement features of this instrument are its abilities to: i) detect minerals and organics at low levels in the dust constituents of surface, subsurface material and rocks on Mars, ii) determine the distribution of trace fluorescent ions with time-resolved fluorescence spectroscopy to learn about the geological conditions under which these minerals formed, iii) inspect material toxicity from a mobile robotic platform during local site characterization, iv) measure dust aerosol and cloud distributions, v) measure near-field atmospheric carbon dioxide, and vi) identify surface CO(2) ice, surface water ice, and surface or subsurface methane hydrate. This prototype instrument and an improved follow-on design are described and have the capability for scientific investigations discussed above, to remotely investigate geological processes from a robotic platform at more than a 20-m radial distance with potential to go beyond 100 m. It also provides single wavelength (532 nm) aerosol/cloud profiling over very long ranges (>10 km with potential to 20 km). Measurement results obtained with this prototype unit from a robotic platform and calculated potential performance are presented in this paper. PMID- 23669822 TI - Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial. AB - BACKGROUND: Treprostinil is a stable prostacyclin analog approved for the treatment of pulmonary arterial hypertension (PAH) as parenteral or inhaled therapy. Treprostinil diolamine, a sustained-release oral formulation of treprostinil, was studied to determine whether it could provide a more convenient prostacyclin treatment option for patients with less severe PAH. The objective of this study was to evaluate the efficacy and safety of oral treprostinil in patients with PAH receiving stable background endothelin receptor antagonist (ERA), phosphodiesterase type 5 inhibitor (PDE-5I) therapy, or both. METHODS: A 16-week, multicenter, double-blind, placebo-controlled study in 310 patients with PAH compared bid administration of oral treprostinil (n = 157) with placebo (n = 153). The primary end point was change in 6-min walk distance at week 16. Secondary efficacy end points were World Health Organization functional class, Borg dyspnea score, dyspnea-fatigue index, signs and symptoms of PAH, and clinical worsening. RESULTS: One hundred thirty-two patients (84%) receiving oral treprostinil and 138 (90%) receiving placebo completed the study. The mean +/- SD dose of oral treprostinil at week 16 was 3.1 +/- 1.9 mg bid. The Hodges-Lehmann placebo-corrected median difference in 6MWD at week 16 was 10.0 m (95% CI, -2 to 22 m; P = .089). There were no significant changes in secondary end points. The most common adverse events associated with oral treprostinil were headache (71%), diarrhea (55%), nausea (46%), flushing (35%), and jaw pain (25%). CONCLUSIONS: The addition of oral treprostinil to background ERA and PDE-5I therapy did not result in a statistically significant improvement in exercise capacity. Side effects were common but tolerated by most subjects. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00887978; URL: www.clinicaltrials.gov. PMID- 23669824 TI - Validation of refractive index structure parameter estimation for certain infrared bands. AB - Variation of the atmospheric refraction index due to turbulent fluctuations is one of the key factors that affect the performance of electro-optical and infrared systems and sensors. Therefore, any prior knowledge about the degree of variation in the refractive index is critical in the success of field studies such as search and rescue missions, military applications, and remote sensing studies where these systems are used frequently. There are many studies in the literature in which the optical turbulence effects are modeled by estimation of the refractive index structure parameter, C(n)(2), from meteorological data for all levels of the atmosphere. This paper presents a modified approach for bulk method-based C(n)(2) estimation. According to this approach, conventional wind speed, humidity, and temperature values above the surface by at least two levels are used as input data for Monin-Obukhov similarity theory in the estimation of similarity scaling constants with a finite difference approximation and a bulk method-based C(n)(2) estimation. Compared with the bulk method, this approach provides the potential for using more than two levels of standard meteorological data, application of the scintillation effects of estimated C(n)(2) on the images, and a much simpler solution than traditional ones due to elimination of the roughness parameters, which are difficult to obtain and which increase the complexity, the execution time, and the number of additional input parameters of the algorithm. As a result of these studies, Atmospheric Turbulence Model Software is developed and the results are validated in comparison to the C(n)(2) model presented by Tunick. PMID- 23669825 TI - 3D phase-shifting fringe projection system on the basis of a tailored free-form mirror. AB - Phase-shifting fringe projection is an effective method to perform 3D shape measurements. Conventionally, fringe projection systems utilize a digital projector that images fringes into the measurement plane. The performance of such systems is limited to the visible spectral range, as most projectors experience technical limitations in UV or IR spectral ranges. However, for certain applications these spectral ranges are of special interest. We present a wideband fringe projector that has been developed on the basis of a picture generating beamshaping mirror. This mirror generates a sinusoidal fringe pattern in the measurement plane without any additional optical elements. Phase shifting is realized without any mechanical movement by a multichip LED. As the system is based on a single mirror, it is wavelength-independent in a wide spectral range and therefore applicable in UV and IR spectral ranges. We present the design and a realized setup of this fringe projection system and the characterization of the generated intensity distribution. Experimental results of 3D shape measurements are presented. PMID- 23669826 TI - Acquisition probability analysis of ultra-wide FOV acquisition scheme in optical links under impact of atmospheric turbulence. AB - Reliable data transmission in optical wireless communication is on the premise of the successful establishment of the optical link. In this paper, we propose an ultra-wide field-of-view (FOV) acquisition scheme, which combines the fisheye lens and Voigt anomalous dispersion optical filter (VADOF) to achieve rapid establishment of wireless optical links. Furthermore, the ultra-wide FOV signal receiving model for this acquisition scheme is presented to analyze the receiving performance. This acquisition scheme utilizes the fisheye lens to obtain the ultra-wide FOV, not only simplifying the system architecture of the spatial acquisition, but also reducing the acquisition time; a VADOF with ultra-narrow pass bandwidth is adopted to resist the strong background radiation induced by the ultra-wide FOV. For this ultra-wide FOV acquisition scheme, the mathematical model of long-term average acquisition probability (LTAAP) is derived based on the gamma-gamma (GG) distribution. In an atmospheric turbulence environment, the average signal count and the acquisition probability are both random variables; therefore, the probability density of the average signal count needs to be considered and LTAAP can be calculated based on the GG distribution. Comprehensive analysis and numerical results of the key parameters of this ultra wide FOV acquisition scheme, such as LTAAP, false-alarm probability, signal-to noise ratio, incident angle of beam, scintillation index, and acquisition threshold, provide an advantageous basis for the actual spatial acquisition system. PMID- 23669827 TI - Four-wave mixing in quantum dot semiconductor optical amplifiers. AB - The theory of four-wave mixing (FWM) in the quantum dot (QD) semiconductor optical amplifiers (SOAs) is discussed by combining the QD rate equations system, the quantum-mechanical density-matrix theory, and the pulse propagation in QD SOAs including the three region of QD structure ground state (GS), excited state (ES), and wetting layer. Also, relations for differential gain, gain integral, and nonlinear susceptibility of both pump, probe, and signal pulses were discussed. Gain and differential gain have been calculated for QD structure. FWM efficiency and its components [spectral hole burning (SHB), carrier heating, and carrier density pulsation] are calculated. It is found that inclusion of ES in the formulas and in the calculations is essential since it works as a carrier reservoir for GS. It is found that QD SOA with enough capture time from ES to GS will reduce the SHB component, and so it is suitable for telecommunication applications that require symmetric conversion and independent detuning. PMID- 23669828 TI - Intermodal interferometer based on a fluid-filled two-mode photonic crystal fiber for sensing applications. AB - A fluid-filled two-mode photonic crystal fiber (PCF)-based intermodal interferometer and its sensing characteristics are demonstrated and investigated. The interferometer works from the interference between LP(01) and LP(11) core modes of the fluid-filled PCF. Solutions to enhance the temperature sensitivity of the interferometer are also discussed. Via choosing a higher fluid-filled length ratio of PCF, a sensitivity of more than -340 pm/ degrees C at 1480 nm is achieved, which is the highest value for a PCF intermodal interferometer-based sensor, to our best knowledge. Furthermore, there exist significant differences in temperature and strain sensitivity for two different interference dips, thus the interferometer can be used as a dual-parameter sensor with a compact structure through matrix demodulation. PMID- 23669829 TI - Electrowetting lenses for compensating phase and curvature distortion in arrayed laser systems. AB - We have demonstrated a one-dimensional array of individually addressable electrowetting tunable liquid lenses that compensate for more than one wave of phase distortion across a wavefront. We report a scheme for piston control using tunable liquid lens arrays in volume-bound cavities that alter the optical path length without affecting the wavefront curvature. Liquid lens arrays with separately tunable focus or phase control hold promise for laser communication systems and adaptive optics. PMID- 23669830 TI - Vertical profiles of pure dust and mixed smoke-dust plumes inferred from inversion of multiwavelength Raman/polarization lidar data and comparison to AERONET retrievals and in situ observations. AB - We present for the first time vertical profiles of microphysical properties of pure mineral dust (largely unaffected by any other aerosol types) on the basis of the inversion of optical data collected with multiwavelength polarization Raman lidar. The data were taken during the Saharan Mineral Dust Experiment (SAMUM) in Morocco in 2006. We also investigated two cases of mixed dust-smoke plumes on the basis of data collected during the second SAMUM field campaign that took place in the Republic of Cape Verde in 2008. Following the experience of the Aerosol Robotic Network (AERONET), the dust is modeled as a mixture of spherical particles and randomly oriented spheroids. The retrieval is performed from the full set of lidar input data (three backscatter coefficients, two extinction coefficients, and one depolarization ratio) and from a reduced set of data in which we exclude the depolarization ratio. We find differences of the microphysical properties depending on what kind of optical data combination we use. For the case of pure mineral dust, the results from these two sets of optical data are consistent and confirm the validity of the spheroid particle model for data inversion. Our results indicate that in the case of pure mineral dust we do not need depolarization information in the inversion. For the mixture of dust and biomass burning, there seem to be more limitations in the retrieval accuracy of the various data products. The evaluation of the quality of our data products is done by comparing our lidar-derived data products (vertically resolved) to results from AERONET Sun photometer observations (column-averaged) carried out at the lidar field site. Our results for dust effective radius show agreement with the AERONET observations within the retrieval uncertainties. Regarding the complex refractive index a comparison is difficult, as AERONET provides this parameter as wavelength-dependent quantity. In contrast, our inversion algorithm provides this parameter as a wavelength-independent quantity. We also show some comparison to results from airborne in situobservation. A detailed comparison to in situ results will be left for a future contribution. PMID- 23669831 TI - Optical properties of liquids for fluidic optics. AB - We present the dispersion characteristics of 18 liquids and one resin, which are widely used as media for liquid lenses in adaptive and tunable optics and for index matching in spectrochemical analysis. These are measured by using a refractometer operating at six different wavelengths. We provide a short description of the measurement setup and present a detailed uncertainty analysis of the measurement system to provide a measure of the reliability of the data. We conclude with a catalog of refractive indices and Sellmeier coefficients of the measured liquids and show the location of the analyzed materials in an Abbe diagram. PMID- 23669832 TI - Polarization-independent adaptive lens with two different blue-phase liquid crystal layers. AB - An adaptive microlens structure is proposed using two polymer-stabilized blue phase liquid-crystal layers whose Kerr constant is largely mismatched. This device exhibits several favorable features, such as polarization independence, simple structure, and good parabolic phase profile. Its applications for 2D/3D switchable displays and other photonic devices are emphasized. PMID- 23669833 TI - Spatial coherence of broad-area laser diodes. AB - We model the spatial coherence of broad-area laser diodes (BALDs) by representing the mutual intensity as superpositions of individually fully coherent but mutually uncorrelated fields. Consideration of spectroscopic modal structure measurements and intensity-based mode recovery shows that the standard Mercer type coherent-mode expansion can lead to unsatisfactory results for real BALDs. However, we show that a so-called shifted elementary-field method provides a sufficiently accurate tool for spatial coherence and propagation modeling even if the modal structure of the BALD is severely distorted. PMID- 23669834 TI - Grating-induced omnidirectional refraction of self-collimated beams at a photonic crystal surface. AB - We report that self-collimated beams from a photonic crystal can be refracted to any direction in air by introducing an additional layer composed of dielectric rods at a photonic crystal surface. The refraction angle can be tuned from negative to positive value by adjusting the period of the additional layer. The refracted beam power can be also controllable by varying the radii of rods in the layer and the distance between the layer and the surface. The grating-induced omnidirectional refraction of self-collimated beams could provide an efficient way to manipulate light propagation and increase the possibility of application of self-collimated beams. PMID- 23669835 TI - Characterization of mirror-based modulation-averaging structures. AB - Modulation-averaging reflectors have recently been proposed as a means for improving the link margin in self-seeded wavelength-division multiplexing in passive optical networks. In this work, we describe simple methods for determining key parameters of such structures and use them to predict their averaging efficiency. We characterize several reflectors built by arraying fiber Bragg gratings along a segment of an optical fiber and show very good agreement between experiments and theoretical models. PMID- 23669836 TI - Time-of-flight laser ranging and imaging at 1550 nm using low-jitter superconducting nanowire single-photon detection system. AB - We developed a time-correlated single-photon counting (TCSPC) system based on the low-jitter superconducting nanowire single-photon detection (SNSPD) technology. The causes of jitters in the TCSPC system were analyzed. Owing to the low jitter of the SNSPD technology, a system jitter of 26.8 ps full width at half-maximum was achieved after optimizing the system. We demonstrated time-of-flight laser ranging at 1550 nm wavelength at a standoff distance of 115 m based on this TCSPC system. A depth resolution of 4 mm was achieved directly by locating the centroids of each of the two return signals. Laser imaging was also performed using the TCSPC system. This low-jitter TCSPC system using the SNSPD technology presents great potential in long-range measurements and imaging applications for low-energy-level and eye-safe laser systems. PMID- 23669837 TI - Long period fiber grating transverse load effect-based sensor for the omnidirectional monitoring of rebar corrosion in concrete. AB - From the angle of sensitivity of the long period fiber grating (LPFG) resonant transmission spectrum, we demonstrate the sensitivity of LPFG resonance peak amplitude changing with transverse loads. The design of a resonant peak modulation-based LPFG rebar corrosion sensor is described by combining the spectral characteristics of LPFG with the expansion state monitoring of rebar corrosion. LPFG spectrum curves corresponding with different rebar corrosion status of the environment under test are captured by the monitoring technique of LPFG transmission spectra, and the relationship between the resonance peak amplitude change and the state of rebar corrosion is obtained, that is, the variation of LPFG resonance peak amplitude increases with the intensifying of the degree of rebar corrosion. The experimental results numerically show that the sensor response has good regularity for a wide range of travel. PMID- 23669838 TI - Surface plasmon resonance sensor based on spectral interferometry: numerical analysis. AB - In this paper, we introduce a numerical simulation of a phase detecting surface plasmon resonance (SPR) scheme based on spectral interference. Based on the simulation, we propose a method to optimize various aspects of SPR sensors, which enables better performance in both measurement range (MR) and sensitivity. In the simulation, four parameters including the spectrum of the broadband light source, incident angle, Au film thickness, and refractive index of the prism coupler are analyzed. The results show that it is a good solution for better performance to use a warm white broadband (625-800 nm) light source, a divergence angle of the collimated incident light less than 0.02 degrees , and an optimized 48 nm thick Au film when a visible broadband light source is used. If a near-IR light source is used, however, the Au film thickness should be somewhat thinner according the specific spectrum. In addition, a wider MR could be obtained if a prism coupler with higher refractive index is used. With all the parameters appropriately set, the SPR MR could be extended to 0.55 refractive index units while keeping the sensitivity at a level of 10(-8). PMID- 23669839 TI - Estimation of channel parameters and background irradiance for free-space optical link. AB - Free-space optical communication can experience severe fading due to optical scintillation in long-range links. Channel estimation is also corrupted by background and electrical noise. Accurate estimation of channel parameters and scintillation index (SI) depends on perfect removal of background irradiance. In this paper, we propose three different methods, the minimum-value (MV), mean power (MP), and maximum-likelihood (ML) based methods, to remove the background irradiance from channel samples. The MV and MP methods do not require knowledge of the scintillation distribution. While the ML-based method assumes gamma-gamma scintillation, it can be easily modified to accommodate other distributions. Each estimator's performance is compared using simulation data as well as experimental measurements. The estimators' performance are evaluated from low- to high-SI areas using simulation data as well as experimental trials. The MV and MP methods have much lower complexity than the ML-based method. However, the ML-based method shows better SI and background-irradiance estimation performance. PMID- 23669840 TI - Studies on the spectral purity of copper-hydrogen bromide laser radiations. AB - This paper presents, for the first time to the best of our knowledge, the linewidth, frequency, and stability characteristics of a copper-HBr laser. These spectral purity attributes were found to be critically linked with the electrical input power and HBr concentration, unlike that of the optical resonator. Variation in green and yellow radiation linewidths from 4 to 4.5 GHz and from 6.5 to 8.8 GHz, linewidth fluctuations from 50 to 150 MHz and from 60 to 530 MHz as well as frequency fluctuations from 10 to 100 MHz and from 410 to 10 MHz were observed when varying the input power and HBr concentration. These results are comprehensively analyzed in terms of isotopic shift, hyperfine splitting, line broadening, and temperature and gain distribution effects relevant to this laser. PMID- 23669841 TI - Comprehensive nanostructure and defect analysis using a simple 3D light-scatter sensor. AB - Light scattering measurement and analysis is a powerful tool for the characterization of optical and nonoptical surfaces. A new 3D scatter measurement system based on a detector matrix is presented. A compact light-scatter sensor is used to characterize the scattering and nanostructures of surfaces and to identify the origins of anisotropic scattering features. The results from the scatter sensor are directly compared with white light interferometry to analyze surface defects as well as surface roughness and the corresponding scattering distributions. The scattering of surface defects is modeled based on the Kirchhoff integral equation and the approach of Beckmann for rough surfaces. PMID- 23669842 TI - Computation of highly off-axis diffracted fields using the band-limited angular spectrum method with suppressed Gibbs related artifacts. AB - The angular spectrum (AS) method is a popular solution to the Helmholtz equation without the use of approximations. Modified band-limited AS methods are of particular interest for the cases of high-off-axis and large distance propagation problems, because conventional AS methods are impractical due to requirements regarding memory and computational effort. However, these techniques make use of rectangular-shaped filters that introduce ringing artifacts in the calculated field that are related to the Gibbs phenomenon. This work proposes AS algorithms based on a smooth band-limiting filter for accurate field computation as well as techniques that evaluate only nonzero components of the field. This enables accurate field calculations with an acceptable level of computational effort that cannot be offered by current AS methods reported in the scientific literature. PMID- 23669843 TI - Comparative research of multichannel slab and discharge tube CO2 lasers. AB - The laser power and beam quality of the high-power CO(2) laser are very important for laser applications. The multichannel slab discharge CO(2) laser (MSDL) and the multichannel discharge tube CO(2) laser (MDTL) are two main lasers, which have different functions. Two lasers and laser beams are compared and studied quantitatively from the following factors: intensity distribution, M(2) factor, phase locking, misalignment, and output power. It is shown that MSDL could obtain the laser beam with high power when the misaligned angle is small, but the beam quality is poor in comparison with that of MDTL. MSDL is more sensitive to the misaligned angle than MDTL. PMID- 23669844 TI - Terahertz polarization splitter based on orthogonal microstructure dual-core photonic crystal fiber. AB - A broadband polarization splitter operating in the terahertz (THz) band is proposed based on dual-core photonic crystal fiber with orthogonal microstructure in the core regions. The Index Converse Matching Coupling method is presented to design the THz polarization splitter for the first time, which exhibits several advantages, such as short splitting length, high extinction ratio, low loss, and broad operation bandwidth. By numerical simulation, it has been found that the strong coupling occurs within a frequency range of 0.4-0.7 THz. The operation bandwidth is more than 0.15 THz (equal to 138 MUm). The shortest splitting length is only 1.83 cm at 0.4 THz. The extinction ratios for both of x and ypolarization are better than -15 dB when the frequency is larger than 0.51 THz. The lowest material absorption loss is only 0.34 dB at 0.4 THz. Moreover, this structure is simple to design and easy to fabricate over its counterparts in the communication band. Our research offers an effective method to design a broadband THz device and would be of significance for future relevant applications. PMID- 23669845 TI - High-speed free-space quantum key distribution system for urban daylight applications. AB - We report a free-space quantum key distribution system designed for high-speed key transmission in urban areas. Clocking the system at gigahertz frequencies and efficiently filtering background enables higher secure key rates than those previously achieved by similar systems. The transmitter and receiver are located in two separate buildings 300 m apart in downtown Madrid and they exchange secure keys at rates up to 1 Mbps. The system operates in full bright daylight conditions with an average secure key rate of 0.5 Mbps and 24 h stability without human intervention. PMID- 23669846 TI - Spectra analysis of nonuniform FBG-based acousto-optic modulator by using Fourier mode coupling theory. AB - Fourier mode coupling theory was first employed in the spectral analysis of several nonuniform fiber Bragg grating (FBG)-based acousto-optic modulators (NU FBG-AOMs) with the effects of Gaussian-apodization (GA), phase shift (PS), and linear chirp (LC). Because of the accuracy and simplicity of the algorithm applied in this model, the modulation performances of these modulators can be acquired effectively and efficiently. Based on the model, the reflected spectra of these modulators were simulated under various acoustic frequencies and acoustically induced strains. The simulation results of the GA-FBG-AOM and PS-FBG AOM showed that the wavelength spacing between the primary reflection peak and the secondary reflection peak is proportional to the acoustic frequency, and the reflectivity of reflection peaks depends on the acoustically induced strains. But for the LC-FBG-AOM, the wavelength spacing between the neighboring reflection peaks increased linearly and inversely with the acoustic frequency, and the extinction ratio of each peak relates to the acoustically induced strain. These numerical analysis results, which were effectively used in the designs and fabrications of these NU-FBG-AOMs, can broaden the AOM-based application scope and shed light on the performance optimization of optical wavelength-division multiplex system. PMID- 23669847 TI - High-resolution simultaneous microscopy of refractive index and fluorescent intensity distributions by using localized surface plasmons. AB - We propose a localized surface plasmon microscope that provides simultaneous imaging of refractive index and fluorescent intensity distributions. We show experimental images of fluorescent and transparent particles under circular pupil illumination to confirm simultaneous high-resolution imaging. Furthermore, we investigate applicability of annular pupil illumination employing two axicons to improve energy efficiency in the fluorescent imaging and find that a brighter image is obtainable by maintaining high spatial resolution for both imaging modes. PMID- 23669848 TI - Modeling of laser interactions with composite materials. AB - We develop models of laser interactions with composite materials consisting of fibers embedded within a matrix. A ray-trace model is shown to determine the absorptivity, absorption depth, and optical power enhancement within the material, as well as the angular distribution of the reflected light. We also develop a macroscopic model, which provides physical insight and overall results. We show that the parameters in this model can be determined from the ray trace model. PMID- 23669849 TI - Numerical investigation on the effects of fabrication conditions on fiber Bragg grating spectra using the phase mask technique. AB - A numerical investigation on how fiber Bragg grating fabrication conditions using the phase mask technique affect the harmonic components of the Bragg wavelength is presented. Both the properties of the phase mask and saturation effects are investigated to determine the underlying cause of the rise of various harmonic reflections other than the Bragg wavelength. Results are compared with published data by various authors. PMID- 23669850 TI - Approach to frequency estimation in self-mixing interferometry: multiple signal classification. AB - Based on the nature of self-mixing signals, we propose the use of the multiple signal classification (MUSIC) algorithm in place of the fast Fourier transform (FFT) for processing signals obtained from self-mixing interferometry (SMI). We apply this algorithm to two representative SMI measurement techniques: range finding and velocimetry. Applying MUSIC to SMI range finding, we find its signal to-noise ratio performance to be significantly better than that of the FFT, allowing for more robust, longer-range measurement systems. We further demonstrate that MUSIC enables a fundamental change in how SMI Doppler velocity measurement is approached, letting one discard the complex fitting procedure and allowing for a real-time frequency estimation process. PMID- 23669851 TI - Block-based mask optimization for optical lithography. AB - Pixel-based optical proximity correction (PBOPC) methods have been developed as a leading-edge resolution enhancement technique (RET) for integrated circuit fabrication. PBOPC independently modulates each pixel on the reticle, which tremendously increases the mask's complexity and, at the same time, deteriorates its manufacturability. Most current PBOPC algorithms recur to regularization methods or a mask manufacturing rule check (MRC) to improve the mask manufacturability. Typically, these approaches either fail to satisfy manufacturing constraints on the practical product line, or lead to suboptimal mask patterns that may degrade the lithographic performance. This paper develops a block-based optical proximity correction (BBOPC) algorithm to pursue the optimal masks with manufacturability compliance, where the mask is shaped by a set of overlapped basis blocks rather than pixels. BBOPC optimization is formulated based on a vector imaging model, which is adequate for both dry lithography with lower numerical aperture (NA), and immersion lithography with hyper-NA. The BBOPC algorithm successively optimizes the main features (MF) and subresolution assist features (SRAF) based on a modified conjugate gradient method. It is effective at smoothing any unmanufacturable jogs along edges. A weight matrix is introduced in the cost function to preserve the edge fidelity of the printed images. Simulations show that the BBOPC algorithm can improve lithographic imaging performance while maintaining mask manufacturing constraints. PMID- 23669852 TI - Generation of sub-100 ps pulses with a peak power of 65 W by gain switching, pulse shortening, and pulse amplification using a semiconductor-based master oscillator-power amplifier system. AB - We present a method of the generation of sub-100 ps pulses with an all semiconductor master oscillator-power amplifier (MOPA) system, consisting of a three section distributed Bragg reflector (DBR) laser as MO and a two section tapered PA. The pulses generated by the gain-switched DBR laser are first shortened by the ridge-waveguide input section of the PA acting as a saturable absorber and then amplified by the tapered gain region section. We generate laser pulses with a minimum duration of 35 ps and a peak power of more than 65 W. The spectral width is less than 0.25 nm around a center wavelength of 1063 nm. PMID- 23669853 TI - Analysis of the chromaticity of near-field binary beam shapers. AB - The chromatic properties of binary beam shapers inducing a spatially dependent transmission on the near field of an optical source after far-field filtering and imaging are derived. Beam shapers using pixels with two transmission states are highly versatile and have been experimentally realized with distributions of amplitude pixels, phase pixels, or polarization pixels that can be designed using a half-toning algorithm. The amplitude of the shaped beam in an image plane has a precisely controlled continuous profile given by the local density of the two pixel types in the object plane. The wavelength dependence of the field transmission corresponding to the full range of design transmission between 0 and 1 is studied analytically to assess the general performance of the corresponding beam shapers for broadband sources, with an example of a specific 2D transmission profile relevant to laser engineering. Amplitude beam shapers have no significant chromaticity, but have low damage threshold. The high-damage-threshold twisted nematic liquid crystal and phase shapers induce a wavelength-dependent transmission and phase on the shaped beam. PMID- 23669854 TI - Iterative phase-shifting algorithm immune to random phase shifts and tilts. AB - An iterative phase-shifting algorithm based on the least-squares principle is developed to overcome the random piston and tilt wavefront errors generated from the phase shifter. The algorithm iteratively calculates the phase distribution and the phase-shifting map to minimize the sum of squared errors in the interferograms. The performance of the algorithm is evaluated via computer simulations and validated by the Fizeau interferometer measurements. The results show that the proposed algorithm has a fast convergence rate and satisfactory phase-estimation accuracy, improving the measurement precision of the phase shifting interferometers with significant phase-shifter errors. PMID- 23669855 TI - Optical coherence tomography for vulnerability assessment of sandstone. AB - Sandstone is an important cultural heritage material, in both architectural and natural settings, such as neolithic rock art panels. The majority of deterioration effects in porous materials such as sandstone are influenced by the presence and movement of water through the material. The presence of water within the porous network of a material results in changes in the optical coherence tomography signal intensity that can be used to monitor the wetting front of water penetration of dry porous materials at various depths. The technique is able to detect wetting front velocities from 1 cm s(-1) to 10(-6) cm s(-1), covering the full range of hydraulic conductivities likely to occur in natural sandstones from pervious to impervious. PMID- 23669856 TI - Computer vision applications for coronagraphic optical alignment and image processing. AB - Modern coronagraphic systems require very precise alignment between optical components and can benefit greatly from automated image processing. We discuss three techniques commonly employed in the fields of computer vision and image analysis as applied to the Gemini Planet Imager, a new facility instrument for the Gemini South Observatory. We describe how feature extraction and clustering methods can be used to aid in automated system alignment tasks, and also present a search algorithm for finding regular features in science images used for calibration and data processing. Along with discussions of each technique, we present our specific implementation and show results of each one in operation. PMID- 23669857 TI - All-optical NAND/NOT/AND/OR logic gates based on combined Brillouin gain and loss in an optical fiber. AB - A combined Brillouin gain and loss process has been proposed in a polarization maintaining optical fiber to realize all-optical NAND/NOT/AND/OR logic gates in the frequency domain. A model describing the interaction of a Stokes, anti Stokes, and continuous wave and two acoustic waves inside a fiber, ranging in length from 350-2300 m, was used to theoretically model the gates. Through the optimization of the pump depletion and gain saturation in the combined gain and loss process, switching contrasts of 20%-83% have been simulated for different configurations. PMID- 23669858 TI - Sputter deposition of PZT piezoelectric films on thin glass substrates for adjustable x-ray optics. AB - Piezoelectric PbZr(0.52)Ti(0.48)O(3) (PZT) thin films deposited on thin glass substrates have been proposed for adjustable optics in future x-ray telescopes. The light weight of these x-ray optics enables large collecting areas, while the capability to correct mirror figure errors with the PZT thin film will allow much higher imaging resolution than possible with conventional lightweight optics. However, the low strain temperature and flexible nature of the thin glass complicate the use of chemical-solution deposition due to warping of the substrate at typical crystallization temperatures for the PZT. RF magnetron sputtering enabled preparation of PZT films with thicknesses up to 3 MUm on Schott D263 glass substrates with much less deformation. X-ray diffraction analysis indicated that the films crystallized with the perovskite phase and showed no indication of secondary phases. Films with 1 cm(2) electrodes exhibited relative permittivity values near 1100 and loss tangents below 0.05. In addition, the remanent polarization was 26 MUC/cm(2) with coercive fields of 33 kV/cm. The transverse piezoelectric coefficient was as high as -6.1+/-0.6 C/m(2). To assess influence functions for the x-ray optics application, the piezoelectrically induced deflection of individual cells was measured and compared with finite element-analysis calculations. The good agreement between the results suggests that actuation of PZT thin films can control mirror figure errors to a precision of about 5 nm, allowing sub-arcsecond imaging. PMID- 23669859 TI - Fabrication, characterization, and simulation of a cantilever-based airflow sensor integrated with optical fiber. AB - In this paper, we present the fabrication and packaging of a cantilever-based airflow sensor integrated with optical fiber. The sensor consists of a micro Fabry-Perot (FP) cavity including a fiber and a micro cantilever that is fabricated using the photolithography method. Airflow causes a small deflection of the micro cantilever and changes the cavity length of the FP, which makes the fringe shift. The pressure distribution and velocity streamlines across the cantilever resulted from the airflow in the channel have been simulated by the finite element method. The experimental results demonstrate that the sensor has a linear sensitivity of 190 [fringe shift (pm)] per (l/min) and a minimum detectable airflow change of 0.05 (l/min). PMID- 23669860 TI - Self-polarization smoothing technique based on 2*2 beam array and type II+II third-harmonic generation system. AB - Polarization smoothing (PS) is highly desired for inertial confinement fusion, high-power laser facilities. A self-PS technique based on 2*2 beam array and type II+II third-harmonic generation (THG) system is proposed in this paper. This scheme takes advantage of a type II+II THG system, which induces a 35 degrees angle between the polarization states of output third-harmonic laser and input fundamental laser. It rotates two THG systems in a 2*2 beam array by 180 degrees to obtain a 70 degrees polarization angle between two sets of output lasers. Simulation results show that the intensity contrast of the overlapped focal spot can be reduced at 1.34* without inserting any additional optics. This approaches the maximum value of various PS techniques (i.e., 1.41*). PMID- 23669861 TI - Schlieren measurements in the round cylinder of an optically accessible internal combustion engine. AB - This paper describes the design and experimental application of an optical system to perform schlieren measurements in the curved geometry of the cylinder of an optically accessible internal combustion engine. Key features of the system are a pair of cylindrical positive meniscus lenses, which keep the beam collimated while passing through the unmodified, thick-walled optical cylinder, and a pulsed, high-power light-emitting diode with narrow spectral width. In combination with a high-speed CMOS camera, the system is used to visualize the fuel jet after injection of hydrogen fuel directly into the cylinder from a high pressure injector. Residual aberrations, which limit the system's sensitivity, are characterized experimentally and are compared to the predictions of ray tracing software. PMID- 23669862 TI - Ammonia solution strengthened three-dimensional macro-porous graphene aerogel. AB - Recently, many approaches were applied for assembling graphene sheets into a three-dimensional structure. However, it is still a great challenge to obtain a three-dimensional macroporous graphene network with high mechanical strength after drying. Herein, an ammonia strengthened three-dimensional graphene aerogel was prepared. Based on graphene chemistry and ice physics, the mechanical strength of graphene aerogel was improved greatly when the graphene hydrogel was treated by ammonia solution at an ambient temperature. The results demonstrated that the three-dimensional structure of graphene aerogels was destroyed thoroughly without ammonia solution treatment; conversely, the three-dimensional structure was maintained and the compressive strength was improved to 152 kPa at the static load after it was treated by ammonia solution at 90 degrees C for only 1 h. This phenomenon is due to two reasons: (1) the low freezing point of ammonia solution, which effectively retarded its freezing and then kept the porous structure undestroyed; (2) the reaction between ammonia and graphene hydrogel, which brought some covalent bonds among graphene sheets. We believe our efforts may pave the way for the development and application of three-dimensional graphene based materials. PMID- 23669863 TI - Increased proliferation of human bladder smooth muscle cells is mediated by physiological cyclic stretch via the PI3K-SGK1-Kv1.3 pathway. AB - It is well known that specific mechanical stimuli induce positive changes in the physiological function and status of a number of cell types. However, an in-depth understanding of the application of mechanical forces has yet to be developed. The aim of the present study was to explore the optimal elongation and frequency of stretch-induced proliferation of human bladder smooth muscle cells (HBSMCs) and to investigate the mechanism involved in this process. HBSMCs were seeded in a silicone membrane and subjected to cyclic stretch of 2.5, 5, 10 and 15% equibiaxial elongation at frequencies of 0.05, 0.1, 0.2, 0.5 and 1 Hz, respectively. Bromodeoxyuridine (BrdU) assays were used to detect the proliferative activity of each group. To further determine the mechanism of the cell proliferation process triggered by physiological cyclic stretch, the expression of PI3K/SGK1/Akt/Kv1.3 was investigated at the transcriptional and translational levels by RT-PCR and western blot analysis, respectively. Optimal physiological stretch was established as 5% elongation at a frequency of 0.1 Hz, whereby HBSMCs revealed a marked increase in proliferative activity compared with the other groups, including the non-stretched group, which served as the control (P<0.05). The expression of PI3K/SGK1/Kv1.3; however, not Akt, were upregulated by cyclic stretch as compared with the control group. When separately treated with inhibitors of SGK1 and Kv1.3, increased stretch-induced proliferation was largely eliminated. These results markedly indicate that cyclic stretch induces the proliferation of HBSMCs and the PI3K-SGK1-Kv1.3 pathway is involved in this process, either fully or at least partially, rather than its related pathway, PI3K-Akt. PMID- 23669864 TI - A micro-rheological method for determination of blood type. AB - The measurement of time and distance can be used for determining agglutination in small (nL) samples of liquid. We demonstrate the use of this new scheme of detection in typing and subtyping blood in a simple microfluidic system that monitors the speed of flow of microdroplets. The system (i) accepts small samples of liquids deposited directly onto the chip, (ii) forms droplets on demand from these samples, (iii) merges the droplets, and (iv) measures their speed in a microchannel. A sequence of measurements on different combinations of blood and antibodies can thus be used to determine blood type with the estimated probability of mistyping being less than 1 in a million tests. In addition, in the agglutinated samples, red blood cells concentrate at the rear of the droplets yielding an additional vista for detection and suggesting a possible mechanism for separations. PMID- 23669865 TI - Neurogastroenterology: Mind-changing IBS therapy. PMID- 23669867 TI - Multiple sclerosis and mitochondrial gene variations: a review. AB - Multiple sclerosis (MS) is a debilitating disease of the central nervous system. Its etiology is still an unanswered enigma; its symptoms are varied and unpredictable; and there is no cure for it. Genetics has been introduced as a contributing factor to MS. Not only may MS stem from nuclear gene variations/mutations, but also it may arise from mitochondrial gene variations/mutations. The association of mitochondrial DNA variations/mutations with the pathogenesis of MS has, so far, been analyzed by several studies. This paper reviews the literature with regard to MS and corresponding mitochondrial DNA variations. PMID- 23669866 TI - [Interferon-beta1b in multiple sclerosis therapy: more than 20 years clinical experience]. AB - The introduction of interferon-beta1b in 1993 in the USA and 2 years later in Europe made it possible for the first time to alter the course of the disease in patients with relapsing-remitting multiple sclerosis (MS). Subsequently, interferon-beta1b was approved for the treatment of patients with active secondary progressive MS (1999) and early relapsing-remitting MS following a first demyelinating event (clinically isolated syndrome, CIS) (2006). Here we provide an overview of the clinical experience gathered during more than 20 years of interferon-beta use focusing on long-term efficacy and safety and the impact of early initiation of treatment. Furthermore, the following aspects will be discussed: putative mechanisms of action of interferon-beta, indications for a disease-modifying therapy, clinical relevance of neutralizing antibodies, importance of adherence in MS therapy, high versus low frequency therapy, combination therapies with interferon-beta and safety of interferon-beta in children and adolescents with MS and during pregnancy. PMID- 23669869 TI - Parents' perceptions of child feeding: a qualitative study based on the theory of planned behavior. AB - OBJECTIVE: The aim of this qualitative study was to investigate the child-feeding behaviors and attitudes of parents of children aged 2 to 5 years, within the theory of planned behavior (TPB) framework. METHODS: Semistructured telephone interviews were conducted in October 2011. The interviewer conducted and recorded the interviews from a community health center, to interviewees who were in their own home environment. Verbatim transcription of interviews preceded manual coding of data. Emergent themes were mapped into a matrix against a priori-coded TPB constructs (attitudes, beliefs, subjective norms, perceived behavioral control, and behavioral intention). RESULTS: Twenty-one consenting parents participated in interviews. Participants were predominantly tertiary-educated (65%) mothers (85%) who were older than 30 years (76%). Parents believed that optimal child nutrition is important but difficult to achieve. Behavioral intention to change feeding practices was limited by a belief that child's dietary intake is above average compared with their peer group. Perceived control over child dietary intake was influenced by food advertising, extended family, and peer influences. Parents supported targeting nutrition education directly at children and a policy approach to offset the costs of fresh foods by taxing "junk" foods. CONCLUSIONS: The application of TPB to child feeding may explain the disparity between parents' child-feeding intentions and behaviors. Parents' feeding behaviors are more influenced by peers than by dietary guidelines. Future interventions need to target parents' perceived child-feeding responsibilities, influence subjective norms, and increase parents' perceived control over child feeding. Peer nutrition education is proposed as an intervention model. PMID- 23669868 TI - Recommendations for the emergency management of complications associated with the new direct oral anticoagulants (DOACs), apixaban, dabigatran and rivaroxaban. AB - Dabigatran, apixaban, and rivaroxaban have been approved for primary and secondary stroke prevention in patients with atrial fibrillation. However, questions have arisen about how to manage emergency situations, such as when thrombolysis would be required for acute ischemic stroke or for the managing intracranial or gastrointestinal bleedings. We summarize the current literature and provide recommendations for the management of these situations. Peak plasma levels of the direct oral anticoagulants (DOACs) apixaban, dabigatran, or rivaroxaban are observed about 2-4 h after intake. Elimination of dabigatran is mainly dependent on renal function. Consequently, if renal function is impaired, there is a risk of drug accumulation that is highest for dabigatran followed by rivaroxaban and then apixaban and thus dosing recommendations are different. To date, no bedside tests are available that reliably assess the anticoagulatory effect of DOACs, nor are specific antidotes available. We recommend performing the following tests if DOAC intake is unknown: dabigatran-associated bleeding risk is minimized or can be neglected if thrombin time, Hemoclot test, or Ecarin clotting time is normal. Apixaban and rivaroxaban effects can be ruled out if findings from the anti-factor Xa activity test are normal. High plasma levels of DOAC are also mostly excluded if PTT and PTZ are normal four or more hours after DOAC intake. However, normal values of global coagulation tests are not sufficient if thrombolysis is indicated for treating acute stroke. The decision for or against thrombolysis is an individual decision; in these cases, thrombolysis use is off-label. In case of bleeding, prothrombin complex concentrates seems to be the most plausible treatment. For severe gastrointestinal bleeding with life-threatening blood loss, the bleeding source needs to be identified and treated by invasive measures. Use of procoagulant drugs (antifibrinolytics) might also be considered. However, there is very limited clinical experience with these products in conjunction with DOAC. PMID- 23669870 TI - Parenting stress in pediatric IBD: relations with child psychopathology, family functioning, and disease severity. AB - OBJECTIVE: Parenting stress in pediatric inflammatory bowel disease (IBD) has been under-examined. Data validating use of the Pediatric Inventory for Parents (PIP), a measure of parenting stress associated with caring for a chronically ill child, in chronic diseases with intermittent, unpredictable disease courses, such as IBD, are needed. This study presents validity data in support of the PIP in pediatric IBD and examines relations between parenting stress and important psychosocial and medical outcomes. METHODS: Adolescents (N = 130) with IBD and their caregivers across 3 sites completed measures of parenting stress, family functioning, and emotional/behavioral functioning. Disease severity was also assessed for each participant. RESULTS: The PIP demonstrates excellent internal consistency. Parenting stress was significantly higher among those with unhealthy general family functioning and those with children with borderline or clinically elevated internalizing symptoms. Caregiving stress was greater among parents of youth with more active Crohn's disease. CONCLUSION: Results supported the reliability and validity of the PIP for assessing caregiving stress in pediatric IBD. Routine assessment of parenting stress is recommended, particularly among parents reporting unhealthy family functioning and parents of youth with borderline or clinically elevated internalizing symptoms and more active disease. PMID- 23669873 TI - Historic condition in a modern child with autism. AB - CASE: Haven is an 11-year-old primary care patient who you have followed since her birth. She was the 9 lb 6 oz product of a 38-week gestation complicated by maternal hypertension and seizure disorder treated with tegretol. Her delivery and neonatal course were uneventful. She was diagnosed with austistic disorder at age 2 years, at which time she used no functional language or gestures, had repetitive motor mannerisms, and limited eye contact. She had strong tactile sensory aversions. Her diet was very restricted including only banana yogurt and drinking milk and apple juice for the first several years of life. She was followed by a developmental-behavioral pediatrician approximately annually through age 8 years and then more frequently. She was healthy other than lead exposure (maximum serum level 18 at age 3 years) and multiple febrile seizures with other possible absence episodes. Her development remained very delayed with use of single words and short phrases. She developed multiple repetitive, anxious, obsessive behaviors (picking up lint, organizing, cleaning, and freezing in certain postures) that were treated with a selective serotonin reuptake inhibitors fluvoxamine. Sensory issues were ongoing, with restrictive eating (primarily peanut butter and jelly sandwiches, cereal bars, milk, and a kiwi strawberry drink). She took a liquid multivitamin until age 8.At age 11 years, 3 weeks prior to admission, Haven developed acute loss of ambulation over the course of 1 day, initially dragging her right leg, and then refusing to walk and her parents brought her in to see you. She had fever, vomiting, and general weakness. She developed extensive bruising over her legs, especially in the popliteal fossae. She was also noted to have friability and dark discoloration of her gums. Initially, you suspected a post-viral syndrome and close monitoring. She was seen twice in the next 2 weeks in a local emergency room where her erythrocyte sedimentation rate was reported to be elevated and juvenile rheumatoid arthritis or a reaction to fluvoxamine were suspected. Antibiotics were also prescribed for gingivitis. She was seen by an orthopedist who felt it was not an orthopedic issue and leg films were unremarkable. With her second emergency room visit, she was transferred to a tertiary medical center and admitted for further evaluation. Where would you go from here? PMID- 23669871 TI - Development of an expressive language sampling procedure in fragile X syndrome: a pilot study. AB - OBJECTIVE: There is a great need for valid outcome measures of functional improvement for impending clinical trials of targeted interventions for fragile X syndrome (FXS). Families often report conversational language improvement during clinical treatment, but no validated measures exist to quantify this outcome. This small-scale study sought to determine the feasibility, reproducibility, and clinical validity of highly structured expressive language sampling as an outcome measure reflecting language ability. METHODS: Narrative and conversation tasks were administered to 36 verbal participants (25 males and 11 females) with FXS (aged 5-36 years, mean, 18 +/- 7 years). Alternate versions were used with randomized task order at 2- to 3-week intervals (mean, 19.6 +/- 6.4 days). Audio recordings of sessions were transcribed and analyzed. Dependent measures reflected talkativeness (total number of utterances), utterance planning (proportion of communication [C] units with mazes), articulation (proportion of unintelligible/partly unintelligible C-units), vocabulary (number of different word roots), and syntactic ability (mean length of utterance [MLU] in words). Reproducibility of measures was evaluated with intraclass correlation coefficients (ICC). RESULTS: All participants could complete the tasks. Coded data were highly reproducible with Pearson's correlations at p < .01 for all measures and ICC values of .911 to .966 (conversation) and .728 to .940 (narration). Some measures including MLU and different word roots were correlated with expressive language subscale scores from the Vineland Adaptive Behavior Scale. CONCLUSIONS: These expressive language sampling tasks appear to be feasible, reproducible, and clinically valid and should be further validated in a larger cohort, as a promising means of assessing functional expressive language outcomes during clinical trials in FXS. PMID- 23669872 TI - Health-related quality of life in children and adolescents with cystic fibrosis: convergent validity with parent-reports and objective measures of pulmonary health. AB - OBJECTIVE: This study examined the convergent validity of health-related quality of life (HRQOL) reported by patients with cystic fibrosis compared with their parents' reports and objective pulmonary measures across 3 time points. METHODS: Ninety-two children (8-13 years) and adolescents (14-18 years) with cystic fibrosis and their parents completed Cystic Fibrosis Questionnaires to examine concordance with Wisconsin chest x-ray (WCXR) scores and pulmonary function tests, for example, forced expiratory volume at 1 second (FEV1), and parent child/adolescent concordance across multiple HRQOL domains. Concordance was analyzed relative to patient age and gender. RESULTS: Parent-reports were closely aligned with WCXR scores, whereas patient reports were more closely aligned with FEV1. Adolescents and parents of both age groups had more HRQOL domains concordant with pulmonary health measures than did child self-reports. Parent child concordance was inversely related to child age, particularly with male adolescents. Children generally reported better HRQOL than parents. Male adolescents and their parents were more likely to have significantly discordant HRQOL scores than female adolescents and their parents. Male and female adolescents reported higher HRQOL than their parents reported for all but vitality and health perception domains. Younger male children showed concordance with their parents on 5 of 7 domains. CONCLUSIONS: Parent-child/adolescent discordance on HRQOL was consistent with normative child development expectations. Findings underscore the value of enlisting perspectives from parents as well as children regarding HRQOL. PMID- 23669874 TI - Why so many epidemics of childhood mental disorder? PMID- 23669875 TI - Effects of feeding flaxseed or sunflower-seed in high-forage diets on beef production, quality and fatty acid composition. AB - Yearling steers were fed 70:30 forage:concentrate diets for 205 d, with either grass hay (GH) or red clover silage (RC) as the forage source, and concentrates containing either sunflower-seed (SS) or flaxseed (FS), each providing 5.4% oil to diets. Feeding diets containing SS versus FS significantly improved growth and carcass attributes (P<0.05), significantly reduced meat off-flavor intensity (P<0.05), and significantly increased intramuscular proportions of vaccenic (t11 18:1), rumenic (c9,t11-CLA) and n-6 fatty acids (FA, P<0.05). Feeding diets containing FS versus SS produced significantly darker and redder meat with greater proportions of atypical dienes (P<0.05). A significant forage * oilseed type interaction (P<0.05) was found for n-3 FA, alpha-linolenic acid, and conjugated linolenic acid, with their greatest intramuscular proportions found when feeding the RC-FS diet. Feeding GH versus RC also significantly improved growth and carcass attributes, sensory tenderness (P<0.05) and significantly influenced intramuscular FA composition (P<0.05), but overall, forage effects on FA profiles were limited compared to effects of oilseed. PMID- 23669876 TI - CK2-NCoR signaling cascade promotes prostate tumorigenesis. AB - The aberrant expressions of casein kinase 2 (CK2) was found in prostate cancer patient and cell lines, but little is known of the detailed mechanisms implicated in prostate tumorigenesis. In this study, we report that both CK2 activity and CK2-mediated NCoR phosphorylation are significantly elevated in the androgen independent prostate cancer cell line DU145 and PC-3 compared with RWPE1 and LNCaP cells. Increased phosphorylation inversely correlates with the mRNA level of the NCoR-regulated gene, interferon-gamma-inducible protein 10 (IP-10). CK2 inhibition abrogated NCoR phosphorylation, IP-10 transcriptional repression, and the invasion activity of PC-3 cells. Inhibition of the CK2-NCoR network significantly reduced in vivo PC-3 cell tumorigenicity, likely due to transcriptional derepression of IP-10. Clinicopathological analyses revealed that increased CK2-mediated NCoR phosphorylation significantly correlates with poor survival among prostate cancer patients. These findings elucidate a CK2-modulated oncogenic cascade in prostate tumorigenesis. PMID- 23669878 TI - Impact of resistance training in cancer survivors: a meta-analysis. AB - PURPOSE: Current evidence suggests many health benefits from physical activity during and after cancer treatment. However, the optimal exercise program for cancer survivors has not yet been established. The purpose of this meta-analysis was to summarize evidence for the efficacy of resistance training (RT) interventions to improve muscle strength and body composition among adult cancer survivors. We also investigate potential dose-response relationships between intensity, duration, and frequency of RT and assessed outcomes. METHODS: A systematic literature review of the Clinical Trial Register, Cochrane Trial Register, MEDLINE, and EMBASE literature databases was undertaken. Studies were included if they were randomized controlled trials (RCT) comparing RT with an exercise or nonexercise control group in cancer survivors during and after treatment. Thirteen articles from 11 RCT met our inclusion criteria. We performed a random-effects meta-analysis to determine weighted mean differences (WMD) with 95% confidence intervals using the Cochrane Review Manager 5.0.25. A random effects metaregression model was performed to examine dose-response relationships between RT variables and assessed outcomes. RESULTS: Quantitative evidence shows a large effect of RT on lower-limb and upper-limb muscle strength (WMD: +14.57 kg, P = 0.0005 and +6.90 kg, P < 0.00001, respectively) and moderate effects on lean body mass and percentage of body fat (WMD: +1.07 kg, P < 0.0001 and -2.08%, P = 0.003, respectively). A small positive effect of RT was noted on Functional Assessment of Cancer Therapy-Fatigue (P = 0.05). Upper-limb muscle strength and percentage of body fat improved to a greater extent when RT interventions were of low to moderate intensity (<= 75% one-repetition maximum, P = 0.042). CONCLUSIONS: RT was shown to be associated with clinically important positive effects on muscular function and body composition in patients during treatment or in long-term follow-up. PMID- 23669877 TI - A comparison of energy expenditure estimation of several physical activity monitors. AB - INTRODUCTION: Accurately and precisely estimating free-living energy expenditure (EE) is important for monitoring energy balance and quantifying physical activity. Recently, single and multisensor devices have been developed that can classify physical activities, potentially resulting in improved estimates of EE. PURPOSE: This study aimed to determine the validity of EE estimation of a footwear-based physical activity monitor and to compare this validity against a variety of research and consumer physical activity monitors. METHODS: Nineteen healthy young adults (10 men, 9 women) completed a 4-h stay in a room calorimeter. Participants wore a footwear-based physical activity monitor as well as Actical, ActiGraph, IDEEA, DirectLife, and Fitbit devices. Each individual performed a series of postures/activities. We developed models to estimate EE from the footwear-based device, and we used the manufacturer's software to estimate EE for all other devices. RESULTS: Estimated EE using the shoe-based device was not significantly different than measured EE (mean +/- SE; 476 +/- 20 vs 478 +/- 18 kcal, respectively) and had a root-mean-square error of 29.6 kcal (6.2%). The IDEEA and the DirectLlife estimates of EE were not significantly different than the measured EE, but the ActiGraph and the Fitbit devices significantly underestimated EE. Root-mean-square errors were 93.5 (19%), 62.1 kcal (14%), 88.2 kcal (18%), 136.6 kcal (27%), 130.1 kcal (26%), and 143.2 kcal (28%) for Actical, DirectLife, IDEEA, ActiGraph, and Fitbit, respectively. CONCLUSIONS: The shoe-based physical activity monitor provides a valid estimate of EE, whereas the other physical activity monitors tested have a wide range of validity when estimating EE. Our results also demonstrate that estimating EE based on classification of physical activities can be more accurate and precise than estimating EE based on total physical activity. PMID- 23669879 TI - Neuromuscular responses to incremental caffeine doses: performance and side effects. AB - PURPOSE: The purpose of this study was to determine the oral dose of caffeine needed to increase muscle force and power output during all-out single multijoint movements. METHODS: Thirteen resistance-trained men underwent a battery of muscle strength and power tests in a randomized, double-blind, crossover design, under four different conditions: (a) placebo ingestion (PLAC) or with caffeine ingestion at doses of (b) 3 mg . kg(-1) body weight (CAFF 3mg), (c) 6 mg . kg(-1) (CAFF 6mg), and (d) 9 mg . kg(-1) (CAFF 9mg). The muscle strength and power tests consisted in the measurement of bar displacement velocity and muscle power output during free-weight full-squat (SQ) and bench press (BP) exercises against four incremental loads (25%, 50%, 75%, and 90% one-repetition maximum [1RM]). Cycling peak power output was measured using a 4-s inertial load test. Caffeine side effects were evaluated at the end of each trial and 24 h later. RESULTS: Mean propulsive velocity at light loads (25%-50% 1RM) increased significantly above PLAC for all caffeine doses (5.4%-8.5%, P = 0.039-0.003). At the medium load (75% 1RM), CAFF 3mg did not improve SQ or BP muscle power or BP velocity. CAFF 9mg was needed to enhance BP velocity and SQ power at the heaviest load (90% 1RM) and cycling peak power output (6.8%-11.7%, P = 0.03-0.05). The CAFF 9mg trial drastically increased the frequency of the adverse side effects (15%-62%). CONCLUSIONS: The ergogenic dose of caffeine required to enhance neuromuscular performance during a single all-out contraction depends on the magnitude of load used. A dose of 3 mg . kg(-1) is enough to improve high-velocity muscle actions against low loads, whereas a higher caffeine dose (9 mg . kg(-1)) is necessary against high loads, despite the appearance of adverse side effects. PMID- 23669880 TI - Insulin responsiveness in metabolic syndrome after eight weeks of cycle training. AB - INTRODUCTION: Insulin resistance in obesity is decreased after successful diet and exercise. Aerobic exercise training alone was evaluated as an intervention in subjects with the metabolic syndrome. METHODS: Eighteen nondiabetic, sedentary subjects, 11 with the metabolic syndrome, participated in 8 wk of increasing intensity stationary cycle training. RESULTS: Cycle training without weight loss did not change insulin resistance in metabolic syndrome subjects or sedentary control subjects. Maximal oxygen consumption (V.O 2max), activated muscle AMP dependent kinase, and muscle mitochondrial marker ATP synthase all increased. Strength, lean body mass, and fat mass did not change. The activated mammalian target of rapamycin was not different after training. Training induced a shift in muscle fiber composition in both groups but in opposite directions. The proportion of type 2* fibers decreased with a concomitant increase in type 2a mixed fibers in the control subjects, but in metabolic syndrome, type 2* fiber proportion increased and type 1 fibers decreased. Muscle fiber diameters increased in all three fiber types in metabolic syndrome subjects. Muscle insulin receptor expression increased in both groups, and GLUT4 expression increased in the metabolic syndrome subjects. The excess phosphorylation of insulin receptor substrate 1 (IRS-1) at Ser337 in metabolic syndrome muscle tended to increase further after training in spite of a decrease in total IRS-1. CONCLUSIONS: In the absence of weight loss, the cycle training of metabolic syndrome subjects resulted in enhanced mitochondrial biogenesis and increased the expression of insulin receptors and GLUT4 in muscle but did not decrease the insulin resistance. The failure for the insulin signal to proceed past IRS-1 tyrosine phosphorylation may be related to excess serine phosphorylation at IRS-1 Ser337, and this is not ameliorated by 8 wk of endurance exercise training. PMID- 23669881 TI - Activity-induced changes in skeletal muscle metabolism measured with optical spectroscopy. AB - PURPOSE: Previous studies have used near-infrared spectroscopy (NIRS) to measure skeletal muscle mitochondrial capacity. This study tested the hypothesis that NIRS-measured mitochondrial capacity would improve with endurance exercise training and decline with detraining. METHODS: Nine young participants performed 4 wk of progressively increasing endurance exercise training of the wrist flexor muscles followed by approximately 5 wk of inactivity. The rate of recovery of muscle oxygen consumption (mV()O2) was measured with NIRS every 3-7 d, indicating mitochondrial oxidative capacity. RESULTS: A linear increase in mitochondrial capacity (NIRS rate constant) was found with a group average of 64% +/- 37% improvement after 4 wk of exercise training (P < 0.05). Mitochondrial capacity declined exponentially upon cessation of exercise training, with a mean half-time of approximately 7.7 d. CONCLUSIONS: Both the magnitude and the time course of mitochondrial adaptations to exercise training and detraining measured with NIRS was consistent with previous studies using both in vitro and in vivo techniques. These findings show that NIRS-based measurements can detect meaningful changes in mitochondrial capacity. PMID- 23669882 TI - Soccer training improves cardiac function in men with type 2 diabetes. AB - INTRODUCTION: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of cardiovascular disease, which is worsened by physical inactivity. Subclinical myocardial dysfunction is associated with increased risk of heart failure and impaired prognosis in T2DM; however, it is not clear if exercise training can counteract the early signs of diabetic heart disease. PURPOSE: This study aimed to evaluate the effects of soccer training on cardiac function, exercise capacity, and blood pressure in middle-age men with T2DM. METHODS: Twenty-one men age 49.8 +/- 1.7 yr with T2DM and no history of cardiovascular disease participated in a soccer training group (n = 12) that trained 1 h twice a week or a control group (n = 9) with no change in lifestyle. Examinations included comprehensive transthoracic echocardiography, measurements of blood pressure, maximal oxygen consumption (V()O(2max)), and intermittent endurance capacity before and after 12 and 24 wk. Two-way repeated-measures ANOVA was applied. RESULTS: After 24 wk of soccer training, left ventricular (LV) end diastolic diameter and volume were increased (P < 0.001) compared to baseline. LV longitudinal systolic displacement was augmented by 23% (P < 0.001) and global longitudinal two-dimensional strain increased by 10% (P < 0.05). LV diastolic function, determined by mitral inflow (E/A ratio) and peak diastolic velocity E', was increased by 18% (P < 0.01) and 29% (P < 0.001), respectively, whereas LV filling pressure E/E' was reduced by 15% (P = 0.05). Systolic, diastolic, and mean arterial pressures were all reduced by 8 mm Hg (P < 0.01, P < 0.001, and P < 0.001, respectively). V()O(2max) and intermittent endurance capacity was 12% and 42% (P < 0.001) higher, respectively. No changes in any of the measured parameters were observed in control group. CONCLUSION: Regular soccer training improves cardiac function, increases exercise capacity, and lowers blood pressure in men with T2DM. PMID- 23669883 TI - In vitro effects of resveratrol on oxidative stress in diabetic platelets. AB - To evaluate the in vitro effects of resveratrol (RSV) incubation on platelets from compensated and decompensated diabetic patients in order to use it as an adjuvant therapy. The study was performed on 77 diabetic patients and divided into two phases: 29 compensated and 48 decompensated diabetic platelets were analyzed at recruitment (T0) and after in vitro RSV incubation (20 MUg/ml) for 3 h at 37 degrees C (T1). Lipoperoxide and nitric oxide (NO) levels, superoxide dismutase (SOD) and Na(+)/K(+) ATPase activities, total antioxidant capacity (TAC), and membrane fluidity tested by anisotropy of fluorescent probes TMA-DPH and DPH were determined. In vitro RSV incubation counteracts oxidative damage associated with diabetes and its complications; it is able to improve platelet function through augmented membrane fluidity and Na(+)/K(+) ATPase activity; it enhances antioxidant systems' functionality by increasing NO levels, SOD activity, and TAC and by decreasing lipoperoxide levels in both compensated and decompensated patients. Such platelet functionality enhancement suggests a new method of secondary prevention of complications associated with platelet dysfunction. Being free from one of the major risks associated with many antidiabetic agents, it can be assumed that RSV utilization in the diabetic diet may have a preventive and protective role in the progression of diabetic oxidative damage. PMID- 23669884 TI - Internet-delivered interpersonal psychotherapy versus internet-delivered cognitive behavioral therapy for adults with depressive symptoms: randomized controlled noninferiority trial. AB - BACKGROUND: Face-to-face cognitive behavioral therapy (CBT) and interpersonal psychotherapy (IPT) are both effective treatments for depressive disorders, but access is limited. Online CBT interventions have demonstrated efficacy in decreasing depressive symptoms and can facilitate the dissemination of therapies among the public. However, the efficacy of Internet-delivered IPT is as yet unknown. OBJECTIVE: This study examines whether IPT is effective, noninferior to, and as feasible as CBT when delivered online to spontaneous visitors of an online therapy website. METHODS: An automated, 3-arm, fully self-guided, online noninferiority trial compared 2 new treatments (IPT: n=620; CBT: n=610) to an active control treatment (MoodGYM: n=613) over a 4-week period in the general population. Outcomes were assessed using online self-report questionnaires, the Center for Epidemiological Studies Depression scale (CES-D) and the Client Satisfaction Questionnaire (CSQ-8) completed immediately following treatment (posttest) and at 6-month follow-up. RESULTS: Completers analyses showed a significant reduction in depressive symptoms at posttest and follow-up for both CBT and IPT, and were noninferior to MoodGYM. Within-group effect sizes were medium to large for all groups. There were no differences in clinical significant change between the programs. Reliable change was shown at posttest and follow-up for all programs, with consistently higher rates for CBT. Participants allocated to IPT showed significantly lower treatment satisfaction compared to CBT and MoodGYM. There was a dropout rate of 1294/1843 (70%) at posttest, highest for MoodGYM. Intention-to-treat analyses confirmed these findings. CONCLUSIONS: Despite a high dropout rate and lower satisfaction scores, this study suggests that Internet-delivered self-guided IPT is effective in reducing depressive symptoms, and may be noninferior to MoodGYM. The completion rates of IPT and CBT were higher than MoodGYM, indicating some progress in refining Internet-based self-help. Internet-delivered treatment options available for people suffering from depression now include IPT. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 69603913; http://www.controlled trials.com/ISRCTN69603913 (Archived by WebCite at http://www.webcitation.org/6FjMhmE1o). PMID- 23669885 TI - Factors affecting quality of anticoagulation control among patients with atrial fibrillation on warfarin: the SAMe-TT2R2 score. AB - BACKGROUND: When oral anticoagulation with adjusted-dose vitamin K antagonist (VKA) is used, the quality of anticoagulation control (as reflected by the time in therapeutic range [TTR] of the international normalized ratio [INR]) is an important determinant of thromboembolism and bleeding. Our objective was to derive a validated scheme using patient-related clinical parameters to assess the likelihood of poor INR control among patients with atrial fibrillation (AF) on VKA therapy. METHODS: The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial population was randomly divided into derivation and internal validation cohorts using a 1:1 ratio. We used linear regression analysis to detect the clinical factors associated with TTR and binary logistic regression to evaluate the predictive performance of a model incorporating these factors for different cutoff values of TTR. The derived model was validated externally in a cohort of patients receiving anticoagulant therapy who were recruited prospectively. RESULTS: In the linear regression model, nine variables emerged as independent predictors of TTR: female sex (P < .0001), age < 50 years (P < .0001), age 50 to 60 years (P = .02), ethnic minority status (P < .0001), smoking (P = .03), more than two comorbidities (P < .0001), and being treated with a beta blocker (P = .02), verapamil (P = .02), or, inversely, with amiodarone (P = .05). We incorporated these factors into a simple clinical prediction scheme with the acronym SAMe-TT2R (sex female, age < 60 years, medical history [more than two comorbidities], treatment [interacting drugs, eg, amiodarone for rhythm control], tobacco use [doubled], race [doubled]). The score demonstrated good discrimination performance in both the internal and external validation cohorts (c-index, 0.72; 95% CI, 0.64-0.795; and c-index, 0.7; 95% CI, 0.57-0.82, respectively). CONCLUSIONS: Common clinical and demographic factors can influence the quality of oral anticoagulation. We incorporated these factors into a simple score (SAMe-TT2R2) that can predict poor INR control and aid decision-making by identifying those patients with AF who would do well on VKA (SAMe-TT2R2 score = 0 1), or conversely, those who require additional interventions to achieve acceptable anticoagulation control (SAMe-TT2R2 score >= 2). PMID- 23669888 TI - Translation inhibition and metabolic stress pathways in the host response to bacterial pathogens. AB - Activation of most major innate immune signalling cascades relies on the detection of microorganisms or their associated danger signals by host pattern recognition molecules. A flurry of recent studies has now uncovered a role for host translation inhibition in innate immune surveillance and the detection of bacterial pathogens. Here, we present the main findings from these studies and discuss whether translation inhibition is an alarm signal that directly drives innate immune responses to bacterial pathogens, or rather one component of a more general metabolic stress response to infection. PMID- 23669892 TI - Deep-sea striving. PMID- 23669886 TI - Antimicrobial activity of metals: mechanisms, molecular targets and applications. AB - Metals have been used as antimicrobial agents since antiquity, but throughout most of history their modes of action have remained unclear. Recent studies indicate that different metals cause discrete and distinct types of injuries to microbial cells as a result of oxidative stress, protein dysfunction or membrane damage. Here, we describe the chemical and toxicological principles that underlie the antimicrobial activity of metals and discuss the preferences of metal atoms for specific microbial targets. Interdisciplinary research is advancing not only our understanding of metal toxicity but also the design of metal-based compounds for use as antimicrobial agents and alternatives to antibiotics. PMID- 23669895 TI - [Bronchial carcinoid tumor: study of 60 patients]. AB - BACKGROUND AND OBJECTIVE: To describe the casuistry of bronchial carcinoid tumor in the last 20 years in our hospital and determine survival after surgical treatment. PATIENTS AND METHOD: We retrospectively reviewed the medical records from January 1992 to June 2012 of patients diagnosed with carcinoid tumor by the pulmonary service. RESULTS: Fifty-two patients (87%) had typical carcinoid and 8 (13%) atypical carcinoid. The mean age at diagnosis was 60 years (SD: 14.4). There was no relationship between consumption of tobacco and carcinoid tumor. Twenty-two per cent were asymptomatic radiographic finding (incidental finding) Three patients showed carcinoid syndrome and one patient had Cushing syndrome. There was a right dominance and the mean lesion size was between 2.1 and 5 cm. Nine per cent had lymph node involvement, predominantly in atypical carcinoid. Overall survival at 3.5 and 10 years was 94%, 86% and 82%. Survival at 5 years was 90% for typical and 86% for atypical and survival at 10 years was 85% for typical and 57% for atypical carcinoids. CONCLUSION: Carcinoid tumors are malignant tumors by their ability to metastasize. In our study, both histological type and staging were predictors of survival. PMID- 23669896 TI - [Reply]. PMID- 23669897 TI - Surface waves in three-dimensional electromagnetic composites and their effect on homogenization. AB - Reflection and transmission of electromagnetic waves at the boundaries of periodic composites (electromagnetic/optical metamaterials) depends in general on both bulk and surface waves. We investigate the interplay of these two contributions using three-dimensional full-wave numerical simulations and a recently developed non-asymptotic homogenization theory. PMID- 23669898 TI - Near-field analysis of metallic DFB lasers at telecom wavelengths. AB - We image in near-field the transverse modes of semiconductor distributed feedback (DFB) lasers operating at lambda ~ 1.3 MUm and employing metallic gratings. The active region is based on tensile-strained InGaAlAs quantum wells emitting transverse magnetic polarized light and is coupled via an extremely thin cladding to a nano-patterned gold grating integrated on the device surface. Single mode emission is achieved, which tunes with the grating periodicity. The near-field measurements confirm laser operation on the fundamental transverse mode. Furthermore--together with a laser threshold reduction observed in the DFB lasers -it suggests that the patterning of the top metal contact can be a strategy to reduce the high plasmonic losses in this kind of systems. PMID- 23669899 TI - Electrically controlled Goos-Hanchen shift of a light beam reflected from the metal-insulator-semiconductor structure. AB - We proposed a scheme to manipulate the Goos-Hanchen shift of a light beam reflected from the depletion-type device via external voltage bias. It is shown that the lateral shift of the reflected probe beam can be easily controlled by adjusting the reverse voltage bias and the incidence angle. Using this scheme, the lateral shift can be tuned from negative to positive, without changing the original structure of the depletion-type device. Numerical calculations further indicate that the influence of structure parameters and light wavelength can be reduced via readjustment of the reverse bias. The proposed structure has the potential application for the integrated electronic devices. PMID- 23669900 TI - Dual-pump parametric amplification in dispersion engineered photonic crystal waveguides. AB - This paper describes a numerical simulation of narrow band parametric amplification in dispersion engineered photonic crystal waveguides. The waveguides we analyze exhibit group velocity dispersion functions which cross zero twice thereby enabling many interesting pumping schemes. We analyze the case of two pulsed pumps each placed near one of the zero dispersion wavelengths. These configurations are compared to conventional single pump schemes. The two pumps may induce phase matching conditions in the same spectral location enabling to control the gain spectrum. This is used to study the gain and fidelity of 40 G bps NRZ data signals. PMID- 23669901 TI - Cloaking and enhanced scattering of core-shell plasmonic nanowires. AB - We study scattering of light from multi-layer plasmonic nanowires and reveal that such structures can demonstrate both enhanced and suppressed scattering regimes. We employ the mode-expansion method and experimental data for material parameters and introduce an optimized core-shell nanowire design which exhibits simultaneously superscattering and cloaking properties at different wavelengths in the visible spectrum. PMID- 23669902 TI - Fast UV-Vis photorefractive response of Zr and Mg codoped LiNbO3:Mo. AB - A series of LN:Mo,Zr and LN:Mo,Mg crystals with different doping concentrations were grown and their holographic properties were investigated from UV to the visible range. Each crystal allows for holographic storage from UV to the visible as LN:Mo. When the concentration of MgO is enhanced to 6.5 mol%, the response time can be dramatically shortened to 0.22 s, 0.33 s, 0.37 s and 1.2 s for 351, 488, 532, and 671 nm laser, respectively. The results show that LN:Mo,Mg is a promising candidate for all-color holographic volume storage with fast response. PMID- 23669903 TI - Highly polarized all-fiber thulium laser with femtosecond-laser-written fiber Bragg gratings. AB - We demonstrate and characterize a highly linearly polarized (18.8 dB) narrow spectral emission (<80 pm) from an all-fiber Tm laser utilizing femtosecond-laser written fiber Bragg gratings. Thermally-dependent anisotropic birefringence is observed in the FBG transmission, the effects of which enable both the generation and elimination of highly linearly polarized output. To our knowledge, this is the first detailed study of such thermal anisotropic birefringence in femtosecond written FBGs. PMID- 23669904 TI - Flexible transformation plasmonics using graphene. AB - The flexible control of surface plasmon polaritons (SPPs) is important and intriguing due to its wide application in novel plasmonic devices. Transformation optics (TO) offers the capability either to confine the SPP propagation on rigid curved/uneven surfaces, or to control the flow of SPPs on planar surfaces. However, TO has not permitted us to confine, manipulate, and control SPP waves on flexible curved surfaces. Here, we propose to confine and freely control flexible SPPs using TO and graphene. We show that SPP waves can be naturally confined and propagate on curved or uneven graphene surfaces with little bending and radiation losses, and the confined SPPs are further manipulated and controlled using TO. Flexible plasmonic devices are presented, including the bending waveguides, wave splitter, and Luneburg lens on curved surfaces. Together with the intrinsic flexibility, graphene can be served as a good platform for flexible transformation plasmonics. PMID- 23669905 TI - Electrically pumped random lasing from FTO/porous insulator/n-ZnO/p(+)-Si devices. AB - Electrically pumped random lasing (RL) has been realized in FTO/porous insulator/n-ZnO/p(+)-Si devices. It is demonstrated that RL originates from the confining and recurrent scattering of light in the random cavities within the insulating layer, which are formed due to the glow discharge. The glow discharge also induces the observed negative differential resistance (NDR) effect following the normal I-V characteristics. The results present a new strategy to realize electrically pumped RL in ZnO-based metal-insulator-semiconductor device by simply modifying the morphology of the insulating layer. PMID- 23669906 TI - Efficient Raman frequency conversion by coherent feedback at low light intensity. AB - We experimentally demonstrate efficient Raman conversion to respective Stokes and anti-Stokes fields in both pulsed and continuous modes with a Rb-87 atomic vapor cell. The conversion efficiency is about 40-50% for the Stokes field and 20-30% for the anti-Stokes field, respectively. This efficient conversion process is realized with coherent feedback of both the Raman pump and the frequency converted fields (Stokes or anti-Stokes). The experimental setup is simple and can be applied easily to produce light sources with larger frequency shifts using other Raman media with long coherence time. They may have potential applications in nonlinear optics, Raman spectroscopy and precision measurement. PMID- 23669907 TI - Analyzing the benefit of optical transmission systems based on Root Raised Cosine PS-QPSK and a flexible channel grid. AB - We numerically investigate the multi-channel transmission performance of Polarization Switched Quadrature Phase Shift Keying (PS-QPSK) and we compare it to the performance of Polarization-Division-Multiplexed QPSK (PDM-QPSK), using Root Raised Cosine (RRC) spectral shaping, in the context of a flexible channel grid. We point out the impact of the roll-off factor and the potential influence of different dispersion compensation scenarios. Finally, the advantage of PS-QPSK against PDM-QPSK is presented as a function of the system parameters, while we also discuss the benefit of a RRC spectral shaping against a tight filtering at the transmitter side with a 2nd order super-Gaussian-shaped filter. PMID- 23669908 TI - Wide-angle near infrared polarizer with extremely high extinction ratio. AB - An infrared polarizer is designed with a predicted extremely high extinction ratio exceeding 3 * 10(16) and transmittance higher than 89% for one polarization in the wavelength region from 1.6 to 2.3 um. Moreover, the performance does not start to deteriorate until 60 degrees tilting angle. The wide-angle high transmission is attributed to the excitation of magnetic polaritons and suitable LC circuit models, which could predict the resonance wavelengths quantitatively, are developed to better understand the underlying mechanisms. The proposed structure can be tuned by controlling the geometrical parameters for different potential applications such as polarizers, beamsplitters, filters, and transparent electrodes. PMID- 23669909 TI - Wigner function measurement using a lenslet array. AB - Geometrical-optical arguments have traditionally been used to explain how a lenslet array measures the distribution of light jointly over space and spatial frequency. Here, we rigorously derive the connection between the intensity measured by a lenslet array and wave-optical representations of such light distributions for partially coherent optical beams by using the Wigner distribution function (WDF). It is shown that the action of the lenslet array is to sample a smoothed version of the beam's WDF (SWDF). We consider the effect of lenslet geometry and coherence properties of the beam on this measurement, and we derive an expression for cross-talk between lenslets that corrupts the measurement. Conditions for a high fidelity measurement of the SWDF and the discrepancies between the measured SWDF and the WDF are investigated for a Schell model beam. PMID- 23669910 TI - Coded aperture compressive temporal imaging. AB - We use mechanical translation of a coded aperture for code division multiple access compression of video. We discuss the compressed video's temporal resolution and present experimental results for reconstructions of > 10 frames of temporal data per coded snapshot. PMID- 23669911 TI - Displacement noise from back scattering and specular reflection of input optics in advanced gravitational wave detectors. AB - The second generation of ground-based interferometric gravitational wave detectors are currently being built and installed. They are designed to be better in strain sensitivity by about a factor 10 with respect to the first generation. Light originating from the laser and following unintended paths, called stray light, has been a major problem during the commissioning of all of the first generation detectors. Indeed, stray light carries information about the phase of the emitting object. Therefore, in the next generation all the optics will be suspended in the vacuum in order to mitigate their associated stray light displacement noise. Despite this additional precaution, the challenging target sensitivity at low frequency which is partially limited by quantum radiation pressure combined with up-conversion effects, requires more detailed investigation. In this paper, we turn our attention to stray light originating from auxiliary optical benches. We use a dedicated formalism to compute the re coupling of back-reflected and back-scattered light. We show, in particular, how much care should be taken in designing and setting requirements for the input bench optics. PMID- 23669912 TI - High resolution irradiance tailoring using multiple freeform surfaces. AB - More and more lighting applications require the design of dedicated optics to achieve a given radiant intensity or irradiance distribution. Freeform optics has the advantage of providing such a functionality with a compact design. It was previously demonstrated in [Bauerle et al., Opt. Exp. 20, 14477-14485 (2012)] that the up-front computation of the light path through the optical system (ray mapping) provides a satisfactory approximation to the problem, and allows the design of multiple freeform surfaces in transmission or in reflection. This article presents one natural extension of this work by introducing an efficient optimization procedure based on the physics of the system. The procedure allows the design of multiple freeform surfaces and can render high resolution irradiance patterns, as demonstrated by several examples, in particular by a lens made of two freeform surfaces projecting a high resolution logo (530 * 160 pixels). PMID- 23669913 TI - Wavelet-based noise-model driven denoising algorithm for differential phase contrast mammography. AB - Traditional mammography can be positively complemented by phase contrast and scattering x-ray imaging, because they can detect subtle differences in the electron density of a material and measure the local small-angle scattering power generated by the microscopic density fluctuations in the specimen, respectively. The grating-based x-ray interferometry technique can produce absorption, differential phase contrast (DPC) and scattering signals of the sample, in parallel, and works well with conventional X-ray sources; thus, it constitutes a promising method for more reliable breast cancer screening and diagnosis. Recently, our team proved that this novel technology can provide images superior to conventional mammography. This new technology was used to image whole native breast samples directly after mastectomy. The images acquired show high potential, but the noise level associated to the DPC and scattering signals is significant, so it is necessary to remove it in order to improve image quality and visualization. The noise models of the three signals have been investigated and the noise variance can be computed. In this work, a wavelet-based denoising algorithm using these noise models is proposed. It was evaluated with both simulated and experimental mammography data. The outcomes demonstrated that our method offers a good denoising quality, while simultaneously preserving the edges and important structural features. Therefore, it can help improve diagnosis and implement further post-processing techniques such as fusion of the three signals acquired. PMID- 23669914 TI - Nanocavities at the surface of three-dimensional photonic crystals. AB - We investigate nanocavities at the surface of three-dimensional (3D) photonic crystals, where the polarization-independent surface-mode gap can be utilized. We consider the formation of various nanocavities by introducing artificial defects utilizing the 3D structures around the surface and discuss the possibilities for increasing the Q-factors of the surface nanocavities with TE-like polarization based on the advanced designs of donor-type defects. We also introduce the design of acceptor-type defects and show that TM-like nanocavities are obtained. We then fabricate the designed nanocavities and examine their resonant characteristics; we successfully demonstrate TE-like nanocavities with Q-factors of ~40,000, which is four-times higher than previous surface cavities and as high as that of the cavities embedded inside 3D photonic crystals. TM-like nanocavities with Q factors of ~22,000 are also demonstrated for the first time. PMID- 23669915 TI - Dynamics of short-pulse generation via spectral filtering from intensely excited gain-switched 1.55-MUm distributed-feedback laser diodes. AB - Picosecond-pulse-generation dynamics and pulse-width limiting factors via spectral filtering from intensely pulse-excited gain-switched 1.55-MUm distributed-feedback laser diodes were studied. The spectral and temporal characteristics of the spectrally filtered pulses indicated that the short wavelength component stems from the initial part of the gain-switched main pulse and has a nearly linear down-chirp of 5.2 ps/nm, whereas long-wavelength components include chirped pulse-lasing components and steady-state-lasing components. Rate-equation calculations with a model of linear change in refractive index with carrier density explained the major features of the experimental results. The analysis of the expected pulse widths with optimum spectral widths was also consistent with the experimental data. PMID- 23669916 TI - Plasmon enhanced upconversion luminescence near gold nanoparticles--simulation and analysis of the interactions: errata. AB - The procedure used in our previous publication [Opt. Express 20, 271, (2012)] to calculate how coupling to a spherical gold nanoparticle changes the upconversion luminescence of Er(3+) ions contained several errors. The errors are corrected here. PMID- 23669917 TI - High-performance LED street lighting using microlens arrays. AB - An efficient LED lamp that illuminates the street with high quality is presented. The luminaire shows high optical efficiency, high optical utilization factor, low glare, and illuminates the street with high uniformity. The concept is simple but effective: a cluster of LEDs with TIR lenses are put inside a reflective box, which is covered with a microlens sheet; the reflective cavity improves efficiency by light recycling; each TIR lens collimates the LED light for the microlens array; and the microlens sheet uniformly distributes light only into the street. We verify its feasibility by Monte Carlo ray-tracing for the main types of road lighting arrangements: central, zigzag, and single-side pole positions. PMID- 23669918 TI - Uniformity of the lasing wavelength of heterogeneously integrated InP microdisk lasers on SOI. AB - We report a high lasing wavelength uniformity of optically pumped InP-based microdisk lasers processed with electron-beam lithography, heterogeneously integrated with adhesive bonding on silicon-on-insulator (SOI) waveguide circuits and evanescently coupled to an underlying waveguide. We study the continuous wave laser emission coupling out of the SOI via a grating coupler etched at one side of the waveguide, and demonstrate a standard deviation in lasing wavelength of nominally identical devices on the same chip lower than 500 pm. The deviation in the diameter of the microdisks as low as a few nanometers makes all-optical signal processing applications requiring cascadability possible. PMID- 23669919 TI - Detection of ion micromotion in a linear Paul trap with a high finesse cavity. AB - We demonstrate minimization of ion micromotion in a linear Paul trap with the use of a high finesse cavity. The excess ion micromotion projected along the optical cavity axis or along the laser propagation direction manifests itself as sideband peaks around the carrier in the ion-cavity emission spectrum. By minimizing the sideband height in the emission spectrum, we are able to reduce the micromotion amplitude along two directions to approximately the spread of the ground state wave function. This method is useful for cavity QED experiments as it describes the possibility of efficient 3-D micromotion compensation despite optical access limitations imposed by the cavity mirrors. We also show that, in principle, sub nanometer micromotion compensation is achievable with our current system. PMID- 23669920 TI - Efficient coupling of propagating broadband terahertz radial beams to metal wires. AB - Bare metal wires have recently been demonstrated as waveguides for transporting terahertz (THz) radiation, where the guiding mode is radially polarized surface Sommerfeld waves. In this study, we demonstrate high-efficiency coupling of a broadband radially polarized THz pulsed beam, which is generated with a polarization-controlled beam by a segmented half-wave-plate mode converter, to bare copper wires. A total coupling efficiency up to 16.8% is observed, and at 0.3 THz, the maximum coupling efficiency is 66.3%. The results of mode-overlap calculation and numerical simulation support the experimental data well. PMID- 23669921 TI - Numerical analysis on the feasibility of a multi-layered dielectric sphere as a three-dimensional photonic crystal. AB - The radiative decay rate of a dipole emitter inside the core of a multi-layered dielectric sphere is theoretically investigated. It is shown that, when the thickness of each layer coincides with a quarter wavelength, the multi-layered sphere has a great potential to work as a three-dimensional photonic crystal with a high quality factor and a small mode volume. From the analysis of the dipole position dependence of a radiative decay rate, we show that a smaller core radius, a quarter wavelength at the smallest, is more suitable for real applications. The investigation on the tolerance for thickness nonuniformity reveals that the thickness variation of 10% is tolerable. PMID- 23669922 TI - Widely tunable single photon source with high purity at telecom wavelength. AB - We theoretically and experimentally investigate the spectral tunability and purity of photon pairs generated from spontaneous parametric down conversion in periodically poled KTiOPO(4) crystal with group-velocity matching condition. The numerical simulation predicts that the spectral purity can be kept higher than 0.81 when the wavelength is tuned from 1460 nm to 1675 nm, which covers the S-, C , L-, and U-band in telecommunication wavelengths. We also experimentally measured the joint spectral intensity at 1565 nm, 1584 nm and 1565 nm, yielding Schmidt numbers of 1.01, 1.02 and 1.04, respectively. Such a photon source is useful for quantum information and communication systems. PMID- 23669923 TI - Upconversion emission obtained in Yb(3+)-Er(3+) doped fluoroindate glasses using silica microspheres as focusing lens. AB - An intensity enhancement of the green upconversion emission from a codoped Er(3+) Yb(3+) fluoroindate glass has been obtained by coating the glass surface with silica microspheres (3.8 um diameter). The microspheres focus an incoming beam (lambda ~ 950 nm) on the surface of the fluoroindate glass. The green emission (lambda ~ 545 nm) of the Er(3+) ions located in the microsphere focus was measured with a microscope in reflection mode, being the peak intensity 4.5 times the emission of the bare substrate. The transversal FWHM of the upconversion spot was experimentally determined by deconvolution with the experimental Point Spread Function of the system, obtaining a value of 309 nm. This value is in good agreement with Finite-Difference Time-Domain simulations taking into account the magnification of the image due to the microsphere. PMID- 23669924 TI - Mitigation of vibrations in adaptive optics by minimization of closed-loop residuals. AB - We describe a new technique to reduce tip and tilt vibrations via the design of adaptive optics controllers in a frequency framework. The method synthesizes controllers by minimizing an H2 norm of the tip and tilt residuals. In this approach, open loop slopes (pseudo-open-loop) are reconstructed from on-sky data and input into off-line simulations of the adaptive optics system. The proposed procedure executes a sequence of off-line closed-loop runs with increasing controller complexity and searches for the controller that minimizes the variance of residuals. Although the method avoids any identification of the vibration and turbulence models during the controller synthesis, the actual models are indirectly constructed as a by-product of the H2 norm minimization. The technique has been implemented on and tested with two operational instruments, namely Paranal's NACO and Gemini-South's GeMS, showing an effective rejection of the main vibrations in the loop and also improving the overall performance of the system over varying turbulence conditions. It is shown that a superior performance is obtained when compared to the standard integrator controller. PMID- 23669925 TI - Monitoring the propagation of mechanical waves using an optical fiber distributed and dynamic strain sensor based on BOTDA. AB - We report a Brillouin-based fully distributed and dynamic monitoring of the strain induced by a propagating mechanical wave along a 20 m long composite strip, to which surface a single-mode optical fiber was glued. Employing a simplified version of the Slope-Assisted Brillouin Optical Time Domain Analysis (SA-BOTDA) technique, the whole length of the strip was interrogated every 10 ms (strip sampling rate of 100 Hz) with a spatial resolution of the order of 1m. A dynamic spatially and temporally continuous map of the strain was obtained, whose temporal behavior at four discrete locations was verified against co-located fiber Bragg gratings. With a trade-off among sampling rate, range and signal to noise ratio, kHz sampling rates and hundreds of meters of range can be obtained with resolution down to a few centimeters. PMID- 23669926 TI - Stability of a laser cavity with non-parabolic phase transformation elements. AB - In this paper we present a general approach to determine the stability of a laser cavity which can include non-conventional phase transformation elements. We consider two pertinent examples of the detailed investigation of the stability of a laser cavity firstly with a lens with spherical aberration and thereafter a lens axicon doublet to illustrate the implementation of the given approach. In the particular case of the intra-cavity elements having parabolic surfaces, the approach comes to the well-known stability condition for conventional laser resonators namely 0 <= (1-z/R(1))(1-z/R(2)) <= 1. PMID- 23669927 TI - Self-stabilizing optical clock pulse-train generator using SOA and saturable absorber for asynchronous optical packet processing. AB - We propose a novel, self-stabilizing optical clock pulse-train generator for processing preamble-free, asynchronous optical packets with variable lengths. The generator is based on an optical loop that includes a semiconductor optical amplifier (SOA) and a high-extinction spin-polarized saturable absorber (SA), with the loop being self-stabilized by balancing out the gain and absorption provided by the SOA and SA, respectively. The optical pulse train is generated by tapping out a small portion of a circulating seed pulse. The convergence of the generated pulse energy is enabled by the loop round-trip gain function that has a negative slope due to gain saturation in the SOA. The amplified spontaneous emission (ASE) of the SOA is effectively suppressed by the SA, and a backward optical pulse launched into the SOA enables overcoming the carrier-recovery speed mismatch between the SOA and SA. Without external control for the loop gain, a stable optical pulse train consisting of more than 50 pulses with low jitter is generated from a single 10-ps seed optical pulse even with a variation of 10 dB in the seed pulse intensity. PMID- 23669928 TI - Investigations on the beam pointing stability of a pulsed optical parametric oscillator. AB - Although the beam pointing stability of optical parametric oscillators and amplifiers is important for various applications few results on this parameter have been published. Here, we investigate the beam pointing stability of an injection-seeded, nanosecond optical parametric oscillator, compare it to its pump laser, and measure correlations between them. Although correlation between both quantities are found, the beam pointing stability of the OPO is significantly better that the one of its pump. Furthermore, the concept of the Allan variance is applied to analyze the temporal components of the pointing stability. PMID- 23669929 TI - Picosecond to femtosecond pulses from high power self mode-locked ytterbium rod type fiber laser. AB - We have designed an ytterbium rod-type fiber laser oscillator with tunable pulse duration. This system that delivers more than 10 W of average power is self mode locked. It yields femtosecond to picosecond laser pulses at a repetition rate of 74 MHz. The pulse duration is adjusted by changing the spectral width of a band pass filter that is inserted in the laser cavity. Using volume Bragg gratings of 0.9 nm and 0.07 nm spectrum bandwidth, this oscillator delivers nearly Fourier limited 2.8 ps and 18.5 ps pulses, respectively. With a 4 nm interference filter, one obtains picosecond pulses that have been externally dechirped down to 130 fs. PMID- 23669930 TI - Highly efficient beam steering with a transparent metasurface. AB - We propose an ultra-thin planar metasurface with phase discontinuities for highly efficient beam steering. The effect benefits from the broadband transparency and flexible phase modulation of stacked metal/dielectric multi-layers that is perforated with coaxial annular apertures. Proof-of-principle experiments verify that an efficiency of 65% and a deflection angle of 18 degrees at 10 GHz are achieved for the transmitted beam, which are also in good agreement with the finite-difference-method-in-time-domain (FDTD) simulations. The scheme shall be general for the design of beam-steering transmitters in all frequencies. PMID- 23669931 TI - Tunable dual-band negative refractive index in ferrite-based metamaterials. AB - A tunable dual-band ferrite-based metamaterial has been investigated by experiments and simulations. The negative permeability is realized around the ferromagnetic resonance (FMR) frequency which can be influenced by the dimension of the ferrites. Due to having two negative permeability frequency regions around the two FMR frequencies, the metamaterials consisting of metallic wires and ferrite rods with different sizes possess two passbands in the transmission spectra. The microwave transmission properties of the ferrite-based metamaterials can be not only tuned by the applied magnetic field, but also adjusted by the dimension of the ferrite rods. A good agreement between experimental and simulated results is demonstrated, which confirms that the tunable dual-band ferrite-based metamaterials can be used for cloaks, antennas and absorbers. PMID- 23669932 TI - Ultra-compact silicon photonic devices reconfigured by an optically induced semiconductor-to-metal transition. AB - Vanadium dioxide (VO(2)) is a promising reconfigurable optical material and has long been a focus of condensed matter research owing to its distinctive semiconductor-to-metal phase transition (SMT), a feature that has stimulated recent development of thermally reconfigurable photonic, plasmonic, and metamaterial structures. Here, we integrate VO(2) onto silicon photonic devices and demonstrate all-optical switching and reconfiguration of ultra-compact broadband Si-VO(2) absorption modulators (L < 1 MUm) and ring-resonators (R ~ lambda(0)). Optically inducing the SMT in a small, ~0.275 MUm(2), active area of polycrystalline VO(2) enables Si-VO(2) structures to achieve record values of absorption modulation, ~4 dB MUm(-1), and intracavity phase modulation, ~pi/5 rad MUm(-1). This in turn yields large, tunable changes to resonant wavelength, |Deltalambda(SMT)| ~ 3 nm, approximately 60 times larger than Si-only control devices, and enables reconfigurable filtering and optical modulation in excess of 7 dB from modest Q-factor (~10(3)), high-bandwidth ring resonators (>100 GHz). All-optical integrated Si-VO(2) devices thus constitute platforms for reconfigurable photonics, bringing new opportunities to realize dynamic on-chip networks and ultrafast optical shutters and modulators. PMID- 23669933 TI - Generation of infrared supercontinuum radiation: spatial mode dispersion and higher-order mode propagation in ZBLAN step-index fibers. AB - Using femtosecond upconversion we investigate the time and wavelength structure of infrared supercontinuum generation. It is shown that radiation is scattered into higher order spatial modes (HOMs) when generating a supercontinuum using fibers that are not single-moded, such as a step-index ZBLAN fiber. As a consequence of intermodal scattering and the difference in group velocity for the modes, the supercontinuum splits up spatially and temporally. Experimental results indicate that a significant part of the radiation propagates in HOMs. Conventional simulations of super-continuum generation do not include scattering into HOMs, and including this provides an extra degree of freedom for tailoring supercontinuum sources. PMID- 23669934 TI - Tunable microwave signal generator with an optically-injected 1310 nm QD-DFB laser. AB - Tunable microwave signal generation with frequencies ranging from below 1 GHz to values over 40 GHz is demonstrated experimentally with a 1310 nm Quantum Dot (QD) Distributed-Feedback (DFB) laser. Microwave signal generation is achieved using the period 1 dynamics induced in the QD DFB under optical injection. Continuous tuning in the positive detuning frequency range of the quantum dot's unique stability map is demonstrated. The simplicity of the experimental configuration offers promise for novel uses of these nanostructure lasers in Radio-over-Fiber (RoF) applications and future mobile networks. PMID- 23669935 TI - Exactly solvable toy model for surface plasmon amplification by stimulated emission of radiation. AB - We propose an exactly solvable electrodynamical model for surface plasmon amplification by stimulated emission of radiation (spaser). The gain medium is described in terms of the nonlinear permittivity with negative losses. The model demonstrates the main feature of a spaser: a self-oscillating state (spasing) arising without an external driving field if the pumping exceeds some threshold value. In addition, it properly describes synchronization of a spaser by an external field within the Arnold tongue and the possibility of compensating for Joule losses when the pumping is below threshold. The model also gives correct qualitative dependencies of spaser characteristics on pumping. PMID- 23669936 TI - Build up of off-diagonal long-range order in microcavity exciton-polaritons across the parametric threshold. AB - We report an experimental study of the spontaneous spatial and temporal coherence of polariton condensates generated in the optical parametric oscillator configuration, below and at the parametric threshold, and as a function of condensate area. Above the threshold we obtain very long coherence times (up to 3 ns) and a spatial coherence extending over the entire condensate (40 MUm). The very long coherence time and its dependence on condensate area and pump power reflect the suppression of polariton-polariton interactions by an effect equivalent to motional narrowing. PMID- 23669937 TI - Impact of power allocation strategies in long-haul few-mode fiber transmission systems. AB - We report for the first time on the limitations in the operational power range of few-mode fiber based transmission systems, employing 28 Gbaud quadrature phase shift keying transponders, over 1,600 km. It is demonstrated that if an additional mode is used on a preexisting few-mode transmission link, and allowed to optimize its performance, it will have a significant impact on the pre existing mode. In particular, we show that for low mode coupling strengths (weak coupling regime), the newly added variable power mode does not considerably impact the fixed power existing mode, with performance penalties less than 2dB (in Q-factor). On the other hand, as mode coupling strength is increased (strong coupling regime), the individual launch power optimization significantly degrades the system performance, with penalties up to ~6 dB. Our results further suggest that mutual power optimization, of both fixed power and variable power modes, reduces power allocation related penalties to less than 3 dB, for any given coupling strength, for both high and low differential mode delays. PMID- 23669938 TI - Stray light analysis and suppression of panoramic annular lens. AB - A new stray light analysis method and some suppression principles of panoramic annular lens (PAL) are introduced in this paper. The proposed method is to find stray light paths which are caused by ray splitting on two refractive surfaces of the PAL block and then cut them off. Following this principle, the stray light paths can be eliminated in the design progress by adding specific merit functions into the optical software. The methods to reduce scatter, diffraction and other stray light are also proposed. A new PAL with a field of view (FOV) of 30 degrees ~ 100 degrees * 360 degrees is designed. The stray light is suppressed more than 80% compared with a similar conventional PAL. The stray light path analysis method also can be used in other catadioptric optics. PMID- 23669939 TI - The absorption tunability and enhanced electromagnetic coupling of terahertz plasmons in grating-gate AlN/GaN plasmonic device. AB - This paper describes the dynamic interaction between plasmons in a two dimensional electron gas system under electrical tuning to the high density regime in AlN/GaN high electron mobility transistor. The results demonstrate an enhanced resonance when the two plasmons are commonly excited, during which the potentially splitting phenomenon of such resonance is explored in detail. An asymmetrical plasmon possess wide frequency tunability has also been demonstrated in the AlN/GaN system, on the contrary, the results also indicate a finite tunable regime of symmetrical-plasmons as limited by the coupling strength between such plasmons. For the devices with narrow gate-fingers, significant near field enhancement can be obtained due to the strong cavity pumping of electromagnetic energy. These properties may have important applications including high-responsivity quantum-dot detection systems, THz modulator etc. PMID- 23669940 TI - 120 nm resolution and 55 nm structure size in STED-lithography. AB - Two-photon direct laser writing (DLW) lithography is limited in the achievable structure size as well as in structure resolution. Adding stimulated emission depletion (STED) to DLW allowed overcoming both restrictions. We now push both to new limits. Using visible light for two-photon DLW (780 nm) and STED (532 nm), we obtain lateral structure sizes of 55 nm, a Sparrow limit of around 100 nm and we present two clearly separated lines spaced only 120 nm apart. The photo-resist used in these experiments is a mixture of tri- and tetra-acrylates and 7 Diethylamino-3-thenoylcoumarin as a photo-starter which can be readily quenched via STED. PMID- 23669941 TI - Generation of polarization-entangled photon pairs in a Bragg reflection waveguide. AB - We demonstrate experimentally that spontaneous parametric down-conversion in an AlxGa(1-x)As semiconductor Bragg reflection waveguide can make for paired photons highly entangled in the polarization degree of freedom at the telecommunication wavelength of 1550 nm. The pairs of photons show visibility higher than 90% in several polarization bases and violate a Clauser-Horne-Shimony-Holt Bell-like inequality by more than 3 standard deviations. This represents a significant step toward the realization of efficient and versatile self pumped sources of entangled photon pairs on-chip. PMID- 23669942 TI - Subaperture correlation based digital adaptive optics for full field optical coherence tomography. AB - This paper proposes a sub-aperture correlation based numerical phase correction method for interferometric full field imaging systems provided the complex object field information can be extracted. This method corrects for the wavefront aberration at the pupil/ Fourier transform plane without the need of any adaptive optics, spatial light modulators (SLM) and additional cameras. We show that this method does not require the knowledge of any system parameters. In the simulation study, we consider a full field swept source OCT (FF SSOCT) system to show the working principle of the algorithm. Experimental results are presented for a technical and biological sample to demonstrate the proof of the principle. PMID- 23669943 TI - Antenna array connections for efficient performance of distributed microbolometers in the IR. AB - Optical antennas and resonant structures have been extensively investigated due to its potential for electromagnetic detection and energy harvesting applications. However their integration into large arrays and the role of connection lines between individual antennas has drawn little attention. This is necessary if we want to exploit its potential constructively and to enable economical large-scale fabrication. In this contribution we point out some features that an efficient antenna array should address. Experimental measurements on aluminum microbolometers are compared to electromagnetic simulations, it is shown that the finite size of a real array and the interconnection lines interact and affect the global performance. PMID- 23669944 TI - Goos-Hanchen shifts in harmonic generation from metals. AB - We present the first calculation of the Goos-Hanchen shifts in the context of the nonlinear generation of fields. We specifically concentrate on shifts of second harmonic generated at metallic surfaces. At metallic surfaces the second harmonic primarily arises from discontinuities of the field at surfaces which not only result in large harmonic generation but also in significant Goos-Hanchen shifts of the generated second harmonic. Our results can be extended to other shifts like angular shifts and Fedorov-Imbert shifts. PMID- 23669945 TI - Efficient perfectly vertical fiber-to-chip grating coupler for silicon horizontal multiple slot waveguides. AB - Horizontal multiple slot waveguides of polysilicon and silicon nanocrystalline oxide were grating coupled to a surface normal fiber array. Measurements yielded a coupling efficiency of 60% per grating. The fabrication-tolerant, four-stage grating design was genetically evolved from a random seed without starting from first-principle design. Theoretical coupling efficiency was 68% and was re designed to 63% after accommodating all sources of fabrication error. To our knowledge, this is the first implementation of a purely polysilicon and silicon nanocrystalline oxide slot waveguide platform. PMID- 23669946 TI - Multi-gigahertz repetition-rate-selectable passive harmonic mode locking of a fiber laser. AB - We demonstrate a passive harmonically mode-locked erbium-doped fiber laser that operates at selectable harmonics spanning from the 6th to the 928th, which corresponds to repetition rates ranging from 153 MHz to 22.2 GHz. The noteworthy laser output stability is attested by supermode suppression levels as large as 41 dB. The influence of a continuous wave background on harmonics stability is tested. PMID- 23669947 TI - Efficient wavelength multiplexers based on asymmetric response filters. AB - We propose integrated photonic wavelength multiplexers based on serially cascaded channel add-drop filters with an asymmetric frequency response. By utilizing the through-port rejection of the previous channel to advantage, the asymmetric response provides optimal rejection of the adjacent channels at each wavelength channel. We show theoretically the basic requirements to realize an asymmetric filter response, and propose and evaluate the possible implementations using coupled resonators. For one implementation, we provide detailed design formulas based on a coupled-mode theory model, and more generally we provide broad guidelines that enumerate all structures that can provide asymmetric passbands in the context of a pole-zero design approach to engineering the device response. Using second-order microring resonator filter stages as an example, we show that the asymmetric multiplexer can provide 2.4 times higher channel packing (bandwidth) density than a multiplexer using the same order stages (number of resonators) using conventional all-pole maximally-flat designs. We also address the sensitivities and constraints of various implementations of our proposed approach, as it affects their applicability to CMOS photonic interconnects. PMID- 23669948 TI - Electrically driven nanopillars for THz quantum cascade lasers. AB - In this work we present a rapid and parallel process for the fabrication of large scale arrays of electrically driven nanopillars for THz quantum cascade active media. We demonstrate electrical injection of pillars of 200 nm diameter and 2 um height, over a surface of 1 mm(2). THz electroluminescence from the nanopillars is reported. This result is a promising step toward the realization of zero dimensional structure for terahertz quantum cascade lasers. PMID- 23669949 TI - Brillouin spectroscopy of a novel baria-doped silica glass optical fiber. AB - Presented here for the first time to the best of our knowledge is a detailed Brillouin spectroscopic study of novel, highly-BaO-doped silica glass optical fibers. The fibers were fabricated utilizing a molten-core method and exhibited baria (BaO) concentrations up to 18.4 mole %. Physical characteristics such as mass density, acoustic velocity, visco-elastic damping, and refractive index are determined for the baria component of the bariosilicate system. It is found that, of each of these parameters, only the acoustic velocity is less than that of pure silica. The effect of temperature and strain on the acoustic velocity also is determined by utilizing estimates of the strain- and thermo-optic coefficients. The dependencies are found to have signs opposite to those of silica, thus suggesting both Brillouin-frequency a-thermal and a-tensic binary compositions. Via the estimate of the strain-optic coefficient and data found in the literature, the Pockels' photoelastic constant p(12) is estimated, and both a calculation and measured estimate of the Brillouin gain versus baria content are presented. Such novel fibers incorporating the unique properties of baria could be of great utility for narrow linewidth fiber lasers, high power passive components (such as couplers and combiners), and Brillouin-based sensor systems. PMID- 23669950 TI - Tunable vacuum-UV to visible ultrafast pulse source based on gas-filled Kagome PCF. AB - An efficient and tunable 176-550 nm source based on the emission of resonant dispersive radiation from ultrafast solitons at 800 nm is demonstrated in a gas filled hollow-core photonic crystal fiber (PCF). By careful optimization and appropriate choice of gas, informed by detailed numerical simulations, we show that bright, high quality, localized bands of UV light (relative widths of a few percent) can be generated at all wavelengths across this range. Pulse energies of more than 75 nJ in the deep-UV, with relative bandwidths of ~3%, are generated from pump pulses of a few MUJ. Excellent agreement is obtained between numerical and experimental results. The effects of positive and negative axial pressure gradients are also experimentally studied, and the coherence of the deep-UV dispersive wave radiation numerically investigated. PMID- 23669951 TI - Modulation of shape and polarization of beam using a liquid crystal q-plate that is fabricated via photo-alignment. AB - A liquid crystal (LC) device, called a "q-plate" (QP), which is based on axially symmetric photo-alignment was investigated. The electrically tunable LC QP device could be modulated to control the shape and polarization of a linearly polarized Gaussian laser beam that propagated through it. The intensity profile and polarization distribution were simulated by MATLAB and 1D-DIMOS. The results of the simulation were consistent with experimental findings. In the fabricated electrically tunable LC QP device, switching between different beam-profile configurations can be realized by applying a voltage. Moreover, the fabrication of an LC QP is relatively simple, and the device has potential for such practical applications as beam shape modulators and spatial polarization converters use in diffractive optics and imaging systems. PMID- 23669952 TI - 30-Gb/s 90-nm CMOS-driven equalized multimode optical link. AB - We report an 850-nm vertical cavity surface emitting laser (VCSEL)-based optical link that achieves a new record in speed. The laser driver and receiver ICs are fabricated in standard 90-nm bulk CMOS, and the optoelectronic devices are commercial components. Operation at 30 Gb/s with a bit-error rate < 10(-12) is achieved, representing to the authors' knowledge the highest speed reported to date for a CMOS-based full optical link. Transmitter feed-forward equalization is shown to improve maximum data rate from 25 to 30 Gb/s, timing margin by 17% at 23.5 Gb/s, and receiver sensitivity by 4 dB at 23.5 Gb/s. PMID- 23669953 TI - Mid-infrared supercontinuum generation in As2S3-silica "nano-spike" step-index waveguide. AB - Efficient generation of a broad-band mid-infrared supercontinuum spectrum is reported in an arsenic trisulphide waveguide embedded in silica. A chalcogenide "nano-spike", designed to transform the incident light adiabatically into the fundamental mode of a 2-mm-long uniform section 1 um in diameter, is used to achieve high launch efficiencies. The nano-spike is fully encapsulated in a fused silica cladding, protecting it from the environment. Nano-spikes provide a convenient means of launching light into sub-wavelength scale waveguides. Ultrashort (65 fs, repetition rate 100 MHz) pulses at wavelength 2 um, delivered from a Tm-doped fiber laser, are launched with an efficiency ~12% into the sub wavelength chalcogenide waveguide. Soliton fission and dispersive wave generation along the uniform section result in spectral broadening out to almost 4 um for launched energies of only 18 pJ. The spectrum generated will have immediate uses in metrology and infrared spectroscopy. PMID- 23669954 TI - Correcting chromatic offset in multicolor super-resolution localization microscopy. AB - Localization based super-resolution microscopy techniques require precise drift correction methods because the achieved spatial resolution is close to both the mechanical and optical performance limits of modern light microscopes. Multi color imaging methods require corrections in addition to those dealing with drift due to the static, but spatially-dependent, chromatic offset between images. We present computer simulations to quantify this effect, which is primarily caused by the high-NA objectives used in super-resolution microscopy. Although the chromatic offset in well corrected systems is only a fraction of an optical wavelength in magnitude (<50 nm) and thus negligible in traditional diffraction limited imaging, we show that object colocalization by multi-color super resolution methods is impossible without appropriate image correction. The simulated data are in excellent agreement with experiments using fluorescent beads excited and localized at multiple wavelengths. Finally we present a rigorous and practical calibration protocol to correct for chromatic optical offset, and demonstrate its efficacy for the imaging of transferrin receptor protein colocalization in HeLa cells using two-color direct stochastic optical reconstruction microscopy (dSTORM). PMID- 23669955 TI - Optical bistability in a silicon nitride microring resonator with azo dye-doped liquid crystal as cladding material. AB - This investigation reports observations of optical bistability in a silicon nitride (SiN) micro-ring resonator with azo dye-doped liquid crystal cladding. The refractive index of the cladding can be changed by switching the liquid crystal between nematic (NLC) and photo-induced isotropic (PHI) states by. Both the NLC and the PHI states can be maintained for many hours, and can be rapidly switched from one state to the other by photo-induced isomerization using 532 nm and 408 nm addressing light, respectively. The proposed device exhibits optical bistable switching of the resonance wavelength without sustained use of a power source. It has a 1.9 nm maximum spectral shift with a Q-factor of over 10000. The hybrid SiN- LC micro-ring resonator possesses easy switching, long memory, and low power consumption. It therefore has the potential to be used in signal processing elements and switching elements in optically integrated circuits. PMID- 23669956 TI - Linearity in the response of photopolymers as optical recording media. AB - Photopolymer are appealing materials for diffractive elements recording. Two of their properties when they are illuminated are useful for this goal: the relief surface changes and the refractive index modifications. To this goal the linearity in the material response is crucial to design the optimum irradiance for each element. In this paper we measured directly some parameters to know how linear is the material response, in terms of the refractive index modulation versus exposure, then we can predict the refractive index distributions during recording. We have analyzed at different recording intensities the evolution of monomer diffusion during recording for photopolymers based on PVA/Acrylamide. This model has been successfully applied to PVA/Acrylamide photopolymers to predict the transmitted diffracted orders and the agreement with experimental values has been increased. PMID- 23669957 TI - Schmidt decompositions of parametric processes II: vector four-wave mixing. AB - In vector four-wave mixing, one or two strong pump waves drive two weak signal and idler waves, each of which has two polarization components. In this paper, vector four-wave mixing processes in a randomly-birefringent fiber (modulation interaction, phase conjugation and Bragg scattering) are studied in detail. For each process, the Schmidt decompositions of the coupling matrices facilitate the solution of the signal-idler equations and the Schmidt decomposition of the associated transfer matrix. The results of this paper are valid for arbitrary pump polarizations. PMID- 23669958 TI - On the long-memory filtering gain in optical high-order QAM transmission systems. AB - In this paper, we verify the effectiveness of the last-stage long memory filter (LMF) in mitigating the long-memory response (LMR) of hardware, i.e. the transmitter and receiver. Based on the experimental results, we draw the following conclusions: 1) LMF can effectively mitigate the LMR impact, such as transmitter reflections, and its efficiency is more significant for high-order QAM signals. 2) Using LMF, a partially-correlated pattern exhibits similar performance to that of an uncorrelated pattern both in back-to-back and after 320 km standard single mode fiber (SSMF) transmission. Moreover, a simple solution to the computational complexity of LMF, effective-tap (ET) LMF, is proposed and demonstrated. PMID- 23669959 TI - Waferscale nanophotonic circuits made from diamond-on-insulator substrates. AB - Wide bandgap dielectrics are attractive materials for the fabrication of photonic devices because they allow broadband optical operation and do not suffer from free-carrier absorption. Here we show that polycrystalline diamond thin films deposited by chemical vapor deposition provide a promising platform for the realization of large scale integrated photonic circuits. We present a full suite of photonic components required for the investigation of on-chip devices, including input grating couplers, millimeter long nanophotonic waveguides and microcavities. In microring resonators we measure loaded optical quality factors up to 11,000. Corresponding propagation loss of 5 dB/mm is also confirmed by measuring transmission through long waveguides. PMID- 23669960 TI - Hybrid photonic-plasmonic molecule based on metal/Si disks. AB - Optical properties of two identical coupled disks forming a "hybrid photonic plasmonic molecule" are investigated. Each disk is a metal-dielectric structure supporting hybrid plasmonic-photonic whispering-gallery (WG) modes. The WG modes of a molecule split into two groups of nearly-degenerate modes, i.e., bonding and anti-bonding modes. The oscillation of quality factor (Q) with the inter-disk gap d and significant enhancement at certain inter-disk gaps can be observed. An enhanced Q factor of 1821 for a hybrid photonic-plasmonic molecule composed of two 1.2 MUm-diameter disks, compared with that for a single disk, is achieved. The corresponding Purcell factor is 191, making the hybrid photonic-plasmonic molecule an optimal choice for subwavelength-scale device miniaturization and light-matter interactions. Moreover, the far-field emission pattern of the hybrid photonic-plasmonic molecule exhibits an enhanced directional light output by tuning the azimuthal mode number for both bonding and anti-bonding modes. PMID- 23669961 TI - Permanent fine tuning of silicon microring devices by femtosecond laser surface amorphization and ablation. AB - We demonstrate the fine tuning capability of femtosecond laser surface modification as a permanent trimming mechanism for silicon photonic components. Silicon microring resonators with a 15 um radius were irradiated with single 400 nm wavelength laser pulses at varying fluences. Below the laser ablation threshold, surface amorphization of the crystalline silicon waveguides yielded a tuning rate of 20 +/- 2 nm/J . cm(-2)with a minimum resonance wavelength shift of 0.10nm. Above that threshold, ablation yielded a minimum resonance shift of -1.7 nm. There was some increase in waveguide loss for both trimming mechanisms. We also demonstrated the application of the method by using it to permanently correct the resonance mismatch of a second-order microring filter. PMID- 23669962 TI - Mixel camera--a new push-broom camera concept for high spatial resolution keystone-free hyperspectral imaging. AB - Current high-resolution push-broom hyperspectral cameras introduce keystone errors to the captured data. Efforts to correct these errors in hardware severely limit the optical design, in particular with respect to light throughput and spatial resolution, while at the same time the residual keystone often remains large. The mixel camera solves this problem by combining a hardware component--an array of light mixing chambers--with a mathematical method that restores the hyperspectral data to its keystone-free form, based on the data that was recorded onto the sensor with large keystone. A Virtual Camera software, that was developed specifically for this purpose, was used to compare the performance of the mixel camera to traditional cameras that correct keystone in hardware. The mixel camera can collect at least four times more light than most current high resolution hyperspectral cameras, and simulations have shown that the mixel camera will be photon-noise limited--even in bright light--with a significantly improved signal-to-noise ratio compared to traditional cameras. A prototype has been built and is being tested. PMID- 23669963 TI - Solution-processed single-emitting-layer white organic light-emitting diodes based on small molecules with efficiency/CRI/color-stability trade-off. AB - By doping blue, green and red dyes into a bipolar host system, a simple single EML white organic light-emitting diode (WOLED) with efficiency and color stability trade-off was achieved by solution process. The resulting WOLED shows high efficiency (i.e., 36.5 cd/A and 15.7% at 1141 cd/m(2)), reduced efficiency roll-off (i.e., critical current density jc is as high as 140 mA/cm(2)) and, especially, extremely stable electroluminescence spectra with a slight CIE coordinate variation of (0.404 +/- 0.004, 0.436 +/- 0.001). The superior performance of the WOLED is attributed to the effective suppression of exciton quenching and charge trapping in the bipolar EML. PMID- 23669964 TI - Flexible bottom-emitting white organic light-emitting diodes with semitransparent Ni/Ag/Ni anode. AB - We fabricated a flexible bottom-emitting white organic light-emitting diode (BEWOLED) with a structure of PET/Ni/Ag/Ni (3/6/3 nm)/ NPB (50 nm)/mCP (10 nm)/7% FIrpic:mCP (10 nm)/3% Ir(pq)(2) acac:TPBi (5 nm)/7% FIrpic:TPBi (5 nm)/TPBi (10 nm)/Liq (2 nm)/ Al (100 nm). To improve the performance of the BEWOLED, a multilayered metal stack anode of Ni/Ag/Ni treated with oxygen plasma for 60 sec was introduced into the OLED devices. The Ni/Ag/Ni anode effectively enhanced the probability of hole-electron recombination due to an efficient hole injection into and charge balance in an emitting layer. By comparing with a reference WOLED using ITO on glass, it is verified that the flexible BEWOLED showed a similar or better electroluminescence (EL) performance. PMID- 23669965 TI - Modulated exciton-plasmon interactions in Au-SiO2-CdTe composite nanoparticles. AB - Well-defined Au-SiO(2)-CdTe composite nanoparticles were synthesized via a multistep chemical approach in water solution to gain insight into the interaction between metal and semiconductor nanostructures. Photoluminescence measurement reveals that the fluorescence of CdTe quantum dots (QDs) in this composite with optimized SiO(2) thickness (4 nm) has over ten times enhancement compared with that of bare CdTe QDs. The considerable fluorescence enhancement of CdTe QDs is attributed to the surface plasmon resonance, which is further confirmed by the lifetime measurement. The enhanced fluorescence can be used to improve the performance of CdTe QDs as fluorescence probe and may find potential applications in biolabeling. PMID- 23669966 TI - Fano resonance in concentric ring apertures. AB - We demonstrate a polarization-independent mid-infrared Fano resonance with extraordinary transmission when light passes through two concentric metallic ring apertures. A high-Q dark mode is indirectly excitated by coupling with a low-Q bright mode. A coupled optical resonator model is used to analyze the coupling process between the bright and dark modes. We find the Q of the dark mode is 3~6 times higher than that of the bright mode. We show that the dark mode can be selectively disabled without affecting the bright mode. PMID- 23669967 TI - Near-infrared surface plasmon polariton dispersion control with hyperbolic metamaterials. AB - We demonstrate experimentally signatures and dispersion control of surface plasmon polaritons from 1 to 1.8 um using periodic multilayer metallo-dielectric hyperbolic metamaterials. The fabricated structures are comprised of smooth films with very low metal filling factor. The measured dispersion properties of these hyperbolic metamaterials agree well with calculations using transfer matrix, finite-difference time-domain, and effective medium approximation methods despite using only 2.5 periods. The enhancement factor in the local photonic density of states from the studied samples in the near-infrared wavelength region is determined to be 2.5-3.5. Development of this type of metamaterial is relevant to sub-wavelength imaging, spontaneous emission and thermophotovoltaic applications. PMID- 23669968 TI - A hybrid analysis method for plasmonic enhanced terahertz photomixer sources. AB - A hybrid analysis of a continuous-wave terahertz photomixer source structure with plasmonic nano-grating electrodes is presented. Using the hybrid analysis, the enhancement of the optical power absorption due to the presence of the one dimensional metallic nano-grating is investigated by defining an absorption enhancement factor. We show that the proposed absorption enhancement factor can be used as a design tool, whose maximization provides the optimum geometrical parameters of the nano-grating. Based on drift-diffusion model, the photocurrent enhancement due to the nano-grating electrodes is studied under three different bias configurations. Moreover, the dependence of the photocurrent on the physical parameters of the photomixer is analyzed. PMID- 23669969 TI - Conical Refraction: new observations and a dual cone model. AB - We propose a paraxial dual-cone model of conical refraction involving the interference of two cones of light behind the exit face of the crystal. The supporting experiment is based on beam selecting elements breaking down the conically refracted beam into two separate hollow cones which are symmetrical with one another. The shape of these cones of light is a product of a 'competition' between the divergence caused by the conical refraction and the convergence due to the focusing by the lens. The developed mathematical description of the conical refraction demonstrates an excellent agreement with experiment. PMID- 23669971 TI - Static FBG strain sensor with high resolution and large dynamic range by dual comb spectroscopy. AB - We demonstrate a fiber Bragg grating (FBG) strain sensor with optical frequency combs. To precisely characterize the optical response of the FBG when strain is applied, dual-comb spectroscopy is used. Highly sensitive dual-comb spectroscopy of the FBG enabled strain measurements with a resolution of 34 nepsilon. The optical spectral bandwidth of the measurement exceeds 1 THz. Compared with conventional FBG strain sensor using a continuous-wave laser that requires rather slow frequency scanning with a limited range, the dynamic range and multiplexing capability are significantly improved by using broadband dual-comb spectroscopy. PMID- 23669970 TI - Image sensor pixel with on-chip high extinction ratio polarizer based on 65-nm standard CMOS technology. AB - In this study, we demonstrate a polarization sensitive pixel for a complementary metal-oxide-semiconductor (CMOS) image sensor based on 65-nm standard CMOS technology. Using such a deep-submicron CMOS technology, it is possible to design fine metal patterns smaller than the wavelengths of visible light by using a metal wire layer. We designed and fabricated a metal wire grid polarizer on a 20 * 20 MUm(2) pixel for image sensor. An extinction ratio of 19.7 dB was observed at a wavelength 750 nm. PMID- 23669972 TI - Enhancing diffractive multi-plane microscopy using colored illumination. AB - We present a method to increase the number of simultaneously imaged focal planes in diffractive multi-plane imaging. We exploit the chromatic properties of diffraction by using multicolor LED illumination and demonstrate time-synchronous imaging of up to 21 focal planes.We discuss the possibilities and limits given by the use of a liquid crystal spatial light modulator to display the diffractive patterns. The method is suitable for wide-field transmission and reflection microscopy. PMID- 23669973 TI - Integrated autocorrelator based on superconducting nanowires. AB - We demonstrate an integrated autocorrelator based on two superconducting single photon detectors patterned on top of a GaAs ridge waveguide. This device enables the on-chip measurement of the second-order intensity correlation function g(2)(tau). A polarization-independent device quantum efficiency in the 1% range is reported, with a timing jitter of 88 ps at 1300 nm. g(2)(tau) measurements of continuous-wave and pulsed laser excitations are demonstrated with no measurable crosstalk within our measurement accuracy. PMID- 23669974 TI - A novel design method for continuous-phase plate. AB - A continuous-phase plate (CPP) is a key element for beam smoothing in a high power laser system. For the beam-smoothing effect, the surface shape of a CPP is one of the most important facts. In this paper, the change law of the transmission direction of light rays has been analyzed according to the geometrical optical principle. It is discovered that the 2-dimensional histogram of a surface gradient can be used to show the far-field distribution of a CPP. Drawing on the experience of histogram modification technology in digital image processing, a novel method is proposed to design a CPP. The design steps of a 1 dimensional CPP are introduced in detail. The far-field distribution and spatial frequency spectrum of this CPP are calculated. The results show that this method is efficient and can reflect the relationship between the surface figure and the far-field distribution of a CPP directly. PMID- 23669975 TI - Reflectance field display. AB - We propose a display for stereoscopically representing an arbitrary object that is responsive to an arbitrary physical illumination source in the display environment. Our scheme is based on the eight-dimensional reflectance field, which contains angular and spatial information of incoming and outgoing light rays of an object, and is also known as the bidirectional scattering surface reflectance distribution function (BSSRDF). This system is composed of an integral photography unit, an integral display unit, and a processor connecting these units. The concept was demonstrated experimentally. In the demonstrations, a stereoscopically represented object responded to changes in physical illumination coming toward the display. PMID- 23669976 TI - A simplified approach to quantitative coded aperture X-ray phase imaging. AB - We recently demonstrated how quantitative X-ray phase contrast imaging may be performed with laboratory sources using the coded aperture technique. This technique required the knowledge of system parameters such as, for example, the source focal spot size and distances between elements of the imaging system. The method also assumes that the absorbing regions of the apertures are perfectly absorbing. In this paper we demonstrate how quantitative imaging can be performed without knowledge of individual system parameters and with partially absorbing apertures. We also show that this method is analogous to that employed in analyser based imaging which uses the rocking curve of an analyser crystal. PMID- 23669977 TI - Direct laser writing of three-dimensional narrow bandgap and high refractive index PbSe structures in a solution. AB - Three-dimensional (3D) micro/nano structures made of narrow electronic bandgap semiconductor materials have important applications in a wide range of disciplines. Direct laser writing (DLW) provides the unparalleled advantage to fabricate 3D arbitrary geometric structures at the micro and nano meter scale. The fabrication of 3D structures within bulk narrow electronic bandgap semiconductor materials by DLW is challenged for the top-down strategy due to their narrow bandgap and high refractive index. Here, we report on the bottom-up strategy for the fabrication of 3D micro/nano structures made from PbSe with an electronic bandgap as narrow as 0.27 eV and a refractive index as high as 4.82 in a solution. PMID- 23669978 TI - Tapered fiber Mach-Zehnder interferometers for vibration and elasticity sensing applications. AB - We demonstrate the optical measurements of heart-beat pulse rate and also elasticity of a polymeric tube, using a tapered fiber Mach-Zehnder interferometer. This device has two abrupt tapers in the Er/Yb codoped fiber and thus fractional amount of core mode is converted into cladding modes at the first abrupt taper. The core and cladding modes propagate through different optical paths and meet again at the second abrupt taper to produce interferences. The mechanical vibration signals generated by the blood vessels and by an inflated polymeric tube can perturb the optical paths of resonant modes to move around the resonant wavelengths. Thus, the cw laser signal is modulated to become pulses to reflect the heart-beat pulse rate and the elasticity of a polymeric tube, respectively. PMID- 23669979 TI - Soliton trapping of dispersive waves in photonic crystal fiber with two zero dispersive wavelengths. AB - Based on the generalized nonlinear Schrodinger equation, we present a numerical study of trapping of dispersive waves by solitons during supercontinuum generation in photonic crystal fibers pumped with femtosecond pulses in the anomalous dispersion region. Numerical simulation results show that the generated supercontinuum is bounded by two branches of dispersive waves, namely blue shifted dispersive waves (B-DWs) and red-shifted dispersive waves (R-DWs). We find a novel phenomenon that not only B-DWs but also R-DWs can be trapped by solitons across the zero-dispersion wavelength when the group-velocity matching between the soliton and the dispersive wave is satisfied, which may led to the generation of new spectral components via mixing of solitons and dispersive waves. Mixing of solitons with dispersive waves has been shown to play an important role in shaping not only the edge of the supercontinuum, but also its central part around the higher zero-dispersion wavelength. Further, we show that the phenomenon of soliton trapping of dispersive waves in photonic crystal fibers with two zero-dispersion wavelengths has a very close relationship with pumping power and the interval between two zero-dispersion wavelengths. In order to clearly display the evolution of soliton trapping of dispersive waves, the spectrogram of output pulses is observed using cross-correlation frequency resolved optical gating technique (XFROG). PMID- 23669980 TI - Optical coupling to nanoscale optomechanical cavities for near quantum-limited motion transduction. AB - A significant challenge in the development of chip-scale cavity-optomechanical devices as testbeds for quantum experiments and classical metrology lies in the coupling of light from nanoscale optical mode volumes to conventional optical components such as lenses and fibers. In this work we demonstrate a high efficiency, single-sided fiber-optic coupling platform for optomechanical cavities. By utilizing an adiabatic waveguide taper to transform a single optical mode between a photonic crystal zipper cavity and a permanently mounted fiber, we achieve a collection efficiency for intracavity photons of 52% at the cavity resonance wavelength of lambda ~ 1538 nm. An optical balanced homodyne measurement of the displacement fluctuations of the fundamental in-plane mechanical resonance at 3.3 MHz reveals that the imprecision noise floor lies a factor of 2.8 above the standard quantum limit (SQL) for continuous position measurement, with a predicted total added noise of 1.4 phonons at the optimal probe power. The combination of extremely low measurement noise and robust fiber alignment presents significant progress towards single-phonon sensitivity for these sorts of integrated micro-optomechanical cavities. PMID- 23669981 TI - A 360-degree floating 3D display based on light field regeneration. AB - Using light field reconstruction technique, we can display a floating 3D scene in the air, which is 360-degree surrounding viewable with correct occlusion effect. A high-frame-rate color projector and flat light field scanning screen are used in the system to create the light field of real 3D scene in the air above the spinning screen. The principle and display performance of this approach are investigated in this paper. The image synthesis method for all the surrounding viewpoints is analyzed, and the 3D spatial resolution and angular resolution of the common display zone are employed to evaluate display performance. The prototype is achieved and the real 3D color animation image has been presented vividly. The experimental results verified the representability of this method. PMID- 23669982 TI - Non-reciprocal magnetoplasmon graphene coupler. AB - The non-reciprocity of the edge magnetoplasmon modes of a graphene strip is leveraged to design a non-reciprocal magnetoplasmon graphene coupler, coupling only in one direction. The proposed coupler consists of two coplanar parallel magnetically biased graphene strips. In the forward direction, the modes along the adjacent strip edges of the strips have the same wavenumber and therefore couple to each other. In the backward direction, the modes along the adjacent strip edges have different wavenumbers and therefore no coupling occurs. PMID- 23669983 TI - First selective mode excitation and amplification in a ribbon core optical fiber. AB - We propose and demonstrate amplification of a single high-order mode in an optical fiber having an elongated, ribbon-like core having an effective mode area of area of 600 um(2) and an aspect ratio of 13:1. When operated as an amplifier, the double-clad, ytterbium doped, photonic crystal fiber produced 50% slope efficiency and a seed-limited power of 10.5 W, corresponding to a gain of 24 dB. The high order mode remained pure through 20 dB of gain without intervention or realignment. PMID- 23669984 TI - Coherent high-order harmonic generation by sawtooth-like laser fields. AB - We theoretically investigate the high-order harmonic generation driven by sawtooth-like laser fields. It is found that the coherence of the high-order harmonic spectrum could be controlled by adjusting the sawtooth shape parameter alpha (0 <= alpha <= 0.5). With proper alpha, the intensity of the high-order harmonic spectra come from the electrons with long trajectories can be greatly weakened and the harmonic photons in the plateau burst with high coherence in a broad frequency range. Selecting these harmonics, a phase-stabilized attosecond pulse train with regular pulse structure could be obtained. PMID- 23669985 TI - Phase-space non-paraxial propagation modes of optical fields in any state of spatial coherence. AB - The non-paraxial marginal power spectrum is decomposed in propagation modes, so that the zeroth-order mode is only emitted by the radiant point sources at the aperture plane, while the modes of higher orders than zero are only emitted by the virtual point sources. It allows representing the non-paraxial propagation of optical fields in arbitrary states of spatial coherence and along arbitrary distances from the aperture plane without approximations, by simply using the power distribution and the spatial coherence state at the aperture plane as entries. This modal expansion is potentially useful in micro-diffraction and spatial coherence modulation. PMID- 23669986 TI - A de-illumination scheme for face recognition based on fast decomposition and detail feature fusion. AB - Almost all the face recognition algorithms are unsatisfied due to illumination variation. Feature with high frequency represents the face intrinsic structure according to the common assumption that illumination varies slowly and the face intrinsic feature varies rapidly. In this paper, we will propose an adaptive scheme based on FBEEMD and detail feature fusion. FBEEMD is a fast version of BEEMD without time-consuming surface interpolation and iteration computation. It can decompose an image into sub-images with high frequency matching detail feature and sub-images with low frequency corresponding to contour feature. However, it is difficult to determine by quantitative analysis that which sub images with high frequency can be used for reconstructing an illumination invariant face. Thus, two measurements are proposed to calculate weights for quantifying the detail feature. With this fusion technique, one can reconstruct a more illumination-neutral facial image to improve face recognition rate. Verification experiments using classical recognition algorithms are tested with Yale B, PIE and FERET databases. The encouraging results show that the proposed scheme is very effective when dealing with face images under variable lighting condition. PMID- 23669987 TI - Apodized distributed feedback fiber laser with asymmetrical outputs for multiplexed sensing applications. AB - The spectral characteristics of four different types of apodized fiber Bragg gratings with a single pi phase shift are analyzed based on the simulation. The 2 discrete Gaussian apodization is proved to have the most effective suppression to grating side mode. A novel asymmetrical distributed feedback fiber laser based on this apodization structure is presented and fabricated as well. The grating has a -20 dB side-mode suppression. The laser exhibits a high power ratio of backward to forward outputs. It has a relative intensity noise of -90 dB/Hz and a linewidth of 20k Hz operating in a single polarization longitudinal mode. PMID- 23669988 TI - Compact bandwidth-tunable polarization filter based on a plasmonic heterograting. AB - A plasmonic heterograting device, consisting of two juxtaposed parallel gratings with different periods, is demonstrated to function as a compact bandwidth tunable polarization filter. The essential aspect of the structure is that the grating couples into a photonic mode of the substrate. Using this device, a linearly polarized spectrum can be conveniently and selectively picked out from nonpolarized white light. The bandwidth depends on the incident angle and the overlap of the first-order diffraction spectra of the two different grating, and can be freely narrowed. The tuning characteristics of the heterograting are investigated both theoretically and experimentally. The unique physical features potentially enable the development of new polarization elements and optical devices. PMID- 23669989 TI - Bacteria species identification by the statistical analysis of bacterial colonies Fresnel patterns. AB - It was demonstrated that statistical analysis of bacteria colonies Fresnel patterns recorded in the optical system with converging spherical wave illumination is suitable for highly effective bacteria species classification. The proposed method includes Fresnel patterns recording followed by image processing and the statistical analysis based on feature extraction, feature selection, classification and classification performance methods. Examination performed on various bacteria species (Salmonella enteritidis, Staphylococcus aureus, Staphylococcus intermedius, Escherichia coli, Proteus mirabilis, Pseudomonas aeruginosa and Citrobacter freundii) revealed that the proposed method achieved very high accuracy of over 98%. PMID- 23669990 TI - Metamaterial slab-based super-absorbers and perfect nanodetectors for single dipole sources. AB - We propose to use double negative (DNG) metamaterial slabs to build effective super-absorbers and perfect nanodetectors for single divergent sources. We demonstrate by numerical simulations that an absorbing nanoparticle properly placed inside a DNG slab back-covered with a perfect electric conductor or perfect magnetic conductor mirror can absorb up to 100% radiation energy of a single dipole source placed outside the slab. Furthermore, we also show that even the simple DNG slab without any absorbing nanoparticle could be used as a perfect absorber for both plane and divergent beams. The proposed systems may focus the radiation in nanoscale and thus have applications in optical nanodevices for a variety of different purposes. PMID- 23669991 TI - Surface enhanced Raman scattering substrate with metallic nanogap array fabricated by etching the assembled polystyrene spheres array. AB - A sensitive surface enhanced Raman scattering (SERS) substrate with metallic nanogap array (MNGA) is fabricated by etching of an assembled polystyrene (PS) spheres array, followed by the coating of a metal film. The substrate is reproducible in fabrication and sensitive due to the nanogap coupling resonance (NGCR) enhancement. The NGCR is analyzed with the finite difference time domain (FDTD) method, and the relationship between the gap parameter and the field enhancement is obtained. Experimental measurements of R6G on demonstrate that the enhancement factor (EF) of the MNGA SERS substrate is increased by more than two fold compared with the control sample. PMID- 23669992 TI - Real-time detection of airborne asbestos by light scattering from magnetically re aligned fibers. AB - Inadvertent inhalation of asbestos fibers and the subsequent development of incurable cancers is a leading cause of work-related deaths worldwide. Currently, there is no real-time in situ method for detecting airborne asbestos. We describe an optical method that seeks to address this deficiency. It is based on the use of laser light scattering patterns to determine the change in angular alignment of individual airborne fibers under the influence of an applied magnetic field. Detection sensitivity estimates are given for both crocidolite (blue) and chrysotile (white) asbestos. The method has been developed with the aim of providing a low-cost warning device to trades people and others at risk from inadvertent exposure to airborne asbestos. PMID- 23669993 TI - Solvent-free fluidic organic dye lasers. AB - We report on the demonstration of liquid organic dye lasers based on 9-(2 ethylhexyl)carbazole (EHCz), so-called liquid carbazole, doped with green- and red-emitting laser dyes. Both waveguide and Fabry-Perot type microcavity fluidic organic dye lasers were prepared by capillary action under solvent-free conditions. Cascade Forster-type energy transfer processes from liquid carbazole to laser dyes were employed to achieve color-variable amplified spontaneous emission and lasing. Overall, this study provides the first step towards the development of solvent-free fluidic organic semiconducting lasers and demonstrates a new kind of optoelectronic applications for liquid organic semiconductors. PMID- 23669994 TI - Amplification of cylindrically polarized laser beams in single crystal fiber amplifiers. AB - Yb:YAG single crystal fiber (SCF) amplifiers have recently drawn much attention in the field of amplification of ultra-short pulses. In this paper, we report on the use of SCF amplifiers for the amplification of cylindrically polarized laser beams, as such beams offer promising properties for numerous applications. While the amplification of cylindrically polarized beams is challenging with other amplifier designs due to thermally induced depolarization, we demonstrate the amplification of 32 W cylindrically polarized beams to an output power of 100 W. A measured degree of radial polarization after the SCF of about 95% indicates an excellent conservation of polarization. PMID- 23669995 TI - Contribution of recollision ionization to the cross-shaped structure in nonsequential double ionization. AB - With the three-dimensional classical ensemble model, we investigate the correlated electron emission in nonsequential double ionization (NSDI) of argon atoms by few-cycle laser pulses. Our calculations well reproduce the experimentally observed cross-shaped structure in the correlated two-electron momentum spectrum [ Nature Commun. 3, 813 (2012)]. By tracing these NSDI trajectories, we find that besides the process of recollision-induced excitation with subsequent ionization just before the next field maximum, the recollision ionization also significantly contributes to the cross-shaped structure. PMID- 23669996 TI - Common-path design criteria for laser datum based measurement of small angle deviations and laser autocollimation method in compliance with the criteria with high accuracy and stability. AB - Common-path design criteria for laser datum based measurement of small angle deviations are proposed to guide the implementation of common-path principle in dealing with laser beam drifts resulting from laser generation mechanism and instability of beam transmission medium. A laser autocollimation method is designed in compliance with the criteria, and can achieve an accuracy of 0.013 arcsec and a two-hour stability of 0.020 arcsec over a measurement distance of two meters. The criteria and the method proposed can be effectively used for laser datum based measurement of small angle deviations with high accuracy and stability, especially over a long measurement distance. PMID- 23669997 TI - Study of the effect of myofibrillar misalignment on the sarcomeric SHG intensity pattern. AB - We present a theoretical simulation of the sarcomeric SHG intensity pattern (SHG IP) that takes into account myofibrillar misalignment that is experimentally observed in SHG images of proteolysed muscles. The model predicts that myofibrillar displacement results in the conversion from one peak (1P) to two peaks (2P) sarcomeric SHG-IP in agreement with experimental results. This study suggests that sarcomeric SHG-IP is a powerful tool for mapping spatial myofibrillar displacement and its related excitation-contraction disruption that could occur during muscle physiological adaptation and disease. PMID- 23669998 TI - Phase-preserving parametric wavelength conversion to SWIR band in highly nonlinear dispersion stabilized fiber. AB - The first successful translation of a phase modulated optical signal over 80 THz, from the near infrared to the short-wave infrared (SWIR) band is demonstrated. A signal, phase-modulated at 10 Gbps, was received in an error-free manner in the SWIR(1.7-2.2 MUm) band. A new class of highly nonlinear fiber with reduced dispersion fluctuation was utilized as the platform for this phase-preserving distant parametric conversion. PMID- 23669999 TI - Self-reconstructing sectioned Bessel beams offer submicron optical sectioning for large fields of view in light-sheet microscopy. AB - One of main challenges in light-sheet microscopy is to design the light-sheet as extended and thin as possible--extended to cover a large field of view, thin to optimize resolution and contrast. However, a decrease of the beam's waist also decreases the illumination beam's depth of field. Here, we introduce a new kind of beam that we call sectioned Bessel beam. These beams can be generated by blocking opposite sections of the beam's angular spectrum. In combination with confocal-line detection the optical sectioning performance of the light-sheet can be decoupled from the depth of field of the illumination beam. By simulations and experiments we demonstrate that these beams exhibit self-reconstruction capabilities and penetration depths into thick scattering media equal to those of conventional Bessel beams. We applied sectioned Bessel beams to illuminate tumor multicellular spheroids and prove the increase in contrast. Sectioned Bessel beams turn out to be highly advantageous for the investigation of large strongly scattering samples in a light-sheet microscope. PMID- 23670000 TI - Impact of wave front and coherence optimization in coherent diffractive imaging. AB - We present single shot nanoscale imaging using a table-top femtosecond soft X-ray laser harmonic source at a wavelength of 32 nm. We show that the phase retrieval process in coherent diffractive imaging critically depends on beam quality. Coherence and image fidelity are measured from single-shot coherent diffraction patterns of isolated nano-patterned slits. Impact of flux, wave front and coherence of the soft X-ray beam on the phase retrieval process and the image quality are discussed. After beam improvements, a final image reconstruction is presented with a spatial resolution of 78 nm (half period) in a single 20 fs laser harmonic shot. PMID- 23670001 TI - Single cuprous oxide films synthesized by radical oxidation at low temperature for PV application. AB - Cuprous oxide (Cu(2)O) films synthesis by radical oxidation with nitrogen (N(2)) plasma treatment and different RF power at low temperature (500 degrees C) are studied in this paper. X-ray diffraction measurements show that synthesized Cu(2)O thin films grow on c-sapphire substrate with preferred (111) orientation. With nitrogen (N(2)) plasma treatment, the optical bandgap energy is increased from 1.69 to 2.42 eV, when N(2) plasma treatment time is increased from 0 min to 40 min. Although the hole density is increased from 10(14) to 10(15) cm(-3) and the resistivity is decreased from 1879 to 780 Omega cm after N(2) plasma treatment, the performance of Cu(2)O films is poorer compared to that of Cu(2)O using RF power of 0. The fabricated ZnO/Cu(2)O solar cells based on Cu(2)O films with RF power of 0 W show a good rectifying behavior with a efficiency of 0.02%, an open-circuit voltage of 0.1 V, and a fill factor of 24%. PMID- 23670002 TI - Lasing characteristic of organic octagonal quasicrystal slabs with single-defect microcavity at low-index contrast. AB - We experimentally demonstrate and characterize an organic octagonal quasicrystal slab with a single-defect microcavity at low-index contrast. The gain medium is the conjugated-polymer, composed by two PPV derivatives, a BEHP-PPV and a MEH PPV. By optical pumping, the lasing action is achieved at 607 nm with a FWHM of 1 nm. The threshold of lasing is 9 MUJ/cm(2). The intensity of the lasing peak depends linearly on the pump energy above the threshold. PMID- 23670003 TI - On the choice of retrieval variables in the inversion of remotely sensed atmospheric measurements. AB - In this paper we introduce new variables that can be used to retrieve the atmospheric continuum emission in the inversion of remote sensing measurements. This modification tackles the so-called sloppy model problem. We test this approach on an extensive set of real measurements from the Michelson Interferometer for Passive Atmospheric Sounding. The newly introduced variables permit to achieve a more stable inversion and a smaller value of the minimum of the cost function. PMID- 23670004 TI - Photonic chirped radio-frequency generator with ultra-fast sweeping rate and ultra-wide sweeping range. AB - A high-performance photonic sweeping-frequency (chirped) radio-frequency (RF) generator has been demonstrated. By use of a novel wavelength sweeping distributed-feedback (DFB) laser, which is operated based on the linewidth enhancement effect, a fixed wavelength narrow-linewidth DFB laser, and a wideband (dc to 50 GHz) photodiode module for the hetero-dyne beating RF signal generation, a very clear chirped RF waveform can be captured by a fast real-time scope. A very-high frequency sweeping rate (10.3 GHz/MUs) with an ultra-wide RF frequency sweeping range (~40 GHz) have been demonstrated. The high-repeatability (~97%) in sweeping frequency has been verified by analyzing tens of repetitive chirped waveforms. PMID- 23670005 TI - High-temperature stability and selective thermal emission of polycrystalline tantalum photonic crystals. AB - We present the results of extensive characterization of selective emitters at high temperatures, including thermal emission measurements and thermal stability testing at 1000 degrees C for 1h and 900 degrees C for up to 144 h. The selective emitters were fabricated as 2D photonic crystals (PhCs) on polycrystalline tantalum (Ta), targeting large-area applications in solid-state heat-to-electricity conversion. We characterized spectral emission as a function of temperature, observing very good selectivity of the emission as compared to flat Ta, with the emission of the PhC approaching the blackbody limit below the target cut-off wavelength of 2 MUm, and a steep cut-off to low emission at longer wavelengths. In addition, we study the use of a thin, conformal layer (20 nm) of HfO(2) deposited by atomic layer deposition (ALD) as a surface protective coating, and confirm experimentally that it acts as a diffusion inhibitor and thermal barrier coating, and prevents the formation of Ta carbide on the surface. Furthermore, we tested the thermal stability of the nanostructured emitters and their optical properties before and after annealing, observing no degradation even after 144 h (6 days) at 900 degrees C, which demonstrates the suitability of these selective emitters for high-temperature applications. PMID- 23670006 TI - Fluorescent polymer coated capillaries as optofluidic refractometric sensors. AB - A capillary microresonator platform for refractometric sensing is demonstrated by coating the interior of thick-walled silica capillaries with a sub-wavelength layer of high refractive index, dye-doped polymer. No intermediate processing, such as etching or tapering, of the capillary is required. Side illumination and detection of the polymer layer reveals a fluorescence spectrum that is periodically modulated by whispering gallery mode resonances within the layer. Using a Fourier technique to calculate the spectral resonance shifts, the fabricated capillary resonators exhibited refractometric sensitivities up to approximately 30 nm/RIU upon flowing aqueous glucose through them. These sensors could be readily integrated with existing biological and chemical separation platforms such as capillary electrophoresis and gas chromatography where such thick walled capillaries are routinely used with polymer coatings. A review of the modelling required to calculate whispering gallery eigenmodes of such inverted cylindrical resonators is also presented. PMID- 23670007 TI - Mlines characterization of the refractive index profile of SiGe gradient waveguides at 2.15 um. AB - SiGe alloys present a large Infra-Red transparency window and a full compatibility with the standard Complementary Metal Oxide Semiconductor processing making them suitable for applications in integrated optics. In this paper we report on Mlines characterization of Si(1-x)Ge(x) graded index waveguides at 2.15 um. First, a law giving the refractive index of a Si(1-x)Ge(x) alloy as a function of the Ge content x: n = 1.342x(2) + 0.295x + 3.451, has been experimentally established in the 0 < x < 0.4 range. Then, we have demonstrated that our methodology based on Mlines measurements can be used as short-loop non destructive technique to provide feedback for sample growth. PMID- 23670008 TI - Broadly tunable femtosecond near- and mid-IR source by direct pumping of an OPA with a 41.7 MHz Yb:KGW oscillator. AB - We generate over half a watt of tunable near-IR (1380-1830 nm) and several hundred milliwatts in the mid-IR (2.4-4.2 um) as well as milliwatt level mid-IR (4.85-9.33 um) femtosecond radiation by pumping an optical parametric amplifier directly with a 7.4 W Yb:KGW oscillator at 41.7 MHz repetition rate. We use 5 mm PPLN and 2 mm GaSe as downconversion crystals and seed this process by a supercontinuum from a tapered fiber. The system is extremely simple and very stable and could replace more complex OPOs as tunable light sources. PMID- 23670009 TI - Quantitative plasmonic measurements using embedded phase stepping confocal interferometry. AB - In previous publications [Opt. Express 20, 7388 (2012), Opt. Express 20, 28039 (2012)] we showed how a confocal configuration can form an surface plasmon microscope involving interference between a path involving the generation of surface plasmons and one involving a directly reflected beam. The relative phase of these contributions changes with axial scan position allowing the phase velocity of the surface plasmon to be measured. In this paper we extend the interferometer concept to produce an 'embedded' phase shifting interferometer, where we can control the phase between the reference and surface plasmon beams with a spatial light modulator. We demonstrate that this approach facilitates extraction of the amplitude and phase of the surface plasmon to measure of the phase velocity and the attenuation of the surface plasmons with greatly improved signal to noise compared to previous measurement approaches. We also show that reliable results are obtained over smaller axial scan ranges giving potentially superior lateral resolution. PMID- 23670010 TI - Towards a full characterization of a plasmonic nanostructure with a fluorescent near-field probe. AB - We report on the experimental and theoretical study of the spatial fluctuations of the local density of states (EM-LDOS) and of the fluorescence intensity in the near-field of a gold nanoantenna. EM-LDOS, fluorescence intensity and topography maps are acquired simultaneously by scanning a fluorescent nanosource grafted on the tip of an atomic force microscope at the surface of the sample. The results are in good quantitative agreement with numerical simulations. This work paves the way for a full near-field characterization of an optical nanoantenna. PMID- 23670011 TI - Stable control of 10 dB two-mode squeezed vacuum states of light. AB - Continuous variable entanglement is a fundamental resource for many quantum information tasks. Important protocols like superactivation of zero-capacity channels and finite-size quantum cryptography that provides security against most general attacks, require about 10 dB two-mode squeezing. Additionally, stable phase control mechanisms are necessary but are difficult to achieve because the total amount of optical loss to the entangled beams needs to be small. Here, we experimentally demonstrate a control scheme for two-mode squeezed vacuum states at the telecommunication wavelength of 1550 nm. Our states exhibited an Einstein Podolsky-Rosen covariance product of 0.0309 +/- 0.0002, where 1 is the critical value, and a Duan inseparability value of 0.360 +/- 0.001, where 4 is the critical value. The latter corresponds to 10.45 +/- 0.01 dB which reflects the average non-classical noise suppression of the two squeezed vacuum states used to generate the entanglement. With the results of this work demanding quantum information protocols will become feasible. PMID- 23670012 TI - Efficient surface second-harmonic generation in slot micro/nano-fibers. AB - We propose to use slot micro/nano-fiber (SMNF) to enhance the second-harmonic generation based on surface dipole nonlinearity. The slot structure is simple and promising to manufacture with high accuracy and reliability by mature micromachining techniques. Light field can be enhanced and confined, and the surface area can be increased in the sub-wavelength low-refractive-index air slot. The maximum conversion efficiency of the SMNFs in our calculations is about 25 times of that in circular micro/nano-fibers. It is promising to provide a competing platform for a new class of fiber-based ultra-tiny light sources spanning the UV- to the mid-infrared spectrum. PMID- 23670013 TI - Near-infrared lasers and self-frequency-doubling in Nd:YCOB cladding waveguides. AB - A design of cladding waveguides in Nd:YCOB nonlinear crystals is demonstrated in this work. Compact Fabry-Perot oscillation cavities are employed for waveguide laser generation at 1062 nm and self-frequency-doubling at 531 nm, under optical pump at 810 nm. The waveguide laser shows slope efficiency as high as 55% at 1062 nm. The SFD green waveguide laser emits at 531 nm with a maximum power of 100 MUW. PMID- 23670014 TI - Fast generation of video holograms of three-dimensional moving objects using a motion compensation-based novel look-up table. AB - A novel approach for fast generation of video holograms of three-dimensional (3 D) moving objects using a motion compensation-based novel-look-up-table (MC-N LUT) method is proposed. Motion compensation has been widely employed in compression of conventional 2-D video data because of its ability to exploit high temporal correlation between successive video frames. Here, this concept of motion-compensation is firstly applied to the N-LUT based on its inherent property of shift-invariance. That is, motion vectors of 3-D moving objects are extracted between the two consecutive video frames, and with them motions of the 3-D objects at each frame are compensated. Then, through this process, 3-D object data to be calculated for its video holograms are massively reduced, which results in a dramatic increase of the computational speed of the proposed method. Experimental results with three kinds of 3-D video scenarios reveal that the average number of calculated object points and the average calculation time for one object point of the proposed method, have found to be reduced down to 86.95%, 86.53% and 34.99%, 32.30%, respectively compared to those of the conventional N LUT and temporal redundancy-based N-LUT (TR-N-LUT) methods. PMID- 23670015 TI - 960-km SSMF transmission of 105.7-Gb/s PDM 3-PAM using directly modulated VCSELs and coherent detection. AB - We generate a 105.7-Gb/s signal by directly modulating a 1.5-um VCSEL with a 33.35-Gbaud 3-level signal and polarization multiplexing. By using digital coherent detection, we successfully transmit the 105.7-Gb/s line rate (88.10 Gb/s net bit rate) signal over 960-km standard single-mode-fiber (SSMF) at a 20% hard decision forward-error correction (FEC) threshold, which is at bit-error ratio (BER) of 1.5 x 10(-2) PMID- 23670016 TI - Transmission of multi-polarization-multiplexed signals: another freedom to explore? AB - We propose a configuration of signal multiplexing with four polarization states, and investigate its transmission performance over single-mode-fiber links. Assisted by coherent detection and digital signal processing (DSP), the demodulation of four-polarization multiplexed (4PM) on-off-keying (OOK) and phase shift-keying (PSK) signals are achieved. We then discuss the impact of the crosstalk from polarization mode dispersion (PMD) on 4PM systems. The transmission distance is extended from ~50-km to ~80 km by employing feedback decision-equalizers. We also compare the back-to-back characteristics of the 40 Gbit/s 4PM-OOK system and 40-Gbit/s PDM-QPSK system with the same spectral efficiency. The results show that the performance of 4PM systems is comparable to that of PDM-QPSK systems, which indicates that the proposed scheme is a potentially promising candidate for future optical networks. PMID- 23670017 TI - Large-mode enhancement cavities. AB - In passive enhancement cavities the achievable power level is limited by mirror damage. Here, we address the design of robust optical resonators with large spot sizes on all mirrors, a measure that promises to mitigate this limitation by decreasing both the intensity and the thermal gradient on the mirror surfaces. We introduce a misalignment sensitivity metric to evaluate the robustness of resonator designs. We identify the standard bow-tie resonator operated close to the inner stability edge as the most robust large-mode cavity and implement this cavity with two spherical mirrors with 600 mm radius of curvature, two plane mirrors and a round trip length of 1.2 m, demonstrating a stable power enhancement of near-infrared laser light by a factor of 2000. Beam radii of 5.7 mm * 2.6 mm (sagittal * tangential 1/e(2) intensity radius) on all mirrors are obtained. We propose a simple all-reflective ellipticity compensation scheme. This will enable a significant increase of the attainable power and intensity levels in enhancement cavities. PMID- 23670018 TI - Etifoxine promotes glial-derived neurotrophic factor-induced neurite outgrowth in PC12 cells. AB - Nerve regeneration and functional recovery are major issues following nerve tissue damage. Etifoxine is currently under investigation as a therapeutic strategy for promoting neuroprotection, accelerating axonal regeneration and modulating inflammation. In the present study, a well-defined PC12 cell model was used to explore the underlying mechanism of etifoxine-stimulated neurite outgrowth. Etifoxine was found to promote glial-derived growth factor (GDNF) induced neurite outgrowth in PC12 cells. Average axon length increased from 50.29+/-9.73 to 22.46+/-5.62 um with the use of etifoxine. However, blockage of GDNF downstream signaling was found to lead to the loss of this phenomenon. The average axon length of the etifoxine group reduces to a normal level after the blockage of the GDNF family receptor alpha1 (GFRalpha1) and receptor tyrosine kinase (RETS) receptors (27.46+/-3.59 vs. 22.46+/-5.62 um and 25.31+/-3.68 um vs. 22.46+/-5.62 um, respectively, p>0.05). In addition, etifoxine markedly increased GDNF mRNA and protein expression (1.55- and 1.36-fold, respectively). However, blockage was not found to downregulate GDNF expression. The results of the current study demonstrated that etifoxine stimulated neurite outgrowth via GDNF, indicating that GDNF represents a key molecule in etifoxine-stimulated neurite outgrowth in PC12 cells. PMID- 23670019 TI - Silica/titania sandwich-like mesoporous nanosheets embedded with metal nanoparticles templated by hyperbranched poly(ether amine) (hPEA). AB - We here demonstrated a novel square silica/titania mesoporous nanosheet which was prepared with hyperbranched poly(ether amine) nanosheets (hPEA-NSs) as a template. TEM and SEM images reveal that the obtained nanosheets possess a large aspect ratio with the average edge length of 1-2 MUm and thickness of ~40 nm, respectively. Various metal nanoparticles such as gold, silver, and platinum can be embedded into these nanosheets with hPEA-NSs decorated with the corresponding nanoparticles as templates. These nanosheets possess a sandwich-like structure, which is comprised of amorphous SiO2 as the inner layer, and the anatase TiO2 as the outer layer determined by a cross-sectional STEM image and EDS mapping. Meanwhile, the obtained nanosheets are mesoporous with a high surface area (~429 m(2) g(-1)), and the SiO2 inner layer can be removed by chemical etching with NaOH solution to obtain anatase TiO2 nanosheet-like boxes embedded with gold nanoparticles (AuNPs). The photodegradation of Methyl Orange (MO) by the obtained nanosheets can be enhanced by the embedding of AuNPs owing to the localized surface plasmon resonance (LSPR) effect from AuNPs. The preparation of a silica/titania mesoporous nanosheet with hPEA-NSs as template is believed to provide a convenient and general method to produce various square inorganic mesoporous nanosheets with a large aspect ratio between edge length and thickness. PMID- 23670021 TI - Cranial electrotherapy stimulation for the treatment of chronically symptomatic bipolar patients. AB - OBJECTIVE: The aim of this study was to determine if cranial electrotherapy stimulation (CES) is beneficial in chronically symptomatic bipolar (CSBP) subjects. METHODS: A retrospective chart review of all consecutive CSBP subjects who were prescribed CES collected demographic and clinical information. RESULTS: The Clinical Global Impression improved significantly [mean (SD), 2.7 (0.6) at baseline vs 2.0 (0.0), t = 0, P < 0.001], but mood symptoms change minimally. There were very few adverse effects of CES. CONCLUSIONS: Patients with CSBP continue to experience symptoms with CES but also are modestly improved. PMID- 23670020 TI - The anti-apoptotic effect of regucalcin is mediated through multisignaling pathways. AB - Regucalcin (RGN/SMP30) was originally discovered in 1978 as a calcium-binding protein that does not contain the EF-hand motif of as a calcium-binding domain. The name, regucalcin, was proposed for this calcium-binding protein, which can regulate various Ca(2+)-dependent enzymes activation in liver cells. The regucalcin gene is localized on the X chromosome, and its expression is mediated through many signaling factors. Regucalcin plays a pivotal role in regulation of intracellular calcium homeostasis in various cell types. Regucalcin also has a suppressive effect on various signaling pathways from the cytoplasm to nucleus in proliferating cells and regulates nuclear function in including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis. Overexpression of endogenous regucalcin was found to suppress apoptosis in modeled rat hepatoma cells and normal rat kidney proximal epithelial NRK52 cells induced by various signaling factors. Suppressive effect of regucalcin on apoptosis is related to inhibition of nuclear Ca(2+)-activated DNA fragmentation, Ca(2+)/calmodulin-dependent nitric oxide synthase, caspase-3, Bax, cytochrome C, protein tyrosine kinase, protein tyrosine phosphatase in the cytoplasm and nucleus. Moreover, regucalcin stimulates Bcl-2 mRNA expression and depresses enhancement of caspase-3, Apaf-1 and Akt-1 mRNAs expression. This review discusses that regucalcin plays a pivotal role in rescue of apoptotic cell death, which is mediated through various signaling factors. PMID- 23670022 TI - Use of electroconvulsive therapy in the presence of arachnoid cyst: a case report and review of existing literature. AB - A caution is advised for the use of electroconvulsive therapy (ECT) in patients with space-occupying intracranial lesions. The use of ECT in the presence of arachnoid cyst has been reported only in 10 cases in the literature. Here, we report a case of severe depression with psychotic symptoms who was found to have an arachnoid cyst of 3.4 * 1.6 cm in the left temporal region. The patient received a course of 12 ECT treatments without any complications and had significant improvement in symptoms. Magnetic resonance imaging after completion of ECT did not reveal any change in size of the arachnoid cyst. PMID- 23670023 TI - Electroconvulsive therapy (ECT) for catatonia in a patient with schizophrenia and synthetic cannabinoid abuse: a case report. AB - We present the case of a young man with a long-standing history of schizophrenia who presented with severe and life-threatening catatonia in the setting of synthetic cannabis use who was successfully treated with electroconvulsive therapy. To our knowledge, this is the first reported case of severe and persistent catatonia in the setting of synthetic cannabis use and the first documented successful treatment. PMID- 23670024 TI - Cavum septum pellucidum and cavum vergae with late-onset catatonia. AB - Associations between large cavum septum pellucidum and functional psychosis disorders, especially schizophrenia, have been reported. We report a case of late onset catatonia associated with enlarged CSP and cavum vergae. A 66-year-old woman was presented with altered mental status and stereotypic movement. She was initially treated with aripiprazole and lorazepam. After 4 weeks, she was treated with electroconvulsive therapy. By 10 treatments, echolalia vanished, and catatonic behavior was alleviated. Developmental anomalies in the midline structure may increase susceptibility to psychosis, even in the elderly. PMID- 23670025 TI - Resolution of electroconvulsive therapy refractory major depressive disorder with unintentional hypoglycemic seizure: a case report. AB - We report a 74-year-old white woman with type 1 diabetes and major depressive disorder refractory to multiple medications who received 15 electroconvulsive therapy treatments with minimal improvement. After an accidental hypoglycemic seizure, the patient's symptoms completely resolved. In conclusion, the present case reveals an instance where electroconvulsive therapy-induced seizures appeared to be minimally effective, whereas a single accidental hypoglycemia induced seizure was incredibly effective for the resolutions of depressive symptoms. Although this case presents a single efficacious use of accidental insulin coma therapy, the applicability is limited because of the known risks of insulin coma therapy. PMID- 23670026 TI - Three decades of quality improvement in electroconvulsive therapy: exploring the role of accreditation. AB - OBJECTIVES: This study aims to track electroconvulsive therapy (ECT) clinics' compliance with standards for the administration of ECT before and after the introduction of the Electroconvulsive Therapy Accreditation Service (ECTAS) in 2003. METHODS: Three audits on the practice of ECT were retrospectively analyzed, and ECTAS data from 2004 to 2011 were prospectively analyzed. Overall compliance with 10 ECT audit standards was presented in 2 ways: annually and for each of the 3 waves of accreditation. RESULTS: There have been continuing improvements since the introduction of the accreditation service in compliance with all 10 ECT audit standards whether measured annually or by accreditation cycle, although these improvements have not been linked to changes in clinical outcomes. CONCLUSIONS: Although improvements in ECT delivery have coincided with the accreditation service, other factors may have also contributed. PMID- 23670027 TI - Satisfaction with electroconvulsive therapy among patients and their relatives. AB - OBJECTIVES: Despite substantial proof of its efficacy, there has been little systematic research of satisfaction with electroconvulsive therapy (ECT) among patients or their relatives. This study sought to evaluate satisfaction with the treatment among patients who had undergone ECT and their relatives present during treatment. METHODS: Of the 110 patients who had received ECT over 2 years, 50 were eventually recruited. Satisfaction with ECT among patients and relatives was evaluated using the Patient Satisfaction Survey, a structured and comprehensive schedule used earlier in a number of similar studies. RESULTS: Slightly more than half of the patients of this study appeared to be satisfied with ECT, as reflected by overall levels of satisfaction (54%), satisfaction with the results of ECT (54%), satisfaction with the staff administering ECT (58%), and satisfaction with the positive effects of ECT on their symptoms (63%). However, a large number of patients (22%-50%) were unsure of their responses, although clear disapproval of ECT was uncommon. Relatives were significantly more satisfied than were patients on almost every aspect of the treatment. Despite high levels of satisfaction, participants expressed dissatisfaction about the amount of information before ECT, fear of ECT, and about the possibility of persisting cognitive impairment. CONCLUSIONS: Most patients, and particularly their relatives, were satisfied with ECT, but there were several areas of concern including the fear of ECT, lack of information, and the possibility of enduring cognitive problems. This study also underlines the need for a well-validated and reliable method of assessing satisfaction with ECT. PMID- 23670028 TI - Postictal ventricular tachycardia after electroconvulsive therapy treatment associated with a lithium-duloxetine combination. AB - This report addresses the dilemma of continuing lithium prophylaxis and antidepressant therapy in view of cardiovascular adverse effects under electroconvulsive therapy (ECT) in patients with a long history of recurrent affective disorders. A severely depressed 48-year-old woman who had been treated with lithium for 18 years developed a ventricular tachycardia during ECT. Possible interaction with succinylcholine was taken into account, and rocuronium was used as an alternative muscle relaxant. Electroconvulsive therapy was continued without adverse effects after reduction of lithium and withdrawal from duloxetine. Systemic studies on cardiac adverse effects of serotonin and norepinephrine reuptake inhibitors and serotonin and norepinephrine reuptake inhibitor-lithium combinations during ECT are needed. PMID- 23670029 TI - P53 mutations in advanced cancers: clinical characteristics, outcomes, and correlation between progression-free survival and bevacizumab-containing therapy. AB - BACKGROUND: Mutations in the p53 gene are amongst the most frequent aberrations seen in human cancer. Our objective was to characterize the clinical characteristics associated with p53 mutation in patients with advanced cancer. METHODS: We retrospectively reviewed and analyzed the clinical features and response to standard systemic therapy of 145 patients with documented tumor p53 mutational status (mutant-type [mtp53] vs. wild-type [wtp53]) referred to the Clinical Center for Targeted Therapy. RESULTS: Sixty-six (45.5%) patients had mtp53. Mutations in p53 occurred more frequently in older patients (p= 0.015) and in Caucasians (p=0.024). The incidence of liver metastases was 69.2% vs. 43%, p=0.002 in mtp53 and wtp53, respectively. PTEN loss by immunohistochemistry was found more frequently in mtp53-bearing tumors compared to wtp53 (33.3% vs. 10%, p=0.007). The best progression-free survival (PFS) on standard systemic therapy was significantly longer with bevacizumab-containing regimens as compared to non bevacizumab containing regimen in patients with mtp53 (median 11.0 [95% CI 5.9 16.0], n=22 vs. 4.0 months [95% CI 3.6-5.7], n=35, p<0.0001) but not those with wtp53 (median 5.0 [95% CI 2.0-7.6] vs. 6.0 [95% CI 4.0-7.5] months, p=0.318. The median overall survival from diagnosis in patients with mtp53 and wtp53 was 7.4 [95% CI 6.3-9.8] vs. 11.8 [95% CI 2.9-21.5] years, respectively (p=0.365). CONCLUSION: Patients with mtp53 tumors were older at diagnosis, had more incidence of liver metastasis, and more frequent PTEN loss. The best PFS on standard systemic therapy was significantly longer with bevacizumab-containing regimens in patients with mutant p53 tumors but not in those with wtp53. PMID- 23670031 TI - Traumatic intracranial hemorrhage in patients taking dabigatran: report of 3 cases and review of the literature. AB - BACKGROUND AND IMPORTANCE: Dabigatran is a direct thrombin inhibitor gaining popularity as a stroke prevention agent in patients with atrial fibrillation. In comparison with warfarin, dabigatran showed superiority in stroke prevention, but lower rates of major hemorrhage and intracerebral hemorrhage. Although warfarin has a well-established reversal strategy, there is far less experience reversing dabigatran. CLINICAL PRESENTATION: We present our experience with 3 patients who experienced an intracranial hemorrhage either spontaneously or after low-energy cranial trauma and review the available literature describing dabigatran use in patients with traumatic brain injury. CONCLUSION: Intracranial hemorrhage in patients taking anticoagulants and/or antiplatelets can have either a benign or malignant clinical course. At this time, there is little experience with dabigatran reversal; however, several strategies for rapid reversal have been proposed. All patients with intracranial hemorrhage taking dabigatran should be admitted for close neurological monitoring and serial imaging. PMID- 23670030 TI - Salinomycin induces cell death with autophagy through activation of endoplasmic reticulum stress in human cancer cells. AB - Salinomycin is perhaps the first promising compound that was discovered through high throughput screening in cancer stem cells. This novel agent can selectively eliminate breast and other cancer stem cells, though the mechanism of action remains unclear. In this study, we found that salinomycin induced autophagy in human non-small cell lung cancer (NSCLC) cells. Furthermore, we demonstrated that salinomycin stimulated endoplasmic reticulum stress and mediated autophagy via the ATF4-DDIT3/CHOP-TRIB3-AKT1-MTOR axis. Moreover, we found that the autophagy induced by salinomycin played a prosurvival role in human NSCLC cells and attenuated the apoptotic cascade. We also showed that salinomycin triggered more apoptosis and less autophagy in A549 cells in which CDH1 expression was inhibited, suggesting that the inhibition of autophagy might represent a promising strategy to target cancer stem cells. In conclusion, these findings provide evidence that combination treatment with salinomycin and pharmacological autophagy inhibitors will be an effective therapeutic strategy for eliminating cancer cells as well as cancer stem cells. PMID- 23670032 TI - Pathology of spinal ependymomas: an institutional experience over 25 years in 134 patients. AB - BACKGROUND: Ependymomas constitute approximately 40% of primary intraspinal tumors. Current World Health Organization (WHO) grading may not correlate with observed progression-free survival (PFS). OBJECTIVE: This retrospective study of prospectively collected data examines whether PFS is influenced by the histological grade or by the extent of resection. It also analyzes the usage and effectiveness of postoperative adjuvant radiotherapy. METHODS: We reviewed 134 consecutive patients with ependymomas of all grades. Pathology slides were re reviewed and the histological grades were confirmed by a single neuropathologist. Postoperative residual or recurrence was evaluated with follow-up magnetic resonance imaging. RESULTS: There were 85 male and 49 female patients, ranging from 10 to 79 (median 41) years of age. Thirty patients had WHO grade I tumors, 101 had grade II tumors, and 3 had grade III tumors. Kaplan-Meier analysis of PFS demonstrated a mean duration of 6 years for grade I, 14.9 years for grade II, and 3.7 years for grade III (P < .001). In grade II ependymomas, mean PFS was 11.2 years with subtotal resection and 17.8 years with gross total resection (P < .01). PFS of patients who underwent subtotal resection was not significantly changed by adjuvant radiotherapy (P < .36). CONCLUSION: Patients with grade II ependymoma have significantly longer PFS than patients with grade I ependymoma. The extent of resection did not affect PFS in grade I ependymoma but it did in grade II. Contrary to its higher grade, WHO grade II ependymoma carries a better prognosis than WHO grade I ependymoma. PMID- 23670033 TI - Transvenous retrograde nidus sclerotherapy under controlled hypotension (TRENSH): hemodynamic analysis and concept validation in a pig arteriovenous malformation model. AB - BACKGROUND: Transvenous retrograde nidus sclerotherapy under controlled hypotension (TRENSH) is a proposed novel concept for endovascular treatment of cerebral arteriovenous malformations (AVMs). OBJECTIVE: To assess the experimental hemodynamic feasibility of TRENSH in a pig AVM model. METHODS: We surgically constructed carotid-jugular fistula-type AVM models in 8 pigs. In 5 pigs (group 1) we hemodynamically assessed the AVM through the main arterial feeder (AF) and draining vein (DV) at systemic normotension (Syst(norm)). We then performed retrograde nidus angiography through the DV at progressively deeper levels of hemorrhagic systemic hypotension (Syst(hypo)), and graded and correlated these angiograms with the degree of Syst(hypo). In another 3 pigs (group 2) we correlated the effects of temporary balloon occlusion of the main AF with the angiographic extent of retrograde nidus filling. RESULTS: In group 1 pigs, the drop in AF pressure correlated strongly (r(2) = 0.93-0.99) with the drop in DV pressure at progressively deeper Syst(hypo). Minimal retrograde nidus filling occurred at Syst(norm). We observed progressively greater extents of retrograde nidus filling as the transnidal pressure gradients fell with deeper Syst(hypo). Near-complete retrograde permeation of the nidus was possible as the transnidal gradients approached 0 mm Hg. As more of the nidus filled, its concurrent emptying was documented through a greater number of DVs. Temporary AF occlusion resulted in improved retrograde nidus filling in all group 2 pigs. CONCLUSION: Endovascular TRENSH appears feasible in a pig AVM model. Further experimental investigations of TRENSH are necessary to assess its full potential before future clinical applications. PMID- 23670034 TI - Chronic 30-Hz deep cerebellar stimulation coupled with training enhances post ischemia motor recovery and peri-infarct synaptophysin expression in rodents. AB - BACKGROUND: Over 500,000 Americans have strokes every year, making stroke the leading cause for disability in the United States and in the industrialized world. New treatments to improve poststroke motor recovery are needed. OBJECTIVE: To investigate a novel approach for enhancing motor recovery that involves chronic, electrical stimulation of ascending cerebellar output combined with motor training. METHODS: Adult Sprague-Dawley rats underwent unilateral endothelin-1 injections in the dominant cerebral cortex and placement of a chronic stimulating electrode in the contralateral lateral cerebellar nucleus. After 1 week, the animals were separated into 2 groups (STIM+ and STIM-), matched for poststroke motor performance in the pasta matrix task. At 2 weeks post ischemia, the treatment phase was initiated, with animals in the STIM+ group receiving pulsed, 30-Hz stimulation for 12 hours/day. Motor training continued for both groups over 3 to 5 weeks. RESULTS: A total of 23 animals were examined after 3 weeks of treatment. STIM+ animals showed a significant improvement in motor function compared with post-ischemia baseline performance as well as in comparison with the STIM- group. Immunohistochemistry revealed a significant increase in the perilesional expression of synaptophysin for the STIM+ vs the STIM- animals. CONCLUSION: These results indicate that chronic activation of ascending cerebellofugal pathways enhances motor recovery after focal cortical ischemia. The recovery was associated with an increase in perilesional cortical plasticity relative to nontreated controls. PMID- 23670035 TI - On-demand droplet loading for automated organic chemistry on digital microfluidics. AB - Organic chemistry applications on digital microfluidic devices often involve reagents that are volatile or sensitive and must be introduced to the chip immediately before use. We present a new technique for automated, on-demand loading of ~1 MUL droplets from large (~1 mL), sealed, off-chip reservoirs to a digital microfluidic chip in order to address this challenge. Unlike aqueous liquids which generally are non-wetting to the hydrophobic surface and must be actively drawn into the electrowetting-on-dielectric (EWOD) chip by electrode activation, organic liquids tend to be wetting and can spontaneously flood the chip, and hence require a retracting force for controlled liquid delivery. Using a combination of compressed inert gas and gravity to exert driving and retracting forces on the liquid, the simple loading technique enables precise loading of droplets of both wetting and non-wetting liquids in a reliable manner. A key feature from a practical point of view is that all of the wetted parts are inexpensive and potentially disposable, thus avoiding cross-contamination in chemical and biochemical applications. We provide a theoretical treatment of the underlying physics, discuss the effect of geometry and liquid properties on its performance, and show repeatable reagent loading using the technique. Its versatility is demonstrated with the loading of several aqueous and non-aqueous liquids on an EWOD digital microfluidic device. PMID- 23670036 TI - Colorectal cancer and hypercoagulability. AB - Since the first report of the spontaneous appearance of venous thrombophlebitis as a sign of visceral cancer by Trousseau in 1865, many other studies have documented the existence of cancer-associated coagulation disorders. In this review, we describe the hypercoagulable state associated with colorectal cancer, from three perspectives: first, the incidence, risk factors and prevention of clinically symptomatic thromboembolic conditions associated with cancer, such as venous thromboembolism and arterial thrombosis; second, the association between hypercoagulable conditions, such as thrombocytosis, hyperfibrinogenemia, or D dimer elevation, and the clinical progression and poor prognosis of cancer patients; third, the experimental approach to elucidate the role of various coagulation-related factors in the process of cancer progression, focusing specifically on the role of platelets and tissue factors. PMID- 23670037 TI - Potential value of sonazoid-enhanced intraoperative laparoscopic ultrasonography for liver assessment during laparoscopy-assisted colectomy. AB - PURPOSE: Laparoscopy-assisted colectomy (LAC) has gained acceptance for the treatment of colorectal cancer. However, conventional palpation of the liver and adequate observation of the abdominal cavity are not achievable during LAC. The aim of this study was to assess the clinical value of using Sonazoid (contrast enhanced)-intraoperative laparoscopic ultrasonography (S-IOLUS) in patients with primary colorectal cancer. METHODS: From May 2005 to August 2008, 454 patients underwent 339 LACs and 115 open colectomies for colorectal cancer. One hundred forty-eight patients with clinical stage II or III colorectal cancer, as determined by preoperative imaging, who were undergoing LACs were prospectively enrolled. RESULTS: Although IOLUS did not detect any lesions, small hypoechoic lesions were detected by the S-IOLUS (n = 71) in the Kupffer-phase view of two patients (2.8%). None of the 71 patients who underwent S-IOLUS showed liver metastases within 6 months after LAC. In the conventional IOLUS group (n = 77), metastatic lesions were identified in two patients (2.6%). The new liver metastases in these two patients were detected within 6 months after LAC. CONCLUSIONS: S-IOLUS of the liver during colorectal cancer surgery is useful for staging and as a diagnostic modality. It can identify lesions that are undetectable by preoperative imaging, and may be considered for routine use during LAC. PMID- 23670038 TI - Laparoscopic mesh-augmented hiatoplasty without fundoplication as a method to treat large hiatal hernias. AB - PURPOSE: Laparoscopic hiatal hernia repair with additional fundoplication is a commonly recommended standard surgical treatment for symptomatic large hiatal hernias with paraesophageal involvement (PEH). However, due to the risk of persistent side effects, this method remains controversial. Laparoscopic mesh augmented hiatoplasty without fundoplication (LMAH), which combines hiatal repair and mesh reinforcement, might therefore be an alternative. METHODS: In this retrospective study of 55 (25 male, 30 female) consecutive PEH patients, the perioperative course and symptomatic outcomes were analyzed after a mean follow up of 72 months. RESULTS: The mean DeMeester symptom score decreased from 5.1 to 1.8 (P < 0.001) and the gas bloating value decreased from 1.2 to 0.5 (P = 0.001). The dysphagia value was 0.7 before surgery and 0.6 (P = 0.379) after surgery. The majority of the patients were able to belch and vomit (96 and 92 %, respectively). Acid-suppressive therapy on a regular basis was discontinued in 68 % of patients. In 4 % of patients, reoperation was necessary due to recurrent or persistent reflux. A mesh-related stenosis that required endoscopic dilatation occurred in 2 % of patients. CONCLUSIONS: LMAH is feasible, safe and provides an anti-reflux effect, even without fundoplication. As operation-related side effects seem to be rare, LMAH is a potential treatment option for large hiatal hernias with paraesophageal involvement. PMID- 23670039 TI - A single-center study of vascular access sites for intravenous ports. AB - PURPOSE: This study evaluated the use of intravenous ports and provides a guide related to clinical decision making. METHODS: This study retrospectively reviewed 1505 patients who had received intravenous ports at Chang Gung Memorial Hospital in 2006. The relationships between the complications and entry routes were assessed. The intervention-free periods were also determined and compared. The patients were followed up until June 2010. RESULTS: Of the 1543 procedures performed, 412 were reinterventions to treat complications, most of which corresponded to fewer than 0.1 episodes per 1000 catheter-days; these were not associated with any particular entry route. There was a higher catheter fracture rate when the right subclavian vein was chosen as the entry vessel (p < 0.05). The intervention-free period ranged from 207 to 533 days. CONCLUSION: The subclavian vein is not recommended for the use of intravenous ports. There is not only a higher risk of iatrogenic pneumothorax or hemothorax using this entry route but also a higher fracture rate, which may be caused by pinch-off syndrome. The greater saphenous vein should only be considered when the patient has superior vena cava syndrome. However, a higher incidence of infection and a lower device survival rate should be expected with this location. PMID- 23670040 TI - Case-matched comparison of the short-term outcomes between laparoscopic and open abdominoperineal resection for rectal cancer. AB - PURPOSE: The aim of this study was to evaluate the short-term surgical outcomes of laparoscopic abdominoperineal resection (APR) for rectal cancer, by comparing it with a case-control series of open APR. METHODS: Fourteen patients with rectal cancer who underwent laparoscopic APR between August 2004 and November 2011 were compared with the open APR group of 14 patients matched for age, gender, and surgical procedure. RESULTS: There were no cases of conversion to laparotomy in the laparoscopic APR group and no mortality in either of the groups. The median operation was longer (P = 0.002), but the median amount of blood loss was smaller (P = 0.019), in the laparoscopic APR group. The median length of hospital stay of the laparoscopic APR group was 8 days, shorter than that of the open APR group (16 days, P < 0.001). The changes of the WBC count and serum CRP level after operations were significantly smaller in the laparoscopic APR group (P < 0.05). There were no significant differences between the groups in terms of the perioperative morbidity and readmission rates within 30 days. CONCLUSION: Patients undergoing laparoscopic APR had superior perioperative outcomes to those undergoing open APR, except for the longer operation. PMID- 23670041 TI - Molecular cloning and characterization of a gene regulating flowering time from Alfalfa (Medicago sativa L.). AB - Genes that regulate flowering time play crucial roles in plant development and biomass formation. Based on the cDNA sequence of Medicago truncatula (accession no. AY690425), the LFY gene of alfalfa was cloned. Sequence similarity analysis revealed high homology with FLO/LFY family genes of other plants. When fused to the green fluorescent protein, MsLFY protein was localized in the nucleus of onion (Allium cepa L.) epidermal cells. The RT-qPCR analysis of MsLFY expression patterns showed that the expression of MsLFY gene was at a low level in roots, stems, leaves and pods, and the expression level in floral buds was the highest. The expression of MsLFY was induced by GA3 and long photoperiod. Plant expression vector was constructed and transformed into Arabidopsis by the agrobacterium mediated methods. PCR amplification with the transgenic Arabidopsis genome DNA indicated that MsLFY gene had integrated in Arabidopsis genome. Overexpression of MsLFY specifically caused early flowering under long day conditions compared with non-transgenic plants. These results indicated MsLFY played roles in promoting flowering time. PMID- 23670042 TI - Molecular cloning and SNP association analysis of chicken PMCH gene. AB - The pre-melanin-concentrating hormone (PMCH) gene is an important gene functionally concerning the regulations of body fat content, feeding behavior and energy balance. In this study, the full-length cDNA of chicken PMCH gene was amplified by SMART RACE method. The single nucleotide polymorphisms (SNPs) in the PMCH gene were screened by comparative sequence analysis. The obtained non synonymous coding SNPs (ncSNPs) were designed for genotyping firstly. Its effects on growth, carcass characteristics and meat quality traits were investigated employing the F2 resource population of Gushi chicken crossed with Anak broiler by AluI CRS-PCR-RFLP. Our results indicated that the cDNA of chicken PMCH shared 67.25 and 66.47% homology with that of human and bovine PMCH, respectively. The deduced amino acid sequence of chicken PMCH (163 amino acids) were 52.07 and 50.89% identical to those of human and bovine PMCH, respectively. The PMCH protein sequence is predicted to have several functional domains, including pro MCH, CSP, IL7, XPGI and some low complexity sequence. It has 8 phosphorylation sites and no signal peptide sequence. gga-miR-18a, gga-miR-18b, gga-miR-499 microRNA targeting site was predicted in the 3' untranslated region of chicken PMCH mRNA. In addition, a total of seven SNPs including an ncSNP and a synonymous coding SNP, were identified in the PMCH gene. The ncSNP c.81 A>T was found to be in moderate polymorphic state (polymorphic index=0.365), and the frequencies for genotype AA, AB and BB were 0.3648, 0.4682 and 0.1670, respectively. Significant associations between the locus and shear force of breast and leg were observed. This polymorphic site may serve as a useful target for the marker assisted selection of the growth and meat quality traits in chicken. PMID- 23670043 TI - Comparative study of putative 9-cis-epoxycarotenoid dioxygenase and abscisic acid accumulation in the responses of Sunki mandarin and Rangpur lime to water deficit. AB - Abscisic acid is a plant hormone that participates in essential plant physiological processes, especially during adaptation to many environmental stresses, such as water deficit. The relationship between ABA accumulation and the expression of putative carotenoid cleavage dioxygenase (CCD) genes was investigated in the pot-cultivated leaves and roots of the 'Rangpur' lime and 'Sunki Maravilha' mandarin plants. Transpiration, stomatal resistance and leaf growth were evaluated when these genotypes were subjected to continuous water deficit. Under water deficit conditions, the 'Rangpur' lime extracts used greater amounts of water when compared to the 'Sunki Maravilha' plants, which reached the greatest stomatal resistance 5 days before 'Rangpur' lime. When subjected to water deficit, the roots and leaves of 'Sunki Maravilha' showed a progressive increase in ABA accumulation; however, in 'Rangpur' lime, alternations between high and low ABA concentrations were observed. These results suggest a retroactive feeding regulation by ABA. In 'Rangpur' lime the NCED2, NCED3 and CCD4a genes were expressed at the highest levels in the roots, and NCED5 was highly expressed in the leaves; in 'Sunki Maravilha', the NCED2 and NCED5 genes were most highly expressed in the roots, and NCED2 was most highly expressed in the leaves. However, for both genotypes, the transcription of these genes only correlated with ABA accumulation during the most severe water deficit conditions. The 'Rangpur' lime behaved as a vigorous rootstock; the leaf growth remained unaltered even when water was scarce. However, 'Sunki Maravilha' adaptation was based on the equilibrium of the response between the root and the aerial tissues due to water restriction. The use of the Sunki mandarin in combination with a scion with similar characteristics as its own, which responds to water deficit stress by accumulating ABA in the leaves, may display good drought tolerance under field conditions. PMID- 23670044 TI - Transcriptional responses of maize seedling root to phosphorus starvation. AB - Maize (Zea mays) is the most widely cultivated crop around the world, however, it is commonly affected by phosphate (Pi) deficiency and the underlying molecular basis of responses mechanism is still unknown. In this study, the transcriptional response of maize roots to Pi starvation at 3 days after the onset of Pi deprivation was assessed. The investigation revealed a total of 283 Pi-responsive genes, of which 199 and 84 genes were found to be either up- or down-regulated respectively, by 2-fold or more. Pi-responsive genes were found to be involved in sugar and nitrogen metabolic pathways, ion transport, signal transduction, transcriptional regulation, and other processes related to growth and development. In addition, the expression patterns of maize inorganic phosphorus transporters, acid phosphatase, phytase, 2-deoxymugineic acid synthase1, POD and MYB transcription factor were validated in 178 roots response to low phosphorus stress. of which, two genes encoding phytase and acid phosphatase were significantly induced by Pi deficiency and may play a pivotal role in the process of absorption and re-utilization of Pi in Maize. These results not only enhance our knowledge about molecular processes associated with Pi deficiency, but also facilitate the identification of key molecular determinants for improving Pi use in maize. Moreover, this work sets a framework to produce Pi-specific maize microarrays to study the changes in global gene expression between Pi-efficient and Pi-inefficient maize genotypes. PMID- 23670045 TI - A novel protein C inhibitor gene mutation in pediatric stroke patients after bone marrow transplantation. AB - Protein C inhibitor is a heparin dependent serine protease inhibitor found in human plasma, urine and other body fluids. It was originally identified as an inhibitor of activated protein C. Stroke is an important cause of morbidity and mortality in the pediatric age group. In this study we analyzed the protein C inhibitor gene mutations in Turkish pediatric stroke patients. We found a missense mutation of G to A at nucleotide 6760 in exon 2, resulting in a transition serine to asparagine (p.Ser188Asp) and in a child and his father and also we found same alteration in exon 2 in an another pediatric stroke case following bone marrow transplantation. PMID- 23670046 TI - What the N-terminal domain of Atg13 looks like and what it does: a HORMA fold required for PtdIns 3-kinase recruitment. AB - Atg13 is a subunit of the Atg1 complex that is involved in autophagy. The middle and C-terminal regions of Atg13 are intrinsically disordered and rich in regulatory phosphorylation sites. Thus far, there have been no structural data for any part of Atg13, and no function assigned to its N-terminal domain. We crystallized this domain, and found that it has a HORMA (Hop1, Rev7, Mad2) fold. We showed that the Atg13 HORMA domain is required for autophagy and for recruitment of the phosphatidylinositol (PtdIns) 3-kinase subunit Atg14, but is not required for Atg1 interaction or Atg13 recruitment to the PAS. The HORMA domain of Atg13 is similar to the closed conformation of the spindle checkpoint protein Mad2. A pair of conserved arginines was identified in the structure, and tested functionally in yeast. These residues are important for autophagy, as mutations abrogate autophagy and block Atg14 recruitment. The location of these Arg residues in the structure suggests that the Atg13 HORMA domain could act as a phosphorylation-dependent conformational switch. PMID- 23670047 TI - Impact of age and comorbidity on cause and outcome in community-acquired pneumonia. AB - BACKGROUND: Prolonged life expectancy has currently increased the proportion of the very elderly among patients with community-acquired pneumonia (CAP). The aim of this study was to determine the influence of age and comorbidity on microbial patterns in patients over 65 years of age with CAP. METHODS: This study was a prospective observational study of adult patients with CAP (excluding those in nursing homes) over a 12-year period. We compared patients aged 65 to 74 years, 75 to 84 years, and > 85 years for potential differences in clinical presentation, comorbidities, severity on admission, microbial investigations, causes, antimicrobial treatment, and outcomes. RESULTS: We studied a total of 2,149 patients: 759 patients (35.3%) aged 65 to 74 years, 941 patients (43.7%) aged 75 to 84 years, and 449 patients (20.8%) aged > 85 years. At least one comorbidity was present in 1,710 patients (79.6%). Streptococcus pneumoniae was the most frequent pathogen in all age groups, regardless of comorbidity. Staphylococcus aureus, Enterobacteriaceae, and Pseudomonas aeruginosa accounted for 9.1% of isolates, and Haemophilus influenzae, 6.4%. All these pathogens were isolated only in patients with at least one comorbidity. Mortality increased with age (65-74 years, 6.9%; 75-84 years, 8.9%; > 85 years, 17.1%; P < .001) and was associated with increased comorbidities (neurologic; OR, 2.1; 95% CI, 1.5-2.1), Pneumonia Severity Index IV or V (OR, 3.2; 95% CI, 1.8-6.0), bacteremia (OR, 1.7; 95% CI, 1.1-2.7), the presence of a potential multidrug-resistant (MDR) pathogen (S. aureus, P. aeruginosa, Enterobacteriaceae; OR, 2.4; 95% CI, 1.3-4.3), and ICU admission (OR, 4.2; 95% CI, 2.9-6.1) on multivariate analysis. CONCLUSIONS: Age does not influence microbial cause itself, whereas comorbidities are associated with specific causes such as H. influenzae and potential MDR pathogens. Mortality in the elderly is mainly driven by the presence of comorbidities and potential MDR pathogens. PMID- 23670049 TI - Analysis of serum proteome profiles in nasopharyngeal carcinoma with different radiosensitivity. AB - PURPOSE: The research is endeavored to establish a serum protein fingerprint model for predicting radiosensitivity of nasopharyngeal carcinoma through the analysis of the serum expressed proteins of the pre- and post-treatment nasopharyngeal carcinoma patients treated with radiotherapy. METHODS: Surface enhanced laser desorption ionization-time of flight-mass spectrometry and CM-10 protein chip were used to detect the serum proteomic patterns of 50 nasopharyngeal carcinoma patients with different radiosensitivity. Thirty-eight of the 50 patients after the treatment were also studied. Biomarker Wizard 3.01 and Biomarker Pattern 5.01 were used in combination to analyze the data and to develop predicting models. RESULTS: At the molecular weight range of 2,000 20,000, the software identified an average of 83 mass peaks between radiation sensitive group and radiation resistant group. 11 protein peaks were significantly different. Of the 83 mass peaks, 4 mass peaks (mass/charge ratio [m/z] 2,575, 3,942, 6,117 and 6,778) were chosen automatically to construct a classification tree. The diagnostic accuracy was 78.0 %. M/z 6,117 and 6,778 of the radiation sensitive group after the treatment trended to those of the radiation resistant group. CONCLUSIONS: The technology of surface-enhanced laser desorption ionization-time of flight-mass spectrometry can be used to screen and identify differentially expressed proteins associated with different radiosensitivity in nasopharyngeal cancer. It should be a very useful tool for predicting radiosensitivity of nasopharyngeal carcinoma. PMID- 23670050 TI - Dual inhibition of autophagy and the AKT pathway in prostate cancer. AB - Genetic inactivation of PTEN through either gene deletion or mutation is common in metastatic prostate cancer, leading to activation of the phosphoinositide 3 kinase (PI3K-AKT) pathway, which is associated with poor clinical outcomes. The PI3K-AKT pathway plays a central role in various cellular processes supporting cell growth and survival of tumor cells. To date, therapeutic approaches to develop inhibitors targeting the PI3K-AKT pathway have failed in both pre clinical and clinical trials. We showed that a novel AKT inhibitor, AZD5363, inhibits the AKT downstream pathway by reducing p-MTOR and p-RPS6KB/p70S6K. We specifically reported that AZD5363 monotherapy induces G2 growth arrest and autophagy, but fails to induce significant apoptosis in PC-3 and DU145 prostate cancer cell lines. Blocking autophagy using pharmacological inhibitors (3 methyladenine, chloroquine and bafilomycin A 1) or genetic inhibitors (siRNA targeting ATG3 and ATG7) enhances cell death induced by AZD5363 in these prostate cancer cells. Importantly, the combination of AZD5363 with chloroquine significantly reduces tumor volume compared with the control group, and compared with either drug alone in prostate tumor xenograft models. Taken together, these data demonstrate that AKT inhibitor AZD5363, synergizes with the lysosomotropic inhibitor of autophagy, chloroquine, to induce apoptosis and delay tumor progression in prostate cancer models that are resistant to monotherapy, with AZD5363 providing a new therapeutic approach potentially translatable to patients. PMID- 23670051 TI - Pheochromocytoma-induced takotsubo-like cardiomyopathy and global heart failure with need for extracorporal life support. PMID- 23670052 TI - New niches for NIV: ahead with caution! PMID- 23670054 TI - Blood-based biomarkers for malignant gliomas. AB - Malignant gliomas remain incurable and present unique challenges to clinicians, radiologists and clinical and translational investigators. One of the major problems in treatment of these tumors is our limited ability to reliably assess tumor response or progression. The most frequently used neuro-imaging studies (contrast-enhanced MRI and CT) rely on changes of blood-brain barrier (BBB) integrity, providing only an indirect assessment of tumor burden. In addition, the BBB can be altered by commonly used interventions including radiation, glucocorticoids and vascular endothelial growth factor inhibitors, further complicating the interpretation of scans. Newer radiologic techniques including PET and magnetic resonance spectroscopy are theoretically promising but thus far have not meaningfully changed the assessment of patients with malignant gliomas. A tumor-specific, blood-based biomarker would be of immediate use to clinicians and investigators if sufficiently sensitive and specific. This review discusses the potential utility of such a biomarker, the general classes of tumor-derived blood-based biomarkers and it summarizes the currently available data on circulating tumor cells, circulating nucleic acids and circulating proteins in patients with malignant gliomas. It is unclear which marker or marker class appears to be the most promising for these tumors. This article provides thoughts on how novel candidate blood-based markers could be discovered and tested in a more comprehensive way and why these efforts should be among the top priorities in neuro-oncologic research in the coming years. PMID- 23670055 TI - Differential expression of cell adhesion molecules in an ionizing radiation induced breast cancer model system. AB - Cell-cell adhesion is mediated by members of the cadherin-catenin system and among them E-cadherin and beta-catenin are important adhesion molecules for epithelial cell function and preservation of tissue integrity. To investigate the importance of cell adhesion molecules in breast carcinogenesis, we developed an in vitro breast cancer model system wherein immortalized human breast epithelial cell line, MCF-10F, was malignantly transformed by exposure to low doses of high linear energy transfer (LET) alpha particle radiation (150 keV/um) and subsequent growth in the presence or absence of 17beta-estradiol. This model consisted of human breast epithelial cells in different stages of transformation: i) parental cell line MCF-10F; ii) MCF-l0F continuously grown with estradiol at 10(-8) (Estrogen); iii) a non-malignant cell line (Alpha3); and iv) a malignant and tumorigenic cell line (Alpha5) and the Tumor2 cell line derived from the nude mouse xenograft of the Alpha5 cell line. Expression levels of important cell adhesion molecules such as alpha-catenin, beta-catenin, gamma-catenin, E-cadherin and integrin were found to be higher at the protein level in the Alpha5 and Tumor2 cell lines relative to these levels in the non-tumorigenic MCF-10F, Estrogen and Alpha3 cell lines. In corroboration, cDNA expression analysis revealed elevated levels of genes involved in the cell adhesion function [E cadherin, integrin beta6 and desmocollin3 (DSc3)] in the Alpha5 and Tumor2 cell lines relative to the levels in the MCF-10F, Estrogen and Alpha3 cell lines. Collectively, our results suggest that cell adhesion molecules are expressed at higher levels in malignantly transformed breast epithelial cells relative to levels in non-malignant cells. However, reduced levels of adhesion molecules observed in the mouse xenograft-derived Tumor 2 cell line compared to the pre tumorigenic Alpha5 cell line suggests that the altered expression levels of adhesion molecules depend on the tumor tissue microenvironment. PMID- 23670056 TI - RNAi silencing of a cytochrome P450 monoxygenase disrupts the ability of a filamentous fungus, Graphium sp., to grow on short-chain gaseous alkanes and ethers. AB - Graphium sp. (ATCC 58400), a filamentous fungus, is one of the few eukaryotes that grows on short-chain alkanes and ethers. In this study, we investigated the genetic underpinnings that enable this fungus to catalyze the first step in the alkane and ether oxidation pathway. A gene, CYP52L1, was identified, cloned and functionally characterized as an alkane-oxidizing cytochrome P450 (GSPALK1). Analysis of CYP52L1 suggests that it is a member of the CYP52 cytochrome P450 family, which is comprised of medium- and long-chain alkane-oxidizing enzymes found in yeasts. However, phylogenetic analysis of GSPALK1 with other CYP52 members suggests they are not closely related. Post-transcriptional ds-RNA mediated gene silencing of CYP52L1 severely reduced the ability of this fungus to oxidize alkanes and ethers, however, downstream metabolic steps in these pathways were unaffected. Collectively, the results of this study suggest that GSPALK1 is the enzyme that catalyzes the initial oxidation of alkanes and ethers but is not involved in the later steps of alkane or ether metabolism. PMID- 23670057 TI - Biodegradation of crude oil saturated fraction supported on clays. AB - The role of clay minerals in crude oil saturated hydrocarbon removal during biodegradation was investigated in aqueous clay/saturated hydrocarbon microcosm experiments with a hydrocarbon degrading microorganism community. The clay minerals used for this study were montmorillonite, palygorskite, saponite and kaolinite. The clay mineral samples were treated with hydrochloric acid and didecyldimethylammonium bromide to produce acid activated- and organoclays respectively which were used in this study. The production of organoclay was restricted to only montmorillonite and saponite because of their relative high CEC. The study indicated that acid activated clays, organoclays and unmodified kaolinite, were inhibitory to biodegradation of the hydrocarbon saturates. Unmodified saponite was neutral to biodegradation of the hydrocarbon saturates. However, unmodified palygorskite and montmorillonite were stimulatory to biodegradation of the hydrocarbon saturated fraction and appears to do so as a result of the clays' ability to provide high surface area for the accumulation of microbes and nutrients such that the nutrients were within the 'vicinity' of the microbes. Adsorption of the saturated hydrocarbons was not significant during biodegradation. PMID- 23670058 TI - Bubble gate for in-plane flow control. AB - We introduce a miniature gate valve as a readily implementable strategy for actively controlling the flow of liquids on-chip, within a footprint of less than one square millimetre. Bubble gates provide for simple, consistent and scalable control of liquid flow in microchannel networks, are compatible with different bulk microfabrication processes and substrate materials, and require neither electrodes nor moving parts. A bubble gate consists of two microchannel sections: a liquid-filled channel and a gas channel that intercepts the liquid channel to form a T-junction. The open or closed state of a bubble gate is determined by selecting between two distinct gas pressure levels: the lower level corresponds to the "open" state while the higher level corresponds to the "closed" state. During closure, a gas bubble penetrates from the gas channel into the liquid, flanked by a column of equidistantly spaced micropillars on each side, until the flow of liquid is completely obstructed. We fabricated bubble gates using single layer soft lithographic and bulk silicon micromachining procedures and evaluated their performance with a combination of theory and experimentation. We assessed the dynamic behaviour during more than 300 open-and-close cycles and report the operating pressure envelope for different bubble gate configurations and for the working fluids: de-ionized water, ethanol and a biological buffer. We obtained excellent agreement between the experimentally determined bubble gate operational envelope and a theoretical prediction based on static wetting behaviour. We report case studies that serve to illustrate the utility of bubble gates for liquid sampling in single and multi-layer microfluidic devices. Scalability of our strategy was demonstrated by simultaneously addressing 128 bubble gates. PMID- 23670059 TI - Why measure quality of life in dermatology? PMID- 23670060 TI - Impact of TNF-alpha antagonists on the quality of life in selected skin diseases. AB - Aim of the study was to investigate the impact of TNF-alpha antagonists on health related quality of life (HRQoL) in selected skin diseases, i.e. chronic plaque psoriasis, Behcet's disease (BD), hidradenitis suppurativa (HS) and pyoderma gangrenosum (PG). We have carried out a systematic literature search of Medline (2000 to April 2013) using the Cochrane highly sensitive and specific search strategy. Citations were screened for randomized, controlled trials of TNF-alpha antagonists (adalimumab, etanercept and infliximab) versus placebo in adults with psoriasis, BD, HS or PG. From the literature it is evident that skin diseases can affect physical, psychological, social and occupational aspects of everyday life. TNF-alpha antagonists induced consistent benefits across health outcomes in psoriasis, but only monoclonal antibodies, infliximab and adalimumab were effective in improving QoL in patients with BD, HS and PG. Dermatology Life Quality Index was the most common used tool for investigating HRQoL. For the majority of patients with skin diseases, the most important negative impacts on QoL were appearance related. Generally, the burden on QoL was correlated to the severity of skin disease and the improvement in QoL achieved by TNF-alpha blockers was proportional to the degree of disease remission. HRQoL issues are becoming even more important in evaluating medical care, including treatment of skin diseases. In general, achieving the highest clearing of skin disease with anti-TNF-alpha agents is required for optimal improvement in QoL. PMID- 23670061 TI - A review on quality of life in keratinocyte carcinoma patients. AB - Health-related quality of life issues in patients with cutaneous malignancies is being re-explored. This is motivated by the heavy burden they put on dermatological care, it is more and more considered a chronic disease and new non invasive therapies are being introduced. The purpose of this review is to identify the relevant quality of life (QOL) issues and to summarize the instruments used for investigating QOL in keratinocyte carcinoma patients. With a systematic literature search in Embase, MEDLINE OvidSP, PubMed publisher and Cochrane Central, 10 questionnaires and 4 studies reporting on quality of life issues were identified. Generic (UK Sickness Impact profile [UKSIP], Short Form 36-item Health Survey [SF-36], Functional Assessment of Cancer Therapy-General [FACT-G]) and dermatology specific (Dermatology Life Quality Index [DLQI] and Skindex-29, -16, -17) instruments demonstrated little to no QOL impairment. This may be explained by failing to capture the relevant domains such as "emotions", "appearance" and "anxiety". Skin cancer specific questionnaires (Skin Cancer Index [SCI], Skin Cancer Quality of Life Impact Tool [SCQOLIT] and Actinic Keratosis Quality of Life [AKQoL]) demonstrated good validity and responsiveness and represent the effect on QOL properly. However, there are some points of critique to these questionnaires. Optimal management of patients with actinic neoplasia syndrome and the selection and evaluation of therapies may benefit from the use of PROs in this ever increasing population. PMID- 23670062 TI - Impact of different skin conditions on quality of life. AB - AIM: Many skin conditions may have a strong impact on quality of life. The impact depends on several factors and in particular on the nature of the disease itself. The aim of the study was to describe the burden of several dermatological conditions on patients and to compare them. METHODS: Dermatological patients were recruited consecutively during the normal outpatient clinics of a large reference hospital. Quality of life data were collected using the Skindex-29. A short form of the questionnaire, the Skindex-17, was derived in order to simplify the presentation of results. The Skindex-17 has two subscales: symptoms and psychosocial. RESULTS: Data were complete for 2478 patients and 2402 patients for the symptomatic and the psychosocial scale of Skindex-17, respectively. The different skin conditions were grouped into 32 categories. Three disease patterns could be recognized, according to quality of life impairment: 1) low symptomatic impairment and low psychosocial impairment: mild conditions such as nevi and benign skin neoplasms, but also melanoma; 2) low symptomatic impairment and high psychosocial impairment: diseases such as alopecia, hirsutism, vitiligo; 3) high symptomatic impairment and high psychosocial impairment: for example, psoriasis, pemphigus, lichen. CONCLUSION: Specialty-specific quality of life questionnaires, such as the Skindex-29 or the Skindex-17, allow to evaluate differences among conditions. Such observations could be used by health policy makers, to show, for example, that some conditions affecting the appearance, even though not clinically severe, may have a strong impact on psychosocial life. PMID- 23670063 TI - Quality of life measurement in dermatology consultation: impact on patient reported outcomes. AB - It is now recognized that therapy should not only seek to cure disease, but also to affect outcomes that matter to the patients the most; those related to their functioning in their everyday life and their overall quality of life. In those situations where elimination of disease/complete cure is not possible for example in chronic conditions, limiting the complications from the illness, so that patients can still maintain a comfortable and satisfying life, becomes the goal of treatment. This coupled with the growing patient rights movement and the need for patients to be a part of treatment decision-making process means that patient's health-related quality of life is no longer just an important consequence of health-care, but it is increasingly regarded as an explicit ultimate goal. PMID- 23670064 TI - Dermatological quality of life instruments in children. AB - The interest to the health related quality of life (HRQoL) in children with dermatologic conditions is growing and it was studied in children with different dermatologic diseases. Generic, dermatology-specific and disease-specific instruments can be used to measure HRQoL in pediatric dermatology. In most cases HRQoL questionnaires to be used in adult population are inappropriate for children. With the help of illustrations and interview forms children are able to assess their HRQoL from the age of 4-5 years. In smaller children proxy ratings can be used. The dermatology-specific instrument Children's Dermatology Life Quality Index (CDLQI) is the most frequently used HRQoL instrument for children with different skin conditions. There is lack of validated dermatology-specific HRQoL proxy instrument to be used in children under 4 years and disease-specific instruments for many skin diseases. Most of the disease-specific HRQoL instruments created especially for children with skin diseases are atopic dermatitis-specific. The assessment of HRQoL in pediatric dermatology helps to assess the impact of single skin disease on child's life, to register patients' view on the efficacy of different treatment methods, educational programs and consultations. It makes possible to compare the impact of skin diseases and results of the treatment in children from different age groups on local, regional, national and international levels. It is used by pharmaceutical industry in clinical trials of new drugs and by health service authorities in national standards. PMID- 23670065 TI - Bioavailability of l-thyroxine and its metabolites after topical treatment with an emulsion containing 0.1% micronised l-thyroxine. AB - AIM: Aim of the study was to assess systemic effects of a cycle of treatment with a topical formulation of l-T4 and escin (Somatoline(r)) in healthy women based on changes in bioavailability of FT4, FT3, rT3, and TSH. METHODS: This study enrolled 20 healthy adult women with body mass index <30, not exposed to iodine containing products. The study called for 28 consecutive days of treatment with Somatoline(r) followed by a 14-day follow-up period. Blood samples for FT4, FT3 and TSH levels were drawn at baseline, 5 and 24 hours after the first application and thereafter on days 14, 28 and 42. Levels of rT3 were measured during the first 24 hours postapplication. RESULTS: Subject mean age was 40.1+/-8.0 years and BMI from 19.1 to 29.8. Levels of FT4 always remained within normal range and did not change in a clinically relevant way from baseline (11+/-1.2 pg/dL), with maximum mean change from pretreatment values of 0.4 pg/mL (P=0.87). Likewise, FT3 and TSH levels did not change significantly from baseline (3+/-0.4 pg/dL and 1.8 +/-0.9 uU/mL, respectively). Levels of rT3 behaved in a similar way, with modest changes from baseline (P=0.29). Local tolerability was defined "excellent" for 19 out of 20 women (95%) and "moderate" in one subject who experienced the onset of folliculitis, for which causal correlation with the treatment was considered "possible". CONCLUSION: Used at the posology foreseen for the marketed formulation, Somatoline(r) does not affect plasma levels of FT4, FT3, rT3 and TSH, either in the short term or after 28 days. PMID- 23670066 TI - DermaSilk in long-term control of infantile atopic dermatitis: a double blind randomized controlled trial. AB - AIM: Atopic dermatitis is a chronic inflammatory disease characterized by severe itching, skin dryness, blistering and remittent-relapse course. The critical feature is a skin barrier dysfunction that leads to epidermal inflammation and to bacterial superinfection. The aim of our study is to assess the usefulness of DermaSilk in reducing dermatitis relapses, in infants affected by atopic dermatitis, previously treated with topical corticosteroid and, if needed, with antibiotics. METHODS: This is a double blind randomized study involving 22 infants, aged 4 to 18 months, affected by atopic dermatitis. Disease severity has been evaluated by the SCORAD Index. To achieve a complete remission, acute phases were managed following international guidelines. Subsequently, infants were randomized to either wear a set of DermaSilk body and tights (group A), or wear clothes in pure cotton (group B) for 24 months with the exception of the warmer months (from mid-May to mid-September). RESULTS: The use of topical steroid per month was significantly lower in the DermaSilk group compared to the cotton group (P=0.006). The subjective evaluation reflecting itching reduction was also statistically significant (P=0.014). CONCLUSION: This study shows that DermaSilk products can reduce relapses in infants with eczema during the maintenance phase and play a pivotal role in itching control, improving the quality of life of children and their family. PMID- 23670067 TI - Sentinel lymph node biopsy or nodal observation in melanoma: study of an Italian series. AB - AIM: The purpose of this study was to investigate the disease-free time (DFT) and overall survival (OS) of patients with intermediate or high-risk cutaneous melanoma who were treated with conventional surgery alone, and to compare them with that of a second group of patients who were treated with surgery and SLN biopsy. METHODS: A retrospective, single-centre study was performed at the Department of Dermatology of the "M. Bufalini" Hospital, Cesena, Italy based on data collected between January 1990 and December 2007. A total of 757 consecutive patients with stage I-II melanoma were identified: the former group (control group), treated with conventional surgery, was composed of 224 patients; the latter, treated with surgery and SLN biopsy (SLN biopsy group), was formed of 529 patients. RESULTS: The 5-year disease free time (DFT) rate, estimated with Kaplan Meyer, was 73.9% (95% CI: 67.5-79.2) in the control group, and 82.2% (95% CI: 78.6-85.3) in the SLN biopsy group. Although the DFT rate was significantly higher in the SLN group than in the control group in univariate analyses (P=0.004), this gain was lost in multivariate analysis (P=0.2). The 5-year overall survival (OS) rate was 88.4% (95% CI: 83.2-92.1) for the control group, and 87.9% (95% CI: 84.6-90.4) for the SLN biopsy group. Statistical comparison of specific OS was not statistically significant (P=0.93). CONCLUSION: On the basis of our follow-up data, we found that patients who underwent SLN biopsy technique experienced a reduction in the proportion of lymph nodal relapse, but DFT and OS were statistically equivalent between the two groups. PMID- 23670068 TI - Allergic contact dermatitis to 6alpha -methylprednisolone aceponate. PMID- 23670069 TI - One case of multiple eruptive milia. PMID- 23670070 TI - Complete remission of Merkel cell carcinoma treated with electrochemotherapy and etoposide. PMID- 23670071 TI - Plasma-enhanced chemical vapor deposition synthesis of vertically oriented graphene nanosheets. AB - Vertically oriented graphene (VG) nanosheets have attracted growing interest for a wide range of applications, from energy storage, catalysis and field emission to gas sensing, due to their unique orientation, exposed sharp edges, non stacking morphology, and huge surface-to-volume ratio. Plasma-enhanced chemical vapor deposition (PECVD) has emerged as a key method for VG synthesis; however, controllable growth of VG with desirable characteristics for specific applications remains a challenge. This paper attempts to summarize the state-of the-art research on PECVD growth of VG nanosheets to provide guidelines on the design of plasma sources and operation parameters, and to offer a perspective on outstanding challenges that need to be overcome to enable commercial applications of VG. The review starts with an overview of various types of existing PECVD processes for VG growth, and then moves on to research on the influences of feedstock gas, temperature, and pressure on VG growth, substrate pretreatment, the growth of VG patterns on planar substrates, and VG growth on cylindrical and carbon nanotube (CNT) substrates. The review ends with a discussion on challenges and future directions for PECVD growth of VG. PMID- 23670073 TI - Through the eyes of a patient .... PMID- 23670072 TI - Development of TaqMan-based qPCR method for detection of caprine arthritis encephalitis virus (CAEV) infection. AB - A specific and sensitive two-step TaqMan real-time PCR has been developed for rapid diagnosis of caprine arthritis-encephalitis virus (CAEV) infection by using a set of specific primers and a TaqMan probe targeting a highly conserved region within the gene encoding the viral capsid protein (CA). The assay successfully detected CAEV proviral DNA in total DNA extracts originating from cell culture, whole blood samples and isolated PBMCs, with a lower detection limit of 10(2) copies and a linear dynamic range of 10(5) to 10(10) copies/ml. There was no cross-reaction with other animal viruses (e.g., goat pox virus, bovine leukemia virus, bovine mucosal disease virus, swine influenza virus and Nipah virus). When applied in parallel with serological AGID and conventional PCR for detection of CAEV in field samples, this assay exhibited a higher sensitivity than these traditional methods, and 7.8 % of the 308 specimens collected in the Shanxi and Tianjin regions of China from 1993 to 2011 were found to be positive. Thus, the TaqMan qPCR assay provides a fast, specific and sensitive means for detecting CAEV proviral DNA in goat specimens and should be useful for large-scale detection in eradication programs and epidemiological studies. PMID- 23670074 TI - Targeting MRSA: is it the right infection prevention goal? AB - Focus on universal infection prevention strategies, instead of targeted approaches, to reduce MRSA and other healthcare-associated infections. PMID- 23670075 TI - Intracellular eukaryotic pathogens in brown macroalgae in the Eastern Mediterranean, including LSU rRNA data for the oomycete Eurychasma dicksonii . AB - For the Mediterranean Sea, and indeed most of the world's oceans, the biodiversity and biogeography of eukaryotic pathogens infecting marine macroalgae remains poorly known, yet their ecological impact is probably significant. Based on 2 sampling campaigns on the Greek island of Lesvos in 2009 and 1 in northern Greece in 2012, this study provides first records of 3 intracellular eukaryotic pathogens infecting filamentous brown algae at these locations: Eurychasma dicksonii, Anisolpidium sphacellarum, and A. ectocarpii. Field and microscopic observations of the 3 pathogens are complemented by the first E. dicksonii large subunit ribosomal RNA (LSU rRNA) gene sequence analyses of isolates from Lesvos and other parts of the world. The latter highlights the monophyly of E. dicksonii worldwide and confirms the basal position of this pathogen within the oomycete lineage (Peronosporomycotina). The results of this study strongly support the notion that the geographic distribution of the relatively few eukaryotic seaweed pathogens is probably much larger than previously thought and that many of the world's marine bioregions remain seriously undersampled and understudied in this respect. PMID- 23670076 TI - Epitheliocystis hyperinfection in captive spotted eagle rays Aetobatus narinari associated with a novel Chlamydiales 16S rDNA signature sequence. AB - This report details 2 cases of epitheliocystis in spotted eagle rays Aetobatus narinari associated with a novel Chlamydiales 16S rDNA signature sequence. Epitheliocystis is a common disease of variable severity affecting >50 species of wild and cultured freshwater and marine teleosts. Disease in elasmobranchs is rarely reported and descriptions are limited. Occurring in gill and skin epithelium, lesions are characterized by large hypertrophied cells with basophilic inclusions containing Gram-negative, chlamydia-like bacteria. Acute lethargy, labored respiration, and abnormal swimming developed in a captive spotted eagle ray following an uneventful quarantine period, and mild epitheliocystis lesions were found microscopically. Three months later, a second animal exhibited similar signs. A gill clip revealed myriad spherical bodies identical to the previous case, and treatment with chloramphenicol and oxytetracycline was initiated. Despite therapy, respiration became irregular and euthanasia was elected. Histologically, epitheliocystis inclusions up to 200 um filled approximately 80% of lamellar troughs. Multifocal mild hypertrophy and hyperplasia of lamellar tips was accompanied by mild to moderate infiltrates of granulocytes and lymphocytes. Electron microscopy revealed a homogeneous population of elongate chlamydia-like bacterial forms similar in size and morphology to the primary long cells described in teleosts. Immunohistochemical staining with a polyclonal anti-chlamydial lipopolysaccharide antibody was positive. Sequence analysis of a unique 296 bp Chlamydiales signature sequence amplicon isolated from the rays showed greatest homology (85 to 87%) to 'Candidatus Piscichlamydia salmonis'. PMID- 23670077 TI - Complex interaction between proliferative kidney disease, water temperature and concurrent nematode infection in brown trout. AB - Proliferative kidney disease (PKD) is a temperature-dependent disease caused by the myxozoan Tetracapsuloides bryosalmonae. It is an emerging threat to wild brown trout Salmo trutta fario populations in Switzerland. Here we examined (1) how PKD prevalence and pathology in young-of-the-year (YOY) brown trout relate to water temperature, (2) whether wild brown trout can completely recover from T. bryosalmonae-induced renal lesions and eliminate T. bryosalmonae over the winter months, and (3) whether this rate and/or extent of the recovery is influenced by concurrent infection. A longitudinal field study on a wild brown trout cohort was conducted over 16 mo. YOY and age 1+ fish were sampled from 7 different field sites with various temperature regimes, and monitored for infection with T. bryosalmonae and the nematode Raphidascaris acus. T. bryosamonae was detectable in brown trout YOY from all sampling sites, with similar renal pathology, independent of water temperature. During winter months, recovery was mainly influenced by the presence or absence of concurrent infection with R. acus larvae. While brown trout without R. acus regenerated completely, concurrently infected brown trout showed incomplete recovery, with chronic renal lesions and incomplete translocation of T. bryosalmonae from the renal interstitium into the tubular lumen. Water temperature seemed to influence complete excretion of T. bryosalmonae, with spores remaining in trout from summer-warm rivers, but absent in trout from summer-cool rivers. In the following summer months, we found PKD infections in 1+ brown trout from all investigated river sites. The pathological lesions indicated a re-infection rather than a proliferation of remaining T. bryosalmonae. However, disease prevalence in 1+ trout was lower than in YOY. PMID- 23670078 TI - Adhesion to brown trout skin mucus, antagonism against cyst adhesion and pathogenicity to rainbow trout of some inhibitory bacteria against Saprolegnia parasitica . AB - Biological control of saprolegniosis with bacteria might be an alternative to the use of chemical compounds. Among criteria for the selection of such bacteria are their absence of pathogenicity to fish and their ability to prevent adhesion of the pathogen to the skin mucus. The pathogenicity to rainbow trout of 21 bacterial isolates with in vitro inhibitory activity against Saprolegnia parasitica was studied. Fifteen of the isolates, identified as Aeromonas sobria, Pantoea agglomerans, Pseudomonas fluorescens, Serratia fonticola, Xanthomonas retroflexus and Yersinia kristensenii, were non-pathogenic when injected into rainbow trout. Their capacity to adhere to the skin mucus of male and female brown trout and to reduce the adhesion of S. parasitica cysts under exclusion, competition and displacement conditions was tested. The 15 bacterial isolates showed a low adhesion rate, ranging between 1.7% (for an A. sobria isolate) and 15.3% (a P. fluorescens isolate). This adhesion was greater in the case of mucus from male brown trout than from females. Similarities in the adhesion to male mucus and other substrates and correlation to that observed to polystyrene suggest that adhesion to skin mucus does not depend on the substrate. A high percentage (88.9%) of the S. parasitica cysts adhered to the skin mucus of male brown trout. Almost all of the bacteria reduced this adhesion ratio significantly under exclusion and competition conditions. However, only half of the isolates displaced cysts from skin mucus, and more bacterial cells were necessary for this effect. A novel method to study the adhesion of S. parasitica cysts to skin mucus of trout and their interactions with inhibitory bacteria is described. PMID- 23670079 TI - Vaccination strategies to protect goldfish Carassius auratus against Aeromonas hydrophila infection. AB - Ornamental goldfish Carassius auratus were treated with whole cell (WC), extracellular product (ECP), outer membrane protein (OMP) and biofilm (BF) vaccines developed from the virulent Aeromonas hydrophila (AHV1; GenBank HQ331525.1) with and without the immunoadjuvant Asparagus racemosus. On various days post-vaccination (dpv), the treated fish were challenged with virulent A. hydrophila. These fish were monitored for survival, growth, specific bacterial reduction, and biochemical, haematological and immunological parameters. C. auratus attained 100% mortality within 7 d in non-vaccinated groups, whereas the vaccines helped to significantly (p <= 0.001) increase survival after 25 and 50 dpv. The vaccines with immunoadjuvant (ECP2, OMP2 and BF2 treatments) helped to reduce the Aeromonas load after the challenge, and serum albumin, globulin and protein levels were significantly (p < 0.01) improved in the OMP2- and BF2 treated groups. Haemoglobin and red blood cell counts were also significantly improved (p < 0.05) in the vaccinated groups compared to the control group. Additionally, haemagglutination occurred at the 1:12 dilution level in the vaccine plus immunoadjuvant-treated groups. Supplementing the vaccines with immunoadjuvant helped to improve phagocytosis to 54.07%, serum bactericidal activity to 14.6% and the albumin:globulin ratio to 7.6% in BF2 after 50 dpv. Its positive effect significantly (p < 0.05) increased in vaccinated groups compared to controls. Based on the results, especially with the OMP and BF vaccines, the immunoadjuvant A. racemosus helped to improve the efficiency of the vaccines. This approach will aid in the development of more efficient vaccines against bacterial infections affecting the aquaculture industry. PMID- 23670080 TI - Molecular characterization of Sphaerospora molnari (Myxozoa), the agent of gill sphaerosporosis in common carp Cyprinus carpio carpio. AB - Sphaerospora molnari Lom, Dykova, Pavlaskova and Grupcheva, 1983 often causes severe infections in the gills and skin of common carp fingerlings Cyprinus carpio carpio in Central Europe. Although most Sphaerospora spp. are coelozoic and affect the excretory system of fish, S. molnari develops mature spores in the epithelia of gill filaments, making it a rare representative of histozoic freshwater species within the genus. On the basis of a partial 18S rDNA sequence assigned as belonging to S. molnari, previous phylogenetic studies located the species within the Myxobolus clade. In the present study, S. molnari isolates from Hungary and the Czech Republic were characterized based on morphology, DNA sequence analysis and phylogenetic comparison. The obtained 3714 bp final consensus 18S rDNA sequence of the parasite showed several, sometimes extremely long inserts in the variable regions of the gene and differed considerably from the one published in GenBank in 2002. In situ hybridization confirmed the validity of the obtained DNA sequence and detected pre-sporogonic blood stages in the interstitium and blood vessels of the kidney. Phylogenetic analysis showed that S. molnari clusters within the Sphaerospora sensu stricto clade with a high support, revealing it as the first known histozoic member of the Sphaerospora subclade comprising parasites of freshwater fish. PMID- 23670081 TI - Development and validation of a quantitative PCR assay for Ichthyophonus spp. AB - Members of the genus Ichthyophonus are trophically transmitted, cosmopolitan parasites that affect numerous fish species worldwide. A quantitative PCR (qPCR) assay specific for genus Ichthyophonus 18S ribosomal DNA was developed for parasite detection and surveillance. The new assay was tested for precision, repeatability, reproducibility, and both analytical sensitivity and specificity. Diagnostic sensitivity and specificity were estimated using tissue samples from a wild population of walleye pollock Theragra chalcogramma. Ichthyophonus sp. presence in tissue samples was determined by qPCR, conventional PCR (cPCR), and histology. Parasite prevalence estimates varied depending upon the detection method employed and tissue type tested. qPCR identified the greatest number of Ichthyophonus sp.-positive cases when applied to walleye pollock skeletal muscle. The qPCR assay proved sensitive and specific for Ichthyophonus spp. DNA, but like cPCR, is only a proxy for infection. When compared to cPCR, qPCR possesses added benefits of parasite DNA quantification and a 100-fold increase in analytical sensitivity. Because this novel assay is specific for known members of the genus, it is likely appropriate for detecting Ichthyophonus spp. DNA in various hosts from multiple regions. However, species-level identification and isotype variability would require DNA sequencing. In addition to distribution and prevalence applications, this assay could be modified and adapted for use with zooplankton or environmental samples. Such applications could aid in investigating alternate routes of transmission and life history strategies typical to members of the genus Ichthyophonus. PMID- 23670082 TI - Rediscovery of the Yesso scallop pathogen Perkinsus qugwadi in Canada, and development of PCR tests. AB - Perkinsus qugwadi, a pathogenic protozoan parasite of Yesso scallops Patinopecten yessoensis, is found only in cultured populations in British Columbia, Canada. This pathogen was first identified in 1988 and caused significant mortalities at some locations during the early 1990s. Prevalence of infection decreased dramatically following 1995, and the disease was last reported in 1997, leading to speculation that the Yesso scallop stocks in Canada had developed resistance to the disease, or that P. qugwadi had disappeared. However, the present study revealed that infection with P. qugwadi and associated mortality is still occurring in scallops from at least one location in British Columbia. One of the PCR tests developed for P. qugwadi detected the parasite in a 105-fold dilution of DNA extracted from a heavily infected sample and detected 52% more positive scallops than histology; however, the assay also cross-reacted with P. honshuensis and P. olseni. The other PCR test was less sensitive and detected 34% more positives, but did not react to any of the other Perkinsus species tested, suggesting that these PCR tests are powerful tools for screening for the presence of P. qugwadi. Phylogenetic analysis of 1796 bp of SSU rRNA gene sequence clearly indicated that P. qugwadi is positioned basally to other Perkinsus species. PMID- 23670083 TI - Vesicoureteral reflux: Association of TNXB mutations with vesicoureteral reflux. PMID- 23670086 TI - Hypertension: Role of renal ACE in response to hypertensive stimuli. PMID- 23670084 TI - Iron metabolism in the pathogenesis of iron-induced kidney injury. AB - In the past 8 years, there has been renewed interest in the role of iron in both acute kidney injury (AKI) and chronic kidney disease (CKD). In patients with kidney diseases, renal tubules are exposed to a high concentration of iron owing to increased glomerular filtration of iron and iron-containing proteins, including haemoglobin, transferrin and neutrophil gelatinase-associated lipocalin (NGAL). Levels of intracellular catalytic iron may increase when glomerular and renal tubular cells are injured. Reducing the excessive luminal or intracellular levels of iron in the kidney could be a promising approach to treat AKI and CKD. Understanding the role of iron in kidney injury and as a therapeutic target requires insight into the mechanisms of iron metabolism in the kidney, the role of endogenous proteins involved in iron chelation and transport, including hepcidin, NGAL, the NGAL receptor and divalent metal transporter 1, and iron induced toxic effects. This Review summarizes emerging knowledge, which suggests that complex mechanisms of iron metabolism exist in the kidney, modulated directly or indirectly by cellular iron content, inflammation, ischaemia and oxidative stress. The potential exists for prevention and treatment of iron induced kidney injury by customized iron removal or relocation, aided by detailed insight into the underlying pathological mechanisms. PMID- 23670087 TI - Usefulness of cardiothoracic chest ultrasound in the management of acute respiratory failure in critical care practice. AB - BACKGROUND: This study investigated the clinical relevance of early general chest ultrasonography (ie, heart and lung recordings) in patients in the ICU with acute respiratory failure (ARF). METHODS: We prospectively compared this diagnostic approach (ultrasound) to a routine evaluation established from clinical, radiologic, and biologic data (standard). Subjects were patients consecutively admitted to the ICU of a university teaching hospital during a 1-year period. Inclusion criteria were age >= 18 years and the presence of severe ARF criteria to justify ICU admission. We compared the diagnostic approaches and the final diagnosis determined by a panel of experts. RESULTS: Seventy-eight patients were included (age, 70 +/- 18 years; sex ratio, 1). Three patients given two or more simultaneous diagnoses were subsequently excluded. The ultrasound approach was more accurate than the standard approach (83% vs 63%, respectively; P < .02). Receiver operating characteristic curve analysis showed greater diagnostic performance of ultrasound in cases of pneumonia (standard, 0.74 +/- 0.12; ultrasound, 0.87 +/- 0.14; P < .02), acute hemodynamic pulmonary edema (standard, 0.79 +/- 0.11; ultrasound, 0.93 +/- 0.08; P < .007), decompensated COPD (standard, 0.8 +/- 0.09; ultrasound, 0.92 +/- 0.15; P < .05), and pulmonary embolism (standard, 0.65 +/- 0.12; ultrasound, 0.81 +/- 0.17; P < .04). Furthermore, we found that the use of ultrasound data could have significantly improved the initial treatment. CONCLUSIONS: The use of cardiothoracic ultrasound appears to be an attractive complementary diagnostic tool and seems able to contribute to an early therapeutic decision based on reproducible physiopathologic data. PMID- 23670085 TI - Peritoneal changes in patients on long-term peritoneal dialysis. AB - Long-term peritoneal dialysis can lead to morphological and functional changes in the peritoneum. Although the range of morphological alterations is known for the peritoneal dialysis population as a whole, these changes will not occur in every patient in the same sequence and to the same extent. Longitudinal studies are therefore required to help identify which patients might develop the changes. Although longitudinal studies using peritoneal biopsies are not possible, analyses of peritoneal effluent biomarkers that represent morphological alterations could provide insight. Longitudinal studies on peritoneal transport have been performed, but follow-up has often been too short and an insufficient number of parameters have been investigated. This Review will firstly describe peritoneal morphology and structure and will then focus on peritoneal effluent biomarkers and their changes over time. Net ultrafiltration will also be discussed together with the transport of small solutes. Data on the peritoneal transport of serum proteins show that serum protein levels do not increase to the same extent as levels of small solutes with long-term peritoneal dialysis. Early alterations in peritoneal transport must be distinguished from alterations that only develop with long-term peritoneal dialysis. Early alterations are related to vasoactive mediators, whereas later alterations are related to neoangiogenesis and fibrosis. Modern peritoneal dialysis should focus on the early detection of long-term membrane alterations by biomarkers--such as cancer antigen 125, interleukin-6 and plasminogen activator inhibitor 1--and the improved assessment of peritoneal transport. PMID- 23670088 TI - Aperture correction with an asymmetrically trimmed Gaussian weight in SPECT with a fan-beam collimator. AB - OBJECTIVES: The aim of the study is to improve the spatial resolution of SPECT images acquired with a fan-beam collimator. METHODS: The aperture angle of a hole in the fan-beam collimator depends on the position of the collimator. To correct the aperture effect in an iterative image reconstruction, an asymmetrically trimmed Gaussian weight was used for a model. To confirm the validity of our method, point source phantoms and brain phantom were used in the simulation, and we applied the method to the clinical data. RESULTS: The results of the simulation showed that the spatial resolution of point sources improved from about 6 to 2 pixels full width at half maximum, and the corrected point sources were isotropic. The results of the simulation with the brain phantom showed that our proposed method could improve the spatial resolution of the phantom, and our method was effective for different fan-beam collimators with different focal lengths. The results of clinical data showed that the quality of the reconstructed image was improved with our proposed method. CONCLUSIONS: Our proposed aperture correction method with the asymmetrically trimmed Gaussian weighting function was effective in improving the spatial resolution of SPECT images acquired with the fan-beam collimator. PMID- 23670089 TI - Proteomic analysis of primary cultured rat cortical neurons in chemical ischemia. AB - To elucidate the molecular events involved in early ischemic neuronal death, we performed two-dimensional proteome profiling of primary cultures of rat cortical neurons following chemical ischemia induced by the administration of sodium azide under glucose-free conditions. Using a lactic dehydrogenase assay and Western blot analysis of dephosporylation of the voltage-gated potassium channel Kv2.1, we determined duration of chemical ischemia of 2 h to be the relevant time-point for early ischemic neuronal death. Sixty-one proteins were differentially expressed, and 26 different proteins were identified by MALDI-TOF with Mascot database searching. The proteome data indicated that chemical ischemia altered the expression of 20 proteins that are involved in stress response/chaperone, brain development, cytoskeletal/structural proteins, metabolic enzymes, and calcium ion homeostasis. Western blotting and immunocytochemical studies of the 6 most functionally significant proteins showed that, in the ischemia-treated group, the expression of glucose-related protein 78, heat shock protein 90 alpha, and alpha-enolase was significantly increased, while the expression of inositol triphosphate receptor 1 and ATP synthase beta subunit was decreased. In addition, the expression of dihydropyrimidinase-like 3 showed a truncated pattern in the ischemia group. The changes in the expression of these proteins might be significant indicators of early ischemic neuronal death. PMID- 23670090 TI - Evaluation of the role of chronic daily melatonin administration and pinealectomy on penicillin-induced focal epileptiform activity and spectral analysis of ECoG in rats: an in vivo electrophysiological study. AB - In the present study, we aimed to investigate the effects of pinealectomy and chronic melatonin administration on focal epileptiform activity induced by penicillin in the rat cortex and to determine the relation between melatonin levels and electrocorticogram (ECoG) power spectrum. For this purpose, male Sprague-Dawley rats were divided into six groups: control, sham operated, ethanol, melatonin, pinealectomy and pinealectomy + melatonin group. Melatonin treated rats was intraperitoneally injected with a daily single dose of 10 mg/kg melatonin for 14 days, but the last dose was given 30 min after local application of penicillin as a convulsant agent. Focal epileptiform activity was produced by intracortical administration of penicillin (200 units/1 MUl). While chronic melatonin application did not affect either the onset latency or the spike frequency of epileptiform activity, pinealectomy significantly reduced latency to onset of initial epileptiform discharges and increased cortical epileptiform activity. However, acute melatonin administration decreased the epileptiform activity. The results also indicated that exogenously applied melatonin did not change the spectral analysis of ECoG, but pinealectomy led to a reduction in the power of the fast bands (gamma) power in ECoG. We conclude that endogenous melatonin signaling seem to have a tonic inhibitory action on neuronal excitability and epileptiform activity, and also a certain concentration of melatonin required for normal cortical excitability. PMID- 23670091 TI - (2S)-5, 2', 5'-trihydroxy-7-methoxyflavanone, a natural product from Abacopteris penangiana, presents neuroprotective effects in vitro and in vivo. AB - The aim of this study was to investigate the neuroprotective effects of (2S)-5, 2', 5'-trihydroxy-7-methoxyflavanone (TMF), a natural product from Abacopteris penangiana (Hook.) Ching, in oxidative stress-induced neurodegeneration models in vitro and in vivo. In PC12 cells, preincubation of TMF (3-20 MUM) for 24 h decreased the dopamine-induced toxicity and attenuated the redox imbalance in PC12 cells through regulating the ratio of reduced glutathione/oxidized glutathione (GSH/GSSG), which is a sensitive marker of oxidative stress. Additionally, long-term intraperitoneal (i.p.) injection of TMF (4 or 8 mg/kg/day) for 2 weeks significantly improved the behavioral performance of D galactose (D-gal) treated mice in a Morris water maze test. Biochemical analysis revealed that TMF inhibited the activation of AP-1 (activator protein-1) and upregulated the level of BDNF (brain derived neurophic factor) as well as the ratio of GSH/GSSG in the hippocampus of D-gal treated mice. Furthermore, western blotting analysis indicated that TMF increased phosphorylation of cAMP-response element-binding protein (CREB). Therefore, the natural product TMF possessed a potential for the treatment of neurodegenerative diseases. PMID- 23670092 TI - Journey to the skin: Somatosensory peripheral axon guidance and morphogenesis. AB - The peripheral axons of vertebrate tactile somatosensory neurons travel long distances from ganglia just outside the central nervous system to the skin. Once in the skin these axons form elaborate terminals whose organization must be regionally patterned to detect and accurately localize different kinds of touch stimuli. This review describes key studies that identified choice points for somatosensory axon growth cones and the extrinsic molecular cues that function at each of those steps. While much has been learned in the past 20 years about the guidance of these axons, there is still much to be learned about how the peripheral axons of different kinds of somatosensory neurons adopt different trajectories and form specific terminal structures. PMID- 23670093 TI - Second-line treatment in advanced pancreatic cancer: a comprehensive analysis of published clinical trials. AB - BACKGROUND: There is currently no standard of care for the second-line treatment of advanced pancreatic cancer. The aim of this analysis was to compare the different therapeutic approaches in this setting. METHODS: We carried out a systematic analysis of second-line studies in advanced pancreatic cancer that have progressed on or following gemcitabine and published or presented from 2000 to 2012. RESULTS: Forty-four clinical trials (t) were identified; of which 34 met the inclusion criteria treating an aggregate total of 1503 patients (n). Patients who received treatments (t: 33; n: 1269) had a median overall survival (OS) of 6 months compared with 2.8 months for patients who received best supportive care only (t: 2; n: 234) (P = 0.013). The gemcitabine and platinum-based combination (t: 5; n: 154) provided a median progression-free survival and OS of 4 and 6 months compared with 1.6 and 5.3 for the rest of the regimens (t: 29; n: 1349) (P = 0.059 and 0.10, respectively) and 2.9 and 5.7 for the combination of 5 fluorouracil and platinum agents (t: 12; n: 450) (P = 0.60 and 0.22, respectively). CONCLUSION(S): Although not conclusive, these data showed that the advantage of second-line chemotherapy in pancreatic cancer is very limited and there is a need for more studies. PMID- 23670095 TI - 'All action no talk': the role of HER2/neu in adjuvant therapy choice for gastric cancer. PMID- 23670094 TI - Consumption of fish and meats and risk of hepatocellular carcinoma: the European Prospective Investigation into Cancer and Nutrition (EPIC). AB - BACKGROUND: While higher intake of fish and lower consumption of red/processed meats have been suggested to play a protective role in the etiology of several cancers, prospective evidence for hepatocellular carcinoma (HCC) is limited, particularly in Western European populations. METHODS: The associations of fish and meats with HCC risk were analyzed in the EPIC cohort. Between 1992 and 2010, 191 incident HCC were identified among 477 206 participants. Baseline diet was assessed using validated dietary questionnaires. A single 24-h diet recall from a cohort subsample was used for calibration. Multivariable proportional hazard regression was utilized to estimate hazard ratios (HR) and 95% confidence intervals (CI). In a nested case-control subset (HCC = 122), HBV/HCV status and liver function biomarkers were measured. RESULTS: HCC risk was inversely associated with intake of total fish (per 20 g/day increase, HR = 0.83, 95% CI 0.74-0.95 and HR = 0.80, 95% CI 0.69-0.97 before and after calibration, respectively). This inverse association was also suggested after adjusting for HBV/HCV status and liver function score (per 20-g/day increase, RR = 0.86, 95% CI 0.66-1.11 and RR = 0.74, 95% CI 0.50-1.09, respectively) in a nested case-control subset. Intakes of total meats or subgroups of red/processed meats, and poultry were not associated with HCC risk. CONCLUSIONS: In this large European cohort, total fish intake is associated with lower HCC risk. PMID- 23670096 TI - Oestrogen receptor co-activator AIB1 is a marker of tamoxifen benefit in postmenopausal breast cancer. AB - BACKGROUND: The oestrogen receptor (ER) co-activator amplified in breast cancer 1 (AIB1) has been suggested as a treatment predictive and prognostic marker in breast cancer. Studies have however not been unanimous. PATIENTS AND METHODS: AIB1 protein expression was analysed by immunohistochemistry on tissue micro arrays with tumour samples from 910 postmenopausal women randomised to tamoxifen treatment or no adjuvant treatment. Associations between AIB1 expression, clinical outcome in the two arms and other clinicopathological variables were examined. RESULTS: In patients with ER-positive breast cancer expressing low tumour levels of AIB1 (<75%), we found no significant difference in recurrence free survival (RFS) or breast cancer-specific survival (BCS) between tamoxifen treated and untreated patients. In patients with high AIB1 expression (>75%), there was a significant decrease in recurrence rate (HR 0.40, 95% CI 0.26-0.61, P < 0.001) and breast cancer mortality rate (HR 0.38, 95% CI 0.21-0.69, P = 0.0015) with tamoxifen treatment. In the untreated arm, we found high expression of AIB1 to be significantly associated with lower RFS (HR 1.74, 95% CI 1.20-2.53, P = 0.0038). CONCLUSION: Our results suggest that high AIB1 is a predictive marker of good response to tamoxifen treatment in postmenopausal women and a prognostic marker of decreased RFS in systemically untreated patients. PMID- 23670097 TI - Specific reversal of tumor-suppressor gene promoter hypermethylation with bovine oocyte extract. AB - Epigenetic silencing of tumor-suppressor genes by promoter hypermethylation contributes considerably to the initiation and progression of cancer. Nucleoside analogs, the most widely used DNA methylation inhibitors, have the drawbacks of inducing repetitive sequence hypomethylation. Here, we aimed to specifically reverse tumor-suppressor gene (TSG) promoter hypermethylation with bovine oocyte extract. H460 human lung cancer cells were reversibly permeabilized and incubated with bovine oocyte extract for 3.5 h. The extract treatment led to significant demethylation of the hypermethylated promoters of the TSGs RUNX3, CDH1, RASSF1A and WIF1; however, the methylation levels of repetitive sequences were not affected. The promoter demethylation induced by bovine oocyte extract substantially upregulated the expression of RUNX3, CDH1, RASSF1A and WIF1, and significantly inhibited the anchorage-independent proliferation, migration and invasion of H460 cells. This study demonstrates that bovine oocyte extract can reverse the malignant phenotype by serving as an efficient and safe DNA demethylator. The active demethylation activity of bovine oocyte extract is valuable for dissecting the epigenetic alterations in cancer cells and developing novel safe anticancer drugs based on epigenetic mechanisms. PMID- 23670098 TI - Metabolomic study of the fever model induced by baker's yeast and the antipyretic effects of aspirin in rats using nuclear magnetic resonance and gas chromatography-mass spectrometry. AB - A metabolomic investigation of baker's yeast-induced fever in rats was carried out. Plasma derived from Sprague-Dawley rats treated by subcutaneous administration of 20% (w/v) baker's yeast was analyzed using gas chromatography mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR). Statistical data analysis using t-test and orthogonal partial least-squares discriminant analysis revealed many significant changes in the metabolic data in the plasma of the fever group. Clear separation was achieved between the fever and control groups. Seventeen marked metabolites were found in the fever group. The metabolites, which include amino acids, carbohydrate, organic acids, and fatty acids, mostly contributed to the discrimination of plasma samples from the control and fever groups. These results suggested that fever may involve in the perturbation of amino acid metabolism coupled with energy metabolism, lipid metabolism, and glycometabolism. After determining the antipyretic effects of aspirin on the fever group, four metabolites in the fever rat plasma were found to be signally regulated and recognized as potential biomarkers, including 3-hydroxybutyric acid, gamma-aminobutyric acid, glucose, and linoleic acid. The metabolic relationships that possibly exist between these potential biomarkers were speculated, and the mechanism of baker's yeast-induced fever was illustrated based on the metabolic relationships. This study found that metabolomic approaches such as GC-MS and NMR could be used as potential powerful tools to investigate the biochemical changes and mechanisms in certain pathological states at the metabolism level. PMID- 23670099 TI - Renal metabolic profiling of early renal injury and renoprotective effects of Poria cocos epidermis using UPLC Q-TOF/HSMS/MSE. AB - Poria cocos epidermis is one of ancient traditional Chinese medicines (TCMs), which is usually used for the treatment of chronic kidney disease (CKD) for thousands of years in China. A metabonomic approach based on ultra performance liquid chromatography coupled with quadrupole time-of-flight high-sensitivity mass spectrometry (UPLC Q-TOF/HSMS) and a mass spectrometry(Elevated Energy) (MS(E)) data collection technique was developed to obtained a systematic view of the development and progression of CKD and biochemistry mechanism of therapeutic effects of P. cocos epidermis (Fu-Ling-Pi, FLP). By partial least squares discriminate analysis, 19 metabolites were identified as potential biomarkers of CKD. Among the 19 biomarkers, 10 biomarkers including eicosapentaenoic acid, docosahexaenoic acid, lysoPC(20:4), lysoPC(18:2), lysoPC(15:0), lysoPE(20:0/0:0), indoxyl sulfate, hippuric acid, p-cresol sulfate and allantoin were reversed to the control level in FLP-treated groups. The study indicates that FLP treatment can ameliorate CKD by intervening in some dominating metabolic pathways, such as fatty acid metabolism, phospholipid metabolism, purine metabolism and tryptophan metabolism. This work was for the first time to investigate the FLP therapeutic effect based on metabonomics technology, which is a potentially powerful tool to study the TCMs. PMID- 23670100 TI - Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays. PMID- 23670101 TI - Chelation of chromium(VI) by combining deferasirox and deferiprone in rats. AB - The present research is aimed to characterize the potential efficiency of two chelators after chromium(VI) administration for 60 days following two doses of 15 and 30 mg/kg chromium(VI) per body weight daily to male rats. However, the hypothesis that the two chelators might be more efficient as combined therapy than as single therapy in removing chromium(VI) from rat organs was considered. In this way, two known chelators deferasirox and deferiprone were chosen and given orally as a single or combined therapy for a period of 1 week. Chromium(VI) and iron concentrations in tissues were determined by flame atomic absorption spectroscopy. The combined chelation therapy results show that deferasirox and deferiprone are able to remove chromium(VI) ions from various tissues while iron concentration returned to normal levels and symptoms also decreased. PMID- 23670102 TI - Tumour thrombosis and patterns of fluorine-18 fluorodeoxyglucose uptake: a pictorial review. AB - Tumour thrombosis (TT) is a very rare but serious complication in oncologic patients. The presence of TT has a significant impact on tumour staging, treatment decisions and prognosis in many malignancies. Current diagnostic techniques show poor ability to differentiate between bland and malignant thrombi; tumour thrombi are also usually inaccessible for biopsies, making their diagnosis difficult. In recent times, fluorine-18 fluorodeoxyglucose PET/computed tomography (F-FDG PET/CT) has well established its role in oncological imaging because of the high metabolic contrast of F-FDG between malignant and normal tissue. Patients with tumour thrombi may benefit from F-FDG PET/CT imaging when TT cannot be diagnosed precisely by other conventional imaging modalities. Here we provide a pictorial review of a few common and unusual sites of tumour thrombus in different malignancies and their patterns of F-FDG uptake. PMID- 23670103 TI - Detection of glioma recurrence by 11C-methionine positron emission tomography and dynamic susceptibility contrast-enhanced magnetic resonance imaging: a meta analysis. AB - PURPOSE: This study aimed to compare the diagnostic value of 11C-methionine (11C MET) PET and dynamic susceptibility contrast-enhanced (DSCE) MRI in detecting glioma recurrence by meta-analysis. MATERIALS AND METHODS: Databases such as PubMed (MEDLINE included), EMBASE, Science Direct, Springerlink, EBSCO, and Cochrane Database of Systematic Review were searched for relevant original articles on the detection of recurrent glioma using DSCE MRI or 11C-MET PET with or without computed tomography. No restriction was imposed over the types and grades of glioma. The included studies were assessed for methodological quality. Results from histopathological analysis and/or close clinical and/or radiological follow-up for at least 3 months were used as the reference standard. The data were extracted by two reviewers independently to analyze the sensitivity, specificity, summary receiver-operating characteristic curve, area under the curve, and heterogeneity. RESULTS: The present study analyzed a total of 17 selected articles including different types and grades of glioma and showed that 11C-MET PET and DSCE MRI had comparable sensitivity (0.870 and 0.884, respectively), specificity (0.813 and 0.853, respectively), positive likelihood ratio (4.355 and 5.806, respectively), negative likelihood ratio (0.192 and 0.134, respectively), and diagnostic odds ratio (21.857 and 41.918, respectively) without statistically significant differences, except for the fact that DSCE MRI displayed higher area under the curve and Q* index compared with 11C-MET PET (P<0.05). CONCLUSION: Both 11C-MET PET and DSCE MRI are accurate tools for detecting glioma recurrence. Although DSCE MRI seems to be superior to 11C-MET PET, the latter can also be used to assess glioma recurrence when the former is not available. PMID- 23670104 TI - Photo-CIDNP NMR spectroscopy of amino acids and proteins. AB - Photo-chemically induced dynamic nuclear polarization (CIDNP) is a nuclear magnetic resonance (NMR) phenomenon which, among other things, is exploited to extract information on biomolecular structure via probing solvent-accessibilities of tryptophan (Trp), tyrosine (Tyr), and histidine (His) amino acid side chains both in polypeptides and proteins in solution. The effect, normally triggered by a (laser) light-induced photochemical reaction in situ, yields both positive and/or negative signal enhancements in the resulting NMR spectra which reflect the solvent exposure of these residues both in equilibrium and during structural transformations in "real time". As such, the method can offer - qualitatively and, to a certain extent, quantitatively - residue-specific structural and kinetic information on both the native and, in particular, the non-native states of proteins which, often, is not readily available from more routine NMR techniques. In this review, basic experimental procedures of the photo-CIDNP technique as applied to amino acids and proteins are discussed, recent improvements to the method highlighted, and future perspectives presented. First, the basic principles of the phenomenon based on the theory of the radical pair mechanism (RPM) are outlined. Second, a description of standard photo-CIDNP applications is given and it is shown how the effect can be exploited to extract residue-specific structural information on the conformational space sampled by unfolded or partially folded proteins on their "path" to the natively folded form. Last, recent methodological advances in the field are highlighted, modern applications of photo-CIDNP in the context of biological NMR evaluated, and an outlook into future perspectives of the method is given. PMID- 23670105 TI - Traumatic brain injury: revisiting the AAN guidelines on sport-related concussion. PMID- 23670106 TI - Can tauopathy shake the amyloid cascade hypothesis? PMID- 23670109 TI - Reply: The amyloid cascade is not the only pathway to AD. PMID- 23670107 TI - Diagnosis and treatment of primary CNS lymphoma. AB - Primary CNS lymphoma (PCNSL) is a rare lymphoma that is confined to the CNS, with low tendency for systemic dissemination and a relatively aggressive course. Outcome in patients with PCNSL is often poor. Owing to its low incidence, current knowledge about optimal treatment of PCNSL is fragmentary. Chemotherapy regimens based on high-dose methotrexate are currently standard treatment for all patients with PCNSL who can tolerate such drugs. Whole-brain radiotherapy alone can lead to remission in up to 90% of patients, but often results in poor long-term disease control when given alone, and in delayed neurotoxicity when given after high-dose methotrexate. In this Review, we describe current approaches to diagnosis and treatment of PCNSL, and discuss novel therapeutic approaches that are currently in development, such as the use of rituximab and high-dose chemotherapy followed by autologous stem-cell transplantation. The possible use of intrathecal and intraventricular chemotherapy, optimal salvage treatment, and specific treatment approaches in elderly, paediatric and immunocompromised patients, are also considered. PMID- 23670110 TI - CD4 counting technologies for HIV therapy monitoring in resource-poor settings- state-of-the-art and emerging microtechnologies. AB - Modern advancements in pharmaceuticals have provided individuals who have been infected with the human immunodeficiency virus (HIV) with the possibility of significantly extending their survival rates. When administered sufficiently soon after infection, antiretroviral therapy (ART) allows medical practitioners to control onset of the symptoms of the associated acquired immune deficiency syndrome (AIDS). Active monitoring of the immune system in both HIV patients and individuals who are regarded as "at-risk" is critical in the decision making process for when to start a patient on ART. A reliable and common method for such monitoring is to observe any decline in the number of CD4 expressing T-helper cells in the blood of a patient. However, the technology, expertise, infrastructure and costs to carry out such a diagnostic cannot be handled by medical services in resource-poor regions where HIV is endemic. Addressing this shortfall, commercialized point-of-care (POC) CD4 cell count systems are now available in such regions. A number of newer devices will also soon be on the market, some the result of recent maturing of charity-funded initiatives. Many of the current and imminent devices are enabled by microfluidic solutions, and this review will critically survey and analyze these POC technologies for CD4 counting, both on-market and near-to-market deployment. Additionally, promising technologies under development that may usher in a new generation of devices will be presented. PMID- 23670111 TI - An online mindfulness intervention targeting socioemotional regulation in fibromyalgia: results of a randomized controlled trial. AB - BACKGROUND: Patients with fibromyalgia (FM) experience pain as well as deficits in positive affect and social relations that are not explicitly addressed in most behavioral treatments. PURPOSE: The purpose of this study is to compare the effects of a 12-module online intervention targeting socioemotional regulation via mindful awareness/acceptance (MSER) with those of an attention-control treatment, healthy lifestyle tips (HT). METHODS: Seventy-nine FM patients were randomly assigned to MSER or HT, with outcomes assessed via online diary reports of pain, coping efficacy, affect, and social relations. Multilevel analyses revealed greater improvements in social functioning, positive affect, and coping efficacy for pain and stress (all ps < .05) in MSER versus HT across the 6-week trial. CONCLUSIONS: FM patients experience increases in self-efficacy for coping with pain and positive engagement in relationships, marginal increases in positive affect, and decreases in relationship stress from an automated online intervention that targets socioemotional regulation skills. Findings highlight the potential utility of widely accessible, low-cost intervention methods for fibromyalgia (Clinicaltrials.gov number NCT01748786). PMID- 23670112 TI - Improving adherence to medication in stroke survivors: a pilot randomised controlled trial. AB - BACKGROUND: Adherence to preventive medication is often poor, and current interventions have had limited success. PURPOSE: This study was conducted to pilot a randomised controlled trial aimed at increasing adherence to preventive medication in stroke survivors using a brief, personalised intervention. METHODS: Sixty-two stroke survivors were randomly allocated to either a two-session intervention aimed at increasing adherence via (a) introducing a plan linked to environmental cues (implementation intentions) to help establish a better medication-taking routine (habit) and (b) eliciting and modifying any mistaken patient beliefs regarding medication/stroke or a control group. Primary outcome was adherence to antihypertensive medication measured objectively over 3 months using an electronic pill bottle. RESULTS: Fifty-eight people used the pill bottle and were analysed as allocated; 54 completed treatment. The intervention resulted in 10 % more doses taken on schedule (intervention, 97 %; control, 87 %; 95 % CI for difference (0.2, 16.2); p = 0.048). CONCLUSIONS: A simple, brief intervention increased medication adherence in stroke survivors, over and above any effect of increased patient contact or mere measurement. PMID- 23670113 TI - The diagnostic accuracy of fecal calprotectin during the investigation of suspected pediatric inflammatory bowel disease: a systematic review and meta analysis. AB - OBJECTIVES: Fecal calprotectin (FC) is increasingly used during the diagnosis of inflammatory bowel disease (IBD), outperforming blood markers during investigation in children. Tests that reduce endoscopy rates in children with suspected gut inflammation would be beneficial. We aimed to determine the usefulness of FC in children undergoing their primary investigation for suspected IBD by systematic review and meta-analysis. METHODS: An electronic search was performed with keywords relating to IBD and calprotectin in multiple electronic resources from 1946 to May 2012; a hand search was also performed. Inclusion criteria were studies that reported FC levels before the endoscopic investigation of IBD in patients less than 18 years old. Studies were evaluated using the Quality Assessment of Diagnostic Accuracy Studies tool, and a meta-analysis was performed using a hierarchical summary receiver operating curve model. RESULTS: Eight papers met the inclusion criteria (six prospective and two retrospective case-control studies); methodological quality was determined in detail for each study. The 8 studies presented FC levels at presentation in 715 patients, 394 pediatric IBD patients, and 321 non-IBD controls. Pooled sensitivity and specificity for the diagnostic utility of FC during the investigation of suspected pediatric IBD were 0.978 (95% confidence interval (CI), 0.947-0.996) and 0.682 (95% CI, 0.502-0.863), respectively; the positive and negative likelihood ratios were 3.07 and 0.03, respectively. CONCLUSIONS: FC has a high sensitivity and a modest specificity during the diagnosis of suspected pediatric IBD. Further work is required to determine the effect of FC levels on endoscopy rates and its role during the re-evaluation of those with confirmed disease. PMID- 23670115 TI - Impact of persistent constipation on health-related quality of life and mortality in older community-dwelling women. AB - OBJECTIVES: Very little is known about whether the reported health-related impact of constipation is worse in people who experience constipation over a long period of time vs. those with more transient symptoms. We aimed to determine the impact of persistent vs. transient constipation on health-related quality of life (QOL), depression, and mortality. METHODS: We analyzed data from 5,107 women (aged 70-75 years in 1996) who answered "Have you had constipation in the past 12 months?" in all five surveys sent out every 3 years of the Australian Longitudinal Study on Women's Health. RESULTS: Of the 5,107 women, 20.9, 54.1, and 24.7% reported having persistent constipation on at least 4 out of 5 surveys, transient constipation reported on 1-3 surveys, or none reported over the 15-year time frame, respectively. Women who reported persistent constipation had significantly lower scores for all domains of QOL on the SF-36 except role-emotional, and had higher levels of self-reported depression, even after adjusting for number of chronic illnesses and fluid intake. Mortality rates were increased when comparing women with no reported constipation with persistently reported constipation (8.2% vs. 11%, odds ratio = 1.32, 95% confidence interval 1.0, 1.74, P = 0.05) controlling for specific chronic illnesses. CONCLUSIONS: Persistent constipation among older women is associated with poor health outcomes. PMID- 23670114 TI - Predictors of colorectal cancer screening variation among primary-care providers and clinics. AB - OBJECTIVES: Colorectal cancer (CRC) screening is underutilized. To effect change, we must understand reasons for underuse at multiple levels of the health-care system. We evaluated patient, provider, and clinic factors that predict variation in CRC screening among primary-care clinics and primary-care providers (PCPs). METHODS: We analyzed electronic medical record (EMR) data for 34,319 adults eligible for CRC screening, 19 clinics, and 97 PCPs in a large, academic physician group. Detailed data on potential patient, provider, and clinic predictors of CRC screening were obtained from the EMR. PCP perceptions of CRC screening barriers were measured via survey. The outcome was completion of CRC screening at the patient level. Multivariate logistic regression with clustering on clinics obtained adjusted odds ratios and 95% confidence intervals for potential predictors of CRC screening at each level. RESULTS: Seventy-one percentage of patients completed CRC screening. Variation in screening rates was seen among clinics (51-80%) and among PCPs (51-82%). Significant predictors of completing CRC screening were identified at all levels: patient (older age, white race, being married, primarily English-speaking, having commercial insurance plans vs. Medicare or Medicaid, and higher health-care resource utilization), provider (larger panel size of patients eligible for CRC screening), and clinic (hospital-owned, shorter distance to nearest optical colonoscopy center). CONCLUSIONS: Variation in CRC screening exists among primary-care clinics and providers within a single clinic. Predictors of variation can be identified at patient, provider, and clinic levels. Quality improvement interventions addressing CRC screening need to be directed at multiple levels of the health care system. PMID- 23670116 TI - Odontometric determination of sex at Mound 72, Cahokia. AB - The mortuary context of Mound 72 at the Cahokia site is one of the most unusual ever described in prehistoric North America. Previous skeletal analyses suggested that four large mass graves within the mound contained only female skeletons. However, these findings were complicated by extremely poor bone preservation that limited the number of skeletal observations that could be made. Furthermore, most skeletons were aged in the 15-25 year range, a time when sexually dimorphic bony traits may still be developing. In this study, dental remains were used to examine sex in the four presumably all-female mass graves in Mound 72. Additional sources of information, including the original field/laboratory notes and new sexing data based on modern standards, were gathered to fully evaluate the dental estimates. Initially, discriminant function analysis was performed on odontometrics using the original Mound 72 sex assignment. Inconsistent results indicated that some of the skeletons may have been misclassified in the original analyses. To overcome this issue, discriminant function equations were generated using a large pooled skeletal sample from two sites in close temporal and geographic proximity to Cahokia. Application of the equations to Mound 72 revealed that each of the four mass burial groups contained individuals classified as male. These assignments were checked against the skeletal remains and the original field/laboratory notes. Discussion centers on how the results affect previous archaeological interpretations as well as the methodological considerations associated with this study. PMID- 23670117 TI - Association of cryoprecipitate and tranexamic acid with improved survival following wartime injury: findings from the MATTERs II Study. AB - OBJECTIVE: To quantify the impact of fibrinogen-containing cryoprecipitate in addition to the antifibrinolytic tranexamic acid on survival in combat injured. DESIGN: Retrospective observational study comparing the mortality of 4 groups: tranexamic acid only, cryoprecipitate only, tranexamic acid and cryoprecipitate, and neither tranexamic acid nor cryoprecipitate. To balance comparisons, propensity scores were developed and added as covariates to logistic regression models predicting mortality. SETTING: A Role 3 Combat Surgical Hospital in southern Afghanistan. PATIENTS: A total of 1332 patients were identified from prospectively collected U.K. and U.S. trauma registries who required 1 U or more of packed red blood cells and composed the following groups: tranexamic acid (n = 148), cryoprecipitate (n = 168), tranexamic acid/cryoprecipitate (n = 258), and no tranexamic acid/cryoprecipitate (n = 758). MAIN OUTCOME MEASURE: In-hospital mortality. RESULTS: Injury severity scores were highest in the cryoprecipitate (mean [SD], 28.3 [15.7]) and tranexamic acid/cryoprecipitate (mean [SD], 26 [14.9]) groups compared with the tranexamic acid (mean [SD], 23.0 [19.2]) and no tranexamic acid/cryoprecipitate (mean [SD], 21.2 [18.5]) (P < .001) groups. Despite greater Injury Severity Scores and packed red blood cell requirements, mortality was lowest in the tranexamic acid/cryoprecipitate (11.6%) and tranexamic acid (18.2%) groups compared with the cryoprecipitate (21.4%) and no tranexamic acid/cryoprecipitate (23.6%) groups. Tranexamic acid and cryoprecipitate were independently associated with a similarly reduced mortality (odds ratio, 0.61; 95% CI, 0.42-0.89; P = .01 and odds ratio, 0.61; 95% CI, 0.40 0.94; P = .02, respectively). The combined tranexamic acid and cryoprecipitate effect vs. neither in a synergy model had an odds ratio of 0.34 (95% CI, 0.20 0.58; P < .001), reflecting nonsignificant interaction (P = .21). CONCLUSIONS: Cryoprecipitate may independently add to the survival benefit of tranexamic acid in the seriously injured requiring transfusion. Additional study is necessary to define the role of fibrinogen in resuscitation from hemorrhagic shock. PMID- 23670119 TI - A simple, safe and painless method for acute anterior glenohumeral joint dislocations: "the forward elevation maneuver". AB - PURPOSE: The glenohumeral joint is the most frequently dislocated joint in the body. Numerous techniques for reducing an acute anterior dislocation of the glenohumeral joint have been described. The goal of this study was to assess the efficacy of Janecki's forward elevation maneuver for reducing a traumatic acute anterior glenohumeral joint dislocation. METHODS: Between May 2010 and November 2011, the forward elevation maneuver was applied to 27 patients who presented to the emergency department of Yuzuncu Yil University Medical School with a traumatic anterior glenohumeral joint dislocation. For each patient, the forward elevation maneuver was used to reduce the anterior glenohumeral joint dislocation. The type of dislocation, the effectiveness of the procedure in achieving reduction, the need for premedication, the ease of performing the reduction and complications (if present) were noted. RESULTS: Janecki's forward elevation maneuver was successful for 25 patients (92.6 %) on the first attempt. Premedication was not used for 22 patients, and reduction was successful for 20 of them. The method was not successful in two cases. Twenty-three of the patients (85.2 %) experienced no pain or mild pain. Complications referred to the reduction technique were not found in any patient. CONCLUSIONS: This paper concludes that Janecki's forward elevation maneuver is a simple, safe, painless, and effective reduction method. Consequently, the forward elevation maneuver seems to be a good method for reducing anterior glenohumeral joint dislocation. PMID- 23670120 TI - Challenges and limitations in the interpretation of systematic reviews: making sense of clopidogrel and CYP2C19 pharmacogenetics. AB - From 2010 to 2012, nine systematic reviews reported highly variable conclusions regarding the association between carriage of a cytochrome P450 2C19 loss-of function allele and the risk of adverse cardiovascular (CV) events in individuals using clopidogrel. Possible contributors to the variable findings include differences in patient populations, CV end points, and statistical models utilized by the systematic reviews, as well as unexplained heterogeneity, inconsistent/incomplete reporting, and risk of publication bias with respect to the primary studies. PMID- 23670121 TI - Bleeding risk in atrial fibrillation patients taking vitamin K antagonists: systematic review and meta-analysis. AB - Vitamin K antagonists (VKAs) prevent stroke in atrial fibrillation (AF) at the cost of bleeding risk. To determine major bleeding rates in AF patients, we conducted a systematic review that identified 51 eligible studies including more than 342,699 patients. The pooled estimate of the rate of major bleeding was 2.51 (99% confidence interval: 2.03-3.11) bleeds per 100 patient-years. The results represent the best estimates of bleeding risk that most patients contemplating VKA use may expect. PMID- 23670122 TI - Association between lymphoma prognosis and aberrant methylation of ID4 and ZO-1 in bone marrow and paraffin-embedded lymphoma tissues of treatment-naive patients. AB - The aim of the present study was to investigate the association between lymphoma prognosis and aberrant methylation of inhibitor of DNA binding factor 4 (ID4) and tight junction protein 1 (ZO-1) genes in samples isolated from the bone marrow and paraffin-embedded lymphoma tissues of treatment-naive lymphoma patients. The bone marrow biopsy and paraffin-embedded lymphoma tissue samples from treatment naive lymphoma patients were obtained, along with corresponding control samples from subjects without lymphoma and from lymph nodes of chronic cholecystitis and reactive lymphadenitis patients. Methylation-specific PCR (MSP) reactions were performed to analyze the methylation status on the promoter regions of ID4 and ZO 1. ID4 and ZO-1 promoter regions in the control group were completely unmethylated, whereas the rates of methylation of ID4 and ZO-1 in paraffin embedded lymphoma tissues of the lymphoma patients were 80.4 and 84.3%, respectively. The methylation positivity rates of both the ID4 or ZO-1 genes in lymphoma patients were 92.2%, which was significantly higher compared to the rates in the control group (0%). The methylation positivity rates of the ID4 and ZO-1 genes in the bone marrow and paraffin-embedded lymphoma tissues of non Hodgkin lymphoma patients were significantly higher compared to the rates in the Hodgkin lymphoma patients. The survival rate of lymphoma patients with methylated ID4 was significantly lower compared to that of patients with unmethylated ID4. The methylation of the ID4 and ZO-1 genes may be a specific molecular marker for lymphoma diagnosis. The methylation of the ID4 gene may be an indicator of poor prognosis in lymphoma patients. PMID- 23670123 TI - In vivo confocal evaluation of the ocular surface morpho-functional unit in dry eye. AB - PURPOSE: To study, by a new, integrated, laser scanning confocal microscopy approach, the ocular surface morpho-functional unit in patients with primary Sjogren syndrome (SSI), non-Sjogren syndrome dry eye (non-SSDE), and meibomian gland disease (MGD). METHODS: Patients and age- and sex-matched control subjects (N = 60; 15 each) were consecutively enrolled in a prospective case-control study. Laser scanning confocal microscopy was used to obtain simultaneous optical sampling of the ocular surface components: cornea, bulbar and tarsal conjunctiva, MGs, and eyelid margin. RESULTS: For all superficial epithelia, except eyelid margins, there were reduced cell densities in each group compared with that in controls (p < 0.001). The lowest cell densities were in the SSI group (p < 0.001). Eyelid margin superficial cell density was decreased only in MGD (p < 0.001). Basal epithelial cell density at the corneal apex was increased in both SSI and non-SSDE compared with that in controls (p < 0.01). In the conjunctiva, it was decreased in each group compared with that in controls (p < 0.01). Subbasal dendritic cell density was significantly increased in both SSI and MGD compared with that in controls (p < 0.01). Conjunctival inflammatory cell density and MG inflammation were increased in each group compared with those in controls (p < 0.001), with the highest values in SSI. Subbasal nerve plexi had fewer fibers and higher bead density in each group compared with those in controls (p < 0.001). There was increased tortuosity in both SSI and MGD (p < 0.001). Patients with MGD had the lowest MG acinar density, the largest diameter of acini and acinar orifices, and the highest secretion reflectivity (p < 0.001). CONCLUSIONS: Laser scanning confocal microscopy can provide an in vivo, noninvasive, high resolution overview of the ocular surface morpho-functional unit. This confocal integrated approach may be useful in both research and clinical settings. PMID- 23670124 TI - Method to identify Demodex in the eyelash follicle without epilation. AB - The ubiquitous skin mite Demodex has been implicated as an instigator of anterior blepharitis. To date, overpopulation of the organism has been verified by cilia epilation (Coston or modified Coston method). This monograph describes an alternate technique to isolate Demodex organisms by eyelash rotation within the follicle. Via this method, without epilation, mites are made visible in follicles that may or may not display the cylindrical cuffing characteristic of demodicidosis. PMID- 23670125 TI - The Glenn A. Fry Award Lecture 2012: Plasticity of the visual system following central vision loss. AB - Following the onset of central vision loss, most patients develop an eccentric retinal location outside the affected macular region, the preferred retinal locus (PRL), as their new reference for visual tasks. The first goal of this article is to present behavioral evidence showing the presence of experience-dependent plasticity in people with central vision loss. The evidence includes the presence of oculomotor re-referencing of fixational saccades to the PRL; the characteristics of the shape of the crowding zone (spatial region within which the presence of other objects affects the recognition of a target) at the PRL are more "foveal-like" instead of resembling those of the normal periphery; and the change in the shape of the crowding zone at a para-PRL location that includes a component referenced to the PRL. These findings suggest that there is a shift in the referencing locus of the oculomotor and the sensory visual system from the fovea to the PRL for people with central vision loss, implying that the visual system for these individuals is still plastic and can be modified through experiences. The second goal of the article is to demonstrate the feasibility of applying perceptual learning, which capitalizes on the presence of plasticity, as a tool to improve functional vision for people with central vision loss. Our finding that visual function could improve with perceptual learning presents an exciting possibility for the development of an alternative rehabilitative strategy for people with central vision loss. PMID- 23670126 TI - Comparison of the quantification of acetaminophen in plasma, cerebrospinal fluid and dried blood spots using high-performance liquid chromatography-tandem mass spectrometry. AB - Acetaminophen (paracetamol, N-(4-hydroxyphenyl) acetamide) is one of the most commonly prescribed drugs for the management of pain in children. Quantification of acetaminophen in pre-term and term neonates and small children requires the availability of highly sensitive assays in small volume blood samples. We developed and validated an LC-MS/MS assay for the quantification of acetaminophen in human plasma, cerebro-spinal fluid (CSF) and dried blood spots (DBS). Reconstitution in water (DBS only) and addition of a protein precipitation solution containing the deuterated internal standard were the only manual steps. Extracted samples were analyzed on a Kinetex 2.6 MUm PFP column using an acetonitrile/formic acid gradient. The analytes were detected in the positive multiple reaction mode. Alternatively, DBS were automatically processed using direct desorption in a sample card and preparation (SCAP) robotic autosampler in combination with online extraction. The range of reliable response in plasma and CSF was 3.05-20,000 ng/ml (r(2)>0.99) and 27.4-20,000 ng/ml (r(2)>0.99) for DBS (manual extraction and automated direct desorption). Inter-day accuracy was always within 85-115% and inter-day precision for plasma, CSF and manually extracted DBS were less than 15%. Deming regression analysis comparing 167 matching pairs of plasma and DBS samples showed a correlation coefficient of 0.98. Bland Altman analysis indicated a 26.6% positive bias in DBS, most likely reflecting the blood: plasma distribution ratio of acetaminophen. DBS are a valid matrix for acetaminophen pharmacokinetic studies. PMID- 23670127 TI - Patient satisfaction after total knee arthroplasty is affected by their general physical well-being. AB - PURPOSE: We hypothesise that patients with a worse post-operative generic physical health, and those with a subclinical improvement, will have a greater rate of dissatisfaction with their total knee arthroplasty (TKA) despite improvement in their knee function. METHODS: Prospectively complied data for 2,330 primary TKA were used. Patient demographics, comorbidity, and pre- and post operative (1 year) Oxford knee scores (OKS) and Short Form (SF-) 12 scores were collected. Patient satisfaction was also assessed 1 year post-operatively. The satisfaction rate of patients with a poor post-operative SF-12 physical component summary (PCS score) (<=40 points) and those with a subclinical improvement (<4 points) in the score were compared to those with a score of more than 40 and a clinically significant improvement, respectively. RESULTS: More than half of the patients (n = 1,220) had a poor post-operative SF-12 PCS, and a third (n = 722) had a subclinical improvement in their general physical health after TKA. These patients were more likely to be older in age, suffer with concomitant back pain, and pain in other joints, and have a significantly worse pre-operative mental well-being score (SF-12) and OKS (all p < 0.04 on regression analysis). Both groups had a clinically significant improvement in their OKS post-operatively (p < 0.001), but it was 10 and 8 points less, respectively, than those patients with a SF-12 PCS of more than 40, and a clinical significant improvement in their PCS score (p < 0.001). Logistic regression analysis demonstrated that patients who had a poor post-operative SF-12 PCS (odds ratio 7.9, p < 0.001) and those with a subclinical improvement in their general physical health (odds ratio 5.1, p < 0.001) after TKA were significantly less likely to be satisfied. CONCLUSION: Despite benefitting from a significant improvement in their OKS after TKA, patients with a poor post-operative SF-12 PCS and those with a subclinical improvement in their general physical well-being are significantly less likely to be satisfied at 1 year. PMID- 23670128 TI - A meta-analysis comparing meniscal repair with meniscectomy in the treatment of meniscal tears: the more meniscus, the better outcome? AB - PURPOSE: The meniscus plays an important role in the knee joint. Meniscal tears are the most common knee injuries, are seen in all age groups and have several causes. Meniscectomy and meniscal repair, including open or arthroscopic procedures, are common operations for orthopaedic surgeons. The purpose of this meta-analysis was to review published articles that compared meniscal repair (open suture and arthroscopic inside-out procedures) with meniscectomy (arthroscopic partial or total meniscectomy) for short- or long-term outcomes and to determine which procedure leads to a better outcome. METHODS: A search was performed in the MEDLINE, EMBASE and OVID databases. All randomized, quasi randomized, and observational clinical trials that reported the outcome of meniscal repair and meniscectomy were included in our meta-analysis. The outcomes were International Knee Documentation Committee Score, Lysholm Score, Tegner Score and failure rate. RESULTS: Seven studies were included in this meta analysis, one of which was a randomized, prospective study. There was a statistically significant difference in favour of meniscal repair for Lysholm Score and Tegner Score. Besides, meniscal repair had a lower failure rate than meniscectomy. CONCLUSION: Meniscal repairs have better long-term patient-reported outcomes and better activity levels than meniscectomy; besides, the former meniscal repairs have a lower failure rate. LEVEL OF EVIDENCE: Meta-analysis, Level III. PMID- 23670129 TI - Micro-computed tomography (Micro-CT): a novel approach for intraoperative breast cancer specimen imaging. AB - Intraoperative radiographic examination of breast specimens is commonly performed to confirm excision of image-detected breast lesions, but it is not reliable for assessing margin status. A more accurate method of intraoperative breast specimen imaging is needed. Micro-CT provides quantitative imaging parameters, image rotation, and virtual "slicing" of intact breast specimens. We explored the use of micro-CT for assessment of a variety of clinical breast specimens. Specimens were evaluated with a table top micro-CT scanner, Skyscan 1173 (Skyscan, Belgium), with a 40-130 kV, 8 W X-ray source. Skyscan software for 3D image analysis (Dataviewer and CTVox) was employed to review 3D graphics of specimens. Scanning for 7 min and another 7 min for image reconstruction provided the desired resolution for breast specimens. Breast lumpectomy specimens, shaved cavity margins, mastectomy specimens, and axillary lymph nodes were imaged by micro-CT. The micro-CT images could be rotated in all directions and cross sections of internal portions of specimens could be visualized from any angle. This provided information about spatial orientation of masses and calcifications relative to margins in intact lumpectomy specimens. Micro-CT is a potentially useful tool for assessment of breast cancer specimens, allowing real-time analysis of tumor location in breast lumpectomy specimens or shaved cavity margins. Micro-CT may also be useful for assessing sentinel lymph nodes and mastectomy specimens. PMID- 23670130 TI - Shared decision-making in metastatic breast cancer: discrepancy between the expected prolongation of life and treatment efficacy between patients and physicians, and influencing factors. AB - Treatment decisions in oncology are based on a balance between the efficacy of therapy and its side effects. Patients with metastases and patients with a limited prognosis are a particular challenge, since communication about the disease situation and the expected therapeutic benefit is difficult not only for patients, but also for physicians. The aim of this study was therefore to compare the benefits expected of therapy by patients and physicians. Questionnaires were sent to 9,000 breast cancer patients and to 6,938 physicians. The questionnaires described 10 cases of breast cancer in the metastatic setting. The patients and physicians were asked to state the treatment benefit they would require to decide for the therapy options chemotherapy, endocrine therapy, antibody therapy, radiotherapy, and bisphosphonates. Additionally, the participants provided data on patient and physician characteristics. Expected treatment benefits were compared between patients and physicians, and influencing factors that modified the expected benefit were identified. Patients expected much greater benefits from the therapies offered than the physicians. For all treatment modalities, about 50 % or more of patients expected more than a 12-month increase in overall survival from all therapies. Among the doctors, this proportion ranged from 7 to 30 %. Among patients, previous experience of side effects and having young children in the family were the strongest influencing factors. Among the doctors, age and level of education had a strong influence on the expected prognostic improvement to indicate a therapy option. As expectations of treatment differ greatly between patients and doctors, a structured approach to solving this conflict is required. There appear to be some indicators that might help address the problem, such as the physicians' level of training and experience and the patients' specific social circumstances. PMID- 23670131 TI - Platform comparisons for identification of breast cancers with a BRCA-like copy number profile. AB - Previously, we employed bacterial artificial chromosome (BAC) array comparative genomic hybridization (aCGH) profiles from BRCA1 and -2 mutation carriers and sporadic tumours to construct classifiers that identify tumour samples most likely to harbour BRCA1 and -2 mutations, designated 'BRCA1 and -2-like' tumours, respectively. The classifiers are used in clinical genetics to evaluate unclassified variants, and patients for which no good quality germline DNA is available. Furthermore, we have shown that breast cancer patients with BRCA-like tumour aCGH profiles benefit substantially from platinum-based chemotherapy, potentially due to their inability to repair DNA double strand breaks (DSB), providing a further important clinical application for the classifiers. The BAC array technology has been replaced with oligonucleotide arrays. To continue clinical use of existing classifiers, we mapped oligonucleotide aCGH data to the BAC domain, such that the oligonucleotide profiles can be employed as in the BAC classifier. We demonstrate that segmented profiles derived from oligonucleotide aCGH show high correlation with BAC aCGH profiles. Furthermore, we trained a support vector machine score to objectify aCGH profile quality. Using the mapped oligonucleotide aCGH data, we show equivalence in classification of biologically relevant cases between BAC and oligonucleotide data. Furthermore, the predicted benefit of DSB inducing chemotherapy due to a homologous recombination defect is retained. We conclude that oligonucleotide aCGH data can be mapped to and used in the previously developed and validated BAC aCGH classifiers. Our findings suggest that it is possible to map copy number data from any other technology in a similar way. PMID- 23670132 TI - The impact of cyclin D1 overexpression on the prognosis of ER-positive breast cancers: a meta-analysis. AB - Cyclin D1 (CCND1), a key regulator of cell cycle progression, is overexpressed in many human cancers, including breast cancer. However, the impact of CCND1 overexpression in these cancers remains unclear and controversial. We conducted a systematic literature search in PubMed and EMBASE with the search terms "cyclin D1", "CCND1", "breast cancer", "prognosis", and potential studies for analysis were selected. Studies with survival data, including progression-free survival (PFS), overall survival (OS) or metastasis-free survival (MFS), were included in this meta-analysis. A total of 33 studies containing 8,537 cases were included. The combined hazard risk (HR) and its 95 % confidence interval (CI) of OS, PFS and MFS were 1.13 (95 % CI 0.87-1.47; P = 0.35), 1.25 (95 % CI 0.95-1.64; P = 0.12), and 1.04 (95 % CI 0.80-1.36; P = 0.76), respectively, for primary breast cancer patients with tumors exhibiting CCND1 overexpression. Interestingly, the impact of CCND1 expression on OS was a 1.67-fold (95 % CI 1.38-2.02; P = 0.00) increased risk for ER-positive breast cancer patients. However, CCND1 overexpression exhibited no association with the PFS or OS of patients who received epirubicin-based neoadjuvant chemotherapy, for which the P values were 0.63 and 0.47, respectively. In summary, CCND1 overexpression impacts the prognosis of ER-positive breast cancer patients, but not patients with unselected primary breast cancer or patients treated with neoadjuvant chemotherapy. PMID- 23670133 TI - Viscoelastic flow-focusing in microchannels: scaling properties of the particle radial distributions. AB - Particles suspended in non-Newtonian liquids flowing in channels may migrate transversally to the main flow direction as a result of normal stress gradients. Viscoelasticity-induced migration has proven to be an efficient mechanism to promote 3D flow-focusing in cylindrical microchannels, avoiding the need for complex and expensive apparati. In this work, we demonstrate the existence of a single dimensionless number (Theta) that governs the migration dynamics of particles in viscoelastic liquids flowing in micropipes at low Deborah numbers (Deborah number is the ratio of fluid and flow characteristic times). The definition of Theta in terms of the relevant fluid, flow and geometrical quantities is obtained by generalizing the particle migration velocity expression given in previous asymptotic analytical theories through numerical simulations. An extensive experimental investigation quantitatively confirms the novel predictions: the experimental particle distributions along the channel axial direction collapse on a single curve when rescaled in terms of the proposed dimensionless number. The results reported in this work give a simple and general way to define the flow-focusing conditions promoted by viscoelastic effects. PMID- 23670135 TI - Paediatric rheumatology: where are the innovations in paediatric rheumatology? PMID- 23670134 TI - The role of vitamin D supplementation in patients with rheumatic diseases. AB - Vitamin D is a dietary vitamin that can also be synthesized in adequate amounts from cholesterol in most mammals exposed to sunlight. Vitamin D has classical roles in calcium and phosphate metabolism, and thus the skeleton; however, this molecule also has nonclassical effects that might influence the function of the immune, cardiovascular and endocrine systems. Vitamin D deficiency, due to insufficient sunlight exposure, dietary uptake and/or abnormalities in its metabolism, has been associated with rheumatic diseases, and both the classical and nonclassical effects of vitamin D might be of relevance to patients with rheumatic disease. However, conclusive data from intervention trials demonstrating the relationship between vitamin D levels and pathogenetic processes separate from classical effects of this molecule are lacking. Furthermore, the majority of studies linking vitamin D to health outcomes, harmful or beneficial, are observational in nature, linking clinical events to vitamin D exposure or serum levels of vitamin D metabolites. Evidence from high quality, prospective, double-blind, placebo-controlled, randomized trials should be obtained before vitamin D supplementation is recommended in the treatment of the many rheumatic conditions in which deficiency of this compound has been implicated. Herein, we review the evidence for vitamin D supplementation in the management of patients with rheumatic diseases. PMID- 23670137 TI - Connective tissue diseases: HMGB1 helps elicit anti-dsDNA antibody production in SLE. PMID- 23670138 TI - Pathological features of highly invasive glioma stem cells in a mouse xenograft model. AB - Glioma stem cells (GSCs) may be a source of tumor progression and recurrence after multimodal therapy, because of their high invasive potential. The purpose of this study was to compare the invasive and migratory properties of GSCs and non-GSCs and examine the distribution of these cells in a mouse xenograft model. Three GSC lines, G144, Y02, and Y10, cultured from human glioblastoma, were used in the study. Matrigel-invasion assays of infiltration and time-lapse studies of migration were performed for comparison of the GSCs with the corresponding differentiated non-GSC lines. Cells were also transplanted into mouse brain and the different distribution of GSCs and non-GSCs was examined in the tumor xenograft model. All 3 GSC lines had greater invasion and migration ability than the corresponding non-GSCs. In vivo, GSCs infiltrated more widely than non-GSCs and reached the contralateral hemisphere via the corpus callosum in the early stage of tumorigenesis. GSCs also primarily penetrated the subventricular zone (SVZ). GSCs have high invasive potential and tend to be present in the outer tumor bulk and infiltrate the contralateral hemisphere via the corpus callosum, in addition to penetrating the SVZ. PMID- 23670139 TI - Perpendicular magnetic anisotropy with enhanced orbital moments of Fe adatoms on a topological surface of Bi2Se3. AB - We have found a perpendicular magnetic anisotropy of iron adatoms on a surface of the prototypical three-dimensional topological insulator Bi2Se3 by using x-ray magnetic circular dichroism measurements. The orbital magnetic moment of Fe is strongly enhanced at lower coverage, where angle-resolved photoemission spectroscopy shows coexistence of non-trivial topological states at the surface. PMID- 23670136 TI - Targeting inflammasomes in rheumatic diseases. AB - Inflammasomes are key inducers of inflammation in response to exogenous and endogenous stimuli, because they regulate the processing and secretion of the proinflammatory cytokines IL-1beta and IL-18. Thus, inflammasomes have a crucial role in host defence against infection, but they can also be involved in inflammatory diseases. Indeed, the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome has been shown to play a part in several inflammatory rheumatic disorders, although the mechanisms involved are better elucidated in some of these diseases than in others. In particular, the pathogenesis of cryopyrin associated periodic syndromes and microcrystal-induced arthritides is thought to be dependent on activation of the NLRP3 inflammasome, and IL-1 inhibition has shown efficacy as a therapeutic strategy in both groups of conditions. In this Review, we describe the current understanding of the mechanisms that trigger the inflammasome, and consider the relevance of the inflammasome to a variety of rheumatic diseases. In addition, we discuss the current therapies targeting this molecular complex, as well as future therapeutic prospects. PMID- 23670141 TI - Research and evaluation of the exeter health care arts project. AB - An arts project was initiated at the newly rebuilt district hospital in the city of Exeter in south west England. This paper describes an independent research evaluation project covering the period from its inception in 1992. The findings include both qualitative and economic aspects and were compared with the authors' wider experience of similar projects. For the first time the responses of clinical staff about the effects of art on the healing process, on therapeutic benefit and on morale are independently assessed. The results provide data and new insights into the interactions of patients, staff and visitors with the arts in the hospital environment. The conclusions offer important guidance for other arts projects and for researchers to develop the methodology in further studies, providing feedback for clinical staff, designers, artists, managers, and policy makers. PMID- 23670142 TI - Writing well: health and the power to make images. AB - There is increasing interest in connections between writing and wellbeing, but a perceived tension between writing well and writing to improve health. This paper gives a brief outline of some dominant literary thinking in this area, explores views of this orthodoxy among two groups of writers, examines the writing process and evidence of how it affects wellbeing, and goes on to relate how such evidence relates to recent psychological/clinical findings. Eighty-four per cent of those interviewed testified to therapeutic effects, but tensions existed around quality and catharsis. Bucci's multiple code account of the referential cycle is related to the creative writing process, and the paper concludes there are indications that the process of writing well is linked to the benefits for wellbeing. It therefore suggests that the importance of literary quality, and the re-writing process involved, as well as the value of disclosure, needs to be examined further as writing is increasingly used therapeutically. PMID- 23670143 TI - Kafka's uncle: scenes from a world of trust infected by suspicion. AB - What happens when we heed a call? Few writers have been as suspicious of their vocation as Franz Kafka (1883-1924). His story, A Country Doctor, (1919) ostensibly about a night visit to a patient that goes badly wrong, suggests a modern writer's journey to the heart of his work. There he discovers that trust, like the tradition which might sustain him, is blighted. This essay also examines Kafka's attitude to illness and the medical profession, and his close relationship with his uncle, Siegfried Lowy (1867-1942), a country doctor in Moravia. PMID- 23670144 TI - Narrative in psychiatry and psychotherapy: the evidence? AB - Psychiatry is perhaps the most "narrative" of all medical specialties, but here as elsewhere clinical skills are in danger of being lost as evidence-based medicine becomes the dominant paradigm in medical culture. Psychotherapy is a quintessentially narrative discipline. Starting from an "attachment" perspective, the uses of narrative in psychotherapy are outlined. These include the importance of metaphor, story-telling, the search for event-scripts, and the role of "narrative competence" as a mark of psychological health. Life history research, the "adult attachment interview" and other research approaches to narrative in psychiatry and psychotherapy are described. The paper calls for an integration of narrative and evidence-based medicine. PMID- 23670145 TI - Working with the metaphor of life and death. AB - The experience of being human is intangible. As a result, descriptions of human experience rely heavily on metaphor to convey something of that whole lived experience. By contrast, contemporary scientific narratives of the mind emphasise the form of human thought and emotion, over the content of people's experience, where constructive attempts are made to explain the experience of self, through metaphorical allusion. This paper considers the importance of metaphor as a vehicle for expressing and exploring selfhood. Examples from the psychiatric literature, as well as from the visual and literary arts, are used to reflect on the importance of metaphor in clarifying the meanings of the constructs of health and illness. PMID- 23670146 TI - Education and debate: A sense of landscape. PMID- 23670147 TI - Five poems by Helen Drucquer and a story by Frederick Nenner. PMID- 23670148 TI - A personal response to: Zen and the Art of Motorcycle Maintenance by Robert Pirsig. PMID- 23670149 TI - University credits, tuition free. PMID- 23670150 TI - Methemoglobinemia from curing salt. PMID- 23670151 TI - Why screening for depression in primary care is impractical. PMID- 23670153 TI - Prison smoking bans: clearing the air. PMID- 23670152 TI - Associations of job strain and lifestyle risk factors with risk of coronary artery disease: a meta-analysis of individual participant data. AB - BACKGROUND: It is unclear whether a healthy lifestyle mitigates the adverse effects of job strain on coronary artery disease. We examined the associations of job strain and lifestyle risk factors with the risk of coronary artery disease. METHODS: We pooled individual-level data from 7 cohort studies comprising 102 128 men and women who were free of existing coronary artery disease at baseline (1985 2000). Questionnaires were used to measure job strain (yes v. no) and 4 lifestyle risk factors: current smoking, physical inactivity, heavy drinking and obesity. We grouped participants into 3 lifestyle categories: healthy (no lifestyle risk factors), moderately unhealthy (1 risk factor) and unhealthy (2-4 risk factors). The primary outcome was incident coronary artery disease (defined as first nonfatal myocardial infarction or cardiac-related death). RESULTS: There were 1086 incident events in 743,948 person-years at risk during a mean follow-up of 7.3 years. The risk of coronary artery disease among people who had an unhealthy lifestyle compared with those who had a healthy lifestyle (hazard ratio [HR] 2.55, 95% confidence interval [CI] 2.18-2.98; population attributable risk 26.4%) was higher than the risk among participants who had job strain compared with those who had no job strain (HR 1.25, 95% CI 1.06-1.47; population attributable risk 3.8%). The 10-year incidence of coronary artery disease among participants with job strain and a healthy lifestyle (14.7 per 1000) was 53% lower than the incidence among those with job strain and an unhealthy lifestyle (31.2 per 1000). INTERPRETATION: The risk of coronary artery disease was highest among participants who reported job strain and an unhealthy lifestyle; those with job strain and a healthy lifestyle had half the rate of disease. A healthy lifestyle may substantially reduce disease risk among people with job strain. PMID- 23670154 TI - Isoniazid toxicity in a 5-year-old boy. PMID- 23670155 TI - Narrative accounts of recovering at home after heart surgery. PMID- 23670156 TI - Needs escalate, capacity stagnates in Syria. PMID- 23670158 TI - Physicians, health facilities targeted in war-torn Syria. PMID- 23670157 TI - Recommendations on screening for depression in adults. PMID- 23670159 TI - Quebec Health Minister blames former CEO for MUHC deficit, resulting cuts. PMID- 23670160 TI - miR-573 regulates melanoma progression by targeting the melanoma cell adhesion molecule. AB - Melanoma is a malignant tumor of the melanocytes. microRNAs (miRNAs) are emerging as important regulators of cancer-related processes. A thorough understanding of miRNAs in melanoma progression is important for developing new therapeutic targets. miRNA expression was detected by quantitative PCR. In vitro, MTT assay, colony formation assay, invasion assay and flow cytometry analysis were performed to test the effect of miR-573 on melanoma cells. The effect of miR-573 in vivo was validated using a murine xenograft model. Using quantitative PCR, we found that the expression levels of miR-573 were lower in melanoma tissues and cell lines compared to normal skin tissues. miR-573 upregulation inhibited melanoma cell proliferation and invasion, and overexpression of melanoma cell adhesion molecule (MCAM) could alleviate the effect of miR-573 on melanoma cells. In vivo, miR-573 overexpression groups showed lower rates of tumor growth compared with the control group. In conclusion, our results demonstrate that the elevated MCAM expression due to miR-573 reduction is essential in melanoma initiation and progression. PMID- 23670161 TI - An incompletely penetrant novel MAFB (p.Ser56Phe) variant in autosomal dominant multicentric carpotarsal osteolysis syndrome. AB - Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare autosomal dominant skeletal dysplasia usually presenting in early childhood with variable phenotypic features and course. Clinical manifestations comprise aggressive osteolysis of the carpal and tarsal bones in particular, an often progressive nephropathy leading to end-stage renal disease, craniofacial anomalies and mental impairment. Recently, heterozygous missense mutations in the V-maf musculoaponeurotic fibrosarcoma oncogene homolog B (avian) (MAFB) gene have been causally related to MCTO patients in 13 unrelated families investigated. Contrary to these findings suggesting complete penetrance, in the present study, we identified a novel missense MAFB variant present not only in the patient, but also in his unaffected mother, sister and maternal grandmother. This observation demonstrates an incomplete penetrance for some MAFB mutations, thereby suggesting that modifier genes, epigenetic mechanisms or environmental factors may modulate the MCTO phenotype. This should be considered in diagnosis and genetic counseling. PMID- 23670164 TI - Botulinum toxin for conditions of the female pelvis: comment. PMID- 23670163 TI - Parkin mitochondrial translocation is achieved through a novel catalytic activity coupled mechanism. AB - Pink1, a mitochondrial kinase, and Parkin, an E3 ubiquitin ligase, function in mitochondrial maintenance. Pink1 accumulates on depolarized mitochondria, where it recruits Parkin to mainly induce K63-linked chain ubiquitination of outer membrane proteins and eventually mitophagy. Parkin belongs to the RBR E3 ligase family. Recently, it has been proposed that the RBR domain transfers ubiquitin to targets via a cysteine~ubiquitin enzyme intermediate, in a manner similar to HECT domain E3 ligases. However, direct evidence for a ubiquitin transfer mechanism and its importance for Parkin's in vivo function is still missing. Here, we report that Parkin E3 activity relies on cysteine-mediated ubiquitin transfer during mitophagy. Mutating the putative catalytic cysteine to serine (Parkin C431S) traps ubiquitin, and surprisingly, also abrogates Parkin mitochondrial translocation, indicating that E3 activity is essential for Parkin translocation. We found that Parkin can bind to K63-linked ubiquitin chains, and that targeting K63-mimicking ubiquitin chains to mitochondria restores Parkin C431S localization. We propose that Parkin translocation is achieved through a novel catalytic activity coupled mechanism. PMID- 23670162 TI - Regulation of APC(Cdh1) E3 ligase activity by the Fbw7/cyclin E signaling axis contributes to the tumor suppressor function of Fbw7. AB - Fbw7 and Cdh1 are substrate-recognition subunits of the SCF- and APC-type E3 ubiquitin ligases, respectively. There is emerging evidence suggesting that both Fbw7 and Cdh1 function as tumor suppressors by targeting oncoproteins for destruction. Loss of Fbw7, but not Cdh1, is frequently observed in various human tumors. However, it remains largely unknown how Fbw7 mechanistically functions as a tumor suppressor and whether there is a signaling crosstalk between Fbw7 and Cdh1. Here, we report that Fbw7-deficient cells not only display elevated expression levels of SCF(Fbw7) substrates, including cyclin E, but also have increased expression of various APC(Cdh1) substrates. We further defined cyclin E as the critical signaling link by which Fbw7 governs APC(Cdh1) activity, as depletion of cyclin E in Fbw7-deficient cells results in decreased expression of APC(Cdh1) substrates to levels comparable to those in wild-type (WT) cells. Conversely, ectopic expression of cyclin E recapitulates the aberrant APC(Cdh1) substrate expression observed in Fbw7-deficient cells. More importantly, 4A-Cdh1 that is resistant to Cdk2/cyclin E-mediated phosphorylation, but not WT-Cdh1, reversed the elevated expression of various APC(Cdh1) substrates in Fbw7 deficient cells. Overexpression of 4A-Cdh1 also resulted in retarded cell growth and decreased anchorage-independent colony formation. Altogether, we have identified a novel regulatory mechanism by which Fbw7 governs Cdh1 activity in a cyclin E-dependent manner. As a result, loss of Fbw7 can lead to aberrant increase in the expression of both SCF(Fbw7) and APC(Cdh1) substrates. Our study provides a better understanding of the tumor suppressor function of Fbw7, and suggests that Cdk2/cyclin E inhibitors could serve as effective therapeutic agents for treating Fbw7-deficient tumors. PMID- 23670165 TI - Local immune response in bladder pain syndrome/interstitial cystitis ESSIC type 3C. AB - INTRODUCTION AND HYPOTHESIS: Bladder pain syndrome/interstitial cystitis (BPS/IC) is identified based on subjective symptoms which lead to heterogeneous patient populations. Previous studies using gene expression arrays for BPS/IC with Hunner's lesions [European Society for the Study of Interstitial Cystitis (ESSIC) type 3C], a subtype of the condition discernible by cystoscopy, have revealed characteristic immune responses and urothelial abnormalities. This current study aimed to further characterize this subtype using a gene expression panel. We hypothesized that B-cell activation with high levels of urinary antibody concentration would be found. METHODS: Cold-cup bladder biopsies, catheterized urine and blood were collected from 15 BPS/IC ESSIC type 3C patients, 11 non inflammatory overactive bladder (OAB) patients and eight healthy controls. Gene expression in biopsies was quantified by real-time quantitative polymerase chain reaction (RT-qPCR), immunohistochemistry was performed on bladder tissue and urinary immunoglobulins G and A were quantified by enzyme-linked immunosorbent assay. Statistical analyses included the Kruskal-Wallis test for non-parametric data and post hoc tests identified differences between groups. RESULTS: High expression of T- and B-cell markers (CTLA4, CD20, CD79A, IGH@), low expression of urothelial markers (KRT20, UPK1B, UPK3A), focal lymphoid aggregates in the submucosa and high immunoglobulin concentration in urine were found exclusively in BPS/IC ESSIC type 3C patients. Results for OAB were in intermediate ranges between the other two groups and UPK1B even reached significantly lower expression when compared to healthy controls. CONCLUSIONS: BPS/IC ESSIC type 3C is characterized by a local adaptive immune response with elevated urinary antibody concentrations. Quantification of urinary immunoglobulin levels could be used for a non-invasive diagnosis of BPS/IC ESSIC type 3C. PMID- 23670166 TI - Simple replica micromolding of biocompatible styrenic elastomers. AB - In this work, we introduce a simple solvent-assisted micromolding technique for the fabrication of high-fidelity styrene-ethylene/butylene-styrene (SEBS) microfluidic devices with high polystyrene (PS) content (42 wt% PS, SEBS42). SEBS triblock copolymers are styrenic thermoplastic elastomers that exhibit both glassy thermoplastic and elastomeric properties resulting from their respective hard PS and rubbery ethylene/butylene segments. The PS fraction gives SEBS microdevices many of the appealing properties of pure PS devices, while the elastomeric properties simplify fabrication of the devices, similar to PDMS. SEBS42 devices have wettable, stable surfaces (both contact angle and zeta potential) that support cell attachment and proliferation consistent with tissue culture dish substrates, do not adsorb hydrophobic molecules, and have high bond strength to wide range of substrates (glass, PS, SEBS). Furthermore, SEBS42 devices are mechanically robust, thermally stable, as well as exhibit low auto fluorescence and high transmissivity. We characterize SEBS42 surface properties by contact angle measurements, cell culture studies, zeta potential measurements, and the adsorption of hydrophobic molecules. The PS surface composition of SEBS microdevices cast on different substrates is determined by time-of-flight secondary ion mass spectrometry (ToF-SIMS). The attractive SEBS42 material properties, coupled with the simple fabrication method, make SEBS42 a quality substrate for microfluidic applications where the properties of PS are desired but the ease of PDMS micromolding is favoured. PMID- 23670167 TI - Randomised trial comparing Lichtenstein vs Trabucco vs Valenti techniques in inguinal hernia repair. AB - PURPOSE: Following Lichtenstein's technique, over the last 15 years several variation have been proposed, such as Trabucco's sutureless technique and the use of two self-regulating prostheses, proposed by Valenti that have given excellent results. The aim of this prospective and randomised study was to determine whether there are differences in the results obtained with these three techniques. METHODS: Of 812 patients submitted to inguinal hernia repair, we selected and randomised 162 patients into three groups of 54 patients each: Lichtenstein (Group L), Trabucco (Group T) and Valenti (Group V). Surgical procedures were performed in all cases by residents in surgery using local anaesthesia. Primary endpoint was intensity of postoperative pain. Median follow up was 8 years. RESULTS: The primary analysis of postoperative pain at 48 h did not report any significant difference between the three groups as for secondary analyses except that the Trabucco procedure took less operative time than the Lichtenstein, and the Valenti group was more painful than the Lichtenstein group at the third postoperative day. In our series median operation time was 60 min. Recurrence rate was 1.85%. CONCLUSIONS: Surgical repair of inguinal hernia according to the Lichtenstein, Trabucco and Valenti techniques is safe and easy to perform regardless of the surgical experience of the operator, with excellent results and no differences due to technique used as regards almost all of the parameters studied. PMID- 23670169 TI - Dairy food intake in relation to semen quality and reproductive hormone levels among physically active young men. AB - STUDY QUESTION: Is increased consumption of dairy foods associated with lower semen quality? SUMMARY ANSWER: We found that intake of full-fat dairy was inversely related to sperm motility and morphology. These associations were driven primarily by intake of cheese and were independent of overall dietary patterns. WHAT IS KNOWN ALREADY: It has been suggested that environmental estrogens could be responsible for the putative secular decline in sperm counts. Dairy foods contain large amounts of estrogens. While some studies have suggested dairy as a possible contributing factor for decreased semen quality, this finding has not been consistent across studies. STUDY DESIGN, SIZE, DURATION: The Rochester Young Men's Study (n = 189) was a cross-sectional study conducted between 2009 and 2010 at the University of Rochester. PARTICIPANTS/MATERIALS, SETTING, METHODS: Men aged 18-22 years were included in this analysis. Diet was assessed via food frequency questionnaire. Linear regression was used to analyze the relation between dairy intake and conventional semen quality parameters (total sperm count, sperm concentration, progressive motility, morphology and ejaculate volume) adjusting for age, abstinence time, race, smoking status, body mass index, recruitment period, moderate-to-intense exercise, TV watching and total calorie intake. MAIN RESULTS AND THE ROLE OF CHANCE: Total dairy food intake was inversely related to sperm morphology (P-trend = 0.004). This association was mostly driven by intake of full-fat dairy foods. The adjusted difference (95% confidence interval) in normal sperm morphology percent was -3.2% (-4.5 to -1.8) between men in the upper half and those in the lower half of full fat dairy intake (P < 0.0001), while the equivalent contrast for low-fat dairy intake was less pronounced [-1.3% (-2.7 to -0.07; P= 0.06)]. Full-fat dairy intake was also associated with significantly lower percent progressively motile sperm (P= 0.05). LIMITATIONS, REASONS FOR CAUTION: As it was a cross-sectional study, causal inference is limited. WIDER IMPLICATIONS OF THE FINDINGS: Further research is needed to prove a causal link between a high consumption of full-fat dairy foods and detrimental effects on semen quality. If verified our findings would mean that intake of full-fat dairy foods should be considered in attempts to explain secular trends in semen quality and that men trying to have children should restrict their intake. STUDY FUNDING/COMPETING INTEREST(S): European Union Seventh Framework Program (Environment), 'Developmental Effects of Environment on Reproductive Health' (DEER) grant 212844. Grant P30 DK046200 and Ruth L. Kirschstein National Research Service Award T32 DK007703-16 from the National Institutes of Health. None of the authors has any conflicts of interest to declare. PMID- 23670170 TI - Paracetamol, aspirin and indomethacin display endocrine disrupting properties in the adult human testis in vitro. AB - STUDY QUESTION: Do mild analgesics affect the endocrine system of the human adult testis? SUMMARY ANSWER: Mild analgesics induce multiple endocrine disturbances in the human adult testis in vitro. WHAT IS KNOWN ALREADY: Mild analgesics have recently been incriminated as potential endocrine disruptors. Studies of the effects of these widely used molecules on the androgenic status of men are limited and somewhat contradictory. This prompted us to investigate whether these compounds could alter the adult human testicular function. We therefore assessed in parallel the effects of paracetamol, aspirin and indomethacin on organo cultured adult human testis and on the NCI-H295R steroid-producing human cell line. STUDY DESIGN, SIZE, DURATION: Adult human testis explants or NCI-H295R adrenocortical human cells were cultured with 10(-4) or 10(-5) M paracetamol, aspirin or indomethacin for 24-48 h. The effect of 10(-5) M ketoconazole, used as an anti-androgenic reference molecule, was also assessed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Testes were obtained from prostate cancer patients, who had not received any hormone therapy. The protocol was approved by the local ethics committee of Rennes, France and informed consent was given by the donors. Only testes displaying spermatogenesis, as assessed by transillumination, were used in this study. Hormone levels in the culture media were determined by radioimmunoassay (testosterone, insulin-like factor 3), Enzyme-Linked Immunosorbent Assay (inhibin B) or Enzyme Immunosorbent Assay [prostaglandin (PG) D2, and PGE2]. Tissues were observed and cells counted using classical immunohistochemical methods. MAIN RESULTS AND THE ROLE OF CHANCE: The three mild analgesics caused multiple endocrine disturbances in the adult human testis. This was particularly apparent in the interstitial compartment. Effective doses were in the same range as those measured in blood plasma following standard analgesic treatment. The production of testosterone and insulin-like factor 3 by Leydig cells was altered by exposure to all these drugs. Inhibin B production by Sertoli cells was marginally affected by aspirin only. Our experiments also revealed that mild analgesics display direct anti-PG activity, which varied depending on the drug used, the dose and the duration of exposure. Nevertheless, associations between the alteration of the PG and testosterone profiles were not systematically observed, suggesting that a combination of mechanisms of endocrine disruption is at play. LIMITATIONS, REASONS FOR CAUTION: Our studies were performed in vitro. WIDER IMPLICATIONS OF THE FINDINGS: We provide the first evidence that direct exposure to mild analgesics can result in multiple endocrine disturbances in the human adult testis. Caution, concerning the consumption of mild analgesics by men, should be strengthened, particularly in high-risk population subgroups such as elite athletes. PMID- 23670171 TI - International geographic correlation study of the prevalence of disorders of male reproductive health. AB - STUDY QUESTION: Is there evidence at the population level of associations between different male genital disorders, outside Scandinavian countries? SUMMARY ANSWER: At an international scale, there is evidence for a number of correlations between rates of four male reproductive disorders (hypospadias, cryptorchidism, testicular cancer and low sperm concentration). WHAT IS KNOWN ALREADY: Some associations between these outcomes have been shown in studies focusing on individuals and mainly in Nordic European countries. These associations, together with histological evidence of a dysgenesis pattern in testicular tissue specimens, have generated the concept of the existence of a 'testicular dysgenesis syndrome' originating in utero. STUDY DESIGN, SIZE, DURATION: This is a geographical correlation study using cancer, malformations rates and sperm quality data collected between the years 1998 and 2005. PARTICIPANTS/MATERIALS, SETTING, METHODS: Incidence rates of testicular cancer were extracted from International Agency for Research on Cancer registries and Globocan, while cryptorchidism and hypospadias prevalence rates were obtained from EUROCAT and International Clearinghouse for Birth Defects Surveillance and Research registries. Sperm concentration data were extracted from recent studies using standardized methodology. A total of 39 registries and 9 sperm studies were selected. Non-parametric Spearman correlation tests were used to test the association between these four disorders. Correlations were computed for all registries together, for registries with high-quality matching coverage only and by continents. Sensitivity analyses were also conducted using data from prospective clinical studies to take into account potential bias related mainly to ascertainment of malformation rates. MAIN RESULTS AND THE ROLE OF CHANCE: We found positive correlations between testicular cancer and hypospadias (r = 0.32, P = 0.05) and between hypospadias and cryptorchidism (r = 0.70, P = 0.008). Stronger correlations were observed when using registries with high-quality matching coverage. Among these registries, differences between Europe and the rest of the world appeared (the positive correlation between testicular cancer and cryptorchidism was stronger outside Europe, r = 0.83, P = 0.01 compared with 0.40, P = 0.60 for European registries). A negative correlation between testicular cancer and sperm concentration was observed (r = -0.88, P = 0.002). These correlations support our initial hypothesis but remain only suggestive due to the intrinsic limitations in the study design (i.e. geographical correlation study) and do not allow causal inference. LIMITATIONS, REASONS FOR CAUTION: Differences in the ascertainment of malformations rates (definition, length of follow-up) make the international comparison difficult. The small number of registries for some conditions (cryptorchidism) or of studies (for sperm quality) and the absence of information about major risk factors such as ethnicity and socioeconomic status in the registries are also limitations. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are in agreement with results of studies focusing on individuals and suggest that shared risk factors are present in the populations studied. PMID- 23670172 TI - Viability of pulp stromal cells in cryopreserved deciduous teeth. AB - The cryopreservation of exfoliated deciduous teeth and harvesting of stem cells from them as required would reduce the costs and efforts associated with banking stem cells from primary teeth. The aim of this study was determine whether the viability of pulp stromal cells from deciduous teeth was influenced by the cryopreservation process itself or the period of cryopreservation. In total, 126 deciduous teeth were divided into three groups: (1) fresh, (2) cryopreserved for <3 months (cryo<3), and (3) cryopreserved for 3-9 months (cryo3-9). The viability of the pulp tissues was compared among the three groups by evaluating the outgrowth from pulp tissues and cell activity within those pulp tissues. In addition, the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay was performed to compare cell apoptosis within fresh pulp tissue and pulp tissue that had been cryopreserved for 4 months. The outgrowth from and cell activity within the pulp tissues did not differ significantly between the fresh and cryo<3 pulp tissues. However, these parameters were significantly reduced in the cryo3-9 pulp tissue. In TUNEL assay, 4-month cryopreserved pulp tissues has more apoptotic cells than fresh group. In conclusion, it is possible to acquire pulp stromal cells from cryopreserved deciduous teeth. However, as the period of cryopreservation becomes longer, it is difficult to get pulp cells due to reduced cell viability. PMID- 23670173 TI - PGP 9.5 neuronal marker may differentiate immunohistochemically HIV-related from Mediterranean and immunosuppression-associated Kaposi's sarcoma. AB - Mediterranean Kaposi's sarcoma (MKS), HIV-related KS (HIV-KS) and immunosuppression-associated KS (IS-KS), caused by human herpes virus 8 (HHV-8), share similar histological features. The aim of this study was to investigate differences in epidermal nerve fibers (ENFs) between the three KS types and controls. Skin biopsies from 23 HIV-KS, 16 MKS, 28 IS-KS patients and 18 controls, age-gender matched, were immunostained with PGP 9.5; ENFs in upper epidermal layer (EL) and penetrating the basement membrane were measured. The mean number of nerve fibers penetrating ENFs was significantly lower in HIV-KS (p < 0.001) compared to all other groups. MKS and IS-KS had comparable ENFs but lower than controls (p < 0.00 1). In the upper EL all groups had comparable ENFs and lower than controls. In conclusion, HIV-KS can be distinguished histologically from other types, by counting ENFs. Moreover, KS is associated with decreased ENFs, which may be a histological reflection of nerve damage. This is even more pronounced in HIV-KS patients and could be explained by a neurotoxic action of HHV-8, HIV, and their co-existence. PMID- 23670174 TI - Auditory profile in superficial siderosis of the central nervous system: a prospective study. AB - OBJECTIVE: To identify auditory pathology resulting from superficial siderosis of the central nervous system (SSCN), auditory site of lesion, and a clinical profile for differential diagnosis and development of recommendations. STUDY DESIGN: Prospective study. SETTING: Academic clinical center. PATIENTS: Ten participants with SSCN (the largest prospective evaluation of audiologic status reported to date). INTERVENTION(S): Demographics, clinical characteristics and history, audiometric evaluation, and Tinnitus Handicap Inventory (THI). MAIN OUTCOME MEASURE(S): Type and degree of hearing loss, relationship to clinical course of SSCN, and expected results based on age and sex. RESULTS: Sensorineural hearing loss (SNHL) is the most common symptom in SSCN (100%). Tinnitus (100%), imbalance (80%), and gait disorder (80%) were also frequently reported. Hearing loss is typically bilateral, asymmetric, progressive, sloping, and exceeds expected hearing loss related to age and sex. Hearing loss may be cochlear and/or retrocochlear in origin. Decreased word recognition is possible, and traditional amplification may offer limited benefit. CONCLUSION: We observed significant audiometric findings in all participants. SSCN variably and pathologically targets the auditory system without regard for duration of disorder. A long asymptomatic phase and lack of predictive relationship between duration and severity of hearing loss makes suspicion of SSCN based solely on audiometric battery difficult; however, asymmetric hearing loss exceeding expectations, particularly with history of head trauma or previous neurosurgical procedure, should raise a red flag and trigger further medical evaluation including MRI. Diagnosis of SSCN may alter expectations for audiologic prognosis and is a critical component for comprehensive management of SSCN patients. PMID- 23670175 TI - Sensitivity and resistance of JAK2 inhibitors to myeloproliferative neoplasms. AB - The discovery of activating mutations in JAK2 and MPL in a majority of patients with myeloproliferative neoplasms (MPN) has led to the rapid clinical development of several JAK kinase inhibitors. Of these, the JAK1/2 inhibitor, ruxolitinib (INCB018424, Incyte Corporation) was recently approved for the treatment of patients with myelofibrosis (MF). JAK inhibitors have effectively reduced splenomegaly and high cytokine levels in patients leading to improvements in quality of life. However, they have not been successful in eliminating the mutant clone in a majority of patients. In vitro studies using saturation mutagenesis screens have revealed several mutations in JAK2 that confer resistance to JAK inhibitors. Nevertheless, these mutations have not been identified so far in JAK inhibitor-treated patients. A recent study from our laboratory demonstrated that chronic JAK kinase inhibition leads to JAK inhibitor persistence via transphosphorylation of JAK2 through other JAK kinase family members. This phenomenon is seen in cell lines, mouse models and patient samples. The JAK inhibitor persistent cells, however, still remain JAK2 dependent and therefore combination therapies that target JAK2 and other components of the JAK-STAT pathway along with JAK inhibitors may provide additional benefits and improve clinical outcomes in these patients. PMID- 23670177 TI - Tamm-Hubbard surface states in the continuum. AB - In the framework of the Bose-Hubbard model, we show that two-particle surface bound states embedded in the continuum (BIC) can be sustained at the edge of a semi-infinite one-dimensional tight-binding lattice for any infinitesimally-small impurity potential V at the lattice boundary. Such thresholdless surface states, which can be referred to as Tamm-Hubbard BIC states, exist provided that the impurity potential V is attractive (repulsive) and the particle-particle Hubbard interaction U is repulsive (attractive), i.e. for UV < 0. PMID- 23670176 TI - Mechanisms of action and resistance to all-trans retinoic acid (ATRA) and arsenic trioxide (As2O 3) in acute promyelocytic leukemia. AB - Since the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) for the treatment of acute promyelocytic leukemia (APL), the overall survival rate has improved dramatically. However, relapse/refractory patients showing resistance to ATRA and/or As2O3 are recognized as a clinically significant problem. Genetic mutations resulting in amino acid substitution in the retinoic acid receptor alpha (RARalpha) ligand binding domain (LBD) and the PML-B2 domain of PML-RARalpha, respectively, have been reported as molecular mechanisms underlying resistance to ATRA and As2O3. In the LBD mutation, ATRA binding with LBD is generally impaired, and ligand-dependent co-repressor dissociation and degradation of PML-RARalpha by the proteasome pathway, leading to cell differentiation, are inhibited. The PML-B2 mutation interferes with the direct binding of As2O3 with PML-B2, and PML-RARalpha SUMOylation with As2O3 followed by multimerization and degradation is impaired. To overcome ATRA resistance, utilization of As2O3 provides a preferable outcome, and recently, a synthetic retinoid Am80, which has a higher binding affinity with PML-RARalpha than ATRA, has been tested in the clinical setting. However, no strategy attempted to date has been successful in overcoming As2O3 resistance. Detailed genomic analyses using patient samples harvested repeatedly may help in predicting the prognosis, selecting the effective targeting drugs, and designing new sophisticated strategies for the treatment of APL. PMID- 23670178 TI - Subcellular mislocalization of the transcription factor NF-E2 in erythroid cells discriminates prefibrotic primary myelofibrosis from essential thrombocythemia. AB - The World Health Organization (WHO) classification of myeloproliferative neoplasms (MPNs) comprises several entities including essential thrombocythemia (ET); primary myelofibrosis (PMF); and MPN, unclassifiable (MPN,U). Differential diagnosis between ET and early, prefibrotic PMF can be challenging but is critical because clinical course and outcome vary considerably between these entities. We have previously shown that the transcription factor nuclear factor erythroid 2 (NF-E2) is aberrantly expressed in MPN patients. Here we demonstrate that NF-E2 is mislocalized in PMF cells and that aberrant NF-E2 localization discriminates statistically highly significantly between ET and PMF. A threshold of 20% nuclear NF-E2 staining was cross-validated by ".682+ bootstrapping." Moreover, this cutoff correctly classifies diagnostic bone marrow biopsies of MPN,U patients specified upon follow-up as ET or PMF with 92% accuracy. Because interobserver concordance between independent pathologists was high (Spearman's rank correlation coefficient, 0.727), we propose that quantitative NF-E2 immunohistochemistry represents a diagnostic tool that can reliably support a differential diagnosis between ET and PMF. PMID- 23670179 TI - Systemic light chain amyloidosis: an update for treating physicians. AB - In immunoglobulin light chain amyloidosis a small, indolent plasma cell clone synthesizes light chains that cause devastating organ damage. Early diagnosis, based on prompt recognition of "red-flags" before advanced cardiomyopathy ensues, is essential for improving outcomes. Differentiation from other systemic amyloidoses may require advanced technologies. Prognosis depends on the extent of cardiac involvement, and cardiac biomarkers guide the choice of therapy. The protean clinical presentation requires individualized treatment. Close monitoring of clonal and organ response guides therapy changes and duration. Conventional or high-dose alkylator-based chemotherapy is effective in almost two-thirds of patients. Combinations of proteasome inhibitors, dexamethasone, and alkylators achieve high response rates, although controlled studies are needed. Risk-adapted stem cell transplant and consolidation with novel agents may be considered in selected patients. Immune-modulatory drugs are good options for refractory/relapsed patients. Novel agents and therapeutic targets are expected to be exploited, in an integrated, more effective and less toxic treatment strategy. PMID- 23670180 TI - Deletion of the NF-kappaB subunit p65/RelA in the hematopoietic compartment leads to defects in hematopoietic stem cell function. AB - Hematopoiesis is a tightly regulated process resulting in the production of blood cells. Self-renewal and differentiation of hematopoietic stem cells (HSCs) are key processes in hematopoietic development. Disruption of these steps can lead to altered cell distribution and disease. To investigate the role of the nuclear factor-kappaB subunit RelA/p65 in the regulation of HSCs in vivo, we generated mice lacking RelA/p65 in the hematopoietic compartment. Using this model system, we show that loss of p65 severely impairs HSC function and occurs in conjunction with increased hematopoietic stem and progenitor cell cycling, extramedullary hematopoiesis, and differentiation defects. Gene array studies of phenotypic HSCs indicate the up-regulation of genes normally expressed in lineage restricted cells, as well as the down-regulation of genes involved in HSC maintenance and homeostasis. We hypothesize that changes in gene expression in p65-deficient cells lead to decreased self-renewal and differentiation efficiency of hematopoietic stem and progenitor cells. These studies demonstrate that p65 is an important regulator of hematopoiesis through the transcription of genes involved in HSC fate. PMID- 23670181 TI - An introduction to acinar pressures in BPH and prostate cancer. AB - Intra-acinar and peri-acinar pressures in the prostate might be key factors in the evolution of its zonal morphology and the pathogenesis of BPH and cancer. Herein, I hypothesize that intra-acinar pressures lead to a decrease in apoptosis by distending or stretching acinar epithelium and its surrounding stroma. Increased prostatic smooth muscle content and tone might generate peri-acinar pressures, which could, in the long-term, counteract intra-acinar pressures and decrease epithelial stretch. Thus, it is proposed that BPH (characterized by increased prostatic smooth muscle and, therefore, raised peri-acinar pressures) might decrease the risk of prostate cancer progression by counteracting intra acinar pressures. In the context of this theory, the transition zone might have evolved as a specialized region within the prostate that can mount a concerted stromal-epithelial response to increased urethral and intra-acinar pressures (BPH), and the urethral angulation, anterior stroma and the prostatic capsule have an adjunctive evolutionary role in this phenomenon. PMID- 23670182 TI - Reducing rectal injury during external beam radiotherapy for prostate cancer. AB - Rectal bleeding and faecal incontinence are serious injuries that men with prostate cancer who receive radiotherapy can experience. Although technical advances--including the use of intensity-modulated radiotherapy coupled with image-guided radiotherapy--have enabled the delivery of dose distributions that conform to the shape of the tumour target with steep dose gradients that reduce the dose given to surrounding tissues, radiotherapy-associated toxicity can not be avoided completely. Many large-scale prospective studies have analysed the correlations of patient-related and treatment-related parameters with acute and late toxicity to optimize patient selection and treatment planning. The careful application of dose-volume constraints and the tuning of these constraints to the individual patient's characteristics are now considered the most effective ways of reducing rectal morbidity. Additionally, the use of endorectal balloons (to reduce the margins between the clinical target volume and planning target volume) and the insertion of tissue spacers into the region between the prostate and anterior rectal wall have been investigated as means to further reduce late rectal injury. Finally, some drugs and other compounds are also being considered to help protect healthy tissue. Overall, a number of approaches exist that must be fully explored in large prospective trials to address the important issue of rectal toxicity in prostate cancer radiotherapy. PMID- 23670183 TI - The role of heat shock proteins in bladder cancer. AB - Heat shock proteins (HSPs) and clusterin (another chaperone protein with HSP-like properties) are present in normal cells and are upregulated by cellular stressors such as hyperthermia, hypoxia, and cytotoxic agents. HSPs are overexpressed in a wide range of cancers. Cancer cells are in a constant state of proteotoxic stress and exploit the HSPs to protect themselves against the toxic effects of aberrant oncoproteins, genomic instability, hypoxia, and acidosis. In many patients with cancer, high levels of HSPs are associated with poor prognosis and treatment resistance as these proteins protect tumour cells from therapeutic stressors such as androgen or oestrogen withdrawal, radiation, and cytotoxic chemotherapy. Differences in the expression levels of HSPs in bladder cancers compared with normal urothelium have led to HSPs being investigated as diagnostic and prognostic biomarkers. Evidence suggests that HSPs are important modulators of the immune system and have a role in BCG-stimulated regression of urothelial cancers. New bladder cancer treatment strategies that target HSPs are being investigated and could have a synergistic role with modern radiotherapy and chemotherapy regimens. A combination of OGX-427 (an antisense oligonucleotide that targets HSP27), gemcitabine, and cisplatin is currently being investigated in a phase II trial of patients with advanced bladder cancer. PMID- 23670185 TI - Prostate cancer: improvements in risk stratification of prostate cancer. PMID- 23670184 TI - The role of phosphodiesterases in bladder pathophysiology. AB - Nitric oxide and the cyclic nucleotide monophosphates cAMP and cGMP have a role in control of the micturition process and hence, are suggested to be involved in the pathophysiology of storage and voiding disorders. Phosphodiesterase enzymes (PDEs) hydrolyse cAMP and cGMP. Inhibition of PDEs increases cAMP and cGMP levels and relaxes urinary bladder smooth musculature. Although many preclinical studies have been conducted, to date, only PDE1 and PDE5 inhibitors have been tested clinically for the management of storage and voiding disorders. Treatment with PDE1 inhibitors might improve micturition frequency in patients with overactive bladder, whereas inhibition of PDE5 improves lower urinary tract symptoms in men, either with or without BPH and erectile dysfunction (ED). Furthermore, the combination of a PDE5 inhibitor and an alpha-adrenoceptor antagonist has superior efficacy to monotherapy with either agent. However, the role of PDE5 inhibitors in the treatment of women with detrusor overactivity remains unclear. The clinical application of agents that inhibit other PDEs, including PDE4, also certainly merits scientific attention. PDE inhibitors seem likely to become a valuable alternative treatment for patients with storage and voiding disorders in the future. PMID- 23670186 TI - The Rb1 gene inhibits the viability of retinoblastoma cells by regulating homologous recombination. AB - Retinoblastoma is a childhood ocular tumor caused by the inactivation of both alleles of the retinoblastoma gene (Rb1). Without Rb1 gene function, chromosomal aberrations are observed in retinoblastoma cells. The instability of the genome is closely associated with the repair of DNA double-strand breaks (DSBs). However, the precise molecular mechanism of action of Rb1 in DNA DSB repair remains unclear. Thus, in this study, we aimed to investigate whether the Rb1 gene affects DNA stability by assaying DNA DSB repair and also whether it regulates the proliferation of retinoblastoma cells. Rb1 immunofluorescence and RT-PCR were performed, demonstrating that the Rb1 gene is silenced in SO-Rb50 retinoblastoma cells, and the karyotype analysis of SO-Rb50 cells indicated that the loss of Rb1 function led to genomic instability; both numerical and structural chromosomal aberrations were observed in our study. In addition, the DNA DSB repair efficiency of the SO-Rb50 cells was measured by gamma-H2AX immunofluorescence, a commonly used in situ marker of DNA DSBs, following exposure to ionizing radiation (IR) (2.5 and 5.0 Gy). We found that the DNA repair efficiency was significantly increased following IR-induced damage (P<0.01). However, there was no significant difference in DNA repair efficiency between the cells expressing exogenous Rb1 and the control (P>0.05). The assay for the screening of the effect of Rb1 on the sub-pathway of DNA DSB repair, non homologous end joining (NHEJ) and homologous recombination (HR), indicated that Rb1 did not affect NHEJ activity, although it significantly promoted the HR pathway (HR levels increased by 2.46-fold) compared with the control (P<0.01). Furthermore, we found that the cell viability of the SO-Rb50 cells transfected with exogenous Rb1 was significantly inhibited (P<0.01) and cell cycle assay indicated that exogenous Rb1 induced S phase arrest (P<0.001) which also inhibited the proliferation of retinoblastoma cells (SO-Rb50) in vitro. Therefore, this study provides new insight into the mechanisms of action of the Rb1 gene in regulating the proliferation of retinoblastoma cells. PMID- 23670187 TI - Cell-autonomous regulation of neutrophil migration by the D6 chemokine decoy receptor. AB - Chemokines, acting on their cognate receptors on infiltrating leukocytes, drive the inflammatory response. We have been interested in determining roles and potential mechanisms for the atypical chemokine-scavenging receptor D6 in the regulation of inflammation. In this study, we show that a psoriasis-like pathology that arises in inflamed skins of D6-deficient mice is characterized by a massive and aberrant localization of neutrophils to the dermal/epidermal junction, which is associated with development of the pathology. Such misplacement of neutrophils is also seen with D6-deficient mice in other inflammatory models, suggesting a role for D6 in the spatial positioning of neutrophils within inflamed sites. We further show that D6 functions cell autonomously in this context and that D6, expressed by neutrophils, limits their migrational responses to CCR1 ligands such as CCL3. Our data therefore indicate that D6 is able to play a cell-autonomous role as a migratory rheostat restricting migration of D6-expressing cells such as neutrophils toward ligands for coexpressed inflammatory chemokine receptors. These data have important implications for our understanding of the roles for D6 in regulating inflammation and for our understanding of the control of spatial positioning of leukocytes at inflamed sites. PMID- 23670188 TI - Th1/Th17-mediated interstitial pneumonia in chronic colitis mice independent of intestinal microbiota. AB - Although intestinal microbiota are essential for the development of T cell mediated colitis, it remains undetermined whether they enhance or suppress the chronic extraintestinal inflammation that often complicates inflammatory bowel diseases. In this study, we investigate the role of intestinal microbiota in the development of colitis and extraintestinal manifestations in a mouse model in which colitis was induced in SCID mice by adoptive transfer of CD4(+)CD45RB(high) T cells. Under specific pathogen-free conditions, these mice developed both colitis and extraintestinal interstitial pneumonia, whereas mice given a mixture of antibiotics did not develop colitis, but, surprisingly, developed Th1/Th17 mediated IP. Irrespective of antibiotic treatment, cotransfer of CD4(+)CD25(+) regulatory T cells suppressed the development of pneumonitis and colitis, with all local CD4(+)CD45RB(high) T cell-derived cells converted to CD44(high)CD62L( )IL-7Ralpha(high) effector-memory T cells. Retransfer of CD4(+) effector-memory T cells from the lungs of antibiotic-treated mice with IP not only induced IP in both antibiotic-treated and -untreated recipients but also induced colitis in the untreated recipients. In summary, we have established a unique model of Th1/Th17 mediated IP in microbiota-free and antibiotic-treated mice. This model may be valuable in investigating the immunological mechanisms underlying extraintestinal disorders in patients with inflammatory bowel disease. PMID- 23670189 TI - Adam8 limits the development of allergic airway inflammation in mice. AB - To determine whether a disintegrin and metalloproteinase-8 (Adam8) regulates allergic airway inflammation (AAI) and airway hyperresponsiveness (AHR), we compared AAI and AHR in wild-type (WT) versus Adam8(-/-) mice in different genetic backgrounds sensitized and challenged with OVA or house dust mite protein extract. OVA- and house dust mite-treated Adam8(-/-) mice had higher lung leukocyte counts, more airway mucus metaplasia, greater lung levels of some Th2 cytokines, and higher methacholine-induced increases in central airway resistance than allergen-treated WT mice. Studies of OVA-treated Adam8 bone marrow chimeric mice confirmed that leukocyte-derived Adam8 predominantly mediated Adam8's anti inflammatory activities in murine airways. Airway eosinophils and macrophages both expressed Adam8 in WT mice with AAI. Adam8 limited AAI and AHR in mice by reducing leukocyte survival because: 1) Adam8(-/-) mice with AAI had fewer apoptotic eosinophils and macrophages in their airways than WT mice with AAI; and 2) Adam8(-/-) macrophages and eosinophils had reduced rates of apoptosis compared with WT leukocytes when the intrinsic (but not the extrinsic) apoptosis pathway was triggered in the cells in vitro. ADAM8 was robustly expressed by airway granulocytes in lung sections from human asthma patients, but, surprisingly, airway macrophages had less ADAM8 staining than airway eosinophils. Thus, ADAM8 has anti-inflammatory activities during AAI in mice by activating the intrinsic apoptosis pathway in myeloid leukocytes. Strategies that increase ADAM8 levels in myeloid leukocytes may have therapeutic efficacy in asthma. PMID- 23670190 TI - Age-associated changes in the differentiation potentials of human circulating hematopoietic progenitors to T- or NK-lineage cells. AB - Age-associated changes of T and NK cell (T/NK) potential of human hematopoietic stem cells are unknown. In this study, we enumerate and characterize T/NK precursors among CD34(+)Lin(-) cell populations circulating in normal human adult peripheral blood (PB) by a limiting-dilution assay using coculture with OP9-DL1 stroma cells expressing Notch 1 ligand, Delta-like 1. The frequency of T cell precursors in CD34(+)Lin(-) cells was found to decrease with donor age, whereas the ratio of NK to T cell precursor frequency (NK/T ratio) increased with age, suggesting that lymphoid differentiation potential of PB progenitors shifts from T to NK cell lineage with aging. Clonal analyses of CD34(+)Lin(-) cells showed that differences in the NK/T ratio were attributable to different distributions of single- and dual-lineage T/NK precursor clones. Because nearly all of the clones retained monocyte and/or granulocyte differentiation potentials in coculture with OP9-DL1 cells, T/NK precursors in PB are considered to be contained in the pool of T/NK/myeloid multipotent progenitors. The age-associated increase in NK over T cell commitment might occur in precursor cells with T/NK/myeloid potential. PMID- 23670191 TI - Propofol inhibits superoxide production, elastase release, and chemotaxis in formyl peptide-activated human neutrophils by blocking formyl peptide receptor 1. AB - Neutrophils play a critical role in acute and chronic inflammatory processes, including myocardial ischemia/reperfusion injury, sepsis, and adult respiratory distress syndrome. Binding of formyl peptide receptor 1 (FPR1) by N-formyl peptides can activate neutrophils and may represent a new therapeutic target in either sterile or septic inflammation. Propofol, a widely used i.v. anesthetic, has been shown to modulate immunoinflammatory responses. However, the mechanism of propofol remains to be established. In this study, we showed that propofol significantly reduced superoxide generation, elastase release, and chemotaxis in human neutrophils activated by fMLF. Propofol did not alter superoxide generation or elastase release in a cell-free system. Neither inhibitors of gamma aminobutyric acid receptors nor an inhibitor of protein kinase A reversed the inhibitory effects of propofol. In addition, propofol showed less inhibitory effects in non-FPR1-induced cell responses. The signaling pathways downstream from FPR1, involving calcium, AKT, and ERK1/2, were also competitively inhibited by propofol. These results show that propofol selectively and competitively inhibits the FPR1-induced human neutrophil activation. Consistent with the hypothesis, propofol inhibited the binding of N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys fluorescein, a fluorescent analog of fMLF, to FPR1 in human neutrophils, differentiated THP-1 cells, and FPR1-transfected human embryonic kidney-293 cells. To our knowledge, our results identify, for the first time, a novel anti inflammatory mechanism of propofol by competitively blocking FPR1 in human neutrophils. Considering the importance of N-formyl peptides in inflammatory processes, our data indicate that propofol may have therapeutic potential to attenuate neutrophil-mediated inflammatory diseases by blocking FPR1. PMID- 23670192 TI - An essential role of antibodies in the control of Chikungunya virus infection. AB - In recent years, Chikungunya virus (CHIKV) was responsible for epidemic outbreaks in intertropical regions. Although acquired immunity has been shown to be crucial during CHIKV infection in both humans and mice, their exact role in the control of CHIKV infection remains unclear. In this study, wild-type (WT), CD4(-/-), and B cell (MUMT) knockout mice were infected with CHIKV. Sera were taken at different days postinfection and measured for anti-CHIKV Ab levels. Isotype and neutralizing capacity of these Abs were assessed in vitro, and specific linear epitopes were mapped. Viremia in CHIKV-infected MUMT mice persisted for more than a year, indicating a direct role for B cells in mediating CHIKV clearance. These animals exhibited a more severe disease than WT mice during the acute phase. Characterization of CHIKV-specific Abs revealed that anti-CHIKV Abs were elicited early and targeted epitopes mainly at the C terminus of the virus E2 glycoprotein. Furthermore, CD4(-/-) mice could still control CHIKV infection despite having lower anti-CHIKV Ab levels with reduced neutralizing capacity. Lastly, pre-existing natural Abs in the sera of normal WT mice recognized CHIKV and were able to partially inhibit CHIKV. Taken together, natural and CHIKV infection-induced specific Abs are essential for controlling CHIKV infections. PMID- 23670193 TI - Critical roles of a dendritic cell subset expressing a chemokine receptor, XCR1. AB - Dendritic cells (DCs) consist of various subsets that play crucial roles in linking innate and adaptive immunity. In the murine spleen, CD8alpha(+) DCs exhibit a propensity to ingest dying/dead cells, produce proinflammatory cytokines, and cross-present Ags to generate CD8(+) T cell responses. To track and ablate CD8alpha(+) DCs in vivo, we generated XCR1-venus and XCR1-DTRvenus mice, in which genes for a fluorescent protein, venus, and a fusion protein consisting of diphtheria toxin receptor and venus were knocked into the gene locus of a chemokine receptor, XCR1, which is highly expressed in CD8alpha(+) DCs. In both mice, venus(+) cells were detected in the majority of CD8alpha(+) DCs, but they were not detected in any other cells, including splenic macrophages. Venus(+)CD8alpha(+) DCs were superior to venus(-)CD8alpha(+) DCs with regard to their cytokine-producing ability in response to TLR stimuli. In other tissues, venus(+) cells were found primarily in lymph node (LN)-resident CD8alpha(+), LN migratory and peripheral CD103(+) DCs, which are closely related to splenic CD8alpha(+) DCs, although some thymic CD8alpha(-)CD11b(-) and LN CD103(-)CD11b(-) DCs were also venus(+). In response to dsRNAs, diphtheria toxin treated XCR1-DTR mice showed impaired CD8(+) T cell responses, with retained cytokine and augmented CD4(+) T cell responses. Furthermore, Listeria monocytogenes infection and anti-L. monocytogenes CD8(+) T cell responses were defective in diphtheria toxin-treated XCR1-DTRvenus mice. Thus, XCR1-expressing DCs were required for dsRNA- or bacteria-induced CD8(+) T cell responses. XCR1 venus and XCR1-DTRvenus mice should be useful for elucidating the functions and behavior of XCR1-expressing DCs, including CD8alpha(+) and CD103(+) DCs, in lymphoid and peripheral tissues. PMID- 23670194 TI - TLR3-triggered reactive oxygen species contribute to inflammatory responses by activating signal transducer and activator of transcription-1. AB - Intracellular reactive oxygen species (ROS) are essential secondary messengers in many signaling cascades governing innate immunity and cellular functions. TLR3 signaling is crucially involved in antiviral innate and inflammatory responses; however, the roles of ROS in TLR3 signaling remain largely unknown. In this study, we show that TLR3-induced ROS generation is required for the activation of NF-kappaB, IFN-regulatory factor 3, and STAT1-mediated innate immune responses in macrophages. TLR3 induction led to a rapid increase in ROS generation and a physical association between components of the NADPH oxidase (NOX) enzyme complex (NOX2 and p47(phox)) and TLR3 via a Ca(2+)-c-Src tyrosine kinase-dependent pathway. TLR3-induced ROS generation, NOX2, and p47(phox) were required for the phosphorylation and nuclear translocation of STAT1 and STAT2. TLR3-induced activation of STAT1 contributed to the generation of inflammatory mediators, which was significantly attenuated in NOX2- and p47(phox)-deficient macrophages, suggesting a role for ROS-STAT1 in TLR3-mediated innate immune responses. Collectively, these results provide a novel insight into the crucial role that TLR3-ROS signaling plays in innate immune responses by activating STAT1. PMID- 23670196 TI - Comments to the response of Rodriguez-Navarro. PMID- 23670195 TI - Lab-on-a-chip technologies for single-molecule studies. AB - Recent developments on various lab-on-a-chip techniques allow miniaturized and integrated devices to perform on-chip single-molecule studies. Fluidic-based platforms that utilize unique microscale fluidic behavior are capable of conducting single-molecule experiments with high sensitivities and throughputs, while biomolecular systems can be studied on-chip using techniques such as DNA curtains, magnetic tweezers, and solid-state nanopores. The advances of these on chip single-molecule techniques lead to next-generation lab-on-a-chip devices, such as DNA transistors, and single-molecule real-time (SMRT) technology for rapid and low-cost whole genome DNA sequencing. In this Focus article, we will discuss some recent successes in the development of lab-on-a-chip techniques for single-molecule studies and expound our thoughts on the near future of on-chip single-molecule studies. PMID- 23670197 TI - Between new genetic discoveries and large randomized trials--neurological research in the era of systems medicine. AB - The 2012 Eibsee meeting on 'Cellular Mechanisms of Neurodegeneration' addressed the need to integrate research on classical neurodegenerative mechanisms with investigations that relate to the immunological, glial and vascular sequels that accompany and often propagate neuronal injury. We report on the central topics that were addressed and discuss future directions towards establishing 'systems neurology' as a new integrated research field. PMID- 23670198 TI - Response to 'How good is research really?'. PMID- 23670199 TI - Prdm14 promotes germline fate and naive pluripotency by repressing FGF signalling and DNA methylation. AB - Primordial germ cells (PGCs) and somatic cells originate from postimplantation epiblast cells in mice. As pluripotency is lost upon differentiation of somatic lineages, a naive epigenome and the pluripotency network are re-established during PGC development. Here we demonstrate that Prdm14 contributes not only to PGC specification, but also to naive pluripotency in embryonic stem (ES) cells by repressing the DNA methylation machinery and fibroblast growth factor (FGF) signalling. This indicates a critical role for Prdm14 in programming PGCs and promoting pluripotency in ES cells. PMID- 23670201 TI - Comparison of wood smoke PM2.5 obtained from the combustion of FIR and beech pellets on inflammation and DNA damage in A549 and THP-1 human cell lines. AB - The aim of this study was to investigate the effect on the induction of interleukin-8 of particulate matter (PM) from fir and beech pellets burnt in domestic appliances on two human cells lines, namely the lung epithelial cell line A549 and the promyelocytic cell line THP-1. The effects of PM2.5 obtained from combustion of beech and fir pellets were compared to reference diesel exhaust particulates (DEP). In parallel, wood smoke PM-induced genotoxicity and oxidative stress were also investigated in A549 cells. Cells were treated for different times (3-72 h) with increasing concentrations of PM2.5 obtained from sequential combustions of fir and beech pellets or reference DEP. Cell viability was assessed by lactate dehydrogenase leakage, and the release of interleukin-8 or CXCL8 (IL-8) was measured to evaluate the pro-inflammatory effect. Oxidative stress was evaluated by the 5(6)-carboxy-2',7'dichlorofluorescein diacetate (DCFH DA) assay and DNA damage by the alkaline comet assay and micronucleus frequency by flow cytometry. Both A549 and THP-1 cells responded in a dose- and time related manner to wood smoke PM2.5 with IL-8 release, particles obtained from late combustions being the most active. THP-1 cells were more sensitive than A549 cells. On a mass base, similar effects were observed for both fir and beech PM2.5. However, the combustion of beech pellets generated approximately three times more PM2.5 than fir pellets. Regarding the mechanism of PM2.5 uptake, in both THP-1 and A549 cells, cytochalasin D prevented PM2.5-induced IL-8 mRNA expression and cytokine release, indicating a key role for actin polymerization in particles uptake and that the production of IL-8 correlated with particle phagocytosis. As signal transduction pathway involvement, in both THP-1 and A549 cells, PM2.5-induced IL-8 release could be completely blocked by the selective inhibitor SB203580, indicating a role of p38 MAPK activation. PM2.5 from both fir and beech pellets also induced modest DNA lesions dose related, measured as strand breaks, whereas no increase in the number of micronucleus was observed. Similar effects were observed with DEP, arguing against less dangerous effects of wood smoke particles than other categories of combustion-derived particles in the same size range. Overall, results suggest that combustion conditions can significantly affect the characteristics of particles and the consequent toxicity, and that different woods can generate different amounts of PM2.5. PMID- 23670202 TI - Evaluation of a human neurite growth assay as specific screen for developmental neurotoxicants. AB - Organ-specific in vitro toxicity assays are often highly sensitive, but they lack specificity. We evaluated here examples of assay features that can affect test specificity, and some general procedures are suggested on how positive hits in complex biological assays may be defined. Differentiating human LUHMES cells were used as potential model for developmental neurotoxicity testing. Forty candidate toxicants were screened, and several hits were obtained and confirmed. Although the cells had a definitive neuronal phenotype, the use of a general cell death endpoint in these cultures did not allow specific identification of neurotoxicants. As alternative approach, neurite growth was measured as an organ specific functional endpoint. We found that neurite extension of developing LUHMES was specifically inhibited by diverse compounds such as colchicine, vincristine, narciclasine, rotenone, cycloheximide, or diquat. These compounds reduced neurite growth at concentrations that did not compromise cell viability, and neurite growth was affected more potently than the integrity of developed neurites of mature neurons. A ratio of the EC50 values of neurite growth inhibition and cell death of >4 provided a robust classifier for compounds associated with a developmental neurotoxic hazard. Screening of unspecific toxicants in the test system always yielded ratios <4. The assay identified also compounds that accelerated neurite growth, such as the rho kinase pathway modifiers blebbistatin or thiazovivin. The negative effects of colchicine or rotenone were completely inhibited by a rho kinase inhibitor. In summary, we suggest that assays using functional endpoints (neurite growth) can specifically identify and characterize (developmental) neurotoxicants. PMID- 23670203 TI - Lanthanum chloride impairs spatial learning and memory and downregulates NF kappaB signalling pathway in rats. AB - Exposure to rare earth elements (REEs) is known to impair intelligence in children and cause neurobehavioral abnormalities in animals. However, the mechanisms underlying these phenomena are not clear. Lanthanum is often used to study the effects of REEs. The aim of this study was to investigate the influence of lanthanum chloride (LaCl3) on spatial learning and memory and a possible underlying mechanism involving nuclear factor-kappa B (NF-kappaB) signalling pathway expression in the hippocampus. The rats were exposed to 0, 0.25, 0.50 or 1.00 % LaCl3 in drinking water during pregnancy and lactation (i.e. while feeding their offspring). After weaning, young rats continued to receive 0, 0.25, 0.50 and 1.00 % LaCl3 in the drinking water for 1 month. LaCl3 exposure impaired the spatial learning and memory of young rats and significantly decreased the expression of phosphorylated IkappaB kinase complex, phosphorylated IkappaBalpha, NF-kappaB, c-fos, c-jun and brain-derived neurotrophic factor in the hippocampus. These results indicate that LaCl3 exposure impairs spatial learning and memory in rats by inhibiting NF-kappaB signalling pathway. PMID- 23670204 TI - Safety and effectiveness of insulin detemir in different age-groups in the a1chieve study. AB - INTRODUCTION: Diabetes therapy should balance glycemic control with risk of adverse events. This sub-analysis of the A1chieve study evaluated clinical safety and effectiveness of insulin detemir in different age-groups (<=40 years, >40-65 years, and >65 years) of insulin-experienced and insulin-naive people with type 2 diabetes. METHODS: A1chieve was an international, open-label, non-interventional, 24-week study in 66,726 people with type 2 diabetes starting/switching to therapy with biphasic insulin aspart 30, insulin detemir or insulin aspart (alone/in combination) in routine clinical practice. This sub-analysis evaluated clinical safety and effectiveness in patients starting/switching to insulin detemir (+/ oral glucose-lowering drugs). RESULTS: In total, 15,241 patients were included in the sub-analysis. In all age-groups, the proportion of participants experiencing any, major or nocturnal hypoglycemia was significantly (all p < 0.05) reduced relative to baseline, except in insulin-naive patients for any and nocturnal hypoglycemia, where there was a significant increase or no significant change in patients aged >65 years and >40-65 years, respectively, and no significant change in major hypoglycemia in insulin-naive patients aged <=40 years. Seven serious adverse drug reactions were reported. Body weight was significantly reduced in patients aged <=40 years and >40-65 years and significantly increased in insulin naive patients aged >65 years at 24 weeks. At 24 weeks, glycated hemoglobin was reduced by 2.3%, 2.0%, and 1.8%, in the <=40 years, >40-65 years, and >65 years age-groups, respectively (all p < 0.001). Fasting and post-prandial plasma glucose were significantly reduced and health-related quality of life (HRQoL) significantly improved across all patient cohorts (all p < 0.001). CONCLUSION: After 24-week treatment with insulin detemir, all age-groups of insulin experienced and insulin-naive patients had significantly improved glycemic control and HRQoL. The proportion of patients experiencing hypoglycemia was reduced in all age-groups but unchanged in insulin-naive patients aged >40-65 years and increased in insulin-naive patients aged >65 years. The safety and effectiveness of insulin detemir may benefit all age-groups. PMID- 23670205 TI - Safety and effectiveness of insulin aspart in Basal-bolus regimens regardless of age: a1chieve study results. AB - INTRODUCTION: Hypoglycemia is a complication in the management of type 2 diabetes, and elderly people are at greater risk of experiencing hypoglycemia events than younger patients. Insulin analogs achieve glycemic control with minimal risk of hypoglycemia and may therefore be a good treatment option for all patients. METHODS: A1chieve was an international, multicenter, prospective, open label, non-interventional, 24-week study in people with type 2 diabetes who started/switched to therapy with biphasic insulin aspart 30, insulin detemir or insulin aspart (alone/in combination) in routine clinical practice. This sub analysis evaluated clinical safety and effectiveness of insulin aspart as part of a basal-bolus regimen (+/-oral glucose-lowering drugs) in three age-groups (<=40, >40-65, and >65 years) of insulin-experienced and insulin-naive people with type 2 diabetes. RESULTS: In total, 4,032 patients were included in the sub-analysis. After 24 weeks of insulin aspart treatment, significant improvements versus baseline were observed in all age-groups for: proportion of people with >=1 hypoglycemia events (18.3-27.1% and 11.0-12.7%, at baseline and 24 weeks, respectively), >=1 major hypoglycemia events (3.3-6.7% and 0-0.2%), and >=1 nocturnal hypoglycemia events (9.2-13.7% and 2.9-4.9%); glycated hemoglobin (9.6 9.8% and 7.4%); fasting plasma glucose (change from baseline ranged from -3.6 to 4.4 mmol/l); and post-breakfast post-prandial plasma glucose (change from baseline ranged from -5.5 to -5.9 mmol/l). Fourteen serious adverse drug reactions were reported. Health-related quality of life was significantly improved for all age-groups (all, p < 0.001). CONCLUSION: All age-groups showed improved glycemic control and reduced risk of hypoglycemia when starting/switching to insulin aspart therapy within a basal-bolus regimen; this may be particularly important for elderly patients given their greater risk of hypoglycemia versus younger patients. PMID- 23670206 TI - Toxicology and pathology of female reproductive tract. PMID- 23670207 TI - Direct colposcopic vision used with the LLETZ procedure for optimal treatment of CIN: results of joint cohort studies. AB - PURPOSE: To assess the value of direct colposcopic vision (DCV) for optimizing large loop excision of the transformation zone (LLETZ) for the treatment of cervical intraepithelial neoplasia (CIN). METHODS: Data from 648 patients who underwent excisional procedures for CIN and were included in two previously published cohort studies were retrospectively reviewed. Women who had a LLETZ were included for analysis (n = 436). Margin status, surgical specimen dimensions and volume were analysed according to the use of colposcopy during procedure. RESULTS: Compared to LLETZ guided by previous colposcopy report only, and to LLETZ performed immediately after colposcopy, DCV allowed for a significantly higher rate of clear margins: 33 (52.4 %), 104 (68.0 %) and 142 (84.5 %), respectively (p < 0.001). It also allowed for a significantly higher probability of achieving both negative margins and depth of specimen <10 mm: 10 (15.9 %) cases, 47 (30.7 %) cases and 125 (74.4 %) cases, respectively (p < 0.001). In multivariate analysis, when compared with the use of previous colposcopy report or with colposcopy immediately before the LLETZ, DCV allowed for a significantly higher probability of negative margins (AOR: 4.61; 95 % CI: 2.37-8.99 and AOR: 2.55; 95 % CI: 1.47-4.41), combined negative margins and depth <75th percentile (AOR: 3.67; 95 % CI: 1.97-6.86 and AOR: 3.05; 95 % CI: 1.91-4.87) and combined negative margins and volume <75th percentile (AOR: 12.96; 95 % CI: 5.99-28.05 and AOR: 6.16; 95 % CI: 3.75-10.14), respectively. CONCLUSIONS: When used with the LLETZ procedure, DCV allows for optimal outcomes in terms of negative resection margins, and minimized depth and volume of the excised specimen; and should therefore be recommended. PMID- 23670209 TI - Irreversible bimolecular reactions with inertia: from the trapping to the target setting at finite densities. AB - We investigate numerically pseudo-first-order irreversible bimolecular reactions of the type A + B -> B between hard spheres undergoing event-driven Brownian dynamics. We study the encounter rate and the survival probability of A particles as functions of the packing fraction phi in the trapping (a single particle diffusing among static non-overlapping traps) and target (many traps diffusing in the presence of a single static target particle) settings, as well as in the case of diffusing traps and particles (full mobility). We show that, since inertial effects are accounted for in our simulation protocol, the standard Smoluchowski theory of coagulation of non-interacting colloids is recovered only at times greater than a characteristic time Deltat, marking the transition from the under damped to the over-damped regime. We show that the survival probability S(t) decays exponentially during this first stage, with a rate 1/tau0 is proportional to phi. Furthermore, we work out a simple analytical expression that is able to capture to an excellent extent the numerical results for t < Deltat at low and intermediate densities. Moreover, we demonstrate that the time constant of the asymptotic exponential decay of S(t) for diffusing traps and particles is k(S)( 1), where kS = 4pi(DA + DB)Rrho is the Smoluchowski rate. Detailed analyses of the effective decay exponent beta = d [log(-logS(t))]/d (logt) and of the steady state encounter rate reveal that the full mobility and trapping problem are characterized by very similar kinetics, rather different from the target problem. Our results do not allow one to ascertain whether the prediction S(t) is proportional to exp(-at(3/2)) (a = const.) as t -> infinity for the trapping problem in 3D is indeed recovered. In fact, at high density, S(t) is dominated by short encounter times, which makes it exceedingly hard to record the events corresponding to the exploration of large, trap-free regions. As a consequence, at high densities the steady-state rate simply tends to 1/tau0. Finally, we work out an analytical formula for the rate that shows a remarkable agreement with the numerics up phi = 0.4. PMID- 23670210 TI - microRNA-330 inhibits cell motility by downregulating Sp1 in prostate cancer cells. AB - microRNAs (miRNAs), small non-coding RNAs, have emerged as key regulators of a large number of genes. The present study aimed to explore novel biological functions of miR-330 in the human prostate cancer cell lines DU145 and PC3. We confirmed that miR-330 was downregulated and inversely correlated with specificity protein 1 (Sp1) expression. Overexpression of miR-330 by transfection of a chemically synthesized miR-330 mimic induced a reduction in expression levels of the Sp1 protein, accompanied by significant suppression of cellular migration and invasion capability. In addition, the Sp1-knockdown experiments presented similar phenomena. Finally, the luciferase reporter assay validated Sp1 as the direct target of miR-330. These findings indicate that miR-330 acts as an anti-metastatic miRNA in prostate cancer. PMID- 23670211 TI - Mycotoxin occurrence in feed and feed raw materials worldwide: long-term analysis with special focus on Europe and Asia. AB - During an 8-year period, 17 316 samples of feed and feed raw materials from all over the world were analysed for contamination with aflatoxins, ochratoxin A, zearalenone, deoxynivalenol and fumonisins. Overall, 72% of the samples tested positive for at least one mycotoxin and 38% were found to be co-contaminated. Mycotoxin concentrations were generally low and the majority of the samples were compliant with the most stringent EU guidance values or maximum levels for mycotoxins in feed. However, in their present state these regulations do not address co-contamination and associated risks. Long-term trends are difficult to establish as strong yearly variations were observed regarding mycotoxin prevalence and contamination levels. In some cases unusual weather conditions can be linked with high observed mycotoxin loads. An exception to this rule is South East Asia, where a steady increase of aflatoxin prevalence has been observed. The percentage of aflatoxin-positive samples in this region rose from 32% in 2005 to 71% in 2011. PMID- 23670212 TI - Large cell lymphoma: correlation of HIV status and prognosis with differentiation profiles assessed by immunophenotyping. AB - Diffuse large B cell lymphoma (DLBCL) and plasmablastic lymphoma (PBL) represent aggressive non-Hodgkin lymphomas, particularly in the setting of HIV infection. Since the introduction of highly active antiretroviral therapy (HAART), recent studies have documented improved survival outcome in patients with AIDS-related lymphomas. This study contributes a South African perspective by correlating the HIV status and prognosis of DLBCL and PBL with differentiation profiles assessed by immunophenotyping. Analysis of the morphologic, immunophenotypic and clinicopathologic features of 52 cases of DLBCL and 9 cases of de novo PBL was performed. The overall survival of patients with PBL was poorer than that of DLBCL (logrank p value 0.002). Despite HAART, the overall survival with DLBCL and HIV infection was significantly poorer than HIV negative patients with DLBCL (p value <0.001). Profound immunosuppression was evident in the HIV positive group as the mean CD4 count was 151 cells/mm(3) in DLBCL and 61 cells/mm(3) in PBL. HIV positive patients were significantly younger at presentation with greater likelihood of extranodal lymphoma. When Hans' and Muris' algorithmic stratification of DLBCL were applied, no statistical significance was demonstrated (p values 0.188 and 0.399 respectively). However, when Bcl-2 expression occurred in germinal center-type DLBCL (Hans' defined), improved survival was conferred by the germinal center immunophenotype (p value 0.007). The study demonstrates that DLBCL and PBL have significant potential for aggressive behaviour and poor outcome in the setting of profound immunosuppression due to HIV infection. Further studies are required to assess the effect of targeted-immunotherapy (Rituximab) in combination with recent amendment of the South African national antiretroviral treatment guidelines which has created tremendous potential for improved survival in patients with AIDS related non-Hodgkin B-cell lymphomas. PMID- 23670213 TI - Rutin, a bioflavonoid antioxidant protects rat pheochromocytoma (PC-12) cells against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. AB - Free radicals are widely known to be the major cause of human diseases such as neurodegenerative diseases, cancer, allergy and autoimmune diseases. Human cells are equipped with a powerful natural antioxidant enzyme network. However, antioxidants, particularly those originating from natural sources such as fruits and vegetables, are still considered essential. Rutin, a quercetin glycoside, has been proven to possess antioxidant potential. However, the neuroprotective effect of rutin in pheochromocytoma (PC-12) cells has not been studied extensively. Therefore, the present study was designed to establish the neuroprotective role of rutin as well as to elucidate the antioxidant mechanism of rutin in 6 hydroxydopamine (6-OHDA)-induced toxicity in PC-12 neuronal cells. PC-12 cells were pretreated with different concentrations of rutin for 4, 8 and 12 h and subsequently incubated with 6-OHDA for 24 h to induce oxidative stress. A significant cytoprotective activity was observed in rutin pretreated cells in a dose-dependent manner. Furthermore, there was marked activation of antioxidant enzymes including superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and total glutathione (GSH) in rutin pretreated cells compared to cells incubated with 6-OHDA alone. Rutin significantly reduced lipid peroxidation in 6 OHDA-induced PC-12 cells. On the basis of these observations, it was concluded that the bioflavonoid rutin inhibited 6-OHDA-induced neurotoxicity in PC-12 cells by improving antioxidant enzyme levels and inhibiting lipid peroxidation. PMID- 23670214 TI - Human-introduced long-term traditions in wild redfronted lemurs? AB - Behavioural traditions have only been described for a small subset of species, and the factors responsible for the maintenance of traditions over time are unclear. Redfronted lemurs are known to learn socially but traditions have not been described in the wild. We conducted a social diffusion experiment over three experimental years with artificial feeding boxes that could be opened in two different ways (pushing or pulling a door). Six out of 14 individuals that participated in at least 2 years exhibited a stable preference: five lemurs maintained a pull and one lemur a push preference, suggesting that habit formation and reinforcement learning may have lead to preferences over time. The remaining individuals exhibited fluctuating preferences and switched between showing a preference or no preference, but never switched between preferences. This instability might have been due to the low level of difficulty and/or the low object specificity of the task. The majority of lemurs additionally scrounged. Scrounging was not influenced by age, sex or success in manipulating the boxes. Thus, redfronted lemurs appear to use the two techniques flexibly but also scrounged opportunistically to get access to the rewards, indicating that traditions might be stabilized by multiple factors. PMID- 23670215 TI - Contagious yawning, social cognition, and arousal: an investigation of the processes underlying shelter dogs' responses to human yawns. AB - Studies of contagious yawning have reported inconsistent findings regarding whether dogs exhibit this behavior and whether it is mediated by social-cognitive processes or the result of physiological arousal. We investigated why some dogs yawn in response to human yawns; particularly, whether these dogs are exceptional in their ability to understand human social cues or whether they were more physiologically aroused. Sixty shelter dogs were exposed to yawning and nonyawning control stimuli demonstrated by an unfamiliar human. We took salivary cortisol samples before and after testing to determine the role of arousal in yawn contagion. Dogs were tested on the object-choice task to assess their sensitivity for interpreting human social cues. We found that 12 dogs yawned only in response to human yawns (i.e., appeared to exhibit yawn contagion), though contagious yawning at the population level was not observed. Dogs that exhibited yawn contagion did not perform better on the object-choice task than other dogs, but their cortisol levels remained elevated after exposure to human yawning, whereas other dogs had reduced cortisol levels following yawning stimuli relative to their baseline levels. We interpret these findings as showing that human yawning, when presented in a stressful context, can further influence arousal in dogs, which then causes some to yawn. Although the precise social-cognitive mechanisms that underlie contagious yawning in dogs are still unclear, yawning between humans and dogs may involve some communicative function that is modulated by context and arousal. PMID- 23670216 TI - Chlorophyll fluorescence kinetics, photosynthetic activity, and pigment composition of blue-shade and half-shade leaves as compared to sun and shade leaves of different trees. AB - The chlorophyll (Chl) fluorescence induction kinetics, net photosynthetic CO2 fixation rates P N, and composition of photosynthetic pigments of differently light exposed leaves of several trees were comparatively measured to determine the differences in photosynthetic activity and pigment adaptation of leaves. The functional measurements were carried out with sun, half-shade and shade leaves of seven different trees species. These were: Acer platanoides L., Ginkgo biloba L., Fagus sylvatica L., Platanus x acerifolia Willd., Populus nigra L., Quercus robur L., Tilia cordata Mill. In three cases (beech, ginkgo, and oak), we compared the Chl fluorescence kinetics and photosynthetic rates of blue-shade leaves of the north tree crown receiving only blue sky light but no direct sunlight with that of sun leaves. In these cases, we also determined in detail the pigment composition of all four leaf types. In addition, we determined the quantum irradiance and spectral irradiance of direct sunlight, blue skylight as well as the irradiance in half shade and full shade. The results indicate that sun leaves possess significantly higher mean values for the net CO2 fixation rates P N (7.8 10.7 MUmol CO2 m(-2) s(-1) leaf area) and the Chl fluorescence ratio R Fd (3.85 4.46) as compared to shade leaves (mean P N of 2.6-3.8 MUmol CO2 m(-2) s(-1) leaf area.; mean R Fd of 1.94-2.56). Sun leaves also exhibit higher mean values for the pigment ratio Chl a/b (3.14-3.31) and considerably lower values for the weight ratio total chlorophylls to total carotenoids, (a + b)/(x + c), (4.07 4.25) as compared to shade leaves (Chl a/b 2.62-2.72) and (a + b)/(x + c) of 5.18 5.54. Blue-shade and half-shade leaves have an intermediate position between sun and shade leaves in all investigated parameters including the ratio F v/F o (maximum quantum yield of PS2 photochemistry) and are significantly different from sun and shade leaves but could not be differentiated from each other. The mean values of the Chl fluorescence decrease ratio R Fd of blue-shade and half shade leaves fit well into the strong linear correlation with the net photosynthetic rates P N of sun and shade leaves, thus unequivocally indicating that the determination of the Chl fluorescence decrease ratio R Fd is a fast and indirect measurement of the photosynthetic activity of leaves. The investigations clearly demonstrate that the photosynthetic capacity and pigment composition of leaves and chloroplasts strongly depend on the amounts and quality of light received by the leaves. PMID- 23670218 TI - Metabolomic analysis of sun exposed skin. AB - It is very well known that exposure of skin to sun chronically accelerates the mechanism of aging as well as making it more susceptible toward skin cancer. This aspect of aging has been studied very well through genomics and proteomics tools. In this study we have used a metabolomic approach for the first time to determine the differences in the metabolome from full thickness skin biopsies from sun exposed and sun protected sites. We have primarily investigated the energy metabolism and the oxidative pathway in sun exposed skin. Biochemical pathway analysis revealed that energy metabolism in photoexposed skin is predominantly anaerobic. The study also validated the increased oxidative stress in skin. PMID- 23670217 TI - Diffusional conductances to CO2 as a target for increasing photosynthesis and photosynthetic water-use efficiency. AB - A key objective for sustainable agriculture and forestry is to breed plants with both high carbon gain and water-use efficiency (WUE). At the level of leaf physiology, this implies increasing net photosynthesis (A N) relative to stomatal conductance (g s). Here, we review evidence for CO2 diffusional constraints on photosynthesis and WUE. Analyzing past observations for an extensive pool of crop and wild plant species that vary widely in mesophyll conductance to CO2 (g m), g s, and foliage A N, it was shown that both g s and g m limit A N, although the relative importance of each of the two conductances depends on species and conditions. Based on Fick's law of diffusion, intrinsic WUE (the ratio A N/g s) should correlate on the ratio g m/g s, and not g m itself. Such a correlation is indeed often observed in the data. However, since besides diffusion A N also depends on photosynthetic capacity (i.e., V c,max), this relationship is not always sustained. It was shown that only in a very few cases, genotype selection has resulted in simultaneous increases of both A N and WUE. In fact, such a response has never been observed in genetically modified plants specifically engineered for either reduced g s or enhanced g m. Although increasing g m alone would result in increasing photosynthesis, and potentially increasing WUE, in practice, higher WUE seems to be only achieved when there are no parallel changes in g s. We conclude that for simultaneous improvement of A N and WUE, genetic manipulation of g m should avoid parallel changes in g s, and we suggest that the appropriate trait for selection for enhanced WUE is increased g m/g s. PMID- 23670219 TI - The association between obesity and outpatient visits for acute respiratory infections in Ontario, Canada. AB - OBJECTIVE: Recent evidence suggests that obesity increases the risk of severe outcomes following respiratory infection. It is less clear whether obesity is associated with the risk of being infected with influenza or other respiratory pathogens. Therefore, we examined the association between obesity and outpatient visits for acute respiratory infections (ARIs). DESIGN: We conducted a retrospective cohort study for a period of over 13 years on 104,665 individuals in Ontario, Canada who responded to population health surveys and agreed to linkage with health administrative data. Individuals aged 18-64 years who responded to a survey within 5 years prior to the start of an influenza season were included. Poisson regression, with adjustment for relevant confounders, was used to measure the association between self-reported body mass index (BMI) and outpatient visits for ARI. We conducted numerous sensitivity analyses to assess the robustness of our findings. RESULTS: We observed higher rates of outpatient visits for ARI during influenza season periods compared with normal weight individuals for those who were overweight (BMI 25-29.9; rate ratio (RR) 1.10; 95% confidence interval (95% CI) 1.07-1.13), obese class I (BMI 30-34.9; RR 1.17; 95% CI 1.13-1.22) and obese class II or III (BMI >=35; RR 1.19; 95% CI 1.12-1.25). Associations of a similar magnitude were observed during non-influenza season periods. Obesity was a greater risk factor for ARIs managed in emergency departments than physician offices. CONCLUSIONS: Obese individuals are at an increased risk of outpatient visits for ARI during both influenza and non influenza season periods, suggesting that the effect of obesity on the risk of respiratory infections is not limited to influenza. Interventions designed to reduce the prevalence of obesity may have the added benefit reducing the population burden of respiratory infections. PMID- 23670220 TI - Association of caesarean delivery with child adiposity from age 6 weeks to 15 years. AB - OBJECTIVES: o assess associations of caesarean section with body mass from birth through adolescence. DESIGN: ongitudinal birth cohort study, following subjects up to 15 years of age. SETTING AND PARTICIPANTS: Children born in 1991-1992 in Avon, UK who participated in the Avon Longitudinal Study of Parents and Children (ALSPAC) (n=10 219). OUTCOME MEASURES: PRIMARY OUTCOME: standardized measures of body mass (weight-for length z-scores at 6 weeks, 10 and 20 months; and body mass index (BMI) z-scores at 38 months, 7, 9, 11 and 15 years). Secondary outcome: categorical overweight or obese (BMI: 85th percentile) for age and gender, at 38 months, 7, 9, 11 and 15 years. RESULTS: Of the 10 219 children, 926 (9.06%) were delivered by caesarean section. Those born by caesarean had lower-birth weights than those born vaginally (-46.1 g, 95% confidence interval(CI): 14.6-77.6 g; P=0.004). In mixed multivariable models adjusting for birth weight, gender, parental body mass, family sociodemographics, gestational factors and infant feeding patterns, caesarean delivery was consistently associated with increased adiposity, starting at 6 weeks (+0.11 s.d. units, 95% CI: 0.03-0.18; P=0.005), through age 15 (BMI z-score increment+0.10 s.d. units, 95% CI: 0.001-0.198; P=0.042). By age 11 caesarean-delivered children had 1.83 times the odds of overweight or obesity (95% CI: 1.24-2.70; P=0.002). When the sample was stratified by maternal pre-pregnancy weight, the association among children born of overweight/obese mothers was strong and long-lasting. In contrast, evidence of an association among children born of normal-weight mothers was weak. CONCLUSION: Cesarean delivery is associated with increased body mass in childhood and adolescence. Research is needed to further characterize the association in children of normal weight women. Additional work is also needed to understand the mechanism underlying the association, which may involve relatively enduring changes in the intestinal microbiome. PMID- 23670221 TI - Fat depot-specific mRNA expression of novel loci associated with waist-hip ratio. AB - OBJECTIVE: We hypothesized that genes within recently identified loci associated with waist-hip ratio (WHR) exhibit fat depot-specific mRNA expression, which correlates with obesity-related traits. METHODS: Adipose tissue (AT) mRNA expression of 6 genes (TBX15/WARS2, STAB1, PIGC, ZNRF3 and GRB14) within these loci showing coincident cis-expression quantitative trait loci was measured in 222 paired samples of human visceral (vis) and subcutaneous (sc) AT. The relationship of mRNA expression levels with obesity-related quantitative traits was assessed by Pearson's correlation analyses. Multivariate linear relationships were assessed by generalized linear regression models. RESULTS: Whereas only PIGC, ZNFR3 and STAB1 mRNA expression in sc AT correlated nominally with WHR (P<0.05, adjusted for age and sex), mRNA expression of all studied genes in at least one of the fat depots correlated significantly with vis and/or sc fat area (P ranging from 0.05 to 4.0 * 10(6), adjusted for age and sex). Consistently, the transcript levels of WARS, PIGC and GRB14 were nominally associated with body mass index (BMI) (P ranging from 0.02 to 9.2 * 10(5), adjusted for age and sex). Moreover, independent of sex, obesity and diabetes status, differential expression between vis and sc AT was observed for all tested genes (P<0.01). Finally, the rs10195252 T-allele was nominally associated with increased GRB14 sc mRNA expression (P=0.025 after adjusting for age, sex and BMI). CONCLUSIONS: Our data including the inter-depot variability of mRNA expression suggests that genes within the WHR-associated loci might be involved in the regulation of fat distribution. PMID- 23670222 TI - Management of pain associated with the insertion of intrauterine contraceptives. AB - BACKGROUND: Most intrauterine contraception (IUC) placements do not require pain relief. However, small proportions of nulliparous (~17%) and parous (~11%) women experience substantial pain that needs to be proactively managed. This review critically evaluates the evidence for pain management strategies, formulates evidence-based recommendations and identifies data gaps and areas for further research. METHODS: A PubMed literature search was undertaken. Relevant articles on management of pain associated with IUC insertion, published in English between 1980 and November 2012, were identified using the following search terms: 'intrauterine contraception', 'insertion' and 'pain'. RCTs were included; further relevant articles were also identified and included as appropriate. RESULTS: Seventeen studies were identified and included: 12 RCTs and one non-randomized study of pre-insertion oral analgesia, cervical priming and local anaesthesia; one systematic review and one RCT on post-insertion analgesia and two non randomized studies on non-pharmacological interventions. There was no conclusive evidence that any prophylactic pharmacological intervention reduces pain associated with IUC insertion. However, most of the regimens studied were adopted from hysteroscopy or abortion and effectiveness in specific subsets of women has not been studied adequately. A systematic review found non-steroidal anti inflammatory agents (NSAID) to be effective in reactively treating post-insertion pain, but no benefit was found with prophylactic use. CONCLUSIONS: No prophylactic pharmacological intervention has been adequately evaluated to support routine use for pain reduction during or after IUC insertion. Women's anxiety about the procedure may contribute to higher levels of perceived pain, which highlights the importance of counselling, and creating a trustworthy, unhurried and professional atmosphere in which the experience of the provider also has a major role; a situation frequently referred to as 'verbal anaesthesia'. PMID- 23670223 TI - Sleep duration and metabolic syndrome in adult populations: a meta-analysis of observational studies. AB - OBJECTIVE: Epidemiological studies have repeatedly investigated the association between sleep duration and metabolic syndrome. However, the results have been inconsistent. This meta-analysis aimed to summarize the current evidence from cross-sectional and prospective cohort studies that evaluated this. DATA SOURCES: Relevant studies were identified by systematically searching the PubMed, Cochrane CENTRAL, EMBASE and PsycINFO databases through November 2012 without language restriction. STUDY SELECTION: We identified 12 cross-sectional studies with 76 027 participants including 14 404 cases of metabolic syndrome, and 3 cohort studies with 2055 participants and 283 incident cases of metabolic syndrome. RESULTS: For short sleep durations (<5 to 6 h), the odds ratios (OR) was 1.27 (95% confidence interval (CI)=1.10-1.48, I(2)=75.5%) in the 12 cross-sectional studies and 1.62 (95% CI=0.74-3.55, I(2)=71.4%) in the 3 cohort studies; for long sleep durations (>8 to 10 h), the OR was 1.23 (95% CI=1.02-1.49, I(2)=75.8%) in the 11 cross-sectional studies and 1.62 (95% CI=0.86-3.04, I(2)=0.0%) in the 2 cohort studies. CONCLUSIONS: Short and long sleep durations are risky behaviors for increasing the risk of metabolic syndrome and thus have important public health implications, as sleep habits are amenable to behavioral interventions. The available data are sparse, and further studies, especially longitudinal studies, are needed to facilitate a better understanding of these associations. PMID- 23670224 TI - Human mediastinal adipose tissue displays certain characteristics of brown fat. AB - BACKGROUND: The amount of intra-thoracic fat, of which mediastinal adipose tissue comprises the major depot, is related to various cardiometabolic risk factors. Autopsy and imaging studies indicate that the mediastinal depot in adult humans could contain brown adipose tissue (BAT). To gain a better understanding of this intra-thoracic fat depot, we examined possible BAT characteristics of human mediastinal in comparison with subcutaneous adipose tissue. MATERIALS AND METHODS: Adipose tissue biopsies from thoracic subcutaneous and mediastinal depots were obtained during open-heart surgery from 33 subjects (26 male, 63.7+/ 13.8 years, body mass index 29.3+/-5.1 kg m(-2)). Microarray analysis was performed on 10 patients and genes of interest confirmed by quantitative PCR (qPCR) in samples from another group of 23 patients. Adipocyte size was determined and uncoupling protein 1 (UCP1) protein expression investigated with immunohistochemistry. RESULTS: The microarray data showed that a number of BAT specific genes had significantly higher expression in the mediastinal depot than in the subcutaneous depot. Higher expression of UCP1 (24-fold, P<0.001) and PPARGC1A (1.7-fold, P=0.0047), and lower expression of SHOX2 (0.12-fold, P<0.001) and HOXC8 (0.14-fold, P<0.001) in the mediastinal depot was confirmed by qPCR. Gene set enrichment analysis identified two gene sets related to mitochondria, which were significantly more highly expressed in the mediastinal than in the subcutaneous depot (P<0.01). No significant changes in UCP1 gene expression were observed in the subcutaneous or mediastinal depots following lowering of body temperature during surgery. UCP1 messenger RNA levels in the mediastinal depot were lower than those in murine BAT and white adipose tissue. In some mediastinal adipose tissue biopsies, a small number of multilocular adipocytes that stained positively for UCP1 were observed. Adipocytes were significantly smaller in the mediastinal than the subcutaneous depot (cross-sectional area 2400+/-810 versus 3260+/-980 MUm(2), P<0.001). CONCLUSIONS: Human mediastinal adipose tissue displays some characteristics of BAT when compared with the subcutaneous depot at microscopic and molecular levels. PMID- 23670225 TI - Discordances in the application of different criteria for quantification of paediatric abdominal obesity: an analysis of two Swiss studies. AB - Several definitions of paediatric abdominal obesity have been proposed but it is unclear whether they lead to similar results. We assessed the prevalence of abdominal obesity using five different waist circumference-based definitions and their agreement with total body fat (TBF) and abdominal fat (AF). Data from 190 girls and 162 boys (Ballabeina), and from 134 girls and 113 boys (Kinder Sportstudie, KISS) aged 5-11 years were used. TBF was assessed by bioimpedance (Ballabeina) or dual energy X-ray absorption (KISS). On the basis of the definition used, the prevalence of abdominal obesity varied between 3.1 and 49.4% in boys, and 4.7 and 55.5% in girls (Ballabeina), and between 1.8 and 36.3% in boys and 4.5 and 37.3% in girls (KISS). Among children considered as abdominally obese by at least one definition, 32.0 (Ballabeina) and 44.7% (KISS) were considered as such by at least two (out of five possible) definitions. Using excess TBF or AF as reference, the areas under the receiver operating curve varied between 0.577 and 0.762 (Ballabeina), and 0.583 and 0.818 (KISS). We conclude that current definitions of abdominal obesity in children lead to wide prevalence estimates and should not be used until a standard definition can be proposed. PMID- 23670226 TI - Nonclinical parameters affecting primary cesarean rates in the United States. AB - OBJECTIVE: Cesarean is the single most common operation in United States and has reached epidemic proportions in recent decades. Our objective was to study the effect of nonclinical parameters on primary cesarean rates in a large contemporary population. STUDY DESIGN: We designed a retrospective multicenter study using data obtained from electronic medical records from 19 U.S. hospitals between 2005 and 2007 (Consortium on Safe Labor Database), which included 145,764 term, singleton, nonanomalous, vertex, live births that included labor. The impact of nonclinical parameters (patient and provider characteristics, time of delivery, institutional policies, and insurance type) was investigated using modified Poisson regression methodology and classification and regression tree analysis. RESULTS: There were 125,517 vaginal and 20,247 cesarean deliveries. Using the multivariable model, the nonclinical parameters with statistical significance for primary cesarean were delivery during evening hours, a male provider, public insurance, and nonwhite race (p < 0.001). CONCLUSIONS: Cesarean rates are associated with several nonclinical factors. Further investigation into these factors might help to develop strategies to reduce their influence and hence the rates of cesarean. PMID- 23670227 TI - Surfactant inadvertent loss using feeding catheters or endotracheal tubes. AB - OBJECTIVE: Surfactant has been administered through endotracheal tubes and also under spontaneous breathing using feeding catheters. We asked if different tube diameters and temperature may affect the amount of surfactant effectively delivered to the lungs. DESIGN: Bench study using high-accuracy, legal balance and tube/catheters of different diameters. We injected 200 mg of poractant alfa into the tubes followed by air boluses. Experiments were performed in triplicate, both at room temperature and at 37 degrees C. Surfactant and phospholipid remaining in the tube were calculated. RESULTS: Surfactant lost into thin catheters (11 +/- 0.4%) was more than that in endotracheal tubes (2-mm diameter: 3.6 +/- 1.4%; 2.5-mm diameter: 3.7 +/- 0.2%; 3-mm diameter: 5.2 +/- 0.4%; p < 0.001 at post hoc test in each comparison against the thin catheter). Similar findings were found at 37 degrees C (2-mm tube: 3.4 +/- 0.4%; 2.5-mm tube: 3.8 +/ 0.2%; 3-mm tube: 3.6 +/- 0.4%; feeding tube: 11.5 +/- 0.6%; p < 0.001 as above). In terms of lost phospholipids, 23 +/- 0.8 mg were lost in the feeding tubes; 7.2 +/- 2.9 mg (2-mm diameter), 7.4 +/- 0.4 mg (2.5-mm diameter), and 10.3 +/- 0.9 mg (3-mm diameter) of phospholipids remained in endotracheal tubes (p < 0.001 in each comparison against the feeding tube). CONCLUSIONS: Surfactant loss using thin catheters is around two to three times higher than using common endotracheal tubes; on average, 20 mg of phospholipids (11% of the administered dose) are lost. These data may be useful to refine surfactant dosing. PMID- 23670229 TI - The phenotypic expression of inflammatory bowel disease in patients with primary sclerosing cholangitis differs in the distribution of colitis. AB - BACKGROUND: Inflammatory bowel disease (IBD) associated with primary sclerosing cholangitis (PSC) is reported to be mild and prone to right-side predominance with rectal sparing. However, no dedicated studies evaluating patterns of presentation of liver disease with respect to IBD are available. METHODS: We performed a detailed histological examination of the colonic biopsies in the context of PSC, identifying 97 patients [89 with ulcerative colitis and ten with Crohn's disease (CD)] stratified into two groups, based on their initial disease presentation: hepatic/biliary (group 1-PSC-IBD; n=56) versus colonic (group 2-IBD PSC; n=41). RESULTS: Inflammatory bowel disease that preceded PSC had a tendency to have a "pan-colitis" distribution; this group included all patients with CD. Inflammatory bowel disease diagnosis that followed PSC presentation was more likely to be right-sided, sparing the descending, sigmoid and rectal regions (p=0.002). In both groups, colitis was mild with focal deep plasmacytosis and occasional mild cryptitis. Active cryptitis with crypt abscesses, surface erosion and ulceration were not identified in any of the patients. CONCLUSION: Colitis associated with PSC shows mild disease activity and the colitis pattern is associated with disease presentation, i.e. colitis preceding PSC (IBD-PSC cohort) typically have a pancolitic distribution, while colitis following PSC (PSC-IBD cohort) demonstrates right-sided predominance. Awareness by pathologists and clinicians of these patterns of inflammatory bowel disease is important and of use in directing appropriate investigations for patients. PMID- 23670230 TI - Association of biomarkers of lipid modification with functional and morphological indices of coronary stenosis severity in stable coronary artery disease. AB - Biomarkers of blood lipid modification and oxidative stress have been associated with increased cardiovascular morbidity. We sought to determine whether these biomarkers were related to functional indices of stenosis severity among patients with stable coronary artery disease. We studied 197 consecutive patients with stable coronary artery disease due to single vessel disease. Fractional flow reserve (FFR) <= 0.80 was assessed as index of a functionally significant lesion. Serum levels of secretory phospholipase A2 (sPLA2) activity, secretory phospholipase A2 type IIA (sPLA2-IIA), myeloperoxydase (MPO), lipoprotein associated phospholipase A2 (Lp-PLA2), and oxidized low-density lipoprotein (OxLDL) were assessed using commercially available assays. Patients with FFR > 0.8 had higher sPLA2 activity, sPLA2 IIA, and OxLDL levels than patients with FFR <= 0.8 (21.25 [16.03-27.28] vs 25.85 [20.58-34.63] U/mL, p < 0.001, 2.0 [1.5-3.4] vs 2.6 [2.0-3.4] ng/mL, p < 0.01; and 53.0 [36.0-71.0] vs 64.5 [50-89.25], p < 0.001 respectively). Patients with FFR > 0.80 had similar Lp-PLA2 and MPO levels versus those with FFR <= 0.8. sPLA2 activity, sPLA2 IIA significantly increased area under the curve over baseline characteristics to predict FFR <= 0.8 (0.67 to 0.77 (95 % confidence interval [CI]: 0.69-0.85) p < 0.01 and 0.67 to 0.77 (95 % CI: 0.69-0.84) p < 0.01, respectively). Serum sPLA2 activity as well as sPLA2-IIA level is related to functional characteristics of coronary stenoses in patients with stable coronary artery disease. PMID- 23670231 TI - Evaluation of heart failure biomarker tests: a survey of statistical considerations. AB - Biomarkers assessing cardiovascular function can encompass a wide range of biochemical or physiological measurements. Medical tests that measure biomarkers are typically evaluated for measurement validation and clinical performance in the context of their intended use. General statistical principles for the evaluation of medical tests are discussed in this paper in the context of heart failure. Statistical aspects of study design and analysis to be considered while assessing the quality of measurements and the clinical performance of tests are highlighted. A discussion of statistical considerations for specific clinical uses is also provided. The remarks in this paper mainly focus on methods and considerations for statistical evaluation of medical tests from the perspective of bias and precision. With such an evaluation of performance, healthcare professionals could have information that leads to a better understanding on the strengths and limitations of tests related to heart failure. PMID- 23670232 TI - Using bilaterally fascioperichondrial flaps with a distal and a proximal base combined with conventional otoplasty. AB - Prominent ears are the most common aesthetic abnormality of the external ear. Mustarde sutures and conchal setback are usually used for otoplasty, additional various cartilage-manipulation methods are also presented. One adjunctive technique that is often used involves the elevation of a fascial flap beneath which is sutured for additional cover, potentially reducing the risk of complications and recurrence. In the literature, this flap is traditionally raised with a proximal or distal base but it can be raised both distally and proximally with a number of advantages as we demonstrate. This article presents a technique to raise the fascioperichondrial flap with both a proximal and a distal base as an addition to conventional otoplasty. One hundred consecutive patients, followed up for at least 12 months, have been reviewed. One hundred ninety otoplasties were performed in 100 patients (10 unilateral), 65 women and 35 men. The mean age was 20.6 years, and the mean follow-up time was 16.3 months, respectively. No patient has developed skin necrosis or suture extrusion. In two patients (One bilateral and one unilateral for a total of three ears) a further procedure has been required to improve symmetry (1.5%). Using the retro auricular fascioperichondrial flap combined with other techniques offers good results and can be used as a standard procedure in the surgical treatment of prominent ears. PMID- 23670233 TI - Factor analyses of the Hospital Anxiety and Depression Scale: a Bayesian structural equation modeling approach. AB - PURPOSE: The latent structure of the Hospital Anxiety and Depression Scale (HADS) has caused inconsistent results in the literature. The HADS is frequently analyzed via maximum likelihood confirmatory factor analysis (ML-CFA). However, the overly restrictive assumption of exact zero cross-loadings and residual correlations in ML-CFA can lead to poor model fits and distorted factor structures. This study applied Bayesian structural equation modeling (BSEM) to evaluate the latent structure of the HADS. METHODS: Three a priori models, the two-factor, three-factor, and bifactor models, were investigated in a Chinese community sample (N = 312) and clinical sample (N = 198) using ML-CFA and BSEM. BSEM specified approximate zero cross-loadings and residual correlations through the use of zero-mean, small-variance informative priors. The model comparison was based on the Bayesian information criterion (BIC). RESULTS: Using ML-CFA, none of the three models provided an adequate fit for either sample. The BSEM two-factor model with approximate zero cross-loadings and residual correlations fitted both samples well with the lowest BIC of the three models and displayed a simple and parsimonious factor-loading pattern. CONCLUSIONS: The study demonstrated that the two-factor structure fitted the HADS well, suggesting its usefulness in assessing the symptoms of anxiety and depression in clinical practice. BSEM is a sophisticated and flexible statistical technique that better reflects substantive theories and locates the source of model misfit. Future use of BSEM is recommended to evaluate the latent structure of other psychological instruments. PMID- 23670234 TI - Natural compounds may open new routes to treatment of amyloid diseases. AB - Protein misfolding disorders, such as Alzheimer's disease and Parkinson's disease, have in common that a protein accumulates in an insoluble form in the affected tissue. The process of aggregation follows a mechanism of seeded polymerization. Although the toxic species is still not well defined, the process, rather than the end product, of fibril formation is likely the main culprit in amyloid toxicity. These findings suggest that therapeutic strategies directed against the protein misfolding cascade should focus on depleting aggregation intermediates rather than on large fibrillar aggregates. Recent studies involving natural compounds have suggested new intervention strategies. The polyphenol epi-gallocatechine-3-gallate (EGCG), the main polyphenol in Camilla sinensis, binds directly to a large number of proteins that are involved in protein misfolding diseases and inhibits their fibrillization. Instead, it promotes the formation of stable, spherical aggregates. These spherical aggregates are not cytotoxic, have a lower beta-sheet content than fibrils, and do not catalyze fibril formation. Correspondingly, epi-gallocatechine-3-gallate remodels amyloid fibrils into aggregates with the same properties. Derivatives of Orcein, which is a phenoxazine dye that can be isolated from the lichen Roccella tinctoria, form a second promising class of natural compounds. They accelerate fibril formation of the Alzheimer's disease-related amyloid-beta peptide. At the same time these compounds deplete oligomeric and protofibrillar forms of the peptide. These compounds may serve as proof-of-principle for the strategies of promoting and redirecting fibril formation. Both may emerge as two promising new therapeutic approaches to intervening into protein misfolding processes. PMID- 23670235 TI - Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development: the example of the novel anticancer agent ABT-751. AB - OBJECTIVE: ABT-751, a novel orally available antitubulin agent, is mainly eliminated as inactive glucuronide (ABT-751G) and sulfate (ABT-751S) conjugates. We performed a pharmacogenetic investigation of ABT-751 pharmacokinetics using in vitro data to guide the selection of genes for genotyping in a phase I trial of ABT-751. METHODS: UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) enzymes were screened for ABT-751 metabolite formation in vitro. Forty-seven cancer patients treated with ABT-751 were genotyped for 21 variants in these genes. RESULTS: UGT1A1, UGT1A4, UGT1A8, UGT2B7, and SULT1A1 were found to be involved in the formation of inactive ABT-751 glucuronide (ABT-751G) and sulfate (ABT-751S). SULT1A1 copy number (>2) was associated with an average 34% increase in ABT-751 clearance (P=0.044), an 18% reduction in ABT-751 AUC (P=0.045), and a 50% increase in sulfation metabolic ratios (P=0.025). UGT1A8 rs6431558 was associated with a 28% increase in glucuronidation metabolic ratios (P=0.022), and UGT1A4*2 was associated with a 65% decrease in ABT-751 C trough (P=0.009). CONCLUSION: These results might represent the first example of a clinical pharmacokinetic effect of the SULT1A1 copy number variant on the clearance of a SULT1A1 substrate. A-priori selection of candidate genes guided by in-vitro metabolic screening enhanced our ability to identify genetic determinants of interpatient pharmacokinetic variability. PMID- 23670237 TI - Effects of freezing and thawing on texture, microstructure and cell wall composition changes in papaya tissues. AB - BACKGROUND: During storage, frozen fruit may be thawed and refrozen many times before consumption, which may be extremely damaging to the texture of the frozen fruit and reverse the advantage of fast freezing. The effects of freezing and thawing on texture, microstructure and cell wall composition changes in papaya tissues were investigated. RESULTS: The frozen-thawed papayas had an increase in drip loss and a decrease in firmness with increasing number of freeze-thaw cycles. Light microscopy showed irregular shapes and cell damage in parenchyma cells of frozen-thawed papayas, whereas transmission electron microscopy showed loss of cell wall materials in middle lamella. Moreover, destruction of cell wall was observed after being subjected to five freeze-thaw cycles. These changes related with a significant decrease in alcohol-insoluble solids, Na2CO3- and 24% KOH-soluble fractions and an increase in the water-, EDTA- and 4% KOH-soluble fractions. This was due to a decrease in the molecular mass of pectic and hemicellulosic polymers in frozen-thawed papayas using high-performance size exclusion chromatography. CONCLUSION: The freezing and thawing processes caused fine structural damage and cell wall composition changes which contributed to a loss of drip volume and firmness of papaya tissues. PMID- 23670236 TI - Insulin resistance: an emerging link in Alzheimer's disease. AB - Relentless progression of Alzheimer's disease (AD) poses a grave situation for the biomedical community to tackle. Agents starting as hot favorites in clinical trials have failed in later stages and it is time we reconsidered our approaches to intervene the disease. Quite some interesting work in the last decade has introduced a new school of thought which factors in neuronal glycemic imbalance as a major component for the development of AD. Insulin resistance in the brain has brought forward subsequent sequelae which might work towards amyloid accretion and/or tau hyperphosphorylation. It is also pointed out that insulin works by distributing iron to neuronal tissue and an insulin resistant state throws it off gear leading to iron overloading of neurons which is ultimately detrimental. A relatively recent investigation finds the role of c-Jun-N-terminal kinase (JNK3) in AD which also seems to bear a link with insulin resistance. PMID- 23670238 TI - miR-150, p53 protein and relevant miRNAs consist of a regulatory network in NSCLC tumorigenesis. AB - microRNAs (miRNAs) are a class of non-coding small RNAs that act as negative regulators of gene expression by binding to the 3'-untranslated region (3'-UTR) of target mRNAs. Tumor protein p53, a transcriptional factor, plays an important role in the progression of tumorigenesis. miR-150 was the only miRNA predicted to target 3'-UTR of p53 by Targetscan. In order to investigate the function of miR 150, p53 and relevant miRNAs in non-small cell lung cancer (NSCLC), we constructed two expression vectors of p53 (pcDNA3.1-p53 and pcDNA3.1-p53-3'-UTR) and two report vectors (pGL3-p53-3'-UTR and pGL3-p53-3'-mUTR). The activity of luciferase transfected with miR-150 mimics was lower by 30% when compared to that of the miRNA-negative control (miRNA-NC). Moreover, the p53 protein was downregulated by at least 50% when miR-150 mimics were cotransfected with pcDNA3.1-p53-3'-UTR when compared to miRNA-NC. We also determined the expression of miR-150 and p53 in NSCLC patient tissue samples. The expression of miR-150 in T2 stage tissue samples was higher than that in T1 stage tissue samples. The corresponding target gene p53 was correlated with miR-150 expression. In the present study, we further analyzed the cell cycle distribution. The cells transfected with pcDNA3.1-p53 were significantly arrested in the G1 phase when compared to the control cells. When miR-150 mimics were cotransfected with pcDNA3.1-p53-3'-UTR, the percentage of cells in the G1 phase was significantly lower by 4% when compared to miRNA-NC. To identify miRNAs that are regulated by the p53 protein, qRT-PCR was performed after pcDNA3.1-p53 transfection. miR-34a, miR-184, miR-181a and miR-148 were upregulated significantly. However, there was no distinct difference in the expression of miR-10a, miR-182 and miR-34c. Our results showed that miR-150 targets the 3'-UTR of p53, and p53 protein promotes the expression of miRNAs which affect cell cycle progression. These findings suggest that miR-150, p53 protein and relevant miRNAs are members of a regulatory network in NSCLC tumorigenesis. PMID- 23670239 TI - New insights into store-independent Ca(2+) entry: secretory pathway calcium ATPase 2 in normal physiology and cancer. AB - Recent studies in secretory pathway calcium ATPases (SPCA) revealed novel functions of SPCA2 in interacting with store-operated Ca(2+) channel Orai1 and inducing Ca(2+) influx at the cell surface. Importantly, SPCA2-mediated Ca(2+) signaling is uncoupled from its conventional role of Ca(2+)-ATPase and independent of store-operated Ca(2+) signaling pathway. SPCA2-induced store independent Ca(2+) entry (SICE) plays essential roles in many important physiological processes, while unbalanced SICE leads to enhanced cell proliferation and tumorigenesis. Finally, we have summarized the clinical implication of SICE in oral cancer prognosis and treatment. Inhibition of SICE may be a new target for the development of cancer therapeutics. PMID- 23670240 TI - COX-2 regulates E-cadherin expression through the NF-kappaB/Snail signaling pathway in gastric cancer. AB - Cyclooxygenase-2 (COX-2) participates in cancer invasion and metastasis by decreasing the expression of E-cadherin. However, the molecular mechanisms through which COX-2 regulates E-cadherin expression and function have not yet been fully elucidated. The aim of this study was to investigate the possible molecular mechanisms through which COX-2 regulates E-cadherin expression in gastric cancer. The mRNA and protein expression of COX-2, nuclear factor-kappaB (NF-kappaB), Snail and E-cadherin was detected in gastric cancer cells by quantitative PCR and western blot analysis, respectively. The expression of these genes was also detected in healthy gastric mucosa and gastric cancer tissues by immunohistochemistry. We detected various levels of COX-2, nuclear factor-kappaB (NF-kappaB), Snail and E-cadherin expression in the normal gastric mucosa and cancer tissues; however, the expression patterns differed: the increased expression of COX-2, NF-kappaB and Snail was observed in the gastric cancer tissues, whereas there was a considerable reduction in E-cadherin expression in the cancer tissues compared to the normal gastric mucosa. The expression patterns of COX-2, NF-kappaB and Snail were similar. The increased expression of COX-2 in the gastric cancer tissues closely correlated with the increased expression of NF kappaB and Snail, but inversely correlated with the expression of E-cadherin. Treatment of the SGC7901 cells (which express high levels of COX-2) with celecoxib, a COX-2 inhibitor, not only led to a marked dose- and time-dependent decrease in the expression of COX-2, NF-kappaB and Snail, but also led to a significant increase in the expression of E-cadherin, and this was associated with a reduction in cell invasion. By contrast, the same treatment did not alter the expression of these genes in another gastric cancer cell line, MGC803 (which barely expresses COX-2). These data suggest that COX-2 regulates the expression of E-cadherin through the NF-kappaB and Snail signaling pathway in gastric cancer. PMID- 23670242 TI - Agent Orange as a risk factor for high-grade prostate cancer. AB - BACKGROUND: Agent Orange (AO) exposure (AOe) is a potential risk factor for the development of prostate cancer (PCa). However, it is unknown whether AOe specifically increases the risk of lethal PCa. The objective of this study was to determine the association between AOe and the risk of detecting high-grade PCa (HGPCa) (Gleason score >=7) on biopsy in a US Veteran cohort. METHODS: Risk factors included clinicodemographic and laboratory data from veterans who were referred for an initial prostate biopsy. Outcomes were defined as the presence versus the absence of PCa, HGPCa, or low-grade PCa (LGPCa) (Gleason score <=6) in biopsy specimens. Risk among AOe veterans relative to unexposed veterans was estimated using multivariate logistic regression. Separate models were used to determine whether AOe was associated with an increased risk of PCa, HGPCa, or LGPCa. RESULTS: Of 2720 veterans who underwent biopsy, PCa was diagnosed in 896 veterans (32.9%), and 459 veterans (16.9%) had HGPCa. AOe was associated with a 52% increase in the overall risk of detecting PCa (adjusted odds ratio, 1.52; 95% confidence interval, 1.07-2.13). AOe did not confer an increase in the risk of LGPCa (adjusted odds ratio, 1.24; 95% confidence interval, 0.81-1.91), although a 75% increase in the risk of HGPCa was observed (adjusted odds ratio, 1.75; 95% confidence interval, 1.12-2.74). AOe was associated with a 2.1-fold increase (95% confidence interval, 1.22-3.62; P < .01) in the risk of detecting PCa with a Gleason score >=8. CONCLUSIONS: The current results indicated that an increased risk of PCa associated with AOe is driven by an increased risk of HGPCa in men who undergo an initial prostate biopsy. These findings may aid in improved PCa screening for Vietnam-era veterans. PMID- 23670244 TI - Worldwide dietary therapies for adults with epilepsy and other disorders. AB - During the 3rd International Symposium on Dietary Therapies held in Chicago, Illinois, there was a first-ever, half-day session devoted to the management of adults with epilepsy and other disorders with dietary treatments. Speakers from 3 different continents shared their successes, challenges, and future directions in their management of these patients. Diets used to treat adults included the classic ketogenic diet, the modified Atkins diet, and a low glycemic index treatment. The utility of dietary therapies was demonstrated not only in patients with epilepsy but also patients with propriospinal myoclonus, astrocytoma, type 2 diabetes, obesity, hyperlipidemia, and metabolic disorder. The session provided evidence that dietary therapies are safe and effective in adults. PMID- 23670243 TI - 1.5 V battery driven reduced graphene oxide-silver nanostructure coated carbon foam (rGO-Ag-CF) for the purification of drinking water. AB - A porous carbon foam (CF) electrode modified with a reduced graphene oxide-Ag (rGO-Ag) nanocomposite has been fabricated to purify water. It can perform as an antibacterial device by killing pathogenic microbes with the aid of a 1.5 V battery, with very little power consumption. The device is recycled ten times with good performance for long term usage. It is shown that the device may be implemented as a fast water purifier to deactivate the pathogens in drinking water. PMID- 23670245 TI - Possessed by evil spirits: a history of seizures in infancy. AB - For 4 millennia, seizures in infancy were believed to be of supranatural origin and were dealt with by incantations, exorcising rituals, and protective amulets. Instead of pursuing scientific research into their causes, gods, devils, mothers, wet nurses, midwives, or obstetricians were blamed. Help from protective gods and patron saints was sought, and amulets against the "evil eye" were recommended by physicians, mostly in the form of necklaces. Infants were despised and hidden away from the community. Among the medical conditions associated with seizures, those most prominent were dentition, gastrointestinal irritation, and "bad" mother's milk. Medical treatment consisted of cutting or rubbing the gums with a hare's brain during dentition, and applying peony or theriac. Even during the 20th century, when laboratory methods, electroencephalography, brain imaging, and powerful pharmaceutical techniques were available, effective treatment evolved empirically rather than systematically. PMID- 23670246 TI - The quantitative effect of serum albumin, serum urea, and valproic acid on unbound phenytoin concentrations in children. AB - Dosing of phenytoin is difficult in children because of its variable pharmacokinetics and protein binding. Possible covariates for this protein binding have mostly been univariately investigated in small, and often adult, adult populations. We conducted a study to identify and quantify these covariates in children. We extracted data on serum phenytoin concentrations, albumin, triglycerides, urea, total bilirubin and creatinine concentrations and data on coadministration of valproic acid or carbamazepine in 186 children. Using nonlinear mixed effects modeling the effects of covariates on the unbound phenytoin fraction were investigated. Serum albumin, serum urea concentrations, and concomitant valproic acid use significantly influenced the unbound phenytoin fraction. For clinical practice, we recommend that unbound phenytoin concentrations are measured routinely. However, if this is impossible, we suggest to use our model to calculate the unbound concentration. In selected children, close treatment monitoring and dose reductions should be considered to prevent toxicity. PMID- 23670247 TI - African Child Neurology Association (ACNA): from Cape to Cairo. PMID- 23670248 TI - Restricted calorie ketogenic diet for the treatment of glioblastoma multiforme. AB - Glioblastoma multiforme is the most common malignant primary brain tumor in adults and generally considered to be universally fatal. Glioblastoma multiforme accounts for 12% to 15% of all intracranial neoplasms and affects 2 to 3 adults per every 100,000 in the United States annually. In children glioblastoma multiforme accounts for only approximately 7% to 9% of central nervous system tumors. The mean survival rate in adults after diagnosis ranges from 12 to 18 months with standard therapy and 3 to 6 months without therapy. The prognosis in children is better compared to adult tumor onset with a mean survival of approximately 4 years following gross total surgical resection and chemotherapy. There have been few advances in the treatment of glioblastoma multiforme in the past 40 years beyond surgery, radiotherapy, chemotherapy, and corticosteroids. For this reason a restrictive calorie ketogenic diet, similar to that used in children to control drug resistant seizure activity, has been advanced as an alternative adjunctive treatment to help prolonged survival. This article reviews the science of tumor metabolism and discusses the mechanism of calorie restriction, cellular energy metabolism, and how dietary induced ketosis can inhibit cancer cell's energy supply to slow tumor growth. PMID- 23670250 TI - Periodic Eye Movements and Epileptic Spasms in West Syndrome. AB - In addition to the typical infantile spasm symptoms, several other symptoms, such as eye movements, have been reported to be associated with infantile spasms, although the relationship between the typical spasms and these other events is not fully understood. Here we present a case with West syndrome. We observed the appearance of periodic eye movements followed by the onset of typical spasms and the appearance/disappearance of periodic eye movements during withdrawal/increases of vigabatrin. We believe that the case strongly supports the notion that periodic eye movements and typical spasms represent a spectrum of symptoms related to the same phenomenon of West syndrome. PMID- 23670251 TI - Intractable vomiting antecedent to optic neuritis: an early clinical clue to neuromyelitis optica. PMID- 23670249 TI - Childhood basilar artery occlusion: a report of 5 cases and review of the literature. AB - Basilar artery occlusion has poor outcome in adults; little is known regarding outcomes in children. Whether intra-arterial treatments improve adult outcomes is controversial. Safety and efficacy of intra-arterial treatments in children are unknown. We report 5 cases of basilar artery occlusion and review published cases. We estimated National Institute of Health Stroke Scale (NIHSS) and modified Rankin Score (mRS) of published cases, compared scores between non-intra arterial treatments and intra-arterial treatments groups, and examined the correlation between NIHSS and mRS. Of our cases, 4 had good outcomes and 1 died. Of 63 published cases, 45 had no intra-arterial treatments and 18 had intra arterial treatments. In the non-intra-arterial treatments group 24 had good outcomes. In the intra-arterial treatments group 13 had good outcomes. There was strong correlation between the NIHSS and the mRS. Children with basilar artery occlusion have better outcomes than adults. Certain children with basilar artery occlusion may be treated conservatively. A registry for childhood basilar artery occlusion is urgently needed. PMID- 23670252 TI - Traumatic brain injury and diet. AB - Increasing attention is being paid to nutritional and metabolic management of traumatic brain injury patients. The gross metabolic changes that occur after injury have been found to be influenced by both macronutrients, that is, dietary ratios of fat, carbohydrates, and protein, and micronutrients, for example, vitamins and minerals. Alterations in diet and nutritional strategies have been shown to decrease both morbidity and mortality after injury. Despite this knowledge, defining optimal nutritional support following traumatic brain injury continues to be an ongoing challenge. PMID- 23670254 TI - Diagnosis and management of epilepsy associated with hypothalamic hamartoma: an evidence-based systematic review. AB - The main objective was to review the evidence for management of epilepsy associated with hypothalamic hamartomas. We performed a systemic review of the literature through July 2012 that studied patients with hypothalamic hamartomas and related epilepsy. Articles meeting selection criteria were rated according to the American Academy of Neurology classification of evidence scheme. Recommendations were linked to the strength of the evidence and as follows: (a) precocious puberty is associated more with the pedunculated type and epilepsy typified by gelastic seizures with the sessile form of hypothalamic hamartomas (class III); (b) significant behavioral and cognitive deficits are associated with patients with hypothalamic hamartomas (class III); (c) video electroencephalography (EEG) findings are extremely variable particularly across the different ages and do not affect surgical outcome (class III); d) various surgical techniques (transcallosal and endoscopic resection) resulted in 49% to 54% seizure freedom, 15% with a pterional approach as well as about 40% with radiosurgery (class III). PMID- 23670253 TI - How does the ketogenic diet work? Four potential mechanisms. AB - The ketogenic diet and its newer variants are clinically useful in treating epilepsy. They can also have antiepileptogenic properties and can eventually have a role in treating other neurologic and nonneurologic conditions. Despite being nearly a century old, identifying the molecular underpinnings of the ketogenic diet has been challenging. However, recent studies provide experimental evidence for 4 distinct mechanisms that could contribute to the antiseizure and other beneficial effects of these diets. These mechanisms include carbohydrate reduction, activation of adenosine triphosphate (ATP)-sensitive potassium channels by mitochondrial metabolism, inhibition of the mammalian target of rapamycin pathway, and inhibition of glutamatergic excitatory synaptic transmission. PMID- 23670255 TI - BRCA1 and p53 regulate critical prostate cancer pathways. AB - BACKGROUND: Loss or mutations of the BRCA1 gene are associated with increased risk of breast and ovarian cancers and with prostate cancer (PCa) aggressiveness. Previously, we identified GADD153 as a target of BRCA1 protein, which increases doxorubicin sensitivity in human p53 -/- PCa cells (PC3). Considering that p53 is a crucial target in cancer therapy, in this work we investigated p53 role in the regulation of transcription of GADD153. METHODS: We performed reverse transcription quantitative PCR (RT-qPCR), western blot and luciferase assays to analyze GADD153 and/or BRCA1 expression in response to ultraviolet or doxorubicin exposure in PC3 p53 stable-transfected cells and LNCaP (p53+/+) cells. BRCA1 protein recruitment to GADD153 promoter was studied by chromatin immunoprecipitation-qPCR. To assess expression of BRCA1 and/or p53 target genes, we used a panel of stable-transfected PCa cell lines. We finally analyzed these genes in vivo using BRCA1-depleted PCa xenograft models. RESULTS: We found that GADD153 was highly induced by doxorubicin in PC3 cells; however, this response was totally abolished in LNCaP (p53wt) and in p53-restituted PC3 cells. Furthermore, BRCA1 protein associates to GADD153 promoter after DNA damage in the presence of p53. Additionally, we demonstrated that BRCA1 and/or p53 modulate genes involved in DNA damage and cell cycle regulation (cyclin D1, BLM, BRCA2, DDB2, p21(WAF1/CIP1), H3F3B, GADD153, GADD45A, FEN1, CCNB2), EMT (E-cadherin, beta-catenin, vimentin, fibronectin, slug, snail) and Hedgehog pathways (SHH, IHH, DHH, Gli1, PATCH1). Furthermore, xenograft studies demonstrated that BRCA1 knockdown in PC3 cells increased tumor growth and modulated these genes in vivo. CONCLUSIONS: Although BRCA1 induces GADD153 in a p53 independent manner, p53 abolished GADD153 induction in response to DNA damage. In addition, several important PCa targets are modulated by BRCA1 and p53. Altogether, these data might be important to understand the therapy response of PCa patients. PMID- 23670256 TI - Oxidative stress in prostate cancer: changing research concepts towards a novel paradigm for prevention and therapeutics. AB - A mounting body of evidence suggests that increased production of reactive oxygen species (ROS) is linked to aging processes and to the etiopathogenesis of aging related diseases, such as cancer, diabetes, atherosclerosis and degenerative diseases like Parkinson's and Alzheimer's. Excess ROS are deleterious to normal cells, while in cancer cells, they can lead to accelerated tumorigenesis. In prostate cancer (PC), oxidative stress, an innate key event characterized by supraphysiological ROS concentrations, has been identified as one of the hallmarks of the aggressive disease phenotype. Specifically, oxidative stress is associated with PC development, progression and the response to therapy. Nevertheless, a thorough understanding of the relationships between oxidative stress, redox homeostasis and the activation of proliferation and survival pathways in healthy and malignant prostate remains elusive. Moreover, the failure of chemoprevention strategies targeting oxidative stress reduced the level of interest in the field after the recent negative results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) trial. Therefore, a revisit of the concept is warranted and several key issues need to be addressed: The consequences of changes in ROS levels with respect to altered redox homeostasis and redox-regulated processes in PC need to be established. Similarly, the key molecular events that cause changes in the generation of ROS in PC and the role for therapeutic strategies aimed at ameliorating oxidative stress need to be identified. Moreover, the issues whether genetic/epigenetic susceptibility for oxidative stress-induced prostatic carcinogenesis is an individual phenomenon and what measurements adequately quantify prostatic oxidative stress are also crucial. Addressing these matters will provide a more rational basis to improve the design of redox-related clinical trials in PC. This review summarizes accepted concepts and principles in redox research, and explores their implications and limitations in PC. PMID- 23670257 TI - [Do high potency statins lead to acute kidney injury?--Benefit of treatment with high dose statins has to be clarified]. PMID- 23670258 TI - [Pathology: pacemaker of advances in medicine]. PMID- 23670259 TI - [CEUS--a robust method in daily clinical practice? A six month retrospective analysis]. AB - BACKGROUND: CEUS is a relatively new imaging method with growing use and broadening applications. It shows excellent accuracy with high negative and positive predictive values under study conditions. It is not well known, whether the study results can be reproduced in daily clinical practice. METHODS: Retrospective analysis of all consecutive CEUS-exams at our institution during a six month period. RESULTS: 68% of CEUS-exams were of the liver. 83% (197 exams) concerned the characterisation of focal lesions. 95% of focal lesions could be clarified via CEUS. In 44% of the exams, CEUS changed the diagnosis of B-mode-US, in 74% of exams, CEUS was the final imaging method. We found a 64% concordance to cross sectional imaging and a 77% concordance to histology, when available. CONCLUSION: CEUS performance in daily clinical practice is comparable to controlled study conditions. CEUS is therefore a robust imaging method. PMID- 23670260 TI - [Recurrent duodenal ulcer bleeding as the first manifestation of a solid pseudopapillary neoplasm of the pancreas with hepatic metastases]. AB - HISTORY AND ADMISSION FINDINGS: In a 17-year-old girl recurrent duodenal ulcer bleeding had led to severe anemia. INVESTIGATIONS: Sonography and computed tomography revealed a partially cystic tumour of the pancreatic head and suspicious hepatic lesions. TREATMENT AND PATHOLOGICAL DIAGNOSIS: A partial duodenopancreatectomy was performed and two liver metastases were resected. Histological examination of the resected pancreatic specimen revealed a solid pseudopapillary neoplasm of the pancreas (SPN) with hepatic metastases. CLINICAL COURSE AND PROGNOSIS: The seven remaining liver metastases were removed in a second procedure (right hepatectomy). One year later two new liver metastases were treated by radiofrequency ablation. Two years after the initial operation, the patient is well and tumor-free. CONCLUSION: SPN is a rare cystic tumor that is mainly found in young women. Direct tumor infiltration of stomach or duodenum can cause gastrointestinal bleedings in rare cases. Resection of the primary tumor and surgical or interventional removal of metastases are the treatment of choice. PMID- 23670261 TI - [New developments in the classification of malign tumors]. AB - In recent years, considerable enthusiasm has come up as to the diagnostic and therapeutic possibilities of personalized medicine. This enthusiam has put out of focus to which extent individualized therapy today is possible by consequently using different tumor classifications. Theses possibilities will be demonstrated briefly, especially with respect to the TNM classification, and will be discussed with regard to actual and future innovations. PMID- 23670262 TI - [33-year-old woman with upper abdominal pain]. PMID- 23670263 TI - [Molecular diagnostics in pathology]. AB - Tissue-based molecular diagnostics is a fast growing diagnostic field, which already complements morphologic classifications in many cases. Pathology based molecular diagnosis is performed almost exclusively on paraffin embedded material and always in conjunction with histopathology. Besides the classic field of tissue based detection of pathogenic organisms such as bacteria, viruses and fungi, molecular diagnostics of tumor tissue is one of the current hot topics in oncology. In this context the detection of predictive molecular biomarkers, such as specific mutations, allows patient stratification for individually tailored treatment strategies and thereby is one of the key components of individualized patient care in oncology. The rapidly growing number of clinically relevant predictive biomarkers together with impressive technical advances, specifically the development of massive parallel sequencing, will modify the care of patients with malignant diseases. Pathology, therefore, has returned in the very center of interdisciplinary patient care. PMID- 23670264 TI - [Research biobanks--development and structure]. PMID- 23670265 TI - [Clinical studies in oncology--a challenge for clinical and academic pathology]. PMID- 23670266 TI - Consequences of a multi-generation exposure to uranium on Caenorhabditis elegans life parameters and sensitivity. AB - The assessment of toxic effects at biologically and ecologically relevant scales is an important challenge in ecosystem protection. Indeed, stressors may impact populations at much longer term than the usual timescale of toxicity tests. It is therefore important to study the evolutionary response of a population under chronic stress. We performed a 16-generation study to assess the evolution of two populations of the ubiquitous nematode Caenorhabditis elegans in control conditions or exposed to 1.1 mM of uranium. Several generations were selected to assess growth, reproduction, survival, and dose-responses relationships, through exposure to a range of concentrations (from 0 to 1.2 mM U) with all endpoints measured daily. Our experiment showed an adaptation of individuals to experimental conditions (increase of maximal length and decrease of fecundity) for both populations. We also observed an increase of adverse effects (reduction of growth and fertility) as a function of uranium concentration. We pointed out the emergence of population differentiation for reproduction traits. In contrast, no differentiation was observed on growth traits. Our results confirm the importance of assessing environmental risk related to pollutant through multi generational studies. PMID- 23670267 TI - Retrospective estimation of population-level effect of pollutants based on local adaptation and fitness cost of tolerance. AB - We present a novel framework for estimating site-specific effects of pollutants on natural populations. Our method is based on fitness optimization and uses observed differences in tolerance (sensitivity) to a particular pollutant between populations at contaminated and uncontaminated sites (i.e., target and reference populations). In addition, the method uses laboratory estimates of the fitness cost of tolerance, that is, the reduction of population growth rate (fitness) of a target population compared to that of a reference population when both are maintained in uncontaminated conditions. As a case study, we applied this framework to analyze observed genetic differentiation in tolerance to the pyrethroid insecticide fenvalerate between Daphnia galeata populations in Lake Kasumigaura and an adjacent agricultural pond. The estimated exposure level at the contaminated site was about 0.015 MUg/L, and the population-level risk corresponded to about a 24 % reduction of the intrinsic rate of natural increase. PMID- 23670268 TI - Growth and phenolic compounds of Lactuca sativa L. grown in a closed-type plant production system with UV-A, -B, or -C lamp. AB - BACKGROUND: The production of high-quality crops based on phytochemicals is a strategy for accelerating the practical use of plant factories. Previous studies have demonstrated that ultraviolet (UV) light is effective in improving phytochemical production. This study aimed to determine the effect of various UV wavelengths on growth and phenolic compound accumulation in lettuce (Lactuca sativa L.) grown in a closed-type plant production system. RESULTS: Seven days, 1 day and 0.25 day were determined as the upper limit of the irradiation periods for UV-A, -B, and -C, respectively, in the lettuce based on physiological disorders and the fluorescence parameter F(v)/F(m). Continuous UV-A treatment significantly induced the accumulation of phenolic compounds and antioxidants until 4 days of treatment without growth inhibition, consistent with an increase in phenylalanine ammonia lyase (PAL) gene expression and PAL activity. Repeated or gradual UV-B exposure yielded approximately 1.4-3.6 times more total phenolics and antioxidants, respectively, than the controls did 2 days after the treatments, although both treatments inhibited lettuce growth. Repeated UV-C exposure increased phenolics but severely inhibited the growth of lettuce plants. CONCLUSION: Our data suggest that UV irradiation can improve the accumulation of phenolic compounds with antioxidant properties in lettuce cultivated in plant factories. PMID- 23670269 TI - Dissociations between vision for perception and vision for action depend on the relative availability of egocentric and allocentric information. AB - In three experiments, we scrutinized the dissociation between perception and action, as reflected by the contributions of egocentric and allocentric information. In Experiment 1, participants stood at the base of a large-scale one tailed version of a Muller-Lyer illusion (with a hoop) and either threw a beanbag to the endpoint of the shaft or verbally estimated the egocentric distance to that location. The results confirmed an effect of the illusion on verbal estimates, but not on throwing, providing evidence for a dissociation between perception and action. In Experiment 2, participants observed a two-tailed version of the Muller-Lyer illusion from a distance of 1.5 m and performed the same tasks as in Experiment 1, yet neither the typical illusion effects nor a dissociation became apparent. Experiment 3 was a replication of Experiment 1, with the difference that participants stood at a distance of 1.5 m from the base of the one-tailed illusion. The results indicated an illusion effect on both the verbal estimate task and the throwing task; hence, there was no dissociation between perception and action. The presence (Exp. 1) and absence (Exp. 3) of a dissociation between perception and action may indicate that dissociations are a function of the relative availability of egocentric and allocentric information. When distance estimates are purely egocentric, dissociations between perception and action occur. However, when egocentric distance estimates have a (complementary) exocentric component, the use of allocentric information is promoted, and dissociations between perception and action are reduced or absent. PMID- 23670270 TI - US hospital charges vary wildly, Medicare data show. PMID- 23670271 TI - Only 5% of British people have made advance care plans, survey finds. PMID- 23670272 TI - Opportunistic screening for depression can improve carers' health, says college. PMID- 23670273 TI - Pre-activation of the p53 pathway through Nutlin-3a sensitises sarcomas to drozitumab therapy. AB - The present study evaluated the efficacy of drozitumab, a human monoclonal agonistic antibody directed against death receptor 5 (DR5), as a new therapeutic avenue for the targeted treatment of bone and soft-tissue sarcomas. The antitumour activity of drozitumab as a monotherapy or in combination with Nutlin 3a was evaluated in a panel of sarcoma cell lines in vitro and human sarcoma patient samples ex vivo. Knockdown experiments were used to investigate the central role of p53 as a regulator of drozitumab cytotoxicity. Pre-activation of the p53 pathway through Nutlin-3a upregulated DR5, subsequently sensitising sarcoma cell lines and human sarcoma specimens to the pro-apoptotic effects of drozitumab. Silencing of p53 strongly decreased DR5 mRNA expression resulting in abrogation of drozitumab-induced apoptosis. Our study provides the first pre clinical evaluation of combination therapy using p53-activating agents with drozitumab to further sensitise sarcomas to the cytotoxic effects of DR5 antibody therapy. PMID- 23670274 TI - Replacement of the C6ORF66 assembly factor (NDUFAF4) restores complex I activity in patient cells. AB - Disorders of the oxidative phosphorylation (OXPHOS) system frequently result in a severe multisystem disease with the consequence of early childhood death. Among these disorders, isolated complex I deficiency is the most frequently diagnosed, accounting for one-third of all cases of respiratory chain deficiency. We chose to focus on complex I deficiency, caused by mutation in the assembly factor chromosome 6, open reading frame 66 (C6ORF66; NADH dehydrogenase [ubiquinone] complex I assembly factor 4 [NDUFAF4]) protein. We used the approach of cell- and organelle-directed protein/enzyme replacement therapy, with the transactivator of transcription (TAT) peptide as the moiety delivery system. This step will enable us to deliver the wild-type assembly factor C6ORF66 into patient cells and their mitochondria, leading to the proper assembly and function of complex I and, as a result, to a functional OXPHOS system. We designed and constructed the TAT-ORF fusion protein by gene fusion techniques, expressed the protein in an Escherichia coli expression system and highly purified it. Our results indicate that TAT-ORF enters patients' cells and their mitochondria rapidly and efficiently. TAT-ORF is biologically active and led to an increase in complex I activity. TAT-ORF also increased the number of patient cells and improved the activity of their mitochondria. Moreover, we observed an increase in ATP production, a decrease in the content of mitochondria and a decrease in the level of reactive oxygen species. Our results suggest that this approach of protein replacement therapy for the treatment of mitochondrial disorders is a promising one. PMID- 23670276 TI - Salt-inducible kinase 1 is involved in high glucose-induced mesangial cell proliferation mediated by the ALK5 signaling pathway. AB - High glucose levels can induce mesangial cell proliferation and extracellular matrix (ECM) accumulation through the type I activin receptor-like kinase 5 (ALK5) signaling pathway. Salt-inducible kinase 1 (SIK1) prevents fibrosis by downregulating ALK5, while the expression level of the SIK1 protein itself is downregulated by glucose in neuronal cells following ischemia. In this study, we investigated the correlation between SIK1 and the ALK5 signaling pathway in a rat glomerular mesangial cell line (HBZY-1 cells). We found that high glucose levels downregulated the expression level of SIK1 and suppressed the phosphorylation of SIK1 at Thr-182. The downregulation of SIK1 by high glucose was accompanied by the activation of the ALK5 signaling pathway, while the overexpression of SIK1 in the HBZY-1 cells resulted in a decrease in the ALK5 protein level, as well in the levels of its downstream targets, including fibronectin and plasminogen activator inhibitor type I. In conclusion, high glucose may activate the ALK5 signaling pathway by downregulating SIK1, and SIK1 may be a protective factor against cellular proliferation and ECM accumulation in glomerular mesangial cells under high glucose conditions. PMID- 23670275 TI - A preformed antibiotic-loaded spacer for treatment for septic arthritis of the shoulder. AB - BACKGROUND: Total shoulder arthroplasty infections are rare, depending on the use of antibiotic prophylaxis, the local blood supply, the axial load gradient and the proximal location of the shoulder. The purpose of this study was to evaluate the results of treatment for infections in total shoulder arthroplasty and septic arthritis using a preformed antibiotic-loaded spacer. MATERIALS AND METHODS: Seven shoulders in as many patients were treated for infected arthroplasty or septic arthritis without previous surgery. A preformed antibiotic-loaded spacer was always applied. Patients were evaluated at the final follow-up with the Constant Score (CS), the Secec Elbow Score (SES), and the American Shoulder and Elbow Society Score (ASESS). RESULTS: The mean follow-up was 40, 71 months after spacer implant. Infection was always confirmed preoperatively by the leukocyte and neutrophil counts in the aspirated synovial fluid, and intra-operative biopsy and pathologic analysis. Positive bacterial cultures were found in 5 cases: 3 MRSA and 2 Staphylococcus epidermidis. The mean SES increased from 34.43 before spacer implant to 77.29 at final follow-up, ASESS ranged from 14.86 to 21.14, and CS from 40.28 to 79.14. CONCLUSION: A preformed antibiotic-loaded spacer is intended to release gentamicin alone, but we can consider adding vancomycin to increase antibiotic spectrum. An early diagnosis and an immediate treatment can prevent a persistent infection and severe soft-tissue damage. The use of a preformed antibiotic spacer allows maintaining joint function at the intermediate stage in two-stage treatment. PMID- 23670277 TI - Another case of "European hantavirus pulmonary syndrome" with severe lung, prior to kidney, involvement, and diagnosed by viral inclusions in lung macrophages. AB - Puumala virus (PUUV) is considered a classic Old World etiologic agent of nephropathia epidemica (NE), or hemorrhagic fever with renal syndrome (HFRS). HFRS is considered to be distinct from hantavirus (cardio-)pulmonary syndrome (HPS or HCPS), described in the New World. Here, we report a severe case, which fulfilled most, if not all, Centers for Disease Control and Prevention (CDC) criteria for HPS, needing non-invasive ventilation and subsequent acute hemodialysis. However, the etiological agent was PUUV, as proved by serological testing, real-time polymerase chain reaction (PCR), and sequencing. Viral antigen was detected by specific anti-PUUV immunostaining, showing, for the first time, greenish intracytoplasmic inclusions in bronchoalveolar lavage (BAL) macrophages. This case definitely confirms that HPS can be encountered during PUUV infections. Interestingly, special findings could render the diagnosis easier, such as greenish homogeneous cytoplasmic inclusions, surrounded by a fine clear halo in BAL macrophages. Therefore, although the diagnosis remains difficult before the onset of renal involvement, the occurrence of severe respiratory failure mimicking community-acquired pneumonia must alert the clinician for possible HPS, especially in endemic areas. PMID- 23670279 TI - Intima-media thickness in patients with obstructive sleep apnea without comorbidities. AB - BACKGROUND: Obstructive sleep apnea (OSA) is associated with elevated risk of cardiovascular events. The early stages of vascular complications can be visualized by means of ultrasound. Intima-media thickness (IMT) correlates with the presence of risk factors of cardiovascular diseases such as hypertension, diabetes, tobacco smoking, or hyperlipidemia. However, little is known whether OSA itself may be the cause of IMT thickening. METHODS: The study group was composed of 28 patients (6 women, 22 men; mean age = 53.8 years, mean BMI = 27.1 kg/m(2), mean AHI = 22.4/h) with OSA who had no comorbidities. The control group consisted of 28 healthy subjects (6 women, 22 men; mean age = 53.9 years; mean BMI = 27.5 kg/m(2)). In both groups IMT was assessed in common carotid arteries with the use of ultrasonography. Additionally, in patients with OSA, pulse wave velocity, echocardiography, 24-h automated blood pressure monitoring, clinical signs and symptoms, and blood tests were performed to investigate possible correlations with IMT. RESULTS: Median IMT was 0.41 mm in OSA patients and 0.46 mm in the control group (p = 0.087). Echocardiography revealed left ventricle hypertrophy in 21%, systolic disorders in 8%, and diastolic disorders in 57% of the patients. In a large majority of patients, pulse wave velocity was found to be normal. IMT correlated with age (r = 0.446, p = 0.017), total cholesterol (r = 0.518, p = 0.005), daytime systolic blood pressure (r = 0.422, p = 0.025), pulse pressure 24 h and daytime (r = 0.424, p = 0.027 and r = 0.449, p = 0.019), early mitral flow/atrial mitral flow (E/A) (r = -0.429, p = 0.023), and posterior wall diameter (PWD) (r = 0.417, p = 0.270). CONCLUSION: In a relatively nonobese group of patients, no significant differences were found in the intima-media thickness between OSA patients without concomitant cardiovascular diseases and healthy controls. This may lead to the conclusion that IMT does not reflect increased risk of cardiovascular events in patients with isolated OSA. PMID- 23670280 TI - N-glycosylamine-mediated isotope labeling for mass spectrometry-based quantitative analysis of N-linked glycans. AB - N-linked glycosylation is a major protein modification involved in many essential cellular functions. Methods capable of quantitative glycan analysis are highly valuable and have been actively pursued. Here we describe a novel N-glycosylamine based strategy for isotopic labeling of N-linked glycans for quantitative analysis by use of mass spectrometry (MS). This strategy relies on the primary amine group on the reducing end of freshly released N-linked glycans for labeling, and eliminates the need for the harsh labeling reaction conditions and/or tedious cleanup procedures required by existing methods. By using NHS ester amine chemistry we used this strategy to label N-linked glycans from a monoclonal antibody with commercially available tandem mass tags (TMT). Only duplex experiments can be performed with currently available TMT reagents, because quantification is based on the intensity of intact labeled glycans. Under mild reaction conditions, greater than 95% derivatization was achieved in 30 min and the labeled glycans, when kept at -20 degrees C, were stable for more than 10 days. By performing glycan release, TMT labeling, and LC-MS analysis continuously in a single volatile aqueous buffer without cleanup steps, we were able to complete the entire analysis in less than 2 h. Quantification was highly accurate and the dynamic range was large. Compared with previously established methods, N-glycosylamine-mediated labeling has the advantages of experimental simplicity, efficient labeling, and preserving glycan integrity. PMID- 23670281 TI - On the road to tolerance--generation and migration of gut regulatory T cells. AB - The intestinal immune system potently supports the generation of induced Treg (iTreg) cells. Within intestinal lymphoid compartments iTreg cells receive homing cues, which direct these cells to the gut lamina propria where they expand and locally suppress immune responses. Yet iTreg cells are but one side of a coin, the other side of which comprises natural Treg (nTreg) cells generated in the thymus. nTreg cells, which act in concert with iTreg cells, also acquire a diversified pattern of homing receptors. Thus iTreg and nTreg cells can enter the gut, and draining lymph nodes to cooperatively ensure intestinal homeostasis. PMID- 23670282 TI - Fermentation products: immunological effects on human and animal models. AB - Infant formulas have been shown to influence the development of the gut microbiota. Besides the probiotic- and prebiotic-containing formulas, fermented milk-based infant formulas offer an additional means for modulation of gut immunity and/or gut microbiota. These formulas are produced by the fermentation of cow's milk with specific lactic acid bacteria strains, followed by heat treatment; they do not contain viable bacteria or added prebiotic oligosaccharides but contain specific products resulting from the fermentation process. This review is focused on the effects of fermentation products, distinguishing them from those of living bacteria and prebiotic compounds on the immune system. Besides the possible modulation of gut microbiota composition, in vitro and in vivo studies suggest that specific fermentation products can actively participate in the establishment of immune balance and oral tolerance. Although further research is needed to confirm the clinical benefits observed in infants to better characterize the active fermentation compounds and to delineate the involved pathways, these fermented formulas appear to deserve interest. PMID- 23670283 TI - An evaluation of the anti-tumor efficacy of oleanolic acid-loaded PEGylated liposomes. AB - The effective delivery of oleanolic acid (OA) to the target site has several benefits in therapy for different pathologies. However, the delivery of OA is challenging due to its poor aqueous solubility. The study aims to evaluate the tumor inhibition effect of the PEGylated OA nanoliposome on the U14 cervical carcinoma cell line. In our previous study, OA was successfully encapsulated into PEGylated liposome with the modified ethanol injection method. Oral administration of PEGylated OA liposome was demonstrated to be more efficient in inhibiting xenograft tumors. The results of organ index indicated that PEG liposome exhibited higher anti-tumor activity and lower cytotoxicity. It was also found that OA and OA liposomes induced tumor cell apoptosis detected by flow cytometry. Furthermore, effects of OA on the morphology of tumor and other tissues were observed by hematoxylin and eosin staining. The histopathology sections did not show pathological changes in kidney or liver in tested mice. In contrast, there was a significant difference in tumor tissues between treatment groups and the negative control group. These observations imply that PEGylated liposomes seem to have advantages for cancer therapy in terms of effective delivery of OA. PMID- 23670284 TI - "Moving to the beat" improves timing perception. AB - Here, we demonstrate that "moving to the beat" can improve the perception of timing, providing an intriguing explanation as to why we often move when listening to music. In the first experiment, participants heard a series of isochronous beats and identified whether the timing of a final tone after a short silence was consistent with the timing of the preceding sequence. On half of the trials, participants tapped along with the beat, and on half of the trials, they listened without moving. When the final tone occurred later than expected, performance in the movement condition was significantly better than performance in the no-movement condition. Two additional experiments illustrate that this improved performance is due to improved timekeeping, rather than to a shift in strategy. This work contributes to a growing literature on sensorimotor integration by demonstrating body movement's objective improvement in timekeeping, complementing previous explorations involving subjective tasks. PMID- 23670285 TI - Influence of hemodialysis on incretin hormones and insulin secretion in diabetic and non-diabetic patients. AB - BACKGROUND: Incretin hormones are secreted in the gut after a meal and stimulate insulin production. Both major incretins, that is, glucagon-like peptide-1 (GLP 1) and glucose-dependent insulinotropic polypeptide (GIP), are eliminated by the kidneys. Little is known about the influence of end-stage renal disease (ESRD) on the incretin axis. The aim of the study was to assess the effect of the commencement of chronic hemodialysis (HD) therapy on serum GLP-1 and GIP, and insulin sensitivity in diabetic and non-diabetic patients. SUBJECTS AND METHODS: The study comprised 56 patients (23 F, 33 M; mean age 57 +/- 14 years) with ESRD in the course of diabetic nephropathy (n = 23) and non-diabetic renal diseases (n = 34) who started chronic HD. Glucose metabolism, including incretin hormones concentration, was assessed before the first HD session and repeated after the first 6 months of the therapy. RESULTS: After 6 months of HD, a significant increase in fasting GLP-1 concentration was observed in both diabetic and non diabetic patients [by 2.27 pmol/l (45 %) and 1.28 pmol/l (22 %), respectively, p = 0.0003]. Serum GIP increased significantly only in diabetic patients [by 30.9 pg/ml (55 %); p = 0.008]. No significant change of fasting glucose was found but HOMA-IR and serum insulin decreased significantly in diabetic patients (p = 0.01 and p = 0.008, respectively). In contrast, HOMA-B was unchanged in both groups. Changes of HOMA-IR did not significantly correlate with serum GLP-1 or GIP concentrations. CONCLUSION: Our results indicate that starting the hemodialysis therapy helps to restore the incretin axis in particular in patients with the diabetic kidney disease. PMID- 23670286 TI - Immunohistochemical detection of SATB1 is independent of thyroid cancer differentiation. AB - OBJECTIVES/HYPOTHESIS: The association of special AT-rich binding protein 1 (SATB1) with a poor prognosis in various cancers has been reported. However, this association is controversial. SATB1 expression in aggressive types of thyroid cancer has not been reported to date. STUDY DESIGN: Retrospective. METHODS: SATB1 expression was immunohistochemically investigated in 35 papillary thyroid cancers, one follicular thyroid cancer, six poorly differentiated thyroid cancers, and two anaplastic thyroid cancers. RESULTS: SATB1 expression was observed in none of two anaplastic thyroid cancers, one of six poorly differentiated thyroid cancers, and nine of 36 well-differentiated thyroid cancers. SATB1 expression was not significantly associated with any high-risk group-related clinicopathologic factors in well-differentiated thyroid cancer. Survival was not associated with SATB1 expression. CONCLUSIONS: SATB1 expression is independent of thyroid cancer differentiation, as well as high-risk-related factors. SATB1 may not play a role in the aggressiveness of thyroid cancer. PMID- 23670287 TI - Coercive control and abused women's decisions about their pets when seeking shelter. AB - The importance of pets in families, especially during major life stressors, is well documented. Research suggests links between pet ownership and intimate partner violence (IPV). This study explored abused women's decisions about pets when seeking help from a shelter. Interviews were conducted with 19 women who were pet owners. Using grounded theory methods, two patterns emerged surrounding abusers' treatment of pets, bonds to pets, women's decisions about pets upon seeking shelter, and future plans for pets. The presence of coercive control was central to these patterns. Women also discussed their experiences with and needs from shelter professionals and veterinarians with implications for practice. PMID- 23670288 TI - Multifocal choroiditis without panuveitis: clinical characteristics and progression. AB - PURPOSE: To describe the clinical characteristics and progression of patients with multifocal choroiditis lesions who had minimal or no evidence of anterior uveitis and/or vitritis. METHODS: Retrospective, observational, single-center consecutive case series. Clinical histories, examination, and multimodal imaging findings were analyzed. RESULTS: Sixty-five eyes of 41 patients were identified. The mean age at diagnosis was 38.4 years (median, 35 years; range, 15-81 years), and 70.7% of the patients were women. Involvement was bilateral in 21 patients (51.2%) at presentation. The 60-month bilateral event-free survival was 75.0% (95% confidence interval, 49.8-91.2%). The mean visual acuity was 20/46 (median, 20/25; range, 20/20 to count fingers at 2 feet) at presentation and 20/42 (median, 20/25; range, 20/20-5/400) at the last recorded visit. The 60-month "20/50 or worse" event-free survival was 100%. Between the first presentation and final follow-up (a mean duration of 92.6 months; range, 0-343 months), 46.7% of the eyes developed new or larger chorioretinal spots and 32.6% developed new or recurrent choroidal neovascularization. The 60-month choroidal neovascularization event-free survival was 68.1% (95% confidence interval, 39.2-85.4%). CONCLUSION: Patients with multifocal choroiditis lesions, but with minimal or no anterior uveitis or vitritis, tended to be young women. Approximately half of the patients presented with bilateral involvement, which is less than has been reported in most case series of multifocal choroiditis with panuveitis. One quarter of all unilaterally affected patients will develop bilateral involvement by 60 months. PMID- 23670289 TI - MARVEL analysis of the rotational-vibrational states of the molecular ions H2D+ and D2H+. AB - Critically evaluated rotational-vibrational line positions and energy levels, with associated critically reviewed labels and uncertainties, are reported for two deuterated isotopologues of the H3(+) molecular ion: H2D(+) and D2H(+). The procedure MARVEL, standing for Measured Active Rotational-Vibrational Energy Levels, is used to determine the validated levels and lines and their self consistent uncertainties based on the experimentally available information. The spectral ranges covered for the isotopologues H2D(+) and D2H(+) are 5.2-7105.5 and 23.0-6581.1 cm(-1), respectively. The MARVEL energy levels of the ortho and para forms of the ions are checked against ones determined from accurate variational nuclear motion computations employing the best available adiabatic ab initio potential energy surfaces of these isotopologues. The number of critically evaluated, validated and recommended experimental (levels, lines) are (109, 185) and (104, 136) for H2D(+) and D2H(+), respectively. The lists of assigned MARVEL lines and levels and variational levels obtained for H2D(+) and D2H(+) as part of this study are deposited in the ESI to this paper. PMID- 23670290 TI - PKC-epsilon pseudosubstrate and catalytic activity are necessary for membrane delivery during IgG-mediated phagocytosis. AB - In RAW 264.7 cells, PKC-epsilon regulates FcgammaR-mediated phagocytosis. BMDM behave similarly; PKC-epsilon concentrates at phagosomes and internalization are reduced in PKC-epsilon-/- cells. Two questions were asked: what is the role of PKC-epsilon? and what domains are necessary for PKC-epsilon concentration? Function was studied using BMDM and frustrated phagocytosis. On IgG surfaces, PKC epsilon-/- macrophages spread less than WT. Patch-clamping revealed that the spreading defect is a result of the failure of PKC-epsilon-/- macrophages to add membrane. The defect is specific for FcgammaR ligation and can be reversed by expression of full-length (but not the isolated RD) PKC-epsilon in PKC-epsilon-/- BMDM. Thus, PKC-epsilon function in phagocytosis requires translocation to phagosomes and the catalytic domain. The expression of chimeric PKC molecules in RAW cells identified the epsilonPS as necessary for PKC-epsilon targeting. When placed into (nonlocalizing) PKC-delta, epsilonPS was sufficient for concentration, albeit to a lesser degree than intact PKC-epsilon. In contrast, translocation of delta(epsilonPSC1B) resembled that of WT PKC-epsilon. Thus, epsilonPS and epsilonC1B cooperate for optimal phagosome targeting. Finally, cells expressing epsilonK437W were significantly less phagocytic than their PKC epsilon-expressing counterparts, blocked at the pseudopod-extension phase. In summary, we have shown that epsilonPS and epsilonC1B are necessary and sufficient for targeting PKC-epsilon to phagosomes, where its catalytic activity is required for membrane delivery and pseudopod extension. PMID- 23670292 TI - Regulation of cell cycle transition and induction of apoptosis in HL-60 leukemia cells by the combination of Coriolus versicolor and Ganoderma lucidum. AB - Medicinal mushrooms have served as the mainstay of treatment for a variety of human illnesses in Asian countries, mostly as supplements by cancer patients. Extracts prepared from Trametes versicolor under the trade name of I'm-Yunity exhibit anti-tumorigenic activities, as supported by inhibition of the proliferation and induction of apoptosis in malignant cells. Similar effects have also been observed for the Reishi mushroom Ganoderma lucidum. The two mushrooms exert their medicinal activities primarily through a family of polysaccharo peptides. Despite the common identity in their bioactive ingredients, whether their combination might elicit an expanded efficacy and mechanism has not been investigated. In the present study, we investigated similarities and differences between extracts prepared from I'm-Yunity and from a formulation denoted I'm Yunity-Too combining I'm-Yunity and Ganoderma lucidum. By assaying their anti proliferative and anti-apoptotic effects using human promyelocytic HL-60 cells, we found that the ethanolic extract of I'm-Yunity-Too was more active in inducing cell death compared to I'm-Yunity, based on measured changes in the expression of caspase 3 and Bax. Moreover, ethanolic extracts of I'm-Yunity-Too exhibited more potent activity compared to its aqueous extracts with regard to suppression of the growth and induction of apoptosis, as assayed by the more pronounced downregulation of phosphorylation of Rb and increased cleavage of poly(ADP ribose) polymerase (PARP) from its native 112-kDa form to the inactive 89-kDa product. These results suggested that the chemopreventive potential of I'm-Yunity may be enhanced by adding Ganoderma lucidum and that their bioactive ingre-dients potentially exhibit mechanistic synergism suggesting a more efficacious adjunct in chemotherapy. PMID- 23670291 TI - Search for mutations in signaling pathways in head and neck squamous cell carcinoma. AB - Mutations in JAK-STAT signaling pathway genes have been associated with the development of various hematological tumors, but have not been investigated in head and neck tumors, and the PIK3CA, BRAF and KRAS genes have been described in a few cases of head and neck squamous cell carcinoma (HNSCC). In the present study, we determined the mutation status in members of the MAPK, PI3K-AKT and JAK STAT pathways in HNSCC. Mutations in the KRAS, BRAF, PIK3CA, JAK1 and JAK2 genes were evaluated in 94 HNSCCs by direct DNA sequencing analysis using cDNA synthesized from RNA extracted from patient tumor cells. All patients evaluated had wild-type KRAS, BRAF and PIK3CA genes. Furthermore, although some known polymorphisms have been found in JAK1 genes (rs45598436, rs17127063, rs2230587, rs3737139, rs2230588 and rs12129819) and JAK2 (rs10429491, rs2230723, rs2230724 and rs41316003), no mutation could be detected. Our data indicate that mutations in these kinase genes seem to be rare events in HNSCC. PMID- 23670293 TI - Ultra-high-ohmic microstripline resistors for Coulomb blockade devices. AB - In this paper, we report on the fabrication and low-temperature characterization of ultra-high-ohmic microstripline resistors made of a thin film of weakly oxidized titanium. Nearly linear voltage-current characteristics were measured at temperatures down to T ~ 20 mK for films with sheet resistivities as high as ~7 kOmega, i.e. about an order of magnitude higher than our previous findings for weakly oxidized Cr. Our analysis indicates that such an improvement can help to create an advantageous high-impedance environment for different Coulomb blockade devices. Further properties of the Ti film addressed in this work show the promise of low-noise behavior of the resistors when applied in different realizations of the quantum standard of current. PMID- 23670295 TI - Understanding the interplay between the proteasome pathway and autophagy in response to dual PI3K/mTOR inhibition in myeloma cells is essential for their effective clinical application. PMID- 23670294 TI - Bcl-xL anti-apoptotic network is dispensable for development and maintenance of CML but is required for disease progression where it represents a new therapeutic target. AB - The dismal outcome of blast crisis chronic myelogenous leukemia (CML-BC) patients underscores the need for a better understanding of the mechanisms responsible for the development of drug resistance. Altered expression of the anti-apoptoticBcl xL has been correlated with BCR-ABL leukemogenesis; however, its involvement in the pathogenesis and evolution of CML has not been formally demonstrated yet. Thus, we generated an inducible mouse model in which simultaneous expression of p210-BCR-ABL1 and deletion of bcl-x occurs within hematopoietic stem and progenitor cells. Absence of Bcl-xL did not affect development of the chronic phase-like myeloproliferative disease, but none of the deficient mice progressed to an advanced phenotype, suggesting the importance of Bcl-xL in survival of progressing early progenitor cells. Indeed, pharmacological antagonism of Bcl-xL, with ABT-263, combined with PP242-induced activation of BAD markedly augmented apoptosis of CML-BC cell lines and primary CD34(+) progenitors but not those from healthy donors, regardless of drug resistance induced by bone marrow stromal cell generated signals. Moreover, studies in which BAD or Bcl-xL expression was molecularly altered strongly support their involvement in ABT-263/PP242-induced apoptosis of CML-BC progenitors. Thus, suppression of the antiapoptotic potential of Bcl-xL together with BAD activation represents an effective pharmacological approach for patients undergoing blastic transformation. PMID- 23670296 TI - Detection of PICALM-MLLT10 (CALM-AF10) and outcome in children with T-lineage acute lymphoblastic leukemia. PMID- 23670297 TI - Treatment outcomes in patients with relapsed and refractory multiple myeloma and high-risk cytogenetics receiving single-agent carfilzomib in the PX-171-003-A1 study. AB - Several cytogenetic abnormalities are associated with poor outcomes in multiple myeloma (MM). We prospectively analyzed the impact of cytogenetic abnormalities on outcomes during the phase 2 PX-171-003-A1 study of single-agent carfilzomib for relapsed and refractory MM. In the response-evaluable population (257/266), fluorescence in situ hybridization (FISH)/conventional cytogenetic profiles were available for 229 patients; 62 (27.1%) had high-risk cytogenetics--del 17p13, t(4;14) or t(14;16) by interphase FISH or deletion 13 or hypodiploidy by metaphase cytogenetics--and 167 (72.9%) had standard-risk profiles. Generally, baseline characteristics were similar between the subgroups, but International Staging System stage III disease was more common in high- vs standard-risk patients (41.9% vs 27.5%) as was Eastern Cooperative Oncology Group performance status 1/2 (85.5% vs 68.3%). Overall response was comparable between the subgroups (25.8% vs 24.6%, respectively; P=0.85), while time-to-event end points showed a trend of shorter duration in high-risk patients, including median duration of response (5.6 months (95% confidence interval (CI) 3.7-7.8) vs 8.3 months (95% CI 5.6-12.3)) and overall survival (9.3 (95% CI 6.5-13.0) vs 19.0 months (95% CI 15.4-NE); P=0.0003). Taken together, these findings demonstrate that single-agent carfilzomib is efficacious and has the potential to at least partially overcome the impact of high-risk cytogenetics in heavily pre-treated patients with MM. PMID- 23670298 TI - Relative atrial natriuretic peptide deficiency and inadequate renin and angiotensin II suppression in obese hypertensive men. AB - Obesity is a strong risk factor for hypertension, but the mechanisms by which obesity leads to hypertension are incompletely understood. On this background, we assessed dietary sodium intake, serum levels of natriuretic peptides (NPs), and the activity of the renin-angiotensin system in 63 obese hypertensive men (obeseHT: body mass index, >=30.0 kg/m(2); 24-hour ambulatory blood pressure, >=130/80 mm Hg), in 40 obese normotensive men (obeseNT: body mass index, >=30.0 kg/m(2); 24-hour ambulatory blood pressure, <130/80 mm Hg), and in 27 lean normotensive men (leanNT: body mass index, 20.0-24.9 kg/m(2); 24-hour ambulatory blood pressure, <130/80 mm Hg). All study subjects were medication free. As a surrogate estimate for dietary sodium intake, we measured sodium excretion in a 24-hour urine collection and we measured serum levels of midregional proatrial NP and plasma levels of renin and angiotensin II. The obese men had higher mean (+/ SD) urinary sodium excretion (obeseHT, 213.6+/-85.2 mmol; obeseNT, 233.0+/-70.0 mmol) than the lean normotensive men (leanNT, 155.5+/-51.7 mmol; P=0.003). ObeseHT had lower (median [interquartile range]) serum midregional proatrial NP levels (49.2 [37.3-64.7] pmol/L) than leanNT (69.3 [54.3-82.9] pmol/L; P=0.003), whereas obeseNT had midregional proatrial NP levels in between (54.1 [43.2-64.7] pmol/L); obeseNT had lower (median [interquartile range]) plasma levels of renin (5.0 [3.0-8.0] mIU/L versus 9.0 [4.0-18.0]) and angiotensin II (2.4 [1.5-3.5] pmol/L versus 4.2 [2.2-7.9]) than obeseHT (P<=0.049), whereas obeseHT had similar plasma levels of renin and angiotensin II as leanNT (P>=0.19). Thus, despite a high sodium intake and a high blood pressure, obese hypertensive men have a relative NP deficiency and an inadequate renin-angiotensin system suppression. PMID- 23670299 TI - Social epidemiology of hypertension in middle-income countries: determinants of prevalence, diagnosis, treatment, and control in the WHO SAGE study. AB - Large-scale hypertension screening campaigns have been recommended for middle income countries. We sought to identify sociodemographic predictors of hypertension prevalence, diagnosis, treatment, and control among middle-income countries. We analyzed data from 47 443 adults in all 6 middle-income countries (China, Ghana, India, Mexico, Russia, and South Africa) sampled in nationally representative household assessments from 2007 to 2010 as part of the World Health Organization Study on Global Aging and Adult Health. We estimated regression models accounting for age, sex, urban/rural location, nutrition, and obesity, as well as hypothesized covariates of healthcare access, such as income and insurance. Hypertension prevalence varied from 23% (India) to 52% (Russia), with between 30% (Russia) and 83% (Ghana) of hypertensives undiagnosed before the survey and between 35% (Russia) and 87% (Ghana) untreated. Although the risk of hypertension significantly increased with age (odds ratio, 4.6; 95% confidence interval, 3.0-7.1; among aged, 60-79 versus <40 years), the risk of being undiagnosed or untreated fell significantly with age. Obesity was a significant correlate to hypertension (odds ratio, 3.7; 95% confidence interval, 2.1-6.8 for obese versus normal weight), and was prevalent even among the lowest income quintile (13% obesity). Insurance status and income also emerged as significant correlates to diagnosis and treatment probability, respectively. More than 90% of hypertension cases were uncontrolled, with men having 3 times the odds as women of being uncontrolled. Overall, the social epidemiology of hypertension in middle income countries seems to be correlated to increasing obesity prevalence, and hypertension control rates are particularly low for adult men across distinct cultures. PMID- 23670300 TI - Reduced macrophage-dependent inflammation improves endothelin-1-induced vascular injury. AB - Transgenic mice with endothelium-specific endothelin-1 (ET-1) overexpression exhibit endothelial dysfunction and vascular remodeling, oxidative stress, and inflammation. We previously observed that monocytes/macrophages play a role in angiotensin II, aldosterone, and deoxycorticosterone acetate/salt-induced vascular remodeling, oxidative stress, and inflammation using a model with reduced monocytes/macrophages, the osteopetrotic (Op) mouse, which has a mutation in the macrophage colony stimulating factor (Csf1) gene. However, it is unknown whether monocytes/macrophages are implicated in adverse vascular effects of ET-1. We hypothesized that reduction in monocytes/macrophages would blunt ET-1-induced vascular injury. We performed a study on 4- to 6-month-old male mice with endothelium-specific ET-1 overexpression (eET-1), reduction in CSF1 (Csf1(Op/+)), or both (eET-1/Csf1(Op/+)), and their wild-type littermate control mice. There was no difference in systolic blood pressure between groups. Endothelial function and vascular structure were determined on a pressurized myograph. Endothelium dependent relaxation in response to acetylcholine was similar in eET-1 and eET 1/Csf1(Op/+) mice. Media:lumen ratio and media cross-sectional area were ~1.5 fold greater in eET-1 than in wild-type mice (P<0.05), which was not observed in mice deficient in CSF1. ET-1-induced oxidative stress measured by dihydroethidium staining (P<0.05) and NADPH oxidase activity assessed with lucigenin chemiluminescence (P<0.05) were blunted by CSF1 deficiency. ET-1 caused a 2.5 fold increase in monocyte/macrophage infiltration compared with wild-type mice (P<0.001), which was blunted in the mice deficient in CSF1. Reduction of monocyte/macrophage-dependent inflammation in mice overexpressing ET-1 in endothelium results in reduced vascular remodeling and oxidative stress, providing evidence for a role of monocytes/macrophages and innate immunity in ET 1-induced vascular injury. PMID- 23670301 TI - Monoamine oxidases are mediators of endothelial dysfunction in the mouse aorta. AB - Monoamine oxidases (MAOs) generate H(2)O(2) as a by-product of their catalytic cycle. Whether MAOs are mediators of endothelial dysfunction is unknown and was determined here in the angiotensin II and lipopolysaccharide-models of vascular dysfunction in mice. Quantitative real-time polymerase chain reaction revealed that mouse aortas contain enzymes involved in catecholamine generation and MAO-A and MAO-B mRNA. MAO-A and -B proteins could be detected by Western blot not only in mouse aortas but also in human umbilical vein endothelial cells. Ex vivo incubation of mouse aorta with recombinant MAO-A increased H(2)O(2) formation and induced endothelial dysfunction that was attenuated by polyethylene glycol catalase and MAO inhibitors. In vivo lipopolysaccharide (8 mg/kg IP overnight) or angiotensin II (1 mg/kg per day, 2 weeks, minipump) treatment induced vascular MAO-A and -B expressions and resulted in attenuated endothelium-dependent relaxation of the aorta in response to acetylcholine. MAO inhibitors reduced the lipopolysaccharide- and angiotensin II-induced aortic reactive oxygen species formation by 50% (ferrous oxidation xylenol orange assay) and partially normalized endothelium-dependent relaxation. MAO-A and MAO-B inhibitors had an additive effect; combined application completely restored endothelium-dependent relaxation. To determine how MAO-dependent H(2)O(2) formation induces endothelial dysfunction, cyclic GMP was measured. Histamine stimulation of human umbilical vein endothelial cells to activate endothelial NO synthase resulted in an increase in cyclic GMP, which was almost abrogated by MAO-A exposure. MAO inhibition prevented this effect, suggesting that MAO-induced H(2)O(2) formation is sufficient to attenuate endothelial NO release. Thus, MAO-A and MAO-B are both expressed in the mouse aorta, induced by in vivo lipopolysaccharide and angiotensin II treatment and contribute via the generation of H(2)O(2) to endothelial dysfunction in vascular disease models. PMID- 23670302 TI - Subfornical organ mediates sympathetic and hemodynamic responses to blood-borne proinflammatory cytokines. AB - Proinflammatory cytokines play an important role in regulating autonomic and cardiovascular function in hypertension and heart failure. Peripherally administered proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF alpha) and interleukin-1beta (IL-1beta), act on the brain to increase blood pressure, heart rate, and sympathetic nerve activity. These molecules are too large to penetrate the blood-brain barrier, and so the mechanisms by which they elicit these responses remain unknown. We tested the hypothesis that the subfornical organ (SFO), a forebrain circumventricular organ that lacks a blood brain barrier, plays a major role in mediating the sympathetic and hemodynamic responses to circulating proinflammatory cytokines. Intracarotid artery injection of TNF-alpha (200 ng) or IL-1beta (200 ng) dramatically increased mean blood pressure, heart rate, and renal sympathetic nerve activity in rats with sham lesions of the SFO (SFO-s). These excitatory responses to intracarotid artery TNF alpha and IL-1beta were significantly attenuated in SFO-lesioned (SFO-x) rats. Similarly, the increases in mean blood pressure, heart rate, and renal sympathetic nerve activity in response to intravenous injections of TNF-alpha (500 ng) or IL-1beta (500 ng) in SFO-s rats were significantly reduced in the SFO x rats. Immunofluorescent staining revealed a dense distribution of the p55 TNF alpha receptor and the IL-1 receptor accessory protein, a subunit of the IL-1 receptor, in the SFO. These data suggest that SFO is a predominant site in the brain at which circulating proinflammatory cytokines act to elicit cardiovascular and sympathetic responses. PMID- 23670303 TI - How to estimate kidney function in kidney transplant recipients with mild to moderate kidney impairment: comparison of estimated glomerular filtration (eGFR) values between creatinine-based GFR equations and cystatin C-based GFR equations for Japanese population. AB - BACKGROUND: With the recent increase in renal transplantations in Japan, accurate assessment of renal function is required. METHODS: This study included 73 patients who had undergone renal transplantation at Nagoya Daini Red Cross Hospital at least 6 months previously and had stable renal function for >3 months. Glomerular filtration rates (GFRs) were measured by inulin clearance (mGFR) and compared with estimated cystatin C-based GFRs (eGFRcys), estimated creatinine-based GFRs (eGFRcre) and their average values (eGFRave). RESULTS: mGFR was 43.3 +/- 14.1 mL/min/1.73 m(2), eGFRcre was 39.6 +/- 11.7, eGFRcys was 56.0 +/- 17.1, and eGFRave was 47.8 +/- 13.7 mL/min/1.73 m(2). Serum cystatin C was 1.39 +/- 0.37 mg/L and serum creatinine was 1.58 +/- 0.51 mg/dL. The correlation coefficients between mGFR and eGFRcre, eGFRcys, and eGFRave were 0.768, 0.831, and 0.841, respectively (P < 0.001, for all).The intraclass correlation coefficients were 0.754, 0.816, and 0.840, respectively (P < 0.001, for all).The mean differences between measured and estimated GFR values were 3.74 mL/min/1.73 m(2) with a root-mean square error (RMSE) of 9.06 for eGFRcre, +12.64 with RMSE of 9.48 for eGFRcys, and +4.45 with RMSE of 7.86 for eGFRave. Bland-Altman plots showed that eGFRcys overestimated GFR values compared with mGFR values in most cases and that eGFRave overestimated GFR values in 53 of 73 cases, whereas eGFRcre underestimated the values in 53 of 73 cases. CONCLUSION: eGFRave may be the best marker to estimate kidney function in Japanese renal transplant recipients with mildly reduced or normal kidney function. PMID- 23670304 TI - Urinary and glomerular podocytes in patients with chronic kidney diseases. AB - BACKGROUNDS: Podocytes are highly differentiated epithelial cells involved in glomerular filtration. This study determines the clinical and histological significance of podocyte detachment and excretion in urine in patients with chronic kidney diseases. METHODS: Renal biopsy was performed in 59 patients (30 males, 29 females; mean age 48 +/- 2 years), including 24 patients with immunoglobulin (Ig)A nephropathy, six each with focal segmental glomerulosclerosis, membranous nephropathy, and minimal change nephrotic syndrome, and 17 with other renal disorders. The number of glomerular podocytes and severity of morphological damage were evaluated in renal biopsy samples. Urinary podocytes were detected by anti-human podocalyxin antibody. The urinary IgG/albumin ratio and urinary peroxide products were assessed by gel electrophoresis and the 2',7'-dichlorodihydrofluorescein-diacetate method, respectively. RESULTS: A decrease in glomerular podocytes was associated with age (r = -0.33; P < 0.05), glomerulosclerosis (r = -0.43; P < 0.01), tubulointerstitial lesions (r = -0.46; P < 0.01), and low estimated glomerular filtration rates (r = 0.32; P < 0.05). Increased urinary podocyte excretion correlated with proteinuria (r = 0.36; P < 0.01), and was observed more frequently in patients with active histological lesions. Podocyte loss correlated with lower selectivity of proteinuria in patients with minimal change nephrotic syndrome and focal segmental glomerulosclerosis (r = -0.90; P < 0.001). Moreover, urinary peroxide products increased in association with glomerulosclerosis (r = 0.39; P < 0.05). CONCLUSIONS: Urinary podocyte excretion reflects ongoing glomerular injury in various kidney diseases, and podocyte loss correlated with glomerulosclerosis and impaired selectivity of proteinuria. PMID- 23670305 TI - Efficacy and safety of SBR759, a novel calcium-free, iron (III)-based phosphate binder, versus placebo in chronic kidney disease stage V Japanese patients on maintenance renal replacement therapy. AB - BACKGROUND: SBR759, an iron (III)-based oral phosphate binder, was developed for the treatment of hyperphosphataemia in chronic kidney disease stage V patients receiving maintenance renal replacement therapy (RRT). Serum phosphate-lowering efficacy and dose response of SBR759 (3-, 6-, 9- and 12-g/day doses) were compared with placebo. METHODS: Japanese patients with hyperphosphataemia (P >= 5.5 mg/dL [>= 1.78 mmol/L]) receiving maintenance RRT (N = 63) were randomised to receive either SBR759 (3-, 6-, 9-, 12-g/day dose) or placebo (12-g/day dose) for 4 weeks. The primary endpoint was change from baseline in 72-h post-dialysis serum phosphate levels at week 4 for different doses of SBR759 versus placebo. Secondary endpoints were change from baseline in serum phosphate levels and dose dependent efficacy of SBR759 during the 4-week treatment period. RESULTS: SBR759 showed significant reduction in serum phosphate levels compared with placebo at week 4, demonstrating a significant linear dose response (P < 0.001). Incidence of adverse events was comparable between the SBR759 treatment groups (7/13 and 5/12 in the 3- and 12-g/day groups, respectively, and 8/13 in the 6- and 9-g/day groups) and was 6/12 in the placebo group. Discoloured faeces and diarrhoea were the most frequently reported adverse events. Two serious adverse events were reported--one in the SBR759 3-g/day group (1/13, skin ulcer) and one in the SBR759 12-g/day group (1/12, arthralgia). CONCLUSIONS: SBR759 showed significant phosphate-lowering efficacy and dose-dependent response compared with placebo in patients with chronic kidney disease receiving RRT. PMID- 23670306 TI - The presentation and management of mandibular tumors in the pediatric population. AB - OBJECTIVES/HYPOTHESIS: To review the presentation and management of malignant tumors of the mandible in children. STUDY DESIGN: Case series. METHODS: Children 0 to 21 years old presenting to a tertiary pediatric hospital with a diagnosis of a malignant tumor involving the mandible were included. Comparison groups included children from the Surveillance, Epidemiology, and End Results database with malignant mandible tumors as well as a group of children with benign mandibular lesions from the same institution. Main outcome measures for the institutional malignant group included presentation, tumor characteristics, treatment modalities, and clinical outcome. RESULTS: Sixteen patients with malignant and 183 patients with benign lesions were identified at the primary institution. The most common presentation in both groups was mandibular swelling or mass. Malignant tumors included sarcoma (n = 11), leukemia/lymphoma (n = 2), squamous cell carcinoma (n = 1), malignant spindle cell tumor (n = 1), and yolk sac tumor (n = 1). The national database identified 56 malignant cases, of which 71% were sarcomas. Thirteen patients at our institution (81%) underwent mandibulectomy and 12 were reconstructed using free tissue transfer. Eleven of the 13 (85%) were treated with adjuvant therapy. After an average follow-up of 32.8 months, seven (44%) had no evidence of disease, three (19%) were deceased, three (19%) were alive with disease, and three (19%) were lost to follow-up. CONCLUSIONS: Malignant mandibular tumors in children are most often sarcomas but can include other rare lesions. Free flap reconstruction is a reasonable option for even very young children requiring extensive mandibular surgery. PMID- 23670307 TI - Anoctamin 5 muscular dystrophy in Denmark: prevalence, genotypes, phenotypes, cardiac findings, and muscle protein expression. AB - Since the initial description in 2010 of anoctamin 5 deficiency as a cause of muscular dystrophy, a handful of papers have described this disease in cases of mixed populations. We report the first large regional study and present data on new aspects of prevalence, muscular and cardiac phenotypic characteristics, and muscle protein expression. All patients in our neuromuscular unit with genetically unclassified, recessive limb girdle muscular dystrophy (LGMD2), Miyoshi-type distal myopathy (MMD) or persistent asymptomatic hyperCK-emia (PACK) were assessed for mutations in the ANO5 gene. Genetically confirmed patients were evaluated with muscular and cardiopulmonary examination. Among 40 unclassified patients (28 LGMD2, 5 MMD, 7 PACK), 20 were homozygous or compound heterozygous for ANO5 mutations, (13 LGMD2, 5 MMD, 2 PACK). Prevalence of ANO5 deficiency in Denmark was estimated at 1:100.000 and ANO5 mutations caused 11 % of our total cohort of LGMD2 cases making it the second most common LGMD2 etiology in Denmark. Eight patients complained of dysphagia and 3 dated symptoms of onset in childhood. Cardiac examinations revealed increased frequency of premature ventricular contractions. Four novel putative pathogenic mutations were discovered. Total prevalence and distribution of phenotypes of ANO5 disease in a representative regional cohort are described for the first time. A high prevalence of ANO5 deficiency was found among patients with unclassified LGMD2 (46 %) and MMD (100 %). The high incidence of reported dysphagia is a new phenotypic feature not previously reported, and cardiac investigations revealed that ANO5-patients may have an increased risk of ventricular arrhythmia. PMID- 23670308 TI - Cerebellar ataxia, mental retardation and dysequilibrium syndrome 1 (CAMRQ1) caused by an unusual constellation of VLDLR mutation. PMID- 23670309 TI - Quantitative assessment of subcortical atrophy and iron content in progressive supranuclear palsy and parkinsonian variant of multiple system atrophy. AB - It is a matter of debate whether increased brain iron levels are the cause or only the consequence of neurodegenerative process in degenerative parkinsonism. The aim of this study is to characterize disease-related changes in volumes and iron-related R2 values of basal ganglia and thalamus. 13 patients with progressive supranuclear palsy (PSP), 15 with a parkinsonian variant of multiple system atrophy (MSA-p), 29 with Parkinson's disease (PD), and 21 age-matched controls underwent 3-Tesla MRI. The R2 values and volumes were calculated for the selected subcortical structures (caudate nucleus, putamen, globus pallidus, and thalamus) using an automated region-based analysis. Voxel-based analysis was also performed to visualize a topographical correlation of R2 value and volume. The PSP group had significantly higher R2 values in globus pallidus and caudate nucleus (p < 0.05), whereas the MSA-p group had higher R2 values in putamen (p < 0.001) than PD and controls. The globus pallidus in PSP and the putamen in MSA-p were the most significant areas of atrophy to differentiate PSP, MSA-p and PD (AUC = 0.856, 0.832, respectively, p < 0.001). The R2 values in both structures increased in parallel with the extent of atrophy. They were negatively correlated with volumes in putamen (r = -0.777, p < 0.001) and globus pallidus (r = -0.409, p = 0.025) of MSA-p, and globus pallidus (r = -0.4, p = 0.043) of PSP. Voxel based analysis identified higher R2 values in more severely atrophic sub-regions in these structures. We observed topographical differences of iron deposition as well as atrophy between MSA-p and PSP. Increased iron levels were related to the structural atrophy in basal ganglia. Our results imply that iron accumulation is likely an epiphenomenon of the degenerative process. PMID- 23670310 TI - Cervical and ocular vestibular-evoked myogenic potentials in vestibular neuritis: comparison between air- and bone-conducted stimulation. AB - To clarify the changes of cervical (cVEMP) and ocular (oVEMP) vestibular evoked myogenic potentials induced by air-conducted sound (ACS) and bone-conducted vibration (BCV) in patients with vestibular neuritis (VN), patients with VN (n = 30) and normal controls (n = 45) underwent recording of cVEMP and oVEMP in response to ACS (1,000 Hz, 5 ms, tone bursts) and BCV (500 Hz, short tone burst). Patients with VN showed a high proportion of oVEMP abnormalities in response to both ACS (80.0 %) and BCV at the forehead (Fz, 73.3 %) or the mastoid (76.7 %). In contrast, cVEMPs were mostly normal with both ACS and BCV in the patients. The dissociations in the abnormalities of cVEMP and oVEMP induced by ACS and BCV at the mastoids and at the forehead in patients with VN suggest that oVEMP reflects functions of the superior vestibular nerve and most likely the utricular function. The results of our study suggest that oVEMP induced by either ACS or BCV appears to depend on integrity of the superior vestibular nerve, possibly due to the utricular afferents travelling in it. In contrast, cVEMP elicited by either ACS or BCV may reflect function of the saccular afferents running in the inferior vestibular nerve. PMID- 23670312 TI - Leguminous plants nodulated by selected strains of Cupriavidus necator grow in heavy metal contaminated soils amended with calcium silicate. AB - Increasing concern regarding mining area environmental contamination with heavy metals has resulted in an emphasis of current research on phytoremediation. The aim of the present study was to assess the efficiency of symbiotic Cupriavidus necator strains on different leguminous plants in soil contaminated with heavy metals following the application of inorganic materials. The application of limestone and calcium silicate induced a significant increase in soil pH, with reductions in zinc and cadmium availability of 99 and 94 %, respectively. In addition, improved nodulation of Mimosa caesalpiniaefolia, Leucaena leucocephala and Mimosa pudica in soil with different levels of contamination was observed. Significant increases in the nitrogen content of the aerial parts of the plant were observed upon nodulation of the root system of Leucaena leucocephala and Mimosa pudica by strain UFLA01-659 (36 and 40 g kg(-1)) and by strain UFLA02-71 in Mimosa caesalpiniaefolia (39 g kg(-1)). The alleviating effect of calcium silicate resulted in higher production of dry matter from the aerial part of the plant, an increase in nodule number and an increase in the nitrogen fixation rate. The results of the present study demonstrate that the combination of rhizobia, leguminous plants and calcium silicate may represent a key factor in the remediation of areas contaminated by heavy metals. PMID- 23670313 TI - Characterization and constitutive expression of an acidic mesophilic endo-1,4 beta-D-xylanohydrolase with high thermotolerance and catalytic efficiency in Pichia pastoris. AB - A putative endo-1,4-beta-D-xylanohydrolase gene xyl11 from Aspergillus niger, encoding a 188-residue xylanase of glycosyl hydrolase family 11, was constitutively expressed in Pichia pastoris. The recombinant Xyl11 exhibited optimal activity at pH 5.0 and 50 degrees C, and displayed more than 68 % of the maximum activity over the temperature range 35-65 degrees C and 33 % over the pH range 2.2-7.0. It maintained more than 40 % of the original activity after incubation at 90 degrees C (pH 5.0) for 10 min and more than 75 % of the original activity after incubation at pH 2.2-11.0 (room temperature) for 2 h. The specific activity, K m and V max of purified Xyl11 were 22,253 U mg(-1), 6.57 mg ml(-1) and 51,546.4 MUmol min(-1) mg(-1). It could degrade xylan to a series of xylooligosaccharides and no xylose was detected. The recombinant enzyme with high stability and catalytic efficiency could work over wide ranges of pH and temperature and thus has the potential for various industrial applications. PMID- 23670314 TI - Comparative study on the properties of lipopeptide products and expression of biosynthetic genes from Bacillus amyloliquefaciens XZ-173 in liquid fermentation and solid-state fermentation. AB - This study compared the compositions and properties of lipopeptide products purified from liquid fermentation (LF) and solid-state fermentation (SSF) and transcription levels involved in lipopeptides under the two systems. Results of Fourier transform infrared spectroscopy and High performance liquid chromatography revealed no significant differences in the polarity and structure of the two lipopeptide products. A higher amino acid proportion was found for lipopeptide product in LF than in SSF. Lipopeptide product produced from LF had better emulsification and antagonistic activities than that from SSF. For SSF, the transcription accumulation levels of the lipopeptide synthetic genes srfAA and sfp were higher than for LF at the same stage. Transcripts for ituD and lpa 14 remained elevated for a longer period of time under SSF conditions, accounting for differences in the production and fermentation periods between SSF and LF. This is the first report that describes differences in lipopeptide product synthesis and molecular behaviors between LF and SSF systems. PMID- 23670315 TI - BJORL--its history until 1996. PMID- 23670316 TI - Steroid use in laryngeal diseases. PMID- 23670317 TI - Intratemporal complications of otitis media. AB - Otitis media (OM) is considered a potentially severe disease due to the risk of complications. OBJECTIVE: To establish the annual incidence of intratemporal complications (ITC) resulting from OM and to prospectively assess patients for epidemiological and clinical factors. METHOD: This prospective cohort study included patients admitted during one year at a university hospital diagnosed with intratemporal complications of OM. Patients were analyzed for age, gender, type of intratemporal complication, treatment, and clinical outcome. The overall incidence of complications and the specific incidence rates of each type of complication were determined. RESULTS: 1,816 patients were diagnosed with OM; 592 (33%) had chronic OM; 1224 (67%) had acute OM. Fifteen patients were diagnosed with OM ITC, adding up to an annual incidence of 0.8%. Nineteen diagnoses of ITC were made in 15 patients. Seven (36.8%) patients were diagnosed with labyrinthine fistula, five (26.3%) with mastoiditis, four (21.1%) with peripheral facial palsy, and three (15.8%) with labyrinthitis. CONCLUSION: The incidence of intratemporal complications remains significant when compared to the rates seen in developed countries. Chronic cholesteatomatous otitis media is the most frequent etiology of intratemporal complications. Labyrinthine fistula is the most common intratemporal complication. PMID- 23670318 TI - Clinical and functional aspects of body balance in elderly subjects with benign paroxysmal positional vertigo. AB - Benign paroxysmal positional vertigo (BPPV) may compromise the balance of elderly subjects. OBJECTIVE: To observe the effects of the Epley maneuver in elderly subjects with BPPV and assess clinical and functional aspects of body balance. METHOD: This is a prospective clinical study. Patients diagnosed with BPPV (Dix Hallpike test) were submitted to the Timed Up & Go (TUG) test, the Clinical Test of Sensory Interaction and Balance (CTSIB), and lower limb testing before and after they were repositioned using the modified Epley maneuver. RESULTS: Most subjects were females, and the group's mean age was 70.10 years (SD = 7.00). All patients had canalithiasis of the posterior canal. The following symptoms improved after the maneuver: postural instability (p = 0.006), nausea and vomiting (p = 0.021), and tinnitus (p = 0.003). Subjects improved their times significantly in the TUG and lower limb tests after the Epley maneuver (p < 0.001). Patients performed better on the CTSIB after the Epley maneuver on condition 2 (p < 0.003), condition 3 (p < 0.001), condition 4 (p < 0.001), condition 5 (p < 0.001), and condition 6 (p < 0.001). CONCLUSION: Clinical and functional aspects of body balance in elderly with BPPV improved after treatment with the modified Epley maneuver. PMID- 23670319 TI - Cochlear implantation through the middle cranial fossa: a novel approach to access the basal turn of the cochlea. AB - The classic approach for cochlear implant surgery includes mastoidectomy and posterior tympanotomy. The middle cranial fossa approach is a proven alternative, but it has been used only sporadically and inconsistently in cochlear implantation. OBJECTIVE: To describe a new approach to expose the basal turn of the cochlea in cochlear implant surgery through the middle cranial fossa. METHOD: Fifty temporal bones were dissected in this anatomic study of the temporal bone. Cochleostomies were performed through the middle cranial fossa approach in the most superficial portion of the basal turn of the cochlea, using the meatal plane and the superior petrous sinus as landmarks. The lateral wall of the internal acoustic canal was dissected after the petrous apex had been drilled and stripped. The dissected wall of the inner acoustic canal was followed longitudinally to the cochleostomy. RESULTS: Only the superficial portion of the basal turn of the cochlea was opened in the fifty temporal bones included in this study. The exposure of the basal turn of the cochlea allowed the visualization of the scala tympani and the scala vestibuli, which enabled the array to be easily inserted through the scala tympani. CONCLUSION: The proposed approach is simple to use and provides sufficient exposure of the basal turn of the cochlea. PMID- 23670320 TI - Pediatric phoniatry outpatient ward: clinical and epidemiological characteristics. AB - Children with language or learning impairment and normal hearing need phoniatric assessment to analyse various communication and development aspects targeting the differential diagnosis and therapeutic indications. OBJECTIVE: Characterize clinical and epidemiological features of a pediatric population treated in a phoniatric outpatient clinic. METHOD: A cross-sectional historical cohort study (retrospective study) was performed involving 68 patients undergoing phoniatric consultation. Outcome measures were age, gender, source of referral for phoniatric consultation, phoniatric diagnosis, mean age at diagnosis, neonatal risks, family history of communication disorders and referrals. RESULTS: 70.58% were male and 29.42% female, mean age 6.85 +/- 2.49 years. 63.23% from external services and 45.59% had no hearing diagnosis. 14 different diagnoses were performed: 50% had Cerebral Palsy, Specific Language Impairment and Pervasive Developmental Disorder. The difference between the average ages was statistically significant (F = 4.369 p = 0.00). 50% had a family history of communication disorders and 51.47% history of neonatal risk. 51.47% were referred for neurological consultation and 79.41% for therapies. CONCLUSION: The population seen was predominantly male, with more complex language development deviations probably due to multiple etiologies. Many of them had no hearing diagnosis. PMID- 23670321 TI - Cervicomastoidfacial versus modified rhytidectomy incision for benign parotid tumors. AB - The modified rhytidectomy incision is an alternative to the classic cervicomastoidfacial approach for parotid surgery, camouflaging the scar in barely visible areas, resulting in better cosmesis. However, there are very few studies comparing the incidence of complications and functional results of patients submitted to parotidectomy through these two different approaches. OBJECTIVE: Compare the incidence of complications and functional results of patients with benign parotid neoplasms submitted to surgery through the classical incision versus the modified rhytidectomy approach. METHOD: Retrospective cohort study evaluating the demographics, surgical and post-operative characteristics of an equally distributed group of sixty patients submitted to parotidectomy via cervicomastoidfacial incision or modified rhytidectomy approach. RESULTS: There were no significant differences in complications rates and functional results between the groups, except for a lower incidence of early facial movement dysfunction for the modified rhytidectomy approach - which was 86% lower in this group of patients. CONCLUSION: Modified rhytidectomy incision has shown comparable complication rates to those of the classic approach and a lower incidence of immediate facial movement impairment. PMID- 23670322 TI - Fat deposition of parotid glands. AB - Parotid gland parenchyma histology may be altered by local or systemic, pathological or nonpathological conditions. OBJECTIVE: This paper aims to highlight the fatty degeneration of the parotid gland, a not well-known non pathological condition. METHOD: In a retrospective study, we collected a series of 6 patients which presented a swelling of the parotid, but even after extensive research, a diagnosis was not reached. RESULTS: Through the retrospective analysis of records we found fatty degeneration of the parotid in an MRI scan of all patients. CONCLUSION: This condition, despite being physiological and expected with aging, may be related to clinical and radiological swelling of these glands. PMID- 23670323 TI - Hearing aids and recovery times: a study according to cognitive status. AB - Studies have shown that elderly people with cognitive impairments benefit more from hearing aids with slower recovery times. OBJECTIVE: To study participation constraints and speech recognition in noise of elderly subjects equipped with hearing aids of different recovery times according to cognitive impairment status. METHOD: Fifty subjects aged between 60 and 80 years were followed for four months. They were divided at first in groups of individuals without (G1; n = 24) and with (G2; n = 26) cognitive impairment based on results of the Alzheimer's Disease Assessment Scale -Cognitive Sub-scale test. Half the members of each group received hearing aids with faster recovery times and half got slower recovery aids, thus forming four groups: two without cognitive impairment (faster recovery - G1F; slower recovery - G1S) and two suspected for cognitive impairment (faster recovery - G2F; slower recovery - G2S). All subjects were interviewed, submitted to basic audiological assessment, asked to answer the Hearing Handicap Inventory for the Elderly questionnaire, and tested for speech recognition in noise. ANOVA, McNemar's test, and the Chi-square test were applied. The significance level was set at 5%. RESULTS: There was significant improvement in participation constraint and speech recognition in noise with hearing aids alone. Sub-group G2F needed more favorable signal-to-noise ratios to recognize 50% of the speech in noise. CONCLUSION: Participation constraint and speech recognition in noise were improved regardless of recovery times or cognitive impairment status. PMID- 23670324 TI - Extraoral implants in irradiated patients. AB - The aim of this study is to analyze the success of extraoral osseointegrated implants used to support designed to rehabilitate craniofacial deformities. METHOD: This study was based on the retrospective assessment of charts from 59 patients submitted to cancer surgery and who received 164 extraoral implants to contain facial prosthesis. RESULTS: Among 164 implants, 42 were fixed in previously irradiated regions. Eight of the implants did not have osseointegration; and from these, two were fixed in irradiated bone. The result show 116 (95.1%) successfully osseointegrated implants in non-irradiated sites. The success rate among 42 implants fixed in previously irradiated bones was 40 (95.3%) osseointegrated implants. CONCLUSION: The use of extraoral craniofacial implants represents a safe and effective approach to treat facial deformities as a support for the rehabilitation prosthesis. Radiotherapy treatment does not prevent osseointegration. PMID- 23670325 TI - Correlation between clinical and pathological data and surgical margins in patients with squamous cell carcinoma of the oral cavity. AB - The importance of having tumor-free margins when resecting oral neoplasms has been known for decades. OBJECTIVE: To correlate clinical and pathology data to surgical margin status in patients with squamous cell carcinoma of the tongue and floor of the mouth. METHOD: This historical cohort cross-sectional study included all patients submitted to squamous cell carcinoma resection for tumors of the oral tongue and floor of the mouth between 2007 and 2011 at the Head and Neck Surgery service of our institution. RESULTS: In the 117 cases included, 68.3% had tongue tumors. The male-to-female ratio was 2.3:1 and patient mean age was 57.6 years. Broad free resection margins were seen in 23.0% of the cases; narrow margins in 60.6% of the cases; and compromised margins in 16.2%. Tumor diameter and thickness were correlated to resection margins. Tumors in more advanced T stages presented more unsatisfactory margins. Patients operated with broad free margins had their tumors resected more commonly through transoral approaches. CONCLUSIONS: Tumors of larger volume both in terms of diameter and thickness were more correlated to unsatisfactory resection margins. Higher complexity procedures were not associated with better resection margins. PMID- 23670326 TI - Use of inhaled versus oral steroids for acute dysphonia. AB - Acute dysphonia is a frequent condition in clinical practice. Its treatment, especially in adults, is not well established in the literature. Steroids are the most recommended drug treatment. However, the existing studies are not enough to establish superiority among the different steroids and the best route of administration. OBJECTIVE: This prospective clinical study aimed at comparing the effect of inhaling steroids as a dry powder with the effect of oral steroids to treat acute dysphonia. METHOD: We assessed 32 adult patients, broken down into two groups of 16 patients in each one of the treatments, before and seven days after the use of the medication. The patients were submitted to videolaryngoscopy and perceptive and acoustic voice assessment. RESULT: Oral and inhalation treatment significantly reduced hyperemia and edema, and improved the muco ondulatory movement; nonetheless, edema reduction was statistically more significant (p = 0.012) in the patients treated with the inhalation form of the drug. However, comparing the values of the auditory perceptive analysis and the acoustic measures after treatment between the groups was not statistically significant. CONCLUSION: There was a significant improvement in the acute laryngitis concerning the assessments carried out in all the patients assessed, concerning the two treatments. The inhalation steroid treatment was significantly more effective in reducing the edema. PMID- 23670327 TI - Brazilian version of the Vestibular Disorders Activities of Daily Living Scale (VADL). AB - The Vestibular Disorders Activities of Daily Living Scale (VADL) assesses the impact of dizziness and body imbalance on the everyday activities of patients with vestibulopathy. The scale encompasses 28 activities divided into three sub scales (functional, ambulation and instrumental). OBJECTIVE: To translate and cross-culturally adapt the VADL to the Brazilian Portuguese language and verify its reliability. METHOD: Questionnaire translation methodological research. Eighty elderly subjects (age > 65 years) with chronic dizziness arising from vestibular disorders were enrolled, of which 40 participated in the pre-testing stage and 40 in reliability analysis. Concordance Correlation Coefficient (CCC) analysis was used to assess reliability. Internal consistency was estimated using Cronbach's alpha (alpha). RESULTS: Pre-test analysis revealed 15% of incomprehension on two activities; these items had to be adapted. The VADL-Brazil had similar levels of test-retest and inter-rater reliability for total score and presented substantial agreement (CCC = 0.79). Internal consistency was excellent for total score (alpha = 0.92), good for the functional (alpha = 0.89) and locomotion (alpha = 0.86) sub-scales, and poor for the instrumental subscale (alpha = 0.56). CONCLUSION: The Brazilian version of the VADL was proven adequate, with good levels of reliability and internal consistency. It might be thus considered as an alternative to assess the functional capacity of vestibulopathy patients. PMID- 23670328 TI - Walk test and school performance in mouth-breathing children. AB - In recent decades, many studies on mouth breathing (MB) have been published; however, little is known about many aspects of this syndrome, including severity, impact on physical and academic performances. OBJECTIVE: Compare the physical performance in a six minutes walk test (6MWT) and the academic performance of MB and nasal-breathing (NB) children and adolescents. METHOD: This is a descriptive, cross-sectional, and prospective study with MB and NB children submitted to the 6MWT and scholar performance assessment. RESULTS: We included 156 children, 87 girls (60 NB and 27 MB) and 69 boys (44 NB and 25 MB). Variables were analyzed during the 6MWT: heart rate (HR), respiratory rate, oxygen saturation, distance walked in six minutes and modified Borg scale. All the variables studied were statistically different between groups NB and MB, with the exception of school performance and HR in 6MWT. CONCLUSION: MB affects physical performance and not the academic performance, we noticed a changed pattern in the 6MWT in the MB group. Since the MBs in our study were classified as non-severe, other studies comparing the academic performance variables and 6MWT are needed to better understand the process of physical and academic performances in MB children. PMID- 23670329 TI - A pilot study on the evaluation of postural strategies in young and elderly subjects using a tridimensional electromagnetic system. AB - One resorts to various postural strategies while attempting to maintain balance. OBJECTIVE: To assess the postural strategies adopted by young and elderly subjects in varying sensory conditions by using a system of tridimensional electromagnetic sensors positioned on the projection of the first thoracic vertebra and on the sacral region. Postural oscillation values for young and elderly subjects were also reported. METHOD: This observational cross-sectional study enrolled 25 young and 16 elderly individuals. A PolhemusTM device equipped with two sensors was used to assess postural oscillation parameters (maximum displacement, mean velocity, and trajectory). Data acquisition was carried out with subjects standing while undergoing a 90-second test in four sensory conditions: eyes opened, eyes closed, on a stable surface, and on an unstable surface. RESULTS: Sensors 1 and 2 presented significant cross-correlations in all sensory conditions for both groups (r > 0.99; p < 0.001). No statistically significant differences were seen when the cross-correlations for both groups were compared. CONCLUSION: This study presented an important tool to analyze postural oscillation and assess the postural strategies of young and elderly subjects in different sensory conditions. Young and elderly individuals presented strong correlations between sensors (ankle strategy), but no statistically significant differences were seen between groups. PMID- 23670330 TI - Newborn and infant hearing health education for nursing professionals. AB - Hearing loss is a sensory deprivation, which can brings several consequences, among them: language development delay, emotional and social problems, and school difficulties. In such settings, we stress the role of nursing professional, who can expand their knowledge about children's hearing health, all the way from pre natal care. OBJECTIVE: To check the knowledge of nursing professional after the educational actions on pediatric hearing. METHOD: A quasi-experimental design with timeseries outline. We had 82 nursing professional participating (nurses, technicians and assistants) working in a university hospital between March and September of 2011. All of the interviewees answered a semi-structured questionnaire before and after the educational actions. RESULTS: We observed a significant change in the knowledge of the nursing professionals after the educational activity in most of the variables; such as: ideal age to perform the newborn hearing screening; ideal age to diagnose hearing loss; ideal age to start intervention against hearing loss and risk indicators for hearing loss. CONCLUSION: It is believed that the methodology used in educational activities, based on problems found in professional practice, education may have contributed greatly to increase knowledge about hearing health, especially concerning neonates and infants. PMID- 23670331 TI - Laryngeal involvement in rheumatoid arthritis. AB - The prevalence of laryngeal involvement in Rheumatoid Arthritis (RA) ranges from 13 to 75%. The specific RA manifestations include the cricoarytenoid arthritis and the presence of rheumatoid nodules in the vocal folds. OBJECTIVE: The objective of this study is to evaluate the prevalence of dysphonia and laryngeal alterations on videolaryngoscopy in RA patients and their association with disease activity. METHOD: This is a clinical cross-sectional study that evaluated patients with rheumatoid arthritis as to their disease activity score in 28 joints (DAS-28), laryngeal symptoms, application of a Portuguese version of the Voice Handicap Index and videolaryngoscopy findings, comparing them with a control group. RESULTS: We evaluated 47 (54%) patients with rheumatoid arthritis and 40 (46%) controls. The prevalence of dysphonia and videolaryngoscopy changes was respectively 12.8% and 72.4% in patients with RA. The mean of DAS-28 was 3.3 +/- 1.2; 26 (74.3%) of 35 patients presenting active disease had laryngeal changes (p = 0.713). Posterior laryngitis was the most common diagnosis (44.7%). CONCLUSION: The prevalence of laryngeal disorders in RA patients was 72.4% and the prevalence of dysphonia was 12.8%. There was no significant relationship between laryngeal disorders and disease activity. PMID- 23670332 TI - Head and neck cancer: causes, prevention and treatment. AB - Although head and neck carcinoma ranks fifth among cancer types, patient survival rates have not changed significantly over the past years. OBJECTIVE: To determine the risk factors, causes, therapies, and prevention measures for head and neck cancer. METHOD: Risk factors, causes, therapies, and preventive measures for this disease were searched on databases PUBMED, MEDLINE, and SCIELO. RESULTS: Alcohol and tobacco are still atop risk factors. Other factors may influence the development of head and neck carcinoma. Surgery is the main treatment option, and the addition of radiotherapy following surgery is frequent for patients in the early stages of the disease. Other therapies target specific genetic molecular components connected to tumor development. Disease preventive measures include smoking cessation, limiting alcohol intake, preventing exposure to tobacco smoke and environmental carcinogenic agents, early detection of infection by HPV, maintaining oral health, good eating habits, and managing stress. CONCLUSION: Additional research is needed for a more thorough understanding of the development of head and neck carcinomas and to shed light on new ways to improve therapeutic approaches and interventions. PMID- 23670333 TI - Hearing loss in people with HIV/AIDS and associated factors: an integrative review. AB - The current scientific literature reports on the incidence of hearing impairments due to HIV/AIDS, and the hearing changes can occur due to damage to the outer, middle or inner ear. Thus, it is important to study how these changes occur, the hearing loss and their associations with the HIV/AIDS infection. OBJECTIVE: To identify the factors related to hearing loss in people with HIV/AIDS in the global scientific literature. METHOD: Study carried out an Integrative Review of the Literature. The key words used were: hearing loss, hearing disorders and deafness, separately associated to the keyword HIV on PUBMED, SciELO, LILACS and ISI databases. We used complete original papers, of free access, in English, Spanish, French and Portuguese. Thirteen quantitative studies from 1994-2010 were selected. CONCLUSION: We did not find any strong direct association between anti retroviral therapy and hearing loss; however, there are indications of hearing loss in the population studied, and their associations and causes need to be better investigated. PMID- 23670334 TI - Tolosa-Hunt syndrome mimicking cavernous sinus tumor. PMID- 23670335 TI - Superficial siderosis of the central nervous system: an usual cause of sensorineural hearing loss. PMID- 23670336 TI - Paraneoplastic pemphigus: initial manifestation of lung cancer. PMID- 23670337 TI - B-cell non-Hodgkin lymphoma of the ethmoid sinus. PMID- 23670339 TI - Nanoscale chemical templating of Si nanowires seeded with Al. AB - We describe a new approach for achieving controlled spatial placement of VLS grown nanowires that uses an oxygen-reactive seed material and an oxygen containing mask. Oxygen-reactive seed materials are of great interest for electronic applications, yet they cannot be patterned using the approaches developed for noble metal seed materials such as Au. This new process, nanoscale chemical templating, takes advantage of the reactivity of the blanket seed layer by depositing it over a patterned oxide that reacts with the seed material to prevent nanowire growth in undesired locations. Here we demonstrate this technique using Al as the seed material and SiO2 as the mask, and we propose that this methodology will be applicable to other reactive metals that are of interest for nanowire growth. The method has other advantages over conventional patterning approaches for certain applications including reducing patterning steps, flexibility in lithographic techniques, and high growth yields. We demonstrate its application with standard and microsphere lithography. We show a high growth yield and fidelity, with no NWs between openings and a majority of openings occupied by a single vertical nanowire, and discuss the dependence of yield on parameters. PMID- 23670340 TI - Collecting response times using Amazon Mechanical Turk and Adobe Flash. AB - Crowdsourcing systems like Amazon's Mechanical Turk (AMT) allow data to be collected from a large sample of people in a short amount of time. This use has garnered considerable interest from behavioral scientists. So far, most experiments conducted on AMT have focused on survey-type instruments because of difficulties inherent in running many experimental paradigms over the Internet. This study investigated the viability of presenting stimuli and collecting response times using Adobe Flash to run ActionScript 3 code in conjunction with AMT. First, the timing properties of Adobe Flash were investigated using a phototransistor and two desktop computers running under several conditions mimicking those that may be present in research using AMT. This experiment revealed some strengths and weaknesses of the timing capabilities of this method. Next, a flanker task and a lexical decision task implemented in Adobe Flash were administered to participants recruited with AMT. The expected effects in these tasks were replicated. Power analyses were conducted to describe the number of participants needed to replicate these effects. A questionnaire was used to investigate previously undescribed computer use habits of 100 participants on AMT. We conclude that a Flash program in conjunction with AMT can be successfully used for running many experimental paradigms that rely on response times, although experimenters must understand the limitations of the method. PMID- 23670342 TI - A hundred years of Lynch syndrome research (1913-2013). PMID- 23670343 TI - Is the risk of narcolepsy also increased with non-adjuvanted flu vaccines? PMID- 23670341 TI - 100 years Lynch syndrome: what have we learned about psychosocial issues? AB - In the care of patients with Lynch Syndrome (LS), a range of psychosocial issues are encountered, which significantly affect patient outcomes. A brief historical background of 'psycho-onco-genetics' (the domain where psychology, oncology and genetics meet) in relation to LS is presented, followed by an overview of important psychosocial issues identified in the past 20 years. The identification of mismatch repair genes in 1993-1994 made possible genetic counseling and testing for patients who had cancer and for potentially high-risk relatives without cancer. At that time, concerns were raised about the potentially negative psychosocial impact of predictive genetic testing. Since 1993, a large number of studies have been conducted to investigate the possible psychosocial benefits and limitations of such testing. This article presents an overview of: the uptake of and motivations for genetic testing, its psychosocial impact (e.g. psychological adaptation, impact on risk perception and self-concept, and concerns about, and experiences of, genetic discrimination), psychological screening instruments, adherence to and decision-making about preventive strategies, family communication, lifestyle changes, reproductive technology utilization, and professional psychosocial support needs of members of families with LS. Finally, challenges for the future are discussed, including population screening and genomic testing. PMID- 23670344 TI - Iatrogenic radiation exposure to patients with early onset spine and chest wall deformities. AB - STUDY DESIGN: Retrospective cohort series. OBJECTIVE: Characterize average iatrogenic radiation dose to a cohort of children with thoracic insufficiency syndrome (TIS) during assessment and treatment at a single center with vertically expandable prosthetic titanium rib. SUMMARY OF BACKGROUND DATA: Children with TIS undergo extensive evaluations to characterize their deformity. No standardized radiographical evaluation exists, but all reports use extensive imaging. The source and level of radiation these patients receive is not currently known. METHODS: We evaluated a retrospective consecutive cohort of 62 children who had surgical treatment of TIS at our center from 2001-2011. Typical care included obtaining serial radiographs, spine and chest computed tomographic (CT) scans, ventilation/perfusion scans, and magnetic resonance images. Epochs of treatment were divided into time of initial evaluation to the end of initial vertically expandable prosthetic titanium rib implantation with each subsequent epoch delineated by the next surgical intervention. The effective dose for each examination was estimated within millisieverts (mSv). Plain radiographs were calculated from references. Effective dose was directly estimated for CT scans since 2007 and an average of effective dose from 2007-2011 was used for scans before 2007. Effective dose from fluoroscopy was directly estimated. All doses were reported in mSv. RESULTS: A cohort of 62 children had a total of 447 procedures. There were a total of 290 CT scans, 4293 radiographs, 147 magnetic resonance images, and 134 ventilation/perfusion scans. The average accumulated effective dose was 59.6 mSv for children who had completed all treatment, 13.0 mSv up to initial surgery, and 3.2 mSv for each subsequent epoch of treatment. CT scans accounted for 74% of total radiation dose. CONCLUSION: Children managed for TIS using a consistent protocol received iatrogenic radiation doses that were on average 4 times the estimated average US background radiation exposure of 3 mSv/yr. CT scans comprised 74% of the total dose. LEVEL OF EVIDENCE: 3. PMID- 23670345 TI - OCT4 is epigenetically regulated by DNA hypomethylation of promoter and exon in primary gliomas. AB - Glioma is the leading cause of tumor-related mortality in the central nervous system. There is increasing evidence that the self-renewal capacity of cancer cells is critical for the initiation, growth and recurrence of tumors. OCT4 is a transcription factor that plays a key role in regulating the self-renewal ability of embryonic stem cells. DNA methylation is involved in the regulation of OCT4 expression during the development and differentiation of embryonic stem cells and neural stem cells. In the present study, we reported that OCT4 was highly expressed in primary gliomas and its expression levels increased in parallel with pathological grades. BSP analysis showed that the methylation levels of OCT4 gene promoter and exon were significantly reduced in comparison with the normal group and were negatively correlated with OCT4 gene expression in primary gliomas. In vitro, OCT4 gene expression was upregulated following treatment by a demethylation reagent in glioma cell lines. Our findings suggest that OCT4 is epigenetically regulated by DNA hypomethylation in primary gliomas, which may provide evidence for the role of DNA methylation in tumor and may present a new direction for developing more powerful strategies to treat glioma in the clinic. PMID- 23670346 TI - The role of leptinemia state as a mediator of inflammation in obese adults. AB - Hyperleptinemia has emerged as a marker of proinflammatory status, while the adiponectin/leptin ratio has been used to identify anti-inflammatory state. In this context, the aims of the present study were to investigate the role of leptinemia, adjusted by tertiles, on inflammatory state in obese adults according to obesity degree. This is a cross-sectional study comprised of 43 obese adults. The anthropometric variables and body composition were analyzed, as well as markers of inflammation such as leptin, adiponectin, and plasminogen activator inhibitor. Subjects were grouped using adjusted tertiles of the leptin levels. The major finding was the negative correlation between leptin concentration with adiponectin/leptin ratio (r=-0.622, p=0.000) and the positive correlation with leptin/adiponectin ratio (r=0.622, p=0.000). Indeed, both ratios were decreased and increased, respectively, according to the obesity degree. Furthermore, in the stepwise multiple linear regression analysis, the high degree of obesity was an independent predictor of leptinemia when adjusted for age and BMI (beta=0.588, p=0.000 and beta=0.778, p=0.005). Finally, the strong negatively correlation between the leptinemia with adiponectin/leptin ratio and the positive correlation with leptin/adiponectin ratio reinforce the role of this adipokine as a biomarker of inflammation in obese adults, according to obesity degree. Our findings can elucidate that hyperleptinemic status was a major factor in the proinflammatory status related to higher obesity degree. All together, these data reinforce the role of leptinemia state as a mediator of inflammation in obese adults. PMID- 23670347 TI - Ultrasonic morphology of uterus and ovaries in girls with pituitary hyperplasia secondary to primary hypothyroidism. AB - We aimed to study uterine and ovarian morphology, hormonal levels, and pituitary height in prepubertal girls with pituitary hyperplasia secondary to primary hypothyroidism (PH) before and after thyroid hormone replacement therapy. We investigated 24 prepubertal girls with severe PH who were divided into 2 groups: secondary pituitary hyperplasia (group A, n=18), without pituitary hyperplasia (group B, n=6). Serum levels of free triiodothyronine (FT3), free thyroxine (FT4), thyrotropin (TSH), follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), testosterone (T) and prolactin (PRL), pituitary height, uterine volume (UV), ovarian volume (OV), follicular diameter (FD), and follicular number (FN) in group A were measured before and 3-month after levothyroxine therapy. Age-matched healthy prepubertal girls (control group, n=30) were also enrolled in the study. The levels of FT3 and FT4 were significantly lower and the values of TSH, FSH, E2, PRL, pituitary height, UV, OV, and FD were significantly higher in group A than in the control group (all p<0.05). In group B, FT4 levels were significantly lower and TSH levels were significantly higher than in the control group (both p<0.05); the values of FSH, E2, PRL, UV, OV, and FD tended to be higher than those in the control group; there were no statistically significant differences (all p>0.05). After 3-month of therapy, hormonal levels regressed and imaging abnormalities decreased. Our results indicate that PH patients with pituitary hyperplasia have enlarged uterus, ovaries and follicles, as well as high values of FSH, E2, PRL, and pituitary height, which are improved after levothyroxine therapy. PMID- 23670348 TI - Adiponectin-induced inhibition of intrinsic and extrinsic apoptotic pathways protects pancreatic beta-cells against apoptosis. AB - Apoptosis is the main form of beta-cell death in type 2 diabetes mellitus. There are 2 major pathways leading to apoptosis, 'intrinsic and extrinsic pathways'. Adiponectin is an adipocyte-derived hormone, which plays an important role in glucose and lipid metabolism. The main aims of this study were to investigate related apoptotic pathways in diabetes and the anti-apoptosis effects of adiponectin on pancreatic beta-cell and the underlying mechanisms. Diabetic mice were generated by intraperitoneal injection of streptozotocin (STZ, 50 mg/kg/d for 5 days) and high-fat diet. Adiponectin overexpressing mice were developed by injecting lentivirus expressing mouse full length adiponectin (plenti-acdc-EGFP) through tail vein. Fourteen days after plenti-acdc-EGFP lentivirus injection, plasma adiponectin protein levels were increased 2-fold. Plasma triglyceride and glucose levels, but not total cholesterol, were significantly reduced in plenti acdc-EGFP-treated mice. Pancreatic beta-cell apoptotic numbers and the expression of caspase-8, -9, -3 in islet increased in diabetic mice, which was reversed by elevated adiponectin in plenti-acdc-EGFP-treated mice. These results suggest that both intrinsic and extrinsic apoptotic pathways have an important role in diabetic beta-cell apoptosis. Adiponectin has antidiabetic and anti-apoptotic effects by regulating glucose and lipid metabolisms and inhibiting intrinsic and extrinsic apoptotic pathway in pancreatic beta-cells. PMID- 23670349 TI - Glucagon-like peptide-1 upregulates visfatin expression in 3T3-L1 adipocytes. AB - The incretin hormone glucagon-like peptide-1 (GLP-1) exerts important functions in controlling glucose homeostasis. Many studies have revealed molecular targets of GLP-1, but its influence on adipokines has not been determined. Visfatin, a recently discovered adipokine, has been shown to attenuate insulin resistance by binding to insulin receptor. Our study shows that GLP-1 induced secretion of visfatin into the culture medium of 3T3-L1 adipocytes due to increased visfatin mRNA expression. Furthermore, the effect of GLP-1 on visfatin was dose- and time dependent. H89, a protein kinase A inhibitor, prevented the induction of visfatin expression by GLP-1. Moreover, inhibition of NF-kappaB by PDTC reduced the basal visfatin release while having no effect on the transcription regulation by GLP-1. In addition, GLP-1 alleviated the decrease of visfatin mRNA expression under endoplasmic reticulum stress induced by thapsigargin. Taken together, our study suggests that GLP-1 promotes the novel insulin-mimetic adipocytokine visfatin expression via the PKA pathway and might influence glucose metabolism. PMID- 23670350 TI - Glucocorticoids increase protein carbonylation and mitochondrial dysfunction. AB - Many major psychiatric illnesses have been associated with excessive and prolonged release of glucocorticoid stress hormones potentially leading to deleterious neuronal effects. Recent studies have suggested that oxidative stress is associated with psychiatric illnesses. Oxidative stress is an overproduction of reactive oxygen species (ROS) that overwhelms the cellular antioxidant capacity. The mitochondria are responsible for most oxygen consumption and are a major source of ROS production. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase also contributes significantly to ROS production. This study aims to elucidate the effects of glucocorticoids on oxidative damage to protein, mitochondrial function, NADPH oxidase activity, and antioxidant capacity. Rat pheochromocytoma PC12 cells were treated with corticosterone at concentrations of 0.031, 0.063, and 0.125 mmol/l for 24 h. Protein carbonylation, activities of mitochondrial complex I and III, activity of NADPH oxidase, total antioxidant capacity, and activities of superoxide dismutase (SOD) and catalase (CAT) were analyzed. We found that chronic treatment with corticosterone increased the amount of protein carbonylation in PC12 cells. Complex I activity was decreased with corticosterone treatment, while no change was seen in complex III activity or NADPH oxidase activity. Total antioxidant capacity was increased at the lowest dosage level tested. Although corticosterone treatment had no effect on CAT activity, corticosterone at the highest dosage significantly decreased SOD activity. These results suggest that excessive glucocorticoid activity can increase oxidative damage to protein, possibly by inhibiting activities of mitochondrial complex I and antioxidant enzyme SOD. PMID- 23670351 TI - Reply: Logistic regression, odds ratio, and factor variables. PMID- 23670352 TI - A statistical description of the evolution of cloud condensation nuclei activity during the heterogeneous oxidation of squalane and bis(2-ethylhexyl) sebacate aerosol by hydroxyl radicals. AB - The heterogeneous reaction of hydroxyl radicals with chemically reduced organic aerosol comprised of either squalane or bis(2-ethylhexyl) sebacate are used as model systems to examine how cloud condensation nuclei (CCN) activity evolves with photochemical oxidation. Over the course of the reaction, the critical super saturation evolves both by the formation of new oxygen functional groups and by changes in aerosol size through the formation of gas phase reaction products. A statistical model of the heterogeneous reaction reveals that it is the formation, volatilization, solubility, and surface activity of many generations of oxidation products that together control the average changes in aerosol hygroscopicity. The experimental observations and model demonstrate the importance of considering the underlying population or subpopulation of species within a particle and how they each uniquely contribute to the average hygroscopicity of a multi-component aerosol. To accurately predict changes in CCN activity upon oxidation requires a reduction in the surface tension of the activating droplet by a subpopulation of squalane reaction products. These results provide additional evidence that surface tension-concentration parameterizations based on macroscopic data should be modified for microscopic droplets. PMID- 23670353 TI - MR detection of LPS-induced neutrophil activation using mannan-coated superparamagnetic iron oxide nanoparticles. AB - PURPOSE: The purpose of this study was to investigate the potential of the phagocytic activity of lipopolysaccharide (LPS) induced neutrophils that are mannan coated with superparamagnetic iron oxide nanoparticles (M-SPION). PROCEDURES: Human neutrophils were divided into control and LPS groups. The neutrophils were labeled with M-SPION and dextran-coated SPION. After labeling of M-SPION, the mean signal intensity (SI) of the LPS group was significantly lower than that of the control group. RESULTS: The labeling of both control and LPS groups with M-SPION showed significantly lower SI than those labeled with D SPION. After labeling with M-SPION, the intracellular iron uptake of neutrophil in Prussian blue staining was markedly demonstrated in the LPS group, but not in the control group. M-SPION was more effective than D-SPION in the labeling of neutrophils in vitro. CONCLUSIONS: The in vitro labeling technique of LPS neutrophil with M-SPION on MR imaging could be developed into a diagnostic method of LPS-induced neutrophils. PMID- 23670354 TI - Aliskiren improves vascular smooth muscle function in the skin microcirculation of type 2 diabetic patients with normal renal function. AB - OBJECTIVE: The objective of this paper is to study the effect of aliskiren on metabolic parameters and micro- and macrovascular reactivity in individuals diagnosed with or at high risk for developing type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: We studied 47 T2DM and 41 at-risk individuals in a randomized, double-blinded, placebo-controlled trial. All subjects were treated with 150 mg aliskiren or placebo daily for 12 weeks. Twenty-six (55%) of T2DM and four (8%) at-risk subjects were also treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers. RESULTS: Aliskiren treatment was associated with improvement in systolic and diastolic blood pressure and endothelium-independent vasodilation at the skin microcirculation in those with T2DM but not in those at risk. There were no incidences of hypotension and no significant changes in serum potassium or creatinine levels with aliskiren treatment in either study group. CONCLUSIONS: Aliskiren improves blood pressure and vascular smooth muscle function in the skin microcirculation of T2DM patients. PMID- 23670355 TI - Nicorandil inhibits hypoxia-induced apoptosis in human pulmonary artery endothelial cells through activation of mitoKATP and regulation of eNOS and the NF-kappaB pathway. AB - Apoptosis of human pulmonary artery endothelial cells (HPAECs) is the initial step and triggering event for pulmonary hypertension (PH). However, little is known about the actions of nicorandil on HPAECs in vitro. In the present study, we investigated the anti-apoptotic effect of nicorandil on HPAECs exposed to hypoxia, and explored the underlying mechanism(s) of action. Cell viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Annexin V and propidium iodide staining, and Hoechst 33342 staining assay were employed to detect apoptosis. In addition, the protein expression of Bax, Bcl-2, caspase-9 and -3, endothelial nitric oxide synthase (eNOS), nuclear factor kappaB (NF-kappaB) and IkappaBalpha were determined by western blotting to investigate the possible mechanisms. We found that exposure to hypoxia for 24 h significantly decreased cell viability and increased cell apoptosis. Pretreatment with nicorandil (100 uM) effectively abolished the influence of hypoxia on HPAECs. However, these protective effects of nicorandil were significantly inhibited by an antagonist of mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channels, 5-hydroxydecanoate (5-HD, 500 uM), and by an eNOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 300 uM). We further observed that nicorandil could upregulate the decreased protein expression of eNOS and IkappaBalpha, and downregulate the increased protein expression of NF-kappaB, induced by hypoxia. In addition, nicorandil inhibited the enhancement of caspase 3 and -9 expression, and the increase in the Bax/Bcl-2 expression ratio, induced by hypoxia. However, these effects were also abolished by 5-HD and L-NAME. Collectively, these findings suggest that nicorandil inhibits hypoxia-induced apoptosis of HPAECs through activation of mitoKATP channels and increased eNOS expression, which in turn inhibits the NF-kappaB pathway and the mitochondrial apoptotic pathway. PMID- 23670356 TI - Protein restriction does not impair adaptations induced in cardiomyocytes by exercise in rats. AB - The effect of a treadmill running program on physical performance and morphofunctional adaptations was investigated in control and malnourished rats. Male 4-week old Wistar rats were randomized in groups of 12 animals: control trained (CT), control sedentary (CS), malnourished trained (MT) and malnourished sedentary (MS). Control and malnourished animals received chow with 12% protein or 6% protein, respectively. Trained groups were subjected to a treadmill running program for 8 weeks. Physical performance, biochemical parameters, cardiomyocytes morphology and biomechanics were determined. Malnourished animals presented reduction in body mass, serum levels of total protein, albumin and hemoglobin compared to the control groups. At 1 and 3 Hz cardiomyocytes from CT and MT showed higher cell shortening, speed of contraction and relaxation compared to the other groups. At 3 Hz cardiomyocytes from MS showed reduction in cell shortening and speed of contraction compared to CS. Protein restriction does not prevent the improvement in physical performance or cardiomyocytes biomechanical efficiency and growth in response to exercise. These findings could represent a modulatory effect of exercise to maintain cardiomyocyte growth at the expense of reducing the rate of body growth in order to ensure proper cellular function in conditions of cardiovascular overload imposed by exercise. PMID- 23670357 TI - Optimum load in various vertical jumps support the maximum dynamic output hypothesis. AB - The aim was to generalize the maximum dynamic output (MDO) hypothesis [i. e., the muscle power output in vertical jumps (VJ) is maximized when loaded with one's own body mass] to variety of VJ. We hypothesized that the subjects' own body (a) would be the optimal load for maximizing the power output (i. e., the no-load condition) and also (b) reveal the maximum benefits of stretch-shortening cycle (SSC). 13 participants performed the maximum squat and various counter-movement jumps when loaded by approximately constant external force ranging from -40% to + 40% of their body weight (BW). Regarding the first hypothesis, the differences in both the peak and mean power recorded under different load magnitudes revealed maxima close to no-load condition (i. e., from -3% BW to + 8% BW; R2=0.65-0.96; all P<0.01). Regarding the second hypothesis, the differences in performance between VJ executed with and without SSC also revealed maxima close to no-load conditions (0-2% BW), while the same differences in the power output were observed under relatively low positive loads (14-25% BW; R2 = 0.56-0.95; all P<0.01). The findings support the concept that maximal power output occurs close to one's own body mass during VJ with and without SSC, thereby providing additional support to MDO hypothesis. PMID- 23670358 TI - Cold drink attenuates heat strain during work-rest cycles. AB - There is limited information on the ingestion of cold drinks after exercise. We investigated the thermoregulatory effects of ingesting drinks at 4 degrees C (COLD) or 28 degrees C (WARM) during work-rest cycles in the heat. On 2 separate occasions, 8 healthy males walked on the treadmill for 2 cycles (45 min work; 15 min rest) at 5.5 km/h with 7.5% gradient. Two aliquots of 400 mL of plain water at either 4 degrees C or 28 degrees C were consumed during each rest period. Rectal temperature (T re ), skin temperature (T sk ), heart rate and subjective ratings were measured. Mean decrease in T re at the end of the final work-rest cycle was greater after the ingestion of COLD drinks (0.5+/-0.2 degrees C) than WARM drinks (0.3+/-0.2 degrees C; P<0.05). Rate of decrease in T sk was greater after ingestion of COLD drinks during the first rest period (P<0.01). Mean heart rate was lower after ingesting COLD drinks (P<0.05). Ratings of thermal sensation were lower during the second rest phase after ingestion of COLD drinks (P<0.05). The ingestion of COLD drinks after exercise resulted in a lesser than expected reduction of T re . Nevertheless, the reduction in T re implies a potential for improved work tolerance during military and occupational settings in the heat. PMID- 23670359 TI - EPO modulation in a 14-days undersea scuba dive. AB - Erythropoiesis is affected during deep saturation dives. The mechanism should be related to a downregulation of serum Erythropoietin (s-EPO) concentration or to a toxic effect of the hyperbaric hyperoxia. We evaluated s-EPO and other haematological parameters in 6 scuba divers before, during and after a 14-days guinness saturation dive (8-10 m). Athletes were breathing air at 1.8-2 ATA, under the control of a team of physicians. Serum parameters were measured before diving (T0) and: 7 days (T1), 14 days (T2) after the beginning of the dive and 2 h (T3) and 24 h (T4) after resurfacing. Hgb, and many other haematological parameters did not change whereas Ht, s-EPO, the ratio between s-EPO predicted and that observed and reticulocytes (absolute, percent) declined progressively from T0 to T3. At T4 a significant rise in s-EPO was observed. Hgb did not vary but erythropoiesis seemed to be affected as s-EPO and reticulocyte counts showed. All these changes were statistically significant. The experiment, conducted in realistic conditions of dive length, oxygen concentration and pressure, allows us to formulate some hypotheses about the role of prolonged hyperbarism on erythropoiesis. The s-EPO rise, 24 h after resurfacing, is clearly documented and related to the "Normobaric Oxygen Paradox". This evidence suggests interesting hypotheses for new clinical applications such as modulation of s-EPO production and Hgb content triggered by appropriate O2 administration in pre-surgical patients or in some anemic disease. PMID- 23670360 TI - Validity and reliability of the G-Cog device for kinematic measurements. AB - The aim of this study was to test the validity and the reliability of the G-Cog which is a new BMX powermeter allowing for the measurements of the acceleration on X-Y-Z axis (250 Hz) at the BMX rear wheel. These measurements allow computing lateral, angular, linear acceleration, angular, linear velocity and the distance. Mechanical measurements at submaximal intensities in standardized laboratory conditions and during maximal exercises in the field conditions were performed to analyse the reliability of the G-Cog accelerometers. The performances were evaluated in comparison with an industrial accelerometer and with 2 powermeters, the SRM and PowerTap. Our results in laboratory conditions show that the G-Cog measurements have low value of variation coefficient (CV=2.35%). These results suggest that the G-cog accelerometers measurements are reproducible. The ratio limits of agreement of the rear hub angular velocity differences between the SRM and the G-Cog were 1.010 * / 1.024 (95%CI=0.986-1.034) and between PowerTap and G Cog were 0.993 * / 1.019 (95%CI=0.974-1.012). In conclusion, our results suggest that the G-Cog angular velocity measurements are valid and reliable compared with SRM and PowerTap and could be used to analyse the kinematics during BMX actual conditions. PMID- 23670361 TI - The spirografic oxygen deficit: its role in cardiopulmonary exercise testing. AB - The increase in oxygen uptake > 100 ml . min-1 during steady state exercise when elevating the inspired fractional air content (FinO2) from 0.21-1.00 defines the "spirografic oxygen deficit" (SOD). The purpose of this study was 2-fold: 1) determine the SOD at different exercise intensities in healthy participants and 2) investigate if a correlation exists among key variables of cardiopulmonary exercise testing. 12 men (24+/-2 yrs; 183+/-4 cm; 83.5+/-5.3 kg) performed cycle tests to determine maximal power output (Pmax), the power output at the first (PVT1) and the second ventilatory threshold (PVT2), at 4 mmol . l-1 blood lactate (P4) and lactate threshold (PLT). When cycling at 30, 40, 50, 60, 70 and 80% Pmax, the FinO2 was increased from 0.21-1.00 after 5 min to assess the power output at the SOD and at which blood lactate increased > 1 mmol?L-1 (PLLAC). The SOD occurred at 70% Pmax accompanied by increased blood lactate concentration (p<0.01). The PSOD correlated with PLACC (p=0.05; r=0.61), but not with PVT1, PVT2, P4, or PLT (best p=0.29; highest r=0.39). In conclusion, the SOD may represent a non-invasive tool for evaluating submaximal endurance performance, especially when evaluating the peripheral contribution to performance. PMID- 23670362 TI - Does the application of kinesiotape change scapular kinematics in healthy female handball players? AB - Elastic taping is widely used in sports medicine for correcting functional alignment and muscle recruitment. However, evidence regarding its influence on scapular dynamic positioning is scarce. This study aimed to investigate the effect of a specific kinesiotaping method on scapular kinematics in female elite handball players without shoulder complaints. 25 athletes (18.0+/-1.5 years) active in the highest national division were recruited. All subjects received an elastic adhesive tape (K-active tape(c)) with the purpose to correct scapular position. 3-dimensional scapular motion measurements were performed (Fastrak(r)) during humeral elevation in the sagittal, frontal and scapular plane. The results showed that taping has a moderate to large effect (Cohen's d>0.7) towards scapular posterior tilting, in all 3 planes of humeral movement and for all angles of elevation (mean posteriorizing effect of 4.23 degrees , 3.23 degrees and 4.33 degrees respectively for elevation in the sagittal, frontal and scapular plane, p<0.001). In addition, taping also moderately increased the scapular upward rotation at 30 degrees , 60 degrees and 90 degrees of humeral abduction (mean increase of 2.90 degrees , Cohen's d>0.7). Together these results suggest that kinesiotape application causes positive changes in scapular motion. This could support its use in sports medicine for preventing shoulder problems in overhead athletes. PMID- 23670363 TI - Hypoxanthine as a predictor of performance in highly trained athletes. AB - Purine metabolism reflects the exercise-induced muscle adaptations and training status. This study evaluated the utility of plasma hypoxanthine in the prediction of actual sport performance. We studied male athletes: 28 triathletes (21.4+/-2.9 years), 12 long-distance runners (23.2+/-1.9 years), 13 middle-distance runners (22.9+/-1.8 years) and 18 sprinters (22.0+/-2.7 years). Season-best race times were considered, achieved over standard triathlon, 5 000 m, 1 500 m and 100 m, respectively. Incremental treadmill test was administered to determine maximum and "threshold" oxygen uptake. Resting and post-exercise plasma concentrations of hypoxanthine, xanthine, uric acid and lactate were measured as well as resting erythrocyte hypoxanthine-guanine phosphoribosyltransferase activity. Simple and multiple regression analyses were used to identify significant contributors to the variance in performance. Hypoxanthine considered alone explained more variance in triathletes, long-distance runners, middle-distance runners and sprinters (r 2=0.81, 0.81, 0.88 and 0.78, respectively) than models based on aerobic capacity and lactate (R 2=0.51, 0.37, 0.59 and 0.31, respectively). Combining purine metabolites and cardiorespiratory variables resulted in the best prediction (R 2=0.86, 0.93, 0.93 and 0.91; r=0.93, 0.96, 0.96 and 0.95, respectively). In summary, hypoxanthine is a strong predictor of performance in highly trained athletes and its prediction ability is very high regardless of sport specialization, spanning the continuum from speed-power to endurance disciplines. PMID- 23670364 TI - Mathematical modeling of a carrier-mediated transport process in a liquid membrane. AB - An analysis of the reaction diffusion in a carrier-mediated transport process through a membrane is presented. A simple approximate analytical expression of concentration profiles is derived in terms of all dimensionless parameters. Furthermore, in this work we employ the homotopy perturbation method to solve the nonlinear reaction-diffusion equations. Moreover, the analytical results have been compared to the numerical simulation using the Matlab program. The simulated results are comparable with the appropriate theories. The results obtained in this work are valid for the entire solution domain. PMID- 23670365 TI - Development of a porous poly(DL-lactic acid-co-glycolic acid)-based scaffold for mastoid air-cell regeneration. AB - OBJECTIVES/HYPOTHESIS: To develop a porous, biodegradable scaffold for mastoid air-cell regeneration. STUDY DESIGN: In vitro development of a temperature sensitive poly(DL-lactic acid-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) scaffold tailored for this application. METHODS: Human mastoid bone microstructure and porosity were investigated using micro-computed tomography. PLGA/PEG-alginate scaffolds were developed, and scaffold porosity was assessed. Human bone marrow mesenchymal stem cells (hBM-MSCs) were cultured on the scaffolds in vitro. Scaffolds were loaded with ciprofloxacin, and release of ciprofloxacin over time in vitro was assessed. RESULTS: Porosity of human mastoid bone was measured at 83% with an average pore size of 1.3 mm. PLGA/PEG-alginate scaffold porosity ranged from 43% to 78% depending on the alginate bead content. The hBM-MSCs proliferate on the scaffolds in vitro, and release of ciprofloxacin from the scaffolds was demonstrated over 7 to 10 weeks. CONCLUSIONS: The PLGA/PEG alginate scaffolds developed in this study demonstrate similar structural features to human mastoid bone, support cell growth, and display sustained antibiotic release. These scaffolds may be of potential clinical use in mastoid air-cell regeneration. Further in vivo studies to assess the suitability of PLGA/PEG-alginate scaffolds for this application are required. PMID- 23670366 TI - [The trajectory of the Brazilian School Nutrition Program between 2003 and 2010: report of the national manager]. AB - The scope of this paper is to study the report of the manager of the Brazilian School Nutrition Program (PNAE), with special emphasis on the period from 2003 to 2010. It is a critical essay based on a review of the literature and the official data. It was revealed that the program spent 954.2 million Brazilian reals in 2003 to assist 37.3 million students, and in 2010 the total resources increased to 3 billion Brazilian reals with 45.6 million students attended. Other important advances were the broadening and strengthening of the role of the School Nutrition Councils and the regulatory strategies of nutritionists as Accountable Technicians. Law No. 11.947/2009 gave a new impetus to the PNAE, extending the program to the entire basic public education grid and youths and adults, and recommending that 30% of the funds transferred from the FNDE should be used to acquire products from small farmers. The progress in technical and operational criteria seeking greater flexibility, efficiency and effectiveness in the management of the Program is clear for all to see. It is hoped that these advances will translate into effective improvement in food and nutrition conditions for schoolchildren. PMID- 23670367 TI - [Reflections on the activities of nutritionists on the Brazilian School Nutrition Program]. AB - The scope of this study is to reflect on the activities of nutritionists in the Brazilian School Nutrition Program, with emphasis on the number of professionals and the attributes, advances and challenges facing these professionals. A critical analysis was conducted based on a review of the literature and official data provided by the National Fund for the Development of Education (NFED) of the Brazilian Ministry of Education. Between the years 2003 to 2011, the percentage of Brazilian municipalities with nutritionists rose from 12% to 79%. The northern region had the lowest percentage of local municipalities covered by nutritionists registered with the NFED (59%) in 2011 and the southern region had the highest percentage (85%), while the national average was 79%. The findings reflect a certain inequality in the distribution of nutritionists among the different regions of Brazil. The diverse activities of these professionals in the Program suggest the need for ongoing updating and training. It is also necessary to comply with and monitor the numerical parameters of reference for hiring nutritionists in the different municipalities and states of the country. PMID- 23670368 TI - [Panorama of purchasing food products from family farmers for the Brazilian School Nutrition Program]. AB - This article seeks to describe the viewpoint of purchasing food products from family farmers, analyzing their performance within the new guidelines of the Brazilian School Nutrition Program (PNAE). It is a critical assessment based on a review of the literature and the official data provided by the National Fund for the Development of Education/Ministry of Education relating to 2010. The program budget in 2010 was approximately R$2.5 billion and attended 45.6 million children, adolescents and adults. From the total amount, R$150,397,052.68 was allocated for the purchase of agricultural products from family farmers. In Brazil, 47.4% of the local councils acquired food products from family farmers for the Brazilian School Nutrition Program and the purchase percentage was, on average, 22.7%. Given the nature of recent legislation, other aspects should be explored in order to strengthen the compliance with the regulations in different Brazilian contexts and thus contribute both to local economic development and the provision of school meals which fulfill the principles of a healthy and adequate diet. PMID- 23670369 TI - [School nutrition and autonomy - challenges and opportunities]. AB - This study seeks to emphasize school food as an important policy to promote student autonomy by means of food and nutrition education included in the curriculum, integrated with different actors and based on the standpoint of citizenship. It seeks to return to fundamental concepts in the context of school food reflecting on them through theoretical assumptions to identify possible strategies to promote citizenship and autonomy in school. The strategies involved food and nutrition education with the daily presence of quality and suitability in school meals, discussions on the various dimensions of food in the curriculum and integrating food in the pedagogical project extended to various areas of the education system. School food fosters the need for integration of actions, actors and the various social spaces interested in the food issue, such as ministries, education systems, departments and schools, so that they may tackle the demands of contemporary reality in an integrated, systematic, consistent and efficient manner. PMID- 23670370 TI - [Instrument for assessment of best practices in school food and nutrition units: from design to validation]. AB - The scope of this study was to elaborate and validate an assessment tool for Best Practices in School Food and Nutrition Units. For this purpose a survey was conducted in the city of Santos (Sao Paulo - Brazil), in two stages: 1) Preparation of a Checklist for Best Practices in School Food and Nutrition Units (BPAE checklist). 2) Validation of the BPAE checklist. This checklist was applied in 76 public schools along with two other reference checklists. Sensitivity and specificity were estimated using the Receiver Operating Characteristics (ROC) Curve and the checklist was evaluated by application of the Likert scale. The thematic groups received weights to calculate the percentage of adequacy. After the application of the checklists in schools, the area under the curve value of 0.79 was found for the SS-196 checklist and 0.85 for the 542/2006 administrative checklist. These values indicate good suitability of the BPAE checklist to identify inadequacies, and it also received a positive assessment from the school food nutritionists. It proved that the checklist will assist in decision-making to ensure quality control. Once the BPAE checklist has been fully tested and validated it should prove an important tool for quality control in school nutrition. PMID- 23670371 TI - [Evaluation of the presence of hygienic and sanitary indicator microorganisms in food served in public schools in Porto Alegre, Brazil]. AB - The objective of this study was to evaluate the presence of hygienic and sanitary indicator microorganisms in samples of food served in public schools in Porto Alegre. All the food served in the meal of the session visited was analyzed for Escherichia coli, coagulase-positive Staphylococcus, Salmonella sp. and Shigella sp. Of the total of 196 food products analyzed in 120 schools, 4 contained and Escherichia coli score above the permitted level, and 2 contained coagulase positive Staphylococcus. Neither Shigella nor Salmonella genus were detected. In the majority of schools studied, it was found that food was of an adequate hygienic-sanitary standard. However, only municipal schools had the supervision of a technician responsible for school food. In the state schools, 60% had never been visited by a nutritionist and in these schools several procedures failed to comply with legal requirements. In most of the schools studied, the food served to students was within adequate standards, though the problems detected revealed the need for the implementation of Best Practices in the school environment. PMID- 23670372 TI - [The Brazilian School Nutrition Program from the standpoint of students attending state schools in Minas Gerais, Brazil]. AB - The scope of this article is to analyze the Brazilian School Nutrition Program from the standpoint of students attending state schools in Minas Gerais. It is a qualitative and quantitative cross-sectional study with a sample of 1500 students, representing the population of the state schools of Minas Gerais, involving the administration of a semi-structured questionnaire. The data were analyzed using simple frequency, mean, standard deviation, Fisher's exact test, the chi-square test and logistic regression (p < 0.05, CI 95%). The effective acceptance of the program was 28.8% and the effective adhesion to the program was 45.1%. Program acceptance was significantly higher among males and students who consumed less extra-institutional food. Acceptance and adhesion to the program was significantly higher among the older students and those who reported participating in activities related to nutritional education. In total, 73.5% of the students suggested improvements in school food. Many of the program's norms and guidelines are not being implemented. The acceptance of school food was negatively influenced by the consumption of extra-institutional foods and positively influenced by food and nutritional education activities. PMID- 23670373 TI - [Municipal School Nutrition Councils in Santa Catarina, Brazil: characterization and performance profile]. AB - The aim of this study is to assess Municipal School Nutrition Councils (CAEs) of the Brazilian School Nutrition Program (PNAE) in the state of Santa Catarina, Brazil. A cross-sectional study was conducted with a sample of municipalities in the state (n = 152; 52%). CAE presidents were interviewed and asked about the counselor profile, attributions performed and the relation of CAEs with other local councils. Poisson regression analysis was conducted to obtain unadjusted and adjusted prevalence ratios and the adjusted model adopted a hierarchic approach. The majority of councils analyzed their accounting reports, monitored resources and strived for quality of the CAEs at all levels. They coordinated the storage of food, participated in establishing the menu, monitored the purchasing of food and had an internal control system. However, only 22.4% carried out all their attributions once or more per year. A positive association was found between an adequate performance of the CAE and relations with other local councils. The awareness of the CAEs, as well as a stimulus to acting jointly with other councils and actors involved with food and nutrition security, are essential to ensure the right to healthy and adequate nutrition at school. PMID- 23670374 TI - [School: a place for studying and eating]. AB - This study seeks to discuss the significance of school nutrition expressed by students in public schools from the state of Bahia, Brazil. The objective is to understand the symbolic aspects associated with school nutrition. The results of a survey into the significance of nutrition offered by the Brazilian School Nutrition Program (PNAE) expressed by students from six public schools in municipalities in the state of Bahia, Brazil, are presented. A qualitative approach to understand nutrition at school and notions about healthy food by analyzing oral and written narratives of adolescents is used. The reports point to opposing stances between food in the home and food outside the home. What is customary can appear strange depending on the time and place. In this sense, they do not make an association between healthy food and PNAE. The food culture requires students to eat food on two occasions: breakfast and lunch (or dinner). These are aspects that are distinct, however they must be combined in school, because for these social actors, studying and eating are necessities that complement each other. PMID- 23670375 TI - [School nutrition in 'quilombola' communities: challenges and opportunities]. AB - The Brazilian School Nutrition Program (PNAE) is a Food and Nutritional Security (SAN) strategy for public school students. This article seeks to discuss the challenges and opportunities of school nutrition in 'quilombola'* communities and report on the experience of the Cooperation Center for Student Food and Nutrition of the Federal University of Goias and the Midwest Region (CECANE UFG/ Centro Oeste). It includes a report on the experience with the systematization on PNAE, SAN and other policies. Continued access and adequate social policies are a challenge for the 'quilombola'* communities. Some economic, structural and social barriers have been identified in PNAE. In this context, Law 11.947/2009 encourages local development, with the acquisition of food from the region, and it establishes differentiated values per capita, which are translated into menus including products inherent to Afro-Brazilian culture that provide at least 30% of daily nutritional requirements. In the nutrition, health and quality of life project of 'quilombola'* schoolchildren, the CECANE UFG/Midwest carry out food and nutritional security actions. The area of school nutrition has proven responsive to local needs and supports the development and promotion of quality of life. PMID- 23670376 TI - [In-service training for pedagogical coordinators in school nutrition: the report of an experience]. AB - This article describes the experience of in-service training for pedagogical coordinators of the Brazilian School Nutrition Program (PNAE) developed by the Cooperation Center for Student Food and Nutrition of the Federal University of Bahia (CECANE-UFBA). Participant observation and analysis of data documented in films, group discussion summaries, procedural and final evaluations and field diaries are used. The formative experiences were in 2011, in two municipalities in Bahia and Sergipe states, involving 118 pedagogical coordinators from 79 municipalities in both states. It was revealed that the objective of raising awareness and guiding pedagogical coordinators for mainstreaming the theme of food and nutrition has been achieved. The educational proposal was evaluated by the coordinators as "dynamic," "productive" and "interactive," promoting the exchange of experiences among participants. Despite considering the theme relevant, the pedagogical coordinators do not have sufficient training about food and nutrition to back their teaching practices. It is considered that their training has some limitations on the impact in the fieldwork, as the knowledge acquired night be dissipated when the coordinators return to their workplace due to the lack of ongoing training. PMID- 23670377 TI - [Training for nutritionists working on the Brazilian School Nutrition Program: an evaluation of its effectiveness]. AB - This article seeks to verify the effectiveness of training for nutritionists conducted by the Cooperation Center for Student Food and Nutrition of the Federal University of Rio Grande do Sul (CECANES UFRGS), between 2007 and 2009. The focus of the evaluation was to observe the perception of those subjects with regard to achieving the objectives of the training and the potential of the training topics covered in the training in order to change the day-to-day work of the Brazilian School Nutrition Program (PNEA). Methodology developed by the CECANES UFRGS team was used for the evaluation of effectiveness. Data collection was conducted with 118 nutritionists who work in school nutrition in the state of Rio Grande do Sul by filling out an electronic questionnaire specifically designed for this study. In the analysis of the results it was revealed that the training fulfilled its objectives (P < 0.05), making the assignments and what is expected of the professionals at PNAE clear to more than 95% of the nutritionists. When the participants were asked about the obstacles encountered, they reported difficulty in adapting the theory covered in the training with the reality in which they act. The themes addressed contributed to the promotion of changes in the implementation of management practices in the PNAE. PMID- 23670378 TI - [The experience of the Permanent Workshop on Health and Nutrition Education - OPEAS: training of professionals for the promotion of healthy nutrition in schools]. AB - This article analyzes the experience of the Permanent Workshop on Nutrition and Health Education, which provides ongoing education on health and nutrition for school nutritionists and educators. In 2009, nutritionists, principals/management assistants, pedagogical coordinators, teachers and nutrition undergraduates attended 10 workshops, which were based on Freire and Pichon-Riviere's framework theories. Data analysis was performed using the Discourse of the Collective Subject method. At the beginning of their participation in the OPEAS, the relationship between educators and nutritionists was distant and few interdisciplinary activities were conducted. Communication among the school team, collaborative work with involvement of the whole school community, inclusion of food and nutrition education in the curricula, and provision of food as the central pedagogical tool were considered central to the promotion of healthy nutrition. In the final evaluation four central ideas were highlighted defining OPEAS as being important for knowledge acquisition, a setting for reflection, an opportunity for integration and a platform for putting ideas into practice. Ongoing education should be implemented with school professionals aiming to foster actions to promote healthy nutrition at school. PMID- 23670379 TI - [Quality of life of professors of higher education community institutions in the state of Rio Grande do Sul, Brazil]. AB - Quality of life is the subjects' perception of their status in society, permeated by culture, values and everyday life and with a view to their life goals and expectations as well as the ways of thinking about life. The study investigated the quality of life of professors of higher education community institutions that have been in operation for more than 40 years and have more than ten thousand students in the State of Rio Grande do Sul. The research, with a qualitative quantitative cross-sectional approach was conducted in August and September 2011 using a professional profile questionnaire and the WHOQQL-BREF questionnaire, in which 203 professors participated, namely 17% of all the professors in the three institutions analyzed. When the quality of life rate was analyzed according to the teachers' education, the 22 specialists scored highest in the psychological field (72.1 +/- 3.1) and lowest in the social field (69.3 +/- 4.4). Among the 125 masters and the 43 PhD's, the highest scores were found in the physical domain (74.8 +/- 1.3 and 75.7 +/- 2.1, respectively) and the lowest in the environmental field (69.4 +/-1.0 and 70.8 +/- 1.8). The conclusion reached was that the quality of life of the professors was considered good in the fields analyzed. There was no significant statistical difference among them. PMID- 23670380 TI - [The prevalence of morbidity and symptoms among the elderly: a comparative study between rural and urban areas]. AB - A cross-sectional study was conducted with the elderly population in rural and urban areas characterized by the prevalence of morbidity and symptoms, and 229 elderly people were interviewed. The average age was 72.3, of which 57.2% lived in the rural zone and 56.3% were female. The morbidities most reported were insomnia (37.7%), anxiety (32.1%), depression (26.7%), and in the rural zone it was diabetes (13.3%). In this zone, Alzheimer's disease was more prevalent among the elderly who handled pesticides (21.7%). The most prevalent symptoms among urban zone residents were: cough/runny nose and sight alterations (41.2%), allergy/itching (11.4%). In the rural zone, dry mouth (25.4%), sight alterations (35.6%) and leg pain (66.1%) were also more prevalent among those who used pesticides. The inadequate use of Individual Protection Equipment was 85.4%, and 45.1% also disposed of pesticide packaging inappropriately. The setting up of public health programs is necessary to promote health among the elderly and the potential exposure to pesticides for this population should be seen as a health risk determinant. PMID- 23670381 TI - [The profile of women with high fertility in a major urban center in Brazil]. AB - A quantitative, descriptive study sought to identify the socio-demographic, reproductive and social protection conditions of women in a large city in Brazil. The target population consisted of women living in Curitiba with the last of five or more children born in the year 2005, identified by the registration system of newborn babies. Interviews in households were carried out with 441 women from 2006 to 2008 using a semi-structured questionnaire. Data obtained from the study were presented in tables with absolute and relative frequencies, averages and standard deviations. The following profile was derived from the results: migrant women from the state interior, living for over ten years in the capital, coming from large families, with a mean age of 35 years and five years of schooling, with more than one marriage, living in consensual union, underemployed, with an average income of around US$ 352 to cover the needs of seven or more dependents. This profile clearly confirms the social vulnerability of these women and their families. The study concludes that a proactive search by family health teams for women with high fertility, in order to prioritize their needs, would assist in reducing their social and health inequalities. PMID- 23670382 TI - [Vulnerability to burnout among physicians at a public hospital in Recife]. AB - This study identified factors associated with burnout among physicians at a public hospital in Recife, Brazil. A self-administered questionnaire (socio demographic characteristics, working conditions and Maslach Burnout Inventory) was completed by 158 physicians (92.4%). Burnout was defined by a superposition of high scores in emotional exhaustion (EE) and depersonalization (DP) and low scores on personal accomplishment at work (PA). Chi-square and Fisher's exact test were used in the analysis and 5.1% had burnout. Female physicians were predominant in the sample (83.5%) especially those for longer than ten years in the profession (81.6%). High levels were found in EE (61.4%) and DP (36.7%) and low levels in PA (13.3%). There was an association between: high EE and "often/always" working very fast and "never/rarely" having enough time for tasks; high level of DP and working ten years in the profession and "often/always" doing tasks very fast; low level of PA and being female and "never/rarely" having enough time for tasks. Burnout and "often/always" working very quickly, "never/sometimes" having enough time for tasks, being male and having no expectation of professional growth. For 37.3%, two of the three dimensions indicate a high propensity to burnout, making transformation in working conditions a priority. PMID- 23670383 TI - [The role of midwives and nurse-midwives in promoting safe motherhood in Brazil]. AB - Brazil needs to improve maternal and perinatal health care, given the high rates of morbidity, mortality and cesarean sections, the medicalization process of the female body and the violation of the sexual and reproductive rights of women during pregnancy and childbirth. Based on the contribution of international researchers and agencies to address these issues, the scope of this text is to provide theoretical input to support the proposal of the promotion of safe motherhood that requires the active participation of midwives and nurse-midwives. These are professionals who, from the perspective of health promotion, can collaborate in the establishment of an effective network of care, whose basic premise is the humanization of care based on scientific evidence in order to improve the experience of women and the family in the process of pregnancy, childbirth and postpartum. PMID- 23670384 TI - [The socio-economic, epidemiological and pharmaco-therapeutic profile of institutionalized elderly individuals in Brasilia, Brazil]. AB - The aim of this study is to describe the socioeconomic, epidemiological and pharmaco-therapeutic profile of 154 elderly individuals from five homes for the aged in Brasilia using a questionnaire adapted from the Dader method and supplemented with information from medical records. The sample is made up of single people and widowers, mostly men, mean age of 74.6 years, with preserved cognition, low income and low education level. The group consumes between four and five medicines and is mainly affected by cardiovascular and psychiatric diseases. The drugs most used are cardiovascular and psychotropic medication. The adherence to pharmacotherapy is prejudiced by lack of knowledge about current medical prescription, difficulty of access and refusal to use prescribed medicines. Results suggest that this profile influences the quality and effectiveness of pharmacotherapy showing the need for pharmacotherapeutic follow up for these patients as well as public health policies more focused on the specificities of the elderly to provide better quality of life and reduction of costs with health assistance. PMID- 23670385 TI - [Child health promotion: a physiotherapeutic approach]. AB - This article seeks to analyze the state-of-the-art physiotherapeutic actions geared to children, with a focus on health promotion, in the available literature. Thus, by questioning ideas present in the production of knowledge, the intention is to contribute with input for the formulation of principles for physiotherapy to promote actions of comprehensive health care for children. In terms of methodology, the study consisted of a bibliographical review of a qualitative nature, focusing on articles available in national and international virtual libraries and databases. Four pivotal themes that permeate the discussion were singled out, namely: physiotherapy from the perspective of promoting the health of children; bodily practices at different levels of care; physiotherapy for children on a community basis; and cooperation between sectors. The discussions of the literature consulted made it possible to establish parameters for the development of physiotherapy geared to children from a health promotion standpoint. PMID- 23670386 TI - [The thesis of judicialization of health care by the elites: medication for mucopolysaccharidosis]. AB - This paper evaluates the hypothesis that the judicialization of medicine for mucopolysaccharidosis in Brazil is an action promoted by economic elites. Previous studies upholding the thesis of judicialization by elites in the case of other types of medication that are more costly for the Unified Health Service are discussed. An analysis of all 196 processes containing information about judicial processes brought to court between February 2006 and December 2010 that ended by determining that the State should provide such medication free of charge to patients was conducted. There is evidence that attorneys' fees were covered by entities interested in the results of judicialization, such as the distributors or pharmaceutical industries. Patients may also be migrating for diagnosis and treatment to university centers that are a benchmark for medical innovation in the country, as the option for public health services is related to their higher technical and scientific capacity. Therefore, the resort to private lawyers, indicators of social exclusion based on the address of patients and the use of public health services, are not adequate class information to corroborate or refute the thesis of judicialization by the elites. PMID- 23670387 TI - [Perception of health professionals from Psychosocial Care Centers (CAPS I) regarding the demands related to the use of crack]. AB - This paper presents qualitative research analyzing two focus groups with twenty workers in Psychosocial Care Centers (CAPS I) in Porto Alegre, southern Brazil, in 2009. They were invited to discuss overwork and dissatisfaction with work in general and also recent demands of crack cocaine users on the local mental health networks. Workers in both groups reported a strong concern about the instability of employment contracts, leading to limited ability to plan their futures. In addition, the accumulation of tasks to replace absenteeism in teams leads to a limited interest in long-term action planning and the option for less complex tasks. Court orders, the interference of public officials and requests of hospitalization, are considered unfavorable routine conditions in the perception of health workers, as well as uncooperative and quarrelsome family members and unmotivated users for resuming treatment. The teams seem to be the center of a conflict between the impossibility of avoiding the emergence of demands of crack users who apply to local health networks and the limits established by management, increasing dissatisfaction and perceived overwork. PMID- 23670388 TI - [Prevalence of eating disorders in urban workers in a city of the northeast of Brazil]. AB - This article seeks to estimate the prevalence of eating disorders among workers living in urban areas of Feira de Santana, Bahia. It involves an epidemiologic, descriptive and exploratory cross-sectional study of 1,273 randomly selected workers. Socio-demographic and work characteristics, lifestyle, psychosocial aspects at work and eating behavior were investigated. Females were predominant (60.2%), the youngest 51.7% were up to 35 years old, married (53.1%), Afro Brazilian descent (55.2%), with high school education (51.5%) and with low incomes (81.2%). The prevalence of Binge Eating Disorder and Bulimia Nervosa were, respectively, 4.3% and 1%. The prevalence of these disorders was higher among workers who indulged in excessive alcohol consumption, were dissatisfied with their personal appearance and weight, reported violence in childhood and had financial problems or related worries. Also included were those involved in house care services and commerce, who had informal work arrangements or were in highly demanding work environments. Besides investigating the relation between eating disorders and work, data was provided about these disorders in a population-based study. It is hoped that this study may encourage investments in health policies for these disorders. PMID- 23670389 TI - [Campaign against smoking in a home for the elderly: the report of an experiment]. AB - Studies on institutionalized elderly smokers are important for developing appropriate preventive measures. This was a cross-sectional population-based study of individuals over 60 admitted to a Home for the Elderly in the Federal District. The following aspects were investigated: smoking prevalence, socio demographic and clinical profile, gender, education, probable depression, degree of motivation to stop smoking, prior use of medication to stop smoking and perception of the harm of smoking to health. Spirometry, the measurement of exhaled carbon monoxide and classification according to severity of nicotine dependence were conducted. The program followed guidelines for stopping smoking, and was evaluated one year later. Results revealed that 25.7% were smokers, 22.8% men and 2.9% women, mean age 68.3 +/- 8.5 years. A significant decrease in smoking among the more elderly was detected. Significant associations emerged between the degree of nicotine dependence and education, probable depression, degree of motivation for stopping smoking and perception of the harm of smoking to health. Higher indices of carbon monoxide were identified in individuals with severe obstruction. Initially, 37.9% of smokers agreed to participate in the campaign, and after a year 9% of them succeeded in stopping smoking. PMID- 23670390 TI - [Contexts and patterns of undue use benzodiazepine among women]. AB - The undue use of benzodiazepines particularly among women has raised concern in the public health area. This qualitative study aimed at understanding the beliefs and values associated with undue use of benzodiazepines among women. Thirty-three participants (aged between 18 and 60) with a history of undue use of benzodiazepines in the past year were selected intentionally using specific criteria. The interviews were fully transcribed and subjected to content analysis using NVivo software. The majority of respondents reported use for longer than the recommended duration (median 7 years) and they purchased the drug with a medical prescription. Reasons for use most given were to deal with anxiety, to improve sleep and to "flee from problems." Even those who acknowledged the possibility of being addicted were not motivated to stop taking the drug. Medical supervision did not necessarily seem to influence the perception of risk of undue use of benzodiazepines and it appears as a factor favoring the maintenance of prolonged use. PMID- 23670391 TI - [Could endogamy explain the higher prevalence of disabilities in the population of the Brazilian Northeast?]. AB - Despite conceptual inaccuracies and methods of measurement, the WHO estimates that about 10% of the world population has some form of disability. In order to investigate the prevalence and etiology of disabilities and to evaluate if they could be associated with inbreeding, a cross-sectional epidemiological study was conducted using the informant method in five communities of the state Rio Grande do Norte in the Brazilian Northeast, in which consanguineous marriages frequencies varied between 9 and 32%. The average prevalence of disabilities in the five sampled communities was 4.53%, obtained by interviews that involved 37.87% of a population of 39,054 inhabitants. On average, 25% of consanguineous and 12% of non-consanguineous couples had one or more children with disabilities. The increased rate of individuals with disabilities in the Brazilian Northeast could be associated with the maintenance of the tradition of consanguineous marriages in these populations and some of these disabilities may be caused by genetic disorders. PMID- 23670392 TI - [Health and gender relations: a reflection on the challenges for the implementation of public policies for health care for indigenous women]. AB - This article presents some contrasts that exist between the discourses of public policies concerning women's health care, especially with respect to indigenous women, and the ethnological discourse which emphasizes the specificity of gender relations within indigenous societies. We worked on the assumption that the development of these public policies as well as the organization of health care services offered, which in fact are necessary, have a transforming effect on prevailing gender relations within Amerindian Societies. On the one hand, gender relations between indigenous people are associated with the domains of kinship and corporeality. On the other hand, the process of creating public policies, by means of biomedical intervention and the medicalization of the female body, constitutes a powerful tool for body modeling and the construction of subjectivities contributing to making women worthy of citizenship. The female gender is under discussion and its content is being negotiated. PMID- 23670393 TI - [Reproductive risk and family income: analysis of the profile of pregnant women]. AB - Faced with the challenge of tackling maternal and perinatal morbidity and mortality, the discussion of reproductive risk and its association with health vulnerability situations is relevant to public health. The research carried out at Instituto Fernandes Figueira/Fiocruz sought to describe the reproductive risk profile of women admitted to prenatal care between 2006 and 2008 and investigating its relation to family income and health vulnerability situations. This is a cross-sectional study which used the prenatal care database as its source. The economic profile of the group under scrutiny is a low income group. An association between low income and fetal malformations, pregnancy before 15 years of age, and HIV was detected. A higher family income was associated with the mother's age over 35 years, abnormal nuchal translucency, gynecopathies, and habitual abortion. The findings may reflect vulnerability situations of low income women, such as unfavorable health conditions and limited access to and use of health services. It is necessary to acquire in-depth knowledge of the reproductive risk profile in Brazil and its distribution according to socio demographic characteristics, seeking to enhance health care practices provided. PMID- 23670394 TI - [In situ genotoxity evaluation of triazines using Tradescantia clone 4430 Trad SHM bioassay]. AB - Tradescantia 4430 clone stamen hair mutation (Trad-SHM) bioassay was used to evaluate the genotoxicity of a herbicide composed of triazines (atrazine and simazine) after in situ exposure. Thirty plant pots were exposed during the herbicide application (test group) and a control group was maintained in a greenhouse (control group). Genotoxicity was expressed in terms of pink mutation events (EMPs) and the data analysis was performed by Student's t test comparing the control and contaminated group after eight-days (C8D = 8-day control; T8D = 8 day test) and peak day (CPD = peak day control; TPD = peak day test). Exposure to the herbicide caused a significantly higher number of EMPs in the test group (T8D = 2.27; TPD = 4.69) than in the control group (C8D = 0.71; CPD = 0.62). This demonstrates that the Trad-SHM bioassay is sensitive and efficient and can be used as tool to assess the genotoxic potential of environmental contaminants like triazines associated with adverse effects on human health. PMID- 23670395 TI - [When does a proposition not become a policy?: the case of the Brazilian Comprehensive Health Care Policy for Adolescents and Youths - PNAISAJ - in Brazil]. AB - The last three decades have been fertile for the establishment of public policies geared to comprehensive health care for various population groups in Brazil. The scope of this article is to present the partial results of the analysis of the narratives of actors who participated in the creation of the Comprehensive Health Care policy for Adolescents and Youths - PNAISAJ in Brazil, in order to explore the lack of consensus in this process. The analysis was based on the narratives of eight actors who participated in the process and sought to identify the thematic units that express the lack of consensus by a comprehensive analysis based on Bourdieu's sociological perspective. We conclude that the non legitimation of a national policy for this population group manifests the non recognition of adolescents and youths as autonomous subjects and protagonists on policy decisions that affect them. Although youth participation in political texts is stated as a new paradigm for comprehensive health care promotion for adolescents and young people, we conclude that what prevails culturally is the legitimation of other significances. These are significances according to the broader interests and understanding of adolescence and youth at social levels, interpreted as cultural policies. PMID- 23670397 TI - [Attitudes related to consent for organ and tissue donation for research in Brazil]. PMID- 23670398 TI - Peripherally applied synthetic peptide isoAsp7-Abeta(1-42) triggers cerebral beta amyloidosis. AB - Intracerebral and intraperitoneal inoculation with beta-amyloid-rich brain extracts originating from patients with Alzheimer's disease as well as intracerebral injection of aggregates composed of synthetic Abeta can induce cerebral beta-amyloidosis, and associated cognitive dysfunctions in susceptible animal hosts. We have found that repetitive intravenous administration of 100 MUg of synthetic peptide corresponding to isoAsp7-containing Abeta(1-42), an abundant age-dependent Abeta isoform present both in the pathological brain and in synthetic Abeta preparations, robustly accelerates formation of classic dense core congophilic amyloid plaques in the brain of beta-amyloid precursor protein transgenic mice. Our findings indicate this peptide as an inductive agent of cerebral beta-amyloidosis in vivo. PMID- 23670399 TI - Population-based analysis of prognostic indicators in sebaceous carcinoma of the head and neck. AB - OBJECTIVES/HYPOTHESIS: Due to the rarity of sebaceous carcinoma of the head and neck, few large series have been reported and prognostic factors remain largely undetermined. This study presents prognostic factors in survival in sebaceous carcinoma of the head and neck. STUDY DESIGN: Retrospective analysis was performed using the Surveillance Epidemiology and End Results (SEER) database for patients diagnosed with sebaceous carcinoma of the head and neck (SCHN). METHODS: Clinicopathologic, treatment data, and 5-year disease specific survival were analyzed using univariable and multivariable regression analysis and Kaplan-Meier methodology. RESULTS: Of the 1,433 patients identified to have SCHN, 16 were node positive (1.14%). On multivariable analysis, independent prognostic indicators were: age at diagnosis (HR = 1.03, P = .021), tumor grade (HR = 4.97, P = .038), and distant metastasis (HR = 7.52, P = .006). Nodal metastasis occurred exclusively with poorly or undifferentiated tumors and was not a significant prognostic factor on multivariable analysis. CONCLUSION: Elderly patients and patients with poorly differentiated tumors and/or distant disease at presentation have the highest risk of disease-specific mortality. Lymph node metastasis does not appear to be an independent prognostic factor in sebaceous cell carcinoma. PMID- 23670400 TI - Development of Cre-loxP technology in zebrafish to study the regulation of fish reproduction. AB - One cannot seek permission to market transgenic fish mainly because there is no field test or any basic research on technological developments for evaluating their biosafety. Infertility is a necessary adjunct to exploiting transgenic fish unless completely secure land-locked facilities are available. In this study, we report the generation of a Cre transgenic zebrafish line using a cytomegalovirus promoter. We also produced fish carrying the Bax1 and Bax2 plasmids; these genes were separated by two loxP sites under a zona pellucida C promoter or were driven by an anti-Mullerian hormone promoter. We inserted a red fluorescent protein gene between the two loxP sites. After obtaining transgenic lines with the two transgenic fish crossed with each other (Cre transgenic zebrafish x loxP transgenic zebrafish), the floxed DNA was found to be specifically eliminated from the female or male zebrafish, and apoptosis gene expressions caused ovarian and testicular growth cessation and degeneration. Overexpression of the Bax1 and Bax2 genes caused various expression levels of apoptosis-related genes. Accordingly, this transgenic zebrafish model system provides a method to produce infertile fish and may be useful for application to genetically modified fish. PMID- 23670401 TI - The evaluation of a fast and simple pesticide multiresidue method in various herbs by gas chromatography. AB - In this study two analytical methods, one based on matrix solid phase dispersion (MSPD) and the other on liquid-solid extraction (LSE), coupled with gas chromatography, were evaluated and used to determine the presence of 163 pesticides (6 acaricides, 62 fungicides, 18 herbicides and 77 insecticides) in various herbs. Both methods were optimized considering different parameters (sample to sorbent mass ratio, extracting solvent, sorbents for clean-up step, etc.). The results of these validated sample preparation procedures were compared. Under optimum conditions, the mean recoveries obtained were in the range of 70-119% for MSPD for most pesticides and 70-118% for LSE, but with several exceptions. Precision values, expressed as relative standard deviation (RSD), were <=16% for MSPD and <18% for LSE. Correlation coefficients were higher than 0.99254 for both methods. LODs (limits of detection) and LOQs (limits of quantification) for MSPD were within the ranges of 0.003-0.03 and 0.005-0.04 mg/kg, respectively. The data demonstrate that the MSPD method was successfully used for the analysis of 163 pesticides in the following herbs: chamomile (Matricaria chamomilla L.), linden (Tilia), lungwort (Pulmonaria L.), melissa (Melissa L.), peppermint (Mentha piperita L.) and thyme (Thymus vulgaris L.). This paper indicates the potential of MSPD for qualitative and quantitative analysis of pesticide residues. This method was therefore validated at three spiking levels (the first ranging from 0.005 to 0.05 mg/kg, the second from 0.05 to 0.5 mg/kg and the third from 0.25 to 2.5 mg/kg) and applied to real samples (n = 15). MSPD proves to be a simple, fast and very useful multiresidue method and can be recommended for routine pesticide monitoring studies in various herbs. PMID- 23670402 TI - High domain wall velocities via spin transfer torque using vertical current injection. AB - Domain walls, nanoscale transition regions separating oppositely oriented ferromagnetic domains, have significant promise for use in spintronic devices for data storage and memristive applications. The state of these devices is related to the wall position and thus rapid operation will require a controllable onset of domain wall motion and high speed wall displacement. These processes are traditionally driven by spin transfer torque due to lateral injection of spin polarized current through a ferromagnetic nanostrip. However, this geometry is often hampered by low maximum wall velocities and/or a need for prohibitively high current densities. Here, using time-resolved magnetotransport measurements, we show that vertical injection of spin currents through a magnetic tunnel junction can drive domain walls over hundreds of nanometers at ~500 m/s using current densities on the order of 6 MA/cm(2). Moreover, these measurements provide information about the stochastic and deterministic aspects of current driven domain wall mediated switching. PMID- 23670403 TI - Exacerbation of symptoms in agricultural pesticide applicators with asthma. AB - PURPOSE: Exacerbation is a critical event in asthma management. We investigated whether exacerbation of symptoms is associated with farming exposures among agricultural pesticide applicators with asthma. METHODS: Participants were pesticide applicators with active asthma (wheezing and breathing problems in past 12 months) who completed enrollment questionnaires for the Agricultural Health Study (AHS). Exacerbation of asthma was defined as having visited a hospital emergency room or doctor for an episode of wheezing or whistling in the past 12 months. Exposures of interest were using 36 specific pesticides in the past 12 months and conducting various agricultural activities. Adjusted odds ratios (ORs) were estimated by logistic regression while controlling for potential confounders. RESULTS: The 926 AHS adult pesticide applicators with active asthma included 202 (22%) with exacerbation. Inverse associations with exacerbation were observed for two herbicides [glyphosate, odds ratio (OR) = 0.5, 95% confidence interval (CI) 0.3, 0.8, and paraquat, OR = 0.3, 95% CI 0.1, 0.9] and several agricultural activities (repairing engines, grinding metal, driving diesel tractors, and performing veterinary procedures). Only asthma cases with allergies (i.e., doctor-diagnosed hay fever or eczema, 46%) had positive exacerbation pesticide associations, with OR = 2.1 (95% CI 1.1, 4.1) for the herbicide pendimethalin and OR = 10.2 (95% CI 1.9, 55) for the insecticide aldicarb. CONCLUSIONS: The inverse associations with two pesticides and specific farm activities are consistent with the possibility that asthma cases prone to exacerbation may avoid exposures that trigger symptoms. Although limited by small sample size and a cross-sectional design, our study suggests that use of specific pesticides may contribute to exacerbation of asthma among individuals with allergies. PMID- 23670405 TI - Cost of care according to disease-modifying therapy in Mexicans with relapsing remitting multiple sclerosis. AB - Limited data exist on the costs of care of patients with multiple sclerosis (MS) in low- to middle-income nations. The purpose of this study was to describe the economic burden associated with care of Mexican patients with relapsing-remitting MS in a representative sample of the largest institution of the Mexican public healthcare system. We analysed individual data of 492 patients (67% women) with relapsing-remitting MS registered from January 2009 to February 2011 at the Mexican Social Security Institute. Direct costs were measured about the use of diagnostic tests, disease-modifying therapies (DMTs), symptoms control, medical consultations, relapses, intensive care and rehabilitation. Four groups were defined according to DMT alternatives: (1) interferon beta (IFNbeta)-1a, 6 million units (MU); (2) IFNbeta-1a, 12MU; (3) IFNbeta-1b, 8MU; and (4) glatiramer acetate. All patients received DMTs for at least 1 year. The most frequently used DMT was glatiramer acetate (45.5%), followed by IFNbeta-1a 12MU (22.6%), IFNbeta 1b 8MU (20.7%), and IFNbeta-1a 6MU (11.2%). The mean cost of a specialised medical consultation was ?74.90 (US $107.00). A single relapse had a mean total cost of ?2,505.97 (US $3,579.96). No differences were found in annualised relapse rates and costs of relapses according to DMT. However, a significant difference was observed in total annual costs according to treatment groups (glatiramer acetate being the most expensive), mainly due to differences in unitary costs of alternatives. From the public institutional perspective, when equipotent DMTs are used in patients with comparable characteristics, the costs of DMTs largely determine the total expenses associated with care of patients with relapsing remitting MS in a middle-income country. PMID- 23670406 TI - Remarkable effect of benzodiazepine in a patient with anti-NMDA receptor encephalitis. PMID- 23670407 TI - DVT and pulmonary embolism with stroke. PMID- 23670408 TI - Spinal dermal sinus with dermoid cyst. PMID- 23670409 TI - Theoretical prediction of new noble-gas molecules FNgBNR (Ng = Ar, Kr, and Xe; R = H, CH3, CCH, CHCH2, F, and OH). AB - We have computationally predicted a new class of stable noble-gas molecules FNgBNR (Ng = Ar, Kr, Xe; R = H, CH3, CCH, CHCH2, F, and OH). The FNgBNR were found to have compact structures with F-Ng bond lengths of 1.9-2.2 A and Ng-B bond lengths of ~1.8 A. The endoergic three-body dissociation energies of FNgBNH to F + Ng + BNH were calculated to be 12.8, 31.7, and 63.9 kcal mol(-1), for Ng = Ar, Kr, and Xe, respectively at the CCSD(T)/CBS level. The energy barriers of the exoergic two-body dissociation to Ng + FBNH were calculated to be 16.1, 24.0, and 33.2 kcal mol(-1) for Ng = Ar, Kr, and Xe, respectively. Our results showed that the dissociation energetics is relatively insensitive to the identities of the terminal R groups. The current study suggested that a wide variety of noble-gas containing molecules with different types of R groups can be thermally stable at low temperature, and the number of potentially stable noble-gas containing molecules would thus increase very significantly. It is expected some of the FNgBNR molecules could be identified in future experiments under cryogenic conditions in noble-gas matrices or in the gas phase. PMID- 23670410 TI - Associations of T helper 1, 2, 17 and regulatory T lymphocytes with mortality in severe sepsis. AB - OBJECTIVE AND DESIGN: T helper 17 (Th17) and regulatory T (Treg) lymphocytes might play important roles in patients with severe sepsis. The association of Th17 or Treg lymphocytes with survival is also unclear. METHODS: Eighty-seven patients with severe sepsis were enrolled from our intensive care units between August 2008 and July 2010. Leukocyte antigens and clinical data were determined on day 1 in all patients and on day 7 in first-year patients. RESULTS: The percentages in peripheral blood mononuclear cells (PBMCs) and circulatory counts of CD4+ and CD8+ lymphocytes in survivors were higher than those in non survivors. Th1/CD4+ ratios and circulatory Th1 lymphocyte counts in survivors were higher than in non-survivors. Absolute counts of Th17 and Treg lymphocytes in survivors were higher than in non-survivors. The percentages of CD4+ and CD8+ in survivors' PBMCs were increased after 6 days. Th17/CD4+ ratios and circulatory Th17 lymphocyte counts in survivors were increased after 6 days. CONCLUSIONS: Higher Th1 differentiation and total CD4+ T lymphocyte counts were associated with higher survival. The association of circulatory Th17 and Treg lymphocytes with mortality in severe sepsis may be due to the change in total CD4+ T lymphocytes. In survivors, Th17 differentiation and counts were restored. PMID- 23670436 TI - Using 2,6-dichlorobenzamide (BAM) degrading Aminobacter sp. MSH1 in flow through biofilters--initial adhesion and BAM degradation potentials. AB - Micropollutants in groundwater are given significant attention by water companies and authorities due to an increasing awareness that they might be present even above the legal threshold values. As part of our investigations of the possibility to remove the common groundwater pollutant 2,6-dichlorobenzamide (BAM) by introducing the efficient BAM degrader Aminobacter sp. MSH1 into biologically active sand filters, we investigated if the strain adheres to filters containing various filter materials and if the initial adherence and subsequent degradation of BAM could be optimized. We found that most of the inoculated MSH1 cells adhered fast and that parameters like pH and ionic strength had only a minor influence on the adhesion despite huge influence on cell surface hydrophobicity. At the given growth protocol, the MSH1 strain apparently developed a subpopulation that had lost its ability to adhere to the filter materials, which was supported by attempted reinoculation of non-adhered cells. Analysis by quantitative PCR showed that most cells adhered in the top of the filters and that some of these were lost from the filters during initial operation, while insignificant losses occurred after 1 day of operation. The inoculated filters were found to degrade 2.7 MUg/L BAM to below 0.1 MUg/L at a 1.1-h residence time with insignificant formation of known degradation products. In conclusion, most filter materials and water types should be feasible for inoculation with the MSH1 strain, while more research into degradation at low concentrations and temperatures is needed before this technology is ready for use at actual waterworks. PMID- 23670437 TI - The ethicist as language czar, or cop: "end of life" v. "ending life". AB - Bioethics promises a considered, unprejudicial approach to areas of medical decision-making. It does this, in theory, from the perspective of moral philosophy. But the promise of fairly considered, insightful commentary fails when word choices used in ethical arguments are prejudicial, foreclosing rather than opening an area of moral discourse. The problem is illustrated through an analysis of the language of The Royal Society Expert Panel Report: End of Life Decision Making advocating medical termination. PMID- 23670438 TI - Facet-dependent catalytic activity of platinum nanocrystals for triiodide reduction in dye-sensitized solar cells. AB - Platinum (Pt) nanocrystals have demonstrated to be an effective catalyst in many heterogeneous catalytic processes. However, pioneer facets with highest activity have been reported differently for various reaction systems. Although Pt has been the most important counter electrode material for dye-sensitized solar cells (DSCs), suitable atomic arrangement on the exposed crystal facet of Pt for triiodide reduction is still inexplicable. Using density functional theory, we have investigated the catalytic reaction processes of triiodide reduction over {100}, {111} and {411} facets, indicating that the activity follows the order of Pt(111) > Pt(411) > Pt(100). Further, Pt nanocrystals mainly bounded by {100}, {111} and {411} facets were synthesized and used as counter electrode materials for DSCs. The highest photovoltaic conversion efficiency of Pt(111) in DSCs confirms the predictions of the theoretical study. These findings have deepened the understanding of the mechanism of triiodide reduction at Pt surfaces and further screened the best facet for DSCs successfully. PMID- 23670439 TI - Connective tissue growth factor induces hepatic progenitor cells to differentiate into hepatocytes. AB - Connective tissue growth factor (CTGF) plays an important role in the proliferation of hepatic progenitors, however, little is known concerning the mechanism(s) through which it influences their differentiation. The differentiation of hepatic progenitors (WB-F344), either stimulated with recombinant CTGF or stably transfected with a CTGF overexpression plasmid, was investigated. Expression of the differentiation markers alpha-fetoprotein (AFP), albumin (ALB) and cytokeratin-19 (CK-19) was assessed. To confirm the effects of CTGF on progenitor differentiation, cells were treated with an inhibitor (WP631) of CTGF. Treatment of WB-F344 cells with recombinant CTGF for 24 h did not change the survival rate significantly, but the progenitors were enlarged with a decreased nuclear/cytoplasmic ratio. CTGF downregulated the expression of the fetal hepatocyte marker, AFP, while it upregulated the mature hepatocyte cell marker, ALB. The effect of CTGF overexpression plasmid on WB-F344 cell differentiation was consistent with a pattern of direct CTGF stimulation, including decreased AFP and increased ALB expression. Furthermore, the suppression of CTGF induction by an inhibitor was associated with significant inhibition of hepatic progenitor cell differentiation into hepatocytes. Importantly, we showed that differentiated WB-F344 cells by CTGF had in vitro functions characteristic of hepatocytes, including ALB production, glycogen storage and cytochrome P450 activity. Both recombinant CTGF and the CTGF overexpression plasmid induced hepatic progenitor differentiation into hepatocytes. This was suppressed by the CTGF inhibitor. PMID- 23670440 TI - Successful prevention of no-reflow phenomenon in a high-risk patient using excimer laser coronary atherectomy. AB - During the treatment of coronary artery disease, the no-reflow phenomenon can lead to severe impairment of viable cardiac muscle and all necessary measures should be taken to prevent it. Excimer laser coronary atherectomy (ELCA) may be indicated for lesions with a large thrombus burden due to potential to ablate thrombi and necrotic plaques. However, there are few reports on the use of ELCA for the prevention of distal embolism. Here, we report a case involving severe left ventricular dysfunction with a previous extensive anterior infarction, where ELCA was used in the right coronary artery to prevent the no-reflow phenomenon. PMID- 23670441 TI - Guide wire shadow assessed by shading index is reduced in sparse spring coil wire in optical coherence tomography. AB - One of the major problems of a Fourier-domain optical coherence tomography (FD OCT) is the guide wire (GW) shadow which disturbs precise coronary assessment. If two or more GWs are used in a bifurcation PCI, the GW shadow becomes larger. In FD-OCT, GWs were usually observed as a crescent shape, but GWs with the sparse spring coil were observed as either round or crescent shape. The measured angle making GW shadow of GW without the sparse spring coil was similar to its theoretical angle (30.4 +/- 1.7 degrees vs. 30.1 +/- 0.7 degrees , p = 0.21); however, the measured angle of GW with the sparse spring coil was significantly smaller than its theoretical angle (16.8 +/- 4.8 degrees vs. 28.7 +/- 1.5 degrees , p < 0.01). For standardization of shading-effect of GW, a virtual diameter of GW which was calculated from a measured angle, an actual diameter of GW, and a distance between an imaging catheter and GW was defined as the shading index. The shading index of GW with the sparse spring coil was significantly smaller than that of GW without the sparse spring coil (0.008 +/- 0.002 vs. 0.014 +/- 0.001, p < 0.01). Shading indices of GWs with the sparse spring coil were smaller than their actual diameters. The sparse spring coil structure could contribute to the reduction of the GW shadow in FD-OCT. Also, we proposed the new and useful shading index to indicate the shading-effect of GW. PMID- 23670442 TI - Total lower lip reconstruction using free neurotendinofasciocutaneous anterolateral thigh composite flap: a case report. AB - Total lower lip reconstructions are challenging procedures because of poor aesthetic and functional outcomes and limited availability of donor tissues that anatomically imitate the lip. We hereby report the free neurotendinofasciocutaneous anterolateral thigh composite flap as a new reconstructive option. A 48-year-old man presenting with a squamous cell carcinoma of the lower lip underwent wide resection of tumor, bilateral neck dissection, and lower lip reconstruction with the mentioned flap where the lateral femoral cutaneous nerve and tensor fascia lata tendon were included. No complication was encountered postoperatively. The flap survived totally. Understandable speech, oral competence, and uneventful nutrition were obtained. Furthermore, tactile, pain and heat sensations, and two-point discrimination of 12 mm at the flap were regained. In reconstruction of the lower lip, this flap was first described in the literature and can be a good candidate as a reconstructive option. PMID- 23670443 TI - Distally based saphenous neurocutaneous perforator flap for reconstructive surgery in the lower leg and the foot: a long-term follow-up study of 70 patients. AB - BACKGROUND: The management of soft-tissue defects in the distal third of the lower leg and foot remains disputed. In this article, we describe a long-term follow-up research study on the clinical results and complications of using this flap for the reconstruction of soft-tissue defects around the lower leg and foot. METHODS: Between 2006 and 2008, 70 patients with soft-tissue defects around the lower leg and foot were treated with distally based saphenous neurocutaneous perforator flaps. The mean age of patients was 46.0 years (range, 22 to 70 years). An end point survey was performed after flap coverage; the mean follow-up was 54.2 months (range, 40 to 68 months), and response rate was 92.9% (65/70). A sensory morbidity was measured with a static two-point discrimination test and Semmes-Weinstein monofilament test. RESULTS: A total of 58 flaps survived completely, 6 flaps developed partial necrosis, and 1 experienced total failure. No severe venous congestion was observed and the skin grafts in the donor sites survived entirely. Sensitivity tests have shown an acceptable sensory recovery at the skin-grafted donor site and on the flap. CONCLUSION: Distally based saphenous neurocutaneous flap is a reliable and safe method for reconstruction of the defects around the lower leg and foot, with a lower sensorial morbidity. PMID- 23670444 TI - Hemodynamic effect of different kinds of venous augmentation in a pig transmidline flap model of DIEP flap. AB - BACKGROUND: Venous augmentation enhances the viability of the deep inferior epigastric perforator (DIEP) flap. We compared the efficacy of three venous superdrainage procedures on survival area and hemodynamics of the DIEP flap model. METHODS: In 24 castrated Yorkshire pigs, a true abdominal perforator-based flap was created based on four perforators arising from the deep superior epigastric vessels. Three remaining venous tracts were alternated to represent different venous augmentations of the DIEP flap. Analyzed were flap perfusion, venous blood pressure, and venous blood gas. In control animals, all three supplemental veins were ligated; the ipsilateral superficial superior epigastric vein (SSEV) was retained in the IS (ipsilateral SSZV augmented) group, the contralateral SSEV in the CS (contralateral SSZV augmented) group and the contralateral deep superior epigastric vein (DSEV) in the CD (contralateral DSZV augmented) group. The flap was then returned to its bed, and animals sacrificed on the seventh day postoperatively. DIEP flap survival was then recorded. RESULTS: All four intraoperative parameters showed improved perfusion of the distal flap area under distal venous augmentation. Efficacy was CDSEV > CSSEV > ISSEV > none. Skin islands of the CD and CS groups survived completely. In the IS and control groups, 96.33 +/- 3.16% and 84.00 +/- 7.55% of skin islands survived, respectively. Test groups were statistically significantly different from the control group but not from each other. CONCLUSIONS: Venous superdrainage effectively enhances DIEP flap survival. Benefit was relatively the same for all procedures. An additional venous route should be preserved with large or multiterritory flaps to improve venous congestion. PMID- 23670445 TI - [Monitoring of performance of health surveillance management: tools and strategies of use]. AB - A tool is proposed to monitor the performance of Health Surveillance at state level and strategies for broadening its use. The use of participatory methodologies in all stages of monitoring is recommended, from designing the tool to the analysis and interpretation of indicators. This can be a way of involving stakeholders and improving their joint responsibilities in decision-making, thus increasing the use of the monitoring tool. The monitoring instrument was built after the design of the logical model of the management of health surveillance and indicators of each component of management were submitted to a validation process. Monitoring is understood as a reflexive practice that promotes personal and institutional learning, continuous enhancement of management processes, greater transparency and accountability, besides its operational use for decision making. PMID- 23670446 TI - [Challenges and potential of monitoring the management of health surveillance in the Unified Health Service (SUS)]. PMID- 23670447 TI - [Reflections on the process of monitoring the management of health surveillance actions]. PMID- 23670448 TI - [From monitoring of performance to the performance of monitoring: new opportunities for evaluation in the management of Health Surveillance]. PMID- 23670449 TI - [The authors reply]. PMID- 23670450 TI - [Production of information on mortality from external causes: meanings and significances in the filling out of death certificates]. AB - The study sought to understand the meanings and significances that physicians attribute to the Death Certificate (DO) and the implications of subjectivity in the production of information on mortality. Guided by qualitative research, semi structured interviews and content analysis, techniques were chosen for understanding representations and experiences involved in the filling out of the DO. The results revealed that different meanings and significances are attributed to the DO depending on how death occurred, in accordance with the different attributes the document acquires from a practical standpoint, in terms of 'epidemiological' and 'legal' functions. The results suggest that the DO used as a technical and objective instrument for data collection and production of health statistics does not lack subjectivity, which turns it into an instrument that in the medical practice and social reality reflects cultural issues, the social position of the subjects who fill it out and their representations of death. PMID- 23670451 TI - [Accidents between motorcycles: analysis of cases that occurred in the state of Parana between July 2010 and June 2011]. AB - Statistics for accidents between two motorcycles have been overlooked in the vast number of traffic accidents in Brazil, though they deserve closer analysis. This study sought to conduct an epidemiological analysis into accidents between two motorcycles compared with other accidents based on data in the state of Parana. Information from the Fire Department site was collected for a period of one year (July 2010 to June 2011), reporting the number and type of accident, day of the week, time, number of victims, gender, age and severity of injuries. Accidents involving two motorcycles represented 3.4% of traffic accidents and 6.2% of accidents involving motorcycles; and the victims of these accidents accounted respectively for 4.4% of victims of traffic accidents and 8.5% victims of motorcycle accidents. Accidents occurring on Saturdays involving males aged between 20 and 29 were more common. Among the ten most populated cities in the state, some revealed high accident rate between two motorcycles, which appears to be related to the total number of motorcycles in the cities concerned. Thus, constant analysis of these indices is essential together with the implementation of measures to ensure safer highway traffic. PMID- 23670452 TI - [Amphetamine use by truck drivers on highways of Sao Paulo State: a risk for the occurrence of traffic accidents?]. AB - The use of amphetamines in Brazil is common among truck drivers, which may be an important factor in the occurrence of traffic accidents. This article seeks to estimate the prevalence of amphetamine use among truck drivers. Drivers (N = 134) were stopped on two different highways in Sao Paulo state and they were asked to answer a questionnaire and provide a urine sample for toxicological analysis. All data were analyzed on Stata 8.0. All participants were males with low levels of schooling, whose mean age was 40.8 years. The presence of amphetamines was detected in 10.8% of all urine samples collected, being commonly justified in order to make truck drivers able to maintain their state of awareness. Amphetamine use was detected among truck drivers on Sao Paulo highways. The problem is that when the stimulant effects wear off, sleepiness due to sleep deprivation reduces concentration and good driver performance, making drivers vulnerable to traffic accidents and the related effects. PMID- 23670453 TI - [Mortality due to bicycle accidents in Pernambuco, Brazil]. AB - The scope of this paper was to conduct a quantitative analysis of deaths resulting from bicycle accidents in the state of Pernambuco by studying secondary data between 2001 and 2010. The sample consisted of all the Deaths recorded in the Mortality Information System of the Unified Health System Database that reported bicycle accidents between 2001 and 2010. Descriptive measures were determined for all variables. Socio-demographic variables were paired with the basic cause of death in order to find a statistical correlation. In Pernambuco, the aforementioned information system recorded 517 deaths resulting from bicycle accidents, with greater frequency in men between 25 and 59 years of age, Afro Brazilians, single and of unknown schooling. The mean age was 36.82 years (SD = 17.026), and the minimum and maximum age of 4 and 86 years old, respectively. The findings highlight the need for the creation of adequate infrastructure and effective legal measures to prevent traffic accidents involving this type of vehicle, relying on the evidence of distribution of cases in most Pernambuco municipalities. PMID- 23670454 TI - [Notification of violence as a strategy for health surveillance: profile of a metropolis in Brazil]. AB - Violence is a serious public health problem and notification of incidents is fundamental for epidemic surveillance and for the definition of priorities and public politics of health prevention and promotion. The study sought to characterize the occurrence of domestic violence, sexual and other forms of violence, based on the information of the database of the Information System of Notification of Offences (Sinan), on the records of violence of the city of Belem in the state of Para, in the period from January 2009 to December 2011. In this period 3,267 notifications were recorded, which represented an increase of 240% in the number of notifications of the year 2009 compared to 2011. In relation to the sex of the victims it was observed that, on average, 83.2% of cases against women and this proportion was similar in all three years analyzed. Sexual violence was the most prevalent with 41.8% of reported cases; followed by psychological violence at 26.3% and physical violence at 24%. The results show that notification is fundamental for understanding the profile of violence and for intervention and elaboration of integrated public politics that promote health and the quality of life in this area of Brazil. PMID- 23670455 TI - [Exposure to violence among adolescents in a low-income community in the northeast of Brazil]. AB - This a cross-sectional study made in Fortaleza, Ceara, 2009, which included 458 teenagers and analyzed their exposure to violence, describing their access to weapons, alcohol abuse, illegal drug use and their self-esteem by investigating their socio-economic, school and family characteristics and exposure to the phenomenon. A questionnaire and/or structured interviews were used for data collection, and analysis involved Pearson's chi-square test, with 95% reliability. Of the 458 participants, 17.7% were considered to be exposed to criminal violence. Significant variables for exposure to violence included: place of birth (p = 0.020), years of schooling (p = 0,009), school absenteeism (p < 0.001), the father as the head of the family (p = 0.026), alcohol-addicted parents (p < 0.001), good/very good family relationships (p = 0.009), and parents' dissatisfaction with their children's friends (p < 0.001). Thus, it is necessary that public policies focus on a support network for care of adolescents and that urban centers organize themselves socially and politically in the quest for understanding the effects of exposure to violence among adolescents in low income communities. PMID- 23670456 TI - [Violence in old age: the issue addressed in indexed national journals]. AB - One of the consequences of increased life expectancy is the increase in the elderly population in many countries, including Brazil. Considering the vulnerability of this age group and the increasing prevalence of violence against the elderly, there is a pressing need for research and control interventions to minimize the phenomenon. This exploratory and descriptive article conducts an analysis into this topic in indexed Brazilian studies in SciELO, with special emphasis on the last five years. The themes were categorized into: Social construction and conceptualizations, 37.5%; Elderly Care and Protection Policies, 43.75%; and Typology of violence against the elderly, 18.75%. The results show that the Policy of protection of the elderly permeates the majority of discussions about violence in old age and the focus of the researchers' attention is on domestic violence, which needs to be broadened in field research. PMID- 23670457 TI - [The configuration of the social network of women living in domestic violence situations]. AB - This article presents the configuration of the social network of women living in domestic violence situations in a city in the metropolitan region of Sao Paulo, Brazil. Interviews were conducted with 9 women and 8 professionals, in addition to observation in three institutions which constitute the network for protection of women. The analysis was underpinned by the theoretical assumptions of social networks. Results show that violence inflicted upon women by their partners make them unable to establish and maintain social bonds, and thus face isolation and ostracism. Professionals and institutions can play a vital role for getting women out of the cycle of violence provided that care networks and services are well organized. Further studies of social networks, focusing on the nature of the links and exchanges among actors may contribute to acquiring knowledge about the relationship dynamics in situation of violence. PMID- 23670458 TI - [The epidemiological profile of HIV-positive individuals and HIV-Leishmaniasis co infection in a referral center in Sao Luis, Maranhao, Brazil]. AB - AIDS is a public health problem and visceral leishmaniasis (VL) is the most frequent co-infection. This study seeks to describe the epidemiological aspects of HIV-positive individuals and to investigate the occurrence of HIV-Leishmania co-infection. It is a descriptive study with 287 HIV=positive individuals assisted at the reference center for HIV/AIDS in Sao Luis, MA. Montenegro's intradermal reaction and bone marrow aspiration were performed for detecting the Leishmania sp. infection. Epidemiological data were collected by means of a questionnaire. The chi-square test was used for gender differences, with p < 0.05 of statistical significance level. There was statistical significance among men regarding the use of septic tanks, and income of up to two salaries. Regarding exposure, heterosexual orientation was the most frequent category for both genders, and we observed an increase in this category among women. Among HIV positive individuals, 4.2% had suggestive symptoms of VL with identification of Leishmania amastigotes in bone marrow aspirate (myelogram). The profile of HIV positive individuals did not differ from what is commonly found in Brazil, with predominance of young people of productive age. Furthermore, a superposition of the transmission areas for HIV-LV co-infection was found. PMID- 23670459 TI - [Predictors of unawareness of HIV serostatus among women submitted to the rapid HIV test at admittance for delivery]. AB - This article aims to analyze factors associated with unawareness of prenatal HIV serostatus at admittance for delivery. A cross-sectional study was performed in 2006 in "Friends of Children" Hospitals from the High-risk Pregnancy System, belonging to the Unified Health System, in Rio de Janeiro City. Data were collected through interviews applied to 873 rooming-in mothers submitted to a rapid HIV test at the hospital. Prevalence ratios (PR) of the lack of HIV serologic status were estimated by Poisson regression with robust variance, controlled by maternal and familiar socio-demographic characteristics, pregnancy and prenatal care. Prevalence of unawareness of HIV status was 32.2%. Mothers with low educational level, low-income, more than one relationship in the last year, enrolling late in prenatal care, and low number of prenatal visits were more likely to have unknown HIV status. The main predictor for unawareness of HIV serostatus at hospital admittance was the low number of prenatal visits. It is recommended that coverage of HIV testing during prenatal care be broadened with timely delivery of results, improving early access of pregnant women and increasing the number of prenatal visits, focusing on clients with low socio economic level. PMID- 23670460 TI - [Methodological problems in the scientific research on HIV /AIDS in Bolivia]. AB - This paper discusses the methodological problems in the scientific research on HIV/AIDS in Bolivia, both in the areas of epidemiology and social sciences. Studies associated with this research served as the basis for the implementation of health programs run by The Global Fund, The Pan-American Health Organization, International Cooperation, Non-Governmental Organizations and the Bolivian Ministry of Health and Sports. An analysis of the methodological contradictions and weaknesses was made by reviewing the bibliography of the studies and by conducting qualitative methodological research, that was focused on the quality of health care available to people living with HIV/AIDS in public hospitals and health centers, and looked at how programs targeted at this sector of the population are designed and delivered. In this manner, it was possible to observe the shortcomings of the methodological design in the epidemiological and social science studies which serve as the basis for the implementation of these health programs. PMID- 23670461 TI - [Prevalence of latent infection of mycobacterium tuberculosis among healthcare students in a public university in Vitoria, state of Espirito Santo, Brazil]. AB - This article seeks to determine the prevalence of Mycobacterium tuberculosis infection in medical and nursing students of the Federal University of Espirito Santo (UFES) This is a cross-sectional study in which data were collected through a questionnaire assessing personal characteristics, information about tuberculosis, use of preventive measures, etc. This was followed by the application of the tuberculin skin test, with readings after 72 hours by trained nurses, the positive cutoff point for the TST being 10 mm of induration in the 72 hour reading. Participants in the study included 225 volunteers, namely 98 Medical students and 127 Nursing students. A positive tuberculin skin test was found in 54 students of both courses, resulting in a prevalence of 24%. Among Nursing Students the result of a positive TST was obtained in 24% and in 23%, of Medical Students, such that this difference was not statistically significant. It is necessary to carry out a routine program of tuberculin testing, for confirmation, combined with interventions to reduce the risk of nosocomial transmission in the workplace, as well as further studies to evaluate the effectiveness of new tests to detect latent tuberculosis infection. PMID- 23670462 TI - [Treatment of syphilis during pregnancy: knowledge, practices and attitudes of health care professionals involved in antenatal care of the Unified Health System (SUS) in Rio de Janeiro City]. AB - This article seeks to evaluate knowledge, practices and attitudes of health care workers (HCW) involved in antenatal care in the Unified Health System (SUS) in Rio de Janeiro City (RJC) and to identify major barriers to the implementation of treatment for syphilis in pregnancy care protocols. A cross-sectional study was conducted with 102 HCW in antenatal care at SUS, corresponding to 70% of the eligible pool. Univariate and bivariate analysis were performed using SPSS version 16.0. A number of barriers were identified with respect to knowledge of and familiarity with the current protocols, difficulties related to DST management, relationship with patients and clinics organizational context, which were distinct according to the type of health unit. HCW who had greater access to training and technical manuals had a better performance, although the overall effect was discrete. Identifying barriers to adherence to health care protocols is essential to formulate intervention strategies. Access to protocols through training and technical manuals showed a discrete effect in the improvement of the care delivered to patients, pointing to the need of innovative ongoing education of HCW. PMID- 23670463 TI - [Factors associated with alterations in lung function among workers in the ceramics industry]. AB - This article seeks to assess lung function in workers of ceramic industries in the municipality of Varzea Grande - Mato Grosso. A cross-sectional study of 183 workers was conducted in the ceramics town of Varzea Grande (MT). A structured questionnaire was used to identify socio-demographic factors, environmental factors and smoking. and spirometry was performed to evaluatie the pulmonary function. Descriptive analysis and bivariate and multiple Poisson regression were performed. The workers are mostly male (94%) with a predominance of individuals aged 39 years (74.9%). The prevalence of respiratory symptoms was 44.9%, 14.8 patients with symptoms considered serious and 30.1% with non-serious symptoms. Associations were found of abnormal pulmonary function with the variables of exposure time and substance inhaled. Employees with four or more years of exposure had 1.99 times more lung function alterations than individuals with exposure time of up to 3 years; individuals who had inhaled dust and mold release had 2.97 times higher alteration in lung function. The change in lung function in workers assessed is related to longer exposure and inhalation of dust and mold release. PMID- 23670464 TI - [Evaluation of the strategy for identification and measurement of the fatal accidents at work]. AB - In order to evaluate the strategy used by the Municipal Health Department of Belo Horizonte (SMSA/BH) for reducing the under-reporting of deaths from work-related accidents during the years of 2008 to 2010, a deterministic comparison of data on deaths from work-related accidents as reported in SINAN and SIM was conducted. As a complementary strategy to the deterministic comparison, the Investigation Data Sheets and Death Certificates were analyzed, which although not clearly declared, were suspected of involving death by work-related accident. Death from work accident was confirmed when the same victim, same accident, with a temporal connection between accident and death, were matched. The complementary strategy used by SMSA reduced the under-reporting identified by deterministic linking, with an increase of 45 deaths. Higher rates of under-reporting of deaths in the SINAN (n = 117) were found than in the SIM (n = 70). Although data linkage between SIM/SINAN is a necessary strategy to reduce the under-reporting of deaths from accidents, it is still insufficient, considering the limitations still present in both systems. The complementary strategy adopted by SMSA/BH, which is simple and easy to perform, yields good results. PMID- 23670465 TI - Neighborhood and postal worker characteristics associated with dog bites in postal workers of the Brazilian National Postal Service in Curitiba. AB - Dog bites are the third most common cause of absenteeism among postal workers of the Brazilian National Postal Service in Southern Brazil, with an average off work time of approximately two days for each biting episode. The objective of this study was to evaluate the neighborhood characteristics involving dog bites that occurred during work time in postal workers, its impact on work and consequent preventive alternatives. A descriptive and analytical cross-sectional study was designed for all Curitiba postal workers. Data were descriptively analyzed and the hypothesis of correlation between median monthly income, population density and occurrence of dog bites was tested. A total of 34.9% of the postal workers answered the questionnaire and 64.6% of them had been bitten while working. The odds of bites occurring in a neighborhood increase by 1.035 times for every increase in one unit in the population density and decrease by 0.998 times for every increase of US$ 1.00 in the neighborhood median monthly income of the head of the family. The occurrence of dog bites among postal workers in Curitiba is related to income and population density and prevention strategies should address mailbox position and adequate fencing to provide protection for postal workers. PMID- 23670466 TI - [Factors associated with the quality of life of community health agents]. AB - This study examined the association of socio-demographic, occupational and risk and health behavioral factors with the loss of quality of life for community health agents of the municipality of Jequie in the state of Bahia. It is a cross sectional study with 316 individuals, in which WHOQOL-Bref was used to evaluate the quality of life. The Poisson regression model was applied adopting the confidence interval of 95%. The variables associated with the largest threat to the Physical domain were gender, age, pain and satisfaction with health. Threats to the Psychological domain were schooling, psycho-social aspects, smoking, pain and satisfaction with health were analyzed. Threats to the Social Relations domain of were sex, marital situation, schooling, psycho-social aspects, and satisfaction with health. Threats to the Environmental domain were sex, family income, workplace, psycho-social aspects and satisfaction with health. It is hoped that this study will foster the development of public policies designed to enhance the conditions of life and work of this group of workers. PMID- 23670467 TI - [Factors associated with self-reported systemic arterial hypertension according to VIGITEL in 26 Brazilian capitals and the Federal District in 2008]. AB - The scope of this article is to study the association between lifestyle, nutritional status and the prevalence of self-reported systemic arterial hypertension, weighted by the system of risk and protective factors for Chronic Non-Communicable Diseases (CNCD) by telephone surveys and standardized by age and sex, in adults from 26 Brazilian state capitals and the Federal District in 2008. For each city the prevalence of hypertension was standardized by the direct method. Multiple linear regression analysis was performed between the factors of interest and the prevalence of hypertension, weighted and standardized by gender and age. After standardization, the prevalence of hypertension tended to increase in capitals with a younger population and decrease in those with a higher proportion of elderly individuals. In regression models, the prevalence of weighted and standardized hypertension remained associated with the prevalence of excess weight and the consumption of fruit and vegetables (FV). However, physical activity was only negatively associated with the weighted prevalence of hypertension. A positive association with weighted and standardized prevalence of hypertension was observed with excess weight and regular consumption of FV. PMID- 23670468 TI - [Blood pressure levels of Surui indigenous adults in Rondonia, Brazil]. AB - Indigenous peoples in Brazil are experiencing rapid epidemiologic and nutritional transition, with non-communicable diseases such as hypertension emerging in their health profile. A cross-sectional study was conducted in 9 Surui Indian villages (n-251 subjects) in Rondonia, Brazilian Amazon, in 2005, in order to assess blood pressure levels in adults (>20 years of age), as well as to investigate its possible relationship with nutritional and socioeconomic status (SES). Mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) were higher in men. On average, an increase in SBP of 7.9 mmHg and of 1.4 mmHg in women and men, respectively, was detected. SBP was positively correlated with waist-hip ratio (WHR) in both sexes and with age in women. DBP showed statistically significant correlations with all anthropometric variables, except height and arm muscle area. The prevalence of hypertension was 2.8% (M: 2.4%, F: 3.1%), being higher in subjects > 40 years with PC or high WHR, especially in women and also in the group that manifested lower SES. The study concludes that hypertension is an emerging health problem among the Surui. PMID- 23670469 TI - [Mortality due to circulatory disorders and the evolution of family health in Brazil: an ecological study]. AB - The scope of this study was to analyze deaths due to circulatory disorders in parallel with the evolution of the Family Health Strategy (FHS) in Brazil. It is an ecological and retrospective study based on the temporal evolution of the FHS and mortality rates due to circulatory disorders in Brazil. A description of the inhabitant x FHS coverage ratio and health indicators related to mortality due to circulatory disorders was carried out. Spearman's rank correlation coefficient test was used for the statistical association. There was a population increase of 15% in Brazil, evolution of 761% in the number of FHS units and 5% increase in mortality due to circulatory disorders. The population x FHS ratio rose from 52,838 (1998) to 7,084 (2006) people assisted by FHS units. North and northeast regions showed growth in mortality rates due to circulatory disorders and in 21 states (81%) there was a positive correlation between this mortality and FHS units (r: > 0.7; p < 0.01). Finally, the FHS is regarded as an important public health policy, which has achieved successful results in Brazil since its implementation. However, in general terms, its expansion has not influenced the reduction of mortality due to circulatory disorders, which is an indicator that has increased in the country. PMID- 23670470 TI - [Prevalence of abdominal obesity and excess fat in students of a city in the mountains of southern Brazil]. AB - Obesity is considered the most important nutritional disorder due to a rapid increase in its prevalence in recent years. The scope of this study was to estimate the prevalence of abdominal obesity and excess fat in students aged 11 to 14 (boys and girls) from a town in the mountains of southern Brazil, and to verify the possible associations with economic classification, gender, age, eating habits, lifestyle habits (physical activity and sedentary activities) and dissatisfaction with body image. A cross-sectional study was conducted with 1230 students. The anthropometric variables studied were the waist circumference and the skin folds of the triceps and calf. A descriptive and bivariate analysis was conducted between the independent variables and the outcome. The prevalence of abdominal obesity and excess body fat were 28.7% and 40.1% respectively. There was a statistically significant association between a greater number of meals and dissatisfaction with body image and abdominal obesity, which was also associated with girls evaluated, and to excess body fat. The prevalence of abdominal obesity and excess body fat are high and justify the implementation of health actions in schools. PMID- 23670471 TI - [Vitamin A deficiency in mothers and children in the state of Pernambuco]. AB - The prevalence and risk factors associated with vitamin A deficiency (VAD) were analyzed in 664 mothers and their 790 children under the age of five in Pernambuco in 2006. A population-based cross-sectional study, with a representative sample in urban and rural areas was conducted. VAD was defined as serum retinol levels < 20 mg/dL for both groups (mothers and children). Bi and multivariate analysis were performed using the complementary log-log model as a link function adopting a model of explanatory hierarchical order of VAD to children and a logistic model for mothers. The prevalence of VAD was 6.9% in mothers and 16.1% in their children, with similar statistics for urban and. rural groups. In the urban area, the housing occupation regime had a significant association with VAD in mothers. After the final adjustment of the model for urban children, the mother's age, the number of pre-natal consultations and birth weight were featured as predictive variables. In rural areas, VAD in mothers is associated with VAD in children; PR= 3.99 (95% CI:1.73-9.19), with their birth weight and the incidence of diarrhea in the previous 15 days. VAD continues to be a public health issue in the state of Pernambuco, with marked variations in prevalence and associated factors in mothers and children. PMID- 23670472 TI - [Use of local level indicators for the spatial analysis of morbidity due to diarrhea and its relation with lifestyle conditions]. AB - Every child had an average of three episodes of diarrhea per year in developing countries in the twentieth century. The decrease of the number of deaths due to diarrhea in Brazil was more closely related to the use of control techniques than to changes in lifestyle conditions. This article seeks to analyze the spatial distribution of morbidity due to diarrhea among children and its relation with lifestyle conditions. This was an ecological study, with the suburbs of the city of Itaborai as units of analysis. The population studied was the number of hospitalizations of children < 5 years for diarrhea between 2006 and 2009, available in Hospital Information Systems. The Diarrhea Hospitalization Ratio (DHR) indicator and Composite Lifestyle Quality (CLQ) indicator were established. Diarrhea still accounts for a large number of hospitalizations of children (15.5% between 2006 and 2009). The DHR was high in this period (69.7 hospitalizations/ 1.000 NV). The spatial analysis identified that the suburbs with the highest DHR were, in most cases, those with the highest population agglomerations and better lifestyle conditions. PMID- 23670473 TI - [Incidence of meningitis caused by Haemophilus influenzae in the state of Rio Grande do Sul 1999-2010: impact of vaccination campaign]. AB - This article seeks to analyze and update the epidemiological situation of meningitis caused by Haemophilus influenzae type b in the past 10 years in the state of Rio Grande do Sul (RS). It is a retrospective, descriptive study, which used the data notification system of meningitis and vaccination campaign coverage, stored in the Epidemiological TABNET online database, for the period from 1999 to 2010. Cases notified and confirmed were used and the selection criteria were the year when the symptoms were detected, age, diagnosis, and evolution. Nineteen health centers in the state of Rio Grande do Sul were analyzed. The z-test was used to evaluate comparisons between the proportions. In the period studied, 3043 confirmed cases of bacterial meningitis were reported, of which 6.77% were caused by H. influenzae. The incidence and mortality rates of meningitis caused by H. influenzae, without taking age group into consideration, fell significantly (95.6%) after 1999. Children under one year old continue to be the most affected (52%), there being no change in lethality. The results presented revealed a positive impact of Hib vaccination strategies in the state of Rio Grande do Sul over the past ten years. PMID- 23670474 TI - [Vaccine coverage related to lower mortality for respiratory diseases]. AB - Respiratory infections are a group of diseases commonly related to the elderly, since the influenza virus is one of the main etiological agents. Vaccination of these individuals is considered by the World Health Organization to be the most effective strategy to reduce morbidity and mortality from the disease. Brazil has sought in recent years to vaccinate 80% of the target population. This study sought to relate the vaccination coverage for influenza and the mortality rate from respiratory diseases in the elderly. This was a cross-sectional study with secondary data analysis. Data on vaccination coverage in 2010 of the 496 municipalities of the elderly in Rio Grande do Sul were obtained from the website of the National Immunization Program and mortality in the Mortality Information System. The results showed that 49% of municipalities reached the target of 80% of seniors vaccinated. In municipalities with below target vaccination coverage, the number of deaths was 5.2 per 1,000 elderly. This average is significantly higher than in municipalities with coverage equal to or above 80%. The conclusion is that the target proposed by the Brazilian Ministry of Health to vaccinate 80% or more of the elderly is effective in reducing mortality from respiratory diseases. PMID- 23670475 TI - Epidemiology of snakebite accidents in the municipalities of the state of Paraiba, Brazil. AB - Accidents involving venomous animals represent an important, albeit neglected, public health issue worldwide. A descriptive study was made of snakebite cases attended and recorded between 2007 and 2010 in the health units of the municipalities of Cariri, State of Paraiba, northeastern Brazil. Data was collected from the Injury Notification Information System data banks of the Health Ministry and a total of 351 records of snakebite victims were reviewed. Victims were predominantly male farm workers over 50. The highest incidence of snakebites occurred in rural areas, between April and June of 2007 and 2010. Snakes of the genus Bothrops were responsible for most cases, and victims were mostly bitten on the feet. The majority of the victims received medical assistance within 1 to 3 hours after being bitten. The most common clinical manifestations were pain, edema and ecchymosis, which were mainly classified as mild or moderate. Two deaths were reported. It was concluded that there is a significant impact of seasonality in snakebites, the prevalence of attacks caused by Bothrops, affecting the lower limbs of adult male farmers in rural areas. The findings of this study may contribute to identify the conditions that increase the risk of snake attacks in the northeastern region. PMID- 23670476 TI - [Mortality Information System in small municipalities of Minas Gerais state: concepts of health professionals]. AB - Strategies to accelerate the consolidation process of health information systems and make it possible to obtain reliable data on vital statistics are urgently needed. This qualitative study sought to understand the concepts of municipal administrators and Epidemiology managers about the Mortality Information System (MIS) in the Northeast region of Minas Gerais, one of the poorest in the state with the highest proportions of deaths with ill-defined causes. Professionals from ten municipalities were interviewed and their answers evaluated by content analysis. It was found that the MIS was perceived as important for management, but there was a general perception among respondents that it served the state and federal managers rather than the municipality in the planning of health actions. Improvements were reported in the physical structure of the municipalities to make the MIS operational, but also shortcomings related to lack of trained human resources for the systematic use and production of data at the local level and with high staff turnover. Partnerships between the health department with other state sectors can contribute to reduce under-registration of events and deaths with ill-defined causes. PMID- 23670477 TI - [SIM and SINASC: social representation of nurses and professional in administrative sectors who work in hospitals in the city of Sao Paulo]. AB - Few studies have analyzed the SINASC (Live Birth Information System) and MIS (Mortality Information System) applying qualitative methodology seeking to understand data production processes and contexts. This article aims to study the social representation of health professionals about Live Birth Certificates (LBC) and perinatal Death Certificates (DC). A total of 24 interviews were conducted with nurses and other professionals of 16 Unified Health System (SUS) and non-SUS hospitals of the city of Sao Paulo in 2009. Qualitative methodology was adopted along with the Collective Subject Discourse technique. Professionals acknowledged that they are an integral part of the information production process of SINASC and their reports indicate that they incorporate it in their work routine. They also perceive that training activities are a tool to understand the information produced by them and are aware of the utility of LBC information. Although physicians are legally responsible for the DC, other professionals frequently provide some of the information to complete it. The professionals see themselves as participants of the SINASC. Despite providing information to complete the DC, they do not see themselves as participants of the MIS operation. PMID- 23670478 TI - [Domestic violence and the adolescent that was infected with HIV through vertical transmission: analysis of protection and vulnerability factors]. AB - The scope of this study was to analyze protection and vulnerability factors in physical and psychological domestic violence among adolescents infected with HIV/AIDS through vertical transmission. This group is especially susceptible as they have vulnerability factors such as chronic disease, orphanhood with consequent change of caregivers and impaired body image. The research was conducted in a public hospital. The first stage used the Parent Child Conflict Tactics and the Degree of Psychological Violence Scale to determine what domestic violence occurred. In the second qualitative stage, the adolescents who scored the most or the least for violence in the quantitative instrument were interviewed. The questionnaires and the interviews revealed a high prevalence of physical and psychological violence and abusive domestic dynamics, thereby corroborating the extant literature. In view of the consequences of this kind of violence, it is essential that the health professional should be able to identify violent situations and recognize vulnerability factors and to promote protection factors against ill-treatment. PMID- 23670479 TI - [Challenges for knowledge generation in environmental health: an ecosystemic approach]. AB - This article examines opportunities and limitations regarding knowledge generation in the field of environmental health. The contention is that understanding the complexity of factors that determine the health of humans and ecosystems requires a redefinition of the traditional distribution of roles and responsibilities in scientific research. These research practices involve inter and transdisciplinary approaches and the application of an ecosystemic approach (ecohealth). Challenges and opportunities associated to the application of inter and transdisciplinarity in environmental health problems are discussed and illustrated by two case studies that use an ecohealth approach: a project on the contamination and exposure to mercury in the Brazilian Amazon, and another on the urban transmission of echinococcosis in Nepal. In the conclusion, the potential benefits of using an ecohealth approach in overcoming the limitations of unidisciplinary practices and in taking advantage of local knowledge and participation is stressed. PMID- 23670481 TI - [With respect to the second assessment of the AP-21 strategy: the strategic benchmark for the enhancement of Primary Health Care in Spain 2007-2012]. PMID- 23670482 TI - Selective contribution of each hamstring muscle to anterior cruciate ligament protection and tibiofemoral joint stability in leg-extension exercise: a simulation study. AB - A biomechanical model was developed to simulate the selective effect of the co contraction force provided by each hamstring muscle on the shear and compressive tibiofemoral joint reaction forces, during open kinetic-chain knee-extension exercises. This model accounts for instantaneous values of knee flexion angle [Formula: see text], angular velocity and acceleration, and for changes in magnitude, orientation, and application point of external resistance. The tibiofemoral shear force (TFSF) largely determines the tensile force on anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL). Biceps femoris is the most effective hamstring muscle in decreasing the ACL-loading TFSF developed by quadriceps contractions for [Formula: see text]. In this range, the semimembranosus generates the dominant tibiofemoral compressive force, which enhances joint stability, opposes anterior/posterior tibial translations, and protects cruciate ligaments. The semitendinosus force provides the greatest decreasing gradient of ACL-loading TFSF for [Formula: see text], and the greatest increasing gradient of tibiofemoral compressive force for [Formula: see text]. However, semitendinosus efficacy is strongly limited by its small physiological section. Hamstring muscles behave as a unique muscle in enhancing the PCL-loading TFSF produced by quadriceps contractions for [Formula: see text]. The levels of hamstrings co-activation that suppress the ACL-loading TFSF considerably shift when the knee angular acceleration is changed while maintaining the same level of knee extensor torque by a concurrent adjustment in the magnitude of external resistance. The knowledge of the specific role and the optimal activation level of each hamstring muscle in ACL protection and tibiofemoral stability are fundamental for planning safe and effective rehabilitative knee-extension exercises. PMID- 23670483 TI - Mesenchymal stem cells play an important role in host protective immune responses against malaria by modulating regulatory T cells. AB - Plasmodium spp. parasites, the causative agents of malaria, survive and replicate in human hosts by modulating host protective immune responses. In a rodent model, malaria manifests as a severe splenomegaly, with infiltration of cells and lympho proliferation as major contributing factors of the immunopathology. However, the cellular contents and the functions of these cells have not been well studied. Here, we report that Plasmodium berghei infection of mice leads to massive recruitment of mesenchymal stem cells (MSCs) in secondary lymphoid organs. Infusion of these cells into naive mice was able to confer host resistance against malaria. Furthermore, MSCs augmented interleukin (IL)-12 production but suppressed IL-10 production in recipient animals. In addition, we observed dramatic reductions of regulatory T (Treg) cells in animals that received MSCs. Taken together, our findings have identified recruitment of MSCs as a novel host protective mechanism adopted by the host to combat malaria by modulating Treg cell responses. PMID- 23670484 TI - Telaprevir and boceprevir: a potential role for therapeutic drug monitoring. PMID- 23670485 TI - The importance of knowing how vancomycin is measured when interpreting its pharmacokinetic results. PMID- 23670486 TI - The effect of unilateral superior laryngeal nerve lesion on swallowing threshold volume. AB - OBJECTIVES/HYPOTHESIS: The superior laryngeal nerve (SLN) is the major sensory nerve for the upper larynx. Damage to this nerve impacts successful swallowing. The first aim of the study was to assess the effect of unilateral SLN lesion on the threshold volume sufficient to elicit swallowing in an intact pig model; this volume was defined radiographically as the maximum bolus area visible in lateral view. The second aim was to determine if a difference existed between ipsilateral and contralateral function as a result of unilateral sensory loss, measured as the radiologic density of fluid seen in the valleculae. Finally, we determined whether there was a relationship between the threshold volume and the occurrence of aspiration after a unilateral SLN lesion. STUDY DESIGN: Repeated measures animal study. METHODS: Four female infant pigs underwent unilateral SLN lesion surgery. The maximum vallecular bolus area in lateral view and the relative vallecular density on each side in the dorsoventral view were obtained from videofluoroscopic recordings in both the prelesion control and postlesion experimental states. RESULTS: In lateral view, the lesioned group had a larger maximum bolus area than the control group (P < .001). Although occasional left right asymmetry in the dorsoventral view was observed, the vallecular densities were, on average, equal on both the left (intact) and right (lesioned) sides (P > .05). A bigger maximum bolus area did not predict aspiration in the lesioned group (P > .05). CONCLUSIONS: Unilateral SLN lesions increased the swallowing threshold volume symmetrically in right and left valleculae, but the increased threshold may not be the main mechanism for the occurrence of aspiration. PMID- 23670487 TI - The effect of perceiving control on glutamatergic function and tolerating stress. PMID- 23670489 TI - Methylation of the promoter of brain-derived neurotrophic factor exon IV and antidepressant response in major depression. PMID- 23670491 TI - Opening up our windows to the world. PMID- 23670490 TI - Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study. AB - Endocannabinoids and their attending cannabinoid type 1 (CB1) receptor have been implicated in animal models of post-traumatic stress disorder (PTSD). However, their specific role has not been studied in people with PTSD. Herein, we present an in vivo imaging study using positron emission tomography (PET) and the CB1 selective radioligand [(11)C]OMAR in individuals with PTSD, and healthy controls with lifetime histories of trauma (trauma-exposed controls (TC)) and those without such histories (healthy controls (HC)). Untreated individuals with PTSD (N=25) with non-combat trauma histories, and TC (N=12) and HC (N=23) participated in a magnetic resonance imaging scan and a resting PET scan with the CB1 receptor antagonist radiotracer [(11)C]OMAR, which measures the volume of distribution (VT) linearly related to CB1 receptor availability. Peripheral levels of anandamide, 2-arachidonoylglycerol, oleoylethanolamide, palmitoylethanolamide and cortisol were also assessed. In the PTSD group, relative to the HC and TC groups, we found elevated brain-wide [(11)C]OMAR VT values (F(2,53)=7.96, P=0.001; 19.5% and 14.5% higher, respectively), which were most pronounced in women (F(1,53)=5.52, P=0.023). Anandamide concentrations were reduced in the PTSD relative to the TC (53.1% lower) and HC (58.2% lower) groups. Cortisol levels were lower in the PTSD and TC groups relative to the HC group. Three biomarkers examined collectively--OMAR VT, anandamide and cortisol--correctly classified nearly 85% of PTSD cases. These results suggest that abnormal CB1 receptor mediated anandamide signaling is implicated in the etiology of PTSD, and provide a promising neurobiological model to develop novel, evidence-based pharmacotherapies for this disorder. PMID- 23670492 TI - Flexor tendon injuries following plate fixation of distal radius fractures: a systematic review of the literature. AB - BACKGROUND: Flexor tendon rupture is a rare but major complication associated with volar plate fixation of distal radius fractures. MATERIALS AND METHODS: We performed a systematic review to evaluate the demographics, clinical profile, treatment and outcome of flexor tendon rupture following volar plate fixation of distal radius fracture. Electronic searches of the MEDLINE, EMBASE, and Cochrane databases for systematic reviews and conference proceedings were performed. Studies were included if they reported flexor tendon rupture (partial or complete) as a complication of distal radius fracture plating (all levels of evidence). RESULT: Our search yielded 21 studies. There were 12 case reports and 9 clinical studies. A total of 47 cases were reported. There were 11 males and 23 females (n = 16 studies). The mean age was 61 years old (range 30-85). The median interval between the surgery and flexor tendon rupture was 9 months (interquartile range, 6-26 months). Twenty-nine plates were locking and 15 were nonlocking (n = 20 studies). FPL was the most commonly ruptured tendon (n = 27 cases, 57 %), with FDP to index finger being the second most common (n = 7 cases, 15 %). Palmaris longus tendon graft and primary end-to-end repair were the most common surgical methods used in cases of FPL tendon rupture. CONCLUSION: Flexor tendon rupture is a recognised complication of volar plating of distal radius fracture. Positioning of the plate proximal to the "watershed" line and early removal of the plate in cases with plate prominence or warning symptoms can reduce the risk of this complication. PMID- 23670493 TI - Surgical treatment of displaced intra-articular calcaneal fractures: is bone grafting necessary? AB - BACKGROUND: The aim of this retrospective study was to determine the need for bone grafting in the surgical treatment of displaced intra-articular calcaneal fractures. We reviewed 390 cases of displaced intra-articular calcaneal fractures treated with plate osteosynthesis with or without autologous iliac bone grafting, and compared outcomes and complications related to fracture stabilization. MATERIALS AND METHODS: Three hundred ninety patients with displaced intra articular calcaneal fractures that were treated with plate osteosynthesis from December 2002 to December 2010 were reviewed. Two hundred two patients (group A) were treated by osteosynthesis with autologous bone grafting, and 188 patients (group B) were treated by osteosynthesis without bone grafting. One hundred eighty-one patients with an AO type 73-C1 fracture (Sanders type II), 182 patients with an AO type 73-C2 fracture (Sanders type III), and 27 patients with an AO type 73-C3 fracture (Sanders type IV) were included in this study. Bohler's angle, the crucial angle of Gissane, and calcaneal height in the immediate postoperative period and at the 2-year follow-up were compared. Any change in the subtalar joint status was documented and analyzed. The final outcomes of all patients were evaluated by the AOFAS Ankle-Hindfoot Scale and compared in both groups. RESULTS: The mean full weight-bearing time in group A (with bone grafting) was significantly lower (median 6.2 months, range 2.8-9.2 months) than that in group B (without bone grafting; median 9.8 months, range 6.8-12.2 months). The immediate-postoperative Bohler's angle and that at the 2-year follow up were significantly higher in group A. The loss of Bohler's angle after 2 years was significantly lower in group A (mean 3.5 degrees ; 95 % CI 0.8 degrees -6.2 degrees ) than in group B (mean 6.2 degrees ; 95 % CI 1.0 degrees -11.2 degrees ). The average change in the crucial angle and the average change in calcaneal height were not statistically significant for either group. The infection rate in the bone grafting group was higher, though statistically insignificantly so, than in the nongrafting group (8.3 vs. 6.3 %). No significant difference was found between the groups in terms of the rates of good reduction, postoperative osteoarthritis, and subtalar fusion. Regarding the efficacy outcomes, the mean AOFAS score was lower (mean 76.4 points; 95 % CI 65.8-82.9 points) in group A than in group B (mean, 81.6 points; 95 % CI, 72.3-88.8 points), but this difference was not significant (p > 0.05). CONCLUSIONS: Bohler's angle showed improved restoration and the patients returned to full weight-bearing earlier when bone grafting was used in the treatment of intra-articular calcaneal fracture. However, the functional outcomes and complication rates of both groups were similar. PMID- 23670494 TI - Diffusion tensor imaging in amyotrophic lateral sclerosis--increased sensitivity with optimized region-of-interest delineation. AB - PURPOSE: Diagnosis of amyotrophic lateral sclerosis (ALS) can be difficult from clinical symptoms alone. Diffusion tensor imaging (DTI) has been suggested as an adjunct diagnostic method. DTI parameter changes have been repeatedly demonstrated, especially in the corticospinal tract (CST) as the predominantly affected structure. However, a recent meta-analysis reported only a modest discriminatory capability, questioning the value of this method as a confirmatory test in single subjects with suspected ALS. We investigated how methodological differences in CST delineation influence the discriminatory capability. METHODS: DTI data were acquired in 13 ALS patients and an age-matched healthy control group. We calculated and compared receiver operation characteristic (ROC) curves of four different analysis methods using either a manual or an atlas-based region of interest (ROI) of the CST in combination with and without tract-based spatial statistics (TBSS). RESULTS: The analysis method combining atlas-based ROIs with TBSS yielded an area under the curve (AUC) of 0.936 and a sensitivity and specificity of 100 % and 91.67 %. These are the best results among the four analysis methods evaluated: manual ROIs (AUC = 0.846, sensitivity: 69.23, specificity: 91.67), atlas-based ROIs alone (AUC = 0.917, sensitivity: 76.92, specificity: 91.67), manual ROIs in combination with TBSS (AUC = 0.885, sensitivity: 76.92, specificity: 91.67). CONCLUSIONS: Sensitivity and specificity strongly depend on the CST delineation approach. The combination of an atlas based ROI with TBSS is a promising fully automatic method with improved discriminatory capability compared to other approaches. It could ultimately serve as a confirmatory test in single ALS patients. PMID- 23670495 TI - Endobronchial ultrasound: from lung cancer diagnosis and staging to translational research. PMID- 23670496 TI - Relationship between exercise capacity and quality of life in adolescents with asthma. AB - OBJECTIVE: To determine whether the quality of life of adolescents with asthma correlates with parameters obtained prior to and after the six-minute step test (6MST); spirometric results after the 6MST; and level of physical activity. METHODS: Nineteen adolescents with asthma, ranging from 11-15 years of age, were assessed with spirometry, 6MST, the International Physical Activity Questionnaire (IPAQ), the Pediatric Asthma Quality of Life Questionnaire (PAQLQ), and the 10 point Borg category-ratio (CR10) scale. RESULTS: Sensation of dyspnea correlated negatively with the total PAQLQ score (r = -0.54) and with the scores of its activity limitation (AL) and symptoms domains (r = -0.64 and r = -0.63, respectively), leg fatigue also correlating negatively with those same domains (r = -0.49 and r = -0.56, respectively). The total IPAQ score correlated with total PAQLQ score (r = 0.47) and with the PAQLQ AL domain (r = 0.51); IPAQ time spent walking correlated with the PAQLQ symptoms domain (r = 0.45); and IPAQ time spent in vigorous activity correlated with the AL domain (r = 0.50). In the regression analysis, only sensation of dyspnea remained significantly correlated with the total PAQLQ score and its AL domain; leg fatigue remained significantly correlated with the symptoms domain. CONCLUSIONS: Higher levels of physical activity indicate better quality of life, as do lower perception of dyspnea and less leg fatigue. The 6MST proved to be a viable option for evaluating exercise capacity in adolescents with asthma, because it reflects the discomfort that asthma causes during activities of daily living. PMID- 23670497 TI - Prevalences of asthma and rhinitis among adolescents in the city of Fortaleza, Brazil: temporal changes. AB - OBJECTIVE: To describe the prevalences of asthma and rhinitis in adolescents (13 14 years of age) in the city of Fortaleza, Brazil, in 2010, comparing the results with those obtained in a prevalence survey conducted in 2006-2007. METHODS: This was a cross-sectional study involving probabilistic samples of 3,015 and 3,020 adolescents in surveys conducted in 2006-2007 and 2010, respectively. The International Study of Asthma and Allergies in Childhood protocol was used on both occasions. RESULTS: Comparing the two periods, there were no significant differences regarding cumulative wheezing, active asthma, four or more wheezing attacks within the last year, sleep disturbed by wheezing more than one night per week, and speech-limiting wheezing. The prevalences of exercise-induced wheezing, dry cough at night, and physician-diagnosed asthma were significantly higher in 2010 than in the 2006-2007 period (p < 0.01 for all). The prevalence of physician diagnosed rhinitis was significantly lower in 2010 (p = 0.01), whereas there were no significant differences between the two periods regarding cumulative rhinitis, current rhinitis, and rhinoconjunctivitis. In both periods, dry cough at night, current rhinitis, and rhinoconjunctivitis were significantly more prevalent in females than in males (p < 0.01 for all). Also in both periods, active asthma, current rhinitis, and rhinoconjunctivitis were more prevalent in private school students than in public school students (p < 0.01 for all). CONCLUSIONS: Our data show that the prevalences of asthma and rhinitis symptoms remain high among 13- and 14-year-olds in Fortaleza, predominantly among females and private school students. PMID- 23670498 TI - A clinical decision support system for venous thromboembolism prophylaxis at a general hospital in a middle-income country. AB - OBJECTIVE: To determine the impact that implementing a combination of a computer based clinical decision support system and a program of training seminars has on the use of appropriate prophylaxis for venous thromboembolism (VTE). METHODS: We conducted a cross-sectional study in two phases (prior to and after the implementation of the new VTE prophylaxis protocol) in order to evaluate the impact that the combined strategy had on the use of appropriate VTE prophylaxis. The study was conducted at Nossa Senhora da Conceicao Hospital, a general hospital in the city of Porto Alegre, Brazil. We included clinical and surgical patients over 18 years of age who were hospitalized for > 48 h. The pre implementation and post-implementation phase samples comprised 262 and 261 patients, respectively. RESULTS: The baseline characteristics of the two samples were similar, including the distribution of patients by risk level. Comparing the pre-implementation and post-implementation periods, we found that the overall use of appropriate VTE prophylaxis increased from 46.2% to 57.9% (p = 0.01). Looking at specific patient populations, we observed that the use of appropriate VTE prophylaxis increased more dramatically among cancer patients (from 18.1% to 44.1%; p = 0.002) and among patients with three or more risk factors (from 25.0% to 42.9%; p = 0.008), two populations that benefit most from prophylaxis. CONCLUSIONS: It is possible to increase the use of appropriate VTE prophylaxis in economically constrained settings through the use of a computerized protocol adhered to by trained professionals. The underutilization of prophylaxis continues to be a major problem, indicative of the need for ongoing improvement in the quality of inpatient care. PMID- 23670499 TI - Tomographic and functional findings in severe COPD: comparison between the wood smoke-related and smoking-related disease. AB - OBJECTIVE: Wood smoke exposure is a risk factor for COPD. For a given degree of airway obstruction, the reduction in DLCO is smaller in individuals with wood smoke-related COPD than in those with smoking-related COPD, suggesting that there is less emphysema in the former. The objective of this study was to compare HRCT findings between women with wood smoke-related COPD and women with smoking related COPD. METHODS: Twenty-two women with severe COPD (FEV1/FVC ratio < 70% and FEV1 < 50%) were divided into two groups: those with wood smoke-related COPD (n = 12) and those with smoking-related COPD (n = 10). The two groups were compared regarding emphysema scores and airway involvement (as determined by HRCT); and functional abnormalities-spirometry results, DLCO, alveolar volume (VA), the DLCO/VA ratio, lung volumes, and specific airway resistance (sRaw). RESULTS: There were no significant differences between the two groups in terms of FEV1, sRaw, or lung hyperinflation. Decreases in DLCO and in the DLCO/VA ratio were greater in the smoking-related COPD group subjects, who also had higher emphysema scores, in comparison with the wood smoke-related COPD group subjects. In the wood smoke-related COPD group, HRCT scans showed no significant emphysema, the main findings being peribronchial thickening, bronchial dilation, and subsegmental atelectasis. CONCLUSIONS: Female patients with severe wood smoke related COPD do not appear to develop emphysema, although they do show severe airway involvement. The reduction in DLCO and VA, with a normal DLCO/VA ratio, is probably due to severe bronchial obstruction and incomplete mixing of inspired gas during the determination of single-breath DLCO. PMID- 23670501 TI - Epidemiological aspects of respiratory symptoms treated in the emergency room of a tertiary care hospital. AB - OBJECTIVE: To evaluate the prevalence of respiratory symptoms as the motive for emergency room visits by adult and pediatric patients, describing the major clinical syndromes diagnosed and the outcomes of the patients. METHODS: A cross sectional study conducted in the emergency room of a tertiary care university hospital. Between November of 2008 and November of 2009, we reviewed the total number of emergency room visits per day. Children and adults who presented with at least one respiratory symptom were included in the study. The electronic medical records were reviewed, and the major characteristics of the patients were recorded. RESULTS: During the study period, there were 37,059 emergency room visits, of which 11,953 (32.3%) were motivated by respiratory symptoms. The prevalence of emergency room visits due to respiratory symptoms was 28.7% and 38.9% among adults and children, respectively. In adults, the rates of hospitalization and mortality were 21.2% and 2.7%, respectively, compared with 11.9% and 0.3%, respectively, in children. Among the adults, the time from symptom onset to emergency room visit correlated positively with the need for hospitalization (p < 0.0001), the length of the hospital stay (p < 0.0001), and the mortality rate (p = 0.028). CONCLUSION: We found a high prevalence of respiratory symptoms as the motive for emergency room visits by adult and pediatric patients. Our results could inform decisions regarding the planning of prevention measures. Further epidemiological studies are needed in order to clarify the risk factors for severe respiratory symptoms. PMID- 23670500 TI - Pulmonary changes on HRCT scans in nonsmoking females with COPD due to wood smoke exposure. AB - OBJECTIVE: To identify and characterize alterations seen on HRCT scans in nonsmoking females with COPD due to wood smoke exposure. METHODS: We evaluated 42 nonsmoking females diagnosed with wood smoke-related COPD and 31 nonsmoking controls with no history of wood smoke exposure or pulmonary disease. The participants completed a questionnaire regarding demographic data, symptoms, and environmental exposure. All of the participants underwent spirometry and HRCT of the chest. The COPD and control groups were adjusted for age (23 patients each). RESULTS: Most of the patients in the study group were diagnosed with mild to moderate COPD (83.3%). The most common findings on HRCT scans in the COPD group were bronchial wall thickening, bronchiectasis, mosaic perfusion pattern, parenchymal bands, tree-in-bud pattern, and laminar atelectasis (p < 0.001 vs. the control group for all). The alterations were generally mild and not extensive. There was a positive association between bronchial wall thickening and hour-years of wood smoke exposure. Centrilobular emphysema was uncommon, and its occurrence did not differ between the groups (p = 0.232). CONCLUSIONS: Wood smoke exposure causes predominantly bronchial changes, which can be detected by HRCT, even in patients with mild COPD. PMID- 23670502 TI - Effects of methylprednisolone on inflammatory activity and oxidative stress in the lungs of brain-dead rats. AB - OBJECTIVE: To evaluate the effects that early and late systemic administration of methylprednisolone have on lungs in a rat model of brain death. METHODS: Twenty four male Wistar rats were anesthetized and randomly divided into four groups (n = 6 per group): sham-operated (sham); brain death only (BD); brain death plus methylprednisolone (30 mg/kg i.v.) after 5 min (MP5); and brain death plus methylprednisolone (30 mg/kg i.v.) after 60 min (MP60). In the BD, MP5, and MP60 group rats, we induced brain death by inflating a balloon catheter in the extradural space. All of the animals were observed and ventilated for 120 min. We determined hemodynamic and arterial blood gas variables; wet/dry weight ratio; histological score; levels of thiobarbituric acid reactive substances (TBARS); superoxide dismutase (SOD) activity; and catalase activity. In BAL fluid, we determined differential white cell counts, total protein, and lactate dehydrogenase levels. Myeloperoxidase activity, lipid peroxidation, and TNF-alpha levels were assessed in lung tissue. RESULTS: No significant differences were found among the groups in terms of hemodynamics, arterial blood gases, wet/dry weight ratio, BAL fluid analysis, or histological score-nor in terms of SOD, myeloperoxidase, and catalase activity. The levels of TBARS were significantly higher in the MP5 and MP60 groups than in the sham and BD groups (p < 0.001). The levels of TNF-alpha were significantly lower in the MP5 and MP60 groups than in the BD group (p < 0.001). CONCLUSIONS: In this model of brain death, the early and late administration of methylprednisolone had similar effects on inflammatory activity and lipid peroxidation in lung tissue. PMID- 23670503 TI - Diagnostic contribution of molecular analysis of the cystic fibrosis transmembrane conductance regulator gene in patients suspected of having mild or atypical cystic fibrosis. AB - OBJECTIVE: To evaluate the diagnostic contribution of molecular analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in patients suspected of having mild or atypical cystic fibrosis (CF). METHODS: This was a cross-sectional study involving adolescents and adults aged > 14 years. Volunteers underwent clinical, laboratory, and radiological evaluation, as well as spirometry, sputum microbiology, liver ultrasound, sweat tests, and molecular analysis of the CFTR gene. We then divided the patients into three groups by the number of mutations identified (none, one, and two or more) and compared those groups in terms of their characteristics. RESULTS: We evaluated 37 patients with phenotypic findings of CF, with or without sweat test confirmation. The mean age of the patients was 32.5 +/- 13.6 years, and females predominated (75.7%). The molecular analysis contributed to the definitive diagnosis of CF in 3 patients (8.1%), all of whom had at least two mutations. There were 7 patients (18.9%) with only one mutation and 26 patients (70.3%) with no mutations. None of the clinical characteristics evaluated was found to be associated with the genetic diagnosis. The most common mutation was p.F508del, which was found in 5 patients. The combination of p.V232D and p.F508del was found in 2 patients. Other mutations identified were p.A559T, p.D1152H, p.T1057A, p.I148T, p.V754M, p.P1290P, p.R1066H, and p.T351S. CONCLUSIONS: The molecular analysis of the CFTR gene coding region showed a limited contribution to the diagnostic investigation of patients suspected of having mild or atypical CF. In addition, there were no associations between the clinical characteristics and the genetic diagnosis. PMID- 23670504 TI - Reference values for the incremental shuttle walk test in healthy subjects: from the walk distance to physiological responses. AB - OBJECTIVE: To determine reference values for incremental shuttle walk distance (ISWD) and peak physiological responses during the incremental shuttle walk test (ISWT), as well as to develop a series of predictive equations for those variables in healthy adults. METHODS: We evaluated 103 healthy participants > 40 years of age (54 women and 49 men). We fitted each participant with a gas analysis system for use during the ISWT. Oxygen consumption (VO2), carbon dioxide production, minute ventilation, heart rate (HR), ISWD, and maximal walking velocity (MWV) were obtained as primary outcomes. We also assessed hand grip strength (HGS) and lean body mass (LBM). RESULTS: The regression analysis models, including physiological variables, ISWD, and MWV (adjusted for age, body mass, height, and sex), produced R2 values ranging from 0.40 to 0.65 (for HR and peak VO2, respectively). Using the models including LBM or HGS, we obtained no significant increase in the R2 values for predicting peak VO2, although the use of those models did result in slight increases in the R2 values for ISWD and MWV (of 8% and 12%, respectively). The variables ISWD, MWV, and ISWD * body mass, respectively, explained 76.7%, 73.3%, and 81.2% of peak VO2 variability. CONCLUSIONS: Our results provide reference values for ISWD and physiological responses to the ISWT, which can be properly estimated by determining simple demographic and anthropometric characteristics in healthy adults > 40 years of age. The ISWT could be used in assessing physical fitness in the general adult population and in designing individualized walking programs. PMID- 23670505 TI - Mortality due to respiratory diseases in the elderly after influenza vaccination campaigns in the Federal District, Brazil, 1996-2009. AB - OBJECTIVE: To compare mortality rates due to respiratory diseases among elderly individuals residing in the Federal District of Brasilia, Brazil, prior to and after the implementation of a national influenza vaccination campaign. METHODS: This was an ecological time series analysis. Data regarding the population of individuals who were over 60 years of age between 1996 and 2009 were obtained from official databases. The variables of interest were the crude mortality rate (CMR), the mortality rate due to the respiratory disease (MRRD), and the proportional mortality ratio (PMR) for respiratory diseases. We performed a qualitative analysis of the data for the period prior to and after the implementation of the vaccination campaign (1996-1999 and 2000-2009, respectively). RESULTS: The CMR increased with advancing age. Over the course of the study period, we observed reductions in the CMR in all of the age brackets studied, particularly among those aged 80 years or older. Reductions in the MRRD were also found in all of the age groups, especially in those aged 80 years or older. In addition, there was a decrease in the PMR for respiratory diseases in all age groups throughout the study period. The most pronounced decrease in the PMR for respiratory diseases in the > 70 year age bracket occurred in 2000 (immediately following the implementation of the national vaccination campaign); in 2001, that rate increased in all age groups, despite the greater adherence to the vaccination campaign in comparison with that recorded for 2000. CONCLUSIONS: Influenza vaccination appears to have a positive impact on the prevention of mortality due to respiratory diseases, particularly in the population aged 70 or over. PMID- 23670506 TI - Experimental study on the efficiency and safety of the manual hyperinflation maneuver as a secretion clearance technique. AB - OBJECTIVE: To evaluate, in a lung model simulating a mechanically ventilated patient, the efficiency and safety of the manual hyperinflation (MH) maneuver as a means of removing pulmonary secretions. METHODS: Eight respiratory therapists (RTs) were asked to use a self-inflating manual resuscitator on a lung model to perform MH as if to remove secretions, under two conditions: as routinely applied during their clinical practice; and after receiving verbal instructions based on expert recommendations. In both conditions, three clinical scenarios were simulated: normal lung function, restrictive lung disease, and obstructive lung disease. RESULTS: Before instruction, it was common for an RT to compress the resuscitator bag two times, in rapid succession. Proximal pressure (Pprox) was higher before instruction than after. However, alveolar pressure (Palv) never exceeded 42.5 cmH2O (median, 16.1; interquartile range [IQR], 11.7-24.5), despite Pprox values as high as 96.6 cmH2O (median, 36.7; IQR, 22.9-49.4). The tidal volume (VT) generated was relatively low (median, 640 mL; IQR, 505-735), and peak inspiratory flow (PIF) often exceeded peak expiratory flow (PEF), the median values being 1.37 L/s (IQR, 0.99-1.90) and 1.01 L/s (IQR, 0.55-1.28), respectively. A PIF/PEF ratio < 0.9 (which theoretically favors mucus migration toward the central airways) was achieved in only 16.7% of the maneuvers. CONCLUSIONS: Under the conditions tested, MH produced safe Palv levels despite high Pprox. However, the MH maneuver was often performed in a way that did not favor secretion removal (PIF exceeding PEF), even after instruction. The unfavorable PIF/ PEF ratio was attributable to overly rapid inflations and low VT. PMID- 23670507 TI - Prevalence of latent tuberculosis infection and risk of infection in patients with chronic kidney disease undergoing hemodialysis in a referral center in Brazil. AB - OBJECTIVE: To determine the prevalence of latent tuberculosis infection (LTBI) and the risk of infection in patients with chronic kidney disease treated at a hemodialysis center. METHODS: We included 307 patients with chronic kidney disease undergoing hemodialysis at the Mineiro Institute of Nephrology, located in the city of Belo Horizonte, Brazil. All of the patients were submitted to tuberculin skin tests (TSTs). We investigated the booster effect and TST conversion. If the initial TST (TST1) was negative, a second TST (TST2) was performed 1-3 weeks later in order to investigate the booster effect. If TST2 was also negative, a third TST (TST3) was performed one year after TST2 in order to determine whether there was TST conversion. RESULTS: When we adopted a cut-off induration of 5 mm, the prevalence of LTBI was 22.2% on TST1, increasing by 11.2% on TST2. When we adopted a cut-off induration of 10 mm, the prevalence of LTBI was 28.5% on TST1, increasing by 9.4% on TST2. The prevalence of LTBI increased significantly from TST1 to TST2 (booster effect), as well as from TST2 to TST3 (p < 0.01 for both). In our sample, the mean annual risk of infection was 1.19%. CONCLUSIONS: In the population studied, the prevalence of LTBI was high, and the mean annual risk of infection was similar to that reported for the general population of Brazil, which suggests recent infection. PMID- 23670508 TI - Completeness of tuberculosis reporting forms in five Brazilian capitals with a high incidence of the disease. AB - The aim of this study was to evaluate the completeness of tuberculosis reporting forms in the greater metropolitan areas of five Brazilian capitals where the incidence of tuberculosis was high in 2010 - Salvador, Rio de Janeiro, Cuiaba, Porto Alegre, and Belem - using tabulations obtained from the Sistema Nacional de Informacao de Agravos de Notificacao (National Case Registry Database). The degree of completeness was highest in Porto Alegre and Cuiaba, whereas it was lowest in Rio de Janeiro, where there are more reported cases of tuberculosis than in any other Brazilian capital. A low degree of completeness of these forms can affect the quality of the Brazilian National Tuberculosis Control Program, which will have negative consequences for health care and decision-making processes. PMID- 23670509 TI - Current status and clinical applicability of endobronchial ultrasound-guided transbronchial needle aspiration. AB - Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has played a key role in the diagnosis of mediastinal, paratracheal, and peribronchial lesions, as well as in lymph node staging for lung cancer. Despite its minimally invasive character, EBUS-TBNA has demonstrated a diagnostic yield comparable with that of established surgical methods. It has therefore gained credibility and has become a routine procedure at various referral centers. A successful EBUS-TBNA procedure requires careful planning, which includes a thorough review of the radiological imaging and special care during specimen collection and preparation, as well as technical expertise, experience with the procedure itself, and knowledge of the potential complications inherent to the procedure. The most common indications for EBUS-TBNA include lymph node staging for lung cancer and the diagnostic investigation of mediastinal/hilar masses and lymph node enlargement. Recently, tumor biomarkers in malignant samples collected during the EBUS-TBNA procedure have begun to be identified, and this molecular analysis has proven to be absolutely feasible. The EBUS-TBNA procedure has yet to be included on the Brazilian Medical Association list of medical procedures approved for reimbursement. The EBUS-TBNA procedure has shown to be a safe and accurate tool for lung cancer staging/restaging, as well as for the diagnosis of mediastinal, paratracheal, and peribronchial lesions/lymph node enlargement. PMID- 23670510 TI - Pulmonary hypertension and pulmonary artery dissection. AB - Pulmonary artery dissection is a fatal complication of long-standing pulmonary hypertension, manifesting as acute, stabbing chest pain, progressive dyspnea, cardiogenic shock, or sudden death. Its incidence has been underestimated, and therapeutic options are still scarce. In patients with pulmonary hypertension, new chest pain, acute chest pain, or cardiogenic shock should raise the suspicion of pulmonary artery dissection, which can result in sudden death. PMID- 23670511 TI - Efficacy of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in evaluating lung cancer recurrence. PMID- 23670512 TI - Impending paradoxical embolism across the interatrial septum. PMID- 23670513 TI - Whole-body magnetic resonance imaging for the evaluation of thoracic involvement in disseminated paracoccidioidomycosis. PMID- 23670514 TI - Successful thoracoscopic thymectomy in an infant. PMID- 23670515 TI - Underdiagnosis of respiratory diseases during an economic downturn and the need for spirometry as a screening test. PMID- 23670516 TI - Authors' reply. PMID- 23670517 TI - Changes of T cells and cytokines TGF-beta1 and IL-10 in mice during liver metastasis of colon carcinoma: implications for liver anti-tumor immunity. AB - BACKGROUND: The local and systemic regulation of the immune system may play important roles in the process of liver metastasis of colorectal carcinoma. The aim of this study was to establish a reproducible experimental liver metastasis model, to identify changes in T cells and cytokines TGF-beta1 and IL-10, and to explore a possible mechanism of liver metastasis of colon carcinoma. METHODS: We used a colon carcinoma liver metastasis model, in which different numbers of CT 26 murine colon carcinoma cells (1 * 10(3), 5 * 10(3), 1 * 10(4), 5 * 10(4), and 1 * 10(5)) were injected into the spleen. The liver and spleen tissues were examined for T cell markers using flow cytometry. Liver tissues were analyzed for IL-10 and transforming growth factor beta 1 (TGF-beta1) expression using immunohistochemistry. RESULTS: Spleen injection of colon carcinoma cells is a reproducible animal model for liver metastases, which resulted in quantity dependent metastatic growth. We provided a snapshot of the hepatic immune microenvironment in the mouse liver metastasis model. Injection of A large number of tumor cells (5 * 10(4) and 1 * 10 (5) ) decreased anti-tumor cell counts, such as CD4(+) and CD8(+) T cells, and increased immune-suppressive cell counts (CD4(+)CD25(+) Treg cells). In addition, the expression levels of immunosuppressive cytokines IL-10 and TGF-beta1 were also increased with the number of tumor cells. CONCLUSIONS: Changes in the systemic and local immunological environment contribute to immunological escape mechanisms during liver metastasis of colon carcinoma, and therapies aiming at immune microenvironment may prove a useful strategy in the treatment of metastatic disease in the future. PMID- 23670518 TI - Stapled hemorrhoidopexy versus Milligan-Morgan hemorrhoidectomy in circumferential third-degree hemorrhoids: long-term results of a randomized controlled trial. AB - BACKGROUND: The literature indicates higher recurrence rates for stapled hemorrhoidopexy than for conventional techniques. This could be due to inappropriate patient selection. OBJECTIVE: The aim of this study was to evaluate the short- and long-term outcome after stapled hemorrhoidopexy compared with the Milligan-Morgan procedure in a homogeneous patient population with circumferential third-degree hemorrhoids. DESIGN AND PATIENTS: One hundred thirty patients were enrolled into a randomized controlled study, of which 122 were clinically evaluated at weeks 1, 2, and 4, and thereafter each year for a minimum of 3 years. Patients completed a questionnaire for symptoms, function, and pain. Pain was assessed using a visual analog scale. Recurrences were determined by anoscopy and self-report. SETTINGS: The study was performed at the University Hospital Hamburg. MAIN OUTCOME MEASURES: Endpoints were pain, recurrence, bleeding, itching/burning, urinary retention, incontinence symptoms, and prolonged rate of wound healing. RESULTS: The cumulative recurrence rates after 5 years were 18 % (n = 11) in the stapled hemorrhoidopexy group and 23 % (n = 14) in the Milligan-Morgan group (p = 0.65). Patients who underwent stapled hemorrhoidopexy had significantly less postoperative pain with mean VAS scores at week 1: 3.1 vs. 6.2; week 2: 0.5 vs. 3; week 4: 0.05 vs. 0.6 (p < 0.001), and demonstrated less burning/itching sensation 4 weeks after surgery compared with the Milligan-Morgan group (4.9 vs. 19.7 %; p < 0.001). The postoperative bleeding rate was 4.9 % in both groups and the rate of urinary retention did not differ significantly (4.9 % vs. 1.6 %; p = 0.309). Postoperative incontinence symptoms (6.6 % versus 3.3 %; p = 0.40) resolved within the first 6 months. LIMITATIONS: Detailed measurement of incontinence was not possible because postoperative symptoms resolved between consultations, and pathological results were examined retrospectively. CONCLUSIONS: The results show a similar rate of recurrence in the long term and suggest increased patient comfort in the early postoperative course after stapled hemorrhoidopexy. In patients with circumferential third degree hemorrhoids, stapled hemorrhoidopexy is as effective as the Milligan Morgan procedure. PMID- 23670519 TI - Pancreatic surgery with vascular reconstruction in patients with locally advanced pancreatic neuroendocrine tumors. AB - INTRODUCTION: Pancreatic neuroendocrine tumors (PNET) are rare neoplasms with better prognosis than most pancreatic malignancies. Surgery of locally advanced PNET remains controversial, and the role of vascular reconstruction in this patient group has yet to be defined. The aim of this study was to evaluate the feasibility and outcome of pancreatic resections with vascular reconstruction in patients with locally advanced PNET. METHODS: Retrospective analysis of patients who underwent pancreatic surgery with vascular reconstruction for locally advanced PNET at a single institution. Furthermore, a review of the relevant literature on the topic was performed. RESULTS: Seven patients who had undergone vascular reconstruction for locally advanced PNET were identified. Four patients had liver metastases at time of surgery. Postoperative complications developed in four patients with no mortality. Median follow-up time of all patients was 21 (range, 3-58) months. Three patients had disease in remission after 58, 42 and 3 months, respectively. One patient died 35 months postoperatively due to progressive disease, whereas three patients had progression of disease after 21, 9, and 4 months postoperatively. CONCLUSION: Pancreatic surgery with vascular reconstruction in patients with locally advanced PNET is feasible with acceptable outcome. PMID- 23670520 TI - Enhanced sulfur resistance of Ni/SiO2 catalyst for methanation via the plasma decomposition of nickel precursor. AB - A Ni/SiO2 catalyst was prepared by the plasma decomposition of a nickel precursor via dielectric barrier discharge (DBD). The obtained Ni/SiO2 catalyst shows an enhanced H2S resistance for methanation of syngas (CO + H2). The plasma decomposition has a significant influence on the structural property of Ni/SiO2. The plasma decomposed catalyst shows less defect sites on Ni particles. The formation of Ni-sulfur species was effectively inhibited. The mechanism of H2S poisoning on different catalysts with and without plasma decomposition was also discussed according to the reaction temperature. PMID- 23670521 TI - Role of 18F-choline PET/CT in suspicion of relapse following definitive radiotherapy for prostate cancer. AB - PURPOSE: The aims of the study were (a) to evaluate the diagnostic role, by means of positive detection rate (PDR), of 18F-choline (CH) positron emission tomography (PET)/CT in patients with prostate cancer treated with radiotherapy, with curative intent, and suspicion of relapse during follow-up, (b) to correlate the PDR with trigger prostate-specific antigen (PSA), (c) to investigate the possible influence of androgen deprivation therapy (ADT) at the time of scan on PDR and (d) to assess distribution of metastatic spread. METHODS: 18F-CH PET/CT exams from 46 consecutive patients (mean age 71.3 years, range 51-84 years) with prostate cancer (mean Gleason score 6.4, range 5-8) previously treated by definitive radiotherapy and with suspicion of relapse with negative or inconclusive conventional imaging were retrospectively evaluated. Of the 46 patients, 12 were treated with brachytherapy and 34 with external beam radiation therapy. Twenty-three patients were under ADT at the time of the examination. Trigger PSA was measured within 1 month before the exam (mean value 6.5 ng/ml, range 1.1-49.4 ng/ml). Patients were subdivided into four groups according to their PSA level: 1.0 < PSA <= 2.0 ng/ml (11 patients), 2.0 < PSA <= 4.0 ng/ml (16 patients), 4.0 < PSA <= 6.0 ng/ml (9 patients) and PSA > 6.0 ng/ml (10 patients). Correlation between ADT and PDR was investigated as well as between PSA and distribution of metastatic spread. RESULTS: The overall PDR of 18F-CH PET/CT was 80.4% (37/46 patients), increasing with the increase of trigger PSA. PDR of 18F CH PET/CT is not influenced by ADT (p = 0.710) even if PET performed under ADT demonstrated an overall higher PDR (82.6%). The majority of the patients (59%, 22/37 patients) showed local relapse only, confined to the prostatic bed; 22% of the PET/CT-positive patients (8/37 patients) showed distant relapse only (bone localizations in all of them), while the remaining 19% (7/37 patients) showed both local and distant (lymph node and bone) spread. CONCLUSION: 18F-CH PET/CT showed a high overall detection rate (80%), proportional to the trigger PSA (both for local and distant relapse) not influenced by ADT. 18F-CH PET/CT is proposed as a first-line imaging procedure in restaging prostate cancer patients primarily treated with radiotherapy. PMID- 23670522 TI - [Unilateral visual field defect in a seemingly normal eye]. PMID- 23670523 TI - [Optical coherence tomography: anatomic and functional outcome after scleral buckling surgery in macula-off rhegmatogenous retinal detachment]. AB - PURPOSE: The aim of this study was to evaluate results of optical coherence tomography (OCT) with regard to anatomic and functional outcome after scleral buckling surgery (SBS) in macula-off rhegmatogenous retinal detachment (RRD). METHODS: Medical charts of 87 patients (87 eyes), who underwent SBS for macula off RRD were analysed retrospectively. Patients with follow-up >= 6 months were included. Exclusion criteria were giant retinal tears, retinal dialysis, chorioretinal dystrophies, proliferative vitreoretinopathy >= grade-C1, schisis detachment and vitreous opacities. Reattachment success rate, pre- and postoperative visual acuity (VA) were examined. Postoperative spectral-domain (SD) OCT images were evaluated. The status of photoreceptor inner segment/outer segment (IS/OS) and external limiting memrane (ELM) junction were analysed. Potential risk factors influencing postoperative VA were evaluated by using linear multivariate logistic regression. RESULTS: The primary anatomic success rate was 93.8 % (81 eyes), final success rate was 98.7 % (86 eyes). Preserved ELM (OR 0.58, p = 0.004) and IS/OS integrity (OR 0.84, p = 0.031), drainage of subretinal fluid (OR 0.42, p < 0.0001) were detected as significant independent factors for influencing postoperative VA favourably. Duration of detachment > 6 days (OR 1.46, p = 0.04), two/three retinal breaks (OR 1.30, OR 1.36, p < 0.0001) were significant independent risk factors for a poor postoperative VA. Severe IS/OS disruption was the most important risk factor for poor postoperative VA (beta 0.724, OR 2.06, p < 0.0001). CONCLUSION: Severe IS/OS disruption may be the most important predictor of postoperative VA after successful surgery in macula off rhegmatogenous retinal detachment. PMID- 23670524 TI - [Influence of corneal thickness in keratoconic corneas on IOP measurement with IOPen, iCare, dynamic contour tonometry and Goldmann applanation tonometry]. AB - BACKGROUND: The aim of this study was to evaluate the effect of central corneal thickness (CCT) of keratoconic corneas on intraocular pressure (IOP) measurements as measured by four different techniques. PATIENTS AND METHODS: Forty-one eyes of forty-one keratoconus patients (group 1) and fifty eyes of fifty healthy subjects (group 2) were enrolled. IOP was measured with iCare, IOPen, Goldmann applanation tonometry (GAT) and dynamic contour tonometry (DCT). CCT was measured by ultrasonic pachymetry. These data were used for statistical analysis. RESULTS: The mean IOPs measured by GAT, DCT, iCare and IOPen were 11.4, 14.7, 10.8, and 15.7 mmHg in group 1; and 14.2, 15.4, 15.4 and 14.3 mmHg in group 2, respectively. Between both groups, there was a statistically significant difference in iCare (p < 0.001), GAT (p < 0.001) and IOPen (p = 0.040) measurements; with no difference between DCT (p = 0.266) measurements. IOPen measurements were significantly associated with CCT (r = - 0.314; p = 0.046). CONCLUSION: IOPen seemed to be affected by CCT. IOP readings by iCare, GAT and DCT were found to be independent of CCT in keratoconic corneas. PMID- 23670525 TI - [Choroidal neovascularisation in pathological myopia: epidemiological data from a health services research study conducted in Germany]. AB - BACKGROUND: Pathological myopia (PM) or high myopia is defined as excessive short sightedness (more than -6 dioptres) caused by a strong dilation of the bulbus oculi, that can induce the development of new and unstable vessel structures [choroidal neovascularisation (CNV)]. Since there are only limited epidemiological data available on PM, this health services research study was conducted. PATIENTS AND METHODS: A health services survey with ophthalmologists throughout Germany was undertaken. Physicians were asked to complete a 51-item questionnaire on CNV in PM as well as on its early stages in their daily practice, diagnosis, control and treatment, patient numbers and evaluation of health care situation. Statistical analyses were entirely descriptive. RESULTS: Of 7,500 ophthalmologists, a representative sample of 800 was randomly selected; 340 physicians took part. The mean prevalence rates/year/practice were 1,765.5 +/ 1,218.1 with myopia, 230.7 +/- 278.6 patients with high myopia, subdivided into 129.3 +/- 242.8 patients with PM without macular degeneration (MD), 39.6 +/- 64.8 patients with PM and MD, and 13.3 +/- 30.3 patients with PM and CNV. Data on diagnosis and control show a lack of clearly defined standardisation. With regard to treatment of CNV in PM the data show the current discrepancy of guideline recommendations and approved treatment options. CONCLUSION: The prevalence and incidence data collected in this study vary considerably between physicians. This may be explained by the various grades of specialisation as well as to possibly existing uncertainties regarding the definition and nomenclature of PM/high myopia and their different stages of the disease that should be harmonised. A generally accepted definition of severity grades, recommendations on diagnosis as well as detailed information and continuous training programmes on this disease is necessary. PMID- 23670526 TI - [Immunoassay for matrix metalloproteinase-9 in the tear film of patients with pseudoexfoliation syndrome - a pilot study]. AB - INTRODUCTION: Matrix-metalloproteinases (MMPs) are proteolytic enzymes released by irritated epithelial cells of the ocular surface. It has been established that the subtype MMP-9 can serve as an inflammatory marker within the tear film. MMP-9 is also attributed to have an effect on the PEX-glaucoma development. Recently, a rapid immunoassay for detection of MMP-9 in the tear film was developed to estimate inflammatory extent during dry eye disease. The aim of this study was to analyse the MMP-9 concentration in tear film in PEX-syndrome. In addition, an assessment of the feasibility, reliability and readability of the test was done. METHODS: We randomly selected 10 patients with PEX-syndrome and 10 healthy control patients and measured tear film MMP-9 of one eye with the RPS InflammaDry DetectorTM (Rapid Pathogen Screening Inc., USA). RESULTS: We detected increased levels of MMP-9 in tear film in PEX-syndrome. 80 % of the PEX-patients and 20 % of the controls showed a positive test result (>or= 40 ng/mL MMP-9) indicating a test specificity and sensitivity of 80 %. This corresponds approximately to the published values for the dry eye (sensitivity 87 %, specificity: 92 %). The performance of the test is simple. The patients tolerated the inclusion of the test strips well. However, it is difficult to estimate whether enough tear film was used and in many cases, the intensity of the "indicator line" was weak. CONCLUSION: The rapid MMP-9-immunoassay is a novel, meaningful approach for the detection of inflammatory activity of the ocular surface. We have shown an up regulation of the non-specific inflammatory marker MMP-9 in tear film in PEX syndrome and suggest an association with a tear film disorder. However, an improvement in the estimation of the amount of collected tears and readability is desirable. PMID- 23670527 TI - High-sequence diversity and structural conservation in the human T-cell receptor beta junctional region during thymic development. AB - The T-cell repertoire depends on intrathymic genetic rearrangement events in the T-cell receptor (TCR) locus, followed by positive and negative selection. The repertoire thus generated is highly diverse, but recent data indicate that the recombination of gene segments is less stochastic than previously suggested. Very little is known of the junctional complementarity determining region 3 (CDR3), which is to a large degree not germline encoded. We have analyzed the development of the human TCR beta CDR3 repertoire, from the nonselected CD4(+) CD8(+) CD3(-) cells up to the fully selected CD4(+) CD8(-) thymocytes. In addition to spectratyping, a fraction of the CDR3 repertoire was sequenced and a structural in silico analysis of the CDR3 loop characteristics performed. Our data show that the thymic TCR repertoire is extremely diverse, and the effect of the selection events can be detected as a measurable loss of polyclonality in the CDR3 loop. However, the main physicochemical features of the CDR3 loop were found already at the nonselected repertoire and showed no progressive changes during the selection. Thus, the main structural characteristics of the CDR3 loop were already determined by the recombination process and not significantly affected by the extensive thymocyte death associated with selection in the thymus. PMID- 23670528 TI - Differential gene expression in cholesteatoma by DNA chip analysis. AB - OBJECTIVES/HYPOTHESIS: In contrast to normal epithelium, the desquamating stratified squamous epithelium of temporal bone cholesteatoma characteristically exhibits sustained hyperproliferative growth and a capacity for bone erosion. We conducted genome-wide microarray analyses to determine the molecular nature of cholesteatoma's biological processes and identify disease-associated, altered gene activity. We tested the hypothesis that genes contributing to the pathophysiology of cholesteatoma are differentially expressed compared to control tissue. STUDY DESIGN: Prospective experimental analysis. METHODS: Using new, enhanced microarray platforms and well-annotated human transcriptome probes, we measured global gene expression levels in surgical specimens of cholesteatoma and in the corresponding normal postauricular skin in four patients. Genes of interest were verified by quantitative real time reverse transcriptase polymerase chain reaction analyses using cholesteatoma and postauricular sample pairs (n = 13). External auditory canal skin from six additional patients was also evaluated as a normal control. Immunohistochemistry detected protein expression in tissue sections and the cells involved. RESULTS: DNA chip analyses identified 282 differentially expressed genes in cholesteatoma compared to control samples. Of these, 104 genes were upregulated and 178 were downregulated. Ontological classifications indicate relationships to cellular processes including receptor binding, cell communication and motion, vitamin metabolism, and cytokine-mediated inflammation. Based on potential involvement in disease pathology, 10 genes were selected and independently verified by quantitative polymerase chain reaction. Immunohistochemical detection of transcobalamin-1 and CCL27 implicates cholesteatoma keratinocytes and dermal endothelial cells as contributors in disease processes. CONCLUSIONS: We present a comprehensive, human genome-wide survey of disease-associated gene expression that extends the public database and provides new evidence for molecular mechanisms involved in cholesteatoma pathology. Laryngoscope, 123:S1-S21, 2013. PMID- 23670529 TI - A comparison of five lipid extraction solvent systems for lipidomic studies of human LDL. AB - Lipidome profile of fluids and tissues is a growing field as the role of lipids as signaling molecules is increasingly understood, relying on an effective and representative extraction of the lipids present. A number of solvent systems suitable for lipid extraction are commonly in use, though no comprehensive investigation of their effectiveness across multiple lipid classes has been carried out. To address this, human LDL from normolipidemic volunteers was used to evaluate five different solvent extraction protocols [Folch, Bligh and Dyer, acidified Bligh and Dyer, methanol (MeOH)-tert-butyl methyl ether (TBME), and hexane-isopropanol] and the extracted lipids were analyzed by LC-MS in a high resolution instrument equipped with polarity switching. Overall, more than 350 different lipid species from 19 lipid subclasses were identified. Solvent composition had a small effect on the extraction of predominant lipid classes (triacylglycerides, cholesterol esters, and phosphatidylcholines). In contrast, extraction of less abundant lipids (phosphatidylinositols, lyso-lipids, ceramides, and cholesterol sulfates) was greatly influenced by the solvent system used. Overall, the Folch method was most effective for the extraction of a broad range of lipid classes in LDL, although the hexane-isopropanol method was best for apolar lipids and the MeOH-TBME method was suitable for lactosyl ceramides. PMID- 23670530 TI - New insights regarding tissue Se and Hg interactions on oxidative stress from plasma IsoP and IsoF measures in the Canadian Inuit population. AB - Despite animal and in vitro studies demonstrating pro-oxidative effects of Hg, previous human work showed no relationship between tissue Hg and plasma levels of F2-isoprostanes (IsoPs), a whole-body oxidative stress marker. We hypothesized that another IsoP species, isofurans (IsoFs), was a more sensitive indicator of Hg-mediated oxidative stress, which can be modified by tissue Se status. A cross sectional study was carried out involving individuals from a random subset (n = 233) of Inuit adults from a population-based survey (n = 2,595) of 36 Canadian Arctic Inuit communities to assess the relationships of plasma IsoPs to Se and Hg status indicators. F2-IsoPs were inversely correlated with blood Se (r = -0.186, P = 0.005) and toenail Se (r = -0.146, P = 0.044), but not correlated with Hg. IsoFs were inversely correlated with blood Se (r = -0.164, P = 0.014) and positively correlated with Hg (r = 0.228, P < 0.001) and Hg:Se (r = 0.340, P < 0.001). The strength of the correlations remained unchanged after multivariate adjustments. Multivariate analysis showed that F2-IsoPs were not positively associated with Hg but with Hg:Se (beta = 0.148, P = 0.021). We conclude that Se and Hg status and their interactions are important factors modulating F2-IsoP and IsoF levels such that the Inuit may be protected from Hg-induced oxidative stress because of their high Se status. PMID- 23670531 TI - Changes in helical content or net charge of apolipoprotein C-I alter its affinity for lipid/water interfaces. AB - Amphipathic alpha-helices mediate binding of exchangeable apolipoproteins to lipoproteins. To probe the role of alpha-helical structure in protein-lipid interactions, we used oil-drop tensiometry to characterize the interfacial behavior of apolipoprotein C-I (apoC-I) variants at triolein/water (TO/W) and 1 palmitoyl-2-oleoylphosphatidylcholine/triolein/water (POPC/TO/W) interfaces. ApoC I, the smallest apolipoprotein, has two amphipathic alpha-helices. Mutants had single Pro or Ala substitutions that resulted in large differences in helical content in solution and on phospholipids. The ability of apoC-I to bind TO/W and POPC/TO/W interfaces correlated strongly with alpha-helical propensity. On binding these interfaces, peptides with higher helical propensity increased surface pressure to a greater extent. Likewise, peptide exclusion pressure at POPC/TO/W interfaces increased with greater helical propensity. ApoC-I retention on TO/W and POPC/TO/W interfaces correlated strongly with phospholipid-bound helical content. On compression of these interfaces, peptides with higher helical content were ejected at higher pressures. Substitution of Arg for Pro in the N terminal alpha-helix altered net charge and reduced apoC-I affinity for POPC/TO/W interfaces. Our results suggest that peptide-lipid interactions drive alpha-helix binding to and retention on lipoproteins. Point mutations in small apolipoproteins could significantly change alpha-helical propensity or charge, thereby disrupting protein-lipid interactions and preventing the proteins from regulating lipoprotein catabolism at high surface pressures. PMID- 23670532 TI - Loss of HOXD10 expression induced by upregulation of miR-10b accelerates the migration and invasion activities of ovarian cancer cells. AB - Small and large non-coding RNAs (ncRNAs) contribute to the acquisition of aggressive tumor behavior in diverse human malignancies. Two types of ncRNAs, miRNA-10b (miR-10b) and homemobox (HOX) transcript antisense RNA (HOTAIR), can suppress the translation of the HOXD10 gene, an mRNA encoding a transcriptional repressor that inhibits the expression of cell migration/invasion-associated genes. Using epithelial ovarian cancer cell lines and primary tumors, we investigated whether miR-10b and/or HOTAIR can regulate the expression of HOXD10, and whether it permits gain of pro-metastatic gene products, matrix metallopeptidase 14 (MMP14) and ras homolog family member C (RHOC). Overexpression of miR-10b induced a decrease in HOXD10 protein expression, and upregulated the migration and invasion abilities in ovarian cancer cell lines (P<0.05). In these cells, a significant increase of MMP14 and RHOC protein was observed. No significant upregulation of the HOXD10 protein was observed in cells with the treatment of HOTAIR-siRNA. Positive signals for HOXD10 and MMP14 proteins were observed in 47 (69%) and 25 (37%) of 68 patients with epithelial ovarian cancers. An inverse correlation between HOXD10 and MMP14 immunoreactivities was observed (P<0.05), and miR-10b expression was also inversely correlated with HOXD10 protein expression (P<0.05). These results suggested that downregulation of HOXD10 expression by miR-10b overexpression may induce an increase of pro-metastatic gene products, such as MMP14 and RHOC, and contribute to the acquisition of metastatic phenotypes in epithelial ovarian cancer cells. PMID- 23670533 TI - Synthesis, characterization, and antibacterial activity of cross-linked chitosan glutaraldehyde. AB - This present study deals with synthesis, characterization and antibacterial activity of cross-linked chitosan-glutaraldehyde. Results from this study indicated that cross-linked chitosan-glutaraldehyde markedly inhibited the growth of antibiotic-resistant Burkholderia cepacia complex regardless of bacterial species and incubation time while bacterial growth was unaffected by solid chitosan. Furthermore, high temperature treated cross-linked chitosan glutaraldehyde showed strong antibacterial activity against the selected strain 0901 although the inhibitory effects varied with different temperatures. In addition, physical-chemical and structural characterization revealed that the cross-linking of chitosan with glutaraldehyde resulted in a rougher surface morphology, a characteristic Fourier transform infrared (FTIR) band at 1559 cm-1, a specific X-ray diffraction peak centered at 2theta = 15 degrees , a lower contents of carbon, hydrogen and nitrogen, and a higher stability of glucose units compared to chitosan based on scanning electron microscopic observation, FTIR spectra, X-ray diffraction pattern, as well as elemental and thermo gravimetric analysis. Overall, this study indicated that cross-linked chitosan glutaraldehyde is promising to be developed as a new antibacterial drug. PMID- 23670534 TI - Spasmolytic effect of caulerpine involves blockade of Ca2+ influx on guinea pig ileum. AB - In this work, we investigated the spasmolytic effect of caulerpine, a bisindole alkaloid isolated from marine algae of the Caulerpa genus, on guinea pig ileum. Our findings indicated that caulerpine inhibited phasic contractions induced by carbachol (IC50 = 7.0 +/- 1.9 * 10-5 M), histamine (IC50 = 1.3 +/- 0.3 * 10-4 M) and serotonin (IC50 = 8.0 +/- 1.4 * 10-5 M) in a non-selective manner. Furthermore, caulerpine concentration-dependently inhibited serotonin-induced cumulative contractions (pD'2 = 4.48 +/- 0.08), shifting the curves to the right with Emax reduction and slope of 2.44 +/- 0.21, suggesting a noncompetitive antagonism pseudo-irreversible. The alkaloid also relaxed the ileum pre contracted by KCl (EC50 = 9.0 +/- 0.9 * 10-5 M) and carbachol (EC50 = 4.6 +/- 0.7 * 10-5 M) in a concentration-dependent manner. This effect was probably due to inhibition of Ca2+ influx through voltage-gated calcium channels (CaV), since caulerpine slightly inhibited the CaCl2-induced contractions in depolarizing medium without Ca2+, shifting the curves to the right and with Emax reduction. According to these results, the spasmolytic effect of caulerpine on guinea pig ileum seems to involve inhibition of Ca2+ influx through CaV. However, other mechanisms are not discarded. PMID- 23670536 TI - The effect of anterior palatine blocks on bleeding in hereditary hemorrhagic telangiectasia nasal surgery. AB - OBJECTIVES/HYPOTHESIS: When combined with local sphenopalatine (SP) injection and moderate hypotension, transoral or transcutaneous local injection of the anterior palatine (AP) vessels reduces intraoperative bleeding in hereditary hemorrhagic telangiectasia (HHT) patients undergoing nasal surgery. STUDY DESIGN: Retrospective chart review of 55 consecutive HHT patients undergoing a bevacizumab injection for recalcitrant epistaxis. Nineteen patients received local injections to only the SP vasculature, and 36 patients received AP and SP injections. METHODS: Main outcome variable was estimated blood loss during nasal surgery. Independent variables included sex, age, epistaxis severity score, surgical techniques (including laser), and blood pressure parameters (baseline, preinduction, and postintubation). RESULTS: The mean blood loss in HHT patients receiving SP injections alone was 111 mL, whereas it was 22 mL for those receiving both AP + SP injections. This difference between groups approached statistical significance (P = .075). Blood pressure parameters were similar in both groups with no appreciable difference between intraoperative systolic and mean arterial blood pressure. CONCLUSIONS: The addition of either sublabial or transcutaneous AP injection to the standard SP block markedly reduces blood loss in HHT epistaxis nasal surgery. PMID- 23670535 TI - Evidence for active antigen presentation by monocyte/macrophages in response to stimulation with particles: the expression of NFkappaB transcription factors and costimulatory molecules. AB - BACKGROUND: The macrophage and lymphocyte response to wear debris contributes to the failure of some joint replacements. Costimulatory molecule expression by particle-containing macrophages is an evidence for antigen presentation. The NFkappaB transcription factors are regulators of costimulatory molecules and are present in tissue near failed joint prostheses. The tissue localisation of NFkappaB and the expression of these factors and costimulatory molecules by U937 cells stimulated with nano- and microparticles are reported, together with the effects of an NFkappaB inhibitor (sc514). MATERIALS AND METHODS: The tissue localisation of RelA, RelB, c-rel, p50, p52 and NF-IL6 was examined by immunohistochemistry in samples from 15 patients with failure of metal against polyethylene total hip replacements. The expression of these NFkappaB factors by U937 cells stimulated with microparticles (CoCr, diamond) and nanoparticles (diamond) was examined by quantified RT-PCR. Lipopolysaccharide provided positive controls while negative controls had no additions to culture. Inhibition of NFkappaB activity by sc-514 was studied. The expression of costimulatory molecules (CD80, CD86 and HLA-DR) was evaluated in parallel cell culture studies by tricolour flow cytometry. RESULTS AND DISCUSSION: Immunohistochemistry of tissue showed the highest expression for NF-IL6 (32.56 +/- 11.61 per cent), RelA (33.66 +/- 9.98 per cent) and p52 (32.07 +/- 12.90 per cent), then RelB (22.63 +/ 7.49 per cent), c-rel (14.07 +/- 6.72 per cent) and p50 (13.07 +/- 5.99 per cent). NF-IL6 was localised to macrophages, RelB to RFD1+ dendritic cells. U937 cells showed an increased expression of all NFkappaB factors (p < 0.01) in response to CoCr and diamond microparticles. Only RelA and c-rel (p < 0.01) were increased by one diamond nanoparticle and p52 and c-rel (p < 0.01) by another nanoparticulate diamond. Inhibition by sc-514 of RelA, c-rel and p50 expression occurred with all four particles, p52 was decreased for all diamond particles (but not CoCr) and RelB was not inhibited with any of the particles. CD86 and HLA DR expression were upregulated by microparticles (CoCr, diamond) (p ? 0.01) with lower levels (significant) of these molecules found with diamond nanoparticles. CD80 expression was much less than CD86 and HLA-DR. Costimulatory molecule expression in the bone-implant interface indicates antigen presentation by macrophages. Functional studies with U937 monocytes show the same molecules expressed on exposure to micro- and nanoparticles. Highest values occur with CoCr while the smallest diamond nanoparticles are the least stimulatory. NFkappaB expression gives an insight into the immunogenic potential of the different particles. PMID- 23670537 TI - The selective control of glycolysis, gluconeogenesis and glycogenesis by temporal insulin patterns. AB - Insulin governs systemic glucose metabolism, including glycolysis, gluconeogenesis and glycogenesis, through temporal change and absolute concentration. However, how insulin-signalling pathway selectively regulates glycolysis, gluconeogenesis and glycogenesis remains to be elucidated. To address this issue, we experimentally measured metabolites in glucose metabolism in response to insulin. Step stimulation of insulin induced transient response of glycolysis and glycogenesis, and sustained response of gluconeogenesis and extracellular glucose concentration (GLC(ex)). Based on the experimental results, we constructed a simple computational model that characterises response of insulin-signalling-dependent glucose metabolism. The model revealed that the network motifs of glycolysis and glycogenesis pathways constitute a feedforward (FF) with substrate depletion and incoherent feedforward loop (iFFL), respectively, enabling glycolysis and glycogenesis responsive to temporal changes of insulin rather than its absolute concentration. In contrast, the network motifs of gluconeogenesis pathway constituted a FF inhibition, enabling gluconeogenesis responsive to absolute concentration of insulin regardless of its temporal patterns. GLC(ex) was regulated by gluconeogenesis and glycolysis. These results demonstrate the selective control mechanism of glucose metabolism by temporal patterns of insulin. PMID- 23670538 TI - Nucleotide degradation and ribose salvage in yeast. AB - Nucleotide degradation is a universal metabolic capability. Here we combine metabolomics, genetics and biochemistry to characterize the yeast pathway. Nutrient starvation, via PKA, AMPK/SNF1, and TOR, triggers autophagic breakdown of ribosomes into nucleotides. A protein not previously associated with nucleotide degradation, Phm8, converts nucleotide monophosphates into nucleosides. Downstream steps, which involve the purine nucleoside phosphorylase, Pnp1, and pyrimidine nucleoside hydrolase, Urh1, funnel ribose into the nonoxidative pentose phosphate pathway. During carbon starvation, the ribose derived carbon accumulates as sedoheptulose-7-phosphate, whose consumption by transaldolase is impaired due to depletion of transaldolase's other substrate, glyceraldehyde-3-phosphate. Oxidative stress increases glyceraldehyde-3 phosphate, resulting in rapid consumption of sedoheptulose-7-phosphate to make NADPH for antioxidant defense. Ablation of Phm8 or double deletion of Pnp1 and Urh1 prevent effective nucleotide salvage, resulting in metabolite depletion and impaired survival of starving yeast. Thus, ribose salvage provides means of surviving nutrient starvation and oxidative stress. PMID- 23670539 TI - Computational meta'omics for microbial community studies. AB - Complex microbial communities are an integral part of the Earth's ecosystem and of our bodies in health and disease. In the last two decades, culture-independent approaches have provided new insights into their structure and function, with the exponentially decreasing cost of high-throughput sequencing resulting in broadly available tools for microbial surveys. However, the field remains far from reaching a technological plateau, as both computational techniques and nucleotide sequencing platforms for microbial genomic and transcriptional content continue to improve. Current microbiome analyses are thus starting to adopt multiple and complementary meta'omic approaches, leading to unprecedented opportunities to comprehensively and accurately characterize microbial communities and their interactions with their environments and hosts. This diversity of available assays, analysis methods, and public data is in turn beginning to enable microbiome-based predictive and modeling tools. We thus review here the technological and computational meta'omics approaches that are already available, those that are under active development, their success in biological discovery, and several outstanding challenges. PMID- 23670540 TI - Cellular activation in limbic brain systems during social play behaviour in rats. AB - Positive social interactions during the juvenile and adolescent phases of life are essential for proper social and cognitive development in mammals, including humans. During this developmental period, there is a marked increase in peer-peer interactions, signified by the abundance of social play behaviour. Despite its importance for behavioural development, our knowledge of the neural underpinnings of social play behaviour is limited. Therefore, the purpose of this study was to map the neural circuits involved in social play behaviour in rats. This was achieved by examining cellular activity after social play using the immediate early gene c-Fos as a marker. After a session of social play behaviour, pronounced increases in c-Fos expression were observed in the medial prefrontal cortex, medial and ventral orbitofrontal cortex, dorsal striatum, nucleus accumbens core and shell, lateral amygdala, several thalamic nuclei, dorsal raphe and the pedunculopontine tegmental nucleus. Importantly, the cellular activity patterns after social play were topographically organized in this network, as indicated by play-specific correlations in c-Fos activity between regions with known direct connections. These correlations suggest involvement in social play behaviour of the projections from the medial prefrontal cortex to the striatum, and of amygdala and monoaminergic inputs to frontal cortex and striatum. The analyses presented here outline a topographically organized neural network implicated in processes such as reward, motivation and cognitive control over behaviour, which mediates social play behaviour in rats. PMID- 23670542 TI - The physical anthropometry, lifestyle habits and blood pressure of people presenting with a first clinical demyelinating event compared to controls: the Ausimmune study. AB - INTRODUCTION: Lifestyle factors prior to a first clinical demyelinating event (FCD), a disorder often preceding the development of clinically definite multiple sclerosis (MS), have not previously been examined in detail. Past tobacco smoking has been consistently associated with MS. METHODS: This was a multicentre incident case-control study. Cases (n = 282) were aged 18-59 years with an FCD and resident within one of four Australian centres (from latitudes 27 degrees S to 43 degrees S), from 1 November 2003 to 31 December 2006. Controls (n = 558) were matched to cases on age, sex and study region, without CNS demyelination. Exposures measured included current and past tobacco and marijuana, alcohol and beverage use, physical activity patterns, blood pressure and physical anthropometry. RESULTS: A history of smoking ever was associated with FCD risk (AOR 1.89 (95%CL 1.82, 3.52)). Marijuana use was not associated with FCD risk after adjusting for confounders such as smoking ever but the estimates were imprecise because of a low prevalence of use. Alcohol consumption was common and not associated with FCD risk. No case-control differences in blood pressure or physical anthropometry were observed. CONCLUSIONS: Past tobacco smoking was positively associated with a risk of FCD but most other lifestyle factors were not. Prevention efforts against type 2 diabetes and cardiovascular disease by increasing physical activity and reducing obesity are unlikely to alter MS incidence, and more targeted campaigns will be required. PMID- 23670543 TI - [Biomarkers in acute kidney failure]. PMID- 23670541 TI - Microtubule alterations occur early in experimental parkinsonism and the microtubule stabilizer epothilone D is neuroprotective. AB - The role of microtubule (MT) dysfunction in Parkinson's disease is emerging. It is still unknown whether it is a cause or a consequence of neurodegeneration. Our objective was to assess whether alterations of MT stability precede or follow axonal transport impairment and neurite degeneration in experimental parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57Bl mice. MPTP induced a time- and dose-dependent increase in fibres with altered mitochondria distribution, and early changes in cytoskeletal proteins and MT stability. Indeed, we observed significant increases in neuron-specific betaIII tubulin and enrichment of deTyr tubulin in dopaminergic neurons. Finally, we showed that repeated daily administrations of the MT stabilizer Epothilone D rescued MT defects and attenuated nigrostriatal degeneration induced by MPTP. These data suggest that alteration of MUTaus is an early event specifically associated with dopaminergic neuron degeneration. Pharmacological stabilization of MTs may be a viable strategy for the management of parkinsonism. PMID- 23670546 TI - The technological invention of disease. AB - Technology has come to play a profound role in medicine since the middle of the 19th century, and many scholars have analysed the role of technology in medicine. Parallel to this development there has been a comprehensive debate on the concept of disease. This article combines these fields and investigates the influence of technology on the concept of disease. With reference to the literature it tries to elaborate an explicit account of the constitutive role of technology in relation to the concept of disease. It will be argued that technology constitutes the concept of disease in three profound ways. Firstly, technology provides the physiological, biochemical, and biomolecular entities that are applied in defining diseases. Secondly, it establishes the way we try to gain knowledge of disease and the way we recognise disease in practice. Technology constitutes the signs, markers and end points that define disease entities and it strongly influences the explanatory models of disease as well as medical taxonomy. Thirdly, technology establishes how we act towards disease: thorough diagnosis and treatment technology establishes the actions that constitute the concept of disease. Altogether, this constitutive technological influence on the concept of disease is considered as a technological invention of disease. PMID- 23670547 TI - A comparison of professionals' and patients' understanding of asthma: evidence of emerging dualities? AB - Despite an increase in the provision of services to patients with asthma, morbidity from the disease remains high. Recent research (outside asthma) has raised the possibility that patients may develop a conceptualisation of illnesses which is not entirely compatible with the prevailing biomedical view. This paper compares the way in which health care professionals and patients with asthma described various aspects of the illness, using an approach which considered the type of knowledge which might be used to construct the respective conceptualisations of asthma. A qualitative method is empliyed, using focus groups. Eight focus groups were convened, four of professionals and four of patients with asthma. Following the initial data analysis, the results were reviewed linguistically, with particular attention to the use of metaphor.The health care professionals and patients participating in this study agreed broadly in their explanations of the aetiology and drug treatment of asthma. The data suggest lack of congruence in the development of treatment strategies and locus of control. Health care professionals and patients in this study used linguistically different metaphors to represent the disease: the former more frequently used metaphors evoking on-going processes, the latter visualising the chest (in their use of metaphor) as a static container, emptying and filling throughout the course of the disease. Two commentaries from philosophical and anthropological literature are considered in order to offer theoretical accounts relevant to this interpretation. The data suggest an emerging duality in the approach to treatment plans, in the roles played by professionals and patients with asthma, and in the different types of knowledge used by professionals and patients to construct their respective working models of asthma. PMID- 23670548 TI - The butler(s) DID it - dissociative identity disorder in cinema. AB - Beginning with classic Hollywood melodramas of the 1940s, cinema has maintained a prolific output of films with their own take on mental illnesses-none more so than the rare syndrome of dissociative identity disorder (DID). DID films are a popular and enduring genre, whose influence can be seen throughout mainstream cinema. Exploration of DID in cinema is a useful exercise in that it touches on issues in film studies, psychiatry and the mythology around mental illness. Despite "detective story" narratives and conformity to the codes of the psychological thriller, DID representations correspond closely to contemporary thinking about its phenomenology and aetiology. That said, some films confuse DID with schizophrenia, and many reinforce two other misconceptions within film psychiatry: mental illness as violence and the belief that every mentally ill person harbours one "great dark secret". Those sceptical about DID have suggested that popular written accounts increase its profile: so too, powerful cinematic images may suggest the possibility of DID to susceptible people, including clinicians. Recent DID films reflect the real debate within psychiatry about the diagnostic validity and scientific basis of DID. PMID- 23670549 TI - Imagination and medical education. AB - Rival and apparently exclusive views have been canvassed about the instrumental use of the humanities in medical education. The novel is seen as offering exemplifications of moral principles on the one hand, whilst on the other such an approach is said to miss the essence of reading a novel by misrepresenting the engagment of the reader. The use of the humanities in medicine as a stimulus to reflective practice is presented as a preferable account which recognises that there is truth in each of the former views. PMID- 23670550 TI - Medicine: the science and the art. AB - Medicine has been said to be both a science and an art. Many practitioners regard this statement as containing an element of "either/or". A brief look at what scientists and artists have written about their work and their world views, however, suggests that the two fields of endeavour form a complementary part of our attempts to understand ourselves and the world about us. Moreover, on occasion, each can perform some of the other's tasks. This paper quotes from the writings of physicians, scientists and people active in the humanities in order to demonstrate how frequently their thoughts converge. It also presents a case report from general practice illustrative of the idea that there is much common ground between the "hard" and the "soft" in medicine. Indeed, the profession's art and science may really be one. PMID- 23670551 TI - Poetry, interpretation and unpredictability: a reply to Neil Pickering. AB - In his article on poetry in health care education, Neil Pickering puts forward an argument of radical unpredictability: as we can never know in advance how a poem will be interpreted, it can be of no external use.(1) It is, however, exactly this potential to give rise to multiple interpretations that makes the poem valuable. We hold that the poem should be read and discussed with no other intention than to discover and reflect on its possible meanings. Exactly this process, preferably in dialogue with other readers, may very well serve as one of the ends of the poem, and the results of it hence constitute its external use. PMID- 23670553 TI - Bird, Woman's Wardrobe and The Birth of Humility. PMID- 23670552 TI - Education and debate: Developing the place of medical humanities in medical education from school to the consulting room. PMID- 23670554 TI - Correction. PMID- 23670555 TI - Multiscale modeling of blood flow: from single cells to blood rheology. AB - Mesoscale simulations of blood flow, where the red blood cells are described as deformable closed shells with a membrane characterized by bending rigidity and stretching elasticity, have made much progress in recent years to predict the flow behavior of blood cells and other components in various flows. To numerically investigate blood flow and blood-related processes in complex geometries, a highly efficient simulation technique for the plasma and solutes is essential. In this review, we focus on the behavior of single and several cells in shear and microcapillary flows, the shear-thinning behavior of blood and its relation to the blood cell structure and interactions, margination of white blood cells and platelets, and modeling hematologic diseases and disorders. Comparisons of the simulation predictions with existing experimental results are made whenever possible, and generally very satisfactory agreement is obtained. PMID- 23670556 TI - Interaction of Mycobacterium leprae with human airway epithelial cells: adherence, entry, survival, and identification of potential adhesins by surface proteome analysis. AB - This study examined the in vitro interaction between Mycobacterium leprae, the causative agent of leprosy, and human alveolar and nasal epithelial cells, demonstrating that M. leprae can enter both cell types and that both are capable of sustaining bacterial survival. Moreover, delivery of M. leprae to the nasal septum of mice resulted in macrophage and epithelial cell infection in the lung tissue, sustaining the idea that the airways constitute an important M. leprae entry route into the human body. Since critical aspects in understanding the mechanisms of infection are the identification and characterization of the adhesins involved in pathogen-host cell interaction, the nude mouse-derived M. leprae cell surface-exposed proteome was studied to uncover potentially relevant adhesin candidates. A total of 279 cell surface-exposed proteins were identified based on selective biotinylation, streptavidin-affinity purification, and shotgun mass spectrometry; 11 of those proteins have been previously described as potential adhesins. In vitro assays with the recombinant forms of the histone like protein (Hlp) and the heparin-binding hemagglutinin (HBHA), considered to be major mycobacterial adhesins, confirmed their capacity to promote bacterial attachment to epithelial cells. Taking our data together, they suggest that the airway epithelium may act as a reservoir and/or portal of entry for M. leprae in humans. Moreover, our report sheds light on the potentially critical adhesins involved in M. leprae-epithelial cell interaction that may be useful in designing more effective tools for leprosy control. PMID- 23670557 TI - Enhancing the protective immune response against botulism. AB - The need for a vaccine against botulism has increased since the discontinuation of the pentavalent (ABCDE) botulinum toxoid vaccine by the Centers for Disease Control and Prevention. The botulinum toxins (BoNTs) are the primary virulence factors and vaccine components against botulism. BoNTs comprise three domains which are involved in catalysis (LC), translocation (HCT), and host receptor binding (HCR). Recombinant HCR subunits have been used to develop the next generation of BoNT vaccines. Using structural studies and the known entry properties of BoNT/A, an HCR subunit vaccine against BoNT/A that contained the point mutation W1266A within the ganglioside binding pocket was designed. HCR/A(W1266A) did not enter primary neurons, and the crystal structure of HCR/A(W1266A) was virtually identical to that of wild-type HCR/A. Using a mouse model, experiments were performed using a high-dose vaccine and a low-dose vaccine. At a high vaccine dose, HCR/A and HCR/A(W1266A) elicited a protective immune response to BoNT/A challenge. At the low-dose vaccination, HCR/A(W1266A) was a more protective vaccine than HCR/A. alpha-HCR IgG titers correlated with protection from BoNT challenge, although titers to block HCR/A entry were greater in serum in HCR/A-vaccinated mice than in HCR/A(W1266A)-vaccinated mice. This study shows that removal of receptor binding capacity enhances potency of the subunit HCR vaccine. Vaccines that lack receptor binding capacity have the added property of limited off-target toxicity. PMID- 23670558 TI - Congenic strains for genetic analysis of virulence traits in Cryptococcus gattii. AB - Cryptococcus gattii is responsible for a large outbreak of potentially fatal disease that started in the late 1990s on Vancouver Island, Canada. How this fungus and the outbreak isolates in particular cause disease in immunocompetent people is unknown, with differing hypotheses. To explore genetic contributions, a pair of congenic a and alpha mating type strains was generated by a series of 11 backcrosses to introgress the MAT locus from a nonoutbreak strain into the background of strain R265, isolated from a Vancouver Island patient. The congenic pair was used to investigate three traits: mitochondrial inheritance, the effect of the MAT alleles on virulence, and the impact of a predicted virulence factor on pathogenicity. The two congenic strains show the same virulence in different models of cryptococcosis and equivalent levels of competition in coinfection assays. These results rule out a role of the MAT locus and mitochondrial genotype as major virulence factors in the outbreak strains. Disruption of Bwc2, a light dependent transcription factor, resulted in reduced virulence, consistent with a similar function in the related species Cryptococcus neoformans. The C. gattii congenic strains represent a new resource for exploring the evolution of virulence in the C. neoformans-C. gattii clade. PMID- 23670559 TI - Congenic strains of the filamentous form of Cryptococcus neoformans for studies of fungal morphogenesis and virulence. AB - Cryptococcus neoformans is an unconventional dimorphic fungus that can grow either as a yeast or in a filamentous form. To facilitate investigation of genetic factors important for its morphogenesis and pathogenicity, congenic a and alpha strains for a filamentous form were constructed. XL280 (alpha) was selected as the background strain because of its robust ability to undergo the morphological transition from yeast to the filamentous form. The MATa allele from a sequenced strain JEC20 was introgressed into the XL280 background to generate the congenic a and alpha pair strains. The resulting congenic strains were then used to test the impact of mating type on virulence. In both the inhalation and the intravenous infection models of murine cryptococcosis, the congenic a and alpha strains displayed comparable levels of high virulence. The a-alpha coinfections displayed equivalent virulence to the individual a or alpha infections in both animal models. Further analyses of the mating type distribution in a-alpha coinfected mice suggested no influence of a-alpha interactions on cryptococcal neurotropism, irrespective of the route of inoculation. Furthermore, deletion or overexpression of a known transcription factor, Znf2, in XL280 abolished or enhanced filamentation and biofilm formation, consistent with its established role. Overexpression of Znf2 in XL280 led to attenuation of virulence and a reduced abundance in the brain but not in other organs, suggesting that Znf2 might interfere with cryptococcal neurotropism upon extrapulmonary dissemination. In summary, the congenic strains provide a new resource for the exploration of the relationship in Cryptococcus between cellular morphology and pathogenesis. PMID- 23670560 TI - Protective role of murine beta-defensins 3 and 4 and cathelin-related antimicrobial peptide in Fusarium solani keratitis. AB - Antimicrobial peptides (AMPs), such as beta-defensins and cathelicidins, are essential components of innate and adaptive immunity owing to their extensive multifunctional activities. However, their role in fungal infection in vivo remains elusive. In this study, we investigated the protective effect of murine beta-defensin 3 (mBD3), mBD4, and the cathelicidin cathelin-related antimicrobial peptide (CRAMP) in a murine model of Fusarium solani keratitis. C57BL/6 mice showed significant corneal disease 1 and 3 days after infection, which was accompanied by enhanced expression of beta-defensins and CRAMP. Disease severity was significantly improved 7 days after infection, at which time AMP expression was returning to baseline. Mice deficient in mBD3 (genetic knockout), mBD4 (short interfering RNA knockdown), or CRAMP (genetic knockout) exhibited enhanced disease severity and progression, increased neutrophil recruitment, and delayed pathogen elimination compared to controls. Taken together, these data suggest a vital role for AMPs in defense against F. solani keratitis, a potentially blinding corneal disease. PMID- 23670561 TI - Fukui and dual-descriptor matrices within the framework of spin-polarized density functional theory. AB - This work deals with the Fukui and dual reactivity descriptors within the framework of the spin-polarized density functional theory. The first and second derivatives of the electron density and the spin density with respect to the total number of electrons N = Nalpha + Nbeta and with respect to the spin number NS = Nalpha-Nbeta have been formulated by means of reduced density matrices in the representation of the spin-orbitals of a given basis set, providing the matrix extension of those descriptors. The analysis of the eigenvalues and eigenvectors of the Fukui and dual-descriptor matrices yields information on the role played by the molecular orbitals in charge-transfer and spin-polarization processes. This matrix formulation enables determining similarity indices which allows one to evaluate quantitatively the quality of the simple frontier molecular orbital model in conceptual density functional theory. Selected closed- and open-shell systems in different spin symmetries have been studied with this matrix formalism at several levels of electronic correlation. The results confirm the suitability of this approach. PMID- 23670562 TI - [Effect of fenestration of the cochlea on the vibration of the round window membrane]. AB - Drilling a promontory window and coupling an FMT into the scala tympani may be a surgical alternative to stapes surgery in obliterative tympanosclerosis. Aim of this experimental study on human temporal bones was to measure changes of the acoustic transfer function from the tympanic membrane to the round window membrane after drilling a promontory window and insertion of a floating mass transducer.Laser vibrometry and acoustic measurements were performed on 11 temporal bone preparations equipped with a microphone attached to the round window. Calibrations were carried out to allow determination of SPLs affecting the cochlea after drilling a promontory window leaving the membranous inner ear intact and after insertion of an FMT into the cavity (with or without slight pressure).Drilling a promontory window does influence the transfer function. Insertion of the FMT with additional slight pressure further changes the transfer function.The presence of a promontory window changes the acoustic transfer function to the round window. Further investigations are needed to correlate the qualitative results with the audiological results after "third window vibroplasty" (inserted floating mass transducer without stimulation). PMID- 23670563 TI - [The costs for different voice prostheses depending on the lifetime]. AB - Voice prostheses are available in different types of architecture und from different producers. Especially the ones with antifungal properties are characterized by a high pricing. The aim of this paper is to check, whether these prices are reflected by the prosthesis life time.A Benchmarking with usage of mean lifetime and prosthesis costs. Comparing Provox 1, Provox 2, Provox Vega, Provox ActiValve, ESKA-Herrmann, Blom Singer Classic, Phonax, Blom Singer Advantage.The voice prosthesis Provox 1 offers the best price-lifetime-ratio (1.0). It's 6.7-times higher than the one of the Provox ActiValve (0.15). In addition, the classic prostheses Provox 2 (0.53), Blom Singer Classic (0.54) and ESKA-Herrmann (0.72) offer a good ratio compared to Provox 1, too.The mean lifetime of the voice prostheses do not reflect the pricing. The Provox 1 offers the best ratio and should be used as a reference in pricing the prostheses. PMID- 23670564 TI - p300, but not PCAF, collaborates with IRF-1 in stimulating TRIM22 expression independently of its histone acetyltransferase activity. AB - Tripartite motif (TRIM) 22 plays an important role in IFN-mediated antiviral activity. We previously demonstrated that IFN regulatory factor-1 (IRF-1) was crucial for constitutive and IFN-induced TRIM22 expression via binding to a special cis-element named 5' extended IFN-stimulating response element. Here, we further investigate the molecular mechanisms of TRIM22 with a focus on the co activators of IRF-1. Using an in vitro DNA affinity binding assay and an in vivo chromatin immunoprecipitation assay, we found that IFN-gamma stimulation significantly enhanced the binding of p300 and p300/CBP-associated factor, but not other co-activators such as general control nondepressible 5, steroid receptor co-activator-1, and activator of thyroid and retinoic, to the 5' extended IFN-stimulating response element containing TRIM22 promoter region together with IRF-1. Overexpression and knockdown analysis demonstrated that it was p300, but not p300/CBP-associated factor, that functioned as a transcriptional co-activator of IRF-1 in IFN-gamma induction of TRIM22. We further show that p300 contributed to both IFN-gamma- and IRF-1-mediated TRIM22 transcription independent of its histone acetyltransferase activity, however, it was required for the recruitment of RNA polymerase II to TRIM22 promoter region. These data indicate that p300 plays a critical role in IFN-gamma-induced TRIM22 expression via recruiting RNA polymerase II to the TRIM22 promoter, and might serve as a bridge between IRF-1 and the basal transcriptional apparatus in TRIM22 induction. PMID- 23670565 TI - Patterns of bone mineral density testing in men receiving androgen deprivation for prostate cancer. AB - BACKGROUND: Practice guidelines recommend bone mineral density (BMD) monitoring for men on androgen deprivation therapy (ADT) for prostate cancer, but single center studies suggest this is underutilized. OBJECTIVE: We examined determinants of BMD testing in men receiving ADT in a large population-based cohort of men with prostate cancer. DESIGN: Retrospective cohort study. PARTICIPANTS: We used the Surveillance, Epidemiology and End-Results (SEER)-Medicare database to identify 84,036 men with prostate cancer initiating ADT from 1996 through 2008. MAIN MEASURES: Rates of BMD testing within the period 12 months prior to 3 months after initiation of ADT were assessed and compared to matched controls without cancer and to men with prostate cancer not receiving ADT. A logistic regression model was performed predicting use of BMD testing, adjusted for patient demographics, indications for ADT use, year of diagnosis and specialty of the physician involved in the care of the patient. KEY RESULTS: Rates of BMD testing increased steadily over time in men receiving ADT, diverging from the control groups such that by 2008, 11.5 % of men were receiving BMD testing versus 4.4 % in men with prostate cancer not on ADT and 3.8 % in the non-cancer controls. In the logistic regression model, year of diagnosis, race/ethnicity, indications for ADT use and geographic region were significant predictors of BMD testing. Patients with only a urologist involved in their care were significantly less likely to receive BMD testing as compared to those with both a urologist and a primary care physician (PCP) (odds ratio 0.71, 95 % confidence interval 0.64 0.80). CONCLUSIONS: There has been a sharp increase in rates of BMD testing among men receiving ADT for prostate cancer over time, beyond rates noted in contemporaneous controls. Absolute rates of BMD testing remain low, however, but are higher in men who have a PCP involved in their care. PMID- 23670568 TI - Transcatheter arterial chemoembolization (TACE) of colorectal cancer liver metastases by irinotecan-eluting microspheres in a salvage patient population. AB - PURPOSE: This prospective study evaluated the effectiveness and safety of TACE using irinotecan loaded superabsorbent polymer (SAP) microspheres for treatment of colorectal cancer liver metastases (CCLM) in a salvage setting of patients. METHODS: A total of 71 TACE procedures were performed in 29 patients with liver only or liver-dominant CCLM. In all patients, systemic chemotherapy before TACE had failed. Two hundred milligrams of irinotecan were loaded into 50-100 mg of SAP microspheres (HepaSphereTM Microspheres) considering tumor size and vascularization. TACE was performed selectively with respect to tumor distribution. Response was evaluated following RECIST and EASL criteria, respectively. Median follow-up after last TACE was 8 (range 1-54) months. All patients had died at time of analysis. RESULTS: All TACE procedures were performed successfully; 35-400 mg (mean 168.3 mg) of irinotecan loaded in 13-100 mg (mean 48.3 mg) SAP microspheres were injected during individual sessions. No major complications occurred. Three, 6, and 12 months after first TACE complete and partial response was present in 72, 32 %, 0 of patients by EASL criteria and stable disease was seen in 86, 48, and 8 % with no complete and no partial response by RECIST criteria. Median overall survival after first TACE was 8 months, and median time to progression was 5 months. Median overall survival was longer in patients with limited (<25 %) compared with extensive (>50 %) intrahepatic disease (21 vs. 5 months, p < 0.005). CONCLUSIONS: TACE using irinotecan loaded SAP microspheres is safe and effective in terms of tumor necrosis. Survival benefit in a salvage setting seems to be limited in patients with advanced intrahepatic tumor load. PMID- 23670569 TI - Cone-beam computed tomography-guided stereotactic liver punctures: a phantom study. AB - PURPOSE: Images from computed tomography (CT), combined with navigation systems, improve the outcomes of local thermal therapies that are dependent on accurate probe placement. Although the usage of CT is desired, its availability for time consuming radiological interventions is limited. Alternatively, three-dimensional images from C-arm cone-beam CT (CBCT) can be used. The goal of this study was to evaluate the accuracy of navigated CBCT-guided needle punctures, controlled with CT scans. METHODS: Five series of five navigated punctures were performed on a nonrigid phantom using a liver specific navigation system and CBCT volumetric dataset for planning and navigation. To mimic targets, five titanium screws were fixed to the phantom. Target positioning accuracy (TPECBCT) was computed from control CT scans and divided into lateral and longitudinal components. Additionally, CBCT-CT guidance accuracy was deducted by performing CBCT-to-CT image coregistration and measuring TPECBCT-CT from fused datasets. Image coregistration was evaluated using fiducial registration error (FRECBCT-CT) and target registration error (TRECBCT-CT). RESULTS: Positioning accuracies in lateral directions pertaining to CBCT (TPECBCT = 2.1 +/- 1.0 mm) were found to be better to those achieved from previous study using CT (TPECT = 2.3 +/- 1.3 mm). Image coregistration error was 0.3 +/- 0.1 mm, resulting in an average TRE of 2.1 +/- 0.7 mm (N = 5 targets) and average Euclidean TPECBCT-CT of 3.1 +/- 1.3 mm. CONCLUSIONS: Stereotactic needle punctures might be planned and performed on volumetric CBCT images and controlled with multidetector CT with positioning accuracy higher or similar to those performed using CT scanners. PMID- 23670570 TI - Outcome after radiofrequency ablation of sarcoma lung metastases. AB - PURPOSE: Resection is the mainstay of management in patients with sarcoma lung metastases, but there is a limit to how many resections can be performed. Some patients with inoperable disease have small-volume lung metastases that are amenable to thermal ablation. We report our results after radiofrequency ablation (RFA). METHODS: This is a retrospective study of patients treated from 2007 to 2012 in whom the intention was to treat all sites of disease and who had a minimum CT follow-up of 4 months. Treatment was performed under general anesthesia/conscious sedation using cool-tip RFA. Follow-up CT scans were analyzed for local control. Primary tumor type, location, grade, disease-free interval, prior resection/chemotherapy, number and size of lung tumors, uni- or bilateral disease, complications, and overall and progression-free survival were recorded. RESULTS: Twenty-two patients [15 women; median age 48 (range 10-78) years] with 55 lung metastases were treated in 30 sessions. Mean and median tumor size and initial number were 0.9 cm and 0.7 (range 0.5-2) cm, and 2.5 and 1 (1-7) respectively. Median CT and clinical follow-up were 12 (4-54) and 20 (8-63) months, respectively. Primary local control rate was 52 of 55 (95 %). There were 2 of 30 (6.6 %) Common Terminology Criteria grade 3 complications with no long term sequelae. Mean (median not reached) and 2- and 3-year overall survival were 51 months, and 94 and 85 %. Median and 1- and 2-year progression-free survival were 12 months, and 53 and 23 %. Prior disease-free interval was the only significant factor to affect overall survival. CONCLUSION: RFA is a safe and effective treatment for patients with small-volume sarcoma metastases. PMID- 23670566 TI - Community-partnered evaluation of depression services for clients of community based agencies in under-resourced communities in Los Angeles. AB - BACKGROUND: As medical homes are developing under health reform, little is known regarding depression services need and use by diverse safety-net populations in under-resourced communities. For chronic conditions like depression, primary care services may face new opportunities to partner with diverse community service providers, such as those in social service and substance abuse centers, to support a collaborative care model of treating depression. OBJECTIVE: To understand the distribution of need and current burden of services for depression in under-resourced, diverse communities in Los Angeles. DESIGN: Baseline phase of a participatory trial to improve depression services with data from client screening and follow-up surveys. PARTICIPANTS: Of 4,440 clients screened from 93 programs (primary care, mental health, substance abuse, homeless, social and other community services) in 50 agencies, 1,322 were depressed according to an eight-item Patient Health Questionnaire (PHQ-8) and gave contact information; 1,246 enrolled and 981 completed surveys. Ninety-three programs, including 17 primary care/public health, 18 mental health, 20 substance abuse, ten homeless services, and 28 social/other community services, participated. MAIN MEASURES: Comparisons by setting in 6-month retrospective recall of depression services use. KEY RESULTS: Depression prevalence ranged from 51.9 % in mental health to 17.2 % in social-community programs. Depressed clients used two settings on average to receive depression services; 82 % used any setting. More clients preferred counseling over medication for depression treatment. CONCLUSIONS: Need for depression care was high, and a broad range of agencies provide depression care. Although most participants had contact with primary care, most depression services occurred outside of primary care settings, emphasizing the need to coordinate and support the quality of community-based services across diverse community settings. PMID- 23670571 TI - High spatial resolution MRI of cystic adventitial disease of the iliofemoral vein communicating with the hip joint. AB - Venous cystic adventitial disease (CAD) is an extremely rare entity, and so far less than 20 cases have been described in the literature. Herein, we describe the imaging findings of CAD of iliofemoral vein in a 51-year-old woman who presented with leg swelling with special emphasis on high spatial resolution MRI, which demonstrated communication of the cyst with the hip joint. To our knowledge, this is the first description of high spatial resolution MRI findings in venous CAD supporting a new theory about the pathogenesis of venous CAD. PMID- 23670572 TI - Abducens palsy after lumbar drain placement: a rare complication in endoscopic skull base surgery. AB - OBJECTIVES/HYPOTHESIS: To study reports of abducens nerve palsy following dural puncture procedures and to discuss possible etiologic theories, treatment, and prognosis. STUDY DESIGN: Systematic review of peer-reviewed literature. METHODS: A systematic literature review was conducted (PubMed, 1950 to September 2011) for cases of sixth cranial nerve palsy following dural puncture procedures. RESULTS: We report a case of abducens nerve palsy following lumbar drain placement for endoscopic trans-sphenoidal pituitary macroadenoma resection. Sixth nerve palsy was noted immediately after surgery. Postoperative computed tomography and magnetic resonance imaging revealed no injury to the nerve or surrounding structures. A systematic literature review conducted for cases of abducens nerve palsy following dural puncture procedures found 22 studies (17 case reports and five case series). Twenty-eight patients with temporary or permanent abducens nerve palsy were reported. Procedures included diagnostic lumbar puncture, spinal anesthesia, intrathecal catheterization, and shunting. Traction and local ischemia due to intracranial hypotension at the petroclival junction were proposed as causes of palsy. CONCLUSIONS: Lumbar puncture procedures carry a rare risk of abducens nerve palsy from ischemic or traction injury. Routine use of lumbar drain during endoscopic skull base surgery is not without risk, and need for its placement should be carefully determined. Knowledge of such rare complications is helpful in risk-benefit analysis as endoscopic skull base techniques gain popularity. PMID- 23670573 TI - Induction of broad cytotoxic T cells by protective DNA vaccination against Marburg and Ebola. AB - Marburg and Ebola hemorrhagic fevers have been described as the most virulent viral diseases known to man due to associative lethality rates of up to 90%. Death can occur within days to weeks of exposure and there is currently no licensed vaccine or therapeutic. Recent evidence suggests an important role for antiviral T cells in conferring protection, but little detailed analysis of this response as driven by a protective vaccine has been reported. We developed a synthetic polyvalent-filovirus DNA vaccine against Marburg marburgvirus (MARV), Zaire ebolavirus (ZEBOV), and Sudan ebolavirus (SUDV). Preclinical efficacy studies were performed in guinea pigs and mice using rodent-adapted viruses, whereas murine T-cell responses were extensively analyzed using a novel modified assay described herein. Vaccination was highly potent, elicited robust neutralizing antibodies, and completely protected against MARV and ZEBOV challenge. Comprehensive T-cell analysis revealed cytotoxic T lymphocytes (CTLs) of great magnitude, epitopic breadth, and Th1-type marker expression. This model provides an important preclinical tool for studying protective immune correlates that could be applied to existing platforms. Data herein support further evaluation of this enhanced gene-based approach in nonhuman primate studies for in depth analyses of T-cell epitopes in understanding protective efficacy. PMID- 23670574 TI - Generation of engraftable hematopoietic stem cells from induced pluripotent stem cells by way of teratoma formation. AB - In vitro generation of hematopoietic stem cells (HSCs) from induced pluripotent stem cells (iPSCs) has the potential to provide novel therapeutic approaches for replacing bone marrow (BM) transplantation without rejection or graft versus host disease. Hitherto, however, it has proved difficult to generate truly functional HSCs transplantable to adult host mice. Here, we demonstrate a unique in vivo differentiation system yielding engraftable HSCs from mouse and human iPSCs in teratoma-bearing animals in combination with a maneuver to facilitate hematopoiesis. In mice, we found that iPSC-derived HSCs migrate from teratomas into the BM and their intravenous injection into irradiated recipients resulted in multilineage and long-term reconstitution of the hematolymphopoietic system in serial transfers. Using this in vivo generation system, we could demonstrate that X-linked severe combined immunodeficiency (X-SCID) mice can be treated by HSCs derived from gene-corrected clonal iPSCs. It should also be noted that neither leukemia nor tumors were observed in recipients after transplantation of iPSC derived HSCs. Taken our findings together, our system presented in this report should provide a useful tool not only for the study of HSCs, but also for practical application of iPSCs in the treatment of hematologic and immunologic diseases. PMID- 23670575 TI - Topical application of recombinant type VII collagen incorporates into the dermal epidermal junction and promotes wound closure. AB - Patients with recessive dystrophic epidermolysis bullosa (RDEB) have incurable skin fragility, blistering, and skin wounds due to mutations in the gene that codes for type VII collagen (C7) that mediates dermal-epidermal adherence in human skin. In this study, we evaluated if topically applied human recombinant C7 (rC7) could restore C7 at the dermal-epidermal junction (DEJ) and enhance wound healing. We found that rC7 applied topically onto murine skin wounds stably incorporated into the newly formed DEJ of healed wounds and accelerated wound closure by increasing re-epithelialization. Topical rC7 decreased the expression of fibrogenic transforming growth factor-beta2 (TGF-beta2) and increased the expression of anti-fibrogenic TGF-beta3. These were accompanied by the reduced expression of connective tissue growth factor, fewer alpha smooth muscle actin (alpha-SMA)-positive myofibroblasts, and less deposition of collagen in the healed neodermis, consistent with less scar formation. In addition, using a mouse model in which skin from C7 knock out mice was grafted onto immunodeficient mice, we showed that applying rC7 onto RDEB grafts with wounds restored C7 and anchoring fibrils (AFs) at the DEJ of the grafts and corrected the dermal epidermal separation. The topical application of rC7 may be useful for treating patients with RDEB and patients who have chronic skin wounds. PMID- 23670576 TI - A phase II, randomized, double-blind, placebo-controlled multicenter trial of Endostar in patients with metastatic melanoma. AB - Endostatin is a potent endogenous angiogenic inhibitor with implicated antitumor activity. However, efficacy of recombinant human endostatin (rhES) in clinical trials is controversial, and application of rhES in treatment of metastatic melanoma awaits further investigations. This phase II trial evaluated the efficacy and safety of a soluble and stable rhES (Endostar) plus dacarbazine in patients with metastatic melanomas that contains no mutations in c-kit and BRAF genes. A total of 110 patients received placebo plus dacarbazine (250 mg/m2, n = 54) or Endostar (7.5 mg/m2) plus dacarbazine (250 mg/m2, n = 56). The primary end points were progression-free survival (PFS) and overall survival (OS). Median PFS in the Endostar plus dacarbazine arm was 4.5 months versus 1.5 months in the placebo plus dacarbazine arm (hazard ratio (HR) = 0.578; P = 0.013). There were statistically significant improvements in OS (median, 12.0 months versus 8.0 months; HR, 0.522; P = 0.005) in favor of the Endostar plus dacarbazine arm. The regimen was generally well tolerated and had a manageable toxicity profile. Our trial suggests that Endostar plus dacarbazine is well tolerated in patients with metastatic melanoma harboring no genetic mutations popular for targeted therapy and yields a significant improvement in PFS and OS. PMID- 23670577 TI - Evidence for distinct cognitive profiles in autism spectrum disorders and specific language impairment. AB - Findings that a subgroup of children with an autism spectrum disorder (ASD) have linguistic capabilities that resemble specific language impairment (SLI) have led some authors to hypothesise that ASD and SLI have a shared aetiology. While considerable research has explored overlap in the language phenotypes of the two conditions, little research has examined possible overlap in cognitive characteristics. In this study, we explored nonword and sentence repetition performance, as well as performance on the Children's Embedded Figures Test (CEFT) for children with ASD or SLI. As expected, 'language impaired' children with ASD (ALI) and children with SLI performed worse than both 'language normal' ASD (ALN) and typically developing (TD) children on the nonword and sentence repetition tests. Further, the SLI children performed worse than all other groups on the CEFT. This finding supports distinct cognitive profiles in ASD and SLI and may provide further evidence for distinct aetiological mechanisms in the two conditions. PMID- 23670578 TI - Basic concepts in the taxonomy of health-related behaviors, habits and lifestyle. AB - BACKGROUND: Health-related Habits (HrH) are a major priority in healthcare. However there is little agreement on whether exercise, diet, smoking or dental hygiene are better described as lifestyles, habits or behaviors, and on what is their hierarchical relationship. This research is aimed at representing the basic concepts which are assumed to constitute the conceptual framework enabling us to interpret and organize the field of HrH. METHODS: A group of 29 experts with different backgrounds agreed on the definition and hierarchy of HrH following an iterative process which involved framing analysis and nominal group techniques. RESULTS: Formal definitions of health-related behavior, habit, life-style and life-style profile were produced. In addition a series of basic descriptors were identified: health reserve, capital, risk and load. Six main categories of HrH were chosen based on relevance to longevity: diet/exercise, vitality/stress, sleep, cognition, substance use and other risk. Attributes of HrH are clinical meaningfulness, quantifiability, temporal stability, associated morbidity, and unitarity (non-redundancy). Two qualifiers (polarity and stages of change) have also been described. CONCLUSIONS: The concepts represented here lay the groundwork for the development of clinical and policy tools related to HrH and lifestyle. An adaptation of this system to define targets of health interventions and to develop the classification of person factors in ICF may be needed in the future. PMID- 23670579 TI - [Anesthesiological acute pain therapy in Germany: telephone-based survey]. AB - INTRODUCTION: The last survey of anesthesiological acute pain therapy in Germany was conducted in 1999. Since then new organisational as well as therapeutic aspects have developed. Amongst others the operation and procedures key (OPS) figure 8-919 complex acute pain therapy has been introduced in the German medical billing system, with the restriction that it cannot currently be redeemed. There is an ongoing debate on the role of epidural analgesia in acute pain therapy and new oral medication concepts have been established. Therefore a survey of the present state of acute pain therapy in Germany was conducted. METHODS: Based on a list of all 1,356 hospitals in Germany a randomized list of 412 hospitals was generated. Out of these 412 hospitals those with anesthesiology departments (378 hospitals) were contacted via telephone and asked to participate in the survey. Out of the 378 hospitals 285 (75.4 %) agreed to take part. The survey consisted of a questionnaire containing closed and open questions regarding organisational and therapeutic aspects of acute pain therapy. The ethics committee of the University of Regensburg rated the survey as not being subject to approval due to the lack of personal patient data. RESULTS: Of the participating hospitals 183 (64.2 %) had an acute pain service (APS) and of these 107 (58.5 %) met the quality criteria of the OPS 8-919. This figure however, was only consistently documented by 40 (37 %) APSs. Epidural analgesia (EA) was offered by 275 (96.5 %) hospitals and patient-controlled intravenous analgesia (PCA) by 255 (89.5 %). Likewise, 255 (89.5 %) hospitals used controlled-released opioids in acute pain therapy. Concerning EA, the medications most used were sufentanil as an opioid and ropivacaine as a local anesthetic in255 (92.7 %) of the hospitals with EA for sufentanil and 253 (92 %] for ropivacaine. An EA was offered on regular wards in 240 (87.3 %) hospitals. Uncertainty existed about concrete limits for coagulation values before removal of an epidural catheter. The opioid most utilized in PCA was piritramide with some hospitals using morphine or oxycodone (92.2 %, 9.4 % and 9.4 %, respectively). Other opioids, such as hydromorphone and tramadol were rarely used and remifentanil was not used at all. Oral medication was widely used with metamizole being the non-opioid analgesic and oxycodone/naloxone the controlled-release opioid being prescribed the most. New antiepileptic drugs, such as gabapentin or pregabalin were rarely employed in acute pain therapy. CONCLUSIONS: Since 1999 the number of hospitals that have implemented an APS has risen from 36.1 % to 64.2 %. The lack of consistent documentation of the OPS 8 919 will probably not increase the likelihood that it will become redeemable in the near future. Certain therapy methods, such as EA and PCA were still well established with oral therapy gaining in significance. The uncertainty regarding limits for coagulation values before removal of an epidural catheter could perhaps be reduced by a statement from the German Society of Anesthesia and Intensive Care. PMID- 23670580 TI - [Quality of postoperative pain therapy: evaluation of an established anesthesiology acute pain service]. AB - BACKGROUND: Despite well-designed concepts of perioperative pain management, recent studies have revealed that a large number of patients still suffer from unacceptable pain after surgery. The purpose of this prospective evaluation was to critically analyze postoperative pain treatment provided by a routinely established, DIN certified acute pain service (APS) at the University Hospital Grobetahadern in Munich. MATERIALS AND METHODS: A total of 1,000 consecutive patients received one of the following analgesic procedures: continuous epidural analgesia (EA, n = 401), continuous and patient-controlled epidural analgesia (PCEA, n = 305), intravenous patient-controlled analgesia with opioids (PCA, n = 169) or continuous peripheral nerve block (CPNB, n = 125). For EA and PCEA, ropivacaine 0.2 % and sufentanil 0.24 ug/ml were administered while peripheral regional analgesia was performed with infusion of ropivacaine 0.2 % only. Patients with PCEA were allowed a 3 mg bolus once per hour on demand. Standardized intravenous PCA was performed with piritramide 2.5 mg/ml, a bolus of 2.5 mg, a lock-out time of 15 min, a maximum of 25 mg/4 h and no background infusion. During the daily visits the APS assessed pain intensity at rest and during movement on a numerical rating scale from 0 (no pain) to 10 (maximum pain), acceptance of pain, satisfaction with the analgesic procedure, demand of additional non-opioid analgesics, the need for optimization including bolus applications and changes of the infusion rate or retraction of the epidural catheter. The duration of the procedures, side effects and complications were documented. The catheter insertion sites were inspected daily for redness and tenderness on palpation. RESULTS: In general, epidural and peripheral regional analgesic techniques were superior in terms of postoperative analgesia to intravenous opioid PCA and were associated with fewer side effects, such as sedation, nausea, vomiting, obstipation and sensorimotor deficits. A subgroup analysis revealed that in major upper abdominal surgery, EA provided significantly better analgesia at rest and during movement than PCA. In lower abdominal surgery PCEA induced significantly better analgesia than both PCA and EA, especially during movement. Patient satisfaction was generally high and was best with PCEA (95 %) followed by CPNB (94 %), EA (91 %) and PCA (88 %). On the first postoperative day analgesic procedures had to be optimized (e.g. by bolus administration, retraction of catheters or changes to standardized PCA) in 23 % of EA patients, 10 % of PCEA patients, 6 % of PCA patients and 12 % of CPNB patients. Major complications, such as neuraxial hematoma, infections or respiratory depression were not observed. CONCLUSIONS: As described in many prospective studies, this evaluation revealed that for postoperative pain control, regional anesthesia is superior to intravenous patient-controlled analgesia with strong opioids in terms of analgesia and side effects. In the setting of a well-organized acute pain service with frequent education and training of all members involved, postoperative pain management is safe and effective. However, regular re-evaluation of the defined and certified procedures is necessary. PMID- 23670582 TI - [Legal position of non-medical personnel in hospitals]. AB - There are currently many assistant professions in the German healthcare system which have either a more nursing or a more medical character. All these assistant professions have in common that as yet they do not require uniform training criteria but members of these professions undertake some aspects of medical activities. At the center lies the difficulty of more political than legal discussion on whether members of these assistant professions and also nursing personnel are allowed to or should undertake medical activities. This article illuminates the legal status quo. PMID- 23670581 TI - Bupivacaine crystal deposits after long-term epidural infusion. AB - The case of a 45-year-old male patient (body weight 52 kg, height 1.61 m) with a locally invasive gastric carcinoma infiltrating into the retroperitoneal space is reported. Because of severe cancer pain a tunnelled thoracic epidural catheter (EC) was placed at thoracic spinal level 7/8 and a local anesthetic (LA) mixture of bupivacaine 0.25 % and morphine 0.005 % was infused continuously at 6 ml h( 1). To optimize pain therapy the concentration was doubled (bupivacaine 0.5 %, morphine 0.01 %) 3 months later but the infusion rate was reduced to 3 ml h(-1) thus the total daily dose did not change. The patient died 6 months after initiation of the epidural analgesia from the underlying disease. The total amount of bupivacaine infused was 69 g and of morphine 1.37 g. The patient never reported any neurological complications. The autopsy revealed large white crystalline deposits in the thoracic epidural space which were identified as bupivacaine base by infrared spectrometry. Morphine could not be detected. A histological examination showed unreactive fatty tissue necrosis within the crystalline deposits but nerve tissue could not be identified. It is concluded that the bupivacaine crystalline deposits arose due to precipitation but the clinical significance with regard to sensory level and neuraxial tissue toxicity is unknown. PMID- 23670583 TI - Hypoglossal-facial-jump-anastomosis without an interposition nerve graft. AB - OBJECTIVES/HYPOTHESIS: The hypoglossal-facial-anastomosis is the most often applied procedure for the reanimation of a long lasting peripheral facial nerve paralysis. The use of an interposition graft and its end-to-side anastomosis to the hypoglossal nerve allows the preservation of the tongue function and also requires two anastomosis sites and a free second donor nerve. We describe the modified technique of the hypoglossal-facial-jump-anastomosis without an interposition and present the first results. STUDY DESIGN: Retrospective case study. METHODS: We performed the facial nerve reconstruction in five patients. The indication for the surgery was a long-standing facial paralysis with preserved portion distal to geniculate ganglion, absent voluntary activity in the needle facial electromyography, and an intact bilateral hypoglossal nerve. Following mastoidectomy, the facial nerve was mobilized in the fallopian canal down to its bifurcation in the parotid gland and cut in its tympanic portion distal to the lesion. Then, a tensionless end-to-side suture to the hypoglossal nerve was performed. The facial function was monitored up to 16 months postoperatively. RESULTS: The reconstruction technique succeeded in all patients: The facial function improved within the average time period of 10 months to the House-Brackmann score 3. CONCLUSION: This modified technique of the hypoglossal facial reanimation is a valid method with good clinical results, especially in cases of a preserved intramastoidal facial nerve. LEVEL OF EVIDENCE: Level 4. PMID- 23670584 TI - Study on molecular imaging and radionuclide therapy of human nasopharyngeal carcinoma cells transfected with baculovirus-mediated sodium/iodine symporter gene. AB - The non-invasive imaging and radiotherapy by sodium/iodine symporter (NIS) gene transfer have been widely used for many experiments and some clinical studies. Baculovirus is an efficient tool for gene delivery into mammalian cells in vitro and in vivo. However, the applications of NIS and/or baculovirus in nasopharyngeal carcinoma (NPC) cells have not been reported yet. In this study, two recombinant baculoviruses expressing, respectively, NIS and green fluorescent protein (GFP), both under the control of the cytomegalovirus promoter (Bac-NIS and Bac-GFP) were successfully constructed. The infection efficiency and GFP fluorescence intensity of the human NPC cell line CNE-2Z infected by Bac-GFP at different setting of multiplicity of infection (MOI) were determined by flow cytometry. NIS protein expression was detected by indirect immunofluorescence. The 125I uptake and efflux of infected CNE-2Z cells by Bac-NIS were measured by a gamma-counter. The cytotoxicity of baculovirus and sodium butyrate and inhibition of iodine uptake by NaClO4 were examined. The radioactivity and GFP fluorescence intensity in co-infected CNE-2Z cells by Bac-NIS and Bac-GFP were measured. Cell colony formation tests were conducted to evaluate the killing effect of Bac-NIS mediated 131I. Based on the results, the transduction efficiency of Bac-GFP at the MOI of 200 or 400 reached 91.16 and 94.79%, respectively. NIS protein was expressed accurately on transfected CNE-2Z cell membranes and performed its normal function in iodine transport. Baculovirus had hardly any cytotoxic effects on infected cells, while relatively high concentration of sodium butyrate generated cytotoxicity. The correlation coefficient between the GFP fluorescence intensity and radioactivity in co-infected CNE-2Z cells was 0.917. Treatment coupled Bac-NIS with 131I killed the infected tumour cells dramatically in vitro. These results suggest that baculovirus is an effective vector of the gene delivery into CNE-2Z cells and NIS-mediated iodine transport is a potential approach for molecular imaging and radionuclide therapy of NPC. PMID- 23670586 TI - Green synthesis of TiO2 nanocrystals with improved photocatalytic activity by ionic-liquid assisted hydrothermal method. AB - Owing to potential industrial applications and fundamental significance, tailored synthesis of well-defined anatase TiO2 nanocrystals with exposed highly reactive {001} facets has stimulated great research interest. In this work, surface fluorinated anatase TiO2 nanocrystals have been successfully prepared by using an ionic liquid (IL) assisted hydrothermal synthetic route. TiCl4 is used as precursor, and 1-butyl-3-methylimidazolium tetrafluoroborate ([Bmim](+)[BF4](-)) as morphology-controlling agent. The anion of the IL plays a key role in controlling the crystallization process via a dissolution-recrystallization process. Compared with the benchmark material Degussa P25, the fluorinated anatase TiO2 nanocrystals exhibit superior photocatalytic activity. PMID- 23670585 TI - A novel vitreous substitute of using a foldable capsular vitreous body injected with polyvinylalcohol hydrogel. AB - Hydrogels may be the ideal vitreous substitutes due to their wonderful physical features and biocompatibility. However, their drawbacks, short residence time, and biodegradation in vivo, have led to the fact that none of them have been approved for clinical use. In this study, we developed a novel approach of using a foldable capsular vitreous body (FCVB) injected with polyvinylalcohol (PVA) hydrogel as a vitreous substitute for long-term tamponade. The 3% PVA hydrogel that was cross-linked by gamma irradiation showed good rheological and physical properties and had no toxicity in vitro. After 180 days retention, the 3% PVA hydrogel inside FCVB remained transparent and showed good viscoelasticity without biodegradation and showed good biocompatibility and retina support. This new approach may develop into a valuable tool to improve the stability performance of PVA hydrogel as a vitreous substitute and to extend the application function of FCVB for long-term implantation in vitreous cavity. PMID- 23670587 TI - Optimization of computed tomography protocols: limitations of a methodology employing a phantom with location-known opacities. AB - This study aimed to determine if phantom-based methodologies for optimization of hepatic lesion detection with computed tomography (CT) require randomization of lesion placement and inclusion of normal images. A phantom containing fixed opacities of varying size (diameters, 2.4, 4.8, and 9.5 mm) was scanned at various exposure and slice thickness settings. Two image sets were compared: All images in the first image set contained opacities with known location; the second image set contained images with opacities in random locations. Following Institutional Review Board approval, nine experienced observers scored opacity visualization using a 4-point confidence scale. Comparisons between image sets were performed using Spearman, Kappa, and Wilcoxon techniques. Observer scores demonstrated strong correlation between both approaches when all opacity sizes were combined (r = 0.92, p < 0.0001), for the 9.5 mm opacity (r = 0.96, p < 0.0001) and for the 2.4 mm opacity (r = 0.64, p < 0.05). There was no significant correlation for the 4.8 mm opacity. A significantly higher sensitivity score for the known compared with the unknown location was found for the 9.5 mm opacity and 4.8 mm opacity for a single slice thickness and exposure condition (p < 0.05). Phantom-based optimization of CT hepatic examinations requires randomized lesion location when investigating challenging conditions; however, a standard phantom with fixed lesion location is suitable for the optimization of routine liver protocols. The development of more sophisticated phantoms or methods than those currently available is indicated for the optimization of CT protocols for diagnostic tasks involving the detection of subtle change. PMID- 23670588 TI - Modifying clinicians use of PACS imaging. AB - The purpose of this study was to determine whether it would be possible to minimise the delay that occurs between the time a radiological image becomes available for viewing on PACS and the time that it is actually seen by the requesting physician. The study was conducted at Sir Charles Gairdner Hospital in Perth Western Australia. Participants in the study were all junior doctors. The first part of the study measured the current time delay between images being available on PACS and actually being viewed. In the second part of the study, the doctors were notified by a paging system when the images were available. The reduction in time delay was then compared. Following pager notification, the mean average time delay reduced from a mean of 180.02 min (95 % confidence interval (CI), 135.1 to 225 min) to a mean of 33.94 min (95 % CI, 24.1 to 43.8 min; P < 0.0001). The study has demonstrated that it is possible to modify clinicians' usage of PACS; however, there remain questions regarding the sustainability of such an intervention and the impact that this may have on overall patient outcome. There may be potential for integration of the rapidly expanding technologies such as tablets, iPads and iPhones in order to automate this type of notification and this may be a focus of future research. PMID- 23670589 TI - Influence of alcohol use on neural response to Go/No-Go task in college drinkers. AB - Impaired inhibition of prepotent motor response may represent an important risk factor for alcoholism. Alcohol use may also increase impulsive behavior, including impaired response inhibition. Little is known about the brain function underlying response inhibition among college-age drinkers based on their drinking patterns, despite college-age drinkers demonstrating high rates of alcohol-use disorders. Our major objective was to compare behavior and associated brain activity measured with fMRI during a response-inhibition task in matched heavy- and light-alcohol-drinking college students. Participants were light (N=36) and heavy (N=56) drinkers, aged 18-20 years. We characterized blood oxygen level dependent (BOLD) responses, while participants performed an fMRI Go/No-Go task to quantify inhibitory behavior and brain activity. Behaviorally, group performance differences were observed for Go correct-hit and No-Go false-alarm reaction times with increased reaction times in heavy compared with light drinkers. During fMRI No-Go correct rejections, light drinkers exhibited greater BOLD response than did heavy drinkers in left supplementary motor area (SMA), bilateral parietal lobule, right hippocampus, bilateral middle frontal gyrus, left superior temporal gyrus, and cingulate gyrus/anterior cingulate cortex (Brodmann area 24). Group differences in Go/No-Go-related regional activations correlated with alcohol- and impulsivity-related measures. These findings suggest that heavy alcohol drinkers may have dysfunction in brain regions underlying attention and response inhibition, leading to diminished abilities to suppress prepotent responding. The extent to which these tendencies relate to impulsive decision-making and behaviors in real-life settings and may guide intervention development warrants additional investigation. PMID- 23670590 TI - P-glycoprotein inhibition increases the brain distribution and antidepressant like activity of escitalopram in rodents. AB - Despite the clinical prevalence of the antidepressant escitalopram, over 30% of escitalopram-treated patients fail to respond to treatment. Recent gene association studies have highlighted a potential link between the drug efflux transporter P-glycoprotein (P-gp) and response to escitalopram. The present studies investigated pharmacokinetic and pharmacodynamic interactions between P gp and escitalopram. In vitro bidirectional transport studies revealed that escitalopram is a transported substrate of human P-gp. Microdialysis-based pharmacokinetic studies demonstrated that administration of the P-gp inhibitor cyclosporin A resulted in increased brain levels of escitalopram without altering plasma escitalopram levels in the rat, thereby showing that P-gp restricts escitalopram transport across the blood-brain barrier (BBB) in vivo. The tail suspension test (TST) was carried out to elucidate the pharmacodynamic impact of P-gp inhibition on escitalopram effect in a mouse model of antidepressant activity. Pre-treatment with the P-gp inhibitor verapamil enhanced the response to escitalopram in the TST. Taken together, these data indicate that P-gp may restrict the BBB transport of escitalopram in humans, potentially resulting in subtherapeutic brain concentrations in certain patients. Moreover, by verifying that increasing escitalopram delivery to the brain by P-gp inhibition results in enhanced antidepressant-like activity, we suggest that adjunctive treatment with a P-gp inhibitor may represent a beneficial approach to augment escitalopram therapy in depression. PMID- 23670591 TI - Upregulation of mGlu2 receptors via NF-kappaB p65 acetylation is involved in the Proneurogenic and antidepressant effects of acetyl-L-carnitine. AB - Acetyl-L-carnitine (ALC) is a naturally occurring molecule with an important role in cellular bioenergetics and as donor of acetyl groups to proteins, including NF kappaB p65. In humans, exogenously administered ALC has been shown to be effective in mood disturbances, with a good tolerability profile. No current information is available on the antidepressant effect of ALC in animal models of depression and on the putative mechanism involved in such effect. Here we report that ALC is a proneurogenic molecule, whose effect on neuronal differentiation of adult hippocampal neural progenitors is independent of its neuroprotective activity. The in vitro proneurogenic effects of ALC appear to be mediated by activation of the NF-kappaB pathway, and in particular by p65 acetylation, and subsequent NF-kappaB-mediated upregulation of metabotropic glutamate receptor 2 (mGlu2) expression. When tested in vivo, chronic ALC treatment could revert depressive-like behavior caused by unpredictable chronic mild stress, a rodent model of depression with high face validity and predictivity, and its behavioral effect correlated with upregulated expression of mGlu2 receptor in hippocampi of stressed mice. Moreover, chronic, but not acute or subchronic, drug treatment significantly increased adult born neurons in hippocampi of stressed and unstressed mice. We now propose that this mechanism could be potentially involved in the antidepressant effect of ALC in humans. These results are potentially relevant from a clinical perspective, as for its high tolerability profile ALC may be ideally employed in patient subpopulations who are sensitive to the side effects associated with classical antidepressants. PMID- 23670593 TI - Chemotaxis of bone marrow derived eosinophils in vivo: a novel method to explore receptor-dependent trafficking in the mouse. AB - Here, we describe a novel method via which ex vivo cultured mouse bone marrow derived eosinophils (bmEos) can be adoptively transferred into recipient mice in order to study receptor-dependent recruitment to lung tissue in vivo. Intratracheal instillation of recombinant human eotaxin-2 (hCCL24) prior to introduction of bmEos via tail vein injection resulted in an approximately fourfold increase in Siglec F-positive/CD11c-negative eosinophils in the lungs of eosinophil-deficient DeltadblGATA recipient mice compared with controls. As anticipated, bmEos generated from CCR3-gene-deleted mice did not migrate to the lung in response to hCCL24 in this model, indicating specific receptor dependence. BmEos generated from GFP-positive BALB/c mice responded similarly to hCCL24 in vitro and were detected in lung tissue of BALB/c WT as well as BALB/c DeltadblGATA eosinophil-deficient recipient mice, at approximately fourfold (at 5 h post-injection) and approximately threefold (at 24 h postinjection) over baseline, respectively. Comparable results were obtained with GFP-positive C57BL/6 bmEos responding to intratracheal hCCL24 in C57BL/6 DeltadblGATA recipient mice. The use of ex vivo cultured bmEos via one or more of these methods offers the possibility of manipulating bmEos prior to transfer into a WT or gene-deleted recipient host. Thus, this chemotaxis model represents a novel and robust tool for pharmacological studies in vivo. PMID- 23670596 TI - On a global level, the use of natural products in women's health care is motivated by completely different reasons. PMID- 23670594 TI - TrkB receptor signalling: implications in neurodegenerative, psychiatric and proliferative disorders. AB - The Trk family of receptors play a wide variety of roles in physiological and disease processes in both neuronal and non-neuronal tissues. Amongst these the TrkB receptor in particular has attracted major attention due to its critical role in signalling for brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4 (NT4). TrkB signalling is indispensable for the survival, development and synaptic plasticity of several subtypes of neurons in the nervous system. Substantial evidence has emerged over the last decade about the involvement of aberrant TrkB signalling and its compromise in various neuropsychiatric and degenerative conditions. Unusual changes in TrkB signalling pathway have also been observed and implicated in a range of cancers. Variations in TrkB pathway have been observed in obesity and hyperphagia related disorders as well. Both BDNF and TrkB have been shown to play critical roles in the survival of retinal ganglion cells in the retina. The ability to specifically modulate TrkB signalling can be critical in various pathological scenarios associated with this pathway. In this review, we discuss the mechanisms underlying TrkB signalling, disease implications and explore plausible ameliorative or preventive approaches. PMID- 23670595 TI - MAPKs and signal transduction in the control of gastrointestinal epithelial cell proliferation and differentiation. AB - Mitogen-activated protein kinase (MAPK) pathways are activated by several stimuli and transduce the signal inside cells, generating diverse responses including cell proliferation, differentiation, migration and apoptosis. Each MAPK cascade comprises a series of molecules, and regulation takes place at different levels. They communicate with each other and with additional pathways, creating a signaling network that is important for cell fate determination. In this review, we focus on ERK, JNK, p38 and ERK5, the major MAPKs, and their interactions with PI3K-Akt, TGFbeta/Smad and Wnt/beta-catenin pathways. More importantly, we describe how MAPKs regulate cell proliferation and differentiation in the rapidly renewing epithelia that lines the gastrointestinal tract and, finally, we highlight the recent findings on nutritional aspects that affect MAPK transduction cascades. PMID- 23670597 TI - Glioma-amplified sequence KUB3 influences double-strand break repair after ionizing radiation. AB - Human glioblastomas are characterized by frequent DNA amplifications most often at chromosome regions 7p11.2 and 12q13-15. Although amplification is a well-known hallmark of glioblastoma genetics the function of most amplified genes in glioblastoma biology is not understood. Previously, we cloned Ku70-binding protein 3 (KUB3) from the amplified domain at 12q13-15. Here, we report that glioblastoma cell cultures with endogenous KUB3 gene amplification and with elevated KUB3 protein expression show an efficient double-strand break (DSB) repair after being irradiated with 1 Gy. A significantly less efficient DSB repair was found in glioma cell cultures without KUB3 amplification and expression. Furthermore, we found that a siRNA-mediated reduction of the endogenous KUB3 expression in glioblastoma cells resulted in a reduction of the repair efficiency. HeLa cells transfected with KUB3 showed an increased DSB repair in comparison to untreated HeLa cells. In addition, KUB3 seems to influence DSB efficiency via the DNA-PK-dependent repair pathway as shown by simultaneous inhibition of KUB3 and DNA-PK. The data provide the first evidence for a link between the level of KUB3 amplification and expression in glioma and DSB repair efficiency. PMID- 23670598 TI - Single nucleotide polymorphisms in the upstream regulatory region alter the expression of myostatin. AB - The expression of the gene encoding myostatin (MSTN), the product of which is a negative regulator of skeletal muscle growth and development in mammals, is regulated by many cis-regulatory elements, including enhancer box (E-box) motifs. While E-box motif mutants of MSTN exhibit altered expression of myostatin in many animal models, the phenotypes of these mutations in chicken are not investigated. In this study, we cloned and sequenced the full encoded DNA sequence of MSTN gene and its upstream promoter region in Wenshang Luhua chicken breed. After analysis of the sequence, 13 E-box motifs were identified in the MSTN promoter region, which were denoted by E1 to E13 according to their positions in the region. Although many single nucleotide polymorphisms (SNPs) were revealed in the MSTN promoter region, only two SNPs were in the E-boxes, i.e., the first nucleotide of the E3 and the fifth nucleotide of E4. The effects of these two polymorphisms on the expression of MSTN gene were explored both with MSTN-GFP reporter constructs in vitro and real-time PCR in vivo. The results suggested that the E-boxes in the chicken MSTN promoter region are involved in the regulation of myostatin expression and the polymorphisms in E3 and E4 altered the expression of myostatin. PMID- 23670599 TI - Efficient generation of biliary epithelial cells from rabbit intrahepatic bile duct by Y-27632 and Matrigel. AB - Efficient culture of primary biliary epithelial cells (BECs) from adult liver is useful for both experimental studies and clinical applications of tissue engineering. However, an effective culture system for long-term proliferation of adult BECs is still unachieved. Laboratory rabbit has been used in a large number of studies; however, there are no reports of BECs from normal adult rabbit. As little as 5 g of normal rabbit liver tissue were minced, digested, and then clonally cultured in medium containing FBS and ITS. Cells were characterized by cell morphology, immunoassaying, and growth rate assay. Different combination of growth factors and substrates, including Y-27632 and Matrigel, were employed to assess their effect on cell proliferation. In the primary culture, the BECs cellular sheets consisting of cuboidal cells, as well as fibroblast-like cells and other hepatic cells, emerged with time of culture. The BECs cellular sheets were then manually split into cells clumps for further characterization. The subcultured cells had typical cell morphology of cholangiocytes, expressed the specific markers of BECs, including GGT, cytokeratin (CK18), and CK19, and possessed the capacity to form duct-like structure in three-dimensional Matrigel. Y-27632 and Matrigel-treated BECs had a steady growth rate as well as colony formation capacity. The BECs were maintained in Y-27632 and Matrigel culture system for more than 3 mo. This is the first example, to our knowledge, of the successful culture of BECs from normal adult rabbit liver. Furthermore, our results indicate that treatment of BECs with Y-27632 and Matrigel is a simple method for efficient output of BECs. PMID- 23670600 TI - Disentangling climate change effects on species interactions: effects of temperature, phenological shifts, and body size. AB - Climate-mediated shifts in species' phenologies are expected to alter species interactions, but predicting the consequences of this is difficult because phenological shifts may be driven by different climate factors that may or may not be correlated. Temperature could be an important factor determining effects of phenological shifts by altering species' growth rates and thereby the relative size ratios of interacting species. We tested this hypothesis by independently manipulating temperature and the relative hatching phenologies of two competing amphibian species. Relative shifts in hatching time generally altered the strength of competition, but the presence and magnitude of this effect was temperature dependent and joint effects of temperature and hatching phenology were non-additive. Species that hatched relatively early or late performed significantly better or worse, respectively, but only at higher temperatures and not at lower temperatures. As a consequence, climate-mediated shifts in hatching phenology or temperature resulted in stronger or weaker effects than expected when both factors acted in concert. Furthermore, consequences of phenological shifts were asymmetric; arriving relatively early had disproportional stronger (or weaker) effects than arriving relatively late, and this varied with species identity. However, consistent with recent theory, these seemingly idiosyncratic effects of phenological shifts could be explained by species-specific differences in growth rates across temperatures and concordant shifts in relative body size of interacting species. Our results emphasize the need to account for environmental conditions when predicting the effects of phenological shifts, and suggest that shifts in size-structured interactions can mediate the impact of climate change on natural communities. PMID- 23670601 TI - [Autopsy records in Vienna since Lorenz Biermayer--a complete documentation of 195 years]. AB - Vienna has a long tradition of clinical autopsies. In the period from 1817 to 2012 there are over 300,000 autopsies documented in the Vienna General Hospital. From five other community hospitals with departments for pathology and some closed hospitals, autopsy reports exist since 1865. Until the nineteenth century the reports are written in Kurrent, then Latin script and since the 1920s they are stored as machine written copies. This incredible high number of preserved reports was only possible because of the tradition started by Rokitansky and the possibility of storing this large amount of records in the Pathologic anatomical collection in the Narrenturm, the Vienna Municipal Archives and various hospitals. The aim of this study was to create a documentary of the repositories of the autopsy records, to make the records available and easier accessible for different kinds of research. The autopsy records should be easier to find and access, be it for the use in statistics or other scientific projects. PMID- 23670602 TI - A "call to action" for an expanded pharmacist role in influencing the quality of nutrition care. PMID- 23670603 TI - Collagen-cellulose composite thin films that mimic soft-tissue and allow stem cell orientation. AB - Mechanical properties of collagen films are less than ideal for biomaterial development towards musculoskeletal repair or cardiovascular applications. Herein, we present a collagen-cellulose composite film (CCCF) compared against swine small intestine submucosa in regards to mechanical properties, cell growth, and histological analysis. CCCF was additionally characterized by FE-SEM, NMR, mass spectrometry, and Raman Microscopy to elucidate its physical structure, collagen-cellulose composition, and structure activity relationships. Mechanical properties of the CCCF were tested in both wet and dry environments, with anisotropic stress-strain curves that mimicked soft-tissue. Mesenchymal stem cells, human umbilical vein endothelial cells, and human coronary artery smooth muscle cells were able to proliferate on the collagen films with specific cell orientation. Mesenchymal stem cells had a higher proliferation index and were able to infiltrate CCCF to a higher degree than small intestine submucosa. With the underlying biological properties, we present a collagen-cellulose composite film towards forthcoming biomaterial-related applications. PMID- 23670604 TI - Saliva improves Streptococcus mitis protective effect on human gingival fibroblasts in presence of 2-hydroxyethyl-methacrylate. AB - This study aimed to investigate the effect of saliva on Streptococcus mitis free cells and on S. mitis/human gingival fibroblasts (HGFs) co-culture model, in presence of 2-hydroxyethyl-methacrylate (HEMA). The bacterial aggregation both in the planktonic phase and on HGFs, as well as the apoptotic and necrotic eukaryotic cells amount were analyzed, in presence of saliva and/or HEMA. The aggregation test revealed a significant saliva aggregation effect on S. mitis strains compared to the untreated sample. No significant differences were recorded in the amount of culturable bacteria in all studied conditions; however, from microscopy images, the saliva/HEMA combining effect induced a significant bacterial aggregation and adhesion on HGFs. HEMA treatment decreased viable eukaryotic cell number with a parallel increment of necrotic cells, but when saliva was added to the co-culture, the viable cells percentage increased to a value comparable to the control sample. PMID- 23670605 TI - Survival of diced and block cartilage grafts in combination with injectable calcium hydroxylapatite. AB - OBJECTIVES/HYPOTHESIS: Dorsal nasal irregularities after trauma, and various procedures such as excessive nasal hump resection, are major problems for patients who have undergone rhinoplasty. Many grafts have been described for the correction of dorsal nasal irregularities. In this study, we used an injectable implant, in combination with diced or block cartilage grafts, to test the efficacy of injectable calcium hydroxylapatite on the survival of diced or block cartilage grafts. STUDY DESIGN: Prospective, controlled, parallel group animal study. METHODS: Fourteen New Zealand white rabbits were used. Block cartilage and diced cartilage grafts, alone and in combination with injectable calcium hydroxylapatite, were placed subcutaneously in the rabbits' dorsal thoracolumbar region. On the 90th day following surgery, the graft areas were extracted immediately after the rabbits were sacrificed. Pathological examination was conducted on all specimens. RESULTS: The pathologic and histochemical findings were compared between groups. There was chronic inflammation observed in all of the groups. However, none of the groups had metaplastic bone formation or calcification. The group that received diced cartilage in combination with the injectable implant received the highest scores for peripheral chondrocyte proliferation, matrix collagen, elastic fiber, and proteoglycan content (P < 0.05). A comparison of the block and diced cartilage grafts revealed that peripheral chondrocyte proliferation was more pronounced in the diced cartilage grafts (P < 0.05). CONCLUSION: The use of calcium hydroxylapatite in combination with diced cartilage grafts does not have any long-term negative effects on chondrocyte viability. PMID- 23670606 TI - Antibodies directed against integration host factor mediate biofilm clearance from Nasopore. AB - OBJECTIVES/HYPOTHESIS: Intranasal resorbable packing, such as Nasopore, is commonly used during sinus surgery despite a paucity of evidence that demonstrates clinical benefit. We theorized that Nasopore supports bacterial growth and biofilm formation. The DNABII family of bacterial nucleic acid binding proteins stabilizes the extracellular polymeric substance of the biofilm, thus protecting bacteria from host defenses and traditional antibiotics. We tested the hypothesis that use of anti-IHF antibodies in conjunction with antibiotics would enhance biofilm eradication from Nasopore. STUDY DESIGN: In vitro experiments. METHODS: Nontypeable Haemophilus influenzae (NTHI) biofilms were grown on Nasopore. Following 24-hour incubation, biofilms were incubated for an additional 16 hours with either medium alone, naive rabbit serum, rabbit anti-IHF serum, amoxicillin/clavulanate, or anti-IHF serum + amoxicillin/clavulanate. Computer statistics (COMSTAT) analysis was performed on images of biofilms obtained via confocal microscopy. RESULTS: NTHI readily formed a biofilm on Nasopore. Treatment with amoxicillin/clavulanate alone mediated an increase in biomass by 92% to 6.63 MU(2) /MU(3) compared to incubation in sterile medium alone (3.46 MU(2) /MU(3)). Treatment with anti-IHF alone reduced the biomass by 77% to 1.29 MU(2) /MU(3) compared to incubation with naive rabbit serum (5.53 MU(2) /MU(3)). Anti-IHF + amoxicillin/clavulanate reduced biomass by 88% to 0.66 MU(2) /MU(3) (P <0.02) compared to incubation with naive rabbit serum. CONCLUSION: Antibiotics alone were ineffective in eradicating NTHI biofilms that had formed on Nasopore in vitro. Anti-IHF antibodies plus amoxicillin/clavulanate therapy synergistically reduced biofilm biomass by 88%. These data support clinical studies for the use of anti-IHF combined with antibiotics to reduce biofilm formation on intranasal packing. PMID- 23670607 TI - An unusual superolateral origin of ophthalmic artery: an anatomic case report. AB - BACKGROUND AND IMPORTANCE: If ophthalmic artery's (OphA) origin anomalies are frequent, the superolateral origin of the OphA was rarely described. CLINICAL PRESENTATION: During an aneurysmal surgery, a superolateral origin of the left OphA was found. This variation was associated with a sylvian aneurysm. The anatomical, embryological features, the neurosurgical implications of this origin such as treatment of carotid-ophthalmic aneurysm or intra arterial retinoblastoma chemotherapy are discussed. CONCLUSION: To the best of our knowledge, this is a very rare operative case of both superolateral origin and initial course of OphA. PMID- 23670608 TI - Supernumerary kidneys--a rare anatomic variant. AB - Supernumerary kidneys are a rare congenital anomaly with fewer than 100 cases reported over the years. A fused supernumerary kidney is a still rarer entity. We present imaging findings in two cases of supernumerary kidneys--the first case is a spectacular image of four kidneys in one patient seen in an excretory phase of intravenous urogram with only four cases described in the literature. The second case is that of three kidneys (fused supernumerary) seen in another patient. PMID- 23670610 TI - Efficient hydrogenation over single-site bimetallic RuSn clusters. AB - Hydrogenation of ethene to ethane over single-site RuN and (RuSn)N clusters is investigated using Density Functional Theory calculations. The critical transition state barrier, namely the last hydrogenation step, correlates linearly for RuN with the adsorption energies of the reactants. Addition of Sn to the Ru clusters breaks this relation and allows for lower reaction barriers. In general, Sn is found to have pronounced effects on the geometrical and electronic properties of RuN clusters with N<= 12. RuN clusters preferably adopt cubic conformations with high spin states, whereas (RuSn)N have low spin states and form compact Ru cores capped with Sn atoms. PMID- 23670611 TI - Selective decoration of Au nanoparticles on monolayer MoS2 single crystals. AB - We report a controllable wet method for effective decoration of 2-dimensional (2D) molybdenum disulfide (MoS2) layers with Au nanoparticles (NPs). Au NPs can be selectively formed on the edge sites or defective sites of MoS2 layers. The Au MoS2 nano-composites are formed by non-covalent bond. The size distribution, morphology and density of the metal nanoparticles can be tuned by changing the defect density in MoS2 layers. Field effect transistors were directly fabricated by placing ion gel gate dielectrics on Au-decorated MoS2 layers without the need to transfer these MoS2 layers to SiO2/Si substrates for bottom gate devices. The ion gel method allows probing the intrinsic electrical properties of the as-grown and Au-decorated MoS2 layers. This study shows that Au NPs impose remarkable p doping effects to the MoS2 transistors without degrading their electrical characteristics. PMID- 23670612 TI - Therapeutic angiogenesis for critical limb ischaemia. AB - Peripheral arterial disease (PAD) is caused by occlusive atherosclerosis in a vascular bed other than the heart. The lower extremity is the most-common location for PAD. Critical limb ischaemia (CLI) is the most-severe clinical manifestation of PAD. Despite improvements in medical care and revascularization, patients with CLI continue to have a high risk of major amputation (below the knee or higher) and cardiovascular death. The primary goal of therapy in CLI is to achieve blood flow to the distal limb vessels with angioplasty or bypass surgery. However, many patients with CLI are unsuitable for revascularization, or the procedure is unsuccessful. Angiogenesis is the growth and proliferation of blood vessels from an existing vascular structure. In therapeutic angiogenesis, attempts are made to utilize blood vessel growth to augment perfusion. In this Review, data from phase II and III clinical trials of therapeutic angiogenesis in patients with PAD will be presented and discussed. Potential explanations for the limited success of therapeutic angiogenesis in humans will be viewed in the context of advances in our understanding of the complex mechanisms underlying angiogenesis and vascular remodelling. This Review will also cover how advances in systems biology, genetics, and gene therapy might still allow the development of new approaches to therapeutic angiogenesis and achieve the goal of restoring perfusion. PMID- 23670614 TI - Risk factors: intestinal microbiota: "a new direction in cardiovascular research". PMID- 23670615 TI - Coronary artery disease: individualize care for multivessel CAD. PMID- 23670613 TI - Surgical treatment of aortic valve disease. AB - The development of intraoperative transoesophageal echocardiography together with improved understanding of the functional anatomy of the aortic valve have allowed the design of several new conservative procedures, such as aortic valve-sparing operations, to treat patients with aortic root aneurysms or aortic insufficiency. The long-term results of these procedures have been excellent, and >90% of patients are free from reoperation on the aortic valve 10-15 years after surgery. Incompetent bicuspid aortic valves can also be repaired if the cusps are pliable and without calcification. Nevertheless, most patients with aortic valve disease, particularly those with aortic stenosis, need aortic valve replacement. Matching a patient to the type and size of prosthetic aortic valve is difficult, because of the limited durability of bioprosthetic valves and the need for lifelong anticoagulation with mechanical valves. Prosthesis-patient mismatch might not affect survival in most patients, but is a determinant of prognosis in patients with impaired ventricular function. Young adults with aortic stenosis, particularly women during childbearing years, can be treated with the Ross procedure. Finally, poor candidates for surgery who have aortic stenosis can now be treated with catheter-based aortic valve implantation but, in this article, the current status of aortic valve surgery is reviewed. PMID- 23670617 TI - [Julius Springer prize for surgery 2013]. PMID- 23670619 TI - Identification of biomarkers for endometriosis in eutopic endometrial cells from patients with endometriosis using a proteomics approach. AB - Endometriosis is a gynecological disease defined as the presence of endometrial tissue outside the uterine cavity, which is caused by various factors. Proteomic analysis of two sets of eutopic endometrial cells collected from the menstrual blood of females with (n=6; n=3) or without (n=6; n=3) endometriosis was performed to identify novel potential biomarkers for endometriosis. The data revealed that samples from endometriosis patients had stem cell characteristics, as they had higher mRNA expression levels of octamer-binding transcription factor 4 (Oct-4), C-X-C chemokine receptor type 4 (CXCR4), SRY-box containing gene 2 (SOX2) and mesenchymal-epithelial transition factor (MET) compared with that of the normal controls. Three proteins, collapsin response mediator protein 2 (CRMP2), ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCH-L1) and myosin regulatory light polypeptide 9 (MYL9), were simultaneously identified from the two sets of samples from females with or without endometriosis by two-dimensional electrophoresis (2-DE). A difference in CRMP2 expression was confirmed with western blotting. Taken together, the results suggest that CRMP2 plays a role in the pathogenesis of endometriosis. PMID- 23670620 TI - Three new xanthones from the resin of Garcinia hanburyi. AB - Three new xanthones, 22,23-dihydroxydihydrogambogenic acid (1), 12 hydroxygambogefic acid A (2), and hanburixanthone (3), along with thirteen known compounds were isolated from the resin of Garcinia hanburyi. The structures of the new compounds were determined by detailed analysis of 1D and 2D NMR spectra and by comparison with related model compounds. All compounds were tested for their cytotoxicities against A549, HCT116, and MDA-MB-231, and most of them showed significant effects on the cell lines. PMID- 23670621 TI - Steroidal glycosides from Reineckia carnea herba and their antitussive activity. AB - Two new steroidal glycosides, 1alpha,3alpha-dihydroxy-5beta-pregn-16-en-20-one 3 O-alpha-L-rhamnopyranoside (1) and 1beta,3beta,27-trihydroxycholest-16-en-22-one 1,3-di-O-alpha-L-rhamnoside (2), along with seven known steroidal glycosides (3 9), were isolated from Reineckia carnea herba. Their structures were determined by detailed analysis of their 1D- and 2D-NMR and MS spectra. Compound 9 was isolated for the first time from the Reineckia genus. Except for 8, compounds 2, 3, 4, 5, 6, 7, and 9 displayed clear in vitro antitussive activity. PMID- 23670622 TI - Antibacterial sesquiterpenoid derivatives from Ferula ferulaeoides. AB - Three new sesquiterpenoid derivatives 1, 2, and 3 were isolated from Ferula ferulaeoides. To confirm the structure, compound 2 was also synthesized via a condensation reaction between compound 1 and 2,2-dimethoxypropane. The structures of these three compounds were elucidated by means of spectroscopic and chemical methods. Their antibacterial activity against drug-resistant Staphylococcus aureus strains were evaluated with MIC values in the range of 0.5-128 ug/mL. Compounds 1 and 3 were capable of inhibiting efflux of ethidium bromide using an in vitro assay. The cytotoxicity of the compounds was evaluated on cultured HEK293 cells, and none of them showed toxicity to HEK293 cells at a concentration of 125 ug/mL. PMID- 23670623 TI - New antibacterial germacrene from Verbesina negrensis. AB - Several health benefits have been attributed to members of the Verbesina genus, including promotion of urinary and gastrointestinal health. Verbesina species are also reported to exhibit antibacterial, antiparasitic, and antioxidant activities. Although members of the Verbesina genus produce various pharmacologically relevant chemicals as secondary metabolites, including eudesmanes, flavonoids, guanidine alkaloids, acetylenic compounds, and germacrenes, the active compounds required for these benefits remain unknown. To investigate potential antimicrobial activities of Verbesina negrensis, crude extracts from plant aerial structures were evaluated. Following chemical fractionation, the chloroformic extract from Verbesina negrensis was subjected to bioassay-guided isolation using disk diffusion assays to determine antimicrobial activity. The active compound was characterized as 6beta-cinnamoyloxy-1beta hydroxy-10alpha-metoxy-3-oxo-germacra-4,5Z-ene (1). Fractions containing 1 inhibited both Enterococcus faecalis (ATCC 29 212) and Staphylococcus aureus (ATCC 29213). The MIC for 1 was determined by microbroth dilution assay to be 64 ug/mL for both E. faecalis and S. aureus. PMID- 23670624 TI - The pharmacokinetics of chelerythrine solution and chelerythrine liposomes after oral administration to rats. AB - Chelerythrine is a quaternary benzo[c]phenanthridine alkaloid which has many potent pharmacological effects and can dissolve well in water; dihydrochelerythrine has recently been identified as a chelerythrine metabolite in rat. Most methods of preparation of liposomes suffer from the drawback of poor incorporation of water-soluble drugs. The emulsion/solvent evaporation method is a relatively simple and efficient way to prepare liposomes loaded with hydrophilic drugs. The aim of this study was therefore to find a suitable formulation to enhance the incorporation of chelerythrine into liposomes by the emulsion/solvent evaporation method and so improve the therapeutic efficacy of chelerythrine. Results showed that the chelerythrine-liposome has been successfully prepared by the emulsion/solvent evaporation method: the entrapment efficiency of chelerythrine was higher at 78.6 %, and the drug loadings reached 7.8 %. The relative bioavailability of chelerythrine and its dihydro derivative in liposomes was significantly increased compared with that of the chelerythrine solution. The area under the plasma concentration-time curve values of chelerythrine and dihydrochelerythrine after oral administration of chelerythrine liposomes were 4.83-fold and 2.02 higher than those obtained with the chelerythrine solution. The half time and peak concentrations of chelerythrine and dihydrochelerythrine were also higher for chelerythrine-liposomes than that for chelerythrine. In contrast, the total body clearance and apparent volume of distribution were lower for chelerythrine-liposomes in comparison to the respective parameters for the chelerythrine solution. It can thus be concluded that incorporation into liposomes prolonged chelerythrine retention within the systemic circulation. PMID- 23670625 TI - Protective effects of alpha-tocopherol and ascorbic acid against cardol-induced cell death and reactive oxygen species generation in Staphylococcus aureus. AB - Cardol (C15:3), isolated from cashew (Anacardium occidentale L.) nut shell liquid, has been shown to exhibit bactericidal activity against various strains of Staphylococcus aureus, including methicillin-resistant strains. The maximum level of reactive oxygen species generation was detected at around the minimum bactericidal concentration of cardol, while reactive oxygen species production drastically decreased at doses above the minimum bactericidal concentration. The primary response for bactericidal activity around the bactericidal concentration was noted to primarily originate from oxidative stress such as intracellular reactive oxygen species generation. High doses of cardol (C15:3) were shown to induce leakage of K+ from S. aureus cells, which may be related to the decrease in reactive oxygen species. Antioxidants such as alpha-tocopherol and ascorbic acid restricted reactive oxygen species generation and restored cellular damage induced by the lipid. Cardol (C15:3) overdose probably disrupts the native membrane-associated function as it acts as a surfactant. The maximum antibacterial activity of cardols against S. aureus depends on their log P values (partition coefficient in octanol/water) and is related to their similarity to those of anacardic acids isolated from the same source. PMID- 23670626 TI - Salvia officinalis for hot flushes: towards determination of mechanism of activity and active principles. AB - Herbal medicinal products are commonly used in alternative treatment of menopausal hot flushes. In a recent clinical study, Salvia officinalis tincture was found to reduce hot flush frequency and intensity. The aim of the current study was the investigation of the mechanism(s) responsible for the anti-hot flush activity of S. officinalis and determination of its active principle(s). The 66% ethanolic tincture, as well as the n-hexane, CHCl3, and aqueous ethanolic subextracts obtained from the tincture were studied in vitro for two of the most relevant activities, estrogenicity and selective serotonin reuptake inhibition. Because of an increased risk of menopausal women to suffer from Alzheimer's disease, an in vitro acetylcholinesterase inhibition assay was also employed. No activity was observed in the selective serotonin reuptake inhibition or the acetylcholinesterase inhibition assays at the highest test concentrations. The tincture showed no estrogenic effects whereas the aqueous ethanolic subextract exhibited estrogenicity in the ERLUX assay with an EC50 value of 64 ug/mL. Estrogenic activity-guided fractionation of the aqueous ethanolic subextract by a combination of reverse-phase vacuum liquid chromatography and gel chromatography identified luteolin-7-O-glucuronide (EC50 129 ug/mL) as the active component of the vacuum liquid chromatography fraction 4 (EC50 69 ug/mL). Luteolin-7-O glucoside was identified as the putative estrogenic principle of the most potent minor fraction (7.6.7.6, EC50 0.7 ug/mL) obtained from the initial vacuum liquid chromatography fraction 7 (EC50 3 ug/mL). This study suggests the involvement of common and ubiquitous estrogenic flavonoids in the anti-hot flush effect of Salvia officinalis, a safe and commonly used herbal medicinal product during the menopause. PMID- 23670627 TI - Evaluation and theoretical study on the anti-inflammatory mechanism of 1-nitro-2 phenylethane. AB - In this study, 1-nitro-2-phenylethane was evaluated with respect to its effects in edema models of acute inflammation induced with carrageenan, dextran, and croton oil. 1-Nitro-2-phenylethane produced inhibition of rat paw edema induced by carrageenan and dextran at the doses of 25 and 50 mg/kg. The same doses caused an inhibition of croton oil-induced ear edema in mice. Our results suggest that 1 nitro-2-phenylethane has anti-inflammatory activity, probably of peripheral origin, acting in the synthesis and/or release of inflammatory mediators. A conformational study of 1-nitro-2-phenylethane was carried out using density functional theory calculations, showing three different groups of conformers corresponding to energy minimum geometries. The stereoelectronic repulsions are responsible for conformational preferences and the one most stable conformer. The prostaglandin endoperoxide synthase mechanism is related more to electrophilic than nucleophilic properties. PMID- 23670628 TI - Triterpenoid saponins with anti-myocardial ischemia activity from the whole plants of Clematis tangutica. AB - Four new triterpenoid saponins named clematangosides A-D (1-4) along with six known saponins (5-10) were isolated from the whole plants of Clematis tangutica. Their structures were determined by extensive spectral analysis and chemical evidences. All saponins were evaluated for their protective effects in hypoxia induced myocardial injury model. Compounds 2-4, 6, and 10 exhibited anti myocardial ischemia activities with ED50 values in the range of 75.77-127.22 uM. PMID- 23670629 TI - Inhibition of lipopolysaccharide-induced iNOS and COX-2 expression by indole alkaloid, 3-(hydroxymethyl)-6,7-dihydroindolo[2,3-a]quinolizin-(12H)-one, via NF kappaB inactivation in RAW 264.7 macrophages. AB - 3-(Hydroxymethyl)-6,7-dihydroindolo[2,3-a]quinolizin-(12H)-one is a bioactive indole alkaloid isolated from Nauclea officinalis, a plant species which is used as a traditional Chinese medicine. We investigated the anti-inflammatory properties of 3-(hydroxymethyl)-6,7-dihydroindolo[2,3-a]quinolizin-(12H)-one in RAW 264.7 murine macrophages. The results indicated that it inhibited the overproduction of NO and the release of TNF-alpha. Furthermore, this compound inhibited the expression of iNOS and COX-2 proteins, the enzymatic activity of iNOS, and the translocation of NF-kappaB to the nucleus induced by LPS. Therefore, we suggested that the effect of 3-(hydroxymethyl)-6,7 dihydroindolo[2,3-a]quinolizin-(12H)-one-mediated inhibition of the expression of LPS-induced iNOS and COX-2 genes is due to the suppression of NF-kappaB activation in the transcriptional level. PMID- 23670630 TI - Inhibitory activity of chemical constituents from Arenaria serpyllifolia on nitric oxide production. AB - Five new compounds, including one new xanthone, 1-hydroxy-5-methoxyxanthone 6-O beta-D-glucopyranoside (1), one new lignan, 3-(beta-D-glucopyranosyloxymethyl)-2 (4-hydroxy-3-methoxyphenyl)-5-(3-acetoxypropyl)-7-methoxy-(2R,3S) dihydrobenzofuran (2), and three new gamma-pyrones, japonicumone A 4'-O-beta-D glucopyranoside (3), japonicumone B 3'-O-beta-D-glucopyranoside (4), and japonicumone B 4'-O-beta-D-glucopyranoside (5), together with eight known compounds (6-13) were isolated from the whole plants of Arenaria serpyllifolia. Their structures were elucidated on the basis of extensive spectroscopic analysis (UV, IR, HRESIMS, 1D- and 2D-NMR, and CD) as well as chemical methods. The isolated compounds were evaluated for their inhibitory effects on nitric oxide production in lipopolysaccharide-activated RAW 264.7 macrophages. Compounds 1-5, sacranoside A (9), and pedunculoside (13) showed potential nitric oxide inhibitory activities with IC50 values ranging from 14.92 uM to 52.23 uM. PMID- 23670631 TI - Coping with uncertainty: nutrient deficiencies motivate insect migration at a cost to immunity. AB - Migration often is associated with movement away from areas with depleted nutrients or other resources, and yet migration itself is energetically demanding. Migrating Mormon crickets Anabrus simplex (Orthoptera: Tettigoniidae) lack nutrients, and supplementation of deficient nutrients slows migratory movements and enhances specific aspects of their immune systems. Migrants deficient in proteins have less spontaneous phenoloxidase (PO) activity, whereas those deficient in carbohydrates have lower lysozyme-like anti-bacterial titers with a proposed compromise between migratory and anti-bacterial activities. To investigate the relationship between diet, movement, and immunity further, we removed Mormon crickets from a migratory band and offered each cricket one of five diets: high protein, high carbohydrate, equal weight of proteins and carbohydrates (P + C), vitamins only, or water only for 1 h. We then attached a radio, returned each to the migratory band, and recaptured them 18-24 h later. Mormon crickets fed protein moved the furthest, those with only water or only vitamins moved less, and those fed carbohydrates or P + C moved the least. Standard intake trials also indicated that the Mormon crickets were deficient in carbohydrates. Consistent with a previous study, lysozyme-like anti-bacterial activity was greatest in those fed carbohydrates, and there was no difference between those fed water, protein, or P + C. Crickets were removed from the same migratory band and fed one of four diets: high P, high C, P + C, or vitamins only, for 1 h. Then the crickets were held in captivity with water only for 4 or 24 h before blood was drawn. Immunity measures did not differ between times of draw. Diet treatments had no effect on anti-bacterial activity of captive Mormon crickets, whereas total PO was greater in those fed protein. These results support the hypothesis of a direct compromise between migratory and anti bacterial activities, whereas PO is compromised by low protein independent of migratory activities. We discuss the potential effects of climate on nutritional deficits and susceptibility to different pathogens. PMID- 23670632 TI - The integrative taxonomic approach applied to porifera: a case study of the homoscleromorpha. AB - The two main scientific tasks of taxonomy are species' delineation and classification. These two tasks are often treated differently, with classification accomplished by newly-developed phylogenetic methods, often based on molecular sequences, while delimitation of species is conducted by what is often considered to be an "old-fashioned" typological approach based on morphological description. A new "integrative taxonomy" has been proposed which maintains that species delimitation should be a multidisciplinary undertaking combining several independent datasets. Here we argue that the same principle is relevant to the classification of species. In the past 20 years, we assembled various datasets based on the external morphology, anatomy, cytology, spicule shapes, geography, reproduction, genetic sequences, and metabolomics of homoscleromorph sponges. We show how we used these datasets to describe new species of homoscleromorph sponges and to elucidate their phylogenetic relationships and their phylogenetic position within the phylum Porifera. PMID- 23670633 TI - Process optimization and production of polyhydroxybutyrate using palm jaggery as economical carbon source by marine sponge-associated Bacillus licheniformis MSBN12. AB - The Polyhydroxybutyrate (PHB) producer, Bacillus licheniformis MSBN12 was isolated from the marine sponge Callyspongia diffusa. The PHB production of B. licheniformis MSBN12 was optimized using a four-factor Box-Behnken design to find the interactive effects of variables such as palm jaggery, wheat bran, seawater, and incubation temperature. The maximum yield of PHB (6.38 g/L) was achieved through response surface methodology-based optimization and the optimized conditions were further used for the batch and fed-batch fermentation. Maximum biomass was reached at 48 and 36 h of incubation with PHB accumulation of 62.91 and 67.16 % (w/w of dry cells) for batch and fed-batch process. The production of PHB under fed-batch process with B. licheniformis MSBN12 was increased threefold over shake flask culture when palm jaggery as sole carbon source. The 1H NMR data was extrapolated with peaks of the PHB reference standard and confirmed as PHB analog. PMID- 23670634 TI - Fabrication of a circular PDMS microchannel for constructing a three-dimensional endothelial cell layer. AB - We describe a simple and efficient fabrication method for generating microfluidic channels with a circular cross-sectional geometry by exploiting the reflow phenomenon of a thick positive photoresist. Initial rectangular shaped positive photoresist micropatterns on a silicon wafer, which were fabricated by a conventional photolithography process, were converted into a half-circular shape by tuning the temperature to around 105 degrees C. Through optimization of the reflow conditions, we could obtain a perfect circular micropattern of the positive photoresist, and control the diameter in a range from 100 to 400 MUm. The resultant convex half-circular photoresist was used as a template for fabricating a concave polydimethylsiloxane (PDMS) through a replica molding process, and a circular PDMS microchannel was produced by bonding two half circular PDMS layers. A variety of channel dimensions and patterns can be easily prepared, including straight, S-curve, X-, Y-, and T-shapes to mimic an in vivo vascular network. To form an endothelial cell layer, we cultured primary human umbilical vein endothelial cells inside circular PDMS microchannels, and demonstrated successful cell adhesion, proliferation, and alignment along the channel. PMID- 23670635 TI - Electrochemical surface modification of carbon mesh anode to improve the performance of air-cathode microbial fuel cells. AB - A convenient and promising alternative to surface modification of carbon mesh anode was fulfilled by electrochemical oxidation in the electrolyte of nitric acid or ammonium nitrate at ambient temperature. It was confirmed that such an anode modification method was low cost and effective not only in improving the efficiency of power generation in microbial fuel cells (MFCs) for synthetic wastewater treatment, but also helping to reduce the period for MFCs start-up. The MFCs with anode modification in electrolyte of nitric acid performed the best, achieving a Coulombic efficiency enhancement of 71 %. As characterized, the electrochemical modification resulted in the decrease of the anode potential and internal resistance but the increase of current response and nitrogen-containing and oxygen-containing functional groups on the carbon surface, which might contribute to the enhancement on the performances of MFCs. PMID- 23670636 TI - D-Lactic acid biosynthesis from biomass-derived sugars via Lactobacillus delbrueckii fermentation. AB - Poly-lactic acid (PLA) derived from renewable resources is considered to be a good substitute for petroleum-based plastics. The number of poly L-lactic acid applications is increased by the introduction of a stereocomplex PLA, which consists of both poly-L and D-lactic acid and has a higher melting temperature. To date, several studies have explored the production of L-lactic acid, but information on biosynthesis of D-lactic acid is limited. Pulp and corn stover are abundant, renewable lignocellulosic materials that can be hydrolyzed to sugars and used in biosynthesis of D-lactic acid. In our study, saccharification of pulp and corn stover was done by cellulase CTec2 and sugars generated from hydrolysis were converted to D-lactic acid by a homofermentative strain, L. delbrueckii, through a sequential hydrolysis and fermentation process (SHF) and a simultaneous saccharification and fermentation process (SSF). 36.3 g L(-1) of D-lactic acid with 99.8 % optical purity was obtained in the batch fermentation of pulp and attained highest yield and productivity of 0.83 g g(-1) and 1.01 g L(-1) h(-1), respectively. Luedeking-Piret model described the mixed growth-associated production of D-lactic acid with a maximum specific growth rate 0.2 h(-1) and product formation rate 0.026 h(-1), obtained for this strain. The efficient synthesis of D-lactic acid having high optical purity and melting point will lead to unique stereocomplex PLA with innovative applications in polymer industry. PMID- 23670637 TI - Pressurized CEC with amperometric detection using mixed-mode monolithic column for rapid analysis of chlorophenols and phenol. AB - A simple analysis of chlorophenols (2-chlorophenol, 2,4-dichlorophenol, 2,4,6 trichlorophenol, and pentachlorophenol) and phenol was accomplished by coupling a pressurized CEC with amperometric detection (AD). Efficient and reproducible separation of these compounds was achieved within 9 min on a capillary monolithic stationary phase bonded with octadecyl ligands and sulfonate groups, where the selectivity and the retention of analytes can be functionally controlled by optimizing experimental variables, including organic modifier content, mobile phase pH, ionic strength, working electrode potential, separation voltage, and supplementary pressure. A mixed-mode retention mechanism consisting of reverse phase chromatographic partition, electrostatic repulsion, and electrophoresis is considered to play roles in the separation. The use of ACN-based media seems effectual in preventing the unfavorable irreversible adsorption on both wall and electrode, and offer higher sensitivity and less electrode fouling in AD of phenols. The LODs were in the range from 0.02 to 0.2 MUg/mL with a wide linear dynamic range of 5000-fold, while the peak area precision ranged from 3.2 to 7.5%. The feasibility of using this method in real analysis was evaluated by recovery estimates and comparative experiment on spiked tap water samples. Good recoveries of 80-110% were achieved. Additionally, a paired t-test was used to correlate the two methods. PMID- 23670638 TI - Carbon and graphene double protection strategy to improve the SnO(x) electrode performance anodes for lithium-ion batteries. AB - SnOx is a promising high-capacity anode material for lithium-ion batteries (LIBs), but it usually exhibits poor cycling stability because of its huge volume variation during the lithium uptake and release process. In this paper, SnOx carbon nanofibers (SnOx@CNFs) are firstly obtained in the form of a nonwoven mat by electrospinning followed by calcination in a 0.02 Mpa environment at 500 degrees C. Then we use a simple mixing method for the synthesis of SnOx@CNF@graphene (SnOx@C@G) nanocomposite. By this technique, the SnOx@CNFs can be homogeneously deposited in graphene nanosheets (GNSs). The highly scattered SnOx@C@G composite exhibits enhanced electrochemical performance as anode material for LIBs. The double protection strategy to improve the electrode performance through producing SnOx@C@G composites is versatile. In addition, the double protection strategy can be extended to the fabrication of various types of composites between metal oxides and graphene nanomaterials, possessing promising applications in catalysis, sensing, supercapacitors and fuel cells. PMID- 23670639 TI - A novel tool in laryngeal surgery: preliminary results of the picosecond infrared laser. AB - OBJECTIVES/HYPOTHESIS: Conventional lasers ablate tissue through photothermal, photomechanical, and/or photoionizing effects, which may result in collateral tissue damage. The novel nonionizing picosecond infrared laser (PIRL) selectively energizes tissue water molecules using ultrafast pulses to drive ablation on timescales faster than energy transport to minimize collateral damage to adjacent cells. STUDY DESIGN: Animal cadaver study. METHODS: Cuts in porcine laryngeal epithelium, lamina propria, and cartilage were made using PIRL and carbon dioxide (CO2) laser. Lateral damage zones and cutting gaps were histologically compared. RESULTS: The mean widths of epithelial (8.5 MUm), subepithelial (10.9 MUm), and cartilage damage zones (8.1 MUm) were significantly lower for cuts made by PIRL compared with CO2 laser (p < 0.001). Mean cutting gaps in vocal fold (174.7 MUm) and epiglottic cartilage (56.3 MUm) were significantly narrower for cuts made by PIRL compared with CO2 laser (P < 0.01, P < 0.05). CONCLUSION: PIRL ablation demonstrates superiority over CO2 laser in cutting precision with less collateral tissue damage. PMID- 23670640 TI - Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. AB - PURPOSE: This phase I clinical trial evaluated the safety, tolerability, and pharmacokinetics of high-dose intravenous (i.v.) ascorbic acid as a monotherapy in patients with advanced solid tumors refractory to standard therapy. METHODS: Five cohorts of three patients received i.v. ascorbic acid administered at 1 g/min for 4 consecutive days/week for 4 weeks, starting at 30 g/m2 in the first cohort. For subsequent cohorts, dose was increased by 20 g/m2 until a maximum tolerated dose was found. RESULTS: Ascorbic acid was eliminated by simple first order kinetics. Half-life and clearance values were similar for all patients of all cohorts (2.0 +/- 0.6 h, 21 +/- 5 dL/h m2, respectively). C(max) and AUC values increased proportionately with dose between 0 and 70 g/m2, but appeared to reach maximal values at 70 g/m2 (49 mM and 220 h mM, respectively). Doses of 70, 90, and 110 g/m2 maintained levels at or above 10-20 mM for 5-6 h. All doses were well tolerated. No patient demonstrated an objective antitumor response. CONCLUSIONS: Ascorbic acid administered i.v. at 1 g/min for 4 consecutive days/week for 4 weeks produced up to 49 mM ascorbic acid in patient's blood and was well tolerated. The recommended dose for future studies is 70-80 g/m2. PMID- 23670641 TI - Clinical features and outcome of leptomeningeal metastasis in patients with breast cancer: a single center experience. AB - BACKGROUND: Leptomeningeal metastasis (LM) is one of the major problems in the management of metastatic breast cancer; typically, LM has a devastating prognosis and often represents a terminal event. The present study analyzed the clinical features and outcome of LM in patients with breast cancer. METHODS: The medical records of patients diagnosed with LM from breast cancer at Asan Medical Center, between 2002 and 2012, were reviewed retrospectively. RESULTS: Of 95 LM patients, 38 (40 %) had an ECOG performance status (PS) <= 2, and the median age was 47 years (range 26-72 years). At the time of LM diagnosis, 46 patients (48.4 %) presented with coincidental failure of systemic disease control. Seventy-eight patients (82.1 %) underwent intrathecal (IT) chemotherapy, resulting in cytologic negative conversion in 26 patients, and 46 patients (48.4 %) received systemic chemotherapy. The median overall survival (OS) time was 3.3 months, and 7.8 % of the patients survived for more than 1 year. OS tended to be higher in patients who achieved cytologic negative conversion from IT chemotherapy than in those who did not (4.5 vs. 2.4 months, P = 0.088). Multivariate analysis demonstrated that ECOG PS <= 2, controlled extracranial disease at the time of LM diagnosis, and systemic chemotherapy after LM diagnosis were independent factors associated with survival. CONCLUSIONS: The prognosis of patients with LM from breast cancer is poor. Systemic chemotherapy, in addition to intrathecal chemotherapy, might confer a survival benefit, even after the detection of LM. PMID- 23670642 TI - Correlation between response to chemotherapy with concomitant bevacizumab for hepatic metastasis of colorectal cancer and degree of enhancement using contrast enhanced computed tomography. AB - PURPOSE: The imaging factor predicting the response to bevacizumab (BV) as concomitant chemotherapy has yet to be determined. This study examined correlation between response to chemotherapy with concomitant BV for hepatic metastasis of colorectal cancer and degree of contrast enhancement (CE) using contrast-enhanced computed tomography (CT). METHODS: Data were analyzed retrospectively for 35 patients treated with oxaliplatin-based chemotherapy as the first-line chemotherapy. Patient data were divided according to treatment with concomitant BV (BV group: n = 20, non-BV group: n = 15). Using an image control system, the degree of CE was evaluated by the ratio of the contrast enhanced CT value of hepatic metastatic lesions to plain CT value, whereby patients were classified into the high-CE and low-CE group. RESULTS: After completion of chemotherapy treatment, the degree of enhancement of hepatic metastasis in the BV group was significantly lower than that in the non-BV group (p = 0.03). In the BV group, a significant correlation between higher contrast enhancement and higher tumor shrinkage rate was observed (R2 = 0.25, p = 0.03), whereas no such correlation was noted in the non-BV group. In the high-CE group (n = 18), the tumor shrinkage rate increased to 29.6 % in the BV group compared with -1.46 % in the non-BV group (p = 0.03), whereas in the low-CE group, no significant difference was noted between patients in the two groups. CONCLUSION: Pretreatment evaluation of the degree of CE correlated with the response to concomitant chemotherapy with BV. PMID- 23670643 TI - Theory-based predictors of multiple clinician behaviors in the management of diabetes. AB - Behavioral theory is often tested on one behavior in isolation from other behaviors and theories. We aimed to test the predictive validity of constructs from motivation and action theories of behavior across six diabetes-related clinician behaviors, within the same sample of primary care clinicians. Physicians and nurses (n = 427 from 99 practices in the United Kingdom) completed questionnaires at baseline and 12 months. PRIMARY OUTCOMES: six self-reported clinician behaviors related to advising, prescribing and examining measured at 12 months; secondary outcomes: baseline intention and patient-scenario-based simulated behavior. Across six behaviors, each theory accounted for a medium amount of variance for 12-month behavior (median R adj (2) = 0.15), large and medium amount of variance for two intention measures (median R adj (2) = 0.66; 0.34), and small amount of variance for simulated behavior (median R adj (2) = 0.05). Intention/proximal goals, self-efficacy, and habit predicted all behaviors. Constructs from social cognitive theory (self-efficacy), learning theory (habit) and action and coping planning consistently predicted multiple clinician behaviors and should be targeted by quality improvement interventions. PMID- 23670644 TI - Adolescent self-control predicts joint trajectories of marijuana use and depressive mood into young adulthood among urban African Americans and Puerto Ricans. AB - Previous studies have identified an association between depressive mood and marijuana use. We examined adolescent self-control as a predictor of membership in joint developmental trajectories of depressive mood and marijuana use from adolescence to young adulthood. Urban African Americans and Puerto Ricans (N = 838) were sampled when participants were on average 14, 19, 24, and 29 years old. Using growth mixture modeling, four joint trajectory groups of depressive mood and marijuana use were established: low marijuana use/low depressive mood, low marijuana use/intermediate depressive mood, high marijuana use/low depressive mood, and high marijuana use/high depressive mood. Weighted logistic regression analysis showed that self-control at age 14 distinguished the high marijuana use/high depressive mood group and the low marijuana use/low depressive mood group from each of the other groups. Findings show that the co-occurrence of high levels of marijuana use and depressive mood from adolescence into young adulthood is predicted by low levels of self-control in adolescence. On the other hand, high selfcontrol is associated with low marijuana use and low levels of depression over time. Thus, while deficits in self-control in adolescence constitute a significant risk for maladjustment over time, high self-control exerts a protective factor with regard to marijuana use and depressive mood into young adulthood. PMID- 23670646 TI - An autofocus method using quasi-Gaussian fitting of image sharpness in ultra-high voltage electron microscopy. AB - An accurate method using image sharpness to determine the best focusing is proposed for ultra-high-voltage electron microscopy. This method maximizes image sharpness for adjusting the focus. Five images with different defocus values are used to calculate the image sharpness. To obtain the best focus value that produces greatest image sharpness, fitting the quasi-Gaussian function to five image sharpness is a suitable alternative. This method, which maximizes image sharpness, gives better accuracy than the wobbler method for the ultra-high voltage electron microscope. The focusing area can be selected without moving the field of view, because the focusing area can be selected at almost any area in the image. PMID- 23670645 TI - Highly-efficient charge separation and polaron delocalization in polymer fullerene bulk-heterojunctions: a comparative multi-frequency EPR and DFT study. AB - The ongoing depletion of fossil fuels has led to an intensive search for additional renewable energy sources. Solar-based technologies could provide sufficient energy to satisfy the global economic demands in the near future. Photovoltaic (PV) cells are the most promising man-made devices for direct solar energy utilization. Understanding the charge separation and charge transport in PV materials at a molecular level is crucial for improving the efficiency of the solar cells. Here, we use light-induced EPR spectroscopy combined with DFT calculations to study the electronic structure of charge separated states in blends of polymers (P3HT, PCDTBT, and PTB7) and fullerene derivatives (C60-PCBM and C70-PCBM). Solar cells made with the same composites as active layers show power conversion efficiencies of 3.3% (P3HT), 6.1% (PCDTBT), and 7.3% (PTB7), respectively. Upon illumination of these composites, two paramagnetic species are formed due to photo-induced electron transfer between the conjugated polymer and the fullerene. They are the positive, P(+), and negative, P(-), polarons on the polymer backbone and fullerene cage, respectively, and correspond to radical cations and radical anions. Using the high spectral resolution of high-frequency EPR (130 GHz), the EPR spectra of these species were resolved and principal components of the g-tensors were assigned. Light-induced pulsed ENDOR spectroscopy allowed the determination of (1)H hyperfine coupling constants of photogenerated positive and negative polarons. The experimental results obtained for the different polymer-fullerene composites have been compared with DFT calculations, revealing that in all three systems the positive polaron is distributed over distances of 40-60 A on the polymer chain. This corresponds to about 15 thiophene units for P3HT, approximately three units for PCDTBT, and about three to four units for PTB7. No spin density delocalization between neighboring fullerene molecules was detected by EPR. Strong delocalization of the positive polaron on the polymer donor is an important reason for the efficient charge separation in bulk heterojunction systems as it minimizes the wasteful process of charge recombination. The combination of advanced EPR spectroscopy and DFT is a powerful approach for investigation of light-induced charge dynamics in organic photovoltaic materials. PMID- 23670647 TI - Structural modifications of dentinal microcracks with human aging. AB - Several studies have reported the mechanism of crack propagation with aging. Although structural modifications of dentinal microcracks with aging have been evaluated by observing the cracked surface using scanning electron microscope (SEM), very few attempts have been made at sectional observation of the microcracks inside dentine using transmission electron microscopy (TEM). The objectives of this study were to: (1) examine the process of dentinal microcrack formation using TEM and (2) to morphologically evaluate the relation between dentinal microcrack propagation and human aging. Molars from 'young' (16-28 years) and 'aged' (62-76 years) subjects were evaluated. Dentine blocks were cracked with an indenter and sectioned using a diamond knife and ultramicrotome after embedding in epoxy resin. Microcracks were observed by TEM and ultra-high voltage electron microscope tomography to determine the characteristics of crack propagation in the young and aged teeth. The results show that, in young teeth, crack propagation tended to pass through the dentinal tubules, while in aged teeth, it tended to deflect to the outer side of peritubular dentine (PTD), especially in coronal dentine. The advantage of this method is that it allows visualization and evaluation of the ultrastructural propagation of microcracks in dentine. The differences in crack propagation between young and aged dentine could be explained by differences in PTD thickness. PMID- 23670648 TI - The predictive value of the in vitro platelet toxicity assay (iPTA) for the diagnosis of hypersensitivity reactions to sulfonamides. AB - Drug hypersensitivity reactions (DHRs) are rare but potentially fatal adverse drug reactions (ADRs). A reliable test to diagnose DHRs would be a major advance in the clinical care for patients and in the evaluation of ADRs during drug development as well as for mechanistic studies of drug hypersensitivity. Available in vitro tests including the lymphocyte toxicity assay (LTA) have been used but are time-consuming, cumbersome, and expensive. We have developed a novel diagnostic test for DHRs, the in vitro platelet toxicity assay (iPTA). The aim of this study was to evaluate the predictive value of the iPTA in diagnosis of DHRs to sulfonamides. We recruited 66 individuals (36 DHS-sulfa patients and 30 healthy controls) to participate in the study. Blood samples were obtained and LTA and iPTA were performed in parallel. There was concentration-dependent toxicity in the cells of patients when incubated with the reactive hydroxylamine metabolite of sulfamethoxazole for both the LTA and iPTA (P < .05). The iPTA was more sensitive than conventional LTA test in detecting susceptibility of patient cells to in vitro toxicity (P < .05). The novel iPTA has considerable potential as an investigative tool for DHS as it is more sensitive and cheaper, requiring no special reagents. PMID- 23670649 TI - Microscopic insight into the bilateral formation of carbon spirals from a symmetric iron core. AB - Mirrored carbon-spirals have been produced from pressured ferrocene via the bilateral extrusion of the spiral pairs from an iron core. A parametric plot of the surface geometry displays the fractal growth of the conical helix made with the logarithmic spiral. Electron microscopy studies show the core is a crystalline cementite which grows and transforms its shape from spherical to biconical as it extrudes two spiralling carbon arms. In a cross section along the arms we observe graphitic flakes arranged in a herringbone structure, normal to which defects propagate. Local-wave-pattern analysis reveals nanoscale defect patterns of two-fold symmetry around the core. The data suggest that the bilateral growth originates from a globular cementite crystal with molten surfaces and the nano-defects shape emerging hexagonal carbon into a fractal structure. Understanding and knowledge obtained provide a basis for the controlled production of advanced carbon materials with designed geometries. PMID- 23670650 TI - Medical education: future-proof? PMID- 23670651 TI - Barriers to the use of evidence-based medicine: knowledge and skills, attitude, and external factors. AB - Although efforts are made to integrate evidence-based medicine (EBM) into clinical practice, physicians experience significant barriers to its implementation. The aim of this study is to quantify the barriers that general practice (GP) trainees experience when using EBM in practice. In September 2008, a questionnaire was administered to 140 GP trainees from three Dutch GP Speciality Training Institutes. The questionnaire focused on barriers that GP trainees meet when using EBM in practice. Factor analysis identified components in which barriers exist, and the validity and reliability of the questionnaire were established. After removing four items that did not fit the questionnaire structure, factor analysis identified three relevant components. All three components had similar mean scores, indicating a similar negative influence of these components on the practice of EBM: knowledge/skills (alpha = 0.72, mean score 2.9 +/- 0.8), attitude (alpha = 0.70, mean score 2.9 +/- 0.6), and external factors (alpha = 0.66, mean score 3.0 +/- 0.5). The barrier that trainees experienced most was lack of time to practise EBM. Barriers to the use of EBM were present in three components: knowledge/skills, attitude, and external factors. PMID- 23670652 TI - Speciality interests and career calling to medicine among first-year medical students. AB - The construct of calling has recently been applied to the vocation of medicine. We explored whether medical students endorse the presence of a calling or a search for a calling and how calling related to initial speciality interest. 574 first-year medical students (84 % response rate) were administered the Brief Calling Survey and indicated their speciality interest. For presence of a calling, the median response was mostly true for: 'I have a calling to a particular kind of work' and moderately true for: 'I have a good understanding of my calling as it applies to my career'. For search for a calling, median response was mildly true: 'I am trying to figure out my calling in my career' and 'I am searching for my calling as it applies to my career'. Mann-Whitney U (p < 0.05) results indicate that students interested in primary care (n = 185) versus non primary care (n = 389) are more likely to endorse the presence of a calling. Students were more likely to endorse the presence of a calling rather than a search for a calling, with those interested in primary care expressing stronger presence of a calling to medicine. PMID- 23670653 TI - Facilitating reflective learning: a PhD thesis report. PMID- 23670654 TI - Mersey deanery ophthalmology trainees' views of the objective assessment of surgical and technical skills (OSATS) workplace-based assessment tool. AB - Objective assessment of surgical and technical skills (OSATS) workplace-based assessment tool is now mandatory during ophthalmology speciality training in the United Kingdom. The opinions of those undergoing this assessment have not been formally sought. This study evaluated the views of ophthalmology trainees on OSATS assessment as applied to cataract surgery. A questionnaire was circulated to 34 ophthalmology speciality trainees of the Mersey deanery. A total of 28 responses were received. The most positive aspects of the process identified were feedback, learning and opportunity for reflective practice. The most negative aspects were time constraints, assessor's availability and case selection. Of the trainees, 93 % mentioned that no previous agreed action was taken into consideration when filling in subsequent forms and their performance was not discussed in their annual summative assessment. This study highlights important aspects of trainees' perceptions of OSATS. Trainees appreciate the formative aspects of OSATS assessment. Some problems came to light, which can be resolved by specification of standards, training of assessors, and commitment from both trainers and trainees. Changes are needed to allow demonstration of surgical progression with time. The issues identified here will be relevant to other specialities as well. A larger survey would be beneficial. PMID- 23670655 TI - Towards organizational development for sustainable high-quality medical teaching. AB - Literature shows that faculty development programmes are not organizationally embedded in academic hospitals. This leaves medical teaching a low and informal status. The purpose of this article is to explore how organizational literature can strengthen our understanding of embedding faculty development in organizational development, and to provide a useful example of organizational development with regards to medical teaching and faculty development. Constructing a framework for organizational development from the literature, based on expert brainstorming. This framework is applied to a case study. A framework for organizational development is described. Applied in a context of medical teaching, these organizational insights show the process (and progress) of embedding faculty development in organizational development. Organizational development is a necessary condition for assuring sustainable faculty development for high-quality medical teaching. Organizational policies can only work in an organization that is developing. Recommendations for further development and future research are discussed. PMID- 23670656 TI - Best abstracts of the NVMO conference. PMID- 23670657 TI - An integrated system for 3D hip joint reconstruction from 2D X-rays: a preliminary validation study. AB - The acquisition of conventional X-ray radiographs remains the standard imaging procedure for the diagnosis of hip-related problems. However, recent studies demonstrated the benefit of using three-dimensional (3D) surface models in the clinical routine. 3D surface models of the hip joint are useful for assessing the dynamic range of motion in order to identify possible pathologies such as femoroacetabular impingement. In this paper, we present an integrated system which consists of X-ray radiograph calibration and subsequent 2D/3D hip joint reconstruction for diagnosis and planning of hip-related problems. A mobile phantom with two different sizes of fiducials was developed for X-ray radiograph calibration, which can be robustly detected within the images. On the basis of the calibrated X-ray images, a 3D reconstruction method of the acetabulum was developed and applied together with existing techniques to reconstruct a 3D surface model of the hip joint. X-ray radiographs of dry cadaveric hip bones and one cadaveric specimen with soft tissue were used to prove the robustness of the developed fiducial detection algorithm. Computed tomography scans of the cadaveric bones were used to validate the accuracy of the integrated system. The fiducial detection sensitivity was in the same range for both sizes of fiducials. While the detection sensitivity was 97.96% for the large fiducials, it was 97.62% for the small fiducials. The acetabulum and the proximal femur were reconstructed with a mean surface distance error of 1.06 and 1.01 mm, respectively. The results for fiducial detection sensitivity and 3D surface reconstruction demonstrated the capability of the integrated system for 3D hip joint reconstruction from 2D calibrated X-ray radiographs. PMID- 23670658 TI - Genetics: the AML mutational landscape. PMID- 23670659 TI - Genetics: new classification for endometrial cancer puts genes in POLE position. PMID- 23670660 TI - Implementation of self management support for long term conditions in routine primary care settings: cluster randomised controlled trial. AB - OBJECTIVE: To determine the effectiveness of an intervention to enhance self management support for patients with chronic conditions in UK primary care. DESIGN: Pragmatic, two arm, cluster randomised controlled trial. SETTING: General practices, serving a population in northwest England with high levels of deprivation. PARTICIPANTS: 5599 patients with a diagnosis of diabetes (n=2546), chronic obstructive pulmonary disease (n=1634), and irritable bowel syndrome (n=1419) from 43 practices (19 intervention and 22 control practices). INTERVENTION: Practice level training in a whole systems approach to self management support. Practices were trained to use a range of resources: a tool to assess the support needs of patients, guidebooks on self management, and a web based directory of local self management resources. Training facilitators were employed by the health management organisation. MAIN OUTCOME MEASURES: Primary outcomes were shared decision making, self efficacy, and generic health related quality of life measured at 12 months. Secondary outcomes were general health, social or role limitations, energy and vitality, psychological wellbeing, self care activity, and enablement. RESULTS: We randomised 44 practices and recruited 5599 patients, representing 43% of the eligible population on the practice lists. 4533 patients (81.0%) completed the six month follow-up and 4076 (72.8%) the 12 month follow-up. No statistically significant differences were found between patients attending trained practices and those attending control practices on any of the primary or secondary outcomes. All effect size estimates were well below the prespecified threshold of clinically important difference. CONCLUSIONS: An intervention to enhance self management support in routine primary care did not add noticeable value to existing care for long term conditions. The active components required for effective self management support need to be better understood, both within primary care and in patients' everyday lives. TRIAL REGISTRATION: Current Controlled Trials ISRCTN90940049. PMID- 23670661 TI - Functional HIV cure is no pipe dream, says codiscoverer of the virus. PMID- 23670662 TI - NHS regulator given new powers to shut hospitals whose clinical care is poor. PMID- 23670663 TI - Save the Children and GSK join forces to develop drugs for children in developing countries. PMID- 23670664 TI - Criminal sanctions for failure to report harms would not deter disclosure, campaigners say. PMID- 23670665 TI - India has world's highest number of cervical cancer deaths. PMID- 23670667 TI - Longitudinal trends in health-related quality of life in adults with cystic fibrosis. AB - BACKGROUND: Health-related quality-of-life (HRQOL) measures have been used as patient-reported outcomes in clinical trials in cystic fibrosis (CF), but there are limited data on HRQOL changes over time in adults with CF. METHODS: The Project on Adult Care in Cystic Fibrosis, a prospective, longitudinal panel study of 333 adults with CF at 10 CF centers in the United States, administered a disease-specific HRQOL measure, the Cystic Fibrosis Questionnaire-Revised (CFQ R), seven times over 21 months. The CFQ-R assesses both physical and psychosocial domains of health. Growth curve regression models were developed for each CFQ-R domain, adjusting for demographic and clinical characteristics. RESULTS: Between 205 and 303 adults completed surveys (response rate, 70%-93%). Mean age at baseline was 33 years (range, 19-64 years); mean FEV1 % predicted was 59.8% (SD, 22%). Over the 21 months of follow-up, lung function, frequency of pulmonary exacerbations, and nutritional indices were associated with physical CFQ-R domain scores. There were no significant population trends over time in the physical domain scores; however, there were population time trends in three psychosocial domains: treatment burden (+8.9 points/y), emotional functioning (+3.2 points/y), and social functioning (-2.4 points/y). Individual variation in both physical and psychosocial subscales was seen over 21 months. CONCLUSIONS: In a longitudinal multicenter population of adults with CF, clinical variables such as FEV1, exacerbation frequency, and weight were correlated with related CFQ-R subscales. For the population as a whole, the physical domains of CFQ-R, such as respiratory symptoms, were stable. In contrast, population changes in several psychosocial domains of CFQ-R suggest that differentiating between the physical and the psychosocial trajectories in health among adults with CF is critical in evaluating patient-reported outcomes. PMID- 23670668 TI - Encapsulated electrodes for microchip devices: microarrays and platinized electrodes for signal enhancement. AB - In this paper, we present two new methodologies of improving the performance of microchip-based electrochemical detection in microfluidic devices. The first part describes the fabrication and characterization of epoxy-embedded gold microelectrode arrays that are evenly spaced and easily modified. Electrodepositions using a gold plating solution can be performed on the electrodes to result in a 3D pillar array that, when used with microchip-based flow injection analysis, leads to an eightfold increase in signal (when compared to a single electrode), with the LOD for catechol being 4 nM. For detecting analytically challenging molecules such as nitric oxide (NO), platinization of electrodes is commonly used to increase the sensitivity. It is shown here that microchip devices containing either the pillar arrays or more traditional glassy carbon electrodes can be modified with platinum black (Pt-black) for NO detection. In the case of using glassy carbon electrodes for NO detection, integration of the resulting platinized electrode with microchip-based flow analysis resulted in a ten times signal increase relative to use of a bare glassy carbon electrode. In addition, it is demonstrated that these electrodes can be coated with Nafion to impart selectivity toward NO over interfering species such as nitrite. The LOD for NO when using the Pt-black /Nafion-coated glassy carbon electrode was 9 nM. These electrodes can also be embedded in a polystyrene substrate, with the applicability of these sensitive and selective electrodes being demonstrated by monitoring the adenosine triphosphate-mediated release of NO from endothelial cells immobilized in a microfluidic network without any adhesion factor. PMID- 23670669 TI - [The university hospital for psychosomatic medicine and psychotherapy turns 60]. PMID- 23670666 TI - Organic nitrate metabolism and action: toward a unifying hypothesis and the future-a dedication to Professor Leslie Z. Benet. AB - This review summarizes the major advances that had been reported since the outstanding contributions that Professor Benet and his group had made in the 1980s and 1990s concerning the metabolism and pharmacologic action of organic nitrates (ORNs). Several pivotal studies have now enhanced our understanding of the metabolism and the bioactivation of ORNs, resulting in the identification of a host of cysteine-containing enzymes that can carry out this function. Three isoforms of aldehyde dehydrogenase, all of which with active catalytic cysteine sites, are now known to metabolize, somewhat selectively, various members of the ORN family. The existence of a long-proposed but unstable thionitrate intermediate from ORN metabolism has now been experimentally observed. ORN induced thiol oxidation in multiple proteins, called the "thionitrate oxidation hypothesis," can be used not only to explain the phenomenon of nitrate tolerance, but also the various consequences of chronic nitrate therapy, namely, rebound vasoconstriction, and increased morbidity and mortality. Thus, a unifying biochemical hypothesis can account for the myriad of pharmacological events resulting from nitrate therapy. Optimization of the future uses of ORN in cardiology and other diseases could benefit from further elaboration of this unifying hypothesis. PMID- 23670670 TI - Surgical technique: Tscherne-Johnson extensile approach for tibial plateau fractures. AB - BACKGROUND: The standard approach to lateral tibial plateau fractures involves elevation of the iliotibial band (IT) and anterior tibialis origin in continuity from Gerdy's tubercle and metaphyseal flare. We describe an alternative approach to increase lateral plateau joint exposure and maintain iliotibial band insertion to Gerdy's tubercle. DESCRIPTION OF TECHNIQUE: The approach entails a partial tenotomy of the anterior half of the IT band leaving the posterior IT band insertion attached to Gerdy's tubercle. Fracture lines around Gerdy's tubercle are completed or the tubercle was osteotomized and externally rotated and the joint overdistracted, allowing direct visualization of the joint depression. Joint elevation, grafting, and internal fixation are performed through this window. METHODS: We retrospectively reviewed 76 patients (two groups), Schatzker Types I to II and IV to VI fractures (66 patients), between 1989 and 2005, and 10 patients, with 10 bicondylar posterior plateau fractures, from 2002 to 2010. All patients were followed a minimum of 12 months (average, 3.9 years; range, 12 months to 10 years). Ten patients, with posterior plateau fractures, received anterolateral plateau intraarticular osteotomy for exposure of centroposterior and posterolateral articular depression. RESULTS: Average knee ROM was 2 degrees of flexion (range, -3 degrees to 5 degrees ) to greater than 120 degrees of flexion (range, 100 degrees -145 degrees ). In 66 patients, average articular depression improved from 7.4 mm to 1 mm (range, 0-5 mm) and, in 10 posterior fractures, from 18 mm to 1 mm (range, 0-4.5 mm). Infection occurred in one of the 76 patients; acute debridement and intravenous antibiotics resulted in control of the infection. CONCLUSIONS: This approach reliably increases direct visualization of the lateral plateau articular fractures and maintains IT band insertion. Articular osteotomy of the anterolateral plateau provides access to extensive posterior plateau fractures. PMID- 23670671 TI - Long-term (20- to 25-year) results of an uncemented tapered titanium femoral component and factors affecting survivorship. AB - BACKGROUND: Uncemented femoral components in primary total hip arthroplasty (THA) are commonly used today, but few studies have evaluated their survival into the third decade. QUESTIONS/PURPOSES: We evaluated (1) survivorship using femoral revision for any reason as the end point; (2) survivorship using femoral revision for aseptic loosening as the end point; and (3) patient-related and surgical risk factors for aseptic stem loosening at a minimum 20-year followup with an uncemented tapered titanium stem. METHODS: We reviewed the clinical and radiographic results of 354 THAs in 326 patients performed between January 1985 and December 1989 using an uncemented grit-blasted, tapered titanium femoral stem. Mean age at surgery was 57 years (range, 13-81 years). Kaplan-Meier survivorship analysis was used to estimate long-term survival. Minimum followup evaluation was 20 years (mean, 22 years; range, 20-25 years); at that time, 120 patients (127 hips) had died, and four patients (five hips) were lost to followup. Multivariate survival analysis using a Cox regression model was performed. RESULTS: Survivorship at 22 years with revision of the femoral component for any reason as the end point was 86% (95% confidence interval [CI], 81%-90%). Survivorship for femoral revision for aseptic loosening as the end point was 93% at 22 years (95% CI, 90%-96%). Undersized stems (canal fill index<=80%) and stems in hips with cup revision were at higher risk for aseptic loosening (hazard ratio, 4.2 and 4.3, respectively). There was a high rate of acetabular revision in this series (38%), mostly related to smooth-threaded, cementless sockets. CONCLUSIONS: Uncemented femoral fixation was reliable into the third decade. Age, male sex, and diagnosis were not associated with a higher risk of aseptic loosening. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 23670672 TI - Tuberculosis of the pubic symphysis: four unusual cases and literature review. AB - BACKGROUND: The incidence of extrapulmonary tuberculosis (TB) has increased in the chemotherapeutic era owing to the increasing presence of immunodeficiency disorders. Pubic symphysis TB, although uncommon, is again important as these infections once were in the prechemotherapeutic era. CASE DESCRIPTION: We present the cases of four patients with pubic symphysis TB in which one patient had a horseshoe-shaped abscess in the pubic region and another had a double lesion of the pelvis leading to vertical shear-type pathologic displacement. Three patients were diagnosed by cytology and PCR. These patients were treated successfully with antituberculosis treatment with or without minimal surgical intervention despite their late presentation and advanced disease. The fourth patient remains under treatment and followup. LITERATURE REVIEW: We identified 40 patients with TB of the pubic symphysis in the English language medical literature. Of these 40 patients, only five are from India despite TB being endemic in this country. Followup information is available for 32 of the 40 patients with followups ranging from 1 to 84 months (mean of approximataly 20 months). PURPOSES AND CLINICAL RELEVANCE: We suspect TB of the pubic symphysis is increasing in frequency owing to drug resistance, use of biologics, immunomodulating drugs, and anticancer drugs. Therefore, it is important for clinicians to have a high index of suspicion in patients at risk. Initially patients may be asymptomatic or present with adductor region pain or spasm, sacroiliac strain, limp, or a hypogastric, inguinal, or thigh mass that mimics an inguinal hernia, genitourinary, abdominal, or thigh tumor. CONCLUSION: It is important to diagnose and treat pubic TB early in the course of the disease before the destructive stage. After relevant investigations most patients can be treated with antitubercular drugs with or without a minor surgical procedure. PMID- 23670673 TI - Percutaneous doxycycline treatment of aneurysmal bone cysts with low recurrence rate: a preliminary report. AB - BACKGROUND: Aneurysmal bone cyst (ABC) has a recurrence rate of between 12% and 71% without en bloc resection or amputation. There is no percutaneous ABC treatment drug regimen demonstrating consistent evidence of bone healing with recurrence of < 12%. Doxycycline has properties that may make it appropriate for percutaneous treatment. QUESTIONS/PURPOSES: We therefore asked: (1) Is there reduction in ABC lytic cyst volume with injectable doxycycline? (2) Is it associated with thickening of involved bony cortex? (3) Is the recurrence rate after percutaneous treatment < 12%? METHODS: We retrospectively reviewed 20 patients who underwent percutaneous treatment of ABCs with doxycycline from 2006 to 2010. The mean age was 10 years (range, 3-18 years). There were 21 treatment locations: humerus (six), spine (five), clavicle (two), fibula (one), femur (two), ulna (two), tibia (two), and scapula (one). Twenty patients completed treatment involving 118 treatment sessions (two to 14 sessions per patient). Treatment response was evaluated radiographically by measuring the lytic component and thickness of involved cortex. Recurrence was indicated by new areas of lytic destruction after completion of treatment. The minimum followup was 24 months (mean, 38 months). RESULTS: Twenty of 20 patients demonstrated reduction in lytic destruction and bony healing. All patients demonstrated cortical thickening. One patient demonstrated recurrent minimal lytic destruction after 20 months of observation. CONCLUSIONS: In this series, patients undergoing percutaneous doxycycline treatment of ABCs demonstrated a healing response and a recurrence rate of 5% at more than 24 months. PMID- 23670674 TI - Can certain benign lesions of the proximal femur be treated without surgery? AB - BACKGROUND: Benign lesions in the proximal femur can cause pathologic fractures. To avoid fracture, benign tumors and tumor-like lesions in this region often are treated surgically, yet there have been few reports regarding the decision-making processes or protocols for nonsurgical treatment of these lesions. QUESTIONS/PURPOSES: In this study, we asked (1) whether some benign lesions of the proximal femur can be managed safely using a conservative protocol, and (2) if observed according to such a protocol, what are the outcomes of such lesions at this anatomic site? METHODS: Fifty-four consecutive patients who had been followed for at least 12 months were enrolled in this study. The mean age of the patients at first visit was 38 years (range, 13-70 years), and the minimum followup was 12 months (mean, 25 months; range, 12-59 months). After ruling out malignancy, lesions were categorized as aggressive benign tumors or nonaggressive benign lesions using a standardized approach. We used conservative treatment for most patients with nonaggressive, benign lesions. Surgery was performed only for patients with nonaggressive lesions who met our fracture risk criteria: pain on initiating hip movement, progressively worsening pain, cortical thinning, and the absence of a sclerotic margin. RESULTS: Of the 47 patients with a nonaggressive, benign lesion without fracture at presentation, 83% were treated conservatively and only 10% of these patients had progression of the lesion. No new pathologic fractures developed during followup. In 88% of patients who presented with pain that was managed conservatively, pain improved either partially or completely at final followup. CONCLUSIONS: Most nonaggressive, benign lesions in the proximal femur can be treated conservatively, and our protocol appears to be a useful outpatient guideline. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 23670675 TI - Complication rates after hip or knee arthroplasty in morbidly obese patients. AB - BACKGROUND: Morbid obesity has been shown to be a risk factor for increased complications after THA and TKA; however, large studies that would determine the effect size are lacking. QUESTIONS/PURPOSES: The purposes of this study were to determine whether morbid obesity increased the risk of: (1) venous thromboembolism (VTE), (2) bleeding, (3) other adverse events, and (4) infections during the early postoperative period (up to 6 to 8 weeks) after THA or TKA? METHODS: Data from the REgulation of Coagulation in ORthopaedic surgery to prevent Deep vein thrombosis and pulmonary embolism (RECORD) clinical trial program of rivaroxaban for prevention of VTE after THA or TKA were analyzed retrospectively. Data for 12,355 patients were reviewed to identify complication rates in morbidly obese patients (BMI>=40 kg/m2) compared with patients with a BMI less than 40 kg/m2. Explorative analyses compared the rates of asymptomatic deep vein thrombosis (DVT), symptomatic DVT, symptomatic pulmonary embolism, bleeding, and other adverse events by BMI group. RESULTS: There were no significant differences in asymptomatic DVT, symptomatic DVT, symptomatic pulmonary embolism, or bleeding, but there were increases in other adverse events (including receipt of blood transfusion, erythema, peripheral edema, diarrhea, gastrointestinal or abdominal pain) and infections (including respiratory tract or lung infections, wound inflammation or infection, and extrasurgical-site infections), in patients with a BMI of 40 kg/m2 or greater compared with patients with a BMI less than 40 kg/m2. CONCLUSIONS: After THA or TKA, morbid obesity is not associated with an increased risk of VTE or bleeding but is associated with increased early postoperative complications, including erythema, peripheral edema, diarrhea and gastrointestinal or abdominal pain, wound inflammation or infection, extrasurgical-site infections, and respiratory tract or lung infections. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 23670676 TI - The relationship between socio-demographic characteristics, family environment, and caregiver coping in families of children with cancer. AB - The factors that influence caregiver coping mechanism preferences after a child's diagnosis with cancer are not fully understood. This study examines the relationship between caregivers' socio-demographic characteristics and the coping strategies they use to adapt to childhood cancer. Sixty caregivers of pediatric cancer patients completed a socio-demographic questionnaire, the Family Environment Scale, and the COPE inventory. There were no significant differences in family environment by income or education. Caregiver educational attainment was positively associated with use of planning and active coping styles, while income was not associated with caregiver coping style. Mothers were more likely than fathers to use active coping, instrumental support, religious coping, and emotional support. Men with lower education engaged in greater substance use coping and lower planning. The findings show that educational attainment and caregiver gender influence caregiver coping styles following a pediatric cancer diagnosis and suggest that educational attainment rather than financial resources drive the association between SES and coping. Programs that address educational gaps and teach caregivers planning and active coping skills may be beneficial for parents with lower educational attainment, particularly men. PMID- 23670677 TI - Knockdown of clusterin inhibits the growth and migration of renal carcinoma cells and leads to differential gene expression. AB - Clusterin (CLU) is a glycoprotein involved in tumor progression, whose expression level correlates with the metastasis of renal cell carcinoma (RCC). However, the mechanism by which CLU plays an oncogenic role in RCC remains unclear. In this study, we used the human renal cancer cell 786-O as an experimental model. We knocked down CLU expression in the 786-O cells using lentiviral vector-mediated delivery of RNAi, and then compared the gene expression profiles between the knocked down CLU 786-O cells and control cells. We observed that CLU knockdown induced apoptosis and inhibited the proliferation and migration of 786-O cells. Microassay analysis revealed changes in the expression of 588 genes between the 786-O cells infected by a si-CLU lentivirus and the control cells, where 356 genes were upregulated and 232 were downregulated. Pathway analysis classified the differentially expressed genes into 17 upregulated and 12 downregulated pathways, including the PI3K/Akt, MAPK and VEGF pathways. In this study, we demonstrated that CLU acts as an oncogene in RCC by promoting cell proliferation and migration and inhibiting apoptosis. Microassay analysis may provide a platform for further characterization of the individual genes implicated in the development of RCC, providing new insights into the oncogenic role of CLU. PMID- 23670678 TI - A viscous two-phase model for contractile actomyosin bundles. AB - A mathematical model in one dimension for a non-sarcomeric actomyosin bundle featuring anti-parallel flows of anti-parallel F-actin is introduced. The model is able to relate these flows to the effect of cross-linking and bundling proteins, to the forces due to myosin-II filaments and to external forces at the extreme tips of the bundle. The modeling is based on a coarse graining approach starting with a microscopic model which includes the description of chemical bonds as elastic springs and the force contribution of myosin filaments. In a second step we consider the asymptotic regime where the filament lengths are small compared to the overall bundle length and restrict to the lowest order contributions. There it becomes apparent that myosin filaments generate forces which are partly compensated by drag forces due to cross-linking proteins. The remaining local contractile forces are then propagated to the tips of the bundle by the viscosity effect of bundling proteins in the filament gel. The model is able to explain how a disordered bundle of comparatively short actin filaments interspersed with myosin filaments can effectively contract the two tips of the actomyosin bundle. It gives a quantitative description of these forces and of the anti-parallel flows of the two phases of anti-parallel F-actin. An asymptotic version of the model with infinite viscosity can be solved explicitly and yields an upper bound to the contractile force of the bundle. PMID- 23670679 TI - [Anatomy of the eustachian tube]. AB - The auditory tube is part of a complex anatomical functional system, which even today is not completely explained. It plays a crucial role in the understanding of the pathogenesis of chronic middle ear infections and possible therapeutic interventions--particularly in infants. This paper summarizes the current knowledge of eustachian tube gross anatomy and histology, its peritubular structures and its topographic relationship to the internal carotid artery in adults. Anatomical aspects specific to infancy are related to their possible influence on tube function. PMID- 23670680 TI - [Chronic dysfunction of the eustachian tube: diagnosis and results of balloon dilatation of the eustachian tube]. PMID- 23670681 TI - Physiologically lucky: the role of medical physiology in modern medical education : An interview with Dr. John E. Hall. PMID- 23670682 TI - E-learning any time any place anywhere on mobile devices. AB - The registered screen resolution of e-learning study moments in MedicalEducation.nl was used in this research to investigate the readiness of students and medical professionals to study e-learning on a mobile device. Between January 2008 and September 2012 the use of e-learning on a mobile device by students has quintupled to 2.29 %, while medical professionals lag behind in this development. If the use of mobile devices for e-learning is better supported, a rapid further increase should be anticipated. Further research on the desire of both students and medical professionals to study e-learning on a mobile device should be conducted. PMID- 23670683 TI - A curriculum focused on informed empathy improves attitudes toward persons with disabilities. AB - Empathy is an important component of the provider-patient relationship. In the United States one in five persons has a disability. Persons with disabilities perceive gaps in health care providers' understanding of their health care preferences and needs. The purpose of this study was to use valid and reliable assessment methods to investigate the association between empathy and attitudes toward persons with disabilities and advocacy. An educational module was developed to enhance health care students' capacity for informed empathy. Pre- and post-assessment measures included the Attitude toward Disabled Persons scale (ATDP), the Attitudes toward Patient Advocacy Microsocial scale (AMIA) and the Interpersonal Reactivity Index (IRI). ATDP (t(94) = -5.95, p = .000) and AMIA (t(92) = -5.99, p = .000) scores increased significantly after the education module. Correlations between the pre- or post-module ATDP or AMIA scores and the IRI scores were not significant. Empathy in general may not be sufficient to ensure optimal attitudes toward persons with disabilities or advocacy in pre health care professionals. However, a curriculum based on informed empathy and focused on the experiences of persons with disabilities can result in more positive attitudes toward and advocacy for people with disabilities. PMID- 23670684 TI - Persistent reservations against the premedical and medical curriculum. PMID- 23670685 TI - The last generation of the pommy medical officer. PMID- 23670686 TI - Written narrative feedback, reflections and action plans in single-encounter observations: an observational study. PMID- 23670687 TI - Moving from knowledge to practice: is it time to move from teaching evidence based medicine (EBM) to knowledge translation competency? PMID- 23670688 TI - Medical student interest in academic medical careers: a multi-institutional study. AB - Little is known about how medical students view academic medicine. This multi institutional study explored student perceptions of this career path. During 2009 2010, third- and fourth-year students at three United States medical schools completed a 30-item online survey. In total, 239 students completed the questionnaire (37 % response rate). Significant predictors of students' desires for academic medical careers included interest in teaching (gamma = 0.74), research (gamma = 0.53), interprofessional practice (gamma = 0.34), administration (gamma = 0.27), and community service opportunities (gamma = 0.16). A positive correlation existed between accumulated debt and interest in academic medicine (gamma = 0.20). Student descriptions of the least and most appealing aspects of academic medicine were classified into five categories: professional, research, personal, teaching and mentoring, and patients/patient care. Students are more likely to be interested in a career in academic medicine if they have participated in research or were influenced by a mentor. Factors that may also influence a medical student's decision to pursue a career in academic medicine include age and debt accumulated prior to medical school. Professional aspects of academic medicine (cutting edge environment, resources) and the opportunity to teach were the most appealing aspects. PMID- 23670690 TI - Rectification: Best abstracts of the NVMO conference. PMID- 23670689 TI - The use of daily questions for educational purposes: a TOPday for students. PMID- 23670691 TI - Research skills for undergraduates: a must! PMID- 23670692 TI - International women physicians' perspectives on choosing an academic medicine career. AB - Concerns about recruiting physicians into academic careers is an international issue. A qualitative study with United States (US) women physicians revealed insights into how, when, and why physicians choose an academic career in medicine. The current study explored international women physicians' perspectives on their career choice of academic medicine and determined if different themes emerged. We expanded the 2012 study of US women physicians by interviewing women physicians in Canada, Pakistan, Mexico, and Sweden to gain an international perspective on choosing an academic career. Interviews were thematically analyzed against themes identified in the previous study. Based on themes identified in the study of US physicians, qualitative analysis of 7 international women physicians revealed parallel themes for the following areas: Why academic medicine? Fit; People; Aspects of academic health centre environment. How the decision to enter academic medicine was made? Decision-making style; Emotionality When the decision to enter academic medicine was made? Practising physician; Fellowship; Medical student. Work-life balance, choosing academic medicine by default, serendipity, intellectual stimulation, mentors, research and teaching were among the areas specifically highlighted. CONCLUSION: Parallel themes exist regarding how, why, and when US and international women physicians choose academic medicine as a career path. PMID- 23670693 TI - Faculty and student perceptions of academic counselling services at an academic health science center. AB - There are limited data on support services that facilitate students' academic success at academic health science centres. The authors explored faculty and students' perceptions of available academic counselling services (ACS) at an academic health science centre in the Southeastern United States. Participants were surveyed in May and June of 2011 regarding the ACS available at the institution. Fifty-nine percent of faculty respondents (N = 471) agreed that academic counselling was a necessary part of the institution, but only 26 % reported knowledge of how to refer students for academic counselling. Only 18 % stated they had previously referred a student for services. Fifty-four percent of student respondents (N = 360) agreed that academic counselling was a necessary part of the institution and 60 % stated that they would seek these services if needed. However, only 35 % of students reported that they were aware of how to access the services. These findings suggest a discrepancy between the belief that academic support services have value and their knowledge about how to utilize the services. It is recommended that academic health science centres consider the promotion of available academic support services amongst both faculty and students when designing and implementing programmes to reduce this potential obstacle to service utilization. PMID- 23670694 TI - The discourse of generational segmentation and the implications for postgraduate medical education. AB - The growing demands for easily accessible, cost effective and efficient health care services are hindering many medical training programs in delivering well prepared physicians, equipped with the competencies to tackle new and complex health care problems. In addition to this, many medical institutions are finding it difficult to design curricula that would prepare today's physicians adequately for the ongoing changes in health care. Targeted customer service is a growing phenomenon in health care, where healthcare institutions are operating as retail service providers, design experiences and deliver care around the convenience of consumers rather than the preferences of providers. Gradually finding its way into medical education, this concept entails investing in understanding the beliefs and values of consumers as a result of their different expectations and differences. Defined by the experiences that create common values among the members of a specific group, the discourse of generation segmentation has proven to be a helpful way of understanding consumer differences. There are four known generations currently impacting the pattern and distribution of healthcare services and in the coming decade, the future of medical education In this paper, medical education is re-examined in the light of this phenomenon of generation segmentation and whether today's physicians are being effectively prepared to practice in a fast changing world. The analysis provided in this paper presents a recommendation for the medical curriculum of a new millennium based on the changing needs and expectations of different generations of consumers. PMID- 23670695 TI - Ownership of patient care: a behavioural definition and stepwise approach to diagnosing problems in trainees. AB - In medical education, behavioural definitions allow for more effective evaluation and supervision. Ownership of patient care is a complex area of trainee development that crosses multiple areas of evaluation and may lack clear behavioural definitions. In an effort to define ownership for educational purposes, the authors surveyed psychiatry teaching faculty and trainees about behaviours that would indicate that a physician is demonstrating ownership of patient care. Emerging themes were identified through analysis of narrative responses in this qualitative descriptive study. Forty-one faculty (54 %) and 29 trainees (52 %) responded. Both faculty and trainees identified seven core elements of ownership: advocacy, autonomy, commitment, communication, follow through, knowledge and teamwork. These seven elements provide a consensus-derived behavioural definition that can be used to determine competency or identify deficits. The proposed two-step process enables supervisors to identify problematic ownership behaviours and determine whether there is a deficit of knowledge, skill or attitude. Further, the theory of planned behaviour is applied to better understand the relationship between attitudes, intentions and subsequent behaviour. By structuring the diagnosis of problems with ownership of patient care, supervisors are able to provide actionable feedback and intervention in a naturalistic setting. Three examples are presented to illustrate this stepwise process. PMID- 23670696 TI - Reflecting on clinical education. PMID- 23670697 TI - Repeated evaluations of the quality of clinical teaching by residents. AB - Many studies report on the validation of instruments for facilitating feedback to clinical supervisors. There is mixed evidence whether evaluations lead to more effective teaching and higher ratings. We assessed changes in resident ratings after an evaluation and feedback session with their supervisors. Supervisors of three medical specialities were evaluated, using a validated instrument (EFFECT). Mean overall scores (MOS) and mean scale scores were calculated and compared using paired T-tests. 24 Supervisors from three departments were evaluated at two subsequent years. MOS increased from 4.36 to 4.49. The MOS of two scales showed an increase >0.2: 'teaching methodology' (4.34-4.55), and 'assessment' (4.11 4.39). Supervisors with an MOS <4.0 at year 1 (n = 5) all demonstrated a strong increase in the MOS (mean overall increase 0.50, range 0.34-0.64). Four supervisors with an MOS between 4.0 and 4.5 (n = 6) demonstrated an increase >0.2 in their MOS (mean overall increase 0.21, range -0.15 to 53). One supervisor with an MOS >4.5 (n = 13) demonstrated an increase >0.02 in the MOS, two demonstrated a decrease >0.2 (mean overall increase -0.06, range -0.42 to 0.42). EFFECT-S was associated with a positive change in residents' ratings of their supervisors, predominantly in supervisors with relatively low initial scores. PMID- 23670698 TI - Medical students' reactions to an experience-based learning model of clinical education. AB - An experience-based learning (ExBL) model proposes: Medical students learn in workplaces by 'supported participation'; affects are an important dimension of support; many learning outcomes are affective; supported participation influences students' professional identity development. The purpose of the study was to check how the model, which is the product of a series of earlier research studies, aligned with students' experiences, akin to the 'member checking' stage of a qualitative research project. In three group discussions, a researcher explained ExBL to 19 junior clinical students, who discussed how it corresponded with their experiences of clinical learning and were given a written precis of it to take away. One to 3 weeks later, they wrote 500-word reflective pieces relating to their subsequent experiences with ExBL. Four researchers conducted a qualitative analysis. Having found many instances of responses 'resonating' to the model, the authors systematically identified and coded respondents' 'resonances' to define how they aligned with their experiences. 120 resonances were identified. Seventy (58 %) were positive experiences and 50 (42 %) negative ones. Salient experiences were triggered by the learning environment in 115 instances (96 %) and by learners themselves in 5 instances (4 %), consistent with a strong effect of environment on learning processes. Affective support was apparent in 129 of 203 statements (64 %) of resonances and 118 learning outcomes (58 %) were also affective. ExBL aligns with medical students' experiences of clinical learning. Subject to further research, these findings suggest ExBL could be used to support the preparation of faculty and students for workplace learning. PMID- 23670699 TI - Long-term utility outcomes in patients undergoing endoscopic sinus surgery. AB - OBJECTIVES/HYPOTHESIS: To define long-term health-state utility outcomes in patients undergoing endoscopic sinus surgery (ESS) for refractory chronic rhinosinusitis (CRS). STUDY DESIGN: Prospective, longitudinal, cohort study. METHODS: The short-form (SF)-12 survey was issued to the 168 patients who were enrolled in an initial study evaluating short-term utility outcomes following ESS. SF-12 responses were converted into SF-6D utility scores using the University of Sheffield algorithm. The primary outcome was mean overall long-term utility level following ESS. Secondary outcomes evaluated annual utility level following ESS and utility outcomes for different subgroups of patients with CRS. RESULTS: A total of 83 patients provided long-term health-state utility outcomes. The mean overall long-term utility level was 0.80 at a mean follow-up of 5.2 years after ESS. Compared to the baseline (0.67) and short-term follow-up (0.75) utility levels in this group, there was a significant improvement at the long term period (P = .002). A total of 54% (45/83) of patients achieved long-term postoperative utility scores higher than the United States norm of 0.81. There was a significant improvement in utility scores for all subsequent years after ESS compared to preoperative responses (all P < .028). All subgroups of CRS received significant long-term utility improvements (all P < .001), and those undergoing revision ESS demonstrated continued improvement past the short-term postoperative period. CONCLUSIONS: This study has demonstrated that patients with refractory CRS achieve stable mean long-term utility levels following ESS and often return to a health state comparable to US population norms. PMID- 23670700 TI - What is "usual care" in dysphagia rehabilitation: a survey of USA dysphagia practice patterns. AB - The scope of dysphagia rehabilitation has been expanding. Therapeutic approaches have begun to move away from the use of behavioral compensations and maneuvers only, toward a greater emphasis on research-supported exercise-based therapies. Given the change in focus and demand for evidence-based practice, this study surveyed licensed speech language pathologists who treat dysphagic adults to ascertain the utilization of exercise-based techniques and supportive research in treatment decision-making. A web-based survey was created using Qualtrics online software. The survey consisted of 29 questions on demographics and treatment options for a deidentified patient in a video-supported fictional scenario. Initially, a field test was conducted by sending the survey to a sample population of 12 local speech pathologists working in adult dysphagia rehabilitation. Responses were collated and analyzed for item agreement and internal consistency. A blast e-mail containing a link to the modified survey was then sent out to members of the American Speech Language Hearing Association Special Interest Group 13. Participants were given 2 months to complete the survey. A total of 254 responses were analyzed using descriptive, correlative, and associative methods. Respondents were experienced speech-language pathologists (SLP) working in primarily acute and rehabilitation settings and treating more than 50 dysphagic cases in a 6-month period. They reported treating dysphagic patients daily for an average of 30 min a session. Follow-up of treated patients was infrequent. Most respondents reported using self-developed assessment techniques, and as a group they recommended 47 different treatment techniques and more than 90 different treatment combinations for the same hypothetical patient case. The majority of respondents also described the common outcome of dysphagia treatment as returning a patient to a safe and functional oral diet, but not preinjury status. Results demonstrate a lack of uniformity in the treatment schemes and strategies used by SLP to treat dysphagic patients. The concept of "usual care practice" for dysphagia is not supported. Utilization of research-supported assessment techniques and exercise-based approaches was also sparse. These data clearly highlight ongoing challenges to professional education and growth in the area of dysphagia management. PMID- 23670701 TI - Microwave dielectric heating of non-aqueous droplets in a microfluidic device for nanoparticle synthesis. AB - We describe a microfluidic device with an integrated microwave heater specifically designed to dielectrically heat non-aqueous droplets using time varying electrical fields with the frequency range between 700 and 900 MHz. The precise control of frequency, power, temperature and duration of the applied field opens up new vistas for experiments not attainable by conventional microwave heating. We use a non-contact temperature measurement system based on fluorescence to directly determine the temperature inside a single droplet. The maximum temperature achieved of the droplets is 50 degrees C in 15 ms which represents an increase of about 25 degrees C above the base temperature of the continuous phase. In addition we use an infrared camera to monitor the thermal characteristics of the device allowing us to ensure that heating is exclusively due to the dielectric heating and not due to other effects like non-dielectric losses due to electrode or contact imperfection. This is crucial for illustrating the potential of dielectric heating of benzyl alcohol droplets for the synthesis of metal oxides. We demonstrate the utility of this technology for metal oxide nanoparticle synthesis, achieving crystallization of tungsten oxide nanoparticles and remarkable microstructure, with a reaction time of 64 ms, a substantial improvement over conventional heating methods. PMID- 23670702 TI - Ab initio folding of extended alpha-helix: a theoretical study about the role of electrostatic polarization in the folding of helical structures. AB - In this work, we report the ab initio folding of three different extended helical peptides namely 2khk, N36, and C34 through conventional molecular dynamics simulation at room temperature using implicit solvation model. Employing adaptive hydrogen bond specific charge (AHBC) scheme to account for the polarization effect of hydrogen bonds established during the simulation, the effective folding of the three extended helices were observed with best backbone RMSDs in comparison to the experimental structures over the helical region determined to be 1.30 A for 2khk, 0.73 A for N36 and 0.72 A for C34. In this study, 2khk will be used as a benchmark case serving as a means to compare the ability of polarized (AHBC) and nonpolarized force field in the folding of an extended helix. Analyses conducted revealed the ability of the AHBC scheme in effectively folding the extended helix by promoting helix growth through the stabilization of backbone hydrogen bonds upon formation during the folding process. Similar observations were also noted when AHBC scheme was employed during the folding of C34 and N36. However, under Amber03 force field, helical structures formed during the folding of 2khk was not accompanied by stabilization thus highlighting the importance of electrostatic polarization in the folding of helical structures. PMID- 23670703 TI - Awake video-thoracoscopic surgery for intractable pneumothorax in pregnancy by using a single portal plus puncture. AB - A 31-year old female patient in the ninth week of pregnancy complained of chest pain and dyspnoea. The patient had experienced an episode of spontaneous pneumothorax on the left side at the age of 20 and had undergone chest tube drainage. Her medical history was unremarkable and she had no history of smoking. She had no family history of pulmonary disease. Thoracic radiography showed a pneumothorax on the right side. The patient underwent chest tube drainage in the thoracic space. When surgical intervention for continuous air leakage was unavoidable, we selected video-assisted thoracic surgery under local and epidural anaesthesia in consideration of her general condition. We conclude that awake surgical intervention is applicable in selected patients with pneumothorax in pregnancy and is particularly useful in those in whom general anaesthesia is best avoided. PMID- 23670704 TI - Selectivity in the impact of P-glycoprotein upon pulmonary absorption of airway dosed substrates: a study in ex vivo lung models using chemical inhibition and genetic knockout. AB - P-glycoprotein (P-gp) mediated efflux is recognised to alter the absorption and disposition of a diverse range of substrates. Despite evidence showing the presence of P-gp within the lung, relatively little is known about the transporter's effect upon the absorption and distribution of drugs delivered via the pulmonary route. Here, we present data from an intact isolated rat lung model, alongside two isolated mouse lung models using either chemical or genetic inhibition of P-gp. Data from all three models show inhibition of P-gp increases the extent of absorption of a subset of P-gp substrates (e.g. rhodamine 123 and loperamide) whose physico-chemical properties are distinct from those whose pulmonary absorption remained unaffected (e.g. digoxin and saquinavir). This is the first study showing direct evidence of P-gp mediated efflux within an intact lung, a finding that should warrant consideration as part of respiratory drug discovery and development as well as in the understanding of pulmonary pharmacokinetic (PK)-pharmacodynamic (PD) relationships. PMID- 23670705 TI - On-line sample preconcentration technique based on a dynamic pH junction in CE amperometric detection for the analysis of biogenic amines in urine. AB - It is difficult to detect biogenic amines (BAs) in biological fluids because of their very low concentrations. In this paper, we reported an on-line sample preconcentration method in CE-amperometric detection (CE-AD) based on a dynamic pH junction, and a concentration enhancement of approximately 100-fold was achieved compared with the classical CE-AD methods in the simultaneous analysis of six BAs in urine (dopamine, epinephrine, norepinephrine, tyramine, tryptamine, and serotonin). The technique is proposed based on the sharp pH change generated at the boundary between an acidic sample and the basic BGE zone. Under optimized conditions, all analytes were successfully focused and well separated within 20 min with high efficiency and sensitivity (LODs at S/N = 3 ranging from 5.34 to 68.3 nM). For the analysis of urine samples by this method, satisfactory recoveries were obtained without a complicated pretreatment step or derivatization process. Therefore, it is self-evident that this approach for the analysis of real biological samples has great potential in the future. PMID- 23670706 TI - Gene-expression differences in peripheral blood between lithium responders and non-responders in the Lithium Treatment-Moderate dose Use Study (LiTMUS). AB - This study was designed to identify genes whose expression in peripheral blood may serve as early markers for treatment response to lithium (Li) in patients with bipolar disorder. Although changes in peripheral blood gene-expression may not relate directly to mood symptoms, differences in treatment response at the biochemical level may underlie some of the heterogeneity in clinical response to Li. Subjects were randomized to treatment with (n=28) or without (n=32) Li. Peripheral blood gene-expression was measured before and 1 month after treatment initiation, and treatment response was assessed after 6 months. In subjects treated with Li, 62 genes were differentially regulated in treatment responders and non-responders. Of these, BCL2L1 showed the greatest difference between Li responders and non-responders. These changes were specific to Li responders (n=9), and were not seen in Li non-responders or patients treated without Li, suggesting that they may have specific roles in treatment response to Li. PMID- 23670707 TI - Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co transporter 2 inhibitor, in subjects with type 2 diabetes mellitus. AB - This study characterized single- and multiple-dose pharmacokinetics of canagliflozin and its O-glucuronide metabolites (M5 and M7) and pharmacodynamics (renal threshold for glucose [RTG ], urinary glucose excretion [UGE0-24h ], and 24-hour mean plasma glucose [MPG0-24h ]) of canagliflozin in subjects with type 2 diabetes. Thirty-six randomized subjects received canagliflozin 50, 100, or 300 mg/day or placebo for 7 days. On Days 1 and 7, area under the plasma concentration-time curve and maximum observed plasma concentration (Cmax ) for canagliflozin and its metabolites increased dose-dependently. Half-life and time at which Cmax was observed were dose-independent. Systemic molar M5 exposure was half that of canagliflozin; M7 exposure was similar to canagliflozin. Steady state plasma canagliflozin concentrations were reached by Day 4 in all active treatment groups. Pharmacodynamic effects were dose- and exposure-dependent. All canagliflozin doses decreased RTG , increased UGE0-24h , and reduced MPG0-24h versus placebo on Days 1 and 7. On Day 7, placebo-subtracted least-squares mean decreases in MPG0-24h ranged from 42-57 mg/dL with canagliflozin treatment. Adverse events (AEs) were balanced between treatments; no treatment-related serious AEs, AE-related discontinuations, or clinically meaningful adverse changes in routine safety evaluations occurred. The observed pharmacokinetic/pharmacodynamic profile of canagliflozin in subjects with type 2 diabetes supports a once-daily dosing regimen. PMID- 23670708 TI - Primary hyperparathyroidism in pregnancy. AB - Primary hyperparathyroidism (PHPT) is rarely diagnosed during pregnancy but is associated with significant maternal and fetal morbidity and mortality. Information on appropriate management is limited. We reviewed the medical literature through December 2012 for key articles on PHPT during pregnancy, focusing on large series. Clinical knowledge in this area is restricted to isolated case reports and a few retrospective studies. Diagnosis can be difficult, owing to the non-specific nature of signs and symptoms of hypercalcemia during pregnancy. Pregnant women with a calcium level over 2.85 mmol/L (11.4 mg/dL) and prior pregnancy loss are at a particularly high risk of maternal complications (hypercalcemic crisis, nephrolithiasis, pancreatitis, etc.) and fetal loss. Around one-half of neonates born to mothers with untreated PHPT have hypocalcemia and tetany. Algorithms proposed for the management of the pregnant woman with PHPT are not evidence based, reflecting the paucity of data. Treatment should thus be individually tailored. Gestational age and the severity of hypercalcemia should be taken into account when assessing the risk-benefit balance of a conservative approach (hyperhydration and vitamin D supplementation) versus parathyroid surgery. Current evidence supports parathyroidectomy as the main treatment, performed preferably during the second trimester, when the serum calcium is above 2.75 mmol/L (11 mg/dL). In the patients with mild forms of PHPT, which are nowadays the most frequent, a conservative management is generally preferred. PMID- 23670709 TI - Evaluation of thyroid diseases and differentiated thyroid cancer in acromegalic patients. AB - Thyroid diseases are frequently seen in patients with acromegaly. The aim of this study is to evaluate thyroid diseases and thyroid cancer in acromegalic patients followed in a single institution. The data of 92 acromegalic (43 male, 49 female) patients followed over 12 years were retrieved retrospectively from the hospital recordings. All available data for gender, age, body weight and height, duration of acromegaly, age at diagnosis of acromegaly, treatment methods for acromegaly and history of thyroid disease, serum GH, IGF-1, thyroid function tests, thyroid ultrasonography (US), thyroid scintigraphy and thyroid fine needle aspiration biopsy (FNAB) results were recorded for the patients. The mean age of the patients was 43.9 +/- 10.8 years and the mean disease duration was 12 +/- 6.9 years. Thyroid US was performed in 64 patients who had nodular or diffuse goiter on palpation during the post-treatment follow-up and nodules were found in 44 (47.8 %) patients. Final diagnosis in 64 patients with thyroid US results and thyroid function tests including 26 patients with FNAB were as follows: 31 (48.4 %) benign multinodular goiter (MNG), 6 (9.4 %) simple nodular goiter, 1 (1.6 %) toxic MNG, 1 (1.6 %) Hurthle cell adenoma, and 5 (7.8 %) differentiated thyroid cancer. In addition, 9 (14.1 %) patients had diffuse goiter. One of the patients with diffuse goiter had amiodarone induced thyrotoxicosis. Eleven (17.1 %) patients had normal thyroid US and no other thyroid disease. Patients with nodules had longer disease duration than patients without nodules (14.2 +/- 6.6 vs. 9.4 +/- 3.4 years, p = 0.043). Thyroid volume was positively correlated with post-treatment GH and post-treatment IGF-1 levels (r = 0.309, p = 0.041 and r = 0.423, p = 0.004), respectively. We found that 7.8 % of our acromegalic patients with thyroid US results were diagnosed with thyroid cancer. Therefore, acromegalic patients must be considered as a high risk group for the development of thyroid cancer and must be closely followed for thyroid nodules and tumors. PMID- 23670710 TI - How does antiretroviral treatment attenuate the stigma of HIV? Evidence from a cohort study in rural Uganda. AB - Program implementers and qualitative researchers have described how increasing availability of HIV antiretroviral therapy (ART) is associated with improvements in psychosocial health and internalized stigma. To determine whether, and through what channels, ART reduces internalized stigma, we analyzed data from 262 HIV infected, treatment-naive persons in rural Uganda followed from ART initiation over a median of 3.4 years. We fitted Poisson regression models with cluster correlated robust estimates of variance, specifying internalized stigma as the dependent variable, adjusting for time on treatment as well as socio-demographic, clinical, and psychosocial variables. Over time on treatment, internalized stigma declined steadily, with the largest decline observed during the first 2 years of treatment. This trend remained statistically significant after multivariable adjustment (chi(2) = 28.3; P = 0.03), and appeared to be driven by ART-induced improvements in HIV symptom burden, physical and psychological wellbeing, and depression symptom severity. PMID- 23670711 TI - Being unaware of being HIV-infected is associated with alcohol use disorders and high-risk sexual behaviors among men who have sex with men in Peru. AB - This study compared the correlates of HIV risk among men who have sex with men (MSM) with newly diagnosed versus previously known HIV infection among 5,148 MSM recruited using modified snowball sampling in 5 Peruvian cities. Participants, if age >=18 years and reporting sex with a male in the previous 12 months, underwent standardized computer-assisted risk assessments and HIV and syphilis testing. Overall, 420 (8.2 %) participants tested HIV seropositive, most of whom (89.8 %) were unaware of their HIV status. Compared to those who knew themselves to be HIV infected, multivariate logistic regression demonstrated that unprotected anal intercourse at last encounter [AOR = 2.84 (95 % CI 1.09-7.40)] and having an alcohol use disorder (AUD) [AOR = 2.14 (95 % CI 1.01-5.54)] were independently associated with a newly diagnosed HIV infection. Being unaware of being HIV infected was associated with high-risk sexual behaviors and AUDs, both of which are amenable to behavioral and medication-assisted therapy interventions. PMID- 23670713 TI - [Depression in late life - what does epidemiology add?]. PMID- 23670712 TI - Assembly of new Mo/Cu/S clusters from [Et4N][Tp*MoS(S4)] and Cu(I) salts: syntheses, structures and third-order nonlinear optical properties. AB - Reactions of [Et4N][Tp*MoS(S)4] (Tp* = hydridotris(3,5-dimethylpyrazol-1 yl)borate) (1) with 3 equiv. of CuX (X = Cl, Br, I, CN) or [Cu(MeCN)4]ClO4 in CH2Cl2-MeCN or CH2Cl2-DMF afforded [Et4N]2[Tp*Mo(MU3-S)3(CuCl)3(MU3-Cl)] (2), [Et4N][Tp*Mo(MU3-S)3(CuX)3] (3: X = Br; 4: X = I), [Et4N][Tp*MoO(MU-S)2(CuX)] (5: X = I; 6: X = CN) and [Tp*Mo(MU3-S)3Cu3(MU3-S')]4 (7). Compounds 2-7 were characterized by elemental analysis, IR spectra, UV-vis spectra, (1)H NMR, electrospray ion mass spectra (ESI-MS) and X-ray crystallography. The cluster dianion of 2 has a complete cubane-like [Tp*Mo(MU3-S)3(CuCl)3(MU3-Cl)] structure while the anion of 3 or 4 consists of an incomplete cubane-like [Tp*Mo(MU3 S)3(CuX)3] structure. The anion of 5 or 6 has a binuclear structure, in which one [Tp*MoO(MU-S)2] moiety and one CuX unit are linked by a pair of MU-S atoms. The structure of 7 may be considered as a supercube whose eight corners are occupied by four incomplete cubane-like [Tp*Mo(MU3-S)3Cu3] fragments and four MU3-S' atoms. The third-order nonlinear optical (NLO) properties of 2-6 in DMF were investigated by femtosecond degenerate four-wave mixing (DFWM) technique with a 80 fs pulse width at 800 nm. Compounds 2-6 exhibited good NLO performances and their NLO responses were enhanced relative to that of 1. PMID- 23670714 TI - [Prevalence of dementia and medical care in German nursing homes: a nationally representative survey]. AB - OBJECTIVE: The study aimed to determine the prevalence of dementia and the degree of medical care among residents of nursing homes based on a nationally representative sample of nursing homes in Germany for the first time. METHODS: Based on a probability sample of 609 long-term care institutions in Germany, we drew a sample of 86 facilities by applying a two-stage random procedure. All residents of the participating care facilities were comprehensively assessed by qualified nurses using a standardized Care and Behavior Assessment (CBA). RESULTS: Of the 4,481 residents assessed in 58 care facilities (mean age 82.6 years;78 % female) on average 68.6 % (95 % CI: 67.0 - 69.8) were affected by a dementia-syndrome, 56.6 % by a severe dementia-syndrome. There were frequent contacts between residents and general practitioners, but provision of specialized medical care seemed to be deficient in many aspects. CONCLUSION: People with dementia form the major group of residents in German nursing homes. The study provides important data on need for care and health care planning. PMID- 23670716 TI - [Reports from the Federal Conference of Directors. Association of Executive Physicians of Psychiatric and Psychotherapy Clinics]. PMID- 23670717 TI - Kruppel-like factor expression and correlation with FAK, MMP-9 and E-cadherin expression in hepatocellular carcinoma. AB - Whether a focal adhesion kinase (FAK)-Kruppel-like factor 8 (KLF8)-matrix metalloproteinase (MMP)-9/E-cadherin signaling axis exists in hepatocellular carcinoma (HCC) remains unknown. In the present study, KLF8 expression and its clinicopathological significance in HCC was investigated to determine the correlation between KLF8 and FAK, MMP-9 and E-cadherin expression. Tissues were obtained from 60 surgically resected HCC and normal tumor-adjacent tissues. KLF8, FAK, MMP-9 and E-cadherin expression levels were examined by quantitative real time reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry. In addition, KLF8, FAK, MMP-9 and E-cadherin protein expression levels were examined by western blot analysis in 5 portal vein cancer emboli and corresponding HCC tissues. The clinicopathological data of the HCC patients were retrospectively analyzed. KLF8 mRNA expression was found to be significantly upregulated in HCC tumor tissues compared with normal tumor adjacent tissues (P<0.05). KLF8 protein was highly expressed in portal vein cancer emboli. KLF8 expression level was significantly higher in tumors with advanced TNM stages and vascular invasion compared with that in tumors with early TNM stage and absence of vascular invasion (P<0.05). KLF8 protein and mRNA expression in HCC positively correlated with that of FAK (r=0.362, P<0.001; and r=0.377, P<0.01, respectively) and MMP-9 (r=0.392, P<0.01; and r=0.336, P<0.01, respectively), but negatively correlated with E-cadherin (r=-0.364, P<0.01; and r=-0.410, P<0.01, respectively). Results of the current study highlight a novel FAK-KLF8-MMP-9/E-cadherin signaling axis during HCC progression. PMID- 23670719 TI - Patient and family experiences of palliative care in hospital: what do we know? An integrative review. AB - BACKGROUND: In most developed countries, acute hospitals play a significant role in palliative care provision and are the setting in which most people die. They are often the setting where a life-limiting diagnosis is made and where patients present when symptoms develop or when they are not well managed. Understanding the experiences of hospital admissions for people with a life-limiting illness and their families is essential in understanding the role acute hospitals play in providing palliative care. AIM: The aim of this review is to synthesise current evidence regarding the experience of palliative care in an acute hospital setting from the perspectives of patient and family. DESIGN: An integrative review was completed using standard processes followed by a process of data extraction and synthesis. DATA SOURCES: Using predefined search terms, literature was sourced from five electronic databases including MEDLINE (EBSCO), CINAHL, EMBASE, Cochrane and PsycINFO between January 1990 and November 2011. Reference lists from relevant articles were cross-checked and pertinent journals hand searched for articles. RESULTS: In total, 32 articles were included in the review. Five recurring themes were identified from the synthesised data: symptom control and burden, communication with health professionals, decision-making related to patient care and management, inadequate hospital environment and interpersonal relationships with health professionals. CONCLUSION: This review has identified that, largely as a result of study design, our knowledge of patient and family experiences of palliative care in an acute hospital remains limited to discrete aspects of care. Further research is required to explore the total patient and family experience taking into account all aspects of care including the potential benefits of hospital admissions in the last year of life. PMID- 23670718 TI - A multicenter survey of Hispanic caregiver preferences for patient decision control in the United States and Latin America. AB - BACKGROUND: Understanding family caregivers' decisional role preferences is important for communication, quality of care, and patient and family satisfaction. The family caregiver has an important role in a patient's decisional role preferences. There are limited studies on family caregivers' preferences of the patient's decision control at the end of life among Hispanics. AIMS: To identify Hispanic caregivers' preferences of the decision control of patients with advanced cancer and to compare the preferences of caregivers in Hispanic Latin American and Hispanic American caregivers. DESIGN: We surveyed patients and their family caregivers referred to outpatient palliative care clinics in the United States, Chile, Argentina, and Guatemala. Caregiver preferences of patient's decision control were evaluated using the Control Preference Scale. Caregivers' and patients' sociodemographic variables, patient performance status, and Hispanic American patient acculturation level were also collected. PARTICIPANTS: A total of 387 caregivers were surveyed: 100 (26%) in Chile, 99 (26%) in Argentina, 97 (25%) in Guatemala, and 91 (24%) in the United States. The median age was 56 years, and 59% were female. RESULTS: Caregiver preference of patient's decision control was passive, shared, and active for 10 (11%), 45 (52%), and 32 (37%) Hispanic American caregivers and 54 (19%), 178 (62%), and 55 (19%) Hispanic Latin American caregivers (p = 0.0023), respectively. Caregiver acculturation level did not affect the preferences of the Hispanic American sample (p = 0.60). CONCLUSIONS: Most Hispanic family caregivers preferred the patient to make shared decisions. Hispanic Latin American caregivers more frequently preferred patients to assume a passive decisional role. Acculturation did not influence the preferences of Hispanic American caregivers. PMID- 23670720 TI - Exploring factors and caregiver outcomes associated with feelings of preparedness for caregiving in family caregivers in palliative care: a correlational, cross sectional study. AB - BACKGROUND: Family caregivers in palliative care often report feeling insufficiently prepared to handle the caregiver role. Preparedness has been confirmed as a variable that may actually protect family caregiver well-being. Preparedness refers to how ready family caregivers perceive they are for the tasks and demands in the caregiving role. AIM: The aim of this study was to explore factors associated with preparedness and to further investigate whether preparedness is associated with caregiver outcomes. DESIGN: This was a correlational study using a cross-sectional design. SETTING/PARTICIPANTS: The study took place in three specialist palliative care units and one haematology unit. A total of 125 family caregivers of patients with life-threatening illness participated. RESULT: Preparedness was significantly associated with higher levels of hope and reward and with a lower level of anxiety. In contrast, preparedness was not associated with depression or health. Being female and cohabiting with the patient were significantly associated with a higher level of preparedness. The relationship to the patient was significantly associated with preparedness, while social support, place of care, time since diagnosis and age of the patients showed no association. CONCLUSION: Feelings of preparedness seem to be important for how family caregivers experience the unique situation when caring for a patient who is severely ill and close to death. Our findings support the inclusion of preparedness in support models for family caregivers in palliative care. Psycho-educational interventions could preferably be designed aiming to increase family caregiver's preparedness to care, including practical care, communication and emotional support. PMID- 23670721 TI - What do patients with advanced incurable cancer want from the management of their pain? A qualitative study. AB - BACKGROUND: Pain is one of the most frequent symptoms among patients with metastatic cancer, yet little is known about what patients with advanced cancer want from the management of their pain. Measuring the effectiveness of the management of pain is challenging as it is a subjective phenomenon and a multifaceted process. Determining how we currently define whether a patient with pain due to advanced cancer has controlled pain (or not) is important, particularly from the patient's perspective. AIM: To explore how patients with advanced cancer describe the control of pain and what they want from management of this pain. DESIGN: Qualitative study using face-to-face interviews. Data were analysed using a constant comparison approach. SETTING/PARTICIPANTS: Purposive sample of patients with advanced cancer known to palliative care services. RESULTS: Twelve interviews took place until saturation of data was achieved. Four themes emerged: maintaining role, self and independence; compromising/modifying expectations; role of healthcare professionals; and meaning of pain in context of advanced cancer. CONCLUSION: Patients determined whether their pain was 'controlled' by whether or not they were able to perform activities or tasks and maintain relationships with family or friends, which determined themselves as individuals. Numerical rating scales did not appear to be useful for patients in measuring whether they are able to perform these activities or maintain a sense of control and independence. Individualised goal/task/role/activity setting for patients with advanced cancer pain may be useful to allow patients themselves to determine what they want from the 'management' of their pain. PMID- 23670722 TI - Interrupting gel layer between Double cuffs prevents fluid leakage past tracheal tube cuffs. AB - BACKGROUND: Current tracheal tubes (TTs) cannot guarantee a perfect seal against pulmonary aspiration of upper airway secretions. The purpose of this study was to investigate whether a gel layer between the tracheal tube with double cuffs (Double cuffs) prevents fluid leakage past TT cuffs. METHODS: In vitro fluid leakage tests were performed using the Double cuff with or without a gel layer between the two cuffs and four commercially available TTs (Euromedical Standard TT, Mallinckrodt Hi-LoTM, Microcuff, and Mallinckrodt TaperGuardTM) when placed in artificial tracheas with three-different internal diameters (ID; 16, 20, and 22 mm). Blue-dyed water (5 ml) was placed above the cuff, and the extent of fluid leakage was observed for 48 h. Each test was repeated five times with new tubes at six different intracuff pressures (15, 20, 25, 30, 40, and 50 cm H2O). RESULTS: In all of the conventional TTs and the Double cuff without a gel layer, fluid leakage was observed even at clinically acceptable intracuff pressures (25 30 cm H2O). However, in the Double cuff with a gel layer, no fluid leakage was observed for 48 h at all intracuff pressures in three-different sized artificial tracheas. At an intracuff pressure of 20 cm H2O in a 20 mm ID trachea, the average volume of injected gel was 2.0 ml. After removal of the TT, the mean volume of the remaining gel in the trachea was 0.10 ml. CONCLUSIONS: A prototype TT with gel-layered Double cuffs completely blocked fluid leakage past the cuffs for 48 h in a bench-top model. Clinical studies are required to determine whether this TT reduces the risk of ventilator-associated pneumonia. PMID- 23670724 TI - Long-term proton pump inhibitor use is associated with vascular calcification in chronic kidney disease: a cross-sectional study using propensity score analysis. AB - BACKGROUND: Proton pump inhibitors (PPIs) are a class of drugs that is extensively used for common gastrointestinal disorders and often prescribed long term for years. Long-term PPI treatment is associated with an increased risk of fractures in the general population. Several studies have suggested a relationship between vascular calcification, which is a predictor of cardiovascular morbidity and mortality, impaired bone metabolism and fractures. In dialysis patients, vascular calcifications are widespread and are connected to bone health. OBJECTIVE: The aim of this study was to assess the association between the use of PPIs and vascular calcifications involving the aorta and iliac arteries in haemodialysis patients. METHODS: Between November 2008 and November 2009, 387 patients receiving long-term dialysis treatment (>=1 year) were enrolled in a multicentre (18 Dialysis Units), cross-sectional study. Overall, 76.2 % of patients were receiving long-term PPI treatment. The main outcome measure was calcification of the aorta and iliac arteries in relation to PPI use. Standardized radiographs were sent to the coordinating centre for centralized evaluation in duplicate by two physicians who were blind to PPI status. RESULTS: Arterial calcifications were significantly more common in the PPI group (p < 0.01). Also, the rates of aortic and iliac calcifications considered separately were higher (+12.2 %, p = 0.0254; and +13.6 %, p = 0.0211, respectively). After correction for the propensity score, the odds ratios [ORs] (95 % CI) related to PPI use were aorta 1.89 (1.01-3.54), p = 0.048; iliac arteries 2.27 (1.31-3.92), p = 0.003; aorta and iliac arteries 2.59 (1.48-4.53), p = 0.008. The ORs (95 % CI) related to the association of warfarin + PPI were aorta 2.19 (0.95-5.00), p = 0.06; iliac arteries 2.90 (1.07-7.86), p = 0.036; aorta and iliac arteries 2.69 (1.03-6.96), p = 0.042. CONCLUSION: In haemodialysis patients, long-term treatment with PPIs, especially in the presence of warfarin treatment, is associated with vascular calcifications. PMID- 23670723 TI - Assessment of case definitions for identifying acute liver injury in large observational databases. AB - BACKGROUND: Determining the aetiology of acute liver injury (ALI) may be challenging to both clinicians and researchers. Observational research is particularly useful in studying rare medical outcomes such as ALI; however, case definitions for ALI in previous observational studies lack consistency and sensitivity. ALI is a clinically important condition with various aetiologies, including drug exposure. OBJECTIVE: The aim of this study was to evaluate four distinct case definitions for ALI across a diverse set of large observational databases, providing a better understanding of ALI prevalence and natural history. DATA SOURCES: Seven healthcare databases: GE Healthcare, MarketScan((r)) Lab Database, Humana Inc., Partners HealthCare System, Regenstrief Institute, SDI Health (now IMS Health, Inc.), and the National Patient Care Database of the Veterans Health Administration. METHODS: We evaluated prevalence of ALI through the application of four distinct case definitions across seven observational healthcare databases. We described how laboratory and clinical characteristics of identified case populations varied across definitions and examined the prevalence of other hepatobiliary disorders among identified ALI cases that may decrease suspicion of drug-induced liver injury (DILI) in particular. RESULTS: This study demonstrated that increasing the restrictiveness of the case definition resulted in fewer cases, but greater prevalence of ALI clinical features. Considerable heterogeneity in the frequency of laboratory testing and results observed among cases meeting the most restrictive definition suggests that the clinical features, monitoring patterns and suspicion of ALI are highly variable among patients. CONCLUSIONS: Creation of four distinct case definitions and application across a disparate set of observational databases resulted in significant variation in the prevalence of ALI. A greater understanding of the natural history of ALI through examination of electronic healthcare data can facilitate development of reliable and valid ALI case definitions that may enhance the ability to accurately identify associations between ALI and drug exposures. Considerable heterogeneity in laboratory values and frequency of laboratory testing among individuals meeting the criteria for ALI suggests that the evaluation of ALI is highly variable. PMID- 23670725 TI - The role of religion in the work lives and coping strategies of Ugandan nurses. AB - Nursing in Uganda is a highly stressful, underpaid profession, leading to worrisome attrition levels; yet some nurses do manage to stay on the job and thrive. This study explored the ways in which religion influences the work lives and coping strategies of Ugandan nurses who thrive despite job stress. Participants were 15 female nurses working in faith-based and non-faith-based facilities in Uganda. The nurses were all actively religious people, a fact not known at the time they were recruited. All the nurses revealed that religious values affected their performance positively, enabling them to find meaning even in the face of adversity. PMID- 23670726 TI - Left ventricular ejection time in acute heart failure complicating precapillary pulmonary hypertension. AB - BACKGROUND: Novel noninvasive tools may improve the management of patients with pulmonary hypertension (PH) experiencing heart failure. Major right ventricle overload leads to decreased stroke volume, which shortens left ventricular ejection time (LVET). Our arterial tonometry study tested the hypothesis that LVET carries prognostic value in patients with precapillary PH with heart failure. METHODS: Clinical, biologic, and radial artery tonometry variables were prospectively obtained at admission and at day 3 to 5 in 53 consecutive patients with PH admitted to our ICU for clinical deterioration. LVET was measured from the reconstructed aortic pressure curve. RESULTS: Overall ICU mortality (median stay, 5 days) was 17%. At admission, the LVET was shorter in patients with unfavorable outcome (median, 228 milliseconds [25th-75th percentiles, 212-278 milliseconds] vs 257 milliseconds [237-277 milliseconds], P = .032), whereas other tonometric indices were similar. The LVET at entry (237 milliseconds) had 73% sensitivity and 89% specificity for identifying death in the ICU. Other prognostic factors at admission were higher serum levels of brain natriuretic peptide (BNP) and creatinine and lower natremia. Dobutamine requirement, higher furosemide dose, and higher oxygen flow were associated with unfavorable outcome. At the second evaluation, higher serum levels of creatinine and BNP, higher furosemide dose and oxygen flow, and dobutamine or norepinephrine requirement were associated with poor outcome. The change in LVET between admission and follow-up measurement was not associated with outcome. The 90-day mortality was 28%. CONCLUSIONS: Shortened LVET at ICU admission was a prognostic factor in patients with precapillary PH with heart failure. Previously documented prognostic factors were also confirmed in this cohort. PMID- 23670727 TI - Can we identify predictive biomarkers for antiangiogenic therapy of cancer using mathematical modeling? PMID- 23670729 TI - Structure-based engineering of streptavidin monomer with a reduced biotin dissociation rate. AB - We recently reported the engineering of monomeric streptavidin, mSA, corresponding to one subunit of wild type (wt) streptavidin tetramer. The monomer was designed by homology modeling, in which the streptavidin and rhizavidin sequences were combined to engineer a high affinity binding pocket containing residues from a single subunit only. Although mSA is stable and binds biotin with nanomolar affinity, its fast off rate (koff ) creates practical challenges during applications. We obtained a 1.9 A crystal structure of mSA bound to biotin to understand their interaction in detail, and used the structure to introduce targeted mutations to improve its binding kinetics. To this end, we compared mSA to shwanavidin, which contains a hydrophobic lid containing F43 in the binding pocket and binds biotin tightly. However, the T48F mutation in mSA, which introduces a comparable hydrophobic lid, only resulted in a modest 20-40% improvement in the measured koff . On the other hand, introducing the S25H mutation near the bicyclic ring of bound biotin increased the dissociation half life (t1/2 ) from 11 to 83 min at 20 degrees C. Molecular dynamics (MD) simulations suggest that H25 stabilizes the binding loop L3,4 by interacting with A47, and protects key intermolecular hydrogen bonds by limiting solvent entry into the binding pocket. Concurrent T48F or T48W mutation clashes with H25 and partially abrogates the beneficial effects of H25. Taken together, this study suggests that stabilization of the binding loop and solvation of the binding pocket are important determinants of the dissociation kinetics in mSA. PMID- 23670730 TI - Iron(III) triflimide as a catalytic substitute for gold(I) in hydroaddition reactions to unsaturated carbon-carbon bonds. AB - In this work it is shown that iron(III) and gold(I) triflimide efficiently catalyze the hydroaddition of a wide array of nucleophiles including water, alcohols, thiols, amines, alkynes, and alkenes to multiple C-C bonds. The study of the catalytic activity and selectivity of iron(III), gold(I), and Bronsted triflimides has unveiled that iron(III) triflimide [Fe(NTf2)3] is a robust catalyst under heating conditions, whereas gold(I) triflimide, even stabilized by PPh3, readily decomposes at 80 degrees C and releases triflimidic acid (HNTf2) that can catalyze the corresponding reaction, as shown by in situ (19)F, (15)N, and (31)P NMR spectroscopy. The results presented here demonstrate that each of the two catalyst types has weaknesses and strengths and complement each other. Iron(III) triflimide can act as a substitute of gold(I) triflimide as a catalyst for hydroaddition reactions to unsaturated carbon-carbon bonds. PMID- 23670728 TI - Effect of tumor microenvironment on tumor VEGF during anti-VEGF treatment: systems biology predictions. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) is known to be a potent promoter of angiogenesis under both physiological and pathological conditions. Given its role in regulating tumor vascularization, VEGF has been targeted in various cancer treatments, and anti-VEGF therapy has been used clinically for treatment of several types of cancer. Systems biology approaches, particularly computational models, provide insight into the complexity of tumor angiogenesis. These models complement experimental studies and aid in the development of effective therapies targeting angiogenesis. METHODS: We developed an experiment based, molecular-detailed compartment model of VEGF kinetics and transport to investigate the distribution of two major VEGF isoforms (VEGF121 and VEGF165) in the body. The model is applied to predict the dynamics of tumor VEGF and, importantly, to gain insight into how tumor VEGF responds to an intravenous injection of an anti-VEGF agent. RESULTS: The model predicts that free VEGF in the tumor interstitium is seven to 13 times higher than plasma VEGF and is predominantly in the form of VEGF121 (>70%), predictions that are validated by experimental data. The model also predicts that tumor VEGF can increase or decrease with anti-VEGF treatment depending on tumor microenvironment, pointing to the importance of personalized medicine. CONCLUSIONS: This computational study suggests that the rate of VEGF secretion by tumor cells may serve as a biomarker to predict the patient population that is likely to respond to anti-VEGF treatment. Thus, the model predictions have important clinical relevance and may aid clinicians and clinical researchers seeking interpretation of pharmacokinetic and pharmacodynamic observations and optimization of anti-VEGF therapies. PMID- 23670731 TI - [Precancerous conditions]. PMID- 23670732 TI - [Monoclonal gammopathy of undetermined significance and monoclonal B lymphocytosis]. AB - Monoclonal gammopathy of undetermined significance (MGUS) and monoclonal B lymphocytosis (MBL) are asymptomatic premalignant conditions which can progress to a symptomatic disease state requiring therapy. Considering the high prevalence rate of these disorders, precursor patients are often diagnosed during routine clinical examinations. Only a minor portion of cases progress to overt malignancies, which raises the question of how to identify patients with the probability of progression. In recent years improvements in the understanding of the pathogenesis of both disorders led to the development of risk models and the estimation of the individual risk of progression. The definition of high-risk and low-risk patients allows a tailored clinical management. This report provides information on the biology, risk stratification, diagnosis, and follow-up of patients with MGUS and MBL. PMID- 23670733 TI - A gold-gold oil microtrench electrode for liquid-liquid anion transfer voltammetry. AB - Two flat gold electrodes are placed vis-a-vis with an epoxy spacer layer that is etched out to give a ca. 100 MUm-deep electrochemically active trench. A water insoluble oil phase, here the redox system N,N-diethyl-N'N'-didodecyl phenylenediamine (DDPD) in 4-(3-phenylpropyl)-pyridine (PPP), is immobilized into the trench to allow anion transfer upon oxidation of DDPD (oil) to DDP+ (oil). In "mono-potentiostatic mode" quantitative transfer/expulsion of anions into the trench oil phase occurs. However, in "bi-potentiostatic mode" feedback currents dominated by rapid plate-to-plate diffusion normal to the electrode surfaces are observed. Comparison of "normal" diffusion and "lateral" diffusion shows that the rate of diffusion-migration charge transport across the oil film is anion hydrophobicity dependent. PMID- 23670734 TI - [Lymphadenopathy: demarcation to malignant lymphomas]. AB - Recognition of the differential diagnosis between lymphadenitis and malignant lymphoma requires good knowledge of the basic forms of the disease as well in depth knowledge of the structure of the individual compartments. There are defined forms of lymphadenitis where the differential diagnosis to certain lymphoma entities is known. Other reactive structural alterations show indistinct limits so that a decision is only possible after using additional techniques, such as immunohistochemistry and molecular analyses. Finally, there are marginal areas which can only be clarified by including clinical data. PMID- 23670739 TI - Hepatocyte composition-based model as a mechanistic tool for predicting the cell suspension: aqueous phase partition coefficient of drugs in in vitro metabolic studies. AB - This study is an extension of a previously published microsome composition-based model by Poulin and Haddad (Poulin and Haddad. 2011. J Pharm Sci 100:4501-4517), which was converted to the hepatocyte composition-based model. The first objective was to investigate the ability of the composition-based model to predict nonspecific binding of drugs in hepatocytes suspended in the incubation medium in in vitro metabolic studies. The hepatocyte composition-based model describes the cell suspension-aqueous phase partition coefficients, which were used to estimate fraction unbound in the incubation medium (fuinc ) for each drug. The second objective was to make a comparative analysis between the proposed hepatocyte composition-based model and an empirical regression equation published in the literature by Austin et al. (Austin RP, Barton P, Mohmed S, Riley RJ. 2004. Drug Metab Dispos 33:419-425). The assessment was confined by the availability of experimentally determined in vitro fuinc values at diverse hepatocyte concentrations for 92 drugs. The model that made use of hepatocyte composition data provides comparable or superior prediction performance compared with the regression equation that relied solely on physicochemical data; therefore, this demonstrates the ability of predicting fuinc also based on mechanisms of drug tissue distribution. The accuracy of the predictions differed depending on the class of drugs (neutrals vs. ionized drugs) and species (rat vs. human) for each method. This study for hepatocytes corroborates a previous study for microsomes. Overall, this work represents a significant first step toward the development of a generic and mechanistic calculation method of fuinc in incubations of hepatocytes, which should facilitate rational interindividual and interspecies extrapolations of fuinc by considering differences in lipid composition of hepatocytes, for clearance prediction in the physiologically-based pharmacokinetics (PBPK) models. PMID- 23670740 TI - Wrong site surgery in otolaryngology-head and neck surgery. AB - OBJECTIVES/HYPOTHESIS: Wrong site surgery has received high public awareness this past decade, yet discussion specific to otolaryngology is limited. STUDY DESIGN: Literature review. METHODS: We searched the MEDLINE database on PubMed from 1980 to 2013 and pursued the citations of key references further. We conducted a review of the literature and public patient safety reports on the scope, root causes, and prevention of wrong site surgery with emphasis on otolaryngology. RESULTS: A review of the literature reveals that otolaryngology procedures constitute 0.3% to 4.5% of all wrong site surgery events, and wrong site surgery accounts for 4% to 6% of all medical errors in otolaryngology. A significant proportion (9% to 21%) of otolaryngologists reported experiences with wrong site surgery over their career, and the events most frequently resulted in temporary injuries to the patient with few cases of permanent disability or death. Although otolaryngology procedures have similar root causes for wrong site events as other specialties, inverted imaging and ambiguity in site marking are particular challenges. Site-marking practices are variable among otolaryngologists, as it is not applicable to many otolaryngology procedures, yet these are common procedures that also constitute the majority of wrong site cases reported in otolaryngology. CONCLUSIONS: Future interventions to address these challenges related to otolaryngology-head and neck surgery might involve a standardized protocol to confirm imaging accuracy, a specialty- or procedure-specific checklist, a standardized alternative to site marking when marking is impractical, and other innovations. Evaluation of these interventions is becoming easier given the increasing mandatory reporting of these events that provides more reliable incidence data. PMID- 23670741 TI - Combined laparoscopic and endoscopic excision of a gastric gist. PMID- 23670742 TI - Single-Access Fetal Endoscopy (SAFE) for myelomeningocele in sheep model I: amniotic carbon dioxide gas approach. AB - BACKGROUND: This study aimed to assess the feasibility of single-access fetal endoscopy (SAFE) for the management of myelomeningocele (MMC) using intrauterine carbon dioxide as a distension medium in a sheep model. METHODS: This prospective experimental case-control study investigated 12 lamb fetuses that had a myelomeningocele-like defect surgically created on the 75th day of gestation. Four fetuses remained untreated (control group), and eight fetuses had MMC repair using two fetoscopic approaches with carbon dioxide used to distend the amniotic cavity. A collagen patch was placed over the defect and secured with surgical sealant. Four animals had a two-port fetoscopic procedure, and four animals had SAFE. Clinical and pathologic studies were performed after delivery. RESULTS: This study confirmed the validity of the animal MMC model. None of the control animals was able to stand or walk, and all had a significant defect in the lumbar area with continuous leakage of cerebrospinal fluid, ventriculomegaly, and a Chiari-II malformation. All the treated animals, independently of the number of ports used in the repair, were able to walk and had a closed defect with resolution of the Chiari malformation. CONCLUSIONS: The SAFE patch and glue coverage of surgically created fetal MMC is feasible and effective in restoring gross neurologic function in the fetal lamb model. PMID- 23670743 TI - Laparoscopic gastrointestinal anastomoses using knotless barbed sutures are safe and reproducible: a single-center experience with 201 patients. AB - BACKGROUND: Intestinal anastomosis is a complex procedure during laparoscopy, mainly due to the difficulties knotting the sutures. Unidirectional barbed sutures have been proposed to simplify wall and mesentery closure, but the results for intestinal anastomosis are not clear. This study aimed to establish the feasibility and the safety of laparoscopic intestinal anastomosis using barbed suture. METHODS: Between June 2011 and May 2012, 15-cm-long unidirectional absorbable barbed sutures (V-Loc; Covidien, Mansfield, MA, USA) were used for all laparoscopic intestinal anastomoses: one suture for closure of intestinal openings after mechanical anastomoses and two sutures for hand-sewn anastomoses. RESULTS: Over a 1-year period, 201 consecutive patients required 220 laparoscopic anastomoses for gastrojejunostomy (n = 177; 172 during Roux-en-Y gastric bypass and 5 after gastrectomy), ileocolostomy (n = 15), colocolostomy (n = 1), esophagojejunostomy (n = 5), and jejunojejunostomy (n = 22; 4 after small bowel resection and 18 during gastric bypass or gastrectomy). Senior and training surgeons performed 209 closures of intestinal openings and 11 hand-sewn anastomoses. There was no conversion to usual sutures. One fistula occurred in an esophagojejunostomy and was managed conservatively. One self-limited anastomotic bleeding occurred, and no anastomotic stenosis occurred during 6 months of follow up evaluation. CONCLUSIONS: The use of knotless barbed suture for laparoscopic intestinal anastomosis is safe and reproducible. PMID- 23670744 TI - A prospective, randomized clinical comparison between UltraCision and the novel sealing and cutting device BiCision in patients with laparoscopic supracervical hysterectomy. AB - BACKGROUND: Various surgical procedures for hysterectomy exist; with laparoscopic supracervical hysterectomy (LASH) becoming an established option in recent years. Therefore, energy-based technologies for rapid tissue sealing and cutting are in the focus of surgeons. The aim of this trial was to prove or disprove investigated noninferiority of the novel device BiCision in comparison to the widely used UltraCision in a routine procedure ( www.clinicaltrials.gov ; study identifier NCT01806012). METHODS: Thirty LASH procedures were performed with UltraCision and BiCision after randomization of the preparation sides. The primary end point was the resection time per side and instrument. The instruments were also compared concerning blood loss and coagulation and cutting qualities as well as postoperative complications. The patients were followed for 3 months. RESULTS: Mean preparation time per side was 8.8 +/- 1.8 min for BiCision and 8.3 +/- 1.9 min for UltraCision (p = 0.31), which was not significantly different. Both instruments achieved complete transection without the need of additional cutting attempts. BiCision was significantly superior regarding the number of coagulations for complete hemostasis before and after the removal of the uterine corpus (before: 6.9 +/- 4.8 for BiCision and 8.6 +/- 4.1 for UltraCision, p = 0.047; after: 5.4 +/- 1.2 for BiCision and 8.6 +/- 3.2 for UltraCision, p < 0.0001) and intraoperative blood loss (score 1.07 +/- 0.25 for BiCision vs. 1.63 +/- 0.49 for UltraCision, p < 0.0001). Tissue sticking to the instrument occurred less often on the BiCision side (score 0.14 +/- 0.35 for BiCision vs. 0.60 +/- 0.81 for UltraCision, p = 0.015). BiCision showed a significantly better fixation of the tissue (grip score 0.23 +/- 0.43 for BiCision vs. 1.00 +/- 0.74 for UltraCision, p < 0.0001). No intraoperative or postoperative complications were seen for both instruments. CONCLUSIONS: The efficacy and quality of vessel sealing and cutting with BiCision is not inferior to the UltraCision device. Resection time was comparable, and complete hemostasis could be achieved faster in a clinical setting. Therefore, BiCision is at least as reliable as UltraCision for laparoscopic indications. PMID- 23670745 TI - Towards automated visual flexible endoscope navigation. AB - BACKGROUND: The design of flexible endoscopes has not changed significantly in the past 50 years. A trend is observed towards a wider application of flexible endoscopes with an increasing role in complex intraluminal therapeutic procedures. The nonintuitive and nonergonomical steering mechanism now forms a barrier in the extension of flexible endoscope applications. Automating the navigation of endoscopes could be a solution for this problem. This paper summarizes the current state of the art in image-based navigation algorithms. The objectives are to find the most promising navigation system(s) to date and to indicate fields for further research. METHODS: A systematic literature search was performed using three general search terms in two medical-technological literature databases. Papers were included according to the inclusion criteria. A total of 135 papers were analyzed. Ultimately, 26 were included. RESULTS: Navigation often is based on visual information, which means steering the endoscope using the images that the endoscope produces. Two main techniques are described: lumen centralization and visual odometry. Although the research results are promising, no successful, commercially available automated flexible endoscopy system exists to date. CONCLUSIONS: Automated systems that employ conventional flexible endoscopes show the most promising prospects in terms of cost and applicability. To produce such a system, the research focus should lie on finding low-cost mechatronics and technologically robust steering algorithms. Additional functionality and increased efficiency can be obtained through software development. The first priority is to find real-time, robust steering algorithms. These algorithms need to handle bubbles, motion blur, and other image artifacts without disrupting the steering process. PMID- 23670746 TI - Pilot study evaluating the efficacy of AlloMEMTM for prevention of intraperitoneal adhesions and peritoneal regeneration after loop ileostomy. AB - OBJECTIVE: This study was designed to evaluate the feasibility of AlloMEMTM, a novel lyophililzed human peritoneal membrane, at peritoneal reconstitution, and decreasing adhesion formation after temporary loop ileostomy. METHODS: In a pilot study, ten patients had AlloMEMTM used during elective formation of a temporary diverting loop ileostomy for benign or malignant colorectal disease. A blinded investigator and the operating surgeon analyzed the change in adhesion formation and peritoneal remodelling using ileostomy mobilization time and a 5-point adhesion scale grading intra-abdominally and at the subcutaneous and fascial levels. RESULTS: The mean body mass index was 31 [standard deviation (SD) 5.6], and 40 % of patients had previous abdominal surgery. Ileostomies were reversed after a mean 14 weeks (SD 6.0). The mean ileostomy mobilization time was 27.2 min (SD 12.0). From baseline to ileostomy reversal, there were significant increases in adhesions at the subcutaneous (p = 0.0002) and fascial levels (p = 0.0024). The increased subcutaneous adhesions were associated with improved peritoneal remodeling. There was no significant increase in adhesions from baseline to ileostomy reversal at the intra-abdominal points (p = 0.9393) or around the ileostomy site (p = 0.6128). The median hospital length of stay was 2.6 days (range, 2-3). A single adverse event related to product packaging led to redesign of the packaging process. CONCLUSIONS: Use of AlloMEMTM in ileostomy closures suggested improvement in adhesions around the fascia and promotion of peritoneal remodeling. AlloMEMTM was safe, feasible, and easy to use in this pilot study. Comparative research is needed to assess the outcomes with this novel product. PMID- 23670748 TI - Microscopic emission and reflectance thermal infrared spectroscopy: instrumentation for quantitative in situ mineralogy of complex planetary surfaces. AB - The diversity of investigations of planetary surfaces, especially Mars, using in situ instrumentation over the last decade is unprecedented in the exploration history of our solar system. The style of instrumentation that landed spacecraft can support is dependent on several parameters, including mass, power consumption, instrument complexity, cost, and desired measurement type (e.g., chemistry, mineralogy, petrology, morphology, etc.), all of which must be evaluated when deciding an appropriate spacecraft payload. We present a laboratory technique for a microscopic emission and reflectance spectrometer for the analysis of martian analog materials as a strong candidate for the next generation of in situ instruments designed to definitively assess sample mineralogy and petrology while preserving geologic context. We discuss the instrument capabilities, signal and noise, and overall system performance. We evaluate the ability of this instrument to quantitatively determine sample mineralogy, including bulk mineral abundances. This capability is greatly enhanced. Whereas the number of mineral components observed from existing emission spectrometers is high (often >5 to 10 depending on the number of accessory and alteration phases present), the number of mineral components at any microscopic measurement spot is low (typically <2 to 3). Since this style of instrument is based on a long heritage of thermal infrared emission spectrometers sent to orbit (the thermal emission spectrometer), sent to planetary surfaces [the mini-thermal emission spectrometers (mini-TES)], and evaluated in laboratory environments (e.g., the Arizona State University emission spectrometer laboratory), direct comparisons to existing data are uniquely possible with this style of instrument. The ability to obtain bulk mineralogy and atmospheric data, much in the same manner as the mini-TESs, is of significant additional value and maintains the long history of atmospheric monitoring for Mars. Miniaturization of this instrument has also been demonstrated, as the same microscope objective has been mounted to a flight-spare mini-TES. Further miniaturization of this instrument is straightforward with modern electronics, and the development of this instrument as an arm-mounted device is the end goal. PMID- 23670747 TI - Real-time near-infrared fluorescent cholangiography could shorten operative time during robotic single-site cholecystectomy. AB - BACKGROUND: With the introduction of a new platform, robotic single-site cholecystectomy (RSSC) has been reported as feasible and safe for selected cases. In parallel, the development of real-time near-infrared fluorescent cholangiography using indocyanine green (ICG) has been seen as a help during the dissection, even if the data are still preliminary. The study purpose is to report our experience with ICG RSSC and compare the outcomes to standard RSSC. METHODS: From February 2011 to December 2011, 44 selected patients underwent RSSC for symptomatic cholelithiasis. Among them, 23 (52.3%) were included in an experimental protocol using the ICG, and the remainder (47.7%) underwent standard RSSC. There was no randomization. The endpoints were the perioperative outcomes. This is a prospective study, approved by our local Ethics Committee. RESULTS: There were no differences in terms of patients' characteristics, except that there were more male patients in the ICG group (47.8 vs. 9.5%; p = 0.008). Regarding the surgical data, the overall operative time was shorter for the ICG group, especially for patients with a body mass index (BMI) <=25 (-24 min) but without reaching statistical significance (p = 0.06). For BMI >25, no differences were observed. Otherwise, there were no differences in terms of conversion, complications, or length of stay between both groups. CONCLUSIONS: A RSSC with a real-time near-infrared fluorescent cholangiography can be performed safely. In addition, for selected patients with a low BMI, ICG could shorten the operative time during RSSC. Larger studies are still required before drawing definitive conclusions. PMID- 23670749 TI - Dielectrically embedded flat mesh lens for millimeter waves applications. AB - A flat lens based on subwavelength periodic metal meshes has been developed using photolithographic techniques. These mesh grids are stacked at specific distances and embedded in polypropylene. A code was developed to optimize more than 1000 transmission line circuits required to vary the device phase shift across the lens flat surface, mimicking the behavior of a classical lens. A W-band mesh-lens prototype was successfully manufactured and its RF performance characterized using a vector network analyzer coupled to corrugated horn antennas. Co polarization far-field beam patterns were measured and compared with finite element method models. The excellent agreement between data and simulations validated our designing tools and manufacturing procedures. This mesh lens is a low-loss, robust, light, and compact device that has many potential applications including millimeter wave quasi-optical systems for future cosmic microwave background polarization instruments. PMID- 23670750 TI - Method to intercalibrate sunphotometer constants using an integrating sphere as a light source in the laboratory. AB - A calibration method is introduced to transfer calibration constants from the reference to secondary sunphotometers using a laboratory integrating sphere as a light source, instead of the traditional transferring approach performed at specific calibration sites based on sunlight. The viewing solid angle and spectral response effects of the photometer are taken into account in the transfer, and thus the method can be applied to different types of sunphotometers widely used in the field of atmospheric observation. A laboratory experiment is performed to illustrate this approach for four types of CIMEL CE318 sunphotometers belonging to the aerosol robotic network (AERONET). The laboratory calibration method shows an average difference of 1.4% from the AERONET operational calibration results, while a detailed error analysis suggests that the uncertainty agrees with the estimation and could be further improved. Using this laboratory calibration approach is expected to avoid weather influences and decrease data interruption due to operationally required periodic calibration operations. It also provides a basis for establishing a network including different sunphotometers for worldwide aerosol measurements, based on a single standard calibration reference. PMID- 23670751 TI - Dual-field-of-view Raman lidar measurements for the retrieval of cloud microphysical properties. AB - Dual-field-of-view Raman lidar measurements, detecting Raman-scattered light with two fields of view simultaneously, are used for the first time to retrieve cloud microphysical properties. The measurements are performed with the Multiwavelength Atmospheric Raman Lidar for Temperature, Humidity, and Aerosol Profiling (MARTHA) at the Leibniz Institute for Tropospheric Research in Leipzig, Germany. Light that is scattered in forward direction by cloud droplets and inelastically backscattered by N2 molecules is detected. A forward iterative algorithm uses the measured signals to derive profiles of the effective cloud droplet radius, extinction coefficient, and liquid-water content of the investigated clouds. The setup, algorithm, error analysis, and a measurement example are presented. The obtained liquid-water path is validated by observations with a microwave radiometer. With the capability to retrieve aerosol properties as well as cloud microphysical properties, the Raman lidar MARTHA is an ideal tool for studies of the aerosol indirect effect. PMID- 23670752 TI - Complete optical throughput analysis of the static polarization wind imaging interferometer. AB - The basic principle of the static polarization wind imaging interferometer (SPWII) is expounded in this paper. By using trigonometric function and complex amplitude methods, the complex vibration amplitude of each polarization device with deviation from its ideal direction is calculated. The variations of the fringe visibility and optical throughput with deviation angles are given analytically and simulated numerically. According to the design parameters of the SPWII, the air-equivalent length L is equal to 16.14 cm and the total transmissivity is greater than 0.4. When the polarization directions of each polarization device are all in the ideal directions, the total optical throughput can be maintained at about 16.4% of the incident optical intensity. When the polarization directions of each polarization device are all 2 degrees deviated from the ideal positions, the total optical throughput is decreased by 0.08%. This work would be useful for the realization and data processing of the SPWII. PMID- 23670753 TI - Multivariate approach for the retrieval of phytoplankton size structure from measured light absorption spectra in the Mediterranean Sea (BOUSSOLE site). AB - Models based on the multivariate partial least squares (PLS) regression technique are developed for the retrieval of phytoplankton size structure from measured light absorption spectra (BOUSSOLE site, northwestern Mediterranean Sea). PLS models trained with data from the Mediterranean Sea showed good accuracy in retrieving, over the nine-year BOUSSOLE time series, the concentrations of total chlorophyll a [Tchl a], of the sum of seven diagnostic pigments and of pigments associated with micro, nano, and picophytoplankton size classes separately. PLS models trained using either total particle or phytoplankton absorption spectra performed similarly, and both reproduced seasonal variations of biomass and size classes derived by high performance liquid chromatography. Satisfactory retrievals were also obtained using PLS-models trained with a data set including various locations of the world's oceans, with however a lower accuracy. These results open the way to an application of this method to absorption spectra derived from hyperspectral and field satellite radiance measurements. PMID- 23670754 TI - Theory of phase locking of Gaussian beam amplifier array based on multidithering technique. AB - The theory of phase locking of a Gaussian beam amplifier array based on the multidithering technique is presented and developed in detail. The role and importance of the pinhole in the coherent beam combination (CBC) system, which had been unsolved for a long time, have been studied in detail. The effects of the size and position of the pinhole on CBC are analyzed based on this theory. PMID- 23670755 TI - Broadband tunable single-frequency Nd:YVO4/LBO green laser with high output power. AB - We present a diode-pumped broadband tunable single-frequency and frequency doubling Nd:YVO4/LBO laser with high output power of 10.5 W in all tuning ranges around 532 nm. An etalon placed inside the resonator and the laser gain medium in a wedge shape are used for the coarse- and fine-tuning elements, respectively. By independently scanning the temperatures of the two tuning elements, broadband tunable ranges of 12 and 24 GHz have been achieved, respectively, for the fundamental and the second-harmonic waves. PMID- 23670756 TI - Three-bit representation of three-dimensional range data. AB - Our previous research has shown that 3D range data sizes can be substantially reduced if they are converted into regular 2D images using the Holoimage technique. Yet, this technique requires all 24 bits of a standard image to represent one 3D point, making it impossible for a regular 2D image to carry 2D texture information as well. This paper proposes an approach to represent 3D range data with 3 bits, further reducing the data size. We demonstrate that more than an 8.2:1 compression ratio can be achieved with compression root-mean-square error of only 0.34%. Moreover, we can use another bit to represent a black-and white 2D texture, and thus both 3D data and 2D texture images can be stored into an 8 bit grayscale image. Both simulation and experiments are presented to verify the performance of the proposed technique. PMID- 23670757 TI - Method to design two aspheric surfaces for imaging system. AB - This paper proposes a method of designing two aspheric surfaces simultaneously for an imaging system. By coupling the three rays (two marginal rays and one chief ray from the exit pupil) of each field of view to their corresponding image point, microspherical lens corresponding to each field of view can be obtained by the refraction law. Profiles of the aspheric surfaces can be obtained by employing the position and normal vector of midpoint of the microsphere corresponding to each field of view. Theoretically, through this method, we can realize any mapping relationship between the object points and their image points in 2D. Combining an original projector with the aspheric lens designed in this paper, an example that realizes projection onto a spherical surface with both low distortion and high image quality is presented. PMID- 23670758 TI - Experimental results of revised Misell algorithm for imaging through weakly scattering biological tissue. AB - A Static random perturbation weakly scattering media may significantly reduce image quality, in many kinds of applications. An example of such a medium can be a soft tissue such as skin or flesh, through which one may wish to image an object, such as a bone, located behind. In this paper we present experimental results of newly developed deblurring approach for obtaining a better image of objects positioned behind static random perturbation media. This approach for extraction of the high spatial frequencies is based on iterative computation similar to the well-known Gerchberg-Saxton algorithm for phase retrieval. By focusing a camera onto three or more planes positioned between the imaging camera and the perturbation media, we are able to retrieve the phase distribution of those planes and then reconstruct the intensity of the object by numerical free space propagation of this extracted complex field, to the estimated position of the object. PMID- 23670759 TI - Coherent two-beam interference fringe projection for highspeed three-dimensional shape measurements. AB - Two-beam interference is a fundamental and well-understood approach to create Fizeau's interference fringes. With a Mach-Zehnder interferometer, we utilize these two-beam interference Fizeau fringes for three-dimensional (3D) shape measurements. By introducing an acousto-optical deflector the phase of the interference fringes can be shifted with a rate of up to 200,000 Hz. When used in conjunction with highspeed cameras, this stereo-photogrammetric approach performs well for highspeed applications in comparison with the commonly used digital light processing projectors for stripe projection. Maximum speed and the achievable accuracy are discussed. Experiments and media substantiate the suitability, accuracy, and speed of this technique for very fast 3D shape measurements. PMID- 23670760 TI - Design and fabrication of a diffractive optical element as a spectrum-splitting solar concentrator for lateral multijunction solar cells. AB - We have designed a single thin planar diffractive optical element (DOE) based on the principle of diffractive optics to simultaneously split and concentrate the incident light into several energy ranges for lateral multijunction solar cells. A prototype with the maximum thickness of 6.95 MUm and 32 quantized levels in depth was fabricated by photolithographic technology. The spectrum-splitting and concentrating performance of the prototype, which were measured quantitatively, show good agreement with the simulation results. As mass production of a DOE can be produced by imprint technology, our design provides a feasible means for low cost, large-scale, and high-efficiency photovoltaic applications. PMID- 23670761 TI - Absolute self-calibrated room-temperature terahertz powermeter. AB - Coupling optical and thermal properties of a terahertz (THz) thermal converter based on the Seebeck effect provides an unsupplied room-temperature measuring device dedicated to THz power metrology. Performance characteristics such as broadband response (0-30 THz), high sensitivity (<25 MUW.Hz(-0.5)), and the possibility to develop an internal absolute self-calibration estimated at 9.93 W.V(-1) are reported. Advantages and drawbacks of this THz powermeter are discussed. PMID- 23670762 TI - Sellmeier and thermo-optic dispersion formulas for GaSe (Revisited). AB - This paper reports high-accuracy Sellmeier and thermo-optic dispersion formulas for GaSe that provide excellent reproduction of the phase-matching conditions for second-, third-, and fourth- harmonic generation of CO2 laser radiation at 10.5910 MUm in the 20 degrees C-200 degrees C range as well as the data points of Feng et al. [Opt. Express16, 9978 (2008)10.1364/OE.16.009978OPEXFF1094-4087] for second-harmonic generation of CO2 laser radiation at 9.5862 MUm and an Er3+:YSGG laser at 2.7960 MUm in the -165 degrees C-230 degrees C range. PMID- 23670763 TI - Influence of amplified spontaneous emission on gain lifetime in high-aperture Ti:sapphire amplifiers. AB - We demonstrate that by lowering gain lifetime, transverse amplified spontaneous emission imposes practical limit on usable aspect ratio of large-aperture amplifiers in a high-energy Ti:sapphire system. PMID- 23670764 TI - Ion-exchanged glass binary phase plates for mode-division multiplexing. AB - Significant efforts are being made to increase optical network capacity in response to ever-growing data traffic. One promising candidate is mode-division multiplexing (MDM) in few-mode fibers. A fundamental element for MDM is a modal transformer. Modal transformation can be implemented in a free-space basis by using multiregion phase plates. In this work, we show that efficient monolithic binary phase plates can be fabricated by ion exchange in glass and used for MDM tasks. We present an optical characterization method of such plates, which is based on a combination of the inverse Wentzel-Kramers-Brillouin (IWKB) method and Mach-Zehnder interferometric techniques. The IWKB method allows us to design and characterize the phase plates in an easy and fast way, whereas interferometry gives us a precise measurement of the phase step. Far-field optical intensities are measured, and a high-quality mode transformation is confirmed. PMID- 23670765 TI - Fiber-optic trap-on-a-chip platform for probing low refractive index contrast biomaterials. AB - Dual-beam fiber trapping is a versatile technique for manipulating microparticles. We fabricate and evaluate the performance of a compact trap-on-a chip design and demonstrate, for what we believe is the first time, trapping of low-contrast (m<1.005) lipid vesicles in solution. Counterpropagating fibers are fixed along the chip channel, and we calibrate the trap by optically displacing polystyrene microspheres from the trap center. Measured scattering forces are ~30 49 pN from each beam. Stable trapping and reversible deformation of lipid vesicles is demonstrated under femtonewton trapping forces. This chip has applications in probing a variety of soft biomaterials, such as biological cells, lipid membranes, and protein assemblies. PMID- 23670766 TI - Wavelet packet energy characterization of low velocity impacts and load localization by optical fiber Bragg grating sensor technique. AB - The low velocity impacts (LVIs) monitoring based on optical fiber Bragg grating (FBG) sensors have attracted more attention in recent years. The center wavelength migrations of FBG sensors were determined by strain and residual strain during and after LVI on composite material structure. We presented a method to discriminate the energy characters of LVI response signals related to LVI locations. By analyzing the wavelet packet energy spectra of LVI response signals monitored by FBG sensors, the sixth node's energy was found to be sensitive to LVI location. Thus, the sixth node's energies as LVI feature values, were used to predict the LVI locations by the method of support vector regression (SVR). By optimization of the SVR models' free parameters, predicting accuracy was 4.62% in the work. PMID- 23670767 TI - Feasibility of utilizing Cherenkov Telescope Array gamma-ray telescopes as free space optical communication ground stations. AB - The signals that will be received on Earth from deep-space probes in future implementations of free-space optical communication will be extremely weak, and new ground stations will have to be developed in order to support these links. This paper addresses the feasibility of using the technology developed in the gamma-ray telescopes that will make up the Cherenkov Telescope Array (CTA) observatory in the implementation of a new kind of ground station. Among the main advantages that these telescopes provide are the much larger apertures needed to overcome the power limitation that ground-based gamma-ray astronomy and optical communication both have. Also, the large number of big telescopes that will be built for CTA will make it possible to reduce costs by economy-scale production, enabling optical communications in the large telescopes that will be needed for future deep-space links. PMID- 23670768 TI - Iterative learning control of a membrane deformable mirror for optimal wavefront correction. AB - We present an iterative learning control (ILC) algorithm for controlling the shape of a membrane deformable mirror (DM). We furthermore give a physical interpretation of the design parameters of the ILC algorithm. On the basis of this insight, we derive a simple tuning procedure for the ILC algorithm that, in practice, guarantees stable and fast convergence of the membrane to the desired shape. In order to demonstrate the performance of the algorithm, we have built an experimental setup that consists of a commercial membrane DM, a wavefront sensor, and a real-time controller. The experimental results show that, by using the ILC algorithm, we are able to achieve a relatively small error between the real and desired shape of the DM while at the same time we are able to control the saturation of the actuators. Moreover, we show that the ILC algorithm outperforms other control algorithms available in the literature. PMID- 23670769 TI - Adaptive regularized method based on homotopy for sparse fluorescence tomography. AB - Determining an appropriate regularization parameter is often challenging work because it has a narrow range and varies with problems, which is likely to lead to large reconstruction errors. In this contribution, an adaptive regularized method based on homotopy is presented for sparse fluorescence tomography reconstruction. Due to the adaptive regularization strategy, the proposed method is always able to reconstruct sources accurately independent of the estimation of the regularization parameter. Moreover, the proposed method is about two orders of magnitude faster than the two contrasting methods. Numerical and in vivo mouse experiments have been employed to validate the robustness and efficiency of the proposed method. PMID- 23670770 TI - Error analysis in parallel two-step phase-shifting method. AB - This paper presents an analysis of error in parallel two-step phase-shifting method. From the analysis, it is clarified that the maximum bandwidth of the object that this technique can capture is a half bandwidth of recording devices. Also, the recording distance must be two times longer than the conventional method to have a good reconstruction image. The analysis was verified by simulations and experimental results. PMID- 23670771 TI - Practical depolarization-ratio-based inversion procedure: lidar measurements of the Eyjafjallajokull ash cloud over the Netherlands. AB - In this paper we present a technique for estimating optical backscatter and extinction profiles using lidar, which exploits the difference between the observed linear volume depolarization ratio at 355 nm and the corresponding expected aerosol-only depolarization ratio. The technique is specific to situations where a single strongly depolarizing species is present and the associated linear particulate depolarization ratio may be presumed to be known to within a reasonable degree of accuracy (on the order of 10%). The basic principle of the technique is extended to deal with situations where a depolarizing fraction is mixed with nondepolarizing aerosol. In general, since the relative depolarization interchannel calibration is much more stable than the absolute system calibration, the depolarization-based technique is easier to implement than conventional techniques that require a profile-by-profile calibration or, equivalently, an identification of aerosol-free altitude intervals. This in particular allows for unattended data analysis and makes the technique well suited to be part of a broader (volcanic ash) surveillance system. The technique is demonstrated by applying it to the analysis of aerosol layers resulting from the 2010 eruptions of the Eyjafjallajokull volcano in Iceland. The measurements were made at the Cabauw remote-sensing site in the central Netherlands. By comparing the results of the depolarization-based inversion with a more conventional manual inversion procedure as well as Raman lidar results, it is demonstrated that the technique can be successfully applied to the particular case of 355 nm depolarization lidar volcanic ash soundings, including cases in which the ash is mixed with nondepolarizing aerosol. PMID- 23670772 TI - Effects of missing low-frequency information on ptychographic and plane-wave coherent diffraction imaging. AB - In coherent diffractive imaging (CDI) experiments, a beamstop (BS) is commonly used to extend the exposure time of the charge-coupled detector and obtain high angle diffraction signals. However, the negative effect of a large BS is also evident, causing low-frequency signals to be missed and making CDI reconstruction unstable or causing it to fail. We performed a systematic simulation investigation of the effects of BSs on the quality of reconstructed images from both plane-wave and ptychographic CDI (PCDI). For the same imaging quality, we found that ptychography can tolerate BSs that are at least 20 times larger than those for plane-wave CDI. For PCDI, a larger overlap ratio and a smaller illumination spot can significantly increase the imaging robustness to the negative influence of BSs. Our results provide guidelines for the usage of BSs in CDI, especially in PCDI experiments, which can help to further improve the spatial resolution of PCDI. PMID- 23670773 TI - Simultaneous physical retrieval of surface emissivity spectrum and atmospheric parameters from infrared atmospheric sounder interferometer spectral radiances. AB - The problem of simultaneous physical retrieval of surface emissivity, skin temperature, and temperature, water-vapor, and ozone atmospheric profiles from high-spectral-resolution observations in the infrared is formulated according to an inverse problem with multiple regularization parameters. A methodology has been set up, which seeks an effective solution to the inverse problem in a generalized L-curve criterion framework. The a priori information for the surface emissivity is obtained on the basis of laboratory data alone, and that for the atmospheric parameters by climatology or weather forecasts. To ensure that we deal with a problem of fewer unknowns than observations, the dimensionality of the emissivity is reduced through expansion in Fourier series. The main objective of this study is to demonstrate the simultaneous retrieval of emissivity, skin temperature, and atmospheric parameters with a two-dimensional L-curve criterion. The procedure has been demonstrated with spectra observed from the infrared atmospheric sounder interferometer, flying onboard the European Meteorological Operational satellite. To check the quality and reliability of the methodology, we have used spectra recorded over regions characterized by known or stable emissivity. These include sea surface, for which effective emissivity models are known, and arid lands (Sahara and Namib Deserts) that are known to exhibit the characteristic spectral signature of quartz-rich sand. PMID- 23670774 TI - Improvement of range accuracy of photon counting chirped AM ladar using phase postprocessing. AB - The photon counting detection of Geiger mode avalanche photodiode is discrete due to its dead time, therefore the intermediate frequency (IF) spectrum is also discrete after the mixing and fast Fourier transform processing. When the peak of the IF spectrum is in the interval of the discrete IF spectrum, it limits the range accuracy without obtaining the exact position of the desired target in the interval. In this paper, the phase postprocessing method is proposed, which extracts not only the frequency of the IF signal, but also the phase of the IF signal that was not exploited before. The theoretical analysis demonstrates significant improvements in the range accuracy of the ladar and the simulation verifies the validity of the method. PMID- 23670775 TI - High-power Ti:sapphire laser at 820 nm for scanning ground-based water-vapor differential absorption lidar. AB - The Ti:sapphire (TISA) laser transmitter of the mobile, three-dimensional scanning water-vapor differential absorption lidar (DIAL) of the University of Hohenheim is described in detail. The dynamically-stable, unidirectional ring resonator contains a single Brewster-cut TISA crystal, which is pumped from both sides with 250 Hz using a diode-pumped frequency-doubled Nd:YAG laser. The resonator is injection seeded and actively frequency-stabilized using a phase sensitive technique. The TISA laser is operating near 820 nm, which is optimum for ground-based water-vapor DIAL measurements. An average output power of up to 6.75 W with a beam quality factor of M2<2 is reached. The pointing stability is <13 MUrad (rms), the depolarization <1%. The overall optical-optical conversion efficiency is up to 19%. The pulse length is 40 ns with a pulse linewidth of <157 MHz. The short- and long-term frequency stabilities are 10 MHz (rms). A spectral purity of 99.9% was determined by pointing to a stratus cloud in low-elevation scanning mode with a cloud bottom height of ~2.4 km. PMID- 23670776 TI - Laser ablation-laser induced breakdown spectroscopy for the measurement of total elemental concentration in soils. AB - The performances of traditional laser-induced breakdown spectroscopy (LIBS) and laser ablation-LIBS (LA-LIBS) were compared by quantifying the total elemental concentration of potassium in highly heterogeneous solid samples, namely soils. Calibration curves for a set of fifteen samples with a wide range of potassium concentrations were generated. The LA-LIBS approach produced a superior linear response different than the traditional LIBS scheme. The analytical response of LA-LIBS was tested with a large set of different soil samples for the quantification of the total concentration of Fe, Mn, Mg, Ca, Na, and K. Results showed an acceptable linear response for Ca, Fe, Mg, and K while poor signal responses were found for Na and Mn. Signs of remaining matrix effects for the LA LIBS approach in the case of soil analysis were found and discussed. Finally, some improvements and possibilities for future studies toward quantitative soil analysis with the LA-LIBS technique are suggested. PMID- 23670777 TI - Wavelength evolution of long-period fiber gratings in a water environment. AB - In a water environment, wavelength evolution behavior of long-period fiber gratings (LPFGs) written in H2-loaded fibers after annealing is studied. The phenomena that wavelength shifts in the longer wavelength direction and then in the shorter wavelength direction is observed. A shift of the grating resonance peak (LP05) of as much as 2.5 nm is found. A water-mediated model that water molecules induce the second diffusion of the remaining H2 in the fiber and a diffusion-reaction mechanism that water molecules penetrate into fiber internal structures are proposed and are combined to explain the wavelength evolution process. Both the calculated balance point time according to the model, and the qualitative analysis according to the mechanism, correspond well with the experimental results. This research indicates that wavelength variation has to be considered or prevented when H2-loaded LPFGs are used in a water environment. PMID- 23670778 TI - Performance comparison of optical interference cancellation system architectures. AB - The performance of three optics-based interference cancellation systems are compared and contrasted with each other, and with traditional electronic techniques for interference cancellation. The comparison is based on a set of common performance metrics that we have developed for this purpose. It is shown that thorough evaluation of our optical approaches takes into account the traditional notions of depth of cancellation and dynamic range, along with notions of link loss and uniformity of cancellation. Our evaluation shows that our use of optical components affords performance that surpasses traditional electronic approaches, and that the optimal choice for an optical interference canceller requires taking into account the performance metrics discussed in this paper. PMID- 23670779 TI - Recipes to make organic phantoms for diffusive optical spectroscopy. AB - Three recipes are presented to make tissue constituent-equivalent phantoms of water and lipids. Different approaches to prepare the emulsion are proposed. Nature phantoms are made using no emulsifying agent, but just a professional disperser; instead Agar and Triton phantoms are made using agar or Triton X-100, respectively, as agents to emulsify water and lipids. Different water-to-lipid ratios ranging from 30% to 70% by mass were tested. A broadband time-resolved diffuse optical spectroscopy system was used to characterize the phantoms in terms of optical properties and composition. For some water/lipid ratios the emulsion fails or the phantom has limited lifetime, but in most cases the recipes provide phantoms with a high degree of homogeneity [coefficient of variation (CV) of 4.6% and 1.5% for the absorption and reduced scattering coefficient, respectively] and good reproducibility (CV of 8.3% and 12.4% for absorption and reduced scattering coefficient, respectively). PMID- 23670780 TI - Accurate measurements of the Raman scattering coefficient and the depolarization ratio in liquid water. AB - Despite a long history, the Raman scattering coefficient of water has so far only been measured with 10% uncertainty using a 95% confidence interval. In this paper, we present an experiment where we have achieved 1.5% uncertainty by using a low concentration of Rhodamine 6G in ethanol as a reference along with accurate consideration of polarization-related effects and the geometry of the experimental setup. We have found that the photon-to-photon Raman scattering coefficient of the OH stretching band of liquid water is (1.84+/-0.03)*10(-4) m( 1) when integrated over the spectral frequency range from 620 to 700 nm while the exciting laser operates at 532 nm. We have also accurately measured the depolarization ratio across this band. PMID- 23670781 TI - Retrieval of relevant parameters of natural multilayer systems by means of bio inspired optimization strategies. AB - Natural photonic structures exhibit remarkable color effects such as metallic appearance and iridescence. A rigorous study of the electromagnetic response of such complex structures requires to accurately determine some of their relevant optical parameters, such as the refractive indices of the materials involved. In this paper, we apply different heuristic optimization strategies to retrieve the real and imaginary parts of the refractive index of the materials comprising natural multilayer systems. Through some examples, we compare the performances of the inversion methods proposed and show that these kinds of algorithms have a great potential as a tool to investigate natural photonic structures. PMID- 23670782 TI - Development of a guided self-help (GSH) program for the treatment of mild-to moderate posttraumatic stress disorder (PTSD). AB - BACKGROUND: There is a shortage of suitably qualified therapists able to deliver evidence-based treatment for posttraumatic stress disorder (PTSD), precluding timely access to intervention. This work aimed to develop an optimally effective, feasible, and acceptable guided self-help (GSH) program for treatment of the disorder. METHODS: The study followed Medical Research Council (MRC) guidance for the development of a complex intervention. A prototype GSH program was developed through an initial modeling phase. Systematic reviews of the literature informed a portfolio of up-to-date information for key stakeholders to consider and discuss in a series of focus groups and semistructured interviews, which included 10 mental health professionals with expertise in the fields of GSH and/or PTSD, and seven former PTSD sufferers. Data were analyzed through a process of Inductive Thematic Analysis and used to inform the content, delivery, and guidance of a GSH program for PTSD. The prototype was piloted with 19 PTSD sufferers in two pilot studies, and refined on the basis of their quantitative results and qualitative feedback. RESULTS: The final version was available online and in hardcopy. It included 11 modules, some being mandatory and others optional, allowing tailoring of the intervention to meet an individual's specific needs. Qualitative and quantitative results of the pilot studies supported its efficacy in terms of reducing traumatic stress symptoms and its acceptability to PTSD sufferers. CONCLUSIONS: Delivering psychological treatment in a GSH format shows promise as an effective and acceptable way of treating mild-to-moderate PTSD. PMID- 23670783 TI - Reliability and validity of the Severity of Dependence Scale for detecting cannabis dependence in frequent cannabis users. AB - The Severity of Dependence Scale (SDS) measures with five items the degree of psychological dependence on several illicit drugs, including cannabis. Its psychometric properties have not yet been examined in young adult frequent cannabis users, an eminently high-risk group for cannabis dependence. Internal consistency and criterion validity of the SDS were investigated within an enriched community based sample of 577 Dutch frequent (>= three days per week in the past 12 months) cannabis users between 18-30 years. Criterion validity was tested against the Composite International Diagnostic Interview (CIDI) 3.0 DSM-IV diagnosis cannabis dependence, and psychometric properties were assessed separately for males and females and for ethnic subgroups. Principal component analysis showed that all items of the scale loaded on a single factor and reliability of the SDS total score was good (Cronbach's alpha = 0.70). However, criterion validity against the CIDI diagnosis cannabis dependence was low: area under curve (AUC) was 0.68 (95% confidence interval: 0.64-0.73) and at the optimal differentiating cut-off (SDS >= 4), sensitivity was 61.3% and specificity 63.5%. Results were similar for subgroups on gender and ethnicity. While internal consistency of the SDS is good, its use as a screener to differentiate between dependence and non-dependence within populations of young adult frequent cannabis users is not recommended. PMID- 23670784 TI - [Screening for depression by telephone using the German version of the Center for Epidemiological Studies Depression Scale (CES-D)]. AB - OBJECTIVE: Analyses of the reliability and validity of the German version of the Center for Epidemiological Studies Depression Scale (CES-D) and the assessment of normative values. METHOD: A representative sample of 868 people (German population, 18 to 94 years) was assessed via structured interviews in a telephone survey. RESULTS: According to the cut-off score of 16 points, 8.5 % of the total sample (11.0 % women and 5.6 % men) showed relevant depressive symptoms. When using the cut-off score of 22 points, 3.5 % of the subjects of the total sample, 4.2 % of the women and 2.5% of the men, were classified as depressed. The analysis of the psychometric properties of the instrument such as internal consistency, test-retest reliability, construct validity and factor structure revealed moderate to good results. Percentile standard values were determined. CONCLUSION: The German version of the CES-D can be described as a reliable and valid instrument for detecting depressive symptoms. The present study offers current normative data for the specific use in telephone surveys. PMID- 23670785 TI - A temperature-based approach to predicting lost data from highly seasonal pollutant data sets. AB - A new technique to predict concentrations of benzo[a]pyrene (BaP) in ambient air during periods of lost data has been developed and tested. This new technique is based on the relationship between ambient temperature and BaP concentration observed at individual monitoring stations over many years. The technique has been tested on monthly data of BaP concentrations in PM10 at individual monitoring stations on the UK PAH Monitoring Network. The annual average concentration values produced with and without the use of predicted data have been compared to the actual annual averages in the absence of any data loss. The use of predicted data is a significant improvement when compared with the averages produced in the absence of any data prediction and outperforms previous prediction strategies associated with intra-year trends. Furthermore the technique is suitable for the prediction of long periods of missing data, which other prediction techniques have not been able to deal with satisfactorily. PMID- 23670786 TI - Role of the heme oxygenase/carbon monoxide pathway in the pathogenesis and prevention of hepatic encephalopathy. AB - Hepatic encephalopathy (HE) is a severe complication of liver cirrhosis and its pathogenesis has yet to be fully elucidated. Previous studies have demonstrated that heme oxygenase-1 (HO-1) is important in the induction of liver cirrhosis. The present study aimed to investigate the role of HO-1 in the pathogenesis of HE. Rats were divided into 5 treatment groups; sham, bile duct ligation (BDL), HE, zinc protoporphyrin (ZnPP) and cobalt protoporphyrin (CoPP). The levels of HO 1 were examined by western blotting and quantitative real-time PCR (qRT-PCR). Serum levels of carboxyhemoglobin (COHb), ammonia levels in the plasma and brain, brain water content and portal vein pressure (PVP) were also quantified. Aquaporin-4 expression levels were measured by immunohistochemistry and qRT-PCR. The results demonstrated that the levels of HO-1 in the brain and the serum levels of COHb were significantly increased in the HE group compared with the BDL group. Brain water content, PVP and ammonia levels in the plasma and brain were increased in the HE and CoPP groups; however, these were reduced following the treatment with ZnPP. The levels of AQP-4 expression and oxidative stress in the brain were reduced following treatment with ZnPP and increased following treatment with CoPP. In conclusion, following the inhibition of HO-1 expression, treatment with ZnPP improved HE due to reducing the expression levels of AQP-4 and oxidative stress. Therefore, ZnPP treatment may represent a novel therapeutic approach for HE. PMID- 23670787 TI - Snare vegetectomy for right-sided endocarditis. AB - INTRODUCTION: A middle-aged male developed right-sided endocarditis from an infection of an implantable cardiac defibrillator (ICD) system. Following percutaneous device and lead explantation, a very large pedunculated vegetation (19 mm * 14 mm) was found on the Eustachian valve. We decided to remove the vegetation percutaneously using a wire snare instead of open heart surgery. CASE REPORT: Real-time three-dimensional transesophageal echocardiography and fluoroscopy were used to guide the procedure. Access was from the right femoral vein. Using a triple-loop wire snare through a deflectable sheath, the vegetation was successfully removed in its entirety without complications. CONCLUSION: Percutaneous snare vegetectomy is feasible and may be a viable option in place of open heart surgery in selected patients. PMID- 23670789 TI - Effects of Rifampin, a potent inducer of drug-metabolizing enzymes and an inhibitor of OATP1B1/3 transport, on the single dose pharmacokinetics of anacetrapib. AB - Anacetrapib is a novel cholesteryl ester transfer protein (CETP) inhibitor in development for treatment of dyslipidemia. This open-label, fixed-sequence, 3 period study was intended to evaluate the potential of anacetrapib to be a victim of OATP1B1/3 inhibition and strong CYP3A induction using acute and chronic dosing of rifampin, respectively, as a probe. In this study, 16 healthy subjects received 100 mg anacetrapib administered without rifampin (Day 1, Period 1), with single-dose (SD) 600 mg rifampin (Day 1, Period 2), and with multiple-dose (MD) 600 mg rifampin for 20 days (Day 14, Period 3). Log-transformed anacetrapib AUC0 infinity and Cmax were analyzed by a linear mixed effects model. The GMRs and 90% CIs for anacetrapib AUC0-infinity and Cmax were 1.25 (1.04, 1.51) and 1.43 (1.13, 1.82) for SD rifampin (Period 2/Period 1) and 0.35 (0.29, 0.42) and 0.26 (0.21, 0.32) for MD rifampin (Period 3/Period 1), respectively. Anacetrapib was generally well tolerated in both the absence/presence of SD and MD rifampin. In conclusion, treatment with SD rifampin, which inhibits the OATP1B1/3 transporter system, did not substantially influence the SD pharmacokinetics of anacetrapib, while chronic (20 days) administration of rifampin, which strongly induces CYP3A isozymes, reduced mean systemic exposure to SD anacetrapib by 65%. PMID- 23670788 TI - Crystal structure of the cataract-causing P23T gammaD-crystallin mutant. AB - Up to now, efforts to crystallize the cataract-associated P23T mutant of human gammaD-crystallin have not been successful. Therefore, insights into the light scattering mechanism of this mutant have been exclusively obtained from solution work. Here we present the first crystal structure of the P23T mutant at 2.5 A resolution. The protein exhibits essentially the same overall structure as seen for the wild-type protein. Based on our structural data, we confirm that no major conformational changes are caused by the mutation, and that solution phase properties of the mutant appear exclusively associated with cataract formation. PMID- 23670790 TI - Small chromosomes among Danish Candida glabrata isolates originated through different mechanisms. AB - We analyzed 192 strains of the pathogenic yeast Candida glabrata from patients, mainly suffering from systemic infection, at Danish hospitals during 1985-1999. Our analysis showed that these strains were closely related but exhibited large karyotype polymorphism. Nine strains contained small chromosomes, which were smaller than 0.5 Mb. Regarding the year, patient and hospital, these C. glabrata strains had independent origin and the analyzed small chromosomes were structurally not related to each other (i.e. they contained different sets of genes). We suggest that at least two mechanisms could participate in their origin: (i) through a segmental duplication which covered the centromeric region, or (ii) by a translocation event moving a larger chromosome arm to another chromosome that leaves the centromere part with the shorter arm. The first type of small chromosomes carrying duplicated genes exhibited mitotic instability, while the second type, which contained the corresponding genes in only one copy in the genome, was mitotically stable. Apparently, in patients C. glabrata chromosomes are frequently reshuffled resulting in new genetic configurations, including appearance of small chromosomes, and some of these resulting "mutant" strains can have increased fitness in a certain patient "environment". PMID- 23670791 TI - Isolation and characterization of novel ginsenoside-hydrolyzing glycosidase from Microbacterium esteraromaticum that transforms ginsenoside Rb2 to rare ginsenoside 20(S)-Rg3. AB - Ginsenoside Rb2 was transformed by recombinant glycosidase (Bgp2) into ginsenosides Rd and 20(S)-Rg3. The bgp2 gene consists of 2,430 bp that encode 809 amino acids, and this gene has homology to the glycosyl hydrolase family 2 protein domain. SDS-PAGE was used to determine that the molecular mass of purified Bgp2 was 87 kDa. Using 0.1 mg ml(-1) of enzyme in 20 mM sodium phosphate buffer at 40 degrees C and pH 7.0, 1.0 mg ml(-1) ginsenoside Rb2 was transformed into 0.47 mg ml(-1) ginsenoside 20(S)-Rg3 within 120 min, with a corresponding molar conversion yield of 65 %. Bgp2 hydrolyzed the ginsenoside Rb2 along the following pathway: Rb2 -> Rd -> 20(S)-Rg3. This is the first report of the biotransformation of ginsenoside Rb2 to ginsenoside 20(S)-Rg3 using the recombinant glycosidase. PMID- 23670792 TI - Jejudonia soesokkakensis gen. nov., sp. nov., a member of the family Flavobacteriaceae isolated from the junction between the ocean and a freshwater spring, and emended description of the genus Aureitalea Park et al. 2012. AB - A Gram-negative, non-flagellated, non-gliding and rod-shaped bacterial strain, designated SSK1-1(T), was isolated from the junction between the ocean and a freshwater spring at Jeju island of South Korea. Strain SSK1-1(T) was found to grow optimally at 30 degrees C, at pH 7.0-7.5 and in the presence of 2 % (w/v) NaCl. Neighbour-joining, maximum-likelihood and maximum-parsimony phylogenetic trees based on 16S rRNA gene sequences revealed that strain SSK1-1(T) is phylogenetically most closely related to members of the genera Ulvibacter and Aureitalea, with which it exhibited 16S rRNA gene sequence similarities of 93.1 95.3 %. The results of chemotaxonomic analyses distinguish strain SSK1-1(T) from the genera Ulvibacter and Aureitalea. Strain SSK1-1(T) was determined to contain MK-6 as the predominant menaquinone and iso-C15:0, anteiso-C15:0 and iso-C16:0 as the major fatty acids. The major polar lipids of strain SSK1-1(T) were identified as phosphatidylethanolamine and one unidentified lipid. The DNA G + C content of strain SSK1-1(T) was determined to be 39.9 mol%. The phylogenetic analysis, chemotaxonomic data and other phenotypic properties revealed that the strain SSK1 1(T) can be distinguished from the members of previously known genera of the family Flavobacteriaceae. On the basis of the data presented, strain SSK1-1(T) is considered to represent a novel genus and species, for which the name Jejudonia soesokkakensis gen. nov., sp. nov. is proposed. The type strain is SSK1-1(T) (=KCTC 32325(T) = CCUG 63830(T)). An emended description of the genus Aureitalea is also proposed. PMID- 23670793 TI - Substituent effects on oxidation-induced formation of quinone methides from arylboronic ester precursors. AB - A series of arylboronic esters containing different aromatic substituents and various benzylic leaving groups (Br or N(+)Me3Br(-)) have been synthesized. The substituent effects on their reactivity with H2O2 and formation of quinone methide (QM) have been investigated. NMR spectroscopy and ethyl vinyl ether (EVE) trapping experiments were used to determine the reaction mechanism and QM formation, respectively. QMs were not generated during oxidative cleavage of the boronic esters but by subsequent transformation of the phenol products under physiological conditions. The oxidative deboronation is facilitated by electron withdrawing substituents, such as aromatic F, NO2, or benzylic N(+)Me3Br(-), whereas electron-donating substituents or a better leaving group favor QM generation. Compounds containing an aromatic CH3 or OMe group, or a good leaving group (Br), efficiently generate QMs under physiological conditions. Finally, a quantitative relationship between the structure and activity has been established for the arylboronic esters by using a Hammett plot. The reactivity of the arylboronic acids/esters and the inhibition or facilitation of QM formation can now be predictably adjusted. This adjustment is important as some applications may benefit and others may be limited by QM generation. PMID- 23670794 TI - Mediterranean diet improves cognition: the PREDIMED-NAVARRA randomised trial. AB - OBJECTIVE: Previous observational studies reported beneficial effects of the Mediterranean diet (MedDiet) on cognitive function, but results were inconsistent. We assessed the effect on cognition of a nutritional intervention using MedDiets in comparison with a low-fat control diet. METHODS: We assessed 522 participants at high vascular risk (44.6% men, age 74.6 +/- 5.7 years at cognitive evaluation) enrolled in a multicentre, randomised, primary prevention trial (PREDIMED), after a nutritional intervention comparing two MedDiets (supplemented with either extra-virgin olive oil (EVOO) or mixed nuts) versus a low-fat control diet. Global cognitive performance was examined by Mini-Mental State Examination (MMSE) and Clock Drawing Test (CDT) after 6.5 years of nutritional intervention. Researchers who assessed the outcome were blinded to group assignment. We used general linear models to control for potential confounding. RESULTS: After adjustment for sex, age, education, Apolipoprotein E genotype, family history of cognitive impairment/dementia, smoking, physical activity, body mass index, hypertension, dyslipidaemia, diabetes, alcohol and total energy intake, participants allocated to the MedDiet+EVOO showed higher mean MMSE and CDT scores with significant differences versus control (adjusted differences: +0.62 95% CI +0.18 to +1.05, p=0.005 for MMSE, and +0.51 95% CI +0.20 to +0.82, p=0.001 for CDT). The adjusted means of MMSE and CDT scores were also higher for participants allocated to the MedDiet+Nuts versus control (adjusted differences: +0.57 (95% CI +0.11 to +1.03), p=0.015 for MMSE and +0.33 (95% CI +0.003 to +0.67), p=0.048 for CDT). These results did not differ after controlling for incident depression. CONCLUSIONS: An intervention with MedDiets enhanced with either EVOO or nuts appears to improve cognition compared with a low-fat diet. ISRCTN:35739639. PMID- 23670795 TI - Synthesis and pharmacological characterization of new tetrahydrofuran based compounds as conformationally constrained histamine receptor ligands. AB - A series of tetrahydrofuran based compounds with a bicyclic core that provides conformational restriction were synthesized and investigated by radioligand displacement studies and functional [(35)S]GTPgammaS binding assays at the human histamine receptor (hHR) subtypes. The amines and ((1S,3R,5S,6R)- and ((1S,3S,5S,6R)-3-(1H-imidazol-5-yl)-2-oxabicyclo[3.1.0]hexan-6-yl)methanamine), exhibited submicromolar Ki values at the hH3R with 10-fold higher affinities than their corresponding (6S)-epimers and 25- and >34-fold selectivity over the hH4R, respectively. Both compounds act as neutral antagonists at the hH3R with KB values of 181 and 32 nM, respectively. The cyanoguanidines of the imidazole series and the oxazole analogues turned out to be inactive at all hHR subtypes. PMID- 23670796 TI - Medication discrepancies at transitions in pediatrics: a review of the literature. AB - Medication reconciliation is an important process in reducing medication errors in many countries. Canada, the USA, and UK have incorporated medication reconciliation as a priority area for national patient safety initiatives and goals. The UK national guidance excludes the pediatric population. The aim of this review was to explore the occurrence of medication discrepancies in the pediatric population. The primary objective was to identify studies reporting the rate and clinical significance of the discrepancies and the secondary objective was to ascertain whether any specific interventions have been used for medication reconciliation in pediatric settings. The following electronic bibliographic databases were used to identify studies: PubMed, OVID EMBASE (1980 to 2012 week 1), ISI Web of Science, ISI Biosis, Cumulative Index to Nursing and Allied Health Literature, and OVID International Pharmaceutical Abstracts (1970 to January 2012). Primary studies were identified that observed medication discrepancies in children under 18 years of age upon hospital admission, transfer and discharge, or had reported medication reconciliation interventions. Two independent reviewers screened titles and abstracts for relevant articles and extracted data using pre-defined data fields, including risk of bias assessment. Ten studies were identified with variances in reportage of stage and rate of discrepancies. Studies were heterogeneous in definitions, methods, and patient populations. Most studies related to admissions and reported consistently high rates of discrepancies ranging from 22 to 72.3 % of patients (sample size ranging from 23 to 272). Seven of the studies were low-quality observational studies and three studies were 'grey literature' non-peer reviewed conference abstracts. Studies involving small numbers of patients have shown that medication discrepancies occur at all transitions of care in children. Further research is required to investigate and demonstrate how implementing medication reconciliation can reduce discrepancies and potential patient harm. PMID- 23670797 TI - Modulatory effects of yerba mate (Ilex paraguariensis) on the PI3K-AKT signaling pathway. AB - The aim of this study was to evaluate the effects of yerba mate (YM) extract on the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway in vivo. The mice were introduced to either standard- or high-fat diet (HFD). After 8 weeks on an HFD, mice were randomly assigned to one of the two treatment conditions, water or yerba mate extract at 1.0 g/kg. After treatment, glucose blood level and hepatic insulin response were evaluated. Liver tissue was examined to determine the mRNA levels using the PI3K-AKT PCR array. The nuclear translocation of forkhead box O1 (FOXO1) was determined by an electrophoretic mobility-shift assay. Our data demonstrated that yerba mate extract significantly decreased the final body weight, glucose blood levels, and insulin resistance of mice. Molecular analysis demonstrated that an HFD downregulated Akt2, Irs1, Irs2, Pi3kca, Pi3kcg, and Pdk1; after yerba mate treatment, the levels of those genes returned to baseline. In addition, an HFD upregulated Pepck and G6pc and increased FOXO1 nuclear translocation. The intervention downregulated these genes by decreasing FOXO1 nuclear translocation. The results obtained demonstrate for the first time the specific action of yerba mate on the PI3K-AKT pathway, which contributed to the observed improvement in hepatic insulin signaling. PMID- 23670798 TI - Nanostructured CaCO3-poly(ethyleneimine) microparticles for phenol sensing in fluidic microsystem. AB - A new and simple strategy based on nanostructured CaCO3-poly(ethyleneimine) (PEI) microparticles (MPs) for phenol sensing using PDMS/glass fluidic microchip is developed. This fluidic microsystem including integrated screen-printed electrodes modified with CaCO3-PEI MPs and tyrosinase (Tyr) through cross-linking with glutaraldehyde, represents a low-cost platform for phenol detection. The designed fluidic microsystem improves the sensitivity of the biosensor allowing the detection of very low concentrations of phenol (up to 10 nM). This device shows high repeatability and low detection limit, is easy to be fabricated, inexpensive, disposable, and amenable to mass production. PMID- 23670799 TI - MicroRNA-148a suppresses epithelial-to-mesenchymal transition by targeting ROCK1 in non-small cell lung cancer cells. AB - Recent studies have implied that miRNAs act as crucial modulators for epithelial to-mesenchymal transition (EMT). We found that miR-148a is significantly downregulated in non-small cell lung cancer (NSCLC) compared to adjacent non cancerous lung tissues, and the downregulated miR-148a was significantly associated with lymph-node metastasis. Functional assays demonstrated that miR 148a inhibited EMT in NSCLC cells. Moreover, miR-148a decreased 3'-untranslated region luciferase activity of ROCK1 and ROCK1 protein expression. Knockdown of ROCK1 reversed EMT resembling that of miR-148a overexpression. Furthermore, ROCK1 was widely upregulated in NSCLC, and its mRNA levels were inversely correlated with miR-148a expression. These findings suggest that miR-148a acts as a novel EMT suppressor in NSCLC cells, at least in part by modulation of ROCK1. PMID- 23670800 TI - Quantitative expression of human drug transporter proteins in lung tissues: analysis of regional, gender, and interindividual differences by liquid chromatography-tandem mass spectrometry. AB - The purpose of the present study was to clarify the expression levels of transporter proteins in human lung tissue and to analyze regional and interindividual differences in primary cultured epithelial cells. Organic cation/carnitine tranporter 1 (OCTN1) protein expression was highest (2.08 +/- 1.19 fmol/MUg protein) in human lung tissue, followed by multidrug resistance associated protein 1 (MRP1) and breast cancer resistance protein expression (1.41 +/- 0.41, 1.30 +/- 1.29 fmol/MUg protein, respectively). Interestingly, the same expression levels of OATP2B1 protein were demonstrated among the epithelial cells derived from all pulmonary regions for the first time. These results suggest that OCTN1 may be the best target transporter protein for pulmonary disease drug design, and OATP2B1 may be an alternative target. MRP1 protein expression was also high and mainly localized in bronchial and alveolar regions. Regarding interindividual differences, the MRP1 protein showed a significant 18-fold maximal difference in the bronchial region among five donors. Sixteen of the 18 transporters showed higher expression in female lungs than in male lungs, especially MRP8 showed a 7.32-fold maximal difference. In conclusion, the protein expression profiles of pulmonary drug transporters and regional, gender, and interindividual differences were clarified. These findings may provide significant insights for pulmonary disease drug design and indicate that administration by inhalation may be viable. PMID- 23670801 TI - Widely applicable synthesis of enantiomerically pure tertiary alkyl-containing 1 alkanols by zirconium-catalyzed asymmetric carboalumination of alkenes and palladium- or copper-catalyzed cross-coupling. AB - A highly enantioselective and widely applicable method for the synthesis of various chiral 2-alkyl-1-alkanols, especially those of feeble chirality, has been developed. It consists of zirconium-catalyzed asymmetric carboalumination of alkenes (ZACA), lipase-catalyzed acetylation, and palladium- or copper-catalyzed cross-coupling. By virtue of the high selectivity factor (E) associated with iodine, either (S)- or (R)-enantiomer of 3-iodo-2-alkyl-1-alkanols (1), prepared by ZACA reaction of allyl alcohol, can be readily purified to the level of >=99% ee by lipase-catalyzed acetylation. A variety of chiral tertiary alkyl-containing alcohols, including those that have been otherwise difficult to prepare, can now be synthesized in high enantiomeric purity by Pd- or Cu-catalyzed cross-coupling of (S)-1 or (R)-2 for introduction of various primary, secondary, and tertiary carbon groups with retention of all carbon skeletal features. These chiral tertiary alkyl-containing alcohols can be further converted into the corresponding acids with full retention of the stereochemistry. The synthetic utility of this method has been demonstrated in the highly enantioselective (>=99% ee) and efficient syntheses of (R)-2-methyl-1-butanol and (R)- and (S) arundic acids. PMID- 23670802 TI - Can anesthetic techniques or drugs affect cancer recurrence in patients undergoing cancer surgery? AB - Despite the development of effective chemotherapy and radiotherapy, surgery remains the mainstay treatment of many cancers, requiring anesthesia. Almost all cancer deaths after primary surgery are attributable to recurrence or metastases. Recently it has been hypothesized that the perioperative anesthetic management of cancer patients could potentially affect the risk of recurrence and metastases, which implies a key role for anesthesiologists in choosing anesthetic agents and techniques that optimize the balance between the metastatic potential of the tumor versus its elimination by antimetastatic immune defenses. This review summarizes available experimental information on the potential effects of common anesthetic agents and techniques on cancer metastases and the conflicting retrospective clinical data on regional anesthesia in various types of cancer. A number of prospective, randomized, multicenter, clinical trials are in progress, and their results are eagerly awaited. PMID- 23670803 TI - Orthostatic intolerance during early mobilization following video-assisted thoracic surgery. AB - PURPOSE: Early postoperative mobilization is crucial for early ambulation to reduce postoperative pulmonary complications after lung resection. However, orthostatic intolerance (OI) may delay patient recovery, leading to complications. It is therefore important to understand the prevalence of and predisposing factors for OI following video-assisted thoracic surgery (VATS), which have not been established. This study evaluated the incidence of OI, impact of OI on delayed ambulation, and predisposing factors associated with OI in patients after VATS. METHODS: This retrospective cohort study consecutively analyzed data from 236 patients who underwent VATS. The primary outcome was defined as OI with symptoms associated with ambulatory challenge on postoperative day 1 (POD1), including dizziness, nausea and vomiting, feeling hot, blurred vision, or transient syncope. Multivariate logistic regression was performed to identify independent factors associated with OI. RESULTS: Of the 236 patients, 35.2 % (83) experienced OI; 45.8 % of these could not ambulate at POD1, compared with 15.7 % of patients without OI (P < 0.001). Factors independently associated with OI included advanced age [odds ratio 2.83 (1.46-5.58); P = 0.002], female gender [odds ratio 2.40 (1.31-4.46); P = 0.004], and postoperative opioid use [odds ratio 2.61 (1.23-5.77); P = 0.012]. Use of thoracic epidural anesthesia was not independently associated with OI [odds ratio 0.72 (0.38-1.37); P = 0.318]. CONCLUSION: Postoperative OI was common in patients after VATS and significantly associated with delayed ambulation. Advanced age, female gender, and postoperative opioid use were identified as independent predisposing factors for OI. PMID- 23670804 TI - Serum macrophage migration inhibitory factor levels are correlated with response to tocilizumab therapy in patients with rheumatoid arthritis. AB - To examine the relationship between serum cytokine levels and response to tocilizumab in patients with RA. The disease status of 21 RA patients was assessed at baseline and after 12 weeks of tocilizumab treatment, using the clinical disease activity index (CDAI). Clinical response to tocilizumab was defined as an improvement of >50% from the baseline CDAI. Serum cytokine levels were quantified using double-ligand ELISA for TNF-alpha, IL-6, CCL2, CCL3, CXCL8, CXCL10, CX3CL1, and macrophage migration inhibitory factor (MIF). After 12 weeks of tocilizumab treatment, there was a significant overall reduction in RA disease activity (CDAI), from 22.4 +/- 11.3 to 9.2 +/- 6.6 (p < 0.0001), across the entire patient group. After 12 weeks of tocilizumab treatment, 14 patients achieved a >50% improvement (the responder group), but there were no significant responses in the other 7 patients (the non-responder group). The erythrocyte sedimentation rate levels, the positive % of anti-cyclic citrullinated protein antibody and patients (%) receiving methotrexate in combination with tocilizumab were significantly higher in the responder group than in the non-responder group. Although serum baseline levels of CCL2 and CXCL8 were higher in the responder group than in the non-responder group, there were no significant changes in these chemokine levels after treatment. The serum MIF levels, but not the levels of other cytokines, in the responder group were significantly decreased after tocilizumab treatment. Our results suggest that tocilizumab differentially regulates serum cytokine profiles in patients with RA, and MIF regulation in patients with active RA may be sensitive to anti-IL-6 therapy. PMID- 23670805 TI - Pilot evaluation of an automated method to decrease false-positive signals induced by co-prescriptions in spontaneous reporting databases. AB - PURPOSE: To test an automated method to decrease the number of false-positive (FP) signals of disproportionate reportings (SDRs) generated by co-prescription. METHODS: Automated backward stepwise removal of reports concerning the drug associated with the highest ranked SDR for an event was tested for gastric and oesophageal haemorrhages (GOH), central nervous system haemorrhages and cerebrovascular accidents (CNSH), ischaemic coronary artery disorders and muscle pains (MP) using the reporting odds ratio in the French spontaneous reporting research database. After ranking SDRs detected in the complete dataset on the lower limit of the reporting odds ratio 95% confidence interval, reports concerning the drug with the highest ranked SDR were removed. In the dataset thus generated, SDRs were again identified, ranked and reports related to the drug involved in the newly highest ranked SDR removed. The process was repeated until no signal was detected. Initially detected SDRs eliminated using this technique were assessed regarding the summary of products characteristics and the literature to determine their FP nature. RESULTS: Seventeen SDRs were successively eliminated for GOH, 37 for CNSH, 15 for ischaemic coronary artery disorders, and 36 for MP. Four were FP for GOH, 29 for CNSH, 7 for ACI and none were FP for MP. The positive predictive value of the backward stepwise removal procedure in identifying FP SDRs ranged from 0% (MP) to 78.4% (CNSH). CONCLUSIONS: Although further adjustment is needed to improve the method presented herein, our results suggest that numerous FP signals because of co prescription bias could be eliminated using an automated method. PMID- 23670807 TI - Cerebellar anaplastic astrocytoma in an adult with neurofibromatosis type 1: case report and review of literature. AB - BACKGROUND: Low-grade gliomas (e.g., pilocytic astrocytomas) are frequently found in patients with neurofibromatosis type 1 (NF1). Whereas most of those lesions are located supratentorially, cerebellar manifestations are described in < 1%. Malignant variants like glioblastoma and anaplastic astrocytoma (AA) are only rarely observed in NF1 patients. Thus, cerebellar AA is very infrequent and has not yet been described in an adult NF1 patient. CLINICAL PRESENTATION: We present the case of a 54-year-old male patient with von Recklinghausen disease who had a diffuse contrast-enhancing cerebellar mass that was resected guided by aminolevulinic acid (ALA)-fluorescence. Histopathological analyses revealed an AA with lack of pilocytic features or O6-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation. Due to the proximity of the tumor to the brainstem, adjuvant temozolomide chemotherapy was administered rather than first-line radiotherapy. Although the patient recovered quickly after the operation and tumor progression was ruled out in follow-up magnetic resonance imaging (MRI), the patient strongly deteriorated during a 16-month follow-up, and MRI revealed severe leukoencephalopathy. Extensive electrophysiological and radiological examination revealed a neurodegenerative disease of unknown etiology. Finally, the patient's condition improved receiving levodopa. CONCLUSIONS: A literature search yielded only one previously published case of an AA in a 9-year-old girl with NF1. Tumor control after resection was achieved in both patients; however, the patient in the mentioned report received radiation instead of temozolomide. In spite of different adjuvant therapies, tumor control for at least 16 months was achieved in both published cases. Thus, even though the role of adjuvant treatment options remains to be further elucidated, surgery is the appropriate therapy in these uncommon tumors providing mass reduction and histological diagnosis as well as tumor control. PMID- 23670806 TI - Myocardial damage following cardiac surgery: comparison between single-dose Celsior cardioplegic solution and cold blood multi-dose cardioplegia. AB - Myocardial protection during cardiac surgery can be accomplished by different cardioplegic solutions. The aim of this study was to assess myocardial damage after heart valve surgery performed with myocardial protection of a single dose of Celsior cardioplegia or with repeated cold blood cardioplegia. After the stratification of 139 valvular patients by means of matching according to cross clamp and cardiopulmonary bypass time, 32 patients were retained for comparison (16 patients received Celsior and 16 patients received cold blood cardioplegia). Creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI) release were evaluated until six days after the operation. Pre-operative characteristics were similar in both groups. In the Celsior group, CK-MB and cTnI values were significantly higher from the first up to the sixth post-operative day. Peak cTnI values were 19.4 +/- 13.4 and 9.7 +/- 7 ng/mL (p=0.01) in the Celsior and the Cold Blood group, respectively. Peak CK-MB values were 79.6 +/- 58.8 and 45.9 +/- 20.6 U/L (p=0.07) in the Celsior and the Cold Blood group, respectively. Cold blood cardioplegia reduces perioperative myocardial damage compared to the Celsior solution in elective cardiac valve operations. PMID- 23670808 TI - Vertebral and pulmonary actinomycosis mimicking metastatic lung cancer. AB - Actinomycosis of the spine with spinal cord compression is rare. Only 22 cases are reported in the literature. The authors describe a remarkable case of a large lesion leading to bony destruction and spinal cord compression in the cervicothoracic junction with a large intrathoracic extension, which was considered to be a metastatic pulmonary disease but turned out to be actinomycosis. CLINICAL PRESENTATION: A 55-year-old man presented with acute tetraparesis. Magnetic resonance imaging (MRI) and computed tomography (CT) imaging showed vertebral body collapse of T1 and partially C7 with spinal cord compression as well as a mass in the right upper lobe with multiple intrapulmonary nodules. Moreover, dorsal elements (laminae and spinous process) were also involved and partially destructed. Differential diagnosis favored metastatic pulmonary disease. INTERVENTION: Decompression surgery was performed by anterior corpectomy of T1, stabilization with an expandable titanium cage and additional anterior plate C7-T2. Histology revealed typical sulfur granules. Microbiology exams were positive for Actinobacillus actinomycetemcomitans. There was no proof of malignancy in thoracic biopsy in the late diagnostic work-up. To prevent instrumentation failure, an external immobilization (halo fixation) was applied until complete fusion was documented in CT during the postoperative course. After an 11-month course of ampicillin/sulbactam, there was complete resolution of the intrapulmonary and spinal pathology. CONCLUSION: Thoracic actinomycosis with spinal involvement is a rare disease. Therefore, diagnosis may be difficult. Surgical intervention, correct diagnosis, and specific long-term antibiotic treatment resulted in favorable outcome. PMID- 23670809 TI - Cost savings associated with prevention of recurrent lumbar disc herniation with a novel annular closure device: a multicenter prospective cohort study. AB - OBJECTIVE: Same-level recurrent disc herniation is a well-defined complication following lumbar discectomy. Reherniation results in increased morbidity and health care costs. Techniques to reduce these consequences may improve outcomes and reduce cost after lumbar discectomy. In a prospective cohort study, we set out to evaluate the cost associated with surgical management of recurrent, same level lumbar disc herniation following primary discectomy. METHODS: Forty-six consecutive European patients undergoing lumbar discectomy for a single-level herniated disc at two institutions were prospectively followed with clinical and radiographic evaluations. A second consecutive cohort of 30 patients undergoing 31 lumbar discectomies with implantation of an annular closure device was followed at the same hospitals and same follow-up intervals. Cost estimates for reherniation were modeled on Medicare national allowable payment amounts (direct cost) and patient work-day losses (indirect cost). RESULTS: Annular closure and control cohorts were matched at baseline. By 2 years follow-up, symptomatic recurrent same-level disc herniation occurred in three (6.5%) patients in the control cohort versus zero (0%) patients in the annular closure cohort. For patients experiencing recurrent disc herniation, mean estimated direct and indirect cost of management of recurrent disc herniation was $34,242 and $3,778, respectively. Use of an annular closure device potentially results in a cost savings of $222,573 per 100 primary discectomy procedures performed (or $2,226 per discectomy), based solely on the reduction of reoperated reherniations when modeled on U.S. Medicare costs. CONCLUSIONS: Recurrent disc herniation did not occur in any patients after annular closure within the 12-month follow-up. The reduction in the incidence of reherniation was associated with potentially significant cost savings. Development of novel techniques to prevent recurrent lumbar disc herniation is warranted to decrease the associated morbidity and health care costs associated with this complication. PMID- 23670810 TI - A randomized study of suprastomal stents in laryngotracheoplasty surgery for grade III subglottic stenosis in children. AB - OBJECTIVES/HYPOTHESIS: Studies comparing the relative effectiveness of suprastomal stents in laryngotracheoplasty surgery are lacking in the literature. The goal of this study was to compare the performance of two widely used short term suprastomal stents in open airway surgery. STUDY DESIGN: Prospective, randomized study of a single surgeon's outcomes for grade III subglottic stenosis (SGS) in children. METHODS: The open Aboulker Teflon stent versus the cut, closed, soft Silastic Montgomery T-tube stent for short-term stenting in double stage laryngotracheoplasty (dsLTP) were compared. RESULTS: Twenty-four patients were recruited into the study; 12 received an Aboulker (A) stent and 12 a cut, soft, Silastic (S) stent. There was no statistically significant difference in the operation specific decannulation rate between the two stent groups. Patients who received S stents were found to tolerate postoperative feeding better than those with A stents. The median time to decannulate, however, was longer for those receiving S stents (5.5 vs. 3.5 months, P = .02). Furthermore, those receiving S stents had increased need for airway dilation after stent removal (1.75 vs. 0.17 dilations per patient, P = .02) and increased presence of granulation tissue in the airway at the time of stent removal. Multivariate analysis showed the type of stent used independently correlated to time to decannulate (P = .022). CONCLUSIONS: Compared to the Teflon Aboulker stents, closed, soft, Silastic stents are associated with improved feeding in the postoperative period. Their use, however, also correlates with worsened granulation tissue formation and longer time to decannulation in patients undergoing dsLTP for grade III SGS. PMID- 23670811 TI - Interactions of genetic and environmental risk factors with respect to body fat mass in children: results from the ALSPAC study. AB - OBJECTIVE: To evaluate if percentile-specific effects of genetic, environmental and lifestyle obesity risk factors on body mass index (BMI) might reflect gene environment interactions with respect to the development of overweight. DESIGN AND METHODS: Retrospective study with data of 2,346 children from the Avon Longitudinal Study of Parents and Children (ALSPAC), using quantile regression with body fat mass index (FMI) for children at the age of 9 years as outcome variable. We assessed interactions of an "obesity-risk-allele-score" with environmental and nutritional factors. RESULTS: There was no evidence of interactions between the obesity-risk-allele score and the environmental variables except for maternal overweight. However, we found a significant interaction with respect to intake of mono- and polyunsaturated fatty acids at the age of 7. In children with low intake, genetic risk was associated with increasing effect sizes by FMI percentile. CONCLUSIONS: Our results suggest an interaction between a low dietary content of unsaturated fatty acids and genetic risk factors for overweight on FMI. This effect is likely to be stronger in children with higher FMI. PMID- 23670812 TI - Pharmacokinetics of immunomodulator treatments after roux-en-y bypass in obese patient. PMID- 23670813 TI - Bulky phosphinines: from a molecular design to an application in homogeneous catalysis. AB - The design and preparation of an asymmetrically substituted and bulky phosphinine was achieved by introducing sterically demanding substituents into specific positions of a rigid phosphorus-heterocyclic framework. Compound 5 shows, at the same time, axial chirality and a sufficiently high energy barrier for internal rotation to prevent enantiomerization. Both enantiomers of 5 were isolated by means of chiral analytical HPLC, and their absolute configurations could be assigned by combining experimental data and DFT calculations. Despite its substitution pattern, 5 can still coordinate to transition-metal centers through the lone pair of electrons on the phosphorus atom. Rapid C-H activation on the adjacent aryl substituent at the 2-position of the phosphorus heterocycle was achieved by using [{Cp*IrCl2}2] (Cp*=1,2,3,4,5-pentamethylcyclopentadienyl) as a metal precursor. A racemic mixture of 5 was applied as a pi-accepting low coordinate phosphorus ligand in the Rh-catalyzed hydroformylation of trans-2 octene, which showed a clear preference for the formation of 2-methyloctanal. PMID- 23670814 TI - A novel Cph-like gene involved in histogenesis and maintenance of midgut in Bombyx mori. AB - BACKGROUND: Male-biased silkworm larva resistance is useful for sericulture and lepidopteran pest control. According to previous research, the mechanism underlying this resistance might be related to midgut-specific proteins. RESULTS: A midgut-specific and novel hypothetical cuticular protein-like (Cph-like) gene was cloned, based on sex-disparity serial analysis of gene expression (SAGE) libraries of the B. mori midgut. The complete cDNA contained 676 bp and encoded 165 amino acid residues. The gene was located on chromosome 19 and it had only one short 75 bp intron. The Cph-like expression level was downregulated by exogenous 20-hydroxyecdysone or starvation, but upregulated by exogenous methoprene or food intake. Knockdown (siRNA) of the Cph-like gene suppressed the appetite and delayed larval development, while it also degraded enterocytes and damaged the midgut morphology. Furthermore, the male-biased cytoplasmic polyhedrosis virus (BmCPV) resistance of larvae was decreased. CONCLUSION: The Cph-like gene is a midgut-specific novel gene in B. mori that may participate in histogenesis and midgut maintenance. PMID- 23670815 TI - Identification of efflux proteins using efficient radial basis function networks with position-specific scoring matrices and biochemical properties. AB - Efflux proteins are membrane proteins, which are involved in the transportation of multidrugs. The annotation of efflux proteins in genomic sequences would aid to understand the function. Although the percentage of membrane proteins in genomes is estimated to be 25-30%, there is no information about the content of efflux proteins. For annotating such class of proteins it is necessary to develop a reliable method to identify efflux proteins from amino acid sequence information. In this work, we have developed a method based on radial basis function networks using position specific scoring matrices (PSSM) and amino acid properties. We noticed that the C-terminal domain of efflux proteins contain vital information for discrimination. Our method showed an accuracy of 78 and 92% in discriminating efflux proteins from transporters and membrane proteins, respectively using fivefold cross-validation. We utilized our method for annotating the genomes E. coli and P. aeruginosa and it predicted 8.7 and 9.2% of proteins as efflux proteins in these genomes, respectively. The predicted efflux proteins have been compared with available experimental data and we observed a very good agreement between them. Further, we developed a web server for classifying efflux proteins and it is freely available at http://rbf.bioinfo.tw/~sachen/EFFLUXpredict/Efflux-RBF.php. We suggest that our method could be an effective tool for annotating efflux proteins in genomic sequences. PMID- 23670817 TI - Differential effects of stress and glucocorticoids on adult neurogenesis. AB - Stress is known to inhibit neuronal growth in the hippocampus. In addition to reducing the size and complexity of the dendritic tree, stress and elevated glucocorticoid levels are known to inhibit adult neurogenesis. Despite the negative effects of stress hormones on progenitor cell proliferation in the hippocampus, some experiences which produce robust increases in glucocorticoid levels actually promote neuronal growth. These experiences, including running, mating, enriched environment living, and intracranial self-stimulation, all share in common a strong hedonic component. Taken together, the findings suggest that rewarding experiences buffer progenitor cells in the dentate gyrus from the negative effects of elevated stress hormones. This chapter considers the evidence that stress and glucocorticoids inhibit neuronal growth along with the paradoxical findings of enhanced neuronal growth under rewarding conditions with a view toward understanding the underlying biological mechanisms. PMID- 23670816 TI - Integration of a graphite/poly(methyl-methacrylate) composite electrode into a poly(methylmethacrylate) substrate for electrochemical detection in microchips. AB - Traditional fabrication methods for polymer microchips, the bonding of two substrates together to form the microchip, can make the integration of carbon electrodes difficult. We have developed a simple and inexpensive method to integrate graphite/PMMA composite electrodes (GPCEs) into a PMMA substrate. These substrates can be bonded to other PMMA layers using a solvent-assisted thermal bonding method. The optimal composition of the GPCEs for electrochemical detection was determined using cyclic voltammetry with dopamine as a test analyte. Using the optimized GPCEs in an all-PMMA flow cell with flow injection analysis, it was possible to detect 50 nM dopamine under the best conditions. These electrodes were also evaluated for the detection of dopamine and catechol following separation by MCE. PMID- 23670818 TI - Prolonged running, not fluoxetine treatment, increases neurogenesis, but does not alter neuropathology, in the 3xTg mouse model of Alzheimer's disease. AB - Reductions in adult neurogenesis have been documented in the original 3xTg mouse model of Alzheimer's disease (AD), notably occurring at the same age when spatial memory deficits and amyloid plaque pathology appeared. As this suggested reduced neurogenesis was associated with behavioral deficits, we tested whether activity and pharmacological stimulation could prevent memory deficits and modify neurogenesis and/or neuropathology in the 3xTg model backcrossed to the C57Bl/6 strain. We chronically administered the antidepressant fluoxetine to one group of mice, allowed access to a running wheel in another, and combined both treatments in a third cohort. All treatments lasted for 11 months. The female 3xTg mice failed to exhibit any deficits in spatial learning and memory as measured in the Morris water maze, indicating that when backcrossed to the C57Bl/6 strain, the 3xTg mice lost the behavioral phenotype that was present in the original 3xTg mouse maintained on a hybrid background. Despite this, the backcrossed 3xTg mice expressed prominent intraneuronal amyloid beta (Abeta) levels in the cortex and amygdala, with lower levels in the CA1 area of the hippocampus. In the combined cohort, fluoxetine treatment interfered with exercise and reduced the total distance run. The extent of Abeta neuropathology, the tau accumulations, or BDNF levels, were not altered by prolonged exercise. Thus, neuropathology was present but not paralleled by spatial memory deficits in the backcrossed 3xTg mouse model of AD. Prolonged exercise for 11 months did improve the long-term survival of newborn neurons generated during middle-age, whereas fluoxetine had no effect. We further review and discuss the relevant literature in this respect. PMID- 23670819 TI - Quantitative analysis of the cochlea using three-dimensional reconstruction based on microcomputed tomographic images. AB - The aim of this study was to provide data on various dimensions of the normal cochlea using three-dimensional reconstruction based on high-resolution micro-CT images. The petrous parts of 39 temporal bones were scanned by micro-computed tomography (CT) with a slice thickness of 35 MUm. The micro-CT images were used in reconstructing three-dimensional volumes of the bony labyrinth using computer software. The volumes were used to measure 12 dimensions of the cochlea, and statistical analysis was carried out. The dimensions of cochleae varied widely between different specimens. The mean height and length of the cochlea were 3.8 and 9.7 mm, respectively. The angle between the basal and middle turns was slightly larger in males than in females, while none of the other 11 dimensions differed significantly between males and females. The cochlear accessory canals were observed in about half of the cases (51.3%). Correlation analysis among measured items revealed positive correlations among several of the measured dimensions. The present study could investigate the detailed anatomy of the normal cochlea using high-resolution imaging technologies. The results of the present study could be helpful for the precise diagnosis of congenital cochlear malformations and for producing optimized cochlear implants. PMID- 23670820 TI - Isolated cerebral susceptibility artefacts in patients with malignant melanoma: metastasis or not? AB - OBJECTIVE: While staging patients with malignant melanoma, cerebral susceptibility artefacts on T2*-weighted/susceptibility-weighted imaging (SWI) sequences without a correlate on contrast-enhanced T1-weighted images can be confusing. Without intravenous contrast enhancement, cavernomas, microhaemorrhages and melanin-containing metastases represent possible differential diagnoses for these findings. The purpose of this study was to find out, how often such lesions correspond to metastases. METHODS: Brain MR images (1.5 T) of 408 patients with malignant melanoma but without cerebral metastases in the initial staging by MRI were reviewed retrospectively. Eighteen patients (5 female, 13 male) with malignant melanoma and signal intensity loss on T2*/SWI were included in our study. The average observation period was 19.6 months (6-46 months, 2006-2009). RESULTS: In each of these 18 patients between one and seven hypointense lesions on T2*/SWI were found. None of these lesions developed into metastasis. CONCLUSION: Focal areas of susceptibility artefacts in the brain parenchyma without corresponding abnormalities in contrast-enhanced T1 weighted images are unlikely to represent brain metastases. KEY POINTS: * In melanoma patients early diagnosis of metastatic brain lesions is mandatory. * Melanin content and haemorrhage are potential reasons for MRI characteristics of melanoma metastases. * Susceptibility-weighted MRI visualises melanin and blood products. * Isolated cerebral susceptibility artefacts do not convert into melanoma metastases. * SWI/T2* sequences cannot replace Gd-enhanced sequences. PMID- 23670821 TI - Expert's comment concerning Grand Rounds case entitled "Lead toxicity and management of gunshot wounds in the lumbar spine" (by B. Rentfrow, R. Vaidya, C. Elia, A. Sethi doi:10.1007/s00586-013-2805-6). PMID- 23670822 TI - Transient neurological deficit following midthoracic decompression for severe stenosis: a series of three cases. AB - PURPOSE: To report three cases of transient perioperative neurological deficit in the absence of direct cord insult following decompression of the severely stenotic thoracic spine. METHODS: The clinical and radiographic electronic medical records of three patients who underwent decompression for severe midthoracic stenosis with transient neurological deficits perioperatively were reviewed. The cases are presented with consideration of possible underlying mechanisms and multimodality intraoperative monitoring (IOM) findings. RESULTS: Two patients had neurologic changes on IOM and Stagnara wake-up test, the remaining patient had absent motor and sensory potentials at baseline and throughout the case. IOM changes were observed immediately following decompression in the absence of direct cord insult or displacement. Postoperatively all patients experienced neurological motor deficits which presented as complete paralysis of the right lower extremity in two of the patients and the left lower extremity in one patient. The deficit was transient improvement of motor strength occurred between 1 and 13 months of follow-up in all patients. CONCLUSION: Decompression of a severely stenotic region of the thoracic spinal cord may lead to a complete yet transient motor deficit in the perioperative period in the absence of direct mechanical cord insult. Potential etiologies include ischemia-reperfusion injury, microthrombi, and altered perfusion due to internal recoil of spinal cord architecture following decompression. IOM may show conspicuous findings in such events, however, may not be relied upon when baseline potentials are sub-optimal. Recognition of this short-lived neurological deficit following decompression of the severely stenotic thoracic spine will improve preoperative patient counseling and merits further study for determination of the precise pathophysiology. PMID- 23670823 TI - Purification and partial characterization of a novel neurotoxic protein from eggs of black widow spiders (Latrodectus tredecimguttatus). AB - Up to now, there have been a few reports on the toxic components purified from black widow spider (Latrodectus tredecimguttatus) eggs. In the present study, a novel neurotoxic protein was purified from the eggs by gel filtration combined with ion-exchange chromatography. Its molecular weight was 23.752 kDa determined by electrospray mass spectrometry. The protein could block the neuromuscular transmission in mouse-isolated phrenic nerve-hemidiaphragm preparations completely in a reversible manner and activate tetrodotoxin-sensitive sodium current in rat dorsal root ganglion cells. The N-terminal sequence of the protein was identified by the Edman degradation to be N-S-I-A-D-D-R-Y-R-W-P-G-Y-P-G-A-G-L I-P-Y-I-I-D-S-. When the sequence was used to search against protein database with a sequence query in Mascot engine there was no matched sequence or protein whereas the Basic Local Alignment Search Tool (BLAST) analysis indicated that no significant similarity was found. These results demonstrated that the protein (named Latroeggtoxin-I) is a novel neurotoxic protein purified from the eggs of black widow spiders. PMID- 23670825 TI - Stereocontrolled total synthesis of polygalolide A. AB - The total synthesis of polygalolide A, a secondary metabolite that was isolated from a Chinese medicinal plant, is reported. A key issue in this synthesis was construction of an oxabicyclo[3.2.1] skeleton, which was solved by the development of an intramolecular Ferrier-type C-glycosylation of a glucal with siloxyfuran as an internal nucleophile. The substrate was prepared from D-glucal by the introduction of trimethylsilylacetylene and siloxyfuran groups. Although C glycosylation did not occur under the conditions found from model experiments, further examination revealed that the combination of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2,4,6-collidine successfully afforded the desired product as a single diastereomer. The siloxy group at the C3 position played a crucial role in the stereocontrol of this reaction. The product was further transformed into a tetracyclic compound as follows: The vinyl ether and acetylenic moieties were reduced and the siloxy group was removed with a Barton McCombie reaction. The construction of the six-membered ether and the gamma lactone provided the tetracyclic compound. Finally, a phenolic moiety was introduced by using a Mukaiyama aldol reaction to furnish polygalolide A. PMID- 23670824 TI - Influence of baclofen on laryngeal and spinal motor drive during cough in the anesthetized cat. AB - OBJECTIVES/HYPOTHESIS: The antitussive properties of (+/-) baclofen on laryngeal muscle activities have not been determined. The hypothesis of this study was that administration of (+/-) baclofen would suppress upper airway muscle motor activity in a dose-dependent manner during cough. STUDY DESIGN: This is a prospective, preclinical, hypothesis-driven, paired design. METHODS: Electromyograms of the parasternal, rectus abdominis, thyroarytenoid, posterior cricoarytenoid, and thyrohyoid were measured, along with esophageal pressure. Cough was elicited by mechanical stimulation of the lumen of the intrathoracic trachea in spontaneously breathing cats. RESULTS: Baclofen (+/-) (3-10 MUg kg(-1) i.a.) induced decreases in the electromyogram amplitude of the rectus abdominis motor drive during coughing, the inspiratory and active expiratory (E1) phases of cough, and cough number per epoch. There was no effect of (+/-) baclofen on the EMG amplitudes of any of the laryngeal muscles, the parasternal, or the duration of the passive expiratory (E2) phase. CONCLUSIONS: Results from the present study indicate differential control mechanisms for laryngeal and inspiratory motor drive during cough, providing evidence of a control system regulating laryngeal activity and inspiratory spinal drive that is divergent from the control of expiratory spinal motoneurons. PMID- 23670826 TI - Suitability of different pollen as alternative food for the predatory mite Amblyseius swirskii (Acari, Phytoseiidae). AB - The predacious mite Amblyseius swirskii Athias-Henriot is used as a biological control agent against various pests in greenhouses. Pollen offered as supplementary food is reported to improve their fast establishment and performance. However, the nutritional suitability of different pollens for A. swirskii is not sufficiently known yet. Pollens of 21 plant species were offered to the mites as exclusive food during preimaginal development. Preimaginal mortality and developmental time have been assessed, followed by a life-table analysis of the emerged adults and a calculation of demographic parameters. Amblyseius swirskii can feed exclusively on pollen, but the nutritional value of the pollens differed significantly. Pollens of Lilium martagon and Hippeastrum sp. were toxic, causing 100 % preimaginal mortality, probably due to secondary plant compounds. Hibiscus syriacus pollen was absolutely incompatible for the juvenile and adult mites, possibly due to their external morphology, differing from all the other pollens tested and leading to 100 % preimaginal mortality also. Considering all parameters, feeding on Aesculus hippocastanum, Crocus vernus, Echinocereus sp. and Paulownia tomentosa pollens lead to the best performance of the mites. Feeding on most pollens resulted in no or low preimaginal mortality of A. swirskii, but affected significantly developmental time, adult longevity, and reproduction parameters. Commercial bee pollen was not able to improve life-table parameters compared to pure pollen of the plant species. Pollens of Helianthus annuus, Corylus avellana and a Poaceae mix were less suitable as food source and resulted in a poor performance of all tested parameters. Compared with literature data, 18 pollens tested proved to be a similar or better food source than cattail pollen, qualifying A. swirskii as a positively omnivorous type IV species. Pollens of Ricinus communis and Zea mays can be recommended as supplementary food offered as banker plants, and A. hippocastanum and Betula pendula pollen is recommended to be used as dispersible pollen in greenhouses. PMID- 23670827 TI - Determination of serum antioxidant vitamins, glutathione and MDA levels in panic disorder patients. AB - There are sufficient experimental evidences to establish the relationship between the elevated level of malondealdehyde (MDA)-the lipid peroxidation product and depleted level of antioxidants (Vitamin A, E, C and glutathione) in several psychiatric disorders. But previously no study was carried out to determine these components in panic disorder (PD) patients of Bangladesh. This study was conducted to assess the serum concentration of antioxidant vitamins, MDA and glutathione in 54 panic disorder patients and 52 healthy volunteers. Patients were recruited from Bangabandhu Sheikh Mujib Medical University, Bangladesh by random sampling. Serum level of MDA, glutathione and vitamin C were determined by UV spectrophotometric method whereas Vitamins A and E were detected by RP-HPLC method. Data were analyzed by independent t test and Pearson's correlation analysis. It had been found that the PD patients had low level of antioxidants like vitamin A (p=0.041) and vitamin E (p=0.018) than the healthy controls whereas the change of vitamin C is not significant. It had been found that the MDA content was significantly higher (p<0.05) in PD patients than that of controls. There was no significant difference for the glutathione content between the 2 groups. Pearson's correlation coefficient suggested that there were significant negative correlation between the glutathione level and vitamin C (p=0.013) and a positive correlation between the vitamin E and vitamin A (p=0.020) in patient group. Our study reveals that panic disorder patients have considerably higher level of MDA, lower level of antioxidant vitamins and glutathione than the healthy control subjects. PMID- 23670828 TI - From social capital to health--and back. AB - We assess the causal relationship between health and social capital, measured by generalized trust, both at the individual and the community level. The paper contributes to the literature in two ways: it tackles the problems of endogeneity and reverse causation between social capital and health by estimating a simultaneous equation model, and it explicitly accounts for mis-reporting in self reported trust. The inter-relationship is tested using data from the first four waves of the European Social Survey for 25 European countries, supplemented by regional data from Eurostat. Our estimates show that a causal and positive relationship between self-perceived health and social capital does exist and that it acts in both directions. In addition, the magnitude of the structural coefficients suggests that individual social capital is a strong determinant of health, whereas community level social capital plays a considerably smaller role in determining health. PMID- 23670829 TI - Late pregnancy reversal from excessive gestational weight gain lowers risk of childhood overweight--a cohort study. AB - OBJECTIVE: Whether reversal to adequate gestational weight gain (GWG) in the third trimester reverses the risk for childhood overweight associated with excessive GWG is assessed. DESIGN AND METHODS: In a retrospective cohort study in 6,665 mother-child pairs, pre-pregnancy weight and the temporal course of GWG were collected from medical records. Overweight as defined by International Obesity Task Force was assessed at a mean age of 5.8 years. Main exposures were exceeding week-specific cut-off values for GWG in the third trimester or any previous trimester. Logistic regression models, adjusted for possible confounding factors, were used to predict the risk of childhood overweight from excessive GWG in the third trimester with stratification by excessive GWG in previous trimesters. RESULTS: In the final model, women who avoided excessive GWG in the third trimester had children with a 31% (odds ratio [OR]: 0.69, 95% confidence interval [CI]: 0.59, 0.82) lower probability being overweight. A similar association was observed for reversing from excessive GWG in the first or second trimester to normal GWG in the third trimester: 27% (OR: 0.73, 95% CI: 0.53, 0.99). CONCLUSIONS: Avoidance of excessive GWG in the third trimester is associated with lower risk of childhood overweight even in case of excessive GWG in the first or second trimester. PMID- 23670830 TI - A safe space to speak above the silences. PMID- 23670831 TI - Bispidine platform grants full control over magnetic state of ferrous chelates in water. AB - A bicyclic ligand platform for iron(II), which allows total control over the complex's magnetic properties in aqueous solution simply by varying one of the six coordination sites of the bispidine ligand, is reported. To achieve this, an efficient synthetic route to an N5 bispidine framework (ligand L4) that features an unsubstituted N-7 site is established. Then, by choosing appropriate N-7 coordinating substituents, the spin state of choice can be imposed on the corresponding ferrous complexes under environmentally relevant conditions in water and near-room temperature. Importantly, the first low-spin and diamagnetic iron(II) chelates in the bispidine series, both in the solid state and in aqueous solution, are reported. The eradication of head-on steric clashes between pendent coordinating arms is at the origin of this success. A new pair of constitutionally similar ferrous coordination compounds of a multidentate ligand system is obtained, which exhibits a distinctly binary (off-on) magnetic relationship. The new synthetic intermediate L4 may be substituted in just one step by any desired pendent arm, thus allowing access to complexes with finely tuned magnetic properties. PMID- 23670832 TI - Forced assembly of water-dispersible carbon nanotubes trapped in paper for cheap gas sensors. AB - A versatile and readily scalable approach to fabricate a cheap and sensitive paper gas sensor is described. Chemically acidified single-walled carbon nanotubes are assembled in paper, forming continuous sensing arrays with a low detection limit and high detection selectivity for ammonia gas. PMID- 23670833 TI - Quantum wave packet and quasiclassical trajectory studies of the reaction H(2S) + CH(X2 Pi; v = 0, j = 1) -> C(1D) + H2 (X1 Sigmag+): Coriolis coupling effects and stereodynamics. AB - The quantum mechanics (QM) and quasiclassical trajectory (QCT) calculations have been carried out for the title reaction with the ground minimal allowed rotational state of CH (j = 1) on the 1 (1)A' potential energy surface. For the reaction probability at total angular momentum J = 0, a similar trend of the QM and QCT calculations is observed, and the QM results are larger than the latter almost in the whole considered energy range (0.1-1.5 eV). The QCT integral cross sections are larger than the QM results with centrifugal sudden approximation, while smaller than those from QM method including Coriolis coupling for collision energies bigger than 0.25 eV. The quantum wave-packet computations show that the Coriolis coupling effects get more and more pronounced with increasing of J. In addition to the scalar properties, the stereodynamical properties, such as the average rotational alignment factor , the angular distributions P(thetar ), P(phir ), P(thetar ,phir ), and the polarization-dependent generalized differential cross sections have been explored in detail by QCT approach. PMID- 23670834 TI - What is the role of molecular markers in the management of "indeterminate" thyroid nodules? PMID- 23670835 TI - Cytological preparations for molecular pathology: Letter to the editor regarding "Ancillary techniques on direct-smear aspirate slides: a significant evolution for cytopathology techniques". PMID- 23670836 TI - Reply to Ancillary techniques on direct-smear aspirate slides: a significant evolution for cytopathology techniques. PMID- 23670837 TI - Nerve cross-sectional area in extremes of age. AB - INTRODUCTION: Nerve cross-sectional area reference values have been reported for many nerves, but there have been few studies in pediatric and geriatric populations. This study was conducted to determine the influence of age on nerve cross-sectional area. METHODS: Thirty-two children (3 months to 16 years) and 20 geriatric adults (67-92 years) without known neurologic conditions underwent bilateral ultrasound to measure the area of the following nerves: median at the wrist and forearm; ulnar at the wrist and elbow; radial in the spiral groove; sciatic in the distal thigh; fibular at the knee; tibial at the knee and ankle; and sural at the ankle. RESULTS: In general, nerve cross-sectional area increased with age. Nerve size correlated most closely with age, but a correlation was also seen with body mass index. CONCLUSIONS: Nerve cross-sectional area increases with age, which is important to note when using ultrasound to evaluate children and geriatric patients. PMID- 23670838 TI - Alternative zinc-binding sites explain the redox sensitivity of zinc-containing anti-sigma factors. AB - Certain bacterial zinc-containing anti-sigma (ZAS) factors respond sensitively to thiol-induced oxidative stress by undergoing conformational changes, which in turn reduce binding affinities for their cognate sigma factors. This redox sensitivity provides a mechanism for coping with oxidative stress by activating the transcription of antioxidant genes. Not all ZAS proteins are redox-sensitive, but the mechanism of redox sensitivity is not fully understood. Here we propose that alternative zinc-binding sites determine redox sensitivity. To support this proposal, we performed protein modeling and zinc docking on redox-sensitive and redox-insensitive ZAS proteins complexed with their cognate sigma factors. At least one strong alternative zinc-binding pocket was detected for all known redox sensitive ZAS factors in actinomycetes, while no strong alternative zinc-binding pocket was identified in redox-insensitive ZAS factors, except for one controversial case. This hypothesis of alternative zinc-binding sites can also explain residue-specific contributions to the redox sensitivity of RsrA, a redox sensing ZAS protein from Streptomyces coelicolor, for which alanine mutagenesis experiments are available. Our results suggest a mechanistic model for redox sensitivity as follows: zinc ion can probabilistically occupy multiple sites in redox-sensitive ZAS proteins, increasing the susceptibility of zinc-coordinating cysteine residues to oxidation. This picture of probabilistic zinc occupation agrees with a previous structure and energy analysis on zinc finger proteins, and thus it may be more widely applicable to other classes of reactive zinc-binding proteins. PMID- 23670839 TI - [Radiation therapy of meningioma of the anterior visual pathway]. AB - Radiotherapy is an established alternative to surgery in the treatment of meningiomas. Particularly in cases of symptomatic tumors of the optical pathways, irradiation is the treatment of choice when the functional risks of surgery are high. Because histological findings are often lacking an interdisciplinary discussion is important to determine neuroradiological and neuro-ophthalmological patterns of the tumor. As a general benefit for immediate irradiation after subtotal resection could not yet be shown and the risk for side effects is increased, a postoperative radiotherapy has to be discussed in each individual patient. The choice of the special irradiation schedule depends on tumor size and its localization in the proximity of critical structures. Three-dimensional treatment planning with magnetic resonance imaging (MRI) information on the tumor and its surroundings is mandatory. A precise immobilization of the patient is necessary for treatment in the area of the anterior visual pathways. PMID- 23670840 TI - [Transplant rejection due to immunological reasons?]. PMID- 23670841 TI - [Ocular myasthenia gravis]. AB - Ocular myasthenia gravis, although clinically often characterized by typical classical features, can cause considerable diagnostic problems. This article aims to provide a pragmatic approach to the pathogenesis, clinical features, diagnostics and therapeutic strategies in the clinical routine. PMID- 23670842 TI - [DOG code for Ethics and Compliance]. PMID- 23670843 TI - Seed-assisted, one-pot synthesis of hollow zeolite beta without using organic structure-directing agents. AB - Hollow aluminosilicate zeolite beta was successfully synthesized by adding CIT-6, that is, zincosilicate zeolite, which has the same topology as beta, as seeds to the Na-aluminosilicate gel without the need for organic structure-directing agents. One important factor in the successful organic structure-directing agent (OSDA)-free synthesis of hollow beta crystals is the solubility of the seed crystals in alkaline media. CIT-6 was less stable than aluminosilicate zeolite beta in alkaline media and the solubility changed depending on whether the crystals were calcined or not. The hollow beta could be obtained by using the uncalcined CIT-6 seed crystals. The volumes of intra-crystalline voids were tuned by changing the reaction time and the initial gel compositions, such as the SiO2/Al2O3 and Na2O/SiO2 ratios. We estimated that the intra-crystalline voids were formed through the dissolution of the seed crystals, just after the crystal growth of new beta on the outer surface of the seeds. In addition, new crystal growth toward inside of the void was also observed by TEM. On the basis of the characterization data, such as chemical analysis, N2-adsorption/desorption measurements, and TEM observation, a formation mechanism of the intra-crystalline voids is proposed and discussed. PMID- 23670844 TI - Enhance knowledge on sustainable use of plant protection products within the framework of the sustainable use directive. AB - BACKGROUND: In 2008-2009, a survey in the Emilia Romagna region of Italy collected information on the farm use of plant protection products (PPPs) and evaluated whether the provisions of the Directive for the Sustainable Use of Pesticides are applicable. It was concluded that the provisions can be implemented, even if some gaps need to be filled and also the behaviour of farmers needs to be improved. Moreover, it was observed that all stages in the use of PPPs on farms could generate risks for the operator and/or the environment. One of the recommendations is to promote training for operators and to adopt good agronomic practices in order to improve sustainable use of PPPs. RESULTS: The findings were used, in the following years, to develop a Guideline for Sustainable Use of PPPs to help the user in identifying the flaws in current practices at farm level as well as their corresponding corrective actions. The Guidelines are accompanied by free online software to be used as a diagnostic tool as well as to provide recommendations for improvements. CONCLUSION: The approach adopted, taking into account the variability in farm structure, cropping pattern, risk attitude and economic availability, is not an instrument to identify the most suitable protection strategy for a given crop in a given period, but to help professional users to improve their practices in managing PPPs on farms and to make the most appropriate choices leading to reduced environmental and human risk, without compromising the profitability of agricultural production and food standards. This work has, as an underlying principle, a holistic approach to link the different elements of the three pillars of sustainability (environment, economy and society) and to enhance knowledge, which represents one of the main aspects of the Directive. PMID- 23670847 TI - Cu nanoclusters with aggregation induced emission enhancement. AB - A facile and versatile method for preparing water-soluble, stable, luminescent Cu nanoclusters (NCs) via the process of size-focusing etching from nonluminescent nanocrystals is presented. Using glutathione as a model ligand, the smallest cluster, Cu2 , is selectively synthesized to form a nearly monodisperse product, eliminating the need for tedious size fractionation. Evolution of photoluminescence and absorption spectra reveal that the formation of stable cluster species occurs through surface etching. Intriguingly, the as-prepared CuNCs exhibit an aggregation-induced emission enhancement effect. The CuNCs emit a faint light when dispersed in aqueous solution, but generate a striking fluorescence intensity enhancement upon aggregation. Armed with these attractive properties, the emissive CuNCs are expected to open new opportunities for the construction of light-emitting diodes, chemosensors, and bioimaging systems. PMID- 23670846 TI - Biomechanical parameters of the BP-enriched bone cement. AB - Bisphosphonates (BPs) are well-known substances with very efficient antiresorptive properties. Their beneficial actions are useful not only in achieving better bone mineral density but also in improving bone microarchitecture, strength and, consequently, its quality. Surgical cement, being a polymer composite, is required to be highly biocompatible and biotolerant. The goal of the presented study was to assess whether the enrichment of cement with pamidronate has changed its biomechanical properties. We compared the biomechanical parameters of clean bone cement and BP-enriched bone cement, which were both used formerly in our rat models. Biomechanical properties of BP enriched bone cement are defined by two basic terms: stress and strain, which are caused by the influence of external force. In the investigatory process of the bone's biomechanical parameters, the compressive test and the three-point flexural tests were used. During the three-point flexural investigation, the sample was supported at both ends and loaded in the middle, resulting in a flexure. After a specific range of flexure, the sample was fractured. In obtained results, there were no significant differences in the values of the stress determined at the point of maximal load and the energy stored in the samples for proportional stress-strain limit (elastic region). There were also no significant differences in the density of the samples. The study shows that the enrichment of bisphosphonates causes yielding of the bone cement material. In the presented data, we conclude that use of pamidronate implanted in bone cement did not have a detrimental effect on its biomechanical properties. Therefore, the obtained results encouraged us to perform further in vivo experiments which assess the biomechanical properties of bones implanted with BP-enriched bone cement. PMID- 23670848 TI - SPARC is up-regulated during skeletal muscle regeneration and inhibits myoblast differentiation. AB - Skeletal muscle repair is mediated primarily by the muscle stem cell, the satellite cell. Several factors, including extracellular matrix, are known to regulate satellite cell function and regeneration. One factor, the matricellular Secreted Protein Acidic and Rich in Cysteine (SPARC) is highly up-regulated during skeletal muscle disease, but its function remains elusive. In the present study, we demonstrate a prominent yet transient increase in SPARC mRNA and protein content during skeletal muscle regeneration that correlates with the expression profile of specific muscle factors like MyoD, Myf5, Myf6, Myogenin, NCAM, CD34, and M-Cadherin, all known to be implicated in satellite cell activation/proliferation following muscle damage. This up regulation was detected in more cell types. Ectopic expression of SPARC in the muscle progenitor cell line C2C12 was performed to mimic the high levels of SPARC seen in muscle disease. SPARC overexpression almost completely abolished myogenic differentiation in these cultures as determined by substantially reduced levels of myogenic factors (Pax7, Myf5, Myod, Mef2B, Myogenin, and Myostatin) and a lack of multinucleated myotubes. These results demonstrate that there is a delicate temporal regulation of SPARC to which more sources in the micro environment contribute, and that disturbances in this, such as extensive up regulation, may have an adverse effect on muscle regeneration. PMID- 23670849 TI - Competition and quality in home health care markets. AB - Market-based solutions are often proposed to improve health care quality; yet evidence on the role of competition in quality in non-hospital settings is sparse. We examine the relationship between competition and quality in home health care. This market is different from other markets in that service delivery takes place in patients' homes, which implies low costs of market entry and exit for agencies. We use 6 years of panel data for Medicare beneficiaries during the early 2000s. We identify the competition effect from within-market variation in competition over time. We analyze three quality measures: functional improvements, the number of home health visits, and discharges without hospitalization. We find that the relationship between competition and home health quality is nonlinear and its pattern differs by quality measure. Competition has positive effects on functional improvements and the number of visits in most ranges, but in the most competitive markets, functional outcomes and the number of visits slightly drop. Competition has a negative effect on discharges without hospitalization that is strongest in the most competitive markets. This finding is different from prior research on hospital markets and suggests that market-specific environments should be considered in developing polices to promote competition. PMID- 23670851 TI - QM/MM study on the light emitters of aequorin chemiluminescence, bioluminescence, and fluorescence: a general understanding of the bioluminescence of several marine organisms. AB - Aequorea victoria is a type of jellyfish that is known by its famous protein, green fluorescent protein (GFP), which has been widely used as a probe in many fields. Aequorea has another important protein, aequorin, which is one of the members of the EF-hand calcium-binding protein family. Aequorin has been used for intracellular calcium measurements for three decades, but its bioluminescence mechanism remains largely unknown. One of the important reasons is the lack of clear and reliable knowledge about the light emitters, which are complex. Several neutral and anionic forms exist in chemiexcited, bioluminescent, and fluorescent states and are connected with the H-bond network of the binding cavity in the protein. We first theoretically investigated aequorin chemiluminescence, bioluminescence, and fluorescence in real proteins by performing hybrid quantum mechanics and molecular mechanics methods combined with a molecular dynamics method. For the first time, this study reported the origin and clear differences in the chemiluminescence, bioluminescence and fluorescence of aequorin, which is important for understanding the bioluminescence not only of jellyfish, but also of many other marine organisms (that have the same coelenterazine caved in different coelenterazine-type luciferases). PMID- 23670850 TI - Ectopic fat and adipokines in metabolically benign overweight/obese women: the Kronos Early Estrogen Prevention Study. AB - OBJECTIVE: It is unclear why despite a comparable cardiometabolic risk profile, "metabolically benign" overweight/obese individuals show an elevated risk of cardiovascular disease compared to normal weight individuals. DESIGN AND METHODS: In cross-sectional analyses, we compared levels of ectopic fat (epicardial, pericardial, and hepatic fat) and adipokines (leptin, soluble leptin receptor, and high molecular weight [HMW] adiponectin) among metabolically benign (MBO) and at-risk overweight/obese (ARO), and metabolically benign normal weight (MBNW) women, screened for the Kronos Early Estrogen Prevention Study. We defined "metabolically benign" with <= 1, and "at-risk" with >=2 components of the metabolic syndrome. RESULTS: Compared to MBO women, ARO women had significantly elevated odds of being in the top tertile of epicardial fat (OR: 1.76, 95% CI: 1.04-2.99), hepatic fat (OR: 1.90, 95% CI:1.12-3.24) and leptin (OR: 2.15, 95% CI: 1.23-3.76), and the bottom tertile of HMW-adiponectin (OR: 2.90, 95% CI: 1.62 5.19). Compared to MBNW women, MBO women had significantly higher odds of being in the top tertile of epicardial fat (OR: 5.17, 95% CI: 3.22-8.29), pericardial fat (OR: 9.27, 95% CI: 5.52-15.56) and hepatic fat (OR: 2.72, 95% CI: 1.77-4.19) and the bottom tertile of HMW adiponectin levels (OR: 2.51, 95% CI: 1.60-3.94). CONCLUSIONS: Levels of ectopic fat and the adverse adipokine profile increase on a continuum of BMI, suggesting that the metabolically benign phenotype may be a transient state. PMID- 23670852 TI - Using lytic bacteriophages to eliminate or significantly reduce contamination of food by foodborne bacterial pathogens. AB - Bacteriophages (also called 'phages') are viruses that kill bacteria. They are arguably the oldest (3 billion years old, by some estimates) and most ubiquitous (total number estimated to be 10(30) -10(32) ) known organisms on Earth. Phages play a key role in maintaining microbial balance in every ecosystem where bacteria exist, and they are part of the normal microflora of all fresh, unprocessed foods. Interest in various practical applications of bacteriophages has been gaining momentum recently, with perhaps the most attention focused on using them to improve food safety. That approach, called 'phage biocontrol', typically includes three main types of applications: (i) using phages to treat domesticated livestock in order to reduce their intestinal colonization with, and shedding of, specific bacterial pathogens; (ii) treatments for decontaminating inanimate surfaces in food-processing facilities and other food establishments, so that foods processed on those surfaces are not cross-contaminated with the targeted pathogens; and (iii) post-harvest treatments involving direct applications of phages onto the harvested foods. This mini-review primarily focuses on the last type of intervention, which has been gaining the most momentum recently. Indeed, the results of recent studies dealing with improving food safety, and several recent regulatory approvals of various commercial phage preparations developed for post-harvest food safety applications, strongly support the idea that lytic phages may provide a safe, environmentally-friendly, and effective approach for significantly reducing contamination of various foods with foodborne bacterial pathogens. However, some important technical and nontechnical problems may need to be addressed before phage biocontrol protocols can become an integral part of routine food safety intervention strategies implemented by food industries in the USA. PMID- 23670853 TI - Obstructive sleep apnea and coronary artery pathology. PMID- 23670854 TI - Comparison between endoscopic and microscopic stapes surgery. AB - OBJECTIVES/HYPOTHESIS: To investigate whether endoscopic stapes surgery is safer and less invasive than conventional stapes surgery using an operating microscope. STUDY DESIGN: Retrospective study. METHODS: The subjects were 15 patients (15 ears) who underwent endoscopic stapes surgery for otosclerosis or congenital stapedial fixation. Another 35 patients (41 ears) in whom microscopic stapes surgery was performed by the same surgeon were assigned to the control group. The procedures for endoscopic surgery were fundamentally the same as those for microscopic surgery, unless there was no anterior or posterior auricular skin incision. The two surgical techniques were compared with respect to the operating time, postoperative hearing, complications, postoperative pain, and the extent of drilling at the posterosuperior part of the external auditory canal. RESULTS: There were no differences of operating time or postoperative hearing between the endoscopic and microscopic groups. There was very little postoperative pain in the endoscopic group. Postoperative dizziness was mild in all patients who received endoscopic surgery. Drilling at the posterosuperior part of the external auditory canal was less extensive in the endoscopic group than in the microscopic group. CONCLUSION: Endoscopic surgery is particularly suitable for stapedial disease. Endoscopic stapes surgery can even be done in patients with a curved and narrow external auditory canal. Endoscopic surgery is also suitable for education: The surgical anatomy can be understood easily and both the surgeon and assistants can observe the procedure on the same monitor. However, it should only be performed by experienced surgeons because one-handed manipulation is required and stereoscopic vision is not available. PMID- 23670855 TI - Cytochrome P450 compound I in the plane wave pseudopotential framework: GGA electronic and geometric structure of thiolate-ligated iron(IV)-oxo porphyrin. AB - The cytochromes P450 constitute a ubiquitous family of metalloenzymes, catalyzing manifold reactions of biological and synthetic importance via a thiolate-ligated iron-oxo (IV) porphyrin radical species denoted compound I (Cpd I). Experimental investigations have implicated this intermediate in a broad spectrum of biophysically interesting phenomena, further augmenting the importance of a Cpd I model system. Ab initio molecular dynamics, including Car-Parrinello and path integral methods, conjoin electronic structure theory with finite temperature simulation, affording tools most valuable to approach such enzymes. These methods are typically driven by density functional theory (DFT) in a plane-wave pseudopotential framework; however, existing studies of Cpd I have been restricted to localized Gaussian basis sets. The appropriate choice of density functional and pseudopotential for such simulations is accordingly not obvious. To remedy this situation, a systematic benchmarking of thiolate-ligated Cpd I is performed using several generalized-gradient approximation (GGA) functionals in the Martins-Troullier and Vanderbilt ultrasoft pseudopotential schemes. The resultant electronic and structural parameters are compared to localized-basis DFT calculations using GGA and hybrid density functionals. The merits and demerits of each scheme are presented in the context of reproducing existing experimental and theoretical results for Cpd I. PMID- 23670856 TI - Substrate versus inhibitor dynamics of P-glycoprotein. AB - By far the most studied multidrug resistance protein is P-glycoprotein. Despite recent structural data, key questions about its function remain. P-glycoprotein (P-gp) is flexible and undergoes large conformational changes as part of its function and in this respect, details not only of the export cycle, but also the recognition stage are currently lacking. Given the flexibility, molecular dynamics (MD) simulations provide an ideal tool to examine this aspect in detail. We have performed MD simulations to examine the behaviour of P-gp. In agreement with previous reports, we found that P-gp undergoes large conformational changes which tended to result in the nucleotide-binding domains coming closer together. In all simulations, the approach of the NBDs was asymmetrical in agreement with previous observations for other ABC transporter proteins. To validate the simulations, we make extensive comparison to previous cross-linking data. Our results show very good agreement with the available data. We then went on to compare the influence of inhibitor compounds bound with simulations of a substrate (daunorubicin) bound. Our results suggest that inhibitors may work by keeping the NBDs apart, thus preventing ATP-hydrolysis. On the other hand, repeat simulations of daunorubicin (substrate) in one particular binding pose suggest that the approach of the NBDs is not impaired and that the structure would be still be competent to perform ATP hydrolysis, thus providing a model for inhibition or substrate transport. Finally we compare the latter to earlier QSAR data to provide a model for the first part of substrate transport within P-gp. PMID- 23670857 TI - Percent body fat prediction equations for 8- to 17-year-old American children. AB - BACKGROUND: Percent body fat equations are usually developed in specific populations and have low generalizability. OBJECTIVES: To use a nationally representative sample of the American youth population (8-17 years old) from the 1999-2004 National Health and Nutrition Examination Survey data to develop gender specific percent body fat equations. METHODS: Percent body fat equations were developed for girls and boys using information on weight, height, waist circumference, triceps skin-folds, age, race/ethnicity and menses status compared to dual-emission X-ray absorptiometry. Terms were selected using forward and backward selection in regression models in a 2/3 development sample and were cross-validated in the remaining sample. Final coefficients were estimated in the full sample. RESULTS: Final equations included ten terms in girls and eight terms in boys including interactions with age and race/ethnicity. In the cross validation sample, the adjusted R2 was 0.818 and the root mean squared error was 2.758 in girls. Comparable estimates in boys were 0.893 and 2.525. Systematic bias was not detected in the estimates by race/ethnicity or by body mass index categories. CONCLUSION: Gender-specific percent body fat equations were developed in youth with a strong potential for generalizability and utilization by other investigators studying adiposity-related issues in youth. PMID- 23670859 TI - Development of a label-free LC-MS/MS strategy to approach the identification of candidate protein biomarkers of disease recurrence in prostate cancer patients in a clinical trial of combined hormone and radiation therapy. AB - PURPOSE: Combined hormone and radiation therapy (CHRT) is one of the principle curative regimes for localised prostate cancer (PCa). Following treatment, many patients subsequently experience disease recurrence however; current diagnostics tests fail to predict the onset of disease recurrence. Biomarkers that address this issue would be of significant advantage. EXPERIMENTAL DESIGN: Label-free LC MS/MS for protein biomarker discovery and MRM for targeted confirmation were applied to patient serum samples accrued in a non-interventional clinical trial of CHRT. RESULTS: Analysis of time-matched patient samples from a patient with disease recurrence compared with a time match disease-free individual supported the identification of 287 proteins. Of these, 141 proteins were quantified, 95 proteins changed in their expression (P <= 0.05 and >=1.5-fold change) and of these 16 were selected for MRM confirmation. The protein expression changes observed in the label-free LC-MS/MS and MRM analysis were found to be highly correlated (R(2) = 0.85). CONCLUSIONS AND CLINICAL RELEVANCE: The establishment of a clinical trial to support the acquisition of samples and development of a pipeline for MS-based biomarker discovery and validation should contribute to the identification of a serum protein signature to predict or monitor the outcome of treatment of patients with PCa. PMID- 23670860 TI - Alfred Werner: a forerunner to modern inorganic chemistry. PMID- 23670858 TI - A specific and sensitive assay for blood levels of glycated CD59: a novel biomarker for diabetes. AB - Increasing evidence links the complement system with complications of human diabetes. The complement regulatory protein CD59, an inhibitor of formation of membrane attack complex (MAC), is inhibited by hyperglycemia-induced glycation fostering increased deposition of MAC, a major effector of complement-mediated tissue damage. CD59, an ubiquitous GPI-anchored membrane protein, is shed from cell membranes by phospholipases generating a soluble form present in blood and urine. We established an enzyme-linked immunosorbent assay (ELISA) to measure serum/plasma glycated human CD59 (hCD59) (GCD59) and evaluated its potential as a diabetes biomarker. We used a synthetic peptide strategy to generate (a) a mouse monoclonal antibody to capture hCD59, (b) a rabbit monoclonal antibody to detect GCD59, and (c) a GCD59 surrogate for assay standardization. ELISA conditions were optimized for precision, reproducibility, and clinical sensitivity. The clinical utility of the assay was initially evaluated in 24 subjects with or without diabetes and further validated in a study that included 100 subjects with and 90 subjects without a diagnosis of diabetes. GCD59 (a) was significantly higher in individuals with than in individual without diabetes, (b) was independently associated with HbA1c, and (c) identified individuals with diabetes with high specificity and sensitivity. We report the development and standardization of a novel, sensitive, and specific ELISA for measuring GCD59 in blood. The assay distinguished individuals with diabetes from those without, and showed strong correlation between GCD59 and HbA1c. Because GCD59 likely contributes to the pathogenesis of diabetes complications, measurement of blood levels of GCD59 may be useful in the diagnosis and management of diabetes. PMID- 23670861 TI - beta-D-glucosidase assisted gold dissolution as non-optical and quantifiable detection technique for immunoassays. AB - Immunoassays are used for detecting protein targets for various applications. Here, a modification of immunoassays to allow a purely electrical detection of the target protein concentration is shown. The modification comprises a beta-D glucosidase as reporter enzyme and a cyanogenic glycoside as substrate. The enzymatic reaction produces cyanide in small quantities. For electrical detection of the cyanide, a novel sensor is developed, based on a gold micro wire. The cyanide dissolves the gold wire and changes the electrical resistance of the wire. Monitoring the resistance change allows a quantitative measurement of the target human C-reactive protein (an inflammatory marker) in blood plasma in the physiological relevant concentration range. PMID- 23670862 TI - Prenatal alcohol exposure in the Republic of the Congo: prevalence and screening strategies. AB - OBJECTIVE: To determine prevalence of prenatal alcohol use in Brazzaville, Congo and to evaluate a prenatal screening tool for use in this population. METHODS: A prospective population screening program of 3099 women at 10 prenatal care clinics in Brazzaville, Congo using the 1-Question screen. To validate the 1 Question screen in this population we screened 764 of these women again using the T-ACE as a gold standard for comparison study. The study outcomes were as follows: prevalence of self-reported prenatal alcohol use in Brazzaville using the 1-Question screen, estimation of number of drinking days, drinks per drinking day, most drinks on any one occasion. We also estimated the epidemiologic performance criteria for the 1-Question screen. RESULTS: The 3099 women screened were classified as follows: no risk 77% (n=2,384); at risk 3.7% (n=115); and as high risk 19.3% (n=600). Of the women reporting drinking during pregnancy, 87.4% reported drinking 4 or more drinks on any occasion. The agreement for detection of alcohol use during pregnancy by the 1-Question Screen and a positive T-ACE score was 94.7%. CONCLUSIONS: 23.3% of women attending prenatal care in Brazzaville reported alcohol use during pregnancy and 83% of them continued to drink after recognition of pregnancy. Prenatal alcohol exposure should be the focus of efforts to improve identification of alcohol use prior to and during pregnancy to improve maternal and child health. Birth Defects Research (Part A) 97:489-496, 2013. (c) 2013 Wiley Periodicals, Inc. PMID- 23670863 TI - The use of fish-derived cell lines for investigation of environmental contaminants: an update following OECD's fish toxicity testing framework No. 171. AB - Protocols for evaluating chemical toxicity at the cellular level using fish cell lines are described in this unit. Routine methodologies for growing salmonid cell lines, and using them in aquatic toxicology studies that support the mandate of the Organization for Economic Co-operation and Development (OECD) to reduce the use of whole animals in toxicity testing, are presented. Rapid, simple, cost effective tests evaluating viability of cells with three indicator dyes per sample provides a broad overview of the sensitivity of cells to chemical contaminants. This fluorometric assay involves: (1) alamar blue for metabolic activity, (2) CFDA-AM for membrane integrity, and (3) neutral red for lysosomal function. These protocols are conveniently performed in semi-unison within the same multiwell plates and read at three different wavelengths. Detailed step-by step descriptions of the assays, parameters to consider, troubleshooting, and guidelines for data interpretation are provided as essential tools for investigating environmental aquatic contaminants at the cellular level. PMID- 23670864 TI - Assessment of adult neurogenesis in mice. AB - Adult neurogenesis is a lifelong developmental process that occurs in two discrete regions in the adult mammalian brain: the subgranular zone of the dentate gyrus (DG) and the subventricular zone (SVZ) along the lateral ventricles. Despite immense interest in the therapeutic potential of adult neural stem cells (aNSCs) residing along these two neurogenic regions, molecular and cellular mechanisms regulating this process are not fully defined. Defining the regulatory mechanisms responsible for the genesis of new neurons in the adult brain is integral to understanding the basic biology of aNSCs. The techniques described here provide a basic blueprint to isolate, culture, and perform experiments using aNSCs in vitro as well as providing methods to perform immunohistochemistry on brain sections. Curr. Protoc. Toxicol. 56:12.20.1 12.20.16. (c) 2013 by John Wiley & Sons, Inc. PMID- 23670865 TI - Simultaneous, untargeted metabolic profiling of polar and nonpolar metabolites by LC-Q-TOF mass spectrometry. AB - At its most ambitious, untargeted metabolomics aims to characterize and quantify all of the metabolites in a given system. Metabolites are often present at a broad range of concentrations and possess diverse physical properties complicating this task. Performing multiple sample extractions, concentrating sample extracts, and using several separation and detection methods are common strategies to overcome these challenges but require a great amount of resources. This protocol describes the untargeted, metabolic profiling of polar and nonpolar metabolites with a single extraction and using a single analytical platform. PMID- 23670866 TI - Exemplary medicine: why doctors should practise what they preach. PMID- 23670867 TI - Warfarin and absolute risk of hemorrhagic stroke. PMID- 23670868 TI - Not all diclofenac is equal. PMID- 23670870 TI - The chemistry of 5-(tetrazol-1-yl)-2H-tetrazole: an extensive study of structural and energetic properties. AB - 5-(Tetrazol-1-yl)-2H-tetrazole (1), or 1,5'-bistetrazole, was synthesized by the cyclization of 5-amino-1H-tetrazole, sodium azide and triethyl orthoformate in glacial acetic acid. A derivative of 1, 2-methyl-5-(tetrazol-1-yl)tetrazole (2) can be obtained by this method starting from 5-amino-2-methyl-tetrazole. Furthermore, selected salts of 1 with nitrogen-rich and metal (alkali and transition metal) cations, including hydroxylammonium (4), triaminoguanidinium (5), copper(I) (8) and silver (9), as well as copper(II) complexes of both 1 and 2 were prepared. An intensive characterization of the compounds is given, including vibrational (IR, Raman) and multinuclear NMR spectroscopy, mass spectrometry, DSC and single-crystal X-ray diffraction. Their sensitivities towards physical stimuli (impact, friction, electrostatic) were determined according to Bundesamt fur Materialforschung (BAM) standard methods. Energetic performance (detonation velocity, pressure, etc.) parameters were calculated with the EXPLO5 program, based on predicted heats of formation derived from enthalpies computed at the CBS-4M level of theory and utilizing the atomization energy method. From the analytical and calculated data, their potential as energetic materials in different applications was evaluated and discussed. PMID- 23670869 TI - Future of the particle replication in nonwetting templates (PRINT) technology. AB - Particle replication in nonwetting templates (PRINT) is a continuous, roll-to roll, high-resolution molding technology which allows the design and synthesis of precisely defined micro- and nanoparticles. This technology adapts the lithographic techniques from the microelectronics industry and marries these with the roll-to-roll processes from the photographic film industry to enable researchers to have unprecedented control over particle size, shape, chemical composition, cargo, modulus, and surface properties. In addition, PRINT is a GMP compliant (GMP=good manufacturing practice) platform amenable for particle fabrication on a large scale. Herein, we describe some of our most recent work involving the PRINT technology for application in the biomedical and material sciences. PMID- 23670872 TI - Corrected small basis set Hartree-Fock method for large systems. AB - A quantum chemical method based on a Hartree-Fock calculation with a small Gaussian AO basis set is presented. Its main area of application is the computation of structures, vibrational frequencies, and noncovalent interaction energies in huge molecular systems. The method is suggested as a partial replacement of semiempirical approaches or density functional theory (DFT) in particular when self-interaction errors are acute. In order to get accurate results three physically plausible atom pair-wise correction terms are applied for London dispersion interactions (D3 scheme), basis set superposition error (gCP scheme), and short-ranged basis set incompleteness effects. In total nine global empirical parameters are used. This so-called Hartee-Fock-3c (HF-3c) method is tested for geometries of small organic molecules, interaction energies and geometries of noncovalently bound complexes, for supramolecular systems, and protein structures. In the majority of realistic test cases good results approaching large basis set DFT quality are obtained at a tiny fraction of computational cost. PMID- 23670871 TI - Folic acid supplementation use and the MTHFR C677T polymorphism in orofacial clefts etiology: An individual participant data pooled-analysis. AB - BACKGROUND: This study examines gene-environment interaction between the MTHFR C667T polymorphism and folic acid in the etiology of orofacial clefts (OFC). We used a pooled-analytical approach on four studies that used similar methods. METHODS: We used logistic regression to analyze the pooled sample of 1149 isolated cases and 1161 controls. Fetal and maternal MTHFR C677T genotypes, and maternal periconceptional exposure to smoking, alcohol, vitamin containing folic acid and folic acid supplements were contrasted between the cleft types [non syndromic clefts lip or without cleft palate (CL(P)) and non-syndromic cleft palate (CP)] and control groups. RESULTS: There was a reduced risk of CL(P) with maternal folic acid use (p = 0.008; OR = 0.70, 95% CI: 0.65-0.94) and with supplements containing folic acid (p = 0.028, OR = 0.80, 95% CI: 0.65-0.94). Maternal smoking increased the risk of both CL(P) (p < 10 e-3; OR = 1.62, 95% CI: 1.35-1.95) and CP (p = 0.028; OR = 1.38, 95% CI: 1.04-1.83). No significant risk was observed with either maternal or fetal MTHFR C677T genotypes. CONCLUSION: This individual participant data (IPD) meta-analysis affords greater statistical power and can help alleviate the problems associated with aggregate-level data sharing. The result of this IPD meta-analysis is consistent with previous reports suggesting that folic acid and smoking influence OFC outcomes. PMID- 23670874 TI - Modeling the effects of immunizations timing on child health outcomes in India. AB - Timely vaccinations of children in developing countries are important for reducing morbidity and mortality, which are Millennium Development Goals. However, a majority of children do not possess vaccination cards compiling information on timing. We investigated the benefits of vaccination cards for the uptake of immunizations against diphtheria, pertussis and tetanus (DPT), polio, tuberculosis (BCG), and measles using data on over 200,000 Indian children from the District Level Health and Facility Survey 3. Methodological issues such as whether parents of children with higher morbidity levels may have them vaccinated were investigated. The results from the models for DPT, polio, measles, and BCG vaccinations showed significant beneficial effects of maternal education, household possessions, and access to health care facilities. Moreover, models for children's ages at the time of vaccination showed significant interactions between maternal education and access to and availability of health care facilities. Finally, models for child morbidity due to diarrhea, cough, and fever showed that timely vaccinations against DPT, access to piped water, and cooking with electricity or natural gas were associated with lower morbidity. Overall, issuing paper or electronic vaccination cards to children is likely to enhance timely uptake of various immunizations thereby reducing child morbidity. PMID- 23670873 TI - Optimization of subcritical fluid extraction of carotenoids and chlorophyll a from Laminaria japonica Aresch by response surface methodology. AB - BACKGROUND: The carotenoids and chlorophyll a of Laminaria japonica Aresch were extracted using ethanol-modified subcritical 1,1,1,2-tetrafluoroethane (R134a). In the present study, the effects of pressure (5-17 MPa), temperature (303-333 K) and the amount of cosolvent(2-6% R134a, w/w)were investigated. Response surface methodology (RSM) combined with a Box-Behnken design was applied to evaluate the significance of the three independent variables on each response. A desirability function was conducted to simultaneously optimize the multiple responses. RESULTS: The optimum extraction conditions were as follows: extraction temperature 324.13 K, extraction pressure 17 MPa and a cosolvent amount of 4.73%. Under these conditions, the yields of carotenoids and chlorophyll a were predicted to be 0.239 and 2.326 g kg(-1), respectively. CONCLUSION: It has been proved that subcritical R134a is a potential solvent, which can be an alternative to supercritical CO2 for extraction of natural ingredients under mild conditions. PMID- 23670875 TI - Elevated CSF serotonin and dopamine metabolite levels in overweight subjects. AB - OBJECTIVE: Neurotransmitter systems participate in the regulation of food intake, and their activities are expected to influence eating behavior. DESIGN AND METHODS: We investigated possible associations between body mass index (BMI) and central noradrenaline, serotonin, and dopamine activities, as reflected by the cerebrospinal fluid levels of their main metabolites methoxyhydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA), respectively. We studied 192 subjects (111 males, 81 females) admitted to neurologic clinic for diagnostic investigations that included CSF analysis, and were found not to suffer from any major neurological disease. Subjects were categorized in three groups, namely in lower, in the two middle, and in upper BMI quartiles, the limits calculated separately for males and females. RESULTS: No differences were found in MHPG levels between groups, while subjects in the upper BMI quartile showed significantly elevated levels of 5-HIAA and HVA compared to the levels of subjects in lower and middle quartiles. CONCLUSIONS: The results provide evidence that in overweight subjects there are enhanced demands in serotoninergic and dopaminergic signaling for their reward system that may lead to increased motivation for food consumption. The implication of reward centers in eating behavior supports the hypothesis of common mechanisms in obesity and drug addiction. PMID- 23670876 TI - Impact of synechiae after endoscopic sinus surgery on long-term outcomes in chronic rhinosinusitis. AB - OBJECTIVES/HYPOTHESIS: Synechiae are one of the most common unwanted outcomes after endoscopic sinus surgery (ESS) for chronic rhinosinusitis (CRS). However, there has been scant investigation into the true significance of synechiae formation after ESS. The aim of this study was to evaluate the impact of synechiae formation on health-related quality of life (HRQoL) outcomes after ESS in patients with CRS. STUDY DESIGN: Prospective, multi-institutional cohort. METHODS: Rhinosinusitis Disability Index (RSDI) and Chronic Sinusitis Survey (CSS) scores were measured in adult patients before and after undergoing ESS for CRS. Differences in HRQoL were evaluated between those who developed sinonasal synechiae and those who did not, controlling for demographic factors, medical comorbidities, and measures of disease severity at baseline. RESULTS: A total of 286 patients underwent ESS, with 55 (19.2%) developing synechiae in the follow-up period. Patients developing synechiae reported significantly less improvement on the RSDI total scores (13.5 vs. 21.4, P = 0.008), RSDI physical subscores (5.3 vs. 8.3, P = 0.007), RSDI emotional subscores (2.9 vs. 5.8, P = 0.008), CSS total scores (14.5 vs. 21.2, P = 0.093), and CSS symptom subscores (19.9 vs 30.3, P = 0.069) compared to those who did not develop synechiae postoperatively. These differences persisted even after controlling for baseline differences in disease severity. CONCLUSIONS: Synechiae of the sinonasal cavity commonly occurs following ESS, particularly in those undergoing revision surgeries. Although both groups improve, the degree of HRQoL improvement appears to be less in those who form postoperative synechiae after surgery compared to those who do not. PMID- 23670877 TI - Proteomics in aortic aneurysm--what have we learnt so far? AB - Aortic aneurysm is a deceptively indolent disease that can cause severe complications such as aortic rupture and dissection. In the normal aorta, vascular smooth muscle cells within the medial layer produce and sustain the extracellular matrix (ECM) that provides structural support but also retains soluble growth factors and regulates their distribution. Although the ECM is an obvious target to identify molecular processes leading to structural failure within the vessel wall, an in-depth proteomics analysis of this important sub proteome has not been performed. Most proteomics analyses of the vasculature to date used homogenized tissue devoid of spatial information. In such homogenates, quantitative proteomics comparisons are hampered by the heterogeneity of clinical samples (i.e. cellular composition) and the dynamic range limitations stemming from highly abundant cellular proteins. An unbiased proteomics discovery approach targeting the ECM instead of the cellular proteome may decipher the complex, multivalent signals that are presented to cells during aortic remodelling. A better understanding of the ECM in healthy and diseased vessels will provide important pathogenic insights and has potential to reveal novel biomarkers. PMID- 23670878 TI - Support mechanisms and vulnerabilities in relation to PTSD in veterans of the Gulf War, Iraq War, and Afghanistan deployments: a systematic review. AB - Pretrauma factors of psychiatric history and neuroticism have been important in highlighting vulnerability to posttraumatic stress disorder (PTSD), whereas posttrauma support mechanisms have been associated with positive health and well being outcomes, particularly in veterans. The relationship between these factors and PTSD has not been the subject of a systematic review in veterans. An online search was conducted, supplemented by reference list and author searches. Two investigators systematically and independently examined eligible studies. From an initial search result of 2,864, 17 met inclusion criteria. A meta-analysis of unit cohesion involving 6 studies found that low unit cohesion was associated with PTSD, standardised mean difference of -1.62, 95% confidence interval (CI) [ 2.80, -0.45]. A meta-analysis of social support involving 7 studies found that low social support was associated with PTSD, standardised mean difference of - 12.40, 95% CI [-3.42, -1.38]. Three of 5 studies found a significant relationship between low-family support and PTSD; insufficient data precluded a meta-analysis. Regarding pretrauma vulnerability, 2 studies on psychiatric history and 1 on neuroticism found positive relationships with PTSD. Posttrauma factors of low support were associated with higher reporting of PTSD. Cross-sectional methodology may be inadequate to capture complex relationships between support and PTSD; more longitudinal research is required. PMID- 23670879 TI - Predictors of neoplastic disease in children with isolated pituitary stalk thickening. AB - BACKGROUND: The significance of pituitary stalk thickening (PST) on magnetic resonance imaging (MRI) is often unclear. We evaluated presenting symptoms, MRI findings, clinical course, and outcome predictors of patients with PST. PROCEDURE: We used a computerized search of the medical record from 1995 to 2008 to identify patients with PST without pituitary mass on MRI. Baseline and follow up MRIs were reviewed in a blinded fashion. Relevant clinical data were abstracted. RESULTS: 69 patients with reported PST and adequate imaging for review were identified; 42 met study criteria. Median age at first abnormal MRI was 13.6 years (range: 0.8-19.7); 43% were male. Median follow-up was 3.4 years (range 0-12.8). Patients with diabetes insipidus (DI) were significantly more likely to have a neoplastic process than those without (P = 0.0008). Of 16 patients with DI, 8 (50%) had a neoplastic process, including germ cell tumor (n = 4), Langerhans cell histiocytosis (n = 3), and lymphoma (n = 1). Among patients with DI, 7 (44%) also developed anterior pituitary hormone dysfunction (APD), either at presentation or on pre-biopsy follow-up, including 6/8 patients with stalk neoplasm and only 1/8 patients with non-neoplastic PST (P = 0.04). Twenty six patients presented without DI; none was found to have neoplasm of the stalk except one patient with craniopharyngioma. Progression of PST on follow-up imaging was significantly associated with a subsequent neoplastic diagnosis (P = 0.04). CONCLUSION: Patients with PST without DI are unlikely to have a neoplastic process. Among patients with DI, APD or progressive stalk increase over time are predictive of neoplasia. PMID- 23670880 TI - A prospective randomized study comparing isolation of the arrhythmogenic vein versus all veins in paroxysmal atrial fibrillation. AB - BACKGROUND: Ablation procedures in patients with paroxysmal atrial fibrillation (PAF) includes isolation of all pulmonary veins (PVs). We hypothesized that an approach using an algorithm to detect arrhythmogenic PVs (aPVs) might lead to shorter procedure duration (PD) and fewer proarrhythmic effects (PE). HYPOTHESIS: Isolation of the aPVs only leads to a reduced PD, reduced PEs, and fewer adverse events, with a success rate comparable to the standard all-PV approach. METHODS: In this prospective trial, 207 patients with PAF were randomized to undergo isolation of the aPV (AG group, n = 105) or isolation of all PVs (VG group, n = 102). The aPV was identified by atrial fibrillation (AF) induction, focal discharge, or short local PV decremental conduction during PV pacing. Patients were followed with repetitive 7-day Holter electrocardiograms (ECGs) after 3, 6, and 12 months in our arrhythmia clinic. RESULTS: In 97% of patients, at least 1 aPV was identified (mean, 2.1). PD did not differ significantly (152.3 +/- 57.1 minutes vs 162 +/- 68 minutes, P = 0.27) between the groups, but the number of radiofrequency (RF) applications and fluoroscopy time (FT) and dose were significantly lower in the AG group than in the VG group. The occurrence of PE (new-onset atrial tachycardia) and adverse events (AE) did not differ between the 2 groups (P = 0.1). Sinus rhythm off antiarrhythmic medication (documented on 7 day Holter ECGs) 12 months after a single procedure was achieved in 53% in the AG group and 59% in the VG group (P = 0.51). CONCLUSIONS: Isolation of the aPVs detected by a straightforward algorithm leads to similar success rates compared to a standard all-PV approach with regard to PD, AE, or PE and is associated with less RF and a shorter FT. PMID- 23670881 TI - Predicate structures, gesture, and simultaneity in the representation of action in British Sign Language: evidence from deaf children and adults. AB - British Sign Language (BSL) signers use a variety of structures, such as constructed action (CA), depicting constructions (DCs), or lexical verbs, to represent action and other verbal meanings. This study examines the use of these verbal predicate structures and their gestural counterparts, both separately and simultaneously, in narratives by deaf children with various levels of exposure to BSL (ages 5;1 to 7;5) and deaf adult native BSL signers. Results reveal that all groups used the same types of predicative structures, including children with minimal BSL exposure. However, adults used CA, DCs, and/or lexical signs simultaneously more frequently than children. These results suggest that simultaneous use of CA with lexical and depicting predicates is more complex than the use of these predicate structures alone and thus may take deaf children more time to master. PMID- 23670882 TI - FeS2 nanocrystal ink as a catalytic electrode for dye-sensitized solar cells. PMID- 23670883 TI - Face-space architectures: evidence for the use of independent color-based features. AB - The concept of psychological face space lies at the core of many theories of face recognition and representation. To date, much of the understanding of face space has been based on principal component analysis (PCA); the structure of the psychological space is thought to reflect some important aspects of a physical face space characterized by PCA applications to face images. In the present experiments, we investigated alternative accounts of face space and found that independent component analysis provided the best fit to human judgments of face similarity and identification. Thus, our results challenge an influential approach to the study of human face space and provide evidence for the role of statistically independent features in face encoding. In addition, our findings support the use of color information in the representation of facial identity, and we thus argue for the inclusion of such information in theoretical and computational constructs of face space. PMID- 23670884 TI - Immediate effect of internal reward on visual adaptation. AB - In the past decade, there has been an increasing interest in the effects of rewards on visual perception. Exogenous rewards have been shown to increase visual sensitivity and to affect attentional selection. Human beings, however, also feel rewarded by the correct execution of a task. It has been proposed that this form of endogenous reward triggers reinforcement signals in the brain, making the sensory system more sensitive to stimuli that have been extensively and repeatedly paired with the rewarding experiences and modulating long-term cortical plasticity. Here, we report the striking observation that a well-known visual illusion, the tilt aftereffect, which is due to a form of short-term cortical plasticity, is immediately enhanced by a concurrent and independent target-recognition process. Our results show that endogenous rewards can alter visual experience with virtually no delay. PMID- 23670885 TI - Physical and biological constraints govern perceived animacy of scrambled human forms. AB - Point-light animations of biological motion are perceived quickly and spontaneously, giving rise to an irresistible sensation of animacy. However, the mechanisms that support judgments of animacy based on biological motion remain unclear. The current study demonstrates that animacy ratings increase when a spatially scrambled animation of human walking maintains consistency with two fundamental constraints: the direction of gravity and congruency between the directions of intrinsic and extrinsic motion. Furthermore, using a reverse correlation method, we show that observers employ structural templates, or form based "priors," reflecting the prototypical mammalian body plan when attributing animacy to scrambled human forms. These findings reveal that perception of animacy in scrambled biological motion involves not only analysis of local intrinsic motion, but also its congruency with global extrinsic motion and global spatial structure. Thus, they suggest a strong influence of prior knowledge about characteristic features of creatures in the natural environment. PMID- 23670886 TI - The ancestral logic of politics: upper-body strength regulates men's assertion of self-interest over economic redistribution. AB - Over human evolutionary history, upper-body strength has been a major component of fighting ability. Evolutionary models of animal conflict predict that actors with greater fighting ability will more actively attempt to acquire or defend resources than less formidable contestants will. Here, we applied these models to political decision making about redistribution of income and wealth among modern humans. In studies conducted in Argentina, Denmark, and the United States, men with greater upper-body strength more strongly endorsed the self-beneficial position: Among men of lower socioeconomic status (SES), strength predicted increased support for redistribution; among men of higher SES, strength predicted increased opposition to redistribution. Because personal upper-body strength is irrelevant to payoffs from economic policies in modern mass democracies, the continuing role of strength suggests that modern political decision making is shaped by an evolved psychology designed for small-scale groups. PMID- 23670887 TI - Highly stereoselective conjugate addition and alpha-alkynylation reaction with electron-deficient alkynes catalyzed by chiral scandium(III) complexes. AB - The highly Z-selective asymmetric conjugate addition of 3-substituted oxindoles to alkynyl carbonyl compounds has been developed by using scandium complexes of chiral N,N'-dioxides under mild conditions. The thermodynamically unstable Z olefin derivatives were obtained in excellent yields and high enantiomeric and geometric control. The catalyst was also found to be effective in the asymmetric acetylenic substitution reaction of 3-substituted oxindoles, giving excellent enantioselectivities. PMID- 23670888 TI - Synthesis and biological evaluation of 4-arylphthalazones bearing benzenesulfonamide as anti-inflammatory and anti-cancer agents. AB - Nine 4-arylphthalazones bearing benzenesulfonamide (2a-i) were synthesized by the condensation of the appropriate 2-aroylbenzoic acid (1a-i) and 4 hydrazinobenzenesulfonamide in ethanol. The structures of these compounds were elucidated by elemental analysis, IR, 1H NMR, 13C NMR, and MS spectroscopy. Two compounds, 2b and 2i, showed significant anti-inflammatory activity comparable to that of the standard drug celecoxib in the carrageenan-induced rat paw edema model. These compounds (2b and 2i) had selective inhibitory activity towards the COX-2 enzyme. Compound 2b had a better selectivity ratio (COX-1/COX-2) compared to that of celecoxib and can be used as a novel template for the design of selective COX-2 inhibitors. Compounds 2d and 2i were screened for their antiproliferative activity toward 60 human cancer cell lines by the National Cancer Institute (USA). The compounds 2d and 2i displayed mild activity toward the renal cancer cell line UO-31. PMID- 23670889 TI - Association of dopamine D2 receptor and leptin receptor genes with clinically severe obesity. AB - OBJECTIVE: The brain reward circuits that promote drug abuse may also be involved in pleasure seeking behavior and food cravings observed in severely obese subjects. Drug addiction polymorphisms such as the TaqI A1 allele of the dopamine D2 receptor (DRD2) are associated with cocaine, alcohol, and opioid use, but few studies have linked DRD2 to food craving. Other genes such as the leptin receptor gene (LEPR) and mu-opioid receptor gene (OPRM1) that affect appetite and pleasure centers in the brain may also influence food addiction and obesity. The three genes together may function synergistically. DESIGN AND METHODS: To evaluate associations between candidate genes, food craving, overeating, and BMI, we administered questionnaires including Power of Food Scale and Food Craving Inventory, conducted anthropometric measures, and collected blood from patients undergoing weight-loss treatment. Questionnaires and DNA specimens were collected for 80 participants. RESULTS: Participants were mostly female (74%) and Caucasian (79%), with an average age of 53 years old. Mean BMI for all participants was 43 kg/m2 and was significantly associated in a linear fashion with Food Craving Inventory scores (P=0.0001) and Power of Food (P=0.02). The DRD2 TaqI A1 allele was significantly associated with BMI (P=0.04), while LEPR Lys109Arg and OPRM1 A118G variants were not. We stratified DRD2 by LEPR and OPRM1, and observed a significant interaction (P = 0.04) between DRD2 and LEPR, and a marginally significant interaction (P=0.06) between DRD2 and OPRM1. CONCLUSION: Genes associated with addictive behavior and appetite control may therefore, in combination, markedly influence development of clinically severe obesity. PMID- 23670890 TI - Effects of gamma irradiation and 15 days of subsequent ex vivo storage on the cytosolic red blood cell proteome analyzed by 2D-DIGE and Orbitrap MS. AB - PURPOSE: Gamma irradiation of red blood cell (RBC) concentrates is routinely used to prevent transfusion-associated graft-versus-host disease. So far, the effects of ionizing radiation on RBC structure and function and especially the proteome are not fully understood. EXPERIMENTAL DESIGN: RBC concentrates were irradiated with 30 Gy and stored for 1 or 15 days at 4 +/- 2 degrees C. Following cell lysis and hemoglobin depletion, 2D-DIGE was used to examine the changes of the cytosolic RBC proteome. Significantly altered spots were analyzed using bottom-up proteomic approaches and selected marker proteins validated by western blotting. RESULTS: Gamma irradiation was found to enhance conventional RBC storage lesions. Following 15 days of postirradiation storage, the abundances of a total of 27 spots were significantly altered and 3 out of 13 identified proteins were selected and validated as potential marker proteins for the assessment of irradiation-induced cytosolic RBC lesions. CONCLUSIONS AND CLINICAL RELEVANCE: Gamma irradiation and subsequent ex vivo storage according to the Council of Europe guidelines were found to affect RBC protein structures. The validated marker proteins can serve as a basis for the development of a screening assay to monitor the quality of irradiated RBC concentrates during ex vivo storage. PMID- 23670891 TI - Tolfenamic acid inhibits colon cancer cell and tumor growth and induces degradation of specificity protein (Sp) transcription factors. AB - Tolfenamic acid (TA) is a non-steroidal anti-inflammatory drug (NSAID) that inhibits lung, esophageal, breast and pancreatic cancer cell and tumor growth, and this study investigated the anticancer activity of TA in colon cancer. TA inhibited growth and induced apoptosis in RKO, SW480, HT-29, and HCT-116 colon cancer cells, and TA (50 mg/kg/d) also inhibited tumor growth in athymic nude mice bearing RKO cells as xenografts. TA downregulated expression of Sp proteins (Sp1, Sp3, and Sp4) in colon cancer cells and this was accompanied by decreased expression of several Sp-regulated growth promoting (cyclin D1, hepatocyte growth factor receptor), angiogenic (vascular endothelial growth factor (VEGF) and its receptor 1), survival (survivin and bcl-2), and inflammatory (NFkappaBp65/p50) gene products. The mechanism of TA-mediated effects on Sp proteins was due to activation of caspases. These results now extend the number of NSAIDs that may have clinical potential for colon cancer chemotherapy and show that the anticancer activity of TA is due, in part, to targeting Sp transcription factors. PMID- 23670892 TI - Castor oil polymer induces bone formation with high matrix metalloproteinase-2 expression. AB - The aim of this study was to evaluate the modulation of matrix metalloproteinase 2 (MMP-2) and -9 (MMP-9) expression in newly formed bone tissue at the interface between implants derived from castor oil (Ricinus communis) polymer and the tibia medullary canal. Forty-four rabbits were assigned to either Group 1 (n = 12; control) or Group 2 (n = 30), which had the tibial medullary canals reamed bilaterally and filled with polymer. CT scans showed no space between the material surface and the bone at the implant/bone marrow interface, and the density of the tissues at this interface was similar to the density measured of other regions of the bone. At 90 days postimplantation, the interface with the polymer presented a thick layer of newly formed bone tissue rich in osteocytes. This tissue exhibited ongoing maturation at 120 and 150 days postimplantation. Overall, bone remodeling process was accompanied by positive modulation of MMP-2 and low MMP-9 expression. Differently, in control group, the internal surface close to the medullary canal was lined by osteoblasts, followed by a bone tissue zone with few lacunae filled with osteocytes. Maturation of the tissue of the medullary internal surface occurred in the inner region, with the bone being nonlamellar. PMID- 23670893 TI - Subclassification of chronic rhinosinusitis with nasal polyp based on eosinophil and neutrophil. AB - OBJECTIVES/HYPOTHESIS: Japanese patients with chronic rhinosinusitis with nasal polyps (CRSwNP), differing from European and U.S. patients, are suggested to show two distinct phenotypes: Th2-polarized and Th1-shifted immunity. The purpose of this study was to conduct clinical subgrouping of CRSwNP based on inflammatory cell infiltration, which was evaluated and supported by clinical backgrounds and immunological characteristics. STUDY DESIGN: A cross-sectional study. METHODS: One hundred thirty Japanese patients with CRSwNP were classified by the infiltration of eosinophils and neutrophils in nasal polyps. Immunohistochemical analysis was performed in 42 patients. RESULTS: The patients were classified into three groups: 1) 42 patients with eosinophilic type, 2) 27 patients with neutrophilic type, and 3) 61 patients with noneosinophilic nonneutrophilic type. Both the number of serum eosinophils and the recurrence rates were significantly higher in the eosinophilic group compared to the other two groups. The IgE value was significantly higher in the eosinophilic group, followed by the noneosinophilic nonneutrophilic and neutrophilic groups. Both the symptomatic and CT scores were significantly greater in the eosinophilic group than in the neutrophilic group. The expressions of eotaxin, IL-17A, MUC5AC, and CD68 were greater in the eosinophilic group than in the other two groups. CONCLUSION: The eosinophilic CRSwNP phenotype is clinically characterized by serum eosinophilia, atopy, extensive disease, and poor prognosis compared to the neutrophilic and the noneosinophilic nonneutrophilic groups. We clearly demonstrated that all three subgroups of CRSwNP had characteristic differences in those inflammatory markers, which allows for pathophysiologically meaningful differentiations with likely therapeutic consequences. PMID- 23670894 TI - Guideline adherence of antithrombotic treatment initiated by general practitioners in patients with nonvalvular atrial fibrillation: a Danish survey. AB - BACKGROUND: The aim of this prospective survey was to describe the demographics, stroke risk profile, and the guideline adherence of antithrombotic treatment in a Danish primary care population of patients with nonvalvular atrial fibrillation (AF). HYPOTHESIS: We hypothesized that a significant proportion of patients with nonvalvular AF do not receive guideline-adherent antithrombotic treatment in primary care. METHODS: We performed a cross-sectional survey of antithrombotic treatment using data of AF patients from general practices. RESULTS: Sixty-four general practitioners enrolled 1743 patients with a mean age of 74.8 +/- 11.2 years. The mean CHADS2 and CHA2 DS2 -VASc scores were 1.9 +/- 1.3 and 3.5 +/- 1.8, respectively. Of the patients, 12.4% and 4.04%, respectively, were at truly low risk, with a CHADS2 and CHA2 DS2 -VASc score 0 (P < 0.001). A score of 1 was seen in 28.0% vs 9.0% (P < 0.001) of the patients. Of all patients, 66.3% were treated with oral anticoagulants, 18.7% with antiplatelet drugs only, and 15% received no antithrombotic therapy. Based on the CHADS2 score, 75.7% of the patients were treated in adherence with the guidelines, 16% were undertreated, and 8.4% overtreated. The corresponding numbers for the CHA2 DS2 -VASc score were 75.4%, 22.7%, and 1.8%, respectively. The differences in guideline adherence applying the 2 scores were significant (P < 0.001). Of patients receiving no antithrombotic therapy, 64.1% were treated in adherence to the guidelines according to the CHADS2 score. Applying the CHA2 DS2 -VASc score, this proportion was only 53.4%. Antiplatelet drug treatment was in adherence to the guidelines (CHADS2 and CHA2 DS2 -VASc score of 1) in only 31% and 12% of the patients, respectively. CONCLUSIONS: Antithrombotic treatment of AF patients is in general well performed in primary care in Denmark. Further improvements may be achieved by thorough stroke risk stratification on the basis of current evidence-based guidelines. PMID- 23670895 TI - Bottom-up formation of dodecane-in-water nanoemulsions from hydrothermal homogeneous solutions. PMID- 23670896 TI - Preventive detention in Germany: an overview and empirical data from two federal states. AB - Eighty years ago, preventive detention for dangerous offenders was implemented in the German Penal Code (Section 66). In 2011, about 500 individuals were incarcerated under a preventive detention order in Germany. Through semi structured clinical interviews and/or collateral file review, the present investigators assessed the sociobiographic, criminological, and clinical characteristics of 58 men for whom preventive detention had been ordered in two German federal states. In addition, risk assessment instruments were administered. The majority of the inmates were sexual offenders. The main mental health problems were antisocial personality disorder (APD), substance abuse/disorder, and paraphilias. Most individuals had a history of poor socialization. Structured clinical judgment as well as actuarial risk assessment instruments identified all inmates as high-risk offenders. Future development of preventive detention in Germany must emphasize treatment interventions. Given the life histories and the mental health problems of the detainees assessed in the present study, the implementation of effective treatment will prove difficult. PMID- 23670897 TI - Fast, reversible lithium storage with a sulfur/long-chain-polysulfide redox couple. AB - The cathodic reactions in Li-S batteries can be divided into two steps. Firstly, elemental sulfur is transformed into long-chain polysulfides (S8 <-> Li2S4), which are highly soluble in the electrolyte. Next, long-chain polysulfides undergo nucleation reaction and convert into solid-state Li2S2 and Li2S (Li2S4 < > Li2S) by slow processes. As a result, the second-step of the electrochemical reaction hinders the high-rate application of Li-S batteries. In this report, the kinetics of the sulfur/long-chain-polysulfide redox couple (theoretical capacity=419 mA h g(-1)) are experimentally demonstrated to be very fast in the Li-S system. A Li-S cell with a blended carbon interlayer retains excellent cycle stability and possesses a high percentage of active material utilization over 250 cycles at high C rates. The meso-/micropores in the interlayer are responsible for accommodating the shuttling polysulfides and offering sufficient electrolyte accessibility. Therefore, utilizing the sulfur/long-chain polysulfide redox couple with an efficient interlayer configuration in Li-S batteries may be a promising choice for high-power applications. PMID- 23670898 TI - Comparison of contrast agents for atherosclerosis imaging using cultured macrophages: FDG versus ultrasmall superparamagnetic iron oxide. AB - Various noninvasive imaging methods have been developed to evaluate atherosclerotic plaques. Among them, (18)F-FDG PET and MR imaging with ultrasmall superparamagnetic iron oxide particles (USPIO) have been used to quantify plaque inflammation. Both methods are based on the efficient uptake of FDG and USPIO by macrophages in atherosclerotic lesions. Differently polarized macrophages have been reported to have different characteristics that are involved in the pathologic development of atherosclerosis. M1 polarized macrophages are considered the more proatherogenic phenotype than M2 polarized macrophages. However, little is known regarding the association between macrophage polarization and FDG or USPIO accumulation. In this study, we investigated intracellular FDG and USPIO accumulation in M1 and M2 polarized macrophages. METHODS: THP-1 macrophages were differentiated into M1 and M2 polarized macrophages. Under optimal glucose conditions, we investigated the (3)H-labeled FDG uptake in M1 and M2 polarized macrophages. We then investigated intracellular USPIO uptake by M1 and M2 macrophages. RESULTS: We found that M1 polarization, compared with M2 polarization, results in increased intracellular accumulation of FDG. To elucidate the mechanism by which FDG was preferentially accumulated in M1 macrophages, we examined messenger RNA expressions of glucose transporters (GLUTs) and hexokinases, which have pivotal roles in glucose uptake, and glucose 6-phosphatase (G6Pase), which catalyzes the reverse reaction of hexokinase. In M1 macrophages, GLUT-1, GLUT-3, hexokinase 1, and hexokinase 2 were upregulated and G6Pase was downregulated. In contrast to FDG, M1 polarization resulted in decreased intracellular accumulation of USPIO. We found that scavenger receptor A and CD11b, which are involved in USPIO binding and uptake, were significantly downregulated by M1 polarization. CONCLUSION: Compared with M2, proatherogenic M1 macrophages preferentially accumulated FDG but not USPIO, suggesting that FDG PET is a useful method for the detection of proinflammatory M1 macrophages. PMID- 23670899 TI - Combination of 18F-FDG PET/CT and diffusion-weighted MR imaging as a predictor of histologic response to neoadjuvant chemotherapy: preliminary results in osteosarcoma. AB - We evaluated the potential of (18)F-FDG PET/CT and diffusion-weighted imaging (DWI) to monitor the histologic response in patients with extremity osteosarcoma receiving neoadjuvant chemotherapy, using sequential PET/CT and MR imaging. METHODS: We prospectively registered 28 patients with high-grade osteosarcoma treated with 2 cycles of neoadjuvant chemotherapy and surgery. All patients underwent sequential (18)F-FDG PET/CT and MR imaging before (PET/MR1) and after neoadjuvant chemotherapy (PET/MR2). Maximum standardized uptake value (SUV), tumor volume based on MR imaging (MRV), and the mean apparent diffusion coefficient (ADC) values were measured on PET/MR1 (SUV1, MRV1, and ADC1) and PET/MR2 (SUV2, MRV2, and ADC2). The percentage changes in maximum SUV (DeltaSUV), MRV (DeltaMRV), and ADC (DeltaADC) were calculated, and the correlations among these parameters were evaluated. After surgery, the effects of neoadjuvant chemotherapy were graded histopathologically: grades III and IV (necrosis of >= 90%) indicated a good response, and grades I and II (necrosis of < 90%) indicated a poor response. The optimum cutoff values of DeltaSUV, DeltaMRV, DeltaADC, and their combination for predicting histologic response were assessed by single- and multi-receiver-operating-characteristic curve analysis. RESULTS: Twenty-seven patients were enrolled in the present study after 1 patient with inadequate acquisition of MR imaging was excluded. DeltaSUV and DeltaADC negatively correlated with each other (rho = -0.593, P = 0.001), and DeltaMRV did not correlate with DeltaSUV or DeltaADC. The cutoff value, sensitivity, specificity, and accuracy for predicting good histologic response were <= -52%, 67%, 87%, and 78%, respectively, for DeltaSUV and > 13%, 83%, 73%, and 78%, respectively, for DeltaADC. However, DeltaMRV did not predict histologic response. Sensitivity, specificity, and accuracy were 83%, 87%, and 85%, respectively, using the combined criterion of DeltaSUV <= -31% and DeltaADC > 13%. CONCLUSION: In the current preliminary study, both PET/CT and DWI are useful for predicting histologic response after neoadjuvant chemotherapy in osteosarcoma. Combining PET/CT and DWI may be an effective method to predict the histologic response of patients to neoadjuvant chemotherapy. PMID- 23670900 TI - 18F-fluorobenzoate-labeled cystine knot peptides for PET imaging of integrin alphavbeta6. AB - Integrin alphavbeta6 is a cell surface receptor minimally expressed by healthy tissue but elevated in lung, colon, skin, ovarian, cervical, and pancreatic cancers. A molecular PET agent for integrin alphavbeta6 could provide significant clinical utility by facilitating both cancer staging and treatment monitoring to more rapidly identify an effective therapeutic approach. METHODS: Here, we evaluated 2 cystine knot peptides, R01 and S02, previously engineered with a 3-6 nM affinity for integrin alphavbeta6, for (18)F radiolabeling and PET imaging of BxPC3 pancreatic adenocarcinoma xenografts in mice. Cystine knot peptides were labeled with N-succinimidyl-4-(18)F-fluorobenzoate and evaluated for binding affinity and serum stability. Peptides conjugated with (18)F-fluorobenzoate (2-3 MBq) were injected via the tail vein into nude mice xenografted with BxPC3 (integrin alphavbeta6-positive) or 293 (integrin alphavbeta6-negative) tumors. Small-animal PET scans were acquired at 0.5, 1, and 2 h after injection. Ex vivo gamma-counting of dissected tissues was performed at 0.5 and 2 h. RESULTS: (18)F fluorobenzoate peptides were produced in 93% ((18)F-fluorobenzoate-R01) and 99% ((18)F-fluorobenzoate-S02) purity. (18)F-fluorobenzoate-R01 and (18)F fluorobenzoate-S02 had affinities of 1.1 +/- 0.2 and 0.7 +/- 0.4 nM, respectively, and were 87% and 94%, respectively, stable in human serum at 37 degrees C for 2 h. (18)F-fluorobenzoate-R01 and (18)F-fluorobenzoate-S02 exhibited 2.3 +/- 0.6 and 1.3 +/- 0.4 percentage injected dose per gram (%ID/g), respectively, in BxPC3 xenografted tumors at 0.5 h (n = 4-5). Target specificity was confirmed by low tumor uptake in integrin alphavbeta6-negative 293 tumors (1.4 +/- 0.6 and 0.5 +/- 0.2 %ID/g, respectively, for (18)F-fluorobenzoate-R01 and (18)F-fluorobenzoate-S02; both P < 0.05; n = 3-4) and low muscle uptake (3.1 +/- 1.0 and 2.7 +/- 0.4 tumor to muscle for (18)F-fluorobenzoate-R01 and (18)F fluorobenzoate-S02, respectively). Small-animal PET data were corroborated by ex vivo gamma-counting of dissected tissues, which demonstrated low uptake in nontarget tissues with only modest kidney uptake (9.2 +/- 3.3 and 1.9 +/- 1.2 %ID/g, respectively, at 2 h for (18)F-fluorobenzoate-R01 and (18)F-fluorobenzoate S02; n = 8). Uptake in healthy pancreas was low (0.3% +/- 0.1% for (18)F fluorobenzoate-R01 and 0.03% +/- 0.01% for (18)F-fluorobenzoate-S02; n = 8). CONCLUSION: These cystine knot peptide tracers, in particular (18)F fluorobenzoate-R01, show translational promise for molecular imaging of integrin alphavbeta6 overexpression in pancreatic and other cancers. PMID- 23670901 TI - Assessment of the 18F-labeled PET tracer LMI1195 for imaging norepinephrine handling in rat hearts. AB - A novel (18)F-labeled tracer, LMI1195 (N-[3-bromo-4-(3-(18)F-fluoro-propoxy) benzyl]-guanidine), is being developed for sympathetic nerve imaging; its high specificity for neural uptake-1 mechanism has previously been demonstrated in cell associative studies and in rabbit and nonhuman primate studies assessing heart uptake. The aim of this study was to investigate the mechanisms of (18)F LMI1195 cardiac uptake in the rat, which is known to contain norepinephrine uptake mechanisms beyond uptake-1. METHODS: Tracer accumulation in the heart was studied over time after intravenous administration of (18)F-LMI1195 in healthy male Wistar rats by quantitative in vivo PET imaging. The uptake mechanism was assessed by pretreatment with the nonselective norepinephrine uptake-1 and norepinephrine uptake-2 inhibitor phenoxybenzamine (50 mg/kg intravenously; n = 4), the selective norepinephrine uptake-1 inhibitor desipramine (2 mg/kg intravenously; n = 4), or saline control (intravenously; n = 4). RESULTS: (18)F LMI1195 produced high and sustained heart uptake allowing clear delineation of the left ventricular wall over 60 min after tracer administration. Pretreatment with phenoxybenzamine markedly reduced the (18)F-LMI1195 cardiac uptake when compared with controls. In contrast, there was preserved (18)F-LMI1195 uptake after desipramine pretreatment. CONCLUSION: In rats, cardiac uptake of (18)F LMI1195 was significantly inhibited by phenoxybenzamine but not desipramine, suggesting (18)F-LMI1195 is a substrate for the uptake-2 mechanism and is consistent with the rat heart having a dominant level of the mechanism. PMID- 23670903 TI - PET with 18F-FDG-labeled T lymphocytes for diagnosis of acute rat renal allograft rejection. AB - We proposed small-animal PET with (18)F-FDG-labeled T lymphocytes as a new method for image-based diagnosis of acute allogeneic renal transplant rejection (AR) established in a rat model. METHODS: One and 2 h after tail vein injection of 30 * 10(6) ex vivo (18)F-FDG-labeled human T cells into male 10-wk-old uninephrectomized, allogeneically transplanted rats (aTX; Lewis-brown Norway [LBN] to Lewis), whole-body radioactivity distribution was assessed in vivo by small-animal PET (postoperative day 4), and percentage injected dose (%ID) as a parameter of T-cell infiltration was assessed and compared between graft and native kidney. In vivo results were confirmed by autoradiography and staining of human CD3 after postmortem dissection. Syngeneically transplanted rats (sTX) (LBN to LBN), rats with ischemia-reperfusion injury (IRI) (45-min warm ischemia), and rats subjected to acute cyclosporine A (CSA) toxicity (50 mg/kg for 2 d intraperitoneally) served as controls. RESULTS: The accumulation of labeled cells was significantly elevated in allografts with AR (1.07 +/- 0.28 %ID), compared with native control kidneys (0.49 +/- 0.18 %ID) (P < 0.0001). No differences were found among native controls, sTX, CSA toxicity, and kidneys with IRI. In vivo uptake of (18)F-FDG cells measured in the PET scanner correlated with results obtained by autoradiography, histologic evaluation, and polymerase chain reaction. CONCLUSION: We proposed graft PET imaging using (18)F-FDG-labeled T cells as a new option to detect rat renal AR with a low dose of (18)F-FDG in a noninvasive, fast, and specific manner in rats. PMID- 23670902 TI - Prognostic value of preoperative metabolic tumor volume and total lesion glycolysis measured by 18F-FDG PET/CT in salivary gland carcinomas. AB - Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) from (18)F-FDG PET/CT are emerging prognostic biomarkers in various human cancers. This study examined the prognostic value of these metabolic tumor parameters measured by pretreatment (18)F-FDG PET/CT in patients with salivary gland carcinomas. METHODS: Forty-nine patients with intermediate- or high-grade salivary gland carcinomas who underwent definitive surgery with or without radiotherapy or chemoradiotherapy were evaluated preoperatively by (18)F-FDG PET/CT. Maximum standardized uptake values (SUV max), MTV, and TLG were measured for each patient. Univariate and multivariate analyses were used to identify clinicopathologic and imaging variables associated with progression-free survival (PFS) and overall survival (OS). Univariate analyses included the following variables: age, sex, pT and pN classifications, overall pTNM stage, histologic grade, resection margin, tumor lymphovascular invasion and perineural invasion, postoperative adjuvant therapy, gross total volume, SUV max, MTV, and TLG. RESULTS: The 3-y PFS and OS rates for all study patients were 66.9% and 81.6%, respectively. The median SUV max, MTV, and TLG were 5.1 (range, 1.7-21.5), 16.2 mL (1.0-115.1 mL), and 24.4 g (2.1-224.4 g), respectively. Univariate analyses showed that there were significant correlations between pT classification, pN classification, MTV, and TLG and both PFS and OS (P < 0.05). However, SUV max was not associated with either PFS (P = 0.111) or OS (P = 0.316). Multivariate analyses revealed that MTV (P = 0.011; hazard ratio, 11.50; 95% confidence interval, 1.45-91.01) and TLG (P = 0.038; hazard ratio, 3.55; 95% confidence interval, 1.07-11.76) were independent variables for PFS. CONCLUSION: Pretreatment values of MTV and TLG are independent prognostic factors in patients with intermediate or high-grade salivary gland carcinomas. PMID- 23670904 TI - Bayesian integrated testing strategy to assess skin sensitization potency: from theory to practice. AB - Frameworks to predict in vivo effects by integration of in vitro, in silico and in chemico information using mechanistic insight are needed to meet the challenges of 21(st) century toxicology. Expert-based approaches that qualitatively integrate multifaceted data are practiced under the term 'weight of evidence', whereas quantitative approaches remain rare. To address this gap we previously developed a methodology to design an Integrated Testing Strategy (ITS) in the form of a Bayesian Network (BN). This study follows up on our proof of concept work and presents an updated ITS to assess skin sensitization potency expressed as local lymph node assay (LLNA) potency classes. Modifications to the ITS structure were introduced to include better mechanistic information. The parameters of the updated ITS were calculated from an extended data set of 124 chemicals. A detailed validation analysis and a case study were carried out to demonstrate the utility of the ITS for practical application. The improved BN ITS predicted correctly 95% and 86% of chemicals in a test set (n = 21) for hazard and LLNA potency classes, respectively. The practical value of using the BN ITS is far more than a prediction framework when all data are available. The BN ITS can develop a hypothesis using subsets of data as small as one data point and can be queried on the value of adding additional tests before testing is commenced. The ITS represents key steps of the skin sensitization process and a mechanistically interpretable testing strategy can be developed. These features are illustrated in the manuscript via practical examples. PMID- 23670905 TI - Probation as a setting for building well-being through integrated service provision: evaluating an Offender Health Trainer service. AB - INTRODUCTION: The NHS Health Trainer Programme was launched in England and Wales in 2005 with the aim of tackling health inequalities. While initially focusing on geographical communities, the initiative has extended its reach to particular population groups, such as offenders and their families, who experience high levels of physical and mental health needs and wider social exclusion. This paper reports on the evaluation of the Offender Health Trainer service delivered in probation settings in Bury, Rochdale and Oldham (Greater Manchester). This service has sought to improve the health of offenders, improve their access to mainstream services, and help reduce health inequalities - as well as facilitate rehabilitation and improve job prospects for ex-offenders through employment as health trainers. AIMS: This evaluative research study aimed to explore the delivery of the Offender Health Trainer service and examine its impact on service users. The study design and limited time frame meant that the research was focused on the journeys of service users rather than on long-term outcomes. METHODS: The evaluation used a mixed-methods approach, comprising two key elements: the interrogation and analysis of routinely collected quantitative data extracted from the National Health Trainer Data Collection Recording System (DCRS); and in-depth qualitative research using interviews and focus groups with clients and health trainers. RESULTS: The evaluation points to the overall success of the service in meeting its aims and impacting positively on the lives of offenders. It reveals promising trends in behaviour change and self-perceived health and well-being, articulating a rich narrative detailing how the service has helped probation clients tackle multiple interwoven problems and build hope and self-belief. Of particular importance was the health trainers' experience of the criminal justice system, which resonated with and inspired clients, developing trust and motivation to change. CONCLUSIONS: While the research inevitably had limitations, this study suggests that the health trainer model can be effectively implemented within the probation setting, making a valuable contribution to the improvement of offenders' health and well-being by working in ways that acknowledge the connections between personal lifestyle and wider determinants of health. Within the context of forthcoming probation reforms, it will be increasingly important to develop services that highlight these links and to invest in appropriate evaluation that can generate further learning about 'what works and why'. PMID- 23670906 TI - Proteomics of plaques and novel sources of potential biomarkers for atherosclerosis. AB - Cardiovascular disease (CVD) is the leading cause of death and loss of productive life years in the world. The underlying syndrome of CVD, atherosclerosis, is a complex disease process, which involves lipid metabolism, inflammation, innate and adaptive immunity, and many other pathophysiological aspects. Furthermore, CVD is influenced by genetic as well as environmental factors. Early detection of CVD and identification of patients at risk are crucial to reduce the burden of disease and to allow personalized treatment. As established risk factors fail to accurately predict which part of the population is likely to suffer from the disease, novel biomarkers are urgently needed. Proteomics can play a significant role in identifying these biomarkers. In this review, we describe the progress made in proteome profiling of the atherosclerotic plaque and several novel sources of potential biomarkers, including circulating cells and plasma extracellular vesicles. The importance of longitudinal biobanking in biomarker discovery is highlighted and exemplified by several plaque proteins identified in the biobank study Athero-Express. Finally, we discuss the PTMs of proteins that are involved in atherosclerosis, which may become one of the foci in the ongoing quest for biomarkers through proteomics of plaque and other matrices relevant to the progression of atherosclerosis. PMID- 23670907 TI - Adverse metabolic risk profiles in Greenlandic Inuit children compared to Danish children. AB - OBJECTIVE: During recent decades, the prevalence of metabolic morbidity has increased rapidly in adult Greenlandic Inuit. To what extent this is also reflected in the juvenile Inuit population is unknown. The objective was, therefore, in the comparison with Danish children, to evaluate metabolic profiles in Greenlandic Inuit children from the capital in the southern and from the northern most villages DESIGN AND METHODS: 187 Inuit and 132 Danish children were examined with anthropometrics, pubertal staging, fasting blood samples, and a maximal aerobic test. RESULTS: Both Inuit children living in Nuuk and the northern villages had significantly higher glucose, total cholesterol, apolipoprotein A1 levels, and diastolic blood pressure compared with Danish children after adjustment for differences in adiposity and aerobic fitness levels. The Inuit children living in Nuuk had significantly higher BMI, body fat %, HbA1 c, and significantly lower aerobic fitness and ApoA1 levels than northern living Inuit children. CONCLUSIONS: Greenlandic Inuit children had adverse metabolic health profile compared to the Danish children, the differences where more pronounced in Inuit children living in Nuuk. The tendencies toward higher prevalence of diabetes and metabolic morbidity in the adult Greenlandic Inuit population may also be present in the Inuit children population. PMID- 23670910 TI - Assessment of the biocompatibility and stability of a gold nanoparticle collagen bioscaffold. AB - Collagen has been utilized as a scaffold for tissue engineering applications due to its many advantageous properties. However, collagen in its purified state is mechanically weak and prone to rapid degradation. To mitigate these effects, collagen can be crosslinked. Although enhanced mechanical properties and stability can be achieved by crosslinking, collagen can be rendered less biocompatible either due to changes in the overall microstructure or due to the cytotoxicity of the crosslinkers. We have investigated crosslinking collagen using gold nanoparticles (AuNPs) to enhance mechanical properties and resistance to degradation while also maintaining its natural microstructure and biocompatibility. Rat tail type I collagen was crosslinked with AuNPs using a zero-length crosslinker, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC). Several characterization studies were performed including electron microscopy, collagenase assays, ROS assays, and biocompatibility assays. The results demonstrated that AuNP-collagen scaffolds had increased resistance to degradation as compared to non-AuNP-collagen while still maintaining an open microstructure. Although the biocompatibility assays showed that the collagen and AuNP-collagen scaffolds are biocompatible, the AuNP-collagen demonstrated enhanced cellularity and glycoaminoglycans (GAG) production over the collagen scaffolds. Additionally, the Reactive Oxygen Species (ROS) assays indicated the ability of the AuNP collagen to reduce oxidation. Overall, the AuNP-collagen scaffolds demonstrated enhanced biocompatibility and stability over non-AuNP scaffolds. PMID- 23670911 TI - In response to What is the role of tympanostomy tubes in the treatment of recurrent acute otitis media? PMID- 23670912 TI - Enantiomeric selection properties of beta-homoDNA: enhanced pairing for heterochiral complexes. PMID- 23670913 TI - Recidivism and characteristics of highly dangerous offenders being released from retrospectively imposed preventive detention: an empirical study. AB - This study examines the recidivism of offenders who are considered to be highly dangerous but who, as a result of a decision of the German Federal High Court, have not been in preventive detention because it was imposed retrospectively (Group II preventive detention cases; S 66b StGB). Taking into consideration the restrictions imposed by the study, the data were evaluated regarding their usefulness for predicting the likelihood of reoffending. The results of this study suggest that it could be useful to describe criteria for the not very severe reoffending group. PMID- 23670914 TI - Impact of smoking status on cardiovascular outcomes following percutaneous coronary intervention. AB - BACKGROUND: Many military veterans in the United States with coronary artery disease continue to smoke despite undergoing percutaneous coronary intervention (PCI). Previous studies have described improved cardiovascular outcomes in smokers, the so-called "smokers' paradox." In this study, we examined the effects of smoking on cardiovascular outcomes following PCI. HYPOTHESIS: Do patients who smoke have different post-PCI outcomes than nonsmokers? METHODS: All patients who underwent PCI at a single US Veterans Administration hospital from 2004 to 2009 were followed. Outcomes of interest included myocardial infarction, unplanned coronary intervention, unplanned cardiac hospitalization, death, and a composite of events for 6 months after PCI. Changes in traditional risk factors were also assessed. RESULTS: Unadjusted analysis revealed that in almost all categories, smokers had lower incidence of adverse events than nonsmokers. However, after adjusting for the older age of the nonsmokers, no favorable statistical trend toward smokers was seen. Significant improvement in blood pressure and lipid levels were seen in both groups. CONCLUSIONS: After adjusting for differences in age, there did not appear to be any protective effect of smoking on cardiovascular outcomes following PCI. Smokers achieved similar degrees of risk factor optimization during the follow-up period as their nonsmoker counterparts. Aggressive efforts to decrease the prevalence of smoking must be maintained. PMID- 23670915 TI - Construction of optically active indolines by formal [4+1] annulation of sulfur ylides and N-(ortho-chloromethyl)aryl amides. AB - Get asymmetric! Asymmetric [4+1] annulation of sulfur ylides and N-(ortho chloromethyl)aryl amides allowed the formation of the desired cycloadduct with moderate to high yields and enantioselectivities (see scheme). The described strategy, taking advantage of chiral sulfur ylides, represents a direct procedure to access chiral 2-substituted indolines. PMID- 23670916 TI - Mixtures of 3,4-methylenedioxymethamphetamine (ecstasy) and its major human metabolites act additively to induce significant toxicity to liver cells when combined at low, non-cytotoxic concentrations. AB - Hepatic injury after 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) intoxications is highly unpredictable and does not seem to correlate with either dosage or frequency of use. The mechanisms involved include the drug metabolic bioactivation and the hyperthermic state of the liver triggered by its thermogenic action and exacerbated by the environmental circumstances of abuse at hot and crowded venues. We became interested in understanding the interaction between ecstasy and its metabolites generated in vivo as users are always exposed to mixtures of parent drug and metabolites. With this purpose, Hep G2 cells were incubated with MDMA and its main human metabolites methylenedioxyamphetamine (MDA), alpha-methyldopamine (alpha-MeDA) and N-methyl-alpha-methyldopamine (N-Me alpha-MeDA), individually and in mixture (drugs combined in proportion to their individual EC01 ), at normal (37 degrees C) and hyperthermic (40.5 degrees C) conditions. After 48 h, viability was assessed by the 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Extensive concentration response analysis was performed with single drugs and the parameters of the individual non-linear logit fits were used to predict joint effects using the well-founded models of concentration addition (CA) and independent action (IA). Experimental testing revealed that mixture effects on cell viability conformed to CA, for both temperature settings. Additionally, substantial combination effects were attained even when each substance was present at concentrations that individually produced unnoticeable effects. Hyperthermic incubations dramatically increased the toxicity of the tested drug and metabolites, both individually and combined. These outcomes suggest that MDMA metabolism has hazard implications to liver cells even when metabolites are found in low concentrations, as they contribute additively to the overall toxic effect of MDMA. PMID- 23670917 TI - Androgenic sex steroids contribute to metabolic risk beyond intra-abdominal fat in overweight/obese black and white women. AB - OBJECTIVE: To determine the independent contribution of androgenic sex hormones beyond visceral adipose tissue (VAT) on metabolic risk. DESIGN AND METHODS: A cross-sectional evaluation of 66 (36 white and 30 black) premenopausal overweight/obese women using multiple regression analyses to determine the independent effects of sex hormone-binding globulin (SHBG), total testosterone (TT), and free testosterone using the free androgen index (FAI) on metabolic variables above VAT. RESULTS: SHBG contributed to the variance in insulin (P = 0.003), insulin resistance using HOMA-IR (P = 0.006), and high-density lipoprotein cholesterol2 (P = 0.029). TT contributed to the variance in systolic and diastolic blood pressure (P < 0.001), total cholesterol (P = 0.003), low density lipoprotein cholesterol (P = 0.003), and apolipoprotein B (P = 0.004). FAI contributed to the variance in the greatest number of metabolic variables beyond VAT. There was also a significant race-FAI interaction for fasting glucose (P = 0.013). A Pearson's correlation coefficient showed a significant relationship between FAI and glucose in white women (r = 0.48, P = 0.003) while showing no relationship in black women (r = -0.01, P = 0.941). CONCLUSIONS: Our study showed that androgenic sex steroids contributed significantly to the variance in metabolic variables associated with health risk. However, they do not provide sufficient information relevant to glucose status in black women. PMID- 23670919 TI - Highly efficient organic light-emitting diode based on a hidden thermally activated delayed fluorescence channel in a heptazine derivative. AB - An orange-red organic light-emitting diode containing a heptazine derivative exhibits high performance with a maximum external quantum efficiency of 17.5 +/- 1.3% and a peak luminance of 17000 +/- 1600 cd m-2 without any light out-coupling enhancement. The high electroluminescence performance can be ascribed to the presence of an efficient up-conversion channel from the lowest triplet state to the lowest singlet state. PMID- 23670918 TI - Nafion-resin-modified mesocellular silica foam catalyst for 5 hydroxymethylfurfural production from D-fructose. AB - Catalytic dehydration of D-fructose to 5-hydroxymethylfurfural (HMF) was investigated over a series of Nafion-modified mesocellular silica foam (MCF) materials. By using an impregnation method, Nafion resin was highly dispersed in the ultra-large pores of the MCFs. Highly efficient and selective dehydration of D-fructose to HMF was achieved in dimethyl sulfoxide solvent; an 89.3% HMF yield with 95.0% selectivity was obtained in the presence of the Nafion(15)/MCF catalyst. The effects of reaction temperature, reaction time, and solvent on the dehydration of D-fructose were systematically investigated. The catalyst could be regenerated through an ion-exchange method and a high yield was retained after being used five times. As a heterogeneous catalytic process, a possible reaction mechanism for the dehydration of D-fructose over Nafion-modified MCF catalysts was proposed. PMID- 23670920 TI - Pharmacoeconomics of Cyclamen europaeum in the management of acute rhinosinusitis. AB - OBJECTIVES/HYPOTHESIS: To carry out a pharmacoeconomic analysis of Cyclamen europaeum (CE) in the management of acute rhinosinusitis (ARS) in Spain using data from the PROSINUS (PROspective epidemiological study of the diagnosis and treatment of acute rhinoSINUSitis) study. STUDY DESIGN: This was a prospective observational study to compare the effectiveness and cost-effectiveness between therapies including CE versus other therapies in the management of ARS. METHODS: The study was carried out as a secondary analysis of the PROSINUS study, combining healthcare resource use, productivity loses, and health outcomes from the observational study, with costs representative of the Spanish Health System. RESULTS: CE given as monotherapy appears to be more effective (cure rate) than other monotherapies (15.3% higher, P < .05) and combination (10.3% higher, P < .05) therapies. The addition of CE to other single-drug or combination therapies showed a statistically significant improvement in terms of cure rates when adding CE to two-drug combinations (93.9% vs. 76.5%; P < .05) and no significant effect when added to combinations of three or more drugs (81.1% vs. 79.8; nonsignificant). CE-based therapies generally showed lower indirect costs, although only the comparison of CE alone versus other monotherapies, with a net cost savings of ?101 per patient, reached statistical significance (?331 vs. ?432, P < .05). In addition, CE-based therapies show lower cost per cured patient in all comparisons, except when CE was used in combination with three or more other drugs. CONCLUSIONS: The use of CE (Nasodren) may be associated to better clinical outcomes at no additional cost for the healthcare system with respect to treatments commonly used for ARS in clinical practice. PMID- 23670921 TI - Design and synthesis of cyclic ADP-4-thioribose as a stable equivalent of cyclic ADP-ribose, a calcium ion-mobilizing second messenger. PMID- 23670922 TI - Medical progress, reason and the imagination. PMID- 23670923 TI - Science and the imagination in the age of reason. AB - The eighteenth century is commonly thought of as the "age of reason", an age in which the imagination was not given a central role in the arts, far less in science. But in Hume's attempts to account for our belief in a continuing external world he is forced into invoking the activity of the imagination. His views on the activity of the imagination greatly influenced Adam Smith, who adapted them to fashion a theory of the psychology of scientific discovery. In this theory the imagination is shown to be active in creating systematic explanations of the phenomena of nature, to the extent that Smith depicts the aim of scientific theory as that of satisfying the imagination. Smith's account of the logic of scientific theory can be defended even in contemporary philosophy of science. In particular, it can be maintained that all scientific theories are works of the imagination and that the concept of truth does not directly apply to them. PMID- 23670924 TI - A fragment of the explanation': the use and abuse of words. AB - This paper explores the normative basis of power in language, story, labels and evidence, and attempts to show how these dimensions of power are used systematically to simplify the reality of exprience, deny ignorance and exclude uncertainty. Through the resulting abuse of words, doctors may often constrain and limit their patients' stories, consigning many of them to stories of failure, and reducing their capacity to celebrate, or even recognise, achievement. PMID- 23670925 TI - Four poems and two stories. PMID- 23670926 TI - Clinical craft: a lesson from Liverpool. AB - Inspiration in medical humanities can be intense and personal, and does not necessarily require the portrayal of health issues. PMID- 23670927 TI - A medical perspective on the adventures of Sherlock Holmes. AB - The adventures of Sherlock Holmes, although primarily famous as stories of detection of crime, offer a considerable amount to interest the medical reader. There are many medical references in the stories, and the influence of Conan Doyle's medical background is clearly seen in the main characters. Aspects of the stories also reflect Conan Doyle's medical career, and also something of his attitude towards the profession. From Holmes's sayings and accounts of his methods, parallels can be drawn between Holmesian deduction and the diagnostic process. It is concluded, however, that deduction cannot be used as a direct paradigm since medical problems are rarely soluble through a process of logic alone. PMID- 23670929 TI - Metaphors for medicine: revealing reflections or just popular parodies? PMID- 23670928 TI - Some medical syndromes encountered in nineteenth-century French literature. AB - The medical content of a hundred selected French novels written between 1815 and 1914 has been examined. These books reflect contemporary public interest in medicine and disease. By means of translated quotations, the spectrum of diseases common at the time, including conditions nowadays rarely or never observed, such as smallpox and diphtheria, are graphically described, along with the effects of treatment of syphilis with mercury and the ravages of tuberculosis including lupus vulgaris. Some diseases which were not understood in the nineteenth century such as cretinism due to iodine deficiency may be recognised by the modern reader while other illnesses, convincingly described, are now unidentifiable. In the novels one can trace the transition from the humoral theory of disease to modern diagnoses and the advent of surgery and its complications. These extracts complement textbooks of the history of medicine by third-party depiction of the observed impact of disease upon the individual. PMID- 23670930 TI - Becoming a doctor. AB - Medical training cannot be equated with merely studying for a degree. It encompasses much more, challenging one's values, self perception and perspective on life itself. During five years at medical school, the individual irreversibly alters to become "a medic", not just "a student of medicine", no matter how much detachment from the course and its associated lifestyle the individual has endeavoured to preserve. In the following article, we intend to explore the different stages of training and discuss how each shapes the student. "Becoming a medic" intellectually, emotionally and spiritually is the inevitable consequence of spending five years at medical school, and the assumption of this role is indeed crucial to survival in medical practice. The importance of bringing our own individual qualities to the profession must, however, not be overlooked. Personal flair and abilities should be nurtured, not suppressed during medical school. A diversity of interests serves both to ease the pressures laid upon us at medical school, and to broaden our characters and deepen our understanding of humanity. Medical students, while necessarily adapting to the role of a doctor, should emerge from their training not as narrow "medics" but as enthusiastic, compassionate people equipped to treat patients to the best of their ability. PMID- 23670931 TI - Developing the medical humanities'-report of a research colloquium, and collected abstracts of papers. PMID- 23670932 TI - From Kafka to Casualty: doctors and medicine in popular culture and the arts-- a special studies module. AB - This paper describes and reflects on the content and teaching methods of a two week medical humanities special studies module (SSM) taken by third-year students at the Royal Free & University College Medical School. It aims to add to the common pool of knowledge, and will be of use to people who are considering setting up something similar. PMID- 23670933 TI - The use and abuse of language in science. PMID- 23670934 TI - Proposal for an academic Association for Medical Humanities. PMID- 23670935 TI - A convergence of cultures & technologies. PMID- 23670936 TI - Medical humanities, kalology and philokalia. PMID- 23670937 TI - What price dissection? Dissection literally dissected. PMID- 23670938 TI - A versatile dithienylethene-functionalized Ph-diazabutadiene (DAB) ligand: from photoswitchable main-group molecules to photochromic polymers. AB - Within the past decade photochromic materials, specifically dithienylethenes (DTEs), have received increased interest because of their ability to function as potential photoswitchable molecular devices and optical memory storage systems. Current research in this area has focused on incorporating organic architectures to functionalize the DTE framework and alter the resulting photophysical properties; however, their syntheses are often not trivial. In this context, we have designed a simple and versatile diimine (2) containing adjacent 2,5 dimethyl(thienyl) rings in the backbone. This redox active diimine (2) acts as a precursor to a novel photochromic ligand and has been used to coordinate to both boron and phosphorus elements, along with the synthesis of a phosphorane-side chain functionalized polymer without further functionalization to the parent DTE framework. A study of the resulting photochromic properties of these compounds revealed that 1) the UV-visible absorption spectra of the closed-ring isomer were dependent of the element present in the N,N'-chelating pocket and 2) incorporating the dithienylethene into a side-functionalized phosphorane polymer greatly increased the closed-/open-ring reversibility and decreased the formation of by-products. PMID- 23670939 TI - Avoiding zero between-study variance estimates in random-effects meta-analysis. AB - Fixed-effects meta-analysis has been criticized because the assumption of homogeneity is often unrealistic and can result in underestimation of parameter uncertainty. Random-effects meta-analysis and meta-regression are therefore typically used to accommodate explained and unexplained between-study variability. However, it is not unusual to obtain a boundary estimate of zero for the (residual) between-study standard deviation, resulting in fixed-effects estimates of the other parameters and their standard errors. To avoid such boundary estimates, we suggest using Bayes modal (BM) estimation with a gamma prior on the between-study standard deviation. When no prior information is available regarding the magnitude of the between-study standard deviation, a weakly informative default prior can be used (with shape parameter 2 and rate parameter close to 0) that produces positive estimates but does not overrule the data, leading to only a small decrease in the log likelihood from its maximum. We review the most commonly used estimation methods for meta-analysis and meta regression including classical and Bayesian methods and apply these methods, as well as our BM estimator, to real datasets. We then perform simulations to compare BM estimation with the other methods and find that BM estimation performs well by (i) avoiding boundary estimates; (ii) having smaller root mean squared error for the between-study standard deviation; and (iii) better coverage for the overall effects than the other methods when the true model has at least a small or moderate amount of unexplained heterogeneity. PMID- 23670940 TI - Statin therapy in the reduction of cardiovascular events in patients undergoing intermediate-risk noncardiac, nonvascular surgery. AB - BACKGROUND: Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) reduce perioperative cardiac events in high-risk patients undergoing cardiovascular surgery. However, there is paucity of data on the role of statins in patients undergoing intermediate-risk noncardiac, nonvascular surgery (NCNVS). HYPOTHESIS: Statins are cardioprotective in intermediate-risk NCNVS. METHODS: We identified a retrospective cohort of patients undergoing intermediate risk NCNVS. Our composite end point (CEP) included 30-day all-cause mortality, atrial fibrillation (AF), and nonfatal myocardial infarction (MI). A stepwise logistic regression with adjustment using propensity scores was performed to determine if statin therapy was independently associated with the risk reduction of adverse postoperative cardiovascular outcomes. RESULTS: We identified 752 patients. Seventy-five of them (9.97%) developed composite end points; 10 (1.33%) had in hospital nonfatal MI, 44 (5.85%) developed AF, and 35 (4.65%) died within 30 days. The 30-day all-cause mortality was 31/478 (6.48%) among statin nonusers vs 4/274 (1.45%) for statin users (P < 0.002). As compared with nonusers, patients on statin therapy had a 5-fold reduced risk of 30-day all-cause mortality. Statin therapy was associated with decreased CEP after adjusting for baseline characteristics, with a propensity score to predict use of statins (odds ratio [OR]: 0.54, 95% confidence interval [CI]: 0.30-0.97, P = 0.039). After further adjustment for propensity score, diabetes mellitus, percutaneous coronary intervention, and prior coronary artery bypass grafting, statin therapy proved beneficial (OR: 0.51, 95% CI: 0.28-0.92, P = 0.026). CONCLUSIONS: Statin use in the perioperative period was associated with a reduction in cardiovascular adverse events and 30-day all-cause mortality in patients undergoing intermediate risk NCNVS. PMID- 23670942 TI - Triggered in situ disruption and inversion of nanoparticle-stabilized droplets. PMID- 23670941 TI - Endogenous oxidative stress, but not ER stress, induces hypoxia-independent VEGF120 release through PI3K-dependent pathways in 3T3-L1 adipocytes. AB - OBJECTIVE: Expressions of vascular endothelial growth factor (VEGF) are increased in obese adipocytes and is secreted from obese adipose tissue through hypoxia independent pathways. Therefore, we investigated the hypoxia-independent mechanism underlying increased expression and release of VEGF in obese adipocytes. DESIGN AND METHODS: We compared signal transduction pathways regulating VEGF with those regulating monocyte chemoattractant protein-1 (MCP-1), which is increased in obese adipocytes, in an in vitro model of artificially hypertrophied 3T3-L1 adipocytes preloaded with palmitate, without the influence of hypoxia. RESULTS: Palmitate-preloaded cells exhibited significantly enhanced oxidative stress (P < 0.01) and showed increased VEGF120 and MCP-1 release (P < 0.01, respectively), while endoplasmic reticulum (ER) stress was not induced. Increased VEGF120 release was significantly decreased with PI3K inhibitor LY294002 (P < 0.01). In addition, antioxidant N-acetyl-cysteine (NAC) markedly diminished not only VEGF120 secretion (P < 0.01) but also augmented Akt phosphorylation on Ser473 (P < 0.01). In contrast, increased MCP-1 release was suppressed with JNK inhibitor SP600125 and p38 MAPK inhibitor SB203580 (P < 0.01). CONCLUSIONS: VEGF120 release from hypertrophied adipocytes can be enhanced through PI3K pathways activated by oxidative stress but not by ER stress, suggesting that VEGF120 secretion is regulated through oxidative stress-dependent pathways distinct from those involved in MCP-1 release through either JNK or p38 MAPK activation. PMID- 23670943 TI - Investigating the effects of repeated Miranda warnings: do they perform a curative function on common Miranda misconceptions? AB - In Miranda v. Arizona (1966), the Supreme Court of the United States required that custodial suspects be apprised of their Constitutional rights against self incrimination. The Court could not have anticipated the rampant popularization of Miranda warnings in subsequent movies and television dramas. Influenced by public media, many arrestees assume that they already "know" their rights, with no awareness of their misconceptions. The current investigation examines whether repeated exposures to Miranda warnings performs any "curative" function (i.e., dispelling common Miranda misconceptions held by pretrial defendants). The accumulative effects of five different Miranda warnings were tested over a several-hour period on 260 detainees. For the nearly half (113 or 43.5%) with three or more misconceptions, improvement (i.e., >=2 fewer misconceptions) occurred for only 35 defendants. Predictably, this improved group also tended to display a better understanding of Miranda-relevant vocabulary words and a better recall of the administered Miranda warnings than their unimproved counterparts. On average, the improved group also performed better on general measures of intelligence, and listening and reading comprehension, while still evidencing substantial cognitive deficits. The curative function of Miranda advisements is considered in light of these findings. PMID- 23670944 TI - Bioactive silicate nanoplatelets for osteogenic differentiation of human mesenchymal stem cells. AB - Novel silicate nanoplatelets that induce osteogenic differentiation of human mesenchymal stem cells (hMSCs) in the absence of any osteoinductive factor are reported. The presence of the silicate triggers a set of events that follows the temporal pattern of osteogenic differentiation. These findings underscore the potential applications of these silicate nanoplatelets in designing bioactive scaffolds for musculoskeletal tissue engineering. PMID- 23670945 TI - Structural characterization of anion-calcium-humate complexes in phosphate-based fertilizers. AB - Fertilizers based on phosphate-metal-humate complexes are a new family of compounds that represents a more sustainable and bioavailable phosphorus source. The characterization of this type of complex by using solid (31)P NMR in several fertilizers, based on single superphosphate (SSP) and triple superphosphate (TSP) matrices, yielded surprising and unexpected trends in the intensity and fine structure of the (31)P NMR peaks. Computational chemistry methods allowed the characterization of phosphate-calcium-humate complexes in both SSP and TSP matrices, but also predicted the formation of a stable sulfate-calcium-humate complex in the SSP fertilizers, which has not been described previously. The stability of this complex has been confirmed by using ultrafiltration techniques. Preference towards the humic substance for the sulfate-metal phase in SSP allowed the explanation of the opposing trends that were observed in the experimental (31)P NMR spectra of SSP and TSP samples. Additionally, computational chemistry has provided an assignment of the (31)P NMR signals to different phosphate ligands as well as valuable information about the relative strength of the phosphate-calcium interactions within the crystals. PMID- 23670946 TI - Rh-catalyzed direct enantioselective alkynylation of alpha-ketiminoesters. AB - A green way to amino acids: alpha-Tetrasubstituted alpha-amino acid derivatives are formed in high yield and enantioselectivity by using a Rh-catalyzed enantioselective alkynylation of alpha-ketiminoesters. This reaction, which involves a proton transfer and can be conducted at room temperature, has high substrate scope (see scheme; Cbz = benzyloxycarbonyl, Fmoc = 9 fluorenylmethyloxycarbonyl). PMID- 23670948 TI - A clinician's guide to the ABCs of cardiovascular disease prevention: the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease and American College of Cardiology Cardiosource Approach to the Million Hearts Initiative. AB - Atherosclerotic cardiovascular disease (CVD) is the leading cause of death in the United States and worldwide. Fortunately, it is often preventable with early adoption of lifestyle modification, prevention of risk factor onset, and aggressive treatment of existing risk factors. The Million Hearts Initiative is an effort by the Centers for Disease Control that aims to prevent 1 million myocardial infarctions and strokes over the next 5 years. As part of this initiative, we present a simply organized "ABCDE" approach for guiding a consistent comprehensive approach to managing cardiovascular risk in daily clinical practice. ABCDE stands for assessment of risk, antiplatelet therapy, blood pressure management, cholesterol management, cigarette/tobacco cessation, diet and weight management, diabetes prevention and treatment, and exercise, interventions regularly used to reduce cardiovascular (CV) risk. Throughout this article we summarize recommendations related to each topic and reference landmark trials and data that support our approach. We believe that the ABCDE approach will be the core framework for addressing CV risk in our effort to prevent CVD. PMID- 23670947 TI - Predicting county-level cancer incidence rates and counts in the USA. AB - Many countries, including the USA, publish predicted numbers of cancer incidence and death in current and future years for the whole country. These predictions provide important information on the cancer burden for cancer control planners, policymakers and the general public. Based on evidence from several empirical studies, the joinpoint (segmented-line linear regression) model (JPM) has been adopted by the American Cancer Society to estimate the number of new cancer cases in the USA and in individual states since 2007. Recently, cancer incidence in smaller geographic regions such as counties, and local policy makers are increasingly interested with Federal Information Processing Standard code regions. The natural extension is to directly apply the JPM to county-level cancer incidence data. The direct application has several drawbacks and its performance has not been evaluated. To address the concerns, we developed a spatial random-effects JPM for county-level cancer incidence data. The proposed model was used to predict both cancer incidence rates and counts at the county level. The standard JPM and the proposed method were compared through a validation study. The proposed method outperformed the standard JPM for almost all cancer sites, especially for moderate or rare cancer sites and for counties with small population sizes. As an application, we predicted county-level prostate cancer incidence rates and counts for the year 2011 in Connecticut. PMID- 23670949 TI - The role of placental protein 14 in the pathogenesis of endometriosis. AB - Placental protein 14 (PP-14) is the principal secretory phase product of endometrium and has been shown to inhibit cell immune function. But its role in the pathogenesis of endometriosis is controversy. The objective of this study is to determine the concentrations of PP-14 in peritoneal fluid (PF) and serum and PP-14 protein expression in endometriotic lesions in women with ovarian endometriosis (n = 75) when compared to women without endometriosis (n = 49) between day 7 and day 20 of their menstrual cycle. Concentrations of PP-14 in PF and serum as well as PP-14 protein expression in endometriotic lesions in women with and without endometriosis were evaluated by using enzyme-linked immunosorbent assay and immunohistochemical staining, respectively. Serum PP-14 concentrations were significantly increased in women with endometriosis (7.5 +/- 1.4 ng/mL) compared to those in women without endometriosis (5.8 +/- 0.9 ng/mL; P < .05) and statistically decreased after surgery and further reduced by using gonadotropin-releasing hormone agonist therapy (P < .05). However, the concentrations of PP-14 in PF did not reach a significant difference between women with and without endometriosis (P > .05). In women with endometriosis, scores of PP-14 protein expression in the lesions (n = 50, 2.2 [0~5.8]) were significantly correlated with serum PP-14 concentrations (n = 50, 7.6 +/- 1.3 ng/mL; P < .01). Our results suggest that PP-14 may play an important role in the pathogenesis of endometriosis. PMID- 23670951 TI - Common and unique gray matter correlates of episodic memory dysfunction in frontotemporal dementia and Alzheimer's disease. AB - Conflicting evidence exists regarding the integrity of episodic memory in the behavioral variant of frontotemporal dementia (bvFTD). Recent converging evidence suggests that episodic memory in progressive cases of bvFTD is compromised to the same extent as in Alzheimer's disease (AD). The underlying neural substrates of these episodic memory deficits, however, likely differ contingent on dementia type. In this study we sought to elucidate the neural substrates of episodic memory performance, across recall and recognition tasks, in both patient groups using voxel-based morphometry (VBM) analyses. We predicted that episodic memory dysfunction would be apparent in both patient groups but would relate to divergent patterns of neural atrophy specific to each dementia type. We assessed episodic memory, across verbal and visual domains, in 19 bvFTD, 18 AD patients, and 19 age- and education-matched controls. Behaviorally, patient groups were indistinguishable for immediate and delayed recall, across verbal and visual domains. Whole-brain VBM analyses revealed regions commonly implicated in episodic retrieval across groups, namely the right temporal pole, right frontal lobe, left paracingulate gyrus, and right anterior hippocampus. Divergent neural networks specific to each group were also identified. Whereas a widespread network including posterior regions such as the posterior cingulate cortex, parietal and occipital cortices was exclusively implicated in AD, the frontal and anterior temporal lobes underpinned the episodic memory deficits in bvFTD. Our results point to distinct neural changes underlying episodic memory decline specific to each dementia syndrome. PMID- 23670953 TI - Oxidative coupling reactions of Grignard reagents with nitrous oxide. PMID- 23670952 TI - A flexible model for the mean and variance functions, with application to medical cost data. AB - Medical cost data are often skewed to the right and heteroscedastic, having a nonlinear relation with covariates. To tackle these issues, we consider an extension to generalized linear models by assuming nonlinear associations of covariates in the mean function and allowing the variance to be an unknown but smooth function of the mean. We make no further assumption on the distributional form. The unknown functions are described by penalized splines, and the estimation is carried out using nonparametric quasi-likelihood. Simulation studies show the flexibility and advantages of our approach. We apply the model to the annual medical costs of heart failure patients in the clinical data repository at the University of Virginia Hospital System. PMID- 23670950 TI - Stem cells from umbilical cord Wharton's jelly from preterm birth have neuroglial differentiation potential. AB - OBJECTIVE: The aim of the study is to determine the neuroglial differentiation potential of human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) from preterm birth when compared to term delivery. STUDY DESIGN: The WJ-MSCs from umbilical cords of preterm birth and term controls were isolated and induced into neural progenitors. The cells were analyzed for neuroglial markers by flow cytometry, real-time polymerase chain reaction, and immunocytochemistry. RESULTS: Independent of gestational age, a subset of WJ-MSC displayed the neural progenitor cell markers Nestin and Musashi-1 and the mature neural markers microtubule-associated protein 2, glial fibrillary acidic protein, and myelin basic protein. Neuroglial induction of WJ-MSCs from term and preterm birth resulted in the enhanced transcription of Nestin and Musashi-1. CONCLUSIONS: Undifferentiated WJ-MSCs from preterm birth express neuroglial markers and can be successfully induced into neural progenitors similar to term controls. Their potential use as cellular graft in neuroregenerative therapy for peripartum brain injury in preterm birth has to be tested. PMID- 23670954 TI - Color in the corners: ITO-free white OLEDs with angular color stability. AB - High-efficiency white OLEDs fabricated on silver nanowire-based composite transparent electrodes show almost perfectly Lambertian emission and superior angular color stability, imparted by electrode light scattering. The OLED efficiencies are comparable to those fabricated using indium tin oxide. The transparent electrodes are fully solution-processable, thin-film compatible, and have a figure of merit suitable for large-area devices. PMID- 23670955 TI - Efficient concomitant and remanence field artifact reduction in ultra-low-field MRI using a frequency-space formulation. AB - PURPOSE: For ultra-low-field MRI, the spatial-encoding magnetic fields generated by gradient coils can have strong concomitant fields leading to prominent image distortion. Additionally, using superconducting magnet to pre-polarize magnetization can improve the signal-to-noise ratio of ultra-low-field MRI. Yet the spatially inhomogeneous remanence field due to the permanently trapped flux inside a superconducting pre-polarizing coil modulates magnetization and causes further image distortion. METHOD: We propose a two-stage frequency-space (f-x) formulation to accurately describe the dynamics of spatially-encoded magnetization under the influence of concomitant and remanence fields, which allows for correcting image distortion due to concomitant and remanence fields. RESULTS: Our method is computationally efficient as it uses a combination of the fast Fourier transform algorithm and a linear equation solver. With sufficiently dense discretization in solving the linear equation, the performance of this f-x method was found to be stable among different choices of the regularization parameter and the regularization matrix. CONCLUSION: We present this method together with numerical simulations and experimental data to demonstrate how concomitant and remanence field artifacts in ultra-low-field MRI can be corrected efficiently. PMID- 23670956 TI - Can statins improve outcomes after isolated cardiac valve surgery? A systematic literature review. AB - BACKGROUND: HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors, or statins, have been associated with an improvement in outcomes after coronary artery surgery for some time; however, their role in isolated valve surgery (IVS) remains undetermined. HYPOTHESIS: The pleiotropic effects of statins may produce similar beneficial effects on outcomes after IVS. METHODS: A systematic review of the literature was performed investigating the role of statins in bioprosthetic valve replacement. RESULTS: Nine observational studies (7 retrospective, 2 prospective) incorporating a total of 18 154 patients were found investigating the role of statin therapy in bioprosthetic valve replacement. CONCLUSIONS: There is presently insufficient evidence to recommend routine statin therapy in IVS, unless concomitant hypercholesterolemia or coronary artery disease is present. A prospective study clearly defining the dose, type, and duration of therapy is now required to finally clarify whether statins alone confer a postoperative benefit in these patients. PMID- 23670957 TI - Composite poly(ethylene oxide) electrolytes plasticized by N-alkyl-N butylpyrrolidinium bis(trifluoromethanesulfonyl)imide for lithium batteries. AB - We report a new class of quaternary polymer electrolyte membranes that comprise poly(ethylene oxide) (PEO), lithium trifluoromethanesulfonylimide (LiTFSI), N alkyl-N-butylpyrrolidinium bis(trifluoromethanesulfonyl)imide (PyrA,4 TFSI) as an ionic liquid, and a SiO2 filler. The results of differential scanning calorimetry indicate that the addition of SiO2 and different ionic liquids induces a decrease in the PEO melting enthalpy, which thereby increases the ionic conductivity and the Li transference number. The electrochemical stability is proved by using impedance spectroscopy and cyclic voltammetry. Galvanostatic cycling of Li/LiFePO4 cells, which comprise the quaternary polymer electrolytes, revealed their superior performance compared to conventional PEO-Li salt electrolytes. In the course of this investigation, a synergistic effect of the combined ionic liquid-ceramic filler modification could be proved at temperatures close to 50 degrees C. PMID- 23670958 TI - A synthetic anti-inflammatory sterol improves insulin sensitivity in insulin resistant obese impaired glucose tolerance subjects. AB - OBJECTIVE: To study the activity of HE3286 (17alpha-ethynylandrost-5-ene 3beta,7beta,17beta-triol), an anti-inflammatory sterol that is active in models of obesity-induced inflammation and insulin resistance in high body mass index (BMI) subjects with impaired glucose tolerance (IGT). DESIGN AND METHODS: HE3286 was explored in high BMI IGT subjects using hyperinsulinemic, euglycemic clamp studies. RESULTS: In insulin-resistant subjects, HE3286 significantly increased day 29 insulin-stimulated glucose disposal and HDL cholesterol, and decreased C reactive protein (CRP) compared to placebo. For HE3286, change in M value showed a significant negative correlation with baseline M value. Subjects with baseline M value below the median (4.2 mg/kg/min) had significantly lower adiponectin and higher lipopolysaccharide-stimulated peripheral blood mononuclear cell cytokine secretion. After 28 days of HE3286 treatment, adiponectin levels were significantly increased in insulin-resistant (baseline M < 4.2), but not insulin sensitive (baseline M > 4.2) subjects, compared to placebo. CONCLUSIONS: HE3286 significantly increased the frequency of subjects with increased insulin stimulated glucose disposal and HDL, and decreased CRP compared to placebo, in insulin-resistant, but not insulin-sensitive subjects. Thus, HE3286 may preferentially benefit insulin-resistant, inflamed, high BMI IGT subjects. PMID- 23670960 TI - Callosal degeneration topographically correlated with cognitive function in amnestic mild cognitive impairment and Alzheimer's disease dementia. AB - Degeneration of the corpus callosum (CC) is evident in the pathogenesis of Alzheimer's disease (AD). However, the correlation of microstructural damage in the CC on the cognitive performance of patients with amnestic mild cognitive impairment (aMCI) and AD dementia is undetermined. We enrolled 26 normal controls, 24 patients with AD dementia, and 40 single-domain aMCI patients with at least grade 1 hippocampal atrophy and isolated memory impairment. Diffusion tensor imaging (DTI) with fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (DA), and radial diffusivity (DR) were measured. The entire CC was parcellated based on fiber trajectories to specific cortical Brodmann areas using a probabilistic tractography method. The relationship between the DTI measures in the subregions of the CC and cognitive performance was examined. Although the callosal degeneration in the patients with aMCI was less extended than in the patients with AD dementia, degeneration was already exhibited in several subregions of the CC at the aMCI stage. Scores of various neuropsychological tests were correlated to the severity of microstructural changes in the subregional CC connecting to functionally corresponding cortical regions. Our results confirm that CC degeneration is noticeable as early as the aMCI stage of AD and the disconnection of the CC subregional fibers to the corresponding Brodmann areas has an apparent impact on the related cognitive performance. PMID- 23670961 TI - Total synthesis of jadomycins B, S, T, and ILEVS1080. AB - Sweetening up jadomycin A: The first total synthesis of jadomycins B, S, T, and ILEVS1080 has been achieved, featuring construction of the unique 8H benz[b]oxazolo[3,3-f]phenanthridine skeleton by biomimetic condensation of a quinone aldehyde with amino acid sodium salts and elaboration of the glycosides by Mitsunobu condensation (see figure). PMID- 23670962 TI - Gold-catalyzed intramolecular regio- and enantioselective cycloisomerization of 1,1-bis(indolyl)-5-alkynes. PMID- 23670963 TI - Surprisingly correct: unexpectedness of observed actions activates the medial prefrontal cortex. AB - Not only committing errors, but also observing errors has been shown to activate the dorsal medial prefrontal cortex, particularly BA 8 and adjacent rostral cingulate zone (RCZ). Currently, there is a debate on whether this activity reflects a response to the incorrectness of the committed action or to its unexpectedness. This article reports two studies investigating whether activity in BA 8/RCZ is due to the unexpectedness of observed errors or the incorrectness of the specific observed action. Both studies employed an action observation paradigm reliant on the observation of an actor tying sailing knots. The reported behavioral experiment delivered evidence that the paradigm successfully induced the expectation of incorrect actions as well as the expectation of correct actions. The functional magnetic resonance imaging study revealed that unexpectedly correct as well as unexpectedly incorrect actions activate the BA 8/RCZ. The same result was confirmed for a coordinate in the vicinity that has been previously reported to be activated in separate studies either by the error observation or by the unexpectedness of committed errors, and has been associated with the error-related negativity. The present results suggest that unexpectedness has an impact on the medial prefrontal correlate of observed errors. PMID- 23670964 TI - Matrix-assisted catalytic printing for the fabrication of multiscale, flexible, foldable, and stretchable metal conductors. AB - Matrix-assisted catalytic printing (MACP) is developed as a low-cost and versatile printing method for the fabrication of multiscale metal conductors on a wide variety of plastic, elastomeric, and textile substrates. Highly conductive Cu interconnects (2.0 * 108 S/m) fabricated by MACP at room temperature display excellent flexibility, foldability, and stretchability. PMID- 23670965 TI - Sample size and power for a logrank test and Cox proportional hazards model with multiple groups and strata, or a quantitative covariate with multiple strata. AB - I describe general expressions for the evaluation of sample size and power for the K group Mantel-logrank test or the Cox proportional hazards (PH) model score test. Under an exponential model, the method of Lachin and Foulkes for the 2 group case is extended to the K ?2 group case using the non-centrality parameter of the K - 1 df chi-square test. I also show similar results to apply to the K group score test in a Cox PH model. Lachin and Foulkes employed a truncated exponential distribution to provide for a non-linear rate of enrollment. I present expressions for the mean time of enrollment and the expected follow-up time in the presence of exponential losses to follow-up. When used with the expression for the noncentrality parameter for the test, equations are derived for the evaluation of sample size and power under specific designs with r years of recruitment and T years total duration. I also describe sample size and power for a stratified-adjusted K group test and for the assessment of a group by stratum interaction. Similarly, I describe computations for a stratified-adjusted analysis of a quantitative covariate and a test of a stratum by covariate interaction in the Cox PH model. PMID- 23670966 TI - Frames of mental illness in the Yoruba genre of Nigerian movies: implications for orthodox mental health care. AB - This study examines the modes of framing mental illness in the Yoruba genre of Nigerian movies. All Yoruba films on display in a convenient sample of movie rental shops in Ibadan (Nigeria) were sampled for content. Of the 103 films studied, 27 (26.2%) contained scenes depicting mental illness. Psychotic symptoms were the most commonly depicted, while effective treatments were mostly depicted as taking place in unorthodox settings. The most commonly depicted aetiology of mental illness was sorcery and enchantment by witches and wizards, as well as other supernatural forces. Scenes of mental illness are common in Nigerian movies and these depictions-though reflecting the popular explanatory models of Yoruba speaking Nigerians about mental illness- may impede utilization of mental health care services and ongoing efforts to reduce psychiatry stigma in this region. Efforts to reduce stigma and improve service utilization should engage the film industry. PMID- 23670967 TI - Magnetism in lithium-oxygen discharge product. AB - Nonaqueous lithium-oxygen batteries have a much superior theoretical gravimetric energy density compared to conventional lithium-ion batteries, and thus could render long-range electric vehicles a reality. A molecular-level understanding of the reversible formation of lithium peroxide in these batteries, the properties of major/minor discharge products, and the stability of the nonaqueous electrolytes is required to achieve successful lithium-oxygen batteries. We demonstrate that the major discharge product formed in the lithium-oxygen cell, lithium peroxide, exhibits a magnetic moment. These results are based on dc magnetization measurements and a lithium-oxygen cell containing an ether-based electrolyte. The results are unexpected because bulk lithium peroxide has a significant band gap. Density functional calculations predict that superoxide type surface oxygen groups with unpaired electrons exist on stoichiometric lithium peroxide crystalline surfaces and on nanoparticle surfaces; these computational results are consistent with the magnetic measurement of the discharged lithium peroxide product as well as EPR measurements on commercial lithium peroxide. The presence of superoxide-type surface oxygen groups with spin can play a role in the reversible formation and decomposition of lithium peroxide as well as the reversible formation and decomposition of electrolyte molecules. PMID- 23670968 TI - Laparoscopic sleeve gastrectomy differentially affects serum concentrations of FGF-19 and FGF-21 in morbidly obese subjects. AB - OBJECTIVE: Fibroblast growth factor (FGF)-19 and FGF-21 are novel metabolic regulators that improve insulin resistance and obesity in rodents. The aim of the study was to assess the effects of laparoscopic sleeve gastrectomy (LSG) on serum concentrations of FGF-19 and FGF-21 along with circulating bile acids and other relevant hormonal and biochemical parameters. DESIGN AND METHODS: Seventeen females with obesity undergoing LSG and 15 lean healthy females were included into the study. Anthropometric and biochemical parameters, serum concentrations of FGF-19 and -21, insulin, adiponectin, leptin, C-reactive protein, resistin, amylin (total), ghrelin (active), glucagon-like peptide 1 (GLP-1, active), glucose-dependent insulinotropic peptide (GIP, total), peptide YY (PYY, total), pancreatic polypeptide (PP), and bile acids, and mRNA expression of selected adipokines and inflammatory markers in bioptic samples of subcutaneous fat were assessed at baseline and 6, 12, and 24 months after LSG. RESULTS: LSG markedly decreased body weight, BMI, waist circumference, and insulin levels and improved systemic inflammation and lipid levels. FGF-19 concentrations increased and FGF 21 concentrations decreased after LSG along with increased adiponectin and decreased leptin, amylin, and ghrelin levels. GLP-1, GIP, PP, and circulating bile acids were not affected by LSG. PYY decreased significantly 24 months after surgery only. mRNA expression analysis in subcutaneous fat showed markedly reduced proinflammatory state. CONCLUSIONS: Our results indicate that increased FGF-19 and decreased ghrelin concentrations could have partially contributed to the improvement of systemic inflammation and some metabolic parameters after LSG, while changes of FGF-21 are rather secondary because of weight loss. PMID- 23670969 TI - Impacts of mitral E/e' on myocardial contractile motion and synchronicity in heart failure patients with reduced ejection fraction: An exercise echocardiography study. AB - BACKGROUND: The association between diastolic abnormality and postexercise contractile decompensation is uncertain in heart failure (HF) patients with reduced left ventricular ejection fraction (LVEF). HYPOTHESIS: The higher mitral E/annular early diastolic velocity (E/e') is relevant to postexercise regional myocardial contractile maladaptation. METHODS: Seventy HF patients with LVEF <50 % (56 males, 58 +/- 15 years) were studied pre- and postexercise using tissue Doppler echocardiography. We evaluated the mean and standard deviation of systolic myocardial velocity (Sm) and electromechanical delay (Ts) of 12 left ventricular segments, and further analyzed the corresponding changes of septal and posterolateral segments. RESULTS: The higher mitral E/e' was associated with more blunted heterogeneity of Sm and greater ventricular dyssynchrony after exercise. This is due to the posterolateral wall not being able to increase Sm with exercise to the same degree as the septum (decreased posterolateral/septal Sm ratio). Furthermore, the postexercise aggravated difference of Ts between septum and posterolateral segments leads to more dyssynchronous contraction in the higher E/e' groups. An E/e' >=10 predicted a postexercise posterolateral/septal Sm <= 1 (odds ratio [OR]: 5.8, 95% confidence interval [CI]: 1.5-22.6, P = 0.011), and a difference of Ts between septum and posterolateral segments >65 ms (OR: 64, 95% CI: = 6-651, P < 0.001) in HF patients with reduced LVEF in multivariate analysis. CONCLUSIONS: The higher mitral E/e'-related postexercise maladaptation of myocardial contractile motion and synchronicity suggests the involvement of systolic abnormality in exercise pathophysiology in HF patients with reduced LVEF. PMID- 23670971 TI - Induction of cytosolic phospholipase a2alpha is required for adipose neutrophil infiltration and hepatic insulin resistance early in the course of high-fat feeding. AB - In established obesity, inflammation and macrophage recruitment likely contribute to the development of insulin resistance. In the current study, we set out to explore whether adipose tissue infiltration by neutrophils that occurs early (3 days) after initiating a high-fat diet (HFD) could contribute to the early occurrence of hepatic insulin resistance and to determine the role of cytosolic phospholipase A2alpha (cPLA2alpha) in this process. The 3-day HFD caused a significant upregulation of cPLA2alpha in periepididymal fat and in the liver. A specific antisense oligonucleotide (AS) effectively prevented cPLA2alpha induction, neutrophil infiltration into adipose tissue (likely involving MIP-2), and protected against 3-day HFD-induced impairment in hepatic insulin signaling and glucose over-production from pyruvate. To sort out the role of adipose neutrophil infiltration independent of cPLA2alpha induction in the liver, mice were injected intraperitoneally with anti-intracellular adhesion molecule-1 (ICAM 1) antibodies. This effectively prevented neutrophil infiltration without affecting cPLA2alpha or MIP-2, but like AS, prevented impairment in hepatic insulin signaling, the enhanced pyruvate-to-glucose flux, and the impaired insulin-mediated suppression of hepatic glucose production (assessed by clamp), which were induced by the 3-day HFD. Adipose tissue secretion of tumor necrosis factor-alpha (TNF-alpha) was increased by the 3-day HFD, but not if mice were treated with AS or ICAM-1 antibodies. Moreover, systemic TNF-alpha neutralization prevented 3-day HFD-induced hepatic insulin resistance, suggesting its mediatory role. We propose that an acute, cPLA2alpha-dependent, neutrophil-dominated inflammatory response of adipose tissue contributes to hepatic insulin resistance and glucose overproduction in the early adaptation to high-fat feeding. PMID- 23670972 TI - Limitations of IL-2 and rapamycin in immunotherapy of type 1 diabetes. AB - Administration of low-dose interleukin-2 (IL-2) alone or combined with rapamycin (RAPA) prevents hyperglycemia in NOD mice. Also, low-dose IL-2 cures recent-onset type 1 diabetes (T1D) in NOD mice, partially by boosting pancreatic regulatory T cells (Treg cells). These approaches are currently being evaluated in humans. Our objective was to study the effect of higher IL-2 doses (250,000-500,000 IU daily) as well as low-dose IL-2 (25,000 IU daily) and RAPA (1 mg/kg daily) (RAPA/IL-2) combination. We show that, despite further boosting of Treg cells, high doses of IL-2 rapidly precipitated T1D in prediabetic female and male mice and increased myeloid cells in the pancreas. Also, we observed that RAPA counteracted IL-2 effects on Treg cells, failed to control IL-2-boosted NK cells, and broke IL-2 induced tolerance in a reversible way. Notably, the RAPA/IL-2 combination failure to cure T1D was associated with an unexpected deleterious effect on glucose homeostasis at multiple levels, including beta-cell division, glucose tolerance, and liver glucose metabolism. Our data help to understand the therapeutic limitations of IL-2 alone or RAPA/IL-2 combination and could lead to the design of improved therapies for T1D. PMID- 23670970 TI - Genetic modifiers of cystic fibrosis-related diabetes. AB - Diabetes is a common age-dependent complication of cystic fibrosis (CF) that is strongly influenced by modifier genes. We conducted a genome-wide association study in 3,059 individuals with CF (644 with CF-related diabetes [CFRD]) and identified single nucleotide polymorphisms (SNPs) within and 5' to the SLC26A9 gene that associated with CFRD (hazard ratio [HR] 1.38; P = 3.6 * 10(-8)). Replication was demonstrated in 694 individuals (124 with CFRD) (HR, 1.47; P = 0.007), with combined analysis significant at P = 9.8 * 10(-10). SLC26A9 is an epithelial chloride/bicarbonate channel that can interact with the CF transmembrane regulator (CFTR), the protein mutated in CF. We also hypothesized that common SNPs associated with type 2 diabetes also might affect risk for CFRD. A previous association of CFRD with SNPs in TCF7L2 was replicated in this study (P = 0.004; combined analysis P = 3.8 * 10(-6)), and type 2 diabetes SNPs at or near CDKAL1, CDKN2A/B, and IGF2BP2 were associated with CFRD (P < 0.004). These five loci accounted for 8.3% of the phenotypic variance in CFRD onset and had a combined population-attributable risk of 68%. Diabetes is a highly prevalent complication of CF, for which susceptibility is determined in part by variants at SLC26A9 (which mediates processes proximate to the CF disease-causing gene) and at four susceptibility loci for type 2 diabetes in the general population. PMID- 23670973 TI - Relation between serum free fatty acids and adiposity, insulin resistance, and cardiovascular risk factors from adolescence to adulthood. AB - The objective of this study was to describe longitudinal relations of serum total free fatty acids (FFAs) to insulin resistance (IR) and cardiovascular (CV) risk factors from adolescence into adulthood. The cohort included participants in a longitudinal study of obesity and IR with complete data, including anthropometric measures, FFAs, IR measured by euglycemic clamp, blood pressure, fasting serum lipids, and insulin at mean 15 and 22 years of age (n = 207) and their parents (n = 272). FFAs and IR were not significantly related at mean 15 years of age but were significantly related at mean age 22 years. FFA did not relate to BMI at either age. FFA at 15 years of age estimated IR at 22 years of age. In parents (mean age 51 years), FFA was significantly correlated with BMI, percent body fat, systolic blood pressure, LDL, and IR. Associations with all risk factors except IR in parents were attenuated by adjustment for BMI. Most 22 years of age correlations with parents were higher than corresponding 15 years of age correlations. This study finds that FFA is associated with IR starting in young adulthood. The relation between FFA and CV risk factors does not become significant until later adulthood. The results support a significant impact of early metabolic dysfunction on later CV risk. PMID- 23670974 TI - Interleukin-18 activates skeletal muscle AMPK and reduces weight gain and insulin resistance in mice. AB - Circulating interleukin (IL)-18 is elevated in obesity, but paradoxically causes hypophagia. We hypothesized that IL-18 may attenuate high-fat diet (HFD)-induced insulin resistance by activating AMP-activated protein kinase (AMPK). We studied mice with a global deletion of the alpha-isoform of the IL-18 receptor (IL-18R(-/ )) fed a standard chow or HFD. We next performed gain-of-function experiments in skeletal muscle, in vitro, ex vivo, and in vivo. We show that IL-18 is implicated in metabolic homeostasis, inflammation, and insulin resistance via mechanisms involving the activation of AMPK in skeletal muscle. IL-18R(-/-) mice display increased weight gain, ectopic lipid deposition, inflammation, and reduced AMPK signaling in skeletal muscle. Treating myotubes or skeletal muscle strips with IL 18 activated AMPK and increased fat oxidation. Moreover, in vivo electroporation of IL-18 into skeletal muscle activated AMPK and concomitantly inhibited HFD induced weight gain. In summary, IL-18 enhances AMPK signaling and lipid oxidation in skeletal muscle implicating IL-18 in metabolic homeostasis. PMID- 23670975 TI - Quality-control culture system restores diabetic endothelial progenitor cell vasculogenesis and accelerates wound closure. AB - Delayed diabetic wound healing is, in part, the result of inadequate endothelial progenitor cell (EPC) proliferation, mobilization, and trafficking. Recently, we developed a serum-free functional culture system called the quality and quantity culture (QQc) system that enhances the number and vasculogenic potential of EPCs. We hypothesize that QQc restoration of diabetic EPC function will improve wound closure. To test this hypothesis, we measured diabetic c-kit(+)Sca-1(+)lin(-) (KSL) cell activity in vitro as well as the effect of KSL cell-adoptive transfer on the rate of euglycemic wound closure before and after QQc. KSL cells were magnetically sorted from control and streptozotocin-induced type I diabetic C57BL6J bone marrow. Freshly isolated control and diabetic KSL cells were cultured in QQc for 7 days and pre-QQc and post-QQc KSL function testing. The number of KSL cells significantly increased after QQc for both diabetic subjects and controls, and diabetic KSL increased vasculogenic potential above the fresh control KSL level. Similarly, fresh diabetic cells form fewer tubules, but QQc increases diabetic tubule formation to levels greater than that of fresh control cells (P < 0.05). Adoptive transfer of post-QQc diabetic KSL cells significantly enhances wound closure compared with fresh diabetic KSL cells and equaled wound closure of post-QQc control KSL cells. Post-QQc diabetic KSL enhancement of wound closure is mediated, in part, via a vasculogenic mechanism. This study demonstrates that QQc can reverse diabetic EPC dysfunction and achieve control levels of EPC function. Finally, post-QQc diabetic EPC therapy effectively improved euglycemic wound closure and may improve diabetic wound healing. PMID- 23670976 TI - Dual organocatalytic activation of isatins and formaldehyde tert-butyl hydrazone: asymmetric synthesis of functionalized 3-hydroxy-2-oxindoles. AB - Two is better than one! Dual activation of isatins and formaldehyde tert-butyl hydrazone by 2,2'-diamino-1,1'-binaphthalene (BINAM)-derived bis(ureas) is the key to achieve high reactivity and excellent enantioselectivities in the synthesis of azo- and azoxy-functionalized 3-hydroxy-2-oxindoles (see scheme). PMID- 23670977 TI - Decoupled roles for the atypical, bifurcated binding pocket of the ybfF hydrolase. AB - Serine hydrolases have diverse intracellular substrates, biological functions, and structural plasticity, and are thus important for biocatalyst design. Amongst serine hydrolases, the recently described ybfF enzyme family are promising novel biocatalysts with an unusual bifurcated substrate-binding cleft and the ability to recognize commercially relevant substrates. We characterized in detail the substrate selectivity of a novel ybfF enzyme from Vibrio cholerae (Vc-ybfF) by using a 21-member library of fluorogenic ester substrates. We assigned the roles of the two substrate-binding clefts in controlling the substrate selectivity and folded stability of Vc-ybfF by comprehensive substitution analysis. The overall substrate preference of Vc-ybfF was for short polar chains, but it retained significant activity with a range of cyclic and extended esters. This broad substrate specificity combined with the substitutional analysis demonstrates that the larger binding cleft controls the substrate specificity of Vc-ybfF. Key selectivity residues (Tyr116, Arg120, Tyr209) are also located at the larger binding pocket and control the substrate specificity profile. In the structure of ybfF the narrower binding cleft contains water molecules prepositioned for hydrolysis, but based on substitution this cleft showed only minimal contribution to catalysis. Instead, the residues surrounding the narrow binding cleft and at the entrance to the binding pocket contributed significantly to the folded stability of Vc-ybfF. The relative contributions of each cleft of the binding pocket to the catalytic activity and folded stability of Vc-ybfF provide a valuable map for designing future biocatalysts based on the ybfF scaffold. PMID- 23670978 TI - Variants in adiponectin signaling pathway genes show little association with subclinical CVD in the diabetes heart study. AB - OBJECTIVE: Understanding the interplay between adiposity, inflammation, and cardiovascular complications in type 2 diabetes mellitus (T2DM) remains a challenge. Signaling from adipocytes is considered important in this context. Adiponectin is the most abundant adipocytokine and has been associated with various measures of cardiovascular disease (CVD). This study examines the relationships between genetic variants in the adiponectin (ADIPOQ) and adiponectin-related signaling pathway genes and measures of subclinical CVD (vascular calcified plaque and carotid intima-media thickness), plasma lipids, and inflammation in T2DM. DESIGN AND METHODS: Single-nucleotide polymorphisms (SNPs) in ADIPOQ (n = 45), SNPs tagging ADIPOR1 (n = 6), APIPOR2 (n = 8), APPL1 (n = 6) and known rare coding variants in KNG1 (n = 3) and LYZL1 (n = 3) were genotyped in 1220 European Americans from the family-based Diabetes Heart Study. Associations between SNPs and phenotypes of interest were assessed using a variance components analysis with adjustment for age, sex, T2DM-affected status, and body mass index. RESULTS: There was minimal evidence of association between SNPs in the adiponectin signaling pathway genes and measures of calcified plaque; eight of the 71 SNPs showed evidence of association with subclinical CVD (P = 0.007-0.046) but not with other phenotypes examined. Nine additional SNPs were associated with at least one of the plasma lipid measures (P = 0.008-0.05). CONCLUSION: Findings from this study do not support a significant role for variants in the adiponectin signaling pathway genes in contributing to risk for vascular calcification in T2DM. However, further understanding the interplay between adiposity, plasma lipids, and inflammation may prove important in the prediction and management of cardiovascular complications in T2DM. PMID- 23670979 TI - SnO2/graphene composites with self-assembled alternating oxide and amine layers for high Li-storage and excellent stability. AB - An alternating stack (SG/GN) consisting of SnO2-functionalized graphene oxide (SG) and amine-functionalized GO (GN) is prepared in solution. The thermally reduced SG/GN (r(SG/GN)) with decreased micro-mesopores and completely eliminated macropores, results in a high reversible capacity and excellent capacity retention (872 mA h g-1 after 200 cycles at 100 mA g-1) when compared to a composite without GN. PMID- 23670980 TI - Top-down and bottom-up influences on the left ventral occipito-temporal cortex during visual word recognition: an analysis of effective connectivity. AB - The functional role of the left ventral occipito-temporal cortex (vOT) in visual word processing has been studied extensively. A prominent observation is higher activation for unfamiliar but pronounceable letter strings compared to regular words in this region. Some functional accounts have interpreted this finding as driven by top-down influences (e.g., Dehaene and Cohen [2011]: Trends Cogn Sci 15:254-262; Price and Devlin [2011]: Trends Cogn Sci 15:246-253), while others have suggested a difference in bottom-up processing (e.g., Glezer et al. [2009]: Neuron 62:199-204; Kronbichler et al. [2007]: J Cogn Neurosci 19:1584-1594). We used dynamic causal modeling for fMRI data to test bottom-up and top-down influences on the left vOT during visual processing of regular words and unfamiliar letter strings. Regular words (e.g., taxi) and unfamiliar letter strings of pseudohomophones (e.g., taksi) were presented in the context of a phonological lexical decision task (i.e., "Does the item sound like a word?"). We found no differences in top-down signaling, but a strong increase in bottom-up signaling from the occipital cortex to the left vOT for pseudohomophones compared to words. This finding can be linked to functional accounts which assume that the left vOT contains neurons tuned to complex orthographic features such as morphemes or words [e.g., Dehaene and Cohen [2011]: Trends Cogn Sci 15:254-262; Kronbichler et al. [2007]: J Cogn Neurosci 19:1584-1594]: For words, bottom-up signals converge onto a matching orthographic representation in the left vOT. For pseudohomophones, the propagated signals do not converge, but (partially) activate multiple orthographic word representations, reflected in increased effective connectivity. PMID- 23670981 TI - Toward real-time availability of 3D temperature maps created with temporally constrained reconstruction. AB - PURPOSE: To extend the previously developed temporally constrained reconstruction (TCR) algorithm to allow for real-time availability of three-dimensional (3D) temperature maps capable of monitoring MR-guided high intensity focused ultrasound applications. METHODS: A real-time TCR (RT-TCR) algorithm is developed that only uses current and previously acquired undersampled k-space data from a 3D segmented EPI pulse sequence, with the image reconstruction done in a graphics processing unit implementation to overcome computation burden. Simulated and experimental data sets of HIFU heating are used to evaluate the performance of the RT-TCR algorithm. RESULTS: The simulation studies demonstrate that the RT-TCR algorithm has subsecond reconstruction time and can accurately measure HIFU induced temperature rises of 20 degrees C in 15 s for 3D volumes of 16 slices (RMSE = 0.1 degrees C), 24 slices (RMSE = 0.2 degrees C), and 32 slices (RMSE = 0.3 degrees C). Experimental results in ex vivo porcine muscle demonstrate that the RT-TCR approach can reconstruct temperature maps with 192 * 162 * 66 mm 3D volume coverage, 1.5 * 1.5 * 3.0 mm resolution, and 1.2-s scan time with an accuracy of +/-0.5 degrees C. CONCLUSION: The RT-TCR algorithm offers an approach to obtaining large coverage 3D temperature maps in real-time for monitoring MR guided high intensity focused ultrasound treatments. PMID- 23670982 TI - Ethnic and sex differences in visceral, subcutaneous, and total body fat in children and adolescents. AB - OBJECTIVE: This study investigated ethnic and sex differences in the distribution of fat during childhood and adolescence. DESIGN AND METHODS: A cross-sectional sample (n = 382), aged 5-18 years, included African American males (n = 84), White males (n = 96), African American females (n = 118), and White females (n = 84). Measures for total body fat (TBF) mass and abdominal adipose tissue (total volume and L4-L5 cross-sectional area) for both subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) depots were assessed by dual-energy X-ray absorptiometry and magnetic resonance image, respectively. Analyses of covariance (ANCOVAs) were used to determine ethnic and sex differences in TBF (adjusted for age) and ethnic and sex differences in SAT and VAT (adjusted for both age and TBF). RESULTS: Age-adjusted TBF was greater in African Americans (P = 0.017) and females (P < 0.0001) compared with Whites and males, respectively. In age- and TBF-adjusted ANCOVAs, no differences were found in the SAT. The VAT volume was, however, greater in Whites (P < 0.0001) and males (P < 0.0001) compared with African Americans and females, respectively. Similar patterns were observed in SAT and VAT area at L4-L5. CONCLUSIONS: The demonstrated ethnic and sex differences are important confounders in the prevalence of obesity and in the assignment of disease risk in children and adolescents. PMID- 23670983 TI - Disclosure control using partially synthetic data for large-scale health surveys, with applications to CanCORS. AB - Statistical agencies have begun to partially synthesize public-use data for major surveys to protect the confidentiality of respondents' identities and sensitive attributes by replacing high disclosure risk and sensitive variables with multiple imputations. To date, there are few applications of synthetic data techniques to large-scale healthcare survey data. Here, we describe partial synthesis of survey data collected by the Cancer Care Outcomes Research and Surveillance (CanCORS) project, a comprehensive observational study of the experiences, treatments, and outcomes of patients with lung or colorectal cancer in the USA. We review inferential methods for partially synthetic data and discuss selection of high disclosure risk variables for synthesis, specification of imputation models, and identification disclosure risk assessment. We evaluate data utility by replicating published analyses and comparing results using original and synthetic data and discuss practical issues in preserving inferential conclusions. We found that important subgroup relationships must be included in the synthetic data imputation model, to preserve the data utility of the observed data for a given analysis procedure. We conclude that synthetic CanCORS data are suited best for preliminary data analyses purposes. These methods address the requirement to share data in clinical research without compromising confidentiality. PMID- 23670989 TI - Assessing the function of the fronto-parietal attention network: insights from resting-state fMRI and the attentional network test. AB - In the recent past, various intrinsic connectivity networks (ICN) have been identified in the resting brain. It has been hypothesized that the fronto parietal ICN is involved in attentional processes. Evidence for this claim stems from task-related activation studies that show a joint activation of the implicated brain regions during tasks that require sustained attention. In this study, we used functional magnetic resonance imaging (fMRI) to demonstrate that functional connectivity within the fronto-parietal network at rest directly relates to attention. We applied graph theory to functional connectivity data from multiple regions of interest and tested for associations with behavioral measures of attention as provided by the attentional network test (ANT), which we acquired in a separate session outside the MRI environment. We found robust statistical associations with centrality measures of global and local connectivity of nodes within the network with the alerting and executive control subfunctions of attention. The results provide further evidence for the functional significance of ICN and the hypothesized role of the fronto-parietal attention network. PMID- 23670990 TI - DTI of human skeletal muscle: the effects of diffusion encoding parameters, signal-to-noise ratio and T2 on tensor indices and fiber tracts. AB - In this study, we have performed simulations to address the effects of diffusion encoding parameters, signal-to-noise ratio (SNR) and T2 on skeletal muscle diffusion tensor indices and fiber tracts. Where appropriate, simulations were corroborated and validated by in vivo diffusion tensor imaging (DTI) of human skeletal muscle. Specifically, we have addressed: (i) the accuracy and precision of the diffusion parameters and eigenvectors at different SNR levels; (ii) the effects of the diffusion gradient direction encoding scheme; (iii) the optimal b value for diffusion tensor estimation; (iv) the effects of changes in skeletal muscle T2; and, finally, the influence of SNR on fiber tractography and derived (v) fiber lengths, (vi) pennation angles and (vii) fiber curvatures. We conclude that accurate DTI of skeletal muscle requires an SNR of at least 25, a b value of between 400 and 500 s/mm(2), and data acquired with at least 12 diffusion gradient directions homogeneously distributed on half a sphere. Furthermore, for DTI studies focusing on skeletal muscle injury or pathology, apparent changes in the diffusion parameters need to be interpreted with great care in view of the confounding effects of T2, particularly for moderate to low SNR values. PMID- 23670992 TI - The tris-urea motif and its incorporation into polydimethylsiloxane-based supramolecular materials presenting self-healing features. AB - Materials of supramolecular nature have attracted much attention owing to their interesting features, such as self-reparability and material robustness, that are imparted by noncovalent interactions to synthetic materials. Among the various structures and synthetic methodologies that may be considered for this purpose, the introduction of extensive arrays of multiple hydrogen bonds allows for the formation of supramolecular materials that may, in principle, present self healing behavior. Hydrogen bonded networks implement dynamic noncovalent interactions. Suitable selection of structural units gives access to novel dynamic self-repairing materials by incrementing the number of hydrogen-bonding sites present within a molecular framework. Herein, we describe the formation of a tris-urea based motif giving access to six hydrogen-bonding sites, easily accessible through reaction of carbohydrazide with an isocyanate derivative. Extension towards the synthesis of multiply hydrogen-bonded supramolecular materials has been achieved by polycondensation of carbohydrazide with a bis isocyanate component derived from poly-dimethylsiloxane chains. Such materials underwent self-repair at a mechanically cut surface. This approach gives access to a broad spectrum of materials of varying flexibility by appropriate selection of the bis-isocyanate component that forms the polymer backbone. PMID- 23670993 TI - Mapping mean and fluctuating velocities by Bayesian multipoint MR velocity encoding-validation against 3D particle tracking velocimetry. AB - PURPOSE: To validate Bayesian multipoint MR velocity encoding against particle tracking velocimetry for measuring velocity vector fields and fluctuating velocities in a realistic aortic model. METHODS: An elastic cast of a human aortic arch equipped with an 80 or 64% stenotic section was driven by a pulsatile pump. Peak velocities and peak turbulent kinetic energies of more than 3 m/s and 1000 J/m(3) could be generated. Velocity vector fields and fluctuating velocities were assessed using Bayesian multipoint MR velocity encoding with varying numbers of velocity encoding points and particle tracking velocimetry in the ascending aorta. RESULTS: Velocities and turbulent kinetic energies measured with 5-fold k t undersampled 10-point MR velocity encoding and particle tracking velocimetry were found to reveal good correlation with mean differences of -4.8 +/- 13.3 cm/s and r(2) = 0.98 for velocities and -21.8 +/- 53.9 J/m(3) and r(2) = 0.98 for turbulent kinetic energies, respectively. Three-dimensional velocity patterns of fast flow downstream of the stenoses and regions of elevated velocity fluctuations were found to agree well. CONCLUSION: Accelerated Bayesian multipoint MR velocity encoding has been demonstrated to be accurate for assessing mean and fluctuating velocities against the reference standard particle tracking velocimetry. The MR method holds considerable potential to map velocity vector fields and turbulent kinetic energies in clinically feasible exam times of <15 min. PMID- 23670991 TI - Advantages of percent weight loss as a method of reporting weight loss after Roux en-Y gastric bypass. AB - OBJECTIVE: Although Roux-en-Y gastric bypass (RYGB) is an effective treatment for severe obesity, weight loss (WL) after this operation is highly variable. Accurate predictors of outcome would thus be useful in identifying those patients who would most benefit from this invasive therapy. WL has been characterized using several different metrics, including the number of BMI units lost (DeltaBMI), percent baseline WL (%WL), and percent excess body WL (%EBWL). To identify clinically relevant predictors most sensitively, it is necessary to avoid confounding by other factors, including preoperative BMI (pBMI), the strongest known predictor of RYGB-induced WL. DESIGN AND METHODS: To determine the WL measure least associated with pBMI, outcomes of 846 patients undergoing RYGB were analyzed. RESULTS: Patients in this cohort had an average pBMI of 50.0 kg/m(2) at baseline. At weight nadir, they lost an average 19.4 kg/m(2), 38.7% WL, and 81.2% EBWL. pBMI was strongly and positively associated with DeltaBMI at both 1 year (r = 0.56, P = 4.7 * 10(-51)) and nadir (r = 0.58, P = 2.8 * 10(-77)) and strongly but negatively associated with %EBWL at 1 year (r = -0.52, P = 3.8 * 10(-44)) and nadir (r = -0.45, P = 7.2*10(-43)). In contrast, pBMI was not significantly associated with %WL at 1 year (r = 0.04, P = 0.33) and only weakly associated at nadir (r = 0.13, P = 0.0002). CONCLUSIONS: Of the metrics examined, %WL is the parameter describing WL after RYGB least influenced by pBMI. It thus improves comparison of WL outcomes across studies of patients undergoing surgery and facilitates the most sensitive identification of novel predictors of surgery induced WL. We therefore is recommend that %WL be adopted more broadly in reporting weight loss after RYGB. PMID- 23670994 TI - Metabolic glycan imaging by isonitrile-tetrazine click chemistry. AB - Seeing the sugar coating: N-Acetyl-glucosamine and mannosamine derivatives tagged with an isonitrile group are metabolically incorporated into cell-surface glycans and can be detected with a fluorescent tetrazine. This bioorthogonal isonitrile tetrazine ligation is also orthogonal to the commonly used azide-cyclooctyne ligation, and so will allow simultaneous detection of the incorporation of two different sugars. PMID- 23670995 TI - Changes in body fat distribution and fitness are associated with changes in hemoglobin A1c after 9 months of exercise training: results from the HART-D study. AB - OBJECTIVE: To investigate the associations between changes in body composition and fitness after exercise training and changes in hemoglobin A1c (HbA1c) in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: Participants (n = 201) were randomized to aerobic, resistance, or combined training for 9 months. HbA1c, waist circumference, total and trunk fat mass, appendicular fat mass, lean body mass, isokinetic leg muscle strength, peak O2 uptake, and estimated METs were assessed at baseline and follow-up. Change in HbA1c was evaluated across quartiles of change in body composition and fitness. RESULTS: Change in HbA1c was associated with changes in body weight (r = 0.13, P = 0.052), waist circumference (r = 0.17, P = 0.013), trunk fat mass (r = 0.19, P = 0.005), and estimated METs (r = -0.16, P = 0.023). There was a trend in change in HbA1c across quartiles of waist circumference (P = 0.011), trunk fat mass (P = 0.020), and estimated METs (P = 0.011). Participants with increased estimated METs and reduced trunk fat mass had greater odds of having reduced HbA1c after training (3.48, 1.46-8.31). Finally, participants with increased estimated METs and reduced waist circumference were 2.81 (1.13-6.98) times more likely to have reduced HbA1c and type 2 diabetes medication use than those without improved fitness and central adiposity. CONCLUSIONS: In patients with type 2 diabetes, a reduction in central adiposity and increase in fitness were the most prominent predictors of the change in HbA1c in response to exercise training. PMID- 23670997 TI - The spontaneous fluctuation of the excitability of a single node modulates the internodes connectivity: a TMS-EEG study. AB - Brain effective connectivity can be tracked by cerebral recruitments evoked by transcranial magnetic stimulation (TMS), as measured by simultaneous electroencephalography (TMS-EEG). When TMS is targeting the primary motor area, motor evoked potentials (MEPs) can be collected from the "target" muscles. The aim of this study was to measure whether or not effective brain connectivity changes with the excitability level of the corticospinal motor pathway (CSMP) as parameterized by MEP amplitude. After averaging two subgroups of EEG-evoked responses corresponding to high and low MEP amplitudes, we calculated the individual differences between them and submitted the grand average to sLORETA algorithm obtaining localized regions of interest (RoIs). Statistical differences of RoI recruitment strength between low and high CSMP excitation was assessed in single subjects. Preceding the feedback arrival, neural recruitment for stronger CSMP activation were weaker at 6-10 ms of homotopic sensorimotor areas BA3/4/5 of the right nonstimulated hemisphere (trend), weaker at 18-25 ms of left parietal BA2/3/40, and stronger at 26-32 ms of bilateral frontal motor areas BA6/8. The proposed method enables the tracking of brain network connectivity during stimulation of one node by measuring the strength of the connected recruited node activations. Spontaneous increases of the excitation of the node originating the transmission within the hand control network gave rise to dynamic recruitment patterns with opposite behaviors, weaker in homotopic and parietal circuits, stronger in frontal ones. The effective connectivity within bilateral circuits orchestrating hand control appeared dynamically modulated in time even in resting state as probed by TMS. PMID- 23670996 TI - Effects of low-dose prednisolone on hepatic and peripheral insulin sensitivity, insulin secretion, and abdominal adiposity in patients with inflammatory rheumatologic disease. AB - OBJECTIVE: The metabolic effects of low-dose prednisolone and optimal management of glucocorticoid-induced diabetes are poorly characterized. The aims were to investigate the acute effects of low-dose prednisolone on carbohydrate metabolism and whether long-term low-dose prednisolone administration increases visceral adiposity, amplifying metabolic perturbations. RESEARCH DESIGN AND METHODS: Subjects with inflammatory rheumatologic disease without diabetes mellitus were recruited. Nine subjects (age, 59 +/- 11 years) not using oral glucocorticoids were studied before and after a 7- to 10-day course of oral prednisolone 6 mg daily. Baseline data were compared with 12 subjects (age, 61 +/- 8 years) using continuous long-term prednisolone (6.3 +/- 2.2 mg/day). Basal endogenous glucose production (EGP) was estimated by 6,6-(2)H2 glucose infusion, insulin sensitivity was estimated by two-step hyperinsulinemic-euglycemic clamp, insulin secretion was estimated by intravenous glucose tolerance test, and adipose tissue areas were estimated by computed tomography. RESULTS: Prednisolone acutely increased basal EGP (2.44 +/- 0.46 to 2.65 +/- 0.35 mg/min/kg; P = 0.05) and reduced insulin suppression of EGP (79 +/- 7 to 67 +/- 14%; P = 0.03), peripheral glucose disposal (8.2 +/- 2.4 to 7.0 +/- 1.6 mg/kg/min; P = 0.01), and first-phase (5.9 +/- 2.0 to 3.9 +/- 1.6 mU/mmol; P = 0.01) and second-phase (4.6 +/- 1.7 to 3.6 +/ 1.4 mU/mmol; P = 0.02) insulin secretion. Long-term prednisolone users had attenuated insulin suppression of EGP (66 +/- 14 vs. 79 +/- 7%; P = 0.03) and nonoxidative glucose disposal (44 +/- 24 vs. 62 +/- 8%; P = 0.02) compared with nonglucocorticoid users, whereas basal EGP, insulin secretion, and adipose tissue areas were not significantly different. CONCLUSIONS: Low-dose prednisolone acutely perturbs all aspects of carbohydrate metabolism. Long-term low-dose prednisolone induces hepatic insulin resistance and reduces peripheral nonoxidative glucose disposal. We conclude that hepatic and peripheral insulin sensitivity should be targeted by glucose-lowering therapy for glucocorticoid induced diabetes. PMID- 23670998 TI - Chemical and functional characterisation of propolis collected from East Andalusia (southern Spain). AB - INTRODUCTION: Propolis is a complex mixture of natural sticky, gummy and resinous components produced by honeybees (Apis mellifera L.) from plant materials. However, phytochemical data of the Andalusian (southern Spain) propolis are scant. OBJECTIVE: The primary objectives of this study were to chemically characterise the compounds and evaluate the anti-oxidant activity found in 28 Andalusian propolis samples. METHODS: Ethanol extracts of propolis (EEP) were prepared and examined for their anti-oxidant activity by 2,2'-azinobis(3 ethylbenzothiazoline-6-sulphonic acid) and 2,2-diphenyl-1-picrylhydrazyl assays. To characterise the phenolic composition, the presence of 11 compounds was identified by HPLC analysis with photodiode array and mass spectrometric detection. RESULTS: All propolis samples had strong anti-oxidant activity, accompanied by high total phenolic content. The most abundant compounds were flavonoids. Concerning the phenolic compounds content, our results showed that the 75% of the samples analysed contained at least 80 mg/g of flavonoids, primarily pinobanksin 3-acetate, pinocembrin, chrysin, galangin and pinobanksin. Caffeic acid phenethyl ester was detected in almost all EEP samples but in smaller proportions (mean 12.9 +/- 2.8 mg/g). CONCLUSION: The present investigation constitutes the first comprehensive report on the phenolics identified in southern Spanish propolis. The results revealed that the samples tested showed a high scavenging activity and therefore indicate the possible use of Andalusian propolis as an important source of natural anti-oxidants. PMID- 23670999 TI - Projection of older Australians with a history of midlife obesity and overweight 2010-2050. AB - OBJECTIVE: This study projects midlife obesity status in future older Australians. DESIGN AND METHODS: Cross-sectional prevalence of being obese or overweight by broad age groups was interpolated to obtain single-year-age data. These estimates were then used to derive prevalence of normal weight and underweight. Data by birth year and year of observation of persons aged 30-70 years were used to construct prediction equations. RESULTS: Results show that older people with a history of midlife obesity is projected to rise substantially in the future. For people aged 65 years, midlife obesity was estimated at 22% in 2010 and is projected to increase to 43% for males and 37% for females in 2050. CONCLUSION: While the proportion of individuals with midlife normal weight is projected to decline substantially, prevalence of midlife overweight remains almost stable. The number of persons aged 65 years and over having a history of midlife obesity is projected to increase nearly six-fold from less than 500,000 persons in 2010 to 2.8 million in 2050. In comparison, between 2010 and 2050, Australia's older population aged 65 years and over is projected to increase by only 2.5-fold. Growing obesity prevalence in the Australian population translates into a large increase in older people with a history of midlife obesity, with major implications for the future burden of disease in older persons. PMID- 23671000 TI - Leveraging material properties in fluorescence anion sensor arrays: a general approach. AB - As the demand for probes suitable for sensor development increases, investigation of approaches that utilize known successful receptors gains in general importance. This study describes a two-prong approach that can be used as a guide to developing sensors from known receptors. First, the conversion of a simple receptor, calix[4]pyrrole, into a fluorescent probe to establish a ratiometric signal is described. Secondly, the sensors that employ an output from a single ratiometric calix[4]pyrrole probe are fabricated by using poly(ether-urethane) hydrogel copolymers. These hydrogels are designed to absorb, internalize and transport aqueous electrolytes. A sensor array of ten different poly(ether urethane) matrices with varying comonomer proportions were doped with a single probe and were exposed to eight different anions: acetate, benzoate, fluoride, chloride, phosphate, pyrophosphate, hydrogen sulfide, and cyanide, eight urine samples and anti-inflammatory drugs (NSAIDs). The poly(ether-urethane) matrices comprise different proportions of anion-binding urethane moieties and different hydrophilicity given by the ratio between ethylene glycol ether and butylene glycol ether. This diversity in the hydration behavior provides different environment polarity, in which the recognition and self-assembly processes display enough diverse behavior to allow for unique response of the probe to the analytes. Furthermore, a single probe is shown to recognize eight different aqueous anions and eight urine samples when embedded in ten different polyurethanes in an array that displays 100 % classification accuracy. To demonstrate the potential of the concept for quantitative studies, an estimation of non-steroidal anti-inflammatory drugs ibuprofen and diclofenac in water and in saliva was performed. A limit of detection of 0.1 ppm and a dynamic range of 0.1 0.6 and 0.05-60 ppm was observed, respectively. Given the general difficulty of chemosensors to recognize aqueous anions, the fact that one probe recognizes eight different analytes attests to an enormous effect of the polymer environment on the recognition process. This method could be used to generate a variety of sensor arrays for various analyses including species that are difficult to recognize, such as small-molecule- and inorganic anions. PMID- 23671001 TI - The long and bumpy road to outcome-oriented management of long-term care in Germany: implementation of the Resident Assessment Instrument in home-care services. AB - OBJECTIVE: Although the quality of long-term care has improved, many problems still remain, and better processes seem to be necessary. Hence, outcome-oriented management is of particular importance. The Resident Assessment Instrument (RAI) is a tool that has been used successfully in many countries to improve quality of care. However, there are problems of implementation and it lacks information on the conditions of successful or failing information of the RAI. The aim of this article is to find out to what extent technical/qualification requirements help to introduce or lead to failure of the implementation of an assessment instrument like RAI. METHODS: Therefore, a cluster randomized controlled trial showed services using RAI intensively tend to have better outcomes after 12 months. But the effects depend on the success of the implementation. Using a factor analysis, an index was built to divide the care providers into "optimal" and "suboptimal" RAI users. RESULTS: Some factors that seem to lead to a rather successful implementation could be detected: A higher proportion of qualified staff, a lower perceived quantitative workload, a small size of care providers, the type of ownership (for-profit) and a late entry in study [Correction made here after initial online publication.]. CONCLUSION: The success or failure of the implementation of an outcome-oriented control instrument is determined by professional, organizational restrictions. The results show that a better implementation leads to better outcomes for clients. PMID- 23671002 TI - Ultrasound-assisted emulsification microextraction combined with injection-port derivatization for the determination of some chlorophenoxyacetic acids in water samples. AB - An efficient method based on ultrasound-assisted emulsification microextraction followed by injection-port derivatization GC analysis was developed to determine 2,4-dichlorophenoxyacetic acid (2,4-D) and 4-chloro-2-methylphenoxyacetic acid (MCPA) in natural water samples. In this procedure, 12.5 MUL of 1-undecanol was injected slowly into a 12 mL home-designed centrifuge glass vial containing an aqueous sample of the analytes located inside an ultrasonic water bath. The resulting emulsion was centrifuged, and 1 MUL of the separated organic solvent together with 1 MUL of the derivatization reagent were injected into a GC equipped with a flame ionization detector. Several factors that influence the derivatization and extraction were optimized. Under the optimal conditions, the LODs were 0.33 and 1.7 MUg/L for MCPA and 2,4-D, respectively. Preconcentration factors of 670 and 836 were obtained for MCPA and 2,4-D, respectively. The precision of the proposed method was evaluated in terms of repeatability, which was <5.7% (n = 5). The applicability of the proposed method was evaluated by extraction and determination of chlorophenoxyacetic acids from some natural waters, which indicated that the matrices of natural waters have no significant effect on the extraction and derivatization efficiency of this method. PMID- 23671003 TI - Pulse radiolysis studies on the reaction of the reduced vitamin B12 complex Cob(II)alamin with superoxide. AB - O2.- scavenger: The rate constant for the rapid reaction of the ROS superoxide with the reduced vitamin B12 radical complex cob(II)alamin was directly determined to be 3.8*10(8) M-1 s-1. This rate was independent of pH over the range 5.5-8.7. These results have implications for studying the use of B12 supplements to combat diseases associated with oxidative stress. PMID- 23671004 TI - Grasping with the foot: goal and motor expertise in action observation. AB - Action observation typically induces an online inner simulation of the observed movements. Here we investigate whether action observation merely activates, in the observer, the muscles involved in the observed movement or also muscles that are typically used to achieve the observed action goal. In a first experiment, hand and foot motor areas were stimulated by means of transcranial magnetic stimulation, while participants viewed a typical hand action (grasping) or a nonspecific action (stepping over an object) performed by either a hand or a foot. Hand motor evoked potentials (MEPs) increased for grasping and stepping over actions performed by the hand and for grasping actions performed by the foot. Conversely, foot MEPs increased only for actions performed by the foot. In a second experiment, participants viewed a typical hand action (grasping a pencil) and a typical foot action (pressing a foot-pedal) performed by either a hand or a foot. Again, hand MEPs increased not only during the observation of both actions performed by the hand but also for grasping actions performed by the foot. Foot MEPs increased not only during the observation of grasping and pressing actions performed by the foot but also for pressing actions performed by the hand. This evidence indicates that motor activations by action observation occur also in the muscles typically used to perform the observed action, even when the action is executed by an unusual effector, hence suggesting a double coding of observed actions: a strict somatotopic coding and an action goal coding based on the observer's motor expertise. PMID- 23671005 TI - Solvent-dependent enantiodivergence in the chlorocyclization of unsaturated carbamates. AB - A remarkable solvent-controlled enantiodivergence is seen in the hydroquinidine 1,4-phthalazinediyl diether ((DHQD)2PHAL)-catalyzed chlorocyclization of unsaturated carbamates. Eyring plot analyses of this previously unreported reaction are used to probe and compare the R- and S-selective pathways. In the CHCl3/hexanes solvent system, the pro-R process shows a surprising increase in selectivity with increasing temperature. These studies point to a strongly solvent-dependent entropy-enthalpy balance between the pro-R and pro-S pathways. PMID- 23671006 TI - Perspectives on treatment of metastatic castration-resistant prostate cancer. AB - The arrival of several new agents--cabazitaxel, abiraterone acetate, enzalutamide, and radium-223--is changing the treatment options and management of patients with metastatic castration-resistant prostate cancer (mCRPC). Many other novel agents are also being investigated. As new drugs become approved, new treatment strategies and markers to best select which patients will best respond to which drug are needed. This review article is a summary of a European Treatment Practices Meeting, which was convened to discuss these latest data on novel agents and current treatment strategies in the mCRPC setting. PMID- 23671007 TI - Concise drug review: azacitidine and decitabine. PMID- 23671008 TI - Agenesis of the fetal corpus callosum: sonographic signs change with advancing gestational age. AB - OBJECTIVES: To assess the presence and degree of indirect signs of agenesis of the corpus callosum (ACC) according to gestational age and determine the percentage of cases in which each sign is present by 24 gestational weeks. METHODS: We analyzed retrospectively 54 cases of ACC which underwent three dimensional neurosonography at our unit between January 2005 and December 2012. A single examination was available in 48 cases and six cases were followed up longitudinally, giving a total of 69 examinations. The following variables were assessed: indication for referral, karyotype, width of the atrium and presence/absence of colpocephaly, the cavum septi pellucidi, dorsal cyst and additional central nervous system (CNS) and non-CNS anomalies. RESULTS: Overall, there were 31 cases of complete ACC (cACC, 42 examinations) and 23 cases of partial ACC (pACC, 27 examinations). The mean gestational age was lower in the cases referred because of anomalies other than ACC than it was in those referred because of ventriculomegaly and/or suspicion of ACC (P < 0.05). Atrial width showed a positive linear correlation with advancing gestational age (P < 0.0001); it was < 10.0 mm in 25/34 (73.5%) examinations < 24 gestational weeks and in 9/35 (25.7%) >= 24 weeks (P < 0.001). Colpocephaly was present in 20.6% (7/34) of examinations < 24 weeks and in 68.6% (24/35) of those after 23 weeks (P < 0.05). The cavum septi pellucidi was present and visible at least in part in 17 (63%) of the 27 pACC examinations. In nine of the 27 (33.3%) pACC examinations, there was neither ventriculomegaly nor absence of the cavum septi pellucidi. Associated anomalies were present in 25/54 (46.3%) cases, and in 11 these included or consisted of CNS abnormalities. Karyotype was abnormal in seven of the 40 (17.5%) cases in which it was available. CONCLUSIONS: In a significant proportion of cases, most of the indirect signs of ACC are either absent or barely visible at the time of the midtrimester screening ultrasound examination. Therefore, ACC may escape diagnosis at midtrimester screening ultrasound. In particular, a third of examinations in fetuses with pACC may not show any abnormality in the transventricular screening view < 24 weeks. The medicolegal implications of such findings are important and should be considered. PMID- 23671009 TI - Primary antiphospholipid antibody syndrome-one further aspect of thrombophilia in overweight and obese patients with venous thromboembolism. AB - OBJECTIVE: Overweight and obesity are established risk factors for venous thromboembolism (VTE). We examined the difference in the frequency of primary antiphospholipid antibody syndrome (PAPS) in VTE patients according to their BMI. DESIGN AND METHODS: We included 998 VTE patients treated at our institution between 2009 and 2011 in a retrospective data analysis. Thrombophilia screening including evaluation for APS (lupus anticoagulant, anti-cardiolipin, and anti-B2 glycoprotein-I IgG and IgM antibodies) was performed in all patients. RESULTS: PAPS was diagnosed in 6.8% (24/355) of normal weight (BMI < 24 kg/m2) VTE patients, in 11.1% (50/452) of overweight (BMI 25-30 kg/m2) VTE patients, and in 15.7% (30/191) of obese (BMI > 31 kg/m2) VTE patients. The difference of PAPS occurrence between these groups was statistically significant (P = 0.001). PAPS patients demonstrated higher fibrinogen levels as compared to non-PAPS patients (median 416.0 md/dl vs. 352.0 mg/dl, P = 0.001). Furthermore, fibrinogen levels increased significantly according to the body weight of patients (median normal weight patients 330.0 mg/dl vs. overweight patients 359.0 mg/dl vs. obese patients 415.0 mg/dl, P = 0.001). CONCLUSION: PAPS seems to be more frequent in overweight and obese patients. As PAPS patients showed significantly higher fibrinogen levels and as fibrinogen levels increased significantly according to the body weight of patients, an elevated inflammatory state in overweight and obese patients as a reason for the increased PAPS occurrence can be assumed. PMID- 23671010 TI - Forum on bone and skeletal muscle interactions: summary of the proceedings of an ASBMR workshop. AB - Annual costs are enormous for musculoskeletal diseases such as osteoporosis and sarcopenia and for bone and muscle injuries, costing billions annually in health care. Although it is clear that muscle and bone development, growth, and function are connected, and that muscle loads bone, little is known regarding cellular and molecular interactions between these two tissues. A conference supported by the National Institutes of Health (NIH) and the American Society for Bone and Mineral Research (ASBMR) was held in July 2012 to address the enormous burden of musculoskeletal disease. National and international experts in either bone or muscle presented their findings and their novel hypotheses regarding muscle-bone interactions to stimulate the exchange of ideas between these two fields. The immediate goal of the conference was to identify critical research themes that would lead to collaborative research interactions and grant applications focusing on interactions between muscle and bone. The ultimate goal of the meeting was to generate a better understanding of how these two tissues integrate and crosstalk in both health and disease to stimulate new therapeutic strategies to enhance and maintain musculoskeletal health. PMID- 23671012 TI - Series circuit of organic thin-film solar cells for conversion of water into hydrogen. AB - A series circuit of bulk hetero-junction (BHJ) organic thin-film solar cells (OSCs) is investigated for electrolyzing water to gaseous hydrogen and oxygen. The BHJ OSCs applied consist of poly(3-hexylthiophene) as a donor and [6,6] phenyl C61 butyric acid methyl ester as an acceptor. A series circuit of six such OSC units has an open circuit voltage (V(oc)) of 3.4 V, which is enough to electrolyze water. The short circuit current (J(sc)), fill factor (FF), and energy conversion efficiency (eta) are independent of the number of unit cells. A maximum electric power of 8.86 mW cm(-2) is obtained at the voltage of 2.35 V. By combining a water electrolysis cell with the series circuit solar cells, the electrolyzing current and voltage obtained are 1.09 mA and 2.3 V under a simulated solar light irradiation (100 mW cm(-2), AM1.5G), and in one hour 0.65 mL hydrogen is generated. PMID- 23671011 TI - Dynamic functional connectomics signatures for characterization and differentiation of PTSD patients. AB - Functional connectomes (FCs) have been recently shown to be powerful in characterizing brain conditions. However, many previous studies assumed temporal stationarity of FCs, while their temporal dynamics are rarely explored. Here, based on the structural connectomes constructed from diffusion tensor imaging data, FCs are derived from resting-state fMRI (R-fMRI) data and are then temporally divided into quasi-stable segments via a sliding time window approach. After integrating and pooling over a large number of those temporally quasi stable FC segments from 44 post-traumatic stress disorder (PTSD) patients and 51 healthy controls, common FC (CFC) patterns are derived via effective dictionary learning and sparse coding algorithms. It is found that there are 16 CFC patterns that are reproducible across healthy controls, and interestingly, two additional CFC patterns with altered connectivity patterns [termed signature FC (SFC) here] exist dominantly in PTSD subjects. These two SFC patterns alone can successfully differentiate 80% of PTSD subjects from healthy controls with only 2% false positive. Furthermore, the temporal transition dynamics of CFC patterns in PTSD subjects are substantially different from those in healthy controls. These results have been replicated in separate testing datasets, suggesting that dynamic functional connectomics signatures can effectively characterize and differentiate PTSD patients. PMID- 23671013 TI - Arabin cervical pessary in women at high risk of preterm birth: a magnetic resonance imaging observational follow-up study. AB - OBJECTIVE: To help elucidate the mechanism of action of the Arabin cervical pessary in pregnancies at high risk for preterm delivery. METHODS: Cervical length and uterocervical angle were evaluated in relation to gestational age in 198 pregnancies not at high risk for preterm birth that underwent clinical fetal magnetic resonance imaging (MRI). Additionally, in 73 singleton pregnancies at high risk for preterm birth, an Arabin cervical pessary was placed at 14-33 weeks' gestation. We performed MRI of the cervix immediately before and after placement and at monthly follow-up until removal of the pessary. In a subgroup of 54 pregnancies with a short cervix and pessary placement at 17-31 weeks' gestation, the uterocervical angle and cervical length at follow-up were compared with the preplacement values. RESULTS: In pregnancies not at high risk for preterm birth, the uterocervical angle did not vary, but cervical length showed a significant decrease with gestational age (r = -0.15, P < 0.05). Among the high risk patients, the cervical pessary was successfully placed at first attempt in 60 (82.2%) and by the second attempt in 66 (90.4%), remaining well positioned until removal. In five patients we failed to place the pessary after two attempts, in one patient the pessary dislodged during follow-up and in one case the pessary was partly placed in the external cervical canal and triggered labor the next day. Among the subgroup of 54 patients, the median uterocervical angle immediately after pessary placement was significantly more acute than that prior to placement in the 46 (85.2%) who delivered after 34 weeks (132 degrees vs 146 degrees , P < 0.01), but was unchanged in the eight patients who delivered before 34 weeks (143 degrees vs 152 degrees , P > 0.05). CONCLUSION: In patients at high risk for preterm delivery, correct placement of the Arabin cervical pessary should be checked immediately; this can be performed quickly and easily using MRI. This study provides some evidence that, in singleton pregnancies with a short cervix, a cervical pessary delays birth through a mechanical effect on the uterocervical angle. PMID- 23671014 TI - The photophysics of pyridine-derivatized ortho-, meta-, and para-dibutylamino cruciforms. AB - The photophysical properties of a series of para-substituted donor-acceptor cruciform fluorophores (p1-4) were investigated and compared with their meta and ortho isomers (m1-4 and o1-4). The structural variations were found to have a significant effect on the solvatochromism, fluorescence quantum yields (Phi(fl)), fluorescence lifetimes (tau(fl)), and response upon addition of trifluoroacetic acid. The observed spectral shifts in absorption and emission caused by protonation of the cruciforms make them promising candidates as chemosensors. Additional computational studies provided more insight into the electronic structure of the systems. PMID- 23671015 TI - Doctor shopping by overweight and obese patients is associated with increased healthcare utilization. AB - OBJECTIVE: Negative interactions with healthcare providers may lead patients to switch physicians or "doctor shop." We hypothesized that overweight and obese patients would be more likely to doctor shop, and as a result, have increased rates of emergency department (ED) visits and hospitalizations as compared to normal weight nonshoppers. DESIGN AND METHODS: We combined claims data from a health plan in one state with information from beneficiaries' health risk assessments. The primary outcome was "doctor shopping," which we defined as having outpatient claims with >=5 different primary care physicians (PCPs) during a 24-month period. The independent variable was standard NIH categories of weight by BMI. We performed multivariate logistic regression to evaluate the association between weight categories and doctor shopping. We conducted multivariate zero inflated negative binominal regression to evaluate the association between weight doctor shopping categories with counts of ED visits and hospitalizations. RESULTS: Of the 20,726 beneficiaries, the mean BMI was 26.3 kg m(-2) (SD 5.1), mean age was 44.4 years (SD 11.1) and 53% were female. As compared to normal weight beneficiaries, overweight beneficiaries had 23% greater adjusted odds of doctor shopping (OR 1.23, 95%CI 1.04-1.46) and obese beneficiaries had 52% greater adjusted odds of doctor shopping (OR 1.52, 95%CI 1.26-1.82). As compared to normal weight non-shoppers, overweight and obese shoppers had higher rates of ED visits (IRR 1.85, 95%CI 1.37-2.45; IRR 1.83, 95%CI 1.34-2.50, respectively), which persisted during within weight group comparisons (Overweight IRR 1.50, 95%CI 1.10-2.03; Obese IRR 1.54, 95%CI 1.12-2.11). CONCLUSION: Frequently changing PCPs may impair continuity and result in increased healthcare utilization. PMID- 23671016 TI - Insight in Alzheimer's disease and its relation to psychiatric and behavioral disturbances. AB - OBJECTIVE: Individuals suffering from Alzheimer's disease (AD) often have impaired awareness or a lack of insight into their cognitive deficits and functional abilities, especially in the later stages of the disease. Previous research has documented a relationship between depression and insight in AD, such that greater awareness of one's disease has been associated with a higher degree of depression. However, little is known about the relationship between insight, cognitive decline, and other psychiatric or behavioral problems associated with AD. METHODS: This study included 107 outpatients who met criteria for probable AD. Instruments included the Neurobehavioral Rating Scale, the Apathy Evaluation Scale, and the mini mental state exam. A series of hierarchical regression analyses were conducted to determine the relationship between insight and depressed mood, anxiety, psychosis, apathy, agitation, and behavioral retardation in AD patients after controlling for cognitive skills. RESULTS: Insight was found to significantly predict depressed mood, anxiety, and apathy even after controlling for global cognition. Greater insight was found to be associated with depressed mood and anxiety. However, impaired insight was associated with higher levels of apathy. CONCLUSION: Insight may be differentially related to mood symptoms and apathy within AD, such that patients with intact insight are more depressed, whereas patients with impaired insight are more apathetic. This suggests that assessment of insight in AD may complement the clinical evaluation of depression and apathy in AD and help guide the most appropriate interventions. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. PMID- 23671017 TI - The lab oddity prevails: discovery of pan-CDK inhibitor (R)-S-cyclopropyl-S-(4 {[4-{[(1R,2R)-2-hydroxy-1-methylpropyl]oxy}-5-(trifluoromethyl)pyrimidin-2 yl]amino}phenyl)sulfoximide (BAY 1000394) for the treatment of cancer. AB - Lead optimization of a high-throughput screening hit led to the rapid identification of aminopyrimidine ZK 304709, a multitargeted CDK and VEGF-R inhibitor that displayed a promising preclinical profile. Nevertheless, ZK 304709 failed in phase I studies due to dose-limited absorption and high inter-patient variability, which was attributed to limited aqueous solubility and off-target activity against carbonic anhydrases. Further lead optimization efforts to address the off-target activity profile finally resulted in the introduction of a sulfoximine group, which is still a rather unusual approach in medicinal chemistry. However, the sulfoximine series of compounds quickly revealed very interesting properties, culminating in the identification of the nanomolar pan CDK inhibitor BAY 1000394, which is currently being investigated in phase I clinical trials. PMID- 23671018 TI - Water and protein dynamics in sedimented systems: a relaxometric investigation. AB - Sedimented proteins have recently been shown to provide solid-state NMR spectra of high quality, suitable for structural investigation. This is ascribed to the strong self-crowding effect, which apparently increases the reorientation time up to the point that the protein can be considered immobile on the NMR timescale. Herein, a relaxometric investigation of sedimented bovine serum albumin is performed to obtain information on the dynamics of the system. The measurement of the proton longitudinal relaxation rates as a function of the applied magnetic field indicates that the sedimented protein has relaxation properties very different from those of the protein in concentrated water solutions, even in the presence of glycerol, and similar to those of slightly rehydrated lyophilized systems. This study confirms the hypothesis that the reorientation of the protein molecules is largely abolished in sediments. PMID- 23671019 TI - Fetal posterior fossa dimensions: normal and anomalous development assessed in mid-sagittal cranial plane by three-dimensional multiplanar sonography. AB - OBJECTIVES: To construct nomograms of the dimensions of the fetal posterior fossa (PF), assessed in the mid-sagittal plane in the second and third trimesters, and to assess how measurements from fetuses with PF abnormalities deviate from our normal ranges. METHODS: This was a prospective cross-sectional study of 378 healthy fetuses in low-risk singleton pregnancies between 15 and 35 weeks. PF size was evaluated in the mid-sagittal plane of the fetal head using three dimensional multiplanar reconstruction (3D-MPR). The borders of the PF were defined from the clivus to the tentorium (clivotentorial distance, CTD) and from the occipital bone to the level of the upper mesencephalic edge (tecto-occipital distance, TOD), and the posterior fossa area (PFA) and perimeter (PFP) were assessed. Growth charts were produced. Thirty-nine fetuses diagnosed with PF malformations were analyzed by calculating the z-scores of PFA, PFP, TOD and CTD, relative to the developed nomograms. RESULTS: Of the 378 healthy fetuses initially included, there were 281 with adequate visualization of the PF borders; i.e. PF mid-sagittal plane morphometry was feasible in 74.3% of cases. There was a linear relationship between each of PFA, PFP, TOD and CTD, and gestational age, with Pearson correlation coefficients of 0.97, 0.97, 0.96 and 0.95, respectively (P < 0.001 for each). Chiari II malformation (CM-II) and Dandy-Walker malformation (DWM) were associated with the greatest difference in PF size compared with normal; PFA z-scores exceeded 2.6 in all five DWM cases and were below -2.66 in all 11 CM-II cases. CONCLUSIONS: Sonographic evaluation of fetal PF size in the mid-sagittal plane is feasible. Our constructed nomograms provide reference data that may be helpful when evaluating PF congenital malformations. PMID- 23671020 TI - Twofold carbon-carbon bond formation by intra- and intermolecular radical reactions of aryl diazonium salts. AB - Cascade reactions: A variety of novel cascade reactions can be performed when the known and well-studied radical 5- or 6-exo-cyclization of an aryl diazonium salt is conducted in the presence of alkenes and further optional scavengers (see scheme). PMID- 23671021 TI - Anatomical correlates of quality of life: evidence from voxel-based morphometry. AB - Quality of life (QOL) has been defined in many ways, and these definitions usually emphasize happiness and satisfaction with life. Health-related problems are known to cause lower QOL. However, the neural mechanisms underlying individual differences in QOL measured by questionnaire (QOLMQ) in young healthy subjects are unknown. QOL is essential to our well-being, and investigation of the neural mechanisms underlying QOL in uncompromised subjects is obviously of great scientific and social interest. We used voxel-based morphometry to investigate the association between regional gray matter volume (rGMV) and QOLMQ across the brain in healthy young adults (age, 21.4 +/- 1.8 years) men (n = 88) and women (n = 68) in humans. We found significant negative relationships between QOLMQ and rGMV in a region in the left rostrolateral prefrontal cortex and regions in the dorsal part of the anterior cingulate gyrus and contingent cingulate regions. These findings show that structural variations in regions associated with processing of negative emotions such as fear and anger as well as those associated with evaluation of internally generated information are associated with QOLMQ. These findings suggest that these processes might be related to QOLMQ in healthy young adults. PMID- 23671022 TI - Effect of different amounts of coffee on dietary intake and appetite of normal weight and overweight/obese individuals. AB - OBJECTIVE: To investigate the effects of different coffee amounts on dietary intake and appetite feelings in normal-weight and overweight/obese individuals. DESIGN AND METHODS: Thirty-three volunteers (16 normal-weight, 17 overweight/obese) participated in three trials: they consumed a standard breakfast along with 200 ml of either coffee with 3 or 6 mg caffeine/kg body weight (Coffee 3 and Coffee 6, respectively), or water. At fasting and at standard time points for the 3 h following breakfast/drink consumption participants recorded their appetite feelings on visual analogue scales. At 180 min, participants consumed an ad libitum meal and the next day they recalled their food intake during the experimental day. RESULTS: A significant intervention effect was found for the energy intake of the ad libitum meal (P = 0.05) and of the whole day (P = 0.02) only in overweight/obese individuals. Specifically, Coffee 6 resulted in a reduced energy intake during the ad libitum meal compared to Coffee 3 (P = 0.03) and in the total day compared to both water (P = 0.04) and Coffee 3 (P = 0.008). No effect was observed for the appetite feelings. CONCLUSIONS: A moderate coffee amount can effectively reduce energy intake in the following meal and in the total day compared to lower or no coffee intake in overweight/obese participants. PMID- 23671023 TI - Increased frequency of cluster of differentiation 14 (CD14+) monocytes expressing interleukin 1 beta (IL-1beta) in Alzheimer's disease patients and intermediate levels in late-onset depression patients. AB - OBJECTIVE: Depression might be a prodromal stage of dementia. Many factors contribute to the etiology of depression and dementia, being inflammation one of those. The present work measured and analyzed immune molecules involved in the innate immunity on cluster of differentiation 14 (CD14+) monocytes trying to investigate any relationship among late-onset depression (LOD) and Alzheimer's disease (AD). METHODS: Immune molecules were evaluated in monocytes of AD, LOD patients, and controls using flow cytometry. RESULTS: Interestingly, interleukin 1 beta (IL-1beta) expressing CD14+ monocytes were increased in AD patients compared with controls. LOD presented intermediate frequency of CD14+ monocytes expressing IL-1beta between controls and AD patients. CONCLUSION: Results suggest that an increased frequency of CD14+ monocytes expressing IL-1beta level could be a stage marker related to the pathophysiology of dementia process between normal aging and AD. PMID- 23671024 TI - Design and synthesis of 4-(2,4,5-trifluorophenyl)butane-1,3-diamines as dipeptidyl peptidase IV inhibitors. AB - The worldwide prevalence of diabetes has spurred numerous studies on the development of new antidiabetic medicines. As a result, dipeptidyl peptidase IV (DPP4) has been recognized as a validated target. In our efforts to discover new DPP4 inhibitors, we analyzed the complexed structures of DPP4 available in Protein Data Bank and designed a series of triazole compounds. After enzyme activity assays and crystallographic verification of the binding interaction patterns, we found that the triazole compounds can inhibit DPP4 with micromolar IC50 values. Liver microsome stability and cytochrome P450 metabolic tests were performed on this series, revealing undesirable pharmacokinetic profiles for the triazole compounds. To overcome this liability, we substituted the triazole ring with an amide or urea group to produce a new series of DPP4 inhibitors. Based on its enzyme activity, metabolic stability, and selectivity over DPP8 and DPP9, we selected compound 21 r for further study of its in vivo effects in mice using an oral glucose tolerance test (OGTT). The results show that 21 r has efficacy similar to that of sitagliptin at a dose of 3 mg kg(-1) . The crystal structure of 21 r bound to DPP4 also reveals that the trifluoromethyl group is directed toward a subpocket different from the subsite bound by sitagliptin, providing clues for the design of new DPP4 inhibitors. PMID- 23671025 TI - Optimal caliper placement: manual vs automated methods. AB - OBJECTIVE: To examine the inter- and intra-operator repeatability of manual placement of callipers in the assessment of basic biometric measurements and to compare the results to an automated calliper placement system. METHODS: Stored ultrasound images of 95 normal fetuses between 19 and 25 weeks' gestation were used. Five operators (two experts, one resident and two students) were asked to measure the BPD, OFD and FL two times manually and automatically. For each operator, intra-operator repeatability of the manual and automated measurements was assessed by within operator standard deviation. For the assessment of the interoperator repeatability, the mean of the four manual measurements by the two experts was used as the gold standard.The relative bias of the manual measurement of the three non-expert operators and the operator-independent automated measurement were compared with the gold standard measurement by means and 95% confidence interval. RESULTS: In 88.4% of the 95 cases, the automated measurement algorithm was able to obtain appropriate measurements of the BPD, OFD, AC and FL. Within operator standard deviations of the manual measurements ranged between 0.15 and 1.56, irrespective of the experience of the operator.Using the automated biometric measurement system, there was no difference between the measurements of each operator. As far as the inter-operator repeatability is concerned, the difference between the manual measurements of the two students, the resident, and the gold standard was between -0.10 and 2.53 mm. The automated measurements tended to be closer to the gold standard but did not reach statistical significance. CONCLUSION: In about 90% of the cases, it was possible to obtain basic biometric measurements with an automated system. The use of automated measurements resulted in a significant improvement of the intra-operator but not of the inter-operator repeatability, but measurements were not significantly closer to the gold standard of expert examiners. PMID- 23671026 TI - Sulfocerebrosides upregulate liposome uptake in human astrocytes without inducing a proinflammatory response. AB - Astrocytes are involved in the pathogenesis of demyelinating diseases, where they actively regulate the secretion of proinflammatory factors, and trigger the recruitment of immune cells in the central nervous system (CNS). Antigen presentation of myelin-derived proteins has been shown to trigger astrocyte response, suggesting that astrocytes can directly sense demyelination. However, the direct response of astrocytes to lipid-debris generated during demyelination has not been investigated. The lipid composition of the myelin sheath is distinct, presenting significant amounts of cerebrosides, sulfocerebrosides (SCB), and ceramides. Studies have shown that microglia are activated in the presence of myelin-derived lipids, pointing to the possibility of lipid-induced astrocyte activation. In this study, a human astrocyte cell line was exposed to liposomes enriched in each myelin lipid component. Although liposome uptake was observed for all compositions, astrocytes had augmented uptake for liposomes containing sulfocerebroside (SCB). This enhanced uptake did not modify their expression of human leukocyte antigen (HLA) molecules or secretion of chemokines. This was in contrast to changes observed in astrocyte cells stimulated with IFNgamma. Contrary to human monocytes, astrocytes did not internalize beads in the size-range of liposomes, indicating that liposome uptake is lipid specific. Epifluorescence microscopy corroborated that liposome uptake takes place through endocytosis. Soluble SCB were found to partially block uptake of liposomes containing this same lipid. Endocytosis was not decreased when cells were treated with cytochalasin D, but it was decreased by cold temperature incubation. The specific uptake of SCB in the absence of a proinflammatory response indicates that astrocytes may participate in the trafficking and regulation of sulfocerebroside metabolism and homeostasis in the CNS. PMID- 23671027 TI - Unusual structure, fluxionality, and reaction mechanism of carbonyl hydrosilylation by silyl hydride complex [(ArN=)Mo(H)(SiH2Ph)(PMe3)3]. AB - The reactions of bis(borohydride) complexes [(RN=)Mo(BH4)2(PMe3)2] (4: R = 2,6 Me2C6H3; 5: R = 2,6-iPr2C6H3) with hydrosilanes afford new silyl hydride derivatives [(RN=)Mo(H)(SiR'3)(PMe3)3] (3: R = Ar, R'3 = H2Ph; 8: R = Ar', R'3 = H2Ph; 9: R = Ar, R'3 = (OEt)3; 10: R = Ar, R'3 = HMePh). These compounds can also be conveniently prepared by reacting [(RN=)Mo(H)(Cl)(PMe3)3] with one equivalent of LiBH4 in the presence of a silane. Complex 3 undergoes intramolecular and intermolecular phosphine exchange, as well as exchange between the silyl ligand and the free silane. Kinetic and DFT studies show that the intermolecular phosphine exchange occurs through the predissociation of a PMe3 group, which, surprisingly, is facilitated by the silane. The intramolecular exchange proceeds through a new non-Bailar-twist pathway. The silyl/silane exchange proceeds through an unusual Mo(VI) intermediate, [(ArN=)Mo(H)2(SiH2Ph)2(PMe3)2] (19). Complex 3 was found to be the catalyst of a variety of hydrosilylation reactions of carbonyl compounds (aldehydes and ketones) and nitriles, as well as of silane alcoholysis. Stoichiometric mechanistic studies of the hydrosilylation of acetone, supported by DFT calculations, suggest the operation of an unexpected mechanism, in that the silyl ligand of compound 3 plays an unusual role as a spectator ligand. The addition of acetone to compound 3 leads to the formation of [trans-(ArN)Mo(OiPr)(SiH2Ph)(PMe3)2] (18). This latter species does not undergo the elimination of a Si-O group (which corresponds to the conventional Ojima's mechanism of hydrosilylation). Rather, complex 18 undergoes unusual reversible beta-CH activation of the isopropoxy ligand. In the hydrosilylation of benzaldehyde, the reaction proceeds through the formation of a new intermediate bis(benzaldehyde) adduct, [(ArN=)Mo(eta(2)-PhC(O)H)2(PMe3)], which reacts further with hydrosilane through a eta(1)-silane complex, as studied by DFT calculations. PMID- 23671028 TI - Role of energy- and nutrient-sensing kinases AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) in adipocyte differentiation. AB - Recent advances have demonstrated that the adipose tissue plays a central role in regulating overall energy balance. Obesity results from a chronic deregulation of energy balance, with energy intake exceeding energy expenditure. Recently, new mechanisms that control the obesity phenotype such as the equilibrium between white and brown adipose tissue function has been identified. In this context, it is becoming increasingly clear that in addition to cellular growth, AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) also regulate lipid metabolism and adipogenesis. Here, we review recent advances in the understanding of the molecular mechanisms involved in white and brown differentiation programs focusing on AMPK and mTOR signaling pathways, which may play differential roles in white adipose tissue and brown adipose tissue development. In view of the worldwide epidemic of obesity and its associated metabolic disorders such as insulin resistance and type 2 diabetes, targeting these kinases may represent a potential approach for reducing adiposity and improving obesity-related diseases. (c) 2013 IUBMB Life, 65(7):572-583, 2013. PMID- 23671029 TI - Effects of diet macronutrient composition on body composition and fat distribution during weight maintenance and weight loss. AB - OBJECTIVE: Qualitative aspects of diet may affect body composition and propensity for weight gain or loss. We tested the hypothesis that consumption of a relatively low glycemic load (GL) diet would reduce total and visceral adipose tissue under both eucaloric and hypocaloric conditions. DESIGN AND METHODS: Participants were 69 healthy overweight men and women. Body composition was assessed by DXA and fat distribution by CT scan at baseline, after 8 weeks of a eucaloric diet intervention, and after 8 weeks of a hypocaloric (1000 kcal/day deficit) diet intervention. Participants were provided all food for both phases, and randomized to either a low GL diet (<45 points per 1000 kcal; n = 40) or high GL diet (>75 points per 1000 kcal, n = 29). RESULTS: After the eucaloric phase, participants who consumed the low GL diet had 11% less intra-abdominal fat (IAAT) than those who consumed the high GL diet (P < 0.05, adjusted for total fat mass and baseline IAAT). Participants lost an average of 5.8 kg during the hypocaloric phase, with no differences in the amount of weight loss with diet assignment (P = 0.39). Following weight loss, participants who consumed the low GL diet had 4.4% less total fat mass than those who consumed the high GL diet (P < 0.05, adjusted for lean mass and baseline fat mass). CONCLUSIONS: Consumption of a relatively low GL diet may affect energy partitioning, both inducing reduction in IAAT independent of weight change, and enhancing loss of fat relative to lean mass during weight loss. PMID- 23671030 TI - Characterization of disease-related covariance topographies with SSMPCA toolbox: effects of spatial normalization and PET scanners. AB - To generate imaging biomarkers from disease-specific brain networks, we have implemented a general toolbox to rapidly perform scaled subprofile modeling (SSM) based on principal component analysis (PCA) on brain images of patients and normals. This SSMPCA toolbox can define spatial covariance patterns whose expression in individual subjects can discriminate patients from controls or predict behavioral measures. The technique may depend on differences in spatial normalization algorithms and brain imaging systems. We have evaluated the reproducibility of characteristic metabolic patterns generated by SSMPCA in patients with Parkinson's disease (PD). We used [(18) F]fluorodeoxyglucose PET scans from patients with PD and normal controls. Motor-related (PDRP) and cognition-related (PDCP) metabolic patterns were derived from images spatially normalized using four versions of SPM software (spm99, spm2, spm5, and spm8). Differences between these patterns and subject scores were compared across multiple independent groups of patients and control subjects. These patterns and subject scores were highly reproducible with different normalization programs in terms of disease discrimination and cognitive correlation. Subject scores were also comparable in patients with PD imaged across multiple PET scanners. Our findings confirm a very high degree of consistency among brain networks and their clinical correlates in PD using images normalized in four different SPM platforms. SSMPCA toolbox can be used reliably for generating disease-specific imaging biomarkers despite the continued evolution of image preprocessing software in the neuroimaging community. Network expressions can be quantified in individual patients independent of different physical characteristics of PET cameras. PMID- 23671032 TI - Non-radioactive protein lysine methyltransferase microplate assay based on reading domains. AB - New protein lysine methyltransferase (PKMT) assays are needed to facilitate screening for improved PKMT inhibitors, because PKMTs are mutated or overexpressed in several cancers. In cells, methylated lysine residues are recognized by reading domains such as the chromodomain of HP1beta, which bind to target proteins in a lysine-methylation-specific manner. Herein we describe a sensitive, robust, and non-radioactive high-throughput PKMT assay that employs the HP1beta chromodomain to detect the methylation of peptide substrates by the human SUV39H1 and SUV39H2 PKMTs. The assay has a very good dynamic range and high signal-to-noise ratio. It can be used to screen for PKMT inhibitors, as illustrated by analyzing the inhibition of SUV39H1 by chaetocin. The IC50 value of this inhibition was found to be 480 nM, which is close to its published value. Our data indicate that natural reading domains can be used as alternates to methyl-specific antibodies in PKMT assays. Reading domains can be produced recombinantly in E. coli at low cost and consistent quality, and they are accessible to protein design. PMID- 23671031 TI - Molecular function prediction for a family exhibiting evolutionary tendencies toward substrate specificity swapping: recurrence of tyrosine aminotransferase activity in the Ialpha subfamily. AB - The subfamily Ialpha aminotransferases are typically categorized as having narrow specificity toward carboxylic amino acids (AATases), or broad specificity that includes aromatic amino acid substrates (TATases). Because of their general role in central metabolism and, more specifically, their association with liver related diseases in humans, this subfamily is biologically interesting. The substrate specificities for only a few members of this subfamily have been reported, and the reliable prediction of substrate specificity from protein sequence has remained elusive. In this study, a diverse set of aminotransferases was chosen for characterization based on a scoring system that measures the sequence divergence of the active site. The enzymes that were experimentally characterized include both narrow-specificity AATases and broad-specificity TATases, as well as AATases with broader-specificity and TATases with narrower specificity than the previously known family members. Molecular function and phylogenetic analyses underscored the complexity of this family's evolution as the TATase function does not follow a single evolutionary thread, but rather appears independently multiple times during the evolution of the subfamily. The additional functional characterizations described in this article, alongside a detailed sequence and phylogenetic analysis, provide some novel clues to understanding the evolutionary mechanisms at work in this family. PMID- 23671033 TI - Perinatal outcome after fetoscopic release of amniotic bands: a single-center experience and review of the literature. AB - OBJECTIVES: To present two successful cases of fetoscopic release of amniotic bands with umbilical cord involvement and provide a review of the literature on fetal intervention for amniotic band syndrome (ABS). METHODS: Two cases of ABS were considered in conjunction with a review of the literature. A total of 14 fetuses with ABS underwent fetoscopic intervention between 1965 and 2012. Two of the authors independently completed literature searches in PubMed, Ovid and MEDLINE for articles related to ABS. RESULTS: Among 14 cases of ABS (12 published and our own two), 57% and 7% were complicated by preterm premature rupture of membranes and spontaneous preterm birth, respectively. Overall, fetoscopic intervention preserved limb function in 50% (7/14) of cases. Three cases involved intraoperative complications including intra-amniotic bleeding and uterine wall bleeding, and incomplete procedure due to ineffective equipment. CONCLUSION: Fetoscopic release of amniotic bands with minimally invasive surgery may allow preservation of life and/or limb function in cases of ABS. The acceptable functional outcome in 50% of cases is reassuring, although more experience and further studies are needed to determine the selection criteria that will justify the risk of this invasive in-utero therapy for ABS. PMID- 23671034 TI - Wolbachia in the Malpighian tubules: evolutionary dead-end or adaptation? AB - Facultative endosymbionts, such as Wolbachia, perpetuate by vertical transmission mostly through colonization of the germline during embryogenesis. The remaining Wolbachia inside the embryo are internalized in progenitor cells of the somatic tissue. This perpetuation strategy triggers a cyclic bacterial bottleneck across host generations. However, throughout the host's life history (Drosophila, for example), some somatic tissues such as the Malpighian tubules (MTs) show large numbers of Wolbachia. It is assumed that Wolbachia present in the progenitor cells of the MTs are confined to this somatic tissue, implicitly considering MTs as an evolutionary dead-end for these bacteria. Nevertheless, the fact that bacteria can survive and proliferate inside MTs suggests a different fate as they may access the host's reproductive system and persist in the host population through vertical transmission. Indeed, based on the particular physiological and developmental characteristics of MT, as well as of Wolbachia, we argue the bacteria present in the MTs may constitute a secondary pool of vertically transmitted bacteria. Moreover, somatic pools of Wolbachia capable of reaching the gonads and insure vertical transmission may also provide an interesting element to the elucidation of horizontal transmission mechanisms. Finally, we also speculate that somatic pools of Wolbachia may play an important role in host fitness, namely during viral infections. In brief, we argue that the somatic pools of Wolbachia, with special emphasis on the MT subset, deserve experimental attention as putative players in the physiology and evolution of both bacteria and hosts. PMID- 23671035 TI - The cloning and expression analysis of Lhx9 during gonadal sex differentiation in the red-eared slider turtle, Trachemys scripta, a species with temperature dependent sex determination. AB - Many reptiles, including the red-eared slider turtle (Trachemys scripta), possess a temperature-dependent sex determination (TSD) mechanism where the temperature at which the developing embryos are incubated dictates the gonadal sex of the animal. A number of mammalian gene orthologues have been identified in the sex determination/differentiation cascade of reptiles with TSD although the exact trigger(s) is not well understood. A potential early regulator of gonadal differentiation, Lhx9, controls the proliferation of gonadal cells in mice and its absence prevents gonadal development and drastically reduces the expression of Sf-1, a gene that regulates the expression of steroidogenic enzymes in the bipotential gonad. In the current study, we cloned Lhx9 from T. scripta and analyzed its expression throughout the thermosensitive period of gonad development using quantitative PCR. We examined the expression profiles of Lhx9 in embryos incubated under control conditions at male- and female-producing temperatures and with the application of exogenous 17beta-estradiol or an aromatase inhibitor, Letrozole, to induce sex reversal. The T. scripta Lhx9 cDNA and predicted amino acid sequence showed high homology to those of chicken, anole, and mouse. Lhx9 was expressed at both male- and female-producing temperatures with expression levels increasing throughout the thermosensitive period. Letrozole induced sex-reversal did not alter Lhx9 expression levels. 17beta-estradiol treatments appeared to inhibit or delay gonadal differentiation and resulted in lower Lhx9 expression from the presumptive gonadal ridge region. The structural homology and temporal expression pattern of Lhx9 suggests that this represents a conserved element in the gonadal differentiation cascade of T. scripta. PMID- 23671036 TI - Uridine adenosine tetraphosphate induces contraction of circular and longitudinal gastric smooth muscle by distinct signaling pathways. AB - Extracellular nucleotides uridine-5'-triphosphate (UTP) and adenosine-5' triphosphate (ATP) induce contraction of gastric smooth muscle (SM). The dinucleotide uridine adenosine tetraphosphate (Up4 A), an endothelium-derived contraction factor, induces vascular SM contraction. Its effect on gastric SM contractions, however, is unknown. We addressed the hypothesis that Up4 A induces gastric SM contraction via a mechanism that may differ between circular and longitudinal muscle (CM and LM, respectively). CM and LM were isolated from rat gastric fundus for the measurement of isometric tension. Up4 A induced transient contractile responses in both CM and LM, which were similar to those induced by ATP and UTP. Up4 A failed to induce contraction of either LM or CM in the absence of extracellular Ca(2+) or in the presence of nimodipine, an inhibitor of voltage gated Ca(2+) channels. P2X1, 2, 4, 5 and 7 and P2Y1, 2, 4 and 6 receptor expression was detected in gastric SM by reverse transcription-polymerase chain reaction. IP5 I (a P2X receptor antagonist) and alpha,beta-methylene-ATP (a P2X receptor agonist) had no effect on Up4 A-induced contractions of either LM or CM, and alpha,beta-methylene-ATP alone failed to induce a contractile response in either tissue. Suramin (a P2Y receptor antagonist), on the other hand, significantly inhibited Up4 A-induced contraction of CM, but not LM. Up4 A induced contraction of CM, but not LM, was also inhibited by pretreatment with Y 27632, an inhibitor of Rho-associated kinase. We conclude that Up4 A induces extracellular Ca(2+) -dependent contractions of rat gastric LM and CM, and Up4 A induced contraction of CM is mediated by suramin-sensitive P2Y receptors and subsequent activation of the Rho-associated kinase pathway. PMID- 23671038 TI - Mapping neurotransmitter networks with PET: an example on serotonin and opioid systems. AB - All functions of the human brain are consequences of altered activity of specific neural pathways and neurotransmitter systems. Although the knowledge of "system level" connectivity in the brain is increasing rapidly, we lack "molecular level" information on brain networks and connectivity patterns. We introduce novel voxel based positron emission tomography (PET) methods for studying internal neurotransmitter network structure and intercorrelations of different neurotransmitter systems in the human brain. We chose serotonin transporter and MU-opioid receptor for this analysis because of their functional interaction at the cellular level and similar regional distribution in the brain. Twenty-one healthy subjects underwent two consecutive PET scans using [(11)C]MADAM, a serotonin transporter tracer, and [(11)C]carfentanil, a MU-opioid receptor tracer. First, voxel-by-voxel "intracorrelations" (hub and seed analyses) were used to study the internal structure of opioid and serotonin systems. Second, voxel-level opioid-serotonin intercorrelations (between neurotransmitters) were computed. Regional MU-opioid receptor binding potentials were uniformly correlated throughout the brain. However, our analyses revealed nonuniformity in the serotonin transporter intracorrelations and identified a highly connected local network (midbrain-striatum-thalamus-amygdala). Regionally specific intercorrelations between the opioid and serotonin tracers were found in anteromedial thalamus, amygdala, anterior cingulate cortex, dorsolateral prefrontal cortex, and left parietal cortex, i.e., in areas relevant for several neuropsychiatric disorders, especially affective disorders. This methodology enables in vivo mapping of connectivity patterns within and between neurotransmitter systems. Quantification of functional neurotransmitter balances may be a useful approach in etiological studies of neuropsychiatric disorders and also in drug development as a biomarker-based rationale for targeted modulation of neurotransmitter networks. PMID- 23671039 TI - Electric double-layer capacitor based on an ionic clathrate hydrate. AB - Herein, we suggest a new approach to an electric double-layer capacitor (EDLC) that is based on a proton-conducting ionic clathrate hydrate (ICH). The ice-like structures of clathrate hydrates, which are comprised of host water molecules and guest ions, make them suitable for applications in EDLC electrolytes, owing to their high proton conductivities and thermal stabilities. The carbon materials in the ICH Me4NOH?5 H2O show a high specific capacitance, reversible charge discharge behavior, and a long cycle life. The ionic-hydrate complex provides the following advantages in comparison with conventional aqueous and polymer electrolytes: 1) The ICH does not cause leakage problems under normal EDLC operating conditions. 2) The hydrate material can be utilized itself, without requiring any pre-treatments or activation for proton conduction, thus shortening the preparation procedure of the EDLC. 3) The crystallization of the ICH makes it possible to tailor practical EDLC dimensions because of its fluidity as a liquid hydrate. 4) The hydrate solid electrolyte exhibits more-favorable electrochemical stability than aqueous and polymer electrolytes. Therefore, ICH materials are expected to find practical applications in versatile energy devices that incorporate electrochemical systems. PMID- 23671037 TI - Pharmacological inhibition of diacylglycerol acyltransferase 1 reduces body weight and modulates gut peptide release--potential insight into mechanism of action. AB - OBJECTIVE: Investigation was conducted to understand the mechanism of action of diacylglycerol acyltransferase 1 (DGAT1) using small molecules DGAT1 inhibitors, compounds K and L. DESIGN AND METHODS: Biochemical and stable-label tracer approaches were applied to interrogate the functional activities of compounds K and L on TG synthesis and changes of carbon flow. Energy homeostasis and gut peptide release upon DGAT1 inhibition was conducted in mouse and dog models. RESULTS: Compounds K and L, dose-dependently inhibits post-prandial TG excursion in mouse and dog models. Weight loss studies in WT and Dgat1(-/-) mice, confirmed that the effects of compound K on body weight loss is mechanism-based. Compounds K and L altered incretin peptide release following oral fat challenge. Immunohistochemical studies with intestinal tissues demonstrate lack of detectable DGAT1 immunoreactivity in enteroendocrine cells. Furthermore, (13) C fatty acid tracing studies indicate that compound K inhibition of DGAT1 increased the production of phosphatidyl choline (PC). CONCLUSION: Treatment with DGAT1 inhibitors improves lipid metabolism and body weight. DGAT1 inhibition leads to enhanced PC production via alternative carbon channeling. Immunohistological studies suggest that DGAT1 inhibitor's effects on plasma gut peptide levels are likely via an indirect mechanism. Overall these data indicate a translational potential towards the clinic. PMID- 23671040 TI - Regulation of cardiac autophagy by insulin-like growth factor 1. AB - Insulin-like growth factor-1 (IGF-1) signaling is a key pathway in the control of cell growth and survival. Three critical nodes in the IGF-1 signaling pathway have been described in cardiomyocytes: protein kinase Akt/mammalian target of rapamycin (mTOR), Ras/Raf/extracellular signal-regulated kinase (ERK), and phospholipase C (PLC)/inositol 1,4,5-triphosphate (InsP3 )/Ca(2+) . The Akt/mTOR and Ras/Raf/ERK signaling arms govern survival in the settings of cardiac stress and hypertrophic growth. By contrast, PLC/InsP3 /Ca(2+) functions to regulate metabolic adaptability and gene transcription. Autophagy is a catabolic process involved in protein degradation, organelle turnover, and nonselective breakdown of cytoplasmic components during nutrient starvation or stress. In the heart, autophagy is observed in a variety of human pathologies, where it can be either adaptive or maladaptive, depending on the context. We proposed the hypothesis that IGF-1 protects the heart by rescuing the mitochondrial metabolism and the energetics state, reducing cell death and controls the potentially exacerbate autophagic response to nutritional stress. In light of the importance of IGF-1 and autophagy in the heart, we review here IGF-1 signaling and autophagy regulation in the context of cardiomyocyte nutritional stress. PMID- 23671042 TI - 'Medical humanities'--what's in a name? PMID- 23671043 TI - Qu'un souffle de vent: an exploration of anorexia nervosa. AB - The spread of anorexia nervosa, especially in Western developed countries, is reaching alarming proportions. According to the International Classification of Diseases, the central feature of anorexia nervosa is "deliberate weight loss". This means that anorexia nervosa is a progressive pursuit of lightness. Moving from this observation, I ask why so many people want to lose weight, why some would die, rather than put on weight. In order to understand what value these people attach to lightness, I look at contexts where lightness is typically celebrated (music, literature, and arts) and provide an analysis of anorexia nervosa, using both theoretical reflection and empirical observations. This analysis shows that anorexia is much more than a pattern of psychiatric symptoms, and much more than unintelligible behaviour. Anorexic behaviour is instead meaningful and coherent behaviour, and expresses ethical values that are deeply rooted in Western culture. PMID- 23671044 TI - Knock: a study in medical cynicism. AB - French literature has shown an enduring fascination with the social figure of the doctor. In Jules Romains' amusing play Knock (1922), and in its later film version (1951), the doctor as deceiver returns to centrestage with a flourish. Moliere's seventeenth-century figures were mostly quacks and mountebanks; Knock is something new: he is a health messiah. By enforcing a mental and social hygiene based on fear, Knock brings a small rural population under his sway. Insouciance is banished by artful consciousness-raising. A society mobilises under the banner of medicine. But who is Dr Knock? PMID- 23671041 TI - Shift-and-persist: a protective factor for elevated BMI among low-socioeconomic status children. AB - OBJECTIVE: Low socioeconomic status (SES) is associated with many adverse health outcomes, including childhood overweight and obesity. However, little is understood about why some children defy this trend by maintaining a healthy weight despite living in obesogenic environments. The objective of this study is to test the hypothesis that the psychological strategy of "shift-and-persist" protects low-SES children from overweight and obesity. Shift-and-persist involves dealing with stressors by reframing them more positively while at the same time persisting in optimistic thoughts about the future. DESIGN AND METHODS: Middle school children (N = 1,523, ages 9-15) enrolled in a school-based obesity prevention trial completed health surveys and physical assessments. Multiple linear regression analysis was used to examine the role of SES, shift-and-persist strategies, and their interaction on BMI z-scores, while controlling for student race/ethnicity, gender, and reported diet and physical activity. RESULTS: Among children reporting engaging in less frequent shift-and-persist strategies, lower SES was associated with significantly higher BMI z-scores (P < 0.05). However, among children reporting engaging in more frequent shift-and-persist strategies, there was no association of SES with BMI z-score (P = 0.16), suggesting that shift-and-persist strategies may be protective against the association between SES and BMI. CONCLUSIONS: Interventions aimed at improving psychological resilience among children of low SES may provide a complementary approach to prevent childhood overweight and obesity among at-risk populations. PMID- 23671045 TI - Transplant: a non-fiction narrative. AB - This narrative is taken from a memoir about my son, Jesse, who died at age 19 in 1995 after a liver transplant. It covers two periods-from May 5, his admission date at the hospital to wait for a transplant, until May 9, when a perforation, caused by cutting through intestinal adhesions during transplant surgery, was discovered, and from May 20 to May 22, when his condition became extremely critical. Since Jesse was largely unconscious or semi-conscious during a good part of the period this narrative covers, his personality and conscious struggles shine through less here than they do in other parts of the memoir. Here, the relative emphasis is on parents and physicians and on facing the critical illness, and possible death, of one's child in an intensive care unit, following the very intervention that was to give him a new chance at a healthy life. PMID- 23671046 TI - Two stories and an ode. PMID- 23671047 TI - Medical humanities in undergraduate medical education--moving on. PMID- 23671048 TI - The University of Birmingham Medical School and the history of medicine. AB - The publication in 1993 by the General Medical Council of Tomorrow's Doctors Recommendations on Undergraduate Medical Education provided the first real opportunity for many medical schools to advance the introduction of the history of medicine into the undergraduate medical curriculum. While the University of Birmingham Medical School, was not one of the first to introduce the subject, it has been at the forefront of the introduction of the history of medicine into the undergraduate medical curriculum since 1997, and can now boast a number of special study modules in the subject and the second largest intercalated BMedSc (History of Medicine) degree programme in the country. This article tells the story of why and how we introduced history into the curriculum and how important it is that tomorrow's doctors know something of the history of the profession they are about to enter. PMID- 23671049 TI - Body image and the innocent eye. AB - This paper describes the development, content, teaching experience, and impact of the course "The body image in medicine and the arts" which is offered annually in a one-month format for medical students and other upper division students at the University of Missouri-Kansas City (UMKC). Literature, photography, art, anthropology, art history, cultural studies, feminism, modernism, and medicine are all employed in the course as a way of encouraging students to consider the broader cultural interpretations of the human body. Any medical humanities instructor wishing to explore new ideas and themes related to teaching students about past and present body image issues and their impact on contemporary biomedical culture can gain insight through an overview of this course. The purpose of the course is to allow medical students a forum for talking more personally and metaphorically about the body as a cultural concept. The teaching faculty involved in this course believe that the majority of students who participate in this class complete it more acutely aware than before of the fact that no single human being, even a "good, caring" doctor, can see with an "innocent eye". The accomplishment of this goal alone justifies faculty participation in the course. PMID- 23671050 TI - Literary narrative in medical practice. AB - It is generally accepted that the practice of medicine could be improved by turning to the humanities in general, and to narrative and text interpretation in particular. Neverthless, there is hardly any agreement as to the nature of the clinical text, whether it be the patient's narrative that needs to be richly understood, or the patient as patient who must be both personally and clinically deciphered.We suggest that literary narratives depicting medical situations might serve as testimonials of the way medicine has or is being practised in a variety of social settings, and of the ways patients experience disease and medical care. By reading these texts, health care professionals could compare the situations and values involved in such narratives with current medical practices, thus perceiving how clinical encounters have changed and improved or, perhaps, continue to carry a burden of past flaws. PMID- 23671051 TI - Making room for medical humanities. AB - Should medical humanities become part of the core curriculum in medicine? This paper describes the experiences of one medical school that decided it should. The paper describes the professional and academic rationale for this decision, the process by which it was implemented, the structure of the course, the strategies for assessment of students' work and the results of a teacher evaluation. PMID- 23671052 TI - Courses, content, and a student essay in medical humanities. AB - Two principled decisions underlay the introduction of the new compulsory medical humanities course. First, it was decided, all lecturers must be trained in the discipline; second, the course content must be relevant to medicine. This paper gives details of the content of eight selective courses. There is also an example of an essay by one of the students, Tiffany Suk. Entitled "Two patients in two rooms with two choices and two ends", it is a brief analysis and critique of Sylvia Plath's poems Tulips and Contusion. It shows how the student took what she had learned from her course in health psychology to further illuminate the poems. The essay is followed by comments from the lecturer, Anna Jackson, giving the context for the essay and her assessment of it. PMID- 23671053 TI - Escape or instruction? A description of a seminar for general practitioners on literature and medicine. AB - We describe the planning and running of a seminar on medicine and literature for general practitioners. This was based on the educational principles of adult learning. We used academic papers, an extract from a novel, a short story, and a cartoon and asked participants to present a piece of literature of their choice. Although the general practitioners (GPs) had not been selected for their specific interest in this area, there was great enthusiasm for this field. Most of the GPs thought literature could contribute to their professional lives and also could be useful for teaching. PMID- 23671054 TI - Oligonorbornenes with hammock-like crown ether pendants as artificial transmembrane ion channel. AB - Trimeric oligonorbornenes with hammock-like crown ether pendants 3b and 3c were selectively synthesized by cascade metathetical cyclopolymerization upon treatment with the first generation Grubbs catalyst. These crown-ether-containing oligonorbornenes are impregnated in egg yolk phosphatidylcholine (EYPC) liposome as an artificial ion channel. The efficiency of the sodium ion transport properties has been examined. Oligomer 3c having a polar hydroxy end group exhibits the highest transport efficiency, which is comparable with the best efficiencies reported in literature. The orientation of the crown ether moieties in these oligomers may be critical for the ion transport properties. PMID- 23671055 TI - Metabolic and endocrine correlates of cognitive function in healthy young women. AB - OBJECTIVE: Obesity has been associated with cognitive decline in longitudinal studies of older individuals. We hypothesized that the cognitive sequelae of obesity may be detectable in the reproductive years. In addition, we explored the hypothesis that these associations may be mediated by the hormonal milieu. DESIGN AND METHODS: Of 49 young healthy lean and overweight women aged 20-45, we investigated the association between performance on a battery of cognitive tests, body composition parameters [body mass index, total fat, abdominal (visceral, subcutaneous, and total) adipose tissue, and muscle], and hormone levels (insulin, adiponectin, leptin, insulin-like growth factor 1 (IGF-1), estrogen, testosterone, and vitamin D). RESULTS: We found a significant negative association between both visceral adiposity and muscle, and performance in the domain of verbal learning and memory, after controlling for age and education. Other body composition parameters showed similar trends (0.05 < P < 0.10). Additionally, the degree of insulin resistance was negatively associated with executive function domain. None of the associations between the other hormones examined (adipokines, IGF-1, gonadal hormones, and vitamin D) and cognitive function were significant. CONCLUSION: These preliminary findings suggest a possible association between obesity and cognitive function in healthy young women of reproductive age. More research is warranted into the potential modulatory effect of insulin resistance on this association. PMID- 23671057 TI - Skeletal muscle adiposity is associated with serum lipid and lipoprotein levels in Afro-Caribbean men. AB - OBJECTIVE: When compared with other ethnic groups, African ancestry individuals have lower triglycerides and higher High-density lipoprotein cholesterol (HDL-C) levels, although the mechanisms for these differences remain unclear. A comprehensive array of factors potentially related to fasting serum lipid and lipoprotein levels in African ancestry men was evaluated. DESIGN AND METHODS: Men (1,821) underwent dual-energy X-ray absorptiometry measures of total body fat and quantitative computed tomography assessments of calf skeletal muscle adiposity [subcutaneous and intermuscular adipose tissue (AT), and muscle density as a measure of intra-muscular AT]. RESULTS: Multivariable linear regression analysis identified age (-), total body fat (+), subcutaneous AT (-), fasting glucose (+), fasting insulin (+), diastolic blood pressure (+), and non-African ancestry (+) as independent correlates of triglycerides (all P < 0.05). Total body fat (+), intra-muscular AT (-), and diastolic blood pressure (+) were independent correlates of Low-density lipoprotein cholesterol (LDL-C) (all P < 0.001). Age (+), waist circumference (-), fasting insulin (-), physical activity (+), and alcohol intake (+) were independent correlates of HDL-C (all P < 0.05). CONCLUSIONS: A novel relationship between skeletal muscle adiposity and serum lipid and lipoprotein levels in African ancestry men, independent of total and central adiposity was illuminated. In African ancestry populations, genetic factors are likely a significant determinant of triglycerides levels. PMID- 23671059 TI - Psychometric properties of the internet addiction test in Chinese adolescents. AB - OBJECTIVE: This study examined the psychometric properties of the Young's Internet Addiction Test (IAT) in 844 Hong Kong Chinese adolescents (37.7% boys) with mean age of 15.9 (standard deviation = 3.5) years. METHODS: Demographic items, Internet use habits, IAT, and the Revised Chen Internet Addiction Scale (CIAS-R) were administered. 3 percent of the participants were classified as addicted and 31.6% as occasional problematic Internet users. Confirmatory factor analysis results indicated that the 18-item second-order three-factor model has the best fit with our data (Satorra-Bentler scaled chi(2) = 160.56, df = 132, p < .05, normed fit index = 0.95, non-normed fit index = 0.99, comparative fit index = 0.99, root mean square error of approximation = 0.02). RESULTS: IAT demonstrated strong internal consistency (Cronbach's alpha = .93). Satisfactory concurrent and convergent validity of IAT were found moderately correlated with CIAS-R (r = .46) and the average online time per day (r = .40 for weekdays; r = .37 for weekends). CONCLUSION: IAT has evidence of being a valid and reliable scale for screening Internet addiction in Chinese adolescents. PMID- 23671058 TI - Motivational interviewing to enhance self-efficacy and promote weight loss in overweight and obese adolescents: a randomized controlled trial. AB - OBJECTIVE: To evaluate the efficacy of Motivational Interviewing (MI) as an intervention for promoting self-efficacy and weight loss in a sample of overweight and obese youth. METHODS: /Design 40 participants (aged 10-18 years) were randomly assigned to control (social skills training) or treatment (MI) group. Both groups received individual therapy (~30 min/month) in addition to usual care of diet/exercise counseling. Pre- and post- (at 6 months follow-up) variables included measures of self-efficacy and anthropometrics. RESULTS: Although significant between-group differences were not found, individuals in the MI group attended more sessions. Overall, participants in both groups showed significant increases in self-efficacy and a trend of decreased body mass index z scores. CONCLUSIONS: Health benefits from participation in individual therapy may have been accrued; however, specific benefits attributable to MI were limited. Findings suggest that more than one type of counseling intervention (i.e., MI and social skills training) may be beneficial when providing integrative treatment for obese youth. PMID- 23671060 TI - Reflections on developing collaborative research in pediatric psychology: implications and future directions. AB - OBJECTIVES: Collaborative research with pediatric colleagues has become increasingly important in the professional agenda of pediatric psychology, and there is a continuing need to articulate the challenges of such research. To address this need, this article describes types of collaborative research, reasons for collaboration, collaborative process, challenges, and strategies to facilitate collaborative research. METHODS: Experiences and lessons learned over the course of a career in collaborative research are described. RESULTS: Challenges in collaborative research can be overcome by effective strategies of engagement and communication. Useful methods of training researchers in collaborative research include modeling and supervised mentored experiences in research initiated by trainees. CONCLUSION: Data are needed to identify the characteristics of successful collaborative research, strategies to promote effective research, and methods of training and career development. PMID- 23671061 TI - Synthesis and characterization of poly(glycerol-co-sebacate-co-epsilon caprolactone) elastomers. AB - In this study, poly(glycerol-co-sebacate-co-epsilon-caprolactone) (PGSCL) elastomers were synthesized for the first time from the respective monomers. The structural analysis of PGSCL elastomers by nuclear magnetic resonance ((1)H-NMR) and Fourier transform infrared spectroscopy (FTIR) revealed that the elastomers have a high number of hydrogen bonds and crosslinks. X-ray diffraction (XRD) and thermal analysis indicated an amorphous state. Differential scanning calorimetry (DSC) analysis showed that the elastomers has a glass transition temperature (T(g)) of -36.96 degrees C. The Young's modulus and compression strength values were calculated as 46.08 MPa and 3.192 MPa, respectively. Calculations based on acid number and end groups analysis revealed a number average molecular weight of 148.15 kDa. Even though the foaming studies conducted by using supercritical CO2 resulted in a porous structure; the obtained morphology tended to disappear after 48 h, leaving small cracks on the surface. This phenomenon was interpreted as an indication of self-healing due to the high number of hydrogen bonds. The PGSCL elastomers synthesized in this study are flexible, robust to compression forces and have self-healing capacity. Thanks to good biocompatibility and poor cell adhesion properties, the elastomers may find diverse applications where a postoperative adhesion barrier is required. PMID- 23671062 TI - Plug and play: combining materials and technologies to improve bone regenerative strategies. AB - Despite recent advances in the development of biomaterials intended to replace natural bone grafts for the regeneration of large, clinically relevant defects, most synthetic solutions that are currently applied in the clinic are still inferior to natural bone grafts with regard to regenerative potential and are limited to non-weight-bearing applications. From a materials science perspective, we always face the conundrum of the preservation of bioactivity of calcium phosphate ceramics in spite of better mechanical and handling properties and processability of polymers. Composites have long been investigated as a method to marry these critical properties for the successful regeneration of bone and, indeed, have shown a significant improvement when used in combination with cells or growth factors. However, when looking at this approach from a clinical and regulatory perspective, the use of cells or biologicals prolongs the path of new treatments from the bench to the bedside. Applying 'smart' synthetic materials alone poses the fascinating challenge of instructing tissue regeneration in situ, thereby tremendously facilitating clinical translation. In the journey to make this possible, and with the aim of adding up the advantages of different biomaterials, combinations of fabrication technologies arise as a new strategy for generating instructive three-dimensional (3D) constructs for bone regeneration. Here we provide a review of recent technologies and approaches to create such constructs and give our perspective on how combinations of technologies and materials can help in obtaining more functional bone regeneration. PMID- 23671063 TI - Nitrogen cycling, forest canopy reflectance, and emergent properties of ecosystems. PMID- 23671064 TI - Is Toso/IgM Fc receptor (FcMUR) expressed by innate immune cells? PMID- 23671065 TI - Docosahexaenoic acid ethyl esters ineffective? PMID- 23671066 TI - Dynamic dual-tracer MRI-guided fluorescence tomography to quantify receptor density in vivo. AB - The up-regulation of cell surface receptors has become a central focus in personalized cancer treatment; however, because of the complex nature of contrast agent pharmacokinetics in tumor tissue, methods to quantify receptor binding in vivo remain elusive. Here, we present a dual-tracer optical technique for noninvasive estimation of specific receptor binding in cancer. A multispectral MRI-coupled fluorescence molecular tomography system was used to image the uptake kinetics of two fluorescent tracers injected simultaneously, one tracer targeted to the receptor of interest and the other tracer a nontargeted reference. These dynamic tracer data were then fit to a dual-tracer compartmental model to estimate the density of receptors available for binding in the tissue. Applying this approach to mice with deep-seated gliomas that overexpress the EGF receptor produced an estimate of available receptor density of 2.3 +/- 0.5 nM (n = 5), consistent with values estimated in comparative invasive imaging and ex vivo studies. PMID- 23671067 TI - Reinstatement of nicotine seeking is mediated by glutamatergic plasticity. AB - Nicotine abuse and addiction is a major health liability. Nicotine, an active alkaloid in tobacco, is self-administered by animals and produces cellular adaptations in brain regions associated with drug reward, such as the nucleus accumbens. However, it is unknown whether, akin to illicit drugs of abuse such as cocaine or heroin, the adaptations endure and contribute to the propensity to relapse after discontinuing nicotine use. Using a rat model of cue-induced relapse, we made morphological and electrophysiological measures of synaptic plasticity, as well as quantified glutamate overflow, in the accumbens after 2 wk of withdrawal with extinction training. We found an enduring basal increase in dendritic spine head diameter and in the ratio of AMPA to NMDA currents in accumbens spiny neurons compared with yoked saline animals at 2 wk after the last nicotine self-administration session. This synaptic potentiation was associated with an increase in both AMPA (GluA1) and NMDA (GluN2A and GluN2B) receptor subunits, and a reduction in the glutamate transporter-1 (GLT-1). When nicotine seeking was reinstated by presentation of conditioned cues, there were parallel increases in behavioral responding, extracellular glutamate, and further increases in dendritic spine head diameter and ratio of AMPA to NMDA currents within 15 min. These findings suggest that targeting glutamate transmission might inhibit cue-induced nicotine seeking. In support of this hypothesis, we found that pharmacological inhibition of GluN2A with 3-Chloro-4-fluoro-N-[4-[[2 (phenylcarbonyl)hydrazino]carbonyl]benzyl]benzenesulfonamide (TCN-201) or GluN2B with ifenprodil abolished reinstated nicotine seeking. These results indicate that up-regulated GluN2A, GluN2B, and rapid synaptic potentiation in the accumbens contribute to cue-induced relapse to nicotine use. PMID- 23671068 TI - PI3Kalpha activates integrin alpha4beta1 to establish a metastatic niche in lymph nodes. AB - Lymph nodes are initial sites of tumor metastasis, yet whether the lymph node microenvironment actively promotes tumor metastasis remains unknown. We show here that VEGF-C/PI3Kalpha-driven remodeling of lymph nodes promotes tumor metastasis by activating integrin alpha4beta1 on lymph node lymphatic endothelium. Activated integrin alpha4beta1 promotes expansion of the lymphatic endothelium in lymph nodes and serves as an adhesive ligand that captures vascular cell adhesion molecule 1 (VCAM-1)(+) metastatic tumor cells, thereby promoting lymph node metastasis. Experimental induction of alpha4beta1 expression in lymph nodes is sufficient to promote tumor cell adhesion to lymphatic endothelium and lymph node metastasis in vivo, whereas genetic or pharmacological blockade of integrin alpha4beta1 or VCAM-1 inhibits it. As lymph node metastases accurately predict poor disease outcome, and integrin alpha4beta1 is a biomarker of lymphatic endothelium in tumor-draining lymph nodes from animals and patients, these results indicate that targeting integrin alpha4beta1 or VCAM to inhibit the interactions of tumor cells with the lymph node microenvironment may be an effective strategy to suppress tumor metastasis. PMID- 23671069 TI - Visualization of pinholin lesions in vivo. AB - Lambdoid phage 21 uses a pinholin-signal anchor release endolysin strategy to effect temporally regulated host lysis. In this strategy, the pinholin S(21)68 accumulates harmlessly in the bilayer until suddenly triggering to form lethal membrane lesions, consisting of S(21)68 heptamers with central pores <2 nm in diameter. The membrane depolarization caused by these pores activates the muralytic endolysin, R(21), leading immediately to peptidoglycan degradation. The lethal S(21)68 complexes have been designated as pinholes to distinguish from the micrometer-scale holes formed by canonical holins. Here, we used GFP fusions of WT and mutant forms of S(21)68 to show that the holin accumulates uniformly throughout the membrane until the time of triggering, when it suddenly redistributes into numerous small foci (rafts). Raft formation correlates with the depletion of the proton motive force, which is indicated by the potential sensitive dye bis-(1,3-dibutylbarbituric acid)pentamethine oxonol. By contrast, GFP fusions of either antiholin variant irsS(21)68, which only forms inactive dimers, or nonlethal mutant S(21)68(S44C), which is blocked at an activated dimer stage of the pinhole formation pathway, were both blocked in a state of uniform distribution. In addition, fluorescence recovery after photobleaching revealed that, although the antiholin irsS(21)68-GFP fusion was highly mobile in the membrane (even when the proton motive force was depleted), more than one-half of the S(21)68-GFP molecules were immobile, and the rest were in mobile states with a much lower diffusion rate than the rate of irsS(21)68-GFP. These results suggest a model in which, after transiting into an oligomeric state, S(21)68 migrates into rafts with heterogeneous sizes, within which the final pinholes form. PMID- 23671070 TI - Circadian patterns of gene expression in the human brain and disruption in major depressive disorder. AB - A cardinal symptom of major depressive disorder (MDD) is the disruption of circadian patterns. However, to date, there is no direct evidence of circadian clock dysregulation in the brains of patients who have MDD. Circadian rhythmicity of gene expression has been observed in animals and peripheral human tissues, but its presence and variability in the human brain were difficult to characterize. Here, we applied time-of-death analysis to gene expression data from high-quality postmortem brains, examining 24-h cyclic patterns in six cortical and limbic regions of 55 subjects with no history of psychiatric or neurological illnesses ("controls") and 34 patients with MDD. Our dataset covered ~12,000 transcripts in the dorsolateral prefrontal cortex, anterior cingulate cortex, hippocampus, amygdala, nucleus accumbens, and cerebellum. Several hundred transcripts in each region showed 24-h cyclic patterns in controls, and >100 transcripts exhibited consistent rhythmicity and phase synchrony across regions. Among the top-ranked rhythmic genes were the canonical clock genes BMAL1(ARNTL), PER1-2-3, NR1D1(REV ERBa), DBP, BHLHE40 (DEC1), and BHLHE41(DEC2). The phasing of known circadian genes was consistent with data derived from other diurnal mammals. Cyclic patterns were much weaker in the brains of patients with MDD due to shifted peak timing and potentially disrupted phase relationships between individual circadian genes. This transcriptome-wide analysis of the human brain demonstrates a rhythmic rise and fall of gene expression in regions outside of the suprachiasmatic nucleus in control subjects. The description of its breakdown in MDD suggests potentially important molecular targets for treatment of mood disorders. PMID- 23671071 TI - Scope for improved eco-efficiency varies among diverse cropping systems. AB - Global food security requires eco-efficient agriculture to produce the required food and fiber products concomitant with ecologically efficient use of resources. This eco-efficiency concept is used to diagnose the state of agricultural production in China (irrigated wheat-maize double-cropping systems), Zimbabwe (rainfed maize systems), and Australia (rainfed wheat systems). More than 3,000 surveyed crop yields in these three countries were compared against simulated grain yields at farmer-specified levels of nitrogen (N) input. Many Australian commercial wheat farmers are both close to existing production frontiers and gain little prospective return from increasing their N input. Significant losses of N from their systems, either as nitrous oxide emissions or as nitrate leached from the soil profile, are infrequent and at low intensities relative to their level of grain production. These Australian farmers operate close to eco-efficient frontiers in regard to N, and so innovations in technologies and practices are essential to increasing their production without added economic or environmental risks. In contrast, many Chinese farmers can reduce N input without sacrificing production through more efficient use of their fertilizer input. In fact, there are real prospects for the double-cropping systems on the North China Plain to achieve both production increases and reduced environmental risks. Zimbabwean farmers have the opportunity for significant production increases by both improving their technical efficiency and increasing their level of input; however, doing so will require improved management expertise and greater access to institutional support for addressing the higher risks. This paper shows that pathways for achieving improved eco-efficiency will differ among diverse cropping systems. PMID- 23671072 TI - Nucleotide specificity in bacterial mRNA recycling. PMID- 23671073 TI - Interactive effects among ecosystem services and management practices on crop production: pollination in coffee agroforestry systems. AB - Crop productivity is improved by ecosystem services, including pollination, but this should be set in the context of trade-offs among multiple management practices. We investigated the impact of pollination services on coffee production, considering variation in fertilization, irrigation, shade cover, and environmental variables such as rainfall (which stimulates coffee flowering across all plantations), soil pH, and nitrogen availability. After accounting for management interventions, bee abundance improved coffee production (number of berries harvested). Some management interventions, such as irrigation, used once to trigger asynchronous flowering, dramatically increased bee abundance at coffee trees. Others, such as the extent and type of tree cover, revealed interacting effects on pollination and, ultimately, crop production. The effects of management interventions, notably irrigation and addition of lime, had, however, far more substantial positive effects on coffee production than tree cover. These results suggest that pollination services matter, but managing the asynchrony of flowering was a more effective tool for securing good pollination than maintaining high shade tree densities as pollinator habitat. Complex interactions across farm and landscape scales, including both management practices and environmental conditions, shape pollination outcomes. Effective production systems therefore require the integrated consideration of management practices in the context of the surrounding habitat structure. This paper points toward a more strategic use of ecosystem services in agricultural systems, where ecosystem services are shaped by the coupling of management interventions and environmental variables. PMID- 23671074 TI - Human frontal lobes are not relatively large. AB - One of the most pervasive assumptions about human brain evolution is that it involved relative enlargement of the frontal lobes. We show that this assumption is without foundation. Analysis of five independent data sets using correctly scaled measures and phylogenetic methods reveals that the size of human frontal lobes, and of specific frontal regions, is as expected relative to the size of other brain structures. Recent claims for relative enlargement of human frontal white matter volume, and for relative enlargement shared by all great apes, seem to be mistaken. Furthermore, using a recently developed method for detecting shifts in evolutionary rates, we find that the rate of change in relative frontal cortex volume along the phylogenetic branch leading to humans was unremarkable and that other branches showed significantly faster rates of change. Although absolute and proportional frontal region size increased rapidly in humans, this change was tightly correlated with corresponding size increases in other areas and whole brain size, and with decreases in frontal neuron densities. The search for the neural basis of human cognitive uniqueness should therefore focus less on the frontal lobes in isolation and more on distributed neural networks. PMID- 23671075 TI - Ultrafast real-time visualization of active site flexibility of flavoenzyme thymidylate synthase ThyX. AB - In many bacteria the flavoenzyme thymidylate synthase ThyX produces the DNA nucleotide deoxythymidine monophosphate from dUMP, using methylenetetrahydrofolate as carbon donor and NADPH as hydride donor. Because all three substrates bind in close proximity to the catalytic flavin adenine dinucleotide group, substantial flexibility of the ThyX active site has been hypothesized. Using femtosecond time-resolved fluorescence spectroscopy, we have studied the conformational heterogeneity and the conformational interconversion dynamics in real time in ThyX from the hyperthermophilic bacterium Thermotoga maritima. The dynamics of electron transfer to excited flavin adenine dinucleotide from a neighboring tyrosine residue are used as a sensitive probe of the functional dynamics of the active site. The fluorescence decay spanned a full three orders of magnitude, demonstrating a very wide range of conformations. In particular, at physiological temperatures, multiple angstrom cofactor-residue displacements occur on the picoseconds timescale. These experimental findings are supported by molecular dynamics simulations. Binding of the dUMP substrate abolishes this flexibility and stabilizes the active site in a configuration where dUMP closely interacts with the flavin cofactor and very efficiently quenches fluorescence itself. Our results indicate a dynamic selected-fit mechanism where binding of the first substrate dUMP at high temperature stabilizes the enzyme in a configuration favorable for interaction with the second substrate NADPH, and more generally have important implications for the role of active site flexibility in enzymes interacting with multiple poly-atom substrates and products. Moreover, our data provide the basis for exploring the effect of inhibitor molecules on the active site dynamics of ThyX and other multisubstrate flavoenzymes. PMID- 23671076 TI - Concordant mast cell and basophil production by individual hematopoietic blast colony-forming cells. AB - Previous studies have shown that mouse bone marrow cells can produce mast cells when stimulated in vitro by stem cell factor (SCF) and interleukin-3 (IL-3). Experiments to define the marrow cells able to generate mast cells showed that the most active subpopulations were the Kit(+) Sca1(-) progenitor cell fraction and the more ancestral Kit(+) Sca1(+) blast colony-forming cell fraction. In clonal cultures, up to 64% of blast colony-forming cells were able to generate mast cells when stimulated by SCF and IL-3, and, of these, the most active were those in the CD34(-) Flt3R(-) long-term repopulating cell fraction. Basophils, identified by the monoclonal antibody mMCP-8 to mouse mast cell serine protease 8, were also produced by 50% of blast colony-forming cells with a strong concordance in the production of both cell types by individual blast colony forming cells. Enriched populations of marrow-derived basophils were shown to generate variable numbers of mast cells after a further incubation with SCF and IL-3. The data extend the repertoire of lineage-committed cells able to be produced by multipotential hematopoietic blast colony-forming cells and show that basophils and mast cells can have common ancestral cells and that basophils can probably generate mast cells at least under defined in vitro conditions. PMID- 23671077 TI - 182Hf-182W age dating of a 26Al-poor inclusion and implications for the origin of short-lived radioisotopes in the early Solar System. AB - Refractory inclusions [calcium-aluminum-rich inclusions, (CAIs)] represent the oldest Solar System solids and provide information regarding the formation of the Sun and its protoplanetary disk. CAIs contain evidence of now extinct short-lived radioisotopes (e.g., (26)Al, (41)Ca, and (182)Hf) synthesized in one or multiple stars and added to the protosolar molecular cloud before or during its collapse. Understanding how and when short-lived radioisotopes were added to the Solar System is necessary to assess their validity as chronometers and constrain the birthplace of the Sun. Whereas most CAIs formed with the canonical abundance of (26)Al corresponding to (26)Al/(27)Al of ~5 * 10(-5), rare CAIs with fractionation and unidentified nuclear isotope effects (FUN CAIs) record nucleosynthetic isotopic heterogeneity and (26)Al/(27)Al of <5 * 10(-6), possibly reflecting their formation before canonical CAIs. Thus, FUN CAIs may provide a unique window into the earliest Solar System, including the origin of short-lived radioisotopes. However, their chronology is unknown. Using the (182)Hf-(182)W chronometer, we show that a FUN CAI recording a condensation origin from a solar gas formed coevally with canonical CAIs, but with (26)Al/(27)Al of ~3 * 10(-6). The decoupling between (182)Hf and (26)Al requires distinct stellar origins: steady-state galactic stellar nucleosynthesis for (182)Hf and late-stage contamination of the protosolar molecular cloud by a massive star(s) for (26)Al. Admixing of stellar-derived (26)Al to the protoplanetary disk occurred during the epoch of CAI formation and, therefore, the (26)Al-(26)Mg systematics of CAIs cannot be used to define their formation interval. In contrast, our results support (182)Hf homogeneity and chronological significance of the (182)Hf-(182)W clock. PMID- 23671078 TI - Mannodendrimers prevent acute lung inflammation by inhibiting neutrophil recruitment. AB - Mycobacterium tuberculosis mannose-capped lipoarabinomannan inhibits the release of proinflammatory cytokines by LPS-stimulated human dendritic cells (DCs) via targeting the C-type lectin receptor DC-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN). With the aim of mimicking the bioactive supramolecular structure of mannose-capped lipoarabinomannan, we designed and synthesized a set of poly(phosphorhydrazone) dendrimers grafted with mannose units, called mannodendrimers, that differed by size and the number and length of their (alpha1->2)-oligommanoside caps. A third-generation dendrimer bearing 48 trimannoside caps (3T) and a fourth-generation dendrimer bearing 96 dimannosides (4D) displayed the highest binding avidity for DC-SIGN. Moreover, these dendrimers inhibited proinflammatory cytokines, including TNF-alpha, production by LPS-stimulated DCs in a DC-SIGN-dependent fashion. Finally, in a model of acute lung inflammation in which mice were exposed to aerosolized LPS, per os administration of 3T mannodendrimer was found to significantly reduce neutrophil influx via targeting the DC-SIGN murine homolog SIGN-related 1. The 3T mannodendrimer therefore represents an innovative fully synthetic compound for the treatment of lung inflammatory diseases. PMID- 23671079 TI - Early hominin auditory ossicles from South Africa. AB - The middle ear ossicles are only rarely preserved in fossil hominins. Here, we report the discovery of a complete ossicular chain (malleus, incus, and stapes) of Paranthropus robustus as well as additional ear ossicles from Australopithecus africanus. The malleus in both early hominin taxa is clearly human-like in the proportions of the manubrium and corpus, whereas the incus and stapes resemble African and Asian great apes more closely. A deep phylogenetic origin is proposed for the derived malleus morphology, and this may represent one of the earliest human-like features to appear in the fossil record. The anatomical differences found in the early hominin incus and stapes, along with other aspects of the outer, middle, and inner ear, are consistent with the suggestion of different auditory capacities in these early hominin taxa compared with modern humans. PMID- 23671080 TI - Nanoscale imaging reveals laterally expanding antimicrobial pores in lipid bilayers. AB - Antimicrobial peptides are postulated to disrupt microbial phospholipid membranes. The prevailing molecular model is based on the formation of stable or transient pores although the direct observation of the fundamental processes is lacking. By combining rational peptide design with topographical (atomic force microscopy) and chemical (nanoscale secondary ion mass spectrometry) imaging on the same samples, we show that pores formed by antimicrobial peptides in supported lipid bilayers are not necessarily limited to a particular diameter, nor they are transient, but can expand laterally at the nano-to-micrometer scale to the point of complete membrane disintegration. The results offer a mechanistic basis for membrane poration as a generic physicochemical process of cooperative and continuous peptide recruitment in the available phospholipid matrix. PMID- 23671081 TI - Molecular layer perforant path-associated cells contribute to feed-forward inhibition in the adult dentate gyrus. AB - New neurons, which have been implicated in pattern separation, are continually generated in the dentate gyrus in the adult hippocampus. Using a genetically modified rabies virus, we demonstrated that molecular layer perforant pathway (MOPP) cells innervated newborn granule neurons in adult mouse brain. Stimulating the perforant pathway resulted in the activation of MOPP cells before the activation of dentate granule neurons. Moreover, activation of MOPP cells by focal uncaging of glutamate induced strong inhibition of granule cells. Together, these results indicate that MOPP cells located in the molecular layer of the dentate gyrus contribute to feed-forward inhibition of granule cells via perforant pathway activation. PMID- 23671082 TI - Integrating the HIV-1 assembly/maturation pathway. PMID- 23671083 TI - Biodegradable synthetic high-density lipoprotein nanoparticles for atherosclerosis. AB - Atherosclerosis remains one of the most common causes of death in the United States and throughout the world because of the lack of early detection. Macrophage apoptosis is a major contributor to the instability of atherosclerotic lesions. Development of an apoptosis targeted high-density lipoprotein (HDL) mimicking nanoparticle (NP) to carry contrast agents for early detection of vulnerable plaques and the initiation of preventative therapies that exploit the vascular protective effects of HDL can be attractive for atherosclerosis. Here, we report the construction of a synthetic, biodegradable HDL-NP platform for detection of vulnerable plaques by targeting the collapse of mitochondrial membrane potential that occurs during apoptosis. This HDL mimic contains a core of biodegradable poly(lactic-co-glycolic acid), cholesteryl oleate, and a phospholipid bilayer coat that is decorated with triphenylphosphonium (TPP) cations for detection of mitochondrial membrane potential collapse. The lipid layer provides the surface for adsorption of apolipoprotein (apo) A-I mimetic 4F peptide, and the core contains diagnostically active quantum dots (QDs) for optical imaging. In vitro uptake, detection of apoptosis, and cholesterol binding studies indicated promising detection ability and therapeutic potential of TPP HDL-apoA-I-QD NPs. In vitro studies indicated the potential of these NPs in reverse cholesterol transport. In vivo biodistribution and pharmacokinetics indicated favorable tissue distribution, controlled pharmacokinetic parameters, and significant triglyceride reduction for i.v.-injected TPP-HDL-apoA-I-QD NPs in rats. These HDL NPs demonstrate excellent biocompatibility, stability, nontoxic, and nonimmunogenic properties, which prove to be promising for future translation in early plaque diagnosis and might find applications to prevent vulnerable plaque progression. PMID- 23671084 TI - Calcium signaling mediates cold sensing in insect tissues. AB - The ability to rapidly respond to changes in temperature is a critical adaptation for insects and other ectotherms living in thermally variable environments. In a process called rapid cold hardening (RCH), insects significantly enhance cold tolerance following brief (i.e., minutes to hours) exposure to nonlethal chilling. Although the ecological relevance of RCH is well-established, the underlying physiological mechanisms that trigger RCH are poorly understood. RCH can be elicited in isolated tissues ex vivo, suggesting cold-sensing and downstream hardening pathways are governed by brain-independent signaling mechanisms. We previously provided preliminary evidence that calcium is involved in RCH, and here we firmly establish that calcium signaling mediates cold sensing in insect tissues. In tracheal cells of the freeze-tolerant goldenrod gall fly, Eurosta solidaginis, chilling to 0 degrees C evoked a 40% increase in intracellular calcium concentration as determined by live-cell confocal imaging. Downstream of calcium entry, RCH conditions significantly increased the activity of calcium/calmodulin-dependent protein kinase II (CaMKII) while reducing phosphorylation of the inhibitory Thr306 residue. Pharmacological inhibitors of calcium entry, calmodulin activation, and CaMKII activity all prevented ex vivo RCH in midgut and salivary gland tissues, indicating that calcium signaling is required for RCH to occur. Similar results were obtained for a freeze-intolerant species, adults of the flesh fly, Sarcophaga bullata, suggesting that calcium mediated cold sensing is a general feature of insects. Our results imply that insect tissues use calcium signaling to instantly detect decreases in temperature and trigger downstream cold-hardening mechanisms. PMID- 23671085 TI - Cyclophilin 20-3 relays a 12-oxo-phytodienoic acid signal during stress responsive regulation of cellular redox homeostasis. AB - The jasmonate family of phytohormones plays central roles in plant development and stress acclimation. However, the architecture of their signaling circuits remains largely unknown. Here we describe a jasmonate family binding protein, cyclophilin 20-3 (CYP20-3), which regulates stress-responsive cellular redox homeostasis. (+)-12-Oxo-phytodienoic acid (OPDA) binding promotes CYP20-3 to form a complex with serine acetyltransferase 1, which triggers the formation of a hetero-oligomeric cysteine synthase complex with O-acetylserine(thiol)lyase B in chloroplasts. The cysteine synthase complex formation then activates sulfur assimilation that leads to increased levels of thiol metabolites and the buildup of cellular reduction potential. The enhanced redox capacity in turn coordinates the expression of a subset of OPDA-responsive genes. Thus, we conclude that CYP20 3 is a key effector protein that links OPDA signaling to amino acid biosynthesis and cellular redox homeostasis in stress responses. PMID- 23671086 TI - Green Revolution research saved an estimated 18 to 27 million hectares from being brought into agricultural production. AB - New estimates of the impacts of germplasm improvement in the major staple crops between 1965 and 2004 on global land-cover change are presented, based on simulations carried out using a global economic model (Global Trade Analysis Project Agro-Ecological Zone), a multicommodity, multiregional computable general equilibrium model linked to a global spatially explicit database on land use. We estimate the impact of removing the gains in cereal productivity attributed to the widespread adoption of improved varieties in developing countries. Here, several different effects--higher yields, lower prices, higher land rents, and trade effects--have been incorporated in a single model of the impact of Green Revolution research (and subsequent advances in yields from crop germplasm improvement) on land-cover change. Our results generally support the Borlaug hypothesis that increases in cereal yields as a result of widespread adoption of improved crop germplasm have saved natural ecosystems from being converted to agriculture. However, this relationship is complex, and the net effect is of a much smaller magnitude than Borlaug proposed. We estimate that the total crop area in 2004 would have been between 17.9 and 26.7 million hectares larger in a world that had not benefited from crop germplasm improvement since 1965. Of these hectares, 12.0-17.7 million would have been in developing countries, displacing pastures and resulting in an estimated 2 million hectares of additional deforestation. However, the negative impacts of higher food prices on poverty and hunger under this scenario would likely have dwarfed the welfare effects of agricultural expansion. PMID- 23671087 TI - High regional climate sensitivity over continental China constrained by glacial recent changes in temperature and the hydrological cycle. AB - The East Asian monsoon is one of Earth's most significant climatic phenomena, and numerous paleoclimate archives have revealed that it exhibits variations on orbital and suborbital time scales. Quantitative constraints on the climate changes associated with these past variations are limited, yet are needed to constrain sensitivity of the region to changes in greenhouse gas levels. Here, we show central China is a region that experienced a much larger temperature change since the Last Glacial Maximum than typically simulated by climate models. We applied clumped isotope thermometry to carbonates from the central Chinese Loess Plateau to reconstruct temperature and water isotope shifts from the Last Glacial Maximum to present. We find a summertime temperature change of 6-7 degrees C that is reproduced by climate model simulations presented here. Proxy data reveal evidence for a shift to lighter isotopic composition of meteoric waters in glacial times, which is also captured by our model. Analysis of model outputs suggests that glacial cooling over continental China is significantly amplified by the influence of stationary waves, which, in turn, are enhanced by continental ice sheets. These results not only support high regional climate sensitivity in Central China but highlight the fundamental role of planetary-scale atmospheric dynamics in the sensitivity of regional climates to continental glaciation, changing greenhouse gas levels, and insolation. PMID- 23671088 TI - Distinct preplay of multiple novel spatial experiences in the rat. AB - The activity of ensembles of hippocampal place cells represents a hallmark of an animal's spatial experience. The neuronal mechanisms that enable the rapid expression of novel place cell sequences are not entirely understood. Here we report that during sleep or rest, distinct sets of hippocampal temporal sequences in the rat preplay multiple corresponding novel spatial experiences with high specificity. These findings suggest that the place cell sequence of a novel spatial experience is determined, in part, by an online selection of a subset of cellular firing sequences from a larger repertoire of preexisting temporal firing sequences in the hippocampal cellular assembly network that become rapidly bound to the novel experience. We estimate that for the given context, the recorded hippocampal network activity has the capacity to preplay an extended repertoire of at least 15 future spatial experiences of similar distinctiveness and complexity. PMID- 23671089 TI - Innovations in capture fisheries are an imperative for nutrition security in the developing world. AB - This article examines two strands of discourse on wild capture fisheries; one that focuses on resource sustainability and environmental impacts, another related to food and nutrition security and human well-being. Available data and research show that, for countries most dependent on fish to meet the nutritional requirements of their population, wild capture fisheries remain the dominant supplier. Although, contrary to popular narratives, the sustainability of these fisheries is not always and everywhere in crisis, securing their sustainability is essential and requires considerable effort across a broad spectrum of fishery systems. An impediment to achieving this is that the current research and policy discourses on environmental sustainability of fisheries and food security remain only loosely and superficially linked. Overcoming this requires adoption of a broader sustainability science paradigm to help harness synergies and negotiate tradeoffs between food security, resource conservation, and macroeconomic development goals. The way society chooses to govern fisheries is, however, an ethical choice, not just a technical one, and we recommend adding an ethical dimension to sustainability science as applied to fisheries. PMID- 23671090 TI - Specialized stem cell niche enables repetitive renewal of alligator teeth. AB - Reptiles and fish have robust regenerative powers for tooth renewal. However, extant mammals can either renew their teeth one time (diphyodont dentition) or not at all (monophyodont dentition). Humans replace their milk teeth with permanent teeth and then lose their ability for tooth renewal. Here, we study tooth renewal in a crocodilian model, the American alligator, which has well organized teeth similar to mammals but can still undergo life-long renewal. Each alligator tooth is a complex family unit composed of the functional tooth, successional tooth, and dental lamina. Using multiple mitotic labeling, we map putative stem cells to the distal enlarged bulge of the dental lamina that contains quiescent odontogenic progenitors that can be activated during physiological exfoliation or artificial extraction. Tooth cycle initiation correlates with beta-catenin activation and soluble frizzled-related protein 1 disappearance in the bulge. The dermal niche adjacent to the dermal lamina dynamically expresses neural cell adhesion molecule, tenascin-C, and other molecules. Furthermore, in development, asymmetric beta-catenin localization leads to the formation of a heterochronous and complex tooth family unit configuration. Understanding how these signaling molecules interact in tooth development in this model may help us to learn how to stimulate growth of adult teeth in mammals. PMID- 23671092 TI - Innovative grassland management systems for environmental and livelihood benefits. AB - Grasslands occupy 40% of the world's land surface (excluding Antarctica and Greenland) and support diverse groups, from traditional extensive nomadic to intense livestock-production systems. Population pressures mean that many of these grasslands are in a degraded state, particularly in less-productive areas of developing countries, affecting not only productivity but also vital environmental services such as hydrology, biodiversity, and carbon cycles; livestock condition is often poor and household incomes are at or below poverty levels. The challenge is to optimize management practices that result in "win win" outcomes for grasslands, the environment, and households. A case study is discussed from northwestern China, where it has been possible to reduce animal numbers considerably by using an energy-balance/market-based approach while improving household incomes, providing conditions within which grassland recovery is possible. This bottom-up approach was supported by informing and working with the six layers of government in China to build appropriate policies. Further policy implications are considered. Additional gains in grassland rehabilitation could be fostered through targeted environmental payment schemes. Other aspects of the livestock production system that can be modified are discussed. This work built a strategy that has implications for many other grassland areas around the world where common problems apply. PMID- 23671093 TI - Graphene field effect transistor without an energy gap. AB - Graphene is a room temperature ballistic electron conductor and also a very good thermal conductor. Thus, it has been regarded as an ideal material for postsilicon electronic applications. A major complication is that the relativistic massless electrons in pristine graphene exhibit unimpeded Klein tunneling penetration through gate potential barriers. Thus, previous efforts to realize a field effect transistor for logic applications have assumed that introduction of a band gap in graphene is a prerequisite. Unfortunately, extrinsic treatments designed to open a band gap seriously degrade device quality, yielding very low mobility and uncontrolled on/off current ratios. To solve this dilemma, we propose a gating mechanism that leads to a hundredfold enhancement in on/off transmittance ratio for normally incident electrons without any band gap engineering. Thus, our saw-shaped geometry gate potential (in place of the conventional bar-shaped geometry) leads to switching to an off state while retaining the ultrahigh electron mobility in the on state. In particular, we report that an on/off transmittance ratio of 130 is achievable for a sawtooth gate with a gate length of 80 nm. Our switching mechanism demonstrates that intrinsic graphene can be used in designing logic devices without serious alteration of the conventional field effect transistor architecture. This suggests a new variable for the optimization of the graphene-based device- geometry of the gate electrode. PMID- 23671091 TI - Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. AB - Cancer cell growth requires fatty acids to replicate cellular membranes. The kinase Akt is known to up-regulate fatty acid synthesis and desaturation, which is carried out by the oxygen-consuming enzyme stearoyl-CoA desaturase (SCD)1. We used (13)C tracers and lipidomics to probe fatty acid metabolism, including desaturation, as a function of oncogene expression and oxygen availability. During hypoxia, flux from glucose to acetyl-CoA decreases, and the fractional contribution of glutamine to fatty acid synthesis increases. In addition, we find that hypoxic cells bypass de novo lipogenesis, and thus, both the need for acetyl CoA and the oxygen-dependent SCD1-reaction, by scavenging serum fatty acids. The preferred substrates for scavenging are phospholipids with one fatty acid tail (lysophospholipids). Hypoxic reprogramming of de novo lipogenesis can be reproduced in normoxic cells by Ras activation. This renders Ras-driven cells, both in culture and in allografts, resistant to SCD1 inhibition. Thus, a mechanism by which oncogenic Ras confers metabolic robustness is through lipid scavenging. PMID- 23671094 TI - Millennial-scale isotope records from a wide-ranging predator show evidence of recent human impact to oceanic food webs. AB - Human exploitation of marine ecosystems is more recent in oceanic than near shore regions, yet our understanding of human impacts on oceanic food webs is comparatively poor. Few records of species that live beyond the continental shelves date back more than 60 y, and the sheer size of oceanic regions makes their food webs difficult to study, even in modern times. Here, we use stable carbon and nitrogen isotopes to study the foraging history of a generalist, oceanic predator, the Hawaiian petrel (Pterodroma sandwichensis), which ranges broadly in the Pacific from the equator to near the Aleutian Islands. Our isotope records from modern and ancient, radiocarbon-dated bones provide evidence of over 3,000 y of dietary stasis followed by a decline of ca. 1.80/00 in delta(15)N over the past 100 y. Fishery-induced trophic decline is the most likely explanation for this sudden shift, which occurs in genetically distinct populations with disparate foraging locations. Our isotope records also show that coincident with the apparent decline in trophic level, foraging segregation among petrel populations decreased markedly. Because variation in the diet of generalist predators can reflect changing availability of their prey, a foraging shift in wide-ranging Hawaiian petrel populations suggests a relatively rapid change in the composition of oceanic food webs in the Northeast Pacific. Understanding and mitigating widespread shifts in prey availability may be a critical step in the conservation of endangered marine predators such as the Hawaiian petrel. PMID- 23671095 TI - Sinuous rivers. PMID- 23671096 TI - New technologies reduce greenhouse gas emissions from nitrogenous fertilizer in China. AB - Synthetic nitrogen (N) fertilizer has played a key role in enhancing food production and keeping half of the world's population adequately fed. However, decades of N fertilizer overuse in many parts of the world have contributed to soil, water, and air pollution; reducing excessive N losses and emissions is a central environmental challenge in the 21st century. China's participation is essential to global efforts in reducing N-related greenhouse gas (GHG) emissions because China is the largest producer and consumer of fertilizer N. To evaluate the impact of China's use of N fertilizer, we quantify the carbon footprint of China's N fertilizer production and consumption chain using life cycle analysis. For every ton of N fertilizer manufactured and used, 13.5 tons of CO2-equivalent (eq) (t CO2-eq) is emitted, compared with 9.7 t CO2-eq in Europe. Emissions in China tripled from 1980 [131 terrogram (Tg) of CO2-eq (Tg CO2-eq)] to 2010 (452 Tg CO2-eq). N fertilizer-related emissions constitute about 7% of GHG emissions from the entire Chinese economy and exceed soil carbon gain resulting from N fertilizer use by several-fold. We identified potential emission reductions by comparing prevailing technologies and management practices in China with more advanced options worldwide. Mitigation opportunities include improving methane recovery during coal mining, enhancing energy efficiency in fertilizer manufacture, and minimizing N overuse in field-level crop production. We find that use of advanced technologies could cut N fertilizer-related emissions by 20 63%, amounting to 102-357 Tg CO2-eq annually. Such reduction would decrease China's total GHG emissions by 2-6%, which is significant on a global scale. PMID- 23671097 TI - Zoonosis emergence linked to agricultural intensification and environmental change. AB - A systematic review was conducted by a multidisciplinary team to analyze qualitatively best available scientific evidence on the effect of agricultural intensification and environmental changes on the risk of zoonoses for which there are epidemiological interactions between wildlife and livestock. The study found several examples in which agricultural intensification and/or environmental change were associated with an increased risk of zoonotic disease emergence, driven by the impact of an expanding human population and changing human behavior on the environment. We conclude that the rate of future zoonotic disease emergence or reemergence will be closely linked to the evolution of the agriculture-environment nexus. However, available research inadequately addresses the complexity and interrelatedness of environmental, biological, economic, and social dimensions of zoonotic pathogen emergence, which significantly limits our ability to predict, prevent, and respond to zoonotic disease emergence. PMID- 23671098 TI - Dependence of hydropower energy generation on forests in the Amazon Basin at local and regional scales. AB - Tropical rainforest regions have large hydropower generation potential that figures prominently in many nations' energy growth strategies. Feasibility studies of hydropower plants typically ignore the effect of future deforestation or assume that deforestation will have a positive effect on river discharge and energy generation resulting from declines in evapotranspiration (ET) associated with forest conversion. Forest loss can also reduce river discharge, however, by inhibiting rainfall. We used land use, hydrological, and climate models to examine the local "direct" effects (through changes in ET within the watershed) and the potential regional "indirect" effects (through changes in rainfall) of deforestation on river discharge and energy generation potential for the Belo Monte energy complex, one of the world's largest hydropower plants that is currently under construction on the Xingu River in the eastern Amazon. In the absence of indirect effects of deforestation, simulated deforestation of 20% and 40% within the Xingu River basin increased discharge by 4-8% and 10-12%, with similar increases in energy generation. When indirect effects were considered, deforestation of the Amazon region inhibited rainfall within the Xingu Basin, counterbalancing declines in ET and decreasing discharge by 6-36%. Under business as-usual projections of forest loss for 2050 (40%), simulated power generation declined to only 25% of maximum plant output and 60% of the industry's own projections. Like other energy sources, hydropower plants present large social and environmental costs. Their reliability as energy sources, however, must take into account their dependence on forests. PMID- 23671099 TI - Perineuronal nets protect fast-spiking interneurons against oxidative stress. AB - A hallmark of schizophrenia pathophysiology is the dysfunction of cortical inhibitory GABA neurons expressing parvalbumin, which are essential for coordinating neuronal synchrony during various sensory and cognitive tasks. The high metabolic requirements of these fast-spiking cells may render them susceptible to redox dysregulation and oxidative stress. Using mice carrying a genetic redox imbalance, we demonstrate that extracellular perineuronal nets, which constitute a specialized polyanionic matrix enwrapping most of these interneurons as they mature, play a critical role in the protection against oxidative stress. These nets limit the effect of genetically impaired antioxidant systems and/or excessive reactive oxygen species produced by severe environmental insults. We observe an inverse relationship between the robustness of the perineuronal nets around parvalbumin cells and the degree of intracellular oxidative stress they display. Enzymatic degradation of the perineuronal nets renders mature parvalbumin cells and fast rhythmic neuronal synchrony more susceptible to oxidative stress. In parallel, parvalbumin cells enwrapped with mature perineuronal nets are better protected than immature parvalbumin cells surrounded by less-condensed perineuronal nets. Although the perineuronal nets act as a protective shield, they are also themselves sensitive to excess oxidative stress. The protection might therefore reflect a balance between the oxidative burden on perineuronal net degradation and the capacity of the system to maintain the nets. Abnormal perineuronal nets, as observed in the postmortem patient brain, may thus underlie the vulnerability and functional impairment of pivotal inhibitory circuits in schizophrenia. PMID- 23671101 TI - Palmitoylation-dependent CDKL5-PSD-95 interaction regulates synaptic targeting of CDKL5 and dendritic spine development. AB - The X-linked gene cyclin-dependent kinase-like 5 (CDKL5) is mutated in severe neurodevelopmental disorders, including some forms of atypical Rett syndrome, but the function and regulation of CDKL5 protein in neurons remain to be elucidated. Here, we show that CDKL5 binds to the scaffolding protein postsynaptic density (PSD)-95, and that this binding promotes the targeting of CDKL5 to excitatory synapses. Interestingly, this binding is not constitutive, but governed by palmitate cycling on PSD-95. Furthermore, pathogenic mutations that truncate the C-terminal tail of CDKL5 diminish its binding to PSD-95 and synaptic accumulation. Importantly, down-regulation of CDKL5 by RNA interference (RNAi) or interference with the CDKL5-PSD-95 interaction inhibits dendritic spine formation and growth. These results demonstrate a critical role of the palmitoylation dependent CDKL5-PSD-95 interaction in localizing CDKL5 to synapses for normal spine development and suggest that disruption of this interaction by pathogenic mutations may be implicated in the pathogenesis of CDKL5-related disorders. PMID- 23671102 TI - Significance of activity peaks in fruit flies, Drosophila melanogaster, under seminatural conditions. AB - Studies on circadian entrainment have traditionally been performed under controlled laboratory conditions. Although these studies have served the purpose of providing a broad framework for our understanding of regulation of rhythmic behaviors under cyclic conditions, they do not reveal how organisms keep time in nature. Although a few recent studies have attempted to address this, it is not yet clear which environmental factors regulate rhythmic behaviors in nature and how. Here, we report the results of our studies aimed at examining (i) whether and how changes in natural light affect activity/rest rhythm and (ii) what the functional significance of this rhythmic behavior might be. We found that wild type strains of fruit flies, Drosophila melanogaster, display morning (M), afternoon (A), and evening (E) peaks of activity under seminatural conditions (SN), whereas under constant darkness in otherwise SN, they exhibited M and E peaks, and under constant light in SN, only the E peak occurred. Unlike the A peak, which requires exposure to bright light in the afternoon, light information is dispensable for the M and E peaks. Visual examination of behaviors suggests that the M peak is associated with courtship-related locomotor activity and the A peak is due to an artifact of the experimental protocol and largely circadian clock independent. PMID- 23671100 TI - Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex. AB - Pathogenic retroviruses have evolved multiple means for evading host restriction factors such as apolipoprotein B editing complex (APOBEC3) proteins. Here, we show that murine leukemia virus (MLV) has a unique means of counteracting APOBEC3 and other cytosolic sensors of viral nucleic acid. Using virus isolated from infected WT and APOBEC3 KO mice, we demonstrate that the MLV glycosylated Gag protein (glyco-Gag) enhances viral core stability. Moreover, in vitro endogenous reverse transcription reactions of the glyco-Gag mutant virus were substantially inhibited compared with WT virus, but only in the presence of APOBEC3. Thus, glyco-Gag rendered the reverse transcription complex in the viral core resistant to APOBEC3. Glyco-Gag in the virion also rendered MLV resistant to other cytosolic sensors of viral reverse transcription products in newly infected cells. Strikingly, glyco-Gag mutant virus reverted to glyco-Gag-containing virus only in WT and not APOBEC3 KO mice, indicating that counteracting APOBEC3 is the major function of glyco-Gag. Thus, in contrast to the HIV viral infectivity factor protein, which prevents APOBEC3 packaging in the virion, the MLV glyco-Gag protein uses a unique mechanism to counteract the antiviral action of APOBEC3 in vivo--namely, protecting the reverse transcription complex in viral cores from APOBEC3. These data suggest that capsid integrity may play a critical role in virus resistance to intrinsic cellular antiviral resistance factors that act at the early stages of infection. PMID- 23671103 TI - Trp replacements for tightly interacting Gly-Gly pairs in LacY stabilize an outward-facing conformation. AB - Trp replacements for conserved Gly-Gly pairs between the N- and C-terminal six helix bundles on the periplasmic side of lactose permease (LacY) cause complete loss of transport activity with little or no effect on sugar binding. Moreover, the detergent-solubilized mutants exhibit much greater thermal stability than WT LacY. A Cys replacement for Asn245, which is inaccessible/unreactive in WT LacY, alkylates readily in the Gly->Trp mutants, indicating that the periplasmic cavity is patent. Stopped-flow kinetic measurements of sugar binding with the Gly->Trp mutants in detergent reveal linear dependence of binding rates on sugar concentration, as observed with WT or the C154G mutant of LacY, and are compatible with free access to the sugar-binding site in the middle of the molecule. Remarkably, after reconstitution of the Gly->Trp mutants into proteoliposomes, the concentration dependence of sugar-binding rates increases sharply with even faster rates than measured in detergent. Such behavior is strikingly different from that observed for reconstituted WT LacY, in which sugar binding rates are independent of sugar concentration because opening of the periplasmic cavity is limiting for sugar binding. The observations clearly indicate that Gly->Trp replacements, which introduce bulky residues into tight Gly-Gly interdomain interactions on the periplasmic side of LacY, prevent closure of the periplasmic cavity and, as a result, shift the distribution of LacY toward an outward-open conformation. PMID- 23671104 TI - Effect of active water movement on energy and nutrient acquisition in coral reef associated benthic organisms. PMID- 23671105 TI - Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. AB - Obesity and type 2 diabetes are characterized by altered gut microbiota, inflammation, and gut barrier disruption. Microbial composition and the mechanisms of interaction with the host that affect gut barrier function during obesity and type 2 diabetes have not been elucidated. We recently isolated Akkermansia muciniphila, which is a mucin-degrading bacterium that resides in the mucus layer. The presence of this bacterium inversely correlates with body weight in rodents and humans. However, the precise physiological roles played by this bacterium during obesity and metabolic disorders are unknown. This study demonstrated that the abundance of A. muciniphila decreased in obese and type 2 diabetic mice. We also observed that prebiotic feeding normalized A. muciniphila abundance, which correlated with an improved metabolic profile. In addition, we demonstrated that A. muciniphila treatment reversed high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance. A. muciniphila administration increased the intestinal levels of endocannabinoids that control inflammation, the gut barrier, and gut peptide secretion. Finally, we demonstrated that all these effects required viable A. muciniphila because treatment with heat-killed cells did not improve the metabolic profile or the mucus layer thickness. In summary, this study provides substantial insight into the intricate mechanisms of bacterial (i.e., A. muciniphila) regulation of the cross-talk between the host and gut microbiota. These results also provide a rationale for the development of a treatment that uses this human mucus colonizer for the prevention or treatment of obesity and its associated metabolic disorders. PMID- 23671106 TI - Music-color associations are mediated by emotion. AB - Experimental evidence demonstrates robust cross-modal matches between music and colors that are mediated by emotional associations. US and Mexican participants chose colors that were most/least consistent with 18 selections of classical orchestral music by Bach, Mozart, and Brahms. In both cultures, faster music in the major mode produced color choices that were more saturated, lighter, and yellower whereas slower, minor music produced the opposite pattern (choices that were desaturated, darker, and bluer). There were strong correlations (0.89 < r < 0.99) between the emotional associations of the music and those of the colors chosen to go with the music, supporting an emotional mediation hypothesis in both cultures. Additional experiments showed similarly robust cross-modal matches from emotionally expressive faces to colors and from music to emotionally expressive faces. These results provide further support that music-to-color associations are mediated by common emotional associations. PMID- 23671107 TI - Role of the ubiquitin ligase E6AP/UBE3A in controlling levels of the synaptic protein Arc. AB - Inactivation of the ubiquitin ligase E6 associated protein (E6AP) encoded by the UBE3A gene has been associated with development of the Angelman syndrome. Recently, it was reported that in mice, loss of E6AP expression results in increased levels of the synaptic protein Arc and a concomitant impaired synaptic function, providing an explanation for some phenotypic features of Angelman syndrome patients. Accordingly, E6AP has been shown to negatively regulate activity-regulated cytoskeleton-associated protein (Arc) and it has been suggested that E6AP targets Arc for ubiquitination and degradation. In our study, we provide evidence that Arc is not a direct substrate for E6AP and binds only weakly to E6AP, if at all. Furthermore, we show that down-regulation of E6AP expression stimulates estradiol-induced transcription of the Arc gene. Thus, we propose that Arc protein levels are controlled by E6AP at the transcriptional rather than at the posttranslational level. PMID- 23671108 TI - Dominant suppression of inflammation by glycan-hydrolyzed IgG. AB - A unique anti-inflammatory property of IgG, independent of antigen specificity, is described. IgG with modification of the heavy-chain glycan on asparagine 297 by the streptococcal enzyme endo-beta-N-acetylglucosaminidase (EndoS) induced a dominant suppression of immune complex (IC)-mediated inflammation, such as arthritis, through destabilization of local ICs by fragment crystallizable fragment crystallizable (Fc-Fc) interactions. Small amounts (250 ug) of EndoS hydrolyzed IgG were sufficient to inhibit arthritis in mice and most effective during the formation of ICs in the target tissue. The presence of EndoS hydrolyzed IgG disrupted larger IC lattice formation both in vitro and in vivo, as visualized with anti-C3b staining. Neither complement binding in vitro nor antigen-antibody binding per se was affected. PMID- 23671111 TI - Coevolution of farming and private property during the early Holocene. AB - The advent of farming around 12 millennia ago was a cultural as well as technological revolution, requiring a new system of property rights. Among mobile hunter-gatherers during the late Pleistocene, food was almost certainly widely shared as it was acquired. If a harvested crop or the meat of a domesticated animal were to have been distributed to other group members, a late Pleistocene would-be farmer would have had little incentive to engage in the required investments in clearing, cultivation, animal tending, and storage. However, the new property rights that farming required--secure individual claims to the products of one's labor--were infeasible because most of the mobile and dispersed resources of a forager economy could not cost-effectively be delimited and defended. The resulting chicken-and-egg puzzle might be resolved if farming had been much more productive than foraging, but initially it was not. Our model and simulations explain how, despite being an unlikely event, farming and a new system of farming-friendly property rights nonetheless jointly emerged when they did. This Holocene revolution was not sparked by a superior technology. It occurred because possession of the wealth of farmers--crops, dwellings, and animals--could be unambiguously demarcated and defended. This facilitated the spread of new property rights that were advantageous to the groups adopting them. Our results thus challenge unicausal models of historical dynamics driven by advances in technology, population pressure, or other exogenous changes. Our approach may be applied to other technological and institutional revolutions such as the 18th- and 19th-century industrial revolution and the information revolution today. PMID- 23671110 TI - Dynamic CREB family activity drives segmentation and posterior polarity specification in mammalian somitogenesis. AB - The segmented body plan of vertebrates is prefigured by reiterated embryonic mesodermal structures called somites. In the mouse embryo, timely somite formation from the presomitic mesoderm (PSM) is controlled by the "segmentation clock," a molecular oscillator that triggers progressive waves of Notch activity throughout the PSM. Notch clock activity is suppressed in the posterior PSM by FGF signaling until it crosses a determination front at which its net activity is sufficiently high to effect segmentation. Here, Notch and Wnt signaling directs somite anterior/posterior (A/P) polarity specification and boundary formation via regulation of the segmentation effector gene Mesoderm posterior 2. How Notch and Wnt signaling becomes coordinated at this front is incompletely defined. Here we show that the activity of the cAMP responsive element binding protein (CREB) family of transcription factors exhibits Wnt3a-dependent oscillatory behavior near the determination front and is in unison with Notch activity. Inhibition of CREB family in the mesoderm causes defects in somite segmentation and a loss in somite posterior polarity leading to fusions of vertebrae and ribs. Among the CREB family downstream genes, several are known to be regulated by Wnt3a. Of those, we show that the CREB family occupies a conserved binding site in the promoter region of Delta-like 1, encoding a Notch ligand, in the anterior PSM as a mechanism to specify posterior identity of somites. Together, these data support that the CREB family acts at the determination front to modulate Wnt signaling and strengthen Notch signaling as a means to orchestrate cells for somite segmentation and anterior/posterior patterning. PMID- 23671109 TI - Molecular evolution of peptidergic signaling systems in bilaterians. AB - Peptide hormones and their receptors are widespread in metazoans, but the knowledge we have of their evolutionary relationships remains unclear. Recently, accumulating genome sequences from many different species have offered the opportunity to reassess the relationships between protostomian and deuterostomian peptidergic systems (PSs). Here we used sequences of all human rhodopsin and secretin-type G protein-coupled receptors as bait to retrieve potential homologs in the genomes of 15 bilaterian species, including nonchordate deuterostomian and lophotrochozoan species. Our phylogenetic analysis of these receptors revealed 29 well-supported subtrees containing mixed sets of protostomian and deuterostomian sequences. This indicated that many vertebrate and arthropod PSs that were previously thought to be phyla specific are in fact of bilaterian origin. By screening sequence databases for potential peptides, we then reconstructed entire bilaterian peptide families and showed that protostomian and deuterostomian peptides that are ligands of orthologous receptors displayed some similarity at the level of their primary sequence, suggesting an ancient coevolution between peptide and receptor genes. In addition to shedding light on the function of human G protein-coupled receptor PSs, this work presents orthology markers to study ancestral neuron types that were probably present in the last common bilaterian ancestor. PMID- 23671112 TI - Mass spectrometry-based metabolomics of single yeast cells. AB - Single-cell level measurements are necessary to characterize the intrinsic biological variability in a population of cells. In this study, we demonstrate that, with the microarrays for mass spectrometry platform, we are able to observe this variability. We monitor environmentally (2-deoxy-D-glucose) and genetically (DeltaPFK2) perturbed Saccharomyces cerevisiae cells at the single-cell, few cell, and population levels. Correlation plots between metabolites from the glycolytic pathway, as well as with the observed ATP/ADP ratio as a measure of cellular energy charge, give biological insight that is not accessible from population-level metabolomic data. PMID- 23671114 TI - Multiple actions of phi-LITX-Lw1a on ryanodine receptors reveal a functional link between scorpion DDH and ICK toxins. AB - We recently reported the isolation of a scorpion toxin named U1-liotoxin-Lw1a (U1 LITX-Lw1a) that adopts an unusual 3D fold termed the disulfide-directed hairpin (DDH) motif, which is the proposed evolutionary structural precursor of the three disulfide-containing inhibitor cystine knot (ICK) motif found widely in animals and plants. Here we reveal that U1-LITX-Lw1a targets and activates the mammalian ryanodine receptor intracellular calcium release channel (RyR) with high (fM) potency and provides a functional link between DDH and ICK scorpion toxins. Moreover, U1-LITX-Lw1a, now described as phi-liotoxin-Lw1a (phi-LITX-Lw1a), has a similar mode of action on RyRs as scorpion calcines, although with significantly greater potency, inducing full channel openings at lower (fM) toxin concentrations whereas at higher pM concentrations increasing the frequency and duration of channel openings to a submaximal state. In addition, we show that the C-terminal residue of phi-LITX-Lw1a is crucial for the increase in full receptor openings but not for the increase in receptor subconductance opening, thereby supporting the two-binding-site hypothesis of scorpion toxins on RyRs. phi-LITX Lw1a has potential both as a pharmacological tool and as a lead molecule for the treatment of human diseases that involve RyRs, such as malignant hyperthermia and polymorphic ventricular tachycardia. PMID- 23671115 TI - Huntington disease skeletal muscle is hyperexcitable owing to chloride and potassium channel dysfunction. AB - Huntington disease is a progressive and fatal genetic disorder with debilitating motor and cognitive defects. Chorea, rigidity, dystonia, and muscle weakness are characteristic motor defects of the disease that are commonly attributed to central neurodegeneration. However, no previous study has examined the membrane properties that control contraction in Huntington disease muscle. We show primary defects in ex vivo adult skeletal muscle from the R6/2 transgenic mouse model of Huntington disease. Action potentials in diseased fibers are more easily triggered and prolonged than in fibers from WT littermates. Furthermore, some action potentials in the diseased fibers self-trigger. These defects occur because of decreases in the resting chloride and potassium conductances. Consistent with this, the expression of the muscle chloride channel, ClC-1, in Huntington disease muscle was compromised by improper splicing and a corresponding reduction in total Clcn1 (gene for ClC-1) mRNA. Additionally, the total Kcnj2 (gene for the Kir2.1 potassium channel) mRNA was reduced in disease muscle. The resulting muscle hyperexcitability causes involuntary and prolonged contractions that may contribute to the chorea, rigidity, and dystonia that characterize Huntington disease. PMID- 23671116 TI - Systematic identification of conserved bacterial c-di-AMP receptor proteins. AB - Nucleotide signaling molecules are important messengers in key pathways that allow cellular responses to changing environments. Canonical secondary signaling molecules act through specific receptor proteins by direct binding to alter their activity. Cyclic diadenosine monophosphate (c-di-AMP) is an essential signaling molecule in bacteria that has only recently been discovered. Here we report on the identification of four Staphylococcus aureus c-di-AMP receptor proteins that are also widely distributed among other bacteria. Using an affinity pull-down assay we identified the potassium transporter-gating component KtrA as a c-di-AMP receptor protein, and it was further shown that this protein, together with c-di AMP, enables S. aureus to grow in low potassium conditions. We defined the c-di AMP binding activity within KtrA to the RCK_C (regulator of conductance of K(+)) domain. This domain is also found in a second S. aureus protein, a predicted cation/proton antiporter, CpaA, which as we show here also directly binds c-di AMP. Because RCK_C domains are found in proteinaceous channels, transporters, and antiporters from all kingdoms of life, these findings have broad implications for the regulation of different pathways through nucleotide-dependent signaling. Using a genome-wide nucleotide protein interaction screen we further identified the histidine kinase protein KdpD that in many bacteria is also involved in the regulation of potassium transport and a PII-like signal transduction protein, which we renamed PstA, as c-di-AMP binding proteins. With the identification of these widely distributed c-di-AMP receptor proteins we link the c-di-AMP signaling network to a central metabolic process in bacteria. PMID- 23671117 TI - Ribonucleolytic resection is required for repair of strand displaced nonhomologous end-joining intermediates. AB - Nonhomologous end-joining (NHEJ) pathways repair DNA double-strand breaks (DSBs) in eukaryotes and many prokaryotes, although it is not reported to operate in the third domain of life, archaea. Here, we describe a complete NHEJ complex, consisting of DNA ligase (Lig), polymerase (Pol), phosphoesterase (PE), and Ku from a mesophillic archaeon, Methanocella paludicola (Mpa). Mpa Lig has limited DNA nick-sealing activity but is efficient in ligating nicks containing a 3' ribonucleotide. Mpa Pol preferentially incorporates nucleoside triphosphates onto a DNA primer strand, filling DNA gaps in annealed breaks. Mpa PE sequentially removes 3' phosphates and ribonucleotides from primer strands, leaving a ligatable terminal 3' monoribonucleotide. These proteins, together with the DNA end-binding protein Ku, form a functional NHEJ break-repair apparatus that is highly homologous to the bacterial complex. Although the major roles of Pol and Lig in break repair have been reported, PE's function in NHEJ has remained obscure. We establish that PE is required for ribonucleolytic resection of RNA intermediates at annealed DSBs. Polymerase-catalyzed strand-displacement synthesis on DNA gaps can result in the formation of nonligatable NHEJ intermediates. The function of PE in NHEJ repair is to detect and remove inappropriately incorporated ribonucleotides or phosphates from 3' ends of annealed DSBs to configure the termini for ligation. Thus, PE prevents the accumulation of abortive genotoxic DNA intermediates arising from strand displacement synthesis that otherwise would be refractory to repair. PMID- 23671118 TI - Nuclease activity of Saccharomyces cerevisiae Dna2 inhibits its potent DNA helicase activity. AB - Dna2 is a nuclease-helicase involved in several key pathways of eukaryotic DNA metabolism. The potent nuclease activity of Saccharomyces cerevisiae Dna2 was reported to be required for all its in vivo functions tested to date. In contrast, its helicase activity was shown to be weak, and its inactivation affected only a subset of Dna2 functions. We describe here a complex interplay of the two enzymatic activities. We show that the nuclease of Dna2 inhibits its helicase by cleaving 5' flaps that are required by the helicase domain for loading onto its substrate. Mutational inactivation of Dna2 nuclease unleashes unexpectedly vigorous DNA unwinding activity, comparable with that of the most potent eukaryotic helicases. Thus, the ssDNA-specific nuclease activity of Dna2 limits and controls the enzyme's capacity to unwind dsDNA. We postulate that regulation of this interplay could modulate the biochemical properties of Dna2 and thus license it to carry out its distinct cellular functions. PMID- 23671119 TI - Essential role for Cdk2 inhibitory phosphorylation during replication stress revealed by a human Cdk2 knockin mutation. AB - Cyclin-dependent kinases (Cdks) coordinate cell division, and their activities are tightly controlled. Phosphorylation of threonine 14 (T14) and tyrosine 15 (Y15) inhibits Cdks and regulates their activities in numerous physiologic contexts. Although the roles of Cdk1 inhibitory phosphorylation during mitosis are well described, studies of Cdk2 inhibitory phosphorylation during S phrase have largely been indirect. To specifically study the functions of Cdk2 inhibitory phosphorylation, we used gene targeting to make an endogenous Cdk2 knockin allele in human cells, termed Cdk2AF, which prevents Cdk2 T14 and Y15 phosphorylation. Cdk2AF caused premature S-phase entry, rapid cyclin E degradation, abnormal DNA replication, and genome instability. Cdk2AF cells also exhibited strikingly abnormal responses to replication stress, accumulated irreparable DNA damage, and permanently exited the cell cycle after transient exposure to S-phase inhibitors. Our results reveal the specific and essential roles of Cdk2 inhibitory phosphorylation in the successful execution of the replication stress checkpoint response and in maintaining genome integrity. PMID- 23671120 TI - PRMT5 modulates the metabolic response to fasting signals. AB - Under fasting conditions, increases in circulating glucagon maintain glucose balance by promoting hepatic gluconeogenesis. Triggering of the cAMP pathway stimulates gluconeogenic gene expression through the PKA-mediated phosphorylation of the cAMP response element binding (CREB) protein and via the dephosphorylation of the latent cytoplasmic CREB regulated transcriptional coactivator 2 (CRTC2). CREB and CRTC2 activities are increased in insulin resistance, in which they promote hyperglycemia because of constitutive induction of the gluconeogenic program. The extent to which CREB and CRTC2 are coordinately up-regulated in response to glucagon, however, remains unclear. Here we show that, following its activation, CRTC2 enhances CREB phosphorylation through an association with the protein arginine methyltransferase 5 (PRMT5). In turn, PRMT5 was found to stimulate CREB phosphorylation via increases in histone H3 Arg2 methylation that enhanced chromatin accessibility at gluconeogenic promoters. Because depletion of PRMT5 lowers hepatic glucose production and gluconeogenic gene expression, these results demonstrate how a chromatin-modifying enzyme regulates a metabolic program through epigenetic changes that impact the phosphorylation of a transcription factor in response to hormonal stimuli. PMID- 23671121 TI - Functional ecology of an Antarctic Dry Valley. AB - The McMurdo Dry Valleys are the largest ice-free region in Antarctica and are critically at risk from climate change. The terrestrial landscape is dominated by oligotrophic mineral soils and extensive exposed rocky surfaces where biota are largely restricted to microbial communities, although their ability to perform the majority of geobiological processes has remained largely uncharacterized. Here, we identified functional traits that drive microbial survival and community assembly, using a metagenomic approach with GeoChip-based functional gene arrays to establish metabolic capabilities in communities inhabiting soil and rock surface niches in McKelvey Valley. Major pathways in primary metabolism were identified, indicating significant plasticity in autotrophic, heterotrophic, and diazotrophic strategies supporting microbial communities. This represents a major advance beyond biodiversity surveys in that we have now identified how putative functional ecology drives microbial community assembly. Significant differences were apparent between open soil, hypolithic, chasmoendolithic, and cryptoendolithic communities. A suite of previously unappreciated Antarctic microbial stress response pathways, thermal, osmotic, and nutrient limitation responses were identified and related to environmental stressors, offering tangible clues to the mechanisms behind the enduring success of microorganisms in this seemingly inhospitable terrain. Rocky substrates exposed to larger fluctuations in environmental stress supported greater functional diversity in stress-response pathways than soils. Soils comprised a unique reservoir of genes involved in transformation of organic hydrocarbons and lignin-like degradative pathways. This has major implications for the evolutionary origin of the organisms, turnover of recalcitrant substrates in Antarctic soils, and predicting future responses to anthropogenic pollution. PMID- 23671122 TI - Transformation of polarized epithelial cells by apical mistrafficking of epiregulin. AB - Establishment and maintenance of apico-basolateral trafficking pathways are critical to epithelial homeostasis. Loss of polarity and trafficking fidelity are thought to occur as a consequence of transformation; however, here we report that selective mistrafficking of the epidermal growth factor receptor (EGFR) ligand epiregulin (EREG) from the basolateral to the apical cell surface drives transformation. Normally, EREG is preferentially delivered to the basolateral surface of polarized Madin-Darby canine kidney cells. EREG basolateral trafficking is regulated by a conserved tyrosine-based basolateral sorting motif in its cytoplasmic domain (YXXPhi: Y(156)ERV). Both Y156 and V159 are required for basolateral sorting of EREG, because Y156A and V159G substitutions redirect EREG to the apical cell surface. We also show that basolateral sorting of EREG is adaptor protein 1B-independent. Apical mistrafficking of EREG has a distinctive phenotype. In contrast to transient EGFR tyrosine phosphorylation after basolateral EREG stimulation, apical EREG leads to prolonged EGFR tyrosine phosphorylation, which may be related, at least in part, to a lack of negative regulatory Y1045 phosphorylation and subsequent ubiquitylation. Notably, Madin Darby canine kidney cells stably expressing apically mistrafficked EREG form significantly larger, hyperproliferative, poorly differentiated, and locally invasive tumors in nude mice compared with WT EREG-expressing cells. PMID- 23671123 TI - Agricultural innovation to protect the environment. PMID- 23671124 TI - The grasshopper: a novel model for assessing vertebrate brain uptake. AB - The aim of the present study was to develop a blood-brain barrier (BBB) permeability model that is applicable in the drug discovery phase. The BBB ensures proper neural function, but it restricts many drugs from entering the brain, and this complicates the development of new drugs against central nervous system diseases. Many in vitro models have been developed to predict BBB permeability, but the permeability characteristics of the human BBB are notoriously complex and hard to predict. Consequently, one single suitable BBB permeability screening model, which is generally applicable in the early drug discovery phase, does not yet exist. A new refined ex vivo insect-based BBB screening model that uses an intact, viable whole brain under controlled in vitro like exposure conditions is presented. This model uses intact brains from desert locusts, which are placed in a well containing the compound solubilized in an insect buffer. After a limited time, the brain is removed and the compound concentration in the brain is measured by conventional liquid chromatography-mass spectrometry. The data presented here include 25 known drugs, and the data show that the ex vivo insect model can be used to measure the brain uptake over the hemolymph-brain barrier of drugs and that the brain uptake shows linear correlation with in situ perfusion data obtained in vertebrates. Moreover, this study shows that the insect ex vivo model is able to identify P-glycoprotein (Pgp) substrates, and the model allows differentiation between low-permeability compounds and compounds that are Pgp substrates. PMID- 23671125 TI - Systemic sclerosis patients with and without pulmonary arterial hypertension: a nailfold capillaroscopy study. AB - OBJECTIVE: Pulmonary arterial hypertension (PAH) is a complication of SSc due to increased vascular resistance, and abnormal vascularity is a well-known feature of the disease as shown by nailfold videocapillaroscopy (NVC). This study investigated for specific NVC changes in SSc patients with and without PAH to assess any useful difference. METHODS: Twenty-four SSc patients, 12 with PAH and 12 without, entered the study. Evidence of PAH was defined as increased systolic pulmonary artery pressure (PAP) (>=35 mmHg), indirectly assessed by echocardiography and confirmed by right heart catheterization (mPAP > 25 mmHg). NVC was performed, and a semi-quantitative rating scale, a rating system for avascular areas and a specific NVC pattern evaluation, namely early, active and late, were used. RESULTS: An NVC score >1 was more frequently found in patients with PAH than those without, 11 cases (92%) vs 5 cases (42%) (P = 0.03); an avascular areas grade >1 was present in 10 (83%) and 2 (17%) cases, respectively (P = 0.003); and a more severe NC pattern (active/late) was described in 11 (92%) and 5 (42%) patients, respectively (P = 0.03). When we compared the mPAP with NVC parameters, we found significant correlations between mPAP values and the NVC score (P < 0.005) and with the avascular areas score (P < 0.001). CONCLUSION: Our results underline the relevance of early microvascular assessment in patients at risk of developing a severe complication such as PAH that can amplify the systemic microvascular impairment in SSc. More severe NVC abnormalities should lead to strict cardiopulmonary surveillance and a complete NVC study is indicated. PMID- 23671126 TI - Histopathological changes in tendinopathy--potential roles of BMPs? AB - The pathogenesis of tendinopathy remains unclear. Chondro-osteogenic BMPs such as BMP-2, BMP-4 and BMP-7 have been reported in clinical samples and animal models of tendinopathy. As chondrocyte-like cells and ossified deposits have been observed in both clinical samples and animal models of failed tendon healing tendinopathy, chondro-osteogenic BMPs might contribute to tissue metaplasia and other histopathological changes in tendinopathy. In this review I have summarized the current evidence supporting the roles of chondro-osteogenic BMPs in the histopathological changes of tendinopathy. The potential targets, effects and sources of these BMPs are discussed. I have also provided directions for future studies about the potential roles of BMPs in the pathogenesis of tendinopathy. Better understanding of the roles of these BMPs in the histopathological changes of tendinopathy could provide new options for the prevention and treatment of this disabling tendon disorder. PMID- 23671127 TI - PTTG1 promotes migration and invasion of human non-small cell lung cancer cells and is modulated by miR-186. AB - Deeper mechanistic understanding of non-small cell lung cancer (NSCLC), a leading cause of total cancer-related deaths, may facilitate the establishment of more effective therapeutic strategies. In this study, pituitary tumor transforming gene (PTTG1) expression was associated with lymph node and distant metastasis in patients with NSCLC and was correlated with patient survival. Reduction of PTTG1 by small interfering RNA (siRNA) inhibits the migration and invasion of NSCLC cells by mediating matrix metalloproteinases expression. To the best of our knowledge, this study is the first to report that PTTG1 promotes epidermal growth factor (EGF) induced the phosphorylation of LIN-11, Isl1 and MEC-3 protein domain kinase and cofilin, a critical step in cofilin recycling and actin polymerization. Additionally, EGF-induced Akt phosphorylation was suppressed through knockdown of PTTG1. Interestingly, miR-186 can modulate PTTG1 protein expression. As observed from the animal experiment in this study, knockdown of PTTG1 through siRNA and overexpression of miR-186 inhibited invasive activity of NSCLC cells toward the SCID mice lung. In summary, our in vitro and in vivo results indicate that PTTG1 modulated by miR-186 has an important function in NSCLC invasion/metastasis. This study identified both PTTG1 and miR-186 as potential anti-invasion targets for therapeutic intervention in NSCLC. PMID- 23671128 TI - Downregulation of ASPP2 in choriocarcinoma contributes to increased migratory potential through Src signaling pathway activation. AB - Gestational choriocarcinoma is a malignant tumor derived from placental trophoblast and the most aggressive member of gestational trophoblastic disease (GTD). Apoptosis-stimulating protein of p53-2 (ASPP2) is a member of ASPP family that transactivates p53 and thereby functions as a tumor suppressor. In this study, the expression profile of ASPP2 in choriocarcinoma was examined in comparison with normal placentas and hydatidiform moles, the latter being a type of GTD that carries malignant potential. Downregulation of ASPP2 messenger RNA and protein was demonstrated in choriocarcinoma by quantitative PCR and immunohistochemistry. ASPP2-transfected choriocarcinoma cells (JEG-3 and JAR) showed an increase in apoptosis and a decrease in cell migration as detected by TdT-mediated dUTP nick end labeling and wound healing assays, respectively, illustrating the complex action of ASPP2 on cell functions other than programmed cell death. Activated Src is known to be important in tumor progression. Transfection of ASPP2 but not ASPP1, another tumor-suppressive ASPP, was found to be related to subsequent decreased Src-pY416 phosphorylation, suggesting an inactivating effect of ASPP2 on Src. Moreover, this ASPP2-mediated inactivation of Src could be abolished by RNA interference with C-terminal Src kinase (Csk), a kinase that can inhibit Src activation. Our findings suggested that the ability of ASPP2 to attenuate Src activation was specific to ASPP2 in a Csk-dependent manner. Taken together, we demonstrated a loss of tumor-suppressive ASPP2 in choriocarcinoma with effects on cell migration and apoptosis. We also unveiled a possible mechanistic link between ASPP2 and Csk/Src signaling pathway, implicating the multiple cellular functions of ASPP2. PMID- 23671129 TI - (S)-N'-Nitrosonornicotine, a constituent of smokeless tobacco, is a powerful oral cavity carcinogen in rats. AB - Currently, smokeless tobacco products are being proposed as an alternative mode of tobacco use associated with less harm. All of these products contain the tobacco-specific carcinogen N'-nitrosonornicotine (NNN). The major form of NNN in tobacco products is (S)-NNN, shown in this study to induce a total of 89 benign and malignant oral cavity tumors in a group of 20 male F-344 rats treated chronically with 14 p.p.m. in the drinking water. The opposite enantiomer (R)-NNN was weakly active, but synergistically enhanced the carcinogenicity of (S)-NNN. Thus, (S)-NNN is identified for the first time as a strong oral cavity carcinogen in smokeless tobacco products and should be significantly reduced or removed from these products without delay in order to prevent debilitating and deadly oral cavity cancer in people who use them. PMID- 23671130 TI - Metastasis suppressor, NDRG1, mediates its activity through signaling pathways and molecular motors. AB - The metastasis suppressor, N-myc downstream regulated gene 1 (NDRG1), is negatively correlated with tumor progression in multiple neoplasms, being a promising new target for cancer treatment. However, the precise molecular effects of NDRG1 remain unclear. Herein, we summarize recent advances in understanding the impact of NDRG1 on cancer metastasis with emphasis on its interactions with the key oncogenic nuclear factor-kappaB, phosphatidylinositol-3 kinase/phosphorylated AKT/mammalian target of rapamycin and Ras/Raf/mitogen activated protein kinase kinase/extracellular signal-regulated kinase signaling pathways. Recent studies demonstrating the inhibitory effects of NDRG1 on the epithelial-mesenchymal transition, a key initial step in metastasis, TGF-beta pathway and the Wnt/beta-catenin pathway are also described. Furthermore, NDRG1 was also demonstrated to regulate molecular motors in cancer cells, leading to inhibition of F-actin polymerization, stress fiber formation and subsequent reduction of cancer cell migration. Collectively, this review summarizes the underlying molecular mechanisms of the antimetastatic effects of NDRG1 in cancer cells. PMID- 23671131 TI - MiR-146a enhances angiogenic activity of endothelial cells in hepatocellular carcinoma by promoting PDGFRA expression. AB - Endothelial cells (ECs) are critical for angiogenesis, and microRNAs play important roles in this process. We investigated the regulatory role of microRNAs in ECs of hepatocellular carcinoma (HCC) by examining the microRNA expression profile of human umbilical vein endothelial cells (HUVECs) in the absence or presence of human HCC cells, and identified miR-146a as the most highly upregulated microRNA. Furthermore, we revealed that miR-146a promoted the expression of platelet-derived growth factor receptor alpha (PDGFRA) in HUVECs, and this process was mediated by BRCA1. Overexpression of PDGFRA in the ECs of HCC tissues was associated with microvascular invasion and predicted a poorer prognosis. These results suggest that miR-146a plays a key role in regulating the angiogenic activity of ECs in HCC through miR-146a-BRCA1-PDGFRA pathway. MiR-146a and PDGFRA may emerge as potential anti-angiogenic targets on ECs for HCC therapy. PMID- 23671132 TI - SB365, Pulsatilla saponin D, targets c-Met and exerts antiangiogenic and antitumor activities. AB - SB365, Pulsatilla saponin D isolated from the root of Pulsatilla koreana, has exhibited potential beneficial effects as a chemopreventive agent for critical health conditions including cancer. However, the molecular mechanisms underlying the activity of SB365 remain unknown. Here, we examined anticancer efficacy of SB365 against gastric cancer and its mechanism of action. SB365 effectively inhibited the growth of gastric cancer cells. Its apoptotic effect was accompanied by increased evidence of cleaved caspase-3 and poly(ADP ribose) polymerase. To elucidate the anticancer mechanism of SB365, we used an array of 42 different receptor tyrosine kinases (RTKs). Of the 42 different phospho-RTKs, SB365 strongly inhibited expression of activated c-mesenchymal-epithelial transition factor (c-Met) in gastric cancer cells. Also, the activation of the c Met signal cascade components, including Akt and mammalian target of rapamycin, was inhibited by SB365 in a dose-dependent manner. In angiogenesis studies, SB365 inhibited tube formation in hepatocyte growth factor (HGF)-induced human umbilical vein endothelial cells and suppressed microvessel sprouting from the rat aortic ring, ex vivo, and blood vessel formation in the Matrigel plug assay in mice. In xenograft animal models, SB365 significantly delayed tumor growth in a dose-dependent manner. In tumor tissue, SB365 suppressed c-Met signaling, proliferation and angiogenesis and induced apoptosis. These findings suggest that SB365 docks at an allosteric site on c-Met and thereby targets c-Met signaling pathway, cell growth/angiogenesis inhibition and apoptosis induction. Therefore, SB365 may be a novel drug candidate for the treatment of gastric cancer. PMID- 23671134 TI - Fluence to Hp(3) conversion coefficients for neutrons from thermal to 15 MeV. AB - The recent statement on tissue reactions issued by the International Commission on Radiological Protection in April 2011 recommends a very significant reduction in the equivalent dose annual limit for the eye lens from 150 to 20 mSv y(-1); this has stimulated a lot of interest in eye lens dosimetry in the radiation protection community. Until now no conversion coefficients were available for the operational quantity Hp(3) for neutrons. The scope of the present work was to extend previous evaluations of H*(10) and Hp(10) performed at the PTB in 1995 to provide also Hp(3) data for neutrons. The present work is also intended to complete the studies carried out on photons during the last 4 y within the European Union-funded ORAMED (optimisation of radiation protection for medical staff) project. PMID- 23671133 TI - Mutagenicity and tumorigenicity of the four enantiopure bay-region 3,4-diol-1,2 epoxide isomers of dibenz[a,h]anthracene. AB - Each enantiomer of the diastereomeric pair of bay-region dibenz[a,h]anthracene 3,4-diol-1,2-epoxides in which the benzylic 4-hydroxyl group and epoxide oxygen are either cis (isomer 1) or trans (isomer 2) were evaluated for mutagenic activity. In strains TA 98 and TA 100 of Salmonella typhimurium, the diol epoxide with (1S,2R,3S,4R) absolute configuration [(-)-diol epoxide-1] had the highest mutagenic activity. In Chinese hamster V-79 cells, the diol epoxide with (1R,2S,3S,4R) absolute configuration [(+)-diol epoxide-2] had the highest mutagenic activity. The (1R,2S,3R,4S) diol epoxide [(+)-diol epoxide-1] also had appreciable activity, whereas the other two bay-region diol epoxide enantiomers had very low activity. In tumor studies, the (1R,2S,3S,4R) enantiomer was the only diol epoxide isomer tested that had strong activity as a tumor initiator on mouse skin and in causing lung and liver tumors when injected into newborn mice. This stereoisomer was about one-third as active as the parent hydrocarbon, dibenz[a,h]anthracene as a tumor initiator on mouse skin; it was several-fold more active than dibenz[a,h]anthracene as a lung and liver carcinogen when injected into newborn mice. (-)-(3R,4R)-3beta,4alpha-dihydroxy-3,4-dihydro dibenz[a,h]anthracene [(-)-3,4-dihydrodiol] was slightly more active than dibenz[a,h]anthracene as a tumor initiator on mouse skin, whereas (+)-(3S,4S) 3alpha,4beta-dihydroxy-3,4-dihydro-dibenz[a,h]anthracene [(+)-3,4-dihydrodiol] had only very weak activity. The present investigation and previous studies with the corresponding four possible enantiopure bay-region diol epoxide enantiomers/diastereomers of benzo[a]pyrene, benz[a]anthracene, chrysene, benzo[c]phenanthrene, dibenz[c,h]acridine, dibenz[a,h]acridine and dibenz[a,h]anthracene indicate that the bay-region diol epoxide enantiomer with [R,S,S,R] absolute stereochemistry has high tumorigenic activity on mouse skin and in newborn mice. PMID- 23671135 TI - Sudden cardiac death with autopsy findings of uncertain significance: potential for erroneous interpretation. AB - BACKGROUND: The sudden death of young individuals is commonly attributed to inherited cardiac disorders, and familial evaluation is advocated. The identification of pathognomonic histopathologic findings, or the absence of cardiac pathology (sudden arrhythmic death syndrome [SADS]) at postmortem, directs familial evaluation targeting structural disorders or primary arrhythmogenic syndromes, respectively. In a proportion of autopsies, structural abnormalities of uncertain significance are reported. We explored the hypothesis that such sudden cardiac deaths represent SADS. METHODS AND RESULTS: Families (n=340) of index cases of sudden cardiac deaths who underwent postmortem evaluation were evaluated in specialist cardiogenetics clinics. Families in whom the deceased exhibited structural abnormalities of uncertain significance (n=41), such as ventricular hypertrophy, myocardial fibrosis, and minor coronary artery disease, were included in the study. Results were compared with 163 families with normal postmortem (SADS). Relatives underwent comprehensive cardiac evaluation. Twenty-one families (51%) with autopsy findings of uncertain significance received a diagnosis based on the identification of an inherited cardiac condition phenotype in >=1 relatives: 14 Brugada syndrome; 4 long-QT syndrome; 1 catecholaminergic polymorphic ventricular tachycardia; and 2 cardiomyopathy. A similar proportion of families (47.2%) received a diagnosis in the SADS cohort (P=0.727). An arrhythmogenic syndrome was the predominant diagnosis in both cohorts (46% versus 45%; P=0.863). CONCLUSIONS: Familial evaluation after sudden cardiac deaths with autopsy findings of uncertain significance identified a similar proportion of primary arrhythmogenic syndromes to a contemporary series of SADS. Our study highlights the need for accurate interpretation of autopsy findings to avoid erroneous diagnoses, with potentially devastating implications. PMID- 23671138 TI - Diseases are invisible. AB - The success of modern medicine is closely related to its ability to transcend the human senses. Technological advances such as stethoscopes, microscopes, and x rays overstep the boundaries of human perception. They enable us to see what is invisible to the unaided senses. These technologies have brought about fundamental changes to medicine-for the most part for the better. But they have also caught us in a tragic trap. They have left us in an odd position where we can no longer trust our senses concerning the health status of our body. Sense transcending technologies have made us aware that we can have a serious disease without experiencing any symptoms at all. In order to benefit from these technologies, we have to live with inescapable side effects. PMID- 23671137 TI - Medical humanities among the healing arts? PMID- 23671136 TI - Risk stratification in arrhythmogenic right ventricular dysplasia/cardiomyopathy associated desmosomal mutation carriers. AB - BACKGROUND: We investigated the role of phenotypic characteristics in stratifying the risk of sustained ventricular arrhythmias in patients harboring arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutations. METHODS AND RESULTS: Clinical, electrocardiographic, and arrhythmic outcome (composite measure of first occurrence of sustained ventricular tachycardia/resuscitated sudden cardiac death/sudden cardiac death/appropriate implantable cardioverter-defibrillator therapy) data were obtained for 215 patients (104 families; 85% PKP-2). During a mean follow-up of 7 years, 86 (40%) patients experienced the arrhythmic outcome. Event-free survival was significantly lower among probands (P<0.001) and symptomatic (P<0.001) patients. Integration of ECG repolarization and depolarization abnormalities allowed for differential risk categorization. Event-free survival at 5 years for the low-risk ECG group (0-1 T inversions or minor depolarization changes) was 97% versus 81% for the intermediate-risk ECG group (2 T inversions+minor depolarization changes) versus 33% for the high-risk ECG group (>=3 T inversions+/-major or minor depolarization changes; P<0.001). Incremental arrhythmic risk was seen in patients with increasing premature ventricular complex count on a Holter (P<0.001). Proband status (hazard ratio, 7.7; 95% confidence interval, 2.8-22.5; P<0.001), >=3 T-wave inversions (hazard ratio, 4.2; 95% confidence interval, 1.2 14.5; P=0.035), and male sex (hazard ratio, 1.8; 95% confidence interval, 1.2 2.8; P=0.004) were independent predictors of the first arrhythmic event on multivariable analysis. CONCLUSIONS: Pedigree evaluation, an ECG, and a Holter examination provide for comprehensive arrhythmic risk stratification in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutations. We propose an approach to risk stratification based on these variables. PMID- 23671139 TI - Art, science, and the existential focus of clinical medicine. AB - The continuing debate over the status of medicine as an art or a science remains far from resolved. The aim of this paper is to clarify what is meant by the art of medicine. In the following interpretation I contrast two current perspectives of the medical art. I argue that the art of medicine is best understood in terms of the Aristotelian notion of techne. It consists of listening skills directed to the lived experience of the patient in such a way that knowledge (principally scientific knowledge) can be applied in a therapeutic way. This constitutes what I call medicine's existential focus. The art of medicine is prior to and independent of medical science which plays an important but subordinate role. PMID- 23671140 TI - Does chaos theory have major implications for philosophy of medicine? AB - In the literature it is sometimes claimed that chaos theory, non-linear dynamics, and the theory of fractals have major implications for philosophy of medicine, especially for our analysis of the concept of disease and the concept of causation. This paper gives a brief introduction to the concepts underlying chaos theory and non-linear dynamics. It is then shown that chaos theory has only very minimal implications for the analysis of the concept of disease and the concept of causation, mainly because the mathematics of chaotic processes entail that these processes are fully deterministic. The practical unpredictability of chaotic processes, caused by their extreme sensitivity to initial conditions, may raise practical problems in diagnosis, prognosis, and treatment, but it raises no major theoretical problems. The relation between chaos theory and the problem of free will is discussed, and it is shown that chaos theory may remove the problem of predictability of decisions, but does not solve the problem of free will. Chaos theory may thus be very important for our understanding of physiological processes, and specific disease entities, without having any major implications for philosophy of medicine. PMID- 23671141 TI - Anticipating deep autumn: a widening lens. AB - Medicine has become one of the most powerful influences of the twentieth century, and currently dominates how we approach and think about another powerful phenomenon: the aging of the world's population. Our reliance on the medical model, with its focus on pathology, physiology, and biomedical interventions, makes it difficult for aging men and women and those in the health care field who care for them to seek alternative ways to attach meaning to the process of growing old. This article explores the role of the humanities as an alternative to the biomedical model which can enlarge our abilities to see the multidimensional aspects of aging. Age related writings and visual images by Kenyon, Neel, Olds, Valadon, and Hemingway are discussed to illustrate how fictive representations can and do serve as a moral impetus or stimulus for meaningful reflection about life stages that have not yet been experienced. PMID- 23671142 TI - Of pipes, persons, and patients. AB - Michel Foucault's analysis of Magritte's painting, Ceci N'est Pas Une Pipe, and the later work, Les Deux Mysteres, serves as a template, that is broadened to consider different representations of persons and patients. Kant's noumenal person is contrasted with phenomenal persons, and the well individual is contrasted with the patient. Patients may be considered as the subject or object of illness, and both versions are "imprisoned" within a psychological and social context that curtails freedom, threatens continuity of existence, and may question the nature of their personhood. PMID- 23671143 TI - Depressive illness delayed Hamlet's revenge. AB - If Hamlet had not delayed his revenge there would have been no play. Many explanations of the delay have been offered in the last four centuries. None is convincing. The interpretation which best fits the evidence best is that Hamlet was suffering from an acute depressive illness, with some obsessional features. He could not make a firm resolve to act. In Shakespeare's time there was no concept of acute depressive illness, although melancholy was well known. Melancholy, however, would have been seen as a character defect. In the tragic model the hero brings himself and others to ruin because of a character defect. Thus, at the time, the play conformed to the tragic model. With today's knowledge, it does not. This analysis adds to, but does not replace, other insights into the play. PMID- 23671145 TI - Acquiring experience in medical humanities teaching: the chicken and egg conundrum. PMID- 23671144 TI - Literature to heal the divide. PMID- 23671146 TI - Creative writing workshops for medical education: learning from a pilot study with hospital staff. AB - A course in creative writing was designed as a possible tool in medical education. Twelve volunteers (six doctors and six non-medical staff) participated in seven workshops held weekly. Four aims were identified: to help put thoughts onto paper; to facilitate interpretation of narrative; to encourage expression of emotions related to illness and death, and to encourage creativity. The course was evaluated using participant observational analysis and two questionnaires. This paper discusses the outcomes in relation to these aims, but identifies additional issues raised by the development.Only six of the 12 participants produced a final piece of written work, with lack of self discipline being cited as the chief reason. There was a strong tendency for self reflection in the group, which needed appropriate support. How creativity can be encouraged remains unclear. The value of multidisciplinary learning in this context was identified.The value of creative writing for medical education remains difficult to measure, but the participants agreed unanimously that the course would be an enjoyable way of encouraging medical students in its stated aims. PMID- 23671147 TI - "You keep telling me what has been lost, and I keep telling you something remains." A personal response to: Scar Tissue by Michael Ignatieff. AB - Michael Ignatieff is well known as a journalist and broadcaster of a distinctly intellectual kind. He has written movingly on the trauma of modern warfare and Europe following the Cold War. His CV also boasts of studies on the Scottish Enlightenment and nineteenth century penal policy. Additionally, his Booker short listed novel Scar Tissue is one of the most interesting studies of medicine and the human consequences of disease of the last decade. PMID- 23671148 TI - The internet and medical humanities: a reflection. PMID- 23671155 TI - Tumors, IGF-2, and hypoglycemia: insights from the clinic, the laboratory, and the historical archive. AB - Tumors of mesenchymal and epithelial origin produce IGF-2, which activates pathways in the tumors. In a minority of patients, the tumors (hepatomas, fibromas, and fibrosarcomas are the most common among many) release into the circulation enough IGF-2-related peptides to mimic the fasting hypoglycemia characteristic of patients with insulin-producing islet-cell tumors. Rarely, markedly elevated IGF-2 levels produce somatic changes suggestive of acromegaly. Typically, the elevated IGF-2 levels are associated with suppressed plasma levels of insulin, IGF-1, and GH. Complicating the pathophysiology are the IGF binding proteins (IGFBPs) that can bind IGF-2 and IGF-1, modifying hormone metabolism and action. IGFBP concentrations are often altered in the presence of these tumors. At the cellular level, the 3 hormone-related ligands, IGF-2, IGF-1, and insulin, all bind to 4 (or more) types of IGF-1 receptor (IGF-1R) and insulin receptor (IR). Each receptor has its own characteristic affinity for each ligand, a tyrosine kinase, and overlapping profiles of action in the target cells. The IGF 2R, in addition to binding mannose-6-phosphate-containing proteins, provides an IGF-2 degradation pathway. Recent evidence suggests IGF-2R involvement also in signal transduction. Surgery, the treatment of choice, can produce a cure. For patients not cured by surgery, multiple therapies exist, for the tumor and for hypoglycemia. Potential future therapeutic approaches are sketched. From 1910 to 1930, hypoglycemia, insulin, insulinomas, and non-islet-cell tumors were recognized. The latter third of the century witnessed the emergence of the immunoassay for insulin; the IGFs, their binding proteins, and assays to measure them; and receptors for the insulin-related peptides as well as the intracellular pathways beyond the receptor. In closing, we replace non-islet-cell tumor hypoglycemia, an outdated and misleading label, with IGF-2-oma, self-explanatory and consistent with names of other hormone-secreting tumors. PMID- 23671156 TI - Long-term survival in patients with refractory angina. AB - AIMS: An increasing number of patients with severe coronary artery disease (CAD) are not candidates for traditional revascularization and experience angina in spite of excellent medical therapy. Despite limited data regarding the natural history and predictors of adverse outcome, these patients have been considered at high risk for early mortality. METHODS AND RESULTS: The OPtions In Myocardial Ischemic Syndrome Therapy (OPTIMIST) program at the Minneapolis Heart Institute offers traditional and investigational therapies for patients with refractory angina. A prospective clinical database includes detailed baseline and yearly follow-up information. Death status and cause were determined using the Social Security Death Index, clinical data, and death certificates. Time to death was analysed using survival analysis methods. For 1200 patients, the mean age was 63.5 years (77.5% male) with 72.4% having prior coronary artery bypass grafting, 74.4% prior percutaneous coronary intervention, 72.6% prior myocardial infarction, 78.3% 3-vessel CAD, 23.0% moderate-to-severe left-ventricular (LV) dysfunction, and 32.6% congestive heart failure (CHF). Overall, 241 patients died (20.1%: 71.8% cardiovascular) during a median follow-up 5.1 years (range 0-16, 14.7% over 9). By Kaplan-Meier analysis, mortality was 3.9% (95% CI 2.8-5.0) at 1 year and 28.4% (95% CI 24.9-32.0) at 9 years. Multivariate predictors of all cause mortality were baseline age, diabetes, angina class, chronic kidney disease, LV dysfunction, and CHF. CONCLUSION: Long-term mortality in patients with refractory angina is lower than previously reported. Therapeutic options for this distinct and growing group of patients should focus on angina relief and improved quality of life. PMID- 23671157 TI - The art of risk stratification in TAVI. PMID- 23671158 TI - Voluntary locomotion linked with cerebral activation is mediated by vasopressin V1a receptors in free-moving mice. AB - We previously reported that cerebral activation suppressed baroreflex control of heart rate (HR) at the onset of voluntary locomotion. In the present study, we examined whether vasopressin V1a receptors in the brain were involved in these responses by using free-moving V1a receptor knockout (KO, n = 8), wild-type mice locally infused with a V1a receptor antagonist into the nucleus tractus solitarii (BLK, n = 8) and control mice (CNT, n = 8). Baroreflex sensitivity (HR/MAP) was determined from HR response (HR) to a spontaneous change in mean arterial pressure (MAP) every 4 s during the total resting period, which was ~8.7 h, of the 12 h measuring period in the three groups. HR/MAP was determined during the periods when the cross-correlation function (R(t)) between HR and MAP was significant (P < 0.05). Cerebral activity was determined from the power density ratio of to delta wave band (/delta) on the electroencephalogram every 4 s. Spontaneous changes in /delta were significantly correlated with R(t) during 62 +/- 3% of the total resting period in CNT (P < 0.05), but only 38 +/- 4% in KO and 47 +/- 2% in BLK (vs. CNT, both P < 0.001). When R(t) and HR/MAP were divided into six bins according to the level of /delta, both were positively correlated with /delta in CNT (both P < 0.001), while neither was correlated in KO or BLK (all P > 0.05). Moreover, the probability that mice started to move after an increase in /delta was 24 +/- 4% in KO and 24 +/- 6% in BLK, markedly lower than 61 +/- 5% in CNT (both P < 0.001), with no suppression of the baroreflex control of HR. Thus, central V1a receptors might play an important role in suppressing baroreflex control of HR during cerebral activation at the onset of voluntary locomotion. PMID- 23671159 TI - Nitric oxide-dependent long-term depression but not endocannabinoid-mediated long term potentiation is crucial for visual recognition memory. AB - Synaptic plasticity in perirhinal cortex is essential for recognition memory. Nitric oxide and endocannabinoids (eCBs), which are produced in the postsynaptic cell and act on the presynaptic terminal, are implicated in mechanisms of long term potentiation (LTP) and long-term depression (LTD) in other brain regions. In this study, we examine these two retrograde signalling cascades in perirhinal cortex synaptic plasticity and in visual recognition memory in the rat. We show that inhibition of NO-dependent signalling prevented both carbachol- and activity (5 Hz)-dependent LTD but not activity (100 Hz theta burst)-dependent LTP in the rat perirhinal cortex in vitro. In contrast, inhibition of the eCB-dependent signalling prevented LTP but not the two forms of LTD in vitro. Local administration into perirhinal cortex of the nitric oxide synthase inhibitor NPA (2 MUm) disrupted acquisition of long-term visual recognition memory. In contrast, AM251 (10 MUm), a cannabinoid receptor 1 antagonist, did not impair visual recognition memory. The results of this study demonstrate dissociation between putative retrograde signalling mechanisms in LTD and LTP in perirhinal cortex. Thus, LTP relies on cannabinoid but not NO signalling, whilst LTD relies on NO- but not eCB-dependent signalling. Critically, these results also establish, for the first time, that NO- but not eCB-dependent signalling is important in perirhinal cortex-dependent visual recognition memory. PMID- 23671160 TI - Paired-pulse facilitation at recurrent Purkinje neuron synapses is independent of calbindin and parvalbumin during high-frequency activation. AB - Paired-pulse facilitation (PPF) is a dynamic enhancement of transmitter release considered crucial in CNS information processing. The mechanisms of PPF remain controversial and may differ between synapses. Endogenous Ca(2+) buffers such as parvalbumin (PV) and calbindin-D28k (CB) are regarded as important modulators of PPF, with PV acting as an anti-facilitating buffer while saturation of CB can promote PPF. We analysed transmitter release and PPF at intracortical, recurrent Purkinje neuron (PN) to PN synapses, which show PPF during high-frequency activation (200 Hz) and strongly express both PV and CB. We quantified presynaptic Ca(2+) dynamics and quantal release parameters in wild-type (WT), and CB and PV deficient mice. Lack of CB resulted in increased volume averaged presynaptic Ca(2+) amplitudes and in increased release probability, while loss of PV had no significant effect on these parameters. Unexpectedly, none of the buffers significantly influenced PPF, indicating that neither CB saturation nor residual free Ca(2+) ([Ca(2+)]res) was the main determinant of PPF. Experimentally constrained, numerical simulations of Ca(2+)-dependent release were used to estimate the contributions of [Ca(2+)]res, CB, PV, calmodulin (CaM), immobile buffer fractions and Ca(2+) remaining bound to the release sensor after the first of two action potentials ('active Ca(2+)') to PPF. This analysis indicates that PPF at PN-PN synapses does not result from either buffer saturation or [Ca(2+)]res but rather from slow Ca(2+) unbinding from the release sensor. PMID- 23671161 TI - Antagonism of orexin receptors significantly lowers blood pressure in spontaneously hypertensive rats. AB - In normal rats, central administration of orexin or exposure to certain forms of stress can induce significant increases in blood pressure and sympathetic nerve activity, which can be blocked by orexin receptor antagonists. The resting blood pressure is, however, unaffected by such antagonists, but is significantly lower in rodents with total loss of orexin, such as prepro-orexin knockout mice and orexin neuron-ablated orexin/ataxin-3 transgenic rats. We hypothesize that orexin is involved in the pathophysiology and maintenance of high blood pressure in the spontaneously hypertensive rat (SHR), a model of primary hypertension. To test this hypothesis, we measured orexin-A mRNA expression in the rostral ventrolateral medulla and antagonized both orexin receptors using an orally administered potent dual orexin receptor antagonist, almorexant, in SHRs and normotensive Wistar-Kyoto rats. In SHRs, there was a strong trend towards an increased orexin-A mRNA expression in the rostral ventrolateral medulla, and blocking orexin receptors markedly lowered blood pressure (from 182/152 +/- 5/6 to 149/119 +/- 9/8 mmHg; P < 0.001), heart rate (P < 0.001), sympathetic vasomotor tone (P < 0.001) and the noradrenaline levels in cerebrospinal fluid and plasma (P < 0.002). The significant antihypertensive effects of almorexant were observed in wakefulness and non-rapid eye movement sleep during both dark and light phases of the diurnal cycle only in SHRs. Blocking orexin receptors had no effect on blood pressure and sympathetic tone in normotensive Wistar-Kyoto rats. Our study links the orexin system to the pathogenesis of high blood pressure in SHRs and suggests that modulation of the orexin system could be a potential target in treating some forms of hypertension. PMID- 23671165 TI - Looking for emerging themes in medical humanities--some invitations to our readers. PMID- 23671163 TI - Heterogeneous responses of nucleus incertus neurons to corticotrophin-releasing factor and coherent activity with hippocampal theta rhythm in the rat. AB - The nucleus incertus (NI) of the rat hindbrain is a putative node in the ascending control of the septohippocampal system and hippocampal theta rhythm and is stress and arousal responsive. NI contains GABA neurons that express multiple neuropeptides, including relaxin-3 (RLN3) and neuropeptide receptors, including corticotrophin-releasing factor receptor-1 (CRF-R1), but the precise anatomical and physiological characteristics of NI neurons are unclear. Therefore, we examined the firing properties of NI neurons and their responses to CRF, the correlation of these responses with occurrence of relaxin-3, and NI neuron morphology in the rat. Most NI neurons excited by intracerebroventricular CRF infusion were RLN3-positive (9 of 10), whereas all inhibited cells were RLN3 negative (8 of 8). The spontaneous firing of RLN3 (n = 6) but not non-RLN3 neurons (n = 6) was strongly modulated and phase-locked with the initial ascending phase of hippocampal theta oscillations. In brain slices, the majority of recorded NI neurons (15 of 19) displayed excitatory responses to CRF, which uniformly increased action potential frequency and membrane potential depolarization in the presence of tetrodotoxin, indicating a direct, postsynaptic action of CRF on NI neurons. This excitation was associated with reduction in the slow component of afterhyperpolarization and a strong depolarization. Quantitative analysis in naive rats of validated CRF-R1, RLN3 and neuronal nuclear antigen (NeuN) immunoreactivity revealed 52% of NI neurons as CRF-R1 positive, of which 53% were RLN3 positive, while 48% of NI neurons lacked CRF-R1 and RLN3. All RLN3 neurons expressed CRF-R1. CRF neurons that projected to the NI were identified in lateral preoptic hypothalamus, but not in paraventricular hypothalamus, bed nucleus of stria terminalis or central amygdala. Our findings suggest NI is an important site for CRF modulation of hippocampal theta rhythm via effects on GABA/RLN3 transmission. PMID- 23671166 TI - Reflections on embodiment and vulnerability. AB - Bodies matter as our experience of them is the basis both for social life and also for much medical and social research. There has been a spectacular increase in academic research on the body in the last twenty years or so. This paper although a review of three ethnographic studies on the seemingly disparate and narrow fields of the embodiment of working class experience, boxing, and ballet illuminates the broader relationships between the body, self, and society. Our paper works on three levels: firstly, as an account of the "lived experience" of embodied vulnerability; secondly, as an application of Bourdieu's theoretical schema, and thirdly, as a philosophically grounded critique of radical social constructionist views of the body. PMID- 23671162 TI - Oxygen sensitivity of mitochondrial function in rat arterial chemoreceptor cells. AB - The mechanism of oxygen sensing in arterial chemoreceptors is unknown but has often been linked to mitochondrial function. A common criticism of this hypothesis is that mitochondrial function is insensitive to physiological levels of hypoxia. Here we investigate the effects of hypoxia (down to 0.5% O2) on mitochondrial function in neonatal rat type-1 cells. The oxygen sensitivity of mitochondrial [NADH] was assessed by monitoring autofluorescence and increased in hypoxia with a P50 of 15 mm Hg (1 mm Hg = 133.3 Pa) in normal Tyrode or 46 mm Hg in Ca(2+)-free Tyrode. Hypoxia also depolarised mitochondrial membrane potential (m, measured using rhodamine 123) with a P50 of 3.1, 3.3 and 2.8 mm Hg in normal Tyrode, Ca(2+)-free Tyrode and Tyrode containing the Ca(2+) channel antagonist Ni(2+), respectively. In the presence of oligomycin and low carbonyl cyanide 4 (trifluoromethoxy) phenylhydrazone (FCCP; 75 nm) m is maintained by electron transport working against an artificial proton leak. Under these conditions hypoxia depolarised m/inhibited electron transport with a P50 of 5.4 mm Hg. The effects of hypoxia upon cytochrome oxidase activity were investigated using rotenone, myxothiazol, antimycin A, oligomycin, ascorbate and the electron donor tetramethyl-p-phenylenediamine. Under these conditions m is maintained by complex IV activity alone. Hypoxia inhibited cytochrome oxidase activity (depolarised m) with a P50 of 2.6 mm Hg. In contrast hypoxia had little or no effect upon NADH (P50 = 0.3 mm Hg), electron transport or cytochrome oxidase activity in sympathetic neurons. In summary, type-1 cell mitochondria display extraordinary oxygen sensitivity commensurate with a role in oxygen sensing. The reasons for this highly unusual behaviour are as yet unexplained. PMID- 23671167 TI - Patient centred medicine: reason, emotion, and human spirit? Some philosophical reflections on being with patients. AB - The ideal of patient centred medicine remains only partially realised. Within modern Western society, the highly individualistic culture and religious decline linked with medicine's reluctance to relinquish an outmoded form of scientific rationalism can act as reductive influences, stifling conceptual development. Some examples of the recent literature on communication skills in medicine are analysed to discern the underlying philosophy. A rationalist stance invites an examination of the possible nature of rationality. Another example accepts the need to accommodate the emotional and the unconscious. Issues of human suffering with an inherent spiritual dimension seem to remain excluded. The need to move beyond a duality of reason and emotion to embrace the existential and spiritual is suggested as a theoretical prerequisite for developing a more inclusive concept of patient centred medicine, which only then may be realised. Some brief examples are considered of the sort of notions and types of discourse that might effectively inform "teaching" of communication skills. PMID- 23671168 TI - Lessons from the past: preventive medicine in early modern England. AB - The history of English medicine used to consist of chronicles of medical progress and great ideas culminating in twentieth century biomedicine. Unlike earlier generations whose medical beliefs and practices were seen to be both futile and dangerous, modern medicine was thought to be able to eradicate illness with a "magic bullet". During the later part of the 20th century, however, the general public began to have doubts about the efficacy and safety of modern medicine. In turn, both the institution of medicine and the biomedical model began to be challenged by the media. These events led to a spreading desire for people to take a greater responsibility for their own health. One of the areas of greatest interest and growth is that of preventive medicine which focuses on a good diet and exercise. Far from being a new concept, however, the idea of a daily health "regimen" goes back to the ancient Greece and was further developed during the Middle Ages, and by the early modern period (1500-1800). PMID- 23671169 TI - Triumph of the light--isopathy and the rise of transcendental homeopathy, 1830 1920. AB - Modern homeopathy dwells in a nebulous and metaphysical realm into which few non homeopathic doctors would venture; a very different world and speaking a language virtually incomprehensible to science. Fundamentally incompatible systems, their highly sophisticated conceptions of "disease" and "cure" are sufficiently divergent to prevent their peaceful coexistence. Can the best of modern scientific medicine be reconciled with this recently resuscitated "medical Lazarus"? Could a creative dialogue be established? This article explores the development of modern homeopathic thinking between 1830 and 1920, charting a discourse within homeopathy initiated in the 1830s with reference to use of "higher potencies" and disease products ("nosodes"). Incorporation of disease products into the homeopathic mainstream killed off and supplanted the earlier allopathic version of homeopathy, encouraged the use of higher potencies, and legitimated a widespread adoption of metaphysical views within the movement, here termed "transcendental homeopathy".Long before the birth of bacteriotherapy ... homeopathic physicians carried out investigation in their own way, and discovered similar medicines, and effected numerous cures ... Hydrophobium was proved in 1833 ... 50 years before Pasteur ... many others followed.(1.) PMID- 23671170 TI - Medical Humanities: a vision and some cautionary notes. AB - This article aims to engender discussion about the nature and future of medical humanities. First, a normative personal vision of medical humanities as an inclusive movement is outlined. Some of the problems that may emerge if medical humanities conceives itself too narrowly are then discussed. The case of the rise of the medical ethics movement is used to show what can happen to a movement that restricts itself too quickly and then the stages of the "death course of a discipline" are described and assayed. The article concludes with a plea for medical humanities to remain a "broad church", exploratory, pluralistic movement rather than aiming to become a paramedical academic discipline. PMID- 23671171 TI - Medical humanities: a vision and some cautionary notes. AB - Stephen Pattison outlines his vision for medical humanities and then offers cautionary notes on what might go wrong with the movement. These notes are based on what he holds has already gone wrong with medical ethics, dramatically described as the "death course of a discipline". I have a great deal of sympathy both with his anxieties about the future development of medical humanities and with his critique of medical ethics. My reasons in both cases are a little different from his, and indeed part of his vision for medical humanities constitutes part of my worries about its future! I shall begin with some comments on Pattison's views on medical humanities, and then more briefly comment on his diagnosis of the ills of medical ethics. PMID- 23671172 TI - "Attempting to say something without saying it ...": writing haiku in health care education. AB - Over a number of years the authors have been running short haiku writing workshops and have been using haiku as an evaluation tool. This paper describes those experiences and uses the haiku generated in these workshops to illustrate how this poetic form can be used as-for example, part of the process of reflection, to explore emotional and practical issues related to clinical health care practice, to refine writing skills and precision and, it is hoped, to convey to others the essence of the experience of health care provision, education and, perhaps, health, illness, and disease. PMID- 23671173 TI - "The dark side of the spectrum ..." a "day of suffering" for medical students. AB - The alleviation of suffering has been described as a central goal of medicine. A familiarity with this subject may have great practical benefit, while promoting reflection upon medicine more generally. This paper describes a study day for medical students that encourages them to think about suffering. A variety of texts in different media were used as the basis of group discussion. Sources reflected the range of suffering that may be encountered, including suffering from causes not normally considered to be "medical". An evaluation of the study day was performed, using the nominal group technique, suggesting that the day was both popular and had achieved its goals. PMID- 23671174 TI - Relativity. PMID- 23671175 TI - Reliability. PMID- 23671176 TI - Editorial: a library of "non-medical" books for medical students: a foot in the door or an obstacle to progress? PMID- 23671177 TI - What do Italian medical students read? A call for a library of good books on physicians for physicians. AB - Humanities are increasingly taught in medical schools based on the premise that sensitive and educated human beings may become better physicians. There have been few reports of what is offered in Italian medical schools and we have not been able to identify any published survey of student opinions. PMID- 23671178 TI - Impact of onset-to-reperfusion time on stroke mortality: a collaborative pooled analysis. AB - BACKGROUND: Onset-to-reperfusion time has been reported to be associated with clinical prognosis. However, its impact on mortality remained to be assessed. Using a collaborative pooled analysis, we examined whether early mortality after successful endovascular treatment is time dependent. METHODS AND RESULTS: In a collaborative pooled analysis of 7 endovascular databases, we assessed the impact of onset-to-reperfusion time in large-artery occlusion (internal carotid artery or middle cerebral artery) on outcomes. Successful reperfusion was defined as complete or partial restoration of blood flow within 8 hours from symptom onset. Primary outcome was 90-day all-cause mortality. Secondary outcomes included 90 day favorable outcome (modified Rankin Scale score, 0-2), 90-day excellent outcome (modified Rankin Scale score, 0-1), and occurrence of any intracerebral hemorrhage within 24 to 36 hours after treatment. A total of 480 cases with successful reperfusion (median time, 285 minutes) contributed to the present pooled analysis (120 with internal carotid artery occlusion and 360 with isolated middle cerebral artery occlusion). Increasing onset-to-reperfusion time was associated with an increased rate of mortality and intracerebral hemorrhage and with a decreased rate of favorable and excellent outcomes, without heterogeneity across studies. The adjusted odds ratio for each 30-minute time increase was 1.21 (95% confidence interval, 1.09-1.34; P<0.001) for mortality, 0.79 (95% confidence interval, 0.72-0.87) for favorable outcome, 0.78 (95% confidence interval, 0.71 0.86) for excellent outcome, and 1.21 (95% confidence interval, 1.10-1.33) for intracerebral hemorrhage. CONCLUSION: Onset-to-reperfusion time affects mortality and favorable outcome and should be considered the main goal in acute stroke patient management. PMID- 23671179 TI - New therapeutic targets in cardiology: heart failure and arrhythmia: HCN channels. PMID- 23671180 TI - Digital clubbing. PMID- 23671181 TI - Extreme right and left atrial enlargement in a patient with rheumatic valvular disease and mitral mechanical prosthesis. PMID- 23671182 TI - Radiating chest pain to the back. PMID- 23671184 TI - Letter by Llau and Ferrandis regarding article, "Bridging evidence-based practice and practice-based evidence in periprocedural anticoagulation". PMID- 23671186 TI - Regionally specific and genome-wide analyses conclusively demonstrate the absence of CpG methylation in human mitochondrial DNA. AB - Although CpG methylation clearly distributes genome-wide in vertebrate nuclear DNA, the state of methylation in the vertebrate mitochondrial genome has been unclear. Several recent reports using immunoprecipitation, mass spectrometry, and enzyme-linked immunosorbent assay methods concluded that human mitochondrial DNA (mtDNA) has much more than the 2 to 5% CpG methylation previously estimated. However, these methods do not provide information as to the sites or frequency of methylation at each CpG site. Here, we have used the more definitive bisulfite genomic sequencing method to examine CpG methylation in HCT116 human cells and primary human cells to independently answer these two questions. We found no evidence of CpG methylation at a biologically significant level in these regions of the human mitochondrial genome. Furthermore, unbiased next-generation sequencing of sodium bisulfite treated total DNA from HCT116 cells and analysis of genome-wide sodium bisulfite sequencing data sets from several other DNA sources confirmed this absence of CpG methylation in mtDNA. Based on our findings using regionally specific and genome-wide approaches with multiple human cell sources, we can definitively conclude that CpG methylation is absent in mtDNA. It is highly unlikely that CpG methylation plays any role in direct control of mitochondrial function. PMID- 23671185 TI - Brain-specific homeobox factor as a target selector for glucocorticoid receptor in energy balance. AB - The molecular basis underlying the physiologically well-defined orexigenic function of glucocorticoid (Gc) is unclear. Brain-specific homeobox factor (Bsx) is a positive regulator of the orexigenic neuropeptide, agouti-related peptide (AgRP), in AgRP neurons of the hypothalamic arcuate nucleus. Here, we show that in response to fasting-elevated Gc levels, Gc receptor (GR) and Bsx synergize to direct activation of AgRP transcription. This synergy is dictated by unique sequence features in a novel Gc response element in AgRP (AgRP-GRE). In contrast to AgRP-GRE, Bsx suppresses transactivation directed by many conventional GREs, functioning as a gene context-dependent modulator of GR actions or a target selector for GR. Consistent with this finding, AgRP-GRE drives fasting-dependent activation of a target gene specifically in GR(+) Bsx(+) AgRP neurons. These results define AgRP as a common orexigenic target gene of GR and Bsx and provide an opportunity to identify their additional common targets, facilitating our understanding of the molecular basis underlying the orexigenic activity of Gc and Bsx. PMID- 23671187 TI - EED and KDM6B coordinate the first mammalian cell lineage commitment to ensure embryo implantation. AB - The first mammalian cell lineage commitment is the formation of the trophectoderm (TE) and the inner cell mass (ICM) lineages during preimplantation development. Proper development of the TE and ICM lineages is dependent upon establishment of specific transcriptional programs. However, the epigenetic mechanisms that functionally contribute to establish TE- and ICM-specific transcriptional programs are poorly understood. Here, we show that proper development of the TE and ICM lineages is coordinated via combinatorial regulation of embryonic ectoderm development (EED) and lysine-specific demethylase 6B (KDM6B). During blastocyst formation, the relative levels of EED and KDM6B expression determine altered polycomb repressor 2 (PRC2) complex recruitment and incorporation of the repressive histone H3 lysine 27 trimethylation (H3K27Me3) mark at the chromatin domains of TE-specific master regulators CDX2 and GATA3, leading to their activation in the TE lineage and repression in the ICM lineage. Furthermore, ectopic gain of EED along with depletion of KDM6B in preimplantation mouse embryos abrogates CDX2 and GATA3 expression in the nascent TE lineage. The loss of CDX2 and GATA3 in the nascent TE lineage results in improper TE development, leading to failure in embryo implantation to the uterus. Our study delineates a novel epigenetic mechanism that orchestrates proper development of the first mammalian cell lineages. PMID- 23671188 TI - Impaired resection of meiotic double-strand breaks channels repair to nonhomologous end joining in Caenorhabditis elegans. AB - Repair of double-strand DNA breaks (DSBs) by the homologous recombination (HR) pathway results in crossovers (COs) required for a successful first meiotic division. Mre11 is one member of the MRX/N (Mre11, Rad50, and Xrs2/Nbs1) complex required for meiotic DSB formation and for resection in Saccharomyces cerevisiae. In Caenorhabditis elegans, evidence for the MRX/N role in DSB resection is limited. We report the first separation-of-function allele, mre-11(iow1) in C. elegans, which is specifically defective in meiotic DSB resection but not in formation. The mre-11(iow1) mutants displayed chromosomal fragmentation and aggregation in late prophase I. Recombination intermediates and crossover formation was greatly reduced in mre-11(iow1) mutants. Irradiation-induced DSBs during meiosis failed to be repaired from early to middle prophase I in mre 11(iow1) mutants. In the absence of a functional HR, our data suggest that some DSBs in mre-11(iow1) mutants are repaired by the nonhomologous end joining (NHEJ) pathway, as removing NHEJ partially suppressed the meiotic defects shown by mre 11(iow1). In the absence of NHEJ and a functional MRX/N, meiotic DSBs are channeled to EXO-1-dependent HR repair. Overall, our analysis supports a role for MRE-11 in the resection of DSBs in middle meiotic prophase I and in blocking NHEJ. PMID- 23671189 TI - Tumor necrosis factor alpha-induced hypoxia-inducible factor 1alpha-beta-catenin axis regulates major histocompatibility complex class I gene activation through chromatin remodeling. AB - Hypoxia-inducible factor 1alpha (HIF-1alpha) plays a crucial role in the progression of glioblastoma multiforme tumors, which are characterized by their effective immune escape mechanisms. As major histocompatibility complex class I (MHC-I) is involved in glioma immune evasion and since HIF-1alpha is a pivotal link between inflammation and glioma progression, the role of tumor necrosis factor alpha (TNF-alpha)-induced inflammation in MHC-I gene regulation was investigated. A TNF-alpha-induced increase in MHC-I expression and transcriptional activation was concurrent with increased HIF-1alpha, NuF kappaBeta, and beta-catenin activities. While knockdown of HIF-1alpha and beta catenin abrogated TNF-alpha-induced MHC-I activation, NF-kappaB had no effect. beta-Catenin inhibition abrogated HIF-1alpha activation and vice versa, and this HIF-1alpha-beta-catenin axis positively regulated CREB phosphorylation. Increased CREB activation was accompanied by its increased association with beta-catenin and CBP. Chromatin immunoprecipitation revealed increased CREB enrichment at CRE/site alpha on the MHC-I promoter in a beta-catenin-dependent manner. beta Catenin replaced human Brahma (hBrm) with Brg1 as the binding partner for CREB at the CRE site. The hBrm-to-Brg1 switch is crucial for MHC-I regulation, as ATPase deficient Brg1 abolished TNF-alpha-induced MHC-I expression. beta-Catenin also increased the association of MHC-I enhanceosome components RFX5 and NF-YB at the SXY module. CREB acts as a platform for assembling coactivators and chromatin remodelers required for MHC-I activation in a HIF-1alpha/beta-catenin-dependent manner. PMID- 23671190 TI - MicroRNA 22 regulates cell cycle length in cerebellar granular neuron precursors. AB - During cerebellum development, Sonic hedgehog (Shh)-induced proliferation of cerebellar granular neuronal precursors (CGNPs) is potently inhibited by bone morphogenetic proteins (BMPs). We have previously reported the upregulation of TIEG-1 and Mash1, two antimitotic factors that modulate MYCN transcription and N Myc activity, in response to BMP2. To gain further insight into the BMP antimitotic mechanism, we used microRNA (miRNA) arrays to compare the miRNAs of CGNPs proliferating in response to Shh with those of CGNPs treated with Shh plus BMP2. The array analysis revealed that miRNA 11 (miR-22) levels significantly increased in cells treated with BMP2. Additionally, in P7 mouse cerebellum, miR 22 distribution mostly recapitulated the combination of BMP2 and BMP4 expression patterns. Accordingly, in CGNP cultures, miR-22 overexpression significantly reduced cell proliferation, whereas miR-22 suppression diminished BMP2 antiproliferative activity. In contrast to BMP2, miR-22 did not induce neural differentiation but instead significantly increased cell cycle length. Consistent with the central role played by N-myc on CGNP proliferation, Max was revealed as a direct target of miR-22, and miR-22 expression caused a significant reduction of Max protein levels and N-myc/Max-dependent promoter activity. Therefore, we conclude that, in addition to the previously described mechanisms, miR-22 plays a specific role on downstream BMPs through cerebellum growth. PMID- 23671194 TI - Protein-protein interaction and pathway analyses of top schizophrenia genes reveal schizophrenia susceptibility genes converge on common molecular networks and enrichment of nucleosome (chromatin) assembly genes in schizophrenia susceptibility loci. AB - Recent genome-wide association studies have identified many promising schizophrenia candidate genes and demonstrated that common polygenic variation contributes to schizophrenia risk. However, whether these genes represent perturbations to a common but limited set of underlying molecular processes (pathways) that modulate risk to schizophrenia remains elusive, and it is not known whether these genes converge on common biological pathways (networks) or represent different pathways. In addition, the theoretical and genetic mechanisms underlying the strong genetic heterogeneity of schizophrenia remain largely unknown. Using 4 well-defined data sets that contain top schizophrenia susceptibility genes and applying protein-protein interaction (PPI) network analysis, we investigated the interactions among proteins encoded by top schizophrenia susceptibility genes. We found proteins encoded by top schizophrenia susceptibility genes formed a highly significant interconnected network, and, compared with random networks, these PPI networks are statistically highly significant for both direct connectivity and indirect connectivity. We further validated these results using empirical functional data (transcriptome data from a clinical sample). These highly significant findings indicate that top schizophrenia susceptibility genes encode proteins that significantly directly interacted and formed a densely interconnected network, suggesting perturbations of common underlying molecular processes or pathways that modulate risk to schizophrenia. Our findings that schizophrenia susceptibility genes encode a highly interconnected protein network may also provide a novel explanation for the observed genetic heterogeneity of schizophrenia, ie, mutation in any member of this molecular network will lead to same functional consequences that eventually contribute to risk of schizophrenia. PMID- 23671195 TI - In vivo neurometabolic profiling to characterize the effects of social isolation and ketamine-induced NMDA antagonism: a rodent study at 7.0 T. AB - Continued efforts are undertaken to develop animal models of schizophrenia with translational value in the quest for much needed novel drugs. Existing models mimic specific neurobiological aspects of schizophrenia, but not its full complexity. Here, we used proton magnetic resonance spectroscopy ((1)H-MRS) to assess the metabolic profile in the prefrontal cortex (PFC) of two established models, rearing in social isolation and acute N-methyl-D-aspartate receptor (NMDA R) antagonism and their combination. Rats reared in social isolation or group housed underwent (1)H-MRS at baseline and dynamically after ketamine challenge (25mg/kg, intraperitoneal) under isoflurane anesthesia. A 7 T animal scanner was used to perform spectra acquisition from the anterior cingulate/medial PFC. LCModel was used for metabolite quantification and effects of rearing and ketamine injection were analyzed. Social isolation did not lead to significant differences in the metabolic profile of the PFC at baseline. Ketamine induced a significant increase in glutamine in both groups with significance specifically reached by the group-housed animals alone. Only rats reared in social isolation showed a significant 11% gamma-aminobutyric acid (GABA) decrease. This study provides preliminary evidence that social interactions in early life predict the glutamatergic and GABAergic response to acute NMDA-R blockade. The similarity between the prefrontal GABA reduction in patients with schizophrenia and in rats reared as social isolates after challenge with ketamine suggests good potential translational value of this combined animal model for drug development. PMID- 23671196 TI - Life events and psychosis: a review and meta-analysis. AB - INTRODUCTION: Recent models of psychosis implicate stressful events in its etiology. However, while evidence has accumulated for childhood trauma, the role of adult life events has received less attention. Therefore, a review of the existing literature on the relationship between life events and onset of psychotic disorder/experiences is timely. METHODS: A search was conducted using PsychInfo, Medline, Embase, and Web of Science to identify studies of life events and the onset of psychosis or psychotic experiences within the general population. Given previous methodological concerns, this review included a novel quality assessment tool and focused on findings from the most robust studies. A meta-analysis was performed on a subgroup of 13 studies. RESULTS: Sixteen studies published between 1968 and 2012 were included. Of these, 14 reported positive associations between exposure to adult life events and subsequent onset of psychotic disorder/experiences. The meta-analysis yielded an overall weighted OR of 3.19 (95% CI 2.15-4.75). However, many studies were limited by small sample sizes and the use of checklist measures of life events, with no consideration of contextual influences on the meaning and interpretation of events. CONCLUSIONS: Few studies have assessed the role of adult life events in the onset of psychosis. There was some evidence that reported exposure to adult life events was associated with increased risk of psychotic disorder and subclinical psychotic experiences. However, the methodological quality of the majority of studies was low, which urges caution in interpreting the results and points toward a need for more methodologically robust studies. PMID- 23671198 TI - Surgery for coincidental infected distal arch and abdominal aortic aneurysms. AB - A 63-year old man was admitted to hospital for the treatment of coincidental infected distal arch and abdominal aortic aneurysms. His haemodynamic state was unstable and uncontrollable because of septic shock. Group A beta-haemolytic Streptococcus pyogenes was the responsible microorganism. An emergent extra anatomical bypass and complete aneurysm excisions were performed without extracorporeal circulation. PMID- 23671199 TI - Editorial comment: When durability is overlooked. PMID- 23671200 TI - Double giant thrombi in the left atrium in a patient with rheumatic mitral valve stenosis and atrial fibrillation. PMID- 23671197 TI - Neurological soft signs are not "soft" in brain structure and functional networks: evidence from ALE meta-analysis. AB - BACKGROUND: Neurological soft signs (NSS) are associated with schizophrenia and related psychotic disorders. NSS have been conventionally considered as clinical neurological signs without localized brain regions. However, recent brain imaging studies suggest that NSS are partly localizable and may be associated with deficits in specific brain areas. METHOD: We conducted an activation likelihood estimation meta-analysis to quantitatively review structural and functional imaging studies that evaluated the brain correlates of NSS in patients with schizophrenia and other psychotic disorders. Six structural magnetic resonance imaging (sMRI) and 15 functional magnetic resonance imaging (fMRI) studies were included. RESULTS: The results from meta-analysis of the sMRI studies indicated that NSS were associated with atrophy of the precentral gyrus, the cerebellum, the inferior frontal gyrus, and the thalamus. The results from meta-analysis of the fMRI studies demonstrated that the NSS-related task was significantly associated with altered brain activation in the inferior frontal gyrus, bilateral putamen, the cerebellum, and the superior temporal gyrus. CONCLUSIONS: Our findings from both sMRI and fMRI meta-analyses further support the conceptualization of NSS as a manifestation of the "cerebello-thalamo-prefrontal" brain network model of schizophrenia and related psychotic disorders. PMID- 23671201 TI - Operative mortality and stroke after on-pump vs off-pump surgery in high-risk patients: an analysis of 83,914 coronary bypass operations. AB - OBJECTIVES: The objective of this study was to compare the early outcomes of off pump and on-pump surgeries in high-risk patient groups. METHODS: The outcomes of 83,914 high-risk patients undergoing off-pump or on-pump isolated coronary bypass surgery identified from the Nationwide Inpatient Sample from 2005 to 2010 were compared using propensity analysis. RESULTS: Off-pump surgery was associated with a significant reduction in stroke rates compared with on-pump surgery in propensity-matched patients >= 80 years (odds ratio [OR] 0.70, 95% confidence interval [CI] 0.52-0.93, P = 0.02), those with peripheral vascular disease (OR 0.53, 95% CI 0.36-0.77, P = 0.001) and those with aortic atherosclerosis (OR 0.30, 95% CI 0.13-0.72, P = 0.007). In these high-risk subgroups, off-pump surgery was associated with an absolute risk reduction in stroke rates of 0.5, 0.5 and 1.2%, respectively: the minimum number needed to treat to prevent one stroke is 200 patients. There was no significant difference in in-hospital mortality or the incidence of postoperative renal failure or respiratory failure between off-pump and on-pump surgeries in these patient subgroups, or in patients with preoperative renal failure, or chronic obstructive airways disease. CONCLUSIONS: High-risk patients undergoing coronary artery bypass surgery gain a short-term benefit from off-pump approaches due to a small absolute reduction in the risk of postoperative stroke. PMID- 23671202 TI - Activation of the receptor activator of the nuclear factor-kappaB ligand pathway during coronary bypass surgery: comparison between on- and off-pump coronary artery bypass surgery procedures. AB - OBJECTIVES: The receptor activator of the nuclear factor kappa-B (NF-kappaB) ligand (RANKL), its membrane receptor RANK and its decoy receptor osteoprotegerin (OPG) are all members of the tumour necrosis factor family involved in bone metabolism and immune response. We evaluated the activation of the OPG/RANKL/RANK pathway in patients undergoing cardiac surgery with and without cardiopulmonary bypass (CPB). METHODS: Twenty consecutive patients undergoing elective coronary artery surgery were enrolled in the study and assigned either to the on-pump or to the off-pump group. Pre- and postoperative serum levels of OPG and RANKL were evaluated by enzyme-linked immunosorbent assay; gene expression of OPG, RANKL, RANK and NF-kappaB p50 subunits were determined by real-time polymerase chain reaction in peripheral blood T-cells and monocytes. RESULTS: Serum levels of OPG significantly increased after surgery in both groups, whereas serum levels of RANKL did not differ over time. T-cells from the on-pump group showed increased gene expression of OPG, RANKL and RANK after the intervention, whereas no mRNA variation for these genes was detected in T-cells from off-pump patients. Gene expression of p50 subunit increased in T-cells and monocytes from both groups. CONCLUSIONS: Cardiac surgery induces the activation of the OPG/RANKL/RANK pathway; both on- and off-pump procedures are associated with increased postoperative OPG serum levels and up-regulation of the NF-kappaB p50 subunit. PMID- 23671204 TI - Reply to Koestenberger and Ravekes. PMID- 23671203 TI - Is anti-platelet therapy needed in continuous flow left ventricular assist device patients? A single-centre experience. AB - OBJECTIVES: We report our 5-year experience of continuous flow left ventricular assist device (LVAD) implantation without the use of anti-platelet therapy. METHODS: Between February 2006 and September 2011, 27 patients (26 men; 1 woman) were implanted with a continuous flow LVAD (HeartMate II, Thoratec Corporation, Pleasanton, CA, USA). The mean age was 55.7 +/- 9.9 years. The mean duration of support was 479 +/- 436 (1-1555) days with 35.4 patient-years on support. Twenty one patients were implanted as a bridge to transplantation and 6 for destination therapy. The anticoagulation regimen was fluindione for all patients, with aspirin for only 4 patients. At the beginning of our experience, aspirin was administered to 4 patients for 6, 15, 60 and 460 days. Due to gastrointestinal (GI) bleeding and epistaxis, aspirin was discontinued, and since August 2006, no patients have received anti-platelet therapy. RESULTS: At 3 years, the survival rate during support was 76%. The most common postoperative adverse event was GI bleeding (19%) and epistaxis (30%) (median time: 26 days) for patients receiving fluindione and aspirin. The mean International Normalized Ratio (INR) was 2.58 +/ 0.74 during support. Fifteen patients have been tested for acquired Von Willebrand disease. A diminished ratio of collagen-binding capacity and ristocetin cofactor activity to Von Willebrand factor antigen was observed in 7 patients. In the postoperative period, 2 patients presented with ischaemic stroke at 1 and 8 months. One of these 2 patients had a previous history of carotid stenosis with ischaemic stroke. There were no patients with haemorrhagic stroke, transient ischaemic attack or pump thrombosis. The event rate of stroke (ischaemic and haemorrhagic) per patient-year was 0.059 among the patients without aspirin with fluindione regimen only. CONCLUSIONS: A fluindione regimen without aspirin in long-duration LVAD support appears to not increase thromboembolic events and could lead to a diminished risk of haemorrhagic stroke. PMID- 23671205 TI - Effect of lipid exposure on graft patency and clinical outcomes: arteries and veins are different. AB - OBJECTIVES: We evaluated the influence of lipid exposure upon conduit patency in long-term follow-up after primary CABG. METHODS: From a prospectively compiled database, we identified 1207 grafts (436 SV and 771 mixed arterial grafts) among 413 CABG patients with 9.4 +/- 2.4 years of follow-up (range 3-13). Surveillance angiography was performed as part of a randomized trial. All available lipid assays were collected from pathology laboratories, and from these, mean annualized lipid exposure was calculated for total cholesterol, HDL, LDL and triglycerides. Angiographical and clinical data were analysed against lipid exposure. Graft failure was defined as occlusion, string sign or >80% stenosis. RESULTS: Six thousand and seventy-seven lipid measurements were obtained, and there were 154 failed grafts. Three hundred and eleven patients received at least one vein graft, and all 413 patients received at least one arterial graft. Overall, only HDL levels were inversely correlated with graft failure, with total cholesterol and LDL showing no associations in a mixed pool of arterial and venous grafts. To assess whether total/LDL cholesterol had no effect or were exerting competing effects in arteries and veins, separate multivariate analyses were performed. Venous graft failure was associated with increased total cholesterol/HDL (P=0.006) and LDL/HDL (P=0.032). By contrast, elevated total cholesterol was correlated with a reduced risk of arterial graft failure (OR for graft failure 0.705, P 0.023) with increasing LDL cholesterol following a similar trend (OR for graft failure 0.729, P=0.051). CONCLUSION: Sub-fractions of dyslipidaemia known to be risk factors for native vessel disease appear to similarly influence vein grafts. Arterial conduits are at least more resistant to the effects of high lipid exposure, and appear to be protective. These results favour the use of arterial grafts in patients with poorly controlled dyslipidaemia. PMID- 23671206 TI - Impairment of tricuspid annular plane systolic excursion and tricuspid annular peak systolic velocity after ventricular septal defect correction. PMID- 23671207 TI - Two sides to every proinflammatory coin: new insights into the role of dendritic cells in the regulation of T-cell driven autoimmune myocarditis. PMID- 23671208 TI - Innate signaling promotes formation of regulatory nitric oxide-producing dendritic cells limiting T-cell expansion in experimental autoimmune myocarditis. AB - BACKGROUND: Activation of innate pattern-recognition receptors promotes CD4+ T cell-mediated autoimmune myocarditis and subsequent inflammatory cardiomyopathy. Mechanisms that counterregulate exaggerated heart-specific autoimmunity are poorly understood. METHODS AND RESULTS: Experimental autoimmune myocarditis was induced in BALB/c mice by immunization with alpha-myosin heavy chain peptide and complete Freund's adjuvant. Together with interferon-gamma, heat-killed Mycobacterium tuberculosis, an essential component of complete Freund's adjuvant, converted CD11b(hi)CD11c(-) monocytes into tumor necrosis factor-alpha- and nitric oxide synthase 2-producing dendritic cells (TipDCs). Heat-killed M. tuberculosis stimulated production of nitric oxide synthase 2 via Toll-like receptor 2-mediated nuclear factor-kappaB activation. TipDCs limited antigen specific T-cell expansion through nitric oxide synthase 2-dependent nitric oxide production. Moreover, they promoted nitric oxide synthase 2 production in hematopoietic and stromal cells in a paracrine manner. Consequently, nitric oxide synthase 2 production by both radiosensitive hematopoietic and radioresistant stromal cells prevented exacerbation of autoimmune myocarditis in vivo. CONCLUSIONS: Innate Toll-like receptor 2 stimulation promotes formation of regulatory TipDCs, which confine autoreactive T-cell responses in experimental autoimmune myocarditis via nitric oxide. Therefore, activation of innate pattern recognition receptors is critical not only for disease induction but also for counterregulatory mechanisms, protecting the heart from exaggerated autoimmunity. PMID- 23671210 TI - Safety and efficacy of a continuous-flow, injection-assisted device in delivery of dermal fillers. AB - BACKGROUND: A device to assist in the delivery of dermal filler may achieve reductions in patient discomfort and adverse events, as well physician fatigue. It may also increase the accuracy of material placement. OBJECTIVES: The authors assess the safety and performance of the Artiste Assisted Injection System (Nordson Micromedics, St Paul, Minnesota) in normal therapeutic use compared with the standard manual administration of dermal fillers. METHODS: At 3 study sites, a total of 52 patients (48 women and 4 men) received bilateral full-correction injections of dermal fillers into randomized nasolabial folds (NLF). Injection into 1 NLF was made via Artiste, and injection into the other NLF was made via manual delivery. Immediately posttreatment and through 29 days, physician investigators, patients, and blinded evaluators recorded treatment durations and volumes, evaluated designated posttreatment characteristics using questionnaires, and documented adverse events (AE) and differences in cosmetic effects. RESULTS: Mean filler volume was 1.25 mL for the Artiste-treated NLF and 1.29 mL for manually treated NLF. One investigator used significantly less volume with Artiste than with manual injection (0.95 mL vs 1.12 mL; P = .001). Blinded evaluators rated Wrinkle Severity Rating Scale (WSRS) results as "identical" in 81% of patients. Investigator questionnaires showed a clear and statistically significant preference for Artiste over manual injection in all parameters (P < .001). CONCLUSIONS: The Artiste device is a viable option for physicians seeking a continuous-flow, injection-assisted device for ease of treatment, better accuracy, and improved results. PMID- 23671211 TI - How to assess non-calcified plaque in CT angiography: delineation methods affect diagnostic accuracy of low-attenuation plaque by CT for lipid-core plaque in histology. AB - AIMS: To compare the accuracy of two plaque delineation methods for coronary computed tomographic angiography (CTA) to identify lipid-core plaque (LCP) using histology as the reference standard. METHODS AND RESULTS: Five ex vivo hearts were analysed by CTA and histology. LCP was defined by histology as fibroatheroma with core diameter/circumference >200 MUm/>60 degrees and cap thickness <450 MUm. In CTA, plaque was manually delineated either as the difference between the inner and outer vessel walls (Method A) or as a direct tracing of plaque (Method B). Low-attenuation plaque was defined as an area with <90 Hounsfield units. Of 446 co-registered cross-sections, 55 (12%) contained LCP. In CTA, low-attenuation plaque area was larger as assessed with Method A compared with Method B (difference: 120 +/- 60%). Although low-attenuation plaque was associated with the presence of LCP, the delineation Method B yielded higher diagnostic accuracy than Method A [area under the curve (AUC): 0.831 vs. 0.780, respectively, P = 0.005]. After excluding 'normal' cross-sections by CTA (n = 117), AUC for detecting LCP became similar between both methods (0.767 vs. 0.729, P = 0.07, respectively). CONCLUSION: Low-attenuation plaque in CTA is a diagnostic tool for LCP but prone to error if plaque is defined as the area between the inner and outer vessel walls and normal cross-sections are included in the assessment. PMID- 23671212 TI - Reply to letter to the editor entitled "conditions that may affect serum bilirubin levels should be kept in mind in patients with STEMI" by Dr Bugan. PMID- 23671213 TI - Both carvedilol and nebivolol may improve platelet function and prothrombotic state in patients with nonischemic heart failure. AB - It is unclear whether carvedilol and nebivolol will produce different effects on platelet function and prothrombotic state in heart failure (HF). Thus, we compared their effects on these functions in patients with nonischemic HF. We included 61 patients with symptomatic nonischemic HF having ejection fraction <=40%. The patients were randomized to carvedilol (n = 31) or nebivolol (n = 30). Analyses were made at baseline, 3, and 6 months. At 6 months, mean platelet volume (MPV) was significantly lowered by both carvedilol and nebivolol therapy. However, MPV tended to be lower in the carvedilol group (7.7 +/- 1.0 vs 8.0 +/- 0.7 fL, P = .05). Fibrinogen and d-dimer levels were significantly decreased in but comparable in both the groups. Carvedilol and nebivolol have similar beneficial effects on platelet function and prothrombotic state in patients with nonischemic HF. PMID- 23671214 TI - Antipsychotic polypharmacy and high-dose prescription in schizophrenia: a 5-year comparison. AB - OBJECTIVE: The co-prescription of multiple antipsychotic drugs continues to increase despite a lack of evidence supporting this practice. The purpose of this study was to quantify and describe recent trends of antipsychotic polypharmacy in Korean schizophrenic inpatients by comparing prescribed medications between the years of 2005 and 2010. METHODS: We reviewed comprehensive medication profiles of schizophrenic patients discharged from a university psychiatric hospital in 2005 (n=194) or 2010 (n=201). Antipsychotic polypharmacy was defined as the concurrent receipt of two or more chemically distinct antipsychotics for at least 14 days. High antipsychotic dose was defined as a prescribed daily dose to defined daily dose ratio of greater than 1.5. RESULTS: Antipsychotic polypharmacy increased between 2005 (37.1%) and 2010 (48.3%, p=0.025). The most frequently used drug within combinations of antipsychotics was haloperidol in 2005 (51.4%) and quetiapine in 2010 (48.5%). Overall, no changes were observed between 2005 and 2010 in the rate of prescribing high-dose antipsychotics. High-dose antipsychotic monotherapy decreased across years (from 30.4 to 18.4%), but high-dose antipsychotic polypharmacy increased (from 34.0 to 45.3%). Regression analysis revealed that antipsychotic polypharmacy was strongly associated with high doses of prescribed antipsychotics (odds ratio=18.60, p<0.001). CONCLUSIONS: The practice of prescribing multiple antipsychotics to patients with schizophrenia is increasing, and high-dose antipsychotic drugs are more likely to be prescribed in combination than in isolation. The reasons for this pattern of prescription and its impact warrants further study. PMID- 23671216 TI - Treatment notes: objective measures of language style point to clinical insights. AB - Application of a computerized text analysis procedure is proposed that has the potential for use by psychoanalytic and psychodynamic clinicians: the systematic examination of linguistic style as reflected by clinicians in their ongoing process and case notes, which are ubiquitous in the mental health field. The studies reported here are, as far as is known, the first attempts to study treatment notes systematically using such procedures. Linguistic measures are used to track the trajectory of the clinical process throughout the treatment in two contrasting cases, one rated successful, the other not. The computerized linguistic analysis used here focuses on two analytically relevant linguistic variables: Mean High Referential Activity (MHW), a measure of the degree to which language is connected to emotional processing, and Reflection (REF), the use of words referring to logical functions. Changes in the relative position of these measures indicate nodal points in the treatment that might be analytically or therapeutically problematic, and that might be overlooked in a solely clinical reading. The analyst's activity as reported in notes during such nodal periods is clinically examined to see how it may have affected the course of the analysis. This method has the potential for use in ongoing treatments, and may help clinicians refine their interventions. PMID- 23671217 TI - Coming of age? Association for Medical Humanities holds first annual conference. PMID- 23671215 TI - Evaluation of MicroScan WalkAway and Vitek 2 for determination of the susceptibility of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae isolates to cefepime, cefotaxime and ceftazidime. AB - OBJECTIVES: The aim of this study was to evaluate the accuracies of these automated susceptibility test systems with cefepime, cefotaxime and ceftazidime using the new CLSI and EUCAST guidelines in extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae. METHODS: A total of 220 ESBL-producing clinical isolates were collected from 12 hospitals in Korea. Susceptibility testing for cefepime, cefotaxime and ceftazidime was performed by MicroScan WalkAway, Vitek 2 and the CLSI broth microdilution test. ESBL genotypes were determined by PCR amplification. RESULTS: The proportion of isolates classified as susceptible to cefepime and ceftazidime with the CLSI and EUCAST guidelines was 35.0% versus 2.3% for cefepime (P < 0.001) and 21.8% versus 8.2% for ceftazidime (P < 0.001), respectively, and the susceptible isolates were mainly the CTX-M-9 group or SHV-type ESBL producers. All of the isolates were resistant to cefotaxime. Against the total of 220 ESBL-producing isolates, using the CLSI (EUCAST) criteria, very major/major error rates of MicroScan and Vitek 2 were as follows: 1.9%/20.8% (1.8%/20.0%) and 27.4%/0% (12.2%/0%) for cefepime and 2.6%/8.3% (1.2%/0%) and 4.5%/0% (2.3%/0%) for ceftazidime, respectively. The very major error rates of MicroScan and Vitek 2 with cefotaxime were 0.9% and 1.4%, respectively. The errors were mainly major errors for MicroScan and very major errors for Vitek 2. CONCLUSIONS: A substantial portion of ESBL-producing isolates were susceptible to cefepime and ceftazidime by using the CLSI and EUCAST breakpoints. Unfortunately, the error rates of the two automated susceptibility systems were not acceptable for cefepime and ceftazidime. PMID- 23671218 TI - Itinerary: Concerning the professional and spiritual objectives of my life. AB - In this paper I look back on my life, on what have I tried to achieve professionally, and on what trends and theories I have opposed. Next I discuss the convictions and considerations that constituted the building blocks for the spiritual foundation of my life. I reach the conclusion that the building blocks were derived from Judaism and explain why that is so. Finally, I conclude that the scientific and the theological ingredients of my life relate reciprocally and do not exist independently. PMID- 23671219 TI - Who's speaking? PMID- 23671220 TI - Editorial: Medical students and arts and humanities research--fostering creativity, inquisitiveness, and lateral thinking. PMID- 23671221 TI - Researching medicine in context: the Arts and Humanities Medical Scholars Program. AB - In 2000, the Arts and Humanities Medical Scholars Program at Stanford University School of Medicine issued its first grants to medical students interested in researching an area of the medical arts or humanities in depth. To date, 34 projects have been funded, including renewals. The projects encompass a range of genres and topics, from a website on Asian American health and culture to an ethnographic study of women physicians in training in Spain. Two projects are highlighted here: an online history of medicine course and a poetry project. Students are mentored by faculty from a wide array of university departments and centres and submit completion documents to the committee overseeing the programme. Students are encouraged to present their work at conferences, such as the programme's annual symposium, as well as in publication or other appropriate formats. Future directions include integration with the scholarly concentrations initiative at the medical school. PMID- 23671225 TI - A time series analysis of presentations to Queensland health facilities for alcohol-related conditions, following the increase in 'alcopops' tax. AB - OBJECTIVE: In response to concerns about the health consequences of high-risk drinking by young people, the Australian Government increased the tax on pre mixed alcoholic beverages ('alcopops') favoured by this demographic. We measured changes in admissions for alcohol-related harm to health throughout Queensland, before and after the tax increase in April 2008. METHODS: We used data from the Queensland Trauma Register, Hospitals Admitted Patients Data Collection, and the Emergency Department Information System to calculate alcohol-related admission rates per 100,000 people, for 15 - 29 year-olds. We analysed data over 3 years (April 2006 - April 2009), using interrupted time-series analyses. This covered 2 years before, and 1 year after, the tax increase. We investigated both mental and behavioural consequences (via F10 codes), and intentional/unintentional injuries (S and T codes). RESULTS: We fitted an auto-regressive integrated moving average (ARIMA) model, to test for any changes following the increased tax. There was no decrease in alcohol-related admissions in 15 - 29 year-olds. We found similar results for males and females, as well as definitions of alcohol-related harms that were narrow (F10 codes only) and broad (F10, S and T codes). CONCLUSIONS: The increased tax on 'alcopops' was not associated with any reduction in hospital admissions for alcohol-related harms in Queensland 15 - 29 year-olds. PMID- 23671224 TI - Oral health of patients on psychotropic medications: a study of outpatients in Queensland. AB - OBJECTIVE: To describe the oral health of psychiatric patients on psychotropic medication, and compare this to Queensland and national data. METHODS: We interviewed and examined 50 patients on medication at two outpatient clinics in South-east Queensland, in 2010. These areas had unfluoridated water till 2009. RESULTS: One-third of the sample had not visited a dentist in the previous 2 years. One-half reported brushing their teeth once a day; 11% stated they never brushed. The mean of decayed, missing and filled teeth (DMFT) was 17.7 (95% confidence interval (CI) = 16.9 - 18.5), significantly higher than the state (13.1) and national (12.8) averages. Almost one-half of dental decay was untreated, compared to the state and national average of one-quarter. CONCLUSIONS: The oral health of this subgroup within the community is substantially worse than the general population and there are substantially greater treatment needs. Achieving equity in oral health care for these individuals has substantial resource and management implications. PMID- 23671226 TI - Improving the social cognitive deficits of schizophrenia: a community trial of Social Cognition and Interaction Training (SCIT). AB - OBJECTIVE: Social Cognition and Interaction Training (SCIT) is a Cognitive and Behavioural Therapy (CBT) informed group therapy with an emerging evidence base in addressing the social cognitive deficits associated with schizophrenia. This paper evaluates the application of this therapy within a community public mental health setting in Australia. METHOD: A mixed methods approach to the evaluation was undertaken, including survey data and thematic analysis. RESULTS: Considerable challenges were met in the trial of SCIT in this 'real-world' setting. The qualitative data suggested that at least a subset of participants viewed the program as valuable and relevant to their needs. CONCLUSIONS: Further research is required to realise the benefits of SCIT found in research settings, in the real world of public community psychiatric practice. PMID- 23671227 TI - Bridging the gap: does a specialist eating disorder service, aimed at developing a continuum of community care, make a difference? AB - OBJECTIVE: In 2010, the authors identified in a separate publication, Mind the evidence gap, the sparse evidence-base for the treatment of adult anorexia nervosa and barriers to accessing care. We report on the ensuing development, implementation and first 18-month results of a novel eating disorder service bridging the primary and specialist continuum of care in Victoria, Australia. METHOD: Using literature review, stakeholder, and consumer and carer consultation, a model for a community eating disorder service was developed and then implemented. All patients entering the service were then assessed at intake and, if they gave consent, at 12 month follow-up. RESULTS: From December 2010 to July 2012, 208 patients accessed The Body Image Eating Disorders Treatment and Recovery Service (BETRS). Fifty-three per cent had a diagnosis of anorexia nervosa and the mean number of co-morbid psychiatric diagnoses was two. Twenty three per cent attended a day patient programme and showed a significant improvement in their body mass index. Measures of depression, anxiety and eating disorder symptomatology showed a concomitant, significant decrease. CONCLUSIONS: The development of BETRS has led to markedly improved access and effectiveness of specialist services in the region. PMID- 23671233 TI - Retraction. Real-time three-dimensional echocardiography integrated with diagnostic catheterization to derive left ventricular pressure-volume relations: a feasibility study. PMID- 23671232 TI - The year 2012 in the European Heart Journal-Cardiovascular Imaging: Part I. AB - The new multi-modality cardiovascular imaging journal, European Heart Journal - Cardiovascular Imaging, was started in 2012. During its first year, the new Journal has published an impressive collection of cardiovascular studies utilizing all cardiovascular imaging modalities. We will summarize the most important studies from its first year in two articles. The present 'Part I' of the review will focus on studies in myocardial function, myocardial ischaemia, and emerging techniques in cardiovascular imaging. PMID- 23671234 TI - Should medical humanities be a multidisciplinary or an interdisciplinary study? PMID- 23671235 TI - Special thematic issue of Medical Humanities: constructions of self in health and illness. PMID- 23671236 TI - The view from the edgelands. PMID- 23671237 TI - My self as an other: on autoimmunity and "other" paradoxes. AB - The rubric autoimmunity currently encompasses sixty to seventy diverse illnesses which affect many of the tissues of the human body. Western medical practice asserts that the crisis known as autoimmune disease arises when a biological organism compromises its own integrity by misrecognising parts of itself as other than itself and then seeks to eliminate these unrecognised and hence antagonistic aspects of itself. That is, autoimmune illnesses seem to manifest the contradictory and sometimes deadly proposition that the "identity": body/self both is and is not "itself". Based on the assumption that under normal circumstances "the self" ought to coincide naturally with "the body"-or at the very least the self ought to inhabit the living location of the body more or less unproblematically-this scientific paradigm depicts autoimmune illness as a vital paradox. Yet for those of us who have lived through the experience of an autoimmune crisis, the living paradox that we embody may also lead us to question the basis upon which these medical assumptions rest. This essay raises some of these questions. PMID- 23671238 TI - Mental illness and cultural issues in West African films: implications for orthodox psychiatric practice. AB - The portrayal of psychiatry and of the activities of supernatural forces in indigenous films produced in West Africa was critically examined in this study. Most often the content of these films is centred on African culture, African mythical stories, or real life events. Over a three year period, 163 such films were studied. Twenty five (15.3%) of them contained scenes of psychiatric illness. In 24 of these, there were "cases of psychoses"; and the remaining one was that of "deliberate self harm" via overdose with hypno-sedative drug. The causative factors of these "illnesses" were largely attributed to supernatural or preternatural forces. The effective treatment or "healing" of the illnesses was portrayed as arising mostly through magical means or traditional forms of care. In addition, sudden death from "spiritual attack" by these agents was shown in 35 (21.5%) of the films. Scenes of witches and occultists wreaking other forms of havoc on victims at night were shown in eight (4.9%) of the films. The implications of these films' portrayals of psychiatry and supernatural forces for the public (particularly viewers with mental illness) and for orthodox psychiatric practice in the region were highlighted. PMID- 23671239 TI - What's it all about, Alfie? Antisocial males in the early films of Sir Michael Caine. AB - Early in his film career the actor Sir Michael Caine portrayed a series of antisocial males: Harry Palmer, Alfie Elkins, Charlie Croker, and Jack Carter. The behaviours exhibited by these fictional males resemble those of "real life" patients acquiring the diagnoses of antisocial or dissocial personality disorder. Prominent among their traits is a disregard for others, a lack of guilt, and a resort to instrumental (goal directed) violence. The exhibition of antisocial conduct may be seen as a rejection of the values of the social hierarchy, the dominant or patriarchal order. Demonstrable through a defiance of dominant males and a recurrent seduction of "their" women, these Caine characters act out an Oedipal theme, repeatedly attempting subversion of the symbolic "father"-society itself. So often, the material of "real life" social behaviour is fleeting and hard to elicit reliably; however, these fictional characters provide a stable source of such exemplars, both entertaining and instructive. PMID- 23671240 TI - Pickled essence of Englishman: Thomas Lovell Beddoes--time to unearth a neglected poet? AB - Thomas Lovell Beddoes (1803-1849) was a doctor and intermittently brilliant poet whose explorations of "the florid Gothic in poetry" (his words) offer some of the most haunting, claustrophobic, and grotesque verse in the English language. Son of the pioneering Bristol scientist Thomas Beddoes and nephew of Maria Edgeworth the novelist, he stemmed, like Mary Shelley, author of the celebrated novel Frankenstein, from a line of influential freethinkers. This article situates Beddoes's work in the transition from the confident empiricism of the eighteenth century to the nineteenth century's imaginative reaction to social and intellectual life after the Napoleonic wars. Having spent most of his adult life in Germany (where he studied anatomy with the famous biologist Blumenbach) and latterly Switzerland, Beddoes engaged in radical politics, dabbled in the occult, and may even have encountered the German doctor/playwright Georg Buchner, whose career parallels his own. Beddoes hoped that by reading the body literally, in terms of its material structure, he would be able to bring about a revival of English theatre. Inevitable defeat led him to develop his signature form of abject irony. In view of the current interest in semiotics (a development of medical semiology), and the subterranean analogies in Beddoes's writing between the corpus and the corpse, his reputation ought to be rescued from the "critical pickle". PMID- 23671241 TI - Talking around embodiment: the views of GPs following participation in medical anthropology courses. AB - OBJECTIVES: To explore the ways in which general practitioners talk around the concept of "embodiment" after participating in introductory courses in medical anthropology, and to contribute to the debate about what persons and bodies mean for biomedicine. DESIGN: This study used a qualitative interview methodology. PARTICIPANTS: PARTICIPANTS were general practitioners who had all completed at least one introductory course in medical anthropology. RESULTS: In talking around embodiment, respondents articulated several interconnected dimensions of meaning. These included a Cartesian derived perspective of personhood involving complex relationships between intertwined components of soul, body, and mind; phenomenological perspectives on experience; the social meanings of the body; the ways in which individual bodies are acted upon by regulatory social and political bodies, and an implicit articulation of embodiment as relational, fluid, and processual. A theme of integrity or wholeness was discernible as a common thread linking all these understandings. CONCLUSIONS: Critical interpretive medical anthropology crosses social science and humanities boundaries with its explicit orientation around the paradigm of embodiment as a means of understanding lived experience, social and personal meanings of the body, and the political economy of the body. Perhaps its major contribution to postgraduate medical education is its power to encourage or facilitate reflection that is grounded in practice. This study shows that it is possible for medical practitioners to problematise the Cartesianism of biomedicine and its effects on both patients and doctors, and to conceptualise the integrative framework encapsulated in the notion of embodiment as lived medicine. PMID- 23671242 TI - Editorial: Death, dying, and bereavement. PMID- 23671243 TI - "I can't cope with life, I'm too different". PMID- 23671244 TI - Marguerite. PMID- 23671245 TI - Editorial: Philosophy in the undergraduate medical curriculum-- beyond medical ethics. PMID- 23671246 TI - An introductory course in philosophy of medicine. AB - Philosophy of medicine, narrowly defined as ontology and epistemology of medicine, is a well developed research field, yet education in this field is less well developed. The aim of this paper is to present an educational development in philosophy of medicine-an introductory course in philosophy of medicine. Central features of the course are described. Participants (medical undergraduate students) scored high on average. The conclusion is that further such educational ventures in philosophy of medicine should be developed and implemented. PMID- 23671247 TI - Headache research: a string of pearls. PMID- 23671248 TI - Ethical considerations in biomedical research: a personal view. AB - PREMISE: Ethical considerations are made when an experiment is planned and take a regulatory system of moral principles into account. DISCUSSION: Ethical considerations should first and foremost be made in order to protect the individual subject/animal from being exposed to any unethical and perhaps even illegal intervention and to ensure that the experimental conditions used are appropriate. SUMMARY: The main role of research ethics committees is to assess the scientific and ethical aspects of submitted protocols and follow up the trial until its closure. PMID- 23671249 TI - Pearls and pitfalls: neurostimulation in headache. AB - CONTEXT: A variety of neuromodulatory approaches available today has broadened our therapeutic options significantly especially in drug refractory patients with chronic cluster headache and chronic migraine. OVERVIEW: It is a dynamic field with a current trend to non-invasive transcutaneous stimulation approaches. However, sound studies providing evidence for the widespread use of these novel approaches are sparse. For invasive approaches, occipital nerve stimulation is now widely considered the treatment of first choice in chronic trigeminal autonomic cephalgias and - with limitations - chronic migraine. Although equally effective, deep brain stimulation is considered second-line treatment in cluster headache because of its potentially life-threatening side effects. Most recently, stimulation of the sphenopalatine ganglion has also been shown to effectively abort acute cluster headache attacks. Interesting other upcoming approaches include transcutaneous supraorbital nerve stimulation and transcutaneous vagal nerve stimulation. CONCLUSION: Pearls and pitfalls of common invasive and non invasive neuromodulatory approaches and open questions are summarised in this review along with recommendations for future studies. PMID- 23671250 TI - Pearls and pitfalls: electrophysiology for primary headaches. AB - BACKGROUND: Primary headaches are functional neurological diseases characterized by a dynamic cyclic pattern over time (ictal/pre-/interictal). Electrophysiological recordings can non-invasively assess the activity of an underlying nervous structure or measure its response to various stimuli, and are therefore particularly appropriate for the study of primary headaches. Their interest, however, is chiefly pathophysiological, as interindividual, and to some extent intraindividual, variations preclude their use as diagnostic tools. AIM OF THE WORK: This article will review the most important findings of electrophysiological studies in primary headache pathophysiology, especially migraine on which numerous studies have been published. RESULTS: In migraine, the most reproducible hallmark is the interictal lack of neuronal habituation to the repetition of various types of sensory stimulations. The mechanism subtending this phenomenon remains uncertain, but it could be the consequence of a thalamocortical dysrythmia that results in a reduced cortical preactivation level. In tension-type headache as well as in cluster headache, there seems to be an impairment of central pain-controlling mechanisms but the studies are scarce and their outcomes are contradictory. The discrepancies between studies might be as a result of methodological differences as well as patients' dissimilarities, which are also discussed. CONCLUSIONS AND PERSPECTIVES: Electrophysiology is complementary to functional neuroimaging and will undoubtedly remain an important tool in headache research. One of its upcoming applications is to help select neurostimulation techniques and protocols that correct best the functional abnormalities detectable in certain headache disorders. PMID- 23671251 TI - Pearls and pitfalls in human pharmacological models of migraine: 30 years' experience. AB - In vitro studies have contributed to the characterization of receptors in cranial blood vessels and the identification of new possible anti-migraine agents. In vivo animal models enable the study of vascular responses, neurogenic inflammation, peptide release and genetic predisposition and thus have provided leads in the search for migraine mechanisms. All animal-based results must, however, be validated in human studies because so far no animal models can predict the efficacy of new therapies for migraine. Given the nature of migraine attacks, fully reversible and treatable, the headache- or migraine-provoking property of naturally occurring signaling molecules can be tested in a human model. If such an endogenous substance can provoke migraine in human patients, then it is likely, although not certain, that blocking its effect will be effective in the treatment of acute migraine attacks. To this end, a human in vivo model of experimental headache and migraine in humans has been developed. Human models of migraine offer unique possibilities to study mechanisms responsible for migraine and to explore the mechanisms of action of existing and future anti-migraine drugs. The human model has played an important role in translational migraine research leading to the identification of three new principally different targets in the treatment of acute migraine attacks and has been used to examine other endogenous signaling molecules as well as genetic susceptibility factors. New additions to the model, such as advanced neuroimaging, may lead to a better understanding of the complex events that constitute a migraine attack, and better and more targeted ways of intervention. PMID- 23671252 TI - Pearls and pitfalls: neuroimaging in headache. AB - PREMISE: One of the most exciting developments in modern neuroscience was the development of imaging techniques providing a non-invasive technique for detection of structure-function relationships characteristic of pain and headache. There is no question that neuroimaging has provided us with a better understanding of how the aura in migraine develops, and it has served as a bridge between neurophysiological studies and clinical findings, although doubtless several questions remain. PEARLS: Neuroimaging drew attention toward central mechanisms in idiopathic headache syndromes. Outstanding functional studies have reinforced the crucial role of the brainstem in acute and chronic migraine and the hypothalamic area in trigemino-autonomic headaches. Several morphometric studies suggest a decreased gray matter in pain-transmitting areas in headache patients; however, those have to be seen in the light of a wealth of pain studies and studies on exercise-dependent plasticity. GOAL: This review focuses on neuroimaging as a scientific tool and highlights the recent advances made in studying primary headache syndromes using functional and structural neuroimaging techniques. It will also point toward open questions and gives recommendations for future studies. PMID- 23671253 TI - Pearls and pitfalls in experimental in vivo models of headache: conscious behavioral research. AB - BACKGROUND: Physiological studies have been determinant for the understanding of migraine pathophysiology and the screening of novel therapeutics. At present, there is no animal model that translates fully the clinical symptoms of migraine, and generally these studies are conducted on anesthetized animals. METHODOLOGY: Pain as well as non-painful symptoms such as photophobia, need to have a conscious individual to be experienced; therefore, the new development and adaptation of behavioral assays assessing pain and other non-painful symptomatology in conscious animals represents a great opportunity for headache research and it is exciting that more and more researchers are using behavioral paradigms. SUMMARY: This review will describe the different behavioral models for the study of headache that are performed in non-anesthetized conscious animals. The pearls and challenges for measuring hypersensitivity in rodents such as the common tests for measuring mechanical allodynia and thermal hyperalgesia have been the landmark for the development of assays that measure hypersensitivity in the craniofacial region. Here we describe the different behavioral assays that measure hypersensitivity in the craniofacial region as well as the established behavioral models of trigeminovascular nociception and non-nociceptive migrainous symptoms. PMID- 23671255 TI - Pearls and pitfalls in neural CGRP immunohistochemistry. AB - This review outlines the pearls and pitfalls of calcitonin-gene related protein (CGRP) immunohistochemistry of the brain. PEARLS: In 1985, CGRP was first described in cerebral arteries using immunohistochemistry. Since then, cerebral CGRP (and, using novel antibodies, its receptor components) has been widely scrutinized. Here, we describe the distribution of cerebral CGRP and pay special attention to the surprising reliability of results over time. PITFALLS: Pitfalls might include a fixation procedure, antibody clone and dilution, and interpretation of results. Standardization of staining protocols and true quantitative methods are lacking. The use of computerized image analysis has led us to believe that our examination is objective. However, in the steps of performing such an analysis, we make subjective choices. By pointing out these pitfalls, we aim to further improve immunohistochemical quality. RECOMMENDATIONS: Having a clear picture of the tissue/cell morphology is a necessity. A primary morphological evaluation with, for example, hematoxylin-eosin, helps to ensure that small changes are not missed and that background and artifactual changes, which may include vacuoles, pigments, and dark neurons, are not over-interpreted as compound-related changes. The antigen-antibody reaction appears simple and clear in theory, but many steps might go wrong. Remember that methods including the antigen-antibody complex rely on handling/fixation of tissues or cells, antibody shipping/storing issues, antibody titration, temperature/duration of antibody incubation, visualization of the antibody and interpretation of the results. Optimize staining protocols to the material you are using. PMID- 23671254 TI - Pearls and pitfalls in experimental in vivo models of migraine: dural trigeminovascular nociception. AB - BACKGROUND: Migraine is a disorder of the brain and is thought to involve activation of the trigeminovascular system, which includes the peripheral afferent projection to the nociceptive specific dura mater, as well as the central afferent projection to the trigeminal nucleus caudalis. Stimulation of the blood vessels of the dura mater produces pain in patients that is referred to the head similar to headache. HEADACHE MECHANISMS: The likely reason for the pain is because the vascular structures of the dura mater, including the superior sagittal sinus and middle meningeal artery, are richly innervated by a plexus of largely unmyelinated sensory nerve fibers from the ophthalmic division of the trigeminal ganglion. METHODOLOGY: Stimulation of these nociceptive specific nerve fibers is painful and produces neuronal activation in the trigeminal nucleus caudalis. Preclinical models of headache have taken advantage of this primarily nociceptive pathway, and various animal models use dural trigeminovascular nociception to assay aspects of head pain. These assays measure responses at the level of the dural vasculature and the central trigeminal nucleus caudalis as a correlate of trigeminovascular activation thought to be involved in headache. SUMMARY: This review will summarize the history of the development of models of dural trigeminovascular nociception, including intravital microscopy and laser Doppler flowmetry at the level of the vasculature, and electrophysiology and Fos techniques used to observe neuronal activation at the trigeminal nucleus caudalis. It will also describe some of pitfalls of these assays and developments for the future. PMID- 23671256 TI - Pearls and pitfalls in experimental models of spreading depression. AB - BACKGROUND: Spreading depression (SD) is the electrophysiological substrate of migraine aura and a potential trigger for headache. Since its discovery by Leao in 1944, SD has transformed from being viewed as an epiphenomenon into a therapeutic target relevant in the pathophysiology of migraine and brain injury. AIM: Despite decades of research, the underpinnings of SD are still poorly understood, hampering our efforts to selectively block its initiation and spread. Experimental models have nevertheless been useful to measure the likelihood of SD occurrence (i.e. SD susceptibility) and characterize genetic, physiological and pharmacological modulation of SD in search of potential therapies, such as in migraine prophylaxis and stroke. Here, I review experimental SD susceptibility endpoints and surrogates, and minimum essential model requirements to improve their utility in drug screening. CONCLUSION: A critical reappraisal of strengths and caveats of experimental models of SD susceptibility is needed to set standards and improve data quality, interpretation and reconciliation. PMID- 23671257 TI - Pearls and pitfalls in genetic studies of migraine. AB - PURPOSE OF REVIEW: Migraine is a prevalent neurovascular brain disorder with a strong genetic component, and different methodological approaches have been implemented to identify the genes involved. This review focuses on pearls and pitfalls of these approaches and genetic findings in migraine. SUMMARY: Common forms of migraine (i.e. migraine with and without aura) are thought to have a polygenic make-up, whereas rare familial hemiplegic migraine (FHM) presents with a monogenic pattern of inheritance. Until a few years ago only studies in FHM yielded causal genes, which were identified by a classical linkage analysis approach. Functional analyses of FHM gene mutations in cellular and transgenic animal models suggest abnormal glutamatergic neurotransmission as a possible key disease mechanism. Recently, a number of genes were discovered for the common forms of migraine using a genome-wide association (GWA) approach, which sheds first light on the pathophysiological mechanisms involved. CONCLUSIONS: Novel technological strategies such as next-generation sequencing, which can be implemented in future genetic migraine research, may aid the identification of novel FHM genes and promote the search for the missing heritability of common migraine. PMID- 23671258 TI - The prevalence of child sexual abuse in out-of-home care: a comparison between abuse in residential and in foster care. AB - We investigated the 2010 year prevalence of child sexual abuse (CSA) in residential and foster care and compared it with prevalence rates in the general population. We used two approaches to estimate the prevalence of CSA. First, 264 professionals working in residential or foster care (sentinels) reported CSA for the children they worked with (N = 6,281). Second, 329 adolescents staying in residential or foster care reported on their own experiences with CSA. Sentinels and adolescents were randomly selected from 82 Dutch out-of-home care facilities. We found that 3.5 per 1,000 children had been victims of CSA based on sentinel reports. In addition, 58 per 1,000 adolescents reported having experienced CSA. Results based on both sentinel report and self-report revealed higher prevalence rates in out-of-home care than in the general population, with the highest prevalence in residential care. Prevalence rates in foster care did not differ from the general population. According to our findings, children and adolescents in residential care are at increased risk of CSA compared to children in foster care. Unfortunately, foster care does not fully protect children against sexual abuse either, and thus its quality needs to be further improved. PMID- 23671259 TI - Redefining the initiation and maintenance of zebrafish interrenal steroidogenesis by characterizing the key enzyme cyp11a2. AB - Zebrafish are emerging as a model to study steroid hormone action and associated disease. However, steroidogenesis in zebrafish is not well characterized. Mammalian P450 side-chain cleavage enzyme (CYP11A1) catalyzes the first step of steroidogenesis, the conversion of cholesterol to pregnenolone. Previous studies describe an essential role for zebrafish Cyp11a1 during early development. Cyp11a1 has been suggested to be the functional equivalent of mammalian CYP11A1 in the zebrafish interrenal gland (equivalent to the mammalian adrenal), gonad, and brain. However, reported cyp11a1 expression is inconsistent in zebrafish larvae, after active cortisol synthesis commences. Recently a duplicated cyp11a gene, cyp11a2, has been described, which shares an 85% identity with cyp11a1. We aimed to elucidate the specific role of the two cyp11a paralogs. cyp11a1 was expressed from 0 to 48 hours post-fertilization (hpf), whereas cyp11a2 expression started after the development of the interrenal primordium (32 hpf) and was the only paralog in larvae. cyp11a2 is expressed in adult steroidogenic tissues, such as the interrenal, gonads, and brain. In contrast, cyp11a1 was mainly restricted to the gonads. Antisense morpholino knockdown studies confirmed abnormal gastrulation in cyp11a1 morphants. cyp11a2 morphants showed impaired steroidogenesis and a phenotype indicative of metabolic abnormalities. The phenotype was rescued by pregnenolone replacement in cyp11a2 morphants. Thus, we conclude that cyp11a1 is required for early development, whereas cyp11a2 is essential for the initiation and maintenance of zebrafish interrenal steroidogenesis. Importantly, this study highlights the need for a comprehensive characterization of steroidogenesis in zebrafish prior to its implementation as a model organism in translational research of adrenal disease. PMID- 23671260 TI - Hypothalamic inflammation without astrogliosis in response to high sucrose intake is modulated by neonatal nutrition in male rats. AB - Hypothalamic inflammation and gliosis are proposed to participate in the pathogenesis of high-fat diet-induced obesity. Because other factors and nutrients also induce weight gain and adiposity, we analyzed the inflammatory and glial responses to a sucrose (S)-enriched diet. Neonatal overnutrition (NON) exacerbates weight gain in response to metabolic challenges; thus, we compared the inflammatory response of male Wistar rats with NON (4 pups/litter) and controls (12 pups/litter) to increased S intake. At weaning rats received water or a 33% sucrose solution and normal chow ad libitum for 2 months. Sucrose increased serum IL-1beta and -6 and hypothalamic IL-6 mRNA levels in NON and TNFalpha mRNA levels in control and NON rats, whereas NON alone had no effect. The astrocyte marker glial fibrillary acidic protein was increased by NON but decreased by S. This was associated with hypothalamic nuclei specific changes in glial fibrillary acidic protein-positive cell number and morphology. Sucrose increased the number of microglia and phosphorylation of inhibitor of -kappaB and c-Jun N-terminal kinase in control but not NON rats, with no effect on microglia activation markers. Proteins highly expressed in astrocytes (glutamate, glucose, and lactate transporters) were increased by NON but not S, with no increase in vimentin expression in astrocytes, further suggesting that S-induced adiposity is not associated with hypothalamic astrogliosis. Hence, activation of hypothalamic inflammatory processes and gliosis depend not only on weight gain but also on the diet inducing this weight gain and the early nutritional status. These diverse inflammatory processes could indicate a differential disposition to obesity induced pathologies. PMID- 23671261 TI - The impact of ventral noradrenergic bundle lesions on increased IL-1 in the PVN and hormonal responses to stress in male sprague dawley rats. AB - The impact of acute stress on inflammatory signaling within the central nervous system is of interest because these factors influence neuroendocrine function both directly and indirectly. Exposure to certain stressors increases expression of the proinflammatory cytokine, Il-1beta in the hypothalamus. Increased IL-1 is reciprocally regulated by norepinephrine (stimulatory) and corticosterone (inhibitory), yet neural pathways underlying increased IL-1 have not been clarified. These experiments explored the impact of bilateral lesions of the ventral noradrenergic bundle (VNAB) on IL-1 expression in the paraventricular nucleus of the hypothalamus (PVN) after foot shock. Adult male Sprague Dawley rats received bilateral 6-hydroxydopamine lesions of the VNAB (VNABx) and were exposed to intermittent foot shock. VNABx depleted approximately 64% of norepinephrine in the PVN and attenuated the IL-1 response produced by foot shock. However, characterization of the hypothalamic-pituitary-adrenal response, a crucial prerequisite for interpreting the effect of VNABx on IL-1 expression, revealed a profound dissociation between ACTH and corticosterone. Specifically, VNABx blocked the intronic CRH response in the PVN and the increase in plasma ACTH, whereas corticosterone was unaffected at all time points examined. Additionally, foot shock led to a rapid and profound increase in cyclooxygenase-2 and IL-1 expression within the adrenal glands, whereas more subtle effects were observed in the pituitary gland. Together the findings were the 1) demonstration that exposure to acute stress increased expression of inflammatory factors more broadly throughout the hypothalamic-pituitary-adrenal axis; 2) implication of a modest role for norepinephrine-containing fibers of the VNAB as an upstream regulator of PVN IL-1; and 3) suggestion of an ACTH-independent mechanism controlling the release of corticosterone in VNABx rats. PMID- 23671262 TI - 5alpha-reductase inhibition suppresses testosterone-induced initial regrowth of regressed xenograft prostate tumors in animal models. AB - Androgen deprivation therapy (ADT) is the standard treatment for patients with prostate-specific antigen progression after treatment for localized prostate cancer. An alternative to continuous ADT is intermittent ADT (IADT), which allows recovery of testosterone during off-cycles to stimulate regrowth and differentiation of the regressed prostate tumor. IADT offers patients a reduction in side effects associated with ADT, improved quality of life, and reduced cost with no difference in overall survival. Our previous studies showed that IADT coupled with 5alpha-reductase inhibitor (5ARI), which blocks testosterone conversion to DHT could prolong survival of animals bearing androgen-sensitive prostate tumors when off-cycle duration was fixed. To further investigate this clinically relevant observation, we measured the time course of testosterone induced regrowth of regressed LuCaP35 and LNCaP xenograft tumors in the presence or absence of a 5ARI. 5alpha-Reductase inhibitors suppressed the initial regrowth of regressed prostate tumors. However, tumors resumed growth and were no longer responsive to 5alpha-reductase inhibition several days after testosterone replacement. This finding was substantiated by bromodeoxyuridine and Ki67 staining of LuCaP35 tumors, which showed inhibition of prostate tumor cell proliferation by 5ARI on day 2, but not day 14, after testosterone replacement. 5alpha-Reductase inhibitors also suppressed testosterone-stimulated proliferation of LNCaP cells precultured in androgen-free media, suggesting that blocking testosterone conversion to DHT can inhibit prostate tumor cell proliferation via an intracrine mechanism. These results suggest that short off-cycle coupled with 5alpha-reductase inhibition could maximize suppression of prostate tumor growth and, thus, improve potential survival benefit achieved in combination with IADT. PMID- 23671263 TI - Insulin and IGF-I inhibit GH synthesis and release in vitro and in vivo by separate mechanisms. AB - IGF-I is considered a primary inhibitor of GH secretion. Insulin may also play an important role in regulating GH levels because insulin, like IGF-I, can suppress GH synthesis and release in primary pituitary cell cultures and insulin is negatively correlated with GH levels in vivo. However, understanding the relative contribution insulin and IGF-I exert on controlling GH secretion has been hampered by the fact that circulating insulin and IGF-I are regulated in parallel and insulin (INSR) and IGF-I (IGFIR) receptors are structurally/functionally related and ubiquitously expressed. To evaluate the separate roles of insulin and IGF-I in directly regulating GH secretion, we used the Cre/loxP system to knock down the INSR and IGFIR in primary mouse pituitary cell cultures and found insulin-mediated suppression of GH is independent of the IGFIR. In addition, pharmacological blockade of intracellular signals in both mouse and baboon cultures revealed insulin requires different pathways from IGF-I to exert a maximal inhibitory effect on GH expression/release. In vivo, somatotrope-specific knockout of INSR (SIRKO) or IGFIR (SIGFRKO) increased GH levels. However, comparison of the pattern of GH release, GH expression, somatotrope morphometry, and pituitary explant sensitivity to acute GHRH challenge in lean SIRKO and SIGFRKO mice strongly suggests the primary role of insulin in vivo is to suppress GH release, whereas IGF-I serves to regulate GH synthesis. Finally, SIRKO and/or SIGFRKO could not prevent high-fat, diet-induced suppression of pituitary GH expression, indicating other factors/tissues are involved in the decline of GH observed with weight gain. PMID- 23671264 TI - Clinical and functional impact of TARBP2 over-expression in adrenocortical carcinoma. AB - Deregulation of microRNA (miRNA) expression in adrenocortical carcinomas (ACCs) has been documented to have diagnostic, prognostic, as well as functional implications. Here, we evaluated the mRNA expression of DROSHA, DGCR8, DICER (DICER1), TARBP2, and PRKRA, the core components in the miRNA biogenesis pathway, in a cohort of 73 adrenocortical tumors (including 43 adenomas and 30 carcinomas) and nine normal adrenal cortices using a RT-qPCR approach. Our results show a significant over-expression of TARBP2, DICER, and DROSHA in the carcinomas compared with adenomas or adrenal cortices (P<0.001 for all comparisons). Using western blot and immunohistochemistry analyses, we confirmed the higher expression of TARBP2, DICER, and DROSHA at the protein level in carcinoma cases. Furthermore, we demonstrate that mRNA expression of TARBP2, but not DICER or DROSHA, is a strong molecular predictor to discriminate between adenomas and carcinomas. Functionally, we showed that inhibition of TARBP2 expression in human NCI-H295R ACC cells resulted in a decreased cell proliferation and induction of apoptosis. TARBP2 over-expression was not related to gene mutations; however, copy number gain of the TARBP2 gene was observed in 57% of the carcinomas analyzed. In addition, we identified that miR-195 and miR-497 could directly regulate TARBP2 and DICER expression in ACC cells. This is the first study to demonstrate the deregulation of miRNA-processing factors in adrenocortical tumors and to show the clinical and biological impact of TARBP2 over-expression in this tumor type. PMID- 23671265 TI - Renin-angiotensin system blockade in heart failure patients on long-term haemodialysis in Taiwan. AB - AIMS: Heart failure is among the most frequent complications of patients on long term haemodialysis. The benefits of renin-angiotensin system (RAS) blockade on the outcomes of these patients have yet to be determined. METHODS AND RESULTS: We conducted a nationwide observational study using data from the Taiwan National Health Insurance claims database, between 1999 and 2010. We enrolled patients aged >=35 years with new-onset heart failure [diagnosed by International Classification of Diseases, 9th revision, clinical modification (ICD-9-CM) codes] under treatment with medications. New users of a RAS blocker (RASB; i.e., an ACE inhibitor or an ARB used as monotherapy or dual therapy) were selected to compare with non-RASB users. We used Cox proportional hazards regression with and without propensity score adjustment to compare the risk of 3-year all-cause and cardiovascular mortality. Stratified analyses and RASB therapy duration as a time dependent covariate were also performed. In all, 4771 were treated with an RASB (n = 3024) or without an RASB (n = 1747). RASB users had a higher prevalence of hypertension and diabetes, and a higher number of hospitalization. Among RASB users, 1148 deaths (38.0%) occurred during 5272 person-years of follow-up compared with 734 deaths (42.0%) among non-RASB users during 2683 person-years of follow-up. Three-year mortality rates were 45.4% and 49.1% for patients receiving and those not receiving an RASB, respectively (log-rank test, P < 0.001). Adjusted hazard analysis revealed that RASB therapeutic effects remained significant on all-cause [hazard ratio (HR) 0.8; 95% confidence interval (CI) 0.72-0.89; P < 0.001] and cardiovascular mortality (HR 0.76; 95% CI 0.64-0.90; P < 0.01). CONCLUSIONS: RASB therapy reduced all-cause and cardiovascular mortality in heart failure patients on long-term haemodialysis. PMID- 23671266 TI - Evaluation of children with heart murmurs. AB - Cardiac murmurs can be a source of anxiety for both physicians and parents until serious cardiac disorders are excluded. The innocent cardiac murmur is still the most common finding in healthy children and can usually be diagnosed through obtaining a complete history and performing a complete physical examination. However, a cardiac murmur may be the first sign of a structural cardiac disease and should not be ignored. Referral to a pediatric cardiologist for further evaluation is required when murmur assessment is not clear and diagnostic uncertainty is present. Educating and reassuring parents remains an important aspect of this evaluation. This article discusses features of innocent and pathological murmurs and provides an approach to cardiac murmurs in children. PMID- 23671267 TI - Bioavailability of Auvi-Q and EpiPen: focus on pharmacokinetics. PMID- 23671268 TI - Factors affecting subspecialty referrals by pediatric primary care providers for children with obesity-related comorbidities. AB - OBJECTIVE: To determine referral patterns from pediatric primary care to subspecialists for overweight/obesity and related comorbidities. METHODS: We used the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey to identify overweight/obesity and 5 related comorbidities in primary care visits between 2005 and 2009 by children 6 to 18 years. The primary outcome was whether the visit ended in referral. We used multivariable analysis to examine factors associated with referral. RESULTS: We identified 34,225 database visits. A total of 17.1% were with overweight (body mass index=85th to 94th percentile) or obese (body mass index>=95th percentile) patients. A total of 7.1% of primary care visits with overweight/obese children ended in referral. Referral was more likely when obesity was the reason for visit (odds ratio=2.83; 95% confidence interval=1.61-4.97) but was not associated with presence of a comorbidity (odds ratio=1.35; 95% confidence interval=0.75-2.44). CONCLUSIONS: Most overweight or obese children are not referred, regardless of comorbidity status. One reason may be low levels of appropriate diagnosis. PMID- 23671269 TI - A college student with muscle cramps and weakness. Diagnosis: Bulimia nervosa, purging subtype, complicated by rhabdomyolysis and acute renal failure. PMID- 23671270 TI - Deliberate practice improves pediatric residents' skills and team behaviors during simulated neonatal resuscitation. AB - OBJECTIVE: To evaluate the skills and team behavior of pediatric residents during resuscitation with a high-fidelity mannequin before and after a deliberate practice intervention. METHODS: Each month residents participate in two 90-minute videorecorded sessions (2-3 weeks apart) in an "off-site" delivery room during their neonatal ICU rotation. Teams responded to a scenario that required 5 skills (positive pressure ventilation, chest compressions, endotracheal intubation, umbilical vein catheterization, and epinephrine administration). Skills were scored for technique and timeliness and team behaviors for communication, management, and leadership. A 2-hour focused intervention was given between sessions. RESULTS: In all, 33 residents (11 teams) completed the sessions. Gaps in procedural skills noted during the first session were corrected. Timeliness for completion of skills remained below expectations. Improvements in team behaviors were noted. CONCLUSIONS: Deliberate practice improved procedural skills and team performance. Lack of improvement in timeliness suggests that a different educational paradigm is required. PMID- 23671271 TI - Therapeutic effect of probiotic dahi on plasma, aortic, and hepatic lipid profile of hypercholesterolemic rats. AB - This study examined the effects of probiotic dahi prepared by Lactobacillus plantarum Lp9 and dahi culture in buffalo milk on lowering cholesterol in rats fed a hypercholesterolemic basal diet. Male Wistar rats were divided into 3 groups and fed with probiotic dahi, dahi, or buffalo milk for 120 days. Following the consumption of supplements (probiotic dahi, dahi or buffalo milk), the animals were fed a basal hypercholesterolemic diet. Plasma total cholesterol and triglycerides (TAGs) were decreased by 35% and 72% in rats fed with probiotic dahi group, while cholesterol levels increased by 70% and TAGs increased by 97% in buffalo milk and 59% in dahi fed groups. Supplementation of probiotic dahi further lowered plasma low-density lipoprotein (LDL) + very-low-density lipoprotein (VLDL)- cholesterol by 59%, while it elevated plasma high-density lipoprotein (HDL)-cholesterol by 116%. As a result, atherogenic index, the ratio of HDL to LDL + VLDL was markedly improved. Deposition of cholesterol and TAGs in liver and aorta were significantly reduced in rats fed with probiotic dahi. These observations suggest that probiotic dahi may have therapeutic potential to decrease plasma, hepatic and aortic lipid profile, and attenuate diet-induced hypercholesterolemia. PMID- 23671272 TI - A novel peptide carrier for efficient targeting of antigens and nucleic acids to dendritic cells. AB - Dendritic cells (DCs) initiate host immune responses by presenting captured antigens to naive T cells. Hence, DC-binding peptides may be used for antigen targeting to boost naive and memory immune responses. By biopanning peptide phage libraries on human monocyte-derived DCs, we identified novel DC-binding peptides. One of the selected phages, displaying the NW peptide (NWYLPWLGTNDW), bound DCs with high affinity, and its binding was inhibited by the corresponding synthetic peptide. Antigenic peptides or proteins conjugated to the NW peptide bound to DCs and were internalized without negative effects on DC phenotype and function. Ex vivo targeted delivery of CMV-pp65 peptides to DCs via the NW peptide increased T cell responses in HLA-A2(+)/CMV(+) donors compared to untargeted peptides (P<0.001). Stimulation of CD45RO-depleted peripheral blood mononuclear cells from CMV(-) donors with the NW-pp65 fusion peptides expanded pp65-specific precursor T cells. Moreover, the NW peptide mediated small interfering RNA delivery to DCs, and a significant gene silencing was obtained. Collectively, the data reveal that proteins and nucleic acids can be directed to DCs through the NW peptide, enabling effective uptake and functional effects such as T-cell activation in the context of MHC class I and II molecules. PMID- 23671273 TI - Elastin sequences trigger transient proinflammatory responses by human dermal fibroblasts. AB - Following penetrating injury of the skin, a highly orchestrated and overlapping sequence of events helps to facilitate wound resolution. Inflammation is a hallmark that is initiated early, but the reciprocal relationship between cells and matrix molecules that triggers and maintains inflammation is poorly appreciated. Elastin is enriched in the deep dermis of skin. We propose that deep tissue injury encompasses elastin damage, yielding solubilized elastin that triggers inflammation. As dermal fibroblasts dominate the deep dermis, this means that a direct interaction between elastin sequences and fibroblasts would reveal a proinflammatory signature. Tropoelastin was used as a surrogate for elastin sequences. Tropoelastin triggered fibroblast expression of the metalloelastase MMP-12, which is normally expressed by macrophages. MMP-12 expression increased 1056 +/- 286-fold by 6 h and persisted for 24 h. Chemokine expression was more transient, as chemokine C-X-C motif ligand 8 (CXCL8), CXCL1, and CXCL5 transcripts increased 11.8 +/- 2.6-, 10.2 +/- 0.4-, and 8593 +/- 996-fold, respectively, by 6-12 h and then decreased. Through the use of specific inhibitors and protein truncation, we found that transduction of the tropoelastin signal was mediated by the fibroblast elastin binding protein (EBP). In silico modeling using a predictive computational fibroblast model confirmed the up regulation, and simulations revealed PKA as a key part of the signaling circuit. We tested this prediction with 1 MUM PKA inhibitor H-89 and found that 2 h of exposure correspondingly reduced expression of MMP-12 (63.9+/-12.3%) and all chemokine markers, consistent with the levels seen with EBP inhibition, and validated PKA as a novel node and druggable target to ameliorate the proinflammatory state. A separate trigger that utilized C-terminal RKRK of tropoelastin reduced marker expression to 65.0-76.5% and suggests the parallel involvement of integrin alphaVbeta3. We propose that the solubilization of elastin as a result of dermal damage leads to rapid chemokine up-regulation by fibroblasts that is quenched when exposed elastin is removed by MMP-12. PMID- 23671274 TI - Carbon monoxide inhibition of Cav3.2 T-type Ca2+ channels reveals tonic modulation by thioredoxin. AB - T-type Ca(2+) channels play diverse roles in tissues such as sensory neurons, vascular smooth muscle, and cancers, where increased expression of the cytoprotective enzyme, heme oxygenase-1 (HO-1) is often found. Here, we report regulation of T-type Ca(2+) channels by carbon monoxide (CO) a HO-1 by-product. CO (applied as CORM-2) caused a concentration-dependent, poorly reversible inhibition of all T-type channel isoforms (Cav3.1-3.3, IC50 ~3 MUM) expressed in HEK293 cells, and native T-type channels in NG108-15 cells and primary rat sensory neurons. No recognized CO-sensitive signaling pathway could account for the CO inhibition of Cav3.2. Instead, CO sensitivity was mediated by an extracellular redox-sensitive site, which was also highly sensitive to thioredoxin (Trx). Trx depletion (using auranofin, 2-5 MUM) reduced Cav3.2 currents and their CO sensitivity by >50% but increased sensitivity to dithiothreitol ~3-fold. By contrast, Cav3.1 and Cav3.3 channels, and their sensitivity to CO, were unaffected in identical experiments. Our data propose a novel signaling pathway in which Trx acts as a tonic, endogenous regulator of Cav3.2 channels, while HO-1-derived CO disrupts this regulation, causing channel inhibition. CO modulation of T-type channels has widespread implications for diverse physiological and pathophysiological mechanisms, such as excitability, contractility, and proliferation. PMID- 23671276 TI - Impaired very long-chain acyl-CoA beta-oxidation in human X-linked adrenoleukodystrophy fibroblasts is a direct consequence of ABCD1 transporter dysfunction. AB - X-linked adrenoleukodystrophy (X-ALD), an inherited peroxisomal disorder, is caused by mutations in the ABCD1 gene encoding the peroxisomal ATP-binding cassette (ABC) transporter ABCD1 (adrenoleukodystrophy protein, ALDP). Biochemically, X-ALD is characterized by an accumulation of very long-chain fatty acids and partially impaired peroxisomal beta-oxidation. In this study, we used primary human fibroblasts from X-ALD and Zellweger syndrome patients to investigate the peroxisomal beta-oxidation defect. Our results show that the degradation of C26:0-CoA esters is as severely impaired as degradation of unesterified very long-chain fatty acids in X-ALD and is abolished in Zellweger syndrome. Interestingly, the beta-oxidation rates for both C26:0-CoA and C22:0 CoA were similarly affected, although C22:0 does not accumulate in patient fibroblasts. Furthermore, we show that the beta-oxidation defect in X-ALD is directly caused by ABCD1 dysfunction as blocking ABCD1 function with a specific antibody reduced beta-oxidation to levels observed in X-ALD fibroblasts. By quantification of mRNA and protein levels of the peroxisomal ABC transporters and by blocking with specific antibodies, we found that residual beta-oxidation activity toward C26:0-CoA in X-ALD fibroblasts is mediated by ABCD3, although the efficacy of ABCD3 appeared to be much lower than that of ABCD1. Finally, using isolated peroxisomes, we show that beta-oxidation of C26:0-CoA is independent of additional CoA but requires a cytosolic factor of >10-kDa molecular mass that is resistant to N-ethylmaleimide and heat inactivation. In conclusion, our findings in human cells suggest that, in contrast to yeast cells, very long-chain acyl-CoA esters are transported into peroxisomes by ABCD1 independently of additional synthetase activity. PMID- 23671275 TI - NMR- and circular dichroism-monitored lipid binding studies suggest a general role for the FATC domain as membrane anchor of phosphatidylinositol 3-kinase related kinases (PIKK). AB - The FATC domain is shared by all members of the family of phosphatidylinositol-3 kinase-related kinases (PIKKs). It has been shown that the FATC domain plays an important role for the regulation of each PIKK. However, other than an involvement in protein-protein interactions, a common principle for the action of the FATC domain has not been detected. A detailed characterization of the structure and lipid binding properties of the FATC domain of the Ser/Thr kinase target of rapamycin (TOR) revealed that it contains a redox-sensitive membrane anchor in its C terminus. Because the C-terminal regions of the FATC domains of all known PIKKs are rather hydrophobic and especially rich in aromatic residues, we examined whether the ability to interact with lipids and membranes might be a general property. Here, we present the characterization of the interactions with lipids and different membrane mimetics for the FATC domains of human DNA-PKcs, human ATM, human ATR, human SMG-1, and human TRRAP by NMR and CD spectroscopy. The data indicate that all of these can interact with different membrane mimetics and may have different preferences only for membrane properties such as surface charge, curvature, and lipid packing. The oxidized form of the TOR FATC domain is well structured overall and forms an alpha-helix that is followed by a disulfide bonded loop. In contrast, the FATC domains of the other PIKKs are rather unstructured in the isolated form and only significantly populate alpha-helical secondary structure upon interaction with membrane mimetics. PMID- 23671277 TI - alpha7 helix region of alphaI domain is crucial for integrin binding to endoplasmic reticulum chaperone gp96: a potential therapeutic target for cancer metastasis. AB - Integrins play important roles in regulating a diverse array of cellular functions crucial to the initiation, progression, and metastasis of tumors. Previous studies have shown that a majority of integrins are folded by the endoplasmic reticulum chaperone gp96. Here, we demonstrate that the dimerization of integrin alphaL and beta2 is highly dependent on gp96. The alphaI domain (AID), a ligand binding domain shared by seven integrin alpha-subunits, is a critical region for integrin binding to gp96. Deletion of AID significantly reduced the interaction between integrin alphaL and gp96. Overexpression of AID intracellularly decreased surface expression of gp96 clients (integrins and Toll like receptors) and cancer cell invasion. The alpha7 helix region is crucial for AID binding to gp96. A cell-permeable alpha7 helix peptide competitively inhibited the interaction between gp96 and integrins and blocked cell invasion. Thus, targeting the binding site of alpha7 helix of AID on gp96 is potentially a new strategy for treatment of cancer metastasis. PMID- 23671278 TI - CD163 binding to haptoglobin-hemoglobin complexes involves a dual-point electrostatic receptor-ligand pairing. AB - Formation of the haptoglobin (Hp)-hemoglobin (Hb) complex in human plasma leads to a high affinity recognition by the endocytic macrophage receptor CD163. A fast segregation of Hp-Hb from CD163 occurs at endosomal conditions (pH <6.5). The ligand binding site of CD163 has previously been shown to involve the scavenger receptor cysteine-rich (SRCR) domain 3. This domain and the adjacent SRCR domain 2 of CD163 contain a consensus motif for a calcium-coordinated acidic amino acid triad cluster as originally identified in the SRCR domain of the scavenger receptor MARCO. Here we show that site-directed mutagenesis in each of these acidic triads of SRCR domains 2 and 3 abrogates the high affinity binding of recombinant CD163 to Hp-Hb. In the ligand, Hp Arg-252 and Lys-262, both present in a previously identified CD163 binding loop of Hp, were revealed as essential residues for the high affinity receptor binding. These findings are in accordance with pairing of the calcium-coordinated acidic clusters in SRCR domains 2 and 3 with the two basic Arg/Lys residues in the Hp loop. Such a two-point electrostatic pairing is mechanistically similar to the pH-sensitive pairings disclosed in crystal structures of ligands in complex with tandem LDL receptor repeats or tandem CUB domains in other endocytic receptors. PMID- 23671279 TI - Receptor for activated C-kinase (RACK1) homolog Cpc2 facilitates the general amino acid control response through Gcn2 kinase in fission yeast. AB - General amino acid control (GAAC) is crucial for sensing and adaptation to nutrient availability. Amino acid starvation activates protein kinase Gcn2, which plays a central role in the GAAC response by phosphorylating the alpha-subunit of eukaryotic initiation factor 2 (eIF2alpha), leading to the translational switch to stimulate selective expression of stress-responsive genes. We report here that in fission yeast Schizosaccharomyces pombe, Cpc2, a homolog of mammalian receptor for activated C-kinase (RACK1), is important for the GAAC response. Deletion of S. pombe cpc2 impairs the amino acid starvation-induced phosphorylation of eIF2alpha and the expression of amino acid biosynthesis genes, thereby rendering cells severely sensitive to amino acid limitation. Unlike the Saccharomyces cerevisiae Cpc2 ortholog, which normally suppresses the GAAC response, our findings suggest that S. pombe Cpc2 promotes the GAAC response. We also found that S. pombe Cpc2 is required for starvation-induced Gcn2 autophosphorylation, which is essential for Gcn2 function. These results indicate that S. pombe Cpc2 facilitates the GAAC response through the regulation of Gcn2 activation and provide a novel insight for the regulatory function of RACK1 on Gcn2-mediated GAAC response. PMID- 23671280 TI - Auto-ubiquitination of Mdm2 enhances its substrate ubiquitin ligase activity. AB - The RING domain E3 ubiquitin ligase Mdm2 is the master regulator of the tumor suppressor p53. It targets p53 for proteasomal degradation, restraining the potent activity of p53 and enabling cell survival and proliferation. Like most E3 ligases, Mdm2 can also ubiquitinate itself. How Mdm2 auto-ubiquitination may influence its substrate ubiquitin ligase activity is undefined. Here we show that auto-ubiquitination of Mdm2 is an activating event. Mdm2 that has been conjugated to polyubiquitin chains, but not to single ubiquitins, exhibits substantially enhanced activity to polyubiquitinate p53. Mechanistically, auto-ubiquitination of Mdm2 facilitates the recruitment of the E2 ubiquitin-conjugating enzyme. This occurs through noncovalent interactions between the ubiquitin chains on Mdm2 and the ubiquitin binding domain on E2s. Mutations that diminish the noncovalent interactions render auto-ubiquitination unable to stimulate Mdm2 substrate E3 activity. These results suggest a model in which polyubiquitin chains on an E3 increase the local concentration of E2 enzymes and permit the processivity of substrate ubiquitination. They also support the notion that autocatalysis may be a prevalent mode for turning on the activity of latent enzymes. PMID- 23671281 TI - Vitamin D receptor inhibits nuclear factor kappaB activation by interacting with IkappaB kinase beta protein. AB - 1,25-Dihydroxyvitamin D (1,25(OH)2D3) is known to suppress NF-kappaB activity, but the underlying mechanism remains poorly understood. Here we show that the vitamin D receptor (VDR) physically interacts with IkappaB kinase beta (IKKbeta) to block NF-kappaB activation. 1,25(OH)2D3 rapidly attenuates TNFalpha-induced p65 nuclear translocation and NF-kappaB activity in a VDR-dependent manner. VDR overexpression inhibits IKKbeta-induced NF-kappaB activity. GST pull-down assays and coimmunoprecipitation experiments demonstrated that VDR physically interacts with IKKbeta and that this interaction is enhanced by 1,25(OH)2D3. Protein mapping reveals that VDR-IKKbeta interaction occurs between the C-terminal portions of the VDR and IKKbeta proteins. Reconstitution of VDR(-/-) cells with the VDR C terminus restores the ability to block TNFalpha-induced NF-kappaB activation and IL-6 up-regulation. VDR-IKKbeta interaction disrupts the formation of the IKK complex and, thus, abrogates IKKbeta phosphorylation at Ser-177 and abolishes IKK activity to phosphorylate IkappaBalpha. Consequently, stabilization of IkappaBalpha arrests p65/p50 nuclear translocation. Together, these data define a novel mechanism whereby 1,25(OH)2D3-VDR inhibits NF-kappaB activation. PMID- 23671282 TI - DEF pocket in p38alpha facilitates substrate selectivity and mediates autophosphorylation. AB - Signaling processes are primarily promoted by molecular recognition and corresponding protein-protein interactions. One of the key eukaryotic signaling pathways is the MAP kinase cascade involved in vital cellular processes such as cell proliferation, differentiation, apoptosis, and stress response. The principle recognition site of MAP kinases, the common docking (CD) region, forms selective interactions with substrates, upstream activators, and phosphatases. A second docking site, defined as the DEF site interaction pocket (DEF pocket), is formed subsequent to ERK2 and p38alpha activation. Both crystal structures of p38alpha in its dually phosphorylated form and of intrinsically active mutants showed the DEF pocket, giving motivation for studying its role in substrate activation and selectivity. Mutating selected DEF pocket residues significantly decreased the phosphorylation levels of three p38alpha substrates (ATFII, Elk-1, and MBP) with no apparent effect on the phosphorylation of MK2 kinase. Conversely, mutating the CD region gave the opposite effect, suggesting p38alpha substrates can be classified into DEF-dependent and DEF-independent substrates. In addition, mutating DEF pocket residues decreased the autophosphorylation capability of intrinsically active p38alpha mutants, suggesting DEF-mediated trans-autophosphorylation in p38alpha. These results could contribute to understanding substrate selectivity of p38alpha and serve as a platform for designing p38alpha-selective DEF site blockers, which partially inhibit p38alpha binding DEF-dependent substrates, whereas maintaining its other functions intact. In this context, preliminary results using synthetic peptides reveal significant inhibition of substrate phosphorylation by activated p38alpha. PMID- 23671283 TI - Role of cystatin C in amyloid precursor protein-induced proliferation of neural stem/progenitor cells. AB - The amyloid precursor protein (APP) is well studied for its role in Alzheimer disease. However, little is known about its normal function. In this study, we examined the role of APP in neural stem/progenitor cell (NSPC) proliferation. NSPCs derived from APP-overexpressing Tg2576 transgenic mice proliferated more rapidly than NSPCs from the corresponding background strain (C57Bl/6xSJL) wild type mice. In contrast, NSPCs from APP knock-out (APP-KO) mice had reduced proliferation rates when compared with NSPCs from the corresponding background strain (C57Bl/6). A secreted factor, identified as cystatin C, was found to be responsible for this effect. Levels of cystatin C were higher in the Tg2576 conditioned medium and lower in the APP-KO conditioned medium. Furthermore, immunodepletion of cystatin C from the conditioned medium completely removed the ability of the conditioned medium to increase NSPC proliferation. The results demonstrate that APP expression stimulates NSPC proliferation and that this effect is mediated via an increase in cystatin C secretion. PMID- 23671284 TI - EPI64B acts as a GTPase-activating protein for Rab27B in pancreatic acinar cells. AB - The small GTPase Rab27B localizes to the zymogen granule membranes and plays an important role in regulating protein secretion by pancreatic acinar cells, as does Rab3D. A common guanine nucleotide exchange factor (GEF) for Rab3 and Rab27 has been reported; however, the GTPase-activating protein (GAP) specific for Rab27B has not been identified. In this study, the expression in mouse pancreatic acini of two candidate Tre-2/Bub2/Cdc16 (TBC) domain-containing proteins, EPI64 (TBC1D10A) and EPI64B (TBC1D10B), was first demonstrated. Their GAP activity on digestive enzyme secretion was examined by adenovirus-mediated overexpression of EPI64 and EPI64B in isolated pancreatic acini. EPI64B almost completely abolished the GTP-bound form of Rab27B, without affecting GTP-Rab3D. Overexpression of EPI64B also enhanced amylase release. This enhanced release was independent of Rab27A, but dependent on Rab27B, as shown using acini from genetically modified mice. EPI64 had a mild effect on both GTP-Rab27B and amylase release. Co overexpression of EPI64B with Rab27B can reverse the inhibitory effect of Rab27B on amylase release. Mutations that block the GAP activity decreased the inhibitory effect of EPI64B on the GTP-bound state of Rab27B and abolished the enhancing effect of EPI64B on the amylase release. These data suggest that EPI64B can serve as a potential physiological GAP for Rab27B and thereby participate in the regulation of exocytosis in pancreatic acinar cells. PMID- 23671285 TI - Polysialic acid is present in mammalian semen as a post-translational modification of the neural cell adhesion molecule NCAM and the polysialyltransferase ST8SiaII. AB - Fertilization in animals is a complex sequence of several biochemical events beginning with the insemination into the female reproductive tract and, finally, leading to embryogenesis. Studies by Kitajima and co-workers (Miyata, S., Sato, C., and Kitajima, K. (2007) Trends Glycosci. Glyc, 19, 85-98) demonstrated the presence of polysialic acid (polySia) on sea urchin sperm. Based on these results, we became interested in the potential involvement of sialic acid polymers in mammalian fertilization. Therefore, we isolated human sperm and performed analyses, including Western blotting and mild 1,2-diamino-4,5 methylenedioxybenzene-HPLC, that revealed the presence alpha2,8-linked polySia chains. Further analysis by a glyco-proteomics approach led to the identification of two polySia carriers. Interestingly, besides the neural cell adhesion molecule, the polysialyltransferase ST8SiaII has also been found to be a target for polysialylation. Further analysis of testis and epididymis tissue sections demonstrated that only epithelial cells of the caput were polySia-positive. During the epididymal transit, polySia carriers were partially integrated into the sperm membrane of the postacrosomal region. Because polySia is known to counteract histone as well as neutrophil extracellular trap-mediated cytotoxicity against host cells, which plays a role after insemination, we propose that polySia in semen represents a cytoprotective element to increase the number of vital sperm. PMID- 23671286 TI - A conserved mechanism for gating in an ionotropic glutamate receptor. AB - Ionotropic glutamate receptor (iGluR) channels control synaptic activity. The crystallographic structure of GluA2, the prototypical iGluR, reveals a clamshell like ligand-binding domain (LBD) that closes in the presence of glutamate to open a gate on the pore lining alpha-helix. How LBD closure leads to gate opening remains unclear. Here, we show that bending the pore helix at a highly conserved alanine residue (Ala-621) below the gate is responsible for channel opening. Substituting Ala-621 with the smaller more flexible glycine resulted in a basally active, nondesensitizing channel with ~39-fold increase in glutamate potency without affecting surface expression or binding. On GluA2(A621G), the partial agonist kainate showed efficacy similar to a full agonist, and competitive antagonists CNQX and DNQX acted as a partial agonists. Met-629 in GluA2 sits above the gate and is critical in transmitting LBD closure to the gate. Substituting Met-629 with the flexible glycine resulted in reduced channel activity and glutamate potency. The pore regions in potassium channels are structurally similar to iGluRs. Whereas potassium channels typically use glycines as a hinge for gating, iGluRs use the less flexible alanine as a hinge at a similar position to maintain low basal activity allowing for ligand-mediated gating. PMID- 23671287 TI - Identification of DNMT1 selective antagonists using a novel scintillation proximity assay. AB - A novel scintillation proximity high throughput assay (SPA) to identify inhibitors of DNA methyltransferases was developed and used to screen over 180,000 compounds. The majority of the validated hits shared a quinone core and several were found to generate the reactive oxygen species, H2O2. Inhibition of the production of H2O2 by the addition of catalase blocked the ability of this group of compounds to inhibit DNA methyltransferase (DNMT) activity. However, a related compound, SW155246, was identified that existed in an already reduced form of the quinone. This compound did not generate H2O2, and catalase did not block its ability to inhibit DNA methyltransferase. SW155246 showed a 30-fold preference for inhibition of human DNMT1 versus human or murine DNMT3A or -3B, inhibited global methylation in HeLa cells, and reactivated expression of the tumor suppressor gene RASSF1A in A549 cells. To our knowledge, this work represents the first description of selective chemical inhibitors of the DNMT1 enzyme. PMID- 23671290 TI - Pain does not suffer misprision: an inquiry into the presence and absence that is pain. AB - The reigning questions of metaphysics generate passion. These are questions such as concern death, a hereafter, and the meaning of suffering. They are questions that haunt us. Philosophical inquiries into these topics are often constructed Socratically. In turn, such logical machinations are founded upon the belief that a discernible outcome or answer to metaphysical questions exists. Western thought labours under the tenet that the impasse of "unknowableness" can be bridged with the brute force of intellect. Pain is not only the motivation for metaphysical inquiry; it becomes the universal metaphor for loss. It absorbs displaced fears and becomes a vehicle for expressing a "lack". The essence of pain, therefore, is negative. It is absence (and hence not an existence). Even though pain is a lack, however, we relate to it as if it were a presence that denies us of our passion for life. PMID- 23671288 TI - Insulin-like growth factor-1 bioactivity plays a prosurvival role in older participants. AB - The aim of this study was to address the intriguing issue of the role of the insulin-like growth factor (IGF)-1 system in longevity looking at the role of different components of IGF system. Vital status was ascertained in 1,197 men and women aged greater than or equal to 65 years from the InCHIANTI study. Hormonal levels were categorized into quartiles, and ratio of IGF-1 to IGF-binding protein (IGFBP)-1 was calculated. The relationship between hormones and mortality was tested by Cox proportional hazard models adjusted for age, sex, and confounders. During the 8-year follow-up period, 240 died and 957 survived. Lowest quartiles of IGF-1 and IGFBP-1 were considered as reference. Compared with the lowest quartiles, IGF-1 in upper quartiles was a negative predictor of mortality independent of age and sex (p = .01) but not independent of IGFBP-1 and other confounders. IGFBP-1 in second-third quartiles was negatively associated and that in the fourth quartiles was positively associated with risk of death. IGF-1/IGFBP 1 ratio in the lowest quartiles was a strong positive predictor of mortality, in age- and sex-adjusted model (p = .005), and independent of additional confounders (p = .037). High IGFBP-1 and low IGF-1/IGFBP-1 ratio are associated with all cause mortality in older population. PMID- 23671291 TI - The patient's lament: hidden key to effective communication: how to recognise and transform. AB - "Our dancing is changed into mourning" Lamentations 5:15 to "you turned my lament into dancing" Psalm 30:12.Numerous studies and well publicised complaints from the public have long revealed a pressing need for physicians to improve their communication skills and their ability to interpret and respond appropriately to what they hear from patients. Rushed and dispirited, physicians are routinely urged to become more compassionate and to spend more time listening. This article challenges the myth that listening is a time consuming art propelled by compassion and demonstrates that it is in fact a highly active professional skill that can be greatly clarified and simplified for practising physicians. The lament is offered as a universally encountered, sometimes masked, expression that patients need to have heard and validated. An intellectual understanding of the lament as a symptom of suffering greatly facilitates the listening process and enables the listener to respond therapeutically. This saves time, improves quality of care, and enhances the wellbeing and satisfaction of both physician and patient. PMID- 23671289 TI - Vocal training mitigates age-related changes within the vocal mechanism in old rats. AB - Aging affects voice production and is associated with reduced communicative ability and quality of life. Voice therapy is a critical component of treatment, but its effects on neuromuscular mechanisms are unknown. The ultrasonic vocalizations (USVs) of rats can be used to test the effects of aging and voice use on the laryngeal neuromuscular system. This study tested the hypothesis that age-related changes in the USVs of rats and laryngeal neuromuscular junctions can be reversed through vocal exercise. Young and old rats were trained for 8 weeks to increase their USVs and were compared with a no intervention group pre- and post-treatment. USV acoustics and aspects of neuromuscular junction (NMJ) morphology were measured in the thyroarytenoid muscle. Vocal training reduced or eliminated some age differences found in both USVs and NMJs. We conclude that vocal exercise may assist in mitigating age-related changes in voice characteristics and underlying neuromuscular adaptations. PMID- 23671292 TI - Transcendence and healing. AB - Healing aims to restore the wholeness of persons by restoring the unity of mind and body disrupted by disease. Transcendence promotes healing by altering or cultivating beliefs that can modulate the body's response to pain or make sense of pain. This in turn can produce an emotional response that enables people to cope with chronic or terminal illness. I explain transcendence in terms of a monistic rather than dualistic conception of mind and body, which supports the idea of medicine as a healing art as well as a curative science. PMID- 23671293 TI - Serjeant Musgrave's disease. AB - The present title takes a liberty with the title of playwright John Arden's Serjeant Musgrave's Dance, but not with the text. Toward the end of the play, Serjeant Musgrave exclaims "There used to be my duty: now there's a disease". So what is the serjeant's "disease"? The play, subtitled "an unhistoric parable" is a commentary on an unspecified late 19th century war in a British protectorate as experienced by four soldiers, now returned to England and visiting a North country colliery town, ostensibly to recruit, but with a deeper motive not initially apparent. Readers of Medical Humanities will know that the arts hold more for doctors than direct clinical relevance, and this play is no exception. There is a powerful account, not inappropriate at the present time, of the disruptive effects of war and violence on the soldiers involved, their families, and the civilian populations. War is contrasted with the industrial unrest in the local colliery. My present concern is to examine Serjeant Musgrave's mental state, and the dynamics within his band. PMID- 23671294 TI - Giselle, madness & death. AB - In this paper the Romantic ballet Giselle (1841) is used as a case study through which to examine the themes of madness and death. Giselle is a heartrending story of the intertwining of love and death. It is argued that Giselle is an evocative example of narratives of hysteria and suicide, and literature in the field of medical history is drawn upon to demonstrate the relations between the cultural fields of ballet, medicine, and the wider social world at the time of Giselle. Finally, it is suggested that the notion of the embodiment of vulnerability provides a fruitful way to meld our understandings of the interconnections between the arts, society, and medicine. PMID- 23671295 TI - Guesswork and guilt--the mind of a suicide. AB - This is an imagined dialogue between the ghost of a young suicide and an old schoolfriend. The living discussant, a doctor now, regrets that he did not realise how deeply troubled his friend was, and wants to know if and in what way he could have dissuaded the depressed schoolboy from his irrevocable decision. The ghost, however, confident in death, free from mental anguish, challenges the doctor's presumptions. What right does he, does society have, to stop, detain, dissuade, and "cure" those who wish to kill themselves? The issues of sanity, free will, and societal judgment are explored in an encounter that can never take place, but which sheds light on the thought processes of the suicidal. PMID- 23671296 TI - "As vast as the world"--reflections on A Very Easy Death by Simone de Beauvoir. AB - In 1964, Simone de Beauvoir, arguably one of the greatest writers of 20th century Europe, published an account of the final 6 weeks of her mother's life. It is a beautifully written, raw, honest, and powerful evocation of that period from the viewpoint of a relative. Its themes are universal-love, ambivalence in family ties, loss, and bereavement. Given that the events preceded the modern palliative care movement, reflections are made on differences in medical practice since the book's publication. PMID- 23671297 TI - Through the looking glass. PMID- 23671298 TI - Anniversary VE day. PMID- 23671299 TI - Warts. PMID- 23671300 TI - Gunman aimed to please. PMID- 23671301 TI - Flawless for tom. PMID- 23671302 TI - Fighting man. PMID- 23671303 TI - Editorial: The medical humanities teaching and research agenda: a symbiotic relationship. PMID- 23671305 TI - A view from the edge: professionalism in an island practice. PMID- 23671304 TI - A literature and medicine special study module run by academics in general practice: two evaluations and the lessons learnt. AB - This paper describes the design, delivery and evaluation of a nine week special study module on literature and medicine for third year undergraduate medical students, by tutors from an academic department of general practice. Three weeks of taught seminars are followed by three weeks of one on one meetings between individual students and tutors, leading to a seminar led by, and based on, materials prepared by the student. The final three weeks of the course are dedicated to completion of essays about areas chosen by students for in depth study.The course was evaluated on two separate occasions, using two different techniques: the first evaluation used a focus group technique to identify and explore relevant themes; the second used nominal group theory to assess whether the course worked educationally, and how it could be improved.In the main, the course was judged to meets its aims, with generally positive student comments, albeit with caveats and reservations. The subject matter was intellectually challenging for students and tutors. Further research into the optimal size for such groups, and a more formal evaluation of tutors' experiences is required. PMID- 23671306 TI - Can Frankenstein be read as an early research ethics text? PMID- 23671307 TI - Victor Ambros: the broad scope of microRNAs. Interview by Caitlin Sedwick. PMID- 23671308 TI - Route to destruction: autophagosomes SNARE lysosomes. AB - Autophagy allows cells to encapsulate parts of their cytosol into unique double membrane structures. These autophagosomes mature to fuse with lysosomes and deliver the enclosed contents for degradation. Three recent papers, including one by Takats et al. (2013. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201211160), have taken different routes to discover a role for Syntaxin 17 in the maturation of autophagosomes. PMID- 23671310 TI - Autophagosomal Syntaxin17-dependent lysosomal degradation maintains neuronal function in Drosophila. AB - During autophagy, phagophores capture portions of cytoplasm and form double membrane autophagosomes to deliver cargo for lysosomal degradation. How autophagosomes gain competence to fuse with late endosomes and lysosomes is not known. In this paper, we show that Syntaxin17 is recruited to the outer membrane of autophagosomes to mediate fusion through its interactions with ubisnap (SNAP 29) and VAMP7 in Drosophila melanogaster. Loss of these genes results in accumulation of autophagosomes and a block of autolysosomal degradation during basal, starvation-induced, and developmental autophagy. Viable Syntaxin17 mutant adults show large-scale accumulation of autophagosomes in neurons, severe locomotion defects, and premature death. These mutant phenotypes cannot be rescued by neuron-specific inhibition of caspases, suggesting that caspase activation and cell death do not play a major role in brain dysfunction. Our findings reveal the molecular mechanism underlying autophagosomal fusion events and show that lysosomal degradation and recycling of sequestered autophagosome content is crucial to maintain proper functioning of the nervous system. PMID- 23671309 TI - The cell biology of disease: cellular and molecular mechanisms underlying muscular dystrophy. AB - The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle. Since the discovery of the first muscular dystrophy gene encoding dystrophin, a large number of genes have been identified that are involved in various muscle-wasting and neuromuscular disorders. Human genetic studies complemented by animal model systems have substantially contributed to our understanding of the molecular pathomechanisms underlying muscle degeneration. Moreover, these studies have revealed distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes. PMID- 23671311 TI - Dynamic bonds and polar ejection force distribution explain kinetochore oscillations in PtK1 cells. AB - Duplicated mitotic chromosomes aligned at the metaphase plate maintain dynamic attachments to spindle microtubules via their kinetochores, and multiple motor and nonmotor proteins cooperate to regulate their behavior. Depending on the system, sister chromatids may display either of two distinct behaviors, namely (1) the presence or (2) the absence of oscillations about the metaphase plate. Significantly, in PtK1 cells, in which chromosome behavior appears to be dependent on the position along the metaphase plate, both types of behavior are observed within the same spindle, but how and why these distinct behaviors are manifested is unclear. Here, we developed a new quantitative model to describe metaphase chromosome dynamics via kinetochore-microtubule interactions mediated by nonmotor viscoelastic linkages. Our model reproduces all the key features of metaphase sister kinetochore dynamics in PtK1 cells and suggests that differences in the distribution of polar ejection forces at the periphery and in the middle of PtK1 cell spindles underlie the observed dichotomy of chromosome behavior. PMID- 23671312 TI - Ligand-induced activation of a formin-NPF pair leads to collaborative actin nucleation. AB - Formins associate with other nucleators and nucleation-promoting factors (NPFs) to stimulate collaborative actin assembly, but the mechanisms regulating these interactions have been unclear. Yeast Bud6 has an established role as an NPF for the formin Bni1, but whether it also directly regulates the formin Bnr1 has remained enigmatic. In this paper, we analyzed NPF-impaired alleles of bud6 in a bni1Delta background and found that Bud6 stimulated Bnr1 activity in vivo. Furthermore, Bud6 bound directly to Bnr1, but its NPF effects were masked by a short regulatory sequence, suggesting that additional factors may be required for activation. We isolated a novel in vivo binding partner of Bud6, Yor304c-a/Bil1, which colocalized with Bud6 and functioned in the Bnr1 pathway for actin assembly. Purified Bil1 bound to the regulatory sequence in Bud6 and triggered NPF effects on Bnr1. These observations define a new mode of formin regulation, which has important implications for understanding NPF-nucleator pairs in diverse systems. PMID- 23671313 TI - A light-triggered protein secretion system. AB - Optical control of protein interactions has emerged as a powerful experimental paradigm for manipulating and studying various cellular processes. Tools are now available for controlling a number of cellular functions, but some fundamental processes, such as protein secretion, have been difficult to engineer using current optical tools. Here we use UVR8, a plant photoreceptor protein that forms photolabile homodimers, to engineer the first light-triggered protein secretion system. UVR8 fusion proteins were conditionally sequestered in the endoplasmic reticulum, and a brief pulse of light triggered robust forward trafficking through the secretory pathway to the plasma membrane. UVR8 was not responsive to excitation light used to image cyan, green, or red fluorescent protein variants, allowing multicolor visualization of cellular markers and secreted protein cargo as it traverses the cellular secretory pathway. We implemented this novel tool in neurons to demonstrate restricted, local trafficking of secretory cargo near dendritic branch points. PMID- 23671314 TI - The relationship between TSH and free T4 in a large population is complex and nonlinear and differs by age and sex. AB - CONTEXT: The relationship between TSH and T4 is thought to be inverse log-linear, but recent studies have challenged this. There are limited data regarding age and sex differences in the TSH-T4 relationship. OBJECTIVE: The purpose of this study was to evaluate the TSH-free T4 relationship in a large sample. METHODS: In a cross-sectional, retrospective study, we analyzed TSH and free T4 results from 152 261 subjects collected over 12 years by a single laboratory. For each free T4 value (in picomoles per liter), the median TSH was calculated and analyzed by sex and age (in 20-year bands). RESULTS: The relationship between log TSH and free T4 was nonlinear. Mathematical modeling confirmed that it was described by 2 sigmoid curves with inflexion points at free T4 concentrations of 7 and 21 pmol/L. For free T4 within the reference range (10-20 pmol/L), median TSH was higher in men than in women (P < .001) and increased across age bands with the highest values in those 80 years and older (P < .001). In contrast, in overt hypothyroidism (n = 4403), TSH was lower in older age groups than in those aged 20-39 years (P < .001). CONCLUSIONS: The TSH-free T4 relationship is not inverse log-linear but can be described by 2 overlapping negative sigmoid curves. At physiological free T4 concentrations, TSH is higher in men and in older people, whereas the TSH response to hypothyroidism is more robust in younger people. These results advance understanding of the TSH-free T4 relationship, which is central to thyroid pathophysiology and laboratory diagnosis of thyroid disease. PMID- 23671315 TI - Hyperthyroidism due to thyroid-stimulating hormone secretion after surgery for Cushing's syndrome: a novel cause of the syndrome of inappropriate secretion of thyroid-stimulating hormone. AB - CONTEXT: Hyperthyroidism with the syndrome of inappropriate secretion of TSH (SITSH) occurred by a decrease in hydrocortisone dose after surgery for Cushing's syndrome. This is a novel cause of SITSH. OBJECTIVE: The aim of this study was to describe and discuss 2 cases of SITSH patients that were found after surgery for Cushing's syndrome. We also checked whether SITSH occurred in 7 consecutive patients with Cushing's syndrome after surgery. PATIENTS AND METHODS: A 45-year old Japanese woman with ACTH-independent Cushing's syndrome and a 37-year-old Japanese man with ACTH-dependent Cushing's syndrome presented SITSH caused by insufficient replacement of hydrocortisone for postoperative adrenal insufficiency. When the dose of hydrocortisone was reduced to less than 20 mg/d within 18 days after surgery, SITSH occurred in both cases. We examined whether the change of the hydrocortisone dose induced the secretion of TSH. Free T3 and TSH were normalized by the hydrocortisone dose increase of 30 mg/d, and these were elevated by the dose decrease of 10 mg/d. We also checked TSH and thyroid hormone levels of the 7 consecutive patients with Cushing's syndrome after surgery. Six (66.6 %) of 9 patients showed SITSH. CONCLUSIONS: This is the first report that insufficient replacement of hydrocortisone after surgery for Cushing's syndrome caused SITSH. Hyperthyroidism by SITSH as well as adrenal insufficiency can contribute to withdrawal symptoms of hydrocortisone replacement. We need to consider the possibility of SITSH for the pathological evaluation of withdrawal syndrome of hydrocortisone replacement. PMID- 23671316 TI - Predicting need for fixation of atypical femoral fracture. AB - CONTEXT: Predictors of the requirement for fixation have not been reported in incomplete atypical femoral fractures. The clinical features of incomplete atypical femoral fractures should be reviewed to predict the requirement for surgical intervention in this condition. OBJECTIVE: Our purposes were (1) to evaluate the clinical results of incomplete atypical femoral fracture and (2) to determine the factors associated with the requirement for fixation in incomplete atypical femoral fractures. DESIGN, SETTING, AND PATIENTS: We retrospectively reviewed the medical records of 51 patients with a total of 65 incomplete atypical femoral fractures from 3 tertiary referral centers. Minimum follow-up was 12 months (mean, 19.8 months; range, 12-82 months). INTERVENTION: The study consisted of fixation-requiring and non-fixation-requiring groups. MAIN OUTCOME MEASURE: The main outcome measure was the requirement for fixation. RESULTS: Thirty-one (47.7 %) hips required internal fixation. Cox regression analysis showed that the subtrochanteric location was significantly associated with the requirement for fixation (hazard ratio, 2.713; 95% confidence interval, 1.189 6.189). CONCLUSIONS: About one-half of incomplete atypical femur fractures required surgical intervention, and subtrochanteric involvement could be used as a predictor of the requirement for fixation in these conditions. PMID- 23671317 TI - Solid pseudopapillary pancreatic tumor mimicking a neuroendocrine neoplasm on 18F FDOPA PET/CT. PMID- 23671318 TI - Questioning the habitual and taken-for-granted. PMID- 23671319 TI - Portraits, patients and practitioners. PMID- 23671328 TI - Dexamethasone induces a putative repressor complex and chromatin modifications in the CRH promoter. AB - Glucocorticoids down-regulate expression of hypothalamic CRH; however, mechanisms by which they do so are not fully understood. The proximal promoter cAMP response element, negative glucocorticoid response element (nGRE), and methylated CpG islands all play a role in crh down-regulation. Dexamethasone (Dex)-repressed crh expression is associated with glucocorticoid receptor (GR) and histone deacetylase 1 (HDAC1) recruitment to the region of the crh promoter. Given that HDAC1 may be present in methylated CpG binding protein 2 (MeCP2) complexes, and that MeCP2 is known to play a role in regulating crh expression, we sought to determine whether or not HDAC1 and/or MeCP2 could interact with the GR. Dex enhanced GR interactions with both proteins. Glucocorticoid regulation of crh has also been associated with CpG methylation; thus we assessed whether GR could interact with a DNA methyltransferase (DnMT). Indeed, the GR interacted with DnMT3b, but not DnMT3a. In addition, Dex-induced occupancy of the crh promoter by HDAC1, MeCP2, and DnMT3b was associated with an increased level of promoter methylation, which appeared to be CpG site specific. Lastly, to extend previous assessment of chromatin modifications in this promoter region, the degree of histone methylation was measured. Dex increased trimethylation of histone 3 lysine 9, a marker of gene suppression; however, levels of di- and trimethylated histone 3-lysine 4, markers of gene activation, were not significantly changed. Taken together, the data suggest that Dex-mediated crh suppression involves formation of a repressor complex consisting of GR, MeCP2, and HDAC1, recruitment of DnMT3b, and associated changes in proximal promoter CpG methylation. PMID- 23671330 TI - Arabidopsis thylakoid formation 1 is a critical regulator for dynamics of PSII LHCII complexes in leaf senescence and excess light. AB - In higher plants, photosystem II (PSII) is a large pigment-protein supramolecular complex composed of the PSII core complex and the plant-specific peripheral light harvesting complexes (LHCII). PSII-LHCII complexes are highly dynamic in their quantity and macro-organization to various environmental conditions. In this study, we reported a critical factor, the Arabidopsis Thylakoid Formation 1 (THF1) protein, which controls PSII-LHCII dynamics during dark-induced senescence and light acclimation. Loss-of-function mutations in THF1 lead to a stay-green phenotype in pathogen-infected and senescent leaves. Both LHCII and PSII core subunits are retained in dark-induced senescent leaves of thf1, indicative of the presence of PSII-LHCII complexes. Blue native (BN)-polyacrylamide gel electrophoresis (PAGE) and immunoblot analysis showed that, in dark- and high light-treated thf1 leaves, a type of PSII-LHCII megacomplex is selectively retained while the stability of PSII-LHCII supercomplexes significantly decreased, suggesting a dual role of THF1 in dynamics of PSII-LHCII complexes. We showed further that THF1 interacts with Lhcb proteins in a pH-dependent manner and that the stay-green phenotype of thf1 relies on the presence of LHCII complexes. Taken together, the data suggest that THF1 is required for dynamics of PSII-LHCII supramolecular organization in higher plants. PMID- 23671329 TI - Suppression of Ser/Thr phosphatase 4 (PP4C/PPP4C) mimics a novel post-mitotic action of fostriecin, producing mitotic slippage followed by tetraploid cell death. AB - Fostriecin is a natural product purified from Sterptomyces extracts with antitumor activity sufficient to warrant human clinical trials. Unfortunately, difficulties associated with supply and stable drug formulation stalled further development. At a molecular level, fostriecin is known to act as a catalytic inhibitor of four PPP-family phosphatases, and reports describing the design of molecules in this class suggest derivatives targeting enzymes within the fostriecin-sensitive subfamily can be successful. However, it is not clear if the tumor-selective cytotoxicity of fostriecin results from the inhibition of a specific phosphatase, multiple phosphatases, or a limited subset of fostriecin sensitive phosphatases. How the inhibition of sensitive phosphatases contributes to tumor-selective cytotoxicity is also not clear. Here, high-content time-lapse imaging of live cells revealed novel insight into the cellular actions of fostriecin, showing that fostriecin-induced apoptosis is not simply induced following a sustained mitotic arrest. Rather, apoptosis occurred in an apparent second interphase produced when tetraploid cells undergo mitotic slippage. Comparison of the actions of fostriecin and antisense-oligonucleotides specifically targeting human fostriecin-sensitive phosphatases revealed that the suppression PP4C alone is sufficient to mimic many actions of fostriecin. Importantly, targeted suppression of PP4C induced apoptosis, with death occurring in tetraploid cells following mitotic slippage. This effect was not observed following the suppression of PP1C, PP2AC, or PP5C. These data clarify PP4C as a fostriecin-sensitive phosphatase and demonstrate that the suppression of PP4C triggers mitotic slippage/apoptosis. IMPLICATIONS: Future development of fostriecin class inhibitors should consider PP4C as a potentially important target. Mol Cancer Res; 11(8); 845-55. (c)2013 AACR. PMID- 23671331 TI - EvoDesign: De novo protein design based on structural and evolutionary profiles. AB - Protein design aims to identify new protein sequences of desirable structure and biological function. Most current de novo protein design methods rely on physics based force fields to search for low free-energy states following Anfinsen's thermodynamic hypothesis. A major obstacle of such approaches is the inaccuracy of the force field design, which cannot accurately describe the atomic interactions or distinguish correct folds. We developed a new web server, EvoDesign, to design optimal protein sequences of given scaffolds along with multiple sequence and structure-based features to assess the foldability and goodness of the designs. EvoDesign uses an evolution-profile-based Monte Carlo search with the profiles constructed from homologous structure families in the Protein Data Bank. A set of local structure features, including secondary structure, torsion angle and solvation, are predicted by single-sequence neural network training and used to smooth the sequence motif and accommodate the physicochemical packing. The EvoDesign algorithm has been extensively tested in large-scale protein design experiments, which demonstrate enhanced foldability and structural stability of designed sequences compared with the physics-based designing methods. The EvoDesign server is freely available at http://zhanglab.ccmb.med.umich.edu/EvoDesign. PMID- 23671332 TI - MoMA-LigPath: a web server to simulate protein-ligand unbinding. AB - Protein-ligand interactions taking place far away from the active site, during ligand binding or release, may determine molecular specificity and activity. However, obtaining information about these interactions with experimental or computational methods remains difficult. The computational tool presented in this article, MoMA-LigPath, is based on a mechanistic representation of the molecular system, considering partial flexibility, and on the application of a robotics inspired algorithm to explore the conformational space. Such a purely geometric approach, together with the efficiency of the exploration algorithm, enables the simulation of ligand unbinding within short computing time. Ligand unbinding pathways generated by MoMA-LigPath are a first approximation that can provide useful information about protein-ligand interactions. When needed, this approximation can be subsequently refined and analyzed using state-of-the-art energy models and molecular modeling methods. MoMA-LigPath is available at http://moma.laas.fr. The web server is free and open to all users, with no login requirement. PMID- 23671334 TI - A new reference implementation of the PSICQUIC web service. AB - The Proteomics Standard Initiative Common QUery InterfaCe (PSICQUIC) specification was created by the Human Proteome Organization Proteomics Standards Initiative (HUPO-PSI) to enable computational access to molecular-interaction data resources by means of a standard Web Service and query language. Currently providing >150 million binary interaction evidences from 28 servers globally, the PSICQUIC interface allows the concurrent search of multiple molecular-interaction information resources using a single query. Here, we present an extension of the PSICQUIC specification (version 1.3), which has been released to be compliant with the enhanced standards in molecular interactions. The new release also includes a new reference implementation of the PSICQUIC server available to the data providers. It offers augmented web service capabilities and improves the user experience. PSICQUIC has been running for almost 5 years, with a user base growing from only 4 data providers to 28 (April 2013) allowing access to 151 310 109 binary interactions. The power of this web service is shown in PSICQUIC View web application, an example of how to simultaneously query, browse and download results from the different PSICQUIC servers. This application is free and open to all users with no login requirement (http://www.ebi.ac.uk/Tools/webservices/psicquic/view/main.xhtml). PMID- 23671333 TI - IgBLAST: an immunoglobulin variable domain sequence analysis tool. AB - The variable domain of an immunoglobulin (IG) sequence is encoded by multiple genes, including the variable (V) gene, the diversity (D) gene and the joining (J) gene. Analysis of IG sequences typically requires identification of each gene, as well as a comparison of sequence variations in the context of defined regions. General purpose tools, such as the BLAST program, have only limited use for such tasks, as the rearranged nature of an IG sequence and the variable length of each gene requires multiple rounds of BLAST searches for a single IG sequence. Additionally, manual assembly of different genes is difficult and error prone. To address these issues and to facilitate other common tasks in analysing IG sequences, we have developed the sequence analysis tool IgBLAST (http://www.ncbi.nlm.nih.gov/igblast/). With this tool, users can view the matches to the germline V, D and J genes, details at rearrangement junctions, the delineation of IG V domain framework regions and complementarity determining regions. IgBLAST has the capability to analyse nucleotide and protein sequences and can process sequences in batches. Furthermore, IgBLAST allows searches against the germline gene databases and other sequence databases simultaneously to minimize the chance of missing possibly the best matching germline V gene. PMID- 23671335 TI - 3DEM Loupe: Analysis of macromolecular dynamics using structures from electron microscopy. AB - Electron microscopy (EM) provides access to structural information of macromolecular complexes in the 3-20 A resolution range. Normal mode analysis has been extensively used with atomic resolution structures and successfully applied to EM structures. The major application of normal modes is the identification of possible conformational changes in proteins. The analysis can throw light on the mechanism following ligand binding, protein-protein interactions, channel opening and other functional macromolecular movements. In this article, we present a new web server, 3DEM Loupe, which allows normal mode analysis of any uploaded EM volume using a user-friendly interface and an intuitive workflow. Results can be fully explored in 3D through animations and movies generated by the server. The application is freely available at http://3demloupe.cnb.csic.es. PMID- 23671336 TI - The telomere lengthening conundrum--artifact or biology? AB - Recent longitudinal studies of age-dependent leukocyte telomere length (LTL) attrition have reported that variable proportions of individuals experience LTL lengthening. Often, LTL lengthening has been taken at face value, and authors have speculated about the biological causation of this finding. Based on empirical data and theoretical considerations, we show that regardless of the method used to measure telomere length (Southern blot or quantitative polymerase chain reaction-based methods), measurement error of telomere length and duration of follow-up explain almost entirely the absence of age-dependent LTL attrition in longitudinal studies. We find that LTL lengthening is far less frequent in studies with long follow-up periods and those that used a high-precision Southern blot method (as compared with quantitative polymerase chain reaction determination, which is associated with larger laboratory error). We conclude that the LTL lengthening observed in longitudinal studies is predominantly, if not entirely, an artifact of measurement error, which is exacerbated by short follow-up periods. We offer specific suggestions for design of longitudinal studies of LTL attrition to diminish this artifact. PMID- 23671337 TI - Crystal structure and functional insights into uracil-DNA glycosylase inhibition by phage Phi29 DNA mimic protein p56. AB - Uracil-DNA glycosylase (UDG) is a key repair enzyme responsible for removing uracil residues from DNA. Interestingly, UDG is the only enzyme known to be inhibited by two different DNA mimic proteins: p56 encoded by the Bacillus subtilis phage 29 and the well-characterized protein Ugi encoded by the B. subtilis phage PBS1/PBS2. Atomic-resolution crystal structures of the B. subtilis UDG both free and in complex with p56, combined with site-directed mutagenesis analysis, allowed us to identify the key amino acid residues required for enzyme activity, DNA binding and complex formation. An important requirement for complex formation is the recognition carried out by p56 of the protruding Phe191 residue from B. subtilis UDG, whose side-chain is inserted into the DNA minor groove to replace the flipped-out uracil. A comparative analysis of both p56 and Ugi inhibitors enabled us to identify their common and distinctive features. Thereby, our results provide an insight into how two DNA mimic proteins with different structural and biochemical properties are able to specifically block the DNA binding domain of the same enzyme. PMID- 23671338 TI - Analysis Tool Web Services from the EMBL-EBI. AB - Since 2004 the European Bioinformatics Institute (EMBL-EBI) has provided access to a wide range of databases and analysis tools via Web Services interfaces. This comprises services to search across the databases available from the EMBL-EBI and to explore the network of cross-references present in the data (e.g. EB-eye), services to retrieve entry data in various data formats and to access the data in specific fields (e.g. dbfetch), and analysis tool services, for example, sequence similarity search (e.g. FASTA and NCBI BLAST), multiple sequence alignment (e.g. Clustal Omega and MUSCLE), pairwise sequence alignment and protein functional analysis (e.g. InterProScan and Phobius). The REST/SOAP Web Services (http://www.ebi.ac.uk/Tools/webservices/) interfaces to these databases and tools allow their integration into other tools, applications, web sites, pipeline processes and analytical workflows. To get users started using the Web Services, sample clients are provided covering a range of programming languages and popular Web Service tool kits, and a brief guide to Web Services technologies, including a set of tutorials, is available for those wishing to learn more and develop their own clients. Users of the Web Services are informed of improvements and updates via a range of methods. PMID- 23671339 TI - r3Cseq: an R/Bioconductor package for the discovery of long-range genomic interactions from chromosome conformation capture and next-generation sequencing data. AB - The coupling of chromosome conformation capture (3C) with next-generation sequencing technologies enables the high-throughput detection of long-range genomic interactions, via the generation of ligation products between DNA sequences, which are closely juxtaposed in vivo. These interactions involve promoter regions, enhancers and other regulatory and structural elements of chromosomes and can reveal key details of the regulation of gene expression. 3C seq is a variant of the method for the detection of interactions between one chosen genomic element (viewpoint) and the rest of the genome. We present r3Cseq, an R/Bioconductor package designed to perform 3C-seq data analysis in a number of different experimental designs. The package reads a common aligned read input format, provides data normalization, allows the visualization of candidate interaction regions and detects statistically significant chromatin interactions, thus greatly facilitating hypothesis generation and the interpretation of experimental results. We further demonstrate its use on a series of real-world applications. PMID- 23671345 TI - Subcortical epilepsy? AB - In the past, the cortex has for the most part been considered to be the site of seizure origin in the different forms of epilepsy. Findings from histopathologic, electrophysiologic, and brain imaging studies now provide ample evidence demonstrating that like normal cerebral function, epileptic seizures involve widespread network interactions between cortical and subcortical structures. These studies show that different forms of generalized and focal epileptiform discharges and seizures engage various subcortical structures in varying ways. This interaction has been the subject of many reviews and is not the focus of the current work. The aim of this review is to examine the evidence suggesting the possibility for some of the subcortical structures to initiate seizures independently and the clinical implications of this. PMID- 23671346 TI - Carotid dissection following a generalized tonic-clonic seizure. PMID- 23671347 TI - Child neurology: Zellweger syndrome. AB - Zellweger syndrome (ZS) is a severe manifestation of disease within the spectrum of peroxisome biogenesis disorders that includes neonatal adrenoleukodystrophy, infantile Refsum disease, and rhizomelic chondroplasia punctata. Patients with ZS present in the neonatal period with a characteristic phenotype of distinctive facial stigmata, pronounced hypotonia, poor feeding, hepatic dysfunction, and often seizures and boney abnormalities. In patients with ZS, a mutation in one of the PEX genes coding for a peroxin (a peroxisome assembly protein) creates functionally incompetent organelles causing an accumulation of very long chain fatty acids (VLCFA), among other complications. Despite an absence of treatment options, prompt diagnosis of ZS is important for providing appropriate symptomatic care, definitive genetic testing, and counseling regarding family planning. PMID- 23671348 TI - Clinical reasoning: a 25-year-old man with headaches and collapse. PMID- 23671349 TI - Teaching NeuroImages: T2 hyperintensities in neurofibromatosis type 1. PMID- 23671350 TI - Teaching NeuroImages: spontaneous tension pneumo-hydrocephalus may be related to otitis media and temporal bony defect. PMID- 23671351 TI - Marital and Cohabitation Dissolution and Parental Depressive Symptoms in Fragile Families. AB - The consequences of divorce are pronounced for parents of young children, and cohabitation dissolution is increasing in this population and has important implications. The mental health consequences of union dissolution were examined, by union type and parental gender, using the Fragile Families and Child Wellbeing Study (n = 1,998 for mothers and 1,764 for fathers). Overall, cohabitation and marital dissolution were both associated with increased maternal and paternal depressive symptoms, though for married mothers, depressive symptoms returned to predissolution levels with time. Difference-in-difference estimates indicated no differences in the magnitude of the increase in depressive symptoms by type of dissolution, though pooled difference models suggested that married fathers increased in depressive symptoms more than cohabiting fathers. Potential time variant mediators did not account for these associations, though greater family chaos was associated with increased maternal depressive symptoms, and decreased social support and father - child contact were associated with increased paternal depressive symptoms. PMID- 23671352 TI - Migration and the Gendered Origin of Migrant Networks among Couples in Mexico. AB - OBJECTIVES: We investigate how the matrilineal vs. patrilineal origin of Mexican couples' migrant networks are associated with the aspirations to migrate and the subsequent migration behavior of each spouse. METHODS: Using longitudinal data from the Mexican Family Life Survey (2002-2005) on 3,923 married couples across 139 municipalities; we estimate multi-level logistic regressions predicting aspirations to migrate to the United States for each spouse and the subsequent migration behavior of the couple in the inter-wave period. RESULTS: The networks of both ego and spouse are associated with U.S. migration aspirations although they matter more for the person from which they originate. Only matrilineal networks predicted a subsequent move to the U.S. for men and women/couples, who were assessed jointly. CONCLUSION: Matrilineal networks are instrumental in the migration process, particularly of the couple. As such, they could prove instrumental in helping understand the migration motivations and dynamics of individuals and families. PMID- 23671354 TI - New Parents' Facebook Use at the Transition to Parenthood. AB - New parents' Facebook use was examined from a social capital perspective. Surveys regarding Facebook use and parenting satisfaction, parenting self-efficacy, and parenting stress were completed by 154 mothers and 150 fathers as part of a larger study of dual-earner, Mid-western U.S. couples making the transition to parenthood. Results indicated that mothers used Facebook more than fathers, and that mothers perceived an increase in use over the transition. When more of mothers' Facebook friends were family members or relatives, and when fathers reported connecting with more of their Facebook friends outside of Facebook, they reported better parental adjustment. For mothers, however, more frequent visits to Facebook accounts and more frequent content management were each associated with higher levels of parenting stress. PMID- 23671353 TI - Ordering Transitions in Liquid Crystals Permit Imaging of Spatial and Temporal Patterns Formed by Proteins Penetrating into Lipid-Laden Interfaces. AB - Recent studies have reported that full monolayers of L-alpha dilaurylphosphatidylcholine (L-DLPC) and D-alpha-dipalmitoylphosphatidylcholine (D-DPPC) formed at interfaces between thermotropic liquid crystals (LCs) and aqueous phases lead to homeotropic (perpendicular) orientations of nematic LCs and that specific binding of proteins to these interfaces (such as phospholipase A2 binding to D-DPPC) can trigger orientational ordering transitions in the liquid crystals. We report on the nonspecific interactions of proteins with aqueous-LC interfaces decorated with partial monolayer coverage of L-DLPC. Whereas nonspecific interactions of four proteins (cytochrome c, bovine serum albumin,immunoglobulins, and neutravidin) do not perturb the ordering of the LC when a full monolayer of L-DLPC is assembled at the aqueous-LC interface, we observe patterned orientational transitions in the LC that reflect penetration of proteins into the interface of the LC with partial monolayer coverage of L-DLPC. The spatial patterns formed by the proteins and lipids at the interface are surprisingly complex, and in some cases the protein domains are found to compartmentalize lipid within the interfaces. These results suggest that phospholipid-decorated interfaces between thermotropic liquid crystals and aqueous phases offer the basis of a simple and versatile tool to study the spatial organization and dynamics ofprotein networks formed at mobile, lipid decorated interfaces. PMID- 23671355 TI - Recertification: Overhyped or need of the hour. PMID- 23671357 TI - The story of the condom. AB - Condoms have been a subject of curiosity throughout history. The idea of safer sex has been explored in ancient and modern history, and has been used to prevent venereal diseases. We conducted a historical and medical review of condoms using primary and secondary sources as well as using the RSM library and the internet. These resources show that the first use of a condom was that of King Minos of Crete. Pasiphae, his wife, employed a goat's bladder in the vagina so that King Minos would not be able to harm her as his semen was said to contain "scorpions and serpents" that killed his mistresses. To Egyptians, condom-like glans caps were dyed in different colours to distinguish between different classes of people and to protect themselves against bilharzia. The Ancient Romans used the bladders of animals to protect the woman; they were worn not to prevent pregnancy but to prevent contraction of venereal diseases. Charles Goodyear, the inventor, utilized vulcanization, the process of transforming rubber into malleable structures, to produce latex condoms. The greater use of condoms all over the world in the 20(th) and 21(st) centuries has been related to HIV. This account of the use of condoms demonstrates how a primitive idea turned into an object that is used globally with a forecast estimated at 18 billion condoms to be used in 2015 alone. PMID- 23671356 TI - The use of botulinum toxin for the treatment of overactive bladder syndrome. AB - Over the last 50 years, botulinum toxin has been transformed from a cause of life threatening disease to an effective medical therapy. It has been used in a variety of specialties for different indications, significantly improving patient quality of life. A recent growing body of evidence suggests that intra-detrusor injection of botulinum toxin may have beneficial effects in patients with medication refractory detrusor overactivity and may offer a new minimally invasive alternative to patients with severe overactive bladder symptoms. To review current data regarding the effects of botulinum toxin in patients with overactive bladder, a MEDLINE((r))/PubMed((r)) literature search was carried out. The mechanism of action, clinical usage, adverse effects, and treatment efficacy were reviewed and the results are presented in this paper. PMID- 23671358 TI - An audit of suprapubic catheter insertion performed by a urological nurse specialist. AB - AIMS: To introduce the concept that a urological Nurse Specialist can perform Suprapubic Catheter (SPC) insertions independently without significant complications, if systematic training is given. SETTINGS AND DESIGN: Retrospective study. MATERIALS AND METHODS: A retrospective audit of Suprapubic Catheter insertions performed by a Urological Nurse Specialist was conducted between April 2009 and April 2011. RESULTS: Of the total 53 patients, in 49 (92.45%) the procedure was successful. Out of the remaining four, two (3.77%) were done by a urologist. One patient's (1.89 %) SPC did not drain after placement and ultrasonography reported that the Foley balloon was lying within the abdominal wall. The other patient's SPC drained well for a month and failed to drain after the first scheduled change in a month. Since the ultrasonography showed the Foley balloon to be anterior to the distended bladder, an exploration was performed and this revealed that the SPC tract had gone through a fold of peritoneum before reaching the bladder. None had bowel injury. CONCLUSIONS: If systematic training is given, a urological Nurse Specialist can perform SPC insertions independently without significant complications. PMID- 23671359 TI - Robotic versus conventional laparoscopic pyeloplasty: A single surgeon concurrent cohort review. AB - INTRODUCTION: The increasing availability of robotic devices has led to an increase in their use for procedures such as pyeloplasty, which have been conventionally performed laparoscopically or through open surgery. We perform both laparoscopic and robotic-assisted pyeloplasty routinely and have compared these techniques in a set of concurrent cohorts, operated by the same surgeon. MATERIALS AND METHODS: A chart review was performed of all cases of Robot assisted laparoscopic pyeloplasty (RALP) and conventional laparoscopic pyeloplasty (CLP) performed by a single surgeon, from September 2006 to July 2010. The choice of procedure depended upon the availability of the robot on the given day. A lateral transperitoneal approach was used in all cases. All anastomoses were stented antegrade. A diuretic renogram was obtained in all patients between six to twelve weeks after stent removal. Success was defined as a resolution of symptoms with non-obstructive outflow on the renogram. RESULTS: Thirty patients underwent 31 laparoscopic pyeloplasties (20 RALPs and 11 CLPs), with one patient undergoing bilateral simultaneous robotic procedures. The robotic procedures were superior in terms of shorter operating time by 20 minutes on an average. Furthermore, 35% of the robotic procedures were performed in under 90 minutes, while the minimum time taken for laparoscopy was 110 minutes. All procedures in both cohorts were successful with no complications in either group. The surgeon recorded subjective ergonomic benefits with the use of the robot. CONCLUSIONS: Robotic assistance helps decrease the operative time for laparoscopic pyeloplasty. It seems ergonomically superior for the surgeon, allowing multiple procedures in the same list. These may be important benefits in busy centers. PMID- 23671360 TI - The impact of color Doppler ultrasound on treatment patterns of epididymitis in a university-based healthcare system. AB - INTRODUCTION AND OBJECTIVES: Evaluate the impact of scrotal color Doppler ultrasound (CDUS) on epididymitis treatment patterns in a university-based institution. MATERIALS AND METHODS: From 1 January 1999 to 30 July 2005, 870 patients from a single institution were diagnosed with epididymitis. A total of 480 men met the inclusion criteria for acute epididymitis. Scrotal ultrasound was included as a part of the diagnostic evaluation in 42.7% of men. Ultrasound reports were available for review in 187 cases. Information regarding patient demographics, diagnostic evaluation, and treatment was reviewed. RESULTS: Ultrasound findings consistent with epididymitis were identified in 69.3% of men. The four most commonly reported irregularities were scrotal wall thickening (84.2%), abnormal epididymal echotexture (74%), increased epididymal vascularity (72.9%), and an enlarged epididymis (71.5%). Scrotal ultrasound was performed in 67% men under age 20 compared to 36% men between ages 30 and 69. Patients presenting to the Emergency Department underwent sonographic evaluation 57% of the time versus 17.2% men presenting to primary care physicians (P < 0.001). Ninety-five per cent (194/204) of patients who underwent CDUS were treated with antibiotics compared to 96% (263/275) of those who did not receive an ultrasound (P = 0.78). CONCLUSIONS: CDUS can be helpful in patients with a potential diagnosis of testicular torsion, however, the use of CDUS as a diagnostic adjunct in the evaluation of epididymitis is of limited value. Treatment patterns and antibiotic usage were not significantly altered by ultrasound findings at this institution. PMID- 23671361 TI - Is urethral stricture only a circumferential disease? Reason for change in the plan of urethroplasty for bulbous urethral strictures shorter than 2 cm. AB - OBJECTIVE: To understand the reasons for choosing the type of urethroplasty for bulbous strictures shorter than 2 cm in length that were ideally suited for anastomotic urethroplasty (AU). MATERIALS AND METHODS: Data of adult men, who underwent urethroplasty between November 2002 and September 2011 for isolated bulbous strictures less than 2 cm in length, as measured intra-operatively, were reviewed. Patients who had undergone urethroplasty before were excluded. Data recorded were details of previous interventions, the etiology of the stricture and the type of urethroplasty performed. RESULTS: Out of 277 men who underwent urethroplasty for bulbous stricture, 65 men fulfilled the inclusion criteria. The etiologies were trauma in 24, post catheterization in 16, and idiopathic in 25. The mean stricture length was 1.60 cm (range 0.8 to 1.9). Anastomotic urethroplasty was performed in 41 men (Group 1). In the remaining 24 men, buccal mucosa graft urethroplasty was performed in 20 and augmented AU in 4 (Group 2). Comparing the two groups we found that Group 2 patients had undergone more internal urethrotomies (mean 2.45+/-0.88 vs. 1.58+/-0.63; P=0.005) and had longer stricture length as compared to men in Group 1 (mean 1.8+/-0.83 vs. 1.48+/-0.23 cm; P=0.005). The reason why AU could not be performed (Group 2) was shortening of the length of the urethra, making mobilization difficult. CONCLUSIONS: Even short strictures are associated with urethral shortening as the fibrosis is not only circumferential but also longitudinal. The surgeon should be prepared for an alternate plan even for bulbous urethral strictures shorter than 2 cm. PMID- 23671363 TI - Asp299Gly and Thr399Ile polymorphism of TLR-4 gene in patients with prostate cancer from North India. AB - BACKGROUND: The etiological factors associated with prostate cancer (CaP) have not been completely understood as yet. Genetic predisposition and inflammation is fast emerging as risk factors for CaP is a key player in the innate immune response and plays role in immune- surveillance and inflammation. The present study was conducted to evaluate TLR-4 gene polymorphism in patients with CaP. MATERIAL AND METHODS: DNA was isolated from blood samples of 198 patients with CaP, 200 cases of Benign Prostatic Hyperplasia (BPH) and 119 controls. TLR-4 gene polymorphisms Asp299Gly and Thr399Ile were determined by Restriction Fragment Length Polymorphism (RFLP) technique using Nco1 and Hinf 1 restriction enzymes. All statistical calculations were performed using SPSS for windows, version 13 (SPSS Inc., Chicago, Illinois, USA). RESULTS: A significantly high proportion of patients with CaP had AG genotype (16.6%) as compared to control (4.2%) [OR-4.4, 95% CI (1.57-13.26), P =0.0013] with respect to Asp299Gly single nucleotide polymorphism (SNP). AA genotype showed a protective effect towards CaP development [OR-0.39, 95% CI (0.18-0.83), P=0.007). A trend was observed towards development of BPH with respect to AG genotype (P=0.06). Thr399Ile SNP was not significantly different among the population groups studied. CONCLUSIONS: This finding highlights the genetic predispositions to CaP with respect to TLR-4 gene. Individuals with Asp299Gly polymorphism having AG genotype appear to have four fold higher risk for development of Prostate cancer. PMID- 23671362 TI - Prevalence and risk factors of urinary incontinence in Indian women: A hospital based survey. AB - BACKGROUND AND OBJECTIVES: Urinary incontinence is a problem that creates both physical and psychological nuisance to a woman. This problem needs to be studied in detail in Indian population because of lack of precise data. The objectives of this study were to study the prevalence and risk factors of urinary incontinence in Indian women. MATERIALS AND METHODS: This hospital-based cross-sectional study conducted from August 2005 to June 2007 included women attending gynecology OPD (consulters) and hospital employees (nonconsulters). Subjects who were incontinent were asked a standard set of questions. Incontinence was classified as urge, stress, or mixed based on symptoms. A univariate followed by multivariate analysis was done to look for risk factors. RESULTS: Of 3000 women enrolled, 21.8% (656/3000) women were incontinent. There was no significant difference in incontinence rate between consulters and nonconsulters [618/2804 (22.1%) vs. 38/196 (19.4%); P value = 0.6). Of the total women having incontinence, highest numbers were found to have stress incontinence [73.8% (484/656)] followed by mixed [16.8% (110/656)] and urge incontinence [9.5% (62/656)]. Age more than 40 years; multiparity; postmenopausal status; body mass index more than 25; history of diabetes and asthma; and habit of taking tea, tobacco, pan, and betel are risk factors found to be associated with increased prevalence of urinary incontinence in univariate analysis. On multivariate analysis, age more than 40 years, multiparity, vaginal delivery, hysterectomy, menopause, tea and tobacco intake, and asthma were found to be significantly associated with overall incontinence. Stress incontinence was separately not associated with menopause. Urge incontinence was not associated with vaginal delivery. CONCLUSION: Urinary incontinence is a bothersome problem for women. Simple questionnaire can help to detect this problem and diagnose associated risk factors, so that necessary steps can be taken in its prevention and treatment. PMID- 23671364 TI - Vascular complication in live related renal transplant: An experience of 1945 cases. AB - INTRODUCTION AND OBJECTIVE: Among the surgical complications in renal transplantation, the vascular complications are probably most dreaded, dramatic, and likely to cause sudden loss of renal allograft. We present our experience and analysis of the outcome of such complications in a series of 1945 live related renal transplants. MATERIALS AND METHODS: One thousand nine hundred and forty five consecutive live related renal transplants were evaluated retrospectively for vascular complications. Complications were recorded and analyzed for frequency, time of presentation, clinical presentation, and their management. RESULTS: The age of patients ranged from 6 to 56 years (mean = 42). Vascular complications were found in 25 patients (1.29%). Most common among these was transplant renal artery stenosis found in 11 (0.58%), followed by transplant reznal artery thrombosis in 9 (0.46%), renal vein thrombosis in 3 (0.15%), and aneurysm formation at arterial anastmosis in 2 (0.10%) patient. The time of presentation also varied amongst complications. All cases of arterial thrombosis had sudden onset anuria with minimal or no abdominal discomfort, while venous thrombosis presented as severe oliguria associated with intense graft site pain and tenderness. Management of cases with vascular thrombosis was done by immediate surgical exploration. Two patients of renal artery stenosis were managed with angioplasty and stent placement. CONCLUSIONS: Major vascular complications are relatively uncommon after renal transplantation but still constitute an important cause of graft loss in early postoperative period. Aneurysm and vessel thrombosis usually require graft nephrectomy. Transplant renal artery stenosis is amenable to correction by endovascular techniques. PMID- 23671365 TI - Single-stage repair of hypospadias using longitudinal dorsal island flap: Single surgeon experience with 102 cases. AB - PURPOSE: There are many techniques of harvesting vascularized skin flaps from penile skin for hypospadias repairs. Here, we review our experience with the use of longitudinal dorsal island flap (LDIF) for mid- and proximal hypospadias repairs and to assess the results and complications of onlay and tubularized repairs. MATERIALS AND METHODS: We retrospectively reviewed the data of all children with hypospadias operated by a single surgeon using the LDIF technique. The severity of hypospadias, technique, complications, and follow-up were assessed. RESULTS: Over a 9.4-year period, 102 children (mean age 4.2 years, range 6 months to 11 years) were operated for primary hypospadias using the LDIF technique. All children had poorly formed urethral plates and hence were considered unsuitable for tubularized incised plate repair. The hypospadias was classified as midpenile, proximal penile/penoscrotal or perineal in 29, 64, and 9 children respectively. Onlay LDIF repair was done in 85 children, while in 17 children, tubularized LDIF repair was performed. At a mean follow-up of 1.8 years, complications occurred in 12 (12%) children. Complications were more common after tubularized repairs than onlay repairs (24% vs. 9.5%). All glans dehiscences occurred after onlay repairs, while meatal stenosis and diverticulum occurred after tubularized repairs. No child had urethral stenosis after onlay repair, and uroflow studies in 16 children demonstrated normal curves and flow rates. CONCLUSIONS: We report the use of LDIF for single-stage mid and proximal hypospadias repair with good success and an acceptable complication rate. Onlay repairs had fewer complications than tubularized repairs. Our results indicate that the specific advantages and versatility of LDIF make it a good option to consider in cases of hypospadias with poorly developed urethral plates where onlay or substitution urethroplasty is indicated. PMID- 23671366 TI - Metanephric stromal tumour: A rare pediatric benign stromal specific renal neoplasm. AB - A case of incidentally detected Metanephric Stromal Tumour (MST) is reported here. This is a rare, recently recognized pediatric benign stromal specific renal neoplasm. A review of the English literature revealed only five cases after its original description by Argani et al. Recognition of this entity can spare a child from potentially toxic adjuvant chemotherapy that might be used to treat malignant lesions which are part of the differential diagnosis, particularly clear cell sarcoma of kidney (CCSK). PMID- 23671367 TI - Penile nodule with inguinal lymphadenopathy: Prostatic adenocarcinoma masquerading as penile cancer. AB - Although anatomically the penis is closely related to the prostate, penile metastasis from prostate cancer is an uncommon phenomenon. These patients usually present late in the course of the disease with wide spread metastasis. We report a patient who presented with a penile mass and inguinal lymphadenopathy. He was clinically diagnosed as a case of penile cancer but the penile mass as well as the inguinal lymphadenopathy was subsequently diagnosed to be metastases from carcinoma of the prostate. PMID- 23671368 TI - Laparoscopic Palanivelu-hydatid-system aided management of retrovesical hydatid cyst. AB - Hydatid cysts of the retrovesical region are rare. They are often adherent to the adjacent bowel and bladder, and complete removal is associated with potential injuries. The Palanivelu hydatid system allows minimally invasive treatment of hydatid cysts with no adjacent organ injuries. We describe the laparoscopic management of a pelvic hydatid cyst using this system. PMID- 23671369 TI - Laparoscopic repair of iatrogenic bladder perforation during transurethral bladder tumor resection: Case report and literature review. AB - An intraperitoneal bladder perforation occurred during transurethral tumor resection under general anesthesia in a 82 year old woman. The bladder was repaired with a laparoscopic closure and an indwelling urethral catheter. The histopathology revealed T1 high grade urothelial carcinoma. The patient recovered well and was discharged home on postoperative day 7. This case highlights the successful use of laparoscopy in the treatment of a rare urological complication. PMID- 23671370 TI - Penile tuberculosis following intravesical Bacille Calmette-Guerin immunotherapy. AB - Bacille Calmette-Guerin (BCG) is an effective treatment for patients with superficial bladder cancer and bladder carcinoma in situ (CIS). It may cause side effects usually due to local and systemic inflammatory effects. We report a case of a male patient with non-invasive urothelial carcinoma of urinary bladder (Stage T1) who developed caseating granulomas on his glans penis as a complication of intravesical BCG immunotherapy. Though there are other reported cases of BCG dissemination noted in the literature, penile granuloma is rare. The first reported case was published in 1992 and since then only eleven cases are reported. It appears that both direct infectious processes and hypersensitivity reactions contribute to the clinical manifestations of a systemic BCG infection. Our case possibly represents a local infection of M bovis involving the glans penis. PMID- 23671371 TI - Nutcracker phenomenon: An unusual presentation of acute aortic dissection. AB - We report a case of acute aortic dissection leading to compression of the left renal vein (LRV), thereby resulting in the nutcracker phenomenon. A 49-year-old previously healthy woman presented with intermittent gross hematuria and mild left flank pain of five days' duration. Laboratory examinations were within normal limits, except for the elevated C-reactive protein. Cystoscopy revealed bleeding from the left ureteral orifice. Contrast-enhanced computed tomography demonstrated acute Type B aortic dissection and compression of LRV between the enlarged aorta and superior mesenteric artery with an associated dilatation of the left gonadal vein as a collateral circulation. PMID- 23671372 TI - Penile lesion with inguinal adenopathy after intravesical Bacillus Calmette Guerin instillation therapy. AB - Intravesical Bacillus Calmette-Guerin (BCG) is widely used as an adjuvant therapy in the treatment of non-muscle-invasive bladder cancer. BCG is generally well tolerated, though localized and systemic infectious complications may occur. Infection of the glans and inguinal adenopathy are rare local complications of intravesical BCG therapy. Traumatic urethral catheterization is one of the main causes. We report the case of a 75-year-old male who developed granulomatous balanitis and enlarged inguinal lymph nodes after five cycles of intravesical BCG treatment for transitional cell carcinoma of the bladder. Histology revealed giant cell granuloma. Oral antituberculous treatment was initiated with subsequent full recovery of penile lesions and adenopathy. Physicians who administer BCG must be familiar with the possible complications and their adequate management and should inform patients about the side-effects accordingly. PMID- 23671373 TI - Laparoscopic management in a rare case of bilateral perirenal lymphangiomatosis. AB - Lymphangiomas are lymphatic malformations commonly seen around the neck, axillary region and the mediastinum. Perirenal lymphangiomatosis is very rare with only a few cases being reported in literature. We present a case of symptomatic perirenal lymphangiomatosis in a female of childbearing age, managed laparoscopically by deroofing and marsupialization. PMID- 23671374 TI - Radiological seminal vesicle stones may actually be in the ureter. AB - Calculi in blind-ending ureters are uncommon. We describe a rare case of calculi in the diverticulum of a blind-ending ureter associated with ipsilateral renal agenesis, which masqueraded as seminal vesicle calculi. PMID- 23671375 TI - Primary intratesticular rhabdomyosarcoma in pediatrics. AB - Testicular sarcomas constitute only 1-2% of all testicular tumors and are mostly associated with germ cell tumor. Primary intratesticular rhabdomyosarcoma is rare and only 14 cases have been reported in the literature till date. It should be differentiated from germ cell tumor with sarcomatous component, other intratesticular spindle-cell sarcomas and paratesticular rhabdomyosarcoma. Accurate diagnosis and early treatment is essential as it is an aggressive tumor with high metastatic potential and poor prognosis. Orchidectomy is the treatment of choice. Chemo-radiotherapy is recommended in case of recurrence and metastasis. PMID- 23671376 TI - Pelvic floor repair. PMID- 23671377 TI - Opportunities and challenges in linking information across databases in pediatric cardiovascular medicine. AB - Multicenter databases are increasingly utilized in pediatric cardiovascular research. In this review, we discuss the rational for using these types of data sources, provide several examples of how large datasets have been utilized in clinical research, and describe different mechanisms for linking databases to enable studies not possible with individual datasets alone. PMID- 23671378 TI - Normative blood pressure and heart rate in pediatric spinal cord injury. AB - BACKGROUND: Cardiovascular measures in children with spinal cord injury (SCI) may vary depending on the child's age and physical development in addition to injury related factors. Developmental changes should be considered when addressing cardiovascular complications in this population. OBJECTIVES: To determine baseline blood pressure (BP) and heart rate (HR) measurements in youth with SCI, and to investigate differences in BP and HR in relation to age, gender, body mass index (BMI), and injury-related factors. METHODS: Retrospective chart review was conducted for youth under 19 years who had been admitted for rehabilitation at 1 of 2 pediatric SCI programs. Systolic (SBP) and diastolic (DBP) blood pressures and HR were collected in the morning and afternoon on 3 consecutive days. Mean SBP, DBP, and HR were compared among 4 age groups (0-5 years, 6-12 years, 13-15 years, and 16-18 years) and by gender. Diurnal variations were determined according to level and severity of injury. Associations with BMI and injury related factors were examined. Charts of 315 youths were reviewed: mean age was 12.3 years, 59% were male, 75% were Caucasian, 62% had complete injury, and 66% had paraplegia. RESULTS: With increasing age, SBP and DBP increased and HR decreased. SBP and DBP were positively correlated with BMI. SBP was higher in males, those with incomplete injury, and those with paraplegia. HR was higher in females. There was no association between cardiovascular measures and injury duration. CONCLUSION: BP and HR are a function of age, BMI, and completeness and level of injury in youth with SCI. Awareness of baseline measures will allow for more effective management of cardiovascular complications, especially in youth presenting with atypical symptoms. PMID- 23671379 TI - Neuromuscular scoliosis in children with spinal cord injury. AB - BACKGROUND: The prevalence of neuromuscular scoliosis in children with spinal cord injury (SCI) is high. Published reports suggest that age at time of injury is the most important determinant. No studies have evaluated neurological characteristics using standardized methods to determine if they are strong predictors of scoliosis. OBJECTIVE: To test the hypothesis that neurological level, motor score, and injury severity are strong predictors of neuromuscular scoliosis. METHODS: Two hundred seventeen children were evaluated using the testing guidelines of the International Standards for Neurological Classification of Spinal Cord Injury. Cobb angles were calculated from plain radiographs as a measure of scoliosis. Multivariate analysis with statistical selection was used to determine predictors of worst Cobb angle and spinal fusion. The odds of having a spine fusion for subjects with at least 2-year follow-up and injured prior to (n=16) and after (n=91) 12 years of age were calculated. RESULTS: The hypothesis was not supported. Although there was a very high prevalence (100%) of scoliosis in the study sample, age at time of injury was the only predictor of worst curve (P < .0001) and spine fusion (P < .007). The calculated odds ratio demonstrated that children injured <12 years were 3.7 times more likely to have a spine fusion (95% CI, 0.31-44.64). CONCLUSION: There is a very high prevalence of neuromuscular scoliosis in pediatric SCI. Neurological level, motor level, and severity of injury are not strong predictors. Age is the only predictor of worst curve and spine fusion. PMID- 23671380 TI - Validity of computer adaptive tests of daily routines for youth with spinal cord injury. AB - OBJECTIVE: To evaluate the accuracy of computer adaptive tests (CATs) of daily routines for child- and parent-reported outcomes following pediatric spinal cord injury (SCI) and to evaluate the validity of the scales. METHODS: One hundred ninety-six daily routine items were administered to 381 youths and 322 parents. Pearson correlations, intraclass correlation coefficients (ICC), and 95% confidence intervals (CI) were calculated to evaluate the accuracy of simulated 5 item, 10-item, and 15-item CATs against the full-item banks and to evaluate concurrent validity. Independent samples t tests and analysis of variance were used to evaluate the ability of the daily routine scales to discriminate between children with tetraplegia and paraplegia and among 5 motor groups. RESULTS: ICC and 95% CI demonstrated that simulated 5-, 10-, and 15-item CATs accurately represented the full-item banks for both child- and parent-report scales. The daily routine scales demonstrated discriminative validity, except between 2 motor groups of children with paraplegia. Concurrent validity of the daily routine scales was demonstrated through significant relationships with the FIM scores. CONCLUSION: Child- and parent-reported outcomes of daily routines can be obtained using CATs with the same relative precision of a full-item bank. Five-item, 10 item, and 15-item CATs have discriminative and concurrent validity. PMID- 23671381 TI - Using a limited number of dermatomes as a predictor of the 56-dermatome test of the international standards for neurological classification of spinal cord injury in the pediatric population. AB - BACKGROUND: For young children with spinal cord injury (SCI), the sensory exam of the International Standards for the Neurological Classification of Spinal Cord Injury (ISNCSCI) is long and arduous, often making it impossible to complete. OBJECTIVES: In this study, we determine whether an abbreviated sensory exam provides comparable information to the full 56-dermatome exam. METHOD: A total of 726 56-dermatome sensory exams were completed with 190 children and youth with SCI ranging in age from 3 to 21 years. The cohort was randomly split into test and validation groups. For the test group, a principal component analysis (PCA) was carried out separately for pin prick (PP) and light touch (LT) scores. From the PCA, a hierarchical cluster analysis was performed to identify the most influential set of 4, 8, 12, and 16 dermatomes. From the sensory exam data obtained from the validation group, a linear regression was performed to compare the limited-dermatome composite scores to the total 56-dermatome scores. RESULTS: For both LT and PP, the 16-dermatome test resulted in the best fit (0.86 and 0.87, respectively) with the 56-dermatome test and was comprised of dermatomes from both the left (7 dermatomes) and right (9 dermatomes) sides and at least 1 dermatome from each vertebral region bilaterally (cervical, thoracic, lumbar, sacral). CONCLUSION: A 16-dermatome sensory exam provided a good correlation to the 56-dermatome exam. The shortened exam may be useful for evaluating children with SCI who cannot tolerate the full examination. PMID- 23671382 TI - Cerebral activation during the test of spinal cord injury severity in children: an FMRI methodological study. AB - BACKGROUND: The International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) are internationally accepted to determine and classify the extent of motor and sensory impairment along with severity (ASIA Impairment Scale [AIS]) following spinal cord injury (SCI). The anorectal examination is a component of the ISNCSCI that determines injury severity. There is a void in the health care literature on the validity of the anorectal examination as an indication of SCI severity. OBJECTIVE: To validate the use of functional magnetic resonance imagining (fMRI) for the purpose of classifying the severity of SCI in children. METHODS: Seventeen patients, with the average age of 14.3 years, underwent 1 complete ISNCSCI examination. Subjects also underwent the anorectal portion of this exam while fMRI data were collected using a 3.0 Tesla Siemens Verio Scanner. Cortical areas of activation were analyzed for possible differences of cortical involvement between complete (AIS A) and incomplete (AIS B, C, and D) SCI subjects. Anxiety/anticipation of the test was also assessed. RESULTS: This study established an fMRI imaging protocol that captures the cortical locations and intensity of activation during the test of sacral sparing. In addition to developing the data acquisition protocol, we also established the postacquisition preprocessing and statistical analysis parameters using SPM8. CONCLUSION: Preliminary findings indicate that fMRI is a useful tool in evaluating the validity of the anorectal examination in determining SCI severity. Assessment of which cortical regions are activated during the testing procedure provides an indication of which pathways are transmitting information to the brain. PMID- 23671383 TI - Overview of psychosocial health among youth with spinal cord injury. AB - BACKGROUND: Psychosocial health can be conceptualized as being mentally, emotionally, and socially well. Little is known about normative psychosocial development among children and adolescents with spinal cord injury (SCI). OBJECTIVE: To provide a comprehensive overview of psychosocial health of 410 youth with SCI from ages 2 to 18 years. To understand developmental trends, data are presented separately for ages 2-5, 6-12, 13-15, and 16-18 years. METHODS: Youth with SCI were recruited from 1 of 3 pediatric specialty hospitals within a single hospital system. Structured surveys assessing community participation, quality of life (QOL), and mental health (including anxiety and depression) were completed by youth with SCI (for ages 6-18) or their primary caregivers (for ages 2-5). Descriptive statistics were used to assess how patients scored on all standardized measures. RESULTS: Of the 410 participants, 56% were male, 64% were Caucasian, 66% had paraplegia, and 55% had complete injuries. On average, the participants were 12 years old (SD 4.87) at interview and 7.26 years old (SD 5.97) at injury. Psychosocial health outcomes were described for each of the 4 age groups: 2-5 years (n = 52), 6-12 (n = 142), 13-15 (n = 82), and 16-18 (n = 134) years. CONCLUSIONS: As compared to published norms, this sample of youth with SCI seemed to be experiencing decreased levels of community participation and QOL, but also decreased levels of anxiety and depression. These data provide needed information to clinicians regarding how youth with SCI may typically experience psychosocial health and where their patients fit into that typical experience. PMID- 23671384 TI - Recommendations for mobility in children with spinal cord injury. AB - BACKGROUND: Mobility is an important aspect of the rehabilitation of children with spinal cord injury (SCI), is a necessary component of life, and is critical in a child's development. Depending upon the individual's age and degree of neurological impairment, the nature of mobility may vary. OBJECTIVES: The objective of this article is to establish recommendations surrounding the selection of mobility for children with SCI. METHODS: Extensive literature review and multidisciplinary peer review. RESULTS: Types of mobility including power, manual, upright, and community are discussed, and recommendations are made based on medical necessity, neurological level, ASIA Impairment Scale score, and developmental considerations and challenges. CONCLUSION: Mobility is critical for proper development to occur in the pediatric population, and it may be challenging to make recommendations for mobility in children with SCI. It is essential for clinicians providing care to children with SCI to address mobility in a comprehensive and longitudinal manner across the children's environments. PMID- 23671385 TI - A retrospective study of the indications and outcomes of capsular tension ring insertion during cataract surgery at a tertiary teaching hospital. AB - BACKGROUND: The purpose was to determine preoperative indications, intraoperative procedures, and outcomes of capsular tension ring (CTR) insertion during cataract surgery. METHODS: A review of all patients undergoing cataract surgery with insertion of a CTR between July 2000 and June 2010 was conducted at The Royal Victorian Eye and Ear Hospital, a large tertiary teaching hospital in Victoria, Australia. Information relating to each patient's demographic details, preoperative assessment, surgical procedure, and postoperative assessment were obtained. RESULTS: Eighty-four eyes of 82 patients were included in this study. The main indications for CTR insertion were previous trauma, pseudoexfoliation syndrome, and mature cataracts. Twenty-one eyes (25.0%) did not have any obvious preoperative indication. A posterior capsule tear was the most common intraoperative complication (3.6%). An intraocular lens was successfully implanted in the bag in 72 eyes (85.7%). Postoperatively, the most common complications were a decentered intraocular lens (8.3%) and persistent corneal edema (6.0%). Overall, 61 eyes (72.6%) had better postoperative visual acuity compared with preoperative acuity, with 67 patients (79.8%) achieving vision of 20/40 or better. CONCLUSION: For the majority of cases, CTR use in complex cataract surgeries is associated with improved postoperative outcomes. CTR implantation is most commonly required in patients with known risk factors for zonular instability. PMID- 23671387 TI - Occupational activity and cognitive reserve: implications in terms of prevention of cognitive aging and Alzheimer's disease. AB - This paper investigates the relationship between the concept of activity (including both professional and nonprofessional) and cognitive functioning among older European individuals. In this research, we used data collected during the first wave of SHARE (Survey on Health, Ageing and Retirement in Europe), and a measurement approach known as stochastic frontier analysis, derived from the economic literature. SHARE includes a large population (n > 25,000) geographically distributed across Europe, and analyzes several dimensions simultaneously, including physical and mental health activity. The main advantages of stochastic frontier analysis are that it allows estimation of parametric function relating cognitive scores and driving factors at the boundary and disentangles frontier noise and distance to frontier components, as well as testing the effect of potential factors on these distances simultaneously. The analysis reveals that all activities are positively related to cognitive functioning in elderly people. Our results are discussed in terms of prevention of cognitive aging and Alzheimer's disease, and regarding the potential impact that some retirement programs might have on cognitive functioning in individuals across Europe. PMID- 23671388 TI - Feasibility, understandability, and usefulness of the STEP self-rating questionnaire: results of a cross-sectional study. AB - The study was designed to evaluate the acceptance of the self-rated version of the Standardized Assessment of Elderly People in primary care in Europe (STEP) by patients and general practitioners, as well as the feasibility, comprehensibility, and usefulness in gaining new information. In all, 1007 of 1540 patients aged 65 and above, from 28 different Saxon general practices took part. We recognized that 96% of the patients were able to fill in the questionnaire by themselves. It took them an average of approximately 20 minutes to do so. Further analysis of 257 randomly selected patients identified 281 previously unknown problems (1.1 per patient). In the practitioners' opinion, 16% of these problems, particularly physiological and mental ones, could lead to immediate consequences. Remarkably, newly identified psychosocial problems were not followed by any consequences. Fourteen of the 75 questionnaire items were not answered by more than 9% of the participants. Eight of the 14 frequently unanswered items were marked as difficult to understand by the patients. Altogether the self-rating version of the STEP was found to be feasible and useful. It was well accepted among patients; however, some questions need further review to improve their comprehensibility. Furthermore, it should be investigated why some identified problems do not have consequences and whether there is a need to record these issues at all. PMID- 23671386 TI - Clinical use of crizotinib for the treatment of non-small cell lung cancer. AB - Discoveries over the last decade have fundamentally transformed the way we define lung cancer. Gone are the days of the simple binary classification system of non small cell lung cancer (NSCLC) and small cell lung cancer. Today, accurate identification of the histological and molecular subtype of NSCLC is required for selecting standard cytotoxic chemotherapy and targeted therapies. The identification of anaplastic lymphoma kinase (ALK) rearrangements in 5-7% of NSCLC patients and the rapid clinical development of crizotinib for these patients is the most recent clinical example necessitating the proper identification of the molecular characteristics of NSCLC for treatment decisions. The discovery of ALK rearrangements in NSCLC serendipitously coincided with the development of crizotinib for other ALK or MET driven malignancies. The clinical development of crizotinib for ALK-positive NSCLC patients has been an amazing success story of translational medicine that relied on the prior clinical experience of other targeted predecessors (i.e. erlotinib in EGFR mutant NSCLC) and a compound ready for clinical development to gain expedited FDA approval. This review discusses the clinical development and use of crizotinib in NSCLC. PMID- 23671389 TI - Investigation of the impact of urine handling procedures on interpretation of urinalysis findings and product safety in subjects treated with ezogabine. AB - BACKGROUND: Ezogabine (also known by the international nonproprietary name of retigabine) is an antiepileptic drug codeveloped and comarketed by Valeant Pharmaceuticals North America and GlaxoSmithKline, which reduces neuronal excitability by enhancing the activity of potassium channels and has the potential to have effects on the urinary system through a pharmacologic action on bladder smooth muscle. In a single post-herpetic neuralgia trial, but not in an extensive epilepsy development program, proteinuria was unexpectedly reported in patients receiving ezogabine. Consequently, investigations were conducted to determine whether the reported proteinuria represented a true or false-positive finding. METHODS: Patients receiving ezogabine 900-1200 mg/day in an open-label extension (Study 303) of a Phase III epilepsy trial voluntarily provided urine samples. Fresh samples were analyzed immediately at the study site, and stabilized aliquots were analyzed 1-3 days after collection at two central laboratories. In an open-label study in healthy volunteers receiving ezogabine 600-900 mg/day (Study RTG114137), urine samples were analyzed fresh (<2 hours after collection) and, using two different stabilizers and storage at room temperature, after 24 and 72 hours. Fluid intake was restricted prior to one sample point. Albumin:creatinine ratios were assessed in both studies. RESULTS: In Study 303, there was notable variation in clarity, color, and proteinuria between fresh and stored urine samples, and between samples analyzed at different laboratories. In RTG114137, reporting rates of proteinuria were elevated following storage using one stabilizer, and the frequency of color change from fresh to stored samples differed between the stabilizers and between 24 and 72 hours with one stabilizer. Following fluid restriction, proteinuria rates were elevated with both stabilizers. Poor tolerability of ezogabine 750-900 mg/day resulted in limited titration beyond 750 mg/day and early termination of RTG114137. CONCLUSION: Hydration status, interval between urine collection and analysis, and the type of stabilizer used are all factors that may lead to false positive proteinuria findings in patients receiving ezogabine and should be borne in mind if abnormalities are reported. PMID- 23671391 TI - Effect and safety of bevacizumab-containing chemotherapy treatment in Chinese patients with metastatic colorectal cancer. AB - PURPOSE: To review the clinical data and treatment efficacy of bevacizumab in Chinese patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: A total of 96 patients with mCRC treated by chemotherapy plus bevacizumab in the PLA General Hospital between December 2005 and August 2012 were analyzed retrospectively by overall response rate, disease-control rate, progression-free survival (PFS), and overall survival (OS). The tumor responses were assessed by the Response Evaluation Criteria in Solid Tumors guidelines. RESULTS: A total of 96 patients with mCRC were identified. Median age was 53.6 years. Eastern Cooperative Oncology Group performance status was 0-2. By the end of follow-up (August 20, 2012), 54 patients exhibited progression (56.3%), and 39 (40.6%) patients had died. A total of 27 (28.1%) achieved partial response, and 48 patients (50.0%) had stable disease, exhibiting an overall response rate of 28.1% and a disease-control rate of 78.1%. The response rates of the first-line, second line, and third-line (or later) therapy were 41.7%, 21.9%, and 15.8%, respectively. The median durations of the PFS and OS were 8.13 months and 14.80 months, respectively. The median durations of the PFS were 12.70 months, 8.30 months, and 6.40 months for first-line, second-line, and third-line (or later) therapy, respectively, and the median durations of the OS were 24.03 months, 14.90 months, and 11.03 months for first-line, second-line, and third-line (or later) therapy, respectively. CONCLUSION: A bevacizumab-containing chemotherapy regimen was well tolerated and effective in Chinese patients with mCRC. PMID- 23671392 TI - Antitumor effects and mechanisms of dendritic cells stimulated by sCD40L on ovarian cancer cells in vitro. AB - OBJECTIVE: This study aimed to examine the expression of immune suppression factors and the mechanisms of antitumor effects of cord blood dendritic cells (DCs) stimulated by soluble cluster of differentiation 40 ligand (sCD40L) and cytokines in vitro in ovarian cancer patients. METHODS: The expression levels of interleukin (IL)-10 and transforming growth factor (TGF)-beta messenger RNA in peripheral blood were detected by reverse transcription polymerase chain reaction; expression levels of CD80 and CD86 in DCs stimulated by sCD40L were detected using flow cytometry and confocal laser scanning microscopy. RESULTS: Expression levels of IL-10 and TGF-beta genes in the peripheral blood of ovarian cancer patients were significantly increased compared with patients with benign ovarian tumors (P < 0.05). The expression levels of CD80 and CD86 in DCs cultured in the granulocyte-macrophage colony-stimulating factor + IL-4 + stem cell factor + Flt-3 ligand + sCD40L group were significantly increased compared with those in the control group, as assessed by flow cytometry and confocal laser scanning microscopy (P < 0.05). CONCLUSION: A variety of cytokines in combination with sCD40L can promote the proliferation of cord blood-derived DCs and induce their maturation as well as stimulating a specific antitumor response. PMID- 23671390 TI - A systematic scoping review of adherence to reporting guidelines in health care literature. AB - BACKGROUND: Reporting guidelines have been available for the past 17 years since the inception of the Consolidated Standards of Reporting Trials statement in 1996. These guidelines were developed to improve the quality of reporting of studies in medical literature. Despite the widespread availability of these guidelines, the quality of reporting of medical literature remained suboptimal. In this study, we assess the current adherence practice to reporting guidelines; determine key factors associated with better adherence to these guidelines; and provide recommendations to enhance adherence to reporting guidelines for future studies. METHODS: We undertook a systematic scoping review of systematic reviews of adherence to reporting guidelines across different clinical areas and study designs. We searched four electronic databases (Cumulative Index to Nursing and Allied Health Literature, Web of Science, Embase, and Medline) from January 1996 to September 2012. Studies were included if they addressed adherence to one of the following guidelines: Consolidated Standards of Reporting Trials (CONSORT), Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), Quality of Reporting of Meta-analysis (QUOROM), Transparent Reporting of Evaluations with Nonrandomized Designs (TREND), Meta-analysis Of Observational Studies in Epidemiology (MOOSE) and Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). A protocol for this study was devised. A literature search, data extraction, and quality assessment were performed independently by two authors in duplicate. This study reporting follows the PRISMA guidelines. RESULTS: Our search retrieved 5159 titles, of which 50 were eligible. Overall, 86.0% of studies reported suboptimal levels of adherence to reporting guidelines. Factors associated with better adherence included journal impact factor and endorsement of guidelines, publication date, funding source, multisite studies, pharmacological interventions and larger studies. CONCLUSION: Reporting guidelines in the clinical literature are important to improve the standards of reporting of clinical studies; however, adherence to these guidelines remains suboptimal. Action is therefore needed to enhance the adherence to these standards. Strategies to enhance adherence include journal editorial policies endorsing these guidelines. PMID- 23671393 TI - Incidence and risk factors for exacerbations of asthma during pregnancy. AB - BACKGROUND: Asthma is one of the most common chronic diseases among pregnant women. Acute exacerbations of asthma during pregnancy have an unfavorable impact on pregnancy outcome. This review provides an overview of current knowledge of incidence, mechanisms, and risk factors for acute exacerbations of asthma during pregnancy. METHODS: A narrative literature review was carried out using the PubMed database. RESULTS: During pregnancy, up to 6% of women with asthma are hospitalized for an acute exacerbation. The maternal immune system is characterized by a very high T-helper-2:T-helper-1 cytokine ratio during pregnancy and thereby provides an environment essential for fetal survival but one that may aggravate asthma. Cells of the innate immune system such as monocytes and neutrophils are also increased during pregnancy, and this too can exacerbate maternal asthma. Severe or difficult-to-control asthma appears to be the major risk factor for exacerbations during pregnancy, but studies also suggest that nonadherence with controller medication and viral infections are important triggers of exacerbations during pregnancy. So far, inconsistent findings have been reported regarding the effect of fetal sex on exacerbations during pregnancy. Other risk factors for exacerbation during pregnancy include obesity, ethnicity, and reflux, whereas atopy does not appear to be a risk factor. DISCUSSION: The incidence of asthma exacerbations during pregnancy is disturbingly high. Severe asthma - better described as difficult-to-control asthma - nonadherence with controller therapy, viral infections, obesity, and ethnicity are likely to be important risk factors for exacerbations of asthma during pregnancy, whereas inconsistent findings have been reported with regard to the importance of sex of the fetus. PMID- 23671394 TI - Neonatal, atopic and infectious disease outcomes among children born to mothers with latent tuberculosis infection. AB - Exposure to microbes may result in maternal immune responses that can affect fetal immune development. Several lines of evidence have shown that mycobacterial antigens can change the onset of atopic disease. We hypothesized that infants born to mothers with a positive tuberculosis (TB) test and a negative chest radiograph, may exhibit differential development of atopic disease during early childhood. The study was designed as a case control study. Birth records for infants born to untreated mothers with a positive TB skin test (TST), as defined by >=10 mm induration were reviewed (n = 145 cases) and compared to a randomly selected unmatched control cohort of 46 women with a negative TST who delivered during the same time period at Scripps Hospital in San Diego, CA, USA. Childhood outcome parameters reviewed were: (1) the onset of physician diagnosed asthma; (2) lower respiratory tract infection (LRTI) with wheezing, latent tuberculosis infection/wheezing diagnosed on physical examination; (3) nonsurgical hospitalization; (4) atopic disease (eye/skin/nasal-sinus disease); (5) infections: ear, LRTI, sinus. LRTI was defined as an infection of the lower airways, eg, pneumonia. Outcomes at the end of years 1, 2, and 3-5 years combined were analyzed. Fisher exact test, Chi-square analysis or Poisson regression analysis were used as appropriate and a P-value of <0.05 was defined as significant. The cases and controls had similar birth weights, gestational ages, maternal ages: 3.34 versus 3.35 kg; 38.3 versus 39.2 weeks, 27.4 versus 26 years (P = non-significant). The childhood outcome parameters of the new onset of asthma was significantly higher than controls by age 2 years, but not at other ages studied, based on available clinic follow up data (P = 0.02). There was a difference in the risk for lung infection at age 2 and 3-5 years (P < 0.0001). There were no differences in the other outcome parameters studied (P = ns). There were no cases of infants with a positive TST, maternal Bacille Calmette-Guerin vaccination or active maternal TB, based on our study findings. There was a higher occurrence of asthma and lung infections at age 2 years among controls (P = 0.02). Our study defines for the first time a possible influence of maternal latent TB infection on fetal and childhood illness. PMID- 23671395 TI - Teneligliptin: a DPP-4 inhibitor for the treatment of type 2 diabetes. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors have recently emerged as a new class of antidiabetic that show favorable results in improving glycemic control with a minimal risk of hypoglycemia and weight gain. Teneligliptin, a novel DPP-4 inhibitor, exhibits a unique structure characterized by five consecutive rings, which produce a potent and long-lasting effect. Teneligliptin is currently used in cases showing insufficient improvement in glycemic control even after diet control and exercise or a combination of diet control, exercise, and sulfonylurea or thiazolidine-class drugs. In adults, teneligliptin is orally administered at a dosage of 20 mg once daily, which can be increased up to 40 mg per day. Because the metabolites of this drug are eliminated via renal and hepatic excretion, no dose adjustment is necessary in patients with renal impairment. The safety profile of teneligliptin is similar to those of other available DPP-4 inhibitors. However, caution needs to be exercised when administering teneligliptin to patients who are prone to QT prolongation. One study has reported that the postprandial blood glucose-lowering effects of teneligliptin administered prior to breakfast were sustained throughout the day, and the effects observed after dinner were similar to those observed after breakfast or lunch. Thus, although clinical data for this new drug are limited, this drug shows promise in stabilizing glycemic fluctuations throughout the day and consequently suppressing the progression of diabetic complications. However, continued evaluation in long term studies and clinical trials is required to evaluate the efficacy and safety of the drug as well as to identify additional indications for its clinical use. PMID- 23671397 TI - Bone formation with disruption of the lamina dura in the mandibular third molar. AB - The lamina dura is a healthy structural component in teeth. This study highlights the association of bone formation with disruption of lamina dura below the crown of the mandibular horizontal incompletely impacted third molar. PMID- 23671396 TI - Peripheral drive in Aalpha/beta-fiber neurons is altered in a rat model of osteoarthritis: changes in following frequency and recovery from inactivation. AB - PURPOSE: To determine conduction fidelity of Aalpha/beta-fiber low threshold mechanoreceptors in a model of osteoarthritis (OA). METHODS: Four weeks after cutting the anterior cruciate ligament and removing the medial meniscus to induce the model, in vivo intracellular recordings were made in ipsilateral L4 dorsal root ganglion neurons. L4 dorsal roots were stimulated to determine the refractory interval and the maximum following frequency of the evoked action potential (AP). Neurons exhibited two types of response to paired pulse stimulation. RESULTS: One type of response was characterized by fractionation of the evoked AP into an initial nonmyelinated-spike and a later larger-amplitude somatic-spike at shorter interstimulus intervals. The other type of response was characterized by an all-or-none AP, where the second evoked AP failed altogether at shorter interstimulus intervals. In OA versus control animals, the refractory interval measured in paired pulse testing was less in all low threshold mechanoreceptors. With train stimulation, the maximum rising rate of the nonmyelinated-spike was greater in OA nonmuscle spindle low threshold mechanoreceptors, possibly due to changes in fast kinetics of currents. Maximum following frequency in Pacinian and muscle spindle neurons was greater in model animals compared to controls. Train stimulation also induced an inactivation and fractionation of the AP in neurons that showed fractionation of the AP in paired pulse testing. However, with train stimulation this fractionation followed a different time course, suggesting more than one type of inactivation. CONCLUSION: The data suggest that joint damage can lead to changes in the fidelity of AP conduction of large diameter sensory neurons, muscle spindle neurons in particular, arising from articular and nonarticular tissues in OA animals compared to controls. These changes might influence peripheral drive of spinal excitability and plasticity, thus contributing to OA sensory abnormalities, including OA pain. PMID- 23671398 TI - The Gay Men Sex Studies: prevalence of sexual dysfunctions in Belgian HIV(+) gay men. AB - The aim of this Internet-based survey was to investigate the prevalence and associated predictors of sexual dysfunctions in Belgian self-reported HIV positive men who have sex with other men. Of the 72 participants, 56% had a mild to-severe erectile dysfunction, and 15% reported a hypoactive sexual desire disorder. The prevalence of premature ejaculation and anodyspareunia was 18% for both. Independent predictors for erectile dysfunction were frequency of masturbation, frequency of sex with partner, use of erectile enhancement drugs, having a passive sex role, and not having a steady relationship. Independent predictors for hypoactive sexual desire disorder were frequency of masturbation and having a lower lifetime number of sexual partners. Independent predictors for premature ejaculation were not having a steady relationship, having a lower lifetime number of sexual partners, and a lower level of education. The only independent predictor for anodyspareunia was having an active sex role. PMID- 23671399 TI - Clinical and pharmacologic aspects of blinatumomab in the treatment of B-cell acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) in adults remains a challenging disease to treat, and novel therapies are needed. Precursor-B ALL comprises 80% of cases, and the CD19 antigen is expressed in nearly all precursor-B ALL patients. Bispecific T-cell-engaging antibodies are novel bioengineered proteins. The bispecific T-cell-engaging antibody blinatumomab engages polyclonal T cells to CD19-expressing B cells. By binding to both CD3 and CD19, blinatumomab physically brings these T cells in close proximity to malignant B cells and potentiates T cell-induced cytotoxic cell kill. Blinatumomab requires continuous intravenous infusion due to its short half-life, the need for continuous exposure for the drug to exert sufficient efficacy, and lessened toxicity. A phase II trial of B cell ALL patients with persistent or relapsed minimal residual disease demonstrated an 80% rate of complete molecular remission. Cytokine-release syndrome and central nervous system events, such as seizures and encephalopathy, are reversible toxicities. Promising results in B-cell ALL with minimal residual disease have led to further evaluation of this drug in newly diagnosed and relapsed B-cell ALL. PMID- 23671400 TI - Laser prostatectomy: holmium laser enucleation and photoselective laser vaporization of the prostate. AB - Historically, transurethral resection of the prostate has been the gold standard for the treatment of benign prostatic hyperplasia (BPH). Laser technology has been used to treat BPH for > 15 years. Over the past decade, it has gained wide acceptance by experienced urologists. This review provides an evidence-based update on laser surgery for BPH with a focus on photoselective laser vaporization and holmium laser enucleation of the prostate surgeries and assesses the safety, efficacy, and durability of these techniques. PMID- 23671402 TI - Physiologic and anesthetic considerations in octogenarians undergoing laparoscopic partial nephrectomy. AB - The number of small renal tumors detected is increasing as imaging becomes both more available and advanced, and as the population ages, with a greater proportion of patients in their 80s emerging with small and treatable renal tumors. The technique of laparoscopic partial nephrectomy is emerging and becoming ever more popular in some centers, and is potentially a safer alternative for the elderly due to improved postoperative pain, shorter hospital stay with faster return to preoperative activities, and lower rates of morbidity and mortality. We present a systematic review of the physiologic and anesthetic considerations in octogenarians undergoing the procedure, highlighting special considerations and the need for expertise throughout the multidisciplinary team when dealing with these patients, in order to minimize risk and optimize outcome. PMID- 23671401 TI - The other bladder syndrome: underactive bladder. AB - Detrusor underactivity, or underactive bladder (UAB), is defined as a contraction of reduced strength and/or duration resulting in prolonged bladder emptying and/or a failure to achieve complete bladder emptying within a normal time span. UAB can be observed in many neurologic conditions and myogenic failure. Diabetic cystopathy is the most important and inevitable disease developing from UAB, and can occur silently and early in the disease course. Careful neurologic and urodynamic examinations are necessary for the diagnosis of UAB. Proper management is focused on prevention of upper tract damage, avoidance of overdistension, and reduction of residual urine. Scheduled voiding, double voiding, al-blockers, and intermittent self-catheterization are the typical conservative treatment options. Sacral nerve stimulation may be an effective treatment option for UAB. New concepts such as stem cell therapy and neurotrophic gene therapy are being explored. Other new agents for UAB that act on prostaglandin E2 and EP2 receptors are currently under development. The pharmaceutical and biotechnology industries that have a pipeline in urology and women's health may want to consider UAB as a potential target condition. Scientific counsel and review of the current pharmaceutical portfolio may uncover agents, including those in other therapeutic fields, that may benefit the management of UAB. PMID- 23671403 TI - Inguinal bladder hernia: four case analyses. AB - A study of four cases presenting as inguinal bladder hernia was performed based on a review of the clinical presentation, circumstances of diagnostics, and surgical management. The mean age of patients was 66.5 years. Presenting symptoms included lower urinary tract symptoms (LUTS; three cases) and decrease in scrotal size after voiding (one case). The diagnostic circumstances were incidental finding during investigation for urethral stricture (one case), preoperative discovery on the basis of decrease in scrotal size after voiding (one case), perioperative discovery during standard herniorrhaphy (one case), and peritoneal effusion secondary to bladder injury in the early postoperative period. All patients were managed successfully by replacement of the bladder in its original position and inguinal herniorrhaphy, the Lichtenstein technique (two cases), Shouldice repair (one case), or modified Bassini repair (one case) through the same inguinal incision. For one patient, bladder injury was diagnosed at the time of inguinal herniorrhaphy and repair was promptly made. For another, bladder injury was discovered only at surgical abdominal exploration. Surgical repair led to the resolution of signs and urologic symptoms in all but one patient who needed medical therapy for residual LUTS. An awareness of this possibility on the part of general surgeons should guide preoperative evaluation and therapy appropriately. Even if the preoperative diagnosis is missed, a perioperative diagnosis is crucial to avoid bladder injury during surgery. PMID- 23671404 TI - Update of randomized trials for prostate cancer screening. PMID- 23671405 TI - Barriers and Facilitators of HIV Disclosure: Perspectives from HIV-Infected Men Who Have Sex with Men. AB - HIV disclosure among sexually active HIV-infected men who have sex with men (MSM) is a complex phenomenon. To better understand factors that impact the decision making process regarding HIV disclosure among HIV-infected MSM, the present study analyzed content from previously conducted counseling sessions where HIV disclosure was selected as the primary focus of the session. The counselor/participant dialogue was audio-recorded, transcribed, and analyzed qualitatively using content analysis. Factors identified as barriers that deter HIV-infected MSM from disclosing include rejection, issues of confidentiality, possible missed sexual opportunities, partner's HIV status, deferred responsibility, sexual partner type, and public sex environments. Participants identified ethical obligation, the potential for a dating relationship, timing of disclosure, and bidirectional communication as facilitators of disclosure. Findings can be used for policy development as well as to guide social workers and other healthcare providers' assessment and development of clinical interventions addressing sexual health among HIV-infected MSM as it relates to HIV disclosure. PMID- 23671406 TI - Acquiring word class distinctions in American Sign Language: Evidence from handshape. AB - Handshape works differently in nouns vs. a class of verbs in American Sign Language (ASL), and thus can serve as a cue to distinguish between these two word classes. Handshapes representing characteristics of the object itself (object handshapes) and handshapes representing how the object is handled (handling handshapes) appear in both nouns and a particular type of verb, classifier predicates, in ASL. When used as nouns, object and handling handshapes are phonemic-that is, they are specified in dictionary entries and do not vary with grammatical context. In contrast, when used as classifier predicates, object and handling handshapes do vary with grammatical context for both morphological and syntactic reasons. We ask here when young deaf children learning ASL acquire the word class distinction signaled by handshape. Specifically, we determined the age at which children systematically vary object vs. handling handshapes as a function of grammatical context in classifier predicates, but not in the nouns that accompany those predicates. We asked 4-6 year old children, 7-10 year old children, and adults, all of whom were native ASL signers, to describe a series of vignettes designed to elicit object and handling handshapes in both nouns and classifier predicates. We found that all of the children behaved like adults with respect to all nouns, systematically varying object and handling handshapes as a function of type of item and not grammatical context. The children also behaved like adults with respect to certain classifiers, systematically varying handshape type as a function of grammatical context for items whose nouns have handling handshapes. The children differed from adults in that they did not systematically vary handshape as a function of grammatical context for items whose nouns have object handshapes. These findings extend previous work by showing that children require developmental time to acquire the full morphological system underlying classifier predicates in sign language, just as children acquiring complex morphology in spoken languages do. In addition, we show for the first time that children acquiring ASL treat object and handling handshapes differently as a function of their status as nouns vs. classifier predicates, and thus display a distinction between these word classes as early as 4 years of age. PMID- 23671407 TI - Intimate partner violence and incident depressive symptoms and suicide attempts: a systematic review of longitudinal studies. AB - BACKGROUND: Depression and suicide are responsible for a substantial burden of disease globally. Evidence suggests that intimate partner violence (IPV) experience is associated with increased risk of depression, but also that people with mental disorders are at increased risk of violence. We aimed to investigate the extent to which IPV experience is associated with incident depression and suicide attempts, and vice versa, in both women and men. METHODS AND FINDINGS: We conducted a systematic review and meta-analysis of longitudinal studies published before February 1, 2013. More than 22,000 records from 20 databases were searched for studies examining physical and/or sexual intimate partner or dating violence and symptoms of depression, diagnosed major depressive disorder, dysthymia, mild depression, or suicide attempts. Random effects meta-analyses were used to generate pooled odds ratios (ORs). Sixteen studies with 36,163 participants met our inclusion criteria. All studies included female participants; four studies also included male participants. Few controlled for key potential confounders other than demographics. All but one depression study measured only depressive symptoms. For women, there was clear evidence of an association between IPV and incident depressive symptoms, with 12 of 13 studies showing a positive direction of association and 11 reaching statistical significance; pooled OR from six studies = 1.97 (95% CI 1.56-2.48, I2 = 50.4%, p(heterogeneity = 0.073). There was also evidence of an association in the reverse direction between depressive symptoms and incident IPV (pooled OR from four studies = 1.93, 95% CI 1.51-2.48, I2 = 0%, p = 0.481). IPV was also associated with incident suicide attempts. For men, evidence suggested that IPV was associated with incident depressive symptoms, but there was no clear evidence of an association between IPV and suicide attempts or depression and incident IPV. CONCLUSIONS: In women, IPV was associated with incident depressive symptoms, and depressive symptoms with incident IPV. IPV was associated with incident suicide attempts. In men, few studies were conducted, but evidence suggested IPV was associated with incident depressive symptoms. There was no clear evidence of association with suicide attempts. PMID- 23671408 TI - Analytic Derivatives of Quartic-Scaling Doubly Hybrid XYGJ-OS Functional: Theory, Implementation, and Benchmark Comparison with M06-2X and MP2 Geometries for Nonbonded Compelexes. AB - Analytic first derivative expression of opposite-spin (OS) ansatz adapted quartic scaling doubly hybrid XYGJ-OS functional is derived and implemented into Q-Chem. The resulting algorithm scales quartically with system size as in OS-MP2 gradient, by utilizing the combination of Laplace transformation and density fitting technique. The performance of XYGJ-OS geometry optimization is assessed by comparing the bond lengths and the intermolecular properties in reference coupled cluster methods. For the selected nonbonded complexes in the S22 and S66 dataset used in the present benchmark test, it is shown that XYGJ-OS geometries are more accurate than M06-2X and RI-MP2, the two quantum chemical methods widely used to obtain accurate geometries for practical systems, and comparable to CCSD(T) geometries. PMID- 23671409 TI - A Web-Based Behavior Therapy Program Influences the Association Between Cognitive Functioning and Retention and Abstinence in Clients Receiving Methadone Maintenance Treatment. AB - OBJECTIVE: Deficits in cognitive functioning have been well-documented in persons with substance use disorders. In addition, some evidence suggests that poorer cognitive functioning predicts poorer engagement in substance abuse treatment and worse treatment outcomes. TRIAL DESIGN: Non-blind, randomized clinical trial with parallel design. METHODS: Clients were recruited from a local methadone maintenance clinic within the first 30 days of treatment. All participants completed a comprehensive, computerized neuropsychological assessment (MicroCog) at the time they entered the clinical trial. Participants were randomized to receive 12 months of either standard methadone maintenance treatment, or methadone maintenance treatment with an integrated web-based intervention as part of treatment. The aims of the current study were to (1) characterize the cognitive functioning of clients entering methadone maintenance treatment; (2) evaluate the impact of cognitive functioning on the primary outcomes of treatment retention and opioid abstinence; and (3) determine whether cognitive functioning had a differential impact on these outcomes across treatment conditions. Randomization was non-blind and participants were stratified on past month cocaine use, prior history of methadone, LAAM or buprenorphine treatment, and counselor. RESULTS: Eighty participants were randomized to each condition (total n=160). Mean scores on MicroCog scales fell in the average and low average ranges and there were no differences in scores between treatment groups. Lower scores on General Cognitive Proficiency predicted longer study retention (chi2=5.03, p < .05), though this effect was quite small. Generalized linear modeling showed that scores on all MicroCog scales except for Spatial Processing significantly predicted opioid abstinence (defined as percent of total weeks and percent of tested weeks with continuous abstinence), with lower scores predicting smaller percentages of continuous weeks of abstinence. This pattern was not evident in regression analyses in which abstinence was defined as number of total weeks of abstinence. An interaction effect was observed, whereby lower cognitive scores predicted lower levels of abstinence for participants in standard methadone maintenance treatment, but not for those who received the web-based intervention as part of methadone maintenance treatment. CONCLUSIONS: Technology-based interventions may hold promise for minimizing the impact of poorer cognitive functioning on treatment outcomes. PMID- 23671411 TI - Novel developmental analyses identify longitudinal patterns of early gut microbiota that affect infant growth. AB - It is acknowledged that some obesity trajectories are set early in life, and that rapid weight gain in infancy is a risk factor for later development of obesity. Identifying modifiable factors associated with early rapid weight gain is a prerequisite for curtailing the growing worldwide obesity epidemic. Recently, much attention has been given to findings indicating that gut microbiota may play a role in obesity development. We aim at identifying how the development of early gut microbiota is associated with expected infant growth. We developed a novel procedure that allows for the identification of longitudinal gut microbiota patterns (corresponding to the gut ecosystem developing), which are associated with an outcome of interest, while appropriately controlling for the false discovery rate. Our method identified developmental pathways of Staphylococcus species and Escherichia coli that were associated with expected growth, and traditional methods indicated that the detection of Bacteroides species at day 30 was associated with growth. Our method should have wide future applicability for studying gut microbiota, and is particularly important for translational considerations, as it is critical to understand the timing of microbiome transitions prior to attempting to manipulate gut microbiota in early life. PMID- 23671412 TI - Improving breast cancer survival analysis through competition-based multidimensional modeling. AB - Breast cancer is the most common malignancy in women and is responsible for hundreds of thousands of deaths annually. As with most cancers, it is a heterogeneous disease and different breast cancer subtypes are treated differently. Understanding the difference in prognosis for breast cancer based on its molecular and phenotypic features is one avenue for improving treatment by matching the proper treatment with molecular subtypes of the disease. In this work, we employed a competition-based approach to modeling breast cancer prognosis using large datasets containing genomic and clinical information and an online real-time leaderboard program used to speed feedback to the modeling team and to encourage each modeler to work towards achieving a higher ranked submission. We find that machine learning methods combined with molecular features selected based on expert prior knowledge can improve survival predictions compared to current best-in-class methodologies and that ensemble models trained across multiple user submissions systematically outperform individual models within the ensemble. We also find that model scores are highly consistent across multiple independent evaluations. This study serves as the pilot phase of a much larger competition open to the whole research community, with the goal of understanding general strategies for model optimization using clinical and molecular profiling data and providing an objective, transparent system for assessing prognostic models. PMID- 23671413 TI - Selection for replicases in protocells. AB - We consider a world of nucleotide sequences and protocells. The sequences have the property of spontaneous self-replication. Some sequences - so-called replicases - have enzymatic activity in the sense of enhancing the replication rate of all (or almost all) sequences. In a well-mixed medium, natural selection would not favor such replicases because their presence equally benefits sequences with or without replicase activity. Here we show that protocells can select for replicases. We assume that sequences replicate within protocells and that protocells undergo spontaneous division. This leads to particular population structures which can augment the abundance of replicases. We explore various assumptions regarding replicase activity and protocell division. We calculate the error threshold that is compatible with selecting for replicases. PMID- 23671414 TI - Effect of regulatory architecture on broad versus narrow sense heritability. AB - Additive genetic variance (VA ) and total genetic variance (VG ) are core concepts in biomedical, evolutionary and production-biology genetics. What determines the large variation in reported VA /VG ratios from line-cross experiments is not well understood. Here we report how the VA /VG ratio, and thus the ratio between narrow and broad sense heritability (h(2) /H(2) ), varies as a function of the regulatory architecture underlying genotype-to-phenotype (GP) maps. We studied five dynamic models (of the cAMP pathway, the glycolysis, the circadian rhythms, the cell cycle, and heart cell dynamics). We assumed genetic variation to be reflected in model parameters and extracted phenotypes summarizing the system dynamics. Even when imposing purely linear genotype to parameter maps and no environmental variation, we observed quite low VA /VG ratios. In particular, systems with positive feedback and cyclic dynamics gave more non-monotone genotype-phenotype maps and much lower VA /VG ratios than those without. The results show that some regulatory architectures consistently maintain a transparent genotype-to-phenotype relationship, whereas other architectures generate more subtle patterns. Our approach can be used to elucidate these relationships across a whole range of biological systems in a systematic fashion. PMID- 23671415 TI - Differences in gastric carcinoma microenvironment stratify according to EBV infection intensity: implications for possible immune adjuvant therapy. AB - Epstein-Barr virus (EBV) is associated with roughly 10% of gastric carcinomas worldwide (EBVaGC). Although previous investigations provide a strong link between EBV and gastric carcinomas, these studies were performed using selected EBV gene probes. Using a cohort of gastric carcinoma RNA-seq data sets from The Cancer Genome Atlas (TCGA), we performed a quantitative and global assessment of EBV gene expression in gastric carcinomas and assessed EBV associated cellular pathway alterations. EBV transcripts were detected in 17% of samples but these samples varied significantly in EBV coverage depth. In four samples with the highest EBV coverage (hiEBVaGC - high EBV associated gastric carcinoma), transcripts from the BamHI A region comprised the majority of EBV reads. Expression of LMP2, and to a lesser extent, LMP1 were also observed as was evidence of abortive lytic replication. Analysis of cellular gene expression indicated significant immune cell infiltration and a predominant IFNG response in samples expressing high levels of EBV transcripts relative to samples expressing low or no EBV transcripts. Despite the apparent immune cell infiltration, high levels of the cytotoxic T-cell (CTL) and natural killer (NK) cell inhibitor, IDO1, was observed in the hiEBVaGCs samples suggesting an active tolerance inducing pathway in this subgroup. These results were confirmed in a separate cohort of 21 Vietnamese gastric carcinoma samples using qRT-PCR and on tissue samples using in situ hybridization and immunohistochemistry. Lastly, a panel of tumor suppressors and candidate oncogenes were expressed at lower levels in hiEBVaGC versus EBV-low and EBV-negative gastric cancers suggesting the direct regulation of tumor pathways by EBV. PMID- 23671416 TI - Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient. AB - There is intense interest in developing curative interventions for HIV. How such a cure will be quantified and defined is not known. We applied a series of measurements of HIV persistence to the study of an HIV-infected adult who has exhibited evidence of cure after allogeneic hematopoietic stem cell transplant from a homozygous CCR5Delta32 donor. Samples from blood, spinal fluid, lymph node, and gut were analyzed in multiple laboratories using different approaches. No HIV DNA or RNA was detected in peripheral blood mononuclear cells (PBMC), spinal fluid, lymph node, or terminal ileum, and no replication-competent virus could be cultured from PBMCs. However, HIV RNA was detected in plasma (2 laboratories) and HIV DNA was detected in the rectum (1 laboratory) at levels considerably lower than those expected in ART-suppressed patients. It was not possible to obtain sequence data from plasma or gut, while an X4 sequence from PBMC did not match the pre-transplant sequence. HIV antibody levels were readily detectable but declined over time; T cell responses were largely absent. The occasional, low-level PCR signals raise the possibility that some HIV nucleic acid might persist, although they could also be false positives. Since HIV levels in well-treated individuals are near the limits of detection of current assays, more sensitive assays need to be developed and validated. The absence of recrudescent HIV replication and waning HIV-specific immune responses five years after withdrawal of treatment provide proof of a clinical cure. PMID- 23671417 TI - Mutualistic polydnaviruses share essential replication gene functions with pathogenic ancestors. AB - Viruses are usually thought to form parasitic associations with hosts, but all members of the family Polydnaviridae are obligate mutualists of insects called parasitoid wasps. Phylogenetic data founded on sequence comparisons of viral genes indicate that polydnaviruses in the genus Bracovirus (BV) are closely related to pathogenic nudiviruses and baculoviruses. However, pronounced differences in the biology of BVs and baculoviruses together with high divergence of many shared genes make it unclear whether BV homologs still retain baculovirus like functions. Here we report that virions from Microplitis demolitor bracovirus (MdBV) contain multiple baculovirus-like and nudivirus-like conserved gene products. We further show that RNA interference effectively and specifically knocks down MdBV gene expression. Coupling RNAi knockdown methods with functional assays, we examined the activity of six genes in the MdBV conserved gene set that are known to have essential roles in transcription (lef-4, lef-9), capsid assembly (vp39, vlf-1), and envelope formation (p74, pif-1) during baculovirus replication. Our results indicated that MdBV produces a baculovirus-like RNA polymerase that transcribes virus structural genes. Our results also supported a conserved role for vp39, vlf-1, p74, and pif-1 as structural components of MdBV virions. Additional experiments suggested that vlf-1 together with the nudivirus like gene int-1 also have novel functions in regulating excision of MdBV proviral DNAs for packaging into virions. Overall, these data provide the first experimental insights into the function of BV genes in virion formation. PMID- 23671418 TI - Antigenic drift of the pandemic 2009 A(H1N1) influenza virus in A ferret model. AB - Surveillance data indicate that most circulating A(H1N1)pdm09 influenza viruses have remained antigenically similar since they emerged in humans in 2009. However, antigenic drift is likely to occur in the future in response to increasing population immunity induced by infection or vaccination. In this study, sequential passaging of A(H1N1)pdm09 virus by contact transmission through two independent series of suboptimally vaccinated ferrets resulted in selection of variant viruses with an amino acid substitution (N156K, H1 numbering without signal peptide; N159K, H3 numbering without signal peptide; N173K, H1 numbering from first methionine) in a known antigenic site of the viral HA. The N156K HA variant replicated and transmitted efficiently between naive ferrets and outgrew wildtype virus in vivo in ferrets in the presence and absence of immune pressure. In vitro, in a range of cell culture systems, the N156K variant rapidly adapted, acquiring additional mutations in the viral HA that also potentially affected antigenic properties. The N156K escape mutant was antigenically distinct from wildtype virus as shown by binding of HA-specific antibodies. Glycan binding assays demonstrated the N156K escape mutant had altered receptor binding preferences compared to wildtype virus, which was supported by computational modeling predictions. The N156K substitution, and culture adaptations, have been detected in human A(H1N1)pdm09 viruses with N156K preferentially reported in sequences from original clinical samples rather than cultured isolates. This study demonstrates the ability of the A(H1N1)pdm09 virus to undergo rapid antigenic change to evade a low level vaccine response, while remaining fit in a ferret transmission model of immunization and infection. Furthermore, the potential changes in receptor binding properties that accompany antigenic changes highlight the importance of routine characterization of clinical samples in human A(H1N1)pdm09 influenza surveillance. PMID- 23671419 TI - Colocalization of different influenza viral RNA segments in the cytoplasm before viral budding as shown by single-molecule sensitivity FISH analysis. AB - The Influenza A virus genome consists of eight negative sense, single-stranded RNA segments. Although it has been established that most virus particles contain a single copy of each of the eight viral RNAs, the packaging selection mechanism remains poorly understood. Influenza viral RNAs are synthesized in the nucleus, exported into the cytoplasm and travel to the plasma membrane where viral budding and genome packaging occurs. Due to the difficulties in analyzing associated vRNPs while preserving information about their positions within the cell, it has remained unclear how and where during cellular trafficking the viral RNAs of different segments encounter each other. Using a multicolor single-molecule sensitivity fluorescence in situ hybridization (smFISH) approach, we have quantitatively monitored the colocalization of pairs of influenza viral RNAs in infected cells. We found that upon infection, the viral RNAs from the incoming particles travel together until they reach the nucleus. The viral RNAs were then detected in distinct locations in the nucleus; they are then exported individually and initially remain separated in the cytoplasm. At later time points, the different viral RNA segments gather together in the cytoplasm in a microtubule independent manner. Viral RNAs of different identities colocalize at a high frequency when they are associated with Rab11 positive vesicles, suggesting that Rab11 positive organelles may facilitate the association of different viral RNAs. Using engineered influenza viruses lacking the expression of HA or M2 protein, we showed that these viral proteins are not essential for the colocalization of two different viral RNAs in the cytoplasm. In sum, our smFISH results reveal that the viral RNAs travel together in the cytoplasm before their arrival at the plasma membrane budding sites. This newly characterized step of the genome packaging process demonstrates the precise spatiotemporal regulation of the infection cycle. PMID- 23671420 TI - Genome-wide analysis in German shepherd dogs reveals association of a locus on CFA 27 with atopic dermatitis. AB - Humans and dogs are both affected by the allergic skin disease atopic dermatitis (AD), caused by an interaction between genetic and environmental factors. The German shepherd dog (GSD) is a high-risk breed for canine AD (CAD). In this study, we used a Swedish cohort of GSDs as a model for human AD. Serum IgA levels are known to be lower in GSDs compared to other breeds. We detected significantly lower IgA levels in the CAD cases compared to controls (p = 1.1 * 10(-5)) in our study population. We also detected a separation within the GSD cohort, where dogs could be grouped into two different subpopulations. Disease prevalence differed significantly between the subpopulations contributing to population stratification (lambda = 1.3), which was successfully corrected for using a mixed model approach. A genome-wide association analysis of CAD was performed (n cases = 91, n controls = 88). IgA levels were included in the model, due to the high correlation between CAD and low IgA levels. In addition, we detected a correlation between IgA levels and the age at the time of sampling (corr = 0.42, p = 3.0 * 10(-9)), thus age was included in the model. A genome-wide significant association was detected on chromosome 27 (praw = 3.1 * 10(-7), pgenome = 0.03). The total associated region was defined as a ~1.5-Mb-long haplotype including eight genes. Through targeted re-sequencing and additional genotyping of a subset of identified SNPs, we defined 11 smaller haplotype blocks within the associated region. Two blocks showed the strongest association to CAD. The ~209-kb region, defined by the two blocks, harbors only the PKP2 gene, encoding Plakophilin 2 expressed in the desmosomes and important for skin structure. Our results may yield further insight into the genetics behind both canine and human AD. PMID- 23671422 TI - A statistical framework for joint eQTL analysis in multiple tissues. AB - Mapping expression Quantitative Trait Loci (eQTLs) represents a powerful and widely adopted approach to identifying putative regulatory variants and linking them to specific genes. Up to now eQTL studies have been conducted in a relatively narrow range of tissues or cell types. However, understanding the biology of organismal phenotypes will involve understanding regulation in multiple tissues, and ongoing studies are collecting eQTL data in dozens of cell types. Here we present a statistical framework for powerfully detecting eQTLs in multiple tissues or cell types (or, more generally, multiple subgroups). The framework explicitly models the potential for each eQTL to be active in some tissues and inactive in others. By modeling the sharing of active eQTLs among tissues, this framework increases power to detect eQTLs that are present in more than one tissue compared with "tissue-by-tissue" analyses that examine each tissue separately. Conversely, by modeling the inactivity of eQTLs in some tissues, the framework allows the proportion of eQTLs shared across different tissues to be formally estimated as parameters of a model, addressing the difficulties of accounting for incomplete power when comparing overlaps of eQTLs identified by tissue-by-tissue analyses. Applying our framework to re-analyze data from transformed B cells, T cells, and fibroblasts, we find that it substantially increases power compared with tissue-by-tissue analysis, identifying 63% more genes with eQTLs (at FDR = 0.05). Further, the results suggest that, in contrast to previous analyses of the same data, the majority of eQTLs detectable in these data are shared among all three tissues. PMID- 23671421 TI - The genomic signature of crop-wild introgression in maize. AB - The evolutionary significance of hybridization and subsequent introgression has long been appreciated, but evaluation of the genome-wide effects of these phenomena has only recently become possible. Crop-wild study systems represent ideal opportunities to examine evolution through hybridization. For example, maize and the conspecific wild teosinte Zea mays ssp. mexicana (hereafter, mexicana) are known to hybridize in the fields of highland Mexico. Despite widespread evidence of gene flow, maize and mexicana maintain distinct morphologies and have done so in sympatry for thousands of years. Neither the genomic extent nor the evolutionary importance of introgression between these taxa is understood. In this study we assessed patterns of genome-wide introgression based on 39,029 single nucleotide polymorphisms genotyped in 189 individuals from nine sympatric maize-mexicana populations and reference allopatric populations. While portions of the maize and mexicana genomes appeared resistant to introgression (notably near known cross-incompatibility and domestication loci), we detected widespread evidence for introgression in both directions of gene flow. Through further characterization of these genomic regions and preliminary growth chamber experiments, we found evidence suggestive of the incorporation of adaptive mexicana alleles into maize during its expansion to the highlands of central Mexico. In contrast, very little evidence was found for adaptive introgression from maize to mexicana. The methods we have applied here can be replicated widely, and such analyses have the potential to greatly inform our understanding of evolution through introgressive hybridization. Crop species, due to their exceptional genomic resources and frequent histories of spread into sympatry with relatives, should be particularly influential in these studies. PMID- 23671423 TI - Loss of expression and promoter methylation of SLIT2 are associated with sessile serrated adenoma formation. AB - Serrated adenomas form a distinct subtype of colorectal pre-malignant lesions that may progress to malignancy along a different molecular pathway than the conventional adenoma-carcinoma pathway. Previous studies have hypothesised that BRAF mutation and promoter hypermethylation plays a role, but the evidence for this is not robust. We aimed to carry out a whole-genome loss of heterozygosity analysis, followed by targeted promoter methylation and expression analysis to identify potential pathways in serrated adenomas. An initial panel of 9 sessile serrated adenomas (SSA) and one TSA were analysed using Illumina Goldengate HumanLinkage panel arrays to ascertain regions of loss of heterozygosity. This was verified via molecular inversion probe analysis and microsatellite analysis of a further 32 samples. Methylation analysis of genes of interest was carried out using methylation specific PCR (verified by pyrosequencing) and immunohistochemistry used to correlate loss of expression of genes of interest. All experiments used adenoma samples and normal tissue samples as control. SSA samples were found on whole-genome analysis to have consistent loss of heterozygosity at 4p15.1-4p15.31, which was not found in the sole TSA, adenomas, or normal tissues. Genes of interest in this region were PDCH7 and SLIT2, and combined MSP/IHC analysis of these genes revealed significant loss of SLIT2 expression associated with promoter methylation of SLIT2. Loss of expression of SLIT2 by promoter hypermethylation and loss of heterozygosity events is significantly associated with serrated adenoma development, and SLIT2 may represent a epimutated tumour suppressor gene according to the Knudson "two hit" hypothesis. PMID- 23671424 TI - Chromosome movements promoted by the mitochondrial protein SPD-3 are required for homology search during Caenorhabditis elegans meiosis. AB - Pairing of homologous chromosomes during early meiosis is essential to prevent the formation of aneuploid gametes. Chromosome pairing includes a step of homology search followed by the stabilization of homolog interactions by the synaptonemal complex (SC). These events coincide with dramatic changes in nuclear organization and rapid chromosome movements that depend on cytoskeletal motors and are mediated by SUN-domain proteins on the nuclear envelope, but how chromosome mobility contributes to the pairing process remains poorly understood. We show that defects in the mitochondria-localizing protein SPD-3 cause a defect in homolog pairing without impairing nuclear reorganization or SC assembly, which results in promiscuous installation of the SC between non-homologous chromosomes. Preventing SC assembly in spd-3 mutants does not improve homolog pairing, demonstrating that SPD-3 is required for homology search at the start of meiosis. Pairing center regions localize to SUN-1 aggregates at meiosis onset in spd-3 mutants; and pairing-promoting proteins, including cytoskeletal motors and polo like kinase 2, are normally recruited to the nuclear envelope. However, quantitative analysis of SUN-1 aggregate movement in spd-3 mutants demonstrates a clear reduction in mobility, although this defect is not as severe as that seen in sun-1(jf18) mutants, which also show a stronger pairing defect, suggesting a correlation between chromosome-end mobility and the efficiency of pairing. SUN-1 aggregate movement is also impaired following inhibition of mitochondrial respiration or dynein knockdown, suggesting that mitochondrial function is required for motor-driven SUN-1 movement. The reduced chromosome-end mobility of spd-3 mutants impairs coupling of SC assembly to homology recognition and causes a delay in meiotic progression mediated by HORMA-domain protein HTP-1. Our work reveals how chromosome mobility impacts the different early meiotic events that promote homolog pairing and suggests that efficient homology search at the onset of meiosis is largely dependent on motor-driven chromosome movement. PMID- 23671425 TI - Identification of Arabidopsis meiotic cyclins reveals functional diversification among plant cyclin genes. AB - Meiosis is a modified cell division in which a single S-phase is followed by two rounds of chromosome segregation resulting in the production of haploid gametes. The meiotic mode of chromosome segregation requires extensive remodeling of the basic cell cycle machinery and employment of unique regulatory mechanisms. Cyclin dependent kinases (CDKs) and cyclins represent an ancient molecular module that drives and regulates cell cycle progression. The cyclin gene family has undergone a massive expansion in angiosperm plants, but only a few cyclins were thoroughly characterized. In this study we performed a systematic immunolocalization screen to identify Arabidopsis thaliana A- and B-type cyclins expressed in meiosis. Many of these cyclins exhibit cell-type-specific expression in vegetative tissues and distinct subcellular localization. We found six A-type cyclins and a single B type cyclin (CYCB3;1) to be expressed in male meiosis. Mutant analysis revealed that these cyclins contribute to distinct meiosis-related processes. While A2 cyclins are important for chromosome segregation, CYCB3;1 prevents ectopic cell wall formation. We further show that cyclin SDS does not contain a D-box and is constitutively expressed throughout meiosis. Analysis of plants carrying cyclin SDS with an introduced D-box motif determined that, in addition to its function in recombination, SDS acts together with CYCB3;1 in suppressing unscheduled cell wall synthesis. Our phenotypic and expression data provide extensive evidence that multiplication of cyclins is in plants accompanied by functional diversification. PMID- 23671426 TI - Filamin and phospholipase C-epsilon are required for calcium signaling in the Caenorhabditis elegans spermatheca. AB - The Caenorhabditis elegans spermatheca is a myoepithelial tube that stores sperm and undergoes cycles of stretching and constriction as oocytes enter, are fertilized, and exit into the uterus. FLN-1/filamin, a stretch-sensitive structural and signaling scaffold, and PLC-1/phospholipase C-epsilon, an enzyme that generates the second messenger IP3, are required for embryos to exit normally after fertilization. Using GCaMP, a genetically encoded calcium indicator, we show that entry of an oocyte into the spermatheca initiates a distinctive series of IP3-dependent calcium oscillations that propagate across the tissue via gap junctions and lead to constriction of the spermatheca. PLC-1 is required for the calcium release mechanism triggered by oocyte entry, and FLN 1 is required for timely initiation of the calcium oscillations. INX-12, a gap junction subunit, coordinates propagation of the calcium transients across the spermatheca. Gain-of-function mutations in ITR-1/IP3R, an IP3-dependent calcium channel, and loss-of-function mutations in LFE-2, a negative regulator of IP3 signaling, increase calcium release and suppress the exit defect in filamin deficient animals. We further demonstrate that a regulatory cassette consisting of MEL-11/myosin phosphatase and NMY-1/non-muscle myosin is required for coordinated contraction of the spermatheca. In summary, this study answers long standing questions concerning calcium signaling dynamics in the C. elegans spermatheca and suggests FLN-1 is needed in response to oocyte entry to trigger calcium release and coordinated contraction of the spermathecal tissue. PMID- 23671427 TI - EGL-13/SoxD specifies distinct O2 and CO2 sensory neuron fates in Caenorhabditis elegans. AB - Animals harbor specialized neuronal systems that are used for sensing and coordinating responses to changes in oxygen (O2) and carbon dioxide (CO2). In Caenorhabditis elegans, the O2/CO2 sensory system comprises functionally and morphologically distinct sensory neurons that mediate rapid behavioral responses to exquisite changes in O2 or CO2 levels via different sensory receptors. How the diversification of the O2- and CO2-sensing neurons is established is poorly understood. We show here that the molecular identity of both the BAG (O2/CO2 sensing) and the URX (O2-sensing) neurons is controlled by the phylogenetically conserved SoxD transcription factor homolog EGL-13. egl-13 mutant animals fail to fully express the distinct terminal gene batteries of the BAG and URX neurons and, as such, are unable to mount behavioral responses to changes in O2 and CO2. We found that the expression of egl-13 is regulated in the BAG and URX neurons by two conserved transcription factors-ETS-5(Ets factor) in the BAG neurons and AHR 1(bHLH factor) in the URX neurons. In addition, we found that EGL-13 acts in partially parallel pathways with both ETS-5 and AHR-1 to direct BAG and URX neuronal fate respectively. Finally, we found that EGL-13 is sufficient to induce O2- and CO2-sensing cell fates in some cellular contexts. Thus, the same core regulatory factor, egl-13, is required and sufficient to specify the distinct fates of O2- and CO2-sensing neurons in C. elegans. These findings extend our understanding of mechanisms of neuronal diversification and the regulation of molecular factors that may be conserved in higher organisms. PMID- 23671428 TI - Biochemistry of adipose tissue: an endocrine organ. AB - Adipose tissue is no longer considered to be an inert tissue that stores fat. This tissue is capable of expanding to accommodate increased lipids through hypertrophy of existing adipocytes and by initiating differentiation of pre adipocytes. Adipose tissue metabolism exerts an impact on whole-body metabolism. As an endocrine organ, adipose tissue is responsible for the synthesis and secretion of several hormones. These are active in a range of processes, such as control of nutritional intake (leptin, angiotensin), control of sensitivity to insulin and inflammatory process mediators (tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6), resistin, visfatin, adiponectin, among others) and pathways (plasminogen activator inhibitor 1 (PAI-1) and acylation stimulating protein (ASP) for example). This paper reviews some of the biochemical and metabolic aspects of adipose tissue and its relationship to inflammatory disease and insulin resistance. PMID- 23671429 TI - The influence of systematic pulse-limited physical exercise on the parameters of the cardiovascular system in patients over 65 years of age. AB - INTRODUCTION: The influence of physical exercise on the parameters of the cardiovascular system of elderly persons has not been sufficiently investigated yet. The aim of the study was to assess the influence of regular 6-week physical exercise using the Nordic walking (NW) method in a group of elderly persons on their physical performance and regulation of selected parameters assessing the cardiovascular system. MATERIAL AND METHODS: Fifty patients over 65 years of age participated in the study. The study encompassed: medical interview, physical examination, resting ECG, spiroergometry examination, 6MWT (6-minute walk test) and 24-hour ambulatory blood pressure monitoring (ABPM). During the exercise programme, the pulse was monitored using pulsometers. After the completion of the training, check-up tests assessing the same parameters were performed. The control group consisted of 18 persons over 65 years of age with similar cardiovascular problems. RESULTS: In the test group, duration of the physical effort increased by 1.02 min (p = 0.0001), the maximum load increased by 10.68 W (p = 0.0001), values of VO2max by 2.10 (p = 0.0218), distance improved in 6MWT by 75.04 m (p = 0.00001), systolic blood pressure decreased by 5.50 mm Hg (p = 0.035) and diastolic blood pressure by 3.50 mm Hg (p = 0.054) as compared to the control group. CONCLUSIONS: Systematic NW physical exercise limited by the pulse had a beneficial effect on the physical performance of elderly persons as assessed with main parameters. A short 6-week programme of endurance exercises had a hypotensive effect in elderly persons over 65 years of age. PMID- 23671430 TI - First report on body image and weight control in a nationally representative sample of a pediatric population in the Middle East and North Africa: the CASPIAN III study. AB - INTRODUCTION: This study explores the associations of weight perceptions with actual body mass index (BMI) and attempts to lose weight in a nationally representative sample of a pediatric population. MATERIAL AND METHODS: Data were collected from school students of 27 provinces in Iran, as part of "the national survey of school student high risk behaviors". We used t-test for continuous data and chi square test for categorical data. The correlation between categorical variables was assessed by Cramer's phi test. A multiple nominal logistic regression model was fitted to data to assess the association between perceived body weight and gender by adjusting for potential confounding variables. RESULTS: The study participants consisted of 5570 (2784 girls, 70% urban) students with mean age of 14.7 +/-2.4 years. Overall, 17.3% of students were underweight, and 17.7% were overweight or obese. Nearly 25% and 50% of participants reported themselves as appropriate weight and very obese, respectively. In both genders, the strength of association between perceived weight and actual BMI was quite high (Cramer's phi coefficient = 0.5, p < 0.0001), and that of perceived body weight with trying to lose weight was moderate (Cramer's phi coefficient = 0.2, p < 0.0001). Overweight students were more likely than their obese peers to try to lose weight. After adjusting for possible confounders, the chance of perceiving oneself as very obese compared to perceiving oneself as very thin was 1.56-fold higher in girls than in boys, i.e. OR (95% CI): 1.56 (1.27-1.91). CONCLUSIONS: This study revealed a considerably frequent "mismatch" between actual weight status and body shape dissatisfaction, which supports the necessity of increasing public awareness in this regard. PMID- 23671431 TI - Health-related behaviours and hypertension prevention in Poland. An environmental study. AB - INTRODUCTION: Primary and secondary prevention of hypertension is difficult and if the condition is not treated it may cause a number of dangerous complications. The objective of this study was to collect and systematize data on the health related behaviours of Poles aiming at the prevention of hypertension in order to determine potential areas where primary health care could be improved. MATERIAL AND METHODS: A group of 1018 participated in the study (60% women and 40% men). The study was conducted in Poland in 2009 by means of an anonymous research questionnaire developed for survey use. The study involved people aged 30-50 years, who had not been diagnosed with hypertension, and who were under the care of a primary care physician. RESULTS: Over 35% of respondents in the potential risk group do not measure blood pressure at all, and just over 10% perform cholesterol and blood glucose level tests more often than once a year. Individuals who pay most attention to prevention in the form of physical activity are women, more often young (67% of people under 35), unmarried (52%), mostly with secondary or higher education. Moreover, one third of the women surveyed (32.4%) and almost half of men (48.4%) stated that they smoke cigarettes, and in most men (66.3%) the amount of alcohol taken in one serving exceeded the pressor threshold (> 20 g). CONCLUSIONS: Desirable health-promoting actions such as stress reduction are effective but actions such as consuming alcohol and eating fats are unsatisfactory and require intensive public education. PMID- 23671432 TI - Association of rs1800471 polymorphism of TGFB1 gene with chronic kidney disease occurrence and progression and hypertension appearance. AB - INTRODUCTION: Transforming growth factor beta1 (TGF-beta1) is a cytokine involved in the process of pathological tissue sclerosis, which is part of the pathophysiological mechanism of end stage renal disease development. The aim of the study was to evaluate the association of the single nucleotide polymorphism rs1800471 of the TGFB1 gene with chronic kidney disease (CKD) occurrence and progression as well as hypertension appearance. MATERIAL AND METHODS: It was a case-control study where 109 patients with CKD and 111 very old people were enrolled. The association of the studied polymorphism with mentioned diseases was assessed in the whole study group as well as in the subgroups stratified according to the underlying etiology of CKD: nephropathy in type 1 diabetes (n = 13), chronic glomerulonephritis (n = 50) and chronic interstitial nephritis (n = 46). RESULTS: No association of CKD progression with rs1800471 polymorphism was observed. The C allele was identified as the one associated with higher risk of the disease occurrence in the dominant model of inheritance (p = 0.035). The C allele in women, opposite to male gender, was associated with higher risk of CKD development (p = 0.038). GG genotype was associated with elevated risk of hypertension appearance (p = 0,0021). CONCLUSIONS: Due to the lack of accordance with previously performed studies it is still impossible to state an unequivocal conclusion regarding the association between rs1800471 polymorphism of the TGFB1 gene and risk of CKD occurrence and progression as well as hypertension appearance. That is why it is necessary to perform further studies in this field. PMID- 23671433 TI - Influence of metabolic syndrome superposition on familial combined hyperlipoproteinemia cardiovascular complication rate. AB - INTRODUCTION: Familial combined hyperlipoproteinemia (FCHL) is a very common and aggressive genetic mixed hyperlipoproteinemia, with many features similar to that of the metabolic syndrome (MS). We aimed to evaluate whether the presence of the MS per se could account for a significant part of the elevated cardiovascular disease (CVD) risk associated with FCHL. MATERIAL AND METHODS: A retrospective cross-sectional evaluation of MS features' influence on CVD prevalence in a large sample of adult Italian FCHL affected patients (64 familial clusters; 867 subjects) was carried out. RESULTS: Age is associated with early cardiovascular complications, both in men (OR 1.08, 95% CI: 1.05-1.11, p < 0.0001) and in women (OR 1.09, 95% CI: 1.04-1.13, p = 0.0001). No MS component appears to be related to cardiovascular complications in men, whilst only low plasma high-density lipoprotein cholesterol (HDL-C) shows such a relation in women. Among non-MS parameters, only low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp(a)) plasma levels are significantly associated with early cardiovascular complications in male FCHL patients (LDL-C: OR 2.24, 95% CI: 1.02-4.91, p = 0.04; Lp(a): OR 4.64, 95% CI: 1.85-11.62, p = 0.001), but not in women (LDL-C: OR 1.83, 95% CI 0.53-6.34, p = 0.34; Lp(a): OR 3.65, 95% CI: 0.89-14.97, p = 0.07). CONCLUSIONS: Our data support the hypothesis that MS is not associated with a higher prevalence of cardiovascular complications in FCHL affected subjects, probably because of the strongest risk increase associated with the FCHL itself. PMID- 23671434 TI - Metabolic syndrome prevalence according to ATP III and IDF criteria and related factors in Turkish adults. AB - INTRODUCTION: The aim of this study is to investigate the prevalence of metabolic syndrome (MS) and its components according to Adult Treatment Panel III (ATP III) and International Diabetes Federation (IDF) criteria and the risk factors affecting MS. Metabolic syndrome prevalence was evaluated according to certain quintet age groups, altitude, location and demographic features. MATERIAL AND METHODS: This study was a cross-sectional survey conducted in 24 provinces from the 7 regions of Turkey. A total of 4309 adults from 7 regions participated in the study (1947 males, 45.2%). RESULTS: The mean age of participants was 47 +/-14 years. Metabolic syndrome prevalence was found as 36.6% according to ATP III and 44.0% according to IDF. The MS rate was found to be higher in females compared to males in both groups (p < 0.01). According to both criteria, MS prevalence was found to be higher in subjects who lived in coastal regions when evaluated according to altitude and in subjects who lived in district centers when evaluated according to location. The MS risk is 1.62-fold higher in females compared to males. Metabolic syndrome risk increases as age increases and is highest in the 61-65 age group. Metabolic syndrome risk increases 2.75-fold in the overweight compared to normal weighing subjects and 7.80-fold in the obese. CONCLUSIONS: Metabolic syndrome prevalence was found to be high in Turkey according to both criteria. Metabolic syndrome prevalence increases as age and body mass index (BMI) increase. Age, female gender and obesity are independent risk factors for MS development. PMID- 23671435 TI - Inflammatory markers in patients with internal carotid artery stenosis. AB - INTRODUCTION: Available reports underline the significance of the inflammatory process in the development, progression and destabilisation of atherosclerotic plaques in the internal carotid artery (ICA). The aim of this study was to evaluate the relationship between the degree of ICA stenosis, ultrasound plaque morphology and serum concentration of selected inflammatory markers. MATERIAL AND METHODS: Sixty-five patients with ICA stenosis > 50% (39 symptomatic) and 30 healthy volunteers were enrolled in the study. Clinical, neurological examination and laboratory evaluation (leucocyte count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fibrinogen, tumour necrosis factor-alpha (TNF-alpha), interleukins (1beta, 6 and 10), anti-cytomegalovirus IgG antibody titre) were performed. Stenosis grade >= 70%, ulcerations on the plaque surface and a hypoechoic (or predominantly hypoechoic) structure of the plaque, obtained by colour-coded duplex examination, were accepted as the characteristics of unstable stenoses. RESULTS: Unstable ultrasound features of ICA stenosis were found significantly more often in symptomatic than in asymptomatic patients (71.79% vs. 30.71% for stenosis degree >= 70%, p = 0.001 and 61.23% vs. 38.46% for unstable plaque morphology, p = 0.01). Patients with ICA stenosis had significantly higher serum concentrations of interleukin-6, fibrinogen, ESR and higher CRP values than the individuals from the control group (p = 0.001, p = 0.009, p = 0.036, p = 0.009 respectively). Patients with unstable plaques structure had significantly higher concentrations of TNF-alpha, interleukin-6, fibrinogen, higher number of leukocytes, monocytes and higher CRP values than patients with stable plaques (p = 0.008, p = 0.049, p = 0.012, p = 0.0002, p = 0.006, p = 0.0003 respectively). No significant differences in above-mentioned parameters between the groups with stenosis < 70% and >= 70% were found. CONCLUSIONS: There is a relationship between the activity of the selected inflammatory markers in serum and atherosclerotic unstable internal carotid artery stenosis. There is no relationship between serum concentration of inflammatory markers and degree of carotid artery stenosis. PMID- 23671436 TI - Non-invasive assessment of cardiac hemodynamics in patients with advanced cancer and with chronic heart failure: a pilot feasibility study. AB - INTRODUCTION: Relationships between cardiac pressure and volume have been suggested as markers of cardiac contractility; parameters include stroke work and the maximal rate of pressure rise during isovolumic contraction (dP/dtmax). Patients with cancer often display dyspnea and fatigue. These are also frequent symptoms in patients with chronic heart failure (HF). The reasons for similar symptoms in cancer patients are unknown. Using the novel Nexfin Finapres technique, we sought to assess measures of cardiac performance in patients with cancer and compare these values with those from control subjects and patients with chronic HF. MATERIAL AND METHODS: We prospectively studied 98 patients (control n = 18, chronic HF n = 37, advanced pancreatic or colorectal cancer n = 43) and assessed blood pressure (BP), stroke volume (SV), cardiac output (CO), and dP/dtmax at rest. RESULTS: All parameters of interest could be assessed using the Nexfin Finapres technique with SV and CO being significantly higher in patients with cancer than in controls (both p < 0.05). The SV was significantly higher in patients with chronic HF than in controls (p < 0.05). In patients with cancer, SV correlated with age (r = -0.45, p < 0.01) and body weight (r = +0.55, p = 0.0001). In chronic HF, SV declined with increasing age (r = -0.49, p < 0.01); in control subjects, SV increased with increasing body weight (r = +0.57, p = 0.01). CONCLUSIONS: Patients with cancer tended to display elevated BP, CO, SV, and dP/dtmax as compared to control subjects and patients with HF. These findings may reveal an elevated risk for cardiovascular diseases in this group. PMID- 23671437 TI - Echocardiographic indices of left ventricular hypertrophy and diastolic function in hypertensive patients with preserved LVEF classified as dippers and non dippers. AB - INTRODUCTION: Long-lasting arterial hypertension causes left ventricular hypertrophy (LVH) and impairs left ventricular diastolic function. Our aim was to compare echocardiographic parameters between hypertensive patients defined as dippers and non-dippers during ambulatory blood pressure (BP) monitoring. MATERIAL AND METHODS: We analysed 61 consecutive subjects with treated hypertension undergoing 24-h BP monitoring and transthoracic echocardiographic examination and included in the study patients with preserved left ventricular ejection fraction (EF >= 50%). Echocardiographic and arterial pressure parameters were compared between the group classified as dippers (n = 26, 57 +/-13 years, 16 males) and non-dippers (n = 35, 60 +/-12 years, 24 males) according to present or absent decrease of BP during the night > 10%. Echocardiographic data were compared between both groups and control subjects without hypertension. RESULTS: Dippers had lower average systolic, diastolic and mean arterial pressure during the night hours but did not differ according to the mean pressure calculated from a 24-hour period. All echocardiographic parameters were similar in dippers and non-dippers. All patients with arterial hypertension presented with larger dimension of both ventricles and left atrium, thicker left ventricular walls, higher LV mass and mass index and preserved EF and E/A ratio as compared with normotensive controls. Normal geometry, concentric remodelling and eccentric hypertrophy were similarly distributed in both groups. Concentric hypertrophy was more prevalent in non-dippers as compared to the dippers (71.4% vs. 38.5%, p < 0.043). CONCLUSIONS: The concentric type of LVH is the prevalent pattern in non dippers. Non-dipping blood pressure pattern may be responsible for the development of left ventricular concentric hypertrophy secondary to hypertension. PMID- 23671438 TI - Correlation between ICAM1 and VCAM1 gene polymorphisms and histopathological changes in kidney allograft biopsies. AB - INTRODUCTION: The immunoglobulin-like molecules intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) are responsible for endothelial cell-leukocyte adhesion followed by transmigration of leukocytes through the endothelial cell lining. The aim of this study was to examine the correlation between polymorphisms in ICAM1 and VCAM1 genes and histopathological changes in transplanted kidney biopsies. MATERIAL AND METHODS: The study enrolled 82 Caucasian renal transplant recipients (48 males, 34 females). Genotyping of the rs5498 ICAM1 and the rs1041163 and rs3170794 VCAM1 gene polymorphisms was performed using real-time polymerase chain reaction (PCR). Biopsies were performed in 82 patients and were reviewed by a renal pathologist and the Banff working classification criteria were used. RESULTS: There were no significant associations between VCAM gene polymorphisms and histopathological changes in kidney allograft biopsies. ICAM1 gene polymorphism was associated with the grade of interstitial fibrosis. Interstitial fibrosis was more severe among individuals with the G allele than those with the A allele (AA vs. GG+AG, p = 0.017). There were no statistically significant associations between ICAM1 gene polymorphism and other histopathological changes in kidney allograft biopsies. CONCLUSIONS: The results of our study suggest that rs5498 ICAM1 gene polymorphism is associated with the grade of interstitial fibrosis in kidney recipients and the changes are more severe in patients with the G allele. PMID- 23671439 TI - Primary ileo-anal pouch anastomosis in patients with acute ulcerative colitis. AB - INTRODUCTION: Proctocolectomy with ileal pouch-anal anastomosis (IPAA) was performed in ulcerative colitis (UC) for emergent or urgent indications in three stages. Since the three-step procedure imposes enormous demands on a patient, there was an attempt to introduce primary IPAA for urgent indications. The aim of this study was to compare early complications after Hartmann's colectomy (HC) and IPAA in a selected group of patients. MATERIAL AND METHODS: Medical records of 274 patients who underwent surgery for UC between 1996 and 2010 were retrospectively evaluated. Finally, a group of 77 patients with acute form of UC entered this study. RESULTS: All patients were divided into two groups. Group 1 consisted of 32 (42%) patients who underwent HC, whereas group 2 comprised 45 (58%) patients after IPAA. There was no postoperative mortality. Respiratory failure occurred in 8 (24%) patients after HC and in 6 (14%) patients who underwent IPAA. Intra-abdominal sepsis developed in 4 (12%) patients after HC and in 8 (17%) undergoing IPAA. Fascia dehiscence was present in 3 (8%) patients after HC and in 4 (9%) with IPAA. Bowel obstruction occurred in 1 (4%) patient after the former operation and in 3 (6%) patients after the latter one. Wound infection was diagnosed in 6 (20%) patients after HC and in 9 (20%) after IPAA. The differences between the investigated groups of patients were not statistically significant. CONCLUSIONS: The IPAA could be performed for urgent indications only in the patients with no critical dilatation of the colon or with active UC but without signs of severe malnutrition. PMID- 23671440 TI - The role of counselling and other factors in compliance of postmenopausal osteoporotic patients to alendronate 70 therapy. AB - INTRODUCTION: The aim of the study was to assess the role of patient counselling, nurse assistance and effects of biochemical examinations in adherence of women with postmenopausal osteoporosis to alendronate 70 administration over 12 months of therapy. MATERIAL AND METHODS: Compliance and persistence to alendronate 70 therapy were assessed in a prospective study of 123 postmenopausal women, followed up for one year. The patients were divided into 4 groups (controls, counselled group, biochemical group and nurse assisted group) with monitoring every 6 months; in the nurse assisted group, additional phone contacts were made after 3 and 9 months of treatment. After 12 months, compliance and persistence were analysed. The medication possession ratio (MPR) was regarded as optimal when its value exceeded 80%. RESULTS: The compliance to alendronate 70 therapy was 54.03% in the control group and the mean persistence with medication was 197 days. The MPR above 80% was observed in 37.5%, and, after 1 year, 43.75% of patients were found persistent with the therapy. In the remaining groups, both compliance and persistence were higher but not statistically significantly, compared to the control group. Neither patient's age, education, diet, nor physical activity influenced the compliance with prescribed therapy. The most common reason to discontinue therapy was either its side effects or smoking. CONCLUSIONS: The obtained results suggest that better adherence with medical recommendations is observed in patients who receive additional attention, e.g. counselling, biochemical tests or nursing care. The critical elements for therapy discontinuation were side effects and smoking. PMID- 23671441 TI - Features of acetabular labral tears on X-ray, magnetic resonance imaging and hip arthroscopy - the observational pilot study. AB - INTRODUCTION: To analyze the X-ray and magnetic resonance imaging (MRI) features of acetabular labral tears, so as to improve the recognition of the disease. MATERIAL AND METHODS: Imaging features of 19 patients with acetabular labral tears confirmed by arthroscopy were analyzed retrospectively. All cases were examined by X-ray. Fourteen patients underwent MRI examinations. RESULTS: Seventeen of the 19 patients had at least one osseous abnormality consistent with femoroacetabular impingement (FAI) under arthroscopy; among them 7 cases were cam impingement, 3 cases were pincer impingement and 7 cases were mixed impingement. X-ray manifestations: 12 of the 19 patients had FAI; among them 6 cases were cam impingement, 2 cases were pincer impingement and 4 cases were mixed impingement. Five cases showed various degrees of degenerations of hip joint. Two patients had no identifiable structural abnormalities. Magnetic resonance imaging showed various degrees of injury of labrum in 6 patients, joint effusion in 5 cases, and bone marrow edema of femoral head in 3 cases. CONCLUSIONS: The FAI has much to do with acetabular labral tears. X-ray examination is important for FAI diagnosis. Given its high sensitivity and accuracy, MRI is an effective preoperative tool for defining the location and extent of labral tears. Combined with X-ray imaging and clinical manifestation, MRI can provide a reliable basis for clinical diagnosis and treatment of acetabular labral tears. PMID- 23671442 TI - Whole-body cryostimulation and oxidative stress in rowers: the preliminary results. AB - INTRODUCTION: The effect of whole-body cryostimulation (WBC) on the biomarkers of oxidative stress, lysosomal enzymes, creatine kinase and cortisol was studied. MATERIAL AND METHODS: The rowers underwent two 6-day training cycles: with pre training daily WBC (temperature: from -125 degrees C to -150 degrees C) and without cryostimulation (control). Blood samples were taken before and after the third and sixth day of training. RESULTS: The activity of superoxide dismutase and glutathione peroxidase was lower (by 44% and 42%, respectively) after the third day of training with WBC than without WBC. The concentration of lipid peroxidation products was also lower after the training preceded by WBC. Moreover, the acid phosphatase activity was 50% lower after the third day of training with WBC than training without WBC. Considering the antioxidant enzymes activity during training without WBC, the increase of superoxide dismutase and glutathione peroxidase activity was observed after the third day of training (by about 74% and 100%, respectively). The level of lipid peroxidation products also increased after the training without WBC. No statistically significant changes were observed in creatine kinase activity after the training preceded with WBC, while after the training without WBC activity of this enzyme was two-fold higher than before the training. CONCLUSIONS: The use of WBC prior to training may reduce the risk of oxidative stress and the extent of muscle fibre injuries provoked by intense exercise. The WBC seems to be an effective and safe method for limiting exercise-induced damage; thus it may be used in biological regeneration of sportsmen. PMID- 23671443 TI - Curriculum gaps in teaching clinical skills to Iranian undergraduate medical students. AB - INTRODUCTION: The inefficacy of clinical skill education during the clerkship has been reported in several studies. The present study was conducted to evaluate the competency of medical students in performing several clinical skills through an Objective Structured Clinical Examination (OSCE), aiming to evaluate the quality of the existing curriculum in the clerkship phase. MATERIAL AND METHODS: The cross sectional study was conducted at the end of the clerkship period, before the students had entered the internship. The OSCE exam was conducted in the morning (2 different tracts) and in the evening (2 similar tracts) and 86 students participated in the exam. Each tract consisted of seven stations. The students' points in the stations assessing history taking and clinical skills were compared. RESULTS: The students gained the highest points in the history taking stations, whereas the procedure stations accounted for the lowest points; there was a significant difference between these stations (p < 0.001). The female students achieved higher scores in the OSCE exam compared to males (p = 0.004). CONCLUSIONS: The OSCE exam revealed the inefficacy of the current medical curriculum in teaching the required clinical skill to undergraduate medical students during the clerkship. PMID- 23671444 TI - Adenovirus-mediated RAR-beta over-expression enhances ATRA-induced neuronal differentiation of rat mesenchymal stem cells. AB - INTRODUCTION: The retinoic acid (RA) signaling pathway plays important roles in neural development. All-trans retinoic acid (ATRA) activates the RA signal by regulating RAR-beta in mesenchymal stem cell (MSC)-derived neuron cells. Here, we try to investigate whether RAR-beta over-expression can affect neuronal differentiation of MSCs. MATERIAL AND METHODS: The RAR-beta gene was constructed into adenovirus Ad-RAR-beta by using the AdEasy system. The MSCs were infected with Ad-RAR-beta. Real time-polymerase chain reaction (RT-PCR), Western blot and immunofluorescence were performed to detect the expression and localization of RAR-beta. The MSCs were treated with 1 umol/l ATRA and modified neuronal induction medium (MNM). Soma size and axon length of induced neurons were measured. Neural specific markers were detected by RT-PCR, western blot and immunofluorescence to evaluate neuronal differentiation. RESULTS: The 1300 bp fragment of RAR-beta gene was confirmed to be correctly cloned in the adenovirus vector. Cloudiness amplification of Ad-RAR-beta was observed in HEK293 cells during package. After 48 h of Ad-RAR-beta infection, about 70% of MSCs were RFP positive. RAR-beta expression was increased by about 1988-fold and located in the nucleus. RAR-beta over-expression did not affect neuronal differentiation efficiency; however, soma size of induced neuron cells enlarged from 716.25 +/ 95.96 um(2) to 1160.12 +/-352.65 um(2) and axon length from 64.17 +/-11.88 um to 83.98 +/-13.69 um. Neural markers other than nestin - NSE, MAP-2, Tau, and Tuj1 - were increased by 4- to 11-fold in RAR-beta over-expressed neuron cells with ATRA/MNM induction compared with the Ad-null control group. CONCLUSIONS: Our results have demonstrated that adenovirus-mediated RAR-beta over-expression could facilitate neuron cell types of MSCs in vitro, indicating that the RAR-beta activated RA signal might be a vital factor in neuronal differentiation. PMID- 23671445 TI - Valproic acid upregulates NKG2D ligand expression and enhances susceptibility of human renal carcinoma cells to NK cell-mediated cytotoxicity. AB - INTRODUCTION: We aimed to investigate the effect of valproic acid (VPA) on NKG2D ligand expression in human renal carcinoma cell lines and to investigate the mechanisms. MATERIAL AND METHODS: Different concentrations of VPA from 0.5 mM to 8.0 mM were applied to 786-O and ACHN cell lines, respectively. Cell viability after treatment with VPA was determined by flow cytometry (FCM). Real-time PCR and FCM were used to detect the changes of mRNA and protein level of NKG2D ligands (MICA/B and ULBPs) in the two cell lines treated with 4 mM VPA. The cytotoxicity assay and CD107a mobilization assay were carried out to detect the cytotoxicity changes of NK cells against renal carcinoma cell lines after the same treatment. RESULTS: Valproic acid can efficiently upregulate MICA/B, ULBP1 and ULBP2 expression in the renal carcinoma cell lines at the mRNA and protein level (p < 0.05). 786-O and ACHN cells treated with VPA were more susceptible to killing by NK cells than untreated cells and the enhanced cytotoxicity of NK cells was blocked by the pretreatment of NK cells with anti-NKG2D monoclonal antibodies (p < 0.05). CONCLUSIONS: Valproic acid can clearly induce the expression of NKG2D ligands of renal carcinoma cell lines, thereby enhancing the cytotoxicity of NK cells against renal carcinoma cell lines. PMID- 23671446 TI - Inhibitory effect of midazolam on MMP-9, MMP-1 and MMP-13 expression in PMA stimulated human chondrocytes via recovery of NF-kappaB signaling. AB - INTRODUCTION: Midazolam, a benzodiazepine, has a hypnotic effect and is widely used as an intravenous sedative. Past studies have clearly established that midazolam has beneficial effects in attenuating ischemia-reperfusion injury more than other currently used sedative drugs. However, the role of midazolam on chondroprotection via inhibition of matrix metalloproteinases (MMPs) is warrant investigation. The aim of this study was to examine the mechanisms of action of midazolam on MMP expression via nuclear factor kappaB (NF-kappaB) signaling in activated chondrosarcoma cells maintained in vitro. MATERIAL AND METHODS: Chondrocytes, SW1353 cells, were stimulated with phorbol 12-myristate 13-acetate (PMA) in the absence or presence of various concentrations of midazolam (5-20 uM). Release of MMP-9 into the culture media was determined by gelatin zymography. The expressions of MMP-1, MMP-9 and MMP-13, phosphorylation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinases and degradation of IkappaB-alpha were determined by western blotting assay. RESULTS: Midazolam significantly down-regulated PMA-induced MMP-9 protein expression at concentrations of 5, 10 and 20 uM, the values were 1.95 +/-0.09 (p < 0.01), 1.71 +/-0.12 (p < 0.01) and 1.35 +/-0.20 (p < 0.001), respectively. At concentrations of 5, 10 and 20 uM, it was significantly inhibited the PMA-induced expressions of MMP-1 (2.27 +/-0.10, 1.98 +/-0.11 and 1.56 +/-0.15; p < 0.001) and MMP-13 (0.89 +/-0.04, 0.81 +/-0.07, and 0.74 +/-0.09; p < 0.001), respectively. Midazolam at concentrations of 10 and 20 uM for 15 min significantly reversed the rate of degradation (0.895 +/-0.051; p < 0.05 and 0.926 +/-0.060; p < 0.01, respectively) of IkappaB-alpha in PMA-chondrocyte cells. In addition, this sedative drug inhibited PMA-induced levels of phos-ERK (1.243 +/-0.12, 1.108 +/ 0.16 and 0.903 +/-0.19, respectively) and phos-p38 (1.146 +/-0.10, 1.063 +/-0.13 and 0.946 +/-0.18, at concentrations of (5, 10 and 20 uM), respectively. CONCLUSIONS: These results are important for understanding the mechanism of midazolam in inhibiting PMA-induced MMP expression through the signaling pathways of either NF-kappaB or ERK/p38 MAPKs down-regulation. PMID- 23671447 TI - Ginkgo suppresses atherosclerosis through downregulating the expression of connexin 43 in rabbits. AB - INTRODUCTION: Ginkgo biloba extract (GBE) EGb761 is widely used for cardiovascular prevention. Here, we investigated the effects of GBE on atherosclerotic lesion development in rabbits with a high-fat diet. MATERIAL AND METHODS: Forty New Zealand white male rabbits were randomly divided into four groups. The first two were the normal diet group (C) and the high-fat group (HF). The remaining two groups were those who received a high cholesterol diet supplemented with either the standard drug (simvastatin 2 mg/kg/day) or GBE (3 mg/kg/day). At 12 weeks, histopathological and chemical analyses were performed. RESULTS: Plasma lipid measurement showed that GBE inhibited high-fat diet-induced increase of serum triglyceride (TG), total cholesterol (TC), and low density lipoprotein cholesterol (LDL-C) by 59.1% (0.9 +/-0.2 4 mmol/l vs. 2.2 +/-0.4 mmol/l), 18.2% (31.1 +/-1.4 mmol/l vs. 38.0 +/-0.4 mmol/l) and 15% (28.9 +/-1.3 mmol/l vs. 34.0+/-1.0 mmol/l), respectively, at 12 weeks (p < 0.01). The en face Sudan IV-positive lesion area of the aorta in the GBE group (51.7 +/-3.1%) was significantly lower compared with that in the HF group (88.2 +/-2.2%; p < 0.01). The mean atherosclerotic lesion area of the GBE group was reduced by 53.2% compared with the HF group (p < 0.01). Immunohistochemistry and western blot analysis showed that GBE markedly suppressed high-fat diet-induced upregulation of connexin 43 (Cx43) in rabbits (p < 0.01). CONCLUSIONS: Thus, our study revealed that GBE prevented atherosclerosis progress through modulating plasma lipid, suppressing atherosclerotic lesion development, and attenuating the expression of Cx43 protein. PMID- 23671448 TI - Contrast imaging and gene delivery through the combined use of novel cationic liposomal microbubbles and ultrasound in rat carotid arteries. AB - INTRODUCTION: Lipid-coated cationic microbubbles represent a new class of agents with both diagnostic and therapeutic applications. The main goal of this study was to evaluate the efficiency of gene transfer through the combined use of microbubbles and ultrasound in rat carotid arteries. Furthermore, we assessed whether the cationic liposomal microbubbles could allow long-term enhanced imaging, comparing with SonoVue((r)). MATERIAL AND METHODS: Normal rat carotid arteries were imaged after intravenous bolus injections of 0.5 ml/kg of two contrast agents (SonoVue((r)) and the cationic liposomal microbubbles). Forty Sprague-Dawley rats were divided into 5 groups according to ultrasound parameters and were treated with or without microbubbles. All rats were sacrificed after being transfected for 2 days. The level of protein expression was determined by western blot analysis. RESULTS: The enhancing time of self-made microbubbles was much longer than that of SonoVue((r)) in rat carotid arteries (p < 0.05). The results of the western blot analysis revealed that the expression of SR-BI DNA in the carotid artery was highest in the SR-BI + US/CLM group (p < 0.05). CONCLUSIONS: These results suggest that the novel cationic liposomal microbubbles enhance image quality over a longer period than does SonoVue((r)). Additionally, the combination of ultrasound and this new type of microbubble can act synergistically to increase SR-BI DNA transfection. PMID- 23671449 TI - The effect of esculentoside A on lupus nephritis-prone BXSB mice. AB - INTRODUCTION: EsA was reported to have the effect of modulating immune response, cell proliferation and apoptosis as well as anti-inflammatory effects in acute and chronic experimental models. However, the effects of EsA on LN remain poorly understood. To investigate the roles of EsA in LN, the effects of EsA were tested on BXSB mice, a SLE model, in which male SB/Le mice and female C57BL/6 mice were hybridized through recombinant inbred species. MATERIAL AND METHODS: Twenty four BXSB mice were divided into three groups. After 4 weeks, blood samples, urine samples and kidney tissues were collected. Measurement of cytokine levels was carried out using sandwich ELISA reagent kits. Apoptotic scores were obtained with a TUNEL assay. PCNA and Caspase-3 mRNA was detected using the In Situ Hybridization Detection Kit. RESULTS: The results demonstrated that compared with the control group, EsA administration markedly controlled urine protein excretion, improved renal function, alleviated kidney damage and promoted the apoptosis of glomerular intrinsic cells and renal tubular epithelial cells in animals of the treated group (p < 0.05). Meanwhile, EsA reduced the serum IL-6 and TNF-alpha levels (p < 0.05), inhibited the expression of PCNA and promoted the expression of caspase-3, Fas and FasL in animals of the treated group (p < 0.05). The effects of EsA on BXSB mice were similar to dexamethasone. CONCLUSIONS: All these findings indicated that EsA might play significant roles in the treatment of BXSB mice through modulation of inflammatory cytokines, inhibition of renal cell proliferation and induction of apoptosis. The special targets of EsA in lupus nephritis are worth further exploration. PMID- 23671450 TI - The effects of budesonide on angiogenesis in a murine asthma model. AB - INTRODUCTION: The aim of this study is to determine the effects and mechanisms of budesonide on angiogenesis in a murine asthma model. MATERIAL AND METHODS: MURINE ASTHMA MODELS WERE ESTABLISHED AND MICE WERE DIVIDED INTO THREE GROUPS: the model group (OVA-sensitized and challenged mice), the BUD group (budesonide-treated mice) and the PBS group (normal control mice). Mice in the BUD group were administered with inhaled budesonide (100 ug/kg) daily. The effects on airway inflammation, angiogenesis, expression of hypoxia inducible factor-1alpha (HIF 1alpha) and vascular endothelial growth factor (VEGF) were examined. RESULTS: Administration of budesonide ameliorated allergic airway inflammation (2.90 +/ 0.18 vs. 4.80 +/-0.20, p < 0.01) and significantly reduced the percentage vascularity (0.78 +/-0.14 vs. 2.83 +/-0.90, p < 0.01) compared with those in the asthmatic model mice. It also reduced the expression of HIF-1alpha (immunohistochemistry results: 71.70 +/-1.40 vs. 89.60 +/-0.79, p < 0.001; western blotting results: 0.88 +/-0.41 vs. 0.97 +/-0.47, p < 0.05), as well as that of VEGF (immunohistochemistry results: 26.30 +/-1.03 vs. 93.30 +/-1.54, p < 0.001; western blotting results: 1.12 +/-0.22 vs. 2.08 +/-0.30, p < 0.01). Percentage vascularity had positive correlation with both HIF-1alpha (r = 0.785, p < 0.01) and VEGF (r = 0.693, p < 0.01) expression. Furthermore, there is positive relationship between HIF-1alpha and VEGF expression (r = 0.641, p < 0.05). CONCLUSIONS: The results demonstrate that budesonide has an important inhibitory effect on angiogenesis in asthma. Inhaled administration of budesonide achieved anti-angiogenic activity through inhibition of HIF-1alpha and VEGF expression. The results support a potential anti-remodeling role for budesonide in the treatment of human asthma. PMID- 23671451 TI - Malathion induces anxiety in the male adult mouse. AB - INTRODUCTION: The cholinergic nervous system and acetylcholine esterase are involved in chronic intoxication with organophosphorous insecticides. The present study aims to investigate the influence of the chronic toxicity of these chemicals on behaviors related to anxiety, using the elevated plus maze (EPM), in the male adult mouse. MATERIAL AND METHODS: Either water or 1% concentration of malathion was applied dermally to the male adult mice (10 s, once daily for 28 days) and, on day 29, the EPM test was done. RESULTS: Time spent in the open arms (TSOA) in intoxicated animals was decreased by over 50% compared to the controls (p = 0.047). In contrast, time spent in closed arms was significantly higher in the malathion-exposed mice (p = 0.025). Percentage of open arm entries (OAE) was slightly smaller in the malathion-treated group in comparison to the control animals. Percentage of closed arm entries (CAE) in the treated group was slightly higher than the value in the control animals. CONCLUSIONS: The results showed that chronic toxicity of malathion may lead to an anxiety-like behavior in the animal model used in this study. It is difficult to extend these findings to clinical situations. However, more experimental work in different animal species as well as epidemiological studies in human subjects in this regard are highly recommended. PMID- 23671452 TI - Amiodarone-induced thyrotoxicosis with paroxysmal supraventricular (ectopic atrial) tachycardia: case report and review of the literature. PMID- 23671453 TI - Brugada electrocardiographic pattern in carbon monoxide poisoning. PMID- 23671455 TI - Infection caused by Aeromonas sobria, complicated by lower extremity paraplegia and the cauda equine syndrome in a patient with well-controlled type 2 diabetes. PMID- 23671454 TI - A rare case of dysphagia in a severely immunocompromised patient. PMID- 23671456 TI - Involvement of the corpus callosum splenium in a case with SSPE: magnetic resonance spectroscopy findings. PMID- 23671457 TI - Hierarchical Multiscale Modeling of Macromolecules and their Assemblies. AB - Soft materials (e.g., enveloped viruses, liposomes, membranes and supercooled liquids) simultaneously deform or display collective behaviors, while undergoing atomic scale vibrations and collisions. While the multiple space-time character of such systems often makes traditional molecular dynamics simulation impractical, a multiscale approach has been presented that allows for long-time simulation with atomic detail based on the co-evolution of slowly-varying order parameters (OPs) with the quasi-equilibrium probability density of atomic configurations. However, this approach breaks down when the structural change is extreme, or when nearest-neighbor connectivity of atoms is not maintained. In the current study, a self-consistent approach is presented wherein OPs and a reference structure co-evolve slowly to yield long-time simulation for dynamical soft-matter phenomena such as structural transitions and self-assembly. The development begins with the Liouville equation for N classical atoms and an ansatz on the form of the associated N-atom probability density. Multiscale techniques are used to derive Langevin equations for the coupled OP configurational dynamics. The net result is a set of equations for the coupled stochastic dynamics of the OPs and centers of mass of the subsystems that constitute a soft material body. The theory is based on an all-atom methodology and an interatomic force field, and therefore enables calibration-free simulations of soft matter, such as macromolecular assemblies. PMID- 23671458 TI - Comparisons of HIV-Affected and Non-HIV-Affected Families Over Time. AB - This study compares HIV-affected families and their non-HIV-affected neighbors' behavioral health outcomes and family conflict. To compare two groups from the same neighborhoods at four points over 18 months, mothers with HIV (MLH) (N=167) and their school-age children (age 6 to 20) were recruited from clinical care settings in Los Angeles, CA and neighborhood control mothers (NCM) without HIV (N=204) were recruited from modal neighborhoods. In addition, children living at home who were 12 years and older were recruited. We assessed parenting behaviors, family conflict, mental health, sexual behavior, substance use, and HIV-related health behaviors over time. MLH perceived greater economic insecurity at baseline, less employment, and involvement in romantic relationships. MLH reported more emotional distress and substance use than NCM. MLH, however, reported lowered HIV transmission risk. The random regressions indicated that MLH exhibited higher levels and became significantly less depressed and less anxious over time than their non-HIV-affected neighbors. MLH also reported less initial family violence and conflict reasoning than NCM; violence decreased and conflict increased over time for MLH relative to NCM. Children of MLH decreased their marijuana use but hard drug users of MLH increased their risk, over time, compared to children of NCM. Moreover, children of MLH reported more internalizing behaviors than children of NCM. Even when compared to other families living in the same economically disadvantaged communities, MLH and their children continue to face challenges surrounding family conflict, and key behavioral health outcomes, especially with respect to substance use and mental health outcomes. These families, however, show much resilience and MLH report lowered levels of HIV transmission risk, their children report no greater levels of HIV transmission risk and levels of family violence were lower than reported by families in the same neighborhoods. PMID- 23671460 TI - A case of Kingella kingae endocarditis complicated by native mitral valve rupture. AB - We report a case of Kingella kingae endocarditis in a patient with a history of recent respiratory tract infection and dental extraction. This case is remarkable for embolic and vasculitic phenomena in association with a large valve vegetation and valve perforation. Kingella kingae is an organism known to cause endocarditis, however early major complications are uncommon. Our case of Kingella endocarditis behaved in a virulent fashion necessitating a combined approach of intravenous antibiotic therapy and a valve replacement. It highlights the importance of expedited investigation for endocarditis in patients with Kingella bacteraemia. PMID- 23671461 TI - Lepromatous leprosy: A rare presentation in Australia. AB - Leprosy (Hansen's disease) is caused by the obligate intracellular organism Mycobacterium leprae. It is an infectious, chronic granulomatous disease transmitted through close contact. The latest current data shows that in 2010, eleven new cases of leprosy were reported to the National Notifiable Diseases Surveillance System in Australia. We report the case of a patient with untreated chronic lepromatous leprosy diagnosed in Queensland, 2012. Delay in diagnosis may have been due to the rarity of this condition. PMID- 23671459 TI - Myocardial perfusion imaging with PET. AB - PET-myocardial perfusion imaging (MPI) allows accurate measurement of myocardial perfusion, absolute myocardial blood flow and function at stress and rest in a single study session performed in approximately 30 min. Various PET tracers are available for MPI, and rubidium-82 or nitrogen-13-ammonia is most commonly used. In addition, a new fluorine-18-based PET-MPI tracer is currently being evaluated. Relative quantification of PET perfusion images shows very high diagnostic accuracy for detection of obstructive coronary artery disease. Dynamic myocardial blood flow analysis has demonstrated additional prognostic value beyond relative perfusion imaging. Patient radiation dose can be reduced and image quality can be improved with latest advances in PET/CT equipment. Simultaneous assessment of both anatomy and perfusion by hybrid PET/CT can result in improved diagnostic accuracy. Compared with SPECT-MPI, PET-MPI provides higher diagnostic accuracy, using lower radiation doses during a shorter examination time period for the detection of coronary artery disease. PMID- 23671462 TI - Incidence and risk factors of ventilator associated pneumonia in a tertiary care hospital. AB - BACKGROUND: Ventilator associated pneumonia (VAP) is a type of nosocomial pneumonia associated with increased morbidity and mortality. Knowledge about the incidence and risk factors is necessary to implement preventive measures to reduce mortality in these patients. METHOD: A prospective study was conducted at a tertiary care teaching hospital for a period of 20 months from November 2009 to July 2011. Patients who were on mechanical ventilation (MV) for more than 48 hours were monitored at frequent intervals for development of VAP using clinical and microbiological criteria until discharge or death. RESULTS: Of the 76 patients, 18 (23.7%) developed VAP during their ICU stay. The incidence of VAP was 53.25 per 1,000 ventilator days. About 94% of VAP cases occurred within the first week of MV. Early-onset and late-onset VAP was observed in 72.2% and 27.8%, respectively. Univariate analysis showed chronic lung failure, H2 blockers usage, and supine head position were significant risk factors for VAP. Logistic regression revealed supine head position as an independent risk factor for VAP. CONCLUSION: VAP occurred in a sizeable number of patients on MV. Chronic lung failure, H2 blockers usage, and supine head position were the risk factors associated with VAP. Awareness about these risk factors can be used to inform simple and effective preventive measures. PMID- 23671463 TI - An investigation into drug-related problems identifiable by commercial medication review software. AB - BACKGROUND: Accredited pharmacists conduct home medicines reviews (HMRs) to detect and resolve potential drug-related problems (DRPs). A commercial expert system, Medscope Review Mentor (MRM), has been developed to assist pharmacists in the detection and resolution of potential DRPs. AIMS: This study compares types of DRPs identified with the commercial system which uses multiple classification ripple down rules (MCRDR) with the findings of pharmacists. METHOD: HMR data from 570 reviews collected from accredited pharmacists was entered into MRM and the DRPs were identified. A list of themes describing the main concept of each DRP identified by MRM was developed to allow comparison with pharmacists. Theme types, frequencies, similarity and dissimilarity were explored. RESULTS: The expert system was capable of detecting a wide range of potential DRPs: 2854 themes; compared to pharmacists: 1680 themes. The system identified the same problems as pharmacists in many patient cases. Ninety of 119 types of themes identifiable by pharmacists were also identifiable by software. MRM could identify the same problems in the same patients as pharmacists for 389 problems, resulting in a low overlap of similarity with an averaged Jaccard Index of 0.09. CONCLUSION: MRM found significantly more potential DRPs than pharmacists. MRM identified a wide scope of DRPs approaching the range of DRPs that were identified by pharmacists. Differences may be associated with system consistency and perhaps human oversight or human selective prioritisation. DRPs identified by the system were still considered relevant even though the system identified a larger number of problems. PMID- 23671464 TI - Recurrent neurofibroma of the orbit. AB - A 55-year-old male patient presented with gradual progressive outward and downward deviation of right eye since last two years, with history of a similar complaint 10 years ago when he was diagnosed as having neurofibroma of the orbit. Computed Tomography imaging revealed a large, multilobulated, heterogeneous, soft tissue density mass lesion in the retro bulbar region on the medial side of right orbit suggestive of a neurofibroma. Excision and histopathology confirmed it to be a recurrence of neurofibroma of the orbit. PMID- 23671465 TI - Radial artery pseudoaneurysm managed by prolonged ultrasound-guided compression repair and aided by interval application of compression device. AB - We report a case of a right radial pseudoaneurysm due to assault. The pseudoaneurysm was treated successfully with prolonged ultrasound-guided compression for more than 300 minutes over multiple sittings coupled with the use of a compression device. We believe that if initial compression fails, a prolonged ultrasound-guided compression repair coupled with a compression device can greatly improve the success rates and can negate the use of more invasive procedures to treat pseudoaneurysms. PMID- 23671466 TI - Medicine an evolving profession. AB - The number of medical practitioners in the developed world has increased but in relative terms their incomes have decreased. Published comments suggest that some doctors are dissatisfied with what they earn. However doctors are still perceived as having a high status in society. Publicly available data suggests that doctors chose to live and work in affluent suburbs where arguably the need for their skills is less than that in neighbouring deprived areas. The gender balance in medicine is also changing with more women entering the workforce and a greater acceptance of parttime working arrangements. In some countries doctors have relinquished the responsibility for emergency out of hours care in general practice and personal continuity of care is no longer on offer. The profession is also challenged by policy makers' enthusiasm for guidelines while the focus on multidisciplinary teamwork makes it more likely that patients will routinely be able to consult professionals other than medical practitioners. At the same time the internet has changed patient expectations so that health care providers will be expected to deploy information technology to satisfy patients. Medicine still has a great deal to offer. Information may be readily available on the internet, but it is not an independently sufficient, prerequisite for people to contend with the physical and psychological distress associated with disease and disability. We need to understand and promote the crucial role doctors play in society at a time of tremendous change in the attitudes to, and within, the profession. PMID- 23671467 TI - Fentanyl for the treatment of tumor-related breakthrough pain. AB - BACKGROUND: Breakthrough cancer pain (BTCP) is common among cancer patients and markedly lowers their quality of life. The treatment for BTCP episodes that is recommended in current guidelines involves extended-release formulations in combination with rapid-onset and short-acting opioids. In the past few years, several new preparations of fentanyl, an opioid with a very rapid onset, have been approved for this indication. Treating physicians need to be aware of the clinical differences between the newer fentanyl preparations and immediate release opioids. METHODS: We searched the PubMed and Embase databases for randomized controlled trials (RCTs) of fentanyl for buccal, sublingual or intranasal administration in comparison with other opioids or a different fentanyl preparation for the treatment of BTCP. RESULTS: In 6 trials of buccal, sublingual or intranasal fentanyl versus oral immediate-release opioids for the treatment of BTCP episodes, the use of fentanyl was associated with significantly less intense pain. In particular, fentanyl more often lowered the intensity of pain by at least 33% (range between studies: 13% to 57%) or by at least 50% (range between studies: 9% to 38%) within 15 minutes. Please change to "versus" if you agree.] Dose titration should begin at the lowest dose. When one fentanyl preparation is exchanged for another, the effective dose will probably differ. CONCLUSION: The newer fentanyl preparations extend the treatment options for BTCP. They relieve pain within a short time better than conventional, immediate release oral opioids do and may therefore be very helpful for patients with suddenly arising, intense, and short-lasting BTCP episodes. Further comparative trials are urgently needed. PMID- 23671468 TI - Chronic tinnitus: an interdisciplinary challenge. AB - BACKGROUND: Tinnitus is defined as the perception of sound in the absence of a corresponding external acoustic stimulus. It is a common problem that markedly impairs the quality of life of about 1% of the general population. METHODS: We selectively reviewed the pertinent literature to provide an overview of the current treatment options for chronic tinnitus. RESULTS: Cognitive behavioral therapy is effective and is the best studied of all currently available treatments. All patients should have a therapeutic interview for counseling. Auditory stimulation can also lessen tinnitus: It is used in tinnitus maskers and hearing aids, as well as in tinnitus retraining therapy. An improved understanding of the neural mechanisms of tinnitus has led to the development of innovative techniques of neuromodulation and neurostimulation, but these are still experimental. Drugs are indicated only for the treatment of tinnitus associated symptoms such as depression, sleep disturbances, and anxiety. CONCLUSION: There are many ways to treat chronic tinnitus, and new treatments are now being developed. As tinnitus has many causes and can be associated with many different comorbid disturbances, multidisciplinary diagnostic evaluation and treatment are important. For many tinnitus patients, long-term therapeutic success depends on the maintenance of a therapeutic relationship with the treating physician, so that the physician and the patient can work together to give careful consideration to each newly proposed diagnostic test or treatment step. PMID- 23671469 TI - Additional treatment options. PMID- 23671470 TI - In reply. PMID- 23671471 TI - Balancing conflicts of interest. PMID- 23671472 TI - Risk awareness and transparency. PMID- 23671473 TI - In reply. PMID- 23671474 TI - Differences between groups. PMID- 23671475 TI - In reply. PMID- 23671477 TI - High heels as a cause. PMID- 23671476 TI - Radical vaginal trachelectomy: a fertility-preserving procedure in early cervical cancer in young women. AB - BACKGROUND: Radical vaginal trachelectomy (RVT) is a fertility-preserving operation for young women who have cervical cancer in an early stage and want to have children. The demand for RVT is increasing, because more than 40% of all cases of cervical carcinoma affect women under the age of 44. Women are increasingly having their first child at later ages. METHODS: We present the results of RVT in more than 300 patients whom we operated on, review pertinent literature retrieved by a selective PubMed search, and evaluate treatment recommendations. RESULTS: The literature contains data on more than 1000 women treated with RVT and nearly 300 pregnancies after RVT. The 5-year recurrence and mortality rates are 2%-5% and 3%-6%, respectively. RVT is an oncologically safe treatment for women who want to have children. The main criteria for treatment with RVT are that the tumor should be no greater than 2 cm in diameter and that the lymph nodes should be histopathologically free of tumor tissue. The laparoscopic-vaginal technique is the best operative approach to assure a high rate of healing. Only one-third of all patients want to have children a short time after RVT. Their pregnancy rates resemble those of women in the general population. 50% of the children are born prematurely, mainly because of premature rupture of the membranes. Thus, pregnancies after RVT are considered high-risk pregnancies. CONCLUSION: As many as 48% of women with early-stage cervical carcinoma meet the criteria for RVT. RVT is an oncologically safe method that enables women with early-stage cervical carcinoma to become pregnant and have children. Pregnancy after RVT is associated with an elevated risk of preterm birth and should be managed according to standardized procedures. PMID- 23671478 TI - Tablets as foreign bodies. PMID- 23671479 TI - Non-ionizing diagnostic evaluation of ingested foreign bodies. PMID- 23671480 TI - Intentional ingestion. PMID- 23671481 TI - Magnet ingestion. PMID- 23671482 TI - Contradictory statements. PMID- 23671483 TI - In reply. PMID- 23671485 TI - Up and running online. PMID- 23671486 TI - CUA leads GU cancer survivorship initiatives. PMID- 23671484 TI - The diagnosis and treatment of generalized anxiety disorder. AB - BACKGROUND: Generalized anxiety disorder (GAD) is a common and serious disease with a lifetime prevalence of 4.3% to 5.9%. It is underdiagnosed in primary care. METHODS: Recommendations on the treatment of GAD are given on the basis of all available findings from pertinent randomized trials, retrieved by a selective search of the literature. RESULTS: Among psychotherapeutic techniques, various kinds of cognitive behavioral therapy (CBT) have been found useful in controlled trials. The drugs of first choice include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephine reuptake inhibitors (SNRIs), and the calcium channel modulator pregabalin. Tricyclic antidepressants are also effective but have more adverse effects than SSRIs. Although benzodiazepines are effective anxiolytic agents for short-term use, they should not be given over the long term because of the danger of addiction. Buspirone, an azapirone, was found to be effective in a small number of trials, but the findings across trials are inconsistent. The response rate of GAD to CBT in published studies lies between 47% and 75%, while its response rate to drug treatment lies between 44% and 81%. CONCLUSION: The treatment of GAD with CBT and drugs is evidence-based and has a good chance of improving the manifestations of the disorder. PMID- 23671487 TI - Measuring bladder strength: Letter. PMID- 23671488 TI - Teaching undergraduate urology: It takes a village. PMID- 23671489 TI - Bladder cancer: Validating what we've got. PMID- 23671490 TI - The incidence of prostate cancer and urothelial cancer in the prostate in cystoprostatectomy specimens in a tertiary care Canadian centre. AB - INTRODUCTION: Radical cystoprostatectomy remains the gold standard treatment for muscle invasive bladder cancer. However, given the treatment related complications of compromised potency and continence with this procedure, prostate/sexuality sparing cystectomy in orthotopic neobladder candidates has emerged in an effort to minimize these quality of life concerns. Recent evidence suggests only a marginal functional benefit from these technical refinements. We sought to determine the incidence of occult prostate cancer and urothelial cancer of the prostate in cystoprostatectomy specimens conducted for muscle invasive bladder cancer. METHODS: We retrospectively reviewed 83 male patients who underwent radical cystoprostatectomy for muscle invasive bladder cancer between April 2004 and March 2007. The median age of our study group was 71 years. Pathologic findings of prostate/urothelial cancer in the prostate were identified. Clinically significant prostate cancer was defined as Gleason score >6, tumour volume >0.5cc, extracapsular extension or perineural invasion. RESULTS: Our review yielded a 30% (+/-10%, 0.95 CI) rate of prostate cancer, with 19% (+/- 8.5%, 0.95 CI) of total specimens being positive for clinically significant prostate cancer. Urothelial cancer in the prostate was identified in 16% (+/-8.5%, 0.95 CI) of patients, with an overlap with prostate cancer in 2 patients. The overall rate of an underlying cancer within the prostate of our cystoprostatectomy specimens was about 46% (+/-10.7%, 0.95 CI). CONCLUSION: These findings suggest that the oncological risk of leaving behind residual cancer may not justify the practice of prostate-sparing cystectomies. PMID- 23671491 TI - Left behind: The potential problem of residual cancer. PMID- 23671492 TI - Evaluating potential live-renal donors: Causes for rejection, deferral and planned procedure type, a single-centre experience. AB - BACKGROUND: Renal transplantation is the preferred therapy to extend life expectancy and quality of life for patients with chronic kidney disease. There are many barriers in the process of live kidney donation that prevent the timely progression from organ requirement to transplantation, including the progression of the live donor through a medical evaluation. We assess how easily patients complete the donor workup, how often the medical evaluation identifies significant incidental findings, and which surgical procedure is planned for organ retrieval. METHODS: We reviewed our donor database and the minutes from our multidisciplinary rounds from 2002 to 2008 to assess how medical, radiological and psychological findings were used to decide on the candidacy of potential donors. RESULTS: Half (50.2%) of patients did not pass the initial health screen. Of the 467 patients who progressed beyond the health screen to the computed tomographic angiogram evaluation, 48 (10.3%) were excluded as donors and 419 (89.7%) were accepted. Of those accepted, 136 (32.5%) were conditional on further medical workup. Of the patients accepted (n=419), 375 (89.5%) were planned for laparoscopic left-sided approach. CONCLUSIONS: The vast majority of patients who passed the initial health screen for kidney donation will be accepted as donors, but about one-third will require further workup. It is rare to identify life threatening disease on screening computerized tomographic angiograph for kidney donor workup. PMID- 23671493 TI - Protecting transplant recipients and live renal donors: Facing the challenges. PMID- 23671494 TI - Anxiety related to sexual abuse: A case of recurrent priapism. AB - Recurrent priapism is notoriously difficult to treat and very distressing to the sufferer. There is little literature about emotional contributors to this condition. We report a case of a man with sexual abuse and severe anxiety who responded acutely to emotion-focused treatment with persistent cessation of severe recurrent priapism episodes. A second case treated with the same method had a similar response to treatment. Emotional factors may be relevant in certain cases of recurrent priapism and these factors warrant clinical management and formal study. PMID- 23671495 TI - Canadian prostate brachytherapy in 2012. AB - Prostate brachytherapy can be used as a monotherapy for low- and intermediate risk patients or in combination with external beam radiation therapy (EBRT) as a form of dose escalation for selected intermediate- and high-risk patients. Prostate brachytherapy with either permanent implants (low dose rate [LDR]) or temporary implants (high dose rate [HDR]) is emerging as the most effective radiation treatment for prostate cancer. Several large Canadian brachytherapy programs were established in the mid- to late-1990s. Prostate brachytherapy is offered in British Columbia, Alberta, Manitoba, Ontario, Quebec and New Brunswick. We anticipate the need for brachytherapy services in Canada will significantly increase in the near future. In this review, we summarize brachytherapy programs across Canada, contemporary eligibility criteria for the procedure, toxicity and prostate-specific antigen recurrence free survival (PRFS), as published from Canadian institutions for both LDR and HDR brachytherapy. PMID- 23671496 TI - A rare but serious complication of GreenLight HPS photoselective vaporization of the prostate: Prostatic capsular perforation with bilateral thigh urinomas and osteitis pubis. AB - The use of lasers to perform photoselective vaporization of the prostate (PVP) has been widely accepted as a safe and effective treatment for benign prostatic hyperplasia with very few reported complications. To date, most of the published data report outcomes for the 80-W potassium-titanyl-phosphate laser. A more potent laser, the 120-W GreenLight HPS, was introduced in 2006 and provides more efficient vaporization of prostatic tissue and decreased operating times. Despite these benefits, the increased energy applied to the prostate evokes concerns of potential serious complications, including capsular perforation and injury to adjacent structures. A more powerful laser system, the 180-W GreenLight XPS laser (American Medical Systems, Minnetonka, MN) has recently become available. We report a rare but serious complication of GreenLight HPS PVP resulting in prostatic capsular perforation with urinary extravasation, presenting with bilateral thigh urinomas and osteitis pubis. PMID- 23671497 TI - Torsion of a seminoma in an intrascrotal testis: A case report and review of the literature. AB - An intrascrotal testicular torsion with malignant testicular tumour is extremely rare. We report a case of a 26-year-old male who was diagnosed with testicular torsion by magnetic resonance imaging and with testicular seminoma after orchiectomy. Through this case, we found that if the possibility of testicular torsion remains during the diagnosis of acute scrotum cases, additional examination adding to colour Doppler sonography should be performed. Furthermore, we should be aware of the possibility of testicular tumours during the diagnosis and treatment of acute scrotums. If the affected testis is preserved in the treatment of testicular torsion, a postoperative examination by ultrasound and/or tumour markers for the remaining testis is essential to confirm the absence of testicular tumour. PMID- 23671498 TI - Penile ossification: A traumatic event or evolutionary throwback? Case report and review of the literature. AB - Penile ossification is very rare, with only a handful of histologically confirmed reported cases. The most common condition leading to penile ossification is Peyronie's disease. Other conditions, such as gout, end-stage renal disease, diabetes mellitus, hyperparathyroidism and local trauma, have also been associated with penile ossification. We report a unique case of near-complete penile ossification of the corporal bodies with histologic confirmation on pathologic review. Our report summarizes the literature regarding this rare entity. PMID- 23671499 TI - Pelvic dural ectasia leading to bilateral ureteric obstruction in the pediatric patient. AB - Large pelvic cysts and moderate to severe hydroureteronephrosis were found after investigating hypertension in a 16-year-old child with Marfan's and known pelvic dural ectasia. Follow-up magnetic resonance imaging demonstrated extensive ectasia of the dural sac at the sacral level with displacement of the bowel, bladder and bilateral ureteric obstruction with accompanying hydroureteronephrosis that was advanced compared to prior imaging. Postural headaches secondary to cerebrospinal fluid leak and progressive hydroureteronephrosis prompted a combined neurosurgical and urologic resection of the pelvic masses. In this report, we discuss the preoperative evaluation and management of this rare form of bilateral ureteric obstruction. PMID- 23671500 TI - Extensive renal infarction following percutaneous biopsy of a small renal mass: A case report. AB - Percutaneous renal biopsy has become increasingly used particularly in patients undergoing active surveillance for small renal masses. We present a patient, who was recently diagnosed with laryngeal squamous cell carcinoma, with significant complication following biopsy of a solid renal mass. The patient was planned for nephron-sparing surgery that was converted to radical nephrectomy due to extensive renal infarction secondary to significant subcapsular hemorrhage inflicted by the biopsy. PMID- 23671502 TI - A singular case of intravesical bleeding angiomyolipoma in a bladder diverticulum. AB - Neoplasms arising from intravesical diverticula are rare and considered by urologists as an important surgical challenge. A hamartomatous lesion noted in a bladder diverticulum has never been reported. To our knowledge, we report the first angiomyolipoma, a subtype of mesenchymal hamartoma uncommonly located extrarenally, seen in a bladder dome diverticulum. We discuss the dilemma on the management of such case, related literature and probable etiology. PMID- 23671501 TI - Indirect inguinal hernia with uterine tissue in a male: A case of persistent Mullerian duct syndrome and literature review. AB - A 32-year-old male presenting with a direct inguinal hernia was found to have uterine tissue extending through the inguinal canal, warranting a diagnosis of persistent Mullerian duct syndrome (PMDS). PMDS is an extremely rare form of internal male pseudo-hermaphroditism in which female internal sex organs, including the uterus, cervix and proximal vagina, persist in a 46XY male with normal external genitalia. The condition results from a congenital insensitivity to anti-Mullerian hormone, or lack of anti-Mullerian hormone, leading to persistence of the female internal sex organs in a male. Clinically, this condition is associated with cryptochoridism. Controversy persists regarding the appropriate treatment of PMDS, since resection of the remnant structures is associated with potential morbidity, but retention risks development of occasional malignancies. We review the literature and discuss various aspects of pathophysiology, diagnosis, and management of PMDS. PMID- 23671503 TI - Transurethral resection of bladder tumour (TURBT) as an optional treatment method on pheochromocytoma of the urinary bladder. AB - Pheochromocytoma of the urinary bladder is rare. We have experienced a case of unexpected pheochromocytoma of the urinary bladder in a 45-year-old female. An ultrasonographic, computed tomography scan and cystoscopic examination showed a submucosal bladder mass. After transurethral resection of bladder tumour was performed, the bladder mass was confirmed as pheochromocytoma by a pathologist. After surgery, the patient underwent a subsequent pelvic magnetic resonance imaging, positron emission tomography and I(131)-methyliodobenzylguanidine (I(131)-MIBG). An image study showed no residual tumour sites and no lymphatic metastasis. The patient has had no tumour recurrence and no voiding symptoms 3 years after the surgery. PMID- 23671504 TI - Idiopathic giant atonic bladder (6000 mL in volume) present for 15 years with no urinary symptoms. AB - Urinary retention is common in patients with neurologic disorders. We present a case of asymptomatic idiopathic giant bladder from which 6000 mL urine was drained. This is the largest volume of bladder that we found in the literature. PMID- 23671505 TI - Intestinal type villous adenoma of the renal pelvis. AB - Intestinal type villous adenomas are uncommon in the genitourinary tract. Most reported cases have been located in the urinary bladder or urachus. Villous adenoma arising in the renal pelvis or ureter is very rare. We present a case of an 81-year-old female who presented with difficulty voiding and mucosuria. A computed tomography scan identified right-sided hydronephrosis, renal parenchymal atrophy, nonobstructing calculi and a lower pole renal mass. She underwent open right nephrectomy. Histopathologic examination of the kidney revealed an intestinal type villous adenoma of the renal pelvis with high-grade dysplasia and focal areas suspicious for invasive adenocarcinoma. We review the four previously reported cases of intestinal type villous adenoma in the renal pelvis and discuss diagnosis and management of this unusual neoplasm. PMID- 23671506 TI - Complete endoscopic management of a retained bullet in the bladder. AB - A 25-year-old male gunshot victim presented at our institution with gross hematuria following Foley catheter insertion. Computed tomography and cystogram did not show a bladder perforation, but were notable for a left ischial fracture and the presence of a bullet within the bladder. After failed attempts at retrieving the bullet with a resectoscope and loop, as well as a cystoscope and stone crusher, a 26 French nephroscope was inserted transurethrally, and the bullet was successfully engaged and removed using a Perc NCircle (Cook Medical, Bloomington, IN) grasper. The extra-peritoneal injury was managed conservatively with catheter drainage. To our knowledge, this represents the first case of successful transurethral management of a retained intravesical bullet. Such an approach may benefit patients with retained intravesical bullets or other challenging intravesical foreign bodies and may be helpful in select circumstances to spare patients from more extensive surgeries. PMID- 23671507 TI - Ureteroiliac fistula secondary to radiotherapy in a patient with single renal metastasis of colon adenocarcinoma. AB - We report the case of a 61-year-old man diagnosed in 2001 with rectal cancer (stage T3N1M0). The patient was treated with surgery, adjuvant chemotherapy and radiotherapy. In 2009, he was admitted to the urology department with a complaint of right hemiabdominal pain. The anatomopathological investigation reported renal metastasis of colon adenocarcinoma. After surgery, he received adjuvant chemotherapy. No tumour recurrence or metastasis was reported at the 22-month follow-up. PMID- 23671509 TI - Urothelial cancer and the diagnosis of subsequent malignancies. AB - PURPOSE: We examine the likelihood of a second primary malignancy diagnosis following the diagnosis of urothelial cancer. METHODS: We identified subjects from the Manitoba Cancer Registry diagnosed with urothelial cancer between April 1, 1985 and December 31, 2007. Data were collected on all subsequent new cancer diagnoses. Standardized incidence ratios (SIRs) were calculated for each major cancer type, matched with the general population by age, sex and period. Further analysis was undertaken stratifying by morphology and invasiveness. The results in males were examined with and without prostate cancer. A competing risk model was used to analyze the data controlling for death. RESULTS: Of the 4412 included urothelial cancer cases, 712 patients (16.1%) subsequently developed a second primary malignancy. Risks were highest within 1 year of diagnosis persisting for 5 years. This risk was highest in males aged less than 70 (SIR = 6.25; 95% Confidence Interval [CI] 5.08-7.04). Overall, the risk was similar between the sexes (female SIR: 1.30, CI 1.09-1.54; males 1.42, CI 1.31-1.54; males excluding prostate SIR: 1.22 CI 1.11-1.35). There was an increased relative risk for developing a second primary for cancers of the kidney (male), lung, breast (female) and prostate. Papillary cancers were associated with increased relative risk of developing lung, prostate, and breast (female and male) cancer. In the competing risks model, patients diagnosed with a papillary or in situ urothelial cancer were more likely to be diagnosed with a second primary than non-papillary and invasive disease, respectively. CONCLUSIONS: Those diagnosed with urothelial cancer have an increased probability of having a second primary cancer detected within the subsequent 5 years, even when prostate cancer is excluded. Papillary tumours in particular may provide a warning for subsequent malignancy. PMID- 23671510 TI - Simultaneous saline irrigation during retrograde rigid ureteroscopic lasertripsy for the prevention of proximal calculus migration. AB - OBJECTIVE: In this paper, we analyze the clinical efficacy of a simultaneous saline irrigation method in treating upper-mid ureteral stone migration and evaluate its effectiveness during ureteroscopic lasertripsy. METHODS: We prospectively evaluated 78 patients with a total of 95 upper-mid ureteral stones, which were treated with holmium:YAG lasertripsy. These patients were randomized into 2 groups. In Group 1 (39 cases with 44 ureteral stones), conventional ureteroscopic lasertripsy was performed. In Group 2, (39 cases with 51 ureteral stones), the simultaneous saline irrigation method was used during lasertripsy. There was no significant difference between the groups with regards to stone site, size or state of the upper urinary tract by spiral computed tomography or excretory urography. Data were analyzed regarding stone migration, lengths of time, and ureteral clearing for various stages of each procedure. RESULTS: One patient in Group 2 (2%) experienced upward stone migration, while this occurred in 8 patients in Group 1 (20%). The operative time in Group 1 ranged from 35 to 55 minutes (mean: 44.8 +/- 5.3), while in Group 2 it ranged from 40 to 69 minutes (mean: 50.4+/-3). There was no significant different in the operative times between the two groups (p < 0.05). Ureteral perforation, urinoma and urosepsis were not seen in both groups. CONCLUSION: The simultaneous saline irrigation method demonstrated a statistically significant advantage over conventional methods. The operation can be performed persistently under clear vision, and since the stones cannot move upward, fragmented portions are easily flushed out. Our data suggest that this method is simple, safe and effective in preventing proximal stone migration during ureteroscopic lasertripsy. PMID- 23671508 TI - Management of small cell carcinoma of the bladder: Consensus guidelines from the Canadian Association of Genitourinary Medical Oncologists (CAGMO). PMID- 23671511 TI - Laparoscopy, dorsal lumbotomy and flank incision live donor nephrectomy: comparison of donor outcomes. AB - BACKGROUND: Flank incision (FL), dorsal lumbotomy (DL) and laparoscopic surgery have been effective approaches to donor nephrectomy. While laparoscopic donor nephrectomy (LDN) has become increasingly popular, there has yet to be a direct comparison of the three modalities. METHODS: We performed a retrospective chart review of FL, DL and LDN operations between 2002 and 2010 within a single institution. Donor and recipient characteristics, as well as surgical outcomes, were assessed. RESULTS: There were 496 donor nephrectomy operations available for analyses. Patients in the LDN group had the lowest estimated blood loss, compared to the DL and FL groups (p < 0.001), lowest rate of complications (p < 0.01), and shortest hospital stay (p < 0.0001). Donors who underwent DL used an average of 60.12 +/- 5.0 mg of morphine, which was significantly less than that used by patients in the LDN (93.2 mg, p < 0.0001) and FL (111.82 mg, p < 0.001) groups. Mean serum creatinine of recipients at day 1 post-op was the highest in the FL group (p < 0.0001 FL vs. LDN, p < 0.001 FL vs. DL), but there were no significant differences between the three groups at 2 weeks, 6, 12, 18, and 24 months post operation (p > 0.45). CONCLUSIONS: Although a lower pain experience of LDN was not indicated, the use of LDN should be favoured over DL and FL as it is associated with fewer complications, and shorter length of stay. Of note, DL appears to be associated with higher complications and is likely not a preferred option for donor nephrectomy. PMID- 23671512 TI - Influence of concurrent medications on outcomes of men with prostate cancer included in the TAX 327 study. AB - OBJECTIVES: The TAX 327 trial was pivotal in establishing docetaxel in castration refractory metastatic prostate cancer. Various commonly prescribed and over-the counter co-administered medications are thought to exhibit anti-neoplastic properties and/or could potentially have pharmacokinectic interactions with docetaxel lessening the effectiveness of chemotherapy. METHODS: To examine the effect of on prostate cancer outcomes within this trial, we examined overall survival, prostate-specific antigen (PSA) response, percent PSA reduction, pain response and QOL responses for 14 families of medications including metformin, digoxin, verapamil, proton pump inhibitors, nitrates, statins, cox-2 inhibitors, warfarin, heparins, ascorbic acid, selenium, tocopherol, antidepressants and erythropoietin. RESULTS: Our findings did not reveal any medication that had a significant additive or synergistic effect with docetaxel. We did note, however, that patients on digoxin or verapamil had poorer overall survival, possibly due to a trend of fewer cycles of administered chemotherapy being administered to the verapamil group, consistent with a pharmacokinectic interaction. CONCLUSIONS: These data are only hypothesis-generating given the statistical limitations, but may form a basis for similar future analysis in other malignancies. The data suggest the need to be aware of pharmacokinectic interactions with medications that may interact with docetaxel. PMID- 23671513 TI - Parameters predicting postoperative unilateral disease in patients with unilateral prostate cancer in diagnostic biopsy: a rationale for selecting hemiablative focal therapy candidates. AB - BACKGROUND: Focal hemiablative therapy for prostate cancer is a new treatment alternative. Unilateral and unifocal disease are its main limitations. The aim of this study was to identify the epidemiological, clinical and pathological parameters that may predict unilateral disease in patients diagnosed with prostate cancer. METHODS: We performed a retrospective analysis of patients at our institution between January 2005 and January 2011. Only patients with unilateral disease in prostate biopsy were part of the study. The analysis included age, preoperative prostate-specific antigen (PSA) and its density, prostate volume, biopsy first and second Gleason pattern and Gleason summary, number of biopsy cores, percentage of cancer in biopsy material and the presence of high-grade prostatic intraepithelial neoplasia. Their role as potential predictors was evaluated by univariate and multivariate analysis. RESULTS: A total of 161 patients had unilateral disease after prostate biopsy. A significant correlation was found between prostate volume, PSA density and percentage of cancer in biopsy material and the presence of unilateral disease in the surgical specimen. These are the same factors significant in the univariate analysis. The results of the multivariate analysis demonstrated that PSA density (p = 0.015) and percentage of cancer in biopsy material (p = 0.028) are the most significant predictors. INTERPRETATION: Our results demonstrate that PSA density and the percentage of cancer in biopsy cores are significant predictors for prostate cancer unilaterality and should be considered for the selection of hemiablative focal therapy candidates. PMID- 23671514 TI - Efficacy and tolerability of combined medication of two different antimuscarinics for treatment of adults with idiopathic overactive bladder in whom a single agent antimuscarinic therapy failed. AB - OBJECTIVE: Recent studies have investigated a combination of two antimuscarinics for adult neurogenic bladder managed with clean intermittent catheterization or pediatric refractory overactive bladder (OAB). We assessed the efficacy and tolerability of this strategy in adults with idiopathic OAB. METHODS: We reviewed 49 patients with idiopathic OAB who received combined antimuscarinic medication. Patients had serially received different kinds of antimuscarinics as monotherapy, but wished to take combined medication due to a lack of sufficient subjective improvement in urgency, even with dosage escalation. Efficacy was measured by changes of episodes of urgency, daytime voiding, nocturia and mean voided volume before and after the addition of the second antimuscarinic. RESULTS: The mean duration of combined medication was 9.3 months. After adding the second antimuscarinic, urgency per day decreased from 3.8 to 1.9 (p < 0.001) and daytime voiding decreased from 10.4 to 7.4 (p < 0.001). The number of nocturia episodes and the mean voided volume also improved, although there was no statistical significance. Efficacy did not differ between the 29 cases, with non-selective and non-selective drugs and 20 cases with non-selective and M3 selective drugs. Thirty-three (67.3%) patients reported to have benefited from combined medication. Maximal flow rate and post-void residual volume did not change in either of the sexes. Eleven (22.4%) patients discontinued the combination due to continued ineffectiveness and dry mouth. CONCLUSION: This retrospective study suggests that combined medication can help adults with refractory idiopathic OAB. Combined medication was tolerated in most of our patients. PMID- 23671515 TI - Clinical and pathological variables that predict changes in tumour grade after radical prostatectomy in patients with prostate cancer. AB - INTRODUCTION: Preoperative Gleason score is crucial, in combination with other preoperative parameters, in selecting the appropriate treatment for patients with clinically localized prostate cancer. The aim of the present study is to determine the clinical and pathological variables that can predict differences in Gleason score between biopsy and radical prostatectomy. METHODS: We retrospectively analyzed the medical records of 302 patients who had a radical prostatectomy between January 2005 and September 2010. The association between grade changes and preoperative Gleason score, age, prostate volume, prostate specific antigen (PSA), PSA density, number of biopsy cores, presence of prostatitis and high-grade prostatic intraepithelial neoplasia was analyzed. We also conducted a secondary analysis of the factors that influence upgrading in patients with preoperative Gleason score <=6 (group 1) and downgrading in patients with Gleason score <=7 (group 2). RESULTS: No difference in Gleason score was noted in 44.3% of patients, while a downgrade was noted in 13.7% and upgrade in 42.1%. About 2/3 of patients with a Gleason score of <=6 upgraded after radical prostatectomy. PSA density (p = 0.008) and prostate volume (p = 0.032) were significantly correlated with upgrade. No significant predictors were found for patients with Gleason score <=7 who downgraded postoperatively. CONCLUSION: Smaller prostate volume and higher values of PSA density are predictors for upgrade in patients with biopsy Gleason score <=6 and this should be considered when deferred treatment modalities are planned. PMID- 23671516 TI - Ambulant monitoring of bladder oxygenation and hemodynamics using wireless near infrared spectroscopy. AB - INTRODUCTION: Near-infrared spectroscopy (NIRS) non-invasively detects changes in the concentration of the chromophores oxygenated (DeltaO2Hb) and deoxygenated hemoglobin (DeltaHHb) as the bladder detrusor muscle contracts during voiding. Such data provide novel information on bladder oxygenation and hemodynamics. We evaluated the feasibility of monitoring ambulant subjects using a wireless NIRS device. METHODS: The wireless device uses paired light-emitting diodes (wavelengths 760 and 850 nm) and a silicon photodiode detector. We monitored 14 asymptomatic subjects (10 adults, 4 children) and 6 symptomatic children with non neurogenic lower urinary tract dysfunction (NLUTD) during spontaneous voiding after natural filling. The device was taped to the abdominal skin 2 cm above the symphysis pubis across the midline. The wireless NIRS data (patterns of change in chromophore concentration) were compared between subjects and to the data obtained using a laser-powered instrument. RESULTS: Graphs of DeltaO2Hb, DeltaHHb and total hemoglobin (DeltatHb) were obtained from all 20 patients. Data during uroflow showed reproducible patterns of bladder chromophore change between asymptomatic subjects (rise in DeltatHb/DeltaO2Hb), consistent with laser instrument data. In contrast, all 6 symptomatic children had a negative trend in DeltatHb, with falls in DeltaO2Hb. One adult experienced "shy" bladder and changes in hemodynamics/oxygenation occurred while bladder volume was unchanged. CONCLUSIONS: Wireless NIRS bladder monitoring is feasible in ambulant adults and children; wireless and laser-derived data in asymptomatic subjects are comparable. Pilot data suggest that subjects with symptomatic NLUTD have impaired bladder oxygenation/hemodynamics. The fact that chromophore changes occur when bladder volume remains constant supports the concept that NIRS data are a physiologic measure. PMID- 23671518 TI - Counting the days to Niagara. PMID- 23671517 TI - Watching the bottom line in urology. PMID- 23671519 TI - Letter: Micro-RNA-125b and its use as a biomarker of systemic malignancies besides urothelial cancers. PMID- 23671520 TI - Hormonal assessment in clinically silent adrenal pheochromocytoma. PMID- 23671521 TI - Still unconvinced on the use of salvage prostatectomy. PMID- 23671522 TI - The importance of quantifying value. PMID- 23671523 TI - Urologists in cyberspace: A review of the quality of health information from American urologists' websites using three validated tools. AB - OBJECTIVES: In this paper, we evaluate a sample of urologists' web-sites, based in the United States, using three validated instruments: the Health on the Net Foundation code of conduct (HONcode), DISCERN and LIDA tools. We also discuss how medical websites can be improved. METHODS: We used the 10 most populous cities in America, identified from the US Census Bureau, and searched using www.google. com to find the first 10 websites using the terms "urologist + city." Each website was scored using the HONcode, DISCERN and LIDA instruments. The median score for each tool was used to dichotomize the cohort and multivariable logistic regression was used to identify independent predictors of higher scores. RESULTS: Of the 100 websites found, 78 were analyzed. There were 18 academic institutions, 43 group and 17 solo practices. A medical website design service had been used by 18 websites. The HONcode badge was seen on 3 websites (4%). Social media was used by 16 websites. Multivariable logistic regression showed predictors of higher scores for each tool. For HONcode, academic centres (OR 6.8, CI 1.2-37.3, p = 0.028) and the use of a medical website design service (OR 17.2, CI 3.8-78.1, p = 0.001) predicted a higher score. With DISCERN, academic centres (OR 23.13, p = 0.002, CI 3.15-169.9 and group practices (OR 7.19, p = 0.022, CI 1.33-38.93) were predictors of higher scores. Finally, with the LIDA tool, there were no predictors of higher scores. Pearson correlation did not show any correlation between the three scores. CONCLUSIONS: Using 3 validated tools for appraising online health information, we found a wide variation in the quality of urologists' websites in the United States. Increased awareness of standards and available resources, coupled with guidance from health professional regulatory bodies, would improve the quality urological health information on medical websites. PMID- 23671524 TI - Paging dr. Google. PMID- 23671525 TI - Cost-utility analysis of radical nephrectomy versus partial nephrectomy in the management of small renal masses: Adjusting for the burden of ensuing chronic kidney disease. AB - OBJECTIVES: We compare the cost-utility of laparoscopic radical nephrectomy (LRN), laparoscopic partial nephrectomy (LPN) and open partial nephrectomy (OPN) in the management of small renal masses (SRMs) when the impact of ensuing chronic kidney disease (CKD) disease is considered. METHODS: We designed a Markov decision analysis model with a 10-year time horizon. Estimates of costs, utilities, complication rates and probabilities of developing CKD were derived from the literature. The base case patient was assumed to be a 65-year-old patient with a <4-cm unilateral renal mass, a normal contralateral kidney and a normal preoperative serum creatinine. Univariate and probabilistic sensitivity analyses were conducted to address the uncertainty associated with the study parameters. RESULTS: OPN was the least costly strategy at $25 941 USD and generated 7.161 quality-adjusted life years (QALYs) over 10 years. LPN yielded 0.098 additional QALYs at an additional cost of $888 for an incremental cost effectiveness ratio of $9057 per QALY, well below a commonly cited willingness-to pay threshold of $50 000 per QALY. LRN was more costly and yielded fewer QALYs than OPN and LPN. Sensitivity analyses demonstrated our model to be robust to changes to key parameters. Age had no effect on preferred strategy. CONCLUSIONS: Partial nephrectomy (PN) is the preferred treatment strategy for SRMs. In centres where LPN is not available, OPN remains considerably more cost-effective than LRN. Furthermore, our study demonstrates that there is no age at which PN is not preferred to LRN. Our study provides additional evidence to advocate PN for the management of all amenable SRMs. PMID- 23671526 TI - Treating small renal masses: Costing it out. PMID- 23671527 TI - Best practices for the treatment and prevention of urinary tract infection in the spinal cord injured population: The Alberta context. AB - The purpose of this review of clinical guidelines and best practices literature is to suggest prevention options and a treatment approach for intermittent catheter users that will minimize urinary tract infections (UTI). Recommendations are based both on evidence in the literature and an understanding of what is currently attainable within the Alberta context. This is done through collaboration between both major tertiary care centres (Edmonton and Calgary) and between various professionals who regularly encounter these patients, including nurses, physiatrists and urologists. PMID- 23671528 TI - A prospective study on pain score with transperineal prostatic gold seed fiducial implantation under local anesthetic alone. AB - BACKGROUND: The purpose of this study was to monitor patient pain score with transperineal prostatic gold seed implantation in the absence of conscious sedation. METHODS: All patients who were scheduled for image-guided external beam radiation (IGRT) and referred for gold seed fiducials were eligible to participate. Gold seed implants were performed by two radiation oncologists between December 2007 and April 2008. Patients received only local and deep anesthetic. No patients had prophylactic IV cannulation for the procedure. Three gold seeds were inserted transperineally into the prostate. A visual analogue scale from 0 to 10 was used to assess the pain at baseline, local and deep anesthetic infiltration, with each seed drop, and after the completion of the procedure. RESULTS: A total of 30 patients were accrued to this study. The highest recorded increase in pain score was at the time point of deep local anesthesia, at which the mean pain score was 3.8. The mean pain scores at each seed drop were 0.8 (standard deviation [SD]=1.24), 1 (SD=1.26), and 0.5 (SD=0.90), respectively. All gold seed insertion procedures were well-tolerated, with no patients having significant pain post-procedure, and no significant procedural complications. There were only slight increases in dysuria, urinary frequency, constipation, urinary retention and flatulence in 7 patients - none of which required intervention. INTERPRETATION: Transperineal ultrasound-guided gold seed implantation without conscious sedation is well-tolerated and associated with a low complication rate. It is a convenient outpatient procedure obviating the need for resource intensive postoperative monitoring. PMID- 23671529 TI - Preoperative hydronephrosis and diabetes mellitus predict poor prognosis in upper urinary tract urothelial carcinoma. AB - INTRODUCTION: We assess the impact of traditional prognostic factors, tumour location, degree of hydronephrosis and diabetes mellitus (DM) on the survival of patients treated for upper urinary tract urothelial carcinoma (UUTUC). METHODS: From January 2004 to March 2010, we analyzed data from 114 patients with UUTUC who underwent nephroureterectomy with a bladder cuff excision. Median patient age was 71 years and median follow-up was 26.5 months. The influence of traditional prognostic factors, including DM, tumour stage, grade, location and degree of hydronephrosis, on recurrence-free survival (RFS) rates were analyzed using Kaplan-Meier analysis and Cox proportional hazards regression model. RESULTS: Among 61 renal pelvis and 53 ureteral tumour cases, recurrence was identified in 71 cases (62.3%). Kaplan-Meier analysis showed that degree of hydronephrosis was associated with RFS (p = 0.001). DM and degree of hydronephrosis were independent factors for RFS in Cox proportional regression analysis (HR=1.8 CI: 1.01-3.55, p = 0.04), (HR=3.7, CI: 2.0-6.5, p = 0.001). All patients with ureteral tumour had no worse prognosis than those with renal pelvis tumour, but the pT2 patients with ureteral tumour had a worse prognosis than those with renal pelvis tumour with a median RFS of 9 months (range: 2.6-15.3 months) and 29 months (range: 8.0-13.2 months), respectively (p = 0.028). CONCLUSIONS: Tumour location is not a factor influencing RFS, except in the pT2 stage. However, severe hydronephrosis is associated with a higher recurrence in UUTUC. Also, DM is related to disease recurrence. Further prospective studies are needed to establish the prognostic significance of DM in large populations. PMID- 23671530 TI - Effect of testosterone undecanoate on hematological profiles, blood lipid and viscosity and plasma testosterone level in castrated rabbits. AB - OBJECTIVE: The association between testosterone replacement therapy and cardiovascular risk remains controversial. Blood viscosity is a known individual risk factor for cardiovascular disease mortality. The objective of the present study was to investigate the effects of the long-acting injectable testosterone undecanoate (TU) on risk factors of cardiovascular disease. METHODS: In total, 24 male New Zealand white rabbits (2.5 kg) were randomly divided into 3 groups of 8. Group 1 was used as control. Group 2 was castrated bilaterally and Group 3 was administrated with 6 mg/kg of TU at day 1 and 6 weeks after castration. Whole blood viscosity, total plasma testosterone, hemoglobin (Hb), hematocrit (Hct), fibrinogen (FBN), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels were measured at baseline, 6 weeks and 18 weeks. RESULTS: In the control group, whole blood viscosity and FBN were significantly increased at 6 and 18 weeks. Castration significantly increased the levels of TC, TG, HDL-C and LDL-C, but decreased Hct and Hb. In the TU injection group, whole blood viscosity was markedly decreased in all share rates, whereas the FBN level was increased. Hb and Hct showed a tendency for higher concentration at 6 weeks. CONCLUSIONS: Long acting injectable TU provides another reliable treatment option for testosterone replacement therapy. Moreover, the patients may receive additional beneficial effect in lowered whole blood viscosity. PMID- 23671531 TI - Clinical significance of suboptimal hormonal levels in men with prostate cancer treated with LHRH agonists. AB - PURPOSE: We examined the serum levels of testosterone (T) (total and bioavailable) dehydroepiandrosterone (DHEA), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prostate-specific antigen (PSA) in men receiving treatment with luteinizing hormone releasing-hormone (LHRH) agonists for metastatic prostate cancer. In doing this, we want to determine the efficacy of these agents in lowering T levels and whether a possible relationship exists between PSA values, as a surrogate measure of tumour activity, and hormone levels. METHODS: This was a single centre prospective study of patients on LHRH agonists. Of all the 100 eligible patients, 31 did not qualify (10 were receiving their first injection, 13 were on intermittent hormonal therapy, 7 refused to enter the trial and 1 patient's blood sample was lost). Therefore in total, 69 patients were included in the final analysis. Each patient had their blood sample drawn immediately before the administration of a LHRH agonist. The new proposed criteria of <20 ng/dL (0.69 nmol/L) of total testosterone was used to define optimal levels of the hormone in this population. RESULTS: Of the 69 patients, 41 were on goserelin injections, 21 on leuprolide, and 7 on buserelin. There was no statistical difference in hormone levels between any of the medications. Overall, 21% of patients failed to reach optimal levels of total testosterone. PSA levels were higher in this group. There was a statistically significant correlation between PSA and testosterone levels, as well as between PSA and FSH. Serum levels of PSA, however, did not correlate with those of bioavailable testosterone. CONCLUSIONS: Failure to reach optimal levels of testosterone occurs in patients on LHRH agonist therapy. Higher PSA values are more commonly found in patients with suboptimal levels of testosterone receiving LHRH analogs, but the clinical importance of this finding has not been established. There is no significant difference with respect to hormonal levels reached among patients on a variety of LHRH agonists. Total testosterone determinations should be considered in patients on LHRH agonist therapy, particularly when the PSA values begin to rise since it may lead to further beneficial hormonal manipulation. PMID- 23671532 TI - Incremental costs of prostate cancer trials: Are clinical trials really a burden on a public payer system? AB - INTRODUCTION: Clinical trials are a critical component of improving cancer prevention and treatment strategies. However, the perception that patients enrolled in trials consume more resources than those receiving the standard-of care (SOC) has contributed to an increasingly research-averse environment. Current economic data pertaining to the per-patient costs of prostate cancer trials relative to SOC treatment are limited. METHODS: A retrospective observational cohort study was conducted to compare costs incurred by 59 prostate cancer patients participating in a mix of industry and non-industry sponsored clinical trials with costs incurred by an equal number of eligible non participants who received SOC over a year. Resource utilization was tracked and quantified to standardized price templates. RESULTS: No difference in overall resource utilization was seen between trial and SOC patients (two-tailed t-test, n = 118, p = 0.99). Variability in the types of resources used by each group indicated that, while trial patients may take up significantly more clinic time (p = 0.001) and undergo more tests and procedures (p = 0.001), SOC patients are more likely to receive other costly interventions, such as radiation therapy (p < 0.001). Other variables (e.g., pathology, diagnostic imaging, prescribed therapies) were statistically indistinguishable between groups. CONCLUSION: This study revealed differences in the cost distribution of patients enrolled in clinical trials versus those receiving SOC, which could be used to improve resource allocation. The lack of evidence for a difference in overall cost provides an argument for payers to more fully support clinical research without fear of adverse financial consequences. Further analysis is required. PMID- 23671533 TI - Inflammatory myofibroblastic tumour of the bladder: Case report and review of the literature. AB - Inflammatory myofibroblastic tumour (IMT) is a rare tumour with malignant potential, and has been described in many major organs. However, bladder location is very uncommon. We report the case of a 23-year-old woman who presented with painless gross hematuria for 2 weeks. Contrast-enhanced computed tomography revealed a bladder tumour. The patient underwent an open partial cystectomy and the final pathologic diagnosis was IMT of bladder. Typical IMTs can be locally aggressive, therefore close follow-up is necessary. PMID- 23671534 TI - Disappearance of a major thrombus in the brachiocephalic vein without anticoagulant therapy in a patient with seminoma: A case report. AB - This is the first case report describing brachiocephalic vein thrombosis without compression by a metastatic tumour during chemotherapy for testicular cancer. According to previous reports of testicular cancer patients with a major thrombus, anticoagulant therapy was required to resolve all cases. However, in the present case, a major thrombus in the brachiocephalic vein disappeared without anticoagulant therapy. This 42-year-old man was diagnosed with testicular seminoma and multiple metastases to the para-aortic lymph nodes. After 3 cycles of cisplatin, etoposide and bleomycin (PEB) therapy, a major thrombus in the right brachiocephalic vein was recognized on a computed tomography (CT) scan. Although no anticoagulant therapy was undertaken, the thrombus in the right brachiocephalic vein was no longer visible on CT after the fourth cycle of PEB therapy. PMID- 23671535 TI - A unique scrotal extratesticular epidermod cyst attached to the seminal vesicles. AB - A 46-year-old man was admitted with a scrotal long standing painless mass. The workup included physical examination, alpha-fetoprotein (alphaFP) and beta-human chorionic gonadotropin (beta-hCG) analyses, scrotal ultrasound, magnetic resonance imaging and urethrocystoscopy. Surgical exploration revealed a separate mass between the testes extending superiorly with a thin stalk. It was dissected easily to the anterior aspect of the seminal vesicles and removed from the junction to the seminal vesicles. Pathology reported an epidermoid cyst. To our knowledge this is the first case of a scrotal extratesticular epidermoid cyst attached to the seminal vesicles. PMID- 23671536 TI - Metastatic prostate cancer with malignant ascites: A case report and literature review. AB - Malignant ascites from advanced prostate cancer is rare and has a poor prognosis. We report a case of a 57-year-old African American male presenting with weight loss, lower urinary tract symptoms and voiding dysfunction. He also had renal failure with metabolic abnormalities associated with significant abdominal distention and pain. Computed tomography showed ascites, which was pathologically confirmed by immunostaining and cytological identification of malignant cells. Prostate biopsy identified high-grade prostate cancer which responded to hormonal therapy with a significant decrease in serum prostatic-specific antigen. Ascites was managed with paracentesis and renal failure with hemodialysis as needed. PMID- 23671537 TI - Transplant renal artery stenosis secondary to mechanical compression from polycystic kidney disease: A case report. AB - Transplant renal artery stenosis (TRAS) is a potentially treatable cause of allograft dysfunction, hypertension and graft loss. The mainstay of treatment includes angioplasty and endovascular stenting, although observation and surgery are at times indicated. We present an unusual case of TRAS secondary to mechanical compression from a patient's enlarged native polycystic kidneys. This was treated with bilateral native nephrectomy and evidence of TRAS improved both clinically and radiographically. Recognition and treatment are important in preventing irreversible complications of TRAS. PMID- 23671538 TI - Adrenal artery pseudoaneurysm in pheochromocytoma presenting with catastrophic retroperitoneal haemorrhage. AB - Spontaneous rupture of adrenal pheochromocytoma is an extremely rare condition which presents as an abdominal catastrophe. Unrecognized, this transformation can rapidly lead to death. We report a case of a 63-year-old male who presented with hemorrhagic shock secondary to ruptured adrenal pheochromocytoma. The clinical course is notable for immediate transarterial catheter embolization for control of bleeding, followed by optimization and elective adrenalectomy. High mortality is associated with an operative intervention in the face of an unrecognized pheochromocytoma. This reinforces the need for maintaining a high index of suspicion in the setting of a suprarenal mass despite hypotension. PMID- 23671539 TI - Fibroepothelial polyp of the glans penis due to pad use for urinary incontinence. AB - A 78-year-old man was admitted to our urology polyclinic with painless penile mass. The lesion was 3.5 cm in size on the ventral aspect of the penis. He had been using a pad for urinary incontinance for 10 months and said that the lesion had been increasing in size for past 3 months. He underwent a wide local excision under local anesthesia. The histopathologic diagnosis was fibroepithelial polyp. A fibroepithelial polyp of the penis is very rare and strongly linked to long term condom catheter use. We present a case of fibroepithelial polyp of the glans which is not associated with condom catheter use. PMID- 23671541 TI - Leptin influence in craving and relapse of alcoholics and smokers. AB - Leptin inhibits signaling of dopamine in the nucleus accumbens, suggesting its role in regulating stress and its possible involvement in the neurobiology of reward system. The aim of this study was to review of the literature on the influence of leptin in the craving for alcohol and tobacco and whether there is already evidence that leptin may be a biomarker to indicate risk for craving and relapse. The review used as data bases Medline, LILACS and SciElo in the period between 2000 and 2012. Keywords were leptin, substance use disorders, craving and withdrawal, in Portuguese and English. Only 12 articles were met the inclusion criteria, relating leptin with craving in alcoholics (n = 10) and smokers (n = 2). No studies were found in the LILACS database. Leptin levels increase during abstinence and this may be related to a reduction of dopaminergic action in mesolimbic system, resulting in a greater intensity of craving and maintenance of addictive behavior. Although there are few studies, the most recent results indicate the usefulness of leptin as a marker of risk for relapse among smokers and alcoholics in abstinence. PMID- 23671540 TI - Chronic pelvic pain in endometriosis: an overview. AB - Chronic pelvic pain (CPP) could be considered nowadays a deep health problem that challenges physicians all over the world. This because its aetiology is still unclear, the course of the disease could vary a lot among different patients and through time in the same patient, and the response to treatments is not every time successful. Among women who underwent laparoscopy for CPP, endometriosis is found in about 1/3 of the cases, while only 25% of women with histological confirmed endometriosis are asymptomatic. A wide range of variables may exert their influence on the resulting pain syndrome in endometriosis; for example, score according to American society for reproductive medicine (rASRM), size of the sub-peritoneal and pelvic wall implants, Douglas obliteration, previous surgery. It is widely accepted nowadays that central nervous system (CNS) and peripheral nervous system (PNS) seems to influence each other and this interconnection play a key role in pain modulation. Moreover, the phenomena induced by endometriosis in the pelvis, including the breakdown of peritoneal homeostasis and the induction of the production of proinflammatory and proangiogenic cytokines, are responsible of altered innervations and modulation of pain pathways in these patients. There are many proposed medical and surgical approach to treat this painful syndrome, although there is necessity of more efforts to create new non-invasive strategies that set a more accurate diagnosis of the causes of endometriotic-related CPP, and therefore facilitate its eradication. PMID- 23671542 TI - Unintentional discontinuation of statins may increase mortality after traumatic brain injury in elderly patients: a preliminary observation. AB - BACKGROUND: The abrupt discontinuation of statin therapy has been suggested as being deleterious to patient outcomes. Although pre-injury statin (PIS) therapy has been shown to have a protective effect in elderly trauma patients, no study has examined how this population is affected by its abrupt discontinuation. This study examined the effects of in-hospital statin discontinuation on patient outcomes in elderly traumatic brain injury (TBI) patients. METHODS: This was a multicenter, retrospective cohort study on consecutively admitted elderly (>= 55) PIS patients who were diagnosed with a blunt TBI and who had a hospital length of stay (LOS) >= 3 days. Patients who received an in-hospital statin within 48 hours of admission were considered continued, and patients who never received an in hospital statin were considered discontinued. Differences in in-hospital mortality, having at least one complication, and LOS > 1 week were examined between those who continued and discontinued PIS. RESULTS: Of 93 PIS patients, 46 continued and 15 discontinued statin therapy. The two groups were equivalent vis a-vis demographic and clinical characteristics. Those who discontinued statin therapy had a 4-fold higher mortality rate than those who continued (n = 4, 27% vs. n = 3, 7%, P = 0.055). Statin discontinuation did not have a higher complication rate, compared to statin continuation (n = 3, 20% vs. n = 7, 15%, P = 0.70), and no difference was seen in the proportion with a hospital LOS > 1 week (P > 0.99). CONCLUSIONS: Though our study is not definitive, it does suggest that the abrupt, unintended discontinuation of statin therapy is associated with increased mortality in the elderly TBI population. Continuing in-hospital statin therapy in PIS users may be an important factor in the prevention of in-hospital mortality in this elderly TBI population. PMID- 23671543 TI - Outcomes of salvage autologous versus allogeneic hematopoietic cell transplantation for relapsed multiple myeloma after initial autologous hematopoietic cell transplantation. AB - BACKGROUND: Standard therapy for multiple myeloma (MM) includes initial autologous hematopoietic cell transplantation (autoHCT1) but this is not curative and most patients will relapse. Role of salvage autoHCT2 or allogeneic HCT (alloHCT2) is undefined. METHODS: MM patients who relapsed after autoHCT1 and had salvage autoHCT2 (N = 27) or alloHCT2 (N = 19) between 1995 - 2011 at our institution were studied retrospectively. RESULTS: Complete and very good partial remission (CR/VGPR) improved from 7% to 56% after autoHCT2 and from 26% to 37% after alloHCT2. Nonrelapse mortality (NRM) at 3 years was 3.7% for autoHCT2 and 5.3% for alloHCT2 (P = 0.901). Median progression free survival (PFS) and overall survival (OS) for autoHCT2 (19 months, 23 months) and alloHCT2 (6 months, 19 months) were not significantly different. On multivariate analysis, time from autoHCT1 to relapse >= 1year (HR 24.81, 95% CI 2.4 - 249.9) and maintenance therapy after autoHCT2 (HR 12.19, 95% CI 2.5 - 249.9) impacted OS after autoHCT2. Time from autoHCT1 to relapse < 1 year vs. >= 1 year (HR 18.55, 95% CI 2.28 - 150.57) impacted PFS after autoHCT2. For alloHCT2, no factors impacted NRM, PFS or OS. For those with relapse from autoHCT1 < 1 year vs. >= 1 year undergoing autoHCT2, median OS was 15 months (range, 1 - 53) vs. not yet reached at 143 months and median PFS was 5 months (range, 1 - 49) vs. not yet reached at 88 months. CONCLUSIONS: Salvage autoHCT2 and alloHCT2 are both feasible for post autoHCT1 MM relapse. Relapse >= 1 year from autoHCT1 predicts for better PFS and OS after autoHCT2. Maintenance therapy after autoHCT2 is beneficial. PMID- 23671544 TI - Characteristics and Causes for Non-Accrued Clinical Research (NACR) at an Academic Medical Institution. AB - BACKGROUND: The impact of non-accrued clinical research (NACR) represents an important economic burden that is under consideration as the U.S. Department of Health and Human Services looks into reforming the regulations governing IRB review. NACR refers to clinical research projects that fail to enroll subjects. A delineation of the issues surrounding NACR is expected to enhance subject accrual and to minimize occurrence of NACR. The authors assessed demographics, characteristics, and reasons for NACR at an academic medical center, including time trends, funding source, research team (principal investigator, department), IRB resource utilization (IRB level of review, number of required IRB reviews, initial IRB turn-around time, and duration of NACR). METHODS: The authors analyzed data from 848 clinical research study closures during 2010 and 2011 to determine proportion, incidence, and characteristics of NACR. Studies with subject enrollment during the same time period were used as a comparative measure. RESULTS: Data from 704 (83.0%) study closures reported enrollment of 1 or more subjects while 144 (17.0 %) reported NACR (zero enrollment). PI-reported reasons for NACR included: 32 (22.2%) contract or funding issues; 43 (30.0%) insufficient study-dedicated resources; 41 (28.4%) recruitment issues; 17 (11.8%) sponsor-initiated study closure and 11 (7.6%) were "other/reason unreported". CONCLUSIONS: NACR is not uncommon, affecting about one in six clinical research projects in the study population and reported to be more common in some other institutions. The complex and fluid nature of research conduct, non-realistic enrollment goals, and delays in both the approval and/or accrual processes contribute to NACR. Results suggest some simple strategies that investigators and institutions may use to reduce NACR, including careful feasibility assessment, reduction of institutional delays, and prompt initiation of subject accrual for multi-center studies using competitive enrollment. Institutional action to support investigators in the conduct clinical research is also encouraged to reduce likelihood of NACR. PMID- 23671545 TI - Trends in the medical management of patients with heart failure. AB - BACKGROUND: Despite the availability of effective therapies, heart failure (HF) remains a highly prevalent disease and the leading cause of hospitalizations in the U.S. Few data are available, however, describing changing trends in the use of various cardiac medications to treat patients with HF and factors associated with treatment. The objectives of this population-based study were to examine decade-long trends (1995 - 2004) in the use of several cardiac medications in patients hospitalized with acute decompensated heart failure (ADHF) and factors associated with evidence-based treatment. METHODS: We reviewed the medical records of 9,748 residents of the Worcester, MA, metropolitan area who were hospitalized with ADHF at all 11 central Massachusetts medical centers in 1995, 2000, 2002, and 2004. RESULTS: Between 1995 and 2004, respectively, the prescription upon hospital discharge of beta-blockers (23%; 67%), angiotensin pathway inhibitors (47%; 55%), statins (5%; 43%), and aspirin (35%; 51%) increased markedly, while the use of digoxin (51%; 29%), nitrates (46%; 24%), and calcium channel blockers (33%; 22%) declined significantly; nearly all patients received diuretics. Patients in the earliest study year, those with a history of obstructive pulmonary disease or anemia, incident HF, non-specific symptoms, and women were less likely to receive beta blockers and angiotensin pathway inhibitors than respective comparison groups. In 2004, 82% of patients were discharged on at least one of these recommended agents; however, only 41% were discharged on medications from both recommended classes. CONCLUSIONS: Our data suggest that opportunities exist to further improve the use of HF therapeutics. PMID- 23671546 TI - The effect of whole body vibration exposure on muscle function in children with cystic fibrosis: a pilot efficacy trial. AB - BACKGROUND: To examine the effects of whole body vibration (WBV) exposure on muscle function in children with Cystic Fibrosis (CF). Non-randomised controlled cross-over trial. METHODS: The setting was home-based WBV exposure. The participants were children (8 - 15 years) with CF (n = 7). INTERVENTION: participants served as their own controls for the first four weeks (usual care), then underwent four weeks of parentally-supervised home-based WBV exposure followed by four weeks washout (usual care). The WBV exposure consisted of 20 - 30 minutes of intermittent (1 min vibration:1 min rest) exposure on a Galileo platform (20 - 22Hz, 1 mm amplitude) 3 days/week. The primary outcome measures of absolute and relative lower body (leg extension (LE), leg press (LP)), upper body (chess press (CP)) strength and power, and power were measured at baseline, and weeks 4, 8 and 12. Secondary exploratory outcomes were cardiorespiratory fitness, pulmonary function and health-related quality of life. RESULTS: Six participants completed the training without adverse events. Muscle function changes following WBV exposure were not statistically significant. However, moderate-to-large relative effect sizes (ES) favouring WBV were evident for leg extension strength (ES = 0.66 (-0.50, 1.82)), LP relative strength (ES = 0.92 (-0.27, 2.11)), leg press peak power (ES = 0.78 (-0.50, 2.07)) and CMJ height (ES = 0.60 (-0.56 to 1.76)). CONCLUSIONS: The results from this first controlled trial indicate that WBV may be a potentially effective exercise modality to safely increase leg strength and explosive power in children with CF. Potentially clinically relevant changes support continued investigation of the efficacy, mechanism and feasibility of this intervention in future large-scale studies. PMID- 23671547 TI - Factors associated with reduced efficacy of sitagliptin therapy: analysis of 93 patients with type 2 diabetes treated for 1.5 years or longer. AB - BACKGROUND: Several studies have shown the effectiveness of sitagliptin, a dipeptidyl peptidase-4 inhibitor, for type 2 diabetes, with a hypoglycemic effect being demonstrated both when it is administered alone or in combination with other oral antidiabetic agents. However, there are few reports about its long term efficacy, although medications for diabetes need to be effective over the long term. This study (as part of ASSET-K) aimed to investigate the efficacy and safety of sitagliptin when it was administered for 1.5 years or longer, and to explore factors associated with reduction of the therapeutic response. METHODS: Out of 375 patients treated with sitagliptin (50 mg/day) at Kanamori Diabetes Clinic between December 2009 and March 2012, 133 could be followed up for 72 weeks without interruption. After excluding 40 patients in whom the dosage and/or types of concomitant medications were modified during that period, the remaining 93 were included in this analysis. Clinical indices, such as blood glucose, HbA1c, and body weight, were investigated retrospectively. Compliance with diet and exercise therapy at 48 weeks was checked by a questionnaire. RESULTS: In the 93 patients analyzed (sitagliptin monotherapy, n = 9; combination therapy, n = 77; and switching from an alpha-glucosidase inhibitor or glinide, n = 7), hemoglobin A1c (HbA1c) showed a significant decrease after 24 weeks (7.70 +/- 0.73% at baseline vs. 6.90 +/- 0.55% at 24 weeks), but then showed a slight increase at 48 weeks. HbA1c was subsequently maintained in the same range with no significant changes until 72 weeks. A positive correlation was noted between the changes of HbA1c and body weight from 24 to 48 weeks. Compliance with diet and exercise therapy was worse in patients showing a >= 0.3% increase of HbA1c (n = 37) from 24 to 48 weeks than in the others (n = 56). Multiple logistic regression analysis showed that both factors were independent determinants of the increase of HbA1c from 24 weeks onward. CONCLUSIONS: Sitagliptin showed good efficacy and safety when administered for 18 months as both monotherapy and combination therapy. Inadequate compliance with diet/exercise therapy and weight again may be associated with an increase of HbA1c over time during treatment with sitagliptin. PMID- 23671548 TI - Cough reflex testing in Dysphagia following stroke: a randomized controlled trial. AB - BACKGROUND: Significant health issues and service delivery costs are associated with post-stroke pneumonia related to dysphagia. Silent aspiration is known to increase pneumonia and mortality in this population. The utility of cough reflex testing (CRT) for reducing pneumonia in acute stroke patients was the subject of this randomised, controlled trial. METHODS: Patients referred for swallowing evaluation (N = 311) were assigned to either 1) a control group receiving standard evaluation or 2) an experimental group receiving standard evaluation with CRT. Participants in the experimental group were administered nebulised citric acid with test results contributing to clinical decisions. Outcomes for both groups were measured by pneumonia rates at 3 months post evaluation and other clinical indices of swallowing management. RESULTS: Analysis of the data identified no significant differences between groups in pneumonia rate (P = 0.38) or mortality (P = 0.15). Results of CRT were shown to influence diet recommendations (P < 0.0001) and referrals for instrumental assessment (P < 0.0001). CONCLUSIONS: Despite differences in clinical management between groups, the end goal of reducing pneumonia in post stroke dysphagia was not achieved. PMID- 23671549 TI - Effect of 1110 MBq Radioiodine in Reducing Thyroid Volume in Multinodular Goiter: A New Protocol. AB - BACKGROUND: There is no consensus on the optimal treatment of multinodular goiter (MNG), but in the past few years, the use of radioiodine has increased. This study's objective was to evaluate adjuvant methimazole (MMI) therapy to increase and standardize radioiodine uptake (RAIU) with a fixed therapeutic (131)I dose of 1110 MBq (30 mCi). METHODS: Our study included 5 women with MNG treated with MMI, 10 - 15 mg/day for 2 to 4 months, prior to the administration of 1110 MBq (131)I (30 mCi); none of the patients developed hypothyroidism during MMI therapy and had average basal TSH levels of 0.32 +/- 0.39 mIU/L that increased to 2.6 +/- 0.9 mIU/L (P = 0.07). RESULTS: RAIU increased from 25.6 +/- 8.7% to 49.2 +/- 8.3% (P = 0.003). All patients were followed for 12 months: median thyroid volume (TV) decreased from 77.2 mL (32.9 - 124.2) to 48.8 ml (12.4 - 68.9) with an average decrease of 46.4 +/- 14.8% (P = 0.01). All patients developed hypothyroidism during the first 6 months after radioiodine therapy. CONCLUSIONS: This new therapeutic protocol using MMI as adjuvant therapy is effective in increasing RAIU as well as the deleterious effects of (131)I, without increasing the required dose, but leading to thyroid volume decreases similar to those reported with the use of recombinant human thyrotropin (rhTSH) or higher radioiodine doses. PMID- 23671550 TI - Pulmonary and cerebral fat embolism syndrome after total knee replacement. AB - Fat embolism occurs after long bone fracture or orthopedic surgery and usually shows mild symptom. But it rarely results in fat embolism syndrome, presenting as multiorgan dysfunction such as lung, brain and skin. Although the diagnosis of fat embolism syndrome is mostly based on clinical features, we experienced fat embolism syndrome involving lung and brain, showing typical imaging findings in pulmonary computed tomography and brain magnetic resonance image. So we present interesting case about fat embolism syndrome after total knee replacement with reviewing associated literatures including imaging findings. PMID- 23671552 TI - Subjective signs of rhegmatogenous retinal detachment associated with acute posterior vitreous detachment. PMID- 23671551 TI - A rare coexistence: drug induced hepatitis and meningitis in association with Ibuprofen. AB - Ibuprofen, a commonly used NSAID is reported to be associated with drug induced liver injury. Ibuprofen is also known to be associated with drug-induced meningitis especially in patients with connective tissue disorders. However presentation of hepatitis and meningitis in association with Ibuprofen use in the same individual has never been reported. We present a case of young woman who developed abnormal liver chemistries and neurological symptoms while on Ibuprofen. Her liver biopsy findings were suggestive of drug induced liver injury and cerebrospinal fluid analysis was suggestive of aseptic meningitis. Clinical and biochemical improvement was noted on cessation of Ibuprofen. PMID- 23671558 TI - Effects of temporal resolution on an inferential model of animal movement. AB - Recently, there has been much interest in describing the behaviour of animals by fitting various movement models to tracking data. Despite this interest, little is known about how the temporal 'grain' of movement trajectories affects the outputs of such models, and how behaviours classified at one timescale may differ from those classified at other scales. Here, we present a study in which random walk state-space models were fit both to nightly geospatial lifelines of common brushtail possums (Trichosurus vulpecula) and synthetic trajectories parameterised from empirical observations. Observed trajectories recorded by GPS collars at 5-min intervals were sub-sampled at periods varying between 10 and 60 min, to approximate the effect of collecting data at lower sampling frequencies. Markov-Chain Monte-Carlo fitting techniques, using information about movement rates and turning angles between sequential fixes, were employed using a Bayesian framework to assign distinct behavioural states to individual location estimates. We found that in trajectories with higher temporal granularities behaviours could be clearly differentiated into 'slow-area-restricted' and 'fast-transiting' states, but for trajectories with longer inter-fix intervals this distinction was markedly less obvious. Specifically, turning-angle distributions varied from being highly peaked around either 0 degrees or 180 degrees at fine temporal scales, to being uniform across all angles at low sampling intervals. Our results highlight the difficulty of comparing model results amongst tracking-data sets that vary substantially in temporal grain, and demonstrate the importance of matching the observed temporal resolution of tracking devices to the timescales of behaviours of interest, otherwise inter-individual comparisons of inferred behaviours may be invalid, or important biological information may be obscured. PMID- 23671559 TI - BMI1 polycomb group protein acts as a master switch for growth and death of tumor cells: regulates TCF4-transcriptional factor-induced BCL2 signaling. AB - For advanced prostate cancer (CaP), the progression of tumors to the state of chemoresistance and paucity of knowledge about the mechanism of chemoresistance are major stumbling blocks in the management of this disease. Here, we provide compelling evidence that BMI1 polycomb group protein and a stem cell factor plays a crucial role in determining the fate of tumors vis-a-vis chemotherapy. We show that progressive increase in the levels of BMI1 occurs during the progression of CaP disease in humans. We show that BMI1-rich tumor cells are non-responsive to chemotherapy whereas BMI1-silenced tumor cells are responsive to therapy. By employing microarray, ChIP, immunoblot and Luciferase reporter assays, we identified a unique mechanism through which BMI1 rescues tumor cells from chemotherapy. We found that BMI1 regulates (i) activity of TCF4 transcriptional factor and (ii) binding of TCF4 to the promoter region of anti-apoptotic BCL2 gene. Notably, an increased TCF4 occupancy on BCL2 gene was observed in prostatic tissues exhibiting high BMI1 levels. Using tumor cells other than CaP, we also showed that regulation of TCF4-mediated BCL2 by BMI1 is universal. It is noteworthy that forced expression of BMI1 was observed to drive normal cells to hyperproliferative mode. We show that targeting BMI1 improves the outcome of docetaxel therapy in animal models bearing chemoresistant prostatic tumors. We suggest that BMI1 could be exploited as a potential molecular target for therapeutics to treat chemoresistant tumors. PMID- 23671561 TI - Correlates between feeding ecology and mercury levels in historical and modern arctic foxes (Vulpes lagopus). AB - Changes in concentration of pollutants and pathogen distribution can vary among ecotypes (e.g. marine versus terrestrial food resources). This may have important implications for the animals that reside within them. We examined 1) canid pathogen presence in an endangered arctic fox (Vulpes lagopus) population and 2) relative total mercury (THg) level as a function of ecotype ('coastal' or 'inland') for arctic foxes to test whether the presence of pathogens or heavy metal concentration correlate with population health. The Bering Sea populations on Bering and Mednyi Islands were compared to Icelandic arctic fox populations with respect to inland and coastal ecotypes. Serological and DNA based pathogen screening techniques were used to examine arctic foxes for pathogens. THg was measured by atomic absorption spectrometry from hair samples of historical and modern collected arctic foxes and samples from their prey species (hair and internal organs). Presence of pathogens did not correlate with population decline from Mednyi Island. However, THg concentration correlated strongly with ecotype and was reflected in the THg concentrations detected in available food sources in each ecotype. The highest concentration of THg was found in ecotypes where foxes depended on marine vertebrates for food. Exclusively inland ecotypes had low THg concentrations. The results suggest that absolute exposure to heavy metals may be less important than the feeding ecology and feeding opportunities of top predators such as arctic foxes which may in turn influence population health and stability. A higher risk to wildlife of heavy metal exposure correlates with feeding strategies that rely primarily on a marine based diet. PMID- 23671560 TI - Amphetamine elicits opposing actions on readily releasable and reserve pools for dopamine. AB - Amphetamine, a highly addictive drug with therapeutic efficacy, exerts paradoxical effects on the fundamental communication modes employed by dopamine neurons in modulating behavior. While amphetamine elevates tonic dopamine signaling by depleting vesicular stores and driving non-exocytotic release through reverse transport, this psychostimulant also activates phasic dopamine signaling by up-regulating vesicular dopamine release. We hypothesized that these seemingly incongruent effects arise from amphetamine depleting the reserve pool and enhancing the readily releasable pool. This novel hypothesis was tested using in vivo voltammetry and stimulus trains of varying duration to access different vesicular stores. We show that amphetamine actions are stimulus dependent in the dorsal striatum. Specifically, amphetamine up-regulated vesicular dopamine release elicited by a short-duration train, which interrogates the readily releasable pool, but depleted release elicited by a long-duration train, which interrogates the reserve pool. These opposing actions of vesicular dopamine release were associated with concurrent increases in tonic and phasic dopamine responses. A link between vesicular depletion and tonic signaling was supported by results obtained for amphetamine in the ventral striatum and cocaine in both striatal sub-regions, which demonstrated augmented vesicular release and phasic signals only. We submit that amphetamine differentially targeting dopamine stores reconciles the paradoxical activation of tonic and phasic dopamine signaling. Overall, these results further highlight the unique and region-distinct cellular mechanisms of amphetamine and may have important implications for its addictive and therapeutic properties. PMID- 23671562 TI - Chronic IL9 and IL-13 exposure leads to an altered differentiation of ciliated cells in a well-differentiated paediatric bronchial epithelial cell model. AB - Asthma is a chronic inflammatory disease characterised by airways remodelling. In mouse models IL-9 and IL-13 have been implicated in airways remodelling including mucus hypersecretion and goblet cell hyperplasia. Their role, especially that of IL-9, has been much less studied in authentic human ex vivo models of the bronchial epithelium from normal and asthmatic children. We assessed the effects of IL-9, IL-13 and an IL-9/IL-13 combination, during differentiation of bronchial epithelial cells from normal (n = 6) and asthmatic (n = 8) children. Cultures were analysed for morphological markers and factors associated with altered differentiation (MUC5AC, SPDEF and MMP-7). IL-9, IL-9/IL-13 combination and IL-13 stimulated bronchial epithelial cells from normal children had fewer ciliated cells [14.8% (SD 8.9), p = 0.048, 12.4 (SD 6.1), p = 0.016 and 7.3% (SD 6.6), p = 0.031] respectively compared with unstimulated [(21.4% (SD 9.6)]. IL-9 stimulation had no effect on goblet cell number in either group whereas IL-9/IL 13 combination and IL-13 significantly increased goblet cell number [24.8% (SD 8.8), p = 0.02), 32.9% (SD 8.6), p = 0.007] compared with unstimulated normal bronchial cells [(18.6% (SD 6.2)]. All stimulations increased MUC5AC mRNA in bronchial epithelial cells from normal children and increased MUC5AC mucin secretion. MMP-7 localisation was dysregulated in normal bronchial epithelium stimulated with Th2 cytokines which resembled the unstimulated bronchial epithelium of asthmatic children. All stimulations resulted in a significant reduction in transepithelial electrical resistance values over time suggesting a role in altered tight junction formation. We conclude that IL-9 does not increase goblet cell numbers in bronchial epithelial cell cultures from normal or asthmatic children. IL-9 and IL-13 alone and in combination, reduce ciliated cell numbers and transepithelial electrical resistance during differentiation of normal epithelium, which clinically could inhibit mucociliary clearance and drive an altered repair mechanism. This suggests an alternative role for IL-9 in airways remodelling and reaffirms IL-9 as a potential therapeutic target. PMID- 23671564 TI - Re-isolating Batrachochytrium dendrobatidis from an amphibian host increases pathogenicity in a subsequent exposure. AB - Controlled exposure experiments can be very informative, however, they are based on the assumption that pathogens maintained on artificial media under long-term storage retain the infective and pathogenic properties of the reproducing pathogen as it occurs in a host. We observed that JEL284, an in vitro cultured and maintained isolate of Batrachochytrium dendrobatidis (Bd), was becoming less infectious with successive uses. We hypothesized that passing an isolate propagated on artificial media through an amphibian host would make the isolate more infectious and pathogenic in subsequent exposures. To test our hypothesis, we used two discreet steps, a reisolation step (step 1) and a comparative exposure step (step 2). In step 1, we exposed eastern spadefoot toads, Scaphiopus holbrooki, to JEL284 and JEL197, another isolate that had been maintained in vitro for over six years. We then re-isolated JEL284 only from a successful infection and named this new isolate JEL284(FMBa). JEL197 did not infect any amphibians and, thus, did not proceed to step 2. In step 2, we compared infectivity and pathogenicity (mortality and survival time) of JEL284 and JEL284(FMBa) by exposing 54 naive S. holbrooki to three treatments (JEL284, JEL284(FMBa), and negative control) with 18 individuals per group. We found that JEL284(FMBa) caused higher mortality and decreased survival time in infected individuals when compared to JEL284 and negative controls. Thus, our data show that pathogenicity of Bd can decrease when cultured successively in media only and can be partially restored by passage through an amphibian host. Therefore, we have demonstrated that pathogenicity shifts can occur rapidly in this pathogen. Given the potential for shifts in pathogenicity demonstrated here, we suspect Bd to have similar potential in natural populations. We suggest that, when possible, the use of freshly isolated or cryopreserved Bd would improve the quality of controlled exposure experiments using this pathogen. PMID- 23671563 TI - Human rotavirus VP6-specific antibodies mediate intracellular neutralization by binding to a quaternary structure in the transcriptional pore. AB - Several live attenuated rotavirus (RV) vaccines have been licensed, but the mechanisms of protective immunity are still poorly understood. The most frequent human B cell response is directed to the internal protein VP6 on the surface of double-layered particles, which is normally exposed only in the intracellular environment. Here, we show that the canonical VP6 antibodies secreted by humans bind to such particles and inhibit viral transcription. Polymeric IgA RV antibodies mediated an inhibitory effect against virus replication inside cells during IgA transcytosis. We defined the recognition site on VP6 as a quaternary epitope containing a high density of charged residues. RV human mAbs appear to bind to a negatively-charged patch on the surface of the Type I channel in the transcriptionally active particle, and they sterically block the channel. This unique mucosal mechanism of viral neutralization, which is not apparent from conventional immunoassays, may contribute significantly to human immunity to RV. PMID- 23671565 TI - Acute phase CD8+ T lymphocytes against alternate reading frame epitopes select for rapid viral escape during SIV infection. AB - CD8+ T Lymphocytes (CTL) can control AIDS virus replication. However, natural selection favoring viral variants that escape CTL recognition is a common feature of both simian immunodeficiency virus (SIV) infection of macaques and HIV infection of humans. Emerging data indicate that CTL directed against alternate reading frame (ARF)-derived epitopes (a.k.a. cryptic epitopes) are important components of the total virus-specific response in SIV and HIV infection but the contributions of these responses during the critical first several weeks of infection have not been determined. We used a focused deep sequencing approach to examine acute phase viral evolution in response to CTL targeting two polypeptides encoded by ARFs of SIVmac239 in SIV-infected rhesus macaques. We report high magnitude CTL responses as early as three weeks post-infection against epitopes within both ARFs, which both overlap the 5' end of the env gene. Further, mutations accumulated in the epitopes by three to four weeks post infection consistent with viral escape. Interestingly, these mutations largely maintained the primary amino acid sequence of the overlapping Envelope protein. Our data show that high frequency CTL target cryptic epitopes and exert selective pressure on SIV during the acute phase, underscoring the importance of these unique immune responses. PMID- 23671566 TI - Mapping lightscapes: spatial patterning of artificial lighting in an urban landscape. AB - Artificial lighting is strongly associated with urbanisation and is increasing in its extent, brightness and spectral range. Changes in urban lighting have both positive and negative effects on city performance, yet little is known about how its character and magnitude vary across the urban landscape. A major barrier to related research, planning and governance has been the lack of lighting data at the city extent, particularly at a fine spatial resolution. Our aims were therefore to capture such data using aerial night photography and to undertake a case study of urban lighting. We present the finest scale multi-spectral lighting dataset available for an entire city and explore how lighting metrics vary with built density and land-use. We found positive relationships between artificial lighting indicators and built density at coarse spatial scales, whilst at a local level lighting varied with land-use. Manufacturing and housing are the primary land-use zones responsible for the city's brightly lit areas, yet manufacturing sites are relatively rare within the city. Our data suggests that efforts to address light pollution should broaden their focus from residential street lighting to include security lighting within manufacturing areas. PMID- 23671567 TI - Developmental gene discovery in a hemimetabolous insect: de novo assembly and annotation of a transcriptome for the cricket Gryllus bimaculatus. AB - Most genomic resources available for insects represent the Holometabola, which are insects that undergo complete metamorphosis like beetles and flies. In contrast, the Hemimetabola (direct developing insects), representing the basal branches of the insect tree, have very few genomic resources. We have therefore created a large and publicly available transcriptome for the hemimetabolous insect Gryllus bimaculatus (cricket), a well-developed laboratory model organism whose potential for functional genetic experiments is currently limited by the absence of genomic resources. cDNA was prepared using mRNA obtained from adult ovaries containing all stages of oogenesis, and from embryo samples on each day of embryogenesis. Using 454 Titanium pyrosequencing, we sequenced over four million raw reads, and assembled them into 21,512 isotigs (predicted transcripts) and 120,805 singletons with an average coverage per base pair of 51.3. We annotated the transcriptome manually for over 400 conserved genes involved in embryonic patterning, gametogenesis, and signaling pathways. BLAST comparison of the transcriptome against the NCBI non-redundant protein database (nr) identified significant similarity to nr sequences for 55.5% of transcriptome sequences, and suggested that the transcriptome may contain 19,874 unique transcripts. For predicted transcripts without significant similarity to known sequences, we assessed their similarity to other orthopteran sequences, and determined that these transcripts contain recognizable protein domains, largely of unknown function. We created a searchable, web-based database to allow public access to all raw, assembled and annotated data. This database is to our knowledge the largest de novo assembled and annotated transcriptome resource available for any hemimetabolous insect. We therefore anticipate that these data will contribute significantly to more effective and higher-throughput deployment of molecular analysis tools in Gryllus. PMID- 23671568 TI - Google matrix analysis of DNA sequences. AB - For DNA sequences of various species we construct the Google matrix [Formula: see text] of Markov transitions between nearby words composed of several letters. The statistical distribution of matrix elements of this matrix is shown to be described by a power law with the exponent being close to those of outgoing links in such scale-free networks as the World Wide Web (WWW). At the same time the sum of ingoing matrix elements is characterized by the exponent being significantly larger than those typical for WWW networks. This results in a slow algebraic decay of the PageRank probability determined by the distribution of ingoing elements. The spectrum of [Formula: see text] is characterized by a large gap leading to a rapid relaxation process on the DNA sequence networks. We introduce the PageRank proximity correlator between different species which determines their statistical similarity from the view point of Markov chains. The properties of other eigenstates of the Google matrix are also discussed. Our results establish scale-free features of DNA sequence networks showing their similarities and distinctions with the WWW and linguistic networks. PMID- 23671569 TI - 3D flow in the venom channel of a spitting cobra: do the ridges in the fangs act as fluid guide vanes? AB - The spitting cobra Naja pallida can eject its venom towards an offender from a distance of up to two meters. The aim of this study was to understand the mechanisms responsible for the relatively large distance covered by the venom jet although the venom channel is only of micro-scale. Therefore, we analysed factors that influence secondary flow and pressure drop in the venom channel, which include the physical-chemical properties of venom liquid and the morphology of the venom channel. The cobra venom showed shear-reducing properties and the venom channel had paired ridges that span from the last third of the channel to its distal end, terminating laterally and in close proximity to the discharge orifice. To analyze the functional significance of these ridges we generated a numerical and an experimental model of the venom channel. Computational fluid dynamics (CFD) and Particle-Image Velocimetry (PIV) revealed that the paired interior ridges shape the flow structure upstream of the sharp 90 degrees bend at the distal end. The occurrence of secondary flow structures resembling Dean type vortical structures in the venom channel can be observed, which induce additional pressure loss. Comparing a venom channel featuring ridges with an identical channel featuring no ridges, one can observe a reduction of pressure loss of about 30%. Therefore it is concluded that the function of the ridges is similar to guide vanes used by engineers to reduce pressure loss in curved flow channels. PMID- 23671570 TI - All-possible-couplings approach to measuring probabilistic context. AB - From behavioral sciences to biology to quantum mechanics, one encounters situations where (i) a system outputs several random variables in response to several inputs, (ii) for each of these responses only some of the inputs may "directly" influence them, but (iii) other inputs provide a "context" for this response by influencing its probabilistic relations to other responses. These contextual influences are very different, say, in classical kinetic theory and in the entanglement paradigm of quantum mechanics, which are traditionally interpreted as representing different forms of physical determinism. One can mathematically construct systems with other types of contextuality, whether or not empirically realizable: those that form special cases of the classical type, those that fall between the classical and quantum ones, and those that violate the quantum type. We show how one can quantify and classify all logically possible contextual influences by studying various sets of probabilistic couplings, i.e., sets of joint distributions imposed on random outputs recorded at different (mutually incompatible) values of inputs. PMID- 23671572 TI - Crosstalk from non-cancerous mitochondria can inhibit tumor properties of metastatic cells by suppressing oncogenic pathways. AB - Mitochondrial-nucleus cross talks and mitochondrial retrograde regulation can play a significant role in cellular properties. Transmitochondrial cybrid systems (cybrids) are an excellent tool to study specific effects of altered mitochondria under a defined nuclear background. The majority of the studies using the cybrid model focused on the significance of specific mitochondrial DNA variations in mitochondrial function or tumor properties. However, most of these variants are benign polymorphisms without known functional significance. From an objective of rectifying mitochondrial defects in cancer cells and to establish mitochondria as a potential anticancer drug target, understanding the role of functional mitochondria in reversing oncogenic properties under a cancer nuclear background is very important. Here we analyzed the potential reversal of oncogenic properties of a highly metastatic cell line with the introduction of non cancerous mitochondria. Cybrids were established by fusing the mitochondria DNA depleted 143B TK- rho0 cells from an aggressive osteosarcoma cell line with mitochondria from benign breast epithelial cell line MCF10A, moderately metastatic breast cancer cell line MDA-MB-468 and 143B cells. In spite of the uniform cancerous nuclear background, as observed with the mitochondria donor cells, cybrids with benign mitochondria showed high mitochondrial functional properties including increased ATP synthesis, oxygen consumption and respiratory chain activities compared to cybrids with cancerous mitochondria. Interestingly, benign mitochondria could reverse different oncogenic characteristics of 143B TK( ) cell including cell proliferation, viability under hypoxic condition, anti apoptotic properties, resistance to anti-cancer drug, invasion, and colony formation in soft agar, and in vivo tumor growth in nude mice. Microarray analysis suggested that several oncogenic pathways observed in cybrids with cancer mitochondria are inhibited in cybrids with non-cancerous mitochondria. These results suggest the critical oncogenic regulation by mitochondrial-nuclear cross talk and highlights rectifying mitochondrial functional properties as a promising target in cancer therapy. PMID- 23671571 TI - Gene expression signatures of energetic acclimatisation in the reef building coral Acropora millepora. AB - BACKGROUND: Understanding the mechanisms by which natural populations cope with environmental stress is paramount to predict their persistence in the face of escalating anthropogenic impacts. Reef-building corals are increasingly exposed to local and global stressors that alter nutritional status causing reduced fitness and mortality, however, these responses can vary considerably across species and populations. METHODOLOGY/PRINCIPAL FINDINGS: We compare the expression of 22 coral host genes in individuals from an inshore and an offshore reef location using quantitative Reverse Transcription-PCR (qRT-PCR) over the course of 26 days following translocation into a shaded, filtered seawater environment. Declines in lipid content and PSII activity of the algal endosymbionts (Symbiodinium ITS-1 type C2) over the course of the experiment indicated that heterotrophic uptake and photosynthesis were limited, creating nutritional deprivation conditions. Regulation of coral host genes involved in metabolism, CO2 transport and oxidative stress could be detected already after five days, whereas PSII activity took twice as long to respond. Opposing expression trajectories of Tgl, which releases fatty acids from the triacylglycerol storage, and Dgat1, which catalyses the formation of triglycerides, indicate that the decline in lipid content can be attributed, at least in part, by mobilisation of triacylglycerol stores. Corals from the inshore location had initially higher lipid content and showed consistently elevated expression levels of two genes involved in metabolism (aldehyde dehydrogenase) and calcification (carbonic anhydrase). CONCLUSIONS/SIGNIFICANCE: Coral host gene expression adjusts rapidly upon change in nutritional conditions, and therefore can serve as an early signature of imminent coral stress. Consistent gene expression differences between populations indicate that corals acclimatize and/or adapt to local environments. Our results set the stage for analysis of these processes in natural coral populations, to better understand the responses of coral communities to global climate change and to develop more efficient management strategies. PMID- 23671573 TI - Adhesion proteins--an impact on skeletal myoblast differentiation. AB - Formation of mammalian skeletal muscle myofibers, that takes place during embryogenesis, muscle growth or regeneration, requires precise regulation of myoblast adhesion and fusion. There are few evidences showing that adhesion proteins play important role in both processes. To follow the function of these molecules in myoblast differentiation we analysed integrin alpha3, integrin beta1, ADAM12, CD9, CD81, M-cadherin, and VCAM-1 during muscle regeneration. We showed that increase in the expression of these proteins accompanies myoblast fusion and myotube formation in vivo. We also showed that during myoblast fusion in vitro integrin alpha3 associates with integrin beta1 and ADAM12, and also CD9 and CD81, but not with M-cadherin or VCAM-1. Moreover, we documented that experimental modification in the expression of integrin alpha3 lead to the modification of myoblast fusion in vitro. Underexpression of integrin alpha3 decreased myoblasts' ability to fuse. This phenomenon was not related to the modifications in the expression of other adhesion proteins, i.e. integrin beta1, CD9, CD81, ADAM12, M-cadherin, or VCAM-1. Apparently, aberrant expression only of one partner of multiprotein adhesion complexes necessary for myoblast fusion, in this case integrin alpha3, prevents its proper function. Summarizing, we demonstrated the importance of analysed adhesion proteins in myoblast fusion both in vivo and in vitro. PMID- 23671575 TI - Computationally efficient locally adaptive demosaicing of color filter array images using the dual-tree complex wavelet packet transform. AB - Most digital cameras use an array of alternating color filters to capture the varied colors in a scene with a single sensor chip. Reconstruction of a full color image from such a color mosaic is what constitutes demosaicing. In this paper, a technique is proposed that performs this demosaicing in a way that incurs a very low computational cost. This is done through a (dual-tree complex) wavelet interpretation of the demosaicing problem. By using a novel locally adaptive approach for demosaicing (complex) wavelet coefficients, we show that many of the common demosaicing artifacts can be avoided in an efficient way. Results demonstrate that the proposed method is competitive with respect to the current state of the art, but incurs a lower computational cost. The wavelet approach also allows for computationally effective denoising or deblurring approaches. PMID- 23671576 TI - Numerical and series solutions for stagnation-point flow of nanofluid over an exponentially stretching sheet. AB - This investigation is concerned with the stagnation-point flow of nanofluid past an exponentially stretching sheet. The presence of Brownian motion and thermophoretic effects yields a coupled nonlinear boundary-value problem (BVP). Similarity transformations are invoked to reduce the partial differential equations into ordinary ones. Local similarity solutions are obtained by homotopy analysis method (HAM), which enables us to investigate the effects of parameters at a fixed location above the sheet. The numerical solutions are also derived using the built-in solver bvp4c of the software MATLAB. The results indicate that temperature and the thermal boundary layer thickness appreciably increase when the Brownian motion and thermophoresis effects are strengthened. Moreover the nanoparticles volume fraction is found to increase when the thermophoretic effect intensifies. PMID- 23671574 TI - Transcriptomic and proteomic responses of sweetpotato whitefly, Bemisia tabaci, to thiamethoxam. AB - BACKGROUND: The sweetpotato whitefly, Bemisia tabaci (Hemiptera: Aleyrodidae), is one of the most widely distributed agricultural pests. Although it has developed resistance to many registered insecticides including the neonicotinoid insecticide thiamethoxam, the mechanisms that regulate the resistance are poorly understood. To understand the molecular basis of thiamethoxam resistance, "omics" analyses were carried out to examine differences between resistant and susceptible B. tabaci at both transcriptional and translational levels. RESULTS: A total of 1,338 mRNAs and 52 proteins were differentially expressed between resistant and susceptible B. tabaci. Among them, 11 transcripts had concurrent transcription and translation profiles. KEGG analysis mapped 318 and 35 differentially expressed genes and proteins, respectively, to 160 and 59 pathways (p<0.05). Thiamethoxam treatment activated metabolic pathways (e.g., drug metabolism), in which 118 transcripts were putatively linked to insecticide resistance, including up-regulated glutathione-S-transferase, UDP glucuronosyltransferase, glucosyl/glucuronosyl transferase, and cytochrome P450. Gene Ontology analysis placed these genes and proteins into protein complex, metabolic process, cellular process, signaling, and response to stimulus categories. Quantitative real-time PCR analysis validated "omics" response, and suggested a highly overexpressed P450, CYP6CX1, as a candidate molecular basis for the mechanistic study of thiamethoxam resistance in whiteflies. Finally, enzymatic activity assays showed elevated detoxification activities in the resistant B. tabaci. CONCLUSIONS: This study demonstrates the applicability of high-throughput omics tools for identifying molecular candidates related to thiamethoxam resistance in an agricultural important insect pest. In addition, transcriptomic and proteomic analyses provide a solid foundation for future functional investigations into the complex molecular mechanisms governing the neonicotinoid resistance in whiteflies. PMID- 23671578 TI - Dicoogle, a PACS featuring profiled content based image retrieval. AB - Content-based image retrieval (CBIR) has been heralded as a mechanism to cope with the increasingly larger volumes of information present in medical imaging repositories. However, generic, extensible CBIR frameworks that work natively with Picture Archive and Communication Systems (PACS) are scarce. In this article we propose a methodology for parametric CBIR based on similarity profiles. The architecture and implementation of a profiled CBIR system, based on query by example, atop Dicoogle, an open-source, full-fletched PACS is also presented and discussed. In this solution, CBIR profiles allow the specification of both a distance function to be applied and the feature set that must be present for that function to operate. The presented framework provides the basis for a CBIR expansion mechanism and the solution developed integrates with DICOM based PACS networks where it provides CBIR functionality in a seamless manner. PMID- 23671577 TI - Vestibular perception following acute unilateral vestibular lesions. AB - Little is known about the vestibulo-perceptual (VP) system, particularly after a unilateral vestibular lesion. We investigated vestibulo-ocular (VO) and VP function in 25 patients with vestibular neuritis (VN) acutely (2 days after onset) and after compensation (recovery phase, 10 weeks). Since the effect of VN on reflex and perceptual function may differ at threshold and supra-threshold acceleration levels, we used two stimulus intensities, acceleration steps of 0.5 degrees /s(2) and velocity steps of 90 degrees /s (acceleration 180 degrees /s(2)). We hypothesised that the vestibular lesion or the compensatory processes could dissociate VO and VP function, particularly if the acute vertiginous sensation interferes with the perceptual tasks. Both in acute and recovery phases, VO and VP thresholds increased, particularly during ipsilesional rotations. In signal detection theory this indicates that signals from the healthy and affected side are still fused, but result in asymmetric thresholds due to a lesion-induced bias. The normal pattern whereby VP thresholds are higher than VO thresholds was preserved, indicating that any 'perceptual noise' added by the vertigo does not disrupt the cognitive decision-making processes inherent to the perceptual task. Overall, the parallel findings in VO and VP thresholds imply little or no additional cortical processing and suggest that vestibular thresholds essentially reflect the sensitivity of the fused peripheral receptors. In contrast, a significant VO-VP dissociation for supra-threshold stimuli was found. Acutely, time constants and duration of the VO and VP responses were reduced - asymmetrically for VO, as expected, but surprisingly symmetrical for perception. At recovery, VP responses normalised but VO responses remained shortened and asymmetric. Thus, unlike threshold data, supra-threshold responses show considerable VO-VP dissociation indicative of additional, higher-order processing of vestibular signals. We provide evidence of perceptual processes (ultimately cortical) participating in vestibular compensation, suppressing asymmetry acutely in unilateral vestibular lesions. PMID- 23671579 TI - The mode of action of recombinant Mycobacterium tuberculosis shikimate kinase: kinetics and thermodynamics analyses. AB - Tuberculosis remains as one of the main cause of mortality worldwide due to a single infectious agent, Mycobacterium tuberculosis. The aroK-encoded M. tuberculosis Shikimate Kinase (MtSK), shown to be essential for survival of bacilli, catalyzes the phosphoryl transfer from ATP to the carbon-3 hydroxyl group of shikimate (SKH), yielding shikimate-3-phosphate and ADP. Here we present purification to homogeneity, and oligomeric state determination of recombinant MtSK. Biochemical and biophysical data suggest that the chemical reaction catalyzed by monomeric MtSK follows a rapid-equilibrium random order of substrate binding, and ordered product release. Isothermal titration calorimetry (ITC) for binding of ligands to MtSK provided thermodynamic signatures of non-covalent interactions to each process. A comparison of steady-state kinetics parameters and equilibrium dissociation constant value determined by ITC showed that ATP binding does not increase the affinity of MtSK for SKH. We suggest that MtSK would more appropriately be described as an aroL-encoded type II shikimate kinase. Our manuscript also gives thermodynamic description of SKH binding to MtSK and data for the number of protons exchanged during this bimolecular interaction. The negative value for the change in constant pressure heat capacity (DeltaCp) and molecular homology model building suggest a pronounced contribution of desolvation of non-polar groups upon binary complex formation. Thermodynamic parameters were deconvoluted into hydrophobic and vibrational contributions upon MtSK:SKH binary complex formation. Data for the number of protons exchanged during this bimolecular interaction are interpreted in light of a structural model to try to propose the likely amino acid side chains that are the proton donors to bulk solvent following MtSK:SKH complex formation. PMID- 23671580 TI - Amelioration of IFN-gamma and TNF-alpha-induced intestinal epithelial barrier dysfunction by berberine via suppression of MLCK-MLC phosphorylation signaling pathway. AB - Intestinal barrier dysfunction occurs in many intestinal diseases, in which proinflammatory cytokines play critical roles. However, researchers are still on the way to defining the underlying mechanisms and to evaluate therapeutic strategies for restoring intestinal barrier function. Berberine, a drug that has clinically been used to treat gastroenteritis and diarrhea for thousands of years, has been shown to protect barrier function in both endothelial and epithelial cells, but the mechanisms are completely unknown. In this study, we investigate the protective actions of berberine on barrier function and the underlying mechanisms in Caco-2 monolayers challenged with IFN-gamma and TNF alpha. Caco-2 monolayers were treated without or with simultaneous IFN-gamma and TNF-alpha in the absence or presence of berberine. Both transepithelial electrical resistance (TER) and paracellular permeability were measured to evaluate barrier function. The expression and distribution of tight junction proteins ZO-1, occluding, and claudin-1 were respectively analyzed by immunoblot or immunofluorescence. The expressions of phosphorylated myosin light chain (pMLC), MLC kinase (MLCK) and hypoxia-inducible factor-1alpha (HIF-1alpha) were determined by immunoblot. The translocation of NF-kappaB p65 to nuclei was analyzed by immunofluorescence and immunoblot, respectively. The results showed that berberine significantly attenuated TER decrease and paracellular permeability increase in Caco-2 monolayers treated with IFN-gamma and TNF-alpha. Berberine also dramatically alleviated IFN-gamma and TNF-alpha-induced morphological alteration of tight junction proteins ZO-1, occluding, and claudin 1. The increase of both MLC phosphorylation and MLCK protein expression induced by IFN-gamma and TNF-alpha was significantly inhibited by berberine treatment. Additionally, berberine suppressed the activation of HIF-1alpha, but not NF kappaB. Taken together, it is suggested that berberine attenuates IFN-gamma and TNF-alpha-induced intestinal epithelial barrier dysfunction by inhibiting the signaling pathway of MLCK-dependent MLC phosphorylation mediated by HIF-1alpha. PMID- 23671581 TI - A novel function of novobiocin: disrupting the interaction of HIF 1alpha and p300/CBP through direct binding to the HIF1alpha C-terminal activation domain. AB - Hypoxia-inducible factor 1alpha (HIF1alpha) is an important cellular survival protein under hypoxic conditions, regulating the cellular response to low oxygen tension via recruitment of a transcriptional co-activator, p300/CBP. p300/CBP induces expression of multiple genes involved in cell survival, proliferation, angiogenesis, and tumor development. Thus, a strategy to inhibit hypoxic responses in tumors may be to target the protein-protein interaction between HIF1alpha and p300/CBP. Here, we document, for the first time, that the aminocoumarin antibiotic, novobiocin, directly blocks the protein-protein interaction between the HIF1alpha C-terminal activation domain (CTAD) and the cysteine-histidine rich (CH1) region of p300/CBP. Also, novobiocin down-regulated HIF1alpha-controlled gene expression, specifically CA9, which is related to tumorigenesis. In a monolayer cell culture, novobiocin inhibited cell proliferation and colony formation in the MCF-7 human breast adenocarcinoma cell line and the A549 human lung cancer cell line. Rescue experiments revealed that the recombinant CTAD fragment of HIF1alpha partially reversed novobiocin's inhibitory effects on cell proliferation and colony formation in MCF-7 cells. These findings suggest a novel mechanism of action for novobiocin which has the potential for innovative therapeutic use in tumor treatment. PMID- 23671582 TI - Synaptic connections between endomorphin 2-immunoreactive terminals and MU-opioid receptor-expressing neurons in the sacral parasympathetic nucleus of the rat. AB - The urinary bladder is innervated by parasympathetic preganglionic neurons (PPNs) that express MU-opioid receptors (MOR) in the sacral parasympathetic nucleus (SPN) at lumbosacral segments L6-S1. The SPN also contains endomorphin 2 (EM2) immunoreactive (IR) fibers and terminals. EM2 is the endogenous ligand of MOR. In the present study, retrograde tract-tracing with cholera toxin subunit b (CTb) or wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP) via the pelvic nerve combined with immunohistochemical staining for EM2 and MOR to identify PPNs within the SPN as well as synaptic connections between the EM2-IR terminals and MOR-expressing PPNs in the SPN of the rat. After CTb was injected into the pelvic nerve, CTb retrogradely labeled neurons were almost exclusively located in the lateral part of the intermediolateral gray matter at L6-S1 of the lumbosacral spinal cord. All of the them also expressed MOR. EM2-IR terminals formed symmetric synapses with MOR-IR, WGA-HRP-labeled and WGA-HRP/MOR double-labeled neuronal cell bodies and dendrites within the SPN. These results provided morphological evidence that EM2-containing axon terminals formed symmetric synapses with MOR-expressing PPNs in the SPN. The present results also show that EM2 and MOR might be involved in both the homeostatic control and information transmission of micturition. PMID- 23671583 TI - A model-based spike sorting algorithm for removing correlation artifacts in multi neuron recordings. AB - We examine the problem of estimating the spike trains of multiple neurons from voltage traces recorded on one or more extracellular electrodes. Traditional spike-sorting methods rely on thresholding or clustering of recorded signals to identify spikes. While these methods can detect a large fraction of the spikes from a recording, they generally fail to identify synchronous or near-synchronous spikes: cases in which multiple spikes overlap. Here we investigate the geometry of failures in traditional sorting algorithms, and document the prevalence of such errors in multi-electrode recordings from primate retina. We then develop a method for multi-neuron spike sorting using a model that explicitly accounts for the superposition of spike waveforms. We model the recorded voltage traces as a linear combination of spike waveforms plus a stochastic background component of correlated Gaussian noise. Combining this measurement model with a Bernoulli prior over binary spike trains yields a posterior distribution for spikes given the recorded data. We introduce a greedy algorithm to maximize this posterior that we call "binary pursuit". The algorithm allows modest variability in spike waveforms and recovers spike times with higher precision than the voltage sampling rate. This method substantially corrects cross-correlation artifacts that arise with conventional methods, and substantially outperforms clustering methods on both real and simulated data. Finally, we develop diagnostic tools that can be used to assess errors in spike sorting in the absence of ground truth. PMID- 23671584 TI - Risk factors of superimposed preeclampsia in women with essential chronic hypertension treated before pregnancy. AB - OBJECTIVE: To determine risk factors of superimposed preeclampsia in women with essential chronic hypertension receiving antihypertensive therapy prior to conception. METHODS: A retrospective study of 211 patients that analyzed risk factors of superimposed preeclampsia at first prenatal visit. Variables with a p<.1 at univariate analysis were included in a logistic regression analysis. P<.05 was considered as significant. RESULTS: Superimposed preeclampsia occurred in 49 (23.2%) women. In logistic regression analysis, previous preeclampsia [OR: 4.05 (1.61-10.16)], and mean arterial blood pressure of 95 mmHg or higher [OR: 4.60 (1.94-10.93)] were associated with increased risk of superimposed preeclampsia. When both variables were present, sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratio for superimposed preeclampsia were 43%, 94%, 70%, 85%, and 7.71 (95% CI: 3.20-18.57), respectively. CONCLUSION: In essential chronic hypertensive women, previous preeclampsia and mean arterial blood pressure of 95 mmHg or higher are associated with increased risks of superimposed preeclampsia. PMID- 23671586 TI - Fine-scale habitat associations of a terrestrial salamander: the role of environmental gradients and implications for population dynamics. AB - Environmental gradients are instrumental in shaping the distribution and local abundance of species because at the most fundamental level, an organism's performance is constrained by the environment it inhabits. In topographically complex landscapes, slope, aspect, and vegetative cover interact to affect solar exposure, creating temperature-moisture gradients and unique microclimates. The significance of the interaction of abiotic gradients and biotic factors such as competition, movement, or physiology has long been recognized, but the scale at which these factors vary on the landscape has generally precluded their inclusion in spatial abundance models. We used fine-scale spatial data relating to surface soil moisture, temperature, and canopy cover to describe the spatial distribution of abundance of a terrestrial salamander, Plethodon albagula, across the landscape. Abundance was greatest in dense-canopy ravine habitats with high moisture and low solar exposure, resulting in a patchy distribution of abundance. We hypothesize that these patterns reflect the physiological constraints of Plethodontid salamanders. Furthermore, demographic cohorts were not uniformly distributed among occupied plots on the landscape. The probability of gravid female occurrence was nearly uniform among occupied plots, but juveniles were much more likely to occur on plots with lower surface temperatures. The disconnect between reproductive effort and recruitment suggests that survival differs across the landscape and that local population dynamics vary spatially. Our study demonstrates a connection between abundance, fine-scale environmental gradients, and population dynamics, providing a foundation for future research concerning movement, population connectivity, and physiology. PMID- 23671585 TI - Novel molecular tumor cell markers in regional lymph nodes and blood samples from patients undergoing surgery for non-small cell lung cancer. AB - INTRODUCTION: Recent evidence suggests that microscopic lymph node metastases and circulating tumor cells may have clinical importance in lung cancer. The purpose of this study was to identify new molecular markers for tumor cells in regional lymph nodes (LNs) and peripheral blood (PB) from patients with non-small cell lung cancer (NSCLC). METHODS: Candidate markers were selected based on digital transcript profiling and previous literature. KRT19, CEACAM5, EPCAM, DSG3, SFTPA, SFTPC and SFTPB mRNA levels were initially validated by real-time reverse transcription PCR-based quantification in 16 NSCLC tumors and 22 LNs and 12 PB samples from individuals without known cancer. Five of the candidate markers were selected for secondary validation by quantification in parallel tumor biopsies, regional LNs and PB samples from 55 patients undergoing surgery for NSCLC. LN and PB marker status were compared to clinicopathological patient data. RESULTS: All selected markers except DSG3 were present at high levels in the primary tumors and at very low or non-detectable levels in normal LNs and PB in the first round of validation, indicating a potential for detecting tumor cells in NSCLC patients. The expression profiles of KRT19, CEACAM5, DSG3, SFTPA and SFTPC mRNA were confirmed in the larger group during the secondary validation. Using the highest normal LN level of each marker as threshold, 39 (71%) of the 55 patients had elevated levels of at least one marker in regional LNs. Similarly, 26 (47%) patients had elevated levels of at least one marker in PB. A significantly higher number of patients with adenocarcinomas had positive LN status for these markers, compared with other histological types (P = 0.004). CONCLUSIONS: Several promising molecular tumor cell markers in regional LNs and PB were identified, including the new SFTPA and SFTPC mRNAs. Clinical follow-up in a larger cohort is needed to elucidate their prognostic value. PMID- 23671587 TI - A20 restricts wnt signaling in intestinal epithelial cells and suppresses colon carcinogenesis. AB - Colon carcinogenesis consists of a multistep process during which a series of genetic and epigenetic adaptations occur that lead to malignant transformation. Here, we have studied the role of A20 (also known as TNFAIP3), a ubiquitin editing enzyme that restricts NFkappaB and cell death signaling, in intestinal homeostasis and tumorigenesis. We have found that A20 expression is consistently reduced in human colonic adenomas than in normal colonic tissues. To further investigate A20's potential roles in regulating colon carcinogenesis, we have generated mice lacking A20 specifically in intestinal epithelial cells and interbred these with mice harboring a mutation in the adenomatous polyposis coli gene (APC(min)). While A20(FL/FL) villin-Cre mice exhibit uninflamed intestines without polyps, A20(FL/FL) villin-Cre APC(min/+) mice contain far greater numbers and larger colonic polyps than control APC(min) mice. We find that A20 binds to the beta-catenin destruction complex and restricts canonical wnt signaling by supporting ubiquitination and degradation of beta-catenin in intestinal epithelial cells. Moreover, acute deletion of A20 from intestinal epithelial cells in vivo leads to enhanced expression of the beta-catenin dependent genes cyclinD1 and c-myc, known promoters of colon cancer. Taken together, these findings demonstrate new roles for A20 in restricting beta-catenin signaling and preventing colon tumorigenesis. PMID- 23671588 TI - Neutrophils are essential as a source of IL-17 in the effector phase of arthritis. AB - OBJECTIVE: Th17 has been shown to have a pivotal role in the development of arthritis. However, the role of IL-17 in the T cell-independent effector phase has not fully been examined. We investigated whether IL-17 is involved in the effector phase of arthritis by using K/BxN serum-induced arthritis model. METHODS: K/BxN serum was transferred into IL-17 knockout (KO) mice, SCID mice and their control mice, and arthritis was evaluated over time. In order to clarify the source of IL-17 in the effector phase, neutrophils or CD4+ T cells collected from IL-17 KO or control mice were injected into IL-17 KO recipient mice together with K/BxN serum. To examine if neutrophils secrete IL-17 upon stimulation, neutrophils were stimulated with immune complex in vitro and IL-17 in the supernatant was measured by ELISA. RESULTS: K/BxN serum-induced arthritis was much less severe in IL-17 KO mice than in WT mice. Since K/BxN serum-transferred SCID mice developed severe arthritis with high serum IL-17 concentration, we speculated neutrophils are the responsible player as an IL-17 source. When wild type (WT) but not IL-17 KO neutrophils were co-injected with K/BxN serum into IL 17 KO mice, arthritis was exacerbated, whereas co-injection of WT CD4+ T cells had no effect. In vitro, stimulation of neutrophils with immune complex caused IL 17 secretion. CONCLUSIONS: Neutrophils are essential as a source of IL-17 in the effector phase of arthritis. The trigger of secreting IL-17 from neutrophils may be immune complex. PMID- 23671589 TI - Validation of an excretory/secretory antigen based-ELISA for the diagnosis of Opisthorchis felineus infection in humans from low trematode endemic areas. AB - Since opisthorchiasis does not show pathognomonic signs or symptoms, physicians can have serious problems to make a differential diagnosis of this infection in non endemic areas, in particular when there is a simultaneous occurrence with other seasonal infections. Moreover, symptomatic infections due to O. felineus can last a few weeks and then the signs and symptoms disappear, but the worms survive in the bile ducts for years causing hepatobiliary diseases including hepatomegaly, cholangitis, fibrosis of the periportal system, cholecystitis, and gallstones. Consequently, an early diagnosis prevents chronicity and loss of working days. The detection of specific antibodies has been considered as a complementary tool to the fecal examination to establish the definitive diagnosis of this infection and for the follow up. Therefore the aim of this work was the development and validation of an enzyme-linked immunosorbent assay (ELISA) using excretory/secretory antigens (ESA) from O. felineus adult worms to detect anti Opisthorchis IgG in human sera. A total of 370 human sera were tested: 144 sera from persons with a confirmed diagnosis of opisthorchiasis, 110 sera from healthy Italian people, and 116 sera from people with other parasitic or non-parasitic infections. Results were analyzed by receiver-operator characteristic (ROC) curve analysis. The accuracy of the test, calculated by the area under curve (AUC), yielded a 0.999 value, indicating the high performance of the test. The sensitivity was 100% (95% CI: 97.40% to 100%) and no false-negative sera were detected; the specificity was 99.09% (95% CI: 95.02% to 99.83%). The validated ELISA shows a good performance in terms of sensitivity, repeatability and reproducibility, and it is suitable to detect anti-Opisthorchis IgG in human sera for diagnostic purposes and for the follow up to assess the efficacy of drug treatment. PMID- 23671591 TI - What can be learnt about disease progression in breast cancer dormancy from relapse data? AB - Breast cancer patients have an anomalously high rate of relapse many years--up to 25 years--after apparently curative surgery removed the primary tumour. Disease progression during the intervening years between resection and relapse is poorly understood. There is evidence that the disease persists as dangerous, tiny metastases that remain at a growth restricted, clinically undetectable size until a transforming event restarts growth. This is the starting point for our study, where patients who have metastases that are all tiny and growth-restricted are said to have cancer dormancy. Can long-term follow-up relapse data from breast cancer patients be used to extract knowledge about the progression of the undetected disease? Here, we evaluate whether this is the case by introducing and analysing four simple mathematical models of cancer dormancy. These models extend the common assumption that a random transforming event, such as a mutation, can restart growth of a tiny, growth-restricted metastasis; thereafter, cancer dormancy progresses to detectable metastasis. We find that physiopathological details, such as the number of random transforming events that metastases must undergo to escape from growth restriction, cannot be extracted from relapse data. This result is unsurprising. However, the same analysis suggested a natural question that does have a surprising answer: why are interesting trends in long term relapse data not more commonly observed? Further, our models indicate that (a) therapies which induce growth restriction among metastases but do not prevent increases in metastases' tumourigenicity may introduce a time post-surgery when more patients are prone to relapse; and (b), if a number of facts about disease progression are first established, how relapse data might be used to estimate clinically relevant variables, such as the likely numbers of undetected growth restricted metastases. This work is a necessary, early step in building a quantitative mechanistic understanding of cancer dormancy. PMID- 23671590 TI - CLCAs - a family of metalloproteases of intriguing phylogenetic distribution and with cases of substituted catalytic sites. AB - The zinc-dependent metalloproteases with His-Glu-x-x-His (HExxH) active site motif, zincins, are a broad group of proteins involved in many metabolic and regulatory functions, and found in all forms of life. Human genome contains more than 100 genes encoding proteins with known zincin-like domains. A survey of all proteins containing the HExxH motif shows that approximately 52% of HExxH occurrences fall within known protein structural domains (as defined in the Pfam database). Domain families with majority of members possessing a conserved HExxH motif include, not surprisingly, many known and putative metalloproteases. Furthermore, several HExxH-containing protein domains thus identified can be confidently predicted to be putative peptidases of zincin fold. Thus, we predict zincin-like fold for eight uncharacterised Pfam families. Besides the domains with the HExxH motif strictly conserved, and those with sporadic occurrences, intermediate families are identified that contain some members with a conserved HExxH motif, but also many homologues with substitutions at the conserved positions. Such substitutions can be evolutionarily conserved and non-random, yet functional roles of these inactive zincins are not known. The CLCAs are a novel zincin-like protease family with many cases of substituted active sites. We show that this allegedly metazoan family has a number of bacterial and archaeal members. An extremely patchy phylogenetic distribution of CLCAs in prokaryotes and their conserved protein domain composition strongly suggests an evolutionary scenario of horizontal gene transfer (HGT) from multicellular eukaryotes to bacteria, providing an example of eukaryote-derived xenologues in bacterial genomes. Additionally, in a protein family identified here as closely homologous to CLCA, the CLCA_X (CLCA-like) family, a number of proteins is found in phages and plasmids, supporting the HGT scenario. PMID- 23671592 TI - Changing risk behaviours and the HIV epidemic: a mathematical analysis in the context of treatment as prevention. AB - BACKGROUND: Expanding access to highly active antiretroviral therapy (HAART) has become an important approach to HIV prevention in recent years. Previous studies suggest that concomitant changes in risk behaviours may either help or hinder programs that use a Treatment as Prevention strategy. ANALYSIS: We consider HIV related risk behaviour as a social contagion in a deterministic compartmental model, which treats risk behaviour and HIV infection as linked processes, where acquiring risk behaviour is a prerequisite for contracting HIV. The equilibrium behaviour of the model is analysed to determine epidemic outcomes under conditions of expanding HAART coverage along with risk behaviours that change with HAART coverage. We determined the potential impact of changes in risk behaviour on the outcomes of Treatment as Prevention strategies. Model results show that HIV incidence and prevalence decline only above threshold levels of HAART coverage, which depends strongly on risk behaviour parameter values. Expanding HAART coverage with simultaneous reduction in risk behaviour act synergistically to accelerate the drop in HIV incidence and prevalence. Above the thresholds, additional HAART coverage is always sufficient to reverse the impact of HAART optimism on incidence and prevalence. Applying the model to an HIV epidemic in Vancouver, Canada, showed no evidence of HAART optimism in that setting. CONCLUSIONS: Our results suggest that Treatment as Prevention has significant potential for controlling the HIV epidemic once HAART coverage reaches a threshold. Furthermore, expanding HAART coverage combined with interventions targeting risk behaviours amplify the preventive impact, potentially driving the HIV epidemic to elimination. PMID- 23671593 TI - AMPK and insulin action--responses to ageing and high fat diet. AB - The 5'-AMP-activated protein kinase (AMPK) is considered "a metabolic master switch" in skeletal muscle reducing ATP- consuming processes whilst stimulating ATP regeneration. Within recent years, AMPK has also been proposed as a potential target to attenuate insulin resistance, although the exact role of AMPK is not well understood. Here we hypothesized that mice lacking alpha2AMPK activity in muscle would be more susceptible to develop insulin resistance associated with ageing alone or in combination with high fat diet. Young (~4 month) or old (~18 month) wild type and muscle specific alpha2AMPK kinase-dead mice on chow diet as well as old mice on 17 weeks of high fat diet were studied for whole body glucose homeostasis (OGTT, ITT and HOMA-IR), insulin signaling and insulin-stimulated glucose uptake in muscle. We demonstrate that high fat diet in old mice results in impaired glucose homeostasis and insulin stimulated glucose uptake in both the soleus and extensor digitorum longus muscle, coinciding with reduced insulin signaling at the level of Akt (pSer473 and pThr308), TBC1D1 (pThr590) and TBC1D4 (pThr642). In contrast to our hypothesis, the impact of ageing and high fat diet on insulin action was not worsened in mice lacking functional alpha2AMPK in muscle. It is concluded that alpha2AMPK deficiency in mouse skeletal muscle does not cause muscle insulin resistance in young and old mice and does not exacerbate obesity-induced insulin resistance in old mice suggesting that decreased alpha2AMPK activity does not increase susceptibility for insulin resistance in skeletal muscle. PMID- 23671594 TI - Habitat and host indicate lineage identity in Colletotrichum gloeosporioides s.l. from wild and agricultural landscapes in North America. AB - Understanding the factors that drive the evolution of pathogenic fungi is central to revealing the mechanisms of virulence and host preference, as well as developing effective disease control measures. Prerequisite to these pursuits is the accurate delimitation of species boundaries. Colletotrichum gloeosporioides s.l. is a species complex of plant pathogens and endophytic fungi for which reliable species recognition has only recently become possible through a multi locus phylogenetic approach. By adopting an intensive regional sampling strategy encompassing multiple hosts within and beyond agricultural zones associated with cranberry (Vaccinium macrocarpon Aiton), we have integrated North America strains of Colletotrichum gloeosporioides s.l. from these habitats into a broader phylogenetic framework. We delimit species on the basis of genealogical concordance phylogenetic species recognition (GCPSR) and quantitatively assess the monophyly of delimited species at each of four nuclear loci and in the combined data set with the genealogical sorting index (gsi). Our analysis resolved two principal lineages within the species complex. Strains isolated from cranberry and sympatric host plants are distributed across both of these lineages and belong to seven distinct species or terminal clades. Strains isolated from V. macrocarpon in commercial cranberry beds belong to four species, three of which are described here as new. Another species, C. rhexiae Ellis & Everh., is epitypified. Intensive regional sampling has revealed a combination of factors, including the host species from which a strain has been isolated, the host organ of origin, and the habitat of the host species, as useful indicators of species identity in the sampled regions. We have identified three broadly distributed temperate species, C. fructivorum, C. rhexiae, and C. nupharicola, that could be useful for understanding the microevolutionary forces that may lead to species divergence in this important complex of endophytes and plant pathogens. PMID- 23671595 TI - The initial dispersal and spread of an intentional invader at three spatial scales. AB - The way an invasion progresses through space is a theme of interest common to invasion ecology and biological pest control. Models and mark-release studies of arthropods have been used extensively to extend and inform invasion processes of establishment and spread. However, the extremely common single-scale approach of monitoring initial spread leads to misinterpretation of rate and mode. Using the intentional release of a novel biological control agent (a parasitic hymenoptera, Eretmocerus hayati Zolnerowich & Rose (Hymenoptera: Aphelinidae), we studied its initial dispersal and spread at three different spatial scales, the local scale (tens of metres), field scale (hundreds of metres) and landscape scale (kilometres) around the release point. We fit models to each observed spread pattern at each spatial scale. We show that E. hayati exhibits stratified dispersal; moving further, faster and by a different mechanism than would have been concluded with a single local-scale post-release sampling design. In fact, interpretation of each scale independent of other scales gave three different models of dispersal, and three different impressions of the dominant dispersal mechanisms. Our findings demonstrate that using a single-scale approach may lead to quite erroneous conclusions, hence the necessity of using a multiple-scale hierarchical sampling design for inferring spread and the dominant dispersal mechanism of either human intended or unintended invasions. PMID- 23671596 TI - Hoplitolyda duolunica gen. et sp. nov. (Insecta, Hymenoptera, Praesiricidae), the Hitherto largest sawfly from the Mesozoic of China. AB - BACKGROUND: Large body size of an insect, in general, enhances its capability of predation, competition, and defense, resulting in better survivability and reproduction. Hymenopterans, most being phytophagous or parasitic, have a relatively small to medium body size, typically under 50.0 mm in body length. PRINCIPAL FINDINGS: Herein, we describe Hoplitolyda duolunica gen. et sp. nov., assigned to Praesiricidae, from the Early Cretaceous Yixian Formation of China. This new species is the largest fossil hymenopteran hitherto with body estimated >55.0 mm long and wing span >92.0 mm. H. duolunica is, to our knowledge, the only sawfly with Sc present in the hind wing but not in the forewing. Its Rs1 and M1 meeting each other at 145 degrees angle represents an intermediate in the transition from "Y" to "T" shapes. Even though Hoplitolyda differs significantly from all previously described genera in two subfamilies of Praesricidae, we leave the new genus unplaced in existing subfamilies, pending discovery of material with more taxonomic structure. CONCLUSIONS/SIGNIFICANCE: Hoplitolyda has many unique and interesting characters which might have benefitted its competition, survival, and reproduction: large body size and head with robust and strong mandibles for defense and/or sexual selection, unique wing venation and setal arrangements for flight capability and mobility, dense hairs on body and legs for sensing and protection, etc. Considering the reported ferocious predators of feathered dinosaurs, pterosaurs, birds, and mammals coexisting in the same eco system, Hoplitolyda is an interesting case of "survival of the fittest" in facing its evolutionary challenges. PMID- 23671597 TI - ODoSE: a webserver for genome-wide calculation of adaptive divergence in prokaryotes. AB - Quantifying patterns of adaptive divergence between taxa is a major goal in the comparative and evolutionary study of prokaryote genomes. When applied appropriately, the McDonald-Kreitman (MK) test is a powerful test of selection based on the relative frequency of non-synonymous and synonymous substitutions between species compared to non-synonymous and synonymous polymorphisms within species. The webserver ODoSE (Ortholog Direction of Selection Engine) allows the calculation of a novel extension of the MK test, the Direction of Selection (DoS) statistic, as well as the calculation of a weighted-average Neutrality Index (NI) statistic for the entire core genome, allowing for systematic analysis of the evolutionary forces shaping core genome divergence in prokaryotes. ODoSE is hosted in a Galaxy environment, which makes it easy to use and amenable to customization and is freely available at www.odose.nl. PMID- 23671598 TI - Intranasal inoculation of white-tailed deer (Odocoileus virginianus) with lyophilized chronic wasting disease prion particulate complexed to montmorillonite clay. AB - Chronic wasting disease (CWD), the only known prion disease endemic in wildlife, is a persistent problem in both wild and captive North American cervid populations. This disease continues to spread and cases are found in new areas each year. Indirect transmission can occur via the environment and is thought to occur by the oral and/or intranasal route. Oral transmission has been experimentally demonstrated and although intranasal transmission has been postulated, it has not been tested in a natural host until recently. Prions have been shown to adsorb strongly to clay particles and upon oral inoculation the prion/clay combination exhibits increased infectivity in rodent models. Deer and elk undoubtedly and chronically inhale dust particles routinely while living in the landscape while foraging and rutting. We therefore hypothesized that dust represents a viable vehicle for intranasal CWD prion exposure. To test this hypothesis, CWD-positive brain homogenate was mixed with montmorillonite clay (Mte), lyophilized, pulverized and inoculated intranasally into white-tailed deer once a week for 6 weeks. Deer were euthanized at 95, 105, 120 and 175 days post final inoculation and tissues examined for CWD-associated prion proteins by immunohistochemistry. Our results demonstrate that CWD can be efficiently transmitted utilizing Mte particles as a prion carrier and intranasal exposure. PMID- 23671599 TI - Factors associated with prevalence, awareness, treatment and control of hypertension among adults in Southern China: a community-based, cross-sectional survey. AB - The aim of this study was to investigate factors associated with prevalence, awareness, treatment and control of hypertension in southern China. A cross sectional, population-based survey was conducted in 180 villages across 15 counties in southern China from July to November 2010. Totally, 17437 persons completed all of the questionnaires, measurement examination and blood specimen collection. Adjusted rate of hypertension was 22.59% (95%CI: 22.52%-22.66%), for men 23.36% (95%CI: 23.25%-23.47%) and for women 21.77% (95%CI: 21.68%-21.86%). Multivariate logistic regression showed that old age, education attainment, alcohol use, diabetes, obesity, high TC and high TG were associated with hypertension. Among the hypertensive individuals, 54.33% were aware of their hypertension, and 46.34% were currently taking antihypertensive medication, but only 18.26% had their blood pressure controlled. Among all the hypertensive subjects, awareness was more common in those who were female, living in the urban, old age, low education attainment, diabetes, overweight, obese, Low HDL-C. Among the subjects aware of their diagnosis of hypertension, medication treatment was more common in those living in the urban, old age, nonsmoker and diabetes. Among the individuals who receiving medication treatment, controlled hypertension were less common in those living in the urban, young age, low education attainment, overweight and obese. Despite high rate of hypertension, awareness, treatment and control of hypertension still need to be strengthened. PMID- 23671600 TI - Histone acetylation-mediated regulation of the Hippo pathway. AB - The Hippo pathway is a signaling cascade recently found to play a key role in tumorigenesis therefore understanding the mechanisms that regulate it should open new opportunities for cancer treatment. Available data indicate that this pathway is controlled by signals from cell-cell junctions however the potential role of nuclear regulation has not yet been described. Here we set out to verify this possibility and define putative mechanism(s) by which it might occur. By using a luciferase reporter of the Hippo pathway, we measured the effects of different nuclear targeting drugs and found that chromatin-modifying agents, and to a lesser extent certain DNA damaging drugs, strongly induced activity of the reporter. This effect was not mediated by upstream core components (i.e. Mst, Lats) of the Hippo pathway, but through enhanced levels of the Hippo transducer TAZ. Investigation of the underlying mechanism led to the finding that cancer cell exposure to histone deacetylase inhibitors induced secretion of growth factors and cytokines, which in turn activate Akt and inhibit the GSK3 beta associated protein degradation complex in drug-affected as well as in their neighboring cells. Consequently, expression of EMT genes, cell migration and resistance to therapy were induced. These processes were suppressed by using pyrvinium, a recently described small molecule activator of the GSK 3 beta associated degradation complex. Overall, these findings shed light on a previously unrecognized phenomenon by which certain anti-cancer agents may paradoxically promote tumor progression by facilitating stabilization of the Hippo transducer TAZ and inducing cancer cell migration and resistance to therapy. Pharmacological targeting of the GSK3 beta associated degradation complex may thus represent a unique approach to treat cancer. PMID- 23671601 TI - Sleeping worries away or worrying away sleep? Physiological evidence on sleep emotion interactions. AB - Recent findings suggest that sleep might serve a role in emotional coping. However, most findings are based on subjective reports of sleep quality, while the relation with underlying sleep physiology is still largely unknown. In this study, the impact of an emotionally distressing experience on the EEG correlates of sleep was assessed. In addition, the association between sleep physiological parameters and the extent of emotional attenuation over sleep was determined. The experimental set up involved presentation of an emotionally neutral or distressing film fragment in the evening, followed by polysomnographic registration of undisturbed, whole-night sleep and assessment of emotional reactivity to film cues on the next evening. We found that emotional distress induced mild sleep deterioration, but also an increase in the proportion of slow wave sleep (SWS) and altered patterning of rapid eye movement (REM) sleep. Indeed, while REM sleep occurrence normally increases over the course of the night, emotional distress flattened this distribution and correlated with an increased number of REM periods. While sleep deterioration was negatively associated to emotional attenuation over sleep, the SWS response was positively related to such attenuation and may form part of a compensatory response to the stressor. Interestingly, trait-like SWS characteristics also correlated positively with the extent of emotion attenuation over sleep. The combined results provide strong evidence for an intimate reciprocal relation between sleep physiology and emotional processing. Moreover, individual differences in subjects' emotional and sleep responses suggest there may be a coupling of certain emotion and sleep traits into distinct emotional sleep types. PMID- 23671602 TI - How do the Chinese perceive ecological risk in freshwater lakes? AB - In this study, we explore the potential contributions of a risk perception framework in understanding public perceptions of unstable ecosystems. In doing so, we characterize one type of common ecological risk- harmful algal blooms (HABs)-in four of the most seriously eutrophicated freshwater lakes in China. These lakes include Chaohu, Dianchi, Hongze, and Taihu, where a total of 2000 residents living near these sites were interviewed. Regional discrepancies existed in the pilot study regarding public perceptions of ecological changes and public concerns for ecological risk. Comparing HABs and other kinds of risks (earthquake, nuclear, and public traffic) through the psychometric paradigm method, Knowledge, Effect, and Trust were three key factors formulating the risk perception model. The results indicated that Knowledge and risk tolerance levels had significant negative correlations in the higher economic situation while correlations in the lower economic situation were significantly positive. Effect and risk tolerance levels had significant negative correlations in the high and middle education situation while correlations in the low education situation were close to zero or insignificant. For residents from Taihu with comparatively higher economic and educational levels, more investment in risk prevention measures and stronger policies are needed. And for residents from Hongze and Dianchi with comparatively low economic and educational levels, improvement of the government's credibility (Trust) was the most important factor of risk tolerance, so efforts to eliminate ecological problems with the stepwise development of economic and educational levels should be implemented and gradually strengthened. In turn, this could prevent public discontent and ensure support for ecological protection policies. PMID- 23671603 TI - The theory of reasoned action as parallel constraint satisfaction: towards a dynamic computational model of health behavior. AB - The reasoned action approach, although ubiquitous in health behavior theory (e.g., Theory of Reasoned Action/Planned Behavior), does not adequately address two key dynamical aspects of health behavior: learning and the effect of immediate social context (i.e., social influence). To remedy this, we put forth a computational implementation of the Theory of Reasoned Action (TRA) using artificial-neural networks. Our model re-conceptualized behavioral intention as arising from a dynamic constraint satisfaction mechanism among a set of beliefs. In two simulations, we show that constraint satisfaction can simultaneously incorporate the effects of past experience (via learning) with the effects of immediate social context to yield behavioral intention, i.e., intention is dynamically constructed from both an individual's pre-existing belief structure and the beliefs of others in the individual's social context. In a third simulation, we illustrate the predictive ability of the model with respect to empirically derived behavioral intention. As the first known computational model of health behavior, it represents a significant advance in theory towards understanding the dynamics of health behavior. Furthermore, our approach may inform the development of population-level agent-based models of health behavior that aim to incorporate psychological theory into models of population dynamics. PMID- 23671605 TI - Late cenozoic history of the genus Micromys (mammalia, rodentia) in Central Europe. AB - Molecular phylogeography suggests that Micromys minutus, the sole extant species of the genus, colonized its extensive range quite recently, during the Late Pleistocene-Holocene period. Rich Pliocene and Pleistocene fossil records both from Europe and China suggest rather continuous and gradual in situ phenotype rearrangements from the Pliocene to the Recent periods. To elucidate the discrepancy we reexamined a considerable part of the European fossil record of the genus (14 sites from MN15 to Q3, 0.4-4.2 Ma, including the type series of M. preaminutus from MN15 Csarnota 2), analyzed them with the aid of detailed morphometric comparisons, and concluded that: (a) The European Pliocene form, M. praeminutus, differs significantly from the extant species; (b) it exhibits a broad phenotypic variation covering the presumptive diagnostic characters of MN16 M. caesaris; (c) despite having smaller dimensions, the Early and Middle Pleistocene forms (MN17-Q3, 2.6-0.4 Ma) seem to be closer to M. praeminutus than to the extant species; (d) the extinction of M. praeminutus during Q3 and the re occupation of its niche by the recent expansion of M. minutus from E-European-C Asiatic sources (suggested by phylogeographic hypotheses) cannot be excluded. Discussing interpretations of the phylogenetic past of the genus we emphasize the distinct history of the West Palearctic clade (Late Miocene-Early Pleistocene) terminating with M. praeminutus and the East Asiatic clade (chalceus, tedfordi, minutus), and the possible identity of the Western clade with the Late Miocene genus Parapodemus. PMID- 23671604 TI - Expression of the chitinase family glycoprotein YKL-40 in undifferentiated, differentiated and trans-differentiated mesenchymal stem cells. AB - The glycoprotein YKL-40 (CHI3L1) is a secreted chitinase family protein that induces angiogenesis, cell survival, and cell proliferation, and plays roles in tissue remodeling and immune regulation. It is expressed primarily in cells of mesenchymal origin, is overexpressed in numerous aggressive carcinomas and sarcomas, but is rarely expressed in normal ectodermal tissues. Bone marrow derived mesenchymal stem cells (MSCs) can be induced to differentiate into various mesenchymal tissues and trans-differentiate into some non-mesenchymal cell types. Since YKL-40 has been used as a mesenchymal marker, we followed YKL 40 expression as undifferentiated MSCs were induced to differentiate into bone, cartilage, and neural phenotypes. Undifferentiated MSCs contain significant levels of YKL-40 mRNA but do not synthesize detectable levels of YKL-40 protein. MSCs induced to differentiate into chondrocytes and osteocytes soon began to express and secrete YKL-40 protein, as do ex vivo cultured chondrocytes and primary osteocytes. In contrast, MSCs induced to trans-differentiate into neurons did not synthesize YKL-40 protein, consistent with the general absence of YKL-40 protein in normal CNS parenchyma. However, these trans-differentiated neurons retained significant levels of YKL-40 mRNA, suggesting the mechanisms which prevented YKL-40 translation in undifferentiated MSCs remained in place, and that these trans-differentiated neurons differ in at least this way from neurons derived from neuronal stem cells. Utilization of a differentiation protocol containing beta-mercaptoethanol resulted in cells that expressed significant amounts of intracellular YKL-40 protein that was not secreted, which is not seen in normal cells. Thus the synthesis of YKL-40 protein is a marker for MSC differentiation into mature mesenchymal phenotypes, and the presence of untranslated YKL-40 mRNA in non-mesenchymal cells derived from MSCs reflects differences between differentiated and trans-differentiated phenotypes. PMID- 23671606 TI - Environmental oxygen tension regulates the energy metabolism and self-renewal of human embryonic stem cells. AB - Energy metabolism is intrinsic to cell viability but surprisingly has been little studied in human embryonic stem cells (hESCs). The current study aims to investigate the effect of environmental O2 tension on carbohydrate utilisation of hESCs. Highly pluripotent hESCs cultured at 5% O2 consumed significantly more glucose, less pyruvate and produced more lactate compared to those maintained at 20% O2. Moreover, hESCs cultured at atmospheric O2 levels expressed significantly less OCT4, SOX2 and NANOG than those maintained at 5% O2. To determine whether this difference in metabolism was a reflection of the pluripotent state, hESCs were cultured at 5% O2 in the absence of FGF2 for 16 hours leading to a significant reduction in the expression of SOX2. In addition, these cells consumed less glucose and produced significantly less lactate compared to those cultured in the presence of FGF2. hESCs maintained at 5% O2 were found to consume significantly less O2 than those cultured in the absence of FGF2, or at 20% O2. GLUT1 expression correlated with glucose consumption and using siRNA and chromatin immunoprecipitation was found to be directly regulated by hypoxia inducible factor (HIF)-2alpha at 5% O2. In conclusion, highly pluripotent cells associated with hypoxic culture consume low levels of O2, high levels of glucose and produce large amounts of lactate, while at atmospheric conditions glucose consumption and lactate production are reduced and there is an increase in oxidative metabolism. These data suggest that environmental O2 regulates energy metabolism and is intrinsic to the self-renewal of hESCs. PMID- 23671607 TI - Chromosome 21 scan in Down syndrome reveals DSCAM as a predisposing locus in Hirschsprung disease. AB - Hirschsprung disease (HSCR) genetics is a paradigm for the study and understanding of multigenic disorders. Association between Down syndrome and HSCR suggests that genetic factors that predispose to HSCR map to chromosome 21. To identify these additional factors, we performed a dose-dependent association study on chromosome 21 in Down syndrome patients with HSCR. Assessing 10,895 SNPs in 26 Caucasian cases and their parents led to identify two associated SNPs (rs2837770 and rs8134673) at chromosome-wide level. Those SNPs, which were located in intron 3 of the DSCAM gene within a 19 kb-linkage disequilibrium block region were in complete association and are consistent with DSCAM expression during enteric nervous system development. We replicated the association of HSCR with this region in an independent sample of 220 non-syndromic HSCR Caucasian patients and their parents. At last, we provide the functional rationale to the involvement of DSCAM by network analysis and assessment of SOX10 regulation. Our results reveal the involvement of DSCAM as a HSCR susceptibility locus, both in Down syndrome and HSCR isolated cases. This study further ascertains the chromosome-scan dose-dependent methodology used herein as a mean to map the genetic bases of other sub-phenotypes both in Down syndrome and other aneuploidies. PMID- 23671608 TI - Analyses of the survival time and the influencing factors of chinese patients with prion diseases based on the surveillance data from 2008-2011. AB - BACKGROUND: Prion diseases are kinds of progressive, incurable neurodegenerative disorders. So far, survival time of the patients with these diseases in China is unclear. METHODS: Based upon the surveillance data from Chinese Creutzfeldt-Jakob disease (CJD) surveillance network from January 2008 to December 2011, a retrospective follow-up survey was performed. The survival times of Chinese patients with prion diseases and the possible influencing factors were analyzed. RESULTS: Median survival time of 121 deceased patients was 7.1 months, while those for sporadic CJD (sCJD), familial CJD (fCJD) and fatal familial insomnia (FFI) cases were 6.1, 3.1 and 8.2 months, respectively. 74.0% of sCJD patients, 100% of fCJD cases and 91.7% FFI cases died within one year. The general socio demographic factors, abnormalities in clinical examinations, clinical manifestations, and social factors did not significantly influence the survival times of Chinese prion patients. CONCLUSIONS: Survival time of Chinese patients with prion diseases was comparable with that of many Western countries, but obviously shorter than that of Japan. Patients with acute onset and rapid progression had significantly short survival times. PMID- 23671609 TI - Prostaglandins, masculinization and its disorders: effects of fetal exposure of the rat to the cyclooxygenase inhibitor- indomethacin. AB - Recent studies have established that masculinization of the male reproductive tract is programmed by androgens in a critical fetal 'masculinization programming window' (MPW). What is peculiar to androgen action during this period is, however, unknown. Studies from 20 years ago in mice implicated prostaglandin (PG) mediation of androgen-induced masculinization, but this has never been followed up. We therefore investigated if PGs might mediate androgen effects in the MPW by exposing pregnant rats to indomethacin (which blocks PG production by inhibiting cyclooxygenase activity) during this period and then examining if androgen production or action (masculinization) was affected. Pregnant rats were treated with indomethacin (0.8 mg/kg/day; e15.5-e18.5) to encompass the MPW. Indomethacin exposure decreased fetal bodyweight (e21.5), testis weight (e21.5) and testicular PGE2 (e17.5, e21.5), but had no effect on intratesticular testosterone (ITT; e17.5) or anogenital index (AGI; e21.5). Postnatally, AGI, testis weight and blood testosterone were unaffected by indomethacin exposure and no cryptorchidism or hypospadias occurred. Penis length was normal in indomethacin-exposed animals at Pnd25 but was reduced by 26% (p<0.001) in adulthood, an effect that is unexplained. Our results demonstrate that indomethacin can effectively decrease intra-testicular PGE2 level. However, the resulting male phenotype does not support a role for PGs in mediating androgen-induced masculinization during the MPW in rats. The contrast with previous mouse studies is unexplained but may reflect a species difference. PMID- 23671610 TI - The association between nonalcoholic fatty pancreas disease and diabetes. AB - BACKGROUND: Fatty infiltration of the pancreas has been shown to interfere with insulin secretion. Both insulin sensitivity and secretion are important in the pathogenesis of diabetes and prediabetes. However, the relationship between diabetes, prediabetes, and fatty pancreas remains unknown. We aim to investigate the relationships that fatty pancreas and nonalcoholic fatty liver disease (NAFLD) have with prediabetes and diabetes in a Chinese population. PATIENTS AND METHODS: This was a cross-sectional study. A total of 7,464 subjects were recruited. NAFLD and fatty pancreas were assessed by sonography. Clinico metabolic parameters were compared among subjects with normoglycemia, prediabetes, and diabetes. Multinomial logistic regression was used to evaluate the relationship between fatty pancreas and NAFLD and diabetes or prediabetes with adjustment for cardiometabolic risk factors. RESULTS: With an increase in glycemia, a significantly greater proportion of subjects had NAFLD and fatty pancreas (test for trend p<0.05). Similar trends were also found for hypertension, general and central obesity, low-HDL cholesterol, and hypertriglyceridemia. In the logistic regression analysis, age, hypertension, male gender, hypertriglyceridemia, and central obesity were significantly associated with prediabetes and diabetes. Furthermore, the ORs of prediabetes and diabetes for NAFLD were 1.798 (95% CI 1.544-2.094) and 2.578 (95% CI 2.024 3.284), respectively. In addition, fatty pancreas was independently related to diabetes (OR, 1.379; 95% CI, 1.047-1.816) and prediabetes (OR, 1.222; 95% CI, 1.002-1.491) in male subjects. CONCLUSIONS: Both NAFLD and fatty pancreas were associated with diabetes independent of age, gender, adiposity, and other cardiometabolic risk factors. Fatty pancreas was also related to prediabetes in males. PMID- 23671611 TI - RsmA regulates Aspergillus fumigatus gliotoxin cluster metabolites including cyclo(L-Phe-L-Ser), a potential new diagnostic marker for invasive aspergillosis. AB - Dimeric basic leucine zipper (bZIP) proteins are conserved transcriptional enhancers found in all eukaryotes. A recently reported and novel function for bZIPs is association of these proteins with secondary metabolite production in filamentous fungi. In particular a Yap-like bZIP termed RsmA (restorer of secondary metabolism A) was identified in Aspergillus nidulans that positively regulates the carcinogen sterigmatocystin. To assess for conserved function for RsmA, we examined a role of this protein in secondary metabolism in the pathogen A. fumigatus. RsmA was found to positively regulate gliotoxin where overexpression (OE) of rsmA led to 2-100 fold increases of twelve gli cluster metabolites in culture medium including the newly identified gli metabolite cyclo(L-Phe-L-Ser). Lungs from both wild type and OErsmA infected mice contained gliotoxin (2.3 fold higher in OErsmA treatment) as well as the gliotoxin precursor cyclo(L-Phe-L-Ser) (3.2 fold higher in OErsmA treatment). The data here presents a conserved role for RsmA in secondary metabolite cluster activation and suggests cyclo(L-Phe-L-Ser) may serve as an alternative marker for diagnosis of invasive aspergillosis. PMID- 23671612 TI - A systematic review and methodological evaluation of published cost-effectiveness analyses of aromatase inhibitors versus tamoxifen in early stage breast cancer. AB - BACKGROUND: A key priority in developing policies for providing affordable cancer care is measuring the value for money of new therapies using cost-effectiveness analyses (CEAs). For CEA to be useful it should focus on relevant outcomes and include thorough investigation of uncertainty. Randomized controlled trials (RCTs) of five years of aromatase inhibitors (AI) versus five years of tamoxifen in the treatment of post-menopausal women with early stage breast cancer, show benefit of AI in terms of disease free survival (DFS) but not overall survival (OS) and indicate higher risk of fracture with AI. Policy-relevant CEA of AI versus tamoxifen should focus on OS and include analysis of uncertainty over key assumptions. METHODS: We conducted a systematic review of published CEAs comparing an AI to tamoxifen. We searched Ovid MEDLINE, EMBASE, PsychINFO, and the Cochrane Database of Systematic Reviews without language restrictions. We selected CEAs with outcomes expressed as cost per life year or cost per quality adjusted life year (QALY). We assessed quality using the Neumann checklist. Using structured forms two abstractors collected descriptive information, sources of data, baseline assumptions on effectiveness and adverse events, and recorded approaches to assessing parameter uncertainty, methodological uncertainty, and structural uncertainty. RESULTS: We identified 1,622 citations and 18 studies met inclusion criteria. All CE estimates assumed a survival benefit for aromatase inhibitors. Twelve studies performed sensitivity analysis on the risk of adverse events and 7 assumed no additional mortality risk with any adverse event. Sub group analysis was limited; 6 studies examined older women, 2 examined women with low recurrence risk, and 1 examined women with multiple comorbidities. CONCLUSION: Published CEAs comparing AIs to tamoxifen assumed an OS benefit though none has been shown in RCTs, leading to an overestimate of the cost effectiveness of AIs. Results of these CEA analyses may be suboptimal for guiding policy. PMID- 23671613 TI - Plasma heme oxygenase-1 levels distinguish latent or successfully treated human tuberculosis from active disease. AB - BACKGROUND: Tuberculosis (TB) is associated with oxidative stress and the induction of host anti-oxidants to counteract this response. Heme oxygenase-1 (HO 1) is a critical promoter of cytoprotection in diverse disease models including mycobacterial infection. Nevertheless, the pattern of expression of HO-1 in human tuberculosis has not been studied. Here, we examine expression of HO-1 in M. tuberculosis-exposed and -infected individuals and test its ability to distinguish active from latent and successfully treated TB cases. In addition, we assess correlations between plasma levels of HO-1 and cytokines closely associated with the immunopathogenesis of TB. METHODS: Cross-sectional and longitudinal analyses of levels of HO-1, acute phase proteins and pro inflammatory cytokines were performed in plasma samples from individuals with active pulmonary, extra-pulmonary or latent TB infection and healthy controls as part of a prospective cohort study in South India. RESULTS: Systemic levels of HO 1 were dramatically increased in individuals with active pulmonary and extra pulmonary tuberculosis and particularly those with bilateral lung lesions and elevated bacillary loads in sputum. HO-1 levels effectively discriminated active from latent tuberculosis with higher predictive values than either C-reactive protein or serum amyloid protein. Moreover, there was a marked reduction in HO-1 levels in active TB cases following anti-tuberculous therapy but not in those who failed treatment. Pulmonary TB patients displaying the highest concentrations of HO-1 in plasma exhibited significantly elevated plasma levels of interleukin (IL) 10, interferon (IFN)-gamma and IL-17 and diminished levels of tumor necrosis factor (TNF)-alpha. CONCLUSION: These findings establish HO-1 levels as a potentially useful parameter for distinguishing active from latent or treated pulmonary tuberculosis, that is superior in this respect to the measurement of other acute inflammatory proteins. PMID- 23671614 TI - Enhancement of proteolytic activity of a thermostable papain-like protease by structure-based rational design. AB - Ervatamins (A, B and C) are papain-like cysteine proteases from the plant Ervatamia coronaria. Among Ervatamins, Ervatamin-C is a thermostable protease, but it shows lower catalytic efficiency. In contrast, Ervatamin-A which has a high amino acid sequence identity (~90%) and structural homology (Calpha rmsd 0.4 A) with Ervatamin-C, has much higher catalytic efficiency (~57 times). From the structural comparison of Ervatamin-A and -C, two residues Thr32 and Tyr67 in the catalytic cleft of Ervatamin-A have been identified whose contributions for higher activity of Ervatamin-A are established in our earlier studies. In this study, these two residues have been introduced in Ervatamin-C by site directed mutagenesis to enhance the catalytic efficiency of the thermostable protease. Two single mutants (S32T and A67Y) and one double mutant (S32T/A67Y) of Ervatamin-C have been generated and characterized. All the three mutants show ~ 8 times higher catalytic efficiency (k cat/K m) than the wild-type. The thermostability of all the three mutant enzymes remained unchanged. The double mutant does not achieve the catalytic efficiency of the template enzyme Ervatamin-A. By modeling the structure of the double mutant and probing the role of active site residues by docking a substrate, the mechanistic insights of higher activity of the mutant protease have been addressed. The in-silico study demonstrates that the residues beyond the catalytic cleft also influence the substrate binding and positioning of the substrate at the catalytic centre, thus controlling the catalytic efficiency of an enzyme. PMID- 23671616 TI - The Profile of Emotional Competence (PEC): development and validation of a self reported measure that fits dimensions of emotional competence theory. AB - Emotional Competence (EC), which refers to individual differences in the identification, understanding, expression, regulation and use of one's own emotions and those of others, has been found to be an important predictor of individuals' adaptation to their environment. Higher EC is associated with greater happiness, better mental and physical health, more satisfying social and marital relationships and greater occupational success. While it is well-known that EC (as a whole) predicts a number of important outcomes, it is unclear so far which specific competency(ies) participate(s) in a given outcome. This is because no measure of EC distinctly measures each of the five core emotional competences, separately for one's own and others' emotions. This lack of information is problematic both theoretically (we do not understand the processes at stake) and practically (we cannot develop customized interventions). This paper aims to address this issue. We developed and validated in four steps a complete (albeit short: 50 items) self-reported measure of EC: the Profile of Emotional Competence. Analyses performed on a representative sample of 5676 subjects revealed promising psychometric properties. The internal consistency of scales and subscales alike was satisfying, factorial structure was as expected, and concurrent/discriminant validity was good. PMID- 23671615 TI - Structure and non-structure of centrosomal proteins. AB - Here we perform a large-scale study of the structural properties and the expression of proteins that constitute the human Centrosome. Centrosomal proteins tend to be larger than generic human proteins (control set), since their genes contain in average more exons (20.3 versus 14.6). They are rich in predicted disordered regions, which cover 57% of their length, compared to 39% in the general human proteome. They also contain several regions that are dually predicted to be disordered and coiled-coil at the same time: 55 proteins (15%) contain disordered and coiled-coil fragments that cover more than 20% of their length. Helices prevail over strands in regions homologous to known structures (47% predicted helical residues against 17% predicted as strands), and even more in the whole centrosomal proteome (52% against 7%), while for control human proteins 34.5% of the residues are predicted as helical and 12.8% are predicted as strands. This difference is mainly due to residues predicted as disordered and helical (30% in centrosomal and 9.4% in control proteins), which may correspond to alpha-helix forming molecular recognition features (alpha-MoRFs). We performed expression assays for 120 full-length centrosomal proteins and 72 domain constructs that we have predicted to be globular. These full-length proteins are often insoluble: Only 39 out of 120 expressed proteins (32%) and 19 out of 72 domains (26%) were soluble. We built or retrieved structural models for 277 out of 361 human proteins whose centrosomal localization has been experimentally verified. We could not find any suitable structural template with more than 20% sequence identity for 84 centrosomal proteins (23%), for which around 74% of the residues are predicted to be disordered or coiled-coils. The three-dimensional models that we built are available at http://ub.cbm.uam.es/centrosome/models/index.php. PMID- 23671617 TI - In situ tip-recordings found no evidence for an Orco-based ionotropic mechanism of pheromone-transduction in Manduca sexta. AB - The mechanisms of insect odor transduction are still controversial. Insect odorant receptors (ORs) are 7TM receptors with inverted membrane topology. They colocalize with a conserved coreceptor (Orco) with chaperone and ion channel function. Some studies suggest that insects employ exclusively ionotropic odor transduction via OR-Orco heteromers. Other studies provide evidence for different metabotropic odor transduction cascades, which employ second messenger-gated ion channel families for odor transduction. The hawkmoth Manduca sexta is an established model organism for studies of insect olfaction, also due to the availability of the hawkmoth-specific pheromone blend with its main component bombykal. Previous patch-clamp studies on primary cell cultures of M. sexta olfactory receptor neurons provided evidence for a pheromone-dependent activation of a phospholipase Cbeta. Pheromone application elicited a sequence of one rapid, apparently IP3-dependent, transient and two slower Ca(2+)-dependent inward currents. It remains unknown whether additionally an ionotropic pheromone transduction mechanism is employed. If indeed an OR-Orco ion channel complex underlies an ionotropic mechanism, then Orco agonist-dependent opening of the OR Orco channel pore should add up to pheromone-dependent opening of the pore. Here, in tip-recordings from intact pheromone-sensitive sensilla, perfusion with the Orco agonist VUAA1 did not increase pheromone-responses within the first 1000 ms. However, VUAA1 increased spontaneous activity of olfactory receptor neurons Zeitgebertime- and dose-dependently. We conclude that we find no evidence for an Orco-dependent ionotropic pheromone transduction cascade in M. sexta. Instead, in M. sexta Orco appears to be a slower, second messenger-dependent pacemaker channel which affects kinetics and threshold of pheromone-detection via changes of intracellular Ca(2+) baseline concentrations. PMID- 23671618 TI - Towards renewed health economic simulation of type 2 diabetes: risk equations for first and second cardiovascular events from Swedish register data. AB - OBJECTIVE: Predicting the risk of future events is an essential part of health economic simulation models. In pursuit of this goal, the current study aims to predict the risk of developing first and second acute myocardial infarction, heart failure, non-acute ischaemic heart disease, and stroke after diagnosis in patients with type 2 diabetes, using data from the Swedish National Diabetes Register. MATERIAL AND METHODS: Register data on 29,034 patients with type 2 diabetes were analysed over five years of follow up (baseline 2003). To develop and validate the risk equations, the sample was randomly divided into training (75%) and test (25%) subsamples. The Weibull proportional hazard model was used to estimate the coefficients of the risk equations, and these were validated in both the training and the test samples. RESULTS: In total, 4,547 first and 2,418 second events were observed during the five years of follow up. Experiencing a first event substantially elevated the risk of subsequent events. There were heterogeneities in the effects of covariates within as well as between events; for example, while for females the hazard ratio of having a first acute myocardial infarction was 0.79 (0.70-0.90), the hazard ratio of a second was 1.21 (0.98-1.48). The hazards of second events decreased as the time since first events elapsed. The equations showed adequate calibration and discrimination (C statistics range: 0.70-0.84 in test samples). CONCLUSION: The accuracy of health economic simulation models of type 2 diabetes can be improved by ensuring that they account for the heterogeneous effects of covariates on the risk of first and second cardiovascular events. Thus it is important to extend such models by including risk equations for second cardiovascular events. PMID- 23671619 TI - Pterostilbene exerts antitumor activity via the Notch1 signaling pathway in human lung adenocarcinoma cells. AB - Although pterostilbene (PTE) has been shown to have potent antitumor activities against various cancer types, the molecular mechanisms of these activities remain unclear. In this study, we investigated the antitumor activity of PTE against human lung adenocarcinoma in vitro and in vivo and explored the role of the Notch1 signaling pathway in this process. PTE treatment resulted in a dose- and time-dependent decrease in the viability of A549 cells. Additionally, PTE exhibited strong antitumor activity, as evidenced not only by a reduced mitochondrial membrane potential (MMP) and a decreased intracellular glutathione content but also by increases in the apoptotic index and the level of reactive oxygen species (ROS). Furthermore, PTE treatment induced the activation of the Notch1 Intracellular Domain (NICD) protein and activated Hes1. DAPT (a gamma secretase inhibitor) and Notch1 siRNA prevented the induction of NICD and Hes1 activation by PTE treatment and sensitized the cells to PTE treatment. The down regulation of Notch signaling also prevented the activation of pro-survival pathways (most notably the PI3K/Akt pathway) after PTE treatment. In summary, lung adenocarcinoma cells may enhance Notch1 activation as a protective mechanism in response to PTE treatment. Combining a gamma secretase inhibitor with PTE treatment may represent a novel approach for treating lung adenocarcinoma by inhibiting the survival pathways of cancer cells. PMID- 23671620 TI - Production of zebrafish offspring from cultured female germline stem cells. AB - Zebrafish female germline stem cell (FGSC) cultures were generated from a transgenic line of fish that expresses Neo and DsRed under the control of the germ cell specific promoter, ziwi [Tg(ziwi:neo);Tg(ziwi:DsRed)]. Homogeneous FGSC cultures were established by G418 selection and continued to express ziwi for more than 6 weeks along with the germ cell markers nanos3, dnd, dazl and vasa. A key component of the cell culture system was the use of a feeder cell line that was initiated from ovaries of a transgenic line of fish [Tg(gsdf:neo)] that expresses Neo controlled by the zebrafish gonadal soma derived factor (gsdf) promoter. The feeder cell line was selected in G418 and engineered to express zebrafish leukemia inhibitory factor (Lif), basic fibroblast growth factor (Fgf2) and glial-cell-line derived neurotrophic factor (Gdnf). These factors were shown to significantly enhance FGSC growth, survival and germline competency in culture. Results from cell transplantation experiments revealed that the cultured FGSCs were able to successfully colonize the gonad of sterile recipient fish and generate functional gametes. Up to 20% of surviving recipient fish that were injected with the cultured FGSCs were fertile and generated multiple batches of normal offspring for at least 6 months. The FGSC cultures will provide an in vitro system for studies of zebrafish germ cell growth and differentiation and their high frequency of germline transmission following transplantation could form the basis of a stem cell-mediated strategy for gene transfer and manipulation of the zebrafish genome. PMID- 23671622 TI - Characterization of the S100A1 protein binding site on TRPC6 C-terminus. AB - The transient receptor potential (TRP) protein superfamily consists of seven major groups, among them the "canonical TRP" family. The TRPC proteins are calcium-permeable nonselective cation channels activated after the emptying of intracellular calcium stores and appear to be gated by various types of messengers. The TRPC6 channel has been shown to be expressed in various tissues and cells, where it modulates the calcium level in response to external signals. Calcium binding proteins such as Calmodulin or the family of S100A proteins are regulators of TRPC channels. Here we characterized the overlapping integrative binding site for S100A1 at the C-tail of TRPC6, which is also able to accomodate various ligands such as Calmodulin and phosphatidyl-inositol-(4,5)-bisphosphate. Several positively charged amino acid residues (Arg852, Lys856, Lys859, Arg860 and Arg864) were determined by fluorescence anisotropy measurements for their participation in the calcium-dependent binding of S100A1 to the C terminus of TRPC6. The triple mutation Arg852/Lys859/Arg860 exhibited significant disruption of the binding of S100A1 to TRPC6. This indicates a unique involvement of these three basic residues in the integrative overlapping binding site for S100A1 on the C tail of TRPC6. PMID- 23671621 TI - Integration of high-resolution physical and genetic map reveals differential recombination frequency between chromosomes and the genome assembling quality in cucumber. AB - Cucumber is an important model crop and the first species sequenced in Cucurbitaceae family. Compared to the fast increasing genetic and genomics resources, the molecular cytogenetic researches in cucumber are still very limited, which results in directly the shortage of relation between plenty of physical sequences or genetic data and chromosome structure. We mapped twenty three fosmids anchored by SSR markers from LG-3, the longest linkage group, and LG-4, the shortest linkage group on pachytene chromosomes 3 and 4, using uorescence in situ hybridization (FISH). Integrated molecular cytogenetic maps of chromosomes 3 and 4 were constructed. Except for three SSR markers located on heterochromatin region, the cytological order of markers was concordant with those on the linkage maps. Distinct structural differences between chromosomes 3 and 4 were revealed by the high resolution pachytene chromosomes. The extreme difference of genetic length between LG-3 and LG-4 was mainly attributed to the difference of overall recombination frequency. The significant differentiation of heterochromatin contents in chromosomes 3 and 4 might have a direct correlation with recombination frequency. Meanwhile, the uneven distribution of recombination frequency along chromosome 4 was observed, and recombination frequency of the long arm was nearly 3.5 times higher than that of the short arm. The severe suppression of recombination was exhibited in centromeric and heterochromatin domains of chromosome 4. Whereas a close correlation between the gene density and recombination frequency was observed in chromosome 4, no significant correlation was observed between them along chromosome 3. The comparison between cytogenetic and sequence maps revealed a large gap on the pericentromeric heterochromatin region of sequence map of chromosome 4. These results showed that integrated molecular cytogenetic maps can provide important information for the study of genetic and genomics in cucumber. PMID- 23671623 TI - Acetylcholinesterase inhibitors reduce neuroinflammation and -degeneration in the cortex and hippocampus of a surgery stress rat model. AB - Exogenous stress like tissue damage and pathogen invasion during surgical trauma could lead to a peripheral inflammatory response and induce neuroinflammation, which can result in postoperative cognitive dysfunction (POCD). The cholinergic anti-inflammatory pathway is a neurohumoral mechanism that plays a prominent role by suppressing the inflammatory response. Treatments with acetylcholinesterase inhibitors enhance cholinergic transmission and may therefore act as a potential approach to prevent neuroinflammation. In the presence or absence of acetylcholinesterase inhibitors, adult Wistar rats underwent surgery alone or were additionally treated with lipopolysaccharide (LPS). Physostigmine, which can overcome the blood-brain barrier or neostigmine acting only peripheral, served as acetylcholinesterase inhibitors. The expression of pro- and anti-inflammatory cytokines in the cortex, hippocampus, spleen and plasma was measured after 1 h, 24 h, 3 d and 7 d using Real-Time PCR, western blot analysis or cytometric bead array (CBA). Fluoro-Jade B staining of brain slices was employed to elucidate neurodegeneration. The activity of acetylcholinesterase was estimated using a spectrofluorometric method. Surgery accompanied by LPS-treatment led to increased IL-1beta gene and protein upregulation in the cortex and hippocampus but was significantly reduced by physostigmine and neostigmine. Furthermore, surgery in combination with LPS-treatment caused increased protein expression of IL-1, TNF alpha and IL-10 in the spleen and plasma. Physostigmine and neostigmine significantly decreased the protein expression of IL-1 and TNF-alpha. Neuronal degeneration and the activity of acetylcholinesterase were elevated after surgery with LPS-treatment and reduced by physostigmine and neostigmine. Along with LPS treatment, acetylcholinesterase inhibitors reduce the pro-inflammatory response as well as neurodegeneration after surgery in the cortex and hippocampus. This combination may represent a tool to break the pathogenesis of POCD. PMID- 23671624 TI - A comparison of the clinical and epidemiological characteristics of adult patients with laboratory-confirmed influenza A or B during the 2011-2012 influenza season in Korea: a multi-center study. AB - BACKGROUND: During the 2011/2012 winter influenza season in the Republic of Korea, influenza A (H3N2) was the predominant virus in the first peak period of influenza activity during the second half of January 2012. On the other hand, influenza B was the predominant virus in the second peak period of influenza activity during the second half of March 2012. The objectives of this study were to compare the clinical and epidemiological characteristics of patients with laboratory-confirmed influenza A or influenza B. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed data from 2,129 adult patients with influenza-like illnesses who visited the emergency rooms of seven university hospitals in Korea from October 2011 to May 2012. Of 850 patients with laboratory-confirmed influenza, 656 (77.2%) had influenza A (H3N2), and 194 (22.8%) influenza B. Age, and the frequencies of cardiovascular disorders, diabetes, hypertension were significantly higher in patients with influenza A (H3N2) (P<0.05). The frequencies of leukopenia or thrombocytopenia in patients with influenza B at initial presentation were statistically higher than those in patients with influenza A (H3N2) (P<0.05). The rate of hospitalization, and length of hospital stay were statistically higher in patients with influenza A (H3N2) (P<0.05), and of the 79 hospitalized patients, the frequency of diabetes, hypertension, cases having at least one of the comorbid conditions, and the proportion of elderly were significantly higher in patients with influenza A (H3N2) (P<0.05). CONCLUSIONS: The proportion of males to females and elderly population were significantly higher for influenza A (H3N2) patients group compared with influenza B group. Hypertension, diabetes, chronic lung diseases, cardiovascular disorders, and neuromuscular diseases were independently associated with hospitalization due to influenza. Physicians should assess and treat the underlying comorbid conditions as well as influenza viral infections for the appropriate management of patients with influenza. PMID- 23671625 TI - Hypoxic preconditioning with cobalt of bone marrow mesenchymal stem cells improves cell migration and enhances therapy for treatment of ischemic acute kidney injury. AB - Mesenchymal stem cell (MSC) administration is known to enhance the recovery of the kidney following injury. Here we tested the potential of hypoxic preconditioned-MSC transplantation to enhance the efficacy of cell therapy on acute kidney injury (AKI) by improving MSC migration to the injured kidney. Cobalt was used as hypoxia mimetic preconditioning (HMP). MSC were subjected to HMP through 24 h culture in 200 umol/L cobalt. Compared to normoxia cultured MSC (NP-MSC), HMP significantly increased the expression of HIF-1alpha and CXCR4 in MSC and enhanced the migration of MSC in vitro. This effect was lost when MSC were treated with siRNA targeting HIF-1alpha or CXCR4 antagonist. SPIO labeled MSC were administered to rats with I/R injury followed immediately by magnetic resonance imaging. Imaging clearly showed that HMP-MSC exhibited greater migration and a longer retention time in the ischemic kidney than NP-MSC. Histological evaluation showed more HMP-MSC in the glomerular capillaries of ischemic kidneys than in the kidneys receiving NP-MSC. Occasional tubules showed iron labeling in the HMP group, while no tubules had iron labeling in NP group, indicating the possibility of tubular transdifferentiation after HMP. These results were also confirmed by fluorescence microscopy study using CM-DiI labeling. The increased recruitment of HMP-MSC was associated with reduced kidney injury and enhanced functional recovery. This effect was also related to the increased paracrine action by HMP-MSC. Thus we suggest that by enhancing MSC migration and prolonging kidney retention, hypoxic preconditioning of MSC may be a useful approach for developing AKI cell therapy. PMID- 23671626 TI - Placing a price on medical device innovation: the example of total knee arthroplasty. AB - BACKGROUND: Total knee arthroplasty (TKA) is common, effective, and cost effective. Innovative implants promising reduced long-term failure at increased cost are under continual development. We sought to define the implant cost and performance thresholds under which innovative TKA implants are cost-effective. METHODS: We performed a cost-effectiveness analysis using a validated, published computer simulation model of knee osteoarthritis. Model inputs were derived using published literature, Medicare claims, and National Health and Nutrition Examination Survey data. We compared projected TKA implant survival, quality adjusted life expectancy (QALE), lifetime costs, and cost-effectiveness (incremental cost-effectiveness ratios or ICERs) of standard versus innovative TKA implants. We assumed innovative implants offered 5-70% decreased long-term TKA failure rates at costs 20-400% increased above standard implants. We examined the impact of patient age, comorbidity, and potential increases in short-term failure on innovative implant cost-effectiveness. RESULTS: Implants offering >=50% decrease in long-term TKA failure at <=50% increased cost offered ICERs <$100,000 regardless of age or baseline comorbidity. An implant offering a 20% decrease in long-term failure at 50% increased cost provided ICERs <$150,000 per QALY gained only among healthy 50-59-year-olds. Increasing short-term failure, consistent with recent device failures, reduced cost-effectiveness across all groups. Increasing the baseline likelihood of long-term TKA failure among younger, healthier and more active individuals further enhanced innovative implant cost-effectiveness among younger patients. CONCLUSIONS: Innovative implants must decrease actual TKA failure, not just radiographic wear, by 50-55% or more over standard implants to be broadly cost-effective. Comorbidity and remaining life span significantly affect innovative implant cost-effectiveness and should be considered in the development, approval and implementation of novel technologies, particularly in orthopedics. Model-based evaluations such as this offer valuable, unique insights for evaluating technological innovation in medical devices. PMID- 23671627 TI - Concentration regimes of biopolymers xanthan, tara, and clairana, comparing dynamic light scattering and distribution of relaxation time. AB - The aim of this work was to evaluate the utilization of analysis of the distribution of relaxation time (DRT) using a dynamic light back-scattering technique as alternative method for the determination of the concentration regimes in aqueous solutions of biopolymers (xanthan, clairana and tara gums) by an analysis of the overlap (c*) and aggregation (c**) concentrations. The diffusion coefficients were obtained over a range of concentrations for each biopolymer using two methods. The first method analysed the behaviour of the diffusion coefficient as a function of the concentration of the gum solution. This method is based on the analysis of the diffusion coefficient versus the concentration curve. Using the slope of the curves, it was possible to determine the c* and c** for xanthan and tara gum. However, it was not possible to determine the concentration regimes for clairana using this method. The second method was based on an analysis of the DRTs, which showed different numbers of relaxation modes. It was observed that the concentrations at which the number of modes changed corresponded to the c* and c**. Thus, the DRT technique provided an alternative method for the determination of the critical concentrations of biopolymers. PMID- 23671628 TI - Prevalence of subjective olfactory dysfunction and its risk factors: korean national health and nutrition examination survey. AB - BACKGROUND: Population-based studies for olfactory dysfunction are lacking. The aim of this study is to evaluate the prevalence of subjective olfactory dysfunction and its risk factors in the Korean general population. METHODS: The data were obtained from the 2009 Korea National Health and Nutrition Examination Survey (KNHANES), which was a cross-sectional survey of non-institutionalized population all around the country (n = 10,533). All interviewees underwent medical interviews, physical examinations, endoscopic examination and blood/urine tests. Whether sense of smell has been normal or abnormal during the last 3 months was asked. Complete olfaction data were obtained from 7,306 participants and the participants were divided into normosmic and hyposmic group. Multivariate logistic regression analyses were performed to identify its risk factors. RESULTS: The weighted prevalence of subjective olfactory dysfunction was 4.5%. Its increased prevalence was significantly associated with the increasing age for both men and women. In the multivariate analyses, low income (adjusted odds ratio [OR] = 1.43, 95% Confidence Interval [CI] = 1.01-2.03), habitual exposure to air pollutants (adjusted OR = 2.18, CI = 1.33-3.55), a history of hepatitis B (adjusted OR = 3.10, CI = 1.25-7.68), rhinitis (adjusted OR = 1.78, CI = 1.26 2.51) and chronic sinusitis (adjusted OR = 14.55, CI = 10.06-21.05) were risk factors of olfactory dysfunction. CONCLUSION: Our population-based study showed that olfactory dysfunction was quite prevalent and several risk factors were associated with impaired sense of smell. Given its prevalence, further researches for its prevention and management are required. PMID- 23671629 TI - The use of colorimetric sensor arrays to discriminate between pathogenic bacteria. AB - A colorimetric sensor array is a high-dimensional chemical sensor that is cheap, compact, disposable, robust, and easy to operate, making it a good candidate technology to detect pathogenic bacteria, especially potential bioterrorism agents like Yersinia pestis and Bacillus anthracis which feature on the Center for Disease Control and Prevention's list of potential biothreats. Here, a colorimetric sensor array was used to continuously monitor the volatile metabolites released by bacteria in solid media culture in an Advisory Committee on Dangerous Pathogen Containment Level 3 laboratory. At inoculum concentrations as low as 8 colony-forming units per plate, 4 different bacterial species were identified with 100% accuracy using logistic regression to classify the kinetic profile of sensor responses to culture headspace gas. The sensor array was able to further discriminate between different strains of the same species, including 5 strains of Yersinia pestis and Bacillus anthracis. These preliminary results suggest that disposable colorimetric sensor arrays can be an effective, low-cost tool to identify pathogenic bacteria. PMID- 23671630 TI - Foraging behaviour of juvenile female New Zealand sea lions (Phocarctos hookeri) in contrasting environments. AB - Foragers can show adaptive responses to changes within their environment through morphological and behavioural plasticity. We investigated the plasticity in body size, at sea movements and diving behaviour of juvenile female New Zealand (NZ) sea lions (Phocarctos hookeri) in two contrasting environments. The NZ sea lion is one of the rarest pinnipeds in the world. Most of the species is based at the subantarctic Auckland Islands (AI; considered to be marginal foraging habitat), with a recolonizing population on the Otago Peninsula, NZ mainland (considered to be more optimal habitat). We investigated how juvenile NZ sea lions adjust their foraging behaviour in contrasting environments by deploying satellite-linked platform transmitting terminals (PTTs) and time-depth recorders (TDRs) on 2-3 year-old females at AI (2007-2010) and Otago (2009-2010). Juvenile female NZ sea lions exhibited plasticity in body size and behaviour. Otago juveniles were significantly heavier than AI juveniles. Linear mixed effects models showed that study site had the most important effect on foraging behaviour, while mass and age had little influence. AI juveniles spent more time at sea, foraged over larger areas, and dove deeper and longer than Otago juveniles. It is difficult to attribute a specific cause to the observed contrasts in foraging behaviour because these differences may be driven by disparities in habitat/prey characteristics, conspecific density levels or interseasonal variation. Nevertheless, the smaller size and increased foraging effort of AI juveniles, combined with the lower productivity in this region, support the hypothesis that AI are less optimal habitat than Otago. It is more difficult for juveniles to forage in suboptimal habitats given their restricted foraging ability and lower tolerance for food limitation compared to adults. Thus, effective management measures should consider the impacts of low resource environments, along with changes that can alter food availability such as potential resource competition with fisheries. PMID- 23671631 TI - Healthy volunteers can be phenotyped using cutaneous sensitization pain models. AB - BACKGROUND: Human experimental pain models leading to development of secondary hyperalgesia are used to estimate efficacy of analgesics and antihyperalgesics. The ability to develop an area of secondary hyperalgesia varies substantially between subjects, but little is known about the agreement following repeated measurements. The aim of this study was to determine if the areas of secondary hyperalgesia were consistently robust to be useful for phenotyping subjects, based on their pattern of sensitization by the heat pain models. METHODS: We performed post-hoc analyses of 10 completed healthy volunteer studies (n = 342 [409 repeated measurements]). Three different models were used to induce secondary hyperalgesia to monofilament stimulation: the heat/capsaicin sensitization (H/C), the brief thermal sensitization (BTS), and the burn injury (BI) models. Three studies included both the H/C and BTS models. RESULTS: Within subject compared to between-subject variability was low, and there was substantial strength of agreement between repeated induction-sessions in most studies. The intraclass correlation coefficient (ICC) improved little with repeated testing beyond two sessions. There was good agreement in categorizing subjects into 'small area' (1(st) quartile [<25%]) and 'large area' (4(th) quartile [>75%]) responders: 56-76% of subjects consistently fell into same 'small-area' or 'large-area' category on two consecutive study days. There was moderate to substantial agreement between the areas of secondary hyperalgesia induced on the same day using the H/C (forearm) and BTS (thigh) models. CONCLUSION: Secondary hyperalgesia induced by experimental heat pain models seem a consistent measure of sensitization in pharmacodynamic and physiological research. The analysis indicates that healthy volunteers can be phenotyped based on their pattern of sensitization by the heat [and heat plus capsaicin] pain models. PMID- 23671632 TI - Observational bias during nutrition surveillance: results of a mixed longitudinal and cross-sectional data collection system in Northern Nigeria. AB - BACKGROUND: The Sahel is subject to seasonal hungry periods with increasing rates of malnutrition. In Northern Nigeria, there is no surveillance system and surveys are rare. The objectives were to analyse possible observational bias in a sentinel surveillance system using repeated mixed longitudinal/cross-sectional data and estimate the extent of seasonal variation. METHODS: Thirty clusters were randomly selected using probability proportional to size (PPS) sampling from Kazaure Local Government Area, Jigawa State. In each cluster, all the children aged 6-59 months within 20 randomly selected households had their mid-upper arm circumference measured and were tested for oedema. The surveys were repeated every 2 or 4 weeks. At each survey round, three of the clusters were randomly selected to be replaced by three new clusters chosen at random by PPS. The seasonal variation of acute malnutrition was assessed using cyclical regression. The effect of repeated visits to the same cluster was examined using general linear mixed effects models adjusted for the seasonal change. RESULTS: There was a significant seasonal fluctuation of Global Acute Malnutrition (GAM) with a peak in October. With each repeat survey of a cluster, the prevalence of GAM decreased by 1.6% (95% CI: 0.4 to 2.7; p = 0.012) relative to the prevalence observed during the previous visit after adjusting for seasonal change. CONCLUSIONS: Northern Nigeria has a seasonal variation in the prevalence of acute malnutrition. Repeated surveys in the same cluster-village, even if different children are selected, lead to a progressive improvement of the nutritional status of that village. Sentinel site surveillance of nutritional status is prone to observational bias, with the sentinel site progressively deviating from that of the community it is presumed to represent. PMID- 23671633 TI - Exploratory analysis on the use of statins with or without n-3 PUFA and major events in patients discharged for acute myocardial infarction: an observational retrospective study. AB - BACKGROUND: Combined treatment (CT) with statins and polyunsaturated fatty acids (n-3 PUFA) resulted in a reduction of death and major cardiovascular events when administered after a myocardial infarction (MI). However, recent data suggests that CT may be ineffective because patients are currently treated aggressively and the risk may not be further decreased. We aimed to study the prevalence and the results on major outcomes with CT among patients discharged with a MI in Italy. METHODOLOGY/PRINCIPAL FINDINGS: Retrospective cohort study that used linked hospital discharge, prescription databases and vital statistics containing information on 14,704 patients who were discharged for MI between 1/2003 and 12/2003 in 117 hospitals in Italy. All analyses were time-dependent and adjusted for major confounders. Sensibility and paired matched analysis were conducted to further verify main results. A total of 11,532 (78.4%) filled a prescription for a statin. Of these, 4302 (37.3%) were on CT. There were 45,528 patients/years of follow-up. As compared with statins alone, CT was associated with an adjusted higher survival rate (HR = 0.59 [0.52-0.66], p<0.001), survival free of atrial fibrillation (HR = 0.78 [0.71-0.86], p<0.001) and survival free of new heart failure development (HR = 0.81 [0.74-0.88], p<0.001), but not with re-infarction (HR = 0.94 [0.86-1.02], p<0.127). Clinically this means that between 2 to 3 fewer events for each 100 patients/year were obtained in the group under CT. CONCLUSIONS/SIGNIFICANCE: Among a representative sample of patients discharged with MI in Italy, we observed clinically significant synergism between the effects of statins and n-3 PUFA for most cardiovascular outcomes, including all cause mortality. PMID- 23671634 TI - An androgenic agricultural contaminant impairs female reproductive behaviour in a freshwater fish. AB - Endocrine disrupting chemicals (EDCs) are a large group of environmental pollutants that can interfere with the endocrine system function of organisms at very low levels. One compound of great concern is trenbolone, which is widely used as a growth promoter in the cattle industry in many parts of the world. The aim of this study was to test how short-term (21-day) exposure to an environmentally relevant concentration of 17beta-trenbolone (measured concentration 6 ng/L) affects reproductive behaviour and fin morphology in the eastern mosquitofish (Gambusia holbrooki). The mosquitofish is a sexually dimorphic livebearer with males inseminating females using their modified anal fin, the gonopodium, as an intromittent organ. Although the species has a coercive mating system, females are able to exert some control over the success of male mating attempts by selectively associating with, or avoiding, certain males over others. We found that females exposed to trenbolone approached males less and spent more time swimming away from males than non-exposed (control) females. By contrast, we found no difference in the behaviour of exposed and non exposed males. Furthermore, exposure did not affect the anal fin morphology of males or females. This is the first study to demonstrate that exposure to an androgenic EDC can impair female (but not male) behaviour. Our study illustrates how anthropogenic contaminants can have sex-specific effects, and highlights the need to examine the behavioural responses of environmental contaminants in both sexes. PMID- 23671635 TI - Handedness in Neandertals from the El Sidron (Asturias, Spain): evidence from instrumental striations with ontogenetic inferences. AB - The developed cognitive capabilities for Homo sapiens seems to be the result of a specialized and lateralized brain, and as a result of this, humans display the highest degree of manual specialization or handedness among the primates. Studies regarding its emergence and distribution within the genus Homo show that handedness is present very early. The mode in which it was articulated and spread across the different species during the course of human evolution could provide information about our own cognitive capacities. Here we report the manual laterality attributed to eleven 49,000 old Neandertal individuals from El Sidron cave (Spain), through the study of instrumental or cultural striations on the anterior dentition. Our results show a predominant pattern addressed to right handers. These results fit within the modern human handedness distribution pattern and provide indirect evidence for behavior and brain lateralization on Neandertals. They support the early establishment of handedness in our genus. Moreover, the individual identified as Juvenile 1 (6-8 years old at death), displays the same striation pattern as the adult Neandertals from the sample, and thereby the ontogenic development of manual laterality in that Neandertal population seems to be similar to that of living modern humans. PMID- 23671636 TI - Perinatal factors and regional brain volume abnormalities at term in a cohort of extremely low birth weight infants. AB - Our objective was to investigate diverse clinical antecedents of total and regional brain volume abnormalities and white matter hyperintensity volume on term MRI in extremely low birth weight (birth weight <=1000 g) survivors. A consecutive cohort of extremely low birth weight infants who survived to 38 weeks postmenstrual age (n = 122) and a control group of 16 healthy term newborns underwent brain MRI at term-equivalent age. Brain volumes were measured using semi-automated and manual segmentation methods. Using multivariable linear regression, clinical antecedents were correlated with volumes of total brain tissue, white matter hyperintensities, and regional tissues/structures, adjusted for age at MRI, total cranial volume, and total tissue volume. Regional brain volumes were markedly reduced in extremely low birth weight infants as compared to term newborns (relative difference range: -11.0%, -35.9%). Significant adverse clinical associations for total brain tissue volume included: small for gestational age, seizures, caffeine therapy/apnea of prematurity, duration of parenteral nutrition, pulmonary hemorrhage, and white matter injury (p<0.01 for each; relative difference range: -1.4% to -15.0%). Surgery for retinopathy of prematurity and surgery for necrotizing enterocolitis or spontaneous intestinal perforation were significantly associated with increasing volume of white matter hyperintensities. Regional brain volumes are sensitive to multiple perinatal factors and neonatal morbidities or interventions. Brain growth measurements in extremely low birth weight infants can advance our understanding of perinatal brain injury and development. PMID- 23671637 TI - Stem cells from wildtype and Friedreich's ataxia mice present similar neuroprotective properties in dorsal root ganglia cells. AB - Many neurodegenerative disorders share a common susceptibility to oxidative stress, including Alzheimer's, Parkinson Disease, Huntington Disease and Friedreich's ataxia. In a previous work, we proved that stem cell-conditioned medium increased the survival of cells isolated from Friedreich's ataxia patients, when submitted to oxidative stress. The aim of the present work is to confirm this same effect in dorsal root ganglia cells isolated from YG8 mice, a mouse model of Friedreich's ataxia. In this disorder, the neurons of the dorsal root ganglia are the first to degenerate. Also, in this work we cultured mesenchymal stem cells isolated from YG8 mice, in order to compare them with their wildtype counterpart. To this end, dorsal root ganglia primary cultures isolated from YG8 mice were exposed to oxidative stress and cultured with conditioned medium from either wildtype or YG8 stem cells. As a result, the conditioned medium increased the survival of the dorsal root ganglia cells. This coincided with an increase in oxidative stress-related markers and frataxin expression levels. BDNF, NT3 and NT4 trophic factors were detected in the conditioned medium of both wild-type and YG8 stem cells, all which bind to the various neuronal cell types present in the dorsal root ganglia. No differences were observed in the stem cells isolated from wildtype and YG8 mice. The results presented confirm the possibility that autologous stem cell transplantation may be a viable therapeutic approach in protecting dorsal root ganglia neurons of Friedreich's ataxia patients. PMID- 23671638 TI - Role of transient receptor potential ion channels and evoked levels of neuropeptides in a formaldehyde-induced model of asthma in BALB/c mice. AB - OBJECTIVE: Asthma is a complex pulmonary inflammatory disease characterized by the hyper-responsiveness, remodeling and inflammation of airways. Formaldehyde is a common indoor air pollutant that can cause asthma in people experiencing long term exposure. The irritant effect and adjuvant effect are the two possible pathways of formaldehyde promoted asthma. METHODOLOGY/PRINCIPAL FINDINGS: To explore the neural mechanisms and adjuvant effect of formaldehyde, 48 Balb/c mice in six experimental groups were exposed to (a) vehicle control; (b) ovalbumin; (c) formaldehyde (3.0 mg/m(3)); (d) ovalbumin+formaldehyde (3.0 mg/m(3)); (e) ovalbumin+formaldehyde (3.0 mg/m(3))+HC-030031 (transient receptor potential ankyrin 1 antagonist); (f) ovalbumin+formaldehyde (3.0 mg/m(3))+ capsazepine (transient receptor potential vanilloid 1 antagonist). Experiments were conducted after 4 weeks of combined exposure and 1-week challenge with aerosolized ovalbumin. Airway hyper-responsiveness, pulmonary tissue damage, eosinophil infiltration, and increased levels of interleukin-4, interleukin-6, interleukin 1beta, immunoglobulin E, substance P and calcitonin gene-related peptide in lung tissues were found in the ovalbumin+formaldehyde (3.0 mg/m(3)) group compared with the values seen in ovalbumin -only immunized mice. Except for interleukin 1beta levels, other changes in the levels of biomarker could be inhibited by HC 030031 and capsazepine. CONCLUSIONS/SIGNIFICANCE: Formaldehyde might be a key risk factor for the rise in asthma cases. Transient receptor potential ion channels and neuropeptides have important roles in formaldehyde promoted-asthma. PMID- 23671639 TI - Decrease of 5-hydroxymethylcytosine is associated with progression of hepatocellular carcinoma through downregulation of TET1. AB - DNA methylation is an important epigenetic modification and is frequently altered in cancer. Convert of 5-methylcytosine (5 mC) to 5-hydroxymethylcytosine (5 hmC) by ten-eleven translocation (TET) family enzymes plays important biological functions in embryonic stem cells, development, aging and disease. Recent reports showed that level of 5 hmC was altered in various types of cancers. However, the change of 5 hmC level in hepatocellular carcinoma (HCC) and association with clinical outcome were not well defined. Here, we reported that level of 5 hmC was decreased in HCC tissues, as compared with non-tumor tissues. Clincopathological analysis showed the decreased level of 5 hmC in HCC was associated with tumor size, AFP level and poor overall survival. We also found that the decreased level of 5 hmC in non-tumor tissues was associated with tumor recurrence in the first year after surgical resection. In an animal model with carcinogen DEN-induced HCC, we found that the level of 5 hmC was gradually decreased in the livers during the period of induction. There was further reduction of 5 hmC in tumor tissues when tumors were developed. In contrast, level of 5 mC was increased in HCC tissues and the increased 5 mC level was associated with capsular invasion, vascular thrombosis, tumor recurrence and overall survival. Furthermore, our data showed that expression of TET1, but not TET2 and TET3, was downregulated in HCC. Taken together, our data indicated 5 hmC may be served as a prognostic marker for HCC and the decreased expression of TET1 is likely one of the mechanisms underlying 5 hmC loss in HCC. PMID- 23671640 TI - The EGF repeat-specific O-GlcNAc-transferase Eogt interacts with notch signaling and pyrimidine metabolism pathways in Drosophila. AB - The O-GlcNAc transferase Eogt modifies EGF repeats in proteins that transit the secretory pathway, including Dumpy and Notch. In this paper, we show that the Notch ligands Delta and Serrate are also substrates of Eogt, that mutation of a putative UDP-GlcNAc binding DXD motif greatly reduces enzyme activity, and that Eogt and the cytoplasmic O-GlcNAc transferase Ogt have distinct substrates in Drosophila larvae. Loss of Eogt is larval lethal and disrupts Dumpy functions, but does not obviously perturb Notch signaling. To identify novel genetic interactions with eogt, we investigated dominant modification of wing blister formation caused by knock-down of eogt. Unexpectedly, heterozygosity for several members of the canonical Notch signaling pathway suppressed wing blister formation. And importantly, extensive genetic interactions with mutants in pyrimidine metabolism were identified. Removal of pyrimidine synthesis alleles suppressed wing blister formation, while removal of uracil catabolism alleles was synthetic lethal with eogt knock-down. Therefore, Eogt may regulate protein functions by O-GlcNAc modification of their EGF repeats, and cellular metabolism by affecting pyrimidine synthesis and catabolism. We propose that eogt knock-down in the wing leads to metabolic and signaling perturbations that increase cytosolic uracil levels, thereby causing wing blister formation. PMID- 23671641 TI - Combining classification with fMRI-derived complex network measures for potential neurodiagnostics. AB - Complex network analysis (CNA), a subset of graph theory, is an emerging approach to the analysis of functional connectivity in the brain, allowing quantitative assessment of network properties such as functional segregation, integration, resilience, and centrality. Here, we show how a classification framework complements complex network analysis by providing an efficient and objective means of selecting the best network model characterizing given functional connectivity data. We describe a novel kernel-sum learning approach, block diagonal optimization (BDopt), which can be applied to CNA features to single out graph-theoretic characteristics and/or anatomical regions of interest underlying discrimination, while mitigating problems of multiple comparisons. As a proof of concept for the method's applicability to future neurodiagnostics, we apply BDopt classification to two resting state fMRI data sets: a trait (between-subjects) classification of patients with schizophrenia vs. controls, and a state (within subjects) classification of wake vs. sleep, demonstrating powerful discriminant accuracy for the proposed framework. PMID- 23671642 TI - Synergies between intrinsic and synaptic plasticity based on information theoretic learning. AB - In experimental and theoretical neuroscience, synaptic plasticity has dominated the area of neural plasticity for a very long time. Recently, neuronal intrinsic plasticity (IP) has become a hot topic in this area. IP is sometimes thought to be an information-maximization mechanism. However, it is still unclear how IP affects the performance of artificial neural networks in supervised learning applications. From an information-theoretical perspective, the error-entropy minimization (MEE) algorithm has newly been proposed as an efficient training method. In this study, we propose a synergistic learning algorithm combining the MEE algorithm as the synaptic plasticity rule and an information-maximization algorithm as the intrinsic plasticity rule. We consider both feedforward and recurrent neural networks and study the interactions between intrinsic and synaptic plasticity. Simulations indicate that the intrinsic plasticity rule can improve the performance of artificial neural networks trained by the MEE algorithm. PMID- 23671643 TI - Flight and walking in locusts-cholinergic co-activation, temporal coupling and its modulation by biogenic amines. AB - Walking and flying in locusts are exemplary rhythmical behaviors generated by central pattern generators (CPG) that are tuned in intact animals by phasic sensory inputs. Although these two behaviors are mutually exclusive and controlled by independent CPGs, leg movements during flight can be coupled to the flight rhythm. To investigate potential central coupling between the underlying CPGs, we used the muscarinic agonist pilocarpine and the amines octopamine and tyramine to initiate fictive flight and walking in deafferented locust preparations. Our data illustrate that fictive walking is readily evoked by comparatively lower concentrations of pilocarpine, whereas higher concentrations are required to elicit fictive flight. Interestingly, fictive flight did not suppress fictive walking so that the two patterns were produced simultaneously. Frequently, leg motor units were temporally coupled to the flight rhythm, so that each spike in a step cycle volley occurred synchronously with wing motor units firing at flight rhythm frequency. Similarly, tyramine also induced fictive walking and flight, but mostly without any coupling between the two rhythms. Octopamine in contrast readily evoked fictive flight but generally failed to elicit fictive walking. Despite this, numerous leg motor units were recruited, whereby each was temporarily coupled to the flight rhythm. Our results support the notion that the CPGs for walking and flight are largely independent, but that coupling can be entrained by aminergic modulation. We speculate that octopamine biases the whole motor machinery of a locust to flight whereas tyramine primarily promotes walking. PMID- 23671644 TI - Low dose decitabine treatment induces CD80 expression in cancer cells and stimulates tumor specific cytotoxic T lymphocyte responses. AB - Lack of immunogenicity of cancer cells has been considered a major reason for their failure in induction of a tumor specific T cell response. In this paper, we present evidence that decitabine (DAC), a DNA methylation inhibitor that is currently used for the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and other malignant neoplasms, is capable of eliciting an anti tumor cytotoxic T lymphocyte (CTL) response in mouse EL4 tumor model. C57BL/6 mice with established EL4 tumors were treated with DAC (1.0 mg/kg body weight) once daily for 5 days. We found that DAC treatment resulted in infiltration of IFN-gamma producing T lymphocytes into tumors and caused tumor rejection. Depletion of CD8(+), but not CD4(+) T cells resumed tumor growth. DAC-induced CTL response appeared to be elicited by the induction of CD80 expression on tumor cells. Epigenetic evidence suggests that DAC induces CD80 expression in EL4 cells via demethylation of CpG dinucleotide sites in the promoter of CD80 gene. In addition, we also showed that a transient, low-dose DAC treatment can induce CD80 gene expression in a variety of human cancer cells. This study provides the first evidence that epigenetic modulation can induce the expression of a major T cell co-stimulatory molecule on cancer cells, which can overcome immune tolerance, and induce an efficient anti-tumor CTL response. The results have important implications in designing DAC-based cancer immunotherapy. PMID- 23671645 TI - Smoking and risk of kidney failure in the Singapore Chinese health study. AB - BACKGROUND: The relationship between smoking and risk of kidney failure, especially in people of Chinese origin, is not clear. We analyzed data from the Singapore Chinese Health Study to investigate whether smoking increases the risk of kidney failure. METHODS: The Singapore Chinese Health Study is a population based cohort of 63,257 Chinese adults enrolled between 1993 and 1998. Information on smoking status was collected at baseline. Incidence of kidney failure was identified via record linkage with the nationwide Singapore Renal Registry until 2008. Kidney failure was defined by one of the following: 1) serum creatinine level of more than or equal to 500 umol/l (5.7 mg/dl), 2) estimated glomerular filtration rate of less than 15 ml/min/1.73 m(2), 3) undergoing hemodialysis or peritoneal dialysis, 4) undergone kidney transplantation. Cox proportional hazard regression analysis was performed for the outcome of kidney failure after adjusting for age, education, dialect, herbal medications, body mass index, sex, physician-diagnosed hypertension and diabetes mellitus. RESULTS: The mean age of subjects was 55.6 years at baseline, and 44% were men. Overall 30.6% were ever smokers (current or former) at baseline. A total of 674 incident cases of kidney failure occurred during a median follow-up of 13.3 years. Among men, smokers had a significant increase in the adjusted risk of kidney failure [hazard ratio (HR): 1.29; 95% CI: 1.02-1.64] compared to never smokers. There was a strong dose dependent association between number of years of smoking and kidney failure, (p for trend = 0.011). The risk decreased with prolonged cessation (quitting >=10 years since baseline). The number of women smokers was too few for conclusive relationship. LIMITATION: Information on baseline kidney function was not available. CONCLUSIONS: Cigarette smoking is associated with increased risk of kidney failure among Chinese men. The risk appears to be dose- and duration dependent and modifiable after long duration of cessation. PMID- 23671646 TI - The metastasis-associated gene MTA3, a component of the Mi-2/NuRD transcriptional repression complex, predicts prognosis of gastroesophageal junction adenocarcinoma. AB - Gastroesophageal junction (GEJ) adenocarcinoma carries a poor prognosis that is largely attributable to early and frequent metastasis. The acquisition of metastatic potential in cancer involves epithelial-to-mesenchymal transition (EMT). The metastasis-associated gene MTA3, a novel component of the Mi-2/NuRD transcriptional repression complex, was identified as master regulator of EMT through inhibition of Snail to increase E-cadherin expression in breast cancer. Here, we evaluated the expression pattern of the components of MTA3 pathway and the corresponding prognostic significance in GEJ adenocarcinoma. MTA3 expression was decreased at both protein and mRNA levels in tumor tissues compared to the non-tumorous and lowed MTA3 levels were noted in tumor cell lines with stronger metastatic potential. Immunohistochemical analysis of a cohort of 128 cases exhibited that patients with lower expression of MTA3 had poorer outcomes. Combined misexpression of MTA3, Snail and E-cadherin had stronger correlation with malignant properties. Collectively, results suggest that the MTA3-regulated EMT pathway is altered to favor EMT and, therefore, disease progression and that MTA3 expression was an independent prognostic factor in patients with GEJ adenocarcinoma. PMID- 23671647 TI - A novel fully automated molecular diagnostic system (AMDS) for colorectal cancer mutation detection. AB - BACKGROUND: KRAS, BRAF and PIK3CA mutations are frequently observed in colorectal cancer (CRC). In particular, KRAS mutations are strong predictors for clinical outcomes of EGFR-targeted treatments such as cetuximab and panitumumab in metastatic colorectal cancer (mCRC). For mutation analysis, the current methods are time-consuming, and not readily available to all oncologists and pathologists. We have developed a novel, simple, sensitive and fully automated molecular diagnostic system (AMDS) for point of care testing (POCT). Here we report the results of a comparison study between AMDS and direct sequencing (DS) in the detection of KRAS, BRAF and PI3KCA somatic mutations. METHODOLOGY/PRINCIPAL FINDING: DNA was extracted from a slice of either frozen (n = 89) or formalin-fixed and paraffin-embedded (FFPE) CRC tissue (n = 70), and then used for mutation analysis by AMDS and DS. All mutations (n = 41 among frozen and 27 among FFPE samples) detected by DS were also successfully (100%) detected by the AMDS. However, 8 frozen and 6 FFPE samples detected as wild-type in the DS analysis were shown as mutants in the AMDS analysis. By cloning sequencing assays, these discordant samples were confirmed as true mutants. One sample had simultaneous "hot spot" mutations of KRAS and PIK3CA, and cloning assay comfirmed that E542K and E545K were not on the same allele. Genotyping call rates for DS were 100.0% (89/89) and 74.3% (52/70) in frozen and FFPE samples, respectively, for the first attempt; whereas that of AMDS was 100.0% for both sample sets. For automated DNA extraction and mutation detection by AMDS, frozen tissues (n = 41) were successfully detected all mutations within 70 minutes. CONCLUSIONS/SIGNIFICANCE: AMDS has superior sensitivity and accuracy over DS, and is much easier to execute than conventional labor intensive manual mutation analysis. AMDS has great potential for POCT equipment for mutation analysis. PMID- 23671648 TI - Similar properties of chondrocytes from osteoarthritis joints and mesenchymal stem cells from healthy donors for tissue engineering of articular cartilage. AB - Lesions of hyaline cartilage do not heal spontaneously, and represent a therapeutic challenge. In vitro engineering of articular cartilage using cells and biomaterials may prove to be the best solution. Patients with osteoarthritis (OA) may require tissue engineered cartilage therapy. Chondrocytes obtained from OA joints are thought to be involved in the disease process, and thus to be of insufficient quality to be used for repair strategies. Bone marrow (BM) derived mesenchymal stem cells (MSCs) from healthy donors may represent an alternative cell source. We have isolated chondrocytes from OA joints, performed cell culture expansion and tissue engineering of cartilage using a disc-shaped alginate scaffold and chondrogenic differentiation medium. We performed real-time reverse transcriptase quantitative PCR and fluorescence immunohistochemistry to evaluate mRNA and protein expression for a range of molecules involved in chondrogenesis and OA pathogenesis. Results were compared with those obtained by using BM-MSCs in an identical tissue engineering strategy. Finally the two populations were compared using genome-wide mRNA arrays. At three weeks of chondrogenic differentiation we found high and similar levels of hyaline cartilage-specific type II collagen and fibrocartilage-specific type I collagen mRNA and protein in discs containing OA and BM-MSC derived chondrocytes. Aggrecan, the dominant proteoglycan in hyaline cartilage, was more abundantly distributed in the OA chondrocyte extracellular matrix. OA chondrocytes expressed higher mRNA levels also of other hyaline extracellular matrix components. Surprisingly BM-MSC derived chondrocytes expressed higher mRNA levels of OA markers such as COL10A1, SSP1 (osteopontin), ALPL, BMP2, VEGFA, PTGES, IHH, and WNT genes, but lower levels of MMP3 and S100A4. Based on the results presented here, OA chondrocytes may be suitable for tissue engineering of articular cartilage. PMID- 23671649 TI - Interaction between obesity and the NFKB1 - 94ins/delATTG promoter polymorphism in relation to incident acute coronary syndrome: a follow up study in three independent cohorts. AB - INTRODUCTION: The NF-kappaB transcription factor family regulates several genes encoding pro-inflammatory and anti-inflammatory proteins in adipose tissues and in atherosclerotic plaques. The deletion variant allele of the NFKB1 - 94ins/delATTG promoter polymorphism leads to lower transcript levels of the p50 subunit, and the variant allele has been associated with the risk of several inflammatory diseases as well as coronary heart disease where inflammation is important in the pathogenesis. The objective of this study was to explore the potential interaction between the NFKB1-94ins/delATTG promoter polymorphism and general, abdominal, and gluteofemoral obesity in relation to the risk of incident acute coronary syndrome (ACS) in three large independent cohorts. METHODS AND RESULTS: The analyses were conducted in the Danish prospective study Diet, Cancer and Health and the two US based cohorts; Nurses' Health Study and Health Professionals Follow-up Study. We conducted sex stratified analyses that included 1202 male and 708 female cases of incident ACS. We observed a positive association for general and abdominal obesity with risk of incident ACS, independent of genotype in both genders. Gluteofemoral obesity was negatively associated with ACS risk in women independent of genotype, whereas there was no clear association for men. We calculated the relative excess risk due to interaction (RERI) and observed a statistically significant excess risk among men jointly exposed to general or abdominal obesity and the variant allele of the NFKB1-94ATTG polymorphism, whereas there was a tendency towards sub-additivity for gluteofemoral obesity. The excess risks in all analyses were, however, small and could not clearly be demonstrated in women. CONCLUSION: The variant allele of the NFKB1-94ins/delATTG promoter polymorphism did not substantially modify the association between obesity and incident ACS. PMID- 23671650 TI - Coordinated regulation of chromatophore differentiation and melanogenesis during the ontogeny of skin pigmentation of Solea senegalensis (Kaup, 1858). AB - Abnormal pigmentation of Senegalese sole has been described as one problem facing the full exploitation of its commercial production. To improve our understanding of flatfish pigmentation of this commercially important species we have evaluated eleven genes related to two different processes of pigmentation: melanophore differentiation, and melanin production. The temporal distribution of gene expression peaks corresponds well with changes in pigmentation patterns and the intensity of skin melanization. Several gene ratios were also examined to put in perspective possible genetic markers for the different stages of normal pigmentation development. Further, the phenotypic changes that occur during morphogenesis correspond well with the main transitions in gene expression that occur. Given the dramatic phenotypic alterations which flatfish undergo, including the asymmetric coloration that occurs between the ocular and the blind side, and the synchrony of the two processes of morphogenesis and pigmentation ontogenesis, these species constitute an interesting model for the study of pigmentation. In this study we present a first approximation towards explaining the genetic mechanisms for regulating pigmentation ontogeny in Senegalese sole, Solea senegalensis. PMID- 23671651 TI - Elemental concentrations in the seed of mutants and natural variants of Arabidopsis thaliana grown under varying soil conditions. AB - The concentrations of mineral nutrients in seeds are critical to both the life cycle of plants as well as human nutrition. These concentrations are strongly influenced by soil conditions, as shown here by quantifying the concentration of 14 elements in seeds from Arabidopsis thaliana plants grown under four different soil conditions: standard, or modified with NaCl, heavy metals, or alkali. Each of the modified soils resulted in a unique change to the seed ionome (the mineral nutrient content of the seeds). To help identify the genetic networks regulating the seed ionome, changes in elemental concentrations were evaluated using mutants corresponding to 760 genes as well as 10 naturally occurring accessions. The frequency of ionomic phenotypes supports an estimate that as much as 11% of the A. thaliana genome encodes proteins of functional relevance to ion homeostasis in seeds. A subset of mutants were analyzed with two independent alleles, providing five examples of genes important for regulation of the seed ionome: SOS2, ABH1, CCC, At3g14280 and CNGC2. In a comparison of nine different accessions to a Col-0 reference, eight accessions were observed to have reproducible differences in elemental concentrations, seven of which were dependent on specific soil conditions. These results indicate that the A. thaliana seed ionome is distinct from the vegetative ionome, and that elemental analysis is a sensitive approach to identify genes controlling ion homeostasis, including those that regulate gene expression, phospho-regulation, and ion transport. PMID- 23671652 TI - Fetal skeletal muscle progenitors have regenerative capacity after intramuscular engraftment in dystrophin deficient mice. AB - Muscle satellite cells (SCs) are stem cells that reside in skeletal muscles and contribute to regeneration upon muscle injury. SCs arise from skeletal muscle progenitors expressing transcription factors Pax3 and/or Pax7 during embryogenesis in mice. However, it is unclear whether these fetal progenitors possess regenerative ability when transplanted in adult muscle. Here we address this question by investigating whether fetal skeletal muscle progenitors (FMPs) isolated from Pax3(GFP/+) embryos have the capacity to regenerate muscle after engraftment into Dystrophin-deficient mice, a model of Duchenne muscular dystrophy. The capacity of FMPs to engraft and enter the myogenic program in regenerating muscle was compared with that of SCs derived from adult Pax3(GFP/+) mice. Transplanted FMPs contributed to the reconstitution of damaged myofibers in Dystrophin-deficient mice. However, despite FMPs and SCs having similar myogenic ability in culture, the regenerative ability of FMPs was less than that of SCs in vivo. FMPs that had activated MyoD engrafted more efficiently to regenerate myofibers than MyoD-negative FMPs. Transcriptome and surface marker analyses of these cells suggest the importance of myogenic priming for the efficient myogenic engraftment. Our findings suggest the regenerative capability of FMPs in the context of muscle repair and cell therapy for degenerative muscle disease. PMID- 23671653 TI - Ectopic expression of a wheat WRKY transcription factor gene TaWRKY71-1 results in hyponastic leaves in Arabidopsis thaliana. AB - Leaf type is an important trait that closely associates with crop yield. WRKY transcription factors exert diverse regulatory effects in plants, but their roles in the determination of leaf type have not been reported so far. In this work, we isolated a WRKY transcription factor gene TaWRKY71-1 from a wheat introgression line SR3, which has larger leaves, superior growth capacity and higher yield than its parent common wheat JN177. TaWRKY71-1 specifically expressed in leaves, and produced more mRNA in SR3 than in JN177. TaWRKY71-1 localized in the nucleus and had no transcriptional activation activity. TaWRKY71-1 overexpression in Arabidopsis resulted in hyponastic rosette leaves, and the hyponastic strength was closely correlative with the transcription level of the transgene. The spongy mesophyll cells at abaxial side of leaves were drastically compacted by TaWRKY71 1 overexpression. In TaWRKY71-1 overexpression Arabidopsis, the expression of IAMT1 that encodes a methyltransferase converting free indole-3-acetic acid (IAA) to methyl-IAA ester (MeIAA) to alter auxin homeostatic level was induced, and the induction level was dependent on the abundance of TaWRKY71-1 transcripts. Besides, several TCP genes that had found to be restricted by IAMT1 had lower expression levels as well. Our results suggest that TaWRKY71-1 causes hyponastic leaves through altering auxin homeostatic level by promoting the conversion of IAA to MeIAA. PMID- 23671654 TI - A novel approach for characterizing microsatellite instability in cancer cells. AB - Microsatellite instability (MSI) is characterized by the expansion or contraction of DNA repeat tracts as a consequence of DNA mismatch repair deficiency (MMRD). Accurate detection of MSI in cancer cells is important since MSI is associated with several cancer subtypes and can help inform therapeutic decisions. Although experimental assays have been developed to detect MSI, they typically depend on a small number of known microsatellite loci or mismatch repair genes and have limited reliability. Here, we report a novel genome-wide approach for MSI detection based on the global detection of insertions and deletions (indels) in microsatellites found in expressed genes. Our large-scale analyses of 20 cancer cell lines and 123 normal individuals revealed striking indel features associated with MSI: there is a significant increase of short microsatellite deletions in MSI samples compared to microsatellite stable (MSS) ones, suggesting a mechanistic bias of repair efficiency between insertions and deletions in normal human cells. By incorporating this observation into our MSI scoring metric, we show that our approach can correctly distinguish between MSI and MSS cancer cell lines. Moreover, when we applied this approach to primal tumor samples, our metric is also well consistent with diagnosed MSI status. Thus, our study offers new insight into DNA mismatch repair system, and also provides a novel MSI diagnosis method for clinical oncology with better reliability. PMID- 23671655 TI - Purification and immunobiochemical characterization of a 31 kDa cross-reactive allergen from Phaseolus vulgaris (kidney bean). AB - BACKGROUND: Legumes are a rich source of proteins but are also potential elicitors of IgE-mediated food allergy. This study aimed to isolate and characterize a major allergen of Phaseolus vulgaris (kidney bean) and determine its allergenicity. METHODOLOGY: Kidney bean allergen was purified using Q Sepharose column (anion exchanger) and eluates with high intensity were pooled to purify protein using Superdex 75 (gel filtration) and C18 column (RP-HPLC). Patients with history of kidney bean allergy were skin prick tested (SPT) with crude kidney bean extract and the purified protein. Specific IgE was estimated in sera by enzyme-linked immunosorbent assay (ELISA). Characterization of purified protein and its cross-reactivity was investigated by immunobiochemical methods. Identification of purified protein was carried out by tandem mass spectrometry. PRINCIPAL FINDINGS: Purified protein appeared as a single band at 31 kDa on SDS PAGE and showed IgE binding to 88% patients' sera by ELISA and immunoblotting. SPT with purified protein identified 78% hypersensitive patients of kidney bean. Significant release of histamine from sensitized basophils was observed after challenge with purified protein. PAS staining suggested it to be a glycoprotein, but no change in IgE binding was observed after periodate oxidation. The 31 kDa protein remained stable for 60 min on incubation with pepsin. The purified protein had high allergenic potential since it required only 102 ng of self protein for 50% IgE inhibition. Mass spectrometric analysis identified it as Phytohemagglutinin. It also showed hemagglutination with human RBCs. Cross reactivity was observed with peanut and black gram with IC50 of 185 and 228 ng respectively. CONCLUSION/SIGNIFICANCE: A 31 kDa major allergen of kidney bean was purified and identified as phytohemagglutinin with cross-reactivity to peanut and black gram. PMID- 23671656 TI - Reconstruction of white matter tracts via repeated deterministic streamline tracking--initial experience. AB - Diffusion Tensor Imaging (DTI) and fiber tractography are established methods to reconstruct major white matter tracts in the human brain in-vivo. Particularly in the context of neurosurgical procedures, reliable information about the course of fiber bundles is important to minimize postoperative deficits while maximizing the tumor resection volume. Since routinely used deterministic streamline tractography approaches often underestimate the spatial extent of white matter tracts, a novel approach to improve fiber segmentation is presented here, considering clinical time constraints. Therefore, fiber tracking visualization is enhanced with statistical information from multiple tracking applications to determine uncertainty in reconstruction based on clinical DTI data. After initial deterministic fiber tracking and centerline calculation, new seed regions are generated along the result's midline. Tracking is applied to all new seed regions afterwards, varying in number and applied offset. The number of fibers passing each voxel is computed to model different levels of fiber bundle membership. Experimental results using an artificial data set of an anatomical software phantom are presented, using the Dice Similarity Coefficient (DSC) as a measure of segmentation quality. Different parameter combinations were classified to be superior to others providing significantly improved results with DSCs of 81.02%+/ 4.12%, 81.32%+/-4.22% and 80.99%+/-3.81% for different levels of added noise in comparison to the deterministic fiber tracking procedure using the two-ROI approach with average DSCs of 65.08%+/-5.31%, 64.73%+/-6.02% and 65.91%+/-6.42%. Whole brain tractography based on the seed volume generated by the calculated seeds delivers average DSCs of 67.12%+/-0.86%, 75.10%+/-0.28% and 72.91%+/-0.15%, original whole brain tractography delivers DSCs of 67.16%, 75.03% and 75.54%, using initial ROIs as combined include regions, which is clearly improved by the repeated fiber tractography method. PMID- 23671657 TI - A nano LC-MALDI mass spectrometry droplet interface for the analysis of complex protein samples. AB - The integration of matrix-assisted laser desorption ionization (MALDI) mass spectrometry with an upstream analytical separations (such as liquid chromatography and electrophoresis) has opened up new opportunities for the automated investigation of complex protein and peptide mixtures. The ability to efficiently analyze complex proteomic mixtures in this manner is primarily determined by the ability to preserve spatial discrimination of sample components as they leave the separation column. Current interfacing methods are problematic in this respect since minimum fraction volumes are limited to several microliters. Herein we show for the first time an LC-MALDI interface based on the formation, processing and destruction of a segmented flow. The interface consists of a droplet-generator to fractionate LC effluent into nL-volume droplets and a deposition probe that transfers the sample (and MALDI matrix) onto a conventional MALDI-MS target. The efficacy of the method is demonstrated through the analysis of Trypsin digests of both BSA and Cytochrome C, with a 50% enhancement in analytical performance when compared to conventional interface technology. PMID- 23671658 TI - Involvement of phosphorylation of adenosine 5'-monophosphate-activated protein kinase in PTTH-stimulated ecdysteroidogenesis in prothoracic glands of the silkworm, Bombyx mori. AB - In this study, we investigated inhibition of the phosphorylation of adenosine 5' monophosphate-activated protein kinase (AMPK) by prothoracicotropic hormone (PTTH) in prothoracic glands of the silkworm, Bombyx mori. We found that treatment with PTTH in vitro inhibited AMPK phosphorylation in time- and dose dependent manners, as seen on Western blots of glandular lysates probed with antibody directed against AMPKalpha phosphorylated at Thr172. Moreover, in vitro inhibition of AMPK phosphorylation by PTTH was also verified by in vivo experiments: injection of PTTH into day 7 last instar larvae greatly inhibited glandular AMPK phosphorylation. PTTH-inhibited AMPK phosphorylation appeared to be partially reversed by treatment with LY294002, indicating involvement of phosphatidylinositol 3-kinase (PI3K) signaling. A chemical activator of AMPK (5 aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside, AICAR) increased both basal and PTTH-inhibited AMPK phosphorylation. Treatment with AICAR also inhibited PTTH stimulated ecdysteroidogenesis of prothoracic glands. The mechanism underlying inhibition of PTTH-stimulated ecdysteroidogenesis by AICAR was further investigated by determining the phosphorylation of eIF4E-binding protein (4E-BP) and p70 ribosomal protein S6 kinase (S6K), two known downstream signaling targets of the target of rapamycin complex 1 (TORC1). Upon treatment with AICAR, decreases in PTTH-stimulated phosphorylation of 4E-BP and S6K were detected. In addition, treatment with AICAR did not affect PTTH-stimulated extracellular signal-regulated kinase (ERK) phosphorylation, indicating that AMPK phosphorylation is not upstream signaling for ERK phosphorylation. Examination of gene expression levels of AMPKalpha, beta, and gamma by quantitative real-time PCR (qRT-PCR) showed that PTTH did not affect AMPK transcription. From these results, it is assumed that inhibition of AMPK phosphorylation, which lies upstream of PTTH-stimulated TOR signaling, may play a role in PTTH stimulation of ecdysteroidogenesis. PMID- 23671659 TI - Significance of anaerobes and oral bacteria in community-acquired pneumonia. AB - BACKGROUND: Molecular biological modalities with better detection rates have been applied to identify the bacteria causing infectious diseases. Approximately 10 48% of bacterial pathogens causing community-acquired pneumonia are not identified using conventional cultivation methods. This study evaluated the bacteriological causes of community-acquired pneumonia using a cultivation independent clone library analysis of the 16S ribosomal RNA gene of bronchoalveolar lavage specimens, and compared the results with those of conventional cultivation methods. METHODS: Patients with community-acquired pneumonia were enrolled based on their clinical and radiological findings. Bronchoalveolar lavage specimens were collected from pulmonary pathological lesions using bronchoscopy and evaluated by both a culture-independent molecular method and conventional cultivation methods. For the culture-independent molecular method, approximately 600 base pairs of 16S ribosomal RNA genes were amplified using polymerase chain reaction with universal primers, followed by the construction of clone libraries. The nucleotide sequences of 96 clones randomly chosen for each specimen were determined, and bacterial homology was searched. Conventional cultivation methods, including anaerobic cultures, were also performed using the same specimens. RESULTS: In addition to known common pathogens of community-acquired pneumonia [Streptococcus pneumoniae (18.8%), Haemophilus influenzae (18.8%), Mycoplasma pneumoniae (17.2%)], molecular analysis of specimens from 64 patients with community-acquired pneumonia showed relatively higher rates of anaerobes (15.6%) and oral bacteria (15.6%) than previous reports. CONCLUSION: Our findings suggest that anaerobes and oral bacteria are more frequently detected in patients with community-acquired pneumonia than previously believed. It is possible that these bacteria may play more important roles in community-acquired pneumonia. PMID- 23671660 TI - Multiplex profiling of cellular invasion in 3D cell culture models. AB - To-date, most invasion or migration assays use a modified Boyden chamber-like design to assess migration as single-cell or scratch assays on coated or uncoated planar plastic surfaces. Here, we describe a 96-well microplate-based, high content, three-dimensional cell culture assay capable of assessing invasion dynamics and molecular signatures thereof. On applying our invasion assay, we were able to demonstrate significant effects on the invasion capacity of fibroblast cell lines, as well as primary lung fibroblasts. Administration of epidermal growth factor resulted in a substantial increase of cellular invasion, thus making this technique suitable for high-throughput pharmacological screening of novel compounds regulating invasive and migratory pathways of primary cells. Our assay also correlates cellular invasiveness to molecular events. Thus, we argue of having developed a powerful and versatile toolbox for an extensive profiling of invasive cells in a 96-well format. This will have a major impact on research in disease areas like fibrosis, metastatic cancers, or chronic inflammatory states. PMID- 23671661 TI - Cross-platform microarray meta-analysis for the mouse jejunum selects novel reference genes with highly uniform levels of expression. AB - Reference genes (RGs) with uniform expression are used for normalization of reverse transcription quantitative PCR (RT-qPCR) data. Their optimization for a specific biological context, e.g. a specific tissue, has been increasingly considered. In this article, we compare RGs identified by expression data meta analysis restricted to the context tissue, the jejunum of Mus musculus domesticus, i) to traditional RGs, ii) to expressed interspersed repeated DNA elements, and iii) to RGs identified by meta-analysis of expression data from diverse tissues and conditions. To select the set of candidate RGs, we developed a novel protocol for the cross-platform meta-analysis of microarray data. The expression stability of twenty-four putative RGs was analysed by RT-qPCR in at least 14 jejunum samples of the mouse strains C57Bl/6N, CD1, and OF1. Across strains, the levels of expression of the novel RGs Plekha7, Zfx, and Ube2v1 as well as of Oaz1 varied less than two-fold irrespective of genotype, sex or their combination. The gene set consisting of Plekha7 and Oaz1 showed superior expression stability analysed with the tool RefFinder. The novel RGs are functionally diverse. This facilitates expression studies over a wide range of conditions. The highly uniform expression of the optimized RGs in the jejunum points towards their involvement in tightly regulated pathways in this tissue. We also applied our novel protocol of cross-microarray platform meta-analysis to the identification of RGs in the duodenum, the ileum and the entire small intestine. The selection of RGs with improved expression stability in a specific biological context can reduce the number of RGs for the normalization step of RT-qPCR expression analysis, thus reducing the number of samples and experimental costs. PMID- 23671662 TI - From multidrug- to extensively drug-resistant tuberculosis: upward trends as seen from a 15-year nationwide study. AB - BACKGROUND: Emergence of extensively drug-resistant tuberculosis (XDR-TB) represents an enormous challenge to Public Health globally. METHODS: Progression towards XDR-TB was investigated in Belgium, a country with a typically low TB incidence, by analyzing the magnitude, characteristics, and treatment success of multidrug-resistant tuberculosis (MDR-TB) through a population-based study from 1994 to 2008. RESULTS: Among the 174 MDR-TB patients, 81% were foreign-born, 48% of these being asylum seekers. Although the number of MDR-TB patients remained stable through the study period at around 15 new cases annually, frequencies of resistance of the patients' first MDR-TB isolate to second-line drugs increased, as well as the total number of antibiotics it was resistant to (p<0.001). XDR-TB cases were detected from 2002 onwards. For 24 patients, additional resistance to several second-line drugs was acquired during treatment. Molecular-guided investigations indicated little to no contribution of in-country clonal spread or exogenous re-infection. The increase of pre-XDR and XDR cases could be attributed to rising proportions of patients from Asia and Central and Eastern Europe (p<0.001) and an increase in the isolation of Beijing strains in these groups (p<0.001). Despite augmented resistance, the treatment success rate improved from 63.0% to 75.8% (p = 0.080) after implementation in 2005 of improved surveillance measures and therapeutic access. CONCLUSIONS: Increasing severity in drug resistance patterns leading to more XDR- and "panresistant" TB cases in a country with a low TB incidence like Belgium represents a strong alert on worsening situations in other world regions and requires intense public health measures. PMID- 23671663 TI - Analyses of the stability and core taxonomic memberships of the human microbiome. AB - Analyses of the taxonomic diversity associated with the human microbiome continue to be an area of great importance. The study of the nature and extent of the commonly shared taxa ("core"), versus those less prevalent, establishes a baseline for comparing healthy and diseased groups by quantifying the variation among people, across body habitats and over time. The National Institutes of Health (NIH) sponsored Human Microbiome Project (HMP) has provided an unprecedented opportunity to examine and better define what constitutes the taxonomic core within and across body habitats and individuals through pyrosequencing-based profiling of 16S rRNA gene sequences from oral, skin, distal gut (stool), and vaginal body habitats from over 200 healthy individuals. A two parameter model is introduced to quantitatively identify the core taxonomic members of each body habitat's microbiota across the healthy cohort. Using only cutoffs for taxonomic ubiquity and abundance, core taxonomic members were identified for each of the 18 body habitats and also for the 4 higher-level body regions. Although many microbes were shared at low abundance, they exhibited a relatively continuous spread in both their abundance and ubiquity, as opposed to a more discretized separation. The numbers of core taxa members in the body regions are comparatively small and stable, reflecting the relatively high, but conserved, interpersonal variability within the cohort. Core sizes increased across the body regions in the order of: vagina, skin, stool, and oral cavity. A number of "minor" oral taxonomic core were also identified by their majority presence across the cohort, but with relatively low and stable abundances. A method for quantifying the difference between two cohorts was introduced and applied to samples collected on a second visit, revealing that over time, the oral, skin, and stool body regions tended to be more transient in their taxonomic structure than the vaginal body region. PMID- 23671664 TI - A mathematical model of the mouse ventricular myocyte contraction. AB - Mathematical models of cardiac function at the cellular level include three major components, such as electrical activity, Ca(2+) dynamics, and cellular shortening. We developed a model for mouse ventricular myocyte contraction which is based on our previously published comprehensive models of action potential and Ca(2+) handling mechanisms. The model was verified with extensive experimental data on mouse myocyte contraction at room temperature. In the model, we implemented variable sarcomere length and indirect modulation of the tropomyosin transition rates by Ca(2+) and troponin. The resulting model described well steady-state force-calcium relationships, dependence of the contraction force on the sarcomere length, time course of the contraction force and myocyte shortening, frequency dependence of the contraction force and cellular contraction, and experimentally measured derivatives of the myocyte length variation. We emphasized the importance of the inclusion of variable sarcomere length into a model for ventricular myocyte contraction. Differences in contraction force and cell shortening for epicardial and endocardial ventricular myocytes were investigated. Model applicability for the experimental studies and model limitations were discussed. PMID- 23671665 TI - Identification and characterization of SMARCAL1 protein complexes. AB - SMARCAL1 is an ATPase in the SNF2 family that functions at damaged replication forks to promote their stability and restart. It acts by translocating on DNA to catalyze DNA strand annealing, branch migration, and fork regression. Many SNF2 enzymes work as motor subunits of large protein complexes. To determine if SMARCAL1 is also a member of a protein complex and to further understand how it functions in the replication stress response, we used a proteomics approach to identify interacting proteins. In addition to the previously characterized interaction with replication protein A (RPA), we found that SMARCAL1 forms complexes with several additional proteins including DNA-PKcs and the WRN helicase. SMARCAL1 and WRN co-localize at stalled replication forks independently of one another. The SMARCAL1 interaction with WRN is indirect and is mediated by RPA acting as a scaffold. SMARCAL1 and WRN act independently to prevent MUS81 cleavage of the stalled fork. Biochemical experiments indicate that both catalyze fork regression with SMARCAL1 acting more efficiently and independently of WRN. These data suggest that RPA brings a complex of SMARCAL1 and WRN to stalled forks, but that they may act in different pathways to promote fork repair and restart. PMID- 23671666 TI - Differential distribution of the Ca (2+) regulator Pcp4 in the branchial arches is regulated by Hoxa2. AB - Branchial arches are externally visible tissue bands in the head region of all vertebrate embryos. Although initially formed from similar components, each arch will give rise to different head and neck structures. In a screen designed to characterize the molecular control of branchial arch identity in mouse, we identified Pcp4 as a second branchial arch-specific molecular signature. We further show that the transcription factor Hoxa2 binds to Pcp4 chromatin and regulates Pcp4 expression in the second arch. Hoxa2 is also sufficient to induce Pcp4 expression in anterior first arch cells, which are Pcp4-negative. PMID- 23671667 TI - Structural insights into the UbiD protein family from the crystal structure of PA0254 from Pseudomonas aeruginosa. AB - The 3-polyprenyl-4-hydroxybenzoate decarboxylase (UbiD) catalyzes the conversion of 3-polyprenyl-4-hydroxybenzoate to 2-polyprenylphenol in the biosynthesis of ubiquinone. Pseudomonas aeruginosa contains two genes (PA0254 and PA5237) that are related in sequence to putative UbiD enzymes. A bioinformatics analysis suggests that the UbiD sequence family can be divided into two subclasses, with PA5237 and PA0254 belonging to different branches of this family. The three dimensional structure of PA0254 has been determined using single wavelength anomalous diffraction and molecular replacement in two different crystal forms to resolutions of 1.95 and 2.3 A, respectively. The subunit of PA0254 consists of three domains, an N-terminal alpha/beta domain, a split beta-barrel with a similar fold of a family of flavin reductases and a C-terminal alpha/beta domain with a topology characteristic for the UbiD protein family. The middle domain contains a metal binding site adjacent to a large open cleft that may represent the active site. The two protein ligands binding a magnesium ion, His188 and Glu229, invariant in the PA0254 subclass, are also conserved in a corresponding metal site found in one of the FMN binding proteins from the split beta-barrel fold family. PA0254 forms, in contrast to the hexameric UbiD from E. coli and P. aeruginosa, a homo-dimer. Insertion of four residues in a loop region in the PA0254 type enzymes results in structural differences that are incompatible with hexamer assembly. PMID- 23671668 TI - Tgf-beta1 inhibits Cftr biogenesis and prevents functional rescue of DeltaF508 Cftr in primary differentiated human bronchial epithelial cells. AB - CFTR is an integral transmembrane glycoprotein and a cAMP-activated Cl(-) channel. Mutations in the CFTR gene lead to Cystic Fibrosis (CF)-an autosomal recessive disease with majority of the morbidity and mortality resulting from airway infection, inflammation, and fibrosis. The most common disease-associated mutation in the CFTR gene-deletion of Phe508 (DeltaF508) leads to a biosynthetic processing defect of CFTR. Correction of the defect and delivery of DeltaF508 CFTR to the cell surface has been highly anticipated as a disease modifying therapy. Compared to promising results in cultured cell this approach was much less effective in CF patients in an early clinical trial. Although the cause of failure to rescue DeltaF508-CFTR in the clinical trial has not been determined, presence of factor(s) that interfere with the rescue in vivo could be considered. The cytokine TGF-beta1 is frequently elevated in CF patients. TGF-beta1 has pleiotropic effects in different disease models and genetic backgrounds and little is known about TGF-beta1 effects on CFTR in human airway epithelial cells. Moreover, there are no published studies examining TGF-beta1 effects on the functional rescue of DeltaF508-CFTR. Here we found that TGF-beta1 inhibits CFTR biogenesis by reducing mRNA levels and protein abundance in primary differentiated human bronchial epithelial (HBE) cells from non-CF individuals. TGF-beta1 inhibits CFTR biogenesis without compromising the epithelial phenotype or integrity of HBE cells. TGF-beta1 also inhibits biogenesis and impairs the functional rescue of DeltaF508-CFTR in HBE cells from patients homozygous for the DeltaF508 mutation. Our data indicate that activation of TGF-beta1 signaling may inhibit CFTR function in non-CF individuals and may interfere with therapies directed at correcting the processing defect of DeltaF508-CFTR in CF patients. PMID- 23671669 TI - Prevalence of non-tuberculous mycobacterial infections among tuberculosis suspects in Nigeria. AB - BACKGROUND: Nigeria is ranked in the top five countries for tuberculosis deaths worldwide. This study investigated the mycobacterial agents associated with presumptive clinical pulmonary tuberculosis (TB) in Nigeria and evaluated the pattern and frequency of mycobacterial infections over twelve calendar months period. METHODS: Sputum samples from 1,603 consecutive new cases with presumptive diagnosis of TB were collected from August 2010 to July 2011. All sputum samples were incubated for detection of mycobacterial growth and those with positive acid fast bacilli (AFB) growth were tested to detect mycobacterium tuberculosis (MTB) complex and characterized to differentiate between MTB complex species. Cultures suggestive of Non-tuberculous mycobacterial infections (NTM) were sub-cultured and characterized. RESULTS: Of the 1,603 patients screened, 444 (28%) culture positive cases of pulmonary tuberculosis were identified. Of these, 375 (85%) were due to strains of MTB complex (354 cases of M. tuberculosis, 20 M. africanum and one case of M. bovis) and 69 (15%) were due to infection with NTM. In contrast to the MTB complex cases, the NTM cases were more likely to have been diagnosed during the calendar months of the Harmattan dust season (OR = 2.34, 1.28-4.29; p = 0.01), and aged older than 35 years (OR = 2.77, 1.52-5.02, p = 0.0007), but less likely to have AFB identified on their sputum smear (OR = 0.06, 0.02-0.14, p<0.0001). Among those with NTM infection, cases 35 years or younger were more likely to have co-infection with HIV (3.76, 1.72-8.22; p = 0.0009) compared to those older than 35 years. INTERPRETATION: The high proportion of younger patients with clinical pulmonary TB due to NTM and co-infection with HIV and the likely role of the seasonal dust exposure in the occurrence of the disease, present novel public health challenges for prevention and treatment. PMID- 23671670 TI - Dynamic nucleosome organization at hox promoters during zebrafish embryogenesis. AB - Nucleosome organization at promoter regions plays an important role in regulating gene activity. Genome-wide studies in yeast, flies, worms, mammalian embryonic stem cells and transformed cell lines have found well-positioned nucleosomes flanking a nucleosome depleted region (NDR) at transcription start sites. This nucleosome arrangement depends on DNA sequence (cis-elements) as well as DNA binding factors and ATP-dependent chromatin modifiers (trans-factors). However, little is understood about how the nascent embryonic genome positions nucleosomes during development. This is particularly intriguing since the embryonic genome must undergo a broad reprogramming event upon fusion of sperm and oocyte. Using four stages of early embryonic zebrafish development, we map nucleosome positions at the promoter region of 37 zebrafish hox genes. We find that nucleosome arrangement at the hox promoters is a progressive process that takes place over several stages. At stages immediately after fertilization, nucleosomes appear to be largely disordered at hox promoter regions. At stages after activation of the embryonic genome, nucleosomes are detectable at hox promoters, with positions becoming more uniform and more highly occupied. Since the genomic sequence is invariant during embryogenesis, this progressive change in nucleosome arrangement suggests that trans-factors play an important role in organizing nucleosomes during embryogenesis. Separating hox genes into expressed and non-expressed groups shows that expressed promoters have better positioned and occupied nucleosomes, as well as distinct NDRs, than non-expressed promoters. Finally, by blocking the retinoic acid-signaling pathway, we disrupt early hox gene transcription, but observe no effect on nucleosome positions, suggesting that active hox transcription is not a driving force behind the arrangement of nucleosomes at the promoters of hox genes during early development. PMID- 23671672 TI - Role of sodium in the RprY-dependent stress response in Porphyromonas gingivalis. AB - Porphyromonas gingivalis is a Gram-negative oral anaerobe which is strongly associated with periodontal disease. Environmental changes in the gingival sulcus trigger the growth of P. gingivalis and a concurrent shift from periodontal health to disease. Bacteria adjust their physiology in response to environmental changes and gene regulation by two-component phospho-relay systems is one mechanism by which such adjustments are effected. In P. gingivalis RprY is an orphan response regulator and previously we showed that the RprY regulon included genes associated with oxidative stress and sodium metabolism. The goals of the present study were to identify environmental signals that induce rprY and clarify the role of the regulator in the stress response. In Escherichia coli an RprY LacZ fusion protein was induced in sodium- depleted medium and a P. gingivalis rprY mutant was unable to grow in similar medium. By several approaches we established that sodium depletion induced up-regulation of genes involved in oxidative stress. In addition, we demonstrated that RprY interacted directly with the promoters of several molecular chaperones. Further, both genetic and transcription data suggest that the regulator acts as a repressor. We conclude that RprY is one of the regulators that controls stress responses in P. gingivalis, possibly by acting as a repressor since an rprY mutant showed a superstress reponse in sodium-depleted medium which we propose inhibited growth. PMID- 23671671 TI - gammadelta T cells acquire effector fates in the thymus and differentiate into cytokine-producing effectors in a Listeria model of infection independently of CD28 costimulation. AB - Both antigen recognition and CD28 costimulation are required for the activation of naive alphabeta T cells and their subsequent differentiation into cytokine producing or cytotoxic effectors. Notably, this two-signal paradigm holds true for all alphabeta T cell subsets, regardless of whether they acquire their effector function in the periphery or the thymus. Because of contradictory results, however, it remains unresolved as to whether CD28 costimulation is necessary for gammadelta T cell activation and differentiation. Given that gammadelta T cells have been recently shown to acquire their effector fates in the thymus, it is conceivable that the contradictory results may be explained, in part, by a differential requirement for CD28 costimulation in the development or differentiation of each gammadelta T cell effector subset. To test this, we examined the role of CD28 in gammadelta T cell effector fate determination and function. We report that, although IFNgamma-producing gammadelta T (gammadelta IFNgamma) cells express higher levels of CD28 than IL-17-producing gammadelta T (gammadelta-17) cells, CD28-deficiency had no effect on the thymic development of either subset. Also, following Listeria infection, we found that the expansion and differentiation of gammadelta-17 and gammadelta-IFNgamma effectors were comparable between CD28(+/+) and CD28(-/-) mice. To understand why CD28 costimulation is dispensable for gammadelta T cell activation and differentiation, we assessed glucose uptake and utilization by gammadelta T cells, as CD28 costimulation is known to promote glycolysis in alphabeta T cells. Importantly, we found that gammadelta T cells express higher surface levels of glucose transporters than alphabeta T cells and, when activated, exhibit effector functions over a broader range of glucose concentrations than activated alphabeta T cells. Together, these data not only demonstrate an enhanced glucose metabolism in gammadelta T cells but also provide an explanation for why gammadelta T cells are less dependent on CD28 costimulation than alphabeta T cells. PMID- 23671673 TI - Identifying early inflammatory changes in monocyte-derived macrophages from a population with IQ-discrepant episodic memory. AB - BACKGROUND: Cells of the innate immune system including monocytes and macrophages are the first line of defence against infections and are critical regulators of the inflammatory response. These cells express toll-like receptors (TLRs), innate immune receptors which govern tailored inflammatory gene expression patterns. Monocytes, which produce pro-inflammatory mediators, are readily recruited to the central nervous system (CNS) in neurodegenerative diseases. METHODS: This study explored the expression of receptors (CD11b, TLR2 and TLR4) on circulating monocyte-derived macrophages (MDMs) and peripheral blood mononuclear cells (PBMCs) isolated from healthy elderly adults who we classified as either IQ memory-consistent (high-performing, HP) or IQ memory-discrepant (low-performing, LP). RESULTS: The expression of CD11b, TLR4 and TLR2 was increased in MDMs from the LP group when compared to HP cohort. MDMs from both groups responded robustly to treatment with the TLR4 activator, lipopolysaccharide (LPS), in terms of cytokine production. Significantly, MDMs from the LP group displayed hypersensitivity to LPS exposure. INTERPRETATION: Overall these findings define differential receptor expression and cytokine profiles that occur in MDMs derived from a cohort of IQ memory-discrepant individuals. These changes are indicative of inflammation and may be involved in the prodromal processes leading to the development of neurodegenerative disease. PMID- 23671674 TI - A microarray-based gene expression analysis to identify diagnostic biomarkers for unknown primary cancer. AB - BACKGROUND: The biological basis for cancer of unknown primary (CUP) at the molecular level remains largely unknown, with no evidence of whether a common biological entity exists. Here, we assessed the possibility of identifying a common diagnostic biomarker for CUP using a microarray gene expression analysis. METHODS: Tumor mRNA samples from 60 patients with CUP were analyzed using the Affymetrix U133A Plus 2.0 GeneChip and were normalized by asinh (hyperbolic arc sine) transformation to construct a mean gene-expression profile specific to CUP. A gene-expression profile specific to non-CUP group was constructed using publicly available raw microarray datasets. The t-tests were performed to compare the CUP with non-CUP groups and the top 59 CUP specific genes with the highest fold change were selected (p-value<0.001). RESULTS: Among the 44 genes that were up-regulated in the CUP group, 6 genes for ribosomal proteins were identified. Two of these genes (RPS7 and RPL11) are known to be involved in the Mdm2-p53 pathway. We also identified several genes related to metastasis and apoptosis, suggesting a biological attribute of CUP. CONCLUSIONS: The protein products of the up-regulated and down-regulated genes identified in this study may be clinically useful as unique biomarkers for CUP. PMID- 23671675 TI - Regulation of hedgehog signaling by Myc-interacting zinc finger protein 1, Miz1. AB - Smoothened (Smo) mediated Hedgehog (Hh) signaling plays an essential role in regulating embryonic development and postnatal tissue homeostasis. Aberrant activation of the Hh pathway contributes to the formation and progression of various cancers. In vertebrates, however, key regulatory mechanisms responsible for transducing signals from Smo to the nucleus remain to be delineated. Here, we report the identification of Myc-interacting Zinc finger protein 1 (Miz1) as a Smo and Gli2 binding protein that positively regulates Hh signaling. Overexpression of Miz1 increases Gli luciferase reporter activity, whereas knockdown of endogenous Miz1 has the opposite effect. Activation of Smo induces translocation of Miz1 to the primary cilia together with Smo and Gli2. Furthermore, Miz1 is localized to the nucleus upon Hh activation in a Smo dependent manner, and loss of Miz1 prevents the nuclear translocation of Gli2. More importantly, silencing Miz1 expression inhibits cell proliferation in vitro and the growth of Hh-driven medulloblastoma tumors allografted in SCID mice. Taken together, these results identify Miz1 as a novel regulator in the Hh pathway that plays an important role in mediating Smo-dependent oncogenic signaling. PMID- 23671676 TI - Biological basis of miRNA action when their targets are located in human protein coding region. AB - Recent analyses have revealed many functional microRNA (miRNA) targets in mammalian protein coding regions. But, the mechanisms that ensure miRNA function when their target sites are located in protein coding regions of mammalian mRNA transcripts are largely unknown. In this paper, we investigate some potential biological factors, such as target site accessibility and local translation efficiency. We computationally analyze these two factors using experimentally identified miRNA targets in human protein coding region. We find site accessibility is significantly increased in miRNA target region to facilitate miRNA binding. At the mean time, local translation efficiency is also selectively decreased near miRNA target region. GC-poor codons are preferred in the flank region of miRNA target sites to ease the access of miRNA targets. Within-genome analysis shows substantial variations of site accessibility and local translation efficiency among different miRNA targets in the genome. Further analyses suggest target gene's GC content and conservation level could explain some of the differences in site accessibility. On the other hand, target gene's functional importance and conservation level can affect local translation efficiency near miRNA target region. We hence propose both site accessibility and local translation efficiency are important in miRNA action when miRNA target sites are located in mammalian protein coding regions. PMID- 23671677 TI - Dosimetry for small fields in stereotactic radiosurgery using gafchromic MD-V2-55 film, TLD-100 and alanine dosimeters. AB - This work investigated the suitability of passive dosimeters for reference dosimetry in small fields with acceptable accuracy. Absorbed dose to water rate was determined in nine small radiation fields with diameters between 4 and 35 mm in a Leksell Gamma Knife (LGK) and a modified linear accelerator (linac) for stereotactic radiosurgery treatments. Measurements were made using Gafchromic film (MD-V2-55), alanine and thermoluminescent (TLD-100) dosimeters and compared with conventional dosimetry systems. Detectors were calibrated in terms of absorbed dose to water in (60)Co gamma-ray and 6 MV x-ray reference (10*10 cm(2)) fields using an ionization chamber calibrated at a standards laboratory. Absorbed dose to water rate computed with MD-V2-55 was higher than that obtained with the others dosimeters, possibly due to a smaller volume averaging effect. Ratio between the dose-rates determined with each dosimeter and those obtained with the film was evaluated for both treatment modalities. For the LGK, the ratio decreased as the dosimeter size increased and remained constant for collimator diameters larger than 8 mm. The same behaviour was observed for the linac and the ratio increased with field size, independent of the dosimeter used. These behaviours could be explained as an averaging volume effect due to dose gradient and lack of electronic equilibrium. Evaluation of the output factors for the LGK collimators indicated that, even when agreement was observed between Monte Carlo simulation and measurements with different dosimeters, this does not warrant that the absorbed dose to water rate in the field was properly known and thus, investigation of the reference dosimetry should be an important issue. These results indicated that alanine dosimeter provides a high degree of accuracy but cannot be used in fields smaller than 20 mm diameter. Gafchromic film can be considered as a suitable methodology for reference dosimetry. TLD dosimeters are not appropriate in fields smaller than 10 mm diameters. PMID- 23671678 TI - Poles apart: Arctic and Antarctic Octadecabacter strains share high genome plasticity and a new type of xanthorhodopsin. AB - The genus Octadecabacter is a member of the ubiquitous marine Roseobacter clade. The two described species of this genus, Octadecabacter arcticus and Octadecabacter antarcticus, are psychrophilic and display a bipolar distribution. Here we provide the manually annotated and finished genome sequences of the type strains O. arcticus 238 and O. antarcticus 307, isolated from sea ice of the Arctic and Antarctic, respectively. Both genomes exhibit a high genome plasticity caused by an unusually high density and diversity of transposable elements. This could explain the discrepancy between the low genome synteny and high 16S rRNA gene sequence similarity between both strains. Numerous characteristic features were identified in the Octadecabacter genomes, which show indications of horizontal gene transfer and may represent specific adaptations to the habitats of the strains. These include a gene cluster encoding the synthesis and degradation of cyanophycin in O. arcticus 238, which is absent in O. antarcticus 307 and unique among the Roseobacter clade. Furthermore, genes representing a new subgroup of xanthorhodopsins as an adaptation to icy environments are present in both Octadecabacter strains. This new xanthorhodopsin subgroup differs from the previously characterized xanthorhodopsins of Salinibacter ruber and Gloeobacter violaceus in phylogeny, biogeography and the potential to bind 4-keto carotenoids. Biochemical characterization of the Octadecabacter xanthorhodopsins revealed that they function as light-driven proton pumps. PMID- 23671679 TI - Social and geographical inequalities in suicide in Japan from 1975 through 2005: a census-based longitudinal analysis. AB - BACKGROUND: Despite advances in our understanding of the countercyclical association between economic contraction and suicide, less is known about the levels of and changes in inequalities in suicide. The authors examined social and geographical inequalities in suicide in Japan from 1975 through 2005. METHODS: Based on quinquennial vital statistics and census data, the authors analyzed the entire population aged 25-64 years. The total number of suicides was 75,840 men and 30,487 women. For each sex, the authors estimated odds ratios (ORs) and 95% credible intervals (CIs) for suicide using multilevel logistic regression models with "cells" (cross-tabulated by age and occupation) at level 1, seven different years at level 2, and 47 prefectures at level 3. Prefecture-level variance was used as an estimate of geographical inequalities in suicide. RESULTS: Adjusting for age and time-trends, the lowest odds for suicide was observed among production process and related workers (the reference group) in both sexes. The highest OR for men was 2.52 (95% CI: 2.43, 2.61) among service workers, whereas the highest OR for women was 9.24 (95% CI: 7.03, 12.13) among security workers. The degree of occupational inequalities increased among men with a striking change in the pattern. Among women, we observed a steady decline in suicide risk across all occupations, except for administrative and managerial workers and transport and communication workers. After adjusting for individual age, occupation, and time-trends, prefecture-specific ORs ranged from 0.76 (Nara Prefecture) to 1.36 (Akita Prefecture) for men and from 0.79 (Kanagawa Prefecture) to 1.22 (Akita Prefecture) for women. Geographical inequalities have increased primarily among men since 1995. CONCLUSIONS: The present findings demonstrate a striking temporal change in the pattern of social inequalities in suicide among men. Further, geographical inequalities in suicide have considerably increased across 47 prefectures, primarily among men, since 1995. PMID- 23671680 TI - Galphao is required for L-canavanine detection in Drosophila. AB - Taste is an essential sense for the survival of most organisms. In insects, taste is particularly important as it allows to detect and avoid ingesting many plant toxins, such as L-canavanine. We previously showed that L-canavanine is toxic for Drosophila melanogaster and that flies are able to detect this toxin in the food. L-canavanine is a ligand of DmXR, a variant G-protein coupled receptor (GPCR) belonging to the metabotropic glutamate receptor subfamily that is expressed in bitter-sensitive taste neurons of Drosophila. To transduce the signal intracellularly, GPCR activate heterotrimeric G proteins constituted of alpha, beta and gamma subunits. The aim of this study was to identify which Galpha protein was required for L-canavanine detection in Drosophila. By using a pharmacological approach, we first demonstrated that DmXR has the best coupling with Galphao protein subtype. Then, by using genetic, behavioral assays and electrophysiology, we found that Galphao47A is required in bitter-sensitive taste neurons for L-canavanine sensitivity. In conclusion, our study revealed that Galphao47A plays a crucial role in L-canavanine detection. PMID- 23671681 TI - Reversal of hyperglycemia by insulin-secreting rat bone marrow- and blastocyst derived hypoblast stem cell-like cells. AB - beta-cell replacement may efficiently cure type 1 diabetic (T1D) patients whose insulin-secreting beta-cells have been selectively destroyed by autoantigen reactive T cells. To generate insulin-secreting cells we used two cell sources: rat multipotent adult progenitor cells (rMAPC) and the highly similar rat extra embryonic endoderm precursor (rXEN-P) cells isolated under rMAPC conditions from blastocysts (rHypoSC). rMAPC/rHypoSC were sequentially committed to definitive endoderm, pancreatic endoderm, and beta-cell like cells. On day 21, 20% of rMAPC/rHypoSC progeny expressed Pdx1 and C-peptide. rMAPCr/HypoSC progeny secreted C-peptide under the stimulus of insulin agonist carbachol, and was inhibited by the L-type voltage-dependent calcium channel blocker nifedipine. When rMAPC or rHypoSC differentiated d21 progeny were grafted under the kidney capsule of streptozotocin-induced diabetic nude mice, hyperglycemia reversed after 4 weeks in 6/10 rMAPC- and 5/10 rHypoSC-transplanted mice. Hyperglycemia recurred within 24 hours of graft removal and the histological analysis of the retrieved grafts revealed presence of Pdx1-, Nkx6.1- and C-peptide-positive cells. The ability of both rMAPC and HypoSC to differentiate to functional beta cell like cells may serve to gain insight into signals that govern beta-cell differentiation and aid in developing culture systems to commit other (pluripotent) stem cells to clinically useful beta-cells for cell therapy of T1D. PMID- 23671682 TI - Reforestation sites show similar and nested AMF communities to an adjacent pristine forest in a tropical mountain area of South Ecuador. AB - Arbuscular mycorrhizae are important for growth and survival of tropical trees. We studied the community of arbuscular mycorrhizal fungi in a tropical mountain rain forest and in neighbouring reforestation plots in the area of Reserva Biologica San Francisco (South Ecuador). The arbuscular mycorrhizal fungi were analysed with molecular methods sequencing part of the 18 S rDNA. The sequences were classified as Operational Taxonomic Units (OTUs). We found high fungal species richness with OTUs belonging to Glomerales, Diversisporales and Archaeosporales. Despite intensive sampling, the rarefaction curves are still unsaturated for the pristine forest and the reforestation plots. The communities consisted of few frequent and many rare species. No specific interactions are recognizable. The plant individuals are associated with one to ten arbuscular mycorrhizal fungi and mostly with one to four. The fungal compositions associated with single plant individuals show a great variability and variety within one plant species. Planted and naturally occurring plants show high similarities in their fungal communities. Pristine forest and reforestation plots showed similar richness, similar diversity and a significantly nested structure of plant-AMF community. The results indicate that small-scale fragmentation presently found in this area has not destroyed the natural AMF community, at least yet. Thus, the regeneration potential of natural forest vegetation at the tested sites is not inhibited by a lack of appropriate mycobionts. PMID- 23671683 TI - Are coastal protected areas always effective in achieving population recovery for nesting sea turtles? AB - Sea turtles are highly migratory and usually dispersed, but aggregate off beaches during the nesting season, rendering them vulnerable to coastal threats. Consequently, coastal Marine Protection Areas (MPAs) have been used to facilitate the recovery of turtle populations, but the effectiveness of these programs is uncertain as most have been operating for less than a single turtle generation (or<20 yr). South Africa, however, hosts one of the longest running conservation programs, protecting nesting loggerhead (Caretta caretta) and leatherback (Dermochelys coriacea) turtles since 1963 in a series of coastal MPAs. This provides a unique opportunity to evaluate the long-term effect of spatial protection on the abundance of two highly migratory turtle species with different life history characteristics. Population responses were assessed by modeling the number of nests over time in an index area (13 km) and an expanded monitoring area (53 km) with varying survey effort. Loggerhead abundance increased dramatically from~250 to>1700 nests pa (index area) especially over the last decade, while leatherback abundance increased initially~10 to 70 nests pa (index area), but then stabilized. Although leatherbacks have higher reproductive output per female and comparable remigration periods and hatching success to loggerheads, the leatherback population failed to expand. Our results suggest that coastal MPAs can work but do not guarantee the recovery of sea turtle populations as pressures change over time. Causes considered for the lack of population growth include factors in the MPA (expansion into unmonitored areas or incubation environment) of outside of the MPA (including carrying capacity and fishing mortality). Conservation areas for migratory species thus require careful design to account for species-specific needs, and need to be monitored to keep track of changing pressures. PMID- 23671684 TI - Enrichment of GABARAP relative to LC3 in the axonal initial segments of neurons. AB - GABAA receptor-associated protein (GABARAP) was initially identified as a protein that interacts with GABAA receptor. Although LC3 (microtubule-associated protein 1 light chain 3), a GABARAP homolog, has been localized in the dendrites and cell bodies of neurons under normal conditions, the subcellular distribution of GABARAP in neurons remains unclear. Subcellular fractionation indicated that endogenous GABARAP was localized to the microsome-enriched and synaptic vesicle enriched fractions of mouse brain as GABARAP-I, an unlipidated form. To investigate the distribution of GABARAP in neurons, we generated GFP-GABARAP transgenic mice. Immunohistochemistry in these transgenic mice showed that positive signals for GFP-GABARAP were widely distributed in neurons in various brain regions, including the hippocampus and cerebellum. Interestingly, intense diffuse and/or fibrillary expression of GFP-GABARAP was detected along the axonal initial segments (AIS) of hippocampal pyramidal neurons and cerebellar Purkinje cells, in addition to the cell bodies and dendrites of these neurons. In contrast, only slight amounts of LC3 were detected along the AIS of these neurons, while diffuse and/or fibrillary staining for LC3 was mainly detected in their cell bodies and dendrites. These results indicated that, compared with LC3, GABARAP is enriched in the AIS, in addition to the cell bodies and dendrites, of these hippocampal pyramidal neurons and cerebellar Purkinje cells. PMID- 23671685 TI - Identifying optimal vaccination strategies for serogroup A Neisseria meningitidis conjugate vaccine in the African meningitis belt. AB - OBJECTIVE: The optimal long-term vaccination strategies to provide population level protection against serogroup A Neisseria meningitidis (MenA) are unknown. We developed an age-structured mathematical model of MenA transmission, colonization, and disease in the African meningitis belt, and used this model to explore the impact of various vaccination strategies. METHODS: The model stratifies the simulated population into groups based on age, infection status, and MenA antibody levels. We defined the model parameters (such as birth and death rates, age-specific incidence rates, and age-specific duration of protection) using published data and maximum likelihood estimation. We assessed the validity of the model by comparing simulated incidence of invasive MenA and prevalence of MenA carriage to observed incidence and carriage data. RESULTS: The model fit well to observed age- and season-specific prevalence of carriage (mean pseudo-R2 0.84) and incidence of invasive disease (mean R2 0.89). The model is able to reproduce the observed dynamics of MenA epidemics in the African meningitis belt, including seasonal increases in incidence, with large epidemics occurring every eight to twelve years. Following a mass vaccination campaign of all persons 1-29 years of age, the most effective modeled vaccination strategy is to conduct mass vaccination campaigns every 5 years for children 1-5 years of age. Less frequent campaigns covering broader age groups would also be effective, although somewhat less so. Introducing conjugate MenA vaccine into the EPI vaccination schedule at 9 months of age results in higher predicted incidence than periodic mass campaigns. DISCUSSION: We have developed the first mathematical model of MenA in Africa to incorporate age structures and progressively waning protection over time. Our model accurately reproduces key features of MenA epidemiology in the African meningitis belt. This model can help policy makers consider vaccine program effectiveness when determining the feasibility and benefits of MenA vaccination strategies. PMID- 23671686 TI - Optimal predator risk assessment by the sonar-jamming arctiine moth Bertholdia trigona. AB - Nearly all animals face a tradeoff between seeking food and mates and avoiding predation. Optimal escape theory holds that an animal confronted with a predator should only flee when benefits of flight (increased survival) outweigh the costs (energetic costs, lost foraging time, etc.). We propose a model for prey risk assessment based on the predator's stage of attack. Risk level should increase rapidly from when the predator detects the prey to when it commits to the attack. We tested this hypothesis using a predator--the echolocating bat--whose active biosonar reveals its stage of attack. We used a prey defense--clicking used for sonar jamming by the tiger moth Bertholdia trigona--that can be readily studied in the field and laboratory and is enacted simultaneously with evasive flight. We predicted that prey employ defenses soon after being detected and targeted, and that prey defensive thresholds discriminate between legitimate predatory threats and false threats where a nearby prey is attacked. Laboratory and field experiments using playbacks of ultrasound signals and naturally behaving bats, respectively, confirmed our predictions. Moths clicked soon after bats detected and targeted them. Also, B. trigona clicking thresholds closely matched predicted optimal thresholds for discriminating legitimate and false predator threats for bats using search and approach phase echolocation--the period when bats are searching for and assessing prey. To our knowledge, this is the first quantitative study to correlate the sensory stimuli that trigger defensive behaviors with measurements of signals provided by predators during natural attacks in the field. We propose theoretical models for explaining prey risk assessment depending on the availability of cues that reveal a predator's stage of attack. PMID- 23671687 TI - Large-scale modelling of the divergent spectrin repeats in nesprins: giant modular proteins. AB - Nesprin-1 and nesprin-2 are nuclear envelope (NE) proteins characterized by a common structure of an SR (spectrin repeat) rod domain and a C-terminal transmembrane KASH [Klarsicht-ANC-Syne-homology] domain and display N-terminal actin-binding CH (calponin homology) domains. Mutations in these proteins have been described in Emery-Dreifuss muscular dystrophy and attributed to disruptions of interactions at the NE with nesprins binding partners, lamin A/C and emerin. Evolutionary analysis of the rod domains of the nesprins has shown that they are almost entirely composed of unbroken SR-like structures. We present a bioinformatical approach to accurate definition of the boundaries of each SR by comparison with canonical SR structures, allowing for a large-scale homology modelling of the 74 nesprin-1 and 56 nesprin-2 SRs. The exposed and evolutionary conserved residues identify important pbs for protein-protein interactions that can guide tailored binding experiments. Most importantly, the bioinformatics analyses and the 3D models have been central to the design of selected constructs for protein expression. 1D NMR and CD spectra have been performed of the expressed SRs, showing a folded, stable, high content alpha-helical structure, typical of SRs. Molecular Dynamics simulations have been performed to study the structural and elastic properties of consecutive SRs, revealing insights in the mechanical properties adopted by these modules in the cell. PMID- 23671688 TI - Presence of adenovirus species C in infiltrating lymphocytes of human sarcoma. AB - Human adenoviruses are known to persist in T-lymphocytes of tonsils, adenoids and intestinal tract. The oncogenic potential of different adenovirus types has been widely studied in rodents, in which adenovirus inoculation can induce multiple tumors such as undifferentiated sarcomas, adenocarcinomas and neuroectodermal tumors. However, the oncogenic potential of this virus has never been proven in human subjects. Using a highly sensitive broad-spectrum qRT-PCR, we have screened a set of different human sarcomas including leiomyosarcoma, liposarcoma and gastro intestinal stroma tumors. Primers binding the viral oncogene E1A and the capsid-coding gene Hexon were used to detect the presence of adenovirus DNA in tumor samples. We found that 18% of the tested leiomyosarcomas and 35% of the liposarcomas were positive for the presence of adenovirus DNA, being species C types the most frequently detected adenoviruses. However, only in one sample of the gastro intestinal stroma tumors the virus DNA could be detected. The occurrence of adenovirus in the tumor sections was confirmed by subsequent fluorescence in-situ-hybridization analysis and co-staining with the transcription factor Bcl11b gives evidence for the presence of the virus in infiltrating T-lymphocytes within the tumors. Together these data underline, for the first time, the persistence of adenovirus in T-lymphocytes infiltrated in muscular and fatty tissue tumor samples. If an impaired immune system leads to the viral persistence and reactivation of the virus is involved in additional diseases needs further investigation. PMID- 23671689 TI - The sRNA RyhB regulates the synthesis of the Escherichia coli methionine sulfoxide reductase MsrB but not MsrA. AB - Controlling iron homeostasis is crucial for all aerobically grown living cells that are exposed to oxidative damage by reactive oxygen species (ROS), as free iron increases the production of ROS. Methionine sulfoxide reductases (Msr) are key enzymes in repairing ROS-mediated damage to proteins, as they reduce oxidized methionine (MetSO) residues to methionine. E. coli synthesizes two Msr, A and B, which exhibit substrate diastereospecificity. The bacterial iron-responsive small RNA (sRNA) RyhB controls iron metabolism by modulating intracellular iron usage. We show in this paper that RyhB is a direct regulator of the msrB gene that encodes the MsrB enzyme. RyhB down-regulates msrB transcripts along with Hfq and RNaseE proteins since mutations in the ryhB, fur, hfq, or RNaseE-encoded genes resulted in iron-insensitive expression of msrB. Our results show that RyhB binds to two sequences within the short 5'UTR of msrB mRNA as identified by reverse transcriptase and RNase and lead (II) protection assays. Toeprinting analysis shows that RyhB pairing to msrB mRNA prevents efficient ribosome binding and thereby inhibits translation initiation. In vivo site directed-mutagenesis experiments in the msrB 5'UTR region indicate that both RyhB-pairing sites are required to decrease msrB expression. Thus, this study suggests a novel mechanism of translational regulation where a same sRNA can basepair to two different locations within the same mRNA species. In contrast, expression of msrA is not influenced by changes in iron levels. PMID- 23671690 TI - An 11bp region with stem formation potential is essential for de novo DNA methylation of the RPS element. AB - The initiation of DNA methylation in Arabidopsis is controlled by the RNA directed DNA methylation (RdDM) pathway that uses 24nt siRNAs to recruit de novo methyltransferase DRM2 to the target site. We previously described the REPETITIVE PETUNIA SEQUENCE (RPS) fragment that acts as a hot spot for de novo methylation, for which it requires the cooperative activity of all three methyltransferases MET1, CMT3 and DRM2, but not the RdDM pathway. RPS contains two identical 11nt elements in inverted orientation, interrupted by a 18nt spacer, which resembles the features of a stemloop structure. The analysis of deletion/substitution derivatives of this region showed that deletion of one 11nt element RPS is sufficient to eliminate de novo methylation of RPS. In addition, deletion of a 10nt region directly adjacent to one of the 11nt elements, significantly reduced de novo methylation. When both 11nt regions were replaced by two 11nt elements with altered DNA sequence but unchanged inverted repeat homology, DNA methylation was not affected, indicating that de novo methylation was not targeted to a specific DNA sequence element. These data suggest that de novo DNA methylation is attracted by a secondary structure to which the two 11nt elements contribute, and that the adjacent 10nt region influences the stability of this structure. This resembles the recognition of structural features by DNA methyltransferases in animals and suggests that similar mechanisms exist in plants. PMID- 23671691 TI - Pre-attentive, context-specific representation of fear memory in the auditory cortex of rat. AB - Neural representation in the auditory cortex is rapidly modulated by both top down attention and bottom-up stimulus properties, in order to improve perception in a given context. Learning-induced, pre-attentive, map plasticity has been also studied in the anesthetized cortex; however, little attention has been paid to rapid, context-dependent modulation. We hypothesize that context-specific learning leads to pre-attentively modulated, multiplex representation in the auditory cortex. Here, we investigate map plasticity in the auditory cortices of anesthetized rats conditioned in a context-dependent manner, such that a conditioned stimulus (CS) of a 20-kHz tone and an unconditioned stimulus (US) of a mild electrical shock were associated only under a noisy auditory context, but not in silence. After the conditioning, although no distinct plasticity was found in the tonotopic map, tone-evoked responses were more noise-resistive than pre conditioning. Yet, the conditioned group showed a reduced spread of activation to each tone with noise, but not with silence, associated with a sharpening of frequency tuning. The encoding accuracy index of neurons showed that conditioning deteriorated the accuracy of tone-frequency representations in noisy condition at off-CS regions, but not at CS regions, suggesting that arbitrary tones around the frequency of the CS were more likely perceived as the CS in a specific context, where CS was associated with US. These results together demonstrate that learning induced plasticity in the auditory cortex occurs in a context-dependent manner. PMID- 23671692 TI - Fasting induced cytoplasmic Fto expression in some neurons of rat hypothalamus. AB - Fat mass and obesity associated protein (Fto) is a nucleic acid demethylase, with a preference for thymine or uracil, according to the recent structural data. This fact suggests that methylated single-stranded RNA, rather than DNA, may be the primary Fto substrate. Fto is abundantly expressed in all hypothalamic sites governing feeding behavior. Considering that selective modulation of Fto levels in the hypothalamus can influence food intake, we set out to investigate the effect of 48 h fasting on the Fto expression in lateral hypothalamic area, paraventricular, ventromedial and arcuate nucleus, the regulatory centres of energy homeostasis. We have demonstrated that 48 h fasting causes not only an increase in the overall hypothalamic levels of both Fto mRNA and protein, but also alters Fto intracellular distribution. This switch happens in some neurons of paraventricular and ventromedial nucleus, as well as lateral hypothalamic area, resulting in the majority of the enzyme being localized outside the cell nuclei. Interestingly, the change in the Fto intracellular localization was not observed in neurons of arcuate nucleus, suggesting that fasting did not universally affect Fto in all of the hypothalmic sites involved in energy homeostasis regulation. Both Fto mRNA and catechol-O-methyltransferaze mRNA were upregulated in the identical time-dependent manner in fasting animals. This fact, combined with the knowledge of the Fto substrate preference, may provide further insight into monoamine metabolism in the state of disturbed energy homeostasis. PMID- 23671693 TI - Event-related potentials elicited by pre-attentive emotional changes in temporal context. AB - The ability to detect emotional change in the environment is essential for adaptive behavior. The current study investigated whether event-related potentials (ERPs) can reflect emotional change in a visual sequence. To assess pre-attentive processing, we examined visual mismatch negativity (vMMN): the negative potentials elicited by a deviant (infrequent) stimulus embedded in a sequence of standard (frequent) stimuli. Participants in two experiments pre attentively viewed visual sequences of Japanese kanji with different emotional connotations while ERPs were recorded. The visual sequence in Experiment 1 consisted of neutral standards and two types of emotional deviants with a strong and weak intensity. Although the results indicated that strongly emotional deviants elicited more occipital negativity than neutral standards, it was unclear whether these negativities were derived from emotional deviation in the sequence or from the emotional significance of the deviants themselves. In Experiment 2, the two identical emotional deviants were presented against different emotional standards. One type of deviants was emotionally incongruent with the standard and the other type of deviants was emotionally congruent with the standard. The results indicated that occipital negativities elicited by deviants resulted from perceptual changes in a visual sequence at a latency of 100-200 ms and from emotional changes at latencies of 200-260 ms. Contrary to the results of the ERP experiment, reaction times to deviants showed no effect of emotional context; negative stimuli were consistently detected more rapidly than were positive stimuli. Taken together, the results suggest that brain signals can reflect emotional change in a temporal context. PMID- 23671694 TI - Analysis of effects of meteorological factors on dengue incidence in Sri Lanka using time series data. AB - In tropical and subtropical regions of eastern and South-eastern Asia, dengue fever (DF) and dengue hemorrhagic fever (DHF) outbreaks occur frequently. Previous studies indicate an association between meteorological variables and dengue incidence using time series analyses. The impacts of meteorological changes can affect dengue outbreak. However, difficulties in collecting detailed time series data in developing countries have led to common use of monthly data in most previous studies. In addition, time series analyses are often limited to one area because of the difficulty in collecting meteorological and dengue incidence data in multiple areas. To gain better understanding, we examined the effects of meteorological factors on dengue incidence in three geographically distinct areas (Ratnapura, Colombo, and Anuradhapura) of Sri Lanka by time series analysis of weekly data. The weekly average maximum temperature and total rainfall and the total number of dengue cases from 2005 to 2011 (7 years) were used as time series data in this study. Subsequently, time series analyses were performed on the basis of ordinary least squares regression analysis followed by the vector autoregressive model (VAR). In conclusion, weekly average maximum temperatures and the weekly total rainfall did not significantly affect dengue incidence in three geographically different areas of Sri Lanka. However, the weekly total rainfall slightly influenced dengue incidence in the cities of Colombo and Anuradhapura. PMID- 23671695 TI - TSHZ3 and SOX9 regulate the timing of smooth muscle cell differentiation in the ureter by reducing myocardin activity. AB - Smooth muscle cells are of key importance for the proper functioning of different visceral organs including those of the urogenital system. In the mouse ureter, the two transcriptional regulators TSHZ3 and SOX9 are independently required for initiation of smooth muscle differentiation from uncommitted mesenchymal precursor cells. However, it has remained unclear whether TSHZ3 and SOX9 act independently or as part of a larger regulatory network. Here, we set out to characterize the molecular function of TSHZ3 in the differentiation of the ureteric mesenchyme. Using a yeast-two-hybrid screen, we identified SOX9 as an interacting protein. We show that TSHZ3 also binds to the master regulator of the smooth muscle program, MYOCD, and displaces it from the coregulator SRF, thereby disrupting the activation of smooth muscle specific genes. We found that the initiation of the expression of smooth muscle specific genes in MYOCD-positive ureteric mesenchyme coincides with the down regulation of Sox9 expression, identifying SOX9 as a possible negative regulator of smooth muscle cell differentiation. To test this hypothesis, we prolonged the expression of Sox9 in the ureteric mesenchyme in vivo. We found that Sox9 does not affect Myocd expression but significantly reduces the expression of MYOCD/SRF-dependent smooth muscle genes, suggesting that down-regulation of Sox9 is a prerequisite for MYOCD activity. We propose that the dynamic expression of Sox9 and the interaction between TSHZ3, SOX9 and MYOCD provide a mechanism that regulates the pace of progression of the myogenic program in the ureter. PMID- 23671697 TI - Nonstructural protein NS80 is crucial in recruiting viral components to form aquareoviral factories. AB - BACKGROUND: Replication and assembly of vertebrate reoviruses occur in specific intracellular compartments known as viral factories. Recently, NS88 and NS80, the nonstructural proteins from aquareoviruses, have been proposed to share common traits with uNS from orthoreoviruses, which are involved in the formation of viral factories. METHODOLOGY/PRINCIPAL FINDINGS: In this study, the NS80 characteristics and its interactions with other viral components were investigated. We observed that the NS80 structure ensured its self-aggregation and selective recruitment of viral proteins to viral factories like structures (VFLS). The minimum amino acids (aa) of NS80 required for VFLS formation included 193 aa at the C-terminal. However, this truncated protein only contained one aa coil and located in the nucleus. Its N-terminal residual regions, aa 1-55 and aa 55-85, were required for recruiting viral nonstructural protein NS38 and structural protein VP3, respectively. A conserved N-terminal region of NS38, which was responsible for the interaction with NS80, was also identified. Moreover, the minimal region of C-terminal residues, aa 506-742 (Delta505), required for NS80 self-aggregation in the cytoplasm, and aa 550-742 (Delta549), which are sufficient for recruiting viral structure proteins VP1, VP2, and VP4 were also identified. CONCLUSIONS/SIGNIFICANCE: The present study shows detailed interactions between NS80 and NS38 or other viral proteins. Sequence and structure characteristics of NS80 ensures its self-aggregation to form VFLS (either in the cytoplasm or nucleus) and recruitment of viral structural or nonstructural proteins. PMID- 23671696 TI - Use of a glycolipid inhibitor to ameliorate renal cancer in a mouse model. AB - In a xenograft model wherein, live renal cancer cells were implanted under the kidney capsule in mice, revealed a 30-fold increase in tumor volume over a period of 26 days and this was accompanied with a 32-fold increase in the level of lactosylceramide (LacCer). Mice fed D- threo-1-phenyl-2-decanoylamino-3 morpholino-1-propanol (D-PDMP), an inhibitor of glucosylceramide synthase and lactosylceramide synthase (LCS: beta-1,4-GalT-V), showed marked reduction in tumor volume. This was accompanied by a decrease in the mass of lactosylceramide and an increase in glucosylceramide (GlcCer) level. Mechanistic studies revealed that D-PDMP inhibited cell proliferation and angiogenesis by inhibiting p44MAPK, p-AKT-1 pathway and mammalian target for rapamycin (mTOR). By linking glycosphingolipid synthesis with tumor growth, renal cancer progression and regression can be evaluated. Thus inhibiting glycosphingolipid synthesis can be a bonafide target to prevent the progression of other types of cancer. PMID- 23671698 TI - Transcriptome sequencing and de novo analysis of the copepod Calanus sinicus using 454 GS FLX. AB - BACKGROUND: Despite their species abundance and primary economic importance, genomic information about copepods is still limited. In particular, genomic resources are lacking for the copepod Calanus sinicus, which is a dominant species in the coastal waters of East Asia. In this study, we performed de novo transcriptome sequencing to produce a large number of expressed sequence tags for the copepod C. sinicus. RESULTS: Copepodid larvae and adults were used as the basic material for transcriptome sequencing. Using 454 pyrosequencing, a total of 1,470,799 reads were obtained, which were assembled into 56,809 high quality expressed sequence tags. Based on their sequence similarity to known proteins, about 14,000 different genes were identified, including members of all major conserved signaling pathways. Transcripts that were putatively involved with growth, lipid metabolism, molting, and diapause were also identified among these genes. Differentially expressed genes related to several processes were found in C. sinicus copepodid larvae and adults. We detected 284,154 single nucleotide polymorphisms (SNPs) that provide a resource for gene function studies. CONCLUSION: Our data provide the most comprehensive transcriptome resource available for C. sinicus. This resource allowed us to identify genes associated with primary physiological processes and SNPs in coding regions, which facilitated the quantitative analysis of differential gene expression. These data should provide foundation for future genetic and genomic studies of this and related species. PMID- 23671699 TI - Cortical dynamics during the preparation of antisaccadic and prosaccadic eye movements in humans in a gap paradigm. AB - To compare the cortical dynamics of different oculomotor tasks, EEG and eye movements were recorded in 21 volunteers. Using a comprehensive approach, subjects were asked to perform saccadic tasks, which included a saccadic eye movement to a peripheral target (prosaccadic), a movement to the opposite side (antisaccadic), or maintain the gaze fixed (no-go). In mixed trials, prosaccadic, antisaccadic and no-go tasks were indicated by a color square (S1) present for 1900-2500 ms (instructive period). S1 disappeared for 370 ms (gap) and a black dot at 8 deg at right or left indicated the beginning of the task. Reaction times, amplitude of eye movements and number of errors were greatest in antisaccadic tasks, suggesting a greater difficulty. The EEG showed a contingent negativity variation (CNV) that increased progressively along the instructive period and suddenly during the gap: higher in antisaccadic, followed by prosaccadic and no-go tasks. Principal component analysis (PCA) disentangled fronto-central and occipital CNV-related and fronto-central gap-related components. The instructive period was characterized by fronto-central and occipital beta desynchronization (ERD) higher in antisaccadic than in no-go and parieto-occipital alpha synchronization higher in no-go than in antisaccadic tasks. During the gap, parieto-occipital beta and alpha ERD were higher in antisaccadic compared to no-go. The gap was further characterized by a fronto central increase of inter-trial coherence in theta: highest during antisaccadic, followed by prosaccadic and no-go tasks. This phase locking in theta was also accompanied by theta ERS, which was significantly higher in antisaccadic than in the other two tasks. In PCA of spectral power two main components had dynamics similar to those extracted from voltage data, suggesting cross-frequency coupling. These results suggest that the more difficult saccadic tasks are associated with top-down control mediated by frontal cortex, while simpler tasks rely more on bottom-up control mediated by posterior cortices. PMID- 23671700 TI - Analysis of antiviral response in human epithelial cells infected with hepatitis E virus. AB - Hepatitis E virus (HEV) is a major cause of enterically transmitted acute hepatitis in developing nations and occurs in sporadic and epidemic forms. The disease may become severe with high mortality (20%) among pregnant women. Due to lack of efficient cell culture system and small animal model, early molecular events of HEV infection are not yet known. In the present study, human lung epithelial cells, A549, were infected with HEV to monitor expression levels of genes/proteins in antiviral pathways. Both live and UV inactivated virus elicited robust induction of inflammatory cytokines/chemokines such as IL-6, IL-8, TNF alpha, and RANTES within 12 h of infection. Cells exposed to soluble capsid protein showed no induction suggesting the capsid structure and not the protein being detected as the pathogen pattern by cells. A delayed up-regulation of type I interferon genes only by the live virus at 48 h post HEV infection indicated the need of virus replication. However, absence of secreted interferons till 96 h suggested possible involvement of post-transcriptional regulation of type I IFN expression. HEV infected cells showed activation of both NF-kappaB and IRF3 transcription factors when seen at protein levels; however, reporter gene assays showed predominant expression via NF-kappaB promoter as compared to IRF3 promoter. Knockdown experiments done using siRNAs showed involvement of MyD88 and TRIF adaptors in generating antiviral response thus indicating role of TLR2, TLR4 and TLR3 in sensing viral molecules. MAVS knockdown surprisingly enhanced only proinflammatory cytokines and not type I IFNs. This suggested that HEV not only down-regulates RIG-I helicase like receptor mediated IFN induction but also employs MAVS in curtailing host inflammatory response. Our findings uncover an early cellular response in HEV infection and associated molecular mechanisms suggesting the potential role of inflammatory response triggered by HEV infection in host immune response and pathogenesis. PMID- 23671701 TI - A comparison of the contractile properties of myometrium from singleton and twin pregnancies. AB - OBJECTIVE: Over half of twin pregnancies in US and UK deliver prematurely but the reasons for this are unclear. The contractility of myometrium from twin pregnancies has not been directly investigated. The objective of this research was to determine if there are differences in the contractile activity and response to oxytocin, between myometrium from singleton and twin pregnancies, across a range of gestational ages. Furthermore, we wished to determine if contractile activity correlates with increasing level of stretch, using neonatal birth weights as a marker of uterine stretch. METHODS: This was an in vitro, laboratory based study of myometrial contractility in women pregnant with one or two babies, using biopsies obtained from non-labouring women undergoing Caesarean section. Spontaneous, oxytocin-stimulated and depolarization induced contractile activity was compared. RESULTS: Direct measurements of myometrial contractility under controlled conditions show that the frequency of contractions and responses to oxytocin are significantly increased in twins compared to singletons. The duration of contraction however was significantly reduced. We find that contractile activity correlates with increasing levels of stretch, using neonatal birth weights as a surrogate for uterine stretch, with response to oxytocin being significantly positively correlated with birth weight. CONCLUSIONS: We have found significant differences in contractile properties between myometrium from singleton and twin pregnancies and that increasing uterine stretch can alter the contractile properties of myometrium. We discuss the implication of these findings to preterm delivery and future studies. PMID- 23671702 TI - Curcumin nanoparticles ameliorate ICAM-1 expression in TNF-alpha-treated lung epithelial cells through p47 (phox) and MAPKs/AP-1 pathways. AB - Upregulation of intercellular adhesion molecule-1 (ICAM-1) involves adhesions between both circulating and resident leukocytes and the human lung epithelial cells during lung inflammatory reactions. We have previously demonstrated that curcumin-loaded polyvinylpyrrolidone nanoparticles (CURN) improve the anti inflammatory and anti-oxidative properties of curcumin in hepatocytes. In this study, we focused on the effects of CURN on the expression of ICAM-1 in TNF-alpha treated lung epithelial cells and compared these to the effects of curcumin water preparation (CURH). TNF-alphainduced ICAM-1 expression, ROS production, and cell cell adhesion were significantly attenuated by the pretreatment with antioxidants (DPI, APO, or NAC) and CURN, but not by CURH, as revealed by western blot analysis, RT-PCR, promoter assay, and ROS detection and adhesion assay. In addition, treatment of TNF-alpha-treated cells with CURN and antioxidants also resulted in an inhibition of activation of p47 (phox) and phosphorylation of MAPKs, as compared to that using CURH. Our findings also suggest that phosphorylation of MAPKs may eventually lead to the activation of transcription factors. We also observed that the effects of TNF-alpha treatment for 30 min, which includes a significant increase in the binding activity of AP-1 and phosphorylation of c-jun and c-fos genes, were reduced by CURN treatment. In vivo studies have revealed that CURN improved the anti-inflammation activities of CURH in the lung epithelial cells of TNF-alpha-treated mice. Our results indicate that curcumin-loaded polyvinylpyrrolidone nanoparticles may potentially serve as an anti-inflammatory drug for the treatment of respiratory diseases. PMID- 23671703 TI - Fidelity index determination of DNA methyltransferases. AB - DNA methylation is the most frequent form of epigenetic modification in the cell, which involves gene regulation in eukaryotes and protection against restriction enzymes in prokaryotes. Even though many methyltransferases exclusively modify their cognate sites, there have been reports of those that exhibit promiscuity. Previous experimental approaches used to characterize these methyltransferases do not provide the exact concentration at which off-target methylation occurs. Here, we present the first reported fidelity index (FI) for a number of DNA methyltransferases. We define the FI as the ratio of the highest amount of methyltransferase that exhibits no star activity (off-target effects) to the lowest amount that exhibits complete modification of the cognate site. Of the methyltransferases assayed, M.MspI and M.AluI exhibited the highest fidelity of >=250 and >=500, respectively, and do not show star activity even at very high concentrations. In contrast, M.HaeIII, M.EcoKDam and M.BamHI have the lowest fidelity of 4, 4 and 2, respectively, and exhibit star activity at concentrations close to complete methylation of the cognate site. The fidelity indexes provide vital information on the usage of methyltransferases and are especially important in applications where site specific methylation is required. PMID- 23671704 TI - Successive invasion-mediated interspecific hybridizations and population structure in the endangered cichlid Oreochromis mossambicus. AB - Hybridization between invasive and native species accounts among the major and pernicious threats to biodiversity. The Mozambique tilapia Oreochromis mossambicus, a widely used freshwater aquaculture species, is especially imperiled by this phenomenon since it is recognized by the IUCN as an endangered taxon due to genetic admixture with O. niloticus an invasive congeneric species. The Lower Limpopo and the intermittent Changane River (Mozambique) drain large wetlands of potentially great importance for conservation of O. mossambicus, but their populations have remained unstudied until today. Therefore we aimed (1) to estimate the autochthonous diversity and population structure among genetically pure O. mossambicus populations to provide a baseline for the conservation genetics of this endangered species, (2) to quantify and describe genetic variation of the invasive populations and investigate the most likely factors influencing their spread, (3) to identify O. mossambicus populations unaffected by hybridization. Bayesian assignment tests based on 423 AFLP loci and the distribution of 36 species-specific mitochondrial haplotypes both indicate a low frequency of invasive and hybrid genotypes throughout the system, but nevertheless reveal evidence for limited expansion of two alien species (O. niloticus and O. andersonii) and their hybrids in the Lower Limpopo. O. mossambicus populations with no traces of hybridization are identified. They exhibit a significant genetic structure. This contrasts with previously published estimates and provides rather promising auspices for the conservation of O. mossambicus. Especially, parts of the Upper Changane drainage and surrounding wetlands are identified as refugial zones for O. mossambicus populations. They should therefore receive high conservation priority and could represent valuable candidates for the development of aquaculture strains based on local genetic resources. PMID- 23671705 TI - Making and maintaining lifestyle changes after participating in group based type 2 diabetes self-management educations: a qualitative study. AB - BACKGROUND: Disease management is crucial in type 2 diabetes. Diabetes self management education aims to provide the knowledge necessary to make and maintain lifestyle changes. However, few studies have investigated the processes after such courses. The aim of this study was to investigate how participants make and maintain lifestyle changes after participating in group-based type 2 diabetes self-management education. METHODS: Data was collected through qualitative semi structured interviews with 23 patients who attended educational group programs in Central Norway. The participants were asked how they had used the advice given and what they had changed after the course. RESULTS: Knowledge was essential for making lifestyle changes following education. Three factors affected whether lifestyle changes were implemented: obtaining new knowledge, taking responsibility, and receiving confirmation of an already healthy lifestyle. Four factors motivated individuals to maintain changes: support from others, experiencing an effect, fear of complications, and the formation of new habits. CONCLUSION: Knowledge was used to make and maintain changes in diet, medication and physical activity. Knowledge also acted as confirmation of an already adequate lifestyle. Knowledge led to no changes if diabetes appeared "not that scary" or if changes appeared too time consuming. Those involved in diabetes education need to be aware of the challenges in convincing asymptomatic patients about the benefits of adherence to self-management behaviour. PMID- 23671707 TI - Global ex-situ crop diversity conservation and the Svalbard Global Seed Vault: assessing the current status. AB - Ex-situ conservation of crop diversity is a global concern, and the development of an efficient and sustainable conservation system is a historic priority recognized in international law and policy. We assess the completeness of the safety duplication collection in the Svalbard Global Seed Vault with respect to data on the world's ex-situ collections as reported by the Food and Agriculture Organization of the United Nations. Currently, 774,601 samples are deposited at Svalbard by 53 genebanks. We estimate that more than one third of the globally distinct accessions of 156 crop genera stored in genebanks as orthodox seeds are conserved in the Seed Vault. The numbers of safety duplicates of Triticum (wheat), Sorghum (sorghum), Pennisetum (pearl millet), Eleusine (finger millet), Cicer (chickpea) and Lens (lentil) exceed 50% of the estimated numbers of distinct accessions in global ex-situ collections. The number of accessions conserved globally generally reflects importance for food production, but there are significant gaps in the safety collection at Svalbard in some genera of high importance for food security in tropical countries, such as Amaranthus (amaranth), Chenopodium (quinoa), Eragrostis (teff) and Abelmoschus (okra). In the 29 food-crop genera with the largest number of accessions stored globally, an average of 5.5 out of the ten largest collections is already represented in the Seed Vault collection or is covered by existing deposit agreements. The high coverage of ITPGRFA Annex 1 crops and of those crops for which there is a CGIAR mandate in the current Seed Vault collection indicates that existence of international policies and institutions are important determinants for accessions to be safety duplicated at Svalbard. As a back-up site for the global conservation system, the Seed Vault plays not only a practical but also a symbolic role for enhanced integration and cooperation for conservation of crop diversity. PMID- 23671706 TI - CERKL knockdown causes retinal degeneration in zebrafish. AB - The human CERKL gene is responsible for common and severe forms of retinal dystrophies. Despite intense in vitro studies at the molecular and cellular level and in vivo analyses of the retina of murine knockout models, CERKL function remains unknown. In this study, we aimed to approach the developmental and functional features of cerkl in Danio rerio within an Evo-Devo framework. We show that gene expression increases from early developmental stages until the formation of the retina in the optic cup. Unlike the high mRNA-CERKL isoform multiplicity shown in mammals, the moderate transcriptional complexity in fish facilitates phenotypic studies derived from gene silencing. Moreover, of relevance to pathogenicity, teleost CERKL shares the two main human protein isoforms. Morpholino injection has been used to generate a cerkl knockdown zebrafish model. The morphant phenotype results in abnormal eye development with lamination defects, failure to develop photoreceptor outer segments, increased apoptosis of retinal cells and small eyes. Our data support that zebrafish Cerkl does not interfere with proliferation and neural differentiation during early developmental stages but is relevant for survival and protection of the retinal tissue. Overall, we propose that this zebrafish model is a powerful tool to unveil CERKL contribution to human retinal degeneration. PMID- 23671708 TI - Discharge competence and pattern formation in peatlands: a meta-ecosystem model of the Everglades ridge-slough landscape. AB - Regular landscape patterning arises from spatially-dependent feedbacks, and can undergo catastrophic loss in response to changing landscape drivers. The central Everglades (Florida, USA) historically exhibited regular, linear, flow-parallel orientation of high-elevation sawgrass ridges and low-elevation sloughs that has degraded due to hydrologic modification. In this study, we use a meta-ecosystem approach to model a mechanism for the establishment, persistence, and loss of this landscape. The discharge competence (or self-organizing canal) hypothesis assumes non-linear relationships between peat accretion and water depth, and describes flow-dependent feedbacks of microtopography on water depth. Closed-form model solutions demonstrate that 1) this mechanism can produce spontaneous divergence of local elevation; 2) divergent and homogenous states can exhibit global bi-stability; and 3) feedbacks that produce divergence act anisotropically. Thus, discharge competence and non-linear peat accretion dynamics may explain the establishment, persistence, and loss of landscape pattern, even in the absence of other spatial feedbacks. Our model provides specific, testable predictions that may allow discrimination between the self organizing canal hypotheses and competing explanations. The potential for global bi-stability suggested by our model suggests that hydrologic restoration may not re-initiate spontaneous pattern establishment, particularly where distinct soil elevation modes have been lost. As a result, we recommend that management efforts should prioritize maintenance of historic hydroperiods in areas of conserved pattern over restoration of hydrologic regimes in degraded regions. This study illustrates the value of simple meta-ecosystem models for investigation of spatial processes. PMID- 23671709 TI - The correlation between Prorocentrum donghaiense blooms and the Taiwan warm current in the East China Sea - evidence for the "Pelagic Seed Bank" hypothesis. AB - During the last two decades, large-scale high biomass algal blooms of the dinoflagellate Prorocentrum donghaiense Lu have occurred frequently in the East China Sea (ECS). The role of increasing nutrient concentrations in driving those blooms is well-established, but the source population that initiates them is poorly understood. We hypothesized that the front of Taiwan Warm Current (TWC) may serve as a 'seed bank' that initiates P. donghaiense blooms in the ECS, as the physiochemical conditions in the TWC are suitable for the growth of P. donghaiense. In order to test this hypothesis, two surveys at different spatio temporal scales were conducted in 2010 and 2011. We found a strong correlation in space and time between the abundance of P. donghaiense and the TWC. The spatial extent of the P. donghaiense bloom coincided with the TWC front in both 2010 and 2011. During the early development of the blooms, P. donghaiense concentration was highest at the TWC front, and then the bloom mass shifted inshore over the course of our 2011 survey. The TWC also moved inshore, albeit after the appearance of P. donghaiense. Overall, these results support our hypothesis that P. donghaiense blooms develop from the population at the TWC front in the ECS, suggesting the role of the ocean current front as a seed bank to dinoflagellate blooms. PMID- 23671710 TI - LGP2 plays a critical role in sensitizing mda-5 to activation by double-stranded RNA. AB - The DExD/H box RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation associated gene-5 (mda-5) sense viral RNA in the cytoplasm of infected cells and activate signal transduction pathways that trigger the production of type I interferons (IFNs). Laboratory of genetics and physiology 2 (LGP2) is thought to influence IFN production by regulating the activity of RIG-I and mda-5, although its mechanism of action is not known and its function is controversial. Here we show that expression of LGP2 potentiates IFN induction by polyinosinic-polycytidylic acid [poly(I:C)], commonly used as a synthetic mimic of viral dsRNA, and that this is particularly significant at limited levels of the inducer. The observed enhancement is mediated through co-operation with mda 5, which depends upon LGP2 for maximal activation in response to poly(I:C). This co-operation is dependent upon dsRNA binding by LGP2, and the presence of helicase domain IV, both of which are required for LGP2 to interact with mda-5. In contrast, although RIG-I can also be activated by poly(I:C), LGP2 does not have the ability to enhance IFN induction by RIG-I, and instead acts as an inhibitor of RIG-I-dependent poly(I:C) signaling. Thus the level of LGP2 expression is a critical factor in determining the cellular sensitivity to induction by dsRNA, and this may be important for rapid activation of the IFN response at early times post-infection when the levels of inducer are low. PMID- 23671712 TI - Comparative proteomics analysis suggests that placental mitochondria are involved in the development of pre-eclampsia. AB - INTRODUCTION: Pre-eclampsia (PE), a severe pregnancy-specific disease characterized by the new onset of hypertension, proteinuria, edema, and a series of other systematic disorders, is a state of widespread mitochondrial dysfunction of the placenta. METHODS: We compared the morphology of mitochondria in pre eclamptic and normotensive placentae using electron microscopy. To reveal the systematic protein expression changes of placental mitochondria that might explain the pathogenesis of PE, we performed iTRAQ analysis combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) on differentially expressed placental mitochondria proteins from 4 normotensive and 4 pre-eclamptic pregnancies. Bioinformatics analysis was used to find the relative processes that these differentially expressed proteins were involved in. Three differentially expressed proteins were chosen to confirm by Western blotting and immunohistochemistry. RESULTS: Morphological data demonstrated degenerative and apoptotic changes in the mitochondria of pre-eclamptic placentae. We found four proteins were upregulated and 22 proteins were downregulated in pre-eclamptic placentae compared with normotensive placentae. Bioinformatics analysis showed that these proteins were involved in many critical processes in the development of pre-eclampsia such as apoptosis, fatty acid oxidation, the respiratory chain, reactive oxygen species generation, the tricarboxylic acid cycle and oxidative stress. CONCLUSIONS: This preliminary work provides a better understanding of the proteomic alterations of mitochondria from pre-eclamptic placentae and may aid in our understanding of the importance of mitochondria in the development of pre eclampsia. PMID- 23671711 TI - A review of potential harmful interactions between anticoagulant/antiplatelet agents and Chinese herbal medicines. AB - BACKGROUND: The risks attributed to drug-herb interactions, even when known, are often ignored or underestimated, especially for those involving anti-clotting drugs and Chinese medicines. The aim of this study was to structurally search and evaluate the existing evidence-based data associated with potential drug interactions between anticoagulant/antiplatelet drugs and Chinese herbal medicines (CHMs) and evaluate the documented mechanisms, consequences, and/or severity of interactions. METHODOLOGY AND FINDINGS: Information related to anticoagulant/antiplatelet drug-CHM interactions was retrieved from eight interaction-based textbooks, four web resources and available primary biomedical literature. The primary literature searches were conducted in English and/or Chinese from January 2000 through December 2011 using the secondary databases (e.g., PubMed, Airiti Library, China Journal full-text database). The search terms included the corresponding medical subject headings and key words. Herbs or natural products not used as a single entity CHM or in Chinese Medicinal Prescriptions were excluded from further review. The corresponding mechanisms and severity ratings of interactions were retrieved using MicroMedex(r), Lexicomp(r) and Natural Medicines Comprehensive Database(r). Finally, we found 90 single entity CHMs contributed to 306 documented drug-CHM interactions. A total of 194 (63.4%) interactions were verified for its evidence describing possible mechanisms and severity. Of them, 155 interactions (79.9%) were attributable to pharmacodynamic interactions, and almost all were rated as moderate to severe interactions. The major consequences of these interactions were increased bleeding risks due to the additive anticoagulant or antiplatelet effects of the CHMs, specifically danshen, dong quai, ginger, ginkgo, licorice, and turmeric. CONCLUSIONS/SIGNIFICANCE: Conventional anticoagulants and antiplatelet drugs were documented to have harmful interactions with some commonly used single entity CHMs. For those patients who are taking conventional anti-clotting medications with CHMs for cardiovascular or cerebrovascular diseases, the potential risks of increased bleeding due to drug-CHM interactions should not be ignored. PMID- 23671713 TI - Visual navigation during colony emigration by the ant Temnothorax curvispinosus [corrected]. AB - Many ants rely on both visual cues and self-generated chemical signals for navigation, but their relative importance varies across species and context. We evaluated the roles of both modalities during colony emigration by Temnothorax curvispinosus [corrected]. Colonies were induced to move from an old nest in the center of an arena to a new nest at the arena edge. In the midst of the emigration the arena floor was rotated 60 degrees around the old nest entrance, thus displacing any substrate-bound odor cues while leaving visual cues unchanged. This manipulation had no effect on orientation, suggesting little influence of substrate cues on navigation. When this rotation was accompanied by the blocking of most visual cues, the ants became highly disoriented, suggesting that they did not fall back on substrate cues even when deprived of visual information. Finally, when the substrate was left in place but the visual surround was rotated, the ants' subsequent headings were strongly rotated in the same direction, showing a clear role for visual navigation. Combined with earlier studies, these results suggest that chemical signals deposited by Temnothorax ants serve more for marking of familiar territory than for orientation. The ants instead navigate visually, showing the importance of this modality even for species with small eyes and coarse visual acuity. PMID- 23671714 TI - Crucial role of membrane potential in heat stress-induced overproduction of reactive oxygen species in avian skeletal muscle mitochondria. AB - Heat stress is an environmental factor that causes oxidative stress. We found previously that acute heat stress stimulates the production of reactive oxygen species (ROS) in the skeletal muscle mitochondria of birds, and that this was accompanied by an increase of the mitochondrial membrane potential (DeltaPsi) due to increased substrate oxidation by the electron transport chain. We also showed that avian uncoupling protein (avUCP) expression is decreased by the heat exposure. The present study clarifies whether DeltaPsi is a major determinant of the overproduction of ROS due to acute heat stress, and if the decrease in avUCP expression is responsible for the elevation in DeltaPsi. Control (24 degrees C) and acute heat-stressed (34 degrees C for 12 h) birds exhibited increased succinate-driven mitochondrial ROS production as indicated by an elevation of DeltaPsi, with this increase being significantly higher in the heat-stressed group compared with the control group. In glutamate/malate-energized mitochondria, no difference in the ROS production between the groups was observed, though the mitochondrial DeltaPsi was significantly higher in the heat stressed groups compared with the control group. Furthermore, mitochondria energized with either succinate/glutamate or succinate/malate showed increased ROS production and DeltaPsi in the heat-stressed group compared with mitochondria from the control group. These results suggest that succinate oxidation could play an important role in the heat stress-induced overproduction of mitochondrial ROS in skeletal muscle. In agreement with the notion of a decrease in avUCP expression in response to heat stress, proton leak, which was likely mediated by UCP (that part which is GDP-inhibited and arachidonic acid-sensitive), was reduced in the heat-exposed group. We suggest that the acute heat stress-induced overproduction of mitochondrial ROS may depend on DeltaPsi, which may in turn result not only from increased substrate oxidation but also from a decrease in the mitochondrial avUCP content. PMID- 23671715 TI - Aristaless-related homeobox plays a key role in hyperplasia of the pancreas islet alpha-like cells in mice deficient in proglucagon-derived peptides. AB - Defects in glucagon action can cause hyperplasia of islet alpha-cells, however, the underlying mechanisms remain largely to be elucidated. Mice homozygous for a glucagon-GFP knock-in allele (Gcg(gfp/gfp) ) completely lack proglucagon-derived peptides and exhibit hyperplasia of GFP-positive alpha-like cells. Expression of the transcription factor, aristaless-related homeobox (ARX), is also increased in the Gcg(gfp/gfp) pancreas. Here, we sought to elucidate the role of ARX in the hyperplasia of alpha-like cells through analyses of two Arx mutant alleles (Arx(P355L/Y) and Arx ([330insGCG]7/Y) ) that have different levels of impairment of their function. Expression of Gfp and Arx genes was higher and the size and number of islets increased in the Gcg(gfp/gfp) pancreas compared to and Gcg(gfp/+) pancreas at 2 weeks of age. In male Gcg(gfp/gfp) mice that are hemizygous for the Arx(P355L/Y) mutation that results in a protein with a P355L amino acid substitution, expression of Gfp mRNA in the pancreas was comparable to that in control Gcg(gfp/+)Arx(+/Y) mice. The increases in islet size and number were also reduced in these mice. Immunohistochemical analysis showed that the number of GFP-positive cells was comparable in Gcg(gfp/gfp) Arx(P355L/Y) and Gcg(gfp/+)Arx(+/Y) mice. These results indicate that the hyperplasia is reduced by introduction of an Arx mutation. Arx(P355L/Y) mice appeared to be phenotypically normal; however, Arx ([330insGCG]7/Y) mice that have a mutant ARX protein with expansion of the polyalanine tract had a reduced body size and shortened life span. The number of GFP positive cells was further reduced in the Gcg(gfp/gfp) Arx ([330insGCG]7/Y) mice. Taken together, our findings show that the function of ARX is one of the key modifiers for hyperplasia of islet alpha like cells in the absence of proglucagon-derived peptides. PMID- 23671716 TI - Comprehensive antigen screening identifies Moraxella catarrhalis proteins that induce protection in a mouse pulmonary clearance model. AB - Moraxella catarrhalis is one of the three most common causative bacterial pathogens of otitis media, however no effective vaccine against M. catarrhalis has been developed so far. To identify M. catarrhalis vaccine candidate antigens, we used carefully selected sera from children with otitis media and healthy individuals to screen small-fragment genomic libraries that are expressed to display frame-selected peptides on a bacterial cell surface. This ANTIGENome technology led to the identification of 214 antigens, 23 of which were selected by in vitro or in vivo studies for additional characterization. Eight of the 23 candidates were tested in a Moraxella mouse pulmonary clearance model, and 3 of these antigens induced significantly faster bacterial clearance compared to adjuvant or to the previously characterized antigen OmpCD. The most significant protection data were obtained with the antigen MCR_1416 (Msp22), which was further investigated for its biological function by in vitro studies suggesting that Msp22 is a heme binding protein. This study comprises one of the most exhaustive studies to identify potential vaccine candidate antigens against the bacterial pathogen M. catarrhalis. PMID- 23671718 TI - In utero transplantation: Disparate ramifications. AB - In utero stem cell transplantation, which promises treatment for a host of genetic disorders early in gestation before disease effect stems from Ray Owen's seminal observation that self-tolerance, is acquired during gestation. To date, in utero transplantation (IUT) has proved useful in characterizing the hematopoietic stem cell. Recent observations support its use as an in vivo method to further understanding of self-tolerance. Preclinical development continues for its application as a treatment for childhood hematolymphoid diseases. In addition, IUT may offer therapeutic options in the treatment of diabetes among other diseases. Thus IUT serves as a technique or system important in both a basic and applied format. This review summarizes these findings. PMID- 23671719 TI - Comparison of phenotypic markers and neural differentiation potential of multipotent adult progenitor cells and mesenchymal stem cells. AB - AIM: To compare the phenotypic and neural differentiation potential of human bone marrow derived multipotent adult progenitor cells (MAPC) and mesenchymal stem cells (MSC). METHODS: Cultures of MAPC and MSC were established in parallel from same samples of human bone marrow (n = 5). Both stem cell types were evaluated for expression of pluripotency markers including Oct-4 and Nanog by immunocytochemistry and reverse-transcription polymerase chain reaction (RT-PCR) and expression of standard mesenchymal markers including CD14, CD34, CD44, CD45, CD73, CD90, CD105 and human leukocyte antigen (HLA)-ABC by flow cytometry. After treatment with neural induction medium both MAPC and MSC were evaluated for expression of neural proteins [neuronal filament-200 (NF-200) and glial fibrillar acidic protein (GFAP)] by immunocytochemistry and Western blotting and neural genes [NF-200, GFAP, Tau, microtubule-associated protein (MAP)-1B, MAP-2, neuron specific enolase (NSE) and oligodendrocyte-1 (Olig-1)] by quantitative real-time PCR. RESULTS: MAPC had small trigonal shaped while MSC had elongated spindle shaped morphology. The MAPC expressed Oct-4 and Nanog both at gene and protein levels, whereas MSC were negative for these pluripotent markers. MAPC were negative for HLA-ABC while MSC had high expression of HLA-ABC. In addition, MAPC as compared to MSC had significantly lower expression of CD44 (36.56% +/- 1.92% vs 98.23% +/- 0.51%), CD73 (15.11% +/- 2.24% vs 98.53% +/- 2.22%) and CD105 (13.81% +/- 3.82% vs 95.12% +/- 5.65%) (P < 0.001, for all) MAPC cultures compared to MSC cultures treated with neural induction medium had significantly higher fold change expression of NF-200 (0.64), GFAP (0.52), Tau (0.59), MAP-2 (0.72), Olig-1 (0.18) and NSE (0.29) proteins (P < 0.01 for Olig-1 and P < 0.001 for rest) as well as higher fold change expression of genes of NF-200 (1.34), GFAP (1.12), Tau (1.08), MAP-1B (0.92), MAP-2 (1.14) and NSE (0.4) (P < 0.001 for all). CONCLUSION: MAPC can be differentially characterized from MSC as Oct-4 and Nanog positive stem cells with no expression of HLA-ABC and low expression of mesenchymal markers CD44, CD73 and CD105 and when compared to MSC they possess greater predilection for differentiation into neuro-ectodermal lineage. PMID- 23671720 TI - Melatonin attenuates high fat diet-induced fatty liver disease in rats. AB - AIM: To investigate melatonin's preventive action in oxidative stress in a rat model with high fat diet-induced non-alcoholic fatty liver disease (NAFLD). METHODS: NAFLD was induced by high fat diet (HFD) in adult, male, Wistar rats, weighing 180-230 g. After acclimatization for one week, they were randomly assigned to 6 experimental groups that comprised animals on regular diet plus 5 or 10 mg/kg melatonin, for 4 or 8 wk; animals on HFD, with or without 5 or 10 mg/kg melatonin, for 4 or 8 wk; and animals on HFD for 8 or 12 wk, with melatonin 10 mg/kg for the last 4 wk. Liver damage was assessed biochemically by the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and histologically. Lipid peroxidation and oxidative stress were assessed by malondialdehyde and glutathione levels in liver tissue. Lipidemic indices and portal vein pressure were also measured. RESULTS: Compared to rats not receiving melatonin, rats on 5 or 10 mg/kg of melatonin had lower mean liver weight (-5.0 g and -4.9 g) (P < 0.001) and lower liver weight to body weight ratio (-1.0%) (P < 0.001), for the two doses, respectively. All rats fed HFD without melatonin developed severe, grade III, steatosis. Rats on HFD with concurrent use of melatonin showed significantly less steatosis, with grade III steatosis observed in 1 of 29 (3.4%) rats on 10 mg/kg melatonin and in 3 of 27 (11.1%) rats on 5 mg/kg melatonin. Melatonin was ineffective in reversing established steatosis. Melatonin also had no effect on any of the common lipidemic serum markers, the levels of which did not differ significantly among the rats on HFD, irrespective of the use or not of melatonin. Liver cell necrosis was significantly less in rats on HFD receiving melatonin than in those not on melatonin, with the AST levels declining by a mean of 170 U/L (P = 0.01) and 224 U/L (P = 0.001), and the ALT levels declining by a mean of 62.9 U/L (P = 0.01) and 93.4 U/L (P < 0.001), for the 5 and 10 mg/kg melatonin dose, respectively. Melatonin mitigated liver damage due to peroxidation and oxidative stress in liver tissue as indicated by a significant decline in MDA production by 12.7 (P < 0.001) and 12.2 (P < 0.001) MUmol/L /mg protein /mg tissue, and a significant increase in glutathione by 20.1 (P = 0.004) and 29.2 (P < 0.001) MUmol/L /mg protein /mg tissue, for the 5 and 10 mg/kg melatonin dose, respectively. CONCLUSION: Melatonin can attenuate oxidative stress, lessen liver damage, and improve liver histology in rats with high fat diet-induced NAFLD, when given concurrently with the diet. PMID- 23671722 TI - Platelet count and sustained virological response in hepatitis C treatment. AB - AIM: To examine the epidemiological data, hematological safety and treatment responses of peginterferon-alpha 2a plus ribavirin therapy for hepatitis C. METHODS: Between March 2008 and February 2011, 196 hepatitis C virus (HCV) genotype 1 infected Japanese (127 treatment-naive and 69 treatment-experienced patients) patients treated with peginterferon-alpha 2a plus ribavirin were enrolled. We examined the epidemiological data and treatment responses were retrospectively analyzed in terms of hematological safety. HCV RNA was measured by the COBAS TaqMan HCV test. RESULTS: Overall sustained virological response (SVR) rates of treatment-naive and treatment-experienced patients were 56% and 39%, respectively. Multivariate logistic regression analysis showed that SVR was attained independently of early virological response in both treatment-naive and treatment-experienced patients. SVR rates did not differ between the pretreatment hemoglobin < 13 g/dL and >= 13 g/dL groups. However, in treatment-naive patients, the SVR rate of the pretreatment platelet count < 130000/uL group was significantly lower than that of the pretreatment platelet count >= 130000/uL group. CONCLUSION: Attention should be paid to potential thrombocytopenia in the treatment of chronic hepatitis C patients. PMID- 23671721 TI - Hypothermia predicts hepatic failure after extensive hepatectomy in mice. AB - AIM: To investigate the effect of hypothermia on the function of the liver remnant (LR) after extended hepatectomy. METHODS: We performed a 75% partial hepatectomy (PH) in male C57BL/6J mice. Body temperature was measured with a rectal probe. The study mice were prospectively grouped as hypothermic (HT) or normothermic (NT) if their body temperature was < 34 degrees C vs >= 34 degrees C, respectively. Blood and liver samples were obtained at 24 and 48 h after 75% PH. Various factors during and after 75% PH were compared at each time point and the most important factor for a good outcome after 75% PH was determined. RESULTS: At 24 and 48 h after 75% PH, LR weight was decreased in HT mice compared with that in NT mice and the assay results in the HT mice were consistent with liver failure. NT mice had normal liver regeneration. Each intra- and post operative factor which showed statistical significance in univariate analysis was evaluated by multivariate analysis. The most important factor for a good outcome after 75% PH was body temperature at both 24 and 48 h after surgery. CONCLUSION: Hypothermia after an extensive hepatectomy predicts impending liver failure and may be a useful clinical marker for early detection of liver failure after extended hepatectomy. PMID- 23671723 TI - CD14 upregulation as a distinct feature of non-alcoholic fatty liver disease after pancreatoduodenectomy. AB - AIM: To investigate the pathogenesis of non-alcoholic fatty liver disease (NAFLD) after pancreatoduodenectomy (PD). METHODS: A cohort of 82 patients who underwent PD at Okayama University Hospital between 2003 and 2009 was enrolled and the clinicopathological features were compared between patients with and without NAFLD after PD. Computed tomography (CT) images were evaluated every 6 mo after PD for follow-up. Hepatic steatosis was diagnosed on CT when hepatic attenuation values were 40 Hounsfield units. Liver biopsy was performed for 4 of 30 patients with NAFLD after PD who consented to undergo biopsies. To compare NAFLD after PD with NAFLD associated with metabolic syndrome, liver samples were obtained from 10 patients with NAFLD associated with metabolic syndrome [fatty liver, n = 5; non-alcoholic steatohepatitis (NASH), n = 5] by percutaneous ultrasonography guided liver biopsy. Double-fluorescence immunohistochemistry was applied to examine CD14 expression as a marker of lipopolysaccharide (LPS)-sensitized macrophage cells (Kupffer cells) in liver biopsy specimens. RESULTS: The incidence of postoperative NAFLD was 36.6% (30/82). Univariate analysis identified cancer of the pancreatic head, sex, diameter of the main pancreatic duct, and dissection of the nerve plexus as factors associated with the development of NAFLD after PD. Those patients who developed NAFLD after PD demonstrated significantly decreased levels of serum albumin, total protein, cholesterol and triglycerides compared to patients without NAFLD after PD, but no glucose intolerance or insulin resistance. Liver biopsy was performed in four patients with NAFLD after PD. All four patients showed moderate-to-severe steatosis and NASH was diagnosed in two. Numbers of cells positive for CD68 (a marker of Kupffer cells) and CD14 (a marker of LPS-sensitized Kupffer cells) were counted in all biopsy specimens. The number of CD68+ cells in specimens of NAFLD after PD was significantly increased from that in specimens of NAFLD associated with metabolic syndrome specimens, which indicated the presence of significantly more Kupffer cells in NAFLD after PD than in NAFLD associated with metabolic syndrome. Similarly, more CD14+ cells, namely, LPS-sensitized Kupffer cells, were observed in NAFLD after PD than in NAFLD associated with metabolic syndrome. Regarding NASH, more CD68+ cells and CD14+ cells were observed in NASH after PD specimens than in NASH associated with metabolic syndrome. This showed that more Kupffer cells and more LPS-sensitized Kupffer cells were present in NASH after PD than in NASH associated with metabolic syndrome. These observations suggest that after PD, Kupffer cells and LPS-sensitized Kupffer cells were significantly upregulated, not only in NASH, but also in simple fatty liver. CONCLUSION: NAFLD after PD is characterized by both malnutrition and the up-regulation of CD14 on Kupffer cells. Gut-derived endotoxin appears central to the development of NAFLD after PD. PMID- 23671724 TI - Epidemiological profiles of human immunodeficiency virus and hepatitis C virus infections in Malian women: Risk factors and relevance of disparities. AB - AIM: To document the epidemiologic patterns and risk factors of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections in Mali in order to develop prevention means for both diseases. METHODS: Two prospective studies were conducted in Bamako in 2009 among 1000 pregnant women (i.e., young women) who consulted six reference health centers, and in 2010, among 231 older women who attended general practice in two hospitals. Antibody tests and molecular analysis (performed only for HCV) were used to quantify the frequencies of both infections. The data were collected from patients recruited through a questionnaire. Transmission risk factors of both diseases were identified by univariate and multivariate analysis. RESULTS: HCV seroprevalence was 0.2% for young and 6.5% for older women. HIV prevalence was similar in both populations (4.1% vs 6.1%). In older women, the analysis of risk factors highlighted an association between HCV infection and episodes of hospitalization (P < 0.01). The study did not show an association between HIV infection and the variables such as hospitalization, transfusion, tattoo, dental care, and endoscopy. A significant decrease of HIV seroprevalence was detected in young women who used condoms for contraception more than for other purposes (P < 0.01). By contrast, HIV seroprevalence was significantly increased in young women using condoms mainly to prevent sexual infections rather than for contraception (P < 0.01). No HCV/HIV coinfection was detected in our study. CONCLUSION: Risk factors and epidemiologic data of HIV and HCV as well as the absence of co-infection strongly suggest epidemiological disparities between these diseases. PMID- 23671725 TI - Differential expression of hepatic apurinic/apyrimidinic endonuclease 1, a DNA repair enzyme, in chronic hepatitis. AB - AIM: To determine hepatic expression of apurinic/apyrimidinic endonuclease 1 (APE 1) and 8-hydroxydeoxyguanosine (8-OHdG) in patients with chronic hepatitis B and C. METHODS: Liver biopsies were obtained from 27 patients with chronic hepatitis B virus (HBV), 30 with chronic hepatitis C virus (HCV), 6 with autoimmune hepatitis (AIH), and 6 with primary biliary cirrhosis (PBC). Normal liver tissue was obtained from surgical resection specimens of four patients. Hepatic APE-1 protein and mRNA expression were assayed by Western blot and by real-time polymerase chain reaction, respectively. Hepatocellular APE-1 and 8-OHdG expression were determined by immunohistochemistry. RESULTS: The staining intensity of hepatocellular nuclear APE-1 was lower in the HBV group than in the other groups (P < 0.05). Hepatic APE-1 protein levels were reduced in the HBV group relative to the other groups. Hepatic APE-1 mRNA levels were also lower in the HBV group. The proportion of hepatocytes with 8-OHdG-positive nuclei was increased in the HCV, AIH and PBC groups (P < 0.05), but not in the HBV group. Hepatocellular nuclear APE-1 levels were positively correlated with hepatocellular 8-OHdG levels in both the HBV and HCV groups (HBV, r = 0.34, P < 0.05; HCV, r = 0.54, P < 0.01). CONCLUSION: An imbalance between oxidative DNA damage and APE-1 expression may contribute to hepatocarcinogenesis in chronic viral hepatitis. PMID- 23671726 TI - Hepatitis B infection among adults in the philippines: A national seroprevalence study. AB - AIM: To determine the prevalence of hepatitis B surface antigen (HBsAg) seropositivity among adult Filipinos. METHODS: Testing for HBsAg was performed on serum samples from persons aged >= 20 years old who participated in the National Nutrition and Health Survey (NNHeS) conducted in 2003. Information on age, sex, marital status, educational attainment, employment status, and income were collected. For this study, marital status was classified as never married or otherwise (i.e., married, divorced, separated, widowed); educational attainment was classified as high school graduate or below or at least some tertiary education; and employment status was classified as currently employed or currently unemployed. Annual income was divided into 4 quartiles in Philippine pesos (PhP): Q1, <= PhP 53064; Q2, PhP 53065-92192; Q3, PhP 92193-173387; and Q4, >= PhP 173388. Prevalence estimates were weighted so that they represented the general population. Social and demographic factors were correlated with HBsAg seropositivity. Multivariate analysis was used to determine independent predictors of HBsAg seropositivity. RESULTS: A total of 2150 randomly selected adults, 20 years and over, out of the 4753 adult participants of NNHeS were tested for HBsAg. The HBsAg seroprevalence was 16.7% (95%CI: 14.3%-19.1%), which corresponded to an estimated 7278968 persons infected with hepatitis B. There was no significant difference between males and females (17.5% vs 16.0%; P = 0.555). This corresponded to an estimated 3721775 men and 3557193 women infected with hepatitis B. The HBsAg seroprevalence peaked at age 20-39 years old, with declining prevalence in the older age groups. The only independent predictor of HBsAg seropositivity was the annual income, with persons in the highest income quartile being less likely to be HBsAg positive (age-adjusted OR = 0.51; 95%CI: 0.30-0.86) compared to subjects in the lowest income quartile. Sex, marital status, educational attainment, and employment status were not found to be independent predictors of HBsAg seropositivity. CONCLUSION: The high HBsAg seroprevalence among adults in the Philippines classifies the country as hyperendemic for HBV infection and appears unchanged over the last few decades. PMID- 23671728 TI - Giant cell hepatitis with autoimmune hemolytic anemia in a nine month old infant. AB - Giant cell hepatitis (GCH) with autoimmune hemolytic anemia is a rare entity, limited to young children, with an unknown pathogenesis. We report the case of 9 mo old who presented with fever, diarrhea and jaundice four days before hospitalization. Physical examination found pallor, jaundice and hepatosplenomegaly. The laboratory workup showed serum total bilirubin at 101 MUmol/L, conjugated bilirubin at 84 MUmol/L, hemolytic anemia, thrombocytopenia and immunoglobulin G (IgG) and anti-C3d positive direct Coombs' test. The antinuclear, anti-smooth muscle and liver kidney microsomes 1 non-organ specific autoantibodies, antiendomisium antibodies were negative. Serological assays for viral hepatitis B and C, cytomegalovirus, herpes simplex and Epstein Barr virus were negative. The association of acute liver failure, Evan's syndrome, positive direct Coomb's test of mixed type (IgG and C3) and the absence of organ and non organ specific autoantibodies suggested the diagnosis of GCH. The diagnosis was confirmed by a needle liver biopsy. The patient was treated by corticosteroids, immunomodulatory therapy and azathioprine but died with septicemia. PMID- 23671727 TI - PPARgamma agonist-induced alterations in Delta6-desaturase and stearoyl-CoA desaturase 1: Role of MEK/ERK1/2 pathway. AB - AIM: To investigate the effect of MEK/ERK1/2 pathway on peroxisome proliferator activated receptors (PPARgamma) agonist-induced alterations in Delta6-desaturase (Delta6D) and stearoyl-CoA desaturase 1 (SCD1) in hepatocellular carcinoma cell line HepG2. METHODS: HepG2 cells cultured in RPMI-1640 were exposed to the commonly used ERK1/2 pathway inhibitor PD98059 and PPARgamma agonist, pioglitazone. Total RNA was isolated and reverse transcribed from treated cells. Changes in gene expression and metabolites ratio, as activity index for Delta6D and SCD1, were then determined using reverse transcription-polymerase chain reaction and gas liquid chromatography, respectively. RESULTS: The expression of both Delta6D (P = 0.03) and SCD1 (P = 0.01) increased following PD98059 treatment, with a higher impact on SCD1 (24.5% vs 62.5%). Although pioglitazone increased the mRNA level (1.47 +/- 0.10 vs 0.88 +/- 0.02, P = 0.006) and activity index (1.40 +/- 0.07 vs 0.79 +/- 0.11, P < 0.001) of Delta6D, no such changes have been observed for SCD1 activity index in pioglitazone-treated cells. SCD1 gene expression (+26.4%, P = 0.041) and activity index (+52.8%, P = 0.035) were significantly increased by MEK inhibition in the presence of pioglitazone, as compared with pioglitazone alone and control cells. However, the response of Delta6D expression and activity index to pioglitazone was unaffected by incubation with PD98059. CONCLUSION: PPARgamma and ERK1/2 signaling pathway affect differentially and may have inhibitory crosstalk effects on the genes expression of ?6D and SCD1, and subsequently on their enzymatic activities. PMID- 23671729 TI - Dermatomyositis associated with gallbladder carcinoma: A case report. AB - Patients with gallbladder carcinoma can present with a variety of paraneoplastic syndromes, including Cushing's syndrome, hypercalcemia, acanthosis nigricans, bullous pemphigoid, dermatomyositis and the sign of Leser-Trelat. Surgical resection of the primary tumor results in resolution of these paraneoplastic syndromes. We present a 67-year old female with facial and cervical erythema who was initially diagnosed with dermatomyositis. However, an abdominal computed tomography (CT) and positron emission tomography-CT scan was suspicious for gallbladder carcinoma with lymph node metastasis. After surgical resection, her dermatomyositis was resolved. This case demonstrates that dermatomyositis may be a manifestation of preexisting gallbladder carcinoma. PMID- 23671730 TI - Epigenetic field defects in progression to cancer. AB - A field defect is a field of pre-malignant tissue in which a new cancer is likely to arise. Field defects often appear to be histologically normal under the microscope. Recent research indicates that cells within a field defect characteristically have an increased frequency of epigenetic alterations and these may be fundamentally important as underlying factors in progression to cancer. However, understanding of epigenetic field defects is at an early stage, and the work of Katsurano et al published this year, is a key contribution to this field. One question examined by Katsurano et al was how early could the formation of an epigenetic field defect be detected in a mouse colitis model of tumorigenesis. They highlighted a number of measurable epigenetic alterations, detected very early in normal appearing tissue undergoing histologically invisible tumorigenesis. They also documented the increasing presence of the epigenetic alterations at successive times during progression to cancer. In this commentary, we offer a perspective on the changes they observed within a broader sequence of epigenetic events that occur in progression to cancer. In particular, we highlight the likely central role of epigenetic deficiencies in DNA repair gene expression that arise during progression to cancer. PMID- 23671731 TI - CagA EPIYA polymorphisms in Colombian Helicobacter pylori strains and their influence on disease-associated cellular responses. AB - AIM: To investigate the influence of the CagA diversity in Helicobacter pylori (H. pylori) strains from Colombia on the host cell biology. METHODS: Eighty-four H. pylori-cagA positive strains with different Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs patterns, isolated from patients with gastritis (n = 17), atrophic gastritis (n = 17), duodenal ulcer (n = 16), intestinal metaplasia (n = 16) and gastric cancer (n = 18), were included. To determine the integrity of the cag pathogenicity island (cagPAI) we evaluated the presence of cagA, cagT, cagE, and cag10 genes by polymerase chain reaction. AGS gastric epithelial cells were infected with each strain and assayed for translocation and tyrosine phosphorylation of CagA by western blot, secretion of interleukin-8 (IL-8) by enzyme-linked immuno sorbent assay after taking supernatants from cocultures and cell elongation induction. For cell elongation quantification, coculture photographs were taken and the proportion of "hummingbird" cells (> 15 MUm) was determined. RESULTS: Overall 72% (60/84) of the strains were found to harbor a functional cagPAI. Levels of phosphorylated CagA were significantly higher for isolates from duodenal ulcer than the ones in strains from gastritis, atrophic gastritis, intestinal metaplasia and gastric cancer (49.1% +/- 23.1% vs 21.1% +/- 19.5%, P < 0.02; 49.1% +/- 23.1% vs 26.2% +/- 14.8%, P < 0.045; 49.1% +/- 23.1% vs 21.5% +/- 19.5%, P < 0.043 and 49.1% +/- 23.1% vs 29.5% +/- 27.1%, P < 0.047 respectively). We observed variable IL-8 expression levels ranging from 0 to 810 pg/mL and from 8.8 to 1442 pg/mL at 6 h and 30 h post-infection, respectively. cagPAI-defective strains did not induce detectable levels of IL-8 at 6 h post-infection. At 30 h post-infection all strains induced IL-8 expression in AGS cells, although cagPAI defective strains induced significantly lower levels of IL-8 than strains with a functional cagPAI (57.1 +/- 56.6 pg/mL vs 513.6 +/- 338.6 pg/mL, P < 0.0001). We did not observe differences in the extent of cell elongation induction between strains with a functional or a defective cagPAI in 6 h cocultures. At 24 h post infection strains with functional cagPAI showed high diversity in the extent of hummingbird phenotype induction ranging from 7% to 34%. cagPAI defective strains induced significantly lower levels of elongation than strains with functional cagPAI with one or more than one EPIYA-C motif (15.1% +/- 5.2% vs 18.9% +/- 4.7%, P < 0.03; and 15.1% +/- 5.2% vs 20.0% +/- 5.1%, P < 0.003 respectively). No differences were observed in cellular elongation induction or IL-8 expression among H. pylori strains bearing one and more than one EPIYA-C motifs, neither at 6 h nor at 24 h of coculture. There were no associations between the levels of induction of cell elongation or IL-8 expression and number of EPIYA motifs or pathology. CONCLUSION: The present work describes a lack of association between H. pylori CagA protein EPIYA motifs variations from Colombian isolates and disease-associated cellular responses. PMID- 23671732 TI - Does in-house availability of multidisciplinary teams increase survival in upper gastrointestinal-cancer? AB - AIM: To investigate the effect of the establishment of in-house multidisciplinary team (MDT) availability (iMDTa) on survival in upper gastrointestinal cancer (UGI) patients. METHODS: In 2001, a cancer centre with irradiation and chemotherapy facilities was established in the Norwegian county of West Agder with a change of iMDTa (WA/MDT-Change). "iMDTa"-status was defined according to the availability of the necessary specialists within one institution on one campus, serving the population of one county. We compared survival rates during 2000-2008 for UGI patients living in counties with (MDT-Yes), without (MDT-No), with a mix (MDT-Mix) and WA/MDT-Change. Survival was calculated with Kaplan-Meier method. Cox model was used to uncover differences between counties with different MDT status when adjusted for age, sex and stage. RESULTS: We analyzed 395 patients from WA/MDT-Change and compared their survival to 12 135 UGI patients from four other Norwegian regions. Median overall survival for UGI patients in WA/MDT-Change increased from 129 to 300 d from 2000-2008, P = 0.001. The regions with the highest level of iMDTa achieved the largest decrease in risk of death for UGI cancers (compared to the county with MDT-Mix: MDT-Yes 11%, P < 0.05 and WA/MDT-Change 15%, P < 0.05). Analyzing the different tumour entities separately, patients living in the WA/MDT-Change county reached a statistically significant reduction in the risk of death [hazard ratios (HR)] compared to patients in the county with MDT-Mix for oesophageal and gastric, but not for pancreatic cancer. HR for the study period 2000-2004 are given first and then for the period 2005 2008: The HR for oesophageal cancers was reduced from [HR = 1.12; 95%CI: 0.75 1.68 to HR = 0.60, 95%CI: 0.38-0.95] and for gastric cancers from [HR = 0.87, 95%CI: 0.66-1.15 to HR = 0.63, 95%CI: 0.43-0.93], but not for pancreatic cancer [HR = 1.04-, 95%CI: 0.83-1.3 for 2000-2004 and HR = 1.01, 95%CI: 0.78-1.3 for 2005-2008]. UGI patients treated during the second study period in the county of WA/MDT-Change had a higher probability of receiving chemotherapy. In the first study period, only one out of 43 patients (2.4%, 95%CI: 0-6.9) received chemotherapy, compared to 18 of 42 patients diagnosed during 2005-2008 (42.9%, 95%CI: 28.0-57.8). CONCLUSION: Introduction of iMDTa led to a two-fold increase of UGI patients, whereas no increase in survival was found in the MDT-No or MDT Mix counties. PMID- 23671733 TI - Gastroesophageal cancer and retroperitoneal fibrosis: Two case reports and review of the literature. AB - Retroperitoneal fibrosis secondary to malignant disease is a rare condition associated with a dismal prognosis. We herein present the first ever reported case of retroperitoneal fibrosis related to esophageal adenocarcinoma in a 63 year-old patient who developed bilateral ureteral obstruction due to extensive retroperitoneal fibrosis 18 mo after having completed neoadjuvant chemoradation followed by surgery for a pT3N0 adenocarcinoma of the distal esophagus. We also report the case of a previously healthy woman who presented with bilateral ureteral obstruction and diffuse narrowing of the common biliary duct and was found to have extensive retroperitoneal fibrosis as a consequence of metastatic gastric adenocarcinoma. Both patients had poor performance status and were unsuitable for palliative chemotherapy. This paper shows that urinary and biliary obstructive symptoms might represent retroperitoneal fibrosis as a consequence of gastroesophageal malignancy. PMID- 23671735 TI - Prognostic factors in resectable cholangiocarcinoma patients: Carcinoembryonic antigen, lymph node, surgical margin and chemotherapy. AB - AIM: To evaluate outcomes in resectable cholangiocarcinoma patients and to determine prognostic factors. METHODS: A retrospective study was conducted among newly-diagnosed cholangiocarcinoma patients from January 2009 to December 2011 who underwent curative resection in Srinakarind Hospital (a 1000-bed university hospital). Two hundred and sixty-three cholangiocarcinoma patients with good performance were enrolled. These patients had pathological reports with clear margins or microscopic margins. Prognostic factors which included clinical factors, serum liver function test as well as serum tumor makers at presentation, tumor data, and receiving adjuvant chemotherapy were determined by uni- and multivariate analysis. RESULTS: The median overall survival time was 17 mo (95%CI: 13.2-20.7); and 1-, 2-, and 3- year survival rates were 65.5%, 45.2% and 35.4%. Serum albumin levels, serum carcinoembryonic antigen (CEA) levels, staging classifications by American Joint Committee on cancer, pathological tumor staging, lymph node metastases, tumor grading, surgical margin status, and if adjuvant chemotherapy was administered, were shown to be significant prognostic factors of resectable cholangiocarcinoma by univariate analysis. Multivariate analysis, however, established that only abnormal serum CEA [hazard ratio (HR) 1.68; P = 0.027] and lymph node metastases (HR 2.27; P = 0.007) were significantly associated with a decrease in overall survival, while adjuvant chemotherapy (HR 0.71; P = 0.067) and surgical margin negative (HR 0.72; P = 0.094) tended to improve survival time. CONCLUSION: Serum CEA and lymph node metastases which were associated with advanced stage tumors become strong negative prognostic factors in cholangiocarcinoma. PMID- 23671736 TI - Clinical presentation predicts the outcome of patients with colon cancer. AB - AIM: To elucidate the relationship between clinical presentation and outcome. METHODS: A single institution retrospective chart review of patients admitted with the diagnosis of colon cancer. We used univariate and a multivariate analysis to identify symptoms association with mortality. An odds ratio based clinical score was created to evaluate the contribution of the quality of symptoms to outcome. Primary measure of outcome was survival. RESULTS: During the study period, 236 patients met the inclusion criteria. Overall survival was 60.6%, mean follow-up 3.0 years. A bivariate analysis showed that increasing number of symptoms is not associated with mortality. However, a symptom-specific analysis performed using a logistic regression model controlling for age, stage and the duration of complaints revealed that the presence of melena was independently associated with mortality [P = 0.04, odds ratio (OR) 7.4], while rectal bleeding was associated with survival (P = 0.004, OR 3.9). Applying the proposed clinical score to an receiver operating characteristic curve showed that score > 1 had a strong association with mortality. The same logistic regression model was applied. The results showed that a score > 1 was an independent predictor of mortality (P < 0.001) and associated with node-positive disease (P = 0.008). CONCLUSION: The quality of symptoms rather than quantity is correlated with outcome among patients with colon cancer. The proposed clinical scoring system may correctly predict the patient's outcome. PMID- 23671734 TI - Current oncologic applications of radiofrequency ablation therapies. AB - Radiofrequency ablation (RFA) uses high frequency alternating current to heat a volume of tissue around a needle electrode to induce focal coagulative necrosis with minimal injury to surrounding tissues. RFA can be performed via an open, laparoscopic, or image guided percutaneous approach and be performed under general or local anesthesia. Advances in delivery mechanisms, electrode designs, and higher power generators have increased the maximum volume that can be ablated, while maximizing oncological outcomes. In general, RFA is used to control local tumor growth, prevent recurrence, palliate symptoms, and improve survival in a subset of patients that are not candidates for surgical resection. It's equivalence to surgical resection has yet to be proven in large randomized control trials. Currently, the use of RFA has been well described as a primary or adjuvant treatment modality of limited but unresectable hepatocellular carcinoma, liver metastasis, especially colorectal cancer metastases, primary lung tumors, renal cell carcinoma, boney metastasis and osteoid osteomas. The role of RFA in the primary treatment of early stage breast cancer is still evolving. This review will discuss the general features of RFA and outline its role in commonly encountered solid tumors. PMID- 23671737 TI - Efficacy of subcutaneous penrose drains for surgical site infections in colorectal surgery. AB - AIM: To investigate whether a subcutaneous penrose drain would decrease the superficial surgical site infection (s-SSI) rate in elective colorectal surgery. METHODS: This is a comparative study of the historical control type. Intervention consisted of the use of penrose drain in elective open colorectal surgical wounds. The outcome was an incidence of s-SSI. The patients were risk stratified according to the depth of subcutaneous tissue. RESULTS: There were 131 patients (40 patients with high s-SSI risk) in the prior period (from July 2008 to June 2009, when no penrose drains were inserted) and 151 patients (75 patients with high s-SSI risk) in the latter period (from June 2010 to November 2011, when penrose drains were inserted). The overall s-SSI rate was 6.1% and 5.3% during the two periods (P = 0.770), and the s-SSI rate in the high s-SSI risk group was 15.0% and 8.0% (P = 0.242). CONCLUSION: Although penrose drain was not observed to significantly reduce s-SSI, there tended to be a reduced risk of s-SSI in the high s-SSI risk group. PMID- 23671738 TI - Effect of Daikenchuto (TJ-100) on abdominal bloating in hepatectomized patients. AB - AIM: To evaluate the clinical usefulness of Daikenchuto (DKT) in hepatecomized patients. METHODS: Twenty patients were enrolled with informed consent. Two patients were excluded because of cancelled operations. The remaining 18 patients were randomly chosen for treatment with DKT alone or combination therapy of DKT and lactulose (n = 9, each group). Data were prospectively collected. Primary end points were Visual Analogue Scale (VAS) score for abdominal bloating, total Gastrointestinal Symptoms Rating Scale (GSRS) score for abdominal symptoms, and GSRS score for abdominal bloating. RESULTS: The VAS score for abdominal bloating and total GSRS score for abdominal symptoms recovered to levels that were not significantly different to preoperative levels by 10 d postoperation. Combination therapy of DKT and lactulose was associated with a significantly poorer outcome in terms of VAS and GSRS scores for abdominal bloating, total GSRS score, and total daily calorie intake, when compared with DKT alone therapy. CONCLUSION: DKT is a potentially effective drug for postoperative management of hepatectomized patients, not only to ameliorate abdominal bloating, but also to promote nutritional support by increasing postoperative dietary intake. PMID- 23671739 TI - Ligation of intersphincteric fistula tract and its modification: Results from treatment of complex fistula. AB - AIM: To compare healing rates between intersphincteric fistula tract (LIFT) and LIFT plus partial fistulectomy procedures. METHODS: A study of complex fistula-in ano patients was carried out from 1(st) March 2010 to 31(th) January 2012. All operations were done by colorectal surgeons at a referral center in a Ministry of Public Health hospital. Data collected included patients' demographic details, fistula type determined by endorectal-ultrasonography, preoperative and postoperative continence status, previous operations, time between diagnosis of fistula-in-ano and operation, type of surgery, healing rates, recurrence rates, and types of failure examined by endorectal-ultrasosnography, re-operation in recurrence or failure cases, and complications. RESULTS: The study involved 41 patients whose average age was 40.78 +/- 11.84 years (range: 21-71 years). The major fistula type was high-transsphincteric type fistula. The median follow-up period was 24 wk. The overall success rate was 83%: in the LIFT (Ligation intersphincteric fistula tract) group the success rate was 81% and in the LIFT plus (LIFT with partial coreout fistulectomy) group it was 85% (P = 0.529). The median wound-healing time was 4 wk in both groups (P = 0.262). The median time to recurrence was 12 wk. Neither group had incontinence (Wexner incontinence score 0) and the difference in healing rates between the two groups was not statistically significant. CONCLUSION: There was no difference in results between LIFT and LIFT plus operations. The LIFT procedure is a good option for maintaining continence in management of fistula-in-ano. PMID- 23671740 TI - Oncological imaging of the abdomen and pelvis: Spectrum of trends and advances. AB - Advancements in medical imaging have brought about unprecedented changes in the assessment, management and post-treatment follow-up of cancer. Sonography, positron emission tomography, computed tomography and magnetic resonance imaging are the primary tools being developed for oncological imaging. Advancements in these modalities, the introduction of new imaging and treatment techniques, as well as recent management of tumors, have led to continuous changes in diagnosis and treatment. Herein, we discuss the wide spectrum of imaging trends and advances. PMID- 23671741 TI - Intraoperative abdominal ultrasound in oncologic imaging. AB - Significant advances in ultrasound technology have created new opportunities for its use in oncologic imaging. The advent of new transducers with focal beam technology and higher frequency has solidified the role of intraoperative sonography (IOUS) as an invaluable imaging modality in oncologic surgery of the liver, kidneys and pancreas. The ability to detect and characterize small lesions and the precise intraoperative localization of such tumors is essential for adequate surgical planning in segmental or lobar hepatic resections, metastasectomy, nephron-sparing surgery, and partial pancreatectomy. Also, diagnostic characterization of small equivocal lesions deemed indeterminate by conventional preoperative imaging such as multidetector computed tomography or magnetic resonance imaging, has become an important application of IOUS. This article will review the current applications of IOUS in the liver, kidneys and pancreas. PMID- 23671742 TI - Virtual colonoscopy: Utility, impact and overview. AB - Computed tomography (CT) colonoscopy is a well-established technique for evaluation of colorectal cancer. Significant advances have been made in the technique of CT colonoscopy since its inception. Excellent results can be achieved in detecting both colorectal cancer and significant sized polyps as long as a meticulous technique is adopted while performing CT colonoscopy. Furthermore, it is important to realize that there is a learning curve involved in interpreting these studies and adequate experience is essential to achieve high sensitivity and specificity with this technique. Indications, contraindications, technique and interpretation, including potential pitfalls in CT colonoscopy imaging, are reviewed in this article. Recent advances and the current role of CT colonoscopy in colorectal cancer screening are also discussed. PMID- 23671743 TI - Abdominal applications of diffusion-weighted magnetic resonance imaging: Where do we stand. AB - Diffusion-weighted imaging (DWI) is one of the magnetic resonance imaging (MRI) sequences providing qualitative as well as quantitative information at a cellular level. It has been widely used for various applications in the central nervous system. Over the past decade, various extracranial applications of DWI have been increasingly explored, as it may detect changes even before signal alterations or morphological abnormalities become apparent on other pulse sequences. Initial results from abdominal MRI applications are promising, particularly in oncological settings and for the detection of abscesses. The purpose of this article is to describe the clinically relevant basic concepts of DWI, techniques to perform abdominal DWI, its analysis and applications in abdominal visceral MR imaging, in addition to a brief overview of whole body DWI MRI. PMID- 23671744 TI - Sonohysterography: Principles, technique and role in diagnosis of endometrial pathology. AB - Sonohysterography (SHG), which provides enhanced endometrial visualization during standard transvaginal ultrasonography, is a relatively safe procedure for the evaluation of endometrial pathology. It can be used to evaluate patients with abnormal vaginal bleeding or infertility. This modality offers real time imaging of the endometrium without exposure to ionizing radiation. SHG is typically used in patients for whom standard transvaginal ultrasonography does not show the endometrium well, show a potential abnormality for which further imaging is required, or in patients without endometrial pathology defined on routine transvaginal imaging but in whom there is a strong clinical suspicion of an abnormality. This article will discuss the utility of the sonohysterogram in evaluation of various endometrial pathologies. Imaging examples of these pathological entities will be illustrated as well. PMID- 23671745 TI - Cross-sectional imaging work-up of adrenal masses. AB - Advances in medical imaging with current cross-section modalities enable non invasive characterization of adrenal lesions. Computed tomography (CT) provides characterization with its non-contrast and wash-out features. Magnetic resonance imaging (MRI) is helpful in further characterization using chemical shift imaging (CSI) and MR spectroscopy. For differentiating between benign and malignant masses, positron emission tomography (PET) imaging is useful with its qualitative analysis, as well as its ability to detect the presence of extra-adrenal metastases in cancer patients. The work-up for an indeterminate adrenal mass includes evaluation with a non-contrast CT. If a lesion is less than 10 Hounsfield Units on a non-contrast CT, it is a benign lipid-rich adenoma and no further work-up is required. For the indeterminate adrenal masses, a lipid-poor adenoma can be differentiated from a metastasis utilizing CT wash-out features. Also, MRI is beneficial with CSI and MR spectroscopy. If a mass remains indeterminate, PET imaging may be of use, in which benign lesions demonstrate low or no fluorodeoxyglucose activity. In the few cases in which adrenal lesions remain indeterminate, surgical sampling such as percutaneous biopsy can be performed. PMID- 23671746 TI - Imaging of pancreatic ductal adenocarcinoma: State of the art. AB - Significant advances in imaging technology have changed the management of pancreatic cancer. In computed tomography (CT), this has included development of multidetector row, rapid, thin-section imaging that has also facilitated the advent of advanced reconstructions, which in turn has offered new perspectives from which to evaluate this disease. In magnetic resonance imaging, advances including higher field strengths, thin-section volumetric acquisitions, diffusion weighted imaging, and liver specific contrast agents have also resulted in new tools for diagnosis and staging. Endoscopic ultrasound has resulted in the ability to provide high-resolution imaging rivaling intraoperative ultrasound, along with the ability to biopsy via real time imaging suspected pancreatic lesions. Positron emission tomography with CT, while still evolving in its role, provides whole body staging as well as the unique imaging characteristic of metabolic activity to aid disease management. This article will review these modalities in the diagnosis and staging of pancreatic cancer. PMID- 23671747 TI - Patterns of peritoneal spread of tumor in the abdomen and pelvis. AB - The spread of tumor in the peritoneum can be understood, although it is a complex organ. A study of its embryology, anatomy and function is of clear benefit. It is formed from a network of folds, reflections, and potential spaces produced by the visceral and parietal peritoneum. These folds and reflections begin as a dorsal and ventral mesentery, supporting the primitive gut in early embryologic development. The dorsal mesentery connects the stomach and other organs to the posterior abdominal wall, while the ventral mesentery connects the stomach to the ventral abdominal wall. As the embryo develops, there is further organ growth, elongation, cavitation and rotation. The dorsal and ventral mesentery also develops along with the viscera, forming ligaments, mesenteries, omenta and potential spaces from the resulting reflections and folds. These ligaments, mesenteries, and omenta, support and nurture the organs of the peritoneum, providing a highway for arteries, veins, nerves and lymphatics. The potential spaces created from these folds and reflections of the visceral and parietal peritoneum are also important to realize. For example, the transverse mesocolon divides the peritoneal cavity into a supramesocolic and inframesocolic space in the abdomen and paravesicular spaces within the pelvis. The falciform ligament is well known in the supramesocolic space, dividing it further into a left and right compartment. Knowledge of the peritoneal vascular anatomy is beneficial in locating the spaces and ligaments about the peritoneum. For example, identifying the left gastric artery or vein will lead to the gastrohepatic ligament, which is part of the supramesocolic space. Besides serving a life sustaining role, the multiple compartments, ligaments, mesenteries and omenta within the peritoneum can also facilitate the spread of disease. Tumors can spread directly from one organ to another, seed metastatic deposits in the peritoneal cavity, and travel through the lymphatic or hematogenous route to invade other organs in the peritoneum. PMID- 23671748 TI - Multimodality imaging of ovarian cystic lesions: Review with an imaging based algorithmic approach. AB - Ovarian cystic masses include a spectrum of benign, borderline and high grade malignant neoplasms. Imaging plays a crucial role in characterization and pretreatment planning of incidentally detected or suspected adnexal masses, as diagnosis of ovarian malignancy at an early stage is correlated with a better prognosis. Knowledge of differential diagnosis, imaging features, management trends and an algorithmic approach of such lesions is important for optimal clinical management. This article illustrates a multi-modality approach in the diagnosis of a spectrum of ovarian cystic masses and also proposes an algorithmic approach for the diagnosis of these lesions. PMID- 23671750 TI - Endovascular treatment of carotid cavernous sinus fistula: A systematic review. AB - Carotid cavernous sinus fistulas are abnormal communications between the carotid system and the cavernous sinus. Several classification schemes have described carotid cavernous sinus fistulas according to etiology, hemodynamic features, or the angiographic arterial architecture. Increased pressure within the cavernous sinus appears to be the main factor in pathophysiology. The clinical features are related to size, exact location, and duration of the fistula, adequacy and route of venous drainage and the presence of arterial/venous collaterals. Noninvasive imaging (computed tomography, magnetic resonance, computed tomography angiography, magnetic resonance angiography, Doppler) is often used in the initial work-up of a possible carotid cavernous sinus fistulas. Cerebral angiography is the gold standard for the definitive diagnosis, classification, and planning of treatment for these lesions. The endovascular approach has evolved as the mainstay therapy for definitive treatment in situations including clinical emergencies. Conservative treatment, surgery and radiosurgery constitute other management options for these lesions. PMID- 23671751 TI - Asymmetrically hypointense veins on T2*w imaging and susceptibility-weighted imaging in ischemic stroke. AB - AIM: To review the literature on the assessment of venous vessels to estimate the penumbra on T2*w imaging and susceptibility-weighted imaging (SWI). METHODS: Literature that reported on the assessment of penumbra by T2*w imaging or SWI and used a validation method was included. PubMed and relevant stroke and magnetic resonance imaging (MRI) related conference abstracts were searched. Abstracts that had overlapping content with full text articles were excluded. The retrieved literature was scanned for further relevant references. Only clinical literature published in English was considered, patients with Moya-Moya syndrome were disregarded. Data is given as cumulative absolute and relative values, ranges are given where appropriate. RESULTS: Forty-three publications including 1145 patients could be identified. T2*w imaging was used in 16 publications (627 patients), SWI in 26 publications (453 patients). Only one publication used both (65 patients). The cumulative presence of hypointense vessel sign was 54% (range 32%-100%) for T2* (668 patients) and 81% (range 34%-100%) for SWI (334 patients). There was rare mentioning of interrater agreement (6 publications, 210 patients) and reliability (1 publication, 20 patients) but the numbers reported ranged from good to excellent. In most publications (n = 22) perfusion MRI was used as a validation method (617 patients). More patients were scanned in the subacute than in the acute phase (596 patients vs 320 patients). Clinical outcome was reported in 13 publications (521 patients) but was not consistent. CONCLUSION: The low presence of vessels signs on T2*w imaging makes SWI much more promising. More research is needed to obtain formal validation and quantification. PMID- 23671749 TI - Evaluation of cancer treatment in the abdomen: Trends and advances. AB - Response evaluation in Oncology has relied primarily on change in tumor size. Inconsistent results in the prediction of clinical outcome when size based criteria are used and the increasing role of targeted and loco-regional therapies have led to the development of new methods of response evaluation that are unrelated to change in tumor size. The goals of this review are to expose briefly the size based criteria and to present the non-size based approaches that are currently applicable in the clinical setting. Other paths that are still being explored are not discussed in details. PMID- 23671752 TI - Microstructural analysis of pineal volume using trueFISP imaging. AB - AIM: To determine the spectrum of pineal microstructures (solid/cystic parts) in a large clinical population using a high-resolution 3D-T2-weighted sequence. METHODS: A total of 347 patients enrolled for cranial magnetic resonance imaging were randomly included in this study. Written informed consent was obtained from all patients. The exclusion criteria were artifacts or mass lesions prohibiting evaluation of the pineal gland in any of the sequences. True-FISP-3D-imaging (1.5 T, isotropic voxel 0.9 mm) was performed in 347 adults (55.4 +/- 18.1 years). Pineal gland volume (PGV), cystic volume, and parenchyma volume (cysts excluded) were measured manually. RESULTS: Overall, 40.3% of pineal glands were cystic. The median PGV was 54.6 mm(3) (78.33 +/- 89.0 mm(3)), the median cystic volume was 5.4 mm(3) (15.8 +/- 37.2 mm(3)), and the median parenchyma volume was 53.6 mm(3) (71.9 +/- 66.7 mm(3)). In cystic glands, the standard deviation of the PGV was substantially higher than in solid glands (98% vs 58% of the mean). PGV declined with age (r = -0.130, P = 0.016). CONCLUSION: The high interindividual volume variation is mainly related to cysts. Pineal parenchyma volume decreased slightly with age, whereas gender-related effects appear to be negligible. PMID- 23671753 TI - Volumetric modulated arc radiotherapy for limited osteosclerotic myeloma. AB - AIM: To assess the feasibility of volumetric intensity-modulated arc radiotherapy (VMAT) in patients with limited polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome. METHODS: A 70-year-old male with histologically confirmed osteosclerotic myeloma was treated in our department in July 2010 with VMAT. Fourty-six Gray in 23 fractions were given on three bone lesions. Doses delivered to target volume and critical organs were compared with a tridimensional conformal radiotherapy (3D-RT) plan. Treatment was well tolerated without any side effects. RESULTS: VMAT improved dose homogeneity within the target volume, as compared to 3D-RT (standard deviations: 2.9 Gy and 1.6 Gy for 3D and VMAT, respectively). VMAT resulted in a better sparing of critical organs. Dose delivered to 20% of organ volume (D20) was reduced from 22 Gy (3D-RT) to 15 Gy (VMAT) for small bowel, from 24 Gy (3D-RT) to 17 Gy (VMAT) for bladder and from 47 Gy (3D-RT) to 3 Gy (VMAT) for spinal cord. Volumes of critical organs that received at least 20 Gy (V20) were decreased by the use of VMAT, as compared to 3D-RT (V20 bladder: 10% vs 99%; V20 small bowel: 6% vs 21%). One year after treatment completion, no tumor progression has been reported. CONCLUSION: VMAT improved dose distribution as compared to 3D-RT for limited osteosclerotic myeloma, with better saving of critical organs. PMID- 23671754 TI - Role of color Doppler in differentiation of Graves' disease and thyroiditis in thyrotoxicosis. AB - AIM: To evaluate the role of thyroid blood flow assessment by color-flow Doppler ultrasonography in the differential diagnosis of thyrotoxicosis and compare it to technetium pertechnetate thyroid scanning. METHODS: Twenty-six patients with thyrotoxicosis were included in the study. Clinical history was taken and physical examination and thyroid function tests were performed for all patients. Thyroid autoantibodies were measured. The thyroid glands of all patients were evaluated by gray scale ultrasonography for size, shape and echotexture. Color flow Doppler ultrasonography of the thyroid tissue was performed and spectral flow analysis of both inferior thyroid arteries was assessed. Technetium99 pertechnetate scanning of the thyroid gland was done for all patients. According to thyroid scintigraphy, the patients were divided into two groups: 18 cases with Graves' disease and 8 cases with Hashimoto's thyroiditis. All patients had suppressed thyrotropin. The diagnosis of Graves' disease and Hashimoto's thyroiditis was supported by the clinical picture and follow up of patients. RESULTS: Peak systolic velocities of the inferior thyroid arteries were significantly higher in patients with Graves' disease than in patients with thyroiditis (P = 0.004 in the right inferior thyroid artery and P = 0.001 in left inferior thyroid artery). Color-flow Doppler ultrasonography parameters demonstrated a sensitivity of 88.9% and a specificity of 87.5% in the differential diagnosis of thyrotoxicosis. CONCLUSION: Color Doppler flow of the inferior thyroid artery can be used in the differential diagnosis of thyrotoxicosis, especially when there is a contraindication of thyroid scintigraphy by radioactive material in some patients. PMID- 23671755 TI - MDCT of right aortic arch with aberrant left subclavian artery associated with kommerell diverticulum and calcified ligamentum arteriosum. AB - We present a case of the right aortic arch with kommerell diverticulum (KD) and aberrant left subclavian artery in a symptomatic 50-year-old patient with a calcification in the presumed attachment site of the ligamentum arteriosum (LA) to the KD. In another 30-year-old male patient, the entire course of a calcified LA was demonstrated using multidetector row computed tomography. PMID- 23671756 TI - Thoracic epidural angiolipoma: A case report and review of the literature. AB - Angiolipoma of the spine is a benign neoplasm consisting of both mature fatty tissue and abnormal vascular elements, and usually presents with a slow progressive clinical course. Our patient presented with bilateral lower extremity weakness and chest-back numbness. Physical examination revealed adipose elements superficial hypesthesia below the T5 level and analgesia below the T6 level. Magnetic resonance imaging (MRI) scan showed an avidly and heterogeneously enhancing mass which was located in the posterior epidural space. Compression of the thoracic cord by the fusiform mass was seen between T3-T4. During the operation, a flesh pink vascular mass (4.7 cm * 1.0 cm * 1.0 cm) with obscure margin and strong but pliable texture was found in the posterior epidural space extending from T3 to T4. There was no infiltration of the dura or the adjacent bony spine. Histopathological study of the surgical specimen showed a typical angiolipoma. We review the previously documented cases of spinal extradural angiolipomas performed with MRI. PMID- 23671758 TI - Psychotrauma research in the Netherlands. PMID- 23671757 TI - Antibiotic susceptibility of Aggregatibacter actinomycetemcomitans JP2 in a biofilm. AB - BACKGROUND: Localized aggressive periodontitis (LAgP) is an inflammatory disease associated with specific bacteria, particularly Aggregatibacter actinomycetemcomitans, which can result in early tooth loss. The bacteria grow as a biofilm known as subgingival plaque. Treatment includes mechanical debridement of the biofilm, often associated with empirical antibiotic treatment. OBJECTIVE: The aims of this study were to test in vitro the sensitivity of A. actinomycetemcomitans JP2 during planktonic and biofilm growth to doxycycline and to the combination of metronidazole and amoxicillin, which are two antibiotic protocols commonly used in clinical practice. DESIGN: Two in vitro biofilm models were used to test the effects of the antibiotics: a static 96-well plate assay was used to investigate the effect of these antibiotics on biofilm formation whilst a flow chamber model was used to examine the effect on established biofilms. RESULTS: Of the antibiotics tested in this model system, doxycycline was most efficacious with a minimal inhibitory concentration (MIC) against planktonic cells of 0.21 mg/L and minimal biofilm inhibitory concentration (MBIC) of 2.10 mg/L. The most commonly prescribed antibiotic regimen, amoxicillin + metronidazole, was much less effective against both planktonic and biofilm cells with an MIC and MBIC of 12.0 mg/L and 20.2 mg/L, respectively. A single treatment of the clinically achievable concentration of 10 mg/L doxycycline to sparse A. actinomycetemcomitans biofilms in the flow chamber model resulted in significant decreases in biofilm thickness, biovolume, and cell viability. Dense A. actinomycetemcomitans biofilms were significantly more resistant to doxycycline treatment. Low concentrations of antibiotics enhanced biofilm formation. CONCLUSION: A. actinomycetemcomitans JP2 homotypic biofilms were more susceptible in vitro to doxycycline than amoxicillin + metronidazole. PMID- 23671759 TI - Bouncing forward of young refugees: a perspective on resilience research directions. AB - While studies on the consequences of trauma and forced migration on young refugees have focused mainly on their pathology, a focus on resilience in young refugees is needed to adequately represent their response to adversity and to help understand their needs. The aim of this article is to present a proposed study of resilience in young refugees which has been informed by an overview of achievements and challenges in the field of resilience. IN ORDER TO ADVANCE THE FIELD OF RESILIENCE, SEVERAL TOPICS NEED CLARIFICATION: definition and assessment of resilience, the relation of resilience to other constructs and the underlying biological and external factors influencing resilience. With respect to young refugees, the cross-cultural applicability of resilience has to be examined. Qualitative research, mixed method designs, comparative studies, and longitudinal studies seem especially promising in furthering this goal. The proposed study compares refugee adolescents with Dutch adolescents. Data from qualitative evidence synthesis, interviews, questionnaires, experiments, and DNA analysis will be combined to provide a multifaceted picture of factors contributing to resilience, resulting in a better understanding and efficient use of "resilience" to meet the needs of traumatised youth. PMID- 23671760 TI - Susceptibility to long-term misinformation effect outside of the laboratory. AB - OBJECTIVE: To test the effect of misinformation outside of the laboratory and to explore correlates of the effect, including arousal, cognitive ability, and neuroticism. METHOD: About 2 months before deployment to Afghanistan, 249 soldiers enrolled in this study, which was embedded in a larger project. Two months after deployment, participants were interviewed about stressors on deployment and they received subtle misinformation about a fictional event on deployment. Seven months later, they were retested, and completed a questionnaire about events on deployment. RESULTS: At 9 months, a total of 26% of participants reported that they had experienced the fictional event, although 7 months earlier they said they had not experienced it. Logistic regression analyses revealed that lower cognitive ability and a combination of high arousal and more stressors on deployment were related to higher susceptibility to the misinformation effect. CONCLUSIONS: Results suggest that information provided by another source may be incorporated into related autobiographical memory, particularly for individuals with lower cognitive ability, high arousal at the time of encoding the information and more related experiences. PMID- 23671761 TI - The role of major depression in neurocognitive functioning in patients with posttraumatic stress disorder. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) frequently co-occur after traumatic experiences and share neurocognitive disturbances in verbal memory and executive functioning. However, few attempts have been made to systematically assess the role of a comorbid MDD diagnosis in neuropsychological studies in PTSD. OBJECTIVE: The purpose of the current study is to investigate neurocognitive deficits in PTSD patients with and without MDD. We hypothesized that PTSD patients with comorbid MDD (PTSD+MDD) would have significantly lower performance on measures of verbal memory and executive functioning than PTSD patients without MDD (PTSD-MDD). METHOD: Participants included in this study were 140 treatment-seeking outpatients who had a diagnosis of PTSD after various single traumatic events and participated in a randomized controlled trial comparing different treatment types. Baseline neuropsychological data were compared between patients with PTSD+MDD (n=84) and patients with PTSD MDD (n=56). RESULTS: The PTSD+MDD patients had more severe verbal memory deficits in learning and retrieving words than patients with PTSD alone. There were no differences between the groups in recall of a coherent paragraph, recognition, shifting of attention, and cognitive interference. CONCLUSIONS: The results of this study suggest that a more impaired neurocognitive profile may be associated with the presence of comorbid MDD, with medium-sized group differences for verbal memory but not for executive functioning. From a clinical standpoint, being aware that certain verbal memory functions are more restricted in patients with comorbid PTSD and MDD may be relevant for treatment outcome of trauma-focused psychotherapy. PMID- 23671762 TI - Acute stress differentially affects spatial configuration learning in high and low cortisol-responding healthy adults. AB - BACKGROUND: Stress and stress hormones modulate memory formation in various ways that are relevant to our understanding of stress-related psychopathology, such as posttraumatic stress disorder (PTSD). Particular relevance is attributed to efficient memory formation sustained by the hippocampus and parahippocampus. This process is thought to reduce the occurrence of intrusions and flashbacks following trauma, but may be negatively affected by acute stress. Moreover, recent evidence suggests that the efficiency of visuo-spatial processing and learning based on the hippocampal area is related to PTSD symptoms. OBJECTIVE: The current study investigated the effect of acute stress on spatial configuration learning using a spatial contextual cueing task (SCCT) known to heavily rely on structures in the parahippocampus. METHOD: Acute stress was induced by subjecting participants (N = 34) to the Maastricht Acute Stress Test (MAST). Following a counterbalanced within-subject approach, the effects of stress and the ensuing hormonal (i.e., cortisol) activity on subsequent SCCT performance were compared to SCCT performance following a no-stress control condition. RESULTS: Acute stress did not impact SCCT learning overall, but opposing effects emerged for high versus low cortisol responders to the MAST. Learning scores following stress were reduced in low cortisol responders, while high cortisol-responding participants showed improved learning. CONCLUSIONS: The effects of stress on spatial configuration learning were moderated by the magnitude of endogenous cortisol secretion. These findings suggest a possible mechanism by which cortisol responses serve an adaptive function during stress and trauma, and this may prove to be a promising route for future research in this area. PMID- 23671763 TI - A cross-cultural validation of the Clinician Administered PTSD Scale for Children and Adolescents in a Dutch population. AB - BACKGROUND: Trauma-focused interventions for children could be administered more efficiently and effectively if posttraumatic stress disorder (PTSD) and related symptoms were first investigated by a reliable and valid instrument. The Clinician Administered PTSD Scale for Children and Adolescents (CAPS-CA) is the gold standard for the assessment of PTSD. Until now no cross-cultural validation study has been published in an English peer-reviewed journal. OBJECTIVE: This study aimed at the cross-cultural validation of the Dutch CAPS-CA. METHOD: A total of 112 children between the age of 8 and 18 were recruited at two trauma centers. Children were interviewed with the CAPS-CA and the Anxiety Disorders Interview Schedule Child (ADIS-C) version, and each filled out the Children's Revised Impact of Events Scale (CRIES-13), the Revised Child Anxiety and Depression Scale (RCADS), and the Strength and Difficulties Questionnaire (SDQ). One caretaker of each child was also interviewed by means of the ADIS Parent (ADIS-P) version and filled out the RCADS and SDQ. RESULTS: The Dutch CAPS-CA showed as good internal consistency, inter-rater reliability, convergent and divergent validity, and concurrent validity as the original English version. Similar to the original version, we found better psychometric properties in terms of internal consistency and convergent validity for children 13 years and older than for children younger than 13 years. CONCLUSIONS: The Dutch CAPS-CA is as reliable and valid as the original English version. PMID- 23671765 TI - Gross human rights violations and reparation under international law: approaching rehabilitation as a form of reparation. AB - The strengthening of international criminal law through an increased focus on the right to reparation and rehabilitation for victims of crimes against humanity represents an important challenge to health professionals, particularly to those in the field of trauma research and treatment. A brief outline of some developments in the field of international law and justice for victims of gross human rights violations is presented, with a focus on the right to reparation including the means for rehabilitation. The fulfillment of this right is a complex endeavor which raises many questions. The road to justice and reparation for those whose rights have been brutally violated is long and burdensome. The active presence of trauma-informed health professionals in this process is a priority. Some of the issues raised within the context of states' obligations to provide and ensure redress and rehabilitation to those subjected to torture and gross human rights violations are discussed, and in particular how rehabilitation can be understood and responded to by health professionals. PMID- 23671764 TI - Psychotraumatology in the Netherlands. AB - The contribution to psychotrauma literature from Dutch authors has a long tradition. The relatively high lifetime prevalence of trauma and posttraumatic stress disorder (PTSD) is not unique for the Netherlands and does not fully explain the interest in trauma and its consequences. In this overview of psychotraumatology in the Netherlands, we will discuss some of the key events and processes that contribute to the current interest. We outlined the historical basis and development of the field in the Netherlands, including the impact of World War II, the effects of major man-made or natural disasters, engagement in military conflicts, as well as smaller scale traumatic events like sexual abuse and traffic accidents. The liberal and open culture may have reduced stigma to trauma, while other sociocultural aspects may have contributed to increased prevalence. Finally, we describe Dutch psychotraumatology today and how history and culture have shaped the current scientific basis. PMID- 23671766 TI - Aggression inoculates against PTSD symptom severity-insights from armed groups in the eastern DR Congo. AB - BACKGROUND: In the ongoing conflict in the Democratic Republic of the Congo (DRC), combatants are exposed to massive forms of violence and other traumatic stressors. Nevertheless, many combatants do not suffer from trauma-related disorders, although they have experienced numerous traumatizing events. Perceiving aggressive behavior as fascinating and arousing might be a defense against trauma-related disorders in the violent environment of war and conflict. OBJECTIVE: Thus, in this study we investigated the relationship between the exposure to traumatic stressors, appetitive aggression, and posttraumatic stress disorder (PTSD) symptom severity. We hypothesized that cumulative traumatic experiences correlated positively and appetitive aggression negatively with PTSD symptom severity. METHOD: In total, 105 voluntary male combatants from different armed groups in the eastern DRC took part in this study. In a semistructured interview, respondents were questioned about their exposure to traumatic stressors, the extent of appetitive aggression (Appetitive Aggression Scale) and their PTSD symptom severity (PTSD Symptom Scale - Interview). RESULTS: A multiple sequential regression analysis showed that traumatic events were positively related to PTSD symptom severity. For participants with low to medium PTSD symptom severity, appetitive aggression correlated negatively with PTSD symptom severity. CONCLUSIONS: The results of this study provide further support for earlier findings that repeated exposure to traumatic stressors cumulatively heightens the risk of PTSD and revealed that appetitive aggression buffers the risk of developing PTSD symptoms under certain circumstances. Thus, the perception of aggressive behavior as fascinating and arousing seem to help combatants to adapt to violent environments but may also be one reason for recurrent failure of reintegration programs for excombatants. PMID- 23671767 TI - Estimating Blood Pressure in Children and Adolescents: Should Body Weight be Included? PMID- 23671769 TI - The relationship between social anxiety and online communication among adolescents in the city of isfahan, iran. AB - BACKGROUND: The internet is a phenomena that changes human, specially the younger generation's, life in the 21(st) century. Online communication is a common way of interacting among adolescents who experience feelings of social anxiety. The aim of this study was to investigate the relationship between social anxiety and online communication in adolescents. METHODS: Three hundred and thirty students aged 13-16 years were selected from eight middle and high schools in Isfahan by multistage cluster sampling. Each of them completed a survey on the amount of time they spent communicating online, the topics they discussed, the partners they engaged with and their purpose for communicating over the internet. They also completed the social anxiety scale of adolescents. Data were analyzed using Pearson correlation and multiple regression. RESULTS: Results of the Pearson analysis showed that online communication has a significant positive relationship with apprehension and fear of negative evaluation (AFNE), and a significant negative relationship with tension and inhibition in social contact (TISC) (P < 0.01). The results of regression analysis showed that the best predictor of online communication is AFNE, TISC. CONCLUSIONS: It is suggested that students from middle school get assessed in terms of the level of social anxiety. Then, the quality and quantity of their online communication should be moderated through group training and consulting and referral to medical centers, if needed. The results of this study may lead to optimal use of online communications and reduce the personal, social and psychological problems of adolescents. PMID- 23671768 TI - Prevention and treatment of respiratory consequences induced by sulfur mustard in Iranian casualties. AB - BACKGROUND: About 100,000 Iranian have been exposed to chemical weapons during Iraq-Iran conflict (1980-88). After being spent of more than two decades, still about 30,000 of them are under follow-up treatment. The main aim of this study was to review various preventive and therapeutic methods for injured patients with sulfur mustard in different phases. METHODS: For gathering information, we have used the electronic databases including Scopus, Medline, ISI, IranMedex, Irandoc sites. According to this search strategy, 104 published articles associated to respiratory problems and among them 50 articles related to prevention and treatment of respiratory problems were found and reviewed. RESULTS: There is not any curative treatment for sulfur mustard induced lung injuries, but some valuable experienced measures for prevention and palliative treatments are available. Some useful measures in acute phase include: Symptomatic management, oxygen supplementation, tracheostomy in laryngospasm, use of moist air, respiratory physical therapy, mucolytic agents and bronchodilators. In the chronic phases, these measures include: Periodic clinical examinations, administration of inhaled corticosteroids alone or with long-acting beta 2 agonists, use of antioxidants, magnesium ions, long term oxygen supplement, therapeutic bronchoscopy, laser therapy, and use of respiratory tract stents. CONCLUSIONS: Most treatments are symptomatic but using preventive points immediately after exposure could improve following outcomes. PMID- 23671770 TI - Knowledge, Attitudes, and Practices Regarding Pandemic H1N1 Influenza Among Medical and Dental Residents and Fellowships in Shiraz, Iran. AB - BACKGROUND: Influenza disease is one of the oldest medical problems that can cause severe illness and high mortality rates, worldwide. In flu pandemics, medical and dental students' knowledge, attitudes, and practices (KAP) is critical to save patients life. The aim of this study was to determine the score of KAP toward the Pandemic H1N1 and their predictor factors among the medical and dental residents and fellowships of Shiraz University of Medical Sciences, Iran. METHODS: In 2009, 125 participants were recruited in a convenient sampling cross sectional survey. Self-reported questionnaire were used and results were analyzed applying appropriate statistical tests. RESULTS: The mean score of participants' knowledge, attitude and practice were 22.6, 21.1 and 26.5 respectively. Participants practice had significant linear positive correlation with knowledge and attitude. Also, their age was significantly and directly correlated to knowledge and practice. The educational major, age, and sex were significant predictors of responder's knowledge score and age was the only significant predictor of both attitude and practice scores. CONCLUSIONS: High knowledge is not sufficient lonely for improve attitude and practices. It seems that traditional educational models are not efficient and governments should emphasize to advanced and motivational education methods including health belief model and motivational interview at postgraduate levels. Perhaps younger students, dentists and males have less motivation to change their attitude and behavior, so we can focuses our interventions in these groups. PMID- 23671771 TI - How much in vitro cholesterol reducing activity of lactobacilli predicts their in vivo cholesterol function? AB - BACKGROUND: Based on literature, in vitro cholesterol removal of lactic acid bacteria has been accounted for their in vivo cholesterol reduction. But recently it has been proposed that such in vitro characteristic may not be directly relevant to their in vivo activity. The objective of this study was to find how much in vitro cholesterol reducing potential of Lactobacillus plantarum A7 (LA7), a native strain isolated from an infant fecal flora, reflects its in vivo efficiency. LA7 previously showed serum cholesterol reducing capability in mice subjected to fatty diet. Here, we investigate whether the given strain is capable of in vitro cholesterol assimilation or consumption. METHOD: LA7 was cultured in whole milk and de-Man-Rogosa-Sharpe (MRS) added with water-soluble cholesterol. Colorimetric method was adopted for cholesterol determination in both cultured media during incubation period. RESULTS: No cholesterol assimilation was detected by growth and incubation of the active culture in either of the medium. Thus, in vivo cholesterol function of LA7 was not caused by cholesterol consumption. A comprehensive review of literature on the related studies also showed that there are other documented studies which evidenced the uncertainty of the direct relation between in vitro and in vivo studies. CONCLUSION: Cholesterol removal from the cultured media may not be considered as an appropriate integral index for selection of Lactobacillus strains with cholesterol-lowering activity. PMID- 23671772 TI - On the Use of Fractional Polynomial Models to Assess Preventive Aspect of Variables: An Example in Prevention of Mortality Following HIV Infection. AB - BACKGROUND: Identification of disease risk factors can help in the prevention of diseases. In assessing the predictive value of continuous variables, a routine procedure is to categorize the factors. This yield to inability to detect non linear relationship, if exist. Multivariate fractional polynomial (MFP) modeling is a flexible method to reveal non-linear associations. We aim to demonstrate the impact of choice of risk function on the significance of variables. METHODS: We selected 6508 HIV-infected persons registered in the Australia National HIV Registry between 1980 and 2003 to assess the predictors associated with the risk of death after HIV infection prior to AIDS. First, CD4 count as a categorical factor with three other categorical variables (age, sex, and HIV exposure category) was entered into the Cox regression model. Second, CD4 counts as a continuous variable along with other categorical variables were entered into the fractional polynomial (FP) model. RESULTS: Both the Cox and FP models showed age >= 40 years and hemophiliac patients were significantly associated with increased risk of death. In the categorized model, the CD4 variable did not reach the significance level. However, this variable was highly significant in the MFP model. The FP model showed slightly better performance in terms of discrimination ability and goodness of fit. CONCLUSIONS: The FP model is a flexible method in detecting the predictive effect of continuous variables. This method enhances the ability to assess the predictive ability of variables and improves model performance. PMID- 23671773 TI - Protective status of end-stage renal disease children against tetanus and diphtheria vaccination. AB - BACKGROUND: Vaccination against fatal viral and bacterial diseases is still the best protective way to lower morbidity and mortality rate in end-stage renal disease (ESRD) patients. It has been reported that there is high incidence of low protective levels of IgG after vaccination in ESRD adult patients. The aim of this study was to evaluate the protective status of vaccination against diphtheria and tetanus in ESRD children after completing routine vaccination. METHODS: This cross-sectional study was carried on 83 participants less than 18 years including 27 patients on hemodialysis or peritoneal dialysis and 56 normal populations from February 2008 until December 2008 at St. Alzahra hospital, Isfahan, Iran. To determine anti-tetanus and anti-diphtheria antibodies level, Tetanus IgG ELISA kit (IBL International, Germany, RE56901) and Diphtheria IgG ELISA kit (IBL International, Germany, RE56191) were used. The participants must not received immunoglobulin, blood products or immunosuppressive medication in the current 6 months. RESULTS: The mean age of case and control group were 12.5 +/- 2.7 years and 11.7 +/- 3.3 years, respectively, P > 0.05. According to IgG levels, 93% of hemodialysis patients and approximately 87% of peritoneal dialysis children needed booster doses of diphtheria vaccination. The results for IgG titer against tetanus revealed that in 91% of hemodialysis patients and 83% of peritoneal dialysis children booster doses of tetanus were recommended. CONCLUSIONS: Booster doses of vaccines may be required in ESRD children. Measuring serum IgG levels against vaccines to define protective levels are recommended. PMID- 23671774 TI - Do our medical colleges inculcate health-promoting lifestyle among medical students: a pilot study from two medical colleges from southern India. AB - BACKGROUND: Behavioral risk factors are responsible for a substantial portion of chronic disease. Educating patients is a professional responsibility of medical practitioners. However, it has been observed that physicians did not practice what they preach. To study whether medical colleges inculcate health-promoting lifestyle among medical students during their stay in medical colleges. METHODS: A cross-sectional study conducted in two conveniently selected medical colleges in southern India. Fourth year MBBS students were included in the study. A pre tested self-administered multiple choice type questionnaire was used to collect data. Information was sought on the behavioral factors, namely smoking, alcohol use, junk food consumption, and physical activity, before joining the medical college and at the time of the study. SPSS version 10.0 was used to analyze the data. Frequencies, proportions, chi-square test. RESULTS: Out of 176 respondents, 94 (53%) were males and 82 (47%) were females. The number of smokers had increased from 24 (13.6%) to 46 (26.1%) and the number of alcohol consumers from 34 (19.3%) to 77 (43.8%) since they joined medical college. The number of students doing any physical activity declined from 76 (43.2%) to 43 (24.4%) and their food habits became unhealthier during the same period. CONCLUSIONS: The study reported an increase in health-risking behavior and a decline in health promoting behavior among medical students during their stay in medical college. PMID- 23671776 TI - Hour glass constriction in advanced carpal tunnel syndrome. AB - BACKGROUND: Compressive neuropathy of median nerve is relatively common but development of an hourglass like constriction is a rare phenomenon. The purpose of this study is to show morphologic changes of median nerve in advances carpal tunnel syndrome. METHODS: Eighty patients with thenar atrophy, anesthesia and paresthesia of first, second and third finger and severe changes of EMG-NCV were chosen for surgery. All the cases were operated by classic approach. RESULTS: At ten cases, nerve was constricted in point and in six patients' area constriction was seen. Internal and external neurolysis was performed in all the cases. In two of them because of the wide and severe constriction, resection and end-to-end repair was performed. All the patients have been examined periodically. Mean follow-up was 12 month (8-40). According to grading, pain degree (from 8-9 pre operation to 3-4 post operation) and two point discrimination (from the mean of 14 mm (13-20 mm) to 8 mm (6-10 mm)) decreased. Grip power was increased from the mean of 10 kg to 21 kg. In 15 cases return of sensation, and in 13 cases improvement of opposition power was seen. CONCLUSION: We recommend epineurolysis for mild to moderate constriction and also end-to-end repair may be needed if extensive and severe constriction was found. It means that if we manage mild to moderate constriction sooner, it can prevent the need for further surgical procedure because of sever constriction. PMID- 23671775 TI - The effect of synchronized running activity with chronic stress on passive avoidance learning and body weight in rats. AB - BACKGROUND: Different stressors induce learning and memory impairment and physical activity influence learning and memory enhancement. In this research, we investigated the effect of synchronized running activity with stress on acquisition and retention time of passive avoidance test. METHODS: MALE WISTAR RATS WERE RANDOMLY DIVIDED INTO FIVE GROUPS AS FOLLOWS: Control (Co), Sham (Sh), Exercise (Ex), Stress (St), synchronized exercise with stress (St and Ex) groups. Chronic restraint stress was applied by 6 h/day for 21 days and treadmill running 1 h/day for 21 days. For evaluation of learning and memory, initial and step through latency were determined at the end of study by using passive avoidance learning test. RESULTS: OUR RESULTS SHOWED THAT: (1) Exercise under no stress provides beneficial effects on memory acquisition and retention time compared to Control group; especially retention time had significantly (P < 0.05) increased in exercised group. (2) Chronic stress with and without synchronized exercise significantly (P < 0.01, P < 0.05, respectively) impaired acquisition and retention time. (3) Body weight differences were significantly (P < 0.01, P < 0.001 and P < 0.001) lower than Control group in exercise, stress and synchronized exercise with stress groups, respectively. (4) Adverse effects of restraint stress (psychical stress) were probably greater than physical activity effects on learning, memory and weight loss. CONCLUSIONS: The data confirmed that synchronized exercise with stress had not significantly protective role in improvement of passive avoidance acquisition and retention time; hence it did not significantly improve learning and memory deficit in stressed rats; whereas exercise alone could improve memory deficit in rats. PMID- 23671777 TI - Effectiveness of motivational interviewing in promoting hand hygiene of nursing personnel. AB - BACKGROUND: Motivational interviewing (M.I.) is an option for modifying an individual's behavior. It is used as an educational method in recent years. The aim of our study was to indicate whether or not education, using lecture alone and lecture with M.I., would affect the performance of nursing personnel regarding their hand hygiene. If so, which of these two methods were most effective for this purpose? METHODS: This was an interventional study conducted in Bahrami Pediatric Hospital in Tehran. The study population consisted of all nursing personnel in the hospital. Considering the responsibilities of different nurses and their educational status, we divided them into three classes. The participants of each class were randomly assigned to either the control or experiment groups training lecture alone or lecture with M.I., respectively. We used Independent-t, Paired-t, Mann-Whitney U and Wilcoxon signed ranks tests for analysis. RESULTS: Education using lecture alone improved the hand hygiene performance of nursing personnel only in the first and third classes (P = 0.002 and P = 0.001, respectively). Similarly, lecture combined with M.I. improved the hand hygiene performance of personnel in the first and third classes (P < 0.001 and P = 0.004, respectively). The latter method was more effective compared to lecture alone in the first and third classes (P < 0.001 and P = 0.013, respectively). CONCLUSIONS: Education based on lecturing improves hand hygiene performance among nursing personnel. It will be more effective if combined with M.I. PMID- 23671778 TI - Major dietary patterns and their associations with overweight and obesity among Iranian children. AB - BACKGROUND: Increasing prevalence of obesity is a major health concern. Lifestyle behaviors and diet play an important role in developing childhood obesity. The aim of this study was to determine the association between major dietary patterns and overweight/obesity in a group of Iranian school-aged children. METHODS: This cross-sectional study was conducted in Isfahan, Iran with 637 elementary school aged children. A semi-quantitative food-frequency questionnaire was used to assess usual dietary intakes. Data on socio-demographic, physical activity and other lifestyle habits were collected using standard questionnaires. Obesity was determined based on national cut-offs. Factor analysis was used for identifying major dietary patterns. RESULTS: Three major dietary patterns were extracted; "Healthy," "Western," and "Sweet-Dairy." After adjusting for confounders, girls in the second quartile of healthy pattern, were more likely to be overweight (odds ratio [OR] =2.23, Confidence intervals [CI] =1.003, 4.96) compared to those in the highest quartile. Likelihood of being overweight was lower for girls in the second quartile of western dietary pattern versus the fourth quartile (OR = 0.46, CI = 0.21, 1.01). Accordingly, lower adherence to sweet and dairy pattern was associated with lower body mass index (BMI) among girls (OR = 0.42, CI = 0.21, 0.85). There was no significant relationship between western and sweet dairy pattern with BMI among boys, however, significant association was observed between lowest and highest quartiles of healthy pattern (OR = 0.36, CI = 0.15, 0.84). CONCLUSIONS: We found significant associations between the three dietary patterns and obesity among girls. Only healthy pattern was related to weight status of schoolboys. Longitudinal studies will be needed to confirm these associations. PMID- 23671779 TI - Are The Predictors of Hookah Smoking Differ From Those of Cigarette Smoking? Report of a population-based study in Shiraz, Iran, 2010. AB - BACKGROUND: The aim of this study was to determine the prevalence of tobacco use and effect of lifestyle factors on cigarette and hookah use among adult residents of Shiraz, Iran. METHODS: In 2010, 1,000 participants were recruited in a multistage, random sampling cross-sectional population-based survey. RESULTS: Response rate was 98%. Prevalence of cigarette smoking was 9.7%. Among cigarette users, 12.6% reported smoking <1 year; 13.4% smoked 1-2 years and 73.9% smoked>2 years. Almost half of those surveyed (48.9%) smoked <10 cigarettes per day (cpd); 28.4% smoked 10-15 cpd; 14.8% smoked 16-19 cpd, and 8%>20 cpd. Almost a quarter (20.4%) of the cigarette smokers tried to quit in the past year. Being male, married, aged 37-54, having higher perceived levels of stress, a non-manual occupation, and sedentary lifestyle were positively associated with cigarette smoking. Manual labor occupations, housewife/jobless status, and going frequently to restaurants were positive predictors of hookah smoking. CONCLUSIONS: Compared to cigarettes, hookah smoking was more prevalent among Iranian adults. Approximately, the prevalence of hookah smoking in women is the same as men, whereas cigarette use was 31 times more common in men. Cigarette and hookah smoking were associated with less healthy lifestyle habits in both men and women. PMID- 23671780 TI - Relationship of body satisfaction, with nutrition and weight control behaviors in women. AB - BACKGROUND: Considering the importance and prevalence of obesity and the desire to lose weight, especially among women, this study intended to investigate the relationship between Body Mass Index, body satisfaction, and weight control behavior among women employees in Isfahan. METHODS: An analytical cross-sectional study was conducted among 408 women who were selected by stratified random sampling method among employees at Isfahan University and Isfahan University of Medical Sciences during 2012. The data collection tool was a multidimensional questionnaire which comprised two sections: Demographic Tool and Body Satisfaction Tool (7 items), Weight Control Behavior Scale (18 items). RESULTS: Age, marital status, educational level, and multiparity were significantly correlated with body size satisfaction. Seventy-five participants were dissatisfied with their weight and 60.5% reported a desire to lose weight; 92.15% of women studied had participated in a healthy dieting behavior and 10.8% of them had participated in an unhealthy one during the past six months. There was an inverse correlation between body satisfaction and Body Mass Index (BMI) (r = 0.64, P = 0.001). Ninety percent of participants had at least one of the dieting behaviors. There was an inverse significant relationship between body satisfaction and dieting behaviors (r = -0.19, P = 0.001). CONCLUSIONS: Due to the importance of the prevention of obesity and the necessity of having a normal BMI in order to prevent subsequent complications, precise self-evaluation of body size can be used to focus on designing and conducting public health programs, especially for women. PMID- 23671781 TI - Salt intake and the association with blood pressure in young Iranian children: first report from the middle East and north Africa. AB - BACKGROUND: This study aimed to assess the salt intake of Iranian children, and to assess the correlation of urinary electrolytes excretion with blood pressure. METHODS: This cross-sectional study was conducted in 2011-2012 among 3-10-year old children, selected by multi-stage cluster sampling from urban and rural areas of Isfahan, Iran. The sodium (Na), potassium (K), and creatinine (Cr) were measured in a random sample of the children's first morning fasting urine. Three day averages of dietary intakes were analyzed by the Nutritionist-4 software. RESULTS: The mean (SD) of urinary Na was 177.17 (28.68) mEq/day without significant difference according to gender and living area. The mean (SD) dietary intakes of Na and K were 2017.76 (117.94) and 1119.06 (76.03) mg/day, respectively. Children of urban and rural areas consumed similar sources of salty foods (bread, cheese, and snacks) and had low intake of vegetables. No significant association was documented between urinary electrolytes excretions and blood pressure. CONCLUSIONS: This study, which to the best of our knowledge is the first of its kind in the Middle East and North Africa region, revealed that Iranian young children consume a large amount of sodium and small amount of potassium. The non-significant associations of electrolyte excretions with blood pressure may be because of the very young age group of participants. Given the development of preference to salt taste from early childhood, and the tracking of risk factors of chronic diseases from this age, reducing salt intake of young children should be emphasized. PMID- 23671782 TI - Thematic Analysis of Iranian Female Adolescents' Perceptions About HIV/AIDS: A Qualitative Study. AB - BACKGROUND: HIV/AIDS continues to be a major global health problem. The aim of this study was to evaluate common opinions and beliefs about HIV/AIDS among Iranian teenager girls. METHODS: This Qualitative study (face-to-face interviews with tape recording) was conducted among fifty female teenager school students in Urmia-Iran. RESULTS: The thematic analysis indicated the main information sources for HIV/AIDS among teenage girls to be their mother and teachers. The participants had little concern about the dissemination of HIV/AIDS in Iran. Using a common syringe is mentioned as the main risk factor for HIV transmission. There were some misconceptions about the at-risk group among teenage girls. CONCLUSIONS: Considering the misconceptions among the teenage girls, their beliefs should be reformed and reorganized in order to reduce the risk of exposure to HIV. The best practice is training life skills in the school level. PMID- 23671783 TI - Vitiligo associated with esophageal adenocarcinoma. AB - Vitiligo is a disease that results in depigmented areas in the skin. It may develop at any age but the average age at onset is 20 years. Association of vitiligo and melanoma has been commonly reported, but malignancies other than melanoma have been rarely associated with vitiligo. We report a 73-year-old patient with new onset vitiligo who developed esophageal adenocarcinoma in the following years. PMID- 23671784 TI - Over-adjustment bias by controlling for overall health. PMID- 23671785 TI - Audit on Early Detection and Primary Prevention of Chronic Kidney Disease in patients Admitted to the Healthcare of the Elderly Wards in a District General Hospital in UK. PMID- 23671786 TI - Tuberculous meningitis in adults in the terms of tertiary prevention: review of 22 cases. PMID- 23671787 TI - Biomarker development for external CO2 injury prediction in apples through exploration of both transcriptome and DNA methylation changes. AB - Several apple cultivars are susceptible to CO2 injury, a physiological disorder that can be expressed either externally or internally, and which can cause major losses of fruit during controlled atmosphere (CA) storage. Disorder development can also be enhanced using SmartFreshTM technology, based on the inhibition of ethylene perception by 1-methylcyclopropene (1-MCP). Injury development is associated with less mature fruit with lower ethylene production, but the aetiology of the disorder is poorly understood. Here we report on the progress made using mRNAseq approaches to explore the transcriptome during the development of external CO2 injury. Next-generation sequencing was used to mine the apple transcriptome for gene expression changes that are associated with the development of external CO2 injury. 'Empire' apples from a single orchard were treated with either 1 uL L(-1) 1-MCP or 1 g L(-1) diphenylamine or left untreated, and then stored in a CA of 5 kPa CO2 and 2 kPa O2. In addition, susceptibility to the disorder in the 'Empire' apples from five different orchards was investigated and the methylation state of the ACS1 promoter investigated using McrBC endonuclease digestion and real-time quantitative polymerase chain reaction. Expression of over 30 000 genes, aligned to the apple genome, was monitored, with clear divergence of expression among treatments after 1 day of CA storage. Symptom development, internal ethylene concentrations (IECs) and methylation state of the ACS1 promoter were different for each of five orchards. With transcriptomic changes affected by treatment, this dataset will be useful in discovering biomarkers that assess disorder susceptibility. An inverse correlation between the frequency of this disorder and the IEC was detected in a multiple orchard trial. Differential methylation state of the ACS1 promoter correlated with both IEC and injury occurrence, indicating epigenetic regulation of ethylene biosynthesis and possibly events leading to disorder development. PMID- 23671788 TI - Genetic diversity in Napier grass (Pennisetum purpureum) cultivars: implications for breeding and conservation. AB - Napier grass is an important forage crop for dairy production in the tropics; as such, its existing genetic diversity needs to be assessed for conservation. The current study assessed the genetic variation of Napier grass collections from selected regions in Eastern Africa and the International Livestock Research Institute Forage Germplasm-Ethiopia. The diversity of 281 cultivars was investigated using five selective amplified fragment length polymorphism (AFLP) markers and classical population genetic parameters analysed using various software. The number of bands generated was 216 with fragments per primer set ranging from 50 to 115. Mean percentage polymorphic loci was 63.40. Genetic diversity coefficients based on Nei's genetic diversity ranged from 0.0783 to 0.2142 and Shannon's information index ranged from 0.1293 to 0.3445. The Fst value obtained was moderately significant (Fst = 0.1688). Neighbour-joining analysis gave two distinct clusters which did not reflect geographical locations. Analysis of molecular variance showed all variance components to be highly significant (P < 0.001), indicating more variation within (91 %) than between populations (9 %). Results suggested moderate genetic differentiation among Napier grass populations sampled, which could imply a high germplasm exchange within the region. The AFLP markers used in this study efficiently discriminate among cultivars and could be useful in identification and germplasm conservation. PMID- 23671789 TI - Mineral nutrient remobilization during corolla senescence in ethylene-sensitive and -insensitive flowers. AB - The flower has a finite lifespan that is controlled largely by its role in sexual reproduction. Once the flower has been pollinated or is no longer receptive to pollination, the petals are programmed to senesce. A majority of the genes that are up-regulated during petal senescence, in both ethylene-sensitive and insensitive flowers, encode proteins involved in the degradation of nucleic acids, proteins, lipids, fatty acids, and cell wall and membrane components. A smaller subset of these genes has a putative role in remobilizing nutrients, and only a few of these have been studied in detail. During senescence, carbohydrates (primarily sucrose) are transported from petals, and the degradation of macromolecules and organelles also allows the plant to salvage mineral nutrients from the petals before cell death. The remobilization of mineral nutrients from a few species has been investigated and will be reviewed in this article. Ethylene's role in nutrient remobilization is discussed by comparing nutrient changes during the senescence of ethylene-sensitive and -insensitive flowers, and by studies in transgenic petunias (Petunia * hybrida) that are insensitive to ethylene. Gene expression studies indicate that remobilization is a key feature of senescence, but some senescence-associated genes have different expression in leaves and petals. These gene expression patterns, along with differences in the nutrient content of leaves and petals, suggest that there are differences in the mechanisms of cellular degradation and nutrient transport in vegetative and floral organs. Autophagy may be the mechanism for large-scale degradation that allows for recycling during senescence, but it is unclear if this causes cell death. Future research should focus on autophagy and the regulation of ATG genes by ethylene during both leaf and petal senescence. We must identify the mechanisms by which individual mineral nutrients are transported out of senescing corollas in both ethylene-sensitive and -insensitive species. PMID- 23671790 TI - Perfluorinated Taddol Phosphoramidite as an L,Z-Ligand on Rh(I) and Co(-I): Evidence for Bidentate Coordination via Metal-C6F5 Interaction. AB - Perfluorinated Taddol-based phosphoramidite, CKphos, is a highly selective ligand for formation of the vinylogous amide cycloadduct in the Rh(I) catalyzed [2+2+2] cycloaddition of alkenyl isocyanates and alkynes. CKphos overrides substrate bias of product selectivity in the cycloaddition, providing indolizinones in excellent product and enantioselectivities. Excellent selectivities are attributed to a shortened Rh-P bond and coordination of one C6F5 to rhodium via a Z-type interaction, making the phosphoramidite a bidentate L,Z-ligand on rhodium. Evidence for the shortened Rh-P and C6F5 coordination is provided by X-ray, NMR and DFT computation analyses. Additionally, an anionic cobalt complex with CKphos was synthesized and two Co-C6F5 interactions are seen. Rh(C2H4)Cl*CKphos catalyst in the [2+2+2] cycloaddition of alkenyl isocyanates and alkynes represents a rare example of metal-C6F5 Z-type interaction affecting selectivity in transition metal catalysis. PMID- 23671791 TI - Click Reaction-Mediated Functionalization of Near-Infrared Pyrrolopyrrole Cyanine Dyes for Biological Imaging Applications. AB - A clickable pyrrolopyrrole cyanine (PPCy) dye was synthesized by incorporating an alkyne moiety, followed by click reaction with azide-functionalized molecules of different polarities. The clickable dyes are readily amenable to labelling diverse molecules and exhibit an exceptionally high photostability and an impressive fluorescence quantum yield. PMID- 23671792 TI - Launching of american journal of stem cells. PMID- 23671793 TI - Mutant SOD1 microglia-generated nitroxidative stress promotes toxicity to human fetal neural stem cell-derived motor neurons through direct damage and noxious interactions with astrocytes. AB - Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease. Human neural stem cells (hNSCs) may have the potential to replace lost motor neurons. The therapeutic efficacy of stem cell therapy depends greatly on the survival of grafted stem cell-derived motor neurons in the microenvironment of the spinal cord in ALS. After transplantation of hNSCs into the spinal cords of transgenic ALS rats, morphological analysis reveals that grafted hNSCs differentiate into motor neurons. However, hNSCs degenerate and show signs of nitroxidative damage at the disease end-stage. Using an in vitro coculture system, we systematically assess interactions between microglia and astroglia derived from both nontransgenic rats and transgenic rats expressing human mutant SOD1(G93A) before and after symptomatic disease onset, and determine the effects of such microglia astroglia interactions on the survival of hNSC-derived motor neurons. We found that ALS microglia, specifically isolated after symptomatic disease onset, are directly toxic to hNSC-derived motor neurons. Furthermore, nontransgenic astrocytes not only lose their protective role in hNSC-derived motor neuron survival in vitro, but also exhibit toxic features when cocultured with mutant SOD1(G93A) microglia. Using inhibitors of inducible nitric oxide synthase and NADPH oxidase, we show that microglia-generated nitric oxide and superoxide partially contribute to motor neuron loss and astrocyte dysfunction in this coculture paradigm. In summary, reactive oxygen/nitrogen species released from overactivated microglia in ALS directly eliminate human neural stem cell-derived motor neurons and reduce the neuroprotective capacities of astrocytes. PMID- 23671794 TI - Specific differentiation of mesenchymal stem cells by small molecules. AB - Mesenchymal stem cells (MSCs) are multipotent, self-renewing cells harboring multi-lineage differentiation potential and immunosuppressive properties that make them an attractive candidate for biological cell-based regenerative medicine. In addition to its undoubted clinical interest, controlling the fate and behaviors of MSCs is a crucial prerequisite for their therapeutic applications in regenerative medicine. Stem cell differentiation and modulation of functional activities are generally controlled by "cocktails" of growth factors, signaling molecules, and/or genetic manipulations. However, these approaches have several limiting factors, such as undefined conditions leading to heterogeneous populations of cells and unexpected risks of virus-mediated genetic modifications. Small molecules targeting specific signaling pathways have been shown to be key modulators in controlling stem cells' fate and function. Small molecules are also important tools for understanding mechanistic and developmental processes. Furthermore, the precise mode of action of small molecules for controlling MSCs fate is still under study. However, Wnt, GSK, and other protein kinases signaling pathways are likely to be involved. These target based manipulations of stem cells fate by small molecules provide new insights into stem cell biology, and facilitate the development of regenerative medicine using stem cells. Here, we review the recent progress in controlling MSCs fate and functional activities by small molecules. PMID- 23671795 TI - HDAC9 is implicated in schizophrenia and expressed specifically in post-mitotic neurons but not in adult neural stem cells. AB - Schizophrenia is a common psychiatric disorder and caused by a combination of environmental, social and genetic factors. Histone deacetylases (HDACs) can translate epigenetic effects to the genome by modifying chromatin structure and gene expression. Inappropriate activity of HDACs is associated with cancer, cardiovascular and neurological diseases, and HDAC inhibitors are shown to improve the derivation of induced pluripotent stem (iPS) cells and to modulate cell lineage differentiation during brain development. We demonstrate that one of the HDAC genes, HDAC9, is hemizygously deleted in a small proportion of schizophrenia patients, and is widely expressed in mouse brain including areas where the neuropathology of schizophrenia is found. High levels of expression are observed in the hippocampus, layers II/III and V of the cerebral cortex, prefrontal and medial prefrontal cortex, piriform and cingulum cortex, basolateral amygdaloid nuclei and choroid plexus. HDAC9 protein is found in the cell body as well as in nerve fibers. Importantly, HDAC9 is not expressed in adult neural stem cells, glia, astrocytes, or oligodendrocytes, but expressed exclusively in post-mitotic and mature neurons. Our data suggest that HDAC9 may play a crucial role in neuronal function of adult brain. PMID- 23671796 TI - Regulators of human adipose-derived stem cell self-renewal. AB - Adipose tissue is an alternative source of mesenchymal stem cells and human adipose-derived stem cells (ASCs) display an attractive and substantial therapeutic potential when transplanted in animal models. To this end, an understanding of ASC biology is necessary and the knowledge of mechanisms that maintain ASCs in an undifferentiated state with no loss of differentiation potential during ex vivo expansion represents a crucial step. However, these mechanisms remain to be identified because appropriate human cellular models are scant. In this review we will describe a cellular model isolated from human adipose tissue displaying all the features of stem cells. Then, we will focus on the identification of intrinsic and extrinsic factors regulating the balance between human ASC proliferation and differentiation. We will point out the role of factors secreted by undifferentiated ASCs, such a FGF2, activin A, BMP4, Hedgehog molecules and secreted by adipose tissue macrophages. Finally, we will outline the role of miRNAs in these processes. PMID- 23671797 TI - Intrinsic regulation of adult subventricular zone neural progenitor cells and the effect of brain injury. AB - Regulation over the generation of adult born neuroblasts and oligodendrocyte precursor cells is governed by a myriad of extracellular signals. These signals must be related into the cell nucleus to regulate cell cycle and cell lineage maturation programmes. This internal regulation is controlled by proneural and anti-neurogenic transcription factors, including Mash1, Pax6, Dlx2 and Olig2. This review will cover how transcription factors regulate adult SVZ neurogenesis; the progression from neural stem cell, to transit amplifying precursor cell, to neuroblast or oligodendrocyte precursor cell, and how transcription factors influence neuronal subtype specification. Changes to transcriptional regulation that occur after brain injury and what this means for endogenous brain repair strategies will also be covered. PMID- 23671799 TI - No factor left behind: generation of transgene-free induced pluripotent stem cells. AB - Induced pluripotent stem cells (iPSCs) hold great potential for regenerative medicine, yet their implementation in the clinic still seems far out of reach due to concerns about their safety. The development of safe and efficient reprogramming methods is a critical step towards clinical application of iPSCs. Recently, much progress has been made in the technology of generating iPSCs that are free of integrated transgenes. The newly developed methods improve genome integrity of iPSCs and will likely replace virus-based reprogramming in the future. Here, we review the recent technological advancements of transgene-free reprogramming and discuss the challenges of ensuring genome integrity of iPSCs. PMID- 23671798 TI - Loss of imprinting of IGF2 and the epigenetic progenitor model of cancer. AB - Among the hypotheses discussing cancer formation, the cancer stem cell (CSC) theory is one receiving widespread support. One version of this theory states that changes in otherwise healthy cells can cause formation of tumor- initiating cells (TICs), which have the potential to create precancerous stem cells that can lead to CSC formation. These CSCs can be rare, in contrast to their differentiated progeny, which give rise to the vast majority of the tumor mass in most cancers. Loss of imprinting (LOI) of the insulin-like growth factor-2 (IGF2) gene is one change that can produce these TICs via an epigenetic progenitor model of tumorigenesis. While IGF2 usually supports normal cellular growth, LOI of IGF2 may lead to overexpression of the gene and moreover global chromatin instability. This modification has been observed in many forms of cancer, and given the effect of LOI of IGF2 and its role in cancer, detecting a loss of imprinting in this gene could serve as a valuable diagnostic tool. Preclinical data has shown some progress in identifying therapeutic approaches seeking to exploit this relationship. Thus, further research surrounding LOI of IGF2 could lead to increased understanding of several cancer types and enhance therapies against these diseases. PMID- 23671800 TI - Towards high throughput tissue engineering: development of chitosan-calcium phosphate scaffolds for engineering bone tissue from embryonic stem cells. AB - Tissue engineering strategies have shown promise for the repair of damaged organs, including bone. One of the major challenges associated with tissue engineering is how to scale up such processes for high throughput manufacturing of biomaterial scaffolds used to support stem cell culture. Generation of certain types of 3D biomaterial scaffolds, including chitosan-calcium phosphate blends, involves a slow fabrication process followed by a lengthy required freeze drying step. This work investigates the use of automated microwave vacuum drying technology as an alternative to traditional freeze drying as a method of fabricating chitosan-calcium phosphate scaffolds for supporting embryonic stem cell cultures. Scaffolds produced using both drying techniques possess similar properties when characterized using scanning electron microscopy and this paper is the first to report that both types of these scaffolds support undifferentiated embryonic stem cell culture as well as promote stem cell differentiation into osteogenic lineages when treated with the appropriate factors. Compared to existing scaffold manufacturing processes using freeze drying, the use of microwave vacuum drying will lead to faster production times while reducing the costs, enabling high-throughput manufacturing of biomaterial scaffolds for stem cell applications. PMID- 23671802 TI - Meninges: from protective membrane to stem cell niche. AB - Meninges are a three tissue membrane primarily known as coverings of the brain. More in depth studies on meningeal function and ultrastructure have recently changed the view of meninges as a merely protective membrane. Accurate evaluation of the anatomical distribution in the CNS reveals that meninges largely penetrate inside the neural tissue. Meninges enter the CNS by projecting between structures, in the stroma of choroid plexus and form the perivascular space (Virchow-Robin) of every parenchymal vessel. Thus, meninges may modulate most of the physiological and pathological events of the CNS throughout the life. Meninges are present since the very early embryonic stages of cortical development and appear to be necessary for normal corticogenesis and brain structures formation. In adulthood meninges contribute to neural tissue homeostasis by secreting several trophic factors including FGF2 and SDF-1. Recently, for the first time, we have identified the presence of a stem cell population with neural differentiation potential in meninges. In addition, we and other groups have further described the presence in meninges of injury responsive neural precursors. In this review we will give a comprehensive view of meninges and their multiple roles in the context of a functional network with the neural tissue. We will highlight the current literature on the developmental feature of meninges and their role in cortical development. Moreover, we will elucidate the anatomical distribution of the meninges and their trophic properties in adult CNS. Finally, we will emphasize recent evidences suggesting the potential role of meninges as stem cell niche harbouring endogenous precursors that can be activated by injury and are able to contribute to CNS parenchymal reaction. PMID- 23671803 TI - Stem cell-based bone repair. AB - To accelerate bone repair, one strategy is to deliver the cells that make bone. The current review focuses on stem cell-based bone repair. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) can self-renew unlimitedly and differentiate into the bone forming cells - osteoblasts. Scientists have been actively investigating culture conditions to stably and efficiently induce differentiation of these stem cells into osteoblasts. However, ESCs have the issues of ethnics, immune response and both ESCs and iPSCs have tumorigenic potential. In contrast, bone marrow stromal/stem cells (BMSCs) hold great potential to enhance bone formation. Use of BMSCs can avoid the ethical issues and can obviate the immune response problem. However, BMSCs are a rare population with limited self-renewal ability and their differentiation ability decreases in elderly individuals. Considering the unlimited self-renewal ability, it is promising to develop protocols to differentiate ESCs into osteoblasts faithfully and efficiently. It is important to eliminate undifferentiated ESCs or iPSCs because of their tumorigenic potential. Therefore, future studies need to identify BMSCs specific cell surface markers since the cell surface markers utilized currently are not specific to BMSCs. Future studies also need to enhance the osteogenic potential without using viral vectors for transgene delivery to eliminate the risk of tumor generation. PMID- 23671804 TI - Reprogramming of bone marrow-derived mesenchymal stem cells into functional insulin-producing cells by chemical regimen. AB - Beta-cell transplantation is considered to be the most effective approach to cure type 1 diabetes (T1D). Unfortunately, the scarce availability of donor tissue limits the applicability of this therapy. Recent stem cell research progress shows stem cell therapy may be a potential means to solve this problem. Bone marrow-derived mesenchymal stem cells (MSCs) are self-renewable and multipotent adult stem cells which can differentiate into the three germ layers. Here we aimed to investigate whether MSCs could be reprogrammed into insulin-producing cells (IPCs). We isolated and characterized MSCs obtained from rat bone marrow. Then MSCs were induced to transdifferentiate into IPCs under specific conditions containing high concentrations of glucose, activin A, all-trans retinoic acid, and other maturation factors. The induced cells expressed multiple genes related to pancreatic beta-cell development and function, such as insulin1, glucagon, Pdx1, Pax6, and Glut-2. Insulin1 and C-peptide production were identified by immunocytochemistry. In vitro glucose challenge studies showed the induced cells secreted insulin in a glucose-dependent manner, as do normal pancreatic beta cells. Transplantation of these MSC-derived insulin-positive cells could reverse the hyperglycemia of streptozotcin (STZ)-induced diabetic rats. These results demonstrated that MSCs could be reprogrammed into IPCs and might be a potential autologous cell source for transplantation therapy of T1D. PMID- 23671805 TI - Successful derivation of EGFP-transgenic embryonic stem cell line from a genetically non-permissive FVB/N mouse. AB - Derivation of embryonic stem (ES)-cell lines from genetically non-permissive mouse strains, such as FVB/N, has been difficult, despite this strain offering advantages for mouse transgenesis for developmental studies. We earlier generated beta-actin promoter-driven enhanced green fluorescent protein (EGFP)-transgenic FVB/N mice, expressing EGFP in all cells. Here, by optimizing culture system and using RESGROTM ES-cell culture medium, we successfully derived EGFP-transgenic ES cell line, 'GS-2' line, from F1 hybrid blastocysts, from wild-type 129/SvJ female X EGFP-transgenic homozygous FVB/N male. The GS-2 ES-cell line exhibited all defining criteria of a typical ES-cell line, including normal colony morphology and karyotype (40,XY), high replication-expansion efficiency (passages: >100), expression of pluripotent markers (Oct-4, Nanog, Sox-2, SSEA-1 and others) and, embryoid body (EB) development and EB differentiation to ecto-/meso-/endo-dermal cell types, expressing nestin, BMP-4 and alpha-fetoprotein, respectively. GS-2 ES cells formed (i) teratoma containing three germ lineage-derived cell types, (ii) chimeric blastocysts and fetuses, following their aggregation with wild-type 8 cell embryos, (iii) functional cardiac clusters and (iv) predominantly neural cell types when EBs were developed in KOSR-supplemented medium. Taken together, we derived a robust EGFP-transgenic GS-2 ES-cell line, from a non-permissive transgenic (FVB/N) mouse by a single cross to 129/SvJ wild-type mouse. The GS-2 ES-cell line exhibited full differentiation potential, in vitro/in vivo, providing enormous opportunity for stem cell research, including experimental cell transplantation studies. PMID- 23671806 TI - Experimental model for coadjuvant treatment with mesenchymal stem cells for aortic aneurysm. AB - Many factors are possibly involved in the inflammatory process which causes the degeneration of the arterial wall in the formation of Abdominal Aortic Aneurysms. During the last years different experimental models have been published to treat this fault of the arterial walls. Parallel the clinical treatment has evolved. With this work we have tried to develop an animal model basing on the clinical current treatment. Finally, we propose a treatment based on mesenchymal cells to disable local immune response, preventing excessive fibrosis, apoptosis, and inducing intrinsic cellular progenitors. OBJECTIVE: To present a reproducible superior animal model of experimentation, intending to show that mesenchymal stem cells inserted in the sac of an artificial aneurysm are able to survive, so that they can be made accountable for a subsequent beneficial effect upon this condition. METHODS: Six Landrace-White pigs, weighing around 25Kg. We generate 2 aneurysms of abdominal aorta (2x1cm) with Dacron's patches. Later we treat the aneurysms endoscopic with a covered endograft. Finally, in one of the aneurysmal sac we introduce 1cc fibrin sealant and in another 1 cc of fibrin sealant with 10 million MSC. Animals were sacrificed at 24 hs and 1, 3, 5, 7 and 9 weeks. Samples of aneurysms were processed histologically (H&E and Masson). The injected cells were located by immunofluorescence (GFP market). RESULTS: The surgical technique is reproducible and similar to those conducted in common clinical practice. Histological cross-section samples of cases treated with MSC and analyzed by a blind researcher present a lower inflammation reaction, or with longer evolution time than in controls. Immunofluorescence studies have detected cells marked with GFP up to three weeks after treatment. CONCLUSION: This reproducible animal model is similar to common clinical treatment. MSC can stand alive at least for three weeks since their implantation within an aneurysm sac. This may improve the results of conventional endovascular treatment by the stabilization of the aneurysmal sac. PMID- 23671807 TI - Specification of neural cell fate and regulation of neural stem cell proliferation by microRNAs. AB - In the approximately 20 years since microRNAs (miRNAs) were first characterized, they have been shown to play important roles in diverse physiologic functions, particularly those requiring coordinated changes in networks of signaling pathways. The ability of miRNAs to silence expression of multiple gene targets hints at complex connections that research has only begun to elucidate. The nervous system, particularly the brain, and its progenitor cells offer opportunities to examine miRNA function due to the myriad different cell types, numerous functionally distinct regions, and fluidly dynamic connections between them. This review aims to summarize current understanding of miRNA regulation in neurodevelopment, beginning with miRNAs that establish a general neural fate in cells. Particular attention is given to miR-124, the most abundant brain-specific miRNA, along with its key regulators and targets as an example of the potentially far-reaching effects of miRNAs. These modulators and mediators enable miRNAs to subtly calibrate cellular proliferation and differentiation. To better understand their mechanisms of action, miRNA profiles in distinct populations and regions of cells have been examined as well as miRNAs that regulate proliferation of stem cells, a process marked by dramatic morphological shifts in response to temporally subtle and refined shifts in gene expression. To tease out the complex interactions of miRNAs and stem cells more accurately, future studies will require more sensitive methods of assessing miRNA expression and more rigorous models of miRNA pathways. Thorough characterization of similarities and differences in specific miRNAs' effects in different species is vital to developing better disease models and therapeutics using miRNAs. PMID- 23671808 TI - Directed differentiation of progenitor cells towards an islet-cell phenotype. AB - Exogenous insulin administration and oral anti-diabetic drugs are the primary means of treating diabetes. However, tight glycaemic control, with its inherent risk of hypoglycaemia, is required to prevent the microvascular and macrovascular complications of the disease. While islet or pancreas transplantations offer a longer-term cure, their widespread application is not possible, primarily because of a lack of donor tissue, the burden of life-long immunosuppression, and eventual graft rejection. The rapid increase in the incidence of diabetes has promoted the search for alternative cell-based therapies. Here we review recent advances in the directed differentiation of both endocrine and non-endocrine progenitors towards an islet-like phenotype. PMID- 23671810 TI - Current applications of mesenchymal stem cells for tissue replacement in otolaryngology-head and neck surgery. AB - Cellular therapy utilizing adult mesenchymal stromal/stem cells (MSCs) may very well revolutionize the treatment of a variety of head and neck diseases through the restoration of normal structure and function. Transplanting allogeneic or autologous MSCs into damaged tissues can serve multiple regenerative functions through their self-renewal, differentiation capacity, immune modulation and secretion of bioactive molecules. Further, trophic factors expressed by MSCs have been shown to influence their microenvironment through the promotion of extracellular matrix remodeling, angiogenesis and wound healing needed to regenerate or replace injured tissues. Although clinical applications of MSC based therapies in Otolaryngology-Head and Neck Surgery are still in their infancy, efforts are being made to understand and exploit MSCs for tissue repair as well as engineering strategies. In this review, we highlight pre clinical and clinical investigations employing MSC based therapies for the reconstruction of bone, cartilage, soft tissue and vocal fold defects. PMID- 23671809 TI - Regulatory pathways associated with bone loss and bone marrow adiposity caused by aging, chemotherapy, glucocorticoid therapy and radiotherapy. AB - The bone marrow is a complex environment that houses haematopoietic and mesenchymal cell populations and regulates bone turnover throughout life. The high proliferative capacity of these cell populations however, makes them susceptible to damage and injury, altering the steady-state of the bone marrow environment. Following cancer chemotherapy, irradiation and long-term glucocorticoid use, reduced bone and increased fat formation of marrow stromal progenitor cells results in a fatty marrow cavity, reduced bone mass and increased fracture risk. These bone and marrow defects are also observed in age related complications such as estrogen deficiency and increased oxidative stress. Although the underlying mechanisms are yet to be clarified, recent investigations have suggested a switch in lineage commitment of bone marrow mesenchymal stem cells down the adipogenic lineage at the expense of osteogenic differentiation following such stress or injury. The Wnt/beta-catenin signalling pathway is however has been recognized the key mechanism regulating stromal commitment, and its involvement in the osteogenic and adipogenic lineage commitment switch under the damaging conditions has been of great interest. This article reviews the effects of various types of stress or injury on the commitment to the adipogenic and osteogenic lineages of bone marrow stromal progenitor cells, and summarizes the roles of the Wnt/beta-catenin and associated signalling pathways in the lineage commitment, switch, and recovery after damage, and as a therapeutic target. PMID- 23671811 TI - Prenatal modulation of breast density and breast stem cells by insulin-like growth factor-1. AB - Biological determinants of breast density, a strong predictor of human breast cancer risk, are postulated to be influenced by prenatal exposures to mitogens. We investigated the extent to which prenatal exposures to insulin-like growth factor-1 (IGF-1) would affect body weight, breast density, and levels of breast stem/progenitor cells in the prepubescent offspring of wild type C57BL/6J and IGF 1 deficient mice. We found that administration of IGF-1 to pregnant mice resulted in significantly heavier birth and postnatal body weights of the offspring when compared to PBS controls. Morphometric analysis of whole mount carmine alum staining of the left fourth inguinal mammary gland revealed that a prenatal dose of 5 MUg IGF-1 resulted in significantly longer ductal elongation in wild type mice and significantly higher breast density in both mouse strains. Furthermore, 5 MUg IGF-1 also resulted in the highest number of putative CD49f(+)CD24(+) and CD49f(+)CD24(+)CD29(+) breast stem/progenitor cells in the wild type offspring when compared to PBS controls, as assessed by flow cytometric analysis of dissociated cells from the right fourth inguinal mammary gland, while significantly higher numbers of these cell populations as well as CD24(+)CD29(+) and CD49f(+)EpCAM(+) cells were observed in IGF-1 deficient mice. These findings provide direct evidence for a prenatal modulation of breast density in the offspring by IGF-1, possibly involving populations of breast stem/progenitor cells. PMID- 23671812 TI - Applications of skeletal muscle progenitor cells for neuromuscular diseases. AB - Neuromuscular diseases affect skeletal muscle and/or nervous control resulting in direct disruption of skeletal muscle and muscle pathology, or nervous system disruption which indirectly disrupts muscle function. Stem cell-based therapy is well-recognized as a promising approach for several types of diseases including those affecting the neuromuscular system. To design a successful therapeutic strategy, it is important to choose the most appropriate stem cell type. Skeletal muscle progenitor cells (SMPCs), also called myogenic progenitors, can contribute to muscle regeneration, differentiate into skeletal muscles, and are valuable cells for therapeutic application. Different types of stem/progenitor cells, including satellite cells, side population cells, muscle derived stem cells, mesenchymal stem cells, myogenic pericytes, and mesoangioblasts, have been identified as possible cell resources of SMPCs. Furthermore, recent advances in stem cell biology allow us to use embryonic stem cells and induced pluripotent stem cells for SMPC derivation. When skeletal muscle is chosen as a target of cell transplantation, the possible criteria for choosing the "best" progenitor/stem cell include preparation strategies, efficiency of intramuscular integration, method of cellular delivery, and functional improvement of the muscle after cell transplantation. Here, we discuss recent findings on various types of SMPCs and their promise for future clinical translation in neuromuscular diseases. PMID- 23671815 TI - Genetic instability of modified stem cells - a first step towards malignant transformation? AB - Induced pluripotent stem cells (iPSC) are important tools in regenerative medicine. Yet, it is becoming increasingly clear that the reprogramming process, including retroviral transduction with potent oncogenes like c-Myc and long-term cultivation, may induce genetic instability. Genetically altered iPS cells can grow out and dominate the cell culture. This review intends to comprehensively summarize the current knowledge on genetic instability of embryonic and iPSCs, with an emphasis on cytogenetic alterations, and compares these data with what is known from tumorigenesis. PMID- 23671814 TI - Mesenchymal stem cell and regenerative medicine: regeneration versus immunomodulatory challenges. AB - Mesenchymal Stem cells (MSC) are now presented with the opportunities of multifunctional therapeutic approaches. Several reports are in support of their self-renewal, capacity for multipotent differentiation, and immunomodulatory properties. They are unique to contribute to the regeneration of mesenchymal tissues such as bone, cartilage, muscle, ligament, tendon, and adipose. In addition to promising trials in regenerative medicine, such as in the treatment of major bone defects and myocardial infarction, MSC has shown a therapeutic effect other than direct hematopoiesis support in hematopoietic reconstruction. MSCs are identified by the expression of many molecules including CD105 (SH2) and CD73(SH3/4) and are negative for the hematopoietic markers CD34, CD45, and CD14. Manufacturing of MSC for clinical trials is also an important aspect as their differentiation, homing and Immunomodulatory properties may differ. Their suppressive effects on immune cells, including T cells, B cells, NK cells and DC cells, suggest MSCs as a novel therapy for GVHD and other autoimmune disorders. Since the cells by themselves are non-immunogenic, tissue matching between MSC donor and recipient is not essential and, MSC may be the first cell type able to be used as an "off-the-shelf" therapeutic product. Following a successful transplantation, the migration of MSC to the site of injury refers to the involvement of chemokines and chemokine receptors of respective specificity. It has been demonstrated that cultured MSCs have the ability to engraft into healthy as well as injured tissue and can differentiate into several cell types in vivo, which facilitates MSC to be an ideal tool for regenerative therapy in different disease types. However, some observations have raised questions about the limitations for proper use of MSC considering some critical factors that warn regular clinical use. PMID- 23671813 TI - BMP9 signaling in stem cell differentiation and osteogenesis. AB - Bone morphogenetic proteins (BMPs) are members of the TGF-beta superfamily and play a critical role in skeletal development, bone formation and stem cell differentiation. Disruptions in BMP signaling result in a variety of skeletal and extraskeletal anomalies. BMP9 is a poorly characterized member of the BMP family and is among the most osteogenic BMPs, promoting osteoblastic differentiation of mesenchymal stem cells (MSCs) both in vitro and in vivo. Recent findings from various in vivo and molecular studies strongly suggest that the mechanisms governing BMP9-mediated osteoinduction differ from other osteogenic BMPs. Many signaling pathways with diverse functions have been found to play a role in BMP9 mediated osteogenesis. Several of these pathways are also critical in the differentiation of other cell lineages, including adipocytes and chondrocytes. While BMP9 is known to be a potent osteogenic factor, it also influences several other pathways including cancer development, angiogenesis and myogenesis. Although BMP9 has been demonstrated as one of the most osteogenic BMPs, relatively little is known about the specific mechanisms responsible for these effects. BMP9 has demonstrated efficacy in promoting spinal fusion and bony non union repair in animal models, demonstrating great translational promise. This review aims to summarize our current knowledge of BMP9-mediated osteogenesis by presenting recently completed work which may help us to further elucidate these pathways. PMID- 23671816 TI - Cancer stem cells and tumor transdifferentiation: implications for novel therapeutic strategies. AB - Highly malignant tumors mostly consist of rapidly proliferating cells. However, tumors also contain a few cells in a quiescent state that can be characterized as slow-cycling, expressing markers of stem cells and possessing the ability to initiate new tumors. These quiescent cells, now generally termed 'cancer stem cells' (CSC) (or 'cancer initiating cells'), are capable of regenerating the entire tumor--as it occurs in metastatic spread. This process of tumor initiation by stem-like cells presumably involves differentiation of quiescent CSC into rapidly proliferating tumor cells. An important implication of the presence of slow cycling, quiescent stem-like cells in the tumor and their ability to initiate tumors is that they contribute to the resistance to treatments by conventional chemo- and radiotherapy directed toward killing rapidly dividing cells. However, similar to normal stem cells, the CSC could also potentially transdifferentiate into cell lineages other than the original lineage from which the tumor arose. Therefore, transdifferentiation of CSC offers a possible therapeutic strategy which has not yet been fully exploited. In this article, we provide a comprehensive review of the concepts in tumor cell transdifferentiation and discuss the mechanisms of transdifferentiation with emphasis on their relevance to potential novel treatment strategies. PMID- 23671817 TI - Effect of extracorporeal shock wave on proliferation and differentiation of equine adipose tissue-derived mesenchymal stem cells in vitro. AB - Mesenchymal stem cells are regarded as common cellular precursors of the musculoskeletal tissue and are responsible for tissue regeneration in the course of musculoskeletal disorders. In equine veterinary medicine extracorporeal shock wave therapy (ESWT) is used to optimize healing processes of bone, tendon and cartilage. Nevertheless, little is known about the effects of the shock waves on cells and tissues. Thus, the aim of this study was to investigate the influence of focused ESWT on the viability, proliferation, and differentiation capacity of adipose tissue-derived mesenchymal stem cells (ASCs) and to explore its effects on gap junctional communication and the activation of signalling cascades associated with cell proliferation and differentiation. ASCs were treated with different pulses of focused ESWT. Treated cells showed increased proliferation and expression of Cx43, as detected by means of qRT-PCR, histological staining, immunocytochemistry and western blot. At the same time, cells responded to ESWT by significant activation (phosphorylation) of Erk1/2, detected in western blots. No significant effects on the differentiation potential of the ASCs were evident. Taken together, the present results show significant effects of shock waves on stem cells in vitro. PMID- 23671820 TI - Morphometric evaluation of seminiferous tubules in aged mice testes after melatonin administration. AB - OBJECTIVE: Melatonin, the pineal gland hormone as a direct or indirect antioxidant and free radical scavenger, is involved in the process of both aging and age-related diseases. This study investigates the effects of melatonin on the histology of testicular seminiferous tubules in aged mice. MATERIALS AND METHODS: Twenty male, white mice, aged 16 months, that weighed 20-23 gr were equally divided into control and experimental groups. The experimental group was intraperitoneally injected with a daily single dose of 10 mg/kg melatonin for 14 days. The control group received only saline. Six days after the last injection, all mice were sacrificed and the testes were excised and processed for light microscope observation. In the morphometric study, we evaluated testicular seminiferous tubule parameters such as height of germinal epithelium, seminiferous tubule diameter, thickness of interstitial connective tissue and spermatogenesis index (SI). SPSS software and student's t-test analyzed all parameters to assess the significance of changes between control and experimental groups. RESULTS: Melatonin-treated mice had seminiferous tubules with a wide lumen lined by low height germinal epithelium. The interstitial connective tissue thickened significantly in the experimental group (p<0.05), tubular diameter and germinal epithelium height decreased significantly (p<0.01), and the SI reduced compared to the control group (p<0.001). CONCLUSION: The results of this study showed the disadvantages of melatonin on seminiferous tubules of aged mice testes. PMID- 23671819 TI - Heart failure with preserved ejection fraction in African Americans: The ARIC (Atherosclerosis Risk In Communities) study. AB - OBJECTIVES: In an entirely African-American cohort, we compared clinical characteristics, cardiac structure and function, and all-cause mortality in patients with heart failure (HF) with preserved ejection fraction (HFpEF) in relation to patients with heart failure with reduced ejection fraction (HFrEF) and those without HF. BACKGROUND: African Americans are at increased risk for HF. Nevertheless, there are limited phenotypic and prognostic data in African Americans with HFpEF compared with those with HFrEF and those without HF. METHODS: Middle-aged African Americans from the Jackson, Mississippi, cohort of the ARIC (Atherosclerosis Risk In Communities) study (n = 2,445) underwent echocardiography between 1993 and 1995. HF prevalence was available in 1,962 patients for whom left ventricular ejection fraction (LVEF) could be quantified. Participants with HF were categorized as having HFpEF (LVEF >=50%), HFrEF (LVEF <50%), or no HF, with comparisons made between groups. RESULTS: HF was identified in 116 (5.9%) participants (HFpEF n = 85 [73%]; HFrEF n = 31 [27%]). Compared with those without HF, those with HFpEF were older, were more likely to be female, and had more frequent comorbidities and concentric hypertrophy. In relation to HFrEF, those with HFpEF were more likely to be female but less likely to have coronary heart disease, diabetes mellitus, chronic kidney disease, left atrial enlargement, and eccentric hypertrophy. Over a median 13.7 years of follow up, risk of death differed between groups, with age- and sex-adjusted hazard ratios of 1.51 (95% confidence interval: 1.01 to 2.25) for HFpEF versus those without HF and 2.50 (95% confidence interval: 1.37 to 4.58) for HFrEF versus HFpEF. CONCLUSIONS: In this cohort of middle-aged African Americans, HFpEF was the most common form of HF and was associated with a substantially better prognosis than HFrEF but worse than those without HF. PMID- 23671821 TI - Histological study of the toxic effects of solder fumes on spermatogenesis in rats. AB - OBJECTIVE: Toxic fumes generated during the soldering process contain various contaminants released at sufficient rates to cause both short- and long-term health problems. Studies have shown that these fumes change the quality and quantity of semen fluid in exposed workers. The aim of the present study was to determine the potentially toxic effects of solder fumes on spermatogenesis in seminiferous tubules of rats as an experimental model, with conditioned media in an exposed chamber. MATERIALS AND METHODS: A total number of 48 male Sprague Dawley adult rats were randomly divided into experimental (n=30) and control (n=18) groups. Based on exposure time, each group was further subdivided into two, four and six subgroups. Rats in the experimental groups were exposed to solder fumes in an exposure chamber for one hour/ day. The concentrations of fumes [formaldehyde, stanum (Sn) and lead (Pb)] were measured by a standard method via atomic absorption and spectrophotometry. According to a timetable, under deep anesthesia, the rats of both experimental and control subgroups were killed. After fixation of testes, specimens were weighed and routinely processed. Paraffin sections were stained by hematoxylin and eosin. Spermiogenesis index was calculated and data analyzed by Mann Whitney NPAR test. RESULTS: ANALYSIS OF AIR SAMPLES IN THE EXPOSURE CHAMBER SHOWED THE FOLLOWING FUME CONCENTRATIONS: 0.193 mg/m(3) for formaldehyde, 0.35 mg/m(3) for Sn and 3 mg/m(3) for Pb. Although there was no significant difference in testes weight between control and experimental subgroups, there was only a significant difference in spermiogenesis index between the six week experimental and control subgroups (p<0.02). CONCLUSION: The results of this study showed that solder fumes can change the spermiogenesis index in experimental groups in a time dependent manner. PMID- 23671822 TI - ROR2 Promoter Methylation Change in Osteoblastic Differentiation of Mesenchymal Stem Cells. AB - OBJECTIVE: Osteoblasts arise from multipotent mesenchymal stem cells (MSCs) present in the bone marrow stroma and undergo further differentiation to osteocytes or bone cells. Many factors such as proteins present in the Wnt signaling pathway affect osteoblast differentiation. ROR2 is an orphan tyrosine kinase receptor that acts as a co-receptor in the non-canonical Wnt signaling pathway. However, ROR2 has been shown to be regulated by both canonical and non canonical Wnt signaling pathways. ROR2 expression increases during differentiation of MSCs to osteoblasts and then decreases as cells differentiate to osteocytes. On the other hand, research has shown that ROR2 changes MSC fate towards osteoblasts by inducing osteogenic transcription factor OSTERIX. Here we speculated whether ROR2 gene expression regulation during osteoblastogenesis is epigenetically determined. MATERIALS AND METHODS: MSCs from bone marrow were isolated, expanded and characterized in vitro according to standard procedures. ROR2 promoter methylation status was determined using methylation specific PCR in a multipotent state and during differentiation to osteoblasts. RESULTS: We determined that the demethylation process in ROR2 promoter occurs during the differentiation process. The process of demethylation begins at day 8 and continues until 21 days of differentiation. CONCLUSION: This result is in concordance with previous works on the role of ROR2 on osteoblast differentiation, which have shown an upregulation of ROR2 expression during this process. PMID- 23671823 TI - The Effect of Retinoic Acid on in vitro Maturation and Fertilization Rate of Mouse Germinal Vesicle Stage Oocytes. AB - OBJECTIVE: Retinoids are recognized as important regulators of cell differention and tissue function. Previous studies, performed both in vivo and in vitro, indicate that retinoids influence several reproductive events. In this study, we investigated the effect of all-trans retinoic acid (t-RA) on maturation and fertilization rate of immature oocytes (germinal vesicle). MATERIALS AND METHODS: Germinal vesicle (GV) oocytes were recovered from 4-6 week old female mice 48 hours after injection of 10 IU pregnant mare serum gonadotropin (PMSG). Collected oocytes were divided into seven groups: control, sham and five experimental groups. t-RA at concentrations of 1, 2, 4, 6, 8 uM were added to oocyte maturation medium in the experimental groups. The maturation rate was recorded after 24 hours of culture in a humidified atmosphere of 5% CO2 at 37C. Fertilization and developmental rates of matured oocytes were recorded after in vitro fertilization (IVF) and 24 hour culture. RESULTS: The rate of oocytes that developed to the metaphase II stage of maturation significantly increased with 2 and 4 uM t-RA compared to the control and sham groups (p<0.05). In addition, the number of fertilized oocytes was significantly higher in 4 uu retinoic acid compared to the control (p<0.05), but the difference between the number of fertilized oocytes which developed to the 2-cell stage was not significant between the two groups. CONCLUSION: The results show that t-RA enhanced mouse oocyte maturation in vitro and improved fertilization and development rates in a dose dependent manner. PMID- 23671824 TI - Neuroprotective properties of melissa officinalis L. Extract against ecstasy induced neurotoxicity. AB - OBJECTIVE: The aim of the present study was to investigate the neuroprotective effects of Melissa officinalis, a major antioxidant plant, against neuron toxicity in hippocampal primary culture induced by 3,4 methylenedioxymethamphetamine (MDMA) or ecstasy, one of the most abused drugs, which causes neurotoxicity. MATERIALS AND METHODS: 3-(4,5-dimethyl-2 thiazoyl) 2,5-diphenyl-tetrazolium bromide (MTT) assay was used to assess mitochondrial activity, reflecting cell survival. Caspase-3 activity assay and Hoechst / propiedium iodide (PI) staining were done to show apoptotic cell death. RESULTS: A high dose of ecstasy caused profound mitochondrial dysfunction, around 40% less than the control value, and increased apoptotic neuronal death to around 35% more than the control value in hippocampal neuronal culture. Co-treatment with Melissa officinalis significantly reversed these damages to around 15% and 20% respectively of the MDMA alone group, and provided protection against MDMA induced mitochondrial dysfunction and apoptosis in neurons. CONCLUSION: Melissa officinalis has revealed neuroprotective effects against apoptosis induced by MDMA in the primary neurons of hippocampal culture, which could be due to its free radical scavenging properties and monoamine oxidase (MAO) inhibitory effects. PMID- 23671825 TI - The Effect of Co-administration of 4-Methylcatechol and Progesterone on Sciatic Nerve Function and Neurohistological Alterations in Streptozotocin-Induced Diabetic Neuropathy in Rats. AB - OBJECTIVE: Diabetic neuropathy is the most common complication of diabetes mellitus affecting the nervous system. In this study, we investigated the in vivo effects of combined administration of 4-methylcatechol (4-MC) and progesterone (P) as a potential therapeutic tool for sciatic nerve function improvement and its role in histomorphological alterations in diabetic neuropathy in rats. MATERIALS AND METHODS: Male adult rats were divided into 3 groups: sham operated control (CO), untreated diabetic (DM) and diabetic treated with progesterone and 4-methylcatechol (DMP4MC) groups. Diabetes was induced by a single dose injection of 55 mg/ kg streptozotocin (STZ). Four weeks after the STZ administration, the DMP4MC group was treated with P and 4-MC for 6 weeks. Then, following anesthesia, the animals' sciatic nerves were removed and processed for light and transmission electron microscopy (TEM) as well as histological evaluation. RESULTS: Diabetic rats showed a statistically significant reduction in motor nerve conduction velocity (MNCV), nerve blood flow (NBF), mean myelinated fiber (MF) diameters and myelin sheath thickness of the sciatic nerve after 10 weeks. In the sciatic nerve of the untreated diabetic group, endoneurial edema and increased number of myelinated fibers with myelin abnormalities such as infolding into the axoplasm, irregularity of fibers and alteration in myelin compaction were also observed. Treatment of diabetic rats with a combination of P and 4-MC significantly increased MNCV and NBF and prevented endoneurial edema and all myelin abnormalities. CONCLUSION: Our findings indicated that co-administration of P and 4-MC may prevent sciatic nerve dysfunction and histomorphological alterations in experimental diabetic neuropathy. PMID- 23671827 TI - Ionocyte Immunolocalization and the Effects of Ultraviolet Radiation on Their Abundance and Distribution in the Alenins of Caspian Sea Salmon, Salmo trutta caspius. AB - OBJECTIVE: On a global scale, stratospheric ozone depletion has caused an increase in UV-B radiation reaching the earth's surface. Ultraviolet radiation has long been suspected to be harmful to aquatic organisms. MATERIALS AND METHODS: In order to study ionocyte localization (by Na(+)/K(+)-ATPase immunolocalization) and the effects of UV radiation on the ionocytes of skin and gills, the alevins of Salmo trutta caspius were exposed to different doses of UV radiation [unit low doses (ULD) of: 60 uw/cm(2) UVC; 100 uw/cm(2) UVB and 40 uw/cm(2) UVA and unit high doses (UHD) of: 90 uw/cm(2) UVC; 130 uw/cm(2) UVB and 50 uw/cm(2) UVA] using two adjustable F8T5 UV-B, 302 nm lamps (Japan) for 15 minutes once a day in laboratory conditions. Alevins not subjected to UV exposure served as a control group. RESULTS: In both UV exposure groups, all the alevins died on the ninth day. No mortality was observed in the control group. The Na(+)/K(+)-ATPase immunolocalization study indicated that ionocytes were located, in lessening order, on the yolk sac, trunk, gills, opercula and rarely on the head skin. Immunohistochemical results showed significant reduction in the number of ionocytes on the yolk sac, with lesser reduction on the trunk in both UV exposure groups. In contrast, the number of immunofluorescence cells on the gill was significantly elevated. Our results also showed that the size of ionocytes was reduced on the trunk and yolk sac in the UV exposure groups, but not significantly. Deformation and destruction of ionocytes on the yolk sac and trunk were observed with scanning electron microscope (SEM) in the UV exposure groups. CONCLUSION: Our results showed that ionocytes were located mainly on the yolk sac, in lesser amounts on the trunk, gills and opercula, and rarely also on the head skin of alevins. UV radiation caused deformation and reduction in the number and size of ionocytes on the trunk and yolk sac. As the skin cells of trout alevins possess essential functions for respiration, osmoregulation, excretion and defense during this stage of life, the observed damage may have contributed to their suddenly mortality in the UV exposure condition. PMID- 23671826 TI - Neuroprotective effects of carnosic Acid in an experimental model of Alzheimer's disease in rats. AB - OBJECTIVE: Alzheimer's disease is the most common type of neurodegenerative disorder. It has been suggested that oxidative stress can be one of the pathological mechanisms of this disease. Carnosic acid (CA) is an effective antioxidant substance and recent studies have shown that its electrophilic compounds play a role in reversing oxidative stress. Thus we tried to find out whether CA administration protects hippocampal neurons, preventing neurodegeneration in rats. MATERIALS AND METHODS: ANIMALS WERE DIVIDED INTO FOUR GROUPS: Sham-operated (sham), CA-pretreated sham-operated (sham+CA), untreated lesion (lesion) and CA-pretreated lesion (lesion+CA). Animals in all groups received vehicle or vehicle plus CA (CA: 10mg/ kg) intra-peritoneally one hour before surgery, again the same solution injected 3-4 hours after surgery (CA: 3 mg/kg) and repeated each afternoon for 12 days. A lesion was made by bilateral intra-hippocampal injection of 4 ul of beta amyloid protein (1.5 nmol/ul) or vehicle in each side. 14 days after surgery, the brains were extracted for histochemical studies. Data was expressed as mean +/- SEM and analyzed using SPSS statistical software. RESULTS: Results showed that pretreatment with carnosic acid can reduce cellular death in the cornu ammonis 1 (CA1) region of the hippocampus in the lesion+CA group, as compared with the lesion group. CONCLUSION: Carnosic acid may be useful in protecting against beta amyloid induced neurodegeneration in the hippocampus. PMID- 23671828 TI - The Frequency of DYT1 (GAG Deletion) Mutation in Primary Dystonia Patients from Iran. AB - OBJECTIVE: To determine the frequency of DYT1 mutation in Iranian patients affected with primary dystonia. MATERIALS AND METHODS: In this study, we investigated 60 patients with primary dystonia who referred to the Tehran Medical Genetics Laboratory (TMGL) to determine the deletional mutation of 904-906 del GAG in the DYT1 gene. DNA extracted from patients' peripheral blood was subjected to PCR-sequencing for exon 5 of the DYT1 gene. The collection of samples was based on random sampling. RESULTS: The deletional mutation of 904-906 del GAG in the DYT1 gene (15099 to 15101 based on reference sequence: NG_008049.1) was identified in 11 patients (18.33%). The average age of affected patients with this mutation was 13.64 +/- 7.4 years. CONCLUSION: It can be concluded that the DYT1 deletional mutation of 904-906 del GAG has a high frequency in Iranian patients in comparison with other non-Jewish populations. Therefore, this particular mutation may be the main representative of pathogenic DYT1 gene for a large proportion of Iranian patients with primary dystonia. PMID- 23671829 TI - Reader's Forum. PMID- 23671830 TI - Use of Reference Ear Plug to improve accuracy of lateral cephalograms generated from cone-beam computed tomography scans. AB - OBJECTIVE: The purpose of this study was to evaluate the effectiveness of the use of Reference Ear Plug (REP) during cone-beam computed tomography (CBCT) scan for the generation of lateral cephalograms from CBCT scan data. METHODS: Two CBCT scans were obtained from 33 adults. One CBCT scan was acquired using conventional methods, and the other scan was acquired with the use of REP. Virtual lateral cephalograms created from each CBCT image were traced and compared with tracings of the real cephalograms obtained from the same subject. RESULTS: CBCT scan with REP resulted in a smaller discrepancy between real and virtual cephalograms. In comparing the real and virtual cephalograms, no measurements significantly differed from real cephalogram values in case of CBCT scan with REP, whereas many measurements significantly differed in the case of CBCT scan without REP. CONCLUSION: Measurements from CBCT-generated cephalograms are more similar to those from real cephalograms when REP are used during CBCT scan. Thus, the use of REP is suggested during CBCT scan to generate accurate virtual cephalograms from CBCT scan data. PMID- 23671831 TI - New three-dimensional cephalometric analyses among adults with a skeletal Class I pattern and normal occlusion. AB - OBJECTIVE: The purpose of this study was to assess new three-dimensional (3D) cephalometric variables, and to evaluate the relationships among skeletal and dentoalveolar variables through 3D cephalometric analysis. METHODS: Cone-beam computed tomography (CBCT) scans were acquired from 38 young adults (18 men and 20 women; 22.6 +/- 3.2 years) with normal occlusion. Thirty-five landmarks were digitized on the 3D-rendered views. Several measurements were obtained for selected landmarks. Correlations among different variables were calculated by means of Pearson's correlation coefficient values. RESULTS: The body of the mandible had a longer curve length in men (102.3 +/- 4.4 mm) than in women (94.5 +/- 4.7 mm) (p < 0.001), but there was no significant difference in the maxillary basal curve length. Men had significantly larger facial dimensions, whereas women had a larger gonial angle (117.0 +/- 4.0 vs. 113.8 +/- 3.3; p < 0.001). Strong-to moderate correlation values were found among the vertical and transverse variables (r = 0.71 to 0.51). CONCLUSIONS: The normative values of new 3D cephalometric parameters, including the maxillary and mandibular curve length, were obtained. Strong-to-moderate correlation values were found among several vertical and transverse variables through 3D cephalometric analysis. This method of cephalometric analyses can be useful in diagnosis and treatment planning for patients with dentofacial deformities. PMID- 23671832 TI - Condylar repositioning using centric relation bite in bimaxillary surgery. AB - OBJECTIVE: The purpose of this study was to evaluate displacement of the mandibular condyle after orthognathic surgery using a condylar-repositioning device. METHODS: The patient group comprised 20 adults who underwent bimaxillary surgery between August 2008 and July 2011. The degree of condylar displacement was measured by pre- and postoperative tomographic analysis using centric relation bite and a wire during surgery. A survey assessing temporomandibular joint (TMJ) sound, pain, and locking was performed. The 20 tomographs and surveys were analyzed using the Wilcoxon signed-rank test and McNemar's test, respectively. RESULTS: No significant changes were observed in the anterior, superior, or posterior joint space of the TMJ (p > 0.05). In addition, no significant change was observed in TMJ sound (p > 0.05). However, TMJ pain and locking both decreased significantly after surgery (p < 0.05). CONCLUSIONS: Due to its simplicity, this method may be feasible and useful for repositioning condyles. PMID- 23671833 TI - Evaluation of alveolar bone loss following rapid maxillary expansion using cone beam computed tomography. AB - OBJECTIVE: To evaluate the changes in cortical bone thickness, alveolar bone height, and the incidence of dehiscence and fenestration in the surrounding alveolar bone of posterior teeth after rapid maxillary expansion (RME) treatment using cone-beam computed tomography (CBCT). METHODS: The CBCT records of 20 subjects (9 boys, mean age: 13.97 +/- 1.17 years; 11 girls, mean age: 13.53 +/- 2.12 year) that underwent RME were selected from the archives. CBCT scans had been taken before (T1) and after (T2) the RME. Moreover, 10 of the subjects had 6 month retention (T3) records. We used the CBCT data to evaluate the buccal and palatal aspects of the canines, first and second premolars, and the first molars at 3 vertical levels. The cortical bone thickness and alveolar bone height at T1 and T2 were evaluated with the paired-samples t-test or the Wilcoxon signed-rank test. Repeated measure ANOVA or the Friedman test was used to evaluate the statistical significance at T1, T2, and T3. Statistical significance was set at p < 0.05. RESULTS: The buccal cortical bone thickness decreased gradually from baseline to the end of the retention period. After expansion, the buccal alveolar bone height was reduced significantly; however, this change was not statistically significant after the 6-month retention period. During the course of the treatment, the incidence of dehiscence and fenestration increased and decreased, respectively. CONCLUSIONS: RME may have detrimental effects on the supporting alveolar bone, since the thickness and height of the buccal alveolar bone decreased during the retention period. PMID- 23671834 TI - Effects of contamination by either blood or a hemostatic agent on the shear bond strength of orthodontic buttons. AB - OBJECTIVE: To evaluate the effects of contamination by either blood or a hemostatic agent on the shear bond strength (SBS) of orthodontic buttons. METHODS: We used 45 freshly extracted, non-carious, impacted third molars that were divided into 3 groups of 15. Each tooth was etched with 37% phosphoric acid gel for 30 s. Human blood or the blood stopper agent was applied to the tooth surface in groups I and II, respectively. Group III teeth were untreated (controls). Orthodontic buttons were bonded to the teeth using light-curing composite resin. After bonding, the SBS of the button was determined using a Universal testing machine. Any adhesive remaining after debonding was assessed and scored according to the modified adhesive remnant index (ARI). ANOVA with post-hoc Tukey's test was used to determine significant differences in SBS and Fisher's exact test, to determine significant differences in ARI scores among groups. RESULTS: ANOVA indicated a significant difference between groups (p < 0.001). The highest SBS values were measured in group III (10.73 +/- 0.96 MPa). The SBS values for teeth in groups I and II were significantly lower than that of group III (p < 0.001). The lowest SBS values were observed in group I teeth (4.17 +/- 1.11 MPa) (p < 0.001). CONCLUSIONS: Contamination of tooth surfaces with either blood or hemostatic agent significantly decreased the SBS of orthodontic buttons. When the contamination risk is high, it is recommended to use the blood stopper agent when bonding orthodontic buttons on impacted teeth. PMID- 23671835 TI - Combined treatment with headgear and the Frog appliance for maxillary molar distalization: a randomized controlled trial. AB - OBJECTIVE: To evaluate the efficiency of the Frog appliance (FA) alone or in combination with headgear for distalizing the maxillary molars. METHODS: Fifty patients (25 males and 25 females) aged 12.6 - 16.7 years who received treatment for Class II malocclusion at the Orthodontic Clinic of Al-Baath University were selected for this study and randomly divided into 2 equal groups. Maxillary molar distalization was achieved using the FA alone (group 1) or a combination of the FA with high-pull headgear worn at night (group 2). Lateral cephalograms were obtained before and after treatment. RESULTS: The maxillary molars moved distally by 5.51 and 5.93 mm in groups 1 and 2, respectively. Distal movements were associated with axial tipping by 4.96 degrees and 1.25 degrees , and with loss of anchorage by mesial movement of the second maxillary premolars by 2.70 and 0.90 mm in groups 1 and 2, respectively. The combined use of the FA and nighttime high-pull headgear decreased the distalization time and improved the ratio of maxillary molar distalization movement relative to the overall opening space between the first maxillary molars and second premolars. CONCLUSIONS: The FA can effectively distalize the maxillary molars, this distalization associates with some unfavorable changes. Nighttime use of high-pull headgear combined with the FA can reduce these unfavorable changes and improve treatment outcomes. PMID- 23671837 TI - Examining DNA fingerprinting as an epidemiology tool in the tuberculosis program in the Northwest Territories, Canada. AB - BACKGROUND: Tuberculosis (TB) is an important public health problem in the Northwest Territories (NWT), particularly among Canadian Aboriginal people. OBJECTIVE: To analyse the transmission patterns of tuberculosis among the population living in the NWT, a territorial jurisdiction located within Northern Canada. METHODS: This population-based retrospective study examined the DNA fingerprints of all laboratory confirmed cases of TB in the NWT, Canada, between 1990 and 2009. An isolate of each lab-confirmed case had genotyping done using IS6110 Restriction Fragment Length Polymorphism. DNA patterns were assigned to each DNA fingerprint, and indistinguishable fingerprints patterns were assigned a cluster. Social network analysis (SNA) was used to examine direct linkages among cases determined through conventional contact tracing (CCT), their DNA fingerprint and home community. RESULTS: Of the 225 lab-confirmed cases identified, the study was limited to 195 subjects due to DNA fingerprinting data availability. The mean age of the cases was 43.8 years (+/-22.6) and 120 (61.5%) males. The Dene (First Nations) encompassed 120 of the cases (87.7%), 8 cases (4.1%) were Inuit, 2 cases (1.0%) were Metis, 7 cases (3.6%) were Immigrants and 1 case had unknown ethnicity. One hundred and eighty six (95.4%) subjects were clustered, resulting in 8 clusters. Trend analysis showed significant relationships between with risk factors for unemployment (p=0.020), geographic location (p<=0.001) and homelessness (p<=0.001). Other significant risk factors included excessive alcohol consumption, prior infection with Mycobacterium tuberculosis and prior contact with a case of TB. CONCLUSIONS: This study demonstrates how DNA fingerprinting and SNA can be additional epidemiological tools, along with CCT method, to determine transmission patterns of TB. PMID- 23671836 TI - Utilizing harmonization and common surveillance methods to consolidate 4 cohorts: the Western Alaska Tribal Collaborative for Health (WATCH) study. AB - BACKGROUND: According to health status reports, chronic disease prevalence appears to be rising in western Alaska Native (AN) people, and accurate population-based data are needed. Four cohort studies of western AN people were conducted in the Norton Sound and Yukon-Kuskokwim regions, but none have been large enough to allow reliable estimates of rates of chronic diseases and evaluate their risk factors. OBJECTIVE: In this article, the methods used to combine 4 major cohort studies of rural western AN people are described and the benefits and challenges encountered in combining data and standardizing surveillance methods for these studies are discussed. DESIGN: Tribal permission was obtained for each cohort study and the consolidated study. Data from baseline exams were directly combined or harmonized into new variables. Common surveillance methods were developed and implemented to identify incidence and risk factors for cardiovascular disease (CVD) events and type 2 diabetes. RESULTS: A cohort of 4,569 western AN participants (2,116 men and 2,453 women), aged 18-95 years, was established to study CVD and diabetes prevalence. Prospective surveillance data over an average 6.7-year follow-up can now be used to study CVD and diabetes incidence and associated risk factors in a subset of 2,754 western AN participants (1,218 men and 1,536 women) who consented to initial surveillance. CONCLUSIONS: The combined cohort provides statistical power to examine incidence rates and risk factors for CVD and diabetes and allows for analyses by geographic region. The data can be used to develop intervention programmes in these populations and others. PMID- 23671838 TI - Is Arctic medicine a distinct science? A Russian perspective. PMID- 23671839 TI - Expression and Functional Analysis of Storage Protein 2 in the Silkworm, Bombyx mori. AB - Storage protein 2 (SP2) not only is an important source of energy for the growth and development of silkworm but also has inhibitory effects on cell apoptosis. Endothelial cell (EC) apoptosis is an important contributing factor in the development of atherosclerosis; therefore, study of the antiapoptotic activity of SP2 on ECs provides information related to the treatment of atherosclerosis and other cardiovascular diseases. In this study, the sp2 gene was cloned and expressed in Escherichia coli to produce a 6xHis-tagged fusion protein, which was then used to generate a polyclonal antibody. Western blot results revealed that SP2 levels were higher in the pupal stage and hemolymph of fifth-instar larvae but low in the egg and adult stages. Subcellular localization results showed that SP2 is located mainly on the cell membrane. In addition, a Bac-to-Bac system was used to construct a recombinant baculovirus for SP2 expression. The purified SP2 was then added to a culture medium for human umbilical vein ECs (HUVECs), which were exposed to staurosporine. A cell viability assay demonstrated that SP2 could significantly enhance the viability of HUVEC. Furthermore, both ELISA and flow cytometry results indicated that SP2 has anti-apoptotic effects on staurosporine induced HUVEC apoptosis. PMID- 23671840 TI - Characterization of the OmyY1 Region on the Rainbow Trout Y Chromosome. AB - We characterized the male-specific region on the Y chromosome of rainbow trout, which contains both sdY (the sex-determining gene) and the male-specific genetic marker, OmyY1. Several clones containing the OmyY1 marker were screened from a BAC library from a YY clonal line and found to be part of an 800 kb BAC contig. Using fluorescence in situ hybridization (FISH), these clones were localized to the end of the short arm of the Y chromosome in rainbow trout, with an additional signal on the end of the X chromosome in many cells. We sequenced a minimum tiling path of these clones using Illumina and 454 pyrosequencing. The region is rich in transposons and rDNA, but also appears to contain several single-copy protein-coding genes. Most of these genes are also found on the X chromosome; and in several cases sex-specific SNPs in these genes were identified between the male (YY) and female (XX) homozygous clonal lines. Additional genes were identified by hybridization of the BACs to the cGRASP salmonid 4x44K oligo microarray. By BLASTn evaluations using hypothetical transcripts of OmyY1-linked candidate genes as query against several EST databases, we conclude at least 12 of these candidate genes are likely functional, and expressed. PMID- 23671841 TI - A New Exon Derived from a Mammalian Apparent LTR Retrotransposon of the SUPT16H Gene. AB - The SUPT16H gene known as FACTP140 is required for the transcription of other genes. For transcription, genes need to be complexed with accessory factors, including transcription factors and RNA polymerase II. One such factor, FACT, interacts with histones H2A/H2B for nucleosome disassembly and transcription elongation. The SUPT16H gene has a transcript and many expressed sequence tags (ESTs). We were especially interested in an MaLR-derived transcript (EST, BX333035) that included a new exon introduced by a transposable element, a mammalian apparent LTR retrotransposon (MaLR). The MaLR was detected ranging from humans to galagos, indicating the MaLR in the SUPT16H gene is integrated into the primate ancestor genome. A new exon was created by alternative donor site provided by the MaLR. The original transcript and the MaLR-derived transcript were expressed in various human, rhesus monkey, and other primate tissues. Additionally, we identified a new alternative transcript that included the MaLR, but there was no significant difference in the expression of the original transcript and the MaLR-derived transcript. Interestingly, the new alternative transcript and the MaLR-derived transcript had the MaLR sequence in the new exon, but they had different structures by adopting different 3' splice sites. From this study, we verified transposable elements that contributed to transcriptome diversity. PMID- 23671842 TI - Implementation of a parallel protein structure alignment service on cloud. AB - Protein structure alignment has become an important strategy by which to identify evolutionary relationships between protein sequences. Several alignment tools are currently available for online comparison of protein structures. In this paper, we propose a parallel protein structure alignment service based on the Hadoop distribution framework. This service includes a protein structure alignment algorithm, a refinement algorithm, and a MapReduce programming model. The refinement algorithm refines the result of alignment. To process vast numbers of protein structures in parallel, the alignment and refinement algorithms are implemented using MapReduce. We analyzed and compared the structure alignments produced by different methods using a dataset randomly selected from the PDB database. The experimental results verify that the proposed algorithm refines the resulting alignments more accurately than existing algorithms. Meanwhile, the computational performance of the proposed service is proportional to the number of processors used in our cloud platform. PMID- 23671843 TI - Open reading frame phylogenetic analysis on the cloud. AB - Phylogenetic analysis has become essential in researching the evolutionary relationships between viruses. These relationships are depicted on phylogenetic trees, in which viruses are grouped based on sequence similarity. Viral evolutionary relationships are identified from open reading frames rather than from complete sequences. Recently, cloud computing has become popular for developing internet-based bioinformatics tools. Biocloud is an efficient, scalable, and robust bioinformatics computing service. In this paper, we propose a cloud-based open reading frame phylogenetic analysis service. The proposed service integrates the Hadoop framework, virtualization technology, and phylogenetic analysis methods to provide a high-availability, large-scale bioservice. In a case study, we analyze the phylogenetic relationships among Norovirus. Evolutionary relationships are elucidated by aligning different open reading frame sequences. The proposed platform correctly identifies the evolutionary relationships between members of Norovirus. PMID- 23671844 TI - Effects of taxon sampling in reconstructions of intron evolution. AB - Introns comprise a considerable portion of eukaryotic genomes; however, their evolution is understudied. Numerous works of the last years largely disagree on many aspects of intron evolution. Interpretation of these differences is hindered because different algorithms and taxon sampling strategies were used. Here, we present the first attempt of a systematic evaluation of the effects of taxon sampling on popular intron evolution estimation algorithms. Using the "taxon jackknife" method, we compared the effect of taxon sampling on the behavior of intron evolution inferring algorithms. We show that taxon sampling can dramatically affect the inferences and identify conditions where algorithms are prone to systematic errors. Presence or absence of some key species is often more important than the taxon sampling size alone. Criteria of representativeness of the taxonomic sampling for reliable reconstructions are outlined. Presence of the deep-branching species with relatively high intron density is more important than sheer number of species. According to these criteria, currently available genomic databases are representative enough to provide reliable inferences of the intron evolution in animals, land plants, and fungi, but they underrepresent many groups of unicellular eukaryotes, including the well-studied Alveolata. PMID- 23671845 TI - Conservation, Divergence, and Genome-Wide Distribution of PAL and POX A Gene Families in Plants. AB - Genome-wide identification and phylogenetic and syntenic comparison were performed for the genes responsible for phenylalanine ammonia lyase (PAL) and peroxidase A (POX A) enzymes in nine plant species representing very diverse groups like legumes (Glycine max and Medicago truncatula), fruits (Vitis vinifera), cereals (Sorghum bicolor, Zea mays, and Oryza sativa), trees (Populus trichocarpa), and model dicot (Arabidopsis thaliana) and monocot (Brachypodium distachyon) species. A total of 87 and 1045 genes in PAL and POX A gene families, respectively, have been identified in these species. The phylogenetic and syntenic comparison along with motif distributions shows a high degree of conservation of PAL genes, suggesting that these genes may predate monocot/eudicot divergence. The POX A family genes, present in clusters at the subtelomeric regions of chromosomes, might be evolving and expanding with higher rate than the PAL gene family. Our analysis showed that during the expansion of POX A gene family, many groups and subgroups have evolved, resulting in a high level of functional divergence among monocots and dicots. These results will act as a first step toward the understanding of monocot/eudicot evolution and functional characterization of these gene families in the future. PMID- 23671846 TI - A mechanistic, stochastic model helps understand multiple sclerosis course and pathogenesis. AB - Heritable and nonheritable factors play a role in multiple sclerosis, but their effect size appears too small, explaining relatively little about disease etiology. Assuming that the factors that trigger the onset of the disease are, to some extent, also those that generate its remissions and relapses, we attempted to model the erratic behaviour of the disease course as observed on a dataset containing the time series of relapses and remissions of 70 patients free of disease-modifying therapies. We show that relapses and remissions follow exponential decaying distributions, excluding periodic recurrences and confirming that relapses manifest randomly in time. It is found that a mechanistic model with a random forcing describes in a satisfactory manner the occurrence of relapses and remissions, and the differences in the length of time spent in each one of the two states. This model may describe how interactions between "soft" etiologic factors occasionally reach the disease threshold thanks to comparably small external random perturbations. The model offers a new context to rethink key problems such as "missing heritability" and "hidden environmental structure" in the etiology of complex traits. PMID- 23671847 TI - A Novel Rat Model of Type 2 Diabetes: The Zucker Fatty Diabetes Mellitus ZFDM Rat. AB - The Zucker fatty (ZF) rat harboring a missense mutation (fatty, fa) in the leptin receptor gene (Lepr) develops obesity without diabetes; Zucker diabetic fatty (ZDF) rats derived from the ZF strain exhibit obesity with diabetes and are widely used for research on type 2 diabetes (T2D). Here we establish a novel diabetic strain derived from normoglycemic ZF rats. In our ZF rat colony, we incidentally found fa/fa homozygous male rats having reproductive ability, which is generally absent in these animals. During maintenance of this strain by mating fa/fa males and fa/+ heterozygous females, we further identified fa/fa male rats exhibiting diabetes. We then performed selective breeding using the fa/fa male rats that exhibited relatively high blood glucose levels at 10 weeks of age, resulting in establishment of a diabetic strain that we designated Hos:ZFDM Lepr(fa) (ZFDM). These fa/fa male rats developed diabetes as early as 10 weeks of age, reaching 100% incidence by 21 weeks of age, while none of the fa/+ male rats developed diabetes. The phenotypic characteristics of this diabetic strain are distinct from those of normoglycemic ZF rats. ZFDM rat strain having high reproductive efficiency should serve as a more useful animal model of T2D. PMID- 23671848 TI - Protection effect of endomorphins on advanced glycation end products induced injury in endothelial cells. AB - Endomorphins (EMs) have a very important bridge-function in cardiovascular, endocrinological, and neurological systems. This study is to investigate the effects of EMs on the synthesis and secretion of vasoactive substances induced by advanced glycation end products in primary cultured human umbilical vein endothelial cells (HUVECs). Firstly, HUVECs were stimulated with AGEs-bovine serum albumin (AGEs-BSA), bovine serum albumin (BSA), or both AGEs-BSA and EMs together, respectively. Then, HUVEC survival rate was calculated by MTT assay, the levels of NO, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS) were detected by colorimetric analysis, and the contents of endothelin-1 (ET-1) were detected by ELISA. The mRNA levels of eNOS and ET-1 were measured by RT-PCR. The expression of p38 mitogen-activated protein kinase (p38 MAPK) was detected by immunofluorescence assay. The results showed that the mRNA expression and secretion of eNOS were significantly enhanced after incubation with EMs compared to those with AGEs-BSA, while the secretion of NO and iNOS, mRNA expression, and secretion of ET-1 had opposite changes. The fluorescence intensity of p38MAPK in nuclear was decreased after pretreatment with EMs compared to incubation with AGEs-BSA. Conclusion. The present study suggests that EMs have certain protection effect on AGEs-BSA-induced injury in HUVEC. PMID- 23671849 TI - Short-term exercise training improves insulin sensitivity but does not inhibit inflammatory pathways in immune cells from insulin-resistant subjects. AB - Background. Exercise has an anti-inflammatory effect against, and immune cells play critical roles in the development, of insulin resistance and atherosclerotic vascular disease (AVD). Thus, the goal of this study was to determine whether exercise improves insulin sensitivity in insulin-resistant subjects by downregulating proinflammatory signaling in immune cells. Methods. Seventeen lean, 8 obese nondiabetic, and 11 obese type 2 diabetic individuals underwent an aerobic exercise program for 15 days and an insulin clamp before and after exercise. Peripheral mononuclear cells (PMNC) were obtained for determination of Toll-like receptor (TLR) 2 and 4 protein content and mitogen-activated protein kinase phosphorylation. Results. Compared with that in lean individuals, TLR4 protein content was increased by 4.2-fold in diabetic subjects. This increase in TLR4 content was accompanied by a 3.0-fold increase in extracellular signal regulated kinase (ERK) phosphorylation. Exercise improved insulin sensitivity in the lean, obese, and type 2 diabetes groups. However, exercise did not affect TLR content or ERK phosphorylation. Conclusions. TLR4 content and ERK phosphorylation are increased in PMNC of type 2 diabetic individuals. While exercise improves insulin sensitivity, this effect is not related to changes in TLR2/TLR4 content or ERK phosphorylation in PMNC of type 2 diabetic individuals. PMID- 23671850 TI - The hypocholesterolemic effect of germinated brown rice involves the upregulation of the apolipoprotein A1 and low-density lipoprotein receptor genes. AB - Germinated brown rice (GBR) is rich in bioactive compounds, which confer GBR with many functional properties. Evidence of its hypocholesterolemic effects is emerging, but the exact mechanisms of action and bioactive compounds involved have not been fully documented. Using type 2 diabetic rats, we studied the effects of white rice, GBR, and brown rice (BR) on lipid profile and on the regulation of selected genes involved in cholesterol metabolism. Our results showed that the upregulation of apolipoprotein A1 and low-density lipoprotein receptor genes was involved in the hypocholesterolemic effects of GBR. Additionally, in vitro studies using HEPG2 cells showed that acylated steryl glycoside, gamma amino butyric acid, and oryzanol and phenolic extracts of GBR contribute to the nutrigenomic regulation of these genes. Transcriptional and nontranscriptional mechanisms are likely involved in the overall hypocholesterolemic effects of GBR suggesting that it may have an impact on the prevention and/or management of hypercholesterolemia due to a wide variety of metabolic perturbations. However, there is need to conduct long-term clinical trials to determine the clinical relevance of the hypocholesterolemic effects of GBR determined through animal studies. PMID- 23671851 TI - Rodent models for investigating the dysregulation of immune responses in type 1 diabetes. AB - Type 1 diabetes (T1D) is an autoimmune disease mediated by T cells that selectively destroy the insulin-producing beta cells. Previous reports based on epidemiological and animal studies have demonstrated that both genetic factors and environmental parameters can either promote or attenuate the progression of autoimmunity. In recent decades, several inbred rodent strains that spontaneously develop diabetes have been applied to the investigation of the pathogenesis of T1D. Because the genetic manipulation of mice is well developed (transgenic, knockout, and conditional knockout/transgenic), most studies are performed using the nonobese diabetic (NOD) mouse model. This paper will focus on the use of genetically manipulated NOD mice to explore the pathogenesis of T1D and to develop potential therapeutic approaches. PMID- 23671852 TI - Impact of serum retinol-binding protein 4 levels on regulation of remnant-like particles triglyceride in type 2 diabetes mellitus. AB - Background. Although retinol-binding protein 4 (RBP4) associates with insulin resistance and remnant-like particles triglyceride (RLP-TG) elevated in the insulin resistant state, few data exist regarding the relationship between RBP4 and RLP-TG. Subjects and Methods. The study included 92 Japanese type 2 diabetic mellitus (T2DM) male patients (age 60.5 +/- 13.6 years, body mass index (BMI) 24.7 +/- 4.1 kg/m(2), waist circumference (WC) 88.4 +/- 10.7 cm, and HbA1c (NGSP) 7.2 +/- 1.9%). Patients on medications affecting insulin sensitivity, including fibrates, biguanides, and thiazolidinedione, were excluded. Visceral fat area (VFA) and subcutaneous fat area (SFA) were measured by computed tomography. Results. RBP4 levels showed a significant positive correlation with RLP-TG (r = 0.2544 and P = 0.0056), TG (r = 0.1852 and P = 0.041), RLP-TG/TG (r = 0.23765 and P = 0.0241), and age (r = -0.2082 and P = 0.0219), although there was no significant correlation with VFA, SFA, adiponectin levels, or homeostasis model of assessment insulin resistance (HOMA-R). Multiple regression analysis revealed that RBP4 was an independent determinant of RLP-TG (P = 0.0193) but was not a determinant of TG. Conclusions. RBP4 correlates positively with serum RLP-TG independent of fat accumulation in T2DM. RBP4 may regulate remnant metabolism independent of glycemic control in T2DM. PMID- 23671853 TI - Insulin Sensitivity and Beta-Cell Function Are Associated with Arterial Stiffness in Individuals without Hypertension. AB - Aim. We investigated the relationship between brachial-ankle pulse wave velocity (baPWV) and glucose levels, insulin sensitivity, and beta-cell function in Chinese individuals with or without hypertension. Methods. We recruited 3137 nondiabetic individuals whose age, body mass index (BMI), glucose levels, blood pressure (BP), lipids, hemoglobin A1C (HbA1c), baPWV, and insulin levels were measured. Results. In normotensive group, 2 h glucose levels (beta = 0.046, P < 0.001) associated with baPWV, showed a significant increase in patients with NG as compared to those with DM (P = 0.032). The hypertensive group showed no such differences. The Matsuda index (beta = 0.114, P < 0.001) and HOMA- beta (beta = 0.045, P < 0.001) were negatively correlated with baPWV while lnHOMA-IR (beta = 0.196, P = 0.076) and the Quantitative Insulin Sensitivity Check Index (QUICKI) (beta = 0.226, P = 0.046) showed a borderline negative correlation. BaPWV significantly decreased (P = 0.032) with an increase in insulin sensitivity in individuals with both normal BP and glucose tolerance. Conclusions. BaPWV was significantly associated with 2 h glucose levels, insulin sensitivity and beta cell function in normotensive population, whereas in hypertensive individuals, BP was the dominant factor influencing arterial stiffness. Individuals with abnormal insulin sensitivity in the absence of diabetes and hypertension are also at an increased risk of arterial stiffness. PMID- 23671854 TI - Comparison of Two New Mouse Models of Polygenic Type 2 Diabetes at the Jackson Laboratory, NONcNZO10Lt/J and TALLYHO/JngJ. AB - This review compares two novel polygenic mouse models of type 2 diabetes (T2D), TALLYHO/JngJ and NONcNZO10/LtJ, and contrasts both with the well-known C57BLKS/J Lepr(db) (db/db) monogenic diabesity model. We posit that the new polygenic models are more representative of the "garden variety" obesity underlying human T2D in terms of their polygenetic rather than monogenic etiology. Moreover, the clinical phenotypes in these new models are less extreme, for example, more moderated development of obesity coupled with less extreme endocrine disturbances. The more progressive development of obesity produces a maturity onset development of hyperglycemia in contrast to the juvenile-onset diabetes observed in the morbidly obese db/db model. Unlike the leptin receptor-deficient db/db models with central leptin resistance, the new models develop a progressive peripheral leptin resistance and are able to maintain reproductive function. Although the T2D pathophysiology in both TALLYHO/JngJ and NONcNZO10/LtJ is remarkably similar, their genetic etiologies are clearly different, underscoring the genetic heterogeneity underlying T2D in humans. PMID- 23671855 TI - Effects of long-term treatment with ranirestat, a potent aldose reductase inhibitor, on diabetic cataract and neuropathy in spontaneously diabetic torii rats. AB - We evaluated ranirestat, an aldose reductase inhibitor, in diabetic cataract and neuropathy (DN) in spontaneously diabetic Torii (SDT) rats compared with epalrestat, the positive control. Animals were divided into groups and treated once daily with oral ranirestat (0.1, 1.0, 10 mg/kg) or epalrestat (100 mg/kg) for 40 weeks, normal Sprague-Dawley rats, and untreated SDT rats. Lens opacification was scored from 0 (normal) to 3 (mature cataract). The combined scores (0-6) from both lenses represented the total for each animal. DN was assessed by measuring the motor nerve conduction velocity (MNCV) in the sciatic nerve. Sorbitol and fructose levels were measured in the lens and sciatic nerve 40 weeks after diabetes onset. Cataracts developed more in untreated rats than normal rats (P < 0.01). Ranirestat significantly (P < 0.01) inhibited rapid cataract development; epalrestat did not. Ranirestat significantly reversed the MNCV decrease (40.7 +/- 0.6 m/s) in SDT rats dose-dependently (P < 0.01). Epalrestat also reversed the prevented MNCV decrease (P < 0.05). Sorbitol levels in the sciatic nerve increased significantly in SDT rats (2.05 +/- 0.10 nmol/g), which ranirestat significantly suppressed dose-dependently, (P < 0.05, <0.01, and <0.01); epalrestat did not. Ranirestat prevents DN and cataract; epalrestat prevents DN only. PMID- 23671856 TI - Protective Effects of Resveratrol on TNF-alpha-Induced Endothelial Cytotoxicity in Baboon Femoral Arterial Endothelial Cells. AB - Endothelial injury induced by inflammatory factors plays a critical role in the pathogenesis of cardiovascular disease. Endothelial cell (EC) apoptosis, proliferation, migration, and cellular adhesion molecule (CAM) expression contribute to the development of atherosclerosis. We investigated the effects of resveratrol (0.1-100 MU M) on the proliferation, migration, and CAM expression of primary cultures of baboon arterial endothelial cells (BAECs). In addition, we tested its effects under normal conditions as well as under inflammatory conditions induced by tumour necrosis factor-alpha (TNF-alpha) administered either by cotreatment, pretreatment, or posttreatment. Immunocytochemistry, MTT, wound-healing, and flow cytometry assays were performed. The resveratrol treatment significantly enhanced BAEC proliferation and attenuated TNF-alpha induced impairment of proliferation at the optimal doses of 1-50 uM. Resveratrol at a high dose (100 MU M) and TNF-alpha impaired BAEC migration, while low doses of resveratrol (1-50 MU M) attenuated TNF-alpha-induced impairment of BAEC migration. Moreover, resveratrol inhibited TNF-alpha-induced ICAM-1 and VCAM-1 expression. Taken together, our results suggest that the resveratrol protects BAECs after inflammatory stimulation as well as ameliorates inflammatory effects at low concentrations. Consequently, resveratrol should be considered as a candidate drug for the prevention and treatment of inflammatory vascular diseases. PMID- 23671858 TI - Relationship between Stage of Diabetic Retinopathy and Pulse Wave Velocity in Japanese Patients with Type 2 Diabetes. AB - Objectives. We investigated the relationship between the stage of diabetic retinopathy and pulse wave velocity (PWV). Methods. This was a cross-sectional study of 689 patients (406 men and 283 women) with type 2 diabetes who were admitted to our hospital from 2004 to 2007. Brachial-ankle pulse wave velocity (baPWV) was measured by an arterial pressure measurement device as PWV/ABI. Diagnosis of diabetic retinopathy was made by ophthalmologists based on the Davis classification: no diabetic retinopathy (NDR), simple retinopathy (SDR), pre proliferative retinopathy (pre-PDR), and proliferative retinopathy (PDR). Results. There was a significant difference in PWV between patients without diabetic retinopathy (1657.0 +/- 417.9 m/s (mean +/- SD)) and with diabetic retinopathy (1847.1 +/- 423.9 m/s) (P < 0.001). In addition, the stage of diabetic retinopathy was associated with aortic PWV (1657.0 +/- 417.9 m/s in NDR (n = 420), 1819.4 +/- 430.3 m/s in SDR (n = 152), 1862.1 +/- 394.0 m/s in pre-PDR (n = 54), and 1901.1 +/- 433.5 m/s in PDR (n = 63) (P < 0.001)). Conclusions. In patients with diabetic retinopathy, even in those with SDR, PWV was higher than that in patients without diabetic retinopathy. Physicians should therefore pay attention to the value of PWV and macroangiopathy regardless of the stage of diabetic retinopathy. PMID- 23671857 TI - Stress and Its Effects on Glucose Metabolism and 11beta-HSD Activities in Rats Fed on a Combination of High-Fat and High-Sucrose Diet with Glycyrrhizic Acid. AB - Chronic stress has been shown to have a strong link towards metabolic syndrome (MetS). Glycyrrhizic acid (GA) meanwhile has been shown to improve MetS symptoms caused by an unhealthy diet by inhibiting 11 beta -HSD 1. This experiment aimed to determine the effects of continuous, moderate-intensity stress on rats with and without GA intake on systolic blood pressure (SBP) across a 28-day period, as well as glucose metabolism, and 11 beta -HSD 1 and 2 activities at the end of the 28-day period. Adaptation to the stressor (as shown by SBP) resulted in no significant defects in glucose metabolism by the end of the experimental duration. However, a weakly significant increase in renal 11 beta -HSD 1 and a significant increase in subcutaneous adipose tissue 11 beta -HSD 1 activities were observed. GA intake did not elicit any significant benefit in glucose metabolism, indicating that the stress response may block its effects. However, GA-induced improvements in 11 beta -HSD activities in certain tissues were observed, although it is uncertain if these effects are manifested after adaptation due to the withdrawal of the stress response. Hence the ability of GA to improve stress-induced disturbances in the absence of adaptation needs to be investigated further. PMID- 23671859 TI - Relationship between Oxidant/Antioxidant Markers and Severity of Microalbuminuria in the Early Stage of Nephropathy in Type 2 Diabetic Patients. AB - A wide range of microalbuminuria cutoff values are currently used for diagnosing the early stage of nephropathy in type 2 diabetes (T2D). This study analyzed the relationships between oxidant and antioxidant markers of nephropathy and the severity of microalbuminuria. The study included 50 healthy controls (Group 1), 50 diabetic patients with no nephropathy (Group 2), 50 diabetic patients with nephropathy and a urinary albumin excretion (UAE) of 30-200 mg/24 h (Group 3), and 50 diabetic patients with UAE 200-300 mg/24 h (Group 4). Serum nitrotyrosine, conjugated dienes, 8-hydroxy-2'-deoxyguanosine (8-OHdG), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC) levels were determined. Oxidative stress is increased in the early stage of nephropathy in patients with T2D. There was a significant correlation between the extent of microalbuminuria and markers of oxidative stress. Multiple linear regression analysis identified lipid oxidative stress as a possible independent marker for evaluating the degree of renal damage in diabetic nephropathy. Stratifying microalbuminuria values during the early stage of nephropathy might be an important factor in facilitating earlier and more specific interventions. PMID- 23671860 TI - Predicting Changes in Cardiovascular Risk Factors in Type 2 Diabetes in the Post UKPDS Era: Longitudinal Analysis of the Swedish National Diabetes Register. AB - The aim of the current study was to provide updated time-path equations for risk factors of type-2-diabetes-related cardiovascular complications for application in risk calculators and health economic models. Observational data from the Swedish National Diabetes Register were analysed using Generalized Method of Moments estimation for dynamic panel models (N = 5,043, aged 25-70 years at diagnosis in 2001-2004). Validation was performed using persons diagnosed in 2005 (n = 414). Results were compared with the UKPDS outcome model. The value of the risk factor in the previous year was the main predictor of the current value of the risk factor. People with high (low) values of risk factor in the year of diagnosis experienced a decreasing (increasing) trend over time. BMI was associated with elevations in all risk factors, while older age at diagnosis and being female generally corresponded to lower levels of risk factors. Updated time path equations predicted risk factors more precisely than UKPDS outcome model equations in a Swedish population. Findings indicate new time paths for cardiovascular risk factors in the post-UKPDS era. The validation analysis confirmed the importance of updating the equations as new data become available; otherwise, the results of health economic analyses may be biased. PMID- 23671861 TI - Role of vitamin d in cardiometabolic diseases. AB - Vitamin D deficiency is a highly prevalent condition. Low vitamin D levels have long been associated with bone diseases, such as rickets in children and osteomalacia and osteoporosis in adults. However, it has become apparent in recent years that adequate vitamin D levels are also important for optimal functioning of many organs and tissues throughout the body, including the cardiovascular system. Evolving data indicate that vitamin D deficiency is associated with an increased risk of cardiovascular disease (CVD). Studies have shown that low vitamin D levels are associated with hypertension, diabetes, metabolic syndrome, left ventricular hypertrophy, and chronic vascular inflammation, all of which are risk factors for CVD. This paper reviews the definition and pathophysiology of vitamin D deficiency, clinical evidence linking vitamin D and CVD risk, diabetes and its complications, and metabolic syndrome. PMID- 23671862 TI - Investigation of the Protective Effects of Phlorizin on Diabetic Cardiomyopathy in db/db Mice by Quantitative Proteomics. AB - Patients with diabetes often develop hypertension and atherosclerosis leading to cardiovascular disease. However, some diabetic patients develop heart failure without hypertension and coronary artery disease, a process termed diabetic cardiomyopathy. Phlorizin has been reported to be effective as an antioxidant in treating diabetes mellitus, but little is known about its cardioprotective effects on diabetic cardiomyopathy. In this study, we investigated the role of phlorizin in preventing diabetic cardiomyopathy in db/db mice. We found that phlorizin significantly decreased body weight gain and the levels of serum fasting blood glucose (FBG), triglycerides (TG), total cholesterol (TC), and advanced glycation end products (AGEs). Morphologic observations showed that normal myocardial structure was better preserved after phlorizin treatment. Using isobaric tag for relative and absolute quantitation (iTRAQ) proteomics, we identified differentially expressed proteins involved in cardiac lipid metabolism, mitochondrial function, and cardiomyopathy, suggesting that phlorizin may prevent the development of diabetic cardiomyopathy by regulating the expression of key proteins in these processes. We used ingenuity pathway analysis (IPA) to generate an interaction network to map the pathways containing these proteins. Our findings provide important information about the mechanism of diabetic cardiomyopathy and also suggest that phlorizin may be a novel therapeutic approach for the treatment of diabetic cardiomyopathy. PMID- 23671863 TI - Antibacterial effect of autologous platelet-rich gel derived from subjects with diabetic dermal ulcers in vitro. AB - Background. Autologous platelet-rich gel (APG) is an effective method to improve ulcer healing. However, the mechanisms are not clear. This study aimed to investigate the antibacterial effect of APG in vitro. Methods. Platelet-rich plasma (PRP), platelet-poor plasma (PPP) and APG were prepared from whole blood of sixteen diabetic patients with dermal ulcers. Antibacterial effects against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa were evaluated by bacteriostasis assay of APG, PRP, and APG-APO (APG combined with apocynin), with phosphate-buffered saline (PBS) and PPP as the control group. Results. (1) Compared to the PBS and PPP, the APG and APG-APO groups showed strong antibacterial activity against Staphylococcus aureus. There was no significant difference (P > 0.05) between APG and APG-APO. (2) Compared to PBS, APG, APG-APO, and PRP showed obvious antibacterial effects against Escherichia coli and Pseudomonas aeruginosa. No significant difference (P > 0.05) was revealed among the three groups. Compared to the PPP group, they did not show antibacterial effect against Escherichia coli and Pseudomonas aeruginosa (P > 0.05). Conclusions. APG has antibacterial effect against Staphylococcus aureus mediated by platelet activation in the diabetic patients with dermal ulcer, and does not present obvious antibacterial effect against Escherichia coli or Pseudomonas aeruginosa. Combination of APG and antibiotics may have synergistic antibacterial effect. PMID- 23671864 TI - The effect of simvastatin on glucose homeostasis in streptozotocin induced type 2 diabetic rats. AB - Objective. To investigate the effect of simvastatin on glucose homeostasis in streptozotocin induced type 2 diabetic rats. Methods. Forty male Wistar rats were randomly divided into four groups. Normal control rats were fed with standard diet, others were fed with high-fat diet. Diabetic rats were induced by a single intraperitoneal injection of STZ. The simvastatin intervention rats were fed with simvastatin during the experiment process, and the simvastatin treatment rats were fed with simvastatin after diabetes rats were induced. We measured body weight, fasting plasma glucose, cholesterol, high-density lipoprotein cholesterol, and triglyceride after an overnight fast. Results. The FPG was higher in diabetic rats when compared to normal control ones; the simvastatin intervention rats had a higher FPG compared to the diabetic rats and were more easily be induced to diabetes at the end of 4 weeks, FPG level of simvastatin treatment rats was increased compared with diabetic model rats after 12 weeks. Conclusion. These data indicate that simvastatin intervention rats may cause hyperglycemia by impairing the function of islet beta cells and have an adverse effect on glucose homeostasis, especially on FPG level. PMID- 23671865 TI - Bone marrow stem cell as a potential treatment for diabetes. AB - Diabetes mellitus (DM) is a group of metabolic diseases in which a person has high blood glucose levels resulting from defects in insulin secretion and insulin action. The chronic hyperglycemia damages the eyes, kidneys, nerves, heart, and blood vessels. Curative therapies mainly include diet, insulin, and oral hypoglycemic agents. However, these therapies fail to maintain blood glucose levels in the normal range all the time. Although pancreas or islet-cell transplantation achieves better glucose control, a major obstacle is the shortage of donor organs. Recently, research has focused on stem cells which can be classified into embryonic stem cells (ESCs) and tissue stem cells (TSCs) to generate functional beta cells. TSCs include the bone-marrow-, liver-, and pancreas-derived stem cells. In this review, we focus on treatment using bone marrow stem cells for type 1 and 2 DM. PMID- 23671866 TI - Serum Proteome Changes in Healthy Subjects with Different Genotypes of NOS1AP in the Chinese Population. AB - Type 2 diabetes and its chronic complications have become a worldwide epidemic nowadays. However, its molecular mechanism is still unknown. We have previously identified a novel variant rs12742393 of NOS1AP for type 2 diabetes susceptibility in the Chinese population. In this study, we analyzed the total serum profiling among three genotypes of rs12742393 to discover potential crosstalk under the variant and the disease through proteomic analyses for the first time. We used OFFGEL peptide fractionation, LC-MS/MS analysis, and label free quantification to profile the fasting human serum samples of the genotypes in rs12742393 (n = 4, for CC, AC, and AA, resp.). Four proteins were identified, including apoA4, alpha1-ACT, HABP2, and keratin 10, with blood levels changed significantly between CC and AA homozygotes of rs12742393. Compared with AA group, the levels of apoA4 increased (P = 0.000265), whereas the concentration of alpha1-ACT, HABP2, and keratin 10 decreased in CC group (P = 0.011116, 0.021175, and 0.015661, resp.). Then we selected additional fasting serum samples for ELISA and western blot validation. However, no significant differences were identified by neither ELISA nor western blot (P > 0.05). The protein profiling changes between the genotypes of rs12742393 indicated that this SNP might play a role in the development of type 2 diabetes. PMID- 23671867 TI - The Relationship between Type 2 Diabetes Mellitus and Related Thyroid Diseases. AB - Type 2 diabetes mellitus (T2DM) has an intersecting underlying pathology with thyroid dysfunction. The literature is punctuated with evidence indicating a contribution of abnormalities of thyroid hormones to type 2 DM. The most probable mechanism leading to T2DM in thyroid dysfunction could be attributed to perturbed genetic expression of a constellation of genes along with physiological aberrations leading to impaired glucose utilization and disposal in muscles, overproduction of hepatic glucose output, and enhanced absorption of splanchnic glucose. These factors contribute to insulin resistance. Insulin resistance is also associated with thyroid dysfunction. Hyper- and hypothyroidism have been associated with insulin resistance which has been reported to be the major cause of impaired glucose metabolism in T2DM. The state-of-art evidence suggests a pivotal role of insulin resistance in underlining the relation between T2DM and thyroid dysfunction. A plethora of preclinical, molecular, and clinical studies have evidenced an undeniable role of thyroid malfunctioning as a comorbid disorder of T2DM. It has been investigated that specifically designed thyroid hormone analogues can be looked upon as the potential therapeutic strategies to alleviate diabetes, obesity, and atherosclerosis. These molecules are in final stages of preclinical and clinical evaluation and may pave the way to unveil a distinct class of drugs to treat metabolic disorders. PMID- 23671868 TI - Spontaneous type 2 diabetic rodent models. AB - Diabetes mellitus, especially type 2 diabetes (T2DM), is one of the most common chronic diseases and continues to increase in numbers with large proportion of health care budget being used. Many animal models have been established in order to investigate the mechanisms and pathophysiologic progress of T2DM and find effective treatments for its complications. On the basis of their strains, features, advantages, and disadvantages, various types of animal models of T2DM can be divided into spontaneously diabetic models, artificially induced diabetic models, and transgenic/knockout diabetic models. Among these models, the spontaneous rodent models are used more frequently because many of them can closely describe the characteristic features of T2DM, especially obesity and insulin resistance. In this paper, we aim to investigate the current available spontaneous rodent models for T2DM with regard to their characteristic features, advantages, and disadvantages, and especially to describe appropriate selection and usefulness of different spontaneous rodent models in testing of various new antidiabetic drugs for the treatment of type 2 diabetes. PMID- 23671869 TI - Angiotensin-Converting Enzyme 2 Deficiency Aggravates Glucose Intolerance via Impairment of Islet Microvascular Density in Mice with High-Fat Diet. AB - The aim of this study was to evaluate the effects of angiotensin-converting enzyme 2 (ACE2) on glucose homeostasis and islet function in mice. Male wildtype (WT) and ACE2 knockout (ACE2 KO) mice were divided into chow diet group and long term high-fat diet (HFD) group. After 16 weeks of feeding, the islet function of the animals was evaluated by intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin releasing test (IPIRT). The pancreas was immunohistochemically stained to analyze the relative content of insulin (IRC), vascular endothelial growth factor (VEGF), and microvessel density (MVD) in islets. There was no difference of body weight, area under curve of glucose (AUCG), area under curve of insulin from 0 to 5 min (AUGI0-5), MVD, and RVC (relative content of VEGF) between WT and ACE2 KO mice with regular chow diet. Under the condition of long-term HFD, the AUCG of ACE2 KO mice was increased obviously in comparison with the WT mice, with decreased IRC, MVD, AUGI0-5, AUCI0 30, and RVC (all P < 0.05). In conclusion, these results show that ACE2 deficiency deteriorates islet function of mice with long-term HFD via impairment of islet microvasculature. PMID- 23671870 TI - Zinc and diabetic retinopathy. AB - Zinc (Zn) is an important nutrient that is involved in various physiological metabolisms. Zn dyshomeostasis is often associated with various pathogeneses of chronic diseases, such as metabolic syndrome, diabetes, and related complications. Zn is present in ocular tissue in high concentrations, particularly in the retina and choroid. Zn deficiencies have been shown to affect ocular development, cataracts, age-related macular degeneration, and even diabetic retinopathy. However, the mechanism by which Zn deficiency increases the prevalence of diabetic retinopathy remains unclear. In addition, due to the negative effect of Zn deficiency on the eye, Zn supplementation should prevent diabetic retinopathy; however, limited available data do not always support this notion. Therefore, the goal of this paper was to summarize these pieces of available information regarding Zn prevention of diabetic retinopathy. Current theories and possible mechanisms underlying the role of Zn in the eye-related diseases are discussed. The possible factors that affect the preventive effect of Zn supplementation on diabetic retinopathy were also discussed. PMID- 23671871 TI - Association of the HLA-DQA1 and HLA-DQB1 Alleles in Type 2 Diabetes Mellitus and Diabetic Nephropathy in the Han Ethnicity of China. AB - HLA gene system is one of the most polymorphic regions of the human genome. The association of HLA class II genes in T1DM pathogenesis has been reported for several ethnicities. Associations of HLA class II genes with T2DM have revealed inconsistent results. Moreover, correlations between DN and HLA alleles remain unclear. We carried out DNA typing chip by specific medium resolution typing probes in 310 T2DM subjects (including 210 patients with DN and 100 patients without DN) in addition to 100 healthy controls. Differences were found between patients with T2DM and the control group in the frequencies of the HLA-DQA1*0301 (15.5% versus 8.0%, P < 0.01) and the HLA-DQA1*0501 alleles (16.6% versus 8.5%, P < 0.01). Differences were found between patients with DN and without DN in the frequencies of the HLA-DQA1*0302 (6.9% versus 13.5%, P < 0.01) and HLA-DQB1*0501 alleles (5.8% versus 14.5%, P < 0.01). Diabetes duration and systolic blood pressure were independent risk factors associated with DN (OR = 2.277 and 1.366, resp., P < 0.05), whereas the HLA-DQB1*0501 llele had a protective effect on DN (OR = 0.53, P < 0.05). These data suggest the HLA-DQA1*0301 and HLA-DQA1*0501 alleles are markers of susceptibility for T2DM, and the HLA-DQB1*0501 allele is associated with a protective effect on DN in Han ethnicity of China. PMID- 23671872 TI - Ethyl pyruvate prevents methyglyoxal-induced retinal vascular injury in rats. AB - Pyruvate is an endogenous antioxidant substance. The aim of this study was to investigate the protective effects of ethyl pyruvate (EP) on retinal vascular injury in diabetic retinopathy. To investigate the protective effect of EP on vascular cell apoptosis and blood-retinal barrier (BRB) breakage, we have used intravitreally methylglyoxal-(MGO-) injected rat eyes. Apoptosis of the retinal vascular cell that was stimulated by the intravitreal injection of MGO was evidently attenuated by the EP treatment. EP exerts inhibitory effect on MGO induced vascular cell apoptosis by blocking oxidative injury. In addition, EP treatment prevented MGO-induced BRB breakage and the degradation of occludin, an important tight junction protein. These observations suggest that EP acts through an antioxidant mechanism to protect against oxidative stress-induced apoptosis in retinal vessels. PMID- 23671873 TI - Cardiopulmonary Profile in Streptozotocin-Induced Type 1 Diabetic Rats during Systemic Endotoxemia. AB - This study was designed to determine the severity of cardiopulmonary dysfunction during systemic endotoxemia in type 1 diabetes. Thirty-two adult male Wistar rats were randomly assigned to a control group or to a group treated with streptozotocin (STZ) to create an animal model of type 1 diabetes. Survival time and cardiovascular parameters were continually monitored in urethane anaesthetized animals receiving intravenous infusion of endotoxin (lipopolysaccharide (LPS)) or saline. We also determined arterial blood gases, lung injury, and tumor necrosis factor-alpha (TNF- alpha ) levels in serum and bronchoalveolar lavage fluid. Before LPS administration, the mean arterial pressure in STZ rats was significantly higher than that in normal rats. After LPS injection, the heart rate drop significantly in STZ rats than that in the control group. Also, the increased levels of TNF- alpha in serum and lavage fluid after LPS treatment were significantly higher in STZ rats than those in normal rats. Survival time in STZ rats was shorter than that in normal rats after LPS application. Albumin content, wet/dry weight ratio of lung, and lung injury were indistinguishable between STZ and normal rats. These results indicate that the cardiopulmonary change which occurs during LPS-induced endotoxemia is minor in STZ-induced diabetic rats. PMID- 23671874 TI - Angiogenic and vasculogenic factors in the vitreous from patients with proliferative diabetic retinopathy. AB - This study was conducted to determine levels of angiogenic and endothelial progenitor cell mobilizing (vasculogenic) factors in vitreous fluid from proliferative diabetic retinopathy (PDR) patients and correlate their levels with clinical disease activity. Vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor-2 (sVEGFR-2), stem cell factor (SCF), soluble c-kit (s-kit), endothelial nitric oxide synthase (eNOS), and prostaglandin E2 (PGE2) levels were measured by ELISA in vitreous samples from 34 PDR and 15 nondiabetic patients. eNOS was not detected. VEGF, sVEGFR-2, SCF, and s-kit levels were significantly higher in PDR with active neovascularization compared with quiescent PDR and nondiabetic patients (P < 0.001; 0.007; 0.001; <0.001, resp.). In contrast, PGE2 levels were significantly higher in nondiabetic patients compared with PDR patients (P < 0.001). There were significant correlations between levels of sVEGFR-2 versus SCF (r = 0.950, P < 0.001), sVEGFR 2 versus s-kit (r = 0.941, P < 0.001), and SCF versus s-kit (r = 0.970, P < 0.001). Our findings suggest that upregulation of VEGF, sVEGFR-2, SCF, and s-kit supports the contributions of angiogenesis and vasculogenesis in pathogenesis of PDR. PMID- 23671875 TI - Adipocytokine associations with insulin resistance in british South asians. AB - Aims. Adipocytokines are implicated in the pathogenesis of type 2 diabetes and may represent identifiable precursors of metabolic disease within high-risk groups. We investigated adiponectin, leptin, and TNF- alpha and assessed the contribution of these molecules to insulin resistance in south Asians. Hypothesis. South Asians have adverse adipocytokine profiles which associate with an HOMA-derived insulin resistance phenotype. Methods. We measured adipocytokine concentrations in south Asians with newly diagnosed impaired glucose tolerance or Type 2 Diabetes Mellitus in a case-control study. 158 (48.5% males) volunteers aged 25-75 years with risk factors for diabetes but no known vascular or metabolic disease provided serum samples for ELISA and bioplex assays. Results. Total adiponectin concentration progressively decreased across the glucose spectrum in both sexes. A reciprocal trend in leptin concentration was observed only in south Asian men. Adiponectin but not leptin independently associated with HOMA-derived insulin resistance after logistic multivariate regression. Conclusion. Diasporic south Asian populations have an adverse adipocytokine profile which deteriorates further with glucose dysregulation. Insulin resistance is inversely associated with adiponectin independent of BMI and waist circumference in south Asians, implying that adipocytokine interplay contributes to the pathogenesis of metabolic disease in this group. PMID- 23671876 TI - IGF-1 Increases with Hyperbaric Oxygen Therapy and Promotes Wound Healing in Diabetic Foot Ulcers. AB - Objectives. To investigate insulin-like growth factor I (IGF-1) levels in response to hyperbaric oxygen therapy (HBOT) for diabetic foot ulcers and to determine whether IGF-1 is a predictive indicator of wound healing in patients with diabetic foot ulcers. Design and Methods. We treated 48 consecutive patients with diabetic foot ulcers with HBOT. Alterations of IGF-1 levels in patients whose wound healed with HBOT were compared with those in patients who did not benefit from HBOT. Results. There was no significant difference in initial IGF-1 levels between the two groups (P = 0.399). The mean IGF-1 level increased with HBOT (P < 0.05). In the healed group, the mean IGF-1 increase and the final values were significantly higher (P < 0.05). In the nonhealed group, the mean IGF 1 increase was minus and the final values were not significantly different (P < 0.05). The increase in IGF-1 level with HBOT was significantly higher in the healed group (P < 0.001). Conclusions. IGF-1 increased significantly in the healed group. We believe that HBOT is effective in the treatment of diabetic foot ulcers, with an elevation of IGF-1. This alteration seems to be a predictive factor for wound healing in diabetic foot ulcers treated with HBOT. PMID- 23671877 TI - Sex disparities in diabetes process of care measures and self-care in high-risk patients. AB - Patients with chronic diabetic complications experience high morbidity and mortality. Sex disparities in modifiable factors such as processes of care or self-care activities have not been explored in detail, particularly in these high risk patients. Sex differences in processes of care and self-care activities were assessed in a cross-sectional analysis of the Pathways Study, an observational cohort of primary care diabetic patients from a managed care organization (N = 4,839). Compared to men, women had decreased odds of dyslipidemia screening (adjusted odds ratio (AOR) 0.73, 95% CI 0.62-0.85), reaching low-density lipoprotein goal (AOR 0.70, 95% CI 0.58-0.86), and statin use (AOR 0.69, 95% CI 0.58-0.81); women had 19% greater odds of reaching hemoglobin A1c <7% (95% CI 1.02-1.41). There were no sex differences in hemoglobin A1c testing, microalbuminuria screening, or angiotensin-converting enzyme inhibitor use. Women were less likely to report regular exercise but had better adherence to healthy diet, glucose monitoring, and self-foot examination compared to men. Patterns of sex differences were consistent in subjects with diabetic complications. Significant sex disparities exist in diabetes process of care measures and self care, even amongst patients known to have chronic diabetic complications. PMID- 23671878 TI - Deoxycholic Acid as a Modifier of the Permeation of Gliclazide through the Blood Brain Barrier of a Rat. AB - Major problem for diabetic patients represents damage of blood vessels and the oxidative stress of the brain cells due to increased concentration of free radicals and poor nutrition of brain cells. Gliclazide has antioxidative properties and poor blood brain barrier (BBB) penetration. Bile acids are known for their hypoglycemic effect and as promoters of drug penetration across biological membranes. Accordingly, the aim of this study is to investigate whether the bile acid (deoxycholic acid) can change the permeation of gliclazide, through the blood brain barrier of a rat model type-1 diabetes. Twenty-four male Wistar rats were randomly allocated to four groups, of which, two were given alloxan intraperitoneally (100 mg/kg) to induce diabetes. One diabetic group and one healthy group were given a bolus gliclazide intra-arterially (20 mg/kg), while the other two groups apart from gliclazide got deoxycholic acid (4 mg/kg) subcutaneously. Blood samples were collected 30, 60, 150, and 240 seconds after dose, brain tissues were immediately excised and blood glucose and gliclazide concentrations were measured. Penetration of gliclazide in groups without deoxycholic acid pretreatment was increased in diabetic animals compared to healthy animals. Also in both, the healthy and diabetic animals, deoxycholic acid increased the permeation of gliclazide through that in BBB. PMID- 23671879 TI - Evaluation of the Effects of STZ-Induced Diabetes on In Vitro Fertilization and Early Embryogenesis Processes. AB - The aim of this study was to investigate the effects of experimentally induced diabetes on (a) germ cells, (b) in vitro fertilization (IVF) success rate, and (c) gap junction and cell adhesion molecule gene and protein expressions during the early blastocyst period. Germ cells were obtained from healthy and diabetic rats, analyzed for number, motility, and morphology, and used for IVF. After reaching the early blastocyst stage, the expressions of genes encoding gap junction proteins and cell adhesion molecules were analyzed by quantitative RT PCR. Histomorphologically and immunohistochemically analyses were also performed. Diabetes significantly affected sperm number and motility and the development of oocytes. Gene expressions of beta -catenin and connexin family members and protein expressions of E-cadherin and connexin-43 significantly decreased in groups including germ cells isolated from diabetic rats. Connective tissue growth factor expression increased in groups that included sperm cells isolated from diabetic male rats, whereas mucin-1 expression increased in the group that included oocytes isolated from diabetic female rats paired with sperm cells isolated from healthy male rats. In summary, experimentally induced diabetes was found to influence gap junctions, cell adhesion molecules, and associated proteins which all have important roles in germ cell maturation, fertilization, and development. PMID- 23671880 TI - Dose effect and mode of inheritance of diabetogenic gene on mouse chromosome 11. AB - The quantitative trait locus (QTL) mapping in segregating crosses of NSY (Nagoya Shibata-Yasuda) mice, an animal model of type 2 diabetes, with nondiabetic strain C3H/He mice has identified diabetogenic QTLs on multiple chromosomes. The QTL on chromosome 11 (Chr11) (Nidd1n) showing the largest effect on hyperglycemia was confirmed by our previous studies with homozygous consomic mice, C3H-11(NSY), in which the NSY-derived whole Chr11 was introgressed onto control C3H background genes. C3H-11(NSY) mice also showed a streptozotocin (STZ) sensitivity. In the present study, we constructed heterozygous C3H-11(NSY) mice and the phenotypes were analyzed in detail in comparison with those of homozygous C3H-11(NSY) and C3H mice. Heterozygous C3H-11(NSY) mice had significantly higher blood glucose levels and STZ sensitivity than those in C3H mice. Hyperglycemia and STZ sensitivity in heterozygous C3H-11(NSY) mice, however, were not as severe as in homozygous C3H-11(NSY) mice. The body weight and fat pad weight in heterozygous C3H-11(NSY) mice were similar to those in C3H and homozygous C3H-11(NSY) mice. These data indicated that the introgression of Chr11 of the diabetes-susceptible NSY strain onto diabetes-resistant C3H caused marked changes in the glucose tolerance and STZ susceptibility even in a heterozygous state, and suggested that the mode of inheritance of a gene or genes on Chr11 for hyperglycemia and STZ sensitivity is additive. PMID- 23671881 TI - Serum concentrations of transforming growth factor-Beta 1 in predicting the occurrence of diabetic retinopathy in juvenile patients with type 1 diabetes mellitus. AB - In the present study, we have decided to evaluate if serum transforming growth factor-beta 1 (TGF- beta 1) concentrations may have diagnostic value in predicting the occurrence of diabetic retinopathy (DR) in juvenile patients with type 1 diabetes mellitus (T1DM). The study included 81 children and adolescents with T1DM and 19 control subjects. All study participants had biochemical parameters examined, underwent an eye examination, and 24-hour blood pressure monitoring. Moreover, serum concentrations of TGF- beta 1 were measured. The group of patients with T1DM and nonproliferative diabetic retinopathy (NPDR) had statistically significant higher serum levels of TGF- beta 1 (P = 0.001) as compared to T1DM patients without retinopathy as well as the healthy control subject. The threshold serum TGF- beta 1 concentrations which had a discriminative ability to predict the presence of DR were calculated using the receiver operating characteristic (ROC) curves analysis and amounted to 443 pg/ml. The area under the ROC curve (AUCROC) was 0.80, and its population value was in the range of 0.66 to 0.94. The sensitivity and specificity were calculated to be 72% and 88%, respectively. Our results suggest that TGF- beta 1 serum concentrations may be an additional parameter in predicting the occurrence of DR in juvenile patients with T1DM. PMID- 23671882 TI - Glucagon-Like Peptide-1 Analog Liraglutide Protects against Diabetic Cardiomyopathy by the Inhibition of the Endoplasmic Reticulum Stress Pathway. AB - Aim. This study aimed to investigate whether the glucagon-like peptide-1 analog liraglutide (LIRA) can protect against diabetic cardiomyopathy and explore the related mechanism. Methods. Rats were divided into 6 groups: a nondiabetic group, diabetic cardiomyopathy rats without LIRA treatment, diabetic cardiomyopathy rats with LIRA treatment (with high-, medium-, and low-dose, resp.), and diabetic cardiomyopathy rats treated with insulin. Cardiac function was examined by echocardiography before and after treatment. The histopathology of the heart was examined with H&E staining. The mRNA levels of XBP1, ATF4, and TRAF2 were analyzed by RT-PCR, and the expression of glucose-regulated protein 78 (Grp78), enhancer-binding protein homologous protein (CHOP), caspase-3, and caspase-12 was detected by western blot. Results. LIRA strongly improved cardiac function from both echocardiographic and histopathologic analyses, but insulin only partly increased cardiac function by improving FS and LVPW values. LIRA treatment can significantly decrease the expression of XBP1, ATF4, and TRAF2 (P < 0.01). LIRA also significantly downregulates the expression of Grp78, caspase-3 (P < 0.01), CHOP, and caspase-12 (P < 0.05). Conclusions. LIRA can protect against diabetic cardiomyopathy by inactivating the ER stress pathway. The improvement in cardiac function by LIRA is independent of glucose control. PMID- 23671883 TI - Therapeutic Potential of Dioscorea Extract (DA-9801) in Comparison with Alpha Lipoic Acid on the Peripheral Nerves in Experimental Diabetes. AB - DA-9801, a mixture of extracts from Dioscorea japonica Thunb. and Dioscorea nipponica Makino, was reported to have neurotrophic activity. Therefore, we investigated the therapeutic potential of DA-9801, in comparison with alpha lipoic acid (ALA), for peripheral nerves preservation in experimental diabetes. Experimental animals were divided into 4 groups, and each group was designated according to the type of treatment administered as follows: normal, DM, DM+DA 9801, and DM+ALA. After 16 weeks, response thresholds to tactile and thermal stimuli were higher in DM+DA-9801 group than in nontreated DM group. This degree of increase in DM+DA-9801 group indicates more therapeutic potency of DA-9801 than ALA. Western blot analysis showed more significant increase in NGF and decrease in TNF-alpha and IL-6 in DM+DA-9801 group than in DM or DM+ALA groups (P < 0.05). IENF density was reduced less significantly in the DM+DA-9801 group than in other DM groups (7.61 +/- 0.32, 4.2 +/- 0.26, and 6.5 +/- 0.30 in DM+DA-9801, DM, and DM+ALA, resp., P < 0.05). Mean myelinated axonal area in the sciatic nerves was significantly greater in DM+DA-9801 group than in other DM groups (69.2 +/- 5.76, 54.0 +/- 6.32, and 63.1 +/- 5.41 in DM+DA-9801, DM, and DM+ALA, resp., P < 0.05). Results of this study demonstrated potential therapeutic applications of DA-9801 for the treatment of diabetic peripheral neuropathy. PMID- 23671884 TI - Transplantation of bone marrow-derived mesenchymal stem cells promotes delayed wound healing in diabetic rats. AB - In this paper, we established a delayed wound healing model on diabetic rat to mimic the pathophysiology of clinical patients who suffered from diabetic foot ulcers. We also evaluated if transplantation of allogeneic bone marrow-derived mesenchymal stem cells could promote the delayed wound healing and investigated the possible underlying biological mechanisms and stem cell behavior involved in this process. The results showed that bone marrow-derived mesenchymal stem cells had a positive effect on delayed wound healing in diabetic rats. Intramuscular transplantation demonstrated the best efficacy. This effect is associated with granulation tissue formation, angiogenesis, cellular proliferation, and high vascular endothelial growth factor expression in wound tissues. In addition, bone marrow-derived mesenchymal stem cells have been shown to mobilize and find home for ischemic and wounded tissues to participate in the process of wound healing. Intramuscular transplantation of exogenous isogeneic stem cells may be suitable for clinical application in the treatment of diabetic foot ulcers although the safety of this therapy should be considered. PMID- 23671885 TI - Skin autofluorescence relates to soluble receptor for advanced glycation end products and albuminuria in diabetes mellitus. AB - The aim of this study was to compare skin autofluorescence caused by advanced glycation end-products (AGEs) with biochemical markers of endothelial dysfunction and soluble receptor for AGEs (sRAGE) in patients with diabetes. Skin autofluorescence (AF) assessed by AGE-Reader was evaluated with sRAGE and other biochemical parameters in 88 patients with diabetes (47 Type 1/T1DM/ and 41 Type 2/T2DM/) and 20 controls. Skin AF was significantly higher in T1DM and T2DM in comparison to controls (2.39 +/- 0.54, 2.63 +/- 0.73 versus 1.96 +/- 0.33 AU; P < 0.0001). Positive correlation of AF with sRAGE was detected in T1DM and T2DM (r = 0.37, P < 0.02 and r = 0.60, P < 0.0001), but not in controls. Significantly higher AF values were found in patients with positive albuminuria as compared to those with normal albuminuria. Similarly, higher AF was detected in patients with endothelial dysfunction expressed by vWF, ICAM-1, and VCAM-1. Multiple regression analysis revealed independent association of skin AF with age, sRAGE, and albumin creatinine ratio in patients with diabetes (R (2) = 0.38). Our study confirms that AF is elevated in patients with diabetes, especially with positive albuminuria and endothelial dysfunction. The strong and independent relationship between AF and sRAGE supports the idea that AF may reflect AGEs/RAGE interactions. The exact mechanism remains to be established. PMID- 23671886 TI - The ERK1/2 Inhibitor U0126 Attenuates Diabetes-Induced Upregulation of MMP-9 and Biomarkers of Inflammation in the Retina. AB - This study was conducted to determine the expression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in a time dependent manner and the effect of extracellular-signal-regulated kinases-1/2 (ERK1/2) inhibition on the expressions of MMP-9, TIMP-1, and inflammatory biomarkers in the retinas of diabetic rats. The expression of MMP-9 was quantified by zymography, and the mRNA level of MMP-9 and TIMP-1 was quantified by RT-PCR. The expression of inducible nitric oxide synthase (iNOS), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF- alpha ) was examined by Western blot analysis. MMP-9 expression was significantly higher in diabetic rat retinas compared to controls at all time points.TIMP-1 expression was nonsignificantly upregulated at 1week of diabetes and was significantly downregulated at 4 and 12 weeks of diabetes. Intravitreal administration of the ERK1/2 inhibitor U0126 prior to induction of diabetes decreased ERK1/2 activation, attenuated diabetes induced upregulation of MMP-9, iNOS, IL-6, and TNF- alpha and upregulated TIMP-1 expression. In MMP-9 knockout mice, diabetes had no effect on retinal iNOS expression and its level remained unchanged. These data provide evidence that ERK1/2 signaling pathway is involved in MMP-9, iNOS, IL-6, and TNF- alpha induction in diabetic retinas and suggest that ERK1/2 can be a novel therapeutic target in diabetic retinopathy. PMID- 23671887 TI - Reduction of methylglyoxal-induced glycation by pyridoxamine improves adipose tissue microvascular lesions. AB - Background and Aims. Adipose tissue dysfunction results from many factors, including glycation-induced microvascular damages. We tested the usefulness of inhibiting methylglyoxal-induced glycation to adipose tissue microvasculature in this work, using the antioxidant and dicarbonyl scavenger drug pyridoxamine. Methods. A group of Wistar rats was treated daily with methylglyoxal (MG, 75 mg/Kg/day, 8 weeks). Half of this group was treated with pyridoxamine in the following 4 weeks (Pyr) (100 mg/Kg/day) and the other half did not have any further treatment (MG). A group of Wistar rats without MG treatment was used as control (C). Results. MG group showed decreased HDL cholesterol and increased plasma free fatty acids levels, what was reverted by pyridoxamine. MG also caused an increase of tissue CEL levels (glycation marker), as well as increased staining of PAS and Masson Trichrome-positive components. Pyridoxamine led to CEL and TGF- beta levels similar to those observed in control rats and inhibited the accumulation of PAS and Masson Trichrome-positive components. MG caused a decrease of Bcl-2/Bax ratio (marker of apoptosis) and vWF staining (microvascular marker), what was partially reverted by the treatment with pyridoxamine. Conclusions. Preventing methylglyoxal-induced accumulation of glycated and fibrotic materials using pyridoxamine improves the microvascular lesions of the adipose tissue. PMID- 23671888 TI - Hypermethylation of the PRKCZ Gene in Type 2 Diabetes Mellitus. AB - Objectives. To study the correlation between the methylation of protein kinase C epsilon zeta (PRKCZ) gene promoters and type 2 diabetes mellitus (T2DM). Methods. The case-control method was implemented in 272 unrelated to one another cases in Shiyan People's Hospital. Of those, 152 were diagnosed as T2DM cases, and the other 120 cases were healthy individuals visiting the hospital for a physical examination. The subjects were first divided into two groups: the T2DM group and the normal control (NC) group. Next, methylated DNA immunoprecipitation chip (MeDIP-chip) was used for detection. Bisulfite sequencing PCR (BSP) and gene sequencing were then performed to detect and analyze the correlation between PRKCZ gene promoter methylation and T2DM. Finally, Western blotting was applied to determine the serum level of PRKCZ. The data were then analyzed with the statistics analyzing software SPSS 17.0. Results. In contrast with cases in NC, T2DM patients showed a high level of methylation, with 7 of 9 CpG sites were shown to be methylated, whereas, in the control group, only one CpG site was found to be methylated. The methylated CpG sites for the two groups showed marked differences (P < 0.01). Additionally, the level of PRKCZ was decreased in T2DM subjects, and the difference between the two groups was statistically significant (P < 0.05). Discussion. This study suggests that the PRKCZ gene is the hypermethylated gene of T2DM and the hypermethylation PRKCZ gene may be involved in the pathogenesis of T2DM. PMID- 23671889 TI - Proving the point. PMID- 23671890 TI - Allergen immunotherapy for allergic rhinitis. AB - Allergic rhinitis, a risk factor for bronchial asthma, is a global health problem that impairs patients' physical and social activity and consequently their quality of life. Specific Immunotherapy (SIT) involves the administration, subcutaneously or sublingually, of increasing doses of the causative allergen, in order to induce clinical and immunologic tolerance. SIT has been shown to be effective in those with a poor response to conventional drug therapy. Immunotherapy has been shown to have disease-modifying effects and result in long term remission of allergic symptoms and reduces the risk of progression from rhinitis to asthma, as well as the chances of developing new sensitizations to allergens. Injection immunotherapy is a safe treatment for allergic rhinitis with/without mild controlled asthma, provided that it is performed in the context of a harmonious interaction between trained medical personnel and appropriately selected patients. Immunotherapy suppresses early and late responses to allergen exposure by modifying both T-cell and B-cell responses to inhaled allergens. Immune deviation of allergen-specific T cell responses in favour of Th1 and/or the induction of regulatory T cells is crucial in achieving immune tolerance. Increased understanding of the mechanisms of immunotherapy has identified potential biomarkers of the response to treatment and highlighted new therapeutic pathways with potential for even more effective future standardized vaccines. PMID- 23671891 TI - Pregnancy-induced rhinitis. AB - BACKGROUND: Pregnancy-induced rhinitis (PIR) is often misclassified and under diagnosed. There is currently no cure or optimum symptomatic treatment. OBJECTIVE: To summarize current knowledge of PIR and assess evidence supporting treatment options. TYPE OF REVIEW: Structured literature search. SEARCH STRATEGY AND EVALUATION METHOD: Review of English-language articles addressing evidence for aetiology, classification, differential diagnosis or treatment options for PIR. Comparisons to management of other types of rhinitis in pregnancy are also considered. RESULTS: Incidence and prevalence of PIR vary widely between studies. Hormonal changes have a presumed aetiological role, although present evidence is scanty. Smoking appears to be the only agreed identifiable risk factor. Distinction between PIR and other types of rhinitis in pregnancy, especially allergic rhinitis, is important as effective treatments differ. Management of PIR focuses on minimal intervention required for symptom relief. CONCLUSIONS: Although PIR is temporary, its impact on patients' quality of life can be profound. Advice and conservative treatment provide the mainstay of clinical management. None of the currently available medical options offer an ideal solution. Any potential benefit gained should be balanced against risks to the foetus. Clarifying the definition of this separate category of rhinitis will lead to better recognition, with prompt and appropriate treatment. PMID- 23671892 TI - Feasibility of balloon sinuplasty in patients with chronic rhinosinusitis: the Graz experience. AB - BACKGROUND: Balloon sinuplasty (BSP) is a catheter-based technique to dilate sinus ostia and drainage pathways to create ventilation and drainage. The aim of this study was to evaluate the feasibility of BSP in routine treatment of patients suffering from chronic rhinosinusitis (CRS). METHODOLOGY: Patients with CRS refractory to medical therapy who had been scheduled for endoscopic sinus surgery between 2009 and 2011 were included in this study. RESULTS: Forty-five consecutive patients were included in this study, in whom 112 sinuses were approached by BSP. Of the 112 sinuses, 68 (60%) were planned as a "Balloon-Only" procedure and 44 (40%) were planned as a "Hybrid" procedure. Of the 68 sinuses in the "Balloon-Only" group, in 44 sinuses BSP failed, equating to a failure rate of 65%. Forty-four sinuses were planned for "Hybrid" procedures. In 29 of these sinuses BSP failed, giving a failure rate of 66%. CONCLUSION: According to literature, BSP can be a useful adjunct technique to standard FESS. In our experience, however, a failure rate of 65% for "Balloon-Only" and of 66% for "Hybrid" procedures occurred, which was regarded as unacceptable by the study group. Therefore, the study initially scheduled for 200 consecutive patients, was abandoned. PMID- 23671893 TI - Diagnosing chronic rhinosinusitis: comparing questionnaire-based and clinical based diagnosis. AB - BACKGROUND: The European Position Paper on Rhinosinusitis and Nasal Polyps (EP3OS) incorporates symptomatic and endo- scopic criteria in the clinical diagnosis of chronic rhinosinusitis (CRS), while in epidemiological studies the definition is based on symptoms only. The aim of this study was to evaluate the correlation between questionnaire-based and clinical-based CRS. METHODS: Based on the GA2LEN postal survey data a total of 366 persons participated at the follow up at the Danish centre and provided information on questionnaire-based CRS. At the same occasion the 366 participants underwent clinical inter- view and examination by an otorhinolaryngologist to provide information for a clinical based CRS diagnosis. The association between questionnaire-based and clinical based CRS diagnosis was determined using logistic regression models and kappa statistics. RESULTS: Mean age of respondents to the postal questionnaire was 45.3 years and 52.9% were female. Persons with asthma were 8.4 % and 26.2 % were actual smokers. There was moderate agreement between questionnaire-based and clinical-based CRS. Sensitivity was [corrected] low comparing questionnaire-based CRS with clinical-based CRS. Incorporation of self reported CRS and medical history in diagnosing CRS by questionnaire increased increased [corrected] the agreement and sensitivity while specificity stayed at a high level. [corrected] CONCLUSION: Evaluating the correlation between questionnaire-based and clinical based CRS showed only moderate agree- ment and questions whether they evaluate the same disease. It brings into consideration that adjustments are needed to justify correlation between questionnaire-based and clinical-based diagnosis of CRS. PMID- 23671894 TI - Comparison of polyvinyl alcohol coated nasal packing with non-absorbable nasal packing. AB - BACKGROUND: A number of different nasal packing materials are available for prevention of nasal bleeding after endoscopic sinus surgery. Polyvinyl alcohol (PVA) coated nasal packing is an expandable packing for use in rhinological surgery. This innovative surf- ace treatment helps to reduce the possibility of adherence to tissue and of blood clotting within the sponge. The present study investigated the effects of PVA coated packing and non-absorbable packing with respect to pain, healing site and postoperative bleeding following endoscopic sinus surgery. METHODOLOGY: Patients between 18-80 years of age undergoing sinus surgery were enrolled. Each patient's ethmoid cavities were randomised to receive PVA coated packing material or the standard non-absorbable sinus packs. The remaining nasal packing material was removed on the 2nd day in the clinic. We determined visual analog scale score, bleeding time and wound healing status. A single rhinologist graded postoperative endoscopic appearance. Length of follow up was 3 months. RESULTS: Thirty three patients were recruited. There was a significant difference in the bleeding time between the two groups, but pain and wound healing were not significantly different between the two groups. CONCLUSION: PVA-coated nasal packing presents comparable characteristics with traditional nasal packing. PMID- 23671895 TI - A Randomized Controlled Trial comparing the efficacy of low-dose amitriptyline, amitriptyline with pindolol and surrogate placebo in the treatment of chronic tension-type facial pain. AB - BACKGROUND: Patients often present to otolaryngologists with chronic facial pain, presumed to be of sinus origin despite normal nasal endoscopy and sinus CT. This pain has increasingly been recognized as being of neurological origin with one of the commonest underlying causes being mid-facial segmental tension-type pain (MFP) which is a version of tension-type headache affecting the midface. OBJECTIVES: PRIMARY OUTCOME MEASURES: 1. To determine whether low-dose amitriptyline reduces pain scores compared to surrogate placebo in patients with chronic MFP. 2. To determine whether the addition of pindolol, a beta blocker with serotonin receptor blocking properties hastens onset of action or improves efficacy of amitriptyline. SECONDARY OUTCOME MEASURE: to determine whether amitriptyline or amitriptyline with pindolol significantly reduces analgesic consumption. METHODOLOGY: Sixty two patients were randomized to three treatment groups (a) amitriptyline 10mg daily (b) amitriptyline 10mg daily with pindolol 5mg twice daily and (c) loratadine 10mg daily. Daily pain scores using a facial pain diary were recorded over eight weeks. RESULTS: At 8 weeks, pain frequency and intensity were significantly reduced in patients treated with amitriptyline and in those receiving amitriptyline with pindolol compared to surrogate placebo. Patients on the combination therapy showed significantly improved clinical outcome and significantly reduced analgesic intake compared to those on amitriptyline alone. CONCLUSION: Low dose amitriptyline is effective in the management of MFP and is enhanced by the addition of pindolol. PMID- 23671896 TI - Immunohistochemical studies of wound healing after monopolar electrocautery and ultrasound submucosal inferior nasal turbinate reduction in sheep. AB - BACKGROUND: Extracellular matrix (ECM) proteins such as fibronectin and collagen III, enzymes such as matrix metalloproteinases and macrophages have been demonstrated to intervene in nasal and paranasal sinuses wound healing. AIM OF THE STUDY: To compare concentration of ECM proteins, enzymes and the recruitment of macrophages during wound repair after monopolar electrocautery in contrast with ultrasound submucosal surgical tissue reduction of inferior nasal turbinate (INT) tested in sheep. MATERIALS AND METHODS: Prospective controlled study in sheep. Immunostaining for collagen III, fibronectin, CD68 and matrix metalloproteinase-9 (MMP9) was applied in tissue specimens of INT mucosa after monopolar electrocoagulation (MEC) and ultrasound tissue reduction (UTR). Twelve INTs were studied 1, 3 and 8 weeks post-operatively in each interventional group (MEC and UTR) and 5 INTs were studied in animals of the control group (without surgery). The immunoreactivity was quantitatively graded between 0% to 100% immunoreactivity by a blinded senior pathologist. RESULTS: At the end of the study period collagen III, fibronectin and MMP9 were increased in both groups compared to the levels of the control group. When compared to control group, CD68 immunoreactivity was found higher in MEC group but not in UTR group. Fibronectin subepithelial immunoreactivity exhibited a substantial negative correlation with mucosal epithelial cell necrosis, a substantial positive correlation with fibrosis in MEC-treated specimens and a significant positive correlation with sinusoid engorgement in UTR-treated specimens. Collagen III tissue immunoreactivity showed a particularly significant negative correlation with sinusoid engorgement in MEC-treated specimens. CONCLUSION: Correlation of fibronectin and collagen III immunoreactivity to histopathologic findings suggests different ECM repair processes between MEC and UTR turbinate tissue reduction. The use of CD68 and MMP9 provides additional clues to the mode of actions of these techniques and to the molecular and cellular events of the nasal mucosa wound healing process. PMID- 23671897 TI - Clinical-radiological correlation after functional endoscopic sinus surgery in patients with chronic rhinosinusitis: interest of a sinonasal aerial volumetry. AB - BACKGROUND: Although a CT scan is often performed after functional endoscopic sinonasal surgery (FESS) in patients with chronic rhinosinusitis, its role hasn't been firmly established. The goal of this study is to investigate the correlation between symptoms and CT findings before and after FESS for chronic rhinosinusitis. In addition, the interobserver agreement for both sinonasal aerial volumetry and CT score is assessed. METHODS: Thirty-three patients surgically treated for chronic rhinosinusitis were included in this prospective study. Conventional and modified Lund-Mackay scores and sinonasal volumetry were determined by two radiologists before (M0), at 3 months (M3) and 1 year (M12) after surgery. The symptoms were evaluated by the 22-item SinoNasal Outcome Test (SNOT-22). RESULTS: Change of SNOT-22 and air volume were significantly correlated between M0 and M12, but not between M0 and M3, for both readers. Compared to other scores, volume had the best intraclass correlation coefficient and reproducibility, according to the Bland-Altman analysis. No correlation was found between SNOT-22 and CT scores before and after surgery, except between M12 and M0 for one reader. CONCLUSION: The correlation between CT scan and symptoms is low or absent. The measurement of sinonasal air volume is best correlated with the symptoms after surgery, with the best inter-observer agreement. PMID- 23671898 TI - Postoperative improvement in acoustic rhinometry measurements after septoplasty correlates with long-term satisfaction. AB - BACKGROUND: Not much is known about long-term satisfaction of septoplasty. Our goal was to compare pre- and postoperative acoustic rhinometry measurements with satisfaction 11 years after surgery. METHODOLOGY: Acoustic rhinometry measurements were performed preoperatively and 3 months postoperatively. Satisfaction was evaluated with semi-structured interviews by telephone 11 years after surgery. Symptoms were evaluated using the NOSE score. RESULTS: In total, 222 patients were interviewed and eligible to enter the study. Of these, 213 had preoperative acoustic rhinometry and 159 had postoperative acoustic rhinometry. In total, 157 patients had a complete data set. Mean follow-up time was 11.3 years. Patients satisfied with surgery had a bigger improvement in total minimum cross-sectional area before decongestion and total nasal cavity volume after decongestion. NOSE scores were not correlated with acoustic rhinometry measurements. CONCLUSION: Acoustic rhinometry could be a valuable tool for evaluating the results of septoplasty. Satisfaction at 11 years follow-up was associated with 3 months postoperative acoustic rhinometry improvements. Acoustic rhinometry did not show preoperative patient selection potential. PMID- 23671899 TI - Asymmetrical nostril axis angle in the post traumatic nose. AB - BACKGROUND: Nasal tip reconstruction is a challenging part of septorhinoplasty in post-traumatic patients. Aesthetic appearance of the nose is dependent on adequate tip definition, projection and rotation. Our aim is to establish if caudal septal dislocation (secondary to fracture or subluxation) is a significant factor in causing asymmetry in nostril axis angle (NAA) to effect surgical intervention. In addition, to assess if there is an association between the side of dislocation and the magnitude of NAA. METHODOLOGY: Photographic assessment of NAA was measured in a study group of 26 patients with caudal dislocation of the septum and a control group of 26 patients without caudal septal dislocation. All 52 patients were awaiting a septorhinoplasty procedure due to nasal trauma. RESULTS: Caudal septal dislocation causes a mean difference in NAA of 7.95o compared to 1.38o difference in the control group. We also found there is a greater degree of upward tip rotation on the side of the dislocation resulting in a larger NAA. CONCLUSION: Caudal dislocation of the septum causes a significant asymmetry in NAA, with a greater degree of rotation on the side of the dislocation. We should be aware of this fallacy prior to surgery. PMID- 23671900 TI - Sphenoid sinus fungall ball: a retrospective study over a 10- year period. AB - A fungal ball consists of a dense conglomerate of fungal hyphae growing at the surface of the sinus mucosa without tissue infiltration. The maxillary sinus is by far the most commonly involved paranasal sinus cavity followed by the sphenoid sinus. The present study is a retrospective study of 25 consecutive cases treated during the last 10 years in the two hospitals be- longing to the Catholic University of Louvain (CHU Mont-Godinne and UCL Saint Luc). We report the symptomatology, the imaging and discuss the different surgical managements. We conclude that the clinician must have a high index of suspicion when dealing with a unilateral rhinosinusitis persisting despite a maximal and well conducted medical treatment. This is particularly so in elderly women when associated with facial pain and post nasal drip, particularly when the computed tomography shows an unilateral opacity of the sphenoid sinus with or without a sclerosis or an erosion of the bony walls, a polyp in the sphenoethmoidal recess or a hyperdensity mimicking a foreign body. An endonasal endoscopic sphenoidotomy is the treatment of choice in most cases, allowing good ventilation of the sinus and radical removal of all the fungal concretion. A biopsy of the sinus mucosa adjacent to fungal elements is of upmost important to confirm the non- invasiveness of the fungi within the tissue. Antifungal medication is not required in uncomplicated forms. All host factors producing some degree of immunosuppression must be corrected when present and must alert the clinician to rule out any forms of invasive disease. PMID- 23671901 TI - Employing aqueous CdTe quantum dots with diversified surface functionalities to discriminate between heme (Fe(II)) and hemin (Fe(III)). AB - The discrimination of ferrous and ferric states in the human body is one of the basic issues for disease control and prevention because Fe(II) and Fe(III) are a crucial redox pair during the process of material and energy metabolism. Herein, aqueous CdTe quantum dots (QDs) with diversified surface functionalities are applied to discriminate between heme (Fe(II)) and hemin (Fe(III)) by virtue of their difference in quenching QD fluorescence. In aqueous media, the interaction between QDs and heme/hemin mainly involves electrostatic interaction, which is greatly determined by the surface functionalities of the QDs. Thus, by combining the different fluorescence quenching behavior of carboxyl- and/or hydroxyl functionalized QDs, heme and hemin are discriminated between. In comparison to the discrimination using QDs with single surface functionality, the current method has improved reliability and accuracy. PMID- 23671902 TI - Solid phase extraction-capillary electrophoresis determination of sulphonamide residues in milk samples by use of C18-carbon nanotubes as hybrid sorbent materials. AB - The exceptional sorption capabilities of carbon nanotubes were used to preconcentrate trace sulphonamides from milk samples. To this end, single walled carbon nanotubes (SWNTs) and multi-walled carbon nanotubes (MWNTs) dispersed in the ionic liquid 1-hexyl-3-methylimidazolium hexafluorophosphate were retained on a C18 stationary phase to obtain a hybrid material in a simple manner. In this approach ionic liquids are an excellent alternative to improve the dispersion of CNTs, without chemical modification or the use of solid substances or organic solvents. MWNTs provided better results than SWNTs. Carbon nanotubes retained in the C18 sorbent matrix were found to confer aromatic character, increasing its preconcentration capacity as a result. The conventional C18 stationary phase played a two-fold role: as a support to retain carbon nanotubes in the cartridge and as a medium to prevent their aggregation. The modified MWNT/C18 and SWNT/C18 materials were used to preconcentrate residual sulphonamides (SAs) in milk samples for their determination at concentrations as low as 0.03-0.069 mg L(-1) by capillary electrophoresis. Analyte recoveries from spiked samples ranged from 103.2 to 98.8% and precision, as RSD, from 8.2 to 5.4%. PMID- 23671903 TI - Solution-free, in situ preparation of nano/micro CuO/ZnO in dielectric barrier discharge for sensitive cataluminescence sensing of acetic acid. AB - The present work describes a new solution-free strategy for preparation of cluster-like nano/micro CuO/ZnO particles in dielectric barrier discharge (DBD) in which the brass acts as the inner electrode. The cataluminescence (CTL) behaviour of such prepared material for acetic acid was studied for analytical application. Under the optimized conditions, the linear range of CTL intensity versus concentration of acetic acid are 6 mg L(-1) to 500 mg L(-1) with the limit of detection (LOD) of 3 mg L(-1), no significant interference was found. The new method shows great advantages because it is a process without any solution and complex equipment. The synthetic material was directly used for the cataluminescence sensing of acetic acid without other preliminary treatment and it shows high selectivity, satisfactory stability, and better sensitivity and linearity. PMID- 23671904 TI - Magnetic particle-based time-resolved fluoroimmunoassay for the simultaneous determination of alpha-fetoprotein and the free beta-subunit of human chorionic gonadotropin. AB - In this paper, a novel time-resolved fluoroimmunoassay (TRFIA) protocol using magnetic particles for the simultaneous determination of alpha-fetoprotein (AFP) and the free beta-subunit of human chorionic gonadotropin (free beta-hCG) in human serum is described. The new approach uses magnetic particles as an immobilization matrix and means of separation, while the luminescent europium and samarium chelates are used as probes. The proposed method was evaluated via a single-step, sandwich-type TRFIA immunoassay of AFP and free beta-hCG as model analytes in serum. With the advantages of magnetic particles, the TRFIA immunoassay exhibited a wide dynamic range for AFP of 0.1-750 ng mL(-1), with a lower detection limit of 0.05 ng mL(-1). The dynamic range for free beta-hCG was 0.16-450 ng mL(-1), with a lower detection limit of 0.08 ng mL(-1). Satisfactory specificity, reproducibility, and recovery of the immunoassay were demonstrated. Good correlations were obtained in the analysis of 446 human serum samples between the proposed method and a commercial TRFIA kit. These results demonstrate the feasibility and potential of the new method as a rapid and highly sensitive immunoassay that could be developed into a platform for multi-analyte determinations in clinical practice. PMID- 23671905 TI - A label-free amplified fluorescence DNA detection based on isothermal circular strand-displacement polymerization reaction and graphene oxide. AB - A label-free fluorescent DNA biosensor has been presented based on isothermal circular strand-displacement polymerization reaction (ICSDPR) combined with graphene oxide (GO) binding. The proposed method is simple and cost-effective with a low detection limit of 4 pM, which compares favorably with other GO-based homogenous DNA detection methods. PMID- 23671906 TI - Chromatographic separation and detection of target analytes from complex samples using inkjet printed SERS substrates. AB - In principle, surface enhanced Raman spectroscopy (SERS) is thought to provide unique identification of a target analyte, even in complex samples or in the presence of multiple analytes. In practice, however, this is not always true for real-world samples due to various forms of interference. In this report, we build upon our previous work on inkjet-printed SERS substrates by using paper and polymer membranes to integrate sample cleanup and analyte separation with SERS detection. Inkjet-printed paper SERS substrates provide a highly sensitive chemical detection platform of unprecedented cost and simplicity. In addition, paper inherently provides unique capabilities, such as capillary-actuated fluid transport and selective molecular retention. Utilizing these properties, we demonstrate two-dimensional chromatographic separation and SERS detection on inkjet-printed paper SERS substrates. Then, we leverage the separation properties of paper and polymer membranes for real applications that feature complex sample matrices, including the detection of down to 5 ppm melamine in infant formula, as well as the quantification of nanograms of heroin in samples contaminated with a highly fluorescent background. The results presented here demonstrate that inkjet printed paper SERS devices not only provide advantages in terms of sensitivity and cost, but the paper provides inherently integrated sample cleanup capabilities that are not available in traditional SERS substrates and microfluidic SERS devices. These unique capabilities of paper SERS devices enable the identification of targeted analytes even in complex real-world samples. PMID- 23671907 TI - Determination of free acidic and alkaline residues of protein via moving reaction boundary titration in microdevice electrophoresis. AB - As two important physico-chemical parameters, the acidic and alkaline residues of protein are of evident significance for the evaluation of protein properties and the design of relevant separation and analysis. However, there is still no electrophoretic method used for the direct detection of free acidic and alkaline residues of protein. Herein, we developed the concepts of moving reaction boundary (MRB) and MRB titration, relevant MRB titration theory, and the method of microdevice electrophoresis for the determination of free acidic and alkaline residues of protein. In the MRB titration, the boundary was created with acid or alkali and target protein immobilized via highly cross-linked polyacrylamide gel (PAG). It was theoretically revealed that the number of free acidic or alkaline residues of protein was as a function of MRB displacement in the electrophoretic titration system. As a proof of concept, seven model proteins were chosen for the determination of acidic or alkaline residues of protein via MRB titration. The results showed that the numbers of free acidic and alkaline residues of proteins detected were in good agreement with those obtained from the relevant amino sequences in the NCBI database, demonstrating the feasibility of the developed concept, theory and technique. The general methodology of MRB titration has potential application for inexpensive, facilitative and informative protein structure analysis of free acidic or alkaline residues of protein. PMID- 23671908 TI - Electrochemical signature of mismatch in overhang DNA films: a scanning electrochemical microscopic study. AB - High throughput DNA basepair mismatch detection is an ultimate goal for earlier and point-of-care diagnostics. However, the size of a target sequence on single nucleotide mismatch detection will critically impact the design of sensors in future. To study the potential impact of target size, the probe and target strands of unequal size were hybridized in the absence and presence of single nucleotide mismatches along the sequence. After hybridization, the shorter target sequences form overhangs in the probe strand while longer target sequences form overhangs in the complementary strand. The resulting double stranded DNA hybrids were printed on gold surfaces and the electrochemical response of the films was studied by scanning electrochemical microscopy without signal amplification and label. The redox mediator, [Fe(CN)(6)](4-), experiences lower repulsion in the vicinity of mismatch containing ds-DNA films, which ultimately manifests into higher feedback current regardless of the size and hybridization position of the complementary strands. Kinetic rate constants monitored right above the ds-DNA films show k(0) = 4.5 +/- 0.1 * 10(-5) cm s(-1) for the short sequence hybridized at the upper portion of the probe while k(0) = 4.1 +/- 0.2 * 10(-5) cm s(-1) for longer complementary strands which has only top overhang. It suggests that hybridization position is important for mismatch detection in short complementary stands. However, in longer complementary strands, mismatches are easily detectable in the absence of bottom overhangs. PMID- 23671909 TI - Profiling intact steroid sulfates and unconjugated steroids in biological fluids by liquid chromatography-tandem mass spectrometry (LC-MS-MS). AB - Within the combined DFG research project "Sulfated Steroids in Reproduction" an analytical method was needed for determining sulfated and unconjugated steroids with highest specificity out of different biological matrices such as aqueous solution, cell lysate and serum. With regard to this analytical challenge, LC-MS MS presents the technique of choice because it permits (1) analysis of the intact steroid conjugate, (2) allows for simultaneous determination of multiple analytes (profiling, targeted metabolomics approach) and (3) is independent of phenomena such as cross-reactivity. Sample work up consisted of incubation of sample with internal standards (deuterium labeled steroids) followed by solid phase extraction. Only serum samples required a protein precipitation step prior to solid phase extraction. The extract was divided in two parts: six steroid sulfates (E1S, E2S, AS, 16-OH-DHEAS, PREGS, DHEAS) were analyzed by C18aQ-ESI-MS MS in negative ion mode and eleven unconjugated steroids (E3, 16-OH-DHEA, E1, E2, (4)A, DHEA, T, 17-OH-PREG, Prog, An, PREG) were analyzed by C18-APCI-MS-MS in positive ion mode. For steroid sulfates, we found high sensitivities with LoQ values ranging from 0.08 to 1 ng mL(-1). Unconjugated steroids showed LoQ values between 0.5 and 10 ng mL(-1). Calibration plots showed excellent linearity. Mean intra- and inter-assay CVs were 2.4% for steroid sulfates and 6.4% for unconjugated steroids. Accuracy - determined in a two-level spike experiment - showed mean relative errors of 5.9% for steroid sulfates and 6.1% for unconjugated steroids. In summary, we describe a novel LC-MS-MS procedure capable of profiling six steroid sulfates and eleven unconjugated steroids from various biological matrices. PMID- 23671910 TI - A tyrosinase biosensor based on ordered mesoporous carbon-Au/L-lysine/Au nanoparticles for simultaneous determination of hydroquinone and catechol. AB - A novel biosensor was developed based on tyrosinase immobilization with ordered mesoporous carbon-Au (OMC-Au), L-lysine membrane and Au nanoparticles on a glassy carbon electrode (GCE). It was applied for the simultaneous determination of dihydroxybenzene isomers using differential pulse voltammetry (DPV). The tyrosinase/OMC-Au/L-lysine/Au film was characterized by scanning electron microscopy (SEM) and impedance spectra. Under optimized conditions, the DPV study results for two isomers, hydroquinone (HQ, 1,4-dihydroxybenzene) and catechol (CC, 1,2-dihydroxybenzene) showed low peak potentials, and the peak-to-peak difference was about 135.85 mV, which ensured the anti-interference ability of the biosensor and made simultaneous detection of dihydroxybenzene isomers possible in real samples. DPV peak currents increased linearly with concentration over the range of 4.0 * 10(-7) to 8.0 * 10(-5) M, and the detection limits of hydroquinone and catechol were 5 * 10(-8) M and 2.5 * 10(-8) M (S/N = 3), respectively. The tyrosinase biosensor exhibited good repeatability and stability. In addition, the response mechanism of enzyme catalysed redox on the OMC-Au/L-lysine/Au film modified electrode based on electrochemical study was discussed. The proposed method could be extended for the development of other enzyme-based biosensors. PMID- 23671911 TI - Introduction to the special issue: new methods in exposure therapy. AB - Exposure-based interventions have been shown to significantly reduce anxiety and avoidance. The efficacy of the approach is robust, and recent efforts have been made to expand the use of exposure as well as identify more effective ways to implement the procedure. This article introduces the special issue devoted to recent novel approaches to the dissemination and implementation of exposure. PMID- 23671912 TI - SOPHE-AAHE partnership: new opportunities for all. PMID- 23671913 TI - Study suggests earlier talks might contribute to care aimed at easing suffering. PMID- 23671914 TI - 20% of youth with HIV didn't know they were infected at first sexual experience: NIH-funded study underscores need for counseling on healthy practices. PMID- 23671915 TI - [From quality of life to palliative care in cancerology]. PMID- 23671916 TI - Mitigating disasters--a promising start. PMID- 23671917 TI - Ireland's abortion debate. PMID- 23671918 TI - The Rockefeller Foundation and the international health agenda. PMID- 23671919 TI - Special section: selected papers from the Third European Workshop on Monte Carlo Treatment Planning (MCTP2012). PMID- 23671920 TI - Pervasive selection or is it...? Why are FST outliers sometimes so frequent? AB - It is now common for population geneticists to estimate FST for a large number of loci across the genome, before testing for selected loci as being outliers to the FST distribution. One surprising result of such FST scans is the often high proportion (>1% and sometimes >10%) of outliers detected, and this is often interpreted as evidence for pervasive local adaptation. In this issue of Molecular Ecolog, Fourcade et al. (2013) observe that a particularly high rate of FST outliers has often been found in river organisms, such as fishes or damselflies, despite there being no obvious reason why selection should affect a larger proportion of the genomes of these organisms. Using computer simulations, Fourcade et al. (2013) show that the strong correlation in co-ancestry produced in long onedimensional landscapes (such as rivers, valleys, peninsulas, oceanic ridges or coastlines) greatly increases the neutral variance in FST, especially when the landscape is further reticulated into fractal networks. As a consequence, outlier tests have a high rate of false positives, unless this correlation can be taken into account. Fourcade et al.'s study highlights an extreme case of the general problem, first noticed by Robertson (1975a,b) and Nei & Maruyama (1975), that correlated co-ancestry inflates the neutral variance in FST when compared to its expectation under an island model of population structure. Similar warnings about the validity of outlier tests have appeared regularly since then but have not been widely cited in the recent genomics literature. We further emphasize that FST outliers can arise in many different ways and that outlier tests are not designed for situations where the genetic architecture of local adaptation involves many loci. PMID- 23671922 TI - Explosive growth: the good news and the bad news. PMID- 23671921 TI - Authors' reply. PMID- 23671924 TI - Steady progresses of the Chinese Journal of Physiology in 2011. PMID- 23671923 TI - Authors' reply. PMID- 23671925 TI - The authors reply. PMID- 23671926 TI - Karl Jaspers and human-based psychiatry. PMID- 23671927 TI - Sustained ERK [corrected] inhibition by EGFR targeting therapies is a predictive factor for synergistic cytotoxicity with PDT as neoadjuvant therapy. AB - BACKGROUND: Tyrosin kinase inhibitors (TKIs) and monoclonal antibodies aimed to target epidermal growth factor receptor (EGFR) have shown limited effect as monotherapies and drug resistance is a major limitation for therapeutic success. Adjuvant therapies to EGFR targeting therapeutics are therefore of high clinical relevance. METHODS: Three EGFR targeting drugs, Cetuximab, Erlotinib and Tyrphostin AG1478 were used in combination with photodynamic therapy (PDT) in two EGFR positive cell lines, A-431 epidermoid skin carcinoma and WiDr colorectal adenocarcinoma cells. The amphiphilic meso-tetraphenylporphine with 2 sulphonate groups on adjacent phenyl rings (TPPS(2a)) was utilized as a photosensitizer for PDT. The cytotoxic outcome of the combined treatments was evaluated by cell counting and MTT. Cellular signalling was explored by Western blotting. RESULTS: PDT as neoadjuvant to Tyrphostin in A-431 cells as well as to Tyrphostin or Erlotinib in WiDr cells revealed synergistic cytotoxicity. In contrast, Erlotinib or Cetuximab combined with neoadjuvant PDT induced an antagonistic effect on cell survival of A-431 cells. Neoadjuvant PDT and EGFR targeting therapies induced a synergistic inhibition of ERK as well as synergistic cytotoxicity only when the EGFR targeting monotherapies caused a prolonged ERK inhibition. There were no correlation between EGFR inhibition by the EGFR targeting monotherapies or the combined therapies and the cytotoxic outcome combination-therapies. CONCLUSIONS: The results suggest that sustained ERK inhibition by EGFR targeting monotherapies is a predictive factor for synergistic cytotoxicity when combined with neoadjuvant PDT. GENERAL SIGNIFICANCE: The present study provides a rationale for selecting anticancer drugs which may benefit from PDT as adjuvant therapy. PMID- 23671928 TI - Green tea catechins can bind and modify ERp57/PDIA3 activity. AB - BACKGROUND: Green tea is a rich source of polyphenols, mainly catechins (flavanols), which significantly contribute to the beneficial health effects of green tea in the prevention and treatment of various diseases. In this study the effects of four green tea catechins on protein ERp57, also known as protein disulfide isomerase isoform A3 (PDIA3), have been investigated in an in vitro model. METHODS: The interaction of catechins with ERp57 was explored by fluorescence quenching and surface plasmon resonance techniques and their effect on ERp57 activities was investigated. RESULTS: A higher affinity was observed for galloylated cathechins, which bind close to the thioredoxin-like redox-sensitive active sites of the protein, with a preference for the oxidized form. The effects of these catechins on ERp57 properties were also investigated and a moderate inhibition of the reductase activity of ERp57 was observed as well as a strong inhibition of ERp57 DNA binding activity. CONCLUSIONS: Considering the high affinity of galloylated catechins for ERp57 and their capability to inhibit ERp57 binding to other macromolecular ligands, some effects of catechins interaction with this protein on eukaryotic cells may be expected. GENERAL SIGNIFICANCE: This study provides information to better understand the molecular mechanisms underlying the biological activities of catechins and to design new polyphenol based ERp57-specific inhibitors. PMID- 23671929 TI - Transport of inorganic phosphate in Leishmania infantum and compensatory regulation at low inorganic phosphate concentration. AB - BACKGROUND: Proliferation of Leishmania infantum depends on exogenous inorganic phosphate (P(i)) but little is known about energy metabolism and transport of P(i) across the plasma membrane in Leishmania sp. METHODS: We investigated the kinetics of 32P(i) transport, the influence of H+ and K+ ionophores and inhibitors, and expression of the genes for the Na+:P(i) and H+:P(i) cotransporters. RESULTS: The proton ionophore FCCP, bafilomycin A1 (vacuolar ATPase inhibitor), nigericin (K+ ionophore) and SCH28080 (an inhibitor of H+, K(+)-ATPase) all inhibited the transport of P(i). This transport showed Michaelis Menten kinetics with K0.5 and V(max) values of 0.016 +/- 0.002 mM and 564.9 +/- 18.06 pmol x h(-1) x 10(-7) cells, respectively. These values classify the P(i) transporter of L. infantum among the high-affinity transporters, a group that includes Pho84 of Saccharomyces cerevisiae. Two sequences were identified in the L. infantum genome that code for phosphate transporters. However, transcription of the PHO84 transporter was 10-fold higher than the PHO89 transporter in this parasite. Accordingly, P(i) transport and LiPho84 gene expression were modulated by environmental P(i) variations. CONCLUSIONS: These findings confirm the presence of a P(i) transporter in L. infantum, similar to PHO84 in S. cerevisiae, that contributes to the acquisition of inorganic phosphate and could be involved in growth and survival of the promastigote forms of L. infantum. GENERAL SIGNIFICANCE: This work provides the first description of a PHO84-like P(i) transporter in a Trypanosomatide parasite of the genus Leishmania, responsible for many infections worldwide. PMID- 23671930 TI - E-cadherin and adherens-junctions stability in gastric carcinoma: functional implications of glycosyltransferases involving N-glycan branching biosynthesis, N acetylglucosaminyltransferases III and V. AB - BACKGROUND: E-cadherin is a cell-cell adhesion molecule and the dysfunction of which is a common feature of more than 70% of all invasive carcinomas, including gastric cancer. Mechanisms behind the loss of E-cadherin function in gastric carcinomas include mutations and silencing at either the DNA or RNA level. Nevertheless, in a high percentage of gastric carcinoma cases displaying E cadherin dysfunction, the mechanism responsible for E-cadherin dysregulation is unknown. We have previously demonstrated the existence of a bi-directional cross talk between E-cadherin and two major N-glycan processing enzymes, N acetylglucosaminyltransferase-III or -V (GnT-III or GnT-V). METHODS: In the present study, we have characterized the functional implications of the N-glycans catalyzed by GnT-III and GnT-V on the regulation of E-cadherin biological functions and in the molecular assembly and stability of adherens-junctions in a gastric cancer model. The results were validated in human gastric carcinoma samples. RESULTS: We demonstrated that GnT-III induced a stabilizing effect on E cadherin at the cell membrane by inducing a delay in the turnover rate of the protein, contributing for the formation of stable and functional adherens junctions, and further preventing clathrin-dependent E-cadherin endocytosis. Conversely, GnT-V promotes the destabilization of E-cadherin, leading to its mislocalization and unstable adherens-junctions with impairment of cell-cell adhesion. CONCLUSIONS: This supports the role of GnT-III on E-cadherin-mediated tumor suppression, and GnT-V on E-cadherin-mediated tumor invasion. GENERAL SIGNIFICANCE: These results contribute to fill the gap of knowledge of those human carcinoma cases harboring E-cadherin dysfunction, opening new insights into the molecular mechanisms underlying E-cadherin regulation in gastric cancer with potential translational clinical applications. PMID- 23671931 TI - IGF dependent modulation of IGF binding protein (IGFBP) proteolysis by pregnancy associated plasma protein-A (PAPP-A): multiple PAPP-A-IGFBP interaction sites. AB - BACKGROUND: Pregnancy-associated plasma protein-A (PAPP-A) is a local regulator of insulin-like growth factor (IGF) bioavailability in physiological systems, but many structural and functional aspects of the metzincin metalloproteinase remain to be elucidated. PAPP-A cleaves IGF binding protein (IGFBP)-4 and IGFBP-5. Cleavage of IGFBP-4, but not IGFBP-5, depends on the binding of IGF before proteolysis by PAPP-A can occur. The paralogue PAPP-A2 has two substrates among the six IGFBPs: IGFBP-3 and IGFBP-5. METHODS: Sets of chimeric proteins between IGFBP-4 and -5, and IGFBP-3 and -5 were constructed to investigate the structural requirements for IGF modulation. At the proteinase level, we investigated the importance of individual acidic amino acids positioned in the proteolytic domain of PAPP-A for proteolytic activity against IGFBP-4 and -5. Interaction between PAPP-A and its substrates was analyzed by surface plasmon resonance. RESULTS AND CONCLUSION: We provide data suggesting that the C-terminal domain of the IGFBPs is responsible for IGF-dependent modulation of access to the scissile bond. Loss or reduction of IGFBP proteolysis by PAPP-A was observed upon mutation of residues positioned in the unique 63-residue stretch separating the zinc and Met turn motifs, and in the short sequence following the Met-turn methionine. A model of the proteolytic domain of PAPP-A suggests the presence of structural calcium ions in the C-terminal subdomain, implicated in IGFBP substrate interactions. GENERAL SIGNIFICANCE: Detailed knowledge of interactions between PAPP-A and its substrates is required to understand the modulatory role of PAPP-A on IGF receptor stimulation. PMID- 23671932 TI - Forces measured with micro-fabricated cantilevers during actomyosin interactions produced by filaments containing different myosin isoforms and loop 1 structures. AB - BACKGROUND: There is evidence that the actin-activated ATP kinetics and the mechanical work produced by muscle myosin molecules are regulated by two surface loops, located near the ATP binding pocket (loop 1), and in a region that interfaces with actin (loop 2). These loops regulate force and velocity of contraction, and have been investigated mostly in single molecules. There is a lack of information of the work produced by myosin molecules ordered in filaments and working cooperatively, which is the actual muscle environment. METHODS: We use micro-fabricated cantilevers to measure forces produced by myosin filaments isolated from mollusk muscles, skeletal muscles, and smooth muscles containing variations in the structure of loop 1 (tonic and phasic myosins). We complemented the experiments with in-vitro assays to measure the velocity of actin motility. RESULTS: Smooth muscle myosin filaments produced more force than skeletal and mollusk myosin filaments when normalized per filament overlap. Skeletal muscle myosin propelled actin filaments in a higher sliding velocity than smooth muscle myosin. The values for force and velocity were consistent with previous studies using myosin molecules, and suggest a close correlation with the myosin isoform and structure of surface loop 1. GENERAL SIGNIFICANCE: The technique using micro fabricated cantilevers to measure force of filaments allows for the investigation of the relation between myosin structure and contractility, allowing experiments to be conducted with an array of different myosin isoforms. Using the technique we observed that the work produced by myosin molecules is regulated by amino-acid sequences aligned in specific loops. PMID- 23671933 TI - Detection and identification of cancerous murine fibroblasts, transformed by murine sarcoma virus in culture, using Raman spectroscopy and advanced statistical methods. AB - BACKGROUND: Cancer is one of the leading worldwide causes of death. It may be induced by a variety of factors, including carcinogens, radiation, genetic factors, or DNA and RNA viruses. The early detection of cancer is critical for its successful therapy, which can result in complete recovery from some types of cancer. METHODS: Raman spectroscopy has been widely used in medicine and biology. It is a noninvasive, nondestructive, and water-insensitive technique that can detect changes in cells and tissues that are caused by different disorders, such as cancer. In this study, Raman spectroscopy was used for the identification and characterization of murine fibroblast cell lines (NIH/3T3) and malignant fibroblast cells transformed by murine sarcoma virus (NIH-MuSV) cells. RESULTS: Using principal component analysis and LDA it was possible to differentiate between the NIH/3T3 and NIH-MuSV cells with an 80-85% success rate based on their Raman shift spectra. CONCLUSIONS: The best results for differentiation were achieved from spectra that were obtained from the rich membrane sites. GENERAL SIGNIFICANCE: Because of its homogeneity and complete control of most factors affecting its growth, cell culture is a preferred model for the detection and identification of specific biomarkers related to cancer transformation or other cellular modifications. PMID- 23671934 TI - Translational repression of the McKusick-Kaufman syndrome transcript by unique upstream open reading frames encoding mitochondrial proteins with alternative polyadenylation sites. AB - BACKGROUND: Upstream open reading frames (uORFs) are commonly found in the 5' untranslated region (UTR) of many genes and function in translational control. However, little is known about the existence of the proteins encoded by uORFs, and the role of the proteins except translational control. There was no report about uORFs of the McKusick-Kaufman syndrome (MKKS) gene that causes a genetic disorder. METHODS: Northern blotting, 3'-RACE, and bioinformatics were used for determining the length of transcripts and their 3' ends. Luciferase assay and in vitro translation were used for evaluation of translational regulatory activity of uORFs. Immunoblotting and immunocytochemical analyses were used for detection of uORF-derived protein products and their subcellular localization. RESULTS: The MKKS gene generates two types of transcripts: a canonical long transcript that encodes both uORFs and MKKS, and a short transcript that encodes only uORFs by using alternative polyadenylation sites at the 5'-UTR. The simultaneous disruption of the uORF initiation codons increased the translation of the downstream ORF. Furthermore, both protein products from the two longest uORFs were detected in the mitochondrial membrane fraction of HeLa cells. Database searches indicated that such uORFs with active alternative polyadenylation sites at the 5'-UTR are atypical but surely exist in human transcripts. CONCLUSIONS: Multiple uORFs at the 5'-UTR of the MKKS long transcript function as translational repressor for MKKS. Two uORFs are translated in vivo and imported onto the mitochondrial membrane. GENERAL SIGNIFICANCE: Our findings provide unique insights into production of uORF-derived peptides and functions of uORFs. PMID- 23671935 TI - Tentative eligibility determinations; presumptive eligibility for psychosis and other mental illness. Final rule. AB - This document amends the Department of Veterans Affairs (VA) regulation authorizing tentative eligibility determinations to comply with amended statutory authority concerning minimum active-duty service requirements. This document also codifies in regulation statutory presumptions of medical care eligibility for veterans of certain wars and conflicts who developed psychosis within specified time periods and for Persian Gulf War veterans who developed a mental illness other than psychosis within 2 years after service and within 2 years after the end of the Persian Gulf War period. PMID- 23671936 TI - [Proceedings of Crossroads of Pathology, November 18-22, 2012, Paris, France]. PMID- 23671937 TI - Medical gripes: the doctor won't see you now. PMID- 23671938 TI - Nursing-home rights & wrongs. PMID- 23671939 TI - Why sleeping less makes you eat more (and more and more). PMID- 23671940 TI - Direct measurement of deuterium-deuterium dipolar coupling and analysis of the ordering of a specifically deuteriated diunsaturated lipid. PMID- 23671941 TI - Parable: the slippery slope. PMID- 23671942 TI - Special issue in tribute to Lloyd Old. PMID- 23671943 TI - Reply of author. PMID- 23671944 TI - Human resources for universal health coverage: a call for papers. PMID- 23671945 TI - Biosynthesis of a specifically deuteriated diunsaturated fatty acid (18:2(Delta)69) for 2H NMR membrane studies. AB - A unique procedure for the biosynthesis and subsequent isolation of a series of specifically deuteriated cis,cis-octadeca-6,9-dienoic acids has been developed. An auxotroph of Tetrahymena, which lacks Delta9 and Delta12 desaturanse activity, is supplemented with specifically deuteriated oleic acid and converts it to the corresponding deuteriated cis,cis, octadeca-6,9-dienoic acid, 18:2Delta69. The deuteriated fatty acid is subsequently isolated by argentation chromatography and HPLC. To demonstrate the utility of the procedure, we describe here the biosynthesis of cis,cis-octadeca-6,9-dienoic acid deuteriated at positions 9 and 10. Gas and thin-layer chromatography of the isolated fatty acid showed that it was greater than 99% pure while 13C NMR and mass spectrometry of the O (trimethylsilyl) derivative confirmed that the 18-carbon fatty acid contains two double bonds located at positions 6 and 9. The yield, from an 11-L culture, was typically 100 mg of which 35% was found to be deuteriated at both the 9- and 10 positions. The deuteriated fatty acid was esterified to 1-hexadecanoyl-sn-glycero 3-phosphocholine, and aqueous, multilamellar dispersions of the lipid were studied by 2H NMR. Each spectrum consists of two overlapping powder patterns and therefore yields two quadrupolar splittings. Over a temperature range from 0 to 40 degrees C, one splitting decreases from 6.6 to 1.8 kHz while the other increases from 4.5 to 5.3 kHz. The magnitudes of the two splittings are equivalent between 10 and 15 degrees C. The values of the splittings, and their response of temperature, differ significantly from those of the corresponding deuteriated oleic acid in microbial membranes [Rance, M., Jeffrey, K.R., Tulloch, A.P., Butler, K W., & Smith, I.C.P. (1980) Biochim. Biophys. Acta 600, 245-262] and in bilayers of 1-hexadecanoyl-2-cis-octadec-9-enoyl-sn-glycero-3 phosphocholine (POPC) [Seelig, J., & Waespe-Sarcevic, N. (1978) Biochemistry 17, 3310-3315]. The results suggests a fatty acyl chain containing two double bonds has physiochemical properties very different from those of the corresponding acyl chain with a single double bond. PMID- 23671946 TI - Benzene-induced changes in hematological parameters and urinary trans, trans muconic acid among gasoline station workers: authors' reply. PMID- 23671947 TI - Linkage disequilibrium characterization of CYP2C and CYP2D genomic regions in European populations. PMID- 23671948 TI - CYP2A6, CYP2B6 and CYP2E1 copy number variation in five ethnic groups. PMID- 23671949 TI - CYP2D6 genotype predicts tamoxifen side effects but not cancer-free or survival benefits in postmenopausal ER+ and/or PgR+ breast cancers. PMID- 23671950 TI - Effect of head circumference on parameters of pattern reversal visual evoked potential in healthy adults of central India. AB - Visual evoked response testing has been one of the most exciting clinical tools to be developed from neurophysiologic research in recent years and has provided us with an objective method of identifying abnormalities of the afferent visual pathways. Investigation were carried out to see whether the head circumference influence the pattern reversal visual evoked potential (PRVEP) parameters. The study comprised of pattern reversal visual evoked potential (PRVEP) recordings in 400 eyes of 200 normal subjects. Two hundred fourty eight eyes were males and 152 eyes were from 76 female subjects recruited from the Central Indian population in the age range of 40-79 years. Visual evoked potential (VEP) recordings were performed in accordance to the standardized methodology of International Federation of Clinical Neurophysiology (IFCN) Committee Recommendations and International Society for Clinical Electrophysiology of Vision (ISCEV) Guidelines and montages were kept as per 10-20 International System of EEG Electrode placements. The stimulus configuration in this study consisted of the transient pattern reversal method in which a black and white checker board was generated (full field) and displayed on a VEP Monitor by an electronic pattern regenerator inbuilt in an Evoked Potential Recorder (RMS EMG EP MARK II). VEP latencies, duration and amplitude were measured in all subjects and the data were analyzed. The correlation of all the electrophysiological parameters with head circumference was evaluated by Pearson's correlation co-efficient (r) and its statistical significance was evaluated. The prediction equations for all the VEP parameters with respect to head circumference were derived. We found a positive correlation of P 100 latency and N 155 latency with mean head circumference, while a highly significant negative correlation were noted of P 100 amplitude with head circumference. N 70 latency was significantly correlated with head circumference. P 100 duration showed in negative correlation with head circumference. These findings suggest that VEP latencies, duration and amplitude are influenced by the head circumference of the individual in a sample of healthy subjects and head circumference can be a useful predictor of VEP peak latencies, amplitude and duration. PMID- 23671951 TI - Intestinal parasitic infections among patients attending Nepal Medical College Teaching Hospital, Kathmandu, Nepal. AB - This study was conducted to find out the prevalence of intestinal parasitic infection among patients attending Nepal Medical College Teaching Hospital, Kathmandu from July 2011 to February 2012. A total of 312 stool samples collected in a clean, dry screw capped plastic container were examined using the formal ether concentration and sucrose-flotation techniques. Overall parasite positivity rate was 30.1% with significant difference between males (34.2%) and Female (26.3%) (p < 0.05). Out of total positive, 90.4% had single parasitism whereas 9.6% had multiple parasitism. Children aged < or = 5 years were found to be highly infected (35.8%), followed by 6-15 years (32.1%) and > 15 years old (26.9%). Rate of infection was significantly higher among patients from inside Kathmandu Valley (31.1%) than outside valley (17.4%) (p < 0.05). E. histolytica (38.5%) and Hookworm (10.6%) were the commonest protozoa and helminthes respectively. Other parasites detected were G. lamblia (26.0%), E. coli (1.0%), T. trichiura (7.7%), A. lumbricoides (6.7%), H. nana (5.8%) and Taenia species (3.8%). Out of total parasites detected, 65.4% were protozoa and 34.6% were helminthes. Positive rate was higher in Dalit (37.5%) and Aadibasi-Janjati (34.3%) than Brahman-Chhetri (22.6%) (p < 0.05). PMID- 23671952 TI - Vitamin D status among individuals attended in Health Home Care Centre, Lalitpur, Nepal. AB - There is widespread prevalence of vitamin D deficiency from new-born to infancy, childhood and adult male and female. Despite the numerous reports of the association of vitamin D with spectrum of development, disease treatment and health maintenance, vitamin D deficiency is common. There is limited information of the vitamin D status in Nepalese people. Based on the information in relation to importance of Vitamin D, we proposed to see the level of vitamin D among the care seeker individuals attended in this Health Home Care Centre, Nepal. Within three months interval (March to May 2012), whole blood test was done by 148 individuals. Among them vitamin D3 test was recommended for 50 individuals done by doctor on the basis of relevant health problems in relation to vitamin D deficiency. Analysis was done with SPSS package 17 version to see the relation between Vitamin D deficiency and other health related tests. The study found significant association between vitamin D deficiency with calcium level and hemoglobin level. There are presences of studies with evidences regarding relation of vitamin D with different health outcomes in different parts of the world. The widespread deficiency of vitamin D merits consideration of widespread policies including increasing the awareness among the public and health care professionals. In addition the study results highlight the need for additional high quality studies in Nepal in order to prevent the impacts of vitamin D deficiency and also to plan for prevention of vitamin D deficiency. PMID- 23671953 TI - Human rotavirus associated diarrhea and strain diversity in Nepal. AB - Two new rotavirus vaccines were recently introduced to the market and have shown a tremendous impact in reducing severe diarrhea due to rotavirus in children. Diarrheal disease is a common cause of morbidity and mortality among Nepalese children. In anticipation of a rotavirus vaccine in Nepal, we systematically reviewed published articles on rotavirus infection in Nepal. Literatures were searched in health related national and international databases. Fifteen rotavirus related articles between 1978 and 2010 were identified. Of these, information from five articles were extracted and analyzed in the present study. Of 3671 participants, 864 were positive for rotavirus infection by ELISA. The prevalence ofrotavirus infection ranged from 12 to 39%. G1P[8] (25%) was the most frequent combined G and P genotype, followed by G12P[6] (23%) and G2P[4] (16%) between 2003 and 2007. Nearly 9% of analyzed rotavirus positive samples (G and P genotype) were non-typable. The data demonstrated that rotavirus is the most identifiable cause of severe diarrhea in children less than 5 years old in Nepal. The wide variety of rotavirus strains circulating in Nepal; underscore the need for continued surveillance. This will be the key to understanding the epidemiological characteristics of rotavirus disease and the impact of vaccination after introduction. PMID- 23671954 TI - Outcome analysis of breast cancer patients treated at Nepal Medical College. AB - Breast carcinoma is second most common malignancy among women in Nepal and is also still a killer carcinoma in our context. We are encountering with more cases of breast cancer, may be due to increase number of cases because of life style modification or due to more diagnostic facilities available in the country. Yet we most often encounter more advanced stage of breast carcinoma. In our study we had total of 21 patients who suffered from breast carcinoma. Among those patients most were elderly with mean age of 54.33 +/- 11.25 years. Among 21 patients, 13 patients were either of locally advanced type or with advanced breast carcinoma with metastasis. In our institution these patients were offered evidence based treatment as per their requirement. Since most of these patients are unaware of self breast examination and hence presented lately. Even though they were managed properly, 1 patient had local recurrence and 4 patients later presented with distant metastasis. PMID- 23671955 TI - Prediction of individuals prone to suffer from early onset of hypertension. AB - The present study was undertaken to predict the persons prone to suffer from early onset of hypertension. Healthy sedentary volunteers (age 18-25 years) having normal blood pressure were asked about their history of familial hypertension, smoking-habit, alcohol consumption, existing worries/anxieties; these being the predisposing factors of hypertension. The blood pressure of them was recorded (casual baseline blood pressure). Maximum voluntary contraction (MVC) was noted as maximum pressure (in Kg) sustained during 3 sec of handgrip using a handgrip dynamometer. Thereafter, the participant was asked to sustain isometric handgrip at one third of MVC for one minute with the same instrument (isometric handgrip-test). Then, blood pressure was measured and the subject was allowed to rest. Three minutes after the handgrip test, the blood pressure was noted again (recovery blood pressure). Handgrip-test produced a rise in systolic blood pressure in all male volunteers. Amongst them, with predisposing factors of hypertension, diastolic blood pressure remained significantly higher than casual baseline diastolic blood pressure even after 3 minutes of withdrawal of stressor. Whereas, in males with no predisposing factors of hypertension, the diastolic blood pressure approached almost the baseline casual blood pressure. In all female participants, no significant difference was noted between the casual baseline blood pressure and blood pressure after recovery. Results indicated that the young men who presented prolonged elevated diastolic blood pressure, in response to handgrip test would be at high risk of early onset of hypertension, as sympathetic over-activity prevails in them for longer time. PMID- 23671956 TI - Experience with common bile duct exploration at Lumbini Medical College. AB - Common bile duct stones represent a significant danger to patients, because they can lead to biliary colic, obstructive jaundice, cholangitis, or pancreatitis. Common bile duct stones either migrate from the gallbladder or form primarily within the bile ducts themselves. Primary stones are more common in South Asia and are usually sequelae of biliary infection and stasis. In the United States and other Western countries, common bile duct stones are predominantly secondary stones, having formed in the gallbladder. In patients who have gallstones, and in whom a cholecystectomy is considered, common bile duct stones can be found preoperatively, intraoperatively, or postoperatively. Ten percent to 15% of patients undergoing a cholecystectomy will be found to have choledocholithiasis at some point during their treatment. We present our case of 16 patients of common bile duct stones with or without cholelithiasis from April 2011 to March 2012. To review the treatment and outcome of patients with common bile duct (CBD) stones who underwent cholecystecomy with open common bile exploration (CBDE). We analysed the fact that cholecystectomy with commonbile duct exploration still holds as a good modality of treatment where ERCP (Endoscopic Retrograde cholangio pancreaticogram) is not available. All 16 persons in age group of 20-65 years, all females with body weight in the range of 45-60 kgs undergoing inpatient common bile duct exploration during April 2011- March 2012 were included. Common bile duct exploration was successful in all patients. Mean operating time was 120 +/- 40 minutes and length of hospital stay was 13 +/- 3days. 3 complications (18.75%) were recorded, 2 cases of retained stone (12.5%) who underwent choledochoduodenostomy. In 16 patients undergoing common bile duct exploration, CBD stones were discovered with flexible choledochoscope and intraoperative cholangiography. None of the Gallbladder specimen revealed any feature of malignancy in final histopatholgical report. All patients are doing fine till date. Open common bile duct exploration can still be a gold standard technique in set up where ERCP is not available. The results of common bile duct exploration are good with less complications in experienced hands. PMID- 23671957 TI - Hanging: nature of ligature material applied and type of hanging according to point of suspension. AB - One of the most common manners of unnatural death that has been rapidly increasing in Nepal is suicide. The choice of method depends on the accessibility and availability of the means. Therefore suicide by hanging with the ligature material ranging from torn clothing, bed sheet to a shoelace is incorporated. Objective of this study is to find the choice of the type of ligature material used by the victims and the type of hanging found in relation to the point of suspension in both genders. This prospective study was conducted in all cases of death due to hanging (44 cases) during the year January 2007to April 2008 coming for post mortem examination at BPKIHS Dharan Nepal. Nearly half of the hanging victims (21 or 47.72%) used rope for hanging and nearly one third victims (14 or 31.81%) used shawl, rest of victims 4 (9.09%) used sari, 2 (4.54%) victims used either bed sheet or woolen muffler in each and belt was used as ligature by one (2.27%) of the victims. It was observed that in more than half of the cases (25 or 56.81%) hanging was partial (i.e. some body parts were touching the ground). Amongst partial hanging cases, female victims (16 or 64%) outnumbered the male victims (9 or 47.37%).While rest 19 (43.18%) cases were complete hanging (i.e. body was not touching the ground). PMID- 23671958 TI - Redo-laparotomies: reasons, morbidity and outcome. AB - A large number of patients undergo various operative procedures every day and laparotomy forms a large proportion. At times, laparotomies have to be redone due to complications like biliary peritonitis, faecal fistula, burst abdomen or anastomotic leak. Our objectives were to determine the causes of Redo-laparotomy evaluate morbidity associated with it and analyze its outcome. A prospective study of patients in BP Koirala Institute of Health Sciences (BPKIHS) from 1. 1. 2009 to 31. 12. 2009 was done. Institutional ethical clearance was taken. The Statistical analyses were done using SPSS version 11.5. Redo-laparotomy was performed in 40(1.99%) cases. The mean age was 31.99 +/- 21.49 years with a M: F ratio of 4:3. The indications of Redo-laparotomy were: burst abdomen (n = 9; 22.5%), followed by intra-abdominal collection and abscess (n = 7; 17.5%), fecal (n = 6; 15%), and biliary peritonitis (n = 5; 12.5%). The mean duration between first laparotomy and Redo was 9.42 +/- 7.56 days and the mean duration of hospitalization was 26.98 +/- 12.50 days. Lower gastrointestinal surgeries usually lead to a Redo. The mortality in our study was 30% and 21/40 patients had to be managed in the intensive care unit. Clinical acumen formed the basis (87.5%) to decide for Redo-laparotomy in the majority. Redo-laparotomies that are performed following complicated abdominal surgeries have high morbidity and mortality rates. Multiple factors may lead to a Redo-laparotomy which is beyond the hands of a clinician yet a vigilant and vigorous management could help reduce the rate of Redo-laparotomies. PMID- 23671959 TI - Profile of ascites patient admitted in Nepal Medical College Teaching Hospital. AB - Ascites is one of the frequently encountered problems in internal medicine. Common causes of ascites are portal hypertension including cirrhosis of liver and congestive heart failure, hypoalbuminemia associated with nephrotic syndrome, intra-abdominal malignancy and abdominal tuberculosis. We evaluated 43 patients presented with ascites in Nepal Medical College Teaching Hospital (NMCTH). After history taking, clinical examination, imaging studies and laboratory evaluation alcoholic liver disease and abdominal tuberculosis were diagnosed in 19 and 5 patients restively. Constrictive pericarditis was diagnosed in 2 patients and 2 patients were suffering from HCV related liver disease. Present study revealed alcoholic liver disease as the commonest cause of ascites. PMID- 23671960 TI - The burden of dengue infection in some vulnerable regions of Nepal. AB - Dengue is an emerging mosquito borne disease of public health importance in Nepal. A descriptive cross sectional study was carried out to estimate sero prevalence and distribution pattern of dengue in certain vulnerable regions of Nepal from June to September 2009. A total of 460 venous blood samples were collected from individuals experiencing a febrile illness clinically consistent with dengue infection visiting nearby hospitals of Kanchanpur, Kailali, Banke, Dang and Chitwan districts. The sero-prevalence of dengue virus specific IgM was determined by enzyme linked immunosorbent assay (ELISA) kit. The anti-dengue IgM positivity was found to be 12.17%. The higher frequency of positive cases (16.4%) were from age group 20-40 years followed by < 20 years age group with 9.7% and 5.3% from > 40 years age group. The association between dengue infection and age is found to be statistically significant (p < 0.05). The male:female ratio was determined as 1.3:1 in IgM positive population. Among sampling areas, Kanchanpur showed highest prevalence of dengue infection (15.5%) followed by Chitwan (11.7%), Kailai (11.1%), Banke (10.7%) and Dang (8.3%). Similarly, 94.6% of the positive cases were indigeneous and had no history of travel to other countries. Dengue is firmly established in terai region with increasing trends of infection and expansion into newer areas raising a public health threat. Regular epidemiological studies are suggested which could further reveal the contributing factors associated with dengue virus infection and help in formulating strategies in reducing the transmission rate and control of the infection. PMID- 23671961 TI - Evaluation of control of blood pressure in chronic kidney disease patients with hypertension attending echo-lab of Nepal Medical College Teaching Hospital. AB - Hypertension and Chronic kidney disease (CKD) are common in Nepal. Control of blood pressure (BP) in general hypertensive patients is poor. Evaluation of adequacy of BP control in CKD patients with hypertension is rare. All consecutive indoor patients (52) with CKD and hypertension, attending echo-lab of Nepal Medical College Teaching Hospital during prospective study of 3 years period from 16th April 2008 to 15th April 2011, were evaluted. Mean age was 45.3 +/- 16.7 years. Male female ratio was 8:5. Brahman and Chhetri (22, 42.3%) were the usual sufferers. There were two peaks in the age group wise distribution; one in age group 20-29 years and the next in 50-59 years. One hypertensive patient's BP was normalized after starting hemodialysis without antihypertensive therapy and was excluded from this study. Others' BP (n = 51) were followed up during admission for the evaluation of the adequacy of their BP control and their antihypertensive medications were reviewed. The control of hypertension in CKD patients was difficult. More than two third of the patients (68.6%) had BP > 140/90 mm Hg. Intensive BP control was present in less than one tenth (7.9%) of the patients. In comparison to intensive group, uncontrolled group received more antihypertensive agents (3.0 +/- 1.3 vs. 2.0 +/- 0.8, p < 0.05). Amlodipine (39, 76.5%) and frusemide (39, 76.5%) were very popular antihypertensives used followed by Prazocin (20, 39.2%) and Metoprolol (11, 21.6%). Despite good efforts, BP control of Nepalese CKD patients with hypertension, were poor. PMID- 23671962 TI - Health seeking behavior during pregnancy and child birth among Muslim women of Biratnagar, Nepal. AB - Maternal mortality remains one of the biggest public health challenges in Nepal. This paper explores the health seeking behavior, during pregnancy and child birth in certain ethnic group. The poverty, illiteracy, women's low status in the society, lack of access and difficult geographical terrain are major reasons for poor maternal health status in Nepal. Cross-sectional study was conducted among 200 Muslim women of ward # 7 of Biratnagar municipality. They were interviewed to understand their health seeking behavior during pregnancy and childbirth, factors associated with use of health services and their role in the family. Information's on usages of health services, education level, family stricture, and occupational status, information were collected using a pretested and structured questionnaire. The overall institutional delivery in study population was found 24.5%. Low socio-economic status, Illiteracy and poverty in women are the major challenging features of pregnancy and child birth. PMID- 23671963 TI - Etiology and antimicrobial susceptibility pattern of bacterial pathogens from urinary tract infection. AB - Urinary tract infection (UTI) is the most common infection in both community and hospital patients. In majority of the cases, empirical antimicrobial treatment is practiced before the laboratory results of urine culture. Thus, antibiotic resistance may increase in urinary bacterial pathogens due to improper use of drugs. This study was designed to find out the etiological agents of UTI and their prevalence, and to determine the antimicrobial susceptibility pattern of the bacterial pathogens isolated from urine culture. This study was conducted in Kathmandu Model Hospital, Kathmandu, Nepal from April to October, 2009. Midstream Urine samples from 1323 patients suspected of UTI were analyzed by microscopy, and conventional semi-quantitative culture technique for the significant growth. Antimicrobial susceptibility test was performed for the isolates by Modified Kirby-Bauer disk diffusion method. Data were analyzed using SPSS software window version 16. The overall prevalence of UTI was found to be 18.89%. The most frequent causative organisms isolated were Escherichia coli (82.30%), Enterococcus faecalis (5.60%), Citrobacter freundii (3.60%), Enterobacter aerogenes (2.40%), Coagulase Negative Staphylococci (2.40%), Pseudomonas aeruginosa (1.20%), Proteus mirabilis (0.8%), Klebsiella pneumoniae (0.4%), and Staphylococcus aureus (0.4%). Nitrofurantoin and Amoxycillin were found to be the most effective antibiotic against gram negative and gram positive isolates respectively. E. coli was found to be the most common etiological agent of UTI and Nitrofurantoin was the most effective drug among the isolates. PMID- 23671964 TI - An evaluation of patients care in Radio Diagnosis Department of Tribhuvan University Teaching Hospital, Kathmandu, Nepal. AB - Patients care involves all the activities that are carried out before, during and after radiological diagnostic procedures. The successful application of medical knowledge depends on what patients think and feel about the medical personnel and the hospital. From the clinical experience, patients usually reacts to some factors that creates problems in the radiology units such as delay, neglect, use of harsh words, unnecessary repeats and preferential treatment. The study was aimed at evaluating patients care in radio diagnosis department of Tribhuvan University Teaching Hospital (TUTH), Kathmandu, Nepal. A cross sectional study was conducted from May to June, 2012 in TUTH, Kathmandu, Nepal. Semi structured both open and closed ended questionnaires were administered among 287 conscious patients who were agreed to participate in the study. A total 287 patients were enrolled in the study. Out of them, 165 (57.49%) patients perceived that instruction was adequate before and after the examination; 219 (76.30%) patients were satisfied with the services rendered in the hospital; 174 (60.62%) patients perceived that privacy was adequate but 229 (79.9%) and 145 (50.5%) perceived that waiting areas and social aspects of patients care were suboptimal and in adequate. This can be improved by hospital management system. PMID- 23671965 TI - Extended spectrum beta-lactamase producing multidrug resistant urinary isolates from children visiting Kathmandu Model Hospital. AB - A study was conducted to analyze the status of the multidrug resistant (MDR) isolates producing Extended Spectrum of beta-lactamase (ESBL) among the uropathogens infecting children less than 15 years from November 2010 to April 2011 in the Bacteriology laboratory, Kathmandu Model Hospital. Urine samples received in the laboratory were processed for routine culture. The antimicrobial susceptibility of bacterial isolates was determined following Clinical and Laboratory Standard Institute (CLSI) recommended Kirby-Bauer Disc Diffusion method. The defining criterion in this study for an isolate to be multidrug resistant was resistance to two or more drugs of different structural classes. Isolates were confirmed for ESBL-production by performing the Inhibitor Potentiated Disk Diffusion (IPDD) Test/ Combined Disk Assay for ESBL confirmation. Out of 252 urine samples received in the laboratory, 59(23.41%) showed significant growth of which 54.23% (32/59) were MDR isolates. Additionally, 25 isolates (21 Escherichia coli and 3 Citrobacter freundii and single Enterobacter aerogenes) among them were ESBL producers. Among the first line drugs used against gram negative isolates, Nitrofurantoin was drug of choice; meanwhile among the second line drugs Cefoperazone/Sulbactum was drug of choice, whereas, Cephotaxime, Ciprofloxacin, Norfloxacin and Gentamicin were the drug of choice for Gram positive isolates. Significant association was found between ESBL production and spectrum of drug resistance (p < 0.05). PMID- 23671966 TI - Reasons for failure of nonsurgical root canal treatment in Nepali population. AB - Non surgical root canal treatment is carried out to salvage the teeth in oral cavity. Although the success rate is found to be ranging from 81-95%, for variety of reasons failure of root canal is still seen in day to day practice. This is a cross sectional study done in Nepali population to evaluate the causes for such failures. It was found that inadequate obturation (45%) was the major cause of failure followed by missed canal, (32%) and fractured or dislodged restoration (14%). This study shows that the basis for successful non surgical root canal treatment depends on operators knowledge on individual tooth anatomy and skill to properly clean, shape, obturate and restore the tooth in function. PMID- 23671967 TI - Spectrum of pediatric dermatoses in tertiary care center in Nepal. AB - Children with dermatological problems constitute a major group presenting to the Outpatient Department. This study was done to see the pattern of skin disorder among the pediatric age group in a tertiary care center in Nepal. To determine the pattern of skin disorders among children visiting the Department of Dermatology and Pediatrics in a tertiary care center in Nepal. All the patients visiting the Dermatological Out patient Department in the age group 0-14 years were enrolled in the study during the time period of 3 years (2009-2011). The cases were diagnosed based on the detailed clinical history and clinical examination, and the patients were investigated as needed. A total of 1086 (22.64%) patients out of 4795 patients were having skin disorder and among them 584 (53.77%) were males and 502 (46.23%) were females. The age range was 0-14 with the mean age of 7 years. Dermatitis and eczema were the most frequently encountered disease 298 (26.46%), followed by bacterial infections 156 (16.13%), urticarial 190 (15.71%), viral infection (14.12%), fungal infection 76 (7.3%), scabies 54 (5.03%), miliaria 25 (2.75%), vitiligo 27 (2%) and others 87 (6.53%). Nutritional disorders, vascular, pigmentary, nevi, drug eruptions had a comparatively low incidence. PMID- 23671968 TI - Significance of adenosine deaminase in diagnosing tuberculous pleural effusion. AB - Tuberculosis (TB) is a major public health problem in developing countries including Nepal. One of the common presentations of TB is pleural effusion. The diagnosis of tubercular pleural effusion can be difficult because of the low rate of detecting tubercule bacilli by direct stain and culture of pleural fluid for acid-fast bacilli (AFB). Pleural biopsy can be useful but is invasive and requires experts. In this context, pleural fluid Adenosine Deaminase (ADA) level has been proposed as easy, cheap and highly sensitive test for diagnosis of TB pleural effusion. The present study was undertaken to define the role ofpleural fluid ADA value in accurate diagnosis of TB pleural effusion. A Prospective analysis of 100 patients admitted in Nepal Medical College and teaching Hospital with pleural effusion was done. Pleural fluid ADA level was evaluated in all patients, and significance of pleural fluid ADA level in TB pleural effusion was studied. It was found that mean ADA level in pleural fluid was 105.8 +/- 67.23 U/L in cases of TB, as compared to 16.83 +/- 8.91 U/L in malignancy, 44.53 +/- 32.84 U/L in parapneumonic effusion and 15.94 +/- 4.88 U/L in patients with miscellaneous diagnosis. For a cut-off value of 42.19 U/L for diagnosis of TB pleural effusion, sensitivity was found to be 90.8% and specificity 82.8%. Almost all patients diagnosed to have TB pleural effusion responded completely to anti tubercular treatment. So, we concluded that pleural fluid ADA analysis could be easy, cheap and highly sensitive and specific test for diagnosis of TB pleural effusion. PMID- 23671969 TI - Psychological impact after mastectomy among Nepalese women: a qualitative study. AB - Breast cancer is one of the leading causes of death in women. Cancer epidemiologists have stated that breast cancer is the most common cancer in women in developed countries, Nepal is not an exception. Breast cancer is the second most common cancer in women of Nepal after cervical cancer. A Qualitative phenomenological study was done to explore the psychological impact of women with mastectomy after diagnosis of breast cancer. In-depth study was done with ten women age ranging from 36 to 50 years. Ten women were interviewed which was recorded, and verbatim were transcribed before taking next interview. The interviews were analyzed in three stages as stated by Miles and Hubermans. Findings revealed that respondents expressed the fear of death, emotional impact of the loss of breast disfigurement, loss of femininity, fear of recurrence of disease, and concern about their family. Breast cancer and mastectomy have impact on women psychosocial state. They develop stress due to loss of body part, loss of femininity, fear of recurrence of disease, fear of cost and prolong treatment protocol. PMID- 23671970 TI - Association of hypertension with microalbuminuria and lipid profile in the local population of Patan. AB - There is increasing prevalence of hypertension worldwide. Hypertension is an important risk factor for cardiovascular disease and renal disease which are the leading cause of death in the world. It is, therefore, very important to prevent progression of hypertension into these fatal diseases through appropriate treatment and monitoring. Microalbuminuria and dyslipidemia has been regarded as a predictor for cardiovascular and renal dysfunction in hypertension. In this study, we have included 130 hypertensive and 100 normotensive individuals of age > or = 25 years. Patients with a history of urinary tract infection, hematuria, renal failure, women with menstruation at the time of sample collection were excluded from this study. Measurements of anthropometric parameters; blood parameters like lipid profile, fasting blood sugar (FBS), creatinine after 8 hrs fasting and urine parameters like microalbumin and creatinine were done. The prevalence of microalbuminuria and macroalbuminuria is 17.7% and 3.1% respectively in hypertensive patients. Also, there was 9% prevalence of microalbuminuria in normotensive people. There was a significant association of hypertension with microalbuminuria and dyslipidemia, triglyceride, low density lipoprotein, high density lipoprotein, microalbumin creatinine ratio (MCR), body mass index (BMI), waist circumference (WC) and waist hip ratio (WHR) were significantly higher in hypertensive than in normotensive persons. These higher lipid levels, WC and MCR in hypertensive patient are established risk factors for progressing into diabetes and cardiovascular diseases. Hence, monitoring of these parameters would be beneficial for hypertensive patients in preventing the disease progression in this population. PMID- 23671971 TI - Elbow dislocation with ipsilateral radius and ulna fracture: is it so common? AB - Elbow dislocation with ipsilateral diaphyseal fracture of both radius and ulna is a rare injury. However, elbow dislocation with either radius or ulnar diaphyseal fracture is commonly reported. We report an uncommon injury of a 16 years old male who had his elbow dislocation with ipsilateral both bones forearm fractures. Elbow dislocation was reduced and fracture both bones were fixed with dynamic compression plate under brachial block. PMID- 23671972 TI - [Lymphoma diagnosis and treatment - second Croatian consensus]. AB - New, extended and modernized recommendations for diagnostics and treatment of lymphomas were accepted at a meeting held in March 2012 with the participation of major Croatian experts. They encompass morphological, radiological and nuclear diagnostics, systemic treatment, radiotherapy and follow-up of most tumors of lymphoid tissues occurring in adults. The recommendations were agreed upon by consensus. Reporters presented data and suggested recommendations which had been first discussed in working groups and then agreed upon on the plenary session. PMID- 23671973 TI - [The first case of radiofrequent ablation of ventricular tachycardia in a patient with ischemic cardiomyopathy in our country]. AB - Ablation of ventricular tachycardia in patients with ischemic cardiomyopathy is more complicated and more difficult than ablation of most supraventricular tachycardias. Arrhythmogenic substrate is complex and its localisation is often unclear. Because of the tachycardia characteristics, more precise mapping methods often can't be utilised. Also, patients are usually seriously ill with decreased systolic function, heart failure, ischemia and various comorbidities where tachycardia induction and ablation procedure may facilitate abrupt hemodynamic disturbance. Uninducibility of the clinical tachycardia can be achieved in 65-95% of patients, but tachycardia recurs in 20-44% of patients. Serious complications were noted in 8% of patients with lethal outcome in 2.7% of patients. Decision about therapeutic strategy should be made individually according to potential risk and procedure benefit. This paper presents the first case of the successful ablation of ventricular tachycardia in a patient with ischemic cardiomyopathy in our country. PMID- 23671974 TI - [Acute coronary syndrome after hornet bite, type II Kounis syndrome - a case report]. AB - Kounis syndrome is an accidental occurrence of acute coronary syndrome associated with anaphylaxis, where acute inflammatory mediators cause the spasm of coronary arteries with the erosion and rupture of atheromatous plaque. We present a 53 year-old male who during the treatment of anaphylaxis after a hornet bite developed acute anteroseptal myocardial infarction. The diagnosis of type II Kounis syndrome was proven by electrocardiographic abnormalities and biochemical markers with clinical manifestation of acute coronary syndrome, and was associated with anaphylaxis which demanded prehospital treatment of the patient after the hornet bite. Anaphylaxis after a hornet bite requires consideration of acute coronary syndrome if patients have chest pain and hemodynamic impairment, as these conditions occur infrequently but demand additional diagnostics and adequate treatment. PMID- 23671975 TI - [Thromboembolic and bleeding risk assessment in patients with non-rheumatic atrial fibrillation using CHA2DS2-VASc and HAS-BLED scoring systems]. AB - It is estimated that approximately 1-2% of the world population are affected with non-rheumatic atrial fibrillation (nAF). The most frequent complications of this arrhythmia are thromboembolic events, primarly ischemic stroke. In comparison with patients in sinus rhythm, stroke affected nAF patients have more severe clinical course and significantly higher mortality rate, and the survivors have significantly lower recovery rate and more serious permanent mental and physical impairments. The administration of anticoagulants to patients with nAF significantly reduces the incidence of stroke, while those who were stroke affected during the anticoagulant therapy show better treatment outcomes. Therefore, professional associations guidelines recommend the anticoagulant treatment for the majority of patients with nAF. The fear of bleeding caused by anticoagulants results in their frequently unjustified omission from the therapy in patients with high thromboembolic risk. This paper presents CHA2DS2-VASc- and HAS-BLED systems recommended for thromboembolic and bleeding risk assessment when deciding on thromboprophylactic therapy in patients with nAF. PMID- 23671976 TI - [Cervicogenic dysphagia: swallowing difficulties caused by functional and organic disorders of the cervical spine]. AB - Cervical spine disorders which can cause swallowing difficulties (cervicogenic dysphagia; CD) are: chronic multisegmental/MS dysfunction (dysfunction=functional blockade) of the facet joints, changes in physiological curvature of the cervical spine, degenerative changes (anterior osteophytes, anterior disc herniation, osteochondrosis, osteoarthritis), inflammatory rheumatic diseases, diffuse idiopathic skeletal hyperostosis, injuries, conditions after anterior cervical spine surgery, congenital malformations and tumors. According to our clinical observations, degenerative changes in the cervical discs and facet joints and chronic MS dysfunction of the cervical spine facet joints are disorders which can cause swallowing difficulties. However, these disorders have not been recognized enough as the causes of dysphagia and they are not even mentioned in differential diagnosis. Because of the close anatomical relationship of cervical spine with the pharynx and cervical part of esophagus, the consequences of the degenerative changes in the cervical discs and facet joints and chronic MS dysfunction of the cervical spine facet joints such as the changes in the physiological curvature of the cervical spine, changes in elasticity and contractility in the neck muscles and decreased mobility of the cervical spine, adversely affect the dimensions of the pharynx and cervical part of esophagus, that is, swallowing capacity which can result in dysphagia. Degenerative changes in the cervical discs and facet joints are common additional cause of dysphagia in elderly people with disorders of the central control of swallowing (stroke, Parkinson's disease, senile dementia etc). The most important therapeutic options in patients with CD are: medicamentous therapy, physical therapy, manual therapy, kinesiotherapy and surgical treatment. The aim of the conservative therapy in patients with CD is to improve the swallowing capacity (for example, soft tissue techniques, stretching of the shortened muscles, passive and active mobilization of the facet joints). As the patients with CD usually respond well to the appropriate therapy, cervical causes of dysphagia cannot be overlooked in patients with difficulty swallowing, including patients with disorders of the central control of swallowing. PMID- 23671977 TI - [Do we need to differentiate between complication and malpractice?]. AB - The paper discusses the issue of justifiability and practical value of deciding between a medical complication and a medical error, the subject which has recently been frequently debated among doctors, at court trials and in media. The authors clearly define the meaning of the terms of medical complication and medical error, pointing out that they belong to an entirely different class of terms and further stating that it is not realistic to decide between them in practice. They go on to emphasise that they should be viewed exclusively as obligatory dependent variables. Medical complication may be declared to be a direct consequence of medical error only when forensic and medical expert reports have established a causal relationship between the two. The paper proposes possible causes and circumstances in which medical complications may occur. Special emphasis is given to the fact that not every adverse event or harmful outcome should be automatically identified as medical error. In order to make such identification, all circumstances leading to an adverse outcome need to be clearly established through expert medical expertise. Instead of conclusion, the authors advocate abandonment of existing erroneous concept of deciding between complication and error and the introduction of a new and better concept that views complication as generally undesirable, adverse and harmful consequence while, in order to decide on the occurrence of medical error and possible link with the resulting complication, an objective and thorough forensic and medical expertise on the mechanism(s) and/or causes of the complication is required. PMID- 23671978 TI - [Why limit the use of tobacco products?]. AB - The scientific evidence strongly shows that there is no safe level of exposure to tobacco smoke. It is indisputable that the only effective way to protect the population from the harmful effects of SHS is a 100% smoke-free environment. Implemented legal regulations of countries and regions that have already implemented a smoke-free policy were not only feasible, but also well received. They have only positive effects on all sectors, especially in regard to health - actual reduction in heart attacks and respiratory illnesses. In accordance with the positive experiences and scientifically substantiated, the WHO makes recommendations for the implementation in the countries signatory of the Convention on Tobacco Control to protect the health of their citizens and workers. Croatia has a modem law in line with the World Health Organisation recommendations, but it is necessary to work on the positive climate of smoke free and cooperation of citizens in protecting and improving their own health. In order to achieve long-term results in accordance with a smoke-free policy, interventions must be comprehensive and continuously incorporated into the system. PMID- 23671979 TI - [3D/4D echocardiography - our first experience]. PMID- 23671980 TI - [Early child development and emotional difficulties in hospitalized children]. PMID- 23671981 TI - [The search for identity of a discipline]. PMID- 23671982 TI - [How to approach the discipline of "nursing science" in France?]. AB - The last four years have seen the development of supports toward research in nursing and other healthcare professionals' research, along with the fact that, nursing education has become part of university programs. Professional and scientific landscapes are changing and the opening perspectives let glimpse a growing professionalization of nurses' activities but also, raise the question of the nursing science construction in France. By considering interdisciplinary work, as an approach for complex situations of care, by specifying the purpose of the production of nursing scientific knowledge in order to meet the population needs of healthcare, by explaining the purpose of nursing research and theoretical elements that allow its construction, the following article offers an epistemological reflection on the evolution of the profession and on the construction of a nursing scientific discipline in France. PMID- 23671983 TI - [The French version of Symptom Management Theory and its application]. AB - Patients with chronic diseases remain a challenge for patient centered care in terms of symptom management. In advancing the nursing profession in this respect, organizing and providing such care in a structured and systematic way benefits from being grounded in a sound theoretical framework. Since 1994, University of California in San Francisco's Symptom Management Theory (SMT) holds promise to provide such theoretical foundation. This paper aims at presenting a French version of the SMT, the "theorie de gestion des symptomes (TGS)" as well as at discussing its application in research and practice. The paper illustrates how different concepts of SMT interrelate for different symptoms or symptom clusters in light of the current state of knowledge. Furthermore, a selection of symptom assessment scales available in French are presented to inform practice, education and research. We believe that providing a French version of the SMT will foster a systematic and structured development of symptom management in nursing practice and research in francophone regions or countries. PMID- 23671984 TI - [Analysis of qualitative data collection methods used in adolescent research]. AB - INTRODUCTION: There has been remarkable growth in research on adolescents in the last decade, particularly in nursing science. OBJECTIVE: The goal of this article is to produce a synthesis of findings justifying the use of qualitative methods in collecting data from adolescents. METHOD: A literature review identified relevant articles (N : 27) from digital databases. FINDINGS: While the studies done on adolescents were on different topics, the data collection methods were often similar. Most of the studies used more than one technique to reconcile scientific rigour and the way the adolescents expressed themselves. In order to understand a phenomenon, its context and the meaning given to the experience proved essential. CONCLUSION: In qualitative research on adolescents, it is important to use data collection methods that make it possible to clearly target the experience explored and to orient and guide the individual in deepening that experience in order to favour the emergence of his or her point of view. Data collection methods based on written communication have to be complemented with other methods more focused on oral communication so as to draw out interpretations reflecting adolescents' points of view as accurately as possible. PMID- 23671985 TI - [A tool to evaluate hospital nursing practices toward smoking cessation]. AB - Nurses in hospitals are not active in smoking cessation because of certain beliefs and attitudes. Beliefs and attitudes must be measured for changing practice in quitting smoking. The objective is to develop and validate a questionnaire on smoking cessation practices of nurses in hospitals. METHODOLOGY: A methodological study was conducted to construct a questionnaire (n = 118) according to the theory of planned behaviour, to validate by four experts, for reliability and validation of instruments constructs (n = 38; n = 29; n = 157). RESULTS: An initial questionnaire on practices in smoking cessation was built according to the beliefs of a convenience sample of 118 nurses. Validation of experts was conducted, and the questionnaire obtained an index of content validation (ICV) of 0.94. Subsequently, after two convenience samples (n = 38; n = 29) and a random sample (n = 157), the questionnaire obtained reliability, measured by Cronbach's alpha ranging in 0.697 and 0.93 1. Finally, moderately high correlations (0.406 to 0.569) were obtained between concepts. CONCLUSION: A reliable and valid questionnaire in French is available to measure smoking cessation practices. PMID- 23671986 TI - [Pain perception in the vegetative state: current status and critical reflections]. AB - INTRODUCTION: According to experts, vegetative state (VS) patients are unable to perceive pain. BACKGROUND: Still, a large portion of nurses believe that VS patients can perceive pain and are uncomfortable when pain is not treated. AIM: To identify the criteria used in clinical practice and in research to detect the presence or the absence of conscious perception of pain in VS patients. PROCEDURE: An integrative review exploring MEDLINE, CINAHL and Cochrane's data bank was conducted. RESULTS: A total of 4 clinical articles and 7 empirical studies were included. According to them, patients in VS may exhibit reflexes (ex : closing fists) when exposed to an external stimulation such as a painful stimuli or a verbal command. However, no voluntary reaction such as localisation of the painful stimuli should be observed in VS patients otherwise the diagnosis should be questioned. When exposed to an external stimulation, use of functional neuroimaging techniques (fMRI or PET scan) in VS patients can be used to detect brain activation in the primary cortical areas, the associative cortical areas, and also in the connections between the two. Those techniques may allow the identification of objective signs of consciousness that were not detected at the bedside. DISCUSSION: Assessment of behavioural reactions is complex and greatly subjective in VS patients. The role of the associative areas in the process of pain perception is still poorly understood. CONCLUSION: Because of this incomplete picture of pain perception in VS patients, many experts recommend the prophylactic treatment on pain in this population. PMID- 23671987 TI - [Good palliative care in the intensive care unit]. AB - The aging population, the complexity and irreversibility of certain conditions lead to the deaths of 20% of patients admitted to intensive care units (ICU). However, in Quebec, as elsewhere in America, few of them currently receive palliative care. METHOD: inspired by a conceptual model considering nursing as a moral practice, this phenomenological study was conducted in four phases: focus groups (n = 6) observation sessions (n = 6) followed by individual interviews and group validation activities (n = 5). In its first part, this study shows that through several caring behaviours, "good palliative care" in the ICU is manifested by the consideration of six dimensions of the person, physical, relational, psychological, moral, social and spiritual. This article presents the second part of this study and reveals three main themes summarizing the conditions facilitating "good the palliative care" according to ICU nurses: Sharing a common vision enhanced by a collective and specific palliative care knowledge, an informed and concerted decision-making process in a favourable organisational and physical environment. PMID- 23671988 TI - [The development of clinical reasoning skills and leadership: personal factors and organizational factors]. AB - Continuing education of newly graduated nurses (NGN) depends on several factors related to the characteristics of skills to be developed, the target population and the organizational context. Few studies describe both how nurses develop their skills and how institutions promote this development. The objectives of this manuscript are to (1) describe the behaviors that the NGN use to develop their reasoning skills and leadership and (2) document the organizational elements that facilitate this development. Method. Individual interviews were conducted with nurses (n = 34) using a grid of semistructured interviews and two group interviews were conducted with nurses (n = 7) and managers (n = 19) in two teaching hospitals in eastern Canada. The results show that nurses develop mainly by reflecting on their professional practice in their workplace. However, the lack of time for reflection in the workspace is a considerable obstacle while managerial leadership is an important asset. PMID- 23671989 TI - [Project evaluation of nursing interventions: an algorithm to support the practice of clinicians]. AB - It is recognized that nurses regularly have to adapt their clinical practice compared to new scientific breakthroughs. However, changes in practice are possible by the implementation of clinical projects but can sometimes be long and difficult to achieve in health care settings, given the context of care or the profile of the clientele, the care organization, work organization, etc. An algorithmic approach (i.e., sequence of actions) to support nurses in the evaluation of new nursing intervention projects, including other members of the interdisciplinary team, researchers, and patients and their relatives, has been developed. This algorithm considers the clinical environment in which the project will operationalize nursing interventions and involves five steps: 1) identification and description of a care problem to solve or a care practice to improve; 2) the development or adaptation of appropriate nursing intervention, and 3) the choice of evaluation design for this nursing intervention, and 4) testing of the intervention and 5) implementation and reflection on the process. PMID- 23671990 TI - [An evolutionary analysis of the concept of self-care]. AB - The nursing community seems to agree on the general meaning of "self-care" as a concept allowing the individual to take care of his health. Yet the terms self care and other "self-concepts" are often used interchangeably. Since this concept is central to nursing, it appeared crucial to lead an effort to clarify and to deepen the understanding of its development within the field of nursing. The objective of this evolutionary concept analysis was to identify the state of precision or clarity of the concept in the available nursing literature. The identification of attributes, antecedents and consequences has highlighted the characteristics as it has been used by various authors and ultimately provides a basis for further research. After this analysis, it is possible to propose that the concept of self-care refers to an activity initiated, consciously and following learning, which is appropriate to the situation and focused on a goal. Furthermore, this concept is widely used in contexts of long-term illnesses and much less so in contexts of acute diseases. In conclusion, work remains to be done to better differentiate the concept of self-care from other self-concepts when used in situations where a third party is involved in the realization of self-care. PMID- 23671991 TI - [Contract learning: effects of professionalization on the student nurse]. AB - The reengineering of nurse training implies the implementation of self development, empowering tools and a reshaping of the function of accompaniment during training which becomes a shared function. This work is part of a psycho socio-educational approach of the accompaniment to self-directed learning and also in the field of practices of health and social work. This study contributes to the identification of the conditions of efficiency of contracting between student nurses, tutors and instructors. It aims to explore the interest of a triangular steering of the learning contract centered on the student's individual project and also the interest of meetings during training as triggers to a process of self-construction of competences. Moreover, the study aims to identify the effects of contract on professionalization. Our study reverts to the basic question of learning by contract as a pillar for the self-directed learning in an alternating training context. The empirical approach takes into account a qualitative study carried out with 15 people (tutors, managers, student nurses and instructors) in 3 health care structures and a quantitative study based on 78 first year students, 106 second year students, and 47 third year students at the same nursing education institute. The study shows that learning by contract is empowering and professionalizing, if the student is placed in favorable conditions of learning and contractual relationship. PMID- 23671992 TI - [Progress of studies in 20-hydroxyeicosatetraenoic acid on vascular endothelium]. AB - 20-Hydroxyeicosatetraenoic acid (20-HETE) is an important metabolite of cytochrome P-450 pathway of arachidonic acid (AA). It has been demonstrated recently that 20-HETE played a significant role in physiology and pathophysiology process of vascular endothelium (EC). 20-HETE exerted oxidative stress and pro inflammation effect through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system and nuclear factor-kappaB (NF-kappaB) pathway; it took part in the modulation of vascular dilation and constriction by mediating dissociation of endothelial nitric oxide synthase (eNOS) and inducing angiotensin converting enzyme in EC; it also promoted the proliferation of EC and angiogenesis. However, the domestic study about 20-HETE is rare. Therefore, the present paper reviewed the recent international studies of 20-HETE on EC. PMID- 23671993 TI - [Aging and aging intervention by coloric restriction in nonhuman primate rhesus monkeys]. AB - Nonhuman primate rhesus monkey is a ideal model for human aging and aging intervention. Same with human aging, rehesus monkey demonstrates age-related aging and diseases in endocrine, neural, immune and cardiovascular system. Coloric restriction can slow down the primary and secondry aging efficently. The mechanism may be to suppress the oxidative stress-inflammaging-DNA damage by mediating the nutrient sensitive metablic signal pathways, and activate damaged DNA repair. However, the differeces of study design, husbandry and diet composition may differently affect CR against the the primary and secondry effects in a long-lived nonhuman primate. Optimization in protocol design, control of the experimetal variables, and shortening the experimental period will be advantageous to understand the mechanistic questions about the anti-aging effects of CR. PMID- 23671994 TI - [The research applications of db/db mouse]. AB - The db/db mice are perfect animal models of type 2 diabetes which have been widely used. The phenotypes of severe obesity, hyperphagia, polydipsia, and polyuria are due to a spontaneous mutation of the leptin receptor (Lepr). The course of the disease is markedly influenced by genetic background, which is more serious in the C57BLKS/J background. And there are many other spontaneous mutations in different sites of Lepr, which produce a series of animal models of obesity, including db(3J)/ db(3J) mice, db(5j)/db(5J) mice, db(pas)/db(pas) mice, Zucker fa/fa rats, and Koletsky fa(k)/fa(k) rats, etc. These rodents appear similar hyperphagia and severe obesity, but different levels of blood glucose, kidney damage and reproductive ability, providing profuse material to investigate the complex function of Lepr. Here we review the history of the discovery of the leptin signaling pathway, the abnormal phenotypes of db/db mice in metabolic, reproductive, immune, etc. Discuss their research applications, reproductive strategy, genotyping guideline, the phenotypic diversity of those animal models with Lepr spontaneous mutation and their mutation patterns, respectively. PMID- 23671995 TI - [The latest research progress on FAM3 gene family]. PMID- 23671996 TI - [Research progress of molecular mechanisms on cardiac remodeling]. PMID- 23671997 TI - [The miRNAs regulating vascular smooth muscle cell function and cardiovascular diseases]. PMID- 23671998 TI - [Pathophysiological roles of calreticulin in endothelial cell associated diseases]. PMID- 23671999 TI - [Advance of microRNA during early development of mammalian]. PMID- 23672000 TI - [The neuroprotective effect and mechanisms of Apelin/APJ system]. PMID- 23672001 TI - [Progress in dermis mesenehymal stem cells]. PMID- 23672002 TI - [The research development of Ghrelin and pain]. PMID- 23672003 TI - [Prohibitin function and molecular mechanisms in cancer]. PMID- 23672004 TI - [Molecular mechanisms of SENPs in regulating tumor progression]. PMID- 23672005 TI - [The regulation effect of PGC-1alpha on skeletal muscle fiber type and exercise performance]. PMID- 23672006 TI - [Gastric hormones and glucose metabolism in skeletal muscle]. PMID- 23672007 TI - [The cytoprotective mechanisms of CIRP upon stresses]. PMID- 23672008 TI - [The regulation of VEGFs/VEGFRs in tumor angiogenesis by Wnt/beta-catenin and NF kappaB signal pathway]. PMID- 23672009 TI - [G protein coupled recepters and signal transduction--introduction to the 2012 Nobel prize in chemistry]. PMID- 23672010 TI - [Synthetic biology toward microbial secondary metabolites and pharmaceuticals]. AB - Microbial secondary metabolites are one of the major sources of anti-bacterial, anti-fungal, antitumor, anti-virus and immunosuppressive agents for clinical use. Present challenges in microbial pharmaceutical development are the discovery of novel secondary metabolites with significant biological activities, improving the fermentation titers of industrial microbial strains, and production of natural product drugs by re-establishing their biosynthetic pathways in suitable microbial hosts. Synthetic biology, which is developed from systematic biology and metabolic engineering, provides a significant driving force for microbial pharmaceutical development. The review describes the major applications of synthetic biology in novel microbial secondary metabolite discovery, improved production of known secondary metabolites and the production of some natural drugs in genetically modified or reconstructed model microorganisms. PMID- 23672011 TI - [Research progress in aromatic prenyltransferases originated from microorganisms]. AB - The prenylation of aromatic compounds plays an important role in the natural product research because it not only gives rise to an astounding diversity of primary and secondary metabolites in plants, fungi and bacteria but also enhances the bioactivities and bioavailabilities of these compounds. However, further investigation of prenylated aromatic compounds is frequently hindered due to their low content in nature and difficulties in chemical synthesis. Cloning aromatic prenyltransferase genes followed by heterologous expression would be attractive tools for the chemoenzymatic synthesis of bioactive molecules. This review summarizes the classifications, structural investigations, enzymatic catalysis and other progress in aromatic prenyltransferases originated from microorganisms. PMID- 23672012 TI - [Advances in the biosynthesis research of ginsenosides]. AB - Ginsenosides are the main active components of medicinal herbs including Panax ginseng and Panax quinquefolium, which have potent effects of anti-tumor, anti inflammatory, antioxidant and apoptosis inhibition. But the low content of ginsenosides limits its development and usage. At present, how to improve the production of ginsenosides by biological technology has been a new research focus. Some advances in the biosynthesis of ginsenosides by tissue culture and biotransformation have been made in recent years. So far at least twenty genes related to the biosynthesis of ginsenosides from Panax genus plants have been cloned and functionally identified, which has laid a good foundation for the study on the synthetic biology of ginsenosides. This review outlines recent advances in several aspects and is expected to provide a theoretical support to the thorough research of the pathway and regulation of ginsenosides biosynthesis. PMID- 23672013 TI - [Glycosyl isomerization based on the biosynthesis of natural-product sugar from microorganism]. AB - Glycosylation, one of the most common and important reactions in biological systems, results in diverse functions and is often found in biologically active small-molecule natural products produced by microorganisms. Furthermore, sugar moieties are generally critical for their activities. Alternating the sugar structures thus provides the potentials for enhancing the biological activities of natural products, which evokes researchers to study the sugar biosynthetic machinery and its application in the modification of sugar moieties with an aim of generating unnaturally glycosylated natural product drugs with better activities. This review will briefly outline current studies on sugar biosynthesis and glycosyltransferase, with a few selected experiments designed to alter natural-product sugar structures. PMID- 23672014 TI - [The advance in synthetic biology: towards a microbe-derived paclitaxel intermediates]. AB - The synthetic biology matures to promote the heterologous biosynthesis of the well-known drug paclitaxel that is one of the most important and active chemotherapeutic agents for the first-line clinical treatment of cancer. This review focuses on the construction and regulation of the biosynthetic pathway of paclitaxel intermediates in both Escherichia coli and Saccharomyces cerevisiae. In particular, the review also features the early efforts to design and overproduce taxadiene and the bottleneck of scale fermentation for producing the intermediates. PMID- 23672015 TI - [Research progresses in synthetic biology of artemisinin]. AB - Abstract: The first-line drug artemisinin is widely used against malaria. Commercially available artemisinin is extracted from plants. However, the lack of sufficient raw material, artemisinin and the cost associated with the drug's manufacture have limited the supply of ACT to most malaria sufferers in the Developing World. As such, it is important to develop a low cost, fine to environment and high-quality method to supply sufficient and reliable quantities of artemisinin in the future. The field of synthetic biology, which utilizes cell factories to manipulate microbial metabolism to enhance the production of artemisinin and its intermediates, has a particularly strong impact by providing new platforms for chemical production. After a brief introduction of the artemisinin biosynthetic pathway, the present review focuses on the introduction of artemisinin biosynthetic genes, such as the genes encoding amorpha-4, 11-diene monooxygenase, NADPH: cytochrome P450 oxidoreductase, artemisinic aldehyde delta 11(13) reductase and aldehyde dehydrogenase. The review also addresses general considerations for potential contributions of synthetic biology to artemisinin production, with an emphasis on factors influencing interest compounds production in chassis cells. PMID- 23672016 TI - [Construction of the coexpression vector containing key element GLCYP450 involved in Ganoderma triterpene biosynthesis and its reductase gene GLNADPH]. AB - Cytochrome P450 (CYP450) is a key element in the Ganoderma triterpenoid biosynthetic pathway. The catalytic reaction process for CYP450 requires NADPH / NADH for electron transfer. After searching the genome dataset of Ganoderma lucidum, the unique sequence encoding CYP450 and NADPH were discovered, separately. The open reading frames of GLCYP450 and GLNADPH were cloned separately using RT-PCR strategy from G lucidum. The appropriate restriction enzyme cutting sites were introduced at the 5' and 3' ends of gene sequence. The genes of GLCYP450 and GLNADPH were recombined into the yeast expression vector pESC-URA, leading to the formation of the yeast expression plasmid pESC-GLNADPH GLCYP450. This study provides a foundation for researching Ganoderma triterpene biosynthesis using the approach of synthetic biology. PMID- 23672017 TI - [Development of the devices for synthetic biology of triterpene saponins at an early stage: cloning and expression profiling of squalene epoxidase genes in panax notoginseng]. AB - Synthetic biology of traditional Chinese medicine (TCM) is a new and developing subject based on the research of secondary metabolite biosynthesis for nature products. The early development of synthetic biology focused on the screening and modification of parts or devices, and establishment of standardized device libraries. Panax notoginseng (Burk.) F.H.Chen is one of the most famous medicinal plants in Panax species. Triterpene saponins have important pharmacological activities in P. notoginseng. Squalene epoxidase (SE) has been considered as a key rate-limiting enzyme in biosynthetic pathways of triterpene saponins and phytosterols. SE acts as one of necessary devices for biosynthesis of triterpene saponins and phytosterols in vitro via synthetic biology approach. Here we cloned two genes encoding squalene epoxidase (PnSE1 and PnSE2) and analyzed the predict amino acid sequences by bioinformatic analysis. Further, we detected the gene expression profiling in different organs and the expression level of SEs in leaves elicited by methyl jasmonate (MeJA) treatment in 4-year-old P notoginseng using real-time quantitative PCR (real-time PCR). The study will provide a foundation for discovery and modification of devices in previous research by TCM synthetic biology. PnSE1 and PnSE2 encoded predicted proteins of 537 and 545 amino acids, respectively. Two amino acid sequences predicted from PnSEs shared strong similarity (79%), but were highly divergent in N-terminal regions (the first 70 amino acids). The genes expression profiling detected by real-time PCR, PnSE1 mRNA abundantly accumulated in all organs, especially in flower. PnSE2 was only weakly expressed and preferentially in flower. MeJA treatment enhanced the accumulation of PnSEI mRNA expression level in leaves, while there is no obvious enhancement of PnSE2 in same condition. Results indicated that the gene expressions of PnSE1 and PnSE2 were differently transcribed in four organs, and two PnSEs differently responded to MeJA stimuli. It was strongly suggested that PnSEs play different roles in secondary metabolite biosynthesis in P. notoginseng. PnSE1 might be involved in triterpenoid biosynthesis and PnSE2 might be involved in phytosterol biosynthesis. PMID- 23672018 TI - [Cloning and expression analysis of a key device of HMGR gene involved in ginsenoside biosynthesis of Panax ginseng via synthetic biology approach]. AB - 3-Hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR), the first enzyme of mavalonic acid pathway, is one of the key devices involved in ginsenoside biosynthesis based on synthetic biology approach. The open reading frame of a novel HMGR gene from Panax ginseng (PgHMGR2) was cloned and analyzed in this study. PgHMGR2-encoding protein showed 71.6% sequence similarity to a P. ginseng HMGR in GenBank. The full-length cDNA sequence of PgHMGR2 containing 1 770 bp, which encodes 589 amino acids, was cloned by RT-PCR strategy from P. ginseng. The bioinformatic analysis showed that PgHMGR2-encoding protein contained two transmembrane regions and the HMG_CoA_reductase domain, without signal peptide. The protein sequence of PgHMGR2 had the highest sequence similarity (99%) with Panax quinquefolius HMGR (GenBank accession No. ACV65036). The expression level of PgHMGR2 was the highest in flower based on a real-time PCR analysis, followed by leaf and root, and the lowest was in stem. The result will provide a foundation for exploring the molecular function of PgHMGR2 involved in ginsenoside biosynthesis based on synthetic biology approach in P. ginseng plants. PMID- 23672019 TI - [Construction and preliminary applications of a Saccharomyces cerevisiae detection plasmid using for screening promoter elements]. AB - Synthetic biology of natural products is the design and construction of new biological systems by transferring a metabolic pathway of interest products into a chassis. Large-scale production of natural products is achieved by coordinate expression of multiple genes involved in genetic pathway of desired products. Promoters are cis-elements and play important roles in the balance of the metabolic pathways controlled by multiple genes by regulating gene expression. A detection plasmid of Saccharomyces cerevisiae was constructed based on DsRed Monomer gene encoding for a red fluorescent protein. This plasmid was used for screening the efficient promoters applying for multiple gene-controlled pathways. First of all, eight pairs of primers specific to DsRed-Monomer gene were synthesized. The rapid cloning of DsRed-Monomer gene was performed based on step by-step extension of a short region of the gene through a series of PCR reactions. All cloned sequences were confirmed by DNA sequencing. A vector named pEASYDs-M containing full-length DsRed-Monomer gene was constructed and was used as the template for the construction of S. cerevisiae expression vector named for pYeDP60-Ds-M. pYeDP60-Ds-M was then transformed into S. cerevisiae for heterologous expression of DsRed-Monomer gene. SDS-PAGE, Western blot and fluorescence microscopy results showed that the recombinant DsRed-Monomer protein was expressed successfully in S. cerevisiae. The well-characterized DsRed-Monomer gene was then cloned into a yeast expression vector pGBT9 to obtain a promoter detection plasmid pGBT9Red. For determination efficacy of pGBT9Red, six promoters (including four inducible promoters and two constitutive promoters) were cloned by PCR from the S. cerevisiae genome, and cloned into pGBT9Red by placing upstream of DsRed-Monomer gene, separately. The fluorescence microscopy results indicated that the six promoters (GAL1, GAL2, GAL7, GAL10, TEF2 and PGK1) can regulate the expression of DsRed-Monomer gene. The successful construction of pGBT9Red lays the foundation for further analysis of promoter activity and screening of promoter element libraries. PMID- 23672020 TI - [Cloning and induced expression analysis of 4-hydroxy-3-methyl-but-2-enyl diphosphate reductase gene (smHDR) of Salvia miltiorrhiza]. AB - This study reported the obtainment of the full-length cDNA of Salvia miltiorrhiza hairy roots (Abbr: SmHDR, GenBank number: JX233817), via extracting Salvia miltiorrhiza hairy roots total RNA, designing specific primers according to the transcriptome data and using the RACE strategy, and then analyzed it with bioinformatics approaches. On this basis, using the real-time PCR to detect SmHDR gene expression after Ag+ induction, and testing tanshinones contents of corresponding samples by UPLC. SmHDR has 1 647 nucleotides, and an open reading frame (ORF) encoding a protein of 463 amino acid residues. The deduced protein has isoelectric point (pI) of 5.72 and a calculated molecular weight about 51.88 kD. In the secondary structure, the percentage of alpha helix, beta turn and random coil were 35.64%, 20.30% and 44.06%, respectively. Sequence alignment and phylogenetic analysis demonstrated that SmHDR had relative close relationship to the HDR of Picrorhiza kurrooa, similar to HDR from other species of plants. Real time PCR results indicated that elicitor of Ag+ stimulated the increase of mRNA expression of SmHDR. At the same time, results of ultra performance liquid chromatography (UPLC), used to examine the accumulation of diterpenoid tanshinones in hairy roots, showed that the contents of diterpenoid tanshinones in hairy roots of Salvia miltiorrhiza were increased dramatically at 12 h after treated with Ag+, and then decreased significantly. This result showed a positive correlation between the levels of mRNA expression and tanshinones accumulation in Salvia miltiorrhiza stimulated by Ag+. The content of tanshinones was gradually raised, and it had an obvious increase at 120 h. The bioinformatics analysis and gene expression indicated that SmHDR might be involved in tanshinones biosynthesis, which laid the foundation for further study of secondary metabolic regulation mechanism of tanshinones. PMID- 23672021 TI - [Enhancement of tropane alkaloids production in transgenic hair roots of Atropa belladonna by overexpressing endogenous genes AbPMT and AbH6H]. AB - Atropa belladonna L. is the officially medicinal plant species and the main commercial source of scopolamine and hyoscyamine in China. In this study, we reported the simultaneous overexpression of two functional genes involved in biosynthesis of scopolamine, which respectively encoded the upstream key enzyme putrescine N-methyltransferase (PMT; EC 2.1.1.53) and the downstream key enzyme hyoscyamine 6beta-hydroxylase (H6H; EC 1.14.11.11) in transgenic hair root cultures of Atropa belladonna L. HPLC results suggested that four transgenic hair root lines produced higher content of scopolamine at different levels compared with nontransgenic hair root cultures. And scopolamine content increased to 8.2 fold in transgenic line PH2 compared with that of control line; and the other four transgenic lines showed an increase of scopolamine compared with the control. Two of the transgenic hair root lines produced higher levels of tropane alkaloids, and the content increased to 2.7 fold in transgenic line PH2 compared with the control. The gene expression profile indicated that both PMT and H6H expressed at a different levels in different transgenic hair root lines, which would be helpful for biosynthesis of scopolamine. Our studies suggested that overexpression of A. belladonna endogenous genes PMT and H6H could enhance tropane alkaloid biosynthesis. PMID- 23672022 TI - [Cloning and bioinformatic analysis of TAGLN2 cDNA of Bufo japonicus formosus]. AB - To study the bioactive polypeptides included in Bufo skin and its secretions the plasmid skin cDNA library of adult Japanese toad Bufo japonicus formosus was prepared. The pSD64TR has been used as the vector and the cloning sites are Xho I and EcoR I. To screen cDNAs encoding bioactive components, the plasmid cDNA library was transformed into E. coli DH5 competent cells, and positive colonies were screened by colony PCR (polymerase chain reaction). The suspension of a single colony in LB medium was used as the template, SP6 (the upstream primer of the plasmid cDNA library) and a primer with Xho I site and polyT were used as the primers. As the result, 465 positive colonies out of 1 344 were obtained and their plasmid were collected and sequenced. By homologous analysis, it was found that one of the cDNAs encoding a peptide with high homolog with transgelin-2, which was registered in GenBank (accession number: JX197456), and it was indicated as a partial cDNA sequence with a deletion at the 5' end. The transcript is 997 bp consisting of 31 bp 5', 618 bp 3' untranslated region (UTR) and an open reading frame (ORF) of 348 bp encoding a polypeptide of 115 amino acids. In the putative protein product, there is a calponin homology domain, two cysteine residues for a disulfide bond and three a-helix domains, and five potential phosphorylation sites. The homologous analysis indicates 90% similarity with Xenopus (Silurana) tropicalis and 89% with Xenopus laevis, and 71%-85% with other species. PMID- 23672023 TI - [Establishment of zebrafish osteopenia model induced by dexamethasone]. AB - Zebrafish was selected as model animal, and glucocorticoid dexamethasone was used as a model compound to establish a rapid and high efficient osteopenia model. Zebrafish larvae at 4 days post fertilization (dpf) were exposed to a serial concentrations of dexamethasone solutions, and 0.5% DMSO was selected as the vehicle control group. All groups were incubated in 24-well plates (28.5 degrees C) until 9 dpf. In addition, effects of 10 micromol x L(-1) dexamethasone on preventing against osteopenia induced by etidronate disodium were also investigated. Zebrafish bones at 9 dpf were stained with alizarin red. Quantitative analysis of the stained area was performed by microscopic inspection and digital imaging methods to reflect the amount of bone mineralization. Results showed that dexamethasone group at 2.5, 10 and 25 micromol x L(-1) can decrease the staining area and the staining optical density values of zebrafish head bones when compared with the vehicle control group (0.5% DMSO), which suggested that dexamethasone can significantly reduce the zebrafish mineralized bone and the bone mineral density. Results also showed that 15 and 30 microg x mL(-1) etidronate disodium can increase the mineralized matrix of zebrafish head bone and prevent against osteopenia induced by dexamethasone. In conclusion, the study indicated that zebrafish can be an idea osteopenia model induced by dexamethasone. PMID- 23672024 TI - [Antitumor activity of the recombinant rClone30-CD/5-FC system]. AB - 5-Flucytosine (5-FC) could be changed to 5-fluorouracil (5-FU) by cytosine deaminase (CD), the latter is able to kill cancer cells. However, there is no efficient method to deliver the CD gene into the tumor cells, which hampers the application of the suicide gene system. In this experiment, for the first time, the NDV has been utilized as a vector to deliver the CD gene into the cancer cells, the virus can infect the cancer cells specifically, replicate and assemble, while the cytosine deaminase is expressed. Then the CD converts the prodrug 5-FC into 5-FU to achieve the purpose of inhibiting tumor. Firstly, the whole genome of E. coli JM109 was extracted, and the CD gene was obtained by cloning method. Then the CD and IRES-EGFP were ligated into the pEE12.4 expression vector to become a recombinant pEE12.4IE-CD eukaryotic expression plasmid. The human liver cancer cells were transfected with the plasmid. The cells were treated with different concentrations of 5-FC, MTT method was used to determine the killing effect of CD/5-FC system on the human liver cancer cells. The cell deaths were 18.07%, 42.98% and 62.20% respectively when the concentrations of prodrug were at 10, 20 and 30 mmol x L(-1). In 5-FC acute toxicity experiment, Kunming mice were injected with different concentrations of 5-FC at intervals of 1:0.5. The LD50 of 5-FC through iv injection was determined by improved Karber's method, the LD50 was 507 mg x kg(-1) and the 95% confidence limit was 374-695 mg x kg(-1). According to the maximum LD0 dose of the LD50, the maximum safe dose was 200 mg x kg(-1). Body weight and clinic symptoms of the experimental animals were observed. These results laid the foundation to verify the antitumor effect and safety of CD/5-FC system in animal models. The CD gene was ligated into the NDV (rClone30) carrier, then the tumor-bearing animal was established to perform the tumor inhibiting experiment. The result showed that the recombinant rClone30-CD/5-FC system has a high antitumor activity in vivo. To summarize, CD gene has been cloned and its bioactivity has been confirmed in the mammalian cells. It is the first time in this study to utilize the recombinant NDV to deliver the CD gene into the tumor cells; our result proves the rClone30 CD/5-FC system is a potential method for cancer therapy. PMID- 23672025 TI - [Design, synthesis and cholinesterase inhibitory activity of quinoline-polyamine conjugates]. AB - A series of quinoline-polyamine conjugates (8a-8n) were designed, synthesized and evaluated as inhibitors of cholinesterases (ChEs). Some of these compounds had potent ChEs inhibitory activity with IC50 values at micromolar range. Compound 8n exhibited the strongest inhibition on acetylcholinesterase (AChE) with an IC50 value of 8.78 micromol x L(-1), and compound 8i showed the most potent inhibition on butyrylcholinesterase (BChE) with IC50 value of 1.60 micromol x L(-1) which was slightly better than rivastigmine. The structure-activity relationship revealed that the chain length of polyamine and linker played important roles for inhibitory activity. Molecular modeling studies showed that 8i targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of cholinesterases. PMID- 23672026 TI - [Chemical constituents of Nauclea officinalis]. AB - In order to study the chemical constituents in the water extract of the stem of Nauclea officinalis, column chromatography over D101 macroporous resin and silica gel and an automatic purification system were used to isolate and purify the chemical constituents from the extract. Nine compounds were obtained. By analysis of the physicochemical properties and spectral data, their structures were identified as naucleamide G (1), 3, 4-dimethoxyphenol-beta-D-apiofuranosyl (1- >6)-beta-D-glucopyranoside (2), kelampayoside A (3), 3alpha, 5alpha tetrahydrodeoxycordifoline lactam (4), naucleamide A-10-O-beta-D-glucopyranoside (5), pumiloside (6), 3-epi-pumiloside (7), strictosamide (8) and vincosamide (9), separately. Among them, compound 1 is a new compound, compound 2 was found in plants of the genus Nauclea for the first time, and compounds 3 and 4 were isolated from this plant for the first time. PMID- 23672027 TI - [Metabolism study of asperosaponin VI by using zebrafish]. AB - Model organism zebrafish was used to study metabolism of asperosaponin VI from Dipsacus asper Wall. ex Henry for the first time. Metabolic components of asperosaponin VI after exposing to zebrafish for 24 h were identified by high performance liquid chromatography--electrospray mass spectrometry (HPLC-ESI-MS), the separation was performed with a Zorbax C18 column using a binary gradient elution of 0.05% formic acetonitrile--0.05% formic acid water. The quasi molecular ions of compounds in both negative and positive mode were observed for molecule mass information, and the potential structures were identified by attentive study on the deglycosylation metabolites and one hydroxylation metabolite of asperosaponin VI. The results were highly in consistent with metabolism of asperosaponin VI in rat. It can be concluded that zebrafish model can wonderfully imitate current metabolic model with advantages of small amount of lower cost, far less amount compound, higher efficiency and more simple, and can reflect integrated metabolism results of in vivo method. Zebrafish metabolic model may become a novel organism model for quick predication on metabolism of even mircoamount compound, which can enrich the available models greatly. PMID- 23672028 TI - [Rationality of the processing methods of aconiti lateralis radix (Fuzi) based on chemical analysis]. AB - In this study, we explored the rationality of processing methods and mechanism of Aconiti Lateralis Radix (Fuzi) through comparing the chemical contents of diester alkaloids (DAs) and monoester alkaloids (MAs) in the raw material of Fuzi and its processed products. The results showed that the toxicity potency of MAs is at least lower than 1/64 to 1/180 of the toxicity potency of DAs. The contents of DAs in processed Fuzi decreased to 1/76.5 to 1/38.3 of the value of raw Fuzi. The contents of MAs in processed Fuzi significantly increased by 4.6 to 5.2 fold or basically the same as that of the raw Fuzi. The values of MAs/DAs of processed Fuzi were enhanced by 30 to 390 fold of the raw Fuzi. It was found that the contents of DAs were insignificantly different between "Wu dan fu pian" (steaming or stir-frying without Danba) and "Dan fu pian" (steaming or stir-frying with Danba). The result suggested that the abilities of "eliminating toxicity" of different processing methods were equivalent at all. In contrast, the contents of MAs contained in "Wu dan fu pian" were of 5.3 to 8.7 fold higher than the values in "Dan fu pian". This result suggested the processing method by steaming or stir frying without Danba might have better effect for "conserving property" than the method processed with Danba stipulated by China Pharmacopoeia. We believe that the new processing method without Danba can be recommended in further application due to it offers a simple procedure and it will not introduce inorganic impurities in the products. PMID- 23672029 TI - [Preliminary study on pH-sensitive lipid bilayer-coated mesoporous silica nanoparticles as a novel drug carrier for antitumor drug]. AB - This study plans to prepare lipid bilayer-coated mesoporous silica nanoparticles (LMSNs) which are pH sensitive with core-shell structure to improve the tumor cell lethality of antitumor drug. The lipid coated mesoporous silica nanoparticles loaded with irinotecan (CPT-11) (CPT-11-LMSNs) were prepared by hot water-film hydration method, and the characterized its morphology, particle size and release in vitro. Meanwhile, the intracellular uptake and cell toxicity of CPT-11-LMSNs and intracellular accumulation of CPT-11 were evaluated on human breast carcinoma cell line (MCF-7). The results indicated that the mean diameter of the spherical LMSNs was (120.27 +/- 5.91) nm. The slow release in simulated normal physiological conditions and a rapid release under simulated intracellular condition demonstrated the pH sensitivity of CPT-11-MSNs in vitro. Moreover, the CPT-11-LMSN could improve the intracellular CPT-11 cumulant 2.1 times and reduce half maximal inhibitory concentration (IC50) values of CPT-11 1.4 times compared with CPT-11-MSNs, demonstrating a stronger cell lethality. PMID- 23672030 TI - [Preparation and in vitro evaluation of pDNA-CaPi-PLGA nanoparticles with a core shell structure]. AB - To develop a core-shell structure pDNA-CaPi-PLGA nanoparticles (CS-pDNA-CaPi-PLGA NPs), calcium phosphate-pDNA nano complexes (CaPi-pDNA) were encapsulated inside of PLGA shells. The characteristics of the nanoparticles, including morphology, average particle size, zeta potential, entrapment efficiency, loading efficiency, stability in medium, pDNA protection ability from nuclease degradation, in vitro release, cytotoxicity and cell transfection were investigated and compared with the embedded structured CaPi modified PLGA nanoparticles (embedded-pDNA-CaPi-PLGA NPs). The results showed that the obtained CS-pDNA-CaPi-PLGA-NPs were spherical in shape with an average particle size of (155 +/- 4.5) nm, zeta potentials of ( 0.38 +/- 0.1) mV, entrapment efficiency of (80.56 +/- 2.5)% and loading efficiency of (1.16 +/- 0.04)%. The CS-pDNA-CaPi-PLGA-NPs were stable in the release media and could protect pDNA against nuclease degradation. And they also exhibited sustained release of pDNA in vitro. The highest gene transfection efficiency of the CS-pDNA-CaPi-PLGA-NPs in vitro reached (24.66 +/- 0.46)% (after 72 h transfection), which was significantly higher than that of free pDNA [(0.33 +/- 0.04)%, P < 0.01] and the pDNA-PLGA-NPs [(1.5 +/- 0.07)%, P < 0.01]. Besides, the transfection lasted for longer time than that of embedded-pDNA-CaPi-PLGA-NPs and the cytotoxicity of it was significantly lower than that of PEI (P < 0.01). These results indicate that CS-pDNA-CaPi-PLGA-NPs are a promising non-viral gene vector. Key words: gene delivery system; polylactic-co-glycolic acid; calcium phosphate; nanoparticle PMID- 23672031 TI - [Principles for molecular identification of traditional Chinese materia medica using DNA barcoding]. AB - Since the research of molecular identification of Chinese Materia Medica (CMM) using DNA barcode is rapidly developing and popularizing, the principle of this method is approved to be listed in the Supplement of the Pharmacopoeia of the People's Republic of China. Based on the study on comprehensive samples, the DNA barcoding systems have been established to identify CMM, i.e. ITS2 as a core barcode and psbA-trnH as a complementary locus for identification of planta medica, and COI as a core barcode and ITS2 as a complementary locus for identification of animal medica. This article introduced the principle of molecular identification of CMM using DNA barcoding and its drafting instructions. Furthermore, its application perspective was discussed. PMID- 23672032 TI - [Cloning and bioinformatics analysis of chalcone synthase (AsCHS1) gene in Aquilaria sinensis]. AB - OBJECTIVE: The study aimed to clone the open reading frame of chalcone synthase (CHS) from Aquilaria sinensis and analyze the bioinformatics and expression of the gene. METHOD: One unique sequence containing CHS domain was discovered in our previous reported wound transcriptome dataset of A. sinensis. The open reading frame of CHS was cloned by RT-PCR strategy with the template of mixed RNA extracted from A. sinensis stem which treated by different wound time. The bioinformatic analysis of this gene and its corresponding protein was performed. The AsCHS1 expression in calli was analyzed with histone gene as an internal control gene under wound condition by qRT-PCR technique. RESULT: One unique sequence of CHS, named as AsCHS1, was cloned from A. sinensis. The full length of AsCHS1 cDNA was containing a 1 192 bp ORF that encoded 397 amino acids. The result of qRT-PCR displayed that the highest expression level was at 12 h, which indicated that it was possibly involved in early-stage response to wound. CONCLUSION: Cloning and analyzing AsCHS1 gene from A. sinensis provided basic information for study the function and expression regulation of AsCHS1 in the flavonoids biosynthesis. PMID- 23672033 TI - [Discrimination of traditional Chinese medicinal materials with different tastes based on electronic tongue]. AB - OBJECTIVE: To investigate the use of the electronic tongue in the evaluation of traditional Chinese medicinal materials with sour, bitter, sweet or salty tastes, and assess the possible application of the sensor in the evaluation of different tastes of traditional Chinese medicinal materials. METHOD: Aqueous extracts of 22 traditional Chinese medicinal materials were measured by the electronic tongue. The data collected with the tongue was evaluated for discrimination of the samples with multivariate statistical methods: principal component analysis (PCA) and discriminant factor analysis (DFA). RESULT: The electronic tongue was capable of discriminating between samples with different taste modalities and could also distinguish different samples eliciting the same basic taste. Twenty-two traditional Chinese medicinal materials could be classified into five clusters based on PCA. These differences seem to derive from the different tastes. DFA was applied to construct a model to discriminate traditional Chinese medicinal materials with different tastes. And the samples yielded about 88.2% accuracy for cross-validation. CONCLUSION: We confirmed that the electronic tongue may provide an analytical procedure for classification of the samples with respect to tastes of the traditional Chinese medicinal materials. PMID- 23672034 TI - [Optimization method of MOS sensor array for identification of traditional Chinese medicine based on electronic nose]. AB - Optimization of sensor array is a significant topic in the application of electronic nose (EN). Stepwise discriminant analysis and cluster analysis combining with screening of typical index were employed to optimize the original array in the classification of 100 samples from 10 kinds of traditional Chinese medicine based on alpha-FOX3000 EN. And the identification ability was evaluated by three algorithm including principle component analysis, Fisher discriminant analysis and random forest. The results showed that the identification ability of EN was improved since not only the effective information was maintained but also the redundant one was eliminated by the optimized array. The optimized method was eventually established, it was accurate and efficient. And the optimized array was built up, that is, S1, S2, S5, S6, S8, S12. PMID- 23672035 TI - [Simultaneous determination of four flavones in root and stem of Cudrania tricuspidata and C. cochinchinensis by HPLC-DAD]. AB - OBJECTIVE: To establish a HPLC-DAD method for the determination of axifolin, naringenin, quercetin and kaempferol in Cudrania tricuspidata and C. cochinchinensis in order to provide a scientific reference for species identification and quality evaluation, by establishing. METHOD: The determination was performed by HPLC-DAD on an Agilent C18 column (4.6 mm x 150 mm, 5 microm) by gradient elution (0-15 min, 35%-50% A; 15-30 min, 50% - 65% A) using methanol (A) and 0.1% phosphoric acid (B) as the mobile phase. The flow rate was 1 mL x min( 1). The detection wavelength was 290 nm for taxifolin and naringenin, 365 nm for quercetin and kaempferol with column temperature at 30 degrees C. RESULT: The content of axifolin and quercetin in the root of C. tricuspidata were remarkably higher than that in the root of C. cochinchinensis, and the content in stem of C. tricuspidata was also higher than that in the stem of C. cochinchinensis, the content of axifolin and quercetin was variable in different species. The content of naringenin and kaempferol in the root of C. cochinchinensis was visibly higher than that in the root of C. tricuspidata, and the content in the stems of the two herbs was similar, the content of naringenin and kaempferol was visibly variable in different medicinal parts of the herb, but similar between the two herbs. CONCLUSION: There's some difference of the content of the four ingredients in different medicinal parts and different herbs, so clinical use should not be confused. PMID- 23672036 TI - [Comparative research on histological and microscopical leaves characters of five species in Chloranthus]. AB - OBJECTIVE: To clarify the origin and provide pharmacognostical evidences for the leaves of 5 species in Chloranthus. METHOD: Histological observation and microscopic identification through different slice-making techniques were applied to the research. RESULT: There were subtle differences between the histological characteristics. In microscopical identification, the different structures of vascular bundles in veins were observed, appendages and non-glandular hairs were distinct. CONCLUSION: The method can be used to distinguish the features of 5 species in Chloranthus. This article offers information for the further research and exploitation of Chloranthus. PMID- 23672037 TI - [Study on solid dispersion of copovidone-based tanshinone II(A)]. AB - OBJECTIVE: To apply PVP-S630 in the preparation of tanshinone II(A) (TS II(A)) solid dispersion, in order to improve its dissolution in vitro and reduce the moisture absorption of the solid dispersion. METHOD: Tanshinone II(A) solid dispersion was prepared by spray drying method. Such analytical methods as SEM, DSC, XRD were used to characterize their phases and detect their dissolution, moisture absorption and stability. RESULT: In the solid dispersion prepared with tanshinone II(A) and copovidone with proportion of 1:10, tanshinone II(A) was scattered on the surface of the carrier in the amorphous form, with a dissolution in vitro up to 100% at 0.5 h and a lower moisture absorption than PVP-K30 solid dispersion prepared with the same proportion. After a three-month accelerated stability test, it showed no significant change in drug dissolution and content. CONCLUSION: The solid dispersion prepared with copovidone as the carrier can significantly improve the dissolution of tanshinone II(A), with a relatively low moisture absorption and high stability, thereby having a good prospect of application. PMID- 23672038 TI - [Change in dissolution of chemical components of frankincense-myrrh before and after their compatibility and effect on no release of LPS-induced macrophage cells]. AB - OBJECTIVE: To analyze the difference of chemical compounds of frankincense-myrrh before and after their compatibility, and evaluate the effect of differentiated compounds on NO generated by LPS-induced peritoneal macrophage cells in rats, in order to discuss synergetic material basis of frankincense-myrrh compatibility from the prospective of change in chemical constituents. METHOD: UPLC-Q-TOF-MS/MS combined technology was used to analyze the chemical components of frankincense myrrh before and after their compatibility. MarkerLynx 4. 1 statistical software was used to analyze differentiated compounds before and after their compatibility. RESULT: The results of PCA showed that there were significant differences in the combined extracts of frankincense-myrrh and the chromatogram of their combined liquid, suggesting significant differences in their chemical compounds before and after their compatibility; after their compatibility, the dissolution of pentacyclic triterpenoid (alpha-boswellic acid, beta-boswellic acid) and tetracyclic triterpenoid (elemonic acid, 3-acetoxy-16-hydroxy-dammar-24 ene, 3-hydroxytirucalla-8,24-dien-21-oic acid or 3-hydroxytirucalla-7,24-dien-21 oic acid) increased notably, while the dissolution of both yclic sesquiterpenes and macrocyclic diterpenoids decreased. According to the evaluation on in vitro activity, 2-methoxy-8, 12-epoxy-germa-1 (10), 7, 11-triene-6-ketone, 2-methoxy-5 acetoxyl-furan-germa-1 (10)-alkene-6-ketone and 3-carbonyl Euphorbia kansui-8, 24 diene-21-carboxylic acid notably inhibited NO generated by LPS-induced peritoneal macrophage cells in rats. CONCLUSION: These findings provide scientific basis and reference for studies on anti-inflammatory material basis of frankincense-myrrh compatibility. PMID- 23672039 TI - [Rapid recognition and identification of chemical constituents in Qinghuo Zhimai tablets by SPE-HPLC-ESI-MS(n)]. AB - OBJECTIVE: To establish a method for analyzing solid phase extraction-high performance liquid chromatography-electrospray ionization tandem mass spectrometry (SPE-HPLC-ESI-MS(n)), in order to recognize and identify the main chemical constituents in Qinghuo Zhimai tablets. METHOD: The possible structures of the compounds were determined according to the structure information of compounds observed from molecular ion peaks and fragment ions in HPLC-ESI-MS(n) negative ion mode and by comparing with literature data or control samples. RESULT: Through the comparative analysis on Qinghuo Zhimai Tablets and components of its formula, 39 chemical constituents were identified, including 7 caffeoylquinic acids, 7 iridoids, 6 diterpenoid lactones, 5 homoisoflavonoids, 13 steroidal saponins and 1 flavone glycoside. CONCLUSION: This study provides a simple and rapid method for identifying chemical components in Qinghuo Zhimai tablets. PMID- 23672040 TI - [Comparison of antioxidant activity between two species of chamomiles produced in Xinjiang by TLC-bioautography]. AB - OBJECTIVE: To compare the antioxidant active components from two species of chamomile-matricaria and Roman chamomile produced in Xinjiang. METHOD: The TLC bioautography was used, with 1,1-Diphenyl-2-picrylhydrazyl (DPPH) radical as the experimental model. The peak areas of various antioxidant components were obtained by TLC-scanning for analyzing antioxidant active components contained in volatile oil extracts and flavone extracts from the two species of chamomiles. The total peak area was taken as the indicator for comparing the antioxidant capacities of the two types of extracts, and comparing them with the total antioxidant activity of flavone extracts of the two species of chamomiles. RESULTS: According to the result of TLC-bioautography in volatile oil extracts from the two species of chamomiles, volatile oil extracts from chamomile showed four white antioxidant spots, including en-yne-dicycloether, and volatile oil extracts from Roman chamomile showed only one white antioxidant spot. The TLC scanning result showed that the peak area of antioxidant spots of volatile oil extracts from chamomile was significantly larger than that of volatile oil extracts from Roman chamomile. According to the test on the antioxidant activity of the two species of chamomiles with ultraviolet-visible spectrophotometry, the concentration of chamomile after scavenging 50% of DPPH radicals was 0.66 g x L( 1), whereas the figure for Roman chamomile was 0.33 g x L(-1). According to the result of TLC-bioautography in flavone extracts from the two species of chamomiles, flavone extracts from chamomile showed seven yellowish antioxidant spots, including apigenin and apigenin-7-glucoside, and flavone extracts of Roman chamomile showed eight yellowish antioxidant spots, including apigenin and apigenin-7-glucoside. The TLC-scanning results showed that the peak area of antioxidant spots of flavone extracts from Roman chamomile was significantly larger than that of flavone extracts from chamomile. CONCLUSION: Volatile oil extracts from the two species of chamomiles have significant difference in the antioxidant activity in TLC-bioautography. Specifically, the antioxidant activity of volatile oil extracts from chamomile is stronger than volatile oil extracts from Roman chamomile; the known antioxidant active components in volatile oil extracts from chamomile is en-yne-dicycloether, while all of the other three antioxidant active components as well as antioxidant active components in volatile oil extracts from Roman chamomile are unknown components and remain to be further determined. Considering the significant difference in the number of antioxidant active spots in volatile oil extracts from the two species of chamomiles, the result can be applied to distinguish the two species of chamomiles. The antioxidant activity determination result for flavone extracts from two species of chamomiles was consistent with the result of TLC bioautography, showing that flavone extracts from chamomile and Roman chamomile are more antioxidant active, while that of Roman chamomile is stronger than chamomile. Flavone extracts from both of the two species of chamomiles contain apigenin and pigenin-7-glucoside, which are known, while all of the other five antioxidant active components contained in flavone extracts from chamomile and the other six antioxidant active components contained in flavone extracts from Roman chamomile are unknown and remain to be further identified. The method lays a foundation for further identification of antioxidant active components contained in chamomile. PMID- 23672041 TI - [Chemical constituents of Rabdosia japonica var. glaucocalyx and their anti complementary activity]. AB - To study the chemical constituents of Rabdosia japonica var. glaucocalyx and their anti-complementary activity on the basis of preliminary studies. Target isolation guided by anti-complementary activity test, compounds in the chloroform and n-butanol fractions were isolated and purified by silica gel and Sephadex LH 20 column chromatographies, and preparative HPLC. The structures were identified by various spectroscopic data including ESI-MS, 1H-NMR and 13C-NMR data. The compounds were evaluated for anti-complementary activity in vitro. Eleven compounds were isolated from the chloroform and n-butanol soluble fractions and identified as stigmasterol (1), stigmas-9 (11) -en-3-ol (2), glaucocalyxin D (3), kamebakaurin (4), maslinic acid (5), corosolic acid (6), minheryins I (7), diosmetin (8), caffeic acid ethylene ester (9), caffeic acid (10) and vitexin (11). Isoquercetrin, rutin, quercetin, 3-methylquercetin, luteolin, 7 methylluteolin, and apigenin which were isolated from the preliminary studies together with compounds 9 and 10 showed inhibition of the complement system by the classical pathway. Compounds 2, 4, 6-9 and 11 were obtained from this plant for the first time. Caffeic acid (10) showed the strongest activity in vitro with a CH50 value of 0.041 g x L(-1). PMID- 23672042 TI - [Chemical constitunents of seeds of Oroxylum indicum]. AB - OBJECTIVE: To study the chemical constituents in the seeds of Oroxylum indicum. METHOD: Twenty compounds were isolated and purified by silica gel, and Sephadex LH-20 column chromatography, and their structures were determined by spectroscopic analysis including NMR and MS. RESULT: Twenty compounds were isolated and identified as oroxin A (1), oroxin B (2), chrysin (3), baicalein (4), quercetin (5), apigenin (6), kaempferol (7), quercetin-3-O-ara binopyranoside (8), lupeol C9), lup-20 (29)-ene-2alpha,3beta-diol (10), pinosylvin (11), dihydropinosylvin (12), cholest-5-ene-3, 7-diol (13), rengyol (14), isorengyol (15), zarzissine (16), (E) -pinosylvin-3-O-beta-D glucopyranoside (17), adenosine (18), sitosterol (19) and daucosterol (20). CONCLUSION: Compounds 11-13 and 15-18 were obtained from the genus Oroxylum for the first time, and except compound 18, the remaining 6 compounds were obtained from the family Bignoniaceae for the first time. PMID- 23672043 TI - [Synthesis and characterization of protocatechuic acid derivants]. AB - To explore the effects of protocatechuic acid (PCA) and its derivants on angiogenesis of the chick embryo chorioallantoic membrane (CAM) and scavenging DPPH radical in vitro. The protection of benzyl and alkaline hydrolysis of benzyl ester were employed. The structures of PCA-1, PCA-2 and PCA-3, the derivates of PCA, were elucidated by 1H, 13C-NMR and MS data The bioactivity of PCA and its derivants was evaluated on the models of DPPH radical and chick embryo chorioallantoic membrane (CAM), respectively. PCA and PCA-1 showed the best activity of scavenging DPPH radical among all the compounds. In contrast to PCA 2, PCA and PCA-3 displayed inhibition to angiogenesis (P < 0.001). Pyrocatechol hydroxyl is the active site of PCA on scavenging DPPH radical in vitro. PCA with carboxyl and without pyrocatechol hydroxyl seems to show promotion to angiogenesis, but it needs more evidences. PMID- 23672044 TI - [Determination of sulfur dioxide in traditional Chinese medicine by derivative fluorometry]. AB - OBJECTIVE: To establish a derivative fluorometry method for the determination of sulfur dioxide residues in traditional Chinese medicine. METHOD: The optimal derivation condition was established. The fluorescence intensity was detected at excitation wavelength of 321 nm, and emission wavelength of 384 nm. RESULT: A linear relationship was obtained between the fluorescence intensity and the addition of reference substance in the range of 0.999 7-17.99 nmol with a correlation coeffient of 0.999 9, and the average recovery was 102.3% with RSD 4.6%. CONCLUSION: This method is simple and sensitive with quick and correct result. It can provide a reference for the determination of sulfur dioxide residues in traditional Chinese medicine. PMID- 23672045 TI - [Classification of Cimicifuga species based on 1H-NMR fingerprint combined with pattern recognition technique]. AB - The metabolomic analysis of three Cimicifuga species was performed using H-NMR spectroscopy and pattern recognition (PR) techniques. A broad range of metabolites could be detected by 'H-NMR spectroscopy without any chromatographic separation. The analysis using principal component analysis (PCA) and discriminant partial least square (DPLS) of the 1H-NMR spectrum showed a clear discrimination between C. foetida and the other two species. The major metabolites responsible for the discrimination were triterpenoid saponins and saccharides. These results indicated that the combination of 1H-NMR and PR provides a useful tool for chemotaxonomic analysis and authentification of Cimicifuga species, and could used for the quality control of plant materials. PMID- 23672046 TI - [Effects and mechanisms of platycladi cacumen carbonisatum on rats with blood heat and hemorrhage syndrome]. AB - OBJECTIVE: To discuss the effect and mechanism of Platycladi Cacumen Carbonisatum (PCC) on rats with blood heat and hemorrhage syndromes. METHOD: Rats were fed with 15 g x kg(-1) water decoctions of Zingiberis Rhizoma and 5% alcohol for 15 days to establish the blood-heat and hemorrhage syndrome model. Yunnan Baiyao was taken as the positive control drug, and PCC decoctions (5.0, 10.0 g x kg(-1)) were given simultaneously, in order to detect changes in general physical signs of rats, such as body weight, daily diet, volume of daily drinking and urine and stool, and rectal temperature. Automatic hematology analyzers was used to determine white blood cell (WBC), red blood cell (RBC), hemoglobin (HGB), and hematocrit (HCT), blood time by docking (BT). Blood rheometers was used to detect whole blood and plasma viscosities, thrombin time (TT), activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrinogen content (FIB). Indexes related to thyroid functions, such as triiodothyronine (T3), tetraiodothyronine (T4), reverse triiodothyronine (rT3) and thyroid stimulating hormone (TSH) were measured by radio-immunoassay, and changes in lung tissues were observed by hematoxylin-eosin (HE) stain. RESULT: After modeling, rats witnessed slow-down in weight growth rate, significant increase in daily diet, volume of daily drinking, urine and temperature, significant decrease in stools and their water content (P < 0.05, P < 0.01), rise in plasma T4 level, notable growth in T3 and rT3 concentrations (P < 0.05), decline in TSH concentration. Additionally, their WBC, RBC, HGB and HCT remarkably increased (P < 0.05, P < 0.01), with significant increase in high, middle and low whole blood viscosities and plasma viscosity (P < 0.01); their BT, TT, APTT were notably prolonged (P < 0.01), with significant increase in FIB content (P < 0.01). After oral administration of Yunnan Baiyao or PCC, rats of all groups showed significant improvement in blood heat syndromes (P < 0.05, P < 0.01), and their blood coagulation indexes including BT, TT, APTT, FIB, thyroid function indexes including T4, T3, rT3, TSH, WBC, RBC, HGB, HCT, whole blood viscosity and plasma viscosity were getting normal (P < 0.05, P < 0.01). CONCLUSION: PCC can ameliorate blood heat symptoms and pathologic hemorrhage among rats with blood heat and hemorrhage syndromes by inhibiting thyroid functions and correcting hemorheological and coagulation disorders. PMID- 23672047 TI - [Effect of hesperidin on behavior and HPA axis of rat model of chronic stress induced depression]. AB - OBJECTIVE: To observe the effect of hesperidin on behavior and hypothalamic pituitary-adrenal (HPA) axis of ratmodel of chronic stress-induced depression. METHOD: Chronic unpredictable mild stress (CUMS) was used to establish the rat depression model. Sixty male SD rats were divided randomly into six groups: the normal group, the model group, the hesperidin (40, 80, 160 mg x kg(-1)) group and the positive fluoxetine (10 mg x kg(-1)) group. They were orally administered with drugs for three weeks. The sucrose preference test and the forced swimming test (FST) were assayed to detect animal behavior. The levels of corticosterone (CORT) in serum, mRNA of corticotropin release factor (CRF) in hypothalamus as well as protein expression of glucocorticoid receptor (GR) in paraventricular nucleus (PVN) were determined to clarify the anti-depression effect and mechanism of hesperidin. RESULT: Compared with the model group, rats in the hesperidin (40, 80, 160 mg x kg(-1)) treatment group showed significant increase in the sucrose consumption and decrease in the immobility time in FST to varying degrees. Meanwhile, the excessively high serum CORT and adrenal index of CUMS rats were reversed by treatment with hesperidin. In addition, hesperidin inhibited CRF mRNA expression in hypothalamus and up-regulated GR protein expression in PVN among CUMS rats. CONCLUSION: Hesperidin could effectively improve the behavior of CUMS rats and show the anti-depression effect. Its mechanisms may be related to the function of regulating HPA axis. PMID- 23672048 TI - [Study on antioxidant interaction of different preparations and proportions of Danggui-Chuanxiong drug pair]. AB - OBJECTIVE: To observe the in vitro antioxidant interaction of different preparations and proportions of Danggui-Chuanxiong drug pair in the DPPH free radical scavenging rate with the response surface methodology. METHOD: The 2,2 diphenyl-1-picryl-hydrazyl (DPPH) free radical scavenging rate method was adopted for determining the antioxidant activity of extracts from Danggui-Chuanxiong with 10 proportions and three extraction processes. The response surface methodology was used to determine the parameters of the dose-effect curve and establish a three-dimensional response surface model. The three-dimensional response surface graph was constructed with Matlab software. RESULT: All of the 30 samples with different proportions and preparations had antioxidant effect in scavenging free radicals and a remarkable dose-effect relationship. Their water extracts had a narrow synergistic range, with only spot distribution. Their antagonist ranges were districted in six bands of various widths. The synergistic ranges of ethanol extracts were districted in small bands, with the antagonist ranges scattered in points. The synergistic ranges of their water-alcohol extracts were distributed in three bands, with their antagonist ranges scattered in points. In short, the water-alcohol extracts showed a wider synergistic range than ethanol extracts, followed by water-extracts. All of the three extraction processes showed no obvious synergistic and antagonist effects. CONCLUSION: The quantitative study on the interaction of traditional Chinese medicines with different compatibilities with the response surface methodology provides reference of thoughts and methods for relevant studies. PMID- 23672049 TI - [Effect of berberine, liensinine and neferine on HERG channel expression]. AB - OBJECTIVE: Immunofluorescence and Western blot methods were adopted for qualitative and quantitative detections of the effect of different concentrations of berberine, liensinine and neferine on the expression of stable transfection in HERG potassium channel in HEK-293 cells, as well as the effect of different concentrations of berberine on protein expression of Ikr channel in cardiac muscular tissues, in order to investigate the anti-arrhythmic mechanism of berberine, liensinine and neferine. METHOD: Western blot method was used to detect protein expression of HERG channel in HERG-HEK cells. Immunofluorescence method as well as confocal laser microscope were used to detect the effect of different concentrations of berberine, liensinine and neferine on protein expression of HERG channel. Western blot method was used to detect the effect of different concentrations of berberine on protein expression of Ikr channel in cardiac muscular tissues as well as the effect of berberine, liensinine and neferine on protein expression of stable transfection in HERG potassium channel in HEK-293 cells. RESULT: Western blot experiment manifested that stable transfection of HEK293 cells containing HERG genes could increase protein expression of HERG channel. Berberine (10, 30 micromol x L(-1)) remarkably inhibited protein expression of HERG channel in HERG-HEK cells (P < 0.01). Berberine (10, 20 mg x kg(-1)) also inhibited protein expression of Ikr channel in rat ventricular tissues (P < 0.05). Liensinine (3, 10, 30 micromol x L(-1)) increased protein expression of HERG channel in HERG-HEK cells (P < 0.05). Neferine showed no effect on protein expression of HERG channel in HERG-HEK cells. CONCLUSION: The stably transfection of HERG-HEK cells can increase protein expression of HERG channel. Berberine shows inhibitory effect on protein expressions of in vitro HERG-HEK cells and Ikr channel in rat ventricular tissues. Liensinine improves protein expression of HERG channe in HERG-HEK cells. Neferine shows no effect on protein expression of HERG channel. PMID- 23672050 TI - [Effects of four kinds of Chinese medicine monomer on growth of PANC-1 xenograft tumor and studying of molecular mechanism]. AB - OBJECTIVE: The antitumor effects of icarisid II, timosaponin A-III, neferine and salidroside were studied in PANC-1 xenograft tumor. METHOD: To establish of the nude mice xenograft tumor model, PANC-1 cells were injected. When the tumor major diameter was reached 3-5 mm, the treatment was initiated. The mice were randomized into vehicle control and treatment groups of six animals per each. Chinese medicine monomer was injected intraperitoneally every day. In 23th day, mice were killed once a day, tumor tissue were isolated and weighed and divided into two parts. One part was fixed with formaldehyde for tissue section and immunohistochemistry, the another of tissue was frozen in liquid nitrogen then in - 80 degrees C refrigerator for gene and protein expression analysis. RESULT: In PANC-1 tumor xenograft experiment, compared with model group, timosaponin A-III (1.0 mg x kg (-1)) exerted significant inhibitory effects on tumor growth. Timosaponin A-III suppressed mRNA expressions of VEGF (P < 0.05), reduced protein expressions of VEGF (P < 0.05), activated Caspase-3 protein. Icarisid II, neferine and salidroside had not an excelled antitumor effect. CONCLUSION: Timosaponin A-III exerted an excelled antitumor effect. The antitumor mechanisms include anti-angiogenesis, apoptosis promotion. PMID- 23672051 TI - [Effects of Tanyu Tongzhi recipe on hemorheology, blood lipid and inflammatory factors in rats with mycardial ischemia-reperfusion injury and hyperlipidemia]. AB - OBJECTIVE: To investigate the influence of Tanyu Tongzhi (TYTZ) recipe on chemorheology, blood lipid and inflammatory factors of hyperlipidemia and myocardial ischemia-reperfusion injury in rats. METHOD: Sixty SD male rats were divided into 5 groups randomly, sham-operated group, model group, high dose group of reproduced by ligation of left descending artery for 30 min followed by releasing the TYTZ and low group of TYTZ. The model of MI/RI injury of the myocardium was ligation for 2 hours in rats. Serum contents of CHO, TG, HDL-L, LDL-L and whole blood viscosity, plasma viscosity and ICAM-1, TNF-alpha, IL-10 were measured after myocardial reperfusion injury. RESULT: Compared with sham operated group, the levels of CHO, TG, LDL-L, whole blood viscosity (1.0,3.0) plasma viscosity and the contents of ICAM-1 were significantly higher, however, HDL-L, IL-10 levels were lower in model group (P < 0.01 and P < 0.05). CHO, TG, whole blood viscosity (1.0, 3.0, 30) and expression of ICAM-1, TNF-alpha were obviously lower in low group than the model group (P < 0.01 and P < 0.05). CONCLUSION: The TYTZ recipe can relieve reperfusion injury through regulating blood lipid, improving hemorheological characteristic and inhibiting inflammatory reaction. PMID- 23672052 TI - [Experimental studies on pharmacokinetics of three components in Buyanghuanwu injection on base of total quantum statistical moment]. AB - OBJECTIVE: To verify established the total quantum statistic moments model with astragaloside IV, paeoniflorin, tetramethylpyrazine in Buyanghuanwu injection, in order to establish a pharmacokinetic experimental method with multi-component traditional Chinese medicine (TCM) compound system. METHOD: The RP-HPLC was adopted, with the chromatographic column of C18, 4.6 mm x 250 mm, 5 microm. As for astragaloside IV, the ELSD detector was adopted with acetonitrile-water (35: 65) as the mobile phase at 1 mL x min(-1); the pressure of column was (15.0 +/- 0.408) MPa, the column temperature was 30 degrees C. Regarding paeoniflorin and tetramethylpyrazine, the detection of wavelengths was 254 nm, with acetonitrile water (35:65) as the mobile phase at 1 mL x min(-1), the column pressure of (15.17 +/- 0.41) MPa. The pharmacokinetic parameters for single component were dealt with DAS and the total quantum statistical moment (TQSM) parameters were calculated using formulations. RESULT: All of the three components followed the two compartmental pharkacokinetic model (P < 0.01) in rats. Compared with the superimposed total concentration, each single component showed difference in parameters up to 10 000 times at most, whereas the RSD of TQSM parameters was 3.510%. The TQSM pharmacokinetic parameters of the three components in Buyanghuanwu injection showed that AUC(t), MRT(t), VRT(t), CL(t), V(t), were (119.8 +/- 27.20) g x min x L(-1), (210.0 +/- 54.49) min, (5.608 +/- 2.723) x 10(4) min2, (0.319 6 +/- 0.068 8) mL x min(-1) x kg(-1) and (64.12 +/- 8.243) mL x kg(-1), respectively, suggesting that the half-life time for the three components were (145.5 +/- 37.76) min and 95% of them were metabolized within 0 674. 2 min. CONCLUSION: The TQSM can be used to study pharmacokinetic parameters of multi-component TCM compound, because the method can characterize the pharmacokinetic regularity of quantum-time change in a multi-component system. PMID- 23672053 TI - [Study on pharmacokinetics of 20 (S) -protopanaxadiol lipid cubic nanoparticles]. AB - OBJECTIVE: To establish a high-performance liquid chromatographic/tandem mass spectrometry (HPLC-MS/MS) method for determining 20(S)-protopanaxadiol (PPD) in rat plasma, in order to analyze pharmacokinetic characteristics of PPD and PPD cubic nanoparticles. METHOD: Sprague-Dawley rats were administered orally with PPD and PPD cubic nanoparticles, respectively. Their blood samples were obtained from fossa orbitalis at regular time points. The mobile phase was 0.05% formic acidac etonitrile-0.05% formic acidac water (95:5). Electrospray ionization (ESI) was adopted for the quadrupole tandem mass spectrum. SCAN mode was used for the quantitative analysis, with m/z 460. 4/425.3 and m/z 622.9/318.3 (Rh2, interior label) as secondary fragment ions. The concentration of PPD in plasma was analyzed. The concentration-time curve was mapped. The data were calculated by DAS program. RESULT: The linearity of the PPD plasma concentration determination method ranged between 10-1 407 microg x L(-1), with the limit of quantification of 2.5 microg x L(-1). Both of the inter-day and intra-day precisions (RSD) were less than 13.25%, and the accuracy (relative error) was between +/- 8.50%. CONCLUSION: The method was so highly specific and sensitive with less plasma that it is suitable for pharmacokinetic studies. The prepared 20(S)-protopanaxadiol lipid cubic nanoparticles can enhance its absorption in vivo. Its relative bioavailability is 166% of the raw material. PMID- 23672054 TI - [Pharmacokinetic effect of Sappan Lignum on hydroxysafflor yellow A in Carthami Flos]. AB - OBJECTIVE: To investigate the pharmacokinetic effect of Sappan Lignum on hydroxysafflor yellow A (HSYA) in Carthami Flos. METHOD: Concentration of HSYA in rat plasma was detected by RP-HPLC after rats were orally administered with extracts of Carthami Flos or Carthami Flos combined with Sappan Lignum. Pharmacokinetic parameters were calculated by DAS 2.0 pharmacokinetic software. RESULT: In vivo pharmacokinetic models of HSYA were two-compartment open models in both of the Carthami Flos group and the Carthami Flos combined with Sappan Lignum group. After compatibility, HSYA showed a significant lower in apparent volumes of distribution of t(1/2Ka), t(1/2alpha) and V1/F, with slight advance in T(max). CONCLUSION: Sappan Lignum can accelerate absorption, distribution and metabolic process of HSYA in vivo and reduce its accumulation in vivo. PMID- 23672055 TI - [Study on efficacy of zaoren anshen capsules in treating senile insomnia and changes in its hemorheology]. AB - OBJECTIVE: To observe the effect of Zaoren Anshen capsules in treating senile insomnia and changes in its hemorheology. METHOD: A total of 120 patients with senile insomnia were randomly divided into the Zaoren Anshen capsules group (five capsules, n = 60) and the Alprazolam group (0.8 mg, n = 60) for treatment and control observation. Pittsburgh sleep quality index (PSQI) was used for evaluating clinical efficacy in the first and fourth week before and after treatment. RESULT: The Zaoren Anshen capsules group had lower higher scores in PSQI (5.91 +/- 1.37) than that before treatment (13.49 +/- 3.87), with great statistical significant in difference (P < 0.01). The alprazolam group had lower higher scores in PSQI than that before treatment, with great statistical significant in difference (P < 0.01). apart from higher PSQI scores in the Zaoren Anshen capsules group than that of the Alprazolam group after treatment for one week (P < 0.05), the comparison between the Zaoren Anshen capsules group and the alprazolam group before and after treatment for four weeks showed no statistical significance. As for hemorheological parameters, the difference in the whole blood viscosity (including high-shear, middle-shear and low-shear) of patients in the Zaoren Anshen capsules showed great statistical significance before and after treatment (P < 0.01), and so did the plasma viscosity (P < 0.05). Zaoren Anshen capsules showed less adverse reactions than alprazolam. CONCLUSION: Zaoren Anshen capsules have similar effect in treating senile insomnia with alprazolam, with less adverse reactions. They are so suitable for patients with senile insomnia that they can improve hemorheological indicators of patients with senile insomnia and have good effect in promoting circulation and removing stasis. PMID- 23672056 TI - [Observation of Qigui Tongfengshu granules in treatment of sixteen cases of gouty arthritis]. AB - OBJECTIVE: To investigate the efficacy of Qigui Tongfengshu granule in treating gouty arthritis. METHOD: Qigui Tongfengshu granule was used to treat 16 patients with gouty arthritis for 14 d. RESULT: The recovery rate, marked effective rate, effective rate and improvement rate were 37.5%, 50%, 6.25%, 6.25%, respectively. The total effective rate was 100%. Before and after treatment, the comparison showed statistical significance. CONCLUSION: Qigui Tongfengshu granule is significantly effective for gouty arthritis, and has the effect of anti inflammation, analgesia and reduction in blood uric acid. PMID- 23672057 TI - [Genetic diversity and genetic structure of endangered wild Sinopodophyllum emodi by start codon targeted polymorphism]. AB - OBJECTIVE: Revealed the genetic diversity level and genetic structure characteristics in Sinopodophyllum emodi, a rare and endangered species in China. METHOD: We detected the genetic polymorphism within and among six wild populations (45 individuals) by the approach of Start Codon Targeted (SCoT) Polymorphism. The associated genetic parameters were calculated by POP-GENE1.31 and the relationship was constructed based on UPGMA method. RESULT: A total of 350 bands were scored by 27 primers and 284 bands of them were polymorphic. The average polymorphic bands of each primer were 10.52. At species level, there was a high level of genetic diversity among six populations (PPB = 79.27%, N(e) = 1.332 7, H = 0.210 9 and H(sp) = 0.328 6). At population level, the genetic diversity level was low (PPB = 10.48% (4.00% -23.71%), N(e) = 1.048 7 (1.020 7 1.103 7), H = 0.029 7 (0.012 9-0.063 1), H(pop) = 0.046 2 (0.019 9-0.098 6). The Nei's coefficient of genetic differentiation was 0.841 1, which was consistent with the Shannon's coefficient of genetic differentiation (0.849 4). Two calculated methods all showed that most of the genetic variation existed among populations. The gene flow (N(m) = 0.094 4) was less among populations, indicating that the degree of genetic differentiation was higher. Genetic similarity coefficient were changed from 0.570 8 to 0.978 7. By clustering analysis, the tested populations were divided into two classes and had a tendency that the same geographical origin or material of similar habitats clustered into one group. CONCLUSION: The genetic diversity of samples of S. emodi is high,which laid a certain foundation for effective protection and improvement of germplasm resources. PMID- 23672058 TI - [Chemical components of essential oils from Meconopsis oliverana and their antioxidant activity]. AB - OBJECTIVE: To study the chemical components of essential oils from Meconopsis oliverana and their antioxidant activity. METHOD: The essential oil was extracted by steam distillation, and GC-MS analysis was used to identify its constituents. The OH free radical scavenging activity of the essential oils was evaluated with an enzyme mark instrument by assay of the ability of DPPH free radical scavenging. BHT was used as positive control. RESULT: Forty-seven compounds, account for 91.866% of the essential oils, were identified. The ability of scavenging OH and DPPH radicals of the essential oils is stronger than that of BHT. CONCLUSION: The main chemical constituents of the essential oils from M. oliverana are n-hexadecanoic acid (27.653%) and 6,10,14-trimethyl-2-pentadecanone (16.330%). And the essential oils showed strong antioxidant activity. PMID- 23672059 TI - [Preliminary construction of studies on "pharmaceutical chemistry of cerebrospinal fluid containing Chinese medicine"]. AB - According to the research methods for pharmaceutical chemistry of serum containing Chinese medicine, we put forward the concept, research ideas and methods of "pharmaceutical chemistry of cerebrospinal fluid containing Chinese medicine" for the first time on the basis of summary of the present situation in research on the base of single and compound Chinese medicine by applying the composition analysis methods on pharmaceutical chemistry of the drug through blood brain barrier. At the same time, scientific research value and prospect of pharmaceutical chemistry of cerebrospinal fluid containing Chinese medicine were discussed. The study on "pharmaceutical chemistry of cerebrospinal fluid containing Chinese medicine" will give an important complement to the study methods of material base of traditional Chinese medicine, and promote the modernization of traditional Chinese medicine prescriptions. PMID- 23672060 TI - [The Russian and international standards of age-related allocation of population for medical statistics, medical demographic analysis and risk assessment]. AB - The actual European standard of age-related allocation of population in action is largely implemented in medical demographic studies of international (WHO etc.) and national organizations. The Rosstat also implements this standard in its demographic yearbooks and other publications. The standard is applied in computing the standardized indicator of population mortality in different countries and territories and also in assessing risk factors. The standard is based on the idea of evaluating mortality with an integrated standard in order to compare between different countries mortality of population, genders and calendar years. The analysis of results of testing calculations of values of standardized indicator of mortality of population of Russia and EU countries applying European standard in action revealed serious shortcomings. For example. unfounded overstating of values of standardized indicator, of mortality for males and its understating for females artificially increases already wide difference in mortality of males and females in the Russian Federation. The calculation on this background of standardized indicator of mortality for particular causes of death results in erroneous values due to neglected concurrence of risks. Because of necessity of improvement of standard a new concept of development of national and international standards is proposed. This concept is based on application of notion of balanced age-related allocation of population and its number values. PMID- 23672061 TI - [The social hygienic assessment of significance of diseases under organization of ambulatory polyclinic care]. AB - The article presents the results of analysis of appealability of adult population of Omsk to municipal polyclinic on the subject of diseases. The coefficients of relative importance of different classes of diseases to determine the groups af their significance were calculated on the basis of integrated evaluation of common and primary morbidity and diseases of patients under dispensarization monitoring. The established character of formation of flows of appealabiliy of population on the subject of diseases is a basic one to determine demand in medical technologies and planning of activities of ambulatory polyclinic section of health care. PMID- 23672062 TI - [The morbidity of malignant neoplasms in industrial metropolis]. AB - The territorial characteristics of malignant neoplasms propagation was analyzed to reveal the risk factors concerning the population oncological morbidity in the City of Ufa. The data of accounting reporting documentation of the Bashkir republican oncological dispenser from 2000 to 2008 was used for analysis. The study revealed that in males and females the level of morbidity of oncological neoplasms is higher as compared with indicator's national level and continues to increase steadily factually in all oncological forms of this pathology. PMID- 23672063 TI - [The morbidity of respiratory diseases among university students]. AB - The article presents actual tendencies in morbidity of students of two universities of Saralov. The characteristics of medical social factors impacting students' health and morbidity of respiratory diseases are given. During, the last five years the increase of common morbidity of students up to 20.3% (from 932.3 to 1121.3 per 1000 students) was established. In the structure of morbidity of students, pathology of respiratory system takes leading position. During the years of monitoring, the increase of rate of new cases of appealability of students to curative preventive establishments on the subject of respiratory diseases up to 3.5 times (from 48.8 to 167.2 cases per 1000 students) was revealed. The issues of preservation and promotion of health have the least importance of 24.3% in variety of value orientation of the youth. PMID- 23672064 TI - [The characteristics of morbidity of workers of nuclear power engineering enterprise]. AB - The article considers the morbidity endocrine, pathology included, of workers of nuclear power station and body-abled population of the district employed in other areas of professional activities. The statistically reliable exceeding of the level of primarily diagnosed endocrine morbidity in the group of working population of the district as compared with the group of workers of nuclear power station is established. In the compared groups, the structure of pathology of endocrine system is characterized by the prevalence of diseases of thyroid gland and obesity. The official statistics data reflects the level of morbidity of working population depending on appealability to curative preventive institutions, ratio and scope of the periodic medical examinations, availability of shop therapeutic service and possibility to involve physicians-specialists to health posts enterprises. Therefore, the foundation of enhancement of quality of medical care to workers is the improvemnent of organizational activities at the level of primary health care. PMID- 23672065 TI - [The awareness of patients with tuberculosis associated with HIV-infection about this pathology]. AB - The article analyses the results of questionnaire survey, of patients with tuberculosis associated with HIV-infection. The insufficient awareness about of issues of clinical course, treatment and prevention of tuberculosis was established. The distinctive feature of this category of patients is a lower medical activity and ignorance of characteristics of clinical manifestations of tuberculosis when associated with HIV-infection. This situation creates serious obstacles for timely detection of tuberculosis. Yet another negative factor also is lower readiness of health institutions to provide medical care to patients with HIV-infection. PMID- 23672066 TI - [The impact of particular factors on the outcome of treatment of patients with craniocerebral injury]. AB - The article considers the relationship between outcomes of treatment of craniocerebral injuries in hospital and gender and age of hospitalized patients, mode of traumatization, time of visiting the physician for medical care, severity of patient condition, duration of stay in hospital. The analysis results demonstrated rather accurate picture of outcomes of treatment of patients with craniocerebral injuries in the Republic of Chechnya. PMID- 23672067 TI - [The resources to decrease infant mortality in the Republic of Tyva]. AB - The article presents the results of study of dynamics, structure of infant morlality and morbidity of children of the first year of life in the Republic of Tyva during 1996-2011. It is demonstrated that indicators of infant mortality in the Republic are twice higher than mean indicators in the Russian Federation. The structure of infant mortality is characterized by prevalence of particular states occurring in perinatal period, congenial malformations and accidents. The polynomial trend analysis of indicators of morbidity and mortality of infants established the priority directions for health professionals and social support agencies of the Republlic of Tyva. PMID- 23672068 TI - [The emergency surgical care in the Russian Federation]. AB - The article presents the results of providing emergency surgical care in case of acute diseases of abdominal organs and extra uterine pregnancy to population of the Russian Federation in 2000-2010. The analysis also considered time between onset of disease and delivery of patient to hospital, structure of diagnosis, operative activity and indicators of lethality. The preventability of lethal outcome under acute diseases of abdominal organs at the expense of hospitalization is calculated. PMID- 23672069 TI - [The standard of position of physician-stomatologist-therapeutist in the conditions of working together with assistant-stomatological]. AB - The article presents scope of work, algorithms of labor operations, standardization of work of stomatologist-therapeutist in the conditions of working together with assistant-stomatological in four hands. The calculations are given concerning the standard numbers of positions of stomatologist in new conditions of work. PMID- 23672070 TI - [The improvement of manpower support of municipal hospitals]. AB - The article demonstrates the importance of analysis of improvement of implementation of manpower support of municipal hospitals in the framework of development of planning their activities. The optimal identification of demand in manpower and other types of resources is considered. PMID- 23672071 TI - [The priority directions of improvement of specialized oncologic out-patient care]. AB - The article presents the priority directions of development and improvement of organization of specialized out-patient care of oncologic patients with propose to enhance quality of their life. PMID- 23672072 TI - [The becoming of public medicine (second half of XVIII-first half of xix centuries). Report I: The origin of concept of medical police, governing bodies of medical sanitary business, physician sanitary legislation]. AB - The present report covers the history of origination of concept of medical police in the second half of XVIII century. This body became one of the most important tool of state governance in Austria. France, Prussia and Russia. The relationship between origin of this concept and the results of scientific studies in area of investigation of epidemic constitutions is demonstrated. Two directions of activity of bodies of state governance are considered concerning the implementation of medical police--imposition of public administration of activities of physicians and development by joint efforts of physicians and lawyers of special physician sanitary legislation. PMID- 23672073 TI - [The House of infant protection in Moscow]. AB - The article deals with short (1918-1922) but exremely important time of reorganization and functioning of the House of infant protection in Moscow established by the initiative of the Department of mother and infant protection. It turned out, because of enthusiasm and professionalism of physicians and in spite of the most severe situation in the country, to organize the departments for healthy infants, to establish clinics for gravely sick little patients, laboratory diagnostic units and children consultation. The House of infant protection became the only practical research center in the Soviet Russia to study physiology and pathology of children of early age and to train physicians and medical nurses specialized in the area of early childhood. The importance of the House of infant protection which was at the origins of the Soviet system of protection of children health, is hard to overestimate. The House was a kind of experiment area to develop the institutions of public system of mother and child protection, to elaborate the Soviet pediatric science and schools of training and advanced training of research and practical specialists in this field of medicine. PMID- 23672074 TI - [About the Cardiologic School of D.D. Pletniev: the revision of views]. AB - The article reconsiders, for the reason of additional archive and literary, sources, the issues of personal staff of cardiologic school of D.D. Pletniev and its impact on the development of therapeutic clinic in the second half of XX centuty. The short characteristic of Moscow eminent cardiologists--major followers of D. D. Pletniev is given. PMID- 23672075 TI - [Philippe Pinel and the psychiatry of late XVII--early XIX centuries]. AB - The article analyzes the social economic premises promoting the psychiatry to distinguish to independent medical specialty with its own ideological base and methodological filling. The ideological concepts and methodological priorities of psychiatry prevailing in this epoch using the example of views of F. Pinel, his disciples and contemporaries are considered. PMID- 23672076 TI - [An attempt to classify patients with dementia by detrended fluctuation analysis of electroencephalographic data --a preliminary study]. AB - We investigated changes of the scaling exponent alpha estimated by detrended fluctuation analysis (DFA) of electroencephalograms (EEG) in patients with dementia including Alzheimer's disease(AD), and attempted to apply a method of pattern recognition using the alpha value-based feature vector to classify dementia. In 9 patients with AD, 8 patients with other types of dementia (vD), and 7 patients without dementia(C), DFA was performed for approximately one minute with background EEG data recorded at 16 different scalp monopoles. The alpha values were significantly higher in patients with AD at electrodes F7, C3, P3, P4, T3, and T5 than in patients without dementia. No significant difference in alpha values was found between patients with vD and without dementia. Then, an artificial neural network (ANN) was trained on the alpha value-based feature vector of EEG to classify patients with dementia into AD and vD. The trained ANN successfully diagnosed all four new test cases of AD. From these observations, it is suggested that AD has a specific pattern in the alpha value-based feature vector. Thus, pattern recognition using alpha value-based feature vector may be useful for the classification of dementia. PMID- 23672077 TI - [Clinical significance of the measurement of serum cytokeratin-18 in patients with non-alcoholic steatohepatitis]. AB - Epidemiologic data suggest that non-alcoholic fatty liver disease (NAFLD) have an increased tendency to occur in patients who are associated with metabolic conditions such as obesity, type 2 diabetes mellitus, and dyslipidemia. NAFLD represents a wide spectrum of conditions ranging from fatty liver, which in general follows a benign, no-progressive clinical course, to non-alcoholic steatohepatitis (NASH), a more serious form of NAFLD that may progress to cirrhosis and end stage liver disease. However, currently the diagnosis of NASH requires an invasive liver biopsy. The aim of this study is to evaluate whether Cytokeratin 18 (CK-18) has potential non-invasive diagnostic capability for the NASH. Serum levels of alanine aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase, adiponectin, leptin, and CK-18 were measured in 27 patients (8 patients with simple fatty liver, 6 fatty liver with fibrosis patients, 13 patients with NASH) and 23 healthy controls. Regarding gender difference in the control group, although both adiponectin and leptin significantly increased in the female compared with the male (p < 0.002 and p < 0.01, respectively), there were no significant gender differences in CK-18. For the conventional liver function tests, there were no significant differences in 4 groups. Serum levels of adiponectin was significantly lower in patients with NASH compared with the control group(p < 0.001), and both leptin and CK-18 were markedly higher in patients with NASH compared with control group (p < 0.001). These results suggested that measurement of serum CK-18 is useful for assessing the NASH. PMID- 23672078 TI - [Molecular heterogeneity of alpha 1-antitrypsin in the urine of the urolithiasis]. AB - Randall's plaque theory is regarded as the most plausible mechanism of urinary stone formation; however, we speculated that urine proteins are necessarily involved in the process of stone formation. We focused on alpha 1-antitrypsin (alpha1-AT), a protein verified to be present in urinary calculi, and which is considered as a protein of inflammation, comparing its presence in healthy subjects and patients with urolithiasis. Quantitative analysis of alpha1-AT was performed with ELISA, whereas qualitative analysis was performed with SDS PAGE, two-dimensional electrophoresis, and western blotting. The results revealed a molecular heterogeneity in alpha1-AT, which can be classified into four patterns, a concentration-independent difference in alpha1-AT molecules found in the urine of patients and healthy subjects. A wider distribution of protein isoelectric points was found in urolithiasis (3.0-8.0) than in healthy subjects (4.0-5.0). We suggest that this new finding with molecular heterogeneity was due to the urolithiasis. PMID- 23672079 TI - [A case of Plasmodium ovale malaria--morphological diagnostic difficulty and utility of rapid diagnostic tests]. AB - A 46-year-old Japanese man was referred to our travel clinic because of high fever for the past 7 days. He worked as an engineer for a month in Zambia and returned to Japan 2 days ago. He had a high-grade fever of 40.5 degrees C. Examination of the palpebral conjunctiva showed no evidence of anemia. Liver and spleen were not palpable. Blood sample was collected at the time of the febrile paroxysm. Malaria parasites were detected by examination of Giemsa-stained thin blood films. The dominant feature of parasite was early trophozoit with a low parasitemia (0.0469%, 1,857.6/microL). The James' stippling was absent. Schizonts and gametocytes were scarce. As ring morphology was quite variable, identification of species might not be possible. Identification of species is more difficult than usual, on the grounds that: 1) the blood sample contains rare early trophozoites, 2) the level of parasitemia is low, and 3) it is quite possible for parasites to be transformed due to the inappropriate treatment. Finally, the diagnosis was confirmed by nested PCR. Examination of Giemsa-stained blood films is the "gold standard" for detection and identification of organisms. However, in non-endemic countries, trained laboratory personnel are scarce and the most may be inexperienced in malaria diagnosis. It is recommended that personnel continue to gain experience by participating in external quality assurance schemes, and that routine laboratories utilize rapid diagnostic tests (RDTs) concurrently. The availability of simple and accurate RDTs could aid the diagnosis in no-endemic countries. PMID- 23672080 TI - [Decrease in number of venipuncture tubes enables us to shorten turnaround times of blood-based testing in clinical laboratories]. AB - We are making efforts to reduce the number of venipuncture tubes for blood-based testing. On the reconstruction of hematology system in 2011, we planned the system to include hemoglobin A1c (HbA1c) assay and to replace the assay instrument for erythrocyte sedimentation rate (ESR) to use EDTA-2K based whole blood. Accordingly, the revised system required a single test tube for hematological testing, resulting in reduction of blood volume collected. It was estimated that the whole blood collected from outpatients in a year decreased from 143 L to 109 L. Also, the times required to complete venipuncture after outpatient accession were significantly shortened to 10(0.71 +/- 0.27) (2.75 9.55) min, and nearly 50% of outpatients experienced < 2 min of waiting. As the times required for venipuncture were shortened, the turnaround times (TATs) from outpatient accession to finally reporting the test results to physicians were also shortened in the blood-based laboratories. The TATs after outpatient accession to reporting the test results in biochemistry and serology ranged 59 to 80 min (90%-tile), indicating 8 to 16 min less when compared with those before system reconstruction. In conclusion, the decrease in number of venipuncture tubes in hematological testing enables us to reduce the blood volume collected, and to shorten (1) times required for venipuncture procedure, (2) waiting times, and (3) TATs for blood-based testing. However, as demonstrated in HbA1c, i.e., a 50%-tile of TAT for HbA1c delayed for 5 min, the configuration of assay system can greatly influence the TATs of individual test parameters. PMID- 23672081 TI - [Rapid identification of microorganisms using MALDI-TOF mass spectrometry]. AB - In a clinical diagnostic microbiology laboratory, the current method of identifying bacterial isolates is based mainly on phenotypic characteristics, such as the growth pattern on different media, colony morphology, Gram stain, and various biochemical reactions. These techniques collectively allow high-level accuracy in identifying most bacterial isolates, but they are costly and time consuming. In our clinical microbiology laboratory, we prospectively assessed the ability of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) to identify bacterial strains that were routinely isolated from clinical samples. Bacterial colonies obtained from a total of 468 strains of 92 bacterial species isolated at the Department of Clinical Laboratory at Chiba University were directly placed on target MALDI plates, followed by the addition of CHCA matrix solution. The plates were then subjected to MALDI-TOF MS measurement, and the microorganisms were identified by pattern matching by the libraries in the BioTyper 2.0 software. The identification rates at species and genus levels were 91.7% (429/468) and 97.0% (454/468), respectively. MALDI-TOF MS is a rapid, simple, and high-throughput proteomic technique for the identification of a variety of bacterial species. Since colony to colony differences and the effects of culture duration on the results are minimal, it can be implemented in a conventional laboratory setting. Although for some pathogens, the preanalytic processes should be refined and current database should be improved to obtain more accurate results, the MALDI-TOF MS-based method generally performs as well as the conventional methods and is a promising technology in clinical laboratories. PMID- 23672082 TI - [Rapid mycobacterium identification and rapid susceptibility testing by the nucleic amplification method]. AB - This review was designed to review mycobacterial infections from the viewpoint of clinical practices. We showed the usefulness of the rapid mycobacterium identification system for the detection of various genes by the nucleic amplification method. However, most PCR-based identifications required NALC-NaOH preprocessing, a special technique, or lengthy, hard work. Although 16S rRNA gene sequences may be provided successfully to identify many mycobacterial species, they lack sufficient discrimination to differentiate certain isolates from some species. We also explained the current methodologies of rapid susceptibility testing for M. tuberculosis and clarified these abilities. Therefore, molecular detection and identification should be considered to isolate these organisms, in settings where bacteria were microscopically visible in clinical samples, involving culturing and performing drug susceptibility testing for mycobacteria. Finally, we should emphasize the importance of collaboration between clinical microbiologists and basic bacterial researchers to promote current and future clinical strategies against mycobacteria. PMID- 23672083 TI - [Chairman's introductory remarks]. AB - Remote medicine, as well as the technological development of IT, has been realized in various fields of medical care. Reports have been published of the actual utilization of a system of remote diagnosis by infectious disease surveillance in each region of Nagano Prefecture, a telepathology system in Nagano, operation case of a radiological image remote diagnosis. Situation in the lack of pathologists and radiologists, that changes in the way of working of the physician, or medical information digitized convey how the doctor involved in the diagnosis, any diagnosis based on the information that was received doctor such as whether to perform, various issues have been raised. Soot digitization of information. PMID- 23672084 TI - [A trial of integrated telepathology (iTP) in Nagano prefecture]. AB - The shortage of pathologists is a major issue in Japan, and telepathology (TP) is considered one of the most innovative solutions to resolve this. About twenty years ago, robotic TP systems (RTS) were developed and are still used in Japan. Virtual slide (VS) systems appeared in the early 2000s and have being replacing RTS because of the ease of handling images, easy reference to previous images and synchronous discussion among pathologists. Both systems are currently used for intra-operative consultations, second opinions and consultations by specialists, and in education and research via the internet. With these systems, pathologists participating in consultations have to obtain a patient's clinical information by other methods, such as fax or e-mail, and they often make a diagnosis without this information and previous histological images. The author proposes an "integrated telepathology (iTP)" system in Nagano prefecture. This system is composed of an anatomic pathology information system (APIS) linking the VS system and is designed to connect all pathologists in community hospitals, including Shinshu University Hospital, using a virtual private network. Any registered pathologist can access APIS and view any pathological images of patients with the clinical information. Therefore, pathologists can make a diagnosis with substantial patient information at any time and from any location, and pathologists in different hospitals can consult one another in a secure network. Our iTP system will be able to streamline diagnosis duties in surgical pathology in Nagano prefecture, and may solve the shortage of pathologists by improving diagnosis efficiency. PMID- 23672085 TI - [The values of physiological function testing accepted in new Japanese medical insurance policy 2012]. AB - Physiological function tests are managed by the clinical laboratory medicine section in most hospitals in Japan. Appropriate usage and refunds for the tests are important for both medical benefits and economically sustainable medical insurance management. The Japanese medical insurance policy was revised this year, and many physiological function tests, mainly respiratory and cardiovascular function testing, were accepted for refunding. These tests are common in each field, but evidence for their medical benefits should be re evaluated in Japanese people. PMID- 23672086 TI - hMLH1 promoter methylation status causes different expression patterns of estrogen receptor protein with endometrial lesion progression. AB - Mismatch repair (MMR) deficiency is reported to be an important factor in the early process of endometrial carcinogenesis. Although estrogen exposure is a crucial risk factor for endometrial carcinoma (EMCa), estrogen function is mediated by the estrogen receptor (ER). However, the relationship between ER and MMR, such as hMLH1 (human mutL homolog 1) activity, remains undetermined. In this study, we investigated the relationship between ER expression and hMLH1 promoter methylation status in atypical hyperplasia (AEH) and EMCa. ER expression was examined by immunohistochemical staining and the hMLH1 methylation status was evaluated using a methylation-specific PCR method. ER expression was significantly high in AEH, and extremely decreased with progression to EMCa. The hMLH1 methylation status allowed classification into methylated and unmethylated groups. Regarding the relationship between ER expression and hMLH1 methylation status, ER expression differed significantly between AEH and EMCa, and decreased with progression of the lesion in the unmethylated group, while it did not decrease with progression in the methylated group. These findings suggest that for a precursor lesion with hMLH1 unmethylated status, a decrease in ER expression is important for the development of carcinogenesis, while progression of a lesion with hMLH1 methylated status is not affected by ER expression. PMID- 23672087 TI - [Clinical significance of hyaline casts in the new CKD risk classification (KDIGO 2009)]. AB - Chronic kidney disease (CKD) significantly contributes to the increased number of dialysis patients with end stage renal disease. A new CKD risk classification (KDIGO 2009) established in 2011, which is defined by albuminuria and estimated glomerular filtration rate (eGFR) values, demonstrates the relative risks of CKD in great detail. In this study, we evaluated the clinical significance of urinary casts by categorizing a risk Group 1 to 5 according to the KDIGO 2009 classification. In the high risk CKD group (risk group 3 and over), we found a significantly higher number of patients who had > 100 hyaline casts/whole field (WF) in their urine than those that had < 100 hyaline casts/WF. Further, we determined the diagnostic accuracy for the high risk CKD group when the cutoff value for the number of hyaline casts was set at > or = 100 hyaline casts/WF (sensitivity: 44.7%, specificity: 96.5%). The eGFR value was significantly lower in the group with > or = 100 hyaline casts/WF, particularly in hypertensive patients, than that in the group with < 100 hyaline casts/ WF. Of interest is that the eGFR value was significantly lower in patients with 100-999 hyaline casts/WF and > or = 1,000 hyaline casts/WF than that in patients with < 100 hyaline casts/WF in A1 stage. Thus, our present study suggests that the presence of > or = 100 hyaline casts/WF indicates decreased eGFR, and the urinary casts counting may be important and useful for the screening and early detection of high-risk CKD. PMID- 23672088 TI - [Current topics on infectious diseases]. AB - In April 2012, the Japanese Health authority recommended the establishment of an inter-hospital connection and cooperation system for infection control in each local area. This system is aimed at improving the risk of hospital-related infection in each local area units. An important role of the system is monitoring the trend of drug-resistant bacteria and detecting outbreaks; therefore, development of a bacterial laboratory system is a major subject for participating hospitals. Increasingly drug-resistant bacteria, such as extended-spectrum beta lactamase-producing bacteria, MRSA, especially relatively high MIC strains against vancomycin (2 microg/ml), multi-drug resistant Gram-negative bacteria including Pseudomonas aeruginosa are serious issues for public health. The isolating ratio of these drug-resistant bacteria is different among hospitals even in the same local area. This is the point of organizing an inter-hospital infection control system. Last year, The Japanese Society for Respiratology developed management guidelines for Nursing Home and Health Care facility associated pneumonia(NHCAP). This Japanese guideline and USA guidelines for similar situations state almost the same position. Namely, such pneumonia patients should be treated empirically with combination antibiotics covering drug resistant bacteria, especially for MRSA and P. aeruginosa; however, in spite of this strengthened antibiotic coverage policy, one multicenter cohort study showed that guideline-based strengthened therapy increased the mortality of patients. The author drew the conclusion that too strong combination antibiotic therapy may be harmful to elderly patients. From these results, it should be considered that the causative agents of pneumonia cannot be determined from respiratory specimens so exactly, because the specimens include merely colonized bacteria and also anaerobic causative agents. PMID- 23672089 TI - [The role of the pharmacist in the proper use of antibacterial drugs]. AB - Treatment of infections is a team medical care operation, utilizing the coordinated expertise of many different professionals. Among these, the duty of the pharmacist, as a drug specialist, is considered to be related to the proper use of antibacterial drugs. When selecting an antibacterial drug, it is important to understand the severity and infection source of the patient, and consider drug susceptibility and tissue transitivity based on the antibiogram at the hospital. Moreover, consideration of the specific clinical conditions of pregnant or nursing women, and children, as well as any organ dysfunctions, is required to determine the appropriate antibacterial drug and its proper use. The dosage and administration method of the selected antibacterial drug are determined based on factors such as PK-PD parameters and organ dysfunction of the patient. For drugs requiring TDM, implementation of TDM, determination and evaluation of efficacy, and suggestions to change the antibacterial drug, its dosage, or administration method when needed, are all considered to play a part in the treatment of infection. The duty of the pharmacist is to promote the proper use of antibacterial drugs and participate in the treatment of patients. Moreover, since the proper use of an antibacterial drug and effective use of PK-PD parameters lead to prevention of the emergence of resistant bacteria, we would like to contribute to the preservation of antibacterial drugs as well. PMID- 23672090 TI - [TDM management system for contribution to proper use of anti-mRSA drugs- establishment of cooperation support system between pharmacy and clinical laboratory in hospital]. AB - In team medicine, highly specialized pharmacists have recently been in demand. As one of the specialties, there is therapeutic drug monitoring (TDM). It is important for the optimal dosing of a wide range of drugs. In our hospital, a TDM service was started in 1987 at the clinical laboratory. A clinical laboratory technologist with the license of a pharmacist has performed administration plans for anti-methicillin-resistant Staphylococcus aureus (MRSA) drugs, vancomycin, teicoplanin, and arbekacin. In particular, the pharmacist in charge of TDM services, a TDM-specialized pharmacist, plays a central role in administration plans for anti MRSA drugs. Furthermore, we examined the active use of the TDM service to expand pharmaceutical care. Therefore, at first, we have worked in partnership with the clinical laboratory, as it is called the "Cooperation Support System", since September 2010. As a result, after the introduction of this system, from August 2011 to July 2012, the rate that the doctor referred to the administration plan was markedly improved by approximately 90%. We have been able to enhance TDM in practical training for pharmacology as an extension of this system. We thought that drug therapy can be performed more appropriately by increasing the number of executions of TDM in the future. For drug therapy to be done more appropriately, efforts made through cooperation with the clinical laboratory are essential for an effective TDM system. Naturally, an effective TDM process requires a collaborative, multidisciplinary approach with input from doctors, nurses, and clinical pharmacists. PMID- 23672091 TI - [New stream for the measurement of anti-platelet factor 4/heparin antibodies]. AB - Heparin-induced thrombocytopenia (HIT) is a 'clinicopathologic syndrome'; therefore, its diagnosis depends on clinical criteria including the presence of thrombocytopenia and/or thrombosis and a pathological criterion implying the detectability of HIT antibodies. Recently, medical reimbursement (390 points) for assays of HIT antibodies using three new assay kits [HemosIL HIT-Ab(PF4-H), HemosIL AcuStar HIT IgG(PF4-H), HemosIL AcuStar HIT-Ab(PF4-H)] was approved in Japan. The HemosIL HIT-Ab(PF4-H) kit is a latex particle-enhanced immunoturbidimetric assay to detect total heparin-associated antibodies found in HIT patients. A monoclonal antibody that mimics human HIT antibodies is coated onto latex particles. HemosIL AcuStar HIT-IgG(PF4-H) (specific for IgG anti PF4/heparin antibodies) and HemosIL AcuStar HIT Ab(PF4-H) (detecting IgG, IgM and IgA anti-PF4/heparin antibodies) are applicable to a fully automated quantitative chemiluminescent immnunoassay instrument 'ACL AcuStar'. HIT can be excluded in all patients by a negative antigen assay using HemosIL HIT-Ab(PF4-H) or HemosIL AcuStar HIT-Ab(PF4-H). Furthermore, in patients with previous HIT who require heparin treatment, pretesting by HemosIL HIT-Ab(PF4-H) or HemosIL AcuStar HIT Ab(PF4-H) might be useful for preventing the onset of rapid-type HIT. PMID- 23672092 TI - [Genetic factors of hypertension]. AB - Essential hypertension (EH) is thought to be a multifactorial disease. In Japan, there are more than 20 million cases of EH, which accounts for 80 to 90% of hypertension cases in Japan. It is very difficult to isolate the susceptibility genes of EH in familial linkage analysis such as sib-pair analysis and association studies such as case-control studies of candidate genes. Over the past few years, genome-wide association studies (GWAS) have begun to identify the primary genetic mechanisms of hypertension. For example, GWAS have identified many loci in or near genes that generally were not expected to be associated with the level of blood pressure or essential hypertension. Considering the high expectations for the studies and the billions of dollars spent to conduct these studies, however, progress has been slow. We believe that next-generation research technologies, such as the whole genome sequencing, may remedy some of these problems encountered thus far. The present paper contains a review of issues and progress in isolation of susceptibility genes of EH, and an introduction to an effective novel method for isolation of susceptibility genes of EH. PMID- 23672093 TI - [Arrhythmia and genetic background]. AB - Recent studies have demonstrated that genetic abnormalities associated with the regulation of myocardial ionic channels, receptors, transporters, cell membranous proteins etc, can create an arrhythmogenic substrate in some patients with structurally normal hearts, and these are called hereditary arrhythmic diseases. Various arrhythmic diseases (such as congenital long or short QT syndrome, Brugada syndrome, catecholamine-sensitive polymorphic ventricular tachycardia, arrhythmogenic right ventricular cardiomyopathy, early repolarization syndrome etc.) are categorized as hereditary arrhythmic diseases. Among them, we focused on long QT syndrome and Brugada syndrome in this review. In congenital long QT syndrome, either attenuation of the net outward current or augmentation of the net inward current is responsible for prolonging the myocardial action potential duration and QT interval on ECG. Premature ventricular beats triggered due to early after-depolarization infringe on the large spatial dispersion of ventricular repolarization and initiate polymorphic ventricular tachycardia with a specific form (torsade de pointes). Currently, thirteen genotypes in Romano Ward syndrome and two genotypes in Jervell-Lange Nielsen syndrome have been reported. In Brugada syndrome, large transient outward current (Ito) creates a deep phase 1 notch in the action potential, especially at the epicardial myocardium of the right ventricular outflow tract. In combination with the delayed completion of repolarization and loss of the phase 2 dome in some epicardial myocardium in this area, coved-type ECG abnormality and ventricular fibrillation due to phase 2 reentry are believed to be induced in Brugada syndrome. Eleven genetic abnormalities are presently listed as a possible cause of Brugada syndrome. PMID- 23672094 TI - [Genetic predisposition to dyslipidemia]. AB - Lipid metabolism is regulated by several factors, such as apolipoproteins, lipoprotein receptors, enzymes, and transfer proteins. From the early 1980s until now, molecular biology has been developing rapidly. Hence, genetic analyses have accelerated all over the world. Using these techniques, many genetic investigations have been performed in large-scale studies, which revealed the close associations between genetic abnormalities of the above-mentioned factors and a variety of dyslipidemic disorders. In recent years, novel genes which regulate cholesterol metabolism were reported. For instance, proprotein convertase subtilisin kexin type 9 (PCSK9) and autosomal recessive hypercholesterolemia (ARH) were found as causal genes in patients whose phenotypes are similar to familial hypercholesterolemia. Niemann-Pick C1-Like 1 (NPC1L1), ATP-binding cassette (ABC) A1 (ABCA1), and G5/G8 (ABCG5/G8) were also identified as cholesterol transporters in intestinal epithelial cells and hepatocytes. NPC1L1 is recognized as a target of ezetimibe, a cholesterol absorption inhibitor classified into a new class of lipid-lowering agents. However, we have not been fully successful in identifying candidate genes for all dyslipidemias. In this review, we summarize major dyslipidemic disorders and their causal genes, pathosis, clinical features, diagnosis, and therapeutic approaches. Because it is difficult to analyze genetic abnormalities in clinical laboratories at present, simple and convenient procedures for genetic analyses are expected to be developed in the near future. Such techniques may reveal unknown pathologics for heritable dyslipidemias, which may lead to the search for potential drug targets. PMID- 23672095 TI - [Genetic background of heart failure: SNP association study for heart failure and the underlying diseases]. AB - Genome wide association studies (GWAS) using single nucleotide polymorphisms (SNP) have identified numerous genetic risk factors for common diseases. In heart diseases, genetic risk loci for coronary artery diseases (CAD) and atrial fibrillation are particularly identified by means of GWAS in several ethnic populations. However, genetic risk loci associated directly with heart failure (HF) have been poorly characterized so far, because the pathology of HF is based on several heart diseases such as hypertensive, coronary heart diseases, valvular disease of the heart, and arrhythmia. In this review, I will discuss recent advances in molecular genetics for HF and its basic diseases such as CAD, hypertension, and atrial fibrillation. PMID- 23672096 TI - [Genetic factors in myocardial infarction]. AB - One of the main mechanisms of acute myocardial infarction (AMI) is plaque rupture or erosion followed by intraluminal thrombus formation and occlusion of the coronary arteries. Thus far, many underlying conditions or environmental factors, such as hypertension, diabetes, dyslipidemia, smoking or obesity, as well as a family history of coronary artery diseases have been identified as risks for the onset of AMI. These risks suggest that AMI occurs due to interactions between underlying conditions and multiple genetic susceptibilities. For this reason, many target gene-disease association studies have been performed with the recent introduction of genome-wide association studies (GWAS) that have further revealed new genetic susceptibilities for AMI. GWAS is a way to examine many common genetic variants in different individuals to see if any variant is associated with a trait in a case-control fashion, and typically focuses on associations between single-nucleotide polymorphisms (SNP) and traits. SNP on chromosome 9p21 is one of the robust susceptibility variants for AMI which has been identified by many GWAS. In this review, we overview the methodology of GWAS, introduce genetic variants identified by GWAS as those with susceptibility for AMI, and describe the foresight of using GWAS to investigate genetic susceptibility to AMI. PMID- 23672097 TI - Plasma level of atherogenic and anti-atherogenic factors among palm wine drinkers of rural southwest Nigeria. AB - BACKGROUND: Scientific evidence indicates that light to moderate drinking on a daily basis may significantly reduce the risks of coronary heart disease (CHD). In contrast, excessive alcohol intake and binge drinking are toxic to both the heart and overall health. There is dearth of knowledge whether palm wine exhibit any these properties. OBJECTIVES: The objective of this study is to evaluate the effect of level of palm wine consumption on the plasma atherogenic and anti atherogenic factors among the rural dwellers. METHODS AND MATERIALS: Fifty-eight male volunteers between the ages of 28-69 yrs were recruited. They were divided into two groups; 28 moderate drinkers with intake of 20-70 grams/day and 30 heavy drinker with intake of >70 grams/day of palm wine at a sitting for 3 to 4days per week with a minimum duration of 5 years. Thirty controls of the same age groups with the same socioeconomic status were recruited. Plasma activities of liver enzymes, plasma concentration of Total Cholesterol (TC), Triglyceride (TG), High Density Lipoprotein (HDL), Low-Density Lipoproteins (LDL) and apolipoprotiens (ApoA1 & Apo B) were determined. TC/HDL, LDL/HDL and ApoB/A1 ratios calculated. RESULTS: There was significant increase in plasma concentration of TG, LDL, ApoB and decrease in HDL and ApoA 1 among heavy drinkers. However, there was an increase in plasma level of ApoA1 and decrease in ApoB among moderate drinkers but not significant when compared to the controls. A positive correlation were observed between level of palm wine consumption (>70gram/day) and plasma levels of TG LDL, ApoB, TC/HDL ratio, ApoB/ApoA1 ratio; but negative correlation with HDL and ApoA1. CONCLUSION: Our finding revealed that heavy consumption of palm wine may promote atherogenic factors, but the benefits of moderate consumption recorded need further investigations. There is also the need to determine the level of polyphenolic substances if any in palm wine. PMID- 23672098 TI - Drug utilization and blood pressure control in a population where antihypertensives are given free: effect of policy change. AB - OBJECTIVES: To assess the current utilization pattern of antihypertensive drugs and blood pressure (BP) control among treated hypertensives where there is a change in payment policy for antihypertensive drugs and to compare with a previous study when drugs were given free in the same setting. METHODS: A cross sectional study of hypertensive subjects being followed-up in the medical clinic of International Institute for Tropical Agriculture. RESULTS: One hundred and sixteen consecutive hypertensive subjects aged 50.9+/-8.6 years were studied. Eighty two (70.7%) of the subjects were fully controlled on the treatment, while 15 (12.9%) were not controlled at all. Systolic BP alone was controlled in 14 (12.1%) while in 5 (4.3%) subjects the Diastolic BP alone was controlled. Systolic BP was 133.4+/-14.0 (106-186) mmHg, while diastolic was 83.5+/-9.1 (59 110) mmHg. Salt use correlated with and was predictive of BP control, r = 0.336 and r2 = 3.383, p=0.001. Frequency of drug use: Diuretics 79.8%, calcium channel blockers (CCB) 51.8%, alpha-methyldopa 21.9%, angiotensin converting enzyme inhibitors 17.5%, beta-blockers 15.8%, vasodilator 1.8%, and prazosin 0.9%. CONCLUSION: In this study, twice as many patients as in the previous study had fully controlled blood pressure in spite of the new policy of co-payment. Health education and patient counselling along with availability of free drug could have contributed to improve adherence to antihypertensive drugs. Physicians managing hypertensive patients should pay attention not only to adequate dosing and appropriate combination of drugs but also to health education and patient counselling. PMID- 23672099 TI - National Health Accounts estimation: lessons from the Nigerian experience. AB - OBJECTIVE: This paper seeks to summarize the estimation of two rounds of Nigeria's National Health Accounts (NHA), 1998-2002 and 2003-2005 and draw some lessons on the NHA methodology and health financing policy challenges towards enhancing government stewardship role in the health sector. METHOD: The paper uses the results of the two rounds of NHA estimations for Nigeria a s basis fo ranalysis. In each round of estimation, three matrices were estimated. Additional three matrices of sub-National Health Accounts were also estimated for 17states in the second round. RESULTS: With Nigeria's per capita Total Health Expenditure (THE) increasing from US 9.39 dollars in 1998 to US 55.04 dollars in 2005, the THE represent about 5% of GDP. The households accounted for around 68.6% of THE, while government shoulders about 25%. Major lessons learnt relate to skewed spending, challenges of recordkeeping and data collection at the federal and state levels, and commitment of government and other stakeholders in ensuring institutionalized procedures for collection, reporting, and retrieval of health financing data. CONCLUSION: Though NHA results indicate increase in spending on health over time, there is a very high burden on households. Besides, there are institutional challenges inhibiting the estimation process. There is need for government to lessen burden on households to improve its stewardship by increasing its contribution. The institutional capacity need to be strengthen to collect and analyse health expenditure data and interpret results in terms of their policy implication, while government takes ownership of the process to ensure the institutionalization and sustainability of the estimation process. PMID- 23672100 TI - Knowledge and attitude of health professional students toward patients living with AIDS. AB - INTRODUCTION: What health professional students know of AIDS and their attitudes towards PLWA enrich our knowledge in assuring quality of care administered to AIDS patients. OBJECTIVES: This study was designed to assess 1) What Nigerian students in various health disciplines know about AIDS and how they behave towards PLWA. and 2) Determine the sociodemographic variables that could influence knowledge of AIDS and behaviour towards PLWA among students of the various health disciplines in a university in North- Eastern Nigeria. METHODS: This cross-sectional study involving student volunteers (n=644) in the last two years of their professional training drawn from six disciplines were surveyed using a two-part questionnaire. Section I of which elicited students' sociodemographic and previous AIDS encounter information, and section II assessed knowledge and behaviour towards PLWA. RESULTS: Students in surveyed health professions had an unsatisfactory level of knowledge on AIDS pathophysiology and their behaviour towards PLWA was negative. Gender, clinical year, religious affiliation, discipline, level of satisfaction with AIDS instructions, knowing a family member or another person with a diagnosis of AIDS and willingness to provide care for an AIDS patient influenced the students' knowledge and behaviour. CONCLUSION AND RECOMMENDATION: The study revealed a real possibility for health professional students to hesitate to care for PLWA, or render uncoordinated or fragmented care at the time of their graduation. It suggests the need for intervention to include methodical and all inclusive clinical clerkship on HIV/AIDS and small group discussions with real life case scenerios involving PLWA while in training. PMID- 23672102 TI - Effect of interval exercise training programme on C-reactive protein in the non pharmacological management of hypertension: a randomized controlled trial. AB - OBJECTIVE: Increased serum levels of inflammatory mediators have been associated with numerous disease states including hypertension. C-reactive protein (CRP) levels are associated with future development of hypertension and cardiovascular event in hypertension, which suggests that hypertension, is in part an inflammatory disorder. The objective of this study was to determine the effect of interval training programme on blood pressure and CRP in the non pharmacological management of hypertension. METHODS: Two hundred and forty five male subjects with mild to moderate (Systolic Blood Pressure [SBP] between 140-179 & Diastolic Blood Pressure [DBP] between 90-109 mmHg) essential hypertension were age-matched and randomly grouped to interval (n=140) and control groups (n=105). The interval (work: rest ratio of 1:1) groups involved in an 8-weeks interval training programs for between 45-60 minutes, at intensities of 60-79% of HR reserve, while the control group remained sedentary during this period. SBP, DBP, VO2max and CRP were assessed. Students't and Pearson correlation tests were used in data analysis. RESULTS: Findings of the study revealed significant effect of interval exercise training program on SBP, DBP and CRP. The study also showed positive significant correlation between changes in CRP and changes in SBP (r=225) and DBP (r= .324) at p<0.05. CONCLUSIONS: It was concluded that moderate intensity interval training programs is effective in the non-pharmacological management of hypertension and may prevent cardiovascular event through the down regulation of CRP in hypertension. PMID- 23672101 TI - Effect of magnesium on gastrointestinal transit time in normal and diabetic rats: possible mechanism of action. AB - BACKGROUND: Many gastrointestinal complications in diabetes are connected to neurohumoral dysfunction resulting in abnormalities of intestinal motility, secretion and absorption. Minerals have been reported as essential cofactors for basic cellular reactions but there is dearth of information on effect of Magnesium on gastrointestinal transit time (GITT) and the mechanism of action. METHODS: Sixty male albino Wistar rats (180 - 200g) were grouped into twelve of five animals each. Group 1 (control) received 0.2ml saline. Groups 2-6 were normal rats treated with magnesium sulphate (as magnesium) (500mg/kg), adrenaline (0.5mg/kg), magnesium (500mg/kg) and adrenaline (0.5mg/kg), prazosin (1mg/kg) and both magnesium (500mg/kg) and prazosin (1mg/kg) respectively. Groups 7 - 12 were diabetic rats treated as in groups 1- 6. Diabetes was induced intraperitoneally with alloxan (120mg/kg bwt). RESULTS: There was significant (p<0.05) reduction in GITT index in normal rats treated with magnesium, prazosin and combination of magnesium and prazosin compared with control. Treatment with adrenaline alone produced significant increase in GITT. However treatment with both magnesium and adrenaline produced significant reduction compared with control. This reduction in GITT was similar to that obtained in magnesium only and prazosin only treated groups. Diabetic groups showed significant reduction in GITT in all treated groups except the adrenaline only treated group which produced significant increase in GITT. CONCLUSION: The significant reduction in GITT produced by magnesium in both normal and diabetic animals was comparable to that produced by prazosin (an a-adrenoceptor antagonist) indicating that magnesium may be inhibiting gastrointestinal smooth muscle contraction through a-adrenoceptor antagonist pathway. PMID- 23672103 TI - Hepatitis B and E viral infections among Nigerian healthcare workers. AB - BACKGROUND: There is dearth of information on Hepatitis E virus (HEV) infection and its co-infection with HBV among Nigerian healthcare workers (HCWs). Hence, there is the need to determine the rate of HEV infection and its association with HBV among HCWs who are at greater risk of nosocomial infections. METHODOLOGY: Sera from 88 HCWs and 44 non-HCWs healthy adults as controls were tested for the presence of antibody to HEV (anti-HEV). The HCWs were also tested for HBsAg and antibody to Hepatitis B core antigen (anti-HBc) using commercially available ELISA kits. RESULTS: The prevalence of anti-HEV obtained among the HCWs and controls were 43% and 94% respectively (p<0.005) while those of HBsAg and anti HBc in HCWs were respective 13% and 56%. Overall among HCWs, the prevalence of HBV infection was 65.9%, higher than HEV infection (p<0.005) with only anti-HBc greater among the male participants (p<0.005) while co-infection of HBV with HEV was 27.3%. HEV infection was least among the Paediatricians (18%) and highest among the Surgeons (55%) while HBV infection was similar in all the different occupational groups of HCWs (44-59%) except among the Gynecologists and Obstetricians (80%). CONCLUSION: Infection with HEV is high among Nigerian HCWs but lower than the rate among non-HCWs. It is also co-infected with HBV especially among the different groups of the HCWs and could occur with the diverse clinico-serological patterns of HBV infection. PMID- 23672104 TI - Influence of clinical and demographic factors on static balance among stroke survivors. AB - BACKGROUND: Stroke is often characterized by disturbance in balance and mobility among the survivors with its attendant rehabilitation potentials. Static balance serves as a foundation for attainment of functions in patients with stroke, yet its determinants are usually under-estimated. AIM: This study was therefore designed to determine the influence of some clinical and demographic factors on static balance in stroke survivors. MATERIAL AND METHODS: Eighty (80) hemiparetic stroke survivors participated in this cross-sectional survey. Demographic variables include age, height, weight and body mass index (BMI) whilst knee range of motion, (ROM) duration of stroke, levels of disability and spasticity of the paretic lower limbs of the participants were the clinical variables. Universal Goniometer, Barthel Index, and Modified Ashworth Scale were used to assess ROM, disability and spasticity levels respectively. The outcome measure for static balance was Functional Reach Test. Pearson's correlation coefficient analysis was performed to establish the correlations between some selected variables and the static balance. Level of significance was set at p<0.05. RESULTS: The mean age of the participants was 56.7+/-12.8 years. They comprised 37(46.2%) right hemiparetic and 43 (53.8%) left hemiparetic patients. Significant positive correlation was observed between functional reach scores and knee ROM, spasticity and disability levels (r=0.3; r=0.5; 0.2) respectively. However, the mean age, weight, height and BMI of the participants were not significantly correlated with functional reach scores. CONCLUSION: Joint range of motion, spasticity and disability levels were the main determinants of static balance in stroke survivors. These factors should be considered whilst priotizing goals during rehabilitation of stroke survivors. PMID- 23672105 TI - Effects of different fractions of Calliandra portoricensis root bark on isolated rat liver mitochondrial membrane permeability transition pore. AB - BACKGROUND: Mitochondrial membrane permeability transition (MMPT) pore ha s emerged as a promisingtarget for various pharmacological interventions because of the consequent release of cytochrome c upon the opening of the pore which is the point of no return for apoptosis, a form of programed cell death that is down regulated in cancercells. AIM: To evaluate the modulatory effects of fractions (Chloroform fraction of calliandra portoricensis( CFCP), Aqueous fraction of calliandra portoricensis (AFCP), and Ethylacetate fraction of Calliandra portoricensis (EFCP) of methanol extracts of the root bark of Calliandra portoricensis (MECP), a medicinal plant used in the traditional treatment of prostate tumour, on mitochondrial membrane permeability transition (MMPT) pore. METHODOLOGY: Opening of the pore was assessed as mitochondrial swelling and was monitored spectrophotometrically as changes in absorbance at 540nm. RESULTS: Varying concentrations of MECP (10microg/ml, 20microg/ml, 40microg/ml, and 60microg/ml) induced opening of the pore, in the absence of calcium, by 1.1, 2.8, 4.5, 13.8 folds, respectively while spermine reversed this inductive effect. Interestingly, unlike MECP, EFCP and AFCP did not have any effect at lower concentrations (<40microg/ml) but induced pore opening at 60microg/ml, 80microg/ ml, 100microg/ml and 120microg/ml by 1.6, 3.1, 12.7, 16.7folds, respectively for EFCP and 1.4, 5.4, 7 and 10 folds respectively, for AFCP. In the presence ofcalcium, the pore was slightly further opened by MECP, EFCP andAFCP. The CFCP however did not have any significant effect on the pore either in the presence or absence of calcium. CONCLUSION: These findings suggest that the bioactive agents that induced the opening of the pore are present in the most potent ethylacetate fraction of the root bark of C. portoricensis. This fraction will therefore be useful for the structural elucidation of the bioactive principle in the plant and for further studies in diseases that require increased apoptosis such as cancer. PMID- 23672106 TI - Pattern of intradialytic complications at the Lagos University Teaching Hospital. AB - BACKGROUND: The safety of haemodialysis (HD) procedure has improved greatly over the years but, the procedure is not without risks; complications still occur during dialysis. In this study, we report on the pattern of intradialytic complications seen over a one year period at the dialysis centre of the Lagos University Teaching Hospital Lagos (LUTH), Nigeria. METHOD: We reviewed the dialysis and hospital records of consecutive patients with chronic kidney disease (CKD) who received haemodialysis treatment in the dialysis centre during the period between January and December 2010. Data comprised patients' demographics, aetiology of kidney failure and complications encountered during the HD treatment sessions. RESULTS: The study involved 201 patients with CKD; there were 113 (56.2%) males, the mean age was 47.5 +/- 15.7years. There were 140 (69.7%) new patients and 61 (30.3%) old patients. The most common aetiology of CKD was hypertension (42.8%) followed by glomerulonephritis (15.9%). A total of 1010 haemodialysis sessions were recorded with complications occurring in 36.2% of the HD sessions. The most frequently encountered complication was hypertension which occurred in 15.2% of HD sessions followed by hypotension 8.5%. Hypotension occurred more frequently during first HD session (18.4%) compared with subsequent sessions (6.1%) X2 = p < 0.001. Patients who experienced hypertension had significantly higher pre-dialysis systolic blood pressure (BP) values (mean 168 +/- 28.6mmHg vs 149.3 +/- 20.1mmHg) and pre-dialysis diastolic BP (100.6 +/- 18mmHg vs 90.3 +/- 11.4mmHg) compared with those who did not p <0.001. CONCLUSION: Hypertension was the most frequently encountered complication. Hypotension was still commonly encountered especially during first HD treatments. Clinicians must make concerted to optimise blood pressure in patients undergoing haemodialysis therapy. PMID- 23672107 TI - Livolin ameliorates elevations in alanine transaminase in HIV infected patients commencing highly active antiretroviral therapy. AB - BACKGROUND: HAART associated hepatoxicity is an important cause of poor adherence to therapy in HIV infected persons. An initial manifestation is elevation in the level ofAlanine Transaminase (ALT) in blood. We sought to evaluate the protective effects of Livolin, a phosphatidylcholine containing preparation, against elevations in this enzyme in persons just commencing HAART. METHODOLOGY: All consenting patients deemed eligible for HAART and who were sero-negative for Hepatitis B and C were recruited into the study. Subjects were divided into a test group which received a thrice daily dose of Livolin capsules for 3 months in addition to HAART and a control group that received only HAART. Blood samples were collected at baseline and after 3 months and analysed for ALT, Aspartate aminotransferase, alkaline phosphatase and creatinine. The specific HAART combination, age and gender were also noted. RESULTS: Seventy nine (79) persons comprised of 43 test and 36 control subjects completed the study. Sixty six percent (79%) of all subjects were on Nevirapine containing combinations. In total, 8.9% and 11.7% of our patients had elevations at baseline and after 3 months respectively. These were mostly grade I, with grade II toxicity being observed in 3.3% of patients after 3 months of HAART. There was no instance of severe toxicity. For individuals with an elevation in ALT values at baseline, the mean drop at 3 months was significantly more in the test group compared with the control group (34.67 iu/L vs. 14.90 iu/L, p=0.005). Among subjects with on Nevirapine, the mean increment in ALT in the control group was 7.73 iu/L compared with 1.73 iu/L for the test group. CONCLUSION: The findings in this study mirror findings in both animal experiments and human studies of a potential benefit of phosphatidylcholine preparations, like Livolin, in protecting against drug induced hepatotoxicity. PMID- 23672108 TI - Incidence and characteristics of injuries during the 2011 West Africa Football Union (WAFU) Nations' Cup. AB - BACKGROUND: Prospective studies on football injuries and their risk factors in the African setting are sparse. Such studies are needed to understand the peculiarities of injuries and hence proffer appropriate intervention for injury prevention in the region. OBJECTIVE: To evaluate the incidence and characteristics of match injuries during the 2011 West Africa Football Union (WAFU) cup. METHODS: Team physiotherapists from the participating teams documented all newly incurred injuries on standardised injury report forms using the Federation of International Football Association's (FIFA) Medical Assessment and Research Centre protocols. RESULTS: An overall of 89 injuries were sustained during the tournament, resulting in 9.9 injuries per match or 289 injuries per 1000 player hours. Seventeen (19.1%) of these injuries resulted in loss of competition activity (time-loss), equivalent to 1.9 injuries per match or 55.2 injuries per 1000 player hours. Over three quarters (73; 82%) of injuries were incurred through contact with another player. The lower leg accounted for almost a quarter of all injuries (21; 23.6%) while the knee recorded the highest number of time-loss injuries (5; 29.4%). The most frequent types of injury were contusion (61; 68.5%) and strain (13; 14.6%). CONCLUSION: The overall incidence of injuries during the WAFU cup was much higher than those of other tournaments ever documented but the characteristics of injuries were similar. In order to fully define the nature of injuries and more reliably identify the risk of injury for the establishment of injury prevention strategies that will be appropriate for this region of the world, it is imperative that further systematic injury recording and analysis in African players are carried out. PMID- 23672109 TI - Morphine-sparing effect of intravenous paracetamol for post operative pain management following gynaecological surgery. AB - OBJECTIVE: The study evaluated the morphine sparing effect of intravenous Paracetamol and the incidence of side effects in the recovery room following lower abdominal gynaecological surgery. METHOD: Fifty six, ASA I and II patients undergoing lower abdominal gynaecological surgery were randomized into two groups, which were either given (A) intravenous (I.V) Paracetamol 1g diluted to 20 mls with normal saline or (B) I.V normal saline 20 mls at the beginning of the skin closure. In the re covery room pain intensity was evaluated and the time of first request for analgesic was noted. Intravenous morphine 2mg bolus was titrated to . Pain relief was evaluated at rest and on movement until pain score at rest Numerical rating score (NRS) < or = was achieved. Total dose of morphine was noted, morphine side effects, adequacy of analgesia and patient's satisfaction were assessed. RESULTS: The mean time of first analgesic request was prolonged significantly in Group A 40.9 +/-18.9 minutes vs. 11.4 +/- 5.5 minutes in Group B ( P = 0.00), with significant difference in morphine consumption 7.1 +/- 1.6 vs. 12.2 +/- 2.1 (P = 0.01) respectively. Morphine related side effects were higher in placebo group (33.3%) compared with (11.1%) in paracetamol group. More patients in the paracetamol group compared with the placebo group felt pain relief was adequate (66.7% vs 44.4%) and also more patients were satisfied with the regimen in paracetamol group compared with placebo group (96% vs 29.6%). CONCLUSION: Intravenous Paracetamol improved analgesia and reduced the amount of morphine consumption in the immediate postoperative period with reduced opioid side effects and better patient satisfaction. PMID- 23672110 TI - Coronal tissue loss in endodontically treated teeth. AB - AIM: To categorize the endodontically treated teeth according to the extent of coronal tissue loss in order to determine the appropriate restoration required. MATERIAL AND METHODS: A two year descriptive study was done at the Conservative Clinic of the Department of Restorative Dentistry, Dental Centre, University College Hospital, Ibadan. Successful endodontically treated teeth were assessed and categorized according to the extent of tissue loss based on standard criteria proposed by Smith and Schuman. RESULTS: Two hundred and ninety endodontically treated teeth were assessed for success both clinically and radiographically. Eighty (27.6%) were anterior teeth, 78 (26.9%) were premolars while 132 (45.5%) were molars. Dental caries was found to be the most common (61.4%) indication for endodontic treatment and caused more coronal tissue damage (moderate and significant) when compared with other indications for endodontic treatment. Two hundred and twenty seven (78.3%) endodontically treated teeth had moderate coronal tissue loss, 41 (14.1%) had minimal damage while 22 (7.6%) had significant tissue damage. Dental caries was the most common indication for endodontic treatment of the posterior teeth while trauma was the most common indication for the anterior teeth. CONCLUSION: Majority of the endodontically treated teeth that were evaluated for tissue loss had moderate coronal tissue damage. It is therefore recommended that proper and prompt evaluation of the remaining coronal tooth tissue following successful endodontic treatment be carried out in order to determine the appropriate definitive restoration required that will be easy for the clinician and less expensive to the patients. PMID- 23672111 TI - Odontogenic and oral soft tissue myxomas: clinicopathologic analysis of 16 cases from Ile-Ife, Nigeria. AB - OBJECTIVES: Odontogenic myxomas (OMs) are considered slow-growing tumours with the potential for extensive bone destruction, cortical expansion, and a relatively high recurrence rate. We analysed the cases histologically diagnosed as OM in our centre and compared these to the data found in the literature. METHOD: A record-based study of OMs histologically diagnosed at the Obafemi Awolowo University Teaching Hospital Complex (OAUTHC), Ile-Ife, Southwest Nigeria between 1990 and 2009 was conducted. The tumours were classified as myxomas, fibromyxomas or myxofibromas depending on the histologic picture. Gingival masses with similar histologic features but not showing bone involvement were included in the series as soft tissue myxomas. RESULTS: A total of 16 histologically diagnosed cases were recorded, 11(68.8%) in females and 5 (31.2%) in males giving a male:female ratio of 1:2.2. The most common tumour site was the maxilla (7 cases, 43.8%) and the mean age of the patients at the time of diagnosis was 31.1+/-18.0 years. Myxomas, exhibiting complete myxomatous tissue (8 cases, 50%) with no appreciable fibrous component were the most common histological type. CONCLUSION: The peak incidence was in the 2nd decade of life and there was a predilection for females (M:F = 1:2.2) and the maxilla. The recommended treatment of choice is radical surgery or conservative excision depending on tumour size. PMID- 23672112 TI - [Gynecology and obstetrics]. PMID- 23672113 TI - [Comparison of the frequency and magnitude of the vasomotor symptoms in premenopausal and postmenopausal women from Mexico City]. AB - BACKGROUND: Decreased ovarian function is associated with several symptoms, being the more frequent the vasomotor and these are associated to several factors. OBJECTIVE: To describe the frequency and magnitude of vasomotor symptoms in premenopausal and postmenopausal women from Mexico City. MATERIAL AND METHODS: A comparative, cross-sectional study was carried out from July 2011 to February 2012 in which somatometry was done and a questionnaire was applied to women beginning from 35 years age, evaluating their menopausal status, educational level, occupation, vasomotor symptoms (hot-flushes and sweats), intensity, frequency and the number of days per week with symptoms. Sample size was calculated considering a confidence interval of 99%, a power of 80%, with a frequency of symptoms presentation in premenopausal women of 55% and 85% in those postmenopausal, with a relationship of 1:1, considering 60 patients in each group. STATISTICAL ANALYSIS: A comparison among the groups was done for continuous variables with Student t test for independent samples and for discontinuous variables with chi2, a p level < 0.05 was considered statistically significant. RESULTS: Of the total population (144 women), 65 (45%) had vasomotor symptoms, 38% did physical exercise and 50% had some chronic illness. Of the 79 premenopausal women (Group 1) 49% was symptomatic and of the 65 postmenopausal women, 46% (Group II). Of the symptomatic ones in the Group I, 100% presented hot flushes and 77% considered their symptoms severe; in Group II 85% had hot-flushes and the symptoms were considered severe by 63%. CONCLUSION: The vasomotor symptoms were only associated to time since menopause. PMID- 23672114 TI - [Parity and menarche as risk factors of osteoporosis in postmenopausal Mexican women]. AB - BACKGROUND: At the moment the studies lead at world-wide level and even in our country have thrown discrepant results about the relation between osteoporosis, parity and age of menarche. OBJECTIVE: To investigate the relation of osteoporosis in postmenopausal Mexican women with multiparity and age of menarche. PATIENTS AND METHOD: A retrospective and analytical cross-sectional study, with a non-probabilistic sampling technique in women rightful claimants of the IMSS, San Luis Potosi. In all of them the bone mineral density was measured with X-ray dual absorptiometry in the distal forearm. Reproductive history and age of menarche were obtained by the addition of these items to the previously validated Albrand questionnaire. Women were divided into groups according to the number of pregnancies in: normal parity (0 to 3 childbirths) conformed by 112 patients (46%) and multiparity (> or = 4 pregnancies), 131 women (54%). In relation to menarche with an average of 12.98 years, from this number we divided them in: early menarche (< 13 yrs) and late menarche (> or = 13 yrs). RESULTS: 243 women were studied, with an average of age of 55.92, rank 31 to 80 years. Using the criteria of the World Health Organization, 18% of postmenopausal women had osteoporosis, 39% had osteopenia and 43% had bone normality. No association was found between the number of pregnancies and osteoporosis. Additionally we observed that the women who had four or more children were older than the other women, average 57.42 against 54.16. Also there was significant negative correlation (r = -0.43) between age and densitometry. We found that an age greater to 13 years in the appearance of the menarche was related to osteoporosis (OR 4.46, p: 0.035). CONCLUSIONS: In postmenopausal women a menarche older than 13 years is a risk factor for osteoporosis. PMID- 23672115 TI - [Perinatal outcome after prenatal diagnosis of intra-abdominal umbilical vein varix]. AB - BACKGROUND: Progress in echographic techniques, particularly, high-resolution echography and color Doppler, as well the higher deep on knowledge and systematization in fetal anatomy exploration, are the main responsible of the increased number of cardiovascular anomalies diagnosed prenatally. OBJECTIVE: To describe the sonographic findings and perinatal outcomes in cases with prenatal ultrasound diagnosis of intra-abdominal umbilical vein varix. MATERIAL AND METHODS: A descriptive and retrospective study of cases with prenatal ultrasound diagnosis of umbilical vein varix. The diagnosis is performed at the level of the abdominal circumference when the diameter of the vessel is above the established parameters for a certain gestational age. Variables concerning maternal-fetal features, ultrasound findings and perinatal outcomes of affected cases are described. RESULTS: From August 2008 to August 2012 14 cases of intraabdominal umbilical vein varix were diagnosed in our center with a mean gestational age at diagnosis of 29 weeks. Of the 14 cases, 35% had associated anomalies, mostly cardiovascular anomalies. No chromosomal defects were detected. Perinatal outcomes in newborns were favorable, with mean gestational age at delivery of 38 weeks. Only one case of monochorionic-monoamniotic twin pregnancy required preterm elective termination secondary to a twin-to-twin transfusion syndrome. CONCLUSION: Prenatal diagnosis of intra-abdominal umbilical vein varix should be followed by further studies given its possible association with other anomalies, chromosomal defects and cases of stillbirth. However, isolated cases of umbilical vein varix, representing a majority, often evolve favorably with few complications. PMID- 23672116 TI - [Inhibition of RANK-L in the pathophysiology of osteoporosis. Clinical evidences of its use]. AB - The increase bone turnover is the most important fact at the physiopathology of postmenopausal osteoporosis. At the molecular level it is the increase of the RANK-L the principal mediator who allows the osteoclasts formation, survival and development of them. Multiple models have been in use in preclinical investigations for evaluating the effects of the inhibition of the RANKL, between which it is included on OPG's over-expression in mice and transgenic mouse and by means of other models that include the treatment with recombinant OPG. The results of these studies show that RANKL's inhibition improves the DMO as well as the geometry and resistance of the bone. Several references clinical trials have investigated the potential of denosumab as antiresorptive drug for the prevention and treatment of bone disease. It is a monoclonal antibody, the first fully human, which were recently published results of randomized clinical trials to eight years for increasing BMD in different locations and five years for the prevention of vertebral and hip fractures. We review the fundamentals of the mechanism of inhibition of RANK-L and the results of several clinical trials of Denosumab. PMID- 23672117 TI - [Twin pregnancy discordant for trisomy 13: three cases]. AB - BACKGROUND: The association between Patau's syndrome and multiple pregnancy is extremely rare. This paper reports three cases with different obstetric treatment. CASE 1: Dichorionic diamniotic twin pregnancy with a fetus affected by trisomy 13 diagnosed at 16 weeks of gestation. The pregnancy was managed conservatively resulting in the delivery of twins at 38 weeks. The structurally normal twin was male survived without sequelae, but the female fetus with trisomy 13 died shortly after delivery. CASE 2: Dichorionic diamniotic twin pregnancy. At 14 weeks of pregnancy, one of the fetus affected by trisomy 13 showed an early intrauterine growth restriction and a cystic hygroma. At 16 weeks of pregnancy the abnormal twin died spontaneously. Avaginal delivery occurred at 38 weeks being born a healthy male. CASE 3: Dichorionic diamniotic twin pregnancy. The trisomy 13 fetus had been diagnosed at 17 weeks of pregnancy and showed a cardiopathy. At 32 weeks of gestation a selective fetal reduction was performed. Vaginal delivery occurred at 35 weeks and a healthy newborn was born. CONCLUSION: Patau's syndrome has an unfortunate fetal and neonatal outcome. It is important an early diagnosis to establish the best strategy to minimize the risk of the healthy twin. PMID- 23672118 TI - [Laparoscopic removal of primary intestinal fibroid]. AB - Uterine fibroids are the most frequent solid benign tumors of the female pelvis. The most frequent location is the uterine corpus; however, it has been also reported in cervical placement and broad ligament. Rarely it has been reported a case of intestinal fibroid after previous history of myomectomy. We report the case of a patient, with no surgical history of interest, who underwent a diagnostic laparoscopy due to suspicion of malignant abdominal mass. Ajejunal fibroid was found, which was removed via laparoscopy without complications. Laparoscopy may be considered in case of intestinal fibriod despite its rarity, due to the better postoperative recovery and cosmetic outcomes compared to laparotomy. PMID- 23672119 TI - [Pseudoaneurysm of the uterine artery after cesarean delivery]. AB - Uterine artery pseudoaneurysm is a rare but serious complication of pelvic surgery (although there are some cases reported following normal delivery), which can manifest as a severe bleeding in the postoperative period. Doppler ultrasound has an important role in the differential diagnosis of the causes of postpartum hemorrhage, and should guide us to this rare complication that can benefit from treatment by uterine artery angiographic embolization. Pseudoaneurysm is typically diagnosed by symptoms associated with the rupture, causing hemorrhage. It can also be asymptomatic, may thrombose, or may cause pain. We report the case of a uterine artery pseudoaneurysm diagnosed in the second episode seven weeks after cesarean delivery. PMID- 23672120 TI - [Mitral comisurotomy during pregnancy. A clinical case. 1958]. PMID- 23672121 TI - [Comparison of short-term effectiveness between minimally invasive surgery- and open-transforaminal lumbar interbody fusion for single-level lumbar degenerative disease]. AB - OBJECTIVE: To compare the short-term effectiveness of minimally invasive surgery transforaminal lumbar interbody fusion (MIS-TLIF) versus open-TLIF in treatment of single-level lumbar degenerative disease. METHODS: Between February 2010 and February 2011, 147 patients with single-level lumbar degenerative diseases underwent open-TLIF in 104 cases (open-TLIF group) and MIS-TLIF in 43 cases (MIS TLIF group), and the clinical data were analyzed retrospectively. There was no significant difference in gender, age, disease type, lesion level, disease duration, preoperative visual analogue scale (VAS), and preoperative Oswestry disability index (ODI) between 2 groups (P > 0.05). The operation time, intraoperative radiological exposure time, intra- and post-operative blood loss, postoperative hospitalization time, and postoperative complications were compared between 2 groups. The VAS score and ODI were observed during follow-up. The imaging examination was done to observe the bone graft fusion and the locations of internal fixator and Cage. RESULTS: There was no significant difference in operation time between 2 groups (t = 0.402, P = 0.688); MIS-TLIF group had a decreased intra- and post-operative blood loss, shortened postoperative hospitalization time, and increased intraoperative radiological exposure time, showing significant differences when compared with open-TLIF group (P < 0.05). Cerebrospinal fluid leakage (2 cases) and superficial infection of incision (2 cases) occurred after operation in open-TLIF group, with a complication incidence of 3.8% (4/104); dorsal root ganglion stimulation symptom (3 cases) occurred in MIS-TLIF group, with a complication incidence of 7.0% (3/43); there was no significant difference in the complication incidence between 2 groups (chi2 = 0.657, P = 0.417). The patients were followed up 18-26 months (mean, 21 months) in MIS-TLIF group, and 18-28 months (mean, 23 months) in open-TLIF group. The VAS scores and ODI of 2 groups at each time point after operation were significantly improved when compared with those before operation (P < 0.05). There was no significant difference in VAS score between 2 groups at discharge and 3 months after operation (P > 0.05); VAS score of MIS-TLIF group was significantly lower than that of open-TLIF group at last follow-up (t = 2.022, P = 0.047). At 3 months and last follow-up, no significant difference was found in the ODI between 2 groups (P > 0.05). The imaging examination showed good positions of Cage and internal fixator, and bone graft fusion in 2 groups. CONCLUSION: The shortterm effectiveness of MIS-TLIF and open-TLIF for single-level degenerative lumbar diseases was similar. MIS-TLIF has the advantages of less invasion and quick recovery, but the long-term effectiveness needs more observation. PMID- 23672122 TI - [Effectiveness of minimally invasive transforaminal lumbar interbody fusion assisted with microscope in treatment of lumbar degenerative disease]. AB - OBJECTIVE: To investigate the effectiveness of minimally invasive transforaminal lumbar interbody fusion (TLIF) assisted with microscope for lumbar degenerative disease. METHODS: Retrospective analysis was made on the clinical data of 82 patients with lumbar degenerative disease (minimally invasive group) undergoing minimally invasive TLIF assisted with microscope between January 2010 and June 2011, which was compared with those of 76 patients (traditional group) undergoing traditional open TLIF. There was no significant difference in age, gender, disease duration, disease type, lesion level, preoperative visual analogue scale (VAS), and preoperative Oswestry disability index (ODI) between 2 groups (P > 0.05). The perioperative related parameters, radiography index, and effectiveness were documented and compared. RESULTS: There was no significant difference in operation time and intraoperative radiological exposure time between 2 groups (P > 0.05), but intraoperative blood loss and postoperative drainage volume in the minimally invasive group were significantly less than those in the traditional group (P < 0.05). Dural tear occurred in 2 patients of the traditional group. Superficial infection of incision occurred in 1 case in each group, respectively; and primary healing of incision was obtained in the other patients. All patients were followed up 12-28 months (mean, 18 months). No failure of internal fixation occurred. Radiological analysis showed that the bone graft fusion rate was 96.1% (73/76) in the traditional group and 95.1% (78/82) in the minimally invasive group at last follow-up, showing no significant difference (chi2 = 0.012 2, P = 0.912 0). The postoperative ODI and VAS score were significantly improved when compared with preoperative ones in 2 groups (P < 0.05); the ODI of the minimally invasive group were significantly better than those of the traditional group at 3 months (t = -11.941 1, P = 0.000 0), and the VAS score of the minimally invasive group was significantly lower than that of the traditional group at 1 day and 3 months (P < 0.05); but no significant difference was found in ODI and VAS score between 2 groups at 1 year and last follow-up (P > 0.05). CONCLUSION: Minimally invasive TLIF is an effective method to treat lumbar degenerative disease. This procedure is safe and reliable because it has less injury, less blood loss, and milder pain than the traditional open TLIF, and the short-term effectiveness is comparable in 2 procedures. PMID- 23672123 TI - [Effectiveness of posterior intrasegmental fixation with pedicle screw-lamina hook system in treatment of lumbar spondylolysis]. AB - OBJECTIVE: To investigate the effectiveness of posterior intrasegmental fixation with pedicle screw-lamina hook system and bone grafting for lumbar spondylolysis. METHODS: Between January 2005 and October 2009, 22 patients with lumbar spondylolysis underwent posterior intrasegmental fixation with pedicle screw lamina hook system and bone grafting. There were 19 males and 3 females with an average age of 18.4 years (range, 12-26 years). The main symptom was low back pain with an average disease duration of 16 months (range, 8-56 months). The visual analogue scale (VAS) was 6.0 +/- 1.2 and Oswestry disability index (ODI) was 72.0% +/- 10.0% preoperatively. The X-ray films showed bilateral spondylolysis at L4 in 9 cases and at L5 in 13 cases. The range of motion (ROM) at upper and lower intervertebral spaces was (11.8 +/- 2.8) degrees and (14.1 +/- 1.9) degrees, respectively. RESULTS: All incisions healed by first intention. All patients were followed up 12-45 months (mean, 25 months). Low back pain was significantly alleviated after operation. The VAS score (0.3 +/- 0.5) and ODI (17.6% +/- 3.4%) were significantly decreased at last follow-up when compared with preoperative scores (P < 0.05). CT showed bone graft fusion in the area of isthmus defects, with no loosening or breaking of internal fixator. At last follow-up, the lateral flexion-extension X-ray films of the lumbar spine showed that the ROM at upper and lower intervertebral spaces was (12.3 +/- 2.1) degrees and (13.5 +/- 1.7) degrees, respectively; showing significant differences when compared with preoperative values (P < 0.05). Pain at donor site of iliac bone occurred in 1 case, and was cured after pain release treatment. CONCLUSION: The posterior intrasegmental fixation with pedicle screw-lamina hook system and bone grafting is a reliable treatment for lumbar spondylolysis, having a high fusion rate, low complication rate, and maximum retention of lumbar ROM. PMID- 23672124 TI - [Total hip arthroplasty with double-tapered cementless femoral stem for hip bony]. AB - OBJECTIVE: To investigate the effectiveness of total hip arthroplasty with double tapered cementless femoral stem for hip bony fusion by comparing with anatomical cementless femoral stem. METHODS: A retrospective analysis was made on clinical data of 50 cases (80 hips) of hip bony fusion undergoing total hip arthroplasty between October 1999 and January 2008. The patients were divided into 2 groups: 31 cases (49 hips) using BetaCone double-tapered cementless femoral stem (trial group), and 19 cases (31 hips) using Ribbed anatomical cementless femoral stem (control group). There was no significant difference in gender, age, disease duration, preoperative Harris score, and abduction angle of the hip between 2 groups (P > 0.05). After operation, X-ray films were used to calculate the ratio of force arm of abductor (a) to the force arm of gravity (b) and analyze the stability of the prosthesis. The abduction angle of the hip and Harris score were measured during follow-up. RESULTS: Fracture occurred during operation in 9 hips of 9 cases (5 in trial group and 4 in control group), and was cured after fixation. The mean follow-up time was 49 months (range, 12-98 months) in trial group and was 53 months (range, 6-105 months) in control group. The ratio of a/b was 0.65 +/- 0.25 in trial group and was 0.56 +/- 0.37 in control group, showing significant difference (t = 2.19, P = 0.03). The abduction angle of hip was (34.49 +/- 7.58) degrees in trial group and was (30.97 +/- 7.24) degrees in control group at 6 months after operation, which was significantly improved when compared with preoperative value in 2 groups (P < 0.05), and significant difference was found between 2 groups (t = 2.06, P = 0.04). Postoperative Harris score was significantly improved in 2 groups when compared with preoperative score (P < 0.05); trial group was better than control group in Harris score at 1 month after operation (t = 3.62, P = 0.01), but no significant difference was found between 2 groups at last follow-up (t = 1.61, P = 0.11). At last follow-up, X-ray films showed stabilized prosthesis in 2 groups. Grade I or II ectopic ossification occurred in 12 cases (14 hips) of trial group and 8 cases (9 hips) of control group at 2 years after operation. CONCLUSION: The total hip arthroplasty with both double-tapered and anatomical cementless femoral stems for hip bony fusion can obtain satisfactory effectiveness, while the double-tapered cementless femoral stem has better abduction angle of hip. PMID- 23672125 TI - [Preliminary clinical application of SL-PLUS MIA femoral stem prosthesis in total hip arthroplasty]. AB - OBJECTIVE: To investigate the short-term effectiveness of total hip arthroplasty (THA) with SL-PLUS MIA femoral stem prosthesis by comparing with the SL-PLUS prosthesis. METHODS: Retrospective analysis was made on the clinical data of 33 patients (38 hips) undergoing THA with SL-PLUS MIA femoral stem prosthesis (trial group) between June and December 2011, which was compared with those of 35 patients (40 hips) with SL-PLUS prosthesis (control group) during the same period. There was no significant difference in gender, age, disease duration, etiology, preoperative range of motion (ROM) of hip, and preoperative Harris score between 2 groups (P > 0.05). The incision length, operation time, and intraoperative blood loss were recorded during operation. The improvement of hip joint function was evaluated according to Harris score criteria. The ROM of hip was measured, and the X-ray film was taken to observe the position of prosthesis. RESULTS: Trial group had shorter incision length, less operation time, and less intraoperative blood loss than control group, showing significant differences (P < 0.05). All wounds healed by first intention. All patients were followed up 10 16 months (mean, 13.6 months). During follow-up, 5 cases (5 hips) of control group and 3 cases (3 hips) of trial group still had pain of hips. At last follow up, the ROM of hip was (152.48 +/- 9.68) degrees in trial group and (152.16 +/- 8.18) degrees in control group, the Harris score was 91.4 +/- 2.9 in trial group and 90.9 +/- 1.8 in control group; there were significant differences when compared with preoperative values (P < 0.05), but no significant difference was found between 2 groups (P > 0.05). X-ray films showed good position of the prosthesis with no displacement, loosening, or subsidence in both groups. CONCLUSION: SL-PLUS MIA femoral stem prosthesis has less surgical trauma and blood loss than SL-PLUS prosthesis during THA. The short-term effectiveness is satisfactory, but the long-term effectiveness still needs further observation. PMID- 23672126 TI - [Effectiveness comparison between arthroscopic and open ankle arthrodeses]. AB - OBJECTIVE: To compare the effectiveness of arthroscopic and open ankle arthrodeses. METHODS: The clinical data were retrospectively analyzed from 30 patients undergoing unilateral ankle arthrodesis between January 2008 and January 2011. Of 30 patients, 14 underwent arthroscopic ankle arthrodesis (arthroscopic group), and 16 underwent open ankle arthrodesis (open group). There was no significant difference in gender, age, lesion type, disease duration, and preoperative American Orthopaedic Foot and Ankle Society (AOFAS) score between 2 groups (P > 0.05). The operation time, intraoperative blood loss, postoperative hospitalization days, postoperative AOFAS score, and bony union rate were observed to evaluate the effectiveness. RESULTS: The operation time of arthroscopic group was significantly longer than that of open group (P < 0.05); the intraoperative blood loss and postoperative hospitalization days of arthroscopic group were significantly less than those of open group (P < 0.05). Superficial infection of incision occurred in 1 case of open group, and healing of incision by first intention was obtained in the other patients. All patients were followed up 12 months. No screw breakage was observed. The X-ray films showed bony fusion in 13 cases (92.86%) of arthroscopic group and in 10 cases (62.50%) of open group at 3 months after operation, showing significant difference (chi2 = 3.850, P = 0.049); but no significant difference was found (chi2 = 0.910, P = 0.341) in bony fusion rate between the arthroscopic group (14/14, 100%) and open group (15/16, 93.75%) at 12 months after operation. The AOFAS scores at 1, 3, 6, and 12 months after operation were significantly higher than preoperative score in 2 groups (P < 0.05). There was no significant difference in AOFAS score between 2 groups at 1 and 3 months (P > 0.05), but significant differences were found at 6 and 12 months (P < 0.05). CONCLUSION: The overall effectiveness of arthroscopic ankle arthrodesis is better than that of open ankle arthrodesis, which can decrease intraoperative blood loss, shorten hospitalization days, get PMID- 23672127 TI - [Application of occlusal guide plate combined with intermaxillary fixation screw in mandibular defect repair with free fibular flap]. AB - OBJECTIVE: To investigate the clinical value of occlusal guide plate combined with intermaxillary fixation screw in mandibular defect repair with free fibular flap. METHODS: Between August and December 2011, 7 patients with mandibular tumor were treated, including 5 cases of ameloblastoma and 2 cases of gingival cancer. Of 7 patients, 4 were males and 3 were females, aged 32-65 years (median, 50 years). Occlusal guide plate was prepared and the implanted position of intermaxillary fixation screws was determined preoperatively. Hemimandibulectomy was performed in 5 cases, half mandibular segmental resection with condyle reservation in the other 2 cases. The free fibular flaps of 11-13 cm in length were harvested for repairing mandibular defects. When the free fibular flaps were fixed, the occlusal guide plate and intermaxillary fixation screws were utilized to restorate the occlusal relation. The donor site was sutured directly. RESULTS: The average operation time was 9.5 hours (range, 7-12 hours). All free fibular flaps survived completely. All incisions at the donor site and recipient site healed by first intention. All patients were followed up 10-14 months with an average of 12.3 months. All patients had symmetrical face, good occlusal relation, normal mouth opening, and normal mandibular lateral movement, and no pain of bilateral temporomandibular joints occurred. Panoramic tomography showed good mandibular contour and the suitable emplacement of fibular flaps postoperatively. No tumor recurrence occurred during follow-up period. CONCLUSION: When repairing the mandibular defect with free fibular flap, occlusal guide plate with intermaxillary fixation screw contributes to simplifying operation, accurate recovery of the appearance and occlusal relation, and improving the oral comfort level postoperatively. PMID- 23672128 TI - [Tissue transplantation with bone transmission for treating large defects of tibial bone and soft tissue]. AB - OBJECTIVE: To investigate the effectiveness of tissue transplantation combined with bone transmission in treatment of large defects of tibial bone and soft tissue. METHODS: Between February 2006 and February 2011, 15 cases of traumatic tibia bone and soft tissue defects were treated. There were 12 males and 3 females, aged from 16 to 54 years (mean, 32 years). After internal and external fixations of fracture, 11 patients with open fracture (Gustilo type III) had skin necrosis, bone exposure, and infection; after open reduction and internal fixation, 2 patients with closed fracture had skin necrosis and infection; and after limb replantation, 2 patients had skin necrosis and bone exposure. The area of soft tissue defect ranged from 5 cm x 5 cm to 22 cm x 17 cm. Eight cases had limb shortening with an average of 3.5 cm (range, 2-5 cm) and angular deformity. The lenghth of bone defect ranged from 4 to 18 cm (mean, 8 cm). The flap transplantation and skin graft were used in 9 and 6 cases, respectively; bone transmission and limb lengthening orthomorphia were performed in all cases at 3 months after wound healing; of them, 2 cases received double osteotomy bone transmission, and 14 cases received autologous bone graft and reset after apposition of fracture ends. RESULTS: All flaps and skin grafts survived; the wound healed at 3.5 months on average (range, 3 weeks-18 months). The length of bone lengthening was 6-22 cm (mean, 8 cm). The time of bone healing and removal of external fixation was 9.5-39.0 months (mean, 15 months). The healing index was 40-65 days/cm (mean, 55 days/cm). All patients were followed up 1-5 years (mean, 4 years). The wounds of all the cases healed well without infection or ulceration. The functions of weight-bearing and walking were recovered; 6 cases had normal gait and 9 cases had claudication. The knee range of motion was 0 degrees in extention, 120-160 degrees in flexion (mean, 150 degrees). According to the American Orthopaedic Foot and Ankle Society (AOFAS) scoring system for ankle function, the results were excellent in 7 cases, good in 4 cases, and fair in 4 cases, with an excellent and good rate of 73.3%. CONCLUSION: Tissue transplantation combined with bone transmission is an effective method to treat large defects of soft tissue and tibial bone, which can increase strength of bone connection and reduce damage to the donor site. PMID- 23672129 TI - [Application of computed tomographic angiography in repairing skin defect after scalp avulsion with free latissimus dorsi flap transplantation]. AB - OBJECTIVE: To investigate the clinical value of computed tomographic angiography (CTA) and three-dimensional reconstruction technique in repairing scalp avulsion wound with large skull exposure by the free latissimus dorsi flap transplantation. METHODS: Between October 2007 and June 2012, 9 female patients with serious scalp avulsion and large skull exposure were treated, aged 23-54 years (mean, 38 years). The injury causes included machine twist injury in 6 cases, traffic accident injury in 2 cases, and falling from height injury in 1 case. Before admission, 3 patients had scalp necrosis after scalp in situ replantation, and 6 patients underwent debridement and dressing. The time from injury to admission was 8 hours to 7 days (mean, 1 day). The avulsed scalp area ranged from 75% to 90% of the scalp area (mean, 81%); the exposed skull area ranged from 55% to 70% of the scalp area (mean, 63%). Two patients had unilateral auricle avulse. CTA was used to observe the superficial temporal artery and vein, facial artery, external jugular vein, dorsal thoracic artery and vein, and measure the blood vessel diameter before operation. According to the CTA results, the latissimus dorsal skin flaps were desinged to repair wounds in 7 cases, the latissimus dorsal muscle flaps combined with skin graft were used to repair wounds in 2 cases. According to preoperative design, operation was successfully completed in 7 cases; great saphenous vein was used as vascular graft in 2 cases having poor images of superficial temporal vessels. The size of latissimus dorsal skin flaps ranged from 20 cm x 14 cm to 25 cm x 20 cm; the donor site was repaired with skin graft. The size of latissimus dorsal muscle flaps were 23 cm x 16 cm and 16 cm x 10 cm; the donor site was directly sutured. RESULTS: The blood vessel diameter measured during operation was close to the value measured before operation. The operation time was 6-8 hours (mean, 6.5 hours). The latissimus dorsal muscle (skin) flap and skin graft survived, with primary healing of wound or incision at donor site. The patients were followed up 3 months-2 years (mean, 6 months). The flap had soft texture and skin had no ulceration. CONCLUSION: The free latissimus dorsi flaps can repair scalp avulsion with large skull exposure. Preoperative CTA can get the vessel anatomical structure and diameter at donor and recipient sites, which will guide the operation program design and implementation so as to shorten the operation time and improve the accuracy rate of vascular anastomosis. PMID- 23672130 TI - [Effectiveness of free flaps in repair of hot-crush injury in dorsum of hand]. AB - OBJECTIVE: To evaluate the effectiveness of free flaps in repairing hot-crush injury in the dorsum of hand. METHODS: Between February 2003 and February 2012, 32 cases of hot-crush injuries in the dorsum of hand were repaired. There were 25 males and 7 females with an average age of 24 years (range, 16-45 years). The injury causes included machine crush injury in 9 cases, machine-press injury in 13 cases, and iron panel injury in 10 cases. The time from injury to admission ranged from 90 minutes to 8 hours (mean, 3 hours). The wound size ranged from 6 cm x 5 cm to 17 cm x 11 cm. Associated injuries included the extensor tendon necrosis in 12 cases, and the second metacarpal bone necrosis in 1 case. One stage emergency debridement was performed in all cases; two-stage flap repair was given at 7-21 days when the necrotic area became determined. The dorsalis pedis flaps were used in 9 cases, the anterolateral thigh flaps in 9 cases, the latissimus dorsi flaps in 3 cases, the thoraco-umbilical flaps in 3 cases, and the lower abdominal flaps in 8 cases. The flap size ranged from 7 cm x 5 cm to 18 cm x 16 cm. The donor site was repaired by skin graft or sutured directly. RESULTS: All the flaps survived. Primary healing of wound was obtained in 25 cases and delayed healing in 7 cases. Skin graft at donor site survived, with healing of incision by first intention. Twenty-three cases were followed up 6-25 months (mean, 13 months). Thinning was carried out in 8 bulky flaps; the other flaps had good appearance and texture. At last follow-up, the range of motion (ROM) of the metacarpophalangeal joint ranged from 40 to 80 degrees (mean, 58 degrees); ROM of the proximal interphalangeal joint ranged from 35 to 70 degrees (mean, 52 degrees); and ROM of the distal interphalangeal joint ranged from 5 to 25 degrees (mean, 12 degrees). The sensation recovery of the flaps were more than S2. No scar formed at donor site. CONCLUSION: Suitable free flap should be selected to repair hot-crush injury in the dorsum of hand according to size of wound, which will achieve satisfactory results. PMID- 23672131 TI - [Pedicled superior gluteal artery perforator bilateral quadrilobed flaps for repair of large sacrococcygeal pressure sores]. AB - OBJECTIVE: To investigate the effectiveness of pedicled superior gluteal artery perforator bilateral quadrilobed flaps for repairing large sacrococcygeal pressure sores. METHODS: Between June 2003 and August 2011, 6 paraplegia patients with large sacrococcygeal pressure sores were repaired with the pedicled superior gluteal artery perforator bilateral quadrilobed flaps. There were 2 males and 4 females with an average age of 45.6 years (range, 37-62 years). The mean disease duration was 8.4 months (range, 3-26 months). According to National Pressure Ulcer Advisory Panel (NPUAP) standard, 6 cases rated as degree IV. The size of pressure sores ranged from 15 cm x 13 cm to 18 cm x 16 cm. The size of flaps ranged from 18 cm x 14 cm to 21 cm x 15 cm. RESULTS: After operation, all flaps survived successfully. The wounds healed by first intention in 5 cases; partial dehiscence of incision occurred in 1 case, which was cured after dressing change for 26 days. Six patients were followed up 6-24 months (mean, 12.5 months). The appearance and texture of the flaps were smooth and soft with good elasticity and no ulceration. CONCLUSION: Pedicled superior gluteal artery perforator bilateral quadrilobed flaps can repair large sacrococcygeal pressure sores. The appearance of flaps is smooth and has good compression-resistance effect. PMID- 23672132 TI - [Endoscopic low-temperature plasma radiofrequency ablation with acellular dermal matrix patch for chronic abdominal wall sinus]. AB - OBJECTIVE: To investigate the effectiveness of endoscopic low-temperature plasma radiofrequency ablation with acellular dermal matrix patch for chronic abdominal wall sinus by comparing with the traditional surgical method. METHODS: Retrospective analysis was made on the clinical data of 53 cases of chronic abdominal wall sinus between January 2006 and May 2012. Of 53 patients, 18 underwent endoscopic low-temperature plasma radiofrequency ablation with acellular dermal matrix patch (trial group), and 35 underwent traditional surgical treatment (control group). No significant difference was found in gender, age, etiology, disease duration, and location between 2 groups (P > 0.05). RESULTS: The blood loss during sinus clearance, postoperative hospitalization days, and sinus union time of the trial group were significantly better than those of the control group (P < 0.05), but no significant difference was found in the operative time for sinus clearance (t = 0.28, P = 0.78). No postoperative sinus bleeding or infection occurred in the trial group, but bleeding and infection in 5 and 3 cases of the control group respectively, showing significant differences between 2 groups (P < 0.05). The follow-up time was 4-18 months (mean, 12.4 months) in the trial group, and was 6-48 months (mean, 38.5 months) in the control group. No sinus recurrence was observed during follow-up. CONCLUSION: Endoscopic low-temperature plasma radiofrequency ablation with acellular dermal matrix patch has the following advantages in treating chronic abdominal wall sinus: clear view, thorough cleaning of granulation necrosis tissues, less bleeding, faster sinus union, and shorter hospitalization days; however, further observations on the long-term effectiveness and the safety are required. PMID- 23672133 TI - [Research of pressure of skin soft tissue expander]. AB - OBJECTIVE: To investigate the change law of the intracapsular pressure in vitro without outside force and the pressure of the expander upon the skin soft tissue in vivo during clinical routine expansion so as to provide some references for the safe application of the expander. METHODS: The rectangle expanders of 50, 80, 100, 150, 200, 250, 300, and 400 mL were used for in vitro expansion at room temperature to 400% volume of the expander capacity. The pressures before and after saline injection were recorded. Twelve patients who needed scar plastic surgery were enrolled; 17 rectangle expanders were implanted in 5 areas (cheek, trunk, forehead and temporal, limb, and head) and expanded routinely. The pressures before and after saline injection were recorded. The pressure of the expander upon the skin soft tissue was calculated and the values of the pressure at 50%, 100%, 150%, and 200% volume of 5 areas were chosen and analyzed statistically. RESULTS: The intracapsular pressure of the expanders at different volumes in vitro without outside force during routine expansion before and after saline injection was beyond 0 mm Hg (1 mm Hg=0.133 kPa) at around 100% volume, increased rapidly from 100% to 250% volume, and kept stable from 250% to 400% volume. In vivo, 16 expanders within 200% volume had the maximum pressure before saline injection, 15 had the maximum pressure after saline injection. Before saline injection, the pressure of the expander upon the skin soft tissue was lowest in the cheek, showing significant difference when compared with those of the forehead and temporal and head (P < 0.05); the pressure in the trunk was significantly lower than that in the head (P < 0.05); and there was no significant difference between the other body sites (P > 0.05). After saline injection, the pressure of the expander upon the skin soft tissue was lowest in the cheek, and showed an increasing trend in the trunk, the limb, the forehead and temporal, and the head; no significant difference was found between in the cheek and in the trunk, and between in the forehead and temporal and in the limb (P > 0.05), and significant differences were found between the other body sites (P < 0.05). CONCLUSION: The pressure of expander upon skin soft tissue at early stage or middle stage is higher than that at late stage during expansion. The pressure is high in the head, and low in the cheek comparatively, and the pressures in the trunk, the forehead and temporal, and the limb are between them. PMID- 23672134 TI - [In vivo experiment of porous bioactive bone cement modified by bioglass and chitosan]. AB - OBJECTIVE: To investigate the biomechanical properties of porous bioactive bone cement (PBC) in vivo and to observe the degradation of PBC and new bone formation histologically. METHODS: According to the weight percentage (W/W, %) of polymethylmethacrylate (PMMA) to bioglass to chitosan, 3 kinds of PBS powders were obtained: PBC I (50: 40:10), PBC II (40:50:10), and PBC III (30:60:10). The bilateral femoral condylar defect model (4 mm in diameter and 10 mm in depth) was established in 32 10-month-old New Zealand white rabbits (male or female, weighing 4.0-4.5 kg), which were randomly divided into 4 groups (n = 8); pure PMMA (group A), PBC I (group B), PBC II (group C), and PBC III (group D) were implanted in the bilateral femoral condylar defects, respectively. Gross observation were done after operation. X-ray films were taken after 1 week. At 3 and 6 months after operation, the bone cement specimens were harvested for mechanical test and histological examination. Four kinds of unplanted cement were also used for biomechanical test as control. RESULTS: All rabbits survived to the end of experiment. The X-ray films revealed the location of bone cement was at the right position after 1 week. Before implantation, at 3 months and 6 months after operation, the compressive strength and elastic modulus of groups C and D decreased significantly when compared with those of group A (P < 0.05), but no significant difference was found between groups C and D (P > 0.05); the compressive strength at each time point and elastic modulus at 3 and 6 months of group B decreased significantly when compared with those of group A (P < 0.05). Before implantation and at 3 months after operation, the compressive strength and elastic modulus of groups C and D decreased significantly when compared with those of group B (P < 0.05); at 6 months after operation, the compressive strength of group C and the elastic modulus of group D were significantly lower than those of group B (P < 0.05). The compressive strength and elastic modulus at 3 and 6 months after operation significantly decreased when compared with those before implantation in groups B, C, and D (P < 0.05), but no significant difference was found in group A (P < 0.05). At 3 months after operation, histological observation showed that a fibrous tissue layer formed between the PMMA cement and bone in group A, while chitosan particles degraded with different levels in groups B, C, and D, especially in group D. At 6 months after operation, chitosan particles partly degraded in groups B, C, and D with an amount of new bone ingrowth, and groups C and D was better than group B in bone growth; group A had no obvious change. Quantitative analysis results showed that the bone tissue percentage was gradually increased in the group A to group D, and the bone tissue percentage at 6 months after operation was significantly higher than that at 3 months within the group. CONCLUSION: According to the weight percentage (W/W, %) of PMMA to bioglass to chitosan, PBCs made by the composition of 40:50:10 and 30:60:10 have better biocompatibility and biomechanical properties than PMMA cement, it may reduce the fracture risk of the adjacent vertebrae after vertebroplasty. PMID- 23672135 TI - [Experimental study on quick preparation of osteoporosis in vitro model]. AB - OBJECTIVE: To establish a rapid, simple, and economic method to prepare osteoporosis (OP) in vitro model. METHODS: Eighty pairs of fresh goat femur were collected from 18-month-old female goats and were randomly divided into 4 groups (20 pairs in each group). The femur was immersed decalcifying solution (18% EDTA) for 1-5 days (group B), 6-10 days (group C), and 11-15 days (group D), while group A had no treatment as control. Four pairs of femur were taken out every day. Quantitative computed tomography was used to scan the medial and lateral femoral condyles, and the bone mineral density (BMD) was calculated. Electronic universal testing machine was used to do three-point bending test and compress and tensile ultimate strenght test, and the mechanical parameters for femur were calculated. RESULTS: With demineralized time passing, BMD of the medial and lateral femoral condyles were downtrend in groups A, B, C, and D, showing significant differences among 4 groups (P < 0.05); BMD of the lateral femoral condyle was significantly higher than that of the medial femoral condyle in each group (P < 0.05). The three-point bending test showed that broken load, ultimate strength, and elastic modulus of groups A and B were significantly higher than those of groups C and D (P < 0.05); but no significant difference was found between groups A and B, and between groups C and D (P > 0.05). Compress and tensile ultimate strength test showed that the compress and tensile ultimate strengths were significantly higher in group A than in groups C and D (P < 0.05), and in group B than in group D (P < 0.05), but no significant difference was found between groups A and B, between groups B and C, and between groups C and D (P > 0.05). CONCLUSION: The 18% EDTA immersing for 6-15 days is a fast, simple, economical method to prepare an OP in vitro model of goat femur. PMID- 23672136 TI - [Trachea repair and reconstruction with new composite artificial trachea transplantation]. AB - OBJECTIVE: To construct a new composite artificial trachea and to investigate the feasibility of trachea repair and reconstruction with the new composite artificial trachea transplantation in dogs. METHODS: The basic skeleton of the new composite artificial trachea was polytetrafluoroethylene vascular prosthesis linked with titanium rings at both ends. Dualmesh was sutured on titanium rings. Sixteen dogs, weighing (14.9 +/- 2.0) kg, female or male, were selected. The 5 cm cervical trachea was resected to prepare the cervical trachea defect model. The trachea repair and reconstruction was performed with the new composite artificial trachea. Then fiberoptic bronchoscope examination, CT scan and three-dimensinal reconstruction were conducted at immediate, 1 month, and 6 months after operation. Gross observation and histological examination were conducted at 14 months to evaluate the repair and reconstruction efficacy. RESULTS: No dog died during operation of trachea reconstruction. One dog died of dyspnea at 37, 41, 55, 66, 140, and 274 days respectively because of anastomotic dehiscence and artificial trachea displacement; the other 10 dogs survived until 14 months. The fiberoptic bronchoscope examination, CT scan and three-dimensinal reconstruction showed that artificial tracheas were all in good location without twisting at immediate after operation; mild stenosis occurred and anastomoses had slight granulation in 6 dogs at 1 month; severe stenosis developed and anastomosis had more granulation in 1 dog and the other dogs were well alive without anastomotic stenosis at 6 months. At 14 months, gross observation revealed that outer surface of the artificial trachea were encapsulated by fibrous connective tissue in all of 10 dogs. Histological examination showed inflammatory infiltration and hyperplasia of fibrous tissue and no epithelium growth on the inner wall of the artificial trachea. CONCLUSION: The new composite artificial trachea can be used to repair and reconstruct defect of the trachea for a short-term. Anastomotic infection and dehiscence are major complications and problems affecting long survival. PMID- 23672137 TI - [Experimental study on human amniotic membrane for repairing tendon sheath defect]. AB - OBJECTIVE: To investigate the feasibility and effect of human amniotic membrane in prevention of tendon adhension after tendon sheat defect repair. METHODS: The amniotic membrane in size of 1.5 cm x 1.0 cm was harvested from human placenta which was voluntary donated from maternal after cesarean. Forty healthy male Leghorn chicken (aged 3-6 months) were selected, weighing (1.86 +/- 0.04) kg. The model of flexor digitorum profundus tendon and tendon sheath defects was established at the third toe. After repair of the flexor digitorum profundus tendon, the human amniotic membrane was used to repair the tendon sheath defect in the right foot (group A), but tendon sheath defect was not repaired in the left foot (group B) . At 1, 2, 4, and 6 weeks after operation, the gross and histological observations were done; the degree of tendon adhesions was graded according to Tang's tendon adhesion general observation grading standards; and the biomechanical properties (tendon slip length and total flexion angle) were tested. RESULTS: All animals survived after operation and incisions healed. Gross and histological observations showed that the new tendon sheath formed with time passing after operation in groups A and B; new tendon sheath was more maturer and smoother in group A than in group B. The degree of tendon adhesions in group A was significantly less than that in group B (P < 0.05) at 1 and 6 weeks after operation. The biomechanical test results showed there was no significant difference in the tendon slip length between 2 groups at 1 and 2 weeks after operation (P > 0.05), but the tendon slip length of group A was significantly longer than that of group B at 4 and 6 weeks after operation (P < 0.05). The total flexion angle of group A was significantly smaller than that of group B at 1, 2, 4, and 6 weeks after operation (P < 0.05). CONCLUSION: It is effective in the prevention of tendon adhesion to use the amniotic membrane for repairing the tendon sheath defect, which is beneficial to recovery of the tendon sliding function. PMID- 23672138 TI - [Targeted combination and anti-inflammatory effects of anti-intercellular adhesion molecule 1 targeted perfluorooctylbromide particles on myocardial ischemia-reperfusion injury in rat model]. AB - OBJECTIVE: To investigate the targeted combination and anti-inflammatory effects of anti-intercellular adhesion molecule 1 (ICAM-1) targeted perfluorooctylbromide (PFOB) particles on myocardial ischemia-reperfusion injury in rat model. METHODS: Seventy-six adult Sprague Dawley rats (male or female, weighing 250-300 g) were selected for experiment. The models of myocardial ischemia-reperfusion injury were established by ligating the left anterior descending coronary artery for 30 minutes in 30 rats. The expression of ICAM-1 protein was detected by immunohistochemistry staining at 6 hours after reperfusion, and the normal myocardium of 10 rats were harvested as control; then the content of interleukin 8 (IL-8) in serum was tested every 6 hours from 6 hours to 48 hours after reperfusion. The other 36 rats were randomly divided into 6 groups (n = 6): ischemia-reperfusion injury model/targeted PFOB particles group (group A), ischemia-reperfusion injury model/untargeted PFOB group (group B), normal control/targeted PFOB particles group (group C), normal control/untargeted PFOB particles group (group D), ischemia-reperfusion injury model/normal saline group (group E), and sham operation group (group F). The ischemia-reperfusion injury models were established in groups A, B, and E; while a thread crossed under the coronary artery, which was not ligated after open-chest in group F. After 6 hours of reperfusion, 1 mL of corresponding PFOB particles was injected through juglar vein in groups A, B, C, and D, while 1 mL of nomal saline was injected in group E. Ultrasonography was performed in groups A, B, C, and D before and after injection. The targeted combination was tested by fluorescence microscope. The content of IL-8 was tested after 6 and 24 hours of reperfusion by liquid chip technology in groups A, B, E, and F. RESULTS: After 6 hours of reperfusion, the expression of ICAM-1 protein significantly increased in the anterior septum and left ventricular anterior wall of the rat model. The content of IL-8 rised markedly from 6 hours after reperfusion, and reached the peak at 24 hours. Ultrasonography observation showed no specific acoustic enhancement after injection of PFOB particles in groups A, B, C, and D. Targeted combination was observed in the anterior septum and left ventricular anterior wall in group A, but no targeted combination in groups B, C, and D. There was no significant difference in the content of IL-8 among groups A, B, and E after 6 hours of reperfusion (P > 0.05), but the content in groups A, B, and E was significantly higher than that in group F (P < 0.05). After 24 hours of reperfusion, no sigificant difference was found in the content of IL-8 between groups A and B (P > 0.05), but the content of IL-8 in groups A and B were significantly lower than that in group E (P < 0.05). CONCLUSION: Anti-ICAM-1 targeted PFOB particles can target to bind and pretect injured myocardium of rat by its anti-inflammation effects. PMID- 23672139 TI - [In vitro differentiation of synovial-derived mesenchymal stem cells infected by adenovirus vector mediated by bone morphogenetic protein 2/7 genes into fibrocartilage cells in rabbits]. AB - OBJECTIVE: To investigate the feasibility of rabbit synovial-derived mesenchymal stem cells (SMSCs) differentiating into fibrocartilage cells by the recombinant adenovirus vector mediated by bone morphogenetic protein 2/7 (BMP-2/7) genes in vitro. METHODS: SMSCs were isolated and purified from 3-month-old New Zealand white rabbits [male or female, weighing (2.1 +/- 0.3) kg]; the morphology was observed; the cells were identified with immunocytological fluorescent staining, flow cytometry, and cell cycles. The adipogenic, osteogenic, and chondrogenic differentiations were detected. The recombinant plasmid of pAdTrack-BMP-2 internal ribosome entry site (IRES)-BMP-7 was constructed and then was used to infect SMSCs. The cell DNA content and the oncogenicity were tested to determine the safety. Then infected SMSCs were cultured in incomplete chondrogenic medium in vitro. Chondrogenic differentiation of infected SMSCs was detected by RT-PCR, immunofluorescent staining, and toluidine blue staining. RESULTS: SMSCs expressed surface markers of stem cells, and had multi-directional potential. The transfection efficiency of SMSCs infected by recombinant plasmid of pAdTrack-BMP 2-IRES-BMP-7 was about 70%. The safety results showed that infected SMSCs had normal double time, normal chromosome number, and normal DNA content and had no oncogenicity. At 21 days after cultured in incomplete chondrocyte medium, RT-PCR results showed SMSCs had increased expressions of collegan type I and collegan type II, particularly collegan type II; the expressions of RhoA and Sox-9 increased obviously. Immunofluorescent staining and toluidine blue staining showed differentiation of SMSCs into fibrocartilage cells. CONCLUSION: It is safe to use pAdTrack-BMP-2-IRES-BMP-7 for infecting SMSCs. SMSCs infected by pAdTrack BMP-2-IRES-BMP-7 can differentiate into fibrocartilage cells spontaneously in vitro. PMID- 23672140 TI - [Experimental study on adipose-derived stem cells transfected by bone morphogenetic protein 14 co-culture with chondrocytes]. AB - OBJECTIVE: To evaluate the synergistic effect of bone morphogenetic protein 14 (BMP-14) and chondrocytes co-culture on chondrogenesis of adipose-derived stem cells (ADSCs) so as to optimize the source of seed cells for cartilage tissue engineering. METHODS: ADSCs and chondrocytes were isolated and cultured respectively from articular cartilage and subcutaneous fat of 2 male New Zealand white rabbits (weighing, 1.5 kg and 2.0 kg). The cells at passage 3 were harvested for experiment. ADSCs were identified by osteogenic induction (alizarin red staining), chondrogenic induction (alcian blue staining), and adipogenic induction (oil red O staining). The optimum multiplicity of infection (MOI) of transfection of adenovirus-cytomegalovirus (CMV)-BMP-14-internal ribosome entry site (IRES)-human renilla reniformis green fluorescent protein 1 (hrGFP-1) was determined and then ADSCs were transfected by the optimum MOI. The experiment was divided into 5 groups: group A, co-culture of ADSCs transfected by BMP-14 and chondrocytes (1:1 in Transwell chambers); group B, co-culture of ADSCs and chondrocytes (1:1 in Transwell chambers); group C, culture of ADSCs transfected by BMP-14; group D, simple chondrocytes culture; and group E, simple ADSCs culture. After 3 weeks, the glycosaminoglycan (GAG) content was detected by alcian blue staining; the expressions of collagen type II and BMP-14 protein were detected by Western blot; expression of Sox-9 gene was detected by RT-PCR. RESULTS: The cultured cells were proved to be ADSCs by identification. Inverted fluorescence microscope showed optimum transfection effect when MOI was 150. GAG content, expressions of collagen type II and BMP-14 protein, expression of Sox-9 gene were significantly higher in groups A and C than in the other 3 groups, in group A than in group C (P < 0.05), and groups B and D were significantly higher than group E (P < 0.05), but no significant difference was found between groups B and D (P > 0.05). CONCLUSION: It can promote differentiation of ADSCs into chondrocytes by BMP-14 co-culture with chondrocytes, and they have a synergistic effect. PMID- 23672141 TI - [Effect of internal fixation on stability of pedicled fascial flap and osteogenesis of exceed critical size defect of bone]. AB - OBJECTIVE: To evaluate the effect of internal fixation on the stability of pedicled fascial flap and the osteogenesis of exceed critical size defect (ECSD) of bone so as to provide theory for the clinical application by the radiography and histology observation. METHODS: The ECSD model of the right ulnar midshaft bone and periosteum defect of 1 cm in length was established in 32 New Zealand white rabbits (aged 4-5 months), which were divided into group A and group B randomly (16 rabbits in each group). The composite tissue engineered bone was prepared by seeding autologous red bone marrow (ARBM) on osteoinductive absorbing material (OAM) containing bone morphogenetic protein and was used repair bone defect. A pedicled fascial flap being close to the bone defect area was prepared to wrap the bone defect in group A (control group). Titanium miniplate internal fixation was used after defect was repair with composite tissue engineered bone and pedicled fascial flap in group B (experimental group). At 2, 4, 6, and 8 weeks, the X-ray films examination, morphology observation, and histology examination were performed; and the imaging 4-score scoring method and the bone morphometry analysis was carried out. RESULTS: All rabbits survived at the end of experiment. By X-ray film observation, group B was superior to group A in the bone texture, the space between the bone ends, the radiographic changes of material absorption and degradation, osteogenesis, diaphysis structure formation, medullary cavity recanalization. The radiographic scores of group B were significantly higher than those of group A at different time points after operation (P < 0.05). By morphology and histology observation, group B was superior to group A in fascial flap stability, tissue engineered bone absorption and substitution rate, external callus formation, the quantity and distribution area of new cartilage cells and mature bone cells, and bone formation such as bone trabecula construction, mature lamellar bone formation, and marrow cavity recanalization. The quantitative ratio of bone morphometry analysis in the repair area of group B were significantly larger than those of group A at different time points after operation (P < 0.05). CONCLUSION: The stability of the membrane structure and the bone defect area can be improved after the internal fixation, which can accelerate bone regeneration rate of the tissue engineered bone, shorten period of bone defect repair, and improve the bone quality. PMID- 23672142 TI - [Research progress of alcohol-induced osteonecrosis of femoral head]. AB - OBJECTIVE: To review the research progress of alcohol-induced osteonecrosis of the femoral head (ONFH). METHODS: Recent literature concerning alcohol-induced ONFH was reviewed and summarized. RESULTS: Alcohol-induced ONFH accounte for approximately 1/3 of total ONFH. Alcohol intake and the incidence of ONFH has a significant dose-effect relationship. There are some correlations between alcohol induced ONFH and lipid metabolism, secretion of corticosteroid, and some gene of alcohol or lipid metabolism. CONCLUSION: The relationships between alcohol and lipid metabolism, and between alcohol and steroid are still the main direction of the research of ONFH. Gene level researches can not demonstrate the pathogenesis, therefore further research should be carried on. PMID- 23672143 TI - [Research progress of secondary fracture of adjacent vertebral body after percutaneous vertebroplasty and percutaneous kyphoplasty]. AB - OBJECTIVE: To summarize the research progress of secondary fracture of adjacent vertebral body after percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP). METHODS: Recent literature concerning PVP and PKP was extensively reviewed and summarized. RESULTS: The main reasons of secondary fracture of adjacent vertebral body after PVP and PKP are the natural process of osteoporosis, the initial fracture type, the bone cement, the surgical approach, the bone mineral density, and other factors. CONCLUSION: Secondary fracture of adjacent vertebral body after PVP and PKP is a challenge for the clinician, a variety of factors need to be suficiently considered and be confirmed by a lot of basic and clinical epidemiological studies. PMID- 23672144 TI - The gambler's fallacy, the therapeutic misconception, and unrealistic optimism. PMID- 23672145 TI - Exploring the ethics and psychological impact of deception in psychological research. PMID- 23672146 TI - A global public incentive database for human subjects research. PMID- 23672147 TI - The Presidential Bioethics Commission's database of human subjects research. PMID- 23672148 TI - [Another reform in our healthcare system]. PMID- 23672149 TI - [The French culture proves to be rather reluctant towards euthanasia]. PMID- 23672150 TI - [Marisol Touraine wants to reaffirm and rethink the role of the hospital]. PMID- 23672151 TI - [Women, the first targets of AIDS]. AB - The specificity of acquired immunodeficiency syndrome (AIDS) with regard to women was first noted some fifteen years ago. The preconception is that the disease mainly affects women of African origin, whereas the reality is much more complex. To contain the pandemic and detect the disease at the earliest stage, it is necessary to carry out prevention campaigns aimed specifically at women, to include them in studies and to generalise the use of the female condom. PMID- 23672152 TI - [Men and women unequal in the face of AIDS]. AB - In most societies, the statuses of men and women differ and are marked by unequal relationships. The spread of the human immunodeficiency virus feeds on this situation and also contributes to strengthening it. Not all women are exposed to the risk of HIV contamination to the same degree: the addition of biological, socio-economic, cultural and legal factors makes them more or less vulnerable. PMID- 23672153 TI - [The treatment of AIDS in women]. AB - Treatments for human immunodeficiency virus infection have evolved considerably. This article provides an overview of the situation with regard to women and the treatments and multi-disciplinary care available to them. PMID- 23672154 TI - [The multiple vulnerabilities of women with AIDS]. AB - How do women today live with the human immunodeficiency virus? This disease impacts on their sex life, their desire for motherhood and pregnancy. It has also brought about a certain perception on the part of society with regard to their illness. What role must caregivers therefore adopt? PMID- 23672155 TI - [Focus on pre-exposure prophylaxis]. AB - Pre-exposure prophylaxis currently has no market authorisation in France, but is still evaluated. This article presents an additional tool for risk reduction, currently the subject of studies. PMID- 23672156 TI - [We must not lose the meaning of our duties]. AB - From the mastering of the skills of technical care to the special relationship with the other, Catherine Barbier presents some of the reflections which have influenced her nursing career for the benefit of patients and their families. PMID- 23672157 TI - [Psychological harassment]. AB - Two types of harassment are distinguished: sexual and psychological. In the private sector, according to French labour laws and the penal code, psychological harassment is actionable. It is up to the employer to prove the absence of harassment. The sanctions incurred can be up to 5 years imprisonment and a 150,000 euro fine and various measures of compensation for damages can be envisaged. PMID- 23672158 TI - [Preventing the risk of blood transfusion accidents by identifying gaps in knowledge]. AB - Working to prevent blood transfusion injury risk, the haemovigilance unit of Tenon hospital in Paris has created a questionnaire to identify staff in need of updating their knowledge. Quick to full in and using the network of partner managers and haemovigilance specialists, this questionnaire enables any latent risks to be identified and an effective training approach to be relaunched. PMID- 23672159 TI - [Technology for improving pain management in the home]. AB - The management of pain at home has developed considerably over the last ten years with the arrival of patient-controlled analgesia pumps. Connected to the internet, some of these medical devices give nurses real-time access to the pump's data and history. This offers greater reactivity in adjusting the prescription and helping to improve pain management. PMID- 23672160 TI - [Improving collaboration between the pharmacy and the nurses]. AB - In hospitals, improving collaboration between the diferent players in the health care chain is an ongoing issue. Numerous tools are available to facilitate interprofessional communication. Satisfaction surveys can be of particular interest. PMID- 23672161 TI - [From patient education to the therapeutic alliance, a motivational challenge]. AB - Motivating patients in their therapeutic care is critical. The therapeutic alliance is key to emancipating the patient and the carer. PMID- 23672162 TI - How to deal with children's head lice. PMID- 23672163 TI - [Nursing care of septic shock]. PMID- 23672164 TI - [Nutritional support of the pregnant or breastfeeding woman]. PMID- 23672165 TI - [Trauma and clinical reasoning]. PMID- 23672166 TI - [Nursing care of patients in casts]. PMID- 23672167 TI - [Evaluation using QFT-2G/TBGL/LAM in the patients with osteoarticular tuberculosis of post-treatment period]. AB - PURPOSE: To evaluate results of QFT-2G/TBGL/ LAM in patients who had been completed the antituberculosis treatment for osteoarticular tuberculosis with various periods after the completion of the treatment, MATERIALS AND METHODS: Fifty-five patients who had been completed the antituberculosis treatment for osteoarticular tuberculosis at least one year after the completion of treatment were evaluated using QFT-2G/TBGL/LAM tests. Forty patients with spinal tuberculosis and 15 patients with articular tuberculosis were included. The patients with the period after the completion of the treatment less than 4 years were classifled as short-term group (33 patients) and those with the period not less than 4 years were classified as mid-long-term group (22 patients). The results of the tests were compared between the two groups. RESULTS: The result of QFT-2G test was positive in 60.6% of the patients in short-term group while 45.5% in mid-long-term group (p=0.12). On the other hand, the result of TBGL test was positive in 75.8% of the patients in short-term group whereas 22.7% in mid-long term group (p=0.0001) and the result of LAM test was positive in 90.9% of the patients in short-term group whereas 63.6% in mid-long-term group (p= 0.01), both of these tests showed significantly low,er positive rate in mid-long-term group. There was no significant difference in the comparisons between patient groups writh/without pulmonary tuberculosis as well as with/without surgical treatment. CONCLUSION: The patients with a history of osteoarticular tuberculosis tend to show positive results of QFT-2-G test for a prolonged period, whereas significantly less positive results of TBGL/LAM tests in mid-long-term. PMID- 23672168 TI - [Study on pulmonary lesions in which nontuberculous mycobacteria were detected by percutaneous aspiration--a proposal to add "culture positivity of percutaneous aspiration material" to the bacteriological diagnostic criteria of pulmonary nontuberculous mycobacterial diseases]. AB - OBJECTIVES: Culture positivity of percutaneous aspiration material" is not included in the current bacteriological criteria for diagnosis of pulmonary nontuberculous mycobacterial (NTM) diseases, which were published by the Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) in 2007 or those released by the Japanese Society for Tuberculosis in 2008. However, percutaneous aspiration is a reliable technique for the detection of causative microorganisms isolated from the focus of infection. We discuss the benefits of including positive culture of percutaneous aspiration material in the bacteriological diagnostic criteria of pulmonary NTM diseases. METHODS: We reviewed the radiological images and clinical courses of pulmonary diseases in which NTM cultures were obtained from percutaneously aspirated materials at our hospital from 1991 to 2011. Aspiration was carried out under local anesthesia, usually with fluoroscopic guidance. After percutaneous insertion of a 22-gauge needle attached to a 20-mL syringe containing about 3 mL of saline, the lesion specimen was withdrawn together with the saline. After the needle was pulled out, the aspirated material and saline were transferred to test tubes for cytological and microbiological examinations. In patients with thin-walled cavitary lesions, saline was injected into the cavity and then aspirated. RESULTS: Percutaneous aspiration was performed in 2,742 patients and NTM disease was detected in 51 patients. Of these 51 patients, 12 had solitary nodular lesions, and in many of these patients, no NTM bacilli could be detected in the sputa or bronchial washing specimens. Mycobacterium avium was identified in 10 of the 12 cases. Four of these 10 patients were followed up after their diagnosis without any treatment: 3 showed spontaneous reduction in lesion size, while 1 patient's condition remained unchanged. Four of the remaining 6 cases were treated with anti-NTM medications, and lesion size reduced in 2 cases, while no change or deterioration was seen in the other 2. Aspiration from solitary small cavitary lesions showed a relatively high number of NTM colonies. Pneumothorax was the only complication of the aspiration procedure. DISCUSSION: If the diagnostic criteria for pulmonary NTM diseases include positive culture in percutaneous aspiration material, the diagnosis of solitary nodular NTM lesions would become easier; at present, these lesions are often diagnosed only upon surgical resection. Further, clinical studies on the possibility of spontaneous shrinkage of the solitary lesion and the value of its medical treatment would be promoted. Aspiration can easily differentiate NTM disease from pulmonary abscess or fungal infection in patients with a solitary lesion or small cavity. PMID- 23672169 TI - [Clinical evaluation of a line probe assay kit for the identification of Mycobacterium species and detection of drug-resistant Mycobacterium tuberculosis]. AB - BACKGROUND: Multidrug resistance (MDR) involves resistance to both isoniazid and rifampicin, which makes the treatment of tuberculosis very difficult. Extensive drug resistance (XDR) occurs when, in addition to isoniazid and rifampicin resistance, the microorganisms are resistant to a fluoroquinolone and an injectable agent (e.g., kanamycin, amikacin, or capreomycin). Generally, drug susceptibility testing takes more than 3-4 weeks after the initial cultivation. There is an urgent need to identify methods that can rapidly detect both the presence of Mycobacterium tuberculosis and the status of drug resistance. PURPOSE: This study was aimed at evaluating the line probe assay (LiPA; Nipro Co.), for the identification of Mycobacterium species and detection of mutations associated with antituberculous drugs. RESULTS: We found that LiPA enabled the rapid identification of M. tuberculosis, M. avium, M. intracellulare, and M. kansasii. When the results of the LiPA and conventional drug susceptibility tests were compared, there was no difference in the susceptibility to rifampicin, pyrazinamide, and levofloxacin; however, there was a difference in the susceptibility to isoniazid. CONCLUSION: Thus, LiPA can be used for the rapid identification of Mycobacterium species and the determination of susceptibility to drugs, which can help in the early initiation of appropriate treatment, leading to a reduction in infectiousness. PMID- 23672170 TI - [Comparison of drug-induced hepatitis occurring in elderly and younger patients during anti-tuberculosis treatment with a regimen including pyrazinamide]. AB - BACKGROUND: In Japan, tuberculosis (TB) patients aged over 80 years are usually treated with a regimen not including pyrazinamide (PZA) because of the risk of drug-induced hepatitis. PURPOSES: The purpose of this study was to investigate the occurrence of drug-induced hepatitis in TB patients over 80 years of age, who are treated with a regimen including PZA, and compare the findings with those of younger patients. [Methods] Thirty-six patients with pulmonary tuberculosis, who were admitted to Yokohama City University Hospital between June 2011 and March 2012 were included. They were treated with isoniazid, rifampicin, ethambutol, and PZA and had their liver function assessed once a week for 2 months. RESULTS: Hepatitis occurred in 4 of 28 (14.3%) patients aged under 80 years and in 1 of 8 (12.5%) patients aged over 80 years. CONCLUSION: There was no difference in the frequency of drug-induced hepatitis between patients aged under and over 80 years. We conclude that elderly patients aged over 80 years should be treated with a short course regimen that includes PZA. PMID- 23672171 TI - [Interpreting "equivocal" results obtained from the QuantiFERON-TB Gold In-Tube test in contact investigations]. AB - OBJECTIVE: In this study, we demonstrate the interpretation of "equivocal" results by the QuantiFERON"-TB Gold In-Tube (QFT-GIT) test in contact investigations. METHODS: The participants of the contact examinations were assessed by the QFT-GIT test after 2 to 4 months from the last contact with smear positive tuberculosis patients. The study was conducted between April 2011 and March 2012. We enrolled 79 contact participants whose QFT-GIT tests produced equivocal results. RESULTS: The average age of the enrolled contacts was 35.9 years and the average interval from the last contact to the first QFT-GIT test was 85.4 days (range 62-118 days). The second QFT-GIT test produced negative results in 42 (53%) participants, equivocal results in 28 (35%), and positive results in 9 (11%). These 9 positive contacts belonged to the group of contacts with an index case whose QFT-GIT positive rate was more than 15%. The contacts belonging to groups with a QFT positive rate higher than 15% in the initial test had significantly higher QFT positive rates in the follow-up test than those belonging to groups with lower initial QFT positive rates (p=0.011). CONCLUSIONS: After retesting contacts with initially equivocal QFT results, 65% demonstrated either negative or positive results. If a contact's second QFT-GIT test is positive, it is highly probable that he/she is infected with tuberculosis and adequate treatment for latent TB infection is indicated. Thus far, no guidelines have been established for the management of contacts with equivocal results by the QFT-GIT test; therefore, further investigations and discussions are mandatory. PMID- 23672172 TI - [A case of pulmonary tuberculosis in which diagnosis was delayed because of prior treatment with fluoroquinolone and metronidazole]. AB - We report the case of a patient with pulmonary tuberculosis, whose diagnosis was delayed because of prior treatment with fluoroquinolone and metronidazole. A 35 year-old woman developed productive cough, fever, and back pain, which lasted for 3 weeks before admission to hospital. She had been diagnosed with lower respiratory infection and was treated with garenoxacin mesilate hydrate for 7 days before admission. As her symptoms did not improve, she was referred to our hospital for further evaluation. A chest computed tomography scan revealed confluent consolidation in the right lower lung, predominantly in segment 7, and lung abscess was initially suspected. Since chemotherapy with ceftriaxone and minomycin did not reduce her symptoms, metronidazole was added on day 4. Her symptoms improved dramatically and she was discharged on day 15. Metronidazole was given for a total of 3 weeks, and 2 weeks after discontinuation of metronidazole, she presented with recurrent chest pain and was diagnosed with active pulmonary tuberculosis. In addition to the atypical imaging findings in this patient, the use of chemotherapeutics such as garenoxacin mesilate hydrate and metronidazole, which have anti-tuberculosis effects, meant that the diagnosis of tuberculosis was complicated and hence delayed. We should keep in mind that some general chemotherapy agents, including linezolid, also have anti tuberculosis effects and may cause similar problems with diagnosis. PMID- 23672173 TI - [Tuberculosis annual report 2010 - (8) treatment of tuberculosis-1]. AB - The standard treatment of tuberculosis (TB) is the key to its control. Here, we report statistics relating to treatment history and first-line anti-TB therapy in the year 2010. The frequency of retreatment among newly notified TB patients might be partly an indicator of previous insufficient treatment. In 2010, 23,261 TB patients were newly notified. Of these, 1,762 cases were reported as having had previous TB treatment. The proportion of retreatment among newly notified cases was 7.7%, excluding those with an unknown treatment history. Regarding the year of previous treatment, more cases had undergone prior anti-TB therapy in 2009 (n=197). As for the initial treatment regimen, a combination of isoniazid (INH), rifampicin (RFP), pyrazinamide (PZA), and ethambutol (EB) or streptomycin (SM) is recommended by the Japanese Society for Tuberculosis. This regimen was initially used in 80.0% of all TB patients aged 15-79 years, excluding those cases with an unknown treatment regimen. Of the 14,922 cases who started a TB treatment regimen including PZA and completed TB treatment by the end of 2010, 10.0% could not complete the full 2-month course of PZA. PMID- 23672174 TI - [Health examination in future at the era of low tuberculosis incidence--from contacts examination toward active epidemiological studies]. AB - Japan is still "intermediate burden" country as medium-incidence of tuberculosis (TB). But the incidence of TB varies by public health units. The priority for TB control would be lowering in the areas where the incidence of TB is relatively low. In addition, younger age groups get low prevalence of TB infection than elderly persons. As a result, fewer experiences for TB diagnosis and treatment in the hospital and the medical facility would cause the delay in the detection of TB patients which eventually cause outbreaks. Although there are differences in population density and population mobility between urban and rural areas, the socially economic vulnerable patients and foreign patients are the common risks. Any public health units' policies of TB should correspond to the individual situation. At the era of low tuberculosis incidence, the infection risk is to be "From ubiquitous to the uneven distribution". This makes TB detection much more difficult. At this symposium, each speaker presented the case for actually experienced with QFT test and/or VNTR analysis. They mainly focused on the paradigm shift in TB control which is indispensable for resolving the gaps in regional differences and the differences in diagnostic capability. Although the cases in this symposium were not for the low incidence situation, the pioneering approaches presented here would boost the future application of QFT and VNTR analysis nationwide. The discussions also partially covered the technical infrastructure for molecular epidemiology which covers the whole country. By making full use of QFT test and VNTR analysis as a contact screening tool, we can appropriately understand the risk of TB infection in the region from a buildup of bacteria and patient information. Now is the time to prepare for. Active surveillance of TB by this way would clarify the risk of the disease and lead to the advocacy essential for the resolution. 1. Current situation and challenge of contact survey by using QFT test in Tokyo: Hideo MAEDA (Bureau of Social Welfare and Public Health, Tokyo Metropolitan Government). 2. Contact investigation of a tuberculosis outbreak: Kenichi MIYAMOTO (Takaido Community Health Center). We have experienced a TB outbreak in integrated junior and senior high school in Tokyo. Index patient was a student with persistent respiratory symptoms for six months before diagnosis of sputum smear-positive TB. Public health center started contact investigation immediately. QFT-positive rates were high in close contacts, especially in classmates. Additionally, a student outside of contact investigation was diagnosed as TB and considered to be infected from the first patient by VNTR analysis. Therefore, public health center expanded QFT-tests to all students and teachers in this school. Finally, 9 students and 2 teachers in this school were diagnosed as sputum smear-negative TB by contact investigation. 3. Utilization of molecular epidemiological procedure in contact investigation in Kyoto City: Masahiro ITO (Public Health Center of Kyoto City) Molecular epidemiological procedure using VNTR analysis has been used for contact investigation of tuberculosis since January 2011 in Kyoto City. One hundred forty four strains of Mycobacterium tuberculosis from patients with tuberculosis were investigated and 130 strains were fully analyzed. Fourteen clusters were found and the number of strains included in the cluster was ranged from two to 11. Epidemiological relationship between patients in one cluster was found, however, significant relationship in another clusters was not demonstrated. It was suggested that VNTR analysis is useful for molecular epidemiological analysis of tuberculosis. 4. The population based molecular epidemiological studies and QFT test in a contact examination: Riyo FUJIYAMA, Keisuke MATSUBAYASHI, Setsuko MIZUSHIRI, Junko HIGUCHIL Chika SHIRAI, Yuko KATAGAMI, Mieko CHIHARA, Akihiro IJICHI (Kobe City Public Health Center), Kentaro ARIKAWA, Noriko NAKANISHI, Tomotada IWAMOTO (Kobe Institute of Health). The population based molecular epidemiological studies should be made good use of contacts examination. In future, we expect the tuberculosis molecular epdimiological study improve search for the process of tuberculosis infection. The QFT positive rates correlated well with closeness of contact. QFT test is considered useful for diagnosing tuberculosis infection. However, in the judgment of tuberculosis infection, we should consider the total result of contact investigation not only QFT test but also the contact situation. 5. Insights into the TB epidemiology through population based molecular epidemiological studies: Tomotada IWAMOTO (Kobe Institute of Health) The population based molecular epidemiological studies unveiled the transmission dynamics of tuberculosis at bacterial clone level. This provides scientific evidences for achieving better TB control programs. In the advanced stage of the tuberculosis molecular epidemiological study, we expect to change the current geno-typing based molecular epidemiology to whole genome typing based molecular epidemiology on the basis of the rapid innovation of next generation sequencing technology. PMID- 23672175 TI - [Biologics and mycobacterial diseases]. AB - Various biologics such as TNF-alpha inhibitor or IL-6 inhibitor are now widely used for treatment of rheumatoid arthritis. Many reports suggested that one of the major issues is high risk of developing tuberculosis (TB) associated with using these agents, which is especially important in Japan where tuberculosis still remains endemic. Another concern is the risk of development of nontuberculous mycobacterial (NTM) diseases and we have only scanty information about it. The purpose of this symposium is to elucidate the role of biologics in the development of mycobacterial diseases and to establish the strategy to control them. First, Dr. Tohma showed the epidemiologic data of TB risks associated with using biologics calculated from the clinical database on National Database of Rheumatic Diseases by iR-net in Japan. He estimated TB risks in rheumatoid arthritis (RA) patients to be about four times higher compared with general populations and to become even higher by using biologics. He also pointed out a low rate of implementation of QuantiFERON test (QFT) as screening test for TB infection. Next, Dr. Tokuda discussed the issue of NTM disease associated with using biologics. He suggested the airway disease in RA patients might play some role in the development of NTM disease, which may conversely lead to overdiagnosis of NTM disease in RA patients. He suggested that NTM disease should not be uniformly considered a contraindication to treatment with biologics, considering from the results of recent multicenter study showing relatively favorable outcome of NTM patients receiving biologics. Patients with latent tuberculosis infection (LTBI) should receive LTBI treatment before starting biologics. Dr. Kato, a chairperson of the Prevention Committee of the Japanese Society for Tuberculosis, proposed a new LTBI guideline including active implementation of LTBI treatment, introducing interferon gamma release assay, and appropriate selection of persons at high risk for developing TB. Lastly, Dr. Matsumoto stressed the risk of discontinuing TNF-alpha inhibitor during treatment for tuberculosis. He showed from his clinical experience that TNF-alpha inhibitor can be safely used in active TB patient receiving effective antituberculosis chemotherapy and it is even more effective for prevention of paradoxical response. Active discussion was done about the four topics, including the matter beyond present guidelines. We hope these discussions will form the basis for the establishment of new guideline for the management of mycobacterial disease when using immunosuppressive agents including biologics. 1. The risk of developing tuberculosis (TB) and situations of screening for TB risk at administration of biologics-the case of rheumatoid arthritis: Shigeto TOHMA (Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital) We calculated the standardized incidence ratio (SIR) of TB from the clinical data on National Database of Rheumatic Diseases by iR-net in Japan (NinJa) and compared with the SIR of TB from the data of the post-marketing surveillances of five biologics. Among 43584 patient-years, forty patients developed TB. The SIR of TB in NinJa was 4.34 (95%CI: 3.00-5.69). According to the post-marketing surveillances of 5 biologics, the SIR of TB were 3.62-34.4. The incidence of TB in patients with RA was higher than general population in Japan, and was increased more by some biologics. We have to recognize the risk of TB when we start biologics therapy to patients with RA. Although the frequency of implementation of QuantiFERON test (QFT) had gradually increased, it was still limited to 41%. In order to predict the risk of developing TB and to prevent TB, it might be better to check all RA patients by QFT at time time of biologics administration. 2. Biologics and nontuberculous mycobacterial diseases: Hitoshi TOKUDA (Social Insurance Central General Hospital) Several topics about the relationship between RA and nontuberculous mycobacterial (NTM) diseases were discussed, which is still poorly understood. It is well known that airway diseases often accompany RA, which may be considered as a possible etiology for development of NTM diseases, but conversely it may lead to overdiagnosis of NTM disease. Next, we evaluated justification for the contraindication of biologics in patients with NTM diseases. Recent multicenter study showed that prognosis of patients developing NTM diseases during treatment with biologics were not always poor, which throws doubt on uniform prohibition of biologics in NTM diseases. 3. Future guideline for treating latent tuberculosis infection: Seiya KATO (Research Institute of Tuberculosis, Japan AntiTuberculosis Association) The Japanese Society for Tuberculosis issued a joint statement on chemoprophylaxis with the Japan College of Rheumatology in 2004. However, issues and challenges due to changing circumstance indicate application of interferon gamma release assay (IGRA), increased variety and indication of biologics, dissemination of knowledge on strategy and system for latent tuberculosis infection (LTBI), etc. Future guideline should include 1) promoting LTBI treatment to achieve low incidence, 2) updated information on IGRAs, 3) treatment strategy and target: contact to infectious cases, immunosuppressive cases (especially HIV and patients treated with biologics), high risk groups, etc. 4) fundamental information on tuberculosis control strategies, especially DOTS. 4. Therapy for RA and tuberculosis in patients with RA and TB activated by anti-TNF treatment: Tomoshige MATSUMOTO (Osaka Prefectural Medical Center for Respiratory and Allergic Diseases) Biologics targeting TNF, including infliximab, have brought about a paradigm shift in the treatment of rheumatoid arthritis (RA). In 2001, tuberculosis, an ancient and also modem scourge, became spotlighted again, because Keane reported in the New England Journal of Medicine that infliximab administration induced reactivation of tuberculosis. How should we treat RA after we successfully treated tuberculosis? Decisions regarding the treatment of patients with refractory RA in the setting of active tuberculosis remain difficult. We successfully treated RA in patients with tuberculosis by anti-TNF therapy. These demonstrate that anti-TNF therapy can be considered for patients with refractory RA who have tuberculosis and in whom antituberculosis therapy can be maintained. PMID- 23672176 TI - [Strategies for Mycobacterium avium complex infection control in Japan: how do they improve the present situation?]. AB - Mycobacterium avium complex (MAC) were the most frequently isolated (about 80%) and most common cause of lung nontuberculosis. Its rate of infection is globally increasing, especially in Japan. In this situation, it is urgently needed to provide scientific evidences and develop therapeutic interventions in MAC infections. Recently, more and more patients are elderly women with no history of smoking, and they have reticulonodular infiltrates and patchy bilateral bronchiectasis. However the prognostic and intractable factors of MAC infections are poorly known. In this symposium, we address five novel strategies for MAC infection, concerning the more accurate incidence and prevalence rates compared with other countries, host defense associated with Th1/Th17 balance, route of MAC infection related soil exposure, MAC IgA antibody as a diagnosis maker, and improved chemotherapy including aminoglycoside or new quinolone. Appropriate clinical intervention may help to reduce the prolongation of MAC infection or enhance the activity of chemotherapy for the improved control of MAC. Below are the abstracts for each of the five speakers. 1. Review of current epidemiological study of pulmonary nontuberculous mycobacterial disease in Japan and the rest of the world: Kozo MORIMOTO (Respiratory Center, Fukujuji Hospital, Japan Anti Tuberculosis Association) The studies on pulmonary nontuberculous mycobacterial (NTM) disease prevalence were started in early 1970s in Japan by the Mycobacteriosis Research Group of National Chest Hospitals. They were followed by a questionnaire survey in 1990s, by the National Tuberculosis and NTM Survey in late 1990s, and recently by the questionnaire surveys conducted by the NTM Disease Research Committee. The latest data in Japan (from 2007) indicated a morbidity rate of 5.7 per 100,000 population. Deaths from NTM disease were reported for the first time in 1970 and showed a marked, steady increase until 2007, with 912 deaths in that year. We estimated NTM prevalence in our country in 2005 to be 33-65/100,000 using death number and the 1-2% fatality rate obtained from in our hospital. Epidemiologic study conducted by some regions, states and countries estimated the incidence or prevalence of NTM by unique methods in each. Although the microbiologic criteria of diagnosis is attractive to get information of prevalence, we think the most reliable method is to use the health insurance claims that should be done in future in Japan. 2. The elucidation of the pathogenesis of pulmonary MAC disease by using gene modified mice: Masashi MATSUYAMA, Yukio ISHII, Nobuyuki HIZAWA (Division of Respiratory Medicine, Institute of Clinical Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba), Kenji OGAWA (Department of Clinical Research, National Hospital Organization Higashi Nagoya National Hospital) Thl immune responses are associated with protective immunity to intracellular pathogens. T-bet is the master regulator for Thl cell differentiation. We therefore investigated the role of T-bet in the host defense against pulmonary MAC infection using T-bet knockout (T-bet-/-) mice and T-bet overexpressing (T-bet tg/tg) mice. Pulmonary MAC infection was induced by intratracheal instillation with 1 X 10(7) CFU of Mycobacterium avium subsp. hominissuis. The degrees of pulmonary inflammation and the number of organisms were much enhanced in T-bet-/- mice than in wild-type mice and T-bet tg/tg mice after MAC infection. A significant decrease in Th1 cytokines and increase in Th17 cytokines were observed in the lungs of T-bett-/ mice, compared with wild-type mice and T-bet tg/tg mice. Interestingly, however, the level of Th2 cytokines was not different among mice genotypes in response to MAC. These findings indicate that T-bet plays a central role in controlling MAC disease progression, through the regulation of both Th1 and Th17, but not Th2 responses. 3. Route of infection in Mycobacterium avium-intracellulare complex disease: Yutaka ITO (Department of Respiratory Medicine, Department of Infection Control and Prevention, Kyoto University) Environmental exposure is considered to be the primary route for Mycobacterium avium-intracellulare complex (MAC) infection. MAC is isolated from drinking water distribution systems, bathroom and showerheads and the genetic relatedness of clinical isolates from MAC patients with water isolates have been reported. We reported that patients with pulmonary MAC disease had significantly more soil exposure (>2 per week) than noninfected control patients after adjustments for the potential confounding diseases and conditions in pulmonary MAC disease. Moreover, we found six pairs of clinical isolates and corresponding soil isolates with identical variable numbers of tandem repeats profiles among patients with high soil exposure, suggesting that residential soils are a likely source of pulmonary MAC infection. 4. Clinical data analysis of Mycobacterium avium complex serodiagnosis kit: Yuta HAYASHI (Department of Respiratory Medicine, National Hospital Organization Higashi Nagoya National Hospital), Taku NAKAGAWA, Kenji OGAWA (Department of Clinical Research, National Hospital Organization Higashi Nagoya National Hospital) Mycobacterium avium complex (MAC) serodiagnosis kit was covered by health insurance in August 2011 in Japan, but experience with this kit in daily clinical practice is still scarce. We analyzed the clinical data of MAC serum diagnostic kit in our hospital. Considering the high diagnostic performance of this kit (specificity 92.9%), that can also be incorporated into the diagnostic criteria. However it should be noted that there can be false-negative even in patients with active pulmonary MAC. Although this test is also expected usefulness as a marker of disease activity, at the present time should be kept for reference. 5. Clinical effect of combined chemotherapy containing aminoglycoside or new quinolone antibiotics for Mycobacterium avium complex disease: Yosihiro KOBASHI, Mikio OKA (Department of Respiratory Medicine, Kawasaki Medical School) Because it was possible to administrate CAM 800 mg/day for the treatment of Mycobacterium avium complex (MAC) disease after 2008, we compared the clinical effect of combined chemotherapy (RFP, EB, CAM 800 mg/day) containing aminoglycoside (SM) and combined chemotherapy (RFP, EB, CAM 400 mg/day or 600 mg/day) containing SM before 2007. Subsequently, the latter treatment was significantly better in the sputum conversion rate and clinical improvement such as clinical symptoms or radiological findings than the former treatment. Concerning the side effects or abnormal laboratory findings, although gastrointestinal symptoms were frequently appeared in the latter period, there was no significant difference between both periods. PMID- 23672177 TI - [Reconsideration of the admission and discharge criteria of tuberculosis patients in Japan]. AB - Japanese Ministry of Health, Labour and Welfare issued new criteria for admission and discharge of tuberculosis patients in 2007. The criteria for admission are extended for the patients of the risk of Mycobacterium tuberculosis transmission and of the possible risk of treatment failure. The criteria for discharge are consisted of the 3 factors, (1) symptoms (cough, fever, etc.) are free after the standard chemotherapy of more than 2 weeks, (2) three different sputum smears are negative for acid-fast bacilli after the standard chemotherapy of more than 2 weeks, (3) patients are estimated to adhere to the chemotherapy after discharge and understand the infection control of M. tuberculosis. Although the criteria were simple, the goal was to treat tuberculosis patients successfully and improve treatment outcomes. For the effective operation of these criteria, the network of primary care facilities for early diagnosis and treatment after discharge, tuberculosis treatment facilities for hospitalization and local government including health care center is important. Four speakers proposed the problems and revealed their own resolutions. Three speakers from tuberculosis treatment facilities were positive for the shortening of hospitalization length by modifying the discharging criteria, however 1 speaker from the Tokyo Metropolitan Government emphasized that the regional medical system should be established for the treatment of discharged tuberculosis patient. 1. Reconsideration of admission and discharge criteria for tuberculosis patients: Kazunari TSUYUGUCHI (Department of Infectious Diseases, Clinical Research Center, National Hospital Organization Kinki-chuo Chest Medical Center) According to the present guideline in Japan, three consecutive negative sputum results for smear or culture are required for discharge of tuberculosis (TB) patients, making their duration of hospitalization extremely long. On the other hand, most of the TB ward in Japan consists of big rooms without air conditioning which carries a potential risk of nosocomial transmission and reinfection. In order to establish effective TB control, suspected or confirmed TB patient should be isolated in a single room equipped with the capacity for airborne infection isolation during hospitalization, as long as sputum smear or culture remains positive. It is reasonable to discharge patients to home before sputum conversion if effective chemotherapy is provided and all household members have been previously exposed. Rapid drug sensitivity testing will be helpful in assuring the effectiveness of chemotherapy for prompt discharge and detecting multidrug-resistance immediately. 2. Reconsideration of admission and discharge criteria for tuberculosis patient in Japan : Taku NAKAGAWA, Kenji OGAWA (Department of Pulmonary Medicine, National Hospital Organization Higashi Nagoya National Hospital) Admission criteria for tuberculosis patient are based on the positive result of sputum AFB smear test in principle. But admission criteria should be applied flexibly depending on the extent and severity of illness, socioeconomic background of the patient, and adherence to treatment in cooperation with the public health center. The Japanese Tuberculosis Society published "Guidelines for Admission and Discharge of Tuberculosis Patient" in January 2005. This guideline was consistent with the notice from Ministry of Health, Labour and Welfare. Improvement of management of patients with tuberculosis is most important, but bacteriological conversion is not necessary to release isolation from the hospital. The patients treated with standard regimen over two weeks and having improvement of clinical symptoms may be able to go home back in the absence of compromised person. As a result of putting this guideline into practice, there were no problems about infectiousness for tuberculosis. But the modified notice from Ministry of Health, Labour and Welfare based on bacteriological conversion was made public in September 2007. This modified notice brought in a prolonged period of hospitalization and created confusion in clinical practice. Based on the result of our study for infectiousness, it is appropriate to use the guideline in January 2005. 3. Consideration of the standard for leaving TB hospital: Masako WADA (Chemotherapy Research Institute, Kaken Hospital) In Japan, infectious pulmonary tuberculosis patients are ordered to receive chemotherapy in admission to tuberculosis treatment facilities according to Infectious Diseases Control Law. Infectious pulmonary tuberculosis is defined as sputum smear positive for acid-fast bacilli (AFB) even it is questionable. And there consecutive negative sputum smear for AFB is needed as a criteria for discharge. In this study we defined our own admission criteria as follows, medical service is needs owing to serious pulmonary tuberculosis, meningitis and other complications. We simulated the cost for hospitalization. During study period 170 patients were admitted and only 36 patients (21%) were needed hospitalization on our own criteria. The other 134 patients were admitted because of infectiousness. The average hospital stay was 63.0 days and 64.8 days, respectively. Total cost of patients cares were 26 million yen and 100 million yen respectively. On the points of saving medical costs, Infectious Diseases Control Law should be revised. 4. Recent problems in tuberculosis hospitalization and countermeasures related to patients support in urban area: Michihiko YOSHIDA (Infectious Control Section, Health and Safety Division, Bureau of Social Welfare and Public Health, Tokyo Metropolitan Govenment) Standard treatment for tuberculosis led to a shortening of hospitalization days. After discharge most patients are treated as outpatient. In the outpatient, the decreased numbers and the bias in the geographical distribution of tuberculosis hospitals impair patients' accessibility and may lead to increase of drop out cases. And there is possible poor adherence to treatment in such as foreign-born patients from high burden countries, so intensive intervention will,be needed for successful treatment. On the other hand, in the tuberculosis hospitals, there are noninfectious tuberculosis patients with chronic complications such as psychiatric disorders and dialysis. In most cases, these patients cannot be transferred to other hospitals or welfare facilities. To resolve these problems, it is necessary to build community DOTS system including the public health centers, tuberculosis hospitals and related community resources such as clinics and welfare facilities. Also, in the near future, it is necessary to review and rebuild tuberculosis medical system comprehensively at the national level. PMID- 23672178 TI - A novel prodrug strategy for extremely hydrophobic agents: conjugation to symmetrically branched glycerol trimer improves pharmacological and pharmacokinetic properties of fenofibrate. AB - Management of a lipophilic-hydrophilic balance is a key element in drug design to achieve desirable pharmacokinetic characters. Therefore we have created unique modular molecules, symmetrically branched oligoglycerols (BGL), as an alternative way to endow hydrophobic molecules with sufficient hydrophilicity. We have successfully demonstrated amelioration of the water solubility and thermal stability of several hydrophobic agents by covalent conjugation to BGL so far. However, it has not been clarified whether the molecular modification by BGL also improves the pharmacological and/or pharmacokinetic properties indeed. Recently, we synthesized a novel BGL-prodrug derivative of fenofibrate, which is an antihyperlipidemic agent and one of the most hydrophobic medicinal compounds currently used clinically, by conjugating fenofibric acid to symmetrically branched glycerol trimer (BGL003), the simplest BGL. We have previously demonstrated that the hydrophilicity and water solubility of fenofibrate are improved more than 2000 times just by conjugation to the BGL003. To verify our hypothesis that the prodrug strategy with BGL should improve pharmacological efficacy and pharmacokinetic properties of extremely hydrophobic agents such as fenofibrate by the rise in hydrophilicity, we evaluated the BGL003-prodrug derivative of fenofibrate (FF-BGL) using rodent models. Here we demonstrate that the lipid-lowering effects of fenofibrate are much potentiated by chemical conjugation to BGL003 without exhibiting significant toxicity. Plasma concentration of fenofibric acid, an active metabolite of fenofibrate, after single oral administration of FF-BGL was more than 3 times higher than that of fenofibrate, in accordance. In fasting rats, plasma concentration of fenofibric acid after fenofibrate administration was curtailed into less than half of that in ad libitum-fed rats, while FF-BGL showed about the same plasma level even in the starving rats. This is the first report showing that BGL-prodrug improves pharmacological and pharmacokinetic properties as well as hydrophilicity of highly hydrophobic compounds. Furthermore, prodrug strategy using BGL suggests the possibility of diminishing the food-drug interaction effects, which should be advantageous for promoting drug compliance. BGL will be a suitable prodrug strategy to ameliorate physical, pharmacological, and pharmacokinetic characteristics of extremely hydrophobic compounds. PMID- 23672179 TI - Conventional and new oral anticoagulants in the treatment of chest disease and its complications. AB - Oral anticoagulants block the coagulation cascade either by an indirect mechanism (e.g., vitamin K antagonists) or by a direct one (e.g., the novel oral anticoagulants). Vitamin K antagonists are widely used as treatment of venous thromboembolism and for stroke prevention in patients with atrial fibrillation. Although low molecular weight heparin remains the first line in venous thromboembolism prophylaxis, more recently the novel oral anticoagulants such as dabigatran (initial dose of 110 mg within 1-4 h after surgery, followed by the full dose of 220 mg once daily), rivaroxaban (dose of 10 mg once daily, with the first dose administered 6-10 h after the surgery), and apixaban (dose of 2.5 mg twice daily, starting 12-24 h after surgery, but available only in Europe) are approved for prophylaxis in patients undergoing major orthopedic surgery. The period in which thromboembolic risk abates remains uncertain, and trials of extended therapy are still ongoing. After showing at least noninferiority to warfarin in RE-LY, ROCKET-AF, and ARISTOTLE trials, dabigatran (110 or 150 mg twice daily), rivaroxaban (20 or 15 mg once daily), and apixaban (5 mg twice daily), respectively, were approved also for stroke prevention in patients with atrial fibrillation. While awaiting long-term safety data, the choice among all these available therapies should be based on patient preferences, compliance, and ease of administration, as well as on local factors affecting cost-effectiveness. PMID- 23672180 TI - Diffusive dynamics of nanoparticles in arrays of nanoposts. AB - The diffusive dynamics of dilute dispersions of nanoparticles of diameter 200-400 nm were studied in microfabricated arrays of nanoposts using differential dynamic microscopy and single particle tracking. Posts of diameter 500 nm and height 10 MUm were spaced by 1.2-10 MUm on a square lattice. As the spacing between posts was decreased, the dynamics of the nanoparticles slowed. Moreover, the dynamics at all length scales were best represented by a stretched exponential rather than a simple exponential. Both the relative diffusivity and the stretching exponent decreased linearly with increased confinement and, equivalently, with decreased void volume. The slowing of the overall diffusive dynamics and the broadening distribution of nanoparticle displacements with increased confinement are consistent with the onset of dynamic heterogeneity and the approach to vitrification. PMID- 23672182 TI - Liquid-phase syntheses and material properties of two-dimensional nanocrystals of rare earth-selenium compound containing planar Se layers: RESe2 nanosheets and RE4O4Se3 nanoplates. AB - Synthesis of diverse two-dimensional nanostructures with unique material properties is of current interest and multidisciplinary importance but remains a challenge for trivalent rare earth (RE)-selenium (Se) compounds because of the weak affinity between hard rare earth cations and soft selenium anions. In this article, for the first time, we report a mild solution approach toward a series of two-dimensional trivalent RE-selenium compound nanocrystals, namely RESe2 nanosheets (RE = La to Nd, for EuSe2, nanobars were obtained) and RE4O4Se3 nanoplates (RE = Nd, Sm, Gd to Ho), under a high chemical potential of selenium obtained by activating SeO2 powder with oleylamine in high boiling point organic solvents. Both kinds of nanocrystals contain Se with -1 valence in planar Se layers, allowing for a great variability in their crystal structures. Satellite diffraction peaks were observed in the electron diffraction pattern of LaSe2 nanosheets, indicating the presence of Peierls distortion in the Se layers. In the RE4O4Se3 nanoplates, the interaction between Se(2-) ions and [Se-Se](2-) dumbbells in the Se layers increases when the radii of the RE(3+) ions decrease along the lanthanide series, resulting in a narrower optical band gap (from 1.96 to 1.73 eV). The LaSe2 nanosheet films fabricated by drop-casting exhibited good electrical conductivity at room temperature (about 1 Omega.cm(-1)). Further, the RE4O4Se3 nanoplates showed very high light extinction capacity in the visible region (extinction coefficient MUi: 4.4 * 10(5) cm(-1) for Nd4O4Se3, and 3.1 * 10(5) cm(-1) for Gd4O4Se3), comparable to that (5 * 10(5) cm(-1)) of CuInS2 commonly used in solar cells. PMID- 23672183 TI - Innovative approach to produce submicron drug particles by vibrational atomization spray drying: influence of the type of solvent and surfactant. AB - Spray drying is a technique used to produce solid particles from liquid solutions, emulsions or suspensions. Buchi Labortechnik developed the latest generation of spray dryers, Nano Spray Dryer B-90. This study aims to obtain, directly, submicron drug particles from an organic solution, employing this equipment and using dexamethasone as a model drug. In addition, we evaluated the influence of both the type of solvent and surfactant on the properties of the powders using a 3(2) full factorial analysis. The particles were obtained with high yields (above 60%), low water content (below 2%) and high drug content (above 80%). The surface tension and the viscosity were strongly influenced by the type of solvent. The highest powder yields were obtained for the highest surface tension and the lowest viscosity of the drug solutions. The use of ionic surfactants led to higher process yields. The laser diffraction technique revealed that the particles deagglomerate into small ones with submicrometric size, (around 1 um) that was also observed by scanning electron microscopy. Interaction between the raw materials in the spray-dried powders was verified by calorimetric analysis. Thus, it was possible to obtain dexamethasone submicrometric particles by vibrational atomization from organic solution. PMID- 23672184 TI - Template-free synthesis of nanostructured Cd(x)Zn(1-x)S with tunable band structure for H2 production and organic dye degradation using solar light. AB - We have demonstrated a template-free large-scale synthesis of nanostructured Cd(x)Zn(1-x)S by a simple and a low-temperature solid-state method. Cadmium oxide, zinc oxide, and thiourea in various concentration ratios are homogenized at moderate temperature to obtain nanostructured Cd(x)Zn(1-x)S. We have also demonstrated that phase purity of the sample can be controlled with a simple adjustment of the amount of Zn content and nanocrystalline Cd(x)Zn(1-x)S(x = 0.5 and 0.9) of the hexagonal phase with 6-8 nm sized and 4-5 nm sized Cd(0.1)Zn(0.9)S of cubic phase can be easily obtained using this simple approach. UV-vis and PL spectrum indicate that the optical properties of as synthesized nanostructures can also be modulated by tuning their compositions. Considering the band gap of the nanostructured Cd(x)Zn(1-x)S well within the visible region, the photocatalytic activity for H2 generation using H2S and methylene blue dye degradation is performed under visible-light irradiation. The maximum H2 evolution of 8320 MUmol h(-1)g(-1) is obtained using nanostructured Cd(0.1)Zn(0.9)S, which is four times higher than that of bulk CdS (2020 MUmol h( 1) g(-1)) and the reported nanostructured CdS (5890 MUmol h(-1)g(-1)). As synthesized Cd(0.9)Zn(0.1)S shows 2-fold enhancement in degradation of methylene blue as compared to the bulk CdS. It is noteworthy that the synthesis method adapted provides an easy, inexpensive, and pollution-free way to synthesize very tiny nanoparticles of Cd(x)Zn(1-x)S with a tunnable band structure on a large scale, which is quite difficult to obtain by other methods. More significantly, environmental benign enhanced H2 production from hazardous H2S using Cd(x)Zn(1 x)S is demonstrated for the first time. PMID- 23672185 TI - Discovery of the first histone deacetylase 6/8 dual inhibitors. AB - We disclose the first small molecule histone deacetylase (HDAC) inhibitor (3, BRD73954) capable of potently and selectively inhibiting both HDAC6 and HDAC8 despite the fact that these isoforms belong to distinct phylogenetic classes within the HDAC family of enzymes. Our data demonstrate that meta substituents of phenyl hydroxamic acids are readily accommodated upon binding to HDAC6 and, furthermore, are necessary for the potent inhibition of HDAC8. PMID- 23672186 TI - Relative group size and minority school success: the role of intergroup friendship and discrimination experiences. AB - From an intergroup relations perspective, relative group size is associated with the quantity and quality of intergroup contact: more positive contact (i.e., intergroup friendship) supports, and negative contact (i.e., experienced discrimination) hampers, minority identity, and school success. Accordingly, we examined intergroup contact as the process through which perceived relative proportions of minority and majority students in school affected minority success (i.e., school performance, satisfaction, and self-efficacy). Turkish minorities (N = 1,060) were compared in four Austrian and Belgian cities which differ in their typical school ethnic composition. Across cities, minority experiences of intergroup contact fully mediated the impact of perceived relative group size on school success. As expected, higher minority presence impaired school success through restricting intergroup friendship and increasing experienced discrimination. The association between minority presence and discrimination was curvilinear, however, so that schools where minority students predominated offered some protection from discrimination. To conclude, the comparative findings reveal positive and negative intergroup contact as key processes that jointly explain when and how higher proportions of minority students affect school success. PMID- 23672188 TI - Comparison of electromagnetic shielding with polyaniline nanopowders produced in solvent-limited conditions. AB - Nanoparticle synthesis (~10-50 nm) of HCl-doped polyaniline elucidates the impact of limiting solvent (water) and oxidizing agent (ammonium peroxydisulfate) on morphology (XRD and TEM), chemical structure (FTIR), conductivity (two-point DC) and electromagnetic shielding effectiveness (SE) in microwave frequencies (i.e., X-band S-parameter measurements). Detailed comparison of these properties with respect to three distinct polymerization environments indicate that a solvent free or limited solvent polymerization accomplished through a wet grinding solid phase reaction produces superior conductivity (27 S/cm) with intermediate crystallinity (66%) for the highest EM shielding-an order of magnitude improvement over conventional polymerization with respect to EM power transmission reduction for all loadings per shielding area (0.04 to 0.17 g/cm(2)). By contrast, the classic oxidation of aniline in a well-dispersed aqueous reaction phase with an abundance of available oxidant in free solution yielded low conductivity (3.3 S/cm), crystallinity (54%), and SE, whereas similar solvent-rich reactions with limiting oxidizer produced similar conductivity (2.9 S/cm) and significantly lower SE with the highest crystallinity (72%). This work is the first to demonstrate that limiting solvent and oxidizer enhances electromagnetic interactions for shielding microwaves in polyaniline nanopowders. This appears connected to having the highest overall extent of oxidation achieved in the wet solid-phase reaction. PMID- 23672187 TI - DROMPA: easy-to-handle peak calling and visualization software for the computational analysis and validation of ChIP-seq data. AB - Chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) can identify genomic regions that bind proteins involved in various chromosomal functions. Although the development of next-generation sequencers offers the technology needed to identify these protein-binding sites, the analysis can be computationally challenging because sequencing data sometimes consist of >100 million reads/sample. Herein, we describe a cost-effective and time-efficient protocol that is generally applicable to ChIP-seq analysis; this protocol uses a novel peak-calling program termed DROMPA to identify peaks and an additional program, parse2wig, to preprocess read-map files. This two-step procedure drastically reduces computational time and memory requirements compared with other programs. DROMPA enables the identification of protein localization sites in repetitive sequences and efficiently identifies both broad and sharp protein localization peaks. Specifically, DROMPA outputs a protein-binding profile map in pdf or png format, which can be easily manipulated by users who have a limited background in bioinformatics. PMID- 23672189 TI - Rapid quantitative analysis of diosgenin in the tubers of Dioscorea zingiberensis C.H. Wright by coupling cellulose enzymolysis and two-phase acid hydrolysis in tandem with HPLC-UV. AB - A rapid method was developed to quantify diosgenin in Rhizoma Dioscoreae Zingiberensis. For the first time, sample solution was prepared by coupling pretreatment of raw material in cellulase and two-phase acid hydrolysis. After reconstitution, analysis was carried out on a C18 column, at 30 degrees C, with acetonitrile and water (70:30, v/v) as mobile phase with flow rate of 1.0 mL min( 1). Detection was carried out at 202 nm. Good linearity (r(2) = 0.9998) was established between concentration of analyte and peak area. The precision was >99% and the RSD of diosgenin contents for repeatability was 1.81%. The accuracy was supported with recoveries at 98.8%, 101.6% and 101.2%. The sample solution prepared using the proposed method contained higher content of diosgenin and was stable for 48 h. Due to the high efficiency of sample preparation and high reliability of the HPLC method, it is feasible to use this method for routine analysis of diosgenin in the herb. PMID- 23672190 TI - Protected sulfur transfer reactions by the Escherichia coli Suf system. AB - The first step in sulfur mobilization for the biosynthesis of Fe-S clusters under oxidative stress and iron starvation in Escherichia coli involves a cysteine desulfurase SufS. Its catalytic reactivity is dependent on the presence of a sulfur acceptor protein, SufE, which acts as the preferred substrate for this enzyme. Kinetic analysis of the cysteine:SufE sulfurtransferase reaction of the E. coli SufS that is partially protected from reducing agents, such as dithiothreitol and glutathione, was conducted. Under these conditions, the reaction displays a biphasic profile in which the first phase involves a fast sulfur transfer reaction from SufS to SufE. The accumulation of persulfurated/polysulfurated forms of SufE accounts for a second phase of the slow catalytic turnover rate. The presence of the SufBCD complex enhances the activity associated with the second phase, while modestly inhibiting the activity associated with the initial sulfur transfer from SufS to SufE. Thus, the rate of sulfur transfer from SufS to the final proposed SufBCD Fe-S cluster scaffold appears to be dependent on the availability of the final sulfur acceptor. The use of a stronger reducing agent [tris(2-carboxyethyl)phosphine hydrochloride] elicited the maximal activity of the SufS-SufE reaction and surpassed the stimulatory effect of SufBCD. This concerted sulfur trafficking path involving sequential transfer from SufS to SufE to SufBCD guarantees the protection of intermediates at a controlled flux to meet cellular demands encountered under conditions detrimental to thiol chemistry and Fe-S cluster metabolism. PMID- 23672192 TI - SF2/ASF binding region within JC virus NCCR limits early gene transcription in glial cells. AB - BACKGROUND: Patients undergoing immune modulatory therapies for the treatment of autoimmune diseases such as multiple sclerosis, and individuals with an impaired immune system, most notably AIDS patients, are in the high risk group of developing progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of the white matter caused by human neurotropic polyomavirus, JC virus. It is now widely accepted that pathologic strains of JCV shows unique rearrangements consist of deletions and insertions within viral NCCR. While these kinds of rearrangements are related to viral tropism and pathology of the disease, their roles in molecular regulation of JCV gene expression and replication are unclear. We have previously identified SF2/ASF as a negative regulator of JCV gene expression in glial cells. This negative impact of SF2/ASF was dependent on its ability to bind a specific region mapped to the tandem repeat within viral promoter. In this report, functional role of SF2/ASF binding region in viral gene expression and replication was investigated by using deletion mutants of viral regulatory sequences. RESULTS: The second 98-base-pair tandem repeat on Mad1 strain was first mutated by deletion and named Mad1-(1X98). In addition to this mutant, the CR3 region which served the binding side for SF2/ASF was also mutated and named Mad1-DeltaCR3 (1X73). Both mutations were tested for SF2/ASF binding by ChIP assay. While SF2/ASF was associated with Mad1 WT and Mad1-(1X98), its interaction was completely abolished on Mad1-DeltaCR3 (1X73) construct as expected. Surprisingly, reporter gene analysis of Mad1-(1X98) and Mad1-DeltaCR3 (1X73) early promoter sequences showed two and three fold increase in promoter activities, respectively. The impact of "CR3" region on JCV propagation was also tested on the viral background. While replication of Mad1 (1X98) strain in glial cells was similar to Mad1-WT strain, propagation of Mad1 DeltaCR3 (1X73) was less productive. Further analysis of the transcription mediated by Mad1-DeltaCR3 (1X73) NCCR revealed that late gene expression was significantly affected. CONCLUSIONS: The results of this study reveal a differential role of CR3 region within JCV NCCR in expression of JCV early and late genes. PMID- 23672191 TI - ARS-interacting multi-functional protein 1 induces proliferation of human bone marrow-derived mesenchymal stem cells by accumulation of beta-catenin via fibroblast growth factor receptor 2-mediated activation of Akt. AB - ARS-Interacting Multi-functional Protein 1 (AIMP1) is a cytokine that is involved in the regulation of angiogenesis, immune activation, and fibroblast proliferation. In this study, fibroblast growth factor receptor 2 (FGFR2) was isolated as a binding partner of AIMP peptide (amino acids 6-46) in affinity purification using human bone marrow-derived mesenchymal stem cells (BMMSCs). AIMP1 peptide induced the proliferation of adult BMMSCs by activating Akt, inhibiting glycogen synthase kinase-3beta, and thereby increasing the level of beta-catenin. In addition, AIMP1 peptide induced the translocation of beta catenin to the nucleus and increased the transcription of c-myc and cyclin D1 by activating the beta-catenin/T-cell factor (TCF) complex. By contrast, transfection of dominant negative TCF abolished the effect of AIMP1. The inhibition of Akt, using LY294002, abolished the accumulation and nuclear translocation of beta-catenin induced by AIMP1, leading to a decrease in c-myc and cyclin D1 expression, which decreased the proliferation of BMMSCs. An intraperitoneal injection of AIMP1 peptide into C57/BL6 mice increased the colony formation of fibroblast-like cells. Fluorescence activated cell sorting analysis showed that the colony-forming cells were CD29(+)/CD44(+)/CD90(+)/CD105(+)/CD34( )/CD45(-), which is characteristic of MSCs. In addition, the fibroblast-like cells differentiated into adipocytes, chondrocytes, and osteocytes. Taken together, these data suggest that AIMP1 peptide promotes the proliferation of BMMSCs by activating the beta-catenin/TCF complex via FGFR2-mediated activation of Akt, which leads to an increase in MSCs in peripheral blood. PMID- 23672193 TI - Spinal haematoma after removal of a thoracic epidural catheter in a patient with coagulopathy resulting from unexpected vitamin K deficiency. AB - Postoperative epidural analgesia is effective and widely utilised after major abdominal surgery. Spinal haematoma is a rare and devastating complication after epidural analgesia. Well-established risk factors for the development of spinal haematoma after neuraxial procedures have been documented. We present the case of a patient with normal pre-operative coagulation parameters who developed a spinal haematoma more than 24 h after removal of an epidural catheter; she had been without oral intake for only 4 days during which time she developed vitamin K deficient coagulopathy. Clinicians should consider pre-operative screening of coagulation (International Normalised Ratio), or giving vitamin K supplementation, before performing neuraxial procedures in patients who are at risk of developing vitamin K deficiency or coagulopathy in the peri-operative period. PMID- 23672194 TI - Intraspecific variation of a desert shrub species in phenotypic plasticity in response to sand burial. AB - Shoot elongation is one of the main plastic responses of plants to burial, a ubiquitous stress factor in dry ecosystems. Yet, intraspecific variation in this response to burial and the extent to which this variation is functionally coordinated with variation in other trait responses are largely unknown. We subjected seedlings of the shrub Caragana intermedia from 18 maternal parents (i.e. different half-sib families) to repeated partial burial to investigate how burial affects shoot growth, stem mechanical traits and associated plasticity. Burial increased both stem elongation and diameter growth of plants, but decreased biomass production. Half-sib families had different rates of shoot elongation, and differed in their response to burial with respect to biomechanical stem properties. Across half-sib families, the magnitude of these responses in mechanical traits was positively correlated with the magnitude of the stem elongation response. These results indicate that plasticity in different stem traits in response to sand burial and intraspecific variation therein are functionally coordinated with respect to mechanical stability. The results emphasize the importance of considering functionally coordinated traits when analyzing phenotypic plasticity in plants. PMID- 23672196 TI - Inhibition of biofilms by glucose oxidase, lactoperoxidase and guaiacol: the active antibacterial component in an enzyme alginogel. AB - The association of biofilms with wound chronicity has prompted a search for antimicrobial interventions that are effective against biofilms. A patented preparation of glucose oxidase, lactoperoxidase and guaiacol (GLG), which is the antibacterial component of Flaminal, has been shown to inhibit a wide range of bacteria, but it has not yet been tested on biofilms. This study aims to determine the effect of GLG on biofilms of Staphylococcus aureus, methicillin resistant S. aureus and Pseudomonas aeruginosa. Static biofilms were grown in microtitre plates and on coverslips and treated with a range of concentrations of GLG. Effects were monitored by estimating biofilm biomass by staining with crystal violet, biofilm activity by staining with either resazurin or fluorescein diacetate and biofilm viability by staining with LIVE/DEAD BacLight Bacterial Viability Kit. GLG was able to prevent the formation of biofilms at concentration <=0.5% (w/v) and higher concentrations were required to inhibit established biofilms. GLG did not disrupt biofilm biomass. Staphylococci were more susceptible to GLG than P. aeruginosa. These in vitro findings must be verified by in vivo studies. PMID- 23672197 TI - Lacrimal system endoscopy assisted endonasal dacryocystorhinostomy. AB - OBJECTIVE: To assess the potential benefit of intra-operative lacrimal system endoscopy during endonasal dacryocystorhinostomy. METHODS: Eight patients (10 cases) underwent lacrimal system endoscopy assisted endonasal dacryocystorhinostomy for nasolacrimal duct obstruction between May 2010 and July 2012 at the New York Presbyterian Hospital/Weill Cornell Medical College. All patients were subsequently followed post-operatively for at least 6 months. Primary outcome measures included post-operative epiphora and infection. RESULTS: Lacrimal system endoscopy assisted endonasal dacryocystorhinostomy was successful in identifying the level of nasolacrimal duct obstruction in all 10 cases. Endoscopy revealed obstruction at the valve of Hasner in 2 cases, while the remaining cases involved obstruction at more proximal locations within the nasolacrimal duct. The location of the rhinostomy created during dacryocystorhinostomy was tailored to the specific level of obstruction. No intra operative complications were encountered. The majority of patients (6 of 8) experienced complete resolution of epiphora within 1 month of surgery, with all patients achieving resolution by 6 months. None of the patients in the study exhibited any signs of post-operative dacryocystitis. CONCLUSION: The evaluation and management of nasolacrimal duct obstruction may be greatly enhanced through the use of intra-operative lacrimal system endoscopy by specifically localizing and identifying the underlying cause of obstruction, while maintaining the excellent success rate of endonasal dacryocystorhinostomy. PMID- 23672198 TI - Intranasal exposure to uranium results in direct transfer to the brain along olfactory nerve bundles. AB - AIMS: Uranium olfactory uptake after intranasal exposure raises some concerns for people potentially exposed to airborne radionuclide contamination as the brain could be a direct target for these contaminants. A model of nasal instillation was used to elucidate the transport mechanisms of uranium to the brain and to map its localization. METHODS: Increasing concentrations of depleted uranium containing solutions were instilled in the nasal cavity of adult male rats. Uranium concentrations were measured using inductively coupled plasma-mass spectrometry (ICP-MS) 4 h after instillation. Olfactory neuroepithelium cytoarchitecture was studied using immunohistochemistry experiments. Secondary ion mass spectrometry (SIMS) microscopy was performed to localize uranium in the olfactory system. RESULTS: ICP-MS analyses showed a frontal accumulation of uranium in the olfactory bulbs associated with a smaller increase in more caudal brain regions (frontal cortex, hippocampus and cerebellum). Uranium concentrations in the olfactory bulbs do not reach a saturation point. Olfactory nerve bundle integrity is not affected by uranium as revealed by immunohistochemistry. SIMS microscopy allowed us to show that uranium localization is mainly restricted to the olfactory neuroepithelium and around olfactory nerve bundles. It is subsequently detected in the olfactory nerve layer of the olfactory bulb. DISCUSSION: These results suggest the existence of a transcellular passage from the mucosa to the perineural space around axon bundles. Uranium bypasses the blood brain barrier and is conveyed to the brain via the cerebrospinal fluid along the olfactory nerve. Future studies might need to integrate this new contamination route to assess uranium neurotoxicity after nasal exposure. PMID- 23672199 TI - Assessment of the effects of intramuscular administration of alfaxalone with and without medetomidine in Horsfield's tortoises (Agrionemys horsfieldii). AB - OBJECTIVE: To characterise four different intramuscular (IM) anaesthetic protocols, two with alfaxalone and two with alfaxalone in combination with medetomidine in terrestrial tortoises. STUDY DESIGN: Blinded, randomized, cross over experimental study. ANIMALS: Nine healthy adult male Horsfield's tortoises (Agrionemys horsfieldii). METHODS: Each tortoise was randomly assigned to one of four different protocols: 1) 10 mg kg(-1) alfaxalone; 2) 10 mg kg(-1) alfaxalone + 0.10 mg kg(-1) medetomidine; 3) 20 mg kg(-1) alfaxalone; and 4) 20 mg kg(-1) alfaxalone + 0.05 mg kg(-1) medetomidine. During the experiment, the following variables were recorded: heart rate; respiratory rate; peripheral nociceptive responses; muscle strength; ability to intubate; palpebral, corneal and tap reflexes; and cloacal temperature. RESULTS: Protocols 1 and 2 resulted in moderate sedation with no analgesia, and moderate to deep sedation with minimal analgesia, respectively. Protocols 3 and 4 resulted in deep sedation or anaesthesia with variable analgesic effect; these two protocols had the longest total anaesthetic time and allowed intubation in 6/9 and 8/9 tortoises respectively. The total anaesthesia/sedation time produced by alfaxalone was significantly increased (p < 0.05) by the addition of medetomidine. There were no significant differences regarding time to plateau phase and duration of plateau phase. Baseline heart rate of 53 +/- 6 beats minute(-1) decreased significantly (p < 0.05) with all protocols, and was lower (p < 0.05) in protocols 3 and 4. Heart rate increased after atipamezole administration, but the increase was transient. In two tortoises, extreme bradycardia with no cardiac activity for 10 minutes was observed with protocols 3 and 4. CONCLUSION AND CLINICAL RELEVANCE: Alfaxalone 10 and 20 mg kg(-1) IM can be used for sedation for non-painful procedures. Alfaxalone in combination with medetomidine can be used for deeper sedation or anaesthesia, but the observed respiratory and cardiovascular depression may limit its use. PMID- 23672200 TI - Proteomic identification of unique photoreceptor disc components reveals the presence of PRCD, a protein linked to retinal degeneration. AB - Visual signal transduction takes place on the surface of flat membrane vesicles called photoreceptor discs, which reside inside the light-sensitive outer segment organelle of vertebrate photoreceptor cells. Although biochemical studies have indicated that discs are built with a handful of highly specialized proteins, proteomic studies have yielded databases consisting of hundreds of entries. We addressed this controversy by employing protein correlation profiling, which allows identification of unique components of organelles that can be fractionated but not purified to absolute homogeneity. We subjected discs to sequential steps of fractionation and identified the relative amounts of proteins in each fraction by label-free quantitative mass spectrometry. This analysis demonstrated that the photoreceptor disc proteome contains only eleven components, which satisfy the hallmark criterion for being unique disc-resident components: the retention of a constant molar ratio among themselves across fractionation steps. Remarkably, one of them is PRCD, a protein whose mutations have been shown to cause blindness, yet cellular localization remained completely unknown. Identification of PRCD as a novel disc-specific protein facilitates understanding its functional role and the pathobiological significance of its mutations. Our study provides a striking example how protein correlation profiling allows a distinction between constitutive components of cellular organelles and their inevitable contaminants. PMID- 23672201 TI - Exploring the adequacy of smoking cessation support for pregnant and postpartum women. AB - BACKGROUND: Smoking in pregnancy exemplifies the relationship between tobacco use and health inequalities. While difficulty reaching and engaging this population in cessation support is often highlighted in the literature, there is limited research that explores the factors that shape the provision and use of support by this subpopulation. Using Ontario, Canada, as a case study, this study examines how the use of cessation support by women is encouraged or discouraged by cessation policy, programming and practice; how geographical and sociocultural factors influence provision and uptake of support; and how barriers and challenges can be addressed through a comprehensive approach. METHODS: Semi structured, in-depth interviews with key informants (31) and pregnant or postpartum women (29) were conducted to examine the cessation needs of this subpopulation, barriers to the provision and uptake of cessation support and directions for policy, service provision and programming. RESULTS: Key barriers included: the absence of a provincial cessation strategy and funding, capacity and engagement/accessibility issues. Geographical features presented additional challenges to provision/uptake, as did the absence of resources tailored to Aboriginal women and adolescents. Key informants recommended a comprehensive cessation strategy to facilitate coordination of cessation resources provincially and locally and elucidated the need for capacity building within tobacco control and within reproductive, child and maternal health. Participants also highlighted the need to further develop tobacco control policies and target the social determinants of health through poverty reduction, housing and education support. The provision of incentives, transportation, childcare and meals/snacks; adoption of woman-centred, harm-reduction and stigma reduction approaches; and promotion of programs through a variety of local venues were recommended by participants to address engagement and accessibility issues. CONCLUSIONS: The current cessation system in Ontario is not equipped to adequately reduce smoking among pregnant and postpartum women. A comprehensive, multi-sector strategy designed to provide tailored and sustainable support through different system entry points is needed. A cultural shift in practice is also necessary to eliminate mixed messaging, strengthen practice and encourage open channels of communication about smoking between women and their providers. The study highlights the need to address smoking among women in a more holistic manner and for capacity building strategies that focus on strengthening providers' competency and confidence in practice. Future research should explore: capacity building strategies, especially among rural and remote communities; the smoking and cessation experiences of different subpopulations of pregnant and postpartum women; the effectiveness of tailored strategies; and interventions that address smoking among partners and other family members. PMID- 23672203 TI - Determinants of antenatal and delivery care utilization in Tigray region, Ethiopia: a cross-sectional study. AB - INTRODUCTION: Despite the international emphasis in the last few years on the need to address the unmet health needs of pregnant women and children, progress in reducing maternal mortality has been slow. This is particularly worrying in sub-Saharan Africa where over 162,000 women still die each year during pregnancy and childbirth, most of them because of the lack of access to skilled delivery attendance and emergency care. With a maternal mortality ratio of 673 per 100,000 live births and 19,000 maternal deaths annually, Ethiopia is a major contributor to the worldwide death toll of mothers. While some studies have looked at different risk factors for antenatal care (ANC) and delivery service utilisation in the country, information coming from community-based studies related to the Health Extension Programme (HEP) in rural areas is limited. This study aims to determine the prevalence of maternal health care utilisation and explore its determinants among rural women aged 15-49 years in Tigray, Ethiopia. METHODS: The study was a community-based cross-sectional survey using a structured questionnaire. A cluster sampling technique was used to select women who had given birth at least once in the five years prior to the survey period. Univariable and multivariable logistic regression analyses were carried out to elicit the impact of each factor on ANC and institutional delivery service utilisation. RESULTS: The response rate was 99% (n=1113). The mean age of the participants was 30.4 years. The proportion of women who received ANC for their recent births was 54%; only 46 (4.1%) of women gave birth at a health facility. Factors associated with ANC utilisation were marital status, education, proximity of health facility to the village, and husband's occupation, while use of institutional delivery was mainly associated with parity, education, having received ANC advice, a history of difficult/prolonged labour, and husbands' occupation. CONCLUSIONS: A relatively acceptable utilisation of ANC services but extremely low institutional delivery was observed. Classical socio-demographic factors were associated with both ANC and institutional delivery attendance. ANC advice can contribute to increase institutional delivery use. Different aspects of HEP need to be strengthened to improve maternal health in Tigray. PMID- 23672202 TI - Preventive effect of irsogladine or omeprazole on non-steroidal anti-inflammatory drug-induced esophagitis, peptic ulcers, and small intestinal lesions in humans, a prospective randomized controlled study. AB - BACKGROUND: Proton-pump inhibitors such as omeprazole are a standard treatment to prevent non-steroidal anti-inflammatory drug-induced upper gastrointestinal mucosal injuries. However, it is unclear which drugs may protect against all NSAID-induced digestive-tract injuries. Here, we compare the efficacy of the gastromucoprotective drug irsogladine with omeprazole in preventing NSAID-induced esophagitis, peptic ulcers, and small-intestinal mucosal injury in healthy subjects. METHODS: Thirty-two healthy volunteers were assigned to an irsogladine group (Group I; n = 16) receiving diclofenac sodium 75 mg and irsogladine 4 mg daily for 14 days, or an omeprazole group (Group O; n = 16) receiving diclofenac sodium 75 mg and omeprazole 10 mg daily for 14 days. Esophagitis and peptic ulcers were evaluated by esophagogastroduodenoscopy and small-intestinal injuries by capsule endoscopy, fecal calprotectin, and fecal occult blood before and after treatment. RESULTS: There was no significant difference between Group I and Group O with respect to the change in lesion score in the esophagus, stomach, and duodenum before and after treatment.NSAID treatment significantly increased the number of small intestinal mucosal breaks per subject by capsule endoscopic evaluation, from a basal level of 0.1 +/- 0.3 up to 1.9 +/- 2.0 lesions in Group O (p = 0.0002). In contrast, there were no significant changes in the mean number of mucosal breaks before and after co-treatment in Group I (0.3 +/- 0.8 to 0.5 +/ 0.7, p = 0.62), and the between-group difference was significant (p = 0.0040). Fecal calprotectin concentration, when the concentration before treatment was defined as 1, was significantly increased both in Group O (from 1.0 +/- 0.0 to 18.1 +/- 37.1, p = 0.0002) and Group I (from 1.0 +/- 0.0 to 6.0 +/- 11.1, p = 0.0280); the degree of increase in Group O was significantly higher compared with that in Group I (p<0.05). In addition, fecal occult blood levels increased significantly in Group O (p = 0.0018), but there was no change in Group I (p = 1.0), and the between-group difference was significant (p = 0.0031). CONCLUSION: Irsogladine protected against NSAID-induced mucosal injuries throughout the gastrointestinal tract, from esophagus to small intestine, significantly better than omeprazole. TRIAL REGISTRATION: This study was registered in the UMIN Clinical Trials Registry (Registry ID number; UMIN000008114). PMID- 23672204 TI - Regulation of de novo ceramide synthesis: the role of dihydroceramide desaturase and transcriptional factors NFATC and Hand2 in the hypoxic mouse heart. AB - We have previously shown that ceramide, a proapoptotic molecule decreases in the mouse heart as it adapts to hypoxia. We have also shown that its precursor, dihydroceramide, accumulates with hypoxia. This implicates the enzyme dihydroceramide desaturase (DHC-DS), which converts dihydroceramide to ceramide, in a potential regulatory checkpoint in cardiomyocytes. We hypothesised that the regulation of de novo ceramide synthesis plays an important role in the cardiomyocyte adaptation to hypoxia. We used an established mouse model to induce acute and chronic hypoxia. Cardiac tissues were extracted and quantitative real time polymerase chain reaction (qRT-PCR) was used to evaluate the expression levels of DHC-DS. Electrophoretic Mobility Shift Assays (EMSAs) and qRT-PCR were used to evaluate the activity and expression levels of an array of transcription factors that might regulate DEGS1 gene expression. We demonstrated that DEGS1 mRNA levels decrease with time in hypoxic mice concurrent with the decrease in HAND2 transcripts. Interestingly, the DEGS1 promoter harbors overlapping sites for Hand2 and Nuclear Factor of Activated T-cells (NFATC) transcription factors. We have demonstrated a physical interaction between NFATC1 and the E-Box proteins with EMSA and coimmunoprecipitation assays. The regulation of de novo ceramide synthesis in response to hypoxia and this newly described interaction between E box and NFATC transcription factors will pave the way to identify new pathways in the adaptation of the cardiomyocyte to stress. The elucidation of these pathways will in the long-term provide insights into potential targets for novel therapeutic regimens. PMID- 23672205 TI - Breastfeeding practices in mothers of high-respiratory-risk NICU infants: impact of depressive symptoms and smoking. AB - AIM: Mothers of infants in the neonatal intensive care unit (NICU) have very low breastfeeding rates and these high-respiratory-risk (HRR) NICU infants may benefit from breastfeeding through decreased risk for respiratory illnesses. This population's increased risk for maternal depression and high rates (22%) of maternal smoking may negatively affect breastfeeding. OBJECTIVE: This exploratory study investigated associations of breastfeeding with depressive symptoms and maternal smoking in mothers of HRR NICU infants (i.e. presence of one household smoker and birth weight <1500 g or mechanical ventilation >=12 h). METHODS: Breastfeeding, depression and smoking data were collected from 104 mothers in the NICU following delivery. RESULTS: Fifty-five (52.9%) mothers reported breastfeeding, 39 (37.5%) had a Center for Epidemiological Studies Depression Scale (CES-D) score (>=16) suggestive of depression, and 36 (34.6%) reported smoking. Mothers with CES-D scores >=16 were less likely to breastfeed compared to those with scores <16 (38.5% versus 61.5%; p = 0.02). Breastfeeding and smoking were not significantly associated (p < 0.10). Mothers of HRR infants with significant depressive symptoms who smoke have significantly lower breastfeeding rates (21%) than mothers who are not depressed and do not smoke (65%). CONCLUSIONS: Interventions to improve breastfeeding initiation and continuation that target depression and smoking are necessary. PMID- 23672206 TI - The effects of heuristic cues, motivation, and ability on systematic processing of information about breast cancer environmental factors. AB - The heuristic systematic model is used to investigate how ability, motivation, and heuristic message cues predict knowledge scores for individuals receiving messages written for different literacy levels about 3 environmental risk factors for breast cancer. The 3 risk factors were the roles of genetics, progesterone, and ingesting perfluorooctanoic acid in breast cancer risk. In this study, more than 4,000 women participated in an online survey. The results showed support for the hypotheses that ability (measured as education, number of science courses, and confidence in scientific ability) predict knowledge gain and that those individuals who presented with the lower literacy level message had significantly higher knowledge scores across all 3 message topics. There was little support for motivation or heuristic cues as direct predictors of knowledge gain across the 3 message topics, although they served as moderators for the perfluorooctanoic acid topic. The authors provide implications for health communication practitioners. PMID- 23672207 TI - Isolation and antifungal properties of cyclo(D-Tyr-L-Leu) diketopiperazine isolated from Bacillus sp. associated with rhabditid entomopathogenic nematode. AB - Bacillus sp. associated with an entomopathogenic nematode is shown to produce diketopiperazine (DKP) that showed stronger antifungal activity against Colletotrichum gloeosporioides [minimum inhibitory concentration (MIC): 8 MUg mL( 1)] than commercial fungicide oligochitosan (MIC: 125 MUg mL(- 1)). DKP identified as cyclo(D-Tyr-L-Leu) was isolated for the first time from a natural source with a d-tyrosine residue. This report also demonstrates for the first time an antifungal property exploration of cyclo(Tyr-Leu) class of dipeptides. The structural elucidation was carried out using 1D, 2D NMR methods and HPLC. PMID- 23672208 TI - Physical rehabilitation in post-conflict settings: analysis of public policy and stakeholder networks. AB - Physical rehabilitation plays a determinant role in post-conflict contexts to restore disabled citizens' mobility and independence. While the main objectives of any physical rehabilitation programme are to ensure that the services provided are accessible and of good quality to meet existing needs, it is intended that the services need to be supported over the long term by public health and social welfare authorities. This article presents the results of a study conducted in three post-conflict countries on the relationships between the level of commitment of national governments to rehabilitation services and the influence of social networks on national policy related to physical rehabilitation. From a policy and resource standpoint, the environment in Nepal is the most favourable for creating leverage at the national level to influence the commitment of ministries in the rehabilitation sector, compared with Cambodia and Somaliland. Stakeholder network analysis in Nepal, furthermore, reveals a dominant civil society and private sector supporting rehabilitation services, including intense involvement of local organisations and user groups. Implications for Rehabilitation Physical rehabilitation is not on the top of the agenda of governments in fragile states. The commitment and involvement of national authorities in the rehabilitation sector is positively influenced by civil society and international organisations. The denser the social network of the rehabilitation sector is, the more influence the actors can exert influence over national authorities. PMID- 23672209 TI - Effectiveness of botulinum toxin injection with and without needle electromyographic guidance for the treatment of spasticity in hemiplegic patients: a randomized controlled trial. AB - PURPOSE: To compare the effects of botulinum toxin injection with and without needle electromyographic guidance for the treatment of spasticity. METHOD: A randomized controlled study was conducted in a tertiary university hospital. Twenty-seven adult hemiplegic patients with spasticity due to brain or spinal cord damage were included. Spastic muscles were injected with botulinum toxin with or without EMG guidance. The modified Ashworth scale and modified Barthel index in each patient pre- and post-injection were documented. RESULTS: In group A, which consisted of 15 patients (55.55%), the injection was administered with needle electromyographic guidance, while in 12 patients (44.44%) of group B without electromyographic guidance with the use of anatomic landmarks only. The follow-up period was 3 months. At 3 weeks post-injection, spasticity was decreased (p < 0.05) in all patients and the mean (SD) reduction of spasticity was higher (p < 0.05) in group A (1.67 (0.5)) than group B (1.25 (0.46)). Similarly, the mean (SD) functional modified Barthel index improved statistically significantly (p < 0.001) post-injection (45.37 (8.43)) than pre-injection (54.07 (9.610), especially in group A (p < 0.05). CONCLUSION: The effectiveness of intramuscular botulinum toxin injection for the treatment of spasticity in hemiplegic patients is superior when performed with needle electromyographic guidance than without electromyography. IMPLICATIONS FOR REHABILITATION: It is recommended that botulinum toxin muscle injections of hemiplegic limbs be performed with EMG guidance More spasticity reduction and functional improvement at 3 months post-injection was observed in patients injected with botulinum toxin by the use of combined EMG guidance and anatomic landmarks EMG guidance might also save amount of botulinum toxin due to less spasticity observed during injection than when injection is performed with anatomic landmarks only. PMID- 23672210 TI - Questionnaire assessment of usual practice in mood and cognitive assessment in Scottish stroke units. AB - PURPOSE: National and International guidelines recommend cognition and mood assessment for all stroke survivors. However, there is no consensus on preferred screening tool or method of assessment. We aimed to describe clinical practice in cognitive and mood assessment across Scottish stroke services. METHOD: We used a questionnaire based survey. After local piloting, we distributed the questionnaire using mixed methodologies (online and paper) across all Stroke Managed Clinical Networks in Scotland. We also distributed the questionnaire to specialist societies representing stroke physicians, nurses and allied health professionals and through the UK Stroke Forum delegate pack. RESULTS: We received 174 responses from nurses, physiotherapists, psychologists, occupational therapists and medical staff. Medical staff made up the largest group of respondents (61, 35%). Of the respondents 148 (85%) routinely assess cognition and 119 (72%) mood. A variety of tools were used (cognitive n = 45 tools; mood n = 17); Mini Mental State Examination (n = 103, 59% of respondents) and the Hospital Anxiety and Depression Scale (n = 76, 44%) were the most commonly employed tools. CONCLUSION: Response rate was modest but included all mainland Scottish regions with active stroke services. Although the majority of responders are assessing cognition and mood there is substantial heterogeneity in measures used and certain commonly used tools are not validated or appropriate for use in stroke. We suggest development of evidence based, standardised assessment protocols. IMPLICATIONS FOR REHABILITATION: Screening stroke survivor's for cognitive and mood issues is recommended but there is little guidance on the preferred assessment strategy Across Scottish stroke services there is a lack of consensus in assessment and management of cognition and mood post stroke Sixty two different cognitive/mood assessment tools were found to be in use across the country Careful consideration must be given when inspecting assessment tools and use of caution when interpreting results. PMID- 23672211 TI - General model for estimating partition coefficients to organisms and their tissues using the biological compositions and polyparameter linear free energy relationships. AB - Equilibrium partition coefficients of organic chemicals from water to an organism or its tissues are typically estimated by using the total lipid content in combination with the octanol-water partition coefficient (K(ow)). This estimation method can cause systematic errors if (1) different lipid types have different sorptive capacities, (2) nonlipid components such as proteins have a significant contribution, and/or (3) K(ow) is not a suitable descriptor. As an alternative, this study proposes a more general model that uses detailed organism and tissue compositions (i.e., contents of storage lipid, membrane lipid, albumin, other proteins, and water) and polyparameter linear free energy relationships (PP LFERs). The values calculated by the established PP-LFER-composition-based model agree well with experimental in vitro partition coefficients and in vivo steady state concentration ratios from the literature with a root mean squared error of 0.32-0.53 log units, without any additional fitting. This model estimates a high contribution of the protein fraction to the overall tissue sorptive capacity in lean tissues (e.g., muscle), in particular for H-bond donor polar compounds. Direct model comparison revealed that the simple lipid-octanol model still calculates many tissue-water partition coefficients within 1 log unit of those calculated by the PP-LFER-composition-based model. Thus, the lipid-octanol model can be used as an order-of-magnitude approximation, for example, for multimedia fate modeling, but may not be suitable for more accurate predictions. Storage lipid-rich phases (e.g., adipose, milk) are prone to particularly large systematic errors. The new model provides useful implications for validity of lipid-normalization of concentrations in organisms, interpretation of biomonitoring results, and assessment of toxicity. PMID- 23672212 TI - Emergency cervical cerclage: effect on pregnancy outcome and mode of delivery. AB - AIM: To evaluate the effectiveness of emergency cervical cerclage (ECC) and its effect on the mode of delivery. PATIENTS AND METHODS: Between April 2007 and July 2011 patients attending MH Diyarbakir Obstetrics and Gynecology Hospital and MH Seferihisar State Necat Hepkon Hospital who underwent ECC were included in this retrospective analysis. RESULTS: At the time of ECC, the mean gestational age, cervical length and cervical dilatation were 21.4 +/- 2.2 weeks, 4.3 +/- 0.8 cm and 11 +/- 2.4 mm, respectively. The average time between the procedure and birth was 13.8 +/- 4.9 weeks and this period was sufficient to maintain a viable pregnancy (p < 0.05). In this study, 12 patients (60%) were delivered vaginally and eight (40%) patients delivered with CS (40%). the difference was statistically insignificant (p = 0.371). Regarding the gestational age at time of delivery, 55% of patients delivered at 36 weeks, 70% at 32 weeks, and 80% of them delivered at 28 weeks. The total live birth rate was 90%. CONCLUSION: ECC provides satisfactory time for the fetus to gain sufficient viability. Pregnancies with emergency cerclage show no difference in terms of birth method, whether cesarean or vaginal birth, and delivery type does not appears to be linked to ECC. PMID- 23672213 TI - Synthesis and in vitro evaluation of bone-seeking superparamagnetic iron oxide nanoparticles as contrast agents for imaging bone metabolic activity. AB - In this article, we report the synthesis and in vitro evaluation of a new class of nonionizing bone-targeting contrast agents based on bisphosphonate-conjugated superparamagnetic iron oxide nanoparticles (SPIONs), for use in imaging of bone turnover with magnetic resonance imaging (MRI). Similar to bone-targeting (99m)Technetium medronate, our novel contrast agent uses bisphosphonates to impart bone-seeking properties, but replaces the former radioisotope with nonionizing SPIONs which enables their subsequent detection using MRI. Our reported method is relatively simple, quick and cost-effective and results in BP SPIONs with a final nanoparticle size of 17 nm under electron microscopy technique (i.e., TEM). In-vitro binding studies of our novel bone tracer have shown selective binding affinity (around 65%) for hydroxyapatite, the principal mineral of bone. Bone-targeting SPIONs offer the potential for use as nonionizing MRI contrast agents capable of imaging dynamic bone turnover, for use in the diagnosis and monitoring of metabolic bone diseases and related bone pathology. PMID- 23672214 TI - Kinetic characterization of hydrolysis of nitrocefin, cefoxitin, and meropenem by beta-lactamase from Mycobacterium tuberculosis. AB - The constitutively expressed, chromosomally encoded beta-lactamase (BlaC) is the enzyme responsible for the intrinsic resistance to beta-lactam antibiotics in Mycobacterium tuberculosis. Previous studies from this laboratory have shown that the enzyme exhibits an extended-spectrum phenotype, with very high levels of penicillinase and cephalosporinase activity, as well as weak carbapenemase activity [Tremblay, L. W., et al. (2008) Biochemistry 47, 5312-5316]. In this report, we have determined the pH dependence of the kinetic parameters, revealing that the maximal velocity depends on the ionization state of two groups: a general base exhibiting a pK value of 4.5 and a general acid exhibiting a pK value of 7.8. Having defined a region where the kinetic parameters are pH independent (pH 6.5), we determined solvent kinetic isotope effects (SKIEs) for three substrates whose kcat values differ by 5.5 orders of magnitude. Nitrocefin is a highly activated, chromogenic cephalosporin derivative that exhibits steady state solvent kinetic isotope effects of 1.4 on both V and V/K. Cefoxitin is a slower cephalosporin derivative that exhibits a large SKIE on V of 3.9 but a small SKIE of 1.8 on V/K in steady-state experiments. Pre-steady-state, stopped flow experiments with cefoxitin revealed a burst of beta-lactam ring opening with associated SKIE values of 1.6 on the acylation step and 3.4 on the deacylation step. Meropenem is an extremely slow substrate for BlaC and exhibits burst kinetics in the steady-state experiments. SKIE determinations with meropenem revealed large SKIEs on both the acylation and deacylation steps of 3.8 and 4.0, respectively. Proton inventories in all cases were linear, indicating the participation of a single solvent-derived proton in the chemical step responsible for the SKIE. The rate-limiting steps for beta-lactam hydrolysis of these substrates are analyzed, and the chemical steps responsible for the observed SKIE are discussed. PMID- 23672215 TI - A new biphenyl and other constituents from the wood of Garcinia schomburgkiana. AB - A new biphenyl, named schomburgbiphenyl (1), and 14 known compounds were isolated from the wood of Garcinia schomburgkiana. The known constituents were identified as follows: three xanthones (2, 8 and 9), two benzophenones (3 and 4), three biphenyls (5-7), three biflavonoids (10-12) and three steroids. Compounds 3 and 4 were highly cytotoxic to SW620 cell line (100 times more than the positive control, doxorubicin) and were also strongly active against KATO-III, HepG2 and CHAGO cell lines. Compound 6 was specifically cytotoxic towards SW620 cells, whereas compound 8 displayed strong cytotoxicity against all five cell lines tested. PMID- 23672217 TI - Editorial for issue 3 of 2012, Journal of Evidence Based Medicine. PMID- 23672218 TI - Lessons learnt from the Wenchuan earthquake: performance evaluation of treatment of critical injuries in hardest-hit areas. AB - OBJECTIVES: Critical injury treatment in the hardest-hit areas after a great earthquake was retrospectively analyzed to determine how best to reduce mortality and disability and increase the rehabilitation rate through postquake medical relief. METHODS: Retrospective analysis, primary sources, and secondary sources were comprehensively retrieved and analyzed. RESULTS: According to incomplete data, 30,620 injured were rescued by themselves among the hardest-hit areas in the 72 hours immediately following the earthquake. Critically injured patients accounted for 22% of total inpatients. Mortality rates declined with greater distance from the epicenter: rates were 12.21% for municipal healthcare centers in the hardest-hit areas, 4.50% for municipal medical units in peripheral quake hit areas, 2.50% for provincial medical units in peripheral quake-hit areas, and 2.17% for Ministry of Health-affiliated hospitals in peripheral quake-hit areas. The number of injured with fractures on body, limbs or unknown-parts, severe conditions as well as other kinds of non-traumatic diseases received in second line hospitals was much more than those treated in first-line hospitals with more severe injuries. Among 10,373 injured in stable condition transferred to third line hospitals, 99.07% were discharged from hospitals within four months, while the mortality rate was 0.017%. CONCLUSIONS: The medical relief model of "supervising body helping subordinate unit, severely stricken areas assisting hardest-hit areas, least-hit areas supporting both hardest-hit and severely stricken areas, and self help and mutual assistance applied between hardest-hit areas" was roughly established for injured from severely stricken areas after the Wenchuan Earthquake. The "four-centralization" treatment principle, which referred to concentrating patients, experts, resources and treatment for those injured in critical condition effectively reduced the mortality from 15.06% to 2.9%. Timely, scientific, and standard on-site triage and postmedical transfer guided by accurate injury information determine rescue effect for the injured, while there is large space to fulfill as for treatment for critical diseases among the hardest-hit areas under extreme conditions after the Wenchuan earthquake. PMID- 23672216 TI - Characterization of a novel long noncoding RNA, SCAL1, induced by cigarette smoke and elevated in lung cancer cell lines. AB - The incidence of lung diseases and cancer caused by cigarette smoke is increasing. The molecular mechanisms of gene regulation induced by cigarette smoke that ultimately lead to cancer remain unclear. This report describes a novel long noncoding RNA (lncRNA) that is induced by cigarette smoke extract (CSE) both in vitro and in vivo and is elevated in numerous lung cancer cell lines. We have termed this lncRNA the smoke and cancer-associated lncRNA-1 (SCAL1). This lncRNA is located in chromosome 5, and initial sequencing analysis reveals a transcript with four exons and three introns. The expression of SCAL1 is regulated transcriptionally by nuclear factor erythroid 2-related factor (NRF2), as determined by the small, interfering RNA (siRNA) knockdown of NRF2 and kelch-like ECH-associated protein 1 (KEAP1). A nuclear factor erythroid-derived 2 (NF-E2) motif was identified in the promoter region that shows binding to NRF2 after its activation. Functionally, the siRNA knockdown of SCAL1 in human bronchial epithelial cells shows a significant potentiation of cytotoxicity induced by CSE in vitro. Altogether, these results identify a novel and intriguing new noncoding RNA that may act downstream of NRF2 to regulate gene expression and mediate oxidative stress protection in airway epithelial cells. PMID- 23672219 TI - Knowledge, skills, and attitudes of medical students to patient safety: a cross sectional pilot investigation in China. AB - BACKGROUND: To reduce harm caused by health care is a global priority. Medical students should be able to recognize unsafe conditions, systematically report errors, and near misses, investigate and improve such systems with a thorough understanding of human fallibility, and disclose errors to patients. Therefore, incorporating knowledge about patient safety into medical school curriculums is an urgent necessity. OBJECTIVES: To describe the extent to which Chinese medical students have patient safety in their knowledge, skills, and attitudes so as to provide evidence for implementation of a patient safety curriculum in medical schools, and to assess the quality of this investigative questionnaire. METHODS: Our questionnaire of 31 items was developed based on a 2008 WHO pilot study for a patient safety curriculum guide. Our investigation was conducted in three university medical schools in China. Year 3 and year 4 medical students were asked to complete an anonymous questionnaire in their classroom settings. All items were scored from 1 to 5. Differences in responses among different universities, genders, and levels, as well as the validity and reliability of the questionnaire, were analyzed using SPSS 15.0. RESULTS: A total of 500 questionnaires were distributed, and 143 male and 262 female students completed the survey. An average of 0.96% of survey questions were not answered, of which the most frequently unanswered item was "what will happen when medical error occurs?" The students' attitudes to learning about patient safety were positive, although their knowledge of medical error and how to report error was poor. There were no statistical differences among different medical schools and levels in any item responses. The only gender difference appeared in the response to "I would like to discuss with others when I made a medical error." There was a good coherence of reliability in sections 2, 3, and 4 of the questionnaire (Cronbach's alpha > 0.8), while sections 5 and 6 scored as less reliable. The validity of the questionnaire was good. CONCLUSIONS: Although medical students' understanding of patient safety is very poor in China, the students have a positive attitudes to learning about the knowledge of patient safety in their future careers. PMID- 23672220 TI - Efficacy and safety of acarbose chewable tablet in patients with type 2 diabetes: a multicentre, randomized, double-blinded, double-dummy positive controlled trial. AB - OBJECTIVE: To evaluate the effect and safety of HbA1c and glycemic control of acarbose chewable tablets in patients with type 2 diabetic. METHOD: A multicentre, randomized, double-blinded, double-dummy, positive controlled clinical trial was conducted. Two hundred thirty-four Chinese patients with type 2 diabetic were enrolled in eight clinical centres, who were divided randomly into the acarbose chewable tablet group (experimental group, n = 116) and the acarbose treatment group (control group, n = 118). RESULTS: Two hundred seven patients (88.5%) took part in the 12-week trial. At the beginning and end of the clinical trial, HbA1c and blood glucose as well as safety indexes were measured. After the treatment, the level of finger two-hour postprandial blood glucose (PPBG) was decreased 4.15 mmol/L (26.82%) and 3.54 mmol/L (22.77%), respectively, in the experiment group and the control group. The levels of venous two-hour PPBG in the experiment group and the control group were decreased 4.04 mmol/L (25.38%) and 2.75 mmol/L (17.26%), respectively, with the means of HbA1c lowering 11.67% and 12.44%, respectively. Fasting blood glucose (FBG) also was reduced significantly in both groups. Patients in both groups showed obvious weight reduction (P < 0.0001). There were no significant differences in the incidence of adverse events between the two groups. CONCLUSION: In summary, acarbose chewable tablets have a definite curative effect in treating type 2 diabetic patients as HbA1c and blood glucose levels decreased significantly after the 12-week treatment. PMID- 23672221 TI - Adoptive transfusion of tolerance dendritic cells prolongs the survival of cardiac allograft: a systematic review of 44 basic studies in mice. AB - BACKGROUND AND OBJECTIVE: Tolerogenic DCs (Tol-DCs), a group of cells with imDC phenotype, can stably induce T cells low-reactivity and immune tolerance. We systematically reviewed the adoptive transfusion of Tol-DCs induced by different ways to prolong cardiac allograft survival and its possible mechanism. METHOD: MEDLINE (1966 to March 2011), EMbase (1980 to March 2011), and ISI (inception to March 2011) were searched for identification of relevant studies. We used allogeneic heart graft survival time as endpoint outcome to analyze the effect of adoptive transfusion of Tol-DC on cardiac allograft. By integrating studies' information, we summarized the mechanisms of Tol-DC in prolonging cardiac grafts. RESULTS: Four methods were used to induce Tol-DC in all of the 44 included studies including gene-modified, drug-intervened, cytokine-induced, and other derived (liver-derived & spleen-derived) DCs. The results showed that all types of Tol-DC can effectively prolong graft survival, and the average extension of graft survival time for each group was as follows: 22.02 +/- 21.9 days (3.2 folds to control group) in the gene modified group, 25.94 +/- 16.9 days (4.3 folds) in the drug-intervened groups, 9.00 +/- 8.13 days (1.9 folds) in the cytokine induced group, and 10.69 +/- 9.94 days (2.1 folds) in the other-derived group. The main mechanisms of Tol-DCs to prolong graft survival were as follows: (1) induceT-cell hyporeactivity (detected by MLR); (2) reduce the effect of cytotoxic lymphocyte (CTL); (3) promote Th2 differentiation; (4) induce Treg; (5) induce chimerism. CONCLUSION: For fully MHC mismatched allogeneic heart transplant recipients of inbred mouse, adoptive transfusion of Tol-DC, which can be gene modified, drug-intervened, cytokine-induced, spleen-derived or liver-derived, can clearly prolong the survival of cardiac allograft or induce immune tolerance. Gene-modified and drug-induced Tol-DC can prolong graft survival most obviously. Having better reliability and stability than drug-induction, gene-modification is the best way to induce Tol-DCs at present. One-time intravenous infusion of 2 * 10(6) Tol-DC is a simple and feasible way to induce long-term graft survival. Multiple infusions will prolong it but increase the risk and cost. Adoptive transfusion of Tol-DC in conjunction with immunosuppressive agents may also prolong the graft survival time. PMID- 23672222 TI - Sitagliptin in the treatment of type 2 diabetes: a meta-analysis. AB - OBJECTIVE: To evaluate the benefits and harms of sitagliptin in people with type 2 diabetes mellitus. METHODS: Randomized controlled trials (RCTs) were retrieved from PubMed, Embase, and the Cochrane central register of controlled trials (Cochrane Library). We used the method recommend by the Cochrane Collaboration to perform a meta-analysis of RCTs of sitagliptin therapy for type 2 diabetes. RESULTS: Of 817 studies retrieved in the literature search, 18 were eligible for inclusion. When sitagliptin was compared with placebo there was a statistically significant reduction in haemoglobin A1C (HbA1c) (MD = 0.74, 95% CI 0.63 to 0.85) and fasting plasma glucose (FPG) (MD = 1.20, 95% CI 1.03 to 1.38). Sitagliptin significantly improved the homeostasis model assessment of beta-cell (HOMA-beta index) (MD =-10.84, 95% CI -14.07 to -7.80) versus placebo. In participants treated with placebo, hypoglycemia adverse experiences (RR = 2.11, 95% CI 1.50 to 2.36) and serious adverse experiences (RR = 1.20, 95% CI 0.89 to 1.63) were less common. Meta-analysis did not show a significant difference in change in FPG (MD =-0.32, 95% CI -0.76 to 0.13) or HOMA-beta index (MD = 4.42, 95% CI -1.22 to 10.07) between the sitagliptin and active control groups, but active treatments provided modestly greater reduction in HbA1c (MD =-0.20, 95% CI -0.37 to -0.03) compared with sitagliptin. No significant difference was observed between the sitagliptin and active treatments in incidence of hypoglycemia adverse experiences (RR = 0.38, 95% CI 0.14 to 1.08) or serious adverse experiences (RR = 1.15, 95% CI 0.83 to 1.65). CONCLUSIONS: Sitagliptin treatment for type 2 diabetes was effective and well tolerated. Sitagliptin offers a novel therapeutic approach for the treatment of type 2 diabetes. Continued assessment in longer term studies is required to determine the role of sitagliptin in type 2 diabetes. PMID- 23672223 TI - Quality and transparency of overviews of systematic reviews. AB - OBJECTIVE: To evaluate the reporting and methodological quality of overviews of systematic reviews. METHOD: We developed an 18-item assessment tool for overviews of systematic reviews. We then performed a systematic search for such overviews using the terms ('overview' AND ('meta analys*' OR 'systematic review*')) OR 'umbrella review' in the title. We only included those overviews that were limited to systematic reviews or meta-analyses. Their methodological and reporting quality were assessed by two independent reviewers using the checklist, and differences were resolved by a third reviewer. Data analyses was conducted by SPSS version 15.0 for Windows. RESULTS: We identified 41 overviews of systematic reviews whose mean total reporting score was 10.78 (SD 3.84) and methodological score 3.05 (SD 2.09). Some important items were not adequately reported: only 69% reported defined eligibility criteria, 76% reported search strategy, 49% reported the process of review selection, 44% reported the data collection process, 5% reported evaluating the reporting quality, 46% reported evaluating methodological quality, and 20% reported assessing the evidence level for each outcome. CONCLUSION: The reporting and methodological quality of overviews of systematic reviews was very poor, and there is still much room for improvement. A checklist for overviews of systematic reviews should be developed and used. PMID- 23672229 TI - Education section - studies within a review (SWAR). PMID- 23672224 TI - Assessment of methodological quality and outcome measures of acute stroke randomized controlled trials in China in recent 15 years. AB - BACKGROUND: Randomized controlled trials (RCTs) are the most important evidence to guide clinical practice in the treatment of acute stroke. This study aims to evaluate the changes of quantity and methodological quality of acute stroke RCTs in Mainland China published in recent 15 years. METHOD: We included un-confounded RCTs on acute stroke from eight databases published in Chinese or English from 1996 to 2010. General characteristics, design methodology, and outcome measures of studies were assessed. RESULTS: Totally, 9061 RCTs were identified. The number of acute stroke RCTs had increased by years, the total of trials published in 2010 was 20 times of that published in 1996. Three thousand four hundred eighty eight trials (38.5%) used western drugs in the treatment, 3026 (33.4%) trials used traditional Chinese medicine (TCM), and 1933 (22.0%) trials used physical therapy. Ischemic stroke was the most common research subject among all trials (65.1%, 5,989). There were 541 (6.0%) RCTs using adequate randomization methods, 34 (0.4%) RCTs using adequate allocation concealment, and 195 (2.2%) using adequate blinding methods. Thirty-three (0.4%) RCTs adopted both adequate randomization methods and allocation concealment. Only 23 (0.3%) trials used all three methods of adequate randomization methods, allocation concealment, and blinding. During the 15 years, only the number of trials using adequate randomized methods and reporting adverse events had significantly increased (both P < 0.001). As for these RCTs, only the number of trials using adequate blinding method in pharmaceutical intervention was statistical differences compared with that of nondrug intervention trials (P = 0.043). Outcomes were assessed blindly in 72 trials. Death was reported by 14.2% of trials, impairment by 85.1%, disability by 22.5%, and handicap or quality of life by 0.4%. 99.7% trials reported positive results. Larger trials were more likely to use adequate randomized methods, allocation concealment and blinding methods, as well as to measure disability. Only 14 large-sample high-quality RCTs were found. CONCLUSION: During 15 years, the number of acute stroke RCTs has increased dramatically, but the quality of trials improves slowly. Most acute stroke trials used inadequate outcome measures in terms of their content, reliability, validity, blinding assessment. PMID- 23672230 TI - OakContigDF159.1, a reference library for studying differential gene expression in Quercus robur during controlled biotic interactions: use for quantitative transcriptomic profiling of oak roots in ectomycorrhizal symbiosis. AB - Oaks (Quercus spp.), which are major forest trees in the northern hemisphere, host many biotic interactions, but molecular investigation of these interactions is limited by fragmentary genome data. To date, only 75 oak expressed sequence tags (ESTs) have been characterized in ectomycorrhizal (EM) symbioses. We synthesized seven beneficial and detrimental biotic interactions between microorganisms and animals and a clone (DF159) of Quercus robur. Sixteen 454 and eight Illumina cDNA libraries from leaves and roots were prepared and merged to establish a reference for RNA-Seq transcriptomic analysis of oak EMs with Piloderma croceum. Using the Mimicking Intelligent Read Assembly (MIRA) and Trinity assembler, the OakContigDF159.1 hybrid assembly, containing 65 712 contigs with a mean length of 1003 bp, was constructed, giving broad coverage of metabolic pathways. This allowed us to identify 3018 oak contigs that were differentially expressed in EMs, with genes encoding proline-rich cell wall proteins and ethylene signalling-related transcription factors showing up regulation while auxin and defence-related genes were down-regulated. In addition to the first report of remorin expression in EMs, the extensive coverage provided by the study permitted detection of differential regulation within large gene families (nitrogen, phosphorus and sugar transporters, aquaporins). This might indicate specific mechanisms of genome regulation in oak EMs compared with other trees. PMID- 23672231 TI - Effectiveness of a workplace-based intervention program to promote mental health among employees in privately owned enterprises in China. AB - This study aims to examine the effectiveness of a workplace-based intervention program to improve mental health, work ability, and work productivity in privately owned enterprises in China. A prospective cohort intervention study design was employed in which the intervention program was implemented for 30 months (from July 2009 to December 2012). Nine privately owned retail enterprises in China participated in the intervention study. Researchers administered a self report survey to 2768 employees. The research team measured participants' job stress, resilience, work ability, absenteeism, depression, and work performance. A comprehensive Health Promotion Enterprise Program was implemented that entailed the following components: policies to support a healthy work environment, psychosocial interventions to promote mental health, provision of health services to people with mental illness, and professional skills training to deal with stress and build resilience. Analysis of variance was used to examine preintervention versus postintervention differences in stress, resilience, and work ability. Logistic regression was used to examine absenteeism related to depression. The results suggest that the intervention program was effective at improving participants' ability to work, their sense of control over their jobs, and, in particular, their ability to meet the mental demands of work. The intervention program also reduced participants' job stress levels and reduced the probability of absenteeism related to depression. The intervention programs incorporating both individual-level and organizational-level factors to promote mental health were effective and have implications for both practice and policy regarding enterprises taking more responsibility for the provision of mental health services to their employees. PMID- 23672232 TI - Analyzing the health care cost curve: a case study. AB - This case study uses data from a self-insured employer plan to perform an analysis into the properties of the health care cost curve. The analysis shows that one statistical property of the health care cost curve is that costs rise continuously, not on an annual or monthly basis. Graphical analysis indicates that managed care techniques used to restrain costs can also smooth utilization, producing the continuously growing cost curve observed. The analysis further illustrates that there is no one "cost curve"-analysis must be segmented by population. Finally, the power of predictive models to fit the cost curve varies by population. To the extent that these results generalize to other health plans, this analysis should be used to inform the implementation of strategies to bend the cost curve. Population health management programs and health policy should be based on continuous analysis and adaption rather than implemented as one-off changes. PMID- 23672233 TI - Improving chronic disease self-management through social networks. PMID- 23672234 TI - Employers' role in cancer prevention and treatment-developing success metrics for use by the CEO Roundtable on Cancer. AB - As evidence accumulates on the risk factors for cancer, it is becoming clearer that employers can play a significant role in the fight against the disease by creating a workplace conducive to lowering health risks. The CEO Roundtable on Cancer's CEO Cancer Gold Standard Program defines what companies can do to prevent cancer, detect it early, and ensure access to the best available treatments for those who are afflicted with the disease. This article describes how Johnson & Johnson incorporated the Cancer Gold Standard Program into its existing health promotion initiatives. Then, a framework is proposed that employers can use to monitor progress in cancer prevention and treatment enhancement efforts. Finally, health care eligibility, claims, and health risk assessment data are analyzed to quantify Johnson & Johnson's progress since implementation of the Cancer Gold Standard Program. Companies interested in initiating or furthering their health promotion efforts should consider joining groups such as the CEO Cancer Gold Standard. Collectively, companies have the ability to influence policy makers, payers, and the industry at large in changing behaviors and creating a culture of health and wellness in the fight against cancer. PMID- 23672235 TI - The antifungal occidiofungin triggers an apoptotic mechanism of cell death in yeast. AB - Occidiofungin is a nonribosomally synthesized cyclic peptide having a base mass of 1200 Da. It is naturally produced by the soil bacterium Burkholderia contaminans MS14 and possesses potent broad-spectrum antifungal properties. The mechanism of action of occidiofungin is unknown. Viability, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), reactive oxygen species (ROS) detection, membrane and cell wall stability, and membrane mimetic assays were used to characterize the effect of occidiofungin on yeast cells. Confocal and electron microscopy experiments were used to visualize morphological changes within treated cells. TUNEL and ROS detection assays revealed an increase in fluorescence with increasing concentrations of the antifungal. Yeast cells appeared to shrink in size and showed the presence of 'dancing bodies' at low drug concentrations (1 MUg/mL). A screen carried out on Saccharomyces cerevisiae gene deletion mutants in the apoptotic and autophagy pathways identified the apoptotic gene for YCA1, as having an important role in occidiofungin response as cells deleted for this gene exhibit a 2-fold increase in resistance. Results from our experiments demonstrate that the mechanism of action for occidiofungin in yeast is different from that of the common classes of antifungals used in the clinic, such as azoles, polyenes, and echinocandins. Our study also indicates that occidiofungin causes cell death in yeast through an apoptotic mechanism of action. PMID- 23672237 TI - Cilostazol prevents foot ulcers in diabetic patients with peripheral vascular disease. AB - Diabetic patients are at high risk of foot ulcerations that may lead to limb amputations with important socio-economic impact. Peripheral vascular disease may be frequently associated in diabetes mellitus type II with its main symptom, intermittent claudication. Many studies reported the known efficacy of cilostazol in treating vascular claudication. Metalloproteinase-9 (MMP-9) seems to be a biochemical marker implicated in chronic wounds and in particular in diabetic foot ulcers. Cilostazol appears to have a lowering effect on MMP-9 levels and this may suggest a beneficial effect in order to prevent or retard the onset of foot ulcer in diabetic patients. In our study, two groups of diabetic patients with peripheral vascular disease were divided into two groups according to the presence of claudication in order to receive cilostazol. Group A (31 patients without claudication) were not eligible to receive cilostazol whereas Group B (47 patients with claudication) received cilostazol administration for 24 weeks (100 mg orally twice daily). Median follow up was of 16 months. During the follow up, 4.25% of patients of Group B and 35.48% of patients of Group A (P < 0.01) showed onset of foot ulceration. Although further randomised and controlled studies are required cilostazol seems to show beneficial effects for primary prevention of diabetic foot ulcers. PMID- 23672238 TI - Erectile dysfunction and the internet: drug company manipulation of public and professional opinion. AB - Given that the Internet is now a major source of information regarding health and mental health problems, and that it is in the interest of the pharmaceutical industry to influence public and professional opinion, this study evaluated 70 websites about erectile dysfunction. The 31 drug company-funded websites (44%) were, compared with the 39 websites that are not industry funded, significantly more biased toward biological factors in general, and toward medication in particular (p < .01). The high proportion of websites that are industry sponsored, and the bias of those websites, confirms previous studies on depression, posttraumatic stress disorder, schizophrenia, and attention deficit hyperactivity disorder, and demonstrates that drug companies are using their financial might to manipulate public and professional opinion on the Internet. PMID- 23672239 TI - Risk factors for surgical site infections in abdominal surgery: a study in Nepal. AB - BACKGROUND: Surgical site infection (SSI) remains a major clinical problem for developing countries in terms of morbidity, mortality, and hospital cost. Little is known about the epidemiology of SSI in Nepal. We conducted a study in Nepal to identify the various pre- and intra-operative risk factors for SSIs that are accessible to interventions. METHODS: The study was a prospective study done on all eligible patients who underwent abdominal surgery in the surgical wards of Tribhuvan University Teaching Hospital (TUTH) in Kathmandu, Nepal, from January 2011 to June 2011. We evaluated some patient-related as well as intra-operative variables that could be risk factors for SSIs. We assessed the association between these risk factors and SSI with the Fisher exact test and logistic regression analysis. RESULTS: Of the 230 patients included in the study, 53 were identified as having a SSI, resulting in an overall rate of SSI of 23%. Multivariable analysis identified the following factors as independent risk factors for SSI: (1) Low hemoglobin concentrations (<12 g/dL) (odds ratio [OR] 2.5; 95% confidence interval [CI] 1.1-6.1); (2) overweight (OR 7.6; 95% CI 2.1 27.0); and (3) surgery performed by residents (OR 3.4; 95% CI 1.4-8.3). CONCLUSIONS: Surgical site infection is common among patients undergoing abdominal surgery at TUTH. This study identified some preventable risk factors associated with SSI at TUTH. Identification of such risk factors is expected to help surgeons improve patient care and decrease mortality and morbidity as well as the hospital-care cost of surgical patients. PMID- 23672241 TI - Outpatient parenteral antibiotic therapy in primary hip and knee arthroplasty infection managed with debridement and retention of prosthesis: a retrospective cohort study. AB - BACKGROUND: Attempted joint salvage of infected primary arthroplasty traditionally has utilized joint washouts in combination with costly long-term inpatient parenteral antibiotic regimens. Outpatient and home parenteral antibiotic therapy (OHPAT) represents a potential alternative. However, there is a lack of published data on its value for primary deep arthroplasty infection. This paper describes the surgical and microbiologic outcomes of a cohort of patients with deep arthroplasty infections treated with OHPAT after surgical washout and debridement. METHODS: Local OHPAT records identified all patients who underwent attempted joint salvage of a primary hip or knee replacement complicated by a deep post-operative infection between February 2006 and February 2009. Minimum follow-up for all patients was 24 mos. For each patient, hospital records were reviewed to ascertain the effectiveness of treatment. RESULTS: In total, 14 patients (10 total knee replacements; four total hip replacements) were identified from the records. Eleven joints (79%) were salvaged. There was a trend toward a higher salvage rate with early infection (<6 mos after primary surgery), with eight of nine joints (89%) being salvaged, versus 60% (three of five) for later presentation. Methicillin-sensitive Staphylococcus aureus was the most common organism identified (43% of cases), and 57% of infections were polymicrobial. The average duration of OHPAT was 58 days. Two patients were readmitted because of clinical deterioration, both of whom later required revision. All patients, regardless of their outcomes, stated they were satisfied with the OHPAT service and believed it was more convenient than inpatient treatment. We estimate OHPAT saved approximately L13,000 per patient episode. CONCLUSIONS: Use of OHPAT for deep infection after primary arthroplasty has a high success rate. It is effective at identifying patients failing treatment, is cost-effective, and has a high level of patient satisfaction. PMID- 23672240 TI - Vancomycin versus linezolid in the treatment of methicillin-resistant Staphylococcus aureus meningitis. AB - BACKGROUND: Vancomycin is the mainstay of treatment for methicillin-resistant Staphylococcus aureus (MRSA) meningitis. However, successful outcomes with linezolid have not been reported in a large series of patients. We conducted a single-center retrospective cohort study to compare vancomycin with linezolid in the treatment of MRSA meningitis. METHODS: We extracted data and outcomes for all adult patients (age >18 years) with culture-proved MRSA meningitis who received vancomycin or linezolid between January 2006 and June 2011. A definite diagnosis of meningitis was based on the isolation of MRSA in at least one cerebrospinal fluid (CSF) culture and findings in CSF that are typical of the infection. Linezolid was given intravenously (IV) at a dosage of 600 mg q12h and vancomycin IV at 500 mg q6h. RESULTS: A total of 8 patients with MRSA meningitis (5 male, 3 female; age [mean+/-SD] 61.6+/-13.2 years) received vancomycin and 9 patients (7 male, 2 female; age 59.1+/-15.6 years) received linezolid. All isolated strains of MRSA were susceptible to both vancomycin and linezolid. The rates of microbiologic success with linezolid or vancomycin, in terms of clearance of MRSA from CSF on day 5, were 7/9 and 2/8 (p=0.044, Fisher exact test). No severe adverse events occurred in either treatment arm of the study. One-month survival of the patients in whom treatment was successful microbiologically was 2/2 in the vancomycin-treated group and 4/7 in the linezolid-treated group. Minimum inhibitory concentration (MIC) data for vancomycin were available for 5/6 treatment failures with vancomycin, and vancomycin MIC values of these five strains were 2 mg/L. CONCLUSION: Analysis of the findings in the limited cohorts in our study suggests that linezolid is superior to vancomycin for treating MRSA meningitis, especially in cases in which there is a high MIC (2 mg/L) for vancomycin. A clinical study involving larger cohorts may increase the evidence available in relation to this question. PMID- 23672242 TI - Pseudomonas aeruginosa post-operative peritonitis: clinical features, risk factors, and prognosis. AB - BACKGROUND: Postoperative peritonitis (PP) is associated with a high rate of multi-drug-resistant micro-organisms. The role of Pseudomonas aeruginosa in this condition has never been assessed. We evaluated the risk factors and prognosis for PP caused by P. aeruginosa. METHODS: Patients hospitalized in the intensive care unit (ICU) after re-operation for PP were identified prospectively. Analyses were performed retrospectively. Specific risk factors were investigated by comparing P. aeruginosa PP with PP having other causes. The main outcome endpoint was death in the hospital. RESULTS: We found 55 P. aeruginosa PP among the 349 cases of PP (16%) in the ICU over 14 years. Factors associated with the presence of P. aeruginosa in peritoneal fluid culture were Acute Physiology and Chronic Health Evaluation (APACHE) II score (odds ratio [OR] 1.1; 95% confidence interval [CI] 1.02-1.09; p=0.004) and respiratory failure (OR 2.3; 95% CI 1.26-4.16; p=0.006). These criteria performed poorly in predicting P. aeruginosa PP. Such infections were associated with a higher hospital mortality rate, but not after adjustment for the severity score. Adequate antibiotic therapy comprising two antibiotics effective against P. aeruginosa was associated with a lower mortality rate for P. aeruginosa PP in the ICU. CONCLUSION: The prevalence of P. aeruginosa PP is not high. Risk factors do not allow accurate prediction of the infection. Our data suggest two drugs effective against P. aeruginosa should be considered for treating these infections. PMID- 23672243 TI - Does transient hypothyroxinemia influence metabolic bone disease of prematurity? AB - OBJECTIVE: To investigate the relationship between Metabolic Bone Disease (MBD) and Transient Hypothyroxinemia of Prematurity (THOP). METHOD: One hundred twenty four infants, born in Marmara University Hospital with a gestational age <=34 weeks, were enrolled. Clinical features were recorded. Serum TSH, free T4, total T4, calcium, phosphorus and total Alkaline Phosphatase (ALP) levels were determined in the first and third postnatal weeks. MBD was defined as a phosphorus level <4.5 mg/dl and/or ALP >900 IU/l. THOP was defined as a serum free and/or total thyroxine level lower than -1 SD for gestational age at the 7th postnatal day. RESULT: THOP was diagnosed in nineteen (15.3%) patients. MBD was diagnosed in 52 (41.9%) at the 3rd month. Low birth weight, low gestational age and prolonged parenteral nutrition were associated with MBD. Multivariate analysis documented a significant relationship solely between MBD and gestational age. CONCLUSION: The risk of MBD does not increase significantly in babies with THOP. PMID- 23672244 TI - 4E-BP1 regulates the differentiation of white adipose tissue. AB - 4E Binding protein 1 (4E-BP1) suppresses translation initiation. The absence of 4E-BP1 drastically reduces the amount of adipose tissue in mice. To address the role of 4E-BP1 in adipocyte differentiation, we characterized 4E-BP1(-/-) mice in this study. The lack of 4E-BP1 decreased the amount of white adipose tissue and increased the amount of brown adipose tissue. In 4E-BP1(-/-) MEF cells, PPARgamma coactivator 1 alpha (PGC-1alpha) expression increased and exogenous 4E-BP1 expression suppressed PGC-1alpha expression. The level of 4E-BP1 expression was higher in white adipocytes than in brown adipocytes and showed significantly greater up-regulation in white adipocytes than in brown adipocytes during preadipocyte differentiation into mature adipocytes. The amount of PGC-1alpha was consistently higher in HB cells (a brown preadipocyte cell line) than in HW cells (a white preadipocyte cell line) during differentiation. Moreover, the ectopic over-expression of 4E-BP1 suppressed PGC-1alpha expression in white adipocytes, but not in brown adipocytes. Thus, the results of our study indicate that 4E-BP1 may suppress brown adipocyte differentiation and PGC-1alpha expression in white adipose tissues. PMID- 23672245 TI - The role of lipid metabolism in the acquisition of desiccation tolerance in Craterostigma plantagineum: a comparative approach. AB - Dehydration leads to different physiological and biochemical responses in plants. We analysed the lipid composition and the expression of genes involved in lipid biosynthesis in the desiccation-tolerant plant Craterostigma plantagineum. A comparative approach was carried out with Lindernia brevidens (desiccation tolerant) and two desiccation-sensitive species, Lindernia subracemosa and Arabidopsis thaliana. In C. plantagineum the total lipid content remained constant while the lipid composition underwent major changes during desiccation. The most prominent change was the removal of monogalactosyldiacylglycerol (MGDG) from the thylakoids. Analysis of molecular species composition revealed that around 50% of 36:x (number of carbons in the acyl chains: number of double bonds) MGDG was hydrolysed and diacylglycerol (DAG) used for phospholipid synthesis, while another MGDG fraction was converted into digalactosyldiacylglycerol via the DGD1/DGD2 pathway and subsequently into oligogalactolipids by SFR2. 36:x-DAG was also employed for the synthesis of triacylglycerol. Phosphatidic acid (PA) increased in C. plantagineum, L. brevidens, and L. subracemosa, in agreement with a role of PA as an intermediate of lipid turnover and of phospholipase D in signalling during desiccation. 34:x-DAG, presumably derived from de novo assembly, was converted into phosphatidylinositol (PI) in C. plantagineum and L. brevidens, but not in desiccation-sensitive plants, suggesting that PI is involved in acquisition of desiccation tolerance. The accumulation of oligogalactolipids and PI in the chloroplast and extraplastidial membranes, respectively, increases the concentration of hydroxyl groups and enhances the ratio of bilayer- to non-bilayer-forming lipids, thus contributing to protein and membrane stabilization. PMID- 23672246 TI - Oesophageal Doppler monitoring, doubt and equipoise: evidence based medicine means change. PMID- 23672247 TI - Indigenous perspectives on active living in remote Australia: a qualitative exploration of the socio-cultural link between health, the environment and economics. AB - BACKGROUND: The burden of chronic disease in Indigenous Australia is more than double that of non-Indigenous populations and even higher in remote Northern Territory (NT) communities. Sufficient levels of physical activity are known to reduce the risk of chronic disease and improve the health of those already suffering from chronic disease. It has been identified that effective promotion of physical activity in Indigenous settings requires the diverse cultural perspectives and participation of Indigenous people. However, Indigenous concepts of physical activity are not represented in the public health literature and examples of Indigenous involvement in physical activity promotion are scarce. This study aimed to explore and describe local perspectives, experiences and meanings of physical activity in two remote NT Indigenous communities. METHODS: Qualitative research methods guided by ethnographic and participatory action research principles were used. Semi-structured interviews conducted with 23 purposively selected community members were the main source of data, augmented by five commissioned paintings by community-based artists and observations recorded in a journal by the first author. RESULTS: The findings reveal that in this cultural context the meaning of physical activity is embedded in socially significant and economically necessary physical engagement with the environment. Participants described physical activities associated with Indigenous natural and cultural resource management, customary spaces, seasonal timing and traditional education as creating and protecting health. These activities were viewed not only as culturally appropriate physical activities that contribute to health but as legitimate, physically active forms of social organisation, education and employment that help to build and maintain relationships, wealth, resources and the environment. CONCLUSION: This different construction of physical activity in remote Indigenous communities highlights the importance of involving Indigenous people in the development and implementation of physical activity promotion. Physical activities associated with traditional Indigenous cultural practices and being active 'on country' need to be viewed as legitimate health promotion activities. Exploring further ways to enable Indigenous people in remote NT to be involved in creating viable active livelihoods on 'traditional country' needs to be considered as imperative to health improvement. PMID- 23672248 TI - Pilot study of the suitability of dorsal vulval skin as a transposition flap: vascular anatomic study and clinical application. AB - OBJECTIVE: To identify the blood supply to the vulval fold and adjacent skin, and evaluate it as a transposition flap for closing perineal wounds in dogs. STUDY DESIGN: Prospective study. ANIMALS OR SAMPLE POPULATION: Five female canine cadavers and 2 cases referred for excision of mast cell tumors adjacent to the vulva. METHODS: Dissection was performed to identify the vascular supply to the vulval fold in two cadavers following arterial injection of red latex and methylene blue, respectively. In three cadavers, barium sulfate mixed 1:1 with water was injected into the terminal aorta. The vulval fold and surrounding perineal skin was excised and radiographed. Transposition flaps using the vulval fold and adjacent skin were used to close skin defects in two dogs presented for wide excision of mast cell tumors situated ventro-lateral and dorso-lateral to the vulva, respectively. RESULTS: The vulval fold and adjacent skin was perfused bilaterally by branches of the ventral perineal and external pudendal arteries, which entered dorsally and ventrally, respectively. As incisions used to create a transposition flaps from the skin surrounding the vulval fold transect these vessels, the flap is dependent on the sub-dermal plexus for survival. There was 100% survival of transposition flaps in the 2 clinical cases and healing proceeded uneventfully with acceptable cosmetic and functional results. CONCLUSIONS: The vulval fold and surrounding skin can be used as a subdermal plexus flap to close large perineal defects in dogs. CLINICAL RELEVANCE: Availability of a defined local skin flap will improve treatment of diseases resulting in large perineal skin defects in female dogs. PMID- 23672249 TI - One-pot preparation and CO2 adsorption modeling of porous carbon, metal oxide, and hybrid beads. AB - Hierarchically porous carbon (C), metal oxide (ZrTi), or carbon-metal oxide (CZrTi) hybrid beads are synthesized in one pot through the in situ self-assembly of Pluronic F127, titanium and zirconium propoxides, and polyacrylonitrile (PAN). Upon contact with water, a precipitation of PAN from the liquid phase occurs concurrently with polymerization and phase separation of the inorganic precursors. The C, ZrTi, and CZrTi materials have similar morphologies but different surface chemistries. The adsorption of carbon dioxide by each material has been studied and modeled using the Langmuir-Freundlich equation, generating parameters that are used to calculate the surface affinity distributions. The Langmuir, Freundlich, Toth, and Temkin models were also applied but gave inferior fits, indicating that the adsorption occurred on an inhomogeneous surface reaching a maximum capacity as available surface sites became saturated. The carbon beads have higher surface affinity for CO2 than the hybrid and metal oxide materials. PMID- 23672250 TI - Effect of amphotericin B on the metabolic profiles of Candida albicans. AB - Amphotericin B (AmB) is a polyene antifungal drug widely used for systemic fungal infections. In this study, a metabonomic method using gas chromatography-mass spectrometry (GC/MS) was developed to characterize the metabolic profiles of Candida albicans cells exposed to AmB. Thirty-one differentially produced metabolites between AmB-treated and the control groups were identified, among which 10 metabolites were upregulated and 21 metabolites were downregulated. These differentially produced metabolites were mainly involved in polyamines synthesis, tricarboxylic acid (TCA) cycle, oxidative stress, glutathione metabolism, lipid synthesis and glycolysis. Further experiments showed that the polyamines including putrescine, spermidine, and spermine played an important role in the sensitivity of C. albicans cells upon AmB treatment, and combined use of AmB and inhibitors of polyamine biosynthesis pathway might be a potential antifungal strategy. This study provided a systemic view of the metabolic pattern in C. albicans upon exposure to AmB, which shed new light on the mechanisms of action of antifungal agents. PMID- 23672251 TI - A new indoloquinazoline alkaloidal glucoside from the nearly ripe fruits of Evodia rutaecarpa. AB - A new indoloquinazoline alkaloidal glucoside, rutaecarpine-10-O-beta-D glucopyranoside (1), together with one known alkaloidal glycoside namely rutaecarpine-10-O-rutinoside (2) was isolated from the nearly ripe fruits of Evodia rutaecarpa (Juss.) Benth.. Their structures were elucidated on the basis of extensive spectroscopic methods. PMID- 23672252 TI - Addressing the challenges of collaborative goal setting with children and their families. AB - Collaborative goal setting between clinicians and clients/families is considered a fundamental component of the pediatric rehabilitation process. However, truly client-centered goal setting is not without its challenges. The purpose of this paper is to highlight theoretical concepts relevant to rehabilitation goal setting, review clinical studies directly evaluating relationships between goal setting and pediatric rehabilitation outcomes, and provide recommendations to facilitate collaborative goal processes. Four theoretical frameworks were identified that may lie behind and help explain the effectiveness of collaborative goal setting. The four relevant outcome studies found in the review revealed that individualized goal setting is an important component of the intervention, engages families more actively in therapy, and is associated to some extent with positive outcomes. The evidence suggests that the impact of fully collaborative goal setting is sufficiently positive to support investment of organizational and individual time, energy, and resources to make it an integral part of the rehabilitation process. PMID- 23672253 TI - Programmed self-assembly of heterometallic [3 * 3] grid [M(II)Cu(II)4Cu(I)4] (M = Fe, Ni, Cu, and Zn). AB - A series of heterometallic [3 * 3] grids have been synthesized readily through a one-pot solvothermal reaction. Given metal ions carrying distinct electronic, magnetic, and optical information can be addressed precisely at specific locations in the array. PMID- 23672255 TI - Polymorphisms of PTPN11 gene could influence serum lipid levels in a sex-specific pattern. AB - BACKGROUND: Previous studies have reported that different genotypes of PTPN11 gene (protein tyrosine phosphatase, non-receptor 11) were associated with different levels of serum lipids. The aim of this study was to explore the relationship between single nucleotide polymorphisms (SNPs) of PTPN11 and serum lipids in Northeast Chinese. METHODS: A total of 1003 subjects, 584 males and 419 females, were included in the study and their serum lipids were determined. Five htSNPs (rs2301756, rs12423190, rs12229892, rs7958372 and rs4767860) of PTPN11 gene were genotyped using TaqMan assay method. RESULTS: All of the five SNPs were in Hardy-Weinberg equilibrium. The male subjects had higher triglyceride (TG), higher low-density lipoprotein cholesterol (LDL-C) and lower high-density lipoprotein cholesterol (HDL-C) level than females. In males, rs4767860 was found to be associated with serum TG and total cholesterol (TC) levels and rs12229892 was associated with TC level. However, these significant associations could not be observed in females. In females, rs2301756 was found to be associated with TG and rs7958372 was associated with LDL-C level. Haplotype analysis showed that the GCGTG haplotype was associated with slightly higher TG level and ATGCG with higher TC level. CONCLUSIONS: SNPs of PTPN11 may play a role in serum lipids in a sex-specific pattern. However, more studies are needed to confirm the conclusion and explore the underlying mechanism. PMID- 23672254 TI - Psychiatric treatment considerations with direct acting antivirals in hepatitis C. AB - BACKGROUND: Despite recent advances in hepatitis C (HCV) treatment, specifically the addition of direct acting antivirals (DAAs), pegylated interferon-alpha remains the backbone of HCV therapy. Therefore, the impact of DAAs on the management of co-morbid psychiatric illness and neuropsychiatric sequalae remains an ongoing concern during HCV therapy. This paper provides a review of the neuropsychiatric adverse effects of DAAs and drug-drug interactions (DDIs) between DAAs and psychiatric medications. METHODS: We conducted a Pubmed search using relevant search terms and hand searched reference lists of related review articles. In addition, we searched abstracts for major hepatology conferences and contacted respective pharmaceutical companies for additional studies. RESULTS: Limited data is available on the neuropsychiatric adverse effects of DAAs; however, data from major clinical trials suggest that DAAs have minimal neuropsychiatric risk. DAAs can potentially interact with a variety of psychotropic agents via cytochrome P450 and p-glycoprotein interactions. Triazolam, oral midazolam, St. John's Wort, carbamazepine and pimozide, are contraindicated with DAAs. DDIs between DAAs and antidepressants, anxiolytics, hypnotics, mood stabilizers, antipsychotics and treatments for opioid dependence are summarized. CONCLUSIONS: Although DAAs do not add significant neuropsychiatric risk, the potential for DDIs is high. Consideration of DDIs is paramount to improving medication adherence and mitigating adverse effects during HCV therapy. PMID- 23672257 TI - Invented fairy tales in groups with onco-haematological children. AB - BACKGROUND: The impact of an onco-haematological illness for children is a traumatic event that opens to pain, hospitalizations and interrupts the continuity of daily life. It is difficult for the child to make meaning, to share the pain or ask a question related to the illness because, often, the parents or doctors cannot find a way to communicate in a suitable way for the child who remains in a situation of 'unspoken', where, fear, anxiety and pain cannot find a space to express. METHODS: The present research-intervention uses the methodology of invented fairy tales in groups with onco-haematological children, in the hospital, in order to explore the organization of the meanings at the base of the tales co-constructed by the participants underlying weaknesses and strengths of the invented fairy tales in groups intervention. The invented fairy tales in groups is used as a tool, such as a play, to express, share and support the experience of the illness of children. Forty-nine children participated to the invented fairy tales in groups in an onco-haematological hospital. Within a quali quantitative framework we performed a thematic analysis of elementary context, cluster analysis, on the fairy tales considered as a unique narrative corpus of the thought of the group. RESULTS: The analysis shows four thematic clusters: fantasy as search for a meaning, 29.71%, the group as a space for illusions, 27.90%, the illness as a family problem, 25.72%, anchoring reality, 16.67%. The results highlighted three main carriers of sense: the representation of illness/the relational world/the representation of the institution. CONCLUSIONS: The use of invented-fairy-tales groups allowed the onco-haematological children to tell and share the experience of illness through a different way, which let them express symbolically their pain. The invented fairy tale in groups becomes a mediator of psychic processes which offer new solutions while improving interpersonal relationships/communication between the participants in group. PMID- 23672256 TI - Human monoclonal ScFv that bind to different functional domains of M2 and inhibit H5N1 influenza virus replication. AB - BACKGROUND: Novel effective anti-influenza agent that tolerates influenza virus antigenic variation is needed. Highly conserved influenza virus M2 protein has multiple pivotal functions including ion channel activity for vRNP uncoating, anti-autophagy and virus assembly, morphogenesis and release. Thus, M2 is an attractive target of anti-influenza agents including small molecular drugs and specific antibodies. METHODS: Fully human monoclonal single chain antibodies (HuScFv) specific to recombinant and native M2 proteins of A/H5N1 virus were produced from huscfv-phagemid transformed E. coli clones selected from a HuScFv phage display library using recombinant M2 of clade 1 A/H5N1 as panning antigen. The HuScFv were tested for their ability to inhibit replication of A/H5N1 of both homologous and heterologous clades. M2 domains bound by HuScFv of individual E. coli clones were identified by phage mimotope searching and computerized molecular docking. RESULTS: HuScFv derived from four huscfv-phagemid transformed E. coli clones (no. 2, 19, 23 and 27) showed different amino acid sequences particularly at the CDRs. Cells infected with A/H5N1 influenza viruses (both adamantane sensitive and resistant) that had been exposed to the HuScFv had reduced virus release and intracellular virus. Phage peptide mimotope search and multiple alignments revealed that conformational epitopes of HuScFv2 located at the residues important for ion channel activity, anti-autophagy and M1 binding; epitopic residues of HuScFv19 located at the M2 amphipathic helix and cytoplasmic tail important for anti-autophagy, virus assembly, morphogenesis and release; epitope of HuScFv23 involved residues important for the M2 activities similar to HuScFv2 and also amphipathic helix residues for viral budding and release while HuScFv27 epitope spanned ectodomain, ion channel and anti-autophagy residues. Results of computerized homology modelling and molecular docking conformed to the epitope identification by phages. CONCLUSIONS: HuScFv that bound to highly conserved epitopes across influenza A subtypes and human pathogenic H5N1clades located on different functional domains of M2 were produced. The HuScFv reduced viral release and intracellular virus of infected cells. While the molecular mechanisms of the HuScFv await experimental validation, the small human antibody fragments have high potential for developing further as a safe, novel and mutation tolerable anti-influenza agent especially against drug resistant variants. PMID- 23672258 TI - Effect of dimerization on dihydrofolate reductase catalysis. AB - Dihydrofolate reductase (DHFR) from the hyperthermophile Thermotoga maritima (TmDHFR) forms a very stable homodimer, while DHFRs from other organisms are monomers. We investigated the effect of dimerization on DHFR catalysis by preparing a dimeric variant, Xet-3, of DHFR from Escherichia coli (EcDHFR). Introducing residues located at the TmDHFR dimer interface into EcDHFR increases the melting temperature to ~60 degrees C, approximately 9 degrees C higher than that measured for EcDHFR. The steady-state and pre-steady-state rate constants measured for Xet-3 were similar to those of dimeric TmDHFR but significantly lower than those of the parent EcDHFR. This reduction in the degree of catalytic competence is likely a consequence of the loss of flexibility of catalytically important loop regions of EcDHFR on dimerization and a compromise of the electrostatic environment of the active site. In contrast, the reduced catalytic ability of TmDHFR relative to that of EcDHFR is not simply a consequence of reduced loop flexibility in the dimeric enzyme. Our studies demonstrate that EcDHFR is not a good model for understanding the properties of other DHFRs, including TmDHFR. PMID- 23672259 TI - Floral isolation in Pedicularis: how do congeners with shared pollinators minimize reproductive interference? AB - To minimize interspecific pollination, it has been suggested that pollen is placed on different parts of a pollinator's body corresponding to the conspecific location of pollen pickup by the stigma. Although Pedicularis is regarded as a classic example of pollinator-mediated floral isolation, such reciprocal pollen placement has not been demonstrated experimentally. This leads us to question previous observations of pollen release in Pedicularis species. Here, we show that pollen grains are released from the tip, rather than the basal opening, of the galea (the hoodlike upper lip of the corolla) in eight nectarless Pedicularis species, mimicking pollen release from poricidal anthers. We used safranin stained pollen within anthers to track pollen placement in three Pedicularis species, and showed that pollen was deposited on numerous parts of the bumblebee's body. However, fluorescent powder placed on the stigmas to detect the contact location on the bumblebee's body was deposited mainly on the major position of pollen placement in each of the three species. Such segregation of pollen placement and pickup between species sharing the same pollinator probably helps to reduce reproductive interference, but the positions of pollen placement and stigma contact on the bumblebee's body were not as precise as previously thought. PMID- 23672262 TI - Flow cytometric analysis of macrophages and dendritic cell subsets in the mouse lung. AB - The lung hosts multiple populations of macrophages and dendritic cells, which play a crucial role in lung pathology. The accurate identification and enumeration of these subsets are essential for understanding their role in lung pathology. Flow cytometry is a mainstream tool for studying the immune system. However, a systematic flow cytometric approach to identify subsets of macrophages and dendritic cells (DCs) accurately and consistently in the normal mouse lung has not been described. Here we developed a panel of surface markers and an analysis strategy that accurately identify all known populations of macrophages and DCs, and their precursors in the lung during steady-state conditions and bleomycin-induced injury. Using this panel, we assessed the polarization of lung macrophages during the course of bleomycin-induced lung injury. Alveolar macrophages expressed markers of alternatively activated macrophages during both acute and fibrotic phases of bleomycin-induced lung injury, whereas markers of classically activated macrophages were expressed only during the acute phase. Taken together, these data suggest that this flow cytometric panel is very helpful in identifying macrophage and DC populations and their state of activation in normal, injured, and fibrotic lungs. PMID- 23672263 TI - Novel deep intronic and missense UNC13D mutations in familial haemophagocytic lymphohistiocytosis type 3. PMID- 23672265 TI - Albumin stabilizes fibrin fiber ultrastructure in low serum albumin type 2 diabetes. AB - Serum albumin is an essential plasma protein that serves an important function in maintaining osmotic pressure. Low levels of this protein are associated with the kidney failure and hemodialysis that are often seen in diabetic patients who are at high risk of thrombotic events. In diabetes, fibrin fiber nets are changed to form dense matted deposits (DMDs, or parafibrin). Here the authors investigate whether parafibrin is also present in diagnosed low-albumin diabetes patients and whether the addition of human albumin to plasma from low-albumin diabetes type 2 individuals may change the architecture of the fibrin nets. The authors show that the addition of albumin to plasma of low-albumin diabetes patients progressively caused the DMDs typically found in these patients to revert back to ultrastructure typically seen in healthy individuals. This disease has an extremely complicated pathophysiology and thus cannot be considered as a simple condition. This study shows that serum albumin levels may play an important role in the structure of fibrin fibrils, making them more susceptible to the fibrinolytic degradation and elimination from the circulation. PMID- 23672264 TI - Whole genome profiling physical map and ancestral annotation of tobacco Hicks Broadleaf. AB - Genomics-based breeding of economically important crops such as banana, coffee, cotton, potato, tobacco and wheat is often hampered by genome size, polyploidy and high repeat content. We adapted sequence-based whole-genome profiling (WGPTM) technology to obtain insight into the polyploidy of the model plant Nicotiana tabacum (tobacco). N. tabacum is assumed to originate from a hybridization event between ancestors of Nicotiana sylvestris and Nicotiana tomentosiformis approximately 200,000 years ago. This resulted in tobacco having a haploid genome size of 4500 million base pairs, approximately four times larger than the related tomato (Solanum lycopersicum) and potato (Solanum tuberosum) genomes. In this study, a physical map containing 9750 contigs of bacterial artificial chromosomes (BACs) was constructed. The mean contig size was 462 kbp, and the calculated genome coverage equaled the estimated tobacco genome size. We used a method for determination of the ancestral origin of the genome by annotation of WGP sequence tags. This assignment agreed with the ancestral annotation available from the tobacco genetic map, and may be used to investigate the evolution of homoeologous genome segments after polyploidization. The map generated is an essential scaffold for the tobacco genome. We propose the combination of WGP physical mapping technology and tag profiling of ancestral lines as a generally applicable method to elucidate the ancestral origin of genome segments of polyploid species. The physical mapping of genes and their origins will enable application of biotechnology to polyploid plants aimed at accelerating and increasing the precision of breeding for abiotic and biotic stress resistance. PMID- 23672266 TI - Rats on a high-energy diet showing no weight gain present with ultrastructural changes associated with liver fibrosis. AB - Sibutramine is widely used as a weight-loss substance in the treatment of obesity and is a selective inhibitor of the neuronal reuptake of serotonin and noradrenaline. Although banned, it is often a hidden ingredient in herbal and dietary supplements that are widely used by the general public. Various weight loss products, including sibutramine, have successfully been tested in animal models of diet-induced obesity. In the female Sprague-Dawley rat model, fed a high-energy diet that did not produce a significant increase in BMI, the cellular structure of the liver was evaluated using transmission electron microscopy. Compared to controls showing no damage, the livers of rats fed a high-energy diet were found to have increased fibrosis without steatosis, while for rats fed high energy diet with sibutramine, fibrosis was increased and steatosis had developed. In conclusion, in female rats fed a high-energy diet that does not result in weight gain hepatic fibrosis occurs without steatosis. In these rats the co administration of sibutramine increases the degree of fibrosis and steatosis develops. Although it has been widely believed that sibutramine is not hepatotoxic, this study clearly shows that at an ultrastructural level, rats fed a high-energy diet treated with sibutramine show signs of hepatotoxicity. PMID- 23672268 TI - Highly flexible, proton-conductive silicate glass electrolytes for medium temperature/low-humidity proton exchange membrane fuel cells. AB - We demonstrate highly flexible, proton-conductive silicate glass electrolytes integrated with polyimide (PI) nonwoven fabrics (referred to as "b-SS glass electrolytes") for potential use in medium-temperature/low-humidity proton exchange membrane fuel cells (PEMFCs). The b-SS glass electrolytes are fabricated via in situ sol-gel synthesis of 3-trihydroxysilyl-1-propanesulfonic acid (THPSA)/3-glycidyloxypropyl trimethoxysilane (GPTMS) mixtures inside PI nonwoven substrates that serve as a porous reinforcing framework. Owing to this structural uniqueness, the b-SS glass electrolytes provide noticeable improvements in mechanical bendability and membrane thickness, in comparison to typical bulk silicate glass electrolytes that are thick and easily fragile. Another salient feature of the b-SS glass electrolytes is the excellent proton conductivity at harsh measurement conditions of medium temperature/low humidity, which is highly important for PEMFC-powered electric vehicle applications. This beneficial performance is attributed to the presence of a highly interconnected, proton conductive (THPSA/GPTMS-based) silicate glass matrix in the PI reinforcing framework. Notably, the b-SS glass electrolyte synthesized from THPSA/GPTMS = 9/1 (mol/mol) exhibits a higher proton conductivity than water-swollen sulfonated polymer electrolyte membranes (here, sulfonated poly(arylene ether sulfone) and Nafion are chosen as control samples). This intriguing behavior in the proton conductivity of the b-SS glass electrolytes is discussed in great detail by considering its structural novelty and Grotthuss mechanism-driven proton migration that is strongly affected by ion exchange capacity (IEC) values and also state of water. PMID- 23672267 TI - Efficacy and safety of short-term administration of recombinant human atrial natriuretic peptide (rhANP) for congestive heart failure: a phase II, multicentre randomized controlled dose-finding study. AB - WHAT IS KNOWN AND OBJECTIVE: Although the long-term infusion of ANP has proved effective to treat heart failure, no published randomized controlled study has been reported to confirm the efficacy of the short-term ANP infusion in congestive heart failure (CHF) patients. This study was designed to assess the efficacy and safety of short-term infusion of recombinant human atrial natriuretic peptide (rhANP) in CHF patients. METHODS: A total of 48 patients with CHF were enrolled and randomized into four groups, treated with standard therapy or rhANP (0.05, 0.1 or 0.2 MUg/kg/min) for 1-hour infusion in addition to standard therapy. The hemodynamics were assessed for 12 h by Swan-Ganz catheter. RESULTS AND DISCUSSION: The effect of the 0.05 MUg/kg/min rhANP dose group on CO was modest and transient. The 0.2 MUg/kg/min rhANP dose group tended to be associated with better effect on SV, CO and dyspnoea improvement, but modest effect on PCWP and more adverse events probably attributed to the study drug. However, the 0.1 MUg/kg/min rhANP infusion was well tolerated and effective both on PCWP decrease (maximum:-9.46 +/- 5.81 mmHg compared with baseline (P = 0.0002) and -6.75 mmHg compared with standard therapy, the 95% confidential interval [ 13.43, -0.06 mmHg] at 1 h) and CO increase (maximum: 1.02 +/- 1.43 L/min [P = 0.0308] at 1 h). WHAT IS NEW AND CONCLUSION: In this small-sample study, 1-hour infusion of rhANP produced beneficial hemodynamic effects in CHF patients compared with standard therapy, and it was well tolerated. 0.1 MUg/kg/min may be the optimum dose for short-term rhANP infusion to treat CHF for the further large sample trial before clinical application. PMID- 23672269 TI - Efficacy of flibanserin in women with hypoactive sexual desire disorder: results from the BEGONIA trial. AB - INTRODUCTION: Hypoactive Sexual Desire Disorder (HSDD) is characterized by low sexual desire that causes marked distress or interpersonal difficulty. AIM: The aim of this study was to assess the efficacy and safety of the 5-HT1A agonist/5 HT2A antagonist flibanserin in premenopausal women with HSDD. METHODS: This was a randomized, placebo-controlled trial in which premenopausal women with HSDD (mean age: 36.6 years) were treated with flibanserin 100 mg once daily at bedtime (qhs) (n = 542) or placebo (n = 545) for 24 weeks. MAIN OUTCOME MEASURES: Coprimary end points were the change from baseline to study end in Female Sexual Function Index (FSFI) desire domain score and in number of satisfying sexual events (SSE) over 28 days. Secondary end points included the change from baseline in FSFI total score, Female Sexual Distress Scale-Revised (FSDS-R) total score, and FSDS-R Item 13 score. RESULTS: Compared with placebo, flibanserin led to increases in mean (standard deviation) SSE of 2.5 (4.6) vs. 1.5 (4.5), mean (standard error [SE]) FSFI desire domain score of 1.0 (0.1) vs. 0.7 (0.1), and mean (SE) FSFI total score of 5.3 (0.3) vs. 3.5 (0.3); and decreases in mean (SE) FSDS-R Item 13 score of -1.0 (0.1) vs. -0.7 (0.1) and mean (SE) FSDS-R total score of -9.4 (0.6) vs. 6.1 (0.6); all P <= 0.0001. The most frequently reported adverse events in the flibanserin group were somnolence, dizziness, and nausea, with adverse events leading to discontinuation in 9.6% of women receiving flibanserin vs. 3.7% on placebo. CONCLUSION: In premenopausal women with HSDD, flibanserin 100 mg qhs resulted in significant improvements in the number of SSE and sexual desire (FSFI desire domain score) vs. placebo. Flibanserin was associated with significant reductions in distress associated with sexual dysfunction (FSDS-R total score) and distress associated with low sexual desire (FSDS-R Item 13) vs. placebo. There were no significant safety concerns associated with the use of flibanserin for 24 weeks. PMID- 23672270 TI - Laparoscopic versus open liver resection: a meta-analysis of long-term outcome. AB - BACKGROUND: Laparoscopic liver resection is growing in popularity, but the long term outcome of patients undergoing laparoscopic liver resection for malignancy has not been established. This paper is a meta-analysis and compares the long term survival of patients undergoing laparoscopic (LHep) versus open (OHep) liver resection for the treatment of malignant liver tumours. METHODS: A PubMed database search identified comparative human studies analysing LHep versus OHep for malignant tumours. Clinical and survival parameters were extracted. The search was last conducted on 18 March 2012. RESULTS: In total, 1002 patients in 15 studies were included (446 LHep and 556 OHep). A meta-analysis of overall survival showed no difference [1-year: odds ratio (OR) 0.71, 95% confidence interval (CI) 0.42 to 1.20, P = 0.202; 3-years: OR 0.76, 95% CI 0.56 to 1.03, P = 0.076; 5-years: OR 0.8, 95% CI 0.59 to 1.10, P = 0.173]. Subset analyses of hepatocellular carcinoma (HCC) and colorectal metastases (CRM) were performed. There was no difference in the 1-, 3-, and 5-year survival for HCC or in the 1 year survival for CRM, however, a survival advantage was found for CRM at 3 years (LHep 80% versus OHep 67.4%, P = 0.036). CONCLUSIONS: Laparoscopic surgery should be considered an acceptable alternative for the treatment of malignant liver tumours. PMID- 23672271 TI - Anti-epileptic drugs for pain #271. AB - TCAs, SNRIs, and the AEDs gabapentin and pregabalin are the best adjuvant analgesics for neuropathic pain. For patients who are intolerant to or who experience pain unresponsive to the above medications, one can consider therapy with carbamazepine, oxcarbazepine, valproic acid, topiramate, or lacosamide. However, as these agents are associated with more side effects and lower rates of efficacy, expert consultation is strongly recommended. PMID- 23672273 TI - Hb AHVAZ [alpha83(F4)Leu->Arg, CTG>CGG (alpha2); HBA2: c.251T>G],a new hemoglobin variant of the alpha2-globin gene. AB - We report a novel mutation on the alpha2-globin gene, codon 83 (T>G), which was detected in two members of two unrelated families from Khuzestan Province, South Iran, that we named Hb Ahvaz. This mutation was detected by cellulose acetate electrophoresis and characterized by molecular studies. Hb Ahvaz does not seem to be responsible for hematological abnormalities in the carriers, but with alpha(0) thalassemia (alpha(0)-thal) defects, might induce severe clinical symptoms. PMID- 23672272 TI - "Girls on the Move" intervention protocol for increasing physical activity among low-active underserved urban girls: a group randomized trial. AB - BACKGROUND: Increasing moderate to vigorous physical activity among urban girls of low socioeconomic status is both a challenge and a public health priority. Physical activity interventions targeting exclusively girls remain limited, and maintenance of moderate to vigorous physical activity during the post intervention period has been difficult to maintain. The main aim of the 5-year "Girls on the Move" group randomized trial is to evaluate the efficacy of a comprehensive school-based intervention in increasing girls' minutes of moderate to vigorous physical activity and improving cardiovascular fitness, body mass index, and percent body fat immediately post-intervention (after 17 weeks) and at 9-month post-intervention follow-up (9 months after end of intervention). METHODS/DESIGN: A total of 24 urban middle schools in the Midwestern U.S. will be randomized to either receive the intervention or serve as a control (N = 1200 girls). The intervention, based on the Health Promotion Model and Self Determination Theory, will include: (1) two face-to-face motivational, individually tailored counseling sessions with a registered nurse, one at the beginning and the other at the end of the intervention period; (2) an interactive Internet-based session during which each girl receives individually tailored motivational and feedback messages via iPad at 11 weeks (shortly after midpoint of intervention); and (3) a 90-minute after-school physical activity club. Racially diverse, low-active, 10- to 14-year-old 5th to 8th-grade girls will complete questionnaires and physical measures at baseline and post-intervention (n = 50 per school). Minutes of moderate to vigorous physical activity will be assessed with accelerometers. Cardiovascular fitness will be assessed by estimating VO2 max with PACER (Progressive Aerobic Cardiovascular Endurance Run) scores. Height and weight will be assessed to calculate body mass index. Percent body fat will be estimated with a foot-to-foot bioelectric impedance scale. Linear mixed effects regression analyses will be performed to assess intervention effects. DISCUSSION: This multi-component approach is expected to improve girls' moderate to vigorous physical activity and related physical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01503333. PMID- 23672274 TI - Influence of antipsychotic treatment type and regimen on the functionality of patients with schizophrenia. AB - BACKGROUND: Enhanced functionality is a major goal in the treatment of schizophrenia. However, possible differences in the effectiveness of first- vs. second-generation antipsychotics or between depot/long-acting injectable (D/LAI) vs. D/LAI plus oral antipsychotics are not clear. AIMS: This study was designed to evaluate possible differences between the effects of different antipsychotic treatment types or regimens on the functionality of patients with schizophrenia. METHODS: 85 outpatients with schizophrenia, who were being treated with D/LAI antipsychotics--co-administered or not with oral antipsychotics--and had been adherent to the treatment during the previous year were evaluated. Socio demographic, clinical, treatment-related, global severity and functionality variables were evaluated. Patients were grouped according to the type of antipsychotic drug (first- vs. second-generation) or according to the co administration (or not) of oral antipsychotics. RESULTS: No differences were found between first- and second-generation antipsychotics in terms of global functionality. Patients treated with LAI risperidone showed better global functionality and better performance in their habitual social activities and personal-social relationships than patients treated with risperidone plus oral second-generation antipsychotics. Better functionality was also found to be associated with higher education level, paranoid subtype of schizophrenia, harmful use of nicotine, adherence to oral treatment and absence of concomitant oral anticholinergic or psychopharmacological treatment. CONCLUSIONS: Our results suggest that D/LAI antipsychotic treatments should be administered in monotherapy whenever possible and that the treatment schedule should be simple, in order to achieve better functionality. PMID- 23672275 TI - Bleomycin-induced pulmonary fibrosis is attenuated by an antibody against KL-6. AB - BACKGROUND: Elevated levels of KL-6 are reported in the serum and/or bronchoalveolar lavage fluid (BALF) of patients with interstitial lung disease (ILD) and are useful to estimate the severity and prognosis of the disease. However, whether the anti-KL-6 antibody could attenuate pulmonary fibrosis remains unclear. OBJECTIVES: This study aims to investigate the therapeutic effects and mechanisms of anti-KL-6 antibody on bleomycin-induced pulmonary fibrosis. METHODS: A mouse model of pulmonary fibrosis was established by intratracheal injection of bleomycin (5 mg/kg). Mouse received anti-KL-6 antibody (20 ug/day, once a day) from day 7 to 21 after bleomycin injection. The effects of anti-KL-6 antibody were evaluated by pathological examination, measuring hydroxyproline measurements in lung tissues, leukocyte counts in BALF and the expression of collagen type I and type III using qRT-PCR. The expression of profibrotic cytokine (transforming growth factor-beta1, TGF-beta1), antifibrotic cytokine (hepatocyte growth factor, HGF), and KL-6 in lung tissues were analyzed by ELISA. The apoptosis of epithelial cell was examined by TUNEL staining. RESULTS: Anti-KL-6 antibody significantly reduced the number of alveolar inflammatory leukocytes (total and differential counts) in BALF of mice with bleomycin-induced pulmonary fibrosis as well as the content of hydroxyproline in the lung tissues. Treatment with anti-KL-6 antibody downregulated the expression of collagen type I, TGF-beta1 and KL-6, upregulated the expression of HGF and inhibited the apoptosis of epithelial cells. CONCLUSIONS: These findings indicated the anti-KL-6 antibody may potentially be developed as a useful inhibitor of pulmonary fibrosis. PMID- 23672277 TI - Lithium and calcium carbides with polymeric carbon structures. AB - We studied the binary carbide systems Li2C2 and CaC2 at high pressure using an evolutionary and ab initio random structure search methodology for crystal structure prediction. At ambient pressure Li2C2 and CaC2 represent salt-like acetylides consisting of C2(2-) dumbbell anions. The systems develop into semimetals (P3m1-Li2C2) and metals (Cmcm-Li2C2, Cmcm-CaC2, and Immm-CaC2) with polymeric anions (chains, layers, strands) at moderate pressures (below 20 GPa). Cmcm-CaC2 is energetically closely competing with the ground state structure. Polyanionic forms of carbon stabilized by electrostatic interactions with surrounding cations add a new feature to carbon chemistry. Semimetallic P3m1 Li2C2 displays an electronic structure close to that of graphene. The pi* band, however, is hybridized with Li-sp states and changed into a bonding valence band. Metallic forms are predicted to be superconductors. Calculated critical temperatures may exceed 10 K for equilibrium volume structures. PMID- 23672276 TI - Association of serum calcium with serum sex steroid hormones in men in NHANES III. AB - BACKGROUND: Bone is a positive regulator of male fertility, which indicates a link between regulation of bone remodeling and reproduction or more specifically a link between calcium and androgens. This possibly suggests how calcium is linked to prostate cancer development through its link with the reproductive system. We studied serum calcium and sex steroid hormones in the Third National Health and Nutrition Examination Survey (NHANES III). METHODS: Serum calcium and sex steroid hormones were measured for 1262 men in NHANES III. We calculated multivariable-adjusted geometric means of serum concentrations of total and estimated free testosterone and estradiol, androstanediol glucuronide (AAG), and sex hormone binding globulin (SHBG) by categories of calcium (lowest 5% [<1.16 mmol/L], mid 90%, top 5% [>=1.30 mmol/L]). RESULTS: Levels of total and free testosterone, total estradiol or AAG did not differ across categories of serum calcium. Adjusted SHBG concentrations were 36.4 for the bottom 5%, 34.2 for the mid 90% and 38.9 nmol/L for the top 5% of serum calcium (Ptrend = 0.006), free estradiol levels were 0.88, 0.92 and 0.80 pg/ml (Ptrend = 0.048). CONCLUSIONS: This link between calcium and sex steroid hormones, in particular the U-shaped pattern with SHBG, may, in part, explain why observational studies have found a link between serum calcium and risk of prostate cancer. PMID- 23672278 TI - Risk factors associated with severe manifestations of 2009 pandemic influenza A (H1N1) infection in China: a case-control study. AB - BACKGROUND: No studies on the risk factors of 2009 pandemic influenza A (H1N1) in China have been reported. We aimed to investigate the risk factors for severe manifestations of 2009 pandemic H1N1 influenza in China METHODS: A case-control study with 343 severe hospitalized patients and 343 randomly selected mild controls was conducted. The diagnosis was established by assessment of clinical symptoms and confirmed by the real-time reverse-transcriptase-polymerase chain reaction assay. Severe or mild patients were classified by uniform criteria issued by the Ministry of Health in China. RESULTS: The multivariable logistic regression analysis showed that the overweight or obese subjects admitted to hospital with H1N1 influenza were more likely to experience severe manifestations. The ORs were 3.70 (95% CI: 2.04-6.72) and 35.61 (95% CI: 7.96 159.21) respectively. Subjects at age less than 5 years or older than 60 years had an increased risk of severe manifestations (OR = 21.14, 95% CI: 7.79-57.33). We also observed increased risk among subjects with longer time interval from symptom onset to hospital admission (OR = 3.26, 95% CI: 2.08-5.11) or peasants (OR = 9.79, 95% CI: 5.11-18.78). Those with chronic disorders had increased risk of severe manifestations of H1N1 influenza. CONCLUSION: We provide evidence on the risk factors associated with severe manifestations of 2009 pandemic H1N1 influenza in a study of hospitalized subjects in China. PMID- 23672279 TI - Combined use of AFP, CEA, CA125 and CAl9-9 improves the sensitivity for the diagnosis of gastric cancer. AB - BACKGROUND: The detection of serum tumor marker becomes a common method for screening tumors. However, this method has not been widely used for routine gastric cancer screening. In this study we aimed to determine whether the combined use of tumor markers may increase the sensitivity for the diagnosis of gastric cancer. METHODS: Serum AFP, CEA, CA125 and CA19-9 levels were measured in 149 patients with gastric cancer, 111 patients with benign gastric diseases and 124 healthy people, who visited the First Affiliated Hospital of Nanchang University from May 2011 to May 2012. Statistical analysis including receiver operating characteristic (ROC) curve, the area under the curve (AUC), and logistic regression analysis was performed to evaluate the diagnostic value of these markers on gastric cancer. RESULTS: Serum levels of CEA, CA125, and CA19-9 in gastric cancer group were higher than that in the benign gastric disease group and the healthy control group (P <0.005). The sensitivity of AFP, CEA, CA125 and CA19-9 in the diagnosis of gastric cancer was 4.7-20.8% individually, and increased to 40.3% in combination. By using optimal cut-off value, the sensitivity of CEA, CA125, and CA19-9 for the diagnosis of gastric cancer was improved. Especially, the sensitivity of CEA increased to 58.4% and the sensitivity of combined use of four markers increased to 69.1%. The age and gender had no effects on the diagnostic value of these markers. CONCLUSIONS: The determination and application of optimal cut-off values based on ROC curve and logistic regression analysis could improve the diagnosis of gastric cancer based on common tumor markers. PMID- 23672280 TI - Influence of low-level laser on bone remodeling during induced tooth movement in rats. AB - OBJECTIVE: To analyze the effect of low-level laser on bone remodeling during induced tooth movement in rats. MATERIALS AND METHODS: A diode laser (808 nm, 100 mW, 54 J on an area of 0.0028 cm(2)) was used. The application was continuous, punctual, and with contact. Forty-two 70-day-old Wistar rats had the maxillary left first molar moved using a force level of 25 g. In two experimental subgroups the movement was performed over 7 days and in three subgroups the movement occurred over 14 days. In the 7-day movement subgroups, one subgroup received laser irradiation on day 1 only; the other subgroup received laser irradiation on days 1, 3, and 5. In the 14-day movement subgroups, one subgroup received laser irradiation on day 1 only; the second on days 1, 3, and 5; and the third on days 1, 3, 5, 7, 9, 11, and 13. The control group was also divided into two subgroups, and movement occurred over two different periods of treatment (7 days and 14 days) without laser application; these were used as controls for the respective experimental subgroups. Inter-subgroup comparison was performed with Kruskal Wallis, followed by Mann-Whitney and analysis of variance, followed by Tukey tests within the 7- and 14-day subgroups. RESULTS: The subgroup with three laser applications showed significantly greater osteoclastic activity and bone resorption than the other subgroups in the 7-day movement subgroups. CONCLUSIONS: Low-level laser application significantly increased the osteoclastic but not the osteoblastic activity during the initial phases of tooth movement. In addition, the osteoclastic activity was dose-dependent. PMID- 23672281 TI - Predicting risk severity and response of fetal neonatal alloimmune thrombocytopenia. AB - Fetal neonatal alloimmune thrombocytopenia (FNAIT) is a devastating bleeding disorder in the fetus or neonate caused by transplacental transport of maternal alloantibodies to paternal-derived antigen on fetal platelets. In Caucasians, up to 80% of FNAIT cases result from maternal immunization to human platelet antigen (HPA)-1a. New methods have developed facilitating detection of common and private antibodies against HPAs triggering FNAIT. Understanding the pathogenesis of FNAIT made it possible to develop a novel strategy to treat this disorder. To date, recombinant monoclonal antibodies directed against the beta3 integrin and Fc receptors have been tested in a mouse model of FNAIT, and seem to be promising. Whether those novel treatments will eventually replace the conventional high dose immunoglobulin G in women with FNAIT is yet unknown. PMID- 23672282 TI - Gigantic splenomegaly in a 27-year-old male of South-East Asian descent with concurrent diagnosis of myeloproliferative neoplasm and hemoglobin H disease. PMID- 23672283 TI - Palmoplantar contractures in childhood: a rare complication of vascular Ehlers Danlos syndrome. AB - Although catastrophic vascular complications in vascular Ehlers-Danlos Syndrome (EDS) are well recognized, other complications such as flexion contractures and tendon nodules are rarely reported and poorly characterized. We report a young man with vascular EDS, who developed flexion contractures and tendon nodules, causing considerable disability. Limited management strategies are available for these complications, which have continued to prove a challenge to management. PMID- 23672284 TI - Modified graphene/polyimide nanocomposites: reinforcing and tribological effects. AB - By taking advantage of design and construction of strong graphene-matrix interfaces, we have prepared modified graphene/polyimide (MG/PI) nanocomposites via a two-stage process consisting of (a) surface modification of graphene and (b) in situ polymerization. The 2 wt % MG/PI nanocomposites exhibited a 20-fold increase in wear resistance and a 12% reduction in friction coefficient, constituting a potential breakthrough for future tribological application. Simultaneously, MG also enhanced thermal stability, electrical conductivity, and mechanical properties, including tensile strength, Young's modulus, storage modulus, and microhardness. Excellent thermal stability and compatibility of interface, strong covalent adhesion interaction and mechanical interlocking at the interface, as well as homogeneous and oriented dispersion of MG were achieved here, contributing to the enhanced properties observed here. The superior wear resistance is ascribed to (a) tribological effect of MG, including suppression effect of MG in the generation of wear debris and protective effect of MG against the friction force, and (b) the increase in mechanical properties. In light of the relatively low cost and the unique properties of graphene, the results of this study highlight a pathway to expand the engineering applications of graphene and solve wear-related mechanical failures of polymer parts. PMID- 23672285 TI - Leptospira interrogans at the human-wildlife interface in northern Botswana: a newly identified public health threat. AB - Leptospirosis is the most widespread zoonosis in the world. In northern Botswana, humans live in close proximity to a diversity of wildlife and peridomestic rodents and may be exposed to a variety of zoonotic pathogens. Little is known regarding the occurrence and epidemiology of L. interrogans in Africa despite the recognized global importance of this zoonotic disease and the threat it poses to public health. In Botswana, banded mongooses (Mungos mungo) live in close proximity to humans across protected and unprotected landscapes and may be a useful sentinel species for assessing the occurrence of zoonotic organisms, such as L. interrogans. We utilized PCR to screen banded mongoose kidneys for leptospiral DNA and identified 41.5% prevalence of renal carriage of L. interrogans (exact binomial 95% CI 27.7-56.7%, n = 41). Renal carriage was also detected in one Selous' mongoose (Paracynictis selousi). This is the first published confirmation of carriage of L. interrogans in either species. This is also the first report of L. interrogans occurrence in northern Botswana and the only report of this organism in a wildlife host in the country. Pathogenic Leptospira are usually transmitted indirectly to humans through soil or water contaminated with infected urine. Other avenues, such as direct contact between humans and wildlife, as well as consumption of mongooses and other wildlife as bushmeat, may pose additional exposure risk and must be considered in public health management of this newly identified zoonotic disease threat. There is a critical need to characterize host species involvement and pathogen transmission dynamics, including human-wildlife interactions that may increase human exposure potential and infection risk. We recommend that public health strategy be modified to include sensitization of medical practitioners to the presence of L. interrogans in the region, the potential for human infection, and implementation of clinical screening. This study illustrates the need for increased focus on neglected zoonotic diseases as they present an important threat to public health. PMID- 23672286 TI - Experimental design affects social behavior outcomes in adult zebrafish developmentally exposed to lead. AB - Lead (Pb(2+)) affects neuronal and endocrine systems that influence social interactions. By providing potential hiding locations, spatial heterogeneity may affect Pb(2+)-induced behavioral outcomes. Therefore, a test chamber was designed into which a refuge could be inserted. The refuge allowed test subjects to escape from the mirror image that stimulated agonistic interactions. Behaviors with a mirror were compared with baseline activity patterns without a mirror. Adult (12 month old) male and female zebrafish, exposed to Pb(2+) (0-10 MUM) as embryos (2 24 hours post fertilization), were tested individually for 5 min in each chamber design within 2 h of feeding. Behaviors were evaluated for % time in mirror zone, distance traveled (=activity level), and attacks on the mirror image. When there was no refuge, significant concentration-dependent increases occurred in male % time in mirror zone, activity level, and number of attacks. Increases in these variables were less pronounced in females. When there was a refuge, there were significant differences for males only in activity level and attacks at the higher developmental exposure concentrations; % time in mirror zone followed a similar pattern and level as without refuge. Females displayed Pb(2+)-induced behavioral changes only for attacks on mirror. Since the presence of refuges that is, environmental enrichment, reduced Pb(2+)-induced agonistic behavior in both sexes, experimental spatial design can be considered an important factor when interpreting behavioral outcomes. PMID- 23672287 TI - Deriving cell lines from zebrafish embryos and tumors. AB - Over the last two decades the zebrafish has emerged as a powerful model organism in science. The experimental accessibility, the broad range of zebrafish mutants, and the highly conserved genetic and biochemical pathways between zebrafish and mammals lifted zebrafish to become one of the most attractive vertebrate models to study gene function and to model human diseases. Zebrafish cell lines are highly attractive to investigate cell biology and zebrafish cell lines complement the experimental tools that are available already. We established a straightforward method to culture cells from a single zebrafish embryo or a single tumor. Here we describe the generation of fibroblast-like cell lines from wild-type and ptenb(-/-) embryos and an endothelial-like cell line from a tumor of an adult ptena(+/-)ptenb(-/-) zebrafish. This protocol can easily be adapted to establish stable cell lines from any mutant or transgenic zebrafish line and the average time to obtain a pro-stable cell line is 3-5 months. PMID- 23672288 TI - Transgenic overexpression of cdx1b induces metaplastic changes of gene expression in zebrafish esophageal squamous epithelium. AB - Cdx2 has been suggested to play an important role in Barrett's esophagus or intestinal metaplasia (IM) in the esophagus. To investigate whether transgenic overexpression of cdx1b, the functional equivalent of mammalian Cdx2 in zebrafish, may lead to IM of zebrafish esophageal squamous epithelium, a transgenic zebrafish system was developed by expressing cdx1b gene under the control of zebrafish keratin 5 promoter (krt5p). Gene expression in the esophageal squamous epithelium of wild-type and transgenic zebrafish was analyzed by Affymetrix microarray and confirmed by in situ hybridization. Morphology, mucin expression, cell proliferation, and apoptosis were analyzed by hematoxylin & eosin (HE) staining, Periodic acid Schiff (PAS) Alcian blue staining, proliferating cell nuclear antigen (PCNA) immunohistochemical staining, and TUNEL assay as well. cdx1b was found to be overexpressed in the nuclei of esophageal squamous epithelial cells of the transgenic zebrafish. Ectopic expression of cdx1b disturbed the development of this epithelium in larval zebrafish and induced metaplastic changes in gene expression in the esophageal squamous epithelial cells of adult zebrafish, that is, up-regulation of intestinal differentiation markers and down-regulation of squamous differentiation markers. However, cdx1b failed to induce histological IM, or to modulate cell proliferation and apoptosis in the squamous epithelium of adult transgenic zebrafish. PMID- 23672290 TI - Effects of serum reduction and VEGF supplementation on angiogenic potential of human adipose stromal cells in vitro. AB - OBJECTIVES: This study investigated effects of reduced serum condition and vascular endothelial growth factor (VEGF) on angiogenic potential of adipose stromal cells (ASCs) in vitro. MATERIALS AND METHODS: Adipose stromal cells were cultured in three different types of medium: (i) F12/DMEM (FD) supplemented with 10% FBS from passage 0 (P0) to P6; (ii) FD supplemented with 2% FBS at P6; and (iii) FD supplemented with 2% FBS plus 50 ng/ml of VEGF at P6. Morphological changes and growth rate of ASCs were recorded. Changes in stemness, angiogenic and endogenic genes' expressions were analysed using Real-Time PCR. RESULTS: Adipose stromal cells changed from fibroblast-like shape when cultured in 10% FBS medium to polygonal when cultured in 2% FBS plus VEGF-supplemented medium. Their growth rate was lower in 2% FBS medium, but increased with addition of VEGF. Real Time PCR showed that ASCs maintained most of their stemness and angiogenic genes' expression in 10% FBS at P1, P5 and P6, but this increased significantly in 2% FBS at P6. Endogenic genes expression such as PECAM-1, VE chaderin and VEGFR-2 decreased after serial passage in 10% FBS, but increased significantly at P6 in 2% FBS. Addition of VEGF did not cause any significant change in gene expression level. CONCLUSION: Adipose stromal cells had greater angiogenic potential when cultured in reduced serum conditions. VEGF did not enhance their angiogenic potential in 2% FBS-supplemented medium. PMID- 23672289 TI - Endocrinology and physiology of pseudocyesis. AB - This literature review on pseudocyesis or false pregnancy aims to find epidemiological, psychiatric/psychologic, gynecological and endocrine traits associated with this condition in order to propose neuroendocrine/endocrine mechanisms leading to the emergence of pseudocyetic traits. Ten women from 5 selected studies were analyzed after applying stringent criteria to discriminate between cases of true pseudocyesis (pseudocyesis vera) versus delusional, simulated or erroneous pseudocyesis. The analysis of the reviewed studies evidenced that pseudocyesis shares many endocrine traits with both polycystic ovarian syndrome and major depressive disorder, although the endocrine traits are more akin to polycystic ovarian syndrome than to major depressive disorder. Data support the notion that pseudocyetic women may have increased sympathetic nervous system activity, dysfunction of central nervous system catecholaminergic pathways and decreased steroid feedback inhibition of gonadotropin-releasing hormone. Although other neuroendocrine/endocrine pathways may be involved, the neuroendocrine/endocrine mechanisms proposed in this review may lead to the development of pseudocyetic traits including hypomenorrhea or amenorrhea, galactorrhea, diurnal and/or nocturnal hyperprolactinemia, abdominal distension and apparent fetal movements and labor pains at the expected date of delivery. PMID- 23672291 TI - Future Saudi doctors and cancer patients agree cancer patients should be informed about their cancer. AB - AIM: To compare attitudes of Saudi medical students and Saudi cancer patients towards disclosure of cancer information and to examine whether differences exist between students and patients, level of education or gender and region of residence. METHODS: Data were collected from 384 students and 368 patients using a nine-question questionnaire on attitudes to cancer. RESULTS: Almost all patients (98%) wanted to receive all the information should they get cancer compared with 93% of students (P = 0.001) and almost no patients and students wanted the information hidden (99 vs 98%, P = 0.273). If they became ill students were more likely to share information with their family and friends than patients. Fewer than 2% of patients did not want to know the benefits of chemotherapy compared to 3% of students, while 99% of patients wanted to know the side-effects compared to 93% of students (P = 0.095 and P = 0.001, respectively). Almost all patients and students (99 vs 98%) would refuse treatment without knowing their diagnosis (P = 0.401). Patients wanted to know the prognosis more than students (98 vs 92%; P = 0.001). In all, 99% of male students wanted their cancer diagnosis disclosed compared with women (98%; P = 0.615). Gender, education level, regions and age did not affect the desire of cancer patients to know their prognosis (P = 0.275, P = 0.664, P = 0.0314 and P = 0.164, respectively). CONCLUSION: There was a consensus among cancer patients and medical students that cancer information, including diagnosis, treatment effects and prognosis, should be disclosed to patients. PMID- 23672293 TI - "Early palliative care: how?" From a conference report to a consensus document, Bentivoglio, May 14, 2012. PMID- 23672294 TI - Predictors of hazardous drinking, tobacco smoking and physical inactivity in vocational school students. AB - BACKGROUND: Tobacco smoking, hazardous drinking and physical inactivity during adolescence are risk factors that are associated with poorer health in adulthood. The identification of subgroups of young people with a high prevalence of one or more of these risk factors allows an optimised allocation of preventive measures. This study aimed at investigating hazardous drinking, tobacco smoking and physical inactivity as well as their associations and demographic predictors in vocational school students. METHODS: Out of 57 contacted vocational schools in Switzerland, a total of 24 schools participated in a survey assessing gender, age, immigrant background, educational attainment and vocational field as well as the above mentioned health risk factors. Out of the 2659 students present in 177 included vocational school classes, 2647 (99.5%) completed the survey. Binary logistic regression analyses were conducted to investigate the demographic predictors of each health risk factor and a multinomial logistic regression analysis was conducted to investigate predictors of different risk factor combinations. RESULTS: Of the surveyed students, 79.4% showed at least one risk factor, 43.6% showed two or more and 9.6% showed all three health risk factors. Hazardous drinking was more prevalent in male, physical inactivity was more prevalent in female vocational school students. The proportion of students with low physical activity and tobacco smoking increased with increasing age. While the combination of hazardous drinking and tobacco smoking was higher in males, the other risk factor combinations were observed particularly among females. CONCLUSIONS: Multiple risk factors were ascertained in a significant proportion of vocational school students. Specifically, tobacco smoking and hazardous drinking were coexistent. The study underlines the need for preventive measures in specific subpopulations of adolescents and young adults with lower educational level. PMID- 23672295 TI - Optimized light-directed synthesis of aptamer microarrays. AB - Aptamer microarrays are a promising high-throughput method for ultrasensitive detection of multiple analytes, but although much is known about the optimal synthesis of oligonucleotide microarrays used in hybridization-based genomics applications, the bioaffinity interactions between aptamers and their targets is qualitatively different and requires significant changes to synthesis parameters. Focusing on streptavidin-binding DNA aptamers, we employed light-directed in situ synthesis of microarrays to analyze the effects of sequence fidelity, linker length, surface probe density, and substrate functionalization on detection sensitivity. Direct comparison with oligonucleotide hybridization experiments indicates that aptamer microarrays are significantly more sensitive to sequence fidelity and substrate functionalization and have different optimal linker length and surface probe density requirements. Whereas microarray hybridization probes generate maximum signal with multiple deletions, aptamer sequences with the same deletion rate result in a 3-fold binding signal reduction compared with the same sequences synthesized for maximized sequence fidelity. The highest hybridization signal was obtained with dT 5mer linkers, and the highest aptamer signal was obtained with dT 11mers, with shorter aptamer linkers significantly reducing the binding signal. The probe hybridization signal was found to be more sensitive to molecular crowding, whereas the aptamer probe signal does not appear to be constrained within the density of functional surface groups commonly used to synthesize microarrays. PMID- 23672296 TI - Patient barriers to follow-up care for breast and cervical cancer abnormalities. AB - BACKGROUND: Women with breast or cervical cancer abnormalities can experience barriers to timely follow-up care, resulting in delays in cancer diagnosis. Patient navigation programs that identify and remove barriers to ensure timely receipt of care are proliferating nationally. The study used a systematic framework to describe barriers, including differences between African American and Latina women; to determine recurrence of barriers; and to examine factors associated with barriers to follow-up care. METHODS: Data originated from 250 women in the intervention arm of the Chicago Patient Navigation Research Program (PNRP). The women had abnormal cancer screening findings and navigator encounters. Women were recruited from a community health center and a publicly owned medical center. After describing proportions of African American and Latina women experiencing particular barriers, logistic regression was used to explore associations between patient characteristics, such as race/ethnicity, and type of barriers. RESULTS: The most frequent barriers occurred at the intrapersonal level (e.g., insurance issues and fear), while institutional-level barriers such as system problems with scheduling care were the most commonly recurring over time (29%). The majority of barriers (58%) were reported in the first navigator encounter. Latinas (81%) reported barriers more often than African American women (19%). Differences in race/ethnicity and employment status were associated with types of barriers. Compared to African American women, Latinas were more likely to report an intrapersonal level barrier. Unemployed women were more likely to report an institutional level barrier. CONCLUSION: In a sample of highly vulnerable women, there is no single characteristic (e.g., uninsured) that predicts what kinds of barriers a woman is likely to have. Nevertheless, navigators appear able to easily resolve intrapersonal-level barriers, but ongoing navigation is needed to address system-level barriers. Patient navigation programs can adopt the PNRP barriers framework to assist their efforts in assuring timely follow-up care. PMID- 23672297 TI - Obese-derived ASCs show impaired migration and angiogenesis properties. AB - Efficient delivery of stem cells to target tissues is a major problem in regenerative medicine. Adipose derived stem cells have been proposed as important tools in cell therapy for recovering tissues after damage. Nevertheless, the ability of these ASCs to migrate or invade in order to reach the tissue of interest has not been tested so far. In this study we present evidence that the ASCs derived from obese subjects present a detrimental ability to migrate and invade in comparison with ASCs derived from control subjects. Besides, obese derived ASCs are unable to respond to certain stimuli and to form enough capillaries after stimulation. We propose that the use of specific cytokines could overcome these deficiencies of the obese environment, offering a tool to optimize cell therapy. PMID- 23672298 TI - Serum level of soluble tumor necrosis factor receptor 2 is associated with the outcome of patients with diffuse large B-cell lymphoma treated with the R-CHOP regimen. AB - BACKGROUND: Serum soluble tumor necrosis factor receptor 2 (sTNFR2) concentration predicted the clinical outcome of patients with aggressive non-Hodgkin's lymphoma including diffuse large B-cell lymphoma (DLBCL) treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) in our previous study. However, after rituximab (R) was introduced in clinical practice, R-CHOP replaced CHOP as the standard therapy for DLBCL. PATIENTS AND METHODS: In this study, we re-evaluated the prognostic significance of serum sTNFR2 in 154 patients with DLBCL treated with R-CHOP. RESULTS: Five-yr overall survival (5-yr OS) rates with sTNFR2 >=20 ng/mL and <20 ng/mL were 29.2% and 83.3% (P < 0.0001), respectively, and the corresponding 5-yr progression-free survival (5-yr PFS) rates were 26.9% and 76.4% (P < 0.0001), respectively. A multivariate analysis revealed that serum sTNFR2 and complete remission (CR) were independent prognostic factors for both OS (CR: P < 0.0001, sTNFR2: P = 0.0001) and PFS (CR: P < 0.0001, sTNFR2: P = 0.0001). The prognosis of patients with poor risk groups according to the revised International Prognostic Index who also had high serum sTNFR2 was especially poor. CONCLUSION: Serum sTNFR2 might be a powerful prognostic factor for patients with DLBCL in the rituximab era. PMID- 23672299 TI - The schema provokes a disparity of false recollection between actions and objects in an everyday scene. AB - We explored the effect of the schema on recognition memories and subjective experiences for actions and objects in an everyday scene. At first, participants watched slides of a man cooking in a kitchen. The man performed schema-consistent actions, and schema-consistent objects were left. After watching the slides, participants completed a recognition test, a remember/know test, and a Perception/Thought/Emotion/Context questionnaire. We confirmed three main results. First, participants made more false recognitions for schema-consistent distracters than for schema-inconsistent distracters with more "remember" judgments accompanied by perceptual, thought, and contextual details, and with more "know" judgments. Second, participants made more false recognitions for schema-consistent object distracters than for schema-consistent action distracters. Third, participants more frequently recognized schema-consistent action targets than schema-consistent object targets with more "remember" judgments. Both action memory and object memory were reconstructed under the schema, provoking false recognitions for schema-consistent distracters. However, the memories of schema-consistent action targets were so recollective that they could prevent false recognitions for schema-consistent action distracters. PMID- 23672300 TI - Cardiac ventricular dimensions predict cognitive decline and cerebral blood flow abnormalities in aging men. AB - BACKGROUND: The aims of this study are to examine possible associations between left cardiac ventricular measures in sixth decade and cognitive performance, both cross sectionally and longitudinally, and to examine if left cardiac ventricular measures could predict future changes in cerebral blood flow (CBF). METHODS: 211 elderly men from a cohort of the population study "Men born in 1914" completed M mode echocardiography and a cognitive test battery at age 68. The cognitive test battery was repeated at age 81. CBF was estimated with 99mTc-HMPAO SPECT in 72 survivors at age 83. Cognitive performance at baseline and at 1st follow up and CBF at 1st follow up were analysed in relation to left ventricular internal dimension in diastole (LVIDd mm/m2) and fractional shortening (FS). RESULTS: Subjects with enlarged LVIDd at age 68 had poorer results on verbal and speed performance tests at baseline and on verbal and visuo-spatial tests 14 years later on. Low FS was associated with decreased results on visuo-spatial tests at baseline. There was an inverse relationship between LVIDd and both verbal and spatial ability at the baseline and after 14 years of follow-up. Normotensive men with lower FS had also decreased CBF in a majority of brain areas 14 years later. CONCLUSIONS: Mild echocardiographic abnormalities in 68 ys.-old men, as increased LVIDd and lower FS, are associated with lower cognitive test results and may predict cognitive decline and silent cerebral perfusion abnormalities 14 years later. PMID- 23672301 TI - Ownership and use of mobile phones among health workers, caregivers of sick children and adult patients in Kenya: cross-sectional national survey. AB - BACKGROUND: The rapid growth in mobile phone penetration and use of Short Message Service (SMS) has been seen as a potential solution to improve medical and public health practice in Africa. Several studies have shown effectiveness of SMS interventions to improve health workers' practices, patients' adherence to medications and availability of health facility commodities. To inform policy makers about the feasibility of facility-based SMS interventions, the coverage data on mobile phone ownership and SMS use among health workers and patients are needed. METHODS: In 2012, a national, cross-sectional, cluster sample survey was undertaken at 172 public health facilities in Kenya. Outpatient health workers and caregivers of sick children and adult patients were interviewed. The main outcomes were personal ownership of mobile phones and use of SMS among phone owners. The predictors analysis examined factors influencing phone ownership and SMS use. RESULTS: The analysis included 219 health workers and 1,177 patients' respondents (767 caregivers and 410 adult patients). All health workers possessed personal mobile phones and 98.6% used SMS. Among patients' respondents, 61.2% owned phones and 71.4% of phone owners used SMS. The phone ownership and SMS use was similar between caregivers of sick children and adult patients. The respondents who were male, more educated, literate and living in urban area were significantly more likely to own the phone and use SMS. The youngest respondents were less likely to own phones, however when the phones were owned, younger age groups were more likely to use SMS. Respondents living in wealthier areas were more likely to own phones; however when phones are owned no significant association between the poverty and SMS use was observed. CONCLUSIONS: Mobile phone ownership and SMS use is ubiquitous among Kenyan health workers in the public sector. Among patients they serve the coverage in phone ownership and SMS use is lower and disparities exist with respect to gender, age, education, literacy, urbanization and poverty. Some of the disparities on SMS use can be addressed through the modalities of mHealth interventions and enhanced implementation processes while further growth in mobile phone penetration is needed to reduce the ownership gap. PMID- 23672302 TI - Sex differences during humor appreciation in child-sibling pairs. AB - The developmental origin of sex differences in adult brain function is poorly understood. Elucidating neural mechanisms underlying comparable cognitive functionality in both children and adults is required to address this gap. Humor appreciation represents a particularly relevant target for such developmental research because explanatory theories apply across the life span, and underlying neurocircuitry shows sex differences in adults. As a positive mood state, humor is also of interest due to sex differences in rates of depression, a disorder afflicting twice as many women as men. In this study, we employed functional magnetic resonance imaging (fMRI) to investigate brain responses to funny versus positive (and neutral) video clips in 22 children, ages 6-13 years, including eight sibling-pairs. Our data revealed increased activity to funny clips in bilateral temporo-occipital cortex, midbrain, and amygdala in girls. Conversely, we found heightened activation to positive clips in bilateral inferior parietal lobule, fusiform gyrus, inferior frontal gyrus, amygdala, and ventromedial prefrontal cortex in boys. Many of these effects persisted when looking at sibling-pairs only. We interpret such findings as reflecting the presence of early sex divergence in reward saliency or expectation and stimulus relevance attribution. These findings are discussed in the context of evolutionary and developmental theories of humor function. PMID- 23672303 TI - Role of tissue engineered collagen based tridimensional implant on the healing response of the experimentally induced large Achilles tendon defect model in rabbits: a long term study with high clinical relevance. AB - BACKGROUND: Tendon injury is one of the orthopedic conditions poses with a significant clinical challenge to both the surgeons and patients. The major limitations to manage these injuries are poor healing response and development of peritendinous adhesions in the injured area. This study investigated the effectiveness of a novel collagen implant on tendon healing in rabbits. RESULTS: Seventy five mature White New-Zealand rabbits were divided into treated (n = 55) and control (n = 20) groups. The left Achilles tendon was completely transected and 2 cm excised. The defects of the treated animals were filled with collagen implants and repaired with sutures, but in control rabbits the defects were sutured similarly but the gap was left untreated. Changes in the injured and normal contralateral tendons were assessed weekly by measuring the diameter, temperature and bioelectrical characteristics of the injured area. Clinical examination was done and scored. Among the treated animals, small pilot groups were euthanized at 5, 10, 15, 20, 30, 40 and 60 (n = 5 at each time interval) and the remainder (n = 20) and the control animals at 120 days post injury (DPI). The lesions of all animals were examined at macroscopic and microscopic levels and the dry matter content, water delivery and water uptake characteristics of the lesions and normal contralateral tendons of both groups were analyzed at 120 DPI. CONCLUSION: This novel collagen implant was biodegradable, biocompatible and possibly could be considered as a substitute for auto and allografts in clinical practice in near future. PMID- 23672304 TI - Solubilization of water-insoluble drugs due to random amphiphilic and degradable poly(dimethylmalic acid) derivatives. AB - Amphotericin B (AmB) and clofazimine are potent drugs hindered by their low water solubilities and their toxicities. Carriers able to increase their apparent water solubilities are needed for these drugs and for other molecules with similar properties. Random amphiphilic copolymers derived from poly(dimethylmalic acid) were obtained using different hydrophobization ratios and side group sizes. Apparent water solubilities of pyrene, clofazimine, and AmB were increased up to 10 000, 20 000 and 1000 times, respectively, in aqueous solutions containing these polymers. The presence of sodium chloride in polymer solution increased pyrene solubility but decreased the solubilities of clofazimine and AmB, compared to the salt-free solutions. Synergy between hydrophobic and electrostatic interactions was observed for polar and cationic molecules. Degradation studies showed that the examined polymers were degradable, but none of them were totally degraded in 28 days. These polymers could be used as a new tool for drug solubilization. PMID- 23672305 TI - Thrombospondin-1 and L-selectin are associated with silent cerebral infarct in children with sickle cell anaemia. PMID- 23672307 TI - Integration of porous coordination polymers and gold nanorods into core-shell mesoscopic composites toward light-induced molecular release. AB - Besides conventional approaches for regulating in-coming molecules for gas storage, separation, or molecular sensing, the control of molecular release from the pores is a prerequisite for extending the range of their application, such as drug delivery. Herein, we report the fabrication of a new porous coordination polymer (PCP)-based composite consisting of a gold nanorod (GNR) used as an optical switch and PCP crystals for controlled molecular release using light irradiation as an external trigger. The delicate core-shell structures of this new platform, composed of an individual GNR core and an aluminum-based PCP shell, were achieved by the selective deposition of an aluminum precursor onto the surface of GNR followed by the replication of the precursor into aluminum-based PCPs. The mesoscopic structure was characterized by electron microscopy, energy dispersive X-ray elemental mapping, and sorption experiments. Combination at the nanoscale of the high storage capacity of PCPs with the photothermal properties of GNRs resulted in the implementation of unique motion-induced molecular release, triggered by the highly efficient conversion of optical energy into heat that occurs when the GNRs are irradiated into their plasmon band. Temporal control of the molecular release was demonstrated with anthracene as a guest molecule and fluorescent probe by means of fluorescence spectroscopy. PMID- 23672308 TI - Controllable two-stage droplet evaporation method and its nanoparticle self assembly mechanism. AB - Bottom-up self-assembly is able to constitute a variety of structures and has been thought to be a promising way for advanced nanofabrication. Droplet evaporation, as the simplest method, has been used in various self-assemblies. However, the assembled area is not large enough and the order is still not well controlled. Here we show a facile and controllable two-stage droplet evaporation method by adjusting the humidity and temperature of the evaporating droplet. Taking the highly monodispersed gold nanorods (GNRs) as an example, large-area, self-assembly monolayer arrays are reproducibly achieved. To understand the self assembly mechanism, we adopted simplified models to analyze the interactions between the nanorods. The results show that a metastable state of secondary energy-minimum exists, especially in the latter stage of the assembly process, leading to the ordered arrays. A large electrostatic barrier between the assembled arrays prevents the formation of the multilayer structures and thereby leads to the preferential monolayers. Moreover, we predict possibilities of different types of assemblies of the nanorods, and a schematic phase diagram is finally given. The results here may offer a way toward high-quality self assembled nanoparticles superlattices for use in enhanced spectroscopy, sensors, or nanodevices. PMID- 23672306 TI - Measuring thyroid peroxidase antibodies on the day nulliparous women present for management of miscarriage: a descriptive cohort study. AB - BACKGROUND: There has been recent evidence suggesting the presence of anti thyroid peroxidase antibodies (TPOAb) increases the risk of miscarriage, and levothyroxine can rescue miscarriages associated with TPOAb. We propose the most clinically pragmatic cohort to screen for TPOAb are women presenting for management of a missed miscarriage and have never birthed a liveborn. We measured serum TPOAb among nulliparous women presenting for management of miscarriage, and compared levels with women who have had 2 or more livebirths (and never miscarried). Given its potential role in immunomodulation, we also measured Vitamin D levels. METHODS: We performed a prospective descriptive cohort study at a tertiary hospital (Mercy Hospital for Women, Victoria, Australia). We measured TPOAb and Vitamin D levels in serum obtained from 118 nulliparous women presenting for management of miscarriage, and 162 controls with 2 or more livebirths (and no miscarriages). Controls were selected from a serum biobank prospectively collected in the first trimester at the same hospital. RESULTS: Nulliparous women with 1 or more miscarriages had higher thyroid peroxidase antibody (TPOAb) levels than those with 2 or more livebirths; TPOAb in miscarriage group was 0.3 mIU/L (interquartile range [IR]: 0.2-0.7) vs 0.2 mIU/L among controls (IR 0.0-0.5; p < 0.0001). We confirmed TPOAb levels were not correlated with serum human chorionic gonadotrophin (hCG) concentrations in either the miscarriage or control groups. In contrast, thyroid stimulating hormone, fT3 and fT4 levels (thyroid hormones) either trended towards a correlation, or were significantly correlated with serum hCG levels in the two groups. Of the entire cohort that was predominantly caucasian, only 12% were Vitamin D sufficient. Low Vitamin D levels were not associated with miscarriage. CONCLUSIONS: We have confirmed the association between miscarriage and increased TPOAb levels. Furthermore, it appears TPOAb levels in maternal blood are not influenced by serum hCG levels. Therefore, we propose the day nulliparous women present for management for miscarriage is a clinically relevant, and pragmatic time to screen for TPOAb. PMID- 23672309 TI - Improved in vivo performance of second-generation cryoballoon for pulmonary vein isolation. AB - INTRODUCTION: A novel cryoballoon with improved refrigerant distribution promises better pulmonary vein (PV) isolation success rate without sacrificing the technology's safety profile. This study aimed to compare the Arctic Front(r) (AF) balloon to the new Arctic Front AdvanceTM (AFA). METHODS AND RESULTS: Twenty pulmonary PVs from 10 healthy dogs weighing 29.8 +/- 1.1 kg were assigned to ablation with AF and AFA, using a 23 mm or 28 mm balloon. A single 4-minute ablation was performed in each vessel, with no phrenic nerve monitoring. The AchieveTM mapping catheter was used to confirm acute isolation. Thirty days post treatment the ablation sites were assessed for electrical PV isolation and ablation completeness via gross and histological examination. The phrenic nerve, PVs, lungs, esophagus, kidneys, and brain were collected for evaluation of potential damage. A preprocedural and prenecropsy CT were performed to assess incidence of PV stenosis. All 10 PVs were fully isolated with AFA; 6 of 10 PVs were fully isolated with AF. In all cases, lesion gaps with AF are believed to stem from inadequate cooling of the most distal balloon segment that was in contact with the unablated PV tissue. No untoward findings were detected on gross examination of the heart, esophagus, kidneys, brain, or PVs. One phrenic nerve had cross-sectional ablation associated with an AFA 23 mm balloon. Superficial regions of subpleural lung fibrosis were noted adjacent to 7 PVs. CONCLUSIONS: PV isolation and lesion completeness were improved with Arctic Front Advance, while no unexpected findings were found related to safety. PMID- 23672310 TI - Efficacy of sorafenib as adjuvant therapy to prevent early recurrence of hepatocellular carcinoma after curative surgery: A pilot study. AB - AIM: Until now, no effective adjuvant therapy to prevent early recurrence of hepatocellular carcinoma (HCC) after curative treatment has been reported. The aim of this study is to evaluate the clinical benefit of sorafenib as adjuvant treatment in subjects with HCC after hepatic resection. METHODS: The pilot study was undertaken involving HCC patients who had undergone curative liver surgery with high recurrence risk factors. Time to recurrence and disease recurrence rate were assessed. Sorafenib 400 mg q.d. was administrated continuously for 4 months after hepatic resection. RESULTS: A total of 31 patients were enrolled and eligible for final data analysis. The median follow-up time was 19 months (range, 9.5-30.2). Time to recurrence in the sorafenib arm was 21.45 +/- 1.98 months (mean +/- standard deviation), compared to 13.44 +/- 2.66 months in the control arm (P = 0.006). The median recurrence-free survival in the sorafenib arm did not reach the data cut-off date compared to 8 months in the control arm (P = 0.006). The recurrence rate between the two groups was significantly different (29.4% vs 70.7%, P = 0.032). Cox regression analysis showed that taking study medicine was the only prognostic variable associated with HCC recurrence (hazard ratio = 0.24, 95% confidence interval = 0.08-0.75, P = 0.014). CONCLUSION: This study showed that setting sorafenib as adjuvant therapy for HCC to prevent early recurrence after hepatic resection could be a potential indication. The cumulative recurrence-free survival rate also demonstrated the preventive effectiveness of sorafenib. PMID- 23672311 TI - Identification of antagonists to the vasotocin receptor sub-type 4 (VT4R) involved in stress by molecular modelling and verification using anterior pituitary cells. AB - The vasotocin receptor family is homologous to the mammalian vasopressin G protein coupled receptor (GPCR) family. The vasotocin receptor 2 (VT2R) and 4 (VT4R) have recently been shown to play important role(s) in the neuroendocrine regulation of stress in birds. A homology-based structural model of VT4R of the domestic chicken, Gallus gallus, was built using the sophisticated SYBYL-X suite. The structure of VT4R built with and without extra- and intracellular unstructured loops showed a seven-helix transmembrane domain, which is a characteristic feature of GPCRs. Several agonists and antagonists were screened by molecular docking to map their potential binding sites on the structure of VT4R. Interestingly, the presence of the N-terminal, intracellular and extracellular loops and C-terminal amino acid sequences emerging from the transmembrane domains during molecular docking appeared to influence the binding interface of the peptide agonists and peptide/non-peptide antagonists on the VT4R. The presence of unstructured loops, however, did not affect the relative binding affinity ranking of the peptide antagonists to VT4R. In general, the natural ligand, arginine vasotocin and the peptide/non-peptide antagonists were observed to be more deeply buried in the receptor. Results of in vitro inhibition experiments, using cultured anterior pituitary cells, showed excellent agreement with the binding affinity of the antagonists predicted by molecular docking. The results of this study provide valuable clues for the rational design of novel pharmaceutical compounds capable of blocking or attenuating the stress response. PMID- 23672312 TI - Guidelines and considerations for conducting experiments using tissue microarrays. AB - Tissue microarrays (TMAs) represent a powerful method for undertaking large-scale tissue-based biomarker studies. While TMAs offer several advantages, there are a number of issues specific to their use which need to be considered when employing this method. Given the investment in TMA-based research, guidance on design and execution of experiments will be of benefit and should help researchers new to TMA-based studies to avoid known pitfalls. Furthermore, a consensus on quality standards for TMA-based experiments should improve the robustness and reproducibility of studies, thereby increasing the likelihood of identifying clinically useful biomarkers. In order to address these issues, the National Cancer Research Institute Biomarker and Imaging Clinical Studies Group organized a 1-day TMA workshop held in Nottingham in May 2012. The document herein summarizes the conclusions from the workshop. It includes guidance and considerations on all aspects of TMA-based research, including the pre-analytical stages of experimental design, the analytical stages of data acquisition, and the postanalytical stages of data analysis. A checklist is presented which can be used both for planning a TMA experiment and interpreting the results of such an experiment. For studies of cancer biomarkers, this checklist could be used as a supplement to the REMARK guidelines. PMID- 23672313 TI - Presence of C11orf95-MKL2 fusion is a consistent finding in chondroid lipomas: a study of eight cases. AB - AIMS: Chondroid lipomas are benign adipose tissue tumours. Their rarity and peculiar morphology can lead to misinterpretation, especially in small biopsies. Based on a recurrent translocation t(11;16)(q13;p13), the C11orf95-MKL2 fusion gene has been found in a few cases. Therefore, it seemed appropriate to look for this fusion gene in a larger cohort. METHODS AND RESULTS: We describe eight further cases from four females and four males with an age range of 21-81 years (median 49 years). The tumours were situated in the lower arm (three), lower leg (two), thigh (one), back (one) and head (one); seven lesions were deep-seated and one was located subcutaneously. Sizes ranged from 3 to 12 cm (median 6.3 cm). All patients were treated by simple excision, and follow-up, available for six patients (range 2 months-12 years; median 15 months), demonstrated recurrence in one case. Histologically, the circumscribed and lobulated tumours showed a variable composition of adipocytes, lipoblasts, hibernoma-like cells and chondroblast-like cells embedded in a chondroid matrix. Immunohistochemistry, performed in four cases, revealed positivity for S-100 and pancytokeratin in two of three neoplasms stained for each marker. A C11orf95-MKL2 fusion gene was shown by RT-PCR analysis in seven of the eight cases. CONCLUSIONS: Molecular analysis can be used to support the diagnosis of chondroid lipoma, especially in small samples. This may be helpful in planning treatment when the differential diagnosis includes malignant lesions. PMID- 23672314 TI - Expression of Ep-CAM, but not of E48, associates with nodal involvement in advanced squamous cell carcinomas of the larynx. AB - AIMS: To evaluate epithelial cell adhesion molecule (Ep-CAM) and E48 expression, and their relationship with histological differentiation and nodal metastasis, in laryngeal squamous cell carcinomas (SCC). METHODS AND RESULTS: The expression of Ep-CAM and E48 was investigated using immunohistochemistry in a series of 66 SCC (stages 3 and 4) and their adjacent non-neoplastic epithelia. Ep-CAM expression increased with the progression from normal squamous epithelium to SCC. It was detected in 96% of carcinomas and high levels of Ep-CAM expression (50% or more positive cells) were associated with poorer differentiation (P = 0.003) and the presence of lymph node metastases (P = 0.001). E48 expression was characteristically strong and diffuse in non-neoplastic squamous epithelium, and decreased with progression to SCC. Poorly differentiated (grade 4) tumours had lower proportions of E48-positive cells than well- to moderately- differentiated cases (P < 0.001). CONCLUSIONS: Expression of both Ep-CAM and E48 correlated with cell differentiation, although in inverse fashion. In particular, the association between high levels of Ep-CAM expression and high frequency of nodal metastases suggests that Ep-CAM plays a role in the development of lymph node metastases in SCC of the larynx. PMID- 23672315 TI - Synthesis and cytotoxicity studies of novel triazolo-benzoxazepine as new anticancer agents. AB - Cancer continues to be one of the biggest threats to the human civilization because there is no cure of it. Small heterocyclic molecule with low molecular weight and novel structural feature is therapeutically highly demanding. These molecules have the capability to disrupt signaling pathways leading to anticancer activities. Therefore, the search for new anticancer agents continues to draw attention to the research community. In this study, a small triazolo benzoxazepine scaffolds was synthesized using a one-pot four-step synthetic methodology involving click reaction. Small libraries of 12 compounds were successfully synthesized and screened them against different cancer cell lines. Low micromolar anticancer activity was recorded using MTT assay, and further confirmation of cell death was obtained by phase contrast, fluorescent, and confocal images. PMID- 23672316 TI - Lattice-matched transition metal disulfide intergrowths: the metallic conductors Ag2Te(MS2)3 (M = V, Nb). AB - We present new chalcogenide compounds, Ag2Te(MS2)3 (M = V, Nb), built up of alternating planes of [MS2] and [Ag2Te]. The Ag and Te atoms are linearly coordinated by S atoms in the [MS2] layers and held in place by covalent interactions. Structural polymorphism was found by single crystal X-ray diffraction studies, where long-range ordering or disorder of the Ag and Te atoms within the hexagonal planar [Ag2Te] layer yielded two distinct crystal forms. When the Ag and Te atoms are ordered, the two isostructural compounds crystallize in the non-centrosymmetric P62m space group, with a = 5.5347(8) A, c = 8.0248(16) A, and V = 212.89(6) A(3) for alpha-Ag2Te(VS2)3 and a = 5.7195(8) A, c = 8.2230(16) A, and V = 232.96(6) A(3) for alpha-Ag2Te(NbS2)3. For the occupationally disordered Ag/Te arrangement, a subcell of the ordered phase that crystallizes in the non-centrosymmetric P6m2 space group, with a = 3.2956(6) A (=a(a)/(3)(1/2)), c = 8.220(2) A, and V = 77.31(3) A(3) for beta-Ag2Te(VS2)3, was identified. Furthermore, pair distribution function analysis revealed local distortions in the [Ag2Te] layer. Band structure calculations at the density functional theory level were carried out to investigate the electronic structure of Ag2Te(MS2)3. Electronic transport measurements on Ag2Te(MS2)3 show that they exhibit p-type metallic behavior. Thermal analyses and temperature-dependent powder X-ray diffraction studies were focused on the stability and transformation/decomposition of the Ag2Te(MS2)3 phases. Magnetic susceptibility data are also reported. The new intercalated Ag2Te(MS2)3 system features a unique hypervalent Te with a three-center, four-electron bonding environment isoelectronic to that found in I3(-). PMID- 23672317 TI - Spermidine promotes adipogenesis of 3T3-L1 cells by preventing interaction of ANP32 with HuR and PP2A. AB - We have shown previously that the polyamine spermidine is indispensable for differentiation of 3T3-L1 preadipocytes. In the present study, we examined the mechanism of spermidine function by using the polyamine biosynthesis inhibitor alpha-difluoromethylornithine in combination with the metabolically stable polyamine analogues gamma-methylspermidine or (R,R)-alpha,omega bismethylspermine. At the early phase of differentiation, spermidine-depleted 3T3 L1 cells showed decreased translation of the transcription factor C/EBPbeta (CCAAT/enhancer-binding protein beta), decreased PP2A (protein phosphatase 2A) activity and increased cytoplasmic localization of the RNA-binding protein HuR (human antigen R). The amount of HuR bound to C/EBPbeta mRNA was reduced, whereas the amount of bound CUGBP2, an inhibitor of C/EBPbeta translation, was increased. ANP32 (acidic nuclear phosphoprotein 32) proteins, which are known PP2A inhibitors and HuR ligands, bound more PP2A and HuR in spermidine-depleted than in control cells, whereas immunodepletion of ANP32 proteins from the lysate of spermidine-depleted cells restored PP2A activity. Taken together, our data shows that spermidine promotes C/EBPbeta translation in differentiating 3T3-L1 cells, and that this process is controlled by the interaction of ANP32 with HuR and PP2A. PMID- 23672318 TI - Comparison of percutaneous nephrolithotomy under spinal versus general anesthesia: a randomized clinical trial. AB - PURPOSE: To evaluate the safety and efficacy of spinal anesthesia compared with general anesthesia in patients who underwent percutaneous nephrolithotomy (PCNL). PATIENTS AND METHODS: One hundred patients with American Society of Anesthesiologists (ASA) score <3 were randomly divided into two groups according to the type of anesthesia. Spinal anesthesia was performed using an injection of 0.25 mg/kg bupivacaine 0.5% in the intrathecal space; no opium (fentanyl) agent was used. All procedures were performed with the patient in the prone position. Stone access was made by using fluoroscopic guidance, and the tract was dilated using a single-stage technique. All patients received a solution including 1 mg/kg morphine in every 100 mL physiologic saline through the volumetric pump during the 3-hour post-PCNL period in the recovery room. Afterward, morphine (0.05 mg/kg) was injected only according to the verbal rating scale greater than 3 after discharge from the recovery room until 24 hours after surgery. RESULTS: The two groups were matched by mean age, distribution of stone location, and stone burden. Mean operative time, hospital stay, stone-free rate and mean hemoglobin drop were comparable between the two groups. The rate of complications according to the Clavien grading system was nearly similar in both groups. Mean analgesic requirement during 24 hours after PCNL was 6.8 mg in the spinal group and 13.2 mg in the general group (P<0.001). CONCLUSION: It seems that using spinal anesthesia by intrathecal injection of local anesthetic solutions vs general anesthesia has comparable surgical outcomes and reduces the requirement for analgesia after PCNL in the early postoperative period. PMID- 23672319 TI - Focusing the direction of our profession: athletic trainers in America's health care system. PMID- 23672320 TI - Distal biceps tendon repair: an analysis of timing of surgery on outcomes. AB - CONTEXT: Surgical repair of the ruptured distal biceps brachaii tendon is an effective treatment in injured patients. Timing of surgery is considered an important factor when managing these patients. OBJECTIVE: To compare our outcomes after distal biceps tendon acute (at 4 weeks or less) or chronic (greater than 4 weeks) repair. DESIGN: Cohort study. SETTING: Clinical practice. PATIENTS OR OTHER PARTICIPANTS: Of 18 patients in a tertiary practice who underwent distal biceps repair, 12 and 6 underwent acute or chronic repair, respectively. The average durations from injury to surgery were 15.3 (range, 9 to 25) and 50.1 (range, 29 to 75) days for the acute and chronic groups, respectively. INTERVENTION(S): Distal biceps tendon repair. MAIN OUTCOME MEASURE(S): Disabilities of the Arm, Shoulder and Hand (DASH) scoring, range of motion, and clinical and radiographic complications. RESULTS: No differences were noted between the groups in DASH scoring or range of motion. No complications occurred, and radiographic outcomes were satisfactory, without evidence of heterotopic ossification in any patients. CONCLUSIONS: Secure repair of a distal biceps tendon injury may yield similar results, whether it is performed in the acute or chronic setting. PMID- 23672321 TI - Scapular bracing and alteration of posture and muscle activity in overhead athletes with poor posture. AB - CONTEXT: Overhead athletes commonly have poor posture. Commercial braces are used to improve posture and function, but few researchers have examined the effects of shoulder or scapular bracing on posture and scapular muscle activity. OBJECTIVE: To examine whether a scapular stabilization brace acutely alters posture and scapular muscle activity in healthy overhead athletes with forward-head, rounded shoulder posture (FHRSP). DESIGN: Randomized controlled clinical trial. SETTING: Applied biomechanics laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirty-eight healthy overhead athletes with FHRSP. INTERVENTION(S): Participants were assigned randomly to 2 groups: compression shirt with no strap tension (S) and compression shirt with the straps fully tensioned (S + T). Posture was measured using lateral view photography with retroreflective markers. Electromyography (EMG) of the upper trapezius (UT), middle trapezius (MT), lower trapezius (LT), and serratus anterior (SA) in the dominant upper extremity was measured during 4 exercises (scapular punches, W's, Y's, T's) and 2 glenohumeral motions (forward flexion, shoulder extension). Posture and exercise EMG measurements were taken with and without the brace applied. MAIN OUTCOME MEASURE(S): Head and shoulder angles were measured from lateral-view digital photographs. Normalized surface EMG was used to assess mean muscle activation of the UT, MT, LT, and SA. RESULTS: Application of the brace decreased forward shoulder angle in the S + T condition. Brace application also caused a small increase in LT EMG during forward flexion and Y's and a small decrease in UT and MT EMG during shoulder extension. Brace application in the S + T group decreased UT EMG during W's, whereas UT EMG increased during W's in the S group. CONCLUSIONS: Application of the scapular brace improved shoulder posture and scapular muscle activity, but EMG changes were highly variable. Use of a scapular brace might improve shoulder posture and muscle activity in overhead athletes with poor posture. PMID- 23672322 TI - Anterior glenohumeral laxity and stiffness after a shoulder-strengthening program in collegiate cheerleaders. AB - CONTEXT: Approximately 62% of all cheerleaders sustain some type of orthopaedic injury during their cheerleading careers. Furthermore, the occurrence of such injuries has led to inquiry regarding optimal prevention techniques. One possible cause of these injuries may be related to inadequate conditioning in cheerleaders. OBJECTIVE: To determine whether a strength and conditioning program produces quantifiable improvements in anterior glenohumeral (GH) laxity and stiffness. DESIGN: Descriptive laboratory study. SETTING: University laboratory. PATIENTS OR OTHER PARTICIPANTS: A sample of 41 collegiate cheerleaders (24 experimental and 17 control participants) volunteered. No participants had a recent history (in the past 6 months) of upper extremity injury or any history of upper extremity surgery. INTERVENTION(S): The experimental group completed a 6 week strength and conditioning program between the pretest and posttest measurements; the control group did not perform any strength training between tests. MAIN OUTCOME MEASURE(S): We measured anterior GH laxity and stiffness with an instrumented arthrometer. We conducted a group * time analysis of variance with repeated measures on time (P < .05) to determine differences between groups. RESULTS: A significant interaction was demonstrated, with the control group having more anterior GH laxity at the posttest session than the strengthening group (P = .03, partial eta2 = 0.11). However, no main effect for time (P = .92) or group (P = .97) was observed. In another significant interaction, the control group had less anterior GH stiffness at the posttest session than the strengthening group (P = .03, partial eta2 = 0.12). Main effects for time (P = .02) and group (P = .004) were also significant. CONCLUSIONS: Cheerleaders who participate in a shoulder-strengthening program developed less anterior GH laxity and more stiffness than cheerleaders in the control group. PMID- 23672323 TI - Knee proprioception and strength and landing kinematics during a single-leg stop jump task. AB - CONTEXT: The importance of the sensorimotor system in maintaining a stable knee joint has been recognized. As individual entities, knee-joint proprioception, landing kinematics, and knee muscles play important roles in functional joint stability. Preventing knee injuries during dynamic tasks requires accurate proprioceptive information and adequate muscular strength. Few investigators have evaluated the relationship between knee proprioception and strength and landing kinematics. OBJECTIVE: To examine the relationship between knee proprioception and strength and landing kinematics. DESIGN: Cross-sectional study. SETTING: University research laboratory. PATIENTS OR OTHER PARTICIPANTS: Fifty physically active men (age = 26.4 +/- 5.8 years, height = 176.5 +/- 8.0 cm, mass = 79.8 +/- 16.6 kg). INTERVENTION(S): Three tests were performed. Knee conscious proprioception was evaluated via threshold to detect passive motion (TTDPM). Knee strength was evaluated with a dynamometer. A 3-dimensional biomechanical analysis of a single-legged stop-jump task was used to calculate initial contact (IC) knee flexion angle and knee-flexion excursion. MAIN OUTCOME MEASURE(S): The TTDPM toward knee flexion and extension, peak knee flexion and extension torque, and IC knee-flexion angle and knee flexion excursion. Linear correlation and stepwise multiple linear regression analyses were used to evaluate the relationships of both proprioception and strength against landing kinematics. The alpha level was set a priori at .05. RESULTS: Enhanced TTDPM and greater knee strength were positively correlated with greater IC knee-flexion angle (r range = 0.281-0.479, P range = .001-.048). The regression analysis revealed that 27.4% of the variance in IC knee-flexion angle could be accounted for by knee-flexion peak torque and TTDPM toward flexion (P = .001). CONCLUSIONS: The current research highlighted the relationship between knee proprioception and strength and landing kinematics. Individuals with enhanced proprioception and muscular strength had better control of IC knee-flexion angle during a dynamic task. PMID- 23672324 TI - Anterior knee stiffness changes in laxity "responders" versus "nonresponders" across the menstrual cycle. AB - CONTEXT: Although changes in anterior knee laxity (AKL) across the menstrual cycle have been reported, the effects of cyclic knee laxity changes on the underlying characteristics of the load-displacement (stiffness) curve generated during anterior loading of the tibia relative to the femur are relatively unknown. OBJECTIVE: To describe the anterior load-displacement curve during anterior loading of the tibia relative to the femur using incremental stiffnesses and to compare underlying stiffness measures between days of the cycle when AKL is at its minimum and maximum. DESIGN: Descriptive laboratory study. SETTING: University laboratory. PATIENTS OR OTHER PARTICIPANTS: Fifty-seven recreationally active women. MAIN OUTCOME MEASURE(S): Anterior knee laxity and 6 incremental stiffness measures (N/mm) were obtained with an instrumented knee arthrometer on days 1-6 of menses and days 0-8 postovulation during 2 consecutive menstrual cycles. Participants were then classified in tertiles based on the maximum change (difference between maximum and minimum) in AKL, and incremental stiffness was compared on days of minimum versus maximum laxity between the lowest (<1.24 mm cyclic laxity change = laxity "nonresponders" [n = 19]) and highest (>1.75 mm cyclic laxity change = laxity "responders" [n = 19]) tertiles. RESULTS: All participants displayed decreasing stiffness initially (0-20 N > 20-40 N and 40-60 N), followed by incrementally increasing stiffness (40-60 N < 60-80 N < 80-100 N < 100-130 N) (P <= .05). Responders demonstrated decreased stiffness between the days of minimum and maximum AKL at the 10-130-N increment versus the 0-20-N and 20-40-N increments (P <= .05); nonresponders had no change in stiffness. CONCLUSIONS: Participants who experienced larger magnitudes of cyclic changes in AKL also experienced decreases in terminal (100-130 N) stiffness during anterior knee joint loading. Decreases in incremental stiffness at higher anterior directed loads may adversely affect passive restraint systems, resulting in altered arthrokinematics during functional activity. PMID- 23672325 TI - Lacrosse helmet facemask removal. AB - CONTEXT: Facemask removal (FMR) is required to access the airway of a catastrophically injured football or ice hockey athlete. However, the best method of caring for the helmeted lacrosse athlete with suspected catastrophic injury remains unclear. OBJECTIVE: To evaluate the effects of sex and grip strength on the speed and ease of use of various FMR methods across different lacrosse helmet types. DESIGN: Cross-sectional study. Setting : Athletic training laboratory. PATIENTS OR OTHER PARTICIPANTS: Fourteen athletic trainers (7 men, 7 women). INTERVENTION(S): Removal method (cordless screwdriver [CSD], Face Mask Extractor 2 [FMX], pruner, Trainer's Angel [TA]), helmet type (Cascade CPX, Cascade Pro7, Riddell Revolution, Brine Triumph, Warrior Venom), and sex. MAIN OUTCOME MEASURE(S): Facemask removal time and participant-reported ease of use of the removal method (6-point Likert scale). RESULTS: We found a 2-way interaction for removal method and sex only for the ease-of-use scores (F3,246 = 4.67, P = .01). A main effect for removal method for time (F3,200 = 19.41, P < .001) and ease of use (F3,200 = 53.78, P < .001) was seen. The fastest times (32.32 +/- 11.70 seconds) and highest ease-of-use scores (4.94 +/- 0.30) were recorded for the CSD. We noted a main effect for helmet type only for time (F4,200 = 5.34, P < .001), with the fastest removal times (72.75 +/- 74.67 seconds) recorded for the CPX. We discovered a main effect for sex only for time (F1,200 = 17.57, P < .001), with slower times recorded for women (115.51 +/- 110.80 seconds) than men (75.71 +/- 83.87 seconds). We found correlations between FMR time and grip strength only when using the FMX (r = -0.40, P = .001), pruner (r = -0.26, P = .04), and TA (r = -0.26, P = .047). CONCLUSIONS: Based on our results, FMR of lacrosse helmets should be attempted with a CSD. We recommend carrying a pruner as a backup cutting tool in case the CSD fails, practicing FMR regularly, and inspecting helmets for faulty hardware to reduce the chance of CSD failure. PMID- 23672326 TI - Does phototherapy enhance skeletal muscle contractile function and postexercise recovery? A systematic review. AB - CONTEXT: Recently, researchers have shown that phototherapy administered to skeletal muscle immediately before resistance exercise can enhance contractile function, prevent exercise-induced cell damage, and improve postexercise recovery of strength and function. OBJECTIVE: To critically evaluate original research addressing the ability of phototherapeutic devices, such as lasers and light emitting diodes (LEDs), to enhance skeletal muscle contractile function, reduce exercise-induced muscle fatigue, and facilitate postexercise recovery. DATA SOURCES: We searched the electronic databases PubMed, SPORTDiscus, Web of Science, Scopus, and Rehabilitation & Physical Medicine without date limitations for the following key words: laser therapy, phototherapy, fatigue, exercise, circulation, microcirculation, and photobiomodulation. STUDY SELECTION: Eligible studies had to be original research published in English as full papers, involve human participants, and receive a minimum score of 7 out of 10 on the Physiotherapy Evidence Database (PEDro) scale. DATA EXTRACTION: Data of interest included elapsed time to fatigue, total number of repetitions to fatigue, total work performed, maximal voluntary isometric contraction (strength), electromyographic activity, and postexercise biomarker levels. We recorded the PEDro scores, beam characteristics, and treatment variables and calculated the therapeutic outcomes and effect sizes for the data sets. DATA SYNTHESIS: In total, 12 randomized controlled trials met the inclusion criteria. However, we excluded data from 2 studies, leaving 32 data sets from 10 studies. Twenty-four of the 32 data sets contained differences between active phototherapy and sham (placebo-control) treatment conditions for the various outcome measures. Exposing skeletal muscle to single-diode and multidiode laser or multidiode LED therapy was shown to positively affect physical performance by delaying the onset of fatigue, reducing the fatigue response, improving postexercise recovery, and protecting cells from exercise-induced damage. CONCLUSIONS: Phototherapy administered before resistance exercise consistently has been found to provide ergogenic and prophylactic benefits to skeletal muscle. PMID- 23672327 TI - Clinical integration and how it affects student retention in undergraduate athletic training programs. AB - CONTEXT: A better understanding of why students leave an undergraduate athletic training education program (ATEP), as well as why they persist, is critical in determining the future membership of our profession. OBJECTIVE: To better understand how clinical experiences affect student retention in undergraduate ATEPs. DESIGN: Survey-based research using a quantitative and qualitative mixed methods approach. SETTING: Three-year undergraduate ATEPs across District 4 of the National Athletic Trainers' Association. PATIENTS OR OTHER PARTICIPANTS: Seventy-one persistent students and 23 students who left the ATEP prematurely. DATA COLLECTION AND ANALYSIS: Data were collected using a modified version of the Athletic Training Education Program Student Retention Questionnaire. Multivariate analysis of variance was performed on the quantitative data, followed by a univariate analysis of variance on any significant findings. The qualitative data were analyzed through inductive content analysis. RESULTS: A difference was identified between the persister and dropout groups (Pillai trace = 0.42, F(1,92) = 12.95, P = .01). The follow-up analysis of variance revealed that the persister and dropout groups differed on the anticipatory factors (F(1,92) = 4.29, P = .04), clinical integration (F(1,92) = 6.99, P = .01), and motivation (F(1,92) = 43.12, P = .01) scales. Several themes emerged in the qualitative data, including networks of support, authentic experiential learning, role identity, time commitment, and major or career change. CONCLUSIONS: A perceived difference exists in how athletic training students are integrated into their clinical experiences between those students who leave an ATEP and those who stay. Educators may improve retention by emphasizing authentic experiential learning opportunities rather than hours worked, by allowing students to take on more responsibility, and by facilitating networks of support within clinical education experiences. PMID- 23672328 TI - Frustrations among graduates of athletic training education programs. AB - CONTEXT: Although previous researchers have begun to identify sources of athletic training student stress, the specific reasons for student frustrations are not yet fully understood. It is important for athletic training administrators to understand sources of student frustration to provide a supportive learning environment. OBJECTIVE: To determine the factors that lead to feelings of frustration while completing a professional athletic training education program (ATEP). DESIGN: Qualitative study. SETTING: National Athletic Trainers' Association (NATA) accredited postprofessional education program. PATIENTS OR OTHER PARTICIPANTS: Fourteen successful graduates (12 women, 2 men) of accredited professional undergraduate ATEPs enrolled in an NATA-accredited postprofessional education program. DATA COLLECTION AND ANALYSIS: We conducted semistructured interviews and analyzed data with a grounded theory approach using open, axial, and selective coding procedures. We negotiated over the coding scheme and performed peer debriefings and member checks to ensure trustworthiness of the results. RESULTS: Four themes emerged from the data: (1) Athletic training student frustrations appear to stem from the amount of stress involved in completing an ATEP, leading to anxiety and feelings of being overwhelmed. (2) The interactions students have with classmates, faculty, and preceptors can also be a source of frustration for athletic training students. (3) Monotonous clinical experiences often left students feeling disengaged. (4) Students questioned entering the athletic training profession because of the fear of work-life balance problems and low compensation. CONCLUSIONS: In order to reduce frustration, athletic training education programs should validate students' decisions to pursue athletic training and validate their contributions to the ATEP; provide clinical education experiences with graded autonomy; encourage positive personal interactions between students, faculty, and preceptors; and successfully model the benefits of a career in athletic training. PMID- 23672329 TI - Perceived skills and abilities required by athletic trainers in hospital and clinical management positions: a Delphi study. AB - CONTEXT: Athletic training has expanded from traditional sport-team settings to varied settings involving active populations. Athletic trainers also use their education and abilities in administration to take on roles of management in hospitals and health care clinics. OBJECTIVE: To begin to explore the knowledge, skills, and abilities needed in the emerging practice setting of health care management. DESIGN: Delphi study. SETTING: Directed surveys. PATIENTS OR OTHER PARTICIPANTS: Eight athletic trainers working as hospital and health care clinic managers in varied geographic settings. DATA COLLECTION AND ANALYSIS: Three rounds of directed surveys were used and included (1) a series of demographic questions and 1 focused, open-ended question, (2) 32 statements scored on a 6 point Likert-type scale with no neutral statement, and (3) 10 statements ranked in order of importance for the athletic trainer working as a health care manager. RESULTS: I grouped the results into 2 categories: leadership skills and management tools. CONCLUSIONS: According to participants, effective health care managers need a strong understanding of business and management tools along with more interpersonal skills in communication and leadership. The results are consistent with the literature and may be applied in athletic training education programs and by athletic trainers seeking health care management positions. PMID- 23672330 TI - Injured athletes' rehabilitation beliefs and subjective well-being: the contribution of hope and social support. AB - CONTEXT: Injuries are a significant problem in the world of sports. Hope and social support are very important features in providing psychological help as people face life challenges such as sport injuries. OBJECTIVE: To examine how hope and social support uniquely and jointly predict postinjury rehabilitation beliefs, rehabilitation behavior, and subjective well-being. DESIGN: Cross sectional study. SETTING: Four sports-injury rehabilitation centers of local universities in Taiwan. PARTICIPANTS: A total of 224 injured Taiwanese collegiate student-athletes. MAIN OUTCOMES MEASURE(S): The Trait Hope Scale, the Sports Injury Rehabilitation Beliefs Survey, the Satisfaction with Life Scale, the Positive Affective and Negative Affective Scale, and the Multidimensional Scale of Perceived Social Support were completed by participants after they received their regular rehabilitation treatment. RESULTS: We conducted hierarchical regressions and found that social support and 2 types of hope in injured athletes predicted their rehabilitation beliefs and subjective well-being. However, only hope agency predicted their rehabilitation behavior. Also, hope and social support had an interactive effect on the prediction of subjective well-being; for participants with low hope pathways, the perception of more social support was associated with higher levels of subjective well-being, whereas social support had only a relatively low association with subjective well-being among participants with high hope pathways. CONCLUSIONS: Enhancing hope perceptions and strengthening injured athletes' social support during rehabilitation are beneficial to rehabilitation behavior and subjective well-being. PMID- 23672331 TI - Practices of weight regulation among elite athletes in combat sports: a matter of mental advantage? AB - CONTEXT: The combination of extensive weight loss and inadequate nutritional strategies used to lose weight rapidly for competition in weight-category sports may negatively affect athletic performance and health. OBJECTIVE: To explore the reasoning of elite combat-sport athletes about rapid weight loss and regaining of weight before competitions. DESIGN: Qualitative study. SETTING: With grounded theory as a theoretical framework, we employed a cross-examinational approach including interviews, observations, and Internet sources. Sports observations were obtained at competitions and statements by combat-sport athletes were collected on the Internet. PATIENTS OR OTHER PARTICIPANTS: Participants in the interviews were 14 Swedish national team athletes (9 men, 5 women; age range, 18 to 36 years) in 3 Olympic combat sports (wrestling, judo, and taekwondo). DATA COLLECTION AND ANALYSIS: Semistructured interviews with 14 athletes from the Swedish national teams in wrestling, judo, and taekwondo were conducted at a location of each participant's choice. The field observations were conducted at European competitions in these 3 sports. In addition, interviews and statements made by athletes in combat sports were collected on the Internet. RESULTS: Positive aspects of weight regulation other than gaining physical advantage emerged from the data during the analysis: sport identity, mental diversion, and mental advantage. Together and individually, these categories point toward the positive aspects of weight regulation experienced by the athletes. Practicing weight regulation mediates a self-image of being "a real athlete." Weight regulation is also considered mentally important as a part of the precompetition preparation, serving as a coping strategy by creating a feeling of increased focus and commitment. Moreover, a mental advantage relative to one's opponents can be gained through the practice of weight regulation. CONCLUSIONS: Weight regulation has mentally important functions extending beyond the common notion that combat-sport athletes reduce their weight merely to gain a physical edge over their opponents. PMID- 23672332 TI - Rapid weight loss and the body fluid balance and hemoglobin mass of elite amateur boxers. AB - CONTEXT: Dehydration is assumed to be a major adverse effect associated with rapid loss of body mass for competing in a lower weight class in combat sports. However, the effects of such weight cutting on body fluid balance in a real-life setting are unknown. OBJECTIVE: To examine the effects of 5% or greater loss of body mass within a few days before competition on body water, blood volume, and plasma volume in elite amateur boxers. DESIGN: Case-control study. SETTING: Sports medicine laboratory. PATIENTS OR OTHER PARTICIPANTS: Seventeen male boxers (age = 19.2 +/- 2.9 years, height = 175.1 +/- 7.0 cm, mass = 65.6 +/- 9.2 kg) were assigned to the weight-loss group (WLG; n = 10) or the control group (CON; n = 7). INTERVENTION(S): The WLG reduced body mass by restricting fluid and food and inducing excessive sweat loss by adhering to individual methods. The CON participated in their usual precompetition training. MAIN OUTCOME MEASURE(S): During an ordinary training period (t-1), 2 days before competition (t-2), and 1 week after competition (t-3), we performed bioelectrical impedance measurements; calculated total body water, intracellular water, and extracellular water; and estimated total hemoglobin mass (tHbmass), blood volume, and plasma volume by the CO-rebreathing method. RESULTS: In the WLG, the loss of body mass (5.6% +/- 1.7%) led to decreases in total body water (6.0% +/- 0.9%), extracellular water (12.4% +/- 7.6%), tHbmass (5.3% +/- 3.8%), blood volume (7.6% +/- 2.1%; P < .001), and plasma volume (8.6% +/- 3.9%). The intracellular water did not change (P > .05). At t-3, total body water, extracellular water, and plasma volume had returned to near baseline values, but tHbmass and blood volume still were less than baseline values (P < .05). In CON, we found no changes (P > .05). CONCLUSIONS: In a real life setting, the loss of approximately 6% body mass within 5 days induced hypohydration, which became evident by the decreases in body water and plasma volume. The reduction in tHbmass was a surprising observation that needs further investigation. PMID- 23672333 TI - Injuries in female dancers aged 8 to 16 years. AB - CONTEXT: Most studies of injured dancers have been carried out on professional adult dancers; data on young, nonprofessional injured dancers are sparse. OBJECTIVE: To identify the types of injuries sustained by recreational dancers and to examine their association with age, joint range of motion, body structure, age at menarche, presence of anatomic anomalies, and physical burden (i.e., practice hours en pointe). DESIGN: Descriptive epidemiology study. SETTING: The Israel Performing Arts Medicine Center, Tel Aviv. PATIENTS OR OTHER PARTICIPANTS: A total of 569 injured female dancers, aged 8 to 16 years. MAIN OUTCOME MEASURE(S): Dependent variables were 61 types of current injuries that were later classified into 4 major categories: knee injuries, foot and ankle tendinopathy, back injuries, and other injuries. Independent variables were age, joint range of motion, body size and shape, age at menarche, anatomic anomalies, and dance discipline (e.g., hours of practice per week en pointe). RESULTS: At least 1 previous injury had been sustained by 42.4% of the dancers. The most common injuries involved the knee (40.4%), followed by other injuries (23.4%). The relative frequency of back injuries and tendinopathy decreased with age, whereas knee injuries increased. Types of injuries were significantly associated with ankle plantar flexion, hip external rotation, hip abduction, and knee flexion. Multinomial regression analysis revealed only 3 predictive variables (with other as baseline), all for back injury: scoliosis, age, and hip external rotation. CONCLUSIONS: Joint range of motion and scoliosis may signal the potential for future injury. Young dancers (less than 10 years of age) should not be exposed to overload (especially of the back) or extensive stretching exercises. PMID- 23672334 TI - National Athletic Trainers' Association position statement: evaluation of dietary supplements for performance nutrition. AB - OBJECTIVES: To help athletic trainers promote a "food-first" philosophy to support health and performance, understand federal and sport governing body rules and regulations regarding dietary supplements and banned substances, and become familiar with reliable resources for evaluating the safety, purity, and efficacy of dietary supplements. BACKGROUND: The dietary supplement industry is poorly regulated and takes in billions of dollars per year. Uneducated athletes need to gain a better understanding of the safety, eligibility, and efficacy concerns associated with choosing to take dietary supplements. The athletic trainer is a valuable athletic team member who can help in the educational process. In many cases, athletic trainers are asked to help evaluate the legality, safety, and efficacy of dietary supplements. For this position statement, our mission is to provide the athletic trainer with the necessary resources for these tasks. RECOMMENDATIONS: Proper nutrition and changes in the athlete's habitual diet should be considered first when improved performance is the goal. Athletes need to understand the level of regulation (or lack thereof) governing the dietary supplement industry at the international, federal, state, and individual sport participation levels. Athletes should not assume a product is safe simply because it is marketed over the counter. All products athletes are considering using should be evaluated for purity (ie, truth in labeling), safety, and efficacy. PMID- 23672335 TI - Determination of ambient ethanol concentrations in aqueous environmental matrixes by two independent analyses. AB - A new method for the determination of ethanol in aqueous environmental matrixes at nanomolar concentrations is presented and compared to an existing method that has been optimized for low-level alcohol determinations. The new analysis is based upon oxidation of ethanol by the enzyme alcohol oxidase obtained from the yeast Hansenula sp. which quantitatively produces acetaldehyde after reaction for 120 min at 40 degrees C and pH 9.0. The acetaldehyde reacts with 2,4 dinitrophenylhydrazine forming a hydrazone that is separated from interfering substances and quantified by high-performance liquid chromatography (HPLC) with UV detection at 370 nm. Comparison of initial acetaldehyde concentration with that after enzymatic oxidation yields the ethanol concentration with a corresponding detection limit of 10 nM. Analytical results were verified by intercomparison with a completely independent technique utilizing a solid-phase microextraction (SPME) Carboxen/PDMS SPME fiber. A 12 mL aqueous phase sample was heated at 50 degrees C for 10 min prior to loading onto the SPME fiber. Extraction of ethanol was performed by introducing the fiber into the headspace above a pH 4.4 buffered sample containing 30% NaCl for 20 min. Samples were agitated during heating and extraction by magnetic stirring at a rate of 750 rpm. The fiber was thermally desorbed for 1 min at 230 degrees C in the injection port of a gas chromatograph equipped with a flame ionization detector (FID) set at 250 degrees C. The resulting ethanol detection limit is 19 nM. Results of an intercomparison study between the enzymatic and SPME analyses produced a trend line with a slope of unity demonstrating that methods produced statistically equivalent ethanol concentrations in several natural waters including rainwater, fresh surface waters, and sediment pore waters. PMID- 23672336 TI - Psychometric properties of the Norwegian version of the Childhood Trauma Questionnaire in high-risk groups. AB - The Childhood Trauma Questionnaire--Short Form (CTQ-SF) is widely used to measure childhood abuse of all types. In the present study, we examined the psychometric properties of the Norwegian version of the instrument. The participants constituted four subsamples (n = 517): substance abusers (n = 126), psychiatric patients (n = 210), prisoners (n = 109) and adolescents in out-of-home placements (n = 72). Confirmatory factor analysis revealed a reasonable fit of the data to the original five-factor structure of the CTQ-SF. Measurement invariance was found across gender and the four subsamples. It was concluded that the Norwegian version of the CTQ-SF has acceptable psychometric properties, with good reliability and satisfactory accuracy, to assess different dimensions of childhood trauma. PMID- 23672337 TI - Analysis of the SERS spectrum by theoretical methodology: evaluating a classical dipole model and the detuning of the excitation frequency. AB - Surface-enhanced Raman scattering (SERS) spectroscopy is gaining prominence as one of the most powerful ultradetection techniques. The SERS outcome is essentially a complicated pattern of vibrational bands that allows multiplex analysis but, at the same time, makes difficult the interpretation of unknown analytes or known substances in the presence of complex unknown chemical environments. Herein, we show two computational methods to reproduce the spectral shape of the SERS spectra. The first, based in the modification of the classical dipole model, reproduces with a notable similarity the experimental spectrum excited far to the red of the localized surface plasmon resonance (LSPR). This light and time-efficient model is of great interest to elucidate the orientation of the target on the plasmonic surface or even to accurately identify suspected unknown targets in real samples. However, the experimental SERS spectrum in resonance with the LSPR is also modeled by using a more classical CPHF approach. This method provides also good agreement with the experiment but at the expense of much more computational time. PMID- 23672338 TI - Dominant heterosexual sexual scripts in emerging adulthood: conceptualization and measurement. AB - Sexual script research (Simon & Gagnon 1969 , 1986 ) bourgeoned following Simon and Gagnon's groundbreaking work. Empirical measurement of sexual script adherence has been limited, however, as no measures exist that have undergone rigorous development and validation. We conducted three studies to examine current dominant sexual scripts of heterosexual adults and to develop a measure of endorsement of these scripts. In Study 1, we conducted three focus groups of men ( n = 19) and four of women ( n = 20) to discuss the current scripts governing sexual behavior. Results supported scripts for sex drive, physical and emotional sex, sexual performance, initiation and gatekeeping, and evaluation of sexual others. In Study 2, we used these qualitative findings to develop a measure of script endorsement, the Sexual Script Scale. Factor analysis of data from 721 participants revealed six interrelated factors demonstrating initial construct validity. In Study 3, confirmatory factor analysis of a separate sample of 289 participants supported the model from Study 2, and evidence of factorial invariance and test-retest reliability was obtained. This article presents the results of these studies, documenting the process of scale development from formative research through to confirmatory testing, and suggests future directions for the continued development of sexual scripting theory. PMID- 23672339 TI - The course of radiographic loosening, pain and functional outcome around the first revision of a total hip arthroplasty. AB - BACKGROUND: The published data on pain and physical function before and after revision of total hip arthroplasty (THA) is scarce. The study reports the course and interrelationships of radiographic loosening, pain and physical function 5 year before and after a first revision THA. METHODS: The study was based on the IDES-THA database. All patients with their first THA revision for aseptic loosening and a documented index surgery on the same side and at least one pre revision and one post-revision follow-up were selected. Only patients with an intact contralateral hip joint (Charnley class-A) were included. Follow-ups within +/-5.5 years around the revision time point were analyzed. Annual prevalences of radiographic component loosening and the non-desired outcomes (moderate/severe/intolerable pain, walking <30 minutes, hip flexion range <90 degrees ) were calculated. RESULTS: Signs of radiographic component loosening started to increase about 4 years before revision surgery. Two years later, a sharp increase of painful hips from 15% to 80% in the revision year was observed. In the year after revision surgery, this rate dropped back to below 10%. Walking capacity started to noticeably deteriorate 3 years before revision and in the revision year about 65% of patients could not walk longer than 30 minutes. As opposed to pain, walking capacity did not recover to pre-revision levels and the best outcome was only reached two years post-revision. Hip flexion range had the slowest and least extent of deterioration (~45% flexed <70 degrees in the revision year) but with the best outcomes at only three years after revision surgery it took the longest to recover. CONCLUSION: Prevalence of radiological loosening signs and/or pain intensity follow an almost parallel course around the first revision of a THA for aseptic component loosening. This process begins about 4 years (radiographic loosening) before the actual revision surgery and intensifies about 2 years later (pain). It also involves walking capacity and hip range of motion. While pain levels go back to levels similar to those after primary surgery, range of motion and even more walking capacity remain moderately compromised. PMID- 23672341 TI - Towards a molecular taxonomy for protists: benefits, risks, and applications in plankton ecology. AB - The increasing use of genetic information for the development of methods to study the diversity, distributions, and activities of protists in nature has spawned a new generation of powerful tools. For ecologists, one lure of these approaches lies in the potential for DNA sequences to provide the only immediately obvious means of normalizing the diverse criteria that presently exist for identifying and counting protists. A single, molecular taxonomy would allow studies of diversity across a broad range of species, as well as the detection and quantification of particular species of interest within complex, natural assemblages; goals that are not feasible using traditional methods. However, these advantages are not without their potential pitfalls and problems. Conflicts involving the species concept, disagreements over the true (physiological/ecological) meaning of genetic diversity, and a perceived threat by some that sequence information will displace knowledge regarding the morphologies, functions and physiologies of protistan taxa, have created debate and doubt regarding the efficacy and appropriateness of some genetic approaches. These concerns need continued discussion and eventual resolution as we move toward the irresistible attraction, and potentially enormous benefits, of the application of genetic approaches to protistan ecology. PMID- 23672340 TI - The new Rapid-i carrier is an effective system for human embryo vitrification at both the blastocyst and cleavage stage. AB - BACKGROUND: The Rapid-i is a new FDA cleared closed carrier for embryo vitrification. The cooling rate of - 1220 degrees C/min is far lower than that reported with open vitrification systems such as the cryoloop (-15,000 degrees C/min). Little published data is currently available on this device. This study presents our initial clinical data, as well as live birth outcomes, with the Rapid-i. The efficacy of this device for the cryopreservation of cleavage, as well as blastocyst stage human embryos is also analyzed. We further compare outcomes to those achieved with the cryoloop, an "open" vitrification system routinely used in our laboratory. METHODS: Human embryos were vitrified at either the 8-10 cell stage or else the blastocyst stage. The vitrification protocol was: 7.5% DMSO/7.5% ethylene glycol (EG) (2-3 min) followed by incubation in 15% DMSO /15% EG (45 sec) before loading on the vitrification carrier. Cryoprotectant was removed during warming by sequential washes in 0.25 M and 0.125 M sucrose in culture medium. Clinical outcome data for frozen cycles between January 2011 and August 2012 were stratified according to carrier and cell stage. The student t test and chi square test were used to compare results. P value of < 0.05 was considered significant. RESULTS: A total of 486 vitrified-warmed embryos were assessed and 92% of them were transferred. The clinical pregnancy rate (CPR) and implantation rate (IR) with Rapid-i vitrified blastocysts were 59% and 49%, versus 47% and 37%, respectively for cleavage stage embryos. This was not statistically different from results with the cryoloop vitrified blastocysts (CPR 46%, IR 38%) nor the cleavage stage vitrified embryos (CPR 49%, IR 35%). To date, there have been 31 deliveries of 34 healthy infants from Rapid-i vitrified embryos, with another 12 pregnancies still on-going. CONCLUSIONS: The Rapid-i offers an excellent alternative to existing open vitrification devices for embryo cryopreservation at the 8-10 cell stage as well as the blastocyst stage. Use of this type of "closed" sealed system that prevents direct contact between the embryos and liquid nitrogen reduces the potential risk of sample cross contamination or infection. These preliminary data and live birth outcomes have paved the way toward transitioning to a closed vitrification system in our own IVF program. PMID- 23672342 TI - Collective activation of MRI agents via encapsulation and disease-triggered release. AB - An activation mechanism based on encapsulated ultrasmall gadolinium oxide nanoparticles (Gd oxide NPs) in bioresponsive polymer capsules capable of triggered release in response to chemical markers of disease (i.e., acidic pH, H2O2) is presented. Inside the hydrophobic polymeric matrices, the Gd oxide NPs are shielded from the aqueous environment, silencing their ability to enhance water proton relaxation. Upon disassembly of the polymeric particles, activation of multiple contrast agents generates a strong positive contrast enhancement of >1 order of magnitude. PMID- 23672344 TI - MIMO: an efficient tool for molecular interaction maps overlap. AB - BACKGROUND: Molecular pathways represent an ensemble of interactions occurring among molecules within the cell and between cells. The identification of similarities between molecular pathways across organisms and functions has a critical role in understanding complex biological processes. For the inference of such novel information, the comparison of molecular pathways requires to account for imperfect matches (flexibility) and to efficiently handle complex network topologies. To date, these characteristics are only partially available in tools designed to compare molecular interaction maps. RESULTS: Our approach MIMO (Molecular Interaction Maps Overlap) addresses the first problem by allowing the introduction of gaps and mismatches between query and template pathways and permits -when necessary- supervised queries incorporating a priori biological information. It then addresses the second issue by relying directly on the rich graph topology described in the Systems Biology Markup Language (SBML) standard, and uses multidigraphs to efficiently handle multiple queries on biological graph databases. The algorithm has been here successfully used to highlight the contact point between various human pathways in the Reactome database. CONCLUSIONS: MIMO offers a flexible and efficient graph-matching tool for comparing complex biological pathways. PMID- 23672343 TI - Lower urinary tract symptoms and falls risk among older women receiving home support: a prospective cohort study. AB - BACKGROUND: Although lower urinary tract symptoms have been associated with falls, few studies have been undertaken to understand this relationship in vulnerable community dwelling older adults. The purpose of this study was to describe the relationship over time of falls risk and lower urinary tract symptoms among community based older women receiving home support services. METHODS: A prospective cohort study which took place in an urban setting in western Canada. Participants were 100 older women receiving home care or residing in assisted living with home support services and were followed for six months. Demographic characteristics were collected at baseline, with the Timed Up and Go (TUG), International Consultation on Incontinence Questionnaire Female Lower Urinary Tract Symptoms (ICIQ-FLUTS), and self-report of falls collected at baseline, 3 and 6 months. Descriptive statistics were used to summarize demographic data. Differences between the three visits were analyzed using the Friedman test with post hoc analysis and associations between variables by the Spearman Rank-Order Correlation Coefficient. RESULTS: One hundred women initially enrolled; 88 and 75 remained at three months and six months. Mean age = 84.3 years; 91% reported at least one urinary symptom at baseline and 35% reported falling in the six months prior to enrollment; 15.9% reported falling between the baseline and three months and 14.6% between three and six months. Mean TUG scores at each time point indicated falls risk (27.21, 29.18 and 27.76 seconds). Significant correlations between TUG and ICIQ-FLUTS (r = 0.33, p < .001; r = 0.39, p < .001) as well as TUG and overactive bladder scores (r = 0.25, p = .005; r = 0.28, p < .008) were found at baseline and three months, but not six months. CONCLUSIONS: The association of lower urinary tract symptoms and falls risk in this group of vulnerable community dwelling older women at baseline and three months has potential clinical relevance. Lack of correlation at six months may be due loss of less robust participants, illuminating the difficulty in following frailer groups over time. Further studies are needed to understand the contribution of urinary symptoms to falls risk, and clinicians should incorporate continence assessment within falls risk assessment. PMID- 23672346 TI - Acute myeloid leukemia with a novel t(8;21) variant: paracentric inversion associated ins(21;8). PMID- 23672347 TI - Impact of pretransplant serum ferritin on outcome in adult patients receiving cord blood transplant for acute leukemia. PMID- 23672348 TI - Structure-based design and experimental engineering of a plant virus nanoparticle for the presentation of immunogenic epitopes and as a drug carrier. AB - Biomaterials research for the discovery of new generation nanoparticles is one of the most active areas of nanotechnology. In the search of nature-made nanometer sized objects, plant virus particles appear as symmetrically defined entities that can be formed by protein self-assembly. In particular, in the field of plant virology, there is plenty of literature available describing the exploitation of plant viral cages to produce safe vaccine vehicles and nanoparticles for drug delivery. In this context, we have investigated on the use of the artichoke mottled crinkle virus (AMCV) capsid both as a carrier of immunogenic epitopes and for the delivery of anticancer molecules. A dual approach that combines both in silico tools and experimental virology was applied for the rational design of immunologically active chimeric virus-like particles (VLPs) carrying immunogenic peptides. The atomic structures of wild type (wt) and chimeric VLPs were obtained by homology modeling. The effects of insertion of the HIV-1 2F5 neutralizing epitope on the structural stability of chimeric VLPs were predicted and assessed by detailed inspection of the nanoparticle intersubunit interactions at atomic level. Wt and chimeric VLPs, exposing on their surface the 2F5 epitope, were successfully produced in plants. In addition, we demonstrated that AMCV capsids could also function as drug delivery vehicles able to load the chemotherapeutic drug doxorubicin. To our knowledge, this is the first systematic predictive and empirical research addressing the question of how this icosahedral virus can be used for the production of both VLPs and viral nanoparticles for biomedical applications. PMID- 23672349 TI - Health-related quality of life and symptoms in patients with myelofibrosis treated with ruxolitinib versus best available therapy. AB - Patients with myelofibrosis (MF) have significant debilitating symptoms, physical disabilities, and poor health-related quality of life (HRQoL). Here, we report post-hoc analyses of the impact of ruxolitinib, a potent and selective JAK1 and JAK2 inhibitor, on disease-related symptoms and HRQoL in MF patients from the large phase 3 COMFORT-II study (N = 219). During the follow-up period of 48 weeks, HRQoL and MF-associated symptoms improved from baseline for ruxolitinib treated patients but remained the same or worsened for best available therapy (BAT)-treated patients. Based on the European Organization for Research and Treatment of Cancer QoL Questionnaire core 30 items (EORTC QLQ-C30), treatment induced differences in physical and role functioning, fatigue, and appetite loss significantly favoured ruxolitinib versus BAT from week 8 (P < 0.05) up to week 48 (P < 0.05). Ruxolitinib resulted in significantly higher response rates in global health status/QoL and Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) summary scores versus BAT at most time points (P < 0.05). Significant improvements in the Lymphoma subscale (including symptoms of pain, fever, itching, fatigue, weight loss, loss of appetite, and other patient concerns), FACT-General, FACT-Lym trial outcome index, and FACT-Lym total were also observed with ruxolitinib versus BAT starting at week 8 and continuing thereafter. Overall, these data demonstrated that ruxolitinib improved HRQoL in MF patients and further support the use of ruxolitinib for the treatment of symptomatic MF. PMID- 23672350 TI - BAALC and WT1 expressions from diagnosis to hematopoietic stem cell transplantation: consecutive monitoring in adult patients with core-binding factor-positive AML. AB - No consecutive analysis of BAALC and WT1 expressions associated with core-binding factor AML (CBF-AML) from diagnosis to hematopoietic stem cell transplantation (HSCT) has yet been reported. We investigated BAALC and WT1 expressions using a method of real-time quantitative polymerase chain reaction (RQ-PCR) at diagnosis, after induction chemotherapy, at pre-HSCT, and at post-HSCT period in 45 consecutive patients [t(8,21) (n = 28), inv(16) (n = 17)], who received HSCT as a post-remission treatment. BAALC and WT1 RQ-PCR decrement ratio (DR) was also calculated at post-induction chemotherapy, at pre-HSCT, and at post-HSCT compared with the diagnostic level. Higher BAALC expression at diagnosis showed significantly inferior OS (P = 0.031), EFS (P = 0.011), and higher CIR (P = 0.002) rates. At post-HSCT, both higher BAALC and WT1 expressions showed significantly inferior OS (P = 0.005, 0.016), EFS (P = 0.002, 0.006), and higher CIR (P = 0.001, 0.003) rates. A subgroup of t(8;21) showing higher BAALC and WT1 expressions at post-HSCT were also associated with inferior OS (P = 0.018, 0.015) and higher CIR rates (P = 0.019, 0.011). While BAALC DR showed no significant results on outcomes, WT1 DR more than 2-log at post-HSCT showed significantly lower CIR rate (P = 0.028). This study showed that higher post-HSCT BAALC and WT1 expressions in patients with CBF-AML may be good markers of minimal residual disease for the prediction of survival and relapse after HSCT. PMID- 23672351 TI - Tumour regression induced by co-administration of MIP-3alpha and CpG in an experimental model of colon carcinoma. AB - CCL20/macrophage inflammatory protein-3alpha (MIP-3alpha) represents one of the potent chemoattractive proteins for dendritic cells (DCs). Herein, we investigated whether in vivo genetic modification of tumour cells aimed at intratumoural production of MIP-3alpha might lead to accumulation of DCs in tumour tissue. Mice injected with CT26, received recombinant adenovirus (Ad) vectors (AdMIP-3alpha) expressing MIP-3alpha protein. This was complemented by injections of CpG. Interestingly, MIP-3alpha gene therapy combined with CpG injections resulted in specific cytotoxicity. This was associated with significant suppression of tumour growth rate. These findings demonstrate the potential of strategies that utilize in vivo overexpression of chemokines. PMID- 23672352 TI - Matrix metalloproteinase-9 as a therapeutic target for the progression of fulminant liver failure with hepatic encephalopathy: A pilot study in mice. AB - AIM: If progressive liver injury and subsequent hepatic encephalopathy can be prohibited in fulminant liver failure (FLF), it would be ideal for intensive care of FLF and provide an expanded opportunity for liver transplantation (LT). We hypothesized that matrix metalloproteinase (MMP)-9 plays an important role in FLF progression, and investigated MMP-9 behaviors in a murine FLF model, especially at the coma stage. METHODS: The murine FLF model with azoxymethane recapitulates FLF in humans. The detailed coma status was evaluated, on the assumption that LT is indicated at early, but not late, stage 3. To investigate whether MMP-9 deletion or reduction has beneficial effects, an MMP-9 inhibitor (GM6001) and transfection of tissue inhibitor of metalloproteinases (TIMP)-1 cDNA were used. Mice were divided into five groups: control; FLF; FLF with GM6001 pretreatment; FLF with TIMP-1 plasmid transfection 24 h before disease onset; and FLF with TIMP 1 plasmid transfection 48 h before disease onset. Neurological findings, including survival, were followed. Samples were obtained at early and late stage 3. Biochemical examinations and histopathological assessments were performed. The expression and function of MMP-9 and TIMP-1 were evaluated by western blotting and zymography. A brain permeability study was also performed. RESULTS: MMP-9 was strongly increased in FLF. The MMP-9 inhibitions worked well, and prolonged the survival, interval to stage 3 and duration of early stage 3. MMP-9 inhibition improved the liver and subsequent brain injuries at early stage 3, with no remarkable improvements at late stage 3. CONCLUSION: MMP-9 has therapeutic potential for FLF progression. PMID- 23672354 TI - Nipple-sparing mastectomy: can preoperative biopsy findings predict retroareolar margin involvement? PMID- 23672353 TI - Clinical assessment of complementary treatment with Qishen Yiqi dripping pills on ischemic heart failure: study protocol for a randomized, double-blind, multicenter, placebo-controlled trial (CACT-IHF). AB - BACKGROUND: Heart failure (HF) is associated with decreased quality of life, high re-admission rate and poor prognosis. In particular, ischemic heart failure (IHF) has a worse prognosis than nonischemic HF. The use of traditional Chinese medicine (TCM) alongside Western medicine to treat HF has developed into an integrative treatment model in China. There have been small clinical trials and experimental studies to demonstrate the efficacy of TCM for treating HF; however, there is still a lack of high-quality trials. Qishen Yiqi dripping pills (QSYQ), a TCM drug, have been commonly used alongside standardized Western medicine to treat IHF. This paper describes the protocol for the clinical assessment of QSYQ in IHF patients. METHOD: A randomized, double-blind, multicenter, placebo controlled trial will assess the efficacy and safety of QSYQ in the treatment of IHF. The trial is to enroll 640 IHF patients from 32 hospitals in China. Besides their standardized Western medicine, patients will be randomized to receive treatment of either QSYQ or placebo for 6 months and follow-up monitoring for at least a further 6 months. The primary outcome is increased exercise capacity of patients, which will be measured using the 6-minute walking test (6MWT). The secondary outcomes include composite endpoints: all-cause mortality, frequency of hospitalization or emergency due to cardiovascular events, brain natriuretic peptide levels, left ventricular ejection fraction, and cardiothoracic ratio will be documented, as well as scores on the New York Heart Association classification and Minnesota quality of life index, and information obtained from the four TCM diagnostic methods. Blood lipid tests will also be administered. DISCUSSION: The integrative treatment model of TCM alongside Western medicine has developed into a treatment model in China. The rigorous design of the trial will assure an objective and scientific assessment of the efficacy and safety of QSYQ in the treatment of IHF. PMID- 23672356 TI - Multicenter observational study of the development of progressive organ dysfunction and therapeutic interventions in normotensive sepsis patients in the emergency department. AB - OBJECTIVES: Progressive organ dysfunction is the leading cause of sepsis associated mortality; however, its incidence and management are incompletely understood. Sepsis patients with moderately impaired perfusion (serum lactate 2.0 to 3.9 mmol/L) who are not in hemodynamic shock ("preshock" sepsis patients) may be at increased risk for progressive organ dysfunction and increased mortality. The objectives of this study were to: 1) quantify the occurrence of progressive organ dysfunction among preshock sepsis patients, 2) examine if there were baseline differences in demographic and physiologic parameters between preshock sepsis patients who experienced progressive organ dysfunction and those who did not, and 3) examine if intravenous (IV) fluid administered in the emergency department (ED) differed between these two groups of patients. METHODS: This was a prospective, observational study in four urban EDs targeting the preshock sepsis population, defined as adults (18 years or older) with suspected infection, serum lactate between 2.0 and 3.9 mmol/L, and without hypotension (systolic blood pressure [sBP] < 90 mm Hg or mean arterial pressure [MAP] < 70 mm Hg) or requiring mechanical ventilation at ED presentation. The primary composite outcome was progressive organ dysfunction, defined as a rise in the Sequential Organ Failure Assessment (SOFA) score of >=1, vasopressor use, mechanical ventilation use within 72 hours after ED presentation, or in-hospital death. The secondary outcomes were any intensive care unit (ICU) admission, and total ICU and hospital lengths of stay (LOS). RESULTS: Among 94 preshock sepsis patients, the primary composite outcome occurred in 24 of 94 (26%). In patients with the primary outcome, 22 of 24 (92%) experienced a rise in SOFA score of >=1, five of 24 (21%) received vasopressor agents, and seven of 24 (30%) required mechanical ventilation. There were no baseline demographic or physiologic parameter differences between patients who met the primary outcome versus those who did not, while patients with the primary outcome had a higher average SOFA score at admission (2.4 vs. 1.3, p = 0.011) and at all subsequent time points. Median IV fluid volume administered to all preshock sepsis patients during their ED stay was 1,225 mL (interquartile range [IQR] = 712 to 2,000 mL) and did not differ significantly between patients with (1,150 mL, IQR = 469 to 2,000 mL) or without (1,250 mL, IQR = 750 to 2,000 mL) the primary outcome (p = 0.73). Patients with progressive organ dysfunction or death were more likely to be admitted to an ICU (50% vs. 20%, p < 0.01) and have an increased median hospital LOS (6 days vs. 3 days, p = 0.005), compared to those without progressive organ dysfunction. CONCLUSIONS: Over one-quarter of preshock sepsis patients developed progressive organ dysfunction with associated increased resource use. Demographic and physiologic parameters were unable to differentiate patients with progressive organ dysfunction, while the initial SOFA score was increased in patients meeting the outcome. Overall, these patients received relatively little IV fluid therapy during their ED stays. Further research to determine if more aggressive therapy can prevent progressive organ dysfunction in this population is warranted. PMID- 23672357 TI - Understanding patient-provider conversations: what are we talking about? AB - OBJECTIVES: Effective patient-provider communication is a critical aspect of the delivery of high-quality patient care; however, research regarding the conversational dynamics of an overall emergency department (ED) visit remains unexplored. Identifying both patterns and relative frequency of utterances within these interactions will help guide future efforts to improve the communication between patients and providers within the ED setting. The objective of this study was to analyze complete audio recordings of ED visits to characterize these conversations and to determine the proportion of the conversation spent on different functional categories of communication. METHODS: Patients at an urban academic ED with four diagnoses (ankle sprain, back pain, head injury, and laceration) were recruited to have their ED visits audio recorded from the time of room placement until discharge. Patients were excluded if they were age < 18 years, were non-English-speaking, had significant history of psychiatric disease or cognitive impairment, or were medically unstable. Audio editing was performed to remove all silent downtime and non-patient-provider conversations. Audiotapes were analyzed using the Roter Interaction Analysis System (RIAS). RIAS is the most widely used medical interaction analysis system; coders assign each "utterance" (or complete thought) spoken by the patient or provider to one of 41 mutually exclusive and exhaustive categories. Descriptive statistics were calculated for all 41 categories and then grouped according to RIAS standards for "functional groupings." The percentage of total utterances in each functional grouping is reported. RESULTS: Twenty-six audio recordings were analyzed. Patient participants had a mean (+/-SD) age of 38.8 (+/-16.0) years, and 30.8% were male. Intercoder reliability was good, with mean intercoder correlations of 0.76 and 0.67 for all categories of provider and patient talk, respectively. Providers accounted for the majority of the conversation in the tapes (median = 239 utterances, interquartile range [IQR] = 168 to 308) compared to patients (median = 145 utterances, IQR = 80 to 198). Providers' utterances focused most on patient education and counseling (34%), followed by patient facilitation and activation (e.g., orienting the patient to the next steps in the ED or asking if the patient understood; 30%). Approximately 15% of the provider talk was spent on data gathering, with the majority (86%) focusing on biomedical topics rather than psychosocial topics (14%). Building a relationship with the patient (e.g., social talk, jokes/laughter, showing approval, or empathetic statements) constituted 22% of providers' talk. Patients' conversation was mainly focused in two areas: information giving (47% of patient utterances: 83% biomedical, 17% psychosocial) and building a relationship (45% of patient utterances). Only 5% of patients' utterances were devoted to question asking. Patient-centeredness scores were low. CONCLUSIONS: In this sample, both providers and patients spent a significant portion of their talk time providing information to one another, as might be expected in the fast-paced ED setting. Less expected was the result that a large percentage of both provider and patient utterances focused on relationship building, despite the lack of traditional, longitudinal provider-patient relationships. PMID- 23672355 TI - Interobserver agreement in the clinical assessment of children with blunt abdominal trauma. AB - OBJECTIVES: The objective was to determine the interobserver agreement of historical and physical examination findings assessed during the emergency department (ED) evaluation of children with blunt abdominal trauma. METHODS: This was a planned substudy of a multicenter, prospective cohort study of children younger than 18 years of age evaluated for blunt abdominal trauma. Patients were excluded if injury occurred more than 24 hours prior to evaluation or if computed tomography (CT) imaging was obtained at another hospital prior to transfer to a study site. Two clinicians independently recorded their clinical assessments of a convenience sample of patients onto data collection forms within 60 minutes of each other and prior to CT imaging (if obtained) or knowledge of laboratory results. The authors categorized variables as either subjective symptoms (i.e., patient history) or objective findings (i.e., physical examination). For each variable recorded by the two observers, the agreement beyond that expected by chance was estimated, using the kappa (kappa) statistic for categorical variables and weighted kappa for ordinal variables. Variables with 95% lower confidence limits (LCLs) kappa >= 0.4 (moderate agreement or better) were considered to have acceptable agreement. RESULTS: A total of 632 pairs of physician observations were obtained on 23 candidate variables. Acceptable agreement was achieved in 16 (70%) of the 23 variables tested. For six subjective symptoms, kappa ranged from 0.48 (complaint of shortness of breath) to 0.90 (mechanism of injury), and only the complaint of shortness of breath had a 95% LCL kappa < 0.4. For the 17 objective findings, kappa ranged from -0.01 (pelvis instability) to 0.82 (seat belt sign present). The 95% LCL for kappa was <0.4 for flank tenderness, abnormal chest auscultation, suspicion of alcohol or drug intoxication, pelvis instability, absence of bowel sounds, and peritoneal irritation. CONCLUSIONS: Observers can achieve at least acceptable agreement on the majority of historical and physical examination variables in children with blunt abdominal trauma evaluated in the ED. Those variables are candidates for consideration for development of a clinical prediction rule for intra-abdominal injury in children with blunt trauma. PMID- 23672359 TI - Improving telephone follow-up for patients discharged from the emergency department: results of a randomized controlled trial. AB - OBJECTIVES: Reliable telephone follow-up offers physicians a timely method to notify patients of unexpected laboratory and imaging results, clarify discharge instructions, evaluate health status changes, and potentially boost patient satisfaction. This study sought to determine if verifying telephone numbers, obtaining best contact times, and informing patients that they will be contacted would increase the proportion of emergency department (ED) patients contacted at 48 to 72 hours postdischarge. Secondary outcomes included estimating successful postdischarge follow-up across demographic categories. METHODS: This was a prospective, randomized controlled trial of adult patients in an inner-city, public hospital ED. Patients were excluded for critical illness, no telephone number, non-English- or non-Spanish-speaking, or anyone admitted as an inpatient. All subjects completed a demographic questionnaire. In the intervention arm, research assistants (RAs) verified the telephone number, obtained best contact times, and informed subjects that they would be called. In the control arm, telephone numbers were obtained from registration materials and were not verified, and subjects were not informed that postdischarge telephone calls were planned. RAs made four telephone attempts to contact each subject 48 to 72 hours after discharge. RESULTS: The intervention did not significantly improve postdischarge contact. Most subjects, 72.8% in the intervention group and 68.2% in the control group, were successfully contacted (difference = 4.6%, 95% confidence interval [CI] = -2.2% to 11.4%). On multivariate analysis, Hispanic ethnicity and owning a mobile phone were associated with increased odds of successful postdischarge follow-up. CONCLUSIONS: Verifying contact information, obtaining best contact times, and notifying patients of impending follow-up calls did not substantially improve postdischarge telephone contact rates. PMID- 23672358 TI - Individual lytic efficacy of recombinant tissue plasminogen activator in an in vitro human clot model: rate of "nonresponse". AB - OBJECTIVES: Recombinant tissue plasminogen activator (rt-PA) is a lytic medication widely used in the emergency department to treat acute thrombotic disorders such as ischemic stroke and myocardial infarction. It is known in the clinical use of this drug that it can be less effective in approximately 25% of individuals receiving such treatment. However, there are no data on the variation of lytic efficacy of rt-PA in decreasing individuals' clot size over time. In this study, in vitro lytic efficacy was determined by measuring the decrease in clot diameter after 30 minutes of drug exposure. The authors sought to explore whether there are individuals who do not respond to this lytic therapy and to estimate the rate of nonresponse. METHODS: Human whole blood clots were made from blood drawn from 22 adult volunteers. The only exclusion criterion was the use of aspirin within 72 hours of the blood draw. Blood clots were allowed to spontaneously form at room temperature and were then incubated at 37 degrees C for 3 hours to ensure complete clot retraction. Sample clots from the same individuals were then exposed to human fresh-frozen plasma (hFFP) control or rt PA in hFFP (rt-PA) at a concentration of 3.15 MUg/mL. All clots were exposed at 37 degrees C for 30 minutes, and clot diameter was measured as a function of time, using a microscopic imaging technique. The fractional clot loss (FCL), which is the percentage decrease in clot diameter at 30 minutes, was used as a measure of lytic efficacy. RESULTS: Means with standard deviation (SD) FCL values were 8.6% (+/-3.0%) for control and 20.6% (+/-9.3%) for rt-PA-treated clots. The mean (+/-SD) difference in FCL values was 12.0% (+/-8.8%) and was significant (p < 0.05, paired t-test). Five of the 22 subjects (23%) were "rt-PA nonresponders," in that their FCL (rt-PA) values fell within that of the FCL control values. CONCLUSIONS: Overall, rt-PA does not produce clot lysis in vitro in clots from a substantial minority of the population, likely due to individual variations in clot composition and structure. PMID- 23672360 TI - Agreement between routine emergency department care and clinical decision support recommended care in patients evaluated for mild traumatic brain injury. AB - OBJECTIVES: Emergency department (ED) computed tomography (CT) use has increased significantly during the past decade. It has been suggested that adherence to clinical decision support (CDS) may result in a safe decrease in CT ordering. In this study, the authors quantified the percentage agreement between routine and CDS-recommended care and the anticipated consequence of strict adherence to CDS on CT use in mild traumatic brain injury (mTBI). METHODS: This was a prospective observational study of patients with mTBI who presented to an urban academic ED of a tertiary care hospital. Patients 18 years or older, presenting within 24 hours of nonpenetrating trauma to the head, from August 2010 to July 2011, were eligible for enrollment. Structured data forms were completed by trained research assistants (RAs). The primary outcome was the percentage agreement between routine head CT use and CDS-recommended head CT use. CDS examined were: the 2008 American College of Emergency Physicians [ACEP] neuroimaging, the New Orleans rule, and the Canadian head CT rule. Differences between outcome groups were assessed using the chi-square test for categorical variables and the Kruskal Wallis rank test for continuous variables. The percentage agreement between routine practice and CDS-recommended practice was calculated. RESULTS: Of the 169 patients enrolled, 130 (76.9%) received head CT scans, and five of the 130 (3.8%) had acute traumatic intracranial findings. For all subjects, agreement between routine practice and CDS-recommended practice was 77.5, 65.7, and 78.1%, for the ACEP, Canadian, and New Orleans CDS, respectively. Strict adherence to the 2008 ACEP neuroimaging CDS would result in no statistically significant difference in head CT use (routine care, 76.9%; CDS-recommended, 82.8%; p = 0.17). Strict adherence to the New Orleans CDS would result in an increase in head CT use (routine care, 76.9%; CDS-recommended, 94.1%; p < 0.01). Strict adherence to the Canadian CDS would result in a decrease in head CT use (routine care, 76.9%; CDS recommended, 56.8%; p < 0.01). CONCLUSIONS: There is a 60% to 80% agreement between routine and CDS-recommended head CT use. Of the three CDS systems examined, the only one that may result in a reduction in head CT use if strictly followed was the Canadian head CT CDS. Further studies are needed to examine reasons for the less than optimal agreement between routine care and care recommended by the Canadian head CT CDS. PMID- 23672361 TI - Prevalence and clinical importance of alternative causes of symptoms using a renal colic computed tomography protocol in patients with flank or back pain and absence of pyuria. AB - OBJECTIVES: The study was undertaken to determine the prevalence and clinical importance of alternative causes of symptoms discovered in patients undergoing flank pain protocol (FPP) computed tomography (CT) scans in patients with classic symptoms of kidney stone (flank pain, back pain, or both) without evidence of urine infection. METHODS: This was a retrospective observational analysis of all adult patients undergoing FPP CT scans at two emergency departments (EDs) between April 2005 and November 2010. All CTs (N = 5,383) were reviewed and categorized as "no cause of symptoms seen on CT," "ureteral stone as cause of symptoms," or "non-kidney stone cause of symptoms." Non-kidney stone scans were further categorized as "acutely important," "follow-up recommended," or "unimportant cause," based on a priori diagnostic classifications. All nonstone causes of pain and a random subset of subjects (n = 1,843; 34%) underwent full record review blinded to CT categorization to determine demographics, whether flank and/or back pain was present, and whether there was objective evidence of pyuria. RESULTS: Of all FPP CT scans during the study period, a ureteral stone was found to cause symptoms in 47.7% of CTs, with no cause of symptoms found in 43.3% of CTs. A non kidney stone diagnosis was found in 9.0% of all CTs, with 6.1% being categorized as "acutely important," 2.2% as "follow-up recommended," and 0.65% with symptoms from an "unimportant cause." In the randomly selected subset undergoing full record review, categorizations were similar, with 49.0% of CTs showing kidney stone as cause of pain and 9.0% a non-kidney stone cause (5.9% "acutely important"). When subjects with evidence of urine infection or without flank or back pain were excluded, ureteral stone was identified as the cause of pain in 54.9% of CTs, while non-kidney stone cause of symptoms was found in 5.4% of scans and acutely important alternate causes in 2.8% of scans. CONCLUSIONS: While a non kidney stone cause for a patient's symptoms are found in nearly 10% of CTs done using a FPP, acutely important findings occur in less than 3% of scans done in patients with flank or back pain and absence of pyuria. PMID- 23672362 TI - National growth in intensive care unit admissions from emergency departments in the United States from 2002 to 2009. AB - OBJECTIVES: The authors describe national trends in use, reasons for visit, most common diagnoses, and resource utilization in patients admitted to intensive care units (ICUs) from hospital-based emergency departments (EDs) in the United States. METHODS: This was an observational study using data from the National Hospital Ambulatory Care Survey, a nationally representative, weighted sample of U.S. hospital-based EDs from 2002 through 2009. The sample comprised a total of 4,267 patients aged 18 years or older admitted to the ICU from the ED, which represent over 14.5 million ED encounters from 2002 through 2009. RESULTS: Over the study period, ICU admissions from EDs increased from 2.79 million in 2002/2003, to 4.14 million in 2008/2009, an absolute increase of 48.8% and a mean biennial increase of 14.2%. By comparison, overall ED visits increased a mean of 5.8% per biennial period. The three most common diagnoses for ICU admissions were unspecified chest pain, congestive heart failure, and pneumonia. Utilization rates of most tests and services delivered to patients admitted to the ICU from the ED increased, with the largest increase occurring in computed tomography (CT) and magnetic resonance imaging (MRI), which increased from 16.8% in 2002/2003 to 37.4% in 2008/2009, a 6.9% mean biennial increase. Across all years, mean ED length of stay (LOS) for ICU admissions was 304 minutes (95% confidence interval [CI] = 286 to 323 minutes), and mean hospital LOS was 6.6 days (95% CI = 6.2 to 7.0 days). There was no significant change in either mean ED or hospital LOS over the study period. CONCLUSIONS: Intensive care unit admissions from EDs are increasing at a greater rate than both population growth and overall ED visits. ED resource use, specifically advanced diagnostic imaging, has increased markedly among ICU admissions. While mean ED and hospital LOS have not changed significantly, the mean ICU admission spends over 5 hours in the ED prior to transfer to an ICU bed. A greater emphasis on the ED-ICU interface and critical care delivered in the ED may be warranted. PMID- 23672363 TI - Validation of the San Francisco Syncope Rule in two hospital emergency departments in an Asian population. AB - OBJECTIVES: The objective was to externally validate the ability of the San Francisco Syncope Rule (SFSR) to accurately identify patients who will experience a 7-day serious clinical event in an Asian population. METHODS: This was a prospective cohort study, with a sample of adult patients with syncope and near syncope enrolled. Patients 12 years old and below and patients with loss of consciousness after head trauma, a witnessed seizure, with known alcohol or illicit drug ingestion, and altered level of consciousness or persistent new neurologic deficits were excluded. The patients were evaluated for the presence of one or more of the five SFSR variables: shortness of breath, history of heart failure, hematocrit <30%, systolic blood pressure <90 mm Hg, and abnormal electrocardiogram (ECG). The patients were followed up by medical record review or telephone interview. Seven-day outcomes were death, arrhythmia, myocardial infarction, acute pulmonary edema, significant structural heart disease, pulmonary embolism, major cardiac procedure, stroke, subarachnoid hemorrhage, major bleeding, and anemia. RESULTS: A total of 1,250 patients from two centers were recruited. Fifty-six patients were excluded from primary analysis because of incomplete data (n = 55) and/or they were noncontactable for follow-up (n = 32). Of the 1,194 patients analyzed, 138 patients (11.6%) experienced adverse outcomes at 7 days. The rule performed with a sensitivity of 94.2% (95% confidence interval [CI] = 89.0% to 97.0%) and a specificity of 50.8% (95% CI = 47.7% to 53.8%). CONCLUSIONS: In this study, SFSR rule had a sensitivity of 94.2%. This suggests caution on the strict application of the rule to all patients presenting with syncope. It should only be used as an aide in clinical decision-making in this population. PMID- 23672364 TI - Weekday psychiatry faculty rounds on emergency department psychiatric patients reduces length of stay. AB - OBJECTIVES: In the face of increasing volume of emergency department (ED) patients with primary psychiatric illness and increasing length of stay (LOS), a department of psychiatry initiated a program whereby faculty members of the department of psychiatry from a hospital conducted rounds in the ED each weekday on these patients. METHODS: A retrospective data review was performed to assess the effect of these rounds on the LOS and disposition of these patients. The LOS and dispositions of subjects before and after the initiation of psychiatry rounds were compared, with a 2-month washout period between. Subjects had a primary psychiatric diagnosis with a LOS of 12 hours or greater. The LOS and disposition of each subject was queried from the hospital data system. Quantile regression analysis and Fisher's exact test were used as appropriate. RESULTS: There were 355 subjects in the preimplementation period and 512 in the postimplementation period. The proportion of patients discharged remained unchanged (preimplementation 49.6%, 95% confidence interval [CI] = 44.3 to 54.9; postimplementation 49.0%, 95% CI = 44.6 to 53.4), but more patients were admitted to the hospital (24.2%, 95% CI = 19.9 to 29.0 vs. 32.8, 95% CI = 28.8 to 37.1) and fewer were transferred to other psychiatric facilities (25.6%, 95% CI = 21.2 to 30.5 vs. 18.0% 95% CI = 14.7 to 21.6; p = 0.005 by Fisher's exact test). Quantile regression demonstrated that among subjects with the longest LOS, those in the postimplementation group experienced a reduction in their waiting times. CONCLUSIONS: Weekday rounds in the ED by psychiatry faculty are associated with a reduction in the LOS for psychiatric patients, mainly due to reduced LOS of those patients with the longest stays. PMID- 23672365 TI - Syncope risk stratification in the ED: directions for future research. PMID- 23672366 TI - Effect of military conflicts on the formation of emergency medical services systems worldwide. AB - OBJECTIVES: This article briefly reviews the evolution of medical support during wars and conflicts from ancient to modern times and discusses the effect warfare has had on the development of civilian health care and emergency medical services (EMS). Medical breakthroughs and discoveries made of necessity during military conflicts have developed into new paradigms of medical care, including novel programs of triage and health assessment, emergency battlefield treatment and stabilization, anesthesia, and other surgical and emergency procedures. The critical role of organizations that provide proper emergency care to help the sick and injured both on the battlefield and in the civilian world is also highlighted. PMID- 23672367 TI - Development of emergency medicine in Europe. AB - Emergency medicine (EM) is emerging worldwide. Its development as a recognized specialty is proceeding at difference rates in different countries. Europe is a region with complex political affiliations and is composed of countries both within and outside the European Union (EU). Europe is seeking greater standardization (harmonization) for mutually improved economic development. Medicine in general, and EM in particular, is no exception. In Europe, as in other regions, EM is struggling for acceptance as a valid field of specialization. The European Union of Medical Specialists requires that once two fifths of countries acknowledge a specialty, all EU countries must address the question. EM had achieved the needed majority by 2011. This article briefly describes the European road to specialty acceptance. PMID- 23672368 TI - Crotaline Fab antivenom reverses platelet dysfunction induced by Crotalus scutulatus venom: an in vitro study. AB - BACKGROUND: Patients sustaining rattlesnake envenomation often develop thrombocytopenia, the etiology of which is not clear. Laboratory studies have demonstrated that venom from several species, including the Mojave rattlesnake (Crotalus scutulatus scutulatus), can inhibit platelet aggregation. In humans, administration of crotaline Fab antivenom has been shown to result in transient improvement of platelet levels; however, it is not known whether platelet aggregation also improves after antivenom administration. OBJECTIVES: The objective was to determine the effect of C. scutulatus venom on platelet aggregation in vitro in the presence and absence of crotaline Fab antivenom. METHODS: Blood was obtained from four healthy male adult volunteers not currently using aspirin, nonsteroidal anti-inflammatory drugs, or other platelet-inhibiting agents. C. scutulatus venom from a single snake with known type B (hemorrhagic) activity was obtained from the National Natural Toxins Research Center. Measurement of platelet aggregation by an aggregometer was performed using five standard concentrations of epinephrine (a known platelet aggregator) on platelet rich plasma over time, and a mean area under the curve (AUC) was calculated. Five different sample groups were measured: 1) blood alone, 2) blood + C. scutulatus venom (0.3 mg/mL), 3) blood + crotaline Fab antivenom (100 mg/mL), 4) blood + venom + antivenom (100 mg/mL), and 5) blood + venom + antivenom (4 mg/mL). Standard errors of the mean (SEM) were calculated for each group, and paired t tests were used to measure differences between groups. RESULTS: Antivenom administration by itself (group 2) did not significantly affect platelet aggregation compared to baseline (103.8%, SEM +/- 3.4%, p = 0.47). Administration of venom (group 3) decreased platelet aggregation (72.0%, SEM +/- 8.5%, p < 0.05). Concentrated antivenom administration in the presence of venom (group 4) normalized platelet aggregation (101.4%, SEM +/- 6.8%) and in the presence of diluted antivenom (group 5) significantly increased aggregation (133.9%, SEM +/- 9.0%; p < 0.05 for both groups when compared to the venom-only group). To further assess the effects of the venom and antivenom, each was run independently in platelet-rich plasma without epinephrine; neither was found to significantly alter platelet aggregation in the absence of epinephrine. CONCLUSIONS: Crotaline Fab antivenom improved platelet aggregation in an in vitro model of platelet dysfunction induced by venom from C. scutulatus. It is unclear at this time whether this improvement in platelet dysfunction translates into improved clinical outcomes in envenomated patients. PMID- 23672369 TI - Western blotting using microchip electrophoresis interfaced to a protein capture membrane. AB - Western blotting is a commonly used assay for proteins. Despite the utility of the method, it is also characterized by long analysis times, manual operation, and lack of established miniaturized counterpart. We report a new way to Western blot that addresses these limitations. In the method, sodium dodecyl sulfate (SDS)-protein complexes are separated by sieving electrophoresis in a microfluidic device or chip. The chip is interfaced to a moving membrane so that proteins are captured in discrete zones as they migrate from the chip. Separations of SDS-protein complexes in the molecular weight range of 11-155 kDa were completed in 2 min with 4 * 10(4) theoretical plates at 460 V/cm. Migration time and peak area relative standard deviations were 3-6% and 0.2%, respectively. Detection limit for actin was 0.7 nM. Assays for actin, AMP-kinase, carbonic anhydrase, and lysozyme are shown to demonstrate versatility of the method. Total analysis time including immunoassay was 22-32 min for a single sample. Because processing membrane for immunoassay is the slow step of the assay, sequential injections from different reservoirs on the chip and capture in different tracks on the same membrane allow increased throughput. As a demonstration, 9 injections were collected on one membrane and analyzed in 43 min (~5 min/sample). Further improvements in throughput are possible with more reservoirs or parallel channels. PMID- 23672370 TI - Photoinduced nonadiabatic decay and dissociation dynamics of dimethylnitramine. AB - Dimethylnitramine (DMNA) is a prototype system used in the investigation of the unimolecular decomposition mechanism of the nitramine-compound family. The photoinduced excited-state nonadiabatic processes and successive unimolecular dissociation of DMNA were investigated by trajectory surface-hopping dynamics at the semiempirical OM2/MRCI level. Two S1/S0 conical intersections (CI01alpha and CI01beta) were found to play essential roles in the nonadiabatic decay dynamics of DMNA. After the S1 -> S0 decay, the excess kinetic energy finally results in the cleavage of the N-N bond in the ground electronic state. The two reaction channels through CI01alpha and CI01beta show differences in molecular motions and decay features. The trajectories passing CI01alpha can hop one or several times, and the intramolecular vibrational energy transfer in the ground state takes place before dissociation, whereas trajectories following the CI01beta channel mainly dissociate directly after only one S1 -> S0 hop. PMID- 23672371 TI - Changing the malaria treatment protocol policy in Timor-Leste: an examination of context, process, and actors' involvement. AB - In 2007 Timor-Leste, a malaria endemic country, changed its Malaria Treatment Protocol for uncomplicated falciparum malaria from sulphadoxine-pyrimethamine to artemether-lumefantrine. The change in treatment policy was based on the rise in morbidity due to malaria and perception of increasing drug resistance. Despite a lack of nationally available evidence on drug resistance, the Ministry of Health decided to change the protocol. The policy process leading to this change was examined through a qualitative study on how the country developed its revised treatment protocol for malaria. This process involved many actors and was led by the Timor-Leste Ministry of Health and the WHO country office. This paper examines the challenges and opportunities identified during this period of treatment protocol change. PMID- 23672372 TI - Pulmonary actinomycosis during the first decade of 21st century: cases of 94 patients. AB - BACKGROUND: Pulmonary actinomycosis is a chronic pulmonary infection caused by Actinomyces. Both improving oral hygiene and early application of antibiotics to the case of suspicious pulmonary infections result in changes in incidences and presentations of pulmonary actinomycosis. However, there are little reports dealt with the recent clinical characteristics of pulmonary actinomycosis. This study aimed to review the characteristics of pulmonary actinomycosis occurred during the first decade of 21st century. METHODS: This retrospective study was performed on 94 subjects with pulmonary actinomycosis diagnosed pathologically from January 2000 to December 2010 in 13 hospitals in Korea. RESULTS: The data of the study showed that pulmonary actinomycosis occurs frequently in middle to old-aged males (mean age; 57.7 years old) and that the most common symptoms are cough, hemoptysis, and sputum production. Various radiologic features such as the consolidation with central low attenuation (74.5%) and no regional predominance were also observed. Most of patients recovered completely with medical and/or surgical treatment, reaching approximately 98% cure rate. CONCLUSIONS: The results demonstrate that pulmonary actinomycosis is one of the cautious pulmonary diseases. More importantly, in cases of persistent hemoptysis or for differential diagnosis from lung malignancy, our data have revealed that surgical resection appears to be a useful intervention and that radiologic diagnosis may not provide decisive information. These findings indicate that it is important for the clinicians to include pulmonary actinomycosis as one of differential diagnoses for refractory pulmonary abnormal lesions to the current usual management. PMID- 23672373 TI - Micro-nanopores fabricated by high-energy electron beam irradiation: suitable structure for controlling pesticide loss. AB - Pesticide sprayed onto crop leaves tends to be washed off by rainwater and discharge into the environment through leaching and runoff, resulting in severe pollution to both soil and water. Here, to control pesticide loss, we developed a loss-control pesticide (LCP) by adding modified natural nanoclay (diatomite) through high-energy electron beam (HEEB) to traditional pesticide. After HEEB treatment, the originally clogged pores in diatomite opened, resulting in plenty of micro-nanopores in diatomite, which are beneficial for the pesticide molecules to access and be adsorbed. This pesticide-diatomite complex tended to be retained by the rough surface of crop leaves, displaying a high adhesion performance onto the leaves, so that the pesticide loss reduced, sufficient pesticide for crops was supplied, and the pollution risk of the pesticide could be substantially lowered. PMID- 23672374 TI - Cost-effectiveness of a FISH assay for the diagnosis of melanoma in the USA. AB - OBJECTIVE: The authors evaluated the cost-effectiveness of a FISH assay in melanoma diagnosis in the USA. METHOD: A model was developed simulating the addition of FISH to the diagnosis of suspected melanoma. A decision analytic module simulated diagnosis using microscopic assessment alone versus addition of FISH (sensitivity: 92%; specificity: 94%). The authors simulated a clinical setting in which an initial excisional biopsy microscopic assessment (sensitivity: 73%; specificity: 78%) was followed by dermatopathologist assessment (sensitivity: 89%; specificity: 79%) for inconclusive results. Diagnostic strategies 1 and 2 added FISH to the initial and dermatopathologist assessments, respectively. A Markov outcomes module simulated patients' remaining lifetime, including treatment. RESULTS: In diagnostic strategies 1 and 2, the cost per quality-adjusted life year gained was US$14,930 and 43,925, respectively, versus no FISH. Cost per misdiagnosis avoided was US$3292 and 3759, respectively. Sensitivity and specificity without FISH were both >=88%; however, addition of FISH exceeded US$100,000/quality-adjusted life year. CONCLUSION: In specific clinical settings, FISH could be cost effective for melanoma diagnosis. PMID- 23672375 TI - Social problem-solving, perceived stress, depression and life-satisfaction in patients suffering from tension type and migraine headaches. AB - This study aimed at investigating social problem solving, perceived stress, depression, and life-satisfaction in patients with tension type and migraine headaches. Forty-nine migraine and 42 tension type headache patients (n = 91) consenting to participate were compared to a total of 49 matched healthy control group. Participants filled in a questionnaire consisting self-report measures of problem solving, perceived stress, depression and life satisfaction. They were also asked about headache duration, frequency, pain severity, psychiatric treatment and sense of control in one's life. T-tests, chi-square, analysis of variance, logistic regression analysis and Pearson product moment correlation coefficient procedures were used to analyze the data. Tension type headache patients reported having had more frequent headaches than the migraine patients but migraine patients reported having had more intense pain than the tension type headache patients. Instances of psychiatric treatment were more common among tension type headache patients than the migraine and the control group. Compared to the healthy controls, headache patients displayed a deficiency in problem solving, higher levels of perceived stress and depression. Levels of problem solving skills in headache patients were related inversely to depression, perceived stress and the number of negative life events but problem solving skills of headache patients was related positively to life-satisfaction. The findings from this study suggested that cognitive behavioral problem solving therapy or training might be a viable option for reducing levels of stress and depression, and to increase life-satisfaction in patients suffering from primary headache. PMID- 23672376 TI - Theoretical prediction and experimental realization of new stable inorganic materials using the inverse design approach. AB - Discovery of new materials is important for all fields of chemistry. Yet, existing compilations of all known ternary inorganic solids still miss many possible combinations. Here, we present an example of accelerated discovery of the missing materials using the inverse design approach, which couples predictive first-principles theoretical calculations with combinatorial and traditional experimental synthesis and characterization. The compounds in focus belong to the equiatomic (1:1:1) ABX family of ternary materials with 18 valence electrons per formula unit. Of the 45 possible V-IX-IV compounds, 29 are missing. Theoretical screening of their thermodynamic stability revealed eight new stable 1:1:1 compounds, including TaCoSn. Experimental synthesis of TaCoSn, the first ternary in the Ta-Co-Sn system, confirmed its predicted zincblende-derived crystal structure. These results demonstrate how discovery of new materials can be accelerated by the combination of high-throughput theoretical and experimental methods. Despite being made of three metallic elements, TaCoSn is predicted and explained to be a semiconductor. The band gap of this material is difficult to measure experimentally, probably due to a high concentration of interstitial cobalt defects. PMID- 23672377 TI - Let's all return to play. PMID- 23672379 TI - Dehydration and performance on clinical concussion measures in collegiate wrestlers. AB - CONTEXT: The effects of dehydration induced by wrestling-related weight-cutting tactics on clinical concussion outcomes, such as neurocognitive function, balance performance, and symptoms, have not been adequately studied. OBJECTIVE: To evaluate the effects of dehydration on the outcome of clinical concussion measures in National Collegiate Athletic Association Division I collegiate wrestlers. DESIGN: Repeated-measures design. SETTING: Clinical research laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirty-two Division I healthy collegiate male wrestlers (age = 20.0 +/- 1.4 years; height = 175.0 +/- 7.5 cm; baseline mass = 79.2 +/- 12.6 kg). INTERVENTION(S): Participants completed preseason concussion baseline testing in early September. Weight and urine samples were also collected at this time. All participants reported to prewrestling practice and postwrestling practice for the same test battery and protocol in mid-October. They had begun practicing weight-cutting tactics a day before prepractice and postpractice testing. Differences between these measures permitted us to evaluate how dehydration and weight-cutting tactics affected concussion measures. MAIN OUTCOME MEASURES: Sport Concussion Assessment Tool 2 (SCAT2), Balance Error Scoring System, Graded Symptom Checklist, and Simple Reaction Time scores. The Simple Reaction Time was measured using the Automated Neuropsychological Assessment Metrics. RESULTS: The SCAT2 measurements were lower at prepractice (P = .002) and postpractice (P < .001) when compared with baseline. The BESS error scores were higher at postpractice when compared with baseline (P = .015). The GSC severity scores were higher at prepractice (P = .011) and postpractice (P < .001) than at baseline and at postpractice when than at prepractice (P = .003). The number of Graded Symptom Checklist symptoms reported was also higher at prepractice (P = .036) and postpractice (P < .001) when compared with baseline, and at postpractice when compared with prepractice (P = .003). CONCLUSIONS: Our results suggest that it is important for wrestlers to be evaluated in a euhydrated state to ensure that dehydration is not influencing the outcome of the clinical measures. PMID- 23672380 TI - Instruction and jump-landing kinematics in college-aged female athletes over time. AB - CONTEXT: Instruction can be used to alter the biomechanical movement patterns associated with anterior cruciate ligament (ACL) injuries. OBJECTIVE: To determine the effects of instruction through combination (self and expert) feedback or self-feedback on lower extremity kinematics during the box-drop-jump task, running-stop-jump task, and sidestep-cutting maneuver over time in college aged female athletes. DESIGN: Randomized controlled clinical trial. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Forty-three physically active women (age = 21.47 +/- 1.55 years, height = 1.65 +/- 0.08 m, mass = 63.78 +/- 12.00 kg) with no history of ACL or lower extremity injuries or surgery in the 2 months before the study were assigned randomly to 3 groups: self-feedback (SE), combination feedback (CB), or control (CT). INTERVENTION(S): Participants performed a box-drop-jump task for the pretest and then received feedback about their landing mechanics. After the intervention, they performed an immediate posttest of the box-drop-jump task and a running-stop-jump transfer test. Participants returned 1 month later for a retention test of each task and a sidestep-cutting maneuver. Kinematic data were collected with an 8-camera system sampled at 500 Hz. MAIN OUTCOME MEASURE(S): The independent variables were feedback group (3), test time (3), and task (3). The dependent variables were knee- and hip-flexion, knee-valgus, and hip- abduction kinematics at initial contact and at peak knee flexion. RESULTS: For the box-drop-jump task, knee- and hip-flexion angles at initial contact were greater at the posttest than at the retention test (P < .001). At peak knee flexion, hip flexion was greater at the posttest than at the pretest (P = .003) and was greater at the retention test than at the pretest (P = .04); knee valgus was greater at the retention test than at the pretest (P = .03) and posttest (P = .02). Peak knee flexion was greater for the CB than the SE group (P = .03) during the box-drop-jump task at posttest. For the running-stop-jump task at the posttest, the CB group had greater peak knee flexion than the SE and CT (P <= .05). CONCLUSIONS: Our results suggest that feedback involving a combination of self-feedback and expert video feedback with oral instruction effectively improved lower extremity kinematics during jump landing tasks. PMID- 23672381 TI - Lower limb kinematics and dynamic postural stability in anterior cruciate ligament-reconstructed female athletes. AB - CONTEXT: Deficits in lower limb kinematics and postural stability are predisposing factors to the development of knee ligamentous injury. The extent to which these deficits are present after anterior cruciate ligament (ACL) reconstruction is still largely unknown. The primary hypothesis of the present study was that female athletes who have undergone ACL reconstruction and who have returned to sport participation would exhibit deficits in dynamic postural stability as well as deficiencies in hip- and knee-joint kinematics when compared with an age-, activity-, and sex-matched uninjured control group. OBJECTIVE: To investigate dynamic postural stability as quantified by the Star Excursion Balance Test (SEBT) and simultaneous hip- and knee-joint kinematic profiles in female athletes who have undergone ACL reconstruction. DESIGN: Descriptive laboratory study. SETTING: University motion-analysis laboratory. PATIENTS OR OTHER PARTICIPANTS: Fourteen female athletes who had previously undergone ACL reconstruction (ACL-R) and 17 age- and sex-matched uninjured controls. INTERVENTION(S): Each participant performed 3 trials of the anterior, posterior medial, and posterior-lateral directional components of the SEBT. MAIN OUTCOME MEASURE(S): Reach distances for each directional component were quantified and expressed as a percentage of leg length. Simultaneous hip- and knee-joint kinematic profiles were recorded using a motion-analysis system. RESULTS: The ACL R group had decreased reach distances on the posterior-medial (P < .01) and posterior-lateral (P < .01) directional components of the SEBT. During performance of the directional components of the SEBT, ACL-R participants demonstrated altered hip-joint frontal-, sagittal-, and transverse-plane kinematic profiles (P < .05), as well as altered knee-joint sagittal-plane kinematic profiles (P < .05). CONCLUSIONS: Deficits in dynamic postural stability and concomitant altered hip- and knee-joint kinematics are present after ACL reconstruction and return to competitive activity. The extent to which these deficits influence potential future injury is worthy of investigation. PMID- 23672382 TI - Pain and effusion and quadriceps activation and strength. AB - CONTEXT: Quadriceps dysfunction is a common consequence of knee joint injury and disease, yet its causes remain elusive. OBJECTIVE: To determine the effects of pain on quadriceps strength and activation and to learn if simultaneous pain and knee joint effusion affect the magnitude of quadriceps dysfunction. DESIGN: Crossover study. SETTING: University research laboratory. PATIENTS OR OTHER PARTICIPANTS: Fourteen (8 men, 6 women; age = 23.6 +/- 4.8 years, height = 170.3 +/- 9.16 cm, mass = 72.9 +/- 11.84 kg) healthy volunteers. INTERVENTION(S): All participants were tested under 4 randomized conditions: normal knee, effused knee, painful knee, and effused and painful knee. MAIN OUTCOME MEASURE(S): Quadriceps strength (Nm/kg) and activation (central activation ratio) were assessed after each condition was induced. RESULTS: Quadriceps strength and activation were highest under the normal knee condition and differed from the 3 experimental knee conditions (P < .05). No differences were noted among the 3 experimental knee conditions for either variable (P > .05). CONCLUSIONS: Both pain and effusion led to quadriceps dysfunction, but the interaction of the 2 stimuli did not increase the magnitude of the strength or activation deficits. Therefore, pain and effusion can be considered equally potent in eliciting quadriceps inhibition. Given that pain and effusion accompany numerous knee conditions, the prevalence of quadriceps dysfunction is likely high. PMID- 23672383 TI - Muscle spindle traffic in functionally unstable ankles during ligamentous stress. AB - CONTEXT: Ankle sprains are common in athletes, with functional ankle instability (FAI) developing in approximately half of cases. The relationship between laxity and FAI has been inconclusive, suggesting that instability may be caused by insufficient sensorimotor function and dynamic restraint. Research has suggested that deafferentation of peripheral mechanoreceptors potentially causes FAI; however, direct evidence confirming peripheral sensory deficits has been elusive because previous investigators relied upon subjective proprioceptive tests. OBJECTIVE: To develop a method for simultaneously recording peripheral sensory traffic, joint forces, and laxity and to quantify differences between healthy ankles and those with reported instability. DESIGN: Case-control study. SETTING: University laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 29 participants (age = 20.9 +/- 2.2 years, height = 173.1 +/- 8.9 cm, mass = 74.5 +/- 12.7 kg) stratified as having healthy (HA, n = 19) or unstable ankles (UA, n = 10). INTERVENTION(S): Sensory traffic from muscle spindle afferents in the peroneal nerve was recorded with microneurography while anterior (AP) and inversion (IE) stress was applied to ligamentous structures using an ankle arthrometer under test and sham conditions. MAIN OUTCOME MEASURE(S): Laxity (millimeters or degrees) and amplitude of sensory traffic (percentage) were determined at 0, 30, 60, 90, and 125 N of AP force and at 0, 1, 2, 3, and 4 Nm of IE torque. Two factor repeated-measures analyses of variance were used to determine differences between groups and conditions. RESULTS: No differences in laxity were observed between groups (P > .05). Afferent traffic increased with increased force and torque in test trials (P < .001). The UA group displayed decreased afferent activity at 30 N of AP force compared with the HA group (HA: 30.2% +/- 9.9%, UA: 17.1% +/- 16.1%, P < .05). CONCLUSIONS: The amplitude of sensory traffic increased simultaneously with greater ankle motion and loading, providing evidence of the integrated role of capsuloligamentous and musculotendinous mechanoreceptors in maintaining joint sensation. Unstable ankles demonstrated diminished afferent traffic at low levels of force, suggesting the early detection of joint loading may be compromised. PMID- 23672384 TI - Fatigue-induced alterations of static and dynamic postural control in athletes with a history of ankle sprain. AB - CONTEXT: Sensorimotor control is impaired after ankle injury and in fatigued conditions. However, little is known about fatigue-induced alterations of postural control in athletes who have experienced an ankle sprain in the past. OBJECTIVE: To investigate the effect of fatiguing exercise on static and dynamic balance abilities in athletes who have successfully returned to preinjury levels of sport activity after an ankle sprain. DESIGN: Cohort study. SETTING: University sport science research laboratory. PATIENTS OR OTHER PARTICIPANTS: 30 active athletes, 14 with a previous severe ankle sprain (return to sport activity 6-36 months before study entry; no residual symptoms or subjective instability) and 16 uninjured controls. INTERVENTION(S): Fatiguing treadmill running in 2 experimental sessions to assess dependent measures. MAIN OUTCOME MEASURE(S): Center-of-pressure sway velocity in single-legged stance and time to stabilization (TTS) after a unilateral jump-landing task (session 1) and maximum reach distance in the Star Excursion Balance Test (SEBT) (session 2) were assessed before and immediately after a fatiguing treadmill exercise. A 2 factorial linear mixed model was specified for each of the main outcomes, and effect sizes (ESs) were calculated as Cohen d. RESULTS: In the unfatigued condition, between-groups differences existed only for the anterior-posterior TTS (P = .05, ES = 0.39). Group-by-fatigue interactions were found for mean SEBT (P = .03, ES = 0.43) and anterior-posterior TTS (P = .02, ES = 0.48). Prefatigue versus postfatigue SEBT and TTS differences were greater in previously injured athletes, whereas static sway velocity increased similarly in both groups. CONCLUSIONS: Fatiguing running significantly affected static and dynamic postural control in participants with a history of ankle sprain. Fatigue-induced alterations of dynamic postural control were greater in athletes with a previous ankle sprain. Thus, even after successful return to competition, ongoing deficits in sensorimotor control may contribute to the enhanced ankle reinjury risk. PMID- 23672385 TI - Resting arterial diameter and blood flow changes with resistance training and detraining in healthy young individuals. AB - CONTEXT: Disruptions to habitual training routines are commonly due to injury or illness and can often lead to detraining adaptations. The implications of such adaptations to the human vasculature in a trained, asymptomatic population are not fully understood. OBJECTIVE: To determine the extent of local and systemic changes in arterial diameter and blood flow to resistance training and subsequent detraining in young adults. DESIGN: Randomized controlled clinical trial. SETTING: University physiology laboratory and fitness suite. PATIENTS OR OTHER PARTICIPANTS: Twenty-one healthy volunteers (aged 20.0 +/- 2.8 years, 11 men and 10 women). INTERVENTION(S): Eight-week lower limb resistance training period and subsequent 4-week detraining period. MAIN OUTCOME MEASURE(S): Quadriceps and hamstrings concentric torque (strength), resting heart rate, arterial diameter, and blood flow velocity in the superficial femoral and carotid arteries were measured at 0, 8, 10, and 12 weeks. RESULTS: Resistance training increased quadriceps and hamstring strength (32% and 35%, respectively, P < .001), whereas strength decreased during detraining (24% and 27%, respectively, P < .05). Resting heart rate decreased after resistance training (16%, P < .01) and increased during detraining (19%, P < .001). Additionally, resistance training significantly increased superficial femoral and carotid resting arterial diameters (27% and 13%, respectively, P < .001) and mean blood flow (53% and 55%, respectively, P < .001). Detraining resulted in a significant decrease in superficial femoral and carotid resting diameter (46% and 10%, respectively, P < .001) and mean blood flow (61% and 38%, respectively, P < .05). CONCLUSIONS: Resistance training initiated both local and systemic changes to arterial diameter and blood flow; these changes appeared to reverse after detraining. The local changes in response to detraining showed a worsening (beyond pretraining values) of the vascular dimensional and blood flow characteristics. PMID- 23672386 TI - Topical menthol, ice, peripheral blood flow, and perceived discomfort. AB - CONTEXT: Injury management commonly includes decreasing arterial blood flow to the affected site in an attempt to reduce microvascular blood flow and edema and limit the induction of inflammation. Applied separately, ice and menthol gel decrease arterial blood flow, but the combined effects of ice and menthol gel on arterial blood flow are unknown. OBJECTIVES: To compare radial artery blood flow, arterial diameter, and perceived discomfort before and after the application of 1 of 4 treatment conditions. DESIGN: Experimental crossover design. SETTING: Clinical laboratory. PARTICIPANTS OR OTHER PARTICIPANTS: Ten healthy men, 9 healthy women (mean age = 25.68 years, mean height = 1.73 m, mean weight = 76.73 kg). INTERVENTION(S): Four treatment conditions were randomly applied for 20 minutes to the right forearm of participants on 4 different days separated by at least 24 hours: (1) 3.5 mL menthol gel, (2) 0.5 kg of crushed ice, (3) 3.5 mL of menthol gel and 0.5 kg of crushed ice, or (4) no treatment (control). MAIN OUTCOME MEASURE(S): Using high-resolution ultrasound, we measured right radial artery diameter (cm) and blood flow (mL/min) every 5 minutes for 20 minutes after the treatment was applied. Discomfort with the treatment was documented using a 1 to-10 intensity scale. RESULTS: Radial artery blood flow decreased (P < .05) from baseline in the ice (-20% to -24%), menthol (-17% to -24%), and ice and menthol ( 36% to -39%) treatments but not in the control (3% to 9%) at 5, 10, and 15 minutes. At 20 minutes after baseline, only the ice (-27%) and combined ice and menthol (-38%) treatments exhibited reductions in blood flow (P < .05). Discomfort was less with menthol than with the ice treatment at 5, 10, and 20 minutes after application (P < .05). Arterial diameter and heart rate did not change. CONCLUSIONS: The application of 3.5 mL of menthol was similar to the application of 0.5 kg of crushed ice in reducing peripheral blood flood. Combining crushed ice with menthol appeared to have an additive effect on reducing blood flow. PMID- 23672387 TI - Graduated compression stockings for runners: friend, foe, or fake? AB - OBJECTIVE: To assess the effect of graduated compression stockings (GCS) on lower leg volume and leg complaints in runners during and after exercise. DESIGN: Cross sectional study. SETTING: Radboud University Nijmegen Medical Centre and an outdoor running track in Nijmegen, The Netherlands. PATIENTS OR OTHER PARTICIPANTS: Thirteen Dutch trained recreational runners. INTERVENTION(S): Participants used a GCS on 1 leg during running. MAIN OUTCOME MEASURES: (1) Lower leg volume of both legs was measured at baseline, directly after running, and at 5 minutes and 30 minutes after running using a validated perometer. (2) Leg complaints were reported on questionnaires at set intervals. RESULTS: (1) In both experiments, the legs with GCS showed a reduction in mean (+/- SEM) leg volume directly after running, as compared with the leg without GCS: -14.1 +/- 7.6 mL (P = .04) for the 10-km running track and -53.5 +/- 17.8 mL (P = .03) for the maximum exercise test. This effect was not observed at 5 and 30 minutes after running. (2) No differences in leg complaints were reported in either experiment. CONCLUSIONS: The GCS prevented an increase in leg volume just after the running exercise. However, this result was not accompanied by a reduction in subjective questionnaire-reported leg complaints. The practical consequences of the present findings need further study. PMID- 23672388 TI - A unique patient population? Health-related quality of life in adolescent athletes versus general, healthy adolescent individuals. AB - CONTEXT: Normative scores for patient-rated outcome (PRO) instruments are important for providing patient-centered, whole-person care and making informed clinical decisions. Although normative values for the Pediatric Quality of Life Generic Core Scale (PedsQL) have been established in the general, healthy adolescent population, whether adolescent athletes demonstrate similar values is unclear. OBJECTIVE: To compare PedsQL scores between adolescent athletes and general, healthy adolescent individuals. DESIGN: Cross-sectional study. SETTING: Secondary schools. PATIENTS OR OTHER PARTICIPANTS: A convenience sample of 2659 interscholastic athletes (males = 2059, females = 600, age = 15.7 +/- 1.1 years) represented the athlete group (ATH), and a previously published normative dataset represented the general, healthy adolescent group (GEN). INTERVENTION(S): All participants completed the PedsQL during 1 testing session. MAIN OUTCOME MEASURE(S): The PedsQL consists of 2 summary scores (total, psychosocial) and 4 subscale scores (physical, emotional, social, school), with higher scores indicating better health-related quality of life (HRQOL). Groups were stratified by age (14, 15, or 16 years old). Independent-samples t tests were conducted to compare between-groups and sex differences. RESULTS: The ATH group scored higher than the GEN group across all ages for total and psychosocial summary scores and for emotional and social functioning subscale scores (P <= .005). For physical functioning, scores of the 15-year-old ATH were higher than for their GEN counterparts (P = .001). Both 14- and 15-year-old ATH scored higher than their GEN counterparts for the school functioning subscale (P <= .013), but differences between 16-year olds were not significant (P = .228). Male adolescent athletes reported higher scores than female adolescent athletes across all scores (P <= .001) except for social functioning (P = .229). CONCLUSIONS: Adolescent athletes reported better HRQOL than GEN, particularly in emotional functioning. These findings further support the notion that ATH constitutes a unique population that requires its own set of normative values for self-reported, patient-rated outcome instruments. PMID- 23672389 TI - High school automated external defibrillator programs as markers of emergency preparedness for sudden cardiac arrest. AB - CONTEXT: School-based automated external defibrillator (AED) programs have demonstrated a high survival rate for individuals suffering sudden cardiac arrest (SCA) in US high schools. OBJECTIVE: To examine the relationship between high schools having an AED on campus and other measures of emergency preparedness for SCA. DESIGN: Cross-sectional study. SETTING: United States high schools, December 2006 to September 2009. PATIENTS OR OTHER PARTICIPANTS: Principals, athletic directors, school nurses, and certified athletic trainers represented 3371 high schools. MAIN OUTCOME MEASURE(S): Comprehensive surveys on emergency planning for SCA submitted by high school representatives to the National Registry for AED Use in Sports from December 2006 to September 2009. Schools with and without AEDs were compared to assess other elements of emergency preparedness for SCA. RESULTS: A total of 2784 schools (82.6%) reported having 1 or more AEDs on campus, with an average of 2.8 AEDs per school; 587 schools (17.4%) had no AEDs. Schools with an enrollment of more than 500 students were more likely to have an AED (relative risk [RR] = 1.12, 95% confidence interval [CI] = 1.08, 1.16, P < .01). Suburban schools were more likely to have an AED than were rural (RR = 1.08, 95% CI = 1.04, 1.11, P < .01), urban (RR = 1.13, 95% CI = 1.04, 1.16, P < .01), or inner-city schools (RR = 1.10, 95% CI = 1.04, 1.23, P < .01). Schools with 1 or more AEDs were more likely to ensure access to early defibrillation (RR = 3.45, 95% CI = 2.97, 3.99, P < .01), establish an emergency action plan for SCA (RR = 1.83, 95% CI = 1.67, 2.00, P < .01), review the emergency action plan at least annually (RR = 1.99, 95% CI = 1.58, 2.50, P < .01), consult emergency medical services to develop the emergency action plan (RR = 1.18, 95% CI = 1.05, 1.32, P < .01), and establish a communication system to activate emergency responders (RR = 1.06, 95% CI = 1.01, 1.08, P < .01). CONCLUSIONS: High schools with AED programs were more likely to establish a comprehensive emergency response plan for SCA. Implementing school-based AED programs is a key step associated with emergency planning for young athletes with SCA. PMID- 23672390 TI - Various methods for assessing static lower extremity alignment: implications for prospective risk-factor screenings. AB - CONTEXT: Accurate, efficient, and reliable measurement methods are essential to prospectively identify risk factors for knee injuries in large cohorts. OBJECTIVE: To determine tester reliability using digital photographs for the measurement of static lower extremity alignment (LEA) and whether values quantified with an electromagnetic motion-tracking system are in agreement with those quantified with clinical methods and digital photographs. DESIGN: Descriptive laboratory study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirty-three individuals participated and included 17 (10 women, 7 men; age = 21.7 +/- 2.7 years, height = 163.4 +/- 6.4 cm, mass = 59.7 +/- 7.8 kg, body mass index = 23.7 +/- 2.6 kg/m2) in study 1, in which we examined the reliability between clinical measures and digital photographs in 1 trained and 1 novice investigator, and 16 (11 women, 5 men; age = 22.3 +/- 1.6 years, height = 170.3 +/- 6.9 cm, mass = 72.9 +/- 16.4 kg, body mass index = 25.2 +/- 5.4 kg/m2) in study 2, in which we examined the agreement among clinical measures, digital photographs, and an electromagnetic tracking system. INTERVENTION(S): We evaluated measures of pelvic angle, quadriceps angle, tibiofemoral angle, genu recurvatum, femur length, and tibia length. Clinical measures were assessed using clinically accepted methods. Frontal- and sagittal-plane digital images were captured and imported into a computer software program. Anatomic landmarks were digitized using an electromagnetic tracking system to calculate static LEA. MAIN OUTCOME MEASURE(S): Intraclass correlation coefficients and standard errors of measurement were calculated to examine tester reliability. We calculated 95% limits of agreement and used Bland-Altman plots to examine agreement among clinical measures, digital photographs, and an electromagnetic tracking system. RESULTS: Using digital photographs, fair to excellent intratester (intraclass correlation coefficient range = 0.70-0.99) and intertester (intraclass correlation coefficient range = 0.75-0.97) reliability were observed for static knee alignment and limb-length measures. An acceptable level of agreement was observed between clinical measures and digital pictures for limb-length measures. When comparing clinical measures and digital photographs with the electromagnetic tracking system, an acceptable level of agreement was observed in measures of static knee angles and limb-length measures. CONCLUSIONS: The use of digital photographs and an electromagnetic tracking system appears to be an efficient and reliable method to assess static knee alignment and limb-length measurements. PMID- 23672391 TI - National Athletic Trainers' Association position statement: lightning safety for athletics and recreation. AB - OBJECTIVE: To present recommendations for the education, prevention, and management of lightning injuries for those involved in athletics or recreation. BACKGROUND: Lightning is the most common severe-storm activity encountered annually in the United States. The majority of lightning injuries can be prevented through an aggressive educational campaign, vacating outdoor activities before the lightning threat, and an understanding of the attributes of a safe place from the hazard. RECOMMENDATIONS: This position statement is focused on supplying information specific to lightning safety and prevention and treatment of lightning injury and providing lightning-safety recommendations for the certified athletic trainer and those who are involved in athletics and recreation. PMID- 23672392 TI - Pancreatic laceration in a female collegiate soccer athlete: a case report. AB - OBJECTIVE: To characterize the diagnosis of pancreatic trauma in an athletic population and to raise awareness among health care providers of the possibility of this life- and organ-threatening injury. BACKGROUND: An 18-year-old, previously healthy female collegiate soccer athlete sustained a direct blow from an opponent's knee between the left and right upper abdominal quadrants while attempting to head the ball. She initially presented with only minimal nausea and discomfort, but this progressed to abdominal pain, tenderness, spasm, and vomiting. She was referred to the emergency department, where she was diagnosed with a pancreatic laceration. DIFFERENTIAL DIAGNOSIS: Duodenal, hepatic, or splenic contusion or laceration; hemorrhagic ovarian cyst. TREATMENT: The patient underwent a distal pancreatectomy and total splenectomy. UNIQUENESS: Pancreatic injuries, particularly those severe enough to warrant surgical intervention, are extremely rare in athletes. CONCLUSIONS: Recognition of a pancreatic injury can be very challenging outside the hospital setting. This is problematic, because a delay in diagnosis is a significant source of preventable morbidity and mortality after this rare injury. Thus, early identification depends on a high index of suspicion, a thorough examination, and close observation. It is imperative that athletic trainers and other health care professionals be able to identify this condition so that referral and management can occur without delay. PMID- 23672393 TI - Pneumomediastinum and pneumopericardium in an 11-year-old rugby player: a case report. AB - OBJECTIVE: Pneumomediastinum and pneumopericardium are rare occurrences in young athletes, but they can result in potentially life-threatening consequences. BACKGROUND: While involved in a rugby match, an 11-year-old boy received a chest compression by 3 players during a tackle. He continued to play, but 2 hours later, he developed sharp retrosternal chest pain. A chest radiograph and an echocardiograph at the nearest emergency department showed pneumopericardium and pneumomediastinum. DIFFERENTIAL DIAGNOSIS: Sternal and rib contusions, rib fractures, heartburn, acute asthma exacerbation, pneumomediastinum, pneumopericardium, pneumothorax, traumatic tracheal rupture, myocardial infarction, and costochondritis (Tietze syndrome). TREATMENT: Acetaminophen for pain control. UNIQUENESS: To our knowledge, this is the only case in the international literature of the simultaneous occurrence of pneumomediastinum and pneumopericardium in a child as a consequence of blunt chest trauma during a rugby match. CONCLUSIONS: Pneumomediastinum and pneumopericardium may be consequences of rugby blunt chest trauma. Symptoms can appear 1 to 2 hours later, and the conditions may result in serious complications. Immediate admission to the emergency department is required. PMID- 23672397 TI - Functional modelling of planar cell polarity: an approach for identifying molecular function. AB - BACKGROUND: Cells in some tissues acquire a polarisation in the plane of the tissue in addition to apical-basal polarity. This polarisation is commonly known as planar cell polarity and has been found to be important in developmental processes, as planar polarity is required to define the in-plane tissue coordinate system at the cellular level. RESULTS: We have built an in-silico functional model of cellular polarisation that includes cellular asymmetry, cell cell signalling and a response to a global cue. The model has been validated and parameterised against domineering non-autonomous wing hair phenotypes in Drosophila. CONCLUSIONS: We have carried out a systematic comparison of in-silico polarity phenotypes with patterns observed in vivo under different genetic manipulations in the wing. This has allowed us to classify the specific functional roles of proteins involved in generating cell polarity, providing new hypotheses about their specific functions, in particular for Pk and Dsh. The predictions from the model allow direct assignment of functional roles of genes from genetic mosaic analysis of Drosophila wings. PMID- 23672398 TI - ATP-dependent regulation of actin monomer-filament equilibrium by cyclase associated protein and ADF/cofilin. AB - CAP (cyclase-associated protein) is a conserved regulator of actin filament dynamics. In the nematode Caenorhabditis elegans, CAS-1 is an isoform of CAP that is expressed in striated muscle and regulates sarcomeric actin assembly. In the present study, we report that CAS-2, a second CAP isoform in C. elegans, attenuates the actin-monomer-sequestering effect of ADF (actin depolymerizing factor)/cofilin to increase the steady-state levels of actin filaments in an ATP dependent manner. CAS-2 binds to actin monomers without a strong preference for either ATP- or ADP-actin. CAS-2 strongly enhances the exchange of actin-bound nucleotides even in the presence of UNC-60A, a C. elegans ADF/cofilin that inhibits nucleotide exchange. UNC-60A induces the depolymerization of actin filaments and sequesters actin monomers, whereas CAS-2 reverses the monomer sequestering effect of UNC-60A in the presence of ATP, but not in the presence of only ADP or the absence of ATP or ADP. A 1:100 molar ratio of CAS-2 to UNC-60A is sufficient to increase actin filaments. CAS-2 has two independent actin-binding sites in its N- and C-terminal halves, and the C-terminal half is necessary and sufficient for the observed activities of the full-length CAS-2. These results suggest that CAS-2 (CAP) and UNC-60A (ADF/cofilin) are important in the ATP dependent regulation of the actin monomer-filament equilibrium. PMID- 23672400 TI - Comparison between sensory and motor transcutaneous electrical nervous stimulation on electromyographic and kinesiographic activity of patients with temporomandibular disorder: a controlled clinical trial. AB - BACKGROUND: The purpose of the present controlled clinical trial was to assess the effect of a single 60 min application of transcutaneous electrical nervous stimulation (TENS) at sensory stimulation threshold (STS), compared to the application of motor stimulation threshold (MTS) as well as to untreatment, on the surface electromyographic (sEMG) and kinesiographic activity of patients with tempormanbibular disorder (TMD). METHODS: Sixty female subjects, selected according to the inclusion/exclusion criteria, suffering from unilateral TMD in remission were assigned to MTS, STS or untreatment. Pre- and post-treatment differences in the sEMG activity of temporalis anterior (TA), masseter (MM), digastric (DA) and sternocleidomastoid muscles (SCM), as well in the interocclusal distance (ID), within group were tested using the Wilcoxon test, while differences among groups were assessed by Kruskal-Wallis test; the level of significance was set at p<=0.05. RESULTS: Significant pre- and post-treatment differences were observed in MTS and STS groups, for TA and MM of both sides; no significant difference was detected between MTS and STS groups. Kinesiographic results showed that the vertical component of ID was significantly increased after TENS in MTS and STS groups. CONCLUSIONS: STS TENS could be effective, as well as MTS, in reduce the sEMG activity of masticatory muscles and to improve the ID of TMD patients in remission. Future studies are needed to confirm the results of the present study. Clinical relevance. The present study demonstrates that the application of TENS is effective in reduce the sEMG activity, as well as in increasing the ID of patients with TMD; our study did not support superior effectiveness of MTS or STS. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01832207. PMID- 23672401 TI - Photodynamic agents with anti-metastatic activities. AB - A new concept in multifunctional anticancer agents is demonstrated. Tetrakis (diisopropyl-guanidino) zinc phthalocyanine (Zn-DIGP) exhibits excellent properties as a photodynamic therapy (PDT) agent, as well as potential anti metastatic activities in vivo. Zn-DIGP exhibits good cellular uptake and low toxicity in the dark (EC50 > 80 MUM) and is well tolerated upon its intravenous injection into mice at 8 mg/kg. Upon photoexcitation with red laser light (660 nm), Zn-DIGP exhibits a high quantum yield for singlet oxygen formation (Phi ~ 0.51) that results in potent phototoxicity to cell cultures (EC50 ~ 0.16 MUM). Zn DIGP is also capable of inhibiting the formation of tumor colonies in the lungs of C57BL/6 mice injected with B16F10 cells. Zn-DIGP therefore inhibits cancer growth by both light-dependent and light-independent pathways. The anti metastatic activities of Zn-DIGP possibly result from its ability to interfere with the signaling between chemokine CXCL10 and the G protein-coupled receptor CXCR3. Zn-DIGP is a competitive inhibitor of CXCR3 activation (IC50 = 3.8 MUM) and selectively inhibits downstream events such as CXCL10-activated cell migration. Consistent with the presence of feedback regulation between CXCR3 binding and CXCL10 expression, Zn-DIGP causes overexpression of CXCL10. Interestingly, Zn-DIGP binds to CXCR3 without activating the receptor yet is able to cause endocytosis and degradation of this GPCR. To the best of our knowledge, Zn-DIGP is the first PDT agent that can facilitate the photodynamic treatment of primary tumors while simultaneously inhibiting the formation of metastatic tumor colonies by a light-independent mode of action. PMID- 23672402 TI - Current status and future perspectives of dendritic cell-based cancer immunotherapy. AB - Dendritic cells (DCs) are considered to be the most potent antigen-presenting cells. Ever since the development of protocols for the in vitro generation of DCs, their application in immunotherapy against various malignancies has been explored. Even though the approach of using tumour antigen-presenting DCs in therapeutic vaccination strategies has been shown to work effectively in mice and look promising in in vitro studies, the actual clinical benefit for patients with cancer has been marginal. There clearly is still room for improvement. In this review, we will summarize recent clinical trials and findings and try to shed some light on the current status and the future of DC-based cancer immunotherapy. PMID- 23672403 TI - Polychlorinated biphenyls and cancer: an epidemiological assessment. AB - Polychlorinated biphenyls (PCBs) are toxic and persistent chemicals produced between 1930s and 1980s primarily for insulating fluids in heavy-duty electrical equipment in power plants, industries, and large buildings. They persist in the environment and accumulate in plants and animals, and have been classified as probable carcinogens to humans. We performed a systematic review and meta analysis of scientific literature on the relationship between PCB exposure and human cancer. Two cohorts of people highly exposed to PCBs through ingestion of contaminated rice oil and some cohorts of occupationally exposed workers failed to show a definite increase in total cancer mortality and provided inconsistent results regarding single cancers. Several cohort and case-control studies investigated the association between PCBs and specific cancers, showing an association between PCB serum levels and non-Hodgkin lymphomas (NHL), with a summary odds ratio of 1.5 (95% confidence interval: 1.1-1.7), but no consistent results for the other cancer sites and types. In conclusion, this review provides some evidence for the role of PCBs in the development of NHL, although the inconsistent results of studies performed on highly polluted people and occupationally exposed workers do not allow a firm conclusion to be drawn. PMID- 23672404 TI - A study on determination of potentially hazardous plutonium isotopes in environmental samples. AB - Due to the lack of stable plutonium isotopes, and the high mobility as well as long half-life, plutonium is considered one of the most important radioelement in safety assessment of environmental radioactivity and nuclear waste management. A number of analytical methods have been developed over the past decades for determination of plutonium in environmental samples. The article discusses different analytical techniques and presents the results of plutonium isotopes determination by alpha spectrometry and accelerator mass spectrometry in environmental samples. The concentrations of plutonium isotopes in analyzed samples indicates its measurement is of great importance for environmental and safety assessment, especially in contaminated areas. PMID- 23672405 TI - Endocrine disruptors and human corpus luteum: in vitro effects of phenols on luteal cells function. AB - Endocrine disruptors are well known to impair fertility. The aim of the present study was to investigate the effects of bisphenol A (BPA) and nonylphenol (p-NP) on human luteal function in vitro. In particular, in luteal cells isolated from 21 human corpora lutea progesterone, prostaglandin (PG) F2alpha, PGE2 and vascular endothelial growth factor (VEGF) release, as well as VEGF expression were evaluated. BPA and p-NP negatively affected both luteal steroidogenesis and luteotrophic/ luteolytic factors balance, without influencing VEGF mRNA expression. Actually, BPA and p-NP impaired human luteal cells function in vitro, underlining the already suggested correlation between phenols and reproductive failure. PMID- 23672406 TI - Understanding the site selectivity in small-sized neutral and charged Al(n) (4 <= N <= 7) clusters using density functional theory based reactivity descriptors: a validation study on water molecule adsorption. AB - Aluminum clusters are now technologically important due to their high catalytic activity. Our present study on the small-sized aluminum clusters applies density functional theory (DFT)-based reactivity descriptors to identify potential sites for adsorption and eventual chemical reaction. Depending on symmetry, susceptibility of various type of reactive sites within a cluster toward an impending electrophilic and/or nucleophilic attack is predicted using the reactivity descriptors. In addition, the study devises general rules as to how the size, shape, and charge of the cluster influences the number of available sites for an electrophilic and/or nucleophilic attack. The predictions by reactivity descriptors are validated by performing an explicit adsorption of water molecule on Al clusters with four atoms. The adsorption studies demonstrate that the most stable water-cluster complex is obtained when the molecule is adsorbed through an oxygen atom on the site with the highest relative electrophilicity. PMID- 23672407 TI - Lower respiratory tract viral infections in pediatric abdominal organ transplant recipients: a single hospital inpatient cohort study. AB - Respiratory viral infections are a major cause of morbidity and mortality in solid organ transplant recipients. Early detection of a viral etiology of a LRTI in a febrile transplant recipient can theoretically reduce the use of antibiotics, trigger modification of immunosuppression and prompt appropriate isolation procedures to reduce nosocomial infections. We retrospectively evaluated pediatric abdominal organ transplant recipients hospitalized with respiratory illnesses to determine the viral pathogens identified by various methods including multiplex RT-PCR performed on nasopharyngeal or endotracheal aspirates. Among 30 symptomatic subjects (median age, 2.5 yr) evaluated using this methodology, 25 (83%) were positive for at least one virus. Rhinovirus was the most frequently identified virus (14 subjects). RSV was identified in five subjects with associated mortality of 40%. Parainfluenza, influenza, metapneumovirus, and adenovirus were also identified. This study indicates that rhinovirus is a significant cause of morbidity in this single center cohort of pediatric abdominal organ transplant recipients. PMID- 23672408 TI - Redox couples with unequal diffusion coefficients: effect on redox cycling. AB - Redox cycling between two electrodes separated by a narrow gap allows dramatic amplification of the faradaic current. Unlike conventional electrochemistry at a single electrode, however, the mass-transport-limited current is controlled by the diffusion coefficient of both the reduced and oxidized forms of the redox active species being detected and, counterintuitively, by the redox state of molecules in the bulk solution outside the gap itself. Using a combination of finite-element simulations, analytical theory, and experimental validation, we elucidate the interplay between these interrelated factors. In so doing, we generalize previous results obtained in the context of scanning electrochemical microscopy and obtain simple analytical results that are generally applicable to experimental situations where efficient redox cycling takes place. PMID- 23672409 TI - Does the availability of snack foods in supermarkets vary internationally? AB - BACKGROUND: Cross-country differences in dietary behaviours and obesity rates have been previously reported. Consumption of energy-dense snack foods and soft drinks are implicated as contributing to weight gain, however little is known about how the availability of these items within supermarkets varies internationally. This study assessed variations in the display of snack foods and soft drinks within a sample of supermarkets across eight countries. METHODS: Within-store audits were used to evaluate and compare the availability of potato chips (crisps), chocolate, confectionery and soft drinks. Displays measured included shelf length and the proportion of checkouts and end-of-aisle displays containing these products. Audits were conducted in a convenience sample of 170 supermarkets across eight developed nations (Australia, Canada, Denmark, Netherlands, New Zealand, Sweden, United Kingdom (UK), and United States of America (US)). RESULTS: The mean total aisle length of snack foods (adjusted for store size) was greatest in supermarkets from the UK (56.4 m) and lowest in New Zealand (21.7 m). When assessed by individual item, the greatest aisle length devoted to chips, chocolate and confectionery was found in UK supermarkets while the greatest aisle length dedicated to soft drinks was in Australian supermarkets. Only stores from the Netherlands (41%) had less than 70% of checkouts featuring displays of snack foods or soft drinks. CONCLUSION: Whilst between-country variations were observed, overall results indicate high levels of snack food and soft drinks displays within supermarkets across the eight countries. Exposure to snack foods is largely unavoidable within supermarkets, increasing the likelihood of purchases and particularly those made impulsively. PMID- 23672411 TI - Src homology phosphotyrosyl phosphatase-2 expression is an independent negative prognostic factor in human breast cancer. AB - AIMS: Src homology phosphotyrosyl phosphatase-2 (SHP2) is a ubiquitously expressed phosphatase that plays an essential role in the downstream signalling pathways of multiple growth factor receptors, thus representing a potential target for cancer therapy. Recent studies suggest that SHP2 contributes to tumour initiation, progression and metastasis in breast cancer, yet the impact of SHP2 expression on prognosis in human breast cancer has not been evaluated. METHODS AND RESULTS: To explore further the role of SHP2 in breast cancer, we conducted an immunohistochemical study using a tissue microarray encompassing 1401 formalin fixed breast cancer specimens with detailed clinical annotation and outcome data. Of 1401 evaluable breast cancers, 651 (46%) were positive for SHP2. SHP2 expression was associated positively with tumour grade, lymph node status and tumour stage. In univariate survival analysis, cases with SHP2 expression had a significantly worse overall survival (OS). In multivariate analysis, SHP2 remained an independent negative prognostic factor for OS. SHP2 expression was a negative prognostic factor for OS in the luminal A and the luminal B HER2(-) intrinsic subtypes. CONCLUSIONS: Our data demonstrate for the first time that SHP2 is an independent predictor of survival in breast cancer, suggesting that SHP2 may be a potential target for therapy. PMID- 23672410 TI - Multiple genetic pathways regulate replicative senescence in telomerase-deficient yeast. AB - Most human tissues express low levels of telomerase and undergo telomere shortening and eventual senescence; the resulting limitation on tissue renewal can lead to a wide range of age-dependent pathophysiologies. Increasing evidence indicates that the decline in cell division capacity in cells that lack telomerase can be influenced by numerous genetic factors. Here, we use telomerase defective strains of budding yeast to probe whether replicative senescence can be attenuated or accelerated by defects in factors previously implicated in handling of DNA termini. We show that the MRX (Mre11-Rad50-Xrs2) complex, as well as negative (Rif2) and positive (Tel1) regulators of this complex, comprise a single pathway that promotes replicative senescence, in a manner that recapitulates how these proteins modulate resection of DNA ends. In contrast, the Rad51 recombinase, which acts downstream of the MRX complex in double-strand break (DSB) repair, regulates replicative senescence through a separate pathway operating in opposition to the MRX-Tel1-Rif2 pathway. Moreover, defects in several additional proteins implicated in DSB repair (Rif1 and Sae2) confer only transient effects during early or late stages of replicative senescence, respectively, further suggesting that a simple analogy between DSBs and eroding telomeres is incomplete. These results indicate that the replicative capacity of telomerase-defective yeast is controlled by a network comprised of multiple pathways. It is likely that telomere shortening in telomerase-depleted human cells is similarly under a complex pattern of genetic control; mechanistic understanding of this process should provide crucial information regarding how human tissues age in response to telomere erosion. PMID- 23672412 TI - Effects of disintegration on in vitro fermentation and conversion patterns of wheat aleurone in a metabolical colon model. AB - This work aimed to elucidate the effect of wheat aleurone integrity on its fermentability, i.e., the formation of short-chain fatty acids (SCFA) and microbial phenolic metabolites, in an in vitro model using human faecal microbiota as an inoculum. The structure of aleurone was modified by mechanical (dry grinding) or enzymatic (xylanase with or without feruloyl esterase) treatments in order to increase its physical accessibility and degrade its complex cell-wall network. The ground aleurone (smaller particle size) produced slightly more SCFA than the native aleurone during the first 8 h but a similar amount at 24 h (102.5 and 101 mmol/L, respectively). Similar colonic metabolism of ferulic acid (FA) was observed for native and ground aleurone. The enzymatic treatments of aleurone allowed a high solubilization of arabinoxylan (up to 82%) and a high release of FA in its conjugated and free forms (up to 87%). The enzymatic disintegration of aleurone's structure led to a higher concentration and formation rate of the colonic metabolites of FA (especially phenylpropionic acids) but did not change significantly the formation of SCFA (81 mmol/L for enzyme treated versus 101 mmol/L for the native aleurone). PMID- 23672413 TI - Model-driven diabetes care: study protocol for a randomized controlled trial. AB - BACKGROUND: People with type 1 diabetes who use electronic self-help tools register a large amount of information about their disease on their participating devices; however, this information is rarely utilized beyond the immediate investigation. We have developed a diabetes diary for mobile phones and a statistics-based feedback module, which we have named Diastat, to give data driven feedback to the patient based on their own data. METHOD: In this study, up to 40 participants will be given a smartphone on which is loaded a diabetes self help application (app), the Few Touch Application (FTA). Participants will be randomized into two groups to be given access to Diastat 4 or 12 weeks, respectively after receiving the smartphone, and will use the FTA with Diastat for 8 weeks after this point. The primary endpoint is the frequency of high and low blood-glucose measurements. DISCUSSION: The study will investigate the effect of data-driven feedback to patients. Our hypothesis is that this will improve glycemic control and reduce variability. The endpoints are robust indicators that can be assembled with minimal effort by the patient beyond normal routine. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01774149. PMID- 23672415 TI - Anticancer carbonic anhydrase inhibitors: a patent review (2008 - 2013). AB - INTRODUCTION: Human carbonic anhydrases (EC 4.2.1.1) IX (hCA IX) and XII (hCA XII) are two tumor-associated proteins, being overexpressed in many tumors and involved in critical processes associated with cancer progression and response to therapy. Both are multi-domain proteins consisting of an extracellular catalytic domain (CA), a transmembrane portion (TM) and an intracytoplasmic (IC) segment. These domains have peculiar biochemical and physiological features. CA IX contains an additional proteoglycan-like (PG) domain at the N-terminus which constitutes a unique feature of this enzyme within the CA family. AREAS COVERED: Starting from a brief description of the main molecular and catalytic features of both enzymes, their role in tumor physiology and their three-dimensional structure, this review describes the main classes of small molecule inhibitors, investigated between 2008 and 2013, able to inhibit these enzymes for both diagnostic and therapeutic applications. EXPERT OPINION: A consistent number of patents on molecules able to inhibit the catalytic activity of CA IX and CA XII have been recently reported. Most patents deal with classical sulfonamide derivatives, demonstrating that introducing suitable substituents on the inhibitor scaffold, good selectivity can be obtained. However, the most impressive results are related to compounds containing novel chemotypes, such as coumarins and thiocumarins. Thus, it is expected that research in next future will be more dedicated to the development of molecules containing new chemotypes and a large number of studies in such field have already been published demonstrating the role of these enzymes in carcinogenesis and metastases formation. PMID- 23672414 TI - The ERCC2 Gln/Gln polymorphism at codon 751 is not associated with leukaemic transformation in primary myelofibrosis. PMID- 23672416 TI - Chemoresistance in ovarian cancer linked to expression of microRNAs. AB - We evaluated the differential expression of several microRNAs (miRNAs) among malignant cells in ascites and matched omental metastasis in patients with epithelial ovarian cancer (EOC). Ascites and omental tumors were collected prospectively from five patients who were undergoing primary surgical cytoreduction. Patient samples were processed and treated with carboplatin, paclitaxel and combination chemotherapy. Cell viability was evaluated and miRNA profiling was performed on both tumor cells from ascites fluid and omental cake. Quantitative real-time PCR (RT-q-PCR) and western blots were used to evaluate expressions of miRNA-21 and miRNA -214 and associated proteins. Malignant cells in ascites showed greater cell viability when treated with carboplatin compared to omental metastasis. A significant up-regulation of miRNA-21 and miRNA-214 was observed in malignant cells of ascites compared to omental metastasis; this was confirmed by both cell viability assay and RT-q-PCR. Ours is the first report that demonstrates significant up-regulation of miRNA-21 and miRNA-214 in tumor cells from ascites of patients with EOC compared to omental metastasis. This finding has important implications for intrinsic carboplatin resistance in these patients. PMID- 23672417 TI - Effects of long term low dose acrylamide exposure on rat bone marrow polychromatic erythrocytes. AB - I investigated whether long term low dose exposure to acrylamide increased micronucleus frequency in rat bone marrow polychromatic erythrocytes (PCEs). Twenty-five male and 25 female Wistar rats were used. Animals of each sex were segregated into two treatment groups and one control group. Each treatment group consisted of ten animals and each control group consisted of five animals. Acrylamide, 2 or 5 mg/kg/day, was administered to the treatment groups in their drinking water for 90 days. Twenty-four hours after the last treatment, bone marrow samples were obtained and analyzed for the frequency of micronucleated polychromatic erythrocytes (MNPCEs). The cytotoxic effect of acrylamide on bone marrow also was tested by assessing the polychromatic erythrocyte/normochromatic erythrocyte (PCE/NCE) ratio. Both doses of acrylamide significantly increased the frequency of MNPCEs in both male and female rats. Acrylamide also decreased the PCE/NCE ratio in both sexes compared to the control group. My study showed that chronic low dose exposure to acrylamide increased the formation of micronuclei in PCEs of male and female rat bone marrow. PMID- 23672418 TI - Renal expression and functions of aquaporin 1 and aquaporin 4 in cattle. AB - Aquaporin (AQP) 1 and AQP 4 are members of the aquaporin water channel family that play an important role in reabsorption of water from the renal tubular fluid to concentrate urine. Studies of renal AQPs have been performed in human, rodents, sheep, dogs and horses. We studied nephron segment-specific expression of AQP 1 and AQP 4 using immunohistochemical staining on paraffin sections of bovine kidneys. AQP 1 was moderately expressed in endothelium of the cortical capillary network, vasa recta, and glomerular capillaries. AQP 4 was moderately expressed only in cytoplasm of epithelial cells in proximal tubules. We concluded that AQP 1 and AQP 4 in the bovine kidney showed some differences from other species in renal trans-epithelial water transport. PMID- 23672419 TI - Asymmetric catalysis with an inert chiral-at-metal iridium complex. AB - The development of a chiral-at-metal iridium(III) complex for the highly efficient catalytic asymmetric transfer hydrogenation of beta,beta'-disubstituted nitroalkenes is reported. Catalysis by this inert, rigid metal complex does not involve any direct metal coordination but operates exclusively through weak interactions with functional groups properly arranged in the ligand sphere of the iridium complex. Although the iridium complex relies only on the formation of three hydrogen bonds, it exceeds the performance of most organocatalysts with respect to enantiomeric excess (up to 99% ee) and catalyst loading (down to 0.1 mol %). This work hints at an advantage of structurally complicated rigid scaffolds for non-covalent catalysis, which especially relies on conformationally constrained cooperative interactions between the catalyst and substrates. PMID- 23672420 TI - Fabrication of novel p-BiOI/n-ZnTiO3 heterojunction for degradation of rhodamine 6G under visible light irradiation. AB - With the purpose of efficient electron-hole separation and enhancement of photocatalytic performance in the visible region, we have fabricated a novel p BiOI/n-ZnTiO3 heterojunction by a precipitation-deposition method and studied its activity toward dye degradation. The physicochemical characteristics of the fabricated BiOI/ZnTiO3 heterojunctions were surveyed by powder X-ray diffraction pattern (PXRD), BET-surface area, diffuse reflectance UV-vis (DRUV-vis), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), photoluminescence spectroscopy (PL spectra), X-ray photoelectron spectroscopy (XPS), and photoelectrochemical measurement. The photosensitization effect of BiOI enhanced the spectral response of ZnTiO3 from UV to visible region, making all the BiOI/ZnTiO3 heterojunctions active under visible light. The PEC measurement confirmed the p-type character of BiOI and n-type character of ZnTiO3. The optimal amount of BiOI in BiOI/ZnTiO3 heterojunctions was found to be 50% which degraded 82% of 50 ppm Rh 6G under visible light irradiation. The degradation rate of 50% BiOI/ZnTiO3 heterojunction was found to be 9.8 and 11.1 times higher than that of bare BiOI and ZnTiO3, respectively. The photosensitization effect of BiOI and the formed heterojunction between p-type BiOI and n-type ZnTiO3 contribute to improved electron-hole separation and enhancement in photocatalytic activity. PMID- 23672421 TI - Utilization of frozen plasma in Ontario: a provincewide audit reveals a high rate of inappropriate transfusions. AB - BACKGROUND: Frozen plasma (FP) is frequently transfused inappropriately, an intervention that results in risk without benefit for the patient. To better understand current utilization practices in our region, we undertook a provincewide prospective audit to evaluate the clinical indications and appropriateness of FP transfusion. STUDY DESIGN AND METHODS: All hospitals in the Canadian province of Ontario with transfusion medicine services were invited to participate in a 5-day audit of FP utilization. FP dose, indication, and clinical patient data were collected for each transfusion request. Indications for FP transfusions were independently adjudicated as appropriate, inappropriate, or indeterminate based on predefined criteria. RESULTS: Seventy-six (49%) of 155 invited hospitals participated in the audit, which included 573 requests for 2012 units of FP. A total of 559 transfusions (1909 units) were administered. Of 573 requests, 164 (28.6%) were deemed inappropriate most often because: 1) they were administered to patients with an international normalized ratio below 1.5 or 2) they were administered in absence of bleeding or emergency surgery. The most frequent indications for FP transfusions were before surgery and warfarin reversal. Overall, patients admitted to the clinical areas of surgery, internal medicine, and the emergency department represented the largest users of FP, but this varied by hospital type (community vs. academic). The most frequently requested doses of FP were 2 and 4 units. CONCLUSION: This point-prevalence hospital audit revealed that transfusion of FP is frequently inappropriate. Focusing on reducing the two most common reasons for inappropriate FP transfusions could lead to a significant improvement in FP utilization. PMID- 23672422 TI - The role of NOI-domain containing proteins in plant immune signaling. AB - Here we present an overview of our existing knowledge on the function of RIN4 as a regulator of plant defense and as a guardee of multiple plant R-proteins. Domain analysis of RIN4 reveals two NOI domains. The NOI domain was originally identified in a screen for nitrate induced genes. The domain is comprised of approximately 30 amino acids and contains 2 conserved motifs (PXFGXW and Y/FTXXF). The NOI gene family contains members exclusively from the plant lineage as far back as moss. In addition to the conserved NOI domain, members within the family also contain conserved C-terminal cysteine residue(s) which are sites for acylation and membrane tethering. Other than these two characteristic features, the sequence of the family of NOI-containing proteins is diverse and, with the exception of RIN4, their functions are not known. Recently published interactome data showing interactions between RIN4 and components of the exocyst complex prompt us to raise the hypothesis that RIN4 might be involved in defense associated vesicle trafficking. PMID- 23672423 TI - Water-assisted self-photoredox of 3-(hydroxymethyl)benzophenone: an unusual photochemistry reaction in aqueous solution. AB - An unusual photochemistry of water-assisted self-photoredox of 3-(hydroxymethyl) benzophenone 1 has been investigated by CASPT2//CASSCF computations. The water assisted self-photoredox is found to proceed via three sequential reactions: an excited-state intermolecular proton transfer (ESIPT), a photoinduced deprotonation, and a self-redox reaction. Upon photoexcitation at 243 nm, the system of 1 is taken to the Franck-Condon region of a short-distance charge transfer (SCT) state of S(SCT)((1)pipi*) and then undergoes ESIPT with a small barrier of ~3.4 kcal/mol producing the intermediate 2. Subsequently, the singlet triplet crossing (STC) of STC ((1)pipi*/(3)pipi*) relays 2 by intersystem crossing to the T(SCT)((3)pipi*) state followed by a deprotonation reaction overcoming a moderate barrier of ~8.0 kcal/mol and finally produces the triplet biradical intermediate 3. Another moderate barrier (~5.8 kcal/mol) in the T(SCT)((3)pipi*) state has to be overcome so as to relax to a second singlet triplet crossing STC(T/S0) that allows an efficient spin-forbidden decay to the ground state. The self-redox reaction aided by water molecules occurs with tiny barriers in the S0 state via two steps, protonation of the benzhydrol carbon to produce intermediate 4 and then deprotonation from the benzylic oxygen to yield the final product 3-formylbenzhydrol 5. PMID- 23672424 TI - Attitude towards antiretroviral Pre-Exposure Prophylaxis (PrEP) prescription among HIV specialists. AB - BACKGROUND: To investigate perceptions and attitude to prescribe Pre-Exposure Prophylaxis (PrEP) among HIV specialists. METHODS: A questionnaire developed through a Focus Group and literature review was administered to a convenience sample of HIV specialists during educational courses in two Regions and an online survey in February-May 2012. Participants were classified as having a positive or negative attitude according to their willingness to prescribe PrEP. Demographic and working information, experience with HIV-infected patients, information and provision of antiretrovirals to uninfected persons, self-reported knowledge, perceptions and concerns regarding PrEP were assessed. The association between a different attitude towards PrEP prescription and selected characteristics was assessed through univariate and multivariate regression analysis. RESULTS: Of 311 specialists, 70% would prescribe PrEP, mainly to serodiscordant partners (64%) but also to people at ongoing, high risk of HIV infection (56%); 66% advocated public support of costs. A negative attitude towards PrEP was significantly associated with lack of provision of information on, and prescription of, antiretroviral post-exposure prophylaxis; specialists with a negative attitude believed behavioural interventions to be more effective than PrEP and were more concerned about toxicity. Overall, 90% of specialists disagreed regarding a lack of time for engaging in prevention counselling and PrEP monitoring; 79% would welcome formal guidelines, while those with a negative attitude did not consider this advisable. CONCLUSIONS: Although conflicting attitudes appear evident, most specialists seem to be willing, with guidance from normative bodies, to promote PrEP within multiple prevention strategies among vulnerable populations. More scientific evidence regarding effectiveness could overcome resistance. PMID- 23672425 TI - Confocal laser endomicroscopy for detection of neoplasia in Barrett's esophagus: a meta-analysis. AB - Barrett's esophagus (BE) is associated with an increased risk of esophageal adenocarcinoma, and the recommended guideline for detection of neoplasia is surveillance endoscopy with random four-quadrant biopsies. Recently, a novel technique, confocal laser endomicroscopy (CLE), has emerged and enabled the endoscopist to perform a real-time histologic assessment of the gastrointestinal tract. We aimed to assess the accuracy of CLE in diagnosing BE-associated neoplasia by pooling data of existing trials. Databases including PubMed, EMBASE, the Cochrane Library, the Science Citation Index and momentous meeting abstracts were searched and evaluated by two reviewers independently. Meta-analysis was performed. Pooling data were conducted in a fixed effect model or a random effects model. Eight studies involving 709 patients and 4008 specimens were analyzed. In a per-patient analysis, the pooled sensitivity of CLE for detection of neoplasia was 89% (95% confidence interval [CI], 0.80-0.95), and the specificity was 75% (95% CI, 0.69-0.81). The area under the curve under the summary receiver operating characteristic was 0.9472. In a per-location analysis, the pooled sensitivity of CLE for detection of neoplasia was 70% (95% CI, 0.65 0.74), and the specificity was 91% (95% CI, 0.90-0.92). The area under the curve under the summary receiver operating characteristic was 0.9509. CLE is a reasonable, promising modality for management of patients with BE; more prospective trials need doing to determine whether it is superior to traditional method in diagnosing BE-associated neoplasia. PMID- 23672426 TI - Assessing the validity and reliability of the perceptions of the Consent To Sex Scale. AB - Although sexual assault prevention education tends to focus on consent promotion as a means to reduce rates of sexual assault, little is known about how college students consent to sexual activity. The current study aimed to better understand college students' consent via the systematic development of the Consent to Sex Scale (CSS), utilizing mixed methods via three phases and two waves of data collection. In Phase 1, qualitative data were collected from college students (n = 185) to provide a foundation for item writing. In Phase 2, closed-ended items were written for a quantitative instrument and reviewed by a team of experts. In Phase 3, a quantitative survey, including items written in Phase 2, was administered to college students (n = 685); the measure was assessed for its psychometric properties. Exploratory factor analysis was utilized, resulting in a five-factor solution. The CSS and corresponding factors demonstrated high internal consistency reliability and expected gender differences, supporting the construct validity of the measure. The CSS assesses college students' cues for indicating consent to sex, a construct not addressed by previous measures. The validated scale may be useful in future research to better understand how consent relates to other behaviors or constructs. PMID- 23672427 TI - Urinary high molecular weight matrix metalloproteinases as non-invasive biomarker for detection of bladder cancer. AB - BACKGROUND: Matrix Metalloproteinases (MMPs) are key molecules for tumor growth, invasion and metastasis. Over-expression of different MMPs in tumor tissues can disturb the homeostasis and increase the level of various body fluids. Many MMPs including high molecular weights (HMWs) were detected in the urine of prostate and bladder cancer patients. Our aim here is to assess the usefulness of HMW MMPs as non invasive biomarkers in bilharzial bladder cancer in Egyptian patients. METHODS: The activity of different MMPs including HMW species was determined using zymographic analysis technique in the urine samples procured from sixty six bladder cancer patients (bilharzial and non-bilharzial) as well as hundred healthy control subjects. Also, the correlation between these HMW MMPs activities and different clinico-pathological parameters was investigated. RESULTS: High frequency of urine MMPs (uMMPs) activity was determined in 63.6% of examined tumor cases, however, none of the control cases showed any uMMPs activity. MMP-9 had the highest activity (62%) followed by MMP9/NGAL (60%), MMP-2 (54.5%), MMP-9 dimer (53%), ADAMTS (25.6%), and the lowest one was MMP-9/TIMP-1 (12%) only. There was no correlation between uMMPs and any of clinico-pathological parameters including age, gender, tumor size and type, bilharziasis, grade, lymph node involvement, and invasion to the prostate. A significant correlation was established only between MMP-9/TIMP-1 activities with the tumor size. CONCLUSIONS: This study revealed that the detection of urinary MMPs including HMWs activity might be sensitive biomarkers for prediction of bladder cancer. It is also demonstrate that the detection of these urinary HMW gelatinases could not differentiate between bilharzial and non bilharzial bladder cancer subtypes. PMID- 23672428 TI - Axial preferences in allylation reactions via the Zimmerman-Traxler transition state. AB - The reaction of a substituted allylmetal with a prostereogenic carbonyl compound can give rise to up to two racemic diastereomers (syn and anti). Classically, in such reactions, when pure E-isomers have afforded anti-selectivity and the Z isomers exhibit syn-selectivity, researchers have used the empirical Zimmerman Traxler model. In this model, chair-like transition states dominate over boat like arrangements. The incoming aldehyde alkyl (aryl) residue occupies a pseudoequatorial rather than a pseudoaxial position to avoid potential 1,3 diaxial steric interactions. However, the reaction of gamma,gamma-disubstituted allylzinc species with carbonyl compounds generates two gauche interactions, which may result in a completely different stereochemical outcome. With these two gauche interactions, would a transition state in which the aldehyde substituent occupies a pseudoequatorial position or a pseudoaxial position be preferred? In this Account, we show that reaction of gamma,gamma-disubstituted allylzinc species with carbonyl compounds proceeds through a chair-like transition state and the substituent of the incoming aldehyde residue prefers to occupy a pseudoaxial position to avoid these two gauche interactions. Theoretical calculations on model systems support our experimental results. We have extended this new stereochemical outcome to describe the formation of alpha alkoxyallylation of aldehydes through the formation of the rather uncommon (E) gamma,gamma-disubstituted alkoxyallylzinc species. We also used this method to transform aromatic ketones and alpha-alkoxyaldehydes and ketones into functionalized adducts. In a one-pot reaction and using simple alkynes, three new carbon-carbon bonds and two to three stereogenic centers, including an all-carbon quaternary stereocenter could be created in acyclic systems. Because 1,3-diaxial interactions are now produced with the axial substituent, an increase in the substituent size on the zinc atom decreases the diastereoselectivity. PMID- 23672429 TI - Mitochondrial-targeted human catalase affords neuroprotection from proton irradiation. AB - Significant past work has linked radiation exposure of the CNS to elevated levels of oxidative stress and inflammation. These secondary reactive processes are both dynamic and persistent and are believed to compromise the functionality of the CNS, in part, by disrupting endogenous neurogenesis in the hippocampus. While evidence has shown neurogenesis to be sensitive to irradiation and redox state, the mechanistic basis underlying these effects is incompletely understood. To clarify the role of reactive oxygen species (ROS) in mediating radiation-induced changes in neurogenesis we have analyzed transgenic mice that overexpress human catalase localized to the mitochondria. With this model, we investigated the consequences of low dose and clinically relevant proton irradiation on neurogenesis, and how that process is modified in response to genetic disruption of mitochondrial ROS levels. In unirradiated animals, basal neurogenesis was improved significantly by reductions in mitochondrial ROS. In animals subjected to proton exposure, hippocampal progenitor cell proliferation was attenuated significantly by overexpression of human catalase in the mitochondria. Furthermore, expression of the MCAT transgene significantly improved neurogenesis in WT animals after low-dose proton exposure (0.5 Gy), with similar trends observed at higher dose (2 Gy). Our report documents for the first time the impact of proton irradiation on hippocampal neurogenesis, and the neuroprotective properties of reducing mitochondrial ROS through the targeted overexpression of catalase. PMID- 23672430 TI - Atrial fibrillation: inflammation in disguise? AB - Atrial fibrillation is highly prevalent, and affected patients are at an increased risk of a number of complications, including heart failure and thrombo embolism. Over the past years, there has been increasing interest in the role of inflammatory processes in atrial fibrillation, from the first occurrence of the arrhythmia to dreaded complications such as strokes or peripheral emboli. As the standard drug combination which aims at rate control and anticoagulation only offers partial protection against complications, newer agents are needed to optimize treatment. In this paper, we review recent knowledge regarding the impact of inflammation on the occurrence, recurrence, perpetuation and complications of the arrhythmia, as well as the role of anti-inflammatory therapies in the treatment for the disease. PMID- 23672431 TI - Formation mechanism of polycyclic aromatic hydrocarbons beyond the second aromatic ring. AB - The formation mechanism of polycyclic aromatic hydrocarbons (PAH) with three fused aromatic rings starting from naphthalene has been studied using accurate ab initio G3(MP2,CC)//B3LYP/6-311G** calculations followed by the kinetic analysis of various reaction pathways and computations of relative product yields. The results reveal new insights into the classical hydrogen abstraction-C2H2 addition (HACA) scheme of PAH growth. The HACA mechanism has been shown to produce mostly cyclopentafused PAHs instead of PAHs with six-member rings only, in contrast to the generally accepted view on this mechanism. Considering naphthalene as the initial reactant, the HACA-type synthesis of higher PAHs with all six-member rings, anthracene and phenanthrene, accounts only for 3-6% of the total product yield at temperatures relevant to combustion (1000-2000 K), whereas cyclopentafused PAHs, including acenaphthalene (41-48%), 4-ethynylacenaphthalene (~14%), 3-ethynylacenaphthalene (~7.5%), 1-methylene-1H-cyclopenta[b]naphthalene (~6%), and 3-methylene-3H-cyclopenta[a]naphthalene (~5%), account for another ~75%. It has been shown that acetylene addition to the radical site adjacent to the bay region in naphthalene (as in 1-naphthyl radical) or other similar PAH with a bay region is highly unlikely to be followed by the addition of a second acetylene molecule; alternatively, the bay region closure with a buildup of a new five-member ring occurs. Acetylene addition to a nonbay carbon atom (as in 2 naphthyl radical) can be followed by the second acetylene addition only at T < 1000 K, producing anthracene and phenanthrene. However, at temperatures relevant to combustion, such pathways give negligible contributions to the total product yield, whereas the dominant reaction product, 2-ethynylnaphthalene, is formed by simple hydrogen atom elimination from the attached ethenyl group. An additional six-member ring buildup may occur only after intermolecular hydrogen abstraction from ethynyl-substituted PAH (2-ethynylnaphthalene), in particular, from the carbon atoms adjacent to the existing ethynyl (C2H) fragment, followed by C2H2 addition producing adducts with two ethynyl C2H and ethenyl C2H2 groups next to each other, which then undergo a fast six-member ring closure. Nevertheless, this process has been shown to be relatively minor (~25%), whereas the major process is a five-member ring closure involving the same C2H and C2H2 groups and leading to a cyclopentafused PAH molecule. Although the computed product yields show a good agreement with experimentally observed concentrations of acenaphthalene and anthracene in various aliphatic and aromatic flames, the yield of phenanthrene, which exhibits an order of magnitude higher concentration than anthracene both in combustion flames and environmental mixtures, via the considered pathways is significantly underpredicted. This result points at the possible existence of another mechanism responsible for the formation of phenanthrene and other all-six member-ring PAHs. The overall kinetic scheme for the HACA buildup process leading to various three-ring PAHs (both with six-member rings only and cyclopentafused) from naphthalene, which can be included in flame kinetic models, has been constructed, with rate constants for all individual reaction steps provided. PMID- 23672432 TI - Isoelectric point determination of live polioviruses by capillary isoelectric focusing with whole column imaging detection. AB - Using a capillary isoelectric focusing-whole column imaging detection (CIEF-WCID) method, the isoelectric points (pI) of complete intact polioviruses were determined. The polioviruses that were analyzed are the commonly used viruses for the production of inactivated polio vaccines (IPV)-Mahoney (type 1), MEF (type 2), and Saukett (type 3)-as well as for attenuated oral polio vaccines (OPV) and Sabin types 1, 2, and 3. A method for analyzing biological hazardous components (biological safety level 2) was set up for the CIEF-WCID analyzer used. This method is based on closed circuits. The determined pI's were 6.2 for Mahoney, 6.7 for MEF-1, and 5.8 for Saukett. The pI's of Sabin types 1, 2, and 3 viruses were 7.4, 7.2, and 6.3, respectively. Resolution of the virus peaks was shown to be reproducible. Using this adjusted CIEF-WCID technique, the pI of biologically hazardous components like toxins or viruses can be determined, which is beneficial for the development of vaccine production methods among others. PMID- 23672433 TI - Human embryonic stem cell-derived epithelial cells in a novel in vitro model of vocal mucosa. AB - A satisfactory in vitro model of vocal fold mucosa does not exist, thus precluding a systematic, controlled study of vocal fold biology and biomechanics. We sought to create a valid, reproducible three-dimensional (3D) in vitro model of human origin of vocal fold mucosa of human origin. We hypothesized that coculture of human embryonic stem cell (hESC)-derived simple epithelial cells with primary vocal fold fibroblasts under appropriate conditions would elicit morphogenesis of progenitor cells into vocal fold epithelial-like cells and creation of a basement membrane. Using an in vitro prospective study design, hESCs were differentiated into cells that coexpressed the simple epithelial cell marker, keratin 18 (K18), and the transcription factor, p63. These simple epithelial cells were cocultured with primary vocal fold fibroblasts seeded in a collagen gel scaffold. The cells were cultured for 3 weeks in a keratinocyte medium at an air-liquid interface. After that time, the engineered mucosa demonstrated a stratified, squamous epithelium and a continuous basement membrane recapitulating the key morphologic and phenotypic characteristics of native vocal fold mucosa. hESC-derived epithelial cells exhibited positive staining for vocal fold stratified, squamous epithelial markers, keratin 13 (K13) and 14 (K14), as well as tight junctions, adherens junctions, gap junctions, and desmosomes. Despite the presence of components critical for epithelial structural integrity, the epithelium demonstrated greater permeability than native tissue indicating compromised functional integrity. While further work is warranted to improve functional barrier integrity, this study demonstrates that hESC-derived epithelial progenitor cells can be engineered to create a replicable 3D in vitro model of vocal fold mucosa featuring a multilayered, terminally differentiated epithelium. PMID- 23672434 TI - The interplay of donor-specific antibodies, allograft C4d deposition, and antibody-mediated rejection. PMID- 23672436 TI - Repetitive dissociation from crocidolite asbestos acts as persistent signal for epidermal growth factor receptor. AB - Mesothelioma is an incurable form of cancer located most commonly in the pleural lining of the lungs and is associated almost exclusively with the inhalation of asbestos. The binding of asbestos to epidermal growth factor receptor (EGFR), a transmembrane signal protein, has been proposed as a trigger for downstream signaling of kinases and expression of genes involved in cell proliferation and inhibition of apoptosis. Here, we investigate the molecular binding of EGFR to crocidolite (blue asbestos; Na2(Fe(2+),Mg)3Fe2(3+)Si8O22(OH)2) in buffer solution. Atomic force microscopy measurements revealed an attractive force of interaction (i.e., bond) as EGFR was pulled from contact with long fibers of crocidolite. The rupture force of this bond increased with loading rate. According to the Bell model, the off-rate of bond dissociation (k(off)) for EGFR was 22 s(-1). Similar experiments with riebeckite crystals, the nonasbestiform variety of crocidolite, yielded a k(off) of 8 s(-1). These k(off) values on crocidolite and riebeckite are very rapid compared to published values for natural agonists of EGFR like transforming growth factor and epidermal growth factor. This suggests binding of EGFR to the surfaces of these minerals could elicit a response that is more potent than biological hormone or cytokine ligands. Signal transduction may cease for endogenous ligands due to endocytosis and subsequent degradation, and even riebeckite particles can be cleared from the lungs due to their short, equant habit. However, the fibrous habit of crocidolite leads to lifelong persistence in the lungs where aberrant, repetitious binding with EGFR may continually trigger the activation switch leading to chronic expression of genes involved in oncogenesis. PMID- 23672435 TI - Perceived neighborhood environment and physical activity in 11 countries: do associations differ by country? AB - BACKGROUND: Increasing empirical evidence supports associations between neighborhood environments and physical activity. However, since most studies were conducted in a single country, particularly western countries, the generalizability of associations in an international setting is not well understood. The current study examined whether associations between perceived attributes of neighborhood environments and physical activity differed by country. METHODS: Population representative samples from 11 countries on five continents were surveyed using comparable methodologies and measurement instruments. Neighborhood environment * country interactions were tested in logistic regression models with meeting physical activity recommendations as the outcome, adjusted for demographic characteristics. Country-specific associations were reported. RESULTS: Significant neighborhood environment attribute * country interactions implied some differences across countries in the association of each neighborhood attribute with meeting physical activity recommendations. Across the 11 countries, land-use mix and sidewalks had the most consistent associations with physical activity. Access to public transit, bicycle facilities, and low cost recreation facilities had some associations with physical activity, but with less consistency across countries. There was little evidence supporting the associations of residential density and crime-related safety with physical activity in most countries. CONCLUSION: There is evidence of generalizability for the associations of land use mix, and presence of sidewalks with physical activity. Associations of other neighborhood characteristics with physical activity tended to differ by country. Future studies should include objective measures of neighborhood environments, compare psychometric properties of reports across countries, and use better specified models to further understand the similarities and differences in associations across countries. PMID- 23672437 TI - Novel acyclic nucleotide analogues GS-343074 and GS-424044 demonstrate antiproliferative and pro-apoptotic activity in canine neoplastic cell lines. AB - GS-9219, a novel prodrug of the nucleotide analogue 9-(2-phosphonylmethoxyethyl) guanine (PMEG) has significant activity as monotherapy in dogs with non-Hodgkin's lymphoma. Phase I trials have been initiated in humans based on the encouraging activity observed in canine lymphoma. Two new analogues of GS-9219 (GS-343074 and GS-424044) were recently produced for evaluation as potential novel antineoplastic agents against solid tumours. As a preclinical step, effect of GS 343074 and GS-424044 were evaluated against ten canine cancer cell lines for antiproliferative effect. Both analogues displayed antiproliferative activity against multiple canine cancer cell lines, although GS-343074 was more potent and of broader spectrum compared to GS-424044. Flow cytometric analysis of cells that experienced growth inhibition support apoptotic death as a mechanism of action for both analogues. On the basis of in vitro results described here, GS-343074 and GS-424044 show promise as novel anticancer agents in canine cancer. PMID- 23672438 TI - Motor imagery in spinal cord injury patients: moving makes the difference. AB - Both real action control and execution and motor imagery abilities require knowledge of the spatial location of body parts, in other words efference copy information and feedbacks from the sensory system (Frith et al., 2000, Philos. Trans. R. Soc. Lond. B. Biol. Sci., 355, 1771). Spinal cord injuries induce severe motor disability, due to a damage of the descending motor pathways (Cramer et al., 2007, Exp. Brain. Res., 177, 233). Patients' motor imagery competences are variably reported as either normal or defective (Decety & Boisson, 1990, Eur. Arch. Psychiatry Clin. Neurosci., 240, 39; Lacourse et al., 1999, Behav. Brain Sci., 104, 73). We explored biomechanical constraint effects in Spinal Cord Injury (SCI) patients, as they are considered the most reliable indexes of motor imagery abilities (Parsons, 1987b, Cogn. Psychol., 19, 178). Sixteen spinal cord injuries patients and 16 neurologically unimpaired subjects have been administered with (1) the Hand Laterality Task (HLT), in which subjects were asked to judge the laterality of a rotated hand; and (2) the Mirror Letter Discrimination Task (MLD), in which subjects were asked to judge if a rotated character was in its correct upright position or mirror-reversed form. Our patients did not present the effect of stimulus orientation, neither did they show any effect related to biomechanical constraints. Based on these data, the hypothesis is that SCI patients' performance may be ascribed to the use of a different strategy to solve the tasks, based on memory rather than on mental rotation. PMID- 23672439 TI - Splenic manifestations of chronic autoimmune disorder: a report of five cases with histiocytic necrotizing change in four cases. AB - AIMS: Autoimmune diseases (AD) are associated with lymphadenopathy and splenomegaly. Changes in the spleen have not been characterized completely in AD; we describe splenectomy specimens from five patients with chronic AD, highlighting the presence of necrotizing histiocytosis. METHODS AND RESULTS: Of the patients (three males and two females; mean 40 years), four had systemic lupus erythematosus; one had rheumatoid arthritis. All had moderate splenomegaly (213-803 g, mean 421 g). Four cases exhibited necrosis with apoptosis and karyorrhectic debris occurring in the white pulp and minimal acute inflammation; one showed florid follicular hyperplasia. Splenic involvement ranged from focal to extensive. Plasma cells were negative for IgG4. Haematoxylin bodies were not identified. Stains for infectious organisms were negative. Immunohistochemical studies showed that lymphocytes surrounding the necrosis were a mixture of CD4(+) and CD8(+) T cells; CD123-positive plasmacytoid dendritic cells were not present, and staining for kappa and lambda light chains showed no clonality. 16S rDNA PCR was performed; no amplification was seen in three of four cases tested for bacteria specific rDNA. Epstein-Barr virus-encoded RNA (EBER) in situ hybridization studies highlighted rare positive cells in four cases. CONCLUSIONS: Splenomegaly in AD is thought to be hyperplasic, but we present four cases showing histiocytic necrosis, a finding which should be considered part of the spectrum of AD in the spleen. PMID- 23672440 TI - The treatment of recurrent epistaxis due to hereditary haemorrhagic telangiectasia with intranasal bevacizumab. PMID- 23672442 TI - Acceptance and commitment therapy for anxious children and adolescents: study protocol for a randomized controlled trial. AB - BACKGROUND: Anxiety disorders affect approximately 10% to 20% of young people, can be enduring if left untreated, and have been associated with psychopathology in later life. Despite this, there is a paucity of empirical research to assist clinicians in determining appropriate treatment options. We describe a protocol for a randomized controlled trial in which we will examine the effectiveness of a group-based acceptance and commitment therapy program for children and adolescents with a primary diagnosis of anxiety disorder. For the adolescent participants we will also evaluate the elements of the intervention that act as mechanisms for change. METHODS/DESIGN: We will recruit 150 young people (90 children and 60 adolescents) diagnosed with an anxiety disorder and their parent or caregiver. After completion of baseline assessment, participants will be randomized to one of three conditions (acceptance and commitment therapy, cognitive behavior therapy or waitlist control). Those in the acceptance and commitment therapy and cognitive behavior therapy groups will receive 10 * 1.5 hour weekly group-therapy sessions using a manualized treatment program, in accordance with the relevant therapy, to be delivered by psychologists. Controls will receive the cognitive behavior therapy program after 10 weeks waitlisted. Repeated measures will be taken immediately post-therapy and at three months after therapy cessation. DISCUSSION: To the best of our knowledge, this study will be the largest trial of acceptance and commitment therapy in the treatment of children and young people to date. It will provide comprehensive data on the use of acceptance and commitment therapy for anxiety disorders and will offer evidence for mechanisms involved in the process of change. Furthermore, additional data will be obtained for the use of cognitive behavior therapy in this population and this research will illustrate the comparative effectiveness of these two interventions, which are currently implemented widely in contemporary clinical practice. Anticipated difficulties for the trial are the recruitment and retention of participants, particularly adolescents. To avert these concerns and maximize recruitment, several strategies will be adopted to optimize referral rates as well as reduce participant drop-outs. TRIAL REGISTRATION: This trial is registered with the Australian and New Zealand Clinical Trials Registry, registration number: ACTRN12611001280998. PMID- 23672443 TI - Embracing a new path to emotional recovery: adopting resilience theory in post TBI psychotherapy. AB - In this commentary, clinical researchers examine the potential benefits of adopting Resilience Theory in the practice of psychotherapy after brain injury. This commentary presents the development of the paradigmatic shift that has given rise to the resilience movement. Additionally, the primary tenets of resilience theory are explored and the utility of the theory in practice is explained. Finally, an argument for the match between the hallmarks of resilient populations and the post-TBI needs related to emotional recovery is presented. PMID- 23672444 TI - Sensitivity of the RBANS to acute traumatic brain injury and length of post traumatic amnesia. AB - OBJECTIVE: Although the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has been shown to be a useful tool in evaluating the cognitive status of patients with dementia, stroke, schizophrenia and post-acute traumatic brain injury (TBI), no studies have examined its utility in an acute TBI setting. The current study investigates the RBANS' sensitivity to acute TBI, hypothesizing that the presence and severity of injury is predictive of worse RBANS performance. METHOD: Neuropsychological testing was conducted an average of 6.1 days after emergence from post-traumatic amnesia (PTA). RBANS results were evaluated based on a normative basis, pre-injury estimates, and brain injury severity. RESULTS: In this sample of acute TBI patients (n = 51), the mean index scores on the RBANS ranged from 1.59-2.36 SD below the mean of the standardization sample. Each WRAT-4 Reading sub-test score was above the corresponding RBANS Total Scale Index score (t(31) = 10.32, p < 0.001). Regression analyses revealed that Delayed Memory (beta = - 0.365, p < 0.007) and Total Score (beta = -0.297, p < 0.023) indices were significantly predicted by PTA length after controlling for age and education. CONCLUSIONS: The RBANS appears to be a useful tool in assessing the presence and severity of acute TBI. PMID- 23672445 TI - Variants of SLC6A4 in depression risk following severe TBI. AB - BACKGROUND: Post-traumatic depression (PTD) may be a result of several factors like secondary injury chemical cascades as well as psycho-social factors following traumatic brain injury (TBI). While the role of serotonin in the pathology and treatment of idiopathic major depression may be somewhat controversial, it is unclear what role serotonin may play in PTD following a TBI. OBJECTIVE: To assess serotonergic function and genetic risk for PTD development over 1 year following TBI. RESEARCH DESIGN: Examination of variation in the serotonin transporter gene [SLC6A4 (5-HTTLPR, rs25331, and a variable number of tandem repeats variant in Intron 2)] in 109 subjects with moderate-severe injury. Depression was assessed using the Patient Health Questionnaire (PHQ-9) at 6 and/or 12 months post-injury. MAIN OUTCOMES AND RESULTS: At 6 months post-injury, subjects with a history of pre-morbid mood disorders and 5-HTTLPR L-homozygotes were at greater risk for PTD. Contrary to major depression, subjects without pre morbid mood disorders (n = 80) and S-carriers were 2.803-times less likely to be depressed compared to L-homozygotes. At 12 months post-injury, LG-carriers were also less likely to experience PTD. Temporal analysis also showed 5-HTTLPR associations in PTD development across recovery. CONCLUSIONS: This study suggests a unique injury- and temporally-specific interaction between TBI and genetic risk for depression. PMID- 23672446 TI - Let the games begin: a preliminary study using attention process training-3 and LumosityTM brain games to remediate attention deficits following traumatic brain injury. AB - PRIMARY OBJECTIVE: Computer-based treatments for attention problems have become increasingly popular and available. The researchers sought to determine whether improved performance by survivors of severe traumatic brain injury (TBI) on two computer-based treatments generalized to improvements on comparable, untrained tasks and ecologically-plausible attention tasks comprising a standardized assessment. RESEARCH DESIGN: The researchers used an -A-B-A-C-A treatment design repeated across four adult survivors of severe TBI. METHODS AND PROCEDURES: Participants engaged in 8 weeks of intervention using both Attention Process Training-3 (APT-3) and LumosityTM (2010) Brain Games. Two participants received APT-3 treatment first, while the other two received LumosityTM treatment first. All participants received both treatments throughout the course of two, 1-month intervention phases. MAIN OUTCOMES AND RESULTS: Individual growth curve analyses showed participants made significant improvements in progressing through both interventions. However, limited generalization occurred: one participant demonstrated significantly improved performance on one of five probe measures and one other participant showed improved performance on some sub-tests of the Test of Everyday Attention; no other significant generalization results emerged. These findings call into question the assumption that intervention using either APT-3 or LumosityTM will prompt generalization beyond the actual tasks performed during treatment. PMID- 23672447 TI - Describing conversations between individuals with traumatic brain injury (TBI) and communication partners following communication partner training: Using exchange structure analysis. AB - PRIMARY OBJECTIVE: To describe conversational discourse change after joint communication training for individuals with TBI and their everyday communication partners (ECPs), as compared to untrained controls. HYPOTHESIS: Joint training would lead to significantly greater changes in the discourse behaviour of trained participants. METHODS AND PROCEDURES: In this multi-centre non-randomized controlled trial, 29 participants with severe TBI and their ECPs were allocated to either the JOINT training or CONTROL group. Social communication training aimed to train ECPs to better support their partner with TBI to produce more effective conversations. Pre- and post-training casual conversations were compared using exchange structure analysis (ESA) and productivity analysis. RESULTS: ESA and productivity analysis revealed significant change in the use of testing moves by trained ECPs and significant change in productivity by trained participants with TBI. ESA facilitated development of discourse profiles (excessive or impoverished) for participants with TBI, which distinguished the groups at baseline. CONCLUSIONS: This study extends one's understanding of individual discourse styles in people with TBI. The impact of different discourse styles on group outcome studies has been highlighted. These discourse findings may facilitate goal-setting in social skills intervention after TBI, with focus on training ECPs to support people with TBI in conversations. PMID- 23672448 TI - Beneficial effect of amyloid beta after controlled cortical impact. AB - BACKGROUND: Worse functional outcomes after controlled cortical impact (CCI) in Bace1(-/-) mice have previously been demonstrated. This study investigated whether reconstitution of amyloid-beta (Abeta) after CCI in Bace1(-/-) animals would reverse the detrimental effect of Bace1 deletion. METHODS: Bace1(-/-) and wild type Bace1(+/+) (C57Bl/6) mice were subjected to CCI (n = 14-23/group) or sham injury (n = 6/group). After injury, mice underwent intracerebroventricular injections of Abeta40 (n = 23 Bace1(-/-) and 17 Bace1(+/+) per group) or vehicle (n = 14 Bace1(-/-) and 22 Bace1(+/+) per group). Functional outcomes were assessed with wire grip (motor) and Morris water maze (spatial memory). Soluble Abeta levels were assessed at 24 hours and 21 days after CCI. Lesion volume was assessed 21 days after injury. RESULTS: At 24 hours after injury, Abeta-treated Bace1(-/-) mice had Abeta40 levels similar to vehicle-treated Bace1(+/+) mice, but by 21 days after injury there were no differences between Abeta-treated versus vehicle-treated Bace1(-/-) mice. Reconstitution with Abeta40 improved motor but not spatial memory or histopathological outcome in injured Bace1(-/-) mice. In contrast, treatment with Abeta40 worsened motor performance in Bace1(+/+) mice. CONCLUSIONS: The data suggest Abeta40 may have some beneficial effects after CCI in young adult mice and that therapies targeting BACE should be approached cautiously. PMID- 23672449 TI - Traumatic thalamic injury demonstrated by diffusion tensor tractography of the spinothalamic pathway. AB - BACKGROUND: This study reports on a patient with traumatic brain injury (TBI) with a thalamic lesion in the ventroposterolateral nucleus which was demonstrated by diffusion tensor tractography (DTT) for the spinothalamic tract and its thalamocortical pathway (STP). METHODS: One patient with TBI and eight normal control subjects were recruited. A 64-year-old woman who had suffered a motor vehicle accident presented with a persisting tingling sensation and pain in her right upper and lower extremities at 3 weeks after onset. The patient showed impaired touch sensation, but normal proprioception. Diffusion tensor imaging was performed at 1 month after onset. Fractional anisotropy (FA) and mean diffusivity were measured using a region of interest method along the STP. RESULTS: DTT showed normal STP integrities as compared with normal controls. However, the FA values of the left STP at the thalamus were more than 2 SD decreased. The diminished FA value of the left STP in the left thalamus seems to indicate injury of the left ventrolateroposterior nucleus. Central pain and impaired touch sensation of right extremities supports the presence of left STP injury at the ventroposterolateral nucleus in this patient. CONCLUSION: It is believed that DTT for the STP provides a useful means of detecting thalamic injury in TBI. PMID- 23672450 TI - Optimizing de novo assembly of short-read RNA-seq data for phylogenomics. AB - BACKGROUND: RNA-seq has shown huge potential for phylogenomic inferences in non model organisms. However, error, incompleteness, and redundant assembled transcripts for each gene in de novo assembly of short reads cause noise in analyses and a large amount of missing data in the aligned matrix. To address these problems, we compare de novo assemblies of paired end 90 bp RNA-seq reads using Oases, Trinity, Trans-ABySS and SOAPdenovo-Trans to transcripts from genome annotation of the model plant Ricinus communis. By doing so we evaluate strategies for optimizing total gene coverage and minimizing assembly chimeras and redundancy. RESULTS: We found that the frequency and structure of chimeras vary dramatically among different software packages. The differences were largely due to the number of trans-self chimeras that contain repeats in the opposite direction. More than half of the total chimeras in Oases and Trinity were trans self chimeras. Within each package, we found a trade-off between maximizing reference coverage and minimizing redundancy and chimera rate. In order to reduce redundancy, we investigated three methods: 1) using cap3 and CD-HIT-EST to combine highly similar transcripts, 2) only retaining the transcript with the highest read coverage, or removing the transcript with the lowest read coverage for each subcomponent in Trinity, and 3) filtering Oases single k-mer assemblies by number of transcripts per locus and relative transcript length, and then finding the transcript with the highest read coverage. We then utilized results from blastx against model protein sequences to effectively remove trans chimeras. After optimization, seven assembly strategies among all four packages successfully assembled 42.9-47.1% of reference genes to more than 200 bp, with a chimera rate of 0.92-2.21%, and on average 1.8-3.1 transcripts per reference gene assembled. CONCLUSIONS: With rapidly improving sequencing and assembly tools, our study provides a framework to benchmark and optimize performance before choosing tools or parameter combinations for analyzing short-read RNA-seq data. Our study demonstrates that choice of assembly package, k-mer sizes, post-assembly redundancy-reduction and chimera cleanup, and strand-specific RNA-seq library preparation and assembly dramatically improves gene coverage by non-redundant and non-chimeric transcripts that are optimized for downstream phylogenomic analyses. PMID- 23672451 TI - Reaction of HppE with substrate analogues: evidence for carbon-phosphorus bond cleavage by a carbocation rearrangement. AB - (S)-2-hydroxypropylphosphonic acid ((S)-2-HPP) epoxidase (HppE) is an unusual mononuclear non-heme iron enzyme that catalyzes the oxidative epoxidation of (S) 2-HPP in the biosynthesis of the antibiotic fosfomycin. Recently, HppE has been shown to accept (R)-1-hydroxypropylphosphonic acid as a substrate and convert it to an aldehyde product in a reaction involving a biologically unprecedented 1,2 phosphono migration. In this study, a series of substrate analogues were designed, synthesized, and used as mechanistic probes to study this novel enzymatic transformation. The resulting data, together with insights obtained from density functional theory calculations, are consistent with a mechanism of HppE-catalyzed phosphono group migration that involves the formation of a carbocation intermediate. As such, this reaction represents a new paradigm for biological C-P bond cleavage. PMID- 23672452 TI - Determinants of suboptimal hepatitis B vaccine uptake among men in the Republic of Korea: where should our efforts be focused: results from cross-sectional study. AB - BACKGROUND: Liver cancer is the second most-frequent cause of cancer death in Korea. Hepatitis B virus (HBV) infection is a major cause of liver cancer, and this disease is effectively prevented by HBV vaccination. This study was conducted to investigate factors associated with the lack of HBV vaccine uptake in the general adult male population in Korea. METHODS: Data of men who participated in a nationwide cross-sectional interview survey were analyzed. A total of 2,174 men 40 years of age and older were interviewed between 2006 and 2008. None of the participants was infected with HBV or was experiencing sequelae of an HBV infection. RESULTS: Only half (50.4%) of the men received one or more dose of the three-dose series of HBV vaccinations, and 32.5% received all three doses. Compared with men who had completed the vaccination regimen, non vaccinated men were more likely to lack supplemental medical insurance for cancer (odds ratio = 0.66, 95% confidence interval: 0.52-0.84), have lower incomes (p trend = 0.010), and be less educated (p-trend = 0.021). Lower education was also more prevalent in the non-vaccinated group compared with the incompletely vaccinated group. Those who had completed the vaccination regimen were likely to be more educated than those in the incompletely vaccinated group (p-trend = 0.044). The most commonly cited reason for not obtaining the HBV vaccine was lack of knowledge regarding the need for the vaccination. The number of men who cited this reason decreased as a function of education. CONCLUSIONS: It is important to develop strategic interventions targeted at less-educated men to increase uptake of a complete three-dose series of HBV vaccinations as a primary approach to preventing liver cancer. PMID- 23672454 TI - Asymmetric total synthesis of caribenol A via an intramolecular Diels-Alder reaction. AB - A total synthesis of the caribenol A (1), a novel natural product with an intriguing tetracyclic framework, has been achieved. The synthesis features an intramolecular Diels-Alder (IMDA) reaction for the facile construction of the tricyclic [5-7-6] skeleton of caribenol A (1) and a biomimetic oxidation reaction for the formation of the 2-hydroxyfuran-2(5H)-one motif of caribenol A (1) as key steps. This synthetic approach also reveals that the sp(2) carbon at C(2) in substrate 8 is a critical factor for the formation of the tricyclic [5-7-6] skeleton in 7. PMID- 23672455 TI - Association, among very-low-birthweight neonates, between red blood cell transfusions in the week after birth and severe intraventricular hemorrhage. AB - BACKGROUND: Previous reports describe a statistical association, among very-low birthweight (VLBW, <1500 g) neonates, between red blood cell (RBC) transfusion in the first days after birth and development of severe intraventricular (brain) hemorrhage (IVH). STUDY DESIGN AND METHODS: We hypothesized that after we established a neonatal intensive care unit (NICU) transfusion management program in 2009, a decrease in early (first week after birth) RBC transfusion rate and a decrease in the incidence of severe IVH occurred concomitantly. RESULTS: During a 9-year period 2716 VLBW neonates were admitted to our NICUs. In 2004, 58% of VLBW neonates received one or more RBC transfusions during the first week. After a transfusion compliance program was established in 2009, this rate declined, reaching 25% by 2012. In parallel, the severe IVH rate also declined, from 17% in 2004 to 8% in 2012 (R(2) = 0.73). IVH occurred in 27% of those who received a RBC transfusion during the first week versus less than 2% of those with no early transfusion (p < 0.001). The decrease in IVH rate occurred exclusively among neonates born in an Intermountain Healthcare perinatal center and not among those initially cared for in an "outside" hospital and subsequently transported to an Intermountain NICU. CONCLUSIONS: It remains unclear whether transfusing VLBW neonates during the first days after birth is a proximate cause of IVH. However, the present report is consistent with previous studies showing that successful efforts to reduce early RBC transfusions is associated with a decrease in the incidence of severe IVH. PMID- 23672453 TI - Simulation techniques in hyperthermia treatment planning. AB - Abstract Clinical trials have shown that hyperthermia (HT), i.e. an increase of tissue temperature to 39-44 degrees C, significantly enhance radiotherapy and chemotherapy effectiveness [1]. Driven by the developments in computational techniques and computing power, personalised hyperthermia treatment planning (HTP) has matured and has become a powerful tool for optimising treatment quality. Electromagnetic, ultrasound, and thermal simulations using realistic clinical set-ups are now being performed to achieve patient-specific treatment optimisation. In addition, extensive studies aimed to properly implement novel HT tools and techniques, and to assess the quality of HT, are becoming more common. In this paper, we review the simulation tools and techniques developed for clinical hyperthermia, and evaluate their current status on the path from 'model' to 'clinic'. In addition, we illustrate the major techniques employed for validation and optimisation. HTP has become an essential tool for improvement, control, and assessment of HT treatment quality. As such, it plays a pivotal role in the quest to establish HT as an efficacious addition to multi-modality treatment of cancer. PMID- 23672457 TI - Interplay between forward and backward scattering of spin-orbit split surface states of Bi(111). AB - The electronic structure at the surface of Bi(111) enables us to study the effect of defects scattering into multiple channels. By performing scanning tunneling spectroscopy near step edges, we analyze the resulting oscillations in the local density of electronic states (LDOS) as function of position. At a given energy, forward and backward scattering not only occur simultaneously but may contribute to the same scattering vector Deltak. If the scattering phase of both processes differs by pi and the amplitudes are almost equal, the oscillations cancel out. A sharp dip in the magnitude of the Fourier transform of the LDOS marks the crossover between forward and backward scattering channels. PMID- 23672456 TI - A structural role for the PHP domain in E. coli DNA polymerase III. AB - BACKGROUND: In addition to the core catalytic machinery, bacterial replicative DNA polymerases contain a Polymerase and Histidinol Phosphatase (PHP) domain whose function is not entirely understood. The PHP domains of some bacterial replicases are active metal-dependent nucleases that may play a role in proofreading. In E. coli DNA polymerase III, however, the PHP domain has lost several metal-coordinating residues and is likely to be catalytically inactive. RESULTS: Genomic searches show that the loss of metal-coordinating residues in polymerase PHP domains is likely to have coevolved with the presence of a separate proofreading exonuclease that works with the polymerase. Although the E. coli Pol III PHP domain has lost metal-coordinating residues, the structure of the domain has been conserved to a remarkable degree when compared to that of metal-binding PHP domains. This is demonstrated by our ability to restore metal binding with only three point mutations, as confirmed by the metal-bound crystal structure of this mutant determined at 2.9 A resolution. We also show that Pol III, a large multi-domain protein, unfolds cooperatively and that mutations in the degenerate metal-binding site of the PHP domain decrease the overall stability of Pol III and reduce its activity. CONCLUSIONS: While the presence of a PHP domain in replicative bacterial polymerases is strictly conserved, its ability to coordinate metals and to perform proofreading exonuclease activity is not, suggesting additional non-enzymatic roles for the domain. Our results show that the PHP domain is a major structural element in Pol III and its integrity modulates both the stability and activity of the polymerase. PMID- 23672458 TI - Acute hematological effects of solar particle event proton radiation in the porcine model. AB - Acute radiation sickness (ARS) is expected to occur in astronauts during large solar particle events (SPEs). One parameter associated with ARS is the hematopoietic syndrome, which can result from decreased numbers of circulating blood cells in those exposed to radiation. The peripheral blood cells are critical for an adequate immune response, and low blood cell counts can result in an increased susceptibility to infection. In this study, Yucatan minipigs were exposed to proton radiation within a range of skin dose levels expected for an SPE (estimated from previous SPEs). The proton-radiation exposure resulted in significant decreases in total white blood cell count (WBC) within 1 day of exposure, 60% below baseline control value or preirradiation values. At the lowest level of the blood cell counts, lymphocytes, neutrophils, monocytes and eosinophils were decreased up to 89.5%, 60.4%, 73.2% and 75.5%, respectively, from the preirradiation values. Monocytes and lymphocytes were decreased by an average of 70% (compared to preirradiation values) as early as 4 h after radiation exposure. Skin doses greater than 5 Gy resulted in decreased blood cell counts up to 90 days after exposure. The results reported here are similar to studies of ARS using the nonhuman primate model, supporting the use of the Yucatan minipig as an alternative. In addition, the high prevalence of hematologic abnormalities resulting from exposure to acute, whole-body SPE-like proton radiation warrants the development of appropriate countermeasures to prevent or treat ARS occurring in astronauts during space travel. PMID- 23672459 TI - Food allergen--induced mast cell degranulation is dependent on PI3K-mediated reactive oxygen species production and upregulation of store-operated calcium channel subunits. AB - The importance of Ca(2+) influx via store-operated calcium channels (SOCs) leading to mast cell degranulation is well known in allergic disease. However, the underlying mechanisms are not fully understood. With food-allergic rat model, the morphology of degranulated mast cell was analysed by toluidine blue stain and electron microscope. Ca(2+) influx via SOCs was checked by Ca(2+) imaging confocal microscope. Furthermore, the mRNA and protein expression of SOCs subunits were investigated using qPCR and Western blot. We found that ovalbumin (OVA) challenge significantly increased the levels of Th2 cytokines and OVA specific IgE in allergic animals. Parallel to mast cell activation, the levels of histamine in serum and supernatant of rat peritoneal lavage solution were remarkably increased after OVA treatment. Moreover, the Ca(2+) entry through SOCs evoked by thapsigargin was increased in OVA-challenged group. The mRNA and protein expressions of SOC subunits, stromal interaction molecule 1 (STIM1) and Orail (calcium-release-activated calcium channel protein 1), were dramatically elevated under food-allergic condition. Administration of Ebselen, a scavenger of reactive oxygen species (ROS), significantly attenuated OVA sensitization-induced intracellular Ca(2+) rise and upregulation of SOCs subunit expressions. Intriguingly, pretreatment with PI3K-specific inhibitor (Wortmannin) partially abolished the production of ROS and subsequent elevation of SOCs activity and their subunit expressions. Taken together, these results imply that enhancement of SOC-mediated Ca(2+) influx induces mast cell activation, contributing to the pathogenesis of OVA-stimulated food allergy. PI3K-dependent ROS generation involves in modulating the activity of SOCs by increasing the expressions of their subunit. PMID- 23672460 TI - Brain glucose-6-phosphate dehydrogenase protects against endogenous oxidative DNA damage and neurodegeneration in aged mice. AB - Glucose-6-phosphate dehydrogenase (G6PD) protects the embryo from endogenous and xenobiotic-enhanced oxidative DNA damage and embryopathies. Here we show in aged mice that G6PD similarly protects against endogenous reactive oxygen species (ROS)-mediated neurodegeneration. In G6PD-normal (G6PD(+/+)) and heterozygous (G6PD(+/def)) and homozygous (G6PD(def/def)) G6PD-deficient male and female mice at about 2 years of age, oxidative DNA damage in various brain regions was assessed by 8-oxo-2'-deoxyguanosine formation using high-performance liquid chromatography and immunohistochemistry. Morphological changes in brain sections were assessed by H&E staining. DNA oxidation was increased in G6PD(def/def) mice in the cortex (p < 0.02), hippocampus (p < 0.01) and cerebellum (p < 0.006) compared to G6PD(+/+) mice, and was localized to distinct cell types. Histologically, in G6PD(+/def) mice, enhanced regionally and cellularly specific neurodegenerative changes were observed in those brain regions exhibiting elevated DNA oxidation, with a 53% reduction in the Purkinje cell count. These results show G6PD is important in protecting against the neurodegenerative effects of endogenous ROS in aging, and suggest that common hereditary G6PD deficiencies may constitute a risk factor for some neurodegenerative diseases. PMID- 23672461 TI - Modified gastric pull-up reconstructions following pharyngolaryngectomy with total esophagectomy. AB - Reconstruction following pharyngolaryngectomy with total esophagectomy is a challenging surgery to perform. Between April 2008 and August 2012, three types of modified gastric pull-up reconstruction procedures, including a gastric tube creation combined with a free jejunal transfer (n = 7), elongated gastric tube creation with vascular anastomoses (n = 2) and pedunculated gastric tube creation with Roux-en-Y anastomosis (n = 5), were performed after pharyngolaryngectomy with total esophagectomy. To clarify feasibility of these reconstructive methods, we retrospectively analyzed the short-term outcomes. There were no graft failures. Salivary fistulae were observed in two cases after high pharyngoenteral anastomoses due to oropharyngeal extension of hypopharyngeal cancers. Overall morbidity rate was 21.4%, and no deaths occurred. Although the operation time was shortest for pedunculated gastric tube reconstructions, morbidity rates were similar among all methods. All three types of modified gastric pull-up reconstruction procedures can be performed safely. We can choose one of these methods according to the tumor status and the patient condition, understanding advantages and disadvantages of each procedure. PMID- 23672462 TI - In vivo efficacy of alpha-galactosidase as possible promise for prolonged durability of bioprosthetic heart valve using alpha1,3-galactosyltransferase knockout mouse. AB - The immune response due to Galalpha1,3-Galbeta1-4GlcNAc-R(alpha-Gal) epitopes is an important factor in bioprosthetic heart valve failure. The aim of this study was to evaluate the immune reaction and anticalcification effect of alpha galactosidase and decellularization for glutaraldehyde (GA)/genipin fixed bovine pericardium using alpha1,3-galactosyltransferase knockout(alpha-Gal KO) mouse(C57BL/6). Bovine pericardial tissues were decellularized and treated with alpha-galactosidase before fixation with 0.25% GA/0.4% genipin in organic solvent (75% ethanol and 5% octanol) and treatment with glycine. The removal of alpha-gal epitope from the bovine pericardium was analyzed by 3,3'-Diaminobenzidine staining intensity. The bovine pericardial tissues were subcutaneously implanted into wild type mice (n=19) and alpha-Gal KO mice (n=66), which had been presensitized with rabbit red blood cells to maximize immunologic response or not, and anti alpha-Gal antibodies were measured at various time intervals. Calcium contents of the explanted tissues (n=104) were measured 3 months after implantation. The treatment of alpha-galactosidase effectively removed the alpha gal epitopes expressed on bovine pericardial tissues. In both GA and genipin groups, titers for both anti alpha-Gal IgM and IgG of alpha-Gal KO mice increased according to the duration of implantation, and were lower in the groups with decellularization than without decellularization, and were lower in the groups with alpha-galactosidase+decellularization than with decellularization. The calcium contents of GA/genipin fixed tissues were lower in the groups with decellularization than without decellularization, and were lower in the groups with alpha-galactosidase+decellularization than with decellularization. Treatment of alpha-galactosidase with decellularization is useful for removal of the immunogenicity, and reduced calcification in both GA and genipin fixed bovine pericardia, supporting the hypothesis that the immune reaction may cause the calcification. Treatment of alpha-galactosidase has possible promise to enhance durability of bioprosthetic heart valve. To our knowledge, this is the first report that demonstrates the in vivo efficacy of alpha-galactosidase using presensitized alpha-Gal KO mouse to mimic the human immunologic environment. PMID- 23672463 TI - Randomized controlled trial assessing the effect of simvastatin in primary biliary cirrhosis. AB - BACKGROUND: This study evaluated the effect of statins in Primary biliary cirrhosis (PBC) on endothelial function, anti-oxidant status and vascular compliance. METHODS: Primary biliary cirrhosis patients with hypercholesterolaemia were randomized to receive 20 mg simvastatin or placebo in a single blind, randomized controlled trial. Body mass index, blood pressure, glucose, liver function, lipid profile, immunoglobulin levels, serological markers of endothelial function and anti-oxidant status were measured as well as vascular compliance, calculated from pulse wave analysis and velocity, at recruitment and again at 3, 6, 9 and 12 months. RESULTS: Twenty-one PBC patients (F = 20, mean age = 55) were randomized to simvastatin 20 mg (n = 11) or matched placebo (n = 10). At completion of the trial, serum cholesterol levels in the simvastatin group were significantly lower compared with the placebo group (4.91 mmol/L vs. 6.15 mmol/L, P = 0.01). Low-density lipoprotein (LDL) levels after 12 months were also significantly lower in the simvastatin group (2.33 mmol/L vs. 3.53 mmol/L, P = 0.01). After 12 months of treatment, lipid hydroperoxides were lower (0.49 MUmol/L vs. 0.59 MUmol/L, P = 0.10) while vitamin C levels were higher (80.54 MUmol/L vs. 77.40 MUmol/L, P = 0.95) in the simvastatin group. Pulse wave velocity remained similar between treatment groups at 12 months (8.45 m/s vs. 8.80 m/s, P = 0.66). Only one patient discontinued medication owing to side effects. No deterioration in liver transaminases was noted in the simvastatin group. CONCLUSIONS: Statin therapy in patients with PBC appears safe and effective towards overall reductions in total cholesterol and LDL levels. Our initial study suggests that simvastatin may also confer advantageous effects on endothelial function and antioxidant status. PMID- 23672465 TI - Potential role for anti-angiogenic therapy in abdominal aortic aneurysms. AB - OBJECTIVE: Abdominal aortic aneurysm (AAA) is a condition that mainly affects elderly men. At present, there is no effective medical therapy that can retard aneurysm growth or prevent aneurysm rupture. There is evidence that angiogenesis within the wall of an aortic aneurysm may play key roles in aneurysm progression as well as rupture. The use of anti-angiogenic therapy as potential medical therapy in AAA is a promising strategy but has never been studied in detail. DESIGN: This paper discusses the basic mechanisms of angiogenesis, the role played by angiogenesis in aortic aneurysms and the potential therapeutic role of anti-angiogenic drugs against aneurysm expansion or rupture. RESULTS: Angiogenesis is a multi-step process which is fundamental for growth and differentiation of various tissues within a multi-cellular organism. Hypoxia and inflammation are key stimuli for activation of neoangiogenesis. Investigations in both human tissues and animal models of AAA have shown that angiogenesis is a pathological hallmark of AAA and appears to play a role in the development and progression of the condition. Pre-clinical studies have shown that anti angiogenic drugs can potentially be effective in reducing the intensity of aneurysm formation, suggesting that such drugs may potentially be useful as novel drug therapy for AAA in humans. CONCLUSION: Current evidence suggests that angiogenesis contributes to the destructive processes within aneurysmal aortic wall. As novel drug therapy for aortic aneurysms (for use in humans) is still eluding researchers, anti-angiogenic pathway appears to be an attractive approach. PMID- 23672464 TI - Scaffold-focused virtual screening: prospective application to the discovery of TTK inhibitors. AB - We describe and apply a scaffold-focused virtual screen based upon scaffold trees to the mitotic kinase TTK (MPS1). Using level 1 of the scaffold tree, we perform both 2D and 3D similarity searches between a query scaffold and a level 1 scaffold library derived from a 2 million compound library; 98 compounds from 27 unique top-ranked level 1 scaffolds are selected for biochemical screening. We show that this scaffold-focused virtual screen prospectively identifies eight confirmed active compounds that are structurally differentiated from the query compound. In comparison, 100 compounds were selected for biochemical screening using a virtual screen based upon whole molecule similarity resulting in 12 confirmed active compounds that are structurally similar to the query compound. We elucidated the binding mode for four of the eight confirmed scaffold hops to TTK by determining their protein-ligand crystal structures; each represents a ligand-efficient scaffold for inhibitor design. PMID- 23672466 TI - Repair of traumatic muscle herniation with acellular porcine collagen matrix. AB - BACKGROUND: Muscle hernias are uncommon clinical conditions with no uniform solution of repair. Biocompatible mesh allows for repair of hernias without the donor site morbidity and complications from direct repair under tension. METHODS: Over a 6-month period at a Level 1 Trauma centre, four consecutive symptomatic muscle hernias were identified, two in the forearm and two in the lower limb. Three resulted from high-speed motorbike accidents, one from a mining accident. All patients had hernia repair at a minimum of 4 months post accident. A 10 * 15 cm * 1.0 mm sheet of acellular collagen matrix was fashioned to fit as an underlay of the fascia defect. Patients were clinically followed at the 2-, 6-, 12- and 26-week mark. Final phone contact was made 18 months post-operatively. RESULTS: All patients were pleased with their cosmetic and functional outcomes. All patients returned to work and sport 3 months after reconstruction. CONCLUSION: Symptomatic hernias as a result of trauma can be safely reconstructed with a biological mesh implant. This approach can prevent complications from previously described methods and return to active lifestyles with good results. PMID- 23672467 TI - Comparative transcriptome analysis and marker development of two closely related Primrose species (Primula poissonii and Primula wilsonii). AB - BACKGROUND: Primula species are important early spring garden plants with a centre of diversity and speciation in the East Himalaya-Hengduan Mountains in Western China. Studies on population genetics, speciation and phylogeny of Primula have been impeded by a lack of genomic resources. In the present study, we sequenced the transcriptomes of two closely related primrose species, Primula poissonii and Primula wilsonii, using short reads on the Illumina Genome Analyzer platform. RESULTS: We obtained 55,284 and 55,011 contigs with N50 values of 938 and 1,085 for P. poissonii and P. wilsonii, respectively, and 6,654 pairs of putative orthologs were identified between the two species. Estimations of non synonymous/synonymous substitution rate ratios for these orthologs indicated that 877 of the pairs may be under positive selection (Ka/Ks > 0.5), and functional enrichment analysis revealed that significant proportions of the orthologs were in the categories DNA repair, stress resistance, which may provide some hints as to how the two closely related Primula species adapted differentially to extreme environments, such as habitats characterized by aridity, high altitude and high levels of ionizing radiation. It was possible for the first time to estimate the divergence time between the radiated species pair, P. poissonii and P. wilsonii; this was found to be approximately 0.90 +/- 0.57 Mya, which falls between the Donau and Gunz glaciation in the Middle Pleistocene. Primers based on 54 pairs of orthologous SSR-containing sequences between the two Primula species were designed and verified. About half of these pairs successfully amplified for both species. Of the 959 single copy nuclear genes shared by four model plants (known as APVO genes), 111 single copy nuclear genes were verified as being present in both Primula species and exon-anchored and intron-spanned primers were designed for use. CONCLUSION: We characterized the transcriptomes for the two Primula species, and produced an unprecedented amount of genomic resources for these important garden plants. Evolutionary analysis of these two Primula species not only revealed a more precise divergence time, but also provided some novel insights into how differential adaptations occurred in extreme habitats. Furthermore, we developed two sets of genetic markers, single copy nuclear genes and nuclear microsatellites (EST-SSR). Both these sets of markers will facilitate studies on the genetic improvement, population genetics and phylogenetics of this rapidly adapting taxon. PMID- 23672468 TI - Early years neurosurgical training in the era of the European Working Time Directive. AB - The past decade has seen significant changes to the face of neurosurgical training in the United Kingdom, driven in part by an increasing focus on patient safety and the introduction of Modernising Medical Careers and the European Working Time Directive (EWTD). Recent reforms to neurosurgical training over the past few years have resulted in creation of an 8-year 'run-through' training programme. In this programme, early years (ST1 and ST2) trainees often lack dedicated time for elective theatre lists and outpatient clinics. Further, any time spent in theatre and clinics is often with different teams. Here we describe a training model for early years trainees at the National Hospital for Neurology and Neurosurgery, who are given the responsibilities traditionally associated with a more senior trainee including dedicated weekly theatre and clinic time under the supervision of a single consultant, in addition to out of hours experience. The advantages and considerations for implementing this model are discussed, including the benefit of guidance under a single consultant in the early stages of training, along with key educational concepts necessary for understanding its utility. We feel that this is an effective model for junior neurosurgical training in the EWTD era, expediting the trainee's development of key technical and non-technical skills, with potentially significant rewards for patient, trainee and trainer. National implementation of this model should be considered. PMID- 23672469 TI - Case report of os odontoideum causing Ondine's curse. AB - Ondine's curse or central hypoventilation syndrome is most common congenital disorder which is diagnosed in infancy. In the majority of cases, no structural abnormality is identified. We describe the case of an 18-year-old patient who presented with Ondine's curse secondary to an os odontoideum. PMID- 23672470 TI - Histidine-rich glycoprotein gene polymorphism in patients with recurrent miscarriage. AB - Association between the histidine-rich glycoprotein (HRG) C633T single nucleotide polymorphism (SNP) and recurrent miscarriage was investigated in a case-control study. The cases constituted 187 women with recurrent miscarriage that were compared with 395 controls who had delivered a child and had no history of miscarriage. Blood samples were collected from each woman, genomic DNA was extracted and genotyped for the HRG C633T SNP. In the whole study population, the percentage of miscarriage was the same, regardless of genotype (C/C 31.2%, C/T 32.9% and T/T 32.5%). However, an association between homozygous T/T carriers and recurrent miscarriage was detected in a subgroup of women with primary recurrent miscarriage (odds ratio 2.44, 95% CI 1.01-5.92). Our results indicate an important role for the HRG C633T SNP in the occurrence of recurrent miscarriage. PMID- 23672471 TI - Metal ion-directed solution-phase tailoring: from large-area graphene oxide into nanoscale pieces. AB - Due to fascinating electronic properties and great potential in various applications, graphene has attracted great interest. Recently, much work have focused on the synthesis of different sizes and properties of graphene or graphene oxides (GOs), for example, graphene nanoribbons, nanosized graphene pieces, and nanosized triangular and hexagonal graphene sheets terminated by zigzag edges. Herein, we have demonstrated a widely available approach to fabricate the nanoscale GO pieces by directly solution-phase cutting a large-area GO sheet into nanoscale pieces via spontaneous redox reactions at room temperature. In this process, GO acts with dual functions as a model and a reducing reagent. With a typical example of silver ions, we have investigated in detail the influence of the reaction time and concentration of metal ions on yield and size of nanoscale GO pieces. Moreover, we also obtain Ag nanoparticle coating on the GO surface. Finally, a possible mechanism is suggested to explain the formation of nanoscale GO pieces. PMID- 23672472 TI - Measuring the risk factors for postpartum depression: development of the Japanese version of the Postpartum Depression Predictors Inventory-Revised (PDPI-R-J). AB - BACKGROUND: Postpartum depression (PPD) is a global phenomenon. Depression in the first month following delivery is experienced by 20% of mothers in Japan. Therefore, a screening instrument that identifies the risk for depression during pregnancy and in the early postpartum period is required for primary prevention. The aims of this study were to develop the Japanese version of the Postpartum Depression Predictors Inventory-Revised (PDPI-R-J) and determine its predictive validity during pregnancy and one month after delivery. METHODS: In order to develop the inventory, two bilingual translators translated the PDPI-R into Japanese. Then, back translation was done and a thorough discussion with the original developer was conducted in order to establish semantic equivalence. After the PDPI-R-J was developed, the study used a prospective cohort design. A total of 84 women in their eighth month of pregnancy participated in the study. Seventy-six mothers completed the PDPI-R-J at the first month after childbirth. Women were diagnosed using Mini-International Neuropsychiatric Interview (M.I.N.I.) to determine the presence of minor or major depression at the first month after childbirth and the receiver operating characteristic curve was plotted to evaluate the predictive capacity of PDPI-R-J. RESULTS: Of the 76 mothers who completed the PDPI-R-J during the first-month assessment, 16 mothers (21%) met the PPD criteria. The prenatal version of the PDPI-R-J administered during pregnancy accurately predicted 62.8% of PPD (95% CI 0.48-0.77) and the postpartum version administered at the first month after delivery predicted 82.0% of PPD (95% CI 0.71-0.93). The cutoffs identified were 5.5 for the prenatal version and 7.5 for the postpartum version. The PDPI-R-J postpartum version, which includes items relating to the infant, increased the predictive validity of PPD (0.67 to 0.82). Comments from the participants included that the use of the PDPI-R-J enhanced the chance to openly communicate about their history and risks for depression with the researchers, if any existed. CONCLUSIONS: The PDPI-R-J was found to be a useful and valid screening tool for predicting PPD. Both the prenatal and postpartum versions should be continuously administered to mothers because delivery and infant-related factors affect the potential for PPD. PMID- 23672473 TI - Reducing Salmonella horizontal transmission during egg incubation by phage therapy. AB - Salmonella is a serious problem for both animal production and public health worldwide. Contaminated poultry is the main vehicle of Salmonella and the most important serotype is Salmonella enterica serovar Enteritidis. In order to test the efficiency of bacteriophages to treat Salmonella enterica serovar Enteritidis infections in poultry, a cocktail of two phages, F1055S and F12013S, isolated from chicken litter was applied by aerosol spray on fertile eggs challenged with Salmonella Enteritidis. To the best of our knowledge, this is the first experiment in which phages were applied by spray on fertile eggs. Two groups of eggs were challenged with Salmonella (3*10(8) colony-forming units [CFU]/mL) and one of them was treated with the phage suspension (2*10(6) plaque-forming units [PFU]/mL). A third group was used as nonchallenged and nontreated control. The phage treatment of challenged Salmonella eggs reduced the disease symptoms in the chicks. The arthritis and pasting after 8 days in the challenged and treated group were similar to those normally occurring in chicks (nonchallenged and nontreated chick control group) (p=1.000 and p=0.828, respectively, for arthritis and pasting) and were significantly lower than the challenged but nontreated ones (p=0.017 and p=0.002 for arthritis and pasting, respectively). The phage-treated group did not lose weight, showing an average weight similar to that of the nonchallenged control group and higher than that of the challenged nontreated group. The results of this study suggest that the application of phages by aerosol spray during the transfer of the eggs from incubators to hatchers may be an effective and inexpensive approach for reducing the horizontal transfer of Salmonella in poultry. PMID- 23672474 TI - Unique class 1 integron and multiple resistance genes co-located on IncHI2 plasmid is associated with the emerging multidrug resistance of Salmonella Indiana isolated from chicken in China. AB - The objective of this study was to clarify the molecular antimicrobial resistance mechanisms of Salmonella enterica serovar Indiana isolated from chickens in China. A total of 327 chicken intestinal content and feces were collected in Shandong, China in 2009. Isolates were serotyped and antimicrobial susceptibility testing was performed. Thirty-five (10.7%) Salmonella isolates were recovered, and 16 (45.7%) were Salmonella enterica serovar Indiana, which were resistant to at least 14 of 15 antimicrobial agents. The 16 Salmonella enterica serovar Indiana detected and other 13 Salmonella enterica serovar Indiana that were selected from 133 Salmonella enterica serovar Indiana isolated in 2008 were subjected to pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Then class 1 integron and drug resistance genes were detected by polymerase chain reaction. Linkage between plasmids and resistance components was determined by conjugation, electrotransformation, S1 nuclease-PFGE, polymerase chain reaction-based replicon typing and Southern blot assays. Regions flanking integrons were sequenced by modified random primer walking strategy. PFGE and MLST suggested that all the 29 Salmonella enterica serovar Indiana isolates that shared >78% similarity in PFGE patterns were of the same MLST type, ST17. Two kinds of class 1 integrons had different integrase genes and the same variable region (dfrA7/aadA4/IS26/aac(6')-Ib/blaOXA-1/catB3/arr-3), and additional antimicrobial resistance genes such as blaCTX-M-24, floR, and so on were detected on IncHI2 plasmids in 29 Salmonella enterica serovar Indiana, and seven plasmids were conjugative. Analysis of the genetic environment of the integrons suggested that these integrons might have been formed by the help of IS26. To our knowledge, the variable region in class 1 integrons is the longest reported in Salmonella to date. The unique integrons and multiple resistance genes co-located on the IncHI2 plasmid contributed to the dissemination of multidrug resistance. PMID- 23672475 TI - Differentially expressed proteins in the skin mucus of Atlantic cod (Gadus morhua) upon natural infection with Vibrio anguillarum. AB - BACKGROUND: Vibriosis caused by V. anguillarum is a commonly encountered disease in Atlantic cod farms and several studies indicate that the initiation of infection occurs after the attachment of the pathogen to the mucosal surfaces (gut, skin and gills) of fish. Therefore it is necessary to investigate the role of different mucosal components in fish upon V. anguillarum infection. The present study has two parts; in the first part we analyzed the differential expression of skin mucus proteins from Atlantic cod naturally infected with V. anguillarum using two dimensional gel electrophoresis coupled with mass spectrometry. In the second part, a separate bath challenge experiment with V. anguillarum was conducted to assess the mRNA levels of the genes in skin tissue, corresponding to the selected proteins identified in the first part. RESULTS: Comparative proteome analysis of skin mucus of cod upon natural infection with V. anguillarum revealed key immune relevant proteins like calpain small subunit 1, glutathione-S-transferase omega 1, proteasome 26S subunit, 14-kDa apolipoprotein, beta 2-tubulin, cold inducible RNA binding protein, malate dehydrogenase 2 (mitochondrial) and type II keratin that exhibited significant differential expression. Additionally a number of protein spots which showed large variability amongst individual fish were also identified. Some of the proteins identified were mapped to the immunologically relevant JNK (c-Jun N-terminal kinases) signalling pathway that is connected to cellular events associated with pathogenesis. A bath challenge experiment with V. anguillarum showed differential expression of beta 2-tubulin, calpain small subunit 1, cold inducible RNA binding protein, flotillin1, and glutathione S-transferase omega 1 transcripts in the skin tissue of cod during early stages of infection. CONCLUSIONS: Differentially expressed proteins identified in the cod skin mucus point towards their possible involvement in V. anguillarum pathogenesis. The role of some of these proteins in vibriosis in cod described in this paper can be considered unconventional with respect to their established functions in higher vertebrates. Based on the differential expression of these proteins they are possibly important components of fish defence against bacteria and innate immunity at large. The feasibility of utilizing these proteins/genes as markers of bacterial infection or stress in cod needs to be explored further. PMID- 23672477 TI - Primary aortoesophageal fistula: a rare but fatal cause of upper gastrointestinal bleeding. PMID- 23672476 TI - The idea of an exact number: children's understanding of cardinality and equinumerosity. AB - Understanding what numbers are means knowing several things. It means knowing how counting relates to numbers (called the cardinal principle or cardinality); it means knowing that each number is generated by adding one to the previous number (called the successor function or succession), and it means knowing that all and only sets whose members can be placed in one-to-one correspondence have the same number of items (called exact equality or equinumerosity). A previous study (Sarnecka & Carey, 2008) linked children's understanding of cardinality to their understanding of succession for the numbers five and six. This study investigates the link between cardinality and equinumerosity for these numbers, finding that children either understand both cardinality and equinumerosity or they understand neither. This suggests that cardinality and equinumerosity (along with succession) are interrelated facets of the concepts five and six, the acquisition of which is an important conceptual achievement of early childhood. PMID- 23672478 TI - Thioacids mediated selective and mild N-acylation of amines. AB - N-Acylated amines are ubiquitous in nature. Selective N-acylation at neutral conditions remains a key area of interest. Here we are reporting the copper sulfate-mediated highly selective, mild, and rapid N-acylation of various aliphatic and aromatic amines using thioacids in methanol at neutral conditions. All N-acylated products of primary and secondary amines were isolated in good to excellent yields. This method is found to be highly selective for the amines and not sensitive to other functional groups such as phenols, alcohols, and thiols. The simple workup, high yields, and high selectivity of this reaction can be an attractive alternative to those of the existing acyl halide- and acid anhydride mediated N-acylation reactions. PMID- 23672479 TI - Terminal olefins to linear alpha,beta-unsaturated ketones: Pd(II)/hypervalent iodine co-catalyzed Wacker oxidation-dehydrogenation. AB - Development of a mild (35 degrees C, no Bronsted acids) tandem Wacker oxidation dehydrogenation of terminal olefins was accomplished using palladium(II) and hypervalent iodine co-catalysis. The reaction affords linear aryl and alkyl alpha,beta-unsaturated ketones directly from readily available terminal olefins in good yields (average 75% per step) with excellent functional group tolerance and chemo- and stereoselectivities. The hypervalent iodine co-catalyst was found to be critical for dehydrogenation but was not effective as a stoichiometric oxidant. PMID- 23672480 TI - Is health a labour, citizenship or human right? Mexican seasonal agricultural workers in Leamington, Canada. AB - Post-North American Free Trade Agreement (NAFTA) trade liberalisation combined with post-9/11 border securitisation means North America increasingly relies on pools of temporary foreign labour, particularly in the agricultural and service sectors. Despite being temporary, these workers often spend most of their years on foreign soil, living and working in isolated rural communities, far from their own families and communities. Migrants' mental and physical health suffers due to hazardous and stressful working conditions, sub-standard housing, lack of social support and limited access to health and social welfare services. Assuming access to health is a basic human right, who is responsible for the health of temporary foreign migrant workers? Is it the nation-state? or the Employers and/or unions? or Civil society? Research and practice show that a combined multisector approach is best; however, such initiatives are often uneven due to questions of sovereignty and citizenship rights. Community-based organisations (CBOs) have emerged to advocate for and serve migrants' social and welfare needs; analysis of CBO projects reveals an uneven application of rights to migrants. Using a comparative case study from Canada, this project contributes to understanding how civil-society helps to activate different types of health care rights for migrants, and to create an informed policy that provides migrant workers with access to a wider range of human and health rights. PMID- 23672481 TI - High efficiency solid-state sensitized solar cell-based on submicrometer rutile TiO2 nanorod and CH3NH3PbI3 perovskite sensitizer. AB - We report a highly efficient solar cell based on a submicrometer (~0.6 MUm) rutile TiO2 nanorod sensitized with CH3NH3PbI3 perovskite nanodots. Rutile nanorods were grown hydrothermally and their lengths were varied through the control of the reaction time. Infiltration of spiro-MeOTAD hole transport material into the perovskite-sensitized nanorod films demonstrated photocurrent density of 15.6 mA/cm(2), voltage of 955 mV, and fill factor of 0.63, leading to a power conversion efficiency (PCE) of 9.4% under the simulated AM 1.5G one sun illumination. Photovoltaic performance was significantly dependent on the length of the nanorods, where both photocurrent and voltage decreased with increasing nanorod lengths. A continuous drop of voltage with increasing nanorod length correlated with charge generation efficiency rather than recombination kinetics with impedance spectroscopic characterization displaying similar recombination regardless of the nanorod length. PMID- 23672482 TI - Differential morphology and homogeneity of tissue-engineered cartilage in hydrodynamic cultivation with transient exposure to insulin-like growth factor-1 and transforming growth factor-beta1. AB - Successful tissue-engineering strategies for cartilage repair must maximize the efficacy of chondrocytes within their limited life span. To that end, the combination of exogenous growth factors with mechanical stimuli holds promise for development of clinically relevant cartilage tissue substitutes. The current study aimed to determine whether incorporation of transient exposure to growth factors into a hydrodynamic bioreactor system can improve the functional maturation of tissue-engineered cartilage. Chondrocyte-seeded polyglycolic acid scaffolds were cultivated within a wavy-walled bioreactor that imparts fluid flow induced shear stress for 4 weeks. Constructs were nourished with 100 ng/mL insulin-like growth factor-1 (IGF-1) or 10 ng/mL transforming growth factor-beta1 (TGF-beta1) either for the first 15 days of the culture (transient) or throughout the entire cultivation (continuous). Transiently treated constructs were found to exhibit better functional properties than continuously nourished constructs. The limited development of engineered tissues continuously stimulated by IGF-1 or TGF beta1 was related to massive growth factor leftovers in the environments that downregulated the expression of the associated receptors. Treatment with TGF beta1 eliminated the formation of a fibrous capsule at the construct periphery possibly through suppression of Smad3 phosphorylation, yielding constructs with greater homogeneity. Furthermore, TGF-beta1 reversely regulated Smad2 and Smad3 pathways in articular chondrocytes under hydrodynamic stimuli partially via Smad7. Collectively, transient exposure to growth factors is likely to maintain chondrocyte homeostasis, and thus promotes their anabolic activities under hydrodynamic stimuli. The present work suggests that robust hydrodynamically engineered neocartilage with a reduced fibrotic response and enhanced tissue homogeneity can be achieved through optimization of growth factor supplementation protocols and potentially through manipulation of intracellular signals such as Smad. PMID- 23672483 TI - Changes in hospital human tissue oversight in the United States between 2005 and 2011: results of a follow-up AABB survey. AB - BACKGROUND: In 2005, The Joint Commission (TJC) implemented tissue storage and issuance standards for hospital oversight, which AABB assessed by survey. This follow-up survey of AABB's membership, 6 years later, ascertained changes after TJC implementation of tissue standards. STUDY DESIGN AND METHODS: AABB's Biovigilance Tissue Working Group conducted a Web-based survey, distributed to 1069 hospital institutional members in June 2011. Human tissue types used, departmental responsibilities, and views of AABB involvement were queried. RESULTS: Of the 336 (31%) total respondents, 84% use allogeneic and/or autologous human tissue. Sixty-one percent have stored tissue on consignment. As in 2005, the department of surgery most often had responsibility for tissue use, followed by the blood bank or transfusion service (BBTS). Overall, the BBTS had a smaller role in oversight of autologous tissue acquisition in 2011 versus 2005, but no change in level of responsibility for storage or issue of tissues. Hospitals reported the BBTS and combined blood and tissue services (CBTS) added responsibilities for storing and monitoring eye tissue and heart valves (p < 0.05) since 2005. The BBTS/CBTS increased their degree of responsibility for reporting suspected postimplant infection and other adverse reactions for musculoskeletal allografts (p < 0.01), eye tissue (p < 0.005), and eye tissue recipients recall notification (p < 0.05). The BBTS/CBTS have more responsibility than any other department for stem cell and cord blood management. CONCLUSIONS: In this survey, AABB institutional members reported that BBTS are more involved than previously in the regulatory aspects of human tissue oversight and remain involved in many operational aspects of hospital tissue management. PMID- 23672484 TI - Fatal skin and pulmonary infection caused by Hormographiella aspergillata in a leukaemic patient: case report and literature overview. AB - Invasive systemic fungal infections are a major cause of morbidity and mortality in patients after hematopoietic stem cell transplantation. We report the case of a fatal infection with Hormographiella aspergillata in a patient undergoing allogenic peripheral blood stem cell transplantation for acute myeloid leukaemia. PMID- 23672485 TI - Two-photon optical interrogation of individual dendritic spines with caged dopamine. AB - We introduce a novel caged dopamine compound (RuBi-Dopa) based on ruthenium photochemistry. RuBi-Dopa has a high uncaging efficiency and can be released with visible (blue-green) and IR light in a two-photon regime. We combine two-photon photorelease of RuBi-Dopa with two-photon calcium imaging for an optical imaging and manipulation of dendritic spines in living brain slices, demonstrating that spines can express functional dopamine receptors. This novel compound allows mapping of functional dopamine receptors in living brain tissue with exquisite spatial resolution. PMID- 23672486 TI - Dietary versus maternal sources of organochlorines in top predator seabird chicks: an experimental approach. AB - We examined the relative importance of dietary sources and maternal transfer on organochlorine concentrations (?OCs) in Great skua chicks (Stercorarius skua) in Shetland by food supplementing parents with known wintering area. We predicted that experimental chicks (whose parents were supplemented) should have (i) higher growth rates and, (ii) lower ?OCs due to growth dilution effect and/or due to being fed with less contaminated food compared to control chicks. We also predicted a significant influence of maternal wintering area on chicks' ?OCs. Plasma ?OCs of adults, assessed prior to the manipulation, significantly differed between wintering areas of birds. Chicks were weighed every 5 days and plasma ?OCs were assessed at 20 days old. Based on nitrogen and carbon stable isotope analysis, the supplementary food contributed on average 20% of the dietary protein of the chicks. Although experimental chicks experienced better developmental conditions, supplementary food did not alleviate their organochlorine burden. Nevertheless, chicks whose mothers wintered in Europe showed ?OCs 50% higher than chicks whose mothers wintered in Africa. Moreover, based on the positive relationship between ?OCs of chicks and females, the contaminant load of Great skua chicks in Shetland appears to be more influenced by maternal transfer than by trophic transfer. PMID- 23672487 TI - Dental caries prevalence, oral health knowledge and practice among indigenous Chepang school children of Nepal. AB - BACKGROUND: Chepang communities are one of the most deprived ethnic communities in Nepal. According to the National Pathfinder Survey, dental caries is a highly prevalent childhood disease in Nepal. There is no data concerning the prevalence of caries along with knowledge, attitude and oral hygiene practices among Chepang schoolchildren. The objectives of this study were to 1) record the prevalence of dental caries 2) report experience of dental pain 3) evaluate knowledge, attitude and preventive practices on oral health of primary Chepang schoolchildren. METHOD: A cross sectional epidemiological study was conducted in 5 government Primary schools of remote Chandibhanjyang Village Development Committee (VDC) in Chitwan district. Ethical approval was taken from the Institutional Review Board within the Research Department of the Institute of Medicine (IOM) Tribhuvan University. Consent was obtained from parents for conducting clinical examination and administrating questionnaire. Permission was taken from the school principal in all schools. Data was collected using a pretested questionnaire on 131 schoolchildren aged 8-16-year- olds attending Grade 3-5. Clinical examination was conducted on 361 school children aged 5-16 -year-olds attending grade 1-5. Criteria set by the World Health Organization (1997) was used for caries diagnosis. The questionnaires, originally constructed in English and translated into Nepali were administered to the schoolchildren by the researchers. SPSS 11software was used for data analysis. RESULTS: Caries prevalence for 5-6 -year old was above the goals recommended by WHO and Federation of Dentistry international (FDI) of less than 50% caries free children. Caries prevalence in 5 6-year-olds was 52% and 12-13-year-olds was 41%. The mean dmft/DMFT score of 5-6 year-olds and 12 -13-year -olds was 1.59, 0.31 and 0.52, 0.84 respectively. The DMFT scores increased with age and the d/D component constituted almost the entire dmft/DMFT index. About 31% of 8-16-year-olds school children who participated in the survey reported having suffered from oral pain. Further, the need for treatment of decayed teeth was reported at 100%. About 76% children perceived teeth as an important component of general health and 75% reported it was required to eat. A total 93% children never visited a dentist or a health care service. Out of 56% children reporting cleaning their teeth daily, only 24% reported brushing their teeth twice daily. About 86% of the children reported using toothbrush and toothpaste to clean their teeth. Although 61% children reported to have received oral health education, 82% children did not know about fluoride and its benefit on dental health. About 50% children reported bacteria as the main cause of tooth decay and 23% as not brushing teeth for gingivitis. Frequency of sugar exposure was low; 75% of children reported eating sugar rich food once daily. CONCLUSIONS: Caries prevalence of 5-6 -year- old Chepang school children is above the recommended target set by FDI/WHO. The study reported 31% schoolchildren aged 8-16-year old suffered oral pain and decayed component constituted almost the entire dmft/DMFT index. The brushing habit was reportedly low with only 24% of the children brushing twice daily. A nationwide scientifically proven, cost effective school based interventions is needed for prevention and control of caries in schoolchildren in Nepal. PMID- 23672488 TI - KHA-CARI guideline: dialysis adequacy (haemodialysis): dialysis membranes. PMID- 23672489 TI - Characterisation of a transcriptome to find sequence differences between two differentially migrating subspecies of the willow warbler Phylloscopus trochilus. AB - BACKGROUND: Animal migration requires adaptations in morphological, physiological and behavioural traits. Several of these traits have been shown to possess a strong heritable component in birds, but little is known about their genetic architecture. Here we used 454 sequencing of brain-derived transcriptomes from two differentially migrating subspecies of the willow warbler Phylloscopus trochilus to detect genes potentially underlying traits associated with migration. RESULTS: The transcriptome sequencing resulted in 1.8 million reads following filtering steps. Most of the reads (84%) were successfully mapped to the genome of the zebra finch Taeniopygia gutatta. The mapped reads were situated within at least 12,101 predicted zebra finch genes, with the greatest sequencing depth in exons. Reads that were mapped to intergenic regions were generally located close to predicted genes and possibly located in uncharacterized untranslated regions (UTRs). Out of 85,000 single nucleotide polymorphisms (SNPs) with a minimum sequencing depth of eight reads from each of two subspecies specific pools, only 55 showed high differentiation, confirming previous studies showing that most of the genetic variation is shared between the subspecies. Validation of a subset of the most highly differentiated SNPs using Sanger sequencing demonstrated that several of them also were differentiated between an independent set of individuals of each subspecies. These SNPs were clustered in two chromosome regions that are likely to be influenced by divergent selection between the subspecies and that could potentially be associated with adaptations to their different migratory strategies. CONCLUSIONS: Our study represents the first large-scale sequencing analysis aiming at detecting genes underlying migratory phenotypes in birds and provides new candidates for genes potentially involved in migration. PMID- 23672490 TI - Asymmetric growth in polyelectrolyte multilayers. AB - Radioactive counterions were used to track the ratio of positive to negative polymer repeat units within a polyelectrolyte multilayer made from poly(diallyldimethylammonium chloride), PDADMAC, and poly(styrene sulfonate), PSS. For this widely employed pair of "linearly" assembled polyelectrolytes it was found that the accepted model of charge overcompensation for each layer is incorrect. In fact, overcompensation at the surface occurs only on the addition of the polycation, whereas PSS merely compensates the PDADMAC. After the assembly of about a dozen layers, excess positive sites begin to accrue in the multilayer. Treating the surface as a reaction-diffusion region for pairing of polymer charges, a model profile was constructed. It is shown that different reaction diffusion ranges of positive and negative polyelectrolyte charge lead to a blanket of glassy, stoichiometric complex growing on top of a layer of rubbery, PDADMAC-rich complex. Though overcompensation and growth was highly asymmetric with respect to the layer number, entirely conventional "linear" assembly of the multilayer was observed. The impact of asymmetric growth on various properties of multilayers is discussed. PMID- 23672491 TI - Conservative management of abnormally invasive placenta: choriocarcinoma with uterine arteriovenous fistula from remnant invasive placenta. PMID- 23672492 TI - Influence of Toll-like receptor gene polymorphisms to tuberculosis susceptibility in humans. AB - Tuberculosis (TB) is caused by Mycobacterium tuberculosis (M. tb), and it remains one of the major bacterial infections worldwide. Innate immunity is an important arm of antimycobacterial host defence mechanism that senses various pathogen associated molecular patterns (PAMP) of microbes by a variety of pattern recognition receptors (PRRs). As per the recent discovery, Toll-like receptors (TLRs) play a crucial role in the recognition of M. tb, this immune activation occurs only in the presence of functional TLRs. Variants of TLRs may influence their expression, function and alters the recognition or signalling mechanism, which leads to the disease susceptibility. Hence, the identification of mutations in these receptors could be used as a marker to screen the individuals who are at risk. In this review, we discuss TLR SNPs and their signalling mechanism to understand the susceptibility to TB for better therapeutic approaches. PMID- 23672494 TI - rptA, a novel gene from Ensifer (Sinorhizobium) meliloti involved in conjugal transfer. AB - We approached the identification of Ensifer (Sinorhizobium) meliloti conjugal functions by random Tn5-B13 mutagenesis of the pSmeLPU88a plasmid of E. meliloti strain LPU88 and the subsequent selection of those mutants that had lost the ability to mobilize the small plasmid pSmeLPU88b. The Tn5-B13-insertion site of one of the mutants was cloned as an EcoRI-restricted DNA fragment that after subsequent isolation and sequencing demonstrated that a small open reading frame of 522 bp (designated rptA, for rhizobium plasmid transfer A) had been disrupted. The predicted gene product encoded by the rptA sequence shows a significant similarity to two hypothetical proteins of the plasmid pSmed03 of Ensifer medicae WSM419 and other rhizobia plasmids. No significant similarity was found to any protein sequence of known function registered in the databases. Although the rptA gene was required for pSmeLPU88b-plasmid mobilization in the strain 2011 background, it was not required in the original strain LPU88 background. PMID- 23672493 TI - Anti-cancer effects of newly developed chemotherapeutic agent, glycoconjugated palladium (II) complex, against cisplatin-resistant gastric cancer cells. AB - BACKGROUND: Cisplatin (CDDP) is the most frequently used chemotherapeutic agent for various types of advanced cancer, including gastric cancer. However, almost all cancer cells acquire resistance against CDDP, and this phenomenon adversely affects prognosis. Thus, new chemotherapeutic agents that can overcome the CDDP resistant cancer cells will improve the survival of advanced cancer patients. METHODS: We synthesized new glycoconjugated platinum (II) and palladium (II) complexes, [PtCl2 (L)] and [PdCl2 (L)]. CDDP-resistant gastric cancer cell lines were established by continuous exposure to CDDP, and gene expression in the CDDP resistant gastric cancer cells was analyzed. The cytotoxicity and apoptosis induced by [PtCl2 (L)] and [PdCl2 (L)] in CDDP-sensitive and CDDP-resistant gastric cancer cells were evaluated. DNA double-strand breaks by drugs were assessed by evaluating phosphorylated histone H2AX. Xenograft tumor mouse models were established and antitumor effects were also examined in vivo. RESULTS: CDDP resistant gastric cancer cells exhibit ABCB1 and CDKN2A gene up-regulation, as compared with CDDP-sensitive gastric cancer cells. In the analyses of CDDP resistant gastric cancer cells, [PdCl2 (L)] overcame cross-resistance to CDDP in vitro and in vivo. [PdCl2 (L)] induced DNA double-strand breaks. CONCLUSION: These results indicate that [PdCl2 (L)] is a potent chemotherapeutic agent for CDDP-resistant gastric cancer and may have clinical applications. PMID- 23672495 TI - Interactions between voltage sensor and pore domains in a hERG K+ channel model from molecular simulations and the effects of a voltage sensor mutation. AB - The hERG K(+) channel is important for establishing normal electrical activity in the human heart. The channel's unique gating response to membrane potential changes indicates specific interactions between voltage sensor and pore domains that are poorly understood. In the absence of a crystal structure we constructed a homology model of the full hERG membrane domain and performed 0.5 MUs molecular dynamics (MD) simulations in a hydrated membrane. The simulations identify potential interactions involving residues at the extracellular surface of S1 in the voltage sensor and at the N-terminal end of the pore helix in the hERG model. In addition, a diffuse interface involving hydrophobic residues on S4 (voltage sensor) and pore domain S5 of an adjacent subunit was stable during 0.5 MUs of simulation. To assess the ability of the model to give insight into the effects of channel mutation we simulated a hERG mutant that contains a Leu to Pro substitution in the voltage sensor S4 helical segment (hERG L532P). Consistent with the retention of gated K(+) conductance, the L532P mutation was accommodated in the S4 helix with little disruption of helical structure. The mutation reduced the extent of interaction across the S4-S5 interface, suggesting a structural basis for the greatly enhanced deactivation rate in hERG L532P. The study indicates that pairwise comparison of wild-type and mutated channel models is a useful approach to interpreting functional data where uncertainty in model structures exist. PMID- 23672496 TI - Methylated arginines and nitric oxide in end-stage renal disease: impact of inflammation, oxidative stress and haemodialysis. AB - OBJECTIVES: To determine whether inflammation (C-reactive protein, CRP), oxidative stress (malondialdehyde, MDA) or haemodialysis (HD) affect associations between asymmetric (ADMA), symmetric (SDMA) dimethylarginine, NG-monomethyl-L arginine (L-NMMA) and nitrite/nitrate (NOx) in end-stage renal disease (ESRD). METHOD: Metabolites were measured pre-HD, after 1 hour and end-HD in 40 ESRD patients (age 63 +/- 14 years). RESULTS: Positive associations between NOx and ADMA (p = 0.04), SDMA (p < 0.001) and L-NMMA (p = 0.04) were observed pre-HD. Associations weakened during HD but were not significantly influenced by CRP or MDA. CONCLUSIONS: HD, oxidative stress or inflammation did not significantly affect the positive associations between methylated arginines and NOx in ESRD. PMID- 23672497 TI - Serum erythropoietin: a useful biomarker for coronary collateral development and potential target for therapeutic angiogenesis among the patients with coronary chronic total occlusion. AB - The study was to investigate the association of endogenous erythropoietin (EPO) and coronary collateral development. Forty-nine patients (31 with chronic total occlusion (CTO), 18 with normal coronary artery) were consecutively enrolled. The serum EPO was positively related with Rentrop class. Increased serum EPO was one of the independent predictors of good collateral development (odds ratio 1.31; p = 0.025). A significantly positive correlation was seen between serum EPO and vascular endothelial growth factor (VEGF) levels (r = 0.96, p < 0.001). Circulatory EPO may be a useful biomarker for coronary collateral development and potential target for therapeutic angiogenesis in patients with CTO. PMID- 23672498 TI - A study of TiO2/carbon black composition as counter electrode materials for dye sensitized solar cells. AB - This study describes a systematic approach of TiO2/carbon black nanoparticles with respect to the loading amount in order to optimize the catalytic ability of triiodide reduction for dye-sensitized solar cells. In particular, the cell using an optimized TiO2 and carbon black electrode presents an energy conversion efficiency of 7.4% with a 5:1 ratio of a 40-nm TiO2 to carbon black. Based on the electrochemical analysis, the charge-transfer resistance of the carbon counter electrode changed based on the carbon black powder content. Electrochemical impedance spectroscopy and cyclic voltammetry study show lower resistance compared to the Pt counter electrode. The obtained nanostructures and photo electrochemical study were characterized. PMID- 23672499 TI - Backtracking and the ethics of framing: lessons from voles and vasopressin. AB - When communicating scientific information, experts often face difficult choices about how to promote public understanding while also maintaining an appropriate level of objectivity. We argue that one way for scientists and others involved in communicating scientific information to alleviate these tensions is to pay closer attention to the major frames employed in the contexts in which they work. By doing so, they can ideally employ useful frames while also enabling the recipients of information to "backtrack" to relatively uncontroversial facts and recognize how these frames relate to their own values and perspectives. Important strategies for promoting this sort of backtracking include identifying the weaknesses of particular frames, preventing misunderstanding of them, differentiating well-supported findings from more speculative claims, and acknowledging major alternative frames. PMID- 23672500 TI - Bronsted acid-controlled [3 + 2] coupling reaction of quinone monoacetals with alkene nucleophiles: a catalytic system of perfluorinated acids and hydrogen bond donor for the construction of benzofurans. AB - We have developed an efficient Bronsted acid-controlled strategy for the [3 + 2] coupling reaction of quinone monoacetals (QMAs) with nucleophilic alkenes, which is triggered by the particular use of a specific acid promoter, perfluorinated acid, and a solvent, fluoroalcohol. This new coupling reaction smoothly proceeded with high regiospecificity in regard with QMAs for introducing pi-nucleophiles to only the carbon alpha to the carbonyl group, thereby providing diverse dihydrobenzofurans and derivatives with high yields, up to quantitative, under mild conditions in short reaction times. The choice of Bronsted acid enabled us to avoid hydrolysis of the QMAs, which gives quinones, and the formation of discrete cationic species from the QMAs. Notably, further investigations in this study with regard to the acid have led to the findings that the originally stoichiometrically used acid could be reduced to a catalytic amount of 5 mol % loading or less and that the stoichiometry of the alkenes could be significantly improved down to only 1.2 equiv. The facts that only a minimal loading (5 mol %) of perfluoroterephthalic acid is required, readily available substrates can be used, and the regioselectivity can be controlled by the acid used make this coupling reaction very fascinating from a practical viewpoint. PMID- 23672501 TI - Temporal dynamics of direct reciprocal and indirect effects in a host-parasite network. AB - 1. Temporal variation in the direct and indirect influence that hosts and parasites exert on each other is still poorly understood. However, variation in species' influence due to species and interactions turnover can have important consequences for host community dynamics and/or for parasite transmission dynamics, and eventually for the risk of zoonotic diseases. 2. We used data on a network of small mammals and their ectoparasites surveyed over 6 years to test hypotheses exploring (i) the temporal variability in direct and indirect influences species exert on each other in a community, and (ii) the differences in temporal variability of direct/indirect influences between temporally persistent (TP) and temporally intermittent species. 3. We modelled the temporal variation in (i) direct reciprocal influence between hosts and parasites (hosts providing resources to parasites and parasites exploiting the resources of hosts), using an asymmetry index, and (ii) indirect influence among species within a community (e.g. facilitation of parasite infestation by other parasites), using betweenness centrality. We also correlated asymmetry and centrality to examine the relationship between them. 4. Network dynamics was determined by TP species but even those species had strong among-species heterogeneity in the temporal variation of the direct/indirect effects they exerted. In addition, there was a significant positive linear correlation between asymmetry and centrality. 5. We conclude that the temporal dynamics of host parasite interactions is driven by TP hosts. However, even within this group of persistent species, some exhibit large temporal variation, such that the functional roles they play (e.g. in promoting parasite transmission) change over time. In addition, parasites having a large negative impact on hosts are also those facilitating the spread of other parasites through the entire host community. Our results provide new insights into community dynamics and can be applied in the management of antagonistic networks aimed at preventing disease outbreaks. PMID- 23672502 TI - Mechanobiological dysregulation of the epidermis and dermis in skin disorders and in degeneration. AB - During growth and development, the skin expands to cover the growing skeleton and soft tissues by constantly responding to the intrinsic forces of underlying skeletal growth as well as to the extrinsic mechanical forces from body movements and external supports. Mechanical forces can be perceived by two types of skin receptors: (1) cellular mechanoreceptors/mechanosensors, such as the cytoskeleton, cell adhesion molecules and mechanosensitive (MS) ion channels, and (2) sensory nerve fibres that produce the somatic sensation of mechanical force. Skin disorders in which there is an abnormality of collagen [e.g. Ehlers-Danlos syndrome (EDS)] or elastic (e.g. cutis laxa) fibres or a malfunction of cutaneous nerve fibres (e.g. neurofibroma, leprosy and diabetes mellitus) are also characterized to some extent by deficiencies in mechanobiological processes. Recent studies have shown that mechanotransduction is crucial for skin development, especially hemidesmosome maturation, which implies that the pathogenesis of skin disorders such as bullous pemphigoid is related to skin mechanobiology. Similarly, autoimmune diseases, including scleroderma and mixed connective tissue disease, and pathological scarring in the form of keloids and hypertrophic scars would seem to be clearly associated with the mechanobiological dysfunction of the skin. Finally, skin ageing can also be considered as a degenerative process associated with mechanobiological dysfunction. Clinically, a therapeutic strategy involving mechanoreceptors or MS nociceptor inhibition or acceleration together with a reduction or augmentation in the relevant mechanical forces is likely to be successful. The development of novel approaches such as these will allow the treatment of a broad range of cutaneous diseases. PMID- 23672503 TI - Distinguishing social and cultural features of cholera in urban and rural areas of Western Kenya: Implications for public health. AB - Urban and rural areas have distinctive health problems, which require consideration. To examine sociocultural features of cholera and its community context, a semi-structured explanatory model interview based on vignettes depicting typical clinical features of cholera was used to interview 379 urban and rural respondents in Western Kenya. Findings included common and distinctive urban and rural ideas about cholera, and its prevention and treatment. The three most commonly perceived causes among urban and rural respondents collectively were drinking contaminated water, living in a dirty environment and lacking latrines. However, a dirty environment and flies were more prominently perceived causes among urban respondents. Rural respondents were less likely to identify additional symptoms and more likely to identify biomedically irrelevant perceived causes of cholera. Oral rehydration therapy was the most frequently reported home treatment. Health facilities were recommended unanimously at both sites. For prevention, rural respondents were more likely to suggest medicines, and urban respondents were more likely to suggest health education and clean food. Findings indicate community priority, demand for and potential effectiveness of enhanced efforts to control cholera in Western Kenya, and they suggest strategies that are particularly well suited for control of cholera in urban and rural areas. PMID- 23672504 TI - Tissue-engineered cartilaginous constructs for the treatment of caprine cartilage defects, including distribution of laminin and type IV collagen. AB - The purpose of this study was the immunohistochemical evaluation of (1) cartilage tissue-engineered constructs; and (2) the tissue filling cartilage defects in a goat model into which the constructs were implanted, particularly for the presence of the basement membrane molecules, laminin and type IV collagen. Basement membrane molecules are localized to the pericellular matrix in normal adult articular cartilage, but have not been examined in tissue-engineered constructs cultured in vitro or in tissue filling cartilage defects into which the constructs were implanted. Cartilaginous constructs were engineered in vitro using caprine chondrocyte-seeded type II collagen scaffolds. Autologous constructs were implanted into 4-mm-diameter defects created to the tidemark in the trochlear groove in the knee joints of skeletally mature goats. Eight weeks after implantation, the animals were sacrificed. Constructs underwent immunohistochemical and histomorphometric evaluation. Widespread staining for the two basement membrane molecules was observed throughout the extracellular matrix of in vitro and in vivo samples in a distribution unlike that previously reported for cartilage. At sacrifice, 70% of the defect site was filled with reparative tissue, which consisted largely of fibrous tissue and some fibrocartilage, with over 70% of the reparative tissue bonded to the adjacent host tissue. A novel finding of this study was the observation of laminin and type IV collagen in in vitro engineered cartilaginous constructs and in vivo cartilage repair samples from defects into which the constructs were implanted, as well as in normal caprine articular cartilage. Future work is needed to elucidate the role of basement membrane molecules during cartilage repair and regeneration. PMID- 23672505 TI - Editorial: discrepancies and pitfalls in diagnosis and therapy of esophageal columnar metaplasia/Barrett's esophagus: a personal view. PMID- 23672506 TI - Enantioselective functionalization of indoles and pyrroles via an in situ-formed spiro intermediate. AB - Herein we report a highly enantioselective synthesis of polycyclic indoles and pyrroles with up to 99% ee by an iridium catalyst system consisting of a commercially available iridium precursor and a readily accessible ligand. Investigation of the reaction mechanism led to the discovery of an unprecedented dearomatized spiro intermediate and its in situ migration phenomenon. The new reaction mode features switching of the substituent from the indole C-3 position to the C-2 position (from the C-2 position to the C-3 position in the case of pyrrole) without loss of the enantiomeric purity, providing a novel concept in designing the asymmetric construction of enantiopure polycyclic indoles and pyrroles. PMID- 23672507 TI - Novel syntheses of fluorenones via nitrile-directed palladium-catalyzed C-H and dual C-H bond activation. AB - Novel procedures for the [Pd]/[Ag]/TFA system catalyzed cascade reactions of nitrile directed remote C-H and dual C-H bond activation with insertion of nitrile were developed, which afforded variously polysubstituted fluorenones in moderate to good yields with tolerance of a wide variety of substrates. PMID- 23672508 TI - To tamponade or not to tamponade? PMID- 23672509 TI - Syphilis as a diagnosis of liver abnormalities in HIV. AB - In order to investigate syphilitic liver involvement in HIV-infected patients, a single-centre retrospective study of a cohort of HIV-infected patients with syphilis was performed at the Infectious Diseases Clinic of Perugia, Italy, between December 2002 and March 2010. Fifty HIV-infected patients were identified with syphilis plus baseline and follow-up liver tests. The following syphilis diagnoses were recorded: 19 secondary (38%), 26 latent (52%), and 5 tertiary/neurosyphilis (12%). Syphilitic hepatitis was found in 5/50 (10%) patients. This finding supports the importance of including syphilis in the differential diagnosis of liver enzyme abnormalities in HIV-infected patients. An early diagnosis of syphilitic hepatitis can lead to rapid normalization of liver function following appropriate therapy, prevents the progression of syphilis, and limits the further spread of sexually transmitted diseases, including HIV. PMID- 23672510 TI - Seroepidemiological study of influenza A (H1N1) pdm09 virus following the 2009 2010 wave in Shandong Province, China. AB - INTRODUCTION: The aims of this study were to understand the geographic extent, risk factors, and attack rate of influenza A (H1N1) pdm09 virus (pH1N1) infection in Shandong Province China and to elucidate influencing factors. METHODS: In January and March 2010, a cross-sectional seroprevalence survey of pH1N1 was carried out. Serum samples from 9022 participants in the survey were subjected to the hemagglutination inhibition assay. RESULTS: Among the 9022 participants, the overall rate of seropositivity against pH1N1 was 22.6%. The weighted rate, adjusted for gender, age, and region, was estimated to be 18.7%. Among 8340 subjects who did not report previous vaccination, the rate was 16.7%, as compared to 50.9% among 682 subjects reporting previous vaccination (p < 0.001). Within the unvaccinated population, the rate of seropositivity among 16-24 and 6-15 y old subjects was 31.8% and 29.9%, respectively, as compared to 9.6% among subjects aged >= 60 y (p < 0.001) and 23% in the 0-5 y age group (p < 0.001). Those aged 6-15 y and aged 16-24 y had higher odds of seropositivity than those aged 0-5 y (odds ratio 1.53 and 1.48, respectively). CONCLUSIONS: These study findings help enhance our understanding of pH1N1 epidemiology and provide valuable information for the vaccination strategy for the influenza season. PMID- 23672511 TI - Hospital-based transfusion error tracking from 2005 to 2010: identifying the key errors threatening patient transfusion safety. AB - BACKGROUND: This report provides a comprehensive analysis of transfusion errors occurring at a large teaching hospital and aims to determine key errors that are threatening transfusion safety, despite implementation of safety measures. STUDY DESIGN AND METHODS: Errors were prospectively identified from 2005 to 2010. Error data were coded on a secure online database called the Transfusion Error Surveillance System. Errors were defined as any deviation from established standard operating procedures. Errors were identified by clinical and laboratory staff. Denominator data for volume of activity were used to calculate rates. RESULTS: A total of 15,134 errors were reported with a median number of 215 errors per month (range, 85-334). Overall, 9083 (60%) errors occurred on the transfusion service and 6051 (40%) on the clinical services. In total, 23 errors resulted in patient harm: 21 of these errors occurred on the clinical services and two in the transfusion service. Of the 23 harm events, 21 involved inappropriate use of blood. Errors with no harm were 657 times more common than events that caused harm. The most common high-severity clinical errors were sample labeling (37.5%) and inappropriate ordering of blood (28.8%). The most common high-severity error in the transfusion service was sample accepted despite not meeting acceptance criteria (18.3%). The cost of product and component loss due to errors was $593,337. CONCLUSION: Errors occurred at every point in the transfusion process, with the greatest potential risk of patient harm resulting from inappropriate ordering of blood products and errors in sample labeling. PMID- 23672512 TI - Developmental defects of enamel in primary teeth and association with early life course events: a study of 6-36 month old children in Manyara, Tanzania. AB - BACKGROUND: Children with low birth weight show an increased prevalence of developmental defects of enamel in the primary dentition that subsequently may predispose to early childhood caries (ECC).Focusing 6-36 months old, the purpose of this study was to assess the frequency of enamel defects in the primary dentition and identify influences of early life course factors; socio demographics, birth weight, child's early illness episodes and mothers' perceived size of the child at birth, whilst controlling for more recent life course events in terms of current breastfeeding and oral hygiene. METHODS: A cross-sectional study was conducted in the high fluoride area of Manyara, northern Tanzania including 1221 child-mother pairs who attended Reproductive and Child Health (RCH) clinics for immunization and/or growth monitoring. After the primary caregivers had completed face to face interviews at the health care facility, children underwent oral clinical examination whereby ECC and developmental defects of enamel were recorded using field criteria. All erupted teeth were examined and the enamel defects were assessed on buccal surfaces according to the modified DDE Index. RESULTS: The prevalence of enamel defects was 33.3%. Diffuse opacities were the most common defects identified (23.1%), followed by hypoplasia (7.6%) and demarcated opacities (5.0%). The most frequently affected teeth were the upper central incisors (29.0% - 30.5%), whereas lower central incisors (4.3% to 4.5%) were least frequently affected. Multiple logistic regression analysis, adjusting for confounding the factors revealed that having normal birth weight (equal or more than 2500 g) associated with lower odds of having enamel hypoplasia [OR 0.2 (95% CI 0.1-0.7)]. No statistically significant association occurred between birth weight and diffuse opacities, demarcated opacities or combined DDE. CONCLUSION: Children with the history of low birth weight were more likely than their normal birth weight counterparts to present with enamel hypoplasia. In view of the frequent occurrence of enamel defects and the fact that hypoplasia may constitute a risk factor for future ECC, enamel defects should be included as a dental health indicator in epidemiological studies of children in northern Tanzania. PMID- 23672513 TI - Using the lymph nodal ratio to predict the risk of locoregional recurrence in lymph node-positive breast cancer patients treated with mastectomy without radiation therapy. AB - BACKGROUND: To evaluate the prognostic value of axillary lymph node ratio (LNR) as compared to the number of involved nodes (pN stage) in patients with axillary lymph node-positive breast cancer treated with mastectomy without radiation. METHODS: We performed a retrospective analysis of the clinical data of patients with stage II-III node-positive breast cancer (N=1068) between 1998 and 2007. Locoregional recurrence-free survival (LRFS) and overall survival (OS) were compared based on the LNR and pN staging. RESULTS: A total of 780 cases were classified as pN1, 183 as pN2, and 105 as pN3. With respect to LNR, 690 cases had a LNR from 0.01-0.20, 269 cases a LNR from 0.21-0.65, and 109 cases a LNR > 0.65. The median follow-up time was 62 months. Univariate analysis showed that both LNR and pN stage were prognostic factors of LRFS and OS (p<0.05). Multivariate analysis indicated that LNR was an independent prognostic factor of LRFS and OS (p<0.05). pN stage had no significant effect on LRFS or OS (p>0.05). In subgroup analysis, the LNR identified groups of patients with different survival rates based on pN stage. CONCLUSIONS: LNR is superior to pN staging as a prognostic factor in lymph node-positive breast cancer after mastectomy, and should be used as one of the indications for adjuvant radiation therapy. PMID- 23672514 TI - Four-year allograft survival in a highly sensitized combined liver-kidney transplant patient despite unsuccessful anti-HLA antibody reduction with rituximab, splenectomy, and bortezomib. AB - Although donor-specific lymphocytotoxic antibodies are regarded as a contraindication for kidney transplantation (KTx), the data available for liver or combined liver or kidney transplantation (cLKTx) are scarce. Here, we report a case of a highly sensitized young man receiving his sixth liver and second kidney graft. Multiple anti-HLA antibodies were present at the time of transplantation. As a result of suspected antibody-mediated graft damage, the patient was treated with rituximab, plasmapheresis, intravenous immunoglobulins, splenectomy, and bortezomib to decrease the antibody production. So far, patient and allograft survival has reached 4 years despite failure to achieve a permanent reduction of anti-HLA antibodies, and particularly nondonor directed antibodies. PMID- 23672515 TI - Comparative genome analysis of an avirulent and two virulent strains of avian Pasteurella multocida reveals candidate genes involved in fitness and pathogenicity. AB - BACKGROUND: Pasteurella multocida is the etiologic agent of fowl cholera, a highly contagious and severe disease of poultry causing significant mortality and morbidity throughout the world. All types of poultry are susceptible to fowl cholera. Turkeys are most susceptible to the peracute/acute forms of the disease while chickens are most susceptible to the acute and chronic forms of the disease. The whole genome of the Pm70 strain of P. multocida was sequenced and annotated in 2001. The Pm70 strain is not virulent to chickens and turkeys. In contrast, strains X73 and P1059 are highly virulent to turkeys, chickens, and other poultry species. In this study, we sequenced the genomes of P. multocida strains X73 and P1059 and undertook a detailed comparative genome analysis with the avirulent Pm70 strain. The goal of this study was to identify candidate genes in the virulent strains that may be involved in pathogenicity of fowl cholera disease. RESULTS: Comparison of virulent versus avirulent avian P. multocida genomes revealed 336 unique genes among the P1059 and/or X73 genomes compared to strain Pm70. Genes of interest within this subset included those encoding an L fucose transport and utilization system, several novel sugar transport systems, and several novel hemagglutinins including one designated PfhB4. Additionally, substantial amino acid variation was observed in many core outer membrane proteins and single nucleotide polymorphism analysis confirmed a higher dN/dS ratio within proteins localized to the outer membrane. CONCLUSIONS: Comparative analyses of highly virulent versus avirulent avian P. multocida identified a number of genomic differences that may shed light on the ability of highly virulent strains to cause disease in the avian host, including those that could be associated with enhanced virulence or fitness. PMID- 23672516 TI - Mechanistic insights into the LsrK kinase required for autoinducer-2 quorum sensing activation. AB - In enteric bacteria, the kinase LsrK catalyzes the phosphorylation of the C5 hydroxyl group in the linear form of 4,5-dihydroxy-2,3-pentanedione (DPD), the precursor of the type II bacterial quorum sensing molecule (AI-2). This phosphorylation is required for AI-2 sequestration in the cytoplasm and subsequent derepression of AI-2-related genes necessary for quorum development. While LsrK is a critical enzyme within the DPD quorum sensing relay system, kinetic details of this kinase have yet to be reported. A continuous UV-vis spectrophotometric assay was developed that allowed steady-state kinetic analysis of LsrK to be undertaken with the substrates ATP and DPD. The data was most consistent with a rapid equilibrium ordered mechanism with ATP binding first: kcat (7.4 +/- 0.6 s(-1)), Km,ATP (150 +/- 30 MUM) and Km(app),DPD (1.0 +/- 0.2 mM). The assay also allowed a DPD substrate profile to be conducted, which provided an unexpected biochemical disconnect between the previous agonist/antagonist cell-based reporter assay and the LsrK assay presented herein. Together these findings raise the importance of LsrK and lay the foundation not only for further understanding of this enzyme and its critical biological role but also for the rational design of regulatory molecules targeting AI-2 quorum sensing in pathogenic bacteria. PMID- 23672517 TI - Corrinoid activation by a RACE protein: studies on the interaction of the proteins involved. AB - The O-demethylases of anaerobes are corrinoid-dependent, ether-cleaving methyltransferase enzyme systems consisting of four components. The interaction of the O-demethylase components of the acetogenic bacterium Acetobacterium dehalogenans was studied by protein mobility on native PAGE, far-Western blot analysis and yeast two-hybrid screen. Using native PAGE and far-Western blot, the interaction of the activating enzyme (AE) with its substrate, the corrinoid protein (CP), could be observed. The interaction occurred with four different CPs of A. dehalogenans and a CP from Desulfitobacterium hafniense DCB-2, all involved in ether cleavage. In the corrinoid reduction assay, the AE reduced all CPs tested. This result indicates a broad substrate specificity of the AE of A. dehalogenans. In addition, an interaction of the A. dehalogenans CP of the vanillate-O-demethylase with the two methyltransferases of the same enzyme system was observed. The interaction of the ether-cleaving methyltransferase with the CP appeared to be significantly less pronounced than that reported for the homologous methanol and methylamine methyltransferase systems of methanogenic archaea. PMID- 23672519 TI - Advanced nasopharyngeal carcinoma radiotherapy with volumetric modulated arcs and the potential role of flattening filter-free beams. AB - PURPOSE: The purpose of this study is to investigate the dosimetric characteristics of volumetric modulated arc therapy (VMAT) with flattening filter free (FFF) beams and assess the role of VMAT in the treatment of advanced nasopharyngeal carcinoma (NPC). METHODS: Ten cases of CT data were randomly selected from advanced NPC patients. Three treatment plans were optimized for each patient, RapidArc with FFF beams (RA-FFF), conventional beams (RA) and static gantry intensity-modulated radiation therapy (IMRT). The doses to the planning target volumes (PTVs), organs at risk (OARs), skin and normal tissue were compared. All the plans were delivered on a Varian TrueBeam linear accelerator and verified using the Delta4 phantom. Technical delivery parameters including the mean gamma score, treatment delivery time and monitor units (MUs) were also analyzed. RESULTS: All the techniques delivered adequate doses to the PTVs. RA-FFF gave the highest D(1%) (dose received by 1% of the volume), but the poorest conformity index (CI) and homogeneity index (HI) among the PTVs except for the planning target volume of involved regional lymph nodes (PTV66) CI, which showed no significant difference among three techniques. For the planning target volume of the primary nasopharyngeal tumor (PTV70), RA-FFF provided for higher mean dose than other techniques. For the planning target volume receiving 60 Gy (PTV60) and PTV66, RA delivered the lowest mean doses whereas IMRT delivered the highest mean doses. IMRT demonstrated the highest percentage of target coverage and D(99%) for PTV60. RA-FFF provided for the highest doses to the brain stem, skin and oral cavity. RA gave the highest D(1%) to the right optic nerve among three techniques while no significant differences were found between each other. IMRT delivered the highest mean doses to the parotid glands and larynx while RA delivered the lowest mean doses. Gamma analysis showed an excellent agreement for all the techniques at 3%/3 mm. Significant differences in the MUs were observed among the three techniques (p < 0.001). Delivery times for RA-FFF and RA were 152 +/- 7s and 153 +/- 7s, respectively, nearly 70% lower than the 493 +/- 24s mean time for IMRT. CONCLUSIONS: All treatment plans met the planning objectives. The dose measurements also showed good agreement with computed doses. RapidArc technique can treat patients with advanced NPC effectively, with good target coverage and sparing of critical structures. RA has a greater dosimetric superiority than RA-FFF. PMID- 23672520 TI - Is home-based pelvic floor muscle training effective in treatment of urinary incontinence after birth in primiparous women? A randomized controlled trial. AB - OBJECTIVE: To assess the effect of pelvic floor muscle training (PFMT) on pelvic floor muscle strength and urinary incontinence (UI) in primiparous women who underwent a home training program between three and 9 months after delivery. DESIGN: Randomized controlled trial. POPULATION: One hundred primiparous women were consecutively recruited from four different antenatal clinics in the urban area of Stockholm, Sweden. Women with UI who had undergone normal term singleton vaginal delivery, 10-16 weeks postpartum were randomly allocated to either intervention or control group. METHODS: Maximally voluntary contraction (MVC) and endurance were measured with a perionometer. The Oxford grading scale was used to manually estimate the strength of the pelvic floor muscle and self-reported symptoms of UI was registered through the Bristol Female Lower Urinary Tract Symptoms Module (ICIQ FLUTS) questionnaire. MAIN OUTCOME MEASURES: Maximally voluntary contraction of the pelvic floor muscle measured with a perionometer. RESULTS: Maximally voluntary contraction increased significantly in both groups between baseline and follow up (p < 0.05). The median MVC in cmHg for the intervention and control group was 16.2 and 12.1 at baseline and 26.0 and 18.2 at follow up, respectively. The median endurance, in seconds, for the intervention and control group was 9.6 and 12.0 at baseline and 26.7 and 23.4 at follow up, respectively. Pelvic floor muscle strength measured with the Oxford Scale increased significantly in both groups between baseline and follow up (p < 0.05). CONCLUSION: The results indicate that home-based PFMT is effective. However, written training instructions were as efficient as home-based training with follow up visits every sixth week. PMID- 23672518 TI - Cell adhesion and mechanical stimulation in the regulation of mesenchymal stem cell differentiation. AB - Stem cells have been shown to have the potential to provide a source of cells for applications to tissue engineering and organ repair. The mechanisms that regulate stem cell fate, however, mostly remain unclear. Mesenchymal stem cells (MSCs) are multipotent progenitor cells that are isolated from bone marrow and other adult tissues, and can be differentiated into multiple cell lineages, such as bone, cartilage, fat, muscles and neurons. Although previous studies have focused intensively on the effects of chemical signals that regulate MSC commitment, the effects of physical/mechanical cues of the microenvironment on MSC fate determination have long been neglected. However, several studies provided evidence that mechanical signals, both direct and indirect, played important roles in regulating a stem cell fate. In this review, we summarize a number of recent studies on how cell adhesion and mechanical cues influence the differentiation of MSCs into specific lineages. Understanding how chemical and mechanical cues in the microenvironment orchestrate stem cell differentiation may provide new insights into ways to improve our techniques in cell therapy and organ repair. PMID- 23672521 TI - Referees often miss obvious errors in computer and electronic publications. AB - Misconduct is extensive and damaging. So-called science is prevalent. Articles resulting from so-called science are often cited in other publications. This can have damaging consequences for society and for science. The present work includes a scientometric study of 350 articles (published by the Association for Computing Machinery; Elsevier; The Institute of Electrical and Electronics Engineers, Inc.; John Wiley; Springer; Taylor & Francis; and World Scientific Publishing Co.). A lower bound of 85.4% articles are found to be incongruous. Authors cite inherently self-contradictory articles more than valid articles. Incorrect informational cascades ruin the literature's signal-to-noise ratio even for uncomplicated cases. PMID- 23672523 TI - Assessment of the immunosuppressive and hemolytic activities of an edible fern, Diplazium esculentum. AB - CONTEXT: Diplazium esculentum is the most commonly consumed fern throughout Asia and Oceania. Systemic toxicity and pathological effects on its consumption have already been demonstrated. But, the immunosuppressive and hemolytic activities of the boiled Diplazium esculentum (BDE), the form in which human consumes it, have not yet been studied. OBJECTIVE: To investigate the immunosuppressive as well as hemolytic activities, if any, of BDE in Swiss albino mice. MATERIALS AND METHODS: Body weight, relative spleen weight, plaque forming cell assay, hemaggutination antibody (HA) titer assay and macrophage counting were performed in BDE treated mice and respective control groups within a span of 180 days, and in vitro assays such as counting of cultured splenocytes, splenocytes proliferation assay and hemolytic assay were performed to justify the immunomodulatory as well as hemolytic activities of D. esculentum. RESULTS: Body weight and relative spleen weight were significantly decreased in BDE fed mice. Significant decreases were observed in the number of plaques formed, HA titer value and in the number of peritoneal macrophages within a span of 180 d. Significant dose-dependent decrease was observed in the number of cultured splenocytes. Significant dose dependent increases in the percentage inhibition of splenocyte proliferation as well as percentage of hemolysis were evident by in vitro assays. DISCUSSION: These results suggest that the intake of D. esculentum may evoke immune dysfunction as well as may cause destruction of erythrocytes even after cooking. CONCLUSION: Therefore, the consumption of D. esculentum is alarming and may act as immunosuppressive agent. PMID- 23672524 TI - Effects of airway exposure to di-(2-ethylhexyl) phthalate on allergic rhinitis. AB - Recent epidemiological studies have suggested a positive link between atopy morbidity and exposure to phthalate esters, which are environmental chemicals mainly involved in house dust. Nevertheless, experimental studies applying several allergic in vivo models (in addition to epidemiological studies) are needed to prove the precise correlation between phthalates and facilitation of the allergic response/pathophysiology. Among the phthalate esters, di-(2 ethylhexyl) phthalate (DEHP) has been widely used in flexible polyvinyl chloride products, including vinyl flooring and wall covering, and has been widely suggested to have immunomodulating potential. In the present study, we examined the effects of airway exposure to DEHP on allergen (ovalbumin: OVA)-induced rhinitis in mice. The repeated administration of OVA via an intranasal route induced nasal inflammation characterized by the infiltration of granulocytes (neutrophils and eosinophils) into the nasal cavity. In this experimental setting, DEHP did not exaggerate OVA-related inflammatory pathology. However, local (nasal) IL-13 levels were significantly higher in mice treated with allergen plus DEHP than with allergen alone. Taken together, phthalate esters including DEHP have the potential to exacerbate the allergic milieu in the nasal system, as well as dermal and respiratory systems. PMID- 23672525 TI - Lactobacillus casei HY7213 ameliorates cyclophosphamide-induced immunosuppression in mice by activating NK, cytotoxic T cells and macrophages. AB - Lactic acid bacteria (LAB) have recently attracted considerable attention as treatment options for immune diseases, the incidence of which has been increasing worldwide. The ability of tumor necrosis factor-alpha producing LAB isolated from cheese to inhibit NF-kappaB activation in lipopolysaccharide (LPS)-stimulated peritoneal macrophages was investigated. Among the tested LAB, Lactobacillus casei HY7213 inhibited NF-kappaB activation most potently. Therefore, we measured its immunopotentiating effect in cyclophosphamide (CP)-immunosuppressed mice. When HY7213 was orally administered for 5 or 15 d, it reversed the CP immunosuppressant effect by increasing body and spleen weights, blood red and white blood cells levels, and splenocyte and bone marrow cells counts. Treatment with CP in mice markedly reduced concanavalin A (ConA)-induced T cell proliferation to 54% compared to the normal group. Oral administration of HY7213 in CP-immunosuppressed mice reversed that value to 95% of the normal group on day 15. Furthermore, oral administration of HY7213 to CP-treated mice significantly enhanced the expression of IL-2 and IFN-gamma in ConA-induced splenic cytotoxic T cells, restored the CP-impaired phagocytosis of macrophage, and increased the cytotoxicity of natural killer (NK) and cytotoxic T cells derived from spleen and bone marrow against YAC-1. Based on these findings, we suggest that HY7213 may promote the recovery of immunosuppression caused by chemotherapeutic agents, such as CP, by activating NK cells, cytotoxic T cells and macrophages. PMID- 23672522 TI - Clinical classification in mental health at the cross-roads: which direction next? AB - BACKGROUND: After 30 years of consensus-derived diagnostic categories in mental health, it is time to head in new directions. Those categories placed great emphasis on enhanced reliability and the capacity to identify them via standardized checklists. Although this enhanced epidemiology and health services planning, it failed to link broad diagnostic groupings to underlying pathophysiology or specific treatment response. DISCUSSION: It is time to adopt new goals that prioritize the validation of clinical entities and foster alternative strategies to support those goals. The value of new dimensions (notably clinical staging), that are both clinically relevant and directly related to emerging developmental and neurobiological research, is proposed. A strong emphasis on 'reverse translation' (that is, working back from the clinic to the laboratory) underpins these novel approaches. However, it relies on using diagnostic groupings that already have strong evidence of links to specific risk factors or patterns of treatment response. SUMMARY: The strategies described abandon the historical divides between clinical neurology, psychiatry and psychology and adopt the promotion of pathways to illness models. PMID- 23672526 TI - Assessing the relationship of paraoxonase-1 Q192R polymorphisms and the severity of lung disease in SM-exposed patients. AB - Late respiratory complications in patients suffering from pulmonary lesions due to sulfur mustard (SM) gas are asthma, chronic obstructive pulmonary disease and bronchiectasis. Recently PON1 antioxidant activity draws attention as the enzyme which prevents the oxidation of lipoproteins during oxidative stress. In this study we aimed to investigate PON1 192 polymorphisms and paraoxonase and arylesterase activity in the serum of SM-exposed lung disease patients. Also, we examined the detection of PON1 and apoA1 proteins in BAL fluid. 101 male patients were included who were categorized to three groups of mild, moderate and severe suffering from pulmonary lesions due to SM. Significant reduction in paraoxonase activity [Healthy: 412.46 +/- 89.1 U/L, Severe: 89.66 +/- 20.7 U/L] (p < 0.0001) and arylesterase activity [Healthy: 25826.4 +/- 4425.23 U/L, Severe: 16760.43 +/- 3814.9 U/L] (p < 0.0001) with increase in severity of disease was demonstrated statistically. With respect to the distribution of the PON1 polymorphism, the RR genotype was more frequent in severe patients [37.2%] than healthy group [10%] (p < 0.05) and no significant regression was found between genotype and PON1 activity. On the other hand, the results of PON1 and apoA1 detection illustrated that only apoA1 protein was found in BAL fluid. According to our findings it seems that increase in the stress oxidative in chemical injured veterans with pulmonary complications comes with reduction in PON1 enzyme activity and appearance of RR genotype rises up with the increase in disease severity. Since a significant correlation between enzyme activity and genotype was not observed altering these two variables with each other requires more studies. PMID- 23672527 TI - Eczematous reactions due to angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. AB - Cutaneous adverse drug reactions (ADRs) to antihypertensive drugs have been frequently reported. We describe a peculiar clinical pattern of cutaneous ADR, represented by an eczematous reaction induced by certain antihypertensive drugs that we observed in elderly patients. The case series consisted of 23 hypertensive patients aged 66-87 years; 19 of them were taking another drug in addition to the suspected antihypertensive medication and 15 were on polytherapy with three or more drugs to treat multiple comorbidities. The antihypertensive culprit agents were angiotensin-converting enzyme (ACE) inhibitors in 9 patients, ACE-inhibitors combined to hydrochlorothiazide (HCT) in 7 subjects, angiotensin II receptor blockers alone in 2 patients and associated with HCT in 5 cases. The cutaneous ADR was characterized by an eczematous rash that was generalized in 16 patients and localized in 7 cases, with predominant involvement of lower limbs. Such lesions developed after a latency of 4-30 months and were associated with moderate-to-severe itch, usually unresponsive to oral antihistamines. Histopathological diagnosis was available for 9 cases, confirming the presence of a spongiotic dermatitis with possible associated psoriasiform skin changes. PMID- 23672528 TI - What is the main source of human exposure to higher alcohols and is there a link to immunotoxicity? PMID- 23672529 TI - Activity profiles of the Australian female netball team players during international competition: implications for training practice. AB - In elite sport, to remain competitive at the international level, it is critical to understand the game demands on players to ensure sport specific training programmes are designed for optimal athlete preparation and conditioning. In netball, recent research examining the activity patterns of players at the elite level is lacking, with only one study undertaken on this level of competition in the past 30 years. Therefore, the aim of this study was to provide coaches with up to date knowledge of player activity patterns as a basis for the design of optimal sport specific training programmes. The Australian female netball team were analysed using video footage of three international test matches. Player activity was categorised into five movement and eight game-based activities; and further classified as work or rest. Results suggest that differences in the current game exist when compared to the previous analysis. Positional differences were also found with regard to player activity confirming the need for an individualised component of training based on player position. PMID- 23672530 TI - Vaginal douching by women with vulvovaginitis and relation to reproductive health hazards. AB - BACKGROUND: Vaginal douching (VD) is a common practice among married women all over the world specially those in the Middle East. It is used for personal hygiene or for other aesthetic reasons in many countries. The current study investigates the prevalence of VD among patients with vulvovaginitis in Egypt. It also compares the reproductive health hazards among women performing routine VD with those using external hygiene. It also investigates why, and how women practice this douching. METHODS: A cross sectional observational study was conducted in a tertiary university affiliated hospital in Assiut, Egypt. An interview administered questionnaire was administered to 620 women by two trained clinic nurses. Women presented to the outpatient clinic and diagnosed to have any type of vaginal infections were approached for participation. The principle outcome was the history of preterm labor in women who routinely performed VD versus those who did not (upon which sample size was estimated). Other outcome measures were the types of vaginal infections, and reproductive implications comprising, ectopic pregnancy, abortion and pelvic inflammatory disease (PID). RESULTS: The participants were predominantly multiparas from semi-urban background and middle socioeconomic level. Considering VD as a religious duty and a kind of personal cleanliness were the most common reasons for performing VD in 88.9% and 80.6% of the studied population, respectively. History of preterm labor was reported in 19.2% versus 11.9% (p=0.048), while history of PID in 13.2% versus 6.0% (p=0.008) in women performing VD compared to those not performing this habit, respectively. There were no significant differences between the two groups as regard the history of ectopic pregnancy or the number of previous abortions. CONCLUSION: Vaginal douching is a prevalent practice in Egypt and has traditional and religious roots within the community. There are many misbeliefs around this habit in Egypt. Vaginal douching increases certain reproductive health hazards especially preterm labor and PID. Much effort and awareness campaigns are needed to increase women awareness about health hazards of this incorrect practice and to limit its use. PMID- 23672531 TI - Mbandakamines A and B, unsymmetrically coupled dimeric naphthylisoquinoline alkaloids, from a Congolese Ancistrocladus species. AB - Mbandakamines A (1) and B (2), isolated from the leaves of an as yet unidentified Congolese Ancistrocladus species, are the first dimeric naphthylisoquinoline alkaloids with an unsymmetrically coupled central biaryl axis. Their novel 6',1" coupling type implies a hitherto unprecedented peri-peri coupling in one of the naphthalene parts, leading to the as yet highest steric hindrance at the central axis and a total of seven elements of chirality. Mbandakamine A exhibits good antimalarial activity. PMID- 23672532 TI - Magnetic resonance imaging volumetric findings in children with Asperger syndrome, nonverbal learning disability, or healthy controls. AB - BACKGROUND: The purpose of the present study was to evaluate selected regions of interest in children and adolescents with nonverbal learning disabilities (NVLD), Asperger syndrome (AS), and age-matched healthy controls using magnetic resonance imaging (MRI). It was hypothesized that children with AS would show larger volumes of the amygdala and hippocampal regions than the other groups. It was also hypothesized that both clinical groups would show differences in the caudate and anterior cingulate cortex (ACC). METHOD: There were a total of 89 children in the final sample (31 controls, 29 NVLD, 29 AS). Each child completed a MRI scan as well as basic cognitive screening measures. High-resolution T1-weighted MR volumetric images were acquired. The volume of gray matter, white matter, cerebrospinal fluid (CSF), amygdala, hippocampus, and anterior cingulate cortex (ACC) was obtained. RESULTS: The hypothesis that the AS group would show larger hippocampal and amygdala volumes than the other groups was confirmed. For the AS and NVLD groups, the ACC was found to be significantly smaller than that of the control group. CONCLUSIONS: These results suggest that the ACC and amygdala/hippocampal regions are deficient in children with AS, likely contributing to difficulty with modulating of emotional reactivity. PMID- 23672533 TI - Access to 2'-substituted binaphthyl monoalcohols via complementary nickel catalyzed Kumada coupling reactions under mild conditions: key role of a P,O ligand. AB - Two complementary Kumada coupling methods for the conversion of monotriflated 1,1'-binaphthalene-2,2'-diol (BINOL) into 2'-substituted binaphthyl monoalcohols under mild conditions are reported. A protocol using NiCl2(dppe), in combination with an improved preparation of the monotriflate, is effective for 1,1' binaphthalene-2-ols containing unsubstituted or electron-poor aryl or benzyl 2' substituents. An alternative procedure, using a potentially hemilabile-bidentate phosphinan-4-ol ligand, is superior for products containing neopentyl or electron rich aryl 2'-substituents. The obtained binaphthyl alcohols represent potentially useful synthons for chiral ligands and auxiliaries. PMID- 23672534 TI - The kinin-kallikrein system: physiological roles, pathophysiology and its relationship to cancer biomarkers. AB - The kinin-kallikrein system (KKS) is an endogenous multiprotein cascade, the activation of which leads to triggering of the intrinsic coagulation pathway and enzymatic hydrolysis of kininogens with the consequent release of bradykinin related peptides. This system plays a crucial role in inflammation, vasodilation, smooth muscle contraction, cardioprotection, vascular permeability, blood pressure control, coagulation and pain. In this review, we will outline the physiology and pathophysiology of the KKS and also highlight the association of this system with carcinogenesis and cancer progression. PMID- 23672535 TI - Enhancement of intestinal immune function in mice by beta-D-glucan from aureobasidium pullulans ADK-34. AB - beta-Glucans, glucose polymers that are the main constituents of the outer cell walls of micro-organisms such as fungi and yeast, are known to play an immunostimulatory role. We prepared beta-glucan (beta-(1-3),(1-6)-D-glucan) from an edible cultured fungus through fermentation techniques using a strain of Aureobasidium pullulans ADK-34. The purity of this beta-glucan preparation (AP FBG) was demonstrated to be high through various instrumental analyses. We then examined the effects of AP-FBG on intestinal immune systems. We prepared Peyer's patch (PP) cells and measured interleukin (IL)-5, IL-6, and IgA production in culture media with AP-FBG. We found that both cytokines and IgA increased; furthermore, IL-6 secreted by PP dendritic cells (PPDCs) cultured in the presence of AP-FBG significantly increased. We tested IgA production after oral administration of AP-FBG for 2 weeks and found that AP-FBG tended to promote the production of IgA in the small intestine. Interestingly, we observed a significant increase in IgA production in the small intestines of mice treated with cyclophosphamide (CY; an immunosuppressant) after oral administration of AP FBG diet compared with CY-treated and control diet mice. Production of IL-6 and IgA by PP cells and IL-6 production by PPDCs in AP-FBG-fed and CY-treated mice also increased. These results demonstrate that AP-FBG has the ability to activate PPDC and induce IL-6 production and IgA secretion in PP cells. These abilities were more clearly expressed when AP-FBG was orally administered in a CY-induced immunosuppressed condition. Therefore, AP-FBG may be a useful ingredient for preparing functional foods with immunomodulatory activities. PMID- 23672536 TI - Fibrinogen concentrate in dilutional coagulopathy: a dose study in pigs. AB - Dilutional coagulopathy can be reversed with fibrinogen concentrate. Effects of different fibrinogen dosages on clot function are not defined; high doses may increase the risk of thromboemboembolism. This study investigated the effect of six fibrinogen dosages on coagulation profile and blood loss in coagulopathic pigs. Forty-two pigs underwent a 60% hemodilution (HD) with hydroxyethylstarch (HES 130/0.4). After a standardized bone injury, animals randomly received 37.5, 75, 150, 300, 450 or 600 mg/kg fibrinogen (FGTW, LFB) or 500 ml of saline. Four hours later, a standardized liver injury was performed. Animals were then observed for two hours or until death. Blood loss was measured after death; Hemodynamic and coagulation parameters (thromboelastometry) were measured at baseline (BL), after HD, 15', 1, 2, 4 hours after fibrinogen administration and 2 hours after liver injury or right before the animals' death. Occurrence of thrombosis was examined in histological slides of internal organs. Statistical significance was set at p < 0.05. Doses of 150 mg/kg fibrinogen and higher reversed dilutional coagulopathy: Maximum clot firmness (MCF) was decreased after hemodilution (36 +/- 3 mm vs. 65 +/- 4 mm at BL, p < 0.05) and returned to BL after fibrinogen administration (69 +/- 5 mm). Blood loss was significantly decreased with increased fibrinogen dosages: 42 +/- 19 (sham), 34 +/- 14 (75 mg/kg), 29 +/- 13 (150 mg/kg), 28 +/- 10 ml/kgbw (600 mg/kg). Fibrinogen (150-600 mg/kg) normalized clot firmness and decreased blood loss. No signs of hypercoagulability or thromboembolism were detected after high dosages. PMID- 23672537 TI - Induction therapy in pancreas transplantation. AB - Induction therapy, the initial high-dose bolus of immunosuppression given perioperatively to transplant patients, is almost ubiquitous in pancreas transplantation. Despite the frequent use, scientific data on the risks and benefits of induction therapy are scarce, especially as it concerns use specifically for pancreas transplantation. Indeed, none of the currently used induction agents are approved as induction therapy for pancreas transplantation, yet potential benefit is largely extrapolated from trials in kidney transplant recipients. This review summarizes which induction therapy agents are available both now and historically, their mechanisms of action, and provides an overview of the published literature describing the use of these agents in simultaneous pancreas-kidney transplant and solitary pancreas transplant recipients. In summary, there are two multicenter randomized trials, several single-center randomized trials, and many other single-center descriptive reports. Overall, the main benefit of induction therapy is the ability to wean steroids earlier, and the main downside is a higher risk of opportunistic infections. Despite a lack of solid evidence, over 90% of pancreas transplants performed annually in the United States receive some type of induction immunosuppression. PMID- 23672539 TI - Intermolecular interactions of the malate synthase of Paracoccidioides spp. AB - BACKGROUND: The fungus Paracoccidioides spp is the agent of paracoccidioidomycosis (PCM), a pulmonary mycosis acquired by the inhalation of fungal propagules. Paracoccidioides malate synthase (PbMLS) is important in the infectious process of Paracoccidioides spp because the transcript is up-regulated during the transition from mycelium to yeast and in yeast cells during phagocytosis by murine macrophages. In addition, PbMLS acts as an adhesin in Paracoccidioides spp. The evidence for the multifunctionality of PbMLS indicates that it could interact with other proteins from the fungus and host. The objective of this study was to identify and analyze proteins that possibly bind to PbMLS (PbMLS-interacting proteins) because protein interactions are intrinsic to cell processes, and it might be possible to infer the function of a protein through the identification of its ligands. RESULTS: The search for interactions was performed using an in vivo assay with a two-hybrid library constructed in S. cerevisiae; the transcripts were sequenced and identified. In addition, an in vitro assay using pull-down GST methodology with different protein extracts (yeast, mycelium, yeast-secreted proteins and macrophage) was performed, and the resulting interactions were identified by mass spectrometry (MS). Some of the protein interactions were confirmed by Far-Western blotting using specific antibodies, and the interaction of PbMLS with macrophages was validated by indirect immunofluorescence and confocal microscopy. In silico analysis using molecular modeling, dynamics and docking identified the amino acids that were involved in the interactions between PbMLS and PbMLS-interacting proteins. Finally, the interactions were visualized graphically using Osprey software. CONCLUSION: These observations indicate that PbMLS interacts with proteins that are in different functional categories, such as cellular transport, protein biosynthesis, modification and degradation of proteins and signal transduction. These data suggest that PbMLS could play different roles in the fungal cell. PMID- 23672540 TI - Overcoming compound fluorescence in the FLiK screening assay with red-shifted fluorophores. AB - In the attempt to discover novel chemical scaffolds that can modulate the activity of disease-associated enzymes, such as kinases, biochemical assays are usually deployed in high-throughput screenings. First-line assays, such as activity-based assays, often rely on fluorescent molecules by measuring a change in the total emission intensity, polarization state, or energy transfer to another fluorescent molecule. However, under certain conditions, intrinsic compound fluorescence can lead to difficult data analysis and to false-positive, as well as false-negative, hits. We have reported previously on a powerful direct binding assay called fluorescent labels in kinases ('FLiK'), which enables a sensitive measurement of conformational changes in kinases upon ligand binding. In this assay system, changes in the emission spectrum of the fluorophore acrylodan, induced by the binding of a ligand, are translated into a robust assay readout. However, under the excitation conditions of acrylodan, intrinsic compound fluorescence derived from highly conjugated compounds complicates data analysis. We therefore optimized this method by identifying novel fluorophores that excite in the far red, thereby avoiding compound fluorescence. With this advancement, even rigid compounds with multiple pi-conjugated ring systems can now be measured reliably. This study was performed on three different kinase constructs with three different labeling sites, each undergoing distinct conformational changes upon ligand binding. It may therefore serve as a guideline for the establishment of novel fluorescence-based detection assays. PMID- 23672538 TI - An intensified systemic trafficking of bone marrow-derived stem/progenitor cells in patients with pancreatic cancer. AB - Various experimental studies indicate potential involvement of bone marrow (BM) derived stem cells (SCs) in malignancy development and progression. In this study, we comprehensively analysed systemic trafficking of various populations of BM-derived SCs (BMSCs), i.e., mesenchymal, haematopoietic, endothelial stem/progenitor cells (MSCs, HSCs, EPCs respectively), and of recently discovered population of very small embryonic/epiblast-like SCs (VSELs) in pancreatic cancer patients. Circulating CD133(+)/Lin(-)/CD45(-)/CD34(+) cells enriched for HSCs, CD105(+)/STRO-1(+)/CD45(-) cells enriched for MSCs, CD34(+)/KDR(+)/CD31(+)/CD45( ) cells enriched for EPCs and small CXCR4(+) CD34(+) CD133(+) subsets of Lin(-) CD45(-) cells that correspond to VSELs were enumerated and sorted from blood samples derived from 29 patients with pancreatic cancer, and 19 healthy controls. In addition, plasma levels of stromal-derived factor-1 (SDF-1), growth/inhibitory factors and sphingosine-1-phosphate (S1P; chemoattractants for SCs), as well as, of complement cascade (CC) molecules (C3a, C5a and C5b-9/membrane attack complex- MAC) were measured. Higher numbers of circulating VSELs and MSCs were detected in pancreatic cancer patients (P < 0.05 and 0.01 respectively). This trafficking of BMSCs was associated with significantly elevated C5a (P < 0.05) and C5b-9/MAC (P < 0.005) levels together with S1P concentrations detected in plasma of cancer patients, and seemed to be executed in a SDF-1 independent manner. In conclusion, we demonstrated that in patients with pancreatic cancer, intensified peripheral trafficking of selected populations of BMSCs occurs. This phenomenon seems to correlate with systemic activation of the CC, hepatocyte growth factor and S1P levels. In contrast to previous studies, we demonstrate herein that systemic SDF 1 levels do not seem to be linked with increased mobilization of stem cells in patients with pancreatic cancer. PMID- 23672541 TI - Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net. AB - Langerhans Cell Histiocytosis (LCH) is an orphan disease of clonal dendritic cells which may affect any organ of the body. Most of the knowledge about the diagnosis and therapy is based on pedriatic studies. Adult LCH patients are often evaluated by physicians who focus on only the most obviously affected organ without sufficient evaluation of other systems, resulting in patients being underdiagnosed and/or incompletely staged. Furthermore they may be treated with pediatric-based therapies which are less effective and sometimes more toxic for adults. The published literature on adult LCH cases lacks a comprehensive discussion on the differences between pediatric and adult patients and there are no recommendations for evaluation and comparative therapies. In order to fill this void, a number of experts in this field cooperated to develop the first recommendations for management of adult patients with LCH. Key questions were selected according to the clinical relevance focusing on diagnostic work up, therapy, and follow up. Based on the available literature up to December 2012, recommendations were established, drafts were commented by the entire group, and redrafted by the executive editor. The quality of evidence of the recommendations is predominantly attributed to the level of expert opinion. Final agreement was by consensus. PMID- 23672542 TI - Toward the future of psychiatric diagnosis: the seven pillars of RDoC. AB - BACKGROUND: Current diagnostic systems for mental disorders rely upon presenting signs and symptoms, with the result that current definitions do not adequately reflect relevant neurobiological and behavioral systems--impeding not only research on etiology and pathophysiology but also the development of new treatments. DISCUSSION: The National Institute of Mental Health began the Research Domain Criteria (RDoC) project in 2009 to develop a research classification system for mental disorders based upon dimensions of neurobiology and observable behavior. RDoC supports research to explicate fundamental biobehavioral dimensions that cut across current heterogeneous disorder categories. We summarize the rationale, status and long-term goals of RDoC, outline challenges in developing a research classification system (such as construct validity and a suitable process for updating the framework) and discuss seven distinct differences in conception and emphasis from current psychiatric nosologies. SUMMARY: Future diagnostic systems cannot reflect ongoing advances in genetics, neuroscience and cognitive science until a literature organized around these disciplines is available to inform the revision efforts. The goal of the RDoC project is to provide a framework for research to transform the approach to the nosology of mental disorders. PMID- 23672543 TI - Comparison of dipolar, H-bonding, and dispersive interactions on gelation efficiency of positional isomers of keto and hydroxy substituted octadecanoic acids. AB - A systematic study of the importance of functional group position and type on the gelator efficiencies of structurally simple, low molecular-mass gelators is reported. Thus, the gelation abilities of a series of positional isomers of ketooctadecanoic acid (n-KSA) are compared in a wide range of liquids. The gelation abilities of the n-KSA as a function of n, the keto group position along the chain, are characterized by several structural, thermal, and rheological techniques and are compared with those of the corresponding hydroxyoctadecanoic acid isomers (n-HSA) and the parent molecule, octadecanoic acid (SA). Analyses of the gels according to the strengths of functional group interactions along the alkyl chain in terms of group position and type are made. The conclusions derived from the study indicate that gel stability is enhanced when the functional group is located relatively far from the carboxylic headgroup and when group-group interactions are stronger (i.e., hydrogen-bonding interactions are stronger in the n-HSA than dipole interactions in the n-KSA, which are stronger than the London dispersion interactions in SA). Co-crystals of the keto- and hydroxy substituted octadecanoic acids are found to be less efficient gelators than even the ketooctadecanoic acids, due to molecular packing and limited group interactions within the gelator networks. PMID- 23672545 TI - Self-management at the tipping point: reaching 100,000 Americans with evidence based programs. PMID- 23672546 TI - Flag folding. PMID- 23672547 TI - Research myocardial infarction after hip fracture repair. PMID- 23672544 TI - Taking financial relationships into account when assessing research. AB - Many scientific journals, government agencies, and universities require disclosure of sources of funding and financial interests related to research, such as stock ownership, consulting arrangements with companies, and patents. Although disclosure has become one of the central approaches for responding to financial conflicts of interest (COIs) in research, critics contend that information about financial COIs does not serve as a reliable indicator of research credibility, and therefore, studies should be evaluated solely based on their scientific merits. We argue that, while it is indeed important to evaluate studies on their scientific merits, it is often difficult to detect significant influences of financial relationships that affect research credibility. Moreover, at least five factors can be examined to determine whether financial relationships are likely to enhance, undermine, or have no impact on the credibility of research. These include as follows: whether sponsors, institutions, or researchers have a significant financial stake in the outcome of a study; whether the financial interests of the sponsors, institutions, or researchers coincide with the goal of conducting research that is objective and reliable; whether the sponsor, institution, or researchers have a history of biasing research in order to promote their financial goals; how easy it is to manipulate the research in order to achieve financial goals; and whether oversight mechanisms are in place which are designed to minimize bias. Since these factors vary from case to case, evaluating the impact of financial relationships depends on the circumstances. In some situations, one may decide that the financial relationships significantly undermine the study's credibility; in others, one may decide that they have no impact on credibility or even enhance it. PMID- 23672548 TI - Analysis of age-related gait speed. PMID- 23672549 TI - Memofilm project: "Man's memory. Cinema against the pathologies of memory". PMID- 23672550 TI - Relationship between blood pressure and physical and cognitive function in the oldest old. PMID- 23672551 TI - Auditing access to primary care for elderly adults with public insurance. PMID- 23672552 TI - Midlife characteristics of older men using statins. PMID- 23672553 TI - Outcome and safety of colonoscopy in minorities aged 85 and older. PMID- 23672554 TI - Muscular volume or fatigue: which is the most important feature for the evaluation of muscular performance in elderly adults? PMID- 23672555 TI - Severe acute leukopenia due to Candida parapsilosis in an old comorbid woman: a case report. PMID- 23672556 TI - Gas-forming pyogenic liver abscess in an elderly adult with diabetes mellitus. PMID- 23672557 TI - Unusual cause of an esophageal perforation in a nonagenarian. PMID- 23672558 TI - Overlooked myasthenia gravis in an elderly adult. PMID- 23672559 TI - A rare case of adrenal insufficiency induced by inhaled corticosteroids. PMID- 23672560 TI - Negotiations in congress continue with the future of geriatric medicine at stake. PMID- 23672561 TI - The real research question about diabetes mellitus in older adults. PMID- 23672562 TI - Aspirin use after diagnosis improves survival in older adults with colon cancer. PMID- 23672563 TI - Evidence from multicomponent interventions: value of process evaluations. PMID- 23672564 TI - Alzheimer's disease: how far have we progressed? Lessons learned from diabetes mellitus, metabolic syndrome, and inflammation. PMID- 23672565 TI - The death rattle and the old man's friend. PMID- 23672566 TI - Comment on "Association between the part D coverage gap and adverse health outcomes". PMID- 23672567 TI - Response letter to Eltonsy and colleagues. PMID- 23672568 TI - Chewing ability and dementia. PMID- 23672569 TI - Response letter to Savikko et al. PMID- 23672570 TI - Perception of bronchoconstriction: a complementary disease marker in children with asthma. AB - INTRODUCTION: Asthma guidelines use symptoms as the most important aspect of asthma control. Symptom perception varies widely between individuals. Over perception as well as underperception of bronchoconstriction could have a negative effect on asthma management. We hypothesized that perception of bronchoconstriction in childhood asthma is not related to common measures of disease control. For that reason, we examined the clinical determinants of the perception of bronchoconstriction and the repeatability of perception measurements. PATIENTS AND METHODS: In school-age children with moderately severe atopic asthma, we measured the perception of bronchoconstriction (decrease in forced expiratory volume in 1 second (FEV(1)) during methacholine bronchoprovocation challenges. The perception of bronchoconstriction was assessed as the slope of the relation between FEV(1) and Borg score, and as the Borg score at a 20% decrease in FEV(1) from baseline during the provocation test (PS(20)). Data from subjects who had a 20% or more decrease in FEV(1) (n = 112) were used for the analysis. Fifty-four children repeated the test after 3 months. Symptoms, use of rescue medication, and peak expiratory flows were scored in diaries during the 2 weeks before testing. RESULTS: Symptom perception was significantly better in children without (PD(20) > 1570 MUg, n = 28) than in children with airway hyperresponsiveness (PD(20) <= 1570 MUg, n = 112), slope 0.22 versus 0.13 respectively (p < .001). Borg scores correlated with PD(20) (p = .01), baseline FEV(1) (only for slope, p = .04), and use of rescue beta agonist (p = .01), but not with other aspects of asthma control. Repeatability of Borg scores was good (slope: R = 0.59, PS(20): R = 0.52). CONCLUSION: Poorer symptom perception in asthmatic children correlated with hyperresponsiveness, and was associated with lower baseline FEV(1) and less use of rescue bronchodilators. This suggests that the measurement of symptom perception should be taken into account in individual management plans for children with asthma. PMID- 23672571 TI - Hand-assisted laparoscopic right colectomy: a consideration of hand-device placement and trocar arrangement. PMID- 23672573 TI - Bifunctional titanocene catalysis in multicomponent couplings: a convergent assembly of beta-alkynyl ketones. AB - Herein is described a titanium-catalyzed three-component coupling to assemble beta-alkynyl ketones in a single operation. Treatment of an aryl aldehyde with an acetylide and silyl enol ether in the presence of a bifunctional titanocene catalyst enables the highly convergent assembly of beta-alkynyl ketones in good to excellent yields. PMID- 23672572 TI - Insights into the activity and specificity of Trypanosoma cruzi trans-sialidase from molecular dynamics simulations. AB - Trypanosoma cruzitrans-sialidase (TcTS), which catalyzes the transfer or hydrolysis of terminal sialic acid residues, is crucial to the development and proliferation of the T. cruzi parasite and thus has emerged as a potential drug target for the treatment of Chagas disease. We here probe the origin of the observed preference for the transfer reaction over hydrolysis where the substrate for TcTS is the natural sialyl donor (represented in this work by sialyllactose). Thus, acceptor lactose preferentially attacks the sialyl-enyzme intermediate rather than water. We compare this with the weaker preference for such transfer shown by a synthetic donor substrate, 4-methylumbelliferyl alpha-d acetylneuraminide. For this reason, we conducted molecular dynamics simulations of TcTS following its sialylation by the substrate to examine the behavior of the asialyl leaving group by the protein. These simulations indicate that, where lactose is released, this leaving group samples well-defined interactions in the acceptor site, some of which are mediated by localized water molecules; also, the extent of the opening of the acceptor site to solvent is reduced as compared with those of unliganded forms of TcTS. However, where there is release of 4 methylumbelliferone, this leaving group explores a range of transient poses; surrounding active site water is also more disordered. The acceptor site explores more open conformations, similar to the case in which the 4-methylumbelliferone is absent. Thus, the predicted solvent accessibility of sialylated TcTS is increased when 4-methylumbelliferyl alpha-d-acetylneuraminide is the substrate compared to sialyllactose; this in turn is likely to contribute to a greater propensity for hydrolysis of the covalent intermediate. These computational simulations, which suggest that protein flexibility has a role in the transferase/sialidase activity of TcTS, have the potential to aid in the design of anti-Chagas inhibitors effective against this neglected tropical disease. PMID- 23672574 TI - Self-assembled benzophenone bis-urea macrocycles facilitate selective oxidations by singlet oxygen. AB - This manuscript investigates how incorporation of benzophenone, a well-known triplet sensitizer, within a bis-urea macrocycle, which self-assembles into a columnar host, influences its photophysical properties and affects the reactivity of bound guest molecules. We further report the generation of a remarkably stable organic radical. As expected, UV irradiation of the host suspended in oxygenated solvents efficiently generates singlet oxygen similar to the parent benzophenone. In addition, this host can bind guests such as 2-methyl-2-butene and cumene to form stable solid host-guest complexes. Subsequent UV irradiation of these complexes facilitated the selective oxidation of 2-methyl-2-butene into the allylic alcohol, 3-methyl-2-buten-1-ol, at 90% selectivity as well as the selective reaction of cumene to the tertiary alcohol, alpha,alpha'-dimethyl benzyl alcohol, at 63% selectivity. However, these products usually arise through radical pathways and are not observed in the presence of benzophenone in solution. In contrast, typical reactions with benzophenone result in the formation of the reactive singlet oxygen that reacts with alkenes to form endoperoxides, diooxetanes, or hydroperoxides, which are not observed in our system. Our results suggest that the confinement, the formation of a stable radical species, and the singlet oxygen photoproduction are responsible for the selective oxidation processes. A greater understanding of the mechanism of this selective oxidation could lead to development of greener oxidants. PMID- 23672575 TI - Association between Helicobacter pylori infection and the risk of colorectal neoplasia: a systematic review and meta-analysis. AB - AIM: The existing evidence on the relationship between Helicobacter pylori infection and the risk of colorectal neoplasia is inconsistent. We conducted a systematic review with a meta-analysis to explore this relationship and to determine whether the relationship varies according to the study characteristics. METHOD: We searched the PubMed database and the reference lists of pertinent articles published up to July 2012. Summary odds ratios (ORs) with their 95% confidence intervals (CIs) were estimated using a random-effects model. RESULTS: Twenty-seven studies including 3792 cases of colorectal adenoma (CRA) and 3488 cases of colorectal cancer (CRC) were identified. Overall, H. pylori infection was associated with an increased risk of CRA (OR = 1.66, 95% CI 1.39-1.97, I(2) = 54.3%) and CRC (OR = 1.39, 95% CI 1.18-1.64, I(2) = 35.8%), although there was significant heterogeneity among the studies. Subgroup analysis revealed that the positive correlation did not differ by sex, geographic variation or subsite of neoplasia, but might vary by the method of detection of H. pylori. The study was underpowered to determine the risk of colorectal neoplasia associated with cytotoxin-associated gene A-positive H. pylori. CONCLUSION: This meta-analysis demonstrates a positive association between H. pylori infection and the risk of colorectal neoplasia. PMID- 23672576 TI - Mechanical properties of the triceps surae: differences between football and non football players. AB - We investigated the mechanical properties of the triceps surae between professional, junior, and non-football players. Fifty-nine men participated in this study. The mechanical properties of the right legs' triceps surae were measured in vivo using a free oscillation technique; no significant differences existed between the groups. The mean results for musculo-articular stiffness, damping coefficient, and damping ratio were as follows: professional football players (21523 N. m-1, 330.8 N . s . m-1, and 0.201); junior football players (21063 N . m-1, 274.4 N . s . m-1, and 0.173); and non-players (19457 N . m-1, 281.5 N . s . m-1, and 0.184). When analysed according to position, the results were as follows: defender (21447 N . m-1, 308.6 N . s . m-1, and 0.189); midfielder (20762 N . m-1, 250.7 N . s . m-1, and 0.157); winger (21322 N . m-1, 335.1 N . s . m-1, and 0.212); forward (22085 N . m-1, 416.2 N . s . m-1, and 0.254); and non-players (19457 N . m-1, 281.5 N . s . m-1, and 0.184). Thus, football training, football games, and the position played had no effect on triceps surae mechanical properties. These results may be attributed to opposing adaptations between different types of training that are usually implemented in football. Alternatively, the minimum strain amplitude and/or frequency threshold of the triceps surae required to trigger adaptations of mechanical properties might not be achieved by football players with football training and matches. PMID- 23672577 TI - Primary cilia in gastric gastrointestinal stromal tumours (GISTs): an ultrastructural study. AB - Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal (non epithelial) neoplasms of the human gastrointestinal (GI) tract. They are thought to derive from interstitial cells of Cajal (ICCs) or an ICC progenitor based on immunophenotypical and ultrastructural similarities. Because ICCs show primary cilium, our hypothesis is based on the possibility that some of these neoplastic cells could also present it. To determine this, an exhaustive ultrastructural study has been developed on four gastric GISTs. Previous studies had demonstrated considerable variability in tumour cells with two dominating phenotypes, spindly and epithelioid. In addition to these two types, we have found another cell type reminiscent of adult ICCs with a voluminous nucleus surrounded by narrow perinuclear cytoplasm with long slender cytoplasmic processes. We have also noted the presence of small undifferentiated cells. In this study, we report for the first time the presence of primary cilia (PCs) in spindle and epithelioid tumour cells, an ultrastructural feature we consider of special interest that has hitherto been ignored in the literature dealing with the ultrastructure of GISTs. We also point out the frequent occurrence of multivesicular bodies (MVBs). The ultrastructural findings described in gastric GISTs in this study appear to be relevant considering the critical roles played by PCs and MVBs recently demonstrated in tumourigenic processes. PMID- 23672579 TI - Neuropsychological functioning of combat veterans with posttraumatic stress disorder and mild traumatic brain injury. AB - This study examined the neuropsychological performance of 125 outpatient Operation Enduring Freedom/Operation Iraqi Freedom combat veterans with posttraumatic stress disorder (PTSD) and nonacute mild traumatic brain injury (TBI) (n = 66) and PTSD (n = 59) across multiple cognitive domains to determine whether mild TBI results in greater impairment among those with PTSD. Profile analyses revealed that veterans with PTSD and mild TBI did not differ significantly from those with just PTSD across domains, suggesting that comorbid mild TBI does not result in an additive effect. A norms-based comparison also revealed that neither group demonstrated impaired performance on any of the objective neuropsychological measures examined. However, both groups endorsed moderately elevated symptoms of depression and anxiety, indicating that comorbid psychopathology may contribute to subjective cognitive complaints. PMID- 23672583 TI - Differential involvement of the gamma-synuclein in cognitive abilities on the model of knockout mice. AB - BACKGROUND: Gamma-synuclein is a member of the synuclein family of cytoplasmic, predominantly neuron-specific proteins. Despite numerous evidences for the importance of gamma-synuclein in the control of monoamine homeostasis, cytoskeleton reorganization and chaperone activity, its role in the regulation of cognitive behavior still remain unknown. Our previous study revealed that gamma synuclein knockout mice are characterized by high habituation scores. Since a number of processes including spatial memory of the environment may affect habituation, in the present study we have carried out behavioral evaluation of spatial and working memory in gamma-synuclein knockout mice. RESULTS: Inactivation of gamma-synuclein gene led to the improvement of working memory in mice as revealed by passive and active avoidance tests. At the same time behavioral tests, designed to assess spatial learning and memory (Morris water maze and Object location tests), showed no differences between gamma-synuclein knockouts and wild type mice. CONCLUSIONS: These findings indicate that young mice with targeted inactivation of gamma-synuclein gene have improved working memory, but not spatial learning and memory. Our results suggest that gamma synuclein is directly involved in the regulation of cognitive functions. PMID- 23672582 TI - Protective effect of genistein on radiation-induced intestinal injury in tumor bearing mice. AB - BACKGROUND: Radiation therapy is the most widely used treatment for cancer, but it causes the side effect of mucositis due to intestinal damage. We examined the protective effect of genistein in tumor-bearing mice after abdominal irradiation by evaluation of apoptosis and intestinal morphological changes. METHODS: Mouse colon cancer CT26 cells were subcutaneously injected at the flank of BALB/c mice to generate tumors. The tumor-bearing mice were treated with abdominal radiation at 5 and 10 Gy, and with genistein at 200 mg/kg body weight per day for 1 d before radiation. The changes in intestinal histology were evaluated 12 h and 3.5 d after irradiation. To assess the effect of the combination treatment on the cancer growth, the tumor volume was determined at sacrifice before tumor overgrowth occurred. RESULTS: Genistein significantly decreased the number of apoptotic nuclei compared with that in the irradiation group 12 h after 5 Gy irradiation. Evaluation of histological changes showed that genistein ameliorated intestinal morphological changes such as decreased crypt survival, villus shortening, and increased length of the basal lamina 3.5 d after 10 Gy irradiation. Moreover, the genistein-treated group exhibited more Ki-67-positive proliferating cells in the jejunum than the irradiated control group, and crypt depths were greater in the genistein-treated group than in the irradiated control group. The mean weight of the CT26 tumors was reduced in the group treated with genistein and radiation compared with the control group. CONCLUSION: Genistein had a protective effect on intestinal damage induced by irradiation and delayed tumor growth. These results suggest that genistein is a useful candidate for preventing radiotherapy-induced intestinal damage in cancer patients. PMID- 23672584 TI - The unstructured domain of colicin N kills Escherichia coli. AB - Bacteria often produce toxins which kill competing bacteria. Colicins, produced by and toxic to Escherichia coli bacteria are three-domain proteins so efficient that one molecule can kill a cell. The C-terminal domain carries the lethal activity and the central domain is required for surface receptor binding. The N terminal domain, required for translocation across the outer membrane, is always intrinsically unstructured. It has always been assumed therefore that the C terminal cytotoxic domain is required for the bactericidal activity. Here we report the unexpected finding that in isolation, the 90-residue unstructured N terminal domain of colicin N is cytotoxic. Furthermore it causes ion leakage from cells but, unlike known antimicrobial peptides (AMPs) with this property, shows no membrane binding behaviour. Finally, its activity remains strictly dependent upon the same receptor proteins (OmpF and TolA) used by full-length colicin N. This mechanism of rapid membrane disruption, via receptor mediated binding of a soluble peptide, may reveal a new target for the development of highly specific antibacterials. PMID- 23672585 TI - Exploring the nature of interprofessional collaboration and family member involvement in an intensive care context. AB - Little is known about the nature of interprofessional collaboration on intensive care units (ICUs), despite its recognition as a key component of patient safety and quality improvement initiatives. This comparative ethnographic study addresses this gap in knowledge and explores the different factors that influence collaborative work in the ICU. It aims to develop an empirically grounded team diagnostic tool, and associated interventions to strengthen team-based care and patient family involvement. This iterative study is comprised of three phases: a scoping review, a multi-site ethnographic study in eight ICUs over 2 years; and the development of a diagnostic tool and associated interprofessional intervention-development. This study's multi-site design and the richness and breadth of its data maximize its potential to improve clinical outcomes through an enhanced understanding of interprofessional dynamics and how patient family members in ICU settings are best included in care processes. Our research dissemination strategy, as well as the diagnostic tool and associated educational interventions developed from this study will help transfer the study's findings to other settings. PMID- 23672586 TI - Species-area relationships and extinction forecasts. AB - The species-area relationship (SAR) predicts that smaller areas contain fewer species. This is the basis of the SAR method that has been used to forecast large numbers of species committed to extinction every year due to deforestation. The method has a number of issues that must be handled with care to avoid error. These include the functional form of the SAR, the choice of equation parameters, the sampling procedure used, extinction debt, and forest regeneration. Concerns about the accuracy of the SAR technique often cite errors not much larger than the natural scatter of the SAR itself. Such errors do not undermine the credibility of forecasts predicting large numbers of extinctions, although they may be a serious obstacle in other SAR applications. Very large errors can arise from misinterpretation of extinction debt, inappropriate functional form, and ignoring forest regeneration. Major challenges remain to understand better the relationship between sampling protocol and the functional form of SARs and the dynamics of relaxation, especially in continental areas, and to widen the testing of extinction forecasts. PMID- 23672587 TI - Informing DSM-5: biological boundaries between bipolar I disorder, schizoaffective disorder, and schizophrenia. AB - BACKGROUND: The fifth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) opted to retain existing diagnostic boundaries between bipolar I disorder, schizoaffective disorder, and schizophrenia. The debate preceding this decision focused on understanding the biologic basis of these major mental illnesses. Evidence from genetics, neuroscience, and pharmacotherapeutics informed the DSM-5 development process. The following discussion will emphasize some of the key factors at the forefront of the debate. DISCUSSION: Family studies suggest a clear genetic link between bipolar I disorder, schizoaffective disorder, and schizophrenia. However, large-scale genome-wide association studies have not been successful in identifying susceptibility genes that make substantial etiological contributions. Boundaries between psychotic disorders are not further clarified by looking at brain morphology. The fact that symptoms of bipolar I disorder, but not schizophrenia, are often responsive to medications such as lithium and other anticonvulsants must be interpreted within a larger framework of biological research. SUMMARY: For DSM-5, existing nosological boundaries between bipolar I disorder and schizophrenia were retained and schizoaffective disorder preserved as an independent diagnosis since the biological data are not yet compelling enough to justify a move to a more neurodevelopmentally continuous model of psychosis. PMID- 23672588 TI - Quantification of nitrate-pi interactions and selective transport of nitrate using calix[4]pyrroles with two aromatic walls. AB - Herein we disclose the results of our investigations regarding the interactions between the biologically relevant nitrate oxoanion and several "two-wall" aryl extended calix[4]pyrroles. There exists a clear relationship between the electronic nature of the aromatic walls of the calix[4]pyrroles and the stability of the nitrate?calix[4]pyrrole complex. This suggests that NO3(-)-pi interactions have an important electrostatic component. We provide energetic estimates for the interaction of nitrate with several phenyl derivatives. Additionally, we report solid-state evidence for a preferred binding geometry of the nitrate anion included in the calix[4]pyrroles. Finally, the "two-wall" aryl-extended calix[4]pyrroles show excellent activity in ion transport through lipid-based lamellar membranes. Notably the best anion transporters are highly selective for transport of nitrate over other anions. PMID- 23672589 TI - Benefits associated with nutrigenomics research and their reporting in the scientific literature: researchers' perspectives. AB - Nutrigenomics and nutrigenetics (NGx) are fields of research that have raised significant expectations about their potential benefits. This article presents empirical data from an online survey seeking the opinions of NGx researchers (n=126) regarding the achievability of the potential benefits of NGx, the time envisioned for their realization, the motives that may lead to their explicit mention in scientific peer-reviewed articles and the audience(s) targeted by NGx researchers when reporting their results in such articles. Results show that caution should be taken to avoid the risks associated with biohype and the premature dissemination of the potential benefits of NGx among various audiences. PMID- 23672590 TI - The mouse ruby-eye 2(d) (ru2(d) /Hps5(ru2-d) ) allele inhibits eumelanin but not pheomelanin synthesis. AB - The novel mutation named ru2(d) /Hps5(ru2-d) , characterized by light-colored coats and ruby-eyes, prohibits differentiation of melanocytes by inhibiting tyrosinase (Tyr) activity, expression of Tyr, Tyr-related protein 1 (Tyrp1), Tyrp2, and Kit. However, it is not known whether the ru2(d) allele affects pheomelanin synthesis in recessive yellow (e/Mc1r(e) ) or in pheomelanic stage in agouti (A) mice. In this study, effects of the ru2(d) allele on pheomelanin synthesis were investigated by chemical analysis of melanin present in dorsal hairs of 5-week-old mice from F2 generation between C57BL/10JHir (B10)-co isogenic ruby-eye 2(d) and B10-congenic recessive yellow or agouti. Eumelanin content was decreased in ruby-eye 2(d) and ruby-eye 2(d) agouti mice, whereas pheomelanin content in ruby-eye 2(d) recessive yellow and ruby-eye 2(d) agouti mice did not differ from the corresponding Ru2(d) /- mice, suggesting that the ru2(d) allele inhibits eumelanin but not pheomelanin synthesis. PMID- 23672591 TI - The role of microparticles in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus. AB - Microparticles (MPs) are small membrane-bound vesicles with potent biological activities that can promote the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus (SLE). These particles contain diverse cellular components and are shed from cells during apoptosis or activation. MPs can drive inflammation and autoimmunity by multiple mechanisms reflecting their content of bioactive molecules and ability to engage multiple receptor systems simultaneously. In the rheumatoid joint, particles can stimulate synovitis via their display of cytokines, chemokines, complement and angiogenesis factors. In SLE, particles can serve as an important source of extracellular nuclear molecules to signal 'danger' and form pathogenic immune complexes. Future studies will define the pathways by which particles promote pathogenesis, strategies to block their activity and their utility as biomarkers to assess disease activity and the response to therapy. PMID- 23672592 TI - An ultrasound needle insertion guide in a porcine phantom model. AB - We compared nerve blockade with and without the Infiniti(TM) needle guide in an ultrasound in-plane porcine simulation. We recruited 30 anaesthetists with varying blockade experience. Using the guide, the needle tip was more visible (for a median (IQR [range]) of 67 (56-100]) % of the time; and invisible for 2 (1 4 [0-19]) s) than when the guide was not used (respectively 23 (13-43 [0-80]) % and 25 (9-52 [1-198]) s; both p < 0.001). The corresponding block times were 8 (6 10 [3-28]) s and 32 (15-67 [5-225]) s, respectively; p < 0.001. The needle guide reduced the block time and the time that the needle was invisible, irrespective of anaesthetist experience. PMID- 23672593 TI - Insights into the phosphoryl transfer catalyzed by cAMP-dependent protein kinase: an X-ray crystallographic study of complexes with various metals and peptide substrate SP20. AB - X-ray structures of several ternary substrate and product complexes of the catalytic subunit of cAMP-dependent protein kinase (PKAc) have been determined with different bound metal ions. In the PKAc complexes, Mg(2+), Ca(2+), Sr(2+), and Ba(2+) metal ions could bind to the active site and facilitate the phosphoryl transfer reaction. ATP and a substrate peptide (SP20) were modified, and the reaction products ADP and the phosphorylated peptide were found trapped in the enzyme active site. Finally, we determined the structure of a pseudo-Michaelis complex containing Mg(2+), nonhydrolyzable AMP-PCP (beta,gamma-methyleneadenosine 5'-triphosphate) and SP20. The product structures together with the pseudo Michaelis complex provide snapshots of different stages of the phosphorylation reaction. Comparison of these structures reveals conformational, coordination, and hydrogen bonding changes that might occur during the reaction and shed new light on its mechanism, roles of metals, and active site residues. PMID- 23672594 TI - Relay catalysis by a multifunctional Cu catalyst in a tandem dehydro /dehalogenation sequence along with N-arylation. AB - A Cu-catalyzed tandem dehydrogenation/dehalogenation sequential reaction along with N-arylation has been developed for the synthesis of pyridazinone derivatives in an aerobic and aqueous environment. To achieve the transformation of three chemical bonds in a one-pot reaction, a multifunctional copper catalyst was used which afforded excellent activity, high selectivity, and recyclability. The catalytic system consists of a water-soluble Cusalen complex and Na2CO3 in neat water and an air atmosphere. PMID- 23672595 TI - Latex-related allergy in hemodialysis patients. AB - BACKGROUND: Incidence of allergic reactions is increased in hemodialysis (HD) patients. However, the prevalence of latex allergy is not exactly known in HD patients. The aim of this present study is to determine the prevalence of latex allergy in HD patients. METHODS: A total of 205 adult HD patients were included in the study. Questionnaires were completed during patient interviews, and their consents were provided. Latex prick test and latex specific IgE test (HY-TEC, K82) were performed. Mean age of the patients was 52 +/- 14 (25-79) years, and 61% was male. Mean dialysis duration was 38 months, and 21% of them were diabetics. Only five patients had allergic complaints in their histories, and none of them had severe anaphylaxis history. Latex prick test was positive in two patients. Latex specific IgE test was positive in five patients. Overall latex sensitivity was defined as 3.4%. CONCLUSION: No increased prevalence in latex allergy was determined in HD patients. Latex allergy incidence may be increased in atopic HD patients. Therefore, the use of latex products should be avoided as much as possible especially in atopic HD patients. PMID- 23672596 TI - Nanotopography modulates mechanotransduction of stem cells and induces differentiation through focal adhesion kinase. AB - Regulated biophysical cues, such as nanotopography, have been shown to be integral for tissue regeneration and embryogenesis in the stem cell niche. Tissue homeostasis involves the interaction of multipotent cells with nanoscaled topographical features in their ECM to regulate aspects of cell behavior. Synthetic nanostructures can drive specific cell differentiation, but the sensing mechanisms for nanocues remain poorly understood. Here, we report that nanotopography-induced human mesenchymal stem cell (hMSC) differentiation through cell mechanotransduction is modulated by the integrin-activated focal adhesion kinase (FAK). On nanogratings with 250 nm line width on polydimethylsiloxane, hMSCs developed aligned stress fibers and showed an upregulation of neurogenic and myogenic differentiation markers. The observed cellular focal adhesions within these cells were also significantly smaller and more elongated on the nanogratings compared to microgratings or unpatterned control. In addition, our mechanistic study confirmed that this regulation was dependent upon actomyosin contractility, suggesting a direct force-dependent mechanism. The topography induced differentiation was observed on different ECM compositions but the response was not indicative of a direct ECM-induced hMSC differentiation pathway. FAK phosphorylation was required for topography-induced hMSC differentiation while FAK overexpression overruled the topographical cues in determining cell lineage bias. The results indicated that FAK activity had a direct impact on topography-induced gene expression, and that this effect of FAK was independent of cell shape. These findings suggest that hMSC sense and transduce nanotopographical signals through focal adhesions and actomyosin cytoskeleton contractility to induce differential gene expression. PMID- 23672598 TI - Bridging the gap: how higher surgical training programmes can produce consultant laparoscopic colorectal surgeons. PMID- 23672597 TI - Chinese herbal medicine for impaired glucose tolerance: a randomized placebo controlled trial. AB - BACKGROUND: Diabetes remains a major health problem worldwide. Low-risk low-cost alternatives to pharmaceutical interventions are needed where lifestyle modifications have failed. We conducted a double-blind randomised placebo controlled trial to investigate the efficacy of a Chinese herbal formula, Jiangtang Xiaozhi, in treating impaired glucose control and insulin resistance in persons with prediabetes and controlled diabetes. METHODS: Seventy-one patients with prediabetes or 'controlled' diabetes were randomised to receive 3 capsules of Jiangtang Xiaozhi (n = 39) or placebo (n = 32) three times daily for 16 weeks with a follow up eight weeks later (week 24). The primary outcome was change in glycaemic control as evidenced by fasting blood glucose (FBG), post-prandial plasma glucose and glycosylated haemoglobin (HbA1c). Other measures included change in fasting insulin, insulin resistance and sensitivity, lipids, C-reactive protein (CRP), body mass index (BMI), waist girth, blood pressure (BP), health related quality of life (HRQoL) and safety. Analysis of covariance (ANCOVA) was used to model outcomes at 16 weeks, by treatment group corrected for baseline level of the outcome variable. RESULTS: In patients receiving Jiangtang Xiaozhi, FBG was not significantly different (p = 0.73) compared to placebo after 16 weeks of treatment (6.3 +/- 1.1 mmol/L vs 6.7 +/- 1.3 mmol/L). There was a significant difference (p = 0.04) in the mean levels of fasting insulin between the treatment group (11.6 +/- 5.5 mmol/L) and the placebo group (22.1 +/- 25.9 mmol/L). Insulin resistance slightly decreased in the treatment group (1.58 +/- 0.74) compared to that of the placebo group (2.43 +/- 1.59) but this change did not reach statistical significance (p = 0.06). Patients taking Jiangtang Xiaozhi had a significant improvement in high-density lipoprotein (HDL) level compared to the placebo group at week 16 (p = 0.03). Mean levels of cholesterol, triglycerides, BMI, waist-girth, HRQoL, BP, CRP and insulin sensitivity were not significantly different between the two groups. The herbal medicine was well tolerated. CONCLUSIONS: In the current study, the 16 week Jiangtang Xiaozhi treatment did not lower fasting blood glucose, but it improved serum insulin and HDL cholesterol in a Western population with prediabetes or controlled diabetes. Our trial may have been underpowered. Dosage needs to be considered before commencing a longer adequately powered trial. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000128897; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=362005. PMID- 23672599 TI - Distraction by a monotube fixator to achieve limb lengthening: predictive factors for tibia trauma. AB - BACKGROUND: Management of post trauma tibia bone gap varied with orthopedic surgeons' experience and tools available. Study aims to determine predictive factors for distraction by a monotube fixator (DMF) outcome in post tibia trauma limb length discrepancy. METHODS: A prospective descriptive cross sectional study of post traumatized tibia bone gap and limb length discrepancy patients at tertiary hospitals. Patient's informed consent and institutional ethical committee approval were obtained. Bio-data, clinical and healing indexes were documented. DMF was applied for patient that met inclusion criteria. The Statistic tests used included the Chi-square, the Student's two-tailed t test, and the Wilcox on rank-sum test when appropriate. Mantel-Haenszel Common Odds Ratio (OR) and 95% confidence intervals for poor outcome potential risk factors were recorded. Bivariate correlation and logistic regression were evaluated. Significance level was set at a p value <0.05. RESULTS: Thirty-six patients with mean age, 37.2 +/- 10.3 year and male/female ratio of 1:1.25 had DMF applied. Motorcycle accident accounted for 50.0% of patients and diaphyseal segment was most commonly affected 25 (69.4%). The mean bone lengthened was 10.1 +/- 4.0 cm (range: 5-21 cm) and mean duration of bone transport was 105.6 +/- 38.2 days. The means of rate of distraction, healing index and percentage of lengthening were 0.99 +/- 0.14 mm/day, 15.6 +/- 4.3 days/cm and 38.0 +/- 14.3 respectively. The mean follow up was 9.7 +/-4.9 months (range: 2-17.0). Per operative complications varied and outcome was satisfactory in 30 (83.3%). Obesity (p <0.0001), multiple surgery (p = 0.012) and transfusion (p = 0.001) correlated to poor outcome. Percentage lengthening >= 50%, bone gap >10 cm, anemia, blood transfusion, general anesthesia administration, distraction rate >1 mm/day, osteomyelitis and prolong partial weight bearing were significant predictive factors for poor outcome in post traumatic tibia distraction. CONCLUSION: Distraction by a monotube fixator appears effective in achieving correction >38.0% original tibia lengthening following traumatic bone gap. Predictive factors for poor outcome were useful for prognostication. PMID- 23672600 TI - Advances in the treatment of Clostridium difficile with fidaxomicin: a narrow spectrum antibiotic. AB - Clostridium difficile infection, also known as C. difficile-associated diarrhea (CDAD), is the most common cause of nosocomial diarrhea, typically initiated by the use of broad-spectrum antibiotics that disrupt gut flora, thereby allowing C. difficile to proliferate. It is an increasing cause of morbidity and mortality, especially in hospitals and long-term care facilities. A particularly challenging aspect to treating CDAD has been maintenance of clinical response: following initial treatment success, recurrence occurs in approximately 15-30% of patients after the first episode and up to 50-60% subsequently. Fidaxomicin, marketed as DIFICID(r) in the United States, is approved in multiple countries and is the first new drug to be approved for this indication in over 25 years. It is a novel, narrow spectrum antibiotic with potent bactericidal activity against C. difficile and low activity against the normal gut microbiota. In clinical trials, fidaxomicin has been shown to be noninferior in initial clinical response to CDAD compared to vancomycin, and superior in limiting recurrence and providing sustained clinical response. In this review, the development and characteristics of fidaxomicin are described. PMID- 23672603 TI - The DSM-5: Hyperbole, Hope or Hypothesis? AB - The furore preceding the release of the new edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) is in contrast to the incremental changes to several diagnostic categories, which are derived from new research since its predecessor's birth in 1990. While many of these changes are indeed controversial, they do reflect the intrinsic ambiguity of the extant literature. Additionally, this may be a mirror of the frustration of the field's limited progress, especially given the false hopes at the dawn of the "decade of the brain". In the absence of a coherent pathophysiology, the DSM remains no more than a set of consensus based operationalized adjectives, albeit with some degree of reliability. It does not cleave nature at its joints, nor does it aim to, but neither does alternate systems. The largest problem with the DSM system is how it's used; sometimes too loosely by clinicians, and too rigidly by regulators, insurers, lawyers and at times researchers, who afford it reference and deference disproportionate to its overt acknowledged limitations. PMID- 23672601 TI - Characterization of the transporterB0AT3 (Slc6a17) in the rodent central nervous system. AB - BACKGROUND: The vesicular B0AT3 transporter (SLC6A17), one of the members of the SLC6 family, is a transporter for neutral amino acids and is exclusively expressed in brain. Here we provide a comprehensive expression profile of B0AT3 in mouse brain using in situ hybridization and immunohistochemistry. RESULTS: We confirmed previous expression data from rat brain and used a novel custom made antibody to obtain detailed co-labelling with several cell type specific markers. B0AT3 was highly expressed in both inhibitory and excitatory neurons. The B0AT3 expression was highly overlapping with those of vesicular glutamate transporter 2 (VGLUT2) and vesicular glutamate transporter 1 (VGLUT1). We also show here that Slc6a17mRNA is up-regulated in animals subjected to short term food deprivation as well as animals treated with the serotonin reuptake inhibitor fluoxetine and the dopamine/noradrenaline reuptake inhibitor bupropion. CONCLUSIONS: This suggests that the B0AT3 transporter have a role in regulation of monoaminergic as well as glutamatergic synapses. PMID- 23672602 TI - Up-regulation of stomatin expression by hypoxia and glucocorticoid stabilizes membrane-associated actin in alveolar epithelial cells. AB - Stomatin is an important lipid raft-associated protein which interacts with membrane proteins and plays a role in the membrane organization. However, it is unknown whether it is involved in the response to hypoxia and glucocorticoid (GC) in alveolar epithelial cells (AEC). In this study we found that hypoxia and dexamethasone (dex), a synthetic GC not only up-regulated the expression of stomatin alone, but also imposed additive effect on the expression of stomatin in A549 cells, primary AEC and lung of rats. Then we investigated whether hypoxia and dex transcriptionally up-regulated the expression of stomatin by reporter gene assay, and found that dex, but not hypoxia could increase the activity of a stomatin promoter-driven reporter gene. Further deletion and mutational studies demonstrated that a GC response element (GRE) within the promoter region mainly contributed to the induction of stomatin by dex. Moreover, we found that hypoxia exposure did not affect membrane-associated actin, but decreased actin in cytoplasm in A549 cells. Inhibiting stomatin expression by stomatin siRNA significantly decreased dense of peripheral actin ring in hypoxia or dex treated A549 cells. Taken all together, these data indicated that dex and/or hypoxia significantly up-regulated the expression of stomatin in vivo and in vitro, which could stabilize membrane-associated actin in AEC. We suppose that the up regulation of stomatin by hypoxia and dex may enhance the barrier function of alveolar epithelia and mediate the adaptive role of GC to hypoxia. PMID- 23672604 TI - Recreating simulation scenarios for interprofessional education: an example of educational interprofessional practice. AB - High-fidelity simulation has proliferated in healthcare education. Once a novelty, simulation is now a mainstay of many curricula and even required by some accrediting bodies. Interprofessional behaviors, manifested through interprofessional education and practice are believed to improve patients' lives. The exciting potential of simulation-interprofessional education (SIM-IPE) is now being explored. This report details a SIM-IPE experience from a university medical simulation center and Schools of Nursing and Medicine. Circumstances required an existing scenario to be "retrofitted" for interprofessional education. Key decision points, challenges and practices are highlighted in the hope that they may be of use to other simulation educators. PMID- 23672605 TI - Evaluating interprofessional learning modules: health students' attitudes to interprofessional practice. AB - Interprofessional learning opportunities are thought to assist health students to work in a more collaborative, patient focussed manner during their career. In line with this thinking, the University of Newcastle's Department of Rural Health delivers monthly interprofessional learning modules (ILMs) to students on a range of health topics. Students' attitudes towards interprofessional learning were assessed pre- and post-ILM, using the Readiness for Interprofessional Learning scale (RIPLS). Thirty-eight students completed both pre- and post-surveys with a return rate of 36%. Our results demonstrated a statistically significant improvement in students' attitudes to interprofessional learning in three of four domains. Based on the findings from this study, ILMs appear to be a worthwhile educational opportunity and may improve student attitudes to interprofessional learning in the short term. PMID- 23672606 TI - Implementing an interprofessional first-year teamwork project: some key reflections. AB - Implementing an interprofessional teamwork project for first-year students presents pedagogical and practical challenges. While transferable skills and attributes are important, engagement of students with limited professional experience in teamwork depends on relevance to current learning needs. This report outlines principles learned from planning and implementing a teamwork project for an interprofessional health administration and service development course. Practising interprofessional teamwork as leaders and teachers, aligning with previous, current and future teamwork content and processes and responding to student feedback and achievement have been the key factors in shaping the project over three semesters. Face-to-face and online interprofessional teamwork learning has necessitated developing resources that support self-direction, using familiar technology and providing enabling physical environments. Implications for first-year interprofessional teamwork are that structured well-resourced processes, responsiveness and alignment of learning all improve student outcomes. PMID- 23672607 TI - Team communications in surgery - creating a culture of safety. AB - As a key department within a healthcare organisation, the operating room is a hazardous environment, where the consequences of errors are high, despite the relatively low rates of occurrence. Team performance in surgery is increasingly being considered crucial for a culture of safety. The aim of this study was to describe team communication and the ways it fostered or threatened safety culture in surgery. Ethnography was used, and involved a 6-month fieldwork period of observation and 19 interviews with 24 informants from nursing, anaesthesia and surgery. Data were collected during 2009 in the operating rooms of a tertiary care facility in Queensland, Australia. Through analysis of the textual data, three themes that exemplified teamwork culture in surgery were generated: "building shared understandings through open communication"; "managing contextual stressors in a hierarchical environment" and "intermittent membership influences team performance". In creating a safety culture in a healthcare organisation, a team's optimal performance relies on the open discussion of teamwork and team expectation, and significantly depends on how the organisational culture promotes such discussions. PMID- 23672608 TI - One-dimensional random walk of a synthetic small molecule toward a thermodynamic sink. AB - We report on the spontaneous intramolecular migration of alpha-methylene-4 nitrostyrene from amine group to amine group along oligoethyleneimine tracks up to eight repeat units in length (number of amine footholds, n = 3, 5, 9). Each track consists of n - 1 aliphatic secondary amine footholds plus a naphthylmethylamine group foothold situated at one end of the track. Under basic conditions the alpha-methylene-4-nitrostyrene unit undergoes a series of reversible intramolecular Michael-retro-Michael reactions between adjacent amine groups that move it up and down the track. For n = 3 and 5 it is possible to monitor the population of every positional isomer on the track by (1)H NMR spectroscopy. On the longest track (n = 9) the fraction of walkers on each end foothold can be quantified with respect to those on the inner footholds. In all cases the naphthylmethylamine foothold acts as a thermodynamic sink with the steady-state distribution significantly biased in favor of the walker at that site. The dynamics of the walker migration is well described by the random walk of a Brownian particle in one dimension. PMID- 23672609 TI - The RNAi machinery regulates growth and development in the filamentous fungus Trichoderma atroviride. AB - The RNAi machinery is generally involved in genome protection in filamentous fungi; however, the physiological role of RNAi has been poorly studied in fungal models. Here, we report that in the filamentous fungus Trichoderma atroviride, the products of the dcr2 and rdr3 genes control reproductive development, because mutations in these genes affect conidiation. In addition, Dcr1 together with Dcr2 control vegetative growth since Deltadcr1, Deltadcr2 and Deltadcr1Deltadcr2 present morphological alterations. Whole-genome transcriptional analysis of WT, Deltadcr1, Deltadcr2 and Deltadcr1Deltadcr2 show that each Dicer controls different biological processes, such as development or metabolism, which could explain the lack of conidiation in the mutants. Finally, we observed sRNAs that are differentially expressed in the WT and Deltadcr2. The expression of some of these sRNAs correlates with the expression of differential transcripts, suggesting that these mRNAs may contain the corresponding targets. Together these data show that in T. atroviride, the RNAi machinery plays a central role in endogenous processes such as development and fitness, beyond controlling genome protection against invasive nucleic acids as reported for other fungi. PMID- 23672610 TI - Inhibitors of BTK and ITK: state of the new drugs for cancer, autoimmunity and inflammatory diseases. AB - BTK and ITK are cytoplasmic tyrosine kinases of crucial importance for B and T cell development, with loss-of-function mutations causing X-linked agammaglobulinemia and susceptibility to severe, frequently lethal, Epstein-Barr virus infection, respectively. Over the last few years, considerable efforts have been made in order to develop small-molecule inhibitors for these kinases to treat lymphocyte malignancies, autoimmunity or allergy/hypersensitivity. The rationale is that even if complete lack of BTK or ITK during development causes severe immunodeficiency, inactivation after birth may result in a less severe phenotype. Moreover, therapy can be transient or only partially block the activity of BTK or ITK. Furthermore, a drug-induced B cell deficiency is treatable by gamma globulin substitution therapy. The newly developed BTK inhibitor PCI-32765, recently renamed Ibrutinib, has already entered several clinical trials for various forms of non-Hodgkin lymphoma as well as for multiple myeloma. Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity. ITK inhibitors are still under the early developmental phase, but it can be expected that such drugs will also become very useful. In this study, we present BTK and ITK with their signalling pathways and review the development of the corresponding inhibitors. PMID- 23672611 TI - Effects of simvastatin on the portal-systemic collateral vascular response to endothelin-1 and shunting degree in portal hypertensive rats. AB - OBJECTIVE: Endothelin-1 (ET-1) exerts vasoconstrictive effect on portal-systemic collateral vascular bed of portal hypertensive rats. Statins are lipid-lowering agents with nitric oxide (NO)-related vasodilatory effects. Considering NO associated vascular hyporesponsiveness to vasoconstrictors and shunting formation in portal hypertension, this study investigated the effects of simvastatin on 1) the portal-systemic collateral vascular responsiveness to ET-1 and 2) the portal systemic shunting degree. MATERIALS/METHODS: Portal hypertension was induced by partial portal vein ligation (PVL) in Sprague-Dawley rats. Simvastatin (20 mg/kg/day) or distilled water (control) was randomly administered by oral gavage since 2 days prior to until 7 days after PVL. Systemic and portal hemodynamics were measured on the 8th day. In another series, collateral perfusion with Krebs solution at different flow rates was performed to get flow-pressure curves which serve as an index of shunting degree. To survey the direct vascular effect, PVL rats randomly underwent preincubation with 1) Krebs solution, that is, the control group; or Krebs solution plus 2) simvastatin; 3) simvastatin + N (omega) nitro-L-arginine (NNA, a NO synthase inhibitor); 4) simvastatin + indomethacin (a cyclooxygenase inhibitor), followed by ET-1 to evaluate the collateral vascular responsiveness. RESULTS: Chronic simvastatin treatment significantly reduced portal pressure. The flow-pressure curves were similar between two groups. Simvastatin preincubation reduced collateral perfusion pressure changes to ET-1 (p < 0.05), which were partially reversed by NNA (p < 0.05), but not by indomethacin. Conclusions. Chronic simvastatin treatment significantly improved portal hypertension. The effect was at least partially exerted by decreased portal-systemic collateral vascular resistance through NO-mediated vascular hyporesponsiveness. The severity of portal-systemic collaterals was not influenced by simvastatin. PMID- 23672612 TI - Melanoma inhibitory activity promotes melanoma development through activation of YBX1. AB - Melanoma inhibitory activity (MIA), a small soluble secreted protein, is functionally important for progression of malignant melanoma. We recently revealed that p54(nrb) acts as a mediator of MIA action. In this study, we characterize the transcriptional regulation of p54(nrb) by MIA to explain MIA's molecular action. We identified one highly conserved region in the p54(nrb) promoter that is necessary and sufficient for MIA-dependent activation. Functional promoter analysis identified the transcription factor YBX1 as the mediator of MIA activation of p54(nrb) transcription. We screened the genome for further potential MIA-regulated genes carrying the element in their promoter regions. Integrating our sequence data with expression data from human melanomas identified a list of 23 potential MIA-YBX1 targets in melanomas. In summary, we present for the first time effects of MIA on transcriptional regulation. Uncovering new potential downstream effectors working via activation of YBX1 supports the important role of MIA in melanoma. PMID- 23672613 TI - Fragment-based ligand design of novel potent inhibitors of tankyrases. AB - Tankyrases constitute potential drug targets for cancer and myelin-degrading diseases. We have applied a structure- and biophysics-driven fragment-based ligand design strategy to discover a novel family of potent inhibitors for human tankyrases. Biophysical screening based on a thermal shift assay identified highly efficient fragments binding in the nicotinamide-binding site, a local hot spot for fragment binding. Evolution of the fragment hit 4-methyl-1,2 dihydroquinolin-2-one (2) along its 7-vector yields dramatic affinity improvements in the first cycle of expansion. A crystal structure of 7-(2 fluorophenyl)-4-methylquinolin-2(1H)-one (11) reveals that the nonplanar compound extends with its fluorine atom into a pocket, which coincides with a region of the active site where structural differences are seen between tankyrases and other poly(ADP-ribose) polymerase (PARP) family members. A further cycle of optimization yielded compounds with affinities and IC50 values in the low nanomolar range and with good solubility, PARP selectivity, and ligand efficiency. PMID- 23672614 TI - Core clerkship in internal medicine at a rural community hospital in Israel. PMID- 23672615 TI - Peer victimisation and its association with psychological and somatic health problems among adolescents in northern Russia. AB - BACKGROUND: A growing body of evidence from countries around the world suggests that school-based peer victimisation is associated with worse health outcomes among adolescents. So far, however, there has been little systematic research on this phenomenon in the countries of the former Soviet Union. The aim of this study was to examine the relation between peer victimisation at school and a range of different psychological and somatic health problems among Russian adolescents. METHODS: This study used data from the Social and Health Assessment (SAHA) - a cross-sectional survey undertaken in Arkhangelsk, Russia in 2003. Information was collected from 2892 adolescents aged 12-17 about their experiences of school-based peer victimisation and on a variety of psychological and somatic health conditions. Logistic regression analysis was used to examine the association between victimisation and health. RESULTS: Peer victimisation in school was commonplace: 22.1% of the students reported that they had experienced frequent victimisation in the current school year (girls - 17.6%; boys - 28.5%). There was a strong relationship between experiencing victimisation and reporting worse health among both boys and girls with more victimisation associated with an increased risk of experiencing worse health. Girls in the highest victimisation category had odds ratios ranging between 1.90 (problems with eyes) and 5.26 (aches/pains) for experiencing somatic complaints when compared to their non victimised counterparts, while the corresponding figures for boys were 2.04 (headaches) and 4.36 (aches/pains). Girls and boys who had the highest victimisation scores were also 2.42 (girls) and 3.33 (boys) times more likely to report symptoms of anxiety, over 5 times more likely to suffer from posttraumatic stress and over 6 times more likely to experience depressive symptoms. CONCLUSION: Peer victimisation at school has a strong association with poor health outcomes among Russian adolescents. Effective school-based interventions are now urgently needed to counter the negative effects of victimisation on adolescents' health in Russia. PMID- 23672616 TI - Fibrous hybrid of graphene and sulfur nanocrystals for high-performance lithium sulfur batteries. AB - Graphene-sulfur (G-S) hybrid materials with sulfur nanocrystals anchored on interconnected fibrous graphene are obtained by a facile one-pot strategy using a sulfur/carbon disulfide/alcohol mixed solution. The reduction of graphene oxide and the formation/binding of sulfur nanocrystals were integrated. The G-S hybrids exhibit a highly porous network structure constructed by fibrous graphene, many electrically conducting pathways, and easily tunable sulfur content, which can be cut and pressed into pellets to be directly used as lithium-sulfur battery cathodes without using a metal current-collector, binder, and conductive additive. The porous network and sulfur nanocrystals enable rapid ion transport and short Li(+) diffusion distance, the interconnected fibrous graphene provides highly conductive electron transport pathways, and the oxygen-containing (mainly hydroxyl/epoxide) groups show strong binding with polysulfides, preventing their dissolution into the electrolyte based on first-principles calculations. As a result, the G-S hybrids show a high capacity, an excellent high-rate performance, and a long life over 100 cycles. These results demonstrate the great potential of this unique hybrid structure as cathodes for high-performance lithium-sulfur batteries. PMID- 23672617 TI - Teaching and assessing procedural skills: a qualitative study. AB - BACKGROUND: Graduating Internal Medicine residents must possess sufficient skills to perform a variety of medical procedures. Little is known about resident experiences of acquiring procedural skills proficiency, of practicing these techniques, or of being assessed on their proficiency. The purpose of this study was to qualitatively investigate resident 1) experiences of the acquisition of procedural skills and 2) perceptions of procedural skills assessment methods available to them. METHODS: Focus groups were conducted in the weeks following an assessment of procedural skills incorporated into an objective structured clinical examination (OSCE). Using fundamental qualitative description, emergent themes were identified and analyzed. RESULTS: Residents perceived procedural skills assessment on the OSCE as a useful formative tool for direct observation and immediate feedback. This positive reaction was regularly expressed in conjunction with a frustration with available assessment systems. Participants reported that proficiency was acquired through resident directed learning with no formal mechanism to ensure acquisition or maintenance of skills. CONCLUSIONS: The acquisition and assessment of procedural skills in Internal Medicine programs should move toward a more structured system of teaching, deliberate practice and objective assessment. We propose that directed, self-guided learning might meet these needs. PMID- 23672619 TI - Simulation study of the initial crystallization processes of poly(3 hexylthiophene) in solution: ordering dynamics of main chains and side chains. AB - We study the initial nucleation dynamics of poly(3-hexylthiophene) (P3HT) in solution, focusing on the relationship between the ordering process of main chains and that of side chains. We carried out Langevin dynamics simulation and found that the initial nucleation processes consist of three steps: the ordering of ring orientation, the ordering of main-chain vectors, and the ordering of side chains. At the start, the normal vectors of thiophene rings aligned in a very short time, followed by alignment of main-chain end-to-end vectors. The flexible side-chain ordering took almost 5 times longer than the rigid-main-chain ordering. The simulation results indicated that the ordering of side chains was induced after the formation of the regular stack structure of main chains. This slow ordering dynamics of flexible side chains is one of the factors that cause anisotropic nuclei growth, which would be closely related to the formation of nanofiber structures without external flow field. Our simulation results revealed how the combined structure of the planar and rigid-main-chain backbones and the sparse flexible side chains lead to specific ordering behaviors that are not observed in ordinary linear polymer crystallization processes. PMID- 23672621 TI - Agricultural work related injuries among the farmers of West Bengal, India. AB - Agriculture is one of the most hazardous industries with high rates of accidental death, injury and occurrences of work related illnesses. The main objective of the study is to assess types, categories and number of incident rate of the accidents along with the causes of accidents as well as with the affected parts of the different parts of the body among the agricultural workers. The number of injuries that occurred during 2006-2010 for male and female farmers was 214 and 109, respectively, in West Bengal. The leading external causes of farm injury were hand tools (64.7%)), farm machinery (29.1%) and others (6.2%). The most frequently involved tools in hand injuries were spade and sickle. Fingers of both limbs are the most affected parts of the body followed by feet, ankle, hand, wrist and lower back. From this study it was also observed that the male agricultural workers are much more affected than female agricultural workers. The incident rate among male and female agricultural workers was 8.99 per 1000 workers per year and 7.89 per 1000 workers per year, respectively. So due to injuries in both groups of agricultiral workers, their health, productivity and work performance were consequently affected. PMID- 23672618 TI - Structural insights into proteasome activation by the 19S regulatory particle. AB - Since its discovery in the late 1970s, the ubiquitin-proteasome system (UPS) has become recognized as the major pathway for regulated cellular proteolysis. Processes such as cell cycle control, pathogen resistance, and protein quality control rely on selective protein degradation at the proteasome for homeostatic function. Perhaps as a consequence of the importance of this pathway, and the genesis of severe diseases upon its dysregulation, protein degradation by the UPS is highly controlled from the level of substrate recognition to proteolysis. Technological advances over the past decade have created an explosion of structural and mechanistic information that has underscored the complexity of the proteasome and its upstream regulatory factors. Significant insights have come from the study of the 19S proteasome regulatory particle (RP) responsible for recognition and processing of ubiquitinated substrates destined for proteolysis. Established as a highly dynamic proteasome activator, the RP has a large number of both permanent and transient components with specialized functional roles that are critical for proteasome function. In this review, we highlight recent mechanistic developments in the study of proteasome activation by the RP and how they provide context to our current understanding of the UPS. PMID- 23672620 TI - The cell morphogenesis ANGUSTIFOLIA (AN) gene, a plant homolog of CtBP/BARS, is involved in abiotic and biotic stress response in higher plants. AB - BACKGROUND: ANGUSTIFOLIA (AN), one of the CtBP family proteins, plays a major role in microtubule-dependent cell morphogenesis. Microarray analysis of mammalian AN homologs suggests that AN might function as a transcriptional activator and regulator of a wide range of genes. Genetic characterization of AN mutants suggests that AN might be involved in multiple biological processes beyond cell morphology regulation. RESULTS: Using a reverse genetic approach, we provide in this paper the genetic, biochemical, and physiological evidence for ANGUSTIFOLIA's role in other new biological functions such as abiotic and biotic stress response in higher plants. The T-DNA knockout an-t1 mutant exhibits not only all the phenotypes of previously described angustifolia null mutants, but also copes better than wild type under dehydration and pathogen attack. The stress tolerance is accompanied by a steady-state modulation of cellular H(2)O(2) content, malondialdehyde (MDA) derived from cellular lipid peroxidation, and over expression of stress responsive genes. Our results indicate that ANGUSTIFOLIA functions beyond cell morphology control through direct or indirect functional protein interaction networks mediating other biological processes such as drought and pathogen attacks. CONCLUSIONS: Our results indicate that the ANGUSTIFOLIA gene participates in several biochemical pathways controlling cell morphogenesis, abiotic, and biotic stress responses in higher plants. Our results suggest that the in vivo function of plant ANGUSTIFOLIA has been overlooked and it needs to be further studied beyond microtubule-dependent cell morphogenesis. PMID- 23672622 TI - Effects of NO(y) aging on the dehydration dynamics of model sea spray aerosol. AB - The reactions of NO(y) species in the atmosphere with sea spray aerosol replace halogen anions with nitrate. These experiments show the effect of increasing the nitrate content of model sea spray aerosol particles on the morphology changes and the phase transitions driven by changes in relative humidity (RH). The components of the model particles include H2O, Na+, Mg2+, Cl-, NO3-, and SO4(2-). Tandem differential mobility analyzer (TDMA) measurements yield the water content and efflorescence relative humidity (ERH) of these particles, and probe molecule spectroscopic measurements reveal subsequent phase transitions and partially characterize the salt composition on the surface of dry particles. The results show three effects of increasing the nitrate composition: decreasing the EFH (46 to 29%), production of a metastable aqueous layer on the surface of effloresced particles, and decreasing the sulfate content near the surface of dry particles. For the mixtures studied here, the initial crystallization event forms a core of NaCl. For particles that contain a substantial metastable aqueous layer following efflorescence, probe molecule spectroscopy shows a second crystallization at a lower RH. This subsequent phase transition is likely the formation of Na2SO4. Homogeneous nucleation theory (HNT) using a semiempirical formulation predicts the ERH of all mixtures within 2.0% RH, with a mean absolute deviation of 1.0%. The calculations suggest that structures associated with highly concentrated or supersaturated magnesium ions strongly affect the interfacial tension between the NaCl crystal nucleus and the droplet from which it forms. PMID- 23672623 TI - Do high fasting glucose levels suggest nocturnal hypoglycaemia? The Somogyi effect-more fiction than fact? AB - AIMS: The Somogyi effect postulates that nocturnal hypoglycaemia causes fasting hyperglycaemia attributable to counter-regulatory hormone release. Although most published evidence has failed to support this hypothesis, this concept remains firmly embedded in clinical practice and often prevents patients and professionals from optimizing overnight insulin. Previous observational data found lower fasting glucose was associated with nocturnal hypoglycaemia, but did not assess the probability of infrequent individual episodes of rebound hypoglycaemia. We analysed continuous glucose monitoring data to explore its prevalence. METHODS: We analysed data from 89 patients with Type 1 diabetes who participated in the UK Hypoglycaemia study. We compared fasting capillary glucose following nights with and without nocturnal hypoglycaemia (sensor glucose < 3.5 mmol/l). RESULTS: Fasting capillary blood glucose was lower after nights with hypoglycaemia than without [5.5 (3.0) vs. 14.5 (4.5) mmol/l, P < 0.0001], and was lower on nights with more severe nocturnal hypoglycaemia [5.5 (3.0) vs. 8.2 (2.3) mmol/l; P = 0.018 on nights with nadir sensor glucose of < 2.2 mmol/l vs. 3.5 mmol/l]. There were only two instances of fasting capillary blood glucose > 10 mmol/l after nocturnal hypoglycaemia, both after likely treatment of the episode. When fasting capillary blood glucose is < 5 mmol/l, there was evidence of nocturnal hypoglycaemia on 94% of nights. CONCLUSION: Our data indicate that, in clinical practice, the Somogyi effect is rare. Fasting capillary blood glucose <= 5 mmol/l appears an important indicator of preceding silent nocturnal hypoglycaemia. PMID- 23672624 TI - Chlorhexidine cleaning of re-usable bougies. AB - Bougies are susceptible to becoming contaminated before or during use. Chlorhexidine wipes may have a residual antibacterial effect, potentially minimising bacterial transmission after bougie use or storage. We evaluated the decontaminant and antibacterial effectiveness of 70% alcohol/2% chlorhexidine wipes in laboratory, clinical and accelerated ageing studies, and conducted a telephone survey of normal practice. In the laboratory tests, chlorhexidine wipes were completely effective against Escherichia coli and methicillin-resistant Staphylococcus aureus, and prevented recontamination for 24 h. Clinical introduction of chlorhexidine wipes reduced bougie contamination from 33% to 0%. Following 150 cleaning episodes, there was no physical or functional damage to the bougies. Eight out of nine hospitals in the East of England Health Region use re-usable bougies. We recommend that following decontamination, bougies should be wiped with 70% alcohol/2% chlorhexidine wipes, to retain antimicrobial activity during handling. PMID- 23672629 TI - Cutting the cake! publication ethics in science. PMID- 23672630 TI - Cardiovascular risk reduction with combination of anti-atherosclerotic medications in younger and older patients. PMID- 23672631 TI - Treatment of depression: are we finally on the right track? PMID- 23672628 TI - Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile. AB - Depression is the most common psychiatric disorder worldwide. The burden of disease for depression goes beyond functioning and quality of life and extends to somatic health. Depression has been shown to subsequently increase the risk of, for example, cardiovascular, stroke, diabetes and obesity morbidity. These somatic consequences could partly be due to metabolic, immuno-inflammatory, autonomic and hypothalamic-pituitary-adrenal (HPA)-axis dysregulations which have been suggested to be more often present among depressed patients. Evidence linking depression to metabolic syndrome abnormalities indicates that depression is especially associated with its obesity-related components (for example, abdominal obesity and dyslipidemia). In addition, systemic inflammation and hyperactivity of the HPA-axis have been consistently observed among depressed patients. Slightly less consistent observations are for autonomic dysregulation among depressed patients. The heterogeneity of the depression concept seems to play a differentiating role: metabolic syndrome and inflammation up-regulations appear more specific to the atypical depression subtype, whereas hypercortisolemia appears more specific for melancholic depression. This review finishes with potential treatment implications for the downward spiral in which different depressive symptom profiles and biological dysregulations may impact on each other and interact with somatic health decline. PMID- 23672632 TI - Efficacy and safety of linagliptin added to metformin and sulphonylurea in Chinese patients with type 2 diabetes: a sub-analysis of data from a randomised clinical trial. AB - OBJECTIVES: To evaluate the efficacy and safety of linagliptin in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin and sulphonylurea. RESEARCH DESIGN AND METHODS: Data for a pre-defined Chinese subgroup who participated in a Phase III randomised, placebo-controlled, 24 week trial (NCT00602472) were analysed. The primary endpoint was change in HbA1c from baseline to 24 weeks. Apart from safety endpoints, secondary endpoints included changes in FPG and measures of insulin secretion and resistance. RESULTS: A total of 192 Chinese patients with T2DM participated in the pre defined analysis; 144 and 48 patients received linagliptin or placebo, respectively, added to metformin and sulphonylurea. Baseline characteristics (mean [+/-SD]) for linagliptin and placebo were similar: HbA1c: 8.1% (+/-0.85) and 8.1% (+/-0.84); body mass index: 25.9 (+/-3.2) and 25.6 (+/-3.4) kg/m2, respectively. Placebo-corrected mean (+/-SE) change in HbA1c from baseline at 24 weeks was -0.68% (0.14) with linagliptin-based treatment (95% CI: -0.96 to -0.39; P<0.0001). Placebo-corrected mean (+/-SE) change in FPG from baseline at 24 weeks with linagliptin was -18.8 (6.5) mg/dL (-1.0 [0.4] mmol/L; 95% CI: -31.7 to -5.9; P=0.0044). Overall adverse event (AE) rates with linagliptin and placebo including background medication were similar (38.9% and 43.8%, respectively). Drug-related AEs were reported by 12.5% and 2.1% of linagliptin and placebo patients, respectively. Differences were due to hypoglycaemia (10.4% and 0.0%, respectively). No severe hypoglycaemia was reported in either group of this sub population. CONCLUSION: Linagliptin in combination with metformin and sulphonylurea has a favourable safety profile and is an efficacious and well tolerated treatment option for Chinese patients with inadequately controlled T2DM. Reduction of sulphonylurea dose should be considered to minimise risk of hypoglycaemia. Although the findings of this pre-specified sub-analysis may be limited by the number of patients in the subgroup, the results were generally consistent with those for the overall population. CLINICALTRIALS IDENTIFIER: NCT00602472. PMID- 23672634 TI - Social outcomes of young adults with cerebral palsy. AB - BACKGROUND: Functional abilities and social outcomes of young adults with cerebral palsy (CP) are relatively under-researched. Improvements in paediatric care have extended the expectation of achieving adulthood to 90%. METHOD: Young adults aged 20-30 years with CP (n = 335) were compared to a population-based control group (n = 2,152) of the same age. Motor function, self-care abilities, educational level, and social outcomes were determined by questionnaire. RESULTS: Half the study group walked independently, but only 35.5% were independent in self-care. In comparison to their peers without disability, the study group's highest educational level was lower (p < .0001), as were rates of employment (36.3% compared with 80%), they were more likely to be living with parents (80% compared with 21%), to be single, and to have limited financial resources. CONCLUSION: Young adults with CP are functionally and socially disadvantaged in contrast with their peers without disability. Self-care dependence, intellectual disability, and communication impairments contribute to these outcomes but are not solely responsible. PMID- 23672636 TI - Vertical rectus abdominis myocutaneous flap reconstruction of the perineal defect after abdominoperineal excision is associated with low morbidity. AB - AIM: To examine the short-term outcomes of perineal reconstruction with a vertical rectus abdominis myocutaneous (VRAM) flap following abdominoperineal excision (APE). METHOD: Retrospective case note review of all patients undergoing APE and primary VRAM reconstruction between July 2001 and February 2012 in a district general hospital tertiary referral centre for APE. Complications were categorized using the Clavien-Dindo classification, which grades complications from I to V in order of increasing severity. RESULTS: Fifty-five consecutive patients (31 men, median age 65, range 38-84 years) underwent APE with VRAM flap reconstruction, 15 for anal cancer and 40 for rectal cancer. Median length of stay was 11 days but was significantly shorter in the laparoscopic group compared with the open group (8 vs 12 days; P < 0.01) and in patients who did not experience any complications (P < 0.05). Four patients (7%) had major complications (Grade 3 and above) directly related to the flap or donor site. CONCLUSION: VRAM reconstruction of the perineum can be safely performed following APE with results that compare favourably with other techniques. Most flap complications are minor, although these are still associated with an increase in the length of hospital stay. PMID- 23672633 TI - Tobramycin inhalation powder manufactured by improved process in cystic fibrosis: the randomized EDIT trial. AB - BACKGROUND: Tobramycin inhalation powder (TIP) was reported to be effective in two Phase III studies in patients with cystic fibrosis (CF) chronically infected with Pseudomonas aeruginosa (Pa). The EDIT study evaluated the efficacy and safety of TIP manufactured by an improved process in CF subjects aged 6-21 years. METHODS: CF patients with a forced expiratory volume in 1 second (FEV1) >=25% to <=80% predicted, positive Pa cultures and inhaled antipseudomonal therapy naive (or at least for past 4 months) were enrolled into this double-blind, multicenter trial. Patients were randomized to receive TIP or placebo (1:1) twice daily for one treatment cycle (28.5 days on drug, 28 days off drug). The primary endpoint was relative change in FEV1 percentage predicted from baseline to day 29. A pre specified sensitivity analysis evaluated absolute change in FEV1% predicted. Other endpoints included Pa sputum density and safety. RESULTS: A total of 62 patients out of a target of 100 (mean age 12.9 years, baseline FEV1 59.2% predicted, Pa sputum density 7.4 log10 colony forming units [CFU] per gram) were randomized. Mean treatment differences (TIP - placebo) were 5.9% (p=0.148) and 4.4% (p<0.05) for relative and absolute change in FEV1% predicted respectively. TIP significantly reduced Pa sputum density by -1.2 log10 CFU (p=0.002). Treatment with TIP was well tolerated. CONCLUSIONS: Relative change in FEV1% predicted with TIP treatment was in the expected range based on the literature, but did not reach statistical significance versus placebo. Placebo control and use of treatment naive patients led to significant recruitment challenges and an underpowered study with consequent impact on the generated data. However, significant improvements in other outcomes including absolute change in FEV1% predicted and reduction in Pa sputum density indicate that TIP is efficacious and well tolerated in CF patients. CLINICALTRIALS.GOV IDENTIFIER: NCT00918957. PMID- 23672637 TI - Mining for hemicellulases in the fungus-growing termite Pseudacanthotermes militaris using functional metagenomics. AB - BACKGROUND: The metagenomic analysis of gut microbiomes has emerged as a powerful strategy for the identification of biomass-degrading enzymes, which will be no doubt useful for the development of advanced biorefining processes. In the present study, we have performed a functional metagenomic analysis on comb and gut microbiomes associated with the fungus-growing termite, Pseudacanthotermes militaris. RESULTS: Using whole termite abdomens and fungal-comb material respectively, two fosmid-based metagenomic libraries were created and screened for the presence of xylan-degrading enzymes. This revealed 101 positive clones, corresponding to an extremely high global hit rate of 0.49%. Many clones displayed either beta-d-xylosidase (EC 3.2.1.37) or alpha-l-arabinofuranosidase (EC 3.2.1.55) activity, while others displayed the ability to degrade AZCL-xylan or AZCL-beta-(1,3)-beta-(1,4)-glucan. Using secondary screening it was possible to pinpoint clones of interest that were used to prepare fosmid DNA. Sequencing of fosmid DNA generated 1.46 Mbp of sequence data, and bioinformatics analysis revealed 63 sequences encoding putative carbohydrate-active enzymes, with many of these forming parts of sequence clusters, probably having carbohydrate degradation and metabolic functions. Taxonomic assignment of the different sequences revealed that Firmicutes and Bacteroidetes were predominant phyla in the gut sample, while microbial diversity in the comb sample resembled that of typical soil samples. Cloning and expression in E. coli of six enzyme candidates identified in the libraries provided access to individual enzyme activities, which all proved to be coherent with the primary and secondary functional screens. CONCLUSIONS: This study shows that the gut microbiome of P. militaris possesses the potential to degrade biomass components, such as arabinoxylans and arabinans. Moreover, the data presented suggests that prokaryotic microorganisms present in the comb could also play a part in the degradation of biomass within the termite mound, although further investigation will be needed to clarify the complex synergies that might exist between the different microbiomes that constitute the termitosphere of fungus-growing termites. This study exemplifies the power of functional metagenomics for the discovery of biomass-active enzymes and has provided a collection of potentially interesting biocatalysts for further study. PMID- 23672638 TI - Celiac disease, eosinophilic esophagitis and gastroesophageal reflux disease, an adult population-based study. AB - OBJECTIVE: Celiac disease (CD) has been linked to gastroesophageal reflux disease (GORD) and eosinophilic esophagitis (EoE), but population-based studies of the prevalence of CD in these conditions are lacking, that is, the aim of this study. MATERIALS AND METHODS: An endoscopic study was carried out in 1000 randomly selected adults from the general population. CD was defined on the basis of positive serology in parallel with mucosal abnormalities of the small intestine. Any eosinophil infiltration of the esophageal epithelium was defined as esophageal eosinophilia and EoE was defined as having at least 15 eosinophils/high-power field in biopsies from the distal esophagus. We used Fisher's exact test to compare the prevalence of GORD, esophageal eosinophilia, and EoE in subjects with CD versus controls. RESULTS: Four hundred subjects (40%) had gastroesophageal reflux symptoms (GORS), 155 (15.5%) had erosive esophagitis, 16 (1.6%) had Barrett's esophagus, 48 (4.8%) had esophageal eosinophilia, and 11 (1.1%) had EoE. CD was diagnosed in 8/400 (2.0%) individuals with GORS (vs. controls: 10/600 (1.7%), p = 0.81), in 3/155 (1.9%) with erosive esophagitis (vs. 15/845 controls (1.8%), p = 0.75), and in 2/48 (4.2%) individuals with esophageal eosinophilia (controls: 16/952 (1.7%), p = 0.21), but in none of those 16 with Barrett's esophagus (vs. 18/984 controls (1.8%), p = 1.0) or of the 11 individuals with EoE (controls: 18/989 (1.8%), p = 1.0). CONCLUSIONS: This population-based study found no increased risk of CD among individuals with GORD, esophageal eosinophilia, or EoE. CD screening of individuals with GORD or EoE of individuals with CD cannot be recommended. PMID- 23672640 TI - Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease. AB - HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy. PMID- 23672641 TI - Humoral pattern recognition and the complement system. AB - In the context of immunity, pattern recognition is the art of discriminating friend from foe and innocuous from noxious. The basis of discrimination is the existence of evolutionarily conserved patterns on microorganisms, which are intrinsic to these microorganisms and necessary for their function and existence. Such immutable or slowly evolving patterns are ideal handles for recognition and have been targeted by early cellular immune defence mechanisms such as Toll-like receptors, NOD-like receptors, RIG-I-like receptors, C-type lectin receptors and by humoral defence mechanisms such as the complement system. Complement is a proteolytic cascade system comprising around 35 different soluble and membrane bound proteins. It constitutes a central part of the innate immune system, mediating several major innate effector functions and modulating adaptive immune responses. The complement cascade proceeds via controlled, limited proteolysis and conformational changes of constituent proteins through three activation pathways: the classical pathway, the alternative pathway and the lectin pathway, which converge in common effector functions. Here, we review the nature of the pattern recognition molecules involved in complement activation, as well as their close relatives with no or unknown capacity for activating complement. We proceed to examine the composition of the pattern recognition complexes involved in complement activation, focusing on those of the lectin pathway, and arrive at a new model for their mechanism of operation, supported by recently emerging evidence. PMID- 23672639 TI - Neurogenic factor-induced Langerhans cell activation in diabetic mice with mechanical allodynia. AB - BACKGROUND: Langerhans cells (LCs) are antigen-presenting dendritic cells located in the skin. It has been reported that LC activation is associated with painful diabetic neuropathy (PDN); however, the mechanism of LC activation is still unclear. METHODS: The db/db mouse, a rodent model of PDN, was used to study the roles of LCs in the development of PDN in type 2 diabetes. Hind foot pads from db/db and control db/+ mice from 5 to 24 weeks of age (encompassing the period of mechanical allodynia development and its abatement) were collected and processed for immunohistochemistry studies. LCs were identified with immunohistochemistry using an antibody against CD207 (Langerin). The intraepidermal nerve fibers and subepidermal nerve plexus were identified by immunohistochemistry of protein gene product 9.5 (PGP 9.5) and tropomyosin-receptor kinase (Trk) A, the high affinity nerve growth factor receptor. RESULTS: CD207-positive LCs increased in the db/db mouse during the period of mechanical allodynia, from 8 to 10 weeks of age, in both the epidermis and subepidermal plexus. At 16 weeks of age, when mechanical allodynia diminishes, LC populations were reduced in the epidermis and subepidermal plexus. Epidermal LCs (ELCs) were positive for Trk A. Subepidermal LCs (SLCs) were positive for CD68, suggesting that they are immature LCs. Additionally, these SLCs were positive for the receptor of advanced glycation end products (RAGE) and were in direct contact with TNF-alpha-positive nerve fibers in the subepidermal nerve plexus during the period of mechanical allodynia. Intrathecal administration of SB203580, a p38 kinase inhibitor, significantly reduced mechanical allodynia, TNF-alpha expression in the subepidermal plexus, and increased both ELC and SLC populations during the period of mechanical allodynia. CONCLUSIONS: Our data support the hypothesis that increased LC populations in PDN are activated by p38-dependent neurogenic factors and may be involved in the pathogenesis of PDN. PMID- 23672642 TI - Lead ammunition and illegal poisoning: further international agreements are needed to preserve vultures and the crucial sanitary service they provide. PMID- 23672643 TI - 2D 1H/1H RFDR and NOESY NMR experiments on a membrane-bound antimicrobial peptide under magic angle spinning. AB - There is significant interest in solving high-resolution dynamic structures of membrane-associated peptides using solid-state NMR spectroscopy. Previous solid state NMR studies have provided valuable insights into the functional properties of an exciting class of biomacromolecules such as antimicrobial peptides and amyloid peptides. However, it has been a major challenge to apply solid-state NMR techniques to study peptides or proteins that are not labeled with specific isotopes such as (13)C, (15)N, and/or (2)H. This study utilizes 2D (1)H/(1)H radio frequency-driven recoupling (RFDR) and nuclear Overhauser effect spectroscopy (NOESY) pulse sequences under magic angle spinning to study a membrane-bound antimicrobial peptide MSI-78 (or also known as pexiganan). We demonstrate that proton resonances can be assigned and structural constraints, NOE and (1)H-(1)H dipolar couplings, can be measured without the need for any isotopic enrichment. The buildup curves, showing the dependence of the cross peak intensity against the mixing time, obtained from 2D (1)H/(1)H NOESY and RFDR experiments are compared. Our results reveal that the RFDR-recovered (1)H-(1)H dipolar couplings associated with alpha and side chain protons are larger than that with the amide-protons. This study provides a means to measure residual (1)H (1)H dipolar couplings for the investigation of structure, dynamics, and aggregation of peptides using a suitable model membrane like micelles or bicelles. PMID- 23672644 TI - Measuring fragmentation of ambulatory care in a tripartite healthcare system. AB - BACKGROUND: Hong Kong has a tripartite healthcare system, where western medicine provided in both public and private sectors coexist with Chinese medicine practice. The purpose of this study is to measure fragmentation of ambulatory care experienced by the non-institutionalized population aged 15 and over in such a tripartite system, thus shed light on the ongoing primary care reform. METHODS: This is a cross-sectional secondary data analysis using the Thematic Household Survey, which was conducted by the Hong Kong Census and Statistics Department during November 2009 to February 2010 to collect territory-wide health-related information. Among 18,226 individuals with two or more ambulatory visits during the past 12 months before interview, we grouped each visit into one of the three care segments-public western, private western and Chinese medicine. Two individual-level measures were used to quantify longitudinal fragmentation of care across segments over the one-year period: Most Frequent Provider Continuity Index (MFPC) and Fragmentation of Care Index (FCI). Both are analyzed for distribution and subgroup comparison. A Tobit model was used to further examine the determinants of fragmentation. RESULTS: More than a quarter of individuals sought care in two or all three segments, with an average MFPC of 65% and FCI of 0.528. Being older, female, married, unemployed, uninsured, or born in mainland China, with lower education, lower income, higher number of chronic conditions or poorer health were found to have experienced higher fragmentation of care. We also found that, fragmentation of care increased with the total number of ambulatory care visits and it varied significantly depending on what segment the individual chose to visit most frequently-those chose private western clinics had lower FCI, compared with those chose public western or Chinese medicine as the most frequently visited segment. CONCLUSIONS: Even measured at healthcare segment level, people in Hong Kong experienced modest fragmentation of care. Individuals' health beliefs-as a result of the persistent habitual tendency and latitude incentivized by the system-may be behind the fragmented care we saw. Efforts are needed to alter health beliefs, targeting subgroups of vulnerable population, and create environments that promote better coordinated primary care. PMID- 23672645 TI - An R package for analyzing and modeling ranking data. AB - BACKGROUND: In medical informatics, psychology, market research and many other fields, researchers often need to analyze and model ranking data. However, there is no statistical software that provides tools for the comprehensive analysis of ranking data. Here, we present pmr, an R package for analyzing and modeling ranking data with a bundle of tools. The pmr package enables descriptive statistics (mean rank, pairwise frequencies, and marginal matrix), Analytic Hierarchy Process models (with Saaty's and Koczkodaj's inconsistencies), probability models (Luce model, distance-based model, and rank-ordered logit model), and the visualization of ranking data with multidimensional preference analysis. RESULTS: Examples of the use of package pmr are given using a real ranking dataset from medical informatics, in which 566 Hong Kong physicians ranked the top five incentives (1: competitive pressures; 2: increased savings; 3: government regulation; 4: improved efficiency; 5: improved quality care; 6: patient demand; 7: financial incentives) to the computerization of clinical practice. The mean rank showed that item 4 is the most preferred item and item 3 is the least preferred item, and significance difference was found between physicians' preferences with respect to their monthly income. A multidimensional preference analysis identified two dimensions that explain 42% of the total variance. The first can be interpreted as the overall preference of the seven items (labeled as "internal/external"), and the second dimension can be interpreted as their overall variance of (labeled as "push/pull factors"). Various statistical models were fitted, and the best were found to be weighted distance-based models with Spearman's footrule distance. CONCLUSIONS: In this paper, we presented the R package pmr, the first package for analyzing and modeling ranking data. The package provides insight to users through descriptive statistics of ranking data. Users can also visualize ranking data by applying a thought multidimensional preference analysis. Various probability models for ranking data are also included, allowing users to choose that which is most suitable to their specific situations. PMID- 23672647 TI - Effects of regularity on the processing of sound omission in a tone sequence in musicians and non-musicians. AB - Numerous studies have reported that perceptual grouping affects the pre-attentive processing of sound omission in a sequence of tones. However, it remains unclear whether or not the perceptual grouping and musical experience affect the attentive processing of sound omission. To this end, we created a sequence of loud (L) and soft (S) tones grouped as 'LLSLLS...' and a random sequence of the L and S tones. The omission of the L tones was inserted pseudo-randomly in the random sequence, and there were two positions at which it was inserted. For within-group omission, the omission was after the first L tone within the 'LLS' pattern. For between-group omission, the omission was inserted between the patterns. The brain response to the omission in musicians and non-musicians was measured using magnetoencephalography. During the magnetoencephalography measurement, the subjects' performance in a task to detect the omission was faster in the random sequence than in the group sequence. Source analysis showed that the omission in the random sequence caused greater activity than that in the group sequence. The increase was found in the right inferior parietal lobe in musicians, whereas it was found in the left superior temporal gyrus in non musicians. These results suggest that the attentive processing of perceptual grouping might implicate the left superior temporal gyrus or right inferior parietal lobe, depending on musical experience. PMID- 23672646 TI - How to minimize children's environmental tobacco smoke exposure: an intervention in a clinical setting in high risk areas. AB - BACKGROUND: Despite the low prevalence of daily smokers in Sweden, children are still being exposed to environmental tobacco smoke (ETS), primarily by their smoking parents. A prospective intervention study using methods from Quality Improvement was performed in Child Health Care (CHC). The aim was to provide nurses with new methods for motivating and supporting parents in their efforts to protect children from ETS exposure. METHOD: Collaborative learning was used to implement and test an intervention bundle. Twenty-two CHC nurses recruited 86 families with small children which had at least one smoking parent. Using a bundle of interventions, nurses met and had dialogues with the parents over a one year period. A detailed questionnaire on cigarette consumption and smoking policies in the home was answered by the parents at the beginning and at the end of the intervention, when children also took urine tests to determine cotinine levels. RESULTS: Seventy-two families completed the study. Ten parents (11%) quit smoking. Thirty-two families (44%) decreased their cigarette consumption. Forty five families (63%) were outdoor smokers at follow up. The proportion of children with urinary cotinine values of >6 ng/ml had decreased. CONCLUSION: The intensified tobacco prevention in CHC improved smoking parents' ability to protect their children from ETS exposure. PMID- 23672648 TI - Progressive mandibular midline deviation after difficult tracheal intubation. AB - We report condylar resorption of the temporomandibular joint after difficult intubation, leading to progressive midline mandibular deviation, subsequently treated by prosthetic joint replacement. PMID- 23672650 TI - Allee effects in ants. AB - 1. Allee effects occur when the aggregation of individuals result in mutually beneficial intraspecific interactions whereby individual fitness, or per capita growth rate, increases with the number of individuals. Allee effects are common in social species due to their cooperative behaviours, such as breeding, feeding or defence. Allee effects have important implications for many aspects of basic and applied ecology. Over the past decades, the study of Allee effects has influenced population dynamics, community ecology, endangered species management and invasion biology. 2. Despite the fact that cooperation is the basis of their social structure, Allee effects have received little attention among eusocial insects. Extreme cooperation is common, and reproductive specialization of individuals occurs due to division of labour. These life-history traits suggest that the potential contribution of each caste to reproduction and survival may be differential and nonadditive. 3. We studied Allee effects in the invasive Argentine ant (Linepithema humile). In this species, many queens and workers are present in colonies, which allowed us to explore the differential effects of castes on the presence of Allee effects. In the laboratory, we measured brood production and individual survival in experimental colonies that differed in the initial numbers of queens and workers.4. Our results highlight the differential effect of queens and workers on survival and productivity. We found three positive density-dependent relationships indicative of component Allee effects at the colony level: both workers and queens had a positive effect on the productivity of the other caste, and queens had a positive effect on worker survivorship. 5. Our experimental results suggest a potential positive feedback between worker and queen abundance, which may have contributed to the evolution of large colony sizes. Our study provides the first evidence of Allee effects in eusocial insects and highlights the need to consider castes separately in population dynamics. Division of labour and differential reproductive rates are factors that should be integrated into the study of Allee effects. PMID- 23672649 TI - In vitro development and characterization of a tissue-engineered conduit resembling esophageal wall using human and pig skeletal myoblast, oral epithelial cells, and biologic scaffolds. AB - INTRODUCTION: Tissue engineering represents a promising approach for esophageal replacement, considering the complexity and drawbacks of conventional techniques. AIM: To create the components necessary to reconstruct in vitro or in vivo an esophageal wall, we analyzed the feasibility and the optimal conditions of human and pig skeletal myoblast (HSM and PSM) and porcine oral epithelial cell (OEC) culture on biologic scaffolds. MATERIALS AND METHODS: PSM and HSM were isolated from striated muscle and porcine OECs were extracted from oral mucosa biopsies. Myoblasts were seeded on an acellular scaffold issue from porcine small intestinal submucosa (SIS) and OEC on decellularized human amniotic membrane (HAM). Seeding conditions (cell concentrations [0.5*10(6) versus 10(6) cells/cm(2)] and culture periods [7, 14 and 21 days]), were analyzed using the methyl thiazoltetrazolium assay, quantitative PCR, flow cytometry, and immunohistochemistry. RESULTS: Phenotypic stability was observed after cellular expansion for PSM and HSM (85% and 97% CD56-positive cells, respectively), and OECs (90% AE1/AE3- positive cells). After PSM and HSM seeding, quantities of viable cells were similar whatever the initial cell concentration used and remained stable at all time points. During cell culture on SIS, a decrease of CD56-positive cells was observed (76% and 76% by D7, 56% and 70% by D14, 28% and 60% by D21, for PSM and HSM, respectively). Multilayered surface of alpha-actin smooth muscle and Desmine-positive cells organized in bundles was seen as soon as D7, with no evidence of cell within the SIS. Myoblasts fusion was observed at D21. Pax3 and Pax7 expression was downregulated and MyoD expression upregulated, at D14.OEC proliferation was observed on HAM with both cell concentrations from D7 to D21. The cell metabolism activity was more important on matrix seeded by 10(6) cells/cm(2). With 0.5*10(6) OEC/cm(2), a single layer of pancytokeratin positive cells was seen at D7, which became pluristratified by D14, while when 10(6) OEC/cm(2) were used, a pluristratified epithelial structure was seen as soon as D7. Proliferative cells (Proliferating Cell Nuclear Antigen staining) were mainly located at the basal layer. CONCLUSION: In this model, the optimal conditions of cell seeding in terms of cell concentration and culture duration were 0.5*10(6) myoblasts/cm(2) and 10(6) OEC/cm(2), and 7 days. PMID- 23672651 TI - Role of components of frailty on quality of life in dialysis patients: a cross sectional study. AB - BACKGROUND: Many people on dialysis suffer a variety of conditions that can affect frailty (the condition or quality of being frail), such as comorbidities, disabilities, dependence, malnutrition, cognitive impairment and poor social conditions. Frailty is suspected to affect quality of life (QoL). OBJECTIVES: The study aimed to evaluate the effect of the different components of frailty on the QoL of people on dialysis. METHODS: We enrolled 203 out of 233 prevalent patients on dialysis in the Trieste area of Italy. We applied the Short-Form 36 (SF-36) questionnaire, Activities of Daily Living, Instrumental Activities of Daily Living, Subjective Global Assessment scales and Karnofsky Index. In addition we analysed their social conditions. RESULTS: Dependence, malnutrition and disability had a negative role on QoL. Living with family and good social economic conditions were significantly related to a better QoL. CONCLUSIONS: Dependence, malnutrition, disability, poor social and economic conditions have a significant effect on life quality. The role of comorbidities appears to be less important. Screening of patients, nutritional and functional rehabilitation and prevention of social isolation appear to be indispensable in guaranteeing a satisfactory life quality. PMID- 23672652 TI - Mn2(2,5-disulfhydrylbenzene-1,4-dicarboxylate): a microporous metal-organic framework with infinite (-Mn-S-)infinity chains and high intrinsic charge mobility. AB - The reaction of MnCl2 with 2,5-disulfhydrylbenzene-1,4-dicarboxylic acid (H4DSBDC), in which the phenol groups in 2,5-dihydroxybenzene-1,4-dicarboxylic acid (H4DOBDC) have been replaced by thiophenol units, led to the isolation of Mn2(DSBDC), a thiolated analogue of the M2(DOBDC) series of metal-organic frameworks (MOFs). The sulfur atoms participate in infinite one-dimensional Mn-S chains, and Mn2(DSBDC) shows a high surface area and high charge mobility similar to that found in some of the most common organic semiconductors. The synthetic approach to Mn2(DSBDC) and its excellent electronic properties provide a blueprint for a potentially rich area of exploration in microporous conductive MOFs with low-dimensional charge transport pathways. PMID- 23672653 TI - Splitting of a vertical multiwalled carbon nanotube carpet to a graphene nanoribbon carpet and its use in supercapacitors. AB - Potassium vapor was used to longitudinally split vertically aligned multiwalled carbon nanotubes carpets (VA-CNTs). The resulting structures have a carpet of partially split MWCNTs and graphene nanoribbons (GNRs). The split structures were characterized by scanning electron microscopy, transmission electron microscopy, atomic force microscopy, Raman spectroscopy and X-ray photoelectron spectroscopy. When compared to the original VA-CNTs carpet, the split VA-CNTs carpet has enhanced electrochemical performance with better specific capacitance in a supercapacitor. Furthermore, the split VA-CNTs carpet has excellent cyclability as a supercapacitor electrode material. There is a measured maximum power density of 103 kW/kg at an energy density of 5.2 Wh/kg and a maximum energy density of 9.4 Wh/kg. The superior electrochemical performances of the split VA-CNTs can be attributed to the increased surface area for ion accessibility after splitting, and the lasting conductivity of the structure with their vertical conductive paths based on the preserved GNR alignment. PMID- 23672654 TI - Impact of 18F-florbetapir PET imaging of beta-amyloid neuritic plaque density on clinical decision-making. AB - 18F-florbetapir positron emission tomography (PET) imaging of the brain is now approved by the Food and Drug Administration (FDA) approved for estimation of beta -amyloid neuritic plaque density when evaluating patients with cognitive impairment. However, its impact on clinical decision-making is not known. We present 11 cases (age range 67-84) of cognitively impaired subjects in whom clinician surveys were done before and after PET scanning to document the theoretical impact of amyloid imaging on the diagnosis and treatment plan of cognitively impaired subjects. Subjects have been clinically followed for about 5 months after the PET scan. Negative scans occurred in five cases, leading to a change in diagnosis for four patients and a change in treatment plan for two of these cases. Positive scans occurred in six cases, leading to a change in diagnosis for four patients and a change in treatment plan for three of these cases. Following the scan, only one case had indeterminate diagnosis. Our series suggests that both positive and negative florbetapir PET scans may enhance diagnostic certainty and impact clinical decision-making. Controlled longitudinal studies are needed to confirm our data and determine best practices. PMID- 23672655 TI - DHEA--finding a role for this enigmatic hormone. PMID- 23672657 TI - SERMs, vulvovaginal atrophy and breast cancer. PMID- 23672656 TI - Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health. PMID- 23672658 TI - Autism spectrum disorder and fetal alcohol spectrum disorder. Part I: a comparison of parenting stress. AB - BACKGROUND: There is a long history of research on parents of children with disabilities, but to the authors' knowledge, no study has compared the stress of parents of children with fetal alcohol spectrum disorder (FASD) to parents of children with autism spectrum disorder (ASD). METHOD: Twenty-five parents of children with ASD and 25 parents of children with FASD completed the Parenting Stress Index - Short Form (PSI-SF) and the Questionnaire on Resources and Stress Friedrich's Version (QRS-F). RESULTS: Although both parent groups reported elevated stress, PSI-SF results indicated that parents of children with FASD were experiencing significantly more stress compared to parents of children with ASD. No significant differences were found between groups on the total QRS-F, but parents of children with FASD had higher scores on the Pessimism subscale. CONCLUSIONS: The authors call for measures grounded in theory as well as mixed methods research that includes the subjective experience of parents' stress. PMID- 23672659 TI - Autism spectrum disorder and fetal alcohol spectrum disorder. Part II: a qualitative comparison of parenting stress. AB - BACKGROUND: Researchers investigating the impact of parenting children with disabilities suggest that regardless of the specific diagnosis, parents experience increased levels of stress. However, particular disabilities may be associated with distinct stressors and strains. METHOD: Parents of children with autism spectrum disorder (ASD) and parents of children with fetal alcohol spectrum disorder (FASD) participated in in-depth qualitative interviews employing a basic interpretative approach. RESULTS: Both groups described some similar stressors, such as multi-tasking, the diagnostic process, and dealing with behavioural issues, but there are distinct differences between families of children with FASD and families of children with ASD. Whereas parents of children with FASD focused on their children's illegal behaviours, parents of children with ASD struggled with their children's tantrums and anxieties. CONCLUSIONS: Supports must be tailored to meet the specific needs of parents of children with different types of disabilities. PMID- 23672660 TI - The experiences of mothers of young adults with an intellectual disability transitioning from secondary school to adult life. AB - BACKGROUND: The transition from school to adulthood for young adults with an intellectual disability involves movement from a generally secure and supported school environment to an emerging adult life that may be characterised by a wide variation in adoption of adult roles related to employment, independent living, friendships, and day activities. METHOD: In this study, we investigated the perspectives of 18 mothers of young adults with either Down syndrome or Rett syndrome through qualitative semistructured interviews. The International Classification of Functioning, Disability and Health (ICF) framework was used as a conceptual basis. RESULTS: Themes that emerged included adult roles assumed during the day, accommodation, quality of life, living a "good" life, and family impact. CONCLUSIONS: In contrast with Rett syndrome, mothers of young adults with Down syndrome described more difficult pathways to attaining stability in adult roles. Environmental facilitators and barriers emerged in the area of support, relationships, services, systems, and policies. PMID- 23672663 TI - Ten-year mortality trends among persons diagnosed with HIV infection in England and Wales in the era of antiretroviral therapy: AIDS remains a silent killer. AB - OBJECTIVES: We present national trends in death rates and the proportion of deaths attributable to AIDS in the era of effective antiretroviral therapy (ART), and examine risk factors associated with an AIDS-related death. METHODS: Analyses of the national HIV-infected cohort for England and Wales linked to death records from the Office of National Statistics were performed. Annual all-cause mortality rates were calculated by age group and sex for the years 1999-2008 and rates for 2008 were compared with death rates in the general population. Risk factors associated with an AIDS-related death were investigated using a case-control study design. RESULTS: The all-cause mortality rate among persons diagnosed with HIV infection aged 15-59 years fell over the decade: from 217 per 10 000 in 1999 to 82 per 10 000 in 2008, with declines in all age groups and exposure categories except women aged 50-59 years and persons who inject drugs (rate fluctuations in both of these groups were probably a result of small numbers). Compared with the general population (15 per 10 000 in 2008), death rates among persons diagnosed with HIV infection remained high, especially in younger persons (aged 15-29 years) and persons who inject drugs (13 and 20 times higher, respectively). AIDS related deaths accounted for 43% of all deaths over the decade (24% in 2008). Late diagnosis (CD4 count < 350 cells/MUL) was the most important predictor of dying of AIDS [odds ratio (OR) 10.55; 95% confidence interval (CI) 8.22-13.54]. Sixty per cent of all-cause mortality and 81% of all AIDS-related deaths were attributable to late diagnosis. CONCLUSIONS: Despite substantial declines, death rates among persons diagnosed with HIV infection continue to exceed those of the general population in the ART era. Earlier diagnosis could have prevented 1600 AIDS-related deaths over the decade. These findings highlight the need to intensify efforts to offer and recommend an HIV test in a wider range of clinical and community settings. PMID- 23672664 TI - Antibacterial and antifungal activities of acetonic extract from Paullinia cupana Mart. seeds. AB - The antibacterial and antifungal activities of the acetone extract from Paullinia cupana var. sorbilis Mart. (Sapindaceae) seeds, commonly called guarana, were assessed against selected bacterial and fungal strains. We tested the extract against both standard American Type Culture Collection (ATCC) and clinically isolated (CI) bacterial strains and three fungal strains. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values for bacteria and MIC and minimum fungicidal concentration for fungi were determined. The extract showed an activity against the nine bacterial strains tested, both CI and ATCC strains (MIC comprised between 32 and 128 MUm/mL and MBC between 128 and 512 MUm/mL), showing a significant antibacterial effect against both Gram negative and Gram-positive bacteria. Also, the tested fungi were sensitive to the extract (MIC between 125 and 250 MUm/mL). The contemporaneous presence of different bioactivities in the extract from guarana suggests this plant as a source of bioactive substances. PMID- 23672665 TI - Surgical checklists: the human factor. AB - BACKGROUND: Surgical checklists has been shown to improve patient safety and teamwork in the operating theatre. However, despite the known benefits of the use of checklists in surgery, in some cases the practical implementation has been found to be less than universal. A questionnaire methodology was used to quantitatively evaluate the attitudes of theatre staff towards a modified version of the World Health Organisation (WHO) surgical checklist with relation to: beliefs about levels of compliance and support, impact on patient safety and teamwork, and barriers to the use of the checklist. METHODS: Using the theory of planned behaviour as a framework, 14 semi-structured interviews were conducted with theatre personnel regarding their attitudes towards, and levels of compliance with, a checklist. Based upon the interviews, a 27-item questionnaire was developed and distribute to all theatre personnel in an Irish hospital. RESULTS: Responses were obtained from 107 theatre staff (42.6% response rate). Particularly for nurses, the overall attitudes towards the effect of the checklist on safety and teamworking were positive. However, there was a lack of rigour with which the checklist was being applied. Nurses were significantly more sensitive to the barriers to the use of the checklist than anaesthetists or surgeons. Moreover, anaesthetists were not as positively disposed to the surgical checklist as surgeons and nurse. This finding was attributed to the tendency for the checklist to be completed during a period of high workload for the anaesthetists, resulting in a lack of engagement with the process. CONCLUSION: In order to improve the rigour with which the surgical checklist is applied, there is a need for: the involvement of all members of the theatre team in the checklist process, demonstrated support for the checklist from senior personnel, on-going education and training, and barriers to the implementation of the checklist to be addressed. PMID- 23672666 TI - Catalytic mechanism of angiotensin-converting enzyme and effects of the chloride ion. AB - The angiotensin-converting enzyme (ACE) exhibits critical functions in the conversion of angiotensin I to angiotensin II and the degradation of bradykinin and other vasoactive peptides. As a result, the ACE inhibition has become a promising approach in the treatment of hypertension, heart failure, and diabetic nephropathy. Extending our recent molecular dynamics simulation of the testis ACE in complex with a bona fide substrate molecule, hippuryl-histidyl-leucine, we presented here a detailed investigation of the hydrolytic process and possible influences of the chloride ion on the reaction using a combined quantum mechanical and molecule mechanical method. Similar to carboxypeptidase A and thermolysin, the promoted water mechanism is established for the catalysis of ACE. The E384 residue was found to have the dual function of a general base for activating the water nucleophile and a general acid for facilitating the cleavage of amide C-N bond. Consistent with experimental observations, the chloride ion at the second binding position is found to accelerate the reaction rate presumably due to the long-range electrostatic interactions but has little influence on the overall substrate binding characteristics. PMID- 23672667 TI - Discovery of a potent boronic acid derived inhibitor of the HCV RNA-dependent RNA polymerase. AB - A boronic acid moiety was found to be a critical pharmacophore for enhanced in vitro potency against wild-type hepatitis C replicons and known clinical polymorphic and resistant HCV mutant replicons. The synthesis, optimization, and structure-activity relationships associated with inhibition of HCV replication in a subgenomic replication system for a series of non-nucleoside boron-containing HCV RNA-dependent RNA polymerase (NS5B) inhibitors are described. A summary of the discovery of 3 (GSK5852), a molecule which entered clinical trials in subjects infected with HCV in 2011, is included. PMID- 23672669 TI - Reclamation and utilization of saline soils in arid northwestern China: a promising halophyte drip-irrigation system. PMID- 23672668 TI - Innate immunity in the Grid2Lc/+ mouse model of cerebellar neurodegeneration: glial CD95/CD95L plays a non-apoptotic role in persistent neuron loss-associated inflammatory reactions in the cerebellum. AB - BACKGROUND: There is growing evidence that the death receptor CD95 has a wider role in non-apoptotic functions. In the brain, it may contribute to neural death and to the associated inflammatory reaction via a non-apoptotic pathway. Brain injury triggers an inflammatory reaction in which the CD95/CD95L system acts principally through peripheral cells recruited to the lesion. In cases of inflammation within the brain, with no blood-brain barrier leakage, the role of the CD95/CD95L system is thus unclear. We investigated the possible role of CD95 and CD95L in such conditions, by studying the relationships between glial cell activation, neuron death and CD95/CD95L expression in the cerebellum of the Lurcher (Grid2(Lc/+)) mutant mouse, a model of cerebellar neurodegeneration. METHODS: Glial cells in slices of wild-type and Lurcher mouse cerebella were observed by light microscopy at various ages overlapping periods of neuron loss and of pre- and post-neurodegeneration. Subcellular organization was studied by electron microscopy. We assessed CD95 levels by western blotting, RT-PCR and glial cell cultures. The levels of CD95L and IL-6 were studied by ELISA and a biological assay, respectively. RESULTS: In the Grid2(Lc/+)cerebellum, neuron loss triggers a typical, but abnormally persistent, inflammatory reaction. We identified two phases of astrogliosis: an early burst of large glial cell activation, peaking at postnatal days 25 to 26, coinciding with peak cerebellar neuron loss, followed by a long period of slow decline indicating that the strength of the glial reaction is modulated by neuron mortality rates. Comparisons of time-courses of glial cell activation, cytokine production and neuron loss revealed that the number of surviving neurons decreased as CD95 increased. Thus, CD95 cannot be directly involved in neuron death, and its role must be limited to a contribution to the inflammatory reaction. The upregulation of CD95 likely on astrocytes coincides with increases in the levels of IL-6, a cytokine produced principally by astrocytes, and soluble CD95L. CONCLUSIONS: These results suggest that CD95 and soluble CD95L contribute, via non-apoptotic signaling, to the inflammatory reaction initiated early in neuron death within the Grid2(Lc/+) cerebellum. PMID- 23672670 TI - Caspase-2 is involved in cell death induction by taxanes in breast cancer cells. AB - BACKGROUND: We studied the role of caspase-2 in apoptosis induction by taxanes (paclitaxel, novel taxane SB-T-1216) in breast cancer cells using SK-BR-3 (nonfunctional p53, functional caspase-3) and MCF-7 (functional p53, nonfunctional caspase-3) cell lines. RESULTS: Both taxanes induced apoptosis in SK-BR-3 as well as MCF-7 cells. Caspase-2 activity in SK-BR-3 cells increased approximately 15-fold within 48 h after the application of both taxanes at the death-inducing concentration (100 nM). In MCF-7 cells, caspase-2 activity increased approximately 11-fold within 60 h after the application of taxanes (300 nM). Caspase-2 activation was confirmed by decreasing levels of procaspase-2, increasing levels of cleaved caspase-2 and the cleavage of caspase-2 substrate golgin-160. The inhibition of caspase-2 expression using siRNA increased the number of surviving cells more than 2-fold in MCF-7 cells, and at least 4-fold in SK-BR-3 cells, 96 h after the application of death-inducing concentration of taxanes. The inhibition of caspase-2 expression also resulted in decreased cleavage of initiator caspases (caspase-8, caspase-9) as well as executioner caspases (caspase-3, caspase-7) in both cell lines after the application of taxanes. In control cells, caspase-2 seemed to be mainly localized in the nucleus. After the application of taxanes, it was released from the nucleus to the cytosol, due to the long-term disintegration of the nuclear envelope, in both cell lines. Taxane application led to some formation of PIDDosome complex in both cell lines within 24 h after the application. After taxane application, p21WAF1/CIP1 expression was only induced in MCF-7 cells with functional p53. However, taxane application did not result in a significant increase of PIDD expression in either SK-BR-3 or MCF-7 cells. The inhibition of RAIDD expression using siRNA did not affect the number of surviving SK-BR-3 and MCF-7 cells after taxane application at all. CONCLUSION: Caspase-2 is required, at least partially, for apoptosis induction by taxanes in tested breast cancer cells. We suggest that caspase-2 plays the role of an apical caspase in these cells. Caspase-2 seems to be activated via other mechanism than PIDDosome formation. It follows the release of caspase-2 from the nucleus to the cytosol. PMID- 23672671 TI - A Rome III survey of functional dyspepsia among the ethnic Malays in a primary care setting. AB - BACKGROUNDS: The study aimed to survey for FD in a primary care setting in a population known to have an extremely low prevalence of Helicobacter pylori (H. pylori) infection, with the hypothesis that in such a population, dyspepsia should have been relatively less common. METHODS: The Rome III FD Diagnostic Questionnaire was translated into the Malay language and later tested for reliability. A prospective cross-sectional survey was then performed involving 160 Malay patients attending primary care clinic after informed consent. Patients positive for symptoms of FD were subjected to upper endoscopy and exclusion of H. pylori infection. Univariable and multivariable analyses were used to test for associated risk factors. RESULTS: The back-translated questionnaire was similar to the original English version and was reliable (Cronbach Alpha-coefficient 0.85). Of the 160 surveyed subjects, 19 of them (11.9%) had symptoms of FD. With exclusion of erosive diseases (3/160 or 1.9%) from endoscopy, 16 subjects or 10% had FD. None of the 19 subjects were positive for H. pylori infection. Epigastric pain syndrome was present in 11/16 (68.8%) and the rest, overlap with postprandial distress syndrome. With multivariable analysis, a married status (OR = 8.1; 95% CI 1.0-36.5) and positive psychosocial alarm symptoms (OR = 3.8; 95% CI 1.0-14.0) were associated with FD. Of those married subjects, females were more likely to have FD and psychosocial symptoms than men (6.3% vs. 1.9%), P = 0.04. CONCLUSIONS: FD was more common than one had expected among Malays attending primary care clinic in an area with low prevalence of H. pylori. PMID- 23672672 TI - Efficacy and safety of olanzapine for treatment of patients with bipolar depression: Japanese subpopulation analysis of a randomized, double-blind, placebo-controlled study. AB - BACKGROUND: The efficacy and safety of olanzapine monotherapy are evaluated in Japanese patients from a large, global study of bipolar depression. METHODS: This is an analysis of Japanese patients from a 6-week, global (Japan, China, Korea, Taiwan, and the United States), randomized, double-blind, placebo-controlled, Phase 3 study of patients with a depressive episode of bipolar I disorder. The primary outcome was baseline-to-endpoint change in the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Secondary outcome measures included the Clinical Global Impressions-Bipolar Version Severity of Illness Scale (CGI BP), the 17-item Hamilton Depression Rating Scale (HAMD-17) total score, the Young Mania Rating Scale (YMRS) total score, and rates of response (>=50% baseline-to-endpoint reduction in MADRS total score), recovery, and remission. RESULTS: Of the 156 Japanese patients, 104 had been allocated to olanzapine and 52 to placebo. All results are baseline-to-endpoint change. Compared to placebo, patients in the olanzapine group experienced greater improvement in the primary outcome measure, MADRS total score (-14.9 vs. -10.7; p = .01). They also had greater reductions in the following secondary measures: CGI- BP Depression (-1.41 vs. -0.89; p = .008), CGI-BP Bipolar (-1.31 vs. -0.83; p = .01), HAMD-17 (-11.7 vs. -7.9; p < .01), and YMRS (-0.32 vs. 0.34; p = .03). Differences in rates of response, recovery, and remission were not statistically significant. A greater proportion of olanzapine-treated patients reported treatment- emergent adverse events (87.5% vs. 59.6%; p < .001). Patients treated with olanzapine had greater increases in weight (p < .001) and fasting total cholesterol (p = .008); fasting triglycerides (p = .02), and fasting low-density lipoprotein (p = .01). There was a greater reduction in fasting high-density lipoprotein in olanzapine-treated patients (p = .01). Compared with placebo-group patients, more olanzapine-group patients shifted from borderline to high cholesterol (25.0% vs. 0.0%; p = .007) and had clinically significant weight gain (>=7% body weight) (20.2% vs. 1.9%; p = .001). CONCLUSIONS: Results of this analysis support the efficacy and tolerability of olanzapine for the treatment of bipolar depression in Japanese patients. Results in this population were consistent with those seen in the more ethnically diverse parent study. In making treatment decisions for individual patients, clinicians should carefully consider the risks and benefits of olanzapine treatment. TRIAL REGISTRATION: Clinicatrials.gov ID NCT00510146 Olanzapine Treatment of Patients with Bipolar I Disorder. PMID- 23672673 TI - Cutaneous metastatic breast carcinoma with clear cell features. AB - Breast carcinoma remains one of the most common sources of skin metastases in women. Cutaneous breast carcinoma metastases have variable clinical and histopathologic presentations that can make diagnosis challenging. We report a unique case of metastatic breast carcinoma with prominent clear cell features, thus mimicking a xanthomatous process. Dermatopathologists should be aware of this entity given its resemblance to other clear cell infiltrates and neoplasms. PMID- 23672674 TI - Theophylline. AB - Theophylline (dimethylxanthine) has been used to treat airway diseases for more than 80 years. It was originally used as a bronchodilator, but the relatively high doses required are associated with frequent side effects, so its use declined as inhaled beta2-agonists became more widely used. More recently it has been shown to have antiinflammatory effects in asthma and chronic obstructive pulmonary disease (COPD) at lower concentrations. The molecular mechanism of bronchodilatation is inhibition of phosphodiesterase (PDE)3, but the antiinflammatory effect may be due to inhibition of PDE4 and histone deacetylase 2 activation, resulting in switching off of activated inflammatory genes. Through this mechanism, theophylline also reverses corticosteroid resistance, and this may be of particular value in severe asthma and COPD, wherein histone deacetylase 2 activity is reduced. Theophylline is given systemically (orally as slow-release preparations for chronic treatment and intravenously for acute exacerbations of asthma). Efficacy is related to blood concentrations, which are determined mainly by hepatic metabolism, which may be increased or decreased in several diseases and by concomitant drug therapy. Theophylline is now usually used as an add-on therapy in patients with asthma not well controlled on inhaled corticosteroids with or without long-acting beta2-agonists and in patients with COPD with severe disease not controlled by bronchodilator therapy. Side effects are related to plasma concentrations and include nausea, vomiting, and headaches due to PDE inhibition and at higher concentrations to cardiac arrhythmias and seizures due to adenosine A1-receptor antagonism. In the future, low-dose theophylline may be useful in reversing corticosteroid resistance in COPD and severe asthma. PMID- 23672675 TI - Comparison of blind and electrically guided tracheal needle insertion in human cadavers. AB - The purpose of this study was to investigate whether an electrically guided needle insertion technique would enable greater success at intratracheal needle tip insertion than the traditional, aspiration-of-air technique. Twenty-seven anaesthesiology residents were assessed in their ability to place a needle tip in the trachea of cadavers using the two methods. Success of needle placement, time to placement and confidence in placement were recorded. Correct intratracheal needle placement was achieved by 22% of residents (6/27) using the aspiration-of air method vs 82% (22/27) using the electrically guided method (p<0.001). For the instances of success, there was no significant difference between the two methods in the median (IQR [range]) time taken (28 (24-49 [18-63]) s aspiration vs 32 (19 49 [15-84]) s electrical; p=0.93). The electrically guided method provides an acceptably quick and accurate way of placing a needle tip into the tracheal lumen and can be learnt easily by anaesthesiology residents. PMID- 23672677 TI - FDA and EMA end points: which outcome end points should we use in clinical trials in patients with irritable bowel syndrome? AB - Trial design and endpoints for the evaluation of drug efficacy in irritable bowel syndrome (IBS) underwent major changes over the last two decades. A systematic review in the early 1990s concluded that there were few well-designed and well executed treatment trials in IBS. Over the next decade, the so-called binary endpoints were used in several clinical trials in IBS in the US, Europe and other parts of the world. In 2006, the Food and Drug Administration (FDA) published a general guidance for the evaluation of symptom benefit in clinical trials based on patient-reported outcome (PRO) measures, which had a major impact on trial design in IBS. In May 2012, the FDA recommended to use as provisional endpoint the quantification of two major IBS aspects, abdominal pain and disordered defecation, to assess the efficacy of pharmacological treatments in IBS. In the present issue of Neurogastroenterology & Motility, the performance of the FDA Responder Endpoint for clinical trials in irritable bowel syndrome with constipation was evaluated using data from two large Phase III clinical trials of linaclotide. The FDA interim endpoints are clinically relevant as they are also able to capture the smallest patient-reported difference in the domain of Abdominal Pain intensity and Abnormal Defecation with good diagnostic accuracy. The FDA responder definition and the European Medicines Agency responder definitions generate similar response rates, while binary endpoints generate higher responder rates. The implications for optimalization and harmonisation are discussed. PMID- 23672676 TI - Nanolayered siRNA dressing for sustained localized knockdown. AB - The success of RNA interference (RNAi) in medicine relies on the development of technology capable of successfully delivering it to tissues of interest. Significant research has focused on the difficult task of systemic delivery of RNAi; however its local delivery could be a more easily realized approach. Localized delivery is of particular interest for many medical applications, including the treatment of localized diseases, the modulation of cellular response to implants or tissue engineering constructs, and the management of wound healing and regenerative medicine. In this work we present an ultrathin electrostatically assembled coating for localized and sustained delivery of short interfering RNA (siRNA). This film was applied to a commercially available woven nylon dressing commonly used for surgical applications and was demonstrated to sustain significant knockdown of protein expression in multiple cell types for more than one week in vitro. Significantly, this coating can be easily applied to a medically relevant device and requires no externally delivered transfection agents for effective delivery of siRNA. These results present promising opportunities for the localized administration of RNAi. PMID- 23672678 TI - Accuracy of 18F-FDG PET/CT for primary tumor visualization and staging in T1 breast cancer. AB - BACKGROUND: The aim of this study was to assess the accuracy of 18F-FDG PET/CT in T1 breast cancer regarding visualization of the primary tumor and the detection of locoregional and distant metastases. METHODS: Sixty-two women with invasive T1 breast cancer underwent a PET/CT. Image acquisition of the thorax was done in prone position with hanging breasts, followed by whole-body scanning in supine position. Primary tumor FDG uptake was evaluated and compared with clinical and histopathological characteristics. Presence of locoregional and distant metastases was assessed and compared with conventional imaging procedures. RESULTS: The primary tumor was visible with PET/CT in 54 (87%) of 62 patients, increasing from 59% (10/17) in tumors <= 10 mm to 98% (44/45) in tumors over 10 mm. All triple negative and HER2-positive tumors and 40/48 (83%) ER-positive/HER2 negative tumors were visualized. Sensitivity and specificity of PET/CT in the detection of axillary metastases were 73% and 100%, respectively. PET/CT depicted periclavicular nodes in two patients. Of 12 distant lesions, one was confirmed to be a lung metastasis, three were false positive, and eight were new primary proliferative lesions. CONCLUSION: Using optimal imaging acquisition, the majority of T1 breast carcinomas can be visualized with PET/CT. Specificity in the detection of axillary metastases is excellent, but sensitivity appears to be limited. Additional whole body imaging has a low yield in this specific patient group. PMID- 23672679 TI - Fe(3-x)Ti(x)O4 nanoparticles as tunable probes of microbial metal oxidation. AB - Present and emerging biotechnological applications for iron (oxyhydr)oxide nanomaterials depend on their interaction with microorganisms, as do their toxicity, transport, and fate in biological and environmental systems. However, mass or electron transfer along key molecular pathways at microbe-nanomaterial interfaces is extremely difficult to quantify because of system complexity. Inspired by Fe(II)-oxidizing microbes widespread in nature, we isolate and characterize one such pathway by examining the oxidation of Fe(3-x)Ti(x)O4 (magnetite-titanomagnetite) nanoparticles by the bacterial electron transfer enzyme MtoA, a decaheme c-type cytochrome. Oxidation by MtoA was studied as a function of the thermodynamic driving force for electron transfer by controlling the Ti(IV) doping content (x), which tunes the solid-state Fe(II)/Fe(III) ratio built into the nanoparticles. A higher Fe(II)/Fe(III) ratio appears to systematically increase the electron transfer kinetics to the cytochrome. In situ X-ray diffraction indicated that, during oxidation, the spinel ferrite lattice remains intact while structural Fe(II) is progressively depleted. Surface and atomic site specific Fe L(2,3)-edge X-ray magnetic circular dichroism indicated that MtoA directly accesses magnetically ordered B-sublattice Fe(II) at the interface. This study provides the first quantitative insights into an isolated molecular pathway for biotransformation of iron (oxyhydr)oxide nanomaterials, and more generally, it also illustrates new techniques for probing these pathways in detail, featuring use of tailored nanoparticles, purified metalloenzyme, and synchrotron X-ray absorption spectroscopies. PMID- 23672680 TI - Defining the diversity of phenotypic respecification using multiple cell lines and reprogramming regimens. AB - To better understand the basis of variation in cellular reprogramming, we performed experiments with two primary objectives: first, to determine the degree of difference, if any, in reprogramming efficiency among cells lines of a similar type after accounting for technical variables, and second, to compare the efficiency of conversion of multiple similar cell lines to two separate reprogramming regimens-induced neurons and induced skeletal muscle. Using two reprogramming regimens, it could be determined whether converted cells are likely derived from a distinct subpopulation that is generally susceptible to reprogramming or are derived from cells with an independent capacity for respecification to a given phenotype. Our results indicated that when technical components of the reprogramming regimen were accounted for, reprogramming efficiency was reproducible within a given primary fibroblast line but varied dramatically between lines. The disparity in reprogramming efficiency between lines was of sufficient magnitude to account for some discrepancies in published results. We also found that the efficiency of conversion to one phenotype was not predictive of reprogramming to the alternate phenotype, suggesting that the capacity for reprogramming does not arise from a specific subpopulation with a generally "weak grip" on cellular identity. Our findings suggest that parallel testing of multiple cell lines from several sources may be needed to accurately assess the efficiency of direct reprogramming procedures, and that testing a larger number of fibroblast lines--even lines with similar origins--is likely the most direct means of improving reprogramming efficiency. PMID- 23672682 TI - Incidence of Leptospirosis infection in the East Zone of Sao Paulo City, Brazil. AB - BACKGROUND: Leptospirosis is a zoonosis which is spread through contamined running water. This contaminations is seriously affected by the flooding which occurs in the area surrounding the Aricanduva river. The transmission of the disease results mainly from the contact of water with soil contaminated by the urine of infected animals. We aimed to conduct an epidemiological survey on Leptospirosis cases in Sao Paulo East Zone area. METHOD: The analysis conducted in this study was based on data collected from the health authorities of that region close the Aricanduva river between 2007 and 2008 years, which give the rates of confirmed cases, mortality and death from human Leptospirosis. Other information concerned with the relationships among rainfall index, points of flooding and incidence of Leptospirosis. RESULTS: We observed a direct and important water contamination. Records of flooding points and dates of the reported cases in the region showed a direct relationship from which the period of higher rainfall also recorded an increase in cases. The annual record of the city and the region and rainfall regions also presented correlation. CONCLUSION: The association between the indices of flooding and Leptospirosis cases indicates that preventive measures are necessary to avoid exposing the community. PMID- 23672683 TI - Mesoporous silica coating on carbon nanotubes: layer-by-layer method. AB - It is of great interest to develop a simple, general, and easy-handling procedure for mesoporous silica coating. A facile, single-step method to coat iron oxide nanoparticles has been reported by Hyeon's group. However, up to present, this method only successfully applied to those zero-dimensional nanostructures heavily capped by cetyltrimethyl ammonium bromide (CTAB); no others are reported. It is unknown how this simple method is feasible in coating those nanostructures not capped by CTAB. Herein, using carbon nanotubes (CNTs) as the model, through an analogous layer-by-layer assembly method, many more CTAB molecules were found to anchor to CNTs, on which uniform mesoporous silica shells can successfully be formed by Hyeon's coating method. We believe that this contribution will pave the way for advancing the single-step method to become a general protocol in the mesoporous silica coating field. PMID- 23672684 TI - Estimation of permanent noise-induced hearing loss in an urban setting. AB - The potential burden of noise-induced permanent threshold shift (NIPTS) in U.S. urban settings is not well-characterized. We used ANSI S3.44-1996 to estimate NIPTS for a sample of 4585 individuals from New York City (NYC) and performed a forward stepwise logistic regression analysis to identify predictors of NIPTS >10 dB. The average individual is projected to develop a small NIPTS when averaged across 1000-4000 Hz for 1- to 20-year durations. For some individuals, NIPTS is expected to be substantial (>25 dB). At 4000 Hz, a greater number of individuals are at risk of NIPTS from MP3 players and stereos, but risk for the greatest NIPTS is for those with high occupational and episodic nonoccupational (e.g., power tool use) exposures. Employment sector and time spent listening to MP3 players and stereos and participating in episodic nonoccupational activities associated with excessive noise levels increased the odds of NIPTS >10 dB at 4000 Hz for 20-year durations. Our results indicate that the risk of NIPTS may be substantial for NYC and perhaps other urban settings. Noise exposures from "noisy" occupational and episodic nonoccupational activities and MP3 players and stereos are important risk factors and should be a priority for public health interventions. PMID- 23672685 TI - Diurnal variation of phenylalanine and tyrosine concentrations in adult patients with phenylketonuria: subcutaneous microdialysis is no adequate tool for the determination of amino acid concentrations. AB - BACKGROUND: Metabolic control and dietary management of patients with phenylketonuria (PKU) are based on single blood samples obtained at variable intervals. Sampling conditions are often not well-specified and intermittent variation of phenylalanine concentrations between two measurements remains unknown. We determined phenylalanine and tyrosine concentrations in blood over 24 hours. Additionally, the impact of food intake and physical exercise on phenylalanine and tyrosine concentrations was examined. Subcutaneous microdialysis was evaluated as a tool for monitoring phenylalanine and tyrosine concentrations in PKU patients. METHODS: Phenylalanine and tyrosine concentrations of eight adult patients with PKU were determined at 60 minute intervals in serum, dried blood and subcutaneous microdialysate and additionally every 30 minutes postprandially in subcutaneous microdialysate. During the study period of 24 hours individually tailored meals with defined phenylalanine and tyrosine contents were served at fixed times and 20 min bicycle-ergometry was performed. RESULTS: Serum phenylalanine concentrations showed only minor variations while tyrosine concentrations varied significantly more over the 24 hour period. Food intake within the patients' individual diet had no consistent effect on the mean phenylalanine concentration but the tyrosine concentration increased up to 300% individually. Mean phenylalanine concentration remained stable after short-term bicycle-exercise whereas mean tyrosine concentration declined significantly. Phenylalanine and tyrosine concentrations in dried blood were significantly lower than serum concentrations. No close correlation has been found between serum and microdialysis fluid for phenylalanine and tyrosine concentrations. CONCLUSIONS: Slight diurnal variation of phenylalanine concentrations in serum implicates that a single blood sample does reliably reflect the metabolic control in this group of adult patients. Phenylalanine concentrations determined by subcutaneous microdialysis do not correlate with the patients' phenylalanine concentrations in serum/blood. PMID- 23672686 TI - Genomic analysis reveals MATH gene(s) as candidate(s) for Plum pox virus (PPV) resistance in apricot (Prunus armeniaca L.). AB - Sharka disease, caused by Plum pox virus (PPV), is the most important viral disease affecting Prunus species. A major PPV resistance locus (PPVres) has been mapped to the upper part of apricot (Prunus armeniaca) linkage group 1. In this study, a physical map of the PPVres locus in the PPV-resistant cultivar 'Goldrich' was constructed. Bacterial artificial chromosome (BAC) clones belonging to the resistant haplotype contig were sequenced using 454/GS-FLX Titanium technology. Concurrently, the whole genome of seven apricot varieties (three PPV-resistant and four PPV-susceptible) and two PPV-susceptible apricot relatives (P. sibirica var. davidiana and P. mume) were obtained using the Illumina-HiSeq2000 platform. Single nucleotide polymorphisms (SNPs) within the mapped interval, recorded from alignments against the peach genome, allowed us to narrow down the PPVres locus to a region of ~196 kb. Searches for polymorphisms linked in coupling with the resistance led to the identification of 68 variants within 23 predicted transcripts according to peach genome annotation. Candidate resistance genes were ranked combining data from variant calling and predicted functions inferred from sequence homology. Together, the results suggest that members of a cluster of meprin and TRAF-C homology domain (MATHd)-containing proteins are the most likely candidate genes for PPV resistance in apricot. Interestingly, MATHd proteins are hypothesized to control long-distance movement (LDM) of potyviruses in Arabidopsis, and restriction for LDM is also a major component of PPV resistance in apricot. Although the PPV resistance gene(s) remains to be unambiguously identified, these results pave the way to the determination of the underlying mechanism and to the development of more accurate breeding strategies. PMID- 23672687 TI - Inhibitory effects of epigenetic modulators and differentiation inducers on human medulloblastoma cell lines. AB - BACKGROUND: Medulloblastoma (MB) is the most common malignant brain tumor in childhood with a 5-year survival of approximately 60%. We have recently shown that treatment of human MB cells with 5-aza-2'-deoxycytidine (5-aza-dC) reduces the clonogenic survival significantly. Here, we tested combinatorial effects of 5 aza-dC with other epigenetic (valproic acid, SAHA) and differentiation-inducing drugs (resveratrol, abacavir, retinoic acid) on human MB cells in vitro to intensify the antitumor therapy further. METHODS: Three human MB cell lines were treated with 5-aza-dC alone or in combination for three or six days. Metabolic activity was measured by WST-1 assay. To determine long-term reproductive survival, clonogenic assays were performed. Induction of DNA double-strand break (DSB) repair was measured by gammaH2AX assay. RESULTS: The applied single drugs, except for ATRA, reduced the metabolic activity dose-dependently in all MB cell lines. Longer treatment times enhanced the reduction of metabolic activity by 5 aza-dC. Combinatorial treatments showed differential, cell line-dependent responses indicating an important impact of the genetic background. 5-Aza-dC together with resveratrol was found to exert the most significant inhibitory effects on metabolic activity in all cell lines. 5-aza-dC alone reduced the clonogenicity of MB cells significantly and induced DSB with no further changes after adjuvant administration of resveratrol. CONCLUSION: The observed significant decrease in metabolic activity by combinatorial treatment of MB cells with 5-aza-dC and resveratrol does not translate into long-term reproductive survival deficiency in vitro. Further studies in animal models are needed to clarify the resveratrol-mediated anticancer mechanisms in vivo. PMID- 23672689 TI - Sexual size dimorphism in ground squirrels (Rodentia: Sciuridae: Marmotini) does not correlate with body size and sociality. AB - INTRODUCTION: Sexual size dimorphism (SSD) is a widespread phenomenon in animals including mammals. It has been demonstrated that across species, the direction and magnitude of sexual dimorphism in body size often corresponds to social systems. Moreover, many animal lineages conform to "Rensch's rule", which states that male-biased SSD increases with body size. We tested whether considerable differences in sociality and large variation in body size were connected with the evolution of SSD in the structural body size of ground squirrels, an otherwise ecologically relatively homogenous group of terrestrial rodents. RESULTS: We found the general trend of male-biased SSD in ground squirrels, however, male size increases nearly perfectly isometrically with female size among species and sociality does not explain departures from this relationship. Species with different sociality grades significantly differ in body size, with the most social species tending to be the largest. CONCLUSIONS: We suggest that lack of conformity with Rensch's rule in ground squirrels may be attributed to their low variation in SSD, and briefly discuss three potential causes of small magnitude of SSD in the structural size in rodents: low selection on SSD in structural dimensions, ontogenetic and genetic constraints and the existence of ecological/selection factors preventing the evolution of extensive SSD. PMID- 23672688 TI - Clinical review: practical approach to hyponatraemia and hypernatraemia in critically ill patients. AB - Disturbances in sodium concentration are common in the critically ill patient and associated with increased mortality. The key principle in treatment and prevention is that plasma [Na+] (P-[Na+]) is determined by external water and cation balances. P-[Na+] determines plasma tonicity. An important exception is hyperglycaemia, where P-[Na+] may be reduced despite plasma hypertonicity. The patient is first treated to secure airway, breathing and circulation to diminish secondary organ damage. Symptoms are critical when handling a patient with hyponatraemia. Severe symptoms are treated with 2 ml/kg 3% NaCl bolus infusions irrespective of the supposed duration of hyponatraemia. The goal is to reduce cerebral symptoms. The bolus therapy ensures an immediate and controllable rise in P-[Na+]. A maximum of three boluses are given (increases P-[Na+] about 6 mmol/l). In all patients with hyponatraemia, correction above 10 mmol/l/day must be avoided to reduce the risk of osmotic demyelination. Practical measures for handling a rapid rise in P-[Na+] are discussed. The risk of overcorrection is associated with the mechanisms that cause hyponatraemia. Traditional classifications according to volume status are notoriously difficult to handle in clinical practice. Moreover, multiple combined mechanisms are common. More than one mechanism must therefore be considered for safe and lasting correction. Hypernatraemia is less common than hyponatraemia, but implies that the patient is more ill and has a worse prognosis. A practical approach includes treatment of the underlying diseases and restoration of the distorted water and salt balances. Multiple combined mechanisms are common and must be searched for. Importantly, hypernatraemia is not only a matter of water deficit, and treatment of the critically ill patient with an accumulated fluid balance of 20 litres and corresponding weight gain should not comprise more water, but measures to invoke a negative cation balance. Reduction of hypernatraemia/hypertonicity is critical, but should not exceed 12 mmol/l/day in order to reduce the risk of rebounding brain oedema. PMID- 23672692 TI - Interplay between 1,3-butadien-1,4-diyl and 2-buten-1,4-dicarbene derivatives: the quest for nucleophilic carbenes. AB - By means of high level quantum chemical calculations, the influence of electron donating heteroatomic groups (O, NH) was investigated on the 1,6-transannular ring closure of 1,6-cyclodecadiyne (8a). In the case of 8a, the bicyclo[4.4.0]deca-1,6-dien-2,7-diyl biradical 12 is generated. It was found that oxygen centers or NH groups next to the triple bond reduce the activation energy of the ring closure considerably. For the intermediate, a 2-buten-1,4-dicarbene derivative is predicted. The extension of the model calculations to two hydroxyl- or aminoacetylenes predicts the formation of the corresponding 1,3-butadien-1,4 diyl intermediates or the 2-buten-1,4-dicarbene derivatives, a member of the nucleophilic carbene family. Moreover, the calculations predict that two separated dimethoxyacetylenes are more than 7 kcal/mol less stable than the corresponding biradical and dicarbene, respectively. Possible reactions of the dicarbenes with transition metal compounds are discussed. PMID- 23672691 TI - Validation of the Spanish version of the Borderline Symptom List, short form (BSL 23). AB - BACKGROUND: The Borderline Symptom List-23 (BSL-23) is a reliable and valid self report instrument for assessing Borderline Personality Disorder (BPD) severity. The psychometric properties of the original version have proven to be adequate. The aim of the present study was to validate the Spanish language version of the BSL-23. METHODS: The BSL-23 was administered to 240 subjects with BPD diagnosis. Factor structure, reliability, test-retest stability, convergent validity, and sensitivity to change were analyzed. RESULTS: The Spanish version of the BSL-23 replicates the one-factor structure of the original version. The scale has high reliability (Cronbach's alpha=.949), as well as good test-retest stability, which was checked in a subsample (n=74; r=.734; p<.01). The Spanish BSL-23 shows moderate to high correlations with depressive symptomatology, state and trait anxiety, hostility and impulsivity scores and BPD measures. The Spanish BSL-23 is able to discriminate among different levels of BPD severity and shows satisfactory sensitivity to change after treatment, which was verified by assessing change before and after 12 group sessions of Dialectical Behavioral Therapy in a subgroup of 31 subjects. CONCLUSIONS: Similar to the original BSL 23, the Spanish BSL-23 is a reliable and valid instrument for assessing BPD severity and sensitivity to change. PMID- 23672690 TI - Contributions of academic laboratories to the discovery and development of chemical biology tools. AB - The academic setting provides an environment that may foster success in the discovery of certain types of small molecule tools while proving less suitable in others. For example, small molecule probes for poorly understood systems, those that exploit a specific resident expertise, and those whose commercial return is not apparent are ideally suited to be pursued in a university setting. In this review, we highlight five projects that emanated from academic research groups and generated valuable tool compounds that have been used to interrogate biological phenomena: reactive oxygen species (ROS) sensors, GPR30 agonists and antagonists, selective CB2 agonists, Hsp70 modulators, and beta-amyloid PET imaging agents. By taking advantage of the unique expertise resident in university settings and the ability to pursue novel projects that may have great scientific value but with limited or no immediate commercial value, probes from academic research groups continue to provide useful tools and generate a long term resource for biomedical researchers. PMID- 23672693 TI - Expression profiling: a cost-effective biomarker discovery tool for the personal genome era. PMID- 23672695 TI - Editorial for issue 2 of 2011, Journal of Evidence Based Medicine. PMID- 23672694 TI - Primary cutaneous CD4 positive small/medium T-cell lymphoma with high proliferation index and CD30-positive large lymphoid cells. AB - Primary cutaneous CD4 positive small/medium pleomorphic T-cell lymphoma (SMPTCL) represents a provisional subtype of primary cutaneous T-cell lymphoma with indolent clinical course. A few aggressive fatal cases with increased proliferation rate and few infiltrating CD8 positive T-cells have been reported. We describe a case of SMPTCL with an increased proliferation rate, admixed CD30 positive large lymphoid cells, and few infiltrating CD8 positive T-cells. The lymphoma cells were positive for CD3, CD4, CD2 and CD5, and negative for CD8. A subset of the lymphoma cells was positive for follicular helper T-cell markers bcl-6 and PD-1. There were approximately 20% CD30-positive large lymphoid cells, and Ki-67 showed a moderately high proliferation rate (~40%), mostly in the large lymphoid cells. CD8 infiltrating T-cells were few (<5%). The patient had an indolent disease with complete response to radiation therapy. To the best of our knowledge, this is the first reported case of SMPTCL with an increased proliferation rate and large CD30+ cells that followed an indolent clinical course. PMID- 23672696 TI - Use of a systems approach and evidence-based One Health for zoonoses research. AB - The World Health Organization estimates that 25% of the 57 million annual deaths that occur globally are caused by microbes. A study reported 1415 species of infectious organisms are known to be pathogenic to humans. Zoonoses constitute 61% of all known infectious diseases, with humans serving as the primary reservoir for only 3% of them. Of the 175 infectious species considered to be emerging, 75% are zoonotic. Zoonotic diseases and their impact on human and animal health are not monitored, prevented, and treated in an integrated way, despite the fact that etiologies and treatments are similar across species. The efficacy and resistance of a drug in one species has a bearing on others, in the context of zoonoses. Further, an RCT involving many species is effective in a natural setting, is robust, and may require fewer human volunteers. One Health is based on a systems approach and a collaborative effort of multiple disciplines - working locally, nationally, and globally - to attain optimal health for people, animals, and the environment. Systematic reviews and meta-analyses have so far been independent and discipline oriented. Pooling of results for diagnostic test accuracies and treatment effects of drugs for zoonoses across species has to be done, since the results of preclinical trials emanate from laboratory animals. The Cochrane Collaboration is the platform of choice to initiate a new group on zoonoses to carry out systematic meta-analyses of diagnostic tests and drug efficacies without bias, thus underpinning the systems approach and One Health. PMID- 23672697 TI - Patient safety research in China: a literature review. AB - OBJECTIVE: A number of articles on patient safety have been published in Chinese language journals in last decade. However, until now there have been no studies of their overall quality or contribution to current thinking. This study explored the themes and designs of studies on patient safety published in Chinese-language journals. METHOD: We searched the major Chinese databases, Chinese Biomedical Literature Database (CBM) and Chinese Journals Full-text Database (CNKI), for Chinese-language patient safety research papers published between January 2001 and December 2010. We analyzed the articles' publication years, research themes, author affiliations, and research methodologies. Quality and statistical methods were only appraised based on study design type. RESULTS: In the decade studied, a total of 6,336 articles were included. 2008 saw the greatest number of patient safety articles published in China (865). There were 11 journals which each published at least 55 relevant articles over 10 years. The most popular topic of patient safety studies was nosocomial infection (5,182/81.79%). Non-comparative studies accounted for the majority of the literature (4,390/ 69.3%); of these, most were case series (4,080/92.94%). Comparative studies accounted for only 2.6% of the studies found (167). Most of the first authors of included articles worked at hospitals (5,193), many in nursing departments (2,044). CONCLUSIONS: There was no change trend in the number of articles on patient safety research published in Chinese in the past 10 years. Most articles described non-comparative studies, which lack rigorous designs. More methodologically rigorous designs are needed to improve the overall quality of patient safety research in China. PMID- 23672698 TI - Visualization studies on evidence-based medicine domain knowledge (series 1): mapping of evidence-based medicine research subjects. AB - OBJECTIVE: To use visualization methods to illustrate and compare major subjects, domains, and developments in evidence-based medicine (EBM) in recent years. METHOD: We analyzed MeSH terms and keywords in EBM articles in the MEDLINE and CNKI databases, and developed subject charts, research field relationship charts, and strategy coordination charts using word co-occurrence, PFNET algorithms, and visualization methods. RESULT: Rapid developments and growth are taking place in EBM in China and around the world. Studies on humans comprised 94.4% of the EBM studies that we identified, while animal studies accounted for 2.6% (three quarters of these animal studies were on primates). The six countries with the largest number of EBM articles and the eight host nations for the 108 journals with the most EBM publications were from high-income countries. In China, 31 provinces, municipalities, and autonomous regions have published EBM articles, although most of these publications come from the more highly-developed areas of the country. The investigation of word co-occurrence showed that EBM articles outside of China involve seven main fields: "Therapy", "Methods", "Standards", "Research", "Education", "Nursing" and "Organization and Administration". Five of these fields ("Therapy", "Nursing", "Research", "Education" and "Management") were common to China but the top seven fields for this country included "Traditional Chinese Medicine (TCM)" and "Information resources"; and did not include "Methods" and "Standards". Furthermore, studies on "Nursing" and "Research" were not as advanced in China as in other countries. CONCLUSION: There are similarities between China and the rest of the world in several areas in the EBM literature but also some important differences. Throughout the world, the most resource-rich regions o organizations tend to have the most well-developed EBM. These regions and organizations are pdocuing more evidence and conducting more methodology research than the less resourced regions and organizations. There is an urgent need for these regions and organizations to strengthen their use of evidence, to learn more about the philosophy that underpins EBM, and to improve accessibility to, and use of, evidence in choices about health care. PMID- 23672699 TI - Visualization studies on evidence-based medicine domain knowledge (series 2): structural diagrams of author networks. AB - OBJECTIVE: To investigate the output of evidence-based medicine (EBM) researchers in China and elsewhere by examining the EBM domains they work within and the networks that exist among them; using visualization methods to analyze these relationships. This maps the current situation and helps with the identification of areas for future growth. METHODS: We used co-citation matrixes with Pathfinder networks and hierarchical clustering algorithms, and constructed a co-author matrix which were analyzed with a whole network approach. The analyzed matrixes were visualized with the UCINET program. RESULTS: Much of the development of EBM has been centered around three authors, David Sackett, Gordon Guyatt and L Manchikanti, within three different clusters. The main authors of EBM articles in China were divided into nine academic domains. The relations among core authors of articles indexed by the Science Citation Index (SCI) was loose. There was a stronger co-authorship network among core authors in the Chinese literature, with three groups and 21 cliques. Nine distinct academic communities appeared to have formed around Li Youping, Liu Ming and Zhang Mingming. CONCLUSION: The EBM literature contains several key clusters, with universities in high-income countries being the source of the majority of articles. Outside China, McMaster University in Canada, the original home of EBM, is the dominant producer of EBM publications. In China, Sichuan University is the main source of EBM publications. The EBM cooperation network in China is comprised of three major groups, the largest and most productive in this sample is led by Li Youping with Liu Ming, Zhang Mingming, Li Jing, Wang Li, Wu Taixiang, and Liu Guanjian as central members. PMID- 23672700 TI - Visualization studies on evidence-based medicine domain knowledge (series 3): visualization for dissemination of evidence based medicine information. AB - PURPOSE: To identify patterns in information sharing between a series of Chinese evidence based medicine (EBM) journals and the Cochrane Database of Systematic Reviews, to determine key evidence dissemination areas for EBM and to provide a scientific basis for improving the dissemination of EBM research. METHOD: Data were collected on citing and cited from the Chinese Journal of Evidence-Based Medicine (CJEBM), Journal of Evidence-Based Medicine (JEBMc), Chinese Journal of Evidence Based Pediatrics (CJEBP), and the Cochrane Database of Systematic Reviews (CDSR). Relationships between citations were visualized. High-frequency key words from these sources were identified, to build a word co-occurrence matrix and to map research subjects. RESULT: CDSR contains a large collection of information of relevance to EBM and its contents are widely cited across many journals, suggesting a well-developed citation environment. The content and citation of the Chinese journals have been increasing in recent years. However, their citation environments are much less developed, and there is a wide variation in the breadth and strength of their knowledge communication, with the ranking from highest to lowest being CJEBM, JEBMc and CJEBP. The content of CDSR is almost exclusively Cochrane intervention reviews examining the effects of healthcare interventions, so it's contribution to EBM is mostly in disease control and treatment. On the other hand, the Chinese journals on evidence-based medicine and practice focused more on areas such as education and research, design and quality of clinical trials, evidence based policymaking, evidence based clinical practice, tumor treatment, and pediatrics. CONCLUSION: Knowledge and findings of EBM are widely communicated and disseminated. However, citation environments and range of knowledge communication differ greatly between the journals examined in this study. This finds that Chinese EBM has focused mainly on clinical medicine, Traditional Chinese Medicine, pediatrics, tumor treatment, nursing, health economic and management, and medical education. Internationally, EBM research topics have begun to shift, from drug treatment to surgery or other non-pharmacological treatments; from therapy to diagnosis, rehabilitation, and prevention; from evidence based clinical practice to evidence based management and policymaking. The philosophy and method of EBM, evidence production and translation are also shifting from well resourced settings to low- and middle income countries, especially those in which English is not a major language. PMID- 23672701 TI - The effect of MICA antigens on transplant outcomes: a systematic review. AB - BACKGROUND AND OBJECTIVE: Human major histocompatibility complex class I-related gene A (MICA) is reportedly associated with poor transplant outcomes and a high risk of acute and chronic rejection in solid organ transplantation. However, studies on these risks have found conflicting results. In order to identify areas in which additional research is needed, we have undertaken the first systematic review of evidence concerning the risk of anti-MICA antibodies in recipients' sera. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Library for original reports of clinical studies involving detection of MICA abs in transplant recipients' sera which used survival rate, acute rejection, and/or chronic rejection as outcome measures. RevMan 5.0.15 was used to calculate relative risk (RR), odds ratios (ORs), and 95% confidence intervals (95%CIs). RESULTS: We found 18 relevant articles, with a total of 6,607 recipients. Follow-up duration ranged from 1 to 15 years. In studies with more than 2 years of follow-up, anti-MICA abs positive in kidney recipients' post-transplant sera was associated with a lower graft survival rate (4 years: RR = 2.04, 95%CI 1.30 to 3.22; 3 years: OR = 3.56, 95%CI 1.47 to 8.62; 2 years: RR = 2.17, 95%CI 1.09 to 4.31) and a higher acute rejection rate (RR = 1.92, 95%CI 1.27 to 2.91), but there was no clear association with chronic rejection. Similar conclusions could not be drawn for heart or liver transplantation due to possible confounding by anti-HLA abs and the small sample sizes of the available studies. CONCLUSION: Anti-MICA antibodies in recipients' sera may associated with poor graft survival rates and high risk of acute and chronic rejection in solid organ transplantation, but more rigorous studies are needed to confirm or refute this relationship. Current immunosuppressive therapy may fail to suppress the harmful effect of MICA antigens. PMID- 23672703 TI - Ethical issues in preparing and publishing systematic reviews. PMID- 23672702 TI - Preventive effects of Mycobacterium vaccae on HIV-associated tuberculosis: a systematic review. AB - OBJECTIVE: To evaluate the effectiveness and safety of Mycobacterium vaccae (M.vaccae, MV) for prevention of HIV-associated tuberculosis (TB). METHODS: MEDLINE, Embase, Biosis, the Cochrane Central Register of Controlled Trials, SCI, CBM, VIP, and CNKI were searched for relevant randomized controlled trials (RCTs) and non-randomized controlled trials (NRCTs). The GRADE approach was used for quality assessment. Data were analyzed using RevMan 5.0 software. RESULTS: were described or pooled using relative risks (RRs) for binary outcomes with 95% confidence intervals (CIs). Results Seven studies were included, and the methodological quality assessment found there was a risk of methodological bias. The evidence quality of the critical endpoint was moderate. The incidence of definite TB was (33/1006 vs. 52/1007, P = 0.03). The levels of IFN-gamma response to M. vaccae sonicate (MVS) in MV recipients increased compared to baseline or control groups after three or five doses. MV recipients' level of lymphocyte proliferation assays (LPAs) in response to MVS was higher than that of the saline group after a five-dose series (RR = 2.49, 95% CI 1.40 to 4.41, P = 0.002). Compared to hepatitis B vaccine (HBV) recipients, LPAs to MVS were not significantly different in the MV group vs. saline group, or vs. HBV, after a three-dose series (RR and 95% CI were 0.20 (-0.03 to 0.44) and 1.13 (0.26 to 4.91), respectively). Changes in CD4+ cell count and HIV viral load after immunization were not statistically significant. MV immunization had no systematic adverse effects. CONCLUSION: The current evidence indicates that MV is safe and well-tolerated. It appears to prevent HIV-infected patients with CD4+>= 200/mm(3) from contracting TB by enhancing their immunogenicity. Yet, because of the relatively low quality of the available evidence, well-designed and conducted RCTs are needed. PMID- 23672704 TI - Conducting a systematic review: finding the evidence. PMID- 23672708 TI - Education section--information for participants in randomised trials. PMID- 23672710 TI - Appropriateness of blood product transfusion in the Obstetrics and Gynaecology (O&G) department of a tertiary hospital in West Africa. AB - BACKGROUND: Misuse of blood by clinicians was suggested to explain blood shortage in sub-Saharan Africa although based on little evidence. This study evaluated whether routine halving (restricted) of blood requests was justified. STUDY DESIGN AND METHODS: On alternated days for 3 months in 2011-2012, restricted or full blood product supply [whole blood (WB), red cell concentrate (RCC)] was provided to the Obstetrics & Gynaecology department (O&G). Patient age, haemoglobin (Hb) level pre- and post-transfusion, clinical condition, blood products request and supply, transfused and returned, clinical outcome were collated. RESULTS: Five hundred and nineteen patients (249 restricted and 270 full supply) received 1001 blood products (94.6% WB, 6.4% RCC). Clinical conditions were severe peri-partum bleeding (72.4%) requiring emergency transfusion (82%) whilst 27.6% of total transfusion was for anaemia, 18% being moderate (8-10 g dL(-1) ). Pre-transfusion Hb level was <6 g dL(-1) in 36.7%, 6-8 g dL(-1) 29.1% and >= 8 g dL(-1) in 33.2% of cases. Fifty-five percent of the transfused blood was stored <= 1 week. Restricted supply triggered additional request (40%) compared to 10% in full supply mode. Whether with restricted or full supply, blood requests, supply and units transfused/patient were similar (restricted 2.3 and 2.1 unit patient(-1) and full 2.9 and 2.3 unit patient(-1) , respectively). Fatal clinical outcome was 3.1% evenly distributed between supply modes and transfusion reactions 0.8%. CONCLUSIONS: O&G clinicians order blood according to clinical need and transfuse 85% of the products supplied. Product supply did not significantly affect use although appropriateness of transfusion was difficult to assess. PMID- 23672711 TI - Effects of functionalization on thermal properties of single-wall and multi-wall carbon nanotube-polymer nanocomposites. AB - Carboxylic functionalization (-COOH groups) of carbon nanotubes is known to improve their dispersion properties and increase the electrical conductivity of carbon-nanotube-polymer nanocomposites. We have studied experimentally the effects of this type of functionalization on the thermal conductivity of the nanocomposites. It was found that while even small quantities of carbon nanotubes (~1 wt %) can increase the electrical conductivity, a larger loading fraction (~3 wt %) is required to enhance the thermal conductivity of nanocomposites. Functionalized multi-wall carbon nanotubes performed the best as filler material leading to a simultaneous improvement of the electrical and thermal properties of the composites. Functionalization of the single-wall carbon nanotubes reduced the thermal conductivity enhancement. The observed trends were explained by the fact that while surface functionalization increases the coupling between carbon nanotube and polymer matrix, it also leads to formation of defects, which impede the acoustic phonon transport in the single-wall carbon nanotubes. The obtained results are important for applications of carbon nanotubes and graphene flakes as fillers for improving thermal, electrical and mechanical properties of composites. PMID- 23672712 TI - Estimating unknown parameters in haemophilia using expert judgement elicitation. AB - The increasing attention to healthcare costs and treatment efficiency has led to an increasing demand for quantitative data concerning patient and treatment characteristics in haemophilia. However, most of these data are difficult to obtain. The aim of this study was to use expert judgement elicitation (EJE) to estimate currently unavailable key parameters for treatment models in severe haemophilia A. Using a formal expert elicitation procedure, 19 international experts provided information on (i) natural bleeding frequency according to age and onset of bleeding, (ii) treatment of bleeds, (iii) time needed to control bleeding after starting secondary prophylaxis, (iv) dose requirements for secondary prophylaxis according to onset of bleeding, and (v) life-expectancy. For each parameter experts provided their quantitative estimates (median, P10, P90), which were combined using a graphical method. In addition, information was obtained concerning key decision parameters of haemophilia treatment. There was most agreement between experts regarding bleeding frequencies for patients treated on demand with an average onset of joint bleeding (1.7 years): median 12 joint bleeds per year (95% confidence interval 0.9-36) for patients <= 18, and 11 (0.8-61) for adult patients. Less agreement was observed concerning estimated effective dose for secondary prophylaxis in adults: median 2000 IU every other day The majority (63%) of experts expected that a single minor joint bleed could cause irreversible damage, and would accept up to three minor joint bleeds or one trauma related joint bleed annually on prophylaxis. Expert judgement elicitation allowed structured capturing of quantitative expert estimates. It generated novel data to be used in computer modelling, clinical care, and trial design. PMID- 23672709 TI - Three-dimensional scaffolds for tissue engineering applications: role of porosity and pore size. AB - Tissue engineering applications commonly encompass the use of three-dimensional (3D) scaffolds to provide a suitable microenvironment for the incorporation of cells or growth factors to regenerate damaged tissues or organs. These scaffolds serve to mimic the actual in vivo microenvironment where cells interact and behave according to the mechanical cues obtained from the surrounding 3D environment. Hence, the material properties of the scaffolds are vital in determining cellular response and fate. These 3D scaffolds are generally highly porous with interconnected pore networks to facilitate nutrient and oxygen diffusion and waste removal. This review focuses on the various fabrication techniques (e.g., conventional and rapid prototyping methods) that have been employed to fabricate 3D scaffolds of different pore sizes and porosity. The different pore size and porosity measurement methods will also be discussed. Scaffolds with graded porosity have also been studied for their ability to better represent the actual in vivo situation where cells are exposed to layers of different tissues with varying properties. In addition, the ability of pore size and porosity of scaffolds to direct cellular responses and alter the mechanical properties of scaffolds will be reviewed, followed by a look at nature's own scaffold, the extracellular matrix. Overall, the limitations of current scaffold fabrication approaches for tissue engineering applications and some novel and promising alternatives will be highlighted. PMID- 23672713 TI - The solution structures of two prophage homologues of the bacteriophage lambda Ea8.5 protein reveal a newly discovered hybrid homeodomain/zinc-finger fold. AB - A cluster of genes in the exoxis region of bacteriophage lambda are capable of inhibiting the initiation of DNA synthesis in Escherichia coli. The most indispensible gene in this region is ea8.5. Here, we report the nuclear magnetic resonance structures of two ea8.5 orthologs from enteropathogenic E. coli and Pseudomonas putida prophages. Both proteins are characterized by a fused homeodomain/zinc-finger fold that escaped detection by primary sequence search methods. While these folds are both associated with a nucleic acid binding function, the amino acid composition suggests otherwise, leading to the possibility that Ea8.5 associates with other viral and host proteins. PMID- 23672714 TI - N-Acetylglucosamine modulates function of the skin fibroblasts. AB - BACKGROUND: Fibroblasts are an important component of the skin determining its properties. N-Acetylglucosamine (NAG) is the substrate for hyaluronan synthesis, and it also has anti-inflammatory and anti-senescent activity in mesothelial cells. METHODS: We tested in in vitro-cultured human skin fibroblasts how supplementation of culture medium with NAG 10 mmol L(-1) changes properties of these cells. RESULTS: Fibroblasts cultured in presence of NAG produced more proteins and that was mainly due to increased synthesis of collagen (+33% vs. control, P < 0.05). Hyaluronan synthesis was increased (+107% vs. control, P < 0.001), but interleukin-6 synthesis was reduced (-22% vs. control, P < 0.05). Fibroblasts cultured in medium with NAG 10 mmol L(-1) demonstrated improved ability to heal the injured layer of cells (+34% vs. control, P < 0.05). Additionally senescence of fibroblasts undergoing replicative ageing in the presence of NAG was less pronounced, as reflected by smaller increase in the population doubling time (-70% vs. control, P < 0.05). CONCLUSION: We conclude that NAG induced changes in the skin fibroblasts' properties maybe important for prevention of the age-dependent changes in its structure and function. PMID- 23672715 TI - Enzyme-catalyzed oxidation facilitates the return of fluorescence for single walled carbon nanotubes. AB - In this work, we studied enzyme-catalyzed oxidation of single-walled carbon nanotubes (SWCNTs) produced by the high-pressure carbon monoxide (HiPco) method. While oxidation via strong acids introduced defect sites on SWCNTs and suppressed their near-infrared (NIR) fluorescence, our results indicated that the fluorescence of SWCNTs was restored upon enzymatic oxidation, providing new evidence that the reaction catalyzed by horseradish peroxidase (HRP) in the presence of H2O2 is mainly a defect-consuming step. These results were further supported by both UV-vis-NIR and Raman spectroscopy. Therefore, when acid oxidation followed by HRP-catalyzed enzyme oxidation was employed, shortened (<300 nm in length) and NIR-fluorescent SWCNTs were produced. In contrast, upon treatment with myeloperoxidase, H2O2, and NaCl, the oxidized HiPco SWCNTs underwent complete oxidation (i.e., degradation). The shortened, NIR-fluorescent SWCNTs resulting from HRP-catalyzed oxidation of acid-cut HiPco SWCNTs may find applications in cellular NIR imaging and drug delivery systems. PMID- 23672716 TI - Acute 5-HT7 receptor activation increases NMDA-evoked currents and differentially alters NMDA receptor subunit phosphorylation and trafficking in hippocampal neurons. AB - BACKGROUND: N-methyl-D-aspartate (NMDA) receptors are regulated by several G protein-coupled receptors (GPCRs) as well as receptor tyrosine kinases. Serotonin (5-HT) type 7 receptors are expressed throughout the brain including the thalamus and hippocampus. Long-term (2-24 h) activation of 5-HT7 receptors promotes the expression of neuroprotective growth factor receptors, including the platelet derived growth factor (PDGF) beta receptors which can protect neurons against NMDA-induced neurotoxicity. RESULTS: In contrast to long-term activation of 5-HT7 receptors, acute (5 min) treatment of isolated hippocampal neurons with the 5-HT7 receptor agonist 5-carboxamidotryptamine (5-CT) enhances NMDA-evoked peak currents and this increase in peak currents is blocked by the 5-HT7 receptor antagonist, SB 269970. In hippocampal slices, acute 5-HT7 receptor activation increases NR1 NMDA receptor subunit phosphorylation and differentially alters the phosphorylation state of the NR2B and NR2A subunits. NMDA receptor subunit cell surface expression is also differentially altered by 5-HT7 receptor agonists: NR2B cell surface expression is decreased whereas NR1 and NR2A surface expression are not significantly altered. CONCLUSIONS: In contrast to the negative regulatory effects of long-term activation of 5-HT7 receptors on NMDA receptor signaling, acute activation of 5-HT7 receptors promotes NMDA receptor activity. These findings highlight the potential for temporally differential regulation of NMDA receptors by the 5-HT7 receptor. PMID- 23672717 TI - HrpE3 is a type III effector protein required for full virulence of Xanthomonas oryzae pv. oryzicola in rice. AB - Xanthomonas oryzae pv. oryzicola (Xoc) is the causal agent of bacterial leaf streak, a devastating disease in rice. Xoc uses a type III secretion (T3S) system, which is encoded by the hrp-hrc-hpa (hypersensitive response and pathogenicity, hrp-conserved and hrp-associated) genes, to inject repertoires of T3S effectors (T3Es) into plant cells. Many of the hrp-hrc-hpa genes have roles in pathogenesis, but the role of hrpE3, which shows homology to hpaE in X. campestris pv. vesicatoria (Xcv), is poorly understood. In this study, hrpE3 was shown to be transcribed independent of the hrpD operon, and its expression was dependent on a promoter within hpaB. The expression of hrpE3 was positively regulated by HrpG and HrpX, a finding probably caused by an imperfect plant inducible promoter (PIP) box (TTCGT-N16 -TTCGA) in the hrpE3 promoter. The secretion of HrpE3 was dependent on T3S, and subcellular localization of HrpE3 was cytoplasmic and nuclear in plant cells. A mutation in hrpE3 reduced the virulence of Xoc by decreasing disease lesion length and bacterial growth in planta. Full virulence was restored to the mutant when Xoc hrpE3, but not Xcv hpaE, was expressed in trans. The differences in transcription, secretion via the T3S system and bacterial virulence in plants were attributed to N-terminal amino acid differences between Xoc HrpE3 and Xcv HpaE. Collectively, the results demonstrate that hrpE3 encodes a T3E protein which is delivered into the plant cell through the T3S system, localizes to the cytoplasm and nucleus, and is required for full virulence in rice. PMID- 23672718 TI - Fibrosing interstitial lung disease. A practical high-resolution computed tomography-based approach to diagnosis and management and a review of the literature. AB - Establishing the etiology of fibrosing interstitial lung disease (FILD) remains a clinical challenge. This is because many disorders resulting in lung fibrosis may be similar in their initial clinical and radiographic appearances. High resolution computed tomography (HRCT) studies are now almost always obtained for patients who present with otherwise nonspecific clinical symptoms and chest radiographic findings. In the majority of cases presenting with FILD, differential diagnosis typically requires differentiating among three most commonly encountered clinical entities: idiopathic pulmonary fibrosis with usual interstitial pneumonia, nonspecific interstitial pneumonia, and chronic hypersensitivity pneumonitis. As a consequence, the development of a simplified diagnostic algorithmic approach initially focusing on the interpretation of HRCT findings may prove of considerable value provided thorough familiarity with optimal HRCT techniques and methods of interpretation. For this purpose, in patients with FILD in whom an underlying etiology is not initially apparent, the recently proposed American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines for the diagnosis of IPF have been modified to create a straightforward, clinically practicable algorithmic approach to clinical management based on the initial interpretation and classification of HRCT findings. PMID- 23672720 TI - Brazilian Clinical Trials Registry and the challenges for clinical research governance. AB - Over the past five years, efforts to set up a Brazilian clinical trials registry have progressed from early discussions in academic forums through to the establishment of the registry as a web-based computer platform. This article describes the process of developing and introducing the Brazilian Clinical Trials Registry (ReBEC), and its relationship with the authorities that regulate clinical research in Brazil. The Brazilian Clinical Trials Registry and the multilingual, free and open source, internet-based software developed to manage it are outcomes of partnerships among Brazilian federal and international health agencies. Information for describing the technical and operational dimensions of Rebec was drawn from technical documents and the records of the OpenTrials software development team and the ReBEC executive and advisory committees, which are available in free-access repositories. The Brazilian Clinical Trials Registry was launched in December 2010, and approved as a primary registry of the WHO ICTRP network in April 2011. ReBEC's arrival on-line and its acceptance as an ICTRP primary registry is a significant step in consolidating a policy of free access to information on clinical research in Brazil. PMID- 23672721 TI - Iranian Registry of Clinical Trials two years on and the timing of registrations. AB - The Iranian Registry of Clinical Trials (IRCT) was established as a primary registry on December 4 2008 and has registered over 1350 trials by June 2011. Many researchers are still unaware of the need for registration of trials before recruiting the first patient and the proportion of retrospectively registered trials is likely to grow until this awareness increases. We sought to investigate the timing of the registrations in IRCT and to explore strategies to overcome this. We used all data in the IRCT database and extracted the date of registration, as well as the dates for the start and the end of recruitment. We categorized trials into 4 groups: those registered before the start of patient enrolment, within 30 days of enrolment, after 30 days but before the end of recruitment, and after the end of recruitment. The proportion of trials in each category was calculated by calendar year. The number of registered trials increased from 26 in the 3 months leading to 2009 to 181 in 2009, 772 in 2010 and 376 in the first 5 months of 2011 (estimate by end of year = 947). The proportions of trials registered after the end of patient recruitment were 55%, 58% and 62% in 2009, 2010 and 2011 respectively. On average, 6.4% of trials were registered within 30 days from the start of patient recruitment and 27% in the time between then and the end of recruitment. The rapid increase in the number of registered trials is an indication of strong implementation of the registration policy. This comes partly at the expense of an increased proportion of retrospective registrations. While this may be understandable at the beginning, it is clearly not acceptable and measures should be adopted to increase the proportion of prospectively registered trials and to make trial registration an integral part of the research culture. PMID- 23672723 TI - Thai clinical trials registry. AB - The Thai Clinical Trials Registry (TCTR) was established in 2009 by a group of university academics. The Thailand Center of Excellence for Life Sciences has supported the registry financially, while the basic infrastructure including the administration, staff and computer servers has been provided by the Clinical Research Collaboration Network and the Medical Research Foundation. In December 2010, the Ministry of Public Health of Thailand endorsed the registry. In addition to the major purposes of reducing publication bias, promoting research transparency, and reducing redundancy in clinical research, TCTR aims to create a collective database of the clinical researches in Thailand, in order to help construct a pool database for local researchers. PMID- 23672724 TI - Australian New Zealand Clinical Trials Registry: history and growth. AB - The problem of publication bias and the need for prospective trial registration to overcome this issue has been recognised for many years. Australia and New Zealand established a national clinical trials registry, the Australian New Zealand Clinical Trials Registry (ANZCTR, http://www.anzctr.org.au), in 2005. Much progress has been made over the past six years on this important research infrastructure resource, with the ANZCTR now housing over 5330 registered trial records. Recent reviews and initiatives have helped encourage prospective registration of Australian/New Zealand trials but several challenges remain. We continue to work to ensure all those interested in clinical trials being conducted in Australia and New Zealand (including consumers, clinicians, researchers, funders and regulators) are able to access information that is comprehensive, complete, current and compatible. PMID- 23672728 TI - Education section - Registration of randomised trials. PMID- 23672730 TI - Quantification of phosphorus transport from a karstic agricultural watershed to emerging spring water. AB - The degree to which waters in a given watershed will be affected by nutrient export can be defined as that watershed's nutrient vulnerability. This study applied concepts of specific phosphorus (P) vulnerability to develop intrinsic groundwater vulnerability risk assessments in a 32 km(2) karst watershed (spring zone of contribution) in a relatively intensive agricultural landscape. To explain why emergent spring water was below an ecological impairment threshold, concepts of P attenuation potential were investigated along the nutrient transfer continuum based on soil P buffering, depth to bedrock, and retention within the aquifer. Surface karst features, such as enclosed depressions, were reclassified based on P attenuation potential in soil at the base. New techniques of high temporal resolution monitoring of P loads in the emergent spring made it possible to estimate P transfer pathways and retention within the aquifer and indicated small-medium fissure flows to be the dominant pathway, delivering 52-90% of P loads during storm events. Annual total P delivery to the main emerging spring was 92.7 and 138.4 kg total P (and 52.4 and 91.3 kg as total reactive P) for two monitored years, respectively. A revised groundwater vulnerability assessment was used to produce a specific P vulnerability map that used the soil and hydrogeological P buffering potential of the watershed as key assumptions in moderating P export to the emergent spring. Using this map and soil P data, the definition of critical source areas in karst landscapes was demonstrated. PMID- 23672731 TI - Controlling and assessing the surface display of cell-binding domains on magnetite conjugated fluorescent liposomes. AB - Biological systems provide us with a diverse source of peptide-based ligands for cellular adhesion. Controlling and assessing the ligand surface density as well as tailoring the surface chemistry to have specific cellular adhesion properties are important in biomaterials design. In the following work, we provide a means for displaying peptide-based ligands on magnetic liposomes in which the surface density and chemistry may be controlled. Simultaneously, the conjugated vesicles provide a fluorescent signal for examining steric hindrance among surface ligands. In addition, the inherent magnetic and fluorescence features of this system revealed potential for magnet-based cell isolation and fluorescent labeling of adhered cells, respectively. Adhered cells were found to remain viable and proliferative, thereby allowing them to be used for subsequent evaluation. In a specific demonstration, we control the density of fibronectin mimetic ligands on the polydiacetylene liposome surfaces. We find that steric limitation occurring at over 20% surface density result in decreased cell adhesion, in accord with related techniques. The magnetic-liposome system offers the means for not only separating cells adhered to the biomaterial, but also providing the ability to control and assess the biomaterial surface. This may prove particularly useful for examining combinations of peptide-based ligands or for evaluating the molecular-level ligand accessibility and its effect on cell attachment to a biomaterial surface. PMID- 23672729 TI - Clinical review: Does it matter which hemodynamic monitoring system is used? AB - Hemodynamic monitoring and management has greatly improved during the past decade. Technologies have evolved from very invasive to non-invasive, and the philosophy has shifted from a static approach to a functional approach. However, despite these major changes, the critical care community still has potential to improve its ability to adopt the most modern standards of research methodology in order to more effectively evaluate new monitoring systems and their impact on patient outcome. Today, despite the huge enthusiasm raised by new hemodynamic monitoring systems, there is still a big gap between clinical research studies evaluating these monitors and clinical practice. A few studies, especially in the perioperative period, have shown that hemodynamic monitoring systems coupled with treatment protocols can improve patient outcome. These trials are small and, overall, the corpus of science related to this topic does not yet fit the standard of clinical research methodology encountered in other specialties such as cardiology and oncology. Larger randomized trials or quality improvement processes will probably answer questions related to the real impact of these systems. PMID- 23672732 TI - A hybrid approach to the simultaneous eliminating of power-line interference and associated ringing artifacts in electrocardiograms. AB - BACKGROUND: The second-order, infinite impulse response notch filter is widely used to remove electrical power line noise in electrocardiograms (ECGs). However this filtering process often introduces spurious ringing artifacts in the vicinity of raw signal with sharp transitions. It is challenging to simultaneously remove these two types of noise without losing vital information about cardiac activities. OBJECTIVE: Our objective is to devise a method to remove the power-line interference without introducing artifacts nor losing vital information. To this end we have developed the "hybrid approach" involving two sided filtration and multi-iterative approximation techniques. The two-sided filtration technique can suppress the interference but some cardiac components are lost. The lost information can be restored using multi-iterative approximation technique. RESULTS: For evaluation, four artificial data sets, each including 91 ECGs of different heart rates, were generated by a dynamical model. Four publicly-accessible sets of clinical data (MIT-BIH Arrhythmia, QT, PTB Diagnostic ECG, and T-Wave Alternans Challenge Databases) were also selected. Our new hybrid approach and the existing method were tested with these two types of signal under various pre-determined conditions. In contrast with the existing method, the hybrid approach can provide more than 27.40 dB and 37.77 dB reduction in signal distortion for 95% and 60% of artificial ECGs respectively; it can provide in excess of 11.78 dB and 17.48 dB reduction in distortion for 95% and 60% of these real records respectively. CONCLUSIONS: Overall, a significant reduction in signal distortion is demonstrated. These test results indicate that the newly proposed approach outperforms the traditional method assessed on both the artificial and clinical ECGs and suggest it could be of practical use for clinicians in the future. PMID- 23672733 TI - Effects of lifestyle education program for type 2 diabetes patients in clinics: a cluster randomized controlled trial. AB - BACKGROUND: The prevalence of type 2 diabetes is rising worldwide, as has been the global mean fasting plasma glucose level. This study aimed to evaluate the effectiveness of a structured individual-based lifestyle education (SILE) program to reduce the hemoglobin A1c (HbA1c) level in type 2 diabetes patients delivered by registered dietitians in primary care clinical settings. METHODS: This was a 6 month prospective cluster randomized controlled trial in a primary care setting with randomization at the practice level. Twenty general practitioners in 20 clinics in Kanagawa prefecture, Japan, were involved. 193 adults (51% men, mean age 61.3 years) with type 2 diabetes and HbA1c >=6.5% who received treatment in medical clinics were the participants. A SILE program was implemented through 4 sessions with trained registered dietitians during the 6-month study period. Results were compared with those of a control group who received usual care. The primary endpoint was the change in HbA1c levels at 6 months from baseline. Secondary endpoints were the changes at 6 months from baseline in fasting plasma glucose, lipid profile, blood pressure, BMI, energy, and nutrient intakes (whole day and each meal). Intention-to-treat analysis was conducted. Mixed-effects linear models were used to examine the effects of the treatment. RESULTS: The mean change at 6 months from baseline in HbA1c was a 0.7% decrease in the intervention group (n = 100) and a 0.2% decrease in the control group (n = 93) (difference -0.5%, 95%CI: -0.2% to -0.8%, p = 0.004). After adjusting for baseline values and other factors, the difference was still significant (p = 0.003 ~ 0.011). The intervention group had a significantly greater decrease in mean energy intake at dinner compared with the control group and a greater increase in mean vegetable intake for the whole day, breakfast, and lunch as shown in crude and adjusted models. A tendency toward improvement was observed in the other secondary endpoints but the improvement was not statistically significant. These results were confirmed by several sensitivity analyses. CONCLUSIONS: The SILE program that was provided in primary care settings for patients with type 2 diabetes resulted in greater improvement in HbA1c levels than usual diabetes care and education. TRIAL REGISTRATION: http://UMIN000004049. PMID- 23672735 TI - Surgical vs ultrasound-guided drainage of deep neck space abscesses: a randomized controlled trial: surgical vs ultrasound drainage. AB - INTRODUCTION: Deep neck space abscesses (DNAs) are relatively common otolaryngology-head and neck surgery emergencies and can result in significant morbidity with potential mortality. Traditionally, surgical incision and drainage (I&D) with antibiotics has been the mainstay of treatment. Some reports have suggested that ultrasound-guided drainage (USD) is a less invasive and effective alternative in select cases. OBJECTIVES: To compare I&D vs USD of well-defined DNAs, using a randomized controlled clinical trial design. The primary outcome measure was effectiveness (length of hospital stay (LOHS) and safety), and the secondary outcome measure was overall cost to the healthcare system. METHODS: Patients presenting to the University of Alberta Emergency Department with a well defined deep neck space abscess were recruited in the study. Patients were randomized to surgical or US-guided drainage, placed on intravenous antibiotics and admitted with airway precautions. Following drainage with either intervention, abscess collections were cultured and drains were left in place until discharge. RESULTS: Seventeen patients were recruited in the study. We found a significant difference in mean LOHS between patients who underwent USD (3.1 days) vs I&D (5.2 days). We identified significant cost savings associated with USD with a 41% cost reduction in comparison to I&D. CONCLUSIONS: USD drainage of deep neck space abscesses in a certain patient population is effective, safe, and results in a significant cost savings to the healthcare system. PMID- 23672736 TI - Head Computed Tomographic measurement as an early predictor of outcome in hypoxic ischemic brain damage patients treated with hypothermia therapy. AB - BACKGROUND: Neurological abnormalities are a key factor in the prognosis of patients with post-cardiac arrest syndrome. In this study, we evaluated whether differences in CT measurements expressed in Hounsfield units (HUs) of the cerebral cortex and white matter can be used as early predictors of neurological outcome in patients treated with hypothermia therapy after hypoxic-ischemic brain damage. METHODS: We performed a retrospective study of 58 patients resuscitated after cardiac arrest between 2007 and 2010 who were treated with hypothermia therapy for the initial 24 hours post resuscitation. We divided the patients into 4 groups according to Glasgow Outcome Scale (GOS) score (GOS 1, GOS 2, GOS 3&4, and GOS 5) and assessed the correlations between GOS scores and HU differences between the cerebral cortex and white matter (DCW). RESULTS: The HU values of the cerebral cortex gradually decreased in accordance with worsening of neurological outcome. There were no significant intergroup differences in the HUs of the white matter among the groups. The DCW values were higher in patients with good neurological outcomes. The cut-off value for DCW indicative of poor neurological outcome was less than 5.5 in the GOS 1&2 groups, with a sensitivity of 63% and a specificity of 100%. CONCLUSIONS: This study showed that DCW values may be used for the prediction of neurological outcome of patients with post-cardiac arrest syndrome in the very early phase following the return of spontaneous circulation. Especially, a cut-off value for DCW of less than 5.5 may indicate poor neurological outcome. PMID- 23672738 TI - One year surveillance of the isolation of pathogenic dermatophyte spores from risk areas in a veterinary medical teaching hospital. PMID- 23672737 TI - Depression is related to an absence of optimistically biased belief updating about future life events. AB - BACKGROUND: When challenged with information about the future, healthy participants show an optimistically biased updating pattern, taking desirable information more into account than undesirable information. However, it is unknown how patients suffering from major depressive disorder (MDD), who express pervasive pessimistic beliefs, update their beliefs when receiving information about their future. Here we tested whether an optimistically biased information processing pattern found in healthy individuals is absent in MDD patients. METHOD: MDD patients (n = 18; 13 medicated; eight with co-morbid anxiety disorder) and healthy controls (n = 19) estimated their personal probability of experiencing 70 adverse life events. After each estimate participants were presented with the average probability of the event occurring to a person living in the same sociocultural environment. This information could be desirable (i.e. average probability better than expected) or undesirable (i.e. average probability worse than expected). To assess how desirable versus undesirable information influenced beliefs, participants estimated their personal probability of experiencing the 70 events a second time. RESULTS: Healthy controls showed an optimistic bias in updating, that is they changed their beliefs more toward desirable versus undesirable information. Overall, this optimistic bias was absent in MDD patients. Symptom severity correlated with biased updating: more severely depressed individuals showed a more pessimistic updating pattern. Furthermore, MDD patients estimated the probability of experiencing adverse life events as higher than healthy controls. CONCLUSIONS: Our findings raise the intriguing possibility that optimistically biased updating of expectations about one's personal future is associated with mental health. PMID- 23672739 TI - Behavioural syndromes and social insects: personality at multiple levels. AB - Animal personalities or behavioural syndromes are consistent and/or correlated behaviours across two or more situations within a population. Social insect biologists have measured consistent individual variation in behaviour within and across colonies for decades. The goal of this review is to illustrate the ways in which both the study of social insects and of behavioural syndromes has overlapped, and to highlight ways in which both fields can move forward through the synergy of knowledge from each. Here we, (i) review work to date on behavioural syndromes (though not always referred to as such) in social insects, and discuss mechanisms and fitness effects of maintaining individual behavioural variation within and between colonies; (ii) summarise approaches and principles from studies of behavioural syndromes, such as trade-offs, feedback, and statistical methods developed specifically to study behavioural consistencies and correlations, and discuss how they might be applied specifically to the study of social insects; (iii) discuss how the study of social insects can enhance our understanding of behavioural syndromes-research in behavioural syndromes is beginning to explore the role of sociality in maintaining or developing behavioural types, and work on social insects can provide new insights in this area; and (iv) suggest future directions for study, with an emphasis on examining behavioural types at multiple levels of organisation (genes, individuals, colonies, or groups of individuals). PMID- 23672740 TI - Runge-Kutta model-based nonlinear observer for synchronization and control of chaotic systems. AB - This paper proposes a novel nonlinear gradient-based observer for synchronization and observer-based control of chaotic systems. The model is based on a Runge Kutta model of the chaotic system where the evolution of the states or parameters is derived based on the error-square minimization. The stability and convergence conditions of observer and control methods are analyzed using a Lyapunov stability approach. In numerical simulations, the proposed observer and well known sliding-mode observer are compared for the synchronization of a Lu chaotic system and observer-based stabilization of a Chen chaotic system. The noisy case for synchronization and parameter uncertainty case for stabilization are also considered for both observer-based methods. PMID- 23672743 TI - Advances in management of thyroid cancer. PMID- 23672744 TI - A survey of patients with haemophilia to understand how they track product used at home. AB - Record keeping among individuals who manage haemophilia at home is an essential tool of communication between patient and Haemophilia Treatment Center (HTC). Complete records help HTCs monitor patients, their use of factor and ensure treatment is optimal. HTCs provide patients with a number of methods to track infusion practices. The study objectives were to: [1] determine the current methods of record keeping; [2] identify previous methods of record keeping; [3] understand the strengths and weaknesses associated with each method; and [4] gather suggestions for improvement. Survey methods were used to address the research objectives. Of the 83 patients in the Hamilton-Niagara region who received the survey distributed through the local HTC, 51 returned surveys were included into the analysis. Descriptive statistics were used. Results indicate individuals with haemophilia record infusion practices using: paper diaries, excel spreadsheets, hand-held PDAs and/or the online EZ-Log Web Client. The most popular method of record keeping was EZ-Log (45.1%) followed by paper diaries (35.2%). Advantages to using paper methods include the visual tracking of information and retaining hardcopies. The disadvantage was the inconvenience of physically submitting the records monthly. Advantages to using the online EZ-Log Web Client included ease of use and improved accuracy. The primary disadvantage was technical errors that were difficult to troubleshoot. Record keeping practices among individuals with haemophilia seem to vary according to personal preference and convenience. Respondents suggested that saving infusion history, incorporating barcode scanners or a copy and paste function could improve electronic methods. PMID- 23672745 TI - Antidepressant-induced differential ubiquitination of beta-arrestins 1 and 2 in mononuclear leucocytes of patients with depression. AB - beta-Arrestins 1 and 2, cytosolic proteins known to mediate receptor desensitization, endocytosis and G protein-independent signalling, are post translationally modified by ubiquitination regulating their ability to serve as adaptors and scaffolds. beta-Arrestins were suggested to play a role in the pathophysiology of depression and in antidepressant mechanism of action. To determine whether a depressive episode or antidepressant treatment induce significant selective differences in beta-arrestin 1 and 2 levels or their ubiquitination patterns in leucocytes of patients with depression, 46 outpatients diagnosed with a depressive episode were examined before and after 4-wk antidepressant treatment compared with age- and gender-matched control subjects. beta-Arrestin levels were measured by immunoblotting using anti-arrestin antibodies. Ubiquitination of beta-arrestins was measured using anti-ubiquitin antibodies followed by an immunoprecipitation step and immunoblotting using anti arrestin antibodies. Antidepressants induced selective alterations in leucocyte beta-arrestin 1 and 2 levels and ubiquitination. The levels of beta-arrestin 1 and 2 and their ubiquitinated forms in leucocytes of yet untreated patients with depression were significantly decreased in a symptom severity correlated manner compared to control subjects. Antidepressants normalized beta-arrestin 1 and 2 levels and uncovered novel differences between the two isoforms: (a) while antidepressants normalized ubiquitination of beta-arrestin 1, ubiquination of beta-arrestin 2 was unaffected; (b) while under antidepressants ubiquitination extent of beta-arrestin 1 positively correlated with its level, an inverse picture of negative correlation was found between ubiquitination extent of beta arrestin 2 and its level. We conclude that antidepressants may serve as a tool to detect functional differences between the two beta-arrestin isoforms and that through these differential effects antidepressants can induce specific alterations in alternative cellular signalling. PMID- 23672746 TI - Retroperitoneal undifferentiated pleomorphic sarcoma having microsatellite instability associated with Muir-Torre syndrome: case report and review of literature. AB - Muir-Torre syndrome represents a rare autosomal dominant familial cancer predisposition disorder defined by the occurrence of cutaneous sebaceous tumors and an internal malignancy, most commonly gastrointestinal carcinoma. Most examples of hereditary non-polyposis cancer syndrome (Lynch syndrome), including the Muir-Torre syndrome, are associated with microsatellite instability (MSI) and germline mutations in mismatch repair genes-most commonly MLH1 or MSH2. We present a 58-year-old man with Muir-Torre syndrome and a large retroperitoneal mass (14.3 cm in greatest dimension) encompassing the left adrenal gland. Sections showed a cellular malignant tumor composed of spindle cells with a high mitotic index and lacking morphologic evidence of adipocytic differentiation. It was weakly reactive for smooth muscle actin (SMA) and negative for desmin, CD117, CD31, CD34, S100 protein and pan-cytokeratin. Further immunohistochemical analysis revealed intact expression of MLH1 but loss of MSH2 in tumor nuclei. Compared to non-neoplastic tissue, the tumor showed MSI in five of seven dinucleotide markers. Fluorescence in situ hybridization (FISH) failed to reveal 12q15 amplification, effectively excluding dedifferentiated liposarcoma as a diagnostic consideration. This is a rare case of a patient with Muir-Torre syndrome who developed a related high-grade undifferentiated pleomorphic sarcoma as the associated internal malignancy. PMID- 23672747 TI - Clinical review: early patient mobilization in the ICU. AB - Early mobilization (EM) of ICU patients is a physiologically logical intervention to attenuate critical illness-associated muscle weakness. However, its long-term value remains controversial. We performed a detailed analytical review of the literature using multiple relevant key terms in order to provide a comprehensive assessment of current knowledge on EM in critically ill patients. We found that the term EM remains undefined and encompasses a range of heterogeneous interventions that have been used alone or in combination. Nonetheless, several studies suggest that different forms of EM may be both safe and feasible in ICU patients, including those receiving mechanical ventilation. Unfortunately, these studies of EM are mostly single center in design, have limited external validity and have highly variable control treatments. In addition, new technology to facilitate EM such as cycle ergometry, transcutaneous electrical muscle stimulation and video therapy are increasingly being used to achieve such EM despite limited evidence of efficacy. We conclude that although preliminary low level evidence suggests that EM in the ICU is safe, feasible and may yield clinical benefits, EM is also labor-intensive and requires appropriate staffing models and equipment. More research is thus required to identify current standard practice, optimal EM techniques and appropriate outcome measures before EM can be introduced into the routine care of critically ill patients. PMID- 23672749 TI - Editorial for issue 4 of 2011, Journal of Evidence Based Medicine. PMID- 23672750 TI - Improving health research governance and management in the Western Pacific: a WHO expert consultation. AB - Repeated calls have been made in recent decades to increase investments in health research, especially in low- and middle-income countries (LMIC). However, the perceived low relevance and quality of health research, poor visibility of outputs, and difficulties in tracking current levels of and returns on investments have undermined efforts to advocate for additional investments in these countries. Some of these issues emanate from inadequate governance and management systems for health research at the national level, which are ineffective in tracking and steering the research portfolio and investments, ensuring quality, and facilitating access to research outputs. In spite of this, the value, necessity, and cost of performing health research management and governance functions are not well appreciated, especially in LMIC. To address this, the World Health Organization (WHO) Regional Office for the Western Pacific organized an expert consultation in August 2011, involving experts from 14 of its developed and developing member states and from leading research organizations such as the Wellcome Trust. The consultation identified essential health research governance and management functions that must be performed by appropriate organizational entities to maximize returns on health research investments. In addition, three specific areas for intervention were considered: (1) prospective research registration in publicly accessible national health research registries; (2) systematic health research data archiving and wider access; and (3) national research ethics systems. A consensus was reached on the need to invest more in essential health research and management functions, including establishing publicly accessible web-based national health research registries for prospective registration of health research, setting up systems to archive and share health research data, and improving the governance of research ethics committees. The consultation also concluded that the costs of performing these functions are legitimate and necessary research costs that must be shouldered by research funding organizations. PMID- 23672748 TI - Intrinsic lens forming potential of mouse lens epithelial versus newt iris pigment epithelial cells in three-dimensional culture. AB - Adult newts (Notophthalmus viridescens) are capable of complete lens regeneration that is mediated through dorsal iris pigment epithelial (IPE) cells transdifferentiation. In contrast, higher vertebrates such as mice demonstrate only limited lens regeneration in the presence of an intact lens capsule with remaining lens epithelial cells. To compare the intrinsic lens regeneration potential of newt IPE versus mouse lens epithelial cells (MLE), we have established a novel culture method that uses cell aggregation before culture in growth factor-reduced Matrigel. Dorsal newt IPE aggregates demonstrated complete lens formation within 1 to 2 weeks of Matrigel culture without basic fibroblast growth factor (bFGF) supplementation, including the establishment of a peripheral cuboidal epithelial cell layer, and the appearance of central lens fibers that were positive for alphaA-crystallin. In contrast, the lens-forming potential of MLE cell aggregates cultured in Matrigel was incomplete and resulted in the formation of defined-size lentoids with partial optical transparency. While the peripheral cell layers of MLE aggregates were nucleated, cells in the center of aggregates demonstrated a nonapoptotic nuclear loss over a time period of 3 weeks that was representative of lens fiber formation. Matrigel culture supplementation with bFGF resulted in higher transparent bigger-size MLE aggregates that demonstrated increased appearance of betaB1-crystallin expression. Our study demonstrates that bFGF is not required for induction of newt IPE aggregate dependent lens formation in Matrigel, while the addition of bFGF seems to be beneficial for the formation of MLE aggregate-derived lens-like structures. In conclusion, the three-dimensional aggregate culture of IPE and MLE in Matrigel allows to a higher extent than older models the indepth study of the intrinsic lens-forming potential and the corresponding identification of lentogenic factors. PMID- 23672751 TI - Joint statement on promoting development of publication ethics among medical journals in China. PMID- 23672752 TI - Analysis of characteristics of randomized clinical trials in leukemia that are associated with how results are reported. AB - BACKGROUND: Since many trials are small, systematic reviews are essential for obtaining statistically reliable results. However, some trials are better reported than others. Non-publication or delayed publication could lead to bias in a review. We identify trial characteristics affecting how quickly or widely results of randomized trials are reported, and hence how likely the trial is to be found by reviewers. METHODS: We analyzed all randomized trials in childhood acute lymphoblastic leukemia that began before 1988 and all articles for these trials published before 2000, as identified by the Childhood Acute Lymphoblastic Leukaemia (ALL) Collaborative Group secretariat. This was the set of 149 trials included in the Second International Collaborative Workshop on Childhood ALL Studies at the end of 1992, comprising 243 randomized comparisons. We used multiple linear regression to analyze time to first mention or to first reporting of results (time to publication), logistic regression for whether a randomization was ever mentioned or reported, and Poisson regression for frequency of mentions or publications. RESULTS: Collectively, the articles mentioned 217 randomizations, with results reported for 188. Highly statistically significant results were published faster, each tenfold reduction in the p-value (e.g., going from 0.5 to 0.05 or from 0.05 to 0.005) resulting in publication on average 20 months earlier (95% confidence interval 6-34, p = 0.005), non-statistically significant results from trials outside North America and Europe took on average 55 months longer than those without these characteristics (95% CI 22-88, p = 0.001), and results from trials in high income countries were more likely to reach publication at some point than were results from other countries (odds ratio 7.8, 95% CI 2.4-25.3, p = 0.0006). Randomizations in high income countries were mentioned 73 months earlier than those in middle or low income countries (95% CI 51-94, p < 0.0001), were more likely to ever be mentioned (OR 13.1, 95% CI 2.1-80.9, p = 0.006), and were mentioned more frequently (incidence ratio 2.5, 95% CI 1.4-4.5, p = 0.003), as were North American trials compared with those conducted elsewhere (IR 1.3, 95% CI 1.1-1.6, p = 0.01). CONCLUSIONS: Systematic reviewers should not rely solely on published reports, but should use additional ways of finding trials in order to minimize biases related to results and other trial characteristics. This relates both to published reports of trial results and to mentions of trials in the literature. PMID- 23672753 TI - Comparison of short-term outcomes and perioperative systemic immunity of laparoscopy-assisted and open radical gastrectomy for gastric cancer. AB - OBJECTIVE: To compare the perioperative systemic immunity of laparoscopy-assisted and open radical gastrectomy for gastric cancer. METHODS: Patients with gastric adenocarcinoma proven by endoscopy and biopsy were eligible, while patients with preoperative staging of T4, N2-3, or M1 were excluded. Eligible patients willing to undertake laparoscopic surgery in the consecutive cohort were assigned to the laparoscopy-assisted gastrectomy (LAG) group, while concurrent patients were assigned to the conventional open gastrectomy (OG) group. All operations were performed with the intention of radical resection. Various immunological parameters were tested in peripheral venous blood collected at preoperative 1(st) day and postoperative 2(nd) day (POD2) and 7(th) day (POD7). SPSS 13.0 software was used for statistical analysis. RESULTS: Thirty patients were included, 15 each in the LAG and OG groups. The general characteristics and short-term outcomes (harvested lymph nodes number, hospital stay, complications, and mortality rate) of the two groups were comparable, but the operation time was significantly longer in LAG (P = 0.001). Moreover, intergroup comparisons indicated no significant differences between the groups in levels of neutrophils, T-lymphocytes, natural killer cells, IgG, IgM, IgA, C3, C4, interleukin-6, or interleukin-10 at any time point (P>0.05). However, there was a gradual decrease in natural killer cell count in the LAG group up to POD7 (P = 0.008). CONCLUSION: The changes in systemic immunity markers were comparable between laparoscopy assisted and open gastrectomy for gastric cancer. However, there was a trend of suppression of natural killer cells in the laparoscopy-assisted gastrectomy group. PMID- 23672754 TI - Effects and patient compliance of sustained-release versus immediate-release glipizides in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. AB - This review aimed to address effects of sustained-release versus immediate release glipizide on glucose control, insulin secretion, and compliance. We searched Medline, EMBASE, the Cochrane Library, and Chinese Biomedical database from inceptions to May 31, 2011, screened reference lists of relevant studies, and contacted pharmaceutical companies. Randomized trials and cohort studies were included. We pooled data using a random-effect model. Nineteen trials involving a total of 1440 patients and 2 retrospective cohort studies with a total of 13452 patients were included. Trials were of low quality. No trials reported patient important outcomes. The reduction of fasting plasma glucose from the baseline appeared larger for sustained-release than for immediate-release glipizide (mean difference -0.26 mmol/L, 95% CI -0.52 to -0.01). The reduction was not significantly different between the two drugs for HbA1c (-0.03%, -0.20% to 0.14%) or 2-hour postprandial plasma glucose (-0.21 mmol/L, -0.96 to 0.55). Sustained release glipizide appeared to reduce insulin secretion from the baseline, whereas the immediate-release formulation increased the secretion (fasting insulin: -1.04 vs. 0.88 MUIU/ml; 2-hour postprandial insulin: -2.94 vs. 0.24 MUIU/ml). Patients administering sustained-release glipizide had less hypoglycemia (Peto odds ratio 0.21, 95% CI 0.08 to 0.52) and lower missed dosing (Peto odds ratio 11. 42, 95% CI 6.47 to 20.18). The cohort studies showed patient compliance results consistent with those of the trials. Sustained-release glipizide appears to achieve similar glucose control with decreased insulin secretion, fewer hypoglycemic episodes, and higher patient compliance than immediate-release glipizide. However, these findings are inconclusive due to inadequate study quality, short follow up, and unavailability of patient important outcomes. PMID- 23672755 TI - Cuff-leak test for predicting postextubation airway complications: a systematic review. AB - BACKGROUND AND OBJECTIVE: Postextubation problems such as laryngeal edema and reintubation are common complications after tracheal intubation. The cuff-leak test has been proposed as a method of identifying those patients at high risk in clinical practice, but its efficacy remains controversial. METHODS: We searched electronic databases including PubMed, the Cochrane Controlled Trials Register, Web of Science, Ovid, and Embase. Studies were included if they were concerned with accuracy of the cuff-leak test and the effect of cuff-leak test screening on patient-important outcomes. Two reviewers independently assessed study quality with the QUADAS tool and extracted data. We compiled diagnostic two by two tables and pooled estimates of sensitivity and specificity, but refrained from pooling when there was considerable clinical or statistical heterogeneity. RESULTS: Sixteen diagnostic tests with 3172 participants and six clinical trials with 2500 patients were identified. The median diagnostic odds ratios for predicting postextubation laryngeal edema and reintubation were 18.16 (range, 3.54 to 356.00) and 10.80 (2.74 to 1665.00), respectively. The accuracy of the cuff-leak test varied with different methods, duration of intubation, and study population. An indirect comparison found significant differences in post-extubation incidence of laryngeal edema (OR = 2.09, 95% CI, 1.28 to 2.89) but not reintubation (OR = 0.94, 95% CI, 0.32 to 1.57) if using cuff-leak test screening. CONCLUSIONS: Our results suggest the cuff-leak test accurately predicts which adult patients are at high risk of postextubation airway complications, but randomized controlled trials are needed to further assess this diagnostic strategy. PMID- 23672756 TI - Do variations in allocation concealment methods influence the effects found in intervention reviews? AB - OBJECTIVE: (i) To explore any discrepancies in intervention effects between a set of Cochrane reviews that includes trials with liberal criteria and a set with restrictive criteria in which trials with liberal design have been removed from the review, and (ii) to suggest ways to improve the quality of evidence. METHODS: A documentary analysis of three Cochrane reviews of intervention studies. The selection of the Cochrane reviews was based on a two-stage sampling. The stability of effect measures after removal of trials with liberal design was investigated. RESULTS: In two of the three reviews, we found changes in the original effect measure of the intervention after removing the studies without allocation concealment. One of these reported an 87% greater relative risk when randomized trials with liberal design were included. In the other, the risk was 19.5% lower when randomized trials with liberal design were included. CONCLUSIONS: The instability of the effect measure indicates the importance of allocation concealment during recruitment for clinical trials. We recommend further research incorporating a large number of intervention reviews and factors other than allocation concealment. PMID- 23672759 TI - Education section - designing a "placebo" to help define the intervention. PMID- 23672760 TI - A comparison of self-assembly and hydrogel encapsulation as a means to engineer functional cartilaginous grafts using culture expanded chondrocytes. AB - Despite an increased interest in the use of hydrogel encapsulation and cellular self-assembly (often termed "self-aggregating" or "scaffold-free" approaches) for tissue-engineering applications, to the best of our knowledge, no study to date has been undertaken to directly compare both approaches for generating functional cartilaginous grafts. The objective of this study was to directly compare self assembly (SA) and agarose hydrogel encapsulation (AE) as a means to engineer such grafts using passaged chondrocytes. Agarose hydrogels (5 mm diameter * 1.5 mm thick) were seeded with chondrocytes at two cell seeding densities (900,000 cells or 4 million cells in total per hydrogel), while SA constructs were generated by adding the same number of cells to custom-made molds. Constructs were either supplemented with transforming growth factor (TGF)-beta3 for 6 weeks, or only supplemented with TGF-beta3 for the first 2 weeks of the 6 week culture period. The SA method was only capable of generating geometrically uniform cartilaginous tissues at high seeding densities (4 million cells). At these high seeding densities, we observed that total sulphated glycosaminoglycan (sGAG) and collagen synthesis was greater with AE than SA, with higher sGAG retention also observed in AE constructs. When normalized to wet weight, however, SA constructs exhibited significantly higher levels of collagen accumulation compared with agarose hydrogels. Furthermore, it was possible to engineer such functionality into these tissues in a shorter timeframe using the SA approach compared with AE. Therefore, while large numbers of chondrocytes are required to engineer cartilaginous grafts using the SA approach, it would appear to lead to the faster generation of a more hyaline-like tissue, with a tissue architecture and a ratio of collagen to sGAG content more closely resembling native articular cartilage. PMID- 23672762 TI - Prehospital analgesia using nasal administration of S-ketamine--a case series. AB - Pain is a problem that often has to be addressed in the prehospital setting. The delivery of analgesia may sometimes prove challenging due to problems establishing intravenous access or a harsh winter environment. To solve the problem of intravenous access, intranasal administration of drugs is used in some settings. In cases where vascular access was foreseen or proved hard to establish (one or two missed attempts) on the scene of the accident we use nasally administered S-Ketamine for prehospital analgesia. Here we describe the use of nasally administered S-Ketamine in 9 cases. The doses used were in the range of 0,45-1,25 mg/kg. 8 patients were treated in outdoor winter-conditions in Sweden. 1 patient was treated indoor. VAS-score decreased from a median of 10 (interquartile range 8-10) to 3 (interquartile range 2-4). Nasally administered S Ketamine offers a possible last resource to be used in cases where establishing vascular access is difficult or impossible. Side-effects in these 9 cases were few and non serious. Nasally administered drugs offer a needleless approach that is advantageous for the patient as well as for health personnel in especially challenging selected cases. Nasal as opposed to intravenous analgesia may reduce the time spent on the scene of the accident and most likely reduces the need to expose the patient to the environment in especially challenging cases of prehospital analgesia. Nasal administration of S-ketamine is off label and as such we only use it as a last resource and propose that the effect and safety of the treatment should be further studied. PMID- 23672761 TI - Percutaneous endoscopic gastrostomy site metastasis from head and neck squamous cell carcinoma: case series and literature review. AB - OBJECTIVES: To present our experience with head and neck squamous cell carcinoma (HNSCC) seeding of percutaneous endoscopic gastrostomy (PEG) sites and to review all reported cases to identify risk factors and develop strategies for complication avoidance. MATERIALS AND METHODS: The records of 4 patients with PEG site metastasis from HNSCC were identified from the authors' institution. Thirty eight further cases were reviewed following a PubMed search and evaluation of references in pertinent articles. RESULTS: Review of 42 cases revealed the average time from PEG to diagnosis of metastatic disease to be 8 months. Average time to death from detection of PEG disease was 5.9 months. One-year survival following PEG metastasis was 35.5% with an overall mortality of 87.1%. CONCLUSION: PEG site metastatic disease portends a poor prognosis. Early detection and aggressive therapy may provide a chance of cure. Changes in PEG technique or in timing of adjunctive therapies are possible avenues in further research to prevent this complication. PMID- 23672765 TI - Bypass therapy assay testing as a strategy to reduce costs for treatment of haemophilia patients with inhibitors. AB - Published studies suggest that bypass therapy assay testing can be used to predict treatment response and dosing requirements for haemophilia patients with inhibitors. The aim of this study was to evaluate the costs of utilizing and not utilizing bypass therapy assay testing before treating mild-to-moderate bleeding episodes on-demand in haemophilia patients with inhibitors from a US third-party payer perspective. In our exploratory decision tree model, the average patient was assumed to be an adult weighing 75 kg. Based on existing head-to-head clinical trials, the efficacy of activated prothrombin complex (aPCC) and recombinant factor VIIa (rFVIIa) was assumed to be equivalent and based on expert opinion of the haematologist in our study it was conservatively assumed that assay testing improves the efficacy of both the bypassing agents by 10%. Probabilistic and one-way sensitivity analyses were used to determine the robustness of the results. Cost savings per bleeding episode were estimated at $6886 (95% CI = $4310-7978) for aPCC and $7647 (95% CI = $3134-10 388) for rFVIIa treatment. This translates in potential cost savings of 24.8% (95% CI = 15.5 28.8%) for aPCC use and 18.2% (95% CI = 8-24.7%) for rFVIIa use. Furthermore, if testing successfully predicts the optimum dose for concomitant therapy at the onset of bleeding, significant cost savings were observed compared with rFVIIa and aPCC therapies alone. Use of bypass therapy assay testing before treatment administration in haemophilia inhibitor patients can potentially reduce treatment costs significantly while optimizing dose and therapy response. PMID- 23672763 TI - Self-perceived physical health predicts cardiovascular disease incidence and death among postmenopausal women. AB - BACKGROUND: Physical and Mental Component Summary (PCS, MCS, respectively) scales of SF- 36 health-related-quality-of-life have been associated with all-cause and cardiovascular disease (CVD) mortality. Their relationships with CVD incidence are unclear. This study purpose was to test whether PCS and/or MCS were associated with CVD incidence and death. METHODS: Postmenopausal women (aged 50 79 years) in control groups of the Women's Health Initiative clinical trials (n = 20,308) completed the SF-36 and standardized questionnaires at trial entry. Health outcomes, assessed semi-annually, were verified with medical records. Cox regressions assessed time to selected outcomes during the trial phase (1993 2005). RESULTS: A total of 1075 incident CVD events, 204 CVD-specific deaths, and 1043 total deaths occurred during the trial phase. Women with low versus high baseline PCS scores had less favorable health profiles at baseline. In multivariable models adjusting for baseline confounders, participants in the lowest PCS quintile (reference = highest quintile) exhibited 1.8 (95%CI: 1.4, 2.3), 4.7 (95%CI: 2.3, 9.4), and 2.1 (95%CI: 1.7, 2.7) times greater risk of CVD incidence, CVD-specific death, and total mortality, respectively, by trial end; whereas, MCS was not significantly associated with CVD incidence or death. CONCLUSION: Physical health, assessed by self-report of physical functioning, is a strong predictor of CVD incidence and death in postmenopausal women; similar self-assessment of mental health is not. PCS should be evaluated as a screening tool to identify older women at high risk for CVD development and death. PMID- 23672766 TI - Somatostatin receptor expression in thyroid disease. AB - Somatostatin analogues are commercially available and used for the management of acromegaly and neuroendocrine tumours, but the expression of the receptors as a target in thyroid disease has not been explored. To assess somatostatin (SST) and somatostatin receptor (SSTR1-5) expression in both normal and thyroid disorders, as a potential target for somatostatin analogue therapy, 67 thyroid tissue specimens were reviewed: 12 differentiated thyroid carcinomas, 14 follicular adenomas, 17 multinodular goitres, 14 Graves disease, 10 Hashimotos thyroiditis specimens and five normal thyroids. Tissue was immunostained for SST and SSTR1-5. Positivity and the degree of positivity were recorded by double-blinded observers. Somatostatin receptor expression was highly expressed in normal tissue for SSTR1, 3, 4 and 5 (5 of 5, 4 of 5, 4 of 5 and 5 of 5 respectively) whilst SST and SSTR 2a and b were not expressed at all. The commonest receptor expressed for all pathological subtypes grouped together was SSTR2b (63 specimens). The commonest receptors expressed in differentiated thyroid cancer were SSTR5 (11 of 12 specimens) and SSTR2b (10 of 12 specimens). The commonest receptor expressed in benign disease was SSTR2b (53 of 55 specimens). SSTR5 was significantly under expressed in Graves disease (P < 0.05). This study illustrates that SSTR 1, 3, 4 and 5 are highly expressed in normal, benign and malignant thyroid tissue. SSTR 2a and 2b appear absent in normal tissue and present in benign and malignant thyroid tissue (P < 0.02). This suggests that focussed SSTR2 treatment may be a potential therapeutic target. PMID- 23672767 TI - Foetal exposure to Panax ginseng extract reverts the effects of prenatal dexamethasone in the synthesis of testosterone by Leydig cells of the adult rat. AB - The aim of this study was to examine the effect of maternal exposure to Panax ginseng extract (GE) on the prenatal dexamethasone (DEXA)-induced increase in testosterone production by isolated Leydig cells in adult rats. Pregnant rats were treated with (i) GE (200 mg/kg) or vehicle on days 10-21; (ii) DEXA (100 MUg/kg) or vehicle on days 14-21; or (iii) a combination of GE plus DEXA at the same doses and with the same regimen. Testosterone production was induced either by the activator of protein kinase A (dbcAMP) or substrates of steroidogenesis [22(R)-hydroxycholesterol (22(R)-OH-C)] and pregnenolone. The capacity of rat Leydig cells exposed to DEXA to synthesize testosterone induced by dbcAMP, 22(R) OH-C or pregnenolone was increased in comparison with the control group. Combined exposure to DEXA + GE prevented the effect of DEXA on the responsiveness of Leydig cells to all inductors of testosterone synthesis, whereas GE alone did not modify the response to inductors. No modifications in testosterone production were observed under basal conditions. StAR immunoexpression in Leydig cells was not modified by prenatal exposure to DEXA, GE or DEXA + GE. P450scc and glucocorticoid receptor immunoexpression was higher in offspring exposed to DEXA in comparison with the control group. This increased expression was prevented by combined treatment with DEXA + GE. The present findings demonstrate that GE is capable of reversing the effect of DEXA on testosterone synthesis by rat Leydig cells. PMID- 23672768 TI - Gearing up for action: attentive tracking dynamically tunes sensory and motor oscillations in the alpha and beta band. AB - Allocation of attention during goal-directed behavior entails simultaneous processing of relevant and attenuation of irrelevant information. How the brain delegates such processes when confronted with dynamic (biological motion) stimuli and harnesses relevant sensory information for sculpting prospective responses remains unclear. We analyzed neuromagnetic signals that were recorded while participants attentively tracked an actor's pointing movement that ended at the location where subsequently the response-cue indicated the required response. We found the observers' spatial allocation of attention to be dynamically reflected in lateralized parieto-occipital alpha (8-12 Hz) activity and to have a lasting influence on motor preparation. Specifically, beta (16-25 Hz) power modulation reflected observers' tendency to selectively prepare for a spatially compatible response even before knowing the required one. We discuss the observed frequency specific and temporally evolving neural activity within a framework of integrated visuomotor processing and point towards possible implications about the mechanisms involved in action observation. PMID- 23672770 TI - Sleep, impulse control, and sensation-seeking predict delinquent behavior in adolescents, emerging adults, and adults. AB - PURPOSE: The present study examined delinquent behavior from adolescence into adulthood within the dual systems model of adolescent risk-taking, which identifies maturational patterns of socioemotional and cognitive control systems as predictors of risk-taking. The role of sleep was also investigated within the relationship. METHODS: Hierarchical regression and path analysis examined delinquency at three waves (1996, 2001, and 2008) of the National Longitudinal Study of Adolescent Health. RESULTS: Impulse control and sensation-seeking predicted concurrent delinquent behavior at all three waves, demonstrating the developmental shift as described within the dual systems model in which the relative contribution of sensation-seeking decreases from adolescence into adulthood, whereas the relative contribution of impulse control improves. Data also revealed that sleep duration and delayed bedtimes had both direct and indirect associations with delinquent behavior during adolescence; sleep duration did not directly predict such activity during later waves. CONCLUSION: The dual systems model of adolescent risk-taking appears to be predictive of delinquent behavior during adolescence and the transition into adulthood. Preliminary findings suggest the importance of considering both adolescent sleep and cognitive and socioemotional development during research and prevention efforts of delinquent behavior. PMID- 23672769 TI - Radial and tangential neuronal migration pathways in the human fetal brain: anatomically distinct patterns of diffusion MRI coherence. AB - Corticogenesis is underpinned by a complex process of subcortical neuroproliferation, followed by highly orchestrated cellular migration. A greater appreciation of the processes involved in human fetal corticogenesis is vital to gaining an understanding of how developmental disturbances originating in gestation could establish a variety of complex neuropathology manifesting in childhood, or even in adult life. Magnetic resonance imaging modalities offer a unique insight into anatomical structure, and increasingly infer information regarding underlying microstructure in the human brain. In this study we applied a combination of high-resolution structural and diffusion-weighted magnetic resonance imaging to a unique cohort of three post-mortem fetal brain specimens, aged between 19 and 22 post-conceptual weeks. Specifically, we sought to assess patterns of diffusion coherence associated with subcortical neuroproliferative structures: the pallial ventricular/subventricular zone and subpallial ganglionic eminence. Two distinct three-dimensional patterns of diffusion coherence were evident: a clear radial pattern originating in ventricular/subventricular zone, and a tangentio-radial patterns originating in ganglionic eminence. These patterns appeared to regress in a caudo-rostral and lateral-ventral to medial dorsal direction across the short period of fetal development under study. Our findings demonstrate for the first time distinct patterns of diffusion coherence associated with known anatomical proliferative structures. The radial pattern associated with dorsopallial ventricular/subventricular zone and the tangentio radial pattern associated with subpallial ganglionic eminence are consistent with reports of radial-glial mediated neuronal migration pathways identified during human corticogenesis, supported by our prior studies of comparative fetal diffusion MRI and histology. The ability to assess such pathways in the fetal brain using MR imaging offers a unique insight into three-dimensional trajectories beyond those visualized using traditional histological techniques. Our results suggest that ex-vivo fetal MRI is a potentially useful modality in understanding normal human development and various disease processes whose etiology may originate in aberrant fetal neuronal migration. PMID- 23672771 TI - Advances in superresolution optical fluctuation imaging (SOFI). AB - We review the concept of superresolution optical fluctuation imaging (SOFI), discuss its attributes and trade-offs (in comparison with other superresolution methods), and present superresolved images taken on samples stained with quantum dots, organic dyes, and plasmonic metal nanoparticles. We also discuss the prospects of SOFI for live cell superresolution imaging and for imaging with other (non-fluorescent) contrasts. PMID- 23672772 TI - Evaluation of adjunct extended-release quetiapine fumarate on sleep disturbance and quality in patients with major depressive disorder and an inadequate response to on-going antidepressant therapy. AB - Sleep disturbance is common in depression and is a risk factor for recurrence and suicide. This analysis evaluated the effects of adjunct extended-release quetiapine fumarate (quetiapine XR) on sleep disturbance and quality in patients with major depressive disorder (MDD) and an inadequate response to on-going antidepressant therapy. Pooled data from two 6-wk, randomized, double-blind, placebo-controlled trials were analysed post hoc. Patients received once-daily quetiapine XR [(150 mg/d), n = 309; (300 mg/d), n = 307] or placebo (n = 303) adjunct to on-going antidepressant therapy. Analyses included: change from randomization in Montgomery-Asberg Depression Rating Scale (MADRS) Item 4 (reduced sleep) score; Hamilton Rating Scale for Depression (HAMD) Items 4 (insomnia-early), 5 (insomnia-middle) and 6 (insomnia-late) scores; HAMD sleep disturbance factor (Items 4+5+6); Pittsburgh Sleep Quality Index (PSQI) global score. Change in MADRS total score was also evaluated in patients stratified by HAMD sleep disturbance factor score (high >= 4 and low < 4) at randomization. At week 6, adjunct quetiapine XR (150 and 300 mg/d) reduced MADRS Item 4, HAMD Items 4, 5 and 6, HAMD sleep disturbance factor and PSQI global scores from randomization vs. placebo (all p < 0.001). In patients with high sleep disturbance, quetiapine XR (both doses) improved depressive symptoms (MADRS total score) vs. placebo from week 1 onwards (p < 0.01). Adjunct quetiapine XR improved sleep disturbance and quality vs. placebo in patients with MDD and an inadequate response to on-going antidepressant treatment, and was effective against depressive symptoms in patients experiencing high sleep disturbance. PMID- 23672773 TI - Zone 1 flexor tendon injuries: a review of the current treatment options for acute injuries. AB - Zone 1 flexor tendon avulsion and laceration injuries are commonly managed by plastic surgeons. These injuries are traditionally repaired using the button pullout technique originally described by Bunnell in 1940. The morbidity related to this method is well documented and this has lead to the development of alternative repair methods. These include modifications of the pullout button technique, internal suture techniques and more recently techniques using bone anchors. However, at present no one technique has been shown to be superior to the others either in terms of outcome or low complication rates. This review examines the published techniques for dealing with these injuries with a view to providing the reader with the available outcome data for each repair type. PMID- 23672774 TI - Commentary to 'Botulinum toxin injection of both sides of the face to treat post paralytic facial synkinesis'. PMID- 23672775 TI - Double trouble: rugby associated simultaneous rupture of flexor digitorum profundus tendon in zones I and III. AB - Sporting-related finger injuries are common in the setting of contact sports. Traumatic rupture of the flexor digitorum profundus tendon (FDP) from its insertion point has been described as 'jersey' or 'rugger' finger. We report a case of jersey finger associated with a zone III intra-tendinous rupture in a 13 year-old boy who presented seven weeks post injury. In the literature to date, only one previous case has described a sporting-related simultaneous 'double' FDP rupture. PMID- 23672776 TI - Bilateral pre-expanded free TFL flaps for reconstruction of severe thoracic scar contractures in an 8-year-old girl. AB - We present the case of an 8-year-old girl who suffered from acute myeloid leukaemia-related necrotising fasciitis in her early childhood resulting in severe skin and soft-tissue loss with subsequent circumferential thoracic scar formation. While tissue expander use yielded successful skin replacement for median scar areas, ribs were covered with ultrathin skin envelope at the lateral thoracic wall leading to growth and shoulder abduction impairment. Skin and soft tissue reconstruction of these extended rib areas was aimed for in a one-step approach. Both lateral thoracic walls were successfully reconstructed with free microsurgical transfer of large pre-expanded tensor fasciae latae flaps, in order to enable future thoracic growth. PMID- 23672777 TI - Merkel cell carcinoma concurrent with Bowen's disease: two cases, one with an unusual immunophenotype. AB - The concurrence of Merkel cell carcinoma (MCC) and squamous cell carcinoma (SCC) is well known, and MCC concurrent with Bowen's disease has also been documented. Herein, we describe two cases of MCC concurrent with Bowen's disease, and one case exhibited an unusual immunophenotype. An 86-year-old male (Patient 1) and an 87-year-old female (Patient 2) presented with nodules of the chest and cheek, respectively. Histopathologic study revealed Bowen's disease and a proliferation of small round cells in the dermis and/or subcutis. Immunohistochemically, the round cells expressed endocrine markers. 'Dot' immunopositivity for cytokeratin (CK) (AE1/AE3) was observed in both patients. However, dot-like CK20 positivity was present only in the second tumor, and thyroid transcription factor-1 (TTF-1) was only positive in the first. Both cases were negative for Merkel cell polyomavirus (MCPyV). MCC concurrent with SCC usually does not involve detectable MCPyV infection, which suggests that combined MCC may develop through different tumorigenetic pathways, such as chronic ultraviolet exposure, as compared to pure MCC. Additionally, concurrent tumors may exhibit an unusual immunophenotype, such as TTF-1(+) /CK20((-)) . PMID- 23672778 TI - Optimization of the ligature-induced periodontitis model in mice. AB - Periodontitis is a prevalent oral inflammatory disease that leads to alveolar bone loss and may exert an adverse impact on systemic health. Experimental animal models are critical tools to investigate mechanisms of periodontal pathogenesis and test new therapeutic approaches. The ligature-induced periodontitis model has been used frequently in relatively large animals, including non-human primates, to assess the host response and its effects on the tooth-supporting tissues (gingiva and bone) under well-controlled conditions. Although mice constitute the most convenient and versatile model for mechanistic immunological research (plethora of genetically engineered strains and immunological reagents), the tiny size of the murine oral cavity has presented technical challenges for ligature placement. In this report, we present a straightforward method for ligating the second maxillary molar tooth, and, moreover, identified the most appropriate sites for evaluating inflammatory bone loss in a valid and reproducible manner. These optimizations are expected to facilitate the use of the mouse ligature induced periodontitis model and consequently contribute to better understanding of the immunopathological mechanisms of periodontitis. PMID- 23672780 TI - Factor XII-independent activation of the bradykinin-forming cascade: Implications for the pathogenesis of hereditary angioedema types I and II. AB - BACKGROUND: We have previously reported that prekallikrein expresses an active site when it is bound to high-molecular-weight kininogen (HK) and can digest HK to produce bradykinin. The reaction is stoichiometric and inhibited by C1 inhibitor (C1-INH) or corn trypsin inhibitor. Addition of heat shock protein 90 leads to conversion of prekallikrein to kallikrein in a zinc-dependent reaction. OBJECTIVE: Our goal was to determine whether these reactions are demonstrable in plasma and distinguish them from activation through factor XII. METHODS: Plasma was incubated in polystyrene plates and assayed for kallikrein formation. C1-INH was removed from factor XII-deficient plasma by means of immunoadsorption. RESULTS: We demonstrate that prekallikrein-HK will activate to kallikrein in phosphate-containing buffers and that the rate is further accelerated on addition of heat shock protein 90. Prolonged incubation of plasma deficient in both factor XII and C1-INH led to conversion of prekallikrein to kallikrein and cleavage of HK, as was seen in plasma from patients with hereditary angioedema but not plasma from healthy subjects. CONCLUSIONS: These results indicate that C1-INH stabilizes the prekallikrein-HK complex to prevent HK cleavage either by prekallikrein or by prekallikrein-HK autoactivation to generate kallikrein. In patients with hereditary angioedema, kallikrein and bradykinin formation can occur without invoking factor XII activation, although the kallikrein formed can rapidly activate factor XII if it is surface bound. PMID- 23672779 TI - Clinical review: Goal-directed therapy-what is the evidence in surgical patients? The effect on different risk groups. AB - Patients with limited cardiac reserve are less likely to survive and develop more complications following major surgery. By augmenting oxygen delivery index (DO2I) with a combination of intravenous fluids and inotropes (goal directed therapy (GDT)), postoperative mortality and morbidity of high-risk patients may be reduced. However, although most studies suggest that GDT may improve outcome in high-risk surgical patients, it is still not widely practiced. We set out to test the hypothesis that GDT results in greatest benefit in terms of mortality and morbidity in patients with the highest risk of mortality and have undertaken a systematic review of the current literature to see if this is correct. We performed a systematic search of Medline, Embase and CENTRAL databases for randomized controlled trials (RCTs) and reviews of GDT in surgical patients. To minimize heterogeneity we excluded studies involving cardiac, trauma, and paediatric surgery. Extremely high risk, high risk and intermediate risks of mortality were defined as >20%, 5 to 20% and <5% mortality rates in the control arms of the trials, respectively. Meta analyses were performed and Forest plots drawn using RevMan software. Data are presented as odd ratios (OR; 95% confidence intervals (CI), and P-values). A total of 32 RCTs including 2,808 patients were reviewed. All studies reported mortality. Five studies (including 300 patients) were excluded from assessment of complication rates as the number of patients with complications was not reported. The mortality benefit of GDT was confined to the extremely high-risk group (OR = 0.20, 95% CI 0.09 to 0.41; P < 0.0001). Complication rates were reduced in all subgroups (OR = 0.45, 95% CI 0.34 to 0.60; P < 0.00001). The morbidity benefit was greatest amongst patients in the extremely high-risk subgroup (OR = 0.27, 95% CI 0.15 to 0.51; P < 0.0001), followed by the intermediate risk subgroup (OR = 0.43, 95% CI 0.27 to 0.67; P = 0.0002), and the high-risk subgroup (OR 0.56, 95% CI 0.36 to 0.89; P = 0.01). Despite heterogeneity in trial quality and design, we found GDT to be beneficial in all high-risk patients undergoing major surgery. The mortality benefit of GDT was confined to the subgroup of patients at extremely high risk of death. The reduction of complication rates was seen across all subgroups of GDT patients. PMID- 23672781 TI - Activation of carbamazepine-responsive T-cell clones with metabolically inert halogenated derivatives. PMID- 23672782 TI - Development of a validated blood test for nickel sensitization. PMID- 23672783 TI - T-cell immunoglobulin and mucin domain 1 deficiency eliminates airway hyperreactivity triggered by the recognition of airway cell death. AB - BACKGROUND: Studies of asthma have been limited by a poor understanding of how nonallergic environmental exposures, such as air pollution and infection, are translated in the lung into inflammation and wheezing. OBJECTIVE: Our goal was to understand the mechanism of nonallergic asthma that leads to airway hyperreactivity (AHR), a cardinal feature of asthma independent of adaptive immunity. METHOD: We examined mouse models of experimental asthma in which AHR was induced by respiratory syncytial virus infection or ozone exposure using mice deficient in T-cell immunoglobulin and mucin domain 1 (TIM1/HAVCR1), an important asthma susceptibility gene. RESULTS: TIM1(-/-) mice did not have airways disease when infected with RSV or when repeatedly exposed to ozone, a major component of air pollution. On the other hand, the TIM1(-/-) mice had allergen-induced experimental asthma, as previously shown. The RSV- and ozone-induced pathways were blocked by treatment with caspase inhibitors, indicating an absolute requirement for programmed cell death and apoptosis. TIM-1-expressing, but not TIM-1-deficient, natural killer T cells responded to apoptotic airway epithelial cells by secreting cytokines, which mediated the development of AHR. CONCLUSION: We defined a novel pathway in which TIM-1, a receptor for phosphatidylserine expressed by apoptotic cells, drives the development of asthma by sensing and responding to injured and apoptotic airway epithelial cells. PMID- 23672785 TI - Disability associated with exposure to traumatic events: results from a cross sectional community survey in South Sudan. AB - BACKGROUND: There is a general lack of knowledge regarding disability and especially factors that are associated with disability in low-income countries. We aimed to study the overall and gender-specific prevalence of disability, and the association between exposure to traumatic events and disability in a post conflict setting. METHODS: We conducted a cross-sectional community based study of four Greater Bahr el Ghazal States, South Sudan (n = 1200). The Harvard Trauma Questionnaire (HTQ) was applied to investigate exposure to trauma events. Disability was measured using the Washington Group Short Measurement Set on Disability, which is an activity-based scale derived from the WHO's International Classification of Disability, Functioning and Health. RESULTS: The estimated prevalence of disability (with severe difficulty) was 3.6% and 13.4% for disability with moderate difficulties. No gender differences were found in disability prevalence. Almost all participants reported exposure to at least one war-related traumatic event. The result of a hierarchical regression analysis showed that, for both men and women, exposure to traumatic events, older age and living in a polygamous marriage increased the likelihood of having a disability. CONCLUSIONS: The finding of association between traumatic experience and disability underlines the precariousness of the human rights situation for individuals with disability in low-income countries. It also has possible implications for the construction of disability services and for the provision of health services to individuals exposed to traumatic events. PMID- 23672787 TI - Characteristics, management, and outcomes for patients during hospitalization due to worsening heart failure-A report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD). AB - BACKGROUND: The characteristics, in-hospital management, and outcomes of patients hospitalized with worsening heart failure (HF) have been described by large-scale registries performed mainly in the USA and Europe. However, little information is available in Japan. We thus clarified the characteristics and clinical status as well as in-hospital management and outcomes among patients hospitalized with worsening HF in Japan and compared them with those reported in previous studies. METHODS: The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE CARD) studied prospectively the characteristics and treatments in patients hospitalized with worsening HF. From the total cohort of JCARE-CARD, 1677 patients were randomly selected and their detailed data during acute phase were collected as another registry database in the present study. The characteristics, in-hospital management, and outcomes were analyzed. RESULTS: The mean age was 70.7 years and 59.4% were male. Etiology was ischemic in 34.0% and mean left ventricular ejection fraction was 42.5%. Carperitide was highly used as in hospital management in Japan (33.5%) compared to the use of nesiritide in the USA (8-11%). The use of angiotensin-converting enzyme inhibitors was lower and angiotensin II receptor blockers (ARB) were more commonly used in this study compared to other studies in the USA and Europe. In-hospital crude mortality rate was comparable among studies (4-8%), however, length of stay was longer in Japan (15-20 versus 4-9 days). CONCLUSIONS: The characteristics, clinical status, and laboratory data on admission in patients hospitalized with worsening HF were similar between the present study and previous Japanese and western studies. Management was also similar except for higher use of carperitide and ARB. The most striking difference between Japanese registries and those from the USA and Europe was the longer length of stay. PMID- 23672786 TI - Systemic vaccination with anti-oligomeric monoclonal antibodies improves cognitive function by reducing Abeta deposition and tau pathology in 3xTg-AD mice. AB - Alzheimer's disease (AD) is a devastating disorder that is clinically characterized by a comprehensive cognitive decline. Accumulation of the amyloid beta (Abeta) peptide plays a pivotal role in the pathogenesis of AD. In AD, the conversion of Abeta from a physiological soluble monomeric form into insoluble fibrillar conformation is an important event. The most toxic form of Abeta is oligomers, which is the intermediate step during the conversion of monomeric form to fibrillar form. There are at least two types of oligomers: oligomers that are immunologically related to fibrils and those that are not. In transgenic AD animal models, both active and passive anti-Abeta immunotherapies improve cognitive function and clear the parenchymal accumulation of amyloid plaques in the brain. In this report we studied effect of immunotherapy of two sequence independent non-fibrillar oligomer specific monoclonal antibodies on the cognitive function, amyloid load and tau pathology in 3xTg-AD mice. Anti oligomeric monoclonal antibodies significantly reduce the amyloid load and improve the cognition. The clearance of amyloid load was significantly correlated with reduced tau hyperphosphorylation and improvement in cognition. These results demonstrate that systemic immunotherapy using oligomer-specific monoclonal antibodies effectively attenuates behavioral and pathological impairments in 3xTg AD mice. These findings demonstrate the potential of using oligomer specific monoclonal antibodies as a therapeutic approach to prevent and treat Alzheimer's disease. PMID- 23672788 TI - Quantitative validation of left atrial structure and function by two-dimensional and three-dimensional speckle tracking echocardiography: a comparative study with three-dimensional computed tomography. AB - BACKGROUND: The aim of this study was to validate the accuracy of three dimensional (3D) speckle tracking echocardiography (STE) and two-dimensional (2D) STE for the assessment of left atrial (LA) volume and function by comparison with 3D-computed tomography (CT) performed on the same day as STE. METHODS: LA phasic volume and emptying function (EF) were measured in 28 patients with paroxysmal atrial fibrillation undergoing catheter ablation (62+/-11 years old) using both 3D-STE and 2D-STE during sinus rhythm. LA phasic volume and function measured by 3D-STE and 2D-STE were validated using 3D-CT as a gold standard. RESULTS: The intraobserver correlation coefficient and variability in maximum LA volume assessed by 3D-STE were 0.99 and 1.4+/-6.0%, respectively. The interobserver correlation coefficient and variability in maximum LA volume assessed by 3D-STE were 0.99 and 0.2+/-4.5%, respectively. There were strong correlations between LA phasic volume measured by 3D-CT and those measured by 3D-STE (r=0.98, p<0.001). There were correlations between LA phasic function measured by 3D-CT and those measured by 3D-STE (r=0.85-0.88, p<0.001). There was a better agreement between 3D-CT and 3D-STE in the assessment of LA phasic volumes and function than between 3D-CT and 2D-STE in apical 2- and 4-chamber view. CONCLUSIONS: 3D-STE allows more accurate measurement of LA volume and function than 2D-STE and has high reproducibility. PMID- 23672790 TI - Heart failure: what does ejection fraction have to do with it? AB - Heart failure (HF) occurs across the entire range of left ventricular (LV) ejection fractions (EF), not just reduced EF. Nearly half or more patients presenting with HF have a preserved EF>0.50 (HFpEF). Diastolic dysfunction is apparent in all patients with HF, regardless of EF. A preserved EF indicates that the end-diastolic volume is appropriate for the stroke volume, and a reduced EF indicates that the end-diastolic volume is enlarged relative to stroke volume (i.e. the LV is dilated). Most therapies proven to be effective in HF with a reduced EF (ACE-inhibitors, angiotensin receptor blockers, beta-blockers, and cardiac resynchronization) reverse LV dilation. These therapies have not been proven to be effective in HFpEF. Increasing c-GMP may be a treatment target in HFpEF, and potential ways of increasing c-GMP are being studied. Finally, comorbidities are important in HFpEF and are additional targets for therapy. PMID- 23672789 TI - Comparison of pitavastatin with atorvastatin in increasing HDL-cholesterol and adiponectin in patients with dyslipidemia and coronary artery disease: the COMPACT-CAD study. AB - BACKGROUND: Many large-scale clinical trials have confirmed that statins are effective in reducing low-density lipoprotein cholesterol (LDL-C) level, resulting in reducing cardiovascular events. Recent studies have focused on the effects of statins on high-density lipoprotein cholesterol (HDL-C). Here we compared the effects of two statins on lipid profile and other metabolic parameters. METHODS: The study population included 129 patients with stable coronary artery disease, hypercholesterolemia, and hypo-HDL-cholesterolemia (HDL C<50mg/dl). They were randomly allocated to treatment by pitavastatin 2-4 mg/day or atorvastatin 10-20mg/day and followed-up for 30 months. The primary endpoint was percent changes in HDL-C and adiponectin during the study. The secondary endpoints were percent and absolute changes in markers of glucose metabolism, serum lipids, and apolipoproteins. RESULTS: The effects of 30-month treatment with pitavastatin on HDL-C were significantly greater than those of atorvastatin (%change: pitavastatin: 20.1 +/- 25.7%, atorvastatin: 6.3 +/- 19.8%, p=0.01; absolute change: pitavastatin: 7.3 +/- 9.1mg/dl, atorvastatin: 2.3 +/- 8.0mg/dl, p=0.02). A similar trend was seen with regard to apolipoprotein-AI (ApoAI) (%change: pitavastatin: 20.8 +/- 19.3%, atorvastatin: 11.4 +/- 17.6%, p=0.03; absolute change: pitavastatin: 23.1 +/- 20.2mg/dl, atorvastatin: 12.1 +/- 19.4 mg/dl, p=0.02). Treatment with pitavastatin, but not atorvastatin, significantly increased adiponectin levels. Neither statin had a significant effect on hemoglobin A1c. No severe adverse events were registered during the study. CONCLUSION: Long-term treatment with pitavastatin resulted in significantly greater increases in serum HDL-C and ApoAI levels without adverse effects on glucose metabolism, compared with atorvastatin. PMID- 23672791 TI - The association between metacarpal ratio, radiographic hand and knee osteoarthritis and its progression after meniscectomy. AB - OBJECTIVE: To examine whether the ratio of the second and fourth metacarpal bone length (MC2:MC4) in subjects with prior meniscectomy of the knee is associated with radiographic hand and knee osteoarthritis (OA) and its progression. DESIGN: We assessed 219 subjects (175 men and 44 women) twice with a follow-up time ranging from 4 to 10 years. Participants had all undergone prior meniscectomy. The subjects were of mean (SD) 53 (11) years of age at the first radiographic examination. One observer measured the metacarpal lengths of both hands. We used the average MC2:MC4 from left and right hand divided into tertiles as the exposure variable, using the highest tertile, i.e., "female" pattern as reference category. Radiographic OA of both hands and knees and its progression were evaluated on subject level as our outcomes. We used logistic regression to evaluate the possible association of MC2:MC4 with hand and knee OA and its progression with adjustment for age, sex, body mass index, and follow-up time. RESULTS: We found no statistically significant association between the lower MC2:MC4 tertile "male" pattern and prevalent hand OA (odds ratio [OR] 0.70; 95% confidence interval [CI] 0.24-1.99) and prevalent knee OA (OR 1.08; 95% CI 0.56 2.07). Neither did we find any corresponding significant association for the progression of hand OA (OR 0.89; 95% CI 0.34-2.32), nor knee OA (OR 0.69; 95% CI 0.33-1.46). CONCLUSIONS: We did not detect any association between MC2:MC4 and radiographic hand and knee OA and its progression in subjects with prior meniscectomy. PMID- 23672792 TI - Bone density is higher in cam-type femoroacetabular impingement deformities compared to normal subchondral bone. AB - OBJECTIVE: Cam-type femoroacetabular impingement (FAI) deformities have been associated with early osteoarthritic degeneration of the hip. Degeneration depends on many factors such as joint morphology and dynamics of motion. Bone mineral density (BMD) appears to be a manifestation of the above, and may be a potentiator. Thus the goal of this study was to assess subchondral BMD of cam deformities in symptomatic and asymptomatic FAI subjects, and to compare to normal controls. METHODS: Subjects undergoing surgical correction of a symptomatic cam-type deformity were recruited ("Surgical"). Asymptomatic volunteers were also recruited and classified as normal ("Control") or having a deformity ("Bump") based on their alpha angle measurement. All subjects (n = 12 per group) underwent computed tomography (CT) with a calibration phantom. BMD was determined in volumes of interest around the femoral head and neck to a depth of 5 mm. BMD was compared between groups in each section using spine BMD as a covariate. RESULTS: No differences were seen between groups in the peripheral bearing surface. The Bump group exhibited higher BMD than Controls within the head/neck junction (P < 0.05). When compared to normal subchondral bone in the peripheral level of Controls, BMD in the deformity was up to 78% higher in Bump subjects and up to 47% higher in Surgical subjects (P < 0.05). CONCLUSION: Subchondral BMD of cam deformities is higher than that of normal subchondral bone in the peripheral region of the femoral head, regardless of symptom status. The expected increased subchondral stiffness may increase contact stresses in the joint tissues leading to accelerated degeneration. PMID- 23672793 TI - Description of a novel viral tool to identify and quantify ovine faecal pollution in the environment. AB - Farmed animals such as sheep, cattle, swine and poultry play an important role in microbial contamination of water, crops and food, and introduce large quantities of pathogens into the environment. The ability to determine the origin of faecal pollution in water resources is essential when establishing a robust and efficient water management system. Animal-specific viruses have previously been suggested as microbial source tracking tools, but specific ovine viral markers have not been reported before now. Previous studies have shown that polyomaviruses are host-specific, highly prevalent and are commonly excreted in urine. Furthermore, they have been reported to infect several vertebrate species but not sheep. That situation encouraged the study of a new putative ovine polyomavirus (OPyV) and its use to determine whether faecal pollution originates from ovine faecal/urine contamination. Putative OPyV DNA was amplified from ovine urine and faecal samples using a broad-spectrum nested PCR (nPCR). Specific nested PCR and quantitative PCR assays were developed and applied to faecal and environmental samples, including sheep slurries, slaughterhouse wastewater effluents, urban sewage and river water samples. Successful amplification by PCR was achieved in sheep urine samples, sheep slaughterhouse wastewater and downstream sewage effluents. The assay was specific and was negative in samples of human, bovine, goat, swine and chicken origin. Ovine faecal pollution was detected in river water samples by applying the designed methods. These results provide a quantitative tool for the analysis of OPyV as a suitable viral indicator of sheep faecal contamination that may be present in the environment. PMID- 23672794 TI - Interaction between density and Cu toxicity for Enchytraeus crypticus--comparing first and second generation effects. AB - Density of organisms varies considerably in nature depending e.g. on seasonality or food availability. A recent investigation on interaction between Cu and density using Enchytraeus crypticus showed that density itself (5-50 per 20 gr dry soil) had an impact on population and individual growth [up to 3000 individuals per test vessel], but the interaction between density and Cu toxicity was not significant. Here, a follow-up study was performed, in which the interactions between density and Cu-exposure were investigated along a two generation exposure using E. crypticus (three factorial: 1. density (5-50), 2. Cu (0-300 mg/kg) and generation (G1-G2)). After G1, the juveniles were retrieved and further exposed under the same conditions along a G2 (using a refined density set - 10 and 50). Results showed an interaction between density and Cu in the reproduction of E. crypticus, this being significant in G2, showing lower toxicity for higher density of organisms whereas in the 1st generation the opposite occurred. Hence, there was an interaction seen along G1 to G2, i.e. animals from density 50 in G1 when further exposed at density 50 in G2 had lower Cu toxicity compared to when further exposed at density 10. Possible explanations include the hydra effect (overcompensation in G2 due to stress in G1) or that for density 50 the organisms are exposed to less Cu than at lower densities, this by e.g. (1) organisms avoid exposure by lumping/clustering which would limit exposure to Cu and (2) there would be less available Cu contaminated soil per individual at high density hence less exposure. PMID- 23672795 TI - Biomechanical comparison of locked plating and spiral blade retrograde nailing of supracondylar femur fractures. AB - OBJECTIVE: Biomechanical comparison between locked plating and retrograde nailing of supracondylar femur fractures with simulated postoperative weight-bearing. METHODS: The Locking Condylar Plate (LCP) and Retrograde/Antegrade EX Femoral Nail (RAFN) were tested using 10 paired elderly cadaveric femurs, divided into Normal and Low Bone Mineral Density (BMD) groups, with a simulated AO/OTA type 33 A3 supracondylar femur fracture. Each specimen was subjected to 200,000 loading cycles in an attempt to simulate six weeks of postoperative recovery with full weight-bearing for an average individual. The construct's subsidence due to cyclic loading, and axial stiffness before and after the cyclic loading were measured and their correlation with BMD was studied. The two implants were compared in a paired study within each BMD group. RESULTS: LCP constructs showed higher axial stiffness compared to RAFN for both Normal and Low BMD groups (80% and 57%, respectively). After cyclic loading, axial stiffness of both constructs decreased by 20% and RAFN constructs resulted in twice as much subsidence (1.9 +/ 0.6mm). Two RAFN constructs with Low BMD failed after a few cycles whereas the matched pairs fixed with LCP failed after 70,000 cycles. CONCLUSIONS: The RAFN constructs experienced greater subsidence and reduced axial stiffness compared to the LCP constructs. In Low BMD specimens, the RAFN constructs had a higher risk of failure. PMID- 23672796 TI - The effects of brain serotonin deficiency on behavioural disinhibition and anxiety-like behaviour following mild early life stress. AB - Aberrant serotonin (5-HT) signalling and exposure to early life stress have both been suggested to play a role in anxiety- and impulsivity-related behaviours. However, whether congenital 5-HT deficiency * early life stress interactions influence the development of anxiety- or impulsivity-like behaviour has not been established. Here, we examined the effects of early life maternal separation (MS) stress on anxiety-like behaviour and behavioural disinhibition, a type of impulsivity-like behaviour, in wild-type (WT) and tryptophan hydroxylase 2 (Tph2) knock-in (Tph2KI) mice, which exhibit ~60-80% reductions in the levels of brain 5 HT due to a R439H mutation in Tph2. We also investigated the effects of 5-HT deficiency and early life stress on adult hippocampal neurogenesis, plasma corticosterone levels and several signal transduction pathways in the amygdala. We demonstrate that MS slightly increases anxiety-like behaviour in WT mice and induces behavioural disinhibition in Tph2KI animals. We also demonstrate that MS leads to a slight decrease in cell proliferation within the hippocampus and potentiates corticosterone responses to acute stress, but these effects are not affected by brain 5-HT deficiency. However, we show that 5-HT deficiency leads to significant alterations in SGK-1 and GSK3beta signalling and NMDA receptor expression in the amygdala in response to MS. Together, these findings support a potential role for 5-HT-dependent signalling in the amygdala in regulating the long-term effects of early life stress on anxiety-like behaviour and behavioural disinhibition. PMID- 23672797 TI - Large animal models for stem cell therapy. AB - The field of regenerative medicine is approaching translation to clinical practice, and significant safety concerns and knowledge gaps have become clear as clinical practitioners are considering the potential risks and benefits of cell based therapy. It is necessary to understand the full spectrum of stem cell actions and preclinical evidence for safety and therapeutic efficacy. The role of animal models for gaining this information has increased substantially. There is an urgent need for novel animal models to expand the range of current studies, most of which have been conducted in rodents. Extant models are providing important information but have limitations for a variety of disease categories and can have different size and physiology relative to humans. These differences can preclude the ability to reproduce the results of animal-based preclinical studies in human trials. Larger animal species, such as rabbits, dogs, pigs, sheep, goats, and non-human primates, are better predictors of responses in humans than are rodents, but in each case it will be necessary to choose the best model for a specific application. There is a wide spectrum of potential stem cell based products that can be used for regenerative medicine, including embryonic and induced pluripotent stem cells, somatic stem cells, and differentiated cellular progeny. The state of knowledge and availability of these cells from large animals vary among species. In most cases, significant effort is required for establishing and characterizing cell lines, comparing behavior to human analogs, and testing potential applications. Stem cell-based therapies present significant safety challenges, which cannot be addressed by traditional procedures and require the development of new protocols and test systems, for which the rigorous use of larger animal species more closely resembling human behavior will be required. In this article, we discuss the current status and challenges of and several major directions for the future development of large animal models to facilitate advances in stem cell-based regenerative medicine. PMID- 23672799 TI - Teledentistry in practice: literature review. AB - Teledentistry can be defined as the remote provision of dental care, advice, or treatment through the medium of information technology, rather than through direct personal contact with any patient(s) involved. Within dental practice, teledentistry is used extensively in disciplines like preventive dentistry, orthodontics, endodontics, oral surgery, periodontal conditions, detection of early dental caries, patient education, oral medicine, and diagnosis. Some of the key modes and methods used in teledentistry are electronic health records, electronic referral systems, digitizing images, teleconsultations, and telediagnosis. All the applications used in teledentistry aim to bring about efficiency, provide access to underserved population, improve quality of care, and reduce oral disease burden. PMID- 23672798 TI - Development and practice of a Telehealthcare Expert System (TES). AB - OBJECTIVE: Expert systems have been widely used in medical and healthcare practice for various purposes. In addition to vital sign data, important concerns in telehealthcare include the compliance with the measurement prescription, the accuracy of vital sign measurements, and the functioning of vital sign meters and home gateways. However, few expert system applications are found in the telehealthcare domain to address these issues. MATERIALS AND METHODS: This article presents an expert system application for one of the largest commercialized telehealthcare practices in Taiwan by Min-Sheng General Hospital. The main function of the Telehealthcare Expert System (TES) developed in this research is to detect and classify events based on the measurement data transmitted to the database at the call center, including abnormality of vital signs, violation of vital sign measurement prescriptions, and malfunction of hardware devices (home gateway and vital sign meter). When the expert system detects an abnormal event, it assigns an "urgent degree" and alerts the nursing team in the call center to take action, such as phoning the patient for counseling or to urge the patient to return to the hospital for further tests. RESULTS: During 2 years of clinical practice, from 2009 to 2011, 19,182 patients were served by the expert system. The expert system detected 41,755 events, of which 22.9% indicated abnormality of vital signs, 75.2% indicated violation of measurement prescription, and 1.9% indicated malfunction of devices. On average, the expert system reduced by 76.5% the time that the nursing team in the call center spent in handling the events. CONCLUSIONS: The expert system helped to reduce cost and improve quality of the telehealthcare service. PMID- 23672800 TI - Home telehealth in high-risk dialysis patients: a 3-year study. AB - OBJECTIVE: This study is a continuation of a previous pilot project that demonstrated improved health outcomes and significant cost savings using home telehealth with nurse oversight in patients with end-stage renal disease undergoing chronic dialysis. We are reporting the results of a larger sample size over a 3-year study period to test the validity of our original observations. SUBJECTS AND METHODS: Ninety-nine patients were included in this study; 43 (18 females, 25 males) with a mean age of 58.6 years were enrolled in the remote technology (RT) group, and 56 (26 females, 30 males) with a mean age of 63.1 years were enrolled in the usual-care (UC) group. Health resource outcome measures included hospitalizations, emergency room (ER) visits, and number of days hospitalized. Economic analysis was conducted on hospital and ER charges. RESULTS: Hospitalizations (RT, 1.8; UC, 3.0), hospital days (RT, 11.6; UC, 25.0), and hospital and ER charges (RT, $66,000; UC, $157,000) were significantly lower in the RT group, as were hospital and ER charges per study day (RT, $159; UC, $317). CONCLUSIONS: The results support our previous findings, that is, home telehealth can contribute to improved health outcomes and cost of care in high risk dialysis patients. PMID- 23672802 TI - Treatment of T1b glottic SCC: laser vs. radiation--a Canadian multicenter study. AB - OBJECTIVE: To assess the oncological and functional outcomes of T1b squamous cell carcinoma (SCC) of the glottic larynx treated with laser in comparison with radiation. DESIGN: A Canadian multicenter cohort study. SETTING: Three tertiary referral centers for head and neck cancer- Dalhousie University in Halifax, Nova Scotia, Western University in London, Ontario and the University of Manitoba, Winnipeg. METHODS: Patients with T1b glottic SCC who underwent transoral laser resection or radiation as the primary modality of treatment. OUTCOME MEASURES: Oncological outcomes were evaluated using local control, laryngeal preservation, disease free survival and disease specific survival. Voice outcomes were assessed using the Voice Handicap Index-10 (VHI-10). RESULTS: 63 patients met study criteria. 21 were treated with laser and 42 with radiation. Oncologic outcomes at 2 years for laser and radiation demonstrated local control of 95% and 85.9%; laryngeal preservation of 100% and 85.9%; disease free survival of 88.7% and 85.9% and overall survival of 94.1% and 94.8% respectively. VHI-10 data was available for 23/63 patients. During the last follow up visit VHI-10 ranged from 0 to 11 (median 6) in the laser group and 0 to 34 (median 7) in the radiation group. CONCLUSION: T1b SCC of the glottis can be effectively treated with transoral laser microsurgery with oncological outcomes that are at least equivalent to radiation. For patients with VHI scores, voice quality was similar between the two groups. To our knowledge this is the first study directly comparing the oncologic and voice outcomes with laser and radiation for the treatment of glottic cancer involving the anterior commissure. PMID- 23672803 TI - Interaction of omega-3 polyunsaturated fatty acids with radiation therapy in two different colorectal cancer cell lines. AB - BACKGROUND & AIMS: This study aims at evaluating if docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) increases the efficacy of radiation therapy (RT) on two human colorectal cancer cell lines with different radio-sensitivity. METHODS: LS174T and HT-29 cells were treated with 20 or 50 MUmol/L EPA or DHA followed by single X-ray RT of 0, 2 or 4 Gy, to evaluate cell survival, apoptosis, peroxide and malondialdehyde productions. Inflammation- and apoptosis-related proteins were analyzed by Western Blot. ANOVAs were used for statistical analysis. RESULTS: LS174T was more sensitive to RT than HT-29. DHA and to a lesser extent EPA increased cell death, apoptosis and peroxide production after RT in LS174T and to a lesser extent in HT-29 (p < 0.05). This was associated with increased expression of heat shock protein 70, decreased expression of NF-kB p65, COX-2 and Bcl-2 proteins. CONCLUSIONS: The effect of RT combination with DHA and to a lesser extent EPA was synergistic in the radio-sensitive LS174T cells, but additive in the radio-resistant HT-29 cells. This enhanced cytotoxicity was provoked at least partly by lipid peroxidation, which consequently modulated inflammatory response and induced apoptosis. PMID- 23672805 TI - Optimal dosage and dwell time of ethanol lock therapy on catheters infected with Candida species. AB - BACKGROUND & AIMS: Anti-infective lock therapy is a treatment strategy in conjunction with systemic antifungal agents for the treatment of intravascular catheter infections caused by fungi. In this study, the optimal dosage and dwell time of ethanol lock solution (ELS) effective against catheters infected by Candida species were assessed. METHODS: Biofilm forming isolates of Candida albicans, Candida parapsilosis and Candida tropicalis was used as the study isolates. Infected catheters were exposed to ELS at 20%, 30%, 40%, 60% and 80% strength for a variety dwell times (15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h). Fungal eradication was evaluated by the quantitative culture techniques. RESULTS: ELS's with 40% and greater strength sterilized the catheters within 30 min. Lower strength of ELS's (20% and 30%) sterilized the catheters in 24 h and 2 h, respectively. CONCLUSIONS: According to the study, lock therapy with >=40% ethanol for 30 min appear to be the optimal schedule in sterilizing Candida infected catheters. Ethanol lock therapy with such concentrations and dwell time may be a useful adjunct to systemic anti-fungal antibiotics in sterilizing (and cleaning) and eradicating fungal catheter related infections in the hope of preserving crucial central venous access. PMID- 23672804 TI - Lipid content in hepatic and gonadal adipose tissue parallel aortic cholesterol accumulation in mice fed diets with different omega-6 PUFA to EPA plus DHA ratios. AB - BACKGROUND & AIMS: Diets with low omega (omega)-6 polyunsaturated fatty acids (PUFA) to eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) ratios have been shown to decrease aortic cholesterol accumulation and have been suggested to promote weight loss. The involvement of the liver and gonadal adipose tissue (GAT) in mediating these effects is not well understood. LDL receptor null mice were used to assess the effect of an atherogenic diet with different omega 6:EPA+DHA ratios on weight gain, hepatic and GAT lipid accumulation, and their relationship to atherosclerosis. METHODS: Four groups of mice were fed a high saturated fat and cholesterol diet (HSF omega-6) alone, or with omega-6 PUFA to EPA+DHA ratios up to 1:1 for 32 weeks. Liver and GAT were collected for lipid and gene expression analysis. RESULTS: The fatty acid profile of liver and GAT reflected the diets. All diets resulted in similar weight gains. Compared to HSF omega-6 diet, the 1:1 ratio diet resulted in lower hepatic total cholesterol (TC) content. Aortic TC was positively correlated with hepatic and GAT TC and triglyceride. These differences were accompanied by significantly lower expression of CD36, ATP-transporter cassette A1, scavenger receptor B class 1, 3 hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), acetyl-CoA carboxylase alpha, acyl-CoA synthetase long-chain family member 5, and stearoyl-coenzyme A desaturase 1 (SCD1) in GAT, and HMGCR, SCD1 and cytochrome P450 7A1 in liver. CONCLUSIONS: Dietary omega-6:EPA+DHA ratios did not affect body weight, but lower omega-6:EPA+DHA ratio diets decreased liver lipid accumulation, which possibly contributed to the lower aortic cholesterol accumulation. PMID- 23672806 TI - Endoscopic gastrostomy replacement tubes: long-term randomized trial with five silicone commercial models. AB - TRIAL DESIGN: No analysis of the long-term performance of percutaneous endoscopic gastrostomy (PEG) replacement tubes was identified. A randomized partially blinded trial was designed hypothesizing that clinically relevant limitations of the tubes would be identified. METHODS: Patients (N = 100, age 58.3 +/- 20.7 years, 42.0% males, time with PEG 27.0 +/- 22.5 months) were randomized in five parallel intervention groups, each with a tested device (Silmag((r)), Bard((r)), Freka((r)), Kangaroo((r)) and Wilson Cook((r))). Eligibility criteria included age 18-90 years, males and females, on home enteral nutrition, and the setting was a large academic hospital. Patients were allocated according to a random numbers list, and independent professionals were responsible for data collection. Primary outcome was tube longevity, calculated by Kaplan-Meier curves and Cox regression analysis. A sample of 18 was calculated based on a 10% effect size and 80% power. RESULTS: Twenty patients were randomized in each group and all were analyzed. There was no morbidity and mortality, however tube dysfunction was common with all models. Fastener sliding occurred in 57.0% and balloon rupture in 32.0%, along with other mishaps. Best tube longevity corresponded to the Wilson Cook model (158.0 +/- 10.0 days, P < 0.05), mostly on account of diminished balloon ruptures. CONCLUSIONS: PEG replacement was safe however relatively frequent and affecting longevity, therefore longer-lasting tubes are needed. Specific attention should be given to cap, feeding line, external clamp, tube fastener; tube length, and notably balloon performance, which may be disappointing. Trial NCT01698827, CNPq Investigator Grant 302915/2011-7. PMID- 23672807 TI - Lipidomic analysis of human plasma reveals ether-linked lipids that are elevated in morbidly obese humans compared to lean. AB - BACKGROUND: Lipidomic analysis was performed to explore differences in lipid profiles between plasma from lean and obese subjects, followed by in vitro methods to examine a role for the identified lipids in endothelial cell pathophysiology. METHODS: Plasma was collected from 15 morbidly obese and 13 control subjects. Lipids were extracted from plasma and analyzed using LC/MS, and MS/MS to characterize lipid profiles and identify lipids that are elevated in obese subjects compared to lean. RESULTS: Orthogonal partial least squares discriminant analysis (OPLS-DA) modelling showed that lipid profiles were significantly different in obese subjects compared to lean. Analysis of lipids that were driving group separation in the OPLS-DA model and that were significantly elevated in the obese group led to identification of a group of ether-linked phosphatidylcholine (PC) and phosphatidylethanolamine (PE) lipids of interest. Treatment of human coronary artery endothelial cells with the ether linked phosphatidylethanolamine induced expression of cell adhesion molecules, a hallmark of endothelial cell activation. However, oxidized phosphatidylcholine products that can induce endothelial cell activation in vitro, were not significantly different between groups in vivo. CONCLUSION: These data suggest a role for ether-linked lipids in obesity associated dyslipidemia and vascular disease. PMID- 23672808 TI - Spatial and temporal distribution of pathogenic Wolbachia strain wMelPop in Drosophila melanogaster central nervous system under different temperature conditions. AB - The pathogenic Wolbachia strain, wMelPop, of Drosophila melanogaster is propagated in the fly's brain and muscles. To determine how wMelPop spreads in the host's central nervous system (CNS) during its life cycle, we used whole mount fluorescent in situ hybridization to demonstrate the spatial distribution of wMelPop in D.melanogaster larvae and adults. To assess the effect of temperature on the pattern of wMelPop spread, we performed this analysis under moderate (25 degrees C) and high (29 degrees C) temperature conditions. Wolbachia distribution pattern in the third instar larva and adult brain was similar at both temperatures. wMelPop was generally localized to the subesophageal ganglion and the central brain of the host, whereas optic lobe anlagen cells of third instar larvae and cells of the optic lobe, lamina and retina of adult flies were mostly free of bacteria. Interestingly, high temperature had no significant effect on wMelPop titer or localization in the brain during larval development, but considerably altered it in adults immediately after eclosion. At both temperatures and within all tested stages of the life cycle, the bacterial titer varied only slightly between individuals. The observed differences in wMelPop titers in the central brain, subesophageal ganglion and optic lobe anlagen cells of third instar larva's CNS, together with the observation that these patterns are conserved in the adult brain, suggest that Wolbachia distribution is determined during fly embryogenesis. PMID- 23672809 TI - Colonoscopy in patients with haemophilia: the duration of clotting factor coverage must be adjusted to suit the procedure. PMID- 23672810 TI - The influence of avoidance temperament and avoidance-based achievement goals on flow. AB - In the present research, we conducted two studies designed to examine the joint influence of avoidance temperament and avoidance-based achievement goals on the experience of flow on a creativity task. In both a laboratory study (N = 101; M(age) = 22.61, SD(age) = 4.03; 74.3% female) and a naturalistic study (N = 102; M(age) = 16.23, SD(age) = 1.13; 48% female), participants high in avoidance temperament were shown to experience greater flow when performance avoidance goals were induced; no differences were found in any of the other three achievement goal conditions from the 2 * 2 achievement goal framework. These findings reveal a short-term benefit for a disposition-goal match grounded in avoidance motivation, and point to the need for more research on both avoidance based matches and the short-term versus long-term implications of such matches. PMID- 23672811 TI - Prevention of mother-to-child HIV transmission in resource-limited settings: assessment of 99 Viramune Donation Programmes in 34 countries, 2000-2011. AB - BACKGROUND: Transmission of HIV from mother-to-child during pregnancy, labor, or breastfeeding is the primary cause of pediatric HIV infection in sub-Saharan Africa. A regimen of single-dose nevirapine administered to both HIV-positive pregnant women and their infants has been shown to lower the risk of mother-to child transmission (MTCT) of HIV. In an effort to facilitate scale-up of PMTCT programs in low-income countries, Boehringer Ingelheim, the manufacturer of Viramune (branded nevirapine), initiated the Viramune Donation Programme (VDP) in 2000. The aim of this study was to evaluate the impact of the VDP on participating institutions. METHODS: A total of 164 institutions in 60 countries were included in the VDP over its 11-year duration. An online quantitative and qualitative questionnaire was submitted to all program managers. The questionnaire collected data on the impact of the VDP on initiation and scale-up of PMTCT services, operational capacity, national PMTCT policies, access to funding, and national and international partnerships. Participants were asked for their opinion of how VDP was perceived by different stakeholders (medical community, patients, government authorities, communities). RESULTS: Ninety-nine managers (60.4%) in 34 countries responded to the online questionnaire; 89 of institutions (89.9%) were located in Africa The most positive aspects of the VDP identified were: helped to expand PMTCT services (85.9% of program managers), reduced stigma against HIV-positive pregnant women, increased social support mechanisms (78.8%), fostered partnerships with national and international organizations (69.0%), and encouraged access to donor funding (63.0%). Implementation of the VDP triggered improvements in training hospitals and logistical capacity and was associated with changes in policy strategies at the national level. CONCLUSION: A drug donation program such as the VDP can act as a catalyst for systemic changes at the institutional and national levels. The VDP provides a model for how private initiatives can have a significant impact on public health issues and foster diverse public-private partnerships among governments, commercial organizations, local institutions, and international NGOs. PMID- 23672812 TI - Novel word retention in sequential bilingual children. AB - Children's ability to learn and retain new words is fundamental to their vocabulary development. This study examined word retention in children learning a home language (L1) from birth and a second language (L2) in preschool settings. Participants were presented with sixteen novel words in L1 and in L2 and were tested for retention after either a 2-month or a 4-month delay. Results showed that children retained more words in L1 than in L2 for both of the retention interval conditions. In addition, children's word retention was associated with their existing language knowledge and their fast-mapping performance within and across language. The patterns of association, however, were different between L1 and L2. These findings suggest that children's word retention might be related to the interactions of various components that are operating within a dynamic system. PMID- 23672814 TI - A reliable severity scoring system for radiographic findings in the limbs of young horses. AB - The validity of methods used to score the severity of radiographic findings (RFs) in horses is uncertain since only one or two joints are usually studied, classification criteria are heterogeneous and the internal validity is not assessed. The aim of this study was to assess the internal validity of a severity scoring system (SSS) of RFs by repeated scoring of a sample of radiographs. This SSS of RFs is based on four criteria that can be applied to every type of RF observed in limb joints. It consists of five weighted severity indexes (0, 1, 2, 4, 8) and was used to assess RFs found on the limbs of 392 young horses. The internal validity of the SSS was assessed using Kappa coefficients calculated on a subsample of 137 horses whose radiographs were interpreted twice. The final RF severity indices from these radiographs were obtained after three experienced veterinarians had reached a consensus, similar to the procedure used at foal and yearling sales. The majority of RFs from the 392 horses were scored either 1 or 2, while scores of 8 were only observed in the stifle and tarsus. Among the subsample, the overall agreement on the presence or absence of RFs was good (kappa=0.63; 95% Confidence Interval [CI], 0.56-0.69), and was excellent for the severity of RFs (weighted kappa=0.82; 95% CI, 0.75-0.87). Most disagreements involved RFs that scored 1. The fore fetlock and the carpus experienced the lowest agreement. The SSS was a stable and reliable procedure applicable to any RF on any limb joint of the horse. It will be of potential interest in clinical practice and in the pre-purchase evaluation of young horses and could also be used in additional studies on the evolution or risk factors of RFs. PMID- 23672813 TI - Clinical review: the role of the intensivist and the rapid response team in nosocomial end-of-life care. AB - In-hospital end-of-life care outside the ICU is a new and increasing aspect of practice for intensive care physicians in countries where rapid response teams have been introduced. As more of these patients die from withdrawal or withholding of artificial life support, determining whether a patient is dying or not has become as important to intensivists as the management of organ support therapy itself. Intensivists have now moved to making such decisions in hospital wards outside the boundaries of their usual closely monitored environment. This strategic change may cause concern to some intensivists; however, as custodians of the highest technology area in the hospital, intensivists are by necessity involved in such processes. Now, more than ever before, intensive care clinicians must consider the usefulness of key concepts surrounding nosocomial death and dying and the importance and value of making a formal diagnosis of dying in the wards. In this article, we assess the conceptual background, reference points, challenges and implications of these emerging aspects of intensive care medicine. PMID- 23672815 TI - Skeletal muscle transcriptome profiles related to different training intensities and detraining in Standardbred horses: a search for overtraining biomarkers. AB - Training horses improves athletic capabilities by inducing skeletal muscle specific and systemic adaptations. However, rest is required to recover from exercise or else overtraining may occur and affect performance and welfare. Biomarkers would be useful to identify early chronic overtraining in animals. The objective of the current study was to investigate skeletal muscle gene expression patterns and underlying biological mechanisms related to training of different intensities and detraining. Untrained 20 month-old Standardbred geldings were exercised at varying intensities (endurance and sprint) followed by detraining (n=5 per phase). The results indicated that training mainly affected skeletal muscle-specific protein metabolism and increased CO2 export from the tissues. Intensive training increased energy metabolism and affected heart and adipose tissues, while having an adverse effect on stress, apoptosis and immune capacity. The intensity of the training could be related to decreased expression of extra cellular matrix proteins (ECM), cell-cell contacts and intracellular signalling pathways. During detraining, most mechanisms were reversed, but heart tissue related changes and increased expression of skeletal muscle-specific proteins were still evident. The study suggested that changes to ECM expression and cell cell contact mechanisms may be long-lasting and related to multifactorial aspects of training and detraining. These biomarkers may be useful to identify horses in the early stages of chronic overloading or early overtraining. PMID- 23672816 TI - Simultaneous quantification of amphetamine, opiates, ketamine and relative metabolites in urine for confirmatory analysis by liquid chromatography tandem mass spectrometry. AB - The rise in amphetamine, ketamine and opiates abuse in Taiwan has created a need for a reliable confirmatory assay. A method that combines superficially porous liquid chromatography tandem mass spectrometry (LC-MS/MS) with solid-phase extraction (SPE) was developed for the simultaneous quantification of amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), ketamine, opiates, and their corresponding metabolites in urine. The total run time of the method was 6.7min including equilibration time. The method was validated in accordance with the European Commission (EC) Decision 2002/642/EC. The within- and between-day precision was below 13.6% and the accuracy ranged from -17.1% to +9.9% for all analytes. Ion suppression was observed but compensated by using deuterated internal standards. No carryover was detected and the analytes were stable at room temperature for 16h, and for 72h at 4 degrees C, and three-thaw cycles. The method was further validated by comparison with a reference gas chromatography mass spectrometry (GC-MS) method, using 52 authentic urine samples. The results indicated that for the target analytes studied, the LC-MS/MS analysis was as precise, accurate, and specific as the GC-MS method. In conclusion, the present LC-MS/MS method is robust and reliable, and suitable for use as a confirmation assay in the simultaneous urine drug testing and quantification of amphetamines, ketamines, and opiates. PMID- 23672818 TI - A head-to-head randomized clinical trial of methylphenidate and atomoxetine treatment for executive function in adults with attention-deficit hyperactivity disorder. AB - Results regarding the effects of methylphenidate and atomoxetine on executive functions were inconsistent and no study has directly compared the efficacy of these two medications in improving executive functions in adults with attention deficit hyperactivity disorder (ADHD). We conducted an 8-10 wk, open-label, head to-head, randomized clinical trial involving adults with a clinical diagnosis of ADHD confirmed by psychiatric interview. The two treatment arms were immediate release methylphenidate (IR-methylphenidate) (n = 31) and atomoxetine once daily (n = 32). Executive functions were assessed by the Cambridge Neuropsychological Test Automated Battery (CANTAB), including spatial working memory, spatial span, intra-extra dimensional set shifts, rapid visual information processing and Stockings of Cambridge (SOC). In addition to the symptom assessments at baseline (week 0), visit 2 (week 4-5) and visit 3 (week 8-10), they received CANTAB assessments at baseline and visit 3 (60.4 +/- 6.3 d). Compared to baseline, adults treated with atomoxetine showed significant improvement in spatial working memory, spatial short-term memory, sustained attention and spatial planning at visit 3; adults treated with IR-methylphenidate showed significant improvement in spatial working memory at visit 3. Comparing the magnitude of improvement in executive functions between these two medications, the effect was generally similar for the two groups, although atomoxetine might have significantly greater efficacy than IR-methylphenidate in terms of improving spatial planning (SOC). Our results provide evidence to support that both IR-methylphenidate and atomoxetine improved various executive functions in adults with ADHD with greater improvement in atomoxetine than IR-methylphenidate in spatial planning. PMID- 23672819 TI - Reduced functional connectivity and asymmetry of the planum temporale in patients with schizophrenia and first-degree relatives. AB - The planum temporale (PT) is a highly lateralized brain area associated with auditory and language processing. In schizophrenia, reduced structural and functional laterality of the PT has been suggested, which is of clinical interest because of its potential role in the generation of auditory verbal hallucinations. We investigated whether resting-state functional imaging (fMRI) of the PT reveals aberrant functional connectivity and laterality in patients with schizophrenia (SZ) and unaffected relatives, and examined possible associations between altered intrinsic functional organization of auditory networks and hallucinations. We estimated functional connectivity between bilateral PT and whole-brain in 24 SZ patients, 22 unaffected first-degree relatives and 24 matched healthy controls. The results indicated reduced functional connectivity between PT and temporal, parietal, limbic and subcortical regions in SZ patients and relatives in comparison with controls. Altered functional connectivity correlated with predisposition towards hallucinations (measured with the Revised Hallucination Scale [RHS]) in both patients and relatives. We also observed reduced functional asymmetry of the superior temporal gyrus in patients and relatives, which correlated significantly with acute severity of hallucinations in the patient group. To conclude, SZ patients and relatives showed abnormal asymmetry and aberrant connectivity in the planum temporale during resting-state, which was related to psychopathology. These results are in line with results from auditory processing and symptom-mapping studies that suggest that the PT is a central node in the generation of hallucinations. Our findings support reduced intrinsic functional hemispheric asymmetry of the auditory network as a possible trait marker in schizophrenia. PMID- 23672820 TI - Cannabis use, cognition and brain structure in first-episode psychosis. AB - Cannabis use is highly prevalent worldwide and it is associated with psychosis, but its effects on brain structure and cognition are still controversial. The aim of this paper is to investigate cognitive functioning and brain structure in patients with their first episode of psychosis who used Cannabis. We examined gray matter and lateral ventricle volumes in 28 patients with first-episode psychosis and a history of Cannabis use, 78 patients without a history of Cannabis use and 80 healthy controls who had not used Cannabis. Cognition was assessed using forward and backwards digit span tests, from the Wechsler Memory Scale-Third Edition (WMS-III) and the Controlled Oral Word Association Test (COWAT). Patients with a history of Cannabis use had less brain abnormalities, characterized by gray matter and lateral ventricle volume preservation, as well as less attentional and executive impairments compared to patients without a history of Cannabis use. Cannabis-using patients who develop psychosis have less neurodevelopmental impairment and better cognitive reserve than other psychotic patients; perhaps reflecting different etiological processes. PMID- 23672821 TI - Micropatterning of cells reveals chiral morphogenesis. AB - Invariant left-right (LR) patterning or chirality is critical for embryonic development. The loss or reversal of LR asymmetry is often associated with malformations and disease. Although several theories have been proposed, the exact mechanism of the initiation of the LR symmetry has not yet been fully elucidated. Recently, chirality has been detected within single cells as well as multicellular structures using several in vitro approaches. These studies demonstrated the universality of cell chirality, its dependence on cell phenotype, and the role of physical boundaries. In this review, we discuss the theories for developmental LR asymmetry, compare various in vitro cell chirality model systems, and highlight possible roles of cell chirality in stem cell differentiation. We emphasize that the in vitro cell chirality systems have great promise for helping unveil the nature of chiral morphogenesis in development. PMID- 23672822 TI - Accelerated bone ingrowth by local delivery of strontium from surface functionalized titanium implants. AB - Studies have indicated systemic treatment with strontium (Sr) as a potential route to increase bone quality and formation around osseointegrating implants. However, adverse effects are linked to such treatment. In this study we present a surface modification method designed for sustained local release of Sr from implants. The four groups used were prepared by a magnetron co-sputtering process and selected on the basis of Sr release data. The composition, morphology and mechanical stability of the coatings were analyzed and the Sr release profiles were investigated in vitro by washout experiments. Mesenchymal stem cells were cultured on the different coatings to evaluate potential cytotoxic effects and the effect on cellular proliferation. No indication of toxicity was found. A rodent study demonstrated a significant increase in direct bone-to-implant contact and peri-implant bone volume, for several of the groups, four weeks after implantation when compared to a Grade 4 titanium reference group. Median values of bone-to-implant contact and new bone formation was found to be 19% and 53%, respectively, for the best group compared to 0% for both parameters with respect to the Grade 4 titanium reference. The results indicate that this method may have applications within the orthopedic and dental industry. PMID- 23672823 TI - Effect of short-term decrease in water temperature on body temperature and involvement of testosterone in steelhead and rainbow trout, Oncorhynchus mykiss. AB - The Pacific salmonid species Oncorhynchus mykiss is separated into a migratory form (steelhead trout) and a non-migratory form (rainbow trout). A decrease in water temperature is likely a cue triggering downstream behavior in the migratory form, and testosterone inhibits onset of this behavior. To elucidate differences in sensitivity to water temperature decreases between the migratory and non migratory forms and effect of testosterone on the sensitivity, we examined two experiments. In experiment 1, we compared changes in body temperature during a short-term decrease in water temperature between both live and dead steelhead and rainbow trout. In experiment 2, we investigated effects of testosterone on body temperature decrease in steelhead trout. Water temperature was decreased by 3 degrees C in 30min. The body temperature of the steelhead decreased faster than that of the rainbow trout. In contrast, there was no significant difference in the decrease in body temperature between dead steelhead and rainbow trout specimens. The body temperature of the testosterone-treated steelhead trout decreased more slowly than that of control fish. Our results suggest that the migratory form is more sensitive to decreases in water temperature than the non migratory form. Moreover, testosterone might play an inhibitory role in sensitivity to such decreases. PMID- 23672824 TI - gamma-Amino-butyric acid (GABA) receptor subunit and transporter expression in the gonad and liver of the fathead minnow (Pimephales promelas). AB - gamma-Amino-butyric acid (GABA) is the major inhibitory neurotransmitter in the vertebrate central nervous system. GABA receptors and synthesizing enzymes have also been localized to peripheral tissues including the liver, oviduct, uterus and ovary of mammals but the distribution and role of GABA in peripheral tissues of fish has not been fully investigated. The objectives of this study were to (1) determine if mRNA encoding GABA synthesizing enzymes (glutamic acid decarboxylase 65 and 67; gad65 and gad67), GABA transporters, and GABAA receptor subunits are localized to liver and gonad of fathead minnow (Pimephales promelas) (FHM) (2) investigate the effects of GABA on ovarian 17beta-estradiol (E2) production, and (3) measure transcript responses in the ovary after in vitro incubation to GABA. Real-time PCR assays were developed for gad65, gad67, vesicular GABA transporter (vgat) and GABA transporter 1 (gat1), and select GABAA receptor subunits (gabra1, gabra5, gabrb1, gabrb2, gabrg1, gabrg2). All transcripts were localized to the brain as expected; however transcripts were also detected in the liver, ovary, and testis of FHMs. In the female liver, gad65 mRNA was significantly higher in expression compared to the male liver. Transcripts for gad67 were the highest in the brain>gonad>liver and in the gonads, gad67 was significantly higher in expression than gad65 mRNA. In the liver and gonad, the relative abundance of the subunits followed a general trend of gabrb1>gabrb2=gabrg1=gabrg2>gabra1=gabra5. To explore the effects of GABA in the ovary, tissue explants from reproductive female FHMs were treated with GABA (10(-10), 10(-8) and 10(-6)M) for 12h. GABA had no significant effect on 17beta-estradiol production or on mRNA abundance for genes involved in ovarian steroidogenesis (e.g., 11betahsd, cyp17, cyp19a). There was a significant decrease in estrogen receptor 2a (esr2a) mRNA with 10(-10)M GABA. This study begins to investigate the GABA system in non-neural tissues of teleost fish and addresses the broader topic regarding the peripheral roles of neurotransmitters. PMID- 23672825 TI - Novel regulation of cardiac Na pump via phospholemman. AB - As the only quantitatively significant Na efflux pathway from cardiac cells, the Na/K ATPase (Na pump) is the primary regulator of intracellular Na. The transmembrane Na gradient it establishes is essential for normal electrical excitability, numerous coupled-transport processes and, as the driving force for Na/Ca exchange, thus setting cardiac Ca load and contractility. As Na influx varies with electrical excitation, heart rate and pathology, the dynamic regulation of Na efflux is essential. It is now widely recognized that phospholemman, a 72 amino acid accessory protein which forms part of the Na pump complex, is the key nexus linking cellular signaling to pump regulation. Phospholemman is the target of a variety of post-translational modifications (including phosphorylation, palmitoylation and glutathionation) and these can dynamically alter the activity of the Na pump. This review summarizes our current understanding of the multiple regulatory mechanisms that converge on phospholemman and govern NA pump activity in the heart. The corrected Fig. 4 is reproduced below. The publisher would like to apologize for any inconvenience caused. [corrected]. PMID- 23672827 TI - Rapid musculoskeletal ultrasound for painful episodes in adult haemophilia patients. AB - Little objective information exists about musculoskeletal bleeding patterns in haemophilic arthropathy. Bleeding is assumed to be the cause of painful joints or muscles. Clotting factor treatment is provided empirically, but often does not alleviate pain. We hypothesized that perception of pain aetiology is unreliable, and introduced point-of-care high-resolution musculoskeletal ultrasound (MSKUS) to differentiate intra-articular bleeds vs. joint inflammation, and intra-muscle bleeds vs. other regional pain syndromes. To assess painful musculoskeletal episodes in adult haemophiliacs, we used rapid MSKUS, employing grey scale and power Doppler examination. Forty episodes in 30 adult haemophiliacs were evaluated. Thirty three of the 40 episodes were patient-reported as 'bleeding', five as 'arthritis-type' pain and two as 'undecided'. Of the 33 bleeding reports, only 12 were confirmed by MSKUS; the other episodes revealed other pathology. In contrast, three of five perceived arthritis flares were reclassified as bleeds. Similarly, physician assessment was incorrect in 18 of 40 instances. Swelling and warmth were present in approximately half of confirmed bleeding and non-bleeding episodes, and therefore not useful clinically. Few of the painful episodes were symptom controlled at the time of MSKUS. Management changed based on objective imaging findings in >70% of episodes, which resulted in symptom improvement >60% of the time. Significant discrepancies exist between MSKUS findings and patient/physician-perceived pain classification as bleeding or other musculoskeletal symptoms. Current practice of prescribing clotting factor or conservative measures based on pain perception seems inadequate and suggests that point-of-care imaging should be included into modern haemophilia care. PMID- 23672826 TI - The connection between inner membrane topology and mitochondrial function. AB - The mitochondrial inner membrane has a complex and dynamic structure that plays an important role in the function of this organelle. The internal compartments called cristae are created by processes that are just beginning to be understood. Crista size and morphology influence the internal diffusion of solutes and the surface area of the inner membrane, which is home to critical membrane proteins including ATP synthase and electron transport chain complexes; metabolite and ion transporters including the adenine nucleotide translocase, the calcium uniporter (MCU), and the sodium/calcium exchanger (NCLX); and many more. Here we provide a brief overview of what is known about crista structure and formation, and discuss mitochondrial function in the context of that structure. We also suggest that mathematical modeling of mitochondria that incorporates accurate information about the organelle's internal architecture can lead to a better understanding of its diverse functions. This article is part of a Special Issue entitled 'Calcium Signalling in Heart'. PMID- 23672828 TI - Food protein induced enterocolitis syndrome caused by rice beverage. AB - Food protein-induced enterocolitis syndrome (FPIES) is an uncommon and potentially severe non IgE-mediated gastrointestinal food allergy. It is usually caused by cow's milk or soy proteins, but may also be triggered by ingestion of solid foods. The diagnosis is made on the basis of clinical history and symptoms. Management of acute phase requires fluid resuscitation and intravenous steroids administration, but avoidance of offending foods is the only effective therapeutic option.Infant with FPIES presented to our emergency department with vomiting, watery stools, hypothension and metabolic acidosis after ingestion of rice beverage. Intravenous fluids and steroids were administered with good clinical response. Subsequently, a double blind placebo control food challenge (DBPCFC) was performed using rice beverage and hydrolyzed formula (eHF) as placebo. The "rice based formula" induced emesis, diarrhoea and lethargy. Laboratory investigations reveal an increase of absolute count of neutrophils and the presence of faecal eosinophils. The patient was treated with both intravenous hydration and steroids. According to Powell criteria, oral food challenge was considered positive and diagnosis of FPIES induced by rice beverage was made. Patient was discharged at home with the indication to avoid rice and any rice beverage as well as to reintroduce hydrolyzed formula. A case of FPIES induced by rice beverage has never been reported. The present case clearly shows that also beverage containing rice proteins can be responsible of FPIES. For this reason, the use of rice beverage as cow's milk substitute for the treatment of non IgE mediated food allergy should be avoided. PMID- 23672829 TI - Enhanced derivation of mouse ESC-derived cortical interneurons by expression of Nkx2.1. AB - Forebrain GABAergic interneurons are divided into subgroups based on their neurochemical markers, connectivity and physiological properties. Abnormal interneuron function is implicated in the pathobiology of neurological disorders such as schizophrenia, autism, and epilepsy. Studies on interneuron development and their role in disease would benefit from an efficient mechanism for the production and selection of specific interneuron subgroups. In this study, we engineered a mouse embryonic stem cell (mESC) line for doxycycline-inducible expression of Nkx2.1, a required transcription factor for cortical interneurons derived from the medial ganglionic eminence (MGE). This mESC line was modified to express GFP in Lhx6(+) cells, a marker of newly postmitotic and mature MGE derived cortical interneurons. The addition of doxycycline to differentiating ESCs efficiently induced Nkx2.1 protein and increased the production of GFP(+) cells. Transplantation of GFP(+) putative interneuron precursors resulted in migratory, morphological, and neurochemical features consistent with cortical interneuron fates. To test the hypothesis that Sonic hedgehog (Shh) primarily influences cortical interneuron fate determination through the induction of Nkx2.1, ESCs were grown with doxycycline and the Shh antagonist cyclopamine. We found induced Nkx2.1 renders Shh signaling dispensable for the generation of MGE derived interneurons. These results demonstrate that inducible expression of fate determining genes in embryonic stem cells can be used to study fate determination of the developing forebrain. PMID- 23672830 TI - Keratocystic odontogenic tumor: a retrospective analysis of genetic, immunohistochemical and therapeutic features. Proposal of a multicenter clinical survey tool. AB - OBJECTIVE: In 2005, the World Health Organization reclassified the parakeratinizing odontogenic keratocyst as a neoplasm. This article reviews the research leading to this reclassification, and validates a new survey tool that can be easily used to pool surgical and recurrence data from multiple offices. STUDY DESIGN: All odontogenic lesions accessioned in the Iowa Surgical Oral Pathology Laboratory between 1949 and 2010 were identified from the database. A survey tool to assess treatment and follow-up was created. A total of 46 surgeons agreed to participate. RESULTS: A total of 70 keratocystic odontogenic tumors (KOTs) had documented recurrences at follow-up intervals ranging from 6 months to 5 years. Primary tumors that recurred ranged in size as measured by greatest radiographic diameter from 0.7 to 6 cm. CONCLUSIONS: This survey tool is recommended as standard allowing treatment of cases by multiple practitioners to be compared retrospectively or prospectively. PMID- 23672831 TI - Endoscopic and clinical variables that predict sustained remission in children with ulcerative colitis treated with infliximab. AB - BACKGROUND & AIMS: We aimed to identify early clinical, laboratory, and endoscopic factors associated with sustained remission in children with ulcerative colitis (UC) treated with infliximab. METHODS: We performed a post hoc analysis of data collected from 51 children (6-17 years old) with moderate-to severe UC treated with infliximab for 1 year in the T72 clinical trial. The primary outcome was steroid-free remission at weeks 30 and 54 of treatment, which was based on patient and physician assessments. We compared the ability of the Pediatric UC Activity Index (PUCAI, a noninvasive clinical index), levels of C reactive protein (CRP), and mucosal healing to predict which patients would be in steroid-free sustained remission after 1 year of treatment. RESULTS: Week 8 PUCAI scores best predicted which patients would be in steroid-free remission after 1 year of treatment; 9 of 17 patients who had PUCAI scores <10 points were in sustained remission (53%), compared with 4 of 20 who had PUCAI scores >=10 (20%) (P = .036). Mucosal healing at week 8 was associated with steroid-free remission at 1 year, but this did not reach significance; 7 of 16 patients with mucosal healing were in remission after 1 year (44%), compared with 6 of 21 without mucosal healing (29%) (P = .34). The area under the receiver operating characteristic curve values for association with steroid-free sustained remission were 0.70 for the PUCAI (95% confidence interval [CI], 0.53-0.88), 0.56 for mucosal healing (95% CI, 0.36-0.76), and 0.44 for level of CRP (95% CI, 0.24 0.65). By using a multivariable logistic regression model, the week 8 PUCAI was the only factor associated with steroid-free remission at 1 year (P = .038). PUCAI-defined remission had a high degree of concordance with complete mucosal healing at week 8 (33% of patients were in remission according to the PUCAI vs 31% with mucosal healing). CONCLUSION: On the basis of a post hoc analysis of data from the T72 clinical trial on the effect of infliximab in pediatric patients with UC, the PUCAI was no less predictive of sustained remission than mucosal healing at week 8, and both were superior to CRP level. Routine endoscopic evaluation in children with UC who are in complete clinical remission (ie, PUCAI <10 points) may not be necessary. PMID- 23672832 TI - Cyclin D1 overexpression is associated with poor prognosis in oropharyngeal cancer. AB - OBJECTIVES: To determine the biological characteristics of oropharyngeal squamous cell carcinoma (OpSCC) and related outcome. DESIGN: Retrospective study. METHODS: Patients (N=60) with primary OpSCC from 2000 to 2005 were retrospectively identified from Pathology database and the outcome was confirmed through chart review. Among these, 41 biopsy samples with enough tissues were retrieved to construct a tissue microarray for detection of the presence of high-risk human papillomavirus (HPV) using Chromogenic in situ hybridization (CISH) as well as the expression of p16 and cyclin D1 using immunohistochemistry. MAIN OUTCOME MEASURES: Disease-free survival. RESULTS: Among 60 patients, 39 (65%) patients had no recurrence or died without disease at the last follow-up (disease-free survival or Group 1), and 21 (35%) patients had persistent disease or died of disease (progression-free survival or Group 2). Although follow-up time was twice as long in group 1 (4.7 +/- 2.2 vs. 2.0 +/- 1.6 years; P < 0.0001), there was no difference between the 2 groups in age, gender, smoking/alcohol habits, TNM staging and treatment modalities. Among those 41 cases with available tumour tissues, there was no difference in HPV status and p16 expression between the 2 groups but a significant difference in cyclin D1 expression (P = 0.05). Using Kaplan-Meir survival analysis and log-rank test, cyclin D1 overexpression was highly associated with a poor prognosis when comparing time to outcome (P < 0.0001). CONCLUSION: Cyclin D1 overexpression is a potential prognostic marker of OpSCC. PMID- 23672833 TI - Neuroimaging markers for the prediction of treatment response to Methylphenidate in ADHD. AB - BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is one of the most prevalent mental disorders of childhood, which often continues into adulthood. Methylphenidate is one the most commonly used medication to treat ADHD, however up to 30% of patients do not respond to it. AIMS: This paper aims to review studies, which employed neuroimaging to predict treatment response to Methylphenidate in ADHD. METHODS: Systematic literature searches were performed using several databases. Selected articles had to describe an original study that identified neuroimaging markers for the prediction of treatment response to Methylphenidate in ADHD. RESULTS: Eighty-three articles were found, of which twelve were selected for the present review. Several neuroimaging markers to predict response to MPH were suggested including DAT status, size of medial prefrontal cortex and corpus callosum. CONCLUSION: Some promising findings have been identified and they should motivate additional work to establish more reliable neuroimaging markers of treatment response to MPH in ADHD. PMID- 23672834 TI - Longitudinal course of lung function and respiratory muscle strength in spinal muscular atrophy type 2 and 3. AB - BACKGROUND: Spinal muscular atrophy (SMA) is a common genetic disorder that causes severe hypotonia and weakness, and often fatal restrictive lung disease. The aim of the study was to describe the natural history of the respiratory involvement in patients with SMA type 2 and 3 in order to assess the relevance of the clinical classification and identify the parameters associated with the earliest and most rapid decline over time. METHODS: Thirty-one patients aged 3-21 years were followed over a 10-year period. Lung function, blood gases, respiratory mechanics and muscle strength with recording of oesogastric pressures were measured during routine follow-up. RESULTS: At least two measurements were available in 16 patients (seven type 2 and nine type 3). Among all the volitional and non-volitional, invasive and non-invasive tests, forced vital capacity (FVC) and sniff nasal inspiratory pressure (SNIP) were shown to be the most informative parameters, showing lower values in SMA type 2, with however a similar rate of decline in patients with SMA type 2 and 3. CONCLUSION: Our results confirm an earlier decline in lung and respiratory muscle function in patients classified as SMA type 2 as compared with patients classified as type 3. This decline can be assessed by two simple non-invasive tests, FVC and SNIP, with the last maneuver being feasible and reliable in the youngest children, underlying its interest for the monitoring of children with SMA. PMID- 23672835 TI - Communication ability in cerebral palsy: a study from the CP register of western Sweden. AB - BACKGROUND: Communication is often impaired in cerebral palsy (CP). Tools are needed to describe this complex function, in order to provide effective support. AIM: To study communication ability and the relationship between the Communication Function Classification System (CFCS) and CP subtype, gross motor function, manual ability, cognitive function and neuroimaging findings in the CP register of western Sweden. METHODS: Sixty-eight children (29 girls), 14 with unilateral spastic CP, 35 with bilateral spastic CP and 19 with dyskinetic CP, participated. The CFCS, Gross Motor Function Classification System (GMFCS) and Manual Ability Classification System (MACS) levels, cognitive impairment and neuroimaging findings were recorded. RESULTS: Half the children used speech, 32% used communication boards/books and 16% relied on body movements, eye gaze and sounds. Twenty-eight per cent were at the most functional CFCS level I, 13% at level II, 21% at level III, 10% at level IV and 28% at level V. CFCS levels I-II were found in 71% of children with unilateral spastic CP, 46% in bilateral spastic CP and 11% in dyskinetic CP (p = 0.03). CFCS correlated with the GMFCS, MACS and cognitive function (p < 0.01). Periventricular lesions were associated with speech and more functional CFCS levels, while cortical/subcortical and basal ganglia lesions were associated with the absence of speech and less functional CFCS levels (p < 0.01). CONCLUSION: Communication function profiles in CP can be derived from the CFCS, which correlates to gross and fine motor and cognitive function. Good communication ability is associated with lesions acquired early, rather than late, in the third trimester. PMID- 23672836 TI - Caregiver's burden and psychosocial issues in alternating hemiplegia of childhood. AB - Alternating hemiplegia of childhood (AHC) is rare disorder characterised by recurrent attacks of hemiplegia followed by developmental delay. We investigated the parental perceptions and psychosocial issues of AHC. Using a questionnaire sent to the French AHC association, we investigated families' concerns and needs of support. Additionally, we evaluated the impact of this disease. RESULTS: We analysed 47 questionnaires from 30 families. At time of diagnosis, the concern of the parents was highest for the hemiplegic spells and abnormal eye movements. These concerns decreased over time. The highest concern at the time of the study was the outcome of the patients with an emphasis on cognitive consequences and the level of autonomy. The results showed that AHC has a significant impact on families. INTERPRETATION: Our data enhance how the explanation of the disease by healthcare professional is important. This study also highlights the need for family support over time. PMID- 23672837 TI - Estimating the burden of pertussis in young children on hospitals and emergency departments: a study using linked routinely collected data. AB - Potential underestimation of the health system burden of pertussis was investigated by linking administrative datasets including pertussis notifications, hospitalizations and emergency department (ED) presentations for 1 304 876 children aged <15 years in NSW, Australia. From 2005 to 2008, 3006 children had a pertussis notification, 455 were hospitalized and 644 had an ED presentation with a coded diagnosis of pertussis. Linking hospital and ED records with pertussis notifications identified 140 hospitalizations and 735 ED presentations which occurred +/- 7 days from notification but did not have a diagnosis of pertussis recorded. These additional events were more likely to have a diagnosis of bronchiolitis, upper respiratory infection and cough compared to all other admissions and presentations. Including these additional events significantly increased the proportion of notified cases that were hospitalized or visited EDs, particularly for those aged 5 to <15 years. Linked administrative data allowed more comprehensive estimation of the health system burden of pertussis. PMID- 23672839 TI - A novel homozygous missense mutation in the factor VII gene of severe factor VII deficiency in a pedigree: a description of two cases. PMID- 23672838 TI - Developing population interventions with migrant women for maternal-child health: a focused ethnography. AB - BACKGROUND: Literature describing effective population interventions related to the pregnancy, birth, and post-birth care of international migrants, as defined by them, is scant. Hence, we sought to determine: 1) what processes are used by migrant women to respond to maternal-child health and psychosocial concerns during the early months and years after birth; 2) which of these enhance or impede their resiliency; and 3) which population interventions they suggest best respond to these concerns. METHODS: Sixteen international migrant women living in Montreal or Toronto who had been identified in a previous study as having a high psychosocial-risk profile and subsequently classified as vulnerable or resilient based on indicators of mental health were recruited. Focused ethnography including in-depth interviews and participant observations were conducted. Data were analyzed thematically and as an integrated whole. RESULTS: Migrant women drew on a wide range of coping strategies and resources to respond to maternal child health and psychosocial concerns. Resilient and vulnerable mothers differed in their use of certain coping strategies. Social inclusion was identified as an overarching factor for enhancing resiliency by all study participants. Social processes and corresponding facilitators relating to social inclusion were identified by participants, with more social processes identified by the vulnerable group. Several interventions related to services were described which varied in type and quality; these were generally found to be effective. Participants identified several categories of interventions which they had used or would have liked to use and recommended improvements for and creation of some programs. The social determinants of health categories within which their suggestions fell included: income and social status, social support network, education, personal health practices and coping skills, healthy child development, and health services. Within each of these, the most common suggestions were related to creating supportive environments and building healthy public policy. CONCLUSIONS: A wealth of data was provided by participants on factors and processes related to the maternal-child health care of international migrants and associated population interventions. Our results offer a challenge to key stakeholders to improve existing interventions and create new ones based on the experiences and views of international migrant women themselves. PMID- 23672840 TI - Clinical review: What are the best hemodynamic targets for noncardiac surgical patients? AB - Perioperative hemodynamic optimization, or goal-directed therapy (GDT), has been show to significantly decrease complications and risk of death in high-risk patients undergoing noncardiac surgery. An important aim of GDT is to prevent an imbalance between oxygen delivery and oxygen consumption in order to avoid the development of multiple organ dysfunction. The utilization of cardiac output monitoring in the perioperative period has been shown to improve outcomes if integrated into a GDT strategy. GDT guided by dynamic predictors of fluid responsiveness or functional hemodynamics with minimally invasive cardiac output monitoring is suitable for the majority of patients undergoing major surgery with expected significant volume shifts due to bleeding or other significant intravascular volume losses. For patients at higher risk of complications and death, such as those with advanced age and limited cardiorespiratory reserve, the addition of dobutamine or dopexamine to the treatment algorithm, to maximize oxygen delivery, is associated with better outcomes. PMID- 23672847 TI - Birth weight correlates with size but not shape of the normal human placenta. AB - INTRODUCTION: Studies on developmental programming rely on various measures of size and form of the human placenta. Size and form are not independent of each other and covariation patterns were not determined systematically. METHODS: Twenty-two morphologic parameters were determined on 418 placentas from uncomplicated singleton pregnancies. We determined (i) placenta weight and birth weight, (ii) form parameters such as diameters, thickness, roundness, and eccentricity of cord insertion, and (iii) shape variability by geometric morphometry. Geometric morphometry analyzes shape variability independent of size. We define the technical terms form and shape according to the language of geometric morphometry. RESULTS: Placenta weight correlated with birth weight. The form parameters correlated variably with placenta weight and shape. Shape variability did not correlate with birth weight and placenta weight. DISCUSSION AND CONCLUSIONS: The correlation of placenta weight with birth weight stays a cornerstone of prenatal programming. Shape analysis shows that form parameters are hybrids of size and shape. Shape variability can be interpreted as an outcome of adaptation of a placenta to maternal factors and the associated uterine habitat. Correlation analysis of the whole data array provides a rigorous statistical frame to interpret published data and plan new studies. PMID- 23672848 TI - Pluripotent stem cells for Parkinson's disease: progress and challenges. AB - Parkinson's disease (PD) is a common debilitating neurodegenerative disease. The motor symptoms of PD are caused mainly by a progressive loss of dopaminergic neurons from the substania nigra, resulting in a loss of dopamine production. Current therapies are palliative and, in the long term, ineffective. In addition, some can result in significant clinical side effects. The relatively localized pathology of PD makes it an ideal candidate for cell replacement therapy. Initial efforts focused on fetal cell transplantation, and significant clinical benefit lasting more than 10 years has been reported in some cases. However, the approach is controversial and results have been inconsistent. Inherent limitations of this approach for widespread use are the limited availability and variability of transplant material. In contrast, the self-renewal and differentiation potential of human pluripotent stem cells (hPSCs) make them a promising alternative cell source for cell replacement therapy for PD. Efforts in the past decade have demonstrated that hPSCs can be induced to differentiate in culture to functional dopaminergic neurons. Studies in delivering these cells into PD animal models have demonstrated survival, engraftment, and behavioral deficit improvements. Several groups are developing these cells with clinical trials in mind. Here, we review the state of the technology and consider the suitability of current manufacturing processes, cell purity, and tumorgenicity for clinical testing. PMID- 23672849 TI - Hippocampal and prefrontal dopamine D1/5 receptor involvement in the memory enhancing effect of reboxetine. AB - Dopamine modulates cognitive functions through regulation of synaptic transmission and plasticity in the hippocampus and prefrontal cortex (PFC). Thus, dopamine dysfunction in depression may be particularly relevant for the cognitive symptoms. The norepinephrine transporter inhibitor reboxetine facilitates memory processing in both healthy volunteers and in depressed patients and increases dopamine release in both the hippocampus and PFC. We investigated the potential involvement of the hippocampal and PFC dopamine D1/5 receptors in the cognitive effects of reboxetine using the object recognition test in rats. Infusion of the D1/5 antagonist SCH23390 into the dorsal hippocampus or medial PFC prior to the exploration of the objects impaired memory. Conversely, infusion of the D1/5 agonist SKF81297 into the dorsal hippocampus or medial PFC facilitated memory. Reboxetine similarly facilitated recognition memory in healthy rats and the D1/5 antagonist SCH23390 reversed this effect when infused into the dorsal PFC, but not when infused into the hippocampus. Moreover, systemic reboxetine increased the levels of the NMDA subunit GluN2A in the PFC but not in the hippocampus. Finally, we demonstrate that a single dose of reboxetine does not affect immobility in the forced swim test but improves recognition memory in the Flinders sensitive line (FSL) rat model for depression. The present data in rats are in line with effects of reboxetine on memory formation in healthy volunteers and depressed patients and indicate the involvement of PFC dopamine D1/5 receptors. PMID- 23672850 TI - Dyke-Davidoff-Masson syndrome: case report of fetal unilateral ventriculomegaly and hypoplastic left middle cerebral artery. AB - Prenatal ultrasonographic detection of unilateral cerebral ventriculomegaly arises suspicion of pathological condition related to cerebrospinal fluid flow obstruction or cerebral parenchimal pathology. Dyke-Davidoff-Masson syndrome is a rare condition characterized by cerebral hemiatrophy, calvarial thickening, skull and facial asymmetry, contralateral hemiparesis, cognitive impairment and seizures. Congenital and acquired types are recognized and have been described, mainly in late childhood, adolescence and adult ages. We describe a female infant with prenatal diagnosis of unilateral left ventriculomegaly in which early brain MRI and contrast enhanced-MRI angiography, showed cerebral left hemiatrophy associated with reduced caliber of the left middle cerebral artery revealing the characteristic findings of the Dyke-Davidoff-Masson syndrome. Prenatal imaging, cerebral vascular anomaly responsible for the cerebral hemiatrophy and the early clinical evolution have never been described before in such a young child and complete the acquired clinical descriptions in older children. Differential diagnosis, genetic investigations, neurophysiologic assessments, short term clinical and developmental follow up are described. Dyke-Davidoff-Masson syndrome must be ruled out in differential diagnosis of fetal unilateral ventriculomegaly. Early clinical assessment, differential diagnosis and cerebral imaging including cerebral MRI angiography allow the clinicians to diagnose also in early infancy this rare condition. PMID- 23672851 TI - Effect of skipping breakfast on subsequent energy intake. AB - The objective was to examine the effect of consuming breakfast on subsequent energy intake. Participants who habitually ate breakfast and those who skipped breakfast were recruited for two studies. Using a randomized crossover design, the first study examined the effect of having participants consume either (a) no breakfast, (b) a high carbohydrate breakfast (335 kcals), or (c) a high fiber breakfast (360 kcals) on three occasions and measured ad libitum intake at lunch. The second study again used a randomized crossover design but with a larger, normal carbohydrate breakfast consumed ad libtum. Intake averaged 624 kcals and subsequent food intake was measured throughout the day. Participants ate only foods served from the Cornell Human Metabolic Research Unit where all foods were weighed before and after consumption. In the first study, neither eating breakfast nor the kind of breakfast consumed had an effect on the amount consumed at lunch despite a reduction in hunger ratings. In the second study, intake at lunch as well as hunger ratings were significantly increased after skipping breakfast (by 144 kcal), leaving a net caloric deficit of 408 kcal by the end of the day. These data are consistent with published literature demonstrating that skipping a meal does not result in accurate energy compensation at subsequent meals and suggests that skipping breakfast may be an effective means to reduce daily energy intake in some adults. PMID- 23672852 TI - Assessment of social interaction and anxiety-like behavior in senescence accelerated-prone and -resistant mice. AB - Two members of the senescence-accelerated mouse group, SAMP8 and SAMP10, are characterized by learning and memory deficits, while the SAMR1 strain is not. In this study, we used two behavioral tests, social approach and object recognition and compared the results observed for the SAMP strains with those seen in the control strain, SAMR1. In social approach experiments, the 2 SAMP strains showed decreased sociability compared to SAMR1 as shown by their reluctance to spend time near a stranger mouse and increased immobility. In object recognition experiments, SAMP strains spent more time in the thigmotaxis zone and less time in the more exposed central zone than SAMR1 mice. From a behavioral standpoint, SAMP mice were less interactive and showed increased anxiety-like behavior compared to SAMR1. PMID- 23672853 TI - Concomitant docosahexaenoic acid administration ameliorates stress-induced cognitive impairment in rats. AB - Long chain n-3 fatty acids, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may slow cognitive decline. DHA plays an important role in neural function and decreased plasma DHA are associated with cognitive decline in healthy elderly adults and in patients with Alzheimer's disease. In this study we tested a hypothesis that DHA protects cognitive functions of male Wistar rats against negative impact of prolonged restraint stress. Specifically, we attempted to characterize the preventive action of prolonged treatment with DHA enriched preparation (daily dose of DHA: 300mg/kg, p.o. for 21days) in comparison with positive control (fluoxetine: 10mg/kg daily, p.o. for 21days) against an impairment caused by chronic restraint stress (2h daily for 21days) on recognition memory tested in a object recognition task and on the spatial working memory tested in Morris water maze. We found that administration of DHA enriched preparation prevented deleterious effects of chronic restraint stress both on recognition (p<0.01) and on the working spatial memory (p<0.001). PMID- 23672854 TI - Comparison of cough reflex test against instrumental assessment of aspiration. AB - BACKGROUND: Silent aspiration is associated with pneumonia and mortality, and is poorly identified by traditional clinical swallowing evaluation (CSE). The aim of this study was to validate cough reflex testing (CRT) for identification of silent aspiration against aspiration confirmed by instrumental assessment. METHODS: Cough reflex threshold testing was completed on all patients using inhaled, nebulised citric acid. Within an hour, 80 patients underwent videofluoroscopic study of swallowing (VFSS) and 101 patients underwent fibreoptic endoscopic evaluation of swallowing (FEES). All tests were recorded and analysed by two researchers blinded to the result of the alternate test. RESULTS: Significant associations between CRT result and cough response to aspiration on VFSS (X(2) (2)=11.046, p=.003) and FEES (X(2) (2)=34.079, p<.001) were identified. Sensitivity and specificity were optimised at 0.6mol/L in patients undergoing VFSS (71%, 60% respectively) and at 0.4mol/L in patients undergoing FEES (69%, 71% respectively). A concentration of 0.8mol/L had the highest odds ratio (OR) for detecting silent aspiration (8 based on VFSS; 7 based on FEES). CONCLUSION: CRT results are significantly associated with aspiration response on instrumental assessment. Lower concentrations of citric acid provide a better predictive measure of silent aspiration. PMID- 23672855 TI - High intrapatient HIV-1 evolutionary rate is associated with CCR5-to-CXCR4 coreceptor switch. AB - In approximately 70% of individuals infected with HIV-1 subtype B, the virus switches coreceptor use from exclusively CCR5 use (R5 virus) to either inclusion of or exclusively CXCR4 use (X4 virus) during infection. This switch is associated with an accelerated loss of CD4(+) T-cells and a faster progression to AIDS. Despite intensive research, the mechanisms responsible for coreceptor switch remains elusive. In the present study, we investigated associations between viral evolutionary rate and selection pressure versus viral coreceptor use and rate of disease progression in eight patients with longitudinally sampled HIV-1 env V1-V3 sequences. By employing a Bayesian hierarchical phylogenetic model, we found that the HIV-1 evolutionary rate was more strongly associated with coreceptor switch than with rate of disease progression in terms of CD4(+)T cell decline. Phylogenetic analyses showed that X4 variants evolved from R5 populations. In addition, coreceptor switch was associated with higher evolutionary rates on both the synonymous and non-synonymous substitution level, but not with dN/dS ratio rates. Our findings suggest that X4 viruses evolved from pre-existing R5 viral populations and that the evolution of coreceptor switch is governed by high replication rates rather than by selective pressure. Furthermore, the association of viral evolutionary rate was more strongly associated with coreceptor switch than disease progression. This adds to the understanding of the complex virus-host interplay that influences the evolutionary dynamics of HIV-1 coreceptor use. PMID- 23672856 TI - Nicotiana attenuata MPK4 suppresses a novel jasmonic acid (JA) signaling independent defense pathway against the specialist insect Manduca sexta, but is not required for the resistance to the generalist Spodoptera littoralis. AB - How plants tailor their defense responses to attack from different insects remains largely unknown. Here, we studied the role of a mitogen-activated protein kinase (MAPK), MPK4, in the resistance of a wild tobacco Nicotiana attenuata to two herbivores, the specialist Manduca sexta and the generalist Spodoptera littoralis. Stably transformed N. attenuata plants silenced in MPK4 (irMPK4) were generated and characterized for traits important for defense against herbivores. Only the oral secretions (OS) from M. sexta, but not the OS from S. littoralis or mechanical wounding, induced elevated levels of jasmonic acid (JA) in irMPK4 plants relative to the wild-type plants. Moreover, silencing of MPK4 strongly increased the resistance of N. attenuata to M. sexta in a fashion that was independent of COI1 (CORONATINE INSENSITIVE1)-mediated JA signaling. Untargeted metabolomic screening identified several new MPK4-dependent putative defensive compounds against M. sexta. By contrast, silencing of MPK4 did not affect the growth of the generalist insect S. littoralis, and we propose that this was because of the very low levels of fatty acid-amino acid conjugates (FACs) in S. littoralis OS. Thus, MPK4 is likely to be a key signaling element that enables plants to tailor defense responses to different attackers. PMID- 23672858 TI - On the regulation of protein phosphatase 2A and its role in controlling entry into and exit from mitosis. AB - The process of mitosis involves a comprehensive reorganization of the cell: chromosomes condense, the nuclear envelope breaks down, the mitotic spindle is assembled, cells round up and release their ties to the substrate and so on and so forth. This reorganization is triggered by the activation of the protein kinase, Cyclin-Dependent Kinase 1 (CDK1). The end of mitosis is marked by the proteolysis of the cyclin subunit of CDK1, which terminates kinase activity. At this point, the phosphate moieties that altered the properties of hundreds of proteins to bring about the cellular reorganization are removed by protein phosphatases. At least one protein phosphatase, PP2A-B55, is completely shut off in mitosis. Depletion of this particular form of PP2A accelerates entry into mitosis, and blocks exit from mitosis. Control of this phosphatase is achieved by an inhibitor protein (alpha-endosulfine or ARPP-19) that becomes inhibitory when phosphorylated by a protein kinase called Greatwall, which is itself a substrate of CDK1. Failure to inhibit PP2A-B55 causes arrest of the cell cycle in G2 phase. I will discuss the role of this control mechanism in the control of mitosis. PMID- 23672859 TI - Intrathecal morphine: the forgotten child. PMID- 23672857 TI - Clinical review: Acute respiratory distress syndrome - clinical ventilator management and adjunct therapy. AB - Acute respiratory distress syndrome (ARDS) is a potentially devastating form of acute inflammatory lung injury with a high short-term mortality rate and significant long-term consequences among survivors. Supportive care, principally with mechanical ventilation, remains the cornerstone of therapy - although the goals of this support have changed in recent years - from maintaining normal physiological parameters to avoiding ventilator-induced lung injury while providing adequate gas exchange. In this article we discuss the current evidence base for ventilatory support and adjunctive therapies in patients with ARDS. Key components of such a strategy include avoiding lung overdistension by limiting tidal volumes and airway pressures, and the use of positive end-expiratory pressure with or without lung recruitment manoeuvres in patients with severe ARDS. Adjunctive therapies discussed include pharmacologic techniques (for example, vasodilators, diuretics, neuromuscular blockade) and nonpharmacologic techniques (for example, prone position, alternative modes of ventilation). PMID- 23672860 TI - Epidural versus ON-Q local anesthetic-infiltrating catheter for post-thoracotomy pain control. AB - OBJECTIVE: The authors compared thoracic epidural with ON-Q infiltrating catheters in patients having open thoracotomy to determine whether one method better relieves postoperative pain and would allow earlier discharge from the hospital and, hence, cost savings. DESIGN: Retrospective chart review. SETTING: University hospital. PARTICIPANTS: Fifty adult patients (24 to 81 years old) undergoing open thoracotomy by one surgeon. INTERVENTIONS: One group had thoracic epidural catheters placed by an anesthesiologist and then managed by the acute pain service. The other group had intraoperative ON-Q (ON-Q; I-Flow; Lake Forest, California) infiltrating catheters placed by the surgeon, wound infiltration with a local anesthetic, plus patient-controlled analgesia with an intravenous opioid. MEASUREMENTS AND MAIN RESULTS: The authors measured and compared average daily pain rating, maximum pain rating, time to discharge from the hospital, and total bill for hospital stay. Patients who received epidural analgesia had lower average pain scores on day 2 than did patients in the ON-Q group. Patients in the ON-Q group reported higher maximum pain scores on days 1 and 2 and at the time of discharge. Patients in the ON-Q group were discharged an average of 1 day earlier; hence, their average total bill was lower. CONCLUSIONS: Even though the maximum pain score was higher in the ON-Q group, patients were comfortable enough to be discharged earlier, resulting in cost savings. ON-Q infiltrating catheters present a good option for providing postoperative analgesia to patients having an open thoracotomy. PMID- 23672861 TI - Thoracic epidural anesthesia improves early outcome in patients undergoing cardiac surgery for mitral regurgitation: a propensity-matched study. AB - OBJECTIVE: There are no large studies that investigate the effect of thoracic epidural anesthesia (TEA) combined with general anesthesia (GA) in patients undergoing valvular surgery. The authors hypothesized that TEA might improve clinically relevant endpoints in patients with primary mitral regurgitation. DESIGN: Propensity-matched study. SETTING: Cardiac surgery. PARTICIPANTS: Patients scheduled for mitral valve repair or replacement were studied. INTERVENTIONS: A propensity model was constructed to match 33 patients receiving TEA combined with GA with 33 patients receiving standard GA alone. MEASUREMENTS AND MAIN RESULTS: Overall, the TEA group suffered fewer adverse events than the GA group: 10 (30%) v 23 (10%) with p = 0.002. In particular, the TEA group had a lower incidence of pulmonary events, 6 (18%) v 15 (45%) with p = 0.02, and of cardiac events, 8 (24%) v 16 (49%) with p = 0.04. Median (interquartile) time on mechanical ventilation was reduced in the TEA group, 11 (9-15) v 17 (12-36) with p = 0.007. CONCLUSIONS: This propensity-matched study suggested that TEA might be advantageous in patients undergoing surgery for mitral regurgitation. PMID- 23672862 TI - Anesthetic management of robotically assisted totally endoscopic coronary artery bypass surgery (TECAB). AB - Over the last decade, TECAB has matured into a reproducible technique associated with low incidence of both mortality and morbidity, as well as superior quality of life, when compared with open CABG surgery. However, TECAB also is associated with important and specific challenges for the anesthesiology team, particularly with regard to the physiologic stresses of OLV, placement of special catheters, and induced capnothorax. As the technology supporting robotic surgery evolves and familiarity with, and confidence in, TECAB increases, the authors anticipate increasingly widespread use of these procedures in an increasingly fragile and problematic patient population who will require the support of a skilled and vigilant anesthesiology team. PMID- 23672864 TI - Difficulty in the diagnosis of a retained guidewire within the central venous catheter. PMID- 23672863 TI - Progress in platelet blockers: the target is the P2Y12 receptor. AB - The considerable progress in P2Y12-platelet blockers has important perioperative implications due to a family of novel agents beyond clopidogrel. Although prasugrel is more potent than clopidogrel due to more efficient hepatic metabolism, it is limited clinically by its irreversibility and bleeding risks. Ticagrelor, as the first approved direct and reversible oral P2Y12 blocker, still is limited clinically by its novel side-effect profile. Intravenous reversible P2Y12 blockade is possible now with both cangrelor and elinogrel, although both agents are still in clinical development. Furthermore, elinogrel offers the possibility of both oral and parenteral P2Y12 blockade with a single agent. Future trials likely will continue to evaluate and compare the safety and efficacy of these agents in multiple clinical settings, including the perioperative period. PMID- 23672865 TI - Bronchial blocker versus double-lumen tube for lung isolation with massive hemoptysis during cardiac surgery. PMID- 23672866 TI - The problems of using unreliable evidence in consensus group decision-making. PMID- 23672867 TI - Reply: summarizing randomized evidence with clinically relevant outcomes performed in the perioperative period. PMID- 23672868 TI - Major pulmonary embolism and patent foramen ovale. PMID- 23672869 TI - Imperfect 'swan'. PMID- 23672870 TI - Should high thoracic epidural analgesia be dismissed in cardiac surgery? PMID- 23672871 TI - High thoracic epidural analgesia and cardiac performance. PMID- 23672872 TI - Further studies should evaluate cardiac output measurement by the Nexfin device. PMID- 23672873 TI - Reply: High thoracic epidural analgesia and cardiac performance. PMID- 23672874 TI - Reply: Further studies ought to evaluate the cardiac output measurement by Nexfin device. PMID- 23672875 TI - Ultrafast molecular motor driven nanoseparation and biosensing. AB - Portable biosensor systems would benefit from reduced dependency on external power supplies as well as from further miniaturization and increased detection rate. Systems built around self-propelled biological molecular motors and cytoskeletal filaments hold significant promise in these regards as they are built from nanoscale components that enable nanoseparation independent of fluidic pumping. Previously reported microtubule-kinesin based devices are slow, however, compared to several existing biosensor systems. Here we demonstrate that this speed limitation can be overcome by using the faster actomyosin motor system. Moreover, due to lower flexural rigidity of the actin filaments, smaller features can be achieved compared to microtubule-based systems, enabling further miniaturization. Using a device designed through optimization by Monte Carlo simulations, we demonstrate extensive myosin driven enrichment of actin filaments on a detector area of less than 10 MUm2, with a concentration half-time of approximately 40 s. We also show accumulation of model analyte (streptavidin at nanomolar concentration in nanoliter effective volume) detecting increased fluorescence intensity within seconds after initiation of motor-driven transportation from capture regions. We discuss further optimizations of the system and incorporation into a complete biosensing workflow. PMID- 23672876 TI - Handy, rapid and multiplex detection of tumor markers based on encoded silica hydrogel hybrid beads array chip. AB - Malignant tumor has become the leading cause of death worldwide; however, multiplex detection technology could provide great assistance in large-scale population screening of diseases which could effectively reduce the mortality of malignant tumors. Here a microbeads array chip, which could be a perfect alternative method for the early screening, was developed. Silica-hydrogel hybrid bead (SHHB) with photonic encoding, which consists of both silica and hydrogel materials, was manufactured as the carrier of microbeads array for the first time. The SHHB has the advantages of the beads made of silica or hydrogel, but does not have their limitations. Reaction conditions of SHHBs array were optimized and then the fluorescent concentration curves of two widely-used tumor markers, human alpha fetoprotein and carcinoembryonic antigen, were constructed. The accuracy of SHHBs array has been proven according to the comparison between the results obtained by detecting 50 clinical samples with SHHBs array and chemiluminescence immunoassay. A cassette like chip device has also been developed to standardize operational processes and benefit automization in the next work. Hence it is concluded that SHHBs array chip is a handy, rapid and multiplex immunoassay technology, which could imply its practical application in clinical immunoassay in the near future. PMID- 23672877 TI - Syndromic surveillance for local outbreak detection and awareness: evaluating outbreak signals of acute gastroenteritis in telephone triage, web-based queries and over-the-counter pharmacy sales. AB - For the purpose of developing a national system for outbreak surveillance, local outbreak signals were compared in three sources of syndromic data--telephone triage of acute gastroenteritis, web queries about symptoms of gastrointestinal illness, and over-the-counter (OTC) pharmacy sales of antidiarrhoeal medication. The data sources were compared against nine known waterborne and foodborne outbreaks in Sweden in 2007-2011. Outbreak signals were identified for the four largest outbreaks in the telephone triage data and the two largest outbreaks in the data on OTC sales of antidiarrhoeal medication. No signals could be identified in the data on web queries. The signal magnitude for the fourth largest outbreak indicated a tenfold larger outbreak than officially reported, supporting the use of telephone triage data for situational awareness. For the two largest outbreaks, telephone triage data on adult diarrhoea provided outbreak signals at an early stage, weeks and months in advance, respectively, potentially serving the purpose of early event detection. In conclusion, telephone triage data provided the most promising source for surveillance of point-source outbreaks. PMID- 23672878 TI - Farnesyltransferase inhibitor R115777 protects against vascular disease in uremic mice. AB - BACKGROUND: Atherosclerosis and vascular calcification are major contributors to cardiovascular morbidity and mortality among chronic kidney disease patients. The mevalonate pathway may play a role in this vascular pathology. Farnesyltransferase inhibitors such as R115777 block one branch of mevalonate pathway. We studied the effects of farnesyltransferase inhibitor R115777 on vascular disease in apolipoprotein E deficient mice with chronic renal failure and on mineral deposition in vitro. METHODS AND RESULTS: Female uremic and non uremic apolipoprotein E deficient mice were randomly assigned to four groups and treated with either farnesyltransferase inhibitor R115777 or vehicle. Farnesyltransferase inhibitor R115777 inhibited protein prenylation in mice with chronic renal failure. It decreased aortic atheromatous lesion area and calcification in these animals, and reduced vascular nitrotyrosine expression and total collagen as well as collagen type I content. Proteomic analysis revealed that farnesyltransferase inhibitor corrected the chronic renal failure-associated increase in serum apolipoprotein IV and alpha globin, and the chronic renal failure-associated decrease in serum fetuin A. Farnesyltransferase inhibitor further inhibited type I collagen synthesis and reduced mineral deposition in vascular smooth muscle cells in vitro, probably involving Ras-Raf pathway. CONCLUSIONS: We show for the first time that farnesyltransferase inhibition slows vascular disease progression in chronic renal failure by both indirect systemic and direct local actions. This beneficial effect was mediated via a reduction in oxidative stress and favorable changes in vasoprotective peptides. PMID- 23672879 TI - Low-dose of oral factor Xa inhibitors in patients with a recent acute coronary syndrome: a systematic review and meta-analysis of randomized trials. AB - BACKGROUND: Recently, randomized controlled trials (RCTs) have shown that therapy with new oral activated factor X (Xa) inhibitors in acute coronary syndrome (ACS) yielded a reduction of ischemic events. However, this therapy was associated with a dose-related increase in major bleeding complications. We aimed to perform a systematic review and meta-analysis to appraise the clinical efficacy and safety of the lowest doses of oral factor Xa inhibitors compared with placebo in patients after a recent ACS. METHODS: The primary endpoint was cardiovascular mortality. The rate of new myocardial infarction (MI) was the secondary efficacy endpoint, whereas major bleeding complications were recorded as a safety endpoint. Five RCTs were included in the meta-analysis enrolling a total of 25,643 patients. RESULTS: There was no significant difference in mortality between patients treated with new antithrombotics compared with those receiving the standard therapy: odds ratio (OR), [95% confidence interval (CI)] = 0.97 [0.72-1.31], p = 0.86. Recurrent MI rates were decreased in the anti-Xa group: OR [95%CI] = 0.86 [0.76-0.98], p = 0.02, number needed to treat (NNT) = 189. The administration of new oral anticoagulants was associated with a strongly increased risk of major bleedings compared with the standard treatment: OR [95%CI] = 3.24 [2.29-4.59], p < 0.001, number needed to harm (NNH) = 104; similarly, intracranial bleeding rates were significantly higher in the anti-Xa arm. CONCLUSIONS: The addition of the new oral anticoagulants on top of standard therapy in the setting of ACS results in an excessive risk of major bleedings without any clear evidence of outweighing clinical benefits. PMID- 23672880 TI - Evaluation of the accuracy of cone beam computerized tomography (CBCT): medical imaging technology in head and neck reconstruction. AB - BACKGROUND: With the introduction, development and commercialization of Cone Beam Computerized Tomography (CBCT) technologies in the field of head and neck reconstruction, clinicians now have increased access to the technology. Given the growth of this new user group, there is an increasing concern regarding proper use, understanding, quality and patient safety. METHODS: The present study was carried out to evaluate data acquisition of CBCT medical imaging technology and the accuracy of the scanning at three different machine warming times. The study also compared the accuracy of CBCT at 0.2 mm slice thickness and Computerized Tomography (CT) at 1 mm slice thickness. A control model was CT scanned at five random intervals, at 1 mm slice thickness and CBCT scanned at specialized intervals, at 0.2 mm slice thickness. The data was then converted and imported into a software program where a digital registration procedure was used to compare the average deviations of the scanned models to the control. RESULTS: The study found that there was no statistically significant difference amongst the three CBCT machine warming times. There was a statistically significant difference between CT scanning with 1 mm slice thickness and CBCT scanning with 0.2 mm slice thickness. CONCLUSIONS: The accuracy of the i-CAT CBCT scans used in the present study with a parameter at voxel size 0.2, will remain consistent and reliable at any warming stage. Also the difference between the CBCT i-CAT scans and the CT scans was not clinically significant based on suggested requirements of clinicians in head and neck reconstruction. PMID- 23672882 TI - Epidemiology of infant ocular and periocular injuries from consumer products in the United States, 2001-2008. AB - PURPOSE: To quantify and characterize eye injuries related to consumer products in the infant population (0-12 months) treated in United States hospital emergency departments during the period from 2001 to 2008. METHODS: This study is a descriptive analysis of consumer-product related eye injury data derived from the National Electronic Injury Surveillance System, a probability sample of 100 hospitals nationwide with 24-hour emergency departments. Narrative data were used to assign each case with the consumer products (CPs) causing the eye injury. The proportions of eye injury visits were calculated by age, sex, diagnosis, disposition, locale of incident, and CP categories. We examined the US Consumer Product Safety Commission National Electronic Injury Surveillance System data for all nonfatal eye injuries (853 cases) in the infant population (0-12 months) treated in US emergency departments from 2001 to 2008. These data can be used to project national, annual, weighted estimates of nonfatal injury treated in US emergency departments. RESULTS: There were an estimated 21,271 visits to US emergency departments by patients aged 0-12 months for CP-related eye injuries during the study period. Of these, 63% involved infants aged 9-12 months and 54% involved male patients; 78% of all injuries occurred at home. The CPs causing the most eye injuries belonged to the categories of chemical (46%) and household items (24%). Contusions and abrasions were the leading eye injuries diagnoses (37%). CONCLUSIONS: This study suggests that most CP-related infant eye injuries in the United States occur at home and are predominantly caused by chemicals and household products. PMID- 23672883 TI - Inferior oblique myectomy for upshoots mimicking inferior oblique overaction in Duane retraction syndrome. AB - PURPOSE: To evaluate the results of inferior oblique myectomy in selected patients with Duane retraction syndrome with upshoot on adduction. METHODS: This was a prospective, interventional study of consecutive patients with types 1, 2, or 3 Duane syndrome with isolated upshoot in adduction operated on from January 2007 to December 2011. Patients underwent inferior oblique myectomy on the side of the upshooting eye. Only patients with gradual elevation of the eye in adduction in a pattern similar to inferior oblique overaction or patients with hypertropia in the primary position were included. All patients were followed for at least 6 months. Ductions, versions, degree of upshoot, degree of fundus torsion, and pattern of strabismus were analyzed in all patients before and after surgery. RESULTS: A total of 11 patients were included in the study. Mean patient age at time of surgery was 6.4 +/- 5.2 years (range, 3-22 years). Two patients had bilateral inferior oblique myectomy and 4 had simultaneous bilateral medial rectus muscle recession to correct horizontal misalignment. Mean duration of follow-up was 8.6 months (range, 6-36 months). Of the 11 patients, 10 (91%) had complete disappearance of the upshoot at last follow-up. None of the patients developed inferior oblique underaction postoperatively. There was a statistically significant improvement of V pattern after surgery (P < 0.01). Mean vertical misalignment in primary position was 5(Delta) before surgery and 1(Delta) after (P = 0.02). Most patients had no significant fundus torsion before or after surgery. CONCLUSIONS: Inferior oblique muscle weakening can improve upshoot in selected patients with Duane retraction syndrome without inducing inferior oblique muscle underaction. PMID- 23672884 TI - Biomechanical study of the efficacy of a new design of wrist guard. AB - BACKGROUND: Upper extremity injuries are frequent in the elderly or those undertaking extreme sporting activities. Commercially available wrist guards reduce the frequency of wrist fractures but are not widely used as they greatly restrict movement. METHODS: A new wrist guard was developed which provided protection to the "impact area" but does not restrict wrist or digital movement. A human hand model and a biomechanical test rig, which allowed the simulation of an adult fall from height, were developed. The ability of the new guard, which was tested with different levels of padding, to reduce peak impact forces and absorb energy on impact was measured and compared to a commercially available wrist guard. FINDINGS: The use of any guard reduced peak impact forces by a minimum of 31.8%. The new guard, despite a substantially reduced impact surface area, demonstrated the same reductions in peak force (48%) and ability to absorb energy on impact as the standard guard when fitted with comparable levels of padding. INTERPRETATION: These results indicate that the new guard, which allows movement of the wrist and digits, demonstrates the same ability to reduce impact forces and absorb energy as a commercially available guard despite its substantially reduced impact area. Such a guard may provide a better compromise between joint flexibility and protection than the status quo. PMID- 23672885 TI - Cell therapy demonstrates promise for acute respiratory distress syndrome - but which cell is best? AB - Acute respiratory distress syndrome (ARDS) constitutes a spectrum of increasingly severe acute respiratory failure and is the leading cause of death and disability in the critically ill. There are no therapies for ARDS, and management remains supportive. Cell therapy, particularly with allogeneic mesenchymal stem/stromal cells (MSCs), has emerged as a promising therapeutic strategy for ARDS, favorably modulating the immune response to reduce lung injury, while facilitating lung regeneration and repair. In this issue of the journal, Rojas and colleagues provide us with a rationale to consider autologous bone marrow-mononuclear cells as an alternative to MSCs for this devastating disease. PMID- 23672887 TI - Inhibition of HIV replication in vitro by clinical immunosuppressants and chemotherapeutic agents. AB - BACKGROUND: Recent studies have suggested that a functional cure for HIV-1 infection, purportedly resultant from allogeneic bone marrow transplantation, may be possible. Additionally, the first such patient was treated with whole-body irradiation, immunosuppressants, and the chemotherapeutic, cytarabine. However, the precise role of the coinciding medical interventions in diminishing detectable HIV reservoirs remains unstudied. FINDINGS: In this article, we demonstrate that the immunosuppressants, mycophenolic acid and cyclosporine, and the chemotherapeutic, cytarabine, are potent antiretroviral agents at clinically relevant dosages. These drugs strongly inhibit HIV-1 replication in a GFP indicator T cell line and peripheral blood mononuclear cells (PBMC). CONCLUSIONS: Our study suggests that certain clinical immunosuppressants and chemotherapeutic agents may act combinatorially to inhibit HIV infection. Additionally, chemotherapy-mediated cytotoxicity may also affect the stability of viral reservoirs. Thus, further study is needed to examine potential therapeutic value of these interventions in patients. PMID- 23672888 TI - Radiologic case study. PMID- 23672889 TI - One-stage total joint arthroplasty for patients with active tuberculosis. PMID- 23672886 TI - Biological substrates underpinning diagnosis of major depression. AB - Major depression is characterized by low mood, a reduced ability to experience pleasure and frequent cognitive, physiological and high anxiety symptoms. It is also the leading cause of years lost due to disability worldwide in women and men, reflecting a lifelong trajectory of recurring episodes, increasing severity and progressive treatment resistance. Yet, antidepressant drugs at best treat only one out of every two patients and have not fundamentally changed since their discovery by chance >50 yr ago. This status quo may reflect an exaggerated emphasis on a categorical disease classification that was not intended for biological research and on oversimplified gene-to-disease models for complex illnesses. Indeed, genetic, molecular and cellular findings in major depression suggest shared risk and continuous pathological changes with other brain-related disorders. So, an alternative is that pathological findings in major depression reflect changes in vulnerable brain-related biological modules, each with their own aetiological factors, pathogenic mechanisms and biological/environment moderators. In this model, pathological entities have low specificity for major depression and instead co-occur, combine and interact within individual subjects across disorders, contributing to the expression of biological endophenotypes and potentially clinical symptom dimensions. Here, we discuss current limitations in depression research, review concepts of gene-to-disease biological scales and summarize human post-mortem brain findings related to pyramidal neurons, gamma amino butyric acid neurons, astrocytes and oligodendrocytes, as prototypical brain circuit biological modules. Finally we discuss nested aetiological factors and implications for dimensional pathology. Evidence suggests that a focus on local cell circuits may provide an appropriate integration point and a critical link between underlying molecular mechanisms and neural network dysfunction in major depression. PMID- 23672890 TI - Operative decisions for endoscopic treatment of cubital tunnel syndrome. AB - The authors review the relevant anatomy and provide technical tips for endoscopic decompression of the cubital tunnel. Cubital tunnel syndrome is the second most common nerve compression syndrome in the upper extremity. Until recently, surgeons focused on open decompression combined with submuscular or subcutaneous transposition of the nerve. Decompression was usually limited to the region of the medial epicondyle, and related morbidity was relatively high. Endoscopic decompression is a promising technique because the dissection range can be extended and the scar length can be reduced. The authors review the relevant anatomy for the endoscopic approach and give some recommendations concerning the details of the surgical technique. PMID- 23672891 TI - Intraoperative contralateral view for assessing accurate syndesmosis reduction. AB - Accurate reduction of ankle syndesmosis following injury is essential to minimize tibiofibular diastasis and optimize patient outcomes. Although several radiographic parameters have been described in the coronal plane to assist in reduction, tibiofibular diastasis following syndesmotic injury often occurs in the sagittal plane, with the fibula displacing posterior relative to the tibia. A technique using lateral fluoroscopic assessment of the uninjured contralateral ankle as a comparison and guide for accurate syndesmotic reduction is described. PMID- 23672892 TI - Deep infections in total joint replacements. Interview with Suhel Kotwal. PMID- 23672893 TI - Skin temperatures generated following plaster splint application. AB - Heat is generated during the exothermic reaction associated with plaster splint application. The amount of heat generated is affected by the plaster thickness, dipping water temperature, and extremity elevation method. The authors assessed the effect of these variables on skin and plaster temperatures. Short-leg posterior splints were applied to noninjured extremities on a volunteer using 2 protocols. Following splint application, the splinted leg was elevated in 4 ways: on plastic-covered urethane pillows in cotton pillowcases, on cotton blankets, on ice packs (short-term cryotherapy) placed on top of cotton blankets, or with heel elevation to promote free air circulation. Skin and plaster temperatures were monitored at 1-minute intervals. The maximum skin temperature generated and the average time that skin temperature was 40 degrees C or higher were recorded. PMID- 23672895 TI - AC separation in a concert violinist. PMID- 23672894 TI - Long bone osteomyelitis in adults: fundamental concepts and current techniques. AB - Osteomyelitis is challenging for orthopedic surgeons. The fundamental basis of osteomyelitis treatment is wide surgical debridement. A variety of operative techniques exist for soft tissue coverage and segmental bony stabilization; however, extensive resection remains the crucial starting point in a comprehensive treatment plan. Antibiotic therapy continues to be a cornerstone of adjuvant therapy; nevertheless, the length of treatment is still debated. With ever-increasing antimicrobial resistance rates, targeted therapy based on accurate cultures has become imperative. Osteomyelitis requires a multidisciplinary team prepared to formulate an individualized surgical and medical plan for each patient. The aim of the current article is to highlight and summarize the current concepts in the management of long bone osteomyelitis. PMID- 23672896 TI - The incidence and consequences of early wound infection after internal fixation for trauma in HIV-positive patients. PMID- 23672897 TI - Comparison of cemented and uncemented fixation in total knee arthroplasty. AB - EDUCATIONAL OBJECTIVES: As a result of reading this article, physicians should be able to :1. Understand the rationale behind using uncemented fixation in total knee arthroplasty.2.Discuss the current literature comparing cemented and uncemented total knee arthroplasty3. Describe the value of radiostereographic analysis in assessing implant stability.4. Appreciate the limitations in the available literature advocating 1 mode of fixation in total knee arthroplasty. Total knee arthroplasty performed worldwide uses either cemented, cementless, or hybrid (cementless femur with a cemented tibia) fixation of the components. No recent literature review concerning the outcomes of cemented vs noncemented components has been performed. Noncemented components offer the potential advantage of a biologic interface between the bone and implants, which could demonstrate the greatest advantage in long-term durable fixation in the follow-up of young patients undergoing arthroplasty. Several advances have been made in the backing of the tibial components that have not been available long enough to yield long-term comparative follow-up studies. Short-term radiostereographic analysis studies have yielded differing results. Although long-term, high-quality studies are still needed, material advances in biologic fixation surfaces, such as trabecular metal and hydroxyapatite, may offer promising results for young and active patients undergoing total knee arthroplasty when compared with traditional cemented options. PMID- 23672898 TI - Kinematic effect of MGHL incorporation into Bankart repair. AB - Surgical treatment for traumatic shoulder instability has progressed in tandem with the evolution of the current understanding of the anatomy and biomechanics of the shoulder. Proponents of incorporating the middle glenohumeral ligament (MGHL) in Bankart repair believe this technique could increase repair strength. The purpose of this biomechanical study was to compare the range of motion and humeral head kinematic changes that result from including the MGHL in a Bankart repair in an effort to identify possible changes in shoulder biomechanics as a result of this addition in surgical repair.Six cadaveric shoulders were tested in 4 conditions: intact, Bankart lesion, repair excluding the MGHL, and repair including the MGHL. Each condition was tested for range of motion, glenohumeral translation, and humeral head apex position. Standard Bankart repair and repair with MGHL inclusion resulted in decreased range of motion, but no statistically significant difference was found between the 2 repair types (P=.846). Anterior translation was significantly reduced with both the Bankart repair (4.8 +/- .9; P=.049) and included MGHL repair (4.6 +/- 0.9; P=.029). No statistically significant difference was found between both repairs (P=.993). Although both repairs showed posterior displacement of the humeral head apex when in external rotation, this trend only reached statistical significance when compared with the Bankart lesion in 90 degrees of external rotation (P=.0456); however, no significant difference was found between the 2 repairs (P=.999). Inclusion or exclusion of the MGHL in a Bankart repair does not significantly affect the range of motion, translation, or kinematics of the glenohumeral joint. PMID- 23672899 TI - Recommendations for driving after right knee arthroscopy. AB - No established guidelines currently exist to assist orthopedic surgeons in determining when a patient may safely control a motor vehicle after undergoing simple right knee arthroscopy. Despite this lack of concrete evidence, premature postoperative driving could expose orthopedic surgeons to legal liability and, more importantly, patients to danger and further injury. Through questionnaires directed at physicians, patients, and insurance companies, the authors attempted to identify common postoperative management trends among orthopedic surgeons in an effort to better identify patterns that could help direct practice for the optimized treatment of patients after right knee arthroscopy.Although 29.7% of physicians always incorporated postoperative driving instructions during routine preoperative consultation, 57% of physicians brought up these conversations half of the time or less. In addition, when the preoperative discussions were conducted, approximately 23.6% of physicians never initiated the conversation. The majority of physicians recommended driving after narcotics were discontinued (70%), when the patient felt they could subjectively control their vehicle (57.1%), and when postoperative symptoms would allow safe driving (38.8%); these achievements were most commonly reached at 1 week postoperatively. After simple right knee arthroscopy, the common consensus indicates that patients may safely return to driving 1 week postoperatively when they are narcotic-free and feel safe to control their vehicle. PMID- 23672900 TI - Extensive subcutaneous emphysema resembling necrotizing fasciitis. AB - Necrotizing fasciitis is an aggressive, invasive soft tissue infection. Because it can rapidly progress to patient instability, prompt diagnosis followed by urgent debridement is critical to decreasing mortality. Despite the importance of early diagnosis, necrotizing fasciitis remains a clinical diagnosis, with little evidence in the literature regarding the effectiveness of diagnostic tools or criteria. Common clinical findings are nonspecific, including pain, blistering, crepitus, and swelling with or without fever and a known infection source.This article describes a patient who was transferred to the authors' institution from another hospital, where she had been taken following seizure activity and was treated with antibiotics for suspected cellulitis at the intravenous catheter placement site on her left dorsal hand. On admission to the current authors' institution, she presented with pain and swelling in the setting of significant left upper-extremity emphysema. She had undergone a left shoulder arthroscopy 4 weeks previously. Vital signs were within normal limits, and a preoperative chest radiograph was read as normal. The patient underwent an emergent fasciotomy, irrigation and debridement of the left upper extremity, and intravenous antibiotics for suspected necrotizing fasciitis. Intraoperative findings indicative of infection were absent, and a left apical pneumothorax was later found on postoperative chest imaging.In a stable patient with a normal chest radiograph on presentation who demonstrates upper-extremity crepitus suspicious for necrotizing fasciitis, a chest computed tomography scan may be indicated to rule out an intrathoracic source. PMID- 23672901 TI - Femoral deformity planning: intentional placement of the apex of deformity. AB - Traditionally, correction of femoral deformity has been performed with osteotomies through the center of rotation of angulation (CORA), but the CORA location is not always practical. If the osteotomy is created at a site adjacent to the CORA, an additional translation must be performed to accurately correct the deformity. However, at times, the ideal osteotomy site may require an unfeasible amount of translation. Multiple osteotomies may also be problematic, and when overcorrection of the mechanical axis is planned, the CORA method is not practical.This article describes a novel method by which the surgeon may choose the location of the osteotomy regardless of the location of the CORA and may consolidate a multiapical deformity into a single corrective osteotomy. Furthermore, intentional mechanical axis overcorrection may be performed to unload knee joint arthritis. Simple, complex, and multiapical deformities may now be corrected via a single familiar surgical procedure, such as a distal femoral osteotomy, and the need for translation is eliminated. PMID- 23672902 TI - Evaluation of patient satisfaction with physical therapy following primary THA. AB - Physical therapy following total hip arthroplasty (THA) is intended to maximize a patient's range of motion and function and improve the quality of life. No universally accepted standard of care exists for physical therapy among physicians or therapists. However, it may be crucial to enhance efforts to more fully elucidate contributing parameters that affect patient experiences. The purpose of this study was to evaluate various factors contributing to patient satisfaction with postoperative physical therapy. One hundred consecutive patients (110 hips) who underwent THA were prospectively surveyed for satisfaction with postoperative physical therapy. All surveys were filled out anonymously by the patients, and investigators were blinded to clinical outcomes and who was surveyed. Seventy-six percent of patients reported being satisfied with their rehabilitation experiences. Factors, including patient age and sex, duration of therapy, number of patients per session, continuity of care with the same therapist, amount of hands-on time spent with the therapist, number of patients per session, and total number of sessions completed, were significantly correlated with patient satisfaction. Co-pay amount did not significantly affect patient satisfaction. These factors may be underappreciated by physicians and physical therapists. To maximize patient satisfaction with physical therapy, physicians should identify institutions whose therapists are willing to spend adequate hands-on time during one-on-one or small-group sessions while maintaining the greatest possible continuity of care with a single provider. PMID- 23672903 TI - Comparison of limb-length discrepancy after THA: with and without computer navigation. AB - Limb-length discrepancy following total hip arthroplasty (THA) is often cited as a reason for patient dissatisfaction and for hip instability. Various intraoperative techniques have been described to help restore normal limb length after THA. The purpose of this study was to assess whether a computer-navigated surgical technique would help restore limb-length equality following THA.A retrospective study of 150 consecutive patients compared a free-hand (non navigated) THA technique vs a computer-navigated THA technique. Each group contained 75 patients. The primary outcome measurement was limb-length discrepancy, which was evaluated using a digital anteroposterior pelvic radiograph. Secondary outcome measurements included a Harris Hip Score questionnaire and a single question evaluating the subjective feeling of the operative limb (longer, shorter, or equal). At a minimum 1-year follow-up, results showed that computer-navigated THA helped restore limb-length equality. An average leg-length difference of 0.3 mm (SD=0.3 mm) was found with computer navigated THA compared with a leg-length difference of 1.8 mm (SD=0.7 mm) when a non-navigated THA was used. This was statistically significant. Both groups had similar Harris Hip Scores (computer-navigated group, 84.8; non-navigated group, 84.2; P=.835), and no difference was found between the 2 groups regarding the patient's perception of the operative limb length.This study demonstrated that computer-navigated THA resulted in improved restoration of normal limb length and limited significant outliers but did not show improvement in Harris Hip Scores or patient's perception of limb-length equality. PMID- 23672905 TI - Application of the cervical subaxial anterior approach at C2 in select patients. AB - The purpose of this study was to assess the feasibility and radiographic indications of using the subaxial anterior approach for decompression and fusion at C2. Anterior exposure at C2 was difficult and associated with increased morbidity. The subaxial anterior approach is easy and familiar to spine surgeons but did not provide satisfying exposure in all patients. This article describes a series of patients undergoing anterior surgery involving C2 through the subaxial anterior approach. Patients were selected based on lateral extension radiographs showing a mandibular angle higher than the C3 upper endplate. Forty-two patients (29 men and 13 women) with average age of 45 years and an average follow-up of 9.7 months were reviewed. Etiologies included Hangman's fracture (n=35), traumatic disk herniation at C2-C3 (n=1), C3 fracture (n=2), ossification of the posterior longitudinal ligament (n=2), and tumor (n=2). Single-level diskectomy (n=36) and corpectomy (n=6) were performed. Exposure was satisfactory, and operations went smoothly in all patients except in 1 man with a muscular neck. One (2.4%) postoperative complication of choking and trouble swallowing liquids was observed and diminished in 3 months with no treatment. Pre- and postoperative Japanese Orthopaedic Association scores were 13.86 +/- 2.25 and 16.50 +/- 0.76, respectively, with an improvement rate of 85% +/- 24% in 14 patients who had preoperative neurological dysfunction. A fusion rate of 100% was achieved. The subaxial anterior approach may be simple and safe for exposure at C2 in select patients. Complicated exposure, such as the transoral or retropharyngeal approach, should be avoided in these patients. PMID- 23672904 TI - One-year postoperative knee pain in patients with semi-extended tibial nailing versus control group. AB - The purpose of this study was to determine whether patients with a tibia fracture who were treated with an intramedullary nail using a semi-extended, extra articular, parapatellar approach had anterior knee pain at a higher than acceptable incidence compared with control patients. Eighteen patients with OTA type 42 A-C tibia fractures nailed using this approach were compared with an uninjured control group (n = 22). Lysholm Knee Score questionnaires were given to all participants and compared between groups. Fracture patients completed the LKS at 6 months and 1 year postoperatively. Additional data collected included age, sex, mechanism of injury, OTA classification, Gustilo/Anderson and Tscherne classification, nail-apex distance, complications, weight-bearing status, additional fixation needed, and postoperative procedures. Mean age and demographics were similar between the fracture and control group: 42.9 vs 47.9 years, respectively, (P=.36) and 11 vs 9 men, respectively (P=.11). Lysholm Knee Scores among the subgroups (age, sex, medial vs lateral parapatellar approach, soft-tissue status, and nail-apex distance) showed no statistically significant differences (P>05 for all comparisons). Mean nail-apex distance was -16.3 mm. Mean LKS score 1-year postoperatively was 87.3 (range, 59-100) in the fracture group and 89.7 (range, 23-100) in the control group (P=.69). At 1-year postoperatively, patients in the fracture group did not have increased anterior knee pain compared with the control group. PMID- 23672906 TI - Intramedullary nailing versus locked plate for treating supracondylar periprosthetic femur fractures. AB - The objective of this study was to compare retrograde intramedullary femoral nailing with supracondylar locked screw-plate fixation for the treatment of periprosthetic femur fractures following total knee arthroplasty. Time to union and full weight bearing were the primary study outcomes, with perioperative blood loss, need for transfusion, need for revision surgery, and infection being the secondary outcomes. A retrospective review of 63 patients who sustained Rorabeck Type II periprosthetic femoral fractures was undertaken. Patients were pooled from 3 academic institutions between 2001 and 2009. Patients eligible for the study were identified from the electronic medical record using an IDX query of International Classification of Diseases 9 and Current Procedural Terminology codes for fixation of femur fracture with intramedullary implant or plate and screws. In the series, 35 patients were treated with intramedullary femoral nailing and 28 with a locked screw-plate. The 2 groups were compared for radiographic union at 6, 12, 24, and 36 weeks. At 36 weeks, radiographic union was significantly greater in the locked screw-plate group. Time to full weight bearing was not significantly different. A greater perioperative transfusion rate was observed in the locking plate group, but it also had an overall lower rate of reoperation, for any reason, compared with the intramedullary femoral nailing group. The results support the use of a laterally based locked plate in the treatment of Rorabeck type II distal femur periprosthetic fractures. PMID- 23672907 TI - Efficiency of ligamentotaxis using PLL for thoracic and lumbar burst fractures in the load-sharing classification. AB - The use of pedicle screws for short-segment implants has been known to be dangerous in patients who score a 7 or higher on McCormack's classification. The efficiency of ligamentotaxis of the posterior longitudinal ligament (PLL) and short-segment implants and fusion in relation to McCormack's classification has not been proven. The purpose of this study was to compare the clinical and radiological results of indirect decompression using PLL ligamentotaxis between patients with a high- (score of 7 or higher) or low-grade (score of 6 or less) fracture. Eighteen patients (19 levels) in the low-grade fracture group were compared with 23 patients (27 levels) in the high-grade fracture group. Clinical outcomes were measured using the Oswestry Disability Index (ODI) and visual analog scale (VAS) scores; radiologic measures were determined using the spinal canal area and mean sagittal diameter; and the complications were evaluated and compared. A significant improvement in each groups was found in the mean pre- and postoperative spinal canal area, mean sagittal diameter, Cobb's angle, and anterior vertebral height compression rate. A significant difference was found between the 2 groups in the mean pre- and postoperative spinal canal area, mean sagittal diameter, and anterior vertebral height compression rate. Moreover, the VAS and ODI scores continued to significantly improve at the last follow-up in each group. No difference was found in the prevalence of complications. Despite a high score, no significant difference was found in the clinical and radiological results and the complications. Therefore, indirect decompression using PLL ligamentotaxis was found to be a useful technique for patients who recieve a high McCormack's classification score. PMID- 23672908 TI - Guided growth for the treatment of moderate leg-length discrepancy. AB - The purpose of this study was to evaluate the effectiveness and complication rate of guided growth for the treatment of patients with a moderate leg-length discrepancy. The authors retrospectively reviewed all patients treated with guided growth for a moderate leg-length discrepancy at their institution between October 2004 and December 2010. Thirty-four patients met the inclusion criteria from an initial cohort of 105 patients. All patients were followed until screw removal or maturity occurred. Nine patients had a developmental leg-length discrepancy, and 25 had a congenital leg-length discrepancy. Average age was 12.6 years (range, 7-16 years). Average leg-length discrepancies, as measured on standing long-leg radiographs from the top of the pelvis, the top of the femoral heads, and the center of the ankle to the top of the femoral heads, were 22, 19, and 17 mm, respectively. Average discrepancies at screw removal or maturity were 13, 10, and 11 mm, respectively. Twenty of 33 patients had a leg-length discrepancy of less than 1 cm at maturity or screw removal. The leg-length discrepancy change in patients who underwent guided growth of the tibia was minimal. Leg-length discrepancies in patients who underwent guided growth of the femur or both the femur and the tibia changed by an average of 10 mm. One patient had a mechanical axis change greater than 1 zone, and 1 patient required treatment for angular deformity after being treated for a leg-length discrepancy. Guided growth is a safe and effective technique for treating moderate leg-length discrepancies. PMID- 23672909 TI - Treatment of osteoid osteoma with CT-guided percutaneous radiofrequency thermoablation. AB - Osteoid osteoma is a benign bone tumor with a male predominance occurring mainly in children and young adults. The most common symptom is intermittent pain that worsens at night and is at least partially relieved by nonsteroidal anti inflammatory drugs. The purpose of this study was to assess the long-term effectiveness of computed tomography-guided percutaneous radiofrequency thermoablation in patients with a minimum follow-up of 2 years. Twenty patients with osteoid osteoma (15 men and 5 women) with a mean age of 20.7 years (range, 4 61 years; 12 patients aged 20 years or younger) underwent computed tomography guided percutaneous radiofrequency thermoablation. Lesion sites were the femur (n=9), tibia (n=7), pelvis (n=1), talus (n=1), cuneiform bone (n=1), and humerus (n=1). Mean follow-up was 44 months (range, 3-106 months). Pain relief was significant in 95% of patients; it disappeared within 24 hours in 14 patients, within 3 days in 4, and within 7 days in 1. The patient with persistent symptoms underwent another percutaneous radiofrequency thermoablation procedure that was successful. The difference between pre- and postoperative pain was significant (P <= .01). No recurrences occurred. Computed tomography-guided percutaneous radiofrequency thermoablation is a safe, minimally invasive, and economical procedure with high technical and clinical success rates, and it effectively and durably enhances quality of life. PMID- 23672910 TI - Optimal graft length for anterior cruciate ligament reconstruction: a biomechanical study in beagles. AB - The anterior cruciate ligament (ACL) is a major ligament that helps maintain the stability of the knee joint. Injury to the ACL can be treated by replacing the torn ligament. This study determined the optimal flexor tendon length in the bone tunnel in ACL reconstruction.Autologous ACL reconstruction was performed using a flexor tendon in 54 male beagles, with the graft length in the bone tunnel at 5, 9, 13, 17, 21, and 25 mm (9 dogs per graft length). The maximum tensile strength and stiffness of the reconstructed joint (tibia-ACL-femur triad) were recorded at 45, 90, and 180 days after ACL reconstruction (6 joints per time point). The experiment also included an intact control group (3 dogs) and a control group tested immediately after the reconstruction (3 dogs). For the intact control group, the normal ACL (unreconstructed) and flexor tendon mechanical testing was performed. For the other control group, the normal ACL (unreconstructed) mechanical testing was performed first and then mechanical testing of the specimens was performed immediately after reconstruction. The maximum tensile strength and stiffness of the reconstructed tibia-ACL-femur triad increased with time after reconstruction, regardless of the graft length in the bone tunnel. Maximum tensile strength and stiffness of the grafts increased with graft length but reached a plateau at 17 mm. Optimal strength and stiffness of the reconstructed ACL are achieved with 17-mm grafts. PMID- 23672911 TI - Development of site-specific locking plates for acetabular fractures. AB - Site-specific locking plates have gained popularity for the treatment of fractures. However, the clinical use of a site-specific locking plate for acetabular fractures remains untested due to production limits. To design a universal site-specific locking plate for acetabular fractures, the 3-dimensional (3D) photographic records of 171 pelvises were retrospectively studied to generate a universal posterior innominate bone surface. Using 3D photographical processing software, the 3D coordinate system was reset according to bony landmarks and was scaled based on the acetabular diameter to allow a direct comparison between surfaces. The measured surface was separated into measurement units. At each measurement unit, the authors calculated the average z-axis values in all samples and obtained the 3D coordinate values of the point cloud that could be reconstructed into the universal surface. A plate was subsequently designed in 3D photographical processing software, and the orientation and distribution of locking screws was included. To manufacture a plate, the data were entered into Unigraphics NX version 6.0 software (Siemens PLM Software, Co, Ltd, Plano, Texas) and a CNC digital milling machine (FANUC Co, Ltd, Yamanashi, Japan). The resulting locking plate fit excellently with the reduced bone surface intraoperatively. Plate contouring was avoided intraoperatively. Universal 3.5-mm locking screws locked successfully into the plate, and their orientations were consistent with the design. No screw yielded to acetabular penetration. This method of designing a site-specific acetabular locking plate is practical, and the plates are suitable for clinical use. These site-specific locking plates may be an option for the treatment of acetabular fractures, particularly in elderly patients. PMID- 23672912 TI - Greater trochanter osteotomy with cementless THA for Crowe type IV DDH. AB - This study explored the surgical method and short-term clinical effect of a greater trochanter osteotomy along with cementless artificial total hip arthroplasty in the treatment of Crowe type IV developmental dysplasia of the hip. The authors conducted a retrospective analysis of 18 patients (22 hips) with Crowe type IV dysplasia who were seen between June 2008 and August 2010. After undergoing cementless artificial total hip arthroplasty using a posterolateral approach, a greater trochanter osteotomy was used to adjust the tension of the gluteal muscle, and an acetabular cup was placed. Average preoperative length shortening of the affected limb was 4.5 cm (range, 3.4-6 cm), and average postoperative length increase was 4.0 cm (range, 3.2-4.8 cm). Average postoperative Harris Hip Score was 87 (range, 79-91), which was higher than the average preoperative score of 38 (range, 32-51). Intraoperatively, 3 hips (3 patients) sustained a proximal femur fracture. Due to the stability of the femoral prosthesis, either no treatment or wire fixation only was given; by 2 months postoperatively, radiographs indicated that all fractures had healed. One patient had symptoms of sciatic nerve paralysis that resolved 3 months postoperatively. Performing a greater trochanter osteotomy after cementless artificial total hip arthroplasty is effective for the treatment of Crowe type IV dysplasia and can rebuild the complex biology and biomechanics of hip dysplasia without increasing the complication risk. PMID- 23672913 TI - Prevalence of adverse reactions to metal debris following metal-on-metal THA. AB - The purpose of this study was to determine the prevalence of adverse reactions to metal debris (ARMD) following large-diameter metal-on-metal total hip arthroplasty. The authors examined the potential for using magnetic resonance imaging to screen for pseudotumors in 108 hips 2 years postoperatively. Serum cobalt and chromium concentrations were measured in 80 hips that underwent unilateral total hip arthroplasty. The authors considered pseudotumors and aseptic lymphocyte-dominated vasculitis-associated lesions to be ARMD and compared metal ion levels between hips with ARMD (ARMD group) with hips with no ARMD (non-ARMD group). Magnetic resonance imaging revealed pseudotumors in 9 patients (10 hips, 9%). Five of these 10 hips were symptomatic and underwent revision surgery. Two other patients underwent revision surgery due to symptomatic cup loosening with aseptic lymphocyte-dominated vasculitis-associated lesions. Ten patients (12 hips) had ARMD. Serum cobalt and chromium concentrations were significantly higher in hips with ARMD than hips without ARMD. Other factors, including age, body mass index, sex, clinical score, acetabular cup inclination angle, and femoral head diameter, were not significantly different between the groups. Elevated metal ion levels suggest that ARMD is associated with increased metal wear. Magnetic resonance imaging provides sensitive screening for pseudotumors following metal-on-metal total hip arthroplasty. PMID- 23672914 TI - Surgical management of 4-level cervical spondylotic myelopathy. AB - The optimal surgical approach for 4-level cervical spondylotic myelopathy is controversial. The authors compared the clinical outcomes, radiographic changes, and complications of 53 patients who underwent either discontinuous corpectomy and fusion (DCF) with reservation of the middle vertebra (n=29) or laminectomy and fusion (n=24). Neurological function was measured using Nurick's grade and modified Japanese Orthopedic Association scores. The Neck Disability Index was recorded for neck-shoulder pain level evaluation. Patients' satisfaction with the surgery was evaluated using the Short Form 36. Segmental lordosis was measured. Both groups demonstrated significantly improved Nurick's grades and Japanese Orthopedic Association scores (P<.001), and the recovery rate was similar between the groups (59.86% +/- 17.63% and 60.18% +/- 12.01%, respectively). In terms of Neck Disability Index scores, Short Form 36 scores, and cervical lordosis measurements, no significant intergroup differences were found preoperatively. Mean postoperative Neck Disability Index scores were significantly lower in the DCF group (12.31 +/- 1.91) than in the laminectomy group (15.04 +/- 3.09; P=.000). Mean postoperative segmental lordosis was significantly higher in the DCF group (14.24 +/- 2.29) than in the laminectomy group (9.96 +/- 2.14; P=.001). The Short Form 36 scores significantly improved in both groups postoperatively (P<.01). Relative to the DCF group, the laminectomy group had a significantly longer operative time (192.25 +/- 33.47 vs 192.25 +/- 33.47 minutes, respectively; P<.01) and significantly more operative blood loss (455.41 +/- 140.46 vs 253.79 +/- 77.94 mL, respectively; P<.01). Discontinuous corpectomy and fusion with reservation of the middle vertebra is a safe and effective surgical treatment for 4-level cervical spondylotic myelopathy that results in significant functional improvement in most patients. PMID- 23672915 TI - Outcomes of arthroscopic Bankart repair in collision versus noncollision athletes. AB - The purpose of the study was to compare the recurrence rate of arthroscopic Bankart repair with suture anchors in collision vs noncollision athletes. Sixty four patients who underwent arthroscopic shoulder stabilization using suture anchors for recurrent anterior dislocation were identified. Forty-three patients (22 collision and 21 noncollision) were evaluated at a minimum 24-month follow up. The recurrence rate was reported, and functional outcomes (American Shoulder and Elbow Society, Western Ontario Shoulder Index, and Short Form 12) were evaluated. Statistical analysis was performed using chi-square test and Student's t test with a 95% confidence interval and a significance level set at a P value less than .05. The overall dislocation recurrence rate was 4.6% (2 of 43 patients); the dislocation recurrence rate in collision athletes was 9% (2 of 22 patients), and no redislocations occurred in noncollision athletes. No statistical differences existed in Western Ontario Shoulder Index score (73.5% in collision and 73.4% in noncollision athletes; P=.831), American Shoulder and Elbow Society score (91.2 in collision and 80.7 in noncollision athletes; P=.228), and Short Form 12 score (108.5 in collision and 101.2 in noncollision athletes; P=.083). Average external rotation loss was 6.8 degrees in collision and 5.5 degrees in noncollision athletes (P=.864). Ninety percent of collision athletes vs 95% of noncollision athletes were satisfied. Seventy-three percent of collision and 81% of noncollision athletes were able to return to sport at their preinjury levels. Collision athletes had higher recurrence rates after arthroscopic shoulder stabilization compared with noncollision athletes, but no statistical difference was found. Functional outcomes according to American Shoulder and Elbow Society, Western Ontario Shoulder Index, and Short Form 12 were similar. PMID- 23672916 TI - Computer-assisted versus manual TKA: no difference in clinical or functional outcomes at 5-year follow-up. AB - The purpose of this study was to determine whether differences in clinical, functional, or radiographic outcomes existed at 5-year follow-up between patients who underwent computer-assisted or manual total knee arthroplasty (TKA). Seventy eight consecutive TKAs were performed by a single surgeon who had extensive experience performing computer-assisted and manual TKA. The manual group (n=40) and computer-assisted group (n=38) were similar with regard to age, sex, diagnosis, body mass index, surgical technique, implants, perioperative management, Knee Society scores, and anteroposterior mechanical axis. Sixty-three (manual group, n=34; computer-assisted group, n=29) patients were available for final follow-up. At 5-year follow-up, no statistically significant differences were found in Knee Society knee score (P=.289), function score (P=.272), range of motion (P=.284), pain score (P=.432), or UCLA activity score (P=.109) between the 2 groups. Postoperative radiographs showed a significant difference in the mechanical axis (P=.004) between the 2 groups; however, both groups achieved a neutral mechanical axis of +/-3 degrees (computer-assisted group mean, 2.0 degrees ; manual group mean, -0.24 degrees ).When TKA was performed by an experienced surgeon, no significant difference was identified at 5-year follow-up between patients who underwent computer-assisted vs manual TKA. PMID- 23672917 TI - Minimum 5-year follow-up for primary THA using a tapered, proximally coated cementless stem. AB - The purpose of this study was to assess the survivorship of a proximally coated, cementless femoral stem used for total hip arthroplasty at a minimum 5-year follow-up by assessing clinical outcomes and implant survival. A total of 936 primary total hip arthroplasties were performed in 854 patients by 3 high-volume surgeons between 2001 and 2007. Patients included 385 men and 469 women with a mean age of 56 years (range, 20-88 years) and a mean follow-up of 7 years (range, 5-11 years). The aseptic revision rate related to the femoral component was 0.3%. Three patients underwent revision of the femoral component. Mean postoperative Harris Hip Score improved to 91 points (range, 70-100 points). When stratified by primary cause of total hip arthroplasty, no differences were found in implant survivorship or postoperative Harris Hip Scores. With the exception of the 3 patients who underwent revision surgery, postoperative radiographic evaluation of the stems demonstrated no progressive radiolucencies, component malalignment, change in component position, or implant subsidence at most recent follow up.These results are encouraging and indicate a 0.3% revision rate for the femoral component. The cause of primary total hip arthroplasty did not affect the clinical outcomes. These types of prostheses will provide patients with a stable implant that is expected to have excellent durability and longevity. PMID- 23672918 TI - Hip resurfacing and conventional THA: comparison of acetabular bone stock removal, leg length, and offset. AB - The purpose of this study was to compare total hip arthroplasty (THA) and hip resurfacing arthroplasty (HRA) with regard to the amount of acetabular bone stock removed and the ability to restore leg length and offset. Anteroposterior pelvis radiographs of 153 consecutive THAs and 84 consecutive HRAs were compared. Excluded patients were those with prior hip surgery, those in which a best-fit circle could not be adequately matched to the femoral head, and those with preoperative radiographic findings that precluded consideration for HRA (ie, disease severity, deformity, leg-length discrepancy). A significant difference was found between THA and HRA with regards to age and sex but not primary diagnosis. Relative differences in acetabular bone removal were compared using a ratio of acetabular implant diameter to preoperative ipsilateral femoral head diameter measured with a best-fit circle. The ratio of acetabular cup diameter to preoperative ipsilateral femoral head diameter was significantly greater following THA than following HRA, indicating relatively more acetabular bone removal in THA procedures. Mean leg-length discrepancy was significantly greater following THA than following HRA. Offset was increased to a greater extent following THA than following HRA. Overall, HRA was associated with relatively less acetabular bone stock removal and less alteration in leg length and offset than was THA. PMID- 23672919 TI - Predicting pulmonary embolus in orthopedic trauma patients using the Wells score. AB - The decision to perform computed tomography pulmonary angiography (CTPA) to rule out pulmonary embolism (PE) in orthopedic trauma patients is challenging. The Wells score is a commonly used clinical probability tool developed to determine the likelihood of PE and assist in determining the need for CTPA examination. This study evaluated the usefulness of the Wells score for predicting PE in patients admitted to the orthopedic trauma service. All patients who were admitted to the orthopedic trauma service at the authors' institution between 2001 and 2011 who underwent CTPA were identified. The Wells score was calculated retrospectively for each patient, and risk categories using the traditional and alternative interpretations of the Wells score were assigned. Pulmonary embolism was diagnosed in 27 (16%) of 169 patients who underwent CTPA. In total, 27 (0.39%) of 6854 patients admitted to the orthopedic trauma service were diagnosed with PE during initial hospitalization. Mean Wells score was 3.31 (95% confidence interval, +/-.28) for the entire population, 3.32 for those without PE (95% confidence interval, +/-.31), and 3.28 for those with PE (95% confidence interval, +/-.72) (P=.91). Average times from admission to CTPA examination for those with and without PE were 6.18 and 5.7 days, respectively (P=.94). No significant correlation existed between the Wells score and CTPA results, indicating that the Wells score is limited in predicting PE risk in orthopedic trauma patients. PMID- 23672920 TI - Autologous collagen-induced chondrogenesis: single-stage arthroscopic cartilage repair technique. AB - Autologous collagen-induced chondrogenesis is a novel, single-staged arthroscopic cartilage repair technique using microdrilling and atelocollagen or fibrin gel application under carbon dioxide insufflation. Atelocollagen is a highly purified type I collagen obtained following the treatment of skin dermis with pepsin and telopeptide removal, making it nonimmunogenic. In this procedure, atelocollagen mixed with fibrinogen and thrombin in a 2-way syringe can maintain the shape of the articular surface approximately 5 minutes after application due to the reaction between the thrombin and fibrinogen. Carbon dioxide insufflation facilitates the application of the gel under dry conditions. Ten patients (mean age, 38 years) with symptomatic chondral defects in the knee who were treated arthroscopically with microdrilling and atelocollagen application were retrospectively analyzed. All defects were International Cartilage Repair Society grade III or IV and were 2 to 8 cm(2) in size intraoperatively. For the clinical assessment, Lysholm score was assessed preoperatively and at 2-year follow-up. All patients underwent morphological magnetic resonance imaging at 1.5-Tesla at 1 year follow-up. Mean Magnetic Resonance Imaging Observation of Cartilage Repair Tissue score at 1-year follow-up was 70.4 +/- 20.2 (range, 15-95). The Magnetic Resonance Imaging Observation of Cartilage Repair Tissue score for patellar lesions was similar to that of lesions in other locations: 73.3 +/- 11.7 vs 68.1 +/- 25.5, respectively. This technique had encouraging clinical results at 2-year follow-up. Morphological magnetic resonance imaging shows good cartilage defect filling, and the biochemical magnetic resonance imaging suggests hyaline-like repair tissue. PMID- 23672921 TI - Pseudotumor associated with metal-on-polyethylene total hip arthroplasty. AB - This case report details the presentation, imaging results, and operative findings of a pseudotumor associated with a press-fit metal-on-polyethylene total hip arthroplasty (THA). An 80-year-old man presented approximately 7 years after undergoing THA with worsening right groin and lateral hip pain with an associated proximal thigh mass. Physical examination demonstrated a tender, large anterolateral thigh mass that was also evident on metal artifact reduction sequence magnetic resonance imaging.An exploratory operative procedure revealed extensive tissue necrosis involving nearly the entire hip capsule, short external rotators, and tendinous portion of the gluteus medius muscle. In addition, marked surface corrosion was discovered about the taper at the head-neck junction of the prosthetic femoral component and the trunnion within the femoral head. The press fit THA components were solidly fixed. The metallic head was replaced with a ceramic component, and the polyethylene liner was exchanged. The patient had complete resolution of his preoperative symptoms but had persistent problems with dislocations.Although reports of pseudotumor and local soft tissue reactions associated with metal-on-metal THAs have become increasingly ubiquitous in the literature, similar reports involving metal-on-polyethylene THA implants are less common. PMID- 23672922 TI - Reversal of acute ischemic stroke after THA using tissue plasminogen activator. AB - Acute ischemic stroke is a potentially catastrophic medical emergency. Recently, successful reversal of the neurologic deficits associated with major ischemic strokes has been accomplished in selected patients through the use of intravenous tissue plasminogen activator (tPA), an agent that can accomplish thrombolysis of arterial clots if given within the first few hours after the onset of stroke. Because tPA works by thrombolysis of fresh clots, a potential exists for catastrophic hemorrhage if given to acute postoperative patients. Therefore, the use of tPA has never been studied in postoperative patients, and the safety of the drug in postoperative patients is unknown.The author describes a patient who had an acute ischemic stroke 2 days after total hip arthroplasty who was successfully treated with tPA without major complications. The patient was 51 years old and developed progressive facial droop, right arm paralysis, and dysarthria 2 days after elective hip arthroplasty. Imaging confirmed occlusion of the left middle cerebral artery. Neurologic recovery was believed to be unlikely without tPA. After tPA administration, the patient had full neurologic recovery within minutes but did develop a large (nondraining) hematoma and severe ecchymosis at the surgical site; a drop in hematocrit required 3 units of packed red blood cell transfusion. The wound did not develop skin necrosis, infection, or compartment syndrome, and the hematoma resolved within several weeks without the need for surgical intervention.The author describes the patient's specific circumstances, the decision-making process behind the use of tPA, and the need for contingency plans in the event that severe uncontrolled hemorrhage occurs. This information may be useful if other surgeons are faced with the dilemma of a major stroke in acute postoperative patients. PMID- 23672923 TI - Totally cystic schwannoma of the lumbar spine. AB - A schwannoma is a benign tumor arising from a schwann cell and occurs mainly in the nerve sheath in the intradural extramedullary region. Schwannomas have been well described as occurring in the lumbar spine, but total cystic degeneration of schwannomas is rarely reported. The authors describe the clinical and radiographic evaluations and treatment of a rare case of an intraextradural totally cystic schwannoma on the lumbar spine.Two patients reported a history of 6 to 12 months of pain accompanied by weakness in the lower extremities. On examination, 1 patient had bilateral lower-extremity muscle strength graded at 4/5, and magnetic resonance imaging revealed a cystic schwannoma (1.5 * 2.0 cm in the sagittal dimension) at L2-L3. The other patient had a right lower-extremity muscle strength graded at 3/5, and magnetic resonance imaging revealed a cystic schwannoma (2.0 * 3.0 cm in the sagittal dimension) at L4-L5. The patients underwent operative treatment, and the tumors were completely removed, as were the filum terminale adhered to the tumor. Pedicle screws were used to maintain stability of the lumbar spine. Gross examination of the tumors showed yellowish white soft contents. Histologic examination confirmed that they were benign totally cystic schwannomas. Postoperatively, the patients' neurologic symptoms completely resolved.Cystic schwannomas can be diagnosed using preoperative magnetic resonance imaging. The filum terminale cut off the tumor walls did not cause the clinical symptoms in the 2 patients. PMID- 23672924 TI - Arthroscopic internal fixation of osteochondritis dissecans of the femoral head. AB - Osteochondritis dessicans of the femoral head is an uncommon problem. Limited literature reports the incidence of osteochondritis dessicans and its treatment. The surgical technique used and outcomes for a 40-year-old man with symptomatic femoral head osteochonditis dissecans who was treated 11 years previously with retrograde drilling and hip arthroscopy are discussed.Despite temporary symptomatic improvement without subchondral collapse after his index procedure, increasing pain a decade later was thought to be caused by a large apical osteochondritic fragment and chondrolabral dysfunction from femoroacetabular impingement. Acetabuloplasty of acetabular overcoverage permitted arthroscopic internal fixation of the bone fragment by improving screw trajectory. Labral refixation and femoroplasty were subsequently performed. At 18-month follow-up, his nonarthritic hip score improved from 53 to 76 and his osteochondritic lesion had healed radiographically.Although clinical improvement with radiographic union has been reported following open screw fixation of femoral head osteochondritis dissecans, to the authors' knowledge this is the first published case with a similar outcome using arthroscopic techniques. Clinical improvement and union of even long-standing osteochondritis dissecans of the femoral head may occur with arthroscopic fragment fixation. Hip arthroscopy may play significant therapeutic and diagnostic roles in the treatment of this condition while offering a less invasive alternative to open osteosynthesis. PMID- 23672925 TI - Graduated driver licensing program component calibrations and their association with fatal crash involvement. AB - Graduated driver licensing (GDL) programs are specialized licensing systems for beginner drivers adopted in all U.S. states, Australia, Canada, and New Zealand. GDL programs reduce novice drivers' exposure to high-risk driving situations while they gain driving experience. Several studies document the success of GDL programs overall in reducing young teen crash rates. However, little is known about which specific components of these programs (e.g., nighttime driving restrictions) and which calibrations of these components (e.g., 10 PM, 11 PM, 12 AM, or 1 AM), are associated with the largest crash reductions. The goal of this study was to identify the GDL component calibrations associated with the largest reductions in fatal crash involvements for 16-17-year-olds. Driver fatal crash involvements for all U.S. states from 1986 to 2007 were analyzed using Poisson regression models to estimate the association of various GDL component calibrations with 16- and 17-year-old driver fatal crash incidence, after adjusting for potential confounders. We found clear evidence that (a) a minimum learner permit holding period of 9-12 months and (b) a passenger restriction allowing only one teen passenger for 6 months or longer are the calibrations for the learner permit holding period and passenger restriction components associated with the largest reductions in 16-17-year-old driver fatal crash involvements. Additionally, the data suggest that (a) disallowing learner driving until age 16, (b) disallowing intermediate licensure until age 161/2 to 17, and (c) a nighttime driving restriction starting at 10 PM or earlier are the calibrations for these components associated with the largest reductions in 16-year-old driver fatal crashes. There was no clear evidence to support particular calibrations for supervised driving hours or unrestricted license ages. PMID- 23672926 TI - Using Bayesian networks to analyze occupational stress caused by work demands: preventing stress through social support. AB - Occupational stress is a major health hazard and a serious challenge to the effective operation of any company and represents a major problem for both individuals and organizations. Previous researches have shown that high demands (e.g. workload, emotional) combined with low resources (e.g. support, control, rewards) are associated with adverse health (e.g. psychological, physical) and organizational impacts (e.g. reduced job satisfaction, sickness absence). The objective of the present work is to create a model to analyze how social support reduces the occupational stress caused by work demands. This study used existing Spanish national data on working conditions collected by the Spanish Ministry of Labour and Immigration in 2007, where 11,054 workers were interviewed by questionnaire. A probabilistic model was built using Bayesian networks to explain the relationships between work demands and occupational stress. The model also explains how social support contributes positively to reducing stress levels. The variables studied were intellectually demanding work, overwork, workday, stress, and social support. The results show the importance of social support and of receiving help from supervisors and co-workers in preventing occupational stress. The study provides a new methodology that explains and quantifies the effects of intellectually demanding work, overwork, and workday in occupational stress. Also, the study quantifies the importance of social support to reduce occupational stress. PMID- 23672927 TI - A simultaneous equations model of crash frequency by severity level for freeway sections. AB - This paper presents a simultaneous equations model of crash frequencies by severity level for freeway sections using five-year crash severity frequency data for 275 multilane freeway segments in the State of Washington. Crash severity is a subject of much interest in the context of freeway safety due to higher speeds of travel on freeways and the desire of transportation professionals to implement measures that could potentially reduce crash severity on such facilities. This paper applies a joint Poisson regression model with multivariate normal heterogeneities using the method of Maximum Simulated Likelihood Estimation (MSLE). MSLE serves as a computationally viable alternative to the Bayesian approach that has been adopted in the literature for estimating multivariate simultaneous equations models of crash frequencies. The empirical results presented in this paper suggest the presence of statistically significant error correlations across crash frequencies by severity level. The significant error correlations point to the presence of common unobserved factors related to driver behavior and roadway, traffic and environmental characteristics that influence crash frequencies of different severity levels. It is found that the joint Poisson regression model can improve the efficiency of most model coefficient estimators by reducing their standard deviations. In addition, the empirical results show that observed factors generally do not have the same impact on crash frequencies at different levels of severity. PMID- 23672928 TI - Phase II study of temsirolimus (CCI-779) in women with recurrent, unresectable, locally advanced or metastatic carcinoma of the cervix. A trial of the NCIC Clinical Trials Group (NCIC CTG IND 199). AB - OBJECTIVE: HPV infection has been associated with deregulation of the PI3K-Akt mTOR pathway in invasive cervical carcinomas. This 2-stage phase II study assessed the activity of the mTOR inhibitor, temsirolimus, in patients with measurable metastatic and/or locally advanced, recurrent carcinoma of the cervix. METHODS: Temsirolimus 25mg i.v. was administered weekly in 4 week cycles. One response among the first 18 patients was required to proceed to the second stage of accrual. Correlative molecular studies were performed on archival tumor tissue. RESULTS: Thirty-eight patients were enrolled. Thirty-seven patients were evaluable for toxicity and 33 for response. One patient experienced a partial response (3.0%). Nineteen patients had stable disease (57.6%) [median duration 6.5 months (range 2.4-12.0mo)]. The 6-month progression free survival rate was 28% (95% CI: 14-43%). The median progression free survival was 3.52 months [95% CI (1.81-4.70)]. Adverse effects were mild-moderate in most cases and similar to other temsirolimus studies. No toxicity>grade 3 was observed. Assessment of PTEN and PIK3CA by IHC, copy number analyses and PTEN promoter methylation status did not reveal subsets associated with disease stability. CONCLUSION: Single agent temsirolimus has modest activity in cervical carcinoma with about two-thirds of patients exhibiting stable disease. Molecular markers for treatment benefit remain to be identified. PMID- 23672929 TI - Optimal (<=1 cm) but visible residual disease: is extensive debulking warranted? AB - OBJECTIVES: To determine if extensive upper abdominal surgery (UAS) affected overall survival (OS) in patients left with <= 1 cm but visible residual disease after undergoing primary cytoreductive surgery for ovarian cancer. Our secondary objective was to determine if leaving <= 1cm but visible residual throughout the small bowel (SB) conferred a worse prognosis. METHODS: All stage IIIB-IV ovarian cancer patients who had visible but <= 1 cm residual disease at time of primary cytoreductive surgery from 2001 to 2010 were identified. Extensive UAS procedures and residual SB involvement were recorded. RESULTS: The 219 patients identified with <=1 cm but visible residual disease had a median OS of 51 months. In this cohort, 127 had extensive UAS performed, and 87 had residual disease involving the SB. Univariate OS analysis was performed. There was no significant difference in OS between patients who did or did not have extensive UAS (45 vs. 52 months, P=0.56), or between patients with or without residual SB disease (45 vs. 51 months, P=0.84). Factors that were significantly associated with OS were age, ASA score, family history, and stage. CONCLUSIONS: Patients cytoreduced to <= 1 cm but visible residual disease who required UAS did not have a worse OS than those who did not require UAS. OS was similar if residual disease involved the SB or not. For ovarian cancer patients with disease not amenable to complete gross resection, extensive surgery should still be considered to achieve <= 1 cm but visible residual disease status, including cases where the residual disease involves the SB. PMID- 23672930 TI - The use of CT findings to predict extent of tumor at primary surgery for ovarian cancer. AB - BACKGROUND: High tumor dissemination (HTD) is a major risk factor for serious morbidity after primary ovarian cancer (OC) surgery, particularly in medically compromised patients. We performed a pilot study of whether CT findings could predict extent of disease and surgical complexity necessary in advanced OC. METHODS: Preoperative CT images for patients with advanced OC from 1997-2003 were evaluated for rigorously defined disease-related findings and compared to both the findings at exploration and the required surgical procedures. Associations were assessed by the chi-square test. RESULTS: Forty-six cases met inclusion criteria. Mean age was 66.4y, and 76% had residual disease (RD) 1cm or less. CT and surgical findings correlated (sensitivity/specificity) as follows: diaphragm disease (48%/100%); surface liver (100%/93%); omental cake (72%/65%); any sigmoid involvement (54%/100%); ascites (44%/100%); extra-pelvic large bowel involvement (29%/91%). When diaphragm disease and omental cake were present, HTD was found in all cases (positive predictive value and specificity=100%, sensitivity 48%). For CT findings of liver, large bowel and spleen involvement there was a strong trend toward resection (P=0.001, P=0.06 and P=0.06, respectively). CONCLUSIONS: The findings of diaphragm disease and omental cake on CT scan are highly predictive for high tumor dissemination (HTD) and thus likelihood of extensive surgery required to achieve low residual disease. In addition, multiple CT findings correlate strongly with the need for higher surgical complexity which should facilitate preoperative planning and/or triage to specialized centers. These preliminary data suggest specific CT findings can be used to optimize treatment planning. PMID- 23672931 TI - Clinical review: Can we predict which patients are at risk of complications following surgery? AB - There are a vast number of operations carried out every year, with a small proportion of patients being at highest risk of mortality and morbidity. There has been considerable work to try and identify these high-risk patients. In this paper, we look in detail at the commonly used perioperative risk prediction models. Finally, we will be looking at the evolution and evidence for functional assessment and the National Surgical Quality Improvement Program (in the USA), both topical and exciting areas of perioperative prediction. PMID- 23672932 TI - Early diagnosis and treatment of HIV infection: magnitude of benefit on short term mortality is greatest in older adults. AB - BACKGROUND: the number and proportion of adults diagnosed with HIV infection aged 50 years and older has risen. This study compares the effect of CD4 counts and anti-retroviral therapy (ART) on mortality rates among adults diagnosed aged >=50 with those diagnosed at a younger age. METHODS: retrospective cohort analysis of national surveillance reports of HIV-diagnosed adults (15 years and older) in England, Wales and Northern Ireland. The relative impacts of age, CD4 count at diagnosis and ART on mortality were determined in Cox proportional hazards models. RESULTS: among 63,805 adults diagnosed with HIV between 2000 and 2009, 9% (5,683) were aged >=50 years; older persons were more likely to be white, heterosexual and present with a CD4 count <200 cells/mm(3) (48 versus 32% P < 0.01) and AIDS at diagnosis (19 versus 9%, P < 0.01). One-year mortality was higher in older adults (10 versus 3%, P < 0.01) and especially in those diagnosed with a CD4 <200 cells/mm(3) left untreated (46 versus 15%, P < 0.01). While the relative mortality risk reduction from ART initiation at CD <200 cells/mm(3) was similar in both age groups, the absolute risk difference was higher among older adults (40 versus 12% fewer deaths) such that the number needed to treat older adults to prevent one death was two compared with eight among younger adults. CONCLUSIONS: the magnitude of benefit from ART is greater in older adults than younger adults. Older persons should be considered as a target for HIV testing. Coupled with prompt treatment, earlier diagnosis is likely to reduce substantially deaths in this group. PMID- 23672933 TI - Prevalence, predictors and covariates of functional status impairment among Finnish Second World War veterans during 1992-2004. AB - BACKGROUND: the functional status is one of the most important health measurements in the elderly. This study aimed to investigate the prevalence of self-reported physical and mental conditions among Finnish Second World War veterans during 1992-2004. We also aimed to study the ability of these conditions in 1992 to predict the functional status impairment in 2004 and to determine whether the worsening of symptoms or the onset of new diseases during 1992-2004 was associated with impaired basic activities of daily living (BADL) and instrumental activities of daily living (IADL) in 2004. METHODS: the study population was 4,999 veterans living in Finland participating in both the Veteran Project 1992 and 2004. Logistic regression models were employed to identify predictors for impaired BADL and IADL. Analyses were conducted separately for men with and without disability and for women. RESULTS: the highest risk estimate for impaired BADL in 2004 was in men without disability who had a neurological disease in 1992 [odds ratios (OR): 5.78, 95% CI: 2.49-13.43], in men with disability with walking difficulties in 1992 (OR: 2.41, 95% CI: 1.79-3.25) and in women with a musculoskeletal disease in 1992 (OR: 2.39, 95% CI: 1.58-3.62). For impaired IADL, walking difficulties had the highest risk estimate in all veteran groups. CONCLUSION: mental and physical conditions, especially walking difficulties, can predict veterans' future functional impairment even 12 years in advance, and worsening of these conditions is associated with impaired ADL. PMID- 23672934 TI - An osteoporotic fracture mimicking cervical dystonia in idiopathic Parkinson's disease. AB - We report on a case of a 65-year-old (CD) woman who sustained an atraumatic neck fracture. A combination of Parkinson's disease with motor fluctuations, chronic cervical dystonia and osteoporosis provided the basis for this interesting diagnosis. Mrs CD had progressed to complex phase idiopathic Parkinson's disease within 13 years of diagnosis. During this time she remained independent, only using a wheelchair when her motor fluctuations were bad. In 2011, she developed a sudden onset of neck spasm and occipital neuralgia, initially attributed to severe spasmodic cervical dystonia. Despite a titration regime of analgesics and weaning off of her Parkinson's disease medications, the pain persisted. An X-ray of her cervical spine showed degenerative discopathies from C4 to C7. Mrs CD underwent a trial of Botox injections to no avail and she was admitted acutely under the spinal team after an MRI of her spine showed abnormal oedema of the odontoid peg. Subsequent CT diagnosed a type II fracture of the odontoid peg on the background of severe osteoporotic bone (spinal T score -3.4 on subsequent DEXA scan) and she underwent a successful occipital cervical fusion of C1-C6. What makes this case interesting is the fact that this lady's profound powerful neck movements on a background of osteoporosis led to fracture of her neck. Post operatively, she admitted to non-adherence to her bisphosphonates, prioritising levodopa in the morning with food rather than taking her alendronate on an empty stomach. She is now pain free and receives annual zolendronate infusions. PMID- 23672935 TI - Potential of Ceiba pentandra (L.) Gaertn. (kapok) fiber as a resource for second generation bioethanol: parametric optimization and comparative study of various pretreatments prior enzymatic saccharification for sugar production. AB - Various pretreatments on Ceiba pentandra (L.) Gaertn. (kapok) fiber prior to enzymatic hydrolysis for sugar production were optimized in this study. The optimum conditions for water, acid, and alkaline pretreatments were 170 degrees C for 45 min, 120 degrees C for 45 min in 1.0% (v/v) H2SO4 solution and 120 degrees C for 60 min in 2.0% (v/v) NaOH solution, respectively. Among the three pretreatments, the alkaline pretreatment achieved the highest total glucose yield (glucose yield calculated based on the untreated fiber) (38.5%), followed by the water (35.0%) and acid (32.8%) pretreatments. As a result, the relative effectiveness of the pretreatment methods for kapok fiber was verified as alkali>water>acid at the condition stated. PMID- 23672936 TI - Comparison of high pressure and ambient pressure aerobic granulation sequential batch reactor processes. AB - Due to granule size, substrate and oxygen become limited in the core of granules leading to cell lysis at the core. Loss of granule stability is still a major barrier for practical application of AG. Compared to ambient pressure condition (AP), operation of AG under high pressure (HP) is a favorable condition for formation and stability of granules. Experimental results show that granulation was facilitated under HP condition. MLSS and size of granules under AP system are higher than those under HP system. However, SS of effluent in AP is higher than those in HP and is consisted mainly of flocculent sludge. Longer SRT and lower biomass yield are obtained in HP system, indicating that less sludge will be produced in HP system. HP system can operate at high nitrogen loading. Complete nitrification was observed earlier in HP, indicating that the growth of NOB was facilitated under high dissolved oxygen. PMID- 23672938 TI - Assessment of syngas composition variability in a pilot-scale downdraft biomass gasifier by an extended equilibrium model. AB - A new simplified approach based on equilibrium modeling is proposed in this work to describe the correlations among syngas species experimentally observed in a pilot scale downdraft biomass gasifier operated with different feedstocks (biomass pellets and vine prunings). The modeling approach is based on experimental evidence on the presence of devolatilization products in the syngas and fluctuations of syngas composition during stationary operation, accounted for by introducing two empirical parameters, a by-pass index and a permeability index. The simplified model correctly reproduces the correlations among the main syngas species (including methane and ethylene) resulting from experimental data of pilot tests with different feedstocks and under a wide range of operating conditions. PMID- 23672937 TI - Pretreatment of the macroalgae Chaetomorpha linum for the production of bioethanol--comparison of five pretreatment technologies. AB - A qualified estimate for pretreatment of the macroalgae Chaetomorpha linum for ethanol production was given, based on the experience of pretreatment of land based biomass. C. linum was subjected to hydrothermal pretreatment (HTT), wet oxidation (WO), steam explosion (STEX), plasma-assisted pretreatment (PAP) and ball milling (BM), to determine effects of the pretreatment methods on the conversion of C. linum into ethanol by simultaneous saccharification and fermentation (SSF). WO and BM showed the highest ethanol yield of 44 g ethanol/100g glucan, which was close to the theoretical ethanol yield of 57 g ethanol/100g glucan. A 64% higher ethanol yield, based on raw material, was reached after pretreatment with WO and BM compared with unpretreated C. linum, however 50% of the biomass was lost during WO. Results indicated that the right combination of pretreatment and marine macroalgae, containing high amounts of glucan and cleaned from salts, enhanced the ethanol yield significantly. PMID- 23672939 TI - Mechanical cell disruption for lipid extraction from microalgal biomass. AB - Cell disruption is an integral part of the downstream operation required to produce biodiesel from microalgae. This study investigated the use of ultrasonication and high-pressure homogenization (HPH) as cell disruption methods for two microalgal species, Tetraselmis suecica (TS) and Chlorococcum sp. (C sp.). The kinetics of cell disruption followed a first-order model (0.655N/cm), there were distinct differences in the stiffness of the three groups, SPMM explants being the stiffest, followed by Gynemesh M explants and native tissue being the most compliant. In uniaxial loading conditions, the two explants were similarly stiff and distinctly stiffer than native tissue at low membrane tensions (<5N/cm) (abdominal wall: 9+/-1N/cm, Gynemesh M: 21+/-5N/cm, and SPMM: 24+/-5N/cm). At high membrane tension (>5N/cm), differences between all groups vanished. Biaxial and uniaxial tests yield different results with respect to the mechanical behavior of mesh explants. These findings demonstrate that an evaluation of the mechanical biocompatibility of prosthetic meshes should be based on an experimental configuration (uniaxial or biaxial tension) which reproduces the expected in vivo conditions of mechanical loading and deformation. PMID- 23672950 TI - Changes in stationary upright standing and proprioceptive reflex control of foot muscles after fatiguing static foot inversion. AB - We searched for the consequences of a maximal static foot inversion sustained until exhaustion on the post-exercise stationary upright standing and the proprioceptive control of the foot muscles. Twelve healthy subjects executed an unilateral maximal static foot inversion during which continuous power spectrum analyses of surface electromyograms of the tibialis anterior (TA), peroneus longus (PL), and gastrocnemius medialis (GM) muscles were performed. Superimposed pulse trains (twitch interpolation) were delivered to the TA muscle to identify "central" or "peripheral" fatigue. Before and after the fatiguing task, we measured (1) the repartition of the plantar and barycentre surfaces with a computerized stationary platform, (2) the peak contractile TA response to electrical stimulation (TA twitch), (3) the tonic vibratory response (TVR) of TA and GM muscles, and (4) the Hoffman reflex. During static exercise, "central" fatigue was diagnosed in 5/12 subjects whereas in the 7 others "peripheral" TA fatigue was deduced from the absence of response to twitch interpolation and the post-exercise decrease in twitch amplitude. The sustained foot inversion was associated with reduced median frequency in TA but not in PL and GM muscles. After static exercise, in all subjects both the mean plantar and rearfoot surfaces increased, indicating a foot eversion, the TVR amplitude decreased in TA but did not vary in GM, and the Hoffman reflex remained unchanged. Whatever was the mechanism of fatigue during the maximal foot inversion task, the facilitating myotatic reflex was constantly altered in foot invertor muscles. This could explain the prevailing action of the antagonistic evertor muscles. PMID- 23672953 TI - Diminished rostral anterior cingulate cortex activation during trauma-unrelated emotional interference in PTSD. AB - BACKGROUND: Previous research suggests that individuals with posttraumatic stress disorder (PTSD) preferentially attend to trauma-related emotional stimuli and have difficulty completing unrelated concurrent tasks. Compared to trauma-exposed control groups, individuals with PTSD also exhibit lower rostral anterior cingulate cortex (rACC) activation during tasks involving interference from trauma-related stimuli. However, it is not clear whether relatively diminished rACC activation in PTSD also occurs during interference tasks involving trauma unrelated emotional stimuli. The present study employed functional magnetic resonance imaging (fMRI) and an interference task that involves emotional facial expressions and elicits rACC activation in healthy participants. FINDINGS: While performing a trauma-unrelated emotional interference task, participants with PTSD (n=17) showed less rACC activation than trauma-exposed non-PTSD (TENP; n=18) participants. In the PTSD group, rACC activation was negatively correlated with the severity of re-experiencing symptoms. The two groups did not significantly differ on behavioral measures (i.e., response times and error rates). CONCLUSIONS: These findings suggest that relatively diminished rACC activation in PTSD can be observed in interference tasks involving trauma-unrelated emotional stimuli, indicating a more general functional brain abnormality in this disorder. Future neuroimaging studies need not employ trauma-related stimuli in order to detect rACC abnormalities in PTSD. PMID- 23672954 TI - Duration of shedding of Verocytotoxin-producing Escherichia coli in children and risk of transmission in childcare facilities in England. AB - Exclusion of children with presumptive Verocytotoxin-producing Escherichia coli (VTEC) from childcare facilities until negative stool specimens are obtained is routine practice that disrupts families. We estimated the shedding and exclusion duration and transmission risk in such facilities. The study population comprised 225 children aged <6 years attending 201 childcare facilities in England with microbiologically confirmed VTEC in 2010-2011. We estimated the interval from onset to first negative specimen, and identified transmission events with secondary cases linked to facilities. The median duration of shedding was 31 days, and median period of exclusion was 39.5 days. Cases attending facilities while shedding VTEC did so for a median of 2 days before exclusion. Secondary cases occurred in 6/83 facilities (7%) attended by infectious cases. Despite evidence of VTEC shedding at facilities, transmission is relatively low. Revised control guidelines could consider supervised return for prolonged asymptomatic shedders. PMID- 23672952 TI - Survival outcomes of patients with advanced oral cavity squamous cell carcinoma treated with multimodal therapy: a multi-institutional analysis. AB - BACKGROUND: The oral cavity is the most common site for head and neck squamous cell carcinoma. Treatment of advanced stage oral cavity squamous cell carcinoma (OCSCC) has classically involved surgical resection with postoperative adjuvant radiotherapy (S-RT).Despite this aggressive dual modality therapy, the disease outcomes have remained poor. The treatment options expanded in 2004 when two international trials showed the addition of postoperative chemotherapy to radiation improved outcomes. These trials were, however not oral cavity site specific. OBJECTIVE: To assess survival outcomes of advanced OCSCC treated by differing modalities. The primary goal was to determine if the addition of postoperative chemotherapy (S-CRT) improves survival compared to other treatment regimens. METHODS: Demographic, pathologic, treatment, and survival data was obtained from patients diagnosed with OCSCC from 1998-2010 in Alberta, Canada. 222 patients were included in the final analysis from 895 OCSCC patients. Actuarial overall, disease-specific, disease-free, and metastasis-free survivals were estimated with Kaplan-Meier and Cox regression analyses. Patients were grouped by treatment. RESULTS: Patients receiving S-CRT had improved overall, disease-specific, disease-free, and metastasis-free survival compared to S-RT, CRT or RT(p < 0.05). Two and five year estimated overall survival was significantly higher in the S-CRT group at 77 and 58% (p < 0.05), versus S-RT with 55 and 40% rates(p < 0.05). Results were similar for disease-specific, disease-free, and metastasis free survival with S-CRT being favoured. Patients with extracapsular spread (ECS) treated with S-CRT versus S-RT had 55% survival advantage at 5 years (p < 0.05). CONCLUSION: This study shows that adding adjuvant chemotherapy to S-RT improves survival outcomes in advanced OCSCC, especially in patients with ECS. PMID- 23672955 TI - Requirement for age-specific peak cortisol responses to insulin-induced hypoglycaemia in children. AB - OBJECTIVE: Based on adult data, a peak cortisol response >=500 nmol/l to insulin induced hypoglycaemia constitutes a normal. Age-specific reference ranges for basal morning cortisol have been developed for clinical use in the paediatric population. Such reference ranges are not clearly established for peak cortisol responses to insulin-induced hypoglycaemia despite limited data suggesting an effect of age on peak cortisol. The aims of this study were to assess factors affecting the cortisol response to insulin-induced hypoglycaemia in children and to determine whether the peak cortisol response was related to age. DESIGN: The present study was a retrospective cohort study. METHODS: Retrospective analysis of children and adolescents aged <=18 years undergoing the insulin tolerance test with adequate hypoglycaemia was undertaken. Patients with hypopituitarism or severe hypothalamic-pituitary-adrenal axis impairment (peak cortisol value <400 nmol/l) or using systemic glucocorticoids were excluded. RESULTS: Two hundred and twenty-three tests were analysed. Peak cortisol responses >=500 nmol/l occurred in 183 (82%) tests. Age was negatively associated with peak cortisol responses (r=-0.15, P=0.03). A peak cortisol response <500 nmol/l was significantly less common in patients aged <12 years (9/97 (9%) vs 31/126 (25%); P=0.004). In children aged <12 years, the median (5th-95th centiles) peak cortisol values were 610 (480-806) nmol/l compared with 574 (442-789) nmol/l in children aged >=12 years (P<0.004). Similarly, median cortisol increment was significantly higher in younger patients (301 nmol/l compared with 226 nmol/l (P=0.0004)). CONCLUSIONS: Use of a single peak cortisol threshold in children of all ages is not appropriate and will result in overdiagnosis of adrenal insufficiency in adolescents. PMID- 23672957 TI - Credibility of industry-funded clinical trials. AB - If the pharmaceutical industry does not adhere to strict ethical standards both internally and externally when collaborating with academia, the public's trust will be further eroded. PMID- 23672956 TI - Subcutaneous hydrocortisone administration for emergency use in adrenal insufficiency. AB - OBJECTIVE: Evaluation of the pharmacokinetics and safety of s.c. hydrocortisone injection for use in adrenal emergency. DESIGN: Single-center, open-label, sequence-randomized, crossover study in a tertiary care center. PATIENTS AND METHODS: Twelve patients with chronic Addison's disease. Comparison of hydrocortisone pharmacokinetics after s.c. and i.m. injection (100 mg) and after s.c. administration of sodium chloride (0.9%) respectively at three different visits. MAIN OUTCOME MEASURE: maximum serum cortisol (Cmax), time to Cmax (tmax), and time to serum cortisol >36 MUg/dl (tserum cortisol >36 MUg/dl) after s.c. administration compared with i.m. administration, safety, and patient preference. RESULTS: Serum cortisol increased rapidly and substantially after both i.m. and s.c. injections (Cmax: 110+/-29 vs 97+/-28 MUg/dl, P=0.27, tmax: 66+/-51 vs 91+/ 34 min, P=0.17, and tserum cortisol >36 MUg/dl: 11+/-5 vs 22+/-11 min, P=0.004 respectively). Both i.m. and s.c. injections were well tolerated. Eleven (91.7%) patients preferred s.c. injection, whereas one patient did not have any preference. CONCLUSIONS: S.c. administration of 100 mg hydrocortisone shows excellent pharmacokinetics for emergency use with only a short delay in cortisol increase compared with i.m. injection. It has a good safety profile and is preferred by patients over i.m. injection. PMID- 23672958 TI - FoxA2 hunting research identifies the early trail of mesenchymal differentiation. AB - Epigenetic regulation offers a flexible means to instruct cell functions and fate. In human embryonic stem cells (hESCs), thousands of genes are targets for histone modifications leading to activation or suppression of transcription. Novel research now indicates that, in hESCs, the transcription start site of FOXA2, encoding a member of the forkhead family of transcription factors, is bivalently marked with histone modifications for both gene activation and repression. Moreover, FOXA2 is remarkably upregulated at an early stage of endothelial differentiation. These discoveries provide better understanding of the natural program of differentiation and also open up new opportunities for large scale production of endothelial progenitors. PMID- 23672959 TI - Identifying patients at risk for augmented renal clearance in the ICU - limitations and challenges. AB - Augmented renal clearance (ARC) is an important determinant of antibiotic exposure in critically ill patients, and identifying patients at risk is therefore an important goal. There is a growing body of evidence that a younger patient with a low to moderate degree of organ dysfunction typically is at risk of ARC and therefore decreased exposure to renally eliminated antibiotics. Mechanisms potentially involved, such as increased cardiac output, have, however, not been identified as appropriate surrogate markers, and the search for suitable alternatives to readily identify patients with ARC continues. PMID- 23672960 TI - Organohalogenated contaminants in domestic cats' plasma in relation to spontaneous acromegaly and type 2 diabetes mellitus: a clue for endocrine disruption in humans? AB - It was recently hypothesized that pets may serve as sentinels to explore human exposure to organohalogenated chemicals (OHCs) via indoor environments and adverse health effects. The current study investigates OHCs contamination in domestic cats suffering from diabetes mellitus (DM), particularly DM induced by acromegaly and a form of DM akin to human type 2 DM (T2DM). Plasma from three groups of domestic cats was analyzed: acromegaly induced DM, T2DM and age matched control cats without DM. Analytes targeted included organochlorine pesticides, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs), together with their hydroxylated (HO-) metabolites. Similar PCB profiles were measured in cat plasma compared to humans, while the PBDE profile (dominated by BDE-99 (48%-55%) and BDE-47 (19%-25%)), the PCB and PBDE metabolite profiles were different in cat plasma than found in humans. Significantly higher OHC concentrations were recorded in plasma of acromegalic cats compared to the other two groups. Group differences in the PCBs/HO-PCBs ratios suggest that acromegalic cats have a lower capacity to metabolize persistent OHCs, like PCBs, than diabetic cats or cats without an endocrinopathy. As pituitary tumorigenesis in animals can be induced by estrogens, and PCBs may act as xenoestrogens, further investigation into whether there could be a causative link with the induction of feline acromegaly is warranted. Interestingly, BDE-47/BDE-99 ratios in cats were similar to the ratios in house dust. The results of this study suggest that domestic cats may represent a good model to assess human exposure to chemicals present in indoor dust. PMID- 23672961 TI - Reprint of: "I'm always entirely happy when I'm here!" Urban blue enhancing human health and well-being in Cologne and Dusseldorf, Germany. AB - Water is one of the most important landscape elements. In settled areas, planners rediscovered urban blue in the form of rivers as a soft location factor in post industrial times. Although the recognition of the need for recreational or 'healthy' places like urban green or urban blue in cities is increasing, current urban planning is mostly conducted without taking beneficial health issues into account. In this paper an extended concept of therapeutic landscapes is used to analyse two promenades on the river Rhine in the centres of two German cities (Cologne and Dusseldorf). A complex of qualitative and quantitative methods from diverse disciplines is applied to obtain a multi-dimensional image of salutogenic health processes. The results show that the promenades are favourite places to spend leisure time and to engage in recreational activities, in addition to providing restoration from everyday stresses. Water is a strong predictor of preference and positive perceptive experiences in urban environments. Users of the promenades also report strong emotional attachments to the place. Urban blue space may be interpreted as a therapeutic landscape in various ways. The study forms a contribution to planning issues, particularly considering benefits for human health, and enhances current research concerning therapeutic landscapes. PMID- 23672962 TI - Dynamic behavior of interfaces: modeling with nonequilibrium thermodynamics. AB - In multiphase systems the transfer of mass, heat, and momentum, both along and across phase interfaces, has an important impact on the overall dynamics of the system. Familiar examples are the effects of surface diffusion on foam drainage (Marangoni effect), or the effect of surface elasticities on the deformation of vesicles or red blood cells in an arterial flow. In this paper we will review recent work on modeling transfer processes associated with interfaces in the context of nonequilibrium thermodynamics (NET). The focus will be on NET frameworks employing the Gibbs dividing surface model, in which the interface is modeled as a two-dimensional plane. This plane has excess variables associated with it, such as a surface mass density, a surface momentum density, a surface energy density, and a surface entropy density. We will review a number of NET frameworks which can be used to derive balance equations and constitutive models for the time rate of change of these excess variables, as a result of in-plane (tangential) transfer processes, and exchange with the adjoining bulk phases. These balance equations must be solved together with mass, momentum, and energy balances for the bulk phases, and a set of boundary conditions coupling the set of bulk and interface equations. This entire set of equations constitutes a comprehensive continuum model for a multiphase system, and allows us to examine the role of the interfacial dynamics on the overall dynamics of the system. With respect to the constitutive equations we will focus primarily on equations for the surface extra stress tensor. PMID- 23672963 TI - Improvement in the practical implementation of neutron source strength calibration using prompt gamma rays. AB - In this study, the neutron emission rate from neutron sources using prompt gamma rays in hydrogen was determined, and several improvements were applied. Using Monte Carlo calculations, the best positions for the source, moderator and detector relative to each other were selected. For (241)Am-Be and (252)Cf sources, the sizes for polyethylene spheres with the highest efficiency were 12- and 10-inch, respectively. In addition, a new shielding cone was designed to account for scattered neutrons and gamma rays. The newly designed shielding cone, which is 45 cm in length, provided suitable attenuation for the source radiation. PMID- 23672964 TI - Monte Carlo simulation for determining gas saturation using three-detector pulsed neutron logging technology in tight gas reservoir and its application. AB - A new method to accurately determine gas saturation in the tight gas reservoir using a three-detector pulsed neutron logging tool was proposed. Formation porosity is varied from 2% to 15% to simulate the distribution of thermal neutron under different borehole and formation conditions by using Monte Carlo method. The study result shows that the difference of three detectors counts can be used to determine gas saturation and have higher sensitivity than counting the ratio of different detectors. PMID- 23672965 TI - Calcium isolation from large-volume human urine samples for 41Ca analysis by accelerator mass spectrometry. AB - Calcium oxalate precipitation is the first step in preparation of biological samples for (41)Ca analysis by accelerator mass spectrometry. A simplified protocol for large-volume human urine samples was characterized, with statistically significant increases in ion current and decreases in interference. This large-volume assay minimizes cost and effort and maximizes time after (41)Ca administration during which human samples, collected over a lifetime, provide (41)Ca:Ca ratios that are significantly above background. PMID- 23672968 TI - Does space make waste? The influence of ICU bed capacity on admission decisions. AB - BACKGROUND: Intensive care unit (ICU) beds are a scarce resource, and admissions may require prioritization when demand exceeds supply. However, there are few empiric data on whether the availability of ICU beds influences triage and processes of care for hospitalized patients who develop sudden clinical deterioration. METHODS RESULTS: The cohort consisted of 3,494 patients. Reduced ICU bed availability was associated with a decreased likelihood of ICU admission within 2 hours of MET activation (P = 0.03) and with an increased likelihood of change in patient goals of care (P <0.01). Patients with sudden clinical deterioration when zero ICU beds were available were 33.0% (95% confidence interval (CI), -5.1% to 57.3%) less likely to be admitted to the ICU and were 89.6% (95% CI, 24.9% to 188.0%) more likely to have their goals of care changed compared with when more than two ICU beds were available. However, hospital mortality did not vary significantly by ICU bed availability (P = 0.82). CONCLUSIONS: For hospitalized patients with sudden clinical deterioration, ICU bed scarcity decreases the probability of ICU admission and increases the probability of initiating comfort measures on the ward but does not influence hospital mortality. PMID- 23672966 TI - Hormonal contraceptive use diminishes salivary cortisol response to psychosocial stress and naltrexone in healthy women. AB - The use of hormonal contraception (HC) may affect salivary cortisol levels at rest and in response to a pharmacological or stress challenge. Therefore, the current study used a secondary data analysis to investigate the effect of HC on salivary cortisol levels in response to the mu-opioid receptor antagonist naltrexone and a psychosocial stressor, and also across the diurnal curve. Two hundred and nine women (n=72 using hormonal contraception; HC+) completed a two session stress response study that consisted of a stress day, in which they were exposed to public speaking and mental arithmetic, and a rest day, in which unstimulated cortisol levels were measured to assess the diurnal rhythm. A subset of seventy women (n=24 HC+) also completed a second study in which they were administered oral naltrexone (50mg) or placebo in a randomized, placebo controlled, double blind fashion. Women who were HC+ had a significantly reduced salivary cortisol response to both the psychosocial stressor (p<0.001) and naltrexone (p<0.05) compared to HC- women. Additionally, HC+ women had a significantly altered morning diurnal cortisol rhythm (p<0.01), with a delayed peak and higher overall levels. The results of the current study confirm that HC attenuates salivary cortisol response to a psychosocial stressor and mu-opioid receptor antagonism, and also alters the morning diurnal cortisol curve. PMID- 23672969 TI - Subclinical macular findings in infants screened for retinopathy of prematurity with spectral-domain optical coherence tomography. AB - OBJECTIVE: To evaluate subclinical macular findings in premature patients at risk of retinopathy of prematurity (ROP) with the use of handheld spectral-domain optical coherence tomography (SD-OCT). DESIGN: Prospective, observational case series. PARTICIPANTS: Forty-nine prematurely born neonates. METHODS: Forty-nine infants were imaged using a handheld SD-OCT. Images were acquired in nonsedated infants in the neonatal intensive care unit (NICU). Some patients were followed and reimaged over the course of several weeks. A total of 300 total images were acquired and evaluated for cystoid macular edema (CME) and persistence of inner retinal layers. MAIN OUTCOME MEASURES: In vivo determination of foveal retinal lamination, image analysis, and clinical observation. RESULTS: A total of 241 (80%) of the images from 46 patients were usable (defined as having scans passing through the fovea with clearly identifiable retinal layers). Persistence of 1 or more inner retinal layers was seen in 43 of the patients with usable images (93%). Of the patients with at least 1 persistent layer, 17, 4, 8, 12, and 1, had a maximum ROP stage of 0, 1, 2, 3, and 4A, respectively. Cystoid macular edema was seen in 25 of the 46 patients (54%) during 1 or more imaging sessions. Cystoid macular edema was present in 9, 1, 5, 9, and 1 patient with maximum ROP stage of 0, 1, 2, 3, and 4A, respectively. CONCLUSIONS: Our data suggest there is persistence of inner retinal layers in premature infants regardless of maximal ROP stage. Subclinical CME is seen in premature infants; however, CME does not appear to be correlated with ROP stage. This suggests that there may be other causes for the CME seen in this patient population. Hand-held SD-OCT imaging is a viable technique for evaluating subclinical macular findings in premature infants, although larger datasets are needed from multiple centers to further evaluate the generalizability of these findings. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23672970 TI - Differentiation of parapapillary atrophy using spectral-domain optical coherence tomography. AB - PURPOSE: To develop a classification of parapapillary atrophy (PPA) based on its relationship with the location of Bruch's membrane (BM) termination in primary open-angle glaucoma (POAG) patients. DESIGN: Cross-sectional observational study. PARTICIPANTS: This study analyzed 161 eyes from 161 POAG patients who had temporal beta-zone PPA, the width of which was more than 200 MUm on at least 1 horizontal scan image obtained by spectral-domain optical coherence tomography within the mid horizontal one third of the optic nerve. METHODS: Based on the extent of BM within the PPA area, eyes were categorized as group A (intact BM; 76 eyes), group B (discontinuous BM; 65 eyes), and group C (lacking BM; 20 eyes). Differences in the demographic, clinical, and ocular characteristics were compared using analysis of variance and chi-square tests among the 3 groups. The distance from the temporal optic disc margin to the temporal margin of the beta zone PPA (PPA width) and to the edge of the BM (width of PPA without BM [PPA-BM]) were measured on 3 horizontal scans within the mid horizontal one third of the optic nerve, and the averages of the measured values were analyzed. The configuration of the border tissue of Elschnig at the temporal disc margin was assessed. MAIN OUTCOME MEASURES: Factors and configuration of the border tissue of Elschnig associated with each PPA type. RESULTS: The mean age of group A was significantly higher than that of groups of B and C (P<0.001). The mean axial length was greatest in group C (group C>group B>group A; P<0.001). In group A, the border tissue mainly had a nonoblique configuration (49/76 eyes; 64.5%), whereas most of the eyes in group B (59/65 eyes; 90.8%) and all eyes in group C (20 eyes) it had an externally oblique configuration (P<0.001). A longer axial length was correlated significantly with a larger PPA-BM width (r = 0.478; P<0.001). CONCLUSIONS: A morphologic classification of PPA, which may reflect differing pathogenesis among the groups, is proposed. Parapapillary atrophy with intact BM may be an age-related atrophic change, whereas PPA lacking BM may result from scleral stretching associated with elongation of the globe. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 23672971 TI - Risk factors for incident myopia in Australian schoolchildren: the Sydney adolescent vascular and eye study. AB - PURPOSE: To examine the risk factors for incident myopia in Australian schoolchildren. DESIGN: Population-based, longitudinal cohort study. PARTICIPANTS: The Sydney Adolescent Vascular and Eye Study (SAVES) was a 5- to 6 year follow-up of the Sydney Myopia Study (SMS). At follow-up, 2103 children were reexamined: 892 (50.5%) from the younger cohort and 1211 (51.5%) from the older cohort. Of these, 863 in the younger cohort and 1196 in the older cohort had complete refraction data. METHODS: Cycloplegic autorefraction (cyclopentolate 1%; Canon RK-F1; Canon, Tokyo, Japan) was measured at baseline and follow-up. Myopia was defined as a spherical equivalent refraction of <=-0.50 diopters (D). Children were classified as having incident myopia if they were nonmyopic at baseline and myopic in either eye at follow-up. A comprehensive questionnaire determined the amount of time children spent outdoors and doing near work per week at baseline, as well as ethnicity, parental myopia, and socioeconomic status. MAIN OUTCOME MEASURES: Incident myopia. RESULTS: Children who became myopic spent less time outdoors compared with children who remained nonmyopic (younger cohort, 16.3 vs. 21.0 hours, respectively, P<0.0001; older cohort, 17.2 vs. 19.6 hours, respectively, P=0.001). Children who became myopic performed significantly more near work (19.4 vs. 17.6 hours; P=0.02) in the younger cohort, but not in the older cohort (P=0.06). Children with 1 or 2 parents who were myopic had greater odds of incident myopia (1 parent: odds ratio [OR], 3.2, 95% confidence interval [CI], 1.9-5.2; both parents: OR, 3.3, 95% CI, 1.6-6.8) in the younger but not the older cohort. Children of East Asian ethnicity had a higher incidence of myopia compared with children of European Caucasian ethnicity (both P<0.0001) and spent less time outdoors (both P<0.0001). A less hyperopic refraction at baseline was the most significant predictor of incident myopia. The addition of time outdoors, near work, parental myopia, and ethnicity to the model significantly improved the predictive power (P<0.0001) in the younger cohort but had little effect in the older cohort. CONCLUSIONS: Time spent outdoors was negatively associated with incident myopia in both age cohorts. Near work and parental myopia were additional significant risk factors for myopia only in the younger cohort. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23672972 TI - Randomized trial on silicone intubation in endoscopic mechanical dacryocystorhinostomy (SEND) for primary nasolacrimal duct obstruction. AB - PURPOSE: To study the effect of bicanalicular silicone intubation on endonasal endoscopic mechanical dacryocystorhinostomy (EEM-DCR) for primary acquired nasolacrimal duct obstruction (PANDO). DESIGN: Randomized clinical trial. PARTICIPANTS: A total of 120 consecutive adults (103 females) with a presenting age of 64 +/- 13.7 years (range, 39-92 years) underwent EEM-DCR for PANDO from November 2005 to May 2009 in a lacrimal referral center. METHODS: The EEM-DCR was performed by 2 lacrimal surgeons using standard techniques. Patients were randomly assigned to receive or not receive bicanalicular silicone intubation for 8 weeks. No antimetabolite was used. All patients received a course of oral antibiotics during nonabsorbable nasal packing for flaps tamponade, which was removed at the first postoperative visit. Patients were assessed at 1, 3, 6, 12, 26, and 52 weeks after the operation. MAIN OUTCOME MEASURES: Surgical success was defined by symptomatic relief of epiphora, reestablishment of nasolacrimal drainage confirmed by irrigation by 1 masked observer, and positive functional endoscopic dye test by the operative surgeon at 12 months postoperatively. Intraoperative and postoperative complications were recorded. RESULTS: A total of 118 of the 120 randomized cases completed 12 months of follow-up. Two patients died of unrelated medical illnesses during follow-up. At 12 months postoperatively, there was no statistical difference in the success rate between patients with (96.3%) and without (95.3%) intubation (P=0.79). The odds ratio of failure without silicone intubation was 1.28 (95% confidence interval, 0.21 7.95). There was no difference in the incidence (P=0.97) or the time to develop (P=0.12) granulation tissue between the 2 groups. No significant difference was found between successful and failed cases in terms of age (P=0.21), sex (P=0.37), laterality (P=0.46), mode of anesthesia (P=0.14), surgeon (P=0.26), use of stent (P=0.79), or presence of granulation tissue postoperatively (P=0.39). CONCLUSIONS: The current study design provided 90% statistical power to detect more than 21% difference in surgical outcome, and no such difference was found whether intubation was used or not used in EEM-DCR for PANDO at the 12-month follow-up. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23672973 TI - A Comparison between Scheimpflug imaging and optical coherence tomography in measuring corneal thickness. AB - PURPOSE: To assess the repeatability and reproducibility of 3 rotating Scheimpflug cameras, the Pentacam (Oculus, Wetzlar, Germany), Sirius (Costruzione Strumenti Oftalmici, Florence, Italy), and Galilei (Ziemer, Biel, Switzerland), and 1 Fourier-domain optical coherence tomography (FD-OCT) system, the RTvue-100 OCT (Optovue Inc., Fremont, CA), in measuring corneal thickness. DESIGN: Evaluation of diagnostic test. PARTICIPANTS: Sixty-six right eyes of 66 healthy volunteers, whose mean age +/- standard deviation (SD) was 35.39+/-10.06 years (range, 18-55 years). METHODS: Corneal thickness measurements obtained by each system included central corneal thickness (CCT), thinnest corneal thickness (TCT), and midperipheral corneal thickness (MPCT), measured at superior, inferior, nasal, and temporal locations at a distance of 1 and 2.5 mm from the corneal apex. In the first session, 3 consecutive measurements were performed by the same operator to assess intraobserver repeatability and by a second operator to assess interobserver reproducibility. Measurements were repeated in the second session scheduled 1 day to 1 week later. The mean values obtained in the 2 sessions by the first operator were used to investigate the intersession reproducibility. MAIN OUTCOME MEASURES: Intraobserver repeatability and interobserver and intersession repeatability of corneal thickness measurements, as calculated by means of within-subject SD, test-retest repeatability, coefficient of variation (COV), and intraclass correlation coefficients. RESULTS: The precision of CCT, TCT, CT2 mm (midperipheral corneal thickness [MPCT] with a distance of 1 mm from the corneal apex), and CT5 mm (midperipheral corneal thickness [MPCT] with a distance of 2.5 mm from the corneal apex) measurements was high with all 4 systems. The COV was <=1.16%, 0.94%, and 1.10% for repeatability, interobserver reproducibility, and intersession reproducibility, respectively. The 4 devices offered better interobserver reproducibility than intersession reproducibility for all measurements. The CTsuperior-5 mm (midperipheral corneal thickness [MPCT], measured at superior locations with a distance of 2.5 mm from the corneal apex) measurements showed the poorest repeatability and reproducibility. The Galilei revealed the best precision of CCT, TCT, and CT2 mm measurements. CONCLUSIONS: Both Scheimpflug imaging and FD OCT offer highly repeatable and reproducible measurements of CCT and MPCT. The precision was lower in the midperipheral superior quadrant. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23672975 TI - Can we achieve high uptakes of influenza vaccination of healthcare workers in hospitals? A cross-sectional survey of acute NHS trusts in England. AB - It is unknown which intervention strategies are used or effective to increase influenza vaccine uptake by healthcare workers (HCWs) in acute hospitals in England. We undertook a survey in acute hospitals, described strategies employed from 2008 to 2012 and used multivariable binomial regression to identify those effective. Eighty out of 166 trusts responded and reported 25 strategies. Every intervention showed increased use: peer vaccination from 3.8% to 38.8% (+921%); educational DVDs from 3.8% to 22.5% (+492%); Twitter from 2.5% to 12.5% (+400%) and Facebook from 1.3% to 6.3% (+384%). Peer vaccination increased uptake by 7.3% [95% confidence interval (CI) 1.1-13.6, P = 0.02] overall; educational DVDs by 9.7% overall (95% CI 1.8-17.6, P = 0.02), 11.9% in non-doctor, non-nurse HCWs (95% CI 0.9-22.8, P = 0.03). For doctors, using a champion doctor increased uptake by 17.8% (95% CI 7.6-28.0, P < 0.01). No intervention increased uptake by nurses. Increasing uptake requires multi-intervention strategies targeted at different HCW groups. PMID- 23672974 TI - Spinal manipulation under anesthesia: a narrative review of the literature and commentary. AB - As exhibited throughout the medical literature over many decades, there is a lack of uniformity in the manner in which spine pain patients have historically qualified for and received manipulation under anesthesia (MUA). Also, for different professions that treat the same types of spinal conditions via the same means, fundamental MUA decision points vary within the published protocols of different professional associations. The more recent chiropractic literature communicates that the evidence to support the efficacy of MUA of the spine remains largely anecdotal. In addition, it has been reported that the types of spinal conditions most suitable for MUA are without clear-cut consensus, with various indications for MUA of the low back resting wholly upon the opinions and experiences of MUA practitioners. This article will provide a narrative review of the MUA literature, followed by a commentary about the current lack of high quality research evidence, the anecdotal and consensus basis of existing clinical protocols, as well as related professional, ethical and legal concerns for the chiropractic practitioner. The limitations of the current medical literature related to MUA via conscious/deep sedation need to be recognized and used as a guide to clinical experience when giving consideration to this procedure. More research, in the form of controlled clinical trials, must be undertaken if this procedure is to remain a potential treatment option for chronic spine pain patients in the chiropractic clinical practice. PMID- 23672976 TI - Application of selected reaction monitoring for multiplex quantification of clinically validated biomarkers in formalin-fixed, paraffin-embedded tumor tissue. AB - One of the critical gaps in the clinical diagnostic space is the lack of quantitative proteomic methods for use on formalin-fixed, paraffin-embedded (FFPE) tissue. Herein, we describe the development of a quantitative, multiplexed, mass spectrometry-based selected reaction monitoring (SRM) assay for four therapeutically important targets: epidermal growth factor receptor, human EGF receptor (HER)-2, HER3, and insulin-like growth factor-1 receptor. These assays were developed using the Liquid Tissue-SRM technology platform, in which FFPE tumor tissues were microdissected, completely solubilized, and then subjected to multiplexed quantitation by SRM mass spectrometry. The assays were preclinically validated by comparing Liquid Tissue-SRM quantitation of FFPE cell lines with enzyme-linked immunosorbent assay/electrochemiluminescence quantitation of fresh cells (R(2) > 0.95). Clinical performance was assessed on two cohorts of breast cancer tissue: one cohort of 10 samples with a wide range of HER2 expression and a second cohort of 19 HER2 IHC 3+ tissues. These clinical data demonstrate the feasibility of quantitative, multiplexed clinical analysis of proteomic markers in FFPE tissue. Our findings represent a significant advancement in cancer tissue analysis because multiplexed, quantitative analysis of protein targets in FFPE tumor tissue can be tailored to specific oncological indications to provide the following: i) complementary support for anatomical pathological diagnoses, ii) patient stratification to optimize treatment outcomes and identify drug resistance, and iii) support for the clinical development of novel therapies. PMID- 23672977 TI - Single priming dose of meningococcal group C conjugate vaccine (NeisVac-C(r)) in infants. AB - Since the introduction of the meningococcal C conjugate (MCC) vaccine in the pediatric population in 1999, numerous clinical studies have confirmed the immunogenicity and safety of the NeisVac-C((r)) vaccine, and several have observed a strong immune response after a single priming dose, which could be successfully boosted. Maximizing protection of infants with as few vaccine doses as possible would increase the general acceptability of the immunization strategies and support broader coverage without increasing vaccination costs. This was a randomized feasibility study of a single priming NeisVac-C((r)) vaccine dose administered at 4 or 6 months of age, compared to the currently licensed two dose priming at 2 and 4 months of age, followed by a booster vaccination at 12-13 months of age. High seroprotection rates and serum bactericidal antibody (rSBA) titers were observed in all study groups, whether a single or two dose priming vaccination was administered, at all time points investigated: one month after the priming vaccination(s) (>99% of subjects rSBA>=8), prior to booster vaccination (>65% of subjects with rSBA>=8, with the lowest titers and GMTs seen in the two dose priming group), as well as after booster vaccination administration (99% with rSBA>=128 in all three study groups, with the highest GMT of 2472 seen in the 4 month single dose group). This study confirmed trends seen in previous reports that a single-dose priming vaccination at 4 or 6 months of age can be considered a valuable alternative to the currently licensed two-dose priming vaccination schedule. PMID- 23672978 TI - Development of a simultaneous multiple solid-phase microextraction-single shot gas chromatography/mass spectrometry method and application to aroma profile analysis of commercial coffee. AB - A simultaneous multiple solid-phase microextraction-single shot-gas chromatography mass spectrometry (smSPME-ss-GC/MS) method has been developed for headspace analysis. Up to four fibers (50/30 MUm DVB/CAR/PDMS) were used simultaneously for the extraction of aroma components from the headspace of a single sample chamber in order to increase sensitivity of aroma extraction. To avoid peak broadening and to maximize resolution, a simple cryofocusing technique was adopted during sequential thermal desorption of multiple SPME fibers prior to a 'single shot' chromatographic run. The method was developed and validated on a model flavor mixture, containing 81 known pure components. With the conditions of 10 min of incubation and 30 min of extraction at 50 degrees C, single, dual, triple and quadruple SPME extractions were compared. The increase in total peak area with increase in the number of fibers showed good linearity (R(2)=0.9917) and the mean precision was 12.0% (RSD) for the total peak sum, with quadruple simultaneous SPME extraction. Using a real sample such as commercial coffee granules, aroma profile analysis was conducted using single, dual, triple and quadruple SPME fibers. The increase in total peak intensity again showed good linearity with increase in the number of SPME fibers used (R(2)=0.9992) and the precision of quadruple SPME extraction was 9.9% (RSD) for the total peak sum. PMID- 23672979 TI - New sample preparation approach for mass spectrometry-based profiling of plasma results in improved coverage of metabolome. AB - Sample preparation remains a challenge in untargeted metabolomics studies and no method currently results in complete extraction of all metabolite classes in human plasma. Because a large variety of molecules, with vast differences in dynamic range, could be involved in human disease, there is an urgent need to develop analytical techniques that result in comprehensive coverage of metabolites. Furthermore, analysis of more focused molecular classes could be necessary to more fully interrogate markers of human disease. However, such techniques, which generally involve multiple steps, often result in high variability. We have optimized a combined liquid-liquid and solid phase extraction method for plasma and have compared that to traditional methanol precipitation using spiked internal standards as controls. This method, based largely on previously published methods, results in 5 separate fractions enriched for aqueous species, phospholipids, fatty acids, neutral lipids, and hydrophobic lipids. Using liquid chromatography mass spectrometry as the analytical method, we detect over 3806 metabolites using the new method versus 1851 metabolites using methanol alone. Qualitative analysis and quantitative analysis of both internal standards (ISTDs) and endogenous metabolites demonstrate excellent reproducibility with CV's below 15% for the combined method compared to 30% using the methanol method. While both methods have applications for clinical metabolomics, fractionation resulted in greater overall coverage and can be used for initial classification of molecular species. PMID- 23672980 TI - Limit of the speed-resolution properties in adiabatic supercritical fluid chromatography. AB - Kinetic Poppe plots for small retained compounds were calculated in HPLC (using pure acetonitrile) and SFC (using pure carbon dioxide) for columns having twenty one different lengths (between 3 cm and 30 m), operated under strict adiabatic conditions (no heat exchange was allowed between the column and the external environment), with a constant pressure drop of 200 bar. The outlet pressures were set at 1 and 160 bar in HPLC and SFC, respectively. The eluent inlet temperature was set at 312 K. The hold-up time t0 and the apparent column efficiency were calculated by taking into account the longitudinal variations of the eluent pressure, its temperature, density, viscosity, heat capacity, thermal expansion coefficient, equilibrium constant, and diffusion coefficient along the column length. Three different classes of stationary phase were considered: fully porous particles and core-shell particles of different diameter and structure, and silica monolithic columns of the second generation. The reduced plate heights of these stationary phases were taken from experimental data obtained with liquid eluents (acetonitrile/water mixtures). The columns were assumed to be radially homogeneous. The Henry's constant of the compound was fixed at Ka=2.0 at the column inlet. The results demonstrate the potential advantage of using sub-3 MUm core-shell particles for fast analysis in both LC and SFC, regardless of the intra-particle diffusivity through the stationary phase. In RPLC conditions, the contribution of surface diffusion to intra-particle diffusivity is important and the 4.6 MUm core-shell particles can perform as well as sub-2 MUm fully porous particles and silica monolithic columns of the second generation. In the absence of surface diffusion or for localized adsorption onto the stationary phase, sub-2 MUm particles and silica monolithic column of the second generation outperform the 4.6 MUm core-shell particles because the solid-liquid mass transfer resistance controls the column efficiency at high speeds. Eventually, for the same stationary phase and speed of analysis, SFC methods using pure CO2 may provide at least a twice column efficiency than LC methods using pure acetonitrile. For a constant pressure drop and resolution power, SFC methods may generate four times faster analyses than LC methods. Ultimately, a standard commercial 4.6mm * 50mm long column packed with 2.6 MUm core-shell particles, operated with an inlet flow rate of 25 mL/min in fast SFC (200 bar back pressure, 40 degrees C) may provide a hold-up time of about 1s requiring data acquisition at a frequency of 400 Hz, with a variance of 0.35 MUL(2). This performance will require the use of new, ultra-low dispersion SFC system. PMID- 23672981 TI - Reservoirs of Acinetobacter baumannii outside the hospital and potential involvement in emerging human community-acquired infections. AB - The objective of the present report was to review briefly the potentially community-acquired Acinetobacter baumannii infections, to update information on the reservoirs of A. baumannii outside the hospital, and to consider their potential interactions with human infections. Most reports on potentially community-acquired A. baumannii have been published during the last 15 years. They concern community-acquired pneumonia, infections in survivors from natural disasters, and infected war wounds in troops from Iraq and Afghanistan. Although the existence of extra-hospital reservoirs of A. baumannii has long been disputed, the recent implementation of molecular methods has allowed the demonstration of the actual presence of this organism in various environmental locations, in human carriage, in pets, slaughter animals, and human lice. Although the origin of the A. baumannii infections in soldiers injured in Southwestern Asia is difficult to determine, there are some arguments to support the involvement of extra-hospital reservoirs in the occurrence of community acquired infections. Overall, the emergence of community-acquired A. baumannii infections could be associated with interactions between animals, environment, and humans that are considered to be potentially involved in the emergence or re emergence of some infectious diseases. PMID- 23672982 TI - Evolved navigation theory and the plateau illusion. AB - Most people anecdotally feel that the distance extending toward a cliff or slope appears shorter than the same distance extending away from it. This odd impression persists, despite the distance being equal across both conditions and humans encountering such a scenario daily in the navigation of stairs, slopes, curbs, and vertical surfaces protected by handrails. We tested three sets of competing predictions about this previously uninvestigated phenomenon. Data from two experiments coincided with the well-established predictions from evolved navigation theory. Contrary to anecdotal expectations, observers perceive the distance extending toward the edge of a steep slope to be longer than the distance extending away from it. We title this the plateau illusion and suggest that it may be an embodied process that arose over evolutionary time in response to navigation risks. PMID- 23672984 TI - Expanding our knowledge of conditions associated with the ASXL gene family. AB - Genome-wide sequencing has identified de novo truncating mutations in ASXL3 in four patients with intellectual disability, feeding problems and distinctive facial features. Their presentation resembles that of Bohring-Opitz syndrome, which is associated with de novo nonsense mutations in ASXL1. This newly defined phenotype provides an important clinical resource for comparison with future cases in which mutations are found in ASXL3. The phenotypes for patients with mutations in each gene will undoubtedly be further delineated as more patients are reported. PMID- 23672983 TI - The power of human gaze on infant learning. AB - Social learning enables infants to acquire information, especially through communication. However, it is unknown whether humans are the prime source of information for infant learning. Here we report that humans have a powerful influence on infants' object learning compared with nonhuman agents (robots). Twelve-month-old infants were shown videos in which a human or a robot gazed at an object. The results demonstrated that the infants followed the gaze direction of both agents, but only human gaze facilitated their object learning: Infants showed enhanced processing of, and preferences for, the target object gazed at by the human but not by the robot. Importantly, an extended fixation on a target object without the orientation of human gaze did not produce these effects. Together, these findings show the importance of humanness in the gazer, suggesting that infants may be predisposed to treat humans as privileged sources of information for learning. PMID- 23672985 TI - Eosinophilic endocarditis and Strongyloides stercoralis. AB - A 40-year-old woman from El Salvador presented with 3 months of abdominal pain and diarrhea followed by 2 weeks of atypical chest pain and exertional dyspnea and was diagnosed with eosinophilic endocarditis secondary to Strongyloides stercoralis infection. Transthoracic echocardiogram revealed apical masses in the left and right ventricles and a thickened posterior mitral valve leaflet and cardiac magnetic resonance imaging confirmed the presence of a left ventricular apical mass with diffuse subendocardial delayed enhancement consistent with endocardial fibrosis. In conclusion, eosinophilic endocarditis is a rare cause of restrictive cardiomyopathy characterized by endomyocardial fibrosis and apical thrombosis and fibrosis with frequent involvement of the posterior mitral valve leaflet. PMID- 23672986 TI - Migration of an AMPLATZER atrial septal occluder to the abdominal aorta. AB - Percutaneous closure of an atrial septal defect has been increasingly used, and complications have been rare. We report the case of a 63-year-old man who had undergone endovascular closure of a secundum atrial septal defect months earlier. The occluder was later found in the abdominal aorta. PMID- 23672987 TI - Procedural outcomes of revascularization of chronic total occlusion of native coronary arteries (from a multicenter United States registry). AB - Percutaneous coronary intervention (PCI) of chronic total occlusions (CTOs) is a rapidly evolving area of interventional cardiology. We sought to examine the immediate procedural and in-hospital clinical outcomes of native coronary artery CTO PCI from a multicenter United States (US) registry. We retrospectively examined the procedural outcomes of 1,361 consecutive native coronary artery CTO PCIs performed at 3 US institutions from January 2006 to November 2011. Mean age was 65 +/- 11 years, 85% of patients were men, 40% had diabetes, 37% had previous coronary artery bypass graft surgery, and 42% had previous PCI. The CTO target vessel was the right coronary artery (55%), circumflex (23%), left anterior descending artery (21%), and left main or bypass graft (1%). The retrograde approach was used in 34% of all procedures. The technical and procedural success rates were 85.5% and 84.2%, respectively. The mean procedural time, fluoroscopy time, and contrast utilization were 113 +/- 61 minutes, 42 +/- 29 minutes, and 294 +/- 158 ml, respectively. In multivariate analysis, female gender, no previous coronary artery bypass surgery, and years since initiation of CTO PCI at each center were independent predictors of procedural success. Major complications occurred in 24 patients (1.8%). In conclusion, among selected US based institutions with experienced operators, native coronary artery CTO PCI can be performed with high success and low major complication rates. PMID- 23672988 TI - Diagnostic utility of a novel leadless arrhythmia monitoring device. AB - Although extending the duration of ambulatory electrocardiographic monitoring beyond 24 to 48 hours can improve the detection of arrhythmias, lead-based (Holter) monitors might be limited by patient compliance and other factors. We, therefore, evaluated compliance, analyzable signal time, interval to arrhythmia detection, and diagnostic yield of the Zio Patch, a novel leadless, electrocardiographic monitoring device in 26,751 consecutive patients. The mean wear time was 7.6 +/- 3.6 days, and the median analyzable time was 99% of the total wear time. Among the patients with detected arrhythmias (60.3% of all patients), 29.9% had their first arrhythmia and 51.1% had their first symptom triggered arrhythmia occur after the initial 48-hour period. Compared with the first 48 hours of monitoring, the overall diagnostic yield was greater when data from the entire Zio Patch wear duration were included for any arrhythmia (62.2% vs 43.9%, p <0.0001) and for any symptomatic arrhythmia (9.7% vs 4.4%, p <0.0001). For paroxysmal atrial fibrillation (AF), the mean interval to the first detection of AF was inversely proportional to the total AF burden, with an increasing proportion occurring after 48 hours (11.2%, 10.5%, 20.8%, and 38.0% for an AF burden of 51% to 75%, 26% to 50%, 1% to 25%, and <1%, respectively). In conclusion, extended monitoring with the Zio Patch for <=14 days is feasible, with high patient compliance, a high analyzable signal time, and an incremental diagnostic yield beyond 48 hours for all arrhythmia types. These findings could have significant implications for device selection, monitoring duration, and care pathways for arrhythmia evaluation and AF surveillance. PMID- 23672989 TI - Role of preablation neutrophil/lymphocyte ratio on outcomes of cryoballoon-based atrial fibrillation ablation. AB - The neutrophil/lymphocyte ratio (NLR) has recently emerged as better indicator of inflammation and oxidative stress and has been widely studied in several cardiovascular diseases. In the present study, we evaluated the role of the preablation NLR in atrial fibrillation (AF) recurrence after cryoballoon-based catheter ablation. A total of 251 patients (47.8% women, age 54.12 +/- 10.9 years, 80.1% with paroxysmal AF) with symptomatic AF underwent cryoablation. At a mean follow-up of 19.0 +/- 6.6 months, 60 patients (23.9%) had developed AF recurrence. The patients who developed AF recurrence had had a greater preablation NLR (3.53 +/- 0.95 vs 2.65 +/- 0.23, p <0.001) and a higher white blood cell count, neutrophil count, and high-sensitivity C-reaction protein levels. On multivariate regression analysis, the preablation NLR (hazard ratio 2.15, 95% confidence interval 1.70 to 2.73, p <0.001), left atrial diameter (hazard ratio 1.09, 95% confidence interval 1.04 to 1.14, p <0.001) and early AF recurrence (hazard ratio 2.99, 95% confidence interval 1.71 to 5.23, p <0.001) were independent predictors of AF recurrence after cryoablation. Using a cutoff level of 3.15, the preablation NLR predicted AF recurrence during follow-up with a sensitivity of 84% and specificity of 75%. Patients with a preablation NLR >3.15 had a 2.5-fold increased risk of developing AF recurrence after cryoablation. In conclusion, an elevated preablation NLR was associated with increased AF recurrence after cryoballoon-based catheter ablation. Our results support the role of a preablation inflammatory environment in the development of AF recurrence after ablation therapy but suggest that other factors are also important. PMID- 23672990 TI - Relation of elevated serum uric acid levels to incidence of atrial fibrillation in patients with type 2 diabetes mellitus. AB - The association between serum uric acid (SUA) levels and atrial fibrillation (AF) is currently poorly known. We examined the association between SUA levels and risk of incident AF in patients with type 2 diabetes mellitus. We followed for 10 years a random sample of 400 type 2 diabetic outpatients, who were free from AF at baseline. A standard 12-lead electrocardiography was undertaken annually and a diagnosis of incident AF was confirmed in affected participants by a single cardiologist. Over 10 years, there were 42 incident AF cases (cumulative incidence of 10.5%). Elevated SUA level was associated with an increased risk of incident AF (odds ratio 2.43, 95% confidence interval 1.8 to 3.4, p <0.0001 for each 1-SD increase in SUA level). Adjustments for age, gender, body mass index, hypertension, chronic kidney disease, electrocardiographic features (left ventricular hypertrophy and PR interval), and use of diuretics and allopurinol did not attenuate the association between SUA and incident AF (adjusted odds ratio 2.44, 95% confidence interval 1.6 to 3.9, p <0.0001). Further adjustment for variables that were included in the 10-year Framingham Heart Study-derived AF risk score did not appreciably weaken this association. Results remained unchanged even when SUA was modeled as a categorical variable (stratifying by either SUA median or hyperuricemia), and when patients with previous coronary heart disease or heart failure were excluded from analysis. In conclusion, our findings suggest that elevated SUA levels are strongly associated with an increased incidence of AF in patients with type 2 diabetes mellitus even after adjustment for multiple clinical risk factors for AF. PMID- 23672991 TI - Thrombocytopenia in patients with atrial fibrillation on oral anticoagulation undergoing percutaneous coronary intervention. AB - Thrombocytopenia is often regarded as a risk factor for bleeding complications in patients undergoing percutaneous coronary intervention (PCI). The risk of mild to moderate baseline and acquired thrombocytopenia on bleeding and thrombotic or thromboembolic complications in patients with atrial fibrillation on oral anticoagulation therapy undergoing PCI, however, remains largely unknown. Management of Patients With Atrial Fibrillation undergoing Coronary Artery Stenting is a multicenter European prospective registry enrolling patients with atrial fibrillation undergoing PCI. We assessed the rate of bleeding complications as defined by Bleeding Academic Research Consortium and a composite of major adverse cardiac and cerebrovascular events (MACCE) including all-cause mortality, myocardial infarction, transient ischemic attack or stroke, stent thrombosis, systemic arterial embolism, or revascularization; and a composite of any harmful event (Bleeding Academic Research Consortium and MACCE) at 12-month follow-up in 861 consecutive patients undergoing PCI. Patients were divided into those with mild to moderate baseline thrombocytopenia (platelet count <150 * 109/L; n = 99) and control group (platelet count >150 * 109/L; n = 762). At hospital discharge, thrombocytopenia had no effect on prescribed antithrombotic treatment, and triple therapy (vitamin K antagonist + aspirin + clopidogrel) was the most common combination in both patient groups (69% vs 73%, p = 0.40). No differences in all-cause mortality (12% vs 11%, p = 0.79), MACCE (23% vs 22%, p = 0.87), or bleeding complications (23% vs 19%, p = 0.26) were detected. Acquired in-hospital thrombocytopenia occurred in 9.7% of patients, and it was associated with similar risk of adverse outcomes compared with control group. In conclusion, mild to moderate baseline thrombocytopenia does not seem to have a clinically significant effect on bleeding or thrombotic or thromboembolic complications after PCI in these frail patients receiving multiple antithrombotic drugs. PMID- 23672992 TI - Application of the Multicenter Automatic Defibrillator Implantation Trial II risk score in a nontrial setting. AB - A post hoc analysis of the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II showed that patients with high mortality risk score did not benefit from implantable cardioverter-defibrillator (ICD) therapy. We sought to determine whether MADIT II risk score can identify patients with greater mortality in a nontrial "real-world" setting. We included 382 consecutive patients who received ICD for primary prevention of sudden cardiac death at the Minneapolis Veterans Affairs Medical Center from 2006 to 2010. MADIT II score was calculated by assigning 1 point each for age >70 years, New York Heart Association class >II, atrial fibrillation, QRS >0.12 seconds, and blood urea nitrogen level >26 mg/dl. Scores 0, 1 to 2, and >=3 were classified as low, intermediate, and high risk, respectively. Of the 382 patients, 14% were low risk, 54% intermediate risk, and 32% high risk. After 3.0 +/- 1.6 years of follow-up, incidence of appropriate ICD shocks was similar (p = 0.21) across MADIT II risk score categories. However, mortality rate was 21, 54, and 134 per 1,000 patient-year follow-up in low, intermediate, and high-risk patients, respectively, p <0.0001. Compared with low risk patients, mortality was 6.4* greater in high-risk patients (hazard ratio 6.36, 95% confidence interval 1.9 to 20.5; p = 0.002). The c-index for the MADIT II score for predicting death was 0.69 (95% confidence interval 0.63 to 0.75). In conclusion, MADIT II risk score successfully identified patients with greater mortality in a nontrial-based, primary-prevention ICD cohort. PMID- 23672993 TI - Long-term follow-up after two years of asthma treatment guided by airway responsiveness in children. AB - INTRODUCTION: Children with persistent asthma may have diminished lung function in early adulthood. In our previous study ('CATO') we showed preservation of lung function in asthmatic children, during 2 years of treatment that was guided by airway hyperresponsiveness (AHR). The aim of the present prospective follow up study was to investigate whether the positive effect of the AHR strategy on lung function had persisted beyond the duration of the intervention study, after several years of usual care by paediatrician and general practitioner. METHODS: With a mean interval of 4.4 y after the last visit, 137 subjects (67% of the original CATO population) participated in this follow-up study. Evaluation consisted of spirometry (n = 137), a methacholine challenge test (n = 83), data on inhaled steroid treatment and asthma exacerbations (n = 137), and an asthma symptom diary during 6 weeks (n = 90). RESULTS: At follow-up, lung function, % symptom-free days and exacerbation rates of both treatment strategy groups was similar. The mean dose of inhaled corticosteroids had diminished from 550 MUg/day at the end of CATO to 235 MUg/day at follow-up. The decrease in AHR measured at the end of CATO was maintained at follow-up for both treatment strategy groups. CONCLUSION: The beneficial effect on lung function of 2 years treatment guided by AHR was lost after 3-7 years of usual care. This suggests that an AHR-guided treatment strategy may need to be sustained in order to preserve lung function. PMID- 23672994 TI - Diagnostic properties of C-reactive protein for detecting pneumonia in children. AB - BACKGROUND: The diagnostic value of C-reactive protein (CRP) level for pneumonia in children is unknown. As a first step in the assessment of the value of CRP, a diagnostic study was performed in children at an emergency department (ED). METHODS: In this cross-sectional study, data were retrospectively collected from children presenting with suspected pneumonia at the ED of Antonius Hospital Nieuwegein in The Netherlands between January 2007 and January 2012. Diagnostic outcome was pneumonia yes/no according to independent radiologist. (Un)adjusted association between CRP level and pneumonia and diagnostic value of CRP were calculated. RESULTS: Of 687 presenting children, 286 underwent both CRP measurement and chest radiography. 148 had pneumonia (52%). The proportion of pneumonia increased with CRP level. Negative predictive values declined, but positive predictive values increased with higher CRP thresholds. Univariable odds ratio for the association between CRP level and pneumonia was 1.2 (95% CI 1.11 1.21) per 10 mg/L increase. After adjustment for baseline characteristics CRP level remained associated with pneumonia. CONCLUSIONS: CRP level has independent diagnostic value for pneumonia in children presenting at the ED with suspected pneumonia, but low levels do not exclude pneumonia in this setting. These results prompt evaluation of CRP in primary care children with LRTI. PMID- 23672995 TI - Phenotyping adults with non-cystic fibrosis bronchiectasis: a prospective observational cohort study. AB - BACKGROUND: Bronchiectasis is the outcome of a number of different airway insults. Very few studies have characterised the aetiology and utility of a dedicated screening proforma in adult patients attending a general bronchiectasis clinic. METHODS: A prospective observational study of 189 bronchiectasis patients attending two centres in the North East of England over a two-year period was performed. RESULTS: The aetiology of bronchiectasis was identified in 107/189(57%) patients. Idiopathic bronchiectasis (IB) represented the largest subgroup (43%). Post-infection bronchiectasis (PIB) constituted the largest proportion (24%) of known causes. Mean age (SD) at diagnosis was 54(20) years with a mean age at symptom onset of 37(24) years, accounting for a diagnostic delay of 17 years. Age of symptom onset was significantly younger in patients with PIB compared to IB (p < 0.0001) and in Pseudomonas sputum positive patients (p = 0.007). Screening for APBA and total immunoglobulin deficiency identified 9 (5%) patients who then had tailored treatment. Routine screening for other aetiologies was deemed unnecessary. CONCLUSION: IB and PIB accounted for two thirds of cases of bronchiectasis in a general population. We recommend routine screening for ABPA and total immunoglobulin deficiency but not for other rarer aetiologies. PMID- 23672996 TI - Human and mouse brain-derived endothelial cells require high levels of growth factors medium for their isolation, in vitro maintenance and survival. AB - BACKGROUND: Brain microvascular endothelial cells (BMVECs) constitute the primary limitation for passage of ions and molecules from the blood into the brain through the blood brain barrier. Numerous multi-step procedures for isolating and culturing BMVECs have been described. However, each one demonstrates major limitations in purity of culture and/or low proliferation rate. Our goal was to study the efficiency of our pending patent medium, Endothelial Proliferation Medium (EndoPM), on the isolation and purification of human and murine BMVECs. METHODS: BMVECs, cultured in EndoPM were compared to those cultured in a commercial medium EBM. Cultures were characterized by flow cytometric analysis, lineage differentiation, the ability to form tube-like structure, immunofluorescence, molecular analyses and also in an in vivo model assay. Moreover permeability was assayed by monitoring the passage of Dextran-FITC through a tight monolayer of BMVECs grown to confluence in Boyden chambers. One way Anova two-tailed test was utilized for all statistical analyses. RESULTS: The properties of ECs in human and murine BMVECs is confirmed by the expression of endothelial markers (CD31, CD105, CD146, Tie-2 and vWF), of representative proangiogenic genes (ICAM1, VCAM1 and integrin ITGAV), of considerable tube forming ability, with low-density lipoprotein uptake, eNOS and GLUT-1 expression. Furthermore cells are able to express markers of the junctional architecture as VE-cadherin, beta-catenin and Claudin-5 and greatly reduce dextran permeability as barrier functional test. Moreover BMVECs spontaneously organize in vascular like structures and maintain the expression of endothelial markers in an in vivo xenograft model assay. The significant effect of EndoPM is confirmed by the study of proliferation index, survival index and the behaviour of BMVECs and fibroblasts in co-culture conditions. CONCLUSION: Herein we describe a simple and reproducible method for the isolation and expansion of human and mouse BMVECs, based on a newly formulated medium (EndoPM) with optimized concentration of growth factors (EGF, FGF-2 and Bovine Brain Extract-BBE). This procedure should facilitate the isolation and expansion of human and mouse BMVECs with extended lifetime, good viability and purity. This approach may provide an effective strategy to aid phenotypical and functional studies of brain vessels under physiological and pathological conditions. PMID- 23672997 TI - Do residents need end-of-life care training? AB - OBJECTIVE: As medical education evolves, emphasis on chronic care management within the medical curriculum becomes essential. Because of the consistent lack of appropriate end-of-life care training, far too many patients die without the benefits of hospice care. This study explores the association between physician knowledge, training status, and level of comfort with hospice care referral of terminally ill patients. METHOD: In 2011, anonymous surveys were distributed to physicians in postgraduate years 1, 2, and 3; fellows; hospital attending physicians; specialists; and other healthcare professionals in five hospitals of a large health system in New York. Demographic comparisons were performed using chi2 and Fisher's exact tests. Spearman correlations were calculated to determine if professional status and experience were associated with comfort and knowledge discussing end-of-life topics with terminal patients. RESULTS: The sample consisted of 280 participants (46.7% response rate). Almost a quarter (22%) did not know key hospice referral criteria. Although 88% of respondents felt that knowledge of hospice care is an important competence, 53.2% still relinquished advance directives discussion to emergency room (ER) physicians. Fear of patient/family anger was the most frequently reported hospice referral barrier, although 96% of physicians rarely experienced reprisals. Physician comfort level discussing end-of-life issues and hospice referral was significantly associated with the number of years practicing medicine and professional status. SIGNIFICANCE OF RESULTS: Physicians continue to relinquish end-of-life care to ER staff and palliative care consultants. Exploring unfounded and preconceived fears associated with hospice referral needs to be integrated into the curriculum, to prepare future generations of physicians. Medical education should focus on delivering the right amount of end-of-life care training, at the right time, within the medical school and residency curriculum. PMID- 23672999 TI - Apolipoprotein E in VLDL and LDL with apolipoprotein C-III is associated with a lower risk of coronary heart disease. AB - BACKGROUND: Low-density lipoprotein (LDL) with apolipoprotein C-III (apoC-III) is the lipoprotein species that most strongly predicts initial and recurring coronary heart disease (CHD) events in several cohorts. Thus, a large portion of the CHD risk conferred by LDL may be attributable to LDL that contains apoC-III. Very-low-density lipoprotein (VLDL) and LDL with apoC-III have varying amounts of apoE. We hypothesized that a high content of apoE lessens the adverse influence of apoC-III on the risk of CHD because it promotes the clearance of VLDL and LDL from plasma. METHODS AND RESULTS: We studied 2 independent cohorts, the Nurses' Health Study, composed of women, and the Health Professionals Follow-up Study, composed of men. These cohorts contributed to this study 322 women and 418 men initially free of CVD who developed a fatal or nonfatal myocardial infarction during 10 to 14 years of follow-up and matched controls who remained free of CHD. The apoE content of LDL with apoC-III was inversely associated with CHD after multivariable adjustment (relative risk for top versus bottom quintile 0.53, 95% CI 0.35 to 0.80). The apoE content of VLDL with apoC-III had a similar inverse association with CHD. The highest risks were associated with a high apoB concentration and a low apoE content of LDL with apoC-III or of VLDL+LDL with apoC-III. The observed associations were in both male and female cohorts and independent of traditional CHD risk factors and of C-reactive protein. CONCLUSIONS: An increased apoE content in VLDL and LDL with apoC-III was associated with a lower risk of CHD. Strategies to enrich VLDL and LDL in apoE are worth exploring for the prevention of CHD. PMID- 23673000 TI - Interleukin-6 mediates the platelet abnormalities and thrombogenesis associated with experimental colitis. AB - Clinical studies and animal experimentation have shown that colonic inflammation is associated with an increased number and reactivity of platelets, coagulation abnormalities, and enhanced thrombus formation. The objective of this study was to define the contribution of IL-6 to the thrombocytosis, exaggerated agonist induced platelet aggregation, and enhanced extra-intestinal thrombosis that occur during experimental colitis. The number of mature and immature platelets, platelet life span, thrombin-induced platelet aggregation response, and light/dye induced thrombus formation in cremaster muscle arterioles were measured in wild type (WT) and IL-6-deficient (IL-6(-/-)) mice with dextran sodium sulfate (DSS) induced colitis. DSS colitis in WT mice was associated with thrombocytosis with an elevated number of both mature and immature platelets and no change in platelet life span. The thrombocytosis response was absent in IL-6(-/-) mice. DSS treatment also enhanced the platelet aggregation response to thrombin and accelerated thrombus development in WT mice, but not in IL-6(-/-) mice. Exogenous IL-6 administered to WT mice elicited a dose-dependent enhancement of thrombus formation. These findings indicate that IL-6 mediates the thrombocytosis, platelet hyperreactivity, and accelerated thrombus development associated with experimental colitis. The IL-6-dependent colitis-induced thrombocytosis appears to result from an enhancement of thrombopoiesis because platelet life span is unchanged. PMID- 23673002 TI - Assessing biomarkers for brain diseases: progress and gaps. AB - A report on the 2nd Wellcome Trust Scientific Conference on Biomarkers for Brain Disorders: Challenges and Opportunities, held at the Moller Centre, Cambridge, UK, February 3-5, 2013. PMID- 23673001 TI - Primary epiphyseal arteriopathy in a mouse model of steroid-induced osteonecrosis. AB - Patients undergoing glucocorticoid therapy for a variety of disorders, including autoimmune diseases and hematological malignancies, are at risk of developing osteonecrosis. Despite extensive research in both patients and animal models, the underlying pathogenesis remains unclear. Proposed inciting mechanisms include intravascular thrombotic occlusion, marrow fat hypertrophy, osteocyte and/or endothelial cell apoptosis, hypercoagulability, and vasoconstriction of specific arteries and arterioles supplying bone. Our laboratory has developed a model of steroid-induced osteonecrosis in BALBcJ mice which reflects clinically relevant exposures to glucocorticoids in which treated mice develop osteonecrosis of the distal femoral epiphysis when administered 4 to 8 mg/L dexamethasone in drinking water for 6 weeks. We identified lesions in arterioles supplying this area, with the mildest occurring in knees without any evidence of osteonecrosis. However, arteriopathy was more common among mice that did versus did not develop osteonecrosis (P < 0.0001); in mice with osteonecrosis, the associated vessels showed transmural necrosis and thickening of the vessel wall progressing to the point of luminal obstruction. In the most severe cases of osteonecrosis, end stage lesions consisted of fully occluded vessels with marrow and bone necrosis involving the entire epiphysis. We propose that a primary arteriopathy is the initiating event in the genesis of steroid-induced osteonecrosis and provides a basis for future investigation of this disease process. PMID- 23673003 TI - Therapeutic implications of mesenchymal stem cells in acute lung injury/acute respiratory distress syndrome. AB - Acute lung injury (ALI), and its more severe form, acute respiratory distress syndrome (ARDS), are syndromes of acute hypoxemic respiratory failure resulting from a variety of direct and indirect injuries to the gas exchange parenchyma of the lungs. Current treatment of ALI/ARDS is primarily supportive, with lung protective ventilation and fluid conserving strategies. Despite improvement in these strategies, recent data indicate that the mortality of ALI/ARDS is still as high as 30 to 50%. Thus, there is a need for innovative therapies to further improve clinical outcomes of ALI/ARDS. Recent studies involving the administration of mesenchymal stem cells (MSCs) for the treatment of experimental ALI/ARDS have shown promising results. This review focuses on existing studies that have tested the use of MSCs in models of ALI/ARDS, and the potential mechanisms underlying their therapeutic effects. PMID- 23673004 TI - An outbreak of cryptosporidiosis at a swimming club--can rapid field epidemiology limit the spread of illness? AB - In September 2010, an outbreak of cryptosporidiosis affected members of a swimming club. A cohort study was undertaken to identify the number affected and risk factors for infection. Of 101 respondents, 48 met the case definition for probable cryptosporidiosis. Multivariate analysis demonstrated a strong and highly significant association between illness and attendance at a training session on 13 September 2010 (adjusted odds ratio 28, P < 0.0001). No faecal incidents were reported and pool monitoring parameters were satisfactory. The competitive nature of club swimming requires frequent training and participation in galas, potentially facilitating contamination into other pools and amplification of outbreaks among wider groups of swimmers. There was a lack of awareness of the 2-week exclusion rule among swimmers and coaches, and a high level of underreporting of illness. The study demonstrates the benefits of rapid field epidemiology in identifying the true burden of illness, the source of infection and limiting spread. PMID- 23673006 TI - Systematic analysis of palladium-graphene nanocomposites and their catalytic applications in Sonogashira reaction. AB - Graphene has been modified with palladium nanoparticles (Pd NPs) to develop high performance catalysts for the Sonogashira cross coupling reaction. In this research, graphite oxide (GO) sheets exfoliated from graphite were impregnated with Pd(OAc)2 to prepare Pd(2+)/GO. Thermal treatments of the Pd(2+)/GO in H2 flow at 100 degrees C produced Pd/graphene (Pd/G) nanocomposites. TEM images show that Pd NPs were distributed quite uniformly on the graphene sheet without obvious aggregation, and the mean size of Pd NPs was determined to be less than 2 nm in diameter. Morphological and chemical structures of the GO, Pd(2+)/GO, and Pd/G were investigated using FT-IR, XRD, XPS, and XAFS. The resulting Pd/G showed excellent catalytic efficiency in the Sonogashira reaction and offers significant advantages over inorganic supported catalysts such as simple recovery and recycling. Finally, deactivation process of the Pd/G in recycling was investigated. We believe that the remarkable reactivity of the Pd/G catalyst toward the Sonogashira reaction is attributed to the high degree of the Pd NP dispersion and thus the increased low coordination numbers of smaller Pd NPs. PMID- 23673005 TI - Classification of ester oils according to their Equivalent Alkane Carbon Number (EACN) and asymmetry of fish diagrams of C10E4/ester oil/water systems. AB - The phase behavior of well-defined C10E4/ester oil/water systems versus temperature was investigated. Fifteen ester oils were studied and their Equivalent Alkane Carbon Numbers (EACNs) were determined from the so-called fish tail temperature T* of the fish diagrams obtained with an equal weight amount of oil and water (f(w)=0.5). The influence of the chemical structure of linear monoester on EACN was quantitatively rationalized in terms of ester bonds position and total carbon number, and explained by the influence of these polar oils on the "effective" packing parameter of the interfacial surfactant, which takes into account its entire physicochemical environment. In order to compare the behaviors of typical mono-, di-, and triester oils, three fish diagrams were entirely plotted with isopropyl myristate, bis (2-ethylhexyl) adipate, and glycerol trioctanoate. When the number of ester bonds increases, a more pronounced asymmetry of the three-phase body of the fish diagram with respect to T* is observed. In this case, T* is much closer to the upper limit temperature Tu than to the lower limit temperature Tl of the three-phase zone. This asymmetry is suggested to be linked to an increased solubility of the surfactant in the oil phase, which decreases the surfactant availability for the interfacial pseudo phase. As a consequence, the asymmetry depends on the water-oil ratio, and a method is proposed to determine the fw value at which T* is located at the mean value of Tu and Tl. PMID- 23673007 TI - Au or Ag nanoparticle-decorated 3D urchin-like TiO2 nanostructures: synthesis, characterization, and enhanced photocatalytic activity. AB - The semiconductors decorated with noble metals have attracted increasing attention due to their interesting physical and chemical properties. Here, 3D urchin-like hierarchical TiO2 nanostructures decorated with Au or Ag nanoparticles were prepared by wet-chemical process. The morphology and structure were characterized by different techniques. It shows that Au or Ag nanoparticles with narrow distribution are uniformly loaded on urchin-like TiO2 nanostructures, and the resulted composite nanostructures show distinct surface plasmon absorption band and quenched photoluminence compared to pure TiO2 nanostructures. Photocatalytic tests show both Au-decorated TiO2 and Ag-decorated TiO2 exhibit enhanced photocatalytic activity for photodegradation of methyl blue in water. PMID- 23673009 TI - The analysis of time-resolved optical waveguide absorption spectroscopy based on positive matrix factorization. AB - Time-resolved optical waveguide absorption spectroscopy (OWAS) makes use of an evanescent field to detect the polarized absorption spectra of sub-monomolecular adlayers. This technique is suitable for the investigation of kinetics at the solid/liquid interface of dyes, pigments, fluorescent molecules, quantum dots, metallic nanoparticles, and proteins with chromophores. In this work, we demonstrate the application of positive matrix factorization (PMF) to analyze time-resolved OWAS for the first time. Meanwhile, PCA is researched to compare with PMF. The absorption/desorption kinetics of Rhodamine 6G (R6G) onto a hydrophilic glass surface and the dynamic process of Meisenheimer complex between Cysteine and TNT are selected as samples to verify experimental system and analytical methods. The results are shown that time-resolved OWAS can well record the absorption/desorption of R6G onto a hydrophilic glass surface and the dynamic formation process of Meisenheimer complexes. The feature of OWAS extracted by PMF is dynamic and consistent with the results analyzed by the traditional function of time/wavelength-absorbance. Moreover, PMF prevents the negative factors from occurring, avoids contradicting physical reality, and makes factors more easily interpretable. Therefore, we believe that PMF will provide a valuable analysis route to allow processing of increasingly large and complex data sets. PMID- 23673008 TI - Facile synthesis of Bi2S3 hierarchical nanostructure with enhanced photocatalytic activity. AB - A simple wet chemistry method was employed for the synthesis of Bi2S3 hierarchical nanostructure using thioglycolic acid as a capping agent under reflux condition. The obtained products were characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), high-resolution transmission electron microscope images (HR-TEMs), energy dispersive spectroscopy (EDS), Fourier transform infrared (FT-IR), and nitrogen sorption measurement. FE-SEM and TEM observations displayed that Bi2S3 hierarchical nanostructure assembled from nanorods of about 100 nm in length and 5-10 nm in diameter was successfully obtained. The photocatalytic activity of the as-prepared samples was evaluated by the photocatalytic degradation of methyl orange under UV irradiation. The results indicated that Bi2S3 hierarchical nanostructure exhibited superior photocatalytic performance to pure Bi2S3, which can be ascribed to large specific surface area, hierarchical nanostructure, and high hydrophilicity. PMID- 23673010 TI - WNK4 inhibits Ca(2+)-activated big-conductance potassium channels (BK) via mitogen-activated protein kinase-dependent pathway. AB - We used the perforated whole-cell recording technique to examine the effect of with-no-lysine kinase 4 (WNK4) on the Ca(2+) activated big-conductance K channels (BK) in HEK293T cells transfected with BK-alpha subunit (BK-alpha). Expression of WNK4 inhibited BK channels and decreased the outward K currents. Coexpression of SGK1 abolished the inhibitory effect of WNK4 on BK channels and restored the outward K currents. Expression of WNK4(S1169D//1196D), in which both SGK1 phosphorylation sites (serine 1169 and 1196) were mutated to aspartate, had no effect on BK channels. Moreover, coexpression of SGK1 had no additional effect on K currents in the cells transfected with BKalpha+WNK4(S1169D//1196D), suggesting that SGK1 reversed WNK4-induced inhibition of BK channels by stimulating WNK4 phosphorylation. Expression of WNK4 but not WNK4(S1169D//1196D) increased the phosphorylation of ERK and p38 mitogen-activated protein kinase (MAPK); an effect was abolished by coexpression of SGK1. The role of ERK and p38 MAPK in mediating the effect of WNK4 on BK channels was further suggested by the finding that the inhibition of ERK and P38 MAPK completely abolished the inhibitory effect of WNK4 on BK channels. In contrast, inhibition of MAPK failed to abolish the inhibitory effect of WNK4 on ROMK channels in both HEK cells and Xenopus oocytes. Expression of dominant negative dynaminK44A (Dyn(K44A)) or treatment of the cells with dynasore, a dynamin inhibitor, not only increased K currents but also largely abolished the inhibitory effect of WNK4 on BK channels. However, inhibition of MAPK still increased the outward K currents in the cells transfected with BKalpha+WNK4 and treated with dynasore. Similar results were obtained in experiments performed in the native tissue in which inhibition of ERK and p38 MAPK increased BK channel activity in the cortical collecting duct (CCD) treated with dynasore. We concluded that WNK4 inhibited BK channels by stimulating ERK and p38 MAPK and that activation of MAPK by WNK4 may inhibit BK channels partially via a mechanism other than stimulating endocytosis. PMID- 23673011 TI - Neuromelanin MRI in a family with mitochondrial parkinsonism harboring a Y955C mutation in POLG1. AB - BACKGROUND: Progressive external ophthalmoplegia (PEO) and parkinsonism can be caused by genetic mutations that affect mitochondrial DNA (mtDNA) maintenance. We characterized parkinsonism in a family with dominantly inherited PEO. METHODS: We conducted clinical, histological and genetic analyses on two affected members suffering from PEO and parkinsonism, and reviewed the cases in the literature. To clarify parkinsonism related to multiple mtDNA deletions, we used 3-T neuromelanin magnetic resonance imaging (MRI) to assess signal changes in the substantia nigra (SN) and locus ceruleus (LC) in our patients, and compared the results to those observed in idiopathic Parkinson's disease (iPD) (n = 35). RESULTS: We report the first case of a Japanese family harboring a heterozygous p.Y955C mutation in POLG1. The clinical features of parkinsonism related to the Y955C mutation in a total of 16 patients, including our two cases, are indistinguishable from iPD. However, neuromelanin MRI showed a distinct pattern in our cases compared to iPD. The neuromelanin imaging results were consistent with the neuropathological findings reported in cases of POLG1 mutations, in which neurons of the SN were profoundly affected while those in the LC were preserved. CONCLUSIONS: Our results suggest that 3-T neuromelanin MRI may be useful for differentiating POLG1 mutation-associated parkinsonism from iPD, and that POLG1 mutations may cause selective neuronal loss in the SN via a mechanism different from that of iPD. PMID- 23673012 TI - Duodenal gastrointestinal stromal tumor: clinicopathological characteristics, surgical outcomes, long term survival and predictors for adverse outcomes. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) occur rarely in the duodenum. Because of their low incidence, data on long-term survival and prognostic factors are limited. The aims of this study were to present the authors' experiences in the diagnosis and treatment of this disease and to evaluate long-term surgical outcomes. METHODS: Clinical data from 22 consecutive patients with duodenal GISTs surgically managed from May 1999 to August 2011 were retrospectively studied. A pooled analysis was done by systematically reviewing other case series reported in the English literature. Recurrence-free survival and independent predictors of adverse outcomes were analyzed using the Kaplan-Meier method and multivariate Cox regression. RESULTS: Duodenal GISTs had a mild male predominance (68.2%), occurring primarily in older adults (median age, 58 years), with a frequency of 7.49% among all GISTs. Clinical presentations were nonspecific, with gastrointestinal bleeding and abdominal pain or discomfort being the most common symptoms. The tumors were located mainly in the second portion of the duodenum, in 14 patients (63.6%), with a median size of 3.75 cm (range, 1.4 to 14). All patients underwent curative surgical resection, including 9 pancreaticoduodenectomy, 3 segmental duodenectomy, and 10 local resection. Eighteen patients were alive without evidence of recurrence after a median follow up period of 67.5 months (range, 3 to 118). The 1-year, 2-year, and 3-year rates of recurrence-free survival were 95%, 89.5%, and 86.7%, respectively. Kaplan Meier analysis and log-rank tests showed that surgical pattern, mitosis, and risk grade were significantly associated with recurrence-free survival (P < .05 for all). However, only high mitosis was a significant predictive factor for adverse outcomes on multivariate analysis (hazard ratio, 16.414; 95% confidence interval, 1.914 to 140.756; P = .011). CONCLUSIONS: Duodenal GIST is an unusual neoplasm with favorable survival after curative resection. Mitotic activity was more influential than tumor size and risk grade in predicting adverse outcomes. All patients with duodenal GISTs require long-term follow-up, because late relapse can occur even if the tumor has low malignant potential. PMID- 23673013 TI - Implementing acute care surgery at a level I trauma center: 1-year prospective evaluation of the impact of this shift on trauma volumes and outcomes. AB - BACKGROUND: The purpose of this study was to evaluate the impact of the transition to acute care surgery (ACS) on trauma volumes and outcomes. METHODS: All admissions from 2 1-year periods from June 2008 to May 2010 (1 year before ACS and 1 year after ACS) to the LAC+USC Medical Center were prospectively collected. In anticipation of this change, trauma patient demographics, clinical data, and outcomes (trauma volume and preventable and potentially preventable deaths and complications) were prospectively collected. RESULTS: Before ACS, there were 5,378 trauma admissions. After ACS, there were 5,726 (66.5%) trauma and 2,886 (33.5%) nontrauma admissions. There were no demographic or clinical differences between trauma patients in the 2 groups. There was no significant difference in overall mortality (3.8% before ACS vs 3.3% after ACS, P = .292). Similarly, there were no differences in the rates of preventable and potentially preventable deaths or complications observed (1.2% vs 1.0%, P = .374) during the study period. CONCLUSIONS: Despite a 60% increase in total patient volume and a 233% increase in operative volume over the study period, the addition of emergency surgery to a trauma service did not compromise trauma patient outcomes. PMID- 23673014 TI - Synthesis and biological evaluation of a novel series of aryl S,N-ketene acetals as antileishmanial agents. AB - A series of aryl S,N-ketene acetals 7(a-f) was synthesized and evaluated for their in vitro and in vivo antileishmanial activity against Leishmania donovani. All the 6 compounds exhibited significant in vitro activity against intracellular amastigotes of L. donovani with IC50 values ranging from 1.2 to 3.5 MUM and were found promising as compared with reference drugs, sodium stibogluconate (SSG) and paromomycin. On the basis of good selectivity indices (SI), they were further tested for their in vivo potential against L. donovani/hamster model. Two compounds 7a and 7b showed significant inhibition of parasite multiplication, 72% and 83%, respectively. These compounds were comparable with SSG and superior to paromomycin. Preliminary in vitro metabolic investigations were also performed to assess the metabolic stability and in vitro hepatic intrinsic clearance (Clint) of compound 7b in hamster liver microsomes. PMID- 23673015 TI - A facile synthesis, anti-inflammatory and analgesic activity of isoxazolyl-2,3 dihydrospiro[benzo[f]isoindole-1,3'-indoline]-2',4,9-triones. AB - A new series of isoxazolyl-2,3-dihydrospiro[benzo[f]isoindole-1,3'-indoline] 2',4,9-triones (14) were synthesized by reaction of 4-amino-3-methyl-5 styrylisoxazole 10 with chloroacetic acid followed by a three component reaction with substituted isatins 12 and 1,4-naphthoquinone 13 using Ceric ammonium nitrate (CAN) catalyst under aerial oxidation condition. Structures of these compounds were established on the basis of IR, (1)H NMR, (13)C NMR and mass spectral data. The title compounds 14a-j were evaluated for their anti inflammatory and analgesic activity. Compounds 14d, 14e and 14f exhibited potent anti-inflammatory and analgesic activity as that of standard drugs. PMID- 23673016 TI - Identification of potent and orally bioavailable nucleotide competing reverse transcriptase inhibitors: in vitro and in vivo optimization of a series of benzofurano[3,2-d]pyrimidin-2-one derived inhibitors. AB - Recently, a new class of HIV reverse transcriptase (HIV-RT) inhibitors has been reported. The novel mechanism of inhibition by this class involves competitive binding to the active site of the RT enzyme and has been termed Nucleotide Competing Reverse Transcriptase Inhibitors (NcRTIs). In this publication we describe the optimization of a novel benzofurano[3,2-d]pyrimidin-2-one series of NcRTIs. The starting point for the current study was inhibitor 2, which had high biochemical and antiviral potency but only moderate permeability in a Caco-2 assay and high B-to-A efflux, resulting in moderate rat bioavailability and low Cmax. We present herein the results and strategies we employed to optimize both the potency as well as the permeability, metabolic stability and pharmacokinetic profile of this series. One of the key observations of the present study was the importance of shielding polar functionality, at least in the context of the current chemotype, to enhance permeability. These studies led to the identification of inhibitors 39 and 45, which display sub-nanomolar antiviral potency in a p24 ELISA assay with significantly reduced efflux ratios (ratios <1.5). These inhibitors also display excellent rat pharmacokinetic profiles with high bioavailabilities and low clearance. PMID- 23673017 TI - Implementation of the world health organization hand hygiene improvement strategy in critical care units. AB - BACKGROUND: To determine hand hygiene compliance before and after an intervention campaign in critical care units, this study was carried out in the Intensive care unit (ICU), Neonatal intensive care unit (NICU), Burns unit (BU) and the Kidney unit of the King Abdul Aziz Specialist Hospital, Taif, Saudi Arabia. The observation using the WHO hand hygiene protocol took place in four phases with phase I, between April 24-May 06 2010 and phase II from May 29-June 09 2010. An educational intervention took place between the Phases I and II. Follow-up Phases III and IV were from 01-15 October 2010 and 15-30 March 2011 respectively. FINDINGS: 1,975 hand hygiene opportunities comprising of 409 in Phase I, 406 in Phase II, 620 in Phase III and 540 Phase IV were observed. Compliance rate was 67% pre-intervention, 81% in phase II, declining to 59% and 65% in phases III and IV. Increased compliance in the ICU from 39% in Phase I to 81% in Phase IV (p < 0.05) was sustained throughout the study. Highest compliance rates were recorded among nurses in all phases. The improved compliance for physicians observed in the post-intervention phase was lost in follow-up phases. Missed opportunities for hand hygiene were before patient contact, after touching patient's surrounding and before aseptic techniques. Team-work and leadership were identified as enhancing factors for compliance. CONCLUSION: The WHO hand hygiene strategy combined with health education, continuous evaluation and team approach resulted in increased compliance but this was not sustained in certain critical care areas. PMID- 23673019 TI - Epidemiological and clinical features of HEV infection: a survey in the district of Foggia (Apulia, Southern Italy). AB - In this study we assessed the seroprevalence of hepatitis E virus (HEV) infection in both the Italian population and immigrants from developing countries in Foggia (Apulia, Southern Italy). The seroprevalence of HEV was determined in 1217 subjects [412 (34%) immigrants and 805 Italian subjects (blood donors, general population, HIV-positive, haemodialysis patients)]. Serum samples were tested for anti-HEV and confirmed by Western blot assay; in positive patients HEV RNA and genotype were also determined. There were 8.8% of patients that were positive to anti-HEV, confirmed by Western blot. The prevalence in immigrants was 19.7%, and in Italians 3.9% (blood donors 1.3%, general population 2.7%, HIV-positive patients 2.0%, haemodialysis patients 9.6%). Anti-HEV IgM was found in 38/107 (35.5%) of the anti-HEV-positive serum samples (34 immigrants, four Italians). This study indicates a higher circulation of HEV in immigrants and Italian haemodialysis patients, whereas a low prevalence of HEV antibodies was seen in the remaining Italian population. PMID- 23673020 TI - Pancreatic cancer genomics: insights and opportunities for clinical translation. AB - Pancreatic cancer is a highly lethal tumor type for which there are few viable therapeutic options. It is also caused by the accumulation of mutations in a variety of genes. These genetic alterations can be grouped into those that accumulate during pancreatic intraepithelial neoplasia (precursor lesions) and thus are present in all cells of the infiltrating carcinoma, and those that accumulate specifically within the infiltrating carcinoma during subclonal evolution, resulting in genetic heterogeneity. Despite this heterogeneity there are nonetheless commonly altered cellular functions, such as pathways controlling the cell cycle, DNA damage repair, intracellular signaling and development, which could provide for a variety of drug targets. This review aims to summarize current knowledge of the genetics and genomics of pancreatic cancer from its inception to metastatic colonization, and to provide examples of how this information can be translated into the clinical setting for therapeutic benefit and personalized medicine. PMID- 23673021 TI - Can quantum probability provide a new direction for cognitive modeling? AB - Classical (Bayesian) probability (CP) theory has led to an influential research tradition for modeling cognitive processes. Cognitive scientists have been trained to work with CP principles for so long that it is hard even to imagine alternative ways to formalize probabilities. However, in physics, quantum probability (QP) theory has been the dominant probabilistic approach for nearly 100 years. Could QP theory provide us with any advantages in cognitive modeling as well? Note first that both CP and QP theory share the fundamental assumption that it is possible to model cognition on the basis of formal, probabilistic principles. But why consider a QP approach? The answers are that (1) there are many well-established empirical findings (e.g., from the influential Tversky, Kahneman research tradition) that are hard to reconcile with CP principles; and (2) these same findings have natural and straightforward explanations with quantum principles. In QP theory, probabilistic assessment is often strongly context- and order-dependent, individual states can be superposition states (that are impossible to associate with specific values), and composite systems can be entangled (they cannot be decomposed into their subsystems). All these characteristics appear perplexing from a classical perspective. However, our thesis is that they provide a more accurate and powerful account of certain cognitive processes. We first introduce QP theory and illustrate its application with psychological examples. We then review empirical findings that motivate the use of quantum theory in cognitive theory, but also discuss ways in which QP and CP theories converge. Finally, we consider the implications of a QP theory approach to cognition for human rationality. PMID- 23673022 TI - Quantum structure and human thought. AB - We support the authors' claims, except that we point out that also quantum structure different from quantum probability abundantly plays a role in human cognition. We put forward several elements to illustrate our point, mentioning entanglement, contextuality, interference, and emergence as effects, and states, observables, complex numbers, and Fock space as specific mathematical structures. PMID- 23673023 TI - At home in the quantum world. AB - One among many misleading quotations about the alleged mysteries of quantum theory is from Feynman (1965): "I think I can safely say that nobody understands quantum mechanics." Today we know that quantum theory describes many aspects of our world in a fully intelligible fashion. Pothos & Busemeyer (P&B) propose ways in which this may include psychology and cognitive science. PMID- 23673024 TI - Signal detection theory in Hilbert space. AB - The Hilbert space formalism is a powerful language to express many cognitive phenomena. Here, relevant concepts from signal detection theory are recast in that language, allowing an empirically testable extension of the quantum probability formalism to psychophysical measures, such as detectability and discriminability. PMID- 23673025 TI - Can quantum probability help analyze the behavior of functional brain networks? AB - Pothos & Busemeyer (P&B) argue how key concepts of quantum probability, for example, order/context, interference, superposition, and entanglement, can be used in cognitive modeling. Here, we suggest that these concepts can be extended to analyze neurophysiological measurements of cognitive tasks in humans, especially in functional neuroimaging investigations of large-scale brain networks. PMID- 23673026 TI - Uncertainty about the value of quantum probability for cognitive modeling. AB - I argue that the overly simplistic scenarios discussed by Pothos & Busemeyer (P&B) establish at best that quantum probability theory (QPT) is a logical possibility allowing distinct predictions from classical probability theory (CPT). The article fails, however, to provide convincing evidence for the proposal that QPT offers unique insights regarding cognition and the nature of human rationality. PMID- 23673027 TI - The (virtual) conceptual necessity of quantum probabilities in cognitive psychology. AB - We propose a way in which Pothos & Busemeyer (P&B) could strengthen their position. Taking a dynamic stance, we consider cognitive tests as functions that transfer a given input state into the state after testing. Under very general conditions, it can be shown that testable properties in cognition form an orthomodular lattice. Gleason's theorem then yields the conceptual necessity of quantum probabilities (QP). PMID- 23673028 TI - On the quantum principles of cognitive learning. AB - Pothos & Busemeyer's (P&B's) query about whether quantum probability can provide a foundation for the cognitive modeling embodies so many underlying implications that the subject is far from exhausted. In this brief commentary, however, I suggest that the conceptual thresholds of the meaningful learning give rise to a typical Boltzmann's weighting measure, which indicates a statistical verisimilitude of quantum behavior in the human cognitive ensemble. PMID- 23673029 TI - Cold and hot cognition: quantum probability theory and realistic psychological modeling. AB - Typically, human decision making is emotionally "hot" and does not conform to "cold" classical probability (CP) theory. As quantum probability (QP) theory emphasises order, context, superimposition states, and nonlinear dynamic effects, one of its major strengths may be its power to unify formal modeling and realistic psychological theory (e.g., information uncertainty, anxiety, and indecision, as seen in the Prisoner's Dilemma). PMID- 23673030 TI - Beyond quantum probability: another formalism shared by quantum physics and psychology. AB - There is another meeting place for quantum physics and psychology, both within and outside of cognitive modeling. In physics it is known as the issue of classical (probabilistic) determinism, and in psychology it is known as the issue of selective influences. The formalisms independently developed in the two areas for dealing with these issues turn out to be identical, opening ways for mutually beneficial interactions. PMID- 23673031 TI - Quantum probability and cognitive modeling: some cautions and a promising direction in modeling physics learning. AB - Quantum probability theory offers a viable alternative to classical probability, although there are some ambiguities inherent in transferring the quantum formalism to a less determined realm. A number of physicists are now looking at the applicability of quantum ideas to the assessment of physics learning, an area particularly suited to quantum probability ideas. PMID- 23673032 TI - Does quantum uncertainty have a place in everyday applied statistics? AB - We are sympathetic to the general ideas presented in the article by Pothos & Busemeyer (P&B): Heisenberg's uncertainty principle seems naturally relevant in the social and behavioral sciences, in which measurements can affect the people being studied. We propose that the best approach for developing quantum probability models in the social and behavioral sciences is not by directly using the complex probability-amplitude formulation proposed in the article, but rather, more generally, to consider marginal probabilities that need not be averages over conditionals. PMID- 23673033 TI - Cognitive architectures combine formal and heuristic approaches. AB - Quantum probability (QP) theory provides an alternative account of empirical phenomena in decision making that classical probability (CP) theory cannot explain. Cognitive architectures combine probabilistic mechanisms with symbolic knowledge-based representations (e.g., heuristics) to address effects that motivate QP. They provide simple and natural explanations of these phenomena based on general cognitive processes such as memory retrieval, similarity-based partial matching, and associative learning. PMID- 23673034 TI - Quantum probability and comparative cognition. AB - Evolution would favor organisms that can make recurrent decisions in accordance with classical probability (CP) theory, because such choices would be optimal in the long run. This is illustrated by the base-rate fallacy and probability matching, where nonhumans choose optimally but humans do not. Quantum probability (QP) theory may be able to account for these species differences in terms of orthogonal versus nonorthogonal representations. PMID- 23673035 TI - Quantum mathematical cognition requires quantum brain biology: the "Orch OR" theory. AB - The "Orch OR" theory suggests that quantum computations in brain neuronal dendritic-somatic microtubules regulate axonal firings to control conscious behavior. Within microtubule subunit proteins, collective dipoles in arrays of contiguous amino acid electron clouds enable "quantum channels" suitable for topological dipole "qubits" able to physically represent cognitive values, for example, those portrayed by Pothos & Busemeyer (P&B) as projections in abstract Hilbert space. PMID- 23673036 TI - Quantum probability and conceptual combination in conjunctions. AB - I consider the general problem of category conjunctions in the light of Pothos & Busemeyer (P&B)'s quantum probability (QP) account of the conjunction fallacy. I argue that their account as presented cannot capture the "guppy effect" - the case in which a class is a better member of a conjunction A^B than it is of either A or B alone. PMID- 23673037 TI - Is quantum probability rational? AB - We concentrate on two aspects of the article by Pothos & Busemeyer (P&B): the relationship between classical and quantum probability and quantum probability as a basis for rational decisions. We argue that the mathematical relationship between classical and quantum probability is not quite what the authors claim. Furthermore, it might be premature to regard quantum probability as the best practical rational scheme for decision making. PMID- 23673038 TI - Limitations of the Dirac formalism as a descriptive framework for cognition. AB - We highlight methodological and theoretical limitations of the authors' Dirac formalism and suggest the von Neumann open systems approach as a resolution. The open systems framework is a generalization of classical probability and we hope it will allow cognitive scientists to extend quantum probability from perception, categorization, memory, decision making, and similarity judgments to phenomena in learning and development. PMID- 23673039 TI - Disentangling the order effect from the context effect: analogies, homologies, and quantum probability. AB - Although the quantum probability (QP) can be useful to model the context effect, it is not relevant to the order effect, conjunction fallacy, and other related biases. Although the issue of potentiality, which is the intuition behind QP, is involved in the context effect, it is not involved in the other biases. PMID- 23673040 TI - The cognitive economy: the probabilistic turn in psychology and human cognition. AB - According to the foundations of economic theory, agents have stable and coherent "global" preferences that guide their choices among alternatives. However, people are constrained by information-processing and memory limitations and hence have a propensity to avoid cognitive load. We propose that this in turn will encourage them to respond to "local" preferences and goals influenced by context and memory representations. PMID- 23673041 TI - Quantum models of cognition as Orwellian newspeak. AB - Faced with probabilistic relationships between causes and effects, quantum theory assumes that deterministic causes do not exist, and that only incomplete probabilistic expressions of knowledge are possible. As in its application to physics, this fundamental epistemological stance severely limits the ability of quantum theory to provide insight and understanding in human cognition. PMID- 23673042 TI - Cognition in Hilbert space. AB - Use of quantum probability as a top-down model of cognition will be enhanced by consideration of the underlying complex-valued wave function, which allows a better account of interference effects and of the structure of learned and ad hoc question operators. Furthermore, the treatment of incompatible questions can be made more quantitative by analyzing them as non-commutative operators. PMID- 23673043 TI - Grounding quantum probability in psychological mechanism. AB - Pothos & Busemeyer (P&B) provide a compelling case that quantum probability (QP) theory is a better match to human judgment than is classical probability (CP) theory. However, any theory (QP, CP, or other) phrased solely at the computational level runs the risk of being underconstrained. One suggestion is to ground QP accounts in mechanism, to leverage a wide range of process-level data. PMID- 23673044 TI - Processes models, environmental analyses, and cognitive architectures: quo vadis quantum probability theory? AB - A lot of research in cognition and decision making suffers from a lack of formalism. The quantum probability program could help to improve this situation, but we wonder whether it would provide even more added value if its presumed focus on outcome models were complemented by process models that are, ideally, informed by ecological analyses and integrated into cognitive architectures. PMID- 23673045 TI - The implicit possibility of dualism in quantum probabilistic cognitive modeling. AB - Pothos & Busemeyer (P&B) argue convincingly that quantum probability offers an improvement over classical Bayesian probability in modeling the empirical data of cognitive science. However, a weakness related to restrictions on the dimensionality of incompatible physical observables flows from the authors' "agnosticism" regarding quantum processes in neural substrates underlying cognition. Addressing this problem will require either future research findings validating quantum neurophysics or theoretical expansion of the uncertainty principle as a new, neurocognitively contextualized, "local" symmetry. PMID- 23673046 TI - What are the mechanics of quantum cognition? AB - Pothos & Busemeyer (P&B) argue that quantum probability (QP) provides a descriptive model of behavior and can also provide a rational analysis of a task. We discuss QP models using Marr's levels of analysis, arguing that they make most sense as algorithmic level theories. We also highlight the importance of having clear interpretations for basic mechanisms such as interference. PMID- 23673047 TI - A quantum of truth? Querying the alternative benchmark for human cognition. AB - We focus on two issues: (1) an unusual, counterintuitive prediction that quantum probability (QP) theory appears to make regarding multiple sequential judgments, and (2) the extent to which QP is an appropriate and comprehensive benchmark for assessing judgment. These issues highlight how QP theory can fall prey to the same problems of arbitrariness that Pothos & Busemeyer (P&B) discuss as plaguing other models. PMID- 23673048 TI - Quantum modeling of common sense. AB - Quantum theory is a powerful framework for probabilistic modeling of cognition. Strong empirical evidence suggests the context- and order-dependent representation of human judgment and decision-making processes, which falls beyond the scope of classical Bayesian probability theories. However, considering behavior as the output of underlying neurobiological processes, a fundamental question remains unanswered: Is cognition a probabilistic process at all? PMID- 23673049 TI - Quantum probability, intuition, and human rationality. AB - This comment suggests that Pothos & Busmeyer (P&B) do not provide an intuitive rational foundation for quantum probability (QP) theory to parallel standard logic and classical probability (CP) theory. In particular, the intuitive foundation for standard logic, which underpins CP, is the elimination of contradictions - that is, believing p and not-p is bad. Quantum logic, which underpins QP, explicitly denies non-contradiction, which seems deeply counterintuitive for the macroscopic world about which people must reason. I propose a possible resolution in situation theory. PMID- 23673050 TI - What's the predicted outcome? Explanatory and predictive properties of the quantum probability framework. AB - Quantum probability (QP) provides a new perspective for cognitive science. However, one must be clear about the outcome the QP model is predicting. We discuss this concern in reference to modeling the subjective probabilities given by people as opposed to modeling the choice proportions of people. These two models would appear to have different cognitive assumptions. PMID- 23673051 TI - If quantum probability = classical probability + bounded cognition; is this good, bad, or unnecessary? AB - Quantum probability models may supersede existing probabilistic models because they account for behaviour inconsistent with classical probability theory that are attributable to normal limitations of cognition. This intriguing position, however, may overstate weaknesses in classical probability theory by underestimating the role of current knowledge states and may under-employ available knowledge about the limitations of cognitive processes. In addition, flexibility in model specification has risks for the use of quantum probability. PMID- 23673052 TI - Quantum probability, choice in large worlds, and the statistical structure of reality. AB - Classical probability models of incentive response are inadequate in "large worlds," where the dimensions of relative risk and the dimensions of similarity in outcome comparisons typically differ. Quantum probability models for choice in large worlds may be motivated pragmatically - there is no third theory - or metaphysically: statistical processing in the brain adapts to the true scale relative structure of the universe. PMID- 23673053 TI - Physics envy: trying to fit a square peg into a round hole. AB - Pothos & Busemeyer (P&B) argue that classical probability (CP) fails to describe human decision processes accurately and should be supplanted by quantum probability. We accept the premise, but reject P&B's conclusion. CP is a prescriptive framework that has inspired a great deal of valuable research. Also, because CP is used across the sciences, it is a cornerstone of interdisciplinary collaboration. PMID- 23673054 TI - Realistic neurons can compute the operations needed by quantum probability theory and other vector symbolic architectures. AB - Quantum probability (QP) theory can be seen as a type of vector symbolic architecture (VSA): mental states are vectors storing structured information and manipulated using algebraic operations. Furthermore, the operations needed by QP match those in other VSAs. This allows existing biologically realistic neural models to be adapted to provide a mechanistic explanation of the cognitive phenomena described in the target article by Pothos & Busemeyer (P&B). PMID- 23673055 TI - Why quantum probability does not explain the conjunction fallacy. AB - We agree with Pothos & Busemeyer (P&B) that formal tools can be fruitfully employed to model human judgment under uncertainty, including well-known departures from principles of classical probability. However, existing findings either contradict P&B's quantum probability approach or support it to a limited extent. The conjunction fallacy serves as a key illustration of both kinds of problems. PMID- 23673057 TI - Effect of temperature and sunlight on the stability of human adenoviruses and MS2 as fecal contaminants on fresh produce surfaces. AB - Determining the stability, or persistence in an infectious state, of foodborne viral pathogens attached to surfaces of soft fruits and salad vegetables is essential to underpin risk assessment studies in food safety. Here, we evaluate the effect of temperature and sunlight on the stability of infectious human adenoviruses type 2 and MS2 bacteriophages on lettuce and strawberry surfaces as representative fresh products. Human adenoviruses have been selected because of their double role as viral pathogens and viral indicators of human fecal contamination. Stability assays were performed with artificially contaminated fresh samples kept in the dark or under sunlight exposure at 4 and 30 degrees C over 24h. The results indicate that temperature is the major factor affecting HAdV stability in fresh produce surfaces, effecting decay between 3 and 4 log after 24h at 30 degrees C. The inactivation times to achieve a reduction between 1 and 4-log are calculated for each experimental condition. This work provides useful information to be considered for improving food safety regarding the transmission of foodborne viruses through supply chains. PMID- 23673056 TI - Age-associated changes in the ecological niche: implications for mesenchymal stem cell aging. AB - Adult stem cells are critical for organ-specific regeneration and self-renewal with advancing age. The prospect of being able to reverse tissue-specific post injury sequelae by harvesting, culturing and transplanting a patient's own stem and progenitor cells is exciting. Mesenchymal stem cells have emerged as a reliable stem cell source for this treatment modality and are currently being tested in numerous ongoing clinical trials. Unfortunately, the fervor over mesenchymal stem cells is mitigated by several lines of evidence suggesting that their efficacy is limited by natural aging. This article discusses the mechanisms and manifestations of age-associated deficiencies in mesenchymal stem cell efficacy. A consideration of recent experimental findings suggests that the ecological niche might be responsible for mesenchymal stem cell aging. PMID- 23673058 TI - Effects of nisin-incorporated films on the microbiological and physicochemical quality of minimally processed mangoes. AB - The aim of this study is to examine the effects of nisin-incorporated cellulose films on the physicochemical and microbiological qualities of minimally processed mangoes. The use of antimicrobial films did not affect the physicochemical characteristics of mangoes and showed antimicrobial activity against Staphylococcus aureus, Listeria monocytogenes, Alicyclobacillus acidoterrestris and Bacillus cereus. The mango slices were inoculated with S. aureus and L. monocytogenes (10(7)CFU/g), and the viable cell numbers remained at 10(5) and 10(6)CFU/g, respectively, after 12days. In samples packed with antimicrobial films, the viable number of L. monocytogenes cells was reduced below the detection level after 4days. After 6days, a reduction of six log units was observed for S. aureus. In conclusion, nisin showed antimicrobial activity in mangoes without interfering with the organoleptic characteristics of the fruit. This result suggests that nisin could potentially be used in active packing to improve the safety of minimally processed mangoes. PMID- 23673059 TI - Investigating the efficacy of Bacillus subtilis SM21 on controlling Rhizopus rot in peach fruit. AB - The efficacy of Bacillus subtilis SM21 on controlling Rhizopus rot caused by Rhizopus stolonifer in postharvest peach fruit and the possible mechanisms were investigated. The results indicated B. subtilis SM21 treatment reduced lesion diameter and disease incidence by 37.2% and 26.7% on the 2nd day of inoculation compared with the control. The in vitro test showed significant inhibitory effect of B. subtilis SM21 on mycelial growth of R. stolonifer with an inhibition rate of 48.9%. B. subtilis SM21 treatment significantly enhanced activities of chitinase and beta-1,3-glucanase, and promoted accumulation of H2O2. Total phenolic content and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity were also increased by this treatment. Transcription of seven defense related genes was much stronger in fruit treated with B. subtilis SM21 or those both treated with B. subtilis SM21 and inoculated with R. stolonifer compared with fruit inoculated with R. stolonifer alone. These results suggest that B. subtilis SM21 can effectively inhibit Rhizopus rot caused by R. stolonifer in postharvest peach fruit, possibly by directly inhibiting growth of the pathogen, and indirectly inducing disease resistance in the fruit. PMID- 23673060 TI - Comparative genomic analysis of Aspergillus oryzae strains 3.042 and RIB40 for soy sauce fermentation. AB - The filamentous fungus Aspergillus oryzae 3.042 (Chinese strain) is a close relative of A. oryzae RIB40 (Japanese strain), which is the important agent used for soy sauce fermentation. The genome of A. oryzae 3.042 was sequenced and compared with A. oryzae RIB40 in an attempt to understand why different soy sauce flavors are produced by these strains. The A. oryzae 3.042 chromosome is 36,547,279bp and contains 11,399 protein-encoding genes. MUMmer analysis revealed that the genomes of A. oryzae 3.042 and RIB40 are mostly collinear. Genome sequence data and comparative analysis of the two strains identified several strain-specific genes that encode putative proteins involved in cell growth, salt tolerance, environmental resistance and flavor formation. A. oryzae 3.042 showed stronger potential for mycelial growth. Some genes unique to A. oryzae RIB40 were related to salt tolerance, especially genes for K(+) transport, while others were associated with ester formation and amino acid metabolism, which likely contribute to flavor formation. In conclusion, comparative genome analysis provided insights into the different genetic traits of the two A. oryzae strains. The unique genes that we found in A. oryzae would make sense to the soy sauce fermentation. PMID- 23673061 TI - Effect of pyrimethanil on Cryptococcus laurentii, Rhodosporidium paludigenum, and Rhodotorula glutinis biocontrol of Penicillium expansum infection in pear fruit. AB - The effect of biocontrol yeasts and pyrimethanil at low concentration on inhibition of blue mold rot caused by Penicillium expansum in pear fruit was investigated. Pyrimethanil at low concentration (40MUg/mL) alone had little inhibitory activity against the P. expansum infection in pear fruit wounds although it was effective in inhibiting the survival of P. expansum on Asp-agar medium. Pyrimethanil at this low concentration significantly enhanced the efficacy of Cryptococcus laurentii at 1*10(7)CFU/mL in reducing blue mold rot in vivo compared with C. laurentii at 1*10(7)CFU/mL alone. However, there was no additive inhibitory activity when pyrimethanil was combined for application with biocontrol yeasts Rhodosporidium paludigenum or Rhodotorula glutinis. Combination of pyrimethanil and C. laurentii at low concentration also inhibited blue mold rot when P. expansum was inoculated into fruit wounds 12h before treatment and fruit was stored at low temperature (4 degrees C). Pyrimethanil at 0.04 to 400MUg/mL did not influence the survival of C. laurentii in vitro, and it only slightly reduced the population growth of C. laurentii after 48h of incubation in the pear fruit wounds. There was no significant difference in quality parameters including total soluble solids, titratable acidity and ascorbic acid of pear fruit wounds among all treatments after 5days of treatment at 25 degrees C. Integration of C. laurentii and pyrimethanil at low concentration might be an effective and safe strategy to control P. expansum infection in pear fruit, especially in an integrated postharvest disease management strategy. PMID- 23673063 TI - Neural mirroring during the observation of live and video actions in infants. AB - OBJECTIVE: Previous infant studies investigated neural mirroring during the observation of live or video actions. However, both methods have their (dis)advantages and studies using one of these methods are not always directly comparable. Therefore, the present study directly compared neural mirroring activity in a video setting with a live setting in infants between 18 and 36 months old. METHODS: Central mu rhythm suppression was measured through EEG recordings during the observation and imitation of the same goal-directed and mimicked actions presented either on video or live. RESULTS: Results revealed significant mu suppression during action imitation in both settings but stronger mu suppression was observed in the live setting during this condition. Significant mu suppression during the observation of goal-directed actions and mimicked actions was only observed in the live setting. CONCLUSION: This study revealed a different influence of video and live actions on neural mirroring activity in infants. SIGNIFICANCE: It is recommended to use live actions to investigate neural mirroring in young children. PMID- 23673062 TI - Fatigue modulates synchronous but not asynchronous soleus activation during stimulation of paralyzed muscle. AB - OBJECTIVE: Electrical stimulation over a motor nerve yields muscle force via a combination of direct and reflex-mediated activation. We determined the influence of fatigue on reflex-mediated responses induced during supra-maximal electrical stimulation in humans with complete paralysis. METHODS: We analyzed soleus electromyographic (EMG) activity during repetitive stimulation (15 Hz, 125 contractions) in 22 individuals with complete paralysis. The bout of stimulation caused significant soleus muscle fatigue (53.1% torque decline). RESULTS: Before fatigue, EMG at all latencies after the M-wave was less than 1% of the maximal M wave amplitude (% MaxM). After fatigue there was a fourfold (p < 0.05) increase in EMG at the H-reflex latency; however, the overall magnitude remained low (< 2% change in % MaxM). There was no increase in "asynchronous" EMG ~ 1 s after the stimulus train. CONCLUSIONS: Fatigue enhanced the activation to the paralyzed soleus muscle, but primarily at the H-reflex latency. The overall influence of this reflex modulation was small. Soleus EMG was not elevated during fatigue at latencies consistent with asynchronous activation. SIGNIFICANCE: These findings support synchronous reflex responses increase while random asynchronous reflex activation does not change during repetitive supra-maximal stimulation, offering a clinical strategy to consistently dose stress to paralyzed tissues. PMID- 23673064 TI - The Perceval S aortic valve has the potential of shortening surgical time: does it also result in improved outcome? AB - BACKGROUND: Sutureless aortic valve prostheses have the potential of shortening surgical time. However, whether shorter operative times may also result in improved patient outcomes remains to be established. METHODS: One hundred patients underwent minimally invasive isolated aortic valve replacement. Of these, 50 patients received a Perceval (Sorin Group, Saluggia, Italy) bioprosthesis (group P) and 50 patients received a non-Perceval valve (group NP). RESULTS: The group P patients were older (77.5 +/- 5.3 versus 71.7 +/- 10 years, p = 0.001) and at higher risk (logistic European System for Cardiac Operative Risk Evaluation [EuroSCORE] 9.9 +/- 6.5 versus 4.3 +/- 1, p = 0.001) than group NP patients. One implant failure occurred in group P (p = 0.5), and conversion to full sternotomy was necessary in 1 patient from each group. Aortic cross-clamp and cardiopulmonary bypass times were 39.4% and 34% shorter in group P (both p < 0.001). Within 30 days, a total of 5 patients died (2 in group P and 3 in group NP, p = 0.5). No significant differences were observed between groups in postoperative arrhythmias and need for pacemaker implantation (p = 0.3 and p = 0.5, respectively). Despite the higher surgical risk, group P patients less frequently required blood transfusion (1.1 +/- 1.1 units versus 2.3 +/- 2.8 units, p = 0.007), and had a shorter intensive care unit stay (1.9 +/- 0.7 versus 2.8 +/- 1.9 days, p = 0.002) and a shorter intubation time (9.2 +/- 3.6 hours versus 15 +/- 13.8 hours, p = 0.01). Group NP patients had a mean prosthesis size significantly smaller than for group P (23 +/- 2 mm versus 23.9 +/- 1.1 mm, p = 0.01). The Perceval valve provided comparable hemodynamic performance to that of non-Perceval valves (mean gradient 8.4 +/- 6 mm Hg versus 10 +/- 4.9 mm Hg, p = 0.24). CONCLUSIONS: Sutureless implantation of the Perceval valve is associated with shorter cross-clamp and cardiopulmonary bypass times, resulting in improved clinical outcome. In addition, it compares favorably with conventional valves in terms of mortality and outcome variables. PMID- 23673065 TI - Surgical treatment of aortic valve endocarditis with left ventricular-aortic discontinuity. AB - BACKGROUND: The periannular expansion of infection is a serious complication of infective endocarditis associated with high morbidity and mortality. The present study evaluates the results of aortic annular reconstruction in active infective endocarditis with left ventricular-aortic discontinuity. METHODS: Left ventricular-aortic discontinuity was diagnosed by echocardiography in 25 (21 men, 4 female; mean age 60.2 +/- 13.2 years) of 269 patients who underwent surgery for active native or prosthetic aortic valve endocarditis between January 2001 and October 2011. Seventeen (68%) and 8 (32%) patients had native and prosthetic valve endocarditis, respectively. Aortic root abscesses were radically debrided in all patients. The aortic annulus was reconstructed using autologous pericardium in 20 patients and a Dacron patch in 2. Isolated aortic valves were replaced with a bioprosthesis in 9 (36%) patients and a mechanical prosthesis in 13 (52%). Mechanical composite grafts were implanted in 3 (12%) patients. The mean follow-up was 29.1 +/- 23.6 months and complete. RESULTS: Thirty-day mortality was 20% (n = 5). Survival at 3 years was 80% +/- 8% with no significant difference between native and prosthetic valve endocarditis (log-rank, p = 0.69). Endocarditis did not recur during follow-up. CONCLUSIONS: Despite procedural progress, surgery for aortic valve endocarditis with left ventricular-aortic discontinuity remains associated with significant in-hospital mortality, but mid term survival after the perioperative period is good. Annular reconstruction with a pericardial patch is technically safe. PMID- 23673066 TI - Norwood reconstruction using continuous coronary perfusion: a safe and translatable technique. AB - BACKGROUND: Continuous coronary perfusion during Norwood reconstruction offers the theoretic advantage of less postoperative cardiac dysfunction. The avoidance of a cardiac and circulatory arrest period allows time for a more deliberate aortic reconstruction while the heart remains beating. This single-center study was designed to compare patient results using this method vs standard cardiac arrest for Norwood reconstruction. METHODS: A retrospective review was done of 32 patients undergoing Norwood reconstruction from November 2004 to July 2011. The operations in the most recent 16 consecutive patients were performed under deep hypothermia with constant coronary and cerebral perfusion. Continuous coronary perfusion was provided by a cannula inserted into the proximal aorta. The operations in the prior 16 consecutive patients were performed using deep hypothermia, selective cerebral perfusion, and cardioplegic arrest during aortic reconstruction. RESULTS: Survival in the beating-heart group was 87.5% (14 of 16) vs 62.5% (10 of 16) in the standard group (p = 0.22). No patients in the beating heart group required extracorporeal membrane oxygenation vs 3 in the standard group. Postoperative cardiac function was similar for both groups. The beating heart cohort had lower peak lactate levels (8.2 mEq/L) than the standard group (10.7 mEq/L, p = 0.022). CONCLUSIONS: This study presents the largest series of Norwood operations in which the entire aorta is augmented while delivering continuous coronary perfusion. The technique is applicable to any size aorta and represents a safe alternative because outcomes for survival, freedom from extracorporeal membrane oxygenation, postoperative cardiac function, and lactate levels were all noninferior compared with the standard technique. PMID- 23673067 TI - A propensity-matched comparison of pleurodesis or tunneled pleural catheter in patients undergoing diagnostic thoracoscopy for malignancy. AB - BACKGROUND: Patients with a suspected malignant pleural effusion occasionally require thoracoscopy to achieve a diagnosis. It is unclear whether chemical pleurodesis or the placement of a tunneled pleural catheter (TPC) that can be used for intermittent pleural drainage produces superior palliation, a shorter hospital stay, and less morbidity. This investigation compares these 2 treatment groups. METHODS: Patients with a recurrent, symptomatic, pleural effusion suspected of having a malignant etiology who underwent a thoracoscopic exploration after at least 2 nondiagnostic thoracenteses were identified. Two patient groups were formed, comprised of patients who received either talc pleurodesis or a TPC at the conclusion of the procedure, using propensity matching. Patient demographics, length of stay, interval until the initiation of systemic therapy, need for further intervention for the pleural effusion, and procedural morbidity and mortality were collected and compared. RESULTS: Over a 6 year period, 60 patients undergoing treatment were identified and propensity matched. No significant differences in mean age or palliation from their effusion were identified. However, the group treated with TPC realized a significantly shorter hospital stay and interval to systemic therapy for their malignancy as well as a lower rate of operative morbidity than patients undergoing talc pleurodesis. CONCLUSIONS: This investigation found that a TPC provided palliation of patients' malignant pleural effusions and freedom from reintervention equal to that of talc pleurodesis after thoracoscopy while resulting in a shorter mean length of hospital stay and interval to the initiation of systemic therapy. Lower rates of operative morbidity were also seen in the TPC treatment group. This method of palliation of a malignant pleural effusion should be considered when diagnostic thoracoscopy reveals a malignant pleural effusion. PMID- 23673068 TI - Late left ventricular function after successful Ross-Konno operation. AB - BACKGROUND: The changes of left ventricular function after undergoing a Ross Konno operation for pediatric patients with multiple-level left ventricular outflow tract obstruction are still unclear. METHODS: From 1996 to 2006, 14 patients younger than 20 years underwent a Ross-Konno operation. The mean age at the time of the operation was 6.6 +/- 5.7 years. A postoperative catheter examination was performed at early (1.0 +/- 0.4 years after the operation, n = 13), mid (3.3 +/- 1.6 years, n = 9), and late (8.5 +/- 2.5 years, n = 6) periods. The mean follow-up period was 10.1 +/- 6.0 years (range, 0.1 to 17.2 years). RESULTS: There was 1 early death and no late deaths. The pressure gradient across the left ventricular outflow tract was well relieved from 62.4 +/- 22.9 mm Hg at the preoperative period to 4.5 +/- 7.2 mm Hg at the early postoperative period, 4.1 +/- 3.5 mm Hg at the mid postoperative period, and 3.8 +/- 3.7 mm Hg at the late postoperative period. The left ventricular ejection fraction significantly decreased from 0.73 +/- 0.12 at the preoperative period to 0.60 +/- 0.10 at the early postoperative period (p = 0.00035), then improved to 0.64 +/- 0.14 at the late postoperative period. The left ventricular end-diastolic volume normalized to 103 +/- 37% of the normal volume at the late postoperative period. However, the left ventricular end-diastolic pressure did not decrease from 15.2 +/- 6.1 mm Hg at the preoperative period, 12.5 +/- 3.3 mm Hg at the early postoperative period, 13.1 +/- 5.1 mm Hg at the mid postoperative period, or 12.7 +/- 5.6 mm Hg at the late postoperative period. CONCLUSIONS: The left ventricular contraction and volume normalized long after the Ross-Konno operation. However, the reduced ventricular compliance did not recover, although left ventricular outflow tract obstruction was well relieved. PMID- 23673069 TI - Major bleeding, transfusions, and anemia: the deadly triad of cardiac surgery. AB - BACKGROUND: Postoperative bleeding is common after cardiac surgery. Major bleeding (MB) is a determinant of red blood cell (RBC) transfusion, especially in patients with preoperative anemia. Preoperative anemia and RBC transfusions are recognized risk factors for operative mortality. The present study investigates the role of MB as an independent determinant of operative mortality in cardiac surgery. METHODS: A single-center retrospective study based on the institutional database of cardiac surgery in the period 2000-2012 was conducted. Sixteen thousand one hundred fifty-four (16,154) consecutive adult patients undergoing cardiac surgery were analyzed. The impact of postoperative bleeding and MB on operative (30 days) mortality was analyzed univariately and after correction for preoperative anemia, RBC transfusions, and other confounders. RESULTS: Postoperative bleeding was significantly (p < 0.001) associated with operative mortality, both in univariate and multivariable models. The main complications associated with MB were thromboembolic complications, infections, and surgical reexploration. In a multivariable model, MB remained an independent predictor of operative mortality (odds ratio, 3.45; 95% confidence interval, 2.78 to 4.28). Preoperative anemia and RBC transfusions coexist in the model, acting with a multiplying effect when associated with MB. CONCLUSIONS: Major bleeding is per se a risk factor for operative mortality. However, its deleterious effects are strongly enhanced by RBC transfusions and, to a lesser extent, preoperative anemia. Major bleeding is a partially modifiable risk factor, and adequate preemptive and treatment strategies should be applied to limit this event. PMID- 23673070 TI - Association of gender and lowest hematocrit on cardiopulmonary bypass with acute kidney injury and operative mortality in patients undergoing cardiac surgery. AB - BACKGROUND: Nadir hematocrit on cardiopulmonary bypass (CPB) is a known risk factor for worse outcomes after cardiac surgery. Whether women, because of lower nadir hematocrit on CPB, are more prone to worse outcomes than men after cardiac surgery remains unknown. METHODS: We evaluated 13,734 patients (31.3% women) undergoing cardiac surgery (6/1/2001 to 06/30/2011) to study the association of hematocrit on CPB and gender with postoperative acute kidney injury (AKI) stage 2 3 (increase in creatinine at least twice the baseline), and operative mortality. RESULTS: Women were older (68 +/- 12 vs 65 +/- 12 years, p < 0.001), with more comorbidities. Baseline (37.4% +/- 4.4% vs 39.8% +/- 4.6%, p < 0.001) and nadir (24.5% +/- 3.5% vs 27.4% +/- 3.6%, p < 0.001) hematocrit were lower, whereas the hematocrit drop on CPB (baseline and nadir) was greater in women (12.9% +/- 4.35 vs 12.4% +/- 4.2%, p < 0.001). Observed AKI stage 2-3 and mortality rates were significantly higher in women than in men (5.8% vs 4.9%, p = 0.025 and 4.3% vs 3.4%, p = 0.009, respectively). While nadir hematocrit was inversely related to AKI stage 2-3 and death in both genders, the subgroup of patients with severe hemodilution (nadir hematocrit <= 22%) demonstrated a nonsignificant higher rate of AKI stage 2-3 in men (9.2% vs 7.8%) and a significant higher mortality in men (11% vs 7.6%) compared with women. CONCLUSIONS: Both men and women undergoing cardiac surgery on CPB were prone to the deleterious effects of hemodilution on renal function and death. Yet, despite greater hemodilution, women had a lower relative risk of AKI and death than men at lower nadir hematocrit values on CPB suggesting better tolerance to hemodilution in women. PMID- 23673072 TI - Spinal cord ischemia after thoracic stent-grafting: causes apart from intercostal artery coverage. AB - BACKGROUND: Examination of a large collective combined with individual case analyses may give new insights into mechanisms and prevention of spinal cord ischemia (SCI) after thoracic endovascular repair. METHODS: In an 11-year period, stent-grafts were implanted in 406 patients for various aortic pathologic conditions. The mean age was 63 years (15-91 years) and 300 (74%) patients were men; 58 patients underwent staged thoracic stent-graft procedures. The length of aorta covered was between 75 and 584 mm (mean, 204 mm). Thoracoabdominal branched or fenestrated stent-grafts were implanted in 11 patients. The left subclavian artery was occluded in 161 patients (39%); this occurred in half of them (n = 78) after protective revascularization. Prophylactic cerebrospinal fluid (CSF) drainage was used selectively in 4 cases; no neuromonitoring was used. RESULTS: The incidence of SCI was 2.7% (n = 11); 6 patients (1.5%) had major permanent deficits. Conditions that had a potential influence on SCI were analyzed. Statistical correlation was found for previous conventional or endovascular abdominal aortic aneurysm repair (odds ratio [OR], 4.8), coverage of the entire descending thoracic aorta (OR, 3.6), and implantation of thoracoabdominal branched and fenestrated stent-grafts (OR, 9.5). Individual analyses revealed other conditions that might have played a role, such as embolization into the segmental arteries, severe visceral ischemia, profound hemorrhagic shock, and heparin-induced thrombocytopenia. CONCLUSIONS: The incidence of SCI is unexpectedly low despite extensive sacrifice of intercostal arteries. Extended coverage of the thoracic and thoracoabdominal aorta seems to have a higher risk, but other factors may contribute to the individual disaster. PMID- 23673071 TI - Predictive factors for node metastasis in patients with clinical stage I non small cell lung cancer. AB - BACKGROUND: Accurate clinical staging of non-small cell lung cancer (NSCLC) is essential for developing a treatment plan and evaluating suitability for minimally invasive surgery. The aim of this study was to evaluate predictive factors for metastasis of N1 and N2 nodes in clinical stage I NSCLC. METHODS: Records of patients with clinical stage I NSCLC who had undergone pulmonary resection with systematic node dissection or node sampling between 2003 and 2011 were retrospectively reviewed. To identify predictive factors for node metastasis, univariate and multivariate logistic regression analyses were performed. RESULTS: Among the 770 patients in this study, the overall prevalence of node metastasis was 19.4%, which included 11.3% of N1 nodes and 8.1% of N2 nodes. Predictive factors for N1 node metastasis included male sex, current smoker, non-adenocarcinoma, solid consistency, centrally located tumor, clinical T stage, cytokeratin fragment 21-1 level, tumor size, maximum standardized uptake value of the mass, and ground-glass opacity proportion. Adenocarcinoma, solid consistency, clinical T stage, carcinoembryonic antigen level, tumor size, and ground-glass opacity proportion were identified as predictors for N2 node metastasis. Both tumor size and solid consistency were independent predictive values of N1 node and N2 node metastasis by multivariate analysis. CONCLUSIONS: Among the patients with clinical stage I NSCLC, 19.4% of the patients showed unexpected node metastasis, and large size and solid consistency of the tumor were predictive factors of node metastasis in clinical stage I NSCLC. Preoperative staging should be performed more thoroughly to increase the accuracy of preoperative staging, especially in those who have the larger size and solid consistency of the tumor. PMID- 23673073 TI - Very prolonged stay in the intensive care unit after cardiac operations: early results and late survival. AB - BACKGROUND: Prolonged intensive care unit (ICU) stay is a surrogate for advanced morbidity or perioperative complications, and resource utilization may become an issue. It is our policy to continue full life support in the ICU, even for patients with a seemingly grim outlook. We examined the effect of duration of ICU stay on early outcomes and late survival. METHODS: Between 1993 and 2011, 6,385 patients were admitted to the ICU after cardiac surgery. Patients were grouped according to length of stay in the ICU: group 1, 2 days or less (n = 4,631; 73%); group 2, 3 to 14 days (n = 1,423; 22%); group 3, more than 14 days (n = 331; 5%). Length of stay in ICU for group 3 patients was 38 +/- 24 days (range, 15 to 160; median 31). Clinical profile and outcomes were compared between groups. RESULTS: Patients requiring prolonged ICU stay were older, underwent more complex surgery, had greater comorbidity, and a higher predicted operative mortality (p < 0.0001). They had a higher incidence of adverse events and increased mortality (p < 0.0001). Of the 331 group 3 patients, 60% were discharged: survival of these patients at 1, 3, and 5 years was 78%, 65%, and 52%, respectively. Operative mortality as well as late survival of discharged patients was proportional to duration of ICU stay. CONCLUSIONS: Current technology enables keeping sick patients alive for extended periods of time. Nearly two thirds of patients requiring prolonged ICU leave hospital, and of these, 50% attain 5-year survival. These data support offering full and continued support even for patients requiring very prolonged ICU stay. PMID- 23673074 TI - Sleeve pneumonectomy for central non-small cell lung cancer: indications, complications, and survival. AB - BACKGROUND: Sleeve pneumonectomy is a challenging therapeutic strategy for patients with non-small cell lung cancer (NSCLC) invading the carina. The aim of this study was to illustrate common indications and individual concepts for surgery and to investigate oncologic outcomes and complications. METHODS: Sixty four consecutive sleeve pneumonectomies were performed between September 2000 and November 2011. All patients had histologically proven central NSCLC. Data were retrospectively reviewed for indications, complications, and factors influencing long-term survival. RESULTS: Sixty-four patients underwent sleeve pneumonectomy for curative (n = 50, 78%) or palliative therapy (n = 14, 22%). Complete resection was achieved in 83%. Pathologic N2 disease was found in 41%. Complications occurred in 41%, with severe anastomotic problems in 8% of cases. Thirty-day mortality was 3% (n = 2). Outcome was significantly influenced by pathologic nodal status with 5-year survival rates of 70%, 35%, and 9% for N0, N1, and N2 subgroups, respectively. Patients with multilevel N2 disease and contraindications for chemotherapy or radiotherapy had a mean survival of 13 months after palliative surgery. CONCLUSIONS: Sleeve pneumonectomy for central NSCLC invading the carina or proximal main bronchus can be performed with tolerable risk and encouraging survival rates in selected cases. Palliative sleeve pneumonectomy displays an option in the absence of alternative therapeutic strategies. PMID- 23673076 TI - Practical aspects of genetic counseling in breast cancer: lights and shadows. AB - In unselected populations, less than 10% of breast cancers are associated with germline mutations in predisposing genes. Breast cancer type 1 and 2 (BRCA1 and BRCA2) susceptibility genes are the most common involved genes and confer a 10-30 times higher risk of developing the disease compared to the general population. A personal or family history suggestive of inherited breast cancer syndrome may be further evaluated to assess the risk of genetic predisposition and the presence of a genetic mutation. Breast cancer genetic counseling should include a careful risk assessment with associated psychosocial evaluation and support, possible molecular testing, personalized discussion of results. Knowledge of BRCA status can influence individualized cancer risk-reduction strategies. i.e. active surveillance, prophylactic surgery and/or pharmacoprevention. PMID- 23673075 TI - In-hospital shunt occlusion in infants undergoing a modified blalock-taussig shunt. AB - BACKGROUND: The clinical variables leading to postoperative thrombotic occlusion of a modified Blalock-Taussig shunt (mBTS) remain elusive. In this investigation, we assess several perioperative variables to determine associations with postoperative in-hospital shunt occlusion. METHODS: We retrospectively reviewed the medical records of infants receiving a mBTS as a first operation between March 1, 2005, and December 31, 2011. Numerous perioperative variables were collected, focusing on those that would increase resistance to blood flow through the shunt or alter coagulation. RESULTS: In all, 207 neonates fit our criteria. In-hospital shunt occlusion occurred in 14 patients (6.8%); 3 patients (21.4%) subsequently died during their hospitalization. Pulmonary atresia/ventricular septal defect with or without major aortopulmonary collateral arteries was the most common diagnosis associated with shunt occlusion (57.1%). Of the collected perioperative variables, pulmonary artery size was significantly associated with shunt occlusion (p = 0.03). Preoperative coagulation values were significantly reduced in those patients who experienced shunt occlusion. Additionally, the immediate postoperative activated partial thromboplastin time was significantly reduced in the occlusion group although values remained well above normal as all infants were treated postoperatively with a heparin infusion. CONCLUSIONS: We found that a patient's anatomy (pulmonary atresia/ventricular septal defect with or without major aortopulmonary collateral arteries) and the size of the pulmonary artery being shunted had a significant impact in predicting postoperative in-hospital shunt occlusion. These results emphasize that technical skills and a low resistance to blood flow are necessary for successful shunt function. Although some perioperative coagulation values were significantly reduced in infants who were destined to experience shunt occlusion, they would be difficult to detect clinically. PMID- 23673077 TI - Two surgeons, one patient: the impact of surgeon-surgeon familiarity on patient outcomes following mastectomy with immediate reconstruction. AB - BACKGROUND: Mastectomy with immediate reconstruction requires the coordination and expertise of two distinct surgeons. This often results in several different combinations of mastectomy and reconstructive surgeons, but with an unknown impact on patient outcomes. We evaluate the effect of different surgical teams on complication rates following mastectomy and immediate reconstruction. METHODS: Retrospective review of consecutive patients that underwent mastectomy with immediate prosthetic reconstruction from 4/1998 to 10/2008 at one institution was performed. Patients of the three highest-volume mastectomy and reconstructive surgeons were stratified by their individual combination of surgeons, resulting in nine different surgical teams. Complications were categorized by end-outcome. Appropriate statistics, including multiple linear regression, were performed. RESULTS: Clinical characteristics were similar among patients (n = 511 patients, 699 breasts) with the same mastectomy surgeon but different reconstructive surgeon. Mean follow-up was 38.4 +/- 25.7 months. For each mastectomy surgeon, the choice of reconstructive surgeon did not affect complication rates. Furthermore, the combined complication rates of the three highest-volume teams (n = 384 breasts) were similar to the remaining lower-volume teams (n = 315 breasts). Patient factors, but not the individual surgeon or surgical team, were independent risk factors for complications. DISCUSSION: Our study suggests that among high-volume surgeons, complication rates following mastectomy with immediate reconstruction are not affected by the surgeon-surgeon familiarity. The individual surgeon's expertise, and patient risk factors, may have a greater impact on outcomes than the team's experience with each other. These results validate the efficacy and safety of the surgeon distribution model currently used by many breast surgery practices. PMID- 23673078 TI - Radioactive seed localisation (RSL) in the treatment of non-palpable breast cancers: systematic review and meta-analysis. AB - INTRODUCTION: This systematic review compares the outcomes of radioactive seed localisation (RSL) versus standard wire-guided localisation (WGL) in the management of non-palpable breast cancers. METHODS: We performed a literature search of PubMed, EMBASE and the Cochrane database to identify clinical studies using RSL. Included studies examined invasive breast cancer and reported objective pathological outcome measurements. Quantitative data analyses were performed. RESULTS: 197 papers were identified with eight being clinically relevant to our study. From these eight studies there was only one identified as being a randomised controlled trial (RCT) and four as cohort studies having a control WGL group and included in the quantitative analysis. This provided an overall combined odds ratio (OR) 0.51 (95% CI, 0.36-0.72; z = 3.88; p = 0.0001) for involved surgical margin status; OR, 0.47 (95% CI, 0.33-0.69; z = 3.96; p < 0.0001) for re-operation rates and mean difference (MD) -1.32 (95% CI, -2.32, 0.32; z = 2.58; p = 0.01) for operative time favouring RSL over WGL. In the case of volume of specimens excised, MD 1.46; (95% CI, -22.35, 25.26; z = 0.12; p = 0.90) showing no statistical significance for volume of tissue excised in specimens between the two groups. CONCLUSIONS: The results of this systematic review demonstrate a statistically significant benefit of RSL over the gold standard of WGL in terms of involved margin status, re-operation rates and reduced operative time but no statistically significant difference with WGL in terms of volume of tissue excised in the treatment of non-palpable breast cancers. Adequately powered, multicentre RCTs are needed to validate these results. PMID- 23673079 TI - Microbial genomics: an increasingly revealing interface in human health and disease. PMID- 23673080 TI - BEBE(tr) and BUBI: J-compensated concurrent shaped pulses for 1H-13C experiments. AB - Shaped pulses designed for broadband excitation, inversion and refocusing are important tools in modern NMR spectroscopy to achieve robust pulse sequences especially in heteronuclear correlation experiments. A large variety of mostly computer-optimized pulse shapes exist for different desired bandwidths, available rf-field strengths, and tolerance to B1-inhomogeneity. They are usually derived for a single spin 1/2, neglecting evolution due to J-couplings. While pulses with constant resulting phase are selfcompensated for heteronuclear coupling evolution as long as they are applied exclusively on a single nucleus, the situation changes for concurrently applied pulse shapes. Using the example of a (1)H,(13)C two spin system, two J-compensated pulse pairs for the application in INEPT-type transfer elements were optimized: a point-to-point pulse sandwich called BEBE(tr), consisting of a broadband excitation and time-reversed excitation pulse, and a combined universal rotation and point-to-point pulse pair called BUBI, which acts as a refocusing pulse on (1)H and a corresponding inversion pulse on (13)C. After a derivation of quality factors and optimization protocols, a theoretical and experimental comparison with conventionally derived BEBOP, BIBOP, and BURBOP-180 degrees pulses is given. While the overall transfer efficiency of a single pulse pair is only reduced by approximately 0.1%, resulting transfer to undesired coherences is reduced by several percent. In experiments this can lead to undesired phase distortions for pairs of uncompensated pulse shapes and even differences in signal intensities of 5-10% in HSQC and up to 68% in more complex COB-HSQC experiments. PMID- 23673081 TI - Cloning-independent plasmid construction for genetic studies in streptococci. AB - Shuttle plasmids are among the few routinely utilized tools in the Streptococcus mutans genetic system that still require the use of classical cloning methodologies and intermediate hosts for genetic manipulation. Accordingly, it typically requires considerably less time and effort to introduce mutations onto the S. mutans chromosome than it does to construct shuttle vectors for expressing genes in trans. Occasionally, shuttle vector constructs also exhibit toxicity in Escherichia coli, which prevents their proper assembly. To circumvent these limitations, we modified a prolonged overlap extension PCR (POE-PCR) protocol to facilitate direct plasmid assembly in S. mutans. Using solely PCR, we created the reporter vector pZX7, which contains a single minimal streptococcal replication origin and harbors a spectinomycin resistance cassette and the gusA gene encoding beta-glucuronidase. We compared the efficiency of pZX7 assembly using multiple strains of S. mutans and were able to obtain from 5 * 103 to 2 * 105 CFU/MUg PCR product. Likewise, we used pZX7 to further demonstrate that Streptococcus sanguinis and Streptococcus gordonii are also excellent hosts for cloning independent plasmid assembly, which suggests that this system is likely to function in numerous other streptococci. Consequently, it should be possible to completely forgo the use of E. coli-Streptococcus shuttle vectors in many streptococcal species, thereby decreasing the time and effort required to assemble constructs and eliminating any toxicity issues associated with intermediate hosts. PMID- 23673082 TI - Prevalence of tracheobronchomalacia and excessive dynamic airway collapse in bronchial asthma of different severity. AB - BACKGROUND: Tracheobronchomalacia (TBM) is a pathologic condition in which softening of tracheal and bronchial cartilage causes the dynamic narrowing of transverse or sagittal diameters of tracheobronchial lumen; an excessive dynamic airway collapse (EDAC) may also be associated, with a substantial invagination of the posterior membrane of trachebronchial tree.The aim of this study was to assess the prevalence of both TBM and EDAC in a population of asthmatics with different degrees of disease severity compared to a reference group of subjects without any bronchial obstruction. METHODS: A cohort of 202 asthmatics was investigated by means of a dynamic flexible videobronchoscopy: 74 mild persistent (MPA - age 18-68 ys; 35 males; mean FEV1 = 88.6% pred. +/- 8.3 sd); 63 moderate (MA - age 21-71 ys; 30 males; mean FEV1 = 71.3% pred. +/- 9.1 sd), 65 severe asthmatics (SA - age 33-70 ys; 25 males; mean FEV1 = 48.5% pred. +/- 7.6 sd), and 62 non obstructed subjects (NO - age 18-71 ys; 38 males; mean FEV1 98.6% pred. +/ 2.7 sd). TBM and EDAC were classified according to FEMOS classification. RESULTS: TBM and EDAC were observed in only 1/62 subjects (both 1.61%) of NO group, while their prevalence was 2.70% and 6.75% in MPA group; 7.93% and 19.04% in MA group; 18.46% and 69.23% in SA group, respectively. The crude prevalence of thyroid disorders in the population was 12.9%. In particular, the prevalence of thyroid disorders was significantly higher in females than in men, but 54-fold higher in females than in men in the presence of EDAC. CONCLUSIONS: 1) The prevalence of both TBM and EDAC is directly related to age, gender (females), and asthma severity; 2) EDAC is much more frequent than TBM in all asthma patients; 3) both tracheal abnormalities proved to be more represented in asthmatics with thyroid disorders, and particularly in female asthmatics with EDAC. PMID- 23673083 TI - Effects of testicular interstitial fluid on the proliferation of the mouse spermatogonial stem cells in vitro. AB - Spermatogenesis is a process in adult male mammals supported by spermatogonial stem cells (SSCs). The cultivation of SSCs has potential value, for example for the treatment of male infertility or spermatogonial transplantation. Testicular interstitial fluid was added to culture medium to a final concentration of 5, 10, 20, 30 or 40%, in order to investigate its effects on proliferation of mouse SSCs in vitro, Alkaline phosphatase (AKP) assay, reverse transcription polymerase chain reaction (RT-PCR) analysis and indirect immunofluorescence of cells were performed to identify SSCs, and the proliferation rate and diameters of the SSCs colonies were measured. The results showed that the optimal addition of testicular interstitial fluid to culture medium was 30%. When medium supplemented with 30% testicular interstitial fluid was used to culture mouse SSCs, the optimum proliferation rate and diameter of the cell colonies were 72.53% and 249 MUm, respectively, after 8 days in culture, values that were significant higher than those found for other groups (P < 0.05). In conclusion, proliferation of mouse SSCs could be promoted significantly by supplementation of the culture medium with 30% testicular interstitial fluid. More research is needed to evaluate and understand the precise physiological role of testicular interstitial fluid during cultivation of SSCs. PMID- 23673085 TI - rTMS for pharmacoresistant major depression in the clinical setting of a psychiatric hospital: effectiveness and effects of age. AB - BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method of brain stimulation used in the treatment of drug-resistant major depressive disorder (MDD). It has been suggested that the efficacy of rTMS decreases with the age of the patient, but the data are contradictory. Here, we analyze in our clinical setting the efficacy of a 3-week rTMS treatment in drug resistant MDD during a 3 month period and the potential influence of age on this efficacy. METHODS: Stimulation consisted of 15 sessions of rTMS over the dorsolateral prefrontal cortex. Clinical evaluations included the Hamilton Depression Rating Scale (HDRS), and the Beck Depression Inventory (BDI) at baseline, after 3 weeks of treatment, and 1 month and 3 months after the last session. RESULTS: Data from 93 patients issued from the 178 patients active file were analyzed. The antidepressant effect observed in the two age groups (<65 and >=65) did not differ at the end of the treatment and 3 months later, with a comparable number of responders (50% decrease in HDRS score from baseline) (53.3% for age <65 versus 46.7% for age >=65, p=0.51). The treatment had a significant effect over time. We found no evidence of the age affecting outcome at 3 months after the last session. LIMITATIONS: Previous antidepressant treatments, and therapeutic drug use modifications after rTMS treatment, degree of pharmaco resistance or duration of current episode are not reported. CONCLUSION: RTMS of the DFPLC is effective as an add-on treatment for cases of pharmacologically refractory major depression, independent of the patient age. PMID- 23673086 TI - Aerobic biotransformation of N-nitrosodimethylamine and N-nitrodimethylamine in methane and benzene amended soil columns. AB - Aerobic biotransformation of N-nitrosodimethylamine (NDMA), an emerging contaminant of concern, and its structural analog N-nitrodimethylamine (DMN), was evaluated in benzene and methane amended groundwater passed through laboratory scale soil columns. Competitive inhibition models were used to model the kinetics for NDMA and DMN cometabolism accounting for the concurrent degradation of the growth and cometabolic substrates. Transformation capacities for NDMA and DMN with benzene (13 and 23MUg (mgcells)(-1)) and methane (0.14 and 8.4MUg (mgcells)( 1)) grown cultures, respectively are comparable to those presented in the literature, as were first order endogenous decay rates estimated to be 2.1*10( 2)+/-1.7*10(-3)d(-1) and 6.5*10(-1)+/-7.1*10(-1)d(-1) for the methane and benzene amended cultures, respectively. These studies highlight possible attenuation mechanisms and rates for NDMA and DMN biotransformation in aerobic aquifers undergoing active remediation, natural attenuation or managed aquifer recharge with treated wastewater (i.e., reclaimed water). PMID- 23673084 TI - Monitoring neurodegeneration in diabetes using adult neural stem cells derived from the olfactory bulb. AB - INTRODUCTION: Neurons have the intrinsic capacity to produce insulin, similar to pancreatic cells. Adult neural stem cells (NSCs), which give rise to functional neurons, can be established and cultured not only by intracerebral collection, which requires difficult surgery, but also by collection from the olfactory bulb (OB), which is relatively easy. Adult neurogenesis in the hippocampus (HPC) is significantly decreased in diabetes patients. As a result, learning and memory functions, for which the HPC is responsible, decrease. METHODS: In the present study, we compared the effect of diabetes on neurogenesis and insulin expression in adult NSCs. Adult NSCs were derived from the HPC or OB of streptozotocin induced diabetic rats. Comparative gene-expression analyses were carried out by using extracted tissues and established adult NSC cultures from the HPC or OB in diabetic rats. RESULTS: Diabetes progression influenced important genes that were required for insulin expression in both OB- and HPC-derived cells. Additionally, we found that the expression levels of several genes, such as voltage-gated sodium channels, glutamate transporters, and glutamate receptors, were significantly different in OB and HPC cells collected from diabetic rats. CONCLUSIONS: By using identified diabetes-response genes, OB NSCs from diabetes patients can be used during diabetes progression to monitor processes that cause neurodegeneration in the central nervous system (CNS). Because hippocampal NSCs and OB NSCs exhibited similar gene-expression profiles during diabetes progression, OB NSCs, which are more easily collected and established than HPC NSCs, may potentially be used for screening of effective drugs for neurodegenerative disorders that cause malignant damage to CNS functions. PMID- 23673087 TI - Evaluating the effects of variable water chemistry on bacterial transport during infiltration. AB - Bacterial infiltration through the subsurface has been studied experimentally under different conditions of interest and is dependent on a variety of physical, chemical and biological factors. However, most bacterial transport studies fail to adequately represent the complex processes occurring in natural systems. Bacteria are frequently detected in stormwater runoff, and may present risk of microbial contamination during stormwater recharge into groundwater. Mixing of stormwater runoff with groundwater during infiltration results in changes in local solution chemistry, which may lead to changes in both bacterial and collector surface properties and subsequent bacterial attachment rates. This study focuses on quantifying changes in bacterial transport behavior under variable solution chemistry, and on comparing the influences of chemical variability and physical variability on bacterial attachment rates. Bacterial attachment rate at the soil-water interface was predicted analytically using a combined rate equation, which varies temporally and spatially with respect to changes in solution chemistry. Two-phase Monte Carlo analysis was conducted and an overall input-output correlation coefficient was calculated to quantitatively describe the importance of physiochemical variation on the estimates of attachment rate. Among physical variables, soil particle size has the highest correlation coefficient, followed by porosity of the soil media, bacterial size and flow velocity. Among chemical variables, ionic strength has the highest correlation coefficient. A semi-reactive microbial transport model was developed within HP1 (HYDRUS1D-PHREEQC) and applied to column transport experiments with constant and variable solution chemistries. Bacterial attachment rates varied from 9.10*10(-3)min(-1) to 3.71*10(-3)min(-1) due to mixing of synthetic stormwater (SSW) with artificial groundwater (AGW), while bacterial attachment remained constant at 9.10*10(-3)min(-1) in a constant solution chemistry (AGW only). The model matched observed bacterial breakthrough curves well. Although limitations exist in the application of a semi-reactive microbial transport model, this method represents one step towards a more realistic model of bacterial transport in complex microbial-water-soil systems. PMID- 23673089 TI - The Surviving Sepsis Campaign: 2013 and beyond. PMID- 23673088 TI - Differences in kinetic asymmetry between injured and noninjured novice runners: a prospective cohort study. AB - PURPOSE: The purpose of this prospective study was to describe natural levels of asymmetry in running, compare levels of asymmetry between injured and noninjured novice runners and compare kinetic variables between the injured and noninjured lower limb within the novice runners with an injury. METHODS: At baseline vertical ground reaction forces and symmetry angles (SA) were assessed with an instrumented treadmill equipped with three force measuring transducers. Female participants ran at 8 and 9 km h(-1) and male runners ran at 9 and 10 km h(-1). Participants were novice female and male recreational runners and were followed during a 9-week running program. RESULTS: Two hundred and ten novice runners enrolled this study, 133 (63.3%) female and 77 (36.7%) male runners. Thirty-four runners reported an RRI. At baseline SA values varied widely for all spatio temporal and kinetic variables. The inter-individual differences in SA were also high. No significant differences in SA were found between female and male runners running at 9 km h(-1). In injured runners the SA of the impact peak was significantly lower compared to noninjured runners. CONCLUSIONS: Natural levels of asymmetry in running were high. The SA of impact peak in injured runners was lower compared to noninjured runners and no differences were seen between the injured and noninjured lower limbs. PMID- 23673090 TI - Critical care medicine in China: history and perspective. PMID- 23673091 TI - Body temperature control in patients with refractory septic shock: too much may be harmful. AB - BACKGROUND: The lowering of body temperature is a common, almost reflexive step in the daily care of septic shock patient. However, the effect of different magnitudes of fever control on the outcome of refractory septic patients with a very poor outcome is controversial and has yet to be explored. METHODS: This prospective trial examined sixty-five refractory septic shock patients with a core temperature higher than 38.5 degrees C. Patients were randomly assigned to a group achieving a "low temperature" range (LT group: 36.0 - 37.5 degrees C) or to a group achieving a "high temperature" range (HT group: 37.5 - 38.3 degrees C) by physical methods including a water-flow cooling blanket and ice packs. A target core temperature was achieved in 1 - 2 hours post-treatment, and maintained for 72 hours. Averaged values of core temperature as well as hemodynamic, respiratory, and laboratory variables were analyzed at baseline and during the first 72 hours after fever control. RESULTS: Thirty-four (52.31%) patients were assigned to the LT group and thirty-one (47.69%) patients were assigned to the HT group. The mean core temperature was significantly lower in the LT group than in the HT group (36.61 vs. 37.85 degrees C, respectively; P < 0.0001). The average heart rate (HR) (75.5 vs. 91.9 beats/min, respectively; P < 0.0001) and the mean cardiac output (CO) (5.35 vs. 6.45 L/min, respectively; P = 0.002) were also statistically significant lower in the LT group than in the HT group. The averaged serum lactate level was significantly higher in the LT group compared to the HT group (5.59 vs. 2.82 mmol/L, respectively; P = 0.008). Fibrinogen and activated partial thromboplatin time were also different between the two groups. The 28 days mortality was significantly higher in the LT group than in the HT group (61.8 vs. 25.8%, respectively; P = 0.003). A Cox-regression model analysis showed that mean core temperature during the 72 h period was an independent predictor of 28 days mortality (odds ratio (OR) = 0.42, 95%CI 0.25, 0.6; P = 0.001). CONCLUSION: Controlling fever to a lower range (36.0 - 37.5 degrees C) may be harmful to patients with refractory septic shock by worsening tissue perfusion, compared to controlling it within a higher range (37.5 - 38.3 degrees C). An understanding of the mechanisms responsible for these observations requires further investigation. PMID- 23673092 TI - Computer-driven automated weaning reduces weaning duration in difficult-to-wean patients. AB - BACKGROUND: Weaning difficulties occur in 31% of total intubated patients, and result in prolonged weaning duration. A computer-driven automated weaning system can perform a spontaneous breathing trial (SBT) automatically and display a message when the trial is successfully passed. Such a system might have a beneficial effect on difficult-to-wean patients. The aim of this study was to examine whether the computer-driven automated weaning system can accelerate discontinuation of mechanical ventilation and improve outcomes in difficult-to wean patients. METHODS: This randomized controlled study included 39 difficult-to wean patients who failed their first spontaneous breathing trial. Before initiating weaning, eligible patients were randomly allocated to wean by computer driven automated weaning system (CDW group, n = 19) or a physician-controlled local protocol (PW group, n = 20). Weaning duration, defined as the time from inclusion until first extubation, was the primary endpoint. Secondary endpoints were total duration of mechanical ventilation, the length of intensive care unit (ICU) stay, the number of reintubations, the mortality rate in the ICU, the number of noninvasive ventilations, the number of complications in the ICU, and the number of ventilator-associated pneumonia cases. RESULTS: The weaning duration was reduced with the computer-driven weaning as compared with the usual protocol (median 29.0 hours vs. 45.5 hours, P = 0.044). Total duration of mechanical ventilation and duration of the ICU stay did not differ between the CDW and PW groups. There was no difference in the number of reintubations between the CDW and PW groups (3 and 4 patients, P = 0.732). The study groups showed comparable numbers of tracheostomy, self-extubations, ventilator-associated pneumonia, and non-invasive ventilation. Mortality in the ICU was similar in the CDW and the PW groups (21.1% vs. 20.0%, P = 0.935). CONCLUSION: The computer driven automated weaning system can reduce weaning duration in difficult-to-wean patients as compared with a physician-controlled weaning protocol. PMID- 23673093 TI - Implementing surviving sepsis campaign bundles in China: a prospective cohort study. AB - BACKGROUND: Surviving sepsis campaign (SSC) bundles have been demonstrated to significantly improve survival in sepsis and septic shock patients worldwide. Compliance with these protocols and resultant mortality in sepsis patients was investigated in intensive care units (ICUs) in China. METHODS: Adult patients with severe sepsis or septic shock treated from September 2007 to October 2008 in 11 ICUs of Chinese teaching hospitals were included. The primary outcome was compliance with resuscitation and management bundles. Secondary outcomes included individual bundle protocol impact and the effects of the completed bundle protocol number on 28-day mortality. RESULTS: Overall compliance during 6-hr resuscitation and 24-hour management bundles were 5.5% and 17.4%, respectively, and 28-day mortality was 33.0%. Compliance with protocols for blood cultures before antibiotics (42.2%), central venous pressure >= 8 mmHg (65.9%), central venous oxygen saturation >= 70% (25.0%), and optimized glucose control (82.1%), were significantly associated with decreased 28-day mortality (P < 0.05). When adjusted for age, acute organ dysfunction, and APACHE II score, compliance with the blood culture before antibiotics protocol produced the most significant decrease in 28-day mortality (OR, 0.33; 95%CI, 0.16 - 0.70; P = 0.004). Compliance with >= 5 protocols in the 6-hour resuscitation bundle was also associated with lower 28-day mortality in septic shock patients (OR, 0.17; 95%CI, 0.06 - 0.54; P = 0.001). CONCLUSIONS: Compliance with resuscitation and management bundles is generally poor in China; however, when applied, 6-hour resuscitation bundle are associated with significant reductions in 28-day mortality for sepsis patients. PMID- 23673094 TI - Sources of multidrug-resistant Acinetobacter baumannii and its role in respiratory tract colonization and nosocomial pneumonia in intensive care unit patients. AB - BACKGROUND: Multidrug-resistant Acinetobacter baumannii (MDRAB) is an important and emerging hospital-acquired pathogen worldwide. This study was conducted to identify the sources of MDRAB and its role in respiratory tract colonization and nosocomial pneumonia in intensive care unit (ICU) patients. METHODS: We conducted a prospective active surveillance study of MDRAB in three ICUs at a Chinese Hospital from April to August 2011, to identify the sources of MDRAB and its role in respiratory tract colonization and nosocomial pneumonia. RESULTS: One hundred and fourteen (13.0%) MDRAB isolates were detected from 876 specimens, with a sensitivity of 11.6% (55/474) in screening of the pharyngeal and tracheal swabs, and 14.7% (59/402) of the sputum/endotracheal aspirates. MDRAB colonization/infection was found in 34 (26.8%) of 127 patients, including 16 (12.6%) cases of pure colonization and 18 (14.2%) cases of pneumonia (two pre-ICU acquired cases of pneumonia and 16 ICU-acquired cases of pneumonia). Previous respiratory tract MDRAB colonization was found in 22 (17.3%) patients: eight (6.3%) were pre-ICU-acquired colonization and 14 (11.0%) ICU-acquired colonization. Of eight pre-ICU-colonized patients, five were transferred from other wards or hospitals with hospitalization > 72 hours, and three came from the community with no previous hospitalization. Overall, 6/22 colonized patients presented with secondary pneumonia; only two (9.1%) colonized MDRAB strains were associated with secondary infections. Respiratory tract MDRAB colonization had no significant relationship with nosocomial pneumonia (P = 0.725). In addition, acute respiratory failure, mechanical ventilation, renal failure, and prior carbapenem use were risk factors for MDRAB colonization/infection. CONCLUSIONS: A high proportion of cases of MDRAB colonization/infection in ICU patients were detected through screening cultures. About one-third were acquired from general wards and the community before ICU admission. The low incidence of MDRAB colonization-related pneumonia questions the appropriateness of targeted antibiotic therapy. PMID- 23673095 TI - Early changes of procalcitonin predict bacteremia in patients with intensive care unit-acquired new fever. AB - BACKGROUND: Rapid detection of bacteremia is important for critically ill patients. Procalcitonin (PCT) has emerged as a marker of sepsis, but its characterization for predicting bacteremia is still unclear. This study aimed to investigate the role of change of PCT within 6 to 12 hours after new fever in predicting bacteremia. METHODS: An observational study was conducted in the ICU of our hospital from January 2009 to March 2010. Adult patients with new fever were included and grouped as bacteremia and non bacteremia group. Serum PCT concentration was measured at admission and within 6 to 12 hours after new fever (designated PCT0 and PCT1). Other results of laboratory tests and therapeutic interventions were recorded. Multivariate Logistic regression analysis was used to identify the risk factors of bacteremia. The area under the ROC curve (AUC) was constructed to evaluate the discriminative power of variables to predict bacteremia. RESULTS: Totally 106 patients were enrolled, 60 of whom had bacteremia and 46 did not have bacteremia,. The acute physiology and chronic health evaluation II (APACHE II) and sequential organ failure assessment (SOFA) scores were 13.1 +/- 7.8 and 5.0 +/- 2.2 at admission, respectively. There was no significant difference in PCT0 between the bacteremia group and nonbacteremia group; 1.27 ug/L (range, 0.10 - 33.3) vs. 0.98 ug/L (range, 0.08 - 25.7), (P = 0.157). However, the PCT1 and the rate of change of PCT were significantly higher in bacteremia group; PCT1 was 6.73 ug/L (1.13 - 120.10) vs. 1.17 ug/L (0.10 - 12.10) (P = 0.001), and the rate of change was 5.62 times (1.05 - 120.6) vs. 0.07 times (-0.03 - 0.18) (P < 0.001). The area under the ROC curve (AUC; 95% confidence interval) of the rate of change of PCT was better for predicting bacteremia than that of PCT1; 0.864 (range, 0.801 - 0.927) vs. 0.715 (range, 0.628 - 0.801), (P < 0.05). The AUCs of PCT0 and other parameters (such as WBC count, granulocyte percentage and temperature) were not significantly different (all P > 0.05). The best cut-off value for the rate of change was 3.54 times, with a sensitivity of 88.5% and a specificity of 98.0%. It was also an independent predictor of bacteremia (odds ratio 29.7, P < 0.0001) and wasn't correlated with the presence or absence of co-infection, neutropenia or immunodeficiency (P > 0.05). CONCLUSION: The rate of change of PCT is useful for early detection of bacteremia during new fever and superior to the PCT absolute value and other parameters in non-selected ICU patients. PMID- 23673096 TI - Responsiveness of stroke volume variation and central venous pressure during acute normovolemic and hypervolemic hemodilution. AB - BACKGROUND: Stroke volume variation (SVV) is a robust indicator of fluid responsiveness during volume change. We compared the sensibility of SVV by Vigileo/Flotrac to central venous pressure (CVP) when volume changes in patients undergoing intraoperative acute normovolemic hemodilution (ANH) and acute hypervolemic hemodilution (AHH). METHODS: Forty patients were randomly divided into an ANH group (n = 20) and an AHH group (n = 20). All patients received general anesthesia and were mechanically ventilated. Data were collected from 7 different time-points in the ANH group: baseline, after withdrawal of 5%, 10%, and 15% of the estimated blood volume (EBV) and after replacement with an equal volume of 6% hydroxyethyl starch 130/0.4 (HES) in 5% EBV increments to baseline. There were four time points in the AHH group: baseline, after 5%, 10%, and 15% expansion of the EBV with 6% HES. At each time-point, CVP, SVV and other hemodynamic parameters measurements were obtained. RESULTS: After removal of 10% and 15% EBV, SVV significantly increased from 10.9 +/- 3.0 to 14.1 +/- 3.4 and 10.9 +/- 3.0 to 16.0 +/- 3.3 (P < 0.01), and returned to a final value of 10.6 +/ 3.4 after volume replacement. The CVP value was unchanged after removal and replacement of 15% of the EBV. There were no significant changes in SVV after 5%, 10% whereas there was a significant reduction after 15% (8.2 +/- 1.7) expansion of the EBV compared with baseline (9.9 +/- 1.8) (P = 0.033). However, there was a significant increase in CVP after 10% (10.3 +/- 2.4), 15% (11.3 +/- 2.2) expansion of the EBV compared with baseline (8.2 +/- 2.7) (P < 0.01). CONCLUSION: SVV is a more sensitive parameter for volume than CVP during hypovolemia, on the contrary CVP is more sensitive than SVV during hypervolemia. PMID- 23673097 TI - Assessment effect of central venous pressure in fluid resuscitation in the patients with shock: a multi-center retrospective research. AB - BACKGROUND: Central venous pressure (CVP) and intrathoracic blood volume index (ITBVI) were used to assess the fluid status. It has previously been shown that CVP is not as accurate as ITBVI for all the shock patients. We therefore hypothesized that the change of CVP has the ability to predict fluid responsiveness in some clinical cases of shock. METHODS: From September 1st 2009 to September 1st 2011, sixty-three patients with shock from different Intensive Care Unit (ICU) were collected into this retrospective study. All the patients received fluid challenge strategy (infusing 300 ml hydroxyethyl starch in 20 minutes), were monitored with CVP and pulse-indicated continuous cardiac output (PICCO). The correlation between changes in cardiac index (DeltaCI), CVP (DeltaCVP) and ITBVI (DeltaITBVI) were analyzed. Fluid responsiveness was defined as an increase in CI >= 10%. Receiver operating characteristic (ROC) curves were generated for DeltaCVP and DeltaITBVI. RESULTS: For all the patients, there was no correlation between DeltaCI and DeltaCVP (P = 0.073), but in the subgroup analysis, the correlation between DeltaCI and DeltaCVP was significant in those younger than 60 years old (P = 0.018) and those with hypovolemic shock (P = 0.001). The difference of areas under the ROC curves of DeltaCVP and DeltaITBVI were not statistically significant in the group younger than 60 years old or hypovolemic shock group (P > 0.05, respectively). However, no similar results can be found in the group older than 60 years old and the other two shock type groups from ROC curves of DeltaCVP and DeltaITBVI. CONCLUSIONS: DeltaCVP is not suitable for evaluating the volume status of the shock patients with fluid resuscitation regardless of their condition. However, in some ways, DeltaCVP have the ability to predict fluid responsiveness in the younger shock patients or in the hypovolemic shock patients. PMID- 23673098 TI - Impact of imipenem treatment on colonic mycobiota in rats with double-hit sepsis. AB - BACKGROUND: Broad-spectrum antibiotic administration promotes intestinal colonization of exogenous fungal pathogens in healthy animals and has been recognized as one of the risk factors of invasive fungal infection in clinical settings. It is unclear whether broad-spectrum antibiotic treatment would change the intestinal mycobiota without exogenous fungal challenge in the context of sepsis. METHODS: We established a rat model of double-hit sepsis using burn injury and endotoxin challenge. Rats with burn injury or double-hit sepsis received imipenem treatment for 3 days or 9 days, and their colon contents were sampled for selective fungal culture and isolation counts. RESULTS: Imipenem treatment promoted the overgrowth of the commensal fungus Geotrichum capitatum in rats with burn injury. Imipenem treatment also promoted colon colonization by exogenous fungi in rats with burn injury and double-hit sepsis, including Trichosporon cutaneum, Candida albicans, Candida krusei, and Candida glabrata. A longer duration of imipenem treatment had a stronger impact on colon colonization by exogenous fungi. CONCLUSION: Imipenem treatment facilitates the overgrowth of commensal fungi and colonization by exogenous, potentially pathogenic fungi in the colons of rats with burn injury or double-hit sepsis. PMID- 23673099 TI - Pretreatment with interleukin-33 reduces warm hepatic ischemia/reperfusion injury in mice. AB - BACKGROUND: Interleukin (IL)-33 is a recently identified member of the IL-1 family that binds to the receptor, ST2L. This study examined IL-33 production in mouse liver and investigated its role in hepatic ischemia/reperfusion (I/R) injury. METHODS: Male BALB/c mice ((22 +/- 3) g) were subjected to 90 minutes partial hepatic ischemia, followed by 6 hours reperfusion. First, mice were randomized into two groups: control group (laparotomy only, without blocking blood supply) and ischemia model group. IL-33 mRNA and serum protein levels were measured at 30, 60, 90 minutes after ischemia and 2 and 6 hours after reperfusion. Second, mice were randomized into four groups: control, model (injection of rabbit IgG polyclonal antibody), recombinant IL-33 intervention and anti-ST2L antibody intervention group. Mice were sacrificed 6 hours after reperfusion. Liver pathology was observed via transmission electron microscopy. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), IL-4, IL 5, IL-13, interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF alpha) levels were measured. RESULTS: Levels of IL-33 mRNA and protein did not change during ischemia (P > 0.05) but increased significantly during reperfusion (P < 0.05). After reperfusion for 6 hours, serum levels of ALT, AST, IL-4, IL-5, IL-13, IFN-gamma and TNF-alpha were significantly increased (P < 0.05), and hepatocellular ultrastructure was damaged. Pretreatment with IL-33 attenuated severity of liver damage compared with controls, but pretreatment with anti-ST2L antibody increased severity. Serum levels of IL-4, IL-5 and IL-13 protein increased whereas IFN-gamma decreased following IL-33 pretreatment. Pretreatment with anti-ST2L antibody significantly decreased serum IL-4, IL-5, IL-13 levels and increased serum IFN-gamma levels compared with controls (P < 0.05). There was no change in the level of TNF-alpha. CONCLUSION: IL-33 is produced systematically and locally in liver during I/R injury. Pretreatment with IL-33 is therapeutic for hepatic I/R injury, possibly via inducing a Th1 to Th2 shift. PMID- 23673100 TI - Role of mitochondrial damage during cardiac apoptosis in septic rats. AB - BACKGROUND: Myocardial apoptosis is involved in the pathogenesis of sepsis related myocardial depression. However, the underlying mechanism remains unknown. This study investigated the role of mitochondrial damage and mitochondria-induced oxidative stress during cardiac apoptosis in septic rats. METHODS: Seventy-two Sprague-Dawley rats were randomly divided into a control group and septic group receiving lipopolysaccharide injection. Heart tissue was removed and changes in cardiac morphology were observed by light microscopy and scanning electron microscopy. In situ apoptosis was examined using terminal transferase-mediated dUTP nick end-labeling assay and nuclear factor-kappa B activation in myocardium by Western blotting to estimate myocardial apoptosis. Appearance of mitochondrial cristae and activation of cytochrome C oxidase were used to evaluate mitochondrial damage. Oxidative stress was assessed by mitochondrial lipid and protein oxidation, and antioxidant defense was assessed by mitochondrial superoxide dismutase and glutathione peroxidase activity. RESULTS: Sepsis-induced inflammatory cell infiltration, myocardium degeneration and dropsy were time dependent. Expanded capillaries were observed in the hearts of infected rats 24 hours post-challenge. Compared with sham-treated rats, the percentage of cell apoptosis increased in a time-dependent manner in hearts from septic rats at 6 hours, 12 hours and 24 hours post-injection (P < 0.05). The expression of nuclear factor-kappa B p65 decreased gradually in the cytosol and increased in the nucleus during sepsis, indicating that septic challenge provoked the progressive activation of nuclear factor-kappa B. Mitochondrial cristae and activation of cytochrome C oxidase increased in a time-dependent manner. Both superoxide dismutase and glutathione peroxidase activities decreased, while mitochondrial lipid and protein oxidation increased between 6 and 24 hours after lipopolysaccharide challenge. CONCLUSIONS: Septic challenge induced myocardial apoptosis and mitochondrial damage. Furthermore, mitochondrial damage via alteration of defenses against reactive oxygen species might play an important role in myocardial apoptosis during sepsis. PMID- 23673101 TI - Etoricoxib versus indometacin in the treatment of Chinese patients with acute gouty arthritis: a randomized double-blind trial. AB - BACKGROUND: Acute gout is an intensely painful, inflammatory arthritis. Although the non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for this condition, the efficacy is based on only a few studies, particularly in China. We tried to assess the safety and efficacy of etoricoxib in the treatment of acute gouty arthritis in China. METHODS: A randomized, double-blind, active comparator study was conducted at 10 sites in China. Patients (n = 178; >= 18 years of age) with acute gouty attack (< 48 hours) were treated for 5 days with etoricoxib (120 mg/d; n = 89) or indometacin (75 mg twice daily; n = 89). The primary efficacy end point was self-assessed pain in the affected joint (0-4 point Likert scale) from days 2 - 5. Secondary end points included investigator assessments of tenderness and swelling, patient/ investigator global assessments of response to therapy, and patients discontinuing treatment. Safety was assessed by adverse events (AEs). RESULTS: Etoricoxib and indometacin had comparable primary and secondary end points. Mean change difference from baseline from days 2 - 5 was 0.03 (95% confidence interval (CI) -0.19 to 0.25; P = 0.6364), which fell within the prespecified comparative bounds of -0.5 to 0.5. No severe AEs were associated with etoricoxib use. Non-severe AEs were mainly digestive and general, and most (73.7%) were mild, although they caused withdrawal of two subjects in the etoricoxib group, due to bilateral renal calculi and uronephrosis of the left kidney (unrelated to etoricoxib) and fever and chills (potentially etoricoxib related). Overall, AEs were similar, although the absolute number of AEs in the etoricoxib group (n = 31) was less than the indometacin group (n = 34). CONCLUSIONS: Etoricoxib (120 mg once daily) is effective in treating acute gout, is generally safe and well-tolerated, and is comparable in efficacy to indometacin (75 mg twice daily). PMID- 23673102 TI - Cytogenetic and molecular aberrations of multiple myeloma patients: a single center study in Singapore. AB - BACKGROUND: Much is known about the cytogenetic lesions that characterize multiple myeloma (MM) patients from the USA, Europe, and East Asia. However, little has been published about the disease among Southeast Asians. The aim of this study was to determine the chromosomal abnormalities of MM patients in our Singapore population. METHODS: Forty-five newly-diagnosed, morphologically confirmed patients comprising 18 males and 27 females, aged 46 - 84 years (median 65 years) were investigated by karyotyping and fluorescence in situ hybridization (FISH). FISH employing standard panel probes and 1p36/1q21 and 6q21/15q22 probes was performed on diagnostic bone marrow samples. RESULTS: Thirty-four cases (75.6%) had karyotypic abnormalities. Including FISH, a total detection rate of 91.1% was attained. Numerical and complex structural aberrations were common to both hyperdiploid and non-hyperdiploid patients. Numerical gains of several recurring chromosomes were frequent among hyperdiploid patients while structural rearrangements of several chromosomes including 8q24.1 and 14q32 characterized non-hyperdiploid patients. With FISH, immunoglobulin heavy chain (IGH) gene rearrangements, especially fibroblast growth factor receptor 3 (FGFR3)/IGH and RB1 deletion/monosomy 13 were the most common abnormalities (43.4%). Amplification 1q21 was 10 times more frequent (42.5%) than del(1p36) and del(6q21). CONCLUSIONS: We have successfully reported the comprehensive cytogenetic profiling of a cohort of newly-diagnosed myeloma patients in our population. This study indicates that the genetic and cytogenetic abnormalities, and their frequencies, in our study group are generally similar to other populations. PMID- 23673103 TI - Clinical isolates of Mycobacterium abscessus in Guangzhou area most possibly from the environmental infection showed variable susceptibility. AB - BACKGROUND: Mycobacterium abscessus (M. abscessus) can cause a variety of human infections, involving the lung, skin and soft tissues, and is generally believed to be acquired from environmental sources. The aim of this study was to investigate the molecular diversity and antibiotic susceptibility of M. abscessus isolates as the basis for strategies to improve control and management of infection. METHODS: Seventy M. abscessus isolates from patients attending the Guangzhou Thoracic Hospital were identified from 2003 to 2005 by biochemical tests, gas chromatography, polymerase chain reaction (PCR)-restriction analysis (PRA) of heat shock protein gene hsp65, and sequencing of the quinolone resistance determining regions (QRDRs) of gyrA. Susceptibilities to six antibiotics were determined by micro-broth dilution. Isolates were genotyped using randomly amplified polymorphic DNA (RAPD) analysis. RESULTS: Most isolates (63/70; 90%) were susceptible to amikacin but rates of susceptibility to other antibiotics varied from moderate, clarithromycin (60%) and imipenem (43%), to low for ciprofloxacin and ofloxacin (3%), and 87% of isolates had intermediate susceptibility to cefoxitin. RAPD analysis showed that the 70 clinical isolates displayed 69 unique RAPD patterns. CONCLUSIONS: The high genetic diversity of isolates suggests that they are not transmitted from person to person but, presumably, are acquired independently from environmental sources. M. abscessus isolates displayed variable levels of susceptibility to all antibiotics tested, other than amikacin, indicating a need for routine susceptibility testing to guide treatment. PMID- 23673105 TI - Arterially transplanted mesenchymal stem cells in a mouse reversible unilateral ureteral obstruction model: in vivo bioluminescence imaging and effects on renal fibrosis. AB - BACKGROUND: Chronic kidney disease (CDK) is a worldwide health problem, but there is currently no effective treatment that can completely cure this disease. Recently, studies with mesenchymal stem cells (MSCs) on treating various renal diseases have shown breakthroughs. This study is to observe the homing features of MSCs transplanted via kidney artery and effects on renal fibrosis in a reversible unilateral ureteral obstruction (R-UUO) model. METHODS: Thirty-six Balb/c mice were divided into UUO group, UUO-MSC group, and sham group randomly, with 12 mice in each group. The MSCs had been infected by a lentiviral vector to express stably the luciferase reporter gene and green fluorescence protein genes (Luc-GFP-MSC). Homing of MSCs was tracked using in vivo imaging system (IVIS) 1, 3, 14, and 28 days after transplantation. Imaging results were verified by detecting GFP expression in frozen section under a fluorescence microscope. E cadherin, alpha-SMA, TGF-beta1, and TNF-alpha mRNA expression in all groups at 1 and 4 weeks after transplantation were analyzed by quantitative PCR. RESULTS: Transplanted Luc-GFP-MSCs showed increased Luciferase expression 3 days after transplantation. The expression decreased from 7 days, weakened thereafter and could not be detected 14 days after transplantation. Quantitative PCR results showed that all gene expressions in UUO group and UUO-MSC group at 1 week had no statistical difference, while at 4 weeks, except TGF-beta expression (P > 0.05), the expression of E-cadherin, alpha-SMA, and TNF-alpha in the above two groups have statistical difference (P < 0.01). CONCLUSION: IVIS enables fast, noninvasive, and intuitive tracking of MSC homing in vivo. MSCs can be taken home to kidney tissues of the diseased side in R-UUO model, and renal interstitial fibrosis can be improved as well. PMID- 23673104 TI - Propofol may protect PC12 cells from beta-amyloid25-35 induced apoptosis through the GSK-3beta signaling pathway. AB - BACKGROUND: There are two major pathological hallmarks of Alzheimer's disease. One is the progressive accumulation of beta-amyloid (Abeta) in the form of senile plaques; the other is hyperphosphorylated tau, causing neuronal apoptosis. Some inhalation anesthetics, such as isoflurane and desflurane, have been suggested to induce Abeta accumulation and cause AD-like neuropathogenesis. Whether intravenous anesthetics have similar effects is still unclear. We therefore set out to determine the relationship between propofol and AD-like pathogenesis. METHODS: PC12 cells were cultured in serum-free medium for 12 hours prior to drug treatment. Various concentrations from 5 umol/L to 80 umol/L of aggregated Abeta25-35 were added to determine a proper concentration for further study. After exposure to 10 umol/L Abeta25-35 alone or with 20 umol/L propofol for 6 hours, PC12 cell viability was determined by MTT assay. Western blotting and immunocytochemical staining were performed to observe the protein expression of the Bcl-2 family, tau phosphorylation at different sites, and tau protein kinases and phosphatases. RESULTS: Abeta25-35 induced a decrease in PC12 cell viability in a dose-dependent manner. Exposure to 10 umol/L Abeta25-35 for 6 hours resulted in the mild cell survival, accompanied by a decline in Bcl-2, and an increase in phosphorylation of GSK-3beta and tau at different sites. Compared with the Abeta25-35 group, cells treated with propofol alone showed no significant difference, while cells co-incubated with propofol and Abeta25-35 showed a significantly higher survival rate (P < 0.01 or P < 0.05). Tau phosphorylation at Ser396, Ser404 and Thr231 and the level of GSK-3beta in PC12 cells increased after exposure to 10 umol/L Abeta25-35. Co-incubation with propofol attenuated cellular apoptosis by inhibiting tau phosphorylation. CONCLUSIONS: These data indicate that propofol may protect PC12 cells from Abeta25-35-induced apoptosis and tau hyperphosphorylation through the GSK-3beta pathway, therefore it may be a safer anesthesia for AD and elderly patients. PMID- 23673106 TI - Effects of Bailing capsules for renal transplant recipients: a retrospective clinical study. AB - BACKGROUND: The administration of immunosuppressive agents is always an important factor affecting the long-term survival of organ transplantation recipients. The best therapeutic regimen which either decreases the side effects of immune inhibitors or enhances the immunosuppressive efficacy is the goal of transplantation surgeons continue to search. This study investigated the effects of Bailing (Cordyceps sinensis) capsules on renal function and other systems of the body after renal transplantation. METHODS: Clinical data of 80 renal transplant recipients who were administered Bailing capsules and 100 renal transplant recipients in the control group were retrospectively analyzed to compare the incidences of graft rejection and infection after transplantation. The results of routine blood and urine tests, liver and kidney functions, uric acid (UA), 24-hour urine protein (24 h-Upro), as well as 1- and 5-year patient renal allograft survival rates were compared between the two groups. RESULTS: The follow-up was 3 - 5 years. The two groups were not shown to have statistically significant differences in age, gender, cold ischemia time, donor-recipient human leukocyte antigen typing, panel reactive antibodies, lymphocytotoxicity tests, and the application of immunosuppressive agents at the baseline. The two groups were also not significantly different in the incidence of acute injection after transplantation, recovery of renal function, and blood glucose level. The Bailing group was significantly lower than the control in the incidence of infection, serum aspartate aminotransferase/alanine aminotransferase, total bilirubin, UA, and 24-hour Upro, but significantly higher than the control group in peripheral red blood cell count and white blood cell count (P < 0.05). One-year and 5-year patient survival rates were 98.7% and 98.0%, respectively in the Bailing group, 95.0% and 93.0%, respectively, in the control group. One-year and 5-year renal allograft survival rates were 97.5% and 95.0%, respectively, in the Bailing group, and 92.5% and 84.0%, respectively, in the control group. The comparison of patient and renal allograft survival rates between the two groups using Kaplan Meier survival curves and log-rank test showed that only the differences in renal allograft survival rates were statistically significant (Log-rank: 5 years: patient survival P = 0.420; renal allograft survival P = 0.049). CONCLUSION: Bailing capsules were effective in preventing allograft rejection, protecting liver and kidney functions, stimulating hematopoiesis, and reducing the incidence of infection and thus are ideal immunoregulators. PMID- 23673107 TI - Tenidap is neuroprotective in a pilocarpine rat model of temporal lobe epilepsy. AB - BACKGROUND: Tenidap is a liposoluble non-steroidal anti-inflammatory drug that is easily distributed in the central nervous system and also inhibits the production and activity of cyclooxygenase-2 (COX-2) and cytokines in vitro. This study aimed to evaluate the neuroprotective effect of tenidap in a pilocarpine rat model of temporal lobe epilepsy (TLE). METHODS: Tenidap was administered daily at 10 mg/kg for 10 days following pilocarpine-induced status epilepticus (SE) in male Wistar rats after which prolonged generalized seizures resulted in TLE. After tenidap treatment, spontaneous recurrent seizures (SRSs) were recorded by video monitoring (for 7 hours per day for 14 days). The frequency and severity of the SRSs were observed. Histological and immunocytochemical analyses were used to evaluate the neuroprotective effect of tenidap and detect COX-2 expression, which may be associated with neuronal death. RESULTS: There were 46.88 +/- 10.70 survival neurons in tenidap-SE group, while there were 27.60 +/- 5.18 survival neurons in saline-SE group at -2.4 mm field in the CA3 area. There were 37.75 +/- 8.78 survival neurons in tenidap-SE group, while there were 33.40 +/- 8.14 survival neurons in saline-SE group at -2.4 mm field in the CA1 area. Tenidap treatment significantly reduced neuronal damage in the CA3 area (P < 0.05) and slightly reduced damage in the CA1 area. Tenidap markedly inhibited COX-2 expression in the hippocampus, especially in the CA3 area. CONCLUSION: Tenidap conferred neuroprotection to the CA3 area in a pilocarpine-induced rat model of TLE by inhibiting COX-2 expression. PMID- 23673109 TI - Poly (ADP-ribose) polymerase inhibitor reduces heart ischaemia/reperfusion injury via inflammation and Akt signalling in rats. AB - BACKGROUND: Poly (ADP-ribose) polymerase (PARP) has been proposed to play an important role in the pathogenesis of heart ischaemia/reperfusion (I/R) injury. 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone (DPQ), a potent PARP inhibitor, has cardiac protective effects. Because the underlying mechanisms are not understood, we investigated the effect of DPQ on heart I/R injury and its mechanisms. METHODS: Studies were performed with I/R rats' hearts. DPQ was used to inhibit the activation of PARP. Cardiac function and cellular apoptosis were assessed. The activation of PARP, transcription factor nuclear factor-kappaB (NF kappaB), intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9) were evaluated. We also evaluated expression of Akt and two of its downstream targets, glycogen synthase kinase-3beta (GSK 3beta) and forkhead transcription factor FOXO3a. RESULTS: Administration of DPQ significantly decreased the activation of PARP and cellular apoptosis from (35 +/ 5)% to (20 +/- 4)% and simultaneously improved the cardiac function. DPQ reduced the expressions of NF-kappaB, ICAM-1, COX-2 and MMP-9 in rat heart and facilitated the activations of phosphor-Akt, phosphor-GSK-3beta and phosphor FOXO3a. CONCLUSION: The protective effects of DPQ were associated with the suppression of inflammation and the activation of the Akt signalling pathways suggesting that the inhibition of poly (ADP-ribose) polymerase reduced heart I/R injury in rats. PMID- 23673108 TI - Oral everolimus inhibits intimal proliferation in injured carotid artery in rats. AB - BACKGROUND: Everolimus, a derivative of sirolimus, is a potent immunosuppressant that has important anti-proliferative properties. In the present study, we demonstrated the inhibiting neointimal hyperplasia in injured carotid arteries in rats by using two different doses of everolimus administrated via the oral route for a long time. METHODS: A rat model of carotid artery injury was established by balloon inflation. Eighty rats were randomly divided into the sham-operated group (n = 20), injury group (n = 20), low dosage of everolimus group (n = 20), and high dosage of everolimus group (n = 20). The low dose of everolimus (1.5 mg/kg) was given one day before injuring the carotid artery by balloon, followed by 0.75 mg/kg per day for 28 days via intragastric gavage. High dose everolimus (2.5 mg/kg) was given one day before injuring the carotid artery by balloon, followed by 1 mg/kg per day for 28 days. Expression of eukaryotic translation initiation factor 4E (eIF-4E) and phosphorylation of ribosomal protein S6 kinase 1 (P70S6K) were determined by reverse transcription-polymerase chain reaction and Western blotting analysis. RESULTS: In the injured carotid artery, neointimal hyperplasia was normally observed four weeks after injury. Everolimus inhibited neointimal hyperplasia after balloon injury in a dose dependent manner. At the same time, the study demonstrated that everolimus reduced the expression of P-P70S6K, eIF 4E, transforming growth factor (TGF)-beta1 and of proliferating cell nuclear antigen (PCNA). CONCLUSIONS: Everolimus significantly inhibited neointimal hyperplasia of the injured carotid artery. The effect depended on dosage and was associated with the reduction of phosphorylation of P70S6K and the eIF-4E expression level. PMID- 23673110 TI - Biomechanical comparisons between a new avascular necrosis of femaral head stem based on Chinese patients with avascular necrosis and two other designs. AB - BACKGROUND: There is a relatively high failure rate of the femoral component in patients with avascular necrosis at the intermediate-term follow-up. Improving the geometrical fit of the femoral stem against the medullary canal may help to provide long-term survivorship of the hip replacement for patients with avascular necrosis. METHODS: We designed a specific stem, based on morphometric studies of proximal femoral canals in Chinese avascular necrosis patients and evaluated the stem by finite element analyses, comparing the novel stem with two commercially available and commonly used stems. RESULTS: The morphometric data from avascular necrosis patients showed specific geometric differences in the proximal femoral canal, including profile curves in both the sagittal and coronary planes than the patients with femoral neck fracture. The shorter stemmed prostheses (Fitmore((r)) and our stem) performed better than the longer stemmed prosthesis (VerSys((r))). CONCLUSIONS: This is the first study to investigate the femoral geometries of Chinese avascular necrosis patients. Our stem provides better stability and is theoretically beneficial to bone ingrowth, which may increase the long-term stability and fixation of the implant. PMID- 23673111 TI - Correlations between papillary thyroid cancer and peripheral blood levels of matrix metalloproteinase-2, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-2. AB - BACKGROUND: The relationship between the presence of metalloproteinases and thyroid cancer remains unknown, and many controversies still exist in this field. The objective of this study was to investigate the correlations between papillary thyroid cancer and peripheral blood levels of matrix metalloproteinase-2, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-2. METHODS: The correlations were studied by detecting the levels of matrix metalloproteinase-2, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-2 by enzyme-linked immunosorbant assay and reverse transcription polymerase chain reaction in the peripheral blood of 30 patients with papillary thyroid carcinoma, 27 patients with benign thyroid disease, and 25 healthy volunteers. RESULTS: The levels of matrix metalloproteinase-2, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-2 in the peripheral blood of patients with papillary thyroid carcinoma were significantly higher than those in the peripheral blood of patients with benign thyroid disease and healthy volunteers (P < 0.05). However, there were no significant differences between patients with benign thyroid disease and healthy volunteers (P > 0.05). The accuracy of detection by both enzyme-linked immunosorbant assay and reverse-transcription polymerase chain reaction in the papillary thyroid cancer group was 83.33%. CONCLUSIONS: The levels of matrix metalloproteinase-2, matrix metalloproteinase 9, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-2 in the peripheral blood are helpful in identifying thyroid carcinoma and aid in preoperative assessment. PMID- 23673112 TI - Urinary metabonomics of stomach cancer assessed by rapid resolution liquid chromatography/time-of-fight mass spectrometry. AB - BACKGROUND: Stomach cancer is among the most commonly occurring malignancies worldwide. It would be beneficial to develop a urine-based assay whereby patients with undiagnosed stomach cancer could be screened and their cancer detected in the earliest stages. METHODS: A urinary metabonomics method based on ultra performance liquid chromatography combined with quadruple time-of-flight mass spectrometry was used to analyze urine samples from patients with stomach cancer and healthy controls. RESULTS: Statistical analysis revealed a clear separation of patients and healthy controls using the aforementioned methodology. Some significantly changed metabolites were identified. CONCLUSIONS: Use of the metabonomics method in patients with stomach cancer could effectively detect distinct changes in urinary metabolites and had the capacity to detect cancer; therefore, it may be a valuable tool in earlier diagnosis. Furthermore, the detection and identification of altered metabolites in the current study may help elucidate possible mechanisms involved in stomach cancer. PMID- 23673113 TI - Effects of meteorological elements on admission rates of cerebral infarction patients with hypertensive nephropathy from nine hospitals in Changchun city, Jilin Province. AB - BACKGROUND: It is well recognized that meteorological factors have important infuences on the onset and development of many kinds of diseases. The present study was undertaken to investigate the effects of the meteorological elements on admission rates of cerebral infarction patients with hypertensive nephropathy at Changchun city, Jilin Province, northeast China. METHODS: A total of 763 medical records of inpatients from nine hospitals at Changchun city, during a period from April 6 to April 17 in 2010, were reviewed. These patients were admitted to hospitals due to the occurrence of cerebral infarction. The hypertensive nephropathy was evidenced with certain diagnosis of essential hypertension and hypertension-related kidney injuries. The cerebral infarction was diagnosed according to the World Health Organization (Stroke) standard. All the meteorological data were from practical monitoring records in Jilin Province Meteorological Observatory. The relationships between the epidemiological prevalence of cerebral infarction and meteorological variables were analyzed using the time series models of statistics. RESULTS: Compared with admission rates before the violent change in meteorological status (April 6 to April 17, 2010), the number of admission patients suffering from cerebral infarction remarkably peaked on April 12. Such an increase was highly correlated with heavy precipitation, elevation of daily average relative humidity, and reduction of average daily air temperature. With the betterment of the meteorological conditions on April 17, the admission rates of cerebral infarction patients dropped to the same level as the dates before snowing (April 6 to April 11). CONCLUSIONS: The meteorological changes are highly associated with the occurrence of cerebral infarction in patients with hypertensive renal injury in northeast China. This study also suggested that an intensive medical interference for those patients with hypertension-induced organ injuries is very necessary in preventing the occurrence of cerebral infarction with hypertensive nephropathy when there is a violent change in meteorological condition. PMID- 23673114 TI - Inhibition of the reinstatement of morphine-induced place preference in rats by high-frequency stimulation of the bilateral nucleus accumbens. AB - BACKGROUND: Opiate addiction remains intractable in a large percentage of patients, and relapse is the biggest hurdle to recovery. Many studies have identified a central role of the nucleus accumbens (NAc) in addiction. Deep brain stimulation (DBS) has the advantages of being reversible, adjustable, and minimally invasive, and it has become a potential neurobiological intervention for addiction. The purpose of our study was to investigate whether high-frequency DBS in the NAc effectively attenuates the reinstatement of morphine seeking in morphine-primed rats. METHODS: A morphine-dependent group of rats was given increasing doses of morphine during conditioned place preference training. A control group of rats was given equal volumes of saline. After the establishment of this model, withdrawal syndromes were precipitated in these two groups by administering naloxone, and the differences in withdrawal symptoms between the groups were analyzed. Electrodes for DBS were implanted in the bilateral shell of the NAc in the experimental group. The rats were stimulated daily in the NAc for 5 hours per day over 30 days. Changes in the conditioned place preference test and withdrawal symptoms in the rats were investigated and place navigation studies were performed using the Morris water maze. The data were assessed statistically with one-way analysis of variance (ANOVA) followed by Tukey's tests for multiple post hoc comparisons. RESULTS: High-frequency stimulation of the bilateral NAc prevented the morphine-induced reinstatement of morphine seeking in the conditioned place preference test. The time spent in the white compartment by rats following 30 days of DBS ((268.25 +/- 25.07) seconds) was not significantly different compared with the time spent in the white compartment after relapse was induced by morphine administration ((303.29 +/- 34.22) seconds). High-frequency stimulation of the bilateral NAc accelerated the innate decay of drug craving in morphine-dependent rats without significantly influencing learning and memory. CONCLUSION: Bilateral high-frequency stimulation of the shell of the NAc may be useful as a novel therapeutic modality for the treatment of severe morphine addiction. PMID- 23673115 TI - Retinal blood flow velocity in patients with active uveitis using the retinal function imager. AB - BACKGROUND: Previous studies suggest a link between macular edema and retinal blood flow velocity (RBFV). The effects of inflammation in the retinal blood vessels are not clearly understood. We want to evaluate the differences in retinal blood flow velocities of patients with active uveitis and healthy controls using the retinal function imager (RFI) and determine the correlation between retinal blood flow velocity and central macular thickness in uveitis patients. METHODS: Twenty-eight eyes of 24 patients with active anterior uveitis and 51 eyes of 51 normal control subjects were enrolled. Retinal blood flow velocities evaluated by RFI and central macular thickness evaluated by optical coherence tomography (SLO-OCT) were obtained. Differences among the groups were assessed using Stata statistical software. RESULTS: Ten eyes had uveitic cystoid macular edema (CME). Median (first quartile, third quartile) venous velocity for uveitic eyes with CME, uveitic eyes without CME, and controls were 2.09 (1.92, 2.44), 2.64 (2.32, 2.86), and 2.82 (2.39, 3.53) mm/s respectively. Median (first and quartile) arterial velocity for uveitic eyes with CME, uveitic eyes without CME, and controls were 3.79 (3.61, 4.09), 3.46 (2.86, 4.12), and 3.93 (3.35, 4.65) mm/s. Uveitic eyes with CME had significantly lower venous velocity than controls (P = 0.044). There was a strong linear relationship between venous velocity and central retinal thickness (P = 0.007). CONCLUSIONS: Retinal venous velocities were significantly decreased in eyes with uveitic CME relative to controls. Decreased venous velocity was correlated with increased central retinal thickness in uveitic eyes. PMID- 23673116 TI - Differential expression of the RNA-binding motif protein 3 in human astrocytoma. AB - BACKGROUND: The RNA-binding motif protein 3 (RBM3), which is transcriptionally induced by low temperature and hypoxia, has recently been found to be upregulated in human tumors. However, its expression status in human astrocytoma is not well defned. This article focuses on the differential expression of RBM3 in human astrocytomas of different grades and normal brain tissues. METHODS: RBM3 was detected in astrocytomas and normal brain tissues by quantitative real-time PCR, immunohistochemistry, and Western blotting. Analysis of variance was performed on the data from quantitative real-time PCR. The Fisher's exact test was used to analyze the immunohistochemistry results. A P-value of less than 0.05 indicates a statistically significant difference. RESULTS: On one hand, the mRNA expression levels of three X-chromosome-related RBM genes (RBMX, RBM3, and RBM10) were detected by quantitative real-time PCR. The results showed that there were no significant differences in RBMX and RBM10 mRNA expression levels in human astrocytomas of different grades and normal brain tissues. However, RBM3 mRNA expression levels were elevated in high-grade (World Health Organization (WHO) Grade III-IV) astrocytomas versus low-grade (WHO Grade I-II) astrocytomas (5.06 +/- 0.66 vs. 1.60 +/- 0.58; P < 0.05) or normal controls (5.06 +/- 0.66 vs. 1.03 +/- 0.22; P < 0.05) as determined by quantitative real-time PCR analysis. On the other hand, immunohistochemistry showed an increased RBM3 labeling index in astrocytomas of different grades and normal brain tissues (positive staining rate: astrocytoma Grade IV, 92.9%; astrocytoma Grade III, 81.8%; astrocytoma Grade I-II, 50%; normal brain tissues, 37.5%; high-grade astrocytoma versus normal brain tissues, P < 0.05; high-grade astrocytoma versus low-grade astrocytoma, P < 0.05). The higher protein levels of RBM3 were also validated in high-grade astrocytomas and low-grade astrocytomas compared with normal brain tissues by Western blotting. CONCLUSIONS: These data suggest that the overexpression of RBM3 may serve as an important molecular mechanism underlying astrocytic carcinogenesis. Moreover, RBM3 may have proliferative and/or proto oncogenic functions in human astrocytomas. PMID- 23673117 TI - Microvascular permeability of brain astrocytoma with contrast-enhanced magnetic resonance imaging: correlation analysis with histopathologic grade. AB - BACKGROUND: The degree of pathological microvascular proliferation is an important element in evaluation of the astrocytoma grade. This study was aimed to quantitatively assess the microvascular permeability of brain astrocytoma with the volume transfer constant (K(trans)) and volume of extravascular extracellular space per unit volume of tissue (Ve) from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and to evaluate the effectiveness of the K(trans) and Ve in the grading of astrocytoma. METHODS: The highest values of the K(trans) and Ve of 67 patients with astrocytoma (27 with grade II, 12 with grade III, and 28 with grade IV) were obtained. The comparisons of the differences of the K(trans) and Ve between the different grades were conducted using the Mann-Whitney rank sum tests. Spearman's rank correlation coefficients were determined between K(trans) values, Ve values and astrocytoma grades. Receiver operating characteristic (ROC) curve analyses were performed to determine the cut-off values for the K(trans) and Ve to distinguish between the different grades of astrocytoma. RESULTS: There were significant differences (P < 0.001) between the different grades in the K(trans) values and Ve values, except for grades III and IV. The K(trans) values and Ve values were both correlated with astrocytoma grades (both P < 0.001). The ROC curve analyses showed that the cut-off values for the K(trans) and Ve provided the best combination of sensitivity and specificity in distinguishing between grade II and grade III or IV astrocytomas. CONCLUSIONS: DCE-MRI can play an important role in assessing the microvascular permeability and the grading of brain astrocytoma. PMID- 23673118 TI - Association between folate intake, serum folate levels and the risk of lung cancer: a systematic review and meta-analysis. AB - BACKGROUND: Folate plays a critical role in nucleotide synthesis and DNA methylation, and was considered to be associated with anti-carcinogenesis. RESULTS: from studies that concern the relationship between the folate intake or serum folate levels and lung cancer risk showed no consistency, which requires our further comprehensive meta-analysis. METHODS: Systematic literature search was conducted to identify the relevant studies (published prior to February 2013) according to standard protocol. Estimated effects were calculated under both random-effects and fixed-effects models. Heterogeneity between studies and publication bias were also evaluated. RESULTS: A total of 4390 cases and 6138 controls from 6 case-control studies revealed a significant overall inverse association between folate intake and lung cancer risk (OR = 0.74, 95%CI = 0.65 - 0.84, P < 0.001). Summary of 1438 cases and 2582 controls from 4 case-control studies and 44 cases out of a cohort of 1988 participants suggested a marginal association without significance (OR = 0.78, 95%CI = 0.60 - 1.02, P = 0.075) between high serum folate levels and less lung cancer susceptibility; however, subgroup analysis about population-based case-control studies showed that high serum folate levels significantly associated with the reduced lung cancer risk (OR = 0.76, 95%CI = 0.58 - 1.00, P = 0.048). CONCLUSION: Higher folate intake can be a protective factor against lung cancer risk, and higher serum folate level is probably associated with reduced lung cancer risk in marginal manner, though more studies are warranted to confirm these associations. PMID- 23673119 TI - Use of real-time polymerase chain reaction for the diagnosis of Pneumocystis pneumonia in immunocompromised patients: a meta-analysis. AB - BACKGROUND: The diagnosis of Pneumocystis pneumonia (PCP) in immunocompromised patients is still challenging today due to the absence of an in vitro culture system and the low diagnostic accuracy of microscopic examinations. Herein, we performed a meta-analysis to evaluate the accuracy of real-time polymerase chain reaction (PCR) in the diagnosis of PCP. METHODS: We searched Web of Knowledge and Medline from 1990 to May 2010 for studies reporting diagnostic accuracy data regarding the use of real-time PCR in the diagnosis of PCP in immunocompromised patients. RESULTS: Ten individual studies were included. Overall, the sensitivity of real-time PCR was 97% (95%CI: 93% - 99%); the specificity was 94% (95%CI: 90% 96%). The area under the HSROC curve (95%CI) for real-time PCR was 0.99 (0.97 - 0.99). In a subgroup analysis regarding studies involving HIV patients among the study population, the sensitivity and specificity were 97% (95%CI: 93% - 99%) and 93% (95%CI: 89% - 96%), respectively. Regarding studies using Bronchoalveolar lavage (BAL) samples only: sensitivity = 98% (95%CI: 94% - 99%); specificity = 93% (95%CI: 89% - 96%), respectively. Regarding studies using microscopy as a reference standard: sensitivity = 97% (95%CI: 92% - 99%); specificity = 93% (95%CI: 88% - 96%). However, high between-study statistical heterogeneity was observed in all analyses. CONCLUSIONS: Real-time PCR has a good diagnostic accuracy and may provide a useful adjunctive tool for the diagnosis of PCP in immunocompromised patients. Further studies are needed in order to identify any differences in the diagnostic performance of real-time PCR in HIV and non-HIV immunocompromised patients. PMID- 23673120 TI - Hemodynamic therapy: timing and targeting. PMID- 23673121 TI - Targeting the mammalian target of rapamycin pathway in osteosarcoma using combinative chemotherapy. PMID- 23673122 TI - Robotic internal thoracic artery harvesting: the learning curve and graft patency. PMID- 23673123 TI - A fast method to detect blood vessel in retinal image. PMID- 23673124 TI - Early goal-directed fluid therapy with fresh frozen plasma reduces severe acute pancreatitis mortality in the intensive care unit. PMID- 23673125 TI - Prevalence and risk factors for cervical cytology abnormality in general female population in Qujing of Yunnan Province, China. PMID- 23673126 TI - Lung cancer: a rare cause of recurrent syncope after pacemaker implantation. PMID- 23673127 TI - Malignant fibrous histiocytoma of right atrium. PMID- 23673128 TI - Peripheral neuropathy caused by cryoglobulinaemia with false-positive serological tests of syphilis. PMID- 23673129 TI - Acute fatty liver of pregnancy. PMID- 23673130 TI - Treatment of bladder invasive adenosquamous carcinoma of the prostate: radical cystoprostatectomy. PMID- 23673131 TI - Nine-month follow-up of an acute respiratory distress syndrome caused by 2009 H1N1 influenza during pregnancy. PMID- 23673132 TI - Screening for arrhythmogenic right ventricular cardiomyopathy: a value of genetic testing. PMID- 23673133 TI - Sulfur-oxidizing bacteria dominate the microbial diversity shift during the pyrite and low-grade pyrolusite bioleaching process. AB - The microbial ecology of the pyrite-pyrolusite bioleaching system and its interaction with ore has not been well-described. A 16S rRNA gene clone library was created to evaluate changes in the microbial community at different stages of the pyrite-pyrolusite bioleaching process in a shaken flask. The results revealed that the bacterial community was disturbed after 5 days of the reaction. Phylogenetic analysis of 16S rRNA sequences demonstrated that the predominant microorganisms were members of a genus of sulfur-oxidizing bacteria, Thiomonas sp., that subsequently remained dominant during the bioleaching process. Compared with iron-oxidizing bacteria, sulfur-oxidizing bacteria were more favorable to the pyrite-pyrolusite bioleaching system. Decreased pH due to microbial acid production was an important condition for bioleaching efficiency. Iron-oxidizing bacteria competed for pyrite reduction power with Mn(IV) in pyrolusite under specific conditions. These results extend our knowledge of microbial dynamics during pyrite-pyrolusite bioleaching, which is a key issue to improve commercial applications. PMID- 23673134 TI - Are randomized trials obsolete or more important than ever in the genomic era? PMID- 23673135 TI - On the potential application of polar and temperate marine microalgae for EPA and DHA production. AB - Long chain polyunsaturated fatty acids (LC-PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are considered essential omega-3 fatty acids in human nutrition. In marine microalgae EPA and/or DHA are allegedly involved in the regulation of membrane fluidity and thylakoid membrane functioning. The cellular content of EPA and DHA may therefore be enhanced at low temperature and irradiance conditions. As a result, polar and cold temperate marine microalgal species might potentially be suitable candidates for commercial EPA and DHA production, given their adaptation to low temperature and irradiance habitats.In the present study we investigated inter- and intraspecific EPA and DHA variability in five polar and (cold) temperate microalgae. Intraspecific EPA and DHA content did not vary significantly in an Antarctic (Chaetoceros brevis) and a temperate (Thalassiosira weissflogii) centric diatom after acclimation to a range of irradiance levels at two temperatures. Interspecific variability was investigated for two Antarctic (Chaetoceros brevis and Pyramimonas sp. (Prasinophyceae)) and three cold-temperate species (Thalassiosira weissflogii, Emiliania huxleyi (Prymnesiophyceae) and Fibrocapsa japonica (Raphidophyceae)) during exponential growth. Interspecific variability was shown to be much more important than intraspecific variability. Highest relative and absolute levels of DHA were measured in the prymnesiophyte E. huxleyi and the prasinophyte Pyramimonas sp., while levels of EPA were high in the raphidophyte F. japonica and the diatoms C. brevis and T. weissflogii. Yet, no significant differences in LC-PUFA content were found between polar and cold-temperate species. Also, EPA and DHA production rates varied strongly between species. Highest EPA production rate (174 MUg L-1 day-1) was found in the Antarctic diatom Chaetoceros brevis, while DHA production was highest in the cold-temperate prymnesiophyte Emiliania huxleyi (164 MUg L-1 day-1). We show that, following careful species selection, effective mass cultivation of marine microalgae for EPA and DHA production may be possible under low temperature and irradiance conditions. PMID- 23673136 TI - Oncolytic immunotherapeutic virus in HCC: can it compete with molecular therapies? PMID- 23673137 TI - Reversal of cirrhosis: an achievable goal of hepatitis B antiviral therapy. PMID- 23673140 TI - Meiosis progression and donor age affect expression profile of DNA repair genes in bovine oocytes. AB - Several genetic and physiological factors increase the risk of DNA damage in mammalian oocytes. Two critical events are: (i) meiosis progression, from maturation to fertilization, due to extensive chromatin remodelling during genome decondensation; and (ii) aging, which is associated with a progressive oxidative stress. In this work, we studied the transcriptional patterns of three genes, RAD51, APEX-1 and MLH1, involved in DNA repair mechanisms. The analyses were performed by real-time quantitative PCR (RT-qPCR) in immature and in vitro matured oocytes collected from 17 +/- 3-month-old heifers and 94 +/- 20-month-old cows. Batches of 30-50 oocytes for each group (three replicates) were collected from ovarian follicles of slaughtered animals. The oocytes were freed from cumulus cells at the time of follicle removal, or after in vitro maturation (IVM) carried out in M199 supplemented with 10% fetal calf serum, 10 IU luteinising hormone (LH)/ml, 0.1 IU follicle-stimulating hormone (FSH)/ml and 1 MUg 17beta oestradiol/ml. Total RNA was extracted by Trizol method. The expression of bovine GAPDH gene was used as the internal standard, while primers for bovine RAD51, APEX-1 and MLH1 genes were designed from DNA sequences retrieved from GenBank. Results obtained indicate a clear up-regulation of RAD51, APEX-1 and MLH1 genes after IVM, ranging between two- and four-fold compared with germinal vesicle (GV) oocytes. However, only RAD51 showed a significant transcript increase between the immature oocytes collected from young or old individuals. This finding highlights RAD51 as a candidate gene marker for discriminating bovine immature oocytes in relation to the donor age. PMID- 23673139 TI - Curcuma oil ameliorates hyperlipidaemia and associated deleterious effects in golden Syrian hamsters. AB - Essential oil components from turmeric (Curcuma longa L.) are documented for neuroprotective, anti-cancer, anti-thrombotic and antioxidant effects. The present study aimed to investigate the disease-modifying potential of curcuma oil (C. oil), a lipophilic component from C. longa L., in hyperlipidaemic hamsters. Male golden Syrian hamsters were fed a chow or high-cholesterol (HC) and fat-rich diet with or without C. oil (30, 100 and 300 mg/kg) for 28 d. In HC diet-fed hamsters, C. oil significantly reduced plasma total cholesterol, LDL-cholesterol and TAG, and increased HDL-cholesterol when compared with the HC group. Similar group comparisons showed that C. oil treatment reduced hepatic cholesterol and oxidative stress, and improved liver function. Hyperlipidaemia-induced platelet activation, vascular dysfunction and repressed eNOS mRNA expression were restored by the C. oil treatment. Furthermore, aortic cholesterol accumulation and CD68 expression were also reduced in the C. oil-treated group. The effect of C. oil at 300 mg/kg was comparable with the standard drug ezetimibe. Delving into the probable anti-hyperlipidaemic mechanism at the transcript level, the C. oil treated groups fed the chow and HC diets were compared with the chow diet-fed group. The C. oil treatment significantly increased the hepatic expression of PPARa, LXRa, CYP7A1, ABCA1, ABCG5, ABCG8 and LPL accompanied by reduced SREBP-2 and HMGCR expression. C. oil also enhanced ABCA1, ABCG5 and ABCG8 expression and suppressed NPC1L1 expression in the jejunum. In the present study, C. oil demonstrated an anti-hyperlipidaemic effect and reduced lipid-induced oxidative stress, platelet activation and vascular dysfunction. The anti-hyperlipidaemic effect exhibited by C. oil seems to be mediated by the modulation of PPARa, LXRa and associated genes involved in lipid metabolism and transport. PMID- 23673141 TI - In the eye of the storm or the bullseye of the media: social media use during Hurricane Sandy as a predictor of post-traumatic stress. PMID- 23673142 TI - Symptomatic brain involvement as the initial manifestation of neuromyelitis optica. AB - Neuromyelitis optica (NMO) is an inflammatory demyelinating disorder that predominantly affects the optic nerve and spinal cord; however, symptomatic brain involvement is not rare and is sometimes an initial manifestation in NMO. In this study, we investigated the characteristic features of patients with NMO with symptomatic brain involvement as the initial manifestation of disease (NMO(brain)) compared with patients with NMO who presented initially with optic neuritis or myelitis (NMO(ON/myelitis)). We retrospectively reviewed 27 consecutive Korean patients with NMO with aquaporin-4 antibodies. Patients with NMO(brain) (n=9) initially presented with intractable hiccup/nausea/vomiting and/or encephalopathy at a younger age than the patients with NMO(ON/myelitis) (n=18) (p<0.01). During the disease course, the patients with NMO(brain) continued to show more frequent symptomatic involvement of the brain than the 18 patients with NMO(ON/myelitis) (p<0.05). At the final visit, the mean age was also significantly lower in patients with NMO(brain) than in patients with NMO(ON/myelitis) (p<0.01); however, the Expanded Disability Status Scale scores, used to evaluate disease progression, were not different between the two groups. Our study suggests that patients with NMO who present initially with symptomatic brain involvement may have earlier disease onset and become disabled at a younger age compared to patients with typical NMO. Additional large scale prospective studies are warranted. PMID- 23673143 TI - Low-grade and anaplastic oligodendrogliomas: differences in tumour microvascular permeability evaluated with dynamic contrast-enhanced magnetic resonance imaging. AB - This study was designed to quantitatively assess the microvascular permeability of oligodendroglioma using the volume transfer constant (K(trans)) and the volume of the extravascular extracellular space per unit volume of tissue (V(e)) with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). We aimed to evaluate the effectiveness of K(trans) and V(e) in distinguishing between low grade and anaplastic oligodendroglioma. The maximal values of K(trans) and V(e) for 65 patients with oligodendroglioma (27 grade II, 38 grade III) were obtained. Differences in K(trans) and V(e) between the two groups were analysed using the Mann-Whitney rank-sum test. Receiver operating characteristic (ROC) curve analyses were performed to determine the cut-off values for the K(trans) and Ve that could differentiate between low-grade and anaplastic oligodendrogliomas. Values for K(trans) and Ve in low-grade oligodendrogliomas were significantly lower than those in anaplastic oligodendrogliomas (p < 0.001 and p < 0.001, respectively). ROC curve analysis showed that cut-off values of the K(trans) (0.037 min(-1)) and Ve (0.079) could be used to distinguish between low-grade and anaplastic oligodendrogliomas in a statistically significant manner. Our results suggest that DCE-MRI can distinguish the differences in microvascular permeability between low-grade and anaplastic oligodendrogliomas. PMID- 23673144 TI - A randomized open-label observational study to compare the efficacy and tolerability between topiramate and valproate in juvenile myoclonic epilepsy. AB - Juvenile myoclonic epilepsy (JME) is managed with valproate in most patients; however, valproate is an antiepileptic drug that has relatively severe adverse effects, especially in women. We performed a prospective, open-label, randomized observational study for comparison of efficacy and tolerability between topiramate and valproate in patients with JME. The inclusion criteria were patients with newly diagnosed JME or previously diagnosed JME with a history of a poor response or adverse effects to other antiepileptic drugs. The primary endpoint of this study was percentage of patients who were free of myoclonic seizures for 24 weeks in the two groups. The frequency and severity of adverse effects were also assessed. Sixteen patients were randomized to topiramate and 17 to valproate. In the topiramate arm, 11 of 16 patients (68.9%) completed 24-week maintenance therapy and seven of the 11 (64%) were seizure-free. In the valproate arm, 16 of 17 patients (94.1%) completed 24-week follow-up and nine of 16 (56%) were seizure-free. The difference (64% topiramate versus 56% valproate) did not reach statistical significance in this study group (p = 0.08, Fisher's exact test). However, the severity of adverse effects was significantly different. Only 1 of 10 adverse effects from topiramate was ranked moderate-to-severe (10%), in comparison with severe rankings for 10 of 17 adverse effects from valproate (59%) (p = 0.018, Fisher's exact test). In summary, the efficacy of topiramate and valproate was not different, but the severity of adverse effects was favourable for topiramate. Our findings suggest that valproate may be replaced with topiramate, especially for the patients with JME who do not tolerate valproate. PMID- 23673145 TI - Reactivity to AQP4 epitopes in relapsing-remitting multiple sclerosis. AB - Autoantibodies against the water channel AQP4, expressed predominately in central nervous system astrocytes, are markers and pathogenic factors in Devic's disease. In this study we examined whether Multiple Sclerosis (MS) patients recognize antigenic epitopes on AQP4 that may define distinct disease subsets. We screened sera from 45 patients with relapsing-remitting MS (RRMS) and 13 patients with primary progressive MS (PMS). 23 Neuromyelitis Optica (NMO) patients previously characterized were used as assay positive/negative controls. Sera from 23 patients with Systemic Lupus Erythematosus, 23 with primary Sjogren syndrome without neurological involvement and from 28 healthy individuals were also used as controls. NMO-positive sera exhibited reactivity against the intracellular epitope AQPaa252-275, confirming previous observations. All RRMS sera tested negative for anti-AQP4 antibodies using a cell-based assay, but surprisingly, 13% of them reacted with the epitope AQPaa252-275. PMS, healthy and disease controls showed no specific reactivity. Whether these antibodies define distinct MS subsets and have a pathogenic potential pointing to convergent pathogenetic mechanism with NMO, or are simply markers of astrocytic damage, remains to be determined. PMID- 23673146 TI - The time-course of hindbrain neuronal activity varies according to location during either intraperitoneal or subcutaneous tumor growth in rats: single Fos and dual Fos/dopamine beta-hydroxylase immunohistochemistry. AB - Neuronal activity in the nucleus of the solitary tract, ventrolateral medulla, area postrema, and parabrachial nucleus was studied in rats with intraperitoneal or subcutaneous tumors on the 7th, 14th, 21st, and 28th day after injection of fibrosarcoma tumor cells. We found that the number of Fos and dopamine beta hydroxylase immunopositive neurons differs between animals with intraperitoneal and subcutaneous tumors and also between tumor-bearing rats at different times following injection. Our data indicate that responses of the brainstem structures to peripheral tumor growth depend on the localization as well as the stage of the tumor growth. PMID- 23673147 TI - Behavioral evidence for photophobia and stress-related ipsilateral head pain in transgenic Cacna1a mutant mice. AB - Migraine is a highly prevalent, disabling and complex episodic brain disorder whose pathogenesis is poorly understood, due in part to the lack of valid animal models. Here we report behavioral evidence of hallmark migraine features, photophobia and unilateral head pain, in transgenic knock-in mice bearing human familial hemiplegic migraine, type 1 (FHM-1) gain-of-function missense mutations (R192Q or S218L) in the Cacna1a gene encoding the CaV2.1 calcium channel alpha1 subunit. Photophobia was demonstrated using a modified elevated plus maze in which the safe closed arms were brightly illuminated; mutant mice avoided the light despite showing no differences in the standard (anxiety) version of the test. Multiple behavioral measures suggestive of spontaneous head pain were found in 192Q mutants subjected to novelty and/or restraint stress. These behaviors were: (1) more frequent in mutant versus wildtype mice; (2) lateralized in mutant but not in wildtype mice; (3) more frequent in females versus males; and (4) dose dependently normalized by systemic administration of 2 different acute analgesics, rizatriptan and morphine. Furthermore, some of these behaviors were found to be more frequent and severe in 218L compared to 192Q mutants, consistent with the clinical presentation in humans. We suggest that Cacna1a transgenic mice can experience migraine-related head pain and can thus serve as unique tools to study the pathogenesis of migraine and test novel antimigraine agents. PMID- 23673148 TI - The genomics of preterm birth: from animal models to human studies. AB - Preterm birth (delivery at less than 37 weeks of gestation) is the leading cause of infant mortality worldwide. So far, the application of animal models to understand human birth timing has not substantially revealed mechanisms that could be used to prevent prematurity. However, with amassing data implicating an important role for genetics in the timing of the onset of human labor, the use of modern genomic approaches, such as genome-wide association studies, rare variant analyses using whole-exome or genome sequencing, and family-based designs, holds enormous potential. Although some progress has been made in the search for causative genes and variants associated with preterm birth, the major genetic determinants remain to be identified. Here, we review insights from and limitations of animal models for understanding the physiology of parturition, recent human genetic and genomic studies to identify genes involved in preterm birth, and emerging areas that are likely to be informative in future investigations. Further advances in understanding fundamental mechanisms, and the development of preventative measures, will depend upon the acquisition of greater numbers of carefully phenotyped pregnancies, large-scale informatics approaches combining genomic information with information on environmental exposures, and new conceptual models for studying the interaction between the maternal and fetal genomes to personalize therapies for mothers and infants. Information emerging from these advances will help us to identify new biomarkers for earlier detection of preterm labor, develop more effective therapeutic agents, and/or promote prophylactic measures even before conception. PMID- 23673150 TI - Estimated prevalence and predictors of undernutrition among children aged 5-17 months in Yerevan, Armenia. AB - OBJECTIVE: Child undernutrition is a serious public health problem in many low- and middle-income countries. Data on child undernutrition prevalence and its risk factors in Armenia are limited. The present study aimed to estimate the prevalence and explore the predictors of undernutrition among children aged 5-17 months in Yerevan. DESIGN: The study was cross-sectional and employed a review of the ambulatory charts of children selected through a multistage cluster sampling. This phase was followed by a case-control study. The cases were undernourished children identified during the record review and randomly matched with normally growing controls of the same age and gender from the same pool of records. Mothers of cases and controls participated in a telephone interview. The study used conditional logistic regression analysis. SETTING: Yerevan, Armenia. SUBJECTS: Children aged 5-17 months residing in Yerevan, Armenia. RESULTS: Review of 570 ambulatory charts suggested the prevalence of stunting, underweight and wasting among 5-17-month-old children in Yerevan to be 17.9 %, 7.3 % and 3.1 %, respectively. The case-control study of eighty-nine matched pairs identified four significant predictors of child undernutrition: family's socio-economic status score (P = 0.030), child's length at birth (P = 0.027), duration of predominant breast-feeding (P = 0.046) and food diversity score (P = 0.039). CONCLUSIONS: The factors determining growth patterns of children in Yerevan are mostly behavioral and environmental, hence modifiable. Reducing poverty and inequalities in food availability, promoting breast-feeding and adequate complementary feeding, and ensuring optimal care before, during and after pregnancy are likely to help reduce child undernutrition in Yerevan, Armenia and societies with similar public health concerns. PMID- 23673151 TI - The diagnostic utility and cost-effectiveness of selective nerve root blocks in patients considered for lumbar decompression surgery: a systematic review and economic model. AB - BACKGROUND: Diagnostic selective nerve root block (SNRB) involves injection of local anaesthetic, sometimes in conjunction with corticosteroids, around spinal nerves. It is used to identify symptomatic nerve roots in patients with probable radicular pain that is not fully concordant with imaging findings. OBJECTIVES: (1) Determine the diagnostic accuracy of SNRB in patients with low back and radiating pain in a lower limb; (2) evaluate whether or not accuracy varies by patient subgroups; (3) review injection-related adverse events; and (4) evaluate the cost-effectiveness of SNRB. DATA SOURCES: MEDLINE, EMBASE, Science Citation Index, Bioscience Information Service (BIOSIS), Latin American and Caribbean Health Sciences Literature (LILACS) and grey literature databases were searched from inception to August 2011. Reference lists of included studies were screened. METHODS: A systematic review (SR) of studies that assessed the accuracy of SNRB or adverse events in patients with low back pain and symptoms in a lower limb for the diagnosis of lumbar radiculopathy. Study quality was assessed using the quality assessment of diagnostic accuracy studies (QUADAS)-2 checklist. We used random-effects meta-analysis to pool diagnostic accuracy data. Decision tree and Markov models were developed, combining SR results with information on the costs and outcomes of surgical and non-surgical care. Uncertainty was assessed using probabilistic and deterministic sensitivity analyses. RESULTS: Five studies assessed diagnostic accuracy: three diagnostic cohort and two within-patient case control studies. All were judged to be at high risk of bias and had high concerns regarding applicability. In individual studies, sensitivity ranged from 57% [95% confidence interval (CI) 43% to 70%] to 100% (95% CI 76% to 100%) and specificity from 9.5% (95% CI 1% to 30%) to 86% (95% CI 76% to 93%). The most reliable estimate was judged to come from two cohort studies that used post-surgery outcome as the reference standard; summary sensitivity and specificity were 93% (95% CI 86% to 97%) and 26% (95% CI 5% to 68%), respectively. No study provided sufficient detail to judge whether or not accuracy varied by patient subgroup. Seven studies assessed adverse events. There were no major or permanent complications; minor complications were reported in 0-6% of patients. The addition of SNRB to the diagnostic work-up was not cost-effective with an incremental cost per quality-adjusted life-year of L1,576,007. Sensitivity analyses confirmed that SNRB was unlikely to be a cost-effective method for diagnosis and planning surgical therapy. LIMITATIONS: We identified very few studies; all were at high risk of bias. The conduct and interpretation of SNRBs varied and there was no gold standard for diagnosis. Limited information about the impact of SNRB on subsequent care and the long-term costs and benefits of surgery increased uncertainty about cost-effectiveness. CONCLUSIONS: There were few studies that estimated the diagnostic accuracy of SNRB in patients with radiculopathy and all were limited by the difficulty of making a reference standard diagnosis. Summary estimates suggest that specificity is low, but results are based on a small number of studies at a high risk of bias. Based on current weak evidence, it is unlikely that SNRB is a cost-effective method for identifying the symptomatic nerve root prior to lumbar spine surgery. Future research should focus on randomised controlled trials to evaluate whether or not SNRB improves patient outcomes at acceptable cost. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 23673152 TI - Bisphosphonate-associated osteonecrosis of the external auditory canal. AB - BACKGROUND: Osteonecrosis is a benign condition characterised by necrotic exposed bone, and is associated with bisphosphonate use. Osteonecrosis of the external auditory canal is rare, with only a few reported cases. METHOD: Two case reports of temporal bone osteonecrosis are presented. RESULTS: A 64-year-old man with a history of immunoglobulin G kappa multiple myeloma developed a right external auditory canal ulcer 6 years after commencement on clodronate. A 72-year-old woman taking alendronate for osteoporosis, initially diagnosed and treated for right-sided otitis externa, was found to have underlying exposed bone in the right external auditory canal, with a computed tomography scan confirming destruction of the temporal bone. CONCLUSION: With increasing use of both oral and intravenous bisphosphonates in the community for benign conditions such as osteoporosis and for malignant conditions such as breast cancer and multiple myeloma, the diagnosis of bisphosphonate-associated osteonecrosis should always be considered in patients with a temporal bone lesion, and a relevant drug history taken. PMID- 23673149 TI - Cyclodextrin-based supramolecular systems for drug delivery: recent progress and future perspective. AB - The excellent biocompatibility and unique inclusion capability as well as powerful functionalization capacity of cyclodextrins and their derivatives make them especially attractive for engineering novel functional materials for biomedical applications. There has been increasing interest recently to fabricate supramolecular systems for drug and gene delivery based on cyclodextrin materials. This review focuses on state of the art and recent advances in the construction of cyclodextrin-based assemblies and their applications for controlled drug delivery. First, we introduce cyclodextrin materials utilized for self-assembly. The fabrication technologies of supramolecular systems including nanoplatforms and hydrogels as well as their applications in nanomedicine and pharmaceutical sciences are then highlighted. At the end, the future directions of this field are discussed. PMID- 23673153 TI - Behavioural intention and user acceptance of research evidence for Queensland nurses: provision of solutions from the clinician. AB - In order to maintain high standards of care in practice, renal nurses must become effective utilisers of research and evidence based practice. Many models for effective evidence based implementation have been published in an attempt to encourage a positive cultural shift in meeting this necessary nurse competency. Yet in reality a great disparity still exists between what the profession knows to be an ideal world and what they are actually able to achieve. This paper presents an evaluation of that reality through the eyes of Queensland renal nurses. Initially known barriers to research or evidence based practice utilisation will be discussed in addition to some home grown solutions from those clinicians. Nurses who participated in this study presented some unique perspectives on known barriers to research utilisation, re-affirming those detailed within the literature and conversely revealing new concepts worth additional exploration. New concepts warranting a broader in-depth exploration included the influence of family on nurse decision making and the effect of overseas trained health professionals on necessary change. In addition Queensland renal nurse's overwhelming supported the need for a filtered or a controlled approach to research activity naming this model in post interview discussions "The Spillway Model". PMID- 23673156 TI - High glucose levels reduce fatty acid oxidation and increase triglyceride accumulation in human placenta. AB - Placentas of women with gestational diabetes mellitus (GDM) exhibit an altered lipid metabolism. The mechanism by which GDM is linked to alterations in placental lipid metabolism remains obscure. We hypothesized that high glucose levels reduce mitochondrial fatty acid oxidation (FAO) and increase triglyceride accumulation in human placenta. To test this hypothesis, we measured FAO, fatty acid esterification, de novo fatty acid synthesis, triglyceride levels, and carnitine palmitoyltransferase activities (CPT) in placental explants of women with GDM or no pregnancy complication. In women with GDM, FAO was reduced by ~30% without change in mitochondrial content, and triglyceride content was threefold higher than in the control group. Likewise, in placental explants of women with no complications, high glucose levels reduced FAO by ~20%, and esterification increased linearly with increasing fatty acid concentrations. However, de novo fatty acid synthesis remained unchanged between high and low glucose levels. In addition, high glucose levels increased triglyceride content approximately twofold compared with low glucose levels. Furthermore, etomoxir-mediated inhibition of FAO enhanced esterification capacity by ~40% and elevated triglyceride content 1.5-fold in placental explants of women, with no complications. Finally, high glucose levels reduced CPT I activity by ~70% and phosphorylation levels of acetyl-CoA carboxylase by ~25% in placental explants of women, with no complications. We reveal an unrecognized regulatory mechanism on placental fatty acid metabolism by which high glucose levels reduce mitochondrial FAO through inhibition of CPT I, shifting flux of fatty acids away from oxidation toward the esterification pathway, leading to accumulation of placental triglycerides. PMID- 23673155 TI - Reduced vasorelaxation to estradiol and G-1 in aged female and adult male rats is associated with GPR30 downregulation. AB - Previously, we reported that chronic activation of the estrogen receptor GPR30 by its selective agonist G-1 decreases blood pressure in ovariectomized hypertensive mRen2.Lewis (mRen2) rats but not intact male littermates. Furthermore, G-1 relaxes female mesenteric resistance arteries via both endothelium-dependent and independent mechanisms. Because of the lack of a blood pressure-lowering effect by G-1 in males and the potential influence of aging on estrogen receptor expression, we hypothesized that GPR30-dependent vasodilation and receptor expression are altered in males and aged females. Thus, we assessed the response to 17beta-estradiol or G-1 in mesenteric arteries obtained from 15-wk-old normotensive Lewis and hypertensive mRen2 females and males as well as 52-wk-old Lewis females. Vasodilation to 17beta-estradiol (E2) and G-1 was significantly attenuated in 15-wk-old Lewis and mRen2 males compared with age-matched females. Pretreatment of male vessels with the nitric oxide synthase inhibitor L-NAME had no significant effect on the estradiol or G-1 response. In aged females, E2 and G 1 vasorelaxation was also significantly blunted; however, L-NAME essentially abolished the response. Associated with the reduced vascular responses, GPR30 expression in mesenteric arteries was approximately 50% lower in males and aged females compared with young females. We conclude that alterations in GPR30 expression and signaling may contribute to vascular dysfunction in aging females and a greater blood pressure in hypertensive males. PMID- 23673157 TI - Muscle-specific Pikfyve gene disruption causes glucose intolerance, insulin resistance, adiposity, and hyperinsulinemia but not muscle fiber-type switching. AB - The evolutionarily conserved kinase PIKfyve that synthesizes PtdIns5P and PtdIns(3,5)P2 has been implicated in insulin-regulated GLUT4 translocation/glucose entry in 3T3-L1 adipocytes. To decipher PIKfyve's role in muscle and systemic glucose metabolism, here we have developed a novel mouse model with Pikfyve gene disruption in striated muscle (MPIfKO). These mice exhibited systemic glucose intolerance and insulin resistance at an early age but had unaltered muscle mass or proportion of slow/fast-twitch muscle fibers. Insulin stimulation of in vivo or ex vivo glucose uptake and GLUT4 surface translocation was severely blunted in skeletal muscle. These changes were associated with premature attenuation of Akt phosphorylation in response to in vivo insulin, as tested in young mice. Starting at 10-11 wk of age, MPIfKO mice progressively accumulated greater body weight and fat mass. Despite increased adiposity, serum free fatty acid and triglyceride levels were normal until adulthood. Together with the undetectable lipid accumulation in liver, these data suggest that lipotoxicity and muscle fiber switching do not contribute to muscle insulin resistance in MPIfKO mice. Furthermore, the 80% increase in total fat mass resulted from increased fat cell size rather than altered fat cell number. The observed profound hyperinsulinemia combined with the documented increases in constitutive Akt activation, in vivo glucose uptake, and gene expression of key enzymes for fatty acid biosynthesis in MPIfKO fat tissue suggest that the latter is being sensitized for de novo lipid anabolism. Our data provide the first in vivo evidence that PIKfyve is essential for systemic glucose homeostasis and insulin-regulated glucose uptake/GLUT4 translocation in skeletal muscle. PMID- 23673160 TI - Civil, sensible, and constructive peer review in APS journals. PMID- 23673159 TI - Adaptive beta-cell proliferation increases early in high-fat feeding in mice, concurrent with metabolic changes, with induction of islet cyclin D2 expression. AB - Type 2 diabetes (T2D) is caused by relative insulin deficiency, due in part to reduced beta-cell mass (11, 62). Therapies aimed at expanding beta-cell mass may be useful to treat T2D (14). Although feeding rodents a high-fat diet (HFD) for an extended period (3-6 mo) increases beta-cell mass by inducing beta-cell proliferation (16, 20, 53, 54), evidence suggests that adult human beta-cells may not meaningfully proliferate in response to obesity. The timing and identity of the earliest initiators of the rodent compensatory growth response, possible therapeutic targets to drive proliferation in refractory human beta-cells, are not known. To develop a model to identify early drivers of beta-cell proliferation, we studied mice during the first week of HFD exposure, determining the onset of proliferation in the context of diet-related physiological changes. Within the first week of HFD, mice consumed more kilocalories, gained weight and fat mass, and developed hyperglycemia, hyperinsulinemia, and glucose intolerance due to impaired insulin secretion. The beta-cell proliferative response also began within the first week of HFD feeding. Intriguingly, beta-cell proliferation increased before insulin resistance was detected. Cyclin D2 protein expression was increased in islets by day 7, suggesting it may be an early effector driving compensatory beta-cell proliferation in mice. This study defines the time frame and physiology to identify novel upstream regulatory signals driving mouse beta cell mass expansion, in order to explore their efficacy, or reasons for inefficacy, in initiating human beta-cell proliferation. PMID- 23673158 TI - Effects of intraportal exenatide on hepatic glucose metabolism in the conscious dog. AB - Incretins improve glucose metabolism through multiple mechanisms. It remains unclear whether direct hepatic effects are an important part of exenatide's (Ex 4) acute action. Therefore, the objective of this study was to determine the effect of intraportal delivery of Ex-4 on hepatic glucose production and uptake. Fasted conscious dogs were studied during a hyperglycemic clamp in which glucose was infused into the hepatic portal vein. At the same time, portal saline (control; n = 8) or exenatide was infused at low (0.3 pmol.kg-1.min-1, Ex-4-low; n = 5) or high (0.9 pmol.kg-1.min-1, Ex-4-high; n = 8) rates. Arterial plasma glucose levels were maintained at 160 mg/dl during the experimental period. This required a greater rate of glucose infusion in the Ex-4-high group (1.5 +/- 0.4, 2.0 +/- 0.7, and 3.7 +/- 0.7 mg.kg-1.min-1 between 30 and 240 min in the control, Ex-4-low, and Ex-4-high groups, respectively). Plasma insulin levels were elevated by Ex-4 (arterial: 4,745 +/- 428, 5,710 +/- 355, and 7,262 +/- 1,053 MUU/ml; hepatic sinusoidal: 14,679 +/- 1,700, 15,341 +/- 2,208, and 20,445 +/- 4,020 MUU/ml, 240 min, area under the curve), whereas the suppression of glucagon was nearly maximal in all groups. Although glucose utilization was greater during Ex-4 infusion (5.92 +/- 0.53, 6.41 +/- 0.57, and 8.12 +/- 0.54 mg.kg-1.min-1), when indices of hepatic, muscle, and whole body glucose uptake were expressed relative to circulating insulin concentrations, there was no indication of insulin-independent effects of Ex-4. Thus, this study does not support the notion that Ex-4 generates acute changes in hepatic glucose metabolism through direct effects on the liver. PMID- 23673161 TI - Mediating factors of coping process in parents of children with type 1 diabetes. AB - BACKGROUND: Type 1 diabetes is a lifelong condition for children and their parents, the management for which imposes a vast responsibility. This study explores the mediating factors that affect Iranian parents' coping processes with their children's type 1 diabetes. METHODS: Research was conducted using the grounded theory method. Participants were selected purposefully, and we continued with theoretical sampling. Constant comparative analysis was used to analyze the data. RESULTS: The mediating factors of the parental coping process with their child's diabetes consist of the child's cooperation, crises and experiences, economic challenges, and parental participation in care. CONCLUSION: Findings highlight the necessity of well-informed nurses with insightful understanding of the mediating factors in parental coping with juvenile diabetes in order to meet the particular needs of this group. PMID- 23673162 TI - Pediatric laryngeal cancer with 5-year follow up: case report. AB - Larynx cancer is the commonest malignancy of upper aerodigestive tract. However, laryngeal cancer is extremely rare in childhood since these tumors are generally not suspected in the differential diagnosis of hoarseness, dysphagia and/or progressive airway obstruction in children; diagnosis can be made relatively late. In this report we would like to present a case of advanced stage pediatric laryngeal carcinoma who was treated with chemoradiotherapy and remained well on her 5-year follow-up. PMID- 23673163 TI - Modified superior pharyngeal flap for the treatment of velopharyngeal insufficiency in children. AB - OBJECTIVE: To describe a modified rolled superior pharyngeal flap for treatment of velopharyngeal insufficiency (VPI) in children. METHODS: Prospective case series at a tertiary care multidisciplinary aerodigestive center. Four children, aged 5-12 years, with VPI refractory to speech therapy resulting after cleft palate (bilateral, submucous, or soft palate only) repair, failed traditional superior pharyngeal flap, fine motor incoordination, or adenoidectomy were studied. All 4 children underwent surgery with a modified superior pharyngeal flap, where aspects of the most commonly employed pharyngeal flap designs were combined to achieve the benefits of each technique and to allow for mucosal covering on either side of the flap, improved control of the lateral port size due to the horizontal-to-horizontal inset technique, and the ability to avoid a vertical or horizontal split in a previously repaired cleft palate. RESULTS: All 4 patients demonstrated resolution of their VPI as measured by subjective and/or objective criteria. Every patient required additional speech therapy postoperatively. CONCLUSIONS: Our modified superior pharyngeal flap technique may be a good option in patients with small velopharyngeal gaps undergoing revision velopharyngeal surgery. A larger, longitudinal study would better address the overall outcomes of this technique. PMID- 23673164 TI - Letter to the Editor regarding the importance of residency programs. PMID- 23673165 TI - Fibronectin from alpha 1,3-galactosyltransferase knockout pigs is a xenoantigen. AB - BACKGROUND: Antibody-mediated rejection continues to be an obstacle for xenotransplantation despite development of alpha1,3-galactosyltransferase knockout (GTKO) pigs. Fibronectin (Fn) from GTKO pigs was identified as a xenoantigen in baboons. N-glycolylneuraminic acid (Neu5Gc), similar to galactose alpha1,3-galactose, is an antigenic carbohydrate found in pigs. We evaluated human antibody reactivity and performed initial antigenic epitope characterization of Fn from GTKO pigs. MATERIALS AND METHODS: GTKO pig aortic endothelial cells (AEC) were isolated and assessed for antibody-mediated complement-dependent cytotoxicity (CDC). Human and GTKO pig Fn were purified and analyzed using immunoblots. GTKO pig and human AEC absorbed human sera were assessed for CDC and anti-GTKO pig Fn antibodies. GTKO pig proteins were assessed for Neu5Gc. Immunoaffinity-purified human IgG anti-GTKO pig (hIgG-GTKOp) Fn using a GTKO pig Fn column were evaluated for cross-reactivity with other proteins. RESULTS: GTKO pig AEC had greater human antibody binding, complement deposition and CDC compared with allogeneic human AEC. Human sera absorbed with GTKO pig AEC resulted in diminished anti-GTKO pig Fn antibody. Neu5Gc was identified on GTKO pig Fn and other proteins. The hIgG-GTKOp Fn cross-reacted with multiple GTKO pig proteins and was enriched with anti-Neu5Gc antibody. CONCLUSIONS: Removal of antigenic epitopes from GTKO pig AEC would improve xenograft compatibility. GTKO pig Fn has antigenic epitopes, one identified as Neu5Gc, which may be responsible for pathology and cross-reactivity of hIgG-GTKOp Fn. Genetic knockout of Neu5Gc appears necessary to address significance and identification of non-Neu5Gc GTKO pig Fn antigenic epitopes. PMID- 23673166 TI - Healthcare delivery system improvements: a way forward to improve health in developing countries and Pakistan. PMID- 23673167 TI - Effectiveness of commonly available surface protecting agents in maintaining microhardness of two cements. AB - OBJECTIVE: To estimate the microhardness of glass ionomer cement (vitrofil) and resin modified glass ionomer cement (vitremere) in the presence and absence of different surface protections. STUDY DESIGN: An in-vitro experimental study. PLACE AND DURATION OF STUDY: The Department of Operative Dentistry, Dr. Ishrat-ul Ebad Khan Institute of Oral Health Sciences, Dow University of Health Sciences and the Department of Material Sciences, NED University, Karachi, from August 2011 to January 2012. METHODOLOGY: Seventy-two discs of each material were made in polytetrafluoroethylene mold which was 10 mm in diameter and 2 mm in thickness. Four groups were made for each material containing 18 discs; G1/G5 (control group), G2/G6 (solid petroleum jelly), G3/G7 vernal (resin varnish), G4/G8 (nail varnish). After initial setting reaction surface protection was applied to discs. Once the surface protection was dried, discs were stored in deionized water at 37 degrees C for 24 hours. After 24 hours, the discs were polished. Microhardness test were performed in digital microhardness tester. The results were statistically analyzed with the help of two-way ANOVA. RESULTS: For glass ionomer cement the only G4 (nail varnish) differed from the G1 (control group) [p < 0.05], No significant difference was seen with other surface protection agents. For resin modified glass ionomer cement, the G7 (resin varnish) and G8 (nail varnish) gave better result from the G5 (control group). CONCLUSION: Nail varnish and resin varnish showed better surface protection for GIC and RMGIC. The presence of toluene in nail varnish have harmful effects so should not be preferred if resin varnish is available. PMID- 23673168 TI - Use of liquid nitrogen and albendazole in successfully treating cutaneous larva migrans. AB - OBJECTIVE: To determine the efficacy of combination treatment of Albendazole along with liquid nitrogen in cutaneous larva migrans. STUDY DESIGN: Quasi experimental study. PLACE AND DURATION OF STUDY: Abbasi Shaheed Hospital and The Aga Khan Hospital, Karachi, from December 2008 to December 2010. METHODOLOGY: Eighteen cases of cutaneous larva migrans were collected and divided into two groups. Group-A was administered oral Albendazole 400 mg once per day along with topical steroid and oral cetrizine 10 mg once at night for 7 days. Group-B also received oral Albendazole 400 mg once per day along with cetrizine 10 mg once at night but they also received single application of liquid nitrogen to freeze the larva. RESULTS: It was found that in Group-A only 2 out of 9 (22%) showed improvement whereas 78% had to be given liquid nitrogen cryotherapy 3 - 7 days after Albendazole to prevent migration of larva. In Group-B, the improvement was 100% and all 9 patients were successfully treated. CONCLUSION: Use of liquid nitrogen along with oral anti-helminths is very effective in treating cutaneous larva migrans than Albendazole alone. PMID- 23673169 TI - Comparison between transcerebellar diameter with biparietal diameter of ultrasound for gestational age measurement in third trimester of pregnancy. AB - OBJECTIVE: To determine the frequency of correct assessment by transcerebeller diameter (TCD) versus biparietal diameter (BPD) for gestational age measurement at 36 weeks of pregnancy using first day of last menstrual period (LMP) for actual period of gestation. STUDY DESIGN: Quasi experimental. PLACE AND DURATION OF STUDY: Department of Obstetrics and Gynaecology, Bahawal Victoria Hospital, Bahawalpur from May to November 2010. METHODOLOGY: This study was performed on 228 patients at 36 weeks of pregnancy fulfilling the inclusion criteria. Ultrasound measurements of TCD and BPD was made and compared with LMP. Collected data was analyzed by SPSS version 10. Proportoin of correct diagnosis by each measurement was determined and compared using chi-square test with significance at p < 0.05. RESULTS: Out of 228 patients, TCD was found to give correct assessment in 209 patients (91.7%; p = 0.001) corresponding to the gestational age by LMP i.e 36 weeks. BPD was found to give correct assessment corresponding to the gestational age by LMP in 176 patients (77.2%). CONCLUSION: Although both BPD and TCD are accurate biometric parameters at 36 weeks of gestation, transcerebellar diameter is more reliable method of gestational age determination in third trimester of pregnancy than biparietal diameter. TCD can be used as a tool to assist in the assessment of gestational age in third trimester. PMID- 23673170 TI - Determination of relative frequency of eosinophils and mast cells in gastric and duodenal mucosal biopsies in adults with non-ulcer dyspepsia. AB - OBJECTIVE: To determine eosinophil and mast cell populations in gastric and duodenal mucosal biopsies of adults with nonulcer dyspepsia (NUD) as compared to non-dyspeptic adults. STUDY DESIGN: A case control study. PLACE AND DURATION OF STUDY: Shahid Sadoughi University of Medical Sciences, Yazd, Iran, from January 2010 to June 2011. METHODOLOGY: A total of 52 (25 non-ulcer dyspeptic patients as case and 27 non-dyspeptic patients as control) patients underwent endoscopy. All patients had a minimum of 2 forceps biopsies obtained from stomach and duodenum. Routine histological evaluation was performed and additionally evaluated to determine eosinophil and mast cell counts. The statistical analysis was performed on SPSS version 17.0, using Mann-Whitney test with significance at p < 0.05. RESULTS: The mean age in the case and control groups was 31.72 +/- 12.17 and 35.74 +/- 12.42 years respectively. The median eosinophil density in gastric mucosa in case group was 5.0 (ranging from 1 to 20) and 4.0 in control group (ranging from 0 to 16; p = 0.140). The median eosinophil density in duodenal mucosa in case group was 16.0 (ranging from 2 to 24) and 13 in control group (ranging from 2 to 45; p = 0.147). The median mast cell density in gastric mucosa in case group was 4.0 (ranging from 0 to 33) and 4.0 in control group (ranging from 0 to 26; p = 0.827). The median mast cell density in duodenal mucosa in case group was 4.0 (ranging from 0 to 31) and 3.0 in control group (ranging from 1 to 23; p = 0.704). The frequency of Helicobacter pylori infection in both the groups was similar. CONCLUSION: Although there were not statistically significant differences in eosinophil and mast cell densities between case and control groups, there was a trend toward mild eosinophilia in gastric and duodenal mucosa. The specific role of eosinophils and mast cells in NUD is yet to be completely defined. PMID- 23673171 TI - Anterior decompression and fixation with Webb-Morley procedure in dorsolumbar spinal injury. AB - OBJECTIVE: To evaluate the neurological outcome of anterior decompression and fixation with Webb-Morley procedure in dorsolumbar spinal injuries. STUDY DESIGN: A case series study. PLACE AND DURATION OF STUDY: The Neurosurgery Department, Jinnah Postgraduate Medical Centre, Karachi, from May 2008 to July 2010. METHODOLOGY: Patients with post-traumatic unstable dorsolumbar spine having compression of the spinal cord with bony fragments of the fractured vertebra were included in the study. Patients below the age of 15 years and patients with bed sores and unfit for anaesthesia were excluded. Plain X-rays and magnetic resonance imaging (MRI) were done. All patients were treated for dorsolumbar fractures by anterior decompression and fixation with Webb-Morley procedure. All patients were assessed clinically by the Frankel's grading before and after surgery. RESULTS: Among 60 patients, 41 were males and 19 were females. Mean age was 37.2 +/- 4 years. Major cause of trauma was road traffic accident. The commonest level of the fracture was at the dorsolumbar junction i.e. 71.66% (n = 43). About 19 (31.66%) patients improved to the Frankel's grade-E, while 41.66% (n = 25) improved to grade-D after surgery. There was no postoperative mortality. CONCLUSION: According to the current study, anterior decompression and fixation with Webb-Morley procedure is an effective and safe approach. Those patients who had complete motor deficit showed no improvement in power but those who had partial motor deficit, had excellent improvement. PMID- 23673172 TI - Aneurysmal subarachnoid haemorrhage: outcome of aneurysm clipping in elderly patients and predictors of unfavourable outcome. AB - OBJECTIVE: To determine the outcome of treatment of microsurgical clipping in elderly (60 - 70 years) patients with aneurysmal subarachnoid hemorrhage and determine the predictors of poor outcome. STUDY DESIGN: Longitudinal analytical study. PLACE AND DURATION OF STUDY: Nishtar Hospital, Multan, Mayo Hospital, Lahore, Department of Neurosurgery, Lahore General Hospital, Lahore, from January 2000 to January 2010. METHODOLOGY: Elderly patients (60 - 70 years) with ruptured cerebral aneurysm were enrolled and graded on the basis of World Federation of Neurosurgeons Scale (WFNS). Aneurysm sac obliteration was done in all the patients with microsurgical clipping. Postoperatively, the patients were assessed upto 3 months for outcome parameters i.e., neurological deterioration (based on WFNS grade and modified Rankin scale as favourable (mRS score 2 2) and unfavourable (mRS score > 2). The factors associated with unfavourable outcome were also noted which included age > 65 years, poor initial WFNS grade, and the occurrence of ischaemia. RESULTS: The mean age of the 48 patients was 65 + 5.45 years. There were 31 (64.6%) male and 17 (35.4%) female patients. Postprocedural neurological deterioration occurred in 23 patients (47.9%) related to ischaemia in 14 (29.16%), rebleeding in 1 (2%), and hydrocephalus in 8 (16.66%). At 03 months, the outcome was favourable in 25 patients (52.08%) and unfavourable in 23 (47.91%). CONCLUSION: In old patients, careful pre-operative assessment, interdisciplinary approach and meticulous tissue handling during aneurysm clipping may decrease the unfavourable outcome. PMID- 23673173 TI - Endoscopic third ventriculostomy for obstructive hydrocephalus. AB - OBJECTIVE: To determine the success rate of endoscopic third ventriculostomy (ETV) for treating obstructive hydrocephalus. STUDY DESIGN: Cross-sectional observational study. PLACE AND DURATION OF STUDY: The Neurosurgery Department of PGMI, Lady Reading Hospital, Peshawar, from May 2010 to November 2011. METHODOLOGY: Patients with obstructive hydrocephalus due to aqueductal stenosis, tectal and non-tectal tumour and already shunted patients for obstructive hydrocephalus presented with blocked shunt were included in the study. Patients with congenital hydrocephalus and secondary to meningitis were excluded. Endoscopic third ventriculostomy was performed. Success, complications and mortality was noted. Data was analyzed by descriptive statistics using SPSS software version 17. RESULTS: There were 155 patients including 72 males and 83 females with ratio of 1: 1.33. Success rate was 71%. Indication of surgery was obstructive hydrocephalus due to aqueductal stenosis, posterior fossa tumour, brain stem and CP angle tumour. Complications were seen in 18 patients including mortality in 3 patients. CONCLUSION: ETV is effective, safe and successful procedure in patients with obstructive hydrocephalus. It may be used as replacement procedure of ventriculo-peritoneal shunt as initial line of management in selected patients. PMID- 23673174 TI - Patients leaving against medical advice: an inpatient psychiatric hospital-based study. AB - OBJECTIVE: To determine the frequency of patients leaving against medical advice (LAMA) in an inpatient psychiatric facility in Rawalpindi, Pakistan. STUDY DESIGN: Descriptive cross-sectional study. PLACE AND DURATION OF STUDY: Institute of Psychiatry, Benazir Bhutto Hospital, Rawalpindi, from August 2010 to February 2011. METHODOLOGY: Patients who got admitted during study period irrespective of duration of illness and mode of admission were recruited through non-probability consecutive sampling and followed till discharge to determine their mode of leaving hospital. A thirteen-item proforma was developed and information was obtained on demographic, socioeconomic, patient related and disease related variables. Descriptive statistics were calculated on SPSS 14. RESULTS: The total number (n) of participants was 246. Among the participants, 96 (39%) left against medical advice (LAMA) whereas 150 (61%) left on regular discharge on physician's advice. Frequency of patients who left against medical advice was found to be more in males (63.5%), younger age groups (21 - 30 years), lesser educated (more than half were under matric) and with the ICD-10 diagnosis of substance abuse (23.9%). About half of patients who LAMA had a prior history of psychiatric illness and a significant number (37.5%) had a history of previous psychiatric admission. CONCLUSION: Leaving against medical advice is a frequent problem in psychiatric inpatients and is a matter of great concern for the treating doctors. PMID- 23673175 TI - Bidirectional ventricular tachycardia of unknown etiology. AB - A 45 years old male presented to the emergency department with palpitations, headache and apprehension. His electrocardiogram revealed bidirectional ventricular tachycardia. He remained vitally stable and responded to intravenous beta-blocker. Initially digitalis toxicity was suspected but history was negative for digitalis intake. The cause remained unidentified in patient despite detailed investigations. During a short follow-up (of 6 months) he remained asymptomatic and no cause was further identified during this period. Some other unseen causes of bidirectional ventricular tachycardia need to be explored. PMID- 23673176 TI - Blunt duodenal trauma. AB - Duodenal trauma presents both diagnostic as well as management dilemma. In majority of duodenal trauma cases, primary duodenal repair is sufficient. But in complex duodenal injuries, adjuvant procedures to protect suture line may prove to be helpful. Herein, we share our experience of managing 4 cases of blunt duodenal injuries who presented in emergency at the hospital from 2008 to 2011. All 4 cases had followed road traffic accidents. Their intra-operative findings, operative procedures, complications, and recovery time were recorded and described. PMID- 23673177 TI - Reticular type parotid myoepithelial carcinoma: an intriguing variant and mimicker. AB - Myoepithelial carcinoma, the malignant counterpart of benign myoepithelioma, is one of the rarest salivary gland neoplasms. It is composed almost exclusively of tumour cells with myoepithelial differentiation, characterized by infiltrative growth and potential for metastasis. We herein, report a case of myoepithelial carcinoma in a 50 years old male with reticular morphology. Reticular variant of myoepithelial carcinoma may be mistaken for a variety of benign and malignant epithelial and mesenchymal tumours including mixed tumour (pleomorphic adenoma), adenoid cystic carcinoma, basal cell adenoma and epithelial myoepithelial carcinoma. Complete surgical excision is the mainstay of therapy. The role of radiation therapy and chemotherapy is not yet established. Awareness of this variant is emphasized to prevent misdiagnosis. PMID- 23673178 TI - Primary angiosarcoma of breast. AB - Primary breast sarcomas, except for phyllodes tumour, are very rare entities, accounting for < 0.1% of all malignant neoplasms. Angiosarcoma of breast is infrequent malignancy and differential diagnosis from other sarcomatous and angiomatous breast tumours holds importance. Two cases of primary angiosarcoma of breast were encountered. One involved a 32 years lady who was treated by wide local excision and six cycles of chemotherapy. The other occurred in a 54 years old lady who was treated with mastectomy, did not receive any radiation or chemotherapy and was later lost to follow-up. Neither of the patient had history of previous breast surgery, chemotherapy or radiotherapy. PMID- 23673179 TI - Primary isolated hepatic tuberculosis. AB - Isolated hepatic tuberculosis without pulmonary or bowel involvement is a diagnostic challenge and can cause considerable morbidity. A young lady from Lahore presented with fever, pain in right hypochondria, nausea and weight loss. CT scan of abdomen showed multiple small hypodense non-enhancing lesions and a heterogeneous texture of liver. Biopsy confirmed the diagnosis of hepatic tuberculosis. It was concluded a case of isolated hepatic tuberculosis without evidence of other primary sites involvement. It is important to consider tuberculosis in the differential diagnosis when suspecting lymphoproliferative or metastatic diseases in a patient with vague symptoms and abnormal hepatic texture on CT. PMID- 23673180 TI - Focal dystonia of right hand with mirror movements upon use of left arm. AB - Dystonia is a movement disorder characterized by sustained muscle contractions, causing twisting and repetitive movements or abnormal postures of affected body parts. Here, we present a novel case of focal dystonia of a 51 years old right handed woman who had developed difficulty in writing and performing fine motor tasks. Due to a discomfort in her right hand at use, she started using her left hand instead and noticed inconsistent mirror movements in her right hand upon use of left hand. She was treated with trihexyphenidyl which allowed her right hand to function better, though writing still remained a problem. PMID- 23673181 TI - Acute presentation of solitary spinal epidural cavernous angioma in a child. AB - Solitary spinal epidural cavernous angiomas are rare lesions, especially in paediatric age group. They are infrequently considered in the differential diagnosis of spinal epidural masses in children. We report a case of solitary epidural cavernous angioma of the thoracic spine in a child presenting with acute onset of back pain and myelopathy. Magnetic resonance imaging of the thoracic spine demonstrated a posterior epidural mass at T6-T8 levels with compression of the spinal cord. Using microsurgical technique and bipolar coagulation, total excision of the lesion was achieved. Histopathological examination confirmed the diagnosis of cavernous angioma. At the five-year follow-up, there was no recurrence of the tumour. PMID- 23673182 TI - Melanotic neuroectodermal tumour of infancy: a rare brain tumour of childhood. AB - Melanotic neuroectodermal tumour of infancy is a rare, mostly benign but locally aggressive tumour of neural crest cell origin occurring in infants. The most commonly affected anatomic site is the maxilla. Such tumours of the brain and skull are very rare. We present the case of an 8 months old baby girl whose presenting complaint was a swelling in the scalp for 6 months. She was otherwise asymptomatic. CT imaging confirmed the presence of an osteolytic tumour in the anterior parasagittal skull with dural involvement. The tumour was surgically excised enbloc. The patient has been well at 2 years follow-up without any evidence of recurrence. PMID- 23673183 TI - Triple-negative phenotype of poorly-differentiated metaplastic breast carcinoma in a male: an oncological rarity. AB - Metaplastic breast carcinoma (MBC) is an extremely rare breast malignancy having highly aggressive clinicopathological behaviour and dismal prognosis. A 75 years old man presented with a painless lump on right side of his chest along with two additional lumps in the ipsilateral axillary and inguinal areas. Microscopic evaluation and immunohistochemistry of trucut tissue biopsies of the lumps and that of mastectomy specimen revealed a triple-negative phenotype of poorlydifferentiated metaplastic breast carcinoma with metastatic deposits to the axillary and inguinal lymph nodes. Exhaustive internet research has revealed only a few case reports of MBC in the men; thus highlighting its absolute oncological rarity. PMID- 23673184 TI - Raised 17-hydroxyprogesterone levels in congenital adrenal hyperplasia. AB - Congenital adrenal hyperplasia (CAH) refers to autosomal recessive diseases resulting from deficiency of enzymes involved in the production of cortisol by the adrenal glands. This study was designed to determine the frequency of suspected congenital adrenal hyperplasia patients by evaluating the laboratory data of blood 17-OHP. The study was conducted at Chemical Pathology Section of Department of Pathology at the Aga Khan University, Karachi. The basic demographic data of 2282 subjects was recorded, screened for blood 17-OHP levels from January 2007 to December 2010. A cutoff of 3 4 ng/ml was considered as suggestive of CAH. The results showed 17-OHP levels 3 4 ng/ml were found predominantly among infants (14.4%) and in females (18.2%). PMID- 23673185 TI - Do general practitioners know what they are prescribing? AB - A cross-sectional study was conducted to explore general practitioners' (GPs) knowledge regarding the major therapeutic use and adverse effects of drug(s) they prescribe. Three drugs namely tablet Montelukast Sodium, tablet Somatriptan and inhaler Fluticasone Propionate were selected from the list of drugs approved by the Ministry of Health in Pakistan. GPs who had prescribed at least one of the three were inquired about the cost, therapeutic use and one common adverse effect. For each question, one correct option and three distracting options were given. Two hundred and ninety four responses of 131 GPs were included in the final analysis. The correct options for therapeutic use and adverse effect were identified by 61.2% (n = 180) and 40.8% (n = 120) respectively. A statistically significant (p < 0.01) deficit of knowledge regarding adverse effects was observed for those GPs who identified pharmaceutical advertisements as their primary source of information for new drugs and those who were less experienced. PMID- 23673186 TI - Need for provision of voluntary HIV counselling and testing (VCT) to injecting drug users (IDUs). PMID- 23673187 TI - Aarskog-Scott syndrome. PMID- 23673188 TI - Vascular endothelial growth factor gene (VEGFA) polymorphisms may serve as prognostic factors for recurrent depressive disorder development. AB - Recurrent depressive disorder (rDD) is a multifactorial disease. Vascular endothelial growth factor (VEGF) is one of the factors that have been suggested to play a role in the etiology and/or development of this disease. Limited information related to the role of VEGFA gene polymorphism in depressive disorder is available. The aim of the study was to analyze the association between VEGFA gene polymorphisms (+405G/C; rs2010963, +936C/T; rs 3025039), VEGFA gene expression, and its serum protein levels in rDD in the Caucasian population. In the current study, 268 patients and 200 healthy controls of the Caucasian origin were involved. Genotyping and gene expression were performed using polymerase chain reaction (PCR)-based methods. Enzyme-linked immunosorbent assay (ELISA) was used for detection of circulating serum VEGF levels. The distribution of VEGFA polymorphism +405G/C differed significantly between rDD patients and healthy subjects. The results of this study indicated that the C allele and CC genotype of VEGFA are risk factors for rDD. Haplotypes CC and TG are the important factors for depression development. Further, VEGFA mRNA expression and VEGF levels were higher in rDD patients than in controls. The VEGFA gene polymorphism may serve as a prognostic factor for rDD development. Our study showed higher levels of both VEGFA mRNA in the peripheral blood cells and serum VEGF in patients diagnosed with rDD than in healthy controls. The obtained results suggest VEGF and the gene encoding the molecule play a role in the etiology of the disease and should be further investigated. PMID- 23673189 TI - Cassandra's prophecy: a response from a sex education perspective. AB - A sex education practitioner's response to the article 'Cassandra's prophecy', focusing on the author's question about the feasibility of introducing in schools more balanced and honest information on reproduction. The response is, sadly, somewhat negative at the present time. PMID- 23673190 TI - Cassandra's prophecy: education, education, education. AB - This is a commentary on the personal account of Jane Everywoman. It reflects on her experiences and thoughts. The author adds context from her own work with the Progress Educational Trust, the Daisy Network Premature Menopause Support Group and the National Infertility Awareness Campaign. Examples of the mixed messages and the confusion surrounding fertility, infertility and the possible solutions which appear in the media have been included to further illustrate many of the issues raised by Jane. The updated NICE fertility guideline is discussed together with its implementation. PMID- 23673191 TI - Cassandra's prophecy: why we need to tell the women of the future about age related fertility decline and 'delayed' childbearing. AB - This anonymized paper describes the author's experience of age-related infertility and unintended childlessness. It outlines her journey from diagnosis to treatment success and clinical pregnancy through assisted reproduction using oocyte donation, followed by subsequent early miscarriage. It makes subjective observations about treatment she received and presents her impressions of how discourses of knowledge dissemination, communication and care were constructed in the organizations she encountered. It sets her own reflections alongside broader observations on the challenges facing women today when planning a family and draws attention to what she perceives to be the misleading myths and misunderstandings concerning reproduction that these women are now subject to. In the light of this, it offers some suggestions for modified public health messages and new approaches to sex education and health screening that may consequently help to empower tomorrow's women (and men) to take full control over their reproductive lives in the 21st century. The paper takes as its mascot the figure of Cassandra, daughter of King Priam and Queen Hecuba. She was loved by Apollo, but resisted him. In consequence, he rendered useless the gift of prophecy that he had bestowed on her by causing her predictions never to be believed. PMID- 23673193 TI - Cassandra's prophecy: a psychological perspective. Why we need to do more than just tell women. AB - The most salient psychological issue in the article 'Cassandra's prophecy' is the lack of fertility knowledge. This lack of knowledge exhibited by both Jane and the medical professionals resulted in a delay in trying to get pregnant and in seeking and receiving appropriate care, ultimately resulting in inadvertent childlessness. We identify five educational initiatives to increase fertility knowledge and personal awareness in order to promote informed decision-making about fertility health issues. These initiatives cover: (i) better sexual education for children; (ii) family planning for young adults that involves value and preference clarification about future parenthood goals; (iii) public health campaigns to increase awareness of the risk factors associated with reduced fertility; (iv) investigation of adherence to fertility guidelines within the medical profession; and (v) clearer information about the benefits and limitations of available fertility treatment. The future of fertility health care must be centred on providing people with information leading to informed choice about all aspects of their own fertility health. Empowerment may mean that people can better optimize their fertility health and be more likely to reach their parenthood goals. PMID- 23673192 TI - Cassandra's prophecy and the trend of delaying childbearing: is there a simple answer to this complex problem? AB - There is a trend to later childbearing, but is the solution offered by Jane Everywoman appropriate or proportionate? Her case is, as she says herself, not necessarily representative and in describing it in such painful detail, might she alarm many women unnecessarily? PMID- 23673194 TI - Evaluation of AERMOD and CALPUFF for predicting ambient concentrations of total suspended particulate matter (TSP) emissions from a quarry in complex terrain. AB - Concentrations of particulate emissions from a quarry located in hilly terrain were calculated by two common atmospheric dispersion models, AERMOD and CALPUFF. Evaluation of these models for emissions from quarries/open pit mines that are located in complex topography is missing from the literature. Due to severe uncertainties in the input parameters, numerous scenarios were simulated and model sensitivity was studied. Model results were compared among themselves, and to measured total suspended particulate (TSP). For a wide range of meteorological and topographical conditions studied, AERMOD predictions were in a better agreement with the measurements than those obtained by CALPUFF. The use of AERMOD's "Open pit" tool seems unnecessary when accurate digital topographic data are available. Onsite meteorological data are shown to be crucial for reliable dispersion calculations in complex terrain. PMID- 23673195 TI - Cyanobacteria biomagnification and amyotrophic lateral sclerosis. PMID- 23673196 TI - An analysis of dislocation of the domed Oxford Lateral Unicompartmental Knee Replacement. AB - BACKGROUND: The Oxford Unicompartmental Knee Replacement (OUKR) uses a mobile bearing to minimise wear. Bearing dislocation is a problem in the lateral compartment as the ligaments are loose in flexion. A domed tibial component has been introduced to minimise the risk of dislocation, yet they still occur, particularly medially. The aim of this mechanical study was to compare the domed and flat tibial components and to identify surgical factors that influence the risk of dislocation. METHOD: A jig was constructed to assess the amount of vertical distraction of the lateral OUKR for a dislocation to occur. Three methods of dislocation were assessed: laterally, medially, 'over the wall' and anteriorly. The study focused on medial dislocation. RESULTS: Significantly (p=0.02) greater vertical distraction was required to dislocate the bearing with the domed tibia rather than the flat. For medial dislocation bearing distance from the wall, femoral component external rotation and tibial rotation were associated with significantly less distraction for dislocation. With the optimal technique with the domed tibia the distraction required to dislocate the bearing medially was 6.4 mm, whereas with poor technique it was 4.6 mm. CONCLUSIONS: This study suggests that to minimise the risk of dislocation the domed tibia should be used. The component should be implanted so the bearing is close to the wall, but does not hit it, and in flexion the femoral and tibial components should be neutrally aligned. PMID- 23673197 TI - Plasma-seq: a novel strategy for metastatic prostate cancer analysis. AB - Personalized genomics will only be useful for monitoring the prognosis of patients with cancer when it becomes much more cost-effective and quicker to apply. A recent study brings this closer to reality with the development of plasma-seq, a rapid, low-cost method that sequences the circulating DNA present in the peripheral blood of patients with cancer. The power of this technique is demonstrated with the examination of tumor genomes from patients with prostate cancer. SEE RELATED RESEARCH ARTICLE: http://genomemedicine.com/content/5/4/30. PMID- 23673198 TI - Population dynamics of Ascaridia galli following single infection in young chickens. AB - The population dynamics of Ascaridia galli was studied in 70 ISA Brown layer pullets, 42 of them were each experimentally infected with 500 embryonated A. galli eggs and 28 chickens were kept as uninfected controls. Six chickens from the infected group and 4 from the control group were necropsied at 3, 7, 10, 14, 21, 28 and 42 days post-infection (d.p.i.). The mean worm recovery varied from 11 20% of the infection dose with the highest recovery at 3 d.p.i. and the lowest at 21 and 42 d.p.i. (P < 0.05). More larvae were recovered from the intestinal wall than from the content (P < 0.0001) and intestinal content larvae were longer than those from the wall (mean length 1.6 and 1 mm, respectively, P < 0.0001). Although larvae were growing over time, a population of small-sized larvae (length < 1 mm) was recovered at all d.p.i. During the first week of infection most of the larvae were located in the anterior half of the jejunoileum but they moved posteriorly with the age of infection. Thus, a subpopulation of larvae mainly in the lumen grew with time while another subpopulation remained small and associated with the mucosa. During the infection both subpopulations moved to a more posterior localization in the gastrointestinal (GI) tract. PMID- 23673200 TI - Increased plasma soluble (pro)renin receptor levels are correlated with renal dysfunction in patients with heart failure. PMID- 23673201 TI - Spermine reduced no-reflow size induced by ischemia-reperfusion through regulating autophagy. PMID- 23673202 TI - Assessment of the right ventricle in pregnant women with and without structural heart disease. PMID- 23673203 TI - Development and evaluation of a novel topical treatment for acne with azelaic acid-loaded nanoparticles. AB - Azelaic acid (AzA) is used in the treatment of acne. However, side effects and low compliance have been associated with several topical treatments with AzA. Nanotechnology presents a strategy that can overcome these problems. Polymeric nanoparticles can control drug release and targeting and reduce local drug toxicity. The aim of this study was to produce and evaluate an innovative topical treatment for acne with AzA-loaded poly-DL-lactide/glycolide copolymer nanoparticles. A soft white powder of nanoparticles was prepared. The mean size of loaded nanoparticles was < 400 nm and zeta potential was negative. Spherical nanoparticles were observed by scanning electron microscopy. Encapsulation efficiency was around 80% and a strong interaction between the polymer and the drug was confirmed by differential scanning calorimetric analysis. In vitro drug release studies suggested a controlled and pulsatile release profile. System efficacy tests suggested similar results between the loaded nanoparticles and the nonencapsulated drug against the most common bacteria associated with acne. Cytotoxicity of AzA-loaded nanoparticles was concentration dependent, although not pronounced. The occluded patch test seemed to indicate that the formulation excipients were safe and thus AzA-loaded nanoparticles appear to be an efficient and safe treatment for acne. PMID- 23673204 TI - Influence of waste management policy on the characteristics of beach litter in Kaohsiung, Taiwan. AB - Marine debris is a ubiquitous problem that poses a serious threat to the global oceans; it has motivated public participation in clean-up campaigns, as well as governmental involvement in developing mitigation strategies. While it is known that the problem of marine litter may be affected by waste management practices on land, beach survey results have seldom been compared with them. In this study, marine litter surveys on four beaches of Cijin Island were conducted to explore the effects of waste management and policy implications. Indirect evidence shows that chances for land-based litter, such as plastic bags and bottles, entering the marine environment can be greatly decreased if they can be properly reduced, reused and recycled. We suggest that mitigation measures should focus on source reduction, waste recycling and management, utilizing effective economic instruments, and pursuing a long-term public education campaign to raise the public awareness of this problem. PMID- 23673205 TI - Application of the CARLIT index along a biogeographical gradient in the Alboran Sea (European Coast). AB - An index, based on littoral communities assemblages (CARLIT), was applied to assess the ecological status of Northwestern Mediterranean coastal waters, following the requirements of the European Water Framework Directive. The biogeographical particularities of the Alboran Sea suggested a reassessment of this index, and that was the main objective of this work. Due to these biogeographical particularities, two regions were proposed in the studied region, with new reference conditions for each region. Subsequently, by means of a multivariate analysis, littoral community abundances and the CARLIT index were compared with factors related to geomorphology, biogeography and anthropogenic pressures. Overall, the biogeographical component determined the distribution of littoral communities. In contrast, the ecological status yielded by the index only was significantly related to anthropogenic pressures. The results pointed out that the reassessment of the CARLIT index was suitable to evaluate the ecological status of the Alboran Sea. PMID- 23673206 TI - Sources, fluxes and risk of organic micropollutants to the Cantabrian Sea (Spain). AB - The sources, distribution and risk of 51 organic micropollutants (OMPs) in the Cantabrian coastal environment (NW Spain) were evaluated. Gas chromatography coupled to tandem mass spectrometry was used to determine polycyclic aromatic hydrocarbons, polychlorinated biphenyls, organochlorinated pesticides, polybrominated diphenyl ethers, phthalates esters, bisphenol A and alkylphenols. 45 OMPs were detected in coastal/estuarine waters. Wastewater treatment plant effluents and emissary discharges were identified as the main sources of contamination. The accumulation of OMPs in sediments and the bioaccumulation in 21 days caged mussels were also assessed. Chemical results were combined with the "Combined Monitoring-based and Modeling-based Priority Setting Scheme" COMMPS procedure for risk assessment analysis. Finally, the chemical status of the different sampling locations was estimated using site risk indexes. Those indexes can be conveniently displayed in quality geographical maps and are considered a valuable tool for the environmental management and risk assessment of the region under study. PMID- 23673207 TI - Retraction: the association between depression, socio-economic factors and dietary intake in mothers having primary school children living in Rey, South of Tehran, Iran. PMID- 23673208 TI - The LuxR family regulator Rv0195 modulates Mycobacterium tuberculosis dormancy and virulence. AB - Tuberculosis is a leading global killer that has not been effectively controlled to date. The ability of the causative agent, Mycobacterium tuberculosis, to become dormant is one of the major reasons for extended chemotherapeutic regimens and wide epidemicity. The underlying mechanisms of M. tuberculosis dormancy are not fully understood. In the present work, a LuxR family transcription factor gene, Rv0195, was deleted in the virulent M. tuberculosis strain H37Rv. Rv0195 deletion did not affect bacterial growth and long-term survival under aerobiosis but decreased cell survival and the ability to rapidly recover from dormancy in an in vitro anaerobiosis model. The deletion also reduced intracellular survivability under hypoxic and reductive stress triggered by vitamin C. Microarray hybridization analysis showed that Rv0195 affected the expression of more than 180 genes under anaerobiosis, and these genes did not overlap with the known anaerobiosis-up-regulated DosR regulon genes. Furthermore, the Rv0195 deletion diminished bacterial virulence in human macrophage-like cells and resulted in reduced bacterial survival and pathogenicity in a C57BL/6 mouse infection model. These findings offer a novel insight into the mechanisms by which M. tuberculosis adapts to and recovers from dormancy and demonstrate that the dormancy regulator Rv0195 contributes to bacterial virulence. PMID- 23673209 TI - Adult separation anxiety disorder in DSM-5. AB - Unlike other DSM-IV anxiety disorders, separation anxiety disorder (SAD) has been considered a disorder that typically begins in childhood, and could be diagnosed only in adults "if onset is before 18." Moreover, SAD is the only DSM-IV anxiety disorder placed under "Disorders Usually First Diagnosed in Infancy, Childhood, or Adolescence" whereas most anxiety disorders typically start--and are diagnosed -in childhood. Therefore, adult SAD may have been under-recognized and under diagnosed. A literature review was carried out on behalf of the Anxiety, Obsessive-Compulsive Spectrum, Posttraumatic, and Dissociative Disorders DSM-5 workgroup to explore the evidence for SAD in adulthood, focusing on potentially relevant clinical characteristics and risk factors. The review revealed that SAD in adulthood is prevalent, often comorbid and debilitating. The DSM-IV age-of onset criterion was not supported as a substantial portion of adults report first onset in adulthood. Research on putative risk factors is limited to childhood SAD: SAD runs in families, albeit patterns of familial aggregation and heritability estimates indicate low specificity. Tentative evidence for biomarkers and biased cognitive processes exists, again pointing to moderate SAD specificity only. Further research on the epidemiology, etiology, and treatment of ASAD, using DSM-5 criteria, is needed, and particularly prospective longitudinal studies to understand the developmental trajectories of separation anxiety disorder from childhood to adulthood. PMID- 23673210 TI - Claudin-8 expression in Sertoli cells and putative spermatogonial stem cells in the bovine testis. AB - Adhesion molecules are expressed by both adult and embryonic stem cells, with different classes of adhesion molecules involved in cell-membrane and intercellular contacts. In this study the expression of the adhesion molecule claudin-8 (CLDN8), a tight-junction protein, was investigated as a potential marker for undifferentiated spermatogonia in the bovine testis. We found that CLDN8 was expressed by both spermatogonia and a subset of Sertoli cells in the bovine testis. We also showed co-expression of GFRalpha1 in testis cells with CLDN8 and with Dolichos biflorus agglutinin-fluorescein isothiocyanate (DBA-FITC) staining. We observed co-enrichment of spermatogonia and CLDN8-expressing Sertoli cells in DBA-FITC-assisted magnetic-activated cell sorting (MACS), an observation supported by results from fluorescence-activated cell sorting analysis, which showed CLDN8-expressing cells were over-represented in the MACS-positive cell fraction, leading to the hypothesis that CLDN8 may play a role in the spermatogonial stem-cell niche. PMID- 23673211 TI - Inhibition of cytoplasmic GSK-3beta increases cisplatin resistance through activation of Wnt/beta-catenin signaling in A549/DDP cells. AB - Cisplatin-based chemotherapy is recommended as the first-line therapy for advanced non-small cell lung cancer (NSCLC). However, acquired cisplatin resistance is ubiquitous in patients with NSCLC, but the molecular mechanism of such resistance remains ambiguous. The present study sought to examine the role of the Wnt/beta-catenin signaling pathway in cisplatin resistance by assessing the phosphorylation and subcellular distribution of GSK-3beta in a human lung adenocarcinoma cell line, A549, and its cisplatin-resistant subline, A549/DDP. Total GSK-3beta, phosphorylated GSK-3beta(ser9) and phosphorylated GSK 3beta(tyr216) in cytoplasmic and nuclear fractions of A549/DDP and A549 cells were examined by western blot analysis. The regulation of cisplatin resistance, apoptosis, beta-catenin and survivin protein expression by inhibition of cytoplasmic GSK-3beta were determined by MTT assay, flow cytometry analysis, immunofluorescence technique and western blot analysis. In the present study, cytoplasmic levels of p-GSK-3beta(ser9) were significantly increased in A549/DDP cells as compared with A549 cells (P<0.01), and these levels were further increased by cisplatin treatment in A549/DDP cells (P<0.01). In contrast, cytoplasmic levels of p-GSK-3beta(ser9) were reduced in A549 cells after treatment with cisplatin (P<0.01). However, cytoplasmic levels of p-GSK 3beta(tyr216) were significantly decreased in A549/DDP cells as compared with A549 cells (P<0.01), and these levels were further decreased by cisplatin treatment in A549/DDP cells (P<0.01). Conversely, cytoplasmic levels of p-GSK 3beta(tyr216) were raised in A549 cells after treatment with cisplatin (P<0.01). Analysis of downstream effectors of the Wnt/beta-catenin signaling pathway revealed upregulation of beta-catenin and survivin expression in A549/DDP cells treated with cisplatin as compared to untreated cells. In A549 cells, cisplatin treatment decreased the expression of beta-catenin and survivin. Furthermore, phosphorylation of GSK-3beta at serine 9 by LiCl and transient interference of GSK-3beta by siRNA increased beta-catenin and survivin protein expression in A549/DDP cells. Low exogenous and endogenous cytoplasmic GSK-3beta expression enhanced the IC50 and inhibited apoptosis. In conclusion, activation of the Wnt/beta-catenin signaling pathway and upregulated survivin expression due to cytoplasmic GSK-3beta inhibition might lead to cisplatin resistance in NSCLC. PMID- 23673212 TI - Identification of a new Schistosoma mansoni SMYB1 partner: putative roles in RNA metabolism. AB - SMYB1 is a Schistosoma mansoni protein highly similar to members of the Y-box binding protein family. Similar to other homologues, SMYB1 is able to bind double and single-stranded DNA, as well as RNA molecules. The characterization of proteins involved in the regulation of gene expression in S. mansoni is of great importance for the understanding of molecular events that control morphological and physiological changes in this parasite. Here we demonstrate that SMYB1 is located in the cytoplasm of cells from different life-cycle stages of S. mansoni, suggesting that this protein is probably acting in mRNA metabolism in the cytoplasm and corroborating previous findings from our group that showed its ability to bind RNA. Protein-protein interactions are important events in all biological processes, since most proteins execute their functions through large supramolecular structures. Yeast two-hybrid screenings using SMYB1 as bait identified a partner in S. mansoni similar to the SmD3 protein of Drosophila melanogaster (SmRNP), which is important in the assembly of small nuclear ribonucleoprotein complexes. Also, pull-down assays were conducted using immobilized GST-SMYB1 proteins and confirmed the SMYB1-SmRNP interaction. The interaction of SMYB1 with a protein involved in mRNA processing suggests that it may act in processes such as turnover, transport and stabilization of RNA molecules. PMID- 23673213 TI - An insight into synthetic Schiff bases revealing antiproliferative activities in vitro. AB - Schiff bases or azomethines are among the most important groups of biomolecules. These compounds have been found to reveal both remarkable biological activities and a variety of valuable practical applications. An interest in the exploration of novel series of synthetic Schiff bases has undoubtedly been growing due to their proven utility as attractive lead structures for the design of novel cytotoxic and cytostatic agents with a mechanism of action that sometimes differs from that of clinically authorized anticancer agents. Therefore, in the present paper we have focussed our attention on the collected synthetic simple Schiff bases of aldimine- and ketimine-types revealing anticancer activities in vitro, that have been described in the scientific literature during the last decade, and on structural variations whose affect the antiproliferative activity in sets of the designed molecules. PMID- 23673214 TI - Remarkable antioxidant properties of a series of hydroxy-3-arylcoumarins. AB - In the present work we synthesized a series of hydroxy-3-arylcoumarins (compounds 1-9), some of them previously described as MAO-B selective inhibitors, with the aim of evaluating their antioxidant properties. Theoretical evaluation of ADME properties of all the derivatives was also carried out. From the ORAC-FL, ESR and CV data it was concluded that these derivatives are very good antioxidants, with a very interesting hydroxyl, DPPH and superoxide radicals scavenging profiles. In particular compound 9 is the most active and effective antioxidant of the series (ORAC-FL=13.5, capacity of scavenging hydroxyl radicals=100%, capacity of scavenging DPPH radicals=65.9% and capacity of scavenging superoxide radicals=71.5%). Kinetics profile for protection fluorescein probe against peroxyl radicals by addition of antioxidant molecule 9 was also performed. Therefore, it can operate as a potential candidate for preventing or minimizing the free radicals overproduction in oxidative-stress related diseases. PMID- 23673215 TI - Synthesis, biological evaluation, and molecular docking studies of novel 1,3,4 oxadiazole derivatives possessing benzotriazole moiety as FAK inhibitors with anticancer activity. AB - 1,3,4-Oxadiazole derivatives have drawn continuing interest over the years because of their varied biological activities. In order to search for novel anticancer agents, we designed and synthesized a series of new 1,3,4-oxadiazole derivatives containing benzotriazole moiety as potential focal adhesion kinase (FAK) inhibitors. All the synthesized compounds were firstly reported. Among the compounds, compound 4 shows the most potent inhibitory activity against MCF-7 and HT29 cell lines with IC50 values of 5.68 MUg/ml and 10.21 MUg/ml, respectively. Besides, all the compounds were assayed for FAK inhibitory activity using the TRAP-PCR-ELISA assay. The results showed compound 4 exhibited the most potent FAK inhibitory activity with IC50 values of 1.2+/-0.3 MUM. Docking simulation by positioning compound 4 into the FAK structure active site was performed to explore the possible binding mode. Apoptosis which was analyzed by flow cytometry, demonstrated that compound 4 induced apoptosis against MCF-7 cells. Therefore, compound 4 may be a potential anticancer agent against MCF-7 cancer cell. PMID- 23673216 TI - Design, synthesis and evaluation of antimicrobial activity of N-terminal modified Leucocin A analogues. AB - Class IIa bacteriocins are potent antimicrobial peptides produced by lactic acid bacteria to destroy competing microorganisms. The N-terminal domain of these peptides consists of a conserved YGNGV sequence and a disulphide bond. The YGNGV motif is essential for activity, whereas, the two cysteines involved in the disulphide bond can be replaced with hydrophobic residues. The C-terminal region has variable sequences, and folds into a conserved amphipathic alpha-helical structure. To elucidate the structure-activity relationship in the N-terminal domain of these peptides, three analogues (1-3) of a class IIa bacteriocin, Leucocin A (LeuA), were designed and synthesized by replacing the N-terminal beta sheet residues of the native peptide with shorter beta-turn motifs. Such replacement abolished the antibacterial activity in the analogues, however, analogue 1 was able to competitively inhibit the activity of native LeuA. Native LeuA (37-mer) was synthesized using native chemical ligation method in high yield. Solution conformation study using circular dichroism spectroscopy and molecular dynamics simulations suggested that the C-terminal region of analogue 1 adopts helical folding as found in LeuA, while the N-terminal region did not fold into beta-sheet conformation. These structure-activity studies highlight the role of proper folding and complete sequence in the activity of class IIa bacteriocins. PMID- 23673217 TI - Brassinolide-2,3-acetonide: a brassinolide-induced rice lamina joint inclination antagonist. AB - A novel chemical tool compound that is an antagonist of brassinolide (BL, 1) induced rice lamina joint inclination was developed. Although 2-O-, 3-O-, 22-O-, or 23-O-methylation of BL causes a critical decrease in biological activity,(5) a crystal structure of the extracellular leucine-rich repeat (LRR) domain of BRASSINOSTEROID-INSENSITIVE I (BRI1) bound to BL(3,4) indicates that the loss of activity of the O-methylated BL may result from not only the low affinity to BRI1, but also from blocking the interaction with another BR signaling factor, a partner protein of BRI1 (e.g., BRI1-ASSOCIATED KINASE 1, BAK1). On the basis of this hypothesis we synthesized the BL 2,3-acetonide 2, the 22,23-acetonide 3, and the 2,3:22,23-diacetonide 4 to assess the possibility of 2-O- and 3-O- or/and 22 O- and 23-O-alkylated BL as an antagonist in BR signaling evoked by exogenously applied BL. The 2,3-acetonide 2 more strongly inhibited the lamina inclination caused by BL relative to the 22,23-acetonide 3, whereas the diacetonide 4 had no effect most likely due to its increased hydrophobicity. This suggested that the 2,3-hydroxyl groups of BL play a more significant role in the interaction with a BRI1 partner protein rather than BRI1 itself in rice lamina joint inclination. Taken together it was demonstrated that BL, the most potent agonist of BRI1, is transformed into an antagonist by functionalization of the 2,3-dihydroxyl groups as the acetonide. This finding opens the door to the potential development of a chemical tool that modulates protein-protein interactions in the BR signaling pathway to dissect the BR-dependent processes. PMID- 23673218 TI - Artemisinin-derived dimer phosphate esters as potent anti-cytomegalovirus (anti CMV) and anti-cancer agents: a structure-activity study. AB - We recently reported the anti-cancer and anti-cytomegalovirus (CMV) activity of artemisinin-derived trioxane diphenylphosphate dimer 838. To probe the relationship between chemical structure and anti-CMV and anti-cancer activities, we now report synthesis and evaluation of a series of eight new dimer phosphate ester analogs of 838. This series of novel molecules was screened against human foreskin fibroblasts (HFFs) infected with CMV and against the human Jurkat T cell acute lymphoblastic leukemia cell line. This SAR study confirms the very high anti-CMV and anti-cancer potencies of dimer diphenyl phosphate ester 838 without its being toxic to normal cells. PMID- 23673219 TI - Small molecule fusion inhibitors: design, synthesis and biological evaluation of (Z)-3-(5-(3-benzyl-4-oxo-2-thioxothiazolidinylidene)methyl)-N-(3-carboxy-4 hydroxy)phenyl-2,5-dimethylpyrroles and related derivatives targeting HIV-1 gp41. AB - By a scaffold elongation strategy, a series of (Z)-3-(5-(3-benzyl-4-oxo-2 thioxothiazolidinylidene)methyl)-N-(3-carboxy-4-hydroxy)phenyl-2,5 dimethylpyrroles and related derivatives with a linear multi-aromatic-ring skeleton were designed, synthesized, and evaluated in HIV-1 gp41 and cellular assays. Among them, the most active compounds, 12e, 12g, and 12k with a one carbon linker (n=1) between the rhodanine (C) and phenyl (D) rings, exhibited very promising inhibitory potency with IC50 values of 1.8-2.6 MUM and EC50 values of 0.3-1.5 MUM against gp41 6-HB formation and HIV-1 replication in MT-2 cells, respectively. Additionally, they were almost equally effective against both T20 sensitive and resistant strains. The related SAR studies and molecular modeling results provided potential for further developing a new class of non-peptide small molecular fusion inhibitors targeting the HIV-1 gp41. PMID- 23673220 TI - Synthesis and biological evaluation of 18F-labled 2-phenylindole derivatives as PET imaging probes for beta-amyloid plaques. AB - A novel series of fluorinated 2-phenylindole derivatives were synthesized and evaluated as beta-amyloid imaging probes for PET. The in vitro inhibition assay demonstrated that their binding affinities for Abeta(1-42) aggregates ranged from 28.4 to 1097.8 nM. One ligand was labeled with (18)F ([(18)F]1a) for its high affinity (K(i)=28.4 nM), which was also confirmed by in vitro autoradiography experiments on brain sections of transgenic mouse (C57BL6, APPswe/PSEN1, 11 months old, male). In vivo biodistribution experiments in normal mice showed that this radiotracer displayed high initial uptake (5.82+/-0.51% ID/g at 2 min) into and moderate washout (2.77+/-0.31% ID/g at 60 min) from the brain. [(18)F]1a could be developed as a promising new PET imaging probe for Abeta plaques although necessary modifications are still needed. PMID- 23673221 TI - Synthesis and pharmacological investigation of new N-hydroxyalkyl-2 aminophenothiazines exhibiting marked MDR inhibitory effect. AB - Novel N-hydroxyalkyl-2-aminophenothiazines implying a tetrazole moiety at the alkyl chain have been synthesized by hydroboration-oxidation of dienes followed by Buchwald-Hartwig cross-coupling reaction. Also, some sulfoxide and sulfone derivatives have been prepared by selective oxidations. MDR inhibition studies on rat hepatocyte cell culture revealed that some derivatives exhibit marked biological efficacy exceeding that of the standard verapamil (e.g., 3h, 4h, 16). Selected derivatives were subjected to chemical resolution to provide both enantiomers which were shown of similar activity on P-gp interaction measurements. The new compounds exhibited no toxicity. PMID- 23673222 TI - Total chemical synthesis of dengue 2 virus capsid protein via native chemical ligation: role of the conserved salt-bridge. AB - The dengue capsid protein C is a highly basic alpha-helical protein of ~100 amino acid residues that forms an emphipathic homodimer to encapsidate the viral genome and to interact with viral membranes. The solution structure of dengue 2 capsid protein C (DEN2C) has been determined by NMR spectroscopy, revealing a large dimer interface formed almost exclusively by hydrophobic residues. The only acidic residue (Glu87) conserved in the capsid proteins of all four serotypes of dengue virus forms a salt bridge with the side chains of Lys45 and Arg55'. To understand the structural and functional significance of this conserved salt bridge, we chemically synthesized an N-terminally truncated form of DEN2C ((WT)DEN2C) and its salt bridge-void analog (E87A)DEN2C using the native chemical ligation technique developed by Kent and colleagues. Comparative biochemical and biophysical studies of these two synthetic proteins using circular dichroism spectroscopy, fluorescence polarization, protein thermal denaturation, and proteolytic susceptibility assay demonstrated that the conserved salt bridge contributed to DEN2C dimerization and stability as well as its resistance to proteolytic degradation. Our work provided insight into the role of a fully conserved structural element of the dengue capsid protein C and paved the way for additional functional studies of this important viral protein. PMID- 23673223 TI - Synthesis and biological evaluation of arctigenin ester and ether derivatives as activators of AMPK. AB - A series of new arctigenin and 9-deoxy-arctigenin derivatives bearing different ester and ether side chains at the phenolic hydroxyl positions are designed, synthesized, and evaluated for activating AMPK potency in L6 myoblasts. Initial biological evaluation indicates that some alkyl ester and phenethyl ether arctigenin derivatives display potential activities in AMPK phosphorylation improvement. Further structure-activity relationship analysis shows that arctigenin ester derivatives 3a, 3h and 9-deoxy-arctigenin phenethyl ether derivatives 6a, 6c, 6d activate AMPK more potently than arctigenin. Moreover, the 2-(3,4-dimethoxyphenyl)ethyl ether moiety of 6c has been demonstrated as a potential functional group to improve the effect of AMPK phosphorylation. The structural optimization of arctigenin leads to the identification of 6c as a promising lead compound that exhibits excellent activity in AMPK activation. PMID- 23673224 TI - Predicting CYP2C19 catalytic parameters for enantioselective oxidations using artificial neural networks and a chirality code. AB - Cytochromes P450 (CYP for isoforms) play a central role in biological processes especially metabolism of chiral molecules; thus, development of computational methods to predict parameters for chiral reactions is important for advancing this field. In this study, we identified the most optimal artificial neural networks using conformation-independent chirality codes to predict CYP2C19 catalytic parameters for enantioselective reactions. Optimization of the neural networks required identifying the most suitable representation of structure among a diverse array of training substrates, normalizing distribution of the corresponding catalytic parameters (k(cat), K(m), and k(cat)/K(m)), and determining the best topology for networks to make predictions. Among different structural descriptors, the use of partial atomic charges according to the CHelpG scheme and inclusion of hydrogens yielded the most optimal artificial neural networks. Their training also required resolution of poorly distributed output catalytic parameters using a Box-Cox transformation. End point leave-one-out cross correlations of the best neural networks revealed that predictions for individual catalytic parameters (k(cat) and K(m)) were more consistent with experimental values than those for catalytic efficiency (k(cat)/K(m)). Lastly, neural networks predicted correctly enantioselectivity and comparable catalytic parameters measured in this study for previously uncharacterized CYP2C19 substrates, R- and S-propranolol. Taken together, these seminal computational studies for CYP2C19 are the first to predict all catalytic parameters for enantioselective reactions using artificial neural networks and thus provide a foundation for expanding the prediction of cytochrome P450 reactions to chiral drugs, pollutants, and other biologically active compounds. PMID- 23673225 TI - Semisynthesis, cytotoxicity, antiviral activity, and drug interaction liability of 7-O-methylated analogues of flavonolignans from milk thistle. AB - Silymarin, an extract of the seeds of milk thistle (Silybum marianum), is used as an herbal remedy, particularly for hepatoprotection. The main chemical constituents in silymarin are seven flavonolignans. Recent studies explored the non-selective methylation of one flavonolignan, silybin B, and then tested those analogues for cytotoxicity and inhibition of both cytochrome P450 (CYP) 2C9 activity in human liver microsomes and hepatitis C virus infection in a human hepatoma (Huh7.5.1) cell line. In general, enhanced bioactivity was observed with the analogues. To further probe the biological consequences of methylation of the seven major flavonolignans, a series of 7-O-methylflavonolignans were generated. Optimization of the reaction conditions permitted selective methylation at the phenol in the 7-position in the presence of each metabolite's 4-5 other phenolic and/or alcoholic positions without the use of protecting groups. These 7-O methylated analogues, in parallel with the corresponding parent compounds, were evaluated for cytotoxicity against Huh7.5.1 cells; in all cases the monomethylated analogues were more cytotoxic than the parent compounds. Moreover, parent compounds that were relatively non-toxic and inactive or weak inhibitors of hepatitis C virus infection had enhanced cytotoxicity and anti-HCV activity upon 7-O-methylation. Also, the compounds were tested for inhibition of major drug metabolizing enzymes (CYP2C9, CYP3A4/5, UDP-glucuronsyltransferases) in pooled human liver or intestinal microsomes. Methylation of flavonolignans differentially modified inhibitory potency, with compounds demonstrating both increased and decreased potency depending upon the compound tested and the enzyme system investigated. In total, these data indicated that monomethylation modulates the cytotoxic, antiviral, and drug interaction potential of silymarin flavonolignans. PMID- 23673226 TI - Genomics and outbreak investigation: from sequence to consequence. AB - Outbreaks of infection can be devastating for individuals and societies. In this review, we examine the applications of new high-throughput sequencing approaches to the identification and characterization of outbreaks, focusing on the application of whole-genome sequencing (WGS) to outbreaks of bacterial infection. We describe traditional epidemiological analysis and show how WGS can be informative at multiple steps in outbreak investigation, as evidenced by many recent studies. We conclude that high-throughput sequencing approaches can make a significant contribution to the investigation of outbreaks of bacterial infection and that the integration of WGS with epidemiological investigation, diagnostic assays and antimicrobial susceptibility testing will precipitate radical changes in clinical microbiology and infectious disease epidemiology in the near future. However, several challenges remain before WGS can be routinely used in outbreak investigation and clinical practice. PMID- 23673227 TI - Exploring the unknowns involved in the transformation of muscle to meat. AB - Meat quality development, or the transformation of muscle to meat, involves a myriad of biochemical pathways that are largely well-studied in living muscle tissue. However, these pathways are less predictable when homeostatic ranges are violated. In addition, there is far less known about how various management or environmental stimuli impact these pathways, either by substrate load or altered cellular environment. Likewise, it is largely accepted that oxygen plays little to no role in the conversion of muscle to meat, as anaerobic metabolism predominates in the muscle tissue. Even so, the oxygen tension within the tissues does not fall precipitously at exsanguination. Therefore, transition to an anaerobic environment may impact energy metabolism postmortem. Antemortem handling, on the other hand, clearly impacts meat quality development, yet the exact mechanisms remain a mystery. In this paper, we will attempt to review those factors known to affect postmortem energy metabolism in muscle and explore those areas where additional work may be fruitful. PMID- 23673228 TI - Socioeconomic status and race as predictors of treatment-seeking behavior for pelvic organ prolapse. AB - OBJECTIVE: We sought to evaluate the prevalence of pelvic organ prolapse (POP) among a diverse group of women and to determine if race/ethnicity and/or socioeconomic status (SES) are factors in treatment-seeking behavior. STUDY DESIGN: All data were collected from the National Institutes of Health-supported Boston Area Community Health Survey. SES was calculated by a 2-factor index that combined household income with years of education. Inferential statistics comprised 1-way analysis of variance, with a post hoc Scheffe test performed to evaluate whether there were differences between individual groups. A chi(2) test was used to evaluate whether distributions were equal among the various questions by race/ethnicity and SES category. RESULTS: A total of 3205 women were included in the analysis. Hispanic ethnicity and younger age were associated with POP (P < .002 and P < .001, respectively) as well as with seeking treatment for prolapse (P = .007 and P < .001, respectively). These factors were also associated with subsequent surgical repair (P = .027 and P = .019, respectively). A regression model showed that women were 4.9% more likely to seek treatment for every year younger they were, across the range of age. Although women of a higher SES were more likely to have POP, SES was neither associated with a higher likelihood of seeking treatment nor with the surgical management of prolapse. CONCLUSION: Hispanic ethnicity and younger age were associated with seeking treatment for POP. Hispanics were more likely than whites or blacks to proceed with surgical management. There was no correlation of SES with any of the above factors. PMID- 23673229 TI - Combined screening for open spina bifida at 11-13 weeks using fetal biparietal diameter and maternal serum markers. AB - OBJECTIVE: Screening at 11-13 weeks with ultrasound biparietal diameter (BPD) can detect half of open spina bifida cases. Maternal serum alpha-fetoprotein (AFP) levels at 15-19 weeks are increased 3- to 4-fold, in open spina bifida. We assessed whether combined screening using BPD, AFP, and other serum markers at 11 13 weeks would increase detection. STUDY DESIGN: Maternal AFP levels were measured on serum stored at 11-13 weeks in 44 open spina bifida and 182 unaffected pregnancies, and results were expressed in multiples of the median (MoM) for gestational age. All samples had been measured for free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein (PAPP) A. A multivariate Gaussian model was used to predict screening performance from the serum data and BPD measurements on 80 cases, including 36 previously published. RESULTS: The median AFP level in cases was 1.201 MoM, significantly higher than in unaffected pregnancies (P < .01, 1 tail). The median free beta-hCG was significantly reduced to 0.820 MoM (P < .02), but the median PAPP-A was similar in cases and controls. Modeling predicted the following: BPD alone would detect 50% of cases for a 5% false-positive rate or 63% for 10%; adding AFP increases detection by 2%; and a combined test with BPD, AFP, and free beta-hCG detects 58% for 5% or 70% for 10%. CONCLUSION: Combining AFP and BPD with free beta-hCG as part of first-trimester aneuploidy screening would also allow early detection about two-thirds of cases with open spina bifida. PMID- 23673230 TI - External funding of obstetrical publications: citation significance and trends over 2 decades. AB - OBJECTIVE: The objective of the study was to identify the external funding status of the most frequently cited obstetrical publications (citation classics) and to assess trends in funded vs nonfunded manuscripts as well as each publication's type of external funding. STUDY DESIGN: For the first objective, the citation classics, which were reported in a previous publication, were reviewed to identify their funding status. For the second objective, all pregnancy-related and obstetrical publications from the 2 US-based leading journals, the American Journal of Obstetrics and Gynecology and Obstetrics and Gynecology, were reviewed to identify the funding status and trends between 1989 and 2012. RESULTS: Twenty seven of 44 of the citation classics (61%) had external funding, whereas only 43% of the reviewed regular (non-citation classic) obstetrical publications had external funding. There was a decreasing trend in the number of obstetrical manuscripts associated with a decreasing trend in the number and proportion of nonfunded manuscripts and an increasing trend in the number and proportion of National Institutes of Health (NIH)-funded manuscripts. Relative to 1989, in 2012 there was a 34.8% decrease in the number of published obstetrical manuscripts, a 59.6% decrease in the number of nonfunded manuscripts, and a 6.8% increase in the number of funded manuscripts accompanied by an 8.2% increase in the number of NIH funded publications. In the last 9 years (2004-2012), there was a 35.1% increase in the proportion of NIH-funded manuscripts accompanied by an 18.8% decrease in the proportion of non-NIH-funded manuscripts. CONCLUSION: Our findings provide useful data regarding the importance of securing NIH-based funding for physicians contemplating academic careers in obstetrics. PMID- 23673231 TI - Mycobacterium fortuitum peritonitis in peritoneal dialysis and its effects on the peritoneum. AB - Mycobacterium fortuitum peritonitis is a rare complication in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). A 47-year-old patient was admitted to our tertiary hospital because of culture-negative peritonitis with persisting signs of infection despite adequate empirical antibiotic treatment. Although M. fortuitum was detected and the antibiotic regime subsequently amended, catheter removal was inevitable and the dialysis modality converted to hemodialysis (HD). After long-term antibiotic treatment and an additional latency of 4 months without signs of residual infection, reinitiation of CAPD was planned. Explorative laparoscopy prior to catheter reinsertion revealed multiple adhesions within the peritoneal cavity, preventing adequate catheter function. The clinical course of M. fortuitum peritonitis, the need for catheter removal and the description of peritoneal changes are discussed regarding to recent literature. PMID- 23673232 TI - Pneumatosis cystoides intestinalis and hepatic portal venous gas on peritoneal dialysis. AB - Pneumatosis cystoides intestinalis is a condition in which polycystic air has entered the submucosa or serosa of the intestine. A 78-year-old man was admitted to our hospital for treatment of end-stage renal disease due to diabetic nephropathy. Peritoneal dialysis was initiated on hospital Day 14. We diagnosed peritonitis and the patient was treated with vancomycin on Day 40. However, computed tomography showed hepatic portal venous gas and dilation of the small intestine with pneumatosis on Day 55, and the patient subsequently died. Autopsy revealed multiple mucosal pneumatoses, up to 1 cm in diameter, from the duodenum to jejunum, which was consistent with pneumatosis cystoides intestinalis. No cystic lesions were found in the colon. Pneumatosis cystoides intestinalis is a rare and usually benign disorder, but in patients with diabetic end-stage renal disease, it may run a malignant course, perhaps due to uremic immune incompetence. PMID- 23673234 TI - Identifying and correcting scan noise and drift in the scanning transmission electron microscope. AB - The aberration-corrected scanning transmission electron microscope has great sensitivity to environmental or instrumental disturbances such as acoustic, mechanical, or electromagnetic interference. This interference can introduce distortions to the images recorded and degrade both signal noise and resolution performance. In addition, sample or stage drift can cause the images to appear warped and leads to unreliable lattice parameters being exhibited. Here a detailed study of the sources, natures, and effects of imaging distortions is presented, and from this analysis a piece of image reconstruction code has been developed that can restore the majority of the effects of these detrimental image distortions for atomic-resolution data. Example data are presented, and the performance of the restored images is compared quantitatively against the as recorded data. An improvement in apparent resolution of 16% and an improvement in signal-to-noise ratio of 30% were achieved, as well as correction of the drift up to the precision to which it can be measured. PMID- 23673235 TI - Psychosocial status 10 years after temporal lobe resection for epilepsy, a longitudinal controlled study. AB - Knowledge about long-term psychosocial outcome of temporal lobe resection (TLR) for epilepsy is limited. The aims of this study were to describe vocational outcome 10 years after TLR and to analyze the effect on the vocational situation by seizures, laterality of resection, verbal memory, and mood. Fifty-one patients were prospectively followed 10 years after TLR. Psychosocial and neuropsychological data were ascertained at baseline and 10 years after surgery and at corresponding time points for 23 controls. Fewer patients worked 10 years post-operatively compared with controls (TLR patients: 61% and controls: 96%). However, seizure-free patients were more likely to retain employment (71%) than patients who had seizures (41%). The odds of working full-time were 9.5 times higher for patients with seizure freedom than for those with continuing seizures. There were no associations between working at 10 years and side of resection or mood, and impairment of verbal memory did not have an influence on vocational outcome. PMID- 23673233 TI - The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer's disease mice. AB - INTRODUCTION: Despite years of research, there are no disease-modifying drugs for Alzheimer's disease (AD), a fatal, age-related neurodegenerative disorder. Screening for potential therapeutics in rodent models of AD has generally relied on testing compounds before pathology is present, thereby modeling disease prevention rather than disease modification. Furthermore, this approach to screening does not reflect the clinical presentation of AD patients which could explain the failure to translate compounds identified as beneficial in animal models to disease modifying compounds in clinical trials. Clearly a better approach to pre-clinical drug screening for AD is required. METHODS: To more accurately reflect the clinical setting, we used an alternative screening strategy involving the treatment of AD mice at a stage in the disease when pathology is already advanced. Aged (20-month-old) transgenic AD mice (APP/swePS1DeltaE9) were fed an exceptionally potent, orally active, memory enhancing and neurotrophic molecule called J147. Cognitive behavioral assays, histology, ELISA and Western blotting were used to assay the effect of J147 on memory, amyloid metabolism and neuroprotective pathways. J147 was also investigated in a scopolamine-induced model of memory impairment in C57Bl/6J mice and compared to donepezil. Details on the pharmacology and safety of J147 are also included. RESULTS: Data presented here demonstrate that J147 has the ability to rescue cognitive deficits when administered at a late stage in the disease. The ability of J147 to improve memory in aged AD mice is correlated with its induction of the neurotrophic factors NGF (nerve growth factor) and BDNF (brain derived neurotrophic factor) as well as several BDNF-responsive proteins which are important for learning and memory. The comparison between J147 and donepezil in the scopolamine model showed that while both compounds were comparable at rescuing short term memory, J147 was superior at rescuing spatial memory and a combination of the two worked best for contextual and cued memory. CONCLUSION: J147 is an exciting new compound that is extremely potent, safe in animal studies and orally active. J147 is a potential AD therapeutic due to its ability to provide immediate cognition benefits, and it also has the potential to halt and perhaps reverse disease progression in symptomatic animals as demonstrated in these studies. PMID- 23673236 TI - Chemical structure of the carbohydrate backbone of the lipopolysaccharide from Piscirickettsia salmonis. AB - Elucidation of the carbohydrate backbone structure of the lipopolysaccharide (LPS) from Piscirickettsia salmonis, the etiological agent of the salmonid rickettsial septicemia, is described. Structural information was established by a combination of monosaccharide and methylation analyses of LPS, and by NMR and mass spectrometries of oligosaccharides obtained through the use of various chemical degradations of the native polymer. The following structure of the backbone sugars was determined on the basis of the combined data from these experiments: [formula see text] The presence of two consecutive residues of diacetylated pseudaminic acid (Pse5,7Ac, 5,7-diacetamido-3,5,7,9-tetradeoxy-l glycero-l-manno-non-2-ulosonic acid) in the LPS appears to be unique among polysaccharides containing this acidic sugar. Similarly, the presence of 4 aminoarabinose (Ara4N, 4-amino-4-deoxy-l-arabinopyranose) on O-4 of the alpha GlcN1P of the lipid A moiety is a unique feature of this LPS. PMID- 23673237 TI - Synthesis of 2-(beta-D-glucopyranosylamino)-5-substituted-1,3,4-oxadiazoles for inhibition of glycogen phosphorylase. AB - Aromatic aldehyde 4-(2,3,4,6-tetra-O-acetyl-beta-d-glucopyranosyl)semicarbazones were synthesized by the addition of different hydrazones onto O-peracetylated beta-d-glucopyranosyl isocyanate. Oxidative transformations of these precursors gave O-protected 2-(beta-d-glucopyranosylamino)-5-substituted-1,3,4-oxadiazoles. Removal of the O-acetyl protecting groups under Zemplen conditions gave test compounds to show low micromolar inhibition against rabbit muscle glycogen phosphorylase b. Best inhibitors of these series were 4-(beta-d glucopyranosyl)semicarbazones of 4-nitrobenzaldehyde (Ki=4.5MUM), 2 naphthaldehyde (Ki=5.5MUM) and 2-(beta-d-glucopyranosylamino)-5-(4-methylphenyl) 1,3,4-oxadiazole (Ki=12MUM). PMID- 23673238 TI - Glycated albumin and diabetes mellitus. AB - BACKGROUND: Diabetes is a growing worldwide problem that is strongly associated with atherosclerosis. Screening and intervention for diabetes in the earliest stages are advocated for the prevention of diabetic complications and cardiovascular disease. SCOPE OF REVIEW: This review gives a background of and discusses the potential clinical utility of glycated albumin (GA) in diabetes. MAJOR CONCLUSIONS: GA is a ketoamine formed via a non-enzymatic glycation reaction of serum albumin and it reflects mean glycemia over two to three weeks. GA can be used for patients with anemia or hemoglobinopathies for whom the clinically measured hemoglobin A1c level may be inaccurate. Because both serum and plasma samples can be used, GA can be analyzed from the same samples as common biological markers. GA is a useful marker for the screening of diabetes in a medical evaluation. It can be also used to determine the effectiveness of treatment before initiating or changing medications for diabetic patients. GA is potentially an atherogenic protein in the development of diabetic atherosclerosis. GENERAL SIGNIFICANCE: GA measurement is useful as part of a routine examination to screen for both diabetes and atherosclerosis. This article is part of a Special Issue entitled Serum Albumin. PMID- 23673239 TI - Analytical analysis of synthesized biosilica from bioresidues. AB - Rice straw and maize stalk are major residues of agriculture field. These residues were utilized to synthesis nano-biosilica by sol-gel route. The structural properties of rice straw ash, maize stalks ash and biosilica were characterized by X-ray diffraction and FTIR. Morphology evaluation by SEM confirms the formation of nano-biosilica of spherical shape. PMID- 23673240 TI - Effect of dielectric material on bipolar nanosecond pulse diffuse dielectric barrier discharge in air at atmospheric pressure. AB - In this paper, dielectric plates made by ceramic, quartz and polytetrafluoroethylene (PTFE) respectively are employed to generate low gas temperature, diffuse dielectric barrier discharge plasma by using a needle-plate electrode configuration in air at atmospheric pressure. Both discharge images and the optical emission spectra are obtained while ceramic, quartz and PTFE are used as dielectric material. Plasma gas temperature is also calculated by comparing the experimental emission spectra with the best fitted spectra of N2 (C(3)Piu >B(3)Pig 1-3) and N2 (C(3)Piu->B(3)Pig 0-2). The effects of different pulse peak voltages and gas gap distances on the emission intensity of N2 (C(3)Piu->B(3)Pig, 0-0, 337.1 nm) and the plasma area on dielectric surface are investigated while ceramic, quartz and PTFE are used as dielectric material. It is found that the permittivity of dielectric material plays an important role in the discharge homogeneity, plasma gas temperature, emission spectra intensity of the discharge, etc. Dielectric with higher permittivity i.e., ceramic means brighter discharge luminosity and stronger emission spectra intensity of N2 (C(3)Piu->B(3)Pig, 0-0, 337.1 nm) among the three dielectric materials. However, more homogeneous, larger plasma area on dielectric surface and lower plasma gas temperature can be obtained under dielectric with lower permittivity i.e., PTFE. The emission spectra intensity and plasma gas temperature of the discharge while the dielectric plate is made by quartz are smaller than that while ceramic is used as dielectric material and bigger than that when PTFE is used as dielectric material. PMID- 23673241 TI - Linear oxygen-sensing response from a rhenium complex induced by heavy atom: synthesis, characterization, photophysical study and sensing performance. AB - In this paper, we synthesized a Br-containing ligand of 2-(4-bromophenyl)-5 (pyridin-2-yl)-1,3,4-oxadiazole and its corresponding Re(I) complex. Their synthesis, characterization, single crystal structure, electronic transitions and photophysical property were presented and discussed in detail. This Re(I) complex was found to be a yellow emitter with slim pi->pi* radiative decay contribution, and its emission was also found to be sensitive towards O2. By doping this Re(I) complex into a polymer matrix, the oxygen-sensing performance of the resulted composite nanofibers was also investigated. Owing to the porous structure of the supporting matrix, the optimal sample gave the highest sensitivity of 3.91 with short response time of only 9 s. In addition, the linearity of the Stern-Volmer plots was greatly improved due to the highly pure emissive center triggered by heavy-atom turbulence effect from Br atom, as indicted by theoretical calculation result. PMID- 23673242 TI - Solvent modulated photophysics of 9-methyl anthroate: exploring the effect of polarity and hydrogen bonding on the emissive state. AB - Photophysical properties of an anthracene derivative 9-methyl anthroate (9-MA) have been investigated using absorption and emission spectroscopy, in combination with quantum chemical calculations. Solvatochromic effects on the Stokes shifted emission band clearly demonstrate the highly polar character of the excited state, which is also supported by the enhancement of dipole moment of the molecule upon photoexcitation. The emission band has been found to be dependent on polarity and hydrogen-bonding ability of the solvents. Multiple linear regression analysis method has been utilized to rationalize the effect of hydrogen bonding interaction on the emissive state, which was further confirmed by the analysis of the non-radiative decay constants and urea induced H-bonding disruption study. The experimental results correlate well with theoretical predictions obtained via density functional theory (DFT). PMID- 23673243 TI - Solvent-free synthesis, spectral correlations and antimicrobial activities of some aryl E 2-propen-1-ones. AB - Totally 38 aryl E 2-propen-1-ones including nine substituted styryl 4-iodophenyl ketones have been synthesised using solvent-free SiO2-H3PO4 catalyzed Aldol condensation between respective methyl ketones and substituted benzaldehydes under microwave irradiation. The yields of the ketones are more than 80%. The synthesised chalcones were characterized by their analytical, physical and spectroscopic data. The spectral frequencies of synthesised substituted styryl 4 iodophenyl ketones have been correlated with Hammett substituent constants, F and R parameters using single and multi-linear regression analysis. The antimicrobial activities of 4-iodophenyl chalcones have been studied using Bauer-Kirby method. PMID- 23673244 TI - Wagging motion of hydrogen-bonded wire in the excited-state multiple proton transfer process of 7-hydroxyquinoline.(NH3)3 cluster. AB - In this work, the dynamics of hydrogen bonds (as well as the hydrogen-bonded wire) in excited-state tautomerization of 7-hydroxyquinoline.(NH3)3 (7HQ.(NH3)3) cluster has been investigated by using time-dependent density functional theory (TDDFT). It shows that upon an excitation, the hydrogen bond between -OH group in 7-hydroxyquinoline (7HQ) and NH3 moiety would extremely strengthened in S1 state, which could effectively facilitate the releasing of the proton from the phenolic group of 7HQ moiety to the hydrogen-bonded wire and the forming an Eigen-like cationic wire (NH3...NH4(+)...NH3) in the cluster. To fulfill the different optimal angles of NH4(+) in the wire, a wagging motion of hydrogen-bonded wire would occur in excited state. Moreover, the wagging motion of the hydrogen-bonded wire would effectively promote excited-state proton transfer reaction. As the results, an excited-state multiple proton transfer (ESMPT) mechanism containing two concerted and asymmetrical processes has been proposed for the proton transfer dynamics of 7HQ.(NH3)3 cluster. PMID- 23673246 TI - Estimating 24-hour urinary sodium excretion from casual urinary sodium concentrations in Western populations: the INTERSALT study. AB - High intakes of dietary sodium are associated with elevated blood pressure levels and an increased risk of cardiovascular disease. National and international guidelines recommend reduced sodium intake in the general population, which necessitates population-wide surveillance. We assessed the utility of casual (spot) urine specimens in estimating 24-hour urinary sodium excretion as a marker of sodium intake in the International Cooperative Study on Salt, Other Factors, and Blood Pressure. There were 5,693 participants recruited in 1984-1987 at the ages of 20-59 years from 29 North American and European samples. Participants were randomly assigned to test or validation data sets. Equations derived from casual urinary sodium concentration and other variables in the test data were applied to the validation data set. Correlations between observed and estimated 24-hour sodium excretion were 0.50 for individual men and 0.51 for individual women; the values were 0.79 and 0.71, respectively, for population samples. Bias in mean values (observed minus estimated) was small; for men and women, the values were -1.6 mmol per 24 hours and 2.3 mmol per 24 hours, respectively, at the individual level and -1.8 mmol per 24 hours and 2.2 mmol per 24 hours, respectively, at the population level. Proportions of individuals with urinary 24 hour sodium excretion above the recommended levels were slightly overestimated by the models. Casual urine specimens may be a useful, low-burden, low-cost alternative to 24-hour urine collections for estimation of population sodium intakes; ongoing calibration with study-specific 24-hour urinary collections is recommended to increase validity. PMID- 23673247 TI - Anthropometric measures and the risk of endometrial cancer, overall and by tumor microsatellite status and histological subtype. AB - Obesity is an established risk factor for endometrial cancer, but this association is not well understood for subtypes of endometrial cancer. We evaluated the association of recent and adult-life obesity with subtypes of endometrial cancer based on microsatellite status (microsatellite-stable (MSS) vs. microsatellite-instable (MSI)) and histology (type I vs. type II). Analyses were based on a population-based case-control study (524 cases and 1,032 controls) conducted in Alberta, Canada (2002-2006) and included the following groupings of subtypes: MSS = 337 and MSI = 130; type I = 458 and type II = 66. Logistic and polytomous logistic regression were used to estimate odds ratios and 95% confidence intervals for overall endometrial cancer and subtypes of endometrial cancer, respectively. The risks of all subtypes of endometrial cancer, except type II, increased with an increase in all of the anthropometric characteristics examined. The risks for MSI tumors were suggestively stronger than those for MSS tumors; the risk with high (>=30) body mass index (weight (kg)/height (m)(2)) was significantly stronger for MSI tumors (odds ratio = 4.96, 95% confidence interval: 2.76, 8.91) than for MSS tumors (odds ratio = 2.33, 95% confidence interval: 1.66, 3.28) (P-heterogeneity = 0.02). Obesity is associated with most subtypes of endometrial cancer, and further studies are warranted to elucidate the biological mechanisms underlying the stronger risk for the MSI subtype with a high body mass index. PMID- 23673248 TI - Invited commentary: Quantifying salt in urine--a complex solution. AB - Reduction of dietary sodium intake has been identified as a priority to reduce the worldwide burden of hypertension and cardiovascular disease. Dietary sodium intake is most precisely ascertained by using timed urine collection. Casual urine sodium measurements are relatively easy to perform, but their relationship to timed urine sodium measurements is unclear. In this issue of the Journal, Brown et al. (Am J Epidemiol. 2013;177(11):1180-1192) report the development and validation of equations to estimate 24-hour urine sodium excretion from casual urine samples. Their study included a large number of participants on 2 continents, a well-collected gold standard, separate discovery and validation samples, and relevant covariates. The resulting equations represent the best available methods to estimate dietary sodium intake from casual urine samples. However, the study is limited by evidence of a suboptimal model fit, restriction to people 20-59 years of age in North America and Europe, and exclusion and adjustment that further limit external validity. In addition, individual-level correlations of estimated and measured 24-hour urine sodium excretion were modest. Properly applied, the results will facilitate tracking of dietary sodium intake within populations over time and identification of communities for which dietary sodium restriction is most likely to be beneficial. Further work is needed to extend estimation to additional populations and improve individual level assessment. PMID- 23673250 TI - No trust on the left side: hemifacial asymmetries for trustworthiness and emotional expressions. AB - People can discriminate cheaters from cooperators by their appearance. However, successful cheater detection can be thwarted by a posed smile, which cheaters display with greater emotional intensity than cooperators. The present study investigated the underlying neural and cognitive mechanisms of a posed smile, which cheaters use to conceal their anti-social attitude, in terms of hemifacial asymmetries of emotional expressions. Raters (50 women and 50 men) performed trustworthiness judgments on composite faces of cheaters and cooperators, operationally defined by the number of deceptions in an economic game. The left left composites of cheaters were judged to be more trustworthy than the right right composites when the models posed a happy expression. This left-hemiface advantage for the happy expression was not observed for cooperators. In addition, the left-hemiface advantage of cheaters disappeared for the angry expression. These results suggest that cheaters used the left hemiface, which is connected to the emotional side of the brain (i.e., the right hemisphere), more effectively than the right hemiface to conceal their anti-social attitude. PMID- 23673249 TI - Infections by Babesia caballi and Theileria equi in Jordanian equids: epidemiology and genetic diversity. AB - Microscopic diagnosis of equine piroplasmoses, caused by Theileria equi and Babesia caballi, is hindered by low parasitaemia during the latent phase of the infections. However, this constraint can be overcome by the application of PCR followed by sequencing. Out of 288 animals examined, the piroplasmid DNA was detected in 78 (27.1%). Multiplex PCR indicated that T. equi (18.8%) was more prevalent than B. caballi (7.3%), while mixed infections were conspicuously absent. Sequences of 69 PCR amplicons obtained by the 'catch-all' PCR were in concordance with those amplified by the multiplex strategy. Computed minimal adequate model analyses for both equine piroplasmid species separately showed a significant effect of host species and age in the case of T. equi, while in the B. caballi infections only the correlation with host sex was significant. Phylogenetic analyses inferred the occurrence of three genotypes of T. equi and B. caballi. Moreover, a novel genotype C of B. caballi was identified. The dendrogram based on obtained sequences of T. equi revealed possible speciation events. The infections with T. equi and B. caballi are enzootic in all ecozones of Jordan and different genotypes circulate wherever dense horse population exists. PMID- 23673251 TI - Exposure to violence reduces empathetic responses to other's pain. AB - Past researches showed that empathy for pain not only triggers a resonance mechanism between other and self, but also is modulated by contextual factors. Using functional magnetic resonance imaging, the present study demonstrated that short-term media violence exposure reduced both pain ratings and also the activation of anterior insula and anterior mid-cingulate cortex to other's pain. Thus, violence exposure modulated empathic responses to other's pain based on a physiological desensitization. PMID- 23673252 TI - Delayed oculomotor inhibition in patients with lesions to the human frontal oculomotor cortex: evidence from a study on saccade averaging. AB - The frontal oculomotor cortex is known to play an important role in oculomotor selection. The aim of the current study was to examine whether previously observed findings concerning the role of the frontal oculomotor cortex in the speed of saccade initiation and oculomotor inhibition might be related to a common underlying role of these areas in oculomotor selection. To this end, six patients with lesions to the frontal oculomotor cortex performed a double stimulus paradigm in which two elements were presented simultaneously in close proximity. Patients performed a block in which no specific task instruction was given and a block in which an instruction was provided about which of the two elements was the target. The rationale behind this manipulation was that the introduction of a specific task instruction would require a stronger involvement of top-down factors. In contrast to the block without a specific task instruction, saccade latencies to the contralesional visual field were longer than the ipsilesional visual field when a task instruction was given. This effect was strongest for saccades that landed away from the target and the distractor, reflecting trials in which strong oculomotor inhibition was applied. The observed deficits can be explained in terms of a slowing of the inhibitory signals associated with the rejection of a distractor. Given the known role of the Frontal Eye Fields and the location of the lesions, we attribute these findings to the Frontal Eye Fields, revealing their important role in the voluntary control of eye movements. PMID- 23673253 TI - The Human Genome Organisation: towards next-generation ethics. PMID- 23673254 TI - Application of ICP-DRC-MS to screening test of strontium and plutonium in environmental samples at Fukushima. AB - An application of sequential automated SPE separation equipment coupled to the quadrupole-based ICPMS instrumentation with a dynamic reaction cell such as a screening test system of (90)Sr and Pu isotopes in environmental samples was developed in this work. So far, during the course of a large number of reports as to various specific radioactivities in environmental samples surveyed at radioactive contaminated area around the Fukushima Daiichi Nuclear Power Plants (FDNPP), there is a much smaller number of reports on (90)Sr and Pu isotopes than that of (134)Cs and (137)Cs since the FDNPP accident, and then it would be expected to develop the simple analysis method of these isotopes instead of radiation measurements currently in use. In particular, a screening for (90)Sr in environmental samples has been accomplished using an isotopic ratio measurement mode in comparison with the characterization on the Solid Phase Elution (SPE) separation between strontium and zirconium isotopes around the mass-90 fraction. As a result, for a trial analysis of environmental samples of a muddy snow water and a soil which were collected at Fukushima, it was found that the present developed system makes it applicable for achieving up to the specific activity levels of several hundreds Bq/kg ((90)Sr) and about 1-2Bq/kg (Pu isotopes) as the screening test system. PMID- 23673255 TI - Application of a wet oxidation method for the quantification of 3H and 14C in low level radwastes. AB - Wet oxidation methods are utilized to separate and quantify (3)H and (14)C radionuclides in inorganic and organic radwastes generated at nuclear facilities. Because (3)H and (14)C are pure beta emitters with half-lives of 12.3 and 5,730 years, respectively, these radionuclides should be chemically separated from other radionuclides present in radwastes for accurate quantification. In particular, a collection technique for (14)C radionuclide in radwastes is needed because it is converted into (14)CO2 gas by an oxidation reaction. To confirm the recoveries of (3)H and (14)C, various standard radioactive sources were used to verify the proposed method. Because the majority of (3)H radionuclides are distributed in tritiated water (HTO), only tritiated water was used as a standard for (3)H radionuclides. Additionally, (14)C-labeled methanol ((14)CH3OH), lauric acid ((14)CH3(CH2)10COOH), sodium bicarbonate (NaH(14)CO3), and toluene (C6H5(14)CH3) were used as (14)C standards. The compounds were oxidized with chemical oxidants and then separated. The individual species were mixed with a scintillation cocktail and counted using a liquid scintillation counter. The recoveries of (14)C and (3)H were 82-97% and 98%, respectively. The wet oxidation method will be applied to RI wastes for clearance. PMID- 23673256 TI - Hydrogen, carbon and oxygen determination in proxy material samples using a LaBr3:Ce detector. AB - Hydrogen, carbon and oxygen concentrations were measured in caffeine, urea, ammonium acetate and melamine bulk samples via 14 MeV neutron inelastic scattering using a LaBr3:Ce detector. The samples tested herein represent drugs, explosives and benign materials, respectively. Despite its intrinsic activity, the LaBr3:Ce detector performed well in detecting the hydrogen, carbon and oxygen elements. Because 5.1 MeV nitrogen gamma rays interfere with silicon and calcium prompt gamma rays from the room background, the nitrogen peak was not detected in the samples. An excellent agreement was observed between the experimental and theoretical yields of 2.22, 4.43 and 6.13 MeV gamma rays from the analyzed samples as a function of H, C and O concentrations, respectively. Within statistical errors, the minimum detectable concentration (MDC) of hydrogen, carbon and oxygen elements in the tested materials were consistent with previously reported MDC values for these elements measured in hydrocarbon samples. PMID- 23673257 TI - A study of production of radioactive environmental reference materials used for proficiency testing program in Taiwan. AB - To realise radioactive environmental reference materials in Taiwan, seven environmental materials of soil, water, vegetation, meat, airborne particles (filter paper), milk and mushroom samples that are frequently encountered were used to establish the preparation of the reference materials. These seven environmental materials were collected, checked for freedom from radioactivity and prepared according to their properties. The preparation was carried out by using activity about 10-100 times that of the minimum detectable activity (MDA) in routine measurements in the radioactive standard used to spike the inactive material and this standard is traceable to national ionising radioactivity standards (TAF, 2004). To demonstrate sample traceability to the added standard, each sample was carefully measured and its uncertainty evaluated. Based on the recommendations of ISO Guide 35 for evaluation of reference materials and with the above assessment and verification procedures, the uncertainties (k=1) of the spike activity used in making reference materials were: (60)Co<=4.6%, (134)Cs<=4.7%, (137)Cs<=5.0%, total beta<=0.6% and (3)H<=1.3%. PMID- 23673258 TI - Poor predictive ability of the risk chart SCORE in a Danish population. AB - INTRODUCTION: In Denmark, the European risk chart Systematic COronary Risk Evaluation (SCORE) from the European Society of Cardiology is recommended for use in cardiovascular prevention. Nevertheless, its predictive ability in a Danish population has never been investigated. The purpose of this study was therefore to assess the predictive ability of the SCORE risk chart with regard to fatal cardiovascular risk according to the socio-demographic factors of age, sex, income and education in a Danish population. MATERIAL AND METHODS: Data from the third Copenhagen City Heart Study (n = 4,224) were linked to the Danish Cause of Death Registry. Calibration (i.e. Hosmer-Lemeshow goodness-of-fit), expected-to observed (E/O) mortality ratios in the total population and for subgroups, as well as discrimination (i.e. sensitivity, specificity, Area Under the Receiver Operator Characteristic (AUROC) and predictive values) were tested. Both SCORE high-risk and low-risk were applied for comparison. RESULTS: The results showed that both SCORE high-risk and low-risk performed acceptably in terms of discrimination (AUROC ~ 0.7-0.8); however, calibration for both SCORE charts was inadequate (chi2 > 20; p < 0.001). E/O-ratios varied with age, sex and socioeconomic status. CONCLUSION: There is a need to recalibrate SCORE to risk levels and risk factor distribution in the Danish population. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23673259 TI - Fast-track surgery for breast cancer is possible. AB - INTRODUCTION: Breast cancer is common among Danish women with more than 4,100 new cases annually. In 2008 the concept of fast-track surgery was introduced at the Department of Breast Surgery at Rigshospitalet, Copenhagen. The aim of this study is to describe the new clinical pathway for breast cancer patients after implementation of a fast-track surgery programme. MATERIAL AND METHODS: A clinical pathway of all involved disciplines was developed including anaesthetic, analgesics, nausea and vomiting, drain and wound management, discharge assessment and psychosocial support. RESULTS: The overall mean length of stay (LOS) decreased from 3.6 days before introduction of fast-track surgery to 1.2 days after its implementation. The largest decrease was observed among patients undergoing mastectomy, where LOS was reduced from 5.0 to 1.6 days. The number of beds at the department was reduced by about 30% and a nurse-led clinic was established which enabled nurses to take charge of wound management, seromas, temporary breast prostheses and psychosocial and rehabilitation aspects in the outpatient clinic. Additionally, the previously available telephone counselling service was intensified to provide immediate advice and support. CONCLUSION: The results confirm that a short stay can be successfully carried out for breast cancer patients. Implementing the fast-track programme involved the introduction of a clear clinical pathway for the patients and more effective daily routines. Patients felt safe and confident after early discharge. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23673260 TI - Abdominal auscultation does not provide clear clinical diagnoses. AB - INTRODUCTION: Abdominal auscultation is a part of the clinical examination of patients, but the determining factors in bowel sound evaluation are poorly described. The aim of this study was to assess inter- and intra-observer agreement in physicians' evaluation of pitch, intensity and quantity in abdominal auscultation. MATERIAL AND METHODS: A total of 100 physicians were presented with 20 bowel sound recordings in a blinded set-up. Recordings had been made in a mix of healthy volunteers and emergency patients. They evaluated pitch, intensity and quantity of bowel sounds in a questionnaire with three, three and four categories of answers, respectively. Fleiss' multi-rater kappa (kappa) coefficients were calculated for inter-observer agreement; for intra-observer agreement, calculation of probability was performed. RESULTS: Inter-observer agreement regarding pitch, intensity and quantity yielded kappa-values of 0.19 (p < 0.0001), 0.30 (p < 0.0001) and 0.24 (p < 0.0001), respectively, corresponding to slight, fair and fair agreement. Regarding intra-observer agreement, the probability of agreement was 0.55 (95% confidence interval (CI): 0.51-0.59), 0.45 (95% CI: 0.42-0.49) and 0.41 (95% CI: 0.38-0.45) for pitch, intensity and quantity, respectively. CONCLUSION: Although relatively poor, observer agreement was slight to fair and thus better than expected by chance. Since the diagnostic value of auscultation increases with addition of history and clinics, and may be further improved by systematic training, it should still be used in the examination of patients with acute abdominal pain. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23673262 TI - Occupational skin cancer may be underreported. AB - INTRODUCTION: Skin cancer may, in some cases, be caused by occupational exposures. The aim of this study was to investigate the prevalence of and exposures leading to occupationally induced skin cancers in Denmark during a ten year period. MATERIAL AND METHODS: The study is a descriptive, register-based study comprising all patients with recognized occupational malignant and premalignant skin conditions in Denmark in the 01/01 2000-31/12 2009 period. Data were obtained from The National Board of Industrial Injuries and comprise information about diagnosis, occupational and domestic exposure, anatomic localization, occupation, degree of permanent disability, age and sex. RESULTS: A total of 36 patients were recognized as occupational skin cancer cases. The mean age was 61 years (44-75 years), 31 men and five women. The most frequent diagnosis was basal cell carcinoma followed by squamous cell carcinoma. No cases of malignant melanoma were recognized. The primary risk factor for development of occupational skin cancer was ultraviolet (UV) exposure during outdoor working. CONCLUSION: Data based on recognized cases of occupational skin cancer during a ten-year period in Denmark show that non-melanoma skin cancer was the most frequent diagnosis, while the primary risk factor was UV radiation in outdoor occupations. A total of 36 cases were reported over a period of ten years, and underreporting may be suspected. The purpose of the present study was to raise the awareness of occupational skin cancer, and on the basis of existing data to contribute to criteria for the diagnosis of occupational skin cancer. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23673261 TI - Biochemical tests cannot differentiate between tonsillar and middle ear-derived infections. AB - INTRODUCTION: Infection markers are appreciated supplements in the clinical diagnosis of ear, nose and throat (ENT) infections. We aimed to examine the differential diagnostic usefulness of C-reactive protein (CRP), white blood cell count (WBC) and absolute neutrophil count (ANC) according to severity of middle ear and tonsillar infections. MATERIAL AND METHODS: This was a retrospective study including all patients admitted to the ENT Department, Aarhus University Hospital, from January 2001 to December 2008 and diagnosed with acute otitis media, mastoidismus, acute mastoiditis, acute tonsillitis, peritonsillar abscess, parapharyngeal abscess and necrotizing fasciitis. RESULTS: A total of 1,773 patients were included. Between the tonsil subgroups, significant differences were found in CRP (p < 0.001), WBC (p < 0.001) and ANC (p < 0.001) levels. However, sensitivities and specificities related to differential diagnostics were low. In the middle ear group, no differences in CRP (p = 0.84), WBC (p = 0.46), and ANC (p = 0.72) levels were found. The number of CRP levels above the reference value was significantly higher than the corresponding number of WBC and ANC levels. A trend (non-significant) was found towards lower parameter levels in acute tonsillitis and peritonsillar abscess patients who grew Staphylococcus aureus compared with patients infected with other bacteria. CONCLUSION: CRP and ANC levels were related to severity of tonsillar-derived infections, but no such relation was found in infections with middle ear origin. None of the infection markers studied were useful for differential diagnostics. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23673263 TI - Traditional SCORE-based health check fails to identify individuals who develop acute myocardial infarction. AB - INTRODUCTION: Atherosclerotic cardiovascular disease (CVD), including acute myocardial infarction (AMI), is caused by well-known risk factors. They constitute important therapeutic targets, but their predictive value is disputed. We evaluated the effectiveness of the risk scoring system (SCORE) and thresholds for pharmacotherapy re-commended in the European guidelines on CVD prevention. MATERIAL AND METHODS: The medical records of 605 consecutive patients hospitalized for a first AMI were reviewed. Patients with pre-existing CVD, diabetes, or incomplete information on risk factors were excluded. Those not treated with statin before AMI were risk stratified based on risk factors. A SCORE >= 5% or >= 10% was considered to qualify for preventive medication in young adults (age <= 60 years) or elderly (age > 60 years), respectively. RESULTS: Before AMI, 40 (9%) used statin. Among non-statin users, only five of the 109 young adults had a SCORE >= 5%, and 23 of the 284 elderly had a SCORE >= 10%. Among women, only three elderly qualified for treatment. More than four times more patients would have qualified for treatment with the high-risk country chart used in 2011. The incremental value of the novel high-density lipoprotein adjusted SCORE charts was limited. CONCLUSION: Few patients admitted with a first AMI used statin. Among non-statin users, SCORE and the recommended thresholds for pharmacotherapy identified no women and less than one out of ten men who untreated were destined for an AMI before 61 years of age. The preventive potential of a traditional risk factor-based health check is limited. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23673264 TI - Clinical characteristics of children with Mycoplasma pneumoniae infection hospitalized during the Danish 2010-2012 epidemic. AB - INTRODUCTION: Mycoplasma pneumoniae is a common cause of community-acquired pneumonia. Pneumonia may be the most severe manifestation of respiratory M. pneumoniae infection. The most typical symptoms in children are cough and wheezing, which are often accompanied by upper respiratory tract manifestations mimicking viralrespiratory syndromes. MATERIAL AND METHODS: This was a retrospective descriptive study. We included all children hospitalized at the Department of Paediatrics, Hvidovre Hospital, Denmark, from 1 August 2010 through May 2012 who tested positive for M. pneumoniae by polymerase chain reaction (PCR). Clinical data were obtained from the medical charts. RESULTS: A total of 671 PCR analyses for M. pneumoniae were performed of which 102 tested positive (15%). Our study included 101 M. pneumoniae-positive children with a median age of six years (range: 57 days-16 years). The cases were distributed throughout the year, but with a peak from October to January. 43% were five years or younger, with 18% being 0-1 years old and almost 7% being less than one year old. Only 17% were 11-16 years old. 58% of the patients reported more than seven days of fever and/or cough prior to admission. In all, 65 of 101 M. pneumoniae-positive children were discharged within 24 hours of admission. CONCLUSION: M. pneumoniae should be kept in mind as a cause not only of community-acquired pneumonia, but also of milder respiratory infections in children younger than five years. PCR from a nasal or throat swap is an easy, reliable and quick diagnostic test in infants and children. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23673265 TI - Surgery versus ultrasound-guided steroid injections for trigger finger disease: protocol of a randomized controlled trial. AB - INTRODUCTION: Trigger fingers have been reported in the literature for over a century; yet, the lack of trials comparing open surgery to corticosteroid injection is pronounced. At the initiation of the present study in 2010, no randomized controlled trials could be found comparing open surgery to corticosteroid injection. In the present randomized controlled trial, we plan to compare the efficacy of a single ultrasound-guided corticosteroid injection with conventional open surgery in terms of ability to correct the trigger finger. MATERIAL AND METHODS: The study is performed as an open-label single-centre, randomised controlled trial with a one-year follow-up. Patients are randomly assigned to either ultrasound-guided corticosteroid injection (n = 83) or to open surgical release of A1-pulley (n = 83). Follow-up is conducted at 12 weeks and one year after treatment. The affected finger will be assessed using a trigger finger score. Furthermore, any treatment complications, absence from work or sport and use of related medical services or additional treatment are also recorded. DISCUSSION: The present study will be the first to compare treatment of trigger finger by conventional open surgery with ultrasound-guided corticosteroid injection in a randomized controlled trial. The results will contribute to evidence-based recommendations for the treatment of trigger finger patients. FUNDING: not relevant. TRIAL REGISTRATION: Danish Data Protection Agency (1-16-02 119-11). The Central Denmark Region Committees on Biomedical Research Ethics (M 20110157). Clinicaltrials.gov: NCT 01486420. PMID- 23673266 TI - Good long-term results after tonsillectomy in ear, nose and throat practices. AB - INTRODUCTION: The objective was to evaluate the long-term results of outpatient tonsillectomy in Danish ear, nose and throat (ENT) practices in terms of satisfaction, quality of life (QoL) and relief of symptoms. MATERIAL AND METHODS: A telephone interview was carried out at least three years after tonsillectomy. Alternatively, a questionnaire was filled in by the patients. The answers were compared to a pre-operative questionnaire. RESULTS: The response rate was 63% (386/614). No differences were found between the responders and the non responders except that the proportion of smokers was higher in the non-responder group. QoL improved significantly and 93% were satisfied with having chosen tonsillectomy. 95% experienced complete or partial relief from their former throat-related symptoms. Eight to 11% had developed new symptoms from the throat including sleep-disordered breathing. CONCLUSION: With regard to QoL, satisfaction and relief of symptoms, the long-term results of outpatient tonsillectomy in Danish ENT practices are comparable to those obtained among hospitalized patients and they are in conformity with international standards. However, as approximately 10% develop new symptoms, it is important that physicians are aware of the indication as well as of any information received during shared decision-making with the patients/parents to adjust expectations. FUNDING: none. TRIAL REGISTRATION: none. PMID- 23673267 TI - Need for better analgesic treatment after tonsillectomy in ear, nose and throat practices. AB - INTRODUCTION: The objective of this study was to investigate patient-reported outcomes on quality (PRO) of outpatient tonsillectomy in Danish ear, nose and throat practices in terms of indicators, standards and prognostic factors. MATERIAL AND METHODS: Patients filled in a post-operative questionnaire three weeks after tonsillectomy. The questions were focused on the preoperative information about the procedure. Unscheduled contacts to Danish health care after the tonsillectomy and number of days absent from work/school were reported. A pain score was indicated daily during the first 14 post-operative days. RESULTS: A total of 89% of the 614 enrolled patients returned the questionnaire. 30% were dissatisfied with the information they had been afforded about post-operative complications and risks and 23% had unscheduled contacts to Danish health care. The daily pain score and absence from work/school were significantly higher among adults (> 15 years) than among children. The pain score correlated significantly with absence from work/school, unscheduled contacts and short observation time. PRO was significantly influenced by the length of the observation time before discharge, and a higher pain score was associated with a lower satisfaction with preoperative information about complications/risks. CONCLUSION: Most patients/parents are satisfied with outpatient tonsillectomy. However, the post operative pain control needs revision, the preoperative information should be intensified and the observation of the patients before discharge should be extended. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23673268 TI - GLP-2 and mesenteric blood flow. AB - The 33 amino acid peptide hormone GLP-2 is produced by enteroendocrine L-cells, the density of which is highest in the ileum and the colon, in response to the presence of nutrients in the lumen. The biological effect of GLP-2 is mediated by activation of a G-protein-coupled 7-transmembrane receptor. GLP-2 receptors are expressed in the brainstem, lungs, stomach, small intestine and colon, but not in the heart. It has been shown in several animal studies that GLP-2 infusion increases intestinal blood flow and that this increase is confined to the small intestine. The aim of the three studies, on which the thesis is based, was to investigate basic physiological effects of GLP-2, in healthy volunteers and in SBS patients, with focus on the effects on mesenteric blood flow, blood flow at other vascular sites and effects on cardiac parameters. These parameters have been evaluated after both meal stimulation and GLP-2 administration. The studies showed the following results: Blood flow: In all three studies, blood flow changes in the SMA after GLP-2 administration were similar regarding changes over time and degree of change. Blood flow changes were similar to changes seen after a standard meal. Only RI changes were registered in all three studies, but the TAMV changes in study 2 and 3 had similar characteristics. Cardiovascular parameters: In all three studies no significant changes in blood pressure were registered in relation to GLP-2 administration. In study two and three, where cardiac parameters also were registered by impedance cardiography, increases in CO and SV were seen. Plasma GLP-2: There were, as expected, supraphysiological GLP-2 plasma levels after SC administration. All three studies have shown rapid changes in mesenteric blood flow after administration GLP-2. The changes have been the same both in regards to time to maximum changes (increase) and relatively close in regards to maximum extent of change. The changes in the SBS patients were less than in the healthy test subjects. The findings leave no doubt about that GLP-2 is a potent regulator of upper splanchnic blood flow. The study findings also support the notion that the observed increased mesenteric blood flow, isolated to the SMA, is secondary to the metabolic responses to GLP-2, and that these are likely due to a paracrine action by GLP-2 acting on GLP-2R bearing cells such as enteric neurons, probably expressing NO. In conclusion GLP-2 increases mesenteric blood flow in healthy subjects and in SBS patients, the increase is equivalent to a standard meal and dose dependent. The blood flow is not increased at other arterial vascular sites. GLP-2 does not acutely alter blood pressure, but increases, probably as compensation, pulse rate and cardiac output. GLP-2 induced vascular response in the superior mesenteric artery is related with the length of remaining intestine in SBS patients. The effect is therefore likely to reflect the metabolic activity in the tissue rather than direct effect on the vascular system. PMID- 23673269 TI - Prostaglandins and prostaglandin receptor antagonism in migraine. AB - Human models of headache may contribute to understanding of prostaglandins' role in migraine pathogenesis. The current thesis investigated the migraine triggering effect of prostaglandin E2 (PGE2) in migraine patients without aura, the efficacy of a novel EP4 receptor antagonist, BGC20-1531, in prevention of PGE2-induced headache and the ability of prostaglandin F2alpha (PGF2alpha) to trigger headache without any vasodilatation in healthy volunteers. All studies were designed as double-blind, placebo-controlled, cross-over experiments, where PGE2/PGF2alpha or saline were infused over 20-25 min. In the study with EP4 receptor antagonist healthy volunteers were pre-treated with two different doses of BGC20-1531 or placebo followed by PGE2 infusion over 25 min. The headache data were collected during the whole study day, whereas the possible vascular changes were measured during the in-hospital phase of 1.5 h. The infusion of PGE2 caused the immediate migraine-like attacks and vasodilatation of the middle cerebral artery in migraine patients without aura. The highly specific and potent EP4 receptor antagonist, BGC20-1531, was not able to attenuate PGE2-induced headache and vasodilatation of both intra- and extra-cerebral arteries. The intravenous infusion of PGF2alpha did not induce headache or statistically significant vasoconstriction of cerebral arteries in healthy volunteers. Novel data on PGE2 provoked immediate migraine-like attacks suggest that PGE2 may be one of the important final products in the pathogenesis of migraine. The lack of efficacy of EP4 receptor antagonist suggests that a single receptor blockade is not sufficient to block PGE2 responses, hence EP2 receptor should be investigated as a potential drug target for the treatment of migraine. The absence of headache during the PGF2alpha infusion demonstrates that vasodilating properties are necessary for the induction of headache and migraine. PMID- 23673270 TI - Development and molecular composition of the hepatic progenitor cell niche. AB - End-stage liver diseases represent major health problems that are currently treated by liver transplantation. However, given the world-wide shortage of donor livers novel strategies are needed for therapeutic treatment. Adult stem cells have the ability to self-renew and differentiate into the more specialized cell types of a given organ and are found in tissues throughout the body. These cells, whose progeny are termed progenitor cells in human liver and oval cells in rodents, have the potential to treat patients through the generation of hepatic parenchymal cells, even from the patient's own tissue. Little is known regarding the nature of the hepatic progenitor cells. Though they are suggested to reside in the most distal part of the biliary tree, the canal of Hering, the lack of unique surface markers for these cells has hindered their isolation and characterization. Upon activation, they proliferate and form ductular structures, termed "ductular reactions", which radiate into the hepatic parenchyma. The ductular reactions contain activated progenitor cells that not only acquire a phenotype resembling that observed in developing liver but also display markers of differentiation shared with the cholangiocytic or hepatocytic lineages, the two parenchymal hepatic cell types. Interactions between the putative progenitor cells, the surrounding support cells and the extracellular matrix scaffold, all constituting the progenitor cell niche, are likely to be important for regulating progenitor cell activity and differentiation. Therefore, identifying novel progenitor cell markers and deciphering their microenvironment could facilitate clinical use. The aims of the present PhD thesis were to expand knowledge of the hepatic progenitor cell niche and characterize it both during development and in disease. Several animal models of hepatic injury are known to induce activation of the progenitor cells. In order to identify possible progenitor cell markers and niche components, we examined several genes upregulated in a global gene expression array conducted on one of these models, in which progenitor cells are activated. The protein expression patterns were evaluated in our collections of human embryonic and fetal livers, human liver diseases, and rodent hepatic injury models. When analyzing standard histological liver sections underlying connections and tissue architecture are not immediately evident. We therefore developed models for digitally reconstructing not only protein expression in serially cut tissue sections, but also vessels of the portal area. Article I constituted our earliest attempts to create 3D reconstructions of biological material. Human embryonic stem cell cultures were previously thought to consist of homogenously undifferentiated cells. The protocols for 3D reconstructions developed in this study demonstrated micro heterogeneity in expression of differentiation markers and provided the basis for later reconstructions of hepatic tissues. In article II we examined the expression patterns of chosen proteins seen upregulated in the gene array as well as classical hepatocytic and cholangiocytic markers in human liver disease and during prenatal development. Previous studies had indicated direct connections between activated progenitor cells apparently isolated in the parenchyma and the intrahepatic biliary tree. Our developed protocols for 3D reconstructions visually demonstrated direct connections between these entities. Analysis of protein expression in prenatal liver revealed the formation of the intrahepatic tree to occur through a special form of asymmetric tubulogenesis, only recently described in mice. In order to describe the composition of the hepatic progenitor cell niche and the localization of cell surface proteins in article III, the expression patterns of certain genes upregulated in the gene array analysis were analyzed in different models of rodent liver regeneration. We observed that the extracellular matrix molecules collagen 1a1, laminin, nidogen-1 and agrin embraced the biliary cells and sharply defined the hepatic progenitor cell niche, which was encircled by desmin positive support cells. In all injury models biliary cells expressed the cell surface proteins matriptase and HAI-1. However, in the so-called 2-AAF/PHx model of progenitor cell activation, a subpopulation of hepatic progenitor cells was positive for Dlk1. 3D reconstructions clarified that the Dlk1-subpopulation was entirely located in the portal area periphery, and connected to the bile ducts via HAI-1 positive biliary cells. The heterogeneous expression patterns of matriptase, HAI-1 and Dlk1 in this particular injury model indicate the presence of a cellular hierarchy containing possibly less differentiated Dlk1-positive hepatic progenitor cells. In conclusion, our studies characterized the hepatic progenitor cell niche in humans and rodents. We successfully developed protocols for digitally visualizing, not only hepatic, but virtually any tissue through two fundamentally distinct approaches. The identification of an asymmetric form of tubulogenesis in humans added new knowledge to the development of the intrahepatic biliary tree, and thereby the formation of the progenitor cell niche. The identification of heterogeneously expressed cell surface proteins and extracellular matrix components provided knowledge of the constituents defining the niche. These pieces of information are important for future isolation and characterization studies of biliary subpopulations and their differentiation abilities in vitro. PMID- 23673271 TI - Endoluminal pharmacologic stimulation of the upper urinary tract. AB - The experiments performed in this PhD thesis were conducted at the Institute of Experimental Surgery, Skejby Hospital, Aarhus, Denmark and at the Laboratory of Animal Science, Odense University Hospital, Denmark. The thesis is based on 3 peer review articles published in international journals and a review. Diagnostic or therapeutic endoscopic upper urinary tract procedures are usually characterised as minimal invasive procedures and associated with a low complication rate. Most often fever or pain are seen and sometimes septicaemia. However, mucosa lesion or even ureteric ruptures are known complications. Research has suggested that high renal pelvic pressures generated during these procedures, might contribute to per-/postoperative complications seen, and even possible renal parenchymal damage. Nevertheless, local administration (endoluminal) of a relaxant drug has not previously been tried in order to lower renal pelvic pressure. The purposes of this thesis were to examine the effect of local administration (endoluminal) of the nonspecific beta-adrenergic agonist ISOproterenol (ISO) on: 1) The normal pressure flow relation in porcine ureter, 2) The effect of endoluminal ISO perfusion during flexible ureterorenoscopy, 3) The pressure flow relation during semirigid ureterorenoscopy and 4) The cardiovascular system. Among other receptor-types beta-adrenergic receptor are located in the upper urinary tract and the activation thereof mediates smooth muscle relaxation. We have shown - in an animal experimental model - that ISO added to the irrigation fluid had significant impact on the renal pelvic pressures generated during upper urinary tract endoscopy. ISO significantly and dose dependently reduced the normal pressure flow relations by approximately 80% without concomitant cardiovascular side effects or measurable plasma levels of ISO. During flexible ureterorenoscopy 0.1 ug/ml ISO added to the irrigation fluid significantly reduced renal pelvic pressure during perfusion compared to saline perfusion alone. Pressures obtained during ISO perfusion were kept below the critical pressure for intrarenal reflux. The pressure flow relation during semirigid ureterorenoscopy was linear and ISO reduced pelvic pressure significantly, but not below the critical level for intrarenal reflux. In conclusion, ISO 0.1 ug/ml added to the irrigation fluid during endoscopic procedures was safe in this porcine model. Alongside this thesis, we have demonstrated the relaxing potency of 0.1 ug/ml ISO added to the irrigation fluid in a human trial and found it safe. Future research in this area, especially randomized clinical trials, regarding the relaxing potency, complication rates, pain episodes etc. should be evaluated. The addition of a relaxant drug to the irrigation fluid may prove to favour therapeutic or diagnostic endoscopic procedures in the upper urinary tract in the future. PMID- 23673273 TI - Microstructural characterization of concrete prepared with recycled aggregates. AB - Several authors have reported the workability, mechanical properties, and durability of concrete produced with construction waste replacing the natural aggregate. However, a systematic microstructural characterization of recycled aggregate concrete has not been reported. This work studies the use of fine recycled aggregate to replace fine natural aggregate in the production of concrete and reports the resulting microstructures. The used raw materials were natural aggregate, recycled aggregate obtained from a standard concrete, and Portland cement. The substitution extent was 0, 10, 50, and 100 vol%; hydration was stopped at 9, 24, and 96 h and 28 days. Microscopy was focused on the cement/aggregate interfacial transition zone, enlightening the effect of incorporating recycled aggregate on the formation and morphology of the different concrete hydration products. The results show that concretes with recycled aggregates exhibit typical microstructural features of the transition zone in normal strength concrete. Although overall porosity increases with increasing replacement, the interfacial bond is apparently stronger when recycled aggregates are used. An addition of 10 vol% results in a decrease in porosity at the interface with a corresponding increase of the material hardness. This provides an opportunity for development of increased strength Portland cement concretes using controlled amounts of concrete waste. PMID- 23673272 TI - Spectrins: a structural platform for stabilization and activation of membrane channels, receptors and transporters. AB - This review focuses on structure and functions of spectrin as a major component of the membrane skeleton. Recent advances on spectrin function as an interface for signal transduction mediation and a number of data concerning interaction of spectrin with membrane channels, adhesion molecules, receptors and transporters draw a picture of multifaceted protein. Here, we attempted to show the current depiction of multitask role of spectrin in cell physiology. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Herve. PMID- 23673275 TI - Functional neuroanatomical correlates of the executive clock drawing task (CLOX) performance in Alzheimer's disease: a FDG-PET study. AB - The executive clock drawing task (CLOX) is one of the widely used clock drawing tests (CDTs) and is composed of CLOX1, an unprompted CDT, and CLOX2, a simple copying CDT. Although it is conceptually believed that CLOX1 is sensitive to both executive function and constructional ability while CLOX2 reflects only constructional ability, there are still lack of studies on the functional neuroanatomical substrates of CLOX1 and 2 performances. This study aimed to identify the functional brain correlates of CLOX1 and 2 performances in patients with Alzheimer's disease (AD). CLOX was administered to 139 AD patients and 50 normal controls, and regional cerebral glucose metabolism (rCMglc) was measured by (18)F-fluoro-2-deoxy-glucose positron emission tomography. Correlations between CLOX scores and rCMglc were examined on a voxel-by-voxel basis in AD patients. For the overall AD group, significant positive correlations between CLOX1 and rCMglc were found in the bilateral temporo-parietal and left middle frontal regions, while CLOX2 was correlated with rCMglc of the bilateral temporo parietal regions. Additional subgroup analysis showed that CLOX1 was associated with the left temporal metabolism in less severe AD, and with the right temporo parietal metabolism in more severe AD. In contrast, CLOX2 was correlated with rCMglc of the diffuse right fronto-temporo-parietal regions in more severe AD, but not with any rCMglc in less severe AD. This is the first neuroimaging study on the functional neuroanatomical correlates of CLOX performances in AD. Given the relationships between specific cognitive performances and regional brain functions, the findings probably support the notion that CLOX1 demands not merely visuospatial functions but also executive control, while CLOX2 depends mainly on visuospatial ability. Our results also indicate that each CLOX performance depends on very different functional brain regions according to AD clinical stages. PMID- 23673274 TI - A novel in vitro bovine cartilage punch model for assessing the regeneration of focal cartilage defects with biocompatible bacterial nanocellulose. AB - INTRODUCTION: Current therapies for articular cartilage defects fail to achieve qualitatively sufficient tissue regeneration, possibly because of a mismatch between the speed of cartilage rebuilding and the resorption of degradable implant polymers. The present study focused on the self-healing capacity of resident cartilage cells in conjunction with cell-free and biocompatible (but non resorbable) bacterial nanocellulose (BNC). This was tested in a novel in vitro bovine cartilage punch model. METHODS: Standardized bovine cartilage discs with a central defect filled with BNC were cultured for up to eight weeks with/without stimulation with transforming growth factor-beta1 (TGF-beta1. Cartilage formation and integrity were analyzed by histology, immunohistochemistry and electron microscopy. Content, release and neosynthesis of the matrix molecules proteoglycan/aggrecan, collagen II and collagen I were also quantified. Finally, gene expression of these molecules was profiled in resident chondrocytes and chondrocytes migrated onto the cartilage surface or the implant material. RESULTS: Non-stimulated and especially TGF-beta1-stimulated cartilage discs displayed a preserved structural and functional integrity of the chondrocytes and surrounding matrix, remained vital in long-term culture (eight weeks) without signs of degeneration and showed substantial synthesis of cartilage-specific molecules at the protein and mRNA level. Whereas mobilization of chondrocytes from the matrix onto the surface of cartilage and implant was pivotal for successful seeding of cell-free BNC, chondrocytes did not immigrate into the central BNC area, possibly due to the relatively small diameter of its pores (2 to 5 MUm). Chondrocytes on the BNC surface showed signs of successful redifferentiation over time, including increase of aggrecan/collagen type II mRNA, decrease of collagen type I mRNA and initial deposition of proteoglycan and collagen type II in long-term high-density pellet cultures. Although TGF-beta1 stimulation showed protective effects on matrix integrity, effects on other parameters were limited. CONCLUSIONS: The present bovine cartilage punch model represents a robust, reproducible and highly suitable tool for the long-term culture of cartilage, maintaining matrix integrity and homoeostasis. As an alternative to animal studies, this model may closely reflect early stages of cartilage regeneration, allowing the evaluation of promising biomaterials with/without chondrogenic factors. PMID- 23673276 TI - Correlation between audio-visual enhancement of speech in different noise environments and SNR: a combined behavioral and electrophysiological study. AB - In the present study, we investigated the multisensory gain as the difference of speech recognition accuracies between the audio-visual (AV) and auditory-only (A) conditions, and the multisensory gain as the difference between the event-related potentials (ERPs) evoked under the AV condition and the sum of the ERPs evoked under the A and visual-only (V) conditions in different noise environments. Videos of a female speaker articulating the Chinese monosyllable words accompanied with different levels of pink noise were used as the stimulus materials. The selected signal-to-noise ratios (SNRs) were -16, -12, -8, -4 and 0 dB. Under the A, V and AV conditions the accuracy of the speech recognition was measured and the ERPs evoked under different conditions were analyzed, respectively. The behavioral results showed that the maximum gain as the difference of speech recognition accuracies between the AV and A conditions was at the -12 dB SNR. The ERP results showed that the multisensory gain as the difference between the ERPs evoked under the AV condition and the sum of ERPs evoked under the A and V conditions at the -12 dB SNR was significantly higher than those at the other SNRs in the time window of 130-200 ms in the area from frontal to central region. The multisensory gains in audio-visual speech recognition at different SNRs were not completely accordant with the principle of inverse effectiveness, but confirmed to cross-modal stochastic resonance. PMID- 23673277 TI - Galactooligosaccharide improves the animal survival and alleviates motor neuron death in SOD1G93A mouse model of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disease caused by selective degeneration and death of motor neurons. So far very limited therapeutic options have emerged to treat this fatal disease. Homocysteine (Hcy) lowering drugs have been suggested to be a palliative therapy of this disease. Folate, Vitamin B12 (VitB12) and Vitamin B6 (VitB6) are important elements involved in the Hcy metabolism and we proposed that medications which could promote the absorption of folate, VitB12 and VitB6 might have benefit for ALS. Galactooligosaccharides (GOS) is a prebiotic which could significantly improve the absorption and syntheses of B Vitamins. To investigate whether GOS could provide neuroprotective effect in ALS, we applied GOS and GOS rich prebiotic yogurt in SOD1(G93A) mice and assessed their effects on the disease progression of ALS. Our results showed that GOS and prebiotics yogurt administration significantly delayed the disease onset and prolonged the lifespan in SOD1(G93A) mice. Also, these products increased the concentration of folate, VitB12 and reduced the level of Hcy. Moreover, we found that both GOS and prebiotics yogurt attenuated motor neurons loss, improved the atrophy and mitochondrial activity in myocyte. Furthermore, we demonstrated that GOS and GOS rich prebiotic treatment suppressed the activation of astrocytes and microglia and regulated several inflammatory- and apoptosis-related factors. Our findings suggested that GOS might have therapeutic potential for ALS, and GOS-rich prebiotic yogurt might be considered as a nutritional therapy for this disease. PMID- 23673279 TI - The neurokinin-3 receptor (NK3R) antagonist SB222200 prevents the apomorphine evoked surface but not nuclear NK3R redistribution in dopaminergic neurons of the rat ventral tegmental area. AB - Schizophrenia is a severe condition that has been associated with functional abnormalities in dopaminergic (DA) neurons of the ventral tegmental area (VTA). Neurokinin-3 receptors (NK3Rs) of the tachykinin family of neuropeptides modulate the activity of VTA DA neurons and might be involved in DA abnormalities relevant to schizophrenia. Recent work from our lab showed that systemic injection of the dopamine D1/D2 receptor agonist apomorphine in rats, which mimics schizophrenia like behaviors in humans, also evoked a redistribution of NK3Rs in DA neurons of the rat VTA. In the present study, VTA microinjection of the selective NK3R antagonist SB222200 (1 nmol/0.2 MUl) or the nuclear import blocker SN50 (2 MUg/0.2 MUl) was performed in awake rats 10 min prior to systemic injection of apomorphine. VTA sections were dual immunolabeled for the NK3R (immunogold) and the dopamine synthesizing enzyme tyrosine hydroxylase (TH, immunoperoxidase). Electron microscopic quantifications of somatic and dendritic densities of NK3 immunogold particles were compared in rats receiving central and systemic injections. In DA (TH-labeled) dendrites, VTA microinjection of SB222200 prevented the apomorphine-evoked decrease in surface NK3R density as well as the apomorphine-induced increase in cytoplasmic NK3R density. In contrast, VTA microinjection of SN50, but not SB222200, prevented the apomorphine-induced increase in nuclear NK3R density. VTA microinjection of SB222200 or SN50 without apomorphine had no effect on the NK3R distribution or density in TH and non-TH profiles within the VTA. In non-TH, presumably GABAergic neurons of the VTA, the NK3R densities in somata and dendrites were not significantly changed by apomorphine with or without SB222200. The results suggest that the NK3R antagonist SB222200 is effective against the apomorphine-evoked NK3R internalization in VTA DA dendrites, but does not prevent nuclear NK3R trafficking in VTA DA neurons. These results might have important implications in targeting NK3R antagonists in basic or clinical studies. PMID- 23673280 TI - Involvement of SMAp in the intention-related long latency stretch reflex modulation: a TMS study. AB - When our movement is perturbed by environmental forces, the Long Latency Stretch Reflex (LLSR), generated by a transcortical loop through the primary motor cortex (M1), is the fastest reaction adapted according to our prior intent. We investigated the involvement of the caudal part of the Supplementary Motor Area (SMAp) in this intention-related LLSR modulation. Subjects were instructed either to not react (i.e. to 'let-go') or to resist a mechanical perturbation extending the wrist and Transcranial Magnetic Stimulation (TMS) was used to transiently inactivate SMAp, either at the time of the LLSR generation (TMS was applied 50 ms before the perturbation), or at the end of the preparation period (TMS was applied 150 ms before the perturbation). The effect of SMAp transient inactivation on the LLSR modulation was compared to the effect of transient inactivation of M1 or of a Control area. Compared to the Control condition, the intention-related LLSR modulation decreased when TMS was applied either over SMAp or over M1 50 ms before perturbation occurrence, suggesting that SMAp, as M1, is involved in the LLSR modulation. Moreover, the LLSR modulation also decreased when TMS was applied over SMAp 150 ms before the perturbation, indicating that anticipatory processes taking place in SMAp participate to the LLSR modulation. In addition, TMS applied over SMAp elicited Motor-Evoked Potentials (MEPs) whose latency and shape were similar to MEPs evoked by TMS over M1, suggesting that they are due to direct corticospinal projections from SMAp. Interestingly, the SMAp MEPs amplitude was modulated depending on the subject's intention to resist or to let-go. Taken together these results strongly favor the idea that, during the expectation of a perturbation, SMAp is the seat of anticipatory processes that are specific to the subject's intent and that preset M1 in order to adapt the LLSR to this intention. PMID- 23673278 TI - The non-selective cannabinoid receptor agonist WIN 55,212-2 attenuates responses of C-fiber nociceptors in a murine model of cancer pain. AB - Pain from cancer can be severe, difficult to treat, and greatly diminishes patients' quality of life. It is therefore important to gain new information on the mechanisms of cancer pain and develop new treatment strategies. We have used a murine model of bone cancer pain to investigate underlying peripheral neural mechanisms and novel treatment approaches. In this model, implantation of fibrosarcoma cells into and around the calcaneous bone produces mechanical and thermal hyperalgesia in mice. C-fiber nociceptors in tumor-bearing mice develop spontaneous ongoing activity and sensitization to thermal stimuli. However, it is unclear whether sensitization of nociceptors to mechanical stimuli underlies the mechanical hyperalgesia seen in tumor-bearing mice. We therefore examined responses of C-fiber nociceptors to suprathreshold mechanical stimuli in tumor bearing mice and found they did not differ from those of C-nociceptors in control mice. Thus, sensitization of C-fiber nociceptors to mechanical stimulation does not appear to underlie tumor-evoked mechanical hyperalgesia in this murine model of bone cancer pain. We also examined the effect of the non-selective cannabinoid receptor agonist, WIN 55,212-2, on spontaneous activity and responses evoked by mechanical stimuli of C-fiber nociceptors innervating the tumor-bearing paw. Selective CB1 and CB2 antagonists were administered to determine the contribution of each receptor subtype to the effects of WIN 55,212-2. Intraplantar administration of WIN 55,212-2 attenuated spontaneous discharge and responses evoked by mechanical stimulation of C-fiber nociceptors. These effects were inhibited by prior intraplantar administration of selective CB1 (AM281) or CB2 (AM630) receptor antagonists but not by vehicle. These results indicate that activation of either CB1 or CB2 receptors reduced the spontaneous activity of C fiber nociceptors associated with tumor growth as well as their evoked responses. Our results provide further evidence that activation of peripheral cannabinoid receptors may be a useful target for the treatment of cancer pain. PMID- 23673281 TI - The impact of gender on outcomes in patients with metastatic urothelial carcinoma. AB - BACKGROUND: Although urothelial cancer is more common in men, women with urothelial cancer have inferior survival outcomes. The potential existence of gender-related disparities in patients with metastatic urothelial cancer has not been extensively explored. PATIENTS AND METHODS: Individual patient data were pooled from 8 phase II and phase III trials evaluating first-line cisplatin-based combination chemotherapy in patients with metastatic urothelial carcinoma. Adverse events, treatment delivery, response proportions, and survival outcomes were compared between male and female patients. RESULTS: Of the 543 patients included in the analysis, 100 patients (18%) were women. There was no significant difference in the number of cycles of chemotherapy administered or in the proportions of patients experiencing severe toxicities when comparing male and female patients. There was no difference in the survival distributions between male and female patients (P = .08); the median survival of male patients was 11.7 months (95% confidence interval [CI], 10.5-13.2) compared with 16.2 months for female patients (95% CI, 12.8-20.4). There was no significant difference in survival between men and women when controlling for baseline performance status and/or the presence of visceral metastases. CONCLUSION: Female patients with metastatic urothelial cancer tolerate cisplatin-based chemotherapy similarly to male patients and achieve comparable clinical outcomes. Although gender associated survival disparities in patients with metastatic urothelial cancer cannot be completely ruled out, if such disparities exist, they are unlikely related to tolerability or efficacy of chemotherapy. PMID- 23673282 TI - Intravenous immune globulin therapy for Stevens-Johnson syndrome/toxic epidermal necrolysis complicated by hemolysis leading to pigment nephropathy and hemodialysis. AB - BACKGROUND: Intravenous immune globulin (IVIG) is generally thought to be of relatively low risk for adverse events and some experts consider this to be the best treatment for Stevens-Johnson syndrome/toxic epidermal necrolysis. OBJECTIVE: We evaluated the underlying cause of anemia and renal failure in 2 consecutive patients being treated with IVIG for Stevens-Johnson syndrome/toxic epidermal necrolysis. METHODS: This is a retrospective chart review. RESULTS: We present 2 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis and severe hemolysis requiring blood transfusion who subsequently developed pigment nephropathy necessitating hemodialysis after treatment with IVIG. Both patients had antibodies to their ABO blood type detected in the eluate from their red blood cell membrane. LIMITATIONS: This is a retrospective review with only 2 cases. CONCLUSIONS: We propose that IVIG-associated hemolysis is an adverse reaction that may not be as rare as once thought, presenting as a mild decrease in hemoglobin and hematocrit. Antibodies to blood type A and B are given as part of pooled immune globulin and are considered to be the cause of hemolysis. More severe anemia requiring transfusion is less common, and the breakdown products produced by hemolysis can lead to pigment nephropathy and renal failure. We present methods by which this severe complication can be anticipated and managed more effectively. PMID- 23673283 TI - Strain measurement at the nanoscale: Comparison between convergent beam electron diffraction, nano-beam electron diffraction, high resolution imaging and dark field electron holography. AB - Convergent beam electron diffraction (CBED), nano-beam electron diffraction (NBED or NBD), high resolution imaging (HRTEM and HRSTEM) and dark field electron holography (DFEH or HoloDark) are five TEM based techniques able to quantitatively measure strain at the nanometer scale. In order to demonstrate the advantages and disadvantages of each technique, two samples composed of epitaxial silicon-germanium layers embedded in a silicon matrix have been investigated. The five techniques are then compared in terms of strain precision and accuracy, spatial resolution, field of view, mapping abilities and ease of performance and analysis. PMID- 23673284 TI - Association study in Romanians confirms IL23A gene haplotype block rs2066808/rs11171806 as conferring risk to psoriatic arthritis. AB - BACKGROUND: The cytokines IL12 and IL23 have been recently implicated in the pathogenesis of psoriatic arthritis (PsA). In this study we investigated the genetic variations in the genes coding for IL12, IL23 and IL23 receptor as a plausible source of susceptibility and modification of clinical symptoms of PsA in Romanian population. METHODS: Twenty five SNPs mapping to IL12A, IL12B, IL23A, IL23R and IL12RB1 genes were genotyped in 94 PsA patients and 161 healthy controls of Romanian ethnicity using the Sequenom genotyping platform. RESULTS: The exonic SNP rs11171806 from IL23A gene was significantly underrepresented in patients versus controls (p=0.03, OR 0.391) and the carriers of rs11171806/rs2066808 AC haplotype had decreased risk for PsA (p=0.03). The two SNPs of the highly conserved gene IL23A are in complete LD in our population. Genetic variants of IL12B gene were associated with polyarticular subtype of PsA. No associations were found between SNPs from IL12A, IL23R and IL12RB1 genes and susceptibility to PsA and its phenotypes. CONCLUSION: We confirm the previously described association of rs2066808 variant with psoriasis and PsA and we show evidence of an extended genomic region inside IL23A gene as carrier of true disease susceptibility factors. These data suggest a role for IL23 in the PsA pathogenesis in Romanians. PMID- 23673285 TI - Interleukin-1beta stimulates platelet-activating factor production in U-937 cells modulating both its biosynthetic and catabolic enzymes. AB - Interleukin-1beta (IL-1beta) is a potent agonist of platelet-activating factor (PAF) synthesis. The monocyte-derived PAF may amplify the inflammatory and thrombotic processes. The IL-1beta-induced enzymatic alterations leading to increased PAF synthesis are ill-defined. In the present study the last enzymatic activities of the remodeling (acetyl-CoA:lyso-PAF acetyltransferase) and de novo (DTT-insensitive CDP-choline:1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase) biosynthetic routes of PAF and its main catabolic enzyme, PAF acetylhydrolase, along with the intracellular and extracellular PAF levels were determined in homogenates and medium of U-937 after their stimulation with recombinant IL-1beta. IL-1beta at 2.5ng/mL induced an early (0.5-3h) and a late (12h) elevation of intracellular PAF levels (2-fold). Only a small portion of intracellular PAF (~10%) was released to the extracellular medium. IL-1beta increased lyso-PAF acetyltrasnferase activity which was peaked at 3h and kept elevated till 12h. A rapid 1.5-fold increase of cholinephosphotransferase activity was observed in IL-1beta stimulated cells. Finally, a transient stimulation of intracellular PAF-AH was induced by IL-1beta at 3h while incubation of U-937 with the PAF acetylhydrolase inhibitor pefabloc in the presence or absence of IL-1beta led to a strong sustained increase of intracellular PAF levels. In conclusion, both biosynthetic routes of PAF, along with its degradation can be modulated by IL-1beta in a time-specific manner. The inhibition of PAF acetylhydrolase strongly augments PAF's intracellular levels implying its crucial role for the regulation of cellular PAF. The regulation of PAF's enzymatic machinery under inflammatory conditions is more complicated than we thought to be. PMID- 23673286 TI - Low dose LPS does not increase TLR4 expression on monocytes in a human in vivo model. AB - BACKGROUND AND PURPOSE: Toll like receptor 4 (TLR4) is the major recognition receptor for lipopolysaccharides and plays a major role in the inflammatory response. CD11b is expressed on the surface of many leukocytes including monocytes. The CD11b/CD18 complex is involved in the inflammatory response by mediating migration and adhesion of leukocytes. The aim of this human in vivo study was to investigate the expression of TLR4 and CD11b on the surface of human monocytes after in vivo low-dose LPS stimulation. METHODS: We performed a double blind, randomized crossover study with 16 healthy males who received a bolus injection of bacterial lipopolysaccharide (LPS; 0.4ng/kg) or normal saline. Vital parameters, blood counts, serum cytokine levels, the expression of TLR4, and CD11b on CD14 positive cells were analyzed. RESULTS: The experimentally induced inflammatory response was reflected by transient increases in body temperature, circulating leukocyte numbers, and plasma levels of pro- (TNF-alpha, IL-6) and anti-inflammatory cytokines (IL-10, IL-1ra). In contrast to a significant increase in CD11b expression, no changes in TLR4 expression on circulating monocytes were detectable. CONCLUSION: Early changes in TLR4 expression on circulating monocytes are not necessarily part of the inflammatory response to low dose LPS in humans whereas the detected increase of CD11b expression might already be sufficient for optimized recognition and signalling. PMID- 23673288 TI - Association between hepatic steatosis and hepatic expression of genes involved in innate immunity in patients with chronic hepatitis C. AB - BACKGROUNDS/AIMS: We investigated the association between hepatic steatosis and hepatic expression of genes involved in innate immunity, both of which are reportedly associated with resistance to peginterferon (PEG-IFN) and ribavirin combination therapy for hepatitis C virus (HCV) infection. METHODS: A total of 122 patients infected with HCV genotype 1b who underwent and completed PEG-IFN and ribavirin combination therapy were studied. Hepatic steatosis was evaluated on the basis of the liver specimen biopsied prior to antiviral therapy. The levels of mRNA of innate immunity genes (RIG-I, MDA5, LGP2, Cardif, RNF125, ISG15, and USP18) were measured by real-time polymerase chain reaction in RNA extracted from biopsied liver tissue and compared between patients with and without hepatic steatosis. RESULTS: The proportion of patients with hepatic steatosis, the hepatic expression levels of RIG-I gene, and RIG-I/Cardif and RIG I/RNF125 ratios were significantly higher in patients in whom serum HCV RNA did not disappear throughout the treatment period. Hepatic expression of RIG-I and the ratios of RIG-I/Cardif and RIG-I/RNF125 were significantly higher in patients with steatosis than those without. CONCLUSIONS: Changes in hepatic expression of some genes involved in innate immunity were observed along with hepatic steatosis, possibly playing a mechanistic role in resistance to IFN-based therapy in patients with hepatic steatosis. PMID- 23673287 TI - Chlamydia trachomatis infection results in a modest pro-inflammatory cytokine response and a decrease in T cell chemokine secretion in human polarized endocervical epithelial cells. AB - The endocervical epithelium is a major reservoir for Chlamydia trachomatis in women, and genital infections are extended in their duration. Epithelial cells act as mucosal sentinels by secreting cytokines and chemokines in response to pathogen challenge and infection. We therefore determined the signature cytokine and chemokine response of primary-like endocervix-derived epithelial cells in response to a common genital serovar (D) of C. trachomatis. For these studies, we used a recently-established polarized, immortalized, endocervical epithelial cell model (polA2EN) that maintains, in vitro, the architectural and functional characteristics of endocervical epithelial cells in vivo including the production of pro-inflammatory cytokines. PolA2EN cells were susceptible to C. trachomatis infection, and chlamydiae in these cells underwent a normal developmental cycle as determined by a one-step growth curve. IL1alpha protein levels were increased in both apical and basolateral secretions of C. trachomatis infected polA2EN cells, but this response did not occur until 72h after infection. Furthermore, protein levels of the pro-inflammatory cytokines and chemokines IL6, TNFalpha and CXCL8 were not significantly different between C. trachomatis infected polA2EN cells and mock infected cells at any time during the chlamydial developmental cycle up to 120h post-infection. Intriguingly, C. trachomatis infection resulted in a significant decrease in the constitutive secretion of T cell chemokines IP10 and RANTES, and this required a productive C. trachomatis infection. Examination of anti-inflammatory cytokines revealed a high constitutive apical secretion of IL1ra from polA2EN cells that was not significantly modulated by C. trachomatis infection. IL-11 was induced by C. trachomatis, although only from the basolateral membrane. These results suggest that C. trachomatis can use evasion strategies to circumvent a robust pro-inflammatory cytokine and chemokine response. These evasion strategies, together with the inherent immune repertoire of endocervical epithelial cells, may aid chlamydiae in establishing, and possibly sustaining, an intracellular niche in microenvironments of the endocervix in vivo. PMID- 23673289 TI - Depression in patients with newly diagnosed epilepsy predicts lamotrigine-induced rash: a short-term observational study. AB - Lamotrigine (LTG) has a good efficacy and tolerability as initial monotherapy for patients with newly diagnosed epilepsy (NDE). However, the occurrence of skin rash is one of the main reasons to discontinue LTG. On the basis of a high frequency of adverse effects associated with antiepileptic drugs in depressed patients, this study investigated whether depression is a likely predictor of LTG induced rash in patients with NDE. Eligible patients received LTG monotherapy and were observed for 12 weeks. Twenty (27%) of 74 enrolled patients had depression. Ten patients (13.5%) developed a skin rash within 5 weeks. Depression was a sole predictor of LTG-induced rash (OR=9.154, 95% CI 2.077-40.344, p=0.003). PMID- 23673290 TI - Father absence and depressive symptoms in adolescence: findings from a UK cohort. AB - BACKGROUND: Previous studies suggest a link between parental separation or divorce and risk of depression in adolescence. There are, however, few studies that have prospectively examined the effects of timing of biological father absence on risk for depressive symptoms in adolescence while controlling for a range of confounding factors. METHOD: We examine the association between father absence occurring in early (the first 5 years) and middle childhood (5-10 years) and adolescent depressive symptoms in a sample comprising 5631 children from the UK-based Avon Longitudinal Study of Parents and Children (ALSPAC). Self-reported depressive symptoms at 14 years were assessed using the Short Mood and Feelings Questionnaire (SMFQ). Father absence was assessed from maternal questionnaires completed at regular intervals from the birth of the study child up to 10 years. RESULTS: There was evidence for an association between father absence in early childhood and increased odds of depressive symptoms at 14 years. This association was stronger in girls than in boys and remained after adjusting for a range of socio-economic, maternal and familial confounders assessed prior to the father's departure. Conversely, there was no evidence for an association between father absence in middle childhood and depressive symptoms at 14 years. CONCLUSIONS: Father absence in early childhood increases risk for adolescent depressive symptoms, particularly in girls. Future research should be aimed at identifying possible biological and psychosocial mechanisms linking father absence to depressive symptomatology to enable the development of family-based early prevention and intervention programmes targeting young children at risk. PMID- 23673291 TI - Bioequivalence of oxycodone hydrochoride extended release tablets to marketed reference products OxyContin(r) in Canada and US. AB - INTRODUCTION: Oxycodone is a semisynthetic opioid agonist used for the relief of moderate to severe pain. A new generic oxycodone hydrochloride (HCl) extended release (ER) tablet is currently being developed by Ranbaxy Pharmaceutical Inc., New Brunswick, NJ, USA. OBJECTIVE: To assess relative bioavailability of a new generic (test) formulation of oxycodone hydrochloride (HCl) extended release (ER) tablets with that of marketed reference products, OxyContin(r), in Canada and USA, in healthy adult subjects under fasting and fed conditions. METHODS: Five studies were conducted in all, three of which were designed to comply with the regulatory criteria for marketing a new generic formulation of OxyContin(r) in Canada and the remaining two to comply with regulatory criteria for marketing a new generic formulation of OxyContin(r) in the USA. Each study was a balanced, randomized two-period, two-treatment, two-sequence, crossover design. A single oral dose of test or reference product was given in Period 1, followed by a 7-day washout period, after which subjects received the alternative product in Period 2. In order to block the pharmacological effects of oxycodone, subjects were administered naltrexone HCl (1 * 50 mg tablet) 12 hours prior to oxycodone HCl administration, concurrent with oxycodone HCl administration, and 12 hours after oxycodone HCl administration. Throughout the confinement portion of the study, adverse events were closely monitored. Serial blood samples were collected, following which oxycodone in plasma was estimated using a validated analytical procedure. RESULTS: Oxycodone was well tolerated by subjects in both periods of each study under both fed and fasted conditions. No serious adverse events were observed. The ratios of geometric means for AUC0-t and Cmax and the affiliated 90% confidence intervals for AUC were within acceptance range recommended by Health Canada. These criteria were met for both the raw data as well as data corrected for measured drug content (potency). The ratios of geometric means and the 90% confidence intervals for AUC0-t, AUC0-infinity and Cmax were within acceptance range recommended by United States Food and Drug Administration (FDA). CONCLUSIONS: Results demonstrate that the test formulation of oxycodone HCl ER tablets is bioequivalent to marketed OxyContin(r) reference formulations in Canada and USA, when administered both under fasted and fed conditions. Additionally, oxycodone HCl ER tablets were well tolerated as a single oral dose when administered to healthy adult subjects under fasted and fed conditions. PMID- 23673292 TI - A review of genomic data warehousing systems. AB - To facilitate the integration and querying of genomics data, a number of generic data warehousing frameworks have been developed. They differ in their design and capabilities, as well as their intended audience. We provide a comprehensive and quantitative review of those genomic data warehousing frameworks in the context of large-scale systems biology. We reviewed in detail four genomic data warehouses (BioMart, BioXRT, InterMine and PathwayTools) freely available to the academic community. We quantified 20 aspects of the warehouses, covering the accuracy of their responses, their computational requirements and development efforts. Performance of the warehouses was evaluated under various hardware configurations to help laboratories optimize hardware expenses. Each aspect of the benchmark may be dynamically weighted by scientists using our online tool BenchDW (http://warehousebenchmark.fungalgenomics.ca/benchmark/) to build custom warehouse profiles and tailor our results to their specific needs. PMID- 23673293 TI - Photoconjugation of molecularly imprinted polymer with magnetic nanoparticles. AB - Because of their synthetic accessibility, molecularly imprinted polymer (MIP) nanoparticles are ideal building blocks for preparing multifunctional composites. In this work, we developed a general photocoupling chemistry to enable simple conjugation of MIP nanoparticles with inorganic magnetic nanoparticles. We first synthesized MIP nanoparticles using propranolol as a model template and perfluorophenyl azide-modified silica-coated magnetic nanoparticles. Using a simple photoactivation followed by facile purification with a magnet, we obtained magnetic composite particles that showed selective uptake of propranolol. We characterized the nanoparticles and composite materials using FT-IR, TEM, fluorescence spectroscopy, and radioligand binding analysis. Through the high molecular selectivity of the magnetic composite, we demonstrated the nondestructive feature and the high efficiency of the photocoupling chemistry. The versatile photoconjugation method developed in this work should also be very useful for combining organic MIPs with other inorganic nanoparticles to enable new chemical sensors and high efficiency photocatalysts. PMID- 23673294 TI - Cancer cachexia decreases specific force and accelerates fatigue in limb muscle. AB - Cancer cachexia is a complex metabolic syndrome that is characterized by the loss of skeletal muscle mass and weakness, which compromises physical function, reduces quality of life, and ultimately can lead to mortality. Experimental models of cancer cachexia have recapitulated this skeletal muscle atrophy and consequent decline in muscle force generating capacity. However, more recently, we provided evidence that during severe cancer cachexia muscle weakness in the diaphragm muscle cannot be entirely accounted for by the muscle atrophy. This indicates that muscle weakness is not just a consequence of muscle atrophy but that there is also significant contractile dysfunction. The current study aimed to determine whether contractile dysfunction is also present in limb muscles during severe Colon-26 (C26) carcinoma cachexia by studying the glycolytic extensor digitorum longus (EDL) muscle and the oxidative soleus muscle, which has an activity pattern that more closely resembles the diaphragm. Severe C-26 cancer cachexia caused significant muscle fiber atrophy and a reduction in maximum absolute force in both the EDL and soleus muscles. However, normalization to muscle cross sectional area further demonstrated a 13% decrease in maximum isometric specific force in the EDL and an even greater decrease (17%) in maximum isometric specific force in the soleus. Time to peak tension and half relaxation time were also significantly slowed in both the EDL and the solei from C-26 mice compared to controls. Since, in addition to postural control, the oxidative soleus is also important for normal locomotion, we further performed a fatigue trial in the soleus and found that the decrease in relative force was greater and more rapid in solei from C-26 mice compared to controls. These data demonstrate that severe cancer cachexia causes profound muscle weakness that is not entirely explained by the muscle atrophy. In addition, cancer cachexia decreases the fatigue resistance of the soleus muscle, a postural muscle typically resistant to fatigue. Thus, specifically targeting contractile dysfunction represents an additional means to counter muscle weakness in cancer cachexia, in addition to targeting the prevention of muscle atrophy. PMID- 23673295 TI - 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) regulates CTL activation and memory programming. AB - 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the major carcinogens in tobacco. NNK has been associated with various cancers in tobacco users, especially lung cancer. However, the effects of NNK on cytotoxic T lymphocytes (CTLs), the cells responsible for destrcution of maligant and pathogen-infected cells, has not been elucidated. Using transgenic CTLs in vitro and in vivo, we show that NNK can directly affect CTL activation. NNK can enhance the expression of adhesion molecule CD62L in CTLs during their activation in vitro, but has no effects on their expansion and production of effector molecules such as IFN and granzyme B. After transferred into recipient mice, however, the NNK pretreated CTLs suffer an early loss in expansion. The percentage of memory precursors is higher in NNK pretreated CTLs, but the total amount of memory precursors is similar to controls. The final memory CTL population from NNK pretreated CTLs is reduced, but sustains a more central memory phenotype. In conclusion, NNK can affect CTL activation by modulating adhension molecule expression and reducing memory programming. PMID- 23673296 TI - Downregulation of miR-497 promotes tumor growth and angiogenesis by targeting HDGF in non-small cell lung cancer. AB - MicroRNAs (miRNAs) play important roles in the development of various cancers. MiRNA-497 functions as a tumor-suppressor that is downregulated in several malignancies; however, its role in non-small cell lung cancer (NSCLC) has not been examined in detail. Here, we showed that miR-497 is downregulated in NSCLC tumors and cell lines and its ectopic expression significantly inhibits cell proliferation and colony formation. Integrated analysis identified HDGF as a downstream target of miR-497, and the downregulation of HDGF by miR-497 overexpression confirmed their association. Rescue experiments showed that the inhibitory effect of miR-497 on cell proliferation and colony formation is predominantly mediated by the modulation of HDGF levels. Furthermore, tumor samples from NSCLC patients showed an inverse relationship between miR-497 and HDGF levels, and ectopic expression of miR-497 significantly inhibited tumor growth and angiogenesis in a SCID mouse xenograft model. Our results suggest that miR-497 may serve as a biomarker in NSCLC, and the modulation of its activity may represent a novel therapeutic strategy for the treatment of NSCLC patients. PMID- 23673298 TI - Molluscum contagiosum infection in mixed martial arts fighting: molluscum gladiatorum. PMID- 23673297 TI - Probing insect odorant receptors with their cognate ligands: insights into structural features. AB - Odorant receptors (ORs) are essential for insect survival in the environment and thus are ideal molecular targets for the design of insect-inspired modern green chemicals to control populations of agricultural pests and insects of medical importance. Although insect ORs are known for more than a decade, their structural biology is still in its infancy. Here, we unravel the first structural features of ORs from the malaria mosquito, the Southern house mosquito and the silkworm moth. The second extracellular loops (ECL-2s) of their predicted structures are much longer than ECL-1s and ECL-3s. The 27 amino-acid-residue-long of the ECL-2s in mosquito and the 43 amino-acid-residue-long ECL2s in moth ORs are well-conserved. About one-third of the residues are identical, including 3-4 Pro residues. Thorough examination of well-conserved residues in these structures, by point mutation and functional assay with the Xenopus oocyte recording system, strongly suggest that these "loops" include three beta-turns and some degree of folding. In the Southern house mosquito three Pro residues in ECL-2 are essential for full activation of the receptor, which is finely tuned to the oviposition attractant 3-methylindole. Additionally, the "corner residues" of prolines, including Gly, Tyr, and Leu are functionally important thus suggesting that turns are stabilized not only by backbone hydrogen bonds, but also by side chain interactions. Examination of ECL-2s from a distant taxonomical group suggests these ECL-2 loops might be functionally important in all insect ORs. Two of the four Pro residues in the predicted ECL-2 of the bombykol receptor in the silkworm moth, BmorOR1, are essential for function. Experimental evidence indicates that these loops may not be specificity determinants, but they may form a cover to the yet-to-be-identified membrane embedded binding cavities of insect ORs. PMID- 23673299 TI - The pathogenesis of vitiligo. AB - BACKGROUND: Vitiligo is a commonly encountered pigmentary disorder. Numerous studies and investigations from all over the world have attempted to determine the mechanisms behind this disease; however, the pathogenesis of vitiligo remains elusive. OBJECTIVE: n this comprehensive review article, we present the findings behind the five overarching theories of what causes this disfiguring and psychologically debilitating disease. METHOD: We begin our discussion with the role of genetic predisposition and move onward to the neural theory first proposed in the 1950s. Next we discuss the autoimmune hypothesis, followed by the reactive oxygen species model, and conclude by describing the findings of the more recent melanocytorrhagy hypothesis. CONCLUSION: Although the exact pathogenesis of vitiligo is uncertain, each of these theories likely plays a role. Understanding each theory would pave the way for therapeutic advances for this disease. PMID- 23673300 TI - Ingenol mebutate: a promising treatment for actinic keratoses and nonmelanoma skin cancers. AB - BACKGROUND: A new treatment for actinic keratoses, ingenol mebutate, was recently approved by the US Food and Drug Administration. OBJECTIVE: To review the mechanisms of action, efficacy and safety data, and practical recommendations for ingenol mebutate. METHODS: The PubMed and clinicaltrials.gov databases were searched in March/April 2012 using the terms PEP005, ingenol mebutate, and ingenol 3-angelate. The abstracts from the Annual Scientific Meeting of the Australian College of Dermatologists (2009-2011) and the Annual Meeting of the American Academy of Dermatology (2009-2012) were also searched. RESULTS: Due to its multiple mechanisms of action, ingenol mebutate treatment resulted in short- and long-term efficacy similar to other topical treatments for actinic keratoses in a shorter period of 2 or 3 days. This short therapy would reduce the duration of adverse events. Premarketing trials for treatment of nonmelanoma skin cancers also showed promising results for ingenol mebutate. CONCLUSION: Ingenol mebutate is a convenient, safe, and effective intervention for precancerous and cancerous skin conditions. PMID- 23673301 TI - Reactive arthritis in India: a dermatologists' perspective. AB - BACKGROUND: The mucocutaneous lesions in Reiter syndrome (RS) or reactive arthritis are seen quite frequently. MATERIALS AND METHODS: The case records of patients admitted with the diagnosis of RS from January 2006 to December 2010 were reviewed. Data regarding the demographic details; course of musculoskeletal, mucocutaneous, and ophthalmic involvement; body surface area affected; morphology of lesions; investigations undertaken; and treatment instituted were recorded. Based on these, the disease was classified as complete or incomplete RS. RESULTS: The case records of 11 patients were evaluated. There were seven males and four females. Only two patients had complete RS, whereas nine patients had incomplete RS. Arthritis and mucocutaneous involvement were seen in all 11 patients, whereas preceding urethritis/dysentery was seen in 4 patients and eye symptoms in 4 patients. Enthesitis was seen in eight patients (72.7%). Circinate balanitis/vulvitis was present in six patients and keratoderma blenorrhagicum in eight patients. The most frequent radiologic finding was juxta-articular osteopenia in eight patients. CONCLUSION: RS may not show the typical triad in all cases, although musculoskeletal disease is seen in a significant proportion of patients. In the absence of typical signs and symptoms, cutaneous manifestations may help establish the diagnosis of RS. PMID- 23673302 TI - Understanding and assessing potential serious adverse events: a practical approach to understanding the benefits and harm of psoriasis treatments. AB - BACKGROUND: Any therapeutic intervention carries with it the potential for benefit and harm. Generally, benefit is far more common than risk; however, risk aversion drives many of the treatment decisions made by patients and their physicians. OBJECTIVE: To provide guidelines to help clinicians improve their understanding of causality and the interpretation of harm. METHODS: A group of dermatologists involved in data safety monitoring boards, clinical trial investigators, and a clinical epidemiologist identified the need for practical advice on how to understand and explain causality and harm and combined to share their knowledge. RESULTS: An explanation of how data are collected and the environment that shapes the data seen by clinicians is presented. The article spans an overview of the regulatory environment that informs trial design for regulatory approval to a description of types of designs that inform safety and techniques, such as the rule of three, to provide guidance to clinicians in interpreting the data. CONCLUSION: Communicating the potential for harm to patients is critical. Placing the potential for rare and serious risks into perspective for the patient is as important as discussing the potential benefits of medication. PMID- 23673303 TI - Treatment of large xanthelasma palpebrarums with full-thickness skin grafts obtained by blepharoplasty. AB - PURPOSE: The treatment of large xanthelasma palpebrarum cases in patients whose lesions could not be closed primarily is reported. All lesions were repaired with full-thickness skin grafts obtained by blepharoplasty of the same upper eyelid. Patient satisfaction, complications, and recurrence rates were investigated. METHODS: Sixteen patients were treated between 2007 and 2012. Bilateral upper eyelids were involved in all patients. Twenty-six large xanthelasma palpebrarum lesions were treated using this method. All lesions were located in the medial canthus of the upper eyelid. RESULTS: The patients were followed up for 6 months to 5 years (mean 3 years). No patients developed complications or required revision surgery. All patients had normally positioned upper eyelids and were satisfied with the aesthetic outcome. Two patients had mild hyperpigmentation at the graft site. CONCLUSIONS: The results of this study suggest that large xanthelasma palpebrarum defects that are not primarily closed after excision should be repaired with full-thickness skin grafts harvested from the lateral aspect of the same upper eyelid. Moreover, good patient satisfaction can be achieved when blepharoplasty of the upper eyelid is performed concurrently in patients who are middle-aged or older. PMID- 23673304 TI - Recurrences of dermatophyte toenail onychomycosis during long-term follow-up after successful treatments with mono- and combined therapy of terbinafine and itraconazole. AB - BACKGROUND: The influence of dosing regimens on the recurrence rates of onychomycosis has not been investigated. OBJECTIVE: To compare recurrence rates for toenail dermatophyte onychomycosis between four dosing regimens. METHODS: A prospective, investigator-blinded, long-term follow-up (1.25 to 7 years postenrolment) study of the following regimens was undertaken with or without booster therapy at week 36: overlapping continuous itraconazole and terbinafine (COMBO), continuous terbinafine (CTERB), intermittent terbinafine (TOT), and pulsed itraconazole (III). RESULTS: One hundred six mycologically and 43 completely cured participants at week 48 were included. Recurrence rates (RR) for mycologically and completely cured participants were respectively termed mycologic recurrence (MRR) and complete cure recurrence (CRR) rates. No statistically significant difference was detected between the four regimens for the two rates. However, lower MRRs were obtained for CTERB (32%) and TOT (36%) compared to III (59%) and COMBO (57%). When participants who received booster therapy were excluded from the analysis, the MRR was lower for CTERB (21%) compared to TOT (39%). CONCLUSIONS: Itraconazole therapy was associated with higher RRs than terbinafine therapy. Combined therapy did not reduce the RRs compared to monotherapies. A difference might exist between continuous and intermittent antifungal regimens, but additional randomized clinical trials are needed for confirmation. PMID- 23673305 TI - Allergic contact dermatitis to medical equipment in a non-health care worker caring for a disabled spouse. AB - BACKGROUND: Allergic contact dermatitis (ACD) to rubber accelerators is a common occurrence, especially in health care workers, but the risks in family caregivers are not as well documented. OBJECTIVE: To document a case of a 66-year-old woman who developed recurrent, extensive flares of ACD from contact with rubber accelerators through caregiving. METHOD AND RESULTS: Patch testing revealed a positive reaction to two common rubber accelerators: carba mix (3+) and thiuram mix (3+). The patient described caring for her disabled husband, which involved handling rubberized medical equipment. CONCLUSION: Physicians should appreciate ACD in non-health care workers caused by rubber accelerators found in medical equipment. Individuals providing care for sick or elderly relatives should be further questioned on exposure to a hospital environment and contact with medical equipment. PMID- 23673306 TI - Ulerythema ophryogenes, a rarely reported cutaneous manifestation of noonan syndrome: case report and review of the literature. AB - BACKGROUND: Ulerythema ophryogenes (also known as keratosis pilaris atrophicans faciei) is a rarely reported cutaneous manifestation of Noonan syndrome. OBJECTIVE: Recognizing ulerythema ophryogenes as a cutaneous association in Noonan syndrome may aid in the diagnosis of this relatively common genetic condition. METHODS: We present a case of a patient with Noonan syndrome and ulerythema ophryogenes associated with a SOS1 mutation and review the literature on this association. RESULTS: To the best of our knowledge, this is the second case of Noonan syndrome proven to be due to an SOS1 mutation in which ulerythema ophryogenes was clinically recognized and specifically diagnosed. CONCLUSIONS: The presence of ulerythema ophryogenes in a patient with Noonan syndrome increases the likelihood of a SOS1 mutation. Further reports by dermatologists and medical geneticists documenting ulerythema ophryogenes and not just descriptions of sparse or absent eyebrows will help support this genotype phenotype correlation. PMID- 23673307 TI - Attention and inhibition in children with ASD, ADHD and co-morbid ASD + ADHD: an event-related potential study. AB - BACKGROUND: Substantial overlap has been reported between attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Deficits in executive function (EF) are characteristic of both disorders but these impairments have not been compared directly across pure and co-morbid cases using event-related potentials (ERPs). METHOD: Behavioural parameters and ERPs were recorded during a flankered cued-continuous performance test (CPT-OX) administered to 8-13-year-old boys with ASD (n = 19), ADHD (n = 18), co-morbid ASD + ADHD (n = 29) and typically developing controls (TD; n = 26). Preparatory processing (contingent negative variation, CNV) and attentional orienting (Cue P3) at cues, response execution at targets (Go-P3), inhibitory processing at non targets (NoGo-P3) and conflict monitoring between target and non-target trials (Go-N2 v. NoGo-N2) were examined. RESULTS: Categorical diagnoses and quantitative trait measures indicated that participants with ADHD (ADHD/ASD + ADHD) made more omission errors and exhibited increased reaction-time (RT) variability and reduced amplitude of the Cue-P3 and NoGo-P3 compared to TD/ASD participants. Participants with ASD (ASD/ ASD + ADHD) demonstrated reduced N2 enhancement from Go to NoGo trials compared to TD/ADHD participants. Participants with ASD-only displayed enhanced CNV amplitude compared to ASD + ADHD and TD participants. CONCLUSIONS: Children with ADHD show deficits in attentional orienting and inhibitory control whereas children with ASD show abnormalities in conflict monitoring and response preparation. Children with co-morbid ASD + ADHD present as an additive co-occurrence with deficits of both disorders, although non additive effects are suggested for response preparation. Measuring ERPs that index attention and inhibition is useful in disentangling cognitive markers of ASD and ADHD and elucidating the basis of co-occurring ASD + ADHD to guide clinical assessment. PMID- 23673308 TI - Blood capillary length estimation from three-dimensional microscopic data by image analysis and stereology. AB - Studies of the capillary bed characterized by its length or length density are relevant in many biomedical studies. A reliable assessment of capillary length from two-dimensional (2D), thin histological sections is a rather difficult task as it requires physical cutting of such sections in randomized directions. This is often technically demanding, inefficient, or outright impossible. However, if 3D image data of the microscopic structure under investigation are available, methods of length estimation that do not require randomized physical cutting of sections may be applied. Two different rat brain regions were optically sliced by confocal microscopy and resulting 3D images processed by three types of capillary length estimation methods: (1) stereological methods based on a computer generation of isotropic uniform random virtual test probes in 3D, either in the form of spatial grids of virtual "slicer" planes or spherical probes; (2) automatic method employing a digital version of the Crofton relations using the Euler characteristic of planar sections of the binary image; and (3) interactive "tracer" method for length measurement based on a manual delineation in 3D of the axes of capillary segments. The presented methods were compared in terms of their practical applicability, efficiency, and precision. PMID- 23673309 TI - Tenascin-C deficiency ameliorates Alzheimer's disease-related pathology in mice. AB - Alzheimer's disease (AD) is a neurodegenerative disease characterized by deposits of amyloid beta peptide (Abeta) and microglia-driven inflammatory activation. Tenascin-C (tnc) is an extracellular matrix protein that is upregulated in inflammation and induces further inflammatory responses. We hypothesized that tnc contributes to the inflammatory pathology in AD. Using real-time polymerase chain reaction, we observed that tnc gene transcription was upregulated in cultured microglia after Abeta challenge and in the brain of an AD mouse model that overexpresses mutated amyloid precursor protein (APP) in neural cells. By cross breeding APP-transgenic mice and tenascin-C-deficient mice, we demonstrated using real-time polymerase chain reaction, Western blot analysis, enzyme-linked immunosorbent assay, and immunohistochemistry that tnc deficiency reduces pro- but enhances anti-inflammatory activation in the mutated APP-transgenic mouse brain, associated with a reduced cerebral Abeta load and higher levels of the postsynaptic density protein 95. Thus, our study indicates that functional inhibition of tnc exerts beneficial effects on AD pathogenesis, suggesting a potential for tnc as a new therapeutic target in AD. PMID- 23673311 TI - The functional tumor necrosis factor-alpha (308A/G) polymorphism modulates attentional selection in elderly individuals. AB - There has been increasing interest in understanding the role of inflammatory processes for cognitive functions in aging using molecular genetic approaches. Though this has mostly been evaluated in pathological aging, little is known about the relevance for cognitive functions in healthy aging in humans. On the basis of behavioral data and neurophysiological data (event-related potentials and time-frequency decomposition) we show that the A-allele of the functional tumor necrosis factor (TNF)-alpha -308 A/G polymorphism confers dysfunction in a number of cognitive processes: prolonged attentional selection indexed by a delayed P1/N1 complex, an increased P3a, which is interpreted as an enhanced distractibility by nonrelevant stimuli and compromised response selection mechanisms, as indexed by a reduced frontocentral N2. Time-frequency analyses show that allelic variations further exert their effects by modulating alpha and beta frequency oscillations. On a neurobiological level, these effects might be because of the interaction of TNF-alpha with glutamatergic neural transmission by which TNF-alpha is known to boost apoptotic mechanisms in elderly individuals. PMID- 23673310 TI - Endolysosome involvement in HIV-1 transactivator protein-induced neuronal amyloid beta production. AB - The increased life expectancy of people living with HIV-1/AIDS is accompanied by increased prevalence of HIV-1-associated neurocognitive disorder. As well, these individuals are increasingly experiencing Alzheimer's disease (AD)-like neurocognitive problems and neuropathological features such as increased deposition of amyloid beta (Abeta) protein. Findings that Abeta production occurs largely in endolysosomes, that HIV-1 transactivator protein (Tat) disrupts endolysosome function-an early pathological feature of AD-and that HIV-1 Tat can increase Abeta levels prompted us to test the hypothesis that endolysosome dysfunction is associated with HIV-1 Tat-induced increases in neuronal Abeta generation. Using primary cultured rat hippocampal neurons, we found that treatment with HIV-1 Tat caused such morphological changes as enlargement of endolysosomes identified with LysoTracker dye and such functional changes as elevated endolysosome pH measured ratiometrically with LysoSensor dye. The HIV-1 Tat-induced changes in endolysosome function preceded temporally HIV-1 Tat induced increases in Abeta generation measured using enzyme-linked immunosorbent assay. In addition, we demonstrated that HIV-1 Tat increased endolysosome accumulation of Abeta precursor protein and Abeta identified using immunostaining with 4G8 antibodies. Furthermore, we demonstrated that treatment of neurons with HIV-1 Tat increased endolysosome accumulation of beta amyloid-converting enzyme, the rate-limiting enzymatic step for Abeta production, and enhanced beta amyloid converting enzyme activity. Together, our findings suggest that HIV-1 Tat increases neuronal Abeta generation and thereby contributes to the development of AD-like pathology in HIV-1-infected individuals by disturbing endolysosome structure and function. PMID- 23673312 TI - Environmental pollution in Mongolia: effects across the lifespan. PMID- 23673313 TI - Effect of honokiol on erythrocytes. AB - Honokiol ((3,5-di-(2-propenyl)-1,1-biphenyl-2,2-diol), a component of Magnolia officinalis, stimulates apoptosis and is thus considered for the treatment of malignancy. In analogy to apoptosis of nucleated cells, erythrocytes may enter eryptosis, a suicidal death characterized by cell shrinkage and by breakdown of cell membrane phosphatidylserine asymmetry with phosphatidylserine-exposure at the erythrocyte surface. Eryptosis may be triggered following increase of cytosolic Ca(2+)-activity ([Ca(2+)]i). The present study explored, whether honokiol elicits eryptosis. Cell volume has been estimated from forward scatter, phosphatidylserine-exposure from annexin V binding, hemolysis from hemoglobin release, [Ca(2+)]i from Fluo3-fluorescence, and ceramide from fluorescent antibodies. As a result, a 48 h exposure to honokiol was followed by a slight but significant increase of [Ca(2+)]i (15 MUM), significant decrease of forward scatter (5 MUM), significant increase of annexin-V-binding (5 MUM) and significant increase of ceramide formation (15 MUM). Honokiol further induced slight, but significant hemolysis. Honokiol (15 MUM) induced annexin-V-binding was significantly blunted but not abrogated in the nominal absence of extracellular Ca(2+). In conclusion, honokiol triggers suicidal erythrocyte death or eryptosis, an effect at least in part due to stimulation of Ca(2+) entry and ceramide formation. PMID- 23673314 TI - The role of SIRT1/AKT/ERK pathway in ultraviolet B induced damage on human retinal pigment epithelial cells. AB - Ultraviolet (UV)-induced damage plays a major role in ocular diseases, such as cataracts and retinal degeneration. UVB may also cause retinal phototoxicity and photic retinopathy. In this study, we explored the effects of UVB on the cell cycle and the role of silent mating type information regulation 2 homolog 1 (SIRT1) in the UVB-induced damage. UVB dose-dependently suppressed the growth of retinal pigment epithelial (RPE) cells by activating the phosphatidylinositol 3 kinase (PI3K) pathway and triggering cell cycle arrest at the S phase. SIRT1, an NAD-dependent histone deacetylase, is involved in multiple biological processes, such as the stress response and the regulation of the cell cycle. However, its role in the effects of UVB on RPE cells is unclear. We showed that UVB down regulates SIRT1 expression in a dose-dependent manner. Resveratrol, an SIRT1 activator, prevented the UVB-induced damage by inhibiting AKT and ERK phosphorylation. A specific PI3K inhibitor attenuated the UVB-induced ERK1/2 and p53 phosphorylation. Finally, UVB activated the PI3K/AKT/ERK pathway by reducing the expression of SIRT1 in ARPE-19 cells. Our study, therefore, illustrated the molecular mechanisms of UVB-induced phototoxicity and damage of RPE cells. SIRT1 and resveratrol may be significant regulators, protecting against UVB-induced injury. PMID- 23673315 TI - Bed bugs reproductive life cycle in the clothes of a patient suffering from Alzheimer's disease results in iron deficiency anemia. AB - We report the case of an 82-year-old patient, hospitalized for malaise. Her clothes were infested by numerous insects and the entomological analysis identified them as being Cimex lectularius (bed bugs). The history of the patient highlighted severe cognitive impairment. The biological assessment initially showed a profound microcytic, aregenerative, iron deficiency anemia. A vitamin B12 deficiency due to pernicious anemia (positive intrinsic factor antibodies) was also highlighted, but this was not enough to explain the anemia without macrocytosis. Laboratory tests, endoscopy and a CT scan eliminated a tumor etiology responsible for occult bleeding. The patient had a mild itchy rash which was linked to the massive colonization by the bed bugs. The C. lectularius bite is most often considered benign because it is not a vector of infectious agents. Far from trivial, a massive human colonization by bed bugs may cause such a hematic depletion that severe microcytic anemia may result. PMID- 23673316 TI - Seasonality and daily flight activity of stable flies (Diptera: Muscidae) on dairy farms in Saraburi Province, Thailand. AB - Knowledge of seasonal abundance and flight activity patterns are required to design effective management programs for insect pests of humans and livestock. In this study, the seasonality and daily flight activity of Stomoxys species were observed on two dairy farms in Saraburi Province, Thailand. Data were assessed throughout 1 year using Vavoua traps from September 2010 to August 2011. A total of 2,520 individuals belonging to four species were collected. Most Stomoxys species peaked in September (rainy season) and gradually decreased in number toward February (dry season); a second peak occurred between March and April (hot season). Stomoxys calcitrans was caught throughout the year and was the most abundant species in this study. The total number of males and females of S. calcitrans differed significantly among seasons and time intervals. The weather parameters of relative humidity and light intensity were significantly correlated with S. calcitrans abundance. PMID- 23673318 TI - Polystyrene/MWCNT/graphite nanoplate nanocomposites: efficient electromagnetic interference shielding material through graphite nanoplate-MWCNT-graphite nanoplate networking. AB - Today, we stand at the edge of exploring carbon nanotube (CNT) and graphene based polymer nanocomposites as next generation multifunctional materials. However, irrespective of the methods of composite preparation, development of electrical conductivity with high electromagnetic interference (EMI) value at very low loading of CNT and (or) graphene is limited due to poor dispersion of these nanofillers in polymer matrix. Here, we demonstrate a novel technique that involves in-situ polymerization of styrene/multiwalled carbon nanotubes (MWCNTs) in the presence of suspension polymerized polystyrene (PS)/graphite nanoplate (GNP) microbeads, for the preparation of electrically conducting PS/MWCNT/GNP nanocomposites with very high (~20.2 dB) EMI shielding value at extremely low loading of MWCNTs (~2 wt %) and GNP (~1.5 wt %). Finally, through optimizing the ratio of PS-GNP bead and MWCNTs in the nanocomposites, an electrical conductivity of ~9.47 * 10(-3) S cm(-1) was achieved at GNP and MWCNTs loading of 0.29 and 0.3 wt %, respectively. The random distribution of the GNPs and MWCNTs with GNP-GNP interconnection through MWCNT in the PS matrix was the key factor in achieving high electrical conductivity and very high EMI shielding value at this low MWCNT and GNP loadings in PS/MWCNT/GNP nanocomposites. With this technique, the formation of continuous conductive network structure of CNT-GNP-CNT and the development of spatial arrangement for strong pi-pi interaction among the electron rich phenyl rings of PS, GNP, and MWCNT could be possible throughout the matrix phase in the nanocomposites, as evident from the field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM) studies. PMID- 23673317 TI - Tissue transglutaminase as a central mediator in inflammation-induced progression of breast cancer. AB - TGM2 is a stress-responsive gene that encodes a multifunctional and structurally complex protein called tissue transglutaminase (abbreviated as TG2 or tTG). TGM2 expression is frequently upregulated during inflammation and wounding. Emerging evidence indicates that TGM2 expression is aberrantly upregulated in multiple cancer cell types, particularly those selected for resistance to chemotherapy and radiation therapy and those isolated from metastatic sites. It is becoming increasingly evident that chronic expression of TG2 in epithelial cancer cells initiates a complex series of signaling networks which contributes to the development of drug resistance and an invasive phenotype. For example, forced or basal high expression of TG2 in mammary epithelial cells is associated with activation of nuclear transcription factor-kappa B (NF-kappaB), Akt, focal adhesion kinase, and hypoxia-inducible factor. All of these changes are considered hallmarks of aggressive tumors. TG2 expression is able to induce the developmentally regulated program of epithelial-to-mesenchymal transition (EMT) and to confer cancer stem cell (CSC) traits in mammary epithelial cells; both EMT and CSCs have been implicated in cancer metastasis and resistance to standard therapies. Importantly, TG2 expression in tumor samples is associated with poor disease outcome, increased drug resistance, and increased incidence of metastasis. These observations imply that TG2 plays a crucial role in promoting an aggressive phenotype in mammary epithelial cells. In this review, we discuss recent evidence that TG2-regulated pathways contribute to the aggressive phenotype in breast cancer. PMID- 23673319 TI - Herbivore-induced phenylacetonitrile is biosynthesized from de novo-synthesized L phenylalanine in the giant knotweed, Fallopia sachalinensis. AB - Plants emit a series of characteristic volatile blends when damaged by insect feeding. Phenylacetonitrile is one of the volatiles from the leaves of the giant knotweed, Fallopia sachalinensis, infested by the Japanese beetle, Popillia japonica, or treated with exogenous airborne methyl jasmonate (MeJA). We examined the precursor of the nitrile and its origin in this system. L-Phenylalanine was determined to be a precursor of the nitrile in F. sachalinensis leaves, and the phenylalanine was also induced by beetle feeding and MeJA treatment. We also found that exogenous MeJA enhanced the biosynthesis of several amino acids in F. sachalinensis leaves. PMID- 23673320 TI - Defining piRNA primary transcripts. PMID- 23673321 TI - MELK inhibitor, novel molecular targeted therapeutics for human cancer stem cells. PMID- 23673322 TI - Chromatin remodeling, BRCA1, SAHF and cellular senescence. PMID- 23673323 TI - Engineering ubiquitin to modulate the ubiquitin proteosome system. PMID- 23673324 TI - Lineage progression from stem cells to new neurons in the adult brain ventricular subventricular zone. PMID- 23673325 TI - Inhibition of Notch recycling by Numb: relevance and mechanism(s). PMID- 23673326 TI - Ponatinib circumvents all types of imatinib resistance in chronic myelogenous leukemia cell lines. PMID- 23673327 TI - Scaling the MAPK signaling threshold during CNS patterning. AB - Morphogenic gradients originating from signaling centers along the CNS developmental axes contribute to CNS patterning. Reporting in this issue of Developmental Cell, Lanctot et al. (2013) show that the Nde1-Lis1 complex interacts with Brap, a mitogen-activated protein kinase pathway negative regulator, to facilitate position-dependent modulation of neural progenitor fate and CNS patterning. PMID- 23673328 TI - When two plus two should equal two. AB - Sexual reproduction in flowering plants is a masterpiece of cell-to-cell communication involving a unique double fertilization process and an intricate sperm delivery system. Reporting in Developmental Cell, Maruyama et al. (2013) and Volz et al. (2013) shed light on an elaborated system that coordinates sperm delivery with fertilization status. PMID- 23673329 TI - The TIKI/TraB/PrgY family: a common protease fold for cell signaling from bacteria to metazoa? AB - We report that the metazoan Wnt protease and signaling inhibitor TIKI shares sequence homology with bacterial TraB/PrgY proteins, inhibitors of pheromone signaling essential for propagation of antibiotic resistance. Our analysis suggests that these proteins represent an ancient metalloprotease clan regulating cellular communications across biological kingdoms. PMID- 23673330 TI - Spatially dependent dynamic MAPK modulation by the Nde1-Lis1-Brap complex patterns mammalian CNS. AB - Regulating cell proliferation and differentiation in CNS development requires both extraordinary complexity and precision. Neural progenitors receive graded overlapping signals from midline signaling centers, yet each makes a unique cell fate decision in a spatiotemporally restricted pattern. The Nde1-Lis1 complex regulates individualized cell fate decisions based on the geographical location with respect to the midline. While cells distant from the midline fail to self renew in the Nde1-Lis1 double-mutant CNS, cells embedded in the signaling centers showed marked overproliferation. A direct interaction between Lis1 and Brap, a mitogen-activated protein kinase (MAPK) signaling threshold modulator, mediates this differential response to mitogenic signal gradients. Nde1-Lis1 deficiency resulted in a spatially dependent alteration of MAPK scaffold Ksr and hyperactivation of MAPK. Epistasis analyses supported synergistic Brap and Lis1 functions. These results suggest that a molecular complex composed of Nde1, Lis1, and Brap regulates the dynamic MAPK signaling threshold in a spatially dependent fashion. PMID- 23673331 TI - Direct binding of SAS-6 to ZYG-1 recruits SAS-6 to the mother centriole for cartwheel assembly. AB - Assembly of SAS-6 dimers to form the centriolar cartwheel requires the ZYG-1/Plk4 kinase. Here, we show that ZYG-1 recruits SAS-6 to the mother centriole independently of its kinase activity; kinase activity is subsequently required for cartwheel assembly. We identify a direct interaction between ZYG-1 and the SAS-6 coiled coil that explains its kinase activity-independent function in SAS-6 recruitment. Perturbing this interaction, or the interaction between an adjacent segment of the SAS-6 coiled coil and SAS-5, prevented SAS-6 recruitment and cartwheel assembly. SAS-6 mutants with alanine substitutions in a previously described ZYG-1 target site or in 37 other residues, either phosphorylated by ZYG 1 in vitro or conserved in closely related nematodes, all supported cartwheel assembly. We propose that ZYG-1 binding to the SAS-6 coiled coil recruits the SAS 6-SAS-5 complex to the mother centriole, where a ZYG-1 kinase activity-dependent step, whose target is unlikely to be SAS-6, triggers cartwheel assembly. PMID- 23673332 TI - Ethylene signaling is required for synergid degeneration and the establishment of a pollen tube block. AB - In flowering plants, sperm cells are delivered by pollen tubes, which are attracted by two egg-cell-adjoining synergids. Successful fertilization terminates pollen tube attraction; however, the underlying mechanisms are not understood. Here, we show that the process of fertilization activates an EIN3- and EIN2-dependent ethylene-response cascade necessary for synergid cell death and the concomitant establishment of a pollen tube block. Microinjection of the ethylene precursor ACC into the female gametophyte or constitutive ethylene response results in premature synergid disintegration. This indicates that the requirement of fertilization for synergid degeneration and associated establishment of a pollen tube block can be bypassed by mimicking a postfertilization ethylene burst. Surprisingly, the persistent synergid in ethylene-hyposensitive plants adopts the molecular profile and cell-cycle regime of the biparental embryo-nourishing tissue, suggesting that ethylene signaling prevents the formation of an asexual maternal endosperm fraction. PMID- 23673333 TI - Independent control by each female gamete prevents the attraction of multiple pollen tubes. AB - In flowering plants, double fertilization is normally accomplished by the first pollen tube, with the fertilized ovule subsequently inhibiting the attraction of a second pollen tube. However, the mechanism of second-pollen-tube avoidance remains unknown. We discovered that failure to fertilize either the egg cell or the central cell compromised second-pollen-tube avoidance in Arabidopsis thaliana. A similar disturbance was caused by disrupting the fertilization independent seed (FIS) class polycomb-repressive complex 2 (FIS-PRC2), a central cell- and endosperm-specific chromatin-modifying complex for gene silencing. Therefore, the two female gametes have evolved their own signaling pathways. Intriguingly, second-pollen-tube attraction induced by half-successful fertilization allowed the ovules to complete double fertilization, producing a genetically distinct embryo and endosperm. We thus propose that each female gamete independently determines second-pollen-tube avoidance to maximize reproductive fitness in flowering plants. PMID- 23673334 TI - Prevalence and correlates of antipsychotic polypharmacy in children and adolescents receiving antipsychotic treatment. AB - Antipsychotic polypharmacy (APP), which is common in adults with psychotic disorders, is of unproven efficacy and raises safety concerns. Although youth are increasingly prescribed antipsychotics, little is known about APP in this population. We performed a systematic PubMed search (last update 26 January 2013) of studies reporting the prevalence of APP in antipsychotic-treated youth. Summary statistics and statistical tests were calculated at the study level and not weighted by sample size. Fifteen studies (n = 58 041, range 68-23 183) reported on APP in youth [mean age = 13.4 +/- 1.7 yr, 67.1 +/- 10.2% male, 77.9 +/- 27.4% treated with second-generation antipsychotics (SGAs)]. Data collected in these studies covered 1993-2008. The most common diagnoses were attention deficit hyperactivity disorder (ADHD; 39.9 +/- 23.5%) and conduct disorder/oppositional defiant disorder (CD/ODD; 33.6 +/- 24.8). In studies including predominantly children (mean age = <13 yr, N = 5), the most common diagnosis were ADHD (50.6 +/- 25.4%) and CD/ODD (39.5 +/- 27.5%); while in studies with predominantly adolescents (mean age = ?13 yr, N = 7) the most common diagnoses were schizophrenia-spectrum disorders (28.6 +/- 23.8%), anxiety disorders (26.9 +/- 14.9%) and bipolar-spectrum disorders (26.6 +/- 7.0%), followed closely by CD/ODD (25.8 +/- 17.7). The prevalence of APP among antipsychotic-treated youth was 9.6 +/- 7.2% (5.9 +/- 4.5% in child studies, 12.0 +/- 7.9% in adolescent studies, p = 0.15). Higher prevalence of APP was correlated with a bipolar disorder or schizophrenia diagnosis (p = 0.019) and APP involving SGA+SGA combinations (p = 0.0027). No correlation was found with APP definition [?1 d (N = 10) vs. >30-?90 d (N = 5), p = 0.88]. Despite lacking safety and efficacy data, APP in youth is not uncommon, even in samples predominantly consisting of non-psychotic patients. The duration, clinical motivations and effectiveness of this practice require further study. PMID- 23673337 TI - Structural, electronic and magnetic properties of transition metal binary alloy clusters with isoelectronic components: case study with MnmTcn, TimZrn and MnmRen. AB - With the goal of achieving an understanding of the properties of bimetallic alloy clusters having atoms of two isoelectronic elements, we have studied the structural, electronic and magnetic properties of MnmTcn, MnmRen and TimZrn clusters with m + n = 13 (n = 0, 1, 4, 6, 9, 12, 13), using first-principles density functional calculations. MnmTcn and MnmRen represent clusters of isoelectronic series with a half-filled d shell, while TimZrn represents an isoelectronic cluster series of early transition metals. Mn-rich alloy clusters are found to prefer compact structures and isoelectronic Tc-rich or Re-rich alloy clusters are found to adopt open structures. In contrast, TimZrn clusters are all found to stabilize in compact structures, irrespective of being Ti-rich or Zr rich. This change in behavior between two isoelectronic series is found to be driven by differences in hybridization effects, due to differences in the evolution of the relative energy positions of the d level with respect to the s and p levels upon moving from 3d to 4d or 5d elements. This effect further competes with the magnetization effect to decide the morphology of the alloy clusters. Focusing on the magnetic properties of the studied clusters, we find that the single Tc atom substituted alloy cluster exhibits markedly improved magnetic properties compared to that of pure Mn clusters. PMID- 23673335 TI - Erroneous class switching and false VDJ recombination: molecular dissection of t(8;14)/MYC-IGH translocations in Burkitt-type lymphoblastic leukemia/B-cell lymphoma. AB - The chromosomal translocation t(8;14)(q24;q32) with juxtaposition of MYC to enhancer elements in the immunoglobulin heavy chain (IGH) gene locus is the genetic hallmark of the majority of Burkitt lymphoma and a subset of Diffuse large B-cell lymphoma patients. Around 3% of adult B-lineage acute lymphoblastic leukemia (ALL) patients show this aberration. Flow cytometry mostly reveals a "mature B-ALL" or "Burkitt-type" ALL immunophenotype. Using long-distance PCR for t(8;14)/MYC-IGH fusion, we investigated bone marrow, peripheral blood and a few other samples with suspected Burkitt-ALL or mature B-ALL and identified 133 MYC IGH-positive cases. The location of the chromosomal breaks in the IGH joining and the 8 different switch regions was determined using a set of long-distance PCRs. The chromosomal breakpoints with the adjacent MYC regions on 8q24 were characterized by direct sequencing in 49 cases. The distribution of chromosomal breaks among the IGH joining and switch regions was the following: JH 23.3%, M 21.8%, G1 15.0%, G2 7.5%, G3 3.8%, G4 4.5%, A1 12.8%, A2 3.8%, E 7.5%. Two breakpoint clusters near MYC were delineated. There was no clear correlation between the degree of somatic hypermutation and the chromosomal break locations. Epstein Barr virus was detected in 5 cases (4%). This detailed and extensive molecular analysis illustrates the molecular complexity of the MYC-IGH translocations and the detected distribution of breakpoints provides additional evidence that this translocation results from failed switch and VDJ recombinations. This study may serve as a model for the analysis of other IGH translocations in B-cell lymphoma. PMID- 23673340 TI - The metabolism of lymphomas. AB - PURPOSE OF REVIEW: Cellular to animal to human studies are shedding light on metabolic pathways that contribute to sustaining lymphomagenesis. Old players with new metabolic tricks and new metabolic players come into the scene. The purpose of this review is to discuss the recent advances made in the field of lymphoma metabolism with special focus on the metabolic modulation of tumor promoting and suppressing pathways and, conversely, on the effect of these pathways on metabolite addiction. RECENT FINDINGS: The basis for the high glucose uptake and glycolytic activity in lymphoma cells is now beginning to be understood. Recent findings suggest a greater role of nucleotide biosynthesis as a major driving force for glycolysis, especially during proliferation and cellular stress conditions. There is new evidence for an increasing contribution of glycine-folate metabolism deregulation in nucleotide biosynthesis, genome integrity and epigenetic maintenance. Expanding roles for MYC, PI3K and TP53 in regulating reactive oxygen production, glycolysis and glutaminolysis in lymphoma cells have been described. The identification of novel pathways has allowed the emergence of new 'antimetabolite' strategies to increase the therapeutic efficacy of current approaches. SUMMARY: Metabolism in lymphomas must fulfill the general demands from cell proliferation and those specific to lymphomagenesis. Data emerging from preclinical studies are elucidating the metabolic pathways that contribute to maintaining the malignant phenotype in lymphomas. This has resulted in identification of novel pathways, some of which may have a clinical impact in the diagnosis, characterization and treatment of lymphoma subtypes. PMID- 23673338 TI - Progress against follicular lymphoma. AB - PURPOSE OF REVIEW: To share the recent progress in research and new therapies against follicular lymphoma and highlight the exciting opportunities to improve the treatment of follicular lymphoma. RECENT FINDINGS: Follicular lymphoma has been somewhat neglected by the research community, but recent genomic studies have identified key genetic lesions in follicular lymphoma. In addition, a new murine model is available to explore the function of these lesions in the development, progression, and treatment of follicular lymphoma. Moreover, new small-molecule inhibitors are now available that target key pathways in follicular lymphoma including B-cell receptor signaling and histone modifiers. SUMMARY: Follicular lymphoma is a very common and still incurable form of lymphoma. However, recent genomic and in-vivo biological studies are beginning to unveil the molecular drivers of follicular lymphoma. This coincides with the development of effective small-molecule inhibitors against key targets. Together these developments suggest that we are at a long overdue watershed moment in the treatment of follicular lymphoma. PMID- 23673339 TI - Beyond NPM-anaplastic lymphoma kinase driven lymphomagenesis: alternative drivers in anaplastic large cell lymphoma. AB - PURPOSE OF REVIEW: Anaplastic large cell lymphomas (ALCLs) are rare entities whose somatic genetic lesions have been identified only in a subset of patients. Thus, an integrated and massive discovery programme is required to define their tumourigenic alterations and to design more successful tailored therapies. RECENT FINDINGS: The discovery of anaplastic lymphoma kinase (ALK) fusions has provided the basis for the characterization of distinct subsets among ALCL patients. Although the oncogenic addiction of ALK signalling is proven, the tumorigenic contribution of coactivating lesions is still missing. As ALK- and ALK+ share common signatures, it is plausible that analogous mechanisms of transformation may be operating in both subsets, as confirmed by the dysregulated activation of c-MYC, RAS and NFkappaB, and the loss of Blimp-1 and p53/p63 axis. Nonetheless, recurrent genetic alterations for ALK- ALCL or refractory leukaemic ALK+ ALCL are lacking. Moreover, although conventional chemotherapies (anthracycline-based) are most successful, that is in ALK+ ALCL patients, the implementation of ALK inhibitors or of anti-CD30 based treatments provides innovative solutions, particularly in paediatric ALK+ ALCL and in chemorefractory/relapsed patients. SUMMARY: The complete portrayal of the landscape of genetic alterations in ALCL will dictate the development of innovative chemotherapeutic and targeted therapies that will fit most with the molecular and clinical profiling of individual patients. PMID- 23673341 TI - The genetic basis of diffuse large B-cell lymphoma. AB - PURPOSE OF REVIEW: Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease featuring heterogeneous genetic, phenotypic, and clinical characteristics. Understanding the basis for this heterogeneity represents a critical step toward further progress in the management of this disease, which remains a clinical challenge in approximately one-third of patients. This review summarizes current knowledge about the molecular pathogenesis of DLBCL, and describes how recent advances in the genomic characterization of this cancer have provided new insights into its biology, revealing several potential targets for improved diagnosis and therapy. RECENT FINDINGS: In the past few years, the development of high-resolution technologies has provided significant help in identifying genetic lesions and/or disrupted signaling pathways that are required for DLBCL initiation and progression. These studies uncovered the involvement of cellular programs that had not been previously appreciated, including histone/chromatin remodeling and immune recognition. Alterations in these pathways could favor epigenetic reprogramming and escape from cellular immunity. SUMMARY: The identification of genetic alterations that contribute to the malignant transformation of a B cell into a DLBCL is helping to better understand the biology of this disease and to identify critical nodes driving tumor progression or resistance to therapy. The rapid pace at which these discoveries are taking place is poised to have significant impact for patient stratification based on molecular predictors and for the development of rational targeted therapies. PMID- 23673342 TI - SUMO regulates proteasome-dependent degradation of FLASH/Casp8AP2. AB - FLASH/Casp8AP2 is a huge multifunctional protein involved in multiple cellular processes, reaching from death receptor signaling to regulation of histone gene transcription and histone mRNA processing. Previous work has shown that FLASH localizes to Cajal bodies and promyelocytic leukemia (PML) bodies. However, the function of its nuclear body association remains unclear. Here we demonstrate that murine FLASH is covalently modified by SUMO at Lys residue 1792. Interestingly, ectopic expression of SUMO results in proteasome-dependent degradation of FLASH. A point mutant of FLASH with a mutated SUMO acceptor lysine residue, FLASH(K1792R), is resistant to SUMO-induced degradation. Finally, we show that arsenic trioxide, a drug known to potentiate SUMO modification and degradation of PML, triggers recruitment of FLASH to PML bodies and concomitant loss of FLASH protein. Our data suggest that SUMO targets FLASH for proteasome dependent degradation, which is associated with recruitment of FLASH to PML bodies. PMID- 23673343 TI - alpha-Fucosidase as a novel convenient biomarker for cellular senescence. AB - Due to its role in aging and antitumor defense, cellular senescence has recently attracted increasing interest. However, there is currently no single specific marker that can unequivocally detect senescent cells. Here, we identified alpha-L fucosidase (alpha-Fuc) as a novel sensitive biomarker for cellular senescence. Regardless of the stress stimulus and cell type, alpha-Fuc activity was induced in all canonical types of cellular senescence, including replicative, DNA damage- and oncogene-induced senescence. Strikingly, in most models the degree of alpha Fuc upregulation was higher than the induction of senescence-associated beta galactosidase (SA-beta-Gal), the current gold standard for senescence detection. As alpha-Fuc is convenient and easy to measure, we suggest its utility as a valuable marker, in particular in cells with low SA-beta-Gal activity. PMID- 23673344 TI - Maternal factors required for oocyte developmental competence in mice: transcriptome analysis of non-surrounded nucleolus (NSN) and surrounded nucleolus (SN) oocytes. AB - During mouse antral follicle development, the oocyte chromatin gradually transforms from a less condensed state with no Hoechst-positive rim surrounding the nucleolus (NSN) to a fully condensed chromatin state with a Hoechst-positive rim surrounding the nucleolus (SN). Compared with SN oocytes, NSN oocytes display a higher gene transcription activity and a lower rate of meiosis resumption (G2/M transition), and they are mostly arrested at the two-cell stage after in vitro fertilization. To explore the differences between NSN and SN oocytes, and the maternal factors required for oocyte developmental competence, we compared the whole-transcriptome profiles between NSN and SN oocytes. First, we found that the NSN and SN oocytes were different in their metabolic pathways. In the phosphatidylinositol signaling pathway, the SN oocytes tend to produce diacylglycerol, whereas the NSN oocytes tend to produce phosphatidylinositol (3,4,5)-trisphosphate. For energy production, the SN oocytes and NSN oocytes differed in the gluconeogenesis and in the synthesis processes. Second, we also found that the key genes associated with oocyte meiosis and/or preimplantation embryo development were differently expressed in the NSN and SN oocytes. Our results illustrate that during the NSN-SN transition, the oocytes change their metabolic activities and accumulate maternal factors for further oocyte maturation and post-fertilization embryo development. PMID- 23673346 TI - Ultrasound line-by-line scanning method of spatial-temporal active cavitation mapping for high-intensity focused ultrasound. AB - This paper presented an ultrasound line-by-line scanning method of spatial temporal active cavitation mapping applicable in a liquid or liquid filled tissue cavities exposed by high-intensity focused ultrasound (HIFU). Scattered signals from cavitation bubbles were obtained in a scan line immediately after one HIFU exposure, and then there was a waiting time of 2 s long enough to make the liquid back to the original state. As this pattern extended, an image was built up by sequentially measuring a series of such lines. The acquisition of the beamformed radiofrequency (RF) signals for a scan line was synchronized with HIFU exposure. The duration of HIFU exposure, as well as the delay of the interrogating pulse relative to the moment while HIFU was turned off, could vary from microseconds to seconds. The feasibility of this method was demonstrated in tap-water and a tap water filled cavity in the tissue-mimicking gelatin-agar phantom as capable of observing temporal evolutions of cavitation bubble cloud with temporal resolution of several microseconds, lateral and axial resolution of 0.50 mm and 0.29 mm respectively. The dissolution process of cavitation bubble cloud and spatial distribution affected by cavitation previously generated were also investigated. Although the application is limited by the requirement for a gassy fluid (e.g. tap water, etc.) that allows replenishment of nuclei between HIFU exposures, the technique may be a useful tool in spatial-temporal cavitation mapping for HIFU with high precision and resolution, providing a reference for clinical therapy. PMID- 23673345 TI - Sex differences in adult cognitive deficits after adolescent nicotine exposure in rats. AB - This study was designed to determine whether deficits in adult serial pattern learning caused by adolescent nicotine exposure persist as impairments in asymptotic performance, whether adolescent nicotine exposure differentially retards learning about pattern elements that are inconsistent with "perfect" pattern structure, and whether there are sex differences in rats' response to adolescent nicotine exposure as assessed by a serial multiple choice task. The current study replicated the results of our initial report (Fountain et al., 2008) using this task by showing that adolescent nicotine exposure (1.0mg/kg/day nicotine for 35days) produced a specific cognitive impairment in male rats that persisted into adulthood at least a month after adolescent nicotine exposure ended. In addition, sex differences were observed even in controls, with additional evidence that adolescent nicotine exposure significantly impaired learning relative to same-sex controls for chunk boundary elements in males and for violation elements in females. All nicotine-induced impairments were overcome by additional training so that groups did not differ at asymptote. An examination of the types of errors rats made indicated that adolescent nicotine exposure slowed learning without affecting rats' cognitive strategy in the task. This data pattern suggests that exposure to nicotine in adolescence may have impaired different aspects of adult stimulus-response discrimination learning processes in males and females, but left abstract rule learning processes relatively spared in both sexes. These effects converge with other findings in the field and reinforce the concern that adolescent nicotine exposure poses an important threat to cognitive capacity in adulthood. PMID- 23673347 TI - Evaluation of the effects of extended release quetiapine fumarate monotherapy on sleep disturbance in patients with major depressive disorder: a pooled analysis of four randomized acute studies. AB - Effects of once-daily extended-release quetiapine fumarate (quetiapine XR) monotherapy on sleep quality and disturbance in patients with major depressive disorder (MDD) were evaluated. Pooled data from four 6- or 8-wk placebo controlled quetiapine XR (50-300 mg/d) monotherapy studies (D1448C00001; D1448C00002; D1448C00003; D1448C00004) were analysed. Primary efficacy end-point was change from randomization in Montgomery Asberg Depression Rating Scale (MADRS) score. Post hoc analyses of secondary end-points were conducted for change from randomization in: MADRS item 4 (reduced sleep); Hamilton Rating Scale for Depression (HAMD) items 4 (insomnia-early), 5 (insomnia-middle), 6 (insomnia late) and sleep disturbance factor (items 4 + 5+6) scores; Pittsburgh Sleep Quality Index (PSQI) global scores. MADRS total score change was also evaluated in patients experiencing high and low baseline sleep disturbance (HAMD sleep disturbance factor scores ?4 and < 4, respectively). In total, 1808 patients were randomized to quetiapine XR or placebo across four studies. At last assessment, quetiapine XR reduced MADRS item 4, HAMD items 4, 5 and 6, HAMD sleep disturbance factor score and PSQI global scores from baseline vs. placebo (p < 0.001). For those experiencing high sleep disturbance (n = 865, quetiapine XR; n = 514, placebo), quetiapine XR improved MADRS total score vs. placebo at all visits (p < 0.001). For those with low sleep disturbance (n = 252, quetiapine XR; n = 121, placebo), quetiapine XR improved MADRS total score vs. placebo at weeks 2 (p < 0.001), 4 and 6 (both p < 0.05). In conclusion, quetiapine XR (50-300 mg/d) monotherapy improved symptoms of sleep disturbance vs. placebo in patients with MDD, including those with either high or low baseline sleep disturbance levels. PMID- 23673349 TI - Use of electronic health records to evaluate the quality of care for hypertensive patients in Mexican family medicine clinics. AB - OBJECTIVES: Patients with hypertension require life-long care and should be monitored to identify whether they are receiving the appropriate healthcare and reach their expected health outcomes. Our objectives were to develop quality of healthcare indicators (QCI) and evaluate the quality of care that hypertensive patients receive in family medicine clinics at the Mexican Institute of Social Security. METHOD: We used a two-stage mixed methods approach: development of QCIs following the RAND-UCLA method; quality of care evaluation using electronic health record (EHR) data from 47 150 hypertensive patients who received care in 2009. We developed 15 QCIs, which were possible to construct using EHR data. The QCIs evaluated the process of care and health outcomes. RESULTS: Most hypertensive patients were women (64%) more than 60 years old; 79% were overweight/obese and 31% had diabetes. On average, these patients attended regularly to the family doctor (>=7 visits a year); however, they received only 27% of recommended care. Among the hypertensive patients without comorbidity, 62% had achieved blood pressure (BP) control, whereas in the group of hypertensive patients with diabetes or chronic kidney disease, only 7% had achieved BP control. CONCLUSION: EHR can become a source of information to evaluate routinely quality of care in developing countries that are beginning to modernize their health information systems. PMID- 23673348 TI - Prevalence, awareness and risk factors of hypertension in a large cohort of Iranian adult population. AB - BACKGROUND: There is considerable variation in hypertension prevalence and awareness, and their correlates, across different geographic locations and ethnic groups. We performed this cross-sectional analysis on data from the Golestan Cohort Study (GCS). METHODS: Enrollment in this study occurred in 2004-2008, and included 50,045 healthy individuals from Golestan Province in northeastern Iran. Hypertension was defined as a SBP at least 140 mmHg, a DBP at least 90 mmHg, a prior diagnosis of hypertension, or the use of antihypertensive drugs. Potential correlates of hypertension and its awareness were analyzed by logistic regression adjusted for sex, age, BMI, place of residence, literacy, ethnicity, physical activity, smoking, black and green tea consumption and wealth score. RESULTS: Of the total cohort participants, 21,350 (42.7%) were hypertensive. Age-standardized prevalence of hypertension, using the 2001 WHO standard world population, was 41.8% (95% confidence interval: 38.3-45.2%). Hypertension was directly associated with female sex, increased BMI, Turkmen ethnicity, and lack of physical activity, and inversely associated with drinking black tea and wealth score. Among hypertensive patients, 46.2% were aware of their disease, 17.6% were receiving antihypertensive medication, and 32.1% of the treated patients had controlled hypertension. Hypertension awareness was greater among women, the elderly, overweight and obese patients, and those with a higher wealth score. CONCLUSION: Hypertension is highly prevalent in rural Iran, many of the affected individuals are unaware of their disease, and the rate of control by antihypertensive medications is low. Increasing hypertension awareness and access to health services, especially among less privileged residents are recommended. PMID- 23673350 TI - Predictive power of home blood pressure and clinic blood pressure in hypertensive patients with impaired glucose metabolism and diabetes. AB - OBJECTIVES: We evaluated the predictive power of home blood pressure and clinic blood pressure based on the long-term cardiovascular outcome in hypertensive patients with and without impaired glucose metabolism (IGM). METHOD: The multicentre Hypertension Objective Treatment Based on Measurement by Electrical Devices Blood Pressure trial (HOMED-BP) involved 3080 patients (50.5% women; mean age 59.7 years) with a baseline, untreated home/clinic blood pressure as well as follow-up, on-treatment blood pressure. Of those, 979 had IGM and 475 of these patients had diabetes. We applied Cox regression pooling all participants in a cohort analysis in which IGM and normal glucose metabolism (NGM) were separated. RESULTS: During median 5.45 years follow-up, cardiovascular events occurred in 48 patients with IGM and 53 patients with NGM. Baseline home SBP significantly predicted cardiovascular outcome among IGM group [hazard ratio 1.68, 95% CI 1.26 2.26, P = 0.0005]. On-treatment home blood pressure was a significant predictor for cardiovascular risk even after the further adjustment of baseline blood pressure level (P <= 0.027), whereas on-treatment clinic blood pressure was not in NGM group (P >= 0.37). The event rate in IGM was approximately two times higher than that in NGM (9.95 vs. 4.88 per 1000 patient-years), resulted to the low 5-year number needed to treat in IGM patients [83 vs. 121 for 1-SD (13.1 mmHg) home SBP reduction, and 62 vs. 104 for 1-SD (9.5 mmHg) home DBP reduction). CONCLUSION: The present findings suggest that long-term cardiovascular risk in IGM patients should be assessed based on home blood pressure, not on clinic blood pressure. PMID- 23673351 TI - Herbivory of maize by southern corn rootworm induces expression of the major intrinsic protein ZmNIP1;1 and leads to the discovery of a novel aquaporin ZmPIP2;8. AB - Aquaporins channel water and other neutral molecules through cell membranes. Aquaporin gene expression is subject to transcriptional control and can be modulated by factors affecting water balance such as salt, abscisic acid and drought. During infestation of maize by southern corn rootworm (SCR), an insect that chews into and significantly damages maize roots, three maize aquaporins were differentially expressed upon prolonged infestation. Using a brief infestation of maize roots ZmNIP1;1 transcript abundance again increased under infestation while expression of a new aquaporin, ZmPIP2;8 and ZmTIP2;2 expression did not change. Since ZmPIP2;8 has not been described previously, the deduced protein sequence was analyzed in silico and found to contain the hallmarks of plant aquaporins, with a predicted protein structure similar to other functionally characterized PIP2s. NIPs characterized to date have been implicated in facilitating the movement of a variety of small molecules, while TIPs and PIPs often have the capacity to facilitate trans-membrane movement of water. Functional assays (using heterologous expression in Xenopus laevis oocytes) of ZmTIP2;2 and ZmPIP2;8 confirmed that these aquaporins demonstrate water channel capacity. PMID- 23673352 TI - The key gluconeogenic enzyme fructose-1,6-bisphosphatase is secreted during prolonged glucose starvation and is internalized following glucose re-feeding via the non-classical secretory and internalizing pathways in Saccharomyces cerevisiae. AB - In Saccharomyces cerevisia, the key gluconeogenic enzyme fructose-1,6 bisphosphatase is secreted into the periplasm during prolonged glucose starvation and is internalized into Vid/endosomes following glucose re-feeding. Fructose-1,6 bisphosphatase does not contain signal sequences required for the classical secretory and endocytic pathways. Hence, the secretion and internalization are mediated via the non-classical pathways. PMID- 23673353 TI - Optimizing stem-loop qPCR assays through multiplexed cDNA synthesis of U6 and miRNAs. AB - We recently reported that hairpin (or stem-loop) priming is better-suited than polyA tailing to generate cDNA for plant microRNA qPCR. One major limitation of this method is the need to perform individual cDNA synthesis reactions for the reference gene and test miRNAs. Here, we report a novel fusion primer that allows multiplexed hairpin cDNA synthesis of the most-commonly used reference gene, nucleolar small RNA U6, together with test miRNAs. We also propose the use of miR1515 as a house keeping control for tropical legumes. We show that multiplexed cDNA synthesis does not result in loss of sensitivity and reduces the amount of RNA required for miRNA gene expression assays. PMID- 23673354 TI - Impact of endoscopic surveillance on mortality from Barrett's esophagus associated esophageal adenocarcinomas. AB - BACKGROUND & AIMS: Although patients with Barrett's esophagus commonly undergo endoscopic surveillance, its effectiveness in reducing mortality from esophageal/gastroesophageal junction adenocarcinomas has not been evaluated rigorously. METHODS: We performed a case-control study in a community-based setting. Among 8272 members with Barrett's esophagus, we identified 351 esophageal adenocarcinoma: 70 in persons who had a prior diagnosis of Barrett's esophagus (who were eligible for surveillance); 51 of these patients died, 38 as a result of the cancers (cases). Surveillance histories were contrasted with a sample of 101 living persons with Barrett's esophagus (controls), matched for age, sex, and duration of follow-up evaluation. RESULTS: Surveillance within 3 years was not associated with a decreased risk of death from esophageal adenocarcinoma (adjusted odds ratio, 0.99; 95% confidence interval, 0.36-2.75). Fatal cases were nearly as likely to have received surveillance (55.3%) as were controls (60.4%). A Barrett's esophagus length longer than 3 cm and prior dysplasia each were associated with subsequent mortality, but adjustment for these did not change the main findings. Although all patients should be included in evaluations of effectiveness, excluding deaths related to cancer treatment and patients who failed to complete treatment, changed the magnitude, but not the significance, of the association (odds ratio, 0.46; 95% confidence interval, 0.13 1.64). CONCLUSIONS: Endoscopic surveillance of patients with Barrett's esophagus was not associated with a substantially decreased risk of death from esophageal adenocarcinoma. The results do not exclude a small to moderate benefit. However, if such a benefit exists, our findings indicate that it is substantially smaller than currently estimated. The effectiveness of surveillance was influenced partially by the acceptability of existing treatments and the occurrence of treatment-associated mortality. PMID- 23673355 TI - Neutralizing antibodies induced by cell culture-derived hepatitis C virus protect against infection in mice. AB - BACKGROUND & AIMS: Hepatitis C virus (HCV) infection is a major cause of liver cancer, so strategies to prevent infection are needed. A system for cell culture of infectious HCV particles (HCVcc) has recently been established; the inactivated HCVcc particles might be used as antigens in vaccine development. We aimed to confirm the potential of HCVcc as an HCV particle vaccine. METHODS: HCVcc derived from the J6/JFH-1 chimeric genome was purified from cultured cells by ultrafiltration and ultracentrifugation purification steps. Purified HCV particles were inactivated and injected into female BALB/c mice with adjuvant. Sera from immunized mice were collected and their ability to neutralize HCV was examined in naive Huh7.5.1 cells and urokinase-type plasminogen activator-severe combined immunodeficiency mice (uPA(+/+)-SCID mice) given transplants of human hepatocytes (humanized livers). RESULTS: Antibodies against HCV envelope proteins were detected in the sera of immunized mice; these sera inhibited infection of cultured cells with HCV genotypes 1a, 1b, and 2a. Immunoglobulin G purified from the sera of HCV-particle-immunized mice (iHCV-IgG) inhibited HCV infection of cultured cells. Injection of IgG from the immunized mice into uPA(+/+)-SCID mice with humanized livers prevented infection with the minimum infectious dose of HCV. CONCLUSIONS: Inactivated HCV particles derived from cultured cells protect chimeric liver uPA(+/+)-SCID mice against HCV infection, and might be used in the development of a prophylactic vaccine. PMID- 23673356 TI - Virus-based photo-responsive nanowires formed by linking site-directed mutagenesis and chemical reaction. AB - Owing to the genetic flexibility and error-free bulk production, bio nanostructures such as filamentous phage showed great potential in materials synthesis, however, their photo-responsive behaviour is neither explored nor unveiled. Here we show M13 phage genetically engineered with tyrosine residues precisely fused to the major coat protein is converted into a photo-responsive organic nanowire by a site-specific chemical reaction with an aromatic amine to form an azo dye structure on the surface. The resulting azo-M13-phage nanowire exhibits reversible photo-responsive properties due to the photo-switchable cis trans isomerisation of the azo unit formed on the phage. This result shows that site-specific display of a peptide on bio-nanostructures through site-directed genetic mutagenesis can be translated into site-directed chemical reaction for developing advanced materials. The photo-responsive properties of the azo-M13 phage nanowires may open the door for the development of light controllable smart devices for use in non-linear optics, holography data storage, molecular antenna, and actuators. PMID- 23673357 TI - Remote-control photocycloreversion of dithienylethene driven by strong push-pull azo chromophores. AB - In this communication, a novel photochromic molecular switch DTE-2(Azo-CN) containing both dithienylethene and push-pull azo chromophores was synthesized. The push-pull azo chromophores can significantly accelerate the ring opening of the C-C bond of DTE closed isomer when irradiated with light far away from the maximum absorption band of the DTE closed isomer. PMID- 23673358 TI - Polycomb subunits Ezh1 and Ezh2 regulate the Merkel cell differentiation program in skin stem cells. AB - While the Polycomb complex is known to regulate cell identity in ES cells, its role in controlling tissue-specific stem cells is not well understood. Here we show that removal of Ezh1 and Ezh2, key Polycomb subunits, from mouse skin results in a marked change in fate determination in epidermal progenitor cells, leading to an increase in the number of lineage-committed Merkel cells, a specialized subtype of skin cells involved in mechanotransduction. By dissecting the genetic mechanism, we showed that the Polycomb complex restricts differentiation of epidermal progenitor cells by repressing the transcription factor Sox2. Ablation of Sox2 results in a dramatic loss of Merkel cells, indicating that Sox2 is a critical regulator of Merkel cell specification. We show that Sox2 directly activates Atoh1, the obligate regulator of Merkel cell differentiation. Concordantly, ablation of Sox2 attenuated the Ezh1/2-null phenotype, confirming the importance of Polycomb-mediated repression of Sox2 in maintaining the epidermal progenitor cell state. Together, these findings define a novel regulatory network by which the Polycomb complex maintains the progenitor cell state and governs differentiation in vivo. PMID- 23673359 TI - Cytonemes extend their reach. PMID- 23673360 TI - Catalyst driven optical properties of the self-assembled ZnS nanostructures. AB - In this paper, we present the effect of different catalysts (Mn, Au and Sn) on the room temperature photoluminescence and Raman spectra of VLS grown ZnS nanostructures. The catalysts found to self-dope the ZnS nanostructures during its growth were confirmed by XRD and XPS results. The extent of self-doping, which depended on the type and size of catalysts, was observed strongly to have affected the optical properties of ZnS nanostructures, particularly intrinsic defects like S and Zn vacancies. Intense broad bands in the visible due to intrinsic defects, namely Zn and S vacancies were observed, which were quite different for each catalyst as well as for the size of the catalyst. Au and Mn catalyzed ZnS nanostructures also showed creation of catalyst related defects, which were absent in the case of Sn. From the PL spectra, an estimation of the Zn and S vacancies was made for each type of catalyzed ZnS nanostructures. Surface optic (SO) phonon modes of the ZnS nanostructures were also observed to behave differently for the three catalysts. The dielectric continuum model was applied to determine the correlation length and variation in the surface potential modulations in these nanostructures. It was deduced from optical studies that the location of dopant in self-doped ZnS nanostructures strongly affected the luminescence properties. Finally it was concluded that self-doping using a suitable catalyst can be a simple and controllable way to dope ZnS nanostructures with tailored optical characteristics. PMID- 23673361 TI - Novel interactions of caffeic acid with different hemoglobins: effects on discoloration and lipid oxidation in different washed muscles. AB - Caffeic acid (CA) accelerated methemoglobin (Hb) formation at pH5.8 and 25 degrees C. This was attributed to electron donation from CA to liganded O2 in Hb. CA inhibited hemin dissociation from metHb. Pig Hb remained mostly as oxyHb and did not promote lipid oxidation in washed cod muscle (WCM) nor washed turkey muscle (WTM) during iced storage at pH5.8. Conversely, perch Hb rapidly was converted to metHb and readily promoted lipid oxidation based on lipid peroxide and hexanal formation. CA strongly inhibited perch Hb-mediated lipid oxidation during storage. Once metHb formation occurred in WCM, CA appeared to maintain the heme protein as metHb during the remainder of iced storage. CA may have become bound to perch Hb based on filtration analysis. CA facilitated the transfer of perch Hb (but not pig Hb) from the aqueous phase to the insoluble components of WCM. Collectively, these results suggest that CA inhibited Hb-mediated lipid oxidation by various mechanisms not related to inhibition of metHb formation. PMID- 23673362 TI - The electronic level structure of lanthanide impurities in REPO4, REBO3, REAlO3, and RE2O3 (RE = La, Gd, Y, Lu, Sc) compounds. AB - The vacuum referred binding energies of electrons in divalent and trivalent lanthanide impurity states and host band states in the rare earth (RE = La, Gd, Y, Lu, Sc) orthophosphates REPO4, orthoborates REBO3, aluminum perovskites REAlO3, and sesqui-oxides RE2O3 have been determined by combining the recently developed chemical shift model with spectroscopic data from the archival literature. The main trends in impurity and host band level locations with changing type of RE, which determines the site size, and with changing P, B, Al, or RE cation, which determines the strength of bonding with the oxygen ligands, are identified. Sc(3+)-based compounds are characterized by a relatively low energy for the conduction band bottom, or equivalently a high electron affinity, which is attributed to a relatively strong electron bonding in the 3d-shell of Sc(2+). PMID- 23673363 TI - Comment on "A computational study on enzymatically driven oxidative coupling of chlorophenols: an indirect dehalogenation reaction [Szatkowski and Dybala Defratyka, Chemosphere 91 (2013) 258-264]". PMID- 23673364 TI - Speciation and formation of iodinated trihalomethane from microbially derived organic matter during the biological treatment of micro-polluted source water. AB - Water sources are micro-polluted by the increasing range of anthropogenic activities around them. Disinfection byproduct (DBP) precursors in water have gradually expanded from humic acid (HA) and fulvic acid to other important sources of potential organic matter. This study aimed to provide further insights into the effects of microbially derived organic matter as precursors on iodinated trihalomethane (I-THM) speciation and formation during the biological treatment of micro-polluted source water. The occurrence of I-THMs in drinking water treated by biological processes was investigated. The results showed for the first time that CHCl2I and CHBrClI are emerging DBPs in China. Biological pre treatment and biological activated carbon can increase levels of microbes, which could serve as DBP precursors. Chlorination experiments with bovine serum albumin (BSA), starch, HA, deoxyribonucleic acid (DNA), and fish oil, confirmed the close correlation between the I-THM species identified during the treatment processes and those predicted from the model compounds. The effects of iodide and bromide on the I-THM speciation and formation were related to the biochemical composition of microbially derived organic precursors. Lipids produced up to 16.98MUgL(-1) of CHCl2I at an initial iodide concentration of 2mgL(-1). HA and starch produced less CHCl2I at 3.88 and 3.54MUgL(-1), respectively, followed by BSA (1.50MUgL( 1)) and DNA (1.35MUgL(-1)). Only fish oil produced I-THMs when iodide and bromide were both present in solution; the four other model compounds formed brominated species. PMID- 23673365 TI - Sorption enhanced CO2 methanation. AB - The transformation from the fatuous consumption of fossil energy towards a sustainable energy circle is most easily marketable by not changing the underlying energy carrier but generating it from renewable energy. Hydrocarbons can be principally produced from renewable hydrogen and carbon dioxide collected by biomass. However, research is needed to increase the energetic and economic efficiency of the process. We demonstrate the enhancement of CO2 methanation by sorption enhanced catalysis. The preparation and catalytic activity of sorption catalysts based on Ni particles in zeolites is reported. The functioning of the sorption catalysis is discussed together with the determination of the reaction mechanism, providing implications for new ways in catalysis. PMID- 23673366 TI - BMP4 is a novel transcriptional target and mediator of mammary cell migration downstream of the Hippo pathway component TAZ. AB - Since the metastatic progression of cancers is often fatal with limited treatment options, understanding the mechanism of metastasis is imperative for designing novel and targeted therapies. TAZ has been identified as a novel oncogene in both breast and lung cancers and is inhibited by the Hippo signaling pathway. In this study we provide convincing evidence that overexpression of TAZ in a mammary epithelial cell line, MCF10A, leads to enhanced cell migration - a fundamental characteristic of the metastatic progression of cancers. In addition, we identified the secreted growth factor BMP4 as a mediator of TAZ-induced cell migration. TAZ induces BMP4 transcription through the TEAD family of transcription factors, which mediate BMP4 promoter activation through binding to TEAD response element 1 (TRE1). Importantly, BMP4 activation by TAZ also enhances signaling downstream of TAZ, in particular, promoting Smad1/5 intracellular signaling. Functionally, short hairpin RNA-mediated knockdown of BMP4 rescued TAZ induced cell migration. Our findings have identified a novel TAZ/TEAD/BMP4 signaling axis responsible for cell migration, with future implications in the development of targeted therapeutics for metastatic breast cancers. PMID- 23673368 TI - Heteropolyacid-functionalized aluminum 2-aminoterephthalate metal-organic frameworks as reactive aldehyde sorbents and catalysts. AB - Porous materials based on aluminum(III) 2-aminoterephthalate metal organic frameworks (MOFs NH2MIL101(Al) and NH2MIL53(Al)) and their composites with phosphotungstic acid (PTA) were studied as sorbents of saturated vapors of acetaldehyde, acrolein, and butyraldehyde. MOF functionalization by PTA impregnation from aqueous/methanol solutions resulted in MOF with the original crystal topology with the presence of an ordered PTA phase in the MOF/PTA composite. The MOF/PTA composites contained 29-32 wt % PTA and were stable against loss of PTA through leaching to the aqueous/organic solvent solutions. The MOF and MOF/PTA materials exhibited equilibrium uptake of acetaldehyde from its saturated vapor phase exceeding 50 and 600 wt %, respectively, at 25 degrees C. The acetaldehyde vapor uptake occurs through the vapor condensation, pore filling mechanism with simultaneous conversion of acetaldehyde to crotonaldehyde and higher-molecular-weight compounds resulting from repeated aldol condensation. The products of aldehyde condensation and polymerization were identified by MALDI TOF and electrospray mass spectrometry. The kinetics of the MOF- and MOF/PTA catalyzed aldol condensation of acetaldehyde were studied in water-acetonitrile mixtures. The aldol condensation kinetics in MOF suspensions were rapid and pseudo-first-order. The apparent second-order rate constants for the aldol condensation catalyzed by MOF/PTA were estimated to be 5 * 10(-4) to 1.5 * 10(-3) M(-1)s(-1), which are higher than those reported in the case of homogeneous catalysis by amino acids or sulfuric acid. MOF and MOF/PTA materials are efficient heterogeneous catalysts for the aldehyde self-condensation in aqueous organic media. PMID- 23673367 TI - mTOR complex 2 mediates Akt phosphorylation that requires PKCepsilon in adult cardiac muscle cells. AB - Our earlier work showed that mammalian target of rapamycin (mTOR) is essential to the development of various hypertrophic responses, including cardiomyocyte survival. mTOR forms two independent complexes, mTORC1 and mTORC2, by associating with common and distinct cellular proteins. Both complexes are sensitive to a pharmacological inhibitor, torin1, although only mTORC1 is inhibited by rapamycin. Since mTORC2 is known to mediate the activation of a prosurvival kinase, Akt, we analyzed whether mTORC2 directly mediates Akt activation or whether it requires the participation of another prosurvival kinase, PKCepsilon (epsilon isoform of protein kinase-C). Our studies reveal that treatment of adult feline cardiomyocytes in vitro with insulin results in Akt phosphorylation at S473 for its activation which could be augmented with rapamycin but blocked by torin1. Silencing the expression of Rictor (rapamycin-insensitive companion of mTOR), an mTORC2 component, with a sh-RNA in cardiomyocytes lowers both insulin stimulated Akt and PKCepsilon phosphorylation. Furthermore, phosphorylation of PKCepsilon and Akt at the critical S729 and S473 sites respectively was blocked by torin1 or Rictor knockdown but not by rapamycin, indicating that the phosphorylation at these specific sites occurs downstream of mTORC2. Additionally, expression of DN-PKCepsilon significantly lowered the insulin stimulated Akt S473 phosphorylation, indicating an upstream role for PKCepsilon in the Akt activation. Biochemical analyses also revealed that PKCepsilon was part of Rictor but not Raptor (a binding partner and component of mTORC1). Together, these studies demonstrate that mTORC2 mediates prosurvival signaling in adult cardiomyocytes where PKCepsilon functions downstream of mTORC2 leading to Akt activation. PMID- 23673369 TI - Guideline implementation strategies for specialist mental healthcare. AB - PURPOSE OF REVIEW: Clinical practice guidelines in mental healthcare are viewed as an essential asset if appropriately developed and implemented. The purpose of this article was to review the existing literature on how guidelines should be implemented to optimize their impact on provider performance and patient outcomes in specialist mental healthcare settings. RECENT FINDINGS: Findings from recent studies suggest a trend toward an improvement in process and patient outcomes following guideline implementation. However, studies are heterogeneous in terms of design, implementation strategies and outcome measures, making it very difficult to draw firm conclusions about which implementation strategy is effective in different healthcare contexts. SUMMARY: Current knowledge about how guidelines should be implemented is still sparse and inconclusive in mental healthcare. Future studies should attempt to employ more rigorous designs, including random allocation of patients or clusters of patients, to shed further light on this compelling issue. Research on guideline implementation strategies should additionally take into account potential barriers to knowledge translation, which can heavily influence the implementability of treatment recommendations. PMID- 23673371 TI - Behavioral characterization of non-copulating male mice. AB - Non-copulating (NC) males are those animals that do not mate in spite of repeated testing with sexually receptive females. They have been observed in several species including rats and mice. The present experiment was designed to perform a detailed behavioral characterization of NC male mice. Thus, we evaluated their sexual incentive motivation for a sexually receptive female or a sexually active male, olfactory preference for volatile and non-volatile odors from females or males, and olfactory discrimination between female and male volatile odors and food related odors (milk versus vinegar). We compared the activity of the accessory olfactory system (AOS) in copulating (C) and NC males in response to estrous bedding using the induction of Fos-immunoreactivity (Fos-IR) as a measure of neuronal activation. We also determined if estradiol or dopamine treatment could induce sexual behavior in NC males. Finally, we compared the testis weight and the number of penile spines in C, NC, and gonadectomized males. In the sexual incentive motivation test C males spend significantly more time in the female incentive zone than in the male incentive zone. On the other hand, NC males spend the same amount of time in both incentive zones. In tests of olfactory preference, NC males spent less time investigating estrous odors than C males. As well, NC males discriminate urine from conspecifics but they spend less time smelling these odors than C males. In addition, no increase in Fos expression is observed in NC males when they are exposed to odors from estrous females. Our data also suggest that the deficits observed in NC males are not due to lower circulating levels of gonadal hormones, because estradiol supplementation does not induce sexual behavior in these animals, and their testis weight and the number of penile spines are normal. The results suggest that NC males are not sexually motivated by the receptive females and their odors. PMID- 23673372 TI - Short-term maximal-intensity resistance training increases volitional function and strength in chronic incomplete spinal cord injury: a pilot study. AB - BACKGROUND AND PURPOSE: Recent research shows that individuals with an incomplete spinal cord injury (SCI) have a reserve of force-generating capability that is observable during repeated intermittent maximal volitional effort contractions. Previous studies suggest that increased neural drive contributes to the enhanced short-term force-generating capabilities. Whether this reserve can be harnessed with repeated training is unclear. The purpose of this pilot study was to investigate the effects of 4 weeks of maximal-intensity resistance training, compared with conventional progressive resistance training, on lower extremity function and strength in chronic incomplete SCI. METHODS: Using a randomized crossover design, 5 individuals with chronic (> 1 year postinjury) SCI American Spinal Injury Association Impairment Scale classification C or D were tested before and after 4 weeks of both maximal-intensity training and progressive resistance training paradigms. Outcomes measures included the 6-Minute Walk Test, the Berg Balance Scale, and peak isometric torque for strength of lower extremity muscles. RESULTS: Maximal-intensity resistance training was associated with an average increase of 12.19 +/- 8.29 m on the 6-Minute Walk Test, 4 +/- 1.9 points on the Berg Balance Scale, 4 +/- 4.5 points on the lower extremity motor score), while no changes on the above scores were seen with conventional training. Furthermore, significant increases in peak volitional isometric torques (mean increase = 20 +/- 8 Nm) were observed following maximal-intensity resistance training when compared with conventional training (mean increase = 0.12 +/- 3 Nm, P = 0.03). DISCUSSION AND CONCLUSIONS: Maximal-intensity training paradigm may facilitate rapid gains in volitional function and strength in persons with chronic motor-incomplete SCI, using a simple short-term training paradigm. PMID- 23673373 TI - Genome-wide identification of translationally inhibited and degraded miR-155 targets using RNA-interacting protein-IP. AB - MicroRNAs (miRNAs) are single-stranded, small, non-coding RNAs, which fine-tune protein expression by degrading and/or translationally inhibiting mRNAs. Manipulation of miRNA expression in animal models frequently results in severe phenotypes indicating their relevance in controlling cellular functions, most likely by interacting with multiple targets. To better understand the effect of miRNA activities, genome-wide analysis of their targets are required. MicroRNA profiling as well as transcriptome analysis upon enforced miRNA expression were frequently used to investigate their relevance. However, these approaches often fail to identify relevant miRNAs targets. Therefore, we tested the precision of RNA-interacting protein immunoprecipitation (RIP) using AGO2-specific antibodies, a core component of the "RNA-induced silencing complex" (RISC), followed by RNA sequencing (Seq) in a defined cellular system, the HEK293T cells with stable, ectopic expression of miR-155. Thereby, we identified 100 AGO2-associated mRNAs in miR-155-expressing cells, of which 67 were in silico predicted miR-155 target genes. An integrated analysis of the corresponding expression profiles indicated that these targets were either regulated by mRNA decay or by translational repression. Of the identified miR-155 targets, 17 were related to cell cycle control, suggesting their involvement in the observed increase in cell proliferation of HEK293T cells upon miR-155 expression. Additional, secondary changes within the gene expression profile were detected and might contribute to this phenotype as well. Interestingly, by analyzing RIP-Seq data of HEK-293T cells and two B-cell lines we identified a recurrent disproportional enrichment of several miRNAs, including miR-155 and miRNAs of the miR-17-92 cluster, in the AGO2-associated precipitates, suggesting discrepancies in miRNA expression and activity. PMID- 23673374 TI - The Manchester-Oxford Foot Questionnaire (MOXFQ): Development and validation of a summary index score. AB - OBJECTIVES: The Manchester-Oxford Foot Questionnaire (MOXFQ) is a validated 16 item, patient-reported outcome measure for evaluating outcomes of foot or ankle surgery. The original development of the instrument identified three domains. This present study examined whether the three domains could legitimately be summed to provide a single summary index score. METHODS: The MOXFQ and Short-Form (SF)-36 were administered to 671 patients before surgery of the foot or ankle. Data from the three domains of the MOXFQ (pain, walking/standing and social interaction) were subjected to higher order factor analysis. Reliability and validity of the summary index score was assessed. RESULTS: The mean age of the participants was 52.8 years (sd 15.68; 18 to 89). Higher order principle components factor analysis produced one factor, accounting for 74.7% of the variance. The newly derived single index score was found to be internally reliable (alpha = 0.93) and valid, achieving at least moderate correlations (r >= 0.5, p < 0.001) with related (pain/function) domains of the SF-36. CONCLUSIONS: Analyses indicated that data from the MOXFQ can be presented in summary form. The MOXFQ summary index score (MOXFQ-Index) provides an overall indication of the outcomes of foot and ankle surgery. Furthermore, the single index reduces the number of statistical comparisons, and hence the role of chance, when exploring MOXFQ data. PMID- 23673375 TI - Muscle 'regenerative potential' determinesphysical recovery following total knee replacement. AB - OBJECTIVES: Lower limb muscle power is thought to influence outcome following total knee replacement (TKR). Post-operative deficits in muscle strength are commonly reported, although not explained. We hypothesised that post-operative recovery of lower limb muscle power would be influenced by the number of satellite cells in the quadriceps muscle at time of surgery. METHODS: Biopsies were obtained from 29 patients undergoing TKR. Power output was assessed pre operatively and at six and 26 weeks post-operatively with a Leg Extensor Power Rig and data were scaled for body weight. Satellite cell content was assessed in two separate analyses, the first cohort (n = 18) using immunohistochemistry and the second (n = 11) by a new quantitative polymerase chain reaction (q-PCR) protocol for Pax-7 (generic satellite cell marker) and Neural Cell Adhesion Molecule (NCAM; marker of activated cells). RESULTS: A significant improvement in power output was observed post-operatively with a mean improvement of 19.7 W (95% confidence interval (CI) 14.43 to 30.07; p < 0.001) in the first cohort and 27.5 W (95% CI 13.2 to 41.9; p = 0.002) in the second. A strong correlation was noted between satellite cell number (immunohistochemistry) and improvement in patient power output (r = 0.64, p = 0.008). Strong correlation was also observed between the expression of Pax-7 and power output (r = 0.79, p = 0.004), and the expression of NCAM and power output (r = 0.84, p = 0.001). The generic marker explained 58% of the variation in power output, and the marker of activated cells 67%. CONCLUSIONS: Muscle satellite cell content may determine improvement in lower limb power generation (and thus function) following TKR. PMID- 23673377 TI - Self-rated health predicts outcome in patients with type 2 diabetes and myocardial infarction: a DIGAMI 2 quality of life sub-study. AB - The Diabetes mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) 2 Quality of Life (QoL) sub-study included 465 patients with type 2 diabetes and acute myocardial infarction (AMI) followed for 2 years. Self-rated health was reported by the rating scale (RS), graded 0 = death to 100 = perfect health. Prospective associations between RS and all-cause mortality, cardiovascular (CV) death and cardiovascular events (CVEs = CV death, non-fatal AMI, stroke) were assessed. Median age was 68 years (range 59-74), 68% male. Patients experiencing CVE (n = 132) or death (n = 71) had lower RS compared with patients free from events: 60 (50-79) versus 70 (55-81) (p < 0.001) and 60 (50 75) versus 70 (51-80) (p = 0.008). The RS score predicted CVE [hazard ratio (HR); 95% confidence interval (CI): 0.87; 0.80-0.95] and all-cause mortality (0.86; 0.76-0.97), and corresponding HRs after adjustment were 0.90; 0.83-0.99 and 0.90; 0.79-1.02, respectively. A low self-rated health is of prognostic importance in patients with type 2 diabetes and AMI and may serve as an easily obtainable indicator of high risk for CVEs supplementing traditional risk factors. PMID- 23673376 TI - The GLP-1 receptor agonist liraglutide inhibits progression of vascular disease via effects on atherogenesis, plaque stability and endothelial function in an ApoE(-/-) mouse model. AB - Liraglutide, a once-daily glucagon-like peptide-1 receptor (GLP-1R) agonist, has been approved as a new treatment for type 2 diabetes and is the subject of a clinical trial programme to evaluate the effects on cardiovascular disease and safety. The current study aimed to determine the in vivo effect of liraglutide on progression of atherosclerotic vascular disease in the apolipoprotein E-deficient (ApoE(-/-)) mouse model and identify underlying mechanisms responsible. Liraglutide treatment inhibited progression of early onset, low-burden atherosclerotic disease in a partially GLP-1R-dependent manner in the ApoE(-/-) mouse model. In addition, liraglutide treatment inhibited progression of atherosclerotic plaque formation and enhanced plaque stability, again in a partially GLP-1R-dependent manner. No significant effect of liraglutide on progression of late onset, high-burden atherosclerotic disease was observed. In addition, no significant endothelial cell dysfunction was identified in ApoE(-/-) mice with early onset, low-burden atherosclerotic disease, although significant prevention of weight gain was observed in liraglutide-treated mice using this dietary protocol. Taken together, these results suggest a potential role for liraglutide in the prevention and stabilisation of atherosclerotic vascular disease together with possible protection against major cardiovascular events. PMID- 23673378 TI - Endothelial dysfunction in patients with type 2 diabetes post acute coronary syndrome. AB - This single visit study examined whether endothelial function, in addition to cardiovascular (CV) risk factors and plasma microparticle content, was normalised in 15 patients with type 2 diabetes + acute coronary syndrome (ACS) (6 weeks-6 months post cardiac event) undergoing standard clinical care compared to 16 sex- and age-matched healthy controls. RESULTS: While total and low-density lipoprotein (LDL) cholesterol levels were well controlled in the patients with type 2 diabetes + ACS, residual CV risk profiles such as increased body mass index (BMI), systolic blood pressure, glucose levels and triglycerides and lower high-density lipoprotein (HDL) levels were still apparent. Endothelium-dependent responses to acetylcholine (ACh) were significantly lower in type 2 diabetes + ACS patients compared to controls. Correspondingly, the reactive hyperaemic index (RHI) was lower in the patient cohort. Endothelial microparticle (EMP) levels (CD31(+), CD41(-)) were 40% lower in the patient cohort. Simultaneous analysis of platelet microparticle (PMP) levels (CD41(+)) showed no difference between cohorts. CONCLUSIONS: Patients with type 2 diabetes suffering from recent ACS exhibit residual CV risk factors despite being on standard clinical care. In addition, these patients continue to present with endothelial dysfunction despite having lower levels of EMPs. PMID- 23673379 TI - Use of a highly sensitive recombinant hepatoma cell method to determine dioxin concentrations in samples of fish and crab from a hotspot area. AB - A new and easy fast-screening test (the Ad-DR (adenoviral vector-dioxin response) bioassay) for dioxins in biological samples from highly dioxin-contaminated areas was developed. The aryl-hydrocarbon-receptor (AhR) reporter system was utilized to transport a dioxin-responsive-element (DRE) via an adenovirus vector into rat hepatoma (H4IIE) cells before each experiment; these DRE-H4IIE cells were utilized in the Ad-DR bioassay. Biological extracts were simultaneously analyzed by the Ad-DR bioassay and high resolution gas chromatography/high resolution mass spectrometry (HRGC/HRMS). A good correlation was found between the results of the HRGC/HRMS assay and those of the Ad-DR bioassay (R(2) = 0.920, p < 0.001). The bio-analytical equivalent (BEQ) value found in fish or crab caught in the abandoned pentachlorophenol plant (AP) was extremely high compared with the BEQ in fish or crab caught in two rivers nearby this abandoned plant. Dioxins were more heavily bioaccumulated in fish viscera than in fish muscles or in the whole fish. Two-way analysis of variance tests identified the significant effects of fish collection site, fish or crab tissue sample and the interaction between them on dioxin levels in the tissues of these aquatic animals. In conclusion, the Ad DR bioassay is a useful tool to determine dioxin levels in samples of fish and crab. Compared with fish tissues, where a sample is taken (in the PCP plant or nearby rivers) is the most important factor to determine bioaccumulation of dioxins in fish. PMID- 23673381 TI - Substitutional C on B sites in AlLiB14. AB - The effect of C substitution in the AlLiB14 lattice is examined using first principles methods. The inter-icosahedra B site is found to be the most favorable B site for C substitution and the formation energy is predicted to be 1.7 eV in B rich conditions. Substituting C does not affect the band gap, nor does it introduce defect states to the gap. An ideal brittle cleavage model is used to study the impact of C doping on the mechanical properties of AlLiB14, and it is concluded that introducing C to the crystal decreases the ideal fracture strength by 3.3 GPa, which is about a 12% reduction in overall strength. PMID- 23673380 TI - Metagenomic sequencing reveals microbiota and its functional potential associated with periodontal disease. AB - Although attempts have been made to reveal the relationships between bacteria and human health, little is known about the species and function of the microbial community associated with oral diseases. In this study, we report the sequencing of 16 metagenomic samples collected from dental swabs and plaques representing four periodontal states. Insights into the microbial community structure and the metabolic variation associated with periodontal health and disease were obtained. We observed a strong correlation between community structure and disease status, and described a core disease-associated community. A number of functional genes and metabolic pathways including bacterial chemotaxis and glycan biosynthesis were over-represented in the microbiomes of periodontal disease. A significant amount of novel species and genes were identified in the metagenomic assemblies. Our study enriches the understanding of the oral microbiome and sheds light on the contribution of microorganisms to the formation and succession of dental plaques and oral diseases. PMID- 23673383 TI - Charge transport study of high mobility polymer thin-film transistors based on thiophene substituted diketopyrrolopyrrole copolymers. AB - In this paper, we report on the device physics and charge transport characteristics of high-mobility dual-gated polymer thin-film transistors with active semiconductor layers consisting of thiophene flanked DPP with thienylene vinylene-thienylene (PDPP-TVT) alternating copolymers. Room temperature mobilities in these devices are high and can exceed 2 cm(2) V(-1) s(-1). Steady state and non-quasi-static measurements have been performed to extract key transport parameters and velocity distributions of charge carriers in this copolymer. Charge transport in this polymer semiconductor can be explained using a Multiple-Trap-and-Release or Monroe-type model. We also compare the activation energy vs. field-effect mobility in a few important polymer semiconductors to gain a better understanding of transport of DPP systems and make appropriate comparisons. PMID- 23673384 TI - Impact of fluid intake in the prevention of urinary system diseases: a brief review. AB - We are often told that we should be drinking more water, but the rationale for this remains unclear and no recommendations currently exist for a healthy fluid intake supported by rigorous scientific evidence. Crucially, the same lack of evidence precludes the claim that a high fluid intake has no clinical benefit. The aim of this study is to describe the mechanisms by which chronic low fluid intake may play a crucial role in the pathologies of four key diseases of the urinary system: urolithiasis, urinary tract infection, chronic kidney disease and bladder cancer. Although primary and secondary intervention studies evaluating the impact of fluid intake are lacking, published data from observational studies appears to suggest that chronic low fluid intake may be an important factor in the pathogenesis of these diseases. PMID- 23673382 TI - Upregulation of a small vault RNA (svtRNA2-1a) is an early event in Parkinson disease and induces neuronal dysfunction. AB - MicroRNAs (miRNAs) and other small non-coding RNAs (sncRNAs) are post transcriptional regulators of gene expression, playing key roles in neuronal development, plasticity, and disease. Transcriptome deregulation caused by miRNA dysfunction has been associated to neurodegenerative diseases. Parkinson disease (PD) is the second most common neurodegenerative disease showing deregulation of the coding and small non-coding transcriptome. On profiling sncRNA in PD brain areas differently affected, we found that upregulation of a small vault RNA (svtRNA2-1a) is widespread in PD brains, occurring early in the course of the disease (at pre-motor stages). SvtRNA2-1a biogenesis was dependent on Dicer activity on its precursor (vtRNA2-1) but independent of Drosha endonuclease, unlike the canonical miRNAs. Although endogenous svtRNA2-1a was enriched in Ago-2 immunoprecipitates in differentiated SH-SY5Y neuronal cells, overexpression of svtRNA2-1a induced subtle transcriptomic changes, suggesting that gene expression regulation may involve other mechanisms than mRNA decay only. Function enrichment analysis of the genes deregulated by svtRNA2-1a overexpression or svtRNA2-1a predicted targets identified pathways related to nervous system development and cell type specification. The expression pattern of svtRNA2-1a during development and aging of the human brain and the detrimental consequences of a svtRNA2-1a mimic overexpression in neuronal cells further indicate that low svtRNA2-1a levels may be important for the maintenance of neurons. Our results suggest that early svtRNA2-1a upregulation in PD may contribute to perturbations of gene expression networks, underlying metabolic impairment and cell dysfunction. A better understanding of the pathways regulated by svtRNA2-a, and also the mechanisms regulating its expression should facilitate the identification of new targets for therapeutic approaches in PD. PMID- 23673385 TI - Formulation approach for the development of a stable, lyophilized formaldehyde containing vaccine. AB - Formaldehyde has been used in the inactivation of a number of viral and bacterial toxins used in vaccines. In some cases, a small amount of formaldehyde may be necessary in order to prevent reversion back to the toxic state during storage. When a lyophilized preparation is required, care must be taken to ensure that formaldehyde is not lost during the process in order to ensure safety of the product. A design of experiments (DOEs) approach was taken to devise a stable, lyophilized, vaccine formulation. A formaldehyde-inactivated bacterial toxin was used as a model antigen. Entrapment of formaldehyde in an amorphous matrix and/or interactions with amorphous components was found to be required for complete recovery of formaldehyde during lyophilization. In formulations consisting of sucrose and citrate, formaldehyde could be recovered across a wide range of excipient concentrations. Stability of the antigen was dependent on formaldehyde concentration, with antigen stability decreasing with increasing formaldehyde concentration. This is in contrast to the risk of reversion which increases with decreasing concentrations of formaldehyde. Finally, variations in temperatures during annealing, primary drying, and secondary drying had no impact on formaldehyde recovery. PMID- 23673386 TI - Histone induced platelet aggregation is inhibited by normal albumin. AB - INTRODUCTION: Histones are small, nuclear proteins that serve to package DNA. Recent reports suggest that extracellular histones, including histone H4, may contribute to the pathogenesis of sepsis; they promote platelet aggregation and thrombosis when released into the circulation during inflammation or cell death. The mechanisms by which the body minimizes the deleterious effects of circulating histones are unclear. Because histones can bind to plasma proteins, including albumin, we hypothesized that normal albumin can prevent histones from activating platelets. MATERIALS AND METHODS: Platelets and platelet-free plasma were obtained from healthy, adult subjects. The dose-dependent effects of histone H4 on platelet aggregation were studied by optical aggregometry. The effects of native and albumin-depleted plasma (prepared by affinity chromatography) on histone-induced platelet aggregation were also assessed. The effects of normal and surface-neutralized albumin (through modification of carboxyl groups) on histone-induced platelet activation and aggregation were evaluated using flow cytometry and aggregometry. RESULTS: Histone H4 induced platelet aggregation in a dose-dependent manner. This histone-induced platelet aggregation was inhibited by both plasma and human serum albumin in a dose-dependent fashion. Furthermore, depletion of albumin from plasma reduced its ability to inhibit aggregation. Finally, surface neutralization of albumin decreased its ability to inhibit histone-induced activation and aggregation. DISCUSSION: These data suggest that normal albumin serves a role in preventing histone-induced platelet aggregation in a charge-dependent manner. PMID- 23673387 TI - Impact of antithrombin deficiency on efficacy of edoxaban and antithrombin dependent anticoagulants, fondaparinux, enoxaparin, and heparin. AB - INTRODUCTION: Oral factor Xa (FXa) inhibitors are a novel class of anticoagulants that, unlike heparins, are expected to demonstrate antithrombotic effects independent of plasma antithrombin (AT) concentrations. We utilized heterozygous AT-deficient (AT+/-) mice to determine the impact of AT deficiency on anticoagulant and antithrombotic effects of edoxaban, a direct FXa inhibitor, and compared with heparins (fondaparinux, enoxaparin, and unfractionated heparin [UHF]). MATERIALS AND METHODS: The effects of edoxaban and heparins on in vitro prothrombin time and activated partial thromboplastin time were measured in plasma obtained from wild type (AT+/+) and AT+/- male mice. To assess the antithrombotic effects of these anticoagulants in vivo, venous thrombosis was induced in the inferior vena cava by FeCl3 treatment. Potency ratios of antithrombotic effects in AT+/- compared with AT+/+ mice were analyzed by a parallel line assay. RESULTS: In vitro studies demonstrated that the clotting time prolongation effects of edoxaban were not affected by heterozygous AT deficiency whereas those of AT-dependent anticoagulants were attenuated. In AT+/- mice, the antithrombotic effects of AT-dependent anticoagulants were less potent than those in AT+/+ mice. In contrast, edoxaban was equipotent in preventing thrombus formation in both wild-type and AT-deficient mice. The attenuated antithrombotic effects of fondaparinux, enoxaparin, and UFH in AT-deficient mice were restored by AT supplementation. Edoxaban exerts a comparable antithrombotic effect even in mice with low plasma AT antigen and activity to that in wild-type mice. CONCLUSION: Edoxaban may potentially be prioritized over AT-dependent anticoagulants in patients with lower plasma AT concentration. PMID- 23673388 TI - Mapping of two suppressors of OVATE (sov) loci in tomato. AB - Tomato fruit shape varies significantly in the cultivated germplasm. To a large extent, this variation can be explained by four genes including OVATE. While most varieties with the OVATE mutation bear elongated fruits, some accessions carry round fruit, suggesting the existence of suppressors of OVATE in the germplasm. We developed three intraspecific F2 populations with parents that carried the OVATE mutation but differed in fruit shape. We used a bulk segregant analysis approach and genotyped the extreme classes using a high-throughput genotyping platform, the SolCAP Infinium Assay. The analyses revealed segregation at two quantitative trait loci (QTLs), sov1 and sov2. These loci were confirmed by genotyping and QTL analyses of the entire population. More precise location of those loci using progeny testing confirmed that sov1 on chromosome 10 controlled obovoid and elongated shape, whereas sov2 on chromosome 11 controlled mainly elongated fruit shape. Both loci were located in intervals of <2.4 Mb on their respective chromosomes. PMID- 23673389 TI - Ratiometric fluorescent nanosensor based on water soluble carbon nanodots with multiple sensing capacities. AB - A construction strategy for ratiometric fluorescent nanosensors based on water soluble C-dots was developed, which could sense temperature (10-82 degrees C), pH values (lower than 6.0 or higher than 8.6) and Fe(3+) ions (>0.04 MUM) by monitoring the intensity ratios of dual fluorescence bands (Ib/Ig) under 380 nm excitation. Ib/Ig decreased nearly linearly with increasing temperature from 10 to 82 degrees C. In the pH range from 8.6 to 6.0, the Ib/Ig was nearly constant at 0.75. Ib/Ig gradually decreased from 0.75 to 0.52 in the pH range from 6.0 to 1.9, and increased nearly linearly from 0.52 to 0.75 in the pH range from 1.9 to 1.0. The dual fluorescence behavior was reversible in the pH range from 1.0 to 8.6. As pH increased from 10.6 to 13.0, the green fluorescence band decreased continuously and blue shifted with a nearly linear increase in Ib/Ig from 0.75 to 2.15, while the green fluorescence band cannot be recovered by decreasing the pH value. Ib/Ig was ultrasensitive and selective in presence of Fe(3+) (>0.04 MUM) in neutral aqueous environments. The two fluorescence bands of the C-dots were attributed to different surface states that may produce different fluorescent signal responses to external physical or chemical stimuli. PMID- 23673390 TI - Review of existing experimental approaches for the clinical evaluation of the benefits of plant food supplements on cardiovascular function. AB - We conducted a survey of the National Centre for Biotechnology Information (NCBI) PubMed database to identify methods most commonly used for the evaluation of the effect of plant food supplements on the cardiovascular system and their relevance to the regulatory status of these products. Particularly, our search strategy was aimed at the selection of studies concerning the clinical evaluation of the beneficial effects of the most commonly studied plant food supplements acting on the cardiovascular system. Following the screening of 3839 papers for inclusion criteria, 48 published reports were retained for this review. Most studies included in this review used a double blind controlled design, and evaluated the effect of plant food supplements on individuals affected by a disease of the cardiovascular system. The majority of the studies were found to be of low methodological quality on the Jadad scale, mainly because of inadequate reporting of adverse events and of patient withdrawals. In comparison, measures used for the evaluation of benefits included mostly cardiovascular risk factors as recommended in international guidelines and in accordance with principles laid down for the evaluation of health claims in food. The risk factors most frequently evaluated belonged to the category of "lipid function and levels", "heart function" and "blood pressure". For the absolute majority of the studies, the study period did not exceed one month. This review highlights critical factors to be considered in the design of studies evaluating the health effects of plant food supplements on the cardiovascular system. Between others, the inclusion of healthy individuals, better reporting and description of the characteristics of the product used could improve the quality and relevance of these studies. PMID- 23673391 TI - The alterations of the sigmoid-rectal junction in diverticular disease of the colon revealed by MR-defecography. AB - PURPOSE: The sigmoidorectal junction (SRJ) has been defined as an anatomical sphincter with particular physiological behavior that regulates sigmoid and rectum evacuation. Its function in clinical conditions, such as diverticular disease has been advocated. The aim of our study is to identify the SRJ and to compare the morphometric and dynamic features of the SRJ between patients with diverticular disease and healthy subjects using MR-defecography. METHODS: Sixteen individuals, eight with uncomplicated diverticular disease and eight healthy subjects, were studied using MR-defecography to identify the SRJ and to compare the morphometric and dynamic features observed. RESULTS: In each subject studied, MR-defecography was able to identify the SRJ. This resulted in the identification of a discrete anatomical entity with a mean length of 31.23 mm, located in front of the first sacral vertebra (S1) and at a mean distance of 15.55 cm from the anal verge, with a mean wall thickness of 4.45 mm, significantly different from the sigmoid and rectal parietal thickness. The SRJ wall was significantly thicker in patients with diverticular disease than the controls (P = 0.005), showing a unique shape and behavior in dynamic sequences. CONCLUSION: Our findings support the hypothesis that SRJ plays a critical role in patients with symptomatic diverticular disease; further investigation may clarify whether specific SRJ analysis, such as MR-defecography, would predict inflammatory complications of this diffuse and heterogenic disease. PMID- 23673392 TI - Assembly of DNA-functionalized gold nanoparticles on electrospun nanofibers as a fluorescent sensor for nucleic acids. AB - A facile approach was developed to assemble DNA-functionalized gold nanoparticles on the electrospun nanofibers. This novel nanocomposite was successfully applied to constructing a highly sensitive and selective fluorescent sensor for nucleic acids. PMID- 23673393 TI - Is medical home enrollment associated with receipt of guideline-concordant follow up care among low-income breast cancer survivors? AB - BACKGROUND: Community Care of North Carolina (CCNC) initiated an innovative medical home program in the 1990 s to improve primary care in Medicaid-insured populations. CCNC has been successful in improving asthma, diabetes, and cardiovascular outcomes but has not been evaluated in the context of cancer care. We explored whether CCNC enrollment was associated with guideline-concordant follow-up care among breast cancer survivors. METHODS: Using state cancer registry records matched to Medicaid claims, we identified women 18 to 64 years old who were diagnosed with stage 0, I, II, or unstaged breast cancer from 2003 to 2007 and tracked their monthly CCNC enrollment. Using published American Society for Clinical Oncology guidelines to define our outcomes, we employed multivariate logistic regressions to examine, as a function of CCNC enrollment, receipt of mammogram and at least 2 physical examinations/history-taking visits within observational windows consistent with the guidelines. RESULTS: Of the 840 women, approximately half were enrolled into the CCNC for some time during the study period. Between 40% and 85% received follow-up mammogram in accordance with guidelines, with significant variation by CCNC status, and 95% of women received at least 2 physical examinations/history-taking visits. In multivariate models, increasing months of CCNC enrollment was significantly positively associated with receipt of follow-up mammogram but not with physical examinations/history-taking visits. CONCLUSIONS: Results suggest that CCNC enrollment is associated with guideline-concordant follow-up care for Medicaid-insured survivors. Given the growing population of cancer survivors and increased emphasis on primary care medical homes, future studies should explore what factors are associated with medical home participation and whether similar findings are observed with extended follow-up. PMID- 23673394 TI - Exploring the frontier of electronic health record surveillance: the case of postoperative complications. AB - BACKGROUND: The aim of this study was to build electronic algorithms using a combination of structured data and natural language processing (NLP) of text notes for potential safety surveillance of 9 postoperative complications. METHODS: Postoperative complications from 6 medical centers in the Southeastern United States were obtained from the Veterans Affairs Surgical Quality Improvement Program (VASQIP) registry. Development and test datasets were constructed using stratification by facility and date of procedure for patients with and without complications. Algorithms were developed from VASQIP outcome definitions using NLP-coded concepts, regular expressions, and structured data. The VASQIP nurse reviewer served as the reference standard for evaluating sensitivity and specificity. The algorithms were designed in the development and evaluated in the test dataset. RESULTS: Sensitivity and specificity in the test set were 85% and 92% for acute renal failure, 80% and 93% for sepsis, 56% and 94% for deep vein thrombosis, 80% and 97% for pulmonary embolism, 88% and 89% for acute myocardial infarction, 88% and 92% for cardiac arrest, 80% and 90% for pneumonia, 95% and 80% for urinary tract infection, and 77% and 63% for wound infection, respectively. A third of the complications occurred outside of the hospital setting. CONCLUSIONS: Computer algorithms on data extracted from the electronic health record produced respectable sensitivity and specificity across a large sample of patients seen in 6 different medical centers. This study demonstrates the utility of combining NLP with structured data for mining the information contained within the electronic health record. PMID- 23673395 TI - Understanding racial and ethnic differences in patient experiences with outpatient health care in Veterans Affairs Medical Centers. AB - BACKGROUND: Racial and ethnic differences in patient health care experiences have not been well examined in the Veterans Affairs (VA) Healthcare System. OBJECTIVES: To examine racial/ethnic differences in outpatient health care experiences within and between VA medical facilities. RESEARCH DESIGN: We assessed within-facility and between-facility racial/ethnic differences in responses to the 2010 VA Survey of Healthcare Experiences of Patients using mixed effects multinomial regression. SUBJECTS: A total of 211,459 respondents (53.2%) to a random survey of outpatients from 910 VA medical facilities (71.9% non Hispanic white, 15.1% non-Hispanic black, 6.4% Hispanic, and 6.7% Other race/ethnicity). MEASURES: Negative and positive patient-reported experiences in 8 domains of health care. RESULTS: Between-facility effects for black race were higher for 7 domains of negative experiences [risk differences (RDs): 0.37% to 1.64%] and lower for 6 domains of positive experiences (RDs: -0.69% to -2.54%). Between-facility effects for Hispanic ethnicity were higher for 5 domains of negative experiences (RDs: 0.60%-1.34%) and lower for 5 domains of positive experiences (RDs: -1.00% to -1.88%). Hispanic ethnicity was also associated with higher within-facility rates of positive experiences for 5 domains of care (RDs: 2.97%-4.08%). Other race/ethnicity was associated with significantly higher within-facility rates of negative experiences (RDs: 2.04%-3.95%) and lower rates of positive experiences for all 8 domains (RDs: -2.05% to -4.70%). CONCLUSIONS: In a national random sample of Veterans managed in the VA Healthcare System, we demonstrated significant within-facility and between-facility racial and ethnic differences in outpatient health care experiences, with differing patterns for each minority group. PMID- 23673396 TI - First-principles study of the structure and band structure of Ga2Se3. AB - Our first-principles calculations show that the ordering of stoichiometric cation vacancies in Ga2Se3 has a large influence on the bandgap, up to 0.55 eV. Therein, the zigzag-line vacancy-ordered Ga2Se3 has the maximum bandgap (~2.56 eV direct bandgap), and the straight-line vacancy-ordered Ga2Se3 has the minimum bandgap (~1.99 eV indirect bandgap) at 0 K, according to scGW calculations. The bandgap difference (0.55 eV) is almost the same for normal density functional theory (DFT) calculations, hybrid DFT calculations and GW calculations. The calculation results are consistent with the experimental bandgap range of 2.0-2.6 eV at room temperature. Also, hydrostatic pressure (<9 GPa) tends to increase the bandgap, consistent with the experiments in the literature. PMID- 23673397 TI - The mini-BESTest can predict parkinsonian recurrent fallers: a 6-month prospective study. AB - OBJECTIVES: To examine whether the Mini-Balance Evaluation Systems Test (Mini BESTest) independently predicts recurrent falls in people with Parkinson's disease. DESIGN: The study used a longitudinal cohort design. SUBJECTS: A total of 110 patients with Parkinson's disease completed the study and were included in the final analysis. Most of the patients had moderate disease severity. METHODS: All subjects were measured to establish a baseline. The tests used were Unified Parkinson's Disease Rating Scale (MDS-UPDRS III), Freezing of Gait Questionnaire, Five-Time-Sit-To-Stand Test, and Mini-BESTest. All patients were followed by telephone interview for 6 months to register the incidence of monthly falls. RESULTS: Twenty-four patients (21.2%) reported more than one fall and were classified as recurrent fallers. Results of the multivariate logistic regression showed that, after adjusting for fall history and MDS-UPDRS III score, the Mini BESTest score remained a significant predictor of recurrent falls. We further established that a cut-off Mini-BESTest score of 19 had the best sensitivity (79%) for predicting future falls in patients with Parkinson's disease. CONCLUSION: The results indicate that those with a Mini-BESTest score < 19 at baseline had a significantly higher risk of sustaining recurrent falls in the next 6 months. These findings highlight the importance of evaluating dynamic balance ability during fall risk assessment in patients with Parkinson's disease. PMID- 23673398 TI - Mechanism of one-electron oxidation of metformin in aqueous solution. AB - Hydroxyl free radical-induced oxidation of metformin was studied in aqueous solution as a function of the pH. Hydroxyl free radicals were generated by gamma radiolysis of water and the oxidation end-products were quantified by high performance liquid chromatography coupled to mass spectrometry (HPLC/MS), as a function of the radiation dose. This work is a joint experimental and theoretical (DFT) approach that has paved the way towards a comprehensive rationalization of the one-electron mechanisms of MTF oxidation, as a function of the pH. PMID- 23673401 TI - Prevalence and prognosis of cor pulmonale during protective ventilation for acute respiratory distress syndrome. AB - PURPOSE: Pulmonary vascular dysfunction is common during acute respiratory distress syndrome (ARDS), but there is controversy concerning prevalence and prognosis of cor pulmonale during protective ventilation for ARDS. METHODS: This was a prospective observational study in an academic medical intensive care unit in France. Two hundred and twenty-six consecutive patients with moderate to severe ARDS (Berlin definition) ventilated with plateau pressure limited at 30 cmH2O (mean PEEP of 8.8 +/- 3.6 cmH2O) underwent transesophageal echocardiography (TEE) within the first 3 days after the diagnosis of ARDS. Cor pulmonale was defined as a dilated right ventricle associated with septal dyskinesia. RESULTS: Cor pulmonale was detected in 49 patients (prevalence of 22%; 95% confidence interval, 16-27%). Multivariate logistic regression identified infectious causes of lung injury and higher driving pressures as independent factors associated with cor pulmonale. Patients with cor pulmonale exhibited a higher incidence of shock (need for vasoactive drug) at the time of TEE and were more often managed with prone positioning and/or nitric oxide as adjunctive therapy for severe hypoxemia during ARDS course. The 28-day mortality rate was significantly higher in the group with cor pulmonale (60 vs. 36%, p < 0.01). Multivariate logistic regression identified McCabe and Jackson class, lung injury not related to pneumonia, aspiration, or sepsis, lactic acidosis, driving pressure, and cor pulmonale as independent risk factors for 28-day mortality. CONCLUSION: Cor pulmonale occurrence is not negligible in ARDS patients ventilated with airway pressure limitation. Cor pulmonale was associated with sepsis and higher values of driving pressure and was an independent risk factor for 28-day mortality in our series. PMID- 23673403 TI - Reduced graphene oxide wrapped FeS nanocomposite for lithium-ion battery anode with improved performance. AB - A new nanocomposite formulation of the FeS-based anode for lithium-ion batteries is proposed, where FeS nanoparticles wrapped in reduced graphene oxide (RGO) are produced via a facile direct-precipitation approach. The resulting nanocomposite FeS@RGO structure has better lithium ion storage properties, exceeding those of FeS prepared without RGO sheets. The enhanced electrochemical performance is attributed to the robust sheet-wrapped structure with smaller FeS nanoparticles and synergetic effects between FeS and RGO sheets, such as increased conductivity, shortened lithium ion diffusion path, and the effective prevention of polysulfide dissolution. PMID- 23673399 TI - Intra-abdominal hypertension and the abdominal compartment syndrome: updated consensus definitions and clinical practice guidelines from the World Society of the Abdominal Compartment Syndrome. AB - PURPOSE: To update the World Society of the Abdominal Compartment Syndrome (WSACS) consensus definitions and management statements relating to intra abdominal hypertension (IAH) and the abdominal compartment syndrome (ACS). METHODS: We conducted systematic or structured reviews to identify relevant studies relating to IAH or ACS. Updated consensus definitions and management statements were then derived using a modified Delphi method and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guidelines, respectively. Quality of evidence was graded from high (A) to very low (D) and management statements from strong RECOMMENDATIONS (desirable effects clearly outweigh potential undesirable ones) to weaker SUGGESTIONS (potential risks and benefits of the intervention are less clear). RESULTS: In addition to reviewing the consensus definitions proposed in 2006, the WSACS defined the open abdomen, lateralization of the abdominal musculature, polycompartment syndrome, and abdominal compliance, and proposed an open abdomen classification system. RECOMMENDATIONS included intra-abdominal pressure (IAP) measurement, avoidance of sustained IAH, protocolized IAP monitoring and management, decompressive laparotomy for overt ACS, and negative pressure wound therapy and efforts to achieve same-hospital-stay fascial closure among patients with an open abdomen. SUGGESTIONS included use of medical therapies and percutaneous catheter drainage for treatment of IAH/ACS, considering the association between body position and IAP, attempts to avoid a positive fluid balance after initial patient resuscitation, use of enhanced ratios of plasma to red blood cells and prophylactic open abdominal strategies, and avoidance of routine early biologic mesh use among patients with open abdominal wounds. NO RECOMMENDATIONS were possible regarding monitoring of abdominal perfusion pressure or the use of diuretics, renal replacement therapies, albumin, or acute component-parts separation. CONCLUSION: Although IAH and ACS are common and frequently associated with poor outcomes, the overall quality of evidence available to guide development of RECOMMENDATIONS was generally low. Appropriately designed intervention trials are urgently needed for patients with IAH and ACS. PMID- 23673402 TI - Levosimendan for the treatment of subarachnoid hemorrhage-related cardiogenic shock. PMID- 23673400 TI - Metabolomics in pneumonia and sepsis: an analysis of the GenIMS cohort study. AB - PURPOSE: To determine the global metabolomic profile as measured in circulating plasma from surviving and non-surviving patients with community-acquired pneumonia (CAP) and sepsis. METHODS: Random, outcome-stratified case-control sample from a prospective study of 1,895 patients hospitalized with CAP and sepsis. Cases (n = 15) were adults who died before 90 days, and controls (n = 15) were adults who survived, matched on demographics, infection type, and procalcitonin. We determined the global metabolomic profile in the first emergency department blood sample using non-targeted mass-spectrometry. We derived metabolite-based prognostic models for 90-day mortality. We determined if metabolites stimulated cytokine production by differentiated Thp1 monocytes in vitro, and validated metabolite profiles in mouse liver and kidney homogenates at 8 h in cecal ligation and puncture (CLP) sepsis. RESULTS: We identified 423 small molecules, of which the relative levels of 70 (17 %) were different between survivors and non-survivors (p <= 0.05). Broad differences were present in pathways of oxidative stress, bile acid metabolism, and stress response. Metabolite-based prognostic models for 90-day survival performed modestly (AUC = 0.67, 95 % CI 0.48, 0.81). Five nucleic acid metabolites were greater in non survivors (p <= 0.05). Of these, pseudouridine increased monocyte expression of TNFalpha and IL1beta versus control (p < 0.05). Pseudouridine was also increased in liver and kidney homogenates from CLP mice versus sham (p < 0.05 for both). CONCLUSIONS: Although replication is required, we show the global metabolomic profile in plasma broadly differs between survivors and non-survivors of CAP and sepsis. Metabolite-based prognostic models had modest performance, though metabolites of oxidative stress may act as putative damage-associated molecular patterns. PMID- 23673406 TI - Charging a supercapacitor-like laminate with ambient moisture: from a humidity sensor to an energy harvester. AB - The electromechanically and mechano-electrically active three-layered laminate composed of a Nafion membrane, carbide-derived carbon-based electrodes, and a 1 ethyl-3-methylimidazolium trifluoromethanesulphonate ionic liquid electrolyte responds to humidity gradient and can therefore serve as a differential humidity sensor or an energy harvesting element. The hydrophilic nature of all constituents of the laminate promotes sorption and diffusion of water across the membrane, causing large volumetric effects. Diffusion of water and the formation of a hydration shell around the ionic groups reorient and dislocate the ionic liquid ions, which in turn induce the formation of an electric charge across the electrodes exposed to different levels of ambient humidity. The generated electric charge can be registered as a voltage or electric current between the electrodes. Furthermore, the supercapacitor-like properties of the laminate allow storage of the electric charge in the same laminate, where it was generated. PMID- 23673404 TI - The in vitro antitumor activity of Siegesbeckia glabrescens against ovarian cancer through suppression of receptor tyrosine kinase expression and the signaling pathways. AB - Siegesbeckia glabrescens (SG) Makino (Compositae) has been used as a traditional medicine for the treatment of a variety of diseases such as allergy, inflammation, acute hepatitis and hypertension. The primary aim of this study was to determine whether the ethanol extract of SG has antitumor activity against ovarian cancer and to identify molecular mechanisms and targets involved in the regulation of cell growth and progression. We demonstrate that SG treatment inhibits proliferation, adhesion, migration and invasion of SKOV-3 human ovarian cancer cells. The anti-proliferative effect of SG on SKOV-3 cells is accompanied by reduced expression of cyclin E and enhanced expression of the cyclin-dependent kinase inhibitor p27(Kip1), leading to inhibition of pRb phosphorylation. We also show that these antitumor activities are found to be mediated through suppression of FAK, ERK, Akt and p70(S6K)-dependent signaling pathways and downregulation of receptor tyrosine kinases such as EGFR, VEGFR-2 and FGFR-1 as well as the cell adhesion molecule N-cadherin. Taken together, our findings suggest further development and evaluation of SG for the treatment of ovarian cancer. PMID- 23673405 TI - DEVD-based hydrogelator minimizes cellular apoptosis induction. AB - Herein, we report the rational design of a DEVD-based heptapeptide hydrogelator 1 which is susceptible to caspase-3 (CASP3), and its isomeric control hydrogelator 2 with a DEDV-based heptapeptide sequence. Self-assembly of 1 in water results in flexuous, long nanofibers to form supramolecular hydrogel I with higher mechanical strength than that of hydrogel II which is composed of rigid, short nanofibers of 2. In vitro enzymatic analysis indicated that 1 is susceptive to CASP3 while 2 is not. 3-(4,5-dimethylthiazol-2-yl) 2,5 diphenyl tetrazolium bromide (MTT) and Western blot analyses indicated that DEDV-based hydrogelator 2 induces cell death via apoptotic pathway while the DEVD-based hydrogelator 1 minimizes cellular apoptosis induction. PMID- 23673407 TI - Does bone compaction around the helical blade of a proximal femoral nail anti rotation (PFNA) decrease the risk of cut-out?: A subject-specific computational study. AB - OBJECTIVES: Because of the contradictory body of evidence related to the potential benefits of helical blades in trochanteric fracture fixation, we studied the effect of bone compaction resulting from the insertion of a proximal femoral nail anti-rotation (PFNA). METHODS: We developed a subject-specific computational model of a trochanteric fracture (31-A2 in the AO classification) with lack of medial support and varied the bone density to account for variability in bone properties among hip fracture patients. RESULTS: We show that for a bone density corresponding to 100% of the bone density of the cadaveric femur, there does not seem to be any advantage in using a PFNA with respect to the risk of blade cut-out. On the other hand, in a more osteoporotic femoral head characterised by a density corresponding to 75% of the initial bone density, local bone compaction around the helical blade provides additional bone purchase, thereby decreasing the risk of cut-out, as quantified by the volume of bone susceptible to yielding. CONCLUSIONS: Our findings indicate benefits of using a PFNA over an intramedullary nail with a conventional lag screw and suggest that any clinical trial reporting surgical outcomes regarding the use of helical blades should include a measure of the femoral head bone density as a covariable. PMID- 23673408 TI - Recommendations for reporting outcome results in abdominal wall repair: results of a Consensus meeting in Palermo, Italy, 28-30 June 2012. AB - BACKGROUND: The literature dealing with abdominal wall surgery is often flawed due to lack of adherence to accepted reporting standards and statistical methodology. MATERIALS AND METHODS: The EuraHS Working Group (European Registry of Abdominal Wall Hernias) organised a consensus meeting of surgical experts and researchers with an interest in abdominal wall surgery, including a statistician, the editors of the journal Hernia and scientists experienced in meta-analysis. Detailed discussions took place to identify the basic ground rules necessary to improve the quality of research reports related to abdominal wall reconstruction. RESULTS: A list of recommendations was formulated including more general issues on the scientific methodology and statistical approach. Standards and statements are available, each depending on the type of study that is being reported: the CONSORT statement for the Randomised Controlled Trials, the TREND statement for non randomised interventional studies, the STROBE statement for observational studies, the STARLITE statement for literature searches, the MOOSE statement for metaanalyses of observational studies and the PRISMA statement for systematic reviews and meta-analyses. A number of recommendations were made, including the use of previously published standard definitions and classifications relating to hernia variables and treatment; the use of the validated Clavien-Dindo classification to report complications in hernia surgery; the use of "time-to event analysis" to report data on "freedom-of-recurrence" rather than the use of recurrence rates, because it is more sensitive and accounts for the patients that are lost to follow-up compared with other reporting methods. CONCLUSION: A set of recommendations for reporting outcome results of abdominal wall surgery was formulated as guidance for researchers. It is anticipated that the use of these recommendations will increase the quality and meaning of abdominal wall surgery research. PMID- 23673409 TI - Supportive care in cancer patients: a unifying concept. PMID- 23673410 TI - Myxoid liposarcoma and the mammalian target of rapamycin pathway. AB - PURPOSE OF REVIEW: Myxoid/round cell liposarcoma (MRCL) represents about 10% of all soft-tissue sarcomas. Therapeutic options for this subgroup of tumours are limited, essentially doxorubicin-based regimens and trabectedin. Recently, the mammalian target of rapamycin (mTOR) pathway has been identified as a therapeutic target in several sarcomas. MRCLs should be included among these, as various molecular aberrations of the mTOR pathway have been recently reported. RECENT FINDINGS: PI3KCA mutations were identified in 10-20% of MRCLs. Other molecular aberrations include loss of PTEN, Akt activation and overexpression of IGF1R. Recently, two minor responses to mTOR inhibitors were reported. SUMMARY: The relatively high frequency of mTOR signalling pathway alterations in MRCL provides a preclinical rationale for considering mTOR inhibition as a potential novel therapeutic strategy warranting further investigation. PMID- 23673411 TI - Academic versus industry-driven research in upper gastrointestinal cancer: sinners and saints. PMID- 23673412 TI - Cardioprotection by farnesol: role of the mevalonate pathway. AB - PURPOSE: Farnesol is a key metabolite of the mevalonate pathway and known as an antioxidant. We examined whether farnesol treatment protects the ischemic heart. METHODS: Male Wistar rats were treated orally with 0.2, 1, 5, and 50 mg/kg/day farnesol/vehicle for 12 days, respectively. On day 13, the effect of farnesol treatment on cardiac ischemic tolerance and biochemical changes was tested. Therefore, hearts were isolated and subjected either to 30 min coronary occlusion followed by 120 min reperfusion to measure infarct size or to 10 min aerobic perfusion to measure cardiac mevalonate pathway end-products (protein prenylation, cholesterol, coenzyme Q9, coenzyme Q10, dolichol), and 3 nitrotyrosine (oxidative/nitrosative stress marker), respectively. The cytoprotective effect of farnesol was also tested in cardiomyocytes subjected to simulated ischemia/reperfusion. RESULTS: Farnesol pretreatment decreased infarct size in a U-shaped dose-response manner where 1 mg/kg/day dose reached a statistically significant reduction (22.3+/-3.9% vs. 40.9+/-6.1% of the area at risk, p<0.05). Farnesol showed a similar cytoprotection in cardiomyocytes. The cardioprotective dose of farnesol (1 mg/kg/day) significantly increased the marker of protein geranylgeranylation, but did not influence protein farnesylation, cardiac tissue cholesterol, coenzyme Q9, coenzyme Q10, and dolichol. While the cardioprotective dose of farnesol did not influence 3 nitrotyrosine, the highest dose of farnesol (50 mg/kg/day) tested did not show cardioprotection, however, it significantly decreased cardiac 3-nitrotyrosine. CONCLUSIONS: This is the first demonstration that oral farnesol treatment reduces infarct size. The cardioprotective effect of farnesol likely involves increased protein geranylgeranylation and seems to be independent of the antioxidant effect of farnesol. PMID- 23673413 TI - Pulmonary embolism: pathophysiologic insights for new treatment trials. PMID- 23673414 TI - Expression of the cell-surface heparan sulfate proteoglycan syndecan-2 in developing rat anterior pituitary gland. AB - In the anterior pituitary gland, folliculo-stellate cells and five types of hormone-producing cells are surrounded by an extracellular matrix (ECM) essential for these cells to perform their respective roles. Syndecans-type I transmembrane cell-surface heparan sulfate proteoglycans act as major ECM coreceptors via their respective heparan sulfate chains and efficiently transduce intracellular signals through the convergent action of their transmembrane and cytoplasmic domains. The syndecans comprise four family members in vertebrates: syndecan-1, -2, -3 and -4. However, whether syndecans are produced in the pituitary gland or whether they have a role as a coreceptor is not known. We therefore used (1) reverse transcription plus the polymerase chain reaction to analyze the expression of syndecan genes and (2) immunohistochemical techniques to identify the cells that produce the syndecans in the anterior pituitary gland of adult rat. Syndecan-2 mRNA expression was clearly detected in the corticotropes of the anterior pituitary gland. Moreover, the expression of syndecan-2 in the developing pituitary gland had a distinct temporospatial pattern. To identify the cells expressing syndecan-2 in the developing pituitary gland, we used double immunohistochemistry for syndecan-2 and the cell markers E-cadherin (immature cells) and Ki-67 (proliferating cells). Some E-cadherin- and Ki-67-immunopositive cells expressed syndecan-2. Therefore, syndecan-2 expression occurs in developmentally regulated patterns and syndecan-2 probably has different roles in adult and developing anterior pituitary glands. PMID- 23673415 TI - Inhibition of the angiotensin-converting enzyme decreases skeletal muscle fibrosis in dystrophic mice by a diminution in the expression and activity of connective tissue growth factor (CTGF/CCN-2). AB - The renin-angiotensin system (RAS), through angiotensin II and the angiotensin converting enzyme (ACE), is involved in the genesis and progression of fibrotic diseases characterized by the replacement of normal tissue by an accumulation of an extracellular matrix (ECM). Duchenne muscular dystrophy (DMD) presents fibrosis and a decrease in muscle strength produced by chronic damage. The mdx mouse is a murine model of DMD and develops the same characteristics as dystrophic patients when subjected to chronic exercise. The connective tissue growth factor (CTGF/CCN2) and transforming growth factor type beta (TGF-beta), which are overexpressed in muscular dystrophies, play a major role in many progressive scarring conditions. We have tested the hypothesis that ACE inhibition decreases fibrosis in dystrophic skeletal muscle by treatment of mdx mice with the ACE inhibitor enalapril. Both sedentary and exercised mdx mice treated with enalapril showed improvement in gastrocnemius muscle strength explained by a reduction in both muscle damage and ECM accumulation. ACE inhibition decreased CTGF expression in sedentary or exercised mdx mice and diminished CTGF-induced pro-fibrotic activity in a model of CTGF overexpression by adenoviral infection. Enalapril did not have an effect on TGF-beta1 expression or its signaling activity in sedentary or exercised dystrophic mice. Thus, ACE inhibition might improve muscle strength and decrease fibrosis by diminishing specifically CTGF expression and activity without affecting TGF-beta1 signaling. Our data provide insights into the pathogenic events in dystrophic muscle. We propose ACE as a target for developing therapies for DMD and related diseases. PMID- 23673417 TI - Hammertoe surgery and the Trim-it Drill pin. AB - Digital deformities are some of the most frequent complaints of patients seeking a surgical solution after the failure of conservative care. A thorough assessment of the actual level of deformity is important to ensure a lasting surgical correction. This article details the options for correcting hammertoe, clawtoe and mallet toe deformities with Trim it Drill pin and the Spin pin. LEVELS OF EVIDENCE: Level 5. PMID- 23673416 TI - Crystal structure of AcrB complexed with linezolid at 3.5 A resolution. AB - AcrB is an inner membrane resistance-nodulation-cell division efflux pump and is part of the AcrAB-TolC tripartite efflux system. We have determined the crystal structure of AcrB with bound Linezolid at a resolution of 3.5 A. The structure shows that Linezolid binds to the A385/F386 loops of the symmetric trimer of AcrB. A conformational change of a loop in the bottom of the periplasmic cleft is also observed. PMID- 23673418 TI - Understanding the relationship of performance with nanofiller content in the biomimetic layered nanocomposites. AB - Montmorillonite/poly(vinyl alcohol) (MMT/PVA) nanocomposites spanning the complete range of MMT content (0-100 wt%) are prepared by simple evaporation induced assembly. Effects of MMT content on the structure and mechanical properties of nanocomposites are systematically investigated and exhibit two important transitions at MMT contents of 30 wt% and 70 wt%. In the range of 0-30 wt%, the nanocomposites show a random structure. With the content of PVA increasing, the mechanical properties of the resultant nanocomposites were dramatically enhanced and were higher than that by prediction according to the conventional composite model. In the range of 30-70 wt%, the nanocomposites show a nacre-like layered structure with alternating MMT platelets and PVA layers, and all PVA is completely restricted by MMT platelets. The mechanical properties of nanocomposites were further improved by increasing the content of MMT, and reached the maximum value at the MMT content of 70 wt%. The 70 wt% MMT/PVA nanocomposite has a tensile strength of 219 +/- 19 MPa, which is 5.5 times higher than that of a pure PVA film and surpasses nacre and reported biomimetic layered clay/PVA composites. When the MMT content is higher than 70 wt%, the layered structure is transformed to tactoids, which deteriorate mechanical properties. These results offer comprehensive understanding for developing high-performance biomimetic layered nanocomposite materials with high nanofiller loading. PMID- 23673419 TI - Comparative studies on the anti-tumor activities of high temperature- and pH modified citrus pectins. AB - High temperature and pH modification could produce functional pectins. In this study, high temperature-modified (HTCP) and pH-modified (MCP) citrus pectins were prepared for studying their anti-tumor activities in eight cancer cell lines and a mouse Sarcoma-180 (S-180) tumor model. HTCP inhibited the proliferation of these cancer cells and induced a caspase-3-dependent cell apoptosis and cell cycle arrest at G2/M phase. It also inhibited the growth of S-180 tumor to 49% of the control at the dose of 200 mg kg(-1) d(-1) and extended the survival time of the tumor-bearing mice. MCP had no anti-proliferative effects on these cancer cells and no anti-tumor effect in the mouse model. The anti-tumor activity of HTCP in the mouse tumor model was not correlated with immunomodulation and galectin-3 inhibition, but correlated well with proliferation inhibition. HTCP might be exploited as a functional food for cancer prevention and/or treatment. PMID- 23673420 TI - Distribution, clinical features and molecular analysis of primary immunodeficiency diseases in Chinese children: a single-center study from 2005 to 2011. AB - METHODS: Two hundred three children with genetically proven primary immunodeficiency diseases (PIDs) from 197 unrelated families were enrolled from January 2005 to December 2011. RESULTS: On the basis of criteria developed by the International Union of Immunological Societies, 79 patients were diagnosed as "other well-defined immunodeficiency syndromes" (38.9%), 62 (30.6%) with "predominant antibody deficiencies," 26 (12.8%) with "congenital defects of phagocyte," 25 (12.3%) with "T- and B-cell immunodeficiency" and 11 (5.4%) with "diseases of immune dysregulation." The median time to the diagnosis was 27.9 months and the patients had a wide range of clinical presentations. In addition, a total of 23 pathogenic genes were identified and 213 mutations were detected, including 42 novel mutations. CONCLUSIONS: With the increase in the awareness of PIDs and diagnostic competence, more PID patients will be diagnosed and we will be able to more accurately identify the frequency and the distribution of PIDs in the most populous country in the world. PMID- 23673421 TI - An updated systematic review and meta-analysis of the predictive value of serum biomarkers in the assessment of fever during neutropenia in children with cancer. AB - BACKGROUND: Fever during neutropenia (FN) is a frequent and potentially life threatening complication of the treatment of childhood cancer. The role of biomarkers in predicting morbidity and mortality associated with FN in children has been explored with varying results. This systematic review identified, critically appraised and synthesized information on the use of biomarkers for the prediction of outcome of FN in children/young adults, updating a review of initial assessment and adding further analysis of their value at reassessment. METHODS: This review was conducted in accordance with the Centre for Reviews and Dissemination Methods, using 3 different random effects meta-analysis models. RESULTS: Thirty-seven studies involving over 4689 episodes of FN in children were assessed, including an additional 13 studies investigating 18 biomarkers in 1670 FN episodes since the original review. Meta-analysis was possible for admission C reactive protein (CRP), procalcitonin (PCT), interleukin-6 and interleukin-8 in their ability to detect significant infection. Marked heterogeneity exists, precluding clear clinical interpretation of the results. Qualitative synthesis of the role of serial biomarkers suggests their predictive ability may be more pronounced at 24 to 48 hours compared with admission. Direct comparisons of the discriminatory power of admission values of PCT and CRP showed PCT generally had a better discriminatory estimate of serious infection than CRP. CONCLUSIONS: There remains a paucity of robust and reproducible data on the use of biomarkers in prediction of serious infection in children with FN. Available evidence suggests PCT has better discriminatory ability than CRP and that the role of serial biomarkers warrants further study. PMID- 23673422 TI - From elusive thio- and selenosilanoic acids to copper(I) complexes with intermolecular Si=E -> Cu-O-Si coordination modes (E = S, Se). AB - The facile synthesis of the first stable selenosilanoic acid-base adduct LSi(=Se)OH(dmap) 3 (L = CH[C(Me)NAr]2, Ar = 2,6-iPr2C6H3, dmap = 4 dimethylaminopyridine), the heavier analogue of the thiosilanoic acid adduct LSi(=S)OH(dmap) 1, is reported. Both adducts 1 and 3 react readily with MesCu (Mes = 2,4,6-trimethylphenyl) to form the novel dimeric Cu(I) complexes [LSi(=E)OCu]2 (4: E = S; 5: E = Se) with unprecedented intermolecular Si=E -> Cu O-Si coordination modes. The latter are efficient pre-catalysts for the Cu(I) mediated aziridination of styrene with PhI=N(Ts) (Ts = tosyl). PMID- 23673423 TI - Self-consistent electronic structure of multiquantum vortices in superconductors at T ? Tc. AB - We investigate the multiquantum vortex states in a type-II superconductor in both 'clean' and 'dirty' regimes defined by impurity scattering rate. Within a quasiclassical approach we calculate self-consistently the order parameter distributions and electronic local density of states (LDOS) profiles. In the clean case we find the low temperature vortex core anomaly predicted analytically by Volovik (1993 JETP Lett. 58 455) and obtain the patterns of LDOS distributions. In the dirty regime multiquantum vortices feature a peculiar plateau in the zero energy LDOS profile, which can be considered as an experimental hallmark of multiquantum vortex formation in mesoscopic superconductors. PMID- 23673425 TI - Guest editorial: Patriots' Day at the Boston Marathon. PMID- 23673424 TI - Case reports: Treatment of traumatic triradiate cartilage epiphysiodesis: what is the role of bridge resection? AB - BACKGROUND: Acetabular fractures are rare in children and can be complicated by premature fusion of the triradiate cartilage resulting in secondary acetabular dysplasia. Early recognition and treatment of a physeal bar in this location can be difficult. The purpose of this case report was to investigate whether early intervention could restore acetabular growth and prevent secondary acetabular dysplasia as measured on plain radiographs. CASE DESCRIPTION: We report a series of three patients (3, 4, and 5 years old) who underwent physeal bridge resection and methylmethacrylate or fat interposition through an extended Pfannenstiel approach. The mean followup was 6 years. After resection of the osseous bridge the physis initially remained open with evident acetabular growth in all three patients. In one patient, the bridge reformed 6 years after the procedure. All patients had a slight increase in the thickness of the acetabular wall relative to the contralateral side but no radiographic evidence of acetabular dysplasia. LITERATURE REVIEW: To our knowledge, there are only two reports of physeal arrest resection of triradiate cartilage with one successful result. CLINICAL RELEVANCE: Posttraumatic, partial physeal arrest of the triradiate cartilage may be treated with resection of the bone bridge resection through an extended Pfannenstiel approach. The potential benefits of this treatment must be weighed against the risks. PMID- 23673426 TI - Ghost imaging without discord. AB - Ragy and Adesso argue that quantum discord is involved in the formation of a pseudothermal ghost image. We show that quantum discord plays no role in spatial light modulator ghost imaging, i.e., ghost-image formation based on structured illumination realized with laser light that has undergone spatial light modulation by the output from a pseudorandom number generator. Our analysis thus casts doubt on the degree to which quantum discord is necessary for ghost imaging. PMID- 23673427 TI - Differential expression of miRNAs in the nervous system of a rat model of bilateral sciatic nerve chronic constriction injury. AB - Chronic neuropathic pain is associated with global changes in gene expression in different areas of the nociceptive pathway. MicroRNAs (miRNAs) are small (~22 nt long) non-coding RNAs, which are able to regulate hundreds of different genes post-transcriptionally. The aim of this study was to determine the miRNA expression patterns in the different regions of the pain transmission pathway using a rat model of human neuropathic pain induced by bilateral sciatic nerve chronic constriction injury (bCCI). Using microarray analysis and quantitative reverse transcriptase-PCR, we observed a significant upregulation in miR-341 expression in the dorsal root ganglion (DRG), but not in the spinal dorsal horn (SDH), hippocampus or anterior cingulate cortex (ACC), in the rats with neuropathic pain compared to rats in the naive and sham-operated groups. By contrast, the expression of miR-203, miR-181a-1* and miR-541* was significantly reduced in the SDH of rats with neuropathic pain. Our data indicate that miR-341 is upregulated in the DRG, whereas miR-203, miR-181a-1* and miR-541* are downregulated in the SDH under neuropathic pain conditions. Thus, the differential expression of miRNAs in the nervous system may play a role in the development of chronic pain. These observations may aid in the development of novel treatment methods for neuropathic pain, which may involve miRNA gene therapy in local regions. PMID- 23673428 TI - Growth of nanostructured nickel sulfide films on Ni foam as high-performance cathodes for lithium ion batteries. AB - We report a facile and reproducible synthesis of nanostructured Ni3S2 films by a hydrothermal route with Ni foam as the precursor reactant and substrate. The synthetic mechanism was examined by investigating the dependence of the films' crystal morphologies on the hydrothermal duration, and uniform nanostructured Ni3S2 films with a porous carpet-like morphology were synthesized on the substrates. The architectures were used as cathodes for lithium ion batteries (LIBs), and their electrochemical performances were evaluated as a function of the film thickness. The first discharge and charge capacities were 596 and 466 mA h g(-1) for the electrode with an optimal film thickness and a higher reversible capacity of 421 mA h g(-1) was obtained after 60 cycles at a current density of 50 mA g(-1). The simplicity of the synthetic methodology and the better electrochemical performance make the synthesized Ni3S2 films a promising cathode material for next-generation LIBs. PMID- 23673429 TI - Insights into protein misfolding and amyloidogenesis. PMID- 23673430 TI - Corneal collagen cross-linking for correction of low myopia? PMID- 23673431 TI - Quercetin synergizes with 2-methoxyestradiol inhibiting cell growth and inducing apoptosis in human prostate cancer cells. AB - Lack of effective treatment options for castration-resistant prostate cancer reinforces the great need to develop novel drug therapies. Quercetin is a plant derived flavonoid that can induce apoptosis in prostate cancer cells. 2 Methoxyestradiol (2-ME) is an endogenous estrogenic metabolite that also has antineoplastic activity. However, these two agents have limited bioavailability. Herein, we explored the antiproliferative and proapoptotic activities of quercetin combined with 2-ME in both androgen-dependent LNCaP and androgen independent PC-3 human prostate cancer cell lines. Compared to quercetin and 2-ME alone, combining quercetin with 2-ME at appropriate concentrations i) showed synergistic antiproliferative and proapoptotic activities; ii) increased G2/M phase population of cells; iii) decreased the ratio of Bcl-2/Bax significantly. The combination of quercetin and 2-ME is a new clinically relevant treatment regimen which has the potential of enhancing the antitumor effect on prostate cancer and lessening the side effect of either quercetin or 2-ME alone. PMID- 23673432 TI - Couples at risk for spinocerebellar ataxia type 2: the Cuban prenatal diagnosis experience. AB - Cuba reports the highest worldwide prevalence of spinocerebellar ataxia type 2 (SCA2) and the greatest number of descendants at risk. A protocol for genetic counseling, presymptomatic testing, and prenatal diagnosis of hereditary ataxias has been under development since 2001. Considering that the revision of the experience with prenatal diagnosis for SCA2 in Cuba would enable comparison of ours with international findings, we designed a descriptive study, based on the retrospective revision of the medical records belonging to the 58 couples that requested their inclusion in the program, during an 11-year period (2001-2011). Most of the participants in the prenatal diagnosis program were known presymptomatic carriers, diagnosed through the presymptomatic testing in the same period of study, for an uptake among them of 22.87 % (51 out of 223). In 28 cases, the fetuses were carriers, 20 of these couples (71.43 %) decided to terminate the pregnancy; the rest continued the pregnancy to term, this resulting in a predictive test for their unborn children. A predominance of females as the at-risk progenitor was observed. Except for a slightly lower average age, the results attained in the Cuban SCA2 prenatal diagnosis program resulted similar to the ones reported for Huntington disease in other countries. It is necessary to have easy access to the Cuban program through its expansion to other genetic centers along the island. Future research is needed to evaluate the long-term impact of both the predictive testing in unborn children and the selection of other reproductive options by the at-risk couples. PMID- 23673433 TI - Extra permeability is required to model dynamic oxygen measurements: evidence for functional recruitment? AB - Neural activation triggers a rapid, focal increase in blood flow and thus oxygen delivery. Local oxygen consumption also increases, although not to the same extent as oxygen delivery. This 'uncoupling' enables a number of widely-used functional neuroimaging techniques; however, the physiologic mechanisms that govern oxygen transport under these conditions remain unclear. Here, we explore this dynamic process using a new mathematical model. Motivated by experimental observations and previous modeling, we hypothesized that functional recruitment of capillaries has an important role during neural activation. Using conventional mechanisms alone, the model predictions were inconsistent with in vivo measurements of oxygen partial pressure. However, dynamically increasing net capillary permeability, a simple description of functional recruitment, led to predictions consistent with the data. Increasing permeability in all vessel types had the same effect, but two alternative mechanisms were unable to produce predictions consistent with the data. These results are further evidence that conventional models of oxygen transport are not sufficient to predict dynamic experimental data. The data and modeling suggest that it is necessary to include a mechanism that dynamically increases net vascular permeability. While the model cannot distinguish between the different possibilities, we speculate that functional recruitment could have this effect in vivo. PMID- 23673434 TI - Imaging brain deoxyglucose uptake and metabolism by glucoCEST MRI. AB - 2-Deoxy-D-glucose (2DG) is a known surrogate molecule that is useful for inferring glucose uptake and metabolism. Although (13)C-labeled 2DG can be detected by nuclear magnetic resonance (NMR), its low sensitivity for detection prohibits imaging to be performed. Using chemical exchange saturation transfer (CEST) as a signal-amplification mechanism, 2DG and the phosphorylated 2DG-6 phosphate (2DG6P) can be indirectly detected in (1)H magnetic resonance imaging (MRI). We showed that the CEST signal changed with 2DG concentration, and was reduced by suppressing cerebral metabolism with increased general anesthetic. The signal changes were not affected by cerebral or plasma pH, and were not correlated with altered cerebral blood flow as demonstrated by hypercapnia; neither were they related to the extracellular glucose amounts as compared with injection of D- and L-glucose. In vivo (31)P NMR revealed similar changes in 2DG6P concentration, suggesting that the CEST signal reflected the rate of glucose assimilation. This method provides a new way to use widely available MRI techniques to image deoxyglucose/glucose uptake and metabolism in vivo without the need for isotopic labeling of the molecules. PMID- 23673435 TI - Brain alanine formation as an ammonia-scavenging pathway during hyperammonemia: effects of glutamine synthetase inhibition in rats and astrocyte-neuron co cultures. AB - Hyperammonemia is a major etiological toxic factor in the development of hepatic encephalopathy. Brain ammonia detoxification occurs primarily in astrocytes by glutamine synthetase (GS), and it has been proposed that elevated glutamine levels during hyperammonemia lead to astrocyte swelling and cerebral edema. However, ammonia may also be detoxified by the concerted action of glutamate dehydrogenase (GDH) and alanine aminotransferase (ALAT) leading to trapping of ammonia in alanine, which in vivo likely leaves the brain. Our aim was to investigate whether the GS inhibitor methionine sulfoximine (MSO) enhances incorporation of (15)NH4(+) in alanine during acute hyperammonemia. We observed a fourfold increased amount of (15)NH4 incorporation in brain alanine in rats treated with MSO. Furthermore, co-cultures of neurons and astrocytes exposed to (15)NH4Cl in the absence or presence of MSO demonstrated a dose-dependent incorporation of (15)NH4 into alanine together with increased (15)N incorporation in glutamate. These findings provide evidence that ammonia is detoxified by the concerted action of GDH and ALAT both in vivo and in vitro, a mechanism that is accelerated in the presence of MSO thereby reducing the glutamine level in brain. Thus, GS could be a potential drug target in the treatment of hyperammonemia in patients with hepatic encephalopathy. PMID- 23673436 TI - Nano-micrometer-architectural acidic silica prepared from iron oxide of Leptothrix ochracea origin. AB - We prepared nano-micrometer-architectural acidic silica from a natural amorphous iron oxide with structural silicon which is a product of the iron-oxidizing bacterium Leptothrix ochracea. The starting material was heat-treated at 500 degrees C in a H2 gas flow leading to segregation of alpha-Fe crystalline particles and then dissolved in 1 M hydrochloric acid to remove the alpha-Fe particles, giving a gray-colored precipitate. It was determined to be amorphous silica containing some amount of iron (Si/Fe = ~60). The amorphous silica maintains the nano-microstructure of the starting material-~1-MUm-diameter micrometer-tubules consisting of inner globular and outer fibrillar structures several tens of nanometer in size-and has many large pores which are most probably formed as a result of segregation of the alpha-Fe particles on the micrometer-tubule wall. The smallest particle size of the amorphous silica is ~10 nm, and it has a large surface area of 550 m(2)/g with micropores (0.7 nm). By using pyridine vapor as a probe molecule to evaluate the active sites in the amorphous silica, we found that it has relatively strong Bronsted and Lewis acidic centers that do not desorb pyridine, even upon evacuation at 400 degrees C. The acidity of this new silica material was confirmed through representative two catalytic reactions: ring-opening reaction and Friedel-Crafts-type reaction, both of which are known to require acid catalysts. PMID- 23673437 TI - Systemic lupus erythematosus-related pancreatitis in children. AB - We report on three patients who developed four episodes of acute pancreatitis while their systemic lupus erythematosus was active and being treated with prednisolone. In all three, gastritis was first considered and treated due to abdominal pain, vomiting, and epigastric tenderness, but their symptoms did not improve. Then pancreatic enzymes were measured, which confirmed pancreatitis. Imaging studies showed an enlarged pancreas in one case, a normal pancreas in two cases, and a focal hypodense nonenhancing parenchyma in one case. Corticosteroids were prescribed for both active SLE and SLE-related pancreatitis. Pulse methylprednisolone was prescribed in one episode, increasing oral prednisolone in one episode, and the same dose of prednisolone continued in the other two episodes. All cases recovered without complications. SLE-related pancreatitis should be considered in SLE patients when the SLE is active and a patient develops abdominal pain and vomiting. PMID- 23673438 TI - Derangement of hemostasis in rheumatoid arthritis: association with demographic, inflammatory and metabolic factors. AB - Disturbance of fibrinolysis is common in rheumatoid arthritis (RA), and it may be associated with the increased cardiovascular risk observed in this population. We aimed to assess coagulation derangement and investigate whether abnormalities are influenced by demographic, inflammatory or metabolic factors in patients with RA. Levels of tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI-1), fibrinogen, prothrombin fragment 1 + 2 (PF1 + 2), thrombomodulin (TM), protein C and Von Willebrand factor (vWF) were compared between 141 RA patients and 50 healthy hospital controls. Within RA, coagulation factors were assessed alongside several demographic, inflammation and metabolic indicators. RA patients had higher levels of coagulation factors than controls. After correction for age and sex, having RA predicted increased tPA (B = 0.15, P < 0.001), PAI-1 (B = 0.21, P < 0.001), fibrinogen (B = 0.86, P < 0.001), PF1 + 2 (B = 0.20, P < 0.001), and TM (B = 0.01, P = 0.03) levels. CRP correlated positively with tPA (P < 0.05), fibrinogen (P < 0.001), TM (P < 0.05), PF1 + 2 (P < 0.001) and vWF (P < 0.001). Metabolic factors linked with coagulation factors were hypertriglyceridaemia (tPA, P < 0.05; PAI-1, P < 0.05; protein C, P < 0.05) and insulin resistance (tPA, P < 0.01; PAI-1, P < 0.01; vWF, P < 0.05). Imbalance of coagulation and fibrinolytic mechanisms is common in RA and associates with age, inflammation, and metabolic factors. Further studies may determine whether these abnormalities are the consequence of acute inflammation or markers of vascular dysfunction. PMID- 23673439 TI - Proprioceptive accuracy in women with early and established knee osteoarthritis and its relation to functional ability, postural control, and muscle strength. AB - The purpose of this study was to identify differences in knee proprioceptive accuracy between subjects with early knee osteoarthritis (OA), established knee OA, and healthy controls. Furthermore, the relation between proprioceptive accuracy on the one hand and functional ability, postural balance, and muscle strength on the other hand was also explored. New MRI-based classification criteria showing evidence of beginning joint degeneration have been used to identify subjects with early knee OA. A total of 45 women with knee OA (early OA, n = 21; established OA, n = 24) and 20 healthy female control subjects participated in the study. Proprioceptive accuracy was evaluated using the repositioning error of a knee joint position sense test using a three-dimensional motion analysis system. Subjective and objective functional ability was assessed by the knee injury and osteoarthritis outcome score, the timed "Up & Go" test, and the stair climbing test. The sensory organization test measured postural control. Muscle strength was measured by isokinetic dynamometry. Early OA subjects showed no significant differences in proprioceptive accuracy compared to healthy controls. In contrast, established OA subjects showed a higher repositioning error compared to early OA subjects (+29 %, P = 0.033) and healthy controls (+25 %, P = 0.068). Proprioceptive accuracy was not significantly associated with functional ability, postural balance, and muscle strength. Knee joint proprioceptive deficits were observed in established OA but not in early OA, suggesting that impaired proprioception is most likely a consequence of structural degeneration, rather than a risk factor in the pathogenesis of knee OA. Impaired proprioceptive accuracy was not associated with disease-related functionality in knee OA patients. Treatment strategies designed to address proprioceptive deficits may be not effective in prevention of knee OA progression and may have no impact on patients' functionality. However, this should be confirmed further in well-designed clinical trials. PMID- 23673440 TI - Depressive symptoms and treatment of women with urgency urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: Depression is more common in patients with urinary incontinence (UI). Drug or rehabilitation therapy have been shown to be effective in reducing urgency UI (UUI) symptoms, but whether these treatments can ameliorate the negative impact of UUI on the psychological aspects of quality of life is unclear. METHODS: A secondary analysis of an assessor-blinded randomized controlled trial was performed. The number of depressive symptoms was the primary outcome as measured by the Center for Epidemiologic Studies Depression scale (CES D). RESULTS: Thirty-six (22%) subjects had a CES-D score >16 at baseline, the cutoff for having depressive symptoms. A significant association was found between having a CES-D score >16 and lower quality of life related to UI at baseline. The mean CES-D score among those with depressive symptoms at baseline was significantly reduced throughout the study, with a mean of 23.7 at baseline, to 18.3 and 15.2 at the 3-month and 1-year follow-up (p < 0.001), respectively. The number of participants who had depressive symptoms decreased during the study period only in the physical therapy groups, from 31 at baseline to 28 and 25, at 3 and 12 months, respectively, while there was no such change in the drug group. CONCLUSIONS: Patients with UUI who had depressive symptoms showed significant improvement in their depressive symptoms with treatment over 1 year. This improvement occurred regardless of the type of treatment. This study emphasizes the increasingly recognized problem of undiagnosed depression among middle-aged women with UUI. PMID- 23673441 TI - Pubic symphysis diastasis with urinary incontinence: collaborative surgical management. AB - Pubic symphysis diastasis during obstetric delivery occurs rarely. Symptoms usually respond to conservative management. A nulliparous 39-year-old delivered spontaneously with an audible pop noted. Pubic symphysis diastasis of 4.6 cm was diagnosed on pelvic X-ray. She developed severe pain with ambulation and stress urinary incontinence. After neither of these symptoms improved significantly in response to conservative management, the patient underwent open reduction internal fixation with plating of her pubic symphysis, and bladder neck sling placement using autologous rectus fascia. Postoperatively she experienced urinary retention, which resolved with continuous bladder drainage for 1 week. Both her urinary incontinence and pain resolved, and she had resumed normal activities 3 months following her surgery. Pubic symphysis diastasis is a rare obstetric complication with a paucity of literature to guide its management. A coordinated multidisciplinary approach to management is necessary when multiple organ systems are involved. PMID- 23673442 TI - Urchin-like nanowire array: a strategy for high-performance ZnO-based electrode utilized in photoelectrochemistry. AB - The electrodes in photoelectrochemical cells responsible for the generation of hydrogen and oxygen by water splitting have been intensively studied because of their high photon-to-electron conversion efficiency. The morphology of nanostructures with these high-efficiency electrodes was systematically compared with the morphology of ZnO structures with vertically aligned nanorod arrays (NA), hollow hemisphere arrays (HA), urchin-like (UL) nanorod arrays, and thin films (TF). The UV-vis light absorption, photoresponse (current-voltage characteristics in the dark and under light), and photoelectrochemistry of the electrodes were measured. The highest photon-to-electron conversion efficiency of 65% at a specific UV wavelength for an electrode with a ZnO UL structure was derived from the UL morphology of high light-trapping efficiency and carrier collection efficiency. The UL morphology also produced a photon-to-electron conversion efficiency of 4.5% under a solar simulator by CdS-sensitization of the ZnO UL electrode. The value was the highest observed thus far among the ZnO-based electrodes. We demonstrated that photoresponse measurement is a practical and simple technique for the estimation of the photon-to-electron conversion efficiency of an electrode. PMID- 23673443 TI - HER2/CEP17 ratio and HER2 immunohistochemistry predict clinical outcome after first-line trastuzumab plus taxane chemotherapy in patients with HER2 fluorescence in situ hybridization-positive metastatic breast cancer. AB - PURPOSE: This study aimed to elucidate the clinical implication of human epidermal growth factor receptor 2/centromeric probe for chromosome 17 (HER2/CEP17) ratio and HER2 immunohistochemistry (IHC) results in patients with HER2 fluorescence in situ hybridization (FISH)-positive metastatic breast cancer (MBC) who received first-line trastuzumab plus taxane chemotherapy. METHODS: Using clinical data of patients with HER2 FISH-positive MBC who received first line trastuzumab plus taxane chemotherapy, we analyzed the clinical outcome according to the HER2/CEP17 ratio and HER2 IHC analysis. RESULTS: Fifty-two women were analyzed. The median age was 50 years (range 27-69 years). Patients with a HER2/CEP17 ratio >=3.0 had significantly longer progression-free survival (PFS) (17.2 vs. 7.4 months; p = 0.002) with a tendency toward higher response rate (RR) (p = 0.325) and longer overall survival (OS) (p = 0.129). Patients with HER2 IHC 1+ had significantly shorter OS (14.0 vs. 42.4 months; p = 0.013) along with a tendency toward lower RR (p = 0.068) and shorter PFS (p = 0.220). In the multivariate analysis, HER2/CEP17 ratio <3.0 (p = 0.004) and Eastern Cooperative Oncology Group (ECOG) PS 2 (p = 0.015) were significant factors for shorter PFS, and HER2 IHC 1+ (p = 0.015) and ECOG PS 2 (p = 0.036) were significant factors for poor OS. CONCLUSIONS: Our data support that HER2/CEP17 ratios and HER2 IHC scores may predict clinical outcome after first-line trastuzumab plus taxane chemotherapy in patients with HER2 FISH-positive MBC. PMID- 23673444 TI - Population pharmacokinetic analysis of free and bound aflibercept in patients with advanced solid tumors. AB - OBJECTIVE: Aflibercept (Zaltrap(r)) is a novel antiangiogenic agent that binds to vascular endothelial growth factor (VEGF) and inhibits VEGF-dependent tumor growth. We aimed to characterize the population pharmacokinetics (PK) of free and bound aflibercept in patients with solid tumors to examine the influence of covariates on their PK and to evaluate the proposed dosing regimens by simulation. METHODS: Data from 9 clinical trials with 1,506 cancer patients receiving aflibercept (2-9 mg/kg every 2 or 3 weeks; 1 h IV infusion) as a monotherapy or in combination with various chemotherapies were included. Free and bound aflibercept concentrations were analyzed using a non-linear mixed-effects modeling approach with MONOLIX 4.1.2. RESULTS: An approximation of a target mediated drug disposition model with irreversible binding of free aflibercept to VEGF adequately described the PK of free and bound aflibercept. The typical estimated clearances for free (CL(f)) and bound aflibercept (CL(b)) were 0.88 and 0.19 L/day, respectively. The volumes of distribution for free (V(p)) and bound (V(b)) aflibercept were similar (~4 L). CL f and V(p) increased with body weight and were lower in women. Patients with low albumin (ALB) or high alkaline phosphatase (ALK) had faster CL(f) compared to a typical patient. Pancreatic cancer may be associated with changes in binding of aflibercept to VEGF. Simulations of different dosing regimens showed that adequate saturation of circulating VEGF was achieved with a dose of 4 mg/kg every 2 weeks. CONCLUSIONS: Aflibercept kinetics was most affected by gender, body weight, ALB, ALK and pancreatic cancer. Simulations supported the rationale for the recommended dose of 4 mg/kg every 2 weeks for aflibercept. PMID- 23673446 TI - Pharmacokinetic interaction between sorafenib and prednisolone in a patient with hepatocellular carcinoma. AB - PURPOSE: Sorafenib is primarily metabolized in the liver, by CYP3A4-mediated oxidation and UGT1A9-mediated glucuronidation. However, there is little information about the pharmacokinetic interaction of sorafenib. Here, we report a pharmacokinetic interaction between sorafenib and the CYP3A4 inducer prednisolone in a patient with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: The patient was a 72-year-old woman diagnosed with HCC. She was treated with sorafenib at 400 mg daily. On day 9, sorafenib was discontinued due to drug eruption. Nine months later, she was rechallenged with sorafenib at 400 mg daily concurrently with oral prednisolone. Prednisolone was started at 20 mg daily and was tapered by 5 mg every 14 days. We assessed the pharmacokinetics of sorafenib and its major metabolite M-2. RESULTS: The concentration of sorafenib was gradually increased following tapering of prednisolone. On day 56 after rechallenge, she developed G3 oral mucositis. At this time, serum trough concentrations of sorafenib and M-2 were at 5.9 and 1.1 MUg/ml, respectively. Consequently, sorafenib dosage was reduced to 200 mg daily, and the oral mucositis was attenuated. The subsequent concentrations of sorafenib and M-2 obtained with a dose of 200 mg daily ranged from 1 to 3 MUg/ml and from 0.1 to 0.4 MUg/ml, respectively. Computed tomography scan showed a complete response of the liver tumor with no further recurrence of the rash. CONCLUSIONS: We have demonstrated for the first time that prednisolone stimulates the sorafenib metabolism and that therapeutic drug monitoring could be useful during sorafenib therapy. PMID- 23673445 TI - PD173074, a selective FGFR inhibitor, reverses ABCB1-mediated drug resistance in cancer cells. AB - PURPOSE: Specific tyrosine kinase inhibitors were recently reported to modulate the activity of ABC transporters, leading to an increase in the intracellular concentration of their substrate drugs. In this study, we determine whether PD173074, a specific fibroblast growth factor receptor (FGFR) inhibitor, could reverse ABC transporter-mediated multidrug resistance. METHODS: 3-(4,5 Dimethylthiazol-yl)-2,5-diphenyllapatinibrazolium bromide assay was used to determine the effect of PD173074 on reversal of ABC transporter-mediated multidrug resistance (MDR). In addition, [3H]-paclitaxel accumulation/efflux assay, western blotting analysis, ATPase, and photoaffinity labeling assays were done to study the interaction of PD173074 on ABC transporters. RESULTS: PD173074 significantly sensitized both ABCB1-transfected and drug-selected cell lines overexpressing this transporter to substrate anticancer drugs colchicine, paclitaxel, and vincristine. This effect of PD173074 is specific to ABCB1, as no significant interaction was detected with other ABC transporters such as ABCC1 and ABCG2. The observed reversal effect seems to be primarily due to the decreased active efflux of [3H]-paclitaxel in ABCB1 overexpressing cells observed in efflux assay. In addition, no significant change in the ABCB1 expression was observed when ABCB1 overexpressing cells were exposed to 5 MUM PD173074 for up to 3 days, thereby further suggesting its role in modulating the function of the transporter. In addition, PD173074 stimulated the ATPase activity of ABCB1 in a concentration-dependent manner, indicating a direct interaction with the transporter. Interestingly, PD173074 did not inhibit photolabeling of ABCB1 with [125I]-iodoarylazidoprazosin (IAAP), showing that it binds at a site different from that of IAAP in the drug-binding pocket. CONCLUSIONS: Here, we report for the first time, PD173074, an inhibitor of the FGFR, to selectively reverse ABCB1 transporter-mediated MDR by directly blocking the efflux function of the transporter. PMID- 23673447 TI - Joining ethnography and history in cultural competence training. PMID- 23673448 TI - Antiphospholipid antibodies in children with Kawasaki disease: a preliminary study from north India. PMID- 23673449 TI - Evaluation of the mean platelet volume in secondary amyloidosis due to familial Mediterranean fever. AB - Familial Mediterranean fever (FMF) is an inflammatory disorder that is leading cause of secondary amyloidosis (AA). This study was designed to investigate the level of mean platelet volume (MPV) in AA. Seventy-four FMF, 29 AA patients and 180 healthy controls, were included. There was no significant difference between the cases in terms of sex and age. MPV levels were measured in all groups. In the FMF group, MPV level was significantly higher when compared to the control group. MPV level was significantly lower in AA group in comparison with the FMF and healthy control groups. In summary, our present study showed low MPV values in AA due to FMF. PMID- 23673450 TI - Management of malignant pleural effusions: questions that need answers. AB - PURPOSE OF REVIEW: Malignant pleural effusion (MPE) is common. However, regardless of the differences between patients, their underlying cancer type, and pleural fluid characteristics, management options are often limited. These have not advanced significantly over the last 80 years since pleurodesis was first described. Correspondingly, patient-related outcome measures have been neglected. The evidence (or lack of) behind the current treatment recommendations is reviewed and key research questions are described. RECENT FINDINGS: Talc continues to be the most effective sclerosant available for pleurodesis in MPE. A recent randomized controlled trial comparing talc pleurodesis and indwelling pleural catheter insertion as first-line therapy suggests these approaches are equally effective, and utilized a patient-based symptom score as the primary outcome. The need to acknowledge the advances in translational medicine and oncological therapies to measure patient-related trial outcomes and to target pleural fluid formation in MPE is discussed. SUMMARY: Pulmonologists should be aware of the staggering lack of progress in the evidence that supports the current 'recommended' management of MPE. The need for a re-think about MPE management with a focus on alternative therapeutic targets and treatment objectives should be appreciated, in order to optimize future patient care. PMID- 23673451 TI - Do we measure pleural fluid pH correctly? AB - PURPOSE OF REVIEW: This review analyzes the current literature available on appropriate measurement of pleural fluid pH and currently used methods of measurement. RECENT FINDINGS: Current literature continues to support the superiority of blood gas analyzers (BGAs) in the accurate measurement of pleural fluid pH. Despite the compelling evidence, roughly 30-50% of the laboratories across the United States continue to use inaccurate methods for pleural fluid pH measurement. Nearly 40% of pulmonologists were incorrect in believing their laboratory uses BGA for the analysis of pleural fluid pH. SUMMARY: It is apparent that the clinical utility of pleural fluid pH is often undermined by its inappropriate measurement. Physicians must be made aware of their laboratory's method of measurement if pleural fluid pH is to be used in the evaluation of pleural diseases. If pleural fluid pH measurement is not done accurately, then other pleural fluid characteristics may be used to aid the clinician. PMID- 23673452 TI - SIRT1 suppresses breast cancer growth through downregulation of the Bcl-2 protein. AB - Silent mating-type information regulation 2 homologue 1 (SIRT1), a member of the class III histone deacetylase (HDAC) family, is the mammalian ortholog of yeast Sir2. It has been reported to play a key role in a variety of physiological processes such as genomic stability, metabolism, neurogenesis and cell survival. The deacetylase function of SIRT1 has been suggested to play a role in prolonging the life of mammals. However, the suggested functions of SIRT1 as a potential tumor promoter have been challenged by observations of their respective downregulation and upregulation in various types of cancer. Breast cancer patients were included in the present study between 2007 and 2008. Their tumor tissues and paired normal breast tissues were collected and used for evaluation of the expression levels of SIRT1 and Ki67. The effects of SIRT1 on human breast cancer cell lines were also investigated. Immunohistochemistry showed that there is a high correlation between SIRT1 and Ki67 expression. Following treatment with sirtinol (inhibitor of SIRT1), the expression of the pro-survival protein Bcl-2 was markedly decreased in both MCF-7 and MDA-MB-231 cell lines, particularly in MDA-MB-231. Results of the present study revealed that inhibition of SIRT1 activity may be a promising chemotherapeutic strategy against breast cancer. PMID- 23673453 TI - PET/CT versus body coil PET/MRI: how low can you go? AB - OBJECTIVES: The purpose of this study was to evaluate if positron emission tomography (PET)/magnetic resonance imaging (MRI) with just one gradient echo sequence using the body coil is diagnostically sufficient compared with a standard, low-dose non-contrast-enhanced PET/computed tomography (CT) concerning overall diagnostic accuracy, lesion detectability, size and conspicuity evaluation. METHODS AND MATERIALS: Sixty-three patients (mean age 58 years, range 19-86 years; 23 women, 40 men) referred for either staging or restaging/follow-up of various malignant tumours (malignant melanoma, lung cancer, breast cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, CUP, gynaecology tumours, pleural mesothelioma, oesophageal cancer, colorectal cancer, stomach cancer) were prospectively included. Imaging was conducted using a tri-modality PET/CT-MR set up (full ring, time-of-flight Discovery PET/CT 690, 3 T Discovery MR 750, both GE Healthcare, Waukesha, WI). All patients were positioned on a dedicated PET/CT- and MR-compatible examination table, allowing for patient transport from the MR system to the PET/CT without patient movement. In accordance with RECIST 1.1 criteria, measurements of the maximum lesion diameters on CT and MR images were obtained. In lymph nodes, the short axis was measured. A four-point scale was used for assessment of lesion conspicuity: 1 (>25 % of lesion borders definable), 2 (25-50 %), 3 (50-75 %) and 4 (>75 %). For each lesion the corresponding anatomical structure was noted based on anatomical information of the spatially co-registered PET/CT and PET/MRI image sections. Additionally, lesions were divided into three categories: "tumour mass", "lymph nodes" and "lesions". Differences in overall lesion detectability and conspicuity in PET/CT and PET/MRI, as well as differences in detectability based on the localisation and lesion type, were analysed by Wilcoxon signed rank test. RESULTS: A total of 126 PET-positive lesions were evaluated. Overall, no statistically significant superiority of PET/CT over PET/MRI or vice versa in terms of lesion conspicuity was found (p = 0.095; mean score CT 2.93, mean score MRI 2.75). A statistically significant superiority concerning conspicuity of PET/CT over PET/MRI was found in pulmonary lesions (p = 0.016). Additionally, a statistically significant superiority of PET/CT over PET/MRI in "lymph nodes" regarding lesion conspicuity was also found (p = 0.033). A higher mean score concerning bone lesions were found for PET/CT compared with PET/MRI; however, these differences did not achieve statistical significance. CONCLUSION: Overall, PET/MRI with body coil acquisition does not match entirely the diagnostic accuracy of standard low-dose PET/CT. Thus, it might only serve as a back-up solution in very few patients. Overall, more time needs to be invested on the MR imaging part (higher matrix, more breath-holds, additional surface coil acquired sequences) to match up with the standard low-dose PET/CT. MAIN MESSAGES: * Evaluation of whether PET/MRI with one sequence using body coil is diagnostically sufficient compared with PET/CT * PET/MRI with body coil does not match entirely the diagnostic accuracy of standard low-dose PET/CT * PET/MRI might only serve as a backup solution in patients. PMID- 23673454 TI - Evaluation of Bosniak category IIF complex renal cysts. AB - PURPOSE: To evaluate moderately complex renal cysts of Bosniak category IIF. MATERIALS AND METHODS: The regional ethics committee approved the study. In the period 2003-2009, radiological CT reports of 8,402 CT examinations of the kidneys were analysed retrospectively by one radiologist. All complex cystic lesions in the kidney (n = 550 in the same number of patients) were reclassified according to the Bosniak classification by two radiologists in consensus. If a patient had more than one lesion, only the highest Bosniak category was recorded. All Bosniak IIF lesions with >=2-year follow-up were included in the study. RESULTS: Thirty two Bosniak IIF lesions were found. Five lesions (16 %) were upgraded during follow-up and the patients were offered surgery. Pathology of three lesions showed papillary carcinoma, clear cell renal carcinoma and chronic inflammation, respectively. Due to comorbidity the remaining two patients were followed with CT without intervention. Ten lesions (31 %) with follow-up periods >5 years had no further radiological changes and clinical follow-up was stopped. CONCLUSION: The use of Bosniak category IIF is clinically applicable, resulting in an overall surgical nephron-sparing approach to complex renal cysts. TEACHING POINTS: * The Bosniak classification is used to categorise complex renal cystic masses * BIIF cysts behave mostly as benign lesions * Radiological progression in complexity occurs in only 16 % of cases * BIIF category seems promising for clinical application, potentially avoiding unnecessary surgery. PMID- 23673455 TI - A national survey on radiation dose in CT in The Netherlands. AB - OBJECTIVES: To assess radiation exposure due to CT in the Netherlands. METHODS: Twenty-one hospitals participated in a dose survey for the 21 most frequently used CT protocols. Hospitals completed a Web survey with detailed parameters for one patient per protocol, including the dose length product (DLP) from the scanner dose report. Only standard-sized patients (1.74 m and 77 kg and BMI 25.4 kg/m(2) +/- 15 %) for each protocol and available scanner were considered. Effective dose (E) per protocol was estimated using ICRP-103-based E/DLP coefficients. Dose levels were compared to surveys from other countries and to diagnostic reference levels. RESULTS: Data of 186 patients (247 scan phases) from 14 hospitals and 19 scanners were used for final analysis of DLP and E. Effective doses varied from 0.2 mSv in sinus CT to 19.4 mSv for multiphase liver. The most frequent exams were brain (1.5 mSv), abdomen (8.0 mSv), and thorax-abdomen (11.5 mSv). These results are lower than in Germany and comparable to those in the UK, and are within reference levels. Results between hospitals varied, with per protocol minimum/maximum E ratios ranging from 1.1-5.4. CONCLUSIONS: Compared to surrounding countries, CT in the Netherlands is associated with relatively low radiation doses in standard patients. Important differences remain between hospitals. MAIN MESSAGES: * A national dose survey providing updated, detailed data for patient dose in the most frequently used CT protocols. * CT in the Netherlands is associated with relatively low individual radiation doses in standard patients compared to surrounding European countries. * Considerable differences remain between hospitals for the most frequently used CT protocols, indicating the need for further optimisation. PMID- 23673456 TI - Configuration dependent demagnetizing field in assemblies of interacting magnetic particles. AB - A mean field model is presented for the configuration dependent effective demagnetizing and anisotropy fields in assemblies of exchange decoupled magnetic particles of arbitrary shape which are expressed in terms of the demagnetizing factors of the particles and the volumetric shape containing the assembly. Perpendicularly magnetized two-dimensional (2D) assemblies have been considered, for which it is shown that the demagnetizing field is lower than the continuous thin film. As an example of these 2D systems, arrays of bistable cylindrical nanowires have been characterized by remanence curves as well as ferromagnetic resonance, serving to show the correspondence of these measurements with the model and also to validate the mean field approach. Linear chains of cylinders and spheres have been analyzed, leading to simple expressions to describe the easy axis rotation induced by the interaction field in chains of low aspect ratio cylindrical particles, and the dipolar magnetic anisotropy observed in the linear chain of spheres. These examples serve to underline the dependence on the dipolar interaction field and effective demagnetizing factor of the contributions that arise from the shape of the outer volume. PMID- 23673457 TI - Comparative investigation of the performances of hematite nanoplates and nanograins in lithium-ion batteries. AB - In this work, we selectively prepared two samples with quite different nanocrystal shapes, i.e. nanoplates and nanograins but with almost identical surface areas to make a clear comparison of nanocrystal shapes on electrochemical performance. The electrochemical results indicate that the thinner hexagonal alpha-Fe2O3 nanoplates considerably enclosed by two larger (0001) basal surfaces exhibit higher capacity and stability than thicker alpha-Fe2O3 nanograins enclosed by a variety of crystal facets. During the conversion reaction, an orientated growth of porous nanostructure with orientated nanowalls as a stable framework is observed for the nanoplate, readily supplying a pathway for long and easy lithiation-delithiation cycling. The improved electrochemical performance of alpha-Fe2O3 nanoplates is surely related to the nanostructure with significantly stacked (0001) lattice planes along [0001] direction for orientated growth of gamma-Fe2O3 nanodomains along one [111] direction. PMID- 23673458 TI - The modern interpretation of the Wittig reaction mechanism. AB - The mechanism of the Wittig reaction has long been a contentious issue in organic chemistry. Even now, more than 50 years after its announcement, its presentation in many modern undergraduate textbooks is either overly simplified or entirely inaccurate. In this review, we gather together the huge body of evidence that has been amassed to show that the Li salt-free Wittig reactions of non-stabilised, semi-stabilised and stabilised ylides all occur under kinetic control by a common mechanism in which oxaphosphetane (OPA) is the first-formed and only intermediate. The numerous recent significant additions to the subject - including computational studies and experimental material pertinent to both steps of the reaction (OPA formation and its decomposition) are discussed in detail, and the currently accepted explanations for the source of the stereoselectivity in Wittig reactions are given. We also present the other mechanistic proposals that have been made during the history of the Wittig reaction, and show how they are unable to account for all of the experimental evidence that is now available. Details of certain experimental facts to do with Wittig reactions in the presence of Li cation are also included, although the precise mechanistic details of such reactions are yet to be established conclusively. We make the case that a clear distinction should henceforth be made between the unknown "Li-present" and the now well-established "Li salt-free" Wittig mechanisms. PMID- 23673459 TI - On the automated removal of artifacts related to head movement from the EEG. AB - Contamination of the electroencephalogram (EEG) by artifacts related to head movement is a major cause of reduced signal quality. This is a problem in both neuroscience and other uses of the EEG. To attempt to reduce the influence, on the EEG, of artifacts related to head movement, an accelerometer is placed on the head and independent component analysis is applied to attempt to separate artifacts which are statistically related to head movements. To evaluate the method, EEG and accelerometer measurements are made from 14 individuals with Cerebral palsy attempting to control a sensorimotor rhythm based brain-computer interface. Results show that the approach significantly reduces the influence of head movement related artifacts in the EEG. PMID- 23673460 TI - Discrimination between control and idle states in asynchronous SSVEP-based brain switches: a pseudo-key-based approach. AB - A steady-state visual evoked potential (SSVEP)-based brain-computer interface (BCI) can operate as an asynchronous brain switch. When SSVEP is detected with the "on/off" button flickering at a fixed frequency, the subject is identified as in the control state. Otherwise, he is in the idle state. Generally, the detection of the idle/control state is based on a predefined threshold, which is related to power. However, due to the variability of the electroencephalogram (EEG) signal, it is difficult to find an optimal threshold to achieve a high true positive rate (TPR) in the control state while maintaining a low false-positive rate (FPR) in the idle state. In this paper, a novel pseudo-key-based approach is presented for better discriminating the control and idle states. A dedicated "on/off" button (target key) and several additional buttons (pseudo-keys) are displayed on the graphical user interface (GUI), and all of these buttons flash at different frequencies. The control state is identified from the EEG signal under two conditions. The first is a common thresholding condition, where the power ratio of the target key frequency component to a certain neighboring frequency band is above a predefined threshold. The second is a comparison condition, where the power of the target key frequency component is higher than any of the pseudo-keys. The effectiveness of the proposed approach is validated by several experiments. Further analysis shows that introducing the pseudo-keys can significantly reduce the probability that the SSVEP will be detected in response to the flickering target key in the idle state without substantially affecting the detection in the control state, providing strong evidence in support of our approach. PMID- 23673461 TI - Airway inflammation and oxidative potential of air pollutant particles in a pediatric asthma panel. AB - Airborne particulate matter (PM) components from fossil fuel combustion can induce oxidative stress initiated by reactive oxygen species (ROS). Reported associations between worsening asthma and PM2.5 mass could be related to PM oxidative potential to induce airway oxidative stress and inflammation (hallmarks of asthma pathology). We followed 45 schoolchildren with persistent asthma in their southern California homes daily over 10 days with offline fractional exhaled nitric oxide (FENO), a biomarker of airway inflammation. Ambient exposures included daily average PM2.5, PM2.5 elemental and organic carbon (EC, OC), NO2, O3, and endotoxin. We assessed PM2.5 oxidative potential using both an abiotic and an in vitro bioassay on aqueous extracts of daily particle filters: (1) dithiothreitol (DTT) assay (abiotic), representing chemically produced ROS; and (2) ROS generated intracellularly in a rat alveolar macrophage model using the fluorescent probe 2'7'-dicholorohidroflourescin diacetate. We analyzed relations of FENO to air pollutants in mixed linear regression models. FENO was significantly positively associated with lag 1-day and 2-day averages of traffic related markers (EC, OC, and NO2), DTT and macrophage ROS, but not PM2.5 mass. DTT associations were nearly twice as strong as other exposures per interquartile range: median FENO increased 8.7-9.9% per 0.43 nmole/min/m(3) DTT. Findings suggest that future research in oxidative stress-related illnesses such as asthma and PM exposure would benefit from assessments of PM oxidative potential and composition. PMID- 23673462 TI - The sensitivity of health effect estimates from time-series studies to fine particulate matter component sampling schedule. AB - The US Environmental Protection Agency air pollution monitoring data have been a valuable resource commonly used for investigating the associations between short term exposures to PM2.5 chemical components and human health. However, the temporally sparse sampling on every third or sixth day may affect health effect estimation. We examined the impact of non-daily monitoring data on health effect estimates using daily data from the Denver Aerosol Sources and Health (DASH) study. Daily concentrations of four PM2.5 chemical components (elemental and organic carbon, sulfate, and nitrate) and hospital admission counts from 2003 through 2007 were used. Three every-third-day time series were created from the daily DASH monitoring data, imitating the US Speciation Trend Network (STN) monitoring schedule. A fourth, partly irregular, every-third-day time series was created by matching existing sampling days at a nearby STN monitor. Relative risks (RRs) of hospital admissions for PM2.5 components at lags 0-3 were estimated for each data set, adjusting for temperature, relative humidity, longer term temporal trends, and day of week using generalized additive models, and compared across different sampling schedules. The estimated RRs varied somewhat between the non-daily and daily sampling schedules and between the four non-daily schedules, and in some instances could lead to different conclusions. It was not evident which features of the data or analysis were responsible for the variation in effect estimates, although seeing similar variability in resampled data sets with relaxation of the every-third-day constraint suggests that limited power may have had a role. The use of non-daily monitoring data can influence interpretation of estimated effects of PM2.5 components on hospital admissions in time-series studies. PMID- 23673463 TI - Profiles of vitamin D insufficiency and deficiency in Japanese men and women: association with biological, environmental, and nutritional factors and coexisting disorders: the ROAD study. AB - Assessments of serum 25-hydroxyvitamin D levels in 1,683 Japanese from a population-based cohort revealed prevalences of vitamin D insufficiency and deficiency were 81.3 and 1.2%, respectively. Vitamin D deficiency was significantly associated with female sex, examined month, current smoking, lack of regular walking, higher intact parathyroid hormone (iPTH), and poor daily vitamin D intake. INTRODUCTION: To clarify the characteristics of subjects with vitamin D insufficiency and deficiency among men and women in the general Japanese population. METHODS: We initiated research on osteoarthritis/osteoporosis against disability (ROAD), a large-scale population based cohort study, in 2005-2007. Blood examination was performed to measure serum 25-hydroxyvitamin D (25D) and iPTH levels and biochemical markers of bone turnover in 1,683 participants (595 men, 1,088 women). Participants completed an interviewer-administered questionnaire, measurements of bone mineral density, and x-ray examination. Vitamin D deficiency and insufficiency were defined by serum 25D levels <10 and >=10 but <30 ng/mL, respectively. RESULTS: The prevalence of vitamin D insufficiency and deficiency was 81.3 and 1.2%, respectively. Multinominal logistic regression analyses using potentially confounding variables revealed vitamin D insufficiency was significantly associated with age (+1 year, relative risk ratio, 0.98; 95% confidence interval, 0.96-0.99), gender (women vs. men, 2.28; 1.59-3.30), residing areas (coastal area vs. mountainous area, 0.58; 0.41-0.81), examined month (October, November, December vs. January, 0.51; 0.34 0.76), and serum levels of iPTH (+1 pg/mL, 1.02; 1.01-1.03). Vitamin D deficiency was significantly characterised by female sex (20.5; 3.1-136.7), examined month (0.28; 0.09-0.95), current smoking habit (6.39; 1.78-23.0), lack of regular outside walking (3.96; 1.34-11.7), higher iPTH (1.02; 1.01-1.03) and poor daily vitamin D intake (+10 MUg/day, 0.48; 0.24-0.93). CONCLUSIONS: A high prevalence of vitamin D insufficiency and a low prevalence of vitamin D deficiency were found in Japanese men and women, and the characteristics of vitamin D status were clarified. PMID- 23673464 TI - Greater intake of fruit and vegetables is associated with a lower risk of osteoporotic hip fractures in elderly Chinese: a 1:1 matched case-control study. AB - In this case-control study, we examined the relationship between the consumption of fruit and vegetables and risk of hip fractures in 646 pairs of incident cases and controls in elderly Chinese. We found that greater consumption of both fruit and vegetables in men and vegetables in women was associated with a lower risk of osteoporotic hip fractures in elderly Chinese. INTRODUCTION: The association between fruit and vegetable consumption and the risk of osteoporotic fractures remains controversial due to limited published evidence. The purpose of this study was to determine whether consuming fruits and vegetables has a protective effect against hip fractures. METHODS: Between January 2008 and December 2012, 646 (162 males, 484 females) incident cases (70.9 +/- 6.8 years) of hip fractures were enrolled from five hospitals, with 646 sex- and age-matched (+/-3 years) controls (70.7 +/- 6.8 years) from hospitals or the community. Face-to-face interviews were conducted to assess habitual dietary intakes using a 79-item food frequency questionnaire and various covariates by structured questionnaires. RESULTS: Multivariate conditional logistic regression analyses showed dose dependent inverse correlations between the intake of total fruit (p-trend = 0.014), total vegetables (p-trend <0.001), fruits and vegetables combined (p trend < 0.001) and the risk of hip fractures after adjustment for sociodemographic characteristics, dietary factors and other potential confounders. The adjusted odds ratios (95% confidence interval) for hip fractures in the top quartiles (vs. the lowest quartiles) for the intake of fruits, vegetables and the combination of fruits and vegetables were 0.53 (0.32-0.87), 0.37 (0.23-0.60) and 0.25 (0.15-0.41), respectively. Stratified analyses showed that the benefits remained significant in males (p = 0.001) but not in females (p = 0.210) (p-interaction 0.045). Among the subcategories of fruits and vegetables, similar associations were observed for all subgroups except light-coloured fruits. CONCLUSIONS: Our findings suggest that greater consumption of both fruits and vegetables in men and vegetables in women may decrease the risk of osteoporotic hip fractures in elderly Chinese. PMID- 23673465 TI - Pharmacokinetic properties of pure xanthones in comparison to a mangosteen fruit extract in rats. AB - The xanthones alpha-mangostin and gamma-mangostin are the major bioactive compounds in Garcinia mangostana (mangosteen) fruit extracts. Previously, we reported the pharmacokinetic properties of alpha-mangostin in rats. The purpose of this follow-up study was to compare the pharmacokinetic characteristics of alpha-mangostin and gamma-mangostin in rats if administered as either a pure compound or as a component of a mangosteen fruit extract. The absolute bioavailability of gamma-mangostin when administered as a pure compound was determined by giving male Sprague Dawley rats 2 mg/kg gamma-mangostin intravenously or 20 mg/kg orally. A 160 mg/kg aliquot of mangosteen fruit extract was administered, containing alpha- and gamma-mangostin doses equal to 20 mg/kg and 4.5 mg/kg of each pure compound, respectively. Plasma samples were collected for both pharmacokinetic studies, and compound concentrations were measured by LC MS/MS. The pharmacokinetic of gamma-mangostin after intravenous administration followed a two-compartment body model. The half-life of the distribution phase was 2.40 min, and that of the elimination phase was 1.52 h. After oral administration, both alpha- and gamma-mangostin underwent intensive first-pass metabolism, and both compounds were conjugated rapidly after oral administration. When given as an extract, the total absorption of alpha- and gamma-mangostin was not increased, but the conjugation was slower, resulting in increased free (unconjugated) compound exposure when compared to pure compound administration. Since reported beneficial biological activities of mangosteen xanthones are based on the free, unconjugated compounds, food supplements containing mangosteen fruit extracts should be preferred over the administration of pure xanthones. PMID- 23673466 TI - Optimisation of tomato Micro-tom regeneration and selection on glufosinate/Basta and dependency of gene silencing on transgene copy number. AB - KEY MESSAGE: An efficient protocol of transformation and selection of transgenic lines of Micro-tom, a widespread model cultivar for tomato, is reported. RNA interference silencing efficiency and stability have been investigated and correlated with the number of insertions. Given its small size and ease of cultivation, the tomato (Solanum lycopersicon) cultivar Micro-tom is of widespread use as a model tomato plant. To create and screen transgenic plants, different selectable markers are commonly used. The bar marker carrying the resistance to the herbicide glufosinate/Basta, has many advantages, but it has been little utilised and with low efficiency for identification of tomato transgenic plants. Here we describe a procedure for accurate selection of transgenic Micro-tom both in vitro and in soil. Immunoblot, Southern blot and phenotypic analyses showed that 100 % of herbicide-resistant plants were transgenic. In addition, regeneration improvement has been obtained by using 2 mg/l Gibberellic acid in the shoot elongation medium; rooting optimisation on medium containing 1 mg/l IAA allowed up to 97 % of shoots developing strong and very healthy roots after only 10 days. Stable transformation frequency by infection of leaf explants with Agrobacterium reached 12 %. Shoots have been induced by combination of 1 mg/l zeatin-trans and 0.1 mg/l IAA. Somatic embryogenesis of cotyledon on medium containing 1 mg/l zeatin + 2 mg/l IAA is described in Micro-tom. The photosynthetic psbS gene has been used as reporter gene for RNA silencing studies. The efficiency of gene silencing has been found equivalent using three different target gene fragments of 519, 398 and 328 bp. Interestingly, silencing efficiency decreased from T0 to the T3 generation in plants containing multiple copies of the inserted T-DNA, while it was stable in plants containing a single insertion. PMID- 23673468 TI - Cognitive control dysfunction and abnormal frontal cortex activation in stimulant drug users and their biological siblings. AB - Cognitive and neural abnormalities are known to accompany chronic drug abuse, with impairments in cognition and changes in cortical structure seen in stimulant dependent individuals. However, premorbid differences have also been observed in the brains and behavior of individuals at risk for substance abuse, before they develop dependence. Endophenotype research has emerged as a useful method for assessing preclinical traits that may be risk factors for pathology by studying patient populations and their undiagnosed first-degree relatives. This study used the color-word Stroop task to assess executive functioning in stimulant-dependent individuals, their unaffected biological siblings and unrelated healthy control volunteers using a functional magnetic resonance imaging paradigm. Both the stimulant-dependent and sibling participants demonstrated impairments in cognitive control and processing speed on the task, registering significantly longer response latencies. However, the two groups generated very different neural responses, with the sibling participants exhibiting a significant decrease in activation in the inferior frontal gyrus compared with both stimulant dependent individuals and control participants. Both target groups also demonstrated a decrease in hemispheric laterality throughout the task, exhibiting a disproportionate increase in right hemispheric activation, which was associated with their behavioral inefficiencies. These findings not only suggest a possible risk factor for stimulant abuse of poor inhibitory control and cortical inefficiency but they also demonstrate possible adaptations in the brains of stimulant users. PMID- 23673469 TI - Scanning electron microscopic surface analysis of cryoconserved skull bone after decompressive craniectomy. AB - Bone flaps removed during decompressive craniectomy are commonly frozen at -80 degrees C and stored until cranioplasty. Histological integrity and regenerative capacity have been shown for cryoconserved bone. The effects of cryoconservation on the surface structure are unknown, although these might cause mechanical instability or facilitate bacterial adhesion. This study evaluates the surface structure of cryoconserved bone by scanning electron microscopy. Five patients were identified who could not receive their autologous bone flaps after decompressive craniectomy. These redundant bone specimens were obtained after cryoconservation for 6-8 months and the outer surface was analyzed by scanning electron microscopy. We found varying surface structures which did not correlate with any variables, such as patient age, gender or duration of freezing, and probably reflect physiological interindividual variation. Pathological findings, such as microscopic crack formation, were not observed. Cryoconservation for up to 8 months does not appear to alter the surface structure of skull bone on scanning electronic microscopy. PMID- 23673467 TI - Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP). AB - Genetic variants in the sortilin-related receptor (SORL1) and the sortilin related vacuolar protein sorting 10 (VPS10) domain-containing receptor 1 (SORCS1) are associated with increased risk of Alzheimer's disease (AD), declining cognitive function and altered amyloid precursor protein (APP) processing. We explored whether other members of the (VPS10) domain-containing receptor protein family (the sortilin-related VPS10 domain-containing receptors 2 and 3 (SORCS2 and SORCS3) and sortilin (SORT1)) would have similar effects either independently or together. We conducted the analyses in a large Caucasian case control data set (n=11,840 cases, 10,931 controls) to determine the associations between single nucleotide polymorphisms (SNPs) in all the five homologous genes and AD risk. Evidence for interactions between SNPs in the five VPS10 domain receptor family genes was determined in epistatic statistical models. We also compared expression levels of SORCS2, SORCS3 and SORT1 in AD and control brains using microarray gene expression analyses and assessed the effects of these genes on gamma-secretase processing of APP. Several SNPs in SORL1, SORCS1, SORCS2 and SORCS3 were associated with AD. In addition, four specific linkage disequilibrium blocks in SORCS1, SORCS2 and SORCS3 showed additive epistatic effects on the risk of AD (P<=0.0006). SORCS3, but not SORCS2 or SORT1, showed reduced expression in AD compared with control brains, but knockdown of all the three genes using short hairpin RNAs in HEK293 cells caused a significant threefold increase in APP processing (from P<0.001 to P<0.05). These findings indicate that in addition to SORL1 and SORCS1, variants in other members of the VPS10 domain receptor family (that is, SORCS1, SORCS2, SORCS3) are associated with AD risk and alter APP processing. More importantly, the results indicate that variants within these genes have epistatic effects on AD risk. PMID- 23673470 TI - Direct and indirect effects of ocean acidification and warming on a marine plant herbivore interaction. AB - The impacts of climatic change on organisms depend on the interaction of multiple stressors and how these may affect the interactions among species. Consumer-prey relationships may be altered by changes to the abundance of either species, or by changes to the per capita interaction strength among species. To examine the effects of multiple stressors on a species interaction, we test the direct, interactive effects of ocean warming and lowered pH on an abundant marine herbivore (the amphipod Peramphithoe parmerong), and whether this herbivore is affected indirectly by these stressors altering the palatability of its algal food (Sargassum linearifolium). Both increased temperature and lowered pH independently reduced amphipod survival and growth, with the impacts of temperature outweighing those associated with reduced pH. Amphipods were further affected indirectly by changes to the palatability of their food source. The temperature and pH conditions in which algae were grown interacted to affect algal palatability, with acidified conditions only affecting feeding rates when algae were also grown at elevated temperatures. Feeding rates were largely unaffected by the conditions faced by the herbivore while feeding. These results indicate that, in addition to the direct effects on herbivore abundance, climatic stressors will affect the strength of plant-herbivore interactions by changes to the susceptibility of plant tissues to herbivory. PMID- 23673471 TI - Expression and distribution of Src in the nucleus of myocytes in cardiac hypertrophy. AB - The Src kinase is involved in signaling events leading to cardiac hypertrophy. The exact effects of tyrosine phosphorylation and subnuclear distribution on cardiac hypertrophy and failure remain to be investigated. In this study, we examined the intranuclear expression and distribution of c-Src, Src phosphorylated at tyrosine 529 (Src[pY529]), Src phosphorylated at tyrosine 418 (Src[pY418]) and Src phosphorylated at tyrosine 215 (Src[pY215]) in the myocardial nuclei of the left ventricle (LV) from 2-, 6-, 12- and 18-month-old spontaneously hypertensive heart failure (SHHF) rats and age-matched Wistar-Kyoto (WKY) rats as normotensive controls by western blot analysis, immunofluorescent labeling and immunoprecipitation. Cellular Src (c-Src) expression in the myocardial nuclei of the LV of the 2-, 6-, 12- and 18-month-old SHHF rats was not significantly different from that in the myocardial nuclei of the LV of the age matched WKY rats. Although there were no significant differences observed between the levels of Src[pY529] and Src[pY418] in the myocardial nuclei of the LV of the 2-month-old SHHF and WKY rats, the expression of Src[pY529] significantly decreased, while that of Src[pY418] significantly increased in the myocardial nuclei of the LV of the 6-, 12- and 18-month-old SHHF rats compared to the age matched WKY controls. Furthermore, as demonstrated by double labeling with antibodies against fibrillarin and Src-associated in mitosis 68 kDa (Sam68), c Src was co-localized with both Sam68 and fibrillarin in the nuclei; Src[pY529] co localized with fibrillarin, but Src[pY418] co-localized with Sam68. The results from the present study suggest that the dephosphorylation of Src tyrosine kinase 529, the phosphorylation of tyrosine 418 and their subnuclear redistribution are involved in endonuclear signal transduction in cardiac myocytes, which regulates the development and progression of LV eccentric hypertrophy induced by hypertension. PMID- 23673472 TI - Practice guidelines for therapeutic drug monitoring of vancomycin: a consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring. PMID- 23673474 TI - Fatal overwhelming postsplenectomy infection caused by Streptococcus pneumoniae in mothers within 1 year after delivery: case report. AB - Invasive pneumococcal disease (IPD) has a high mortality. Although preventive strategies including vaccination have been established for children, less attention has been devoted to pregnant and postnatal women and to mothers caring for their infants. As a significant number of women have either undergone splenectomy or are in a hyposplenic state and have not received adequate pneumococcal vaccinations, they can potentially develop overwhelming postsplenectomy infections. A 34-year-old woman with an 8-month-old baby, who underwent splenectomy at the age of 10 for benign pancreatic tumor, presented with fever and petechial eruption. Despite extensive treatment, she died 17 h after admission. A 40-year-old woman with a 11-month-old baby, who underwent splenectomy at 2 years of age for hemolytic anemia, was admitted for septic shock and disseminated intravascular coagulation. Despite extensive treatment, she died 2 h after admission. Blood cultures from both women were positive for Streptococcus pneumoniae and neither of them had been vaccinated against the bacterium. IPD rapidly progressed and developed to multiple organ dysfunction syndromes in mothers caring for their infants, particularly those who had undergone splenectomy or were in a hyposplenic state. Thus, routine pneumococcal vaccination is recommended for pregnant women. In addition, we suggest a thorough medical interview and checkup for splenectomy or hyposplenism in prenatal women. PMID- 23673475 TI - Magnetic entropy change plateau in a geometrically frustrated layered system: FeCrAs-like iron-pnictide structure as a magnetocaloric prototype. AB - Monte Carlo modeling suggests that the magnetothermal features of the Fe2P structured FeCrAs-like compound offer a promising route for the design of magnetocaloric materials. The prototype structure is modeled as antiferromagnetically coupled layered Heisenberg systems mimicking the distorted Kagome/triangular stacked architecture of FeCrAs iron-pnictide. The magnetic entropy change DeltaSm(T) presents a plateau-like behavior which can be tailored by tuning either the JCr-Fe/JCr-Cr exchange energy ratio or the magnetic field. The plateau is defined by cooperative spin ordering within a ferrimagnetic region which exists between two critical temperatures separating at the lower bound (Tac) a canted antiferromagnetic phase and at the upper bound (Tdc) the thermally disordered phase. The refrigerant capacity and adiabatic change of temperature are A(H)(Tdc - Tac) and A(H)Tp/Cm respectively, with Tac < Tp < Tdc, A(H) an increasing positive function of the field defining the height of the plateau and Cm the magnetic specific heat, whose critical behavior is related to the T(a,d)(c) values. PMID- 23673473 TI - Practice guidelines for therapeutic drug monitoring of voriconazole: a consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring. PMID- 23673476 TI - miR-146a and miR-150 promote the differentiation of CD133+ cells into T-lymphoid lineage. AB - MicroRNAs control the genes involved in hematopoietic stem cell (HSCs) survival, proliferation and differentiation. The over-expression of miR-146 and miR-150 has been reported during differentiation of HSCs into T-lymphoid lineage. Therefore, in this study we evaluated the effect of their over-expression on CD133+ cells differentiation to T cells. miR-146a and miR-150 were separately and jointly transduced to human cord blood derived CD133+ cells (>97% purity). We used qRT PCR to assess the expression of CD2, CD3epsilon, CD4, CD8, CD25, T cell receptor alpha (TCR-alpha) and Ikaros genes in differentiated cells 4 and 8 days after transduction of the miRNAs. Following the over-expression of miR-146a, significant up-regulation of CD2, CD4, CD25 and Ikaros genes were observed (P<0.01). On the other hand, over-expression of miR-150 caused an increase in the expression of Ikaros, CD4, CD25 and TCR-alpha. To evaluate the combinatorial effect of miR-146a and miR-150, transduction of both miRNAs was concurrently performed which led to increase in the expression of Ikaros, CD4 and CD3 genes. In conclusion, it seems that the effect of miR-150 and miR-146a on the promotion of T cell differentiation is time-dependant. Moreover, miRNAs could be used either as substitutes or complements of the conventional differentiation protocols for higher efficiency. PMID- 23673477 TI - Molecular cloning, characterization and heterologous expression of bile salt hydrolase (Bsh) from Lactobacillus fermentum NCDO394. AB - Bile salt hydrolase (Bsh) active probiotic strains hydrolyze bile acid amino conjugates in vivo, which triggers cholesterol consumption in liver to synthesize new bile leading to consequential cholesterol lowering. Hence, bile salt hydrolyzing potential was the criterion to select L. fermentum NCDO394 for this study and its gene encoding Bsh was identified and cloned. The resulting nucleotide sequence of bsh gene contained an open reading frame (ORF) of 978 nucleotides encoding a predicted protein of 325 amino acids with a theoretical pI of 6.39. Moreover, deduced Bsh protein had high similarity with the Bshs of L. fermentum only and also exhibited significant similarity to the Pencillin V amidases of other Lactobacillus spp. Five catalytically important amino acids were highly conserved in L. fermentum Bsh while four amino acid motifs around these active sites, were not as consistent as in other Bsh proteins. Furthermore, L. fermentum bsh gene was sub-cloned into pET-28b(+) vector, and its expression was induced with 0.05 mM isopropylthiogalactopyranoside (IPTG) in Escherichia coli BL21(DE3). The recombinant Bsh (rBsh) was purified with homogeneity using Ni+2-NTA column and characterized for substrate specificity, pH and temperature. The rBsh hydrolyzed six major human bile salts with a slight preference towards glycine-conjugated bile salts. The optimum pH of rBsh was six, and its enzymatic activity declined below pH 5 and above pH 7. The enzyme was stable and functional even at 65 degrees C while showed its maximum activity at 37 degrees C. In conclusion, L. fermentum NCDO394 may be a promising candidate probiotic which may affect cholesterol metabolism in vivo. PMID- 23673478 TI - The effects of endothelial lipase gene (LIPG) variants on inflammation marker levels and atherosclerosis development. AB - Atherosclerosis is a major pathological process related with several important adverse vascular events including coronary artery disease, stroke, and peripheral arterial disease. Endothelial lipase is an enzyme the activity of which affects all of lipoproteins, whereas HDL is the main substrate. The purpose of our study was to investigate the effects of endothelial lipase gene polymorphism and inflammation markers (CRP, IL-1beta, IL-6, IL-8 and TNF-alpha) in the atherosclerosis. 104 patients with atherosclerosis and 76 healthy individuals were included in the study. LIPG -584C/T polymorphism gene polymorphisms were assessed with PCR-RFLP method. The serum CRP levels were measured by turbidimetric method using a biochemistry autoanalyzer, whereas serum IL-1beta, IL-6, IL-8, TNF-alpha levels were determined by enzyme-linked immunosorbent assay. In this study, we found that the frequencies of TC genotype are more prevalent in patients than controls. We found a statistically significant difference of IL-6 levels between patient and control group. Our findings suggest that T allele might play a potential role in the susceptibility to atherogenesis in the Turkish population. PMID- 23673480 TI - Potent anti-cancer effects of citrus peel flavonoids in human prostate xenograft tumors. AB - Prostate cancer is one of the most prevalent malignancies and is the second leading cause of cancer-related deaths in men. Fruit and vegetable consumption is a novel, non-toxic therapeutic approach that can be used to prevent and treat prostate cancer. Citrus peels and their extracts have been reported to have potent pharmacological activities and health benefits due to the abundance of flavonoids in citrus fruits, particularly in the peels. Our previous studies demonstrated that oral administration of Gold Lotion (GL), an extract of multiple varieties of citrus peels containing abundant flavonoids, including a large percentage of polymethoxyflavones (PMFs), effectively suppressed azoxymethane (AOM)-induced colonic tumorigenesis. However, the efficacy of GL against prostate cancer has not yet been investigated. Here, we explored the anti-tumor effects of GL using a human prostate tumor xenograft mouse model. Our data demonstrated that treatment with GL by both intraperitoneal (i.p.) injection and oral administration dramatically reduced both the weights (57%-100% inhibition) and volumes (78%-94% inhibition) of the tumors without any observed toxicity. These inhibitory effects were accompanied by mechanistic down-regulation of the protein levels of inflammatory enzymes (inducible nitric oxide synthase, iNOS and cyclooxygenase-2, COX-2), metastasis (matrix metallopeptidase-2, MMP-2 and MMP 9), angiogenesis (vascular endothelial growth factor, VEGF), and proliferative molecules, as well as by the induction of apoptosis in prostate tumors. Our findings suggest that GL is an effective anti-cancer agent that may potentially serve as a novel therapeutic option for prostate cancer treatment. PMID- 23673479 TI - DNA repair genes polymorphism and lung cancer risk with the emphasis to sex differences. AB - Polymorphisms in nucleotide and base excision repair genes are associated with the variability in the risk of developing lung cancer. In the present study, we investigated the polymorphisms of following selected DNA repair genes: XPC (Lys939Gln), XPD (Lys751Gln), hOGG1 (Ser326Cys) and XRCC1 (Arg399Gln), and the risks they present towards the development of lung cancer with the emphasis to gender differences within the Slovak population. We analyzed 761 individuals comprising 382 patients with diagnosed lung cancer and 379 healthy controls. Genotypes were determined by polymerase chain reaction/restriction fragment length polymorphism method. We found out statistically significant increased risk for lung cancer development between genders. Female carrying XPC Gln/Gln, XPC Lys/Gln+Gln/Gln and XRCC1 Arg/Gln, XRCC1 Arg/Gln+Gln/Gln genotypes had significantly increased risk of lung cancer corresponding to OR = 2.06; p = 0.04, OR = 1.66; p = 0.04 and OR = 1.62; p = 0.04, OR = 1.69; p = 0.02 respectively. In total, significantly increased risk of developing lung cancer was found in the following combinations of genotypes: XPD Lys/Gln+XPC Lys/Lys (OR = 1.62; p = 0.04), XRCC1 Gln/Gln+hOGG1 Ser/Ser (OR = 2.14; p = 0.02). After stratification for genders, the following combinations of genotype were found to be significant in male: XPD Lys/Gln+XPC Lys/Lys (OR = 1.87; p = 0.03), XRCC1 Arg/Gln+XPC Lys/Lys (OR = 4.52; p = 0.0007), XRCC1 Arg/Gln+XPC Lys/Gln (OR = 5.44; p < 0.0001). In female, different combinations of the following genotypes were found to be significant: XRCC1 Arg/Gln+hOGG1 Ser/Ser (OR = 1.98; p = 0.04), XRCC1 Gln/Gln+hOGG1 Ser/Ser (OR = 3.75; p = 0.02), XRCC1 Arg/Gln+XPC Lys/Gln (OR = 2.40; p = 0.04), XRCC1 Arg/Gln+XPC Gln/Gln (OR = 3.03; p = 0.04). We found out decreased cancer risk in genotype combinations between female patients and healthy controls: XPD Lys/Lys+XPC Lys/Gln (OR = 0.45; p = 0.02), XPD Lys/Gln+XPC Lys/Lys (OR = 0.32; p = 0.005), XPD Lys/Gln+XPC Lys/Gln (OR = 0.48; p = 0.02). Our results did not show any difference between pooled smokers and non-smokers in observed gene polymorphisms in the association to the lung cancer risk. However, gender stratification indicated the possible effect of heterozygous constitution of hOGG1 gene (Ser/Cys) on lung cancer risk in female non-smokers (OR = 0.20; p = 0.01) and heterozygous constitution of XPC gene (Lys/Gln) in male smokers (OR = 2.70; p = 0.01). PMID- 23673481 TI - Fabrication of (001)-oriented monoclinic WO3 films on FTO substrates. AB - (001)-oriented monoclinic nanorod and microplate WO3 films are fabricated on commercial FTO-coated glass substrates by a rubbing seed layer and a spin-coating seed layer assisted by hydrothermal reactions. The nanorod film obtained by the rubbing seed layer assisted by hydrothermal reactions is more regular and perpendicular to the substrate. PMID- 23673482 TI - Frequency-dependent magnetic susceptibility of magnetite and cobalt ferrite nanoparticles embedded in PAA hydrogel. AB - Chemically responsive hydrogels with embedded magnetic nanoparticles are of interest for biosensors that magnetically detect chemical changes. A crucial point is the irreversible linkage of nanoparticles to the hydrogel network, preventing loss of nanoparticles upon repeated swelling and shrinking of the gel. Here, acrylic acid monomers are adsorbed onto ferrite nanoparticles, which subsequently participate in polymerization during synthesis of poly(acrylic acid) based hydrogels (PAA). To demonstrate the fixation of the nanoparticles to the polymer, our original approach is to measure low-field AC magnetic susceptibility spectra in the 0.1 Hz to 1 MHz range. In the hydrogel, the magnetization dynamics of small iron oxide nanoparticles are comparable to those of the particles dispersed in a liquid, due to fast Neel relaxation inside the particles; this renders the ferrogel useful for chemical sensing at frequencies of several kHz. However, ferrogels holding thermally blocked iron oxide or cobalt ferrite nanoparticles show significant decrease of the magnetic susceptibility resulting from a frozen magnetic structure. This confirms that the nanoparticles are unable to rotate thermally inside the hydrogel, in agreement with their irreversible fixation to the polymer network. PMID- 23673483 TI - Structural and dynamic features of HLA-B27 subtypes. AB - PURPOSE OF REVIEW: The differential association of HLA-B27 subtypes with ankylosing spondylitis provides the rationale for a comparative investigation of these proteins. Results from the last 2 years of research on minimally distinct HLA-B27 subtypes, primarily using biochemical and biophysical techniques, are presented and discussed. RECENT FINDINGS: We summarize evidence that micropolymorphisms within the molecules' peptide-binding groove influence wide ranging biochemical, biophysical and antigenic properties of HLA-B27 molecules, and suggest that distinct, subtype and peptide-dependent dynamics of peptide - heavy chain - beta(2)-microglobulin heterotrimers could be instrumental for an understanding of the initiation of disease processes that are connected with certain HLA-B27 subtypes. SUMMARY: The results indicate that mAbs that bind only to structurally distinguishable subsets of HLA-B27 molecules as well as techniques that assess the flexibility of these antigens may hold the key to comprehend molecular events contributing to the initial stages of disease pathogenesis in spondyloarthropathies. PMID- 23673484 TI - Magnifying narrow-band imaging of surface patterns for diagnosing colorectal cancer. AB - Narrow-band imaging (NBI) of surface microvessels of colorectal lesions is useful for differentiating neoplasms from non-neoplasms and for predicting histopathological diagnosis. Furthermore, NBI of surface microstructure, or 'surface pattern', is valuable for predicting histopathology in colorectal cancer. The aim of the present study was to investigate whether surface patterns could be used to predict invasion depth in colorectal cancer, and to compare the accuracy of surface pattern diagnosis in each macroscopic type. Between January 2010 and March 2011, a series of 357 consecutive patients with 378 early colorectal cancers were observed by magnifying NBI and the surface pattern was prospectively evaluated. Surface pattern was classified into 3 types: type I, microstructure was clearly recognised with uniform arrangement and form; type II, microstructure was obscured with heterogeneous arrangement and form; and type III, microstructure was invisible. We also classified the macroscopic type into 3 categories: depressed, protruded and flat elevated. Assuming that type III was an index of massively invasive lesions in the submucosal layer (SMm), the sensitivity, specificity and accuracy were 56.9, 91.7 and 85.7%, respectively. The sensitivity, specificity and accuracy of type III for the diagnosis of SMm in each macroscopic type were: depressed, 88.9, 40.0 and 63.2%, respectively; protruded: 34.8, 96.4 and 90.0%, respectively; and flat elevated, 54.2, 92.7 and 85.0%, respectively. These results suggest that the diagnostic accuracy of surface pattern was insufficient and particularly poor for depressed-type lesions. PMID- 23673485 TI - Regulation of water-soluble phenolic acid biosynthesis in Salvia miltiorrhiza Bunge. AB - Salvia miltiorrhiza Bunge (Lamiaceae) root, generally called Danshen, is an important herb in Chinese medicine widely used for treatment of various diseases. Phenolic acids in S. miltiorrhiza, as important effective compounds, have become a new research focus in plant secondary metabolism in recent years. This review summarizes the recent advances in the regulation of water-soluble phenolic acid biosynthesis in S. miltiorrhiza via regulators at molecular level, such as the phenylalanine ammonia-lyase gene (PAL), cinnamic acid 4-hydroxylase gene (C4H), 4 coumarate-CoA ligase gene (4CL), tyrosine aminotransferase gene (TAT), 4 hydroxyphenylpyruvate reductase gene (HPPR), 4-hydroxyphenylpyruvated dioxygenase gene (HPPD), hydroxycinnamoyl-CoA:hydroxyphenyllactate hydroxycinnamoyl transferase-like gene (RAS-like), and v-myb avian myeloblastosis viral oncogene homolog 4 gene (MYB4), and production of anthocyanin pigmentation 1 gene (AtPAP1), and via regulators at cell level, such as methyl jasmonate, salicylic acid, abscisic acid, polyamines, metal ions, hydrogen peroxide (H2O2), ultraviolet-B radiation, and yeast elicitor. PMID- 23673486 TI - Biodiesel production via the transesterification of soybean oil using waste starfish (Asterina pectinifera). AB - Calcined waste starfish was used as a base catalyst for the production of biodiesel from soybean oil for the first time. A batch reactor was used for the transesterification reaction. The thermal characteristics and crystal structures of the waste starfish were investigated by thermo-gravimetric analysis and X-ray diffraction. The biodiesel yield was determined by measuring the content of fatty acid methyl esters (FAME). The calcination temperature appeared to be a very important parameter affecting the catalytic activity. The starfish-derived catalyst calcined at 750 degrees C or higher exhibited high activity for the transesterification reaction. The FAME content increased with increasing catalyst dose and methanol-over-oil ratio. PMID- 23673487 TI - Analysis of salt-tolerance genes in Zygosaccharomyces rouxii. AB - Zygosaccharomyces rouxii was mostly used in high-salt liquid fermentation of soy sauce. To better understand the osmo-adaption mechanism, two key salt-tolerance genes GPD1 coding for glycerol-3-phosphate dehydrogenase and FPS1 coding for a putative glycerol transporter were evaluated in the wild-type Z. rouxii (S) and a higher salt-tolerant mutant strain Z. rouxii 3-2 (S3-2) previously constructed. It was found that several mutations occurred in ZrGPD1 and ZrFPS1 in S3-2 compared with the control strain S. The mutation of ZrGPD1 in S3-2 resulted in the increase of transcription level of ZrGPD1 compared with the control. At the same time, the mutation of ZrFPS1 resulted in the decrease of transcription level of ZrFPS1. In addition, overexpression of S3-2GPD1 and S3-2FPS1 in Saccharomyces cerevisiae could cause the stronger salt tolerance compared to SGPD1 and SFPS1, respectively. The results suggested the improvement of salt tolerance in S3-2 was due to the increase of glycerol contents, which was resulted from the increase of transcription level of ZrGPD1 and the decrease of transcription level of ZrFPS1. PMID- 23673488 TI - A ratiometric naphthalimide sensor for live cell imaging of copper(I). AB - A new naphthalimide derivative bearing a tetrathia-azacrown for high affinity and selective binding to Cu(+) was synthesised. Copper recognition properties in solution were evaluated using (1)H NMR and fluorescence spectroscopy. Live cell imaging by confocal microscopy highlighted the capabilities of the new sensor for the two-wavelength detection of intracellular monovalent copper in neuronal cells. PMID- 23673489 TI - Copper doped TiO2 nanoparticles characterized by X-ray absorption spectroscopy, total scattering, and powder diffraction--a benchmark structure-property study. AB - Metal functionalized nanoparticles potentially have improved properties e.g. in catalytic applications, but their precise structures are often very challenging to determine. Here we report a structural benchmark study based on tetragonal anatase TiO2 nanoparticles containing 0-2 wt% copper. The particles were synthesized by continuous flow synthesis under supercritical water-isopropanol conditions. Size determination using synchrotron PXRD, TEM, and X-ray total scattering reveals 5-7 nm monodisperse particles. The precise dopant structure and thermal stability of the highly crystalline powders were characterized by X ray absorption spectroscopy and multi-temperature synchrotron PXRD (300-1000 K). The combined evidence reveals that copper is present as a dopant on the particle surfaces, most likely in an amorphous oxide or hydroxide shell. UV-VIS spectroscopy shows that copper presence at concentrations higher than 0.3 wt% lowers the band gap energy. The particles are unaffected by heating to 600 K, while growth and partial transformation to rutile TiO2 occur at higher temperatures. Anisotropic unit cell behavior of anatase is observed as a consequence of the particle growth (a decreases and c increases). PMID- 23673490 TI - Large scale preparation of graphene quantum dots from graphite with tunable fluorescence properties. AB - We report an improved Hummers method for synthesizing graphene quantum dots (GQDs) by directly oxidizing and etching graphite powders. The yield of GQDs is as high as 63 +/- 7% (by weight, wt%), suggesting this technique is suitable for producing GQDs on a large scale. The GQDs are nanocrystals with lateral dimensions in the range of 2-4 nm and an average thickness of around 1.3 nm. The emission peaks of as-prepared GQDs can be tuned in the range of 440 to 510 nm by varying the reaction conditions. Their fluorescence quantum yields were tested to be around 1%, which could be further increased to about 3% by hydrothermal treatment. These GQDs have low cytotoxicity and excellent biocompatibility, indicating that they are promising for biological applications. PMID- 23673491 TI - Effect of natural borneol on the pharmacokinetics and distribution of nimodipine in mice. AB - The purpose of this study was to investigate the effect of natural borneol (NB) on the pharmacokinetics and distribution of nimodipine in mice. A single dose of nimodipine was administered intravenously (2 mg/kg) to mice pretreated with NB (250 mg/kg) or vehicle. Blood as well as brain, liver, and kidney tissue samples were collected at 5, 10, 20, 40, and 60 min post-dose nimodipine. The concentrations of nimodipine in plasma and tissues were determined by ultra performance liquid chromatography (UPLC) coupled with UV detection, and the pharmacokinetic parameters were calculated based on non-compartmental analysis. NB increased the plasma AUC5-60 min by 26 % compared to the vehicle. In addition, brain concentrations of nimodipine in NB-treated mice were significantly higher than those in control mice with the increased AUC5-60 min by 30 %. In liver and kidney, NB also caused 26 and 47 % increase in AUC5-60 min, respectively. These results implicated that NB may inhibit the metabolism or elimination of nimodipine and enhance its distribution in brain and kidney tissue. PMID- 23673496 TI - Pseudoxanthoma elasticum: progress in research toward treatment: summary of the 2012 PXE international research meeting. PMID- 23673492 TI - Is pomegranate juice a potential perpetrator of clinical drug-drug interactions? Review of the in vitro, preclinical and clinical evidence. AB - The area of fruit juice-drug interaction has received wide attention with numerous scientific and clinical investigations performed and reported for scores of drugs metabolized by CYP3A4/CYP2C9. While grapefruit juice has been extensively studied with respect to its drug-drug interaction potential, numerous other fruit juices such as cranberry juice, orange juice, grape juice, pineapple juice and pomegranate juice have also been investigated for its potential to show drug-drug interaction of any clinical relevance. This review focuses on establishing any relevance for clinical drug-drug interaction potential with pomegranate juice, which has been shown to produce therapeutic benefits over a wide range of disease areas. The review collates and evaluates relevant published in vitro, preclinical and clinical evidence of the potential of pomegranate juice to be a perpetrator in drug-drug interactions mediated by CYP3A4 and CYP2C9. In vitro and animal pharmacokinetic data support the possibility of CYP3A4/CYP2C9 inhibition by pomegranate juice; however, the human relevance for drug-drug interaction was not established based on the limited case studies. PMID- 23673497 TI - Many paths to alopecia via compromised regeneration of hair follicle stem cells. AB - Alopecia can be caused by defective formation, defective regeneration, or increased destruction of hair follicles. Much work has elucidated the roles of diffusible morphogens in modulating hair follicle stem cell activities. Recent studies have revealed novel molecular events within the nucleus, which are required for the activation and progression of hair stem cells. These studies will provide new clues and targets for designing therapeutic strategies for hair loss. PMID- 23673498 TI - Phenotypic heterogeneity in hidradenitis suppurativa (acne inversa): classification is an essential step toward personalized therapy. AB - Awareness is increasing that there is phenotypic heterogeneity within the hidradenitis suppurativa (HS) disease spectrum. However, the few randomized HS trials that are available have not distinguished between the subtypes of the disease. In this issue, Canoui-Poitrine et al. used latent class (LC) analysis of the largest HS cohort described to date to generate three phenotypic subtypes. LC 1 correlates with "typical" European HS, mainly involving the axilla, groin, and, in women, the inframammary region. "Atypical" HS, which may be linked to gamma secretase gene mutations, was subdivided further into LC2 and LC3 subtypes. PMID- 23673499 TI - Cutaneous human papillomavirus infection and Basal cell carcinoma of the skin. AB - Human papillomavirus (HPV) is ubiquitous in skin and has been associated with nonmelanoma skin cancer. Iannacone et al. investigate the role of HPV in basal cell carcinoma (BCC) by assessing the presence of HPV antibodies, HPV DNA in tumors, and the relationship between these two markers and BCC. In contrast to squamous cell carcinoma (SCC), there is no association between HPV and BCC. PMID- 23673500 TI - What lies beneath? Scanning probe tomography may have the answer. AB - Scanning probe microscopy facilitates high-resolution noninvasive imaging of surface topography on even the most delicate of biological structures. Moreover, the local probe nature of the instrument architecture lends itself to the measurement of many important physical properties. To date, biological investigations have largely been constrained to imaging surface (membrane)-borne phenomena; however, the advent of extremely high aspect-ratio 'needle' probe tips, as reported by Beard et al. (2013), suggests that the approach can now be extended to address the particular challenges associated with measuring subsurface microscopic targets, including the intracellular components of the stratum corneum. PMID- 23673501 TI - Circulating melanoma cells as a predictive biomarker. AB - The prognosis of patients with metastatic melanoma has improved significantly with targeted therapeutic agents and immunotherapies. Detection of early melanoma recurrence after treatment will be beneficial to switch patients who fail on one therapy to different modalities. Circulating tumor cells (CTCs) are cancer cells released by a tumor into the peripheral blood. These cells hold potential as prognostic, predictive, and pharmacodynamic biomarkers for treatment. In this issue, Khoja et al. report that melanoma CTCs can be detected using Melcam and high molecular weight melanoma-associated antibody. They found that in 101 stage IV melanoma patients, CTC numbers ranged between 0 and 36/7.5 ml blood; 26% of the patients had >= 2 CTCs at baseline. The CTC number (>= 2 CTCs) at baseline was significantly prognostic for median overall survival (OS) in univariate and multivariate analysis. Patients receiving treatment where CTC numbers remained >= 2 CTCs during their treatment had shorter median OS than those who maintained <2 CTCs (7 vs. 10 months, hazard ratio 0.34, 95% confidence interval 0.14-0.81, log rank test P=0.015). The implications of this work are substantial in counseling patients about their prognosis and in helping to assess responses to systemic therapies. PMID- 23673502 TI - The dark side of cyclophosphamide: cyclophosphamide-mediated ablation of regulatory T cells. AB - Cancer immune escape is frequently associated with the induction of an inappropriate immune response, i.e., a response that does not inhibit but perhaps even promotes the tumor. Indeed, increased frequencies of tumor-infiltrating regulatory T cells (Tregs) are associated with an impaired prognosis in several cancers. Thus, depletion of Tregs, e.g., by cyclophosphamide, was proposed as a means to boost immune responses to cancer. In the present issue of the Journal, Sevko et al., however, provide evidence that cyclophosphamide exerted the unexpected effect of induction of myeloid-derived suppressor cells. PMID- 23673503 TI - Recapitulating atopic dermatitis in three dimensions: cross talk between keratinocytes and nerve fibers. AB - Roggenkamp et al. (2013) report a significant advance in the in vitro reconstruction of atopic dermatitis (AD) by coculturing lesional human keratinocytes with sensory nerve fibers. This work has important implications for understanding the interaction between the resident skin cells and the peripheral nervous system in AD, and it sheds light on the pathways leading to the pruritus that typifies this disease. PMID- 23673504 TI - Photosensitivity in the elderly-think of late-onset protoporphyria. AB - Photosensitivity is the clinical hallmark of both erythropoietic protoporphyria (EPP) and X-linked dominant protoporphyria (XLDPP). Both disorders result from a hereditary dysfunction in heme biosynthesis. Disease onset is usually in early childhood. However, rare patients with late-onset EPP in association with a myeloproliferative disorder or myelodysplastic syndrome have been reported. In this issue, Livideanu et al. describe the first patient with late-onset XLDPP. PMID- 23673507 TI - Genome-wide epigenetics. PMID- 23673508 TI - Spontaneous clearance of Helicobacter pylori after pylorus-preserving gastrectomy for gastric cancer. AB - Residual mucosa in the gastric stump after pylorus-preserving gastrectomy (PPG) is considered a risk factor for the development of gastric stump carcinoma (GSC). Duodenogastric reflux (DGR) and Helicobacter pylori (H. pylori) infection are suspected to contribute to the development of GSC. The aim of this study was to investigate the prevalence of H. pylori in the residual stomach after PPG for gastric cancer and to assess factors associated with the presence of H. pylori. We investigated 72 patients who had undergone PPG at least 1 year prior to the study and were confirmed to be positive for H. pylori infection on presurgical endoscopic biopsy. The extent of DGR, the prevalence of H. pylori infection based on H. pylori stool antigen (HpSA) tests and the severity of gastritis were analyzed in these post-PPG patients. None of the patients had DGR, as shown by (99m)Tc-PMT. Of the 72 post-PPG patients, 33 (46%) were positive for HpSA. The prevalence of H. pylori infection was significantly lower after surgery than before surgery. The endoscopic severity of remnant gastritis, as well as histological inflammation and activity, were higher in H. pylori-positive patients than in H. pylori-negative patients. In conclusion, some patients who undergo PPG and are negative for DGR experience spontaneous clearance of H. pylori infection. PMID- 23673509 TI - Full-field thickness distribution of human tympanic membrane obtained with optical coherence tomography. AB - The full-field thickness distribution, three-dimensional surface model and general morphological data of six human tympanic membranes are presented. Cross sectional images were taken perpendicular through the membranes using a high resolution optical coherence tomography setup. Five normal membranes and one membrane containing a pathological site are included in this study. The thickness varies strongly across each membrane, and a great deal of inter-specimen variability can be seen in the measurement results, though all membranes show similar features in their respective relative thickness distributions. Mean thickness values across the pars tensa ranged between 79 and 97 MUm; all membranes were thinnest in the central region between umbo and annular ring (50 70 MUm), and thickness increased steeply over a small distance to approximately 100-120 MUm when moving from the central region either towards the peripheral rim of the pars tensa or towards the manubrium. Furthermore, a local thickening was noticed in the antero-inferior quadrant of the membranes, and a strong linear correlation was observed between inferior-posterior length and mean thickness of the membrane. These features were combined into a single three-dimensional model to form an averaged representation of the human tympanic membrane. 3D reconstruction of the pathological tympanic membrane shows a structural atrophy with retraction pocket in the inferior portion of the pars tensa. The change of form at the pathological site of the membrane corresponds well with the decreased thickness values that can be measured there. PMID- 23673511 TI - Abdominal approaches to pelvic prolapse repairs. AB - PURPOSE OF REVIEW: Abdominal sacrocolpopexy has been considered the gold standard for vaginal vault prolapse repair for several decades. Although transvaginal approaches gained popularity as minimally invasive alternatives, complications related to the use of vaginal mesh have led surgeons to perform these repairs less frequently. By incorporating laparoscopic and robotic techniques into the traditional open abdominal sacrocolpopexy, surgeons can offer the benefits of minimally invasive surgery while avoiding risks of vaginal mesh. This review article aims to evaluate the efficacy and outcomes of abdominal sacrocolpopexy by comparing open, laparoscopic, and robotic assisted laparoscopic surgery. RECENT FINDINGS: The excellent outcomes of open abdominal sacrocolpopexy have repeatedly been shown in published, randomized data. This has been further validated in minimally invasive techniques through randomized data evaluating the outcomes of laparoscopic sacrocolpopexy. Among the various sacrocolpopexy techniques, outcomes are similar among the open, laparoscopic, and robotic approaches. Minimally invasive surgeries have been shown to have advantages in terms of perioperative morbidity. SUMMARY: The superior outcomes of abdominal sacrocolpopexy are available using minimally invasive techniques for pelvic organ prolapse repair. Further research with randomized data is required to establish how these approaches compare to each other. Given the inherent advantages of minimally invasive surgery, robotic or laparoscopic abdominal sacrocolpopexy may become the preferred approach to abdominal pelvic organ prolapse repair. PMID- 23673510 TI - The role of tumor-associated macrophages in breast cancer progression (review). AB - It is well established that the tumor microenvironment plays a major role in the aggressive behavior of malignant solid tumors. Among cell types associated with tumor microenvironment, tumor-associated macrophages (TAMs) are the most influential for tumor progression. Breast cancer is characterized by having a large population of TAMs, and experimental models have exposed multiple mechanisms by which TAMs interact with and influence the surrounding tumor cells. The process of metastasis involves tumor cells gaining access to the tissue outside the immediate tumor environment and invading the confining extracellular matrix (ECM). Supporting this process, TAMs secrete proangiogenic factors such as VEGF to build a network of vessels that provide nutrition for tumor cells, but also function as channels of transport into the ECM. Additionally, TAMs release factors to decrease the local pro-inflammatory antitumor response, suppressing it and providing a means of escape of the tumor cells. Similarly, hypoxia in the tumor microenvironment stimulates macrophages to further produce VEGF and suppress the T-cell immune responses, thus, enhancing the evasion of tumor cells and ultimately metastasis. Given the multiple roles of TAMS in breast cancer progression and metastasis, therapies targeting these cells are in development and demonstrate promising results. PMID- 23673512 TI - High-risk prostate cancer: combination of high-dose, high-precision radiotherapy and androgen deprivation therapy. AB - PURPOSE OF REVIEW: High-risk prostate cancer (PCa) harbours a risk of local, regional and systemic relapse requiring the combination of a loco-regional treatment such as external beam radiotherapy for controlling the pelvic-confined disease, combined with an androgen deprivation therapy (ADT) to potentiate irradiation and to destroy the infraclinical androgen-dependent disease outside the irradiated volume. RECENT FINDINGS: Many phase III randomized trials issued from the Radiation Therapy Oncology Group (USA) and from the EORTC Radiation Oncology Group have paved the way for establishing the indications of this combined approach. SUMMARY: For locally advanced PCa, the combination needs a long-term ADT (>=2 years) with luteinizing hormone-releasing hormone agonists. For high-risk localized PCa, the combination requires a 6-month complete androgen blockade. Image-guided intensity-modulated radiotherapy has replaced conventional irradiation and allows a dose escalation, improving the local control without increasing the toxicity. A multidisciplinary approach will enable physicians to tailor the treatment policy and a close cooperation with general practitioners and specialists will be set up to prevent as much as possible the side-effects of ADT. PMID- 23673514 TI - Prognostic role for diffusion-weighted imaging of pediatric optic pathway glioma. AB - Optic pathway glioma (OPG) has an unpredictable course, with poor correlation between conventional imaging features and tumor progression. We investigated whether diffusion-weighted MRI (DWI) predicts the clinical behavior of these tumors. Twelve children with OPG (median age 2.7 years; range 0.4-6.2 years) were followed for a median 4.4 years with DWI. Progression-free survival (time to requiring therapy) was compared between tumors stratified by apparent diffusion coefficient (ADC) from initial pre-treatment scans. Tumors with baseline ADC greater than 1,400 * 10(-6) mm(2)/s required treatment earlier than those with lower ADC (log-rank p = 0.002). In some cases, ADC increased leading up to treatment, and declined following treatment with surgery, chemotherapy, or radiation. Baseline ADC was higher in tumors that eventually required treatment (1,562 +/- 192 * 10(-6) mm(2)/s), compared with those conservatively managed (1,123 +/- 114 * 10(-6) mm(2)/s) (Kruskal-Wallis test p = 0.013). Higher ADC predicted earlier tumor progression in this cohort and in some cases declined after therapy. Evaluation of OPG with DWI may therefore be useful for predicting tumor behavior and assessing treatment response. PMID- 23673513 TI - Immediate post-operative brachytherapy prior to irradiation and temozolomide for newly diagnosed glioblastoma. AB - To determine whether immediate post-operative brachytherapy can be safely applied to newly diagnosed glioblastomas to retard tumor progression prior to initiation of external beam radiation therapy (EBRT) and temozolomide. Between 1996 and 2011, eleven patients underwent implantation of GliaSite (n = 9) or MammoSite (n = 2) at the time of surgical resection. Brachytherapy was carried out on post operative day 2-3, with 45-60 Gy delivered to a 1 cm margin. All patients underwent subsequent standard radiation/temozolomide treatment 4-5 weeks post irradiation. There were no wound related complications. Toxicity was observed in two patients (2/11 or 18 %), including one post-operative seizure and one case of cerebral edema that resolved after a course of steroid treatment. Immediate post operative and pre-irradiation/temozolomide magnetic resonance imaging assessment was available for 9 of the 11 patients. Two of these nine patients (22 %) developed new regions of contrast enhancement prior to irradiation/temozolomide. This compares favorably to historical data where 53 % of patient suffer such tumor progression. While there was a trend toward improved 6 month progression free survival in the brachytherapy/temozolomide/radiation treated patients, the overall survival of these patients were comparable to historical controls. This case series demonstrates the safety of immediate post-operative brachytherapy when applied prior to EBRT and temozolomide in the treatment of newly diagnosed glioblastomas. PMID- 23673516 TI - [Results of the pilot project of the Techniker-Krankenkasse "quality monitoring in outpatient psychotherapy" - a commentary by the project's scientific advisory board]. AB - In order to objectify the discussion about a project of the TK, a German health insurance company, which aimed to analyse the effects of a specific quality monitoring system on psychotherapy outcomes, the scientific advisory board summarized the main results of the study. The main results were cited from the final report which confirms the confirmatory character of the study design that aimed to test the hypothesis of the superiority of the quality monitoring system compared to the system of peer review-based approval of therapies. The quality monitoring system represents a complex intervention which is composed of several single intervention elements. Thus, the study results allow only the conclusion that the overall complex interven-tion did not prove to be superior. Further studies are needed with regard to the effectiveness of single components. Finally, the issues of representativeness and selectivity of the study and the sample are discussed and their importance is -underlined by reference to the literature. PMID- 23673515 TI - New avenues in the medical treatment of Cushing's disease: corticotroph tumor targeted therapy. AB - Cushing's disease (CD) is a condition of chronic hypercortisolism caused by an adrenocorticotropic hormone-secreting pituitary adenoma. First-line transsphenoidal surgery is not always curative and disease sometimes recurs. Radiotherapy often requires months or years to be effective, and is also not curative in many cases. Consequently, effective medical therapies for patients with CD are needed. Corticotroph adenomas frequently express both dopamine (D2) and somatostatin receptors (predominantly sstr5). Pasireotide, a somatostatin analog with high sstr5 binding affinity, has shown urinary free cortisol (UFC) reductions in most patients with CD in a large phase 3 trial, with UFC normalization and tumor shrinkage in a subset of patients. Adverse events were similar to other somatostatin analogs, with the exception of the degree and severity of hyperglycemia. Two small trials (one prospective and one retrospective) have suggested that cabergoline, a D2 receptor agonist, could be effective in normalizing UFC, but current long-term data results are conflicting. Combination treatment with pasireotide plus cabergoline and the adrenal steroidogenesis inhibitor ketoconazole has been successful, but further investigation in larger trials is necessary. Retinoic acid also showed interesting results in a recent very small prospective study. Glucocorticoid receptor blockade with mifepristone has recently demonstrated improvement in signs and symptoms of Cushing's and glycemic control; however, this modality does not address the etiology of the disease and has inherent adverse events related to its mechanism of action. Pituitary-targeted medical therapies will soon play a more prominent role in treating CD, and may potentially become first-line medical therapy when surgery fails or is contraindicated. PMID- 23673517 TI - Selectively reduction of tobacco specific nitrosamines in cigarette smoke by use of nanostructural titanates. AB - In this study, titanate nanosheets, nanotubes, and nanowires, were synthesized by hydrothermal treatment anatase TiO2 in different temperatures. The obtained products are characterized by X-ray powder diffraction (XRD), scanning electron microscopy (SEM), transmission electron micrograph (TEM) and Brunauer-Emmett Teller (BET) nitrogen sorption-desorption measurement. Then, the nanostructural titanates were used as additives for selectively reducing tobacco-specific nitrosamines (TNSAs) in mainstream cigarette smoke (CS) for the first time. These nanomaterials exhibited high reduction ability of TSNAs which was related to their intrinsic properties. The N-NO functional group of TSNAs with a negative charge would react with H(+) on the surface of nanomaterials via chemical absorption and can be retained on the surface of the titanates. Among these materials, titanate nanowires (TNW) captured more TNSAs owing to their network structure, which resulted in the selective reduction ratio of TSNAs being improved significantly. Thus, TNW is a useful additive for selectively reducing the TSNAs in CS without changing the cigarette flavor. PMID- 23673518 TI - Phosphorylation of FOXO3a by PI3K/Akt pathway in HK-2 renal proximal tubular epithelial cells exposed to cadmium. AB - We examined the effects of cadmium chloride (CdCl2) exposure on the phosphorylation and function of the forkhead box class O (FOXO) transcription factor FOXO3a in HK-2 human renal proximal tubular cells. Phosphorylation of FOXO3a (at Thr32 and Ser253) and its upstream kinase, Akt (at Thr308 and Ser473) were markedly increased following exposure to 10 or 20 MUM CdCl2. Treatment with wortmannin (500 nM), an inhibitor of phosphoinositide-3-kinase (PI3K), suppressed CdCl2-induced phosphorylation of Akt and FOXO3a at their Akt phosphorylation sites. CdCl2-induced phosphorylation of FOXO3a was markedly suppressed by the epidermal growth factor receptor inhibitor, AG1478 (1 MUM), the Ca(2+)/calmodulin dependent kinase II inhibitor, KN-93 (10 MUM), and the Src inhibitor, PP2 (10 MUM), but only partially suppressed by the insulin-like growth factor-1 receptor inhibitor, PPP (2.5 MUM). Furthermore, the p38 inhibitor, SB203580 (20 MUM), suppressed CdCl2-induced phosphorylation of Akt and FOXO3a, suggesting possible cross-talk between p38 mitogen-activated protein kinase and Akt. Although phosphorylation of FOXO3a was associated with reduced levels of nuclear FOXO3a, this change in cellular localization was transient. Silencing of FOXO3a expression using short interfering RNA suppressed CdCl2-induced cellular damage and accumulation of cytoplasmic nucleosomes in HK-2 cells. These results show that cadmium exposure induces phosphorylation of FOXO3a through the PI3K/Akt signaling pathway and suggest that FOXO3a phosphorylation (inactivation) transiently promotes survival of HK-2 cells. Phosphorylation of FOXO3a by the PI3K/Akt pathway may regulate cell fate in proximal tubules exposed to cadmium. PMID- 23673519 TI - A prospective study on dinghy sailors' training habits and injury incidence with a comparison between elite sailor and club sailor during a 12-month period. AB - BACKGROUND: Sailing is an Olympic sport practiced by both men and women of all ages. Despite being a popular sport, we have found no prospective studies investigating the injury incidence and training quantity such as found for other sports. The purpose of this study was to do an inventory over dinghy sailors' training habits, injury incidence and type of injury. METHODS: In this prospective cohort study, 45 sailors (17 women and 28 men), age 17-31 years, were included. 24 sailors belonged to the SWE Sailing Team and 21 were club sailors. All the participants kept a training diary, and once a month for 12 months they reported their training and injuries through a web-based questionnaire. Each time a sailor reported an injury, they were contacted by the researchers and an injury form was completed. RESULTS: The SWE Sailing Team performed significantly (p=0.006) more physical training than the club sailor. There was no significant difference (p=0.7) in hours of sail training. A total of 144 injuries were reported. The most common injury location was the knee (19%), followed by the lower leg (13%) and shoulder (12%). 30% of the injuries occurred during physical training, 17% during sail training and 12% during sail racing. CONCLUSIONS: The most common injury location was the knee. The largest proportion of injuries occurred during physical training and unspecified activities. The least number of injuries occurred during sail racing. The injury location was different between the older more experienced sailor (more upper extremity injuries) compared with the younger sailors (more trunk injuries). PMID- 23673520 TI - Sex differences in the risk of injury in World Cup alpine skiers: a 6-year cohort study. AB - BACKGROUND: In competitive alpine skiing, there is a controversy regarding the sex-related risk of injury. OBJECTIVE: To compare the risk of injury in female versus male World Cup (WC) alpine skiers. METHODS: Injuries were recorded through the International Ski Federation Injury Surveillance System for six consecutive winter seasons (2006-2012), based on retrospective interviews with athletes from 10 teams at the end of each season. All acute training and competition injuries which required medical attention were recorded. Race exposure was calculated based on the exact number of runs started in the WC for each of the interviewed athletes each season. RESULTS: Men had a higher overall rate of injury (relative risk (RR) 1.24, 95% CI 1.05 to 1.47), as well as a higher rate of time-loss injury (RR 1.23, 95% CI 1.03 to 1.48) than women in training and competitions, expressed as injuries/100 athletes/season. These sex differences were even more pronounced during WC races (RR 1.58, 95% CI 1.22 to 2.04 and RR 1.72, 95% CI 1.29 to 2.31, for overall and time-loss injuries, respectively). There was no sex difference in the risk of knee/anterior cruciate ligament (ACL) injuries. CONCLUSIONS: No previous studies from competitive skiing have reported a significantly higher risk of injuries in men than women. In contrast to recreational skiing and team sports, there was no sex difference in the risk of knee/ACL injuries and prevention efforts should be directed as much towards male as female competitive skiers. PMID- 23673522 TI - 25th ASMS Sanibel Conference on Top Down Mass Spectrometry. PMID- 23673521 TI - Injury initiates unfavourable weight gain and obesity markers in youth. AB - OBJECTIVE: The purpose of this study was to examine the association of knee injuries with subsequent changes in body mass index and body composition during maturation in young females. METHODS: A prospective longitudinal study design was employed to evaluate young females active in soccer or basketball (N=862). Participants who completed at least 1-year follow-up to provide consecutive annual measures of BMIZ and %fat were included in the study analysis to determine the effect of knee injuries on the trajectory of these obesity markers in youth. RESULTS: Of the 71 reported knee injuries, 12 (17%) occurred in athletes at the prepubertal stage, 24 (34%) in athletes at the pubertal stage, and 35 (49%) in postpubertal athletes. Controlling for the effects of maturation, female athletes who reported knee injury demonstrated a greater yearly increase in BMIZ (LS means and 95% CI for the injured group=0.039 (-0.012 to 0.089), for the non-injured group=-0.019 (-0.066 to 0.029), and group difference=0.057 (0.005 to 0.11), p=0.03) and in %body fat (LS means and 95% CI for the injured group=1.05 (0.45 to 1.65), for the non-injured group=0.22 (-0.21 to 0.064), and group difference=0.83 (0.21 to 1.45), p=0.009), compared to those without knee injuries. This indicates that the athletes with knee injuries will increase their body mass index percentile by up to 5 units more than someone of the same age without an injury, and in body fat by up to 1.5%, compared to their non-injured peers. CONCLUSIONS: The present findings indicate that knee injury during the growing years may be associated with unfavourable changes in body composition. PMID- 23673523 TI - Assessing competence for reentry: what matters most? PMID- 23673524 TI - In situ study of the catalytic mechanism for the oxygen reduction reaction on a polypyrrole modified carbon supported cobalt hydroxide cathode in direct borohydride fuel cells. AB - An in situ test method has been developed to study the Co(OH)2-PPy-BP cathode status during DBFC operation. It is found that some Co(2+) ions are oxidized to Co(3+) present in CoOOH during cell operation. A mechanism for the oxygen reduction reaction on the Co(OH)2-PPy-BP cathode in alkaline media has been proposed. PMID- 23673525 TI - Direct object resolution by image subtraction: a new molecular ruler for nanometric measurements on complexed fluorophores. AB - A technique for measuring distances between two or more fluorophores spaced in the 10-100 nm range is described. We identify a linear correlation between the intensity-amplitude in the difference-image of single molecules undergoing fluorescence fluctuations and their separation. The transform is used to map distances between coupled fluorophores. PMID- 23673526 TI - Excessive fluoride consumption leads to accelerated death of erythrocytes and anemia in rats. AB - The present study was performed to evaluate an overall effect of long-term consumption of excessive fluoride (F) amounts by rats on their erythrocytes. The animals were administered regular drinking water (0.4 ppm F) or the same water supplemented with 2, 10, and 20 ppm F (as NaF) for 12 months. Chronic exposure of the rats to increasing F doses induced a progressive rise of the plasma F concentration accompanied by a dose-dependent fall of hematocrit and decrease in the mean erythrocyte volume. Consumption of 10 and 20 ppm F resulted in appearance of morphologically abnormal cells (stomatocytes and echinocytes) in the peripheral blood. Rise of the water F concentration to 20 ppm F led to significant increase in the number of phosphatidylserine-exposing erythrocytes, although suppression of cell viability was revealed in all three groups of F poisoned rats. A compensatory enhanced release of reticulocytes was not sufficient to compensate for erythrocyte loss. Dose-dependent accumulation of free cytosolic Ca(2+) appears to be a major pathophysiological process underlying the development of F-induced death processes in rat erythrocytes. In addition, 10 and 20 ppm F induced ATP depletion and generation of peroxides in erythrocytes, whereas superoxide and glutathione levels were not altered. Thus, long-term intoxication of the rats with F triggers premature death of their erythrocytes due to intrinsic death-associated biochemical defects and development of anemia. PMID- 23673527 TI - Water extractable arabinoxylan aerogels prepared by supercritical CO2 drying. AB - Water extractable arabinoxylan (WEAX) aerogels were prepared by extracting the solvent from the alcogels (WEAX hydrogels with an alcohol as the solvent) with carbon dioxide under supercritical conditions. WEAX aerogels were characterized using scanning electron microscopy and adsorption and desorption nitrogen isotherms. The micrographs indicate a heterogeneous porous network structure in WEAX aerogel. Adsorption/desorption nitrogen isotherms of this material were type IV, which confirm that this material possess a mesoporous structure. WEAX aerogels rehydration capability was evaluated and the water absorption mechanism was determined. The WEAX aerogels water absorption mechanism was non-Fickian (n = 0.54). PMID- 23673529 TI - Three new multiflorane-type triterpenes from pumpkin (Cucurbita maxima) seeds. AB - Three new multiflorane-type triterpenes; 7a-methoxymultiflor-8-ene-3a,29-diol 3 acetate-29-benzoate (1), 7-oxomultiflor-8-ene-3a,29-diol 3-acetate-29-benzoate (2), and multiflora-7,9(11)-diene-3a,29-diol 3-p-hydroxybenzoate-29-benzoate (3), were isolated from seeds of Cucurbita maxima, along with three known compounds. Compound 3 and multiflora-7,9(11)-diene-3a-29-diol 3-benzoate (5) exhibited potent inhibitory effects on melanogenesis, with low cytotoxicities, and 2 exhibited single-digit micromolar cytotoxicity against HL-60 and P388 cells. PMID- 23673528 TI - Isotope effects as probes for enzyme catalyzed hydrogen-transfer reactions. AB - Kinetic Isotope effects (KIEs) have long served as a probe for the mechanisms of both enzymatic and solution reactions. Here, we discuss various models for the physical sources of KIEs, how experimentalists can use those models to interpret their data, and how the focus of traditional models has grown to a model that includes motion of the enzyme and quantum mechanical nuclear tunneling. We then present two case studies of enzymes, thymidylate synthase and alcohol dehydrogenase, and discuss how KIEs have shed light on the C-H bond cleavages those enzymes catalyze. We will show how the combination of both experimental and computational studies has changed our notion of how these enzymes exert their catalytic powers. PMID- 23673530 TI - Dabigatran: is there a role for coagulation assays in guiding therapy? AB - OBJECTIVE: To determine the usefulness of coagulation assay monitoring for dabigatran etexilate in certain high-risk clinical situations. DATA SOURCES: Literature retrieval was accessed through MEDLINE (1948-February 2013), Web of Science (1980-February 2013), International Pharmaceutical Abstracts (1977 February 2013), and Google Scholar using the terms dabigatran, dabigatran etexilate, BIBR 1048, BIBR 953, direct thrombin inhibitor, therapeutic monitoring, and atrial fibrillation. In addition, abstracts presented at the 2011 2012 American Society of Hematology, American College of Cardiology, International Society of Thrombosis and Haemostasis, and European Society of Cardiology annual meetings were reviewed. A search of Clinicaltrials.gov was performed to identify relevant ongoing or completed research. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were evaluated for inclusion. Priority was placed on all data derived from controlled clinical studies. DATA SYNTHESIS: Of the 6 published Phase 3 studies, only the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial evaluated the safety and efficacy of dabigatran for the prevention of stroke in patients with nonvalvular atrial fibrillation. Post hoc analyses of the RE-LY trial have provided additional information in special situations. Several published reports highlight the potential for complications with dabigatran, the importance of determining the most optimal candidates, and the need for therapeutic monitoring. Activated partial thromboplastin time and thrombin time are effective qualitative assays for dabigatran. Ecarin clotting time and the dilute thrombin time (ie, Hemoclot direct thrombin inhibitor) assays are suitable for quantitative measurement. CONCLUSIONS: The correlation between coagulation based assays and clinical out comes among dabigatran-treated patients has not been definitively established. However, coagulation-based assays may be useful in the management of several clinical scenarios. PMID- 23673531 TI - Aflibercept: newly approved for the treatment of macular edema following central retinal vein occlusion. AB - OBJECTIVE: To review the pharmacology, efficacy, and safety data available for aflibercept and compare the drug to other therapeutic options for treatment of macular edema following central retinal vein occlusion (CRVO) to determine its likely role in therapy. DATA SOURCES: A PubMed search using the terms aflibercept and VEGF trap-eye was conducted to identify initial literature sources. No timeframe was used for exclusion of older trials. All trials referenced were published between January 1995 and December 2012. STUDY SELECTION AND DATA EXTRACTION: Trials pertaining to oncologic use were excluded, as were studies conducted in animals and those written in a language other than English. Abstracts of the remaining trials were evaluated for determination of relevance to this review. Additional information sources were obtained via Internet and PubMed following a review of references. DATA SYNTHESIS: While previous Phase 1, 2, and 3 trials for other indications (age-related macular degeneration and diabetic macular edema) have shown intravitreal injections of aflibercept to be safe and well tolerated in many patients, preliminary results from the ongoing COPERNICUS and GALILEO trials proved the efficacy of this medication in treating macular edema secondary to CRVO. Of the combined 358 patients studied in COPERNICUS and GALILEO, 56% and 60%, respectively, of the patients receiving aflibercept 2 mg monthly achieved at least a 15-letter improvement in best corrected visual acuity (BCVA) from baseline over 6 months compared with just 12% and 22% in the control group (p < 0.01 for both). Additionally, in COPERNICUS and GALILEO, patients achieved a 21.3- and 14.7-letter improvement, respectively, in BCVA compared with placebo (p < 0.01 for both). CONCLUSIONS: In September 2012, aflibercept became the second vascular endothelial growth factor (VEGF) inhibitor approved for treatment of macular edema secondary to CRVO. While efficacy and safety appear similar to other anti-VEGF treatments, the higher potency, binding affinity, and duration of action make aflibercept an appealing new option. PMID- 23673532 TI - Subtherapeutic linezolid concentrations in a patient with morbid obesity and methicillin-resistant Staphylococcus aureus pneumonia: case report and review of the literature. AB - OBJECTIVE: To report a case of subtherapeutic linezolid concentrations in a patient with morbid obesity. CASE SUMMARY: A 34-year-old male with morbid obesity (265 kg, body mass index 82 kg/m(2)) was admitted for severe sepsis due to respiratory failure requiring emergent intubation and treatment of community acquired pneumonia. Admission tracheal aspirate culture revealed methicillin resistant Staphylococcus aureus (MRSA) for which vancomycin was prescribed. Therapy subsequently was changed to linezolid, because the patient's clinical status worsened, with significant hypoxia (partial pressure of arterial oxygen/fraction of inspired oxygen [PaO2/FiO2] ratio 145), increasing leukocytosis (white blood cell count from 10,800/MUL on admission to 15,400/MUL on hospital day 6), and persistent fever (38.3 degrees C). After 48 hours of linezolid monotherapy, the patient remained febrile with continued leukocytosis, worsening hypoxemia, and a persistently positive MRSA culture from a repeat endotracheal aspirate. Linezolid serum concentrations were obtained and vancomycin was reinstituted, after which the patient began to improve (afebrile, improving PaO2/FiO2 ratio, decreasing leukocytosis). On hospital day 12, the patient removed his endotracheal tube, and a sputum sample was obtained for culture. The patient's clinical status subsequently declined, prompting addition of cefepime to his antibiotic regimen. This sputum culture revealed not only MRSA, but also quinolone-resistant Escherichia coli. After completing treatment for both organisms the patient was discharged home. DISCUSSION: Limited data on linezolid dosing in the morbidly obese population show lower serum drug concentrations than those in nonobese patients, but no clinical failure has been reported when treating MRSA skin and soft tissue infections or MRSA tracheitis. In our patient, low steady-state linezolid serum concentrations (peak 4.13 MUg/mL [reference 15-27] and trough 1.27 MUg/mL [reference 2-9]) were thought to contribute to his poor clinical response. CONCLUSIONS: To our knowledge, this is the first report of subtherapeutic linezolid concentrations correlated with decreased clinical effectiveness when during treatment of MRSA pneumonia in a patient with morbid obesity. PMID- 23673534 TI - Mental health treatment associated with community-based depression screening: considerations for planning multidisciplinary collaborative care. AB - BACKGROUND: Depression places a large economic burden on the US health care system. Routine screening has been recognized as a fundamental step in the effective treatment of depression, but should be undertaken only when support systems are available to ensure proper diagnosis, treatment, and follow-up. OBJECTIVE: To estimate differences in prescribing new antidepressants and referral to stress management, psychotherapy, and other mental health (OMH) counseling at physician visits when documented depression screening was and was not performed. METHODS: Cross-sectional physician visit data for adults from the 2005-2007 National Ambulatory Medical Care Survey were used. The final analytical sample included 55,143 visits, representing a national population estimate of 1,741,080,686 physician visits. Four dependent variables were considered: (1) order for new antidepressant(s), and referral to (2) stress management, (3) psycho therapy, or (4) OMH counseling. Bivariable and multivariable associations between depression screening and each measure of depression follow-up care were evaluated using the design-based F statistic and multivariable logistic regression models. RESULTS: New antidepressant prescribing increased significantly (2.12% of visits without depression screening vs 10.61% with depression screening resulted in a new prescription of an antidepressant). Referral to stress management was the behavioral treatment with the greatest absolute change (3.31% of visits without depression screening vs 33.10% of visits with depression screening resulted in a referral to stress management). After controlling for background sociodemographic characteristics, the adjusted odds ratio of a new antidepressant order remained significantly higher at visits involving depression screening (AOR 5.36; 99.9% CI 2.92-9.82), as did referrals for all behavioral health care services (ie, stress management, psychotherapy, and OMH counseling). CONCLUSIONS: At the national level, depression screening was associated with increased new antidepressant prescribing and referral for behavioral health care. It is critical for policy planners to recognize changes in follow-up depression care when implementing screening programs to ensure adequate capacity. Pharmacists are poised to assume a role in collaborative depression care, particularly with antidepressant medication therapy management. PMID- 23673535 TI - Abdominal migraine in adults: a review of pharmacotherapeutic options. AB - OBJECTIVE: To report the case of a 32-year-old woman with abdominal migraine and present a literature review to evaluate abdominal migraine in adults, with particular regard to effective treatment. CASE SUMMARY: A 32-year-old African American female presented with recurrent, severe abdominal pain. The patient had several previous admissions with similar symptoms and an extensive gastrointestinal workup in which findings were normal. Attacks of abdominal pain occurred despite treatment with analgesics and antiemetics. She had a family history of migraine headaches. A diagnosis of abdominal migraine was presumed and prophylactic therapy with topiramate 50 mg twice daily relieved the symptoms. DISCUSSION: Most published cases of adult abdominal migraine describe females who had a long history of abdominal pain refractory to conventional therapies. The majority of patients had a strong family history of migraine and reported similar episodic abdominal pain. Patients responded to prophylactic migraine therapies, including calcium channel blockers, beta-blockers, topiramate, and antihistamines; a few responded to abortive sumatriptan therapy. CONCLUSIONS: Abdominal migraine should be considered a possible source of incurable abdominal pain in adults when accompanied by a complete gastrointestinal workup with normal results. We recommend a trial of topiramate as prophylactic therapy if abdominal migraine is the likely source of the pain. PMID- 23673538 TI - Successful treatment of pulmonary blastomycosis with continuously infused amphotericin B deoxycholate after failure with liposomal amphotericin B. AB - OBJECTIVE: To describe a case of successful treatment of severe pulmonary blastomycosis with amphotericin B deoxycholate after failure of liposomal amphotericin B. CASE SUMMARY: A 35-year-old male was exposed to damp decomposing wood while cleaning his basement. He subsequently developed a cough, malaise, fever, nausea, vomiting, and diarrhea. He was admitted to the hospital and intubated for worsening pulmonary symptoms. Microscopic examination of his sputum indicated Blastomyces dermatitidis. Liposomal amphotericin B was administered for 6 days, but the patient's temperature reached 39.6 degrees C and his white blood cell (WBC) count reached 52,300/MUL. Extensive consolidation of both lungs fields was observed on chest X-ray. Because of progressive clinical deterioration, the treatment was switched to amphotericin B deoxycholate by continuous infusion. That change resulted in clinical improvement, with abrupt reductions (within 48 hours) in temperature and the WBC count. By day 14 of therapy (day 8 of amphotericin B deoxycholate), the chest X-ray showed improvement in diffuse airspace filling. After 16 days of amphotericin B treatment, intravenous followed by oral voriconazole was administered for 3 months. Eight months later the patient's strength had improved significantly, but he still had occasional episodes of shortness of breath. DISCUSSION: The management of blastomycosis is challenging because of the lack of clinically supporting data. The gold standard for severe pulmonary blastomycosis had been amphotericin B deoxycholate; however, improved safety data with liposomal amphotericin B for other fungal infections has suggested this as an effective alternative. This report describes a patient with severe pulmonary blastomycosis failing 6 days of liposomal amphotericin B, yet he tolerated and clinically responded to continuous infusion of amphotericin B deoxycholate. Based on this case report and a simulated pharmacokinetic/pharmaco dynamic analysis, continuous infusion of amphotericin B deoxycholate may be a reasonable option for enhanced efficacy and minimal toxicity in patients with blastomycosis. CONCLUSIONS: Ours is the first case report to use continuous infusion of amphotericin B deoxycholate for the management of pulmonary blastomycosis. These results suggest that liposomal amphotericin B may not be adequate in some patients for the management of B. dermatitidis pulmonary infections. PMID- 23673537 TI - Gabapentin therapy of hiccups. AB - OBJECTIVE: To determine whether gabapentin is effective in the treatment of persistent or intractable hiccups. DATA SOURCES: A search of MEDLINE (1966-March 2013) using the MeSH search terms gabapentin, hiccups, and hiccups/drug therapy was performed. Additional databases searched included Web of Science (1945-March 2013) and International Pharmaceutical Abstracts (1970-March 2013) using the text words gabapentin and hiccups. Bibliographies of relevant articles were reviewed for additional citations. STUDY SELECTION AND DATA EXTRACTION: All data sources were considered for inclusion. Preference was given for articles written in English, although one abstract in German was used. DATA SYNTHESIS: Because of the low incidence of persistent or intractable hiccups, few if any controlled clinical trials are conducted on the efficacy of drug treatment. Therefore, most of the data involve case reports or case series. We evaluated 17 case reports and 2 case series involving gabapentin therapy for persistent or intractable hiccups. Therapeutic outcomes with gabapentin were positive in all cases, with temporal evidence suggesting an effect, but outcomes often were obscured by combination therapy and comorbidities in some cases. Case reports suggest that gabapentin might be useful as a second-line agent in patients undergoing stroke rehabilitation or in the palliative care setting where chlorpromazine adverse effects are undesirable. Gabapentin was very well tolerated, with only a few minor adverse effects. CONCLUSIONS: Gabapentin has a similar body of evidence as other pharmacotherapeutic agents used to treat hiccups. Gabapentin is well tolerated and should be considered as a second-line agent in selected patients. PMID- 23673541 TI - Current developments and recent advances in musculoskeletal tumor imaging. (Preface). PMID- 23673540 TI - Structural variation in ethylenediamine and -diphosphine adducts of (2,6 Me2C6H3S)2Pb: a single crystal X-ray diffraction and 207Pb solid-state NMR spectroscopy study. AB - Coordination complexes of (2,6-Me2C6H3S)2Pb (1) with flexible bidentate ligands have been prepared to explore new bonding environments for Pb(II) thiolates. The reaction of 1 with a series of ethylenediamine and ethylenediphosphine ligands resulted in isolation of the adducts [(2,6-Me2C6H3S)2Pb]2(tmeda) (9), [(2,6 Me2C6H3S)2Pb]3(dmpe) (10) and [(2,6-Me2C6H3S)2Pb]2(dppe) (11) [tmeda = N,N,N',N' tetramethylethylenediamine; dmpe = bis(dimethylphosphino)ethane; dppe = bis(diphenylphosphino)ethane]. The X-ray crystal structure of 9 shows a dinuclear species in which tmeda is chelating a psi-trigonal bipyramidal S2N2 Pb centre via axial and equatorial sites. The structure of 10 displays a trinuclear structural unit in which dmpe is chelating a psi-trigonal bipyramidal S2P2 Pb centre via equatorial sites. Compounds 9 and 10 also contain a second unique metal centre with psi-tetrahedral S3Pb bonding motifs. The structure of 11 shows the dppe ligand bridging two Pb psi-tetrahedral S2P metal bonding environments. Static (207)Pb solid-state NMR (SSNMR) spectra of 9-11 and [Ph4As][(PhS)3Pb] (12) were acquired with cross polarization (CP)-CPMG and frequency swept pulse (WURST)-CPMG pulse sequences, and the efficiencies of these pulse sequences are compared. The (207)Pb SSNMR spectra reveal that the lead chemical shift anisotropies (CSA) vary greatly between the different Pb sites, and are generally large in magnitude. DFT calculations are utilized to relate the orientations of the (207)Pb nuclear magnetic shielding tensors to the molecular structures, and to aid in spectral assignment where multiple Pb centres are present. The combination of X-ray diffraction, (207)Pb SSNMR and DFT is shown to be invaluable for the structural characterization of these important structural motifs, and should find wide ranging application to numerous lead coordination compounds. PMID- 23673542 TI - Chondrosarcoma: A Diagnostic Imager's Guide to Decision Making and Patient Management. AB - Chondrosarcoma is the third most common primary malignant bone tumor. Currently, outcomes are based largely on a histologic grading scale described by the World Health Organization (WHO) Classification of Bone Tumors (2002). This classification scheme possesses evident utility in the evaluation and management of higher grade tumors, but it is often unable to distinguish enchondromas from low-grade chondrosarcomas. This is problematic when low-grade lesions that are histologically similar to enchondromas demonstrate aggressive imaging features. Because histologic classification alone often belies the clinical significance of chondroid lesions, it is also important to consider radiologic staging as part of the clinical decision making process. This article focuses on medical decision support considerations relevant when confronted with this challenging subset of chondroid tumors, particularly differentiating the benign enchondroma from its notorious relative, the low-grade chondrosarcoma. In doing so, we present a review of the salient imaging features and discuss key differentiating characteristics. PMID- 23673539 TI - U1 Adaptor Oligonucleotides Targeting BCL2 and GRM1 Suppress Growth of Human Melanoma Xenografts In Vivo. AB - U1 Adaptor is a recently discovered oligonucleotide-based gene-silencing technology with a unique mechanism of action that targets nuclear pre-mRNA processing. U1 Adaptors have two distinct functional domains, both of which must be present on the same oligonucleotide to exert their gene-silencing function. Here, we present the first in vivo use of U1 Adaptors by targeting two different human genes implicated in melanomagenesis, B-cell lymphoma 2 (BCL2) and metabotropic glutamate receptor 1 (GRM1), in a human melanoma cell xenograft mouse model system. Using a newly developed dendrimer delivery system, anti-BCL2 U1 Adaptors were very potent and suppressed tumor growth at doses as low as 34 ug/kg with twice weekly intravenous (iv) administration. Anti-GRM1 U1 Adaptors suppressed tumor xenograft growth with similar potency. Mechanism of action was demonstrated by showing target gene suppression in tumors and by observing that negative control U1 Adaptors with just one functional domain show no tumor suppression activity. The anti-BCL2 and anti-GRM1 treatments were equally effective against cell lines harboring either wild-type or a mutant V600E B-RAF allele, the most common mutation in melanoma. Treatment of normal immune competent mice (C57BL6) indicated no organ toxicity or immune stimulation. These proof-of-concept studies represent an in-depth (over 800 mice in ~108 treatment groups) validation that U1 Adaptors are a highly potent gene-silencing therapeutic and open the way for their further development to treat other human diseases.Molecular Therapy - Nucleic Acids (2013) 2, e92; doi:10.1038/mtna.2013.24; published online 14 May 2013. PMID- 23673543 TI - Benign osteoid-producing bone lesions: update on imaging and treatment. AB - Benign osteoid-producing osseous tumors are frequently encountered in a typical musculoskeletal radiology practice. Enostoses are extremely common, but osteomas, osteoid osteomas, and osteoblastomas are diagnosed less often. A thorough discussion of the typical clinical presentation, histology, imaging findings, treatment and prognosis for each tumor is provided, with particular emphasis on more current imaging techniques and treatments. PMID- 23673544 TI - Osteosarcoma: review of the various types with emphasis on recent advancements in imaging. AB - Osteosarcoma is the classic malignant osteoid-forming bone tumor. The typical clinical presentation, histology, imaging findings, treatment, and prognosis for each subtype of osteosarcoma is provided. Particular emphasis is placed on more current magnetic resonance imaging and nuclear medicine imaging techniques that may soon improve the ability to determine the most appropriate therapy and ultimately improve patient survival. PMID- 23673545 TI - Current concepts in MRI of focal and diffuse malignancy of bone marrow. AB - Bone marrow is a ubiquitous component of musculoskeletal imaging studies. The ability to identify and characterize pathology accurately in the bone marrow can be challenging given the broad spectrum of imaging features of normal bone marrow. Knowledge regarding the ability to differentiate normal from abnormal marrow has been enhanced with MR imaging with numerous techniques available to aid in distinguishing benign from malignant lesions in the bone marrow. T1 weighted fast spin echo (FSE) and fluid-sensitive sequences, fat-saturated T2 weighted FSE, and short tau inversion recovery provide valuable tools for the evaluation of a focal bone marrow lesion. Gadolinium enhancement, chemical shift, diffusion-weighted, and MR spectroscopy imaging are additional tools available for focal bone marrow lesion evaluation. Whole-body MRI and fluorodeoxyglucose positron emission tomography-computed tomography have evolved to be useful studies for staging and monitoring of therapeutic response in whole-body imaging. The relative advantages and disadvantages of the whole-body techniques are reviewed for metastases, myeloma, and lymphoma. PMID- 23673546 TI - Current developments and recent advances in musculoskeletal tumor imaging. AB - The radiologic evaluation of musculoskeletal masses has changed dramatically within recent years. This article addresses the current developments and recent advances in musculoskeletal tumor imaging. We include new MR imaging techniques to better define anatomy, especially in difficult to image areas such as the chest wall and abdomen; the use of chemical shift imaging to separate hematopoietic marrow from pathologic marrow infiltration; as well as the use of diffusion and spectroscopy to help distinguish benign and malignant processes. We also briefly address dual-energy computed tomography and positron emission tomography imaging. Our intention is not to provide a comprehensive review of imaging techniques but to offer an update and perspective on current technology. PMID- 23673547 TI - Imaging of benign soft tissue tumors. AB - The evaluation of soft tissue tumors should be approached systematically, with careful assessment of the patient's age, clinical presentation, anatomical location of the mass, and MRI characteristics. The imaging evaluation of a suspected soft tissue mass begins with conventional radiography to exclude an underlying osseous lesion and assess for any lesional calcification. MRI is particularly useful in evaluating the signal intensity, enhancement pattern, and extent of soft tissue masses that can expand beyond fascial planes and involve the neurovascular bundle, joint, or bone. Among the common benign soft tissue tumors, a fairly definitive imaging diagnosis can be made in cases of lipoma, elastofibroma dorsi, hemangiomas, myositis ossificans, giant cell tumor of tendon sheath, and peripheral nerve sheath tumors. In the remaining cases, the differential diagnosis can be narrowed by knowing the patient's demographics and any associated syndromes, in conjunction with recognizing specific MRI features. Knowledge of the World Health Organization's tumor designations and the incidence of specific tumors based on patient age and anatomical location are vital tools for the interpreting radiologist. PMID- 23673548 TI - Current imaging and therapy of malignant soft tissue tumors and tumor-like lesions. AB - Soft tissue tumors are histologically classified based on the tissue type they reflect. MR and computed tomography imaging remains the mainstay for the evaluation of a soft tissue mass including guiding the biopsy to the most aggressive portion of the lesion, tumor staging, and evaluating local recurrence and metastatic disease. Although some lesions may be readily identified based on their imaging characteristics, many soft tissue tumors remain indeterminate and require biopsy for diagnosis of histologic type and lesion grade, factors that have an impact on therapeutic options and long-term disease-free survival.In this article we review the current literature regarding imaging and treatment of soft tissue lesions in the musculoskeletal system. Positron emission tomography and specialized MR techniques, such as spectroscopy and diffusion-weighted imaging, are useful in the diagnosis of high-grade soft tissue sarcomas, although imaging overlap exists with benign and low-grade sarcomas. These modalities are proving useful in primary tumor staging, evaluation of therapeutic response, and metastatic disease assessment. We also discuss the roles of percutaneous ablation in the treatment of focal disease and palliative pain control, and review current targeted cancer therapies. PMID- 23673549 TI - Benign synovial tumors and proliferative processes. AB - This article discusses several benign tumors and proliferative processes of the synovium including giant cell tumor of the tendon sheath, pigmented villonodular synovitis, synovial chondromatosis, lipoma arborescens, and synovial hemangioma, lipoma, and fibroma. We review the clinical features and imaging characteristics of each entity, with a special focus on the unique imaging findings that can enable a confident diagnosis or a limited differential diagnosis. PMID- 23673550 TI - Image-guided biopsy and treatment of musculoskeletal tumors. AB - This article reviews the basics of image-guided intervention of musculoskeletal neoplasms. Image-guided procedures are playing an ever-increasing role in the diagnosis, staging, and treatment of musculoskeletal tumors. The successful handling of these lesions necessitates a multidisciplinary approach, with the radiologist working closely with the orthopedic oncologic surgeon, medical oncologist, radiation oncologist, and pathologist to ensure that the procedure is performed in a way that maximizes the chance of definitive diagnosis and/or the treatment effect while minimizing potential complications. To accomplish these goals, the radiologist must be familiar with the indications and contraindications for any biopsy or treatment, effective procedure planning (e.g., selection of biopsy path, type of imaging guidance and biopsy needle, etc.), proper specimen handling, and potential treatment options such as thermal ablation or cement augmentation. Continued involvement after the procedure including follow-up to ensure that pathology is concordant with imaging-is also crucial. PMID- 23673551 TI - Primary osseous tumors of the spine. AB - Primary osseous spinal tumors are relatively rare in comparison with metastatic disease, myeloma, and lymphoma. Despite their rarity, the interpreting radiologist must be aware of the typical imaging features to provide appropriate diagnosis for guidance of clinical management. The age of occurrence, distribution longitudinally in the spine, and distribution axially within the vertebra combined with typical imaging appearances can help indicate the correct diagnosis. This article reviews the diagnostic features of benign and malignant primary bone spinal tumors. PMID- 23673552 TI - Musculoskeletal tumor imaging: an orthopedic oncologist perspective. AB - Imaging of a musculoskeletal tumor or lesion is vital for the proper diagnosis and treatment of a patient. There are critical questions for the orthopedic oncologist that musculoskeletal imaging should answer. Is the lesion demonstrating benign or malignant characteristics? Where are the vital structures located in relationship to the lesion? Are there any other regional metastases? Where should an image-guided or open biopsy be performed to allow for limb salvage? What surgical resection will allow adequate margins with the goal of preserving as much function as possible? Decisions regarding biopsies and surgical planning are ideally made by a collaborative discussion between the treating orthopedic oncologist and the radiologist. PMID- 23673553 TI - Rapid assessment of homogeneity and stability of amorphous solid dispersions by atomic force microscopy--from bench to batch. AB - PURPOSE: To verify the robustness and fundamental value of Atomic Force Microscopy (AFM) and AFM-based assays to rapidly examine the molecular homogeneity and physical stability of amorphous solid dispersions on Hot-Melt Extrudates. METHODS: Amorphous solid dispersions were prepared with a Hot-Melt Extruder (HME) and profiled by Raman Microscopy and AFM following a sequential analytical routine (Multi-Scale-Imaging-of-Miscibiliy (MIMix)). Extrudates were analyzed before and after incubation at elevated temperature and humidity. The data were compared with published results as collected on miniaturized melt models. The value of molecular phase separation rates for long term stability prediction was assessed. RESULTS: Data recorded on the extrudates are consistent with those published, and they can be compared side by side. Such direct data comparisons allow the identification of possible sources of extrudate heterogeneities. The surface roughness analysis of fracture-exposed interfaces is a novel quantitative way to trace on the nanometer scale the efficiencies of differently conducted HME-processes. Molecular phase separation rates are shown to be relevant for long term stability predictions. CONCLUSIONS: The AFM-based assessment of API:excipient combinations is a robust method to rapidly identify miscible and stable solid dispersions in a routine manner. It provides a novel analytical tool for the optimization of HME processes. PMID- 23673554 TI - The immunogenicity of polyethylene glycol: facts and fiction. AB - An increasing number of pegylated therapeutic proteins and drug targeting compounds are being introduced in the clinic. Pegylation is intended to increase circulation time and to reduce an immunogenic response. Recently however a number of publications have appeared claiming that the polyethylene glycol (PEG) moiety of these products in itself may be immunogenic and that the induced anti-PEG antibodies are linked to enhanced blood clearance and reduced efficacy of the products. A critical review of the literature shows that most, if not all assays for anti-PEG antibodies are flawed and lack specificity. Also the biological effects induced by anti-PEG antibodies lack the characteristics of a bona fide antibody reaction. Standardization of the anti-PEG assays and the development of reference sera are urgently needed. PMID- 23673555 TI - Cellular uptake mechanism and therapeutic utility of a novel peptide in targeted delivery of proteins into neuronal cells. AB - PURPOSE: The peptide-based delivery system constitutes a potent approach to overcome the limitations of drug delivery in vitro and in vivo. We recently proposed a novel peptide RDP, which enables brain-targeting delivery of proteins into neuronal cells. Here we investigate the possible internalization mechanism of RDP, and identify the therapeutic effects of functional proteins when linked with RDP in brain disease. METHODS: The RDP fusion proteins are produced through recombinant DNA technology, and cell culture is used to investigate the uptake mechanism of RDP and its fusion protein. Experimental Parkinson's disease (PD) model is prepared in mice by intra-striatal injection of 6-hydroxydopamine, and is tested by apomorphine- and amphetamine-induced rotation. RESULTS: The results suggest that the possible route for RDP cellular uptake might involve GABA receptor-dependent, clathrin-mediated endocytosis pathway. Additionally, the conjugate of RDP and glial cell-derived neurotrophic factor (GDNF) exhibits the neuroprotective effect in experimental PD animals, including reduction of apomorphine- and amphetamine-induced rotation following toxin administration. CONCLUSIONS: RDP may become an effective tool for the targeted delivery of proteins into brain for disease treatment. PMID- 23673556 TI - The co-delivery of oxaliplatin abrogates the immunogenic response to PEGylated siRNA-lipoplex. AB - PURPOSE: In vivo application of siRNA/PEGylated cationic liposome complex (lipoplex) is impeded by two main obstacles: cytokine responses and anti-PEG IgM responses to PEGylated siRNA-lipoplex. Here, we investigated whether co administration of oxaliplatin (l-OHP) abrogates the cytokine release and anti-PEG IgM production by PEGylated siRNA-lipoplex. METHODS: Free l-OHP was administered either simultaneously or 30 min prior to PEGylated siRNA-lipoplex administration, and cytokine response and anti-PEG IgM production were evaluated. In addition, the effect of the liposomal encapsulation of l-OHP on the immunogenic response of PEGylated siRNA-lipoplex was investigated. RESULTS: Simultaneous co administration of free l-OHP with PEGylated siRNA-lipoplex caused a significant reduction in anti-PEG IgM production, along with an increase in the cytokine response. Free l-OHP injected prior to the lipoplex injection, however, successfully reduced cytokine release and anti-PEG IgM response. Platination of siRNA by simultaneously administered free l-OHP might facilitate the dissociation of double-stranded siRNA to single-stranded siRNA, resulting in the inducement of a potent immuno-stimulation of siRNA via endosomal toll-like receptors (TLRs). On the other hand, encapsulation of l-OHP into the siRNA-lipoplex resulted in a reduction of both anti-PEG IgM production and cytokine responses. CONCLUSIONS: Our results suggest that, besides the expected therapeutic efficacy of co administration, encapsulation of l-OHP into the PEGylated siRNA-lipoplex has great potential for minimizing the immunostimulation of PEGylated siRNA-lipoplex, resulting in a safe, applicable, and compliant treatment regimen for sequential clinical administration. PMID- 23673557 TI - The benefit of intraperitoneal chemotherapy for the treatment of colorectal carcinomatosis. AB - The clinical practice of hyperthermic intraperitoneal chemoperfusion (HIPEC) for carcinomatosis has lacked preclinical justification. A standardized mouse model was created to evaluate the independent effects of intraperitoneal chemotherapy. Diffuse colorectal carcinomatosis was generated in mice prior to intraperitoneal lavage with mitomycin C (MMC) at clinically comparable dosing for variable lengths of time. Tumor volumes, MMC tissue concentrations and survival were measured in comparison to saline lavage and intravenous MMC. Magnetic resonance imaging revealed a direct correlation between tumor volume, MMC dose and exposure time and survival. Intravenous MMC demonstrated a rapid clearance from the blood, lower peritoneal tissue concentrations, less tumor growth inhibition and decreased survival compared to intraperitoneal administration. Intraperitoneal chemotherapy inhibited tumor growth independent of cytoreduction or hyperthermia, demonstrated improved peritoneal tissue concentration and was associated with increased survival. These data support the clinical utility of the intraperitoneal chemotherapy component of HIPEC. PMID- 23673559 TI - Cloning, chromosomal characterization and FISH mapping of the NAD(+)-dependent histone deacetylase gene sirtuin 5 in the mouse. AB - Sirtuin 5 (SIRT5) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, belonging to the silent information regulator 2 (Sir2) family of sirtuin histone deacetylases (sirtuins). The yeast Sir2 protein and its mammalian derivatives are important in epigenetic gene silencing, DNA repair and recombination, cell cycle, microtubule organization and in the regulation of aging. In mammals, 7 sirtuin isoforms have been identified to date of which three (SIRT3, SIRT4 and SIRT5) are localized in the mitochondria, which serve as the center of energy management and the initiation of cellular apoptosis. In the study presented herein, we report the genomic organization and chromosomal localization of the murine sirt5 gene. We have isolated and characterized the murine sirt5 genomic sequence, which spans a region of 24,449 bp and which has one single genomic locus. The murine sirt5 gene consists of 8 exons and encodes a 310-aa protein with a predictive mo-lecular weight of 34.1 kDa and an isoelectric point of 8.90. For the murine sirt5 gene only one single genomic locus has been identified. The gene has been localized to mouse chromosome 13A4 and is flanked by STS-marker 164522 (synonymous WI MRC-RH: 506859). PMID- 23673558 TI - Low BRAF and NRAS expression levels are associated with clinical benefit from DTIC therapy and prognosis in metastatic melanoma. AB - Metastatic melanoma is characterized by a poor response to chemotherapy. Furthermore, there is a lack of established predictive and prognostic markers. In this single institution study, we correlated mutation status and expression levels of BRAF and NRAS to dacarbazine (DTIC) treatment response as well as progression-free and overall survival in a cohort of 85 patients diagnosed with advanced melanoma. Neither BRAF nor NRAS mutation status correlated to treatment response. However, patients with tumors harboring NRAS mutations had a shorter overall survival (p < 0.001) compared to patients with tumors wild-type for NRAS. Patients having a clinical benefit (objective response or stable disease at 3 months) on DTIC therapy had lower BRAF and NRAS expression levels compared to patients progressing on therapy (p = 0.037 and 0.003, respectively). For BRAF expression, this association was stronger among patients with tumors wild-type for BRAF (p = 0.005). Further, low BRAF as well as NRAS expression levels were associated with a longer progression-free survival in the total population (p = 0.004 and <0.001, respectively). Contrasting low NRAS expression levels, which were associated with improved overall survival in the total population (p = 0.01), low BRAF levels were associated with improved overall survival only among patients with tumors wild-type for BRAF (p = 0.013). These findings indicate that BRAF and NRAS expression levels may influence responses to DTIC as well as prognosis in patients with advanced melanoma. PMID- 23673560 TI - Behavioral recovery from tetraparesis in a captive chimpanzee. AB - An adult male chimpanzee living in a captive social group at the Primate Research Institute of Kyoto University developed acute tetraparesis. He was paralyzed and received intensive care and veterinary treatment as previously reported in Miyabe Nishiwaki et al. (J Med Primatol 39:336-346, 2010). The behavioral recovery of the chimpanzee was longitudinally monitored using an index of upright posture between 0 and 41 months after the onset of tetraparesis. Four phases were identified during the course of behavioral recovery. During Phase 0 (0-13 months), the chimpanzee remained lying on his back during the absence of human caretakers. An increase in upright posture occurred in Phase I (14-17 months), then remained at a stable level of around 50-70 % in Phase II (18-29 months). During Phases I and II, the subject's small treatment cage represented a spatial limitation. Thus, behavioral recovery was mainly mediated by arm muscle strengthening caused by raising the body trunk with the aid of materials attached to the cage walls as environmental enrichment. When the chimpanzee was moved to a larger rehabilitation room in Phase III (30-41 months), the percentage of upright posture constantly exceeded 80 %, except in the 40th month when he injured his ankle and was inactive for several days. The enlargement of the living space had a positive effect on behavioral recovery by increasing the types of locomotion exhibited by the subject, including the use of legs during walking. Rehabilitation works were applied in face-to-face situations which enabled the use of rehabilitation methods used in humans. The process of behavioral recovery reported in this study provides a basic data set for planning future rehabilitation programs and for comparisons with further cases of physical disability in non-human primates. PMID- 23673561 TI - 20m. PMID- 23673563 TI - Expansion abdominoplasty for a pregnant woman with severe abdominal wall contracture due to a major burn during childhood: a case report. AB - Normal abdominal expansion that occurs as a result of hormonal actions during pregnancy may be prevented by the presence of excessive scar tissue in individuals who have received severe burns. In these instances, the lack of abdominal expansion may cause maternal pain and put the infant at risk. A 23-year old pregnant woman presented with severe abdominal wall contracture due to a major burn sustained during childhood. At 20 weeks of pregnancy, expansion abdominoplasty, consisting of zigzag incisions in the fascia to release the contracture and a split-thickness skin graft, was performed. The patient gave birth, via a planned cesarean operation at 36 weeks of pregnancy, to a baby girl in good condition; the postpartum course was uneventful. PMID- 23673564 TI - A nationwide review of the treatment patterns of traumatic thumb amputations. AB - Traumatic thumb amputations are a common problem with significant associated cost to patients, hospitals, and society.The purpose of this study was to review practice patterns for traumatic thumb amputations using the National Trauma Data Bank. By using a large nationwide database, we hoped to better understand the epidemiology and predictors of attempts and successful replantation.The design was a retrospective review of the National Trauma Data Bank between the years 2007 and 2010, investigating patients with traumatic thumb amputations. Analyses of these patients based on replantation attempt, mechanism of injury, and demographics were performed. Comparisons were made between hospitals based on teaching status and on patient volume for replant attempt and success rates.There were 3341 traumatic thumb amputations with 550 (16.5%) attempts at replantation and an overall success rate of 84.9%. Nonteaching hospitals treated 1238 (37.1%) patients, and attempted 123 (9.9%) replantations with a success rate of 80.5%. Teaching hospitals treated 2103 (63.0%) patients, and attempted 427 (20.3%) replantations with a success rate of 86.2%. Being in a teaching hospital increased the odds of attempted replantation by a factor of 3.1 (P < 0.001) when compared to a nonteaching hospital. Treatment at a high-volume center increased the rate of attempted replantation by a factor of 3.4 (P < 0.001), as compared to low-volume hospitals.Practice patterns show that teaching and high-volume hospitals attempt to replant a higher percentage of amputated thumbs. Success rates are similar across practice settings. PMID- 23673565 TI - Surgical treatment of superimposed, lower extremity, peripheral nerve entrapments with diabetic and idiopathic neuropathy. AB - BACKGROUND: Although it is recognized that people with peripheral neuropathy have an increased prevalence of chronic nerve entrapment, controversy still exists over their management. The present report details the evaluation, surgical approach, and outcome of a large cohort of people with diabetic and with idiopathic neuropathy. METHODS: A retrospective review of 158 consecutive patients, 96 with diabetic and 62 with idiopathic neuropathy, was done to analyze the results of neurolysis of multiple sites of chronic nerve compression in the lower extremity. Of these patients, 50 had a contralateral limb decompressed for a total of 208 limbs included in the study. Outcomes included visual analog scale (VAS) for pain in the 109 patients who had pain level greater than 8.0, measurement of the cutaneous pressure threshold for sensibility, self-reported change in pain medication usage, and self-reported change in balance. RESULTS: With a minimum follow-up of 1 year, 88% of patients with preoperative numbness reported improvement in sensation (P < 0.001). Of the 84 patients with impaired balance, 81% reported improvement in balance. Of those whose VAS was greater than 8, 83% reported an improvement in VAS (P < 0.001). There was a concomitant reduction in pain medication usage. There was no difference in outcomes between patients with diabetic versus idiopathic neuropathy in response to nerve decompression. CONCLUSIONS: Neurolysis of lower extremity chronic nerve compressions in patients with neuropathy and superimposed nerve compressions is an effective method for relieving pain, restoring sensation, and improving balance. PMID- 23673566 TI - Recent trends in resident career choices after plastic surgery training. AB - The purpose of this study is to determine the initial career choice of plastic surgery residents after completion of training during the last five years and to identify any factors that may influence choice of career path. Demographic data were obtained from graduates of Accreditation Council for Graduate Medical Education (ACGME)-accredited US plastic surgery residency programs between the years of 2005 and 2010. The type of practice and pursuit of fellowship were recorded for each graduate. Sex, age at graduation, marital status, dependents, advanced degrees, previous research, type of training program, primary residency, and length of plastic surgery training were also documented. Comparison of outcomes between the two plastic surgery training pathways (integrated vs independent) was analyzed. Data were collected for 424 graduates from 37 different training programs. Of these programs, 11% were from the West coast, 32% from Midwest, 33% from East coast, and 24% from the South. Seventy-nine percent of residents were male, mean age at graduation was 35 (2.89) years. Forty-nine percent of residents were married, 30% had one or more dependents, 6% had advanced degrees, and 18% had previous research experience. Fifty-eight percent of graduates were from independent programs. Forty-eight percent of residents pursued private practice immediately after graduation, 8% pursued academic practice, 41% pursued specialty fellowships, and 3% had military commitments. Most of the residents chose to pursue private practice on completion of residency. Independent residents were significantly more likely to pursue private practice immediately compared to integrated/combined residents. No other factors were significant for practice choice. PMID- 23673567 TI - The plastic surgery match: predicting success and improving the process. AB - Plastic surgery continues to be a very competitive program to match into out of medical school. To analyze the match process, all applicants to our plastic surgery residency program in 2012 were surveyed. Our results showed that with matching into plastic surgery as the primary outcome measure, those who matched applied to more plastic surgery programs, received and accepted more interview invitations, were younger, were less likely to be foreign medical graduates, reported higher costs, had higher Step 1 and Step 2 scores, were more likely to be an Alpha Omega Alpha member, and conducted more research. In addition to looking at variables that affected the success of the match, other questions regarding the match process were posed. Most interestingly, 10% of applicants still reported violations of the match communication guidelines. Furthermore, the mean cost of interviewing for the plastic surgery match was $6073.In summary, applicants with diversified strengths had the best chance of matching. On the basis of the results of this study, applicants should attend a large number of interviews to optimize their match success. With medical student debt a growing problem, programs need to find ways to control interview costs. Residency program compliance with match communication guidelines has improved, but compliance should be universal. With these data, applicants can be better prepared for the match to optimize their success and programs can work to improve the match process. PMID- 23673568 TI - Management of zygomatic fractures. PMID- 23673570 TI - Cross-validation and evaluation of the performance of methods for the elemental analysis of forensic glass by MU-XRF, ICP-MS, and LA-ICP-MS. AB - Elemental analysis of glass was conducted by 16 forensic science laboratories, providing a direct comparison between three analytical methods [micro-x-ray fluorescence spectroscopy (MU-XRF), solution analysis using inductively coupled plasma mass spectrometry (ICP-MS), and laser ablation inductively coupled plasma mass spectrometry]. Interlaboratory studies using glass standard reference materials and other glass samples were designed to (a) evaluate the analytical performance between different laboratories using the same method, (b) evaluate the analytical performance of the different methods, (c) evaluate the capabilities of the methods to correctly associate glass that originated from the same source and to correctly discriminate glass samples that do not share the same source, and (d) standardize the methods of analysis and interpretation of results. Reference materials NIST 612, NIST 1831, FGS 1, and FGS 2 were employed to cross-validate these sensitive techniques and to optimize and standardize the analytical protocols. The resulting figures of merit for the ICP-MS methods include repeatability better than 5% RSD, reproducibility between laboratories better than 10% RSD, bias better than 10%, and limits of detection between 0.03 and 9 MUg g(-1) for the majority of the elements monitored. The figures of merit for the MU-XRF methods include repeatability better than 11% RSD, reproducibility between laboratories after normalization of the data better than 16% RSD, and limits of detection between 5.8 and 7,400 MUg g(-1). The results from this study also compare the analytical performance of different forensic science laboratories conducting elemental analysis of glass evidence fragments using the three analytical methods. PMID- 23673569 TI - In situ NMR spectroelectrochemistry for the structure elucidation of unstable intermediate metabolites. AB - In situ NMR spectroelectrochemistry is presented in this study as a useful hybrid technique for the chemical structure elucidation of unstable intermediate species. An experimental setting was designed to follow the reaction in real time during the experimental electrochemical process. The analysis of (1)H NMR spectra recorded in situ permitted us (1) to elucidate the reaction pathway of the electrochemical oxidation of phenacetin and (2) to reveal the quinone imine as a reactive intermediate species without using any trapping reaction. Phenacetin has been considered as hepatotoxic at high therapeutic amounts, which is why it was chosen as a model to prove the applicability of the analytical method. The use of 1D and 2D NMR experiments led to the elucidation of the major species produced from the oxidation process. We demonstrated that in situ NMR spectroelectrochemistry constitutes a fast way for monitoring unstable quinone imines and elucidating their chemical structures. PMID- 23673571 TI - Amino acid analysis of dried blood spots for diagnosis of phenylketonuria using capillary electrophoresis-mass spectrometry equipped with a sheathless electrospray ionization interface. AB - We describe a capillary electrophoresis-mass spectrometry (CE-MS) method for newborn screening of a representative amino acid metabolic disease, namely, phenylketonuria (PKU). Underivatized phenylalanine and tyrosine in a dried blood spot (DBS) were simultaneously determined by CE-MS equipped with an ionophore membrane-packed sheathless electrospray ionization interface, which was developed by our group. The method was optimized for rapid determination of the underivatized amino acids, phenylalanine and tyrosine extracted from a DBS. Under the optimized conditions, the limit of detection of phenylalanine and tyrosine (signal-to-noise ratio, 3) was 0.03 and 0.07 mg/L in DBS, respectively, with a CE run time of less than 3 min. For repeated runs of a sample, coefficients of variation (CVs) for migration time were less than 3.7%, whereas CVs for the area ratio under the curve were 2.1 and 2.9% for 20 consecutive runs of 49.5 mg/kg Phe and 36.2 mg/kg Tyr, respectively. However, the relative standard deviations of intra- and interday assays for DBS samples were <6.2 and <5.8%, respectively, which were substantially due to sample extraction from DBS. The analytical method was applied to real clinical samples of Korean neonates, and results were compared with those of conventional methods for PKU diagnosis, which required reference analytical methods such as isotope dilution CE-MS or high-performance liquid chromatography-mass spectrometry for quality assurance of the conventional kit-based assays. The distinct advantages of high sensitivity and extremely low sample volume, as well as a simple, easy, and economic sample pretreatment, were demonstrated for the proposed method. PMID- 23673572 TI - Shear-wave elastography in the diagnosis of solid breast masses: what leads to false-negative or false-positive results? AB - OBJECTIVE: To investigate the factors that have an effect on false-positive or false-negative shear-wave elastography (SWE) results in solid breast masses. METHODS: From June to December 2012, 222 breast lesions of 199 consecutive women (mean age: 45.3 +/- 10.1 years; range, 21 to 88 years) who had been scheduled for biopsy or surgical excision were included. Greyscale ultrasound and SWE were performed in all women before biopsy. Final ultrasound assessments and SWE parameters (pattern classification and maximum elasticity) were recorded and compared with histopathology results. Patient and lesion factors in the 'true' and 'false' groups were compared. RESULTS: Of the 222 masses, 175 (78.8 %) were benign, and 47 (21.2 %) were malignant. False-positive rates of benign masses were significantly higher than false-negative rates of malignancy in SWE patterns, 36.6 % to 6.4 % (P < 0.001). Among both benign and malignant masses, factors showing significance among false SWE features were lesion size, breast thickness and lesion depth (all P < 0.05). All 47 malignant breast masses had SWE images of good quality. CONCLUSIONS: False SWE features were more significantly seen in benign masses. Lesion size, breast thickness and lesion depth have significance in producing false results, and this needs consideration in SWE image acquisition. KEY POINTS: * Shear-wave elastography (SWE) is widely used during breast imaging * At SWE, false-positive rates were significantly higher than false-negative rates * Larger size, breast thickness, depth and fair quality influences false-positive SWE features * Smaller size, larger breast thickness and depth influences false-negative SWE features. PMID- 23673573 TI - Digital breast tomosynthesis versus mammography and breast ultrasound: a multireader performance study. AB - OBJECTIVES: To compare the diagnostic performance of single-view breast tomosynthesis (BT) with that of dual-view mammography (MX); to assess the benefit of adding the craniocaudal (CC) mammographic view to BT, and of adding BT to MX plus breast ultrasound, considered to be the reference work-up. METHODS: One hundred and fifty-five consenting patients with unresolved mammographic and/or ultrasound findings or breast symptoms underwent conventional work-up plus mediolateral oblique-view BT of the affected breast. The final study set in 130 patients resulted in 55 malignant and 76 benign and normal cases. Seven breast radiologists rated the cases through five sequential techniques using a BIRADS based scale: MX, MX + ultrasound, MX + ultrasound + BT, BT, BT + MX(CC). Multireader, multicase receiver operating characteristic (ROC) analysis was performed and performance of the techniques was assessed from the areas under ROC curves. The performance of BT and of BT + MX(CC) was tested versus MX; the performance of MX + ultrasound + BT tested versus MX + ultrasound. RESULTS: Tomosynthesis was found to be non-inferior to mammography. BT + MX(CC) did not appear to be superior to MX, and MX + ultrasound + BT not superior to MX + ultrasound. CONCLUSIONS: Overall, none of the five techniques tested outperformed the others. Further clinical studies are needed to clarify the role of BT as a substitute for traditional work-up in the diagnostic environment. KEY POINTS: * Digital breast tomosynthesis is a new adjunct to mammography and breast ultrasound. * We compared the diagnostic performance of these investigations in an experimental observer study. * Single-view breast tomosynthesis was confirmed as non-inferior to dual-view mammography. * None of the investigations (or combinations) tested outperformed the others. * Further prospective studies are needed to clarify precise role of tomosynthesis for diagnostic application. PMID- 23673574 TI - Stiffness of tumours measured by shear-wave elastography correlated with subtypes of breast cancer. AB - OBJECTIVE: To evaluate the correlation between stiffness values obtained by shear wave elastography (SWE) and breast cancer subtypes. METHODS: This was an institutional review board-approved retrospective study with a waiver of informed consent. The stiffness of 337 invasive breast cancers in 337 women was evaluated by SWE and mean stiffness values (kPa) and qualitative colour scores (1-5) of tumours were obtained. The results were analysed according to BI-RADS category, tumour size, grade and tumour subtype (triple-negative [TN], human epidermal growth factor receptor 2 [HER2]-positive, and oestrogen receptor [ER]-positive) using a multiple linear regression analysis. RESULTS: The mean stiffness values and colour scores were: 146.8 kPa +/- 57.0 and 4.1 +/- 1.1; 165.8 kPa +/- 48.5 and 4.6 +/- 0.7 for TN tumours (n = 64), 160.3 kPa +/- 56.2 and 4.3 +/- 1.0 for HER2-positive tumours (n = 55) and 136.9 kPa +/- 57.2 and 4.0 +/- 1.1 for ER positive tumours (n = 218; P < 0.0001). All three breast cancers classified as BI RADS category 3 on B-mode ultrasound were TN subtype. A multiple linear regression analysis revealed that tumour size, histological grade and tumour subtype were independent factors that influenced the stiffness values. CONCLUSION: High stiffness values correlated with aggressive subtypes of breast cancer. KEY POINTS: * Shear-wave elastography is increasingly used to measure the stiffness of breast tumours. * Triple-negative and HER2-positive tumours showed greater stiffness than ER-positive tumours. * All breast cancers classified as BI RADS 3 on B-mode ultrasound were triple-negative subtype. * Tumour size, histological grade and subtype were independent factors influencing SWE stiffness. PMID- 23673575 TI - Layered double hydroxide-based catalysts: nanostructure design and catalytic performance. AB - Layered double hydroxides (LDHs) are a class of clays with brucite-like layers and intercalated anions which have attracted increasing interest in the field of catalysis. Benefiting from the atomic-scale uniform distribution of metal cations in the brucite-like layers and the ability to intercalate a diverse range of interlayer anions, LDHs display great potential as precursors/supports to prepare catalysts, in that the catalytic sites can be preferentially orientated, highly dispersed, and firmly stabilized to afford excellent catalytic performance and recyclability. The approaches to prepare catalysts based on LDH materials include, but are not limited to, exfoliation of the brucite-like layers, lattice orientation/lattice confinement by the brucite-like layers, and intercalation. This Feature Article summarizes the latest developments in the design and preparation of nanocatalysts by using LDHs as precursors/supports. PMID- 23673576 TI - The fine things on earth. PMID- 23673578 TI - Climate change: should family physicians and family medicine organizations pay attention? PMID- 23673579 TI - Uranium mining and health. PMID- 23673580 TI - Adverse health effects of industrial wind turbines. PMID- 23673581 TI - The waiting room "wait": from annoyance to opportunity. PMID- 23673583 TI - Recreational water-related illness: office management and prevention. AB - OBJECTIVE: To review the risk factors, management, and prevention of recreational water-related illness in family practice. SOURCES OF INFORMATION: Original and review articles from January 1998 to February 2012 were identified using PubMed and the search terms water-related illness, recreational water illness, and swimmer illness. MAIN MESSAGE: There is a 3% to 8% risk of acute gastrointestinal illness (AGI) after swimming. The high-risk groups for AGI are children younger than 5 years, especially if they have not been vaccinated for rotavirus, and elderly and immunocompromised patients. Children are at higher risk because they swallow more water when swimming, stay in the water longer, and play in the shallow water and sand, which are more contaminated. Participants in sports with a lot of water contact like triathlon and kite surfing are also at high risk, and even activities involving partial water contact like boating and fishing carry a 40% to 50% increase in risk of AGI compared with nonwater recreational activities. Stool cultures should be done when a recreational water illness is suspected, and the clinical dehydration scale is a useful clinical tool for assessing the treatment needs of affected children. CONCLUSION: Recreational water illness is the main attributable cause of AGI during swimming season. Recognition that swimming is a substantial source of illness can help prevent recurrent and secondary cases. Rotavirus vaccine is highly recommended for children who will swim frequently. PMID- 23673584 TI - Tdap vaccination during pregnancy to reduce pertussis infection in young infants. AB - QUESTION: What is the basis for the new recommendations to vaccinate pregnant women against pertussis after the first trimester? ANSWER: There have been outbreaks of epidemic proportions of pertussis, mostly among young infants who have not received sufficient passive immunity from their mothers. This strategy of vaccination during pregnancy aims at stopping these life-threatening epidemics. PMID- 23673585 TI - Pacifier use in the first month of life. AB - QUESTION: As a family physician who frequently attends deliveries and follows up with neonates, parents often ask me if they can provide their newborns with pacifiers in order to calm infants down, reduce crying, and improve sleep. Is pacifier use safe in the first month of life? ANSWER: While pacifiers are useful for soothing, there is concern that their use might cause early weaning of breastfeeding owing to "nipple confusion." Several organizations, such as the World Health Organization and the United Nations Children's Fund, recommend avoiding use of pacifiers in term infants who breastfeed. However, evidence suggests that it might not be pacifier use that causes premature cessation of breastfeeding, and that use of pacifiers might only be a sign of a maternal decision to stop breastfeeding. PMID- 23673586 TI - Vitamins for age-related macular degeneration demonstrate minimal differences. PMID- 23673587 TI - Rheumatoid arthritis and atypical cardiovascular disease: inflammation changing the clinical presentation. PMID- 23673588 TI - Anoscopy. PMID- 23673589 TI - Dermacase. Can you identify this condition? Median canaliform nail dystrophy. PMID- 23673590 TI - Risk assessment for physical activity and exercise clearance: in pregnant women without contraindications. PMID- 23673591 TI - Effects of continuing professional development on clinical performance: results of a study involving family practitioners in Quebec. AB - OBJECTIVE: To evaluate the link between the quantity and quality of continuing professional development (CPD) activities completed by family physicians in Quebec and the quality of their practice. DESIGN: Retrospective analysis of data collected during professional inspection visits (PIVs). SETTING: Quebec. PARTICIPANTS: Three groups were created from among Quebec family physicians who had been subject to PIVs (peer evaluation) by the College des medecins du Quebec between 1998 and 2005. Group 1 was composed of physicians who were members of the College of Family Physicians of Canada, which requires participation in 250 hours of CPD in every 5-year cycle. Group 2 was composed of family physicians who were not members of the College of Family Physicians of Canada but who had declared at least 50 hours a year of CPD on their College des medecins du Quebec annual notice of assessment for the same period. Group 3 was composed of family physicians who had declared fewer than 10 hours of CPD a year. MAIN OUTCOME MEASURES: During the PIV, the following characteristics were examined: record keeping, quality and number of hours of CPD activities, and quality of professional practice based on 3 components- clinical investigation, accuracy of diagnosis, and appropriateness of treatment plan and follow-up. RESULTS: The factors associated with a high quality of practice were privileges in a hospital or local community health centre (institution) and a substantial number of accredited CPD hours (Mainpro-M1, Credit I, or Mainpro-C). The factors associated with a poor quality of practice were advanced age of the physician, absence of privileges in an institution (hospital or local community health centre), and participation in CPD activities that were more informal, such as reading and non accredited activities (Mainpro-M2). CONCLUSION: This study supports earlier research showing that CPD activities of sufficient quality and quantity are correlated with a high quality of professional practice by family physicians. PMID- 23673592 TI - With warm hearts and strong wills: hospital volunteering in Japan. PMID- 23673593 TI - Kathleen Ross MSc MD. PMID- 23673594 TI - Embracing the wild: conceptualizing wilderness medicine in Canada. PMID- 23673595 TI - On the road to the future: CFPC strategic plan 2013 to 2017. PMID- 23673598 TI - "Generational" malaise. PMID- 23673603 TI - Effect of a course-based intervention and effect of medical regulation on physicians' opioid prescribing. AB - OBJECTIVE: To examine the effects of an intensive 2-day course on physicians' prescribing of opioids. DESIGN: Population-based retrospective observational study. SETTING: College of Physicians and Surgeons of Ontario (CPSO) in Toronto. PARTICIPANTS: Ontario physicians who took the course between April 1, 2000, and May 30, 2008. INTERVENTION: A 2-day opioid-prescribing course with a maximum of 12 physician participants. Educational methods included didactic presentations, case discussions, and standardized patients. A detailed syllabus and office materials were provided. MAIN OUTCOME MEASURES: Participants were matched with control physicians using specific variables. The primary outcome was the rate of opioid prescribing, expressed as milligrams of morphine equivalent per quarter. RESULTS: One hundred thirty-eight course participants (120 family physicians, 15 specialists, and 3 physicians whose status was uncertain) were eligible for analysis. Of these, 68.1% were self-referred and 31.9% were referred by the CPSO. Overall, among physicians referred by the CPSO, the rate of opioid prescribing decreased dramatically in the year before course participation compared with matched control physicians. The course had no added effect on the rate of physicians' opioid prescribing in the subsequent 2 years. There was no statistically significant effect on the rate of opioid prescribing observed among the self-referred physicians. Among 15 of the self-referred physicians who, owing to the high quantities of opioids they prescribed, were not matched with control physicians, the rate of opioid prescribing decreased by 43.9% in the year following course completion. CONCLUSION: Physicians markedly reduced the quantities of opioids they prescribed after medical regulators referred them to an opioid-prescribing course. The course itself did not lead to significant additional reductions; however, a subgroup of physicians who prescribed high quantities of opioids might have responded to what was taught in the course. PMID- 23673604 TI - Laboratory test use and primary care physician supply. AB - OBJECTIVE: To determine the relative effects of population size, FP and GP supply, and other specialist supply on chemistry and hematology test volumes (ie, number of tests performed). DESIGN: Population-level analysis using secondary data from the Calgary Health Zone for 2004 to 2009. SETTING: Calgary, Alta. MAIN OUTCOME MEASURES: The relative effects of population size, FP and GP supply, and other specialist supply on laboratory test use. RESULTS: Population size was the strongest predictor of test volumes in a multivariate analysis. The FP and GP supply was significantly negatively correlated with chemistry test volume (partial r(2) = 0.186, P = .045). There was a trend toward decreasing use of hematology tests with increasing FP and GP supply (partial r(2) = 0.117, P = .119). CONCLUSION: The relationship between FP and GP supply and laboratory test use is complex, but increasing numbers of FPs do not necessarily indicate an increase in laboratory test use and might be associated with a decrease in test use when other factors are controlled for. PMID- 23673607 TI - Vitamin D insufficiency and bone mineral status in a population of newcomer children in Canada. AB - BACKGROUND: Low levels of circulating vitamin D are more likely to be found in those with darker skin pigmentation, who live in areas of high latitude, and who wear more clothing. We examined the prevalence of vitamin D deficiency and inadequacy in newcomer immigrant and refugee children. METHODS: We evaluated circulating vitamin D status of immigrant children at the national level. Subsequently, we investigated vitamin D intake, circulating vitamin D status, and total body bone mineral content (TBBMC) in newcomer children living in Saskatchewan. RESULTS: In the sample of newcomer children in Saskatchewan, the prevalence of inadequacy in calcium and vitamin D intakes was 76% and 89.4%, respectively. Vitamin D intake from food/supplement was significantly higher in immigrants compared to refugees, which accords with the significant difference in serum status. Circulating vitamin D status indicated that 29% of participants were deficient and another 44% had inadequate levels of serum 25(OH)D for bone health. Dietary vitamin D intake, sex, region of origin, and length of stay in Canada were significant predictors of serum vitamin D status. RESULTS for TBBMC revealed that 38.6% were found to have low TBBMC compared to estimated values for age, sex, and ethnicity. In the regression model, after controlling for possible confounders, children who were taller and had greater circulating vitamin D also had greater TBBMC. Nationally, immigrant children, particularly girls, have significantly lower plasma 25(OH)D than non-immigrant children. INTERPRETATION: Newcomer immigrant and refugee children are at a high risk of vitamin D deficiency and inadequacy, which may have serious negative consequences for their health. PMID- 23673608 TI - Chocolate in history: food, medicine, medi-food. AB - Throughout history, chocolate has been used to treat a wide variety of ailments, and in recent years, multiple studies have found that chocolate can have positive health effects, providing evidence to a centuries-long established use; this acknowledgement, however, did not have a straight course, having been involved in religious, medical and cultural controversies. Christian Europe, in fact, feared the exhilarating effects of new drinks, such as chocolate, coffee and tea. Therefore, these beverages would have been banished, had not doctors and scientists explained that they were good for the body. The scientific debate, which reached its peak in Florence in the 18th century, regarded the therapeutic effectiveness of the various chocolate components: it was necessary to know their properties first, in order to prepare the best cacao concoction for every patient. When Dietetics separated from Medicine, however, chocolate acquired the role of vehicle for easing the administration of bitter medicines, being associated to different health problems. The recent rediscovery of the beneficial use of cacao and chocolate focuses upon its value as supplemental nutrition. Building a bridge to the past may be helpful to detect the areas where the potential health benefits of chocolate are likely to be further explored. PMID- 23673609 TI - Zn(x)Cd(1-x)Se nanomultipods with tunable band gaps: synthesis and first principles calculations. AB - In this paper, we demonstrate that ZnxCd1-xSe nanomultipods can be synthesized via a facile and nontoxic solution-based method. Interesting aspects of composition, morphology and optical properties were deeply explored. The value of Zn/(Zn+Cd) could be altered across the entire range from 0.08 to 0.86 by varying the ratio of cation precursor contents. The band gap energy could be linearly tuned from 1.88 to 2.48 eV with respect to the value of Zn/(Zn+Cd). The experiment also showed that oleylamine played a dominant role in the formation of multipod structure. A possible growth mechanism was further suggested. First principles calculations of band gap energy and density of states in the Vienna ab initio simulation package code were performed to verify the experimental variation tendency of the band gap. Computational results indicated that dissimilarities of electronic band structures and orbital constitutions determined the tunable band gap of the as-synthesized nanomultipod, which might be promising for versatile applications in relevant areas of solar cells, biomedicine, sensors, catalysts and so on. PMID- 23673610 TI - A novel paradigm reveals the role of reentrant visual processes in object substitution masking. AB - Object substitution masking (OSM) occurs when an initial display of a target and mask continues with the mask alone, creating a mismatch between the reentrant hypothesis, triggered by the initial display, and the ongoing low-level activity. We tested the proposition that the critical factor in OSM is not whether the mask remains in view after target offset, but whether the representation of the mask is sufficiently stronger than that of the target when the reentrant signal arrives. In Experiment 1, a variable interstimulus interval (ISI) was inserted between the initial display and the mask alone. The trailing mask was presumed to selectively boost the strength of the mask representation relative to that of the target. As predicted, OSM occurred at intermediate ISIs, at which the mask was presented before the arrival of the reentrant signal, creating a mismatch, but not at long ISIs, at which a comparison between the reentrant signal and the low level activity had already been made. Experiment 2, conducted in dark-adapted viewing, ruled out the possibility that low-level inhibitory contour interactions (metacontrast masking) had played a significant role in Experiment 1. Metacontrast masking was further ruled out in Experiment 3, in which the masking contours were reduced to four small dots. We concluded that OSM does not depend on extended presentation of the mask alone, but on a mismatch between the reentrant signals and the ongoing activity at the lower level. The present results place constraints on estimates of the timing of reentrant signals involved in OSM. PMID- 23673611 TI - Sensory memory of structure-from-motion is shape-specific. AB - Perceptual priming can stabilize the phenomenal appearance of multistable visual displays (Leopold, Wilke, Maier, & Logothetis, Nature Neuroscience, 5, 605-609, 2002). Prior exposure to such displays induces a sensory memory of their appearance, which persists over long intervals and intervening stimulation, and which facilitates renewed perception of the same appearance. Here, we investigated perceptual priming for the apparent rotation in depth of ambiguous structure-from-motion (SFM) displays. Specifically, we generated SFM objects with different three-dimensional shapes and presented them in random order and with intervening blank periods. To assess perceptual priming, we established the probability that a perceived direction of rotation would persist between successive objects. In general, persistence was greatest between identical objects, intermediate between similar objects, and negligible between dissimilar objects. These results demonstrate unequivocally that sensory memory for apparent rotation is specific to three-dimensional shape, contrary to previous reports (e.g., Maier, Wilke, Logothetis, & Leopold, Current Biology, 13, 1076-1085, 2003). Because persistence did not depend on presentation order for any pair of objects, it provides a commutative measure for the similarity of object shapes. However, it is not clear exactly which features or aspects of object shape determine similarity. At least, we did not find simple, low-level features (such as volume overlap, heterogeneity, or rotational symmetry) that could have accounted for all observations. Accordingly, it seems that sensory memory of SFM (which underlies priming of ambiguous rotation) engages higher-level representations of object surface and shape. PMID- 23673612 TI - Structural specificity of alkoxy radical formation in crystalline carbohydrates. AB - A DFT study of radiation induced alkoxy radical formation in crystalline alpha-l rhamnose has been performed to better understand the processes leading to selective radical formation in carbohydrates upon exposure to ionizing radiation at low temperatures. The apparent specificity of radiation damage to carbohydrates is of great interest for understanding radiation damage processes in the ribose backbone of the DNA molecule. Alkoxy radicals are formed by deprotonation from hydroxyl groups in oxidized sugar molecules. In alpha-l rhamnose only one alkoxy radical is observed experimentally even though there are four possible sites for alkoxy radical formation. In the present work, the origin of this apparently specific action of radiation damage is investigated by computationally examining all four possible deprotonation reactions from oxygen in the oxidized molecule. All calculations are performed in a periodic approach and include estimates of the energy barriers for the deprotonation reactions using the Nudged Elastic Band (NEB) method. One of the four possible radical sites is ruled out due to the lack of a suitable proton acceptor. For the other three possible sites, the reaction paths and energy profiles from primary cationic radicals to stable, neutral alkoxy radicals are compared. It is found that deprotonation from one site (corresponding to the experimentally observed radical) differs from the others in that the reaction path is less energy demanding. Hence, it is suggested that the alkoxy radical formation is not necessarily site specific, but that the observed radical is formed in much greater abundance than the others due to the different energetics of the processes and reaction products. PMID- 23673613 TI - Erythrocyte membrane properties in patients with essential hypertension. AB - In spite of the extensive research efforts that have been conducted over the last decades, it is still very difficult to point out genetic determinants or environmental conditions responsible for the development of essential hypertension. We searched for differences in the RBC membrane skeleton structure and O2 membrane permeability between RBCs from patients with both essential arterial hypertension and hypercholesterolemia, from patients having only hypercholesterolemia and from healthy donors. The topography of RBCs and the content of various hemoglobin forms were detected using atomic force microscopy and Mossbauer spectroscopy, respectively. We found that the membrane skeleton of RBCs from healthy donors displayed a well-known honeycomb pattern, whereas in patients with essential hypertension and/or hypercholesterolemia, who had never received anti-hypertensive therapy, it displayed a corncob pattern. Hypertensive RBCs had an oval shape and the average lateral to longitudinal diameter ratio for the changed cells (about 70%) did not exceed 0.80. We observed that after the incubation of RBCs under high nitrogen (low O2) pressure at room temperature and then their transfer into 85 K, a content of oxyHb (deoxyHbOH) already after 1 h reached a stable level of about 85 +/- 3% (15 +/- 3%) in hypertensives, whereas in healthy individuals it showed a decrease for deoxyHbOH and an increase for oxyHb, which stabilized at a level of about 81 +/- 5% and 19 +/- 5%, respectively, only after 9 h. Quantitative analysis of the Delta(oxyHb) change estimated as the difference between the oxyHb level measured after 9 and 2 h at 85 K under low N2 pressure (to slow down oxyHb formation) was significantly higher in normotensives than in hypertensive patients with or without hypercholesterolemia, 19.9 versus -4.2, p < 0.02. Our findings indicate an impaired oxygen release by Hb in RBCs of patients with hypertension under low oxygen pressure which if present in vivo may cause hypoxemia and, in turn, further increase of blood pressure. PMID- 23673614 TI - In-peptide synthesis of di-oxazolidinone and dehydroamino acid-oxazolidinone motifs as beta-turn inducers. AB - Small and easy-to-do mimetics of beta-turns are of great interest to interfere with protein-protein recognition events mediated by beta-turn recognition motifs. We propose a straightforward procedure for constraining the conformation of tetrapeptides lacking a pre-formed scaffold. According to the stereochemistry array, N-Ts tetrapeptides including Thr or PhSer (phenylserine) at the positions 2 or 3 gave rise in a single step to the sequences Oxd(2)-Oxd(3) or DeltaAbu(2) Oxd(3) (Oxd, oxazolidin-2-one; DeltaAbu, 2,3-dehydro-2-aminobutyric). These pseudo-Pro residues displayed highly constrained phi, psi, and chi dihedral angles, and induced clear beta-turns or inverse turns of type I or II, as determined by extensive spectroscopic and computational analyses. PMID- 23673616 TI - Multifunctional nanocomposites of lanthanide (Eu3+, Tb3+) complexes functionalized magnetic mesoporous silica nanospheres covalently bonded with polymer modified ZnO. AB - Methacrylic-group-modified ZnO nanoparticles (designated ZnO-MAA) prepared through the sol-gel process are copolymerized with 2-hydroxyethyl methacrylate (HEMA) to form ZnO-MAA-PHEMA hybrid system. ZnO-MAA-PHEMA unit is functionalized with 3-(triethoxysilyl)-propyl isocyanate (TEPIC) to form ZnO-MAA-PHEMA-Si hybrids, and then is incorporated with oleic acid-modified Fe3O4 nanoparticles by co-condensation of tetraethoxysilane (TEOS) and ZnO-MAA-PHEMA-Si. Subsequently, ZnO-polymer covalently bonded mesoporous silica nanospheres are assembled using cetyltrimethylammonium bromide (CTAB) surfactant as template. Furthermore, lanthanide (Eu(3+), Tb(3+)) complexes with nicotinic acid (NTA), isonicotinic acid (INTA) and 2-chloronicotinic (CNTA) are introduced by coordination bonds, resulting in the final multifunctional nanocomposites. The detailed physical characterization of these hybrids is discussed in detail. It reveals that they possess both magnetic and luminescent properties. Especially Eu(ZnO-MMS)(CNTA)3 and Tb(ZnO-MMS)(NTA)3 present high quantum yield values of 32.2% and 68.5%, respectively. The results will lay the foundation for further application in biomedical and biopharmaceutical fields. PMID- 23673615 TI - Effects of age on the tuning of the cVEMP and oVEMP. AB - OBJECTIVES: The purpose of the present investigation was to define for young, middle-aged, and older adults the optimal frequency (cies) to record both the cervical vestibular-evoked myogenic potential (cVEMP) and the ocular vestibular evoked myogenic potential (oVEMP). Further, this study aimed to describe age related changes in the tuning of these two vestibular-evoked myogenic potentials. DESIGN: This was a prospective study. Participants were 39 healthy adults (mean age 46.3 +/- 15.7 years; range = 22 to 78 years; 15 men) equally divided into 3 age groups of 13 participants each: young adult (18 to 39 years), middle age (40 to 59 years), and old adult (>=60 years). cVEMPs and oVEMPs were recorded using air-conduction tone bursts at stimulus frequencies of 125, 250, 500, 750, 1000, 1500, and 2000 Hz presented at 127 dB pSPL. RESULTS: There was a significant main effect of age group and frequency on the amplitude of both the cVEMP and the oVEMP. Amplitudes were largest for the Young adult group for the cVEMP and for the young adult and Middle age group for the oVEMP. The largest average peak-to peak amplitude occurred in response to a 750 Hz tone burst for both responses. No significant differences in mean amplitude of the cVEMP or oVEMP were observed for 500, 750, or 1000 Hz stimuli. There was a significant interaction of age group and frequency for the cVEMP, suggesting a loss of tuning for the old adult group. Compared with the young adult group, the tuning of the cVEMP and oVEMP for the older adjults appeared to shift to a higher frequency. CONCLUSION: There is no sharp tuning in the saccule and utricle. Instead, there is a range of best frequencies that may be used to evoke the cVEMP and oVEMP responses. The results of the present investigation also demonstrate that the optimal stimulus frequency to elicit a VEMP may change with age. Accordingly, 500 Hz may not be the ideal frequency to elicit VEMPs for all age groups. For this reason, in cases where the VEMP response is absent at 500 Hz it is recommended that attempts be made to record the VEMP for tone-burst frequencies of 750 or 1000 Hz. PMID- 23673618 TI - Toll-like receptor 3 recognizes incomplete stem structures in single-stranded viral RNA. AB - Endosomal Toll-like receptor 3 (TLR3) serves as a sensor of viral infection and sterile tissue necrosis. Although TLR3 recognizes double-stranded RNA, little is known about structural features of virus- or host-derived RNAs that activate TLR3 in infection/inflammatory states. Here we demonstrate that poliovirus-derived single-stranded RNA segments harbouring stem structures with bulge/internal loops are potent TLR3 agonists. Functional poliovirus-RNAs are resistant to degradation and efficiently induce interferon-alpha/beta and proinflammatory cytokines in human and mouse cells in a TLR3-dependent manner. The N- and C-terminal double stranded RNA-binding sites of TLR3 are required for poliovirus-RNA-mediated TLR3 activation. Like polyriboinosinic:polyribocytidylic acid, a synthetic double stranded RNA, these RNAs are internalized into cells via raftlin-mediated endocytosis and colocalized with TLR3. Raftlin-associated RNA uptake machinery and the TLR3 RNA-sensing system appear to recognize an appropriate topology of multiple RNA duplexes in poliovirus-RNAs. Hence, TLR3 is a sensor of extracellular viral/host RNA with stable stem structures derived from infection or inflammation-damaged cells. PMID- 23673617 TI - ALKBH4-dependent demethylation of actin regulates actomyosin dynamics. AB - Regulation of actomyosin dynamics by post-transcriptional modifications in cytoplasmic actin is still poorly understood. Here we demonstrate that dioxygenase ALKBH4-mediated demethylation of a monomethylated site in actin (K84me1) regulates actin-myosin interaction and actomyosin-dependent processes such as cytokinesis and cell migration. ALKBH4-deficient cells display elevated K84me1 levels. Non-muscle myosin II only interacts with unmethylated actin and its proper recruitment to and interaction with actin depend on ALKBH4. ALKBH4 co localizes with the actomyosin-based contractile ring and midbody via association with methylated actin. ALKBH4-mediated regulation of actomyosin dynamics is completely dependent on its catalytic activity. Disorganization of cleavage furrow components and multinucleation associated with ALKBH4 deficiency can all be restored by reconstitution with wild-type but not catalytically inactive ALKBH4. Similar to actin and myosin knock-out mice, homozygous Alkbh4 mutant mice display early embryonic lethality. These findings imply that ALKBH4-dependent actin demethylation regulates actomyosin function by promoting actin-non-muscle myosin II interaction. PMID- 23673619 TI - Spatial segregation of polarity factors into distinct cortical clusters is required for cell polarity control. AB - Cell polarity is regulated by evolutionarily conserved polarity factors whose precise higher-order organization at the cell cortex is largely unknown. Here we image frontally the cortex of live fission yeast cells using time-lapse and super resolution microscopy. Interestingly, we find that polarity factors are organized in discrete cortical clusters resolvable to ~50-100 nm in size, which can form and become cortically enriched by oligomerization. We show that forced co localization of the polarity factors Tea1 and Tea3 results in polarity defects, suggesting that the maintenance of both factors in distinct clusters is required for polarity. However, during mitosis, their co-localization increases, and Tea3 helps to retain the cortical localization of the Tea1 growth landmark in preparation for growth reactivation following mitosis. Thus, regulated spatial segregation of polarity factor clusters provides a means to spatio-temporally control cell polarity at the cell cortex. We observe similar clusters in Saccharomyces cerevisiae and Caenorhabditis elegans cells, indicating this could be a universal regulatory feature. PMID- 23673620 TI - Measurement of the first ionization potential of astatine by laser ionization spectroscopy. AB - The radioactive element astatine exists only in trace amounts in nature. Its properties can therefore only be explored by study of the minute quantities of artificially produced isotopes or by performing theoretical calculations. One of the most important properties influencing the chemical behaviour is the energy required to remove one electron from the valence shell, referred to as the ionization potential. Here we use laser spectroscopy to probe the optical spectrum of astatine near the ionization threshold. The observed series of Rydberg states enabled the first determination of the ionization potential of the astatine atom, 9.31751(8) eV. New ab initio calculations are performed to support the experimental result. The measured value serves as a benchmark for quantum chemistry calculations of the properties of astatine as well as for the theoretical prediction of the ionization potential of superheavy element 117, the heaviest homologue of astatine. PMID- 23673621 TI - PAD4 regulates proliferation of multipotent haematopoietic cells by controlling c myc expression. AB - Peptidylarginine deiminase 4 (PAD4) functions as a transcriptional coregulator by catalyzing the conversion of histone H3 arginine residues to citrulline residues. Although the high level of PAD4 expression in bone marrow cells suggests its involvement in haematopoiesis, its precise contribution remains unclear. Here we show that PAD4, which is highly expressed in lineage(-) Sca-1(+) c-Kit(+) (LSK) cells of mouse bone marrow compared with other progenitor cells, controls c-myc expression by catalyzing the citrullination of histone H3 on its promoter. Furthermore, PAD4 is associated with lymphoid enhancer-binding factor 1 and histone deacetylase 1 at the upstream region of the c-myc gene. Supporting these findings, LSK cells, especially multipotent progenitors, in PAD4-deficient mice show increased proliferation in a cell-autonomous fashion compared with those in wild-type mice. Together, our results strongly suggest that PAD4 regulates the proliferation of multipotent progenitors in the bone marrow by controlling c-myc expression. PMID- 23673623 TI - Anisotropic two-dimensional electron gas at the LaAlO3/SrTiO3 (110) interface. AB - The observation of a high-mobility two-dimensional electron gas between two insulating complex oxides, especially LaAlO3/SrTiO3, has enhanced the potential of oxides for electronics. The occurrence of this conductivity is believed to be driven by polarization discontinuity, leading to an electronic reconstruction. In this scenario, the crystal orientation has an important role and no conductivity would be expected, for example, for the interface between LaAlO3 and (110) oriented SrTiO3, which should not have a polarization discontinuity. Here we report the observation of unexpected conductivity at the LaAlO3/SrTiO3 interface prepared on (110)-oriented SrTiO3, with a LaAlO3-layer thickness-dependent metal insulator transition. Density functional theory calculation reveals that electronic reconstruction, and thus conductivity, is still possible at this (110) interface by considering the energetically favourable (110) interface structure, that is, buckled TiO2/LaO, in which the polarization discontinuity is still present. The conductivity was further found to be strongly anisotropic along the different crystallographic directions with potential for anisotropic superconductivity and magnetism, leading to possible new physics and applications. PMID- 23673622 TI - Calfacilitin is a calcium channel modulator essential for initiation of neural plate development. AB - Calcium fluxes have been implicated in the specification of the vertebrate embryonic nervous system for some time, but how these fluxes are regulated and how they relate to the rest of the neural induction cascade is unknown. Here we describe Calfacilitin, a transmembrane calcium channel facilitator that increases calcium flux by generating a larger window current and slowing inactivation of the L-type CaV1.2 channel. Calfacilitin binds to this channel and is co-expressed with it in the embryo. Regulation of intracellular calcium by Calfacilitin is required for expression of the neural plate specifiers Geminin and Sox2 and for neural plate formation. Loss-of-function of Calfacilitin can be rescued by ionomycin, which increases intracellular calcium. Our results elucidate the role of calcium fluxes in early neural development and uncover a new factor in the modulation of calcium signalling. PMID- 23673624 TI - Separation of neutral and charge modes in one-dimensional chiral edge channels. AB - Coulomb interactions have a major role in one-dimensional electronic transport. They modify the nature of the elementary excitations from Landau quasiparticles in higher dimensions to collective excitations in one dimension. Here we report the direct observation of the collective neutral and charge modes of the two chiral co-propagating edge channels of opposite spins of the quantum Hall effect at filling factor 2. Generating a charge density wave at frequency f in the outer channel, we measure the current induced by inter-channel Coulomb interaction in the inner channel after a 3-MUm propagation length. Varying the driving frequency from 0.7 to 11 GHz, we observe damped oscillations in the induced current that result from the phase shift between the fast charge and slow neutral eigenmodes. We measure the dispersion relation and dissipation of the neutral mode from which we deduce quantitative information on the interaction range and parameters. PMID- 23673626 TI - Quantum Faraday and Kerr rotations in graphene. AB - Graphene, a monolayer sheet of carbon atoms, exhibits intriguing electronic properties that arise from its massless Dirac dispersion of electrons. A striking example is the half-integer quantum Hall effect, which endorses the presence of Dirac cones or, equivalently, a non-zero (pi) Berry's (topological) phase. It is curious how these anomalous features of Dirac electrons would affect optical properties. Here we observe the quantum magneto-optical Faraday and Kerr effects in graphene in the terahertz frequency range. Our results detect the quantum plateaus in the Faraday and Kerr rotations at precisely the quantum Hall steps that hallmark the Dirac electrons, with the rotation angle defined by the fine structure constant. The robust quantum Hall plateaus in the optical regime, besides being conceptually interesting, may open avenues for new graphene-based optoelectronic applications. PMID- 23673625 TI - Dendrogenin A arises from cholesterol and histamine metabolism and shows cell differentiation and anti-tumour properties. AB - We previously synthesized dendrogenin A and hypothesized that it could be a natural metabolite occurring in mammals. Here we explore this hypothesis and report the discovery of dendrogenin A in mammalian tissues and normal cells as an enzymatic product of the conjugation of 5,6alpha-epoxy-cholesterol and histamine. Dendrogenin A was not detected in cancer cell lines and was fivefold lower in human breast tumours compared with normal tissues, suggesting a deregulation of dendrogenin A metabolism during carcinogenesis. We established that dendrogenin A is a selective inhibitor of cholesterol epoxide hydrolase and it triggered tumour re-differentiation and growth control in mice and improved animal survival. The properties of dendrogenin A and its decreased level in tumours suggest a physiological function in maintaining cell integrity and differentiation. The discovery of dendrogenin A reveals a new metabolic pathway at the crossroads of cholesterol and histamine metabolism and the existence of steroidal alkaloids in mammals. PMID- 23673627 TI - Photoconductive response in organic charge transfer interfaces with high quantum efficiency. AB - Organic semiconductors have unique optical, mechanical and electronic properties that can be combined with customized chemical functionality. In the crystalline form, determinant features for electronic applications, such as molecular purity, the charge mobility or the exciton diffusion length, reveal a superior improved performance when compared with materials in a more disordered form. However, the use of organic single crystals in devices is still limited to a few applications, such as field-effect transistors. Here we report the first example of photoconductive behaviour of single-crystal charge-transfer interfaces. The system composed of rubrene and 7,7,8,8-tetracyanoquinodimethane presents a responsivity reaching 1 AW(-1), corresponding to an external quantum efficiency of nearly 100%. This result opens the possibility of using organic single-crystal interfaces in photonic applications. PMID- 23673628 TI - Constitutively active Foxo3 in oocytes preserves ovarian reserve in mice. AB - During female reproductive life, ovarian follicle reserve is reduced by maturation and atresia until menopause ensues. Foxo3 is required to maintain the ovarian reserve in mice. Here we show that overexpression of constitutively active FOXO3 can increase ovarian reproductive capacity in mice. We find increased follicle numbers and decreased gonadotropin levels in aging FOXO3 transgenic mice compared with wild-type littermates, suggesting maintenance of a greater ovarian reserve. Based on cumulative progeny in aging animals, we find 31 49% increased fertility in transgenic females. The gene expression profile of Foxo3-/- knockout ovaries appears older than that of wild-type littermates, and the transgene induces a younger-looking profile, restoring much of the wild-type transcriptome. This is the first gain-of-function model of augmented reproductive reserve in mice, thus emphasizing the role of Foxo3 as a guardian of the ovarian follicle pool in mammals and a potential determinant of the onset of menopause. PMID- 23673630 TI - Casimir forces on a silicon micromechanical chip. AB - Quantum fluctuations give rise to van der Waals and Casimir forces that dominate the interaction between electrically neutral objects at sub-micron separations. Under the trend of miniaturization, such quantum electrodynamical effects are expected to play an important role in micro- and nano-mechanical devices. Nevertheless, utilization of Casimir forces on the chip level remains a major challenge because all experiments so far require an external object to be manually positioned close to the mechanical element. Here by integrating a force sensing micromechanical beam and an electrostatic actuator on a single chip, we demonstrate the Casimir effect between two micromachined silicon components on the same substrate. A high degree of parallelism between the two near-planar interacting surfaces can be achieved because they are defined in a single lithographic step. Apart from providing a compact platform for Casimir force measurements, this scheme also opens the possibility of tailoring the Casimir force using lithographically defined components of non-conventional shapes. PMID- 23673629 TI - GATA simple sequence repeats function as enhancer blocker boundaries. AB - Simple sequence repeats (SSRs) account for ~3% of the human genome, but their functional significance still remains unclear. One of the prominent SSRs the GATA tetranucleotide repeat has preferentially accumulated in complex organisms. GATA repeats are particularly enriched on the human Y chromosome, and their non-random distribution and exclusive association with genes expressed during early development indicate their role in coordinated gene regulation. Here we show that GATA repeats have enhancer blocker activity in Drosophila and human cells. This enhancer blocker activity is seen in transgenic as well as native context of the enhancers at various developmental stages. These findings ascribe functional significance to SSRs and offer an explanation as to why SSRs, especially GATA, may have accumulated in complex organisms. PMID- 23673631 TI - Prions disturb post-Golgi trafficking of membrane proteins. AB - Conformational conversion of normal cellular prion protein PrP(C) into pathogenic PrP(Sc) is central to the pathogenesis of prion diseases. However, the pathogenic mechanism remains unknown. Here we show that post-Golgi vesicular trafficking is significantly delayed in prion-infected N2a cells. Accordingly, cell surface expression of membrane proteins examined, including PrP(C), insulin receptor involved in neuroprotection, and attractin, whose mutation causes prion disease like spongiform neurodegeneration, is reduced. Instead, they accumulate in the Golgi apparatus. PrP(Sc) is detected throughout endosomal compartments, being particularly abundant in recycling endosome. We also show reduced surface expression of PrP(C) and insulin receptor in prion-infected mouse brains well before the onset of disease. These results suggest that prion infection might impair post-Golgi trafficking of membrane proteins to the cell surface in neurons via PrP(Sc) accumulated in recycling endosome, and eventually induce neuronal dysfunctions associated with prion diseases. PMID- 23673632 TI - InVERT molding for scalable control of tissue microarchitecture. AB - Complex tissues contain multiple cell types that are hierarchically organized within morphologically and functionally distinct compartments. Construction of engineered tissues with optimized tissue architecture has been limited by tissue fabrication techniques, which do not enable versatile microscale organization of multiple cell types in tissues of size adequate for physiological studies and tissue therapies. Here we present an 'Intaglio-Void/Embed-Relief Topographic molding' method for microscale organization of many cell types, including induced pluripotent stem cell-derived progeny, within a variety of synthetic and natural extracellular matrices and across tissues of sizes appropriate for in vitro, pre clinical, and clinical studies. We demonstrate that compartmental placement of non-parenchymal cells relative to primary or induced pluripotent stem cell derived hepatocytes, compartment microstructure, and cellular composition modulate hepatic functions. Configurations found to sustain physiological function in vitro also result in survival and function in mice for at least 4 weeks, demonstrating the importance of architectural optimization before implantation. PMID- 23673633 TI - Picosecond pulses from wavelength-swept continuous-wave Fourier domain mode locked lasers. AB - Ultrafast lasers have a crucial function in many fields of science; however, up to now, high-energy pulses directly from compact, efficient and low-power semiconductor lasers are not available. Therefore, we introduce a new approach based on temporal compression of the continuous-wave, wavelength-swept output of Fourier domain mode-locked lasers, where a narrowband optical filter is tuned synchronously to the round-trip time of light in a kilometre-long laser cavity. So far, these rapidly swept lasers enabled orders-of-magnitude speed increase in optical coherence tomography. Here we report on the generation of ~60-70 ps pulses at 390 kHz repetition rate. As energy is stored optically in the long fibre delay line and not as population inversion in the laser-gain medium, high energy pulses can now be generated directly from a low-power, compact semiconductor-based oscillator. Our theory predicts subpicosecond pulses with this new technique in the future. PMID- 23673634 TI - Coordinated activation of the Rac-GAP beta2-chimaerin by an atypical proline-rich domain and diacylglycerol. AB - Chimaerins, a family of GTPase activating proteins for the small G-protein Rac, have been implicated in development, neuritogenesis and cancer. These Rac-GTPase activating proteins are regulated by the lipid second messenger diacylglycerol generated by tyrosine kinases such as the epidermal growth factor receptor. Here we identify an atypical proline-rich motif in chimaerins that binds to the adaptor protein Nck1. Unlike most Nck1 partners, chimaerins bind to the third SH3 domain of Nck1. This association is mediated by electrostatic interactions of basic residues within the Pro-rich motif with acidic clusters in the SH3 domain. Epidermal growth factor promotes the binding of beta2-chimaerin to Nck1 in the cell periphery in a diacylglycerol-dependent manner. Moreover, beta2-chimaerin translocation to the plasma membrane and its peripheral association with Rac1 requires Nck1. Our studies underscore a coordinated mechanism for beta2-chimaerin activation that involves lipid interactions via the C1 domain and protein-protein interactions via the N-terminal proline-rich region. PMID- 23673636 TI - An information-theoretic principle implies that any discrete physical theory is classical. AB - It has been suggested that nature could be discrete in the sense that the underlying state space of a physical system has only a finite number of pure states. Here we present a strong physical argument for the quantum theoretical property that every state space has infinitely many pure states. We propose a simple physical postulate that dictates that the only possible discrete theory is classical theory. More specifically, we postulate that no information gain implies no disturbance or, read in the contrapositive, that disturbance leads to some form of information gain. Furthermore, we show that non-classical discrete theories are still ruled out even if we relax the postulate to hold only approximately in the sense that no information gain only causes a small amount of disturbance. Our postulate also rules out popular generalizations such as the Popescu-Rohrlich-box that allows non-local correlations beyond the limits of quantum theory. PMID- 23673635 TI - SUMO2/3 modification of cyclin E contributes to the control of replication origin firing. AB - The small ubiquitin-like modifier (SUMO) pathway is essential for the maintenance of genome stability. We investigated its possible involvement in the control of DNA replication during S phase by using the Xenopus cell-free system. Here we show that the SUMO pathway is critical to limit the number and, thus, the density of replication origins that are activated in early S phase. We identified cyclin E, which regulates cyclin-dependent kinase 2 (Cdk2) to trigger origin firing, as an S-phase substrate of this pathway. We show that cyclin E is dynamically and highly conjugated to SUMO2/3 on chromatin, independently of Cdk2 activity and origin activation. Moreover, cyclin E is the predominant SUMO2/3 target on chromatin in early S phase, as cyclin E depletion abolishes, while its readdition restores, the SUMO2/3 signal. Together, our data indicate that cyclin E SUMOylation is important for controlling origin firing once the cyclin E-Cdk2 complex is recruited onto replication origins. PMID- 23673637 TI - High doses of CpG oligodeoxynucleotides stimulate a tolerogenic TLR9-TRIF pathway. AB - CpG-rich oligodeoxynucleotides activate the immune system, leading to innate and acquired immune responses. The immune-stimulatory effects of CpG-rich oligodeoxynucleotides are being exploited as a therapeutic approach. Here we show that at high doses, CpG-rich oligodeoxynucleotides promote an opposite, tolerogenic response in mouse plasmacytoid dendritic cells in vivo and in a human in vitro model. Unveiling a previously undescribed role for TRIF and TRAF6 proteins in Toll-like receptor 9 (TLR9) signalling, we demonstrate that physical association of TLR9, TRIF and TRAF6 leads to activation of noncanonical NF-kappaB signalling and the induction of IRF3- and TGF-beta-dependent immune-suppressive tryptophan catabolism. In vivo, the TLR9-TRIF circuit--but not MyD88 signalling- was required for CpG protection against allergic inflammation. Our findings may be relevant to an increased understanding of the complexity of Toll-like receptor signalling and optimal exploitation of CpG-rich oligodeoxynucleotides as immune modulators. PMID- 23673638 TI - Primary tumours modulate innate immune signalling to create pre-metastatic vascular hyperpermeability foci. AB - In mouse models of lung metastasis, before the appearance of significant metastases, localized changes in vascular permeability have been observed, which appear to set the stage for tumour growth. However, it is unclear whether this is also true in human patients. Here, we show that MD-2, a coreceptor for Toll-like receptor 4 that has a key role in the innate immune response, triggers the formation of regions of hyperpermeability in mice by upregulating C-C chemokine receptor type 2 (CCR2) expression. The CCR2-CCL2 system induces the abundant secretion of permeability factors such as serum amyloid A3 and S100A8. Disruption of MD-2 or CCR2 abrogates the formation of hyperpermeable regions, resulting in reduced tumour cell homing. Furthermore, fibrinogen, which is processed during permeability-mediated coagulation, is also localized in areas of elevated CCR2 expression in tumour-bearing human lungs. Our findings raise the possibility that CCR2 upregulation might represent a marker for regions of increased susceptibility to metastatic homing in lung cancer. PMID- 23673640 TI - Selective isolation of gold facilitated by second-sphere coordination with alpha cyclodextrin. AB - Gold recovery using environmentally benign chemistry is imperative from an environmental perspective. Here we report the spontaneous assembly of a one dimensional supramolecular complex with an extended {[K(OH2)6][AuBr4](alpha cyclodextrin)2}n chain superstructure formed during the rapid co-precipitation of alpha-cyclodextrin and KAuBr4 in water. This phase change is selective for this gold salt, even in the presence of other square-planar palladium and platinum complexes. From single-crystal X-ray analyses of six inclusion complexes between alpha-, beta- and gamma-cyclodextrins with KAuBr4 and KAuCl4, we hypothesize that a perfect match in molecular recognition between alpha-cyclodextrin and [AuBr4]( ) leads to a near-axial orientation of the ion with respect to the alpha cyclodextrin channel, which facilitates a highly specific second-sphere coordination involving [AuBr4](-) and [K(OH2)6](+) and drives the co precipitation of the 1:2 adduct. This discovery heralds a green host-guest procedure for gold recovery from gold-bearing raw materials making use of alpha cyclodextrin-an inexpensive and environmentally benign carbohydrate. PMID- 23673639 TI - Single-cell and metagenomic analyses indicate a fermentative and saccharolytic lifestyle for members of the OP9 lineage. AB - OP9 is a yet-uncultivated bacterial lineage found in geothermal systems, petroleum reservoirs, anaerobic digesters and wastewater treatment facilities. Here we use single-cell and metagenome sequencing to obtain two distinct, nearly complete OP9 genomes, one constructed from single cells sorted from hot spring sediments and the other derived from binned metagenomic contigs from an in situ enriched cellulolytic, thermophilic community. Phylogenomic analyses support the designation of OP9 as a candidate phylum for which we propose the name 'Atribacteria'. Although a plurality of predicted proteins is most similar to those from Firmicutes, the presence of key genes suggests a diderm cell envelope. Metabolic reconstruction from the core genome suggests an anaerobic lifestyle based on sugar fermentation by Embden-Meyerhof glycolysis with production of hydrogen, acetate and ethanol. Putative glycohydrolases and an endoglucanase may enable catabolism of (hemi)cellulose in thermal environments. This study lays a foundation for understanding the physiology and ecological role of the 'Atribacteria'. PMID- 23673641 TI - A mutation in the receptor Methoprene-tolerant alters juvenile hormone response in insects and crustaceans. AB - Juvenile hormone is an essential regulator of major developmental and life history events in arthropods. Most of the insects use juvenile hormone III as the innate juvenile hormone ligand. By contrast, crustaceans use methyl farnesoate. Despite this difference that is tied to their deep evolutionary divergence, the process of this ligand transition is unknown. Here we show that a single amino acid substitution in the receptor Methoprene-tolerant has an important role during evolution of the arthropod juvenile hormone pathway. Microcrustacea Daphnia pulex and D. magna share a juvenile hormone signal transduction pathway with insects, involving Methoprene-tolerant and steroid receptor coactivator proteins that form a heterodimer in response to various juvenoids. Juvenile hormone-binding pockets of the orthologous genes differ by only two amino acids, yet a single substitution within Daphnia Met enhances the receptor's responsiveness to juvenile hormone III. These results indicate that this mutation within an ancestral insect lineage contributed to the evolution of a juvenile hormone III receptor system. PMID- 23673642 TI - Periodic Wnt1 expression in response to ecdysteroid generates twin-spot markings on caterpillars. AB - Among various pigmentation patterns on caterpillars, sequential spot markings are often observed and used for aposematic colouration. In contrast to adult wings, caterpillar cuticle markings are repeatedly generated at each moult, but little is known about how the patterns are formed and maintained periodically. Here we focus on a silkworm mutant, multi lunar (L), with twin-spot markings on sequential segments. Positional cloning of L and expression analyses reveal that cis-regulatory change in Wnt1 is responsible for the spot patterning. The periodical upregulation of Wnt1 in response to ecdysteroid is detected only in epidermis within spot marking area. We verify by transgenic expression that the ectopic Wnt1 induces the additional pigmentation. Furthermore, the association of Wnt1 expression with spot markings is observed in the wild Bombyx species and swallowtail butterfly Papilio machaon. Taken together, we anticipate that periodic Wnt1 expression may contribute to natural variations of spot patterning on caterpillar cuticle. PMID- 23673643 TI - Draft genome sequence of the Tibetan antelope. AB - The Tibetan antelope (Pantholops hodgsonii) is endemic to the extremely inhospitable high-altitude environment of the Qinghai-Tibetan Plateau, a region that has a low partial pressure of oxygen and high ultraviolet radiation. Here we generate a draft genome of this artiodactyl and use it to detect the potential genetic bases of highland adaptation. Compared with other plain-dwelling mammals, the genome of the Tibetan antelope shows signals of adaptive evolution and gene family expansion in genes associated with energy metabolism and oxygen transmission. Both the highland American pika, and the Tibetan antelope have signals of positive selection for genes involved in DNA repair and the production of ATPase. Genes associated with hypoxia seem to have experienced convergent evolution. Thus, our study suggests that common genetic mechanisms might have been utilized to enable high-altitude adaptation. PMID- 23673644 TI - Flexible polymer transistors with high pressure sensitivity for application in electronic skin and health monitoring. AB - Flexible pressure sensors are essential parts of an electronic skin to allow future biomedical prostheses and robots to naturally interact with humans and the environment. Mobile biomonitoring in long-term medical diagnostics is another attractive application for these sensors. Here we report the fabrication of flexible pressure-sensitive organic thin film transistors with a maximum sensitivity of 8.4 kPa(-1), a fast response time of <10 ms, high stability over >15,000 cycles and a low power consumption of <1 mW. The combination of a microstructured polydimethylsiloxane dielectric and the high-mobility semiconducting polyisoindigobithiophene-siloxane in a monolithic transistor design enabled us to operate the devices in the subthreshold regime, where the capacitance change upon compression of the dielectric is strongly amplified. We demonstrate that our sensors can be used for non-invasive, high fidelity, continuous radial artery pulse wave monitoring, which may lead to the use of flexible pressure sensors in mobile health monitoring and remote diagnostics in cardiovascular medicine. PMID- 23673645 TI - The genomics of selection in dogs and the parallel evolution between dogs and humans. AB - The genetic bases of demographic changes and artificial selection underlying domestication are of great interest in evolutionary biology. Here we perform whole-genome sequencing of multiple grey wolves, Chinese indigenous dogs and dogs of diverse breeds. Demographic analysis show that the split between wolves and Chinese indigenous dogs occurred 32,000 years ago and that the subsequent bottlenecks were mild. Therefore, dogs may have been under human selection over a much longer time than previously concluded, based on molecular data, perhaps by initially scavenging with humans. Population genetic analysis identifies a list of genes under positive selection during domestication, which overlaps extensively with the corresponding list of positively selected genes in humans. Parallel evolution is most apparent in genes for digestion and metabolism, neurological process and cancer. Our study, for the first time, draws together humans and dogs in their recent genomic evolution. PMID- 23673646 TI - A European population in Minoan Bronze Age Crete. AB - The first advanced Bronze Age civilization of Europe was established by the Minoans about 5,000 years before present. Since Sir Arthur Evans exposed the Minoan civic centre of Knossos, archaeologists have speculated on the origin of the founders of the civilization. Evans proposed a North African origin; Cycladic, Balkan, Anatolian and Middle Eastern origins have also been proposed. Here we address the question of the origin of the Minoans by analysing mitochondrial DNA from Minoan osseous remains from a cave ossuary in the Lassithi plateau of Crete dated 4,400-3,700 years before present. Shared haplotypes, principal component and pairwise distance analyses refute the Evans North African hypothesis. Minoans show the strongest relationships with Neolithic and modern European populations and with the modern inhabitants of the Lassithi plateau. Our data are compatible with the hypothesis of an autochthonous development of the Minoan civilization by the descendants of the Neolithic settlers of the island. PMID- 23673647 TI - Clusterin and LRP2 are critical components of the hypothalamic feeding regulatory pathway. AB - Hypothalamic feeding circuits are essential for the maintenance of energy balance. There have been intensive efforts to discover new biological molecules involved in these pathways. Here we report that central administration of clusterin, also called apolipoprotein J, causes anorexia, weight loss and activation of hypothalamic signal transduction-activated transcript-3 in mice. In contrast, inhibition of hypothalamic clusterin action results in increased food intake and body weight, leading to adiposity. These effects are likely mediated through the mutual actions of the low-density lipoprotein receptor-related protein-2, a potential receptor for clusterin, and the long-form leptin receptor. In response to clusterin, the low-density lipoprotein receptor-related protein-2 binding to long-form leptin receptor is greatly enhanced in cultured neuronal cells. Furthermore, long-form leptin receptor deficiency or hypothalamic low density lipoprotein receptor-related protein-2 suppression in mice leads to impaired hypothalamic clusterin signalling and actions. Our study identifies the hypothalamic clusterin-low-density lipoprotein receptor-related protein-2 axis as a novel anorexigenic signalling pathway that is tightly coupled with long-form leptin receptor-mediated signalling. PMID- 23673649 TI - Transcription factor binding kinetics constrain noise suppression via negative feedback. AB - Negative autoregulation, where a transcription factor regulates its own expression by preventing transcription, is commonly used to suppress fluctuations in gene expression. Recent single molecule in vivo imaging has shown that it takes significant time for a transcription factor molecule to bind its chromosomal binding site. Given the slow association kinetics, transcription factor mediated feedback cannot at the same time be fast and strong. Here we show that with a limited association rate follows an optimal transcription factor binding strength where noise is maximally suppressed. At the optimal binding strength the binding site is free a fixed fraction of the time independent of the transcription factor concentration. One consequence is that high-copy number transcription factors should bind weakly to their operators, which is observed for transcription factors in Escherichia coli. The results demonstrate that a binding site's strength may be uncorrelated to its functional importance. PMID- 23673648 TI - A protein phosphatase 2A complex spatially controls plant cell division. AB - In the absence of cell migration, the orientation of cell divisions is crucial for body plan determination in plants. The position of the division plane in plant cells is set up premitotically via a transient cytoskeletal array, the preprophase band, which precisely delineates the cortical plane of division. Here we describe a protein complex that targets protein phosphatase 2A activity to microtubules, regulating the transition from the interphase to the premitotic microtubule array. This complex, which comprises TONNEAU1 and a PP2A heterotrimeric holoenzyme with FASS as regulatory subunit, is recruited to the cytoskeleton via the TONNEAU1-recruiting motif family of proteins. Despite the acentrosomal nature of plant cells, all members of this complex share similarity with animal centrosomal proteins involved in ciliary and centriolar/centrosomal functions, revealing an evolutionary link between the cortical cytoskeleton of plant cells and microtubule organizers in other eukaryotes. PMID- 23673650 TI - Controlled formation and reflection of a bright solitary matter-wave. AB - Bright solitons are non-dispersive wave solutions, arising in a diverse range of nonlinear, one-dimensional systems, including atomic Bose-Einstein condensates with attractive interactions. In reality, cold-atom experiments can only approach the idealized one-dimensional limit necessary for the realization of true solitons. Nevertheless, it remains possible to create bright solitary waves, the three-dimensional analogue of solitons, which maintain many of the key properties of their one-dimensional counterparts. Such solitary waves offer many potential applications and provide a rich testing ground for theoretical treatments of many body quantum systems. Here we report the controlled formation of a bright solitary matter-wave from a Bose-Einstein condensate of (85)Rb, which is observed to propagate over a distance of ~1.1 mm in 150 ms with no observable dispersion. We demonstrate the reflection of a solitary wave from a repulsive Gaussian barrier and contrast this to the case of a repulsive condensate, in both cases finding excellent agreement with theoretical simulations using the three dimensional Gross-Pitaevskii equation. PMID- 23673651 TI - Magnetically ultraresponsive nanoscavengers for next-generation water purification systems. AB - The development of sustainable, robust and energy efficient water purification technology is still challenging. Although use of nanoparticles is promising, methods are needed for their efficient recovery post treatment. Here we address this issue by fabrication of magnetically ultraresponsive 'nanoscavengers', nanoparticles containing synthetic antiferromagnetic core layers and functional capping layers. When dispersed in water, the nanoscavengers efficiently interact with contaminants to remove them from the water. They are then quickly collected (<5 min) with a permanent magnet, owing to their magnetically ultraresponsive core layers. Specifically, we demonstrate fabrication and deployment of Ag-capped nanoscavengers for disinfection followed by application of an external magnetic field for separation. We also develop and validate a collision-based model for pathogen inactivation, and propose a cyclical water purification scheme in which nanoscavengers are recovered and recycled for contaminant removal. PMID- 23673652 TI - An arthroscopic approach for the treatment of osteochondral focal defects with cell-free and cell-loaded PLGA scaffolds in sheep. AB - Osteochondral injuries are common in humans and are relatively difficult to manage with current treatment options. The combination of novel biomaterials and expanded progenitor or stem cells provides a source of therapeutic and immunologically compatible medicines that can be used in regenerative medicine. However, such new medicinal products need to be tested in translational animal models using the intended route of administration in humans and the intended delivery device. In this study, we evaluated the feasibility of an arthroscopic approach for the implantation of biocompatible copolymeric poly-D,L-lactide-co glycolide (PLGA) scaffolds in an ovine preclinical model of knee osteochondral defects. Moreover this procedure was further tested using ex vivo expanded autologous chondrocytes derived from cartilaginous tissue, which were loaded in PLGA scaffolds and their potential to generate hyaline cartilage was evaluated. All scaffolds were successfully implanted arthroscopically and the clinical evolution of the animals was followed by non invasive MRI techniques, similar to the standard in human clinical practice. No clinical complications occurred after the transplantation procedures in any of the animals. Interestingly, the macroscopic evaluation demonstrated significant improvement after treatment with scaffolds loaded with cells compared to untreated controls. PMID- 23673653 TI - Improved computational fluid dynamic simulations of blood flow in membrane oxygenators from X-ray imaging. AB - Computational fluid dynamics (CFD) is a useful tool in characterizing artificial lung designs by providing predictions of device performance through analyses of pressure distribution, perfusion dynamics, and gas transport properties. Validation of numerical results in membrane oxygenators has been predominantly based on experimental pressure measurements with little emphasis placed on confirmation of the velocity fields due to opacity of the fiber membrane and limitations of optical velocimetric methods. Biplane X-ray digital subtraction angiography was used to visualize flow of a blood analogue through a commercial membrane oxygenator at 1-4.5 L/min. Permeability and inertial coefficients of the Ergun equation were experimentally determined to be 180 and 2.4, respectively. Numerical simulations treating the fiber bundle as a single momentum sink according to the Ergun equation accurately predicted pressure losses across the fiber membrane, but significantly underestimated velocity magnitudes in the fiber bundle. A scaling constant was incorporated into the numerical porosity and reduced the average difference between experimental and numerical values in the porous media regions from 44 +/- 4% to 6 +/- 5%. PMID- 23673654 TI - Functional activity of the anterior and posterior cruciate ligaments under in vivo gait and static physiological loads. AB - The loading of the anterior and posterior cruciate ligaments (ACL and PCL) during normal gait has not been quantified. Also, it is not clear whether ligaments under "static" physiological loads commonly used in cadaveric studies behave similarly to normal gait experienced in vivo. We measured the in vivo kinematics of the stifle joint of sheep (N = 4) during "normal gait," then reproduced these gait paths using a robotic system. The loads borne by the cruciate ligaments were determined using the principle of superposition and plotted against each other. This indicated some functional interaction between the ACL and PCL under in vivo physiological loads. To examine this relationship under static loading conditions, cadaveric knees (N = 6) were tested in the anterior-posterior (AP) direction, along the axes of the ACL and the PCL, as well as under combined AP and tibial rotations. The same process was repeated after either the ACL (N = 3) or the PCL (N = 3) was transected. Our results show a mutually exclusive relationship in ACL and PCL load bearing under both "in vivo gait" and "static" loading conditions. High ACL loads were associated with low PCL loads and vice versa. This is a novel study quantifying the actions of the cruciate ligaments during gait and comparing them to commonly used static loading conditions in cadaveric studies. PMID- 23673655 TI - Use of monoclonal antibodies for metastatic colorectal cancer in the Andalusian public health system. AB - BACKGROUND: The place of monoclonal antibodies in metastatic colorectal cancer has not been clearly defined. OBJECTIVE: To determine the treatment pattern of monoclonal antibodies in colorectal cancer patients in the Andalusian Public Healthcare System. METHOD: Data were collected from all patients treated with these drugs from July 2009 to December 2010 from pharmacy programs and medical records. RESULTS: Three hundred patients were included, of whom 227 received the antibody at the forefront. The proportion of patients who received bevacizumab in the first line is greater than that of cetuximab (62.1 vs. 37.5 % respectively) and similar in the second line and subsequent (47.8 vs. 53.8 % and 48.5 vs. 46.2 % respectively). XELOXbevacizumab was the most frequently prescribed scheme (35.3 %) followed by FOLFOX-monoclonal antibody schemes, regardless that this was bevacizumab or cetuximab (22.5 %). The median progression free survival (PFS) was 11.7 months for patients receiving cetuximab, 9.6 months for patients receiving bevacizumab and 8.2 months for those who received no monoclonal antibody in the first line. CONCLUSION: Bevacizumab was the antibody of choice in first line, showing utilization rates similar to cetuximab in second line and subsequent. The median PFS in our study is related to the PFS of the major clinical trials. PMID- 23673656 TI - Notch1 gene mutations target KRAS G12D-expressing CD8+ cells and contribute to their leukemogenic transformation. AB - Acute T-cell lymphoblastic leukemia/lymphoma (T-ALL) is an aggressive hematopoietic malignancy affecting both children and adults. Previous studies of T-ALL mouse models induced by different genetic mutations have provided highly diverse results on the issues of T-cell leukemia/lymphoma-initiating cells (T LICs) and potential mechanisms contributing to T-LIC transformation. Here, we show that oncogenic Kras (Kras G12D) expressed from its endogenous locus is a potent inducer of T-ALL even in a less sensitized BALB/c background. Notch1 mutations, including exon 34 mutations and recently characterized type 1 and 2 deletions, are detected in 100% of Kras G12D-induced T-ALL tumors. Although these mutations are not detected at the pre-leukemia stage, incremental up-regulation of NOTCH1 surface expression is observed at the pre-leukemia and leukemia stages. As secondary genetic hits in the Kras G12D model, Notch1 mutations target CD8(+) T-cells but not hematopoietic stem cells to further promote T-ALL progression. Pre-leukemia T-cells without detectable Notch1 mutations do not induce T-ALL in secondary recipient mice compared with T-ALL tumor cells with Notch1 mutations. We found huge variations in T-LIC frequency and immunophenotypes of cells enriched for T-LICs. Unlike Pten deficiency-induced T-ALL, oncogenic Kras initiated T-ALL is not associated with up-regulation of the Wnt/beta-catenin pathway. Our results suggest that up-regulation of NOTCH1 signaling, through either overexpression of surface NOTCH1 or acquired gain-of-function mutations, is involved in both T-ALL initiation and progression. Notch1 mutations and Kras G12D contribute cooperatively to leukemogenic transformation of normal T-cells. PMID- 23673657 TI - Insulin receptor signaling in cones. AB - In humans, age-related macular degeneration and diabetic retinopathy are the most common disorders affecting cones. In retinitis pigmentosa (RP), cone cell death precedes rod cell death. Systemic administration of insulin delays the death of cones in RP mouse models lacking rods. To date there are no studies on the insulin receptor signaling in cones; however, mRNA levels of IR signaling proteins are significantly higher in cone-dominant neural retina leucine zipper (Nrl) knock-out mouse retinas compared with wild type rod-dominant retinas. We previously reported that conditional deletion of the p85alpha subunit of phosphoinositide 3-kinase (PI3K) in cones resulted in age-related cone degeneration, and the phenotype was not rescued by healthy rods, raising the question of why cones are not protected by the rod-derived cone survival factors. Interestingly, systemic administration of insulin has been shown to delay the death of cones in mouse models of RP lacking rods. These observations led to the hypothesis that cones may have their own endogenous neuroprotective pathway, or rod-derived cone survival factors may be signaled through cone PI3K. To test this hypothesis we generated p85alpha(-/-)/Nrl(-/-) double knock-out mice and also rhodopsin mutant mice lacking p85alpha and examined the effect of the p85alpha subunit of PI3K on cone survival. We found that the rate of cone degeneration is significantly faster in both of these models compared with respective mice with competent p85alpha. These studies suggest that cones may have their own endogenous PI3K-mediated neuroprotective pathway in addition to the cone viability survival signals derived from rods. PMID- 23673658 TI - A metabolomics-driven elucidation of the anti-obesity mechanisms of xanthohumol. AB - Mild, mitochondrial uncoupling increases energy expenditure and can reduce the generation of reactive oxygen species (ROS). Activation of cellular, adaptive stress response pathways can result in an enhanced capacity to reduce oxidative damage. Together, these strategies target energy imbalance and oxidative stress, both underlying factors of obesity and related conditions such as type 2 diabetes. Here we describe a metabolomics-driven effort to uncover the anti obesity mechanism(s) of xanthohumol (XN), a prenylated flavonoid from hops. Metabolomics analysis of fasting plasma from obese, Zucker rats treated with XN revealed decreases in products of dysfunctional fatty acid oxidation and ROS, prompting us to explore the effects of XN on muscle cell bioenergetics. At low micromolar concentrations, XN acutely increased uncoupled respiration in several different cell types, including myocytes. Tetrahydroxanthohumol also increased respiration, suggesting electrophilicity did not play a role. At higher concentrations, XN inhibited respiration in a ROS-dependent manner. In myocytes, time course metabolomics revealed acute activation of glutathione recycling and long term induction of glutathione synthesis as well as several other changes indicative of short term elevated cellular stress and a concerted adaptive response. Based on these findings, we hypothesize that XN may ameliorate metabolic syndrome, at least in part, through mitochondrial uncoupling and stress response induction. In addition, time course metabolomics appears to be an effective strategy for uncovering metabolic events that occur during a stress response. PMID- 23673660 TI - Regulation of the yeast triacylglycerol lipase TGl3p by formation of nonpolar lipids. AB - Tgl3p, the major triacylglycerol lipase of the yeast Saccharomyces cerevisiae, is a component of lipid droplets but is also present in the endoplasmic reticulum in a minor amount. Recently, it was shown that this enzyme can also serve as a lysophospholipid acyltransferase (Rajakumari, S., and Daum, G. (2010) Mol. Biol. Cell 21, 501-510). Here, we describe the effects of the presence/absence of triacylglycerols and lipid droplets on the functionality of Tgl3p. In a dga1Deltalro1Deltaare1Deltaare2Delta quadruple mutant lacking all four triacylglycerol- and steryl ester-synthesizing acyltransferases and consequently the lipid droplets, the gene expression of TGL3 was only slightly altered. In contrast, protein level and stability of Tgl3p were markedly reduced in the absence of lipid droplets. Under these conditions, the enzyme was localized to the endoplasmic reticulum. Even the lack of the substrate, triacylglycerol, affected stability and localization of Tgl3p to some extent. Interestingly, Tgl3p present in the endoplasmic reticulum seems to lack lipolytic as well as acyltransferase activity as shown by enzymatic analysis and lipid profiling. Thus, we propose that the activity of Tgl3p is restricted to lipid droplets, whereas the endoplasmic reticulum may serve as a parking lot for this enzyme. PMID- 23673659 TI - New approaches to prevent LEOPARD syndrome-associated cardiac hypertrophy by specifically targeting Shp2-dependent signaling. AB - In LEOPARD syndrome (LS) patients, mutations in the protein tyrosine phosphatase Shp2 cause hypertrophic cardiomyopathy. The prohypertrophic effects of mutant Shp2 are mediated downstream by hyperactivation of mammalian target of rapamycin. Our goal was to further define the signaling cascade that is essential for the underlying pathomechanism, thus expanding the list of potential future therapeutic targets. Using cultured neonatal rat cardiomyocytes with adenoviral gene delivery and pharmacological inhibitors, we found that hypertrophy induced by a particularly aggressive LS mutation in Shp2 depends on hyperactivation of Akt and focal adhesion kinase as well as mammalian target of rapamycin. Dissecting domain-specific functions of Shp2 using double and truncation mutants, we determined that the hypertrophic effects of mutant Shp2 depend on the two SH2 domains and on an intact catalytic center. The latter finding prompted us to test the efficacy of a Shp2 inhibitor targeted directly at the catalytic pocket. This compound, PHPS1, effectively prevented mutant Shp2-induced hypertrophy. In summary, we identified three novel targets for pharmacological therapy of LS associated cardiac hypertrophy. Of particular importance is the finding that intervention directly at the mutant Shp2 protein is effective because this would facilitate custom-tailored therapeutic approaches for patients carrying LS mutations in Shp2. PMID- 23673662 TI - High mobility group protein N5 (HMGN5) and lamina-associated polypeptide 2alpha (LAP2alpha) interact and reciprocally affect their genome-wide chromatin organization. AB - The interactions of nuclear lamins with the chromatin fiber play an important role in regulating nuclear architecture and chromatin function; however, the full spectrum of these interactions is not known. We report that the N-terminal domain of the nucleosome-binding protein HMGN5 interacts with the C-terminal domain of the lamin-binding protein LAP2alpha and that these proteins reciprocally alter their interaction with chromatin. Chromatin immunoprecipitation analysis of cells lacking either HMGN5 or LAP2alpha reveals that loss of either protein affects the genome-wide distribution of the remaining partner. Our study identifies a new functional link between chromatin-binding and lamin-binding proteins. PMID- 23673661 TI - A matriptase-prostasin reciprocal zymogen activation complex with unique features: prostasin as a non-enzymatic co-factor for matriptase activation. AB - Matriptase and prostasin are part of a cell surface proteolytic pathway critical for epithelial development and homeostasis. Here we have used a reconstituted cell-based system and transgenic mice to investigate the mechanistic interrelationship between the two proteases. We show that matriptase and prostasin form a reciprocal zymogen activation complex with unique features. Prostasin serves as a critical co-factor for matriptase activation. Unexpectedly, however, prostasin-induced matriptase activation requires neither prostasin zymogen conversion nor prostasin catalytic activity. Prostasin zymogen conversion to active prostasin is dependent on matriptase but does not require matriptase zymogen conversion. Consistent with these findings, wild type prostasin, activation cleavage site-mutated prostasin, and catalytically inactive prostasin all were biologically active in vivo when overexpressed in the epidermis of transgenic mice, giving rise to a severe skin phenotype. Our finding of non enzymatic stimulation of matriptase activation by prostasin and activation of prostasin by the matriptase zymogen provides a tentative mechanistic explanation for several hitherto unaccounted for genetic and biochemical observations regarding these two membrane-anchored serine proteases and their downstream targets. PMID- 23673663 TI - The antiprion compound 6-aminophenanthridine inhibits the protein folding activity of the ribosome by direct competition. AB - Domain V of the 23S/25S/28S rRNA of the large ribosomal subunit constitutes the active center for the protein folding activity of the ribosome (PFAR). Using in vitro transcribed domain V rRNAs from Escherichia coli and Saccharomyces cerevisiae as the folding modulators and human carbonic anhydrase as a model protein, we demonstrate that PFAR is conserved from prokaryotes to eukaryotes. It was shown previously that 6-aminophenanthridine (6AP), an antiprion compound, inhibits PFAR. Here, using UV cross-linking followed by primer extension, we show that the protein substrates and 6AP interact with a common set of nucleotides on domain V of 23S rRNA. Mutations at the interaction sites decreased PFAR and resulted in loss or change of the binding pattern for both the protein substrates and 6AP. Moreover, kinetic analysis of human carbonic anhydrase refolding showed that 6AP decreased the yield of the refolded protein but did not affect the rate of refolding. Thus, we conclude that 6AP competitively occludes the protein substrates from binding to rRNA and thereby inhibits PFAR. Finally, we propose a scheme clarifying the mechanism by which 6AP inhibits PFAR. PMID- 23673664 TI - Unexpected histone H3 tail-clipping activity of glutamate dehydrogenase. AB - Clipping of histone tails has been reported in several organisms. However, the significance and regulation of histone tail clipping largely remains unclear. According to recent discoveries H3 clipping has been found to be involved in regulation of gene expression and chromatin dynamics. Earlier we had provided evidence of tissue-specific proteolytic processing of histone H3 in White Leghorn chicken liver nuclei. In this study we identify a novel activity of glutamate dehydrogenase (GDH) as a histone H3-specific protease in chicken liver tissue. This protease activity is regulated by divalent ions and thiol-disulfide conversion in vitro. GDH specifically clips H3 in its free as well as chromatin bound form. Furthermore, we have found an inhibitor that inhibits the H3-clipping activity of GDH. Like previously reported proteases, GDH too may have the potential to regulate/modulate post-translational modifications of histone H3 by removing the N-terminal residues of the histone. In short, our findings identify an unexpected proteolytic activity of GDH specific to histone H3 that is regulated by redox state, ionic concentrations, and a cellular inhibitor in vitro. PMID- 23673665 TI - Chondroadherin fragmentation mediated by the protease HTRA1 distinguishes human intervertebral disc degeneration from normal aging. AB - Chondroadherin, a member of the leucine-rich repeat family, has previously been demonstrated to be fragmented in some juveniles with idiopathic scoliosis. This observation led us to investigate adults with disc degeneration. Immunoblotting analysis demonstrated that non-degenerate discs from three different age groups show no chondroadherin fragmentation. Furthermore, the chondroadherin fragments in adult degenerate disc and the juvenile scoliotic disc were compared via immunoblot analysis and appeared to have a similar size. We then investigated whether or not chondroadherin fragmentation increases with the severity of disc degeneration. Three different samples with different severities were chosen from the same disc, and chondroadherin fragmentation was found to be more abundant with increasing severity of degeneration. This observation led us to the creation of a neoepitope antibody to the cleavage site observed. We then observed that the cleavage site in adult degenerate discs and juvenile scoliotic discs was identical as confirmed by the neoepitope antibody. Consequently, investigation of the protease capable of cleaving chondroadherin at this site was necessary. In vitro digests of disc tissue demonstrated that ADAMTS-4 and -5; cathepsins K, B, and L; and MMP-3, -7, -12, and -13 were incapable of cleavage of chondroadherin at this site and that HTRA1 was indeed the only protease capable. Furthermore, increased protein levels of the processed form of HTRA1 were demonstrated in degenerate disc tissues via immunoblotting. The results suggest that chondroadherin fragmentation can be used as a biomarker to distinguish the processes of disc degeneration from normal aging. PMID- 23673666 TI - Identification of canonical tyrosine-dependent and non-canonical tyrosine independent STAT3 activation sites in the intracellular domain of the interleukin 23 receptor. AB - Signaling of interleukin 23 (IL-23) via the IL-23 receptor (IL-23R) and the shared IL-12 receptor beta1 (IL-12Rbeta1) controls innate and adaptive immune responses and is involved in the differentiation and expansion of IL-17-producing CD4(+) T helper (TH17) cells. Activation of signal transducer and activator of transcription 3 (STAT3) appears to be the major signaling pathway of IL-23, and STAT binding sites were predicted in the IL-23R but not in the IL-12Rbeta1 chain. Using site-directed mutagenesis and deletion variants of the murine and human IL 23R, we showed that the predicted STAT binding sites (pYXXQ; including Tyr-504 and Tyr-626 in murine IL-23R and Tyr-484 and Tyr-611 in human IL-23R) mediated STAT3 activation. Furthermore, we identified two uncommon STAT3 binding/activation sites within the murine IL-23R. First, the murine IL-23R carried the Y(542)PNFQ sequence, which acts as an unusual Src homology 2 (SH2) domain-binding protein activation site of STAT3. Second, we identified a non canonical, phosphotyrosine-independent STAT3 activation motif within the IL-23R. A third predicted site, Tyr-416 in murine and Tyr-397 in human IL-23R, is involved in the activation of PI3K/Akt and the MAPK pathway leading to STAT3 independent proliferation of Ba/F3 cells upon stimulation with IL-23. In contrast to IL-6-induced short term STAT3 phosphorylation, cellular activation by IL-23 resulted in a slower but long term STAT3 phosphorylation, indicating that the IL 23R might not be a major target of negative feedback inhibition by suppressor of cytokine signaling (SOCS) proteins. In summary, we characterized IL-23-dependent signal transduction with a focus on STAT3 phosphorylation and identified canonical tyrosine-dependent and non-canonical tyrosine-independent STAT3 activation sites in the IL-23R. PMID- 23673667 TI - Covalent small ubiquitin-like modifier (SUMO) modification of Maf1 protein controls RNA polymerase III-dependent transcription repression. AB - RNA polymerase (pol) III transcribes genes that determine biosynthetic capacity. Induction of these genes is required for oncogenic transformation. The transcriptional repressor, Maf1, plays a central role in the repression of these and other genes that promote oncogenesis. Our studies identify an important new role for SUMOylation in repressing RNA pol III-dependent transcription. We show that a key mechanism by which this occurs is through small ubiquitin-like modifier (SUMO) modification of Maf1 by both SUMO1 and SUMO2. Mutation of each lysine residue revealed that Lys-35 is the major SUMOylation site on Maf1 and that the deSUMOylase, SENP1, is responsible for controlling Maf1K35 SUMOylation. SUMOylation of Maf1 is unaffected by rapamycin inhibition of mammalian target of rapamycin (mTOR) and mTOR-dependent Maf1 phosphorylation. By preventing SUMOylation at Lys-35, Maf1 is impaired in its ability to both repress transcription and suppress colony growth. Although SUMOylation does not alter Maf1 subcellular localization, Maf1K35R is defective in its ability to associate with RNA pol III. This impairs Maf1 recruitment to tRNA gene promoters and its ability to facilitate the dissociation of RNA pol III from these promoters. These studies identify a novel role for SUMOylation in controlling Maf1 and RNA pol III mediated transcription. Given the emerging roles of SENP1, Maf1, and RNA pol III transcription in oncogenesis, our studies support the idea that deSUMOylation of Maf1 and induction of its gene targets play a critical role in cancer development. PMID- 23673668 TI - Enhanced autophagic flux by endoplasmic reticulum stress in human hepatocellular carcinoma cells contributes to the maintenance of cell viability. AB - Endoplasmic reticulum (ER) stress and autophagy are important adaptive responses in eukaryotes. The aim of this study was to investigate the autophagic responses in hepatocellular carcinoma (HCC) cells under ER stress and the effect of autophagy on cell survival and death. The human HCC cell line HepG2 was stimulated with tunicamycin to induce ER stress. Cell viability was detected using the Cell Counting Kit-8. The accumulation of autophagic compartments was observed using transmission electron microscopy. The expression of ER and autophagy-related proteins was assessed by western blotting. Autophagic flux was assessed by microtubule-associated protein 1-light chain 3 (MAP1-LC3) turnover assay in the presence of chloroquine to inhibit lysosomes. HepG2 cells subjected to the ER stress presented a significant accumulation of autophagosomes and increased conversion of LC3-I to LC3-II as well as enhanced autophagic flux as detected by the LC3 turnover assay. Inhibition of autophagy with 3-methyladenine facilitated ER stress-related cell death. We conclude that ER stress enhances the autophagic flux in HepG2 cells, which may contribute to the maintenance of cell viability. PMID- 23673669 TI - Minimally invasive lateral retroperitoneal corpectomy for treatment of focal thoracolumbar kyphotic deformity: case report and review of the literature. AB - BACKGROUND: Corpectomy is a frequently performed procedure for pathologies of the anterior spine including neoplasms, fractures, deformities, and osteomyelitis. Traditional approaches to the anterior thoracic spine and thoracolumbar junction are associated with significant perioperative pulmonary complications and morbidity. Posterior and posterolateral approaches minimize some of these complications but are somewhat limited in visualization of the anterior elements. PATIENT AND METHODS: Here we report the case of a 49-year-old man with a remote thoracolumbar fracture and subsequent focal deformity treated with a minimally invasive lateral retroperitoneal corpectomy and open posterior arthrodesis. CONCLUSION: Minimally invasive lateral corpectomy is a safe and effective option for deformity correction. We discuss the relative advantages and disadvantages of this approach and review the relevant literature. PMID- 23673670 TI - The suprameatal dural flap for superior petrosal vein protection during the retrosigmoid intradural suprameatal approach. AB - OBJECT: The drilling of the suprameatal bone during the retrosigmoid intradural suprameatal approach (RISA) puts the superior petrosal vein complex at risk of heating and mechanical injury, which may lead to cerebellar swelling and infarction. We present a new technique to protect the superior petrosal venous complex during suprameatal bone drilling. MATERIAL AND METHODS: A microanatomical laboratory investigation on cadaver was conducted. The surgical technique is described and intraoperative schematic pictures are provided. RESULTS: The surgical steps of this technique and the related intraoperative images are reported. One case illustration regarding the removal of a large petrous apex meningioma with Meckel cave extension is described to demonstrate the application of the technique in a clinical setting. CONCLUSIONS: Reflecting a dural flap onto the posterior trigeminal nerve root and the superior petrosal vein complex can be a simple way to protect the nerve and the vein during the suprameatal bone drilling during the RISA. PMID- 23673671 TI - A simple and reliable methodology to detect egg white in art samples. AB - A protocol for a simple and reliable dot-blot immunoassay was developed and optimized to test work of art samples for the presence of specific proteinaceus material (i.e. ovalbumin-based). The analytical protocol has been extensively set up with respect, among the other, to protein extraction conditions, to densitometric analysis and to the colorimetric reaction conditions. Feasibility evaluation demonstrated that a commercial scanner and a free image analysis software can be used for the data acquisition and elaboration, thus facilitating the application of the proposed protocol to commonly equipped laboratories and to laboratories of museums and conservation centres. The introduction of method of standard additions in the analysis of fresh and artificially aged laboratory prepared samples, containing egg white and various pigments, allowed us to evaluate the matrix effect and the effect of sample aging and to generate threshold density values useful for the detection of ovalbumin in samples from ancient works of art. The efficacy of the developed dot-blot immunoassay was proved testing microsamples from 13th-16th century mural paintings of Saint Francesco Church in Lodi (Italy). Despite the aging, the altered conditions of conservation, the complex matrix, and the micro-size of samples, the presence of ovalbumin was detected in all those mural painting samples where mass spectrometry-based proteomic analysis unambiguously detected ovalbumin peptides. PMID- 23673673 TI - Gene expression analysis in combat veterans with and without post-traumatic stress disorder. AB - Post-traumatic stress disorder (PTSD) is a common, debilitating and complex disorder. Numerous genetic and environmental factors are important in the genesis and maintenance of PTSD. Thus, gene expression analysis (GEA) is a critical technology for PTSD research since it detects essential genetic output affected by gene-environment interactions. Quality control methods are rarely reported in gene expression studies. The present study aimed to identify reliably expressed genes in whole blood samples from subjects with combat-induced PTSD (n=6) and, secondly, to investigate the expression of genes that may be differentially expressed in PTSD compared with an appropriate control group (n=11). Strict quality control methods were used. From a theoretically driven set of 42 genes, 17 were reliably detected using quantitative PCR on samples from 17 combat exposed veterans. Four of these 17 genes were consistently and modestly correlated with clinical phenotypes and had significant expression effects on phenotypes. These genes regulate inflammatory systems and are regulated by the adrenergic system, consistent with peripheral markers important in PTSD. Inflammatory disinhibition may be involved in combat-induced PTSD, and may be responsible for the increased prevalence of inflammatory-related illnesses observed in PTSD. This is a preliminary study with a small sample size. A number of genes are not reliably detected by the current methodology. Improved detection methods are important to extend the current study and to further understand mechanisms in PTSD. PMID- 23673674 TI - Micro-drilling of polymer tubular ultramicroelectrode arrays for electrochemical sensors. AB - We present a reproducible fast prototyping procedure based on micro-drilling to produce homogeneous tubular ultramicroelectrode arrays made from poly(3,4 ethylenedioxythiophene) (PEDOT), a conductive polymer. Arrays of O 100 um tubular electrodes each having a height of 0.37 +/- 0.06 um were reproducibly fabricated. The electrode dimensions were analyzed by SEM after deposition of silver dendrites to visualize the electroactive electrode area. The electrochemical applicability of the electrodes was demonstrated by voltammetric and amperometric detection of ferri-/ferrocyanide. Recorded signals were in agreement with results from finite element modelling of the system. The tubular PEDOT ultramicroelectrode arrays were modified by prussian blue to enable the detection of hydrogen peroxide. A linear sensor response was demonstrated for hydrogen peroxide concentrations from 0.1 mM to 1 mM. PMID- 23673675 TI - A ubiquitous NFC solution for the development of tailored marketing strategies based on discount vouchers and loyalty cards. AB - Because of the global economic turmoil, nowadays a lot of companies are adopting a "deal of the day" business model, some of them with great success. Generally, they try to attract and retain customers through discount coupons and gift cards, using, generally, traditional distribution media. This paper describes a framework, which integrates intelligent environments by using NFC, oriented to the full management of this kind of businesses. The system is responsible for diffusion, distribution, sourcing, validation, redemption and managing of vouchers, loyalty cards and all kind of mobile coupons using NFC, as well as QR codes. WingBonus can be fully adapted to the requirements of marketing campaigns, voucher providers, shop or retailer infrastructures and mobile devices and purchasing habits. Security of the voucher is granted by the system by synchronizing procedures using secure encriptation algorithms. The WingBonus website and mobile applications can be adapted to any requirement of the system actors. PMID- 23673676 TI - An all fiber intrinsic Fabry-Perot Interferometer based on an air-microcavity. AB - In this work an Intrinsic Fabry-Perot Interferometer (IFPI) based on an air microcavity is presented. Here the air microcavity, with silica walls, is formed at a segment of a hollow core photonic crystal fiber (HCPCF), which is fusion spliced with a single mode fiber (SMF). Moreover, the spectral response of the IFPI is experimentally characterized and some results are provided. Finally, the viability to use the IFPI to implement a simple, compact size, and low cost refractive index sensor is briefly analyzed. PMID- 23673677 TI - Acoustic emission detection of macro-cracks on engraving tool steel inserts during the injection molding cycle using PZT sensors. AB - This paper presents an improved monitoring system for the failure detection of engraving tool steel inserts during the injection molding cycle. This system uses acoustic emission PZT sensors mounted through acoustic waveguides on the engraving insert. We were thus able to clearly distinguish the defect through measured AE signals. Two engraving tool steel inserts were tested during the production of standard test specimens, each under the same processing conditions. By closely comparing the captured AE signals on both engraving inserts during the filling and packing stages, we were able to detect the presence of macro-cracks on one engraving insert. Gabor wavelet analysis was used for closer examination of the captured AE signals' peak amplitudes during the filling and packing stages. The obtained results revealed that such a system could be used successfully as an improved tool for monitoring the integrity of an injection molding process. PMID- 23673678 TI - Analysis of the accuracy and robustness of the leap motion controller. AB - The Leap Motion Controller is a new device for hand gesture controlled user interfaces with declared sub-millimeter accuracy. However, up to this point its capabilities in real environments have not been analyzed. Therefore, this paper presents a first study of a Leap Motion Controller. The main focus of attention is on the evaluation of the accuracy and repeatability. For an appropriate evaluation, a novel experimental setup was developed making use of an industrial robot with a reference pen allowing a position accuracy of 0.2 mm. Thereby, a deviation between a desired 3D position and the average measured positions below 0.2 mm has been obtained for static setups and of 1.2 mm for dynamic setups. Using the conclusion of this analysis can improve the development of applications for the Leap Motion controller in the field of Human-Computer Interaction. PMID- 23673679 TI - Performance of a cyanobacteria whole cell-based fluorescence biosensor for heavy metal and pesticide detection. AB - Whole cell biosensors always face the challenge of low stability of biological components and short storage life. This paper reports the effects of poly(2 hydroxyethyl methacrylate) (pHEMA) immobilization on a whole cell fluorescence biosensor for the detection of heavy metals (Cu, Pb, Cd), and pesticides (dichlorophenoxyacetic acid (2,4-D), and chlorpyrifos). The biosensor was produced by entrapping the cyanobacterium Anabaena torulosa on a cellulose membrane, followed by applying a layer of pHEMA, and attaching it to a well. The well was then fixed to an optical probe which was connected to a fluorescence spectrophotometer and an electronic reader. The optimization of the biosensor using several factors such as amount of HEMA and drying temperature were undertaken. The detection limits of biosensor without pHEMA for Cu, Cd, Pb, 2,4-D and chlorpyrifos were 1.195, 0.027, 0.0100, 0.025 and 0.025 ug/L respectively. The presence of pHEMA increased the limits of detection to 1.410, 0.250, 0.500, 0.235 and 0.117 ug/L respectively. pHEMA is known to enhance the reproducibility of the biosensor with average relative standard deviation (RSD) of +/-1.76% for all the pollutants tested, 48% better than the biosensor without pHEMA (RSD = +/ 3.73%). In storability test with Cu 5 ug/L, the biosensor with pHEMA performed 11.5% better than the test without pHEMA on day-10 and 5.2% better on day-25. pHEMA is therefore a good candidate to be used in whole cell biosensors as it increases reproducibility and enhances biosensor storability. PMID- 23673680 TI - Hardware accelerated compression of LIDAR data using FPGA devices. AB - Airborne Light Detection and Ranging (LIDAR) has become a mainstream technology for terrain data acquisition and mapping. High sampling density of LIDAR enables the acquisition of high details of the terrain, but on the other hand, it results in a vast amount of gathered data, which requires huge storage space as well as substantial processing effort. The data are usually stored in the LAS format which has become the de facto standard for LIDAR data storage and exchange. In the paper, a hardware accelerated compression of LIDAR data is presented. The compression and decompression of LIDAR data is performed by a dedicated FPGA based circuit and interfaced to the computer via a PCI-E general bus. The hardware compressor consists of three modules: LIDAR data predictor, variable length coder, and arithmetic coder. Hardware compression is considerably faster than software compression, while it also alleviates the processor load. PMID- 23673682 TI - Meeting report of the 26th International Mammalian Genome Conference. PMID- 23673681 TI - Biosensors in clinical practice: focus on oncohematology. AB - Biosensors are devices that are capable of detecting specific biological analytes and converting their presence or concentration into some electrical, thermal, optical or other signal that can be easily analysed. The first biosensor was designed by Clark and Lyons in 1962 as a means of measuring glucose. Since then, much progress has been made and the applications of biosensors are today potentially boundless. This review is limited to their clinical applications, particularly in the field of oncohematology. Biosensors have recently been developed in order to improve the diagnosis and treatment of patients affected by hematological malignancies, such as the biosensor for assessing the in vitro pre treatment efficacy of cytarabine in acute myeloid leukemia, and the fluorescence resonance energy transfer-based biosensor for assessing the efficacy of imatinib in chronic myeloid leukemia. The review also considers the challenges and future perspectives of biosensors in clinical practice. PMID- 23673684 TI - A straightforward access to guaiazulene derivatives using palladium-catalysed sp2 or sp3 C-H bond functionalisation. AB - A novel palladium-catalysed direct arylation of guaiazulenes with a variety of aryl bromides is reported. Both sp(2) and sp(3) C-H bonds have been functionalised, as the nature of the cation of the base was found to allow the control of the regioselectivity of the arylation giving rise to C2 or C3 arylated guaiazulenes and also to 4-benzylguaiazulenes. PMID- 23673683 TI - Meeting report of the European mouse complex genetics network SYSGENET. AB - The second scientific meeting of the European systems genetics network for the study of complex genetic human disease using genetic reference populations (SYSGENET) took place at the Center for Cooperative Research in Biosciences in Bilbao, Spain, December 10-12, 2012. SYSGENET is funded by the European Cooperation in the Field of Scientific and Technological Research (COST) and represents a network of scientists in Europe that use mouse genetic reference populations (GRPs) to identify complex genetic factors influencing disease phenotypes (Schughart, Mamm Genome 21:331-336, 2010). About 50 researchers working in the field of systems genetics attended the meeting, which consisted of 27 oral presentations, a poster session, and a management committee meeting. Participants exchanged results, set up future collaborations, and shared phenotyping and data analysis methodologies. This meeting was particularly instrumental for conveying the current status of the US, Israeli, and Australian Collaborative Cross (CC) mouse GRP. The CC is an open source project initiated nearly a decade ago by members of the Complex Trait Consortium to aid the mapping of multigenetic traits (Threadgill, Mamm Genome 13:175-178, 2002). In addition, representatives of the International Mouse Phenotyping Consortium were invited to exchange ongoing activities between the knockout and complex genetics communities and to discuss and explore potential fields for future interactions. PMID- 23673685 TI - Erosions after laparoscopic adjustable gastric banding: diagnosis and management. AB - OBJECTIVE: To define the changing prevalence of erosion after Laparoscopic Adjustable Gastric Banding (LAGB), describing the range of clinical presentations, the approaches to treatment and the outcomes from these approaches over a 15-year study period. BACKGROUND: A recent systematic review of the literature of erosion after LAGB identified 25 relevant studies and reported a total of 231 erosions in 15,775 patients giving an overall incidence of 1.46%. The review highlighted a broad variation of incidence from 0.2% to 33%. The review was unable to identify either common presentations or an optimal pattern of management. METHODS: Patients who underwent a primary LAGB operation between September 1994 and January 2010 by 2 surgeons (P.O.B. and W.B.) were identified in a prospectively maintained database. Those patients who had an erosion of their LAGB were identified. Presentation, operative details, demographics, body mass index, weight history, and perioperative problems were analyzed. RESULTS: In total, 2986 patients were identified. All bands placed were Lap-Bands (Allergan, CA). Hundred erosions were experienced by 85 patients (2.85%) at a median time of 33 months from initial surgery to the erosion (range: 11-170 months). The rate of erosion was highest when the band was placed by the perigastric approach at 6.77%. Since the adoption of the pars flaccida approach, the rate of erosion has dropped to 1.07%. The majority of patients who had experienced an erosion (71 patients; 83.5%) experienced only 1 erosion, 13 patients (15.3%) had 2 erosions, and 1 patient had 3 erosions. The most common presentation was loss of satiety. The band has been successfully replaced in 56 patients. It has been explanted in 27 patients and 2 patients were converted to other bariatric procedures. The weight loss in patients who had a LAGB reinserted after erosion was not significantly different to the background cohort. CONCLUSIONS: Erosion of LAGB is uncommon and its clinical course is benign. It is best treated with a staged surgical approach; initially, with removal and repair followed later by replacement. With this approach, weight loss is maintained and reerosion is uncommon. PMID- 23673686 TI - Preparation and characterization of titania-entrapped silica hollow particles: effective dye removal and evidence of selectivity. AB - A titania-entrapped silica hollow nanostructure was prepared using two consecutive coating processes, followed by calcination. The hydrothermal treatment of D-glucose assisted by polyethylene glycol was used to form a carbon layer over the titania surface. The resulting composite was used to fabricate a silica layer on top by hydrolyzing tetraethyl orthosilicate in strong base. The titania nanoparticles were then released but still trapped inside the silica hollow after calcination. Scanning and transmission electron microscopic techniques were employed to determine the morphology of the obtained product; nitrogen gas adsorption and X-ray diffraction methods were also used. Photocatalytic studies on five organic dyes showed that efficient dye-removal due to photocatalysis and adsorption with selectivity based on the charge-charge interaction between the dye and silica surface was possible. Other factors including the structures of the dyes and their molecular interaction also influenced the observed removal efficiency. PMID- 23673687 TI - Biocompatible, multifunctional, and well-defined OEG-based dendritic platforms for biomedical applications. AB - Given the growing importance of drug and gene delivery systems, imaging agents, biosensors, and theranostics, there is a need to develop new multifunctional and biocompatible platforms. Here we synthesized and fully characterized a family of novel multifunctional and completely monodisperse dendritic platforms. Our synthetic methodology, based on compatible protecting groups and the attachment of monodisperse triethylene glycol units, allows the control of the generation and differentiation of terminal groups, thus giving rise to multifunctional and perfectly-defined products. A family of dendrons was synthesized and four distinct dendritic structures were chosen from the family in order to determine the effect of the generation and surface groups on their biocompatibility. The stability in serum, cytotoxicity, and hemocompatibility of these products were studied. Our results indicate that these non-toxic, hemocompatible, non immunogenic, stable and versatile scaffolds may be very interesting candidates for biomedical applications. PMID- 23673688 TI - Comparison of three techniques for calculation of the Parkland formula to aid fluid resuscitation in paediatric burns. AB - CONTEXT: Inadequate fluid resuscitation of acute burns may result in hypovolaemic shock. Excessive fluid resuscitation may result in fluid overload. A nomogram which uses the popular Parkland formula and '4-2-1' regime has been recently described to facilitate the calculation of fluid requirements in children during the first 24 h following burn injury. OBJECTIVE: To compare the accuracy and speed of calculation of three different methods (pen and paper, electronic calculator and nomogram), which all use the Parkland formula and '4-2-1' regime to calculate maintenance and resuscitation fluid requirements for children in the first 24 h after burn injury. DESIGN: A randomised volunteer study using computer generated simulated patient data. SETTING: Welsh Centre for Burns, ABM University Local Health Board, Swansea, UK. Data were collected between February 2011 and October 2011. PARTICIPANTS: The group consisted of 36 volunteers including trainee and consultant surgeons and anaesthetists. INTERVENTION: Thirty-six participants performed 318 calculations, using each of the three methods of calculation up to three times. MAIN OUTCOME MEASURES: Accuracy, speed and acceptability of the different methods. RESULTS: For nomogram, calculator and pen and paper: magnitude of error [low (>=25%), medium (>=50%) and high (>=75%)]: [5.7, 4.7 and 3.8%], [12.1, 12.1 and 7.5%], [28.6, 21.9 and 16.2%]; [P <0.001, P = 0.001 and P = 0.006]. Calculation time: [s; mean (SD)]: 121 (48), 109 (52) and 240 (140); P <0.001. The mean (SD) of the difficulty scores were 17.3 (13), 20.6 (13.4) and 62.2 (23.4); P <0.001. CONCLUSION: The nomogram was the most accurate method of calculating fluid requirements using the Parkland formula, was only slightly slower than the electronic calculator and was deemed the easiest to use. The nomogram is also low cost, robust, and provides a rapid means of detecting and preventing the large errors that we have shown can occur when an electronic device is used as the primary method of resuscitation fluid calculation. We, therefore, suggest that the nomogram is a suitable method for the calculation of the Parkland formula to guide resuscitation and maintenance fluid requirements in the first 24 h of paediatric burns or for cross-checking the results obtained by other means of calculation. PMID- 23673689 TI - Development of a practical screening tool to predict low muscle mass using NHANES 1999-2004. AB - BACKGROUND: Skeletal muscle mass declines after the age of 50. Loss of skeletal muscle mass is associated with increased morbidity and mortality. OBJECTIVE: This study aims to identify predictors of low skeletal muscle mass in older adults toward development of a practical clinical assessment tool for use by clinicians to identify patients requiring dual-energy X-ray absorptiometry (DXA) screening for muscle mass. METHODS: Data were drawn from the National Health and Nutrition Examination Surveys (NHANES) from 1999 to 2004. Appendicular skeletal mass (ASM) was calculated based on DXA scans. Skeletal muscle mass index (SMI) was defined as the ratio of ASM divided by height in square centimeters. Elderly participants were classified as having low muscle mass if the SMI was 1 standard deviation (SD) below the mean SMI of young adults (20-40 years old). Logistic regression was conducted separately in males and females age >=65 years of age to examine the relationship between patients identified as having low muscle mass and health behavior characteristics, adjusting for comorbid conditions. The model was validated on a separate sample of 200 patients. RESULTS: Among the NHANES study population, 551 (39.7 %) males and 374 (27.5 %) females had a SMI below the 1 SD cutoff point. NHANES study subjects with a low SMI were older (mean age, 76.2 vs. 72.7 for male; 76.0 vs. 73.7 for female; and both p < 0.0001) and had a lower body mass index (mean BMI, 24.1 vs. 29.4 for male; 22.9 vs. 29.7 for female; p < 0.0001). In adjusted logistic regression analyses, age (for males) and BMI (for both males and females) remained statistically significant. A parsimonious logistic regression model adjusting for age and BMI only had a C statistic of 0.89 for both males and females. The discriminatory power of the parsimonious model increased to 0.93 for males and 0.95 for females when the cutoff defining low SMI was set to 2 SD below the SMI of young adults. In the validation sample, the sensitivity was 81.6 % for males and 90.6 % for females. The specificity was 66.2 % for males and females. CONCLUSIONS: BMI was strongly associated with a low SMI and may be an informative predictor in the primary care setting. The predictive model worked well in a validation sample. PMID- 23673690 TI - A new species of Grillotia Guiart, 1927 (Cestoda: Trypanorhyncha) with redescriptions of congeners and new synonyms. AB - A new species of Grillotia, G. gastrica n. sp., is described from the stomach musculature of the teleosts Upeneichthys lineatus (Bloch & Schneider) and Sillaginodes punctatus (Cuvier) from off Perth, Western Australia. The new species most closely resembles G. pristiophori Beveridge & Campbell, 2001 in having six hooks in each principal row of the metabasal tentacular armature but differs in having a smooth scolex tegument and in having a band of hooklets running the entire length of the external surface of the tentacle rather than diminishing in width to a single hooklet as occurs in G. pristiophori. Grillotia heptanchi (Vaullegeard, 1899) is redescribed and the details of the mature segment are described for the first time. Grillotia adenoplusius (Pintner, 1903) is redescribed from the type-specimens and is considered to be the larval stage of G. acanthoscolex Rees, 1944 (syns G. spinosissima Dollfus, 1969 and G. microthrix Dollfus, 1969). The adult of G. adenoplusius is also redescribed based on the types of G. spinosissima. The type-specimens of G. dolichocephala Guiart, 1935 and G. minor Guiart, 1935 were re-examined and G. minor is considered to be a synonym of G. dolichocephala as is G. meteori Palm & Schroder, 2001. Based on an examination of the type-specimens, G. scolecina (Rudolphi, 1819) is treated as a species inquirenda. A list is provided of the species currently placed in Grillotia. PMID- 23673691 TI - Ligophorus abditus n. sp. (Monogenea: Ancyrocephalidae) and other species of Ligophorus Euzet & Suriano, 1977 infecting the flathead grey mullet Mugil cephalus L. in the Sea of Japan and the Yellow Sea. AB - As a result of the re-examination of museum slides and new material of monogeneans collected from Mugil cephalus L. in the Sea of Japan, the estuary of a river which flows into the Sea of Japan, the Yellow Sea (off Zhifu, at the boundary of the Bohai Sea) and the East China Sea (off the Ryukyu Islands), five species of Ligophorus Euzet & Suriano, 1977 were identified, one of which is new. The known species are L. chabaudi Euzet & Suriano, 1977, L. cheleus Rubtsova, Balbuena & Sarabeev, 2007, L. domnichi Rubtsova, Balbuena & Sarabeev, 2007 and L. pacificus Rubtsova, Balbuena & Sarabeev, 2007, which are reported from the Yellow Sea; in addition, L. domnichi is reported for the first time from the East China Sea. Ligophorus abditus n. sp., from the Sea of Japan, differs from its most similar congeners, L. pacificus and L. domnichi, in the shapes of the dorsal anchors and the accessory piece of the male copulatory organ. A comparison of all of the species of Ligophorus recovered from M. cephalus in the Sea of Japan was carried out using Principal Component Analysis, and their distribution and origin are discussed. PMID- 23673692 TI - New species of Kiluluma Skrjabin, 1916 (Nematoda: Strongylida) from the white rhinoceros Ceratotherium simium (Burchell), with a redescription of K. solitaria Thapar, 1924. AB - Three species of Kiluluma Skrjabin, 1916 were identified in Ceratotherium simium (Burchell) from a captive population in New South Wales, Australia, based on analysis of the second internal transcribed spacer (ITS-2) of ribosomal DNA. One species was identified as K. solitaria Thapar, 1924 and is redescribed. A second species is new and is described here as K. ceratotherii n. sp. The third species is new but was represented by two individuals only and is described but is not named. PMID- 23673693 TI - Three species of opisthomonorchiine monorchiids (Digenea) in Carangoides spp. (Perciformes: Carangidae) from off New Caledonia, with a description of Opisthomonorchis dinema n. sp. AB - Three opisthomonorchiinae species are described from fishes obtained at the Fish Market in Noumea, New Caledonia. Opisthomonorchis dinema n. sp. from Carangoides dinema Bleeker differs from the other recognised species in the genus by the long recurved genital atrium, arcing anteriorly. Also described are Opisthomonorchis carangis Yamaguti, 1952 from Carangoides sp. and Pseudopisthomonorchis thapari (Varma & Singh, 1979) n. comb. for Opisthomonorchis thapari Varma & Singh, 1979 from Carangoides chrysophrys (Cuvier). The features distinguishing Opisthomonorchis Yamaguti, 1952 and Pseudopisthomonorchis Madhavi, 1974 are discussed. PMID- 23673694 TI - Morphological and molecular characterisation of Xiphinema macroacanthum Lamberti, Roca & Agostinelli, 1989 (Nematoda: Longidoridae) from olive orchards in southern Italy. AB - A population of Xiphinema macroacanthum Lamberti, Roca & Agostinelli, 1989 originating from olive orchards in Brindisi, Italy and containing both adults and all juvenile stages, is described and illustrated. The first juvenile stage is reported for the first time. Molecular characterisation of this species, using the D2-D3 expansion domains of the 28S rDNA and ITS region, was carried out. PCR RFLP analyses of the ribosomal gene regions determined species-specific patterns that clearly differentiate X. macroacanthum. Sequences of the D2-D3 domains and the partial 18S-ITS1 rRNA genes were analysed using several methods for inferring phylogeny to reconstruct the relationships between X. macroacanthum and other Xiphinema species. PMID- 23673695 TI - New data on Longidorus aetnaeus Roca, Lamberti, Agostinelli & Vinciguerra, 1986 (Nematoda: Longidoridae) from Iran and Ajaria (Georgia). AB - Longidorus aetnaeus Roca, Lamberti, Agostinelli & Vinciguerra, 1986 is reported for the first time from Iran and Ajaria (Georgia). Morphological and morphometric data are provided for two Iranian and one Ajarian populations. The D2-D3 region of 28S rDNA for both Iranian populations was sequenced for the first time and the data reported. A detailed study of juveniles of L. aetnaeus from Iran, Georgia and Bulgaria demonstrated that this species develops through three juvenile stages. Furthermore, phylogenetic studies inferred from sequences for the D2-D3 region of 28S rRNA gene revealed that L. aetnaeus is most closely related to L. leptocephalus. PMID- 23673696 TI - Redescription of Eimeria zarudnyi Alyousif & Al-Shawa, 2003 as Choleoeimeria zarudnyi n. comb. (Apicomplexa: Eimeriidae). AB - Coprological examination of the worm lizard Diplometopon zarudnyi Nikolskii revealed the presence of oocysts of Choleoeimeria zarudnyi (Alyousif & Al-Shawa, 2003) n. comb. in five (17%) of the 30 lizards examined. Sporulated oocysts were found in the faeces and the gallbladder contents. These are tetrasporocystic, ellipsoidal, 25-32 * 18-25 (mean 27 * 22) MUm, with a smooth bi-layered wall. The dizoic sporocysts are ovoidal, 10-13 * 6-9 (mean 11 * 7) MUm, with a granulated sporocyst residuum. Sporozoites are banana-shaped with an average size of 13 * 3 MUm. Endogenous stages (meronts, gamonts and gametes) are confined to the gallbladder epithelium and the infected cells were hypertrophied. Based on the morphological features of the exogenous stages and the endogenous development of the present parasite, its generic affiliation is revised and Eimeria zarudnyi Alyousif & Al-Shawa, 2003 is transferred to the genus Choleoeimeria. PMID- 23673697 TI - A new species of Caryospora Leger, 1904 (Apicomplexa: Eimeriidae) from the snake Philodryas olfersii Lichtenstein (Colubridae) from a coastal habitat in Brazil. AB - A new coccidian species of the genus Caryospora Leger, 1904 (Protozoa, Apicomplexa, Eimeriidae) is reported from the colubrid snake host Philodryas olfersii Lichtenstein at a coastal area in the State of Rio de Janeiro, south eastern Brazil. Oocysts of Caryospora olfersii n. sp. are spherical to sub spherical, 33.1 * 31.2 MUm, with smooth, colourless, three-layered wall, c.1.4; middle layer lightly striated. Micropyle, oocyst residuum and polar granule are all absent. Sporocysts are ovoid, 22.9 * 17.4 MUm on average, with one extremity in the shape of a short neck. Stieda body present, 3.2 * 1.3 MUm, sub-Stieda body present, homogeneous, larger than Stieda body, 4.5 * 1.7 MUm. Sporozoites are inserted in a bulky sporocyst residuum. PMID- 23673698 TI - [History of pelvic prolapse]. AB - The history of pelvic prolapse back to the era of the pharaohs, about 1500 years before Christ. Hippocrates practiced succussion. Grenades, pieces of soaked linen were used as pessaries.Over the centuries, the eolution in understanding of this female pathology led to different treatment modalities, some of which we can currently seem strange. PMID- 23673699 TI - Prognostic factors in Crohn's disease: a systematic review. AB - BACKGROUND: The natural history of Crohn's disease is associated with several factors that affect the prognostic of the patients. AIMS: To determine the most prognostic factors in Crohn's disease, based on a systematic review. METHODS: Literature review. RESULTS: The most important factors to consider in patients with Crohn's disease are the need for immunosuppressive therapy, the need for intestinal resection and disabling disease. Prognostic factors for these events are ileal involvement, perianal disease and initial treatment by corticosteroid. Other factors such young age, CRP level and smoking status, has not been found in all population-based studies. Protective role of anti-TNF drugs is strongly suggested but need to be confirmed in further studies. CONCLUSION: In a selected subgroup of patients with Crohn's disease characterized by the presence of these prognostic markers, the "topdown" strategy can be proposed. PMID- 23673700 TI - [Prevalence and correlates of major depressive episodes in Sousse primary care setting: assessment with the Tunisian version of CIDI]. AB - BACKGROUND: Major depression is a mental disorder that is associated with high morbidity and significant mortality. It is common among primary care attenders. Few is known about major depression prevalence and associated factors, which would prevent general practitioners from diagnosing it in primary care centres and treating it adequately. AIM: To determine prevalence and correlates of major depressive episodes (MDE) in a representative sample of primary care attenders in the area of Sousse (Tunisia). METHODS: A random and representative sample of primary care attenders was obtained by a two-stage sampling procedure. First, 30 primary care centres (20 urban and 10 rural) were selected, with stratification according to residency location. Second, 1246 consenting participants were systematically recruited among those centres attenders. Participants were screened, by trained interviewers, with Tunisian version of " Composite International Diagnostic Interview " CIDI.2.1. After data entry in ishell program, MDE diagnosis was obtained according to ICD-10 criteria. RESULTS: Mean age in our sample was 43.4 +/- 17.62 years, with feminine (70.9 %) and urban (67.8 %) predominance. MDE was found in 26.4 % of participants. Associated factors were female gender, marital statute of widowed or divorced and rural residency. CONCLUSION: This study provided data about high prevalence of MDE in the area of Sousse primary care centres and its correlated factors. PMID- 23673701 TI - Antepartum detection of macrosomic fetus: the effect of misdiagnosis. AB - AIM: To determine the effect of misdiagnosis of macrosomia on maternal and perinatal outcomes. METHODS: We conducted a retrospective study ,between January 2007 and December 2008 of women (n = 464) who delivered singleton neonates with actual birth weight over 4000g and in whom fetal weight was estimated, by both methods :sonographic and clinical, up to 3 days before delivery.Statistical comparisons were made between patients in whom fetal macrosomia was predicted : "prediction " group (n=336)and those in whom it was not " non prediction "group (n=128) for outcome variables. RESULTS: The cesarean delivery was performed in 35.9% in " non predicted " group, and in 35.7% in the " predicted " group.The difference was not statistically significant. Failure to detect macrosomia was associated with higher rates of maternal and fetal complications in the group " non predicted " compared with the group " predicted " :perineal trauma,post partum hemorrhage, 5- minute Apgar scores less than 7, and shoulder dystocia, mostly related to the higher rate of surgical vaginal deliveries. CONCLUSIONS: The misdiagnosis of fetal macrosomia substantially did not modify the cesarean section rate but leads to increase the maternal and neonatal complications. PMID- 23673702 TI - Natural history of atrial septal defect in the sixth decade : study of 5 cases. AB - BACKGROUND: Atrial septal defect (ASD) is one of the most common causes of congenital heart disease manifested in adulthood. AIM: To describe clinical and likelihood picture of adults over 60 years born with an ASD type II. METHODS: We performed a retrospective study of adult'sASD referred toourinstitutionfrom 1985 through 2010. Clinical, electrocardiographic, echocardiographic and hemodynamic data were reviewed. On follow up study, patients were investigated by echocardiography, ECG and assessed for quality of life by a questionnaire RESULTS: Among forty ASD type II manifested in adulthood which were referred to our department of cardiology five cases of ASD manifested in the sixth decades (2 men and 3 women). Complaints were dyspnea and palpitations in 4 cases and chest pain in only one patient. Slight anterior chest deformity was present in the older patient. Systolic murmur was found in the 3rd left intercostals space and the pulmonary second heart sound was accentuated in all patients. Complete right bundle branch block and right ventricular hypertrophy were found in all cases. Three patients presented atrial fibrillation. There was marked cardiomegaly in four patients. The pulmonary arteries were markedly enlarged and the peripheral vascular markings were increased. Echocardiographic data revealed large secundum ASD (mean 20 mm, ranged between 10 and 30mm), severe systolic pulmonary pressure in two cases (>5O mmhg). MeanQP/QS was 2.2 and contrast revealed bidirectional shunt in one patient. All patients were studied by venous cardiac catheterization. They showed a significant increase in the oxygen content of right atrial blood. Three patients underwent surgical atrial septal defect closure under general anesthesia. There were no operative or peri operative deaths. At mean follow up of 50+/-75 months, there was one late death from heart failure in a patient with advanced preoperative heart failure. The oldest patient is in the medical group and he is 75years old. Most survival patients remain in good clinical condition. Some of them were symptomatic at the last follow up and complained of shortness of breath on effort and palpitations in two cases. Two patients were in chronic atrial fibrillation developed during follow up. However, chest RX showed reduction in cardiothoracic ratio postoperatively. Echocardiographic examination confirmed that there was no residual shunt in across the atrial septum in any patient. Systolic pulmonary pressure felled only in 2 patients in the surgery group. CONCLUSION: To our knowledge, thesepatients havealongue life span, although survivors with ASD described in the world. There is a lack of evidence regarding treatment options for adults with an ASD aged more than 60years. Given the higher risks of surgery in advanced age, the defect should be repaired as early as possible to prevent hemodynamic complications. PMID- 23673703 TI - [Pulmonary function in rheumatoid arthritis in a Tunisian population]. AB - BACKGROUND: The rheumatoid polyarthritis (PR) is a frequent pathology in Tunisia. The most frequent extra articular expression of this disease is in the respiratory tract. AIM: To determine the lung functional profile of PR of the Tunisian population by establishing possible relations between ventilatory variables and clinico-biological parameters of PR. METHODS: It is a cross sectional study which concerned 87 patients (77 women) having a confirmed PR. They benefited from a measure of the lung function by a total physical Plethysmography and by the technique of double transfer NO-CO. Clinical and biological checkup were realized. RESULTS: Three kinds of pulmonary function defects were found: obstructive ventilatory defect (13%), restrictive defect (7%) and mixed defect (1%). Ventilatory flows and the lung volumes correlated negatively with the inflammatory syndrome (p<0.05). Alveolar-capillary diffusion capacity (DLco) was altered in an isolated way or associated with the respiratory functional syndromes (obstructive and restrictive) (6%). This abnormality had a vascular origin with an isolated fall of the lung capillary volume (Vc), a membrane origin with an isolated fall of the diffusion membrane (DM) or a combined origin with the decline of Vc and DM. This latter case was found at a late stage of PR. 58% of PR patients had a normal pulmonary function. CONCLUSION: All these functional findings were linked to PR itself (inflammatory and auto immune origin) or to the lung toxicity due to the treatment by Methotrexate (alveolar and bronchial damage). PMID- 23673704 TI - [Ultrasound diagnosis of ectopic pregnancy : prospective study of 200 cases]. AB - BACKGROUND: the ectopic pregnancy is responsible for 10% of maternal mortality in the first quarter. Progress in transvaginal ultrasound; have revolutionized the diagnosis of ectopic pregnancy, allowing her diagnosis earlier. AIM: To evaluate the contribution of ultrasonography in the diagnosis of ectopic pregnancy. METHODS: A prospective study about 200 patients hospitalized for ectopic pregnancy between July 2009 and July 2011. All patients underwent a transvaginal ultrasound. RESULTS: The average age was 25.4 years. The study of the endometrium showed an endometrial thickness of 10.1mm in 152 cases. An haematosalpinx was observed in 71% of cases. The average size was 30.5mm. Hemoperitoneum was observed in 64.5% of cases. An ectopic gestational sac with embryo was found in 9 cases (4.5%). In 51 cases no pathological sonographic signs were noted. CONCLUSION: The transvaginal ultrasound is the method of choice in the diagnosis of ectopic pregnancy. However the use of BHCG is still necessary. PMID- 23673705 TI - [Primary distal renal tubular acidosis in children in the South of Tunisia: study of 15 cases]. AB - BACKGROUND: primary distal renal tubular acidosis in children (RTA) is characterized by metabolic acidosis due to defect in urinary excretion of hydrogen (H+) in the distal tubular. AIM: To report the epidemiological, clinical, therapeutic and evolutionary of distal RTA in our patients. PATIENTS AND METHODS: We conducted a retrospective study of all cases of distal RTA collected in the department of pediatrics of Hedi Chaker University hospital in the south of Tunisia, during a period of 23 years (1988-2010). We studied the epidemiological, clinical, biological, evolutionary and therapeutic data. RESULTS: During the study period 15 cases of distal RTA were collected. The average age was 6 months (1 month -2 years). Most common presenting symptoms were vomiting (8cases), failure to thrive (4cases), lack of appetite, polyuria polydipsia syndrome (1case) and urinary infection (2cases). The clinical examination showed staturoponderal delay (9 cases), dehydration (6 cases), signs of rickets (3 cases) and polyuria (10 cases). Biological data showed high urine pH in the presence of metabolic acidosis in 11 cases, hypokalaemia in 10 cases and hypercalciuria in all cases. Urine acidification test with ammonium chloride was performed in 4 cases, the urinary pH was always higher than 5.5 in all cases. Ammoniuria performed in 9 cases was less than 40mmol/l. Radiological investigation objectified a nephrocalcinosis in fourteen patients and signs of rickets in three cases. Deafness was found in three patients. Genetic study performed in two cases showed mutation of ATP6V1B1 gene. The medical treatment involved an alkali load. Long-term outcome was favorable in 7 cases. CONCLUSION: The distal renal tubular acidosis is a rare pathology in our country but probably under diagnosed. The clinical gravity of this disease and the risk of evolution towards the terminal renal insufficiency justify an antenatal diagnosis to establish a neonatal management or propose a therapeutic interruption of the pregnancy if the distal RTA is associated with a severe pathology. PMID- 23673706 TI - [Predictive factors of esophagojejunal fistula after total gastrectomy in gastric cancer patients]. AB - BACKGROUND: The main complication observed after total gastrectomy is the oesophagojejunal anastomosic fistla. Its incidence varies between 7.4% and 11.5%. The mortality after anastomic leafage is high at around 20%, representing 30% and 54% of global mortality after total gastrectomy. AIM: This study aimed to evaluate mortality and morbidity after total gastrectomy and to determine their predictive factor METHODS: this is retrospective study about 80 cases of total gastrectomy for gastric cancer, collected in the departmentof General Surgery of the University Hospital Habib Thameur Tunis during the period 1 January 1995 to 31 December 2010. Reconstruction of the alimentary tract was achieved by Roux-en Y-jejunal-loop. RESULTS: Esophagojejunal anastomotic leeakage developed in 14 patients (17%). In 8 patients treatment of anastomotic leakage consisted of re operation with surgical drainage and confection of jejunostomy. in one patient treatment required resutre of the anastomosis and drainage of an abscess. In one patient treatment required resuture of the anastomosis and drainage of an abscess. in 5 of the 14 patients with a proven leak of oesophagojejunal anastomosis, conservative treatment with parental alimentation, placement of an irrigation-aspiration system and systemic antibiotics was performed. This treatment was successful in all cases. The presence of anastomic fistula extends the median lenght of post operative stay in the hospital of 20 days compared for the payents withiut fistula.Global mortalilty was 8/80 (10%). After esophagojejunal anastomotic leakage, the mortality was 3/8 (21%). CONCLUSION: Leakage of the oesophago-intestinal anastomosis may occur after total gastrectomy for gastric cancer. it's serious complication contributes to mortality after total gastrectomy. Knowledge of the predective factors of esophagojejunal fistula after total gastrectomy in gastric cancer can decrease its incidence . PMID- 23673707 TI - [The usefulness of elastase measurement in the sperm for the diagnosis of urogenital male inflammation and infection]. AB - BACKGROUND: Genital tract inflammation is a frequent cause of infertility among men, usually clinically silent with only leukocytospermia defined as the presence of white blood cells (WBC)>1.106/ml in semen. During the inflammation process, granulocytes discharge large amounts of proteases such as elastase. The elastase linked to its inhibitor in the form of a complex the elastase alpha1-protease inhibitor in semen is suggested as a potential marker of genital tract inflammation. AIM: To assess the measurement of elastase as a biomarker of genital tract inflammation by comparing this technique with the detection of leukocytospermia according to the WHO guidelines. METHODS: This study interested 83 infertile men attending the andrology center for semen analysis. Leukocytospermia was assessed by a peroxydase test and elastase concentration by immunoassay in the seminal plasma. RESULTS: An elevated elastase was found in 38% of men. A similarity was found between leukocytospermia and elastase in 79% of cases, kappa coefficient concordance with leukocytospermia is good (0.78). The sensitivity of the elastase is 100%, the specificity= 75%. The positive predictive value is 47%, the negative predictive value is 100% with a Youden index=0.75. All patients with leukocytospermia>1.106/ml had an elastase>250ng/ml, 73% of them a concentration>1000 ng/ml. In the group of patients with no leucocytospermia, 75% had elastase<250ng/ml, 21% had concentration between 250 and 1000ng/ml and 4% (3 patients) a concentration>1000ng/ml. CONCLUSION: Seminal elastase is a more sensitive marker than leucocytospermia in the diagnosis of male urogenital inflammation and infection. PMID- 23673708 TI - Unbalanced bone remodeling in Tunisian patients with inflammatory bowel diseases. AB - BACKGROUND: Bone loss is an ignored complication in inflammatory bowel diseases. Its underling mechanisms are not fully elucidated. OBJECTIVES: To investigate bone turnover in patients with inflammatory bowel diseases. METHODS: The study included 67 patients with inflammatory bowel diseases and 54 age- and sex-matched healthy subjects. Urinary degradation products of C-terminal telopeptide of type I collagen, serum osteocalcin, parathyroid hormone, 25 hydroxy vitamin D and interleukin-6 were assessed. Bone mineral density was measured by dual energy-X ray absorptiometry and osteoporosis was defined as T score < -2.5 SD. RESULTS: Patients showed significantly higher levels of C-terminal telopeptide of type I collagen and interleukin-6 and lower levels of 25 hydroxy vitamin D. Serum osteocalcin and parathyroid hormone were in normal range. In multivariate analysis, urinary degradation products of C-terminal telopeptide of type I collagen were associated with disease activity (p=0.04) and osteocalcin was associated with parathyroid hormone (p=0.04). Urinary degradation products of Cterminal telopeptide of type I collagen and interleukin-6 were significantly increased in inflammatory bowel disease patients with osteoporosis. No association was found between osteoporosis and serum osteocalcin, parathyroid hormone and 25 hydroxy vitamin D. CONCLUSION: Bone resorption rate is increased and is associated with osteoporosis in inflammatory bowel disease patients. Inflammation, malnutrition, and hypovitaminosis D may contribute to the bone loss. PMID- 23673709 TI - Bowen's disease: epidemiological and clinical study of 9 Tunisian cases. AB - BACKGROUND: Bowen's disease (BD) is a form of in situ SCC, characterized by chronic and progressive course, with low potential for invasive malignancy. AIM: To assess epidemiology and clinical features of BD in a Tunisian cohort. METHODS: A retrospective study of 9 cases of BD managed in a Tunisian dermatology department. RESULTS: There were 7 males (77.8%) and 2 females (22.2%). The mean age of patients was about 68.8 years (46-89). Lesions were solitary in 7 cases and occurred in various sites: face (1 patient), trunk (2 patients), limbs (6 patients). The mean diameter of the tumour was about 3.4 cm. Lesions presented clinically as an enlarging well demarcated erythematous plaque with irregular borders and crusted or scaling surface. Histological examination showed in all cases abnormal keratinocytes with disordered maturation and loss of polarity replacing the epidermis in its whole thickness. The main treatment was surgery (N=5). Only one patient had radiotherapy (case 1). Outcome was mentioned in 2 patients who remained free from recurrence respectively after a follow-up of 1 and 12 years. CONCLUSION: Our series outlines epidemiological and clinical features of BD in Tunisia through a small but representative sample. As in the literature, this condition prevailed mainly over 60 years. In our study, BD occurred predominantly in men and affected nonexposed sites in 8 cases. This profile is uncommon in a sunny country in Tunisia, in the absence of other aetiological agents. PMID- 23673710 TI - [Nephroblastomas in adults]. PMID- 23673711 TI - [Currarino's disease in a young Togolease]. PMID- 23673712 TI - [Laparoscopic management of borderline malignancy ovarian tumors discovered during pregnancy]. PMID- 23673713 TI - [Dermatophytosis: Tunisian characteristics]. PMID- 23673714 TI - [Desmoid tumors associated with familial adenomatous polyposis]. PMID- 23673715 TI - [Incidental discovery of a left paraduodenal internal hernia]. PMID- 23673717 TI - [Cavernous hemangioma: a cause of hematuria in children]. PMID- 23673716 TI - Primary pulmonary carcinosarcoma. PMID- 23673718 TI - [Acquired combined deficiency of Factor V and VIII]. PMID- 23673720 TI - High field strength magnetic resonance imaging in paediatric brain tumour surgery -its role in prevention of early repeat resections. AB - PURPOSE: The purpose of this study is to compare the surgical and imaging outcome in children who underwent brain tumour surgery with intention of complete tumour resection, prior to and following the start of intra-operative MRI (ioMRI) service. METHODS: ioMRI service for brain tumour resection commenced in October 2009. A cohort of patients operated between June 2007 and September 2009 with a pre-surgical intention of complete tumour resection were selected (Group A). A similar number of consecutive cases were selected from a prospective database of patients undergoing ioMRI (Group B). The demographics, imaging, pathology and surgical outcome of both groups were compared. RESULTS: Thirty-six of 47 cases from Group A met the inclusion criterion and 36 cases were selected from Group B; 7 of the 36 cases in Group A had unequivocal evidence of residual tumour on the post-operative scan; 5 (14%) of them underwent repeat resection within 6 months post-surgery. In Group B, ioMRI revealed unequivocal evidence of residual tumour in 11 of the 36 cases following initial resection. In 10 of these 11 cases, repeat resections were performed during the same surgical episode and none of these 11 cases required repeat surgery in the following 6 months. Early repeat resection rate was significantly different between both groups (p = 0.003). CONCLUSION: Following the advent of ioMRI at our institution, the need for repeat resection within 6 months has been prevented in cases where ioMRI revealed unequivocal evidence of residual tumour. PMID- 23673719 TI - Biochemical and functional interactions of human papillomavirus proteins with polycomb group proteins. AB - The role of enzymes involved in polycomb repression of gene transcription has been studied extensively in human cancer. Polycomb repressive complexes mediate oncogene-induced senescence, a principal innate cell-intrinsic tumor suppressor pathway that thwarts expansion of cells that have suffered oncogenic hits. Infections with human cancer viruses including human papillomaviruses (HPVs) and Epstein-Barr virus can trigger oncogene-induced senescence, and the viruses have evolved strategies to abrogate this response in order to establish an infection and reprogram their host cells to establish a long-term persistent infection. As a consequence of inhibiting polycomb repression and evading oncogene induced senescence, HPV infected cells have an altered epigenetic program as evidenced by aberrant homeobox gene expression. Similar alterations are frequently observed in non-virus associated human cancers and may be harnessed for diagnosis and therapy. PMID- 23673721 TI - Usefulness of three-dimensional T1-weighted spoiled gradient-recalled echo and three-dimensional heavily T2-weighted images in preoperative evaluation of spinal dysraphism. AB - PURPOSE: The aim of this study was to evaluate the usefulness of three dimensional T1-weighted spoiled gradient-recalled echo (3D T1-GRE) images for the preoperative anatomical evaluation of lumbosacral lipoma, thick filum terminale, and myelomeningocele as a means of compensating for the drawbacks of 3D heavily T2-weighted (3D hT2-W) images. METHODS: Nine patients with lumbosacral lipomas, one patient with tight filum terminale, and five patients with myelomeningoceles were included in this study. 3D T1-GRE images were compared with 3D hT2-W images or conventional magnetic resonance images in terms of delineation of lipomas and other structures in the patients with lipomas and tight filum terminale. For patients with myelomeningoceles, 3D T1-GRE images were compared with 3D hT2-W images in terms of artifacts in the cerebrospinal fluid (CSF) space. RESULTS: The 3D T1-GRE images demonstrated lipomas with good contrast to the spinal cord and CSF space and more clearly delineated the anatomical relationship between lipomas and these structures than did the 3D hT2-W images. The 3D T1-GRE images delineated dural defects through which extradural lipomas penetrated into the intradural space. The 3D T1-GRE images also demonstrated the presence or absence of lipomas in the filum terminale and the absence of artifact in the myelomeningoceles. Furthermore, they were useful for differentiating artifacts observed on the 3D hT2-W images from nerve elements. CONCLUSIONS: The complementary use of 3D T1-GRE and 3D hT2-W images may compensate for the drawbacks of 3D hT2-W images and may eventually improve lesion visualization and surgical decision making. PMID- 23673722 TI - The chemical nature of the polar functional group of oxidized acyl chain uniquely modifies the physicochemical properties of oxidized phospholipid-containing lipid particles. AB - Oxidative modification of phospholipids generates a variety of oxidized phospholipid (Ox-PL) species which differ considerably in their chemical compositions and molecular structures. Recent results suggest that even closely related Ox-PL species can have considerably different biological effects. However, the molecular mechanism for this is not yet clear. In truncated Ox-PLs (tOx-PLs) the fatty acyl chain is shorter in length than the parent nonoxidized phospholipid molecules and contains a polar functional group(s). In a previous study we showed that two closely related tOx-PL species having a similar polar functional group and differing only in the length of the oxidized fatty acyl chain exerts significantly different effects on the physicochemical properties of the nonoxidized phospholipid particles containing these lipids (Kar et al., Chem Phys Lipids 164:54-61, 2011). In this study we have characterized the effect of polar functional groups of oxidized fatty acyl chain on the physicochemical properties of the nonoxidized phospholipid particles containing these lipids. Our results show that Ox-PL species differing only in the chemical nature of polar functional groups in their oxidized fatty acyl chain modify the properties of nonoxidized phospholipid particles containing them in a distinctive way. These results indicate that different species of Ox-PLs induce unique changes in the physicochemical properties of lipid particles/membranes containing them and that this may lead to their different biological effects. PMID- 23673723 TI - Interactions of alkylphosphocholines with model membranes-the Langmuir monolayer study. AB - Alkylphosphocholines (APCs) belong to a class of synthetic antitumor lipids, which are new-generation anticancer agents. In contrast to traditional antitumor drugs, they do not attack the cell nucleus but, rather, the cellular membrane; however, their mechanism of action is not fully understood. This work compared the interactions of selected APCs [namely, hexadecylphosphocholine (miltefosine), octadecylphosphocholine and erucylphosphocholine] with the most important membrane lipids [cholesterol, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)] and examined their influence on a model membrane of tumor and normal cells. As a simple model of membranes, Langmuir monolayers prepared by mixing cholesterol either with a saturated phosphatidylcholine (DPPC), for a normal cell membrane, or with an unsaturated one (POPC), for a tumor cell membrane, have been applied. The APC lipid interactions, based on experimental surface pressure (pi) versus mean molecular area (A) isotherms, were analyzed qualitatively (with mean molecular area values) as well as quantitatively (with the DeltaG(exc) function). Strong attractive interactions were observed for mixtures of APCs with cholesterol, contrary to the investigated phosphatidylcholines, for which the interactions were found to be weak with a tendency to separation of film components. In ternary monolayers it has been found that the investigated model systems (cholesterol/DPPC/APC vs cholesterol/POPC/APC) differ significantly as regards the interactions between film-forming molecules. The results demonstrate stronger interactions between the components of cholesterol/POPC/APC monolayers compared to cholesterol/POPC film, mimicking tumor cell membranes. In contrast, the interactions in cholesterol/DPPC/APC films were found to be weaker than those in the cholesterol/DPPC system, serving as a model of healthy cell membranes, thus proving that the incorporation of APCs is, from a thermodynamic point of view, unfavorable for binary cholesterol/DPPC monolayers. It can be concluded that the composition of healthy cell membranes is a natural barrier preventing the incorporation of APCs into normal cells. PMID- 23673724 TI - The effects of levosimendan exposure on oxidant/antioxidant status and trace element levels in the pulmonary artery of rats. AB - We investigated both the effect of levosimendan and the role of oxidant/antioxidant status and trace element levels in the pulmonary artery of rats. Fourteen male Wistar albino rats were randomly divided into two groups of seven animals each. Group 1 was not exposed to levosimendan and served as a control. Levosimendan (12 MUg/kg) diluted in 10 ml 0.9 % NaCl was administered intraperitoneally to group 2. Animals of both groups were killed after 3 days, and their pulmonary arteries were harvested to determine changes in tissue oxidant/antioxidant status and trace element levels. The animals in both groups were killed 72 h after the levosimendan exposure treatment, and pulmonary arteries were harvested to determine levels of the lipid peroxidation product MDA and the antioxidant GSH as well as the decreased activity of antioxidant enzymes such as SOD, GSH-Px and CAT. It was found that MDA levels increased in pulmonary artery tissues of rats after levosimendan administration. The GSH level decreased in the pulmonary artery of rats after levosimendan treatment. Co, Mn, Fe, Cd and Pb levels were significantly higher (P < 0.001) and Mg, Zn and Cu levels significantly lower (P < 0.001) in the levosimendan group compared to the control group. These results suggest that levosimendan treatment caused an increase in free radical production and a decrease in antioxidant enzyme activity in the pulmonary artery of levosimendan-treated rats. It also caused a decrease or increase in the levels of many minerals in the pulmonary artery, which is an undesirable condition for normal pharmacological function. PMID- 23673725 TI - microRNA expression profile in stage III colorectal cancer: circulating miR-18a and miR-29a as promising biomarkers. AB - Biomarkers that can facilitate disease detection, staging and prediction of outcome are highly desirable to improve survival and to help determine optimized treatment for colorectal cancer patients. microRNAs (miRNAs) are small non-coding RNAs that play a crucial role in gene regulatory networks. The deregulation of miRNA expression has been found in several types of cancer and may represent a novel class of cancer biomarkers. Our aim was to determine the miRNA signature of stage III colorectal cancer (CRC) tumors and to identify potential circulating miRNAs that may represent non-invasive biomarkers in CRC patients. Genome-wide microarray analysis of miRNA expression was performed on 12 paired tumor and non tumor formalin-fixed paraffin-embedded tissues from stage III CRC patients. A selection of differentially overexpressed miRNAs was validated by quantitative real-time polymerase chain reaction (qRT-PCR) and determined in the serum of a set of 56 individuals (30 stage III CRC patients and 26 healthy individuals). Using 1.5-fold expression difference as a cut-off level, 43 miRNAs were identified as differentially expressed in tumor versus normal tissue. Using reverse transcription and qRT-PCR, 11 miRNAs (miR-135b, miR-141, miR-18a, miR 20a, miR-21, miR-224, miR-29a, miR-31, miR-34a, miR-92a and miR-96) were confirmed as significantly overexpressed in tumor samples when compared with normal samples. We were able to detect 9 of these 11 miRNAs in serum samples from CRC patients and healthy individuals. Serum levels of miR-18a and miR-29a were significantly higher in CRC patients when compared to levels in the controls (p<0.05). In conclusion, this study identified a substantial number of miRNAs which were differentially expressed in stage III colorectal tumors. Moreover, the findings provide relevant information concerning overexpressed tumoral miRNAs as potential circulating biomarkers and highlight serum miR-18a and miR-29a as promising biomarkers for the screening and monitoring of CRC patients. PMID- 23673727 TI - Reply: To PMID 23225136. PMID- 23673726 TI - 11CO2 fixation: a renaissance in PET radiochemistry. AB - Carbon-11 labelled carbon dioxide is the cyclotron-generated feedstock reagent for most positron emission tomography (PET) tracers using this radionuclide. Most carbon-11 labels, however, are installed using derivative reagents generated from [(11)C]CO2. In recent years, [(11)C]CO2 has seen a revival in applications for the direct incorporation of carbon-11 into functional groups such as ureas, carbamates, oxazolidinones, carboxylic acids, esters, and amides. This review summarizes classical [(11)C]CO2 fixation strategies using organometallic reagents and then focuses on newly developed methods that employ strong organic bases to reversibly capture [(11)C]CO2 into solution, thereby enabling highly functionalized labelled compounds to be prepared. Labelled compounds and radiopharmaceuticals that have been translated to the clinic are highlighted. PMID- 23673728 TI - Genetic architecture of Wistar-Kyoto rat and spontaneously hypertensive rat substrains from different sources. AB - The spontaneously hypertensive rat (SHR) has been widely used as a model for studies of hypertension and attention deficit/hyperactivity disorder. The inbred Wistar-Kyoto (WKY) rat, derived from the same ancestral outbred Wistar rat as the SHR, are normotensive and have been used as the closest genetic control for the SHR, although the WKY has also been used as a model for depression. Notably, however, substantial behavioral and genetic differences among the WKY substrains, usually from the different vendors and breeders, have been observed. These differences have often been overlooked in prior studies, leading to inconsistent and even contradictory findings. The complicated breeding history of the SHR and WKY rats and the lack of a comprehensive understanding of the genetic background of different commercial substrains make the selection of control rats a daunting task, even for researchers who are mindful of their genetic heterogeneity. In this study, we examined the genetic relationship of 16 commonly used WKY and SHR rat substrains using genome-wide SNP genotyping data. Our results confirmed a large genetic divergence and complex relationships among the SHR and WKY substrains. This understanding, although incomplete without the genome sequence, provides useful guidance in selecting substrains and helps to interpret previous reports when the source of the animals was known. Moreover, we found two closely related, yet distinct WKY substrains that may provide novel opportunities in modeling psychiatric disorders. PMID- 23673730 TI - A method of experimental rheumatoid arthritis induction using collagen type II isolated from chicken sternal cartilage. AB - At present, collagen-induced arthritis (CIA) is the best known and most extensively used model for the immunological and pathological characteristics of human rheumatoid arthritis (RA). This model is useful not only in aiding our understanding of the pathogenesis of this disease, but also in the development of new therapies. Bovine, porcine and human collagen has been used to induce CIA; however, response has been identified to vary between strains and injection conditions, and false positive results and reduced potency are common as a result of minor contaminants or deglycosylated protein. Therefore, in the present study, type II collagen (CII) was isolated and purified from chicken sternal cartilage and was found to successfully induce the RA model. Furthermore, T helper 17 (Th17) cells were observed to infiltrate the joint on day 45 following induction by CII. In vitro, expression of toll-like receptor 2 (TLR2) increased in peritoneal macrophages stimulated by CII. In addition, blockage of TLR2 was identified to markedly decrease levels of TGF-beta and IL-6 in the cell culture supernatant. The results indicate that CII isolated from chicken sternal cartilage may be recognized by TLR2 on macrophages, leading to TGF-beta and IL-6 production and subsequent activation of Th17 cells which mediates CIA development. PMID- 23673731 TI - Unraveling the adsorption mechanism of aromatic and aliphatic diols on the TiO2 surface: a density functional theory analysis. AB - Understanding the adsorption mechanism of organic molecules on inorganic semiconductors is of great importance for generating and control functions in organic-inorganic materials. Here we have comprehensively investigated, by means of the density functional theory, the adsorption structure and energetic stability of aliphatic and aromatic diols on TiO2 using ethylene glycol, 1,2-n decanediol, and catechol. Our calculations clearly show that the non-dissociative bidentate adsorption is more stable than the dissociative one for the aliphatic diol, both at low and high coverage conditions, result far differently from many other chemical anchor cases for which the dissociative mechanism usually prevails. On the other hand, for catechol the dissociative bidentate is the most stable at low coverage conditions, whereas, surprisingly, increasing the coverage with catechol makes the non-dissociative mechanism the most stable one, revealing possible coexistence of a dissociative and non-dissociative anchoring at high coverage. This work unraveled a variety of adsorption fashions of the diol compounds in conjunction with the impact of the coverage effect, highly dependent on the nature of the lateral chain of the anchor group. PMID- 23673729 TI - Allelic expression imbalance screening of genes in chromosome 1q21-24 region to identify functional variants for Type 2 diabetes susceptibility. AB - Type 2 diabetes (T2D)-associated SNPs are more likely to be expression quantitative trait loci (eQTLs). The allelic expression imbalance (AEI) analysis is the measure of relative expression between two allelic transcripts and is the most sensitive measurement to detect cis-regulatory effects. We performed AEI screening to detect cis-regulators for genes expressed in transformed lymphocytes of 190 Caucasian (CA) and African American (AA) subjects to identify functional variants for T2D susceptibility in the chromosome 1q21-24 region of linkage. Among transcribed SNPs studied in 115 genes, significant AEI (P < 0.001) occurred in 28 and 30 genes in CA and AA subjects, respectively. Analysis of the effect of selected AEI-SNPs (>=10% mean AEI) on total gene expression further established the cis-eQTLs in thioesterase superfamily member-4 (THEM4) (rs13320, P = 0.027), and IGSF8 (rs1131891, P = 0.02). Examination of published genome-wide association data identified significant associations (P < 0.01) of three AEI-SNPs with T2D in the DIAGRAM-v3 dataset. Six AEI single nucleotide polymorphisms, including rs13320 (P = 1.35E-04) in THEM4, were associated with glucose homeostasis traits in the MAGIC dataset. Evaluation of AEI-SNPs for association with glucose homeostasis traits in 611 nondiabetic subjects showed lower AIRG (P = 0.005) in those with TT/TC genotype for rs13320. THEM4 expression in adipose was higher (P = 0.005) in subjects carrying the T allele; in vitro analysis with luciferase construct confirmed the higher expression of the T allele. Resequencing of THEM4 exons in 192 CA subjects revealed four coding nonsynonymous variants, but did not explain transmission of T2D in 718 subjects from 67 Caucasian pedigrees. Our study indicates the role of a cis-regulatory SNP in THEM4 that may influence T2D predisposition by modulating glucose homeostasis. PMID- 23673732 TI - A young scientist to watch. PMID- 23673733 TI - Removal of sulfamethazine by hypercrosslinked adsorbents in aquatic systems. AB - Four hundred tons of sulfamethazine are fed to livestock annually in North America to prevent disease and promote growth, but most of the drug is excreted unmetabolized into the environment. Because of slow degradation and high mobility, sulfamethazine contaminates groundwater supplies and causes aquatic ecosystem damage. Current water treatment methods to remove pharmaceuticals are not universally effective and have considerable limitations, which necessitate newer remediation techniques. Hypercrosslinked adsorbents, polystyrene polymers 100% crosslinked with methylene bridges, show promise because of high surface areas, high mechanical strength, and regenerable properties. This study screened four Purolite hypercrosslinked adsorbents (MN152, MN250, PAD400, and PAD600) to remove sulfamethazine from contaminated water and then characterized the most efficient resin, MN250, with batch adsorption and desorption experiments to optimize its use. Sulfamethazine adsorption onto MN250 displayed an L-class isotherm shape consistent with monolayer adsorption, negligible solute-solute interactions at the adsorbent surface, and decreasing activation energies of desorption with increasing surface coverage. MN250 had a maximum experimental adsorption capacity of 111 mg g, showing high correlation to the Langmuir and Freundlich models. Adsorption kinetics revealed prolonged adsorption over 59 h and were best described by Ho's pseudo-second-order model. There was minimal desorption from MN250 in distilled water, indicating an irreversible adsorption process. MN250's high capacity for sulfamethazine adsorption, minimal desorption in water, and ability to be regenerated make it a practical solution for sulfamethazine removal in areas that have contaminated groundwater supplies (e.g., areas near concentrated livestock operations), especially as current treatment methods have significant drawbacks. PMID- 23673734 TI - Greenhouse gas and ammonia emissions from an open-freestall dairy in southern idaho. AB - Concentrated dairy operations emit trace gases such as ammonia (NH), methane (CH), and nitrous oxide (NO) to the atmosphere. The implementation of air quality regulations in livestock-producing states increases the need for accurate on-farm determination of emission rates. Our objective was to determine the emission rates of NH, CH, and NO from the open-freestall and wastewater pond source areas on a commercial dairy in southern Idaho using a flush system with anaerobic digestion. Gas concentrations and wind statistics were measured and used with an inverse dispersion model to calculate emission rates. Average emissions per cow per day from the open-freestall source area were 0.08 kg NH, 0.41 kg CH, and 0.02 kg NO. Average emissions from the wastewater ponds (g m d) were 6.8 NH, 22 CH, and 0.2 NO. The combined emissions on a per cow per day basis from the open freestall and wastewater pond areas averaged 0.20 kg NH and 0.75 kg CH. Combined NO emissions were not calculated due to limited available data. The wastewater ponds were the greatest source of total farm NH emissions (67%) in spring and summer. The emissions of CH were approximately equal from the two source areas in spring and summer. During the late fall and winter months, the open-freestall area constituted the greatest source area of NH and CH emissions. Data from this study can be used to develop trace gas emissions factors from open-freestall dairies in southern Idaho and other open-freestall production systems in similar climatic regions. PMID- 23673735 TI - Preliminary assessment of an economical fugitive road dust sampler for the collection of bulk samples for geochemical analysis. AB - Fugitive road dust collection for chemical analysis and interpretation has been limited by the quantity and representativeness of samples. Traditional methods of fugitive dust collection generally focus on point-collections that limit data interpretation to a small area or require the investigator to make gross assumptions about the origin of the sample collected. These collection methods often produce a limited quantity of sample that may hinder efforts to characterize the samples by multiple geochemical techniques, preserve a reference archive, and provide a spatially integrated characterization of the road dust health hazard. To achieve a "better sampling" for fugitive road dust studies, a cyclonic fugitive dust (CFD) sampler was constructed and tested. Through repeated and identical sample collection routes at two collection heights (50.8 and 88.9 cm above the road surface), the products of the CFD sampler were characterized using particle size and chemical analysis. The average particle size collected by the cyclone was 17.9 MUm, whereas particles collected by a secondary filter were 0.625 MUm. No significant difference was observed between the two sample heights tested and duplicates collected at the same height; however, greater sample quantity was achieved at 50.8 cm above the road surface than at 88.9 cm. The cyclone effectively removed 94% of the particles >1 MUm, which substantially reduced the loading on the secondary filter used to collect the finer particles; therefore, suction is maintained for longer periods of time, allowing for an average sample collection rate of about 2 g mi. PMID- 23673736 TI - Nitrous oxide emissions from clayey soils amended with paper sludges and biosolids of separated pig slurry. AB - Wastes from animal production and from the paper industry are often used as amendments to agricultural soils. Although data exist on the impacts of raw animal wastes on NO production, little is known regarding the effects of paper wastes and biosolids from treated animal waste. We measured NO emissions for two consecutive snow-free seasons (mid-May through the end of October) from poorly drained clayey soils under corn ( L.). Soils were amended with raw pig slurry (PS) or biosolids (four PS-derived and two paper sludges) and compared with soils with mineral N fertilizer (CaNHNO) or without N addition (Control). Area-based NO emissions from the mineral N fertilizer (average, 8.2 kg NO-N ha; 4.2% of applied N) were higher ( < 0.001) than emissions from the organic amendments, which ranged from 1.5 to 6.1 kg NO-N ha (-0.4 to 2.5% of applied N). The NO emissions were positively correlated with mean soil NO availability (calculated as "NO exposure"), which was highest with mineral N fertilizer. In plots treated with organic amendments (i.e., biosolids and raw PS), NO exposure was negatively correlated to the C:N ratio of the amendment. This resulted in lower NO emissions from the higher C:N ratio biosolids, especially compared with the low C:N ratio PS. Application of paper sludge or PS-derived biosolids to these fine-textured soils, therefore, reduced NO emissions compared with raw PS and/or mineral N fertilizers ( < 0.01). PMID- 23673737 TI - A survey of particulate matter on california dairy farms. AB - Over the past 30 yr, individual California dairy operations have grown in size; however, little is known about the distribution and determinants of particulate matter (PM) concentrations on these dairies. Elevated exposure to PM is associated with respiratory and cardiovascular health effects, particularly in occupational settings. The purpose of this study was to quantify the concentrations of PM and all inhalable PM (0-100 um) on California dairies. Samplers were placed at various locations (e.g., milking parlor, grain storage area, drylot corral, and freestall barns) on 13 different dairies to collect PM and all inhalable PM during the 2008 summer months. The PM and all inhalable PM concentrations varied between different areas on a dairy and from dairy to dairy. Geometric mean concentrations for PM and inhalable PM were 24 ug m (range, 2-116 ug m) and 332 MUg m (range, 74-1690 ug m). A key variable for explaining variation in PM concentrations with a mixed effects model was regional background ambient concentrations of PM No significant differences were observed in mean concentrations between upwind and downwind fence line concentrations (adjusted geometric mean ratio [AGMR] = 0.7; 95% CI, 0.4-1.3), although significant differences were found between upwind and central location mean values (AGMR = 0.5; 95% CI, 0.3-0.8; < 0.01). These results indicate dairy PM sources and, thus, elevated occupational exposure. Covariates, such as the age of the dairy and number of cows in the freestall barn and drylot corral, were important variables in explaining PM concentration variability. Levels of PM were lower compared with dairies in other U.S. states and other countries. PMID- 23673738 TI - Assessing cellulolysis in passive treatment systems for mine drainage: a modified enzyme assay. AB - A modified cellulase enzyme assay was developed to monitor organic matter degradation in passive treatment systems for mine drainage. This fluorogenic substrate method facilitates assessment of exo-(1,4)-beta-D-glucanase, endo-(1,4) beta-D-glucanase, and beta-glucosidase, which compose an important cellulase enzyme system. The modified method was developed and refined using samples of organic carbon-amended mine tailings from field experiments where sulfate reduction was induced as a strategy for managing water quality. Sample masses (3 g) and the number of replicates ( >= 3) were optimized. Matrix interferences within these metal-rich samples were found to be insignificant. Application of this modified cellulase assay method provided insight into the availability and degradation of organic carbon within the amended tailings. Results of this study indicate that cellulase enzyme assays can be applied to passive treatment systems for mine drainage, which commonly contain elevated concentrations of metals. PMID- 23673739 TI - Tetrachlorofluorescein TInsP as a Substrate Analog Probe for Measuring Phytase Activity in Surface Water: Proof of Concept. AB - An innovative approach for measuring phytase activity (PA) in surface water is presented. A substrate analog of -inositol hexakis(dihydrogen) phosphate (InsP), commonly referred to as phytic acid, 1--5--(1-oxo-1-(2' ,4,7,7' -tetrachloro 3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-6-yl)-5,8,11-trioxa-2 azatridecan-13-yl)-inositol 1,2,3,4,6-pentakis--(dihydrogen) phosphate, referred to as tetrachlorofluorescein (TET) tethered (T)InsP, has been developed that can be used to monitor the (phytase-catalyzed) phosphate ester bond-cleavage reaction. Test phytases, (wheat [4-] and [3-] phytase) sequentially remove phosphate groups from TET TInsP, producing dephosphorylated probe species that were readily separated by reversed-phase high-performance liquid chromatography (RP-HPLC). Because dephosphorylated probe species retain the TET group, highly sensitive quantification could be achieved using fluorescence detection (excitation/emission ' = 245/540 nm). Calibration curves for TET TInsP, which could be used as a standard for quantifying all probe species, were linear ( > 0.999) over the range of concentrations tested. Phytase-generated dephosphorylated probe species were characterized or identified using RP-HPLC with mass spectrometry. Results of mass spectrometry analysis show that the RP HPLC system was capable of distinguishing between dephosphorylated probe species at the regioisomeric level. The TET TInsP molecular probe was used to successfully measure PA in pond water. We found that the PA associated with the particulate plus water-soluble fraction was greater than that observed for the water-soluble fraction alone. Moreover, it appeared that 4- and 3-phytase were active in pond water based on an analysis of the chromatographic profile (i.e., elution sequence) of dephosphorylated probe species produced. The advent of a fluorescent substrate analog of InsP affords environmental scientists with the means to unambiguously quantify an extremely small amount of phytase-generated dephosphorylated product(s), enabling the measurement of PA over a reasonably short time duration, in an environmental sample containing low concentrations of enzyme. PMID- 23673740 TI - Effect of bedding materials on concentration of odorous compounds and in beef cattle bedded manure packs. AB - The objectives of this study were to determine the effect of bedding material (corn stover, soybean stover, wheat straw, switchgrass, wood chips, wood shavings, corn cobs, and shredded paper) on concentration of odorous volatile organic compounds (VOC) in bedded pack material and to determine the effect of bedding material on the levels of total in laboratory-scaled bedded manure packs. Four bedded packs of each bedding material were maintained for two 6-wk periods ( = 64). Straight- and branched-chained fatty acids and aromatic compounds were measured. Corn cob bedding had the highest concentration of odorous VOC, and wood shavings had the lowest ( < 0.01). Calculated odor activity values were highest for corn cob bedding and shredded paper and lowest for wood shavings ( < 0.01). concentrations decreased from week to week for all treatments from Week 2 to Week 6. At Week 6, levels in bedded packs with shredded paper were higher ( < 0.05) than bedded packs containing wood shavings, wood chips, or switchgrass ( < 0.05). At Weeks 4, 5, and 6, concentrations in bedded packs with wood shavings were lower ( < 0.05) than bedded packs of all treatments except wood chips. Results of this study indicate that ground corn cobs or shredded paper may increase odor production and shredded paper may increase when used in deep-bedded livestock facilities, whereas wood shavings may have the least impact on air quality and . PMID- 23673741 TI - Biochar reduces short-term nitrate leaching from a horizon in an apple orchard. AB - Nitrogen leaching in croplands is a worldwide problem with implications both on human health and on the environment. Efforts should be taken to increase nutrient use efficiency and minimize N losses from terrestrial to water ecosystems. Soil applied biochar has been reported to increase soil fertility and decrease nutrient leaching in tropical soils and under laboratory conditions. Our objective was to evaluate the effect of biochar addition on short-term N leaching from A soil horizon in a mature apple orchard growing on subalkaline soils located in the Po Valley (Italy). In spring 2009, 10 Mg of biochar per hectare was incorporated into the surface 20-cm soil layer by soil plowing. Cumulative nitrate (NO) and ammonium (NH) leaching was measured in treated and control plots 4 mo after the addition of biochar and the following year by using ion-exchange resin lysimeters installed below the plowed soil layer. Cumulative NO leaching was not affected by biochar after 4 mo, whereas in the following year it was significantly ( < 0.05) reduced by 75% over the control (from 5.5 to 1.4 kg ha). Conversely, NH leaching was very low and unaffected by soil biochar treatment. The present study shows that soil biochar addition can significantly decrease short-term nitrate leaching from the surface layer of a subalkaline soil under temperate climatic conditions. PMID- 23673742 TI - Quantification of chemical transport processes from the soil to surface runoff. AB - There is a good conceptual understanding of the processes that govern chemical transport from the soil to surface runoff, but few studies have actually quantified these processes separately. Thus, we designed a laboratory flow cell and experimental procedures to quantify the chemical transport from soil to runoff water in the following individual processes: (i) convection with a vertical hydraulic gradient, (ii) convection via surface flow or the Bernoulli effect, (iii) diffusion, and (iv) soil loss. We applied different vertical hydraulic gradients by setting the flow cell to generate different seepage or drainage conditions. Our data confirmed the general form of the convection diffusion equation. However, we now have additional quantitative data that describe the contribution of each individual chemical loading process in different surface runoff and soil hydrological conditions. The results of this study will be useful for enhancing our understanding of different geochemical processes in the surface soil mixing zone. PMID- 23673743 TI - Effect of long-term application of biosolids for mine land reclamation on groundwater chemistry: nutrients and other selected qualities. AB - Leaching of nitrogen (N) and phosphorus (P) to groundwater can limit the land application of fertilizer, biosolids, and other soil amendments. Groundwater quality monitoring data collected over a 34-yr period at a 1790-ha site in Fulton County, Illinois, where strip-mined land was reclaimed with biosolids, were used to evaluate long-term impacts of biosolids on groundwater N, P, and other parameters. Seven strip-mined fields repeatedly treated with biosolids at 801 to 1815 Mg ha cumulative rate (equivalent to 24-55 dry Mg ha yr) between 1972 and 2004 were compared with another seven fields treated annually with chemical fertilizer at agronomic rates. Groundwater from wells installed in each of the fields and two public wells that served as background (reference) were sampled for 35 yr, monthly between 1972 and 1986 and quarterly between 1987 and 2006. Data show greater chloride (Cl), sulfate (SO) and electrical conductivity (EC) of groundwater from wells in biosolids fields than those in fertilizer fields. Also, groundwater nitrate N (NO-N) concentrations were greater in biosolids-amended fields than in fertilizer fields, but below regulatory limit of 10 mg L in Illinois Part 620 regulation. Conversely, groundwater P concentrations were consistently lower in biosolids than in chemical fertilizer wells throughout the 35-yr monitoring period. The study demonstrates that the repeated application of biosolids, even at higher than agronomic rate, would cause only minor nitrate increase and no P increase in groundwater. PMID- 23673744 TI - Effects of land use and parent materials on trace elements accumulation in topsoil. AB - To determine the effects of parent material and land use on the concentration of trace elements in the agricultural topsoil of Guizhou Province, China, a total of 584 agricultural topsoil samples were collected in a typical region. The results indicate that the contents of trace elements (As, Cd, Cr, Hg, and Pb) in agricultural soils were greater than in the uncultivated soils, and the paddy fields exhibited higher contents of trace elements than dry lands. The enrichments of most trace elements in agricultural topsoil derived from carbonate rock were more serious. In paddy fields, Cd, Cr, and As showed positive relationships with soil organic matter ( < 0.01) but were not affected by pH, carbon-to-nitrogen (C/N) ratio, and clay ( > 0.05). Lead and Hg formed the second component in principal component analysis (PCA) and were closely related to pH and clay content. In dry lands, the trace elements were well correlated with pH, C/N, and clay ( < 0.05). Analysis of PCA and correlation showed that Cd, Cr, and Hg were mainly derived from inorganic fertilizers, whereas Pb and As were primarily from organic manures. These results suggest that the effect of anthropogenic activities on paddy fields is more serious than on dry lands. Parent materials not only serve as sources of soil trace elements but also control the loss and accumulation of trace elements by affecting soil physicochemical properties, especially in dry lands. PMID- 23673745 TI - Characterization of chromium species in urban runoff. AB - Little is known about the presence of the element Cr in its toxic hexavalent form Cr(VI) in stormwater runoff from urban areas. Most studies report only total Cr concentration, i.e., including also the nontoxic Cr(III) molecular form. The objective of this study was to evaluate a field method based on cation-exchange for characterization of Cr species in urban stormwater runoff and soil leachate. We used a 0.05 mol L Na and Ca solution and a soil leachate as matrices and spiked these with Cr(III), Cr(VI), or both in the concentration range of 1 to 100 MUg L. We then filtered the test samples through cation-exchange cartridges. In the Na-Ca salt matrix, the Cr(III) was retained 100% and recovery values of Cr(VI) were 86 to 100%. Furthermore, in such a matrix, each cartridge could be reused at least nine times without a drop in retention of Cr(III) or recovery of Cr(VI). In a soil leachate matrix, the method appeared less applicable. Apparently Cr(III) forms complexes with dissolved organic matter, allowing it to bypass the cartridge, resulting in incomplete Cr(III) retention and thus incomplete speciation. The complexes are formed rapidly after spiking, thus changes in the Cr-species distribution are likely to occur within a few hours when fresh samples are stored. Furthermore, we concluded that Cr(III) at neutral pH in pure solution or complexed with dissolved organic C can sorb irreversibly to polyethylene and polypropylene containers. Our findings show that there is still a need for a method that can be applied to urban runoff in the field. Furthermore, cartridge speciation methods should ideally be tested before being applied on solutions containing organic matter. PMID- 23673746 TI - Establishing the Origin of Elevated Uranium Concentrations in Groundwater near the Central Ogcheon Metamorphic Belt, Korea. AB - We examined the origin of the U-enriched groundwater in Daejeon, near the Ogcheon U zone in Korea. For this study, groundwater ionic species and C, S, and Sr isotopic compositions were analyzed. The U-enriched groundwater occurred only in the Daejeon granite region, while all the groundwater in the Ogcheon Supergroup showed very low U concentrations. In the granite region, the pedospheric or atmospheric origin of dissolved C and S means that the aquifer has been well connected to the oxidized surface environment. The Sr/Sr ratios indicated a lithospheric origin of Sr. Groundwater isotopic compositions in the Ogcheon belt varied greatly, indicating their complex sources. In this region, dissolved C originated from graphite-rich slate and limestone. The broad range of deltaS suggested that the composite sources included atmospheric SO for most groundwater, lithogenic SO for mine drainage and quarry water, and anthropogenic SO for polluted groundwater. This study indicates that the U-enriched groundwater is not related to the present U ores in the Ogcheon belt but is genetically associated with the granite body itself. The varying but considerable U contents within the granite body can be present as isolated groups. We infer that locally high U contents in the Daejeon granite might inherently be due to assimilation of the Ogcheon U-mineralized zone into granitic melt during the Mesozoic; however, the pH and Eh conditions except aquifer geology were very important factors in developing highly enriched U groundwater in the Daejeon granite region. Thermodynamic modeling highlights the importance of dissolved Ca and (bi )carbonate in U geochemistry. PMID- 23673747 TI - Characterization and application results of two magnetic nanomaterials. AB - The toxicity of heavy metals for the environment can be solved by using the adsorption properties of magnetic nanomaterials. These types of nanomaterials can remove pollutants, especially from wastewaters. This study was conducted to determine whether two magnetic nanomaterials can be used as adsorbents for heavy metals (Cr, Cd, Cu, Zn, and Ni) from aqueous solutions under acidic conditions. Qualitative and quantitative elemental information and structural and surface characteristics before and after use as adsorbents were investigated by X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The obtained data showed a good correlation with the Langmuir adsorption model using the two magnetic nanomaterials in aqueous solutions. The crystalline structure of the FeO powder was identified with XRD. The TEM images of FeO nanoparticles indicated a good dispersion of particles of 85.5 nm. The SEM analysis for FeO-PAA (magnetite covered with sodium alginate) showed spherical particles of magnetite wrapped into the polymer with dimension of ~200 nm. According to the adsorption Langmuir model, the removal efficiency for uncoated FeO decreased in order: Cr(VI) > Cu(II) > Zn(II) > Ni(II) > Cd(II). For the FeO PAA nanocomposite (45% w/w Fe in a mass of polymer), the adsorption phenomena appears as follows: Cr(VI) > Cd(II) > Cu(II) ~ Zn(II) > Ni(II). Langmuir parameters indicated a favorable monolayer adsorption at pH 2.5. The nanocomposite FeO-PAA can be used as an adsorbent with the same performance as uncoated FeO but with the advantage of stability under conditions where industrial wastewaters have an acidic pH. PMID- 23673748 TI - Ammonium, Nitrate, and Phosphate Sorption to and Solute Leaching from Biochars Prepared from Corn Stover ( L.) and Oak Wood ( spp.). AB - Biochar (BC) was evaluated for nitrogen (N) and phosphorus (P) removal from aqueous solution to quantify its nutrient pollution mitigation potential in agroecosystems. Sorption isotherms were prepared for solutions of ammonium (NH), nitrate (NO), and phosphate (PO-P) using BC of corn ( L.) and oak ( spp.) feedstock, each pyrolyzed at 350 and 550 degrees C highest treatment temperature (HTT). Sorption experiments were performed on original BC as well as on BC that went through a water extraction pretreatment (denoted WX-BC). Ammonium sorption was observed for WX-Oak-BC and WX-Corn-BC, and Freundlich model linearization showed that a 200 degrees C increase in HTT resulted in a 55% decrease in * values for WX-Oak-BC and a 69% decrease in * for WX-Corn-BC. Nitrate sorption was not observed for any BC. Removing metals by water extraction from WX-Oak-350 and WX-Oak-550 resulted in a 25 to 100% decrease in phosphate removal efficiency relative to original Oak-350 and Oak-550, respectively. No PO-P sorption was observed using any Corn-BC. Calcium (Ca) leached from BC produced at 550 degrees C was 63 and 104% higher than from BC produced at 350 degrees C for corn and oak, respectively. Leaching of P was two orders of magnitude lower in WX-Oak-BC than in WX-Corn-BC, concurrent with similar difference in magnesium (Mg). Nitrate and NH leaching from consecutive water extractions of all tested BCs was mostly below detection limits. PMID- 23673749 TI - The impact of relict organic materials on the denitrification capacity in the unsaturated-saturated zone continuum of three volcanic profiles. AB - The denitrification capacity of wetlands, riparian zones, and aquifers in glacial outwash areas is well documented, but little or no information exists for volcanic profiles, particularly those containing relict organic matter contained in or on top of paleosols (old soils buried by volcanic deposits) below the groundwater table. Relict carbon contained in these layers could provide the necessary electrons to fuel heterotrophic denitrification. To the best of our knowledge, this is the first study investigating the denitrification capacity in both the unsaturated and saturated zone of volcanic profiles. Samples from three profile types with differing organic matter distribution were amended with N enriched nitrate (NO-) and incubated in the laboratory under anaerobic conditions. Dinitrogen (N) dominated the N gas fluxes; averaged across all samples, it accounted for 96% of the total N (nitrous oxide [NO] and N) gas fluxes. Dinitrogen fluxes were generally highest in the A horizon samples (4.1 6.2 nmol N g h), but substantial fluxes were also observed in some paleosol layers (up to 0.72 nmol N g h). A significant correlation ( < 0.001) was found between the concentration of extractable dissolved organic carbon and the total N gas flux produced in samples from below the A horizon, suggesting that heterotrophic denitrification was the dominant NO attenuation process in this study. Extrapolation of lab-derived denitrification capacities to field conditions suggests that the denitrification capacity of profiles containing relict soil organic matter in the saturated zone exceeds the estimated N leaching from the root zone. PMID- 23673750 TI - Carbon export from the raccoon river, iowa: patterns, processes, and opportunities. AB - Farmed landscapes are engineered for productivity, and research suggests they contribute a disproportionate share of inorganic C to the Mississippi River and Gulf of Mexico. Here we use alkalinity and total organic C (TOC) measurements collected from the Raccoon River of Iowa to (i) evaluate inorganic and organic C concentrations and export patterns, (ii) compare current trends to historical conditions, and (iii) link C transport processes to current land use management. Export of inorganic C averaged 106,000 Mg per year and contributes 90% of the C flux from the basin. Alkalinity concentrations are unchanged from 1931 to 1944 levels (~53 mg L C), but inorganic C loads have doubled due to increasing discharge. Carbonate-rich glacial deposits and agricultural lime provide a large source of inorganic C, and results confirm that alkalinity export in the Raccoon Basin is transport limited. Although fertilization and tillage practices have possibly helped increase C fluxes over the last 70+ yr, the overriding factor on inorganic C export is discharge. Discharge control over C export provides an opportunity for agriculture in terms of quantifying C sequestration for potential C trading. Controlling water flux through soils can limit inorganic C export similar to practices such as reduced tillage and managed rotations. PMID- 23673751 TI - Biochar affected by composting with farmyard manure. AB - Biochar applications to soils can improve soil fertility by increasing the soil's cation exchange capacity (CEC) and nutrient retention. Because biochar amendment may occur with the applications of organic fertilizers, we tested to which extent composting with farmyard manure increases CEC and nutrient content of charcoal and gasification coke. Both types of biochar absorbed leachate generated during the composting process. As a result, the moisture content of gasification coke increased from 0.02 to 0.94 g g, and that of charcoal increased from 0.03 to 0.52 g g. With the leachate, the chars absorbed organic matter and nutrients, increasing contents of water-extractable organic carbon (gasification coke: from 0.09 to 7.00 g kg; charcoal: from 0.03 to 3.52 g kg), total soluble nitrogen (gasification coke: from not detected to 705.5 mg kg; charcoal: from 3.2 to 377.2 mg kg), plant-available phosphorus (gasification coke: from 351 to 635 mg kg; charcoal: from 44 to 190 mg kg), and plant-available potassium (gasification coke: from 6.0 to 15.3 g kg; charcoal: from 0.6 to 8.5 g kg). The potential CEC increased from 22.4 to 88.6 mmol kg for the gasification coke and from 20.8 to 39.0 mmol kg for the charcoal. There were little if any changes in the contents and patterns of benzene polycarboxylic acids of the biochars, suggesting that degradation of black carbon during the composting process was negligible. The surface area of the biochars declined during the composting process due to the clogging of micropores by sorbed compost-derived materials. Interactions with composting substrate thus enhance the nutrient loads but alter the surface properties of biochars. PMID- 23673752 TI - Accelerated Biodegradation of Veterinary Antibiotics in Agricultural Soil following Long-Term Exposure, and Isolation of a Sulfamethazine-degrading sp. AB - The World Health Organization has identified antibiotic resistance as one of the top three threats to global health. There is concern that the use of antibiotics as growth promoting agents in livestock production contributes to the increasingly problematic development of antibiotic resistance. Many antibiotics are excreted at high rates, and the land application of animal manures represents a significant source of environmental exposure to these agents. To evaluate the long-term effects of antibiotic exposure on soil microbial populations, a series of field plots were established in 1999 that have since received annual applications of a mixture of sulfamethazine (SMZ), tylosin (TYL), and chlortetracycline (CTC). During the first 6 yr (1999-2004) soils were treated at concentrations of 0, 0.01 0.1, and 1.0 mg kg soil, in subsequent years at concentrations of 0, 0.1, 1.0, and 10 mg kg soil. The lower end of this concentration range is within that which would result from an annual application of manure from medicated swine. Following ten annual applications, the fate of the drugs in the soil was evaluated. Residues of SMZ and TYL, but not CTC were removed much more rapidly in soil with a history of exposure to 10 mg/kg drugs than in untreated control soil. Residues of C-SMZ were rapidly and thoroughly mineralized to CO in the historically treated soils, but not in the untreated soil. A SMZ-degrading sp. was isolated from the treated soil. Overall, these results indicate that soil bacteria adapt to long-term exposure to some veterinary antibiotics resulting in sharply reduced persistence. Accelerated biodegradation of antibiotics in matrices exposed to agricultural, wastewater, or pharmaceutical manufacturing effluents would attenuate environmental exposure to antibiotics, and merits investigation in the context of assessing potential risks of antibiotic resistance development in environmental matrices. PMID- 23673753 TI - Effects of crop rotation and management system on water-extractable organic matter concentration, structure, and bioavailability in a chernozemic agricultural soil. AB - Water-extractable organic matter (WEOM) in soil affects contaminant mobility and toxicity, heterotrophic production, and nutrient cycling in terrestrial and aquatic ecosystems. This study focuses on the influences of land use history and agricultural management practices on the water extractability of organic matter and nutrients from soils. Water-extractable organic matter was extracted from soils under different crop rotations (an annual rotation of wheat-pea/bean-wheat flax or a perennial-based rotation of wheat-alfalfa-alfalfa-flax) and management systems (organic or conventional) and examined for its concentration, composition, and biodegradability. The results show that crop rotations including perennial legumes increased the concentration of water-extractable organic carbon (WEOC) and water-extractable organic nitrogen (WEON) and the biodegradability of WEOC in soil but depleted the quantity of water-extractable organic phosphorus (WEOP) and water-extractable reactive phosphorus. The 30-d incubation experiments showed that bioavailable WEOC varied from 12.5% in annual systems to 22% for perennial systems. The value of bioavailable WEOC was found to positively correlate with WEON concentrations and to negatively correlate with C:N ratio and the specific ultraviolet absorbance of WEOM. No significant treatment effect was present with the conventional and organic management practices, which suggested that WEOM, as the relatively labile pool in soil organic matter, is more responsive to the change in crop rotation than to mineral fertilizer application. Our results indicated that agricultural landscapes with contrasting crop rotations are likely to differentially affect rates of microbial cycling of organic matter leached to soil waters. PMID- 23673754 TI - Graphene nanosheets and graphite oxide as promising adsorbents for removal of organic contaminants from aqueous solution. AB - Graphenes are an emerging class of carbon nanomaterials whose adsorption properties toward organic compounds have not been well understood. In the present study, graphene nanosheets were prepared by reoxidation and abrupt heating of graphite oxide, which was prepared by sequential chemical oxidation of commercial nonporous graphite powder. Adsorption properties of three aromatic compounds (naphthalene, 2-naphthol, and 1-naphthylamine) and one pharmaceutical compound (tylosin) on graphene nanosheets and graphite oxide were examined to explore the potential of these two adsorbents for the removal of organic contaminants from aqueous solutions. Compared with the literature data of adsorption on carbon nanotubes, adsorption of bulky, flexible tylosin on graphene nanosheets exhibited markedly faster adsorption kinetics, which can be attributed to their opened-up layer structure. Graphene nanosheets and graphite oxide showed similar sequences of adsorption affinity: 1-naphthylamine > 2-naphthol > tylosin > naphthalene (with much larger differences observed on graphite oxide). It was proposed that the strong adsorption of the three aromatic compounds was mainly due to pi-pi electron donor-acceptor interactions with the graphitic surfaces of adsorbents. Additionally, Lewis acid-base interaction was likely an important factor contributing to the strong adsorption of 1-naphthylamine and tylosin, especially for the O-functionality-abundant graphite oxide. After being normalized on the basis of adsorbent surface area, adsorption affinities of all four tested adsorbates on graphene nanosheets were very close to those on nonporous graphite powder, reflecting complete accessibility of the adsorbent surface area in adsorption. PMID- 23673755 TI - Hydrothermal carbonization of biomass residues: mass spectrometric characterization for ecological effects in the soil-plant system. AB - Hydrochars, technically manufactured by hydrothermal carbonization (HTC) of biomass residues, are recently tested in high numbers for their suitability as feedstock for bioenergy production, the bioproduct industry, and as long-term carbon storage in soil, but ecological effects in the soil-plant system are not sufficiently known. Therefore, we investigated the influence of different biomass residues and process duration on the molecular composition of hydrochars, and how hydrochar addition to soils affected the germination of spring barley ( L.) seeds. Samples from biomass residues and the corresponding hydrochars were analyzed by pyrolysis-field ionization mass spectrometry (Py-FIMS) and gaseous emissions from the germination experiments with different soil-hydrochar mixtures by gas chromatography/mass spectrometry (GC/MS). The molecular-level characterization of various hydrochars by Py-FIMS clearly showed that the kind of biomass residue influenced the chemical composition of the corresponding hydrochars more strongly than the process duration. In addition to various detected possible toxic substances, two independent mass spectrometric methods (Py-FIMS and GC/MS) indicated long C-chain aliphatic compounds which are typically degraded to the C-unit ethylene that can evoke phytotoxic effects in high concentrations. This showed for the first time possible chemical compounds to explain toxic effects of hydrochars on plant growth. It is concluded that the HTC process did not result in a consistent product with defined chemical composition. Furthermore, possible toxic effects urgently need to be investigated for each individual hydrochar to assess effects on the soil organic matter composition and the soil biota before hydrochar applications as an amendment on agricultural soils. PMID- 23673756 TI - Predicting perchlorate uptake in greenhouse lettuce from perchlorate, nitrate, and chloride irrigation water concentrations. AB - Perchlorate (ClO) has been detected in edible leafy vegetables irrigated with Colorado River water. The primary concern has been the ClO concentration in lettuce ( L. var. L.). There has been a limited number of studies on ClO uptake, but the interactive effect of other anions on ClO uptake is not known in detail. We conducted a greenhouse ClO uptake experiment using two types of lettuce (iceberg and butterhead) to investigate the interaction of uptake of ClO, Cl, and NO on ClO uptake under controlled conditions. We examined three concentrations of ClO, 40, 220, and 400 nmol/L; Cl at 2.5, 13.75, and 25 mmol/L; and NO at 2, 11, and 20 mmol/L. Perchlorate was taken up the most in lettuce when ClO was the greatest and NO and Cl were lowest in concentration in the irrigation water. More ClO was detected in leafy material than in root tissue. In general, the outer leaves of iceberg and butterhead lettuce contained more ClO than did the inner leaves. The results indicate that selective ClO uptake occurs for green leaf lettuce. A predictive model was developed to describe the ClO concentration in lettuce as related to the Cl, NO, and ClO concentration in the irrigation water. Research results can be utilized to elucidate the effect of salts on the accumulation and uptake of ClO by edible leafy vegetables. PMID- 23673757 TI - Reduced nitrogen losses after conversion of row crop agriculture to perennial biofuel crops. AB - Current biofuel feedstock crops such as corn lead to large environmental losses of N through nitrate leaching and NO emissions; second-generation cellulosic crops have the potential to reduce these N losses. We measured N losses and cycling in establishing miscanthus (), switchgrass ( L. fertilized with 56 kg N ha yr), and mixed prairie, along with a corn ( L.)-corn-soybean [ (L.) Merr.] rotation (corn fertilized at 168-202 kg N ha). Nitrous oxide emissions, soil N mineralization, mid-profile nitrate leaching, and tile flow and nitrate concentrations were measured. Perennial crops quickly reduced nitrate leaching at a 50-cm soil depth as well as concentrations and loads from the tile systems (year 1 tile nitrate concentrations of 10-15 mg N L declined significantly by year 4 in all perennial crops to <0.6 mg N L, with losses of <0.8 kg N ha yr). Nitrous oxide emissions were 2.2 to 7.7 kg N ha yr in the corn-corn-soybean rotation but were <1.0 kg N ha yr by year 4 in the perennial crops. Overall N balances (atmospheric deposition + fertilization + soybean N fixation - harvest, leaching losses, and NO emissions) were positive for corn and soybean (22 kg N ha yr) as well as switchgrass (9.7 kg N ha yr) but were -18 and -29 kg N ha yr for prairie and miscanthus, respectively. Our results demonstrate rapid tightening of the N cycle as perennial biofuel crops established on a rich Mollisol soil. PMID- 23673758 TI - Spatial and Temporal Dynamics of Fecal Coliform and Associated with Suspended Solids and Water within Five Northern California Estuaries. AB - Fecal coliform and associated with suspended solids (SS) and water in five northern California estuaries were studied to document process influences and water quality monitoring biases affecting indicator bacteria concentrations. We collected and analyzed 2371 samples during 10 sampling events for the five studied estuaries. Concentrations during wet-season stormflow conditions were greater than during wet-season base flow and dry-season base flow conditions. Results also document concentration gradients across the length of the studied estuaries and with depth of sample collection. Highest concentrations were associated with shallow samples collected furthest inland. Corresponding decreases occurred the deeper and closer to the estuary mouth a sample was collected. Results also identify direct relationships of wind speed and discharge velocity and indirect relationship of tide stage to indicator bacteria concentrations. Bacteria associated with suspended solids (SS), after conversion to the same units of measurement (mass), were three orders of magnitude greater than in the water fraction. However, the mean proportion contributed by SS to composite water sample concentrations was 8% (SE 0.3) for fecal coliform and 7% (SE 0.3) for . Bacteria from the SS proportion is related to seasonality, tide stage, and discharge velocity that are consistent with mechanisms for entrainment, transport of SS, and reduced particle settling. These results are important for both managing and monitoring these systems by improving sample spatial and temporal context and corresponding bacteria concentration values across the freshwater-saltwater interface. PMID- 23673759 TI - Ecosystem characteristics of remnant, headwater tallgrass prairie streams. AB - North America has lost >95% of its native tallgrass prairie due to land conversion, making prairie streams one of the most endangered ecosystems. Research on the basic ecosystem characteristics of the remaining natural prairie streams will inform conservation and management. We examined the structure and function of headwater streams draining tallgrass prairie tracts at Osage Prairie in Missouri and the Konza Prairie Biological Station in Kansas and compared those values with literature values for streams draining agricultural watersheds in the region. We quantified physicochemical and biological characteristics for 2 yr. Streams at Osage and Konza were characterized by low nutrients and low suspended sediments (substantially lower than impacted sites in the region), slight heterotrophic status, and high temporal variability. Suspended sediments and nutrient concentrations were generally low in all prairie streams, but storms increased concentrations of both by 3- to 12-fold. Spring prescribed burns were followed by a slight increase in chlorophyll and decreased nutrients, potentially due to greater light availability. Benthic macroinvertebrate communities at Osage showed seasonal patterns that were probably linked to variable hydrology. We found nine amphibian species using the Osage streams as habitat or breeding sites, but little usage at Konza was probably due to dry conditions and low discharge. Our study indicates that two remnant tallgrass prairie streams along a longitudinal gradient are fairly similar in terms of physicochemical features and have good water quality relative to agricultural watersheds but can differ considerably in macroinvertebrate and amphibian abundance. PMID- 23673760 TI - Reducing phosphorus loading of surface water using iron-coated sand. AB - Phosphorus losses from agricultural soils is an important source of P in surface waters leading to surface water quality impairment. In addition to reducing P inputs, mitigation measures are needed to reduce P enrichment of surface waters. Because drainage of agricultural land by pipe drainage is an important pathway of P to surface waters, removing P from drainage water has a large potential to reduce P losses. In a field trial, we tested the performance of a pipe drain enveloped with Fe-coated sand, a side product of the drinking water industry with a high ability to bind P, to remove P from the drainage water. The results of this trial, encompassing more than one hydrological season, are very encouraging because the efficiency of this mitigation measure to remove P amounted to 94%. During the trial, the pipe drains were below the groundwater level for a prolonged time. Nevertheless, no reduction of Fe(III) in the Fe-coated sand occurred, which was most likely prevented by reduction of Mn oxides present in this material. The enveloped pipe drain was estimated to be able to lower the P concentration in the effluent to the desired water quality criterion for about 14 yr. Manganese oxides are expected to be depleted after 5 to 10 yr. The performance of the enveloped pipe drain, both in terms of its ability to remove P to a sufficiently low level and the stability of the Fe-coated sand under submerged conditions in the long term, needs prolonged experimental research. PMID- 23673761 TI - Nutrient Leaching during Establishment of Simulated Residential Landscapes. AB - Research evaluating nutrient losses during the establishment of plant material in mixed residential landscapes is limited. The objectives of this study were to determine the effect of vegetative cover type, compost application, and tillage on nutrient losses during the establishment of landscape plants. Twenty-four small plots constructed with subsoil fill were planted with St. Augustinegrass [ (Walter) Kuntze] and mixed ornamental species in a randomized complete block design. Plots received composted dairy manure solids at a rate of 0 or 50.8 m ha- in combination with shallow tillage or aeration. Cumulative leachate loads and flow-weighted mean concentrations of NH-N, NO + NO-N, and dissolved reactive P (DRP) were calculated periodically and annually to assess nutrient leaching from landscape plots. Higher cumulative leachate volume, inorganic N and DRP loads, and mean NO + NO-N and DRP concentrations were observed under ornamental cover during one or more study periods, which we attribute to differences in root density and shoot biomass between mixed ornamental species and turfgrass during establishment. Greater cumulative leachate inorganic N loads were reported from composted soils than from unamended soils or soils receiving only tillage or aeration. Inorganic N and DRP loads were similar in magnitude to reported leaching losses from agricultural systems. Better management of nutrients and water in woody ornamental plant beds during plant establishment is needed due to differences in plant growth habits compared with turfgrass. Nutrient content of organic amendments should be considered when applying these materials as a soil conditioner in new residential landscapes. PMID- 23673762 TI - Comparative mapping of soil physical-chemical and structural parameters at field scale to identify zones of enhanced leaching risk. AB - Preferential flow and particle-facilitated transport through macropores contributes significantly to the transport of strongly sorbing substances such as pesticides and phosphorus. The aim of this study was to perform a field-scale characterization of basic soil physical properties like clay and organic carbon content and investigate whether it was possible to relate these to derived structural parameters such as bulk density and conservative tracer parameters and to actual particle and phosphorus leaching patterns obtained from laboratory leaching experiments. Sixty-five cylindrical soil columns of 20-cm height and 20 cm diameter and bulk soil were sampled from the topsoil in a 15-m * 15-m grid in an agricultural loamy field. Highest clay contents and highest bulk densities were found in the northern part of the field. Leaching experiments with a conservative tracer showed fast 5% tracer arrival times and high tracer recovery percentages from columns sampled from the northern part of the field, and the leached mass of particles and particulate phosphorus was also largest from this area. Strong correlations were obtained between 5% tracer arrival time, tracer recovery, and bulk density, indicating that a few well-aligned and better connected macropores might change the hydraulic conductivity between the macropores and the soil matrix, triggering an onset of preferential flow at lower rain intensities compared with less compacted soil. Overall, a comparison mapping of basic and structural characteristics including soil texture, bulk density, dissolved tracer, particle and phosphorus transport parameters identified the northern one-third of the field as a zone with higher leaching risk. This risk assessment based on parameter mapping from measurements on intact samples was in good agreement with 9 yr of pesticide detections in two horizontal wells and with particle and phosphorus leaching patterns from a distributed, shallow drainage pipe system across the field. PMID- 23673763 TI - Runoff quality from no-till cotton fertilized with broiler litter in subsurface bands. AB - Surface broadcast of broiler litter to no-till row crops exposes the litter and its nutrients to risks of loss in runoff water and volatilization and may limit the potential benefit of litter to the crops. Subsurface banding of litter could alleviate these risks. A field study was conducted in 2008 and 2009 on an upland Falkner silt loam soil to determine the effect of broiler litter placement on runoff nutrient losses from no-till cotton ( L.). Treatments included surface broadcast broiler litter applied manually, subsurface-banded litter applied by tractor-drawn equipment, and no broiler litter, all in combination with or without winter wheat ( L.) cover crop residue. Broiler litter rate was 5.6 Mg ha. The experimental design was a randomized complete block with a split-plot arrangement of treatments replicated three times. In 2008, simulated rainfall was used to generate runoff 27 d after litter application. Subsurface-banded litter reduced runoff total C, N, P, NH, NO, Cu, Zn and water-soluble P (WP) concentrations by 72, 64, 51, 49, 70, 36, 65, and 77%, respectively, compared with surface broadcast. The reductions were greater in 2009 where runoff occurred 1 d after litter application. Bacterial runoff was decreased by one log with subsurface-banded litter compared to surface broadcast. Except for C, NH, N, and WP, the presence of winter cover crop residue did not affect the load or runoff nutrient concentrations in either year. The results indicate that subsurface banding litter to no-till cotton substantially reduces nutrient and bacterial losses in runoff compared with surface broadcasting. PMID- 23673764 TI - Living in denial: climate change, emotions, and everyday life. PMID- 23673765 TI - The restoring ecological health to your land workbook. PMID- 23673766 TI - A single institution's 26-year experience with nonfunctional pancreatic neuroendocrine tumors: a validation of current staging systems and a new prognostic nomogram. AB - OBJECTIVE: To validate the 2010 American Joint Committee on Cancer (AJCC) and 2006 European Neuroendocrine Tumor Society (ENETS) tumor staging systems for pancreatic neuroendocrine tumors (PanNETs) using the largest, single-institution series of surgically resected patients in the literature. BACKGROUND: The natural history and prognosis of PanNETs have been poorly defined because of the rarity and heterogeneity of these neoplasms. Currently, there are 2 main staging systems for PanNETs, which can complicate comparisons of reports in the literature and thereby hinder progress against this disease. METHODS: Univariate and multivariate analyses were conducted on the prognostic factors of survival using 326 sporadic, nonfunctional, surgically resected PanNET patients who were cared for at our institution between 1984 and 2011. Current and proposed models were tested for survival prognostication validity as measured by discrimination (Harrel's c-index, HCI) and calibration. RESULTS: Five-year overall-survival rates for AJCC stages I, II, and IV are 93% (88%-99%), 74% (65%-83%), and 56% (42%-73%), respectively, whereas ENETS stages I, II, III, and IV are 97% (92% 100%), 87% (80%-95%), 73% (63%-84%), and 56% (42%-73%), respectively. Each model has an HCI of 0.68, and they are no different in their ability to predict survival. We developed a simple prognostic tool just using grade, as measured by continuous Ki-67 labeling, sex, and binary age that has an HCI of 0.74. CONCLUSIONS: Both the AJCC and ENETS staging systems are valid and indistinguishable in their survival prognostication. A new, simpler prognostic tool can be used to predict survival and decrease interinstitutional mistakes and uncertainties regarding these neoplasms. PMID- 23673767 TI - Burn injury enhances bone formation in heterotopic ossification model. AB - OBJECTIVE: To demonstrate the pro-osteogenic effect of burn injury on heterotopic bone formation using a novel burn ossicle in vivo model. BACKGROUND: Heterotopic ossification (HO), or the abnormal formation of bone in soft tissue, is a troubling sequela of burn and trauma injuries. The exact mechanism by which burn injury influences bone formation is unknown. The aim of this study was to develop a mouse model to study the effect of burn injury on heterotopic bone formation. We hypothesized that burn injury would enhance early vascularization and subsequent bone formation of subcutaneously implanted mesenchymal stem cells. METHODS: Mouse adipose-derived stem cells were harvested from C57/BL6 mice, transfected with a BMP-2 adenovirus, seeded on collagen scaffolds (ossicles), and implanted subcutaneously in the flank region of 8 adult mice. Burn and sham groups were created with exposure of 30% surface area on the dorsum to 60 degrees C water or 30 degrees C water for 18 seconds, respectively (n = 4/group). Heterotopic bone volume was analyzed in vivo by micro-computed tomography for 3 months. Histological analysis of vasculogenesis was performed with platelet endothelial cell adhesion molecule staining. Osteogenic histological analysis was performed by Safranin O, Picrosirius red, and aniline blue staining. Qualitative analysis of heterotopic bone composition was completed with ex vivo Raman spectroscopy. RESULTS: Subcutaneously implanted ossicles formed heterotopic bone. Ossicles from mice with burn injuries developed significantly more bone than sham control mice, analyzed by micro-computed tomography at 1, 2, and 3 months (P < 0.05), and had enhanced early and late endochondral ossification as demonstrated by Safranin O, Picrosirius red, and aniline blue staining. In addition, burn injury enhanced vascularization of the ossicles (P < 0.05). All ossicles demonstrated chemical composition characteristic of bone as demonstrated by Raman spectroscopy. CONCLUSIONS: Burn injury increases the predilection to osteogenic differentiation of ectopically implanted ossicles. Early differences in vascularity correlated with later bone development. Understanding the role of burn injury on heterotopic bone formation is an important first step toward the development of treatment strategies aimed to prevent unwanted and detrimental heterotopic bone formation. PMID- 23673769 TI - Limits of neuromonitoring in thyroid surgery. PMID- 23673768 TI - Nationwide study of 4741 patients with non-B non-C hepatocellular carcinoma with special reference to the therapeutic impact. AB - OBJECTIVE: To examine the prognostic factors and outcomes after several types of treatments in patients with hepatocellular carcinoma (HCC) negative for hepatitis B surface antigen and hepatitis C antibody, so-called "non-B non-C HCC" using the data of a nationwide survey. BACKGROUND: The proportion of non-B non-C HCC is rapidly increasing in Japan. METHODS: A total of 4741 patients with non-B non-C HCC, who underwent hepatic resection (HR, n = 2872), radiofrequency ablation (RFA, n = 432), and transcatheter arterial chemoembolization (TACE, n = 1437) as the initial treatment, were enrolled in this study. The exclusion criteria included extrahepatic metastases and/or Child-Pugh C. Significant prognostic variables determined by a univariate analysis were subjected to a multivariate analysis using a Cox proportional hazard regression model. RESULTS: The degree of liver damage in the HR group was significantly lower than that in the RFA and TACE groups. The HR and TACE groups had significantly more advanced HCC than the RFA group. The 5-year survival rates after HR, RFA, and TACE were 66%, 49%, and 32%, respectively. Stratifying the survival rates, according to the TNM stage and the Japan Integrated Staging (JIS) score, showed the HR group to have a significantly better prognosis than the RFA group in the stage II and in the JIS scores "1" and "2." The multivariate analysis showed 12 independent prognostic factors. HR offers significant prognostic advantages over TACE and RFA. CONCLUSIONS: The findings of this large prospective cohort study indicated that HR may be recommended, especially in patients with TNM stage II and JIS scores "1" and "2" of non-B non-C HCC. PMID- 23673770 TI - A systematic review of economic evaluations of enhanced recovery pathways for colorectal surgery. AB - OBJECTIVE: To perform a systematic review of economic evaluations of enhanced recovery pathways (ERP) for colorectal surgery. BACKGROUND: Although there is extensive literature investigating the clinical effectiveness of ERP, little is known regarding its cost-effectiveness. METHODS: A systematic literature search identified all relevant articles published between 1997 and 2012 that performed an economic evaluation of ERP for colorectal surgery. Studies were included only if their ERP included all 5 of the key components (patient information, preservation of GI function, minimization of organ dysfunction, active pain control, and promotion of patient autonomy). Quality assessment was performed using the Consensus on Health Economic Criteria instrument (scored 0-19; high quality >= 12). Incremental cost-effectiveness ratios were calculated if sufficient data were provided, using difference in length of stay and overall complication rates as effectiveness measures. RESULTS: Of a total of 263 unique records identified (253 from databases and 10 from other sources), 10 studies met our inclusion criteria and were included for full qualitative synthesis. Overall quality was poor (mean quality 7.8). Eight reported lower costs for ERP. The majority (8 of 10) of studies were performed from an institutional perspective and therefore did not include costs related to changes in productivity and other indirect costs (eg, caregiver burden). Five studies provided enough information to calculate ICERs, of which ERP was dominant (less costly and more effective) in all cases for reduction in length of stay and was dominant or potentially cost effective in 4 and questionable (no difference in costs nor effectiveness) in 1 for reduction in overall complications. CONCLUSIONS: The quality of the current evidence is limited but tends to support the cost-effectiveness of ERP. There is need for well-designed trials to determine the cost-effectiveness of ERP from both the institutional and societal perspectives. PMID- 23673771 TI - Prognostic difference between Eastern and Western patients with gastric cancer: quality of care, ethnicity, or biology? PMID- 23673772 TI - Dibenzotetraaza[14]annulene-adenine conjugate recognizes complementary poly dT among ss-DNA/ss-RNA sequences. AB - Among three novel DBTAA derivatives only the DBTAA-propyl-adenine conjugate showed recognition of the consecutive oligo dT sequence by increased affinity and specific induced chirooptical response in comparison to other single stranded RNA and DNA; whereby of particular importance is the up until now unique efficient differentiation between dT and rU. At variance, its close analogue DBTAA-hexyl adenine did not reveal any selectivity between ss-DNA/RNA pointing out the important role of steric factors (linker length); moreover non-selectivity of the reference compound (, lacking adenine) stressed the importance of adenine interactions in the selectivity. PMID- 23673773 TI - Assembling 1D magnetic chain based on octacyanotungstate(V) and [Cu2L2Ln] sub building units (Ln = Eu, Gd, Tb and Dy). AB - Reaction of (NBu3H)3[W(CN)8].H2O and linear trinuclear complexes [Cu(II)2L2Ln(III)(NO3)3] (L = 2,6-di(acetoacetyl)pyridine, Ln = Eu (1), Gd (2), Tb (3) and Dy (4)) leads to the formation of four one-dimensional (1D) complexes. Single crystal X-ray analysis reveals that [W(CN)8](3-) bridges between the [Cu(II)2L2Ln(III)] sub-building units to construct the alternative chains. Magnetic investigation indicates that ferromagnetic interaction occurred between all paramagnetic ions and the slow magnetic relaxation properties were observed in complexes 3 and 4. PMID- 23673776 TI - Peripheral Treg count and it's determinants in unsensitized and sensitized chronic kidney disease patients. AB - PURPOSE: Sensitization to HLA antigens resulting in anti-HLA antibodies (panel reactive antibodies; PRA) is a major problem in chronic kidney disease (CKD) patients awaiting transplantation. Induction of anti-HLA antibodies normally occurs through blood transfusion, pregnancy and prior transplantation. However, some patients develop these antibodies for unknown immunological reasons. It is hypothesized that deviations in immune regulation may account for PRA positivity in these patients. We, therefore, investigated whether a quantitative deficiency in peripheral natural regulatory T cells (CD4(+)CD25(high)Foxp3(+); nTreg) plays a role in this phenomenon. METHODS: Peripheral blood mononuclear cells from 14 patients with positive (Class I and Class II; 10-100 %) and 25 patients with negative PRA, who had not previously been sensitized by blood transfusion, pregnancy and prior transplantation and who had not received any immunomodulatory treatment within the last year, were analyzed for absolute lymphocyte and nTreg numbers through flow cytometry. Samples from 10 healthy people were also used as control. RESULTS: Mean absolute nTreg numbers were determined to be severely reduced in CKD patients (12 +/- 9; n = 39) compared with healthy individuals (53 +/- 17; n = 10) (p = 0.008). However, absolute nTreg numbers were similar between PRA- (12 +/- 11) and PRA+ (11 +/- 8) groups. Interestingly, there was a moderate correlation between the nTreg numbers and HLADR2 genotype (n = 9, r = 0.508, p < 0.05). CONCLUSION: This is the first study to demonstrate that the quantitative peripheral nTreg deficiency in CKD patients does not show a causal relationship with the presence of anti-HLA antibodies. PMID- 23673775 TI - Current developments in early diagnosis of acute kidney injury. AB - Acute kidney injury (AKI) is a very frequent and serious clinical problem, accounting for overall high morbidity and mortality. Up to date, mortality due to AKI is virtually unchanged over the past 50 years. This may partly be explained due to a delay in initiating renal protective and appropriate therapeutic measures since until now there are no reliable early-detecting biomarkers. The gold standard, serum creatinine, displays poor specificity and sensitivity with regard to identification of the incipient phase of AKI, and this is also true for cystatin C. We aimed to review novel biomarkers of AKI in urine and serum which have now progressed to the clinical phase. The main focus refers to their diagnostic and prognostic value. For this purpose, a web-based literature search using PubMed was performed comprising the following terms: renal failure, acute kidney injury and biomarkers. New molecules such as neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), N-acetyl-beta-D glucosaminidase (NAG), monocyte chemotactic peptide (MCP-1), Il-18, liver-type fatty acid-binding protein (L-FABP) and Netrin-1 are available and represent promising new markers that, however, need to be further evaluated in the clinical setting for suitability. In clinical settings with incipient AKI, not only the development and the implementation of more sensitive, practicable and accurate biomarkers are required for well-timed treatment initiation. Just as important is a substantial improvement of refined and applicable prophylactic therapeutic options in these situations. Before full adoption in clinical practice can be accomplished, adequately powered clinical trials testing a row of biomarkers are strongly warranted. PMID- 23673777 TI - Urinary turbidity as a marker of crystallization: is spectrophotometric assessment useful? AB - PURPOSE: We propose a simple and inexpensive in vitro crystallization assay of measuring turbidity by spectrophotometry in synthetic urine. We validated our method by investigating the effect of potassium (K) citrate on the crystallization of calcium oxalate monohydrate (CaOx), calcium phosphate, and magnesium ammonium phosphate using synthetic urine. METHODS: The crystallization of CaOx was studied using turbidimetric measurements of solution produced by mixing calcium chloride and sodium oxalate at 37 degrees C, pH 5.7. The turbidity of the crystal suspension was measured immediately with double-beam spectrophotometer as the absorbance of light at 660 nm wavelength. The rates of crystal formation and aggregation were obtained by measuring optical density (OD) over 30 min. The obtained results were compared to CaOx crystal concentration with and without citrate assessed by optical microscopy. RESULTS: The sensitivity of spectrophotometry in measuring turbidity was confirmed by the linear correlation between the crystal concentration and OD readings at 660 nm seen on the standard curve. Under similar experimental conditions, the results were comparable to the ones obtained by optical microscopy. The OD readings over 30 min revealed an instant decrease in the number of crystals, with maximum aggregation noted at 18 min. Addition of K-citrate at 1.25 mg/ml led to initial less crystal formation (OD = 0.236 nm vs. OD = 0.527 nm), with a maximum aggregation reached at 18 min. Overall, citrate addition decreased nucleation with a small change in the aggregation (OD = 0.316 vs. OD = 0.359). CONCLUSION: Spectrophotometric measurement of urinary turbidity is feasible and sensitive in assessing the potential clinical usefulness of different medications in inhibiting crystallization in urine. PMID- 23673780 TI - Pickering syndrome: high-risk stenting of a renal artery stenosis in a multimorbid patient presenting with progressive congestive heart failure. PMID- 23673781 TI - Morality and its relation to political ideology: the role of promotion and prevention concerns. AB - Our research investigated whether promotion concerns with advancement and prevention concerns with security related to moral beliefs and political ideology. Study 1 found that chronic prevention and promotion focus had opposite relations to binding foundation endorsement (as measured by the Moral Foundations Questionnaire), that is, positive for prevention and negative for promotion, and opposite relations to political ideology, that is, more conservative for prevention and more liberal for promotion, and the relation between focus and political ideology was partially mediated by binding foundation endorsement. Study 2 showed that promotion and prevention, even as situationally induced states, can contribute to differences in binding foundation endorsement, with prevention producing stronger endorsement (compared with a control) and promotion producing weaker endorsement. PMID- 23673782 TI - Mid-Staffordshire--the Francis Report. PMID- 23673783 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 1: Can biological markers predict alcohol withdrawal syndrome? AB - A short-cut review of the literature was carried out to establish whether biological markers (namely carbohydrate-deficient transferrin (CDT), gamma glutamyl transferase (GGT) and mean corpuscular volume (MCV)) could reliably predict patients at risk of developing alcohol withdrawal syndrome. Using the below outlined search method and after exclusion of the non-relevant papers, five papers were found to be relevant to the specific question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these are shown in table 1. The clinical bottom line is that CDT/GGT/MCV are not reliable enough as stand-alone markers to predict alcohol withdrawal syndrome in chronic alcohol abusers. PMID- 23673785 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 2: Immobilisation of stable ankle fractures: plaster cast or functional brace? AB - A short-cut review of the literature was carried out to establish whether a functional brace was as good as a traditional plaster of Paris to immobilise a stable ankle fracture in terms of functionality and recovery speed. A total of 260 papers was found using the below outlined search method, of which five were thought to represent the best evidence to answer the specific clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these are shown in table 2. The clinical bottom line is that the limited evidence seems to suggest that a functional brace appears to give more favourable outcomes. Good quality studies involving large populations are, however, needed to delineate a clear answer to this specific question. PMID- 23673786 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 3: In well-appearing children suspected of meningococcal disease can procalcitonin reduce the need for empiric antibiotic treatment? AB - A short-cut review of the literature was carried out to establish whether the biological marker procalcitonin could safely rule out the diagnosis of meningococcal disease (MCD) in children. Using the below outlined search method and after the exclusion of the non-relevant papers, two were found to be relevant to the specific question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these are shown in table 3. The clinical bottom line is that the currently available evidence is not sufficient to support the sole use of procalcitonin to rule out the diagnosis of MCD. PMID- 23673774 TI - The long-term safety of antiepileptic drugs. AB - Antiepileptic drugs (AEDs) are used by millions of people worldwide for the treatment of epilepsy, as well as in many other neurological and psychiatric conditions. They are frequently associated with adverse effects (AEs), which have an impact on the tolerability and success of treatment. Half the people who develop intolerable AEs discontinue treatment early on after initiation, while the majority of people will continue to be exposed to their effects for long periods of time. The long-term safety of AEDs reflects their potential for chronic, cumulative dose effects; rare, but potentially serious late idiosyncratic effects; late, dose-related effects; and delayed, teratogenic or neurodevelopmental effects. These AEs can affect every body system and are usually insidious. With the exception of delayed effects, most other late or chronic AEs are reversible. To date, there is no clear evidence of a carcinogenic effect of AEDs in humans. While physicians are aware of the long-term AEs of old AEDs (the traditional liver enzyme-inducing AEDs and valproate), information about AEs of new AEDs (such as lamotrigine, levetiracetam, oxcarbazepine, topiramate or zonisamide), particularly of their teratogenic effects, has emerged over the years. Sporadic publications have raised issues about AEs of the newer AEDs eslicarbazepine, retigabine, rufinamide, lacosamide and perampanel but their long-term safety profiles may take years to be fully appreciated. Physicians should not only be aware of the late and chronic AEs of AEDs but should systematically enquire and screen for these according to the individual AED AE profile. Care should be taken for individuals with comorbid conditions that may render them more susceptible to specific AEs. Prevention and appropriate management of long-term AED AEs is expected to improve adherence to treatment, quality of life and control of epilepsy. PMID- 23673788 TI - Clinicopathologic characteristics of STAT1 positive/interleukin-8 negative subgroup in triple negative breast cancer defined by surrogate immunohistochemistry. AB - BACKGROUND: The aim of this study was to define immune-related triple negative breast cancer (TNBC) using immunohistochemistry for STAT1, CD20, CD3, IL-8, and IFN-gamma and to assess its clinicopathologic characteristics. MATERIAL AND METHODS: Tissues from 133 cases of TNBC were used for a tissue microarray. Expression of STAT1, CD20, CD3, IL-8, and IFN-gamma were evaluated by immunohistochemical staining of the tissue microarrays. Immune-related type was defined as TNBC which was positive for STAT1 and negative for IL-8. A separate assessment of IL-8 and STAT1 status in tumor and stroma compartment was used to further classify immune-related type into tumor-based and stroma-based immune related TNBC. RESULTS: Stroma-based, immune-related TNBC showed a significantly smaller central acellular zone (p=0.043), more lymphocytic infiltration (p?0.001), higher CD20 index (p=0.001), and higher CD3 index (p=0.018) than stroma-based, non-immune-related TNBC. IL-8 was independently associated with shorter disease-free survival (Hazard ratio: 3.804, 95% CI: 1.234-11.729, p=0.020) and shorter overall survival (Hazard ratio: 3.434, 95% CI: 1.132-10.414, p=0.029). CONCLUSIONS: Immune-related proteins such as STAT1, IFN-gamma, IL-8, and CD20 were variably expressed in TNBCs. Stroma-based, immune-related TNBC (when positive for stromal STAT1 and negative for stromal IL-8) showed significantly higher lymphocytic infiltration including both CD3 positive T cell and CD20 positive B cell. PMID- 23673790 TI - Could FDA approval of pre-exposure prophylaxis make a difference? A qualitative study of PrEP acceptability and FDA perceptions among men who have sex with men. AB - The FDA has approved tenofovir-emtricitabine for use as HIV pre-exposure prophylaxis, but it is unknown how approval may affect PrEP acceptability among US men who have sex with men. We conducted 8 focus groups among 38 Rhode Island MSM, including 3 groups among 16 male sex workers and 5 groups among 22 men in the general MSM community. Participants reported wide-ranging beliefs regarding consequences and meanings of FDA approval. Some participants would not use PrEP without approval, while others perceived approval as irrelevant or less significant than other sources of information. Our results suggest that FDA approval sends a signal that directly shapes PrEP acceptability among some MSM, while indirect influences of approval may affect uptake by others. Efforts to educate MSM about PrEP can increase acceptability by incorporating information about FDA approval, and outreach strategies should consider how this information may factor into personal decisions about PrEP use. PMID- 23673789 TI - Non-cigarette tobacco and the lung. AB - Cigarette smoking is known to cause a wide range of damaging health outcomes; however, the effects of non-cigarette tobacco products are either unknown or perceived as less harmful than cigarettes. Smokeless tobacco, cigar smoking, and waterpipe smoking have increased in usage over the past few decades. Some experts believe that their use is reaching epidemic proportions. Factors such as a perception of harm reduction, targeted advertising, and unrecognized addiction may drive the increased consumption of non-cigarette tobacco products. In particular, the need for social acceptance, enjoyment of communal smoking activities, and exotic nature of waterpipe smoking fuels, in part, its popularity. The public is looking for "safer" alternatives to smoking cigarettes, and some groups advertise products such as smokeless tobacco and electronic cigarettes as the alternatives they seek. Though it is clear that cigar and waterpipe tobacco smoking are probably as dangerous to health as cigarette smoking, there is an opinion among users that the health risks are less compared to cigarette smoking. This is particularly true in younger age groups. In the cases of smokeless tobacco and electronic cigarettes, the risks to health are less clear and there may be evidence of a harm reduction compared to cigarettes. In this article, we discuss commonly used forms of non-cigarette tobacco products, their impacts on lung health, and relevant controversies surrounding their use. PMID- 23673791 TI - Developing an online health intervention for young gay and bisexual men. AB - Young gay and bisexual men continue to experience increases in HIV incidence in the US highlighting a need for competent health services, while the prominence of the internet in their social and sexual lives calls for novel preventive modalities. Toward this goal, we adapted an efficacious in-office HIV risk reduction intervention for online delivery. This paper describes the development of the online intervention and highlights the results of interviews and focus groups with the original intervention participants regarding effective adaptation and online delivery recommendations. The final intervention incorporates strategies for overcoming barriers to online intervention with this population and capitalizes on the unique strengths of online intervention delivery. The systematic process described in this paper can be used as a template for other researchers to develop online risk reduction programs and fills an important gap in the field's ability to maximally reach a critical risk group. PMID- 23673792 TI - Contribution of substance use disorders on HIV treatment outcomes and antiretroviral medication adherence among HIV-infected persons entering jail. AB - HIV and substance use are inextricably intertwined. One-sixth of people living with HIV/AIDS (PLWHA) transition through the correctional system annually. There is paucity of evidence on the impact of substance use disorders on HIV treatment engagement among jail detainees. We examined correlates of HIV treatment in the largest sample of PLWHA transitioning through jail in 10 US sites from 2007 to 2011. Cocaine, alcohol, cannabis, and heroin were the most commonly used substances. Drug use severity was negatively and independently correlated with three outcomes just before incarceration: (1) having an HIV care provider (AOR = 0.28; 95 % CI 0.09-0.89); (2) being prescribed antiretroviral therapy (AOR = 0.12; 95 % CI 0.04-0.35) and (3) high levels (>95 %) of antiretroviral medication adherence (AOR = 0.18; 95 % CI 0.05-0.62). Demographic, medical and psychiatric comorbidity, and social factors also contributed to poor outcomes. Evidence-based drug treatments that include multi-faceted interventions, including medication assisted therapies, are urgently needed to effectively engage this vulnerable population. PMID- 23673794 TI - One-year follow-up of the Polish subset of the RecordAF registry of patients with newly diagnosed atrial fibrillation. AB - INTRODUCTION: Data on real-life management of atrial fibrillation (AF) in Poland is limited. OBJECTIVES: To present data on 1-year follow-up of patients from Poland included in a worldwide registry on patients with AF (RecordAF). PATIENTS AND METHODS: Patients with recent onset AF were included (n=303). Treatment strategy (rhythm or rate control) was noted at baseline. Therapeutic success (control of AF, with no incidence of cardiovascular events and no switch between the strategies) was assessed after one year. RESULTS: Data from 289 patients were assessable. A rhythm control strategy was noted in 70% of patients. Rhythm control patients received anti-thrombotic therapy less frequently than rate control patients (90.4% vs. 97.6%) but more often received class I (19.8% vs. 4.8%) and class III (20.8% vs. 4.8%) antiarrhythmic drugs (p<0.05 for all comparisons). Therapeutic success was noted in 71.5% of rhythm control patients vs. 29.1% of rate control patients (p<0.0001), a result driven by control of AF (89.3% in the rhythm control group vs. 56.1% in the rate control group, p<0.0001). The rate of cardiovascular events was similar in both groups (20.6% of all patients). Progression to permanent AF occurred in 5.9% of rhythm control patients vs. 73.2% of rate control patients (p<0.001). CONCLUSIONS: Most of the patients received thromboembolic prevention and the majority was assigned to rhythm control. Despite infrequent use of anti-arrhythmic drugs, a rhythm control strategy was associated with better AF control and slower progression but not with lower rate of cardiovascular events in patients with recent-onset AF in Poland. PMID- 23673795 TI - A "core curriculum" for the medical humanities? PMID- 23673796 TI - Narratives of psychiatric malingering in works of fiction. AB - This paper argues that the representation of psychiatric malingering in literary and cinematographic narratives informs societal stereotypes, and thus influences the clinical phenomenology of malingering. The study aims to identify sociocultural models of malingering in contemporary Western society based on the narrative analysis of about 60 fictional and non-fiction texts. Two behavioural patterns derived from the Foucauldian categories folly and madness are recognisable in naive conceptualisations of fake insanity. Fabricated significations of deviation originate in grand societal narratives rather than in medical discourse, and construct characters such as animal like underdeveloped simpletons or detached, irrational, violent madmen. Each pattern stems from its own archaic conceptual basis and dictates a distinct framework for strategies of malingering. The semiotic structure of artistic narratives of malingering is discussed in comparison with the symptomatology of existing psychiatric models. PMID- 23673793 TI - Feasibility, acceptability, and preliminary efficacy of an online HIV prevention program for diverse young men who have sex with men: the keep it up! intervention. AB - Young men who have sex with men (YMSM) are disproportionately infected with HIV/AIDS and there are few prevention programs with published efficacy for this population. This study evaluated the feasibility, acceptability, and preliminary efficacy of an online, interactive, and highly engaging HIV prevention program called Keep It Up! The intervention was designed to be delivered to diverse YMSM upon receiving an HIV negative text result, with the goal for them to "Keep It Up" and stay negative. In a randomized clinical trial, the intervention was compared to an online didactic HIV knowledge condition. The study sample included 102 sexually active YMSM. Participants reported completing online modules in settings that were private and not distracting. Mixed methods data showed intervention participants felt the program was valuable and acceptable. Compared to the control condition, participants in the intervention arm had a 44 % lower rate of unprotected anal sex acts at the 12-week follow-up (p < 0.05). PMID- 23673797 TI - Envying Cinderella and the future of medical enhancements. AB - The medical profession is increasingly absorbing technologies that offer medical care that is more luxury than need. From foot sculpting surgeries to breast and pectoral implants, physicians are increasingly putting patients under the knife to improve on the normal, to make better than well. Medicine's enthusiasm for absorbing such technologies may corrode the moral priority that it has traditionally held as a profession. Medicine's moral status declines when it both provides medical luxuries and meets medical needs. Patients without health care will increasingly envy patients who receive healthcare luxuries. Instead, however, of doing away with such luxuries, medicine can institute a pay scheme whereby medical luxuries help subsidise care for those without health care. In this fashion, any feelings of envy are pre-empted and the profession retains its moral status. PMID- 23673798 TI - Enhancement: are ethicists excessively influenced by baseless speculations? AB - Most commentators draw a sharp distinction between therapy and enhancement, applauding therapy and rejecting enhancement. Not only is this distinction unclear but enhancement is often seen in grandiose terms in which human beings are radically transformed. Such far-reaching visions are then used to reject current procedures such as pre-implantation genetic diagnosis. To overcome this highly problematic impasse, enhancement has been divided into three categories, ranging from the health-related enhancement of category 1, through the non-health related enhancement of category 2, to the transhumanism or posthumanism of category 3. Arguably, most enhancements are of the category 1 variety, and hence closely related to treatment. Also, we are already enhanced, when compared with our forebears. It is only when we accept this and dispense with baseless speculation will we be in a position to conduct ethical discussions within a realistic framework. PMID- 23673799 TI - The novel Arrowsmith, Paul de Kruif (1890-1971) and Jacques Loeb (1859-1924): a literary portrait of "medical science". AB - Shortly after bacteriologist Paul de Kruif had been dismissed from a research position at the Rockefeller Institute for Medical Research, he started contributing to a novel in collaboration with the future Nobel laureate Sinclair Lewis. The novel, Arrowsmith, would become one of the most famous satires on medicine and science. Using de Kruif's correspondence with his idol Jacques Loeb, this paper describes the many ways in which medical science is depicted in Arrowsmith. This article compares the novel with de Kruif's and Loeb's biographies, and (1) focuses on the struggles of the main character, Martin Arrowsmith, as an allegory of the institutionalisation of medical research in the US, (2) shows that (influenced by de Kruif) Sinclair's purpose is to caricaturise scientific work in modern medical research institutions anywhere and (3) shows that the novel depicts a reductionist philosophy of research that seems to contradict the "messiness" of medical practice. PMID- 23673800 TI - The missing future tense in medical narrative. AB - Medical narrative is normally assumed to be a past tense narrative. Patients' and students' past tense narratives should be supplemented by future tense narratives, and in particular by what we call hypothetical narratives-narratives such as those offered by a medical student in response to the instruction "Tell me a story about when you are a doctor". These narratives are suggested to be especially useful in clinical and educational contexts because they offer greater insight into the narrator's hopes and expectations than past tense narratives, which can be helpful in planning management and teaching. The narrator's ethical principles are also exposed more clearly than when using the past tense narrative. Some ethical concerns raised by analysing narratives offered by patients or students, as if they were literary narratives, are avoided by hypothetical narratives. This suggestion is based on Ricoeur's account of the ethical importance of veracity in narrative, or "attestation of what has occurred". The patient/doctor or student/teacher relationship is found to have an implicit concern for the narrator's intention that makes the assumptions underlying literary analysis untenable. PMID- 23673801 TI - Need humanities be so useless? Justifying the place and role of humanities as a critical resource for performance and practice. AB - Justifying the existence, position, and relevance of academic humanities scholarship may be difficult in the face of chronic practical needs in health care. Such scholarship may seem parasitic on human activity and performance that directly contributes to human wellbeing and health care. Here, a possible and partial justification for the importance of scholarship in the humanities as a critical resource for practice and performance is undertaken by two humanities scholars. Human identity and emotion are reflected and defined by performances, both in the traditional disciplines of the humanities, such as art and literature, and in the sciences and medicine. The critical attitude that such performances might inadvertently undermine is sustained by the humanities. The humanities disciplines ask the question: "What is it to be human?" Uncritical emotion and expression, arising, for example, from understanding developments in medicine and science, which might exclude or corrupt much that is of value in the healthcare sector and other areas of practical performance, can be constrained by this. PMID- 23673802 TI - Discourse ethics in practical medicine. AB - Problems emerge in practical medicine because the binary ethics of the classic patient/doctor relationship has been replaced by multiagent interaction between those engaged in the process of diagnosis and treatment. New methods are required to deal with complex problems in every patient. Where and why the current practice can fail is illustrated with an example of an unspectacular routine case of cancer. The failure may result from basing the procedure on mechanistic methods or from the deficit and difficulty in communication. Whether rule based algorithms could have improved the treatment in the patient with cancer is discussed. How discourse ethics may fit better with the course of the case is described. Clinical Medicine follows a similar logic to that modelled by discursive ethics, ethics thinking should essentially contribute to the procedural logic of medical practice. Discourse ethics can be used as a procedural model that copes with the complexity and temporality of practical medicine. Applied discourse ethics can turn out to be both instrumental in mediating inherent conflicts and constitutive for value based problem solving in modern medical practice. PMID- 23673803 TI - Correspondence. PMID- 23673804 TI - Graduation. PMID- 23673805 TI - Nietzsche's morality: a genealogy of medical malpractice. AB - Medical malpractice is of increasing concern and 60 billion dollars are added annually to healthcare costs. The practice of defensive medicine, decreased availability of doctors, and increased health insurance premiums are all results of medical malpractice. An argument is made from the perspective of Friedrich Nietzsche's On the Genealogy of Morals that a primal cause of the litigiousness of the public against doctors results from resentment or "ressentiment". The relationship of promises, responsibility, and guilt between doctors and patients is explored, as well as what may be necessary to reduce the public's ressentiment. Modern malpractice in the US is covered by Nietzsche's line of reasoning in On the Genealogy of Morals, although his reasoning is condemned by most Western philosophers. Doctors may be able to better manage their interactions with patients and limit their exposure to litigation by understanding and exploring alternative philosophical and historical origins-or aetiologies-of patient/doctor conflict. PMID- 23673806 TI - Autopathography and humane medicine: The diving bell and the butterfly--an interpretation. AB - Autopathographies are an expanding genre of books and articles that are a potential resource for students interested in the medical humanities. New curricula emphasise the need to familiarise medical students with the patient's point of view. Different specialities compete for the student's attention and the medical humanities are not an exception. Some form of assessment is necessary to reflect the importance of the patient's perspective. One way may be to request students analyse their chosen autopathography. The article presents an example based on one of the better know accounts. The identified themes reflect the sudden disruption in the author's biography. The topics are connected to the medical disorder and illustrated by quotations. The different categories of autopathography can be helpful in understanding the author's perspective. In this instance the author was a full time editor before his stroke. The style of the book employs professional distance from the narrative. This is more compatible with the description of metapathography rather than the original classification of autopathogrphies as religious, angry or alternative. PMID- 23673807 TI - Opening the word hoard. PMID- 23673808 TI - Medical humanities: a personal view. PMID- 23673809 TI - A silly expression: Consultants' implicit and explicit understanding of Medical Humanities. A qualitative analysis. AB - The term Medical Humanities has still not been established in the wider medical, educational and academic communities. This qualitative study, conducted across three acute care trusts, is an exploration of whether clinicians were familiar with the term Medical Humanities, and if so, what the term meant to them and whether they considered the associated concepts relevant to medical practice and education. Reactions to the term Medical Humanities were varied: many clinicians had not heard of the term before, some were unsure what it meant, others displayed mistrust or contempt for it. Explicit definitions that were elicited were categorised (inductively) according to three main approaches to the understanding of Medical Humanities: Humanistic-holistic, Humanities-medicine seperate and Intellectual exercise. Findings indicate that the lack of clarity about the term Medical Humanities among experienced healthcare professionals, contrasts with their sophisticated implicit knowledge of key issues frequently associated with Medical Humanities. Thus, while some clinicians could not define Medical Humanities and some definitions separated humanities from medicine, all clinicians implicitly acknowledged the importance of Medical Humanities issues within their clinical and teaching practices during conversations prior to any mention of the term. It appears that clinicians as role models for medical students can inadvertently convey an ambivalent position towards the Medical Humanities that encompass the very values and attitudes they are trying to inculcate, sending out mixed messages to the novices. PMID- 23673810 TI - A new curcumin analogue exhibits enhanced antitumor activity in nasopharyngeal carcinoma. AB - The aim of the present study was to evaluate the antitumor effects of the curcumin analogue GL63 on radioresistant nasopharyngeal carcinoma (NPC) CNE2R cells and parental CNE2 cells. The cell viability and proliferation of NPC cells were detected by MTT assay and colony formation assay. The suppressive effect on tumor growth was examined using in vivo subcutaneously inoculated NPC tumor models using nude mice. The cell cycle distribution was detected using flow cytometry. Apoptosis was examined by Hoechst 33342 and Annexin V/PI staining assay. The protein expression of endoplasmic reticulum (ER) stress pathway markers, XBP-1, ATF-4 and CHOP, were examined by western blotting. A growth inhibitory effect was observed following treatment with GL63 in a dose-dependent manner and was more potent when compared to curcumin. GL63 at 5 uM induced significant G2/M arrest and apoptosis in NPC. The tumor-suppressive activity of GL63 in NPC xenograft models was more potent when compared to curcumin. Furthermore, GL63 induced an ER stress response, upregulation of CHOP, XBP-1 and ATF-4 expression, while the same concentration of curcumin had no effect on ER stress. These results suggest that GL63 has more potent antitumor activity than curcumin, which is associated with activation of ER stress, induction of G2/M arrest and apoptosis in NPC cells. PMID- 23673811 TI - Stability and electronic properties of ultrathin films of silicon and germanium. AB - Recent studies have examined the possibility of growing honeycomb silicene and germanene, the silicon and germanium analogues of graphene. Here we use first principles calculations to examine the relative stability of a number of other single-layer structures that are derived from prominent surface reconstructions of group-IV semiconductors. We find that Si single-layers with the geometry of the ?3 * ?3 reconstruction are more stable than honeycomb silicene. Likewise, honeycomb germanene is less stable than germanium ultrathin films with a ?3 * ?3 or 7 * 7 arrangement. ?3 * ?3 Si and Ge single layers are metals with strong peaks at the Fermi level, and, in the case of Ge, they bear a magnetic moment. Overall, the results demonstrate that free-standing Si and Ge nano-sheets differ in key structural and electronic properties from graphene, and may thus provide systems with alternative functionalities. PMID- 23673812 TI - Al-H sigma-bond coordination: expanded ring carbene adducts of AlH3 as neutral bi and tri-functional donor ligands. AB - Thermally robust expanded ring carbene adducts of AlH3 have been synthesized with a view to probing their ligating abilities via Al-H sigma-bond coordination. While kappa(2) binding to the 14-electron [Mo(CO)4] fragment is readily demonstrated, interaction with [Mo(CO)3] results in MU:kappa(1),kappa(1) and MU:kappa(2),kappa(2) bridging linkages rather than terminal kappa(3) binding. PMID- 23673813 TI - Knockdown of NF-E2-related factor 2 inhibits the proliferation and growth of U251MG human glioma cells in a mouse xenograft model. AB - NF-E2-related factor 2 (Nrf2) is a pivotal transcription factor of cellular responses to oxidative stress and recent evidence suggests that Nrf2 plays an important role in cancer pathobiology. However, the underlying mechanism has yet to be elucidated, particularly in glioma. In the present study, we investigated the role of Nrf2 in the clinical prognosis, cell proliferation and tumor growth of human glioblastoma multiforme (GBM). We detected overexpression of Nrf2 protein levels in GBM compared to normal brain tissues. Notably, higher protein levels of Nrf2 were significantly associated with poorer overall survival and 1 year survival for GBM patients. Furthermore, we constructed the plasmid Si-Nrf2 and transduced it into U251MG cells to downregulate the expression of Nrf2 and established stable Nrf2 knockdown cells. The downregulation of Nrf2 suppressed cell proliferation in vitro and tumor growth in mouse xenograft models. We performed immunohistochemistry staining to detect the protein levels of Nrf2, Ki 67, caspase-3 and CD31 in the xenograft tumors and found that the expression levels of Nrf2 and Ki-67 were much lower in the Si-Nrf2 group compared to the Si control group. In addition, the number of caspase-3-positive cells was significantly increased in the Si-Nrf2 group. By analysis of microvessel density (MVD) assessed by CD31, the MVD value in the Si-Nrf2 group decreased significantly compared to the Si-control group. These findings indicate that the knockdown of Nrf2 may suppress tumor growth by inhibiting cell proliferation, increasing cell apoptosis and inhibiting angiogenesis. These results highlight the potential of Nrf2 as a candidate molecular target to control GBM cell proliferation and tumor growth. PMID- 23673814 TI - Tetrahydrofurofuran-type lignans inhibit breast cancer-mediated bone destruction by blocking the vicious cycle between cancer cells, osteoblasts and osteoclasts. AB - Breast cancer frequently spreads to bone. The interaction between bone metastases and microenvironment, referred as the "vicious cycle", increases both tumor burden and bone destruction. Therefore, inhibition at any point in this "vicious cycle" can reduce malignant osteolytic lesions in patients with advanced breast cancer. In this study, we evaluated whether tetrahydrofurofuran-type lignans derived from Magnoliae Flos, commonly used in traditional Asian medicine to treat inflammatory diseases, could block breast cancer-mediated bone loss. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin at noncytotoxic concentrations suppressed mRNA expression and secretion of osteolytic factor PTHrP in MDA-MB-231 metastatic human breast cancer cells. Fargesin inhibited TGF beta-stimulated cell viability, migration, and invasion and decreased TGF-beta induced PTHrP production in MDA-MB-231 cells. In addition, these lignans reduced RANKL/OPG ratio in PTHrP-treated hFOB1.19 human osteoblastic cells and inhibited RANKL-mediated osteoclast differentiation in mouse bone marrow macrophages. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin substantially reduced bone-resorbing activity of osteoclasts by inhibiting MMP-9 and cathepsin K activities. Furthermore, orally administered fargesin inhibited tumor growth and cancer-mediated bone destruction in mice with MDA-MB-231 cells injected into calvarial tissues. Aschatin, fargesin, lirioresinol B dimethyl ether, and magnolin blocked initiation and progression of the "vicious cycle" between breast cancer metastases and bone microenvironment by inhibiting PTHrP production in breast cancer cells and osteoclastic bone resorption. Therefore, these tetrahydrofurofuran-type lignans have the potential to serve as beneficial agents to prevent and treat cancer-induced bone destruction in breast cancer patients. PMID- 23673815 TI - Probabilistic record linkage for monitoring the safety of artemisinin-based combination therapy in the first trimester of pregnancy in Senegal. AB - BACKGROUND: There are insufficient data on the safety in early pregnancy of the artemisinins, a new class of antimalarials. Assessment of drug teratogenicity requires large sample sizes for an adequate risk-benefit assessment. There is currently limited pharmacovigilance infrastructure in malaria-endemic countries. Monitoring drug safety in early pregnancy is especially challenging, as it requires early pregnancy detection to assess any potential increased risk of miscarriage, prospective follow-up to reduce recall and survival biases, and accurate data on gestational age assessment. Record linkage approaches for pregnancy pharmacovigilance using routinely generated health records could be a pragmatic and cost-effective approach for pharmacovigilance in early pregnancy, but has not been evaluated in resource-poor settings. OBJECTIVE: Our objective was to assess the feasibility of record linkage using routinely collected healthcare data as a pragmatic means of monitoring the safety in early pregnancy of artemisinin-based combination therapies (ACTs) in Senegal. METHODS: Data (2004 2008) from paper-based registers from outpatient clinics, antenatal care services (ANC) and the delivery unit from the St Joseph dispensary in Mlomp, south-western Senegal, were entered into databases. Record linkage based on a probabilistic matching approach was used to identify pregnancies exposed to ACTs in the first trimester of pregnancy. Two record linkage software packages (Link-Plus and FRIL) were compared and output data were reviewed independently by two investigators. RESULTS: Information on 685 pregnancies was extracted, 536 of which were from the geographic catchment area and eligible for record linkage; 94.6 % of them resulted in live births, 2.6 % in stillbirths and 2.8 % in miscarriages. Major congenital malformations were identified in 1.6 % of births. Seventy-three and 75 true matches between pregnancy outcome and the outpatient treatment registers were identified by two different record linkage software packages, respectively. Record linkage identified seven exposures to ACTs in the first trimester, all of which resulted in normal live-births. CONCLUSION: Probabilistic record linkage is a potentially cost-effective method to assess the safety of antimalarials in early pregnancy in resource-constrained settings to assess increased risk of overall birth defects, and stillbirths in settings with good existing health records and well defined target populations. PMID- 23673816 TI - Illustration of the weibull shape parameter signal detection tool using electronic healthcare record data. AB - BACKGROUND: The WSP tool has previously been proposed as a method to detect signals for adverse drug reactions utilising time-to-event data without the need for a reference population. The aim of this study was to assess the performance of the tool on two well-known and two suspected adverse drug reactions for bisphosphonates that varied in both frequency and accuracy of reporting time. METHODS: The use of the WSP tool was investigated on data from a matched population cohort study involving data from UK primary care patients exposed to oral bisphosphonates. Four listed/suspected ADRs were selected for investigation: headache, musculoskeletal pain, alopecia and carpal tunnel syndrome. For each suspected ADR, a graphical exploratory analysis was performed and the WSP tool was applied for two censoring periods each. RESULTS: Both of the well-known and common ADRs (headache and musculoskeletal pain) were detected using the WSP tool, and the signals were present regardless of the censoring intervals used. A signal was also detected when the event was uncommon and the timing was likely to be an accurate reflection of onset time (alopecia). This signal was only present for some of the censoring intervals. As anticipated, no signals were raised in the control groups for these events regardless of the censoring interval used. The suspected ADR, which was uncommon and where reporting times may not reflect onset time accurately (carpal tunnel syndrome), was not detected. A signal was raised in the control group but its false-positive nature was visible in the exploratory graphical analysis, which led to it (frequent but for only a limited number of consecutive dates). CONCLUSION: This study illustrates the usability and examines the reliability of the WSP tool as a method for signal detection in electronic health records. When the events are uncommon the success of this method may depend on the reporting time accurately reflecting the true event onset time. The study has shown that further work is required to define the censoring periods. The addition of a control group is not required but may enhance causal inference by showing that other causes than the exposure may lead to a signal. PMID- 23673818 TI - Synthesis of a selective inhibitor of a fucose binding bacterial lectin from Burkholderia ambifaria. AB - Burkholderia ambifaria is a bacterium member of the Burkholderia cepacia complex (BCC), a closely related group of Gram-negative bacteria responsible for "cepacia syndrome" in immunocompromised patients. B. ambifaria produces BambL, a fucose binding lectin that displays fine specificity to human fucosylated epitopes. Here, we report the first example of a synthetic ligand able to selectively bind, in the micromolar range, the pathogen-lectin BambL. The synthetic routes for the preparation of the alpha conformationally constrained fucoside are described, focusing on a totally diastereoselective inverse electron demand [4 + 2] Diels Alder reaction. Isothermal titration calorimetry (ITC) demonstrated that this compound binds to the pathogen-associated lectin BambL with an affinity comparable to that of natural fucose-containing oligosaccharides. No binding was observed by LecB, a fucose-binding lectin from Pseudomonas aeruginosa, and the differences in affinity between the two lectins could be rationalized by modeling. Furthermore, SPR analyses showed that this fucomimetic does not bind to the human fucose-binding lectin DC-SIGN, thus supporting the selective binding profile towards B. ambifaria lectin. PMID- 23673817 TI - A potential event-competition bias in safety signal detection: results from a spontaneous reporting research database in France. AB - BACKGROUND: In spontaneous reporting databases, reports of well-established drug event associations may mask alerts that arise from other drugs (drug competition bias). However, a symmetrical event-competition bias has not yet been explored whereby known events may mask an association with new events for a given drug or drug class. OBJECTIVE: The objective of this study was to explore the effects of event-competition bias on safety signals generated from spontaneous reporting databases. METHODS: The drug classes tested included statins, oral anticoagulants, antipsychotics and HIV antiretrovirals. For each, a type A reaction was selected, and its potential competitive effect on the generation of other safety signals for the drug was explored. These were rhabdomyolysis/myopathy for statins, haemorrhage for oral anticoagulants, extrapyramidal syndrome for antipsychotics and lipodystrophy for HIV antiretrovirals. Signals of disproportionate reporting (SDRs) were detected using the case/non-case approach in the French research spontaneous reporting database (which contains reports from 1 January 1986 to 31 December 2001), before and after removing all reports concerning these competitor events. SDRs were considered as potential signals if not reported in the literature before 1 January 2002 but confirmed since. RESULTS: The whole database included 207,236 reports, 4,355 of which included statins as one of the suspected drugs. The removal of reports of rhabdomyolysis/myopathy concerned 8,425 reports among which 867 involved statins. After this removal, 11 new SDRs appeared for statins that had not been detected initially. Similarly, 15 SDRs were unmasked for oral anticoagulants, six for antipsychotics and nine for HIV antiretrovirals. After literature-based assessment, five of the 41 unmasked SDRs appeared related to potential safety signals confirmed after 2002. CONCLUSION: This study demonstrated that a masking phenomenon resulting from an event-competition effect could occur when performing signal detection using disproportionality analyses of spontaneous reporting databases. This should be taken into account when routine signal detection is performed. PMID- 23673819 TI - Dimeric copper(II) complex of a new Schiff base ligand: effect of morphology on the catalytic oxidation of aromatic alcohol. AB - An antiferromagnetically coupled, dimeric MU-naphthanoxo bridged copper(II) complex is used heterogeneously to catalyze oxidation of p-chlorobenzylalcohol to aldehyde selectively. PL and PXRD studies reveal that during recycling the catalyst remains essentially intact. However loss of catalytic efficiency upon reuse is in consonance with a loss in morphology as indicated by SEM. PMID- 23673821 TI - Phosphorus mitigation to control river eutrophication: murky waters, inconvenient truths, and "postnormal" science. AB - This commentary examines an "inconvenient truth" that phosphorus (P)-based nutrient mitigation, long regarded as the key tool in eutrophication management, in many cases has not yet yielded the desired reductions in water quality and nuisance algal growth in rivers and their associated downstream ecosystems. We examine why the water quality and aquatic ecology have not recovered, in some case after two decades or more of reduced P inputs, including (i) legacies of past land-use management, (ii) decoupling of algal growth responses to river P loading in eutrophically impaired rivers; and (iii) recovery trajectories, which may be nonlinear and characterized by thresholds and alternative stable states. It is possible that baselines have shifted and that some disturbed river environments may never return to predisturbance conditions or may require P reductions below those that originally triggered ecological degradation. We discuss the practical implications of setting P-based nutrient criteria to protect and improve river water quality and ecology, drawing on a case study from the Red River Basin in the United States. We conclude that the challenges facing nutrient management and eutrophication control bear the hallmarks of "postnormal" science, where uncertainties are large, management intervention is urgently required, and decision stakes are high. We argue a case for a more holistic approach to eutrophication management that includes more sophisticated regime based nutrient criteria and considers other nutrient and pollutant controls and river restoration (e.g., physical habitat and functional food web interactions) to promote more resilient water quality and ecosystem functioning along the land freshwater continuum. PMID- 23673822 TI - Spatial and temporal patterns of bioindicator mercury in pennsylvania oak forest. AB - We monitored spatial and temporal patterns of total Hg in forest bioindicators to assess possible local, regional, and global changes in atmospheric Hg deposition. Total Hg concentrations were monitored in leaves and fresh litterfall of northern red oak ( L.), on an epiphytic moss ( Hedw.) on northern red oak stems, and in surface soil organic matter (O and O horizons) in Pennsylvania oak-dominated forests. Variously configured plots were used to monitor Hg deposition near local coal-fired generating stations and an industrial city and along an extended regional transect. Linearly decreasing temporal trends in Hg concentrations occurred in leaves, litterfall, moss, and soil O and O. Mean annual Hg concentrations were often greater near local emissions sources compared with remote areas, especially in the initial monitoring period. Decreasing time trends for different impact areas tended to converge due to greater rates of Hg decrease where initial bioindicator Hg levels were higher. Fresh litter and soil O showed the greatest overall potential as Hg bioindicators. We conclude that Hg deposition has been significantly decreasing over time throughout the study area as a result of locally and regionally declining Hg emissions. Reductions in Hg emissions are likely a co-benefit of the 1990 Clean Air Act regulations and changing industrial activities. Recent leveling of several bioindicator Hg time trends may foretell a shift in Hg depositional patterns. Mercury monitoring studies such as this fulfill a need for documenting local and regional effects of emissions reduction. PMID- 23673823 TI - Nitrogen placement and source effects on nitrous oxide emissions and yields of irrigated corn. AB - Limited information is available on how N fertilizer placement affects soil nitrous oxide (NO) emissions under irrigated conditions in the semiarid western United States. Our objective was to compare surface banding near corn row and broadcasting of three N sources (urea, polymer-coated urea [PCU], and stabilized urea [SU] containing urease and nitrification inhibitors) on NO emissions from a clay loam soil under sprinkler-irrigated continuous corn production. The N fertilizers were applied at a rate of 202 kg N ha to strip-till (2010 and 2011) and no-till (2011) corn at crop emergence, with ~19 mm irrigation water applied the next day. Band-applied N had a 1.46-fold greater NO emission than broadcast N averaged over N sources and three studies. Soil NO-N emissions from urea were 1.48- and 1.74-fold greater than from PCU and SU, respectively, when averaged over N placement and studies. The N placement * source interaction was not significant. Averaged across studies, grain yield and N uptake did not vary with N placement, whereas grain yields were greater for SU than PCU but were not different from urea. Nitrous oxide emissions per unit of N applied, per unit of grain yield, and per unit N uptake were 59, 49, and 47% greater, respectively, with banded than with broadcast N fertilizer. These studies show that N placement and N source selection are important manageable factors that can affect NO emissions and need to be considered when developing NO mitigation practices in irrigated cropping systems in the semiarid western United States. PMID- 23673825 TI - Estimating Chemical Exchange between Atmospheric Deposition and Forest Canopy in Guizhou, China. AB - To evaluate the effects of atmospheric deposition on forest ecosystems, wet-only precipitation and throughfall samples were collected in two forest types (Masson pine [ Lamb.] forests and mixed conifer and broadleaf forests) in the Longli forest in the Guizhou province of southwestern China for a period of 21 successive months from April 2007 to December 2008. The pH and chemical components of precipitation and throughfall were analyzed. In addition, the canopy budget model was applied to distinguish between in-canopy and atmospheric sources of chemical compounds. Canopy leaching and total potentially acidifying deposition fluxes were calculated. The results showed that the average pH and the concentration of ions in throughfall were higher than those in precipitation, with the exception of the NH concentration. Dry deposition of S and N accumulated more in Masson pine forests than in mixed conifer and broadleaf forests. Canopy leaching was the most significant source of base cations in forest throughfall, which was higher in the mixed forests than in the coniferous forests. Anions in throughfall deposition in Masson pine forests exceeded those in the mixed forests. Higher total potentially acidifying deposition fluxes reflected the more effective amounts of acid delivered to Masson pine forests compared with mixed conifer and broadleaf forests. In addition, acid deposition induced the leaching and loss of nutrient ions such as Mg, K, and Ca. Although the trees of the studied areas have not shown any symptoms of cation loss, a potentially harmful influence was engendered by atmospheric deposition in the two forest types in the Longli area. PMID- 23673824 TI - Nitrous oxide emissions from in situ deposition of N-labeled ryegrass litter in a pasture soil. AB - During pasture grazing, freshly harvested herbage (litterfall) is dropped onto soils from the mouths of dairy cattle, potentially inducing nitrous oxide (NO) emissions. Although the Intergovernmental Panel on Climate Change (IPCC) recommends accounting for NO emissions from arable crop residues in national inventories, emissions from the litterfall of grazed pasture systems are not recognized. The objective of this study was to investigate the potential of litterfall to contribute to NO emissions in a field study located on a pasture site in Canterbury, New Zealand (43 degrees 38.50' S, 172 degrees 27.17' E). We applied N-labeled perennial ryegrass ( L.) to the surface of a pastoral soil (Temuka clay loam) and, for up to 139 d thereafter, quantified the contribution of herbage decomposition to NO production and soil N dynamics. Litterfall contributed to the N enrichment of soil NO-N and NO-N pools. After 49 d, N recovery as NO equated to 0.93% of the surface-applied litter N, with 38 to 75% of the cumulative NO flux occurring within 4 to 10 d of treatment application. Emissions of NO likely resulted from ammonification followed by a coupling of nitrification and denitrification during litter decomposition on the soil surface. The emission factor of the litter deposited in situ was 1.2 +/- 0.2%, which is not substantially greater than the IPCC default emission factor value of 1% for crop residues. Further in situ studies using different pasture species and litterfall rates are required to understand the microbial processes responsible for litter-induced NO emissions. PMID- 23673826 TI - Ecological risk assessment of heavy metals in surface sediments of six major chinese freshwater lakes. AB - An overall and comparative ecological risk assessment of heavy metal pollution (including Cu, Zn, Pb, Cd, Hg, Cr, As, and Ni) in surface sediments was conducted for six major shallow freshwater lakes (Taihu Lake, Chaohu Lake, Nansihu Lake, Dongting Lake, Poyang Lake, and Hongze Lake) in China. A spatial database with 339 sediment samples was created through an extensive literature survey. Consensus-based sediment quality guidelines (SQGs) were used as the effect thresholds due to the lack of local eco-toxicological information about heavy metals in the six lakes. The results show that the ecological risk of heavy metal pollution in surface sediments is highest in Dongting Lake, followed by Taihu Lake. Lakes Chaohu, Nansihu, Poyang, and Hongze are at a similar risk level, which is a little lower than that of Lake Taihu. High-risk areas that should be given more attention were identified by spatial analysis. The estuaries of the inlets and outlets of Dongting Lake and the Meiliang Bay in Taihu Lake were found to be such areas. Ineffective environmental supervision and management during the recent years of rapid economic and industrial development in China have led to the pollution of lake sediments by heavy metals. Rigid control and effective management measures to prevent heavy metal pollution are urgently needed in China. In addition, it is necessary for China to develop basic research on the local eco-toxicity and SQGs of freshwater sediments to provide a scientific basis for the management of lake sediment pollution. PMID- 23673820 TI - Protein aggregation in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the aggregation of ubiquitinated proteins in affected motor neurons. Recent studies have identified several new molecular constituents of ALS-linked cellular aggregates, including FUS, TDP-43, OPTN, UBQLN2 and the translational product of intronic repeats in the gene C9ORF72. Mutations in the genes encoding these proteins are found in a subgroup of ALS patients and segregate with disease in familial cases, indicating a causal relationship with disease pathogenesis. Furthermore, these proteins are often detected in aggregates of non-mutation carriers and those observed in other neurodegenerative disorders, supporting a widespread role in neuronal degeneration. The molecular characteristics and distribution of different types of protein aggregates in ALS can be linked to specific genetic alterations and shows a remarkable overlap hinting at a convergence of underlying cellular processes and pathological effects. Thus far, self-aggregating properties of prion-like domains, altered RNA granule formation and dysfunction of the protein quality control system have been suggested to contribute to protein aggregation in ALS. The precise pathological effects of protein aggregation remain largely unknown, but experimental evidence hints at both gain- and loss-of-function mechanisms. Here, we discuss recent advances in our understanding of the molecular make-up, formation, and mechanism-of-action of protein aggregates in ALS. Further insight into protein aggregation will not only deepen our understanding of ALS pathogenesis but also may provide novel avenues for therapeutic intervention. PMID- 23673827 TI - Revegetation of non-Acid-generating, thickened tailings with boreal trees: a greenhouse study. AB - Tree planting presents clear advantages for mine reclamation that is aimed at achieving rapid reclamation of forested landscapes. A greenhouse study was conducted to evaluate the capacity of non-acid-generating, thickened tailings to support six boreal tree species during two growing seasons. One treatment was thickened tailings alone fertilized with inorganic N, P, and K fertilizer or chicken () manure. A thin layer of overburden topsoil was used to cover the tailings and was compared with topsoil alone, where normal tree growth was expected. Two amendments were also tested: overburden topsoil and vermicompost from food wastes. The presence of alkaline thickened tailings under the thin layer of acidic topsoil had a positive effect on tree height and root biomass (broadleaved and jack pine [ Lamb.]) by increasing topsoil pH and available Ca concentrations, which decreased Al, Zn, and Mn phytoavailability to trees; however, root contact with the tailings also increased their Cu concentrations. In thickened tailings that were mixed with topsoil, C/N ratios increased along the experiment from 21 to 40, a value where N immobilization by microorganisms occurred, as suggested by low N concentrations in tree tissues. In consequence, tree height growth (broadleaved) and biomass (conifers) were reduced. Amendment with compost raised the electrical conductivity (3.4 dS cm) to thresholds limiting broadleaved survival, while conifers showed a generalized decrease in biomass production. No trace metal contamination of the trees occurred in the mixtures, probably due to the near-neutral pH conferred by the tailings. PMID- 23673828 TI - Simulation of Organic Matter and Pollutant Evolution during Composting: The COP Compost Model. AB - Organic pollutants (OPs) are potentially present in composts and the assessment of their content and bioaccessibility in these composts is of paramount importance. In this work, we proposed a model to simulate the behavior of OPs and the dynamic of organic C during composting. This model, named COP-Compost, includes two modules. An existing organic C module is based on the biochemical composition of the initial waste mixture and simulates the organic matter transformation during composting. An additional OP module simulates OP mineralization and the evolution of its bioaccessibility. Coupling hypotheses were proposed to describe the interactions between organic C and OP modules. The organic C module, evaluated using experimental data obtained from 4-L composting pilots, was independently tested. The COP-Compost model was evaluated during composting experiments containing four OPs representative of the major pollutants detected in compost and targeted by current and future regulations. These OPs included a polycyclic aromatic hydrocarbon (fluoranthene), two surfactants (4- nonylphenol and a linear alkylbenzene sulfonate), and an herbicide (glyphosate). Residues of C-labeled OP with different bioaccessibility were characterized by sequential extraction and quantified as soluble, sorbed, and nonextractable fractions. The model was calibrated and coupling the organic C and OP modules improved the simulation of the OP behavior and bioaccessibility during composting. PMID- 23673829 TI - Pesticides exposure assessment of kettleman city using the industrial source complex short-term model version 3. AB - Kettleman City, California, reported a higher than expected number of birth defect cases between 2007 and 2010, raising the concern of community and government agencies. A pesticide exposure evaluation was conducted as part of a complete assessment of community chemical exposure. Nineteen pesticides that potentially cause birth defects were investigated. The Industrial Source Complex Short-Term Model Version 3 (ISCST3) was used to estimate off-site air concentrations associated with pesticide applications within 8 km of the community from late 2006 to 2009. The health screening levels were designed to indicate potential health effects and used for preliminary health evaluations of estimated air concentrations. A tiered approach was conducted. The first tier modeled simple, hypothetical worst-case situations for each of 19 pesticides. The second tier modeled specific applications of the pesticides with estimated concentrations exceeding health screening levels in the first tier. The pesticide use report database of the California Department of Pesticide Regulation provided application information. Weather input data were summarized from the measurements of a local weather station in the California Irrigation Management Information System. The ISCST3 modeling results showed that during the target period, only two application days of one pesticide (methyl isothiocyanate) produced air concentration estimates above the health screening level for developmental effects at the boundary of Kettleman City. These results suggest that the likelihood of birth defects caused by pesticide exposure was low. PMID- 23673830 TI - Groundwater Ecosystems Vary with Land Use across a Mixed Agricultural Landscape. AB - Changes in surface land use may threaten groundwater quality and ecosystem integrity, particularly in shallow aquifers where links between groundwater and surface activities are most intimate. In this study we examine the response of groundwater ecosystem to agricultural land uses in the shallow alluvial aquifer of the Gwydir River valley, New South Wales, Australia. We compared groundwater quality and microbial and stygofauna assemblages among sites under irrigated cropping, non-irrigated cropping and grazing land uses. Stygofauna abundance and richness was greatest at irrigated sites, with the composition of the assemblage suggestive of disturbance. Microbial assemblages and water quality also varied with land use. Our study demonstrates significant differences in the composition of groundwater ecosystems in areas with different surface land use, and highlights the utility of groundwater biota for biomonitoring, particularly in agricultural landscapes. PMID- 23673831 TI - Assessing potential impacts of a wastewater rapid infiltration basin system on groundwater quality: a delaware case study. AB - Rapid infiltration basin systems (RIBS) are receiving increased interest for domestic wastewater disposal in rural areas. They rely on natural treatment processes to filter pollutants and use extremely high effluent loading rates, much greater than natural precipitation, applied to a small geographic area instead of disposal to surface water. Concerns exist today that adopting RIBS in areas with shallow groundwater and sandy soils may increase ground and surface water pollution. We conducted a field study of RIBS effects on N and P concentrations in soils and groundwater at Cape Henlopen State Park, Delaware, where a RIBS designed and operated following USEPA guidance has been used for >25 yr. Site and wastewater characteristics (water table of 8 m, Fe- and Al-oxide coatings on soils, organic-rich effluent) were favorable for denitrification and P sorption; however, we found high P saturation, reduced soil P sorption capacity, and significant total P accumulation at depths >1.5 m, factors that could lead to dissolved P leaching. Very low soil inorganic N levels suggest that wastewater N was converted rapidly to NO-N and leached from the RIBS. Extensive groundwater monitoring supported these concerns and showed rapid offsite transport of N and P at concentrations similar to the effluent. Results suggest that high hydraulic loads and preferential flow led to flow velocities that were too large, and contact times between effluent and soils that were too short, for effective N and P attenuation processes. These findings indicate the need for better site characterization and facility designs to reduce and monitor contaminant loss from RIBS in similar settings. PMID- 23673832 TI - Bone char: a clean and renewable phosphorus fertilizer with cadmium immobilization capability. AB - Soil contamination with Cd from P fertilizer and other anthropogenic and geogenic sources is a serious problem. In situ immobilization by P application to soil is known as an applicable remediation technique leading to reduced Cd uptake by plants, and use of a Cd-free P fertilizer from renewable sources would be most favorable. Bone char (BC) (15% P, 28% Ca, 0.7% Mg) may be used as such a quality P fertilizer, but it is unknown if its dissolution in soil provides sufficient P and immobilizes Cd in moderately contaminated soils. We incubated BC and triple superphosphate (TSP) in 11 soils that contained between 0.3 to 19.6 mg Cd kg and determined the kinetics of P dissolution during a time period of 145 d. The concomitant Cd immobilization was determined by extracting the mobile Cd with 1 mol L NHNO solution. For most soils, BC increased the concentration of labile P immediately after application, reaching a maximum after 34 d, although the solubility was below that of TSP (2.9-19.3 vs. 4.1-24.0%). Among five kinetic models, the Langmuir-type equation provided the best description of P dissolution from BC and TSP. The Cd immobilization resulting from BC dissolution exceeded that of TSP by a factor of 1.4 to 2.7. The P dissolution from BC was negatively correlated with pH and positively with P sorption capacity, whereas Cd immobilization was positively correlated with soil pH. These causal relationships were expressed in multiple equations that enable predictions of P dissolution and Cd immobilization and thus may help to introduce BC as sustainable P fertilizer and useful soil amendment. PMID- 23673833 TI - Metal Availability following Paper Mill and Alkaline Residuals Application to Field Crops. AB - Land application of residuals from the forest industry can help to restore soil fertility, but few studies have assessed the effects of metal accumulation in plants. An experimental study was initiated in 2000 on a loamy soil at Yamachiche, QC, Canada, to evaluate the effects of repeated annual applications of combined paper mill biosolids, when applied alone or with several liming by products. This study assessed the accumulation of Cu, Zn, Mo, and Cd in plants and soil after 6 (soybean [ (L.) Merr.]) and 9 [corn ( L.)] crop yr. Wet paper mill biosolids at 0, 30, 60, or 90 Mg ha were surface applied after seeding. Calcitic lime, lime mud, and wood ash were applied wet each at 3 Mg ha with 30 Mg wet paper mill biosolids ha. Repeated applications of paper mill biosolids increased plant and soil metal concentrations after 6 and 9 yr in the order of Cd > Mo (soybean) > Zn > Cu. Liming increased soil pH and Mo availability and decreased Zn and Cd availability. Metals in crop stover responded more positively to applications than those in grains, but the concentrations in plant tissues were generally well below critical values. The Cu/Mo ratio of soybean plants at pH > 6.8 fell below 2:1, however, and may pose a risk for inducing Cu metabolism disorder in ruminants. Results of this study indicate that paper mill biosolids and alkaline residuals, when applied with respect to regulations and soil pH, have a limited effect on metal accumulation in plants and soil. PMID- 23673834 TI - Effect of sewage sludge amendment on heavy metal uptake and yield of ryegrass seedling in a mudflat soil. AB - Mudflat soil amendment by sewage sludge is a potential way to dispose of solid wastes and increase fertility of mudflat soils for crop growth. The present study aimed to assess the impact of sewage sludge amendment (SSA) on heavy metal accumulation and growth of ryegrass ( L.) in a seedling stage. We investigated the metal availability, plant uptake, and plant yield in response to SSA at rates of 0, 30, 75, 150, and 300 t ha. The SSA increased the metal availability in a mudflat soil and subsequently metal accumulation in ryegrass. The SSA increased the bioavailable fraction of the metals by 4550, 58.8, 898, 189, 35.8, and 84.8% for Zn, Mn, Cu, Ni, Cr, and Cd, respectively, at an SSA rate of 300 t ha as compared to unamended soil. Consequently, the metal concentrations in ryegrass increased by 1130, 12.9, 355, 108, 2230, and 497% in roots and by 431, -4.3, 92.6, 58.3, 890, and 211% in aboveground parts, for Zn, Mn, Cu, Ni, Cr, and Cd, respectively, at the 300 t ha rate as compared to unamended soil. The enhanced metal accumulation, however, did not induce growth inhibition of ryegrass. Fresh weight of aboveground parts and roots of ryegrass at 300 t ha SSA rate increased by 555 and 128%, respectively, as compared to those grown in unamended soil. The study suggests that SSA can promote yield of ryegrass seedlings grown in mudflat soils. None of metal concentrations at all SSA rates was above the Chinese permissible limits. Despite the data at only the seedling stage, our results indicate that SSA in mudflat soils might be a potential way for mudflat soil fertility improvement and sewage sludge disposal. Further study at plants' maturity stage is warranted to fully assess the suitability of sewage sludge amendment on mudflat soils. PMID- 23673835 TI - Characterization, stability, and plant effects of kiln-produced wheat straw biochar. AB - Biochar is a promising technology for improving soil quality and sequestering C in the long term. Although modern pyrolysis technologies are being developed, kiln technologies often remain the most accessible method for biochar production. The objective of the present study was to assess biochar characteristics, stability in soil, and agronomic effects of a kiln-produced biochar. Wheat-straw biochar was produced in a double-barrel kiln and analyzed by solid-state C nuclear magneticresonance spectroscopy. Two experiments were conducted with biochar mixed into an Ap-horizon sandy loam. In the first experiment, CO efflux was monitored for 3 mo in plant-free soil columns across four treatments (0, 10, 50, and 100 Mg biochar ha). In the second experiment, ryegrass was grown in pots having received 17 and 54 Mg biochar ha combined with four N rates from 144 to 288 kg N ha. Our kiln method generated a wheat-straw biochar with carbon content composed of 92% of aromatic structures. Our results suggest that the biochar lost <0.16% C as CO over the 90-d incubation period. Biomass yields were not significantly modified by biochar treatments, except for a slight decrease at the 144 kg N ha rate. Foliar N concentrations were significantly reduced by biochar application. Biochar significantly increased soil water content; however, this increase did not result in increased biomass yield. In conclusion, our kiln produced biochar was highly aromatic and appeared quite recalcitrant in soil but had no overall significant impact on ryegrass yields. PMID- 23673836 TI - Sestonic Chlorophyll- Shows Hierarchical Structure and Thresholds with Nutrients across the Red River Basin, USA. AB - The Red River is a transboundary, multijurisdictional basin where water-quality standards are often different across state lines. The state agencies with USEPA Region VI focused resources to organize water-quality data from within this basin and have it statistically analyzed to evaluate the relationships between nutrients and sestonic chlorophyll- (chl-a). There were 152 sites within the Red River basin that had nutrient and sestonic chl-a measurements; these sites were narrowed down to 132 when a minimum number of observations was required. Sestonic chl-a levels increased with increasing nutrient concentrations; these regressions were used to predict nutrient concentrations at 10 MUg chl-a L. Total nitrogen (TN) and phosphorus (TP) concentrations (at 10 MUg chl-a L) varied across the Red River basin and its ecoregions from 0.10 to 0.22 mg TP L and 0.75 to 2.11 mg TN L. Nutrient thresholds were also observed with sestonic chl-a at 0.14 mg TP L and 0.74 mg TN L using categorical and regression tree analysis (CART). The CART analysis also revealed that hierarchical structure was important when attempting to predict sestonic chl-a from TN, TP, and conductivity. The ranges of TN and TP concentrations that resulted in chl-a concentrations that exceeded 10 MUg chl-a L were similar in magnitude to the threshold in TN and TP that resulted in increased sestonic chl-a. This corroborating evidence provides useful guidance to the states with jurisdiction within the Red River basin for establishing nutrient criteria, which may be similar when the Red River and its tributaries cross political boundaries. PMID- 23673837 TI - Phosphorus losses from low-emission slurry spreading techniques. AB - Low emission slurry spreading techniques are known to improve nitrogen use efficiency, but their impact on phosphorus (P) losses in surface runoff has received little attention. The current study was designed to examine the effect of slurry spreading technique on P losses in runoff. Twelve treatments were examined on 0.5- m by 1.0-m plots in a nominal 2 * 6 factorial design experiment. Treatments comprised grass swards at two different stages of growth, a stubble and a 4-wk regrowth, and six different slurry application treatments: control (no slurry), and slurry applied to simulate splash-plate, injection (across and down slope), and trailing shoe (across and down slope) spreading. Slurry was applied by hand (40 m ha). Rainfall simulations (40 mm h) were conducted at 2, 9, and 28 d post-slurry application. When slurry was applied to the stubble, dissolved reactive P (DRP) concentrations in runoff at Day 2 were 47 and 37% lower ( < 0.05) from the injection and trailing shoe treatments compared with the splash plate treatment. Similarly, at Day 2, TP concentrations in runoff from the injection treatments were 27% lower ( < 0.05) than the splash-plate treatment. In contrast, application technique had no effect ( 0.05) on P concentrations in runoff following slurry application to the regrowth treatment. Phosphorus concentrations in runoff were unaffected by direction of slurry spreading (across or down) at both applications. Our results indicate that trailing shoe and injection techniques offer the potential to reduce DRP concentrations in runoff during the period immediately after slurry application. PMID- 23673838 TI - Topsoil and subsoil properties influence phosphorus leaching from four agricultural soils. AB - Eutrophication, a major problem in many fresh and brackish waters, is largely caused by nonpoint-source pollution by P from agricultural soils. This lysimeter study examined the influence of P content, physical properties, and sorption characteristics in topsoil and subsoil on P leaching measured during 21 mo in 1-m long, undisturbed soil columns of two clay and two sandy soils. Total P losses during the period varied between 0.65 and 7.40 kg ha. Dissolved reactive P was the dominant form in leachate from the sandy soils and one clay soil, varying from 48 to 76%. Particulate P dominated in leachate from the other clay soil, where low pH (5.2) in the subsoil decreased aggregate stability and thereby probably increased the dispersion of clay particles. Phosphorus leaching was small from soils with high P sorption index (PSI) and low P saturation (<10% of PSI) in the subsoil, even though extractable P (Olsen P) in the topsoil was high, and large from a soil with low sorption capacity and high P saturation (>35% of PSI) in the profile. High sorption capacity in the subsoil was more important for P leaching in sandy soils than in clay soils with macropore flow, where the effect of high sorption capacity was reduced due to less interaction between percolating water and the soil matrix. The results suggest that P leaching is greatly affected by subsoil properties and that topsoil studies, which dominate current research, are insufficient for assessing P leaching in many soils. PMID- 23673839 TI - Characterization of colloidal phosphorus species in drainage waters from a clay soil using asymmetric flow field-flow fractionation. AB - Phosphorus transport from agricultural land contributes to eutrophication of surface waters. Pipe drain and trench waters from a grassland field on a heavy clay soil in the Netherlands were sampled before and after manure application. Phosphorus speciation was analyzed by physicochemical P fractionation, and the colloidal P fraction in the dissolved fraction (<0.45 MUm) was analyzed by asymmetric flow field-flow fractionation (AF4) coupled to high-resolution inductively coupled plasma-mass spectrometry and ultraviolet diode array detector. When no manure was applied for almost 7 mo, total P (TP) concentrations were low (<21 MUmol L), and TP was almost evenly distributed among dissolved reactive P (DRP), dissolved unreactive P (DUP), and particulate P (PP). Total P concentrations increased by a factor of 60 and 4 when rainfall followed shortly after application of cattle slurry or its solid fraction, respectively. Under these conditions, DRP contributed 50% or more to TP. The P speciation within the DUP and PP fractions varied among the different sampling times. Phosphorus associated with dissolved organic matter, probably via cation bridging, comprised a small fraction of DUP at all sampling times. Colloidal P coeluted with clay particles when P application was withheld for almost 7 mo and after application of the solid cattle slurry fraction. At these sampling times, PP correlated well with particulate Fe, Al, and Si, indicating that P is associated with colloidal clay particles. After cattle slurry application, part of DUP was probably present as phospholipids. Physicochemical fractionation combined with AF4 analysis is a promising tool to unravel the speciation of colloidal P in environmental water samples. PMID- 23673840 TI - Floodwater metal contaminants in an Australian dryland river: a baseline for assessing change downstream of a major lead-zinc-silver and copper mine. AB - The variations in the quality of floodwaters from the upper Leichhardt River catchment (1113 km), Mount Isa, in northwest Queensland, Australia, were examined to better understand the impact of urban, mining, and industrial activity on receiving waters. Water sampling was conducted during the 2006-2007 wet season and captured during rainfall and runoff events. Samples were analyzed for total and dissolved (0.45-MUm filter) metals (Cd, Cu, Pb, and Zn) and water quality indicators (pH, electrical conductivity, and total suspended solids). The results show that tributaries draining the large Cu and Pb-Zn-Ag mines and smelters complex located at Mount Isa contained the highest concentrations of dissolved (780 MUg L Cu, 61 MUg L Pb, and 1500 MUg L Zn) and total (3600 MUg L Cu, 3600 MUg L Pb, and 4900 MUg L Zn) metals. The results indicate that total and dissolved Cu, Pb, and Zn are well correlated (Pearson correlation >= 0.343; < 0.05) and that floodwater metals are primarily particulate bound. Water management and remediation strategies should target the mine-side tributaries and should include improvements to stormwater retention infrastructure, bank stabilization works, and installation of appropriate signage along the upper Leichhardt River indicating the potential environmental and human health hazards of floodwaters. PMID- 23673841 TI - Critical factors affecting field-scale losses of nitrogen and phosphorus in spring snowmelt runoff in the canadian prairies. AB - A long-term, field-scale study in southern Manitoba, Canada, was used to identify the critical factors controlling yearly transport of nitrogen (N) and phosphorus (P) by snowmelt runoff. Flow monitoring and water sampling for total and dissolved N and P were performed at the edge of field. The flow-weighted mean concentrations and loads of N and P for the early (the first half of yearly total volume of snowmelt runoff), late (the second half of yearly total volume of snowmelt runoff), and yearly snowmelt runoff were calculated as response variables. A data set of management practices, weather variables, and hydrologic variables was generated and used as predictor variables. Partial least squares regression analysis indicated that critical factors affecting the water chemistry of snowmelt runoff depended on the water quality variable and stage of runoff. Management practices within each year, such as nitrogen application rate, number of tillage passes, and residue burial ratio, were critical factors for flow weighted mean concentration of N, but not for P concentration or nutrient loads. However, the most important factors controlling nutrient concentrations and loads were those related to the volume of runoff, including snow water equivalent, flow rate, and runoff duration. The critical factors identified for field-scale yearly snowmelt losses provide the basis for modeling of nutrient losses in southern Manitoba and potentially throughout areas with similar climate in the northern Great Plains region, and will aid in the design of effective practices to reduce agricultural nonpoint nutrient pollution in downstream waters. PMID- 23673842 TI - Relative phosphorus load inputs from wastewater treatment plants in a northern colorado watershed. AB - Excess nutrients are among the leading sources of water quality impairment in the Unites States, and the USEPA has been working with state regulatory agencies to develop nutrient criteria for wastewater treatment plants (WWTPs). The Colorado Department of Public Health and Environment is scheduled to establish nutrient regulations in 2013, and stream total P (TP) concentration standards of 0.16 mg L in warm water and 0.11 mg L in cold water have been proposed for the rivers in the state. The objectives of this study were to monitor TP concentrations and loads along the Cache La Poudre River as it flows from the pristine upstream area through urban regions and finally through a mixture of agricultural and urban land uses. The study attempts to evaluate the sources and influences of TP under different hydrologic conditions. Twelve sampling events were completed from April 2010 to August 2011 to assess the influence of various flow and precipitation conditions on aqueous TP concentrations. During midrange flows and dry conditions, WWTPs were the major sources of TP, but other sources were more significant under high-flow and wet conditions according to a load analysis. The analysis indicates that reducing the TP load from WWTPs will only marginally affect the TP load in the river, and therefore it appears that other sources (e.g., stormwater and agricultural runoff) need to be addressed before the aquatic life-based stream standard can be achieved. PMID- 23673843 TI - Inhibition of methane oxidation in a slurry surface crust by inorganic nitrogen: an incubation study. AB - Livestock slurry is an important source of methane (CH). However, depending on the dry matter content of the slurry, a floating crust may form where methane oxidizing bacteria (MOB) and CH oxidation activity have been found, suggesting that surface crusts may reduce CH emissions from slurry. However, it is not known how MOB in this environment interact with inorganic nitrogen (N). We studied inhibitory effects of ammonium (NH), nitrate (NO), and nitrite (NO) on potential CH oxidation in a cattle slurry surface crust. At headspace concentrations of 100 and 10,000 ppmv, CH oxidation was assayed at salt concentrations up to 500 mM. First-order rate constants were used to evaluate the strength of inhibition. Nitrite was the most potent inhibitor, reducing methanotrophic activity by up to 70% at only 1 mM NO. Methane-oxidizing bacteria were least sensitive to NO, tolerating up to 30 mM NO at 100 ppmv CH and 50 mM NO at 10,000 ppmv CH without any decline in activity. The inhibition by NH increased progressively, and no range of tolerance was observed. Methane concentrations of 10,000 ppmv resulted in 50- to 100-fold higher specific CH uptake rates than 100 ppmv CH but did not change the inhibition patterns of N salts. In slurry surface crusts, MOB maintained activity at higher concentrations of NH and NO than reported for MOB in soils and sediments, possibly showing adaptation to high N concentrations in the slurry environment. Yet it appears that the effectiveness of surface crusts as CH sinks will depend on inorganic N concentrations. PMID- 23673844 TI - Biosolids applications to tall fescue have long-term influence on soil nitrogen, carbon, and phosphorus. AB - Repeated applications of biosolids provide long-term benefits by increasing soil organic matter and N supply but can cause excess accumulation of P. Our objective was to determine the residual effects of repeated surface applications of biosolids on N availability and fate, tall fescue ( Schreb.) response, soil C, and P. A field experiment was started in 1993 to compare two biosolids products, each applied at three rates (6.7, 13.4, and 20.1 Mg ha yr), with synthetic N fertilizer (0 and 403 kg N ha yr as ammonium nitrate). Treatments were surface applied for 10 yr, followed by a 9-yr residual period where all plots received a reduced rate of inorganic N (202 kg N ha yr). Annual measurements included forage yield, N uptake, and soil nitrate N. Soil samples collected in 2002 and 2011 were analyzed for total C and N and Bray-1 P. Cumulative apparent N recoveries in harvested grass (1993-2010) were 51% for biosolids N and 72% for ammonium nitrate. Net fall soil nitrate N summed for the period 1993-2002 ranged from <1 to 3% of N applied. The N applied that was accounted for in forage and soil averaged 74% for biosolids and 73% for ammonium nitrate. Soil C increased in the biosolids treatments, and the increase was equivalent to 27% of biosolids C. Bray 1 P remained at excessive levels (338-629 mg P kg soil) 9 yr after the last biosolids application. PMID- 23673845 TI - Land application of municipal landfill leachate: fate of ions and ammonia volatilization. AB - Landfill leachates are pollutants rich in ammoniacal N, Na, and K, but land application potentially offers an alternative for recycling these leachate nutrients. We applied landfill leachate corresponding to 0, 110, 220, 330, and 440 kg ha of total N, divided in three applications (July, August, and October 2008), onto the surface of an acidic (pH 5.5-6.0) clay (79% clay) Ultisol and monitored NH volatilization just after applications and microbiological (0-10 cm) and chemical attributes (0-60-cm soil depth) in August 2008, January 2009, and May 2009. Ammonium (up to 30 mg kg), NO (up to 160 mg kg), Na, K (up to 1.1 cmol kg each), and electrical conductivity (up to 1 dS m) increased transiently in soil following applications. Despite >90% of the total leachate N being ammoniacal, NO predominated in the first soil sampling, 14 d after the second application, suggesting fast nitrification, but it decreased in the soil profile thereafter. From 5 to 25% of the total applied N volatilized as NH, with maximum losses within the first 3 d. Applications inhibited (50%) the relative nitrification rate and increased (50%) hot-water-soluble carbohydrates in the soil at the highest rate. No effects were observed on soil microbial biomass C (114-205 mg kg) and activity (5-8 mg CO-C kg d) or on corn grain yields (6349 7233 kg ha). Controlled land application seems to be a viable alternative for landfill leachate management, but NO leaching, NH volatilization, and accumulation of salinizing ions must be monitored in the long term to prevent environmental degradation. PMID- 23673846 TI - Soil Nutrients, Bacteria Populations, and Veterinary Pharmaceuticals across a Backgrounding Beef Feedlot. AB - Beef cattle backgrounding operations that grow out weaned calves for feedlot finishing contain several environmentally significant constituents. A better understanding of these constituents and their environmental distribution will aid in the development of effective management guidelines for sustainable beef production. This research investigated soil nutrients, bacterial, and veterinary pharmaceutical concentrations across a small backgrounding beef feedlot on a karst landscape. Results indicated that all contaminants were highly concentrated in the feeder area (FD) and were lower in the other feedlot areas. The FD soils had a pH of 8.2, 59 mg kg soil organic matter (SOM), 2002 mg kg soil test phosphorus (STP), 99.7 mg kg NH-N, and 18.3 mg kg NO-N. The other locations were acidic (5.9-6.9 pH) and contained 39 mg kg SOM, 273 mg kg STP, 21.5 mg kg NH-N, and 2.0 NO-N mg kg. Bacteria populations in the FD averaged 2.7 * 10 total cells, 3.9 * 10 spp., 2.9 * 10 spp, and 4.5 * 10 cells per gram of soil. spp. and spp. concentrations were 1 to 4 orders of magnitude lower at the other locations. showed lower dynamic range and was generally uniformly distributed across the landscape. Antibiotic and parasiticide concentrations in the FD were 86.9 ng g monensin, 25.0 ng g lasalocid, and 10.3 ng g doramectin. Their concentrations were 6- to 27-fold lower in the other feedlot locations. Contaminant management plans for this small feedlot will therefore focus on the feeder and nearby grazing areas where soil nutrients, bacteria populations, and veterinary pharmaceuticals were most concentrated. PMID- 23673847 TI - Mineral constituents profile of biochar derived from diversified waste biomasses: implications for agricultural applications. AB - The wide distribution and high heterogeneity of different elements in biochars derived from diverse feedstocks make it difficult to regulate their application in soil and to evaluate the maximum potential contribution of the nutrients and trace metals as well as the potential risk of toxic metals. This study classified 20 biochars, covering six typical categories, into three clusters according to their similarity and distance on nutrients and minerals using cluster analysis. Four principle components (PC) were extracted using factor analysis to reduce dimension and clearly characterize the mineral profile of these biochars. The contribution of each group of elements in the PCs to every cluster was clarified. PC1 had a high loading for Mg, Cu, Zn, Al, and Fe; PC2 was related to N, K, and Mn; and PC3 and PC4 mainly represented P and Ca. Cluster 1 included bone dregs and eggshell biochars with PC3 and PC4 as the main contributors. Cluster 2 included waterweeds and waste paper biochars, which were close to shrimp hull and chlorella biochars, with the main contributions being from PC2 and PC4. Cluster 3 included biochars with PC1 as the main contributor. At a soil biochar amendment rate of 50 t ha, the soil nutrients were significantly elevated, whereas the rise in toxic metals was negligible compared with Class I of the China Environmental Quality Standards for Soil. Biochar can potentially supply soil nutrients and trace metals, and different cluster biochars can be applied appropriately to different soils so that excessive or deficient nutrient and metal applications can be avoided. PMID- 23673849 TI - Plant decomposition in wetlands: effects of hydrologic variation in a re-created everglades. AB - The effects of water depth and flow on marsh plant litter decomposition and soil chemistry were measured in the Loxahatchee Impoundment Landscape Assessment (LILA) facility (Boynton Beach, FL), where macrocosms mimic Everglades ridge-and slough landscape features. Experiments were conducted in two macrocosms that differed in flow but had ridge, shallow slough, and deep slough habitats that differed in water depth. Decomposition of three common Everglades species, Crantz, Torr., and Aiton, were measured using litter bags incubated in the macrocosms under both wet and dry conditions. Litter decomposition was similar among flow treatments and habitats but differed by species and between wet and dry conditions. Decomposition rates from fastest to slowest were > > litter had more total P than the other two species, confirming the importance of P availability in controlling decomposition in the Everglades. Planted species had no effect on soil nutrient content during the ~4 yr of plant growth. Average water velocities of ~0.5 cm s attained in the flow treatment had no effect on decomposition or soil chemistry. The plant species used in this study are major contributors to Everglades' organic soils, so their decomposition rates can be used to parameterize models for how restoration manipulations will affect soil building processes and to predict the temporal sequence of landscape responses to these manipulations. The results suggest that longer periods and flows greater than studied here may be necessary to see restoration effects on soil building processes. PMID- 23673848 TI - The Effects of Dosed versus Gravity-Fed Loading Methods on the Performance and Reliability of Contour Trench Disposal Fields Used for Onsite Wastewater Treatment. AB - In Nova Scotia, Canada, contour trench disposal fields are the most common type of onsite wastewater system. In this study, two identical contour trench disposal fields were monitored for 3 yr to compare performance under gravity-fed versus periodically dosed loading conditions. Influent and effluent from both systems were analyzed for a suite of water quality parameters, and the hydraulics of the systems were assessed using tracer studies and measurements of ponded water depth in the distribution trenches. Ponded water depths in the distribution trench of the gravity-fed disposal field were observed to increase steadily during the monitoring period, indicating progressive clogging. This was not observed in the periodically dosed field. Regarding treatment, both systems performed well, consistently producing effluent with 5-d biochemical oxygen demand and total suspended solids (TSS) concentrations <10 mg L and achieving >5 log reductions in . However, the gravity-fed system produced statistically lower average effluent concentrations for total P and TSS. It is speculated that the slightly better treatment performance achieved by the gravity-fed system is due to enhanced biomat formation. This study demonstrated adequate treatment of residential wastewater by contour trench disposal fields regardless of loading method. However, because the hydraulic performance of these systems is heavily dependent on pretreatment and loading methods, it is recommended that a dosing system be used to distribute wastewater to contour trench disposal fields to help prevent hydraulic failure. PMID- 23673850 TI - Wetland management reduces sediment and nutrient loading to the upper Mississippi river. AB - Restored riparian wetlands in the Upper Mississippi River basin have potential to remove sediment and nutrients from tributaries before they flow into the Mississippi River. For 3 yr we calculated retention efficiencies of a marsh complex, which consisted of a restored marsh and an adjacent natural marsh that were connected to Halfway Creek, a small tributary of the Mississippi. We measured sediment, N, and P removal through a mass balance budget approach, N removal through denitrification, and N and P removal through mechanical soil excavation. The marsh complex had average retention rates of approximately 30 Mg sediment ha yr, 26 kg total N ha yr, and 20 kg total P ha yr. Water flowed into the restored marsh only during high-discharge events. Although the majority of retention occurred in the natural marsh, portions of the natural marsh were hydrologically disconnected at low discharge due to historical over-bank sedimentation. The natural marsh removed >60% of sediment, >10% of P, and >5% of N loads (except the first year, when it was a N source). The marsh complex was a source of NH and soluble reactive P. The average denitrification rate for the marsh complex was 2.88 mg N m h. Soil excavation removed 3600 Mg of sediment, 5.6 Mg of N, and 2.7 Mg of P from the restored marsh. The marsh complex was effective in removing sediment and nutrients from storm flows; however, retention could be increased if more water was diverted into both restored and natural marshes before entering the river. PMID- 23673851 TI - Exchange of Nitrogen through an Urban Tidal Freshwater Wetland in Philadelphia, Pennsylvania. AB - Tidal freshwater wetlands in urban settings can be subject to elevated N concentrations, which can promote the exchange of N between the marsh, water, and atmosphere, including denitrification. We used a multitiered approach consisting of direct measurements of N fluxes and denitrification, tidal hypsometry, and N load modeling to examine N exchanges in an urban tidal freshwater wetland of the Delaware River Estuary, Philadelphia, PA. Sediment cores and aboveground biomass were collected at 20 locations across a range of elevations and plant communities in April, July, and October 2010. Nitrate was taken up by the marsh during all seasons. In the spring, the high rate of NH production from the sediment was correlated with NO uptake, suggesting dissimilatory reduction to NH as a potentially important process. Denitrification rates were greatest in July, averaging 5.5 +/- 0.6 mg N m h. Adjusted for tidal inundation using a refined digital elevation model, denitrification averaged 0.08, 0.5, and 0.2 g N m mo for April, July, and October, respectively. Less than 10% of the modeled N load was estimated to have been removed in the months measured. A combination of high N load, limited marsh area that represented ~1% of the watershed area, and conservative extrapolation of denitrification rates contributed to the low estimate of the N load attenuated. PMID- 23673852 TI - Phosphorus retention in a newly constructed wetland receiving agricultural tile drainage water. AB - One measure used in Sweden to mitigate eutrophication of waters is the construction of small wetlands (free water surface wetland for phosphorus retention [P wetlands]) to trap particulate phosphorus (PP) transported in ditches and streams. This study evaluated P retention dynamics in a newly constructed P wetland serving a 26-ha agricultural catchment with clay soil. Flow proportional composite water samples were collected at the wetland inlet and outlet over 2 yr (2010-2011) and analyzed for total P (TP), dissolved P (DP), particulate P (PP), and total suspended solids (TSS). Both winters had unusually long periods of snow accumulation, and additional time-proportional water samples were frequently collected during snowmelt. Inflow TP and DP concentrations varied greatly (0.02-1.09 mg L) during the sampling period. During snowmelt in 2010, there was a daily oscillation in P concentration and water flow in line with air temperature variations. Outflow P concentrations were generally lower than inflow concentrations, with net P losses observed only in August and December 2010. On an annual basis, the wetland acted as a net P sink, with mean specific retention of 69 kg TP, 17 kg DP, and 30 t TSS ha yr, corresponding to a reduction in losses of 0.22 kg TP ha yr from the agricultural catchment. Relative retention was high (36% TP, 9% DP, and 36% TSS), indicating that small constructed wetlands (0.3% of catchment area) can substantially reduce P loads from agricultural clay soils with moderately undulating topography. PMID- 23673853 TI - Automated, low-power chamber system for measuring nitrous oxide emissions. AB - Continuous measurement of soil NO emissions is needed to constrain NO budget and emission factors. Here, we describe the performance of a low-power Teledyne NO analyzer and automated chamber system, powered by wind and solar, that can continuously measure soil NO emissions. Laboratory testing of the analyzer revealed significant temperature sensitivity, causing zero drift of -10.6 nmol mol degrees C. However, temperature-induced span drift was negligible, so the associated error in flux measurement for a typical chamber sampling period was on the order of 0.016 nmol m s. The 1-Hz precision of the analyzer over a 10-min averaging interval, after wavelet decomposition, was 1.5 nmol mol, equal to that of a tunable diode laser NO analyzer. The solar/wind hybrid power system performed well during summer, but system failures increased in frequency in spring and fall, usually at night. Although increased battery storage capacity would decrease down time, supplemental power from additional sources may be needed to continuously run the system during spring and fall. The hourly flux data were numerically subsampled at weekly intervals to assess the accuracy of integrated estimates derived from manually sampling static chambers. Weekly sampling was simulated for each of the five weekdays and for various times during each day. For each weekday, the cumulative N emissions estimate using only morning measurements was similar (within 15%) to the estimate using only afternoon measurements. Often, weekly sampling partially or completely missed large episodic NO emissions that continuous automated chamber measurements captured, causing weekly measurements to underestimate cumulative N emissions for 9 of the 10 sampling scenarios. PMID- 23673854 TI - Use of standardized procedures to evaluate metal leaching from waste foundry sands. AB - As part of the casting process, foundries create sand molds and cores to hold the molten metal to specific dimensional tolerances. Although most of the waste foundry sands (WFSs) from this process are land filled, there is great interest in diverting them for use in agricultural and geotechnical applications. One potential limitation to their beneficial use is concern that the WFSs will leach high levels of trace metals. The aim of this study was to quantify Ag, Ba, Cd, Cr, Cu, Ni, Pb, and Zn in leaching extracts from 96 waste molding and core sands from ferrous and nonferrous foundries. The procedures used to assess leaching in the WFSs were the Extraction Procedure, the Toxicity Characteristic Leaching Procedure, and the American Society for Testing and Materials water extraction procedure. The metal extract concentrations were compared with those found in virgin silica sands and Argentinean and U.S. hazardous waste laws to determine if the WFSs met toxicity limits. Regardless of metal cast and sand binder type, the majority of the WFS extracts analyzed contained metal concentrations similar to those found in virgin sand extracts and were below levels considered hazardous. However, 4 of 28 sands that used alkyd urethane binder were deemed hazardous because Pb concentrations in these sands were found to exceed regulatory thresholds. Although other regulated metals, such as As, Hg, and Se, were not analyzed in the extracts, this dataset provides additional evidence that many WFSs have a low metal leaching potential. PMID- 23673855 TI - Climate change policy failures: why conventional mitigation approaches cannot succeed. PMID- 23673856 TI - Trace metal dynamics in floodplain soils of the river elbe: a review. PMID- 23673857 TI - Results of the AIEOP AML 2002/01 multicenter prospective trial for the treatment of children with acute myeloid leukemia. AB - We evaluated the outcome of 482 children with acute myeloid leukemia (AML) enrolled in the Associazione Italiana di Ematologia e Oncologia Pediatrica AML 2002/01 trial. Treatment was stratified according to risk group; hematopoietic stem cell transplantation (HSCT) was used in high-risk (HR) children. Patients with core binding factor leukemia achieving complete remission (CR) after the first induction course were considered standard risk (SR; 99 patients), whereas the others (n = 383) were assigned to the HR group. Allogeneic (ALLO) or autologous (AUTO) HSCT was employed, respectively, in 141 and 102 HR patients after consolidation therapy. CR, early death, and induction failure rates were 87%, 3%, and 10%, respectively. Relapse occurred in 24% of patients achieving CR. The 8-year overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 68%, 55%, and 63%, respectively. OS, EFS, and DFS for SR and HR patients were 83%, 63%, and 66% and 64%, 53%, and 62%. DFS was 63% and 73% for HR patients given AUTO-HSCT and ALLO-HSCT, respectively. In multivariate analysis, risk group, white blood cell >100 * 10(9)/L at diagnosis, and monosomal karyotype predicted poorer EFS. Risk-oriented treatment and broad use of HSCT result in a long-term EFS comparing favorably with previously published studies on childhood AML. PMID- 23673859 TI - How I treat older patients with ALL. AB - The treatment of older patients with acute lymphoblastic leukemia (ALL) is an unmet medical need. In Western countries, the population is aging, which means there will be an increasing number of older patients. However, in the past few decades, there has been little improvement in treating them, and few clinical trials specifically designed for older patients with ALL have been reported. Older patients with ALL have a significantly lower complete response rate, higher early mortality, higher relapse rate, and poorer survival compared with younger patients. This is partly explained by a higher incidence of poor prognostic factors. Most importantly, intensive chemotherapy with or without stem cell transplantation, both of which are successful in younger patients, is less well tolerated in older patients. For the future, the most promising approaches are optimized supportive care, targeted therapies, moderately intensified consolidation, and reduced-intensity stem cell transplantation. One of the most important challenges for physicians is to differentiate between fit and unfit older patients in order to offer both groups optimal treatment regarding toxicity and mortality risks, quality of life, and long-term outcome. Prospective trials for older patients with ALL are urgently needed. PMID- 23673858 TI - CpG pretreatment enhances antiviral T-cell immunity against cytomegalovirus. AB - Major histocompatibility complex class I-restricted T-cell immunity is essential to control infection with cytomegalovirus (CMV), a clinically important virus that causes significant disease in immunocompromised individuals. Cross presentation is considered the primary mode of antigen presentation to generate protective antiviral CD8+ T-cell immunity. Herpesviruses, including CMV, encode numerous proteins that interfere with direct antigen presentation, leading to the paradigm that T-cell immunity to these pathogens necessitates cross-presentation. However, the antigen presentation requirements needed to generate a protective T cell response to CMV remain unknown. Here, we show that a fully functional antiviral CD8+ T-cell response can be generated in a system where cross presentation is shut down by pretreatment with CpG. Notably, in this setting, CD8+ T cells demonstrate accelerated control of infection, and organ pathology is limited. These data indicate that protective antiviral T-cell immunity to CMV is generated by direct presentation and can be enhanced by pretreatment with CpG. PMID- 23673860 TI - New MLLT10 gene recombinations in pediatric T-acute lymphoblastic leukemia. AB - The MLLT10 gene, located at 10p13, is a known partner of MLL and PICALM in specific leukemic fusions generated from recurrent 11q23 and 11q14 chromosome translocations. Deep sequencing recently identified NAP1L1/12q21 as another MLLT10 partner in T-cell acute lymphoblastic leukemia (T-ALL). In pediatric T ALL, we have identified 2 RNA processing genes, that is, HNRNPH1/5q35 and DDX3X/Xp11.3 as new MLLT10 fusion partners. Gene expression profile signatures of the HNRNPH1- and DDX3X-MLLT10 fusions placed them in the HOXA subgroup. Remarkably, they were highly similar only to PICALM-MLLT10-positive cases. The present study showed MLLT10 promiscuity in pediatric T-ALL and identified a specific MLLT10 signature within the HOXA subgroup. PMID- 23673861 TI - Complex formation with nucleic acids and aptamers alters the antigenic properties of platelet factor 4. AB - The tight electrostatic binding of the chemokine platelet factor 4 (PF4) to polyanions induces heparin-induced thrombocytopenia, a prothrombotic adverse drug reaction caused by immunoglobulin G directed against PF4/polyanion complexes. This study demonstrates that nucleic acids, including aptamers, also bind to PF4 and enhance PF4 binding to platelets. Systematic assessment of RNA and DNA constructs, as well as 4 aptamers of different lengths and secondary structures, revealed that increasing length and double-stranded segments of nucleic acids augment complex formation with PF4, while single nucleotides or single-stranded polyA or polyC constructs do not. Aptamers were shown by circular dichroism spectroscopy to induce structural changes in PF4 that resemble those induced by heparin. Moreover, heparin-induced anti-human-PF4/heparin antibodies cross reacted with human PF4/nucleic acid and PF4/aptamer complexes, as shown by an enzyme immunoassay and a functional platelet activation assay. Finally, administration of PF4/44mer-DNA protein C aptamer complexes in mice induced anti PF4/aptamer antibodies, which cross-reacted with murine PF4/heparin complexes. These data indicate that the formation of anti-PF4/heparin antibodies in postoperative patients may be augmented by PF4/nucleic acid complexes. Moreover, administration of therapeutic aptamers has the potential to induce anti PF4/polyanion antibodies and a prothrombotic diathesis. PMID- 23673862 TI - Enhanced-affinity murine T-cell receptors for tumor/self-antigens can be safe in gene therapy despite surpassing the threshold for thymic selection. AB - Many of the most promising tumor antigens for T-cell-based cancer immunotherapies are unmodified self-antigens. Unfortunately, the avidity of T cells specific for these antigens is limited by central tolerance during T-cell development in the thymus, resulting in decreased anti-tumor efficacy of these T cells. One approach to overcoming this obstacle is to mutate T-cell receptor (TCR) genes from naturally occurring T cells to enhance the affinity for the target antigen. These enhanced-affinity TCRs can then be developed for use in TCR gene therapy. Although TCRs with significantly enhanced affinity have been generated using this approach, it is not clear whether these TCRs, which bypass the affinity limits imposed by negative selection, remain unresponsive to the low levels of self antigen generally expressed by some normal tissues. Here we show that 2 variants of a high-affinity WT1-specific TCR with enhanced affinity for WT1 are safe and do not mediate autoimmune tissue infiltration or damage when transduced into peripheral CD8 T cells and transferred in vivo. However, if expressed in developing T cells and subjected to thymic selection, the same enhanced-affinity TCRs signal tolerance mechanisms in the thymus, resulting in T cells with attenuated antigen sensitivity in the periphery. PMID- 23673863 TI - Umbilical cord blood transplantation: the first 25 years and beyond. AB - Umbilical cord blood is an alternative hematopoietic stem cell source for patients with hematologic diseases who can be cured by allogeneic hematopoietic cell transplantation. Initially, umbilical cord blood transplantation was limited to children, given the low cell dose infused. Both related and unrelated cord blood transplants have been performed with high rates of success for a variety of hematologic disorders and metabolic storage diseases in the pediatric setting. The results for adult umbilical cord blood transplantation have improved, with greater emphasis on cord blood units of sufficient cell dose and human leukocyte antigen match and with the use of double umbilical cord blood units and improved supportive care techniques. Cord blood expansion trials have recently shown improvement in time to engraftment. Umbilical cord blood is being compared with other graft sources in both retrospective and prospective trials. The growth of the field over the last 25 years and the plans for future exploration are discussed. PMID- 23673866 TI - Lack of association between OSAS and hypothyroidism. PMID- 23673864 TI - Hippocampal network connectivity and activation differentiates post-traumatic stress disorder from generalized anxiety disorder. AB - Anxiety disorders are a diverse group of clinical states. Post-traumatic stress disorder (PTSD) and generalized anxiety disorder (GAD), eg, share elevated anxiety symptoms, but differ with respect to fear-related memory dysregulation. As the hippocampus is implicated in both general anxiety and fear memory, it may be an important brain locus for mapping the similarities and differences among anxiety disorders. Anxiety and fear also functionally associate with different subdivisions of the hippocampus along its longitudinal axis: the human posterior (rodent dorsal) hippocampus is involved in memory, through connectivity with the medial prefrontal-medial parietal default-mode network, whereas the anterior (rodent ventral) hippocampus is involved in anxiety, through connectivity with limbic-prefrontal circuits. We examined whether differential hippocampal network functioning may help account for similarities and differences in symptoms in PTSD and GAD. Network-sensitive functional magnetic resonance imaging-based resting state intrinsic connectivity methods, along with task-based assessment of posterior hippocampal/default-mode network function, were used. As predicted, in healthy subjects resting-state connectivity dissociated between posterior hippocampal connectivity with the default-mode network, and anterior hippocampal connectivity to limbic-prefrontal circuitry. The posterior hippocampus and the associated default-mode network, across both resting-state connectivity and task based measures, were perturbed in PTSD relative to each of the other groups. By contrast, we found only modest support for similarly blunted anterior hippocampal connectivity across both patient groups. These findings provide new insights into the neural circuit-level dysfunctions that account for similar vs different features of two major anxiety disorders, through a translational framework built on animal work and carefully selected clinical disorders. PMID- 23673865 TI - Inferior frontal cortex modulation with an acute dose of heroin during cognitive control. AB - Impairments in inhibitory control and in stimulus-driven attention are hallmarks of drug addiction and are associated with decreased activation in the right inferior frontal gyrus (IFG). Although previous studies indicate that the response inhibition function is impaired in abstinent heroin dependents, and that this is mediated by reduced IFG activity, it remains completely unknown whether and how an acute dose of heroin modulates IFG activity during cognitive control in heroin-dependent patients. This study investigates the acute effects of heroin administration on IFG activity during response inhibition and stimulus-driven attention in heroin-dependent patients. Using a cross-over, double-blind, placebo controlled design, saline and heroin were administered to 26 heroin-dependent patients from stable heroin-assisted treatment, while performing a Go/No-Go event related functional magnetic resonance imaging task to assess right IFG activity during motor response inhibition, as well as during oddball-driven attention allocation. Relative to saline, heroin significantly reduced right IFG activity during both successful response inhibition and oddball-driven attention allocation, whereas it did not change right IFG activity during response inhibition after correction for the effect of attention allocation. These heroin induced effects were not related to changes in drug craving, state anxiety, behavioral performance, or co-consumption of psychostimulant drugs. This study demonstrates that heroin administration acutely impairs stimulus-driven attention allocation, as indicated by reduced IFG activity in response to infrequently presented stimuli, and does not specifically modulate IFG activity during response inhibition. PMID- 23673867 TI - Early radiological clues in diagnosis of adrenocortical carcinoma: lessons from a missed opportunity. PMID- 23673868 TI - Patient's comfort with and tolerability of thyroid core needle biopsy. AB - Recently, the core needle biopsy (CNB) has been proposed as a complementary test for thyroid nodules with inconclusive cytology by fine-needle aspiration (FNA). However, there have been no reports regarding patient comfort during and after CNB or tolerability of this procedure. Here we aimed to investigate and compare comfort with and tolerability of the CNB and FNA procedures. A 21 gauge needle was used for collection in CNB procedures, and a 23 gauge needle was used for collection in FNA procedures. Sixty-one consecutive patients underwent both biopsies and were asked to evaluate their comfort during and after these procedures by a structured questionnaire. A total of 58 (95 %) patients reported local pain during both biopsies. Two patients reported pain only during CNB, and one reported no pain. Mild pain was reported in 87 % of CNB cases. Local pain after biopsy was reported in 29 % of FNA and 45 % of CNB. The occurrence of pain in the first minutes following CNB was significantly higher than FNA (p = 0.008), while there was not a significant difference in pain at later time points after the procedures. Finally, patients were asked to evaluate the degree of tolerability of the two sampling techniques, and FNA and CNB were reported as tolerable in 82 and 83 %, respectively. The results from a questionnaire evaluating patients' comfort level showed no significant difference between the tolerability of CNB and FNA. This finding suggests that CNB may be performed with a reasonable level of patient comfort. PMID- 23673869 TI - Clinical presentation of Von Hippel Lindau syndrome type 2B associated with VHL p.A149S mutation in a large Turkish family. AB - Von Hippel Lindau (VHL) syndrome is an autosomal dominant disorder characterized by benign and malignant tumors. This study presents the clinical and genetic features of VHL syndrome in a Turkish family. For the diagnosis of pheochromocytoma-related diseases, 49 family members from three generations were evaluated between March 2008 and January 2013. Family members were examined to identify components of pheochromocytoma-related genetic syndromes through physical examination, laboratory tests, and imaging methods. For the causative mutation, sequence analysis of VHL gene was performed. Nine patients were diagnosed with pheochromocytoma. Lumbal spinal hemangioblastoma and pancreatic neuroendocrine tumor without pheochromocytoma were detected in one patient. In patients with pheochromocytoma, additional tumors, such as retinal angioma, renal cell carcinoma, pancreatic serous cystadenoma, and pancreatic neuroendocrine tumors were detected. All patients were diagnosed as VHL syndrome type 2B. Sequence analysis of VHL gene revealed heterozygous p.A149S mutation in all symptomatic patients and in seven of the asymptomatic family members. This is the first study that identified VHL p.A149S mutation in a Turkish family with VHL syndrome. However, VHL p.A149S mutation was identified in an American family by Atuk et al. (J Clin Endocrinol Metab, 83:117-120, 14) and the family was defined as VHL type 2A. In our study, the family was identified as VHL type 2B. This variability in the phenotypic features suggests that further studies are required to beter assess the genotype-phenotype correlation in such cases. PMID- 23673870 TI - MicroRNA-17-92 cluster regulates osteoblast proliferation and differentiation. AB - MicroRNAs (miRNAs) have been identified to play important functions during osteoblast proliferation, differentiation, and apoptosis. The miR-17~92 cluster is highly conserved in all vertebrates. Loss-of-function of the miR-17-92 cluster results in smaller embryos and immediate postnatal death of all animals. Germline hemizygous deletions of MIR17HG are accounted for microcephaly, short stature, and digital abnormalities in a few cases of Feingold syndrome. These reports indicate that miR-17~92 may play important function in skeletal development and mature. To determine the functional roles of miR-17~92 in bone metabolism as well as osteoblast proliferation and differentiation. Murine embryonic stem cells D3 and osteoprogenitor cell line MC3T3-E1 were induced to differentiate into osteoblasts; the expression of miR-17-92 was assayed by quantitative real-time RT PCR. The skeletal phenotypes were assayed in mice heterozygous for miR-17~92 (miR 17~92 (+/Delta) ). To determine the possibly direct function of miR-17~92 in bone cells, osteoblasts from miR-17~92 (+/Delta) mice were investigated by ex vivo cell culture. miR-17, miR-92a, and miR-20a within miR-17-92 cluster were expressed at high level in bone tissue and osteoblasts. The expression of miR-17 92 was down-regulated along with osteoblast differentiation, the lowest level was found in mature osteoblasts. Compared to wildtype controls, miR-17-92 (+/Delta) mice showed significantly lower trabecular and cortical bone mineral density, bone volume and trabecular number at 10 weeks old. mRNA expression of Runx2 and type I collagen was significantly lower in bone from miR-17-92 (+/Delta) mice. Osteoblasts from miR-17-92 (+/Delta) mice showed lower proliferation rate, ALP activity and less calcification. Our research suggests that the miR-17-92 cluster critically regulates bone metabolism, and this regulation is mostly through its function in osteoblasts. PMID- 23673871 TI - Society of anesthesia and sleep medicine: proceedings of 2012 annual meeting. AB - INTRODUCTION: We present the proceedings of the second annual meeting of the Society of Anesthesia and Sleep Medicine. The theme of the meeting was "Anesthesia and Sleep Medicine: What Every Health Professional Needs to Know." DISCUSSION: While upper airway obstruction during sleep and anesthesia received concentrated attention, with particular regard to perioperative assessment and managment of obstuctive sleep apnea, a diversity of issues were raised including: the genetic basis for variations in ventilatory control; shared charactertics of sleep and anesthesia; hazards posed by narcotic use in patients with obstructive sleep apnea (OSA); the respiratory complication that follow surgery in such patients; who amongst them is suitable for ambulatory surgery; and the special circumstances that apply to anesthesia for children with OSA. How principles based on these considerations have been applied to protocol development at two major centers was presented towards the end of the meeting. The proceedings highlight issues discussed by each of the invited speakers but do not include the research abstracts discussed during the poster session. PMID- 23673872 TI - The impact of obesity on cardiac dysfunction in patients with sleep-disordered breathing. AB - INTRODUCTION: Obesity and heart failure are strongly associated with sleep disordered breathing (SDB). However, the determinants of cardiac dysfunction in patients with SDB are not known. METHODS: We studied 90 patients suspected of having SDB (66 % women and 67 % black), age 50.4 +/- 13.4 years and body mass index (BMI) 38.6 +/- 9.8 kg/m(2). Apnea-hypopnea index (AHI) and nadir pulse oximetry (SpO2) were determined by polysomnography recordings. Left atrial (LA) diameter and left ventricular posterior wall (LVPW) thickness were determined by echocardiography. Patients who had EF<50 %, estimated right ventricular systolic pressure >45 mmHg or valvular heart disease were excluded. RESULTS: Univariate analysis revealed a positive correlation between LA diameter and each of BMI, neck circumference (NC), and AHI (coefficients, 0.28, 0.34, and 0.36, respectively; p<0.05). Multivariable linear regression analysis revealed that BMI was the only independent predictor of LA enlargement (coefficient 0.02, p<0.05). LVPW thickness correlated with BMI, NC, and AHI (correlation coefficients were 0.43, 0.47, and 0.33, respectively; p<0.05). Multivariable linear regression analysis revealed a significant relationship between LVPW thickness and each of BMI and NC (coefficients 0.016 and 0.007, respectively; p<0.05) but not AHI. BMI and LVPW associated with nadir SpO2 (r=-0.60, p<0.01 and r=-0.21, p=0.05; respectively), and BMI was a predictor of nadir SpO2 during sleep (B=-0.59; CI: 0.84, -0.33; p=0.01). CONCLUSIONS: Obesity can predict cardiovascular morbidity and nocturnal hypoxemia independent of the severity of the SDB. Our findings suggest the independent contribution of excess body weight on cardiac dysfunction and hypoxia in SDB patients. PMID- 23673873 TI - Identification of the rhizobial symbiont of Astragalus glombiformis in Eastern Morocco as Mesorhizobium camelthorni. AB - Astragalus gombiformis is a desert symbiotic nitrogen-fixing legume of great nutritional value as fodder for camels and goats. However, there are no data published on the rhizobial bacteria that nodulate this wild legume in northern Africa. Thirty-four rhizobial bacteria were isolated from root nodules of A. gombifomis grown in sandy soils of the South-Eastern of Morocco. Twenty-five isolates were able to renodulate their original host and possessed a nodC gene copy. The phenotypic and genotypic characterizations carried out illustrated the diversity of the isolates. Phenotypic analysis showed that isolates used a great number of carbohydrates as sole carbon source. However, although they were isolated from arid sandy soils, the isolates do not tolerate drought stress applied in vitro. The phenotypic diversity corresponded mainly to the diversity in the use of some carbohydrates. The genetic analysis as assessed by repetitive extragenic palindromic (REP)-polymerase chain reaction (PCR) showed that the isolates clustered into 3 groups at a similarity coefficient of 81 %. The nearly complete 16S rRNA gene sequence from a representative strain of each PCR-group showed they were closely related to members of the genus Mesorhizobium of the family Phyllobactericeae within the Alphaproteobacteria. Sequencing of the housekeeping genes atpD, glnII and recA, and their concatenated phylogenetic analysis, showed they are closely related to Mesorhizobium camelthorni. Sequencing of the symbiotic nodC gene from each strain revealed they had 83.53 % identity with the nodC sequence of the type strain M. camelthorni CCNWXJ 40-4(T.) PMID- 23673874 TI - The effects of propofol on cerebral perfusion MRI in children. AB - INTRODUCTION: The effects of anesthesia are infrequently considered when interpreting pediatric perfusion magnetic resonance imaging (MRI). The objectives of this study were to test for measurable differences in MR measures of cerebral blood flow (CBF) and cerebral blood volume (CBV) between non-sedated and propofol sedated children, and to identify influential factors. METHODS: Supratentorial cortical CBF and CBV measured by dynamic susceptibility contrast perfusion MRI in 37 children (1.8-18 years) treated for infratentorial brain tumors receiving propofol (IV, n = 19) or no sedation (NS, n = 18) were compared between groups and correlated with age, hematocrit (Hct), end-tidal CO2 (ETCO2), dose, weight, and history of radiation therapy (RT). The model most predictive of CBF and CBV was identified by multiple linear regression. RESULTS: Anterior cerebral artery (ACA) and middle cerebral artery (MCA) territory CBF were significantly lower, and MCA territory CBV greater (p = 0.03), in IV than NS patients (p = 0.01, 0.04). The usual trend of decreasing CBF with age was reversed with propofol in ACA and MCA territories (r = 0.53, r = 0.47; p < 0.05). ACA and MCA CBF (r = 0.59, 0.49; p < 0.05) and CBV in ACA, MCA, and posterior cerebral artery territories (r = 0.73, 0.80, 0.52; p < 0.05) increased with weight in propofol sedated children, with no significant additional influence from age, ETCO2, hematocrit, or RT. CONCLUSION: In propofol-sedated children, usual age-related decreases in CBF were reversed, and increases in CBF and CBV were weight dependent, not previously described. Weight-dependent increases in propofol clearance may diminish suppression of CBF and CBV. Prospective study is required to establish anesthetic-specific models of CBF and CBV in children. PMID- 23673875 TI - Correlation between pathology and neuromelanin MR imaging in Parkinson's disease and dementia with Lewy bodies. AB - INTRODUCTION: Direct correlation between neuropathological findings and postmortem neuromelanin MR imaging (NmMRI) was performed in the substantia nigra pars compacta (SNc) to clarify the pathological background of the signal changes in normal, Parkinson's disease (PD), and dementia with Lewy bodies (DLB) cases. METHODS: NmMRI of 10 % formalin-fixed autopsied midbrains was performed in three cases (normal control, DLB, and PD) with a 3T imaging system, using a 3D gradient echo T1-weighted sequence with a magnetization transfer contrast pulse. Neuropathological examinations of the midbrains were performed, and the density of neuromelanin-positive neurons (number per square millimeter) was determined. The extent of iron deposition in the midbrain was also evaluated using ferritin immunohistochemistry. Furthermore, we directly correlated the contrast signal ratio in the SNc and the density of neuromelanin-containing neurons. RESULTS: Diffuse hyperintense areas in the SNc reflected well-preserved neuromelanin containing neurons in the normal control case, whereas an iso-intense area in the SNc showed severe loss of neuromelanin-containing neurons in the DLB and PD cases. Increased signal intensity in the SNc was apparently not influenced by iron deposition. Furthermore, a significant positive correlation between signal intensity and the density of neuromelanin-containing neurons was seen in the SNc. CONCLUSION: Based on the direct correlation between postportem NmMRI and neuropathological findings, signal intensity in the SNc is closely related to the quantity of neuromelanin-containing neurons but is not influenced by iron deposition. PMID- 23673876 TI - The vertebrae of prematurely aging mice as a skeletal model of involutional osteoporosis. AB - Oxidative stress in bone increases with age, which leads to bone frailty and a high fracture risk. Animal models show that early changes in trabecular structure occur in age-related osteopenia. These models might be valuable to assess the contribution of oxidative stress in age-related bone loss. Premature aging mice (PAM) have previously been characterized as a model of premature immunological and neurological senescence. PAM long bones (mainly consisting of cortical bone) display features of aging bone. Thus, we aimed to evaluate the vertebrae, representing a unique poorly loaded type of trabecular bone in mice, in PAM and no PAM (NPAM) controls. PAM showed an anxious behaviour, based on physical activity evaluation. These mice had decreased bone mineral density (0.078 mg/cm2 in NPAM vs 0.070 g/cm2 in PAM; p?0.05); a decreased number of osteocytes per bone field (404+/-36 in NPAM vs 320+/-27 in PAM; p?0.01); and downregulation of various osteoblastic genes and low eroded surface/bone surface, 4.2+/-0.5 in NPAM vs 1.9+/-0.2 in PAM; p?0.01). This was associated with increased expression of oxidative stress markers, Foxo1 and GADD45, in PAM vertebrae. Mesenchymal progenitors in the bone marrow of PAM have a poor mineralization capacity (assessed by the number of mineralized nodules and suface), and showed a lower response to an osteogenic input -represented by parathormone-related protein-, compared to NPAM. Collectively, these results indicate that PAM vertebrae show osteopenia related to diminished bone formation and remodeling. Our findings further support the validity of PAM as a suitable model for involutional osteoporosis and its treatment. PMID- 23673877 TI - A strategy for antimicrobial regulation based on fluorescent conjugated oligomer DNA hybrid hydrogels. AB - New fluorescent oligo(phenylene ethynylene)-DNA hydrogels have been prepared and used for the controllable biocidal activity driven by DNase. This study opens a new way of controllable drug release and antimicrobial regulation. PMID- 23673878 TI - The social and behavioral sciences research network: translational research to reduce disparities in HIV. PMID- 23673879 TI - Emerging technologies for HIV prevention for MSM: what we have learned, and ways forward. AB - Technology-enabled HIV research and prevention has emerged in the past 10 years as an exciting dynamic field that offers great potential to help bring HIV prevention efforts to scale in key risk communities. Evolutions in technologies and in HIV epidemics suggest mutual opportunities to reach most at risk populations in novel ways. New technologies cannot completely replace interventions and services currently delivered by the people. However, we suggest that emerging technologies hold promise to bring services to scale and produce efficiencies in reaching rural populations of men who have sex with men (MSM), connecting with populations who are not reached in current urban outreach efforts, and providing services or research surveys that can be described algorithmically. Furthermore, the types of technologies (eg, internet-based, smartphone-based, text messaging) should be matched with both the content to be delivered and the technology usage patterns of target populations. We suggest several key principles and lessons learned that comprise a framework in which to consider the opportunities of technologies and HIV prevention and research. Future directions include improvement of data quality in online surveying, better characterization of biases, developing improved sampling approaches, working with funders to ensure compatibility of funding mechanisms and online research proposals, and promoting consensus approaches to the duplication and presentation of research and program evaluation results from online research. Given the current calls for comprehensive packages of prevention services for MSM, effective prevention might require an intentional combination of technology enabled prevention services to achieve scale and strategic use of personally delivered package components in cases where non-algorithmic services, such as individualized counseling, are needed. PMID- 23673880 TI - A new paradigm for optimizing HIV intervention synergy: the role of interdependence in integrating HIV prevention interventions. PMID- 23673882 TI - Implementation science perspectives and opportunities for HIV/AIDS research: integrating science, practice, and policy. AB - BACKGROUND: Disparities in the incidence and mortality of HIV/AIDS persist, challenging researchers, practitioners, and communities to develop improved strategies to reach vulnerable and marginalized populations. METHODS: The emerging field of Implementation Science, with its focus on context, external validity, and innovative design approaches, is well suited to respond to this challenge. We provide an overview of Implementation Science, including its frameworks, tools, and strategies, and how they can inform the response to HIV/AIDS. RESULTS: We summarize pioneering Implementation Science frameworks, and then present examples using newer models, including RE-AIM (Reach, Effectiveness/Efficacy, Adoption, Implementation, Maintenance) and the Evidence Integration Triangle, a framework for combining research and practice using participatory and adaptive processes in a multilevel context. CONCLUSIONS: Although still developing, the international field of Implementation Science can offer helpful perspectives for facilitating the more rapid integration of HIV/AIDS research, practice, and policy. PMID- 23673883 TI - Using community-based participatory research to prevent HIV disparities: assumptions and opportunities identified by the Latino partnership. AB - BACKGROUND: HIV disproportionately affects vulnerable populations in the United States, including recently arrived immigrant Latinos. However, the current arsenal of effective approaches to increase adherence to risk-reduction strategies and treatment within Latino populations remains insufficient. METHODS: Our community-based participatory research (CBPR) partnership blends multiple perspectives of community members, organizational representatives, local business leaders, and academic researchers to explore and intervene on HIV risk within Latino populations. We used CBPR to develop, implement, and evaluate 2 interventions that were found to be efficacious. RESULTS: We identified 7 assumptions of CBPR as an approach to research, including more authentic study designs, stronger measurement, and improved quality of knowledge gained; increased community capacity to tackle other health disparities; the need to focus on community priorities; increased participation and retention rates; more successful interventions; reduced generalizability; and increased sustainability. CONCLUSIONS: Despite the advancement of CBPR as an approach to research, key assumptions remain. Further research is needed to compare CBPR with other more traditional approaches to research. Such research would move us from assuming the value of CBPR to identifying its actual value in health disparity reduction. After all, communities carrying a disproportionate burden of HIV, including immigrant Latino communities, deserve the best science possible. PMID- 23673884 TI - Efficacy of an HIV intervention in reducing high-risk human papillomavirus, nonviral sexually transmitted infections, and concurrency among African American women: a randomized-controlled trial. AB - OBJECTIVE: This trial evaluated the efficacy of an HIV-intervention condition, relative to a health-promotion condition, in reducing incidence of nonviral sexually transmitted infections (STIs; Chlamydia, gonorrhea, and trichomoniasis), oncogenic human papillomavirus (HPV) subtypes 16 and 18, sexual concurrency, and other HIV-associated behaviors over a 12-month period. DESIGN: Randomized controlled trial. Data analysts blinded to treatment allocation. SETTING: Kaiser Permanente, GA. SUBJECTS: A random sample of 848 African American women. INTERVENTION: The two 4-hour HIV intervention sessions were based on Social Cognitive Theory and the Theory of Gender and Power. The intervention was designed to enhance participants' self-sufficiency and attitudes and skills associated with condom use. The HIV intervention also encouraged STI testing and treatment of male sex partners and reducing vaginal douching and individual and male partner concurrency. MAIN OUTCOME MEASURE: Incident nonviral STIs. RESULTS: In generalized estimating equations' analyses, over the 12-month follow-up, participants in the HIV intervention, relative to the comparison, were less likely to have nonviral incident STIs (odds ratio [OR] = 0.62; 95% confidence interval [CI]: 0.40 to 0.96; P = 0.033) and incident high-risk HPV infection (OR = 0.37; 95% CI: 0.18 to 0.77; P = 0.008) or concurrent male sex partners (OR = 0.55; 95% CI: 0.37 to 0.83; P = 0.005). In addition, intervention participants were less likely to report multiple male sex partners, more likely to use condoms during oral sex, more likely to inform their main partner of their STI test results, encourage their main partner to seek STI testing, report that their main partner was treated for STIs, and report not douching. CONCLUSIONS: This is the first trial to demonstrate that an HIV intervention can achieve reductions in nonviral STIs, high-risk HPV, and individual concurrency. PMID- 23673885 TI - Translating social and behavioral science research to the AIDS epidemic: a center for AIDS research perspective. AB - Integration of innovative social and behavioral science with public health approaches for HIV prevention and treatment is of critical importance for slowing the global HIV epidemic. Strengthening and focusing social and behavioral research linking testing and treatment strategies to populations at greatest risk for HIV is crucial. The Social and Behavioral Science Research Network(SBSRN), originated in 2006, involves twenty NIH-funded CFAR Centers and is responding to this challenge. PMID- 23673881 TI - Translation of biomedical prevention strategies for HIV: prospects and pitfalls. AB - Early achievements in biomedical approaches for HIV prevention included physical barriers (condoms), clean injection equipment (both for medical use and for injection drug users), blood and blood product safety, and prevention of mother to-child transmission. In recent years, antiretroviral drugs to reduce the risk of transmission (when the infected person takes the medicines; treatment as prevention) or reduce the risk of acquisition (when the seronegative person takes them; preexposure prophylaxis) have proven to be efficacious. Circumcision of men has also been a major tool relevant for higher prevalence regions such as sub Saharan Africa. Well-established prevention strategies in the control of sexually transmitted diseases and tuberculosis are highly relevant for HIV (ie, screening, linkage to care, early treatment, and contact tracing). Unfortunately, only slow progress is being made in some available HIV-prevention strategies such as family planning for HIV-infected women who do not want more children and prevention of mother-to-child HIV transmission. Current studies seek to integrate strategies into approaches that combine biomedical, behavioral, and structural methods to achieve prevention synergies. This review identifies the major biomedical approaches demonstrated to be efficacious that are now available. We also highlight the need for behavioral risk reduction and adherence as essential components of any biomedical approach. PMID- 23673886 TI - Tailored treatment for HIV+ persons with mental illness: the intervention cascade. AB - The public health literature demonstrates disturbingly high HIV risk for persons with a serious mental illness, who are concurrently comorbid for substance abuse. Many HIV positives have not been tested and therefore do not know their status, but for individuals who are triply diagnosed, adherence to HIV treatment results in meaningful reductions in viral loads and CD4 counts. Barriers to treatment compliance are reviewed, low-threshold/low-intensity community-based interventions are discussed, and preliminary evidence is presented for the efficacy of the intervention cascade, defined as an integrated intervention delivered by specially trained nurses who individualize a treatment compliance intervention in real time as an adaptive response to demand characteristics of the individual. PMID- 23673888 TI - Social network approaches to recruitment, HIV prevention, medical care, and medication adherence. AB - This article reviews the current issues and advancements in social network approaches to HIV prevention and care. Social network analysis can provide a method to understand health disparities in HIV rates, treatment access, and outcomes. Social network analysis is a valuable tool to link social structural factors to individual behaviors. Social networks provide an avenue for low-cost and sustainable HIV prevention interventions that can be adapted and translated into diverse populations. Social networks can be utilized as a viable approach to recruitment for HIV testing and counseling, HIV prevention interventions, optimizing HIV medical care, and medication adherence. Social network interventions may be face-to-face or through social media. Key issues in designing social network interventions are contamination due to social diffusion, network stability, density, and the choice and training of network members. There are also ethical issues involved in the development and implementation of social network interventions. Social network analyses can also be used to understand HIV transmission dynamics. PMID- 23673889 TI - Efficacy of SISTA South Africa on sexual behavior and relationship control among isiXhosa women in South Africa: results of a randomized-controlled trial. AB - BACKGROUND: The HIV epidemic has a devastating impact among South African women. The current study evaluated the efficacy of SISTA South Africa, a culturally congruent HIV intervention for isiXhosa women in South Africa, which was adapted from SISTA, an HIV intervention for African American women. METHODS: A randomized controlled trial recruited 342 isiXhosa women aged 18-35 years. Participants were randomized to the general health comparison or the SISTA South Africa intervention. Xhosa-speaking peer health educators tailored the SISTA South Africa curriculum, while maintaining the core elements of the original SISTA intervention. Participants completed assessments at baseline and 6 months follow up. RESULTS: Relative to participants in the comparison, participants in the HIV intervention reduced the frequency of unprotected vaginal intercourse acts (adjusted mean difference = 1.06; P = 0.02), were more likely to report not desiring dry sex (adjusted odds ratio = 0.229; 95% confidence interval = 0.10 to 0.47; P = 0.0001), and were more likely to perceive that their main sexual partner did not desire dry sex (adjusted odds ratio = 0.24; 95% confidence interval = 0.11 to 0.52; P = 0.0001). In addition, women randomized to the intervention also reported an increase in HIV knowledge, greater relationship control, and had more opposing attitudes toward HIV stigma. The HIV intervention did not reduce sexually transmitted infection incidence. CONCLUSIONS: This trial demonstrates that an HIV intervention, which is adapted to enhance its gender and cultural relevance for rural isiXhosa women, can reduce self-reported sexual risk behaviors and enhance mediators of HIV among this vulnerable population. PMID- 23673887 TI - Correctional facilities as partners in reducing HIV disparities. AB - The United States now has the highest incarceration rate in the world. The majority of prison and jail inmates come from predominantly nonwhite and medically underserved communities. Although incarceration has adverse effects on both individual and community health, prisons and jails have also been used successfully as venues to provide health services to people with HIV who frequently lack stable health care. We review demographic trends shaping the difficulties in providing care to incarcerated people with HIV and recommend the Centers for AIDS Research Collaboration on HIV in Corrections as a model of interdisciplinary collaboration in addressing those difficulties. PMID- 23673890 TI - Integrating behavioral and biomedical research in HIV interventions: challenges and opportunities. AB - Recent clinical trials have demonstrated overwhelming success of biomedical tools to prevent the spread of HIV infection. However, the complex and somewhat disparate results of some of these trials have highlighted the need for effective integration of biomedical and behavioral sciences in the design and implementation of any future intervention trial. Integrating behavioral and biomedical sciences will require appropriate behavioral theories that can be used in the context of biomedical clinical trials and multidisciplinary teams working together from the earliest stages of trial design through to completion. It is also clear that integration of behavioral science will be necessary to implement prevention at the population level and reverse the HIV epidemic. PMID- 23673891 TI - Adoption and implementation of a computer-delivered HIV/STD risk-reduction intervention for African American adolescent females seeking services at county health departments: implementation optimization is urgently needed. AB - Although group-delivered HIV/sexually transmitted disease (STD) risk-reduction interventions for African American adolescent females have proven efficacious, they require significant financial and staffing resources to implement and may not be feasible in personnel- and resource-constrained public health clinics. We conducted a study assessing adoption and implementation of an evidence-based HIV/STD risk-reduction intervention that was translated from a group-delivered modality to a computer-delivered modality to facilitate use in county public health departments. Usage of the computer-delivered intervention was low across 8 participating public health clinics. Further investigation is needed to optimize implementation by identifying, understanding, and surmounting barriers that hamper timely and efficient implementation of technology-delivered HIV/STD risk reduction interventions in county public health clinics. PMID- 23673893 TI - Rate of decay in proportion of condom-protected sex acts among adolescents after participation in an HIV risk-reduction intervention. AB - OBJECTIVE: HIV risk-reduction interventions have demonstrated efficacy in enhancing the proportion of condom-protected sex (CPS) acts among diverse populations. Although postintervention exposure increase in CPS are often observed, there is scant empirical data quantifying decay of intervention efficacy (declines in CPS after cessation of the intervention among participants reporting an initial postintervention increase in CPS). Thus, the objective of this study was to quantify the rate of decay in intervention efficacy over a 24 month follow-up. DESIGN: African American adolescent females (ages: 14-20; n = 349) completed a baseline audio computer-assisted self-administered interview, participated in an HIV risk-reduction intervention, and were assessed at 6-month intervals for 24 months postintervention. Intervention efficacy was conceptualized as an increase in participants' CPS relative to baseline. METHODS: Analyses focused on the subset of participants who reported an initial increase in CPS from baseline to the 6-month postintervention assessment (n = 121) to quantify the rate of decay in intervention efficacy over a 24-month follow-up period. RESULTS: CPS increased markedly from baseline to 6-month follow-up assessment. However, from 6 to 12 months, a marked decline in CPS was observed. Further CPS declines, though not statistically significant, were observed from 12 to 18 months and 18 to 24 months. Cumulative reductions in CPS over the entire 24 month follow-up resulted in no statistical difference between baseline and 24 month follow-up; indicative of a nonsignificant intervention effect at 24-month assessment. CONCLUSIONS: Innovative postintervention optimization strategies are needed to minimize CPS decay over protracted time periods by reinforcing, sustaining, and potentially amplifying initial gains in condom use. PMID- 23673894 TI - Racial disparities in HIV prevalence and risk behaviors among injection drug users and members of their risk networks. AB - In the United States, racial differences in the prevalence and incidence of HIV infection and AIDS diagnoses are dramatic. These differences are large, have been recognized for nearly 20 years, and are as yet not well investigated. These disparities show no signs of diminishing and, in fact, are widening, particularly among drug users and women. Most observers of the racial disparities in prevalence and incidence of HIV infections and AIDS diagnoses in the United States have concluded that these disparities exist because prevention messages, supplies, and/or interventions do not effectively reach those at greatest risk of infection. In essence, such interpretations suggest that Blacks and Latinos continue to practice more risk behaviors than Whites. There are much data to suggest that this is, in fact, not true. Evidence from 232 'index' injection drug users and 465 of their drug and sexual network members participating in HIV Prevention Trials Network 037 is presented. These data describe lower use and/or access to drug treatment and needle exchange programs by Black injectors. In addition, data indicate the coexistence of increased prevalence of HIV in the networks of uninfected Black drug users and fewer associated risk behaviors in the networks of Black and Latino indices compared with networks of White indices. Understanding racial disparities in HIV is a critical challenge; yet, risk behaviors alone do not explain observed disparities in infection rates. PMID- 23673895 TI - Racial differences and correlates of potential adoption of preexposure prophylaxis: results of a national survey. AB - OBJECTIVE: To examine the association between sociodemographic factors, sexual behaviors, and social factors on potential uptake of preexposure prophylaxis (PrEP) among African American and White adult women in the United States. METHODS: Participants were recruited through a nationally representative, random digit dial telephone household survey. Participants comprised a nationally representative, random sample of unmarried African American (N = 1042) and White women (N = 411) aged 20-44 years. Interviews were conducted using computer assisted telephone interviewing technology. Bivariate and multivariate analyses examined the relationship between sociodemographics, sexual behaviors, and social influences on women's potential uptake of PrEP. RESULTS: In multivariate analyses, women with lower educational status, greater lifetime sexual partners, provider recommendations supportive of PrEP, and peer norms supportive of PrEP use were more likely to report potential PrEP uptake. Racial analyses revealed that compared with White women, African American women were significantly more likely to report potential use of PrEP [adjusted odds ratio (aOR) = 1.76, P <= 0.001], more likely to report use of PrEP if recommended by a health-care provider (aOR = 1.65, P <= 0.001), less likely to report that they would be embarrassed to ask a health-care provider for PrEP (aOR = 0.59, P <= 0.05), and more likely to report use of PrEP if their female friends also used PrEP (aOR = 2.2, P <= 0.001). The potential cost for PrEP was identified as a barrier to adoption by both African American and White women. CONCLUSIONS: Findings suggest that women at increased risk for HIV, including those with less education and greater number of sexual partners, may be more likely to use PrEP, although cost may serve as a barrier. PMID- 23673896 TI - Immobilization and characterisation of a lipase from a new source, Bacillus sp. ITP-001. AB - A new source of lipase from Bacillus sp. ITP-001 was immobilized by physical adsorption on the polymer poly(3-hydroxybutyrate-co-hydroxyvalerate) (PHBV) in aqueous solution. The support and immobilized lipase were characterised, compared to the lyophilised lipase, with regard to the specific surface area, adsorption desorption isotherms, pore volume (V(p)) and size (dp) by nitrogen adsorption, differential scanning calorimetry, thermogravimetric analysis, chemical composition analysis, Fourier transform infrared spectroscopy and biochemical properties. The immobilized enzyme displayed a shift in optimum pH towards the acidic side with an optimum at pH 4.0, whereas the optimum pH for the free enzyme was at pH 7.0; the optimum temperature of activity was 80 and 37 degrees C for the free and immobilized enzyme, respectively. The inactivation rate constant for the immobilized enzyme at 37 degrees C was 0.0038 h-1 and the half-life was 182.41 h. The kinetic parameters obtained for the immobilized enzyme gave a Michaelis-Menten constant (K(m)) of 49.10 mM and a maximum reaction velocity (V(max)) of 205.03 U/g. Furthermore, the reuse of the lipase immobilized by adsorption allowed us to observe that it could be reused for 10 successive cycles, duration of each cycle (1 h), maintaining 33 % of the initial activity. PMID- 23673892 TI - A computational future for preventing HIV in minority communities: how advanced technology can improve implementation of effective programs. AB - African Americans and Hispanics in the United States have much higher rates of HIV than non-minorities. There is now strong evidence that a range of behavioral interventions are efficacious in reducing sexual risk behavior in these populations. Although a handful of these programs are just beginning to be disseminated widely, we still have not implemented effective programs to a level that would reduce the population incidence of HIV for minorities. We proposed that innovative approaches involving computational technologies be explored for their use in both developing new interventions and in supporting wide-scale implementation of effective behavioral interventions. Mobile technologies have a place in both of these activities. First, mobile technologies can be used in sensing contexts and interacting to the unique preferences and needs of individuals at times where intervention to reduce risk would be most impactful. Second, mobile technologies can be used to improve the delivery of interventions by facilitators and their agencies. Systems science methods including social network analysis, agent-based models, computational linguistics, intelligent data analysis, and systems and software engineering all have strategic roles that can bring about advances in HIV prevention in minority communities. Using an existing mobile technology for depression and 3 effective HIV prevention programs, we illustrated how 8 areas in the intervention/implementation process can use innovative computational approaches to advance intervention adoption, fidelity, and sustainability. PMID- 23673897 TI - Batch, fed-batch and repeated fed-batch fermentation processes of the marine thraustochytrid Schizochytrium sp. for producing docosahexaenoic acid. AB - Different fermentation processes, including batch, fed-batch and repeated fed batch processes by Schizochytrium sp., were studied and compared for the effective DHA-rich microbial lipids production. The comparison between different fermentation processes showed that fed-batch process was a more efficient cultivation strategy than the batch process. Among the four different feeding strategies, the glucose concentration feed-back feeding strategy had achieved the highest fermentation results of final cell dry weight, total lipids content, DHA content and DHA productivity of 72.37, 48.86, 18.38 g l(-1) and 138.8 mg l(-1) h( 1), respectively. The repeated fed-batch process had the advantages of reducing the time and cost for seed culture and inoculation between each fermentation cycles. The results of fermentation characteristics and lipid characterization of the repeated fed-batch process indicated that this repeated fed-batch process had promising industrialization prospect for the production of DHA-rich microbial lipids. PMID- 23673898 TI - Melanoma antigen gene family A as a molecular marker of gastric and colorectal cancers. AB - The present study aimed to evaluate the role of melanoma antigen family A (MAGEA) in gastric and colorectal cancer cell lines and clinical tissue samples. we used 10 gastric and 9 colorectal cancer cell lines, 20 early-stage and 21 advanced stage gastric cancer tissues, 20 colon adenomas and 19 colorectal cancer tissues. Real-time RT-PCR assay was used for the determination of MAGEA mRNA levels. Western blot analysis and immunohistochemistry were used for the determination of MAGEA protein levels in cell lines and tissues, respectively. Gastric and colorectal cancer cell lines showed variable mRNA expression levels of MAGEA. The MAGEA protein was detected in 30% of gastric cancer cell lines and in 22.2% of colorectal cancer cell lines. There was a high correlation between mRNA and protein expression. Regarding the clinical samples, MAGEA expression was noted in 25, 28.6 and 31.6%, respectively in early-stage, advanced-stage gastric cancer tissues and colon adenocarcinoma, but was negative in the adjacent normal tissues of the stomach and colon as well as colon adenoma. These results indicate that MAGEA is involved in the carcinogenesis of gastric and colorectal cancer and, therefore, can be used as a diagnostic marker to predict these cancers. PMID- 23673899 TI - Do primary care physicians follow the current recommendations for hypertensive pharmacotherapy? AB - INTRODUCTION: In 2007, the joint recommendations of the European Society of Cardiology and the European Society of Hypertension (ESC/ESH) were announced. OBJECTIVES: The aim of this survey was to evaluate the implementation rate of the new ESC/ESH recommendations by primary care physicians and to assess the effectiveness of antihypertensive therapy. PATIENTS AND METHODS: Data concerning pharmacotherapy, blood pressure (BP) measurements, and compliance with the guidelines were collected in 10,880 hypertensive patients during 3 subsequent follow-up visits. RESULTS: Combined antihypertensive treatment (angiotensin converting enzyme inhibitors with beta-blocker, diuretic, or calcium-channel blocker) was used in 69.2% of the patients at baseline. A combination of beta blocker with diuretic was prescribed in 7.4% of the patients. In 71% of these patients no history of cardiovascular events was reported (myocardial infarction, revascularization, or heart failure). Diuretics were not used in 20.7% of the patients receiving a 3-drug regimen and in 6.7% of those receiving a 4-drug regimen. BP target levels set by individual physicians were frequently lower than those recommended by the guidelines. The percentage of patients who reached the recommended BP target increased during the survey to 25.3%. CONCLUSIONS: A combination of beta-blocker and diuretic is still commonly used in the treatment of hypertension in patients without coronary artery disease and heart failure. Despite the use of combination treatment in about 90% of hypertensive patients and attempts at reaching lower target BP values than those recommended by the guidelines, treatment targets were achieved only in one-fourth of the patients. PMID- 23673901 TI - Structures of hydrogen bond networks formed by a few tens of methanol molecules in the gas phase: size-selective infrared spectroscopy of neutral and protonated methanol clusters. AB - In this work, we report infrared spectra of large neutral and protonated methanol clusters, (MeOH)n and H(+)(MeOH)n, in the CH and OH stretching vibrational region in the size range of n = 10-50. The infrared-ultraviolet double resonance scheme combined with mass spectrometry was employed to achieve moderate size selection of the neutral clusters with the addition of a phenol molecule as a chromophore. Infrared dissociation spectroscopy was performed on the protonated methanol clusters by using a tandem quadrupole mass spectrometer to enable the precise size selection of the clusters. While the neutral clusters showed essentially the same spectra in all the observed size range, the protonated clusters showed remarkable narrowing of the H-bonded OH stretch band with increasing n. In n>=~30, the spectra of the neutral and protonated clusters become almost identical. These spectral features demonstrate that hydrogen bond networks of methanol prefer simple cyclic structures (or "bicyclic" structures in protonated methanol) and branching of the hydrogen bond networks (side-chain formation) is almost negligible. Implications of the spectra of the clusters are also discussed by comparison with spectra of bulk phases. PMID- 23673902 TI - Trace amount Cu (ppm)-catalyzed intramolecular cyclization of 2-(gem dibromovinyl)phenols(thiophenols) to 2-bromobenzofurans(thiophenes). AB - An intramolecular cyclization of 2-(gem-dibromovinyl)phenols(thiophenols) to give 2-bromobenzofurans(thiophenes) in the presence of a trace amount of Cu (0.0064 mol%, 25 ppm) has been developed. The reaction provides the desired products in excellent yields under fluoride-free and mild reaction conditions and with a TON (turnover number) of up to 1.5 * 10(4). PMID- 23673900 TI - The role of preameloblast-conditioned medium in dental pulp regeneration. AB - Pulp regeneration using human dental pulp stem cells (hDPSCs) maintains tooth vitality compared with conventional root canal therapy. Our previous study demonstrated that preameloblast-conditioned medium (PA-CM) from murine apical bud cells induces the odontogenic differentiation of hDPSCs and promoted dentin formation in mouse subcutaneous tissue. The purpose of the present study is to evaluate the effects of PA-CM with human whole pulp cells on pulp regeneration in an empty root canal space. Human pulp cells were seeded in the pulp cavities of 5 mm-thick human tooth segments with or without PA-CM treatment, and then transplanted subcutaneously into immunocompromised mice. In the pulp cell-only group, skeletal muscle with pulp-like tissue was generated in the pulp cavity. A reparative dentin-like structure with entrapped cells lined the existing dentin wall. However, in the PA-CM-treated group, only pulp-like tissue was regenerated without muscle or a reparative dentin-like structure. Moreover, human odontoblast like cells exhibited palisade arrangement around the pulp, and typical odontoblast processes elongated into dentinal tubules. The results suggest that PA-CM can induce pulp regeneration of human pulp cells with physiological structures in an empty root canal space. PMID- 23673903 TI - Monascin improves diabetes and dyslipidemia by regulating PPARgamma and inhibiting lipogenesis in fructose-rich diet-induced C57BL/6 mice. AB - Monascin (MS) is a yellow compound isolated from Monascus-fermented products that has pancreatic protective, anti-inflammatory, anti-oxidative, and hypolipidemic activity. We recently found that MS also acts as a peroxisome proliferator activated receptor-gamma (PPARgamma) agonist, thereby promoting insulin sensitivity in C2C12 cells. However, the attenuation of hyperglycemia by MS treatment in vivo remains uncertain. In the present study, both MS and pioglitazone significantly down-regulated blood glucose and hyperinsulinemia in fructose-rich diet (FRD)-induced C57BL/6 mice (8 weeks). In addition, inhibitions of inflammatory factor production, serum dyslipidemia, and hepatic fatty acid accumulation by MS and pioglitazone were attenuated by GW9662 (PPARgamma antagonist). These results were mediated by MS-suppressing FRD-elevated lipogenic transcription factors, including sterol regulatory element-binding protein-1c (SREBP-1c), carbohydrate response element-binding protein (ChREBP), PPARgamma coactivator-1alpha (PGC-1alpha), and PPARgamma coactivator-1beta (PGC-1beta). Taken together, de novo lipogenesis results in hyperlipidemia and hyperglycemia by fructose induction thereby leading to diabetes development; we found that MS may inhibit lipogenesis in FRD-induced mice. These findings suggest that MS acts as an antidiabetic agent and thus may have therapeutic potential for prevention of diabetes. PMID- 23673904 TI - The cost and public health burden of invasive meningococcal disease outbreaks: a systematic review. AB - BACKGROUND: Invasive meningococcal disease (IMD) is a serious disease with a rapid onset, high mortality rate, and risk of long-term complications. Numerous reports in the literature conclude that IMD outbreaks are associated with substantial costs to society and significant burden on communities due to the cost associated with the prevention of secondary cases. OBJECTIVE: To systematically review the literature on the costs and public health burden associated with IMD outbreaks. METHODS: Studies were primarily identified through searching MEDLINE and EMBASE. Reports were included if they provided cost data related to the containment of an IMD outbreak after 1990 and were written in English, French, or Spanish. Costs were converted to 2010 United States dollars. Outbreaks were categorized by low-income countries (LIC) and high-income countries (HIC) based on gross domestic product per capita. Outbreak containment strategies were classified as small (e.g., targeting members of the school/institution where the outbreak occurred) or large (e.g., targeting everyone in the community). RESULTS: Sixteen articles reporting data on 93 IMD outbreaks fulfilled the eligibility criteria and were included. The majority of outbreaks occurred in HIC. Five studies reported the use of small containment strategies including targeted vaccination and chemoprophylaxis, all occurring in HIC. The average cost per small containment strategy was $299,641 and the average cost per IMD case was $41,857. Eight studies reported large containment strategies involving widespread vaccination targeting a specific age group or community. For HIC, the average cost per large containment strategy was $579,851 and the average cost per IMD case was $55,755. In LIC, the average cost per large containment strategy was $3,407,590 and the average cost per IMD case was $2,222. CONCLUSION: IMD outbreaks were associated with substantial costs. We found that although there were numerous reports on IMD outbreaks, data on containment costs were very limited. More research in this area is warranted. PMID- 23673905 TI - Overview of parametric survival analysis for health-economic applications. AB - Health economic models rely on data from trials to project the risk of events (e.g., death) over time beyond the span of the available data. Parametric survival analysis methods can be applied to identify an appropriate statistical model for the observed data, which can then be extrapolated to derive a complete time-to-event curve. This paper describes the properties of the most commonly used statistical distributions as a basis for these models and describes an objective process of identifying the most suitable parametric distribution in a given dataset. The approach can be applied with both individual-patient data as well as with survival probabilities derived from published Kaplan-Meier curves. Both are illustrated with analyses of overall survival from the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol trial. PMID- 23673906 TI - Isolated conduction within the left His-Purkenje system during sinus rhythm and idiopathic left ventricle tachycardia: findings from mapping the whole conduction system. AB - BACKGROUND: Functionally, left His-Purkenje system (HPS) is insulated from the adjacent myocardium and exhibits isolated conduction during sinus rhythm (SR), but in vivo human study is rare. Meanwhile, whether the isolated conduction also exists during idiopathic left ventricle tachycardia (ILVT) is not clearly defined. The current study aimed to delineate the activation sequence and gross anatomy of left HPS during SR and ILVT. METHODS AND RESULTS: The study involved 25 consecutive patients with ILVT. During SR, left HPS exhibited antegrade activation sequence, and its surrounding myocardium depolarized after HPS in an apical to base direction. During ILVT, the earliest retrograde presystolic potentials were mainly located at the middle portion of left posterior fascicle (0.5+/-0.1 [95% confidence interval, 0.46-0.58] of its full length) with an average of 29.5+/-6.0 mm (19.8-41.5) away from the His position. Left posterior fascicle was depolarized from the earliest retrograde presystolic potentials via 2 opposite wavefronts with significantly shorter activation time than that during SR (15.1+/-2.1 versus 30.0+/-3.2 ms; P<0.001). The left anterior fascicle was depolarized after left posterior fascicle with an antegrade activation sequence and comparable activation time with that during SR (21.9+/-2.9 versus 22.0+/-4.1 ms; P=0.932). The depolarization of ventricle septum also occurred after HPS in an apical to base direction. CONCLUSIONS: During SR, isolated conduction within the HPS is demonstrated by documenting the reverse activation sequence with its surrounding myocardium. During ILVT, the earliest retrograde presystolic potentials were usually recorded at the middle segment of left posterior fascicle, and the isolated conduction within the HPS remained. PMID- 23673907 TI - Implantable cardioverter defibrillators in arrhythmogenic right ventricular dysplasia/cardiomyopathy: patient outcomes, incidence of appropriate and inappropriate interventions, and complications. AB - BACKGROUND: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a cardiomyopathy characterized by ventricular arrhythmias and an abnormal right ventricle. Implantable cardioverter defibrillator (ICD) therapy may prevent sudden cardiac death in patients with ARVD/C. Currently, an overview of outcomes, appropriate and inappropriate interventions, and complications of ICD therapy in ARVD/C is lacking. METHODS AND RESULTS: A literature search was performed to identify studies reporting outcome and complications in patients with ARVD/C who underwent ICD implantation. Of 641 articles screened, 24 studies on 18 cohorts were eligible for inclusion. In case of multiple publications on a cohort, the most recent publication was included in the meta-analysis. There were 610 patients (mean age, 40.4 years; 42% women), who had an ICD for primary or secondary prevention of sudden cardiac death. Risk factors for sudden cardiac death were presyncope (61%), syncope (31%), previous cardiac arrest (14%), ventricular tachycardia (58%), and ventricular fibrillation (6%). Antiarrhythmic medication consisted mostly of beta-blockers (38%), amiodarone (14%), or sotalol (30%). During the 3.8-year follow-up, annualized cardiac mortality rate was 0.9%, annualized noncardiac mortality rate was 0.8%, and annualized heart transplant rate was 0.9%. The annualized appropriate and inappropriate ICD intervention rates were 9.5% and 3.7%, respectively. ICD-related complications consisted of difficult lead placement (18.4%), lead malfunction (9.8%), infection (1.4%), lead displacement (3.3%), and any complication (20.3%). CONCLUSIONS: Cardiac and noncardiac mortality rates after ICD implantation in patients with ARVD/C are low. Appropriate ICD interventions occur at a rate of 9.5%/y. Inappropriate ICD interventions and complications lead to considerable ICD-related morbidity. PMID- 23673908 TI - Curcumin as an add-on to antidepressive treatment: a randomized, double-blind, placebo-controlled, pilot clinical study. AB - OBJECTIVES: Depression is a widespread mental disorder in which nearly half of the affected people have recurrent symptoms. Drug combinations may produce cumulative adverse effects, especially in elderly and physically ill patients. It was demonstrated that curcumin possesses antidepressive activity in various animal models of depression, and a combination of curcumin with some antidepressants potentiates the antidepressive effect of these agents. We sought to evaluate the efficacy of curcumin as an antidepressive agent in a combination with other antidepressants in patients with major depression. METHODS: Forty patients with a first episode of depression participated in a 5-week, double blind, randomized, placebo-controlled study. The subjects were treated with either 500-mg/d curcumin or placebo together with antidepressants (escitalopram or venlafaxine) during August 2010 until June 2011. The outcome measures were Clinical Global Impression-Severity Scale, Hamilton Depression Rating Scale, and Montgomery-Asberg Depression Rating Scale. RESULTS: Analysis of variance showed significant positive changes in both groups from baseline to the end of the study in all scales of measurement. These changes became significant from the first visit after 7 days of treatment. There was no difference between curcumin and placebo, which means negative results. However, the patients in the curcumin group demonstrated a trend to a more rapid relief of depressive symptoms in comparison to those in the placebo group. None of the patients complained of any adverse effect during the study. CONCLUSIONS: Although there is no definitive proof that curcumin can induce an earlier beneficial effect of antidepressive agents, it seems like an extended study is needed to prove it, using higher therapeutic doses of curcumin. PMID- 23673909 TI - Neurological outcome in cerebrotendinous xanthomatosis treated with chenodeoxycholic acid: early versus late diagnosis. AB - OBJECTIVE: To present the long-term neurological outcome of Jewish Israeli patients with cerebrotendinous xanthomatosis (CTX) after several years of chenodeoxycholic acid (CDCA) treatment. METHODS: A cross sectional observational study of all patients with a diagnosis of CTX followed in a referral outpatient clinic during the years 2003-2012. RESULTS: Eighteen patients (10 men) from 11 families were enrolled. Sixteen patients were included in the analysis (2 patients had low compliance for treatment). The mean +/- SD age at last evaluation was 35.0 +/- 9.2 years (range, 16-45 years). After their diagnosis, at age 22.6 +/- 10.8 years, all patients were treated with CDCA. Patients who started treatment after the age of 25 years had worse outcome and were significantly more limited in ambulation (P = 0.004) and more cognitively impaired (P = 0.047). Five patients who started treatment after 25 years of age continued to deteriorate despite CDCA treatment. CONCLUSIONS: Beginning CDCA treatment as early as possible is crucial to preventing neurological damage and deterioration in CTX. After significant neurological pathology is established, the effect of treatment is limited and deterioration may continue. PMID- 23673910 TI - Pharmacokinetic considerations for the use of levodopa in the treatment of Parkinson disease: focus on levodopa/carbidopa/entacapone for treatment of levodopa-associated motor complications. AB - Parkinson disease (PD) is a progressive, disabling, neurodegenerative disorder characterized by both motor and nonmotor symptoms. Monoamine oxidase B inhibitors, dopamine agonists, N-methyl-D-aspartate antagonists and levodopa (LD), with its various formulations and administration modes, mainly improve the motor symptoms in PD, which are thought to be related to decreased dopamine levels in the brain. Of these therapeutic drug options, LD represents the most effective and best tolerated compound when it is administered several times a day. Pharmacokinetic trials of oral LD/dopa decarboxylase inhibitor (DDCI) formulations with and without the catechol-O-methyltransferase inhibitor, entacapone, showed that repeated administration with entacapone causes an increase in both the maximum concentration (Cmax) and time to Cmax (Tmax) of LD. In addition, gastrointestinal motility may also impact plasma LD behavior. These peripheral components of LD metabolism contribute to the onset of motor complications, which are predominantly associated with LD/DDCI owing to its short plasma half-life. The increase in Tmax is related to a slower increase in plasma LD concentrations after repeated LD/DDCI intake, which may also increase the risk of wearing off. An elevation in Cmax after reiterated LD intake increases the risk of peak-dose dyskinesia. Therefore, it may be useful to start with higher doses of LD formulations in the morning and then to titrate with different LD doses during the day according to the individual patient's motor behavior, which is particularly characterized by the onset of motor complications, such as off periods and dyskinesia, in more advanced stages of PD. PMID- 23673911 TI - Tardive dyskinesia caused by tetrabenazine. AB - OBJECTIVE: Although tetrabenazine is widely used as an effective treatment for chorea and other hyperkinetic movement disorders, it has been associated with rare instances of parkinsonism and acute dystonic reactions. There have been no prior reports of tardive dyskinesia with this drug. METHODS: Case report. RESULTS: Generalized choreiform dyskinesia developed after 10 months of conventional-dosage tetrabenazine treatment, persisting for several weeks after the drug was discontinued. CONCLUSIONS: As might be anticipated from its pharmacological profile, tetrabenazine has the potential to cause tardive dyskinesia. Such an occurrence may be difficult to detect in a clinical population already affected with involuntary movements. PMID- 23673912 TI - Lamotrigine abolished aggression in a patient with treatment-resistant posttraumatic stress disorder. AB - Lamotrigine is an antiepileptic drug with broad spectrum of actions, also approved for the treatment of bipolar disorder. Growing number of reports document the antiaggressive effect of lamotrigine in various psychiatric diseases. However, there has been only 1 study in the literature investigating the role of lamotrigine in posttraumatic stress disorder (PTSD), but its antiaggressive aspect was not observed. Although aggression is commonly associated with PTSD, there is paucity of data considering its management. We report a case of a patient with treatment-resistant PTSD, whose aggressive outbursts dominated his clinical picture and which were greatly improved after introducing lamotrigine in therapy. Our case suggests that lamotrigine may be useful in treating aggression and aggression-related symptoms in PTSD. PMID- 23673913 TI - Cetirizine-associated delusions and depression in an 18-year-old woman. AB - INTRODUCTION: Cetirizine is a second-generation H1 histamine receptor antagonist that is commonly used for symptomatic relief of hay fever and other allergies and can be combined with pseudoephedrine hydrochloride, a decongestant. The most common adverse effects include headache, nausea, nasopharyngitis, vomiting, and coughing. OBJECTIVE: To report on an adolescent 18-year-old woman who developed delusional thinking and depression after starting treatment with cetirizine. CASE REPORT: We report on an adolescent 18-year-old woman who developed delusional thinking and depression after starting treatment with cetirizine. Once cetirizine was discontinued, the patient returned to her clinical baseline. CONCLUSIONS: Physicians need to be aware of the potential psychiatric adverse effects associated with cetirizine. PMID- 23673914 TI - Aripiprazole for treating cannabis-induced psychotic symptoms in ultrahigh-risk individuals. AB - Cannabis-induced psychotic symptoms (CIPSs) have both similarities and differences with positive symptoms of schizophrenia, and it remains unclear whether CIPSs result from dopaminergic mechanisms and can be treated with antipsychotics. We report the case of a 22-year-old male patient with ultrahigh risk criteria for psychosis, who reported cannabis addiction and recurrent CIPSs. Aripiprazole 10 mg/d could totally and durably suppress CIPSs in the patient, but had no effect on the smoking level. Treating CIPSs in ultrahigh risk individuals who cannot stop or refuse stopping cannabis might fit a harm-reduction strategy by preventing transition into psychosis. PMID- 23673915 TI - Polydrug abuse by intravenous use of heroin and tropicamide-containing eyedrops. AB - BACKGROUND: Drug abuse is rarely limited to a single substance; polydrug use is the norm rather than the exception. In many cases, the misuse of potentially psychoactive substances can lead to serious intoxications and results in addictive behavior. CASE DESCRIPTION: A 22-year-old heroin-addicted woman presented in our clinic reporting a 2-year history of intravenous injection of an eyedrop solution containing 1% tropicamide, an antimuscarinic agent. She reported injecting tropicamide because it attenuated symptoms and signs of opiate withdrawal and it also has hallucinogenic and euphorigenic effects. Despite the large amounts (up to 1.5 g), the rapidity of injection, and the long-term use, tropicamide was relatively well tolerated, without life-threatening consequences.An outpatient detoxification program was performed without any sign or symptom caused by discontinuing tropicamide. CONCLUSIONS: The present case claims a role for pharmacological interactions, in addition to rewarding effects, in influencing drug association in polyabuse pattern. Moreover, this case underlines the need for physicians to be aware of the potential emergence of tropicamide as a drug of misuse, to prevent further harm. PMID- 23673916 TI - Scopolamine as an antidepressant. PMID- 23673917 TI - Pure glycogen-rich clear cell adenocarcinoma of the stomach. PMID- 23673918 TI - Cuprous hydroxide in a solid form: does it exist? AB - Experimental studies have been performed to obtain the unknown cuprous hydroxide compound, which has recently been predicted theoretically (P. A. Korzhavyi et. al., Proc. Natl. Acad. Sci. U. S. A., 2012, 109, 686-689) to be metastable in a solid form. The reduction of Cu(2+) with ferrous ethylenediamine tetraacetate (EDTA) results in the formation of a yellow powder precipitate whose composition corresponds to CuOH * H2O as probed by Fourier Transform Infrared Spectroscopy (FTIR) and cryogenic X-ray Photoelectron Spectroscopy (XPS). A similar compound has been found on the surface of Cu-CuH powder stored in water, as detected by XPS. The reduction of Cu(2+) to Cu(+) with free radicals in aqueous solutions results in a Cu2O precipitate as the final product, while the formation of the yellow cuprous hydroxide colloids may be an intermediate step. Our studies reveal that cuprous hydroxide does exist in a solid form and most likely has a hydrated form, CuOH * H2O. PMID- 23673919 TI - Cadmium in blood of Tunisian men and risk of bladder cancer: interactions with arsenic exposure and smoking. AB - Prior investigations identified an association between low-level blood arsenic (As) and bladder cancer risk among Tunisian men but questions remain regarding confounding by cadmium (Cd), a well-established bladder carcinogen. A case control study of Tunisian men was re-examined to assess the levels of cadmium in blood and reparse the association between the simultaneous exposure to these metals and bladder cancer risk. Levels of blood Cd were significantly twice higher among cases than in controls (P<0.05) and were positively correlated with smoking and age. Additionally, analysis of metal levels among non-smokers according to the region of residence showed very high blood Cd and As levels for the coastal regions of Sfax and central Tunisia. After controlling for potential confounders, for low blood As levels (<0.67 MUg/L), the OR for blood Cd was 4.10 (95 % CI 1.64-10.81), while for higher levels (>0.67 MUg/L), it was reduced to 2.10 (CI, 1.06-4.17). Adjustment for Cd exposure did not alter the risk associated to As exposure. This study is the first to report the relationship between Cd exposure and risk of bladder cancer occurrence in interaction with smoking and As exposure. Smoking is shown to be the main exposure source to Cd in the Tunisian population but also environmental pollution seems to be responsible of Cd exposure among non-smokers. Exposure assessment studies encompassing a wider population are needed. PMID- 23673920 TI - Effects of perchlorate on growth of four wetland plants and its accumulation in plant tissues. AB - Perchlorate contamination in water is of concern because of uncertainties about toxicity and health effects, impact on ecosystems, and possible indirect exposure pathways to humans. Therefore, it is very important to investigate the ecotoxicology of perchlorate and to screen plant species for phytoremediation. Effects of perchlorate (20, 200, and 500 mg/L) on the growth of four wetland plants (Eichhornia crassipes, Acorus calamus L., Thalia dealbata, and Canna indica) as well as its accumulation in different plant tissues were investigated through water culture experiments. Twenty milligrams per liter of perchlorate had no significant effects on height, root length, aboveground part weight, root weight, and oxidizing power of roots of four plants, except A. calamus, and increasing concentrations of perchlorate showed that out of the four wetland plants, only A. calamus had a significant (p<0.05) dose-dependent decrease in these parameters. When treated with 500 mg/L perchlorate, these parameters and chlorophyll content in the leaf of plants showed significant decline contrasted to control groups, except the root length of E. crassipes and C. indica. The order of inhibition rates of perchlorate on root length, aboveground part weight and root weight, and oxidizing power of roots was: A. calamus > C. indica > T. dealbata > E. crassipes and on chlorophyll content in the leaf it was: A. calamus > T. dealbata > C. indica > E. crassipes. The higher the concentration of perchlorate used, the higher the amount of perchlorate accumulation in plants. Perchlorate accumulation in aboveground tissues was much higher than that in underground tissues and leaf was the main tissue for perchlorate accumulation. The order of perchlorate accumulation content and the bioconcentration factor in leaf of four plants was: E. crassipes > C. indica > T. dealbata > A. calamus. Therefore, E. crassipes might be an ideal plant with high tolerance ability and accumulation ability for constructing wetland to remediate high levels of perchlorate polluted water. PMID- 23673921 TI - Xenobiotics removal by adsorption in the context of tertiary treatment: a mini review. AB - Many xenobiotics, including several pharmaceuticals and pesticides, are poorly treated in domestic wastewater treatment plants. Adsorption processes, such as with activated carbons, could be a solution to curb their discharge into the aquatic environment. As adsorbent-like activated carbon is known to be expensive, identifying promising alternative adsorbent materials is a key challenge for efficient yet affordable xenobiotic removal from wastewaters. As part of the effort to address this challenge, we surveyed the literature on pharmaceutical and pesticide xenobiotics and built a database compiling data from 38 scientific publications covering 65 xenobiotics and 58 materials. Special focus was given to the relevance and comparability of the data to the characteristics of the adsorbent materials used and to the operating conditions of the batch tests inventoried. This paper gives an in-depth overview of the adsorption capacities of various adsorbents. The little data on alternative adsorbent materials, especially for the adsorption of pharmaceuticals, makes it difficult to single out any one activated carbon alternative capable of adsorbing pesticides and pharmaceuticals at the tertiary stage of treatment. There is a pressing need for further lab-scale experiments to investigate the tertiary treatment of discharged effluents. We conclude with recommendations on how future data should best be used and interpreted. PMID- 23673923 TI - Wastewater treatment to enhance the economic viability of microalgae culture. AB - Microalgae culture is still not economically viable and it presents some negative environmental impacts, concerning water, nutrient and energy requirements. In this context, this study aims to review the recent advances on microalgal cultures in wastewaters to enhance their economic viability. We focused on three different culture concepts: (1) suspended cell systems, (2) cell immobilization, and (3) microalgae consortia. Cultures with suspended cells are the most studied. The nutrient removal efficiencies are usually high for wastewaters of different sources. However, biomass harvesting is difficult and a costly process due to the small cell size and lower culture density. On the other hand, the cell immobilization systems showed to be the solution for this problem, having as main limitation the nutrient diffusion from bulk to cells, which results in a reduced nutrient removal efficiency. The consortium between microalgae and bacteria enhances the growth of both microorganisms. This culture concept showed to be a promising technology to improve wastewater treatment, regarding not only nutrient removal but also biomass harvesting by bioflocculation. The aggregation mechanism must be studied in depth to find the process parameters that would lead to an effective and cheap harvesting process. PMID- 23673922 TI - Sediment quality guidelines: challenges and opportunities for improving sediment management. AB - During the International Conference on Deriving Environmental Quality Standards for the Protection of Aquatic Ecosystems held in Hong Kong in December 2011, an expert group, comprising scientists, government officials, and consultants from four continents, was formed to discuss the important scientific and regulatory challenges with developing sediment quality guidelines (SQGs). We identified the problems associated with SQG development and made a series of recommendations to ensure that the methods being applied were scientifically defensible and internationally applicable. This document summarizes the key findings from the expert group. To enable evaluation of current SQG derivation and application systems, a feedback mechanism is required to communicate confounding factors and effects in differing environments, while field validation is necessary to gauge the effectiveness of SQG values in sediment quality assessments. International collaboration is instrumental to knowledge exchange and method advancement, as well as promotion of 'best practices'. Since the paucity of sediment toxicity data poses the largest obstacle to improving current SQGs and deriving new SQGs, a standardized international database should be established as an information resource for sediment toxicity testing and monitoring data. We also identify several areas of scientific research that are needed to improve sediment quality assessment, including determining the importance of dietary exposure in sediment toxicity, mixture toxicity studies, toxicity screening of emerging chemicals, how climate change influence sediments and its biota, and possible use of new toxicity study approaches such as high throughput omic-based toxicity screenings. PMID- 23673924 TI - Females as intraguild predators of males in cross-pairing experiments with phytoseiid mites. AB - Studies on intraguild interactions between phytoseiid species have shown that intraguild predation occurs and is most commonly manifested as adult females of one species feeding on juveniles of another. Whether such intraguild interactions can also occur between adult females of one species and adult males of another, is not known. Herein, we report on intraguild interactions between adults of the two sexes in cross-pairing experiments involving three related phytoseiid species (Neoseiulus paspalivorus, N. baraki and N. neobaraki) that are potential candidates for controlling the coconut mite Aceria guerreronis, a serious pest of coconut palms in tropical countries. For comparative reasons, the experiments were repeated with larvae instead of males, and with only males or only females of two different species together. In the presence of an ample supply of prey, females of N. neobaraki never fed on individuals of their own species, yet appeared to be very aggressive against males, as well as larvae of the other two phytoseiid species. They also fed on females of N. paspalivorus, but rarely on females of N. baraki. Males of N. neobaraki did not suffer mortality when together with females of either of the two other phytoseiid species. Males of N. baraki did not suffer predation from females of N. paspalivorus, but males of N. paspalivorus suffered some mortality (15 %) from N. baraki females. Larvae of each of the three species were vulnerable to intraguild predation by heterospecific adult females, except for N. neobaraki larvae when together with N. baraki females. The absence or presence of intraguild predation is largely explained by the size ratios of the individuals that were put together: large individuals feed on smaller ones, but never the reverse. For each sex, size declines in the following order: N. neobaraki > N. baraki > N. paspalivorus. Moreover, for each species, females are larger than males and males are larger than larvae. Strikingly, however, females did not kill males and larvae of their own species. We propose that niche competition between related phytoseiid species is not only determined by intraguild predation on heterospecific larvae, but also by imposing great mortality on males from the intraguild prey because phytoseiid females being pseudo-arrhenotokous require insemination to produce offspring of both sexes. PMID- 23673926 TI - Epigenetic silencing of Bcl-2, CEBPA and p14(ARF) by the AML1-ETO oncoprotein contributing to growth arrest and differentiation block in the U937 cell line. AB - The AML1-ETO fusion transcription factor generated by the t(8;21) translocation is considered to deregulate the expression of genes that are crucial for normal differentiation and proliferation of hematopoietic progenitors, resulting in acute myelogenous leukemia by recruiting co-repressor complexes to DNA. To investigate the role of AML1-ETO in leukemogenesis, we transfected the cloned AML1-ETO cDNA and expressed the AML1-ETO protein in U937 myelomonocytic leukemia cells. By focusing on the anti-apoptotic gene Bcl-2, the key regulator gene of granulocytic differentiation CCAAT/enhancer-binding protein alpha (CEBPA) and the tumor suppressor gene p14(ARF), we found that both AML1-ETO-expressing cell lines and t(8;21) leukemia samples displayed low levels of these three genes. Chromatin immunoprecipitation assays demonstrated that Bcl-2, CEBPA and p14(ARF) were direct transcriptional targets of AML1-ETO. The universal binding of AML1-ETO to genomic DNA resulted in recruitment of methyl-CpG binding protein 2 (MeCP2), reduction of histone H3 or H4 acetylation and increased trimethylation of histone H3 lysine 9 as well as lysine 27 indicating that AML1-ETO induced heterochromatic silencing of Bcl-2, CEBPA and p14(ARF). These results suggested that the aberrant transcription factor AML1-ETO epigenetically silenced the function of the Bcl-2, CEBPA and p14(ARF) genes by inducing repressed chromatin configurations at their promoters through histone modifications. PMID- 23673925 TI - Uncomfortable issues in radiation protection posed by low-dose radiobiology. AB - This paper aims to stimulate discussion about the relevance for radiation protection of recent findings in low-dose radiobiology. Issues are raised which suggest that low-dose effects are much more complex than has been previously assumed. These include genomic instability, bystander effects, multiple stressor exposures and chronic exposures. To date, these have been accepted as being relevant issues, but there is no clear way to integrate knowledge about these effects into the existing radiation protection framework. A further issue which might actually lead to some fruitful approaches for human radiation protection is the need to develop a new framework for protecting non-human biota. The brainstorming that is being applied to develop effective and practical ways to protect ecosystems widens the debate from the narrow focus of human protection which is currently about protecting humans from radiation-induced cancers. PMID- 23673927 TI - A robust method to heterogenise and recycle group 9 catalysts. AB - This paper provides a viable, reproducible and robust method for immobilising hydroxyl tethered iridium-rhodium complexes. The materials have been shown to be both effective and recyclable in the process of catalytic transfer hydrogenation with minimal metal leaching. PMID- 23673928 TI - Measuring environmental change in forest ecosystems by repeated soil sampling: a north american perspective. AB - Environmental change is monitored in North America through repeated measurements of weather, stream and river flow, air and water quality, and most recently, soil properties. Some skepticism remains, however, about whether repeated soil sampling can effectively distinguish between temporal and spatial variability, and efforts to document soil change in forest ecosystems through repeated measurements are largely nascent and uncoordinated. In eastern North America, repeated soil sampling has begun to provide valuable information on environmental problems such as air pollution. This review synthesizes the current state of the science to further the development and use of soil resampling as an integral method for recording and understanding environmental change in forested settings. The origins of soil resampling reach back to the 19th century in England and Russia. The concepts and methodologies involved in forest soil resampling are reviewed and evaluated through a discussion of how temporal and spatial variability can be addressed with a variety of sampling approaches. Key resampling studies demonstrate the type of results that can be obtained through differing approaches. Ongoing, large-scale issues such as recovery from acidification, long-term N deposition, C sequestration, effects of climate change, impacts from invasive species, and the increasing intensification of soil management all warrant the use of soil resampling as an essential tool for environmental monitoring and assessment. Furthermore, with better awareness of the value of soil resampling, studies can be designed with a long-term perspective so that information can be efficiently obtained well into the future to address problems that have not yet surfaced. PMID- 23673929 TI - Modeling approaches of competitive sorption and transport of trace metals and metalloids in soils: a review. AB - Competition among various heavy metal species for available adsorption sites on soil matrix surfaces can enhance the mobility of contaminants in the soil environment. Accurate predictions of the fate and behavior of heavy metals in soils and geologic media requires the understanding of the underlying competitive sorption and transport processes. In this review, we present equilibrium and kinetic models for competitive heavy metal sorption and transport in soils. Several examples are summarized to illustrate the impact of competing ions on the reactivities and mobility of heavy metals in the soil-water environment. We demonstrate that equilibrium Freundlich approaches can be extended to account for competitive sorption of cations and anions with the incorporation of competition coefficients associated with each reaction. Furthermore, retention models of the multiple-reaction type including the two-site nonlinear equilibrium-kinetic models and the concurrent- and consecutive-multireaction models were modified to describe commonly observed time-dependent behaviors of heavy metals in soils. We also show that equilibrium Langmuir and kinetic second-order models can be extended to simulate the competitive sorption and transport in soils, although the use of such models is limited due to their simplifying assumptions. A major drawback of the empirically based Freundlich and Langmuir approaches is that their associated parameters are specific for each soil. Alternatively, geochemical models that are based on ion-exchange and surface-complexation concepts are capable of quantifying the competitive behavior of several chemical species under a wide range of environmental conditions. Such geochemical models, however, are incapable of describing the time-dependent sorption behavior of heavy metal ions in competitive systems. Further research is needed to develop a general-purpose model based on physical and chemical mechanisms governing competitive sorption in soils. PMID- 23673930 TI - Questioning the accuracy of greenhouse gas accounting from agricultural waste: a case study. AB - The New Zealand Greenhouse Gas Inventory (the NZ Inventory) uses country-specific data to quantify CH emissions from anaerobic ponds treating dairy farm effluent (315 Gg CO equivalent [CO-e] in 2009). In this study, we used literature data to: (i) evaluate the accuracy of the NZ Inventory's parameters used to quantify these CH emissions; and (ii) determine whether the NZ Inventory's scope is capturing the full spectrum of sources with bio-CH potential entering anaerobic ponds. The research indicated that the current NZ Inventory methodology is underestimating CH emissions from anaerobic ponds across New Zealand by 264 to 603 Gg CO-e annually. Moreover, the NZ Inventory is currently not accounting for (i) manure from supplementary feed pads and stand-off pads (annual CH emissions = 207-330 Gg CO-e); (ii) waste milk (153-280 Gg CO-e); and (iii) supplementary feed waste (90 216 Gg CO-e). Annual CH emissions from anaerobic ponds on dairy farms across New Zealand are thus more likely to be 1029 to 1744 Gg CO-e, indicating that the NZ Inventory is reporting as little as 18% of actual CH emissions produced by this sector. These additional wastes are not accounted for in the methodology prescribed by the Intergovernmental Panel on Climate Change for estimating CH emissions from dairy manure. Consequently, other significant dairying nations will also probably be underestimating their waste CH emissions. Our research highlights that, if governments attempt to include country-specific emission factors in their greenhouse gas inventories, these factors must be based on an assessment of the full spectrum of sources contributing to greenhouse gas emissions within any given sector. PMID- 23673931 TI - Protecting groundwater resources at biosolids recycling sites. AB - In developing the national biosolids recycling rule (Title 40 of the Code of Federal Regulation Part 503 or Part 503), the USEPA conducted deterministic risk assessments whose results indicated that the probability of groundwater impairment associated with biosolids recycling was insignificant. Unfortunately, the computational capabilities available for performing risk assessments of pollutant fate and transport at that time were limited. Using recent advances in USEPA risk assessment methodology, the present study evaluates whether the current national biosolids pollutant limits remain protective of groundwater quality. To take advantage of new risk assessment approaches, a computer-based groundwater risk characterization screening tool (RCST) was developed using USEPA's Multimedia, Multi-pathway, Multi-receptor Exposure and Risk Assessment program. The RCST, which generates a noncarcinogenic human health risk estimate (i.e., hazard quotient [HQ] value), has the ability to conduct screening-level risk characterizations. The regulated heavy metals modeled in this study were As, Cd, Ni, Se, and Zn. Results from RCST application to biosolids recycling sites located in Yakima County, Washington, indicated that biosolids could be recycled at rates as high as 90 Mg ha, with no negative human health effects associated with groundwater consumption. Only under unrealistically high biosolids land application rates were public health risks characterized as significant (HQ >= 1.0). For example, by increasing the biosolids application rate and pollutant concentrations to 900 Mg ha and 10 times the regulatory limit, respectively, the HQ values varied from 1.4 (Zn) to 324.0 (Se). Since promulgation of Part 503, no verifiable cases of groundwater contamination by regulated biosolids pollutants have been reported. PMID- 23673932 TI - Arrhenius equation for modeling feedyard ammonia emissions using temperature and diet crude protein. AB - Temperature controls many processes of NH volatilization. For example, urea hydrolysis is an enzymatically catalyzed reaction described by the Arrhenius equation. Diet crude protein (CP) controls NH emission by affecting N excretion. Our objectives were to use the Arrhenius equation to model NH emissions from beef cattle () feedyards and test predictions against observed emissions. Per capita NH emission rate (PCER), air temperature (), and CP were measured for 2 yr at two Texas Panhandle feedyards. Data were fitted to analogs of the Arrhenius equation: PCER = () and PCER = (,CP). The models were applied at a third feedyard to predict NH emissions and compare predicted to measured emissions. Predicted mean NH emissions were within -9 and 2% of observed emissions for the () and (T,CP) models, respectively. Annual emission factors calculated from models underestimated annual NH emission by 11% [() model] or overestimated emission by 8% [(,CP) model]. When from a regional weather station and three classes of CP drove the models, the () model overpredicted annual NH emission of the low CP class by 14% and underpredicted emissions of the optimum and high CP classes by 1 and 39%, respectively. The (,CP) model underpredicted NH emissions by 15, 4, and 23% for low, optimum, and high CP classes, respectively. Ammonia emission was successfully modeled using only, but including CP improved predictions. The empirical () and (,CP) models can successfully model NH emissions in the Texas Panhandle. Researchers are encouraged to test the models in other regions where high-quality NH emissions data are available. PMID- 23673933 TI - Biochar diminishes nitrous oxide and nitrate leaching from diverse nutrient sources. AB - Manure generated by intensive livestock operations poses potential ecological risk in the form of water pollution and greenhouse gas emission. To assess the impact of biochar on coarse-textured soils under contrasting nutrient management regimes, a 55-d incubation was conducted using unplanted soil columns amended with manure, slurry, or fertilizer (plus unamended control), each with or without biochar applied at 2% soil mass (dry weight basis). Under repeated leaching, the cumulative NO emission from the columns was significantly affected by the presence of biochar ( < 0.0001), although these data were not normally distributed. Results indicated that the biochar-amended soils emitted significantly less NO than their unamended counterparts, with the exception of manure-amended soils. The presence of biochar increased the pH of column leachate by 0.08 to 1.70 and significantly decreased the cumulative amount of mineral N leached from the soil. The presence of biochar significantly increased the amount of PO-P in soil leachate, but there was no significant difference between the means for any of the amendments used on their own relative to their biochar amended counterparts. The data demonstrate that biochar could potentially aid in the mitigation of NO emissions from certain soils and in N loss in leachate from soil amended with slurry, manure, or fertilizer used in livestock systems. PMID- 23673934 TI - Centimeter-scale spatial variability in 2-methyl-4-chlorophenoxyacetic Acid mineralization increases with depth in agricultural soil. AB - Mineralization of organic chemicals in soil is typically studied using large homogenized samples, but little is known about the small-scale spatial distribution of mineralization potential. We studied centimeter-scale spatial distribution of 2-methyl-4-chlorophenoxyacetic acid (MCPA) mineralization activity at different depths (8-115 cm) in a Danish agricultural soil profile using a 96-well microplate C-radiorespirometric method for small-volume samples. The heterotrophic microbial population and specific MCPA degraders decreased 10- to 100-fold from the plow layer to a depth of 115 cm. MCPA was mineralized in all samples in the plow layer, but only about 60% in the transition zone immediately below the plow layer showed mineralization; at greater depth even fewer samples showed mineralization. A patchy spatial distribution of mineralization activity was observed from right below the plow layer and in the subsoil, with a few clearly defined active zones surrounded by areas devoid of mineralization activity. Due to the patchy distribution of mineralization activity at the centimeter scale just beneath the plow layer, MCPA and presumably other weakly sorbing pesticides might be at risk of leaching to the groundwater if transported from the plow layer into the subsoil. PMID- 23673935 TI - Survival and growth of chestnut backcross seeds and seedlings on surface mines. AB - Some scientists consider the loss of the American chestnut from forests in the eastern United States as one of the greatest forest ecological disasters in the 20th century. The American Chestnut Foundation has been attempting to restore chestnut by backcrossing blight-resistant Chinese chestnut to American chestnut and selecting those strains with blight resistance. Third-generation backcross seeds and seedlings have been produced and planted by researchers. Surface-mined lands provide a land base where these backcross chestnut seedlings may be introduced back into forests. In 2008, seeds of two parent species of chestnut (100% American and 100% Chinese) and three breeding generations (BF, BF, and BF backcrosses) were planted into loosely graded mine soils with and without tree shelters. First-year establishment from seeds averaged 81%. After the fourth year, survival without shelters declined for all chestnut stock types except for Chinese (80%): American 40%, BF 70%, BF 40%, and BF 55%. Survival with shelters was only slightly better after the fourth year (average, 60% with shelters and 57% without). Height growth was not different among stock types, and average height after the fourth year was 43 cm without shelters and 56 cm with shelters. In 2009, seeds and seedlings of the same chestnut stock types were planted into brown (pH 4.5) or gray (pH 6.6) mine soils. Only six out of 250 seeds germinated, which was very poor considering 81% average seed germination in 2008. Transplanted chestnut seedling survival was much better. After the third year, seedling survival was 85% in brown and 80% in gray soil, but significant differences were found with stock types. Survival was significantly higher with American, Chinese, and BF stock types (75%) than with BF and BF (60%). Height after the third season averaged 90 cm on brown and 62 cm on gray soil. Chestnut backcrosses displayed no hybrid vigor and were not better in survival and growth than the parent stock. All five stock types grew on mine soils in West Virginia, and we found surface mines to be promising sites for introducing blight-resistant chestnut backcross trees into the Appalachian forest. PMID- 23673936 TI - Switchgrass yield on reclaimed surface mines for bioenergy production. AB - The high cost of transportation fuels and the environmental risks associated with acquiring and using nonrenewable energy sources have created a demand for developing renewable bioenergy crops. Switchgrass ( L.), a warm-season perennial grass, is a promising feedstock due to its high biomass production under a wide range of growing conditions and its satisfactory forage quality and chemical composition. West Virginia contains vast expanses of reclaimed surface mine lands that could be used to produce switchgrass as a bioenergy feedstock. This study determined dry matter yields of three switchgrass varieties (Cave-In-Rock, Shawnee, and Carthage) during the second to fourth years of production. Two research sites were established on reclaimed surface mines in southern West Virginia: Hobet and Hampshire. The Hobet site was prepared using crushed, unweathered sandstone as the soil material, and yields were significantly lower at 803 kg ha averaged across varieties and years than annual yields at Hampshire. The highest yield at Hobet, with Shawnee in the third year, was 1964 kg ha. The Hamphire site, which was reclaimed in the late 1990s using topsoil and treated municipal sludge, averaged 5760 kg ha of switchgrass across varieties and years. The highest yield, obtained with Cave-in-Rock during the third year, was 9222 kg ha. Switchgrass yields on agricultural lands in this region averaged 12,000 kg ha. Although average switchgrass yields at Hampshire were about 50% lower than agricultural lands, they were greater than a target yield of 5000 kg ha, a threshold for economically feasible production. Yields during the fourth year from a two-harvest per year system were not significantly different from a single, end-of-year harvest at both sites. Reclaimed lands show promise for growing bioenergy crops such as switchgrass on areas where topsoil materials are replaced and amended like that at the Hampshire site. PMID- 23673938 TI - Evaluating the occurrence of host-specific , general fecal indicators, and bacterial pathogens in a mixed-use watershed. AB - Fecal contamination of water is very common, and, in the United States, prevention is complicated by the colossal span of waterways (>3.5 million miles), heterogeneous sources of pollution, and competing interests in water monitoring. The focus of this study was the Upper Sugar Creek Watershed, a mixed-use watershed with many headwater streams and one of the most contaminated waterways in Ohio. Quantitative polymerase chain reaction (qPCR) and host-specific PCR for were evaluated for the potential to discern sources of fecal contamination. Pathogen-specific qPCR and culturable by most probable number (MPN) were compared at 21 established water quality monitoring sites in the watershed headwaters. Lower numbers of ruminant-specific markers were detected in the base flow water samples compared with the human-specific marker, suggesting the presence of hotspots of human fecal contamination. qPCR and MPN showed significant correlation ( = 0.57; < 0.001). Correlation between general fecal indicator and pathogen concentrations was weak or nonexistent. Coexistence of and human specific was common ( = 0.015). qPCR may have a greater potential for predicting fecal contamination due to its sensitivity, rapid analysis, and availability of host-specific assays. However, the lack of a strong correlation between pathogens and general fecal indicators suggests that assessment of health risk associated with fecal contamination will require a complement of approaches. PMID- 23673937 TI - Microbial-based inoculants impact nitrous oxide emissions from an incubated soil medium containing urea fertilizers. AB - There is currently much interest in developing crop management practices that will decrease NO emissions from agricultural soils. Many different approaches are being investigated, but to date, no studies have been published on how microbial inoculants affect NO emissions. This study was conducted to test the hypothesis that microbial-based inoculants known to promote root growth and nutrient uptake can reduce NO emissions in the presence of N fertilizers under controlled conditions. Carbon dioxide and CH fluxes were also measured to evaluate microbial respiration and determine the aerobic and anaerobic conditions of the incubated soil. The microbial-based treatments investigated were SoilBuilder (SB), a metabolite extract of SoilBuilder (SBF), and a mixture of four strains of plant growth-promoting spp. Experiments included two different N fertilizer treatments, urea and urea-NHNO 32% N (UAN), and an unfertilized control. Emissions of NO and CO were determined from soil incubations and analyzed with gas chromatography. After 29 d of incubation, cumulative NO emissions were reduced 80% by SB and 44% by SBF in soils fertilized with UAN. Treatment with spp. significantly reduced NO production on Days 1 and 2 of the incubation in soils fertilized with UAN. In the unfertilized treatment, cumulative emissions of NO were significantly reduced 92% by SBF. Microbial-based treatments did not reduce NO emissions associated with urea application. Microbial-based treatments increased CO emissions from soils fertilized with UAN, suggesting a possible increase in microbial activity. Overall, the results demonstrated that microbial-based inoculants can reduce NO emissions associated with N fertilizer application, and this response varies with the type of microbial-based inoculant and fertilizer. PMID- 23673939 TI - Agricultural Policy Environmental eXtender Simulation of Three Adjacent Row-Crop Watersheds in the Claypan Region. AB - The Agricultural Policy Environmental Extender (APEX) model is used to evaluate best management practices on pollutant loading in whole farms or small watersheds. The objectives of this study were to conduct a sensitivity analysis to determine the effect of model parameters on APEX output and use the parameterized, calibrated, and validated model to evaluate long-term benefits of grass waterways. The APEX model was used to model three (East, Center, and West) adjacent field-size watersheds with claypan soils under a no-till corn ( L.)/soybean [ (L.) Merr.] rotation. Twenty-seven parameters were sensitive for crop yield, runoff, sediment, nitrogen (dissolved and total), and phosphorous (dissolved and total) simulations. The model was calibrated using measured event based data from the Center watershed from 1993 to 1997 and validated with data from the West and East watersheds. Simulated crop yields were within +/-13% of the measured yield. The model performance for event-based runoff was excellent, with calibration and validation > 0.9 and Nash-Sutcliffe coefficients (NSC) > 0.8, respectively. Sediment and total nitrogen calibration results were satisfactory for larger rainfall events (>50 mm), with > 0.5 and NSC > 0.4, but validation results remained poor, with NSC between 0.18 and 0.3. Total phosphorous was well calibrated and validated, with > 0.8 and NSC > 0.7, respectively. The presence of grass waterways reduced annual total phosphorus loadings by 13 to 25%. The replicated study indicates that APEX provides a convenient and efficient tool to evaluate long-term benefits of conservation practices. PMID- 23673940 TI - Effects of Road Salt on Connecticut's Groundwater: A Statewide Centennial Perspective. AB - This study examined the extent to which development and road salting has affected Connecticut's groundwater. We gathered water quality data from different time periods between 1894 and the present and analyzed the data using maps generated with ESRI ArcGIS. Historical reports illustrate a statewide baseline trend of decreasing chloride concentration northward across the State (average, 2 ppm). Since then, statewide chloride concentrations in ground water have increased by more than an order of magnitude on average. Analysis indicates spatial correlation between chloride impacts and major roadways. Furthermore, increases in statewide chloride concentration parallel increases in road salt application. Projected trends suggest that statewide baseline concentrations will increase by an amount equal to five times background levels between the present and the year 2030. The analytical process outlined herein can be readily applied to any region to investigate salt impacts on large spatial and temporal scales. PMID- 23673941 TI - Orthophosphate Leaching in St. Augustinegrass and Zoysiagrass Grown in Sandy Soil under Field Conditions. AB - Phosphorus (P) is required to maintain healthy, high-quality, warm-season turf. However, excessive P applications to soils with poor P retention capabilities may lead to leaching losses to groundwater. This field study was conducted to determine the maximum P fertilizer application rate to (Walt.) [Kuntze] 'Floratam' St. Augustinegrass (St. Augustinegrass) and 'Empire' zoysiagrass (zoysiagrass) below which P leaching is minimized. Five P levels ranging from 0 to 5.0 g P m yr were surface applied as triple superphosphate. Turf was established on an uncoated, low-P sand with negligible P retention capacity. Leaf and root growth, tissue P concentration, soil P concentration, soil P saturation, leachate volume, and orthophosphate (P) concentration in leachates were measured. Mehlich 1-extractable soil P (M1-P) and soil P saturation ratio (PSR) increased with time as the P rate increased. Lower M1-P and PSR values were measured with St. Augustinegrass, which absorbed more P than did zoysiagrass. The root system of St. Augustinegrass was larger and deeper compared with zoysiagrass, promoting greater P uptake and less P leaching. If tissue analysis indicates that P fertilization is required and the soil has the capacity to retain additional P, application of 0.8 g P m yr to zoysiagrass and 1.07 g P m yr to St. Augustinegrass is appropriate and does not result in increased P leaching. PMID- 23673942 TI - Accumulation of chromium in pak choi ( L.) grown on representative chinese soils. AB - Anthropogenic chromium (Cr) pollution in soils poses a great threat to human health through the food chain. It is imperative to understand Cr accumulation properties in common vegetables because the proportion of vegetables consumed has increased with the improvement of living standards. This study investigated Cr accumulation in pak choi ( L.) grown on six representative agricultural soils in China. Chromium concentration in the edible parts of pak choi generally increased with soil Cr concentrations following the order: Ustic Cambosols > Periudic Argosols > Mollisols > Calcaric Regosols > Stagnic Anthrosols > Udic Ferrisols. Simple correlation analysis indicated that Cr concentration in pak choi was significantly correlated with the total Cr, Mehlich-3-extractable Cr, and Cr(VI). Stepwise multiple regression analysis also demonstrated that the phytoavailability of Cr was strongly correlated with the extractable fraction by Mehlich-3, total Cr concentration, soil organic matter, and Fe(II). Critical Cr concentrations in these six soils were evaluated for pak choi based on the maximum safe level for daily intake of Cr. Total soil Cr can be used as Cr thresholds for potential dietary toxicity in pak choi. Mehlich-3-extractable Cr is most suitable to be used as Cr thresholds for Periudic Argosols, Udic Ferrisols, Mollisols, and Ustic Cambosols, with values of 20.7, 15.8, 21.2, and 20.4 mg kg, respectively, whereas Cr(VI) is most suitable for Calcaric Regosols and Stagnic Anthrosols, with values of 26.5 and 28.0 mg kg, respectively. PMID- 23673943 TI - Hexavalent chromium reduction in solution and in chromite ore processing residue enriched soil by tartaric Acid with isopropyl alcohol and divalent manganese as co-reductants. AB - Chromite ore processing residue (COPR), the solid waste product from the high temperature alkaline processing of ferrochromite (FeO.CrO), contains Cr(VI) in soluble and insoluble compounds formed in the roasting process. This research investigated tartaric acid in combination with Mn and isopropyl alcohol (IPOH ) as co-reductants for reagent- and COPR-derived Cr(VI). The reduction of Cr(VI) by tartaric acid alone at pH 5.0 or greater was negligible; however, in the presence of Mn or IPOH, reduction occurred in hours. Isopropyl alcohol enhanced Cr(VI) reduction, probably via formation of a termolecular complex with the alcohol, tartaric acid, and Cr(VI). In aqueous solutions of reagent-derived Cr(VI) at pH 4, 12 mmol L tartaric acid with 1.0 mmol L Mn or 1.0 mmol L Mn and 0.29 mol L (2% v/v) IPOH reduced 1.0 mmol L Cr(VI) in 48 h. The same treatments at pH 5.5 reduced 0.60 and 0.58 mmol L Cr(VI) (60%) in 96 h, respectively. A minimum half life of 10.2 h was calculated from first-order rate constants obtained from Mn and IPOH-Mn co-reductant treatments with tartaric acid at pH 4. The most COPR derived Cr(VI) reduced in suspension was by IPOH and Mn at high acidity (pH 5.8), which reduced 0.52 mmol L (52%) of the COPR-derived soluble Cr(VI) at 96 h. The enhanced reduction of soluble Cr(VI) by tartaric acid by the addition of Mn proceeds within a complex formed by an esterification reaction between tartaric acid and Cr(VI) with Mn bound to tartaric acid. The combined treatment of tartaric acid, IPOH, Mn, and a strong acid to lower the pH of COPR-enriched soils would be effective in field applications of this chemistry. By creating a slurry of the field soil with these amendments, mass transfer limitations would be overcome, and Cr(VI) would be reduced to Cr(III) in days. PMID- 23673944 TI - Arsenic mobilization by citrate and malate from a red mud-treated contaminated soil. AB - The mobility and bioavailability of As in the soil-plant system can be affected by a number of organic acids that originate from the activity of plants and microorganisms. In this study we evaluated the ability of citrate and malate anions to mobilize As in a polluted subacidic soil (UP soil) treated with red mud (RM soil). Both anions promoted the mobilization of As from UP and RM soils, with citrate being more effective than malate. The RM treatment induced a greater mobility of As. The amounts of As released in RM and UP soils treated with 3.0 mmol L citric acid solution were 2.78 and 1.83 MUmol g respectively, whereas an amount equal to 1.73 and 1.06 MUmol g was found after the treatment with a 3.0 mmol L malic acid solution. The release of As in both soils increased with increasing concentration of organic acids, and the co-release of Al and Fe in solution also increased. The sequential extraction showed that Fe/Al (oxi)hydroxides in RM were the main phases involved in As binding in RM soil. Two possible mechanisms could be responsible for As solubilization: (i) competition of the organic anions for As adsorption sites and (ii) partial dissolution of the adsorbents (e.g., dissolution of iron and aluminum oxi-hydroxides) induced by citrate or malate and formation of complexes between dissolved Fe and Al and organic anions. This is the first report on the effect of malate and citrate on the As mobility in a polluted soil treated with RM. PMID- 23673945 TI - Herbicide transport in surface runoff from conventional and zero-tillage fields. AB - During the past four decades of crop production in the prairie region of Canada, there has been a dramatic shift from conventional management (CM) to conservation tillage management in which one or more tillage operations has been replaced by herbicide application. To determine whether this management shift has affected the quality of snowmelt runoff, field-scale side-by-side runoff watersheds were used in a 6-yr study. Herbicide concentrations and fluxes in snowmelt runoff water from CM and zero-till management (ZTM) systems were compared relative to an organic production system used as the control. Snowmelt runoff volume from the ZTM watershed exceeded that from the CM watershed in 5 yr of the 6-yr study. Frequencies of detection, concentrations and mass loss (mg ha) of the fall applied herbicides were generally higher in snowmelt runoff relative to those of the spring-applied herbicides. On days when multiple consecutive samples were collected, herbicide concentrations generally decreased as runoff flow increased. Incorporation of trifluralin and triallate reduced their losses in snowmelt runoff by approximately 5 and 8 times, respectively. Regarding the amount of herbicide applied during the 6-yr study, percent loss varied from 0.002% for trifluralin to 0.15% for 2,4-D. Edge-of-field concentrations of 2,4-D, trifluralin, and triallate in snowmelt runoff frequently exceeded Canadian aquatic life water quality guidelines. The adoption of conservation tillage strategies for crop production resulted in increased (~20%) herbicide use and an increased amount (~25%) of herbicide transported in snowmelt runoff (8.6 versus 6.9 g ha). PMID- 23673947 TI - Evidence of micropore filling for sorption of nonpolar organic contaminants by condensed organic matter. AB - Although microporosity and surface area of natural organic matter (NOM) are crucial for mechanistic evaluation of the sorption process for nonpolar organic contaminants (NOCs), they have been underestimated by the N adsorption technique. We investigated the CO-derived internal hydrophobic microporosity () and specific surface area (SSA) obtained on dry samples and related them to sorption behaviors of NOCs in water for a wide range of condensed NOM samples. The is obtained from the total CO-derived microporosity by subtracting out the contribution of the outer surfaces of minerals and NOM using N adsorption-derived parameters. The correlation between or CO-SSA and fractional organic carbon content () is very significant, demonstrating that much of the microporosity is associated with internal NOM matrices. The average and CO-SSA are, respectively, 75.1 MUL g organic carbon (OC) and 185 m g OC from the correlation analysis. The rigid aliphatic carbon significantly contributes to the microporosity of the Pahokee peat. A strong linear correlation is demonstrated between / and the OC-normalized sorption capacity at the liquid or subcooled liquid-state water solubility calculated via the Freundlich equation for each of four NOCs (phenanthrene, naphthalene, 1,3,5-trichlorobenzene, and 1,2-dichlorobenzene). We concluded that micropore filling ("adsorption") contributes to NOC sorption by condensed NOM, but the exact contribution requires knowing the relationship between the dry state, CO-determined microporosity and the wet-state, NOC-available microporosity of the organic matter. The findings offer new clues for explaining the nonideal sorption behaviors of NOCs. PMID- 23673946 TI - Sulfamethazine Sorption to Soil: Vegetative Management, pH, and Dissolved Organic Matter Effects. AB - Elucidating veterinary antibiotic interactions with soil is important for assessing and mitigating possible environmental hazards. The objectives of this study were to investigate the effects of vegetative management, soil properties, and >1000 Da dissolved organic matter (DOM) on sulfamethazine (SMZ) behavior in soil. Sorption experiments were performed over a range of SMZ concentrations (2.5 50 MUmol L) using samples from three soils (Armstrong, Huntington, and Menfro), each planted to one of three vegetation treatments: agroforestry buffers strips (ABS), grass buffer strips (GBS), and row crops (RC). Our results show that SMZ sorption isotherms are well fitted by the Freundlich isotherm model (log = 0.44 0.93; Freundlich nonlinearity parameter = 0.59-0.79). Further investigation of solid-to-solution distribution coefficients () demonstrated that vegetative management significantly ( < 0.05) influences SMZ sorption (ABS > GBS > RC). Multiple linear regression analyses indicated that organic carbon (OC) content, pH, and initial SMZ concentration were important properties controlling SMZ sorption. Study of the two most contrasting soils in our sample set revealed that increasing solution pH (pH 6.0-7.5) reduced SMZ sorption to the Armstrong GBS soil, but little pH effect was observed for the Huntington GBS soil containing 50% kaolinite in the clay fraction. The presence of DOM (150 mg L OC) had little significant effect on the Freundlich nonlinearity parameter; however, DOM slightly reduced SMZ values overall. Our results support the use of vegetative buffers to mitigate veterinary antibiotic loss from agroecosystems, provide guidance for properly managing vegetative buffer strips to increase SMZ sorption, and enhance understanding of SMZ sorption to soil. PMID- 23673948 TI - Black carbon-mediated reduction of 2,4-dinitrotoluene by dithiothreitol. AB - By using various types of black carbon (BC), including chemically converted graphene (CCG), multiwalled carbon nanotubes (MWCNT), and granular activated carbon (GAC), BC-mediated reduction was investigated with 2,4-dinitrotoluene (DNT), a model nitroaromatic compound. We hypothesized that by providing sorption and electron transfer sites, BC can be used as a catalyst to accelerate DNT reduction by dithiothreitol (DTL), a thiol reductant. Results from batch experiments showed that CCG, MWCNT, and GAC could promote reduction of DNT by DTL. The yield ratio of the two aminonitro intermediates was approximately 1:1, which was consistent with that in a graphite system. However, fullerene did not significantly enhance the reduction of DNT, likely due to being a pi acceptor. Kinetic data analysis showed that removal of DNT in the presence of BC and DTL was linearly proportional to the electrical conductivity of BC, suggesting that the graphitic structure of BC may be responsible for DNT removal. Our results indicate that the presence of BC materials may affect the fate of nitroaromatic compounds under electron-rich conditions. PMID- 23673949 TI - In situ attenuated total reflectance fourier-transform infrared study of oxytetracycline sorption on magnetite. AB - Adsorption of antibiotics on the surfaces of common mineral sorbents plays a major role in determining their fate in soils and sediments. The mechanisms of these reactions are, therefore, important for understanding and predicting the environmental fate of antibiotics. We used in situ attenuated total reflectance Fourier-transform infrared spectroscopy to elucidate the binding mechanisms of oxytetracycline (OTC) onto the surface of magnetite [FeO], a common Fe oxide mineral in soils and sediments, as a function of pH (3-9) and aqueous OTC concentration (5-150 MUmol L). Comparison of dissolved OTC spectra to those of OTC-magnetite surface complexes indicated strong interactions of OTC molecules with the FeO surface via carbonyl (C=O) and amine (-NH) moieties of the amide group (-CONH) and the N atom of the dimethyl amino group [-N(CH)]. Increasing the aqueous OTC concentration led to increased OTC adsorption but did not notably alter the OTC binding mode at the magnetite surface. The results of this study would help to assess the importance of Fe oxide minerals in determining the environmental fate of OTC in soils and sediments. PMID- 23673950 TI - Determining potential for microbial atrazine degradation in agricultural drainage ditches. AB - Passage of agricultural runoff through vegetated drainage ditches has been shown to reduce the amount of pesticides, such as atrazine, exiting out of agricultural watersheds. Previous studies have found that microbial communities in soil from fields treated with atrazine display enhanced rates of atrazine degradation. However, no studies have examined the potential for atrazine degradation in ditches used to drain these lands. The purpose of the current study was to determine the potential of the drainage ditch soil microbial community for atrazine degradation. Soil samples were collected from fields and adjacent drainage ditches and from nonagricultural land with no previous exposure to atrazine. Polymerase chain reaction analysis indicated widespread presence of atrazine degradation genes in fields and ditches. Potential for degradation was determined by following the decrease of atrazine in spiked soil samples over a 28 d incubation period. Greater than 95% of atrazine was degraded in field and ditch soils, whereas only 68.5 +/- 1.3% was degraded in the nonagricultural control. Comparison with autoclaved soil samples indicated the primary mechanism of atrazine degradation in agricultural soils was microbially mediated, whereas its breakdown in nonagricultural soil appeared to be the byproduct of abiotic processes. Therefore, microbial communities in drainage ditch sediments have the potential to play a role in atrazine removal from agricultural runoff by breaking down atrazine deposited in sediments and limiting the amount of this herbicide carried into downstream ecosystems. PMID- 23673951 TI - Nitrogen mineralization from sludge in an alkaline, saline coal gasification ash environment. AB - Rehabilitating coal gasification ash dumps by amendment with waste-activated sludge has been shown to improve the physical and chemical properties of ash and to facilitate the establishment of vegetation. However, mineralization of organic N from sludge in such an alkaline and saline medium and the effect that ash weathering has on the process are poorly understood and need to be ascertained to make decisions regarding the suitability of this rehabilitation option. This study investigated the rate and pattern of N mineralization from sludge in a coal gasification ash medium to determine the prevalent inorganic N form in the system and assess the effect of ash weathering on N mineralization. An incubation experiment was performed in which fresh ash, weathered ash, and soil were amended with the equivalent of 90 Mg ha sludge, and N mineralization was evaluated over 63 d. More N (24%) was mineralized in fresh ash than in weathered ash and soil, both of which mineralized 15% of the initial organic N in sludge. More nitrification occurred in soil, and most of the N mineralized in ash was in the form of ammonium, indicating an inhibition of nitrifying organisms in the ash medium and suggesting that, at least initially, plants used for rehabilitation of coal gasification ash dumps will take up N mostly as ammonium. PMID- 23673952 TI - Volatilization of pesticides from the bare soil surface: evaluation of the humidity effect. AB - Volatilization of pesticides from soils under dry conditions (water content below the permanent wilting point) can be significantly influenced by sorption to hydrated mineral surfaces. This sorption process strongly depends on the water activity, expressed as equilibrium relative humidity in the pore space of the soil, and on the available surface area of the hydrated minerals. In this study, the influence of different humidity regimes on the volatilization of two pesticides (triallate and trifluralin) was demonstrated with a bench-scale wind tunnel system that allowed the establishment of well controlled humidity conditions within the soil. In the experiment starting with very dry conditions, increasing the relative humidity in the adjacent air from 60 to 85% resulted in an up to 8 times higher volatilization rate of the pesticides. An additional strong increase in volatilization (up to 3 times higher) was caused by a simulated rain event, which eliminates all sorption sites associated to mineral surfaces. In agreement with this interpretation, the comparison of two soils suggested that mineral surface area was the soil property that governs the volatilization under dry conditions, whereas soil organic matter was the controlling variable under wet conditions. In contrast to expectations, the use of a novel capsulated suspension for triallate showed the same humidity effects and no substantially lower volatilization rates in comparison to the regular formulation. This study demonstrated that humidity effects on pesticide volatilization can be interpreted via the mechanism of sorption to mineral surfaces under dry conditions. PMID- 23673953 TI - Modeling sorption of neutral organic compound mixtures to simulated aquifer sorbents with pseudocompounds. AB - The feasibility of the ideal adsorbed solution theory (IAST) in reducing the complexity associated with predicting the sorption behaviors of 12 neutral organic compounds (NOCs) contained in complex mixtures as a fewer number (four to six) of pseudocompounds (groups of compounds) to simulated aquifer sorbents was investigated. All sorption isotherms from individual- and multiple-pseudocompound systems were fit reasonably well ( >= 0.953) by the Freundlich sorption model over the range of aqueous concentrations evaluated (i.e., <=200 MUmol L). The presence and magnitude of mutual competition among pseudocompounds varied depending on the composition of the mixtures (i.e., concentrations and polarities of pseudocompounds) and the properties of sorbents (i.e., the fraction of organic carbon and the availability of hydrophilic specific sorption sites). Finally, comparisons between the IAST-based predictions with individual-pseudocompound sorption parameters and experimentally measured data revealed that the accuracy in predicting the sorption behaviors of several NOCs in terms of a fewer number of pseudocompounds decreased with increasing deviations from the assumption of equal and ideal competition in the IAST (i.e., differential availability of sorption sites and nonideal competitions among pseudocompounds). PMID- 23673954 TI - Implications of inorganic fertilization of irrigated corn on soil properties: lessons learned after 50 years. AB - Inorganic fertilizers are widely used for crop production, but their long-term impacts on soil organic carbon (SOC) pools and soil physical attributes are not fully understood. We studied how half a century of N application at 0, 45, 90, 134, 179, and 224 kg ha and P application at 0, 20, and 40 kg ha (since 1992) affected SOC pools and soil structural and hydraulic parameters in irrigated continuous corn ( L.) under conventional till on an Aridic Haplustoll in the central Great Plains. Application of 45, 90, 134, 179, and 224 kg N ha increased the SOC pool by 4.6, 6.8, 7.6, 7.9, and 9.7 Mg ha, respectively, relative to nonfertilized plots in the 0- to 45-cm depth. Application of 20 kg P ha increased the SOC pool by 2.9 Mg ha in the 0- to 30-cm depth. The highest N rate increased the SOC pool by 195 kg ha yr. The C gains may be, however, offset by the C hidden costs of N fertilization. Application of >45 kg N ha reduced the proportion of soil macroaggregates (>0.25 mm) in the 7.5- to 30-cm depth. Fertilization did not affect hydraulic properties, but application of >=90 kg N ha slightly increased aggregate water repellency. An increase in SOC concentration did not increase the mean weight diameter of wet aggregates ( = 0.1; > 0.10), but it slightly increased aggregate water repellency ( = 0.5; 0.005). Overall, long-term inorganic fertilization to irrigated corn can increase SOC pool, but it may reduce soil structural stability. PMID- 23673955 TI - Leaching potential of phosphorus from cattle excreta patches in the central highlands of Florida. AB - Research is limited for cow-calf operations as a potential nonpoint source of P within Florida's central highlands region (CHR). The study was conducted in a bahiagrass ( Flugge) pasture. The soil is an excessively drained 'Candler' sand. In dung-designated plots, 2 kg of fresh cattle dung was deposited across the surface of a 15-cm-radius circular zone (Zone 1 [Z1]) centered within 3 * 3 m plots. In urine plots, 1 L of urine was deposited on Z1 and 1 L on Zone 2 (Z2), an area extending outward from Z1 to 30 cm from plot center. In dung and urine plots, Zone 3 (Z3) extended from Z2 to 45 cm from plot center and Zone 4 (Z4) from Z3 to 60 cm. Excreta deposition frequencies (DFs) were 0, 1, 2, and 3 times per year during 2006 and 2007. Total apparent remaining P (ARP = [fertilizer P + excreta P] - forage P removal) for Z1 of dung plots was 21, 447, 905, and 1249 kg ha for DF0, DF1, DF2, and DF3, respectively. In 2008, soil was incrementally sampled to a depth of 120 cm in all zones. Urine deposition did not increase soil P. Soil P levels and the degree of P saturation percentages increased with DF but only in the upper 10 cm of topsoil beneath Z1 of dung plots. Our results suggest that the risk of dung P reaching groundwater is low due to a considerable P retention capacity within the rooting zone of the Candler soil. PMID- 23673957 TI - Biochar from Swine solids and digestate influence nutrient dynamics and carbon dioxide release in soil. AB - Large amounts of livestock manure solids are expected to become available in the near future due to the development of technologies for the separation of the solid fraction of animal effluents. The charring of manure solids for biochar (BC) production represents an opportunity for recycling organic matter (OM) of high nutrient value. The objectives of this study were to evaluate the suitability of BC from swine solids (SS) to improve soil fertility through nutrient supply and decomposition of the OM incorporated into soil and to verify a possible interaction effect on soil nutrient dynamics between digestate application and soil amendment with BC. We monitored at laboratory scale the soil mineral nitrogen (N) and Olsen phosphorus (P) content, and the cumulative carbon dioxide (CO-C) release in treatments with or without a supply of digestate obtained from a biogas plant. The experiment was performed in laboratory microcosms during a 3-mo incubation period. Compared treatments were soil amendments with SS, BC from SS, wood chip, BC from wood chip, and soil with no amendment, each of them with and without incorporation of digestate (10 treatments in total). Soil N levels were unaffected by BC amendments and only increased temporarily when digestate was applied to soil amended with SS or BC from SS. For the same N content, the BC from SS supplied much more P than the nontreated OM. The amount of cumulative CO-C released from soil with BC with or without digestate did not differ from that in the unamended control soil and was lower than that in the soils with noncharred amendments. Soil amendment with BC from SS does not modify soil N availability, whereas it increases the content of P available for crops and reduces the release of CO-C from digestate applied to soil for agricultural purposes. PMID- 23673956 TI - Tile Drainage Management Influences on Surface-Water and Groundwater Quality following Liquid Manure Application. AB - This study investigated the potential for controlled tile drainage (CD) to reduce bacteria and nutrient loading to surface water and groundwater from fall-season liquid manure application (LMA) on four macroporous clay loam plots, of which two had CD and two had free-draining (FD) tiles. Rhodamine WT (RWT) was mixed into the manure and monitored in the tile water and groundwater following LMA. Tile water and groundwater quality were influenced by drainage management. Following LMA on the FD plots, RWT, nutrients, and bacteria moved rapidly via tiles to surface water; at the CD plots, tiles did not flow until the first post-LMA rainfall, so the immediate risk of LMA-induced contamination of surface water was abated. During the 36-d monitoring period, flow-weighted average specific conductance, redox potential, and turbidity, as well as total Kjeldahl N (TKN), total P (TP), NH-N, reactive P, and RWT concentrations, were higher in the CD tile effluent; however, because of lower tile discharge from the CD plots, there was no significant ( <= 0.05) difference in surface water nutrient and RWT loading between the CD and FD plots when all tiles were flowing. The TKN, TP, and RWT concentrations in groundwater also tended to be higher at the CD plots. Bacteria behaved differently than nutrients and RWT, with no significant difference in total coliform, , fecal coliform, fecal streptococcus, and concentrations between the CD and FD tile effluent; however, for all but , hourly loading was higher from the FD plots. Results indicate that CD has potential for mitigating bacteria movement to surface water. PMID- 23673958 TI - Selection of pecan shell-based activated carbons for removal of organic and inorganic impurities from water. AB - Activated carbons are a byproduct from pyrolysis and have value as a purifying agent. The effectiveness of activated carbons is dependent on feedstock selection and pyrolysis conditions that modify their surface properties. Therefore, pecan shell-based activated carbons (PSACs) were prepared by soaking shells in 50% (v/v) HPO or 25 to 50% of KOH-NaHCO followed by pyrolysis at 400 to 700 degrees C under a N atmosphere. Physically activated PSACs were produced by pyrolysis at 700 degrees C under N followed by activation with steam or CO at 700 to 900 degrees C. Physicochemical, surface, and adsorption properties of the PSACs were compared with two commercially available activated carbons. The average mass yield of PSACs with respect to the initial mass of the biomass was about 20 and 34% for physically activated and chemically activated carbons, respectively. Acid activated carbons exhibited higher surface area, higher bulk density, and lower ash content compared with steam- or CO-activated carbons and the two commercial products. Base activation led to the development of biochar with moderate to high surface area with surface charges suitable for adsorption of anionic species. Regardless of the activation method, PSACs had high total surface area ranging from 400 to 1000 m g, better pore size distribution, and more surface charges than commercial samples. Our results also showed that PSACs were effective in removing inorganic contaminants such as Cu and NO as well as organic contaminants such as atrazine and metolachlor. This study showed that pyrolysis conditions and activation had a large influence on the PSAC's surface characteristics, which can limit its effectiveness as a custom sorbent for targeted water contaminants. PMID- 23673959 TI - Quantifying the effects of green waste compost application, water content and nitrogen fertilization on nitrous oxide emissions in 10 agricultural soils. AB - Common management practices, such as the application of green waste compost, soil moisture manipulation, and nitrogen fertilization, affect nitrous oxide (NO) emissions from agricultural soils. To expand our understanding of how soils interact with these controls, we studied their effects in 10 agricultural soils. Application of compost slightly increased NO emissions in soils with low initial levels of inorganic N and low background emission. For soils in which compost caused a decrease in emission, this decrease was larger than any of the observed increases in the other soils. The five most important factors driving emission across all soils, in order of increasing importance, were native dissolved organic carbon (DOC), treatment-induced change in DOC, native inorganic N, change in pH, and soil iron (Fe). Notable was the prominence of Fe as a regulator of NO emission. In general, compost is a viable amendment, considering the agronomic benefits it provides against the risk of producing a small increase in NO emissions. However, if soil properties and conditions are taken into account, management can recognize the potential effect of compost and thereby reduce NO emissions from susceptible soils, particularly by avoiding application of compost under wet conditions and together with ammonium fertilizer. PMID- 23673960 TI - Investigation of copper sorption by sugar beet processing lime waste. AB - In the western United States, sugar beet processing for sugar recovery generates a lime-based waste product (~250,000 Mg yr) that has little liming value in the region's calcareous soils. This area has recently experienced an increase in dairy production, with dairies using copper (Cu)-based hoof baths to prevent hoof diseases. A concern exists regarding soil Cu accumulation because spent hoof baths may be disposed of in waste ponds, with pond waters being used for irrigation. The objective of this preliminary study was to evaluate the ability of lime waste to sorb Cu. Lime waste was mixed with increasing Cu-containing solutions (up to 100,000 mg Cu kg lime waste) at various buffered pH values (pH 6, 7, 8, and 9) and shaken over various time periods (up to 30 d). Copper sorption phenomenon was quantified using sorption maximum fitting, and the sorption mechanism was investigated using X-ray absorption spectroscopy. Results showed that sorption onto lime waste increased with decreasing pH and that the maximum Cu sorption of ~45,000 mg kg occurred at pH 6. X-ray absorption spectroscopy indicated that Cu(OH) was the probable species present, although the precipitate existed as small multinuclear precipitates on the surface of the lime waste. Such structures may be precursors for larger surface precipitates that develop over longer incubation times. Findings suggest that sugar beet processing lime waste can viably sorb Cu from liquid waste streams, and thus it may have the ability to remove Cu from spent hoof baths. PMID- 23673961 TI - Improved fluorescence excitation-emission matrix regional integration to quantify spectra for fluorescent dissolved organic matter. AB - The purpose of this short communication is to demonstrate the importance of numerical analysis and wavelength increment selection when characterizing fluorescent dissolved organic matter (FDOM) using fluorescence excitation emission matrix (EEM) regional integration. A variety of water samples, representing a landscape gradient and different types of FDOM, were analyzed for their percentage distribution of five operationally defined FDOM fractions (aromatic protein I, aromatic protein II, fulvic acid-like, soluble microbial byproduct-like, and humic acid-like) using three numerical methods in integrating volume under the surface of the fluorescence EEMs: Riemann summation, composite trapezoidal rule, and composite Simpson's rule. The influence of wavelength increment was also examined for the precision of the percentage distribution of each fraction. Our results show that the FDOM fraction estimated by Riemann summation with a 10- or 5-nm excitation wavelength can cause >40% or >5% errors, respectively, when compared with the best estimated values obtained by averaging results from composite trapezoidal rule and composite Simpson's rule with 1-nm excitation wavelength at the same emission increment. Also, our experiments show that fluorescence matrix regional integration could underestimate the two aromatic protein fractions but could overestimate the soluble microbial byproduct like and humic acid-like fractions if improper increment and integral methods are used. The error can be reduced if a smaller wavelength increment is used. The smallest increment in a spectrofluorometer and composite Simpson's rule should be used for scanning fluorescence EEMs and calculating the percentage distribution of each FDOM fraction. Alternatively, 5-nm wavelength increments with composite Simpson's rule could be cost effective, and the error of each FDOM fraction commonly falls within 5% compared with those estimated by 1-nm increments. PMID- 23673964 TI - Effect of hydrogen bonds on the modulus of bulk polybenzoxazines in the glassy state. AB - In this paper, the critical role of hydrogen bonds on the modulus of bulk polybenzoxazines in the glassy state was proved through introducing an additional hydrogen bond, C=O...HO, into the polybenzoxazine. Thorough studies were carried out to resolve the different modulus behaviors of polybenzoxazines with and without this additional hydrogen bond as the temperature increases. With the aid of dynamic mechanical analysis and in situ Fourier transform infrared spectroscopy, we found that the different performances in modulus were in accordance with the changes of C=O...HO and, therefore, revealed that the hydrogen bonds played a crucial role on the modulus of bulk polybenzoxazines in the glassy state. We believe this improved insight into the roles of hydrogen bonds is expected to help researchers explore novel polybenzoxazine resins with excellent thermal and mechanical properties. PMID- 23673965 TI - Intracardiac echocardiographic thrombus detection just before transseptal puncture: a nightmare outside the door. PMID- 23673966 TI - Metabolism: a cold, brite start. PMID- 23673967 TI - Cell signalling: New G protein family rules. PMID- 23673968 TI - Cell signalling: Crystallizing active arrestins. PMID- 23673970 TI - Cholecalciferol supplementation reduces soluble Klotho concentration in hemodialysis patients. AB - INTRODUCTION: Low levels of vitamin D are linked to numerous adverse clinical conditions in hemodialysis (HD) patients, including disturbances of mineral and bone metabolism and increased mortality. Klotho, a molecule involved in such processes as phosphate homeostasis and aging, exists in 2 forms: a transmembrane protein acting as a coreceptor for fibroblast growth factor 23 (FGF-23) and soluble form, which is formed by cleavage of the extracellular domain of this molecule. OBJECTIVES: The aim of the study was to evaluate the effect of cholecalciferol supplementation on soluble Klotho levels in HD patients. PATIENTS AND METHODS: This was a prospective, open-label trial examining the effects of cholecalciferol supplementation on selected laboratory markers in 22 patients on HD. Vitamin D deficiency was assessed by the measurement of 25-hydroxyvitamin D [25(OH)D] levels. Soluble Klotho, intact FGF-23, intact parathormone (iPTH), and markers of bone formation and resorption were measured at baseline and after 12 weeks of cholecalciferol supplementation. RESULTS: The levels of 25(OH)D increased, while those of iPTH and cross-linked C-telopeptide of type 1 collagen decreased significantly. Cholecalciferol treatment reduced the median concentration of soluble Klotho (from 438.73 pg/ml; interquartile range, 257.99 865.51 pg/ml; to 370.94 pg/ml; 181.72-710.91 pg/ml; P <0.05). FGF-23 levels were not affected by the treatment. CONCLUSIONS: Supplementation with cholecalciferol in HD patients decreases soluble Klotho levels without affecting the FGF-23 concentration. Replenishment of vitamin D stores results in a decrease in iPTH levels and reduced bone resorption. PMID- 23673969 TI - Origins and implications of pluripotent stem cell variability and heterogeneity. AB - Pluripotent stem cells constitute a platform to model disease and developmental processes and can potentially be used in regenerative medicine. However, not all pluripotent cell lines are equal in their capacity to differentiate into desired cell types in vitro. Genetic and epigenetic variations contribute to functional variability between cell lines and heterogeneity within clones. These genetic and epigenetic variations could 'lock' the pluripotency network resulting in residual pluripotent cells or alter the signalling response of developmental pathways leading to lineage bias. The molecular contributors to functional variability and heterogeneity in both embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are only beginning to emerge, yet they are crucial to the future of the stem cell field. PMID- 23673971 TI - Impulsivity moderates promotive environmental influences on adolescent delinquency: a comparison across family, school, and neighborhood contexts. AB - The present study examined moderating effects of impulsivity on the relationships between promotive factors from family (family warmth, parental knowledge), school (school connectedness), and neighborhood (neighborhood cohesion) contexts with delinquency using data collected from N = 2,978 sixth to eighth graders from 16 schools surrounding a major city in the Midwestern United States. More than half of the respondents were non-Caucasian (M age = 12.48; 41.0 % male). Multilevel modeling analyses were conducted to take into account the clustering of the participants within schools. Impulsivity was positively associated with adolescent delinquency. Additionally, family warmth, parental knowledge, and school connectedness, but not neighborhood cohesion, were independently and inversely related to adolescent delinquency. Finally, impulsivity moderated relationships between family warmth and parental knowledge with delinquency but not relationships between school attachment and neighborhood cohesion with delinquency. Specifically, the negative relationship between family warmth and delinquency was significant for adolescents with high levels of, but not for those with below-average levels of, impulsivity. In addition, parental knowledge had a stronger association with decreased levels of delinquency for adolescents reporting higher levels of impulsivity. The moderating effects of impulsivity did not differ for males and females or for minority and non-minority participants. Findings indicate that impulsivity may have greater impact on adolescents' susceptibility to positive family influences than on their susceptibility to promotive factors from school or neighborhood contexts. Implications for future research and practice are discussed. PMID- 23673972 TI - Urine NGAL and KIM-1 in children and adolescents with hyperuricemia. AB - BACKGROUND: The aim of this study was to test the hypothesis that urine levels of neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) are enhanced in pediatric patients with hyperuricemia. METHODS: The study included 88 children and adolescents (60 males, 28 females) with a median age of 16 (range 11-18.5) years who had been referred to our department to rule out or confirm hypertension. The subjects were divided into two groups: the hyperuricemic (HU) group comprising 59 subjects with hyperuricemia (defined as serum uric acid >4.8 and >5.5 mg/dl in girls and boys, respectively) and the reference group comprising 29 patients with normouricemia. Urine NGAL and KIM-1 levels were evaluated using a commercially available kit. RESULTS: Concentrations of the examined biomarkers [urine NGAL, NGAL/creatinine (cr.) ratio, urine KIM-1, KIM-1/cr. ratio] were increased in the HU group compared with the reference group (p < 0.01). There were positive correlations between the serum uric acid and urine NGAL/cr. ratio (R = 0.67, p < 0.001) and the urine KIM-1/cr. ratio (R = 0.36, p < 0.001). In the multiple regression models, serum uric acid, systolic blood pressure and cholesterol accounted for more than 49 % of the variation in the NGAL/cr. ratio (R = 0.702, p < 0.001). In the second model, serum uric acid, gender, age and systolic blood pressure accounted for more than 36 % of the variation in the KIM-1/cr. ratio (R = 0.604, p < 0.001). CONCLUSION: We demonstrated that male, obese, hypertensive adolescents with hyperuricemia have higher urine NGAL and KIM-1 levels relative to a reference group with normouricemia. PMID- 23673973 TI - Cryoablation of right-sided accessory pathways in children: report of efficacy and safety after 10-year experience and follow-up. AB - AIMS: The aim of this study was to report the 10-year experience of our Institution in cryoablation of supraventricular tachycardia due to a right accessory pathway (AP). METHODS AND RESULTS: Seventy-one cryoablations of right AP were performed between July 2002 and October 2011 in our Institution in 66 patients (mean age 12 + 3 years, 56% males). Acute procedural success rate was 97%: 80% in patients with concealed AP and 100% in those with manifest AP (P < 0.05). Acute procedural success rate was not related to institutional experience. No permanent complication occurred. Sixteen patients had recurrences during the follow-up (18.6 +/- 6.6 months; range 3-111), 13 within the first month of follow up, 2 within the 6 months of follow-up, and 1 within 12 months of follow-up. Cox regression showed that sex, patient age, number of delivered cryo-bonus, and presence of manifest or concealed AP are not independent predictors of procedural success. Among the 16 patients with recurrences, in 10 a cryoablation redo was successful and with no further AP recurrences. The mean fluoroscopy time was 28.4 min (range 19.7-44.6) with a significant decrease (P = 0.033) in relation to the increase of the institutional experience. There were no permanent ablation related complications. CONCLUSION: Cryoablation of right-sided AP is effective and very safe in children. Better results are achieved in manifest AP. The learning curve has a real impact in the attempt to reduce the fluoroscopy time. PMID- 23673974 TI - Obesity and atrial fibrillation: the evidence is gaining weight. PMID- 23673975 TI - Synthesis and antiproliferative activity of selenoindirubins and selenoindirubin N-glycosides. AB - Selenoindirubins and selenoindirubin-N-glycosides were prepared by the reaction of isatins and isatin-N-glycosides with 3-acetoxy-benzo[b]selenophene, respectively. While selenoindirubin-N-glycosides have not been reported before, three non-glycosylated selenoindirubins were previously reported, but without quantities, yields, scales, experimental details and spectroscopic data. In addition, the work could, in our hands, not be reproduced to prepare pure products. The present paper includes an optimized procedure for the synthesis of selenoindirubins and their complete characterization. Both selenoindirubins and selenoindirubin-N-glycosides showed antiproliferative activity in lung cancer cell lines. In melanoma cells, antiproliferative effects were further accompanied by induced apoptosis in combination with the death ligand TRAIL. PMID- 23673976 TI - Application of supercritical CO2 for extraction of polyisoprenoid alcohols and their esters from plant tissues. AB - In this study, a method of supercritical fluid extraction (SFE) with carbon dioxide of polyisoprenoids from plant photosynthetic tissues is described. SFE was an effective extraction method for short- and medium-chain compounds with even higher yield than that observed for the "classical extraction" method with organic solvents. Moreover, SFE-derived extracts contained lower amounts of impurities (e.g., chlorophylls) than those obtained by extraction of the same tissue with organic solvents. Elevated temperature and extended extraction time of SFE resulted in a higher rate of extraction of long-chain polyisoprenoids. Ethanol cofeeding did not increase the extraction efficiency of polyisoprenoids; instead, it increased the content of impurities in the lipid extract. Optimization of SFE time and temperature gives the opportunity of prefractionation of complex polyisoprenoid mixtures accumulated in plant tissues. Extracts obtained with application of SFE are very stable and free from organic solvents and can further be used directly in experimental diet supplementation or as starting material for preparation of semisynthetic polyisoprenoid derivatives, e.g., polyisoprenoid phosphates. PMID- 23673978 TI - Protective effect of apigenin on mouse acute liver injury induced by acetaminophen is associated with increment of hepatic glutathione reductase activity. AB - Apigenin, a natural plant flavone, has many beneficial effects, but there is no report about treatment of acetaminophen-induced liver injury. Our aim was to examine the protective effect of apigenin on acetaminophen-induced mouse acute liver injury and to investigate the potential mechanisms. A mouse model with acute liver injury was induced by intraperitoneally given acetaminophen 350 mg kg(-1) after oral administration of apigenin 100 and 200 mg kg(-1) for 7 days. The results showed that after treatment with apigenin, the levels of serum alanine aminotransferase and aspartate aminotransferase were gradually decreased, and the severity of liver injury was decreased. In particular, significant changes in liver necrosis were observed in the apigenin 200 mg kg(-1) group. Apigenin could gradually increase the hepatic glutathione reductase (GR) activity and reduced glutathione (GSH) content, and decrease the hepatic malondialdehyde content, but the activities of glutathione peroxidase and glutathione S transferase in hepatic tissues between the model group and the apigenin-treated groups were not significantly different. It was concluded that apigenin could protect against acetaminophen-induced acute liver injury in mice, and the mechanisms might be associated with enhancing hepatic GSH content via increment of GR activity. PMID- 23673977 TI - The immune system in stroke: clinical challenges and their translation to experimental research. AB - Stroke represents an unresolved challenge for both developed and developing countries and has a huge socio-economic impact. Although considerable effort has been made to limit stroke incidence and improve outcome, strategies aimed at protecting injured neurons in the brain have all failed. This failure is likely to be due to both the incompleteness of modelling the disease and its causes in experimental research, and also the lack of understanding of how systemic mechanisms lead to an acute cerebrovascular event or contribute to outcome. Inflammation has been implicated in all forms of brain injury and it is now clear that immune mechanisms profoundly influence (and are responsible for the development of) risk and causation of stroke, and the outcome following the onset of cerebral ischemia. Until very recently, systemic inflammatory mechanisms, with respect to common comorbidities in stroke, have largely been ignored in experimental studies. The main aim is therefore to understand interactions between the immune system and brain injury in order to develop novel therapeutic approaches. Recent data from clinical and experimental research clearly show that systemic inflammatory diseases -such as atherosclerosis, obesity, diabetes or infection - similar to stress and advanced age, are associated with dysregulated immune responses which can profoundly contribute to cerebrovascular inflammation and injury in the central nervous system. In this review, we summarize recent advances in the field of inflammation and stroke, focusing on the challenges of translation between pre-clinical and clinical studies, and potential anti inflammatory/immunomodulatory therapeutic approaches. PMID- 23673979 TI - Inactivation of plasma membrane-localized CDPK-RELATED KINASE5 decelerates PIN2 exocytosis and root gravitropic response in Arabidopsis. AB - CRK5 is a member of the Arabidopsis thaliana Ca(2+)/calmodulin-dependent kinase related kinase family. Here, we show that inactivation of CRK5 inhibits primary root elongation and delays gravitropic bending of shoots and roots. Reduced activity of the auxin-induced DR5-green fluorescent protein reporter suggests that auxin is depleted from crk5 root tips. However, no tip collapse is observed and the transcription of genes for auxin biosynthesis, AUXIN TRANSPORTER/AUXIN TRANSPORTER-LIKE PROTEIN (AUX/LAX) auxin influx, and PIN-FORMED (PIN) efflux carriers is unaffected by the crk5 mutation. Whereas AUX1, PIN1, PIN3, PIN4, and PIN7 display normal localization, PIN2 is depleted from apical membranes of epidermal cells and shows basal to apical relocalization in the cortex of the crk5 root transition zone. This, together with an increase in the number of crk5 lateral root primordia, suggests facilitated auxin efflux through the cortex toward the elongation zone. CRK5 is a plasma membrane-associated kinase that forms U-shaped patterns facing outer lateral walls of epidermis and cortex cells. Brefeldin inhibition of exocytosis stimulates CRK5 internalization into brefeldin bodies. CRK5 phosphorylates the hydrophilic loop of PIN2 in vitro, and PIN2 shows accelerated accumulation in brefeldin bodies in the crk5 mutant. Delayed gravitropic response of the crk5 mutant thus likely reflects defective phosphorylation of PIN2 and deceleration of its brefeldin-sensitive membrane recycling. PMID- 23673980 TI - Golgi traffic and integrity depend on N-myristoyl transferase-1 in Arabidopsis. AB - N-myristoylation is a crucial irreversible eukaryotic lipid modification allowing a key subset of proteins to be targeted at the periphery of specific membrane compartments. Eukaryotes have conserved N-myristoylation enzymes, involving one or two N-myristoyltransferases (NMT1 and NMT2), among which NMT1 is the major enzyme. In the postembryonic developmental stages, defects in NMT1 lead to aberrant cell polarity, flower differentiation, fruit maturation, and innate immunity; however, no specific NMT1 target responsible for such deficiencies has hitherto been identified. Using a confocal microscopy forward genetics screen for the identification of Arabidopsis thaliana secretory mutants, we isolated STINGY, a recessive mutant with defective Golgi traffic and integrity. We mapped STINGY to a substitution at position 160 of Arabidopsis NMT1 (NMT1A160T). In vitro kinetic studies with purified NMT1A160T enzyme revealed a significant reduction in its activity due to a remarkable decrease in affinity for both myristoyl-CoA and peptide substrates. We show here that this recessive mutation is responsible for the alteration of Golgi traffic and integrity by predominantly affecting the Golgi membrane/cytosol partitioning of ADP-ribosylation factor proteins. Our results provide important functional insight into N-myristoylation in plants by ascribing postembryonic functions of Arabidopsis NMT1 that involve regulation of the functional and morphological integrity of the plant endomembranes. PMID- 23673981 TI - Loss of plastoglobule kinases ABC1K1 and ABC1K3 causes conditional degreening, modified prenyl-lipids, and recruitment of the jasmonic acid pathway. AB - Plastoglobules (PGs) are plastid lipid-protein particles. This study examines the function of PG-localized kinases ABC1K1 and ABC1K3 in Arabidopsis thaliana. Several lines of evidence suggested that ABC1K1 and ABC1K3 form a protein complex. Null mutants for both genes (abc1k1 and abc1k3) and the double mutant (k1 k3) displayed rapid chlorosis upon high light stress. Also, k1 k3 showed a slower, but irreversible, senescence-like phenotype during moderate light stress that was phenocopied by drought and nitrogen limitation, but not cold stress. This senescence-like phenotype involved degradation of the photosystem II core and upregulation of chlorophyll degradation. The senescence-like phenotype was independent of the EXECUTER pathway that mediates genetically controlled cell death from the chloroplast and correlated with increased levels of the singlet oxygen-derived carotenoid beta-cyclocitral, a retrograde plastid signal. Total PG volume increased during light stress in wild type and k1 k3 plants, but with different size distributions. Isolated PGs from k1 k3 showed a modified prenyl lipid composition, suggesting reduced activity of PG-localized tocopherol cyclase (VTE1), and was consistent with loss of carotenoid cleavage dioxygenase 4. Plastid jasmonate biosynthesis enzymes were recruited to the k1 k3 PGs but not wild-type PGs, while pheophytinase, which is involved in chlorophyll degradation, was induced in k1 k3 and not wild-type plants and was localized to PGs. Thus, the ABC1K1/3 complex contributes to PG function in prenyl-lipid metabolism, stress response, and thylakoid remodeling. PMID- 23673982 TI - A bHLH-type transcription factor, ABA-INDUCIBLE BHLH-TYPE TRANSCRIPTION FACTOR/JA ASSOCIATED MYC2-LIKE1, acts as a repressor to negatively regulate jasmonate signaling in arabidopsis. AB - Jasmonates (JAs) are plant hormones that regulate the balance between plant growth and responses to biotic and abiotic stresses. Although recent studies have uncovered the mechanisms for JA-induced responses in Arabidopsis thaliana, the mechanisms by which plants attenuate the JA-induced responses remain elusive. Here, we report that a basic helix-loop-helix-type transcription factor, ABA INDUCIBLE BHLH-TYPE TRANSCRIPTION FACTOR/JA-ASSOCIATED MYC2-LIKE1 (JAM1), acts as a transcriptional repressor and negatively regulates JA signaling. Gain-of function transgenic plants expressing the chimeric repressor for JAM1 exhibited substantial reduction of JA responses, including JA-induced inhibition of root growth, accumulation of anthocyanin, and male fertility. These plants were also compromised in resistance to attack by the insect herbivore Spodoptera exigua. Conversely, jam1 loss-of-function mutants showed enhanced JA responsiveness, including increased resistance to insect attack. JAM1 and MYC2 competitively bind to the target sequence of MYC2, which likely provides the mechanism for negative regulation of JA signaling and suppression of MYC2 functions by JAM1. These results indicate that JAM1 negatively regulates JA signaling, thereby playing a pivotal role in fine-tuning of JA-mediated stress responses and plant growth. PMID- 23673983 TI - The multiple activities of BMPs during spinal cord development. AB - Bone morphogenetic proteins (BMPs) are one of the main classes of multi-faceted secreted factors that drive vertebrate development. A growing body of evidence indicates that BMPs contribute to the formation of the central nervous system throughout its development, from the initial shaping of the neural primordium to the generation and maturation of the different cell types that form the functional adult nervous tissue. In this review, we focus on the multiple activities of BMPs during spinal cord development, paying particular attention to recent results that highlight the complexity of BMP signaling during this process. These findings emphasize the unique capacity of these signals to mediate various functions in the same tissue throughout development, recruiting diverse effectors and strategies to instruct their target cells. PMID- 23673985 TI - Tumor lysis syndrome and malignant melanoma. AB - Tumor lysis syndrome (TLS) is an oncological emergency that results from massive cytolysis of malignant cells with a sudden release of their contents into the systemic circulation. TLS was rarely described in patients with malignant melanoma. In this article, we describe two patients with malignant melanoma who developed this syndrome. In one of them, the syndrome occurred spontaneously, and this is the second description of spontaneous tumor lysis in a patient with melanoma. We reviewed the previous patients with melanoma-induced TLS and discussed the manifestations and the pathophysiology of the syndrome in our patients. PMID- 23673984 TI - Damage-associated molecular patterns and their receptors in upper airway pathologies. AB - Inflammation of the nasal (rhinitis) and sinus mucosa (sinusitis) are prevalent medical conditions of the upper airways that are concurrent in many patients; hence the terminology "rhinosinusitis". The disease status is further defined to be "chronic" in case symptoms persist for more than 12 weeks without resolution. A diverse spectrum of external factors including viral and bacterial insults together with epithelial barrier malfunctions could be implicated in the chronicity of the inflammatory responses in chronic rhinosinusitis (CRS). However, despite massive research efforts in an attempt to unveil the pathophysiology, the exact reason for a lack of resolution still remains poorly understood. A novel set of molecules that could be implicated in sustaining the inflammatory reaction may be found within the host itself. Indeed, besides mediators of inflammation originating from outside, some endogenous intracellular and/or extracellular matrix (ECM) components from the host can be released into the extracellular space upon damage induced during the initial inflammatory reaction where they gain functions distinct from those during normal physiology. These "host-self" molecules are known to modulate inflammatory responses under pathological conditions, potentially preventing resolution and contributing to the development of chronic inflammation. These molecules are collectively classified as damage-associated molecular patterns (DAMPs). This review summarizes the current knowledge regarding DAMPs in upper airway pathologies, also covering those that were previously investigated for their intracellular and/or ECM functions often acting as an antimicrobial agent or implicated in tissue/cell homeostasis, and for which their function as a danger signaling molecule was not assessed. It is, however, of importance to assess these molecules again from a point of view as a DAMP in order to further unravel the pathogenesis of CRS. PMID- 23673987 TI - Tumor cavitation among lung cancer patients receiving first-line chemotherapy at a tertiary care centre in India: association with histology and overall survival. AB - Clinical significance of tumor cavitation (TC) prior to and following first-line chemotherapy of lung cancer is unclear. An evaluation of the incidence and prognostic role of TC among treatment naive lung cancer patients undergoing chemotherapy at a tertiary care institute in North India was undertaken. Retrospective data analysis and radiological review of newly diagnosed lung cancer patients initiated on chemotherapy over a 2-year period were carried out. Demographic characteristics and overall survival (OS) were compared between patients with and without TC at baseline. Patients who received 3 or more cycles of chemotherapy were included in analysis for response rates and new onset TC. Overall, 27 (7.8 %) of 347 patients had baseline TC. Among 271 non-small cell lung cancer (NSCLC) patients with (n = 26) and without (n = 245) baseline TC, histology was the only demographic characteristic that differed significantly [squamous 76.9 vs. 46.9 %; p = 0.004]. Majority (82.7 %) of NSCLC patients had advanced (stage IIIB/IV) disease. NSCLC patients with and without baseline TC alive at 6 months, 1 and 2 years were 34.6 versus 53.9 %, 11.5 versus 25.7 % and 3.8 versus 7.8 %, respectively. NSCLC patients with baseline TC had shorter median OS than those without (174 days [95 % confidence interval (CI) 106-242 days] vs. 235 days [95 % CI 207-263 days]). On multivariate Cox proportional hazard analysis, age [hazard ratio (HR) = 1.02, 95 % CI 1.01-1.04] and baseline TC [HR = 1.66, 95 % CI 1.03-2.69] were found significant. Response rates were similar between the two groups. Patients with TC after chemotherapy differed from those without in frequency of squamous histology (77.8 vs. 38.9 %; p < 0.001) and presence of metastatic disease (19.4 vs. 40.9 %; p = 0.016). Squamous histology has a significant association with presence of baseline TC and of new onset TC after chemotherapy. Presence of baseline TC has an independent association with shorter OS among NSCLC patients undergoing first-line chemotherapy. PMID- 23673988 TI - Differential expression of Yes-associated protein and phosphorylated Yes associated protein is correlated with expression of Ki-67 and phospho-ERK in colorectal adenocarcinoma. AB - Yes-associated protein (YAP) is a transcriptional co-activator and functions as a nuclear downstream effector of the Hippo pathway. Differential expression of YAP and phosphorylated Yes-associated protein (pYAP), which are involved in the expression of Ki-67 and phosphorylated extracellular signal-regulated kinase (pERK) in colorectal adenocarcinoma (CRAC), is not clear. Herein, we hypothesized that nuclear expression of YAP could predict cell proliferation and poor prognosis, while cytoplasmic expression of pYAP would show a reverse correlation with cell proliferation. Paraffin-embedded samples from 144 CRAC patients were studied using immunohistochemistry for YAP, pYAP, Ki-67 and pERK. Frozen samples from 20 CRAC patients were examined for YAP mRNA in tumor and non-tumor tissues, using quantitative real-time PCR. High nuclear YAP expression coincided with high Ki-67 expression (P=0.002). The high nuclear YAP expression group tended to display a poor overall and disease-free survival (P=0.089 and P=0.089, respectively), but YAP mRNA levels in the 20 CRAC tissues were not significantly different in comparison with the 20 non-tumor tissues (P=0.929). We observed an inverse correlation between high cytoplasmic pYAP expression and high Ki-67 expression (P=0.001). Nuclear pERK expression was positively correlated with nuclear YAP expression, but negatively correlated with cytoplasmic pYAP expression (P=0.017 and P=0.020, respectively). Activated nuclear YAP and inactivated cytoplasmic pYAP in CRAC showed a positive correlation with Ki-67 and nuclear pERK expression, suggesting that the expression of YAP and pYAP is a possible predictor of tumor cell proliferation and prognosis in CRAC. PMID- 23673986 TI - Clinical significance of integrin alphavbeta6 expression effects on gastric carcinoma invasiveness and progression via cancer-associated fibroblasts. AB - Over-expression of integrin alphavbeta6 and increased numbers of cancer associated fibroblasts (CAFs) play an important role in the development and progression of cancers. The aim of this study is to investigate the expression level of integrin alphavbeta6 and CAF numbers, their correlation with clinicopathologic features and their role in the prognosis of human gastric cancers. The expression levels of integrin alphavbeta6 and alpha-SMA in CAFs were analyzed by immunohistochemistry. Their correlation with clinicopathologic features, the relationships and the survival time of patients were also analyzed. The integrin alphavbeta6 expression levels were analyzed mainly in gastric cancers. The alpha-SMA expression levels were analyzed mainly in gastric cancers and paraneoplastic tissues. Patients with positive integrin beta6 and alpha-SMA expression have a significantly lower overall survival rate than those with negative integrin beta6 and alpha-SMA expression (P < 0.05). A multivariate analysis using a log-rank test indicated that patients with positive integrin beta6 and alpha-SMA expression and/or a diffuse type of gastric cancer had a significantly poorer overall survival rate than did those with negative integrin beta6 expression (P < 0.05). Integrin beta6 expression correlated significantly with CAF numbers and served as a valuable prognostic indicator for human gastric cancers. PMID- 23673989 TI - Apoptosis-inducing factor (AIF) and leukocyte elastase inhibitor/L-DNase II (LEI/LDNaseII), can interact to conduct caspase-independent cell death. AB - Programmed cell death is an important factor in tissue homeostasis. Lot of work has been performed to characterize the caspase-dependent cell death. Caspase independent cell death, although important in many physiological situations, is less investigated. In this work we show that two caspase-independent effectors of cell death, namely apoptosis-inducing factor and leukocyte elastase inhibitor derived DNase II interact and can cooperate to induce cell death. These results contribute to the knowledge of molecular pathways of cell death, an important issue in the development of new therapeutic strategies for the treatment of cancer or neurodegenerative diseases. PMID- 23673990 TI - Continuous renal replacement therapy with regional citrate anticoagulation: do we really know the details? AB - PURPOSE OF REVIEW: A significant proportion of critically ill patients with acute kidney injury require continuous renal replacement therapy (CRRT). This article summarizes current evidence on the diagnosis and treatment of acute kidney injury. Regional citrate anticoagulation (RCA) is an emerging but complex technique. A variety of solutions and systems are currently used for RCA. Descriptions of the dosage and methods differ significantly and may cause confusion in everyday practice. This article reviews important scientific findings and highlights pharmacological and pathophysiological aspects of RCA, with a special emphasis on practical clinical issues regarding dosage and available citrate solutions. RECENT FINDINGS: RCA provides a similar or even longer circuit run, with manageable metabolic complications. Although large-scale multicentre trials are needed, there is increasing evidence for the benefits of citrate solutions in CRRT. International guidelines recommend using citrate anticoagulation rather than heparin in patients without contraindications against citrate. SUMMARY: RCA-CRRT is a technique that can be safely used in the majority of intensive care patients with severe multiple-organ failure. The range of citrate solutions available, the different methods in use--continuous venovenous haemofiltration, continuous venovenous haemodialysis and continuous venovenous haemodiafiltration--and the lack of a generally accepted complete CRRT 'set' have impeded implementation of the technique in clinical practice. Unresolved questions regarding dosage and assessment preclude evidence-based comparison in prospective, multicentre studies. For the moment, each institution has to develop a local working protocol. In clinical practice, detailed staff training and monitoring of possible metabolic disturbances for this complex intervention is essential. PMID- 23673991 TI - Regional anesthesia for trauma outside the operating theatre. AB - PURPOSE OF REVIEW: Pain management in the trauma patient can be challenging, especially outside the operating room setting. Traditional analgesics such as opioids and NSAIDs are also problematic in trauma care. In this review, the use of regional anesthetic techniques outside the operating theatre is discussed. RECENT FINDINGS: Regional anesthesia is an increasing but still underutilized clinical tool for the trauma patient outside the operating room. Regional anesthesia provides well tolerated and effective analgesia and anesthesia for many indications in the trauma setting including hip fracture, reduction of joint dislocation, wound debridement, laceration repair, and multiple rib fractures. Its use can increase safety and resource allocation in emergency departments. Performance of peripheral nerve blocks, especially with ultrasound, is amenable in various medical environments with minimal training. SUMMARY: Pain is often poorly managed in the trauma patient. In addition to quality analgesia, regional anesthesia provides a variety of benefits in the trauma setting outside the traditional operating room setting. While further utilization requires increased training and structural changes, existing tools such as ultrasound are removing barriers to the widespread use of peripheral nerve block techniques across multiple disciplines. PMID- 23673992 TI - An upside to adversity?: moderate cumulative lifetime adversity is associated with resilient responses in the face of controlled stressors. AB - Despite common findings suggesting that lack of negative life events should be optimal, recent work has revealed a curvilinear pattern, such that some cumulative lifetime adversity is instead associated with optimal well-being. This work, however, is limited in that responses to specific stressors as they occurred were not assessed, thereby precluding investigation of resilience. The current research addressed this critical gap by directly testing the relationship between adversity history and resilience to stressors. Specifically, we used a multimethod approach across two studies to assess responses to controlled laboratory stressors (respectively requiring passive endurance and active instrumental performance). Results revealed hypothesized U-shaped relationships: Relative to a history of either no adversity or nonextreme high adversity, a moderate number of adverse life events was associated with less negative responses to pain and more positive psychophysiological responses while taking a test. These results provide novel evidence in support of adversity-derived propensity for resilience that generalizes across stressors. PMID- 23673993 TI - Shifting selection may control apparent motion. PMID- 23673995 TI - Alkyne metathesis by molybdenum and tungsten alkylidyne complexes. AB - Alkyne metathesis by molybdenum and tungsten alkylidyne complexes is now ~45 years old. Progress in the practical aspects of alkyne metathesis reactions with well-defined complexes, as well as applications, in the last decade, guarantees that it is destined to become a useful method for the synthesis of organic molecules. PMID- 23673994 TI - Coming to grips with the past: effect of repeated simulation on the perceived plausibility of episodic counterfactual thoughts. AB - When people revisit previous experiences, they often engage in episodic counterfactual thinking: mental simulations of alternative ways in which personal past events could have occurred. The present study employed a novel experimental paradigm to examine the influence of repeated simulation on the perceived plausibility of upward, downward, and neutral episodic counterfactual thoughts. Participants were asked to remember negative, positive, and neutral autobiographical memories. One week later, they self-generated upward, downward, and neutral counterfactual alternatives to those memories. The following day, they resimulated each of those counterfactuals either once or four times. The results indicate that repeated simulation of upward, downward, and neutral episodic counterfactual events decreases their perceived plausibility while increasing ratings of the ease, detail, and valence of the simulations. This finding suggests a difference between episodic counterfactual thoughts and other kinds of self-referential simulations. Possible implications of this finding for pathological and nonpathological anxiety are discussed. PMID- 23673996 TI - Molecular characteristics of homologous salivary adenoid cystic carcinoma cell lines with different lung metastasis ability. AB - Although the homologous salivary adenoid cystic carcinoma (SACC) cell lines SACC 83 and SACC-LM have already been used as SACC models to investigate the underlying mechanisms of metastasis, the molecular features of these SACC cell lines remain unclear. We screened 136 genes related to metastasis in order to investigate the biological and molecular properties of these two cell lines by short tandem repeat (STR) profiling, immunostaining, transwell invasion assay, real-time PCR and western blotting. STR and immunostaining results showed that SACC-83 and SACC-LM are homologous cancer cell lines, derived from adenoepithelial cells and, to date, are not contaminated by each other or other cancer cell lines. Transwell invasion assay results showed that SACC-LM had increased invasion ability compared to SACC-83. 29 of the 136 differentially expressed genes including EREG, S100P, cyclooxygenase (COX)-2, phospho-Akt (p Akt), matrix metalloproteinase (MMP)-1, MMP-2, MMP-3, MMP-9, MMP-13 and MMP-14 were found following gene screening in SACC-83 and SACC-LM cells. Compared with SACC-83, SACC-LM presents higher expression of COX-2, S100P and lower expression of MMP-2, p-Akt, which could be candidates for identifying the homologous pair cell lines. PMID- 23673997 TI - The Aphasia Rapid Test: an NIHSS-like aphasia test. AB - The Aphasia Rapid Test (ART) is a 26-point scale developed as a bedside assessment to rate aphasia severity in acute stroke patients in <3 min. We tested its inter-rater reproducibility, its sensitivity to detect changes from Day 1 to Day 8, and the predictive value of D8 ART scores on the 3-month aphasia outcome assessed with the Aphasia Handicap Score (AHS), a 0-5 "Rankin-like" score for aphasic disability. The reproducibility was tested in 91 aphasic patients within one week of stroke onset. The inter-rater concordance coefficient was 0.99 and the weighted Kappa value (kappaw) was 0.93. The sensitivity was tested in 70 aphasic patients by measuring changes in ART values between D1 and D8. Improvement occurred in 46 patients (66 %) and aggravation in three patients (4 %). In these patients, a logistic regression analysis showed that D8 ART was the only significant predictor of good (AHS 0-2) or poor (AHS 4-5) outcome. The ROC curves analyzes showed areas under the curve above 0.9 for good and poor outcome and revealed D8 ART best cut-off values of <12 for good and >21 for poor outcome, with more than 90 % sensitivity and 80 % specificity. The ART is a simple, rapid and reproducible language task, useful in monitoring early aphasic changes in acute stroke patients and highly predictive of the 3-month verbal communication outcome. It should be easy to adapt to other languages. PMID- 23673998 TI - Shunting for normal pressure hydrocephalus in patients with neurodegenerative disorders. PMID- 23673999 TI - Comparative evaluation of 3-dimensional pseudocontinuous arterial spin labeling with dynamic contrast-enhanced perfusion magnetic resonance imaging in grading of human glioma. AB - INTRODUCTION: The study was performed to compare dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) with 3-dimensional (3D) pseudocontinuous arterial spin labeling (PCASL) MRI in gliomas with an aim to see whether arterial spin labeling (ASL)-derived cerebral blood flow (CBF) values can be used as an alternative to DCE-MRI for its grading. MATERIALS AND METHODS: Sixty-four patients with glioma (37 male; mean age, 43 years; 38 high grade and 26 low grade) underwent 3D-PCASL and DCE-MRI. The DCE indices (relative cerebral blood volume, rCBV; relative CBF, rCBF; permeability, k and kep; and leakage, ve) and ASL (absolute and rCBF) values were quantified from the tumors. Student independent t test was used to compare ASL and DCE-MRI indices. Pearson correlation was used to see correlation between DCE- and ASL-derived CBF values in tumor and normal parenchyma. RESULTS: On Student t test, neither ASL-derived absolute CBF (P = 0.78) nor rCBF (P = 0.12) values were found to be significantly different in 2 groups, whereas DCE indices except ve were significantly higher in high-grade gliomas. Arterial spin labeling-derived rCBF values weakly correlated with DCE-derived rCBF values, whereas these did not show correlation in normal grey (P = 0.12, r = 0.2) and white (P = 0.26, r = 0.14) matter regions. CONCLUSIONS: Three-dimensional pseudocontinuous arterial spin labeling does not appear to be a reliable technique in the current form and may not be a suitable replacement for DCE in grading of glioma. PMID- 23674000 TI - Leukoaraiosis and carotid artery stenosis: evaluation with CT angiography. AB - OBJECTIVE: We aim to determine the relationship between leukoaraiosis and carotid artery stenosis. METHODS: Carotid-cerebral multislice computed tomography angiographies of 194 patients (mean age, 63.5 years) were retrospectively evaluated. Presence and severity of leukoaraiosis and carotid artery stenosis were compared to each other. Carotid artery stenosis was defined by the criteria of the North American Symptomatic Carotid Endarterectomy Trial; leukoaraiosis was evaluated based on the European Task Force on Age-Related White Matter Changes criteria. RESULTS: The frequency of leukoaraiosis was 52%. The correlations between age and presence and severity of leukoaraiosis as well as the degree of carotid artery stenosis were significant. There was a significant relationship between the presence of leukoaraiosis and carotid artery stenosis; also, a positive correlation was found between the severity of the leukoaraiosis and the degree of carotid artery stenosis. CONCLUSIONS: Leukoaraiosis is more common among the elderly. Significant relationship between the severity of leukoaraiosis and the degree of carotid artery stenosis points out that leukoaraiosis may be an advanced stage of atherosclerosis. PMID- 23674001 TI - Efficacy and safety of computer-assisted stereotactic transplantation of human retinal pigment epithelium cells in the treatment of Parkinson disease. AB - OBJECTIVE: This study explores the efficacy and safety of computer-assisted stereotactic transplantation of human retinal pigment epithelium (hRPE) cells in the treatment of Parkinson disease (PD). METHODS: Guided by computed tomography and magnetic resonance imaging image mergence, we transplanted 4 * 10 hRPE cells into the putamina and lateral ventricles of 17 PD cases by stereotactic surgery. The transplantation site was located in the contralateral side of the symptoms and signs. RESULTS: At 3 months after operation, the effective rates of cell transplantation were 82.4% in the contralateral site and 64.7% in the ipsilateral site. Minority of the cases had mild dizziness and hemiparesis, but the durations were short. CONCLUSIONS: Computer-assisted stereotactic transplantation of hRPE for the treatment of PD is safe and efficient. PMID- 23674002 TI - Added value of high-b-value (b = 3000 s/mm2) diffusion-weighted imaging at 3 T in relation to fluid-attenuated inversion recovery images for the evaluation of cortical lesions in inflammatory brain diseases. AB - OBJECTIVE: The purpose of this study was to determine how the gray-to-white matter contrast in healthy subjects changes on high-b-value diffusion-weighted imaging (DWI) acquired at 3 T and evaluate whether high-b-value DWI at 3 T is useful for the detection of cortical lesions in inflammatory brain diseases. METHODS: Ten healthy volunteers underwent DWI at b = 1000, 2000, 3000, 4000, and 5000 s/mm(2) on a 3-T MRI unit. On DW images, 1 radiologist performed region-of interest measurements of the signal intensity of 8 gray matter structures. The gray-to-white matter contrast ratio (GWCR) was calculated. Ten patients with inflammatory cortical lesions were also included. All patients underwent conventional MRI and DWI at b = 1000 and 3000 s/mm(2). Using a 4-point grading system, 2 radiologists independently assessed the presence of additional information on DW images compared with fluid-attenuated inversion recovery images. Interobserver agreement was assessed by kappa statistics. RESULTS: In the healthy subjects, the b value increased as the GWCR decreased in all evaluated gray matter structures. On DW images acquired at b = 3000 s/mm(2), mean GWCR was less than 1.0 in 7 of 8 structures. For both reviewers, DWI at b = 3000 s/mm(2) yielded significantly more additional information than did DWI at b = 1000 s/mm(2) (P < 0.05). Interobserver agreement for DWI at b = 1000 s/mm(2) and b = 3000 s/mm(2) was fair (kappa = 0.35) and excellent (kappa = 1.0), respectively. CONCLUSIONS: At 3-T DWI, the gray-to-white matter contrast in most gray matter structures reverses at b = 3000 s/mm. In the evaluation of cortical lesions in patients with inflammatory brain diseases, 3-T DWI at b = 3000 s/mm was more useful than b = 1000 s/mm(2). PMID- 23674003 TI - Intranodal cystic changes: a potential radiologic signature/biomarker to assess the human papillomavirus status of cases with oropharyngeal malignancies. AB - OBJECTIVE: The aim of this study was to determine if lymph node imaging findings can predict human papillomavirus (HPV) positivity in oropharyngeal squamous cell cancers. METHODS AND MATERIALS: Pretreatment postcontrast neck computed tomographic scans of 49 patients (male, 35; female, 14; age range, 45-76 years) diagnosed with oropharyngeal malignancies and with available HPV data were retrospectively reviewed. Metastatic lymph nodes were identified based on standardly accepted size and morphological criteria. Various lymph node parameters were studied, including presence of cystic foci in the metastatic lymph nodes, abnormal lymph nodes showing low-attenuation foci, matted lymph nodes, and morphologically normal smaller (<1.5 cm) lymph nodes. These parameters were then independently correlated with the available HPV status of these patients. Finally, an extended criterion, that is, intranodal cystic changes in cases with morphologically normal small (<1.5 cm) lymph nodes, was correlated with HPV status. Sensitivity, specificity, and positive predictive values (PPVs) and negative predictive values (NPVs) were calculated. RESULTS: Of these 49 cases with oropharyngeal cancers, 27 were HPV positive, and 22 cases were HPV negative. Eight cases (3 HPV positive and 5 HPV negative) did not have metastatic lymph nodes. Of remaining 41 cases with metastatic abnormal lymph nodes, 26 were HPV positive, and 15 were HPV negative. Of these 41 cases with metastatic lymph nodes, 14 had 1 or more lymph nodes with cystic foci. Of these 14 cases, 10 (71.4%) were HPV positive. Resultant sensitivity, specificity, PPV, and NPV of cystic foci for the presence of HPV status were 38.4%, 73.3%, 71.4%, and 40.7%, respectively. Intranodal cystic changes in cases with morphologically normal small (<1.5 cm) lymph nodes were found in 5 cases; all 5 were HPV positive. Resultant accuracy was specificity and PPV of 100%, sensitivity of 19.2% and NPV of 41.6%. CONCLUSIONS: Intranodal cystic changes seen on the pretreatment postcontrast neck computed tomographic scan of patients with oropharyngeal malignancies are radiologic signatures strongly associated with the HPV status of the patient. The results in this initial study warrant larger prospective studies to determine if this finding may be used in addition to other molecular biomarkers to help identify those patients who may be amenable to the most appropriate treatment options. PMID- 23674005 TI - Contour-based brain segmentation method for magnetic resonance imaging human head scans. AB - The high-resolution magnetic resonance brain images often contain some nonbrain tissues (ie, skin, fat, muscle, neck, eye balls, etc) compared with the functional images such as positron emission tomography, single-photon emission computed tomography, and functional magnetic resonance imaging (MRI) scans, which usually contain few nonbrain tissues. Automatic segmentation of brain tissues from MRI scans remains a challenging task due to the variation in shape and size, use of different pulse sequences, overlapping signal intensities and imaging artifacts. This article presents a contour-based automatic brain segmentation method to segment the brain regions from T1-, T2-, and proton density-weighted MRI of human head scans. The proposed method consists of 2 stages. In stage 1, the brain regions in the middle slice is extracted. Many of the existing methods failed to extract brain regions in the lower and upper slices of the brain volume, where the brain appears in more than 1 connected region. To overcome this problem, in the proposed method, a landmark circle is drawn at the center of the extracted brain region of a middle slice and is likely to pass through all the brain regions in the remaining lower and upper slices irrespective of whether the brain is composed of 1 or more connected components. In stage 2, the brain regions in the remaining slices are extracted with reference to the landmark circle obtained in stage 1. The proposed method is robust to the variability of brain anatomy, image orientation, and image type, and it extracts the brain regions accurately in T1-, T2-, and proton density-weighted normal and abnormal brain images. Experimental results by applying the proposed method on 100 volumes of brain images show that the proposed method exhibits best and consistent performance than by the popular existing methods brain extraction tool, brain surface extraction, watershed algorithm, hybrid watershed algorithm, and skull stripping using graph cuts. PMID- 23674006 TI - Nasal hamartoma associated with duplicated pituitary. AB - Nasal hamartomas are rare congenital lesions. We describe a case of nasal hamartoma associated with pituitary duplication and other midline anomalies. A 40 year-old female with a history of breast cancer presented with nasal obstruction. Computed tomography and magnetic resonance imaging revealed a mass arising from the nasal septum, as well as duplication of the pituitary and a skull base canal that extended from the margin of the left pituitary fossa to the nasal mass. The mass was subsequently resected via a transnasal endoscopic approach and histology confirmed the presence of hamartoma. Nasal hamartomas are benign lesions that can be associated with other midline anomalies, such as duplicated pituitary, and can be managed conservatively. PMID- 23674004 TI - Comparing primary tumors and metastatic nodes in head and neck cancer using intravoxel incoherent motion imaging: a preliminary experience. AB - OBJECTIVE: This study aimed to use intravoxel incoherent motion (IVIM) imaging for investigating differences between primary head and neck tumors and nodal metastases and to evaluate IVIM efficacy in predicting outcome. METHODS: Sixteen patients with head and neck cancer underwent IVIM diffusion-weighted imaging on a 1.5-T magnetic resonance imaging scanner. The significance of parametric difference between primary tumors and metastatic nodes were tested. Probabilities of progression-free survival and overall survival were estimated using the Kaplan Meier method. RESULTS: In comparison with metastatic nodes, the primary tumors had significantly higher vascular volume fraction (f) (P < 0.0009) and lower diffusion coefficient (D) (P < 0.0002). Patients with lower SD for D had prolonged progression-free survival and overall survival (P < 0.05). CONCLUSIONS: Pretreatment IVIM measures were feasible in investigating the physiologic differences between the 2 tumor tissues. After appropriate validation, these findings might be useful in optimizing treatment planning and improving patient care. PMID- 23674007 TI - Fast whole-body magnetic resonance imaging of healthy, term neonates: spectrum of incidental and birth-related findings. AB - PURPOSE: The objective of this study was to describe normal postpartum findings seen with fast whole-body magnetic resonance imaging of healthy, term neonates. METHOD: We prospectively analyzed whole-body 3.0-T magnetic resonance imaging of 53 normal neonates scanned within 72 hours of birth to assess for postpartum related findings. RESULTS: Increased T2 signal within the subcutaneous and fascial tissues was the most common finding. This pattern was seen in 73.5% of neonates, within 32% of the upper extremities and 62% of the lower extremities. Additional patterns of increased T2 signal were seen in the cervical region, joint spaces, groin, and axilla. Several of these patterns were more common in larger infants. No significant differences were seen between vaginal and cesarean deliveries. CONCLUSIONS: The presence of fascial fluid as demonstrated with whole body magnetic resonance imaging is considered a normal finding in postpartum neonates, likely related to the birthing process of labor and not an indication of underlying pathology. PMID- 23674008 TI - Quantitative and qualitative comparison of standard-dose and low-dose pediatric head computed tomography: a retrospective study assessing the effect of adaptive statistical iterative reconstruction. AB - OBJECTIVES: Our aim was to assess the effect of adaptive statistical iterative reconstruction (ASIR) on pediatric head computed tomography (CT) examinations. METHODS: We retrospectively reviewed 305 pediatric head CT examinations. The study population consisted of standard dose (STD, n = 152) examinations reconstructed with filtered back projection and low dose (LD, n = 153) examinations reconstructed with 30% (LD30) and 0% (LD0) ASIR. We compared groups by means of radiation dose, noise measures, and visual grading. Student t test, 1 way analysis of variance test, and Mann-Whitney U test were used for statistical analysis. RESULTS: The dose in the LD30 group was significantly lower (29%) than that in the STD group (P < 0.001). The noise in the white matter (P < 0.001), SNR (P < 0.001), and subjective image noise (P = 0.044) was significantly better in the STD group than those in the LD30 group. There was no significant difference between LD30 and STD groups in the sharpness (P = 0.141), diagnostic acceptability (P = 0.079), and artifacts (P = 0.750) and contrast-to-noise ratio (P = 0.718). CONCLUSIONS: In conclusion, we found that a blend of 30% ASIR in a 16-slice multidetector CT produces diagnostically acceptable pediatric head CT examinations with a 29% less dose. PMID- 23674009 TI - Noncardiac findings in clinical cardiac magnetic resonance: prevalence in 300 examinations after blind reassessment. AB - PURPOSE: To assess the prevalence of noncardiac findings (NCFs) in a consecutive series of 300 cardiac magnetic resonance (CMR) studies. METHODS: We retrospectively evaluated CMRs of 192 males and 108 females (42 +/- 22 years), comparing findings included in reports to those detected after focused reassessment of CMR images. Noncardiac findings were classified as relevant if additional workup was required. RESULTS: We found 19 NCFs, 14 (4.7%) tagged as nonrelevant and 5 (1.7%) as relevant. Images' reassessment presented 45 NCFs, 26 (8.7%) nonrelevant and 16 (5.3%) relevant (P < 0.003). CONCLUSIONS: Cardiac magnetic resonance involves the study of areas larger than the heart alone, and NCFs are found in 1 of 7 patients; more than a half of them are not included in the initial CMR report. A small part is relevant, but detection can be unnecessarily stressful and harmful for patients and could increase costs. Risks of overdiagnosis or underreporting are to be taken into account. PMID- 23674010 TI - Accuracy and predictive value of coronary computed tomography angiography for the detection of obstructive coronary heart disease in patients with an Agatston calcium score above 400. AB - PURPOSE: We assessed the accuracy of coronary computed tomography angiography (CTA) in patients with an Agatston calcium score (ACS) of greater than 400 by comparing it with invasive coronary angiography (ICA), and we evaluated the predictive value of CTA for obstructive coronary heart disease (CHD) compared with traditional clinical risk assessment. METHODS: A total of 253 patients who had an ACS of greater than 400 were enrolled in this study. The degree of coronary stenosis was visually and quantitatively estimated by postprocessing imaging using 15-segment coronary models. All patients underwent ICA after a mean (SD) of 34 (24) days, and the degree of coronary stenosis was compared with the results of CTA. RESULTS: Computed tomography angiography accurately diagnosed significant stenosis in 204 (99.0%) of 206 patients and in 649 (83.5%) of 777 segments. When the patients were considered based on their ACS (group A, 400 < ACS <= 1000, vs group B, ACS > 1000), group B showed lower specificity (9.1% vs 41.7%) and poorer agreement (k = 0.149 vs 0.495) than for ICA. By segment-based analysis, the agreement between CTA and ICA was good (k = 0.729), and there was no significant difference between groups A (k = 0.728) and B (k = 0.727). Computed tomography angiography was the most powerful predictor (odds ratio = 52.645, P < 0.001), whereas the 10-year CHD risk and pretest probability were not significantly correlated with obstructive CHD. CONCLUSIONS: Despite good overall diagnostic accuracy, coronary CTA in this group of patients was limited by low specificity. However, CTA was a better predictor of obstructive CHD compared with clinical predictors, and it avoided unnecessary ICA, even in patients with extensive coronary artery calcification. PMID- 23674011 TI - Multidetector computed tomography for coronary stents imaging: high-voltage (140 kVp) prospective ECG-triggered versus standard-voltage (120-kVp) retrospective ECG-gated helical scanning. AB - OBJECTIVE: To compare prospective electrocardiogram (ECG)-triggered high-voltage coronary computed tomography (CT) angiography (CTA; 140-kVp P-cCTA) with retrospective ECG-gated standard-voltage cCTA (120-kVp R-cCTA), in patients with coronary stents. METHODS: Fifty-two patients with coronary stents were studied with 64-slice multidetector scanner. Ninety-three stents were analyzed: 55 with 140-kVp P-cCTA and 38 with 120-kVp R-cCTA. Image quality (IQ), diagnostic confidence (DC), in-stent assessable lumen, artificial narrowing, and effective radiation dose were compared between techniques. RESULTS: Image quality and DC were significantly better for the 140-kVp P-cCTA in comparison with the 120-kVp R cCTA (IQ, 1.1 +/- 0.36 vs 1.7 +/- 0.60, respectively; P < 0.00001. Diagnostic confidence: 1.1 +/- 0.29 vs 1.5 +/- 0.65 respectively; P < 0.0001). In-stent assessable lumen and artificial narrowing were comparable between the techniques. Effective dose was lower for the 140-kVp P-cCTA (6.7 +/- 2.07 mSv vs 15.8 +/- 6.89 mSv; P < 0.0001). CONCLUSIONS: High voltage combined with axial prospective ECG-triggered scan improved IQ and DC in stent cCTA imaging but failed to improve the diameter of in-stent assessable lumen and to reduce the artificial narrowing compared with the 120-kVp R-cCTA. Effective dose was 60% lower for the 140-kVp P cCTA. PMID- 23674012 TI - In vivo evaluation of carotid artery stents using multi-detector-row computed tomography angiography: comparison of 3 kernels. AB - OBJECTIVE: The objective of this study was to assess the lumen visibility of carotid artery stents using multi-detector-row computed tomography (MDCT) angiography; compare medium-smooth, medium-sharp, and sharp kernels; and correlate these results to those of digital subtraction angiography (DSA). METHODS: We retrospectively evaluated 52 stents from 51 patients who underwent 16 and 64-slice MDCT angiography. Lumen diameters were measured 3 times by 2 neuroradiologists, and artificial luminal narrowing was calculated. To assess detection of in-stent restenosis (>50%), 2 neuroradiologists evaluated all MDCT and DSA images. RESULTS: Excellent intraobserver and interobserver agreements were obtained for the lumen diameter measurements (P < 0.001). Lumen diameter visibility improved, and artificial luminal narrowing decreased from the medium smooth kernel to the sharp kernel. Visual estimation of all CT angiography using the 3 kernels showed high accuracy for detection of in-stent restenosis (>50%), compared with DSA. CONCLUSIONS: Computed tomography angiography using a sharp kernel allows for more accurate assessment of lumen visibility after carotid artery stenting. PMID- 23674013 TI - Multiphase multi-detector row computed tomography in the setting of chronic liver disease and orthotopic liver transplantation: can a series be eliminated in order to reduce radiation dose? AB - OBJECTIVE: The objectives of this study were to explore utilization of multi detector row computed tomography (MDCT) in screening for hepatocellular carcinoma (HCC) and to modify a liver CT protocol with a goal of dose reduction. METHODS: An electronic mail survey querying HCC surveillance practices was sent. One hundred forty consecutive patients referred for HCC indications underwent 4-phase MDCT of the liver. The unenhanced and delayed phases were evaluated by 3 readers for identification of HCC and reader confidence. The estimated effective dose (ED) was calculated. RESULTS: Computed tomography is primarily used to screen for HCC. Average estimated ED was 35.5 mSv. Unenhanced phase did not add to reader confidence; delayed phase increased confidence in 47% of cases. Thirty-two percent of the screening population had cumulative ED of greater than 200 mSv. CONCLUSIONS: Multi-detector row CT of the liver is used frequently in screening for HCC. Unenhanced phase imaging does not add to HCC detection and may be eliminated to reduce radiation dose. PMID- 23674014 TI - Incidental detection of nutcracker phenomenon on multidetector CT in an asymptomatic population: prevalence and associated findings. AB - OBJECTIVE: To determine the prevalence of nutcracker phenomenon (left renal vein compression by the superior mesenteric artery) and secondary anatomic findings using multidetector computed tomographic (CT) angiography in an asymptomatic population. METHODS: Ninety-nine consecutive CT angiograms for potential renal transplant donors (mean age, 39.0 years; 42 males) without variant renal vein anatomy were reviewed retrospectively. The diameters of the maximal left renal vein, left renal vein between the aorta and superior mesenteric artery, and draining gonadal and lumbar veins were measured. Sex, age, hematuria, proteinuria, and abdominal or flank pain were recorded. RESULTS: Twenty-three patients had 50% to 70% stenosis, and 4 patients had greater than 70% stenosis of the left renal vein. Dilated gonadal and lumbar veins were found in 16 and 28 patients, respectively. Four patients had hematuria. These findings were not significantly associated with left renal vein compression. CONCLUSIONS: Nutcracker phenomenon and dilated veins originating from the left renal vein are common incidental CT findings and nonspecific for the diagnosis of nutcracker syndrome. PMID- 23674015 TI - Diagnostic accuracy of CT angiography in the evaluation of stenosis in lower limbs: comparison between visual score and quantitative analysis using a semiautomated 3D software. AB - OBJECTIVE: To assess the accuracy of a semiautomated 3-dimensional (3D) computed tomographic angiography software in the evaluation of lower limb stenoses compared to reader evaluation, using digital subtraction angiography (DSA) as standard of reference. MATERIALS AND METHODS: Forty patients with peripheral vascular occlusive disease underwent both DSA and computed tomographic angiography. The vascular tree was divided into 6 segments from distal aorta to popliteal artery. Each district was evaluated for significant stenosis by one experienced vascular radiologist (on axial as well as 3D images) and by a semiautomated 3D software analysis, independently. Evaluation of the vessel evaluation was then repeated by a poorly experienced radiologist twice, first without 3D software analysis and then supported by 3D software analysis. RESULTS: Both experienced radiologist and automated evaluations obtained high statistical results when compared to DSA. The analysis by poorly experienced radiologist obtained lower statistical results, which significantly improved when supported by 3D software analysis. CONCLUSIONS: Three-dimensional analysis software should be feasible to identify significant vascular stenoses and may help a poorly experienced radiologist to significantly improve diagnostic accuracy. PMID- 23674016 TI - Low-dose computed tomographic urography using adaptive iterative dose reduction 3 dimensional: comparison with routine-dose computed tomography with filtered back projection. AB - OBJECTIVE: The aim of this study was to evaluate the image quality of low-dose computed tomographic (CT) urography using adaptive iterative dose reduction 3 dimensional (AIDR 3D) compared with routine-dose CT using filtered back projection (FBP). METHODS: Thirty patients underwent low- and routine-dose CT scans in the nephrographic and excretory phases of CT urography. Low-dose CT was reconstructed with AIDR 3D, and routine-dose CT was reconstructed with FBP. In quantitative analyses, image noises were measured on the renal cortex, aorta, retroperitoneal fat, and psoas muscle in both CT scans and compared. Qualitative analyses of the urinary system were performed in both CT scans and compared. These results were compared on the basis of the body mass index (BMI) of the patients. The CT dose index (CTDIvol) was measured, and the dose reduction was calculated. RESULTS: In quantitative analyses, image noises in all organs on low dose CT were less than those on routine-dose CT in both phases independently of the patient's BMI. There were no statistical differences between low- and routine dose CT for diagnostic acceptability on all urinary systems in both phases independently of the patient's BMI. The average CTDIvol on routine-dose CT was 14.5 mGy in the nephrographic phase and 9.2 mGy in the excretory phase. The average CTDIvol on low-dose CT was 4.2 mGy in the nephrographic phase and 2.7 mGy in the excretory phase. CONCLUSIONS: Low-dose CT urography using AIDR 3D can offer diagnostic acceptability comparable with routine-dose CT urography with FBP with approximately 70% dose reduction. PMID- 23674017 TI - Magnetic resonance imaging enhancement features before and after neoadjuvant chemotherapy in patients with breast cancer: a predictive value for responders. AB - PURPOSE: This study examined the ability of magnetic resonance imaging (MRI) enhancement features to predict the response to neoadjuvant chemotherapy (NAC) in patients with breast cancer. METHODS: This retrospective study included 107 patients with breast cancer. All patients underwent a baseline breast MRI before NAC and follow-up MRI a mean of 3.7 months later. Breast MRI scans were evaluated using the Breast Imaging Reporting and Data System MRI lexicon. In addition, whole-breast vascularity (WBV) in the cancer-bearing breast was graded according to increased vessel number in comparison with the contralateral breast. Histopathologic tumor regression was graded semiquantitatively based on the Miller-Payne grading system. The ability of each MRI feature to predict the response was evaluated using a logistic regression analysis. Correlations between changes in MRI features and response were also evaluated using the Spearman rank correlation test. RESULTS: There were 73 responders (68%), including 59 partial and 14 complete responders. No significant difference in baseline MRI features was found between the responders and nonresponders, except for tumor size (P = 0.044). No dynamic enhancement feature on baseline MRI was useful for the early prediction of a response. In addition, an increased WBV did not predict a response, and the WBV change on the follow-up MRI was not correlated with the response. However, the change in the initial enhancement pattern (P = 0.007) and kinetic curve type (P = 0.003) were significantly correlated with response. CONCLUSIONS: No baseline MRI feature described using the Breast Imaging Reporting and Data System MRI lexicon was useful for early prediction of the response to NAC. PMID- 23674018 TI - Clinical value of acute pyelonephritis grade based on computed tomography in predicting severity and course of acute pyelonephritis. AB - PURPOSE: This study aimed to evaluate the efficacy of computed tomography (CT) based acute pyelonephritis (APN) grades for predicting clinical severity and disease course. MATERIALS AND METHODS: This study involved the analysis of the data of 204 consecutive patients with APN who underwent a CT examination at admission. Patients who had undergone prior treatment and those with ureteral calculi or an abscess by CT were excluded. Computed tomographic findings were divided into 4 grades according to renal parenchymal involvement, as follows: no renal parenchyma involvement (grade 1), less than 25% involvement (grade 2), 25% to 50% involvement (grade 3), and greater than 50% (grade 4). Patients with these grades were compared with respect to APN severity index (highest body temperature, initial C-reactive protein, and leukocytosis) and recovery index (hospital stay, fever duration, and leukocytosis duration). RESULTS: A total of 204 patients of mean age 39.3 years were included. Acute pyelonephritis severity indices and recovery indices increased with APN grade. Mean highest body temperature values were 38.3 degrees C and 38.9 degrees C in grades 1 and 4, respectively (P = 0.002). Mean hospital stay increased from 5.7 days for grade 1 to 7.6 days for grade 4 (P < 0.001). Initial C-reactive protein, initial leukocytosis, fever duration, and leukocytosis duration also increased with APN grade. CONCLUSIONS: This study suggests that APN grades, as determined by CT examination, valuably predict the clinical course of APN. PMID- 23674019 TI - Comparison of multidetector computed tomography angiography and cholangiography performed at 80 and 120 kVp in live liver donors. AB - OBJECTIVE: The objective of this study was to compare the radiation exposure and image quality of contrast-enhanced multidetector computed tomography angiography (CTA) and computed tomography cholangiography (CTC) performed for living liver donor evaluation using 80 and 120 kVp. METHODS: Ninety-three potential liver donors who underwent preoperative contrast-enhanced 64 multidetector CTA and CTC were retrospectively divided into 2 groups: at 80 and at 120 kVp. An institutional review board waiver was obtained. Signal-to-noise ratio and contrast-to-noise ratio of the hepatic artery and common bile duct were obtained. The dose-length product was recorded. Image quality and visibility of hepatic artery and biliary tract anatomy were evaluated. Mann-Whitney U test was used for statistical evaluation. RESULTS: Mean hepatic artery/common bile duct signal-to noise ratio was 28.9/28.6 (SD, 14.2/10.0) at 80 kVp and 27.6/25.8 (SD, 8.0/6.2) at 120 kVp (P = 0.61/0.099). Mean hepatic artery/common bile duct contrast-to noise ratio was 24.8/23.3 (SD, 12.9/8.6) at 80 kVp and 22.2/19.3 (SD, 7.7/5.0) at 120 kVp (P = 0.76/0.005). Mean CTA/CTC dose-length product was 279/281 (SD, 42/52) mGy-cm at 80 kVp and 407/451 (SD, 208/243) mGy-cm at 120 kVp (P = 0.026/0.002). Computed tomography cholangiography image quality and visibility of biliary tract anatomy were not significantly different at 80 versus 120 kVp (all P > 0.13). Computed tomography angiography image quality was significantly lower (P < 0.01), and the noise scores significantly higher (P < 0.01) at 80 versus 120 kVp, but diagnostic. CONCLUSIONS: Contrast-enhanced CTA and CTC performed at 80 kVp result in comparable image quality and anatomical evaluation with reduced radiation exposure when compared with 120 kVp. PMID- 23674020 TI - Perirenal fat invasion on renal cell carcinoma: evaluation with multidetector computed tomography-multivariate analysis. AB - OBJECTIVE: The objective of this study was to assess the accuracy of multidetector computed tomography (CT) in diagnosing perinephric (PN) and/or renal sinus (RS) fat invasion in patients with renal cell carcinoma (RCC), with reference to the CT findings predictive for the diagnosis of invasion. METHODS: This was a retrospective study of 48 RCCs. Examinations were performed on a 16 row CT scanner, including unenhanced and 3-phase contrast-enhanced CT scanning. Unenhanced transverse images and multiplanar reformations of each contrast enhanced CT phase were evaluated. The predictive value of CT findings in diagnosing PN and/or RS fat invasion was determined using multivariate logistic regression analysis. RESULTS: The CT findings that were most predictive for the diagnosis of PN fat invasion were the presence of contrast-enhancing nodules in the PN fat and tumoral margins. Invasion of the pelvicaliceal system was the most significant predictor in the diagnosis of RS fat invasion. CONCLUSIONS: Multidetector CT provides satisfactory results in detecting PN and/or RS fat invasion in RCC. PMID- 23674021 TI - Bone marrow enhancement during time-resolved magnetic resonance angiography of the pelvis. AB - OBJECTIVE: This study aimed to determine whether visible bone marrow enhancement (BME) at pelvic magnetic resonance angiography (MRA) correlates with anemia. METHODS: This is an institutional review board-approved, Health Insurance Portability and Accountability Act-compliant retrospective study. Seventy-five female patients with a hemoglobin (Hb) test within 10 days of an MRA examination of the pelvis are included, mean age of 46 years (range, 18-81 years). The BME was graded using a 4-point scale. Fifteen subjects had sufficient imaging data for calculation of quantitative perfusion parameters. Receiver operating characteristic and analysis of covariance were performed for 2 levels of anemia. RESULTS: Enhancement was visually present in 44% (33/75) of cases; 66% (19/29) of anemic subjects (Hb < 12 g/dL), and 30% (14/46) of nonanemic subjects (P = 0.002). Enhancement had a sensitivity of 87.5% and a specificity of 92.5% for the diagnosis of severe anemia (Hb < 10 g/dL); 88% (7/8) of these subjects had moderate to marked enhancement. A high extraction coefficient (Kep) in the iliac crest was associated with anemia, with an area under the curve of the receiver operating characteristic of 0.85 for mild anemia and 0.92 for severe anemia. CONCLUSIONS: Visible BME during time-resolved MRA is common and may be related to anemia. PMID- 23674022 TI - Metastatic colon carcinoma to the prostate gland. AB - We present a case report of a 70-year-old man with a known history of sigmoid adenocarcinoma, treated with chemotherapy and surgical resection of synchronous lung metastases. Four years after initial diagnosis, the patient was diagnosed with metastases to the prostate gland, proven pathologically. To our knowledge, colon adenocarcinoma metastasizing to the prostate has not been previously described on magnetic resonance imaging and positron emission tomography-computed tomography. PMID- 23674023 TI - Early hepatocellular carcinomas showing isointensity or hyperintensity in gadoxetic acid-enhanced, hepatocyte-phase magnetic resonance images. AB - Hypointensity in the hepatocyte phase is believed to be a key feature of hypovascular early hepatocellular carcinoma, which indicates malignancy. The 3 cases we present suggest that the converse is not true. Three small hepatocellular lesions showed isointensity/hyperintensity on gadoxetic acid enhanced, hepatocyte-phase magnetic resonance images and were pathologically confirmed as early hepatocellular carcinomas. We conclude that isointensity or hyperintensity in the hepatocyte phase does not always represent benignity of hepatocellular lesions in the cirrhotic liver. PMID- 23674025 TI - Achilles tendinopathy and partial tear diagnosis using dual-energy computed tomography collagen material decomposition application. AB - Computed tomographic (CT) scans of the ankle and foot are frequently obtained with in-patients with hind foot and ankle pain to identify fractures, arthritis, and bone lesions. Soft tissue detail is limited, however. Dual-energy CT provides additional information on soft tissue structures, including tendons, with no additional radiation dose to the patient. We present a case of an Achilles tendon tear visualized on DECT, which was subsequently confirmed with magnetic resonance imaging. PMID- 23674024 TI - A new assessment of patellar instability using coronal magnetic resonance images of the patella superimposed on the femur and its clinical utility. AB - OBJECTIVE: This study aimed to evaluate the clinical utility of a new assessment for patellar subluxation using magnetic resonance (MR) images of the patella superimposed on the femur and to determine its correlation with the tibial tuberosity-trochlear groove (TT-TG) distance. MATERIALS AND METHODS: This retrospective study included 81 men and 44 women who underwent MR imaging at our institution. There were 19 cases of patellar dislocation. The control group consisted of 116 patients. An assessment of the distance of subluxation was carried out using coronal superimposed MR images. The results were correlated with the TT-TG distance calculated using the axial combined MR images. The sensitivity and specificity of various distances of subluxation were evaluated as diagnostic thresholds for patellar dislocation, where the clinical diagnosis was used as the standard of reference. RESULTS: The use of the distance of subluxation on coronal superimposed MR images showed discrete difference between patellar dislocation and controls. The mean distance of subluxation was approximately 3 times larger for patients with patellar dislocation compared with controls (P < 0.001). Likewise, the mean TT-TG distance was approximately 50% greater for patients with patellar dislocation compared with controls (P < 0.001). However, there was no correlation between the distance of subluxation and the TT-TG distance. The best diagnostic discrimination was achieved at the 7-mm threshold of subluxation. CONCLUSIONS: The use of the distance of subluxation on coronal superimposed MR images can be a useful method to evaluate patellar dislocation. The best diagnostic discrimination was achieved at a threshold of 7 mm. PMID- 23674026 TI - Plantar plate tear diagnosis using dual-energy computed tomography collagen material decomposition application. AB - Computed tomography (CT) scans of the feet are often obtained in the context of trauma or suspected stress fracture mainly for assessment of osseous pathology. However, compared with magnetic resonance imaging (MRI), soft-tissue assessment on CT is typically limited. Plantar plate injury is a common cause of metatarsalgia and, along with other soft-tissue injuries, is typically diagnosed with MRI. We present a case of plantar plate tear detected on dual-energy CT scan using a collagen material decomposition algorithm confirmed on subsequent MRI. PMID- 23674030 TI - [Solitary pulmonary lesion developed after the resection of primary lung cancer]. AB - The purpose of this study was to evaluate the characteristics of solitary pulmonary lesion developed after the resection of primary lung cancer and the outcome. Between 1990 and 2011, 1,004 patients underwent complete resection for primary lung cancer in our hospital and we retrospectively analyzed 53 patients with a history of primary lung cancer resection who had a solitary pulmonary lesion. Pulmonary resections were performed in 43 patients. Wedge resection and segmentectomy were performed in 42( 98%) of them. There was no operative death. The diagnosis was 2nd primary lung cancer in 28 patients, recurrent lesion in 9, and benign lesions in 6. Malignant tumor ratio of resected cases was 86%.Other unresected 10 cases were not diagnosed historogically and 9 of them underwent radiation therapy. The 5-year survival rate was 57.3% in those with 2nd primary lung cancer, 55.5% in those with recurrent lesion, and 64.3% in those with undiagnosed-unresected lesions( no significant difference). It is important to take a surgical approach for a diagnosis and to treat with standard therapy for both 2nd primary lung cancer and recurrent lesion. Sublobar resection may be adequate. In patients with a undiagnosed nodule who were not able to have 2nd surgery, radiation therapy may be permitted and effective. PMID- 23674031 TI - [Simplified aortic root replacement in the era of complex operation]. AB - OBJECTIVES: The purpose of the present study is to assess the clinical results of aortic root replacement using the Carbo-Seal composite graft( CS) compared with the other type of homemade composite grafts. Fifty-nine patients who underwent aortic root replacement between January 1998 to December 2010 were retrospectively analyzed. Twenty-six received homemade composite graft( group 1;1998 ~ 2005) and 33 received CS( group 2;2005 ~ 2010). RESULTS: The duration of operation was longer in group 1:469.2+/-143.5 min versus 380.3+/-153.9 min (p=0.03). Although there was no statistically significant difference, group 2 had a higher complex operation rate compared with group1(23.1% versus 45.5%, p=0.07). Overall hospital mortality was 11.5% in group1 versus 3.0% in group2. Prevalence of major complication was significantly lower in group 2 (46.2% versus 18.2%, p=0.02).Requirement of intraoperative blood transfusion (group 1;1,130.8+/-854.7 ml versus group 2;598.2+/-836.4 ml) and amount of blood loss in the 1st 12 hours post operation (group 1;628.3+/-474.6 ml versus group 2;447.8+/-253.2 ml) were significantly lower in group 2. By univariate analysis, duration of operation, duration of cardio-pulmonary bypass (CPB), blood transfusion, acute dissection were independent risk factors and CS use was negative risk factor for major events. Aortic root replacement with use of CS can be performed with a relatively low early mortality and morbidity. Because a complicated operation is increasing in recent years, use of CS graft may simplify a Bentall operation. PMID- 23674032 TI - [Management of cardiopulmonary bypass during cardiac surgery for patients with heparin-induced thrombocytopenia]. AB - We experienced 4 cases of open heart surgeries under preoperative diagnosis of heparin-induced thrombocytopenia(HIT). We performed operation with argatroban instead of heparin. The argatroban was administered intravenously with a bolus of 100 MUg/kg. After activated clotting time(ACT)reached over 200 seconds, continuous infusion of argatroban was started, 1~2 MUg/kg/min until the level of ACT over 250 in the case of off-pump coronary artery bypass grafting(OPCAB), with 6~10 MUg/kg/min, or the level of ACT over 400 with the use of cardiopulmonary bypass (CPB). All cases required more than 60 minutes to achieve the target ACT level after starting the argatroban. In 1 case it was impossible to achieve target level of ACT by argatroban alone, and heparin was used concomitantly. In 1 case there was a complication of membrane occlusion of CPB. Open cardiac surgery with the use of argatroban required specific care for coagulation to complete operation. PMID- 23674033 TI - [Axillo-axillary bypass for coronary-subclavian steal syndrome]. AB - We describe a case of coronary-subclavian steal syndrome in a 77-year-old man who presented with progressive coronary ischemia 8 years after coronary artery bypass grafting with an in-situ left internal thoracic artery graft. Coronary and left subclavian artery angiogram revealed completely patent internal thoracic artery graft and 90% stenosis in the proximal left subclavian artery. We performed axilloaxillary artery bypass using expanded polytetrafluoroethylene (ePTFE)[8 mm] graft. No coronary ischemia was noted postoperatively. Axillo-axillary artery bypass grafting was effective for coronary subclavian steal syndrome. PMID- 23674034 TI - [Thoracoscopic surgery for traumatic mediastinal hematoma]. AB - We report a rare case of traumatic mediastinal hematoma treated by thoracoscopic surgery. A 78-year-old man accidentally fell down from the roof, and he was urgently transferred to our hospital. Soon after the arrival, he showed breathlessness followed by cardiopulmonary arrest, necessitating tracheal intubation and resuscitation. Computed tomography (CT) showed a large cervical hematoma extending to the tracheal bifurcation level of mediastinum, causing tracheal obstruction. Five days later, the large mediastinal hematoma was removed by thoracoscopic surgery. The patient recovered without any complications after our treatments. PMID- 23674035 TI - [Combined surgical and endovascular treatment( hybrid-procedure) of thoracoabdominal dissecting aneurysm]. AB - A 50-year-old man was admitted because of enlargement in diameter of the descending thoracoabdominal aorta. Seven years previously, he had undergone Bentall operation and graft replacement of the aortic arch due to an acute dissecting aneurysm, and he had also received graft replacement of the descending aorta due to a rupture of dissecting aneurysm 2 years before. The surgical stress of conventional repair under left lateral thoracotomy and laparotomy was considered to be excessive, and the 3-dimensional computed tomography (3D-CT) image revealed the reconstruction of intercostals artery was difficult. Hence, extra-anatomic bypasses were created to perfuse the visceral and renal vessels, and endovascular thoracic stent-grafts were deployed into the false lumen, because of the severe narrowing of the true lumen( hybrid-procedure). The postoperative course was uneventful and the patient was discharged on postoperative 30 days. Hybrid-procedure of aortic aneurysm is feasible, and may be an alternative to standard open procedures in high-risk patients and emergency cases. PMID- 23674036 TI - [Open heart surgery using cardiopulmonary bypass in a patient with heparin induced thrombocytopenia(HIT)]. AB - Heparin-induced thrombocytopenia (HIT) is a life-threatening side effect of heparin therapy. We report an open heart surgery with cardiopulmonary bypass( CPB) using argatroban as an anticoagulant for a patient with HIT. A 72-year-old male with a history of percutaneous coronary intervention 5 years ago, was admitted to our hospital due to congestive heart failure and heparin 10,000 units/day was administered. At 10th hospital day, his platelet count was significantly decreased and antibodies positive for type II HIT was found, so he was diagnosed HIT. Echocardiogram and coronary angiography revealed severe functional mitral regurgitation and coronary stenosis. At 24th hospital day we performed coronary artery bypass grafting( CABG) and mitral valve replacement (MVR) with CPB using argatroban as an anticoagulant. During CPB, we monitored the activated clotting time (ACT) to adjust the dose of argatroban. Though the surgical procedure itself was uneventful. We required about 4 hours to achieve adequate hemostasis after CPB. Postoperative course was uneventful. PMID- 23674037 TI - [Foreign body granuloma with positive 18-fluorodeoxyglucose positoron emission tomography( FDGPET)3 years after thymectomy]. AB - A seventies year-old woman underwent thymo-thymectomy through a median sternotomy for type B2 thymoma. Annual screening with fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography( CT) did not show any abnormality until 3 years after surgery, when a FDG-positive lesion, 1.5 cm in diameter, was found in the top of the anterior mediastinum. The lesion was resected under the diagnosis of thymoma recurrence, but was pathologically diagnosed as a foreign body granuloma including a suture thread. False-positive results with FDG-PET are related to FDG-uptake by inflammatory cells (e.g. macrophages and lymphocytes in the granuloma). Although FDG-PET is useful for diagnosing the postoperative recurrence of tumors, it should be noted that a foreign body granuloma and local recurrence of tumor have similar growth rates and both appear positive on FDGPET. PMID- 23674038 TI - [Intrathoracic washing with urokinase was effective for empyema with atelectasis]. AB - A 60-year-old man had a medical examination because of fever in the emergency hospital and had a diagnosis of pneumonia and was treated, but he was admitted to our hospital 2 days later because there was not the improvement of his symptom. The chest computed tomography(CT)image showed multilocular pleural effusions and lower lobe atelectasis with the air bronchogram on the left side. We diagnosed the case as empyema and inserted a catheter, but drainage was very few and injected 60,000 urokinase units for 3 days from the next day. We removed a drain 2 days after the 3rd infusion, and the pleural thickening became mild, and atelectasis was gradually improved in the chest CT image, and the inflammatory reaction was reduced, too. The intrathoracic washing with urokinase was thought to be effective for empyema with atelectasis. PMID- 23674039 TI - [Development of hemostatic sealant for arterial anastomosis; clinical application]. AB - For the purpose of examining the clinical applicability of a newly developed surgical sealant, animal experiments were performed, and clinical trial was followed. In animal experiments, several animal models, including carotid artery anastomosis model and coronary artery bypass grafting model were undertaken. In each model, complete hemostasis of the anastomoses using four simple interrupted sutures, was obtained. In addition, elastomeric property of the sealant prevented thinning of the arterial wall. The clinical trial performed in patients with thoracic aortic surgery showed significantly better hemostasis even under heparinized condition. Based on these excellent results, clinical usage of the sealant was approved. PMID- 23674040 TI - [The research purposes and design of clinical database]. AB - We discussed clarification of research purposes and designing of data collection form in large clinical databases. Research purposes are 1)assessment of healthcare quality, 2)evaluation of diagnosis and treatment, and 3)evaluation of health policy. In designing clinical databases, the researchers should consider the following themes;assurance of clinical utility, international collaboration, alleviation of data entry burden and assurance of scientific accuracy. PMID- 23674041 TI - [Successful repair of descending aortic aneurysm with narrowed elephant trunk after total arch replacement; report of a case]. AB - A 40-year-old man had undergone total arch replacement using the elephant trunk technique. Three years after the initial operation, stenosis of the elephant trunk due to enlargement of a false lumen was detected. Replacement of the descending thoracic aorta was performed. A narrow segment of the elephant trunk was compressed by old hematoma and lapped around the connective tissue. A new graft was anastomosed to the narrow segment of the elephant trunk in an end-to side fashion. Postoperative course was uneventful, and he was discharged 18 days after the operation. PMID- 23674042 TI - [An adult case of tricuspid valve endocarditis with ventricular septal defect; report of a case]. AB - A 50-year-old man was admitted to hospital because of an elevated fever. He had been diagnosed with ventricular septal defect in his childhood, but surgery had not been recommended. An echocardiogram showed vegetations on the tricuspid valve, severe tricuspid regurgitation and perimembranous ventricular septal defect. He was diagnosed with infective endocarditis( IE) and treated with antibiotics and diuretics. Five serious dental caries, which had probably caused IE, were found and extracted before surgery. After 4 weeks of medical treatment, we performed tricuspid valve repair and closed the ventricular septal defect. The postoperative course was uneventful. He has been free from any complication for over 3 years. PMID- 23674043 TI - [Staged operation of aortic valve stenosis with concomitant sigmoid colon cancer by minimally invasive cardiac surgery; report of a case]. AB - Severe aortic stenosis was found by preoperative echocardiography in a 79-year old female patient with sigmoid colon cancer. Staged operation was planned. First, bioprosthetic aortic valve replacement was performed by minimally invasive cardiac surgery. She underwent concomitant colostomy to avoid malnutrition which may have occurred in case of colon obstruction. On 25th day after cardiac surgery, curative sigmoidectomy was performed. One year after the operation, she is doing well without any major complications. PMID- 23674044 TI - [Catamenial pneumothrax treated in portable pneumothorax drainage kit; report of a case]. AB - A 37-year-old woman visited our hospital for right pneumothorax and was treated using a portable thoracic drainage kit(Thoracic Egg). A month later, she had relapse of right pneumothorax with onset of a menestration. Catamenial pneumothorax was diagnosed clinically and the surgical treatment and a hormone therapy were recommended. But she refused our proposal and desired a treatment using Thoracic Egg again. Thereafter, she relapsed pneumothorax 3 times, and was treated by rest or using Thoracic Egg. A Thoracic Egg was useful for management of spontaneous pneumothorax, but there is no report concerning the catamenial pneumothorax. Thoracic Egg may be a choice of treatment for catamenial pneumothorax of minor or moderate grade. PMID- 23674045 TI - [Delayed laryngeal nerve paralysis after lung cancer surgery; report of a case]. AB - A 75-year-old woman with mesopharyngeal adenocarcinoma underwent left upper lobectomy for lung adenocarcinoma. Before the operation, computed tomography showed no stricture of the trachea, and laryngoscope showed no abnormality of vocal cord. Spiral tube( 7.5 mm I.D.) was used instead. One lung ventilation was achieved using balloon. It took 4 hours and 3 minutes to finish the surgical procedure. After extubation in the operation room, we did not recognize the breathing abnormality and laryngeal nerve palsy. 4 days after the operation, stridor was noticed, and laryngoscopic examination revealed stenosis of glottis due to bilateral laryngeal nerve paralysis. We performed the emergent tracheotomy. 7 days after the operation, nerve paralysis improved. PMID- 23674046 TI - [Very elderly case of spontaneous esophageal rupture successfully treated by conservative treatment;report of a case]. AB - A 94-year-old female patient presenting with vomiting and hematemesis, was transferred to our hospital. On a chest computed tomography (CT) image, mediastinal emphysema was seen with a little amount of bilateral pleural effusion, therefore, a diagnosis of spontaneous esophageal rupture was made. It took 6 hours to make a definite diagnosis of this disease, and conservative therapies were done including administration of antibiotics and proton-pump inhibitor. The patient was able to drink water on 4th hospital day, and was discharged on 19th hospital day. At about 2 months after the onset, a gastrointestinal fiberscope showed just only scar at the lower thoracic esophagus. PMID- 23674047 TI - Effect of postconditioning on infarction size, adverse left ventricular remodeling, and improvement in left ventricular systolic function in patients with first anterior ST-segment elevation myocardial infarction. AB - INTRODUCTION: A key method in the treatment of ST-elevation myocardial infarction (STEMI) is recanalization of the infarct-related artery, but this causes heart reperfusion injury. One of the methods to reduce this injury is postconditioning. The available data on the efficacy of this method are contradictory. OBJECTIVES: The aim of the study was to determine the safety of postconditioning as well as its effect on infarction size, improvement in left ventricular ejection fraction (LVEF), and adverse LV remodeling during a 3-month follow-up. PATIENTS AND METHODS: The study involved 39 patients with first anterior STEMI (aged 58 +/- 10 years) up to 12 hours from the onset of symptoms. They were randomly assigned to a traditional-reperfusion group (n = 21) or to a postconditioning group (n = 18). The area at risk (AAR) was assessed angiographically. LV remodeling and LVEF were evaluated using echocardiography at 6 days and at 3 months. The infarction size was defined on the basis of magnetic resonance imaging (MRI) at 3 months. RESULTS: In a univariate logistic regression analysis, postconditioning did not affect the improvement of LVEF (odds ratio [OR], 1.63; 95% confidence interval [CI], 0.34-7.7; P = 0.52) or the development of adverse LV remodeling (OR, 0.62; 95% CI, 0.15-2.53; P = 0.5). Moreover, there were no significant differences in infarction size between the groups as measured by MRI after adjustment for the AAR, time to reperfusion, and ST-segment elevation prior to percutaneous coronary intervention. CONCLUSIONS: Postconditioning is a safe method but its application did not affect the volume of the infarction as well as did not improve LVEF or the development of adverse LV remodeling in a 3-month follow-up. PMID- 23674048 TI - Identification of sparse neural functional connectivity using penalized likelihood estimation and basis functions. AB - One key problem in computational neuroscience and neural engineering is the identification and modeling of functional connectivity in the brain using spike train data. To reduce model complexity, alleviate overfitting, and thus facilitate model interpretation, sparse representation and estimation of functional connectivity is needed. Sparsities include global sparsity, which captures the sparse connectivities between neurons, and local sparsity, which reflects the active temporal ranges of the input-output dynamical interactions. In this paper, we formulate a generalized functional additive model (GFAM) and develop the associated penalized likelihood estimation methods for such a modeling problem. A GFAM consists of a set of basis functions convolving the input signals, and a link function generating the firing probability of the output neuron from the summation of the convolutions weighted by the sought model coefficients. Model sparsities are achieved by using various penalized likelihood estimations and basis functions. Specifically, we introduce two variations of the GFAM using a global basis (e.g., Laguerre basis) and group LASSO estimation, and a local basis (e.g., B-spline basis) and group bridge estimation, respectively. We further develop an optimization method based on quadratic approximation of the likelihood function for the estimation of these models. Simulation and experimental results show that both group-LASSO-Laguerre and group-bridge-B spline can capture faithfully the global sparsities, while the latter can replicate accurately and simultaneously both global and local sparsities. The sparse models outperform the full models estimated with the standard maximum likelihood method in out-of-sample predictions. PMID- 23674049 TI - Investigation of porosity and heterojunction effects of a mesoporous hematite electrode on photoelectrochemical water splitting. AB - In this paper, we report the porosity and heterojunction effects of hematite (alpha-Fe2O3) on the photoelectrochemical (PEC) water splitting properties. The worm-like mesoporous hematite thin films (MHFs) with a pore size of ~9 nm and a wall thickness of ~5 nm were successfully obtained through the self-assembly process. MHFs formed on FTO showed much better PEC properties than those of nonporous hematite thin films (NP-HF) owing to the suppression of charge recombination. The PEC data of MHFs under front and back illumination conditions indicated that the porous structure allows the diffusion of electrolyte deep inside the MHF increasing the number of holes to be utilized in the water oxidation reaction. A heterojunction structure was formed by introducing a thin layer of SnO2 (~15 nm in thickness) between the MHF and FTO for a dramatically enhanced PEC response, which is attributed to the efficient electron transfer. Our spectroscopic and electrochemical data show that the SnO2 layer functions as an efficient electron transmitter, but does not affect the recombination kinetics of MHFs. PMID- 23674050 TI - [Opinion of the Austrian Society of Radiology and the Austrian Society of Pneumology]. AB - The National Lung Screening Trial (NLST) could demonstrate, for the first time, in a prospective randomized trial, that low-dose CT screening (LD-CT) may decrease lung cancer mortality. At the moment, it is unclear how these results will be applicable to Austria. Specifically, the definition of the population at an increased risk for lung cancer and management of the high rate of false positive results are problematic. As a consequence, lung cancer screening in Austria is recommended following the guidelines of the Austrian Society of Radiology and the Austrian Society of Pneumology. The recommendations suggest that only individuals with a significantly increased risk for lung cancer should be screened (age > 55 years, 30 pack-years, active or former smokers since < 15 years). The screened individuals must be informed about the high probability of false-positive screening results and the necessity for additional follow-up examinations or invasive examinations. The screened individuals must be informed that a CT screening may not prevent them from developing an inoperable lung cancer. In addition, CT screening examinations should be performed with a low dose CT technique for at least three years at yearly intervals. In view of the high probability of false-positive findings, the evaluation of detected pulmonary nodules should be performed according to an already established standardized protocol. PMID- 23674051 TI - Crystal structures and variable magnetism of PbCu2(XO3)2Cl2 with X = Se, Te. AB - Novel Cu(2+)-based compounds PbCu2(SeO3)2Cl2 (space group C2/c; a = 13.056(1) A; b = 9.5567(9) A; c = 6.9006(6) A; beta = 90.529(7) degrees ; RI = 0.0371) and PbCu2(TeO3)2Cl2 (space group P2(1); a = 7.2401(2) A; b = 7.2688(2) A; c = 8.2846(2) A; beta = 96.416(2) degrees ; R(I) = 0.0570) have been obtained by solid-state synthesis. Their crystal structures are remarkably dissimilar and underlie a very different magnetic behavior. While PbCu2(SeO3)2Cl2 can be well described by a spin-chain model with an exchange coupling of J1 ? 160 K, PbCu2(TeO3)2Cl2 is a spin-dimer system that, however, features a comparable magnetic nearest-neighbor coupling of J ? 213 K. PbCu2(SeO3)2Cl2 orders antiferromagnetically below 12 K, whereas PbCu2(TeO3)2Cl2 lacks long-range magnetic order down to at least 2 K, owing to the strong dimerization of the Cu(2+) spins. Crystal structures of both compounds are rationalized in terms of relevant magnetic exchange pathways, and the implications for a broader range of Cu(2+) compounds are discussed. PMID- 23674052 TI - O-Benzoxazolyl imidates as versatile glycosyl donors for chemical glycosylation. AB - Herein, we report a new class of glycosyl donors, benzoxazolyl imidates, for chemical glycosylation. The O-benzoxazolyl (OBox) leaving group was designed with an aim to compare the relative reactivity and stability of similarly structured S benzoxazolyl (SBox) glycosides (thioimidates) developed in our lab and glycosyl trichloroacetimidates (TCAI, O-imidates) developed by Schmidt. Novel OBox donors can be activated under catalytic conditions and provided excellent yields in glycosylation. The OBox imidates were found to be more reactive than either SBox or TCAI donors. The high reactivity profile was confirmed in direct competitive experiments and was found beneficial for HPLC-assisted solid-phase synthesis. PMID- 23674054 TI - Sensory systems: Encoding aversion. PMID- 23674055 TI - Synaptic transmission: Summer blues. PMID- 23674056 TI - Cardiac stem cell therapy: review of the native cardiac progenitor cells and future direction. AB - Various stem cell types have been tested for regenerating damaged myocardium after myocardial infarction. However, the results of clinical trials have not been consistent, with only some of the trials reporting small improvements in cardiac function. It seems that engraftment and survival of injected cells is limited and transplanted stem cells either do not differentiate into cardiac cells or differentiate into only limited number of cardiac cells. The exact mechanism(s) of cardiac functional improvement by cell therapy are unclear, but paracrine effect may play a central role. The resident cardiac progenitor cells identified within the adult myocardium have distinct advantages over other stem cell types for cardiac cell therapy, as they are likely precommitted to the cardiovascular fate. However, isolating and expanding these cells from cardiac biopsies is a challenge. More recently, direct reprogramming of fibroblasts into cardiomyocytes has given new hope for myocardial regeneration. Here we will review different stem cells used in cardiac cell therapy with a focus on the native cardiac progenitor cells and briefly outline future directions of cardiac cell therapy. PMID- 23674053 TI - BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. AB - Increasing evidence suggests that synaptic dysfunction is a key pathophysiological hallmark in neurodegenerative disorders, including Alzheimer's disease. Understanding the role of brain-derived neurotrophic factor (BDNF) in synaptic plasticity and synaptogenesis, the impact of the BDNF Val66Met polymorphism in Alzheimer's disease-relevant endophenotypes - including episodic memory and hippocampal volume - and the technological progress in measuring synaptic changes in humans all pave the way for a 'synaptic repair' therapy for neurodegenerative diseases that targets pathophysiology rather than pathogenesis. This article reviews the key issues in translating BDNF biology into synaptic repair therapies. PMID- 23674057 TI - Microparticles prepared from biodegradable polyhydroxyalkanoates as matrix for encapsulation of cytostatic drug. AB - Microparticles made from degradable polyhydroxyalkanoates of different chemical compositions a homopolymer of 3-hydroxybutyric acid, copolymers of 3 hydroxybutyric and 4-hydroxybutyric acids (P3HB/4HB), 3-hydroxybutyric and 3 hydroxyvaleric acids (P3HB/3HV), 3-hydroxybutyric and 3-hydroxyhexanoic acids (P3HB/3HHx) were prepared using the solvent evaporation technique, from double emulsions. The study addresses the influence of the chemical compositions on the size and xi-potential of microparticles. P3HB microparticles loaded with doxorubicin have been prepared and investigated. Their average diameter and xi potential have been found to be dependent upon the level of loading (1, 5, and 10 % of the polymer mass). Investigation of the in vitro drug release behavior showed that the total drug released from the microparticle into the medium increased with mass concentration of the drug. In this study mouse fibroblast NIH 3T3 cells were cultivated on PHA microparticles, and results of using fluorescent DAPI DNA stain, and MTT assay showed that microparticles prepared from PHAs of different chemical compositions did not exhibit cytotoxicity to cells cultured on them and proved to be highly biocompatible. Cell attachment and proliferation on PHA microparticles were similar to those on polystyrene. The cytostatic drug encapsulated in P3HB/3HV microparticles has been proven to be effective against HeLa tumor cells. PMID- 23674058 TI - Porous CaP/silk composite scaffolds to repair femur defects in an osteoporotic model. AB - The most common complication for patients with postmenopausal osteoporosis is bone-related defects and fractures. While routine medication has a high probability of undesirable side effects, new approaches have aimed to develop regeneration procedures that stimulate new bone formation while reversing bone loss. Recently, we have synthesized a new hybrid CaP/silk scaffold with a CaP phase distribution and pore architecture better suited to facilitate cell differentiation and bone formation. The aim of the present study was to compare the involved remodeling process and therapeutic effect of porous CaP/silk composite scaffolds upon local implantation into osteoporotic defects. Wistar rats were used to induce postmenopausal osteoporotic model by bilateral ovariectomy. The pure silk and hybrid CaP/silk scaffolds were implanted into critical sized defects created in distal femoral epiphysis. After 14 and 28 days, the in vivo osteogenetic efficiency was evaluated by MUCT analysis, hematoxylin and eosin staining, Safranin O staining, tartrate-resistant acid phosphatase staining, and immunohistochemical assessment. Animals with or without critical sized defects were used as drill or blank controls, respectively. The osteoporotic defect model was well established with significantly decreased MUCT parameters of BV/TV, Tb.N and increased Tb.Sp, porosity, combined with changes in histological observations. During the healing process, the critical-sized drill control defects failed to regenerate appreciable bone tissue, while more significantly increased bone formation and mineralization with dynamic scaffold degradation and decreased osteoclastic bone resorption could be detected within defects with hybrid CaP/silk scaffolds compared to pure silk scaffolds. PMID- 23674059 TI - Synthesis of poly-(3-hydroxybutyrate-co-12 mol % 3-hydroxyvalerate) by Bacillus cereus FB11: its characterization and application as a drug carrier. AB - The synthesis of microbial polyhydroxyalkanoate is investigated in this work for it potential application as drug carrier for cancer therapy. The bacterial isolate Bacillus cereus FB11 has synthesized poly-(3-hydroxybutyrate-co-3 hydroxyvalerate) copolymer under nutrient stress conditions using glucose as a sole carbon source. The FTIR spectrum of the purified copolymer showed the characteristic absorption bands at 1,719, 1,260 and 2,931 cm(-1) attributing to C=O, C-O stretching and C-H vibrations, respectively. The result of (1)H-NMR confirmed that it was composed of 88 mol % of 3-hydroxybutyrate and 12 mol % of 3 hydroxyvalerate monomeric subunits. The nanoparticles were fabricated from copolymer and used as a carrier for anticancer drug ellipticine. The in vitro drug release studies showed that % inhibition of A549 cancer cell line receiving ellipticine loaded poly-(3-hydroxybutyrate-co-3-hydroxyvalerate) nanoparticles was two-fold higher in comparison to ellipticine alone. This drug delivery system offers exciting possibilities for cancer therapy by increasing the bioavailability of anti-neoplastic drug to the tumor site. PMID- 23674062 TI - Asymmetric zinc(II) complexes as functional and structural models for phosphoesterases. AB - We report two asymmetric ligands for the generation of structural and functional dinuclear metal complexes as phosphoesterase mimics. Two zinc(II) complexes, [Zn2(CH3L4)(CH3CO2)2](+) (CH3HL4 = 2-(((2-methoxyethyl)(pyridin-2 ylmethyl)amino)methyl)-4-methyl-6-(((pyridin-2-ylmethyl)amino)methyl)phenol) and [Zn2(CH3L5)(CH3CO2)2](+) (CH3HL5 = 2-(((2-methoxyethyl)(pyridine-2 ylmethyl)amino)methyl)-4-methyl-6-(((pyridin-2-ylmethyl)(4 vinylbenzyl)amino)methyl)phenol) were synthesized and characterized by X-ray crystallography. The structures showed that the ligands enforce a mixed 6,5 coordinate environment in the solid state. (1)H-, (13)C- and (31)P-NMR, mass spectrometry and infrared spectroscopy were used to further characterize the compounds in the solid state and in solution. The zinc(II) complexes hydrolyzed the organophosphate substrate bis-(2,4-dinitrophenol)phosphate (BDNPP), the nucleophile proposed to be a terminal water molecule (pK(a) 7.2). The ligand CH3HL4 was immobilised on Merrifield resin and its zinc(II) complex generated. Infrared spectroscopy, microanalysis and XPS measurements confirmed successful immobilisation, with a catalyst loading of ~1.45 mmol g(-1) resin. The resin bound complex was active towards BDNPP and displayed similar pH dependence to the complex in solution. PMID- 23674060 TI - Aortic root disease in athletes: aortic root dilation, anomalous coronary artery, bicuspid aortic valve, and Marfan's syndrome. AB - Two professional athletes in the U.S. National Basketball Association required surgery for aortic root dilation in 2012. These cases have attracted attention in sports medicine to the importance of aortic root disease in athletes. In addition to aortic root dilation, other forms of aortic disease include anomalous coronary artery, bicuspid aortic valve, and Marfan's syndrome. In this review, electronic database literature searches were performed using the terms "aortic root" and "athletes." The literature search produced 122 manuscripts. Of these, 22 were on aortic root dilation, 21 on anomalous coronary arteries, 12 on bicuspid aortic valves, and 8 on Marfan's syndrome. Aortic root dilation is a condition involving pathologic dilation of the aortic root, which can lead to life-threatening sequelae. Prevalence of the condition among athletes and higher risk athletes in particular sports needs to be better delineated. Normative parameters for aortic root diameter in the general population are proportionate to anthropomorphic variables, but this has not been validated for athletes at the extremes of anthropomorphic indices. Although echocardiography is the favored screening modality, computed tomography (CT) and cardiac magnetic resonance imaging (MRI) are also used for diagnosis and surgical planning. Medical management has utilized beta-blockers, with more recent use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and statins. Indications for surgery are based on comorbidities, degree of dilation, and rate of progression. Management decisions for aortic root dilation in athletes are nuanced and will benefit from the development of evidence-based guidelines. Anomalous coronary artery is another form of aortic disease with relevance in athletes. Diagnosis has traditionally been through cardiac catheterization, but more recently has included evaluation with echocardiography, multislice CT, and MRI. Athletes with this condition should be restricted from participation in competitive sports, but can be cleared for participation 6 months after surgical repair. Bicuspid aortic valve is another form of aortic root disease with significance in athletes. Although echocardiography has traditionally been used for diagnosis, CT and MRI have proven more sensitive and specific. Management of bicuspid aortic valve consists of surveillance through echocardiography, medical therapy with beta-blockers and ARBs, and surgery. Guidelines for sports participation are based on the presence of aortic stenosis, aortic regurgitation, and aortic root dilation. Marfan's syndrome is a genetic disorder with a number of cardiac manifestations including aortic root dilation, aneurysm, and dissection. Medical management involves beta-blockers and ARBs. Thresholds for surgical management differ from the general population. With regard to sports participation, the most important consideration is early detection. Athletes with the stigmata of Marfan's syndrome or with family history should be tested. Further research should determine whether more aggressive screening is warranted in sports with taller athletes. Athletes with Marfan's syndrome should be restricted from activities involving collision and heavy contact, avoid isometric exercise, and only participate in activities with low intensity, low dynamic, and low static components. In summary, many forms of aortic root disease afflict athletes and need to be appreciated by sports medicine practitioners because of their potential to lead to tragic but preventable deaths in an otherwise healthy population. PMID- 23674061 TI - 20-Hydroxyecdysone upregulates Atg genes to induce autophagy in the Bombyx fat body. AB - Autophagy is finely regulated at multiple levels and plays crucial roles in development and disease. In the fat body of the silkworm, Bombyx mori, autophagy occurs and Atg gene expression peaks during the nonfeeding molting and pupation stages when the steroid hormone (20-hydroxyecdysone; 20E) is high. Injection of 20E into the feeding larvae upregulated Atg genes and reduced TORC1 activity resulting in autophagy induction in the fat body. Conversely, RNAi knockdown of the 20E receptor partner (USP) or targeted overexpression of a dominant negative mutant of the 20E receptor (EcR (DN) ) in the larval fat body reduced autophagy and downregulated the Atg genes, confirming the importance of 20E-induction of Atg gene expression during pupation. Moreover, in vitro treatments of the larval fat body with 20E upregulated the Atg genes. Five Atg genes were potentially 20E primary-responsive, and a 20E response element was identified in the Atg1 (ortholog of human ULK1) promoter region. Furthermore, RNAi knockdown of 4 key genes (namely Br-C, E74, HR3 and betaftz-F1) in the 20E-triggered transcriptional cascade reduced autophagy and downregulated Atg genes to different levels. Taken together, we conclude that in addition to blocking TORC1 activity for autophagosome initiation, 20E upregulates Atg genes to induce autophagy in the Bombyx fat body. PMID- 23674063 TI - A transition metal-free tandem process to pyridazinopyrido[3,2-f][1,4]thiazepine diones via Smiles rearrangement. AB - A transition metal-free methodology for the synthesis of pyridazinopyrido[3,2 f][1,4]thiazepine-diones was studied. The construction of this tricyclic system went through a one-pot coupling/Smiles rearrangement/cyclization process. The high yields of pure products were obtained through simple recrystallization. PMID- 23674065 TI - Understanding neuronal dysfunction and loss in neurodegenerative disease. PMID- 23674064 TI - Role of Epg5 in selective neurodegeneration and Vici syndrome. AB - Autophagy activity is essential for the survival of neural cells. Impairment of autophagy has been implicated in the pathogenesis of neurodegenerative disorders. Unlike the massive neuron loss in mice deficient for autophagy genes essential for autophagosome formation, we demonstrated that mice deficient for the metazoan specific autophagy gene Epg5 develop selective neuronal damage and exhibit key characteristics of amyotrophic lateral sclerosis. Epg5 deficiency blocks the maturation of autophagosomes into degradative autolysosomes, slows endocytic degradation and also impairs endocytic recycling. Recessive mutations in human EPG5 have recently been causally associated with the multisystem disorder Vici syndrome. Here we show that while Epg5 knockout mice display some features of Vici syndrome, many phenotypes are absent. PMID- 23674066 TI - Comparison of postprandial phenolic acid excretions and glucose responses after ingestion of breads with bioprocessed or native rye bran. AB - Rye bran contains a high amount of phenolic acids with potential health promoting effects. However, due to binding to dietary fibre, the phenolic acids are poorly absorbed in human body. We used bioprocessing with enzymes and yeast to release phenolic acids from the fibre complex and studied the effect of bioprocessing on absorption of phenolic acids in healthy humans. White wheat breads fortified with bioprocessed or native rye bran, and wholegrain rye bread and white wheat bread as controls were served to 15 subjects in a randomized order in the cross-over design. Urine was collected at the basal state and over 24 hours in four-, eight , and twelve-hour periods and analyzed for phenolic acids and their metabolites with gas chromatography. A total of six blood samples were taken over four hours to study the effect of the bread ingestion on postprandial glucose and insulin responses. Bioprocessing of rye bran increased the proportion of free ferulic acid (FA) and soluble arabinoxylan in the bread. Ingestion of the white wheat bread fortified with bioprocessed rye bran increased (p < 0.001) urinary excretion of FA particularly during the first four hours, indicating increased absorption of FA from the small intestine. The postprandial glucose and insulin responses were similar between these breads. Bioprocessing of rye bran did not affect excretion of benzoic, phenylpropionic, and phenylacetic acid metabolites. As a conclusion, bioprocessed rye bran as compared with native rye bran increased absorption of FA from the small intestine, but did not improve postprandial glucose and insulin responses. PMID- 23674067 TI - Prevalence of women's sexual desire problems: what criteria do we use? AB - Problems of sexual desire are often cited as the most prevalent of the female sexual dysfunctions. Despite this finding, considerable variability exists when comparing prevalence figures across studies, highlighting the inconsistency in how these problems are defined and therefore measured. The current study was designed to determine how the prevalence estimates of women's sexual desire problems varied according to the diagnostic criteria adopted to define such problems. The sample consisted of 741 women from Australia, the Americas, Europe, and Asia. Participants were between 18 and 71 years of age and were involved in a heterosexual relationship spanning between 3 months and 49 years duration. Sexual desire problems were defined using a variety of criteria, including (1) meeting DSM-IV-TR criteria for hypoactive sexual desire disorder (HSDD), (2) meeting DSM IV-TR criteria for HSDD, removing the sexual thoughts/fantasy requirement, (3) self-identified "lack of sexual interest," and (4) low average ratings of sexual desire levels, as assessed using the female sexual desire questionnaire. The prevalence of sexual desire problems varied from 3.0 to 31.0% depending upon the criteria used to define such problems. It is important to reach a consensus with regard to the criteria used to define sexual desire problems, in order to standardize and compare studies investigating these problems. How women's sexual desire problems are conceptualized has implications for their treatment. Therapists may or may not need to address absent sexual thoughts/fantasies and may be working with low normative levels of desire versus subjective evaluations of low desire. PMID- 23674068 TI - Transcriptional regulatory network shapes the genome structure of Saccharomyces cerevisiae. AB - Among cellular processes gene transcription is central. More and more evidence is mounting that transcription is tightly connected with the spatial organization of the chromosomes. Spatial proximity of genes sharing transcriptional machinery is one of the consequences of this organization. Motivated by information on the physical relationship among genes identified via chromosomal conformation capture methods, we complement the spatial organization with the idea that genes under similar transcription factor control, but possible scattered throughout the genome, might be in physically proximity to facilitate the access of their commonly used transcription factors. Unlike the transcription factory model, "interacting" genes in our "Gene Proximity Model" are not necessarily immediate physical neighbors but are in spatial proximity. Considering the stochastic nature of TF-promoter binding, this local condensation mechanism could serve as a tie to recruit co-regulated genes to guarantee the swiftness of biological reactions. We tested this idea with a simple eukaryotic organism, Saccharomyces cerevisiae. Chromosomal interaction patterns and folding behavior generated by our model re-construct those obtained from experiments. We show that the transcriptional regulatory network has a close linkage with the genome organization in budding yeast, which is fundamental and instrumental to later studies on other more complex eukaryotes. PMID- 23674069 TI - Fluorescent-based methods for gene knockdown and functional cardiac imaging in zebrafish. AB - A notable advantage of zebrafish as a model organism is the ease of gene knockdown using morpholino antisense oligonucleotide (MO). However, zebrafish morphants injected with MO for a target protein often show heterogeneous phenotypes, despite controlling the injection volume of the MO solution in all embryos. We developed a method for estimating the quantity of MO injected into each living morphant, based on the co-injection of a control MO labeled with the fluorophore lissamine. By applying this method for knockdown of cardiac troponin T (tnnt2a) in zebrafish, we could efficiently select the partial tnnt2a-depleted zebrafish with a decreased heart rate and impairment of cardiac contraction. To investigate cardiac impairment of the tnnt2a morphant, we performed fluorescent cardiac imaging using Bodipy-ceramide. Cardiac image analysis showed moderate reduction of tnnt2a impaired diastolic distensibility and decreased contraction and relaxation velocities. To the best of our knowledge, this is the first report to analyze the role of tnnt2a in cardiac function in tnnt2a-depleted living animals. Our combinatorial approach can be applied for analyzing the molecular function of any protein associated with human cardiac diseases. PMID- 23674070 TI - Inhibition of pancreatic cancer and potentiation of gemcitabine effects by the extract of Pao Pereira. AB - Lack of effective therapy is a major problem in the treatment of pancreatic cancer. In the present study, we investigated a natural product, the extract of Pao Pereira (Pao), for its anti-pancreatic cancer effect in vitro and in vivo, either alone or in combination with the first-line chemotherapeutic drug gemcitabine (Gem). Pao induced dose-dependent apoptosis to all five tested pancreatic cancer cell lines. The combination of Pao and Gem had a synergistic effect in the inhibition of cell growth, with combination indices (CIs) <1 by Chou-Talalay's median effect analysis based on the isobologram principle. Adding Pao to Gem treatment reduced the concentration of Gem to produce an equitoxic effect on pancreatic cancer cells. In an orthotopic pancreatic xenograft mouse model, mice bearing PACN-1 tumors were treated with Pao and Gem, either alone or in combination. The progression of tumors was monitored longitudinally by imaging of live animals. While Gem did not provide significant inhibition, Pao treatment significantly suppressed tumor growth by 70-72%. Combined Pao and Gem treatment further enhanced the tumor inhibitory effect compared to Gem alone, and markedly reduced metastatic lesions in the peritoneum. Collectively, these data suggest that the extract of Pao possesses anti-pancreatic cancer activity and can enhance the effects of Gem in vitro and in vivo. PMID- 23674071 TI - Heart rate variability indices for very short-term (30 beat) analysis. Part 1: survey and toolbox. AB - Heart rate variability (HRV) analysis over very short (<60 s) periods may be useful for monitoring dynamic changes in autonomic nervous system activity where steady-state conditions are not maintained (e.g. during drug administration, or the start or end of exercise). From the 1980s there has been a wealth of HRV indices produced in the quest for better measures of the change in parasympathetic and sympathetic activity. Many of the indices have been sparingly used and have not been investigated for application to short-term use. This study surveyed published methods of HRV analysis searching for indices that could be applied to very short time HRV analysis. The survey included measures of time domain, frequency domain, respiratory sinus arrhythmia, Poincare plot, and heart rate characteristics. Indices were tested with short segments of archived data to remove those that produced invalid results, or were mathematically equivalent to, but less well known than other indices. The survey identified a comprehensive list of 115 indices that were subsequently coded and screened. Of these, 70 were unique and produced a finite number with 60 s data, so are included in the Toolbox. These indices require validation against physiological data before they can be applied to short-term HRV analysis of cardiac autonomic nervous system activity. PMID- 23674072 TI - Downregulation of BMP6 enhances cell proliferation and chemoresistance via activation of the ERK signaling pathway in breast cancer. AB - Previous studies indicate that bone morphogenetic protein (BMP) 6 is involved in breast cancer development and progression. However, the mechanism underlying the role of BMP6 in breast cancer cell proliferation, differentiation and chemoresistance remains unknown. In this study, we confirmed that BMP6 expression was downregulated in breast cancer tissues compared with the adjacent normal breast tissues. We further demonstrated that the downregulation of BMP6 was correlated with the estrogen receptor (ER) and progesterone receptor (PR) status, tumor grade and enhanced proliferation (Ki67 proliferation index). In vitro functional experiments showed that the suppression of BMP6 expression by a specific small hairpin (sh)RNA vector led to increased proliferation in the MCF7 breast cancer cell line. Furthermore, knockdown of BMP6 in MCF7 cells enhanced the chemoresistance to doxorubicin by upregulation of mdr-1/P-gp expression and activation of the ERK signaling pathway. Taken together, our data suggest that BMP6 plays a critical role in breast cancer cell aberrant proliferation and chemoresistance and may serve as a novel diagnostic biomarker or therapeutic target for breast cancer. PMID- 23674073 TI - Do gut microbial communities differ in pediatric IBS and health? AB - Human gastrointestinal microbial communities are recognized as important determinants of the host health and disease status. We have recently examined the distal gut microbiota of two groups of children: healthy adolescents and those diagnosed with diarrhea-predominant irritable bowel syndrome (IBS). We have revealed the common core of phylotypes shared among all children, identified genera differentially abundant between two groups and surveyed possible relationships among intestinal microbial genera and phylotypes. In this article we explored the use of supervised and unsupervised ordination and classification methods to separate and classify child fecal samples based on their quantitative microbial profile. We observed sample separation according to the participant health status, and this separation could often be attributed to the abundance levels of several specific microbial genera. We also extended our original correlation network analysis of the relative abundances of bacterial genera across samples and determined possible association networks separately for healthy and IBS groups. Interestingly, the number of significant genus abundance associations was drastically lower among the IBS samples, which can potentially be attributed to the existence of multiple routes to microbiota disbalance in IBS or to the loss of microbial interactions during IBS development. PMID- 23674074 TI - Monitoring the on-off switching of the electronic communication in diethynylplatinum(II)-bridged dyads using triplet energy transfer. AB - Despite conjugation and downhill manifolds in [Ir]-[Pt]-[ZnTPP] ([ZnTPP] = (tetraphenylporphyrin)zinc(II), [Ir] = bis(phenylpyridinato)(bipyridine)iridium(III), [Pt] = trans-C=CPt(PBu3)2-C=C), essentially no T1[Ir] -> S1/T1[ZnTTP] energy transfer occurs. PMID- 23674075 TI - Structural and electronic properties of Li8ZrO6 and its CO2 capture capabilities: an ab initio thermodynamic approach. AB - The structural, electronic, and phonon properties of Li8ZrO6 are investigated with the application of density functional theory and lattice phonon dynamics. Based on the calculated data, the thermodynamics of CO2 absorption-desorption for Li8ZrO6 is analyzed and compared with those of Li2ZrO3 and Li6Zr2O7. The band gap of Li8ZrO6 is indirect along Gamma-L with a value of 4.74 eV. From the calculated thermodynamic properties of Li8ZrO6 reacting with CO2, we found that Li8ZrO6 could be regenerated at high temperatures (>1100 K). Our results indicated that the lithium zirconate with a lower Li2O/ZrO2 ratio has a lower turnover temperature. Hence, by mixing or doping two or more materials to form a new material, it is possible to find or synthesize CO2 sorbents that can fit the industrial needs for optimal performance. Although the CO2 capture capacity of Li8ZrO6 is much higher than that of Li2ZrO3, the high energy required for regeneration, the capacity loss during long absorption-desorption cycles, solid sintering at high temperature, and the material cost may affect its overall capture performance. Our results also provided some general guidelines for designing new CO2 sorbents. PMID- 23674076 TI - Atrial septal defect in an adult patient. PMID- 23674077 TI - Mammography use among women ages 40-49 after the 2009 U.S. Preventive Services Task Force recommendation. AB - BACKGROUND: In 2009, the U.S. Preventive Service Task Force changed its recommendation regarding screening mammography in average-risk women aged 40-49 years. OBJECTIVE: To evaluate the effects of the 2009 recommendation on reported mammogram use in a population-based survey. DESIGN: Secondary data analysis of data collected in the 2006, 2008, and 2010 Behavioral Risk Factor Surveillance System surveys. PARTICIPANTS: Women ages 40-74 years in the 50 states and Washington, DC who were not pregnant at time of survey and reported data on mammogram use during the 2006, 2008, or 2010 survey. MAIN MEASURES: Mammogram use was compared between women ages 40-49 and women ages 50-74 before and after the recommendation. We performed a difference-in-difference estimation adjusted for access to care, education, race, and health status, and stratified analyses by whether women reported having a routine checkup in the prior year. KEY RESULTS: Reported prevalence of mammogram use in the past year among women ages 40-49 and 50-74 was 53.2 % and 65.2 %, respectively in 2008, and 51.7 % and 62.4 % in 2010. In 2010, mammography use did not significantly decline from 2006-2008 in women ages 40-49 relative to women ages 50-74. CONCLUSION: There was no reduction in mammography use among younger women in 2010 compared to older women and previous years. Patients and providers may have been hesitant to comply with the 2009 recommendation. PMID- 23674078 TI - Carboxylation of alkynylsilanes with carbon dioxide mediated by cesium fluoride in DMSO. AB - The facile syntheses of a variety functionalized propiolic acids were achieved by carboxylation of alkynylsilanes with carbon dioxide mediated by cesium fluoride under ambient conditions. PMID- 23674079 TI - Live imaging of early mouse embryos using fluorescently labeled transgenic mice. AB - Live imaging is a powerful approach to understanding the dynamic processes that occur during development. Periimplantation mouse embryos are transparent, making them suitable for live imaging. In this chapter we describe the culturing and live imaging of mouse embryos, and also introduce the reporter mouse lines for organelle labeling we recently established. PMID- 23674080 TI - Protein-protein interaction analysis in single microfluidic droplets using FRET and fluorescence lifetime detection. AB - Herein, we demonstrate the feasibility of a protein-protein interaction analysis and reaction progress monitoring in microfluidic droplets using FRET and microscopic fluorescence lifetime measurements. The fabrication of microdroplet chips using soft- and photolithographic techniques is demonstrated and the resulting chips reliably generate microdroplets of 630 pL and 6.71 nL at frequencies of 7.9 and 0.75 Hz, respectively. They were used for detection of protein-protein interactions in microdroplets using a model system of Alexa Fluor 488 labelled biotinylated BSA, Alexa Fluor 594 labelled streptavidin and unlabelled chicken egg white avidin. These microchips could be used for quantitative detection of avidin and streptavidin in microdroplets in direct and competitive assay formats with nanomolar detection limits, corresponding to attomole protein amounts. Four droplets were found to be sufficient for analytical determination. Fluorescence intensity ratio and fluorescence lifetime measurements were performed and compared for microdroplet FRET determination. A competitive on-chip binding assay for determination of unlabelled avidin using fluorescence lifetime detection could be performed within 135 s only. PMID- 23674081 TI - Design and validation of a colorimetric test for the genetic diagnosis of hemochromatosis using alpha-phosphorothioate nucleotides. AB - Hereditary hemochromatosis is an autosomal recessive disease highly prevalent in Northern Europe. Here we describe the performance of a genetic test for two mutations of the HFE gene (C282Y and H63D). It is based on a solid-phase PCR coupled with an alpha-phosphorothioate-mediated primer extension, conferring resistance to hydrolysis by ExoIII. Next, Elisa-like detection allows a colorimetric reading of the genetic test. We performed 322 tests (212 on the C282Y mutation, 110 on the H63D mutation) and compared the results with the RFLP method. Using OD ranges giving the minimum of uncertainty, the tests lead to high specificity and sensitivity, and they address the detection of mutated or normal bases in the HFE gene or the deduced phenotype (safe or ill), with positive predictive values or negative ones greater than 0.96. This method is therefore proposed as a primary test or as a confirming test. PMID- 23674082 TI - Biological implants in abdominal wall repair. PMID- 23674084 TI - Comment on 'High MET expression is an adverse prognostic factor in patients with triple-negative breast cancer'. PMID- 23674083 TI - Multicentre external validation of IOTA prediction models and RMI by operators with varied training. AB - BACKGROUND: Correct characterisation of ovarian tumours is critical to optimise patient care. The purpose of this study is to evaluate the diagnostic performance of the International Ovarian Tumour Analysis (IOTA) logistic regression model (LR2), ultrasound Simple Rules (SR), the Risk of Malignancy Index (RMI) and subjective assessment (SA) for preoperative characterisation of adnexal masses, when ultrasonography is performed by examiners with different background training and experience. METHODS: A 2-year prospective multicentre cross-sectional study. Thirty-five level II ultrasound examiners contributed in three UK hospitals. Transvaginal ultrasonography was performed using a standardised approach. The final outcome was the surgical findings and histological diagnosis. To characterise the adnexal masses, the six-variable prediction model (LR2) with a cutoff of 0.1, the RMI with cutoff of 200, ten SR (five rules for malignancy and five rules for benignity) and SA were applied. The area under the curves (AUCs) for performance of LR2 and RMI were calculated. Diagnostic performance measures for all models assessed were sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-), and the diagnostic odds ratio (DOR). RESULTS: Nine-hundred and sixty-two women with adnexal masses underwent transvaginal ultrasonography, whereas 255 had surgery. Prevalence of malignancy was 29% (49 primary invasive epithelial ovarian cancers, 18 borderline ovarian tumours, and 7 metastatic tumours). The AUCs for LR2 and RMI for all masses were 0.94 (95% confidence interval (CI): 0.89-0.97) and 0.90 (95% CI: 0.83-0.94), respectively. In premenopausal women, LR2-RMI difference was 0.09 (95% CI: 0.03-0.15) compared with -0.02 (95% CI: -0.08 to 0.04) in postmenopausal women. For all masses, the DORs for LR2, RMI, SR+SA (using SA when SR inapplicable), SR+MA (assuming malignancy when SR inapplicable), and SA were 62 (95% CI: 27-142), 43 (95% CI: 19 97), 109 (95% CI: 44-274), 66 (95% CI: 27-158), and 70 (95% CI: 30-163), respectively. CONCLUSION: Overall, the test performance of IOTA prediction models and rules as well as the RMI was maintained in examiners with varying levels of training and experience. PMID- 23674085 TI - Treatment of local-regional prostate cancer detected by PSA screening: benefits and harms according to prognostic factors. AB - BACKGROUND: Men with screen-detected prostate cancer can choose to undergo immediate curative treatment or enter into an expectant management programme. We quantified how the benefits and harms of immediate treatment vary according to the prognostic factors of clinical T-stage, Gleason score, and patient age. METHODS: A microsimulation model based on European Randomized Study of Screening for Prostate Cancer data was used to predict the benefits and harms of immediate treatment versus delayed treatment of local-regional prostate cancer in men aged 55-74 years. Benefits included life-years gained and reduced probability of death from prostate cancer. Harms included lead time and probability of overdiagnosis. RESULTS: The ratio of mean lead time to mean life-years gained ranged from 1.8 to 31.2, and the additional number of treatments required per prostate cancer death prevented ranged from 0.3 to 11.6 across the different prognostic groups. Both harm-benefit ratios were lowest, most favourable, for men aged 55-59 years and diagnosed with moderate-risk prostate cancer. Ratios were high for men aged 70-74 years regardless of clinical T-stage and Gleason score. CONCLUSION: Men aged 55 59 years with moderate-risk prostate cancer are predicted to derive greatest benefit from immediate curative treatment. Immediate treatment is least favourable for men aged 70-74 years with either low-risk or high-risk prostate cancer. PMID- 23674086 TI - Individually tailored screening of breast cancer with genes, tumour phenotypes, clinical attributes, and conventional risk factors. AB - BACKGROUND: We demonstrated how to comprehensively translate the existing and updated scientific evidence on genomic discovery, tumour phenotype, clinical features, and conventional risk factors in association with breast cancer to facilitate individually tailored screening for breast cancer. METHODS: We proposed an individual-risk-score-based approach that translates state-of-the-art scientific evidence into the initiators and promoters affecting onset and subsequent progression of breast tumour underpinning a novel multi-variable three state temporal natural history model. We applied such a quantitative approach to a population-based Taiwanese women periodical screening cohort. RESULTS: Risk prediction for pre-clinical detectable and clinical-detected breast cancer was made by the two risk scores to stratify the underlying population to assess the optimal age to begin screening and the inter-screening interval for each category and to ascertain which high-risk group requires an alternative image technique. The risk-score-based approach significantly reduced the interval cancer rate as a percentage of the expected rate in the absence of screening by 30% and also reduced 8.2% false positive cases compared with triennial universal screening. CONCLUSION: We developed a novel quantitative approach following the principle of translational research to provide a roadmap with state-of-the-art genomic discovery and clinical parameters to facilitate individually tailored breast cancer screening. PMID- 23674087 TI - Does age really matter in the choice of treatment for bladder cancer? PMID- 23674088 TI - Coffee consumption and the risk of prostate cancer: the Ohsaki Cohort Study. AB - BACKGROUND: Epidemiological evidence regarding the effect of coffee on the incidence of prostate cancer is inconsistent. We aimed to investigate coffee consumption and the risk of prostate cancer risk in a general Japanese population. METHODS: We conducted a prospective cohort study in Ohsaki city, Japan, where 18 853 men aged 40-79 years participated in a baseline survey. Coffee consumption was assessed via a validated self-administered questionnaire. During 11 years of follow-up (from January 1 1995 to December 31, 2005), 318 incident cases of prostate cancer were detected. The Cox proportional hazards regression model was used to calculate the hazard ratios (HRs) and 95% confidence interval (CIs). RESULTS: There was a significant inverse association between coffee consumption and the incidence risk of prostate cancer. Compared with those who did not drink coffee, the multivariate adjusted HRs were 0.81 (95% CI: 0.61 1.07), 0.73 (95% CI: 0.53-1.00), and 0.63 (095% CI: 0.39-1.00) for those who drank coffee occasionally, 1-2 cups per day, and > or =3 cups per day, respectively, with a P for trend of 0.02. CONCLUSION: This prospective finding from a Japanese population adds evidence that coffee intake is inversely associated with the incidence of prostate cancer. PMID- 23674089 TI - TNF-receptor-1 adaptor protein FAN mediates TNF-induced B16 melanoma motility and invasion. AB - BACKGROUND: Locomotion of cancer cells can be induced by TNF and other motogenic factors secreted by cells of the tumour microenvironment such as macrophages. Based on our recent findings that the TNF receptor adaptor protein FAN mediates TNF-induced actin reorganisation and regulates the directed migration of immune cells responding to chemotactic cues, we addressed the role of FAN in cancer cell motility and the formation of invadopodia, a crucial feature in tumour invasion. METHODS: In B16 mouse melanoma cells, FAN was downregulated and the impact on FAN on cell motility and invasion was determined using in vitro assays and in vivo animal models. RESULTS: Like FAN(-/-) murine embryonic fibroblasts, FAN-deficient B16 melanoma cells showed defective motility responses to TNF in vitro. In vivo FAN-deficient B16 melanoma cells produced significantly less disseminated tumours after i.v. injection into mice. Danio rerio used as a second in vivo model also revealed impaired spreading of FAN-deficient B16 melanoma cells. Furthermore, FAN mediated TNF-induced paxillin phosphorylation, metalloproteinase activation and increased extracellular matrix degradation, the hallmarks of functionally active invadopodia. CONCLUSION: The results of our study suggest that FAN through promoting melanoma cellular motility and tumour invasiveness is critical for the tumour-promoting action of TNF. PMID- 23674090 TI - Prognostic significance of Bcl-xL expression and efficacy of Bcl-xL targeting therapy in urothelial carcinoma. AB - BACKGROUND: Bcl-xL has an important role in the control of cell death through its inhibition of apoptosis. The aim of this study was to investigate the clinicopathological significance of Bcl-xL in upper urinary tract urothelial carcinoma (UTUC) and the therapeutic effect of targeting Bcl-xL protein in urothelial carcinoma (UC) cells. METHODS: We evaluated the immunohistochemical expression of Bcl-xL in 175 UTUC patients to determine the clinical role of Bcl xL expression in clinical outcome. We used bafilomycin A1 (BMA) as a specific inhibitor of Bcl-xL to examine the biological effects in UC cells in vitro and in vivo. RESULTS: Immunohistochemical analysis of Bcl-xL expression revealed that patients with a high Bcl-xL score had a significantly lower 5-year cancer specific survival (CSS) rate (53.2%) than those with a low Bcl-xL score (77.2%) (P=0.0011). Multivariate analysis indicated that a high Bcl-xL score was an independent prognostic factor of CSS (P=0.023). BMA inhibited UMUC-3 cell proliferation in vitro by induction of apoptosis. Treatment with BMA significantly inhibited tumour growth in UMUC-3 tumours in this mouse xenograft model accompanied by an elevated apoptosis induction. CONCLUSION: Bcl-xL appears to be a significant molecular marker for the prognosis of UTUCs. Targeting Bcl-xL may be a promising therapeutic strategy for patients with UC. PMID- 23674091 TI - Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951-2004. AB - BACKGROUND: Retinoblastoma is an eye tumour of childhood that occurs in heritable and non-heritable forms. In the heritable form, there is a predisposition to the development of non-ocular subsequent primary tumours (SPTs). METHODS: This study included 1927 retinoblastoma patients diagnosed in Britain from 1951 to 2004. Ascertainment was through the (UK) National Registry of Childhood Tumours; cases were followed-up for the occurrence of SPTs. Standardised incidence ratios (SIRs) were calculated. RESULTS: We identified 169 SPTs in 152 patients. The SIR analysis included 145 SPTs with cancer registrations from the years 1971 to 2009. These tumours occurred in 132 patients: 112 of the 781 heritable and 20 of the 1075 (presumed) non-heritable cases under surveillance at the start of this period developed at least one registered SPT. The SIRs for all tumours combined were 13.7 (95% confidence interval 11.3-16.5) in heritable cases and 1.5 (0.9 2.3) in non-heritable cases. The main types of SPT in the heritable cases were leiomyosarcoma, (31 cases; SIR 1018.7 (692.2-1446.0)), osteosarcoma (26 cases; SIR 444.6 (290.4-651.4)), and skin melanoma (12 cases; SIR 18.6 (9.6-32.4)). CONCLUSION: The risk of SPTs in heritable retinoblastoma is extremely high. This has important implications for the clinical follow-up and counselling of survivors and their families. PMID- 23674092 TI - Endurance training enhances LXRalpha gene expression in Wistar male rats. AB - Liver X receptor alpha (LXRalpha) is a member of the ligand-activated transcription factor of nuclear hormonal receptor superfamily, whose activation leads to modulation in the expression of genes involved in cholesterol homeostasis including ATP-binding cassette transporter A1 (ABCA1), which plays a crucial role in plasma high-density lipoprotein cholesterol (HDL-C) remodeling. The purpose of this study was to investigate whether endurance training enhanced the expression level of liver LXRalpha gene. Twelve adult male Wistar rats (200 220 g) were divided into control and training groups. Training group received exercise on a motor-driven treadmill at 28 m/min (0 % grade) for 60 min/day, 5 days/week for 8 weeks. Twenty-four hours after the last exercise session, the rats were killed and blood was taken from the right ventricle of each rat. Plasma was collected for HDL-C, low-density lipoprotein cholesterol (LDL-C), TC and TG measurements. Furthermore, a portion of the liver of each rat was excised and washed in ice-cold saline and frozen in liquid nitrogen for assessment of LXRalpha and ABCA1 mRNA levels. Data indicated significant increase in both LXRalpha and ABCA1 mRNA levels in trained rats, compared to control rats. Plasma HDL-C concentration was significantly higher (P < 0.001) in trained rats at the end of treadmill exercise. However, there was a significant decrease in LDL-C (P < 0.003), TG, TC concentration, TC/HDL-C and LDL/HDL-C ratios in trained rats compared with those in the control group (P < 0.001). In conclusion, we found that endurance training induced significant elevation in LXRalpha gene expression, which correlated with enhanced levels of ABCA1 mRNA and plasma HDL-C concentration. PMID- 23674093 TI - Extracellular signal-regulated kinase 2 mediates the expression of granulocyte colony-stimulating factor in invasive cancer cells. AB - Granulocyte colony-stimulating factor (G-CSF) affects granulopoiesis and is important for mobilizing neutrophils into blood circulation. Due to the hematopoietic properties of G-CSF, it has been widely used to clinically treat chemotherapy-induced neutropenia. However, G-CSF can promote tumors by inhibiting innate and adaptive immunity and enhancing angiogenesis and neoplastic growth. Most G-CSF-producing tumors are associated with a poor prognosis. This indicates that G-CSF promotes cancer progression. Thus, identifying regulatory molecules involved in tumor-derived G-CSF expression may provide therapeutic targets for cancer treatment. This study identified considerable G-CSF expression in malignant breast, lung and oral cancer cells. However, G-CSF expression was barely detectable in non-invasive cell lines. Expression of G-CSF mRNA and protein increased during exposure to tumor necrosis factor-alpha (TNF-alpha). Treatment with U0126 (a mitogen-activated protein kinase inhibitor) drastically reduced basal levels of G-CSF and TNF-alpha-induced G-CSF in aggressive cancer cells. This study also showed that knockdown of extracellular signal-regulated kinase (ERK) 2 by shRNA was necessary and sufficient to eliminate the expression of tumor-derived G-CSF. This did not apply to ERK1. Therefore, ERK2 (but not ERK1) is responsible for the transcriptional regulation of tumor-derived G-CSF. The results indicate the pharmaceutical value of specific ERK2 inhibitors in treating patients with G-CSF-producing tumors. PMID- 23674094 TI - Information theory, gene expression, and combinatorial regulation: a quantitative analysis. AB - According to a functional definition of the term "gene", a protein-coding gene corresponds to a polypeptide and, hence, a coding sequence. It is therefore as such not yet present at the DNA level, but assembled from possibly heterogeneous pieces in the course of RNA processing. Assembly and regulation of genes require, thus, information about when and in which quantity specific polypeptides are to be produced. To assess this, we draw upon precise biochemical data. On the basis of our conceptual framework, we also develop formal models for the coordinated expression of specific sets of genes through the interaction of transcripts and mRNAs and with proteins via a precise putative regulatory code. Thus, the nucleotides in transcripts and mRNA are not only arranged into amino acid-coding triplets, but at the same time may participate in regulatory oligomotifs that provide binding sites for specific proteins. We can then quantify and compare product and regulatory information involved in gene expression and regulation. PMID- 23674095 TI - Evolution, reproduction and definition of life. AB - Synthetic theory of evolution is a superior integrative biological theory. Therefore, there is nothing surprising about the fact that multiple attempts of defining life are based on this theory. One of them even has a status of NASA's working definition. According to this definition, 'life is a self-sustained chemical system capable of undergoing Darwinian evolution' Luisi (Orig Life Evol Bios 28:613-622, 1998); Cleland, Chyba (Orig Life Evol Bios 32:387-393, 2002). This definition is often considered as one of the more theoretically mature definitions of life. This Darwinian definition has nonetheless provoked a lot of criticism. One of the major arguments claims that this definition is wrong due to 'mule's problem'. Mules (and other infertile hybrids), despite being obviously living organisms, in the light of this definition are considered inanimate objects. It is strongly counterintuitive. The aim of this article was to demonstrate that this reasoning is false. In the later part of the text, I also discuss some other arguments against the Darwinian approach to defining life. PMID- 23674096 TI - In situ surface-enhanced Raman spectroscopic study of formic acid electrooxidation on spontaneously deposited platinum on gold. AB - Present formic acid fuel cell efficiency is limited by low kinetics at the anode, indicating the need for effective catalysts to improve the formic acid oxidation. As a prerequisite, the nature of adsorbed species and specifically the reaction intermediates formed in this process needs to be examined. This work focuses on the electrooxidation of formic acid and the nature of the intermediates at a platinum-modified gold surface prepared through spontaneous deposition using a combination of electrochemistry and in situ surface enhanced Raman spectroscopy (SERS). This Pt-modified gold electrode surface assists in oxidizing formic acid at potentials as low as 0.0 V vs. Ag/AgCl which is 0.15 V more negative than a bare Pt surface. The oxidation current obtained on the Pt-modified gold electrode is 72 times higher than on a bare Au surface and 5 times higher than on a bare Pt surface at the same potential. In situ SERS has revealed the involvement of formate at a low frequency as the primary intermediate in this electrooxidation process. While previous studies mainly focused on the formate mode at ca. 1322 cm(-1), it is the first time that a formate peak at ca. 300 cm(-1) was observed on a Pt or Pt-associated surface. A unique relationship has been observed between the formic acid oxidation currents and the SERS intensity of this formate adsorbate. Furthermore, the characteristic Stark effect of the formate proves the strong interaction between the adsorbate and the catalyst. Both electrochemical and spectroscopic results suggest that the formic acid electrooxidation takes place by the dehydrogenation pathway involving a low frequency formate intermediate on the Pt-modified gold electrode catalyst. PMID- 23674097 TI - RuBiGABA-2: a hydrophilic caged GABA with long wavelength sensitivity. AB - We have devised a new caged GABA based on ruthenium bipyridyl coordination chemistry. This phototrigger delivers GABA upon irradiation with wavelengths up to 532 nm undergoing heterolytic photocleavage, in a clean and very fast (a few nanoseconds) photoreaction. With an absorptivity coefficient epsilon(MAX) = 5300 M(-1) cm(-1) at 447 nm and a quantum efficiency phi ~ 0.09, RuBiGABA-2 is among the most active caged-GABAs, especially at long wavelengths. This highly hydrophilic caged GABA can be synthesized in a simple one-pot reaction. The synthesis, chemical characterization and photochemical properties are presented. Finally, the usefulness of this caged compound is demonstrated by photodelivering free GABA on leech motoneurons. PMID- 23674098 TI - Structural transitions at the nanoscale: the example of palladium phosphides synthesized from white phosphorus. AB - Stoichiometric reactions of Pd(0) nanoparticles with various amounts of white phosphorus (P4) are an efficient route to convert them into the corresponding Pd phosphides Pd(x)P(y). Formation of crystallized palladium phosphide nanoparticles is a two-step process, which allows exploring in detail the phase transitions of the Pd(x)P(y) system, from amorphous Pd-P nanoparticles (formed in a first step at moderate temperature) to crystallization (at higher temperature). The second temperature was found to be strongly dependent on the Pd/P ratio: PdP2, Pd5P2 and Pd3P stoichiometries form the amorphous phases, but only PdP2 and Pd5P2 could be further crystallized from them. Although it exists as a bulk crystalline material, Pd3P could only be crystallized by starting from the more Pd-rich Pd6P composition. Phase-to-phase transformations from P-poor phosphides (Pd3P and Pd5P2) to the P-rich PdP2 were also demonstrated, and a first Pd-P phase diagram at the nanoscale was tentatively produced. PMID- 23674102 TI - Chemiluminescence detector based on a single planar transparent digital microfluidic device. AB - We report on a compact and portable prototype of chemiluminescence detector based on a single planar single polar transparent electrowetting-on-dielectrics (EWOD) device. The coupling ground model was proposed to build the EWOD device, which could be driven under a single polar voltage. Such a design not only simplified the chip construction and control circuit, but also had the potential for the ball-like droplet to focus the fluorescence and enhance the detection sensitivity. Simulations and experiments both confirmed that the greater the contact angle, the stronger the detected optical signal, and thus the higher the sensitivity. The sensitivity of the prototype detector to H2O2 was 5.45 mV (mmol L(-1))(-1) and the detection limit was 0.01 mmol L(-1) when the contact angle of the EWOD surface was 120 degrees . To further increase the sensitivity and decrease the detection limit, the contact angle of the EWOD device could be increased and the dark current of the photomultiplier decreased. The prototype shows potential applications as highly sensitive, cost effective and portable immuno-detectors, especially as a blood glucose monitor. PMID- 23674099 TI - Na/K pump regulation of cardiac repolarization: insights from a systems biology approach. AB - The sodium-potassium pump is widely recognized as the principal mechanism for active ion transport across the cellular membrane of cardiac tissue, being responsible for the creation and maintenance of the transarcolemmal sodium and potassium gradients, crucial for cardiac cell electrophysiology. Importantly, sodium-potassium pump activity is impaired in a number of major diseased conditions, including ischemia and heart failure. However, its subtle ways of action on cardiac electrophysiology, both directly through its electrogenic nature and indirectly via the regulation of cell homeostasis, make it hard to predict the electrophysiological consequences of reduced sodium-potassium pump activity in cardiac repolarization. In this review, we discuss how recent studies adopting the systems biology approach, through the integration of experimental and modeling methodologies, have identified the sodium-potassium pump as one of the most important ionic mechanisms in regulating key properties of cardiac repolarization and its rate dependence, from subcellular to whole organ levels. These include the role of the pump in the biphasic modulation of cellular repolarization and refractoriness, the rate control of intracellular sodium and calcium dynamics and therefore of the adaptation of repolarization to changes in heart rate, as well as its importance in regulating pro-arrhythmic substrates through modulation of dispersion of repolarization and restitution. Theoretical findings are consistent across a variety of cell types and species including human, and widely in agreement with experimental findings. The novel insights and hypotheses on the role of the pump in cardiac electrophysiology obtained through this integrative approach could eventually lead to novel therapeutic and diagnostic strategies. PMID- 23674103 TI - Ten years of successful pain management for complex regional pain syndrome by epidural anesthesia with implanted port: a case report. PMID- 23674104 TI - Diurnal changes of polysome loading track sucrose content in the rosette of wild type arabidopsis and the starchless pgm mutant. AB - Growth is driven by newly fixed carbon in the light, but at night it depends on reserves, like starch, that are laid down in the light. Unless plants coordinate their growth with diurnal changes in the carbon supply, they will experience acute carbon starvation during the night. Protein synthesis represents a major component of cellular growth. Polysome loading was investigated during the diurnal cycle, an extended night, and low CO2 in Arabidopsis (Arabidopsis thaliana) Columbia (Col-0) and in the starchless phosphoglucomutase (pgm) mutant. In Col-0, polysome loading was 60% to 70% in the light, 40% to 45% for much of the night, and less than 20% in an extended night, while in pgm, it fell to less than 25% early in the night. Quantification of ribosomal RNA species using quantitative reverse transcription-polymerase chain reaction revealed that polysome loading remained high for much of the night in the cytosol, was strongly light dependent in the plastid, and was always high in mitochondria. The rosette sucrose content correlated with overall and with cytosolic polysome loading. Ribosome abundance did not show significant diurnal changes. However, compared with Col-0, pgm had decreased and increased abundance of plastidic and mitochondrial ribosomes, respectively. Incorporation of label from (13)CO2 into protein confirmed that protein synthesis continues at a diminished rate in the dark. Modeling revealed that a decrease in polysome loading at night is required to balance protein synthesis with the availability of carbon from starch breakdown. Costs are also reduced by using amino acids that accumulated in the previous light period. These results uncover a tight coordination of protein synthesis with the momentary supply of carbon. PMID- 23674105 TI - Phototropins function in high-intensity blue light-induced hypocotyl phototropism in Arabidopsis by altering cytosolic calcium. AB - Phototropins (phot1 and phot2), the blue light receptors in plants, regulate hypocotyl phototropism in a fluence-dependent manner. Especially under high fluence rates of blue light (HBL), the redundant function mediated by both phot1 and phot2 drastically restricts the understanding of the roles of phot2. Here, systematic analysis of phototropin-related mutants and overexpression transgenic lines revealed that HBL specifically induced a transient increase in cytosolic Ca(2+) concentration ([Ca(2+)]cyt) in Arabidopsis (Arabidopsis thaliana) hypocotyls and that the increase in [Ca(2+)]cyt was primarily attributed to phot2. Pharmacological and genetic experiments illustrated that HBL-induced Ca(2+) increases were modulated differently by phot1 and phot2. Phot2 mediated the HBL-induced increase in [Ca(2+)]cyt mainly by an inner store-dependent Ca(2+) release pathway, not by activating plasma membrane Ca(2+) channels. Further analysis showed that the increase in [Ca(2+)]cyt was possibly responsible for HBL induced hypocotyl phototropism. An inhibitor of auxin efflux carrier exhibited significant inhibitions of both phototropism and increases in [Ca(2+)]cyt, which indicates that polar auxin transport is possibly involved in HBL-induced responses. Moreover, PHYTOCHROME KINASE SUBSTRATE1 (PKS1), the phototropin related signaling element identified, interacted physically with phototropins, auxin efflux carrier PIN-FORMED1 and calcium-binding protein CALMODULIN4, in vitro and in vivo, respectively, and HBL-induced phototropism was impaired in pks multiple mutants, indicating the role of the PKS family in HBL-induced phototropism. Together, these results provide new insights into the functions of phototropins and highlight a potential integration point through which Ca(2+) signaling-related HBL modulates hypocotyl phototropic responses. PMID- 23674107 TI - Comparing nebulized water versus saline after laryngeal desiccation challenge in Sjogren's Syndrome. AB - OBJECTIVES/HYPOTHESIS: This study examined the effects of a laryngeal desiccation challenge and two nebulized hydration treatments on phonation threshold pressure (PTP), vocal effort, and throat dryness in patients with chronic airway dryness. STUDY DESIGN: Double-blind, within-subjects crossover design. METHODS: Eleven individuals with Primary Sjogren's Syndrome received a 15-minute laryngeal desiccation challenge (breathing dry air-<1% relative humidity-transorally), followed by nebulized isotonic saline or nebulized water treatments (3 mL) on 2 consecutive weeks. PTP, as well as self-perceived vocal effort, mouth, and throat dryness were assessed before and after the desiccation challenge, and at 5, 35, and 65 minutes after the nebulized treatment. RESULTS: The laryngeal desiccation challenge produced statistically significant increases in PTP, vocal effort, and mouth and throat dryness (P < 0.05). Nebulized saline produced greater-but not statistically significant-treatment effects than water. PTP was more correlated with throat dryness than vocal effort. CONCLUSION: Patients with chronic airway dryness experienced phonatory changes following dry air exposure. Nebulized isotonic saline may offset this effect. Future research should explore dose response relationships among dry air exposure, nebulized treatments, voice change, and self-perceived throat dryness. PMID- 23674106 TI - Are mammal olfactory signals hiding right under our noses? AB - Chemical communication via olfactory semiochemicals plays a central role in the social behaviour and reproduction of mammals, but even after four decades of research, only a few mammal semiochemicals have been chemically characterized. Expectations that mammal chemical signals are coded by quantitative relationships among multiple components have persisted since the earliest studies of mammal semiochemistry, and continue to direct research strategies. Nonetheless, the chemistry of mammal excretions and secretions and the characteristics of those semiochemicals that have been identified show that mammal semiochemicals are as likely to be single compounds as to be mixtures, and are as likely to be coded by the presence and absence of chemical compounds as by their quantities. There is very scant support for the view that mammal semiochemicals code signals as specific ratios between components, and no evidence that they depend on a Gestalt or a chemical image. Of 31 semiochemicals whose chemical composition is known, 15 have a single component and 16 are coded by presence/absence, one may depend on a ratio between two compounds and none of them are chemical images. The expectation that mammal chemical signals have multiple components underpins the use of multivariate statistical analyses of chromatographic data, but the ways in which multivariate statistics are commonly used to search for active mixtures leads to single messenger compounds and signals that are sent by the presence and absence of compounds being overlooked. Research on mammal semiochemicals needs to accommodate the possibility that simple qualitative differences are no less likely than complex quantitative differences to encode chemical signals. PMID- 23674108 TI - Raf kinase inhibitor protein inhibits esophageal cancer cell invasion through downregulation of matrix metalloproteinase expression. AB - Esophageal cancer is the eighth most common malignant tumor in the world and is a common cause of tumor-related death. The development of esophageal cancer is a complex process involving many pathogenetic factors, multiple stages and accumulation of multiple gene mutations and interactions. This study aimed to investigate the effects of Raf kinase inhibitor protein (RKIP) on the proliferation, apoptosis and invasion of TE-1 esophageal cancer cells. Surgical specimens from esophageal cancer patients were classified into esophageal cancer tissues, tumor-adjacent tissues and normal esophageal tissues. The tissues were fixed in 4% paraformaldehyde solution for hematoxylin and eosin and immunohistochemical staining. RKIP expression in esophageal tissues was detected by immunohistochemical staining. The esophageal cancer cell line TE-1 was exposed to four different viruses: RKIP-RNAi-AD, NC-RNAi-GFP-AD, RKIP-AD and GFP-AD. Cell proliferation was detected by MTT assay and cell apoptosis was detected by flow cytometry. Cell invasion was determined by a Transwell coated with Matrigel. RKIP, phospho-RKIP, Raf-1, phospho-Raf-1, ERK1/2, phospho-ERK1/2, GRK-2 and GAPDH expression was assayed by western blotting. LIN28 and MMP-14 mRNA was assayed by qPCR. The results showed that RKIP expression was reduced in esophageal cancer tissues in comparison with expression in normal esophageal epithelium tissues and tumor-adjacent tissues. Reduced RKIP expression was associated with lymph node or distant metastasis in esophageal cancer. RKIP inhibited the invasive and metastatic abilities of esophageal cancer cell line TE-1 by downregulating mRNA expression of LIN28 and MMP-14. RKIP had no effect on the MAPK signaling pathway in the esophageal cancer cell line TE-1, but was involved in the G protein coupled signaling pathway. Our findings clearly demonstrate that RKIP inhibits esophageal cancer cell invasion by downregulating the expression of GRK-2, LIN28 and MMP-14. PMID- 23674109 TI - Volume transmission and its different forms in the central nervous system. AB - Volume transmission (VT) is a widespread mode of intercellular communication that occurs in the extracellular fluid (ECF) and in the cerebrospinal fluid (CSF) of the brain with VT signals moving from source to target cells via energy gradients leading to diffusion and convection (flow). The VT channels are diffuse forming a plexus in the extracellular space, while in wiring transmission (WT) the channels (axons, terminals) are private. The speed is slow (seconds-minutes) in VT while rapid in the millisecond range in WT. The extracellular space is the substrate for VT, which is modulated by the extracellular matrix. Extrasynaptic VT is linked to synaptic transmission and likely often takes place due to incomplete diffusion barriers with the synaptic transmitter reaching extrasynaptic domains of the pre-and post-synaptic membrane of the synapse, the astroglia, and even adjacent synapses. Indications exist for the existence of striatal D2-like receptor-mediated extrasynaptic form of dopamine (DA) VT at the local circuit level in vivo in the human striatum. Synaptic glutamate via extrasynaptic VT can act on extrasynaptic metabotropic glutamate receptors located on the astroglia leading to Ca(2+) mediated astrocytic glutamate release into the extracellular space (ECS). Long distance peptide VT and CSF VT is the major long distance VT with distances more than 1 mm and flow in the CSF. Indications for long distance VT of beta-endorphin and oxytocin are obtained. We propose that monogamy in the female prairie vole may take place through an increase in oxytocin VT, especially in nucleus accumbens. Release of extracellular vesicles containing receptors, proteins, RNAs and mtDNA from cellular networks in the central nervous system (CNS) into the ECF and CSF may be a fundamental communication in the CNS. It represents a special form of volume transmission, the Roamer subtype of VT. It may greatly contribute to dynamic events of synaptic plasticity but also to spread of pathological proteins in protein conformational disorders. VT also occurs in the peripheral nervous system and associated cells. Short and long distance VT may take place in meridian channels via diffusion and flow in the interstitial fluid. Acupuncture can produce VT signals by releasing transmitters and modulators from nerve terminals and mast cells. PMID- 23674110 TI - Understanding propagated sensation along meridians by volume transmission in peripheral tissue. AB - Propagated sensation along meridians (PSM) is a phenomenon that a sensation moves along meridians during stimulation of an acupoint. PSM has an appearance rate of 1.3% among people and have characteristics of low speed, going toward afflicted sites and being blocked by physical pressure which is difficult to be explained by known neural and blood transmission. Volume transmission (VT) is a widespread mode of intercellular communication in the central nervous system that occurs in the extracellular fluid and in the cerebrospinal fluid. VT signals moves from source to target cells via energy gradients leading to diffusion and convection (flow) which is slow, long distance and much less space filling. VT channel diffuse forming a plexus in the extracellular space with two parameters of volume fraction and tortuosity. Some experiments showed an information transmission between adjacent and distant acupoints along meridians cross spinal segments. This process is a cross-excitation between peripheral nerve terminals which is related to nonsynaptic transmission. Some neurotransmitters or neuropeptides such as glutamate, adenosine triphosphate (ATP) and neuropeptide such as substance P, neurokinin A and calcitonin gene-related peptide relate with the cross-excitation which can be regards as VT signals. Comparing the characteristics of PSM and VT, many similar aspects can be found leading to an assumption that PSM is a process of VT in peripheral tissue along meridians. The reason why VT signals transmit along meridians is that the meridian is rich in interstitial fluid under the condition of low hydraulic resistance which has been proven experimentally. According to Darcy's law which descript the flow of interstitial fluid and conservation equation, interstitial fluid will move toward meridians and flow along meridians that restrict the VT signals within the channel and accelerate the flow according to Fick's diffusion law. During the process, a degranulation of histamine from mast cells happens on the route which can expand capillary and increase the blood perfusion and interstitial fluid which had already been observed. The mechanism of PSM is featured by alternative axon reflex (wired transmission, WT) and VT in peripheral tissue along meridians, sending simultaneously a continuous sensate signal to control nerve system which can be felt like a PSM. PMID- 23674111 TI - Effects of Shenshao Decoction on the inflammatory response in the aorta of a rat atherosclerotic model. AB - OBJECTIVE: To investigate the effect of Shenshao Decoction on the inflammatory status: in the aorta in a rat model of atherosclerosis. METHODS: Forty Sprague Dawley rats were randomly divided into: five groups, 8 rats in each group: control untreated group, atherosclerosis group, atherosclerosis with Shenshao Decoction (low dose) group, atherosclerosis with Shenshao Decoction (high dose) group, atherosclerosis with simvastatin group. To stimulate atherosclerosis, the rats were fed vitamin D3 and a high-cholesterol diet. Four weeks later, treatments were maintained for eight weeks. Morphology changes were investigated by hematoxylin and eosin staining. Serum levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) were obtained by enzymatic assays with use of an automated biochemical analyzer. The expression of malondialdehyde (MDA), glutathione peroxidase (GSH-PX) were detected by enzyme enzymelinked immunosorbent assay. The expression levels of interleukin (IL) 1beta, IL-17A, and IL-23 were detected by linked immunoblotting. RESULTS: Shenshao Decoction treatment decreased TC, TG, LDL-C and MDA and increased: GSH PX levels (P<0.01). Compared with the control group, IL-1beta, IL-17A, and IL-23 were lower in the high and corn starch > microcrystalline cellulose > dicalcium phosphate. Hence, these carriers could be used to enhance the dissolution rate of poorly water-soluble drug. PMID- 23674129 TI - Reversal of multidrug resistance in cancer cells by novel asymmetrical 1,4 dihydropyridines. AB - Multidrug resistance (MDR) is an important obstacle that limits the efficacy of chemotherapy in many types of cancer. In this study, 14 novel asymmetrical DHPs possessing pyridyl alkyl carboxylate substitutions at C3 and alkyl carboxylate groups at C5 in addition to a nitroimidazole or nitrophenyl moiety at C4 position were synthesized. Calcium channel blocking (CCB) activity was measured in guinea pig ileal longitudinal smooth muscle. Cytotoxicity was tested on 4 human cancer cell lines, while MDR reversal capacity was examined on P-glycoprotein overexpressing doxorubicin resistant MES-SA-DX5 and compared with non-resistant MES-SA cells. Compounds showed different CCB (IC50: 29.3 nM-4.75 MUM) and cytotoxic activities (IC50: 6.4 to more than 100 MUM). Several compounds having nitrophenyl moiety at C4, could significantly reverse resistance to doxorubicin at 0.5 and 1 MUM. The most active ones were 7e and 7g containing ethyl carboxylate and isopropyl carboxylate at C5, respectively. CCB activity, which is considered an undesirable effect for these agents, of 7e and 7g were 33 and 20 times lower than nifedipine, respectively. In conclusion, the newly synthesized asymmetrical DHP compounds showed promising MDR reversal and antitumoral activities with low CCB effects and could be of therapeutic value in drug resistant cancer. PMID- 23674130 TI - If this was my daughter . . . PMID- 23674131 TI - The PROTOE intramedullary hammertoe device: an alternative to Kirschner wires. AB - Hammertoe digital deformity correction is a very controversial topic among foot and ankle surgeons. Hammertoes are characterized by an extension deformity at the metatarsophalangeal joint (MTPJ) and flexion deformity at the proximal interphalangeal joint (PIPJ). Current treatment options are often guided by the patient's discomfort as well as the reducibility of the affected digit. Kirschner wires (K-wires) have long been considered the gold standard for hammertoe digital repair. Although K-wires are simplistic to use as fixation, they carry inherit risks such as pin tract infections, migration, and breakage. This has lead to multiple intramedullary hammertoe devices including the PROTOE intramedullary device. This paper will discuss the usage and benefits the PROTOE has to offer over the conventional K - wire. PMID- 23674132 TI - Genome-wide SNP discovery in mungbean by Illumina HiSeq. AB - Mungbean [Vigna radiata (L.) Wilczek], a self-pollinated diploid plant with 2n = 22 chromosomes, is an important legume crop with a high-quality amino acid profile. Sequence variation at the whole-genome level was examined by comparing two mungbean cultivars, Sunhwanokdu and Gyeonggijaerae 5, using Illumina HiSeq sequencing data. More than 40 billion bp from both mungbean cultivars were sequenced to a depth of 72*. After de novo assembly of Sunhwanokdu contigs by ABySS 1.3.2 (N50 = 9,958 bp), those longer than 10 kb were aligned with Gyeonggijaerae 5 reads using the Burrows-Wheeler Aligner. SAMTools was used for retrieving single nucleotide polymorphisms (SNPs) between Sunhwanokdu and Gyeonggijaerae 5, defining the lowest and highest depths as 5 and 100, respectively, and the sequence quality as 100. Of the 305,504 single-base changes identified, 40,503 SNPs were considered heterozygous in Gyeonggijaerae 5. Among the remaining 265,001 SNPs, 65.9 % (174,579 cases) were transitions and 34.1 % (90,422 cases) were transversions. For SNP validation, a total of 42 SNPs were chosen among Sunhwanokdu contigs longer than 10 kb and sharing at least 80 % sequence identity with common bean expressed sequence tags as determined with est2genome. Using seven mungbean cultivars from various origins in addition to Sunhwanokdu and Gyeonggijaerae 5, most of the SNPs identified by bioinformatics tools were confirmed by Sanger sequencing. These genome-wide SNP markers could enrich the current molecular resources and might be of value for the construction of a mungbean genetic map and the investigation of genetic diversity. PMID- 23674133 TI - Inhibition of melanocortin-4 receptor dimerization by substitutions in intracellular loop 2. AB - Obesity is one of the most challenging global health problems. One key player in energy homeostasis is the melanocortin-4 receptor (MC4R), which is a family A G protein-coupled receptor (GPCR). It has recently been shown that MC4R has the capacity to form homo- or heterodimers. Dimerization of GPCRs is of great importance for signaling regulation, with major pharmacological implications. Unfortunately, not enough is yet known about the detailed structural properties of MC4R dimers or the functional consequences of receptor dimerization. Our goal, therefore, was to explore specific properties related to MC4R dimerization. First, we aimed to induce the dissociation of dimers to monomers and to compare the functional parameters of wild-type and MC4R variants. To inhibit homodimerization, we designed MC4R chimeras with the cannabinoid-1 receptor, a receptor that does not interact with MC4R. Indeed, we identified several substitutions in the intracellular loop 2 (ICL2) and adjacent regions of transmembrane helix 3 (TMH3) and TMH4 that lead to partial dimer dissociation. Interestingly, the capacity for signaling activity was generally increased in these MC4R variants, although receptor expression remained unchanged. This increase in activity for dissociated receptors might indicate a link between receptor dimerization and signaling capacity. Moreover, dimer dissociation was also observed in a naturally occurring activating MC4R mutation in ICL2. Taken together, this study provides new information on the structural prerequisites for MC4R dimerization and identifies an approach to induce the dissociation of MC4R dimers. This might be useful for further investigation of pharmacological properties. PMID- 23674134 TI - G-protein-coupled receptor 30 interacts with receptor activity-modifying protein 3 and confers sex-dependent cardioprotection. AB - Receptor activity-modifying protein 3 (RAMP3) is a single-pass transmembrane protein known to interact with and affect the trafficking of several G-protein coupled receptors (GPCRs). We sought to determine whether RAMP3 interacts with GPR30, also known as G-protein-coupled estrogen receptor 1. GPR30 is a GPCR that binds estradiol and has important roles in cardiovascular and endocrine physiology. Using bioluminescence resonance energy transfer titration studies, co immunoprecipitation, and confocal microscopy, we show that GPR30 and RAMP3 interact. Furthermore, the presence of GPR30 leads to increased expression of RAMP3 at the plasma membrane in HEK293 cells. In vivo, there are marked sex differences in the subcellular localization of GPR30 in cardiac cells, and the hearts of Ramp3(-/-) mice also show signs of GPR30 mislocalization. To determine whether this interaction might play a role in cardiovascular disease, we treated Ramp3(+)(/)(+) and Ramp3(-/-) mice on a heart disease-prone genetic background with G-1, a specific agonist for GPR30. Importantly, this in vivo activation of GPR30 resulted in a significant reduction in cardiac hypertrophy and perivascular fibrosis that is both RAMP3 and sex dependent. Our results demonstrate that GPR30 RAMP3 interaction has functional consequences on the localization of these proteins both in vitro and in vivo and that RAMP3 is required for GPR30-mediated cardioprotection. PMID- 23674135 TI - Phase 1 study of cetuximab in combination with 5-fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma. AB - BACKGROUND: This study sought to determine the feasibility and recommended phase 2 dose (RP2D) of the combination of cetuximab with chemoradiotherapy based on 5 fluorouracil (5-FU) and cisplatin (CP) in locally advanced anal canal carcinoma. METHODS: Cetuximab was administered on days 1, 8, 15, 29, 36, 43, and 50 (400 mg/m(2) initial dose, then 250 mg/m(2) /week) concurrent with total dose radiation of 55 to 59 Gy, both starting on day 1. Escalating doses of 5-FU (96 hour infusion) and CP (2-hour infusion), both on days 1 and 29, were administered according to the following design: starting dose level (0) 5-FU/CP = 800/60 mg/m(2) /day and up to dose level (+2) 5-FU/CP = 1000/80 mg/m(2) /day. RESULTS: Dose-limiting toxicity (DLT) events (uncontrolled diarrhea or febrile neutropenia) occurred in 3 of 14 assessable patients receiving escalated dose of 5-FU/CP, with 1 in dose level (0) and 2 in dose level (+2). The RP2D was 5-FU/CP = 800/80 mg/m(2) /day. Because of unexpected non-DLT treatment-related grade 3 (G3) adverse events (AEs) such as thrombosis/embolism, syncope, and infection occurring in >= 20% of patients, a safety expansion cohort with an additional 9 patients was investigated with the RP2D. The most frequent G3/G4 AEs evaluated in 23 patients were radiation dermatitis (12 patients), diarrhea (10 patients), thrombosis/embolism (6 patients), and infection (5 patients). The study was closed due to these severe AEs, although no G5 AEs occurred. Twenty of 21 patients (95%) achieved pathological complete response at primary tumor. With a median follow-up of 43.4 months, the 3-year locoregional control rate was 64.2%. CONCLUSIONS: Cetuximab could not be integrated with chemoradiotherapy-cisplatin based therapy due to the high toxicity rate. However, efficacy is encouraging and further investigation of an epidermal growth factor receptor-targeted agent (other than cetuximab) concurrent with chemoradiation should be pursued. PMID- 23674136 TI - Let the patient revolution begin. PMID- 23674138 TI - The future of medicine lies in truly shared decision making. PMID- 23674137 TI - Helmet legislation and admissions to hospital for cycling related head injuries in Canadian provinces and territories: interrupted time series analysis. AB - OBJECTIVE: To investigate the association between helmet legislation and admissions to hospital for cycling related head injuries among young people and adults in Canada. DESIGN: Interrupted time series analysis using data from the National Trauma Registry Minimum Data Set. SETTING: Canadian provinces and territories; between 1994 and 2003, six of 10 provinces implemented helmet legislation. PARTICIPANTS: All admissions (n=66,716) to acute care hospitals in Canada owing to cycling related injury between 1994 and 2008. MAIN OUTCOME MEASURE: Rate of admissions to hospital for cycling related head injuries before and after the implementation of provincial helmet legislation. RESULTS: Between 1994 and 2008, 66,716 hospital admissions were for cycling related injuries in Canada. Between 1994 and 2003, the rate of head injuries among young people decreased by 54.0% (95% confidence interval 48.2% to 59.8%) in provinces with helmet legislation compared with 33.1% (23.3% to 42.9%) in provinces and territories without legislation. Among adults, the rate of head injuries decreased by 26.0% (16.0% to 36.3%) in provinces with legislation but remained constant in provinces and territories without legislation. After taking baseline trends into consideration, however, we were unable to detect an independent effect of legislation on the rate of hospital admissions for cycling related head injuries. CONCLUSIONS: Reductions in the rates of admissions to hospital for cycling related head injuries were greater in provinces with helmet legislation, but injury rates were already decreasing before the implementation of legislation and the rate of decline was not appreciably altered on introduction of legislation. While helmets reduce the risk of head injuries and we encourage their use, in the Canadian context of existing safety campaigns, improvements to the cycling infrastructure, and the passive uptake of helmets, the incremental contribution of provincial helmet legislation to reduce hospital admissions for head injuries seems to have been minimal. PMID- 23674139 TI - A call to challenge the "Selling of Sickness". PMID- 23674140 TI - Doctors' understanding of rheumatoid disease does not align with patients' experiences. PMID- 23674141 TI - Premature death among people with mental illness. PMID- 23674142 TI - miR-449b inhibits the proliferation of SW1116 colon cancer stem cells through downregulation of CCND1 and E2F3 expression. AB - Colorectal cancer is one of the leading causes of cancer-related mortality worldwide. Cancer stem cells are cell populations with stem cell nature presenting in tumor tissues and are the root of tumor formation and metastasis. CCND1 and E2F3 play important roles in cell cycle regulation. The 3'UTRs of CCND1 and E2F3 contain miR-449 binding sites. By transfecting pre-miR-449b and inhibiting miR-449b, we found that cell cycle, cell proliferation ability and cell cycle regulatory protein expression levels of colon cancer stem cells were altered. The correlation between CCND1, E2F3 and miR-449b showed that miR-449b could downregulate CCND1 and E2F3 expression. This, in turn, reduced the proliferative ability of colon cancer stem cells. These data suggest that miR 449b plays a tumor-suppressive role in colon cancer stem cells. PMID- 23674143 TI - Selective bacterial patterning using the submerged properties of microbeads on agarose gel. AB - We proposed a new bacteria patterning method on the restricted region of microbeads, using the submerged property of polystyrene microbeads on various concentrations of agarose gel. Moreover, we fabricated a bacterial microrobot using attenuated Salmonella typhimurium through the new patterning methods. We controlled the submerged degree of polystyrene microbeads through the regulation of the hardness of the agarose gel. The polystyrene microbeads on agarose gel were transferred onto a poly-dimethylsiloxane (PDMS) surface for easy manipulation of the microbeads. Then, we treated the polystyrene microbeads on the PDMS surface with antibacterial adherent factors, such as O2 plasma and bovine serum albumin (BSA). The Salmonella typhimurium was attached to the entire surface of the untreated polystyrene microbeads, whereas Salmonella typhimurium were only attached to the restricted surface region of the treated polystyrene microbeads through the proposed patterning method. The bacteria-attached microbeads gain motility by the propulsion of the attached bacteria, and the selective-bacteria-attached microbeads showed enhanced motility. Compared with whole-bacteria-attached polystyrene microbeads (1.74 +/- 1.62 MUm/s), the selective bacteria-attached polystyrene microbeads, using O2 plasma and BSA, showed 9.18 +/- 1.88 MUm/s and 14.65 +/- 8.66 MUm/s faster moving velocities, respectively. Through the results, we expected that the proposed patterning methodology of microbeads could contribute to the development of biomedical bacterial microrobots. PMID- 23674144 TI - Dermatitis herpetiformis. AB - Dermatitis herpetiformis (DH) is an autoimmune, pleiomorphic, papulovesicular disorder associated with celiac disease and gluten sensitivity. DH is characterized by subepidermal bullae on hematoxylin and eosin staining and granular immunoglobulin A deposits in the dermal papillae using the direct immunofluorescence method. Antibodies to tissue transglutaminase and epidermal transgulatminase can be measured serologically, although biopsy is still required for definitive diagnosis of DH. Gluten free diet (GFD) is the first-line therapeutic approach that can alleviate both cutaneous and intestinal manifestations of this condition, while dapsone and sulfones target the skin eruption only. Combined therapy with GFD and dapsone is an initial treatment of choice to control the cutaneous manifestations of DH. This article will provide a comprehensive review of DH, including its epidemiology, clinical and pathological findings, diagnostic evaluation, and management. PMID- 23674145 TI - Methotrexate: role of treatment in skin disease. AB - Methotrexate has been used for over half a century to treat a wide spectrum of skin conditions. It is a valuable steroid sparing agent, preventing protracted steroid courses and their undesirable side effects. While many alternative therapies exist and continue to emerge to treat these dermatologic conditions, the long history, affordability, and relative safety associated with methotrexate ensure its enduring utility. Further, ongoing research focusing on the pharmacogenetic properties of the drug may allow for more effective and targeted therapeutic strategies. PMID- 23674146 TI - A coarse-grained protein model in a water-like solvent. AB - Simulations employing an explicit atom description of proteins in solvent can be computationally expensive. On the other hand, coarse-grained protein models in implicit solvent miss essential features of the hydrophobic effect, especially its temperature dependence, and have limited ability to capture the kinetics of protein folding. We propose a free space two-letter protein ("H-P") model in a simple, but qualitatively accurate description for water, the Jagla model, which coarse-grains water into an isotropically interacting sphere. Using Monte Carlo simulations, we design protein-like sequences that can undergo a collapse, exposing the "Jagla-philic" monomers to the solvent, while maintaining a "hydrophobic" core. This protein-like model manifests heat and cold denaturation in a manner that is reminiscent of proteins. While this protein-like model lacks the details that would introduce secondary structure formation, we believe that these ideas represent a first step in developing a useful, but computationally expedient, means of modeling proteins. PMID- 23674147 TI - Incidence of hip fractures in Germany, 1995-2010. AB - We analyzed hip fracture incidence trends in Germany in 1995-2010, using national hospital discharge register. Overall, after age-sex-region adjustment, there was no significant trend. However, stratified analyses showed a significant decrease in younger people. In the elderly, there was a moderate increase in men and decrease in women. Incidences were still higher in Western Germany (each significant). BACKGROUND: Whereas most studies from US and European countries found trends of a decreasing hip fracture incidence in the last years, in Germany, an increase has been still observed up to 2003. METHODS: Analysis of annual hip fracture incidences in Germany was carried out using the national hospital discharge register and a correction factor of 0.89. Estimate of age-sex adjusted changes was determined using the Poisson regression (incidence rate ratios, IRR; with 95 % confidence intervals, CI), overall and in age-sex-region strata. RESULTS: The number of patients with at least one hospital admission for hip fracture increased (1995: n = 99,146; 2010: n = 128,240). Overall, after adjustment for age, sex, and region, there was no significant trend during the observation period. However, in stratified analyses, a significant decrease was seen in people aged less than 40 years in both sexes and regions. Also, in women aged 60 years or older, the incidence decreased (Western Germany p = 0.001) or remained (Eastern Germany p = 0.053) (IRR 1995-2010, 95 % CI: 0.95, 0.92-0.98; and 1.05, 0.999-1.11). In contrast, the incidence in men 40-59 and 60 years older increased in both regions (West: 1.03, 0.97-1.09; and 1.11, 1.07-1.14; East: 1.12, 1.01-1.25; and 1.29, 1.22-1.36). While incidences were still significantly higher in Western Germany overall and in most strata, they tended to converge. CONCLUSIONS: In line with most European countries, the overall hip fracture incidence in Germany no longer increases. However, differences between age, sex, and region exist. PMID- 23674148 TI - Generation and application of signaling pathway reporter lines in zebrafish. AB - In the last years, we have seen the emergence of different tools that have changed the face of biology from a simple modeling level to a more systematic science. The transparent zebrafish embryo is one of the living models in which, after germline transformation with reporter protein-coding genes, specific fluorescent cell populations can be followed at single-cell resolution. The genetically modified embryos, larvae and adults, resulting from the transformation, are individuals in which time lapse analysis, digital imaging quantification, FACS sorting and next-generation sequencing can be performed in specific times and tissues. These multifaceted genetic and cellular approaches have permitted to dissect molecular interactions at the subcellular, intercellular, tissue and whole-animal level, thus allowing integration of cellular and developmental genetics with molecular imaging in the resulting frame of modern biology. In this review, we describe a new step in the zebrafish road to system biology, based on the use of transgenic biosensor animals expressing fluorescent proteins under the control of signaling pathway-responsive cis elements. In particular, we provide here the rationale and details of this powerful tool, trying to focus on its huge potentialities in basic and applied research, while also discussing limits and potential technological evolutions of this approach. PMID- 23674149 TI - Proteome analysis of virus-host cell interaction: rabies virus replication in Vero cells in two different media. AB - The use of Vero cells for rabies vaccine production was recommended from the WHO in 2005. A controlled production process is necessary to reduce the risk of contaminants in the product. One step towards this is to turn away from animal derived components (e.g. serum, trypsin, bovine serum albumin) and face a production process in animal component-free medium. In this study, a proteomic approach was applied, using 2-D differential gel electrophoresis and mass spectrometry to compare rabies virus propagation in Vero cells under different cultivation conditions in microcarrier culture. Protein alterations were investigated for uninfected and infected Vero cells over a time span from 1 to 8 days post-infection in two different types of media (serum-free versus serum containing media). For mock-infected cells, proteins involved in stress response, redox status, protease activity or glycolysis, and protein components in the endoplasmic reticulum were found to be differentially expressed comparing both cultivation media at all sampling points. For virus-infected cells, additionally changes in protein expression involved in general cell regulation and in calcium homeostasis were identified under both cultivation conditions. The fact that neither of these additional proteins was identified for cells during mock infection, but similar protein expression changes were found for both systems during virus propagation, indicates for a specific response of the Vero cell proteome on rabies virus infection. PMID- 23674150 TI - Penicillin G acylase from Achromobacter sp. CCM 4824 : an efficient biocatalyst for syntheses of beta-lactam antibiotics under conditions employed in large-scale processes. AB - Penicillin G acylase from Achromobacter sp. (NPGA) was studied in the enzymatic synthesis of beta-lactam antibiotics by kinetically controlled N-acylation. When compared with penicillin acylase of Escherichia coli (PGA), the NPGA was significantly more efficient at syntheses of ampicillin and amoxicillin (higher S/H ratio and product accumulation) in the whole range of substrate concentrations. The degree of conversion of 6-aminopenicillanic acid to amoxicillin and ampicillin (160 mM 6-APA, 350 mM acyl donor methylester[Symbol: see text]HCl, pH 6.3, 25 degrees C, reaction time of 200 min) with immobilized NPGA equaled 96.9 % and 91.1 %, respectively. The enzyme was highly thermostable with maximum activity at 60 degrees C (pH 8.0) and 65 degrees C (pH 6.0). Activity half-life at 60 degrees C (pH 8.0) and at 60 degrees C (pH 6.0) was 24 min and 6.9 h, respectively. Immobilized NPGA exhibited long operational stability with half-life of about 2,000 cycles for synthesis of amoxicillin at conversion conditions used in large-scale processes (230 mM 6-APA, 340 mM D-4 hydroxyphenylglycine methylester[Symbol: see text]HCl, 27.5 degrees C, pH 6.25). We discuss our results with literature data available for related penicillin acylases in terms of their industrial potential. PMID- 23674151 TI - Amide-transforming activity of Streptomyces: possible application to the formation of hydroxy amides and aminoalcohols. AB - To develop an efficient bioconversion process for amides, we screened our collection of Streptomyces strains, mostly obtained from soil, for effective transformers. Five strains, including the SY007 (NBRC 109343) and SY435 (NBRC 109344) of Streptomyces sp., exhibited marked conversion activities from the approximately 700 strains analyzed. These strains transformed diverse amide compounds such as N-acetyltetrahydroquinoline, N-benzoylpyrrolidine, and N benzoylpiperidine into alcohols or N,O-acetals with high activity and regioselectivity. N,O-acetal was transformed into alcohol by serial tautomerization and reduction reactions. As such, Streptomyces spp. can potentially be used for the efficient preparation of hydroxy amides and aminoalcohols. PMID- 23674152 TI - Metabolic engineering of Candida utilis for isopropanol production. AB - A genetically-engineered strain of the yeast Candida utilis harboring genes encoding (1) an acetoacetyl-CoA transferase from Clostridium acetobutylicum ATCC 824, (2) an acetoacetate decarboxylase, and (3) a primary-secondary alcohol dehydrogenase derived from Clostridium beijerinckii NRRL B593 produced up to 0.21 g/L of isopropanol. Because the engineered strain accumulated acetate, isopropanol titer was improved to 1.2 g/L under neutralized fermentation conditions. Optimization of isopropanol production was attempted by the overexpression and disruption of several endogenous genes. Simultaneous overexpression of two genes encoding acetyl-CoA synthetase and acetyl-CoA acetyltransferase increased isopropanol titer to 9.5 g/L. Moreover, in fed-batch cultivation, the resultant recombinant strain produced 27.2 g/L of isopropanol from glucose with a yield of 41.5 % (mol/mol). This is the first demonstration of the production of isopropanol by genetically engineered yeast. PMID- 23674153 TI - High cell density cultivation of a novel Aurantiochytrium sp. strain TC 20 in a fed-batch system using glycerol to produce feedstock for biodiesel and omega-3 oils. AB - A recently isolated Australian Aurantiochytrium sp. strain TC 20 was investigated using small-scale (2 L) bioreactors for the potential of co-producing biodiesel and high-value omega-3 long-chain polyunsaturated fatty acids. Higher initial glucose concentration (100 g/L compared to 40 g/L) did not result in markedly different biomass (48 g/L) or fatty acid (12-14 g/L) yields by 69 h. This comparison suggests factors other than carbon source were limiting biomass production. The effect of both glucose and glycerol as carbon sources for Aurantiochytrium sp. strain TC 20 was evaluated in a fed-batch process. Both glucose and glycerol resulted in similar biomass yields (57 and 56 g/L, respectively) by 69 h. The agro-industrial waste from biodiesel production glycerol-is a suitable carbon source for Aurantiochytrium sp. strain TC 20. Approximately half the fatty acids from Aurantiochytrium sp. strain TC 20 are suitable for development of sustainable, low emission sources of transportation fuels and bioproducts. To further improve biomass and oil production, fortification of the feed with additional nutrients (nitrogen sources, trace metals and vitamins) improved the biomass yield from 56 g/L (34 % total fatty acids) to 71 g/L (52 % total fatty acids, cell dry weight) at 69 h; these yields are to our knowledge around 70 % of the biomass yields achieved, however, in less than half of the time by other researchers using glycerol and markedly greater than achieved using other industrial wastes. The fast growth and suitable fatty acid profile of this newly isolated Aurantiochytrium sp. strain TC 20 highlights the potential of co-producing the drop-in biodiesel and high value omega-3 oils. PMID- 23674154 TI - Characterization of genes for chitin catabolism in Haloferax mediterranei. AB - Chitin is the second most abundant natural polysaccharide after cellulose. But degradation of chitin has never been reported in haloarchaea. In this study, we revealed that Haloferax mediterranei, a metabolically versatile haloarchaeon, could utilize colloidal or powdered chitin for growth and poly(3-hydroxybutyrate co-3-hydroxyvalerate) (PHBV) accumulation, and the gene cluster (HFX_5025-5039) for the chitin catabolism pathway was experimentally identified. First, reverse transcription polymerase chain reaction results showed that the expression of the genes encoding the four putative chitinases (ChiAHme, ChiBHme, ChiCHme, and ChiDHme, HFX_5036-5039), the LmbE-like deacetylase (DacHme, HFX_5027), and the glycosidase (GlyAHme, HFX_5029) was induced by colloidal or powdered chitin, and chiA Hme, chiB Hme, and chiC Hme were cotranscribed. Knockout of chiABC Hme or chiD Hme had a significant effect on cell growth and PHBV production when chitin was used as the sole carbon source, and the chiABCD Hme knockout mutant lost the capability to utilize chitin. Knockout of dac Hme or glyA Hme also decreased PHBV accumulation on chitin. These results suggested that ChiABCDHme, DacHme, and GlyAHme were indeed involved in chitin degradation in H. mediterranei. Additionally, the chitinase assay showed that each chitinase possessed hydrolytic activity toward colloidal or powdered chitin, and the major product of colloidal chitin hydrolysis by ChiABCDHme was diacetylchitobiose, which was likely further degraded to monosaccharides by DacHme, GlyAHme, and other related enzymes for both cell growth and PHBV biosynthesis. Taken together, this study revealed the genes and enzymes involved in chitin catabolism in haloarchaea for the first time and indicated the potential of H. mediterranei as a whole-cell biocatalyst in chitin bioconversion. PMID- 23674155 TI - Dependence on the structure and surface polarity of ZnS photocatalytic activities of water splitting: first-principles calculations. AB - It has been reported that phase structure and surface polarity largely affect the photocatalytic efficiency of semiconductor nanostructures. To understand the chemical activity of ZnS at the electronic level, we investigate electron structures and carrier transportation ability for bulk intrinsic zinc blende (ZB) and wurtzite (WZ) ZnS, as well as the reaction pathway of hydrogen generation from water splitting on Zn- and S-terminated polar surfaces. The electron structure calculations prove that the WZ phase possesses a higher reducing ability than the ZB phase. The conductivity of the bulk ZB phase surpasses that of the WZ phase at or above room temperature. As the temperature increases, the asymptotic conductivity ratio of WZ/ZB is close to the Golden Ratio, 0.62. Reaction kinetics studies indicate that Zn-terminated polar surfaces are more chemically active than S-terminated polar surfaces in the reaction of hydrogen generation from water splitting. The calculation results suggest that the first H splitting from water on Zn-terminated polar surfaces can occur with ground state electronic structures, while photo-assistance is necessary for the first H splitting on the S-terminated surfaces. Electronic triplet states calculations further show that Zn-terminated surfaces are more photosensitive than S terminated surfaces. PMID- 23674156 TI - Nucleus N5 CI500 series implant recall: hard failure rate at a major Cochlear implantation center. AB - OBJECTIVES/HYPOTHESIS: To compare the cumulative failure percentage of the Cochlear Nucleus N5 CI500 series implant observed, both before and after the voluntary recall of unimplanted devices, to that of the Cochlear Nucleus Freedom CI24RE series implant. STUDY DESIGN: Retrospective review of 411 patients implanted with either the Nucleus Freedom or the Nucleus N5 device. METHODS: Cochlear implantation was performed in standard fashion. A database was created by combining information obtained from operative case logs, an integrated clinical electronic medical records system, and an external database of devices maintained by Cochlear Corporation. RESULTS: Of the 289 implants of the Nucleus Freedom CI24RE series device at this institution, the cumulative failure percentage was 0%. There were 122 implants of the Nucleus N5 CI500 series device, yielding a 9.8% cumulative failure percent; 82 were manufactured before the voluntary recall and 40 were produced afterward. The 82 implants manufactured before the recall had two associated failures, while the 40 produced afterward had 10 failures. CONCLUSIONS: It is possible that the cumulative failure percentage (CFP) of the Cochlear Nucleus N5 CI500 series implant is not fully defined. While the CFP of the Nucleus Freedom CI24RE series implant at this institution was 0%, it was 9.8% for the Nucleus N5. The CFP of Nucleus N5 devices manufactured before the voluntary recall was 2.4%, while the CFP afterward was 25.0%-nearly 6-fold higher than the company-published value of 4.2% for all Nucleus N5 implants registered globally. PMID- 23674158 TI - Inhibition of calcitonin gene-related peptide (CGRP) has the potential to extend first-phase insulin secretion. AB - The neuropeptide calcitonin gene-related peptide (CGRP), known to have a strong vasodilation effect, has also been reported to inhibit insulin secretion. However, the physiological effect of CGRP related to insulin secretion is still unknown. Here, we evaluated the effect of whole-body CGRP inhibition by anti-CGRP antibodies in mice using an oral glucose tolerance test. CGRP has 2 isotypes, alpha-CGRP and beta-CGRP, and we confirmed the antibody used in this study inhibits function of both. Then, we evaluated the effect of CGRP inhibition on insulin secretion and discovered that CGRP inhibition lead to extend first-phase insulin secretion in an antibody dose-dependent manner and nearly plateaued at 10 mg/kg, although the effect was not so large and didn't affect plasma glucose level. We then measured the plasma antibody concentration and it was increased depending on administration dose. So, the effect of first-phase insulin secretion extension was determined to be the result of complete inhibition of CGRP by the antibody. These results indicate that CGRP has the potential to inhibit insulin secretion and shorten first-phase insulin secretion. However the effect of CGRP inhibition was not so large at least on healthy condition, and it indicates the effect of CGRP related to insulin secretion on healthy physiological condition may be limited. PMID- 23674159 TI - Feasibility and efficacy of an isocaloric high-protein vs. standard diet on insulin requirement, body weight and metabolic parameters in patients with type 2 diabetes on insulin therapy. AB - AIMS: To determine the feasibility and efficacy of a high-protein diet compared with a standard diet aiming for weight maintenance in insulin treated type-2 diabetic patients on insulin requirement, body weight and metabolic parameters over 12 weeks. METHODS: In a randomized controlled trial we assigned 44 type-2 diabetic patients on insulin therapy either to high-protein or standard diet over 12 weeks. Parameters were evaluated at baseline and monthly. RESULTS: After 12 weeks, the high protein diet significantly decreased insulin requirement (9.4 +/- 16.3 vs. +0.8 +/- 4.8 IU, mean +/- SD; p=0.007), fasting plasma glucose (41.7 +/- 62.5 vs. 2.1 +/- 39.0 mg dl(-1); p=0.02), body mass index (1.1 +/- 0.8 vs. 0.3 +/ 0.7 kg m(-2); p=0.003), fat-free (0.8 +/- 0.5 vs. 0.2 +/- 0.5 kg; p=0.001), fat mass (2.6 +/- 1.7 vs. 0.8 +/- 1.6 kg; p=0.001) and increased serum folate (4.2 +/ 8.3 vs. - 0.8 +/- 5.5 nmol l(-1); p=0.04) compared to the standard diet. These beneficial metabolic effects are most likely related to the achieved weight loss. No significant differences between groups in renal function were observed. CONCLUSIONS: In this study we demonstrate that a high protein diet with emphasis on plant source protein vs. a standard diet is feasible in insulin-treated type-2 diabetic patients and reduces insulin requirement and body weight and improves metabolic parameters up to 12 weeks. A high protein diet can thus be considered as an appropriate diet choice for type-2 diabetic patients. PMID- 23674160 TI - AIP mutation identified in a patient with acromegaly caused by pituitary somatotroph adenoma with neuronal choristoma. AB - Pituitary adenoma with neuronal choristoma (PANCH) is a rare condition that includes ganglion cells and GH-producing tumor that is characterized by sparsely granulated somatotroph cell type. However, the pathophysiology of this condition remains to be elucidated. We report a case of 46-year-old woman with acromegaly caused by PANCH. The patient had a large and invasive macroadenoma that was resistant to preoperative therapy with somatostatin analogue (SSA) and dopamine agonist. Histological examination showed typical diffuse, chromophobe-type adenoma containing ganglion cells, and sparsely granulated somatotroph cell type, which were consistent with PANCH. Genetic analysis showed heterozygous germline missense mutation in the AIP gene that results in Y261X amino acid substitution. The clinical characteristics of acromegaly associated with AIP mutations are reportedly macroadenomas with tumor extension and invasion, lower decreases in GH and IGF-I and less tumor shrinkage with SSA treatment, and sparsely granulated somatotroph cell type, which are comparable with those observed in PANCH. Taken together, the mutation in AIP gene may explain the clinical characteristics and pathogenesis of PANCH. PMID- 23674161 TI - Precision synthesis of silicon nanowires with crystalline core and amorphous shell. AB - A synthetic route to crystalline silicon (Si) nanowires with an amorphous Si shell is reported. Trisilane (Si3H8) and Sn(HMDS)2 are decomposed in supercritical toluene at 450 degrees C. Sn(HMDS)2 creates Sn nanoparticles that seed Si nanowire growth by the supercritical fluid-liquid-solid (SFLS) mechanism. The Si : Sn ratio in the reaction determines the growth of amorphous Si shell. No amorphous shell forms at relatively low Si : Sn ratios of 20 : 1, whereas higher Si : Sn ratio of 40 : 1 leads to significant amorphous shell. We propose that hydrogen evolved from trisilane decomposition etches away the Sn seed particles as nanowires grow, which promotes the amorphous Si shell deposition when the higher Si : Sn ratios are used. PMID- 23674162 TI - Evaluation of intervertebral disc cartilaginous endplate structure using magnetic resonance imaging. AB - PURPOSE: The cartilaginous endplate (CEP) is a thin layer of hyaline cartilage positioned between the vertebral endplate and nucleus pulposus (NP) that functions both as a mechanical barrier and as a gateway for nutrient transport into the disc. Despite its critical role in disc nutrition and degeneration, the morphology of the CEP has not been well characterized. The objective of this study was to visualize and report observations of the CEP three-dimensional morphology, and quantify CEP thickness using an MRI FLASH (fast low-angle shot) pulse sequence. METHODS: MR imaging of ex vivo human cadaveric lumbar spine segments (N = 17) was performed in a 7T MRI scanner with sequence parameters that were selected by utilizing high-resolution T1 mapping, and an analytical MRI signal model to optimize image contrast between CEP and NP. The CEP thickness at five locations along the mid-sagittal AP direction (center, 5 mm, 10 mm off center towards anterior and posterior) was measured, and analyzed using two-way ANOVA and a post hoc Bonferonni test. For further investigation, six in vivo volunteers were imaged with a similar sequence in a 3T MRI scanner. In addition, decalcified and undecalcified histology was performed, which confirmed that the FLASH sequence successfully detected the CEP. RESULTS: CEP thickness determined by MRI in the mid-sagittal plane across all lumbar disc levels and locations was 0.77 +/- 0.24 mm ex vivo. The CEP thickness was not different across disc levels, but was thinner toward the center of the disc. CONCLUSIONS: This study demonstrates the potential of MRI FLASH imaging for structural quantification of the CEP geometry, which may be developed as a technique to evaluate changes in the CEP with disc degeneration in future applications. PMID- 23674163 TI - Assessment of alveolar bone mineral density as a predictor of lumbar fracture probability. AB - INTRODUCTION: Osteoporosis and tooth loss have been linked with advancing age, but no clear relationship between these conditions has been proven. Several studies of bone mineral density measurements of the jaw and spine have shown similarities in their rate of age-related deterioration. Thus, measurements of jawbone density may predict lumbar vertebral bone density. Using jawbone density as a proxy marker would circumvent the need for lumbar bone measurements and facilitate prediction of osteoporotic spinal fracture susceptibility at dental clinics. We aimed to characterize the correlation between bone density in the jaw and spine and the incidence of osteoporotic spinal fractures. METHODS: We used computerized radiogrammetry to measure alveolar bone mineral density (al-BMD) and dual-energy X-ray absorptiometry to measure lumbar bone mineral density (L-BMD). L-BMD and al-BMD in 30 female patients (average age: 59 +/- 5 years) were correlated with various patient attributes. Statistical analysis included area under the curve (AUC) and probability of asymptomatic significance (PAS) in a receiver operating characteristic curve. The predictive strength of L-BMD T scores (L-BMD[T]) and al-BMD measurements for fracture occurrence was then compared using multivariate analysis with category weight scoring. RESULTS: L-BMD and al-BMD were significantly correlated with age, years since menopause, and alveolar bone thickness. Both were also negatively correlated with fracture incidence. Category weight scores were -0.275 for a L-BMD(T) <80%; +0.183 for a L BMD(T) >= 80%; -0.860 for al-BMD <84.9 (brightness); and +0.860 for al-BMD >= 84.9. AUC and PAS analyses suggested that al-BMD had a higher association with fracture occurrence than L-BMD. CONCLUSIONS: Our results suggest the possible association between al-BMD and vertebral fracture risk. Assessment of alveolar bone density may be useful in patients receiving routine dental exams to monitor the clinical picture and the potential course of osteoporosis in patients who may be at a higher risk of developing osteoporosis. PMID- 23674164 TI - Current Lynch syndrome tumor screening practices: a survey of genetic counselors. AB - An electronic survey of the National Society of Genetic Counselors Cancer Special Interest Group was conducted in July 2011 to assess Lynch syndrome tumor screening programs and identify barriers to implementation. Over half of respondents (52.8 %) reported having a routine Lynch syndrome tumor screening protocol for newly diagnosed colon and/or endometrial cancers, and approximately half of these used a universal approach. There was an increase in the number of those screening over time, especially in the past 3 years. Tumor screening methods varied; 34/53 (64.2 %) started with immunohistochemistry, 11/53 (20.8 %) started with microsatellite instability testing and 8/53 (15.1 %) performed both on newly diagnosed colorectal tumors. Just 21.7 % (23/106) of respondents indicated they have a tumor screening program in place for newly diagnosed endometrial cancers. Written consent is rarely obtained (7.1 %) and the method of how results were returned to the patient was variable among respondents. Prevalent barriers to implementation were concern about cost, bringing key players together and convincing medical staff of the necessity. Use of Lynch syndrome tumor screening is in clinical practice, but protocols vary widely. This survey provides a glimpse of current practices and common barriers, and identifies the need for tumor screening algorithms with outcomes data. PMID- 23674165 TI - The efficacy and safety of prophylactic closure for a large mucosal defect after colorectal endoscopic submucosal dissection. AB - Endoscopic submucosal dissection (ESD) is not a common treatment for colorectal neoplasms because of its technical difficulties and has a higher incidence of complication. In particular, perforation is one of the severe complications and these patients require surgical intervention. However, whether prophylactic closure after colorectal ESD prevents perforation and other complications is not known. In the present study, we assessed the efficacy and safety of prophylactic closure for a large mucosal defect after colorectal ESD using a conventional clip and over-the-scope clip (OTSC) system. From April 2010 to December 2012, 68 patients with colorectal tumors were treated with ESD. The prohylactic closure was indicated for patients with excessive coagulation in the muscularis propria or larger resection size. The closure group reduced the peritoneal inflammatory reaction and abdominal symptoms without increasing complications. The closure group also had a significantly lower WBC count (post operative day 1), CRP (post operative day 4) and abdominal pain after colorectal ESD compared to the non closure group. Perforation occurred in 1 case, and postoperative bleeding in 2 cases, with only 1 bleeding case needing an emergency endoscopy in the non closure group. One perforation case needed emergency surgery because the endoscopic treatment was ineffective. Without increasing adverse effects, the prophylactic closure efficiently reduced the inflammatory reaction and abdominal symptoms of colorectal ESD in patients with large superficial colorectal neoplasms. PMID- 23674166 TI - A nanofluidic device for single molecule studies with in situ control of environmental solution conditions. AB - We report an approach to study the in situ conformational response of single biomolecules such as DNA to a change in environmental solution conditions. These conditions are, for example, the composition of the buffer or the presence of protein. For this purpose, we designed and fabricated a nanofluidic device featuring two arrays of parallel nanochannels in a perpendicular configuration. The cross-sections of the channels are rectangular with a diameter down to 175 nm. These lab-on-a-chip devices were made of polydimethylsiloxane (PDMS) cast on a high quality master stamp, obtained by proton beam writing and UV lithography. Biomolecules can be inserted into the device through the array of channels in one direction, whereas the buffer can be exchanged through the intersecting array of channels in the other direction. A buffer exchange time inside the grid of nanochannels of less than one second was measured by monitoring the conductivity of salt solutions. The exchange time of a protein was typically a few seconds, as determined by imaging the influx of fluorescence labelled protamine. We demonstrate the functionality of the device by investigating the compaction of DNA by protamine and the unpacking of pre-compacted DNA through an increase in the concentration of salt. PMID- 23674169 TI - Growth of fcc(111) Dy multi-height islands on 6H-SiC(0001) graphene. AB - Graphene based spintronic devices require an understanding of the growth of magnetic metals. Rare earth metals have large bulk magnetic moments so they are good candidates for such applications, and it is important to identify their growth mode. Dysprosium was deposited on epitaxial graphene, prepared by thermally annealing 6H-SiC(0001). The majority of the grown islands have triangular instead of hexagonal shapes. This is observed both for single layer islands nucleating at the top of incomplete islands and for fully completed multi height islands. We analyze the island shape distribution and stacking sequence of successively grown islands to deduce that the Dy islands have fcc(111) structure, and that the triangular shapes result from asymmetric barriers to corner crossing. PMID- 23674167 TI - Pathophysiology of fatty acid oxidation disorders and resultant phenotypic variability. AB - Fatty acids are a major fuel for the body and fatty acid oxidation is particularly important during fasting, sustained aerobic exercise and stress. The myocardium and resting skeletal muscle utilise long-chain fatty acids as a major source of energy. Inherited disorders affecting fatty acid oxidation seriously compromise the function of muscle and other highly energy-dependent tissues such as brain, nerve, heart, kidney and liver. Such defects encompass a wide spectrum of clinical disease, presenting in the neonatal period or infancy with recurrent hypoketotic hypoglycaemic encephalopathy, liver dysfunction, hyperammonaemia and often cardiac dysfunction. In older children, adolescence or adults there is often exercise intolerance with episodic myalgia or rhabdomyolysis in association with prolonged aerobic exercise or other exacerbating factors. Some disorders are particularly associated with toxic metabolites that may contribute to encephalopathy, polyneuropathy, axonopathy and pigmentary retinopathy. The phenotypic diversity encountered in defects of fat oxidation is partly explained by genotype/phenotype correlation and certain identifiable environmental factors but there remain many unresolved questions regarding the complex interaction of genetic, epigenetic and environmental influences that dictate phenotypic expression. It is becoming increasingly clear that the view that most inherited disorders are purely monogenic diseases is a naive concept. In the future our approach to understanding the phenotypic diversity and management of patients will be more realistically achieved from a polygenic perspective. PMID- 23674168 TI - Gastrointestinal and hepatic manifestations of mitochondrial disorders. AB - Inherited defects of oxidative phosphorylation lead to heterogeneous, often multisystem, mitochondrial diseases. This review highlights those mitochondrial syndromes with prominent gastrointestinal and hepatic symptoms, categorised according to underlying disease mechanism. Mitochondrial encephalopathies with major gastrointestinal involvement include mitochondrial neurogastrointestinal encephalopathy and ethylmalonic encephalopathy, which are each associated with highly specific clinical and metabolic profiles. Mitochondrial hepatopathies are most frequently caused by defects of mitochondrial DNA maintenance and expression. Although mitochondrial disorders are notorious for extreme clinical, biochemical and genetic heterogeneity, there are some pathognomonic clinical and metabolic clues that suggest a specific diagnosis, and these are highlighted. An approach to diagnosis of these complex disorders is presented, together with a genetic classification, including mitochondrial DNA disorders and nuclear-encoded defects of mitochondrial DNA maintenance and translation, OXPHOS complex assembly and mitochondrial membrane lipids. Finally, supportive and experimental therapeutic options for these currently incurable diseases are reviewed, including liver transplantation, allogeneic haematopoietic stem cell transplantation and gene therapy. PMID- 23674170 TI - Oxidized lipoprotein(a) increases endothelial cell monolayer permeability via ROS generation. AB - Oxidized lipoprotein(a) (oxLp(a)) is a more potent marker of atherogenesis than native Lp(a). However, the molecular mechanisms of oxLp(a) activity are not clear. Reactive oxygen species (ROS) have recently been suggested as acting as intracellular second messengers. In this study, the effects of oxLp(a) on endothelial cell monolayer permeability and the role of reactive oxygen species (ROS) generation in these effects were investigated. Our results showed that oxLp(a) inhibited desmoglein-1 (DSG1) and desmocollin-2 (DSC2) expression at both mRNA and protein levels in a dose- and time-dependent manner, and increased the generation of cellular ROS. Down-regulation of DSG1 and DSC2 was strengthened by pretreatment with H2O2 and attenuated by superoxide dismutase (SOD) treatment. Furthermore, oxLp(a) increased endothelial cell monolayer permeability, and this effect was enhanced by H2O2 and blunted by SOD. Taken together, these results demonstrate that oxLp(a) increases endothelial cell monolayer permeability, which is mediated at least in part via ROS generation. PMID- 23674171 TI - Reply to association of EGFR mutation or ALK rearrangement with expression of DNA repair and synthesis genes in never-smoker women with pulmonary adenocarcinoma. PMID- 23674172 TI - Identification of circulating microRNAs in HNF1A-MODY carriers. AB - AIMS/HYPOTHESIS: HNF1A-MODY is a monogenic form of diabetes caused by mutations in the HNF1A gene. Here we identify, for the first time, HNF1A-MODY-associated microRNAs (miRNAs) that can be detected in the serum of HNF1A-MODY carriers. METHODS: An miRNA array was carried out in rat INS-1 insulinoma cells inducibly expressing the common human Pro291fsinsC-HNF1A frame shift mutation. Differentially expressed miRNAs were validated by quantitative real-time PCR. Expression of miRNAs in the serum of HNF1A-MODY carriers (n = 31), MODY-negative family members (n = 10) and individuals with type 2 diabetes mellitus (n = 17) was quantified by absolute real-time PCR analysis. RESULTS: Inducible expression of Pro291fsinsC-HNF1A in INS-1 cells caused a significant upregulation of three miRNAs (miR-103, miR-224, miR-292-3p). The differential expression of two miRNAs (miR-103 and miR-224) was validated in vitro. Strongly elevated levels of miR-103 and miR-224 could be detected in the serum of HNF1A-MODY carriers compared with MODY-negative family controls. Serum levels of miR-103 distinguished HNF1A-MODY carriers from HbA1c-matched individuals with type 2 diabetes mellitus. CONCLUSIONS/INTERPRETATION: Our study demonstrates that the pathophysiology of HNF1A-MODY is associated with the overexpression of miR-103 and miR-224. Furthermore, our study demonstrates that these miRNAs can be readily detected in the serum of HNF1A-MODY carriers. PMID- 23674173 TI - Reply to Townsend et al. PMID- 23674174 TI - Autonomy and the patient's right 'not to know' in clinical whole-genomic sequencing. PMID- 23674176 TI - Ultrafast excited state dynamics of trans-[4-(4'-dimethylaminostyryl)] pyridine N oxide in solution: femtosecond fluorescence up-conversion and theoretical calculations. AB - The results of the steady-state and time-resolved fluorescence-spectroscopy measurements and DFT calculations for trans-[4-(4'-dimethylaminostyryl)] pyridine N-oxide (trans-DPO) in various solvents are presented. These results are similar to those reported in the literature for trans-4-(dimethylamino)-4'-cyanostilbene (DCS) where the S1 emissive state shows the charge-transfer (CT) nature. Alcohol solvents, however, have aroused our particular interest because hydrogen-bonded complexes are formed between them and the trans-DPO molecule. They demonstrate a stronger CT character of the lower lying excited state and a larger separation between the first and the second absorption band than in the free trans-DPO molecule. The different effects found in time-dependent femtosecond up-conversion (performed for several emission wavelengths in dioxane and methanol solution over the time range 0-40 ps) were assigned to the hydrogen bond assisted charge transfer process in trans-DPO in methanol, to the excited-state solvation dynamics and mainly to solvent relaxation of trans-DPO dissolved in dioxane and methanol. PMID- 23674175 TI - Expanding the phenotype of IQSEC2 mutations: truncating mutations in severe intellectual disability. AB - Intellectual disability (ID) is frequent in the general population, with 1 in 50 individuals directly affected worldwide. The multiple etiologies include X-linked ID (XLID). Among syndromic XLID, few syndromes present severe ID associated with postnatal microcephaly and midline stereotypic hand movements. We report on three male patients with ID, midline stereotypic hand movements, hypotonia, hyperkinesia, strabismus, as well as seizures (2/3), and non-inherited and postnatal onset microcephaly (2/3). Using array CGH and exome sequencing we characterised two truncating mutations in IQSEC2, namely two de novo intragenic duplication mapped to the Xp11.22 region and a nonsense mutation in exon 7. We propose that truncating mutations in IQSEC2 are responsible for syndromic severe ID in male patients and should be screened in patients without mutations in MECP2, FOXG1, CDKL5 and MEF2C. PMID- 23674177 TI - Prospective clinical investigation of the relationship between idiopathic benign paroxysmal positional vertigo and bone turnover: a pilot study. AB - OBJECTIVE/HYPOTHESIS: Idiopathic benign paroxysmal positional vertigo (BPPV) is a strong indicator of decreased bone density (osteopenia/osteoporosis) in postmenopausal women, and there is a correlation between BPPV and serum levels of biochemical markers of bone turnover. STUDY DESIGN: Prospective pilot clinical trial. METHODS: Two groups of postmenopausal women were recruited. The BPPV group consisted of 16 women with a diagnosis of BPPV. The OSTEO group consisted of 13 women with history of osteopenia/osteoporosis. Dual-energy x-ray absorptiometry scan results were compared, along with serum levels of ionized calcium (iCa), vitamin D, aminoterminal propeptide of protocollagen type I (P1NP), and aminoterminal telopeptides of collagen (sNTX). RESULTS: Prevalence of decreased bone mass density among BPPV subjects was 81%, and prevalence of BPPV among OSTEO subjects was 31%. BPPV subjects had higher P1NP levels. Multiple regression analysis showed that among BPPV subjects, there was positive correlation between P1NP and sNTX and a negative correlation between P1NP and vitamin D level. Age was positively correlated with serum levels of both biomarkers among the BPPV subjects. T score, serum iCa, and serum vitamin D levels did not appear to correlate with presence of BPPV. CONCLUSIONS: Idiopathic BPPV subjects have a high prevalence of osteopenia/osteoporosis. Levels of biochemical markers of bone turnover correlate with presence of BPPV. Our results, based on a sample of U.S. subjects, support an association between idiopathic BPPV and disorders of bone turnover. PMID- 23674178 TI - Organic n-type materials for charge transport and charge storage applications. AB - Conjugated materials have attracted much attention toward applications in organic electronics in recent years. These organic species offer many advantages as potential replacement for conventional materials (i.e., silicon and metals) in terms of cheap fabrication and environmentally benign devices. While p-type (electron-donating or hole-conducting) materials have been extensively reviewed and researched, their counterpart n-type (electron-accepting or electron conducting) materials have seen much less popularity despite the greater need for improvement. In addition to developing efficient charge transport materials, it is equally important to provide a means of charge storage, where energy can be used on an on-demand basis. This perspective is focused on discussing a selection of representative n-type materials and the efforts toward improving their charge transport efficiencies. Additionally, this perspective will also highlight recent organic materials for battery components and the efforts that have been made to improve their environmental appeal. PMID- 23674179 TI - Human papillomavirus (HPV) prevalence and HPV type distribution in cervical, vulvar, and anal cancers in central and eastern Europe. AB - INTRODUCTION: High-risk human papillomaviruses (HPV) play the leading etiological role in the development of cervical, anal, and vaginal cancers and a substantial proportion of penile, vulvar, and oropharyngeal (tonsillar) cancers. METHODS: The article summarizes the results of the most important studies that examined tissue specimens of cervical, anal, and vulvar carcinoma from 16 central and eastern European countries for the presence of HPV DNA. RESULTS: Twenty-eight eligible studies were identified. Among 2,531 invasive cervical cancers, 86.6% were HPV positive. The combined prevalence of HPV-16/18 among HPV-positive cervical cancers was 87.5%. The overall prevalence of HPV DNA in six studies of anal carcinomas (43 cases) and vulvar carcinomas (164 cases) was 90.7% and 32.9%, respectively. HPV-16 DNA was detected in 86% of all anal carcinomas studied, and the proportion of HPV-16 positive vulvar carcinomas varied from 10.9% to 27.5%. HPV-18 DNA was not detected in any anal or vulvar carcinoma studied. CONCLUSIONS: HPV prevalence and type distribution among women with cervical cancer in central and eastern Europe is comparable with other European regions. Several gaps in knowledge exist in the region concerning HPV prevalence and type distribution among women with HPV-related cancers other than cervical cancer and in the general population. PMID- 23674180 TI - Cervical cancer screening practices in central and eastern Europe in 2012. AB - The burden of cervical cancer in central and eastern Europe is generally higher compared to western or northern Europe due to a history of mostly opportunistic cervical cancer screening practices and due to the strong influence of political and economic changes in post-communist transition. This article describes the current cervical cancer screening practices, organizational plans for the future, and main obstacles that need to be overcome in 16 countries in central and eastern Europe: Albania, Bosnia and Herzegovina, Bulgaria, Croatia, the Czech Republic, Estonia, Hungary, Latvia, Lithuania, Montenegro, Poland, Romania, Serbia, Slovakia, Slovenia and The former Yugoslav Republic of Macedonia. Unfortunately, only a few countries have managed to establish an organized and well-functioning cervical cancer screening program in recent years, whereas most countries in the region are still struggling with implementation-related issues of organized cervical cancer screening. Encouragingly, even in the countries where only opportunistic screening is performed, well-prepared plans and strategies have been established for switching to organized screening in the near future. PMID- 23674181 TI - Current status of human papillomavirus vaccination implementation in central and eastern Europe. AB - We present a review of the current implementation status of vaccination against human papillomaviruses (HPV) and available data concerning the burden of HPV infection and HPV type-specific distribution in 16 central and eastern European countries: Albania, Bosnia and Herzegovina, Bulgaria, Croatia, the Czech Republic, Estonia, Montenegro, Poland, Romania, Serbia, Slovakia, Slovenia, and The Former Yugoslav Republic of Macedonia. At least one current HPV prophylactic vaccine is registered in all central and eastern European countries except Montenegro. Six counties-Bulgaria, the Czech Republic, Latvia, Romania, Slovenia, and Former Yugoslav Republic of Macedonia-have integrated the HPV vaccination into their national immunization program and currently provide routine vaccination free of charge to the primary target population. Ten countries have not integrated HPV vaccination into the national immunization program. The key reasons for lack of implementation of HPV vaccination into the national immunization program are the high vaccine cost and negative public perception. Vaccination of males is not recommended in any country in the region. PMID- 23674182 TI - Cervical cancer screening in Latvia: a brief history and recent improvements (2009-2011). AB - Screening for cervical cancer (CC) has been an important part of prevention strategies in Latvia since the early 1960s, reducing its incidence from 31.7/100,000 women in 1963 to 8.9/100,000 in 1989. Political and socioeconomic changes after 1991 greatly affected the entire healthcare system, including CC screening, which was temporarily suspended. In 2005, CC screening targeting all women 25 to 69 years old was officially reintroduced in Latvia, with revision in 2007. However, the nature of the screening program remained opportunistic. The inactivity of women, lack of availability of the required services, overloaded general practitioners, and lack of involvement of gynecologists and obstetricians resulted in low coverage of the target population (10% in 2005-2006). Organized screening was finally implemented in Latvia in 2009. Currently, the national Health Payment Center is responsible for inviting women for screening. Cytological smears, principally performed in a 3-year interval, are read by cytopathologists and cytotechnologists at 25 government-based and private laboratories. Cytological testing outside the program is still very frequent and performed on an ongoing basis in parallel with the organized screening. The results of the first round of screening (2009-2011) show encouraging trends, with a stepwise increase in positive responses to the invitation letter, an increase in coverage inside the program, and increasing detection of cervical high-grade lesions and carcinoma in situ. Unfortunately there is still no cytology quality control monitoring in place, and there are no clear recommendations for human papillomavirus (HPV) testing. Because HPV testing is not reimbursed, it is rarely performed. PMID- 23674183 TI - Genetic diversity of HPV-6 in concurrent multiple anogenital warts. AB - INTRODUCTION: Anogenital warts (AGW) are the most common benign tumors in the anogenital area. They are etiologically associated with alpha human papillomaviruses (HPV), in more than 90% of cases with HPV-6 and HPV-11. AGW frequently displays a multifocal and multicentric appearance. However, it is not clear whether the occurrence of multiple AGW in a particular patient is a consequence of infection with single or multiple HPV genomic variants of a given HPV genotype. METHODS: Forty-five HPV-6 isolates from fresh-frozen AGW tissue specimens, obtained from 18 patients with concurrent multiple AGW, were included. The entire HPV-6 L1, E5a, E5b ORFs, and LCR genomic region was sequenced. RESULTS: Fourteen different HPV-6 L1-LCR-E5a-E5b genomic variants were identified among 18 patients with concurrent multiple AGW. In 17 out of 18 patients, a single identical HPV-6 L1-E5a-E5b-LCR genomic variant was identified in all concurrent multiple AGW collected in an individual patient. Co-infection with two different HPV-6 genomic variants was identified in one patient. DISCUSSION: The presence of an identical HPV genomic variant in all concurrently present multiple AGW within an individual patient supports the hypothesis that the occurrence of multiple concurrent AGW is a consequence of infection with a single HPV-6 genomic variant, rather than infection with multiple genomic variants of HPV-6. PMID- 23674184 TI - Hyaluronic acid-based hydrogel enhances neuronal survival in spinal cord slice cultures from postnatal mice. AB - Numerous biomaterials based on extracellular matrix-components have been developed. It was our aim to investigate whether a hyaluronic acid-based hydrogel improves neuronal survival and tissue preservation in organotypic spinal cord slice cultures. Organotypic spinal cord slice cultures were cultured for 4 days in vitro (div), either on hyaluronic acid-based hydrogel (hyaluronic acid-gel group), collagen gel (collagen group), directly on polyethylene terephthalate membrane inserts (control group), or in the presence of soluble hyaluronic acid (soluble hyaluronic acid group). Cultures were immunohistochemically stained against neuronal antigen NeuN and analyzed by confocal laser scanning microscopy. Histochemistry for choline acetyltransferance, glial fibrillary acidic protein, and Griffonia simplicifolia isolectin B4 followed by quantitative analysis was performed to assess motorneurons and different glial populations. Confocal microscopic analysis showed a 4-fold increase in the number of NeuN-positive neurons in the hyaluronic acid-gel group compared to both collagen (p < 0.001) and control groups (p < 0.001). Compared to controls, organotypic spinal cord slice cultures maintained on hyaluronic acid-based hydrogel showed 5.9-fold increased survival of choline acetyltransferance-positive motorneurons (p = 0.008), 2-fold more numerous resting microglial cells in the white matter (p = 0.031), and a 61.4% reduction in the number of activated microglial cells within the grey matter (p = 0.05). Hyaluronic acid-based hydrogel had a shear modulus (G') of ~1200 Pascals (Pa), which was considerably higher than the ~25 Pa measured for collagen gel. Soluble hyaluronic acid failed to improve tissue preservation. In conclusion, hyaluronic acid-based hydrogel improves neuronal and - most notably - motorneuron survival in organotypic spinal cord slice cultures and microglial activation is limited. The positive effects of hyaluronic acid based hydrogel may at least in part be due to its mechanical properties. PMID- 23674185 TI - The carpometacarpal joint of the thumb: MR appearance in asymptomatic volunteers. AB - PURPOSE: To prospectively characterize the MR appearance of the carpometacarpal (CMC) joint of the thumb in asymptomatic volunteers. MATERIALS AND METHODS: Thirty-four asymptomatic volunteers (17 women, 17 men, mean age, 33.9 +/- 9.2 years) underwent MR imaging of the thumb after approval by the local ethical committee. Two musculoskeletal radiologists independently classified visibility and signal intensity (SI) characteristics of the anterior oblique (AOL/beak ligament), the posterior oblique (POL), the intermetacarpal (IML), and the dorsoradial ligaments (DRL) on a three-point Likert scale. The thickness of all ligaments, cartilage integrity, and presence of joint fluid were assessed. The alignment of the first metacarpal base with the trapezium was quantified on sagittal and coronal planes. RESULTS: The ligaments of the CMC joint were constantly visible in all volunteers for the POL and IML, and in all but one for the AOL and DRL. On intermediate-weighted fat-saturated images the POL (65 %/74 % reader 1/reader 2) and DRL (58 %/64 %) were commonly of increased SI, while the IML had a striated appearance in 91 %/76 % of subjects. The AOL showed a variable SI (36 %/42 % low, 27 %/27 % increased, 36 %/30 % striated). The IML was the thickest ligament with a mean of 2.9 mm/3.1 mm and the DRL the thinnest (1.2 mm/1.4 mm). There was a mean dorsal subluxation of 1.8 mm/2.0 mm and radial subluxation of 2.8 mm/3.4 mm of the metacarpal base. The AOL was significantly thicker in men (1.7 mm) than in women (1.2 mm; p = 0.02). Radial subluxation was significantly larger in men (3.4 mm) than in women (2.2 mm; p = 0.02). No subluxation in palmar or ulnar direction was seen. CONCLUSIONS: Radial and dorsal subluxation of the CMC joint can be a normal finding in a resting position at MR imaging. The CMC ligaments showed a considerable variability of signal intensity with a typically striated IML; thickness of the AOL is typically less than 2.2 mm, of the POL typically less than 2.9 mm. PMID- 23674186 TI - Painful left thigh mass. PMID- 23674187 TI - Subsquamous intestinal metaplasia after ablation of Barrett's esophagus: frequency and importance. AB - PURPOSE OF REVIEW: This article reviews reports on the prevalence of subsquamous intestinal metaplasia (SSIM) in patients with Barrett's esophagus, and the implications of SSIM in the neoplastic progression of Barrett's esophagus to esophageal adenocarcinoma. RECENT FINDINGS: Endoscopic eradication therapy for dysplastic Barrett's esophagus has become an encouraging alternative to esophagectomy or continued endoscopic surveillance. However, the presence of SSIM before and after ablation is concerning because this tissue may have potential for malignant progression, is not visible by conventional endoscopy, and may evade detection by random esophageal biopsy sampling methods. Advances in endoscopic high-resolution three-dimensional optical coherence tomography recently have revealed SSIM in a majority of patients both before and after complete eradication of Barrett's esophagus by radiofrequency ablation. Studies suggest that although cells of Barrett's glands are highly proliferative, the cells of these buried glands are more dormant. Nevertheless, the malignant potential of SSIM cells remains undetermined. SUMMARY: Novel endoscopic imaging demonstrates that SSIM is present in the majority of patients with Barrett's esophagus, both before and after ablative therapy. Although these subsquamous cells exhibit less proliferative activity than those of typical surface Barrett's glands, the malignant potential of the buried glands, especially when challenged by injurious factors, remains largely unknown. Future methods to detect subsurface dysplasia will be needed. PMID- 23674188 TI - Histologic definition of gastro-esophageal reflux disease. AB - PURPOSE OF REVIEW: To review recent data supporting the development of new histology-based definitions of gastro-esophageal reflux disease (GERD). RECENT FINDINGS: Three precisely definable columnar epithelial types--cardiac, oxyntocardiac and intestinal--may be interposed between esophageal squamous epithelium and gastric oxyntic (acid secreting) mucosa. This enables definition of a new histologic concept: the squamo-oxyntic gap. The squamo-oxyntic gap is zero or very small in autopsies performed on patients without evidence of GERD. The gap progressively increases in length with the severity of GERD, indicating that the squamo-oxyntic gap is a marker for chronic GERD. The distal part of the gap lines gastric-type rugal folds and, therefore, is distal to the present endoscopic definition of the gastro-esophageal junction. I contend that this distal gap segment (which has esophageal submucosal glands) is actually the dilated distal esophagus; this is the pathologic correlate of destruction of the abdominal segment of the lower esophageal sphincter. The dilated distal esophagus is mistaken for 'gastric cardia' by present endoscopic definitions. SUMMARY: I believe that these data support the adoption of novel histologic definitions of GERD as follows: the presence of any squamo-oxyntic gap defines GERD; the length of the gap is a measure of severity of chronic GERD; and the presence of intestinal metaplasia in the gap defines Barrett esophagus and cancer risk. PMID- 23674189 TI - pi-Excess sigma2P ligands: synthesis of biaryl-type 1,3-benzazaphosphole hybrid ligands and formation of P^P'-M(CO)4 chelate complexes. AB - Acid-catalyzed cyclocondensations of 2-phosphanylanilines 1 with substituted benzaldehydes or heteroaryl aldehydes open a convenient route to new biaryl-type 1H-1,3-benzazaphosphole hybrid ligands 2a-f with o-phosphanylphenyl, pyridyl, imidazolyl, thienyl or o-methoxyphenyl donor groups (in addition to the sigma(2)P donor) and to bromophenyl substituted benzazaphospholes 2g,h. Excess aldehyde leads to concomitant reductive N-alkylation, as shown by formation of 3h besides 2h. The reactions proceed via dihydrobenzazaphospholes 4, which can be detected under mild conditions. The aromaticity-driven dehydrogenation does not liberate dihydrogen but is accomplished by transfer hydrogenations, mainly by reduction of some of the aldehyde. N-Secondary 2-phosphanylanilines 5 also react with aldehydes to form the corresponding N-substituted benzazaphospholes 6. The formation of (P^P')M(CO)4-chelate complexes 8a (M = Cr) and 9a,b (M = Mo) was demonstrated by reaction with M(CO)4(norbornadiene). The crystal structure of 9a, determined in addition to the solution structure elucidation by multinuclear NMR spectra, confirms the chelate formation and reveals a trigonal environment for the low coordinated phosphorus, with the P-Mo(0) vector bent out of the benzazaphosphole ring plane by 14.4 degrees (0.57 A), together with axial chirality of the molecules in the racemic crystals by twisting of the benzazaphosphole and phenyl pi-planes around the common C(2)-C(21) bond. PMID- 23674190 TI - Pitfalls in statistical methods. PMID- 23674191 TI - DNA promoter hypermethylation profiles in breast duct fluid. AB - DNA methylation of tumor-suppressor genes occurs early in the molecular transformation of precursor events to breast cancer and is therefore of interest to screening in high-risk women. The aim of this study was to use tumor suppressor genes that have previously been shown to be cancer predictive in tissue to evaluate the potential of DNA methylation assays in cells from duct lavage (DL) fluid. The frequency of target gene DNA methylation in tissue and DL of cancer and healthy control patients was assessed, and an association of DNA methylation between different duct systems in the same breast was explored. The cancer and control groups were identified in the outpatient clinic when surgical treatment was finalized. Tumor, adjacent tissue and bilateral DL samples for comparative DNA methylation studies were obtained during surgery from women with cancer. In the healthy control group, samples of tissue and DL were collected. Reverse transcriptase methylation-specific PCR was conducted on modified DNA purified from 42 cancer biopsies, 41 benign excision cavity biopsies (internal control), 29 benign biopsies (external control), and 119 DL specimens. A validated panel of cancer predictive genes was analyzed in the study bank of tissue and DL samples from cancer and healthy patients. The sensitivity of DNA methylation in DL samples compared with matched cancer tissue was highest for SCGB3A1 (90 %), CDH13 (91 %), and RARB (83 %). The genetic algorithm selected RASSF1A, RARB, and IGFBP7 as the optimum predictor set for detecting DNA methylation in cancer tissue. The optimum area under the ROC curve for DNA methylation in cancer compared with internal control healthy tissue from excision margins was 0.84. The area under the ROC curve for DNA methylation in cancer DL compared with contralateral benign DL was 0.76. DL cytology was not a helpful predictor of breast cancer. This study shows that relative patterns of tumor suppressor gene hypermethylation in breast cancer tissue are significantly reflected in the DL from the cancer affected breast. Using DL, nonconcordant patterns of DNA methylation between different duct systems confer independent oncologic potential for distinct breast lobes. The approach of DNA methylation in DL may be substantiated by a larger trial of breast cancer biomarkers. PMID- 23674193 TI - Combined AFM and STM measurements of a silicene sheet grown on the Ag(111) surface. AB - In this paper, we present the first non-contact atomic force microscopy (nc-AFM) of a silicene on a silver (Ag) surface, obtained by combining non-contact atomic force microscopy and scanning tunneling microscopy (STM). STM images over large areas of silicene grown on the Ag(111) surface show both (?13 * ?13)R13.9 degrees and (4 * 4) superstructures. For the widely observed (4 * 4) structure, the observed nc-AFM image is very similar to the one recorded by STM. The structure resolved by nc-AFM is compatible with only one out of two silicon atoms being visible. This indicates unambiguously a strong buckling of the silicene honeycomb layer. PMID- 23674192 TI - Ki-67 is a prognostic parameter in breast cancer patients: results of a large population-based cohort of a cancer registry. AB - The proliferation marker Ki-67 is one of the most controversially discussed parameters for treatment decisions in breast cancer patients. The purpose of this study was to evaluate the routine use and value of Ki-67 as a prognostic marker, and to analyze the associations between Ki-67 and common histopathological parameters in the routine clinical setting. Data from the clinical cancer registry Regensburg (Bavaria, Germany) were analyzed. Within the total data pool of 4,692 female patients, who had been diagnosed between 2005 and 2011, in 3,658 cases Ki-67 was routinely determined. Thus, a total of 3,658 patients with invasive breast cancer were included in the present study and used for statistical analysis. Ki-67 expression was associated with the common histopathological parameters. The strongest correlation was found between grading and Ki-67 (P < 0.001). In terms of survival analyses, Ki-67 was categorized into five categories (reference category Ki-67 <=15 %) due to a nonlinear relationship to overall survival (OS). In multivariable analysis, Ki-67 was an independent prognostic parameter both for disease-free survival (DFS) (Ki-67 > 45 %, HR = 1.96, P = 0.001) as well as for OS (Ki-67: 26-35 %, HR = 1.71, P = 0.017; Ki-67: 36-45 %, HR = 2.05, P = 0.011; Ki-67 > 45 %, HR = 2.06, P = 0.002) independent of common clinical and histopathological factors. The 5-year DFS (OS) rate was 86.7 % (89.3 %) in patients with a Ki-67 value <=15 % compared to 75.8 % (82.8 %) in patients with a Ki-67 value >45 %. Based on the data from a large cohort of a clinical cancer registry, it was demonstrated that Ki-67 is frequently determined in routine clinical work. Ki-67 expression is associated with common histopathological parameters, but is an additional independent prognostic parameter for DFS and OS in breast cancer patients. Future work should focus on standardization of Ki-67 assessment and specification of its role in treatment decisions. PMID- 23674194 TI - Mobile mammography in underserved populations: analysis of outcomes of 3,923 women. AB - Mobile health units are increasingly utilized to address barriers to mammography screening. Despite the existence of mobile mammography outreach throughout the US, there is a paucity of data describing the populations served by mobile units and the ability of these programs to reach underserved populations, address disparities, and report on outcomes of screening performance. To evaluate the association of variables associated with outcomes for women undergoing breast cancer screening and clinical evaluation on a mobile unit. Retrospective analysis of women undergoing mammography screening during the period 2008-2010. Logistic regression was fitted using generalized estimating equations to account for potential repeat annual visits to the mobile unit. In total, 4,543 mammograms and/or clinical breast exams were conducted on 3,923 women with a mean age of 54.6, 29 % of whom had either never been screened or had not had a screening in 5 years. Age < 50 years, lack of insurance, Hispanic ethnicity, current smoking, or having a family relative (<50 years of age) with a diagnosis of cancer were associated with increased odds of a suspicious mammogram finding (BIRADS 4,5,6). Thirty-one breast cancers were detected. The mobile outreach initiative successfully engaged many women who had not had a recent mammogram. Lack of insurance and current smoking were modifiable variables associated with abnormal screens requiring follow up. PMID- 23674195 TI - Advertising of toothpaste in parenting magazines. AB - We assessed advertisements for children's toothpaste in two widely read US parenting magazines. Data on the number and type of toothpaste advertisements in two parenting magazines were collected from 116 magazine issues between 2007 and 2011. The number of children's toothpaste advertisements per year and across magazines was computed. The amount of toothpaste presented in each advertisement was categorized. We noted whether the toothpaste advertisement stated that the toothpaste was fluoridated. We identified a total of 117 children's toothpaste advertisements in these magazines and confirmed that the majority of the magazine issues contained at least one toothpaste advertisement. Of the 31 advertisements that depicted a picture of a toothbrush with toothpaste, all but one (96.8 %) depicted a full swirl of toothpaste covering the entire toothbrush head, which is well over the recommended amount. The pictures on the advertisements show an excessive amount of toothpaste on the brush, which directly conflicts with the instructions on many toothpastes and dentist recommendations. Those advertisements with photographs that depict a toothbrush with a full brush head of toothpaste are showing over four times the recommended amount for children. PMID- 23674196 TI - Characteristics and prognosis of gastric cancer in young patients. AB - The clinicopathological features of gastric cancer (GC) differ between younger and older patients, and it is thought that younger patients have a worse prognosis than older patients due to delayed diagnosis and more aggressive tumor behavior. These characteristics, however, remain controversial. A total of 3,818 patients with pathologically confirmed primary gastric adenocarcinoma were treated at our institution. We analyzed the difference in demographic and clinicopathological characteristics between 169 young [<=40 years of age, younger group (YG)] and 3,649 older [>40 years of age, older group (OG)] GC patients. There was a significantly higher proportion of females in the YG compared with the OG (53.3 and 31.0%, respectively; P<0.0001). The 5-year overall survival of the YG was significantly lower compared to that of the OG (59.7 and 65.9%, respectively; P=0.049). However, YG patients with curative resection had a similar 5-year survival rate to OG patients with curative resection (88.0 and 85.8%, respectively; P=0.547). Female patients in the YG showed a significantly lower survival rate than males in the YG (44.3 and 73.1%, respectively; P=0.0002). Multivariate analyses revealed that macroscopic type, depth of invasion, peritoneal metastasis, distant metastasis and curative resection were independent prognostic factors for the YG with GC. Young GC patients who undergo curative resection do not have a worse prognosis than older patients. Early diagnosis is important in successfully carrying out a curative resection and offering a better prognosis, particularly in females. PMID- 23674197 TI - [New options for digital photo documentation during routine examination for ophthalmologists]. AB - BACKGROUND: Many clinical investigations cannot be carried out at the examination unit or a slit lamp. Here we present three new options to obtain digital pictures in a routine clinic at a slit lamp and evaluate how user friendly they are. METHODS: A) First, a digital photo documentation is examined at a conventional slit lamp by a modified binocular ray splitter. One ray of the binocular ray splitter is connected to a digital camera, while the second ray in this patented prototype is connected to the light sources of a synchronised flash light. B) A Smartphone generated fundus images via the monocular of a microscope. Macroscopic details up to 60* at the external eye were obtained by a magnifying gadget of the iPhone. C) With a USB microscope, high resolutions pictures were generated without large technical expense directly at the job and digitally were archived over an USB connection. RESULTS: A trained ophthalmologist demonstrated an excellent documentation at a slit lamp using all 3 digital camera systems. The new ray splitter allows enhanced the image quality at the anterior and posterior segments of the eye. Also the Smartphone obtained by its autofocus and automatic exposure control stunningly high resolution images at the fundus. An attached magnifying aperture glass enables documentation with a 20-fold magnification and is already used in dermatology as the "Handyskope". The USB microscope may be used to record macroscopic details with a 200-fold magnification and resolution of 2 million pixels. It is connected to a PC desktop at the workstation and has only a limited depth resolution, requiring a precise focus. CONCLUSION: The increasing distribution of the Smartphone and significant improvement of its digital camera make its use in medicine meaningful. Low-priced attempts and mobile applications open new implications in the evaluation of ophthalmological patients. PMID- 23674198 TI - Interpersonal functioning deficits in association with DSM-IV personality disorder dimensions. AB - PURPOSE: According to DSM, interpersonal functioning deficits are a main criterion for the general definition of personality disorders (PDs), but some PD diagnoses do not appear to be related to impaired interpersonal functioning. Social deficits have rarely been studied in all PD dimensions to date. METHODS: We analyzed 511 adults aged 20-41 years from the general population of the canton of Zurich, Switzerland, using data from the Epidemiology Survey of the Zurich Programme for Sustainable Development of Mental Health Services (ZInEP). PD dimensions were measured with a questionnaire and indicators of interpersonal functioning with a semi-structured interview. Associations were analyzed with generalized linear models. RESULTS: All PD dimensions were significantly associated with various indicators of interpersonal functioning deficits, such as distress and conflicts in friendships and partnership, feeling lonely, few close friends, and reduced social support. Schizotypal and borderline PD were relatively strongly associated with distress in friendships when compared with other PD dimensions. Furthermore, both dimensions were significantly related to all indicators of interpersonal functioning deficits. CONCLUSIONS: Subjects scoring high on any PD dimension reported considerable deficits in interpersonal functioning as characterized by a solitary lifestyle, conflictual and distressful social relations, and lack of social support. All DSM-IV PDs are associated with poor interpersonal functioning, but there is some evidence that schizotypal and borderline symptomatology affects deficits in social interactions even more profoundly and pervasively than other PD dimensions. PMID- 23674199 TI - A microfluidic concentration-gradient droplet array generator for the production of multi-color nanoparticles. AB - A microfluidic concentration-gradient droplet array generator (CDrAG) with parallel multi-channels and multi-layers was developed with 64 outlet channels producing 33 droplet gradient concentrations. A droplet production rate of 5 * 10(4) min(-1) was obtained, and the RSD value of droplet diameters in 64 groups is 5.5% (n = 64). Using the concentration gradient droplet array as parallel microreactors, 33 Au/Ag ratio nanoparticles were synthesized. The absorption spectra of the Au/Ag nanoparticles shifted from the spectrum of pure gold to one of pure silver. This demonstrates the CDrAG platform's promising potential to produce specific nanoparticle barcodes for high-throughput screening in chemistry, biology and a broad range of life science applications. PMID- 23674200 TI - Successful resection of a primary cardiac fibroma in a neonate: report of a case. AB - During the fetal-neonatal period, a primary cardiac tumor may be completely asymptomatic and such tumors may be incidentally discovered by echocardiography. A four-hour-old male was diagnosed to have a cardiac tumor by post-natal echocardiography and was observed closely. Surgery was indicated immediately at the 3 week follow-up examination when the tumor was found to have obstructed the right ventricle outflow. The tumor was resected successfully and its histopathology indicated that it was a fibroma. Follow-up echocardiograms and magnetic resonance imaging 5 months postoperatively demonstrated no evidence of any remaining tumor and his RV function was good. PMID- 23674201 TI - Landiolol hydrochloride for early postoperative tachycardia after transthoracic esophagectomy. AB - PURPOSE: To validate the safety and efficacy of landiolol, a beta1-selective blocker, as a primary care option for postoperative tachycardia after transthoracic esophagectomy. METHODS: The subjects were 74 consecutive patients who underwent esophagectomy between May 2008 and December 2009. Patients who developed tachycardia with a heart rate >120 bpm for >5 min were defined as candidates for the use of landiolol. The rate of successful heart control without adverse effects was the primary endpoint. The reduction of the rate pressure product (RPP) and heart rate were used as secondary endpoints. RESULTS: Thirteen patients (18 %) were treated with landiolol for postoperative tachycardia. No adverse effects were observed. Successful management using landiolol alone was achieved in 10 of the 13 patients (77 %). Of the three patients for whom landiolol treatment was unsuccessful, two were also not successfully managed promptly by other treatments. The heart rate and RPP were reduced by landiolol, with median changes of 38 and 44 %, respectively, without significant negative inotropic effects. CONCLUSIONS: Although our sample size was small, an improved cardiac performance and no severe negative inotropic effects were observed with the use of landiolol. Landiolol could therefore be an efficient and safe choice for the management of postoperative tachycardia after esophagectomy. PMID- 23674202 TI - Atrial fibrillation after esophageal cancer surgery: an analysis of 207 consecutive patients. AB - PURPOSE: The aim of this study was to identify perioperative risk factors that are associated with postoperative atrial fibrillation (AF) and the outcomes of different pharmacological interventions in esophageal cancer patients who underwent transthoracic esophagectomy. METHODS: This study included 207 patients who underwent a transthoracic esophagectomy for esophageal cancer resection by a single surgeon from January 1, 2004, through December 31, 2010. RESULTS: Postoperative AF occurred in 19 patients (9.2 %), all of whom received antiarrhythmic drug therapy at the early stage. Antiarrhythmic treatment was effective in 12 cases (63.2 %). In this study, landiolol hydrochloride, an ultrashort-acting beta1-selective beta-blocker, was the first-line therapy for postoperative AF. A multivariate logistic regression analysis showed that postoperative AF was significantly associated with the use of an ileo-colon for reconstruction after esophagectomy (P = 0.0023, odds ratios [OR] = 13.6) and with the presence of tachycardia with a heart rate of >100 bpm on postoperative day (POD) 1 (P = 0.0004, OR = 18.4). CONCLUSIONS: Postoperative AF is associated with the use of a colon conduit for reconstruction after esophagectomy and with tachycardia with a heart rate >100 bpm on POD 1. Identifying patients at high risk for postoperative AF will allow for more direct application of pharmacological methods of prophylaxis. PMID- 23674203 TI - Hemorrhage from the pancreatic cut end into the jejunum after binding pancreaticojejunostomy: report of a case. AB - Recent studies have described that binding pancreaticojejunostomy (PJ) decreased the incidence of postoperative pancreatic fistulas and complications after pancreaticoduodenectomy. We herein describe the case of a 77-year-old male with papilla of Vater cancer who underwent subtotal stomach-preserving pancreaticoduodenectomy with end-to-side binding PJ. He developed postoperative gastrointestinal bleeding from the pancreatic cut end three separate times. Transcatheter arterial embolization was performed for the first bleeding event. Surgical hemostasis was performed and a temporary jejunostomy was constructed at the jejunal stump for the second event. For the third bleeding event, endoscopic coagulation through the jejunostomy was performed successfully, and no further bleeding was noted. PMID- 23674205 TI - Optical imaging as an expansion of nuclear medicine: Cerenkov-based luminescence vs fluorescence-based luminescence. AB - Integration of optical imaging technologies can further strengthen the field of radioguided surgery. Rather than using two separate chemical entities to achieve this extension, hybrid imaging agents can be used that contain both radionuclear and optical properties. Two types of such hybrid imaging agents are available: (1) hybrid imaging agents generated by Cerenkov luminescence imaging (CLI) of beta-emitters and (2) hybrid imaging agents that contain both a radioactive moiety and a fluorescent dye. One major challenge clinicians are now facing is to determine the potential value of these approaches. With this tutorial review we intend to clarify the differences between the two approaches and highlight the clinical potential of hybrid imaging during image-guided surgery applications. PMID- 23674206 TI - MicroPET/CT imaging of alphavbeta3 integrin via a novel 68Ga-NOTA-RGD peptidomimetic conjugate in rat myocardial infarction. AB - PURPOSE: The alphavbeta3 integrin is expressed in angiogenic vessels and is a potential target for molecular imaging of evolving pathological processes. Its expression is upregulated in cancer lesions and metastases as well as in acute myocardial infarction (MI) as part of the infarct healing process. The purpose of our study was to determine the feasibility of a new imaging approach with a novel (68)Ga-2,2',2"-(1,4,7-triazonane-1,4,7-triyl)triacetic acid (NOTA)-arginine glycine-aspartic acid (RGD) construct to assess integrin expression in the evolving MI. METHODS: A straightforward labelling chemistry to attach the radionuclide (68)Ga to a NOTA-based chelating agent conjugated with a cyclic RGD peptidomimetic is described. Affinity for alphavbeta3 integrin was assessed by in vitro receptor binding assay. The proof-of-concept in vivo studies combined the (68)Ga-NOTA-RGD with the flow tracer (13)N-NH3 imaging in order to obtain positron emission tomography (PET)/CT imaging of both integrin expression and perfusion defect at 4 weeks after infarction. Hearts were then processed for immunostaining of integrin beta3. RESULTS: NOTA-RGD conjugate displayed a binding affinity for alphavbeta3 integrin of 27.9 +/- 6.8 nM. (68)Ga-NOTA-RGD showed stability without detectable degradation or formation of by-products in urine up to 2 h following injection in the rat. MI hearts exhibited (68)Ga-NOTA-RGD uptake in correspondence to infarcted and border zone regions. The tracer signal drew a parallel with vascular remodelling due to ischaemia-induced angiogenesis as assessed by immunohistochemistry. CONCLUSION: As compared to similar imaging approaches using the (18)F-galacto-derivative, we documented for the first time with microPET/CT imaging the (68)Ga-NOTA-RGD derivative that appears eligible for PET imaging in animal models of vascular remodelling during evolving MI. The simple chemistry employed to synthesize the (68)Ga-based radiotracer may greatly facilitate its translation to a clinical setting. PMID- 23674207 TI - Pretargeted immuno-PET and radioimmunotherapy of prostate cancer with an anti TROP-2 x anti-HSG bispecific antibody. AB - PURPOSE: TF12 is a trivalent bispecific antibody that consists of two anti-TROP-2 Fab fragments and one anti-histamine-succinyl-glycine (HSG) Fab fragment. The TROP-2 antigen is found in many epithelial cancers, including prostate cancer (PC), and therefore this bispecific antibody could be suitable for pretargeting in this cancer. In this study, the characteristics and the potential for pretargeted radioimmunoimaging and radioimmunotherapy with TF12 and the radiolabeled di-HSG peptide IMP288 in mice with human PC were investigated. METHODS: The optimal TF12 protein dose, IMP288 peptide dose, and dose interval for PC targeting were assessed in nude mice with s.c. PC3 xenografts. Immuno positron emission tomography (PET)/CT was performed using TF12/68Ga-IMP288 at optimized conditions. The potential of pretargeted radioimmunotherapy (PRIT) using the TF12 pretargeted 177Lu-IMP288 was determined. RESULTS: TF12 and 111In IMP288 showed high and fast accumulation in the tumor [20.4 +/- 0.6%ID/g at 1 h post-injection (p.i.)] at optimized conditions, despite the internalizing properties of TF12. The potential for PRIT was shown by retention of 50% of the 111In-IMP288 in the tumor at 48 h p.i. One cycle of treatment with TF12 and 177Lu IMP288 showed significant improvement of survival compared to treatment with 177Lu-IMP288 alone (90 vs. 67 days, p<0.0001) with no renal or hematological toxicity. CONCLUSION: TROP-2-expressing PC can be pretargeted efficiently with TF12, with very rapid uptake of the radiolabeled hapten-peptide, IMP288, sensitive immuno-PET, and effective therapy. PMID- 23674208 TI - Predictive variables for hard cardiac events and coronary revascularization in patients with normal left ventricular myocardial perfusion and systolic function. AB - BACKGROUND: The objective of this study was to investigate the impact of clinical, electrocardiographic and stress testing variables in predicting hard cardiac events (HE) and coronary revascularization (CR) in patients with normal stress-rest gated SPECT. MATERIALS AND METHODS: Included in the study were 2,004 patients (63.5 +/- 12.5 years, 41.6% men) with normal myocardial perfusion and left ventricular ejection fraction (LVEF) >50% on gated SPECT who were followed for HE (cardiovascular death or acute myocardial infarction) and CR. RESULTS: During a follow-up of 4.3 +/- 2.4 years, 33 patients (1.6 %; 0.4%/year) had HE and 50 patients (2.5%; 0.6%/year) underwent CR. In a univariate analysis, age >=65 years, insulin-dependent diabetes mellitus (IDDM), left bundle branch block (LBBB), and pharmacological stress were associated with HE. Independent predictors of HE were age >=65 years (p < 0.001; HR 6.9), IDDM (p = 0.014; HR 3.4), and LBBB (p = 0.002; HR 4.6). In the univariate analysis, male gender, LVEF, known coronary artery disease (CAD), LBBB, and a positive stress test were associated with CR. Independent predictors of CR were known CAD (p = 0.016; HR 2.1), and a positive stress test (p = 0.006; HR 2.3). CONCLUSION: Age >=65 years, IDDM, and LBBB are HE-independent predictors in patients with normal myocardial perfusion and normal LVEF on gated SPECT. The presence of known CAD or a positive stress test significantly increases the probability of CR during follow-up. PMID- 23674209 TI - The isotope bone scan: we can do better. PMID- 23674210 TI - Optimisation and harmonisation: two sides of the same coin? PMID- 23674211 TI - Prognostic value of whole-body metabolic tumour volume and total lesion glycolysis measured on 18F-FDG PET/CT in patients with extranodal NK/T-cell lymphoma. AB - PURPOSE: The aim of this study was to determine whether maximum standardized uptake value (SUVmax), whole-body metabolic tumour volume (WBMTV), and whole-body total lesion glycolysis (WBTLG) measured on pretreatment 18F-FDG PET/CT can predict prognosis in patients with extranodal natural killer/T-cell lymphoma (ENKTL). METHODS: We conducted a retrospective analysis of 20 patients with newly diagnosed ENKTL who underwent pretreatment 18F-FDG PET/CT. WBMTV and WBTLG were measured automatically using the boundaries of voxels presenting SUV>3.0. Uni- and multivariate analyses for survival and disease progression were performed using clinical variables and PET parameters (SUVmax, WBMTV, and WBTLG). RESULTS: During the follow-up period (median 26.3 months), 12 patients showed disease progression and 10 patients died from the disease. Receiver operating characteristic curve analysis showed cut-off values for SUVmax, WBMTV and WBTLG of 8.1, 14.4 cm3 and 52.7, respectively. Univariate analysis showed that the International Prognostic Index (IPI) score and PET parameters were significant predictors of overall survival (OS) and progression-free survival (PFS). Multivariate analysis, even after adjustment for the IPI score, showed that high WBMTV was the best predictor of OS and PFS, and high SUVmax and WBTLG were significant predictors of PFS. CONCLUSION: Our results suggested that the use of PET parameters together with the IPI score may be useful for detailed prediction of prognosis in ENKTL patients. Therefore, despite a lower IPI score, patients with high PET parameter values might be considered candidates for aggressive therapy to improve clinical outcomes. PMID- 23674212 TI - Temporary closure of congenital tracheoesophageal fistula with Fogarty catheter. PMID- 23674213 TI - Association of EGFR mutation or ALK rearrangement with expression of DNA repair and synthesis genes in never-smoker women with pulmonary adenocarcinoma. PMID- 23674214 TI - The influence of dead time related distortions on live cell fluorescence lifetime imaging (FLIM) experiments. AB - Recent developments in the field of fluorescence lifetime imaging microscopy (FLIM) techniques allow the use of high repetition rate light sources in live cell experiments. For light sources with a repetition rate of 20-100 MHz, the time-correlated single photon counting (TCSPC) FLIM systems suffer serious dead time related distortions, known as "inter-pulse pile-up". The objective of this paper is to present a new method to quantify the level of signal distortion in TCSPC FLIM experiments, in order to determine the most efficient laser repetition rate for different FLT ranges. Optimization of the F -value, which is the relation between the relative standard deviation (RSD) in the measured FLT to the RSD in the measured fluorescence intensity (FI), allows quantification of the level of FI signal distortion, as well as determination of the correct FLT of the measurement. It is shown that by using a very high repetition rate (80 MHz) for samples characterized by high real FLT's (4-5 ns), virtual short FLT components are added to the FLT histogram while a F -value that is higher than 1 is obtained. For samples characterized with short real FLT's, virtual long FLT components are added to the FLT histogram with the lower repetition rate (20-50 MHz), while by using a higher repetition rate (80 MHz) the "inter-pulse pile-up" is eliminated as the F -value is close to 1. PMID- 23674215 TI - [Unsuccessful duraplasty technique or persisting/recanalized Sternberg's canal?]. AB - Spontaneous rhinoliquorrhea with or without meningo-encephaloceles in the region of the sphenoid sinus occurs very infrequently. It is not uncommon that the attempt of transnasal endoscopic duraplasty in this region leads to recurrence of the CSF leak. The existence of a lateral craniopharyngeal canal can be a possible explanation for these failures.Retrospective analysis of 23 patients with rhinoliquorrhea of different pathogenesis in the region of the frontal and central skull base that were treated with transnasal, video-endoscopic surgical procedures in our department between 2006 and 2011.2 of 23 patients with proven rhinoliquorrhea following a transnasal video endoscopic duraplasty procedure showed a recurrence of the CSF leak. The computertomographic analysis with respect to the current literature indicated the presence of a craniopharyngeal canal at the lateral side of the sphenoid sinus. This canal is also known in the literature as Sternberg's canal. In contrast to the other 21 treated cases there were no planar skull base defects of different pathogenesis in these 2 cases, but a ontogenetically bony canal. The canal can reopen spontaneously or due to an external mechanical impact.The closure of this bony canal requires a modified surgical procedure such as sufficient padding of the bony canal and its sealing by a vascularized pedicle flap in contrast to the ordinary planar bony skull base defects. PMID- 23674216 TI - Protocol: ex vivo culture of mouse embryonic mammary buds. AB - The explant culture techniques of embryonic tissues allow continuous monitoring of organ growth and morphogenesis ex vivo. The effect of growth factors and other soluble molecules can be examined by applying them to the culture medium. Relatively few studies have reported application of tissue culture techniques to analysis of embryonic mammary glands. Here we describe a protocol for murine mammary rudiments that permits ex vivo development up to branching stage. PMID- 23674217 TI - The nipple: a simple intersection of mammary gland and integument, but focal point of organ function. AB - Having glands that secrete milk to nourish neonatal offspring characterizes all mammals. We provide a brief overview of the development and anatomy of nipples and mammary glands in monotremes, marsupials, and marine mammals, and focus on the nipples and mammary glands in terrestrial eutherian species. We first classify eutherians into three groups: the altricial, precocial, and arboreal types based on their rearing system. We then summarize the physiology of lactation and the cell biology of nipples with specific focus on comparing these in the mouse, cow, and human, which represent the three different groups. Finally we propose that the nipple is an example of specialized epidermis. As specialized epidermis, it is dependent the underlying stroma for development and maintenance in adult life. The development of the nipple and signaling pathways that regulate its formation are described. PMID- 23674218 TI - Coracoclavicular ligament attachment regions of the Chinese population: a quantitative anatomic study. AB - It is reported that the coracoclavicular (CC) ligaments arise at a constant region, which is proportional to the size of the clavicle and the coracoid process. However, all cadavers in those studies were from whites or African Americans. The aim of this study was to evaluate dimension and orientation of CC footprints in Chinese cadavers and to determine whether race-dependent differences in these measurements exist. A total of 172 shoulders from 87 Chinese cadavers were used in this study, and the CC ligaments including the coracoid and the lateral clavicle were exposed. After measurement of the length of the CC ligaments, the ligaments were dissected and the insertion sites as well as the footprint centers were identified and marked. Each CC insertion dimension and its distance to the bony landmarks were recorded. Ratios representing the distance from the clavicular landmarks to each footprint center divided by clavicular length and clavicular width were calculated. These ratios were calculated for the coracoid process as well. The mean length of the clavicle and the coracoid process was 139.9 +/- 9.4 and 40.5 +/- 4.0 mm. The distance from the lateral edge of the clavicle to the conoidal center and to the trapezoidal center was 35.7 +/- 3.4 and 21.8 +/- 2.7 mm, respectively. The distance from the tip of the coracoid to the conoidal center and to the trapezoidal center was 35.1 +/- 3.2 and 29.7 +/ 2.9 mm, respectively. The ratios of the distance to the conoidal center and to the trapezoidal center divided by clavicular length and coracoidal length were 25.5, 15.6, 86.8 and 73.4 %, respectively. While absolute differences in the origin of the CC ligaments exist between different races, the ratio of these origins to the size of the clavicle and the coracoid process is constant. PMID- 23674220 TI - Carbaryl-induced histopathologic alterations on testes of levantine frog, Pelophylax bedriagae (Anura: Ranidae). AB - The aim of the study was to investigate for the first time histopathologic effects of carbaryl on the testes of adult frog, Pelophylax bedriagae. Frogs were exposed to carbaryl once by oral gavage in concentrations of 0.05, 0.1 and 0.2 mg/g. After 96 h, frogs were euthanized and dissected. Histopathological changes were more prominent in medium- (0.1 mg/g) and high-dose (0.2 mg/g) groups than in the low-dose (0.05 mg/g) group. In the low-dose group, shrinkage of some seminiferous tubules was observed. In the medium-dose group, an enlargement of interstitial spaces and germ cell necrosis were detected. In the high-dose group, prominent tubule deformation was determined. Germ cell necrosis in seminiferous tubules was frequently seen. In addition, congestion, hemorrhage, cellular infiltration and fibrosis were detected. According to these findings, it is clear that carbaryl affects male fertility in P. bedriagae. PMID- 23674219 TI - Genetic variants in the JAK1 gene confer higher risk of Behcet's disease with ocular involvement in Han Chinese. AB - Recent surveys have identified SLC22A4, SLC22A5, RUNX1, JAK1 as susceptibility genes for various immune-related diseases. An association study was performed in 738 Behcet's patients with ocular involvement and 1,873 controls using the iPLEX system method. The first-stage study for 30 SNPs showed that SNPs rs2780815, rs310241, rs3790532 in JAK1 were associated with Behcet's disease in Han Chinese (Pc(Bonferroni correction) = 0.022-7.7 * 10(-3)). The G allele and AA genotype of SNP rs2834643 in RUNX1 (Pc = 0.041-1.75 * 10(-3)), but none of the other SNPs, were associated with Behcet's disease. Haplotype analysis for the SLC22A4, SLC22A5 genes showed an increased tendency for AGTCTGCCGC frequency in patients compared with controls; however, the significance was lost after Bonferroni correction (P = 0.004, Pc > 0.05). Subsequently, we further replicated the significantly associated SNPs using another independent cohort. Replication and combining studies showed that three SNPs rs2780815, rs310241, rs3790532 in JAK1, but not SNP rs2834643 in RUNX1, were consistently associated with Behcet's disease (replication: Pc = 0.012-9.60 * 10(-4); combining: Pc = 0.030-1.90 * 10( 4)). SNPs rs2780815, rs310241, rs3790532 were estimated to confer a population attributable risk of 35.0, 28.0, 27.0 %, respectively. We found a strong association between HLA-B51 with Behcet's disease in Chinese Han population (P = 1.35 * 10(-73); OR = 5.15; 95 % CI 4.28-6.19). GMDR analysis showed that no gene gene interaction was detectable between JAK1 and HLA-B51. Logistic analysis indicated that the JAK1 gene was an independent risk factor for Behcet's disease (P > 0.05). Real-time PCR analysis showed that no difference on the expression of JAK1 in PBMCs or LPS-stimulated PBMCs between individuals with the different rs1762780815 genotypes studied (P > 0.05). In conclusion, this study suggests that JAK1, but not SLC22A4, SLC22A5 and RUNX1, contributes to the genetic susceptibility to Behcet's disease with ocular involvement. PMID- 23674221 TI - Effects of ammonia on fertilization, development, and larval survival in the Northern Pacific asteroid, Asterias amurensis. AB - For developing a complementary test organism to sea urchin during winter in Korea, sensitivities of sperm, embryo, and larvae of Asterias amurensis to un ionized ammonia were evaluated. The EC50s (Mean +/- SD, n = 3) for fertilization and development were 169 +/- 62 and 70 +/- 19 MUg/L, respectively. The 48, 72, and 96-h LC50s for larval survival were 1,674 +/- 583, 498 +/- 221, and 336 +/- 107 MUg/L, respectively. The sensitivities of fertilization, development, and larval survival tests with A. amurensis are higher than or comparable to those of sea urchin and other taxonomic groups. Therefore, fertilization, development, and larval survival tests using A. amurensis are suitable for assessing pore water toxicity of marine sediments in Korea. PMID- 23674222 TI - Miniature stick-packaging--an industrial technology for pre-storage and release of reagents in lab-on-a-chip systems. AB - Stick-packaging of goods in tubular-shaped composite-foil pouches has become a popular technology for food and drug packaging. We miniaturized stick-packaging for use in lab-on-a-chip (LOAC) systems to pre-store and on-demand release the liquid and dry reagents in a volume range of 80-500 MUl. An integrated frangible seal enables the pressure-controlled release of reagents and simplifies the layout of LOAC systems, thereby making the package a functional microfluidic release unit. The frangible seal is adjusted to defined burst pressures ranging from 20 to 140 kPa. The applied ultrasonic welding process allows the packaging of temperature sensitive reagents. Stick-packs have been successfully tested applying recovery tests (where 99% (STDV = 1%) of 250 MUl pre-stored liquid is released), long-term storage tests (where there is loss of only <0.5% for simulated 2 years) and air transport simulation tests. The developed technology enables the storage of a combination of liquid and dry reagents. It is a scalable technology suitable for rapid prototyping and low-cost mass production. PMID- 23674223 TI - Central and peripheral nervous systems: master controllers in cancer metastasis. AB - Central and sympathetic nervous systems govern functional activities of many organs. Solid tumors like organs are also innervated by sympathetic nerve fibers. Neurotransmitters released from sympathetic nerve fibers can modulate biological behaviors of tumor cells. Multiple physiologic processes of tumor development may be dominated by central and sympathetic nervous systems as well. Recent studies suggest that dysfunction of central and sympathetic nervous systems and disorder of the hormone network induced by psychological stress may influence malignant progression of cancer by inhibiting the functions of immune system, regulating metabolic reprogramming of tumor cells, and inducing interactions between tumor and stromal cells. Over-release of inflammatory cytokines by tumors may aggravate emotional disorder, triggering the vicious cycles in tumor microenvironment and host macroenvironment. It is reasonable to hypothesize that cancer progression may be controlled by central and sympathetic nervous systems. In this review, we will focus on the recent information about the impacts of central and sympathetic nervous systems on tumor invasion and metastasis. PMID- 23674224 TI - Alternative plasmonic materials: beyond gold and silver. AB - Materials research plays a vital role in transforming breakthrough scientific ideas into next-generation technology. Similar to the way silicon revolutionized the microelectronics industry, the proper materials can greatly impact the field of plasmonics and metamaterials. Currently, research in plasmonics and metamaterials lacks good material building blocks in order to realize useful devices. Such devices suffer from many drawbacks arising from the undesirable properties of their material building blocks, especially metals. There are many materials, other than conventional metallic components such as gold and silver, that exhibit metallic properties and provide advantages in device performance, design flexibility, fabrication, integration, and tunability. This review explores different material classes for plasmonic and metamaterial applications, such as conventional semiconductors, transparent conducting oxides, perovskite oxides, metal nitrides, silicides, germanides, and 2D materials such as graphene. This review provides a summary of the recent developments in the search for better plasmonic materials and an outlook of further research directions. PMID- 23674225 TI - Effect of depressor septi nasi muscle activity on nasal lengthening with time. AB - BACKGROUND: The depressor septi nasi (DSN) muscle is an important muscle in nose dynamics. Its hyperactivity causes smile deformity including nasal tip depression. The nasal tip of individuals with a hyperactive DSN muscle depresses repeatedly while they are speaking and smiling. This may result in nasal lengthening as they age. METHODS: Pairs of cases consisting of a child and one of his or her parents were studied in two groups: case group (with DSN muscle hyperactivity) and the control group (with DSN muscle inactivity in both child and parent). Nasal length from nasion to tip and facial length from nasion to menton were measured during repose and during smiling. RESULTS: This study investigated 80 pairs of children and parents. In both groups, a significant linear correlation between the nasal length of the parent and the child was found. In both groups (case and control), the nasal length of the child differed significantly from that of the parent. The increase in the nasal length of the parents compared with the children was greater in the control group. CONCLUSIONS: This study demonstrated that nasal length increases with age and that DSN muscle hyperactivity is not an effective factor in this increase. This unpredictable result may affect the presumption that patients with DSN muscle hyperactivity will have longer noses in the future. Long-term prospective studies investigating cohort groups are required to clarify the variables affecting nasal lengthening with aging, and interventional studies are needed to examine the effects of DSN muscle resection on this phenomenon. PMID- 23674226 TI - Mitigating effects of external ventricular drain usage in the management of severe head injury. PMID- 23674227 TI - Hydrocephalus associated with vestibular schwannomas: perioperative changes in cerebrospinal fluid. AB - BACKGROUND: Cerebrospinal fluid (CSF) protein levels are known to increase in patients with vestibular schwannomas (VS) with concomitant hydrocephalus, however the only information available on perioperative changes in CSF in these patients comes from case reports. Here, we investigated the relation between CSF protein and hydrocephalus in a large series of patients undergoing resection of VS. METHOD: We classified 376 patients undergoing resection for VS at our institute into two groups, namely VS and no hydrocephalus (control, n = 319) and VS with concomitant hydrocephalus (n = 57), and compared clinical parameters. Among the 57 patients diagnosed with hydrocephalus, hydrocephalus status was examined by lumbar puncture in 20 patients with communicative hydrocephalus, and pre- and postoperative scores in CSF properties were compared. RESULTS: Patients in the hydrocephalus group were significantly older than those in the control group (mean, 55.8 vs. 43.8 years), and had a longer disease duration (median, 76 vs. 12 months), larger tumors (median, 15.6 vs. 5.5 ml), and a higher protein concentration in CSF (median, 147.3 vs. 65.1 mg/dl). Perioperative CSF samples of hydrocephalus patients showed a significantly decrease in cerebrospinal pressure after tumor removal (median, -75mmH2O), followed by a decrease in CSF protein (median, -74.5 mg/dl). No patients required the placement of a shunt. CONCLUSIONS: Extended disease duration and elevated CSF protein secondary to the presence of a tumor contribute to the occurrence of hydrocephalus. Primary maximal tumor removal for VS with coexisting hydrocephalus avoids an unnecessary shunt. PMID- 23674228 TI - Neuroradiology in Duckburg. PMID- 23674229 TI - Community consultation in emergency neurotrauma research: results from a pre protocol survey. AB - BACKGROUND: Uncertainty remains as to the role of decompressive craniectomy (DC) for primary evacuation of an acute subdural haematoma (ASDH). In 2011, a collaborative group of neurosurgeons, neuro-intensive care physicians and trial methodologists was formed in the UK with the aim of answering the following question: "What is the clinical- and cost-effectiveness of DC, in comparison to simple craniotomy for adult patients undergoing primary evacuation of an ASDH?" The proposed RESCUE-ASDH trial (Randomised Evaluation of Surgery with Craniectomy for patients Undergoing Evacuation of Acute Subdural Haematoma) is a multi centre, pragmatic, parallel group randomised trial of DC versus simple craniotomy for adult head-injured patients with an ASDH. Clinical trials in the emergency setting face the problem that potential participants may be incapacitated and their next of kin initially unavailable. As a result, consent and enrolment of participants can often be difficult. METHOD: In the current study, we aimed to assess public opinion regarding participation in the RESCUE-ASDH trial and acceptability of surrogate consent by conducting a pre-protocol community consultation survey. RESULTS: One hundred and seventy-one subjects completed the survey. Eighty-four percent of participants responded positively when asked if they would participate in the proposed trial. Ninety-six percent and 91 % answered positively when asked if they found surrogate consent by their next of kin and an independent doctor acceptable, respectively. None of the characteristics of the study population were found to affect the decision to participate or the acceptability of surrogate consent by the next of kin. Being religious showed a trend towards higher acceptability of surrogate consent by a doctor. Conversely, an education to degree level and above showed a trend towards reduced acceptability of surrogate consent by a doctor. CONCLUSIONS: Our community consultation survey shows that the proposed trial is acceptable to the public. In addition, the results suggest high levels of acceptability of surrogate consent by next of kin or independent doctor amongst our community. PMID- 23674230 TI - A new susceptibility-weighted image reconstruction method for the reduction of background phase artifacts. AB - PURPOSE: To significantly reduce the background phase effects, especially at the air-tissue interface, and to enhance the desirable local structures of veins in susceptibility-weighted imaging. METHODS: In the proposed reconstruction method called Magnitude of Complex Filtering, a complex-valued magnetic resonance image is acquired using a flow-compensated high-resolution 3D gradient-echo sequence and the magnitude of the complex-valued image is set to 1 so that the phase information, which contains details of the local susceptibility, is emphasized. Then, the nonlinear filter of the Magnitude of Complex Filtering method is applied to the complex-valued image with a constant magnitude. This filter utilizes the magnitude of the low-pass and high-pass filtered complex data to selectively reduce the background phase effects while enhancing the local structures. The filter output is then processed to generate a susceptibility weighted image. RESULTS: Compared with the conventional susceptibility-weighted images generated by a homodyne high-pass filter, the susceptibility-weighted images from the proposed Magnitude of Complex Filtering method show significant improvement; the undesirable artifacts at the air-tissue interface regions and the brain boundaries are significantly reduced, while the contrast of the local structures of veins is enhanced. CONCLUSION: The Magnitude of Complex Filtering method successfully reduced most background phase effects without requiring additional processing or scan time. PMID- 23674231 TI - An update on diets in clinical practice. AB - Ketogenic diet therapies involve a collaborative healthcare team and therefore are typically offered in tertiary care centers. Centers that utilize these therapies with frequency gain valuable experience and become skilled in their practice. This chapter is a summary from the presentations of 5 practitioners including a nurse, pharmacist, and 3 dietitians who shared their expertise during the clinical session of the 2012 International Symposium. PMID- 23674232 TI - Analysis of plasma multiplex cytokines for children with febrile seizures and severe acute encephalitis. AB - We investigated the plasma cytokine profiles of children with febrile seizures or severe acute encephalitis using multiplex cytometry to evaluate the role of cytokines in these diseases. Interleukin-6, -10, -12p70, -17A, -2, -4, -5, -9, 13, -22, and -1beta, interferon-gamma, and tumor necrosis factor-alpha were measured in the plasma from children with febrile seizures (n = 9) or severe acute encephalitis (n = 21). In multivariate analysis, interleukin-6 was significantly increased in the plasma of the febrile seizure patients compared to those with severe acute encephalitis, suggesting that interleukin-6 is activated during the acute stage of a febrile seizure. A lower plasma interleukin-6 concentration was significantly associated with severe acute encephalitis. The cytokine network may be deregulated in severe acute encephalitis via the persistence of an uncontrolled inflammatory state in the brain. PMID- 23674233 TI - Mouse cochleostomy: a minimally invasive dorsal approach for modeling cochlear implantation. AB - OBJECTIVES/HYPOTHESIS: The murine model has been used extensively to model and study human deafness. Technical difficulty in the surgical approach due to the small size of the tympanic bulla and a robust stapedial artery has limited its application for studies of cochlear implantation and electrical stimulation. We describe a minimally traumatic, stapedial artery-sparing approach to the round window that may be used to access the mouse cochlea for acute or chronic studies of implantation and stimulation. STUDY DESIGN: Animal model. METHODS: Fifteen C57BL6J mice were used to validate this approach. Auditory brainstem response threshold and distortion product otoacoustic emissions were obtained preoperatively and 2 weeks postoperatively to determine hearing preservation results. RESULTS: The approach provided excellent exposure for round-window implantation. Substantial hearing was preserved in all animals with a mean postimplantation auditory brainstem response threshold increase of 27.8 dB. Otoacoustic emissions were lost in subjects with the largest threshold shifts. CONCLUSIONS: Residual hearing after cochlear implantation is a determinant of success both with standard cochlear implant electrodes and with electrodes designed to optimize hearing preservation. Here, we have preserved usable hearing after implantation of C57BL6J mice, an endogenous model of human presbycusia. The murine model may become a powerful tool to assay the effects of cochlear intervention in different genetic backgrounds. PMID- 23674234 TI - Coherent anti-Stokes Raman scattering microscopy: overcoming technical barriers for clinical translation. AB - Clinical translation of coherent anti-Stokes Raman scattering microscopy is of great interest because of the advantages of noninvasive label-free imaging, high sensitivity, and chemical specificity. For this to happen, we have identified and review the technical barriers that must be overcome. Prior investigations have developed advanced techniques (features), each of which can be used to effectively overcome one particular technical barrier. However, the implementation of one or a small number of these advanced features in previous attempts for clinical translation has often introduced more tradeoffs than benefits. In this review, we outline a strategy that would integrate multiple advanced features to overcome all the technical barriers simultaneously, effectively reduce tradeoffs, and synergistically optimize CARS microscopy for clinical translation. The operation of the envisioned system incorporates coherent Raman micro-spectroscopy for identifying vibrational biomolecular markers of disease and single-frequency (or hyperspectral) Raman imaging of these specific biomarkers for real-time in vivo diagnostics and monitoring. PMID- 23674235 TI - Current and future treatments for malignant pheochromocytoma and sympathetic paraganglioma. AB - Pheochromocytomas (PHs) and sympathetic paragangliomas (SPGs) are rare neuroendocrine tumors. Approximately 17 % of these tumors are malignant, but because no molecular or histologic markers for malignancy exist, patients are often diagnosed with malignant PHs or SPGs after unresectable disease has formed. Patients with progressive metastatic tumors and overwhelming symptoms are currently treated with systemic chemotherapy and radiopharmaceutical agents such as metaiodobenzylguanidine. These therapies lead to partial radiographic response, disease stabilization, and symptomatic improvement in approximately 40 % of patients, and systemic chemotherapy is associated with a modest improvement in overall survival duration. However, over the past decade, substantial progress has been made in clinical, biochemical, and radiographic diagnosis of PHs and SPGs. Approximately 50 % of patients with malignant PHs and SPGs have been found to carry hereditary germline mutations in the succinate dehydrogenase subunit B gene (SDHB), and anti-angiogenic agents such as sunitinib have been found to potentially play a role in the treatment of malignant disease, especially in patients with SDHB mutations. In some patients, treatment with sunitinib has been associated with partial radiographic response, disease stabilization, decreased fluorodeoxyglucose uptake on positron emission tomography, and improved blood pressure control. These findings have led to the development of prospective clinical trials of new targeted therapies for metastatic disease. Here, we provide an updated review of the clinical and genetic predictors of malignant disease, radiographic diagnosis of malignant disease, and information from the most relevant studies of systemic therapies, as well as proposed treatment guidelines for patients with metastatic or potentially malignant PHs and SPGs. PMID- 23674237 TI - Multidrug resistance in relapsed acute myeloid leukemia: evidence of biological heterogeneity. AB - BACKGROUND: Studies of mechanisms mediating resistance to chemotherapy led to the discovery of the multidrug transporter ABCB1 (ATP-binding cassette, subfamily B, member 1), often expressed in leukemic cells of patients with acute myeloid leukemia (AML). Most clinical trials evaluating the strategy of inhibiting efflux mediated chemotherapeutic resistance have been unsuccessful, clearly indicating the need for a better approach. METHODS: This study investigated the clinical relevance of 380 genes whose expression has been shown to affect the response to chemotherapy, mostly through in vitro studies, in 11 paired samples obtained at AML diagnosis and at relapse. The expression profiling of these 380 genes was performed using TaqMan-based quantitative reverse-transcription polymerase chain reaction. Patients had a median age of 58 years at diagnosis, a median duration of complete remission of 284.5 days, and a median overall survival of 563 days. Cytogenetic abnormalities were detected at diagnosis in 4 patients, whereas 5 displayed a normal karyotype and 2 were not investigated. RESULTS: Hierarchical clustering shows that samples taken at diagnosis and relapse clustered in pairs for 6 patients of the 11 studied, suggesting recurrence of the same leukemic blast, whereas for the other 5 patients, the data indicate their relapse blasts arose from different origins. A patient-by-patient analysis of the paired samples led to the striking observation that each had a unique gene signature representing different mechanisms of resistance. CONCLUSIONS: The data underline the need for personalized molecular analysis to tailor treatment for patients with AML. PMID- 23674236 TI - EGFR tyrosine kinase inhibitors: difference in efficacy and resistance. AB - Lung cancer will be diagnosed in 230,000 patients in the U.S. in 2013. Adenocarcinoma will be the most common histology, and 10 % of lung cancers will be diagnosed in never or former light smokers. These patients will be those most likely to harbor targetable mutations, in particular, mutations in epidermal growth factor (EGFR). Preclinical work beginning in the 1980s led to the development of EGFR-targeted therapy in lung cancer patients. Analysis of the responders to gefitinib and erlotinib led to the discovery of activating mutations underlying sensitivity to EGFR-directed treatment. Although EGFR-mutant patients have higher response rates, better quality of life, and longer progression free survival, all patients eventually develop resistance. Mutations in the tyrosine kinase domain that render tumors resistant to erlotinib and gefitinib are the most common mechanism of resistance. A second generation of EGFR inhibitors are now making their way to the clinic, with hopes of thwarting these resistance mechanisms or providing more durable responses via irreversible inhibition, as well as targeting of additional HER receptors. Here we review the evolution of EGFR as a target in lung cancer, and the second generation of EGFR inhibitors in development. PMID- 23674238 TI - Pristine nanomaterials: synthesis, stability and applications. AB - Capping-free and linker-free nanostructures/hybrids possess superior properties due to the presence of pristine surfaces and interfaces. In this review, various methods for synthesizing pristine nanomaterials are presented along with the general principles involved in their morphology control. In wet chemical synthesis, the interplay between various reaction parameters results in diverse morphology. The fundamental principles behind the evolution of morphology including nanoporous aggregates of metals and other inorganic materials, 2D nanocrystals of metals is elucidated by capping-free methods in aqueous medium. In addition, strategies leading to the attachment of bare noble metal nanoparticles to functional oxide supports/reduced graphene oxide has been demonstrated which can serve as a simple solution for obtaining thermally stable and efficient supported catalysts with free surfaces. Solution based synthesis of linker-free oxide-semiconductor hybrids and capping-free metal nanowires on substrates are also discussed in this context with ZnO/CdS and ultrathin Au nanowires as examples. A simple and rapid microwave-assisted method is highlighted for obtaining such hybrids which can be employed for high-yield production of similar materials. PMID- 23674241 TI - Combining analytical hierarchy process and agglomerative hierarchical clustering in search of expert consensus in green corridors development management. AB - Environmental management and planning are instrumental in resolving conflicts arising between societal needs for economic development on the one hand and for open green landscapes on the other hand. Allocating green corridors between fragmented core green areas may provide a partial solution to these conflicts. Decisions regarding green corridor development require the assessment of alternative allocations based on multiple criteria evaluations. Analytical Hierarchy Process provides a methodology for both a structured and consistent extraction of such evaluations and for the search for consensus among experts regarding weights assigned to the different criteria. Implementing this methodology using 15 Israeli experts-landscape architects, regional planners, and geographers-revealed inherent differences in expert opinions in this field beyond professional divisions. The use of Agglomerative Hierarchical Clustering allowed to identify clusters representing common decisions regarding criterion weights. Aggregating the evaluations of these clusters revealed an important dichotomy between a pragmatist approach that emphasizes the weight of statutory criteria and an ecological approach that emphasizes the role of the natural conditions in allocating green landscape corridors. PMID- 23674240 TI - Herders' perceptions of and responses to climate change in northern Pakistan. AB - Migratory pastoralism is an adaptation to a harsh and unstable environment, and pastoral herders have traditionally adapted to environmental and climatic change by building on their in-depth knowledge of this environment. In the Hindu Kush Himalayan region, and particularly in the arid and semiarid areas of northern Pakistan, pastoralism, the main livelihood, is vulnerable to climate change. Little detailed information is available about climate trends and impacts in remote mountain regions; herders' perceptions of climate change can provide the information needed by policy makers to address problems and make decisions on adaptive strategies in high pastoral areas. A survey was conducted in Gilgit Baltistan province of Pakistan to assess herders' perceptions of, and adaptation strategies to climate change. Herders' perceptions were gathered in individual interviews and focus group discussions. The herders perceived a change in climate over the past 10-15 years with longer and more intense droughts in summer, more frequent and heavier snowfall in winter, and prolonged summers and relatively shorter winters. These perceptions were validated by published scientific evidence. The herders considered that the change in climate had directly impacted pastures and then livestock by changing vegetation composition and reducing forage yield. They had adopted some adaptive strategies in response to the change such as altering the migration pattern and diversifying livelihoods. The findings show that the herder communities have practical lessons and indigenous knowledge related to rangeland management and adaptation to climate change that should be shared with the scientific community and integrated into development planning. PMID- 23674239 TI - Aldose reductase inhibitors of plant origin. AB - Diabetic complications are attributed to hyperglycaemic condition which is in turn associated with the polyol pathway and advanced glycation end products. Aldose reductase (AR) is the principal enzyme of polyol pathway which plays a vital role in the development of diabetic complications. AR inhibitory activity can be screened by both in vitro and in vivo methods. In vitro assays for AR enzyme are further classified on the basis of the source of enzyme such as rat lens, rat kidney, cataracted human eye lens, bovine eyes and human recombinant AR enzymes, whereas the in vivo model is based on the determination of lens galactitol levels. A number of synthetic AR inhibitors (ARIs) including tolrestat and sorbinil have been developed, but all of these suffer from drawbacks such as poor permeation and safety issues. Therefore, pharmaceutical companies and many researchers have been carrying out research to find new, potent and safe ARIs from natural sources. Thus, many naturally occurring compounds have been reported to have AR inhibitory activity. The present review attempts to highlight phytochemicals and plant extracts with potential AR inhibitory activity. It also summarizes the classes of compounds which have proven AR inhibitory activity. Phytochemicals such as quercetin, kaempferol and ellagic acid are found to be the most promising ARIs. The exhaustive literature presented in this article clearly indicates the role of plant extracts and phytochemicals as potential ARIs. PMID- 23674242 TI - Agency and the Annunciation. AB - Prior research has revealed that when healthy participants, who are not artists, are asked to draw a person who is performing an action, they are more likely to position the agent on the left and the person or object receiving this action, the patient, on the right. Thus, the goal of this study was to learn whether in works of art, such as those portraying the Annunciation of the angel Gabriel to the Blessed Virgin Mary, artists would be more likely to place the angel, who is the agent, on the left of Mary, who is the patient. We found that in our sample of 604 paintings of the Annunciation by different artists that the agent Gabriel is significantly more frequently portrayed to left of Mary. Whereas this result supports the left-agent, right-patient hypothesis, the reason for this spatial bias is not entirely known, but may be related to several factors such as the learned left to right direction of reading/writing in European languages, left versus right-sided emotional facial expressive asymmetries, a left-sided spatial attentional bias and a spatial motor-action preference of upper extremity for making abductive (left to right) movements when using the right upper extremity. Additionally, biblical explanations and theological principles may have influenced the organization of this scene. PMID- 23674243 TI - Participation in church or religious groups and its association with health: a national study of young Canadians. AB - The purpose of this study was to determine how participation of young Canadians in a church or religious group correlated with holistic health indicators. Health was viewed in terms of risk and protective behaviors, outward looking prosocial behaviors, and measures of internal feelings, with the composite picture of health connecting to the Hebrew concept of shalom. A separate analysis of sports involved children was used as a comparator. Children involved in religious groups reported lower participation in risk behaviors, higher prosocial behaviors, but poorer levels of the more holistic measures of health. Sports-connected youth reported more positive holistic measures of health and some increases in overt risk-taking. Our findings raise theological and practical issues regarding how the church understands itself and lives out its mission. They suggest an emphasis on teaching about behaviors and morality rather than an understanding of shalom that is grounded in the Incarnation and in the deeply integrative nature of the Christian life. PMID- 23674245 TI - Changing the shape of molecular ions: photoisomerization action spectroscopy in the gas phase. AB - A new approach for studying the photoisomerization of molecular ions in the gas phase is described. Packets of molecular ions are injected into a drift tube filled with helium buffer gas, where they are irradiated with tunable laser light. Photoisomerization changes the ions' cross section for collisions with helium atoms so that they arrive at the ion detector slightly earlier or later than the parent ions. By monitoring the photo-isomer peak as a function of laser wavelength one can record an action spectrum that is related to the ions' absorption spectrum modulated by the photoisomerization probability. The approach is demonstrated using the polymethine dye HITC (1,3,3,1',3',3' hexamethylindotricarbocyanine). The data show that both trans and cis forms of HITC(+) exist in the gas phase with trans->cis photoisomerization predominating over the 550-710 nm range and cis->trans photoisomerization occurring over the 735-770 nm range. The gas-phase photoisomerization action spectrum is comparable to the absorption spectra of trans HITC and cis HTIC in the condensed phase, but with the absorption peaks shifted to shorter wavelength. The gas-phase photoisomerization action spectrum of the (HITC)2(2+) dication dimer is also reported. (HITC)2(2+) cations photoisomerize over the 550-770 nm range to form more compact structures. PMID- 23674244 TI - History of religious delusions and psychosocial functioning among Mexican patients with paranoid schizophrenia. AB - The association between global functionality and religiosity among patients from developing and predominantly Catholic countries warrants attention. To compare religiosity and psychosocial functioning in Mexican schizophrenia patients with and without a history of religious delusions, seventy-four patients with paranoid schizophrenia were recruited. Patients with a history of religious delusions had more psychiatric hospitalizations and poorer psychosocial functioning compared with those without a history of religious delusions. No differences emerged between groups in the total scores of religiosity scales. A history of religious delusions rather than religiosity itself may have an influence on psychosocial functioning among Mexican patients with schizophrenia. PMID- 23674247 TI - Highlight: bacteria shed DNA as they adapt to hot temperatures. PMID- 23674249 TI - Oligocarbazole-based chromophores for efficient thin-film dye-sensitized solar cells. AB - Carb your enthusiasm: Carbazole-based sensitizers with high extinction coefficients are synthesized for application in dye-sensitized solar cells (DSCs). The dyes perform efficiently with both iodine and cobalt electrolytes, showing power conversion efficiencies of up to 5.8% on TiO2 films of 15 MUm thickness, and retaining 90% of their efficiency in devices with thinner films. PMID- 23674246 TI - The functional neuroanatomy of male psychosexual and physiosexual arousal: a quantitative meta-analysis. AB - Reproductive behavior is mandatory for conservation of species and mediated by a state of sexual arousal (SA), involving both complex mental processes and bodily reactions. An early neurobehavioral model of SA proposes cognitive, emotional, motivational, and autonomic components. In a comprehensive quantitative meta analysis on previous neuroimaging findings, we provide here evidence for distinct brain networks underlying psychosexual and physiosexual arousal. Psychosexual (i.e., mental sexual) arousal recruits brain areas crucial for cognitive evaluation, top-down modulation of attention and exteroceptive sensory processing, relevance detection and affective evaluation, as well as regions implicated in the representation of urges and in triggering autonomic processes. In contrast, physiosexual (i.e., physiological sexual) arousal is mediated by regions responsible for regulation and monitoring of initiated autonomic processes and emotions and for somatosensory processing. These circuits are interconnected by subcortical structures (putamen and claustrum) that provide exchange of sensorimotor information and crossmodal processing between and within the networks. Brain deactivations may imply attenuation of introspective processes and social cognition, but be necessary to release intrinsic inhibition of SA. PMID- 23674248 TI - Using phenotypic heterogeneity to increase the power of genome-wide association studies: application to age at onset of ischaemic stroke subphenotypes. AB - Genome-wide association studies (GWAS) have been successful in identifying common variants related to complex disorders. However, some disorders have proved resistant to this strategy with few associations confirmed, despite evidence from twin and family studies of a genetic component. Sophisticated strategies that account for phenotypic heterogeneity may be required to uncover these genetic contributions. Age at onset is an example of a potential source of this heterogeneity in ischaemic stroke. We explore the contribution of age at onset in the Wellcome Trust Case-Control Consortium 2 ischaemic stroke study. We first examine four established stroke loci in younger onset cases. We extend this to all single-nucleotide polymorphisms (SNPs) genome-wide, testing for stronger association signals in younger subsets of cases. Finally, we estimate the pseudoheritability accounted for by common SNPs present on genome-wide genotyping arrays for cases stratified by age at onset. We find evidence for stronger associations in younger onset cases for the four established stroke loci. Genome wide, in cardioembolic and small vessel stroke subphenotypes, a significant number of SNPs show stronger association P-values when the oldest cases are removed. Finally, we show that the pseudoheritability estimated by common SNPs in cardioembolic stroke increased from 16.5% for older onset cases to 28.5% for younger onset cases. Our results indicate that age at onset is a valuable measure for case ascertainment and in analysis of GWAS in ischaemic stroke: focussing on younger cases who may have a stronger genetic predisposition increases power to detect associations. PMID- 23674250 TI - Isolation of influenza A(H3N2)v virus from pigs and characterization of its biological properties in pigs and mice. AB - Recently, a novel reassortant virus, influenza A(H3N2)v [A(H3N2)v], was identified as the causative pathogen in 307 human cases of influenza in the United States. A(H3N2)v contains the matrix gene from the 2009 pandemic H1N1 (pH1N1) virus, while its other genes originate from H3N2 viruses with triple reassorted internal genes. In this study, we isolated three A(H3N2)v viruses from commercial pigs in Korea that showed similarities with published human A(H3N2)v viruses in eight segment sequence alignments. After genetic characterization, the pathogenicity of one of these viruses was assessed in pigs and mice. Infection of pigs with this novel virus resulted in mild interstitial pneumonia with marked oronasal shedding of viral RNA for about 14 days. In mice, the virus replicated efficiently in the lungs; viral RNA was detected up to 9 days post-inoculation. However, the virus did not cause severe disease or death in mice, despite the administration of a high infectious dose (10(5.2) TCID50). This study demonstrates that A(H3N2)v causes a high morbidity rate with low virulence; however, global monitoring of A(H3N2)v outbreaks in mammals will be needed to determine whether this novel subtype will shift to a highly pathogenic virus. PMID- 23674251 TI - Extended lymphadenectomy in patients with pancreatic cancer is debatable. AB - Lymph node staging is one of the most important factors in determining the prognosis after resection of pancreatic ductal adenocarcinoma. Despite ongoing efforts to further refine lymph node staging, the debate on the extent of lymphadenectomy during pancreaticoduodenectomy is still open. The purpose of this review was to summarize the evidence about performing standard lymphadenectomy during curative resection of pancreatic cancer. All four prospective randomized controlled trials published concluded that extended lymphadenectomy does not contribute to better oncologic outcome for patients with adenocarcinoma of the pancreatic head. Indeed, one major drawback of extended lymphadenectomy is the higher risk of persistent postoperative diarrhea. No prospective randomized studies could be found on the role of extended lymphadenectomy in patients with adenocarcinoma of the corpus and tail. Based on current evidence there is no indication that extended lymphadenectomy should be performed routinely during resection of pancreatic cancer. PMID- 23674252 TI - Prospective study examining clinical outcomes associated with a negative pressure wound therapy system and Barker's vacuum packing technique. AB - BACKGROUND: The open abdomen has become a common procedure in the management of complex abdominal problems and has improved patient survival. The method of temporary abdominal closure (TAC) may play a role in patient outcome. METHODS: A prospective, observational, open-label study was performed to evaluate two TAC techniques in surgical and trauma patients requiring open abdomen management: Barker's vacuum-packing technique (BVPT) and the ABThera(TM) open abdomen negative pressure therapy system (NPWT). Study endpoints were days to and rate of 30-day primary fascial closure (PFC) and 30-day all-cause mortality. RESULTS: Altogether, 280 patients were enrolled from 20 study sites. Among them, 168 patients underwent at least 48 hours of consistent TAC therapy (111 NPWT, 57 BVPT). The two study groups were well matched demographically. Median days to PFC were 9 days for NPWT versus 12 days for BVPT (p = 0.12). The 30-day PFC rate was 69 % for NPWT and 51 % for BVPT (p = 0.03). The 30-day all-cause mortality was 14 % for NPWT and 30 % for BVPT (p = 0.01). Multivariate logistic regression analysis identified that patients treated with NPWT were significantly more likely to survive than the BVPT patients [odds ratio 3.17 (95 % confidence interval 1.22-8.26); p = 0.02] after controlling for age, severity of illness, and cumulative fluid administration. CONCLUSIONS: Active NPWT is associated with significantly higher 30-day PFC rates and lower 30-day all-cause mortality among patients who require an open abdomen for at least 48 h during treatment for critical illness. PMID- 23674253 TI - Patients' preferences on information and involvement in decision making for gastrointestinal surgery. AB - BACKGROUND: The relationship between physicians and patients has undergone important changes, and the current emancipation of patients has led to a real partnership in medical decision making. The present study aimed to assess patients' preferences on different aspects of decision making during treatment and potential complications, as well as the amount and type of preoperative information wanted before visceral surgery. METHODS: This was a prospective non randomized study based on a questionnaire given to 253 consecutive patients scheduled for elective gastrointestinal surgery. RESULTS: In considering surgical complications or treatment in the intensive care unit, 64 % of patients wished to take an active role in any medical decisions. The respective figures for cardiac resuscitation and treatment limitations were 89 and 60 %. As for information, 73, 77, and 47 % of patients wish detailed information, information on a potential ICU hospitalization, and knowledge of cardiac resuscitation, respectively. Elderly and low-educated patients were significantly less interested in shared medical decision making (p = 0.003 and 0.015), and in receiving information (p = 0.03 and 0.05). Similarly, involvement of the family in decision making was significantly less important to elderly and male patients (p = 0.05 and 0.03, respectively). Neither the type of operation (minor or major) nor the severity of disease (malignancies versus non-malignancies) was a significant factor for shared decision making, information, or family involvement. CONCLUSIONS: The vast majority of surgical patients clearly want to get adequate preoperative information about their disease and the planned treatment. They also consider it crucial to be involved in any kind of decision making for treatment and complications. For most patients, the family role is limited to supporting the treating physicians if the patient is unable to participate in decision making. PMID- 23674254 TI - Early enteral nutrition prevents intra-abdominal hypertension and reduces the severity of severe acute pancreatitis compared with delayed enteral nutrition: a prospective pilot study. AB - BACKGROUND: To investigate the effects of early enteral nutrition (EEN) on intra abdominal pressure (IAP) and disease severity in patients with severe acute pancreatitis (SAP). METHODS: Enteral nutrition (EN) was started within 48 h after admission in the EEN group and from the 8th day in the delayed enteral nutrition (DEN) group. The IAP and intra-abdominal hypertension (IAH) incidence were recorded for 2 weeks. The caloric intake and feeding intolerance (FI) incidence were recorded daily after EN was started. The severity markers and clinical outcome variables were also recorded. RESULTS: Sixty patients were enrolled to this study. No difference about IAP was found. The IAH incidence of the EEN group was significantly lower than that of the DEN group from the 9th day (8/30 versus 18/30; P = 0.009) after admission. The FI incidence of the EEN group was higher than that of the DEN group during the initial 3 days of feeding (25/30 versus 12/30; P = 0.001; 22/30 versus 9/30; P = 0.001; 15/30 versus 4/30; P = 0.002). Patients with an IAP <15 mmHg had lower FI incidence than those with an IAP >=15 mmHg on the 1st day (20/22 versus 17/38; P < 0.001), the 3rd day (11/13 versus 8/47; P < 0.001), and the 7th day (3/5 versus 3/55; P = 0.005) of feeding. The severity markers and clinical outcome variables of the EEN group were significantly improved. CONCLUSIONS: Early enteral nutrition did not increase IAP. In contrast, it might prevent the development of IAH. In addition, EEN might be not appropriate during the initial 3-4 days of SAP onset. Moreover, EN might be of benefit to patients with an IAP <15 mmHg. Early enteral nutrition could improve disease severity and clinical outcome, but did not decrease mortality of SAP. PMID- 23674255 TI - Cancer or no cancer: the influence of trait anxiety and diagnosis on quality of life with breast cancer and benign disease: a prospective, longitudinal study. AB - BACKGROUND: High trait anxiety (HTA) causes an impaired quality of life (QOL) and fatigue in women with breast cancer (BC) and benign breast disease (BBD). We examined whether the lowered QOL was determined solely by the personality characteristic HTA or by the combination of personality and diagnosis. METHODS: In a prospective longitudinal study, women with BC (n = 152), BBD (n = 205), or gallstone disease (GD) before laparoscopic cholecystectomy (n = 128) were included. Questionnaires concerning trait anxiety (baseline), fatigue, and QOL were completed at baseline and at 6 months. Multivariate linear regression analysis was performed to analyze the predictors for QOL at 6 months. RESULTS: At 6 months QOL scores were increased in the GD group, especially in women without HTA. For women without HTA, in the BBD group the scores for fatigue and physical QOL had improved at 6 months, whereas in the BC group physical QOL and fatigue was impaired. Women with HTA scored unfavorably on fatigue and QOL. HTA was the most important factor influencing QOL. CONCLUSIONS: The course of QOL and fatigue during follow-up were significantly different for each diagnosis. Particularly HTA had a negative impact on QOL and fatigue. Especially the combination HTA and BC caused impaired QOL and fatigue. We recommend identifying women with BC and HTA and offer them a tailor-made follow-up protocol. PMID- 23674256 TI - Relevance of bilateral cervical thymectomy in patients with renal hyperparathyroidism: analysis of 161 patients undergoing reoperative parathyroidectomy. AB - BACKGROUND: The most frequent location of ectopic or supernumerary inferior parathyroid is the thymus. Bilateral cervical thymectomy has therefore been recommended as an essential part of the initial surgery for renal hyperparathyroidism (rHPT) to avoid persistent or recurrent cervical disease. The aim of this study was to evaluate how often reoperation might have been avoidable if an appropriate cervical thymectomy had been performed during initial surgery. METHODS: A prospective database of patients with rHPT was screened for patients on permanent dialysis who underwent reoperative parathyroidectomy (PTX) between 1976 and 2010. Data were retrospectively analyzed for the performance of bilateral cervical thymectomy during previous surgeries and the presence of ectopic and/or supernumerary intrathymic parathyroid glands during reoperative PTX. RESULTS: Of 161 patients who underwent reoperative PTX, 95 had neck reexploration. Among them were 29 patients with total PTX and autotransplantation, seven with subtotal PTX (3.5 glands resected), and 59 with incomplete PTX during the initial surgery. Bilateral cervical thymectomy during the initial PTX was performed in only 12 of 95 patients (12.6 %). It was revealed to be incomplete in six of them, inheriting an intrathymic parathyroid gland during reoperative interventions. Reoperative PTX revealed intrathymic parathyroid glands in 27 of 95 patients (28.4 %). The intrathymic parathyroid glands were ectopic in 17 (63.0 %) patients and supernumerary in 8 (29.6 %). Both ectopic and supernumerary intrathymic parathyroid glands were found in two patients (7.4 %). CONCLUSIONS: The risk for persistent and recurrent disease based on intrathymic parathyroid glands is a relevant problem during initial surgery for rHPT. Thus, routine bilateral cervical thymectomy that is as complete as possible is essential during the initial PTX for rHPT. PMID- 23674258 TI - Confronting the global burden of surgical disease. PMID- 23674257 TI - Robot-assisted gastrectomy for gastric cancer: current status and technical considerations. AB - BACKGROUND: Robot-assisted gastrectomy has been reported as a safe alternative to the conventional laparoscopy or open approach for treating early gastric carcinoma. To date, however, there are a limited number of published reports available in the literature. METHODS: We assess the current status of robotic surgery in the treatment of gastric cancer, focusing on the technical details and oncological considerations. RESULTS: In gastric surgery, the biggest advantage of robotic surgery is the ease and reproducibility of D2-lymphadenectomy. Reports show that even the intracorporeal digestive restoration is facilitated by use of the robotic approach, particularly following total gastrectomy. Additionally, the accuracy of robotic dissection is confirmed by decreased blood loss, as reported in series comparing robot-assisted with laparoscopic gastrectomy. The learning curve and technical reproducibility also appear to be shorter with robotic surgery and, consequently, robotics can help to standardize and diffuse minimally invasive surgery in the treatment of gastric cancer, even in the later stages. This is important because the application of minimally invasive surgery is limited by the complexity of performing a D2-lymphadenectomy. The potential to reproduce D2-lymphadenectomy, enlarged resections, and complex reconstructions provides robotic surgery with an important role in the therapeutic strategy of advanced gastric cancer. CONCLUSIONS: While published reports have shown no significant differences in surgical morbidity, mortality, or oncological adequacy between robot-assisted and conventional laparoscopic gastrectomy, more studies are needed to assess the indications and oncological effectiveness of robotic use in the treatment of gastric carcinoma. Herein, the authors assess the current status of robotic surgery in the treatment of gastric cancer, focusing on the technical details and oncological considerations. PMID- 23674260 TI - Hesperidin prevents androgen deficiency-induced bone loss in male mice. AB - The purpose of this study was to examine whether hesperidin inhibits bone loss in androgen-deficient male mice. Male ddY mice aged 7 weeks underwent either a sham operation or orchidectomy (ORX) and were divided into five groups: a sham operated group fed a control diet (Sham) based on AIN-93G formulation with corn oil instead of soy bean oil, an ORX group fed the control diet (ORX), a group fed the control diet containing 0.5% hesperidin (ORX + H), a group fed the control diet containing 0.7% alpha-glucosylhesperidin (ORX + alphaG), and a group fed the control diet containing 0.013% simvastatin (ORX + St). Four weeks after intervention, ORX mice showed a striking decrease in seminal vesicle weight, which was not affected by the administration of hesperidin, alpha glucosylhesperidin, or simvastatin. Femoral BMD was significantly reduced by ORX, and bone loss was inhibited by the administration of hesperidin, alpha glucosylhesperidin or simvastatin. Histomorphometric analysis showed that the bone volume and trabecular thickness were significantly lower, and the osteoclast number was higher in the distal femoral cancellous bone in the ORX group than in the Sham group, and these were normalized in the ORX + H, ORX + alphaG and ORX + St groups. These results indicate that hesperidin inhibited bone resorption and hyperlipidemia, in ORX mice, and the preventive effect was stronger than that observed in ovariectomized mice in our previous study. PMID- 23674261 TI - Oxidation of PtNi nanoparticles studied by a scanning X-ray fluorescence microscope with multi-layer Laue lenses. AB - We report a study of the oxidation process of individual PtNi nanoparticles (NPs) conducted with a novel scanning multi-layer Laue lens X-ray microscope. The elemental maps reveal that alloyed PtNi NPs were transformed into Pt/NiO core shell NPs by thermal oxidation. The observations furthermore indicate that a coalescence of Pt/NiO core-shell NPs occurred during oxidation. PMID- 23674259 TI - Characterization of the inhibitor of kappaB kinase (IKK) complex in granulosa cell tumors of the ovary and granulosa cell tumor-derived cell lines. AB - Granulosa cell tumors of the ovary (GCT) are a distinct, hormonally active subset of ovarian cancers. Although it has recently been shown that ~97 % of all adult GCT harbor a novel somatic missense mutation in the FOXL2 gene, given its almost universal presence, it does not explain differences in tumor stage and/or recurrence. The nuclear factor kappaB (NFkappaB) transcription factor is constitutively active in two human GCT-derived cell lines, COV434 and KGN, which are useful in vitro models to investigate juvenile and adult GCT, respectively. This study aimed to determine the molecular basis and pathogenetic significance of this aberrant NFkappaB activity. Selective chemical inhibitors were used to target candidate components of the pathway. The constitutive activity was blocked by two independent inhibitors of IkappaBalpha phosphorylation, suggesting that aberrant activation occurs upstream of this point. NFkappaB inhibition resulted in a dose-dependent decrease in cell proliferation and viability and a dose dependent increase in apoptosis. Inhibitors of earlier components of the pathway were without effect. Two independent inhibitors of inhibitor of kappaB kinase (IKK)beta, a catalytic subunit of the NFkappaB activation complex, were unable to inhibit the constitutive activity, but surprisingly also ligand-induced activity. These findings suggest a central role for IKKbeta; however, no mutations or altered expression of the IKKbeta, IKKalpha, or IKKgamma genes was observed in the cell lines or in a panel of human GCT samples. This study highlights unresolved issues in understanding the pathogenesis of GCT and in the use of the COV434 and KGN cells lines as model systems. PMID- 23674262 TI - Paranasal sinus squamous cell carcinoma incidence and survival based on Surveillance, Epidemiology, and End Results data, 1973 to 2009. AB - BACKGROUND: Paranasal sinus squamous cell carcinomas (PNSSCC) account for 3% of all head and neck malignancies. There has been little information on the trends in incidence and survival, and no randomized trials have been conducted to guide therapy. METHODS: Patients with PNSSCC reported to the Surveillance, Epidemiology, and End Results (SEER) Program from 1973 through 2009 were categorized by sex, age, year of diagnosis, primary site, stage, and treatment. The incidence and survival were then compared across different demographic and disease-related categories by calculating rate ratios (RRs) and mortality hazard ratios along with the corresponding 95% confidence intervals (CIs). RESULTS: In total, 2553 patients with PNSSCC were identified. While incidence of PNSSCC showed a gradual decline, survival remained largely unchanged. The proportion of patients with advanced disease decreased from 14.7% during the period from 1983 to 1992 to 12.4% during 1993-2002 and to 9.5% during 2003-2009. Compared with whites, incidence was higher among African Americans (RR 1.63; 95% CI, 1.39, 1.90) and among all other racial groups (RR, 1.78; 95% CI: 1.53-2.07). After adjusting for age, sex, disease stage, tumor site, and treatment, mortality among African American patients also was increased (hazard ratio, 1.22; 95% CI, 1.04 1.43). Among patients with localized disease, the relation between race and mortality was no longer evident once the results were controlled for tumor classification. CONCLUSIONS: The current findings point to racial disparities in the incidence of PNSSCC and, to a lesser extent, in the outcome of patients with PNSSCC. Although there has been a decline in the proportion of patients presenting with advanced PNSSCC, the overall survival remained stable over time. PMID- 23674263 TI - Microbial geography of the oral cavity. AB - We aimed to determine the bacterial diversity of different oral micro-niches and to assess whether saliva and plaque samples are representative of oral microbial composition. We took minute samples from each surface of the individual teeth and gingival crevices of two healthy volunteers (112 samples per donor), as well as samples from the tongue dorsum and non-stimulated and stimulated saliva. DNA was extracted from 67 selected samples of each donor, and the 16S rRNA gene was amplified by PCR and pyrosequenced to obtain, on average, over 2,700 reads per sample, which were taxonomically assigned to obtain a geographic map of bacterial diversity at each tooth and sulcus location. Analysis of the data shows considerable differences in bacterial composition between teeth at different intra-oral locations and between surfaces of the same tooth. The most pronounced differences were observed in incisors and canines, where genera like Streptococcus were found at 40% to 70% on the vestibular surfaces but were almost absent on the lingual sides. Saliva samples, especially non-stimulated saliva, were not representative of supra-and subgingival plaque in the two individuals tested. We suggest that more precise sampling is required for the proper determination of oral microbial composition and to relate that diversity to epidemiological, clinical, and etiological parameters. PMID- 23674264 TI - Overall survival advantage with partial nephrectomy: a bias of observational data? AB - BACKGROUND: Partial nephrectomy (PN) and radical nephrectomy (RN) are standard treatments for a small renal mass. Retrospective studies suggest an overall survival (OS) advantage, however a randomized phase 3 trial suggests otherwise. The effects of both surgical modalities on OS were evaluated compared with controls. METHODS: A matched cohort study was performed using the Surveillance, Epidemiology, and End Results (SEER)-Medicare dataset. Individuals treated with PN or RN for localized renal cell carcinoma (RCC) measuring <=4 cm were compared with 2 control groups (non-muscle-invasive bladder cancer (BCC) and noncancer controls (NCC). Using a greedy algorithm, RCC groups were matched with controls by demographics and comorbidities. OS for surgical groups and controls were compared. The cause of death was evaluated for cancer groups when differences in OS were noted. RESULTS: Patients undergoing PN and RN were matched with controls. All cancer groups had >95% 10-year cancer-specific survival (CSS). Median OS was similar between RN (9.05 years) and BCC (8.67 years; P = .067) and NCC (8.77 years; P = .49). Median OS was improved for PN (10.45 years) compared with BCC (8.75 years; P<.001) and NCC controls (8.76 years; P<.001). A multivariate Cox hazards model demonstrated that PN improved OS compared with NCC (hazard ratio, 1.257; P<.001) and BCC (hazard ratio, 1.364; P<.001). CONCLUSIONS: RN patients had similar OS compared with controls, suggesting that this treatment modality does not compromise survival. Patients undergoing PN had improved OS compared with controls, suggesting possible selection bias. The apparent survival advantage conferred by PN in SEER-Medicare case series is likely the result of selection bias involving unmeasured confounders. PMID- 23674265 TI - Dehydrogenation of dodecahydro-N-ethylcarbazole on Pt(111). AB - Sloshing hydrogen: Liquid organic hydrogen carriers are high-boiling organic molecules, which can be reversibly hydrogenated and dehydrogenated in catalytic processes and are, therefore, a promising chemical hydrogen storage material. One of the promising candidates is the pair N-ethylcarbazole/perhydro-N ethylcarbazole (NEC/H12-NEC). The dehydrogenation and possible side reactions on a Pt(111) surface are evaluated in unprecedented detail. PMID- 23674266 TI - Muscle weakness, fatigue, and torque variability: effects of age and mobility status. AB - INTRODUCTION: Whereas deficits in muscle function, particularly power production, develop in old age and are risk factors for mobility impairment, a complete understanding of muscle fatigue during dynamic contractions is lacking. We tested hypotheses related to torque-producing capacity, fatigue resistance, and variability of torque production during repeated maximal contractions in healthy older, mobility-impaired older, and young women. METHODS: Knee extensor fatigue (decline in torque) was measured during 4 min of dynamic contractions. Torque variability was characterized using a novel 4-component logistic regression model. RESULTS: Young women produced more torque at baseline and during the protocol than older women (P < 0.001). Although fatigue did not differ between groups (P = 0.53), torque variability differed by group (P = 0.022) and was greater in older impaired compared with young women (P = 0.010). CONCLUSIONS: These results suggest that increased torque variability may combine with baseline muscle weakness to limit function, particularly in older adults with mobility impairments. PMID- 23674267 TI - The rhizobacterium Arthrobacter agilis produces dimethylhexadecylamine, a compound that inhibits growth of phytopathogenic fungi in vitro. AB - Plant diseases caused by fungal pathogens such as Botrytis cinerea and the oomycete Phytophthora cinnamomi affect agricultural production worldwide. Control of these pests can be done by the use of fungicides such as captan, which may have deleterious effects on human health. This study demonstrates that the rhizobacterium Arthrobacter agilis UMCV2 produces volatile organic compounds that inhibit the growth of B. cinerea in vitro. A single compound from the volatile blends, namely dimethylhexadecylamine (DMHDA), could inhibit the growth of both B. cinerea and P. cinnamomi when supplied to the growth medium in low concentrations. DMHDA also inhibited the growth of beneficial fungi Trichoderma virens and Trichoderma atroviride but at much higher concentrations. DMHDA related aminolipids containing 4, 8, 10, 12, and 14 carbons in the alkyl chain were tested for their inhibitory effect on the growth of the pathogens. The results show that the most active compound from those tested was dimethyldodecylamine. This effect correlates with a decrease in the number of membrane lipids present in the mycelium of the pathogen including eicosanoic acid, (Z)-9-hexadecenoic acid, methyl ester, and (Z)-9-octadecenoic acid, methyl ester. Strawberry leaflets treated with DMHDA were not injured by the compound. These data indicate that DMHDA and related compounds, which can be produced by microorganisms may effectively inhibit the proliferation of certain plant pathogens. PMID- 23674268 TI - Do restrictive and bingeing/purging subtypes of anorexia nervosa differ on central coherence and set shifting? AB - OBJECTIVE: Anorexia nervosa (AN) has been associated with weak central coherence (CC) and weak set shifting (SS). The main aim of this study was to examine possible differences between restrictive AN (AN-R) and bingeing/purging AN (AN BP) on these features. METHODS: A total of 31 patients with AN-R, 20 patients with AN-BP and 26 healthy controls (HC) completed five neuropsychological tests (Block Design, Object Assembly, an adapted task-switching paradigm, Wisconsin Card Sorting Test and Trail Making Test). RESULTS: Using Block Design and Object Assembly, indicative for CC, AN-R patients performed significantly worse than AN BP patients and HC, without any difference between AN-BP and HC. On SS measures, no group differences were observed. DISCUSSION: The results suggest that cognitive profiles of AN-R and AN-BP patients differ significantly on CC and not on SS. Our current findings support the idea that the two subtypes of AN have a distinctive underlying nature and might need a different approach in cognitive remediation. PMID- 23674269 TI - The study of the effects of cooling conditions on high quality graphene growth by the APCVD method. AB - The effects of cooling conditions on graphene growth by the atmospheric pressure chemical vapor deposition (APCVD) method on platinum are investigated. It is found that the cooling conditions are the key to better control of the coverage, thickness and uniformity of the graphene films. A series of experiments were carried out with different cooling rates and gas atmospheres. Various characterization techniques (SEM, Raman, AFM and TEM) were applied to examine the graphene morphology and quality. A "three competitive reactions" mechanism is proposed to explain the cooling condition effects. Based on optimized growth conditions, a high-coverage, single-layer graphene film could be grown on Pt using the APCVD method. Back-gated field effect transistors were fabricated and the measured carrier mobility is about 1600 cm(2) V(-1) s(-1). PMID- 23674271 TI - Evaluation of the effect of blackcurrant products on gut microbiota and on markers of risk for colon cancer in humans. AB - The purpose of this study was to determine in healthy humans whether First Leaf (FL; composed of blackcurrant extract powder, lactoferrin and lutein) and Cassis Anthomix 30 (CAM30; blackcurrant extract powder) can positively modify the colonic microbiota by enhancing the growth of the beneficial bacteria and inactivating the toxic bacterial enzymes which are known to be involved in colonic carcinogenesis. Thirty healthy adult male and female volunteers were recruited for this study. Fluorescent in situ hybridization was carried out to analyse the populations of fecal microbiota. Consumption of FL and CAM30 led to significant increases (P < 0.0001) in the population sizes of lactobacilli and bifidobacteria whereas the population sizes of Clostridium spp. and Bacteroides spp were decreased significantly (P < 0.0001). In addition, feeding of FL and CAM30 decreases the activity of beta-glucuronidase (bacterial enzyme which is considered to be one of the enzymes that increases risk for colorectal cancer) and significantly decreased (P < 0.05) the fecal pH. In conclusion, the results of this study open up the possibility that consumption of FL and CAM30 can offer various benefits to human health through acting as novel prebiotic agents via increasing the numbers of beneficial bacteria (lactobacilli and bifidobacteria) in the gut. PMID- 23674272 TI - Nontarget embolisation or local effect of infarction? PMID- 23674270 TI - BRCA1 polymorphisms and breast cancer epidemiology in the Western New York exposures and breast cancer (WEB) study. AB - Results of studies for the association of BRCA1 genotypes and haplotypes with sporadic breast cancer have been inconsistent. Therefore, a candidate single nucleotide polymorphism (SNP) approach was used in a breast cancer case-control study to explore genotypes and haplotypes that have the potential to affect protein functions or levels. In a breast cancer case-control study, genotyping of BRCA1 polymorphisms Q356R, D693N, and E1038G was performed on 1,005 cases and 1,765 controls. Unconditional, polytomous logistic regression and chi(2) -tests were used to examine the associations of breast cancer with genotypes and haplotypes. In addition, interactions between genotype and smoking, benign breast disease, family history of breast cancer, body mass index (BMI), alcohol consumption, and hormonal risk factors, hormone receptor status, and breast cancer pathology were calculated also using logistic regression and chi(2) . Although sporadic breast cancer was not associated with BRCA1 genotypes or haplotypes overall or by menopausal status, there was evidence of an interaction between the E1038G BRCA1 genotype, smoking, and BMI among premenopausal women (P for interaction = 0.01 and 0.045, respectively) and between E1038G and D693N BRCA1 genotypes and hormone therapy use among postmenopausal women (P for interaction = 0.01 and 0.02, respectively). There were no other associations found between BRCA1 genotypes and stage, histological grade, or nuclear grade. However, the D693N SNP was associated with the risk of triple negative breast cancer (odds ratio = 2.31 95% confidence interval 1.08-4.93). The BRCA1 variants studied may play a role in the etiology of triple negative breast cancer and may interact with environmental factors such as hormone therapy or smoking and increase sporadic breast cancer risk. PMID- 23674273 TI - Endovascular embolization of bronchial artery originating from the upper portion of aortic arch in patients with massive hemoptysis. AB - PURPOSE: Our experience with endovascular embolization (EVE) of the bronchial artery (BA) originating from the upper portion of the aortic arch (AA) in six patients is described. METHODS: Altogether, 818 patients with hemoptysis underwent multidetector row computed tomography angiography (MDCTA) before EVE or AA angiography during EVE. Aberrant BAs originating from the upper portion of the AA were the source of massive hemoptysis in six patients (0.73 %). MDCT angiograms and/or Digital subtraction angiograms were retrospectively reviewed. Selective catheterization and embolization were performed. RESULTS: The ostia of the BAs were located on the superior surface of the AA between the brachiocephalic trunk and left common carotid artery in three patients, the junction of the aorta and medial surface of the left subclavian artery in two, and the posterior wall of the upper portion of the AA in one. The six BAs comprised two common trunks, three single right sides, and one single left side. The targeted vessels were successfully catheterized and embolized by a coaxial microcatheter system using polyvinyl alcohol particles. Other pathologic BAs and nonbronchial systemic arteries also were embolized. Bleeding was immediately controlled in all patients with no recurrence of hemoptysis. No procedure-related complications occurred. CONCLUSIONS: Application of EVE of anomalous origin of BAs in patients with hemoptysis is important, as demonstrated in the six reported patients. MDCTA before EVE or AA angiography during EVE is critical to avoid missing a rare aberrant BA originating from the upper portion of the AA. PMID- 23674275 TI - Reply to letter re: Non-target embolization or local effect of infarction? PMID- 23674274 TI - Endovascular aortic aneurysm repair with chimney and snorkel grafts: indications, techniques and results. AB - The chimney technique in endovascular aortic aneurysm repair (Ch-EVAR) involves placement of a stent or stent-graft parallel to the main aortic stent-graft to extend the proximal or distal sealing zone while maintaining side branch patency. Ch-EVAR can facilitate endovascular repair of juxtarenal and aortic arch pathology using available standard aortic stent-grafts, therefore, eliminating the manufacturing delays required for customised fenestrated and branched stent grafts. Several case series have demonstrated the feasibility of Ch-EVAR both in acute and elective cases with good early results. This review discusses indications, technique, and the current available clinical data on Ch-EVAR. PMID- 23674276 TI - Doped semiconductor nanocrystal based fluorescent cellular imaging probes. AB - Doped semiconductor nanocrystals such as Mn doped ZnS, Mn doped ZnSe and Cu doped InZnS, are considered as new classes of fluorescent biological probes with low toxicity. Although the synthesis in high quality of such nanomaterials is now well established, transforming them into functional fluorescent probes remains a challenge. Here we report a fluorescent cellular imaging probe made of high quality doped semiconductor nanocrystals. We have identified two different coating approaches suitable for transforming the as synthesized hydrophobic doped semiconductor nanocrystals into water-soluble functional nanoparticles. Following these approaches we have synthesized TAT-peptide- and folate-functionalized nanoparticles of 10-80 nm hydrodynamic diameter and used them as a fluorescent cell label. The results shows that doped semiconductor nanocrystals can be an attractive alternative for conventional cadmium based quantum dots with low toxicity. PMID- 23674277 TI - Identification of reducing and nonreducing neutral carbohydrates by laser enhanced in-source decay (LEISD) MALDI MS. AB - In this work, laser-enhanced in-source decay (LEISD) technique of matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance mass spectrometry (MALDI-FT-ICR-MS) was used to distinguish reducing and nonreducing carbohydrates. Interestingly, easier cleavage of (1 -> 2)-linked glycosidic bonds for nonreducing carbohydrates containing D-fructofuranosyl units was observed in MALDI-FT-ICR-MS, which was in agreement with the result of theoretical calculation by the software package Gaussian 09. Importantly, no cross-ring cleavage of fructofuranosyl residues was detected in the LEISD spectra of nonreducing carbohydrates. LEISD method therefore offers an attractive alternative for fast and efficient differentiation of reducing and nonreducing carbohydrates, and the positions of nonreducing monosaccharide residues in a carbohydrate chain could be easily speculated. PMID- 23674278 TI - High-throughput determination of Sudan Azo-dyes within powdered chili pepper by paper spray mass spectrometry. AB - A high-throughput mass spectrometric method is presented for the simultaneous detection of Sudan I, II, III, IV and Para-Red azo-dyes in foodstuff. The method is based on the use of paper spray mass spectrometry (MS) and deuterium-labeled internal standards on a triple-quadrupole instrument. A detailed assay of each azo-dye was performed by the isotope dilution method, through the precursor ion scan approach, using deuterium-labeled internal standards. The gas-phase breakdown pattern of each labeled and unlabeled analogue displays the naphthoic moiety as a common fragment. Sudan dyes can be determined above the threshold of 1 ppm. Paper spray allows for a wide range of analytes and samples to be investigated by MS in the open air and without sample preparation and bypassing chromatography. PMID- 23674279 TI - Differentiation of isomeric beta-(1-4) hexose disaccharides by positive electrospray tandem mass spectrometry. PMID- 23674280 TI - Protein analysis by desorption electrospray ionization mass spectrometry and related methods. AB - Desorption electrospray ionization mass spectrometry (DESI-MS) requires little to no sample preparation and has been successfully applied to the study of biologically significant macromolecules such as proteins. However, DESI-MS and other ambient methods that use spray desorption to process samples during ionization appear limited to smaller proteins with molecular masses of 25 kDa or less, and a decreasing instrumental response with increasing protein size has often been reported. It has been proposed that this limit results from the inability of some proteins to easily desorb from the surface during DESI sampling. The present study investigates the apparent mass dependence of the instrumental response observed during the DESI-MS analysis of proteins using spray desorption collection and reflective electrospray ionization. Proteins, as large as 66 kDa, are shown to be quantitatively removed from surfaces by using spray desorption collection. However, incomplete dissolution and the formation of protein-protein and protein-contaminant clusters appear to be responsible for the mass-dependent loss in sensitivity for protein analysis. Alternative ambient mass spectrometry approaches that address some of the problems encountered by spray desorption techniques for protein analysis are also discussed. PMID- 23674282 TI - Identification tree based on fragmentation rules for structure elucidation of organophosphorus esters by electrospray mass spectrometry. AB - Organophosphorus compounds have played important roles as pesticides, chemical warfare agents and extractors of radioactive material. Structural elucidation of phosphonates poses a particular challenge because their initial forms can be hydrolyzed, thus, degradation products may predominate in samples acquired in the field. The analysis of non-volatile organophosphorus compounds and their degradation products is possible using electrospray tandem mass spectrometry ESI MS/MS. Here, we present a generic strategy that allows the unambiguous identification of substituents for two families of organophosphorus compounds: the phosphonates and phosphates. General fragmentation rules were deduced based on the study of decomposition pathways of 55 organophosphorus esters, including examples found in the literature. Multistage MS (MS(n)) experiments at high resolution in a hybrid mass spectrometer provide accurate mass measurements, whereas collision-induced dissociation experiments in a triple quadrupole give access to small fragment ions. The creation of a specific nomenclature for each possible structure of organophosphorus compound, depending on the alkyl side chain linked to the oxygen, was achieved by applying these fragmentation rules. This led to the creation of an 'identification tree' based upon the unique consecutive decomposition pathways uncovered for each individual compound. Hence, seven structural motifs were created that orient an unequivocal identification using the 'identification tree'. Despite the similar structures of the ensemble of phosphate and phosphonate esters, distinct identifications based upon characteristic neutral losses and diagnostic fragment ions were possible in all cases. PMID- 23674281 TI - Structure-oriented UHPLC-LTQ Orbitrap-based approach as a dereplication strategy for the identification of isoflavonoids from Amphimas pterocarpoides crude extract. AB - Hyphenated techniques and especially ultra-high performance liquid chromatography mass spectrometry (UHPLC-MS) are nowadays widely employed in natural products research. However, the complex nature of plant extracts complicates considerably the analysis and the identification of their constituents. Nevertheless, new MS analyzers with increased resolving power and accuracy such as the orbital trap (Orbitrap) could facilitate drastically this process. The objective of this study is the development of a new structure-oriented approach based on fast UHPLC-high resolution (HR)MS and HRMS/MS methodologies for the identification of isoflavonoids in crude extracts. In addition, aims to assist dereplication procedures, to decrease the laborious isolation steps and orient the focused isolation of compounds of interest. As a proof of concept, the methanol extract of the stem bark of Amphimas pterocarpoides (Leguminosae) was selected. Based on chromatographic (retention time, polarity) and spectrometric features (ultraviolet spectra, accurate m/z, proposed elemental composition, ring double bond equivalent, and relative isotopic abundance) as well as HRMS/MS spectra, several isoflavonoids were identified. In order to verify the proposed structures, 11 isoflavonoids were selectively isolated and unambiguously identified using 1&2D nuclear magnetic resonance techniques. Moreover, the isolated isoflavonoids were studied in HRMS/MS level, employing electrospray ionization and atmospheric pressure chemical ionization sources, in both modes. Useful information regarding their fragmentation patterns was obtained, and characteristic diagnostic ions were defined for the identification of methoxylated isoflavones, dihydroisoflavones and 5-hydroxylated isoflavonoids. Based on the current results, the proposed dereplication strategy was verified and could comprise a novel approach for the analysis of crude extracts in the future not only for isoflavonoids but also for other chemical classes of natural products. PMID- 23674283 TI - Direct detection of chlorpropham on potato skin using desorption electrospray ionization. AB - Most pesticides, herbicides and other plant treatment agents are applied to the crop surface. Direct mass spectrometric methods, such as desorption electrospray ionization (DESI), offer new ways to analyze plant samples directly and rapidly. A strategy for the development and optimization of a DESI method for the direct determination of chemicals on complex surfaces is described. Chlorpropham (CP) was applied to potato surfaces as an example for a crop protection agent and analyzed using a self-made DESI source. Aspects such as instrument selectivity, sensitivity and reproducibility were investigated. The MS(4) fragmentation pattern of CP was analyzed to achieve the necessary detection selectivity, and is discussed in detail. Similar fragmentation was found in the ESI and DESI mass spectra, indicating that the mechanisms of ESI and DESI are closely related. A DESI method for semi-quantification of CP on potatoes was developed. Detection limits of 6.5 ug/kg were found using MS/MS. The reproducibility, in the range of 12% (signal variation), appears to be sufficient for semi-quantitative measurements. PMID- 23674284 TI - Comparison of direct mass spectrometry methods for the on-line analysis of volatile compounds in foods. AB - For the on-line monitoring of flavour compound release, atmospheric pressure chemical ionization (APCI) and proton transfer reaction (PTR) combined to mass spectrometry (MS) are the most often used ionization technologies. APCI-MS was questioned for the quantification of volatiles in complex mixtures, but direct comparisons of APCI and PTR techniques applied on the same samples remain scarce. The aim of this work was to compare the potentialities of both techniques for the study of in vitro and in vivo flavour release. Aroma release from flavoured aqueous solutions (in vitro measurements in Teflon bags and glass vials) or flavoured candies (in vivo measurements on six panellists) was studied using APCI and PTR-MS. Very similar results were obtained with both techniques. Their sensitivities, expressed as limit of detection of 2,5-dimethylpyrazine, were found equivalent at 12 ng/l air. Analyses of Teflon bag headspace revealed a poor repeatability and important ionization competitions with both APCI- and PTR-MS, particularly between an ester and a secondary alcohol. These phenomena were attributed to dependency on moisture content, gas/liquid volume ratio, proton affinities and product ion distribution, together with inherent drawbacks of Teflon bags (adsorption, condensation of water and polar molecules). Concerning the analyses of vial headspace and in vivo analyses, similar results were obtained with both techniques, revealing no competition phenomena. This study highlighted the equivalent performances of APCI-MS and PTR-MS for in vitro and in vivo flavour release investigations and provided useful data on the problematic use of sample bags for headspace analyses. PMID- 23674285 TI - A quantitative analysis of histone methylation and acetylation isoforms from their deuteroacetylated derivatives: application to a series of knockout mutants. AB - The core histones, H2A, H2B, H3 and H4, undergo post-translational modifications (PTMs) including lysine acetylation, methylation and ubiquitylation, arginine methylation and serine phosphorylation. Lysine residues may be mono-, di- and trimethylated, the latter resulting in an addition of mass to the protein that differs from acetylation by only 0.03639 Da, but that can be distinguished either on high-performance mass spectrometers with sufficient mass accuracy and mass resolution or via retention times. Here we describe the use of chemical derivatization to quantify methylated and acetylated histone isoforms by forming deuteroacetylated histone derivatives prior to tryptic digestion and bottom-up liquid chromatography-mass spectrometric analysis. The deuteroacetylation of unmodified or mono-methylated lysine residues produces a chemically identical set of tryptic peptides when comparing the unmodified and modified versions of a protein, making it possible to directly quantify lysine acetylation. In this work, the deuteroacetylation technique is used to examine a single histone H3 peptide with methyl and acetyl modifications at different lysine residues and to quantify the relative abundance of each modification in different deacetylase and methylase knockout yeast strains. This application demonstrates the use of the deuteroacetylation technique to characterize modification 'cross-talk' by correlating different PTMs on the same histone tail. PMID- 23674286 TI - A validated assay by liquid chromatography-tandem mass spectrometry for the simultaneous quantification of elvitegravir and rilpivirine in HIV positive patients. AB - Because of the large variability in the pharmacokinetics of anti-HIV drugs, therapeutic drug monitoring in patients may contribute to optimize the overall efficacy and safety of antiretroviral therapy. An LC-MS/MS method for the simultaneous assay in plasma of the novel antiretroviral agents rilpivirine (RPV) and elvitegravir (EVG) has been developed to that endeavor. Plasma samples (100 MUL) extraction is performed by protein precipitation with acetonitrile, and the supernatant is subsequently diluted 1:1 with 20-mM ammonium acetate/MeOH 50:50. After reverse-phase chromatography, quantification of RPV and EVG, using matrix matched calibration samples, is performed by electrospray ionization-triple quadrupole mass spectrometry by selected reaction monitoring detection using the positive mode. The stable isotopic-labeled compounds RPV-(13) C6 and EVG-D6 were used as internal standards. The method was validated according to FDA recommendations, including assessment of extraction yield, matrix effects variability (<6.4%), as well as EVG and RPV short and long-term stability in plasma. Calibration curves were validated over the clinically relevant concentrations ranging from 5 to 2500 ng/ml for RPV and from 50 to 5000 ng/ml for EVG. The method is precise (inter-day CV%: 3-6.3%) and accurate (3.8-7.2%). Plasma samples were found to be stable (<15%) in all considered conditions (RT/48 h, +4 degrees C/48 h, -20 degrees C/3 months and 60 degrees C/1 h). Selected metabolite profiles analysis in patients' samples revealed the presence of EVG glucuronide, that was well separated from parent EVG, allowing to exclude potential interferences through the in-source dissociation of glucuronide to parent drug. This new, rapid and robust LCMS/MS assay for the simultaneous quantification of plasma concentrations of these two major new anti-HIV drugs EVG and RPV offers an efficient analytical tool for clinical pharmacokinetics studies and routine therapeutic drug monitoring service. PMID- 23674288 TI - The nutritive and immunoprotective quality of human milk beyond 1 year postpartum: are lactation-duration-based donor exclusions justified? AB - Donor human milk is critical for the fragile preterm infant who does not have access to his or her mother's milk, improving survival rates and quality of survival and decreasing hospital stay. Despite the opening of donor milk banks around the world, shortages continue as demand for donor milk exceeds supply. One potential means of increasing supply is by reducing exclusion criteria that prohibit mothers from donating milk based on duration of lactation. Minimal research has been done on the composition of human milk during the second year of lactation, with most research focusing on the nutritive compounds and not the immunoprotective compounds. Several immunoprotective compounds, including lysozyme, lactoferrin, secretory immunoglobulin A, and oligosaccharides, are abundant in human milk compared to bovine-based infant formula and are partially or fully retained during Holder pasteurization, making them an important differentiating feature of donor milk. A PubMed search was conducted to review studies in human milk composition during the second year of lactation. Limitations of existing research include sample collection protocols, small study sizes, and use of populations that may have been at risk for nutritional deficiencies. Stable concentrations of several components were reported including protein, lactose, iron, copper, lactoferrin, and secretory immunoglobulin A. Lysozyme concentration increased during extended lactation, while zinc and calcium concentrations declined into the second year. Conflicting findings were reported on fat content, and no information was available regarding oligosaccharide content. More research is needed to create evidence-based guidelines regarding the nutritive and immunoprotective value of donor milk throughout the course of lactation. PMID- 23674290 TI - Applicability of randomized trials in radiation oncology to standard clinical practice. AB - BACKGROUND: Randomized controlled trials (RCTs) are commonly used to inform clinical practice; however, it is unclear how generalizable RCT data are to patients in routine clinical practice. The authors of this report assessed the availability and applicability of randomized evidence guiding medical decisions in a cohort of patients who were evaluated for consideration of definitive management in a radiation oncology clinic. METHODS: The medical records of consecutive, new patient consultations between January and March 2007 were reviewed. Patient medical decisions were classified as those with (Group 1) or without (Group 2) available, relevant level I evidence (phase 3 RCT) supporting recommended treatments. Group 1 medical decisions were further divided into 3 groups based on the extent of fulfilling eligibility criteria for each RCT: Group 1A included decisions that fulfilled all eligibility criteria; Group 1B, decisions that did not fulfill at least 1 minor eligibility criteria; or Group 1C, decisions that did not fulfill at least 1 major eligibility criteria. Patient and clinical characteristics were tested for correlations with the availability of evidence. RESULTS: Of the 393 evaluable patients, malignancies of the breast (30%), head and neck (18%), and genitourinary system (14%) were the most common presenting primary disease sites. Forty-seven percent of all medical decisions (n = 451) were made without available (36%) or applicable (11%) randomized evidence to inform clinical decision making. Primary tumor diagnosis was significantly associated with the availability of evidence (P < .0001). CONCLUSIONS: A significant proportion of medical decisions in an academic radiation oncology clinic were made without available or applicable level I evidence, underscoring the limitations of relying solely on RCTs for the development of evidence-based health care. PMID- 23674291 TI - On association analysis of rare variants under population substructure: an approach for the detection of subjects that can cause bias in the analysis--T opt: an outlier detection method. AB - For the analysis of rare-variant data in population-based designs, we propose a method to detect study subjects that may create population substructure in the study sample. Our approach is computationally fast and simple, permitting applications to whole-genome sequencing studies. The method does not require the variants to be in linkage equilibrium and can be applied to all the genetic loci that are available in the study. For both rare and common variants, we assess the performance of our approach by its application to the 1000 Genome Project data, and in simulation studies. The results are compared to the commonly used outlier detection algorithm based on principal component analysis (PCA). The statistical power of both approaches to detect outliers are comparable in most of the scenarios, but the power of PCA to detect outliers is lower than the novel approach in the presence of linkage disequilibrium and for subpopulations that are genetically similar. The data analysis and the simulation studies suggest that the number of false-positive results appears to be different for the two approaches. Our approach maintains the type I error rate while the outlier detection approach based on PCA does not. Taking additionally into account the minimal computational requirements of our approach and the ability to incorporate all the marker information, the proposed method will have important application in sequencing studies and genome-wide association studies. PMID- 23674292 TI - A new immunoassay to quantify fungal antigens from the indoor mould Aspergillus versicolor. AB - Aspergillus versicolor is among the most commonly found moulds in moisture damaged buildings and can be associated with adverse health effects in humans. This paper reports the development, validation and application of an enzyme immunoassay to quantify A. versicolor antigens. A sandwich ELISA was developed using polyclonal antibodies that recognize a broad range of A. versicolor proteins present in fungal spores and in mycelia fragments. To validate the new method, A. versicolor antigens were quantified in samples collected from homes with visible mould growth, including dust from vacuumed walls and bulk samples of building materials. Antigen concentrations were compared to the results of a commercial ELISA based on monoclonal antibodies (AveX ELISA, Indoor Biotechnologies, Charlottesville, USA) and correlated with colony forming units (CFU) of A. versicolor. The A. versicolor ELISA was very sensitive with a lower detection limit of 120 pg ml(-1). The assay also showed some reactivity to other moulds with strongest reactions with other Aspergillus species (1-3% reactivity). The new assay detected A. versicolor antigens in a much higher percentage of dust samples (88% vs. 27%) and bulk samples (89% vs. 24%) than the AveX assay. A significant correlation (r = 0.67, and p < 0.0001) was found between antigen concentrations and CFU of A. versicolor. Based on its low detection limit and good correlation with the culture-based method, this new immunoassay seems to be a useful tool for the measurement of A. versicolor exposure levels and a reliable complement to the traditional monitoring techniques, such as mould cultivation or microscopy. PMID- 23674289 TI - The 6-minute walk test and other clinical endpoints in duchenne muscular dystrophy: reliability, concurrent validity, and minimal clinically important differences from a multicenter study. AB - INTRODUCTION: An international clinical trial enrolled 174 ambulatory males >=5 years old with nonsense mutation Duchenne muscular dystrophy (nmDMD). Pretreatment data provide insight into reliability, concurrent validity, and minimal clinically important differences (MCIDs) of the 6-minute walk test (6MWT) and other endpoints. METHODS: Screening and baseline evaluations included the 6 minute walk distance (6MWD), timed function tests (TFTs), quantitative strength by myometry, the PedsQL, heart rate-determined energy expenditure index, and other exploratory endpoints. RESULTS: The 6MWT proved feasible and reliable in a multicenter context. Concurrent validity with other endpoints was excellent. The MCID for 6MWD was 28.5 and 31.7 meters based on 2 statistical distribution methods. CONCLUSIONS: The ratio of MCID to baseline mean is lower for 6MWD than for other endpoints. The 6MWD is an optimal primary endpoint for Duchenne muscular dystrophy (DMD) clinical trials that are focused therapeutically on preservation of ambulation and slowing of disease progression. PMID- 23674293 TI - Early European attitudes towards "good death": Eugenios Voulgaris, Treatise on euthanasia, St Petersburg, 1804. AB - Eugenios Voulgaris (Corfu, Greece, 1716; St Petersburg, Russia, 1806) was an eminent theologian and scholar, and bishop of Kherson, Ukraine. He copiously wrote treatises in theology, philosophy and sciences, greatly influenced the development of modern Greek thought, and contributed to the perception of Western thought throughout the Eastern Christian world. In his Treatise on euthanasia (1804), Voulgaris tried to moderate the fear of death by exalting the power of faith and trust in the divine providence, and by presenting death as a universal necessity, a curative physician and a safe harbour. Voulgaris presented his views in the form of a consoling sermon, abundantly enriched with references to classical texts, the Bible and the Church Fathers, as well as to secular sources, including vital statistics from his contemporary England and France. Besides euthanasia, he introduced terms such as dysthanasia, etoimothanasia and prothanasia. The Treatise on euthanasia is one of the first books, if not the very first, devoted to euthanasia in modern European thought and a remarkable text for the study of the very early European attitudes towards "good death". In the Treatise, euthanasia is clearly meant as a spiritual preparation and reconciliation with dying rather than a physician-related mercy killing, as the term progressed to mean during the 19th and the 20th centuries. This early text is worthy of study not only for the historian of medical ethics or of religious ethics, but for everybody who is trying to courageously confront death, either in private or in professional settings. PMID- 23674294 TI - Venerable or vulnerable: ageing and old age in JRR Tolkien's The lord of the rings. AB - An underappreciated aspect of The lord of the rings (TLOTR) by JRR Tolkien is in how the author dealt with death, longevity and ageing in the work. During his early years, Tolkien endured first the passing of both parents and then the deaths of most of his friends during the First World War. It was not surprising that a search for the meaning of life and death became a preoccupation of Tolkien. Tolkien's Roman Catholic faith underpinned his thoughts about mortality. He also found solace in Northern myths that held that there was intrinsic worth to courage in the face of our inevitable demise. Along with his colleague, CS Lewis, he took an opposing stand to JBS Haldane, Olaf Stapledon and other precursors of transhumanists, who felt that bioengineering would allow us to extend human life span virtually without limit. Although Tolkien acknowledged the urge to try to escape our mortality, TLOTR is a story about accepting the need to let go with all of the attendant regrets and sorrow. PMID- 23674295 TI - Now bounded, now immeasurable: perspectives on time in disability, in suffering and at end of life. AB - Novels, films, poems and visual art can expand our view of time in ways that can be useful in dealing with disability, suffering and end of life. In particular, they can reveal more complex ways to view time. This can be effective both for the person suffering and for those who care for them. Our typical ways of viewing time include linear sequential clock time, which progresses in an evenly parsed, ordered, unidirectional way, and memory or narrative time-time as we remember it. These two ways of viewing time often do not agree. Since these can compete as the best predictors of outcomes in different circumstances, neither can make an exclusive claim to be "real time." A third view of time that has potential application is one that is multilayered, extending endlessly and evidencing expansiveness in each moment. Examples of the usefulness of this third, more complex view of time in asthma, pain, end of life and disability are presented. The arts can introduce this more complex view in a way that can help one fold it into life. All these ways of viewing time in combination can broaden the perspective clinicians have when co-creating with patients good decisions in difficult situations. PMID- 23674296 TI - My mother, the smoker. AB - Watching a frail parent, with a pack-a-day smoking habit, decline into dementia, I wrote a blog and morphed it into a narrative of my mother's smoking, paralleling her habit with the rise and fall of smoking through the ages. I imagine that some readers might be grappling with similar anguish and I offer this part memoir, part history, part health ethics discussion to understand what is so compelling about her experience with tobacco. PMID- 23674297 TI - "To observe well ... and thence to make himself rules": John Locke's principles and practice of child healthcare. AB - It is often forgotten that the philosopher John Locke (1632-1704) was a highly regarded physician with a lifelong interest in medicine and was frequently consulted on medical matters, including the health of children. This child health aspect in Locke's history has been largely ignored, with even modern commentaries on Locke and medicine giving it only a cursory mention. However, it is clear that, in child health, Locke's influence is far more substantial than GF Still's and George Jackson's opinions, which limited Locke solely to Thoughts concerning education (1692/3). That a fundamental reappraisal of Locke's role in child healthcare is necessary and that his place as a pioneer of modern child healthcare needs to be proclaimed are emphasised here. As modern day child healthcare has evolved to embrace advocacy and learning disability, Locke's importance through his influence on paediatrics, child healthcare and human rights becomes more evident. Locke's influence in child healthcare comes not only through his other celebrated philosophical writings, but also through extensive personal correspondence and case records. As well as throwing light onto the 17th century aspects of child healthcare, Locke, through his enquiry and self-evident humility in his correspondence on medical matters, inspires and educates us with his pragmatic approach to the practice of medicine. PMID- 23674298 TI - Rembrandt's doctors. AB - Medical doctors appear in numerous Rembrandt paintings and reciprocally, physicians interested in art have used their diagnostic skills in dissecting the painter's work, especially his lifetime of self-portraits. The possible existence of skin and eye diseases, hypothyroidism and Horton's disease, and psychiatric and psychological traits has been a matter of everlasting debate, as summarised in the present paper. Most of all, the ageing process reveals itself over time in the continuity of the self-portraits. In the quest for signs of illness, the slightest bump in the canvas can be considered a symptom, and the examination of Rembrandt's self-portraits is a difficult exercise. However, the resulting published papers have given rise to a great number of diagnostic hypotheses. PMID- 23674299 TI - "The stroke is eighty nine": understanding unprofessional behaviour through physician-authored prose. AB - The unprofessional behaviour of medics is explored through their depiction in two physician-authored books-the novel Bodies and the autobiography Bedside stories: confessions of a junior doctor. Using the Integrative Model of Behavioural Prediction, not only the range and nature of professionalism lapses outlined in these books but also the reasons behind such unprofessional behaviours are examined. The books contained examples of lapses in professionalism outlined in research investigating the unprofessional behaviour of medical students, such as communication violations, objectification of patients and causing harm to patients. More interestingly, various reasons behind lapses in professionalism were found. Most examples of unprofessional behaviour were unintentional acts and therefore due to environmental constraints and skill deficits. Seemingly intentional acts were largely influenced by normative beliefs-that is, people feeling pressurised to act unprofessionally. Further research is needed to examine the depiction of lapses in professionalism in a wider range of physician authored prose. PMID- 23674300 TI - "Medicalisation of falling in love": medical students' responses to Thomas Mann's The Black Swan. AB - The value of implementing literature in medical education is widely accepted. The initial responses of medical students to Thomas Mann's short story The Black Swan are described and their resources for making sense of the story are presented. Their written responses revealed that the students interpreted the story mainly through a medical framework and were capable of understanding the story's complex and existential issues related to medicine. Evident gaps in the students' interpretations and understanding are discussed and suggestions on using such kinds of intellectual texts in medical teaching are offered. PMID- 23674301 TI - Dialogue in the narrative process. AB - This article draws on VM's doctoral research into the narratives of illness and surgery, and their impact on conceptions of self and life story. This article was the result of conference presentations held during June/July 2005 in Belfast (Arts-Based Educational Research) and Truro (Association of Medical Humanities), UK. The aim of this article is to explore the topic of "dialogue" in the research relationship. This is done primarily through a story, Shoes, butterflies and devils, which is intended to evoke a sense of the relationship between Patricia and VM, through which the connections between the autobiographical roots of her research and Patricia's experience of kidney failure, dialysis, transplant and heart failure are portrayed. The story is preceded by a brief introduction and account of her methodology, followed by a discussion of some of the conceptual aspects of dialogue that she has tried to highlight in the story. PMID- 23674302 TI - Appreciation of art in a workers' hospital in Chile. AB - To assess the impact of selected murals in the Workers' Hospital in Santiago on different groups of clients, a quantitative and qualitative approach, including a semantic differential scale, was applied. The sample was composed of 120 subjects 40 patients, 40 visitors and 40 hospital staff. Appreciation of the paintings (45 87%) and assessment of the benefit of each painting (56-84%) varied widely. Differences in perceptions according to age, gender and educational level were not significant. Over two-thirds of the sample had a positive appreciation of the murals and considered them beneficial. Differences in perception relate to personal characteristics of the subjects and are also associated with certain characteristics of the murals, such as location, or the structure and style of the work. This study, the first of its kind in Chile, provides grounds for the development of an art-for-health policy in the future, showing that most people are willing to participate by giving their opinions and assessments. PMID- 23674303 TI - Wittgenstein's neurophenomenology. AB - Wittgenstein, despite being considered an analytical philosopher, has been quoted extensively by neurologists like Oliver Sacks. This paper explores how Wittgenstein, despite suggesting that science was antithetical to philosophy, made observations relevant to cognitive neuroscience. His work on the inner and the outer, the relation between language and sensation or perception, and on the embodied nature of emotion and its communication, is important for an understanding of neurological impairment beyond our experience. In some of his enigmatic short writing his insights are pertinent to patients' experience, say of pain, Capgras' Syndrome and spinal cord injury. He also made observations on movement sense, will and action. He did not engage in empirical science, nor obtain data in any conventional sense. But his genius was not confined to abstract philosophy. His powers of observation and introspection led him to explore lived experience in new ways, some of which are only now being approached empirically. The method of science, he once wrote, leads philosophy into complete darkness. Had he lived today, one hopes that even he might have changed his mind. PMID- 23674304 TI - Classic models for dynamic contrast-enhanced MRI. AB - Dynamic contrast-enhanced MRI (DCE-MRI) is a functional MRI method where T1 weighted MR images are acquired dynamically after bolus injection of a contrast agent. The data can be interpreted in terms of physiological tissue characteristics by applying the principles of tracer-kinetic modelling. In the brain, DCE-MRI enables measurement of cerebral blood flow (CBF), cerebral blood volume (CBV), blood-brain barrier (BBB) permeability-surface area product (PS) and the volume of the interstitium (ve ). These parameters can be combined to form others such as the volume-transfer constant K(trans) , the extraction fraction E and the contrast-agent mean transit times through the intra- and extravascular spaces. A first generation of tracer-kinetic models for DCE-MRI was developed in the early 1990s and has become a standard in many applications. Subsequent improvements in DCE-MRI data quality have driven the development of a second generation of more complex models. They are increasingly used, but it is not always clear how they relate to the models of the first generation or to the model-free deconvolution methods for tissues with intact BBB. This lack of understanding is leading to increasing confusion on when to use which model and how to interpret the parameters. The purpose of this review is to clarify the relation between models of the first and second generations and between model based and model-free methods. All quantities are defined using a generic terminology to ensure the widest possible scope and to reveal the link between applications in the brain and in other organs. PMID- 23674305 TI - Genomic architecture of adaptive color pattern divergence and convergence in Heliconius butterflies. AB - Identifying the genetic changes driving adaptive variation in natural populations is key to understanding the origins of biodiversity. The mosaic of mimetic wing patterns in Heliconius butterflies makes an excellent system for exploring adaptive variation using next-generation sequencing. In this study, we use a combination of techniques to annotate the genomic interval modulating red color pattern variation, identify a narrow region responsible for adaptive divergence and convergence in Heliconius wing color patterns, and explore the evolutionary history of these adaptive alleles. We use whole genome resequencing from four hybrid zones between divergent color pattern races of Heliconius erato and two hybrid zones of the co-mimic Heliconius melpomene to examine genetic variation across 2.2 Mb of a partial reference sequence. In the intergenic region near optix, the gene previously shown to be responsible for the complex red pattern variation in Heliconius, population genetic analyses identify a shared 65-kb region of divergence that includes several sites perfectly associated with phenotype within each species. This region likely contains multiple cis regulatory elements that control discrete expression domains of optix. The parallel signatures of genetic differentiation in H. erato and H. melpomene support a shared genetic architecture between the two distantly related co mimics; however, phylogenetic analysis suggests mimetic patterns in each species evolved independently. Using a combination of next-generation sequencing analyses, we have refined our understanding of the genetic architecture of wing pattern variation in Heliconius and gained important insights into the evolution of novel adaptive phenotypes in natural populations. PMID- 23674307 TI - Diabetes mellitus and cardiovascular events in older patients with myocardial infarction prescribed intensive-dose and moderate-dose statins. AB - BACKGROUND: Practice guidelines recommend intensive-dose statins for patients with acute coronary syndrome, but recent data about the risk of new-onset diabetes mellitus have raised concerns about its use. Our main objective was to evaluate the association between intensive statin therapy and new-onset diabetes mellitus in patients with myocardial infarction and to evaluate the association of intensive statin therapy with long-term adverse clinical outcomes. METHODS AND RESULTS: A propensity score-matched cohort was created consisting of 17 080 patients with myocardial infarction aged >65 years old, hospitalized in Ontario, Canada, from 2004 to 2010. Clinical outcomes were compared in patients prescribed intensive-dose versus moderate-dose statins at hospital discharge. At 5 years, 13.6% of patients receiving intensive-dose statins and 13.0% of patients receiving moderate-dose statins had new-onset diabetes, which was not significantly different (P=0.19). By contrast, the 5-year rate of death or acute coronary syndrome was significantly lower at 44.8% in the intensive-dose statin group compared with 46.5% in the moderate-dose group (P=0.044). The reduction in combined clinical outcome was driven mainly by a significantly lower rate of acute coronary syndrome (P=0.039) associated with intensive-dose statins. No significant difference in mortality rates (34.8% in both groups) was observed between the treatment groups during the study period (P=0.89). CONCLUSIONS: In older patients with myocardial infarction, we found intensive-dose statin therapy to be effective in reducing repeat hospitalization for acute coronary syndrome. The rate of new-onset diabetes mellitus at long term was not significantly different between intensive-dose and moderate-dose statins. PMID- 23674308 TI - Most important outcomes research papers on treatment of stable coronary artery disease. AB - The following are highlights from the new series, Circulation: Cardiovascular Quality and Outcomes Topic Review. This series will summarize the most important manuscripts, as selected by the Editor, that have been published in the Circulation portfolio. The objective of this series is to provide our readership with a timely, comprehensive selection of important papers that are relevant to the quality and outcomes, and general cardiology audience. The studies included in this article represent the most significant research related to treatment of stable coronary artery disease (CAD). PMID- 23674309 TI - Goodbye, thank you, and welcome. PMID- 23674306 TI - Proteome-wide discovery of mislocated proteins in cancer. AB - Several studies have sought systematically to identify protein subcellular locations, but an even larger task is to map which of these proteins conditionally relocates in disease (the mislocalizome). Here, we report an integrative computational framework for mapping conditional location and mislocation of proteins on a proteome-wide scale, called a conditional location predictor (CoLP). Using CoLP, we mapped the locations of over 10,000 proteins in normal human brain and in glioma. The prediction showed 0.9 accuracy using 100 location tests of 20 randomly selected proteins. Of the 10,000 proteins, over 150 have a strong likelihood of mislocation under glioma, which is striking considering that few mislocation events have been identified in this disease previously. Using immunofluorescence and Western blotting in both primary cells and tissues, we successfully experimentally confirmed 15 mislocations. The most common type of mislocation occurs between the endoplasmic reticulum and the nucleus; for example, for RNF138, TLX3, and NFRKB. In particular, we found that the gene for the mislocating protein GFRA4 had a nonsynonymous point mutation in exon 2. Moreover, redirection of GFRA4 to its normal location, the plasma membrane, led to marked reductions in phospho-STAT3 and proliferation of glioma cells. This framework has the potential to track changes in protein location in many human diseases. PMID- 23674310 TI - Journey through cholesteryl ester transfer protein inhibition: from bench to bedside. PMID- 23674311 TI - Individual and community determinants of calling 911 for stroke among African Americans in an urban community. AB - BACKGROUND: African Americans receive acute stroke treatment less often than non Hispanic whites. Interventions to increase stroke preparedness (recognizing stroke warning signs and calling 911) may decrease the devastating effects of stroke by allowing more patients to be candidates for acute stroke therapy. In preparation for such an intervention, we used a community-based participatory research approach to conduct a qualitative study exploring perceptions of emergency medical care and stroke among urban African American youth and adults. METHODS AND RESULTS: Community partners, church health teams, and church leaders identified and recruited focus group participants from 3 black churches in Flint, MI. We conducted 5 youth (11-16 years) and 4 adult focus groups from November 2011 to March 2012. A content analysis approach was taken for analysis. Thirty nine youth and 38 adults participated. Women comprised 64% of youth and 90% of adult focus group participants. All participants were black. Three themes emerged from the adult and youth data: (1) recognition that stroke is a medical emergency; (2) perceptions of difficulties within the medical system in an under resourced community, and; (3) need for greater stroke education in the community. CONCLUSIONS: Black adults and youth have a strong interest in stroke preparedness. Designs of behavioral interventions to increase stroke preparedness should be sensitive to both individual and community factors contributing to the likelihood of seeking emergency care for stroke. PMID- 23674312 TI - Ischemia-driven revascularization: demonstrating and delivering a mature procedure in a mature way. PMID- 23674313 TI - Contemporary use of prasugrel in clinical practice: insights from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium. AB - BACKGROUND: Prasugrel is a recently approved thienopyridine for use in patients with acute coronary syndromes undergoing percutaneous coronary intervention. There are no data on contemporary use of prasugrel in routine clinical practice. METHODS AND RESULTS: We assessed the patterns of prasugrel use among 55 821 patients who underwent percutaneous coronary intervention and were discharged alive from January 2010 to December 2011 at 44 hospitals participating in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium. Potential inappropriate therapy was defined as use in patients who had a history of cerebrovascular disease, weighed <60 kg, or were aged >=75 years old. Clopidogrel was prescribed to 83% (n=46 574) and 17% (n=9247) of patients received prasugrel on hospital discharge. A steady, linear increase in prasugrel use was seen during the study period, with discharge prescription increasing from 8.4% in quarter 1 of 2010 to 22.3% in quarter 4 of 2011. Of the total cohort, 69.1% of patients presented with acute coronary syndrome, and in this group, 17.2% received prasugrel. Among patients prescribed prasugrel, 28.3% (n=2614) received the medication for indications outside of acute coronary syndromes. One or more known contraindications to the drug were present in 6% to 10% of patients discharged on this agent. CONCLUSIONS: There has been a steady increase in the use of prasugrel with the drug being used in ~22% of patients undergoing percutaneous coronary intervention by study end. Prasugrel use in patients with known contraindications is not uncommon and may be a suitable target for focused quality improvement efforts. PMID- 23674315 TI - Prasugrel: the real-life perspective. PMID- 23674314 TI - Mortality in Medicare patients undergoing elective percutaneous coronary intervention with or without antecedent stress testing. AB - BACKGROUND: Guidelines advise testing for ischemia, such as with stress testing, before elective percutaneous coronary intervention (PCI). However, pre-PCI stress testing is not always done; the implications of this practice are not known. Our objective was to evaluate whether receipt of stress testing before elective PCI predicts mortality. METHODS AND RESULTS: Using claims data from a 20% random sample of Medicare beneficiaries, we identified patients who had elective PCI in 2004 and followed them for a median of 3.4 years (n=23 887). Cox proportional hazards models were used to test the relationship of pre-PCI stress testing to survival. Population-based rates of elective PCI and stress testing were calculated for 306 hospital referral regions and categorized into 4 groups: high stress test/high PCI, low stress test/low PCI, low stress test/high PCI, and high stress/low PCI regions. Cox modeling was used to test whether category of hospital referral regions is related to survival. Patients who underwent pre-PCI stress testing had a 13% lower risk of mortality than those who did not (adjusted hazard ratio, 0.87; 95% confidence interval, 0.81-0.92) after median follow-up of 3.4 years. Patients in low stress test/high PCI regions had a 14% higher risk of mortality than those in high stress test/high PCI regions (adjusted hazard ratio, 1.14; 95% confidence interval, 1.03-1.26). CONCLUSIONS: Pre-PCI stress testing is associated with lower mortality in patients undergoing elective PCI. Greater adherence to guidelines with respect to documenting ischemia before elective PCI may result in improved outcomes for patients. PMID- 23674316 TI - The role of noninvasive prenatal testing as a diagnostic versus a screening tool- a cost-effectiveness analysis. AB - OBJECTIVE: As the sensitivity and specificity of noninvasive prenatal testing (NIPT) that uses cell-free fetal DNA in maternal serum to identify Down syndrome (DS) in utero improves, NIPT could be considered a diagnostic test, thus avoiding the complications of chorionic villus sampling or amniocentesis. This study investigates the cost-effectiveness of NIPT as a diagnostic versus a screening tool. METHOD: A decision-analytic model compared NIPT as a diagnostic tool (NIPT Dx) that did not require a confirmatory amniocentesis versus NIPT used for screening (NIPT Scr) that allowed a confirmatory amniocentesis for screen positive results. Baseline case, univariate, and multivariate sensitivity analyses were performed. RESULTS: For a high-risk population, NIPT Dx would result in three more DS babies born and 2432 more elective terminations compared with NIPT Scr. Furthermore, there would be many more terminations of fetuses without DS with NIPT Dx (2424) than procedure-related losses associated with NIPT Scr (29). NIPT Scr is more expensive but cost-effective at $7687 per quality associated life year (QALY), less than the standard cost-effectiveness limit of $100 000/QALY. CONCLUSIONS: Noninvasive prenatal testing as a screening tool that requires a confirmatory amniocentesis is cost-effective compared with its use as a diagnostic tool and leads to far fewer losses of normal pregnancies. PMID- 23674317 TI - Large-scale gold nanoparticle superlattice and its SERS properties for the quantitative detection of toxic carbaryl. AB - Large scale and well-ordered gold nanoparticle superlattices were fabricated by self-assembly as an active substrate for surface-enhanced Raman scattering (SERS) that can quantitatively detect carbaryl with a detection limit of 1 ppm. These fabricated superlattices with a dimension of several hundred micrometers exhibited high, reproducible SERS activity. PMID- 23674318 TI - Inclusion of minorities and women in cancer clinical trials, a decade later: Have we improved? AB - BACKGROUND: Inclusion of diverse groups of participants in cancer clinical trials is an important methodological and clinical issue. The quality of the science and generalizability of results depends on the inclusion of study participants who represent all populations among whom these treatment and prevention approaches will be used. METHODS: We conducted a systematic review using OVID as the primary source of reports included. Based on 304 peer-reviewed publications, diversity in the inclusion and reporting of study participants during a decade of cancer treatment and prevention trials (2001-2010) is summarized. Recommendations are made for improvements in the science and reporting of cancer clinical trials. RESULTS: Of the 277 treatment trials and 27 prevention trials included in this report, more than 80% of participants were white and 59.8% were male. In the recent decade, race and sex are rarely used as selection criteria unless the trial is focused on a sex-specific cancer. CONCLUSIONS: Women and racial/ethnic minorities remain severely underrepresented in cancer clinical trials, thus limiting the generalizability of cancer clinical research. PMID- 23674319 TI - Transitions, access, conversations: editor's introduction. PMID- 23674320 TI - Aging respectably by rejecting medicalization: Mexican men's reasons for not using erectile dysfunction drugs. AB - As lifestyle drug production and medical interest in geriatrics increase, the medicalization of aging and sexuality have become intertwined. Drugs like Viagra naturalize lifelong performance of phallocentric sex as a marker of healthy aging. Yet despite the ubiquity of medical aids for having "youthful" sex in older age, this article argues that having no or less sex can be a conscious strategy for embodying respectable aging. Based on ethnographic research in a Cuernavaca, Mexico, hospital urology department, this article shows that despite the traditional association of penetrative sex with successful masculinity, many older, working-class Mexican men faced with erectile difficulty reject "youthful" sexuality and drugs that facilitate it in order to embody a "mature" masculinity focused on home and family. This article argues that social encouragement and structural disincentives for medicalizing erectile difficulty encouraged men to interpret decreasing erectile function as natural and appropriate. PMID- 23674321 TI - Men's narratives of vasectomy: rearticulating masculinity and contraceptive responsibility in San Jose, Costa Rica. AB - This article interrogates the modes by which cultural constructions of male contraceptive use emerge in Costa Rica by analyzing men's narratives of vasectomy. Drawing on ethnographic research data, I examine men's contraceptive decision making and perspectives on vasectomy and specify the ways they work through their vasectomy to rearticulate the relationship between masculinity and contraceptive responsibility and tensions in an emerging Costa Rican social modernity. Following Oudshoorn's (2003) analysis on male contraceptive research, this article highlights contraceptive technologies and men's narratives of these technologies as key sites for examining gender politics in contemporary societies and the materialization of new social orders. In the discussion, I argue that the men's narratives examined here potentiate creation of an "alternative technosociality" (Oudshoorn 2003) in Costa Rica, in which men taking contraceptive responsibility does not constitute performing a subordinate masculinity, but simply another way of acting as men. PMID- 23674322 TI - Plot and irony in childbirth narratives of middle-class Brazilian women. AB - Brazil's rate of cesarean deliveries is among the highest in the world and constitutes the majority of childbirths in private hospitals. This study examines ways middle-class Brazilian women are exercising agency in this context. It draws from sociolinguistics to examine narrative structure and dramatic properties of 120 childbirth narratives of 68 low- to high-income women. Surgical delivery constituted 62% of the total. I focus on 20 young middle-class women, of whom 17 had C-sections. Doctors determined mode of childbirth pre-emptively or appeared to accommodate women's wishes, while framing the scenario as necessitating surgical delivery. The women strove to imbue C-section deliveries with value and meaning through staging, filming, familial presence, attempting induced labor, or humanized childbirth. Their stories indicate that class privilege does not lead to choice over childbirth mode. The women nonetheless struggle over the significance of their agency in childbirth. PMID- 23674323 TI - "The weight on our shoulders is too much, and we are falling": Suicide among Inuit male youth in Nunavut, Canada. AB - Inuit youth suicide is at an epidemic level in the circumpolar north. Rapid culture change has left Inuit in a state of coloniality that destabilized their kin-based social organization, and in spite of advances in self-governance social problems such as suicide continue. Drawing on ethnographic fieldwork I carried out in Nunavut, Canada (2004-2005), including 27 interviews with Inuit between the ages of 17 and 61, I examine male youth in particular in the context of recent colonial change, gender ideologies and behavior, youth autonomy, and the family. Anger is common among Inuit male youth, often directed toward girlfriends and parents, and suicide is embedded in some of these relationships. Many Inuit male youth are struggling with a new cultural model of love and sexuality. Inuit speak about a need for more responsible parenting. Evidence is beginning to show, however, that local, community-based suicide prevention may be working. PMID- 23674324 TI - "Love isn't there in your stomach": a moral economy of medical citizenship among Nicaraguan community health workers. AB - Drawing on participant-observation in Nicaraguan dengue prevention campaigns and a series of semistructured interviews with Nicaraguan health ministry personnel, this article shows how community health workers (CHWs) balanced two kinds of "medical citizenship." In some situations, CHWs acted as professional monitors and models of hygienic behavior. At other times, CHWs acted as compassionate advocates for their poor neighbors. In 2008, Nicaragua's Sandinista government moved to end a long-standing policy of paying CHWs, recasting them as citizen volunteers in a "popular struggle" against dengue. Although CHWs approved of the revival of grassroots advocacy, they were hostile to the elimination of compensation. Framing this ambivalence as part of CHWs' desire to serve as "brokers" between the poor and the state, I suggest that attention to medical citizenship provides insight into the sometimes contradictory ways in which CHWs engage the participatory health policies now taking hold in Latin America and elsewhere. PMID- 23674325 TI - Malicious whites, greedy women, and virtuous volunteers: negotiating social relations through clinical trial narratives in South Africa. AB - As clinical trial research increasingly permeates sub-Saharan Africa, tales of purposeful HIV infection, blood theft, and other harmful outcomes are widely reported by participants and community members. Examining responses to the Microbicide Development Programme 301-a randomized, double-blind, placebo controlled microbicide trial-we investigate the ways in which these accounts embed medical research within postcolonial contexts. We explore three popular narratives circulating around the Johannesburg trial site: malicious whites killing participants and selling their blood, greedy women enrolling in the trial solely for financial gain, and virtuous volunteers attempting to ensure their health and aid others through trial participation. We argue that trial participants and community members transform medical research into a meaningful tool that alternately affirms, debates, and challenges contemporary social relations. PMID- 23674326 TI - Somos muchos (we are so many): population politics and "reproductive othering" in Mexican fertility clinics. AB - Although Mexican state officials have long attributed Mexico's "overpopulation problem" to its "high" fertility rate, that rate is almost at replacement level today. Nevertheless, anxieties about overpopulation rooted in reproduction persist. Based on my ethnographic fieldwork in Mexico City fertility clinics, this article examines how overpopulation anxieties affect infertile women as they use assisted reproductive technologies (ARTs) to try to conceive children. I examine how these women attempt to justify their seemingly out-of-place use of ARTs in this "overpopulated" context by evoking discourses of "reproductive othering." Through these discourses they lay claim to a whiter, worthier status than racialized Others on the basis of their purported reproductive practices. I contend that their discourses reveal that infertility and its care are potent sites for the local production and reproduction of personhood, parenthood, and citizenship. PMID- 23674327 TI - Induction of CaSR expression circumvents the molecular features of malignant CaSR null colon cancer cells. AB - We recently reported on the isolation and characterization of calcium sensing receptor (CaSR) null human colon cancer cells (Singh et al., Int J Cancer 2013; 132: 1996-2005). CaSR null cells possess a myriad of molecular features that are linked to a highly malignant and drug resistant phenotype of colon cancer. The CaSR null phenotype can be maintained in defined human embryonic stem cell culture medium. We now show that the CaSR null cells can be induced to differentiate in conventional culture medium, regained the expression of CaSR with a concurrent reversal of the cellular and molecular features associated with the null phenotype. These features include cellular morphology, expression of colon cancer stem cell markers, expression of survivin and thymidylate synthase and sensitivity to fluorouracil. Other features include the expression of epithelial mesenchymal transition linked molecules and transcription factors, oncogenic miRNAs and tumor suppressive molecule and miRNA. With the exception of cancer stem cell markers, the reversal of molecular features, upon the induction of CaSR expression, is directly linked to the expression and function of CaSR because blocking CaSR induction by shRNA circumvented such reversal. We further report that methylation and demethylation of the CaSR gene promoter underlie CaSR expression. Due to the malignant nature of the CaSR null cells, inclusion of the CaSR null phenotype in disease management may improve on the mortality of this disease. Because CaSR is a robust promoter of differentiation and mediates its action through diverse mechanisms and pathways, inactivation of CaSR may serve as a new paradigm in colon carcinogenesis. PMID- 23674328 TI - How best can we define double outlet right ventricle when describing congenitally malformed hearts? PMID- 23674330 TI - From cavum septi pellucidi to anterior complex: how to improve detection of midline cerebral abnormalities. PMID- 23674329 TI - Insight into the toxic effects of cis-dichloridoplatinum(II) complexes containing 7-azaindole halogeno derivatives in tumor cells. AB - The cisplatin analogues cis-[PtCl2(3ClHaza)2] (1) and cis-[PtCl2(3IHaza)2] (2) (3ClHaza and 3IHaza are 3-chloro-7-azaindole and 3-iodo-7-azaindole, respectively) are quite toxic to ovarian tumor cells, with moderately better IC50 values than for cisplatin in the cisplatin-sensitive cell line A2780. We investigated potential factors which might be involved in the mechanism underlying the cytotoxic effects of 1 and 2 and compared these factors with those involved in the mechanism underlying the effects of conventional cisplatin. Our data indicate that the higher cytotoxicity of 1 and 2 originates mainly from their efficient cellular accumulation, different effects at the level of cell cycle regulation, and reduced propensity for DNA adduct repair. Studies of their reactivity toward cellular components reveal efficient binding to DNA, which is typically required for an active platinum drug. Further results suggest that 1 and 2 are capable of circumventing resistance to cisplatin induced by alterations in cellular accumulation and DNA repair. Hence, the latter two factors appear to be responsible for differences in the toxicity of 1 or 2, and cisplatin in tumor cells. The results of this work reinforce the idea that direct analogues of conventional cisplatin-containing halogeno-substituted 7-azaindoles offer much promise for the design of novel therapeutic agents. PMID- 23674331 TI - Safeguarding adults at risk of harm. PMID- 23674332 TI - Demystifying trial networks and network meta-analysis. PMID- 23674333 TI - Piquancy. PMID- 23674334 TI - Are "friends and family tests" useful: agree, disagree, neither, don't know? PMID- 23674335 TI - India must raise the status of primary care. PMID- 23674336 TI - Should we be reassured about sitagliptin? PMID- 23674337 TI - How different are NHS systems across the UK since devolution? PMID- 23674338 TI - Medical students perform operations in Syria's depleted health system. PMID- 23674339 TI - Two cases of novel coronavirus are confirmed in France. PMID- 23674340 TI - Antibiotics for back pain: hope or hype? PMID- 23674341 TI - Maternal cfDNA screening for Down syndrome--a cost sensitivity analysis. AB - OBJECTIVE: This study aimed to determine the principal factors contributing to the cost of avoiding a birth with Down syndrome by using cell-free DNA (cfDNA) to replace conventional screening. METHODS: A range of unit costs were assigned to each item in the screening process. Detection rates were estimated by meta analysis and modeling. The marginal cost associated with the detection of additional cases using cfDNA was estimated from the difference in average costs divided by the difference in detection. RESULTS: The main factor was the unit cost of cfDNA testing. For example, replacing a combined test costing $150 with 3% false-positive rate and invasive testing at $1000, by cfDNA tests at $2000, $1500, $1000, and $500, the marginal cost is $8.0, $5.8, $3.6, and $1.4m, respectively. Costs were lower when replacing a quadruple test and higher for a 5% false-positive rate, but the relative importance of cfDNA unit cost was unchanged. A contingent policy whereby 10% to 20% women were selected for cfDNA testing by conventional screening was considerably more cost-efficient. Costs were sensitive to cfDNA uptake. CONCLUSION: Universal cfDNA screening for Down syndrome will only become affordable by public health purchasers if costs fall substantially. Until this happens, the contingent use of cfDNA is recommended. PMID- 23674342 TI - Small-angle electron scattering of magnetic fine structures. AB - Magnetic structures in magnetic artificial lattices and chiral magnetic orders in chiral magnets have been quantitatively analyzed in the reciprocal space by means of small-angle electron scattering (SAES) method. Lorentz deflection due to magnetic moments and Bragg diffraction due to periodicity are simultaneously recorded at an angle of the order of or less than 1 * 10(-6) rad, using a camera length of more than 100 m. The present SAES method, together with TEM real-space imaging methods such as in-situ Lorentz microscopy, is very powerful in analyzing magnetic fine structures in magnetic materials. Indeed, the existence of both a chiral helimagnetic structure and a chiral magnetic soliton lattice in a chiral magnet CrNb3S6 has been successfully verified for the first time using the present complementary methods. PMID- 23674343 TI - Coniothyrione: anatomy of a structure revision. AB - Coniothyrione is a xanthone-derived antibiotic reported several years ago by researchers at Merck & Co. Inc. Revision of the position of the chloro substitution was recently proposed on the basis of empirical reinterpretation of the carbon chemical shift data and a hypothetical biosynthetic argument without the acquisition of any new spectral data to support the postulated change in substituent location. The originally published HMBC data lead to an equivocal assignment of the structure and do not provide a solid basis of support for either structure. Neural network (13)C chemical shift calculations and density functional theory calculations also led to undifferentiated structures. Definitive confirmation of the structure of coniothyrione based on the acquisition and interpretation of 1,1-ADEQUATE and inverted (1)J(CC) 1,n-ADEQUATE data is now reported. PMID- 23674345 TI - The superficial glia limitans of mouse and monkey brain and spinal cord. AB - Using the double immunostaining method, the glia limitans on the surfaces of mouse and monkey brain and spinal cord were studied systematically. The results showed that the superficial glia limitans of mouse brain and spinal cord comprise a layer of surface astrocytes, while the glia limitans of monkey comprise a layer of foot-plates from marginal regions as described in histology and neuroscience textbooks. These surface astrocytes first appear at embryonic day (E)16 in spinal cord and at E17 on the ventral surface of the brain. At postnatal day (P)1, a layer of astrocytes covered the outermost regions of the spinal cord. At P10, the layer of astrocytes also covered the brain surface. The highest proliferation rates of surface astrocytes were found at E17 in the spinal cord and at E18 in the forebrain. PMID- 23674344 TI - A prospective analysis of telomere length and pancreatic cancer in the alpha tocopherol beta-carotene cancer (ATBC) prevention study. AB - Smoking and diabetes, consistent risk factors for pancreatic cancer, are also factors that influence telomere length maintenance. To test whether telomere length is associated with pancreatic cancer risk, we conducted a nested case control study in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort of male smokers, aged 50-69 years at baseline. Between 1992 and 2004, 193 incident cases of pancreatic adenocarcinoma occurred (mean follow-up from blood draw: 6.3 years) among participants with whole blood samples available for telomere length assays. For these cases and 660 controls, we calculated odds ratios (OR) and 95% confidence intervals using unconditional logistic regression, adjusting for age, number of years smoked regularly, and history of diabetes mellitus. Telomere length was categorized into quartiles (shortest to longest) and analyzed as both a categorical and a continuous normal variable (reported per 0.2 unit increase in telomere length). All statistical tests were two-sided. Longer telomere length was significantly associated with increased pancreatic cancer risk (continuous OR = 1.26 95% CI = 1.09-1.46; highest quartile compared to lowest, OR = 1.57, 95% CI = 1.01-2.43, p-trend = 0.007). This association remained for subjects diagnosed within the first five years of blood draw (continuous OR = 1.46, 95% CI = 1.19-1.79 highest quartile OR = 2.92, 95% CI = 1.47-5.77, p-trend = 0.002), but not those diagnosed greater than five years after blood draw (continuous OR = 1.03, 95% CI = 0.85-1.22; highest quartile OR = 1.04, 95% CI = 0.60-1.79). This is the first prospective study to suggest an association between longer blood leukocyte telomere length and increased pancreatic cancer risk. PMID- 23674346 TI - Incidence of, and risk factors for, postoperative venous thromboembolism in patients with benign or malignant musculoskeletal tumors. AB - BACKGROUND: Venous thromboembolism is a serious complication after surgery for malignant musculoskeletal tumors in the lower extremity. However, the incidence of postoperative venous thromboembolism in patients with benign musculoskeletal tumors and musculoskeletal tumors in the upper extremity or trunk remains unclear. Identifying risk factors may provide useful information for selecting patients who should receive chemoprophylaxis. METHODS: A retrospective study of 833 patients with musculoskeletal tumors who underwent surgery was conducted. Patients were divided into four groups: 364 patients with benign tumors in the upper extremity or trunk (group 1); 315 patients with benign tumors in the lower extremity or pelvis (group 2); 50 patients with malignant tumors in the upper extremity or trunk (group 3); and 104 patients with malignant tumors in the lower extremity or pelvis (group 4). The incidence of venous thromboembolism was investigated, and risk factors were examined for group 4. RESULTS: The incidence of postoperative venous thromboembolism was 0, 0.95, 0, and 4.8 % in groups 1, 2, 3, and 4, respectively. The incidence of venous thromboembolism in the malignant tumor group (groups 3 + group 4) was significantly higher than that in the benign tumor group (group 1 + group 2). The incidence of postoperative venous thromboembolism in the upper extremity or trunk group (group 1 + group 3) was significantly lower than that in the lower extremity or pelvis group (group 2 + group 4). In group 4, a higher incidence of postoperative venous thromboembolism was significantly correlated with a history of cerebrovascular disease and surgery in the prone position. CONCLUSIONS: Patients with malignant tumors in the lower extremity or pelvis, particularly those with a history of cerebrovascular disease and surgery in a prone position, were at high risk of venous thromboembolism. Patients with benign tumors in the lower extremity or pelvis were at intermediate risk. This is important information for predicting the incidence of postoperative venous thromboembolism and determining who should receive chemoprophylaxis after surgery for musculoskeletal tumors. PMID- 23674347 TI - Severe valgus knee deformity caused by chondronecrosis after using a radiofrequency device. PMID- 23674348 TI - Innervation pattern at the undersurface of the extensor carpi radialis brevis tendon in recalcitrant tennis elbow. AB - PURPOSE: We investigated the general, sensory, and sympathetic innervation patterns at the undersurface of the extensor carpi radialis brevis (ECRB) origin in patients with recalcitrant tennis elbow. METHODS: Eight elbows in eight consecutive patients (6 females and 2 males) with tennis elbow who underwent arthroscopic surgery were included in this study. The mean age was 45 years (38 66 years), and the mean duration of symptoms before surgery was 23 months (13-52 months). Operative treatment consisted of an arthroscopic inspection and debridement of the ECRB origin. Control tissues were obtained from biopsy of the ECRB capsule in two patients with osteochondritis dissecance of the capitellum who underwent arthroscopic resection of loose bodies. The tissue specimens were investigated immunohistochemically with antibodies delineating general (PGP9.5), sensory (SP/CGRP), and sympathetic (NPY) nerve patterns. RESULTS: In the non tendinosis control tissue, SP/CGRP and NPY immunoreactions were heterogeneously distributed in association with blood vessels. Pathologic evaluation of the biopsy tissue showed atypical fibrous granulation containing numerous vessels and nerve structures in all eight patients. Marked reactions to PGP 9.5 took the form of nerve fibers associated with arteries and arterioles in the atypical granulation. Most of the perivascular innervation was found to express NPY. The immunoreactions for SP and CGRP were invariably weak. CONCLUSION: Increased perivascular sympathetic innervation accompanied with loss of sensory innervation at the undersurface of the ECRB tendon may play a role in chronic pain generation in recalcitrant tennis elbow. LEVEL OF EVIDENCE: Diagnostic, Level IV. PMID- 23674349 TI - EGFR: tale of the C-terminal tail. AB - The carboxy terminal tail of epidermal growth factor receptor (EGFR) plays a critical role in the regulation of the enzyme activity of the kinase. There is a good structural model for the mechanism by which the C-terminal tail proximal to the kinase domain contributes to the negative regulation of the activity. Its conformation in the active state, conversely, has remained elusive due to its dynamic nature. A recently published structure of EGFR kinase domain shows the conformation of the proximal C-terminal tail in the active kinase. Analysis of this conformational state of the C-terminal tail is presented, and some of the mutagenesis data is revisited. PMID- 23674350 TI - Trikatu, a herbal compound that suppresses monosodium urate crystal-induced inflammation in rats, an experimental model for acute gouty arthritis. AB - Gout is an inflammatory joint disorder characterized by hyperuricaemia and precipitation of monosodium urate crystals in the joints. In the present study, we aimed to investigate the anti-inflammatory effect of trikatu, a herbal compound in monosodium urate crystal-induced inflammation in rats, an experimental model for acute gouty arthritis. Paw volume and levels/activities of lysosomal enzymes, lipid peroxidation, anti-oxidant status and histopathological examination of ankle joints were determined in control and monosodium urate crystal-induced rats. In addition, analgesic (acetic acid-induced writhing response), anti-pyretic (yeast-induced pyrexia) and gastric ulceration effects were tested. The levels of lysosomal enzymes, lipid peroxidation and paw volume were significantly increased, and anti-oxidant status was found to be reduced in monosodium urate crystal-induced rats, whereas the biochemical changes were reverted to near normal levels upon trikatu (1000 mg/kg b.wt) administration. The trikatu has also been found to exhibit significant analgesic and anti-pyretic effects with the absence of gastric damage. In conclusion, the present results clearly indicated that trikatu exert a potent anti-inflammatory effect against monosodium urate crystal-induced inflammation in rats in association with analgesic and anti-pyretic effects in the absence of gastrointestinal damage. PMID- 23674351 TI - Without integrated care within five years we risk another Mid Staffs, warns government. PMID- 23674352 TI - Sorafenib and HDAC inhibitors synergize with TRAIL to kill tumor cells. AB - The present studies were designed to compare and contrast the abilities of TRAIL (death receptor agonist) and obatoclax (BCL-2 family inhibitor) to enhance sorafenib + HDAC inhibitor toxicity in GI tumor cells. Sorafenib and HDAC inhibitor treatment required expression of CD95 to kill GI tumor cells in vitro and in vivo. In cells lacking CD95 expression, TRAIL treatment, and to a lesser extent obatoclax, enhanced the lethal effects of sorafenib + HDAC inhibitor exposure. In hepatoma cells expressing CD95 a similar data pattern emerged with respect to the actions of TRAIL. Downstream of the death receptor the ability of TRAIL to enhance cell killing correlated with reduced AKT, ERK1/2, p70 S6K, and mTOR activity and enhanced cleavage of pro-caspase 3 and reduced expression of MCL-1 and BCL-XL. Over-expression of BCL-XL or MCL-1 or expression of dominant negative pro-caspase 9 protected cells from drug toxicity. Expression of activated AKT, p70 S6K, mTOR, and to a lesser extent MEK1EE also protected cells that correlated with maintained c-FLIP-s expression, reduced BIM expression, and increased BAD phosphorylation. In vivo sorafenib + HDAC inhibitor toxicity against tumors was increased in a greater than additive fashion by TRAIL. Collectively, our data argue that TRAIL, rather than obatoclax, is the most efficacious agent at promoting sorafenib + HDAC inhibitor lethality. PMID- 23674354 TI - Ontogenetic patterns of morphological variation in the ectocranial human vault. AB - The skull is considered a modular structure in which different parts are influenced by different factors and, as a result, achieve adult shape at different ages. Previous studies have suggested that the basicranium presents a modular pattern that distinguishes sagittal and lateral parts, probably affected by the brain and masticatory structures, respectively. The vault of modern humans, in contrast, has been considered as a highly integrated system mainly influenced by brain growth. Here, we explored developmental shape variation in sagittal and lateral ectocranial vault in humans in order to assess if both regions are ontogenetically dissociated. We used a sample of 135 cranial computed tomography images from 0 to 31 ages. Landmarks and semilandmarks were collected on sagittal and lateral regions and geometric morphometric techniques were applied separately for each region. On the shape coordinates, we used Goodall's F test in order to assess the age when the adult configuration is attained. Principal component analysis enabled us to evaluate shape variation during ontogeny. Results indicated that both sagittal and lateral structures attain adult shape at early adolescence. Both regions express coordinated shape modifications probably due to shared developmental factors. It is concluded that masticatory muscles may not exert a strong enough influence to produce independent variation in the lateral traits. Thus, it is likely that the brain integrates sagittal and lateral parts of the vault across human ontogeny. PMID- 23674353 TI - An inter-order horizontal gene transfer event enables the catabolism of compatible solutes by Colwellia psychrerythraea 34H. AB - Colwellia is a genus of mostly psychrophilic halophilic Gammaproteobacteria frequently isolated from polar marine sediments and sea ice. In exploring the capacity of Colwellia psychrerythraea 34H to survive and grow in the liquid brines of sea ice, we detected a duplicated 37 kbp genomic island in its genome based on the abnormally high G + C content. This island contains an operon encoding for heterotetrameric sarcosine oxidase and is located adjacent to several genes used in the serial demethylation of glycine betaine, a compatible solute commonly used for osmoregulation, to dimethylglycine, sarcosine, and glycine. Molecular clock inferences of important events in the adaptation of C. psychrerythraea 34H to compatible solute utilization reflect the geological evolution of the polar regions. Validating genomic predictions, C. psychrerythraea 34H was shown to grow on defined media containing either choline or glycine betaine, and on a medium with sarcosine as the sole organic source of carbon and nitrogen. Growth by 8 of 9 tested Colwellia species on a newly developed sarcosine-based defined medium suggested that the ability to catabolize glycine betaine (the catabolic precursor of sarcosine) is likely widespread in the genus Colwellia. This capacity likely provides a selective advantage to Colwellia species in cold, salty environments like sea ice, and may have contributed to the ability of Colwellia to invade these extreme niches. PMID- 23674355 TI - On the state of scientific English and how to improve it--part 2: define what you mean. PMID- 23674356 TI - Coiled-coil motifs enhance the toxicity of polyQ proteins (comment on DOI 10.1002/bies.201300001). PMID- 23674361 TI - Preoperative serum albumin levels predict 1-year postoperative survival of patients undergoing heart transplantation. AB - BACKGROUND: Serum albumin concentration has been recognized as a marker of nutrition, severity of inflammation, and hepatic function in patients with various chronic diseases. The purpose of this study was to investigate the impact of pretransplant serum albumin concentration on post-transplant outcome in heart transplant recipients. METHODS AND RESULTS: Preoperative laboratory variables, including albumin concentration and donor-related information, were obtained from 822 consecutive patients undergoing heart transplant at Columbia University Medical Center between 1999 and 2010. The association between pretransplant albumin concentration and post-transplant 1-year survival was analyzed. Available data from the United Network for Organ Sharing (n=13671) were also analyzed to evaluate the impact of preoperative albumin levels on post-transplant outcome. In our cohort, multivariable analysis revealed that preoperative albumin (mg/dL; hazard ratio, 0.46; P<0.0001) and preoperative total bilirubin (mg/dL; hazard ratio, 1.26; P=0.0002) were associated with post-transplant 1-year mortality. This implied that for every 1 mg/dL increase in albumin concentration, the post transplant 1-year mortality rate decreased by 54%. The Kaplan-Meier analysis based on our patients cohort and the United Network for Organ Sharing dataset showed lower survival rate at 1-year post-transplant in patients with albumin levels <= 3.5 mg/dL compared with those with >3.5 mg/dL (our patients, 91.3 versus 72.4%; P<0.0001; United Network for Organ Sharing, 88.4 versus 84.8%; P<0.0001). CONCLUSIONS: Pretransplant serum albumin concentration is a strong prognostic marker for post-transplant survival in heart transplant recipients. PMID- 23674363 TI - The impact of renal tubular damage, as assessed by urinary beta2-microglobulin creatinine ratio, on cardiac prognosis in patients with chronic heart failure. AB - BACKGROUND: Renal dysfunction was reported to be closely associated with clinical outcomes in patients with chronic heart failure (CHF). Renal tubulointerstitial damage has been shown to be an important factor in the development of renal dysfunction as well as glomerular damage. However, the impact of renal tubular damage on clinical outcomes in patients with CHF remains to be determined. METHODS AND RESULTS: Urinary beta2-microglobulin-creatinine ratio was measured in 315 patients with CHF. Renal tubular damage was defined as a urinary beta2 microglobulin-creatinine ratio >= 300 MUg/g, as previously reported. Patients were prospectively followed up for a median period of 1097 days. There were 91 cardiac events, including 16 cardiac deaths and 75 rehospitalizations for worsening heart failure. Log10 urinary beta2-microglobulin-creatinine ratio was increased with worsening New York Heart Association functional class. Multivariate analysis revealed that renal tubular damage was an independent predictor of cardiac events. Kaplan-Meier analysis demonstrated that the rate of cardiac events was higher in patients with renal tubular damage compared with those without it. Patients were divided into 4 groups according to the presence of chronic kidney disease and renal tubular damage. The Cox proportional hazard analysis revealed that comorbidity of chronic kidney disease and renal tubular damage was associated with the highest risk for cardiac events compared with other groups. CONCLUSIONS: Renal tubular damage was related to the severity of heart failure and was associated with poor outcomes in patients with CHF. Renal tubular damage could add clinical information to chronic kidney disease in patients with CHF. PMID- 23674362 TI - Preoperative INTERMACS profiles determine postoperative outcomes in critically ill patients undergoing emergency heart transplantation: analysis of the Spanish National Heart Transplant Registry. AB - BACKGROUND: Postoperative outcomes of patients with advanced heart failure undergoing ventricular assist device implantation are strongly influenced by their preoperative Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles. We sought to investigate whether a similar association exists in patients undergoing emergency heart transplantation. METHODS AND RESULTS: By means of the Spanish National Heart Transplant Registry database, we identified 704 adult patients treated with emergency heart transplantation in 15 Spanish centers between 2000 and 2009. Post-transplant outcomes were analyzed pertaining to patient preoperative INTERMACS profiles, which were retrospectively assigned by 2 blinded cardiologists. Before transplantation, INTERMACS profile 1 (critical cardiogenic shock) was present in 207 patients, INTERMACS profile 2 (progressive decline) in 291, INTERMACS profile 3 (inotropic dependence) in 176, and INTERMACS profile 4 (resting symptoms) was present in 30 patients. In-hospital postoperative mortality rates were, respectively, 43%, 26.8%, and 18% in patients with profiles 1, 2, and 3 to 4 (P<0.001). INTERMACS 1 patients also presented the highest incidence of primary graft failure (1: 31.3%, 2: 22.3%, 3-4: 21.8%; P=0.03) and postoperative need for dialysis (1: 33.2%, 2: 18.9%, 3-4: 21.5%; P<0.001). Adjusted odds-ratios for in hospital postoperative mortality were 4.38 (95% confidence interval, 2.51-7.66) for profile 1 versus 3 to 4, 2.49 (95% confidence interval, 1.56-3.97) for profile 1 versus 2, and 1.76 (95% confidence interval, 1.02-3.03) for profile 2 versus 3 to 4. Long-term survival after hospital discharge was not influenced by preoperative INTERMACS profiles. CONCLUSIONS: Preoperative INTERMACS profiles determine outcomes after emergency heart transplantation. Results call for a change in policies related to the management of heart transplant candidates presenting with INTERMACS profiles 1 and 2. PMID- 23674364 TI - CT stress perfusion imaging for detection of haemodynamically relevant coronary stenosis as defined by FFR. AB - OBJECTIVES: To evaluate the diagnostic accuracy (DA) of CT-myocardial perfusion imaging (CT-MPI) and a combined approach with CT angiography (CTA) for the detection of haemodynamically relevant coronary stenoses in patients with both suspected and known coronary artery disease. DESIGN: Prospective, non-randomised, diagnostic study. SETTING: Academic hospital-based study. PATIENTS: 65 patients (42 men age 70.4+/-9) with typical or atypical chest pain. INTERVENTIONS: CTA and CT-MPI with adenosine stress using a fast dual-source CT system. At subsequent invasive angiography, FFR measurement was performed in coronary arteries to define haemodynamic relevance of stenosis. MAIN OUTCOME MEASURES: We tried to correlate haemodynamically relevant stenosis (FFR < 0.80) to a reduced myocardial blood flow (MBF) as assessed by CT-MPI and determined the DA of CT-MPI for the detection of haemodynamically relevant stenosis. RESULTS: Sensitivity and negative predictive value (NPV) of CTA alone were very high (100% respectively) for ruling out haemodynamically significant stenoses, specificity, Positive predictive value (PPV) and DA were low (43.8, 67.3 and 72%, respectively). CT-MPI showed a significant increase in specificity, PPV and DA for the detection of haemodynamically relevant stenoses (65.6, 74.4 and 81.5%, respectively) with persisting high sensitivity and NPV for ruling out haemodynamically relevant stenoses (97% and 95.5% respectively). The combination of CTA and CT-MPI showed no further increase in detection of haemodynamically significant stenosis compared with CT-MPI alone. CONCLUSIONS: Our data suggest that CT-MPI permits the detection of haemodynamically relevant coronary artery stenoses with a moderate DA. CT may, therefore, allow the simultaneous assessment of both coronary morphology and function. PMID- 23674365 TI - A systematic review and meta-analysis of genotype-phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations. AB - BACKGROUND: The genetic basis of familial hypertrophic cardiomyopathy (HCM) is well described, but the relation between genotype and clinical phenotype is still poorly characterised. OBJECTIVE: To summarise and critically review the current literature on genotype-phenotype associations in patients with HCM and to perform a meta-analysis on selected clinical features. DATA SOURCES: PubMed/Medline was searched up to January 2013. Retrieved articles were checked for additional publications. SELECTION CRITERIA: Observational, cross-sectional and prospectively designed English language human studies that analysed the relationship between the presence of mutations in sarcomeric protein genes and clinical parameters. DATA EXTRACTION AND ANALYSIS: The pooled analysis was confined to studies reporting on cohorts of unrelated and consecutive patients in which at least two sarcomere genes were sequenced. A random effect meta regression model was used to determine the overall prevalence of predefined clinical features: age at presentation, gender, family history of HCM, family history of sudden cardiac death (SCD), and maximum left ventricular wall thickness (MLVWT). The I(2) statistic was used to estimate the proportion of total variability in the prevalence data attributable to the heterogeneity between studies. RESULTS: Eighteen publications (corresponding to a total of 2459 patients) were selected for the pooled analysis. The presence of any sarcomere gene mutation was associated with a younger age at presentation (38.4 vs 46.0 years, p<0.0005), a family history of HCM (50.6% vs 23.1%, p<0.0005), a family history of SCD (27.0% vs 14.9%, p<0.0005) and greater MLVWT (21.0 vs 19.3 mm, p=0.03). There were no differences when the two most frequently affected genes, MYBPC3 and MYH7, were compared. A total of 53 family studies were also included in the review. These were characterised by pronounced variability and the majority of studies reporting on outcomes analysed small cross-sectional cohorts and were unsuitable for pooled analyses. CONCLUSIONS: The presence of a mutation in any sarcomere gene is associated with a number of clinical features. The heterogeneous nature of the disease and the inconsistency of study design precludes the establishment of more precise genotype-phenotype relationships. Large scale studies examining the relation between genotype, disease severity, and prognosis are required. PMID- 23674366 TI - Cytoplasmic reactive oxygen species and SOD1 regulate bone mass during mechanical unloading. AB - Oxidative stress contributes to the pathogenesis of age-related diseases as well as bone fragility. Our previous study demonstrated that copper/zinc superoxide dismutase (Sod1)-deficient mice exhibit the induction of intracellular reactive oxygen species (ROS) and bone fragility resulting from low-turnover bone loss and impaired collagen cross-linking (Nojiri et al. J Bone Miner Res. 2011;26:2682 94). Mechanical stress also plays an important role in the maintenance of homeostasis in bone tissue. However, the molecular links between oxidative and mechanical stresses in bone tissue have not been fully elucidated. We herein report that mechanical unloading significantly increased intracellular ROS production and the specific upregulation of Sod1 in bone tissue in a tail suspension experiment. We also reveal that Sod1 loss exacerbated bone loss via reduced osteoblastic abilities during mechanical unloading. Interestingly, we found that the administration of an antioxidant, vitamin C, significantly attenuated bone loss during unloading. These results indicate that mechanical unloading, in part, regulates bone mass via intracellular ROS generation and the Sod1 expression, suggesting that activating Sod1 may be a preventive strategy for ameliorating mechanical unloading-induced bone loss. PMID- 23674367 TI - Treating eating disorders over the internet: a systematic review and future research directions. AB - OBJECTIVE: To review the literature regarding internet-based treatment of eating disorders (ED). METHOD: Relevant studies were identified by searching electronic databases (including Medline, Embase, PsycInfo, and Web of Science). Eligible studies evaluated an internet-based treatment for ED, or an ED treatment that included at least one internet-based component. RESULTS: Twenty-one studies were included. Methodological quality varied. Internet-based treatments were superior to waiting lists in reducing ED psychopathology, frequency of binge eating and purging, and in improving (ED-related) quality of life. Internet-based treatment was more effective for individuals with less comorbid psychopathology, binge eating as opposed to restrictive problems, and individuals with binge eating disorder as opposed to bulimia nervosa. Higher levels of compliance were related to more improvements in ED symptoms. Study dropout ranged from 5.3 to 76.8%. Inclusion of face-to-face assessments and therapist support seemed to enhance study compliance. Overall, the internet can be considered an acceptable vehicle for delivering ED treatment. DISCUSSION: Future research should determine the utility of internet-based treatment by comparing them to face-to-face treatment. Research should furthermore focus on unraveling predictors and mediators of treatment outcome, compliance, and dropout, respectively. Studies with good methodological quality are needed with reports according to CONSORT guidelines. PMID- 23674368 TI - Methylation-specific digital karyotyping of HPV16E6E7-expressing human keratinocytes identifies novel methylation events in cervical carcinogenesis. AB - Transformation of epithelial cells by high-risk human papillomavirus (hrHPV) types can lead to anogenital carcinomas, particularly cervical cancer, and oropharyngeal cancers. This process is associated with DNA methylation alterations, often affecting tumour suppressor gene expression. This study aimed to comprehensively unravel genome-wide DNA methylation events linked to a transforming hrHPV-infection, which is driven by deregulated expression of the viral oncogenes E6 and E7 in dividing cells. Primary human keratinocytes transduced with HPV16E6E7 and their untransduced counterparts were subjected to methylation-specific digital karyotyping (MSDK) to screen for genome-wide DNA methylation changes at different stages of HPV-induced transformation. Integration of the obtained methylation profiles with genome-wide gene expression patterns of cervical carcinomas identified 34 genes with increased methylation in HPV-transformed cells and reduced expression in cervical carcinomas. For 12 genes (CLIC3, CREB3L1, FAM19A4, LFNG, LHX1, MRC2, NKX2-8, NPTX-1, PHACTR3, PRDM14, SOST and TNFSF13) specific methylation in HPV-containing cell lines was confirmed by semi-quantitative methylation-specific PCR. Subsequent analysis of FAM19A4, LHX1, NKX2-8, NPTX-1, PHACTR3 and PRDM14 in cervical tissue specimens showed increasing methylation levels for all genes with disease progression. All six genes were frequently methylated in cervical carcinomas, with highest frequencies (up to 100%) seen for FAM19A4, PHACTR3 and PRDM14. Analysis of hrHPV-positive cervical scrapes revealed significantly increased methylation levels of the latter three genes in women with high-grade cervical disease compared to controls. In conclusion, MSDK analysis of HPV16-transduced keratinocytes at different stages of HPV-induced transformation resulted in the identification of novel DNA methylation events, involving FAM19A4, LHX1, NKX2-8, PHACTR3 and PRDM14 genes in cervical carcinogenesis. These genes may provide promising triage markers to assess the presence of (pre)cancerous cervical lesions in hrHPV-positive women. PMID- 23674369 TI - Insight into the 3D structure of ADP-glucose pyrophosphorylase from rice (Oryza sativa L.). AB - ADP-glucose pyrophosphorylase (E.C. 2.7.7.27; AGPase) is a key regulatory enzyme that catalyzes the rate-limiting step of starch biosynthesis in higher plants. AGPase consists of pair of small (SS) and large (LS) subunits thereby constituting a heterotetrameric structure. No crystal structure of the native heterotetrameric enzyme is available for any species, thus limiting the complete understanding of structure-function relationships of this enzyme. In this study, an attempt was made to deduce the heterotetrameric assembly of AGPase in rice. Homology modeling of the three-dimensional structure of the LS and SS was performed using the Swiss Model Server, and the models were evaluated and docked using GRAMM-X to obtain the stable heterodimer orientation (LS as receptor and SS as ligand) and then the heterotetrameric orientation. The initial heterotetrameric orientation was further refined using the RosettaDock Server. MD simulation of the representative heterodimer/tetramer was performed using NAMD, which indicated that the tail-to-tail interaction of LS and SS was more stable than the head-to-head orientation, and the heterotetramer energy was also minimized to -767,011 kcal mol(-1). Subunit-subunit interaction studies were then carried out using the programs NACCESS and Dimplot. A total of 57 interface residues were listed in SS and 63 in LS. The residues plotted by Dimplot were similar to those listed by NACCESS. Multiple sequence alignment of the sequences of LS and SS from potato, maize and rice validated the interactions inferred in the study. RMSD of 1.093 A was obtained on superimposition of the deduced heterotetramer on the template homo-tetramer (1YP2), showing the similarity between the two structures. PMID- 23674370 TI - Structural and energetic properties of canonical and oxidized telomeric complexes studied by molecular dynamics simulations. AB - The structural and energetic properties of native and oxidized telomeric complexes were defined by means of molecular dynamic (MD) simulations. As a starting point, the experimental conformation of B-DNA d(GpTpTpApGpGpGpTpTpApGpGpG) oligomer bound to human protein telomeric repeat binding factor 1 (TRF1) was used. The influence on the stability of the telomeric complex of the presence of 8-oxoguanine (8oxoG) in the central telomeric triad (CTT) was estimated based on trajectories collected during 130 ns MD runs. The data obtained indicate that the system analyzed is highly sensitive to the presence of oxidative damage in the CTT of the B-DNA telomeric sequence. The most important changes were observed in the immediate vicinity of the 8-oxoguanine molecule. The significantly higher mobility of arginine 425 interacting directly with the oxidized guanine molecule has a large influence on the structural, dynamic and energetic properties of neighboring amino acids. Local changes observed for individual hydrogen bonded interactions localized in the major groove of B-DNA also have significant impact on the properties of hydrophobic clusters, which are the second type of force responsible for stability of the studied bio-system. All the changes reported in detail here unambiguously indicate a significant decrease in telomer binding affinity after oxidation. PMID- 23674371 TI - Electron-induced reductive debromination of 2,3,4-tribromodiphenyl ether: a computational study. AB - To better understand the mechanism of the electron induced elimination of the bromide anion, we examined at the B3LYP/6-31+G(d) level electron capture by 2,3,4 tribromodiphenyl ether (BDE-21) followed by the release of the bromide anion and a radical. Both the geometry and energy of the BDE-21 neutral and its possible anionic states were studied. A significant relationship was found between the total energy and the length of the C-Br bonds by the analysis of the potential energy surface for the anionic states. Debromination preference for the bromine substituted positions was theoretically evaluated as meta-Br > ortho-Br > para Br. The reaction profiles of the electron-induced debromination of BDE-21 demonstrated that, in general, the presence of a solvent makes the electron induced reductive debromination of BDE-21 significantly more advantageous, and the stabilization effect of the solvent on the reaction intermediates would make the electron attachment and dissociation relatively effective in comparison with the results from the gas-phase calculations. PMID- 23674372 TI - Endosalpingiosis in peritoneal washings in women with benign gynecologic conditions: thirty-eight cases confirmed with paired box-8 immunohistochemical staining and correlation with surgical biopsy findings. AB - BACKGROUND: To better define the cytomorphologic spectrum of endosalpingiosis in peritoneal washings (PWs) and thereby facilitate their distinction from well differentiated serous carcinoma, the authors examined PWs from women who underwent surgery and pathologic staging of lesions other than Mullerian malignancies and correlated the findings with surgical specimens. METHODS: This was a retrospective review of medical records and PW specimens from 100 consecutive patients who had PWs coded as both "endosalpingiosis" and "negative for carcinoma" between 2002 and 2012. Thirty-eight of these patients had no gynecologic malignancies. Specimens had been prepared using cytocentrifugation and were stained using the Papanicolaou method. The cytologic findings evaluated were cell arrangement, number of cell groups per case, cellular atypia, and psammoma bodies. Smears also were assessed for paired box-8 (PAX8) immunostaining. The authors compared patients' staging biopsy findings with the findings from a review of the PWs. RESULTS: PW specimens from 35 of 38 patients (92%) exhibited classic endosalpingiosis features: tubular or small branching papillary structures, some with psammoma bodies. Specimens from the 3 remaining patients displayed nonclassic features consistent with dislodged fallopian tube epithelium or endometriosis. From 2 to 20 clusters per slide and from 4 to 50 groups per case were identified. In a few cases, some cell clusters exhibited up to moderate cytologic atypia. Surgical findings included endometriosis, endosalpingiosis, both endometriosis and endosalpingiosis (12 patients; 31.6%), and a variety of unrelated pelvic lesions. All cases were PAX8-positive, confirming their Mullerian origin. CONCLUSIONS: Endosalpingiosis in PWs can be diagnostically challenging. Awareness of intraoperative techniques and correlation with surgical biopsy findings are necessary to avoid a misdiagnosis of malignancy. PMID- 23674374 TI - Population management of diabetes in a high-need urban community in the Bronx: the experience of Montefiore Medical Center. AB - PURPOSE: The purpose of this study is to examine the impact of a Care Management Organization (CMO) Diabetes Disease Management Program (DDMP) in improving diabetes outcomes among high-risk patients with type 2 diabetes (T2DM) in the Bronx, New York. METHODS: An interventional, nonrandomized study design was used to assess the effectiveness of the DDMP. Patients older than 18 years who had T2DM and an A1C persistently 8% or greater or with a cardiovascular comorbidity were characterized as high risk and received intensive disease management. Patients served as their own controls, with data collection and analysis occurring 12 months prior to and 12 months after enrollment in DDMP. Data collection included screening rates for A1C, low-density lipoprotein (LDL) cholesterol, depression, smoking status, and annual influenza vaccine administration. Changes in A1C and LDL cholesterol were also analyzed. Statistical analyses were conducted using Minitab. McNemar's chi-square and paired t tests were used to assess within-group changes from baseline to final outcomes. RESULTS: Significant improvements in screening rates for A1C, LDL, depression, smoking status, and annual influenza vaccine administration were found among high-risk/intensively managed patients in the DDMP. Improvements in clinical measures were also achieved in this group. Provider and patient satisfaction surveys were positive, with 92% of patients believing that the program helped them better understand their disease. CONCLUSIONS: A DDMP among high-risk patients has shown promise in improving the quality of care for patients with diabetes. This program has relevance for other integrated delivery systems that are developing accountable care approaches. PMID- 23674373 TI - Quantitative assessment of CA1 local circuits: knowledge base for interneuron pyramidal cell connectivity. AB - In this work, through a detailed literature review, data-mining, and extensive calculations, we provide a current, quantitative estimate of the cellular and synaptic constituents of the CA1 region of the rat hippocampus. Beyond estimating the cell numbers of GABAergic interneuron types, we calculate their convergence onto CA1 pyramidal cells and compare it with the known input synapses on CA1 pyramidal cells. The convergence calculation and comparison are also made for excitatory inputs to CA1 pyramidal cells. In addition, we provide a summary of the excitatory and inhibitory convergence onto interneurons. The quantitative knowledge base assembled and synthesized here forms the basis for data-driven, large-scale computational modeling efforts. Additionally, this work highlights specific instances where the available data are incomplete, which should inspire targeted experimental projects toward a more complete quantification of the CA1 neurons and their connectivity. PMID- 23674375 TI - Celiac disease in patients with type 1 diabetes: screening and diagnostic practices. AB - OBJECTIVE: The purpose of this study was to investigate screening practices for celiac disease in patients with type 1 diabetes across North America. The research question investigated was whether diabetes centers screen for celiac disease in type 1 diabetes more frequently than other facilities. RESEARCH DESIGN AND METHODS: A survey with 27 questions on screening practices for celiac disease in patients with type 1 diabetes was designed by experts in celiac disease and diabetes. Surveys were sent by email to diabetes educators and dietitians throughout the United States and Canada between December 2010 and May 2011. RESULTS: There were 514 respondents from 484 endocrine clinics, diabetes clinics, private practices, community nutrition centers, and inpatient centers. Thirty five percent of work locations screened for celiac disease, with endocrine clinics reporting screening at the highest frequency (80%). Tissue transglutaminase was the most common screening test used. The most frequently recommended treatment of confirmed celiac disease was a gluten-free diet. However, only 71% of respondents recommended biopsy in patients with positive serologies. Most respondents (55.3%) reported that the gluten-free diet resulted in symptom improvement in the majority of patients. CONCLUSIONS: Staff at endocrine clinics were more likely to suggest screening for celiac disease in patients with type 1 diabetes. Both low screening frequency as well as inconsistency in management of positive celiac disease serological tests indicated an increase in education regarding celiac disease in patients with type 1 diabetes is required. In addition uniform guidelines should be developed. PMID- 23674376 TI - Volume-outcomes relationship in the era of modern coronary intervention-results from the prospective multicenter German DES.DE Registry. AB - OBJECTIVE: We compare clinical outcomes among unselected patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES) stratified in categories of treating hospital PCI volume. BACKGROUND: Previous observational evidence suggests an inverse relation between hospital volume and patients' outcomes. However, there are no mid-term outcomes data with the use of DES. METHODS: We used data from DES.DE (German Drug-Eluting Stent) registry to compare in-hospital and 1-year outcomes among unselected patients. Primary endpoints at one year follow-up were the rate of major adverse cardiac and cerebrovascular events (MACCE) and target vessel revascularization (TVR). RESULTS: Between 2005 and 2006, 2,075 patients were treated in group I hospitals (<1,000 PCIs/year), 1,624 in group II hospitals (1,000-1,500 PCIs/year), and 1,790 in group III hospitals (>1,500 PCIs/year). Compared with group II and group III, group I allocation was associated with higher rates of overall hospital mortality (1.1% versus 0.2% versus 0.2%; P < 0.0001) and severe bleeding (1.0% versus 0.4% versus 0.5%; P < 0.05); similarly, poorer outcomes with respect to MACCE (7.2% versus 6.5% versus 4.7%; P < 0.01), stent thrombosis (5.2% versus 5.0% versus 3.0%; P < 0.01), and non-fatal stroke (1.5% versus 0.9% versus 0.7%; P < 0.05) were documented in group I. Conversely, TVR rates were highest in group II (10.2% versus 14.2% versus 11.7%; P < 0.01); these differences persisted after risk adjustment for heterogeneous baseline characteristics. CONCLUSIONS: In the era of modern coronary intervention technological advances such as DES have not offset the inverse relation between procedural volume and both in-hospital and 1 year outcomes after PCI. PMID- 23674377 TI - Development and validation of a LC-MS/MS method for the in vitro analysis of 1 hydroxymidazolam in human liver microsomes: application for determining CYP3A4 inhibition in complex matrix mixtures. AB - Complementary and alternative medicines (CAM) can affect the pharmacokinetics of anticancer drugs by interacting with the metabolizing enzyme cytochrome P450 (CYP) 3A4. To evaluate changes in the activity of CYP3A4 in patients, levels of 1 hydroxymidazolam in plasma are often determined with liquid chromatography quadrupole mass spectrometry (LC-MS/MS). However, validated LC-MS/MS methods to determine in vitro CYP3A4 inhibition in human liver microsomes are scarce and not optimized for evaluating CYP3A4 inhibition by CAM. The latter is necessary because CAM are often complex mixtures of numerous compounds that can interfere with the selective measurement of 1-hydroxymidazolam. Therefore, the aim was to validate and optimize an LC-MS/MS method for the adequate determination of CYP3A4 inhibition by CAM in human liver microsomes. After incubation of human liver microsomes with midazolam, liquid-liquid extraction with tert-butyl methyl ether was applied and dried samples were reconstituted in 50% methanol. These samples were injected onto a reversed-phase chromatography consisting of a Zorbax Extend C18 column (2.1 * 150 mm, 5.0 um particle size), connected to a triple quadrupole mass spectrometer with electrospray ionization. The described LC-MS/MS method was validated over linear range of 1.0-500 nm for 1-hydroxymidazolam. The results revealed good inter-assay accuracy (>=85% and <=115%) and within-day and between day precisions (coefficient of variation <= 4.43%). Furthermore, the applicability of this assay for the determination of CYP3A4 inhibition in complex matrix mixtures was successfully demonstrated in an in vitro experiment in which CYP3A4 inhibition by known CAM (beta-carotene, green tea, milk thistle and St. John's wort) was determined. PMID- 23674378 TI - Detecting intentional insulin omission for weight loss in girls with type 1 diabetes mellitus. AB - OBJECTIVE: Intentional insulin omission is a unique inappropriate compensatory behavior that occurs in patients with type 1 diabetes mellitus, mostly in females, who omit or restrict their required insulin doses in order to lose weight. Diagnosis of this underlying disorder is difficult. We aimed to use clinical and laboratory criteria to create an algorithm to assist in the detection of intentional insulin omission. METHOD: The distribution of HbA1c levels from 287 (181 females) patients with type 1 diabetes were used as reference. Data from 26 patients with type 1 diabetes and intentional insulin omission were analysed. The Weka (Waikato Environment for Knowledge Analysis) machine learning software, decision tree classifier with 10-fold cross validation was used to developed prediction models. Model performance was assessed by cross validation in a further 43 patients. RESULTS: Adolescents with intentional insulin omission were discriminated by: female sex, HbA1c>9.2%, more than 20% of HbA1c measurements above the 90th percentile, the mean of 3 highest delta HbA1c z scores>1.28, current age and age at diagnosis. The models developed showed good discrimination (sensitivity and specificity 0.88 and 0.74, respectively). The external test dataset revealed good performance of the model with a sensitivity and specificity of 1.00 and 0.97, respectively. DISCUSSION: Using data mining methods we developed a clinical prediction model to determine an individual's probability of intentionally omitting insulin. This model provides a decision support system for the detection of intentional insulin omission for weight loss in adolescent females with type 1 diabetes mellitus. PMID- 23674379 TI - Abnormal propagation of calcium waves and ultrastructural remodeling in recessive catecholaminergic polymorphic ventricular tachycardia. AB - RATIONALE: The recessive form of catecholaminergic polymorphic ventricular tachycardia is caused by mutations in the cardiac calsequestrin-2 gene; this variant of catecholaminergic polymorphic ventricular tachycardia is less well characterized than the autosomal-dominant form caused by mutations in the ryanodine receptor-2 gene. OBJECTIVE: We characterized the intracellular Ca2+ homeostasis, electrophysiological properties, and ultrastructural features of the Ca2+ release units in the homozygous calsequestrin 2-R33Q knock-in mouse model (R33Q) R33Q knock-in mouse model. METHODS AND RESULTS: We studied isolated R33Q and wild-type ventricular myocytes and observed properties not previously identified in a catecholaminergic polymorphic ventricular tachycardia model. As compared with wild-type cells, R33Q myocytes (1) show spontaneous Ca2+ waves unable to propagate as cell-wide waves; (2) show smaller Ca2+sparks with shortened coupling intervals, suggesting a reduced refractoriness of Ca2+ release events; (3) have a reduction of the area of membrane contact, of the junctions between junctional sarcoplasmic reticulum and T tubules (couplons), and of junctional sarcoplasmic reticulum volume; (4) have a propensity to develop phase 2 to 4 afterdepolarizations that can elicit triggered beats; and (5) involve viral gene transfer with wild-type cardiac calsequestrin-2 that is able to normalize structural abnormalities and to restore cell-wide calcium wave propagation. CONCLUSIONS: Our data show that homozygous cardiac calsequestrin-2 R33Q myocytes develop spontaneous Ca2+ release events with a broad range of intervals coupled to preceding beats, leading to the formation of early and delayed afterdepolarizations. They also display a major disruption of the Ca2+ release unit architecture that leads to fragmentation of spontaneous Ca2+ waves. We propose that these 2 substrates in R33Q myocytes synergize to provide a new arrhythmogenic mechanism for catecholaminergic polymorphic ventricular tachycardia. PMID- 23674380 TI - Combined prospective United States clinical study data for the GORE((r)) HELEX((r)) septal occluder device. AB - OBJECTIVES: Our goal was to summarize the outcome for all subjects evaluated during a prospective clinical study in the United States with the GORE((r)) HELEX((r)) Septal Occluder for transcatheter repair of secundum atrial septal defects (ASD). BACKGROUND: The GORE((r)) HELEX((r)) Septal Occluder is currently utilized for repair of secundum ASD. No previous reports are available that summarize the combined clinical trial outcomes for this device. METHODS: In the United States between 1999 and 2009, 435 subjects were enrolled through the Feasibility, Pivotal, Continued Access, and Post-Approval Studies. All subjects enrolled through these studies were collectively reviewed as the "study cohort." Clinical success, defined as a composite evaluation of safety and efficacy, is reported for subjects at the 12-month follow-up period. RESULTS: Of the 435 device subjects enrolled in the four clinical studies, 412 subjects were eligible for follow-up. Device efficacy, as represented by clinical closure at 12 months, was achieved in 98.3% of subjects, and in 99.5% of those receiving a device whose nominal diameter was greater or equal to twice the balloon sized defect diameter. Through 12 months following implantation, freedom from major adverse events was 95.2%. Together, these results yield a 93.0% composite clinical success at 12 months following the index procedure. CONCLUSIONS: The combined clinical study cohort represents the largest prospective, controlled clinical trial data set available for the GORE((r)) HELEX((r)) Septal Occluder. The clinical data presented in this report reaffirm the safety and efficacy of the GORE((r)) HELEX((r)) Septal Occluder when utilized for secundum atrial septal defect repair. PMID- 23674381 TI - Osteogenesis imperfecta without features of type V caused by a mutation in the IFITM5 gene. AB - Osteogenesis imperfecta (OI) is typically caused by mutations in type 1 collagen genes, but in recent years new recessive and dominant forms caused by mutations in a plethora of different genes have been characterized. OI type V is a dominant form caused by the recurrent (c.-14C > T) mutation in the 5'UTR of the IFITM5 gene. The mutation adds five residues to the N-terminus of the IFITM5, but the pathophysiology of the disease remains to be elucidated. Typical clinical features present in the majority of OI type V patients include interosseous membrane calcification between the radius and ulna and between the tibia and fibula, radial head dislocation, and significant hyperplastic callus formation at the site of fractures. We report a 5-year-old child with clinical features of OI type III or severe OI type IV (characteristic facies, gray sclerae, typical fractures) and absence of classical features of OI type V with a de novo recurrent IFITM5 mutation (c.-14C > T), now typical of OI type V. This highlights the variability of OI caused by IFITM5 mutations and suggests screening for mutations in this gene in most cases of OI where type 1 collagen mutations are absent. PMID- 23674382 TI - Immunohistochemical analysis of E-cadherin and zeste homolog 2 expression in endoscopic ultrasound-guided fine-needle aspiration of pancreatic adenocarcinoma. AB - BACKGROUND: Recent studies have demonstrated that partial or complete loss of E cadherin (EC) and nuclear accumulation of zeste homolog 2 (EZH2) are hallmarks of poorly differentiated pancreatic adenocarcinoma (PAC). Depletion of EZH2 sensitizes cancer cells to chemotherapy in vitro. The objective of this study was to determine EC and EZH2 expression by immunohistochemistry (IHC) in samples obtained by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) as potential biomarkers for treatment and disease prognosis. METHODS: Thirty-eight EUS-FNA samples from patients with a PAC diagnosis were analyzed by IHC for EC and EZH2 expression. Seven corresponding surgical resection specimens were included in the study. The intensity of EZH2 and EC expression in PAC and in normal gastrointestinal pick-ups (internal positive control) was scored by using a 4-tier grading system. RESULTS: EC demonstrated a focal, weak-to-moderate decrease in 24 PAC samples. Complete loss of EC expression was observed in the poorly differentiated areas represented by single tumor cells. The average staining intensity of EC in samples of poorly differentiated PAC was significantly lower than that of moderately differentiated PAC samples (P = .0005). EZH2 was variably positive in 31 of 38 PAC samples. The average staining intensity of EZH2 in moderately and poorly differentiated PACs did not differ significantly (P = .81). CONCLUSIONS: EC and EZH2 expression was determined reliably by IHC on paraffin sections of EUS-FNA cell block specimens. The current results were consistent with prior reports indicating a decrease or loss of EC expression in poorly differentiated PAC. However, EZH2 expression did not always correlate inversely with EC expression and was more heterogeneous. PMID- 23674383 TI - A role for prolyl hydroxylase domain proteins in hippocampal synaptic plasticity. AB - Hypoxia-inducible factors (HIFs) are key transcriptional regulators that play a major role in oxygen homeostasis. HIF activity is tightly regulated by oxygen dependent hydroxylases, which additionally require iron and 2-oxoglutarate as cofactors. Inhibition of these enzymes has become a novel target to modulate the hypoxic response for therapeutic benefit. Inhibition of prolyl-4-hydroxylase domains (PHDs) have been shown to delay neuronal cell death and protect against ischemic injury in the hippocampus. In this study we have examined the effects of prolyl hydroxylase inhibition on synaptic transmission and plasticity in the hippocampus. Field excitatory postsynaptic potentials (fEPSPs) and excitatory postsynaptic currents (EPSCs) were elicited by stimulation of the Schaffer collateral pathway in the CA1 region of the hippocampus. Treatment of rat hippocampal slices with low concentrations (10 uM) of the iron chelator deferosoxamine (DFO) or the 2-oxoglutarate analogue dimethyloxalyl glycine (DMOG) had no effect on fEPSP. In contrast, application of 1 mM DMOG resulted in a significant decrease in fEPSP slope. Antagonism of the NMDA receptor attenuated the effects of DMOG on baseline synaptic signalling. In rat hippocampal slices pretreated with DMOG and DFO the induction of long-term potentiation (LTP) by tetanic stimulation was strongly impaired. Similarly, neuronal knockout of the single PHD family member PHD2 prevented murine hippocampal LTP. Preconditioning of PHD2 deficient hippocampi with either DMOG, DFO, or the PHD specific inhibitor JNJ-42041935, did not further decrease LTP suggesting that DMOG and DFO influences synaptic plasticity primarily by inhibiting PHDs rather than unspecific effects. These findings provide striking evidence for a modulatory role of PHD proteins on synaptic plasticity in the hippocampus. PMID- 23674384 TI - Correcting for rater bias in scores on a continuous scale, with application to breast density. AB - Existing literature on inter-rater reliability focuses on quantifying the disagreement between raters. In this paper, we introduce a method to correct for inter-rater disagreement (or observer bias), where raters are assigning scores on a continuous scale. To do this, we propose a two-stage approach. In the first stage, we standardise the distributions of rater scores to account for each rater's subjective interpretation of the continuous scale. In the second stage, we correct for case-mix differences between raters by exploiting pairwise information where two raters have read the same entity on a case. We illustrate the use of our procedure on clinicians' visual assessments of breast density (a risk factor for breast cancer). After applying our procedure, 229 out of 1398 women who were originally classified as high density were re-classified as non high density, and 382 out of 12 348 women were re-classified from non-high to high density. A simulation study also demonstrates good performance of the proposed method over a range of scenarios. PMID- 23674385 TI - Single-stent crossover technique from distal unprotected left main coronary artery to the left circumflex artery. AB - OBJECTIVES: To report the clinical outcomes of single-stenting from distal unprotected left main coronary artery (LMCA) to the left circumflex artery (LCx). BACKGROUND: Percutaneous coronary intervention of distal LMCA is usually performed by stenting into the left anterior descending artery (LAD). In some cases, stenting from LMCA to LCx alone is performed. METHODS: Between April 2002 and April 2011, single-stenting with drug-eluting stents for distal unprotected LMCA disease was performed in 584 patients. Thirty-one patients underwent LMCA LCx stenting, who were compared with the remaining 553 LMCA-LAD stented patients. RESULTS: At 3-year follow-up, there were no significant differences between LMCA LCx and LMCA-LAD stenting groups in major adverse cardiac events (24.1% vs. 19.6%; P = 0.540), cardiac death, and myocardial infarction. A trend toward higher target lesion revascularization (TLR) in the LMCA-LCx stenting group was noted. This was significant when the stented branch was only considered (18.2% vs. 3.0%; P < 0.001). In both TLR subgroups, LCx ostium was frequently involved (83.3% in LMCA-LCx vs. 66.2% in LMCA-LAD TLR subgroups; P = 0.39). The LAD ostium was more frequently involved in LMCA-LCx TLR subgroup (83.3% vs. 21.0%; P < 0.001). On the multivariable Cox regression analysis, LMCA-LCx stenting was an independent predictor of TLR for restenosis at the ostium of the stented branch (HR 6.49; 95% CI 2.27-18.53; P < 0.001). CONCLUSIONS: TLR rate at the LCx ostium is high irrespective of LMCA-LCx or LMCA-LAD stenting. The former also seems to be associated with high TLR at the LAD ostium. It may therefore be important to evaluate alternative strategies for treating distal LMCA disease that extends into the LCx but not LAD. PMID- 23674386 TI - SNCA: major genetic modifier of age at onset of Parkinson's disease. AB - Age at onset serves as a predictor of progression and mortality in sporadic Parkinson's disease (PD). Therefore, the identification of genetic modifiers for age at onset might lead to a better understanding of disease pathogenesis. We performed multivariate linear regression analysis in 1396 sporadic PD patients assessing 21 single-nucleotide polymorphisms (SNPs) that have been previously suggested to be associated with sporadic PD. Moreover, a cumulative risk score was assigned to each patient and correlated with age at onset. We identified the rs356219 risk allele in the SNCA gene as significantly contributing to earlier age at onset. Neither one of the other 21 SNPs tested in this analysis nor the cumulative number of risk alleles showed a significant impact on PD onset. Because sequence variants in the SNCA gene are not only associated with autosomal dominantly inherited PD and increased susceptibility for sporadic PD but also have been found to modify the phenotype such as age at onset in both sporadic and various monogenic forms of PD, this gene serves as an outstanding target for further research on PD pathogenesis, which in return might provide potential therapeutic options. (c) 2013 Movement Disorder Society. PMID- 23674387 TI - Dopamine D1 receptor activity modulates object recognition memory consolidation in the perirhinal cortex but not in the hippocampus. AB - It has been proposed that distributed neuronal networks in the medial temporal lobe process different characteristics of a recognition event; the hippocampus has been associated with contextual recollection while the perirhinal cortex has been linked with familiarity. Here we show that D1 dopamine receptor activity in these two structures participates differentially in object recognition memory consolidation. The D1 receptor antagonist SCH23390 was infused bilaterally 15 min before a 5 min sample phase in either rats' perirhinal cortex or dorsal hippocampus, and they were tested 90 min for short-term memory or 24 h later for long-term memory. SCH23390 impaired long-term memory when infused in the perirhinal cortex but not when infused in the hippocampus. Conversely, when the D1 receptor agonist SKF38393 was infused 10 min before a 3 min sample phase in the perirhinal cortex, long-term memory was enhanced, however, this was not observed when the D1 agonist was infused in the hippocampus. Short-term memory was spared when SCH23390 or SKF38393 were infused in the perirhinal cortex or the dorsal hippocampus suggesting that acquisition was unaffected. These results suggest that dopaminergic transmission in these medial temporal lobe structures have a differential involvement in object recognition memory consolidation. PMID- 23674388 TI - Microfluidic analysis of cellular deformability of normal and oxidatively damaged red blood cells. AB - Microfluidic analysis of blood has potential clinical value for determining normal and abnormal erythrocyte deformability. To determine if a microfluidic device could reliably measure intra- and inter-personal variations of normal and oxidized human red blood cell (RBC), venous blood samples were collected from repeat donors over time. RBC deformability was defined by the cortical tension (pN/um), as determined from the threshold pressure required to deform RBC through 2-2.5 MUm funnel-shaped constrictions. Oxidized RBC were prepared by treatment with phenazine methosulphate (PMS; 50 uM). Analysis of the control and oxidized RBC demonstrated that the microfluidic device could clearly differentiate between normal and mildly oxidized (20.13 +/- 1.47 versus 27.51 +/- 3.64 pN/um) RBC. In vivo murine studies further established that the PMS-mediated loss of deformability correlated with premature clearance. Deformability variation within an individual over three independent samplings (over 21 days) demonstrated minimal changes in the mean pN/um. Moreover, inter-individual variation in mean control RBC deformability was similarly small (range: 19.37-21.40 pN/um). In contrast, PMS-oxidized cells demonstrated a greater inter-individual range (range: 25.97-29.90 pN/um) reflecting the differential oxidant sensitivity of an individual's RBC. Importantly, similar deformability profiles (mean and distribution width; 20.49 +/- 1.67 pN/um) were obtained from whole blood via finger prick sampling. These studies demonstrated that a low cost microfluidic device could be used to reproducibly discriminate between normal and oxidized RBC. Advanced microfluidic devices could be of clinical value in analyzing populations for hemoglobinopathies or in evaluating donor RBC products post storage to assess transfusion suitability. PMID- 23674389 TI - Kinetic and thermodynamic hysteresis imposed by intercalation of proflavine in ferrocene-modified double-stranded DNA. AB - Surface-confined immobilized redox species often do not show the expected zero peak separation in slow-scan cyclic voltammograms. This phenomenon is frequently associated to experimental drawbacks and hence neglected. However, a nonzero peak separation, which is common to many electrochemical systems with high structural flexibility, can be rationally assigned to a thermodynamic hysteresis. To study this phenomenon, a surface-confined redox species was used. Specifically, a DNA strand which is tagged with ferrocene (Fc) moieties at its 5' end and its complementary capture probe is thiolated at the 3' end was self-assembled in a monolayer at a Au electrode with the Fc moieties being located at the bottom plane of the double-stranded DNA (dsDNA). The DNA-bound Fc undergoes rapid electron transfer with the electrode surface as evaluated by fast scan cyclic voltammetry. The electron transfer is sensitive to the ion transport along the DNA strands, a phenomenon which is modulated upon specific intercalation of proflavine into surface-bound dsDNA. The electron transfer rate of the Fc(0/+) redox process is influenced by the cationic permselectivity of the DNA monolayer. In addition to the kinetic hindrance, a thermodynamic effect correlated with changes in the activity coefficients of the Fc(0/+) moieties near the gold-dsDNA interface is observed and discussed as source of the observed hysteresis causing the non-zero peak separation in the voltammograms. PMID- 23674390 TI - High hematocrit resulting from administration of erythropoiesis-stimulating agents is not fully predictive of mortality or toxicities in preclinical species. AB - We conducted a retrospective analysis of publicly available preclinical toxicology studies with erythropoiesis-stimulating agents (ESAs) to examine common adverse events in rats, Beagle dogs, and cynomolgus monkeys. Mortality and/or thrombotic events were reported sporadically in a subset of studies and attributed to the high hematocrit (HCT) achieved in the animals. However, similarly high HCT was achieved in both high-dose and low-dose groups, but there were no reported adverse events in the low-dose group suggesting HCT was not the sole contributing factor leading to toxicity. Our analysis indicated that increased dose, dose frequency, and dosing duration in addition to high HCT contributed to mortality and thrombosis. To further evaluate this relationship, the incidence of toxicities was compared in rats administered an experimental hyperglycosylated analog of recombinant human erythropoietin (AMG 114) at varying dosing schedules in 1-month toxicity studies. The incidence of mortality and thrombotic events increased in higher dose groups and when dosed more frequently, despite a similarly high HCT in all animals. The results from the investigative study and retrospective analysis demonstrate that ESA-related toxicities in preclinical species are associated with dose level, dose frequency, and dosing duration, and not solely dependent upon a high HCT. PMID- 23674391 TI - Dose-related differences in the pharmacodynamic and toxicologic response to a novel hyperglycosylated analog of recombinant human erythropoietin in Sprague Dawley rats with similarly high hematocrit. AB - We recently reported results that erythropoiesis-stimulating agent (ESA)-related thrombotic toxicities in preclinical species were not solely dependent on a high hematocrit (HCT) but also associated with increased ESA dose level, dose frequency, and dosing duration. In this article, we conclude that sequelae of an increased magnitude of ESA-stimulated erythropoiesis potentially contributed to thrombosis in the highest ESA dose groups. The results were obtained from two investigative studies we conducted in Sprague-Dawley rats administered a low (no thrombotic toxicities) or high (with thrombotic toxicities) dose level of a hyperglycosylated analog of recombinant human erythropoietin (AMG 114), 3 times weekly for up to 9 days or for 1 month. Despite similarly increased HCT at both dose levels, animals in the high-dose group had an increased magnitude of erythropoiesis measured by spleen weights, splenic erythropoiesis, and circulating reticulocytes. Resulting prothrombotic risk factors identified predominantly or uniquely in the high-dose group were higher numbers of immature reticulocytes and nucleated red blood cells in circulation, severe functional iron deficiency, and increased intravascular destruction of iron-deficient reticulocyte/red blood cells. No thrombotic events were detected in rats dosed up to 9 days suggesting a sustained high HCT is a requisite cofactor for development of ESA-related thrombotic toxicities. PMID- 23674392 TI - Cytokines associated with increased erythropoiesis in Sprague-Dawley rats administered a novel hyperglycosylated analog of recombinant human erythropoietin. AB - We previously reported an increased incidence of thrombotic toxicities in Sprague Dawley rats administered the highest dose level of a hyperglycosylated analog of recombinant human erythropoietin (AMG 114) for 1 month as not solely dependent on high hematocrit (HCT). Thereafter, we identified increased erythropoiesis as a prothrombotic risk factor increased in the AMG 114 high-dose group with thrombotic toxicities, compared to a low-dose group with no toxicities but similar HCT. Here, we identified pleiotropic cytokines as prothrombotic factors associated with AMG 114 dose level. Before a high HCT was achieved, rats in the AMG 114 high, but not the low-dose group, had imbalanced hemostasis (increased von Willebrand factor and prothrombin time, decreased antithrombin III) coexistent with cytokines implicated in thrombosis: monocyte chemotactic protein 1 (MCP-1), MCP-3, tissue inhibitor of metalloproteinases 1, macrophage inhibitory protein-2, oncostatin M, T-cell-specific protein, stem cell factor, vascular endothelial growth factor, and interleukin-11. While no unique pathway to erythropoiesis stimulating agent-related thrombosis was identified, cytokines associated with increased erythropoiesis contributed to a prothrombotic intravascular environment in the AMG 114 high-dose group, but not in lower dose groups with a similar high HCT. PMID- 23674393 TI - Comparative analysis of reference gene stability in human mesenchymal stromal cells during osteogenic differentiation. AB - Mesenchymal stromal cells (MSCs) are one of the most frequently used cell sources for tissue engineering strategies. Cultivation of osteogenic MSCs is a prerequisite for cell-based concepts that aim at bone regeneration. Quantitative real time reverse transcription polymerase chain reaction (qRT-PCR) analysis is a commonly used method for the examination of mRNA expression levels. However, data on suitable reference genes for osteogenically cultivated MSCs is scarce. Hence, the aim of the study was to compare the regulation of different potential reference genes in osteogenically stimulated MSCs. Human MSCs were isolated from bone marrow aspirates of N = 6 hematologically healthy individuals, expanded by polystyrene-adherence, and maintained with and without osteogenic supplements for 14 days. Cellular proliferation and osteogenic differentiation were assessed by total DNA quantification, cell-specific alkaline phosphatase (ALP) activity and by qualitative staining for ALP and alizarin red, respectively. mRNA expression levels of N = 32 potential reference genes were quantified using the human Endogenous Control TaqMan(r) assays. mRNA expression stability was calculated using geNorm. The combined use of the most stable reference genes and DNA-damage inducible alpha, Pumilio homolog 1, and large ribosomal protein P0 significantly improved gene expression accuracy as compared to the use of the commonly used reference genes beta actin and glyceraldehyde-3-phosphate dehydrogenase during qRT-PCR-based target gene expression analysis of osteogenically stimulated MSCs. PMID- 23674394 TI - Blockade of BDNF signaling turns chemically-induced long-term potentiation into long-term depression. AB - Long-term potentiation (LTP) is accompanied by increased spine density and dimensions triggered by signaling cascades involving activation of the neurotrophin brain-derived neurotrophic factor (BDNF) and cytoskeleton remodeling. Chemically-induced long-term potentiation (c-LTP) is a widely used cellular model of plasticity, whose effects on spines have been poorly investigated. We induced c-LTP by bath-application of the N-methyl-d-aspartate receptor (NMDAR) coagonist glycine or by the K(+) channel blocker tetraethylammonium (TEA) chloride in cultured hippocampal neurons and compared the changes in dendritic spines induced by the two models of c-LTP and determined if they depend on BDNF/TrkB signaling. We found that both TEA and glycine induced a significant increase in stubby spine density in primary and secondary apical dendrites, whereas a specific increase in mushroom spine density was observed upon TEA application only in primary dendrites. Both TEA and glycine increased BDNF levels and the blockade of tropomyosin-receptor-kinase receptors (TrkRs) by the nonselective tyrosine kinase inhibitor K-252a or the selective allosteric TrkB receptor (TrkBR) inhibitor ANA-12, abolished the c-LTP-induced increase in spine density. Surprisingly, a blockade of TrkBRs did not change basal spontaneous glutamatergic transmission but completely changed the synaptic plasticity induced by c-LTP, provoking a shift from a long-term increase to a long-term depression (LTD) in miniature excitatory postsynaptic current (mEPSC) frequency. In conclusion, these results suggest that BDNF/TrkB signaling is necessary for c-LTP-induced plasticity in hippocampal neurons and its blockade leads to a switch of c-LTP into chemical-LTD (c-LTD). PMID- 23674395 TI - Efficacy and safety of transulnar coronary angiography and interventions--a single center experience. AB - OBJECTIVES: To evaluate the efficacy and long-term safety of transulnar approach in complex coronary interventions. BACKGROUND: The success rate of transulnar approach in complex coronary interventions and its long-term safety remains to be proven. METHODS: We conducted a retrospective chart review of patients undergoing transulnar coronary angiography and interventions at our institution from January 2004 through July 2009. Primary endpoint of the study was the success rate of the procedure. Secondary endpoints were major bleeding, local vascular and neurological complications, cerebrovascular accident (CVA)/transient ischemic attack (TIA), myocardial infarction (MI), all-cause mortality, and major adverse cardiovascular events (MACE) rate that was a composite of MI, CVA/TIA, and all cause mortality. RESULTS: Of 81 patients undergoing transulnar approach, 41 (50.6%) patients underwent intervention on 65 lesions. Twelve percent of the interventions were performed on coronary bypass grafts and 9.2% on the left main coronary artery. Success rates for transulnar access, coronary angiography, and coronary/bypass graft interventions were 93.8%, 100%, and 92.6%, respectively. Follow-up data was available on 71 patients at short term (30 days) and 58 patients at long term (1 year). At 30-day follow-up, vascular complication rate was 2.8 %. At 1-year follow-up, there were no residual deficits from vascular or neurological complications associated with the index procedure and the overall MACE rate was 3.4%. CONCLUSION: In this first study evaluating long-term safety and feasibility of transulnar coronary angiography and complex coronary interventions, we conclude that transulnar approach appears to be safe and effective. PMID- 23674396 TI - Bayesian methods for evidence evaluation: are we there yet? PMID- 23674397 TI - Bayesian methods affirm the use of percutaneous coronary intervention to improve survival in patients with unprotected left main coronary artery disease. AB - BACKGROUND: Several randomized clinical trials support the use of coronary artery bypass grafting (CABG) for patients with unprotected left main coronary artery disease. Studies suggesting the equivalence of percutaneous coronary intervention (PCI) with CABG for this indication indirectly support the 2011 American College of Cardiology Foundation/American Heart Association Class IIa recommendation for PCI to improve survival in patients with unprotected left main coronary artery disease. We tested whether bayesian approaches uphold the new recommendation. METHODS AND RESULTS: We performed a bayesian cross-design and network meta analysis of 12 studies (4 randomized clinical trials and 8 observational studies) comparing CABG with PCI (n=4574 patients) and of 7 studies (2 randomized clinical trials and 5 observational studies) comparing CABG with medical therapy (n=3224 patients). The odds ratios of 1-year mortality after PCI compared with CABG using bayesian cross-design meta-analysis were not different among randomized clinical trials (odds ratio, 0.99; 95% bayesian credible interval, 0.67-1.43), matched cohort studies (odds ratio, 1.10; 95% bayesian credible interval, 0.76-1.73), and other types of cohort studies (odds ratio, 0.93; 95% bayesian credible interval, 0.58-1.35). A network meta-analysis suggested that medical therapy is associated with higher 1-year mortality than the use of PCI for patients with unprotected left main coronary artery disease (odds ratio, 3.22; 95% bayesian credible interval, 1.96-5.30). CONCLUSIONS: Bayesian methods support the current guidelines, which were based on traditional statistical methods and have proposed that PCI, like CABG, improves survival for patients with unprotected left main coronary artery disease compared with medical therapy. An integrated approach using both direct and indirect evidence may yield new insights to enhance the translation of clinical trial data into practice. PMID- 23674398 TI - High-dose statin therapy in patients with stable coronary artery disease: treating the right patients based on individualized prediction of treatment effect. AB - BACKGROUND: Clinicians need to identify coronary artery disease patients for whom the benefits of high-dose versus usual-dose statin therapy outweigh potential harm. We therefore aimed to develop and validate a model for prediction of the incremental treatment effect of high-dose statins for individual patients in terms of reduction of 5-year absolute risk for myocardial infarction, stroke, coronary death, or cardiac resuscitation. METHODS AND RESULTS: Based on data from the Treating to New Targets trial (TNT; n=10 001), a Cox proportional hazards model was developed comprising 13 easy-to-measure clinical predictors: age, sex, smoking, diabetes mellitus, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, history of myocardial infarction, coronary artery bypass grafting, congestive heart failure or abdominal aortic aneurysm, glomerular filtration rate, and treatment status (ie, atorvastatin 80 mg or 10 mg). External validation in the Incremental Decrease in End Points Through Aggressive Lipid Lowering trial (IDEAL; n=8888) confirmed adequate goodness-of fit and calibration, but moderate discrimination (C-statistic, 0.63; 95% confidence interval, 0.62-0.65). Still, among participants of both trials combined, the model identified a group of 11.7% whose predicted 5-year number needed to treat was <=25 and a group of 41.9% whose predicted needed to treat was >=50. A decision curve shows that making treatment decisions on the basis of predictions using our model may improve net benefit. CONCLUSIONS: Estimation of the incremental treatment effect of high-dose versus usual-dose statin therapy in individual coronary artery disease patients enables selection of high-risk patients that benefit most from more aggressive therapy. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00327691 and NCT00159835. PMID- 23674399 TI - Late extramedullary recurrence of adult onset Burkitt's lymphoma mimicking peritoneal carcinomatosis. PMID- 23674401 TI - Chitosan-cross-linked osmium polymer composites as an efficient platform for electrochemical biosensors. AB - A new family of chitosan-cross-linked osmium polymer composites was prepared and its electrochemical properties were examined. The composites were prepared by quaternization of the poly(4-vinylpyridine) osmium bipyridyl polymer (PVP-Os) which was then cross-linked with chitosan, yielding PVP-Os/chitosan. Films made of the composites showed improved mass and electron transport owing to the porous and hydrophilic structure which is derived from the cross-links between the Os polymer and chitosan. The rate for glucose oxidation was enhanced four times when glucose oxidase (GOx) was immobilized on PVP-Os/chitosan compared immobilization on PVP-Os. PMID- 23674400 TI - Diffusion tensor imaging of Parkinson's disease, atypical parkinsonism, and essential tremor. AB - Diffusion tensor imaging could be useful in characterizing movement disorders because it noninvasively examines multiple brain regions simultaneously. We report a multitarget imaging approach focused on the basal ganglia and cerebellum in Parkinson's disease, parkinsonian variant of multiple system atrophy, progressive supranuclear palsy, and essential tremor and in healthy controls. Seventy-two subjects were studied with a diffusion tensor imaging protocol at 3 Tesla. Receiver operating characteristic analysis was performed to directly compare groups. Sensitivity and specificity values were quantified for control versus movement disorder (92% sensitivity, 88% specificity), control versus parkinsonism (93% sensitivity, 91% specificity), Parkinson's disease versus atypical parkinsonism (90% sensitivity, 100% specificity), Parkinson's disease versus multiple system atrophy (94% sensitivity, 100% specificity), Parkinson's disease versus progressive supranuclear palsy (87% sensitivity, 100% specificity), multiple system atrophy versus progressive supranuclear palsy (90% sensitivity, 100% specificity), and Parkinson's disease versus essential tremor (92% sensitivity, 87% specificity). The brain targets varied for each comparison, but the substantia nigra, putamen, caudate, and middle cerebellar peduncle were the most frequently selected brain regions across classifications. These results indicate that using diffusion tensor imaging of the basal ganglia and cerebellum accurately classifies subjects diagnosed with Parkinson's disease, atypical parkinsonism, and essential tremor and clearly distinguishes them from control subjects. PMID- 23674402 TI - Chemotherapy-induced prospective memory impairment in patients with breast cancer. AB - OBJECTIVE: This study aimed to investigate the event-based prospective memory (EBPM) and time-based prospective memory (TBPM) in chemotherapy-induced cognitive impairment in patients with breast cancer. METHODS: Forty patients with breast cancer who underwent adjuvant chemotherapy and 40 age-matched and education matched healthy women were administered with a battery of neuropsychological tests including EBPM and TBPM tasks. RESULTS: A significant difference between breast cancer patients and controls was found in the scores on the mini-mental state examination (t = -11.684, p < 0.01), verbal fluency test (t = -7.939, p < 0.01), and digit span (t = -2.538, p < 0.05). Compared with healthy controls, breast cancer patients exhibited a poorer performance on EBPM (t = -7.096, p < 0.01) but not on TBPM (t = -1.921, p > 0.05). CONCLUSIONS: Our results suggest that breast cancer patients who had undergone adjuvant chemotherapy show deficits in EBPM but not in TBPM. PMID- 23674403 TI - Device closure of a pseudoaneurysm of the right ventricular outflow tract in an infant with right ventricle-to-pulmonary artery homograft. AB - Pseudoaneurysm of the right ventricular outflow tract (RVOT) is a rare complication following surgical repair of congenital heart disease involving a homograft or conduit. Traditionally, surgical intervention is indicated due to risk for rupture, thrombosis, compression of adjacent structures, and infection. We describe a case of a RVOT pseudoaneurysm in a 5 kg patient that was palliated with interventional catheterization utilizing an Amplatzer Ductal Occluder with four years follow-up. Interventional catheterization can successfully manage this complication in small patients for the long-term and thus avoids additional surgery and delays conduit replacement. PMID- 23674404 TI - Choreo-acanthocytosis. PMID- 23674405 TI - Variability in neuronal expression of dopamine receptors and transporters in the substantia nigra. AB - Parkinson's disease (PD) patients have increased susceptibility to impulse control disorders. Recent studies have suggested that alterations in dopamine receptors in the midbrain underlie impulsive behaviors and that more impulsive individuals, including patients with PD, exhibit increased occupancy of their midbrain dopamine receptors. The cellular location of dopamine receptor subtypes and transporters within the human midbrain may therefore have important implications for the development of impulse control disorders in PD. The localization of the dopamine receptors (D1-D5) and dopamine transporter proteins in the upper brain stems of elderly adult humans (n = 8) was assessed using single immunoperoxidase and double immunofluorescence (with tyrosine hydroxylase to identify dopamine neurons). The relative amount of protein expressed in dopamine neurons from different regions was assessed by comparing their relative immunofluorescent intensities. The midbrain dopamine regions associated with impulsivity (medial nigra and ventral tegmental area [VTA]) expressed less dopamine transporter on their neurons than other midbrain dopamine regions. Medial nigral dopamine neurons expressed significantly greater amounts of D1 and D2 receptors and vesicular monoamine transporter than VTA dopamine neurons. The heterogeneous pattern of dopamine receptors and transporters in the human midbrain suggests that the effects of dopamine and dopamine agonists are likely to be nonuniform. The expression of excitatory D1 receptors on nigral dopamine neurons in midbrain regions associated with impulsivity, and their variable loss as seen in PD, may be of particular interest for impulse control. PMID- 23674406 TI - AFM study of Gibbs films of semifluorinated alkanes at liquid crystal/air interfaces. AB - Forming micelles: The first in situ AFM study of Gibbs films of semifluorinated alkanes at liquid crystal/air interfaces is presented. The Gibbs films self organize in a hexagonal close packing of surface micelles with shapes and lateral dimensions that are similar to micelles forming on aqueous and solid surfaces. It is concluded that he formation of surfaces micelles and their self-organization in large-area dense hexagonal arrays are intrinsic properties of semifluorinated alkane molecules. PMID- 23674407 TI - A fully adaptive multiresolution algorithm for atrial arrhythmia simulation on anatomically realistic unstructured meshes. AB - Biophysically detailed and anatomically realistic atrial models are emerging as a valuable tool in the study of atrial arrhythmias, nevertheless clinical use of these models would be favored by a reduction of computational times. This paper introduces a novel adaptive mesh algorithm, based on multiresolution representation (MR), for the efficient integration of cardiac ordinary differential equation (ODE)-partial differential equation (PDE) systems on unstructured triangle meshes. The algorithm applies a dynamically adapted node centered finite volume method (FVM) scheme for integration of diffusion. The method accuracy and efficiency were evaluated by simulating propagation scenarios of increasing complexity levels (pacing, stable spirals, atrial fibrillation) on tomography-derived three-dimensional monolayer atrial models, based on a monodomain reaction-diffusion formulation coupled with the Courtemanche atrial ionic model. All simulated propagation patterns were accurately reproduced with substantially reduced computational times (10%-30% of the full-resolution simulation time). The proposed algorithm, combining the MR computational efficiency with the geometrical flexibility of unstructured meshes, may favor the development of patient-specific multiscale models of atrial arrhythmias and their application in the clinical setting. PMID- 23674408 TI - Automatic distortion correction of endoscopic images captured with wide-angle zoom lens. AB - Operation in minimally invasive surgery is more difficult since the surgeons perform operations without haptic feedback or depth perception. Moreover, the field of view perceived by the surgeons through endoscopy is usually quite limited. The goal of this paper is to allow surgeons to see wide-angle images from endoscopy without the drawback of lens distortion. The proposed distortion correction process consists of lens calibration and real-time image warping. The calibration step is to estimate the parameters in the lens distortion model. We propose a fully automatic Hough-entropy-based calibration algorithm, which provides calibration results comparable to the previous manual calibration method. To achieve real-time correction, we use graphics processing unit to warp the image in parallel. In addition, surgeons may adjust the focal length of a lens during the operation. Real-time distortion correction of a zoomable lens is impossible by using traditional calibration methods because the tedious calibration process has to repeat again if focal length is changed. We derive a formula to describe the relationship between the distortion parameter, focal length, and image boundary. Hence, we can estimate the focal length for a zoomable lens from endoscopic images online and achieve real-time lens distortion correction. PMID- 23674409 TI - Quantitative analysis of superparamagnetic contrast agent in sentinel lymph nodes using ex vivo vibrating sample magnetometry. AB - As the first step in developing a new clinical technique for the magnetic detection of colorectal sentinel lymph nodes (SLNs), a method is developed to measure the magnetic content in intact, formalin fixated lymph nodes using a vibrating sample magnetometer (VSM). A suspension of superparamagnetic nanoparticles is injected ex vivo around the tumor in the resected colon segments. A selection of three lymph nodes is excised from the region around the tumor and is separately measured in the VSM. The iron content in the lymph nodes is quantified from the magnetic moment curve using the Langevin model for superparamagnetism and a bimodal particle size distribution. Adverse, parasitic movements of the sample were successfully reduced by tight fixation of the soft tissue and using a small vibration amplitude. Iron content in the lymph nodes is detected with 0.5 MUg accuracy and ranged from 1 to 51 MUg. Histological staining confirmed iron presence. The current method of measuring intact biological tissue in a VSM is suitable to show the feasibility and merit of magnetic detection of SLNs in colorectal cancer. For clinical validation of magnetic SLN selection in colorectal cancer, a new magnetometer with high specificity for superparamagnetic nanoparticles is required. PMID- 23674410 TI - An online semi-supervised brain-computer interface. AB - Practical brain-computer interface (BCI) systems should require only low training effort for the user, and the algorithms used to classify the intent of the user should be computationally efficient. However, due to inter- and intra-subject variations in EEG signal, intermittent training/calibration is often unavoidable. In this paper, we present an online semi-supervised P300 BCI speller system. After a short initial training (around or less than 1 min in our experiments), the system is switched to a mode where the user can input characters through selective attention. In this mode, a self-training least squares support vector machine (LS-SVM) classifier is gradually enhanced in back end with the unlabeled EEG data collected online after every character input. In this way, the classifier is gradually enhanced. Even though the user may experience some errors in input at the beginning due to the small initial training dataset, the accuracy approaches that of fully supervised method in a few minutes. The algorithm based on LS-SVM and its sequential update has low computational complexity; thus, it is suitable for online applications. The effectiveness of the algorithm has been validated through data analysis on BCI Competition III dataset II (P300 speller BCI data). The performance of the online system was evaluated through experimental results on eight healthy subjects, where all of them achieved the spelling accuracy of 85 % or above within an average online semi-supervised learning time of around 3 min. PMID- 23674411 TI - Electronic cleansing for 24-h limited bowel preparation CT colonography using principal curvature flow. AB - CT colonography (CTC) is one of the recommended methods for colorectal cancer screening. The subject's preparation is one of the most burdensome aspects of CTC with a cathartic bowel preparation. Tagging of the bowel content with an oral contrast medium facilitates CTC with limited bowel preparation. Unfortunately, such preparations adversely affect the 3-D image quality. Thus far, data acquired after very limited bowel preparation were evaluated with a 2-D reading strategy only. Existing cleansing algorithms do not work sufficiently well to allow a primary 3-D reading strategy. We developed an electronic cleansing algorithm, aimed to realize optimal 3-D image quality for low-dose CTC with 24-h limited bowel preparation. The method employs a principal curvature flow algorithm to remove heterogeneities within poorly tagged fecal residue. In addition, a pattern recognition-based approach is used to prevent polyp-like protrusions on the colon surface from being removed by the method. Two experts independently evaluated 40 CTC cases by means of a primary 2-D approach without involvement of electronic cleansing as well as by a primary 3-D method after electronic cleansing. The data contained four variations of 24-h limited bowel preparation and was based on a low radiation dose scanning protocol. The sensitivity for lesions >= 6 mm was significantly higher for the primary 3-D reading strategy (84%) than for the primary 2-D reading strategy (68%) (p = 0.031). The reading time was increased from 5:39 min (2-D) to 7:09 min (3-D) (p = 0.005); the readers' confidence was reduced from 2.3 (2-D) to 2.1 (3-D) ( p = 0.013) on a three-point Likert scale. Polyp conspicuity for cleansed submerged lesions was similar to not submerged lesions (p = 0.06). To our knowledge, this study is the first to describe and clinically validate an electronic cleansing algorithm that facilitates low-dose CTC with 24-h limited bowel preparation. PMID- 23674412 TI - Multimodal sparse representation-based classification for lung needle biopsy images. AB - Lung needle biopsy image classification is a critical task for computer-aided lung cancer diagnosis. In this study, a novel method, multimodal sparse representation-based classification (mSRC), is proposed for classifying lung needle biopsy images. In the data acquisition procedure of our method, the cell nuclei are automatically segmented from the images captured by needle biopsy specimens. Then, features of three modalities (shape, color, and texture) are extracted from the segmented cell nuclei. After this procedure, mSRC goes through a training phase and a testing phase. In the training phase, three discriminative subdictionaries corresponding to the shape, color, and texture information are jointly learned by a genetic algorithm guided multimodal dictionary learning approach. The dictionary learning aims to select the topmost discriminative samples and encourage large disagreement among different subdictionaries. In the testing phase, when a new image comes, a hierarchical fusion strategy is applied, which first predicts the labels of the cell nuclei by fusing three modalities, then predicts the label of the image by majority voting. Our method is evaluated on a real image set of 4372 cell nuclei regions segmented from 271 images. These cell nuclei regions can be divided into five classes: four cancerous classes (corresponding to four types of lung cancer) plus one normal class (no cancer). The results demonstrate that the multimodal information is important for lung needle biopsy image classification. Moreover, compared to several state-of-the art methods (LapRLS, MCMI-AB, mcSVM, ESRC, KSRC), the proposed mSRC can achieve significant improvement (mean accuracy of 88.1%, precision of 85.2%, recall of 92.8%, etc.), especially for classifying different cancerous types. PMID- 23674413 TI - Intensity-modulated microbend fiber optic sensor for respiratory monitoring and gating during MRI. AB - This paper describes a novel microbend fiber optic sensor system for respiratory monitoring and respiratory gating in the MRI environment. The system enables the noninvasive real-time monitoring and measurement of breathing rate and respiratory/body movement pattern of healthy subjects inside the MRI gantry, and has potential application in respiratory-gated image acquisition based on respiratory cues. The working principle behind this sensor is based on the microbending effect of an optical fiber on light transmission. The sensor system comprises of a 1.0-mm-thin graded-index multimode optical fiber-embedded plastic sensor mat, a photoelectronic transceiver, and a computer with a digital signal processing algorithm. In vitro testing showed that our sensor has a typical signal-to-noise ratio better than 28 dB. Clinical MRI trials conducted on 20 healthy human subjects showed good and comparable breathing rate detection (with an accuracy of +/-2 bpm) and respiratory-gated image quality produced using the sensor system, with reference to current predicate hospital device/system. The MRI safe, ease of operation characteristics, low fabrication cost, and extra patient comfort offered by this system suggest its good potential in replacing predicate device/system and serve as a dual function in real-time respiratory monitoring and respiratory-gated image acquisition at the same time during MRI. PMID- 23674414 TI - Electroporation of intracellular liposomes using nanosecond electric pulses--a theoretical study. AB - Nanosecond (ns) electric pulses of sufficient amplitude can provoke electroporation of intracellular organelles. This paper investigates whether such pulses could provide a method for controlled intracellular release of a content of small internalized artificial lipid vesicles (liposomes). To estimate the pulse parameters needed to selectively electroporate liposomes while keeping the plasma and nuclear membranes intact, we constructed a numerical model of a biological cell containing a nucleus and liposomes of different sizes (with radii from 50 to 500 nm), which were placed in various sites in the cytoplasm. Our results show that under physiological conditions selective electroporation is only possible for the largest liposomes and when using very short pulses (few ns). By increasing the liposome interior conductivity and/or decreasing the cytoplasmic conductivity, selective electroporation of even smaller liposomes could be achieved. The location of the liposomes inside the cell does not play a significant role, meaning that liposomes of similar size could all be electroporated simultaneously. Our results indicate the possibility of using ns pulse treatment for liposomal drug release. PMID- 23674415 TI - Denoising depth EEG signals during DBS using filtering and subspace decomposition. AB - In difficult epileptic patients, the brain structures are explored by means of depth multicontact electrodes [stereoelectroencephalography (SEEG)]. Recently, a novel diagnostic technique allows an accurate definition of the epileptogenic zone using deep brain stimulation (DBS). The stimulation signal propagates in the brain and thus it appears on most of the other SEEG electrodes, masking the local brain electrophysiological activity. The objective of this paper is the DBS-SEEG signals detrending and denoising in order to recover the masked physiological sources. We review the main filtering methods and put forward an approach based on the combination of filtering with generalized eigenvalue decomposition (GEVD). An experimental study on simulated and real SEEG shows that our approach is able to separate DBS sources from brain activity. The best results are obtained by an original singular spectrum analysis-GEVD approach. PMID- 23674416 TI - An augmented reality system for epidural anesthesia (AREA): prepuncture identification of vertebrae. AB - We propose an augmented reality system to identify lumbar vertebral levels to assist in spinal needle insertion for epidural anesthesia. These procedures require careful placement of a needle to ensure effective delivery of anesthetics and to avoid damaging sensitive tissue such as nerves. In this system, a trinocular camera tracks an ultrasound transducer during the acquisition of a sequence of B-mode images. The system generates an ultrasound panorama image of the lumbar spine, automatically identifies the lumbar levels in the panorama image, and overlays the identified levels on a live camera view of the patient's back. Validation is performed to test the accuracy of panorama generation, lumbar level identification, overall system accuracy, and the effect of changes in the curvature of the spine during the examination. The results from 17 subjects demonstrate the feasibility and capability of achieving an error within clinically acceptable range for epidural anaesthesia. PMID- 23674417 TI - Predicting targets of human reaching motions using different sensing technologies. AB - Rapid recognition of voluntary motions is crucial in human-computer interaction, but few studies compare the predictive abilities of different sensing technologies. This paper thus compares performances of different technologies when predicting targets of human reaching motions: electroencephalography (EEG), electrooculography, camera-based eye tracking, electromyography (EMG), hand position, and the user's preferences. Supervised machine learning is used to make predictions at different points in time (before and during limb motion) with each individual sensing modality. Different modalities are then combined using an algorithm that takes into account the different times at which modalities provide useful information. Results show that EEG can make predictions before limb motion onset, but requires subject-specific training and exhibits decreased performance as the number of possible targets increases. EMG and hand position give high accuracy, but only once the motion has begun. Eye tracking is robust and exhibits high accuracy at the very onset of limb motion. Several advantages of combining different modalities are also shown, including advantages of combining measurements with contextual data. Finally, some recommendations are given for sensing modalities with regard to different criteria and applications. The information could aid human-computer interaction designers in selecting and evaluating appropriate equipment for their applications. PMID- 23674418 TI - Automatic localization of the da Vinci surgical instrument tips in 3-D transrectal ultrasound. AB - Robot-assisted laparoscopic radical prostatectomy (RALRP) using the da Vinci surgical system is the current state-of-the-art treatment option for clinically confined prostate cancer. Given the limited field of view of the surgical site in RALRP, several groups have proposed the integration of transrectal ultrasound (TRUS) imaging in the surgical workflow to assist with accurate resection of the prostate and the sparing of the neurovascular bundles (NVBs). We previously introduced a robotic TRUS manipulator and a method for automatically tracking da Vinci surgical instruments with the TRUS imaging plane, in order to facilitate the integration of intraoperative TRUS in RALRP. Rapid and automatic registration of the kinematic frames of the da Vinci surgical system and the robotic TRUS probe manipulator is a critical component of the instrument tracking system. In this paper, we propose a fully automatic registration technique based on automatic 3-D TRUS localization of robot instrument tips pressed against the air tissue boundary anterior to the prostate. The detection approach uses a multiscale filtering technique to identify and localize surgical instrument tips in the TRUS volume, and could also be used to detect other surface fiducials in 3 D ultrasound. Experiments have been performed using a tissue phantom and two ex vivo tissue samples to show the feasibility of the proposed methods. Also, an initial in vivo evaluation of the system has been carried out on a live anaesthetized dog with a da Vinci Si surgical system and a target registration error (defined as the root mean square distance of corresponding points after registration) of 2.68 mm has been achieved. Results show this method's accuracy and consistency for automatic registration of TRUS images to the da Vinci surgical system. PMID- 23674419 TI - A unified probabilistic approach to improve spelling in an event-related potential-based brain-computer interface. AB - In recent years, in an attempt to maximize performance, machine learning approaches for event-related potential (ERP) spelling have become more and more complex. In this paper, we have taken a step back as we wanted to improve the performance without building an overly complex model, that cannot be used by the community. Our research resulted in a unified probabilistic model for ERP spelling, which is based on only three assumptions and incorporates language information. On top of that, the probabilistic nature of our classifier yields a natural dynamic stopping strategy. Furthermore, our method uses the same parameters across 25 subjects from three different datasets. We show that our classifier, when enhanced with language models and dynamic stopping, improves the spelling speed and accuracy drastically. Additionally, we would like to point out that as our model is entirely probabilistic, it can easily be used as the foundation for complex systems in future work. All our experiments are executed on publicly available datasets to allow for future comparison with similar techniques. PMID- 23674420 TI - Quaternionic attitude estimation for robotic and human motion tracking using sequential Monte Carlo methods with von Mises-Fisher and nonuniform densities simulations. AB - In recent years, wireless positioning and tracking devices based on semiconductor micro electro-mechanical system (MEMS) sensors have successfully integrated into the consumer electronics market. Information from the sensors is processed by an attitude estimation program. Many of these algorithms were developed primarily for aeronautical applications. The parameters affecting the accuracy and stability of the system vary with the intended application. The performance of these algorithms occasionally destabilize during human motion tracking activities, which does not satisfy the reliability and high accuracy demand in biomedical application. A previous study accessed the feasibility of using semiconductor based inertial measurement units (IMUs) for human motion tracking. IMU hardware has been redesigned and an attitude estimation algorithm using sequential Monte Carlo (SMC) methods, or particle filter, for quaternions was developed. The method presented in this paper uses von Mises-Fisher and a nonuniform simulation to provide density estimation of the rotation group SO(3). Synthetic signal simulation, robotics applications, and human applications have been investigated. PMID- 23674421 TI - Fusion of electromagnetic trackers to improve needle deflection estimation: simulation study. AB - We present a needle deflection estimation method to anticipate needle bending during insertion into deformable tissue. Using limited additional sensory information, our approach reduces the estimation error caused by uncertainties inherent in the conventional needle deflection estimation methods. We use Kalman filters to combine a kinematic needle deflection model with the position measurements of the base and the tip of the needle taken by electromagnetic (EM) trackers. One EM tracker is installed on the needle base and estimates the needle tip position indirectly using the kinematic needle deflection model. Another EM tracker is installed on the needle tip and estimates the needle tip position through direct, but noisy measurements. Kalman filters are then employed to fuse these two estimates in real time and provide a reliable estimate of the needle tip position, with reduced variance in the estimation error. We implemented this method to compensate for needle deflection during simulated needle insertions and performed sensitivity analysis for various conditions. At an insertion depth of 150 mm, we observed needle tip estimation error reductions in the range of 28% (from 1.8 to 1.3 mm) to 74% (from 4.8 to 1.2 mm), which demonstrates the effectiveness of our method, offering a clinically practical solution. PMID- 23674423 TI - Absent friends in medical humanities. PMID- 23674422 TI - Design and evaluation of a personal digital assistant-based research platform for cochlear implants. AB - This paper discusses the design, development, features, and clinical evaluation of a personal digital assistant (PDA)-based platform for cochlear implant research. This highly versatile and portable research platform allows researchers to design and perform complex experiments with cochlear implants manufactured by Cochlear Corporation with great ease and flexibility. The research platform includes a portable processor for implementing and evaluating novel speech processing algorithms, a stimulator unit which can be used for electrical stimulation and neurophysiologic studies with animals, and a recording unit for collecting electroencephalogram/evoked potentials from human subjects. The design of the platform for real time and offline stimulation modes is discussed for electric-only and electric plus acoustic stimulation followed by results from an acute study with implant users for speech intelligibility in quiet and noisy conditions. The results are comparable with users' clinical processor and very promising for undertaking chronic studies. PMID- 23674424 TI - The body as metaphor: digestive bodies and political surgery in Shakespeare's Macbeth. AB - The article aims to reconstruct the perspective of bodily pathology underpinning Shakespeare's Macbeth. In the play, Scotland's body politic is frequently depicted as a macro-system suffering from a complexional imbalance of digestive origins. More specifically, Scotland comes over as a huge stomach strangled by a carcinogenic foreign body in need of being "raze[d] out". Since traditional purgative drugs such as "rhubarb" and "cynne" turn out to be totally inefficient to cure the body of Scotland, the resolution to adopt a drastic medical measure becomes more than urgent. The conclusion of the play coincides with the most terrible form of political surgery: Shakespeare's reiterated use of verbs such as "pluck" and "purge", commonly used in Renaissance herbals and handbooks, suggests that Macbeth's physical body is suffering from a kind of "blockage", for which herbal treatments are no longer sufficient. Nothing less than a surgical operation is needed to "purge" the corrupt entrails of the State dominated by Macbeth's tyranny. PMID- 23674425 TI - Literature and the "good doctor" in Ian McEwan's Saturday. AB - There is widespread acceptance in medical humanities circles that reading is good for doctors and that, in medical educational terms, it is particularly good at making better doctors by widening perspective and developing the sensibilities. Recent recommendations on medical education in the UK have allowed medical students to take courses in literature as a component of their degrees, and some have suggested that this option should be compulsory for all doctors. It is possible, however, that in our eagerness to assert the primacy of a literary education for personal development, we can ignore other routes to enlightened, sensitive doctoring. This paper appraises the instrumental role of a literary education for doctors through an analysis of Ian McEwan's novel Saturday, which deals with the dramatic events in the day in the life of a neurosurgeon. PMID- 23674426 TI - The intersubjective and the intrasubjective in the patient physician dyad: implications for medical humanities education. AB - At the heart of medicine is the patient, and the fundamental relationship in medicine is the patient-physician dyad. Smith's argument for the intersubjective creation of knowledge, which is itself indebted to Bakhtin's notion of the utterance and of the necessity of "the other" in the development of meaning, enables an exploration of the creation of meaning during the patient-physician encounter. The analysis is enriched by Haraway's concepts of partial perspectives and of dispersion, which expose the many roles and voices in which the physician and patient may interact. This approach emphasises the use of the medical humanities as a tool to teach medical students about the ambiguities of clinical practice, in which there is often no "right answer" except what is appropriate for the individual patient. PMID- 23674427 TI - Narratives in specialist palliative medicine. AB - Where modern medicine has been criticised for having lost sight of the individual on account of its biomedical focus, the profile of narrative in medicine has gained prominence. Within any medical encounter it is possible to identify the existence of several narratives. The aim of this article is to demonstrate this characteristic within the context of specialist palliative care. The emphasis is to see how an awareness of these narratives might improve upon how we attend to the suffering of dying patients. A narrative approach to this work could also help doctors and other healthcare professionals find meaning and understanding in themselves while working in an environment of death and dying. This can expose many challenging personal dimensions that demand reflection, possibly through narrative. The nature of the narratives identified is such that they can weave together and interlink into a greater whole to achieve a much wider set of meanings and shared understandings. However, they can exist in a fragmented state, in which ambiguity, uncertainty and incoherence are sustained. The effect of this should be to encourage us to engage in a more active process of finding meaning, and certainly to recognise that there could be more than one reading or interpretation. PMID- 23674428 TI - Thinking historically about public health. AB - This paper argues that analysing past public health policies calls for scholarship that integrates insights not just from medical history but from a broad range of historical fields. Recent studies of historic infectious disease management make this evident: they confirm that prior practices inhere in current perceptions and policies, which, like their antecedents, unfold amidst shifting amalgams of politics, culture, law and economics. Thus, explaining public health policy of the past purely in medical or epidemiological terms ignores evidence that it was rarely, if ever, designed solely on medical grounds at the time. PMID- 23674429 TI - Metaphors for illness in contemporary media. AB - Essayist Susan Sontag alerted us more than 20 years ago to the way in which clusters of metaphors attach themselves to our discussion of certain diseases, and the influence these metaphors exert on public attitudes to the diseases themselves and to those who experience them. This study of feature articles on five diseases-avian flu, cancer, diabetes, heart disease, and HIV/AIDS-published recently in the New York Times reveals distinct patterns of metaphor usage around each. While the metaphors used in relation to the diseases Sontag studied-cancer and HIV/AIDS-have become less emotive and more positively informative, the sensationalist connotations of the metaphor clusters that have formed around two diseases that were not on the agenda for wide public debate in her time-avian flu and diabetes-are hardly congruent with the serious intent of the articles in which they appeared. By contrast, discussion of heart disease involved very limited use of metaphor. The article ends with a call for journalists and medical professionals to become more aware of the impact of the metaphors they use and to collaborate in developing sets of metaphors that are factually informative and enhance communication between doctors and their patients. PMID- 23674430 TI - Reading between the lines: the experiences of taking part in a community reading project. AB - Despite the popularity of reading groups, and the increased number of general practitioner-referred bibliotherapy schemes in the UK, there has been relatively little research on the effects of reading works of literature on the well-being and health of readers. This paper reports the findings of a study set up to explore people's experiences of taking part in community reading groups run by the Get into Reading Project in Wirral, Merseyside, UK. A qualitative approach was adopted, using three methods. These were participant observation with five reading groups, a key stakeholder interview and, with a sixth group, a single case study that consisted of observation and interviews with group members. The fieldwork conducted with the six groups took place in a variety of settings, including libraries, a residential drug rehabilitation unit and a hostel for homeless men. The research participants were all over 18 years of age, and all were members or facilitators of Get into Reading reading groups. The data were analysed thematically using NVivo qualitative analysis software. The findings show that the groups do not have a specific, targeted, therapeutic function, their primary purpose being more broadly literary, with literature itself trusted both to serve a coalescing social purpose and to offer non-specified but individual therapeutic benefits. Further work should be undertaken to explore the social and therapeutic benefits of reading literature in community settings. PMID- 23674431 TI - Teaching medical students professionalism: what role for the medical humanities? PMID- 23674432 TI - Written role models in professionalism education. AB - After more than a generation of neglect in medical education, professionalism has now been restored to the classroom and clinic. However, the current emphasis on teaching and evaluating professionalism in clinical education risks failure because of the large gap between explicit professional ideals and today's culture of medical education. For professionalism curricula to be successful, they must be narrative-based, rather than rule-based. This requires substantial increases in appropriate role modeling, opportunities to develop self-awareness, development of narrative competence and investment in community service. Fictional and non-fictional written narratives can play an important supplemental role throughout medical training by introducing additional role model physicians and, more importantly, by promoting discussion and analysis of professional virtue in practice. Using "The Steel Windpipe", "Darkness", "Malingerers" and "The Good Doctor" as examples, the author illustrates the use of short stories to help medical students explore the meaning of professionalism from a narrative perspective. PMID- 23674433 TI - Opening the word hoard. PMID- 23674434 TI - Percutaneous management of left atrial appendage perforation during device closure. AB - A 76-year-old male patient was admitted for percutaneous left atrial appendage (LAA) closure because of chronic atrial fibrillation and a history of gastrointestinal bleeding under oral anticoagulation. The procedure was complicated by perforation of the LAA with the lobe of the closure device being placed in the pericardial space. Keeping access to the pericardial space with the delivery sheath, the LAA closure device was replaced by an atrial septal defect closure device to seal the perforation. Then the initial LAA closure device was reimplanted in a correct position. Needle pericardiocentesis was required but the subsequent course was uneventful. PMID- 23674435 TI - Relationship between cancer-related fatigue and personality in patients with breast cancer after chemotherapy. AB - BACKGROUND: This study aimed to explore the relationship between cancer-related fatigue (CRF) and personality in patients with breast cancer after chemotherapy. METHODS: A cross-sectional study was conducted to study the relationship between CRF and personality in breast cancer patients after chemotherapy. CRF and personality were measured by the cancer fatigue score and the Eysenck Personality Questionnaire, respectively. RESULTS: A total of 300 breast cancer patients who had received chemotherapy were recruited to this study. Eysenck Personality Questionnaire scores of psychoticism, introversion, and extroversion in the patients were lower than the norm level (p < 0.01), but those of neuroticism and lie were higher than the norm level (p < 0.01). Multivariate analyses showed positive correlation between psychoticism and affective fatigue, neuroticism and total fatigue, and physical fatigue and cognitive fatigue. Multivariate analyses also showed negative correlation between introversion or extroversion and total fatigue, physical fatigue or affective fatigue, and lie and total fatigue or cognitive fatigue. CONCLUSIONS: There was CRF in patients with breast cancer after chemotherapy. Psychoticism, extroversion/introversion, neuroticism, and lie are correlated with CRF in breast cancer patients after chemotherapy. PMID- 23674436 TI - White blood cell count and mortality in patients with acute pulmonary embolism. AB - Although associated with adverse outcomes in other cardiovascular diseases, the prognostic value of an elevated white blood cell (WBC) count, a marker of inflammation and hypercoagulability, is uncertain in patients with pulmonary embolism (PE). We therefore sought to assess the prognostic impact of the WBC in a large, state-wide retrospective cohort of patients with PE. We evaluated 14,228 patient discharges with a primary diagnosis of PE from 186 hospitals in Pennsylvania. We used random-intercept logistic regression to assess the independent association between WBC count levels at the time of presentation and mortality and hospital readmission within 30 days, adjusting for patient and hospital characteristics. Patients with an admission WBC count <5.0, 5.0-7.8, 7.9 9.8, 9.9-12.6, and >12.6 * 10(9) /L had a cumulative 30-day mortality of 10.9%, 6.2%, 5.4%, 8.3%, and 16.3% (P < 0.001), and a readmission rate of 17.6%, 11.9%, 10.9%, 11.5%, and 15.0%, respectively (P < 0.001). Compared with patients with a WBC count 7.9-9.8 * 10(9) /L, adjusted odds of 30-day mortality were significantly greater for patients with a WBC count <5.0 * 10(9) /L (odds ratio [OR] 1.52, 95% confidence interval [CI] 1.14-2.03), 9.9-12.6 * 10(9) /L (OR 1.55, 95% CI 1.26-1.91), or >12.6 * 10(9) /L (OR 2.22, 95% CI 1.83-2.69), respectively. The adjusted odds of readmission were also significantly increased for patients with a WBC count <5.0 * 10(9) /L (OR 1.34, 95% CI 1.07-1.68) or >12.6 * 10(9) /L (OR 1.29, 95% CI 1.10-1.51). In patients presenting with PE, WBC count is an independent predictor of short-term mortality and hospital readmission. PMID- 23674437 TI - 3-D residual eddy current field characterisation: applied to diffusion weighted magnetic resonance imaging. AB - Clinical use of the Stejskal-Tanner diffusion weighted images is hampered by the geometric distortions that result from the large residual 3-D eddy current field induced. In this work, we aimed to predict, using linear response theory, the residual 3-D eddy current field required for geometric distortion correction based on phantom eddy current field measurements. The predicted 3-D eddy current field induced by the diffusion-weighting gradients was able to reduce the root mean square error of the residual eddy current field to ~1 Hz. The model's performance was tested on diffusion weighted images of four normal volunteers, following distortion correction, the quality of the Stejskal-Tanner diffusion weighted images was found to have comparable quality to image registration based corrections (FSL) at low b-values. Unlike registration techniques the correction was not hindered by low SNR at high b-values, and results in improved image quality relative to FSL. Characterization of the 3-D eddy current field with linear response theory enables the prediction of the 3-D eddy current field required to correct eddy current induced geometric distortions for a wide range of clinical and high b-value protocols. PMID- 23674438 TI - Anatomical labeling of the Circle of Willis using maximum a posteriori probability estimation. AB - Anatomical labeling of the cerebral arteries forming the Circle of Willis (CoW) enables inter-subject comparison, which is required for geometric characterization and discovering risk factors associated with cerebrovascular pathologies. We present a method for automated anatomical labeling of the CoW by detecting its main bifurcations. The CoW is modeled as rooted attributed relational graph, with bifurcations as its vertices, whose attributes are characterized as points on a Riemannian manifold. The method is first trained on a set of pre-labeled examples, where it learns the variability of local bifurcation features as well as the variability in the topology. Then, the labeling of the target vasculature is obtained as maximum a posteriori probability (MAP) estimate where the likelihood of labeling individual bifurcations is regularized by the prior structural knowledge of the graph they span. The method was evaluated by cross-validation on 50 subjects, imaged with magnetic resonance angiography, and showed a mean detection accuracy of 95%. In addition, besides providing the MAP, the method can rank the labelings. The proposed method naturally handles anatomical structural variability and is demonstrated to be suitable for labeling arterial segments of the CoW. PMID- 23674439 TI - 3D strain assessment in ultrasound (Straus): a synthetic comparison of five tracking methodologies. AB - This paper evaluates five 3D ultrasound tracking algorithms regarding their ability to quantify abnormal deformation in timing or amplitude. A synthetic database of B-mode image sequences modeling healthy, ischemic and dyssynchrony cases was generated for that purpose. This database is made publicly available to the community. It combines recent advances in electromechanical and ultrasound modeling. For modeling heart mechanics, the Bestel-Clement-Sorine electromechanical model was applied to a realistic geometry. For ultrasound modeling, we applied a fast simulation technique to produce realistic images on a set of scatterers moving according to the electromechanical simulation result. Tracking and strain accuracies were computed and compared for all evaluated algorithms. For tracking, all methods were estimating myocardial displacements with an error below 1 mm on the ischemic sequences. The introduction of a dilated geometry was found to have a significant impact on accuracy. Regarding strain, all methods were able to recover timing differences between segments, as well as low strain values. On all cases, radial strain was found to have a low accuracy in comparison to longitudinal and circumferential components. PMID- 23674440 TI - Hybrid feature-based diffeomorphic registration for tumor tracking in 2-D liver ultrasound images. AB - Real-time ultrasound image acquisition is a pivotal resource in the medical community, in spite of its limited image quality. This poses challenges to image registration methods, particularly to those driven by intensity values. We address these difficulties in a novel diffeomorphic registration technique for tumor tracking in series of 2-D liver ultrasound. Our method has two main characteristics: 1) each voxel is described by three image features: intensity, local phase, and phase congruency; 2) we compute a set of forces from either local information (Demons-type of forces), or spatial correspondences supplied by a block-matching scheme, from each image feature. A family of update deformation fields which are defined by these forces, and inform upon the local or regional contribution of each image feature are then composed to form the final transformation. The method is diffeomorphic, which ensures the invertibility of deformations. The qualitative and quantitative results yielded by both synthetic and real clinical data show the suitability of our method for the application at hand. PMID- 23674441 TI - Case-control and prospective studies of dietary alpha-linolenic acid intake and prostate cancer risk: a meta-analysis. AB - OBJECTIVE: alpha-Linolenic acid (ALA) is considered to be a cardioprotective nutrient; however, some epidemiological studies have suggested that dietary ALA intake increases the risk of prostate cancer. The main objective was to conduct a systematic review and meta-analysis of case-control and prospective studies investigating the association between dietary ALA intake and prostate cancer risk. DESIGN: A systematic review and meta-analysis were conducted by searching MEDLINE and EMBASE for relevant prospective and case-control studies. INCLUDED STUDIES: We included all prospective cohort, case-control, nested case-cohort and nested case-control studies that investigated the effect of dietary ALA intake on the incidence (or diagnosis) of prostate cancer and provided relative risk (RR), HR or OR estimates. PRIMARY OUTCOME MEASURE: Data were pooled using the generic inverse variance method with a random effects model from studies that compared the highest ALA quantile with the lowest ALA quantile. Risk estimates were expressed as RR with 95% CIs. Heterogeneity was assessed by chi(2) and quantified by I(2). RESULTS: Data from five prospective and seven case-control studies were pooled. The overall RR estimate showed ALA intake to be positively but non significantly associated with prostate cancer risk (1.08 (0.90 to 1.29), p=0.40; I(2)=85%), but the interpretation was complicated by evidence of heterogeneity not explained by study design. A weak, non-significant protective effect of ALA intake on prostate cancer risk in the prospective studies became significant (0.91 (0.83 to 0.99), p=0.02) without evidence of heterogeneity (I(2)=8%, p=0.35) on removal of one study during sensitivity analyses. CONCLUSIONS: This analysis failed to confirm an association between dietary ALA intake and prostate cancer risk. Larger and longer observational and interventional studies are needed to define the role of ALA and prostate cancer. PMID- 23674442 TI - Determinants of vulnerability in early childhood development in Ireland: a cross sectional study. AB - OBJECTIVES: Early childhood development strongly influences lifelong health. The Early Development Instrument (EDI) is a well-validated population-level measure of five developmental domains (physical health and well-being, social competence, emotional maturity, language and cognitive skills, and communication skills and general knowledge) at school entry age. The aim of this study was to explore the potential of EDI as an indicator of early development in Ireland. DESIGN: A cross sectional design was used. SETTING: The study was conducted in 42 of 47 primary schools in a major Irish urban centre. PARTICIPANTS: EDI (teacher completed) scores were calculated for 1243 children in their first year of full-time education. Contextual data from a subset of 865 children were collected using a parental questionnaire. PRIMARY AND SECONDARY OUTCOME MEASURES: Children scoring in the lowest 10% of the population in one or more domains were deemed 'developmentally vulnerable'. Scores were correlated with contextual data from the parental questionnaire. RESULTS: In the sample population, 29% of children were not developmentally ready to engage in school. Factors associated with increased risk of vulnerability were being male OR 2.1 (CI 1.6 to 2.7); under 5 years OR 1.5 (CI 1.1 to 2.1) and having English as a second language OR 3.7 (CI 2.6 to 5.2). Adjusted for these demographics, low birth weight, poor parent/child interaction and mother's lower level of education showed the most significant ORs for developmental vulnerability. Calculating population attributable fractions, the greatest population-level risk factors were being male (35%), mother's education (27%) and having English as a second language (12%). CONCLUSIONS: The EDI and linked parental questionnaires are promising indicators of the extent, distribution and determinants of developmental vulnerability among children in their first year of primary school in Ireland. PMID- 23674443 TI - Cost-effectiveness of a telephone-delivered education programme to prevent early childhood caries in a disadvantaged area: a cohort study. AB - OBJECTIVES: Early childhood caries is a highly destructive dental disease which is compounded by the need for young children to be treated under general anaesthesia. In Australia, there are long waiting periods for treatment at public hospitals. In this paper, we examined the costs and patient outcomes of a prevention programme for early childhood caries to assess its value for government services. DESIGN: Cost-effectiveness analysis using a Markov model. SETTING: Public dental patients in a low socioeconomic, socially disadvantaged area in the State of Queensland, Australia. PARTICIPANTS: Children aged 6 months to 6 years received either a telephone prevention programme or usual care. PRIMARY AND SECONDARY OUTCOME MEASURES: A mathematical model was used to assess caries incidence and public dental treatment costs for a cohort of children. Healthcare costs, treatment probabilities and caries incidence were modelled from 6 months to 6 years of age based on trial data from mothers and their children who received either a telephone prevention programme or usual care. Sensitivity analyses were used to assess the robustness of the findings to uncertainty in the model estimates. RESULTS: By age 6 years, the telephone intervention programme had prevented an estimated 43 carious teeth and saved L69 984 in healthcare costs per 100 children. The results were sensitive to the cost of general anaesthesia (cost-savings range L36 043-L97 298) and the incidence of caries in the prevention group (cost-savings range L59 496-L83 368) and usual care (cost savings range L46 833-L93 328), but there were cost savings in all scenarios. CONCLUSIONS: A telephone intervention that aims to prevent early childhood caries is likely to generate considerable and immediate patient benefits and cost savings to the public dental health service in disadvantaged communities. PMID- 23674444 TI - Falling sex ratios and emerging evidence of sex-selective abortion in Nepal: evidence from nationally representative survey data. AB - OBJECTIVES: To quantify trends in changing sex ratios of births before and after the legalisation of abortion in Nepal. While sex-selective abortion is common in some Asian countries, it is not clear whether the legal status of abortion is associated with the prevalence of sex-selection when sex-selection is illegal. In this context, Nepal provides an interesting case study. Abortion was legalised in 2002 and prior to that, there was no evidence of sex-selective abortion. Changes in the sex ratio at birth since legalisation would suggest an association with legalisation, even though sex-selection is expressly prohibited. DESIGN: Analysis of data from four Demographic and Health Surveys, conducted in 1996, 2001, 2006 and 2011. SETTING: Nepal. PARTICIPANTS: 31 842 women aged 15-49. MAIN OUTCOME MEASURE: Conditional sex ratios (CSRs) were calculated, specifically the CSR for second-born children where the first-born was female. This CSR is where the evidence of sex-selective abortion will be most visible. CSRs were looked at over time to assess the impact of legalisation as well as for population sub-groups in order to identify characteristics of women using sex-selection. RESULTS: From 2007 to 2010, the CSR for second-order births where the first-born was a girl was found to be 742 girls per 1000 boys (95% CI 599 to 913). Prior to legalisation of abortion (1998-2000), the same CSR was 1021 (906-1150). After legalisation, it dropped most among educated and richer women, especially in urban areas. Just 325 girls were born for every 1000 boys among the richest urban women. CONCLUSIONS: The fall in CSRs witnessed post-legalisation indicates that sex-selective abortion is becoming more common. This change is very likely driven by both supply and demand factors. Falling fertility has intensified the need to bear a son sooner, while legal abortion services have reduced the costs and risks associated with obtaining an abortion. PMID- 23674445 TI - The relationship between osteoarthritis and cardiovascular disease in a population health survey: a cross-sectional study. AB - OBJECTIVES: Our objective was to determine the relationship between osteoarthritis (OA) and heart diseases (myocardial infarction (MI), angina, congestive heart failure (CHF)) and stroke using population-based survey data. DESIGN: Cross-sectional study. SETTING: Canadian Community Health Survey (CCHS). PARTICIPANTS: Adult participants in the CCHS cycles 1.1, 2.1 and 3.1 were included. CCHS provides nationally representative data on health determinants, health status and health system utilisation. We have identified 40 817 self reported OA subjects and selected 1:1 matched non-OA respondents by age, sex and CCHS cycles. MAIN OUTCOME MEASURES: Self-reported heart disease was the primary outcome and MI, angina, CHF and stroke were considered as secondary outcomes. Multivariable logistic regression models were used to estimate the ORs after adjusting for sociodemographic status, obesity, physical activity, smoking status, fruit and vegetable consumption, medication use, diabetes, hypertension and chronic obstructive pulmonary disease. RESULTS: The mean age of OA cases was 66 years and 71.6% were women. OA exhibited increased odds of prevalent heart disease, and adjusted overall OR (95% CI) was 1.45 (1.36 to 1.54), 1.35 (1.21 to 1.50) among men and 1.51 (1.39 to 1.64) among women with OA. OA showed increased ORs for angina and CHF in both men and women, and for MI in women. ORs (95% CI) for men and women, respectively, were 1.08 (0.91 to 1.28) and 1.49 (1.28 to 1.75) for MI, 1.76 (1.43 to 2.17) and 1.84 (1.59 to 2.14) for angina, 1.50 (1.13 to 1.97) and 1.81 (1.49 to 2.21) for CHF, and 1.08 (0.83 to 1.40) and 1.13 (0.93 to 1.37) for stroke. CONCLUSIONS: Prevalent OA was associated with self-reported heart disease, particularly angina, and CHF in both men and women, after controlling for established risk factors for these conditions. This study provides a rationale for further investigation of the association between OA and heart disease in longitudinal studies for investigating possible biological and behavioural mechanisms. PMID- 23674446 TI - Addressing the human resources crisis: a case study of Cambodia's efforts to reduce maternal mortality (1980-2012). AB - OBJECTIVE: To identify factors that have contributed to the systematic development of the Cambodian human resources for health (HRH) system with a focus on midwifery services in response to high maternal mortality in fragile resource constrained countries. DESIGN: Qualitative case study. Review of the published and grey literature and in-depth interviews with key informants and stakeholders using an HRH system conceptual framework developed by the authors ('House Model'; Fujita et al, 2011). Interviews focused on the perceptions of respondents regarding their contributions to strengthening midwifery services and the other external influences which may have influenced the HRH system and reduction in the maternal mortality ratio (MMR). SETTING: Three rounds of interviews were conducted with senior and mid-level managers of the Ministries of Health (MoH) and Education, educational institutes and development partners. PARTICIPANTS: A total of 49 interviewees, who were identified through a snowball sampling technique. MAIN OUTCOME MEASURES: Scaling up the availability of 24 h maternal health services at all health centres contributing to MMR reduction. RESULTS: The incremental development of the Cambodian HRH system since 2005 focused on the production, deployment and retention of midwives in rural areas as part of a systematic strategy to reduce maternal mortality. The improved availability and access to midwifery services contributed to significant MMR reduction. Other contributing factors included improved mechanisms for decision-making and implementation; political commitment backed up with necessary resources; leadership from the top along with a growing capacity of mid-level managers; increased MoH capacity to plan and coordinate; and supportive development partners in the context of a conducive external environment. CONCLUSIONS: Lessons from this case study point to the importance of a systemic and comprehensive approach to health and HRH system strengthening and of ongoing capacity enhancement and leadership development to ensure effective planning, implementation and monitoring of HRH policies and strategies. PMID- 23674447 TI - Nocturnal sweating--a common symptom of obstructive sleep apnoea: the Icelandic sleep apnoea cohort. AB - OBJECTIVES: To estimate the prevalence and characteristics of frequent nocturnal sweating in obstructive sleep apnoea (OSA) patients compared with the general population and evaluate the possible changes with positive airway pressure (PAP) treatment. Nocturnal sweating can be very bothersome to the patient and bed partner. DESIGN: Case-control and longitudinal cohort study. SETTING: Landspitali The National University Hospital, Iceland. PARTICIPANTS: The Icelandic Sleep Apnea Cohort consisted of 822 untreated patients with OSA, referred for treatment with PAP. Of these, 700 patients were also assessed at a 2-year follow-up. The control group consisted of 703 randomly selected subjects from the general population. INTERVENTION: PAP therapy in the OSA cohort. MAIN OUTCOME MEASURES: Subjective reporting of nocturnal sweating on a frequency scale of 1-5: (1) never or very seldom, (2) less than once a week, (3) once to twice a week, (4) 3-5 times a week and (5) every night or almost every night. Full PAP treatment was defined objectively as the use for >=4 h/day and >=5 days/week. RESULTS: Frequent nocturnal sweating (>=3* a week) was reported by 30.6% of male and 33.3% of female OSA patients compared with 9.3% of men and 12.4% of women in the general population (p<0.001). This difference remained significant after adjustment for demographic factors. Nocturnal sweating was related to younger age, cardiovascular disease, hypertension, sleepiness and insomnia symptoms. The prevalence of frequent nocturnal sweating decreased with full PAP treatment (from 33.2% to 11.5%, p<0.003 compared with the change in non-users). CONCLUSIONS: The prevalence of frequent nocturnal sweating was threefold higher in untreated OSA patients than in the general population and decreased to general population levels with successful PAP therapy. Practitioners should consider the possibility of OSA in their patients who complain of nocturnal sweating. PMID- 23674448 TI - Sustainability of knowledge translation interventions in healthcare decision making: protocol for a scoping review. AB - INTRODUCTION: Knowledge translation (KT also known as research utilisation, translational medicine and implementation science) is a dynamic and iterative process that includes the synthesis, dissemination, exchange and ethically sound application of knowledge to improve health. After the implementation of KT interventions, their impact on relevant outcomes should be monitored. The objectives of this scoping review are to: (1) conduct a systematic search of the literature to identify the impact on healthcare outcomes beyond 1 year, or beyond the termination of funding of the initiative of KT interventions targeting chronic disease management for end-users including patients, clinicians, public health officials, health services managers and policy-makers; (2) identify factors that influence sustainability of effective KT interventions; (3) identify how sustained change from KT interventions should be measured; and (4) develop a framework for assessing sustainability of KT interventions. METHODS AND ANALYSIS: Comprehensive searches of relevant electronic databases (eg, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials), websites of funding agencies and websites of healthcare provider organisations will be conducted to identify relevant material. We will include experimental, quasi-experimental and observational studies providing information on the sustainability of KT interventions targeting chronic disease management in adults and focusing on end users including patients, clinicians, public health officials, health services managers and policy-makers. Two reviewers will pilot-test the screening criteria and data abstraction form. They will then screen all citations, full articles and abstract data in duplicate independently. The results of the scoping review will be synthesised descriptively and used to develop a framework to assess the sustainability of KT interventions. DISCUSSION AND DISSEMINATION: Our results will help inform end-users (ie, patients, clinicians, public health officials, health services managers and policy-makers) regarding the sustainability of KT interventions. Our dissemination plan includes publications, presentations, website posting and a stakeholder meeting. PMID- 23674449 TI - Single image dehazing by multi-scale fusion. AB - Haze is an atmospheric phenomenon that significantly degrades the visibility of outdoor scenes. This is mainly due to the atmosphere particles that absorb and scatter the light. This paper introduces a novel single image approach that enhances the visibility of such degraded images. Our method is a fusion-based strategy that derives from two original hazy image inputs by applying a white balance and a contrast enhancing procedure. To blend effectively the information of the derived inputs to preserve the regions with good visibility, we filter their important features by computing three measures (weight maps): luminance, chromaticity, and saliency. To minimize artifacts introduced by the weight maps, our approach is designed in a multiscale fashion, using a Laplacian pyramid representation. We are the first to demonstrate the utility and effectiveness of a fusion-based technique for dehazing based on a single degraded image. The method performs in a per-pixel fashion, which is straightforward to implement. The experimental results demonstrate that the method yields results comparative to and even better than the more complex state-of-the-art techniques, having the advantage of being appropriate for real-time applications. PMID- 23674450 TI - Two-dimensional maximum local variation based on image euclidean distance for face recognition. AB - Manifold learning concerns the local manifold structure of high dimensional data, and many related algorithms are developed to improve image classification performance. None of them, however, consider both the relationships among pixels in images and the geometrical properties of various images during learning the reduced space. In this paper, we propose a linear approach, called two dimensional maximum local variation (2DMLV), for face recognition. In 2DMLV, we encode the relationships among pixels in images using the image Euclidean distance instead of conventional Euclidean distance in estimating the variation of values of images, and then incorporate the local variation, which characterizes the diversity of images and discriminating information, into the objective function of dimensionality reduction. Extensive experiments demonstrate the effectiveness of our approach. PMID- 23674451 TI - Non-linear direct multi-scale image enhancement based on the luminance and contrast masking characteristics of the human visual system. AB - Image enhancement is a crucial pre-processing step for various image processing applications and vision systems. Many enhancement algorithms have been proposed based on different sets of criteria. However, a direct multi-scale image enhancement algorithm capable of independently and/or simultaneously providing adequate contrast enhancement, tonal rendition, dynamic range compression, and accurate edge preservation in a controlled manner has yet to be produced. In this paper, a multi-scale image enhancement algorithm based on a new parametric contrast measure is presented. The parametric contrast measure incorporates not only the luminance masking characteristic, but also the contrast masking characteristic of the human visual system. The formulation of the contrast measure can be adapted for any multi-resolution decomposition scheme in order to yield new human visual system-inspired multi-scale transforms. In this article, it is exemplified using the Laplacian pyramid, discrete wavelet transform, stationary wavelet transform, and dual-tree complex wavelet transform. Consequently, the proposed enhancement procedure is developed. The advantages of the proposed method include: 1) the integration of both the luminance and contrast masking phenomena; 2) the extension of non-linear mapping schemes to human visual system inspired multi-scale contrast coefficients; 3) the extension of human visual system-based image enhancement approaches to the stationary and dual-tree complex wavelet transforms, and a direct means of; 4) adjusting overall brightness; and 5) achieving dynamic range compression for image enhancement within a direct multi-scale enhancement framework. Experimental results demonstrate the ability of the proposed algorithm to achieve simultaneous local and global enhancements. PMID- 23674452 TI - Luma-chroma space filter design for subpixel-based monochrome image downsampling. AB - In general, subpixel-based downsampling can achieve higher apparent resolution of the down-sampled images on LCD or OLED displays than pixel-based downsampling. With the frequency domain analysis of subpixel-based downsampling, we discover special characteristics of the luma-chroma color transform choice for monochrome images. With these, we model the anti-aliasing filter design for subpixel-based monochrome image downsampling as a human visual system-based optimization problem with a two-term cost function and obtain a closed-form solution. One cost term measures the luminance distortion and the other term measures the chrominance aliasing in our chosen luma-chroma space. Simulation results suggest that the proposed method can achieve sharper down-sampled gray/font images compared with conventional pixel and subpixel-based methods, without noticeable color fringing artifacts. PMID- 23674453 TI - Enhancing training collections for image annotation: an instance-weighted mixture modeling approach. AB - Tagged Web images provide an abundance of labeled training examples for visual concept learning. However, the performance of automatic training data selection is susceptible to highly inaccurate tags and atypical images. Consequently, manually curated training data sets are still a preferred choice for many image annotation systems. This paper introduces ARTEMIS - a scheme to enhance automatic selection of training images using an instance-weighted mixture modeling framework. An optimization algorithm is derived to learn instance-weights in addition to mixture parameter estimation, essentially adapting to the noise associated with each example. The mechanism of hypothetical local mapping is evoked so that data in diverse mathematical forms or modalities can be cohesively treated as the system maintains tractability in optimization. Finally, training examples are selected from top-ranked images of a likelihood-based image ranking. Experiments indicate that ARTEMIS exhibits higher resilience to noise than several baselines for large training data collection. The performance of ARTEMIS trained image annotation system is comparable with usage of manually curated data sets. PMID- 23674454 TI - Image size invariant visual cryptography for general access structures subject to display quality constraints. AB - Conventional visual cryptography (VC) suffers from a pixel-expansion problem, or an uncontrollable display quality problem for recovered images, and lacks a general approach to construct visual secret sharing schemes for general access structures. We propose a general and systematic approach to address these issues without sophisticated codebook design. This approach can be used for binary secret images in non-computer-aided decryption environments. To avoid pixel expansion, we design a set of column vectors to encrypt secret pixels rather than using the conventional VC-based approach. We begin by formulating a mathematic model for the VC construction problem to find the column vectors for the optimal VC construction, after which we develop a simulated-annealing-based algorithm to solve the problem. The experimental results show that the display quality of the recovered image is superior to that of previous papers. PMID- 23674455 TI - An efficient algorithm for multiphase image segmentation with intensity bias correction. AB - This paper presents a variational model for simultaneous multiphase segmentation and intensity bias estimation for images corrupted by strong noise and intensity inhomogeneity. Since the pixel intensities are not reliable samples for region statistics due to the presence of noise and intensity bias, we use local information based on the joint density within image patches to perform image partition. Hence, the pixel intensity has a multiplicative distribution structure. Then, the maximum-a-posteriori (MAP) principle with those pixel density functions generates the model. To tackle the computational problem of the resultant nonsmooth nonconvex minimization, we relax the constraint on the characteristic functions of partition regions, and apply primal-dual alternating gradient projections to construct a very efficient numerical algorithm. We show that all the variables have closed-form solutions in each iteration, and the computation complexity is very low. In particular, the algorithm involves only regular convolutions and pointwise projections onto the unit ball and canonical simplex. Numerical tests on a variety of images demonstrate that the proposed algorithm is robust, stable, and attains significant improvements on accuracy and efficiency over the state-of-the-arts. PMID- 23674457 TI - A call for holistic education scholarship. PMID- 23674456 TI - Fast l1-minimization algorithms for robust face recognition. AB - l1-minimization refers to finding the minimum l1-norm solution to an underdetermined linear system [Formula: see text]. Under certain conditions as described in compressive sensing theory, the minimum l1-norm solution is also the sparsest solution. In this paper, we study the speed and scalability of its algorithms. In particular, we focus on the numerical implementation of a sparsity based classification framework in robust face recognition, where sparse representation is sought to recover human identities from high-dimensional facial images that may be corrupted by illumination, facial disguise, and pose variation. Although the underlying numerical problem is a linear program, traditional algorithms are known to suffer poor scalability for large-scale applications. We investigate a new solution based on a classical convex optimization framework, known as augmented Lagrangian methods. We conduct extensive experiments to validate and compare its performance against several popular l1-minimization solvers, including interior-point method, Homotopy, FISTA, SESOP-PCD, approximate message passing, and TFOCS. To aid peer evaluation, the code for all the algorithms has been made publicly available. PMID- 23674458 TI - The many faces of alpha-synuclein mutations. AB - Since the first description of alpha-synuclein (SNCA) mutations in 1997, this gene has probably become the most intensely investigated one associated with monogenic Parkinson disease (PD). Prompted by the finding of a novel SNCA mutation, H50Q, we systematically explored the 145 published SNCA mutation carriers for a possible mutation (type)-specific clinical expression, which appears to be rather unique to SNCA mutations compared with other PD genes. The A53T mutation is associated with an approximately 10-year earlier age at onset than the other 3 known missense mutations, including the new H50Q mutation. Similarly, SNCA triplication carriers have an approximately 10-year earlier onset and a more rapid disease course than duplication carriers, who, overall closely resemble patients with idiopathic PD. Furthermore, higher order SNCA multiplications are associated with additional neurologic features, such as myoclonus. For the nonmotor features, their mere frequency appears less striking than their severity, with an early age of onset of depression or dementia, suicidal ideation, and multimodal hallucinations. We conclude that, (1) although SNCA mutations are a rare cause of PD, it remains worth testing for new mutations in this gene; (2) a differential view of SNCA mutations and variants may allow important pathophysiologic inferences even beyond monogenic PD and is warranted in the context of clinical counseling. PMID- 23674459 TI - Global Synchronization Measurement of Multivariate Neural Signals with Massively Parallel Nonlinear Interdependence Analysis. AB - The estimation of synchronization amongst multiple brain regions is a critical issue in understanding brain functions. There is a lack of an appropriate approach which is capable of 1) measuring the direction and strength of synchronization of activities of multiple brain regions, and 2) adapting to the quickly increasing sizes and scales of neural signals. Nonlinear Interdependence (NLI) analysis is an effective method for measuring synchronization direction and strength of bivariate neural signal. However, the method currently does not directly apply in handling multivariate signal. Its application in practice has also long been largely hampered by the ultra-high complexity of NLI algorithms. Aiming at these problems, this study 1) extends the conventional NLI to quantify the global synchronization of multivariate neural signals, and 2) develops a parallelized NLI method with general-purpose computing on the graphics processing unit (GPGPU), namely, G-NLI. The approach performs synchronization measurement in a massively parallel manner. The G-NLI has improved the runtime performance by more than 1000 times comparing to the original sequential NLI. Meanwhile, the G NLI was employed to analyze 10-channel local field potential (LFP) recordings from a patient suffering from temporal lobe epilepsy. The results demonstrate that the proposed G-NLI method can support real-time global synchronization measurement and it could be successful in localization of epileptic focus. PMID- 23674460 TI - Cholesterol granuloma associated with otitis media in a cat. AB - An 8-year-old, male neutered Siamese cat was presented with Horner syndrome and right head tilt. A soft tissue mass was observed in the right tympanic cavity, and bulla osteotomy was performed. Tissue samples retrieved from the tympanic cavity were sent for histology, and a middle ear fluid swab was sent for bacterial culture and sensitivity. Histologic diagnosis was of otitis media associated with cholesterol granuloma (CG). Bacterial culture yielded Pasteurella multocida and Leifsonia (Corynebacterium) aquaticum. Middle ear CG is frequently seen in human beings and is associated with a variety of middle ear diseases including otitis media. Cholesterol granuloma of the middle ear has been experimentally induced in cats. The clinical and pathological findings of a spontaneous case of CG in the tympanic cavity of a cat with otitis media are described herein. PMID- 23674461 TI - Francisella tularensis infection in a stone marten (Martes foina) without classic pathological lesions consistent with tularemia. AB - The current report describes the isolation and typing of a strain of Francisella tularensis, the causative agent of tularemia, from the spleen of a stone marten (Martes foina) showing no classic lesions consistent with the disease. The identification of this bacterium, belonging to the World Health Organization risk 3 category and considered to have a low infectious dose, could be performed only because of an ongoing project screening F. tularensis in the environment sensu lato. The findings described herein should alert diagnostic laboratories of the possible presence of F. tularensis in clinical samples in countries where tularemia is endemic even in cases with no consistent anamnesis and from unsuspected animal species. PMID- 23674462 TI - Hepatitis and splenitis due to systemic tetratrichomoniasis in an American white pelican (Pelecanus erythrorhynchos). AB - A free-ranging, young adult, female American white pelican (Pelecanus erythrorhynchos), found dead on the grounds of the San Diego Zoo Safari Park in Southern California, had severe multifocal to coalescing necrotizing hepatitis and splenitis on postmortem examination. Histologically, within the large areas of necrosis were myriad pleomorphic, 5-20 um in diameter, protozoal organisms with 1 to multiple nuclei. Ultrastructurally, the organisms were consistent with a trichomonad flagellate. Polymerase chain reaction and sequencing of the small subunit ribosomal RNA gene identified nucleotide sequences with 99% identity to Tetratrichomonas gallinarum, which is a common inhabitant of the intestinal tract of galliform and anseriform birds that has occasionally been associated with disease, including typhlitis and hepatitis. Damage to the cecal mucosa in the pelican from trematodes and secondary bacterial infection could have allowed invasion and systemic dissemination of the organism. Exposure of the pelican to a variety of native and exotic anseriform and galliform birds at the zoological institution could have led to cross-species infection and severe manifestation of disease in a novel host. PMID- 23674463 TI - Identification of brachyspina syndrome carriers in Chinese Holstein cattle. AB - Brachyspina syndrome (BS) is a rare monogenic autosomal recessive hereditary disorder identified in the Holstein breed caused by a 3.3-kb deletion in the bovine Fanconi anemia complementation group I (FANCI) gene on chromosome 21. In previous reports, the BS mutant allele was identified in North American and European Holstein populations. Because frozen semen and embryos have been imported into China from such regions during the past few years, BS has potentially spread into the dairy cattle population in China. In the present study, 206 Holstein bulls and 136 Holstein cows were tested for BS, with 10 BS carrier bulls and 3 carrier cows identified. Pedigree analysis showed that all 10 BS carrier bulls could be traced back to a common ancestor, the U.S. Holstein sire Sweet Haven Tradition. It is recommended that effective selection and mating strategies should be carried out to gradually eliminate this recessive gene from the Chinese Holstein population. PMID- 23674464 TI - Cognitive behavioural therapy and the psychopathology of schizophrenia: systematic review and meta-analysis. AB - PURPOSE: To examine whether cognitive behaviour therapy (CBT) reduces psychopathology in patients with schizophrenia more effectively than the use of non-cognitive psychotherapies. METHOD: Systematic review and meta-analysis of the literature was performed. All Randomized Controlled Trials meeting the inclusion criteria were analysed using RevMan software. This design was used to maximize power and study efficacy. Medline, PsycINFO, and Embase were searched using free text keywords to identify potential papers. Nine were included in the final meta analysis. Change in psychopathology at the end of therapy was the end point investigated. A random effects model was used to assess the standard mean difference between the CBT and supportive control groups. RESULTS: Meta-analysis of CBT versus supportive therapy did not find significant differences between the therapy groups at the end of treatment in respect of psychopathology. There was no evidence of publication bias. Post hoc power analysis using the Z test ruled out type one error. CONCLUSIONS: Theoretically based CBT therapies, although proving effective, may not out perform more accessible and simpler forms of therapy for patients with schizophrenia in reducing psychopathology. Consideration of supportive therapy should be made for patients with psychotic mental disorder. PMID- 23674465 TI - Cognitive-behavioural therapy for schizophrenia: a critical commentary on the Newton-Howes and Wood meta-analysis. AB - Newton-Howes and Wood (published online, this journal, 8 Dec 2011) report the results of their systematic review and meta-analysis of clinical trials of cognitive-behavioural therapy (CBT) for schizophrenia. They ran a random effects analysis of endpoint data from trials where participants were randomly allocated to receive either CBT or a control therapy, which could be inactive (e.g., befriending) or active (e.g., analytic supportive psychotherapy), found no difference between the groups and concluded 'it (CBT) does not outperform supportive therapy in effecting change in phenomenology.' Such a conclusion is premature, if not unwarranted, for a number of reasons, including basic mistakes, lack of transparency, and failure to consider dose. PMID- 23674466 TI - 'Poor me' versus 'Bad me' paranoia: the association between self-beliefs and the instability of persecutory ideation. AB - OBJECTIVES: To investigate whether different self-attributes would be associated with different degrees of deservedness of persecution in a clinical paranoid sample. BACKGROUND: Some studies have shown differences between the self-esteem (SE) of individuals with 'Poor Me' (PM) and 'Bad Me' (BM) paranoia (Bentall et al., 2009; Chadwick, Trower, Juusti-Butler, & Maguire, 2005). Most studies investigating this relationship have employed a cross-sectional design, precluding the investigation of changes over time. METHODS: In the cross sectional part of the study, 45 clinical participants and 25 controls were assessed in terms of paranoia, deservedness of persecution, SE, self discrepancies, daily events, and coping strategies. In the longitudinal part of the study, the clinical group was re-assessed over a period of another 2 days, in order to study changes in these variables. RESULTS: At baseline, there were no differences between the SE of the two paranoia presentations, which was significantly lower than the controls'. However, the paired-samples repeated analysis found the SE of individuals when in a PM presentation was higher than when they were BM. Only BM paranoia was found to be associated with higher self ideal:self-actual self-discrepancies than the other groups. The longitudinal analysis indicated that, having been PM and having low SE at the previous assessment day made it more likely that individuals would be in BM subsequently. No differences in causal attributions made for ecological events were found between the groups. Higher SE was found to be more likely when individuals coped with adversities by using social support. CONCLUSIONS: Both deservedness of persecution and self-views appear to be unstable in individuals with paranoia and to change consistently over time, a finding which is in keeping with Bentall et al.'s (2001) dynamic model of paranoia. PMID- 23674467 TI - Attachment styles and affect regulation among outpatients with schizophrenia: relationships to symptomatology and emotional distress. AB - OBJECTIVES: Using the model of activation and dynamics of the attachment system (Shaver & Mikulincer, 2002) and dynamic stress-vulnerability models of psychosis (Ingmar & Luxton, 2005) as the analytical frameworks, the authors tested the hypothesis that the insecure attachment styles are differentially associated with the severity of psychopathological symptoms and emotional distress among outpatients with International Classification of Diseases, Tenth edition (ICD-10) diagnosis of schizophrenia. METHODS: Attachment styles were identified using the Relationship Questionnaire (Bartholomew & Horowitz, 1991) among 100 outpatients with an ICD-10 schizophrenia diagnosis. Current symptom severity was measured by the Positive and Negative Syndromes Scale (Kay, Fiszbein, & Opler, 1987) and emotional distress by the General Health Questionnaire (Goldberg & Williams, 1988). Univariate and multivariate analyses were performed to test the hypotheses. RESULTS: The preoccupied and fearful-avoidant attachment patterns were associated with higher scores of psychotic (delusions, suspiciousness/persecution, and hallucinatory behaviour) and affective (anxiety, tension, guilt feeling, and depression) symptoms, whereas the dismissing-avoidant style was associated with only anxiety. All the insecure attachment styles were associated with elevated emotional distress. CONCLUSIONS: The findings support the hypothesis of a predisposing role of the preoccupied and fearful-avoidant styles in psychotic symptom formation and call for cognitive interpersonal interventions geared to reduce symptom and emotional distress severity. PMID- 23674468 TI - Biased thinking assessed by external observers in borderline personality disorder. AB - OBJECTIVES: Biased thinking (to some extent overlapping with the concepts of cognitive distortions and cognitive errors) is a key concept in cognitive therapy of borderline personality disorder (BPD). Specific contents and cognitive processes related to BPD functioning are known. However, most studies are based on self-report measures which present a number of important limitations, in particular the difficulty in assessing non-conscious processes infused by affect. So far, no studies were conducted using valid observer-rated methodology addressing the question of biased thinking in BPD as it unfolds spontaneously in session. DESIGN: This is a controlled interview study comparing two matched groups, BPD patients and healthy controls. METHODS: A total of N= 25 clinical dynamic interviews with patients presenting with BPD were transcribed and rated using the Cognitive Errors Rating Scale (Drapeau, Perry, & Dunkley, 2008); their cognitive profiles were compared to those of N= 25 healthy controls who underwent the same procedure. RESULTS: Overall, results indicated that no between-group difference in the frequency of specific biases was found. However, heightened levels of negative cognitive biases, in particular over-generalizing and fortune telling, were associated with BPD. Furthermore, negative over-generalizing was associated with the number of BPD symptoms. CONCLUSIONS: These results have high levels of ecological validity and are promising for the refinement of cognitive theory of BPD. Clinical implications for assessment and intervention are discussed. PMID- 23674469 TI - Relatives' responses to psychosis: an exploratory investigation of low expressed emotion relatives. AB - OBJECTIVE: Expressed emotion (EE) refers to the emotional climate within a family. High EE significantly increases the risk of relapse in people with psychosis. The focus of research to date has largely been on understanding mechanisms underlying high EE. A greater understanding of low EE would help guide family interventions to build strengths within the family. The aim of this study was to understand how low EE relatives respond to having a close family member with psychosis. DESIGN: A subsample of eight low EE relatives, from a larger study investigating relatives' adaptation to recent onset psychosis, was interviewed. Transcripts were analysed following the principles of interpretive phenomenological analysis (IPA). METHOD: Semi-structured interviews were carried out with each relative covering broad areas of their experience, including their awareness of the development of mental health problems and relationship with their relative. RESULTS: Four core themes emerged: witnessing the distress; empathy through acceptance and understanding; a broad range of coping strategies to reduce distress; and realistic optimism for the future. CONCLUSIONS: The study highlights that, although relatives described distressing experiences and feelings of frustration and anger, they showed empathy and commitment to support the person. They demonstrated psychological mindedness about the psychosis and related behaviours, had developed coping strategies, and had adjusted their expectations for the future. Further research is warranted to investigate the findings in larger samples, with a view to informing the development of more effective ways of supporting families. PMID- 23674470 TI - 'A different world' individuals' experience of an integrated family intervention for psychosis and its contribution to recovery. AB - OBJECTIVES: The aim of this study is to explore the meaning and significance of family interventions (FI) for the individual who experiences psychosis, and its significance for recovery. DESIGN: A qualitative in-depth interview design was used to explore individuals' experience of FI and its meaning to them. METHODS: Seven individuals recovering from psychosis attending integrated FI sessions were interviewed using a semi-structured interview schedule developed with service user input. Interviews were recorded, transcribed verbatim, and explored using Interpretative Phenomenological Analysis. RESULTS: Three central themes highlighted the participants' experience: (1) They welcomed the shared experience with their families and felt contained and valued by the therapists; (2) They felt the sessions contributed to changed patterns of relating within the family and the creation of new meaning through the validation of multiple perspectives; and (3) They described how the family sessions supported a new positioning in the world, a sense of their own empowerment and personal responsibility, greater self acceptance, an increased ability to manage emotions, and hope for the future. CONCLUSIONS: Conditions in the family sessions provided an environment for changes in patterns of relating, personal meaning, and emotions to take place. Recovery, for these individuals, appeared to be about repositioning themselves in the world. The shared experience of sessions and the recognition of multiple perspectives within a containing environment may be related to recovery via the development of new perspectives and a more robust sense of self. This has clinical implications for the focus of FI sessions. PMID- 23674471 TI - Working with despair: a phenomenological investigation. AB - OBJECTIVES: Psychotherapy as an appropriate treatment for clients in despair is an important area of inquiry, particularly given its problematic nature in the therapy and the resulting impact on the therapeutic relationship. This study aimed to explore how psychotherapists experience working with a client in despair through a phenomenological investigation. DESIGN: A phenomenological epistemology and methodology was adopted as the study was focused on understanding the phenomenon in terms of the participant's meanings of the lived situation. METHOD: In-depth, semi-structured interviews were conducted with eight accredited psychotherapists who had worked with clients in despair. The interviews were transcribed and analysed using the method of Empirical Phenomenological Analysis (EPA). RESULTS: Four main themes emerged from the analysis: Psychotherapist's experience of client's despair, Evocation in the psychotherapist, Therapeutic ways of responding, and Supporting the psychotherapist. CONCLUSIONS: The phenomenological findings inform and support the idea of a client's despair as something that challenges the psychotherapist personally and professionally. With implications for practice, the findings also suggest that in order to prevent the despair from encompassing the psychotherapist, they must locate a therapeutic balance; one that allows them to be with the client's despair, whilst allowing a certain degree of distance from the despair which may enable the psychotherapist to consider hope and to see the client's situation from different perspectives. PMID- 23674472 TI - Bleeding from the eyes and through intact skin: physiologic, structural, spiritual, or faked? AB - Patients with an apparent bleeding disorder can usually be diagnosed by a careful history, physical examination, and screening laboratory tests. However, at times the constellation of bleeding signs and symptoms fail to be explained by test results and/or our current understanding of hemostatic mechanisms. One such patient is the subject of the current report. She is a 13-year-old female with a history of striking bleeding manifestations, including spontaneous hemorrhage from her eyes, scalp, hands, and feet. She was evaluated by one of the authors at a teaching hospital in Mumbai, India in March 2009 during the filming of a National Geographic Channel documentary characterizing puzzling medical disorders encountered in India. Given her unusual bleeding manifestations, she received international media attention at the time. National Geographic and a film company in the United Kingdom subsequently expressed interest in highlighting the patient to document her seemingly rare hematologic disorder and contacted the American Society of Hematology to identify an American hematologist to further investigate the case. With consent of the family and collaboration with a hematologist practicing at a teaching hospital in Mumbai, filming commenced during March 2009 in an attempt to capture the patient's diagnosis and the cultural and medical milieu in which the bleeding events occurred. PMID- 23674478 TI - Mutations in extracellular matrix genes NID1 and LAMC1 cause autosomal dominant Dandy-Walker malformation and occipital cephaloceles. AB - We performed whole-exome sequencing of a family with autosomal dominant Dandy Walker malformation and occipital cephaloceles and detected a mutation in the extracellular matrix (ECM) protein-encoding gene NID1. In a second family, protein interaction network analysis identified a mutation in LAMC1, which encodes a NID1-binding partner. Structural modeling of the NID1-LAMC1 complex demonstrated that each mutation disrupts the interaction. These findings implicate the ECM in the pathogenesis of Dandy-Walker spectrum disorders. PMID- 23674479 TI - Management of severe aortic regurgitation in a patient with cardiogenic shock using a percutaneous left ventricular assist device and transcatheter occlusion of the failed aortic valve homograft as a bridge to surgical valve replacement. AB - Acute hemodynamic compromise due to severe aortic regurgitation remains a difficult problem. The optimal management strategy and timing of surgery continues to evolve as new technologies become available. Here, we report the case of a young woman presenting with severe regurgitation of an aortic homograft who developed precipitous cardiogenic shock and multi-organ dysfunction. Her mortality risk with emergent surgery was prohibitive, and no percutaneous valve in-valve device was available. We stabilized her condition by placing an Amplatz type Atrial Septal Defect (ASD) occluder across her aortic valve in conjunction with a percutaneous left ventricular assist device as a bridge to surgical valve replacement. She went on to a successful surgery and recovered well. PMID- 23674480 TI - Pharmacological treatment of chorea in Huntington's disease-good clinical practice versus evidence-based guideline. AB - Recently, the American Academy of Neurology published an evidence-based guideline for the pharmacological treatment of chorea in Huntington's disease. Although the progress in medical care because of the implementation of criteria of evidence based medicine is undisputed, the guideline classifies the level of evidence for drugs to reduce chorea based on anchors in the Unified Huntington's Disease Rating Scale-Total Motor Score chorea sum score, which were chosen arbitrarily and do not reflect validated or generally accepted levels of clinical relevance. Thus, the guideline faces several serious limitations and delivers clinical recommendations that do not represent current clinical practice; these are reviewed in detail, and arguments are presented why these recommendations should not be followed. To remedy the lack of evidence-based recommendations and provide guidance to a pragmatic symptomatic therapy of chorea in HD, a flow-chart pathway that follows currently established clinical standards based on expert opinion is presented. PMID- 23674481 TI - Effects of dietary phytophenols on the expression of microRNAs involved in mammalian cell homeostasis. AB - Besides synthesizing nutritive substances (proteins, fats and carbohydrates) for energy and growth, plants produce numerous non-energetic so-called secondary metabolites (mainly polyphenols) that allow them to protect themselves against infections and other types of hostile environments. Interestingly, these polyphenols often provide cells with valuable bioactive properties for the maintenance of their functions and homeostasis (signaling, gene regulation, protection against acquired or infectious diseases, etc.) both in humans and animals. Namely, from a nutritional point of view, and based on epidemiological data, it is now well accepted that the regular consumption of green vegetables, fruits and fibers has protective effects against the onset of cancer as well as of inflammatory, neurodegenerative, metabolic and cardiovascular diseases, and consequently increases the overall longevity. In particular, grapevine plants produce large amounts of a wide variety of polyphenols. The most prominent of those-resveratrol-has been shown to impair or delay cardiovascular alterations, cancer, inflammation, aging, etc. Until recently, the molecular bases of the pleiotropic effects of resveratrol remained largely unclear despite numerous studies on a variety of signaling pathways and the transcriptional networks that they control. However, it has been recently proposed that the protective properties of resveratrol may arise from its modulation of small non-coding regulatory RNAs, namely microRNAs. The aim of this review is to present up-to date data on the control of microRNA expression by dietary phytophenols in different types of human cells, and their impact on cell differentiation, cancer development and the regulation of the inflammatory response. PMID- 23674482 TI - Concentrations and potential health risks of metals in lip products. AB - BACKGROUND: Metal content in lip products has been an issue of concern. OBJECTIVES: We measured lead and eight other metals in a convenience sample of 32 lip products used by young Asian women in Oakland, California, and assessed potential health risks related to estimated intakes of these metals. METHODS: We analyzed lip products by inductively coupled plasma optical emission spectrometry and used previous estimates of lip product usage rates to determine daily oral intakes. We derived acceptable daily intakes (ADIs) based on information used to determine public health goals for exposure, and compared ADIs with estimated intakes to assess potential risks. RESULTS: Most of the tested lip products contained high concentrations of titanium and aluminum. All examined products had detectable manganese. Lead was detected in 24 products (75%), with an average concentration of 0.36 +/- 0.39 ppm, including one sample with 1.32 ppm. When used at the estimated average daily rate, estimated intakes were > 20% of ADIs derived for aluminum, cadmium, chromium, and manganese. In addition, average daily use of 10 products tested would result in chromium intake exceeding our estimated ADI for chromium. For high rates of product use (above the 95th percentile), the percentages of samples with estimated metal intakes exceeding ADIs were 3% for aluminum, 68% for chromium, and 22% for manganese. Estimated intakes of lead were < 20% of ADIs for average and high use. CONCLUSIONS: Cosmetics safety should be assessed not only by the presence of hazardous contents, but also by comparing estimated exposures with health-based standards. In addition to lead, metals such as aluminum, cadmium, chromium, and manganese require further investigation. PMID- 23674483 TI - Adoptive regulatory T-cell therapy protects against cerebral ischemia. AB - OBJECTIVE: Recent evidence suggests that functional deficiency in regulatory T cells (Tregs), an innate immunomodulator, exacerbates brain damage after cerebral ischemia. We therefore evaluated the effect of Treg transfer in rodent models of ischemic stroke and further investigated the mechanism underlying Treg-afforded neuroprotection. METHODS: We examined the therapeutic potential of Tregs and the mechanisms of neuroprotection in vivo in 2 rodent models of ischemic stroke and in vitro in Treg-neutrophil cocultures using a combined approach including cell specific depletion, gene knockout mice, and bone marrow chimeras. RESULTS: Systemic administration of purified Tregs at 2, 6, or even 24 hours after middle cerebral artery occlusion resulted in a marked reduction of brain infarct and prolonged improvement of neurological functions lasting out to 4 weeks. Treg afforded neuroprotection was accompanied by attenuated blood-brain barrier (BBB) disruption during early stages of ischemia, decreased cerebral inflammation, and reduced infiltration of peripheral inflammatory cells into the lesioned brain. Surprisingly, Tregs exerted early neuroprotection without penetrating into the brain parenchyma or inhibiting the activation of residential microglia. Rather, both in vivo and in vitro studies demonstrated that Tregs suppressed peripheral neutrophil-derived matrix metallopeptidase-9 production, thus preventing proteolytic damage of the BBB. In addition to its potent central neuroprotection, Treg treatment was shown to ameliorate poststroke lymphopenia, suggesting a beneficial effect on immune status. INTERPRETATION: Our study suggests that Treg adoptive therapy is a novel and potent cell-based therapy targeting poststroke inflammatory dysregulation and neurovascular disruption. PMID- 23674485 TI - 0.5 Mb array as a first-line prenatal cytogenetic test in cases without ultrasound abnormalities and its implementation in clinical practice. AB - Using whole-genome array testing instead of karyotyping in prenatal diagnosis for all indications may be desirable because of the higher diagnostic yield and shorter reporting time. The goal of this research was finding the optimal array resolution that could replace routine prenatal karyotyping in cases without ultrasound abnormalities, for example, referred for advanced maternal age or abnormal first trimester screening. As variants of unknown clinical significance (VOUS), if reported, might complicate decision-making about continuation of pregnancy, such an optimal array resolution should have a high abnormality detection rate and reveal a minimal amount of VOUS. The array data of 465 fetuses were retrospectively evaluated with several resolution levels, and the Decipher microdeletion/microduplication syndrome list was reviewed to assess what could be theoretically missed with a lower resolution. A 0.5-Mb resolution showed a high diagnostic yield potential and significantly minimized the number of VOUS. Based on our experience, we recommend genomic SNP array as a first-tier test in prenatal diagnosis. The resolution should be chosen based on the indication. In cases of fetal ultrasound abnormalities or intrauterine fetal death (IUFD), high resolution analysis should be done. In other cases, we advise replacing karyotyping by SNP array analysis with 0.5 Mb resolution. PMID- 23674484 TI - Methods, quality control and specimen management in an international multicentre investigation of type 1 diabetes: TEDDY. AB - BACKGROUND: The vast array and quantity of longitudinal samples collected in The Environmental Determinants of Diabetes in the Young study present a series of challenges in terms of quality control procedures and data validity. To address this, pilot studies have been conducted to standardize and enhance both biospecimen collection and sample obtainment in terms of autoantibody collection, stool sample preservation, RNA, biomarker stability, metabolic biomarkers and T cell viability. RESEARCH DESIGN AND METHODS: The Environmental Determinants of Diabetes in the Young is a multicentre, international prospective study (n = 8677) designed to identify environmental triggers of type 1 diabetes (T1D) in genetically at-risk children from ages 3 months until 15 years. The study is conducted through six primary clinical centres located in four countries. RESULTS: As of May 2012, over three million biological samples and 250 million total data points have been collected, which will be analysed to assess autoimmunity status, presence of inflammatory biomarkers, genetic factors, exposure to infectious agents, dietary biomarkers and other potentially important environmental exposures in relation to autoimmunity and progression to T1D. CONCLUSIONS: Detailed procedures were utilized to standardize both data harmonization and management when handling a large quantity of longitudinal samples obtained from multiple locations. In addition, a description of the available specimens is provided that serve as an invaluable repository for the elucidation of determinants in T1D focusing on autoantibody concordance and harmonization, transglutaminase autoantibody, inflammatory biomarkers (T-cells), genetic proficiency testing, RNA lab internal quality control testing, infectious agents (monitoring cross-contamination, virus preservation and nasal swab collection validity) and HbA1c testing. PMID- 23674486 TI - Insights into the binding of paclitaxel to human serum albumin: multispectroscopic studies. AB - The interaction of paclitaxel with human serum albumin (HSA) was studied using fluorescence, resonance light scattering, ultraviolet-visible, circular dichroism and Fourier transform infrared spectroscopy at pH 7.4. Fluorescence data revealed that the fluorescence quenching of HSA by paclitaxel was a static quenching procedure. Time-resolved fluorescence data also confirmed the quenching mode, which present a constant decay time of about 5 ns. The binding sites were approximately 1 and the binding constant suggested a weak association (324/M at 298 K), which is helpful for the release of the drug to targeted organs. The thermodynamic parameters, DeltaG(?), DeltaH degrees and DeltaS degrees were calculated as - 1.06 * 10(4) J/mol, 361 J/mol per K and 9.7 * 10(4) J/mol respectively at 298 K, suggesting that binding was spontaneous and was driven mainly by hydrophobic interactions. The binding distance between HSA and paclitaxel was determined to be 2.23 nm based on the Forster theory. Analysis of circular dichroism, ultraviolet-visible, three-dimensional fluorescence, Fourier transform infrared and resonance light scattering spectra demonstrated that HSA conformation was slightly altered in the presence of paclitaxel and dimension of the individual HSA molecules were larger after interacting with paclitaxel. These results were confirmed by a molecular docking study. PMID- 23674487 TI - Brain iron takes off: a new propeller protein links neurodegeneration with autophagy. PMID- 23674488 TI - A functional magnetic resonance imaging study mapping the episodic memory encoding network in temporal lobe epilepsy. AB - Functional magnetic resonance imaging has demonstrated reorganization of memory encoding networks within the temporal lobe in temporal lobe epilepsy, but little is known of the extra-temporal networks in these patients. We investigated the temporal and extra-temporal reorganization of memory encoding networks in refractory temporal lobe epilepsy and the neural correlates of successful subsequent memory formation. We studied 44 patients with unilateral temporal lobe epilepsy and hippocampal sclerosis (24 left) and 26 healthy control subjects. All participants performed a functional magnetic resonance imaging memory encoding paradigm of faces and words with subsequent out-of-scanner recognition assessments. A blocked analysis was used to investigate activations during encoding and neural correlates of subsequent memory were investigated using an event-related analysis. Event-related activations were then correlated with out of-scanner verbal and visual memory scores. During word encoding, control subjects activated the left prefrontal cortex and left hippocampus whereas patients with left hippocampal sclerosis showed significant additional right temporal and extra-temporal activations. Control subjects displayed subsequent verbal memory effects within left parahippocampal gyrus, left orbitofrontal cortex and fusiform gyrus whereas patients with left hippocampal sclerosis activated only right posterior hippocampus, parahippocampus and fusiform gyrus. Correlational analysis showed that patients with left hippocampal sclerosis with better verbal memory additionally activated left orbitofrontal cortex, anterior cingulate cortex and left posterior hippocampus. During face encoding, control subjects showed right lateralized prefrontal cortex and bilateral hippocampal activations. Patients with right hippocampal sclerosis showed increased temporal activations within the superior temporal gyri bilaterally and no increased extra temporal areas of activation compared with control subjects. Control subjects showed subsequent visual memory effects within right amygdala, hippocampus, fusiform gyrus and orbitofrontal cortex. Patients with right hippocampal sclerosis showed subsequent visual memory effects within right posterior hippocampus, parahippocampal and fusiform gyri, and predominantly left hemisphere extra-temporal activations within the insula and orbitofrontal cortex. Correlational analysis showed that patients with right hippocampal sclerosis with better visual memory activated the amygdala bilaterally, right anterior parahippocampal gyrus and left insula. Right sided extra-temporal areas of reorganization observed in patients with left hippocampal sclerosis during word encoding and bilateral lateral temporal reorganization in patients with right hippocampal sclerosis during face encoding were not associated with subsequent memory formation. Reorganization within the medial temporal lobe, however, is an efficient process. The orbitofrontal cortex is critical to subsequent memory formation in control subjects and patients. Activations within anterior cingulum and insula correlated with better verbal and visual subsequent memory in patients with left and right hippocampal sclerosis, respectively, representing effective extra-temporal recruitment. PMID- 23674491 TI - Effect of pre-harvest sprouting on physicochemical changes of proteins in wheat. AB - BACKGROUND: High moisture before harvest can cause sprouting of the wheat kernel, which is termed pre-harvest sprouting (PHS). The aim of this study was to examine the variation in physicochemical properties of proteins in PHS-damaged (sprouted) hard red and white spring wheat genotypes. Specifically, protein content, enzyme activity and degradation of proteins were evaluated in sound and PHS-damaged wheat. RESULTS: Protein contents of sprouted wheat samples were lower than that of non-sprouted samples; however, their differences were not significantly (P > 0.05) correlated with sprouting score. Sodium dodecyl sulfate (SDS) buffer extractable proteins (EXP) and unextractable proteins (UNP) were analyzed by high performance size exclusion chromatography. PHS damage elevated endoprotease activity and consequently increased the degradation of polymeric UNP and free asparagine concentration in wheat samples. Free asparagine is known to be a precursor for formation of carcinogenic acrylamide during high heat treatment, such as baking bread. Free asparagine content had significant correlations (P < 0.01) with sprouting score, endoprotease activity and protein degradation. CONCLUSIONS: Genotypes with higher endoprotease activity tend to exhibit a larger degree of degradation of UNP and higher free asparagine concentration in sprouted wheat samples. PMID- 23674490 TI - Somatic alpha-synuclein mutations in Parkinson's disease: hypothesis and preliminary data. AB - Alpha-synuclein (SNCA) is crucial in the pathogenesis of Parkinson's disease (PD), yet mutations in the SNCA gene are rare. Evidence for somatic genetic variation in normal humans, also involving the brain, is increasing, but its role in disease is unknown. Somatic SNCA mutations, arising in early development and leading to mosaicism, could contribute to PD pathogenesis and yet be absent or undetectable in DNA derived from peripheral lymphocytes. Such mutations could underlie the widespread pathology in PD, with the precise clinical outcome dependent on their type and the timing and location of their occurrence. We recently reported a novel SNCA mutation (c.150T>G, p.H50Q) in PD brain-derived DNA. To determine if there was mosaicism for this, a PCR and cloning strategy was used to take advantage of a nearby heterozygous intronic polymorphism. No evidence of mosaicism was found. High-resolution melting curve analysis of SNCA coding exons, which was shown to be sensitive enough to detect low proportions of 2 known mutations, did not reveal any further mutations in DNA from 28 PD brain derived samples. We outline the grounds that make the somatic SNCA mutation hypothesis consistent with genetic, embryological, and pathological data. Further studies of brain-derived DNA are warranted and should include DNA from multiple regions and methods for detecting other types of genomic variation. PMID- 23674492 TI - NMS-E973, a novel synthetic inhibitor of Hsp90 with activity against multiple models of drug resistance to targeted agents, including intracranial metastases. AB - PURPOSE: Recent developments of second generation Hsp90 inhibitors suggested a potential for development of this class of molecules also in tumors that have become resistant to molecular targeted agents. Disease progression is often due to brain metastases, sometimes related to insufficient drug concentrations within the brain. Our objective was to identify and characterize a novel inhibitor of Hsp90 able to cross the blood-brain barrier (BBB). EXPERIMENTAL DESIGN: Here is described a detailed biochemical and crystallographic characterization of NMS E973. Mechanism-based anticancer activity was described in cell models, including models of resistance to kinase inhibitors. Pharmacokinetics properties were followed in plasma, tumor, liver, and brain. In vivo activity and pharmacodynamics, as well as the pharmacokinetic/pharmacodynamic relationships, were evaluated in xenografts, including an intracranially implanted melanoma model. RESULTS: NMS-E973, representative of a novel isoxazole-derived class of Hsp90 inhibitors, binds Hsp90alpha with subnanomolar affinity and high selectivity towards kinases, as well as other ATPases. It possesses potent antiproliferative activity against tumor cell lines and a favorable pharmacokinetic profile, with selective retention in tumor tissue and ability to cross the BBB. NMS-E973 induces tumor shrinkage in different human tumor xenografts, and is highly active in models of resistance to kinase inhibitors. Moreover, consistent with its brain penetration, NMS-E973 is active also in an intracranially implanted melanoma model. CONCLUSIONS: Overall, the efficacy profile of NMS-E973 suggests a potential for development in different clinical settings, including tumors that have become resistant to molecular targeted agents, particularly in cases of tumors which reside beyond the BBB. PMID- 23674493 TI - PI3K pathway dependencies in endometrioid endometrial cancer cell lines. AB - PURPOSE: Endometrioid endometrial cancers (EEC) frequently harbor coexisting mutations in phosphoinositide 3-kinase (PI3K) pathway genes, including PTEN, PIK3CA, PIK3R1, and KRAS. We sought to define the genetic determinants of PI3K pathway inhibitor response in EEC cells, and whether PTEN-mutant EEC cell lines rely on p110beta signaling for survival. EXPERIMENTAL DESIGN: Twenty-four human EEC cell lines were characterized for their mutation profile and activation state of PI3K and mitogen-activated protein kinase (MAPK) signaling pathway proteins. Cells were treated with pan-class I PI3K, p110alpha, and p110beta isoform specific, allosteric mTOR, mTOR kinase, dual PI3K/mTOR, mitogen-activated protein/extracellular signal-regulated kinase (MEK), and RAF inhibitors. RNA interference (RNAi) was used to assess effects of KRAS silencing in EEC cells. RESULTS: EEC cell lines harboring PIK3CA and PTEN mutations were selectively sensitive to the pan-class I PI3K inhibitor GDC-0941 and allosteric mTOR inhibitor temsirolimus, respectively. Subsets of EEC cells with concurrent PIK3CA and/or PTEN and KRAS mutations were sensitive to PI3K pathway inhibition, and only 2 of 6 KRAS-mutant cell lines showed response to MEK inhibition. KRAS RNAi silencing did not induce apoptosis in KRAS-mutant EEC cells. PTEN-mutant EEC cell lines were resistant to the p110beta inhibitors GSK2636771 and AZD6482, and only in combination with the p110alpha selective inhibitor A66 was a decrease in cell viability observed. CONCLUSIONS: Targeted pan-PI3K and mTOR inhibition in EEC cells may be most effective in PIK3CA- and PTEN-mutant tumors, respectively, even in a subset of EECs concurrently harboring KRAS mutations. Inhibition of p110beta alone may not be sufficient to sensitize PTEN-mutant EEC cells and combination with other targeted agents may be required. PMID- 23674494 TI - Optical image-guided cancer surgery: challenges and limitations. AB - Optical image-guided cancer surgery is a promising technique to adequately determine tumor margins by tumor-specific targeting, potentially resulting in complete resection of tumor tissue with improved survival. However, identification of the photons coming from the fluorescent contrast agent is complicated by autofluorescence, optical tissue properties, and accurate fluorescent targeting agents and imaging systems. All these factors have an important influence on the image that is presented to the surgeon. Considering the clinical consequences at stake, it is a prerequisite to answer the questions that are essential for the surgeon. What is optical image-guided surgery and how can it improve patient care? What should the oncologic surgeon know about the fundamental principles of optical imaging to understand which conclusions can be drawn from the images? And how do the limitations influence clinical decision making? This article discusses these questions and provides a clear overview of the basic principles and practical applications. Although there are limitations to the intrinsic capacity of the technique, when practical and technical surgical possibilities are considered, optical imaging can be a very powerful intraoperative tool in guiding the future oncologic surgeon toward radical resection and optimal clinical results. PMID- 23674495 TI - PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. AB - PURPOSE: Programmed cell death ligand 1 (PD-L1) is an immunomodulatory molecule expressed by antigen-presenting cells and select tumors that engages receptors on T cells to inhibit T-cell immunity. Immunotherapies targeting the PD-1/PD-L1 pathway have shown durable antitumor effects in a subset of patients with solid tumors. PD-L1 can be expressed by Reed-Sternberg cells comprising classical Hodgkin lymphoma (CHL) and by malignant B cells comprising EBV-positive posttransplant lymphoproliferative disorders (PTLD). We sought to determine whether the expression of PD-L1 represents a general strategy of immune evasion among aggressive B-cell lymphomas and virus- and immunodeficiency-associated tumors. EXPERIMENTAL DESIGN: Using novel antibodies and formalin-fixed, paraffin embedded (FFPE) tissue biopsies, we examined 237 primary tumors for expression of PD-L1. RESULTS: Robust PD-L1 protein expression was found in the majority of nodular sclerosis and mixed cellularity CHL, primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich B-cell lymphoma, EBV-positive and -negative PTLD, and EBV-associated diffuse large B-cell lymphoma (DLBCL), plasmablastic lymphoma, extranodal NK/T-cell lymphoma, nasopharyngeal carcinoma, and HHV8 associated primary effusion lymphoma. Within these tumors, PD-L1 was highly expressed by malignant cells and tumor-infiltrating macrophages. In contrast, neither the malignant nor the nonmalignant cells comprising nodular lymphocyte predominant Hodgkin lymphoma, DLBCL-not otherwise specified, Burkitt lymphoma, and HHV8-associated Kaposi sarcoma expressed detectable PD-L1. CONCLUSION: Certain aggressive B-cell lymphomas and virus- and immunodeficiency-associated malignancies associated with an ineffective T-cell immune response express PD-L1 on tumor cells and infiltrating macrophages. These results identify a group of neoplasms that should be considered for PD-1/PD-L1-directed therapies, and validate methods to detect PD-L1 in FFPE tissue biopsies. PMID- 23674496 TI - Identification and selective degradation of neopeptide-containing truncated mutant proteins in the tumors with high microsatellite instability. AB - PURPOSE: Frameshift mutations in coding mononucleotide repeats (cMNR) are common in tumors with high microsatellite instability (MSI-H). These mutations generate mRNAs containing abnormal coding sequences and premature termination codons (PTC). Normally, mRNAs containing PTCs are degraded by nonsense-mediated mRNA decay (NMD). However, mRNAs containing PTCs located in the last exon are not subject to degradation by NMD (NMD-irrelevant). This study aimed to discover whether genes with frameshift mutations in the last exon generate truncated mutant proteins. EXPERIMENTAL DESIGN: We identified 66 genes containing cMNRs in the last exon by bioinformatic analysis. We found frequent insertion/deletion mutations in the cMNRs of 29 genes in 10 MSI-H cancer cell lines and in the cMNRs of 3 genes in 19 MSI-H cancer tissues. We selected 7 genes (TTK, TCF7L2, MARCKS, ASTE1, INO80E, CYHR1, and EBPL) for mutant mRNA expression analysis and 3 genes (TTK, TCF7L2, and MARCKS) for mutant protein expression analysis. RESULTS: The PTC-containing NMD-irrelevant mRNAs from mutated genes were not degraded. However, only faint amounts of endogenous mutant TTK and TCF7L2 were detected, and we failed to detect endogenous mutant MARCKS. By polysome analysis, we showed that mRNAs from genomic mutant MARCKS constructs are normally translated. After inhibiting 3 protein degradation pathways, we found that only inhibition of the proteasomal pathway facilitated the rescue of endogenous mutant TTK, TCF7L2, and MARCKS. CONCLUSIONS: Our findings indicate that cancer cells scavenge potentially harmful neopeptide-containing mutant proteins derived from NMD-irrelevant abnormal mRNAs via the ubiquitin-proteasome system, and these mutant proteins may be important substrates for tumor-specific antigens. PMID- 23674497 TI - Therapeutic enhancement of ER stress by insulin-like growth factor I sensitizes myeloma cells to proteasomal inhibitors. AB - PURPOSE: Multiple myeloma is a clonal plasma cell disorder in which growth and proliferation are linked to a variety of growth factors, including insulin-like growth factor type I (IGF-I). Bortezomib, the first-in-class proteasome inhibitor, has displayed significant antitumor activity in multiple myeloma. EXPERIMENTAL DESIGN: We analyzed the impact of IGF-I combined with proteasome inhibitors on multiple myeloma cell lines in vivo and in vitro as well as on fresh human myeloma cells. RESULTS: Our study shows that IGF-I enhances the cytotoxic effect of proteasome inhibitors against myeloma cells. The effect of bortezomib on the content of proapoptotic proteins such as Bax, Bad, Bak, and BimS and antiapoptotic proteins such as Bcl-2, Bcl-XL, XIAP, Bfl-1, and survivin was enhanced by IGF-I. The addition of IGF-I to bortezomib had a minor effect on NF-kappaB signaling in MM.1S cells while strongly enhancing reticulum stress. This resulted in an unfolded protein response (UPR), which was required for the potentiating effect of IGF-I on bortezomib cytotoxicity as shown by siRNA mediated inhibition of GADD153 expression. CONCLUSIONS: These results suggest that the high baseline level of protein synthesis in myeloma can be exploited therapeutically by combining proteasome inhibitors with IGF-I, which possesses a "priming" effect on myeloma cells for this family of compounds. PMID- 23674499 TI - Variation in susceptibility of laboratory and field strains of three stored-grain insect species to beta-cyfluthrin and chlorpyrifos-methyl plus deltamethrin applied to concrete surfaces. AB - BACKGROUND: The efficacy of commercial formulations of beta-cyfluthrin and chlorpyrifos-methyl plus deltamethrin applied to clean, concrete surfaces similar to that of empty bins against field strains of stored-grain insects is unknown. We exposed adults of 16 strains of the red flour beetle, Tribolium castaneum (Herbst); eight strains of the sawtoothed grain beetle, Oryzaephilus surinamensis (L.); and two strains of the lesser grain borer, Rhyzopertha dominica (F.), collected mainly from farm-stored grain in Kansas, USA, to beta-cyfluthrin and chlorpyrifos-methyl plus deltamethrin applied to concrete surfaces and determined knockdown and mortality. RESULTS: Knockdown and mortality differences among species and strains to the insecticides tested were significant. Mortality of all species was less than that of knockdown, suggesting recovery when placed on food after insecticide exposure. beta-Cyfluthrin was effective against R. dominica but ineffective against T. castaneum and O. surinamensis field strains. Chlorpyrifos methyl plus deltamethrin was only partially effective against field strains of the three species. CONCLUSION: Reduced susceptibility in field strains may be due to inherent formulation deficiency and low levels of tolerance or resistance to beta-cyfluthrin. No single insecticide provided adequate control of the three species tested. PMID- 23674498 TI - Functional MRI of cerebellar activity during eyeblink classical conditioning in children and adults. AB - This study characterized human cerebellar activity during eyeblink classical conditioning (EBC) in children and adults using functional magnetic resonance imaging (fMRI). During fMRI, participants were administered delay conditioning trials, in which the conditioned stimulus (a tone) precedes, overlaps, and coterminates with the unconditioned stimulus (a corneal airpuff). Behavioral eyeblink responses and brain activation were measured concurrently during two phases: pseudoconditioning, involving presentations of tone alone and airpuff alone, and conditioning, during which the tone and airpuff were paired. Although all participants demonstrated significant conditioning, the adults produced more conditioned responses (CRs) than the children. When brain activations during pseudoconditioning were subtracted from those elicited during conditioning, significant activity was distributed throughout the cerebellar cortex (Crus I-II, lateral lobules IV-IX, and vermis IV-VI) in all participants, suggesting multiple sites of associative learning-related plasticity. Despite their less optimal behavioral performance, the children showed greater responding in the pons, lateral lobules VIII, IX, and Crus I, and vermis VI, suggesting that they may require greater activation and/or the recruitment of supplementary structures to achieve successful conditioning. Correlation analyses relating brain activations to behavioral CRs showed a positive association of activity in cerebellar deep nuclei (including dentate, fastigial, and interposed nuclei) and vermis VI with CRs in the children. This is the first study to compare cerebellar cortical and deep nuclei activations in children versus adults during EBC. PMID- 23674500 TI - KEAP1 is a redox sensitive target that arbitrates the opposing radiosensitive effects of parthenolide in normal and cancer cells. AB - Elevated oxidative stress is observed more frequently in cancer cells than in normal cells. It is therefore expected that additional exposure to a low level of reactive oxygen species (ROS) will push cancer cells toward death, whereas normal cells might maintain redox homeostasis through adaptive antioxidant responses. We previously showed that parthenolide enhances ROS production in prostate cancer cells through activation of NADPH oxidase. The present study identifies KEAP1 as the downstream redox target that contributes to parthenolide's radiosensitization effect in prostate cancer cells. In vivo, parthenolide increases radiosensitivity of mouse xenograft tumors but protects normal prostate and bladder tissues against radiation-induced injury. Mechanistically, parthenolide increases the level of cellular ROS and causes oxidation of thioredoxin (TrX) in prostate cancer cells, leading to a TrX-dependent increase in a reduced state of KEAP1, which in turn leads to KEAP1-mediated PGAM5 and Bcl-xL (BCL2L1) degradation. In contrast, parthenolide increases oxidation of KEAP1 in normal prostate epithelial cells, leading to increased Nrf2 (NFE2L2) levels and subsequent Nrf2-dependent expression of antioxidant enzymes. These results reveal a novel redox-mediated modification of KEAP1 in controlling the differential effect of parthenolide on tumor and normal cell radiosensitivity. Furthermore, they show it is possible to develop a tumor-specific radiosensitizing agent with radioprotective properties in normal cells. PMID- 23674501 TI - A mir-153 binding site variation in SNCA in a patient with Parkinson's disease. PMID- 23674502 TI - Solid fuel use for household cooking: country and regional estimates for 1980 2010. AB - BACKGROUND: Exposure to household air pollution from cooking with solid fuels in simple stoves is a major health risk. Modeling reliable estimates of solid fuel use is needed for monitoring trends and informing policy. OBJECTIVES: In order to revise the disease burden attributed to household air pollution for the Global Burden of Disease 2010 project and for international reporting purposes, we estimated annual trends in the world population using solid fuels. METHODS: We developed a multilevel model based on national survey data on primary cooking fuel. RESULTS: The proportion of households relying mainly on solid fuels for cooking has decreased from 62% (95% CI: 58, 66%) to 41% (95% CI: 37, 44%) between 1980 and 2010. Yet because of population growth, the actual number of persons exposed has remained stable at around 2.8 billion during three decades. Solid fuel use is most prevalent in Africa and Southeast Asia where > 60% of households cook with solid fuels. In other regions, primary solid fuel use ranges from 46% in the Western Pacific, to 35% in the Eastern Mediterranean and < 20% in the Americas and Europe. CONCLUSION: Multilevel modeling is a suitable technique for deriving reliable solid-fuel use estimates. Worldwide, the proportion of households cooking mainly with solid fuels is decreasing. The absolute number of persons using solid fuels, however, has remained steady globally and is increasing in some regions. Surveys require enhancement to better capture the health implications of new technologies and multiple fuel use. PMID- 23674503 TI - The PhosphoGRID Saccharomyces cerevisiae protein phosphorylation site database: version 2.0 update. AB - PhosphoGRID is an online database that curates and houses experimentally verified in vivo phosphorylation sites in the Saccharomyces cerevisiae proteome (www.phosphogrid.org). Phosphosites are annotated with specific protein kinases and/or phosphatases, along with the condition(s) under which the phosphorylation occurs and/or the effects on protein function. We report here an updated data set, including nine additional high-throughput (HTP) mass spectrometry studies. The version 2.0 data set contains information on 20 177 unique phosphorylated residues, representing a 4-fold increase from version 1.0, and includes 1614 unique phosphosites derived from focused low-throughput (LTP) studies. The overlap between HTP and LTP studies represents only ~3% of the total unique sites, but importantly 45% of sites from LTP studies with defined function were discovered in at least two independent HTP studies. The majority of new phosphosites in this update occur on previously documented proteins, suggesting that coverage of phosphoproteins in the yeast proteome is approaching saturation. We will continue to update the PhosphoGRID data set, with the expectation that the integration of information from LTP and HTP studies will enable the development of predictive models of phosphorylation-based signaling networks. Database URL: http://www.phosphogrid.org/ PMID- 23674504 TI - Bcl-2 level as a biomarker for 13q14 deletion in CLL. AB - BACKGROUND: Deletion 13q14.3 is the most common cytogenetic abnormality in chronic lymphocytic leukemia (CLL). Previously it was reported that miR-15/16 is the target of 13q14 deletions and plays a tumor suppressor role by suppressing Bcl-2. Therefore, Bcl-2 expression was examined more closely to determine whether it would predict 13q14 deletion status. METHODS: A multi-color flow panel consisting of anti-Bcl-2/anti-lambda/anti-kappa/CD19/CD5/CD3/CD20 was performed. The ability of Bcl-2 to predict 13q14 deletion was tested using the conventional Bcl-2 index (c-index): mean fluorescence intensity (MFI) of CLL clone/MFI of residual T cells. Fifty-four untreated CLL/MBL patients were studied. Bimodal Bcl 2 expression was evaluated to test the ability of Bcl-2 to detect intraclonal heterogeneity. Other CLL prognostic markers including CD38, CD49d, CD26, and CD69 were evaluated. FISH was performed on selected sorted populations. RESULTS: The Bcl-2 c-index strongly predicts del13q14 P < 0.0001. A statistically significant association was observed between the percentage of cells carrying the deletion and the level of Bcl-2 expression P < 0.05. Cells sorted based on Bcl-2 expression showed enrichment of both hemizygous and homozygous del 13q14 cells. Also, we observed that an alteration in Bcl-2 level over time predicts changes in 13q14 deletion status. And a statistically significant correlation between the bimodal pattern of CD69 expression and the presence of 13q14 deletion was found P < 0.0001. CONCLUSION: Bcl-2 expression using the c-index strongly predicts 13q14 deletion and can be used to distinguish homozygous, heterozygous, and diploid CLL clonal cells. Further systematic studies of this biomarker are needed for confirmation and expansion of these findings. PMID- 23674505 TI - Ocular tremor in Parkinson's disease: the debate is not over. AB - Recent evidence tends to suggest that ocular tremor can be present in patients with Parkinson's disease (PD). This ocular tremor may have frequency characteristics similar to those of PD limb tremor. This fact was recently challenged in an article demonstrating that ocular tremor could simply be the consequence of vestibulo-ocular reflex activity induced by head movement. Although this hypothesis can be valid in some circumstances, we previously presented evidence that, in fact, these ocular may exist. Here, we address the shortcomings of previous studies describing the possible origins of these ocular tremors and propose solutions to circumvent those shortcomings. PMID- 23674506 TI - Diabetes, metabolic syndrome, and obesity in relation to serum dioxin concentrations: the Seveso women's health study. AB - BACKGROUND: In animal studies, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters glucose transport and increases serum lipid levels and blood pressure. Epidemiologic evidence suggests an association between TCDD and metabolic disease. OBJECTIVES: On 10 July 1976, a chemical explosion in Seveso, Italy, resulted in the highest known residential exposure to TCDD. Using data from the Seveso Women's Health Study (SWHS), a cohort study of the health of the women, we examined the relation of serum TCDD to diabetes, metabolic syndrome, and obesity > 30 years later. METHODS: In 1996, we enrolled 981 women who were newborn to 40 years of age in 1976 and resided in the most contaminated areas. Individual TCDD concentration was measured in archived serum that had been collected soon after the explosion. In 2008, 833 women participated in a follow-up study. Diabetes was classified based on self-report or fasting serum glucose and glycated hemoglobin levels. Metabolic syndrome was defined by International Diabetes Federation criteria. Obesity was defined as body mass index >= 30 kg/m2. RESULTS: A 10-fold increase in serum TCDD (log10TCDD) was not associated with diabetes (adjusted hazard ratio = 0.76; 95% CI: 0.45, 1.28) or obesity [adjusted odds ratio (OR) = 0.80; 95% CI: 0.58, 1.10]. Log10TCDD was associated with metabolic syndrome, but only among women who were <= 12 years of age at the time of the explosion (adjusted OR = 2.03; 95% CI: 1.25, 3.29; pinteraction = 0.01). CONCLUSIONS: We found an increased prevalence of metabolic syndrome associated with TCDD, but only among women who were the youngest at the time of the explosion. Continued follow-up of the SWHS cohort will be informative. PMID- 23674507 TI - Stabilization media increases recovery in paucicellular cerebrospinal fluid specimens submitted for flow cytometry testing. AB - BACKGROUND: Flow cytometric immunophenotpying (FCI) of cerebrospinal fluid (CSF) and other paucicellular fluids has been demonstrated to have increased sensitivity in detection of lymphoma and leukemia when compared to cytomorphology [(1) de Graaf et al., Cytometry Part B 2011, 80B:271-281; (2) Szamosi et al., CLSI Document H56-A-Body Fluid Analysis for Cellular Composition; Approved Guideline, Wayne, PA: Clinical and Laboratory Standards Institute, 2006; (3) Kraan et al., Flow Cytometric Immunophenotyping of Cerebrospinal Fluid. Current Protocols in Cytometry, Hoboken, NJ: Wiley, 2008]. However, low cellularity has been an historical problem with these samples. Several studies indicate that immediate addition of a stabilization media (e.g., RPMI with fetal calf serum (FCS)) to CSF improves the cell yield for FCI [(1) de Graaf et al.]. Such stabilization medias can, however, significantly increase cost. METHODS: We compared FCI results in CSF stabilized with RPMI 1640 (without additional additives) to results obtained using non-stabilized CSF. Samples were processed according to published CLSI guidelines [(2) Szamosi et al.]. RESULTS: About 98/105 (93%) CSF specimens stabilized with RPMI had adequate numbers of viable cells (>100) for performing FCI. About 65/217 (30%) CSF specimens without stabilization had adequate numbers of viable cells for analysis (70% either quantity not sufficient (QNS) or specimen viability below analytical limits). CONCLUSIONS: Utilizing RMPI without FCS as a stabilization media results in increased cell yield and improved FCI results. We have found FCS is not required to achieve high quality results in FCI of paucicellular CSF specimens. PMID- 23674508 TI - Comparison of intake and systemic relative effect potencies of dioxin-like compounds in female mice after a single oral dose. AB - BACKGROUND: Risk assessment for mixtures of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) is performed using the toxic equivalency factor (TEF) approach. These TEF values are derived mainly from relative effect potencies (REPs) linking an administered dose to an in vivo toxic or biological effect, resulting in "intake" TEFs. At present, there is insufficient data available to conclude that intake TEFs are also applicable for systemic concentrations (e.g., blood and tissues). OBJECTIVE: We compared intake and systemic REPs of 1,2,3,7,8 pentachlorodibenzodioxin (PeCDD), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB-126), 2,3',4,4',5-pentachlorobiphenyl (PCB 118), and 2,3,3',4,4',5-hexachlorobiphenyl (PCB-156) in female C57BL/6 mice 3 days after a single oral dose. METHODS: We calculated intake REPs and systemic REPs based on administered dose and liver, adipose, or plasma concentrations relative to TCDD. Hepatic cytochrome P450 1A1-associated ethoxyresorufin-O deethylase (EROD) activity and gene expression of Cyp1a1, 1a2 and 1b1 in the liver and peripheral blood lymphocytes (PBLs) were used as biological end points. RESULTS: We observed up to one order of magnitude difference between intake REPs and systemic REPs. Two different patterns were discerned. Compared with intake REPs, systemic REPs based on plasma or adipose levels were higher for PeCDD, 4 PeCDF, and PCB-126 but lower for the mono-ortho PCBs 118 and 156. CONCLUSIONS: Based on these mouse data, the comparison between intake REPs and systemic REPs reveals significant congener-specific differences that warrants the development of systemic TEFs to calculate toxic equivalents (TEQs) in blood and body tissues. PMID- 23674509 TI - Use of TransFixTM cerebrospinal fluid storage tubes prevents cellular loss and enhances flow cytometric detection of malignant hematological cells after 18 hours of storage. AB - Flow cytometry is a sensitive method for detection of leptomeningeal localizations of hematological malignancies (LHM) in cerebrospinal fluid (CSF). Rapid processing of CSF is needed, as leukocyte numbers appear to decline quickly after lumbar puncture. The cell-stabilizing agent TransFixTM may enhance the detection of LHM in CSF by preventing cellular loss. To study the effects of TransFix on leukocyte numbers and the detection of LHM, we prospectively collected 99 CSF samples from patients with suspected or proven LHM in tubes with (i) TransFix; (ii) serum-containing medium; and (iii) no cell-stabilizing agents (native CSF). Presence of LHM and absolute leukocyte numbers were determined by flow cytometry after 30 minutes and 18 hours of storage. Leukocyte numbers in TransFix-stabilized CSF were higher than in the corresponding native samples at both time points (1.4* and 2.3* respectively, P < 0.0001 on each occasion). After 18 hours of storage, TransFix enhanced the detection of LHM in CSF. In all discordant paired observations (13/99, P = 0.005), the level of suspicion (classified as positive, suspicious, or negative) in CSF with TransFix was higher than in native CSF. We conclude that the use of TransFix-containing CSF storage tubes prevents cellular loss and enhances flow cytometric detection of LHM after 18 hours of storage. PMID- 23674510 TI - The emergent malignant obesity hypoventilation syndrome: a new critical care syndrome. PMID- 23674511 TI - Detection of single DNA molecule hybridization on a surface by atomic force microscopy. AB - Improving the detection of DNA hybridization is a critical issue for several challenging applications encountered in microarray and biosensor domains. Herein, it is demonstrated that hybridization between complementary single-stranded DNA (ssDNA) molecules loosely adsorbed on a mica surface can be achieved thanks to fine-tuning of the composition of the hybridization buffer. Single-molecule DNA hybridization occurs in only a few minutes upon encounters of freely diffusing complementary strands on the mica surface. Interestingly, the specific hybridization between complementary ssDNA is not altered in the presence of large amounts of nonrelated DNA. The detection of single-molecule DNA hybridization events is performed by measuring the contour length of DNA in atomic force microscopy images. Besides the advantage provided by facilitated diffusion, which promotes hybridization between probes and targets on mica, the present approach also allows the detection of single isolated DNA duplexes and thus requires a very low amount of both probe and target molecules. PMID- 23674512 TI - Response: Raised troponin levels in COPD: a possible mechanism. PMID- 23674513 TI - Mutations in MYH7 reduce the force generating capacity of sarcomeres in human familial hypertrophic cardiomyopathy. AB - AIMS: Familial hypertrophic cardiomyopathy (HCM), frequently caused by sarcomeric gene mutations, is characterized by cellular dysfunction and asymmetric left ventricular (LV) hypertrophy. We studied whether cellular dysfunction is due to an intrinsic sarcomere defect or cardiomyocyte remodelling. METHODS AND RESULTS: Cardiac samples from 43 sarcomere mutation-positive patients (HCMmut: mutations in thick (MYBPC3, MYH7) and thin (TPM1, TNNI3, TNNT2) myofilament genes) were compared with 14 sarcomere mutation-negative patients (HCMsmn), eight patients with secondary LV hypertrophy due to aortic stenosis (LVHao) and 13 donors. Force measurements in single membrane-permeabilized cardiomyocytes revealed significantly lower maximal force generating capacity (Fmax) in HCMmut (21 +/- 1 kN/m2) and HCMsmn (26 +/- 3 kN/m2) compared with donor (36 +/- 2 kN/m2). Cardiomyocyte remodelling was more severe in HCMmut compared with HCMsmn based on significantly lower myofibril density (49 +/- 2 vs. 63 +/- 5%) and significantly higher cardiomyocyte area (915 +/- 15 vs. 612 +/- 11 MUm2). Low Fmax in MYBPC3mut, TNNI3mut, HCMsmn, and LVHao was normalized to donor values after correction for myofibril density. However, Fmax was significantly lower in MYH7mut, TPM1mut, and TNNT2mut even after correction for myofibril density. In accordance, measurements in single myofibrils showed very low Fmax in MYH7mut, TPM1mut, and TNNT2mut compared with donor (respectively, 73 +/- 3, 70 +/- 7, 83 +/- 6, and 113 +/- 5 kN/m2). In addition, force was lower in MYH7mut cardiomyocytes compared with MYBPC3mut, HCMsmn, and donor at submaximal [Ca2+]. CONCLUSION: Low cardiomyocyte Fmax in HCM patients is largely explained by hypertrophy and reduced myofibril density. MYH7 mutations reduce force generating capacity of sarcomeres at maximal and submaximal [Ca2+]. These hypocontractile sarcomeres may represent the primary abnormality in patients with MYH7 mutations. PMID- 23674514 TI - Macrophage migration inhibitory factor plays a permissive role in the maintenance of cardiac contractile function under starvation through regulation of autophagy. AB - AIMS: The cytokine macrophage migration inhibitory factor (MIF) protects the heart through AMPK activation. Autophagy, a conserved pathway for bulk degradation of intracellular proteins and organelles, helps preserve and recycle energy and nutrients for cells to survive under starvation. This study was designed to examine the role of MIF in cardiac homeostasis and autophagy regulation following an acute starvation challenge. METHODS AND RESULTS: Wild type (WT) and MIF knockout mice were starved for 48 h. Echocardiographic data revealed little effect of starvation on cardiac geometry, contractile and intracellular Ca2+ properties. MIF deficiency unmasked an increase in left ventricular end-systolic diameter, a drop in fractional shortening associated with cardiomyocyte contractile and intracellular Ca2+ anomalies following starvation. Interestingly, the unfavourable effect of MIF deficiency was associated with interruption of starvation-induced autophagy. Furthermore, restoration of autophagy using rapamycin partially protected against starvation induced cardiomyocyte contractile defects. In our in vitro model of starvation, neonatal mouse cardiomyocytes from WT and MIF-/- mice and H9C2 cells were treated with serum free-glucose free DMEM for 2 h. MIF depletion dramatically attenuated starvation-induced autophagic vacuole formation in neonatal mouse cardiomyocytes and exacerbated starvation-induced cell death in H9C2 cells. CONCLUSION: In summary, these results indicate that MIF plays a permissive role in the maintenance of cardiac contractile function under starvation by regulation of autophagy. PMID- 23674515 TI - Vimentin is an endogenous ligand for the pattern recognition receptor Dectin-1. AB - AIMS: Atherosclerosis is a chronic inflammatory disorder of cholesterol deposition in monocyte-derived macrophages (MDM) within the arterial wall leading to impingement on the lumen of the vessel. In atherosclerotic lesions, MDM are the primary source of NADPH oxidase-derived superoxide anion (O2-) inducing low density lipoprotein (LDL) oxidation leading to their unregulated uptake of oxidized LDL and foam cell formation. We recently discovered that zymosan potently activates monocyte NADPH oxidase via the non-toll pattern recognition receptor (PRR), Dectin-1. Other PRRs bind endogenous human ligands, yet no such ligands have been identified for Dectin-1. Our hypothesis was that inflammation generates endogenous ligands for Dectin-1 that activate O2- production and thereby contributes to atherogenesis. METHODS AND RESULTS: Human: anti-zymosan antibodies were used to identify similar, cross-reactive epitopes in human atherosclerotic tissue extracts. Immunoblot analysis revealed consistent antibody reactive protein bands on one- and two-dimensional gel electrophoreses. Vimentin was identified by mass spectrometry in the immunoreactive bands across different tissue samples. Direct binding of vimentin to Dectin-1 was observed using BIACORE. Further data revealed that vimentin induces O2- production by human monocytes. Analysis of human atherosclerotic lesions revealed that vimentin was detected extracellularly in the necrotic core and in areas of active inflammation. Vimentin also co-localized with Dectin-1 in macrophage-rich regions where O2- is produced. CONCLUSION: We conclude that vimentin is an endogenous, activating ligand for Dectin-1. Its presence in areas of artery wall inflammation and O2- production suggests that vimentin activates Dectin-1 and contributes to the oxidation of lipids and cholesterol accumulation in atherosclerosis. PMID- 23674516 TI - Adiponectin protects against Toll-like receptor 4-mediated cardiac inflammation and injury. AB - AIMS: Adiponectin (APN) is an immunomodulatory and cardioprotective adipocytokine. Toll-like receptor (TLR) 4 mediates autoimmune reactions that cause myocarditis resulting in inflammation-induced cardiac injury. Here, we investigated whether APN inhibits inflammation and injury in autoimmune myocarditis by interfering with TLR4 signalling. METHODS AND RESULTS: APN overexpression in murine experimental autoimmune myocarditis (EAM) down-regulated cardiac expression of TLR4 and its downstream targets tumour necrosis factor (TNF)alpha, interleukin (IL)-6, IL-12, CC chemokine ligand (CCL)2, and intercellular adhesion molecule (ICAM)-1 resulting in reduced infiltration with cluster of differentiation (CD)3+, CD14+, and CD45+ immune cells as well as diminished myocardial apoptosis. Expression of TLR4 signalling pathway components was unchanged in hearts and spleens of APN-knockout (APN-KO) mice. In vitro APN had no effect on TLR4 expression in cardiac and immune cells but induced dissociation of APN receptors from the activated TLR4/CD14 signalling complex. APN inhibited the expression of a TLR4-mediated inflammatory phenotype induced by exogenous and endogenous TLR4 ligands as assessed by attenuated nuclear factor (NF)-kappaB activation and reduced expression of TNFalpha, IL-6, CCL2, and ICAM 1. Accordingly, following TLR4 ligation, splenocytes from APN-KO mice showed enhanced expression of TNFalpha, IL-6, IL-12, CCL2, and ICAM-1, whereas dendritic cells (DCs) from APN-KO mice demonstrated increased activation and T-cell priming capacity. Moreover, APN diminished TLR4-mediated splenocyte migration towards cardiac cells as well as cardiomyocyte apoptosis after co-cultivation with splenocytes. Mechanistically, APN inhibited TLR4 signalling through cyclooxygenase (COX)-2, protein kinase A (PKA), and meiosis-specific serine/threonine kinase (MEK)1. CONCLUSION: Our observations indicate that APN protects against inflammation and injury in autoimmune myocarditis by diminishing TLR4 signalling thereby attenuating inflammatory activation and interaction of cardiac and immune cells. PMID- 23674517 TI - Extremely low frequency electromagnetic field and wound healing: implication of cytokines as biological mediators. AB - Wound healing is a highly coordinated and complex process involving various cell types, chemical mediators and the surrounding extracellular matrix, resulting in a tightly orchestrated re-establishment of tissue integrity by specific cytokines. It consists of various dynamic processes including a series of overlapping phases: inflammation, proliferation, re-epithelialization and remodeling. One of the underlying mechanisms responsible for the disturbances in wound healing is an out-of-control inflammatory response that can cause pathological consequences, such as hypertrophic scars, keloids or chronic wounds and ulcers. Recently, several reports have evaluated the effects of extremely low frequency electromagnetic fields (EMFs) on tissue repair. In particular, the data analysis supports an anti-inflammatory effect of EMFs by the modulation of cytokine profiles that drive the transition from a chronic pro-inflammatory state to an anti-inflammatory state of the healing process. In this review, we focus on the effect of EMFs on skin wound healing showing emerging details of the anti inflammatory effects of EMFs, with a view to cytokines as candidate biomarkers. Molecular clarification of the mechanisms involved in the modulation of inflammatory factors following exposure to EMFs will provide a better understanding of the cellular responses induced by EMFs and a potential, additional treatment in non-responding, chronic wounds. PMID- 23674518 TI - The lost correlation between leptin and CRP in type 2 diabetes. AB - C reactive protein (CRP) is an inflammatory marker believed to be of value in the early prediction of type 2 diabetes (T2DM). Recent studies have shown a positive correlation between leptin and CRP levels. Here, we aimed to study the correlation between leptin and CRP in patients with T2DM. We also studied the effect of metformin therapy on the CRP-leptin correlation in patients with newly diagnosed diabetes. We performed a follow-up study on three groups of participants defined as 1: patients with newly diagnosed T2DM, 2: patients with long-standing T2DM, and 3: healthy controls. Patients with newly diagnosed diabetes were followed for three months after the initiation of metformin therapy. The homeostatic model assessment of insulin resistance (HOMA-IR) decreased, while leptin levels (15.9 +/- 1.6 versus 21.4 +/- 2.5, p<0.01) increased after metformin therapy. Leptin levels correlated significantly with CRP in healthy controls (r = 0.48; p<0.01); patients with newly diagnosed diabetes before (r = 0.35; p<0.05), and after (r = 0.55, p<0.001) metformin therapy, while there was no significant correlation between leptin and CRP in patients with long-standing diabetes (r = 0.15; p = 0.55). After multiple adjustments for potential confounders, leptin was the best predictor of CRP in controls (beta coefficient = 0.433, p<0.01), and patients with newly diagnosed T2DM who received metformin (beta coefficient = 0.584, p<0.01). Statin treatment did not have any significant effect on the results. This is the first report demonstrating the restorative role of metformin on the leptin-CRP correlation in patients with newly diagnosed diabetes. PMID- 23674519 TI - Physiological and molecular aspects of degradation of plant polysaccharides by fungi: what have we learned from Aspergillus? AB - Plant biomass is the most abundant and usable carbon source for many fungal species. Due to its diverse and complex structure, fungi need to produce a large range of enzymes to degrade these polysaccharides into monomeric components. The fine-tuned production of such diverse enzyme sets requires control through a set of transcriptional regulators. Aspergillus has a strong potential for degrading biomass, thus this genus has become the most widely studied group of filamentous fungi in this area. This review examines Aspergillus as a successful degrader of plant polysaccharides, and reviews its potential in many industries such as biofuel and as a production host of homologous and heterologous proteins. PMID- 23674520 TI - Pharmacological chaperones as a potential therapeutic option in methylmalonic aciduria cblB type. AB - Methylmalonic aciduria (MMA) cblB type is caused by mutations in the MMAB gene. This encodes the enzyme ATP:cob(I)alamin adenosyltransferase (ATR), which converts reduced cob(I)alamin to an active adenosylcobalamin cofactor. We recently reported the presence of destabilizing pathogenic mutations that retain some residual ATR activity. The aim of the present study was to seek pharmacological chaperones as a tailored therapy for stabilizing the ATR protein. High-throughput ligand screening of over 2000 compounds was performed; six were found to enhance the thermal stability of purified recombinant ATR. Further studies using a well-established bacterial system in which the recombinant ATR protein was expressed in the presence of these six compounds, showed them all to increase the stability of the wild-type ATR and the p.Ile96Thr mutant proteins. Compound V (N-{[(4-chlorophenyl)carbamothioyl]amino}-2-phenylacetamide) significantly increased this stability and did not act as an inhibitor of the purified protein. Importantly, compound V increased the activity of ATR in patient-derived fibroblasts harboring the destabilizing p.Ile96Thr mutation in a hemizygous state to within control range. When cobalamin was coadministrated with compound V, mutant ATR activity further improved. Oral administration of low doses of compound V to C57BL/6J mice for 12 days, led to increase in steady-state levels of ATR protein in liver and brain (disease-relevant organs). These results hold promise for the clinical use of pharmacological chaperones in MMA cblB type patients harboring chaperone-responsive mutations. PMID- 23674522 TI - Sex differences in risk taking behavior among Dutch cyclists. AB - The majority of research examining sex differences in risk-taking behavior focuses on overt physical risk measures in which failed risk attempts may result in serious injury or death. The present research describes sex differences in patterns of risk taking in day-to-day behavior among Dutch cyclists. Through three observational studies we test sex differences in risk taking in situations of financial risk (fines for failing to use bike lights, Study 1), theft risk (bike locking behavior, Study 2) as well as physical risk (risky maneuvers, Study 3). Results corroborate previous findings by showing that across these domains men are more inclined to take risks than women. We discuss how these findings might be used in an applied context. PMID- 23674523 TI - Insertable cardiac event recorder in detection of atrial fibrillation after cryptogenic stroke: an audit report. AB - BACKGROUND AND PURPOSE: Atrial fibrillation (AF) is the most frequent risk factor in ischemic stroke but often remains undetected. We analyzed the value of insertable cardiac event recorder in detection of AF in a 1-year cohort of patients with cryptogenic ischemic stroke. METHODS: All patients with cryptogenic stroke and eligibility for oral anticoagulation were offered the insertion of a cardiac event recorder. Regular follow-up for 1 year recorded the incidence of AF. RESULTS: Of the 393 patients with ischemic stroke, 65 (16.5%) had a cryptogenic stroke, and in 22 eligible patients, an event recorder was inserted. After 1 year, in 6 of 22 patients (27.3%), AF was detected. CONCLUSIONS: These preliminary data show that insertion of cardiac event recorder was eligible in approximately one third of patients with cryptogenic stroke and detected in approximately one quarter of these patients new AF. PMID- 23674521 TI - MicroRNA-22 and promoter motif polymorphisms at the Chga locus in genetic hypertension: functional and therapeutic implications for gene expression and the pathogenesis of hypertension. AB - Hypertension is a common hereditary syndrome with unclear pathogenesis. Chromogranin A (Chga), which catalyzes formation and cargo storage of regulated secretory granules in neuroendocrine cells, contributes to blood pressure homeostasis centrally and peripherally. Elevated Chga occurs in spontaneously hypertensive rat (SHR) adrenal glands and plasma, but central expression is unexplored. In this report, we measured SHR and Wistar-Kyoto rat (control) Chga expression in central and peripheral nervous systems, and found Chga protein to be decreased in the SHR brainstem, yet increased in the adrenal and the plasma. By re-sequencing, we systematically identified five promoter, two coding and one 3'-untranslated region (3'-UTR) polymorphism at the SHR (versus WKY or BN) Chga locus. Using HXB/BXH recombinant inbred (RI) strain linkage and correlations, we demonstrated genetic determination of Chga expression in SHR, including a cis quantitative trait loci (QTLs) (i.e. at the Chga locus), and such expression influenced biochemical determinants of blood pressure, including a cascade of catecholamine biosynthetic enzymes, catecholamines themselves and steroids. Luciferase reporter assays demonstrated that the 3'-UTR polymorphism (which disrupts a microRNA miR-22 motif) and promoter polymorphisms altered gene expression consistent with the decline in SHR central Chga expression. Coding region polymorphisms did not account for changes in Chga expression or function. Thus, we hypothesized that the 3'-UTR and promoter mutations lead to dysregulation (diminution) of Chga in brainstem cardiovascular control nuclei, ultimately contributing to the pathogenesis of hypertension in SHR. Accordingly, we demonstrated that in vivo administration of miR-22 antagomir to SHR causes substantial (~18 mmHg) reductions in blood pressure, opening a novel therapeutic avenue for hypertension. PMID- 23674525 TI - The striate artery, hematoma, and spot sign on coronal images of computed tomography angiography in putaminal intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: A spot sign is a bright spot on computed tomography angiography source images, which is predictive of hematoma growth in spontaneous intracerebral hemorrhage, although the cause of the spot sign is unclear. Our aim was to investigate the spot sign seen on computed tomography angiography and a striate artery, which is a presumed site of intracerebral hemorrhage bleeding origin in the putamen. METHODS: In consecutive cases of spontaneous intracerebral hemorrhage in the putamen, spot signs and striate arteries were evaluated. Coronal reformat images of computed tomography angiography were created to visualize the striate arteries. Acute deterioration, defined as hematoma enlargement, emergency hematoma removal, or death within the day of admission, was reviewed. RESULTS: Of the 141 patients undergoing computed tomography angiography, 15 of the 30 patients (50%) who had spot signs showed an intrahematoma striate artery (termed spot and tail sign), which was a linear density extending from the middle cerebral artery toward the spot sign. Acute deterioration occurred more frequently in patients who had a spot and tail sign compared with patients who had spot signs without intrahematoma striate arteries (P<0.05). Multivariate analysis revealed that hematoma volume, spot signs, and intrahematoma striate arteries were independent predictors of acute deterioration (P<0.05). CONCLUSIONS: The presence of a spot and tail sign, assumed to indicate active bleeding from the striate artery, could be a more sensitive predictor of acute deterioration than the presence of a simple spot sign. PMID- 23674524 TI - Explicit consideration of baseline factors to assess recombinant tissue-type plasminogen activator response with respect to race and sex. AB - BACKGROUND AND PURPOSE: Sex and race reportedly influence outcome after recombinant tissue-type plasminogen activator (rtPA). It is, however, unclear whether baseline imbalances (eg, stroke severity) or lack of response to thrombolysis is responsible. We applied balancing methods to test the hypothesis that race and sex influence outcome after rtPA independent of baseline conditions. METHODS: We mapped group outcomes from the National Institute of Neurological Disorders and Stroke (NINDS) dataset based on race and sex onto a surrogate-control function to assess differences from expected outcomes at their respective National Institutes of Health Stroke Scale and age. Outcomes were also compared for subjects matched individually on key baseline factors using NINDS and 2 recent datasets from southeastern United States. RESULTS: At similar National Institutes of Health Stroke Scale and age, 90-day good outcomes (modified Rankin Score, 0-2) in NINDS were similarly improved after rtPA for white men and women. There was a strong trend for improvement in black men. Conversely, black women treated with rtPA showed response rates no different from the controls. After baseline matching, there were nonsignificant trends in outcomes except for significantly fewer good outcomes in black versus matched white women (37% versus 63%; P=0.027). Pooling the 3 datasets showed a similar trend for poorer short-term outcome for black women (P=0.054; modified Rankin Score, 0-1). CONCLUSIONS: Matching for key baseline factors indicated that race and sex influence outcome most strikingly in black women who demonstrated poorest outcomes after rtPA. This finding supports the hypothesis that poor response to rtPA, rather than differences in baseline conditions, contributes to the worse outcome. This finding requires prospective confirmation. PMID- 23674526 TI - Immunohistochemical analysis of thrombi retrieved during treatment of acute ischemic stroke: does stent-retriever cause intimal damage? AB - BACKGROUND AND PURPOSE: To provide evidence whether mechanical thrombectomy with stent-retrievers in the treatment of acute ischemic stroke causes intimal damage. METHODS: This study analyzed thrombi retrieved by mechanical thrombectomy from cerebral arteries in 48 consecutive patients with acute ischemic stroke for the presence of endothelial cells using CD34 antibodies. RESULTS: Of 48 thrombi analyzed, CD34-positive cells were absent in 20, present as isolated cells in 21, and found in clusters in 7 thrombi. We did not find any subendothelial vessel wall structures. CONCLUSIONS: Our findings suggest that mechanical thrombectomy with stent-retrievers does not cause relevant intimal damage in acute ischemic stroke treatment. Clinical Trial Registration- URL: http://www.germanctr.de. Unique identifier: DRKS00004695. PMID- 23674527 TI - Transient receptor potential canonical 3 inhibitor Pyr3 improves outcomes and attenuates astrogliosis after intracerebral hemorrhage in mice. AB - BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) stems from the rupture of blood vessels in the brain, with the subsequent accumulation of blood in the parenchyma. Increasing evidence suggests that blood-derived factors induce excessive inflammatory responses that are involved in the progression of ICH induced brain injury. Thrombin, a major blood-derived factor, leaks into the brain parenchyma on blood-brain barrier disruption and induces brain injury and astrogliosis. Furthermore, thrombin dynamically upregulates transient receptor potential canonical 3 channel, which contributes to pathological astrogliosis through a feed-forward upregulation of its own expression. The present study investigated whether Ethyl-1-(4-(2,3,3-trichloroacrylamide)phenyl)-5 (trifluoromethyl)-1H-pyrazole-4-carboxylate (Pyr3), a specific transient receptor potential canonical 3 inhibitor, can improve functional outcomes and attenuate astrogliosis after ICH in mice. METHODS: Male C57BL6 mice received an intracerebral infusion of collagenase or autologous blood to induce ICH. Pyr3 was given both intracerebroventricularly and intraperitoneally after ICH induction. ICH-induced brain injury was evaluated by quantitative assessment of neurological deficits, brain swelling, and injury volume after ICH. Astrocyte activation was evaluated by immunohistochemical assessment of changes in S100 protein expression. RESULTS: Neurological deficits, neuronal injury, brain edema, and astrocyte activation were all significantly improved by administration of Pyr3. Moreover, delayed administration of Pyr3 at 6 hours or 1 day after blood or collagenase infusion, respectively, also improved the symptoms. CONCLUSIONS: Pyr3, a specific inhibitor of transient receptor potential canonical 3, reduced the perihematomal accumulation of astrocytes and ameliorated ICH-induced brain injury. Therefore, transient receptor potential canonical 3 provides a new therapeutic target for the treatment of hemorrhagic brain injury. PMID- 23674529 TI - Letter by Bhupali and Labovitz regarding article, "Clinical scores for predicting recurrence after transient ischemic attack or stroke: how good are they?". PMID- 23674530 TI - Low serum calcium levels contribute to larger hematoma volume in acute intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: We investigate whether admission serum calcium levels are associated with hematoma volume, stroke severity, and outcomes in patients with acute intracerebral hemorrhage. METHODS: A total of 273 patients admitted within 24 hours after intracerebral hemorrhage onset was divided into quartiles based on admission serum calcium levels (Q1 [<=9.0], Q2 [9.1-9.3], Q3 [9.4-9.7], Q4 [>=9.8] mg/dL). RESULTS: Median hematoma volumes for each quartile (Q1 to Q4) were 18, 9, 10, and 9 mL (P=0.005), and median National Institutes of Health Stroke Scale scores were 16, 11, 11, and 9 (P=0.010), respectively. On multivariate analysis, Q1 had larger hematoma volume (P=0.025) and higher National Institutes of Health Stroke Scale score (P=0.020) than Q4. There were fewer patients with modified Rankin Scale scores 0 to 2 in Q1 than Q4 after adjustment for risk factors and comorbidities (odds ratio, 0.31; 95% confidence interval, 0.11-0.84) but not after additional adjustment for hematoma volume and National Institutes of Health Stroke Scale score. There were more patients with modified Rankin Scale scores 5 to 6 (P=0.016) and with fatal outcomes (P=0.048) in Q1 than Q4 as crude values, but not after adjustment. CONCLUSIONS: Low admission serum calcium levels were associated with larger hematoma volume and higher National Institutes of Health Stroke Scale score among patients with acute intracerebral hemorrhage. PMID- 23674531 TI - Is there a stroke belt in China and why? AB - BACKGROUND AND PURPOSE: In 1960s, a stroke belt with high stroke mortality was discovered in the southeast United States. In China, where stroke is the leading cause of death, we aimed to determine whether a focal region of high stroke incidence (stroke belt) exits and, if so, the possible causal and modifiable factors. METHODS: We systematically reviewed all studies of stroke incidence in China between 1980 and 2010, and included those which met our criteria for a high quality study. Criteria for a provincial region of high stroke incidence were ranking in the top one third of all provinces for stroke incidence and ranking of more than one third of prefectural regions within the province in the top two sevenths of all prefectural regions for stroke incidence. We also reviewed regional distribution of major vascular risk factors, socioeconomic status, and demographic profiles in China. RESULTS: Nine eligible studies provided data on the incidence of stroke in 32 of 34 provincial regions of China (with Hong Kong and Macao as exceptions) and 52% of the 347 prefectural regions. Nine provincial regions (Heilongjiang, Tibet, Jilin, Liaoning, Xinjiang, Hebei, Inner Mongolia, Beijing, and Ningxia) met our criteria for a region of high stroke incidence and constitute a stroke belt in north and west China. The incidence of stroke in the stroke belt was 236.2 per 100 000 population compared with 109.7 in regions outside the belt (rate ratio, 2.16; 95% confidence interval, 2.10-2.22). The mean population prevalence of hypertension and overweight (body mass index, >25) was greater in the stroke belt than that in other regions (15.3% versus 10.3%, P<0.001; 21.1% versus 12.3%, P=0.013, respectively). The prevalence of hypertension and overweight also correlated significantly with regional stroke incidence (R=0.642, P<0.001; R=0.438, P=0.014, respectively, by Spearman rank correlation). CONCLUSIONS: A stroke belt of high stroke incidence exists in 9 provincial regions of north and west China. The stroke belt may be caused, at least in part, by a higher population prevalence of hypertension and excess body weight. Lowering blood pressure and body weight in the stroke belt may reduce the geographic disparity in stroke risk and incidence in China. PMID- 23674532 TI - The end of the beginning ... PMID- 23674533 TI - Being Lister: ethos and Victorian medical discourse. AB - Stylistic analysis and rhetorical theory are used in this study to inform our understanding of impediments to the successful uptake of a new medical idea. Through examination of the work of the Victorian surgeon Joseph Lister, who was described by one biographer as suffering from "stylistic ham-handedness", the study provides insights into the difficulty that Lister had in explaining his theory of antiseptic surgery. Using three comparisons-Lister's scientific style in public discourse with that of his students, and Lister's scientific style in private discourse with those of both a surbordinate and a superior-the study suggests that the rhetorical concept of ethos played a major role in his communication difficulties. In this way, it presents a more nuanced perspective on modern presentations of "model" communications versus communication failures: that is, that problematic written discourse offers as useful a heuristic device as does exemplary discourse. PMID- 23674528 TI - 17q25 Locus is associated with white matter hyperintensity volume in ischemic stroke, but not with lacunar stroke status. AB - BACKGROUND AND PURPOSE: Recently, a novel locus at 17q25 was associated with white matter hyperintensities (WMH) on MRI in stroke-free individuals. We aimed to replicate the association with WMH volume (WMHV) in patients with ischemic stroke. If the association acts by promoting a small vessel arteriopathy, it might be expected to also associate with lacunar stroke. METHODS: We quantified WMH on MRI in the stroke-free hemisphere of 2588 ischemic stroke cases. Association between WMHV and 6 single-nucleotide polymorphisms at chromosome 17q25 was assessed by linear regression. These single-nucleotide polymorphisms were also investigated for association with lacunar stroke in 1854 cases and 51 939 stroke-free controls from METASTROKE. Meta-analyses with previous reports and a genetic risk score approach were applied to identify other novel WMHV risk variants and uncover shared genetic contributions to WMHV in community participants without stroke and ischemic stroke. RESULTS: Single-nucleotide polymorphisms at 17q25 were associated with WMHV in ischemic stroke, the most significant being rs9894383 (P=0.0006). In contrast, there was no association between any single-nucleotide polymorphism and lacunar stroke. A genetic risk score analysis revealed further genetic components to WMHV shared between community participants without stroke and ischemic stroke. CONCLUSIONS: This study provides support for an association between the 17q25 locus and WMH. In contrast, it is not associated with lacunar stroke, suggesting that the association does not act by promoting small-vessel arteriopathy or the same arteriopathy responsible for lacunar infarction. PMID- 23674534 TI - Evidence-based medicine? Patient case studies in English surgical treatises, 1660 1700. AB - The implications of the presence of case information included in English surgical treatises published from 1660 to 1700 are discussed. While such casework has been frequently examined and cited, the phenomenon of including case information in treatises has yet to be studied in any depth. The context, presentation and origins of the case information are discussed, and the reasons behind the inclusion of casework are explored in terms of "blame-narratives", teaching models and evidence-based medicine. It was found that, while the reasons behind the inclusion of case information varied, English surgeons practised evidence based medicine. This finding is significant, as it proposes that evidence-based medicine was practised a century earlier than-and across the Channel from-its supposed first emergence in modern medical practice. PMID- 23674535 TI - The inference from a single case: moral versus scientific inferences in implementing new biotechnologies. AB - Are there similarities between scientific and moral inference? This is the key question in this article. It takes as its point of departure an instance of one person's story in the media changing both Norwegian public opinion and a brand new Norwegian law prohibiting the use of saviour siblings. The case appears to falsify existing norms and to establish new ones. The analysis of this case reveals similarities in the modes of inference in science and morals, inasmuch as (a) a single case functions as a counter-example to an existing rule; (b) there is a common presupposition of stability, similarity and order, which makes it possible to reason from a few cases to a general rule; and (c) this makes it possible to hold things together and retain order. In science, these modes of inference are referred to as falsification, induction and consistency. In morals, they have a variety of other names. Hence, even without abandoning the fact-value divide, there appear to be similarities between inference in science and inference in morals, which may encourage communication across the boundaries between "the two cultures" and which are relevant to medical humanities. PMID- 23674536 TI - Camille Claudel: trajectory of a psychosis. AB - The French sculptor Camille Claudel at about the age of 40 developed a psychotic illness that proved to be chronic. Delusions of persecution, focused on her former mentor and lover Auguste Rodin, gradually became systematised until they dominated her life completely. She abandoned artistic work, withdrew into social isolation and lived alone in conditions of squalor and severe self-neglect until eventually, after her father's death, she was committed to an asylum and spent the remainder of her life in institutional confinement. Only within the past 20 years has her achievement been recognised and her fate drawn wide sympathy. Previous psychiatric studies have dismissed or downplayed the significance of Camille's adverse life experiences for her case history. The present reassessment, drawing on modern interactionist models of the genesis and course of psychosis, sets out to place both her creative drive and her mental instability within a broader life-course perspective and to arrive at a more balanced judgement of the case. PMID- 23674537 TI - Putting it bluntly: communication skills in the Iliad. AB - In current undergraduate medical curricula, much emphasis is placed on learning the skills of communication. This paper looks at Homer's Iliad and argues that from it we may learn that our skills can be mechanistic, shallow and simplistic. Homer was regarded in the Greek and Roman world as the father of rhetoric. This reputation rested greatly on book 9 of the Iliad, the embassy from the Greek leaders to the bitter, wrathful Achilles. The mission of the three emissaries is to persuade him to return to the ranks of the Greeks, who are being routed since his refusal to fight. We learn how the outcome of a conversation may be predetermined by the previous relationship of the speakers, and how a man beyond reason responds to reason; we should reflect that Homer's audience heard the piece knowing the outcome, giving it a tragic inevitability. We, the audience, cannot analyse the discourse rationally, because in this, as in all communication, reason is disturbed by emotion. PMID- 23674538 TI - The year of magical thinking: Joan Didion and the dialectic of grief. AB - Joan Didion is a prominent American writer. In late 2003, while her only child lay critically ill, her husband, John, died suddenly. Theirs was a marriage of great intimacy and love. Grief enveloped her. Eventually she began to write an account of the first 12 months of her bereavement and the vigil for her child: The year of magical thinking. Raw, insightful and challenging, it is a rich, generous and graceful document. Didion draws on the literature of grief, personal and professional. Here, those readings are examined and reflections are made on the singular, unique grief of the author in the context of current theories on bereavement. PMID- 23674539 TI - "Writing is a way of saying things I can't say"--therapeutic creative writing: a qualitative study of its value to people with cancer cared for in cancer and palliative healthcare. AB - This paper reports on a therapeutic creative writing project undertaken at King's College London and University College Hospital London, funded by Arts Council England. The project sought to increase understanding of experiences of personal expressive and explorative writing by cancer patients receiving palliative care. Narrative methods were used to analyse and interpret patients' written and oral (transcripts of semistructured interviews) responses, researchers' field notes and written responses of staff. These indicated that writing: (1) facilitated patients' ability and opportunity to discover what they thought, felt, remembered; (2) enhanced their awareness of, and ability to express, issues to which focused attention needed to be paid; and (3) offered satisfaction and fulfilment of creative expression and exploration and the production of writings which to them and close others were vital. Illuminatively drawing upon patients' writings and responses, this paper is underpinned by discussion of therapeutic writing and its relationship to creative writing, with reference to a range of previous research. PMID- 23674541 TI - Fourteen stories: doctors, patients, and other strangers. PMID- 23674540 TI - Opening the word hoard. PMID- 23674542 TI - Doctors and paintings: Insights and replenishment for health professionals. PMID- 23674543 TI - Stories of illness and healing: women write their bodies. PMID- 23674544 TI - Leonardo da Vinci: the marvellous works of nature and man. PMID- 23674545 TI - How to think clearly about Medicare administrative costs: data sources and measurement. AB - The Centers for Medicare and Medicaid Services (CMS) annually publishes two measures of Medicare's administrative expenditures. One of these appears in the reports of the Medicare Boards of Trustees and the other in the National Health Expenditure Accounts (NHEA). The latest trustees' report indicates Medicare's administrative expenditures are 1 percent of total Medicare spending, while the latest NHEA indicates the figure is 6 percent. The debate about Medicare's administrative expenditures, which emerged several years ago, reflects widespread confusion about these data. Critics of Medicare argue that the official reports on Medicare's overhead ignore or hide numerous types of administrative spending, such as the cost of collecting taxes and Part B premiums. Defenders of Medicare claim the official statistics are accurate. But participants on both sides of this debate fail to cite the official documents and do not analyze CMS's methodology. This article examines the controversy over the methodology CMS uses to calculate the trustees' and NHEA's measures and the sources of confusion and ignorance about them. It concludes with a discussion of how the two measures should be used. PMID- 23674546 TI - Behind the scenes of the Patient Protection and Affordable Care Act: the making of a health care co-op. AB - A primary goal of the Patient Protection and Affordable Care Act (PPACA) is to reduce the number of uninsured by making health insurance more affordable for small businesses and individuals. Toward that end, the PPACA encourages the creation of nonprofit, member-owned health insurance cooperatives to operate inside each state exchange. Co-ops face significant challenges in entering mature insurance markets, but they also possess unique characteristics that may help them survive and thrive. Using Common Ground Healthcare Cooperative in Wisconsin as a case study, this article traces the origins of co-ops in health care reform at national and state levels and analyzes the political and technical challenges and opportunities facing these organizations. PMID- 23674547 TI - Prescription drugs and administrative costs. PMID- 23674549 TI - Benefit finding in fathers of childhood cancer survivors: a retrospective pilot study. AB - There is a growing literature examining positive outcomes following traumatic experiences. Although the diagnosis of a child with cancer poses extraordinary challenges for the family, awareness is growing that such a life-changing event can be a catalyst for positive growth. The current mixed methods study investigated benefit finding in fathers (N = 25) of childhood cancer survivors. Benefit finding included positive changes resulting from adversity. Participants completed a benefit finding measure and an interview describing their experience and benefits from the challenges faced during their child's cancer journey. Findings indicated that fathers endorsed high levels of benefit finding (mean = 4.1 out of 5) specifically in personal growth, spiritual change, and relationships with others. Our study extends the literature by examining how their child's cancer journey contributed to specific domains of paternal benefit finding. These results support the use of a positive psychology framework for understanding effects of a child's cancer diagnosis on caregivers. PMID- 23674550 TI - Incremental value of T-SPOT.TB for diagnosis of active pulmonary tuberculosis in children in a high-burden setting: a multivariable analysis. AB - INTRODUCTION: Interferon gamma release assays (IGRAs) are increasingly used for tuberculosis (TB) infection, but their incremental value beyond patient demographics, clinical signs and conventional tests for active disease has not been evaluated in children. METHODS: The incremental value of T-SPOT.TB was assessed in 491 smear-negative children from two hospitals in Cape Town, South Africa. Bayesian model averaging was used to select the optimal set of patient demographics and clinical signs for predicting culture-confirmed TB. The added value of T-SPOT.TB over and above patient characteristics and conventional tests was measured using statistics such as the difference in the area under the receiver operating characteristic curve (AUC), the net reclassification improvement (NRI) and the integrated discrimination improvement (IDI). RESULTS: Cough longer than 2 weeks, fever longer than 2 weeks, night sweats, malaise, history of household contact and HIV status were the most important predictors of culture-confirmed TB. Binary T-SPOT.TB results did not have incremental value when added to the baseline model with clinical predictors, chest radiography and the tuberculin skin test. The AUC difference was 3% (95% CI 0% to 7%). Using risk cut-offs of <10%, 10-30% and >30%, the NRI was 7% (95% CI -8% to 31%) but the CI included the null value. The IDI was 3% (95% CI 0% to 11%), meaning that the average predicted probability across all possible cut-offs improved marginally by 3%. CONCLUSIONS: In a high-burden setting, the T-SPOT.TB did not have added value beyond clinical data and conventional tests for diagnosis of TB disease in smear negative children. PMID- 23674551 TI - The mammalian-specific Tex19.1 gene plays an essential role in spermatogenesis and placenta-supported development. AB - STUDY QUESTION: What is the consequence of Tex19.1 gene deletion in mice? SUMMARY ANSWER: The Tex19.1 gene is important in spermatogenesis and placenta-supported development. WHAT IS KNOWN ALREADY: Tex19.1 is expressed in embryonic stem (ES) cells, primordial germ cells (PGCs), placenta and adult gonads. Its invalidation in mice leads to a variable impairment in spermatogenesis and reduction of perinatal survival. STUDY DESIGN, SIZE, DURATION: We generated knock-out mice and ES cells and compared them with wild-type counterparts. The phenotype of the Tex19.1 knock-out mouse line was investigated during embryogenesis, fetal development and placentation as well as during adulthood. PARTICIPANTS/MATERIALS, SETTING, METHODS: We used a mouse model system to generate a mutant mouse line in which the Tex19.1 gene was deleted in the germline. We performed an extensive analysis of Tex19.1-deficient ES cells and assessed their in vivo differentiation potential by generating chimeric mice after injection of the ES cells into wild type blastocysts. For mutant animals, a morphological characterization was performed for testes and ovaries and placenta. Finally, we characterized semen parameters of mutant animals and performed real-time RT-PCR for expression levels of retrotransposons in mutant testes and ES cells. MAIN RESULTS AND THE ROLE OF CHANCE: While Tex19.1 is not essential in ES cells, our study points out that it is important for spermatogenesis and for placenta-supported development. Furthermore, we observed an overexpression of the class II LTR-retrotransposon MMERVK10C in Tex19.1-deficient ES cells and testes. LIMITATIONS, REASONS FOR CAUTION: The Tex19.1 knock-out phenotype is variable with testis morphology ranging from severely altered (in sterile males) to almost indistinguishable compared with the control counterparts (in fertile males). This variability in the testis phenotype subsequently hampered the molecular analysis of mutant testes. Furthermore, these results were obtained in the mouse, which has a second isoform (i.e. Tex19.2), while other mammals possess only one Tex19 (e.g. in humans). WIDER IMPLICATIONS OF THE FINDINGS: The fact that one gene has a role in both placentation and spermatogenesis might open new ways of studying human pathologies that might link male fertility impairment and placenta-related pregnancy disorders. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Sante et de la Recherche Medicale (INSERM) (Grant Avenir), the Ministere de l'Education Nationale, de l'Enseignement Superieur et de la Recherche, the Universite de Strasbourg, the Association Francaise contre les Myopathies (AFM) and the Fondation pour la Recherche Medicale (FRM) and Hopitaux Universitaires de Strasbourg.The authors have nothing to disclose. PMID- 23674553 TI - Using principles of quality and safety education for nurses in school nurse continuing education. AB - School nurses require ongoing continuing education in a number of areas. The Quality and Safety Education for Nurses (QSEN) framework can be utilized in considering school nurses' roles and developing continuing education. Focusing on neurology continuing education, the QSEN framework is illustrated with the example of concussion management in athletes. QSEN strategies can stimulate change to the status quo and outline the knowledge, skills, and attitudes that need to be adapted. With their competencies and knowledge, professional school nurses can incorporate evidence-based practices in conjunction with input from health care providers and families to create high-quality care and positive outcomes for students. PMID- 23674552 TI - Body size and endometriosis: results from 20 years of follow-up within the Nurses' Health Study II prospective cohort. AB - STUDY QUESTION: Is there a relationship between body mass index (BMI), body shape and endometriosis? SUMMARY ANSWER: Endometriosis is inversely associated with early adult BMI and may correlate with a peripheral body fat distribution. WHAT IS KNOWN ALREADY: The literature suggests an inverse relation between endometriosis and BMI, although few studies have specifically explored this association in depth. STUDY DESIGN, SIZE, DURATION: Prospective cohort study using data collected from 116 430 female nurses from September 1989 to June 2011 as part of the Nurses' Health Study II cohort. PARTICIPANTS/MATERIALS, METHODS AND SETTING: Cases were restricted to laparoscopically confirmed endometriosis. Weight at age 18 and height were reported at baseline, and current weight was updated every 2 years. Waist and hip measurements were first taken in 1993 and updated in 2005. Rate ratios (RR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models with time-varying covariates. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 5504 incident cases of endometriosis were reported during 1 299 349 woman-years (incidence rate = 385 per 100 000 woman-years). BMI at age 18 and current BMI were each significantly inversely associated with endometriosis (P-value, test for linear trend <0.0001). Both associations were stronger among infertile women. Obese infertile women with current BMIs of 35-39.9 kg/m(2) and >= 40 kg/m(2) had a 55% (95% CI 0.30-0.67) and a 62% (95% CI 0.23-0.62) lower risk of endometriosis, respectively, compared with the low-normal BMI referent (18.5-22.4 kg/m(2)). Rates of endometriosis were nearly 3-fold higher in women with waist-to-hip ratios <0.60 (RR = 2.78, 95% CI 1.38-5.60) compared with those with waist-to-hip ratios between 0.70 and 0.79, although the sample size for this category was very small. LIMITATIONS AND REASONS FOR CAUTION: Although women with undiagnosed endometriosis certainly remain in the comparison population even in this prospective cohort study, the community prevalence of endometriosis in an asymptomatic population is very low. Moreover, the characteristics of this small proportion of undiagnosed cases are diluted among the >90 000 women accurately defined as being endometriosis-free and are, therefore, unlikely to impact on effect estimation. Although geographically diverse, the NHS II cohort is overwhelmingly Caucasian, which may limit generalizability to more ethnically diverse populations. WIDER IMPLICATIONS OF THE STUDY: The results of this study suggest that endometriosis is inversely associated with early adult BMI and may correlate with a peripheral body fat distribution. PMID- 23674554 TI - Adolescent self-reported health in relation to school factors: a multilevel analysis. AB - The aim of the study was to examine school-related determinants of self-reported health among adolescents. Questionnaire survey data comprising 4,972 students, Grades 7 through 9, from 20 schools in northern Sweden were used. Also, complimentary data about each school were collected from the Swedish National Agency for Education. Using multilevel logistic regression analyses, results showed that most variation in self-reported health was explained by individual level differences. Truancy, bullying, and poor relations with teachers significantly increased the odds ratio of reporting poor general health, for boys and for girls. Most variables at the school level, for example, school size and student-teacher ratio, did not render significant associations with students' self-reported health. In conclusion, this study indicates that health promotion at school, including school health services, may benefit from focusing primarily on individual-level determinants of health, that is, students' relations to peers and teachers, without ignoring that bullying and weak student-teacher relationships also may induce school-level interventions. PMID- 23674555 TI - Re-examining "temporal niche". AB - The circadian system temporally organizes physiology and behavior throughout the 24-h day. At the core of this organization lies a network of multiple circadian oscillators located within the central nervous system as well as in virtually every peripheral organ. These oscillators define a 24-h temporal landscape of mutually interacting circadian rhythms that is known as the temporal niche of a species. This temporal niche is constituted by the collective phases of all biological rhythms emerging from this multi-oscillatory system. We review evidence showing that under different environmental conditions, this system can adopt different harmonic configurations. Thus, the classic chronobiological approach of searching for "the" circadian phase of an animal-typically by studying circadian rhythms of locomotor activity-represents a narrow look into the circadian system of an animal. We propose that the study of hormonal rhythms may lead to a more insightful assessment of a species' temporal niche. PMID- 23674556 TI - Peripheral cementifying fibroma: a clinical diagnostic dilemma. AB - The peripheral ossifying fibroma (POF) is a reactive gingival overgrowth occurring frequently in the anterior maxilla. It originates in the cells of the periodontal ligament and is more common in children and young adults. In the current article a case of gingival over growth, which was thought to be puberty induced gingivitis was seen in the lower anterior maxillary gingiva. Histology of the excised tissue showed cellular, fibrous connective tissue stroma with calcified osseous calcifications indicative of POF. The definitive diagnosis is established only by histological examination, which revealed the presence of highly cellular connective tissue with focal calcifications. Surgery is the treatment of choice, though the recurrence rate can reach 20% in case of POF. After histological confirmation the recall and clinical evaluation protocol of POF varies due to its increased recurrence rate, which the general dentist should be aware of. PMID- 23674557 TI - McConnell sign and S1Q3T3 pattern in pulmonary embolism: revisited. PMID- 23674558 TI - Reversibility of myocardial hypertrophy 8 years after adrenal adenoma excision and drugs and alcohol addiction withdrawal. PMID- 23674559 TI - Chronic non-suppurative osteomyelitis with proliferative periostitis or Garre's osteomyelitis. PMID- 23674560 TI - A rare cause of pulsus paradoxus: acute tension hydrothorax. PMID- 23674561 TI - Post-infarction biventricular free wall rupture with extracardiac shunt presenting as ventricular septal rupture. AB - Ventricular free wall rupture is a rare, usually fatal complication of acute myocardial infarction. Subacute free wall rupture with pseudoaneurysm formation is even rarer, but may be associated with a chance of survival if surgery is performed expeditiously. Although rupture of the left ventricle is more common, right-sided rupture has also been reported. We report an unusual case of post infarct biventricular rupture masquerading as a ventricular septal defect, due to an extracardiac shunt within the pseudoaneurysm. Our patient underwent urgent surgery, made an excellent recovery and was discharged home in a fully functional condition within a week post-surgery. PMID- 23674562 TI - Surgery for secondary spontaneous pneumothorax: risk factors for recurrence and morbidity. AB - OBJECTIVES: Secondary spontaneous pneumothorax (SSP) is more common in elderly patients; it has high rates of recurrence and mortality, even if surgery is performed. There has been little study on the surgical treatment of SSP. Therefore, we analysed the outcomes of surgical treatment of SSP patients, and investigated the risk factors of recurrence and morbidity. METHODS: We studied 97 consecutive surgical treatments on 94 patients with SSP who had emphysematous changes of lung retrospectively. Emphysematous changes on preoperative computed tomography image were evaluated by the Goddard score, which is a visual scoring system. First, video-assisted thoracoscopic surgery was performed, followed by bullectomy for the responsible lesions. RESULTS: The rate of morbidity was 20.6% and that of mortality was 4.1%. Recurrence rate was 9.3%. By multivariate analysis, a Goddard score>=7 (odds ratio: 8.93, P=0.033) and treatment of bulla without the use of staplers (odds ratio: 11.57, P=0.019) were significant risk factors for morbidity, while pulmonary fibrosis tended to increase the risk of recurrence (hazard ratio: 4.21, P=0.051), and a Goddard score>=7 (hazard ratio: 7.79, P=0.023) was a significant risk factor for recurrence. CONCLUSIONS: Surgical treatment in patients with SSP had favourable results. Treatment in which the base of the bulla cannot be definitely shut off with staplers is associated with increased morbidity. Significant emphysematous change on preoperative computed tomography image and pulmonary fibrosis are predictors of recurrence. Patients with these findings should be investigated in terms of the indications of surgery and additional treatment, not only bullectomy. PMID- 23674563 TI - The role of surgical lung biopsy in the management of interstitial lung disease: experience from a single institution in the UK. AB - OBJECTIVES: Interstitial lung disease (ILD) includes a wide spectrum of pulmonary pathologies. The role of surgical lung biopsy (SLB) in the diagnosis of ILD is still controversial. The purpose of this study was to ascertain whether SLB is worthwhile in the management of ILD. METHODS: One hundred and three patients underwent SLB for ILD from April 2008 to March 2010 at a single institution. Outcomes included patient demographics, preoperative investigations, preoperative diagnosis and treatment, surgical approach, number and site of biopsies, complications, length of postoperative stay and postoperative pathological diagnosis and treatment. RESULTS: Fifty-one (49.6%) patients were male and 52 (50.4%) were female. The median age was 58 (range 26-78). Major complications were seen in 7 patients (6.8%). Five patients (4.9%) died within 30 days following surgery. Definitive pathological diagnosis (DPD) was reached in 72 (69.9%) patients, whereas no DPD was achieved in 31 (30.1%). Within the group of patients who received DPD, this differed from the clinical diagnosis in 53 patients (51.5%), and was concordant in 19 (18.4%). The DPD was helpful in guiding the management of 47 patients (45.6%), who had a change in their treatment following the procedure. The median hospital stay was 4 days (range 2 42 days). CONCLUSIONS: SLB is a well-recognized procedure. Although it provides a diagnosis for the majority of patients, in our series SLB was inconclusive in a considerable number of cases and did not lead to a therapeutic change for more than half of all patients. Furthermore, SLB is not without risk and can be associated with a prolonged hospital stay. We believe that SLB should be performed in a select group of patients with ILD after discussion by a multidisciplinary panel. PMID- 23674564 TI - Retrieval practice is a robust memory aid for memory-impaired patients with MS. AB - Memory impairment is prevalent in multiple sclerosis (MS). Retrieval practice is a powerful memory technique whereby retrieving information (quizzing oneself) leads to better memory than restudying. In a within-subjects experiment, 12 memory-impaired MS patients encoded verbal paired associates (VPAs) through massed restudy (MR), spaced restudy (SR), or retrieval practice (RP). Half of VPAs were tested after short delay (30 minutes) and half after long delay (one week). RP robustly improved memory more than restudy. Short delay: MR=15.6%, SR=27.1%, RP=72.9%. Long delay: MR=1.0%, SR=4.2%, RP=24.0%. RP was the best memory technique for nearly all patients after both short and long delays. PMID- 23674565 TI - B cell responses to the 2011/12-influenza vaccine in the aged. AB - Antibody and B cell responses to influenza A viruses were measured over a period of 2 months in 30 aged and 15 middle-aged individuals following vaccination with the 2011/12 trivalent inactivated influenza vaccine by micro-neutralization assays, ELISAs, ELISpot assays and cell surface staining with lineage-defining antibodies followed by multicolor flow cytometry. Both cohorts developed comparable antibody responses to the H3N2 virus of the vaccine while responses to the H1N1 virus were compromised in the aged. ELISpot assays of peripheral blood mononuclear cells (PBMCs) gave comparable results for the two cohorts. Analysis by flow cytometry upon staining of CD19+IgD-CD20- PBMCs with antibodies to CD27 and CD38 showed markedly reduced increases of such cells following vaccination in the aged. Additional analysis of cells from a subset of 10 younger and 10 aged individuals indicated that in the aged a portion of IgG producing cells lose expression of CD27 and reduce expression of CD38. PMID- 23674567 TI - An indicator of probable semicircular canal dehiscence: ocular vestibular evoked myogenic potentials to high frequencies. AB - The n10 component of the ocular vestibular evoked myogenic potential (oVEMP) to sound and vibration stimuli is a crossed response that has enhanced amplitude and decreased threshold in patients with CT-verified superior semicircular canal dehiscence (SSCD). However, demonstrating enhanced VEMP amplitude and reduced VEMP thresholds requires multiple trials and can be very time consuming and tiring for patients, so a specific indicator of probable SCD that is fast and not tiring would be preferred. Here we report a 1-trial indicator: that the oVEMP n10 in response to a very high frequency stimulus (4000 Hz), either air-conducted sound (ACS) or bone conducted vibration (BCV), is such a fast indicator of probable SCD. In 22 healthy subjects, oVEMP n10 at 4000 Hz was not detectable; however, in all 22 CT-verified SSCD patients tested, oVEMP n10 responses were clearly present to 4000 Hz to either ACS or BCV stimuli. PMID- 23674568 TI - Tympanoplasty with intact canal wall mastoidectomy for cholesteatoma: long-term surgical outcomes. AB - OBJECTIVE: With different mastoidectomy approaches available to the surgeon for treatment of cholesteatoma, we review long-term outcomes of intact canal wall (ICW) mastoidectomy with tympanoplasty. STUDY DESIGN: Case series with chart review. SETTING: Academic medical center. SUBJECTS AND METHODS: All cases of cholesteatoma treated with ICW mastoidectomy by the senior author over a period of 9 years for which at least 2 years of follow-up data exist. Patient and disease information was collected retrospectively and analyzed. RESULTS: One hundred forty-eight patients with 156 affected ears were treated and followed for a median of 5.3 years (range, 2.1-14.8). The majority of the operations (144/156, 92%) were staged. Of those that were staged, 51/144 (35%) had residual cholesteatoma at the second stage. Thirteen patients (8%) had recurrence of their cholesteatoma, of which 6 required a subsequent canal wall down (CWD) mastoidectomy. CONCLUSIONS: ICW mastoidectomy with tympanoplasty continues to be a successful treatment for cholesteatoma. We found a substantial residual rate at the second stage, justifying the necessity of staging in most cases. Recurrence rate of cholesteatoma using this technique is low, as is the progression to CWD mastoidectomy. PMID- 23674566 TI - Constitutively-active androgen receptor variants function independently of the HSP90 chaperone but do not confer resistance to HSP90 inhibitors. AB - The development of lethal, castration resistant prostate cancer is associated with adaptive changes to the androgen receptor (AR), including the emergence of mutant receptors and truncated, constitutively active AR variants. AR relies on the molecular chaperone HSP90 for its function in both normal and malignant prostate cells, but the requirement for HSP90 in environments with aberrant AR expression is largely unknown. Here, we investigated the efficacy of three HSP90 inhibitors, 17-AAG, HSP990 and AUY922, against clinically-relevant AR missense mutants and truncated variants. HSP90 inhibition effectively suppressed the signaling of wild-type AR and all AR missense mutants tested. By contrast, two truncated AR variants, AR-V7 and ARv567es, exhibited marked resistance to HSP90 inhibitors. Supporting this observation, nuclear localization of the truncated AR variants was not affected by HSP90 inhibition and AR variant:HSP90 complexes could not be detected in prostate cancer cells. Interestingly, HSP90 inhibition resulted in accumulation of AR-V7 and ARv567es in both cell lines and human tumor explants. Despite the apparent independence of AR variants from HSP90 and their treatment-associated induction, the growth of cell lines with endogenous or enforced expression of AR-V7 or ARv567es remained highly sensitive to AUY922. This study demonstrates that functional AR variant signaling does not confer resistance to HSP90 inhibition, yields insight into the interaction between AR and HSP90 and provides further impetus for the clinical application of HSP90 inhibitors in advanced prostate cancer. PMID- 23674569 TI - Perioperative strategies to improve sinus surgery outcomes in patients with cystic fibrosis: a systematic review. AB - OBJECTIVES: Review the literature for intraoperative techniques and postoperative practices after functional endoscopy sinus surgery (FESS) that may improve outcomes in patients with cystic fibrosis (CF). DATA SOURCES: PubMed and the Cochrane Library. REVIEW METHODS: A systematic review of the literature was performed. Articles from 1990 to 2012 were searched using the terms sinus surgery and cystic fibrosis with studies limited to the English language and human subjects. Abstracts were reviewed to identify relevant original manuscripts. Bibliographies of relevant articles were examined to identify additional manuscripts. RESULTS: The initial PubMed search identified 169 articles. One additional article was identified through the Cochrane Library. After reviewing the abstracts, 41 selected studies were examined in further detail, and 22 articles were ultimately selected for suitability for this review. The bibliographies of these articles were reviewed and no additional articles were identified. Perioperative strategies included postoperative medical therapies, intraoperative techniques and image guidance, intranasal corticosteroid injection, dornase alfa, gene therapy, and second-look procedures. Most studies were limited to case series with relatively small numbers of patients. Very few randomized controlled studies were identified. CONCLUSION: Despite the prevalence of recurrent sinonasal disease after FESS in patients with CF, evidence for definitive perioperative management in this population is lacking. Most recommendations are based on small case series. Multicenter studies to evaluate perioperative strategies that improve FESS outcomes in patients with CF are warranted. PMID- 23674573 TI - Risk prediction and treatment monitoring are crucial for prevention and management of compulsive dopamine use in Parkinson's disease. PMID- 23674574 TI - From parenteral to enteral nutrition: a nutrition-based approach for evaluating postnatal growth failure in preterm infants. AB - BACKGROUND: Nutrition practices for preterm infants include phases of parenteral nutrition (PN), full enteral nutrition (EN), and the transitional phase in between. Our aim was to identify the nutrition phases during which infants are most likely to exhibit poor growth that would affect risk for growth failure (GF) at discharge and to examine factors associated with GF. METHODS: A retrospective chart review was conducted on infants born <32 weeks' gestation. The neonatal intensive care unit stay was divided into 3 nutrition phases: (1) full PN, (2) transitional PN + EN, and (3) full EN. Weekly growth rates were calculated, and for each growth velocity <10 g/kg/d, the coinciding phase was recorded. GF was defined as a discharge weight below the 10th percentile. The nutrition phases during which growth inadequacy predicted GF at discharge were determined, correcting for other clinical factors associated with GF. RESULTS: In total, 156 eligible infants were identified. Seventy-six infants (49%) were discharged with weights <10%. Incidence of poor growth was highest during the transitional phase (46%) and was predictive of GF when adjusted for gestational age, birth weight, and severity of illness. Although energy intakes during the transitional phase were comparable to baseline parenteral provision, protein intakes progressively decreased ( P < .0001), consistently providing 3 g/kg/d as PN was weaned. Serum urea nitrogen also declined and was correlated with protein intake (r = -0.32, P < .001). CONCLUSION: Growth was compromised during the transitional phase, likely related to decreased protein intake. Optimizing protein provision while PN is weaned is an important strategy to prevent postnatal growth failure. PMID- 23674575 TI - Drug-nutrient interactions. AB - Drug-nutrient interactions are defined as physical, chemical, physiologic, or pathophysiologic relationships between a drug and a nutrient. The causes of most clinically significant drug-nutrient interactions are usually multifactorial. Failure to identify and properly manage drug-nutrient interactions can lead to very serious consequences and have a negative impact on patient outcomes. Nevertheless, with thorough review and assessment of the patient's history and treatment regimens and a carefully executed management strategy, adverse events associated with drug-nutrient interactions can be prevented. Based on the physiologic sequence of events after a drug or a nutrient has entered the body and the mechanism of interactions, drug-nutrient interactions can be categorized into 4 main types. Each type of interaction can be managed using similar strategies. The existing data that guide the clinical management of most drug nutrient interactions are mostly anecdotal experience, uncontrolled observations, and opinions, whereas the science in understanding the mechanism of drug-nutrient interactions remains limited. The challenge for researchers and clinicians is to increase both basic and higher level clinical research in this field to bridge the gap between the science and practice. The research should aim to establish a better understanding of the function, regulation, and substrate specificity of the nutrient-related enzymes and transport proteins present in the gastrointestinal tract, as well as assess how the incidence and management of drug-nutrient interactions can be affected by sex, ethnicity, environmental factors, and genetic polymorphisms. This knowledge can help us develop a true personalized medicine approach in the prevention and management of drug-nutrient interactions. PMID- 23674576 TI - PET imaging of proliferation with pyrimidines. AB - Several new tracers are being developed for use with PET to assess pathways that are altered in cancers, including energy use, cellular signaling, transport, and proliferation. Because increased proliferation is a hallmark of many cancers, several tracers have been tested to track the DNA synthesis pathway. Thymidine, which is incorporated into DNA but not RNA, has been used in laboratory studies to measure tumor growth. Because thymidine labeled with (11)C undergoes rapid biologic degradation and has a short physical half-life, tracers labeled with (18)F have been preferred in PET imaging. One such tracer is (18)F-labeled 3' deoxy-3'-fluorothymidine ((18)F-FLT). (18)F-FLT is trapped after phosphorylation by thymidine kinase 1, whose expression is increased in replicating cells. Several studies on breast, lung, and brain tumors have demonstrated that retention of (18)F-FLT correlated with tumor proliferation. Although (18)F-FLT has been used to image and stage several tumor types, the standardized uptake value is generally lower than that obtained with (18)F-FDG. (18)F-FLT can be used to image many areas of the body, but background uptake is high in the liver, marrow, and renal system, limiting use in these organs. (18)F-FLT PET imaging has primarily been studied in the assessment of treatment response. Rapid declines in (18)F-FLT retention within days to weeks have been demonstrated in several tumor types treated with cytotoxic drugs, targeted agents, and radiotherapy. Further work is ongoing to validate this approach and determine its utility in the development of new drugs and in the clinical evaluation of standard treatment approaches. PMID- 23674577 TI - In newly diagnosed diffuse large B-cell lymphoma, determination of bone marrow involvement with 18F-FDG PET/CT provides better diagnostic performance and prognostic stratification than does biopsy. AB - In newly diagnosed diffuse large B-cell lymphoma (DLBCL), the sensitivity of bone marrow biopsy (BMB) for the detection of bone marrow involvement (BMI) can be low because of sampling error if the BMI is focal and not diffuse. Although (18)F-FDG PET/CT is now recommended for initial staging of DLBCL, its role regarding BMI is not well defined. This study evaluated whether (18)F-FDG PET/CT, in comparison with BMB, is useful for the detection of BMI and predictive of outcome. METHODS: From the 142 patients who were referred to our institution for newly diagnosed DLBCL from June 2006 to October 2011, 133 were retrospectively enrolled in our study. All patients underwent whole-body (18)F-FDG PET/CT and a BMB from the iliac crest before any treatment. (18)F-FDG PET/CT was considered positive for BMI in cases of uni- or multifocal bone marrow (18)F-FDG uptake that could not be explained by benign findings on the underlying CT image or history. A final diagnosis of BMI was considered if the BMB was positive or if the positive (18)F FDG PET/CT was confirmed by guided biopsy or targeted MR imaging or in cases of disappearance of focal bone marrow uptake concomitant with the disappearance of uptake in other lymphoma lesions on (18)F-FDG PET/CT monitoring. Progression-free survival and overall survival were analyzed using the Cox proportional hazards regression model. RESULTS: Thirty-three patients were considered to have BMI. Of these, 8 were positive according to the BMB and 32 were positive according to (18)F-FDG PET/CT. (18)F-FDG PET/CT was more sensitive (94% vs. 24%; P < 0.001), showed a higher negative predictive value (98% vs. 80%), and was more accurate (98% vs. 81%) than BMB. Median follow-up was 24 mo (range, 1-67 mo). Twenty-nine patients (22%) experienced recurrence or disease progression during follow-up, and 20 patients died (15%). In multivariate analysis, only the International Prognostic Index and the (18)F-FDG PET/CT bone marrow status were independent predictors of progression-free survival (P = 0.005 and 0.02, respectively), whereas only the International Prognostic Index remained an independent predictor of overall survival (P = 0.004). CONCLUSION: Assessment of BMI with (18)F-FDG PET/CT provides better diagnostic performance and prognostic stratification in newly diagnosed DLBCL than does BMB. PMID- 23674578 TI - Apparent elastic modulus of ex vivo trabecular bovine bone increases with dynamic loading. AB - Although it is widely known that bone tissue responds to mechanical stimuli, the underlying biological control is still not completely understood. The purpose of this study was to validate required methods necessary to maintain active osteocytes and minimize bone tissue injury in an ex vivo three-dimensional model that could mimic in vivo cellular function. The response of 22 bovine trabecular bone cores to uniaxial compressive load was investigated by using the ZETOS bone loading and bioreactor system while perfused with culture medium for 21 days. Two groups were formed, the "treatment" group (n = 12) was stimulated with a physiological compressive strain (4000 uepsilon) in the form of a "jump" wave, while the "control" group (n = 10) was loaded only during three measurements for apparent elastic modulus on days 3, 10, and 21. At the end of the experiment, apoptosis and active osteocytes were quantified with histological analysis, and bone formation was identified by means of the calcium-binding dye, calcein. It was demonstrated that the treatment group increased the elastic modulus by 61%, whereas the control group increased by 28% (p<0.05). Of the total osteocytes observed at the end of 21 days, 1.7% (+/-0.3%) stained positive for apoptosis in the loaded group, whereas 2.7% (+/-0.4%) stained positive in the control group. Apoptosis in the center of the bone cores of both groups at the end of 21 days was similar to that observed in vivo. Therefore, the three-dimensional model used in this research permitted the investigation of physiological responses to mechanical loads on morphology adaptation of trabecular bone in a controlled defined load and chemical environment. PMID- 23674579 TI - Application of design rationale for a robotic system for single-incision laparoscopic surgery and natural orifice transluminal endoscopic surgery. AB - Current endoscopes and instruments are inadequate in some respects for complex intra-abdominal surgery because they are too flexible and cannot provide robust grasping and anatomic retraction. Minimal invasive surgery devices represent a sophisticated class of mechanical instruments making use of a range of mechanisms integrated into modular platforms that can be combined to undertake complex medical procedures. Although the machine elements concerned represent classic mechanical engineering devices, issues of miniaturization, surgical procedure compliance and location control conspire to present a design challenge. In order to capture, document and resolve the design requirements for this complex application, quality functional deployment has been applied in combination with design rationale, captured through issue-based information system mapping. This article reports the use of these tools to produce robot designs with improved dexterity and triangulation that are basic requirements in laparoscopy. PMID- 23674580 TI - The relation between gaze behavior and categorization: does where we look determine what we see? AB - When categorizing an object, we fixate our eyes on informative parts of that object. In the current study, morphed figures were used to investigate whether the interpretation of such unclear objects is reflected in the eye movement pattern. The morphed figures were created by interpolating two concrete objects. The intermediate steps represent figures that contain properties of both objects but in different proportions. Three experiments were conducted to investigate the relation between categorization and gaze behavior. In all three experiments, free naming responses and eye movements were recorded simultaneously. In the first experiment, the relation between the interpretation and the fixated part of the figure was investigated: A strong relation was observed. Subsequently, it was investigated whether gaze patterns drive categorization or vice versa. In the second experiment, morphed figures were preceded by a prime word. A priming effect on categorization was found but not on gaze behavior. In the third experiment, a cue directed the observer's gaze to a particular location on the morphed figure. Interestingly, the cueing experiment showed a cueing effect not only on gaze behavior but also on categorization. Taken together, these findings suggest that where we look affects how we interpret a perceptually uncertain stimulus. PMID- 23674581 TI - Lessons in pity and caring from Dickens and Melville. PMID- 23674582 TI - The limits of pity in Bartleby and Moby Dick. AB - Failures in the emotional connection between doctors and their patients tend to be reported in terms of compassion fatigue, burn-out, secondary trauma and depression in overlapping and somewhat interchangeable ways. In Moby Dick and Bartleby, Melville interrogates the culturally accepted descriptions of pity and explores the reasons for the limits in human pity he observed and depicted. In an attempt to understand whether the feelings of pity that a patient's suffering can evoke in physicians are sustainable, desirable, or counter-productive, Melville's narratives, along with that of a woman who, while living with advanced cancer experiences the breakdown of a key medical relationship, will be considered. PMID- 23674583 TI - Dickens' characters on the couch: an example of teaching psychiatry using literature. AB - The value of literature in medical education is widely accepted by medical teachers. There are examples of psychopathology in the characters of novels that provide illustrations of particular psychiatric diagnoses. Characters created by Charles Dickens, often eccentric, have been deemed to suffer from mental disorders. This may be because Dickens could draw on his extensive contact with Victorian psychiatry and interest in psychopathology to create authentic characters. He is widely acknowledged to have described many other medical conditions in his fiction and his writing is already used to teach medical students. This article reviews Dickens' contact with psychiatry and outlines the mental disorders possibly suffered by the characters under ICD 10 diagnostic headings. These descriptions, while interesting in their own right, may also prove useful to clinicians and teachers. PMID- 23674584 TI - Two Georgian fathers: diverse in experience, united in grief. AB - The history of paediatrics and child health is increasingly recognised to be about children themselves and how they and their families cope and adapt to their medical condition rather than about medical practitioners and august institutions. This article considers two case studies, showing how two Georgian fathers cared for their children when sickness struck and their reactions when the children died. Davies (Giddy) Gilbert, FRS (1767-1840), was a member of Parliament first for Helston and later for Bodmin. (He married Ann Mary Gilbert in 1808 and formally changed his name to Gilbert; the change received royal approbation in January 1817.) Gilbert recorded the birth and development of his son Charles (1810-1813), in one of the very earliest developmental chronicles. He regularly recorded his child's progress, including height, weight, social interaction, communication skills and speech. Apparently in good health for most of his life, Charles developed an acute abdominal disorder and died unexpectedly. John Tremayne (1780-1851) was a member of Parliament for Cornwall. His son Harry (1814-1823) had increasing bilious attacks, headaches and a squint from the age of 6 years, and died despite the best medical advice available. Current medical opinion would presume an intracranial tumour. Tremayne graphically expressed his pain as he closely observed his son suffer, apparently as much from the treatments as from the disease itself. This study sheds light on clinical aspects of Georgian medical practice, the medical marketplace and the nature of relationships between these fathers and their children. PMID- 23674585 TI - Brainwashing: the power of the psychiatrist portrayed in 1960s visual media. AB - A comparatively neglected representation of the psychiatrist is that of coercive agent using drugs and behavioural psychology to serve a sinister goal. Rather than treat illness or relieve distress, psychiatrists undermine the mental health of an individual through "brainwashing" techniques, transforming the thoughts and actions of their subjects to devastating effect. Portrayals of psychiatrists as unsympathetic agents of the state or malevolent manipulators were popular in British film and television of the 1960s. Such characterisations are compared with historical experiences of "brainwashing" originating from the Korean War, examining their development and the possible reasons why they resonated so powerfully with contemporary audiences. PMID- 23674586 TI - A portrait of a female body: Rubens and Helena's legs. AB - For a long time the Western world was in a state of denial about the human body. There were conventions governing its representation and it could be regarded as an element of discourse. Between 1636 and 1638, Peter Paul Rubens painted a portrait of his second wife, Helena Fourment, entitled The little fur. This may be a turning-point in the perception of the body. We see in this work that the skin of this 22-year-old woman has lost its elasticity, her breasts are not symmetrical and her ankles are pink, contrasting with the pearly white of the rest of her body. The inside of her left thigh shows signs of a varicose saphenous vein. While today's doctors can suggest the possibility of venous insufficiency and benign familial hyperelasticity, and talk of the consequences of breast-feeding, what this canvas is doing above all is showing the body of a real, named individual, "warts and all". This may be one of the first portraits of a body in the history of European painting. PMID- 23674587 TI - Literary appreciation for medical students at International Medical University, Kuala Lumpur: the learner's experience. AB - BACKGROUND: : A literature in medicine module was offered to second-year undergraduate medical students at the International Medical University. The general aim of this educational initiative was to enhance the selected medical students' understanding of medical practice through literature. OBJECTIVE: : This study was carried out to discover the selected students' learning experience through the literature in medicine module. METHODS: : A qualitative study was conducted by using two different semi-structured questionnaires which were administered respectively at the beginning and end of the course. The data were explored using grounded theory and by coding responses for emerging themes. RESULTS: : Students identified the following key benefits that enhanced their learning experience: "opportunity to identify, explore and develop self"; "gained patient's perspective of suffering and emotional needs"; "abilities to understand the mechanics and influences of society". CONCLUSION: : The literature in medicine selective has directed the selected students towards developing self, reflecting on the profession and understanding the dynamics of society. By diversifying the design and delivery of the module, the students have gained a holistic medical education. Therefore, this module has the potential for development, exploration and implementation within this region. PMID- 23674588 TI - Medical paternalism in House M.D. AB - The popular television series House M.D. is drawn upon to provide a critical examination of medical paternalism and how it is presented in the show. Dr Gregory House, the character named in the title of the series, is a paradigm of a paternalistic physician. He believes that he knows what is best for his patients, and he repeatedly disregards their wishes in order to diagnose and treat their illnesses. This paper examines several examples of medical paternalism and the means used to portray it favourably in the series. It is argued that the positive depiction of medical paternalism in the fictional world of the series does not apply in the real world. The paper also considers why a show that features a paternalistic physician who so blatantly flouts mainstream medical ethics might appeal to health professionals and members of the general public. PMID- 23674589 TI - "Sharing the impact of the disease": a workshop on suffering for medical students. AB - OBJECTIVES: : To investigate the attitudes of early clinical students to the concept of suffering and the work of Eric Cassell. DESIGN: : Qualitative case study using group interviews and questionnaires. SETTING: : A United Kingdom medical school. PARTICIPANTS: : Two whole-year cohorts of third-year medical students (n = 557). INTERVENTIONS: : Group interviews involving 57 randomly selected students, with exploration of emergent themes using free text and Lickert scale questionnaires. RESULTS: : Students engaged readily with the concept of suffering and were able to identify a patient they had encountered who was suffering. Barriers to student involvement with suffering were identified. Students saw engaging with patient suffering as a clinical skill. Many students saw the ideas of Eric Cassell as plausible, although few were convinced that relief of suffering should be the central goal of medicine. CONCLUSIONS: : The work of Eric Cassell formed the basis of a teaching intervention with medical students who identified engaging with suffering as a clinical skill. PMID- 23674590 TI - Rethinking the placebo effect. AB - There is a rather wide range of meanings for placebo and placebo effect, and some of the controversy has arisen when the proponents of various positions have ignored each other. An attempt is made to clarify some of the conceptual issues related to these concepts. Five uses of placebos as inert substances or treatments are listed. The problem of the placebo effect and the discussion of its existence are examined, and other terms that could cover the phenomenon are suggested. It is suggested that the concept placebo is appropriate only to the research context and that the term care effect be introduced to replace it in clinical contexts. PMID- 23674592 TI - Crossing over and delineating disease. PMID- 23674591 TI - Mental health in an age of celebrity: the courage to care. AB - Modern psychiatry, which once focused only on the containment and "cure" of madness, has evolved into a mental health industry, where almost every aspect of human life, may be cast as a "mental disorder". In Western countries, a narcissistic appetite for self-improvement and "well-being" has evolved over the past 50 years, mirroring the emergence of the celebrity culture. These developments appear linked to a fading of interest in the traditional concept of human caring, leading to a further marginalisation of people with serious "mental health problems" and to increased use of authoritarian forms of control and containment. In this paper, the idea of vocation in the field of mental health is explored. What exactly are we called to do as people-whether as professionals, friends or fellow travellers-when someone experiences a significant problem in human living? PMID- 23674593 TI - Shadows in wonderland: a hospital odyssey. PMID- 23674594 TI - The best of the belleville literary review. PMID- 23674595 TI - Music and medicine. PMID- 23674596 TI - Medical humanities in Nepal: questions and challenges. PMID- 23674597 TI - Iranian model of living, non-related kidney donation: a style to be condemned ethically. PMID- 23674598 TI - The neural crest. AB - The neural crest (NC) is a highly migratory multipotent cell population that forms at the interface between the neuroepithelium and the prospective epidermis of a developing embryo. Following extensive migration throughout the embryo, NC cells eventually settle to differentiate into multiple cell types, ranging from neurons and glial cells of the peripheral nervous system to pigment cells, fibroblasts to smooth muscle cells, and odontoblasts to adipocytes. NC cells migrate in large numbers and their migration is regulated by multiple mechanisms, including chemotaxis, contact-inhibition of locomotion and cell sorting. Here, we provide an overview of NC formation, differentiation and migration, highlighting the molecular mechanisms governing NC migration. PMID- 23674599 TI - Polar auxin transport: models and mechanisms. AB - Spatial patterns of the hormone auxin are important drivers of plant development. The observed feedback between the active, directed transport that generates auxin patterns and the auxin distribution that influences transport orientation has rendered this a popular subject for modelling studies. Here we propose a new mathematical framework for the analysis of polar auxin transport and present a detailed mathematical analysis of published models. We show that most models allow for self-organised patterning for similar biological assumptions, and find that the pattern generated is typically unidirectional, unless additional assumptions or mechanisms are incorporated. Our analysis thus suggests that current models cannot explain the bidirectional fountain-type patterns found in plant meristems in a fully self-organised manner, and we discuss future research directions to address the gaps in our understanding of auxin transport mechanisms. PMID- 23674601 TI - SRF selectively controls tip cell invasive behavior in angiogenesis. AB - Efficient angiogenic sprouting is essential for embryonic, postnatal and tumor development. Serum response factor (SRF) is known to be important for embryonic vascular development. Here, we studied the effect of inducible endothelial specific deletion of Srf in postnatal and adult mice. We find that endothelial SRF activity is vital for postnatal growth and survival, and is equally required for developmental and pathological angiogenesis, including during tumor growth. Our results demonstrate that SRF is selectively required for endothelial filopodia formation and cell contractility during sprouting angiogenesis, but seems dispensable for vascular remodeling. At the molecular level, we observe that vascular endothelial growth factor A induces nuclear accumulation of myocardin-related transcription factors (MRTFs) and regulates MRTF/SRF-dependent target genes including Myl9, which is important for endothelial cell migration in vitro. We conclude that SRF has a unique function in regulating migratory tip cell behavior during sprouting angiogenesis. We hypothesize that targeting the SRF pathway could provide an opportunity to selectively target tip cell filopodia driven angiogenesis to restrict tumor growth. PMID- 23674600 TI - Inhibition of Sox2-dependent activation of Shh in the ventral diencephalon by Tbx3 is required for formation of the neurohypophysis. AB - Tbx2 and Tbx3 are two highly related members of the T-box transcription factor gene family that regulate patterning and differentiation of a number of tissue rudiments in the mouse. Both genes are partially co-expressed in the ventral diencephalon and the infundibulum; however, a functional requirement in murine pituitary development has not been reported. Here, we show by genetic lineage tracing that Tbx2(+) cells constitute the precursor population of the neurohypophysis. However, Tbx2 is dispensable for neurohypophysis development as revealed by normal formation of this organ in Tbx2-deficient mice. By contrast, loss of Tbx3 from the ventral diencephalon results in a failure to establish the Tbx2(+) domain in this region, and a lack of evagination of the infundibulum and formation of the neurohypophysis. Rathke's pouch is severely hypoplastic, exhibits defects in dorsoventral patterning, and degenerates after E12.5. In Tbx3 deficient embryos, the ventral diencephalon is hyperproliferative and displays an abnormal cellular architecture, probably resulting from a failure to repress transcription of Shh. We further show that Tbx3 and Tbx2 repress Shh by sequestering the SRY box-containing transcription factor Sox2 away from a Shh forebrain enhancer (SBE2), thus preventing its activation. These data suggest that Tbx3 is required in the ventral diencephalon to establish a Shh(-) domain to allow formation of the infundibulum. PMID- 23674602 TI - Tbx2/3 is an essential mediator within the Brachyury gene network during Ciona notochord development. AB - T-box genes are potent regulators of mesoderm development in many metazoans. In chordate embryos, the T-box transcription factor Brachyury (Bra) is required for specification and differentiation of the notochord. In some chordates, including the ascidian Ciona, members of the Tbx2 subfamily of T-box genes are also expressed in this tissue; however, their regulatory relationships with Bra and their contributions to the development of the notochord remain uncharacterized. We determined that the notochord expression of Ciona Tbx2/3 (Ci-Tbx2/3) requires Ci-Bra, and identified a Ci-Tbx2/3 notochord CRM that necessitates multiple Ci Bra binding sites for its activity. Expression of mutant forms of Ci-Tbx2/3 in the developing notochord revealed a role for this transcription factor primarily in convergent extension. Through microarray screens, we uncovered numerous Ci Tbx2/3 targets, some of which overlap with known Ci-Bra-downstream notochord genes. Among the Ci-Tbx2/3 notochord targets are evolutionarily conserved genes, including caspases, lineage-specific genes, such as Noto4, and newly identified genes, such as MLKL. This work sheds light on a large section of the notochord regulatory circuitry controlled by T-box factors, and reveals new components of the complement of genes required for the proper formation of this structure. PMID- 23674603 TI - Antipruritic effect of the topical phosphodiesterase 4 inhibitor E6005 ameliorates skin lesions in a mouse atopic dermatitis model. AB - Phosphodiesterase (PDE) 4 inhibition is a well-known anti-inflammatory mechanism, but the development of PDE4 inhibitors has been hampered by side effects such as nausea and emesis. Local delivery of a PDE4 inhibitor to the site of inflammation may overcome these issues. The purpose of this study was to assess the therapeutic potential of E6005 (methyl 4-[({3-[6,7-dimethoxy-2 (methylamino)quinazolin-4-yl]phenyl}amino)carbonyl]benzoate), a novel PDE4 inhibitor developed as a topical agent for atopic dermatitis (AD). E6005 potently and selectively inhibited human PDE4 activity with an IC50 of 2.8 nM and suppressed the production of various cytokines from human lymphocytes and monocytes with IC50 values ranging from 0.49 to 3.1 nM. In mice models, the topical application of E6005 produced an immediate antipruritic effect as well as an anti-inflammatory effect with reduced expression of cytokines/adhesion molecules. On the basis of these observed effects, topical E6005 ameliorated the appearance of atopic dermatitis-like skin lesions in two types of AD models, hapten- and mite-elicited models, exhibiting inhibitory effects comparable to that of tacrolimus. The use of 14C-labeled E6005 showed rapid clearance from the blood and low distribution to the brain, contributing to the low emetic potential of this compound. These results suggest that E6005 may be a promising novel therapeutic agent with antipruritic activity for the treatment of AD. PMID- 23674604 TI - Pharmacology of AMG 416 (Velcalcetide), a novel peptide agonist of the calcium sensing receptor, for the treatment of secondary hyperparathyroidism in hemodialysis patients. AB - A novel peptide, AMG 416 (formerly KAI-4169, and with a United States Adopted Name: velcalcetide), has been identified that acts as an agonist of the calcium sensing receptor (CaSR). This article summarizes the in vitro and in vivo characterization of AMG 416 activity and the potential clinical utility of this novel compound. AMG 416 activates the human CaSR in vitro, acting by a mechanism distinct from that of cinacalcet, the only approved calcimimetic, since it can activate the CaSR both in the presence or the absence of physiologic levels of extracellular calcium. Administration of AMG 416 in vivo into either normal or renally compromised rats results in dose-dependent reductions in parathyroid hormone (PTH) levels and corresponding decreases in serum calcium, regardless of the baseline level of PTH. Treatment of 5/6 nephrectomized rats with AMG 416 resulted in dramatic improvements in their metabolic profile, including lower PTH and serum creatinine levels, reduced amounts of vascular calcification, attenuated parathyroid hyperplasia, and greater expression of the parathyroid gland regulators CaSR, vitamin D receptor, and FGF23 receptor compared with vehicle-treated animals. No drug accumulation was observed under this dosing regimen, and the terminal half-life of AMG 416 was estimated to be 2-4.5 hours. As a long-acting CaSR agonist, AMG 416 is an innovative new therapy for the treatment of hemodialysis patients with secondary hyperparathyroidism. PMID- 23674606 TI - Exercise prevents fructose-induced hypertriglyceridemia in healthy young subjects. AB - Excess fructose intake causes hypertriglyceridemia and hepatic insulin resistance in sedentary humans. Since exercise improves insulin sensitivity in insulin resistant patients, we hypothesized that it would also prevent fructose-induced hypertriglyceridemia. This study was therefore designed to evaluate the effects of exercise on circulating lipids in healthy subjects fed a weight-maintenance, high-fructose diet. Eight healthy males were studied on three occasions after 4 days of 1) a diet low in fructose and no exercise (C), 2) a diet with 30% fructose and no exercise (HFr), or 3) a diet with 30% fructose and moderate aerobic exercise (HFrEx). On all three occasions, a 9-h oral [(13)C]-labeled fructose loading test was performed on the fifth day to measure [(13)C]palmitate in triglyceride-rich lipoprotein (TRL)-triglycerides (TG). Compared with C, HFr significantly increased fasting glucose, total TG, TRL-TG concentrations, and apolipoprotein (apo)B48 concentrations as well as postfructose glucose, total TG, TRL-TG, and [(13)C]palmitate in TRL-TG. HFrEx completely normalized fasting and postfructose TG, TRL-TG, and [(13)C]palmitate concentration in TRL-TG and apoB48 concentrations. In addition, it increased lipid oxidation and plasma nonesterified fatty acid concentrations compared with HFr. These data indicate that exercise prevents the dyslipidemia induced by high fructose intake independently of energy balance. PMID- 23674605 TI - The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway. AB - The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances beta-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (30-40%) on GLP-1-stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P <= 8.8 * 10(-7)). rs7202877 near CTRB1/2, a known diabetes risk locus, also associated with an absolute 0.51 +/- 0.16% (5.6 +/- 1.7 mmol/mol) lower A1C response to DPP-4 inhibitor treatment in G-allele carriers, but there was no effect on GLP-1 RA treatment in type 2 diabetic patients (n = 527). Furthermore, in pancreatic tissue, we show that rs7202877 acts as expression quantitative trait locus for CTRB1 and CTRB2, encoding chymotrypsinogen, and increases fecal chymotrypsin activity in healthy carriers. Chymotrypsin is one of the most abundant digestive enzymes in the gut where it cleaves food proteins into smaller peptide fragments. Our data identify chymotrypsin in the regulation of the incretin pathway, development of diabetes, and response to DPP-4 inhibitor treatment. PMID- 23674607 TI - Comparison of the repair of potentially lethal damage after low- and high-LET radiation exposure, assessed from the kinetics and fidelity of chromosome rejoining in normal human fibroblasts. AB - Potentially lethal damage (PLD) and its repair (PLDR) were studied in confluent human fibroblasts by analyzing the kinetics of chromosome break rejoining after X ray or heavy-ion exposures. Cells were either held in the non-cycling G0 phase of the cell cycle for 12 h, or forced to proliferate immediately after irradiation. Fusion premature chromosome condensation (PCC) was combined with fluorescence in situ hybridization (FISH) to study chromosomal aberrations in interphase. The culture condition had no impact on the rejoining kinetics of PCC breaks during the 12 h after X-ray or heavy-ion irradiation. However, 12 h after X-ray and silicon irradiation, cycling cells had more chromosome exchanges than non-cycling cells. After 6 Gy X-rays, the yield of exchanges in cycling cells was 2.8 times higher than that in non-cycling cells, and after 2 Gy of 55 keV/MUm silicon ions the yield of exchanges in cycling cells was twice that of non-cycling cells. In contrast, after exposure to 2 Gy 200-keV/MUm or 440-keV/MUm iron ions the yield of exchanges was similar in non-cycling and cycling cells. Since the majority of repair in G0/G1 occurs via the non-homologous end joining process (NHEJ), increased PLDR in X-ray and silicon-ion irradiated cells may result from improved cell cycle-specific rejoining fidelity through the NHEJ pathway, which is not the case in high-LET iron-ion irradiated cells. PMID- 23674608 TI - Comparison of endogenous 4beta-hydroxycholesterol with midazolam as markers for CYP3A4 induction by rifampicin. AB - CYP3A4, considered the most important enzyme in drug metabolism, is often involved in drug-drug interactions. When developing new drugs, appropriate markers for detecting CYP3A4 induction are needed. Our study compared endogenously formed 4beta-hydroxycholesterol with the midazolam clearance in plasma and the 6beta-hydroxycortisol/cortisol ratio in urine as markers for CYP3A4 induction. To this end, we performed a clinical trial in which 24 healthy subjects were randomized to 10, 20, or 100 mg daily doses of rifampicin for 14 days (n = 8 in each group) to achieve a low and moderate CYP3A4 induction. The CYP3A4 induction could be detected even at the lowest dose of rifampicin (10 mg) via the estimated midazolam clearance, the 4beta-hydroxycholesterol ratio (both P < 0.01), and the 6beta-hydroxycortisol ratio (P < 0.05). For the three dosing groups (10, 20, and 100 mg), the median fold induction from baseline was 2.0, 2.6, and 4.0 for the estimated midazolam clearance; 1.3, 1.6, and 2.5 for the 4beta-hydroxycholesterol/cholesterol ratio; and 1.7, 2.9, and 3.1 for the 6beta hydroxycortisol/cortisol ratio. In conclusion, the 4beta-hydroxycholesterol ratio is comparable to midazolam clearance as a marker of CYP3A4 induction, and each may be used to evaluate CYP3A4 induction in clinical trials evaluating drug-drug interactions for new drugs. PMID- 23674609 TI - Milk thistle's active components silybin and isosilybin: novel inhibitors of PXR mediated CYP3A4 induction. AB - Because cancer is often treated with combination therapy, unexpected pharmacological effects can occur because of drug-drug interactions. Several drugs are able to cause upregulation or downregulation of drug transporters or cytochrome P450 enzymes, particularly CYP3A4. Induction of CYP3A4 may result in decreased plasma levels and therapeutic efficacy of anticancer drugs. Since the pregnane X receptor (PXR) is one of the major transcriptional regulators of CYP3A4, PXR antagonists can possibly prevent CYP3A4 induction. Currently, a limited number of PXR antagonists are available. Some of these antagonists, such as sulphoraphane and coumestrol, belong to the so-called complementary and alternative medicines (CAM). Therefore, the aim was to determine the potential of selected CAM (beta-carotene, Echinacea purpurea, garlic, Ginkgo biloba, ginseng, grape seed, green tea, milk thistle, saw palmetto, valerian, St. John's Wort, and vitamins B6, B12, and C) to inhibit PXR-mediated CYP3A4 induction at the transcriptional level, using a reporter gene assay and a real-time polymerase chain reaction assay in LS180 colon adenocarcinoma cells. Furthermore, computational molecular docking and a LanthaScreen time-resolved fluorescence resonance energy transfer (TR-FRET) PXR competitive binding assay were performed to explore whether the inhibiting CAM components interact with PXR. The results demonstrated that milk thistle is a strong inhibitor of PXR-mediated CYP3A4 induction. The components of milk thistle responsible for this effect were identified as silybin and isosilybin. Furthermore, computational molecular docking revealed a strong interaction between both silybin and isosilybin and PXR, which was confirmed in the TR-FRET PXR assay. In conclusion, silybin and isosilybin might be suitable candidates to design potent PXR antagonists to prevent drug-drug interactions via CYP3A4 in cancer patients. PMID- 23674610 TI - Regulation of murine hepatic hydroxysteroid sulfotransferase expression in hyposulfatemic mice and in a cell model of 3'-phosphoadenosine-5'-phosphosulfate deficiency. AB - The cytosolic sulfotransferases (SULTs) catalyze the sulfate conjugation of nucleophilic substrates, and the cofactor for sulfonation, 3'-phosphoadenosine-5' phosphosulfate (PAPS), is biosynthesized from sulfate and ATP. The phenotype of male knockout mice for the NaS1 sodium sulfate cotransporter includes hyposulfatemia and increased hepatic expression of mouse cytoplasmic sulfotransferase Sult2a and Sult3a1. Here we report that in 8-week-old female NaS1-null mice, hepatic Sult2a1 mRNA levels were ~51-fold higher than they were in a wild-type liver but expression of no other Sult was affected. To address whether hyposulfatemia-inducible Sult2a1 expression might be due to reduced PAPS levels, we stably knocked down PAPS synthases 1 and 2 in HepG2 cells (shPAPSS1/2 cells). When a reporter plasmid containing at least 233 nucleotides (nt) of Sult2a1 5'-flanking sequence was transfected into shPAPSS1/2 cells, reporter activity was significantly increased relative to the activity that was seen for reporters containing 179 or fewer nucleotides. Mutation of an IR0 (inverted repeat of AGGTCA, with 0 intervening bases) nuclear receptor motif at nt -191 to 180 significantly attenuated the PAPSS1/2 knockdown-mediated increase. PAPSS1/2 knockdown significantly activated farnesoid X receptor (FXR), retinoid-related orphan receptor, and pregnane X receptor responsive reporters, and treatment with the FXR agonist GW4064 [3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilben-4 yl)oxymethyl-5-isopropylisoxazole] increased Sult2a1 promoter activity when the IR0 was intact. Transfection of shPAPSS1/2 cells with FXR small interfering RNA (siRNA) significantly reduced the Sult2a1 promoter activity. The impact of PAPSS1/2 knockdown on Sult2a1 promoter activity was recapitulated by knocking down endogenous SULT2A1 expression in HepG2 cells. We propose that hyposulfatemia leads to hepatic PAPS depletion, which causes loss of SULT2A1 activity and results in accumulation of nonsulfated bile acids and FXR activation. PMID- 23674611 TI - Highly dynamic cellular-level response of symbiotic coral to a sudden increase in environmental nitrogen. AB - Metabolic interactions with endosymbiotic photosynthetic dinoflagellate Symbiodinium spp. are fundamental to reef-building corals (Scleractinia) thriving in nutrient-poor tropical seas. Yet, detailed understanding at the single-cell level of nutrient assimilation, translocation, and utilization within this fundamental symbiosis is lacking. Using pulse-chase (15)N labeling and quantitative ion microprobe isotopic imaging (NanoSIMS; nanoscale secondary-ion mass spectrometry), we visualized these dynamic processes in tissues of the symbiotic coral Pocillopora damicornis at the subcellular level. Assimilation of ammonium, nitrate, and aspartic acid resulted in rapid incorporation of nitrogen into uric acid crystals (after ~45 min), forming temporary N storage sites within the dinoflagellate endosymbionts. Subsequent intracellular remobilization of this metabolite was accompanied by translocation of nitrogenous compounds to the coral host, starting at ~6 h. Within the coral tissue, nitrogen is utilized in specific cellular compartments in all four epithelia, including mucus chambers, Golgi bodies, and vesicles in calicoblastic cells. Our study shows how nitrogen-limited symbiotic corals take advantage of sudden changes in nitrogen availability; this opens new perspectives for functional studies of nutrient storage and remobilization in microbial symbioses in changing reef environments. IMPORTANCE: The methodology applied, combining transmission electron microscopy with nanoscale secondary-ion mass spectrometry (NanoSIMS) imaging of coral tissue labeled with stable isotope tracers, allows quantification and submicrometric localization of metabolic fluxes in an intact symbiosis. This study opens the way for investigations of physiological adaptations of symbiotic systems to nutrient availability and for increasing knowledge of global nitrogen and carbon biogeochemical cycling. PMID- 23674612 TI - Reovirus activates a caspase-independent cell death pathway. AB - Virus-induced apoptosis is thought to be the primary mechanism of cell death following reovirus infection. Induction of cell death following reovirus infection is initiated by the incoming viral capsid proteins during cell entry and occurs via NF-kappaB-dependent activation of classical apoptotic pathways. Prototype reovirus strain T3D displays a higher cell-killing potential than strain T1L. To investigate how signaling pathways initiated by T3D and T1L differ, we methodically analyzed cell death pathways activated by these two viruses in L929 cells. We found that T3D activates NF-kappaB, initiator caspases, and effector caspases to a significantly greater extent than T1L. Surprisingly, blockade of NF-kappaB or caspases did not affect T3D-induced cell death. Cell death following T3D infection resulted in a reduction in cellular ATP levels and was sensitive to inhibition of the kinase activity of receptor interacting protein 1 (RIP1). Furthermore, membranes of T3D-infected cells were compromised. Based on the dispensability of caspases, a requirement for RIP1 kinase function, and the physiological status of infected cells, we conclude that reovirus can also induce an alternate, necrotic form of cell death described as necroptosis. We also found that induction of necroptosis requires synthesis of viral RNA or proteins, a step distinct from that necessary for the induction of apoptosis. Thus, our studies reveal that two different events in the reovirus replication cycle can injure host cells by distinct mechanisms. IMPORTANCE: Virus-induced cell death is a determinant of pathogenesis. Mammalian reovirus is a versatile experimental model for identifying viral and host intermediaries that contribute to cell death and for examining how these factors influence viral disease. In this study, we identified that in addition to apoptosis, a regulated form of cell death, reovirus is capable of inducing an alternate form of controlled cell death known as necroptosis. Death by this pathway perturbs the integrity of host membranes and likely triggers inflammation. We also found that apoptosis and necroptosis following viral infection are activated by distinct mechanisms. Our results suggest that host cells can detect different stages of viral infection and attempt to limit viral replication through different forms of cellular suicide. While these death responses may aid in curbing viral spread, they can also exacerbate tissue injury and disease following infection. PMID- 23674613 TI - The outer surface lipoprotein VolA mediates utilization of exogenous lipids by Vibrio cholerae. AB - Previous work from our laboratory showed that the Gram-negative aquatic pathogen Vibrio cholerae can take up a much wider repertoire of fatty acids than other Gram-negative organisms. The current work elaborated on the ability of V. cholerae to exploit an even more diverse pool of lipid nutrients from its environment. We have demonstrated that the bacterium can use lysophosphatidylcholine as a metabolite for growth. Using a combination of thin layer chromatography and mass spectrometry, we also showed that lysophosphatidylcholine-derived fatty acid moieties can be used for remodeling the V. cholerae membrane architecture. Furthermore, we have identified a lysophospholipase, VolA (Vibrio outer membrane lysophospholipase A), required for these activities. The enzyme is well conserved in Vibrio species, is coexpressed with the outer membrane fatty acid transporter FadL, is one of very few surface exposed lipoprotein enzymes to be identified in Gram-negative bacteria and the first instance of a surface lipoprotein phospholipase. We propose a model whereby the bacterium efficiently couples the liberation of fatty acid from lysophosphatidylcholine to its subsequent metabolic uptake. An expanded ability to scavenge diverse environmental lipids at the bacterial surface increases overall bacterial fitness and promotes homeoviscous adaptation through membrane remodeling. IMPORTANCE: Our understanding of how bacteria utilize environmental lipid sources has been limited to lipids such as fatty acids and cholesterol. This narrow scope may be attributed to both the intricate nature of lipid uptake mechanisms and the diversity of lipid substrates encountered within an ecological niche. By examining the ability of the pathogen Vibrio cholerae to utilize exogenous lipids, we uncovered a surface-exposed lipoprotein (VolA) that is required for processing the prevalent host lipid lysophosphatidylcholine. VolA functions as a lipase liberating a fatty acid from exogenous lysophospholipids. The freed fatty acid is then transported into the cell, serving as a carbon source, or shunted into phospholipid synthesis for membrane assembly. A limited number of surface-exposed lipoproteins have been found in Gram-negative organisms, and few have enzymatic function. This work highlights the ability of bacteria to exploit exogenous lipids for both maintenance of the membrane and carbon source acquisition. PMID- 23674614 TI - The effect of 3 T MRI on microleakage of amalgam restorations. AB - OBJECTIVES: To evaluate the effects of 3 T magnetic field on microleakage of amalgam restorations containing three different types of silver (Ag). METHODS: 60 extracted teeth were restored with three different types of amalgam filling materials. Restored teeth were sectioned mesiodistally and divided into experimental and control groups. Experimental groups were exposed to a magnetic field of 3 T for 20 min. All samples were plunged into 2% basic fuchsin solution and examined under a digital microscope by three different observers with regard to microleakage. RESULTS: Statistical analysis showed significant differences in microleakage between the groups exposed to MRI and controls, whereas differences in microleakage between amalgam types were insignificant. CONCLUSIONS: The primary risk of MRI systems arises from the effects of its strong magnetic field on objects containing ferromagnetic materials. An MRI of 1.5 T is known to be safe for amalgam restorations. However, our research indicates that MRI is not completely devoid of any effects on amalgam restorations. PMID- 23674615 TI - Mapping the extracellular and membrane proteome associated with the vasculature and the stroma in the embryo. AB - In order to map the extracellular or membrane proteome associated with the vasculature and the stroma in an embryonic organism in vivo, we developed a biotinylation technique for chicken embryo and combined it with mass spectrometry and bioinformatic analysis. We also applied this procedure to implanted tumors growing on the chorioallantoic membrane or after the induction of granulation tissue. Membrane and extracellular matrix proteins were the most abundant components identified. Relative quantitative analysis revealed differential protein expression patterns in several tissues. Through a bioinformatic approach, we determined endothelial cell protein expression signatures, which allowed us to identify several proteins not yet reported to be associated with endothelial cells or the vasculature. This is the first study reported so far that applies in vivo biotinylation, in combination with robust label-free quantitative proteomics approaches and bioinformatic analysis, to an embryonic organism. It also provides the first description of the vascular and matrix proteome of the embryo that might constitute the starting point for further developments. PMID- 23674616 TI - Identification of a metabolizing enzyme in human kidney by proteomic correlation profiling. AB - Molecular identification of endogenous enzymes and biologically active substances from complex biological sources remains a challenging task, and although traditional biochemical purification is sometimes regarded as outdated, it remains one of the most powerful methodologies for this purpose. While biochemical purification usually requires large amounts of starting material and many separation steps, we developed an advanced method named "proteomic correlation profiling" in our previous study. In proteomic correlation profiling, we first fractionated biological material by column chromatography, and then calculated each protein's correlation coefficient between the enzyme activity profile and protein abundance profile determined by proteomics technology toward fractions. Thereafter, we could choose possible candidates for the enzyme among proteins with a high correlation value by domain predictions using informatics tools. Ultimately, this streamlined procedure requires fewer purification steps and reduces starting materials dramatically due to low required purity compared with conventional approaches. To demonstrate the generality of this approach, we have now applied an improved workflow of proteomic correlation profiling to a drug metabolizing enzyme and successfully identified alkaline phosphatase, tissue nonspecific isozyme (ALPL) as a phosphatase of CS-0777 phosphate (CS-0777-P), a selective sphingosine 1-phosphate receptor 1 modulator with potential benefits in the treatment of autoimmune diseases including multiple sclerosis, from human kidney extract. We identified ALPL as a candidate protein only by the 200-fold purification and only from 1 g of human kidney. The identification of ALPL as CS 0777-P phosphatase was strongly supported by a recombinant protein, and contribution of the enzyme in human kidney extract was validated by immunodepletion and a specific inhibitor. This approach can be applied to any kind of enzyme class and biologically active substance; therefore, we believe that we have provided a fast and practical option by combination of traditional biochemistry and state-of-the-art proteomic technology. PMID- 23674617 TI - Quantitative proteomics reveals the induction of mitophagy in tumor necrosis factor-alpha-activated (TNFalpha) macrophages. AB - Macrophages play an important role in innate and adaptive immunity as professional phagocytes capable of internalizing and degrading pathogens to derive antigens for presentation to T cells. They also produce pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) that mediate local and systemic responses and direct the development of adaptive immunity. The present work describes the use of label-free quantitative proteomics to profile the dynamic changes of proteins from resting and TNF-alpha-activated mouse macrophages. These analyses revealed that TNF-alpha activation of macrophages led to the down-regulation of mitochondrial proteins and the differential regulation of several proteins involved in vesicle trafficking and immune response. Importantly, we found that the down-regulation of mitochondria proteins occurred through mitophagy and was specific to TNF-alpha, as other cytokines such as IL 1beta and IFN-gamma had no effect on mitochondria degradation. Furthermore, using a novel antigen presentation system, we observed that the induction of mitophagy by TNF-alpha enabled the processing and presentation of mitochondrial antigens at the cell surface by MHC class I molecules. These findings highlight an unsuspected role of TNF-alpha in mitophagy and expanded our understanding of the mechanisms responsible for MHC presentation of self-antigens. PMID- 23674619 TI - Tracking Burmese pythons. PMID- 23674621 TI - Ancient answers to modern maladies: the art of actively seeking out the patient's voice. PMID- 23674618 TI - Protective effects of angiopoietin-like 4 on cerebrovascular and functional damages in ischaemic stroke. AB - AIMS: Given the impact of vascular injuries and oedema on brain damage caused during stroke, vascular protection represents a major medical need. We hypothesized that angiopoietin-like 4 (ANGPTL4), a regulator of endothelial barrier integrity, might exert a protective effect during ischaemic stroke. METHODS AND RESULTS: Using a murine transient ischaemic stroke model, treatment with recombinant ANGPTL4 led to significantly decreased infarct size and improved behaviour. Quantitative characteristics of the vascular network (density and branchpoints) were preserved in ANGPTL4-treated mice. Integrity of tight and adherens junctions was also quantified and ANGPTL4-treated mice displayed increased VE-cadherin and claudin-5-positive areas. Brain oedema was thus significantly decreased in ANGPTL4-treated mice. In accordance, vascular damage and infarct severity were increased in angptl4-deficient mice thus providing genetic evidence that ANGPTL4 preserves brain tissue from ischaemia-induced alterations. Altogether, these data show that ANGPTL4 protects not only the global vascular network, but also interendothelial junctions and controls both deleterious inflammatory response and oedema. Mechanistically, ANGPTL4 counteracted VEGF signalling and thereby diminished Src-signalling downstream from VEGFR2. This led to decreased VEGFR2-VE-cadherin complex disruption, increased stability of junctions and thus increased endothelial cell barrier integrity of the cerebral microcirculation. In addition, ANGPTL4 prevented neuronal loss in the ischaemic area. CONCLUSION: These results, therefore, show ANGPTL4 counteracts the loss of vascular integrity in ischaemic stroke, by restricting Src kinase signalling downstream from VEGFR2. ANGPTL4 treatment thus reduces oedema, infarct size, neuronal loss, and improves mice behaviour. These results suggest that ANGPTL4 constitutes a relevant target for vasculoprotection and cerebral protection during stroke. PMID- 23674622 TI - Medical humanities: demarcations, dilemmas and delights. PMID- 23674623 TI - Hearing Australian Aboriginal voices on neglect and sustainability. PMID- 23674624 TI - Borderlands: professional life lived precariously but happily in anthropology and medicine. PMID- 23674625 TI - The death of Hector: pity in Homer, empathy in medical education. AB - Empathy is thought a desirable quality in doctors as a key component of communication skills and professionalism. It is therefore thought desirable to teach it to medical students. Yet empathy is a quality whose essence is difficult to capture but easy to enact. We problematise empathy in an era where empathy has been literalised and instrumentalised, including its measurement. Even if we could agree a universally acceptable definition of empathy, engendering it in the student requires a more subtle approach than seems the case currently. We therefore examine this modern concept and compare it with others such as pity and compassion, using the medium of Homer's Iliad. Two famous scenes from the Iliad elicit pity in the characters and the audience. Pity and compassion are, however, given a complexity within the narrative that often seems lacking in modern ways of conceptualising and teaching empathy. PMID- 23674626 TI - Correction. PMID- 23674627 TI - Language, games and the role of interpreters in psychiatric diagnosis: a Wittgensteinian thought experiment. AB - British society is becoming increasingly culturally and linguistically diverse. This poses a major challenge to mental health services charged with the responsibility to work in ways that respect cultural and linguistic difference. In this paper we investigate the problems of interpretation in the diagnosis of depression using a thought experiment to demonstrate important features of language-games, an idea introduced by Ludwig Wittgenstein in his late work, Philosophical investigations. The thought experiment draws attention to the importance of culture and contexts in understanding the meaning of particular utterances. This has implications not only for how we understand the role of interpreters in clinical settings, and who might best be suited to function in such a role, but more generally it draws attention to the importance of involving members of black minority ethnic (BME) communities in working alongside mainstream mental health services. We conclude that the involvement of BME community development workers inside, alongside and outside statutory services can potentially improve the quality of care for people from BME communities who use these services. PMID- 23674628 TI - Storying the street: transition narratives of homeless youth. AB - Toronto Youth Street Stories is an innovative, web-based storytelling project that was conducted with homeless youths in Toronto. As a collaborative knowledge dissemination initiative, the project engaged youthful participants, authors, community mentors, youth service agencies and university-based researchers. Over 50 youths were encouraged to express their personal perspectives through author led, creative writing workshops, resulting in youth-created stories, poems and pictures about a wide array of feelings and experiences. Across the dozens of pieces of writing, there is evidence of a chronology of street life, or an "arc of experience", that ranges from living with abuse and despair, leaving home, living on the street, experiencing a crisis or turning point, accessing services and gradually moving away from street life toward self-sustaining independence and security. This arc of experience includes the stories of youth who have transitioned away from the street as well as those still facing homelessness. This paper describes this arc of experience and illustrates it with the subjective material generated by the youths' stories about their lives on the streets of Toronto. We conclude that this project provided an important, creative outlet for the youths, and increased understanding of the challenges, stigma and resilience of homeless youth. PMID- 23674629 TI - Narrating the Holocaust: in pursuit of poetic representations of health. AB - This paper considers the scope of poetic representation for exploring notions of health and wellbeing in the testimony of Holocaust survivors. The paper is based on the representation, through poetic form, of testimony derived from multiple in depth interviews with a Holocaust survivor, Anka, in south-east Wales. This paper concentrates on two of those interviews, the first a life story and the second an interview focusing on health, illness and wellbeing. Two poetic representations, one derived from each interview, provide examples of the principal investigator's response to the oral testimony, and the authors explore how these forms can present authentic and rigorous data distillates without detracting from the emotive, contextualised and powerful messages of the original text. The poetic representations offer an analysis of the survivor's life experiences, especially in Auschwitz concentration camp, and her personal perspective on her health and wellbeing. The authors discuss the value of poetic representation as a methodological approach, consider the poetic form for working with survivor stories and suggest how others might judge these pieces, to highlight the strengths and weaknesses of these alternative forms of data representation. They also consider the role of the researcher and Anka in creating the final product and the effect of Anka's voice on the researchers' work. PMID- 23674630 TI - Troubling dimensions of heart transplantation. AB - Heart transplantation is now the accepted therapy for end-stage heart failure that is resistant to medical treatment. Families of deceased donors routinely are urged to view the heart as a "gift of life" that will enable the donor to live on by extending and sustaining the life of a stranger. In contrast, heart recipients are encouraged to view the organ mechanistically-as a new pump that was rendered a spare, reusable part when a generous stranger died. Psychosocial and psychoanalytic research, anecdotal evidence and first-person accounts indicate that after transplant, many recipients experience unexpected changes or distress that cannot be understood adequately using biomedical explanatory models alone. In this paper it is argued that phenomenological philosophy offers a promising way to frame an ongoing empirical study that asks recipients to reflect on what it is like to incorporate the heart of another person. Merleau-Ponty and others have posited that any change to the body inevitably transforms the self. Hence, it is argued in this paper that replacing failing hearts with functioning hearts from deceased persons must be considered much more than a complex technical procedure. Acknowledging the disturbances to embodiment and personal identity associated with transplantation may explain adverse outcomes that heretofore have been inexplicable. Ultimately, a phenomenological understanding could lead to improvements in the consent process, preoperative teaching and follow-up care. PMID- 23674632 TI - George Eliot's Middlemarch: a contribution to medical professionalism. AB - The qualities of medical professionalism have been questioned in the last few years. George Eliot's 19(th) century novel Middlemarch illustrates some of the truths that should underlie the physician-patient relationship, and depicts prophetically some of the developments that were to occur in reality in the medicine of the 20(th) and 21(st) century. Her insight into the problems facing a medical researcher and the fictional conflicts between vocation and marriage are real issues of medical professionalism even today. PMID- 23674631 TI - An ethical and social examination of dementia as depicted in Japanese film. AB - The ageing population means that dementia is a serious social problem in Japan. Attitudes toward ageing in Japan are increasingly negative, and views of life and death among older people vary. Numerous ethical problems exist in the medical treatment of dementia. Amidst such conditions, it is important and beneficial to examine films that depict demented patients and to consider the issues raised by these films. Through film we see many aspects of a country and its times: culture and ideology, morality and religion, medical treatments, views on life and death, social conditions and what issues are viewed as problems. The best films both entertain audiences and provide viewers with opportunities to think about social problems. In the past 30 years, 10 films about dementia had been made in Japan and two of these-The Twilight Years (Kokotsu no hito) and Memories of Tomorrow (Ashita no kioku) are the main focus of this paper. In our analysis we consider three points: how the patients are informed of their disease, the characters' wishes for death, and terminal medical care. PMID- 23674633 TI - Using Indigenous Australian drama to break cultural barriers in healthcare relationships. AB - Since colonisation, the marginalisation of Indigenous Australians has adversely affected their language, culture and health. Mainstream society has failed to address social differences and establish culturally-appropriate health programmes for these groups. This paper extracts important humanistic themes within the context of health from four Indigenous Australian plays written during a period of social unrest in response to past oppression: (1) The dreamers, by Jack David; (2) Murras, by Eva Johnson; (3) Coordah, by Richard Walley; and (4) The keepers, by Bob Maza. These plays will be analysed to (a) illuminate human suffering from an indigenous perspective, based upon social and cultural planes of analysis; (b) understand the socio-cultural basis of poor health; and (c) instruct healthcare professionals that health is a social construct that can be interpreted as the product of select plays that are not solely based upon an illness narrative. PMID- 23674634 TI - Developing narrative competence in medical students. PMID- 23674635 TI - Salt bridges: fluid interactions between artists and scientists in the lab, Department of New Biochemistry, Oxford. PMID- 23674636 TI - A balcony in Nepal: glimpses of a Himalayan village. PMID- 23674637 TI - The making of Mr Gray's anatomy: bodies, books, fortune, fame. PMID- 23674638 TI - Grey's Anatomy: scalpels, sex and stereotypes. PMID- 23674639 TI - The english surgeon. PMID- 23674640 TI - Doctors as Nietzschean supermen? PMID- 23674641 TI - Doctors as Nietzschean supermen? Author's reply. PMID- 23674643 TI - Jane Austen's lifelong health problems and final illness: New evidence points to a fatal Hodgkin's disease and excludes the widely accepted Addison's. AB - Jane Austen is typically described as having excellent health until the age of 40 and the onset of a mysterious and fatal illness, initially identified by Sir Zachary Cope in 1964 as Addison's disease. Her biographers, deceived both by Cassandra Austen's destruction of letters containing medical detail, and the cheerful high spirits of the existing letters, have seriously underestimated the extent to which illness affected Austen's life. A medical history reveals that she was particularly susceptible to infection, and suffered unusually severe infective illnesses, as well as a chronic conjunctivitis that impeded her ability to write. There is evidence that Austen was already suffering from an immune deficiency and fatal lymphoma in January 1813, when her second and most popular novel, Pride and Prejudice, was published. Four more novels would follow, written or revised in the shadow of her increasing illness and debility. Whilst it is impossible now to conclusively establish the cause of her death, the existing medical evidence tends to exclude Addison's disease, and suggests there is a high possibility that Jane Austen's fatal illness was Hodgkin's disease, a form of lymphoma. PMID- 23674642 TI - Why pay attention to the artist? PMID- 23674644 TI - The medical palimpsest of The Scarlet Letter: an interdisciplinary reading. AB - The multiple historical layers of Roger Chillingworth's character have been overlooked in criticism of The Scarlet Letter. By considering the possible influence of Robert Browning's dramatic poem Paracelsus (1835) on Hawthorne's romance (1850), as well as the ways in which overtones of both herbalism and clinical medicine complicate Chillingworth's character, one rediscovers Chillingworth as Hawthorne's audience likely experienced him: as a fictional palimpsest bearing multiple inscriptions of medical history that reveal an interplay between integrity and corruption. Thus, an interdisciplinary reading of The Scarlet Letter challenges the conventional critical assessment of Chillingworth as a satanic or Faustian figure. PMID- 23674645 TI - Medicine through the novel: Lying Awake. AB - Narrative fiction can engage readers in generating imaginative recreations of the inner worlds of doctors and patients, which are largely inaccessible through typical clinical case analysis. Fiction about medicine can yield insight into patients' subjective experience of illness and can highlight the need for an empathetic response from doctors to patients affected by illness. Mark Salzman's novel, Lying Awake, invites us to reflect on social, psychological, and spiritual dimensions of neurological illness in particular and of the doctor/patient relationship in general. PMID- 23674646 TI - Quotation. PMID- 23674647 TI - Painting as policy. AB - Ours is, at its heart, a profession of service predicated on mutual trust. All too often policies aimed at resolving a particular problem in health care are inadequate not because they fail at what they were intended to do, but rather because of the unintended consequences, both direct and indirect, that are inevitable in complex systems where competing interests preclude unity of purpose. Ultimately, these policy "layers" distance us from our foundational principles and the disjointed complexity that ensues alienates the patient, disheartens and disillusions the physician, and further undermines the relationship that is so crucial to proper health care delivery. Importantly, we must realise that legislative complexity simply cannot make up for an absence of trust and instead work to foster such trust by reflecting our profession's tradition of service to the public through a blatant, highly visible pursuit of patient welfare. PMID- 23674648 TI - "Of the edgelands": broadening the scope of qualitative methodology. AB - In an editorial in a previous issue of this journal Rapport et al introduced the metaphor of the edgelands, arguing that the area between urban and rural landscapes serves to illustrate some of the difficulties of interdisciplinarity experienced by those who work in the medical humanities. In this paper the authors explore some specific issues of qualitative research methodology in health care research. The paper describes a broadening out of the scope of qualitative inquiry in social scientific research in health and social care. The paper explains why some new methodologies have emerged and how both old and new methodologies are grouped around three interlocking strands: narrative based, arts based, and redefined, methodology. In order to illustrate developments in this field, the authors present three examples of the use of these methodologies in practice: photo elicitation technique; discourse analytic, and interpretive anthropological, method. Finally the authors illustrate how these methodologies can give added value to health services research. PMID- 23674650 TI - The Humanities in Medicine - Distancing and the distance between us. PMID- 23674649 TI - Opening the word hoard. PMID- 23674651 TI - How to make the most of history and literature in the teaching of medical humanities: the experience of the University of Geneva. AB - In this paper the authors discuss the benefits of history and literature in the teaching of medical humanities. They suggest that human sciences produce a common effect, which they call distancing. Distancing is the awareness that one natural way to describe a given situation does not exist and that any point of view scientific or not-is context dependant and culturally shaped. Distancing is important to medical students, by allowing them to become aware of the specificity of their own professional point of view. The authors offer a reflection on the specificities of both historical and literary approaches and on the tools they provide for medical students. This paper assumes there is a close link between the theoretical debate on the benefits provided by human sciences and the concrete framework of a given programme. The authors describe team teaching, which has been the solution adopted in the School of Medicine at the University of Geneva to obtain the most from history and literature. PMID- 23674652 TI - Visual broadcast in schizophrenia. PMID- 23674653 TI - The European Commission's proposals for a new regulation to govern medical devices. PMID- 23674654 TI - Reply to Tao et al. PMID- 23674655 TI - Five years after the SYNTAX trial: what have we learnt? PMID- 23674656 TI - Intentional preservation of collateral circulation to the artery of Adamkiewicz using axillo-axillary bypass, concomitant with thoracic endovascular aneurysm repair. PMID- 23674657 TI - Solitary peripheral pulmonary artery aneurysm. PMID- 23674659 TI - Preoperative anaemia is a negative factor in aortic valve surgery. PMID- 23674658 TI - 18F-fluorodeoxyglucose positron emission tomography/computed tomography and the relationship between fluorodeoxyglucose uptake and the expression of hypoxia inducible factor-1alpha, glucose transporter-1 and vascular endothelial growth factor in thymic epithelial tumours. AB - OBJECTIVES: The objective of this study was to evaluate the usefulness of (18)F fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) and the relationships among the expressions of hypoxia-inducible factor-1alpha (HIF-1alpha), glucose transporter-1 (Glut-1) and vascular endothelial growth factor (VEGF), histological type, other clinical factors and FDG uptake in thymic epithelial tumours. METHODS: Thirty-three patients who underwent FDG-PET/CT before treatment were reviewed. All types of tumours were reclassified into three subgroups: low-risk thymomas (types A, AB and B1), high-risk thymomas (types B2 and B3) and thymic carcinomas. Tumour contour, pattern of FDG uptake, tumour size and maximum standardized uptake value (SUVmax) were obtained. Expressions of HIF 1alpha, Glut-1 and VEGF were analysed immunohistochemically, and these expressions were evaluated using grading scales. RESULTS: FDG uptake was visually recognized in all (100%) tumours. A homogeneous pattern of FDG uptake was increasingly observed in the order of low-risk thymomas to high-risk thymomas to thymic carcinomas (P = 0.016). SUVmax for thymic carcinomas was significantly higher than that for thymomas (P = 0.008). With the optimal cut-off value of SUVmax of 5.6, the sensitivity, specificity and accuracy for diagnosing thymic carcinoma were 0.75, 0.80 and 0.79, respectively. Regarding the mean scoring of HIF-1alpha, Glut-1 and VEGF, increasing trends were observed in the order of low risk thymomas to high-risk thymomas to thymic carcinomas. Tumour size revealed a significant correlation with SUVmax (r = 0.60, P < 0.001), and the expression of HIF-1alpha showed a moderate association, but the expression of Glut-1 showed no correlation with SUVmax. Regarding correlations between the expression of the three markers, there were moderate associations between HIF-1alpha and Glut-1, and HIF-1alpha and VEGF, and a significant correlation between Glut-1 and VEGF (r = 0.60, P < 0.001). In type B1 thymoma, HIF-1alpha and Glut-1 were partly expressed in non-neoplastic immature lymphocytes. CONCLUSIONS: FDG-PET/CT should be performed in patients with tumours in the anterior mediastinum because the pattern of FDG uptake and SUVmax are useful in the differential diagnosis of thymic epithelial tumours. Furthermore, the expressions of HIF-1alpha, Glut-1 and VEGF might be associated with malignancy of thymic epithelial tumours. In contrast, FDG uptake might be dependent on tumour size rather than Glut-1 overexpression. PMID- 23674660 TI - Initial experience with video-assisted thoracoscopic bronchoplasty. AB - OBJECTIVES: Bronchial-origin involvement by endobronchial tumours or direct invasion by tumour or metastatic lymph nodes is a relative contraindication for video-assisted thoracoscopic (VATS) lobectomy. However, selected cases can be resected by VATS bronchoplasty. METHODS: Between 2006 and 2009, 21 of 231 (9.1%) VATS lobectomy cases underwent VATS bronchoplasty. Cases with endobronchial involvement and limited non-bulky invasion of bronchus by tumour or metastatic nodes without major vascular invasion were selected for bronchoplasty by preoperative bronchosocpy and CT scan thorax. Patients underwent a simple/wedge bronchoplasty (bronchus divided at origin and closed flush or transversely), sleeve bronchoplasty or others (bronchoplasty combined with other extended resections). All bronchoplasties were done totally endoscopically by directly watching a TV monitor. Bronchial margins were all subjected to intraoperative pathological analysis. Anastomosis was done with interrupted sutures. Integrity of anastomosis was checked by intraoperative bronchoscopy. The follow-up was done by 6-monthly CT scans and bronchoscopy. RESULTS: Eleven patients were females. Mean age was 64.9 years (range, 47-83 years). Indications were endobronchial tumours in 3, direct invasion in 6 and metastatic nodes in 12. In 4 cases, invasion was detected at the time of surgery. Mean hospital stay was 5.2 days (range, 3-8 days). Mean duration of surgery was 287 min (range, 135-540 min). Nine had simple/wedge bronchoplasty, 8, sleeve bronchoplasty and 4, extended bronchoplasties. Histology was non-small-cell carcinoma (NSCLC) in 19, carcinoid in 1 and colonic metastasis in 1. In the NSCLC, 5 patients were in stage IB, 5 in stage IIA, 2 in stage IIB and 7 were in IIIA. All bronchial margins were negative for malignancy. The mean follow-up was 26.2 months (range, 6-32 months). There was no operative mortality, but 1 patient developed bronchopleural fistula. To date, there have been no local tumour recurrences. CONCLUSIONS: Selected endobronchial and non bulky tumours with limited invasion at bronchial origin can be resected by VATS bronchoplasty. PMID- 23674662 TI - The nature of self and how it is experienced within and beyond the health care setting. PMID- 23674661 TI - An unusual case of a calcified carcinoid tumour. PMID- 23674663 TI - The power of the projected self: a case study in self artistry. AB - The "projected self" is an individual engaged in a life project. The power that enables an individual to formulate, to embark on, and to effect a life project is of an "existential", embodied kind: something fuelled metabolically within the body of the individual, and conceived of by way of his or her ongoing, individual acts of interpretation. In this article the life of the English artist Stanley Spencer is looked to as a case study through which to flesh out and apply the above conceptual terms and their argument. To what extent can there be said to be a relationship between the "work of art" that Spencer created in and as his life, and his influence over those forces and those others that might otherwise have claimed a hold over his life? Spencer's construction of a beautiful, involved, and extensive worldview, the article argues, does translate into him exercising a conscious control over the course of his life and enjoying a wellbeing of identity. PMID- 23674664 TI - Some body wants to be normal: an account of an HIV narrative. AB - Narrative accounts of illness often focus on the sociological construction of illness and neglect the body. This paper explores themes of seeing and being seen in the narrative of an HIV positive man to show the importance of uncovering the psychological and corporeal experience of HIV. Such accounts complement and enhance conventional medical accounts of illness. Poignantly, it is a story of how he understands others as reading his body and writing on it. Further, his story is not one that is in circulation. Accounts of positive heterosexual males are few. This paper seeks to add at least one account to the public record so that others may have narrative resources to draw upon. Narrative analysis provides new perspectives on the lived experience of HIV, which are crucial to appreciate how it might be possible to live a positive life. PMID- 23674665 TI - When narratives matter: men, sport, and spinal cord injury. AB - Experiencing a spinal cord injury (SCI) and becoming disabled through sport is a major disruptive life event that instigates a multiplicity of difficult and complex issues that the person has to deal with. One of these problems is how to restory a life and construct new body/self relationships and identities over time. To explore this process, we focus on the life stories of a small group of men (n = 14) who have suffered SCI and become disabled through playing rugby football. We illustrate the ways in which certain metaphors, notions of time, and kinds of hope, congregate and coalesce within three specific narrative types and how these operate to shape the individual experiences of these men following SCI. The implications of this dynamic process for the storied body/self and identity construction are highlighted throughout. PMID- 23674666 TI - We are all artists. PMID- 23674667 TI - Self and narrative in schizophrenia: time to author a new story. AB - The prevailing, clinical view of schizophrenia, as reflected in the psychiatric literature, suggests both that people with schizophrenia have lost their sense of self and that they have a diminished capacity to create coherent narratives about their own lives. Drawing on our empirical research in the growing area of recovery, we describe not only the disruptions and discontinuities introduced by the illness and its social and personal consequences, but also the person's efforts to overcome these, to reconstruct a sense of self, to regain agency and to create a coherent life narrative. We suggest in closing that, rather than simply being a byproduct of recovery, these processes of re-authoring one's life story are actually integral components of the recovery process itself. PMID- 23674668 TI - Becoming a nurse: "it's just who I am". AB - In any research study, researchers situate themselves, either explicitly or implicitly, within a variety of frameworks when studying phenomena. From a research perspective, the study will be more robust if these frameworks and the accompanying assumptions are compatible with each other; otherwise, the project may lack coherence. Ricoeur offers a methodological perspective-that is, an interpretive theory as reflected in mimesis, which is congruent with his ontological theory of self identity (ipse- and idem-identity). To illustrate Ricoeur's frameworks when researching the self identities, I use examples from a research study in which I asked senior nursing students to explore their experience of becoming a nurse. I do not intend for this article to be a comprehensive research report, but I present it as an exemplar of how Ricoeur's ideas can guide other researchers studying self identity. I labelled my study a narrative research project and assumed that becoming a nurse means developing a self identity as a nurse. While self identity is often framed in psychological terms, Ricoeur uses a philosophical perspective when exploring this concept. I conclude the paper by suggesting (a) that Ricoeur can guide any project in which researchers ask participants to describe "becoming" a person with illness, sickness or disease, and (b) that educators of healthcare professional students can improve the educative experience by purposefully considering how a student's ontological self affects that student's practice. PMID- 23674669 TI - They stole my baby's soul: narratives of embodiment and loss. AB - The controversy over retained organs, arising from the Bristol and Alder Hey findings about postmortem uses of body parts, has revealed a gulf between medical and lay understandings of the human body and its relationship with the human person. There is a clear utility in having a "doctor's story", which is different from the way patients and their families understand the significance of the body, since this enables medical diagnosis and treatment to be effective. When, however, the medical narrative intrudes uncritically into areas where the key issue is the integration of the body with the person, experienced or remembered, things go badly wrong with communications in medicine. For the lay person disrespectful treatment of the body of a loved one represents a personal attack. In this respect, strong emotion, seen as irrelevant or distracting by scientific medicine, is a central aspect of the narrative concerned with loss of a loved person. For doctor and lay person alike, a narrative of the self which pays proper attention to the embodiment of the self, offers the possibility of a genuinely humane medicine. PMID- 23674670 TI - The experience of stroke and the life of the Spirit. AB - In this paper, I have tried in the first instance to describe the experience of stroke, and to set my own story in the context of more general observations on strokes and on the appropriate care of stroke patients. The paper makes clear that the stroke brought my active working life to an abrupt end, but I am keen to stress that in my case at least the thinking must go on. The production of this paper offers a test case of this last proposition. The paper does not attempt to survey my whole working life (mainly as a Church of England parish priest) and its interaction with my faith, but it does try to explore some of the consequences for faith, and for prayer, prompted by the stroke.There is a personal story of sometimes bewildering complexity behind every stroke. "But why is stroke any different from other serious illness?" This paper seeks to identify some of the distinctive characteristics of strokes; but I leave it to others to answer the question more adequately. It only needs to be stated here that all strokes, in some measure, affect mental processes, sometimes profoundly; and we easily underestimate the extent to which our performance is affected by our states of mind. PMID- 23674671 TI - CD134 is a cellular receptor specific for human herpesvirus-6B entry. AB - Human herpesvirus-6B (HHV-6B) is a T lymphotropic beta-herpesvirus that is clearly distinct from human herpesvirus-6A (HHV-6A) according to molecular biological features. The International Committee on Taxonomy of Viruses recently classified HHV-6B as a separate species. The primary HHV-6B infection causes exanthem subitum and is sometimes associated with severe encephalopathy. More than 90% of the general population is infected with HHV-6B during childhood, and the virus remains throughout life as a latent infection. HHV-6B reactivation causes encephalitis in immunosuppressed patients. The cellular receptor for HHV 6A entry was identified as human CD46, but the receptor for HHV-6B has not been clear. Here we found that CD134, a member of the TNF receptor superfamily, functions as a specific entry receptor for HHV-6B. A T-cell line that is normally nonpermissive for HHV-6B infection became highly susceptible to infection when CD134 was overexpressed. CD134 was down-regulated in HHV-6B-infected T cells. Soluble CD134 interacted with the HHV-6B glycoprotein complex that serves as a viral ligand for cellular receptor, which inhibited HHV-6B but not HHV-6A infection in target cells. The identification of CD134 as an HHV-6B specific entry receptor provides important insight into understanding HHV-6B entry and its pathogenesis. PMID- 23674672 TI - Dynamic FtsA and FtsZ localization and outer membrane alterations during polar growth and cell division in Agrobacterium tumefaciens. AB - Growth and cell division in rod-shaped bacteria have been primarily studied in species that grow predominantly by peptidoglycan (PG) synthesis along the length of the cell. Rhizobiales species, however, predominantly grow by PG synthesis at a single pole. Here we characterize the dynamic localization of several Agrobacterium tumefaciens components during the cell cycle. First, the lipophilic dye FM 4-64 predominantly stains the outer membranes of old poles versus growing poles. In cells about to divide, however, both poles are equally labeled with FM 4-64, but the constriction site is not. Second, the cell-division protein FtsA alternates from unipolar foci in the shortest cells to unipolar and midcell localization in cells of intermediate length, to strictly midcell localization in the longest cells undergoing septation. Third, the cell division protein FtsZ localizes in a cell-cycle pattern similar to, but more complex than, FtsA. Finally, because PG synthesis is spatially and temporally regulated during the cell cycle, we treated cells with sublethal concentrations of carbenicillin (Cb) to assess the role of penicillin-binding proteins in growth and cell division. Cb treated cells formed midcell circumferential bulges, suggesting that interrupted PG synthesis destabilizes the septum. Midcell bulges contained bands or foci of FtsA-GFP and FtsZ-GFP and no FM 4-64 label, as in untreated cells. There were no abnormal morphologies at the growth poles in Cb-treated cells, suggesting unipolar growth uses Cb-insensitive PG synthesis enzymes. PMID- 23674673 TI - In vivo imaging of CD8+ T cell-mediated elimination of malaria liver stages. AB - CD8(+) T cells are specialized cells of the adaptive immune system capable of finding and eliminating pathogen-infected cells. To date it has not been possible to observe the destruction of any pathogen by CD8(+) T cells in vivo. Here we demonstrate a technique for imaging the killing of liver-stage malaria parasites by CD8(+) T cells bearing a transgenic T cell receptor specific for a parasite epitope. We report several features that have not been described by in vitro analysis of the process, chiefly the formation of large clusters of effector CD8(+) T cells around infected hepatocytes. The formation of clusters requires antigen-specific CD8(+) T cells and signaling by G protein-coupled receptors, although CD8(+) T cells of unrelated specificity are also recruited to clusters. By combining mathematical modeling and data analysis, we suggest that formation of clusters is mainly driven by enhanced recruitment of T cells into larger clusters. We further show various death phenotypes of the parasite, which typically follow prolonged interactions between infected hepatocytes and CD8(+) T cells. These findings stress the need for intravital imaging for dissecting the fine mechanisms of pathogen recognition and killing by CD8(+) T cells. PMID- 23674674 TI - Emergence of hierarchy in cost-driven growth of spatial networks. AB - One of the most important features of spatial networks--such as transportation networks, power grids, the Internet, and neural networks--is the existence of a cost associated with the length of links. Such a cost has a profound influence on the global structure of these networks, which usually display a hierarchical spatial organization. The link between local constraints and large-scale structure is not elucidated, however, and we introduce here a generic model for the growth of spatial networks based on the general concept of cost-benefit analysis. This model depends essentially on a single scale and produces a family of networks that range from the star graph to the minimum spanning tree and are characterized by a continuously varying exponent. We show that spatial hierarchy emerges naturally, with structures composed of various hubs controlling geographically separated service areas, and appears as a large-scale consequence of local cost-benefit considerations. Our model thus provides the basic building blocks for a better understanding of the evolution of spatial networks and their properties. We also find that, surprisingly, the average detour is minimal in the intermediate regime as a result of a large diversity in link lengths. Finally, we estimate the important parameters for various world railway networks and find that, remarkably, they all fall in this intermediate regime, suggesting that spatial hierarchy is a crucial feature for these systems and probably possesses an important evolutionary advantage. PMID- 23674675 TI - Influence of organic films on the evaporation and condensation of water in aerosol. AB - Uncertainties in quantifying the kinetics of evaporation and condensation of water from atmospheric aerosol are a significant contributor to the uncertainty in predicting cloud droplet number and the indirect effect of aerosols on climate. The influence of aerosol particle surface composition, particularly the impact of surface active organic films, on the condensation and evaporation coefficients remains ambiguous. Here, we report measurements of the influence of organic films on the evaporation and condensation of water from aerosol particles. Significant reductions in the evaporation coefficient are shown to result when condensed films are formed by monolayers of long-chain alcohols [C(n)H(2n+1)OH], with the value decreasing from 2.4 * 10(-3) to 1.7 * 10(-5) as n increases from 12 to 17. Temperature-dependent measurements confirm that a condensed film of long-range order must be formed to suppress the evaporation coefficient below 0.05. The condensation of water on a droplet coated in a condensed film is shown to be fast, with strong coherence of the long-chain alcohol molecules leading to islanding as the water droplet grows, opening up broad areas of uncoated surface on which water can condense rapidly. We conclude that multicomponent composition of organic films on the surface of atmospheric aerosol particles is likely to preclude the formation of condensed films and that the kinetics of water condensation during the activation of aerosol to form cloud droplets is likely to remain rapid. PMID- 23674676 TI - Experimental evidence that evolutionarily diverse assemblages result in higher productivity. AB - There now is ample experimental evidence that speciose assemblages are more productive and provide a greater amount of ecosystem services than depauperate ones. However, these experiments often conclude that there is a higher probability of including complementary species combinations in assemblages with more species and lack a priori prediction about which species combinations maximize function. Here, I report the results of an experiment manipulating the evolutionary relatedness of constituent plant species across a richness gradient. I show that assemblages with distantly related species contributed most to the higher biomass production in multispecies assemblages, through species complementarity. Species produced more biomass than predicted from their monocultures when they were in plots with distantly related species and produced the amount of biomass predicted from monoculture when sown with close relatives. This finding suggests that in the absence of any other information, combining distantly related species in restored or managed landscapes may serve to maximize biomass production and carbon sequestration, thus merging calls to conserve evolutionary history and maximize ecosystem function. PMID- 23674677 TI - Posttranslational protein knockdown coupled to receptor tyrosine kinase activation with phosphoPROTACs. AB - Posttranslational knockdown of a specific protein is an attractive approach for examining its function within a system. Here we introduce phospho-dependent proteolysis targeting chimeras (phosphoPROTACs), a method to couple the conditional degradation of targeted proteins to the activation state of particular kinase-signaling pathways. We generated two phosphoPROTACs that couple the tyrosine phosphorylation sequences of either the nerve growth factor receptor, TrkA (tropomyosin receptor kinase A), or the neuregulin receptor, ErbB3 (erythroblastosis oncogene B3), with a peptide ligand for the E3 ubiquitin ligase von Hippel Lindau protein. These phosphoPROTACs recruit either the neurotrophic signaling effector fibroblast growth factor receptor substrate 2alpha or the survival-promoting phosphatidylinositol-3-kinase, respectively, to be ubiquitinated and degraded upon activation of specific receptor tyrosine kinases and phosphorylation of the phosphoPROTACs. We demonstrate the ability of these phosphoPROTACs to suppress the short- and long-term effects of their respective activating receptor tyrosine kinase pathways both in vitro and in vivo. In addition, we show that activation of phosphoPROTACs is entirely dependent on their kinase-mediated phosphorylation, as phenylalanine-containing null variants are inactive. Furthermore, stimulation of unrelated growth factor receptors does not induce target protein knockdown. Although comparable in efficiency to RNAi, this approach has the added advantage of providing a degree of temporal and dosing control as well as cell-type selectivity unavailable using nucleic acid based strategies. By varying the autophosphorylation sequence of a phosphoPROTAC, it is conceivable that other receptor tyrosine kinase/effector pairings could be similarly exploited to achieve other biological effects. PMID- 23674678 TI - Experimental interrogation of the path dependence and stochasticity of protein evolution using phage-assisted continuous evolution. AB - To what extent are evolutionary outcomes determined by a population's recent environment, and to what extent do they depend on historical contingency and random chance? Here we apply a unique experimental system to investigate evolutionary reproducibility and path dependence at the protein level. We combined phage-assisted continuous evolution with high-throughput sequencing to analyze evolving protein populations as they adapted to divergent and then convergent selection pressures over hundreds of generations. Independent populations of T7 RNA polymerase genes were subjected to one of two selection histories ("pathways") demanding recognition of distinct intermediate promoters followed by a common final promoter. We observed distinct classes of solutions with unequal phenotypic activity and evolutionary potential evolve from the two pathways, as well as from replicate populations exposed to identical selection conditions. Mutational analysis revealed specific epistatic interactions that explained the observed path dependence and irreproducibility. Our results reveal in molecular detail how protein adaptation to different environments, as well as stochasticity among populations evolved in the same environment, can both generate evolutionary outcomes that preclude subsequent convergence. PMID- 23674679 TI - Role of aspartate 132 at the orifice of a proton pathway in cytochrome c oxidase. AB - Proton transfer across biological membranes underpins central processes in biological systems, such as energy conservation and transport of ions and molecules. In the membrane proteins involved in these processes, proton transfer takes place through specific pathways connecting the two sides of the membrane via control elements within the protein. It is commonly believed that acidic residues are required near the orifice of such proton pathways to facilitate proton uptake. In cytochrome c oxidase, one such pathway starts near a conserved Asp-132 residue. Results from earlier studies have shown that replacement of Asp 132 by, e.g., Asn, slows proton uptake by a factor of ~5,000. Here, we show that proton uptake at full speed (~10(4) s(-1)) can be restored in the Asp-132-Asn oxidase upon introduction of a second structural modification further inside the pathway (Asn-139-Thr) without compensating for the loss of the negative charge. This proton-uptake rate was insensitive to Zn(2+) addition, which in the wild type cytochrome c oxidase slows the reaction, indicating that Asp-132 is required for Zn(2+) binding. Furthermore, in the absence of Asp-132 and with Thr at position 139, at high pH (>9), proton uptake was significantly accelerated. Thus, the data indicate that Asp-132 is not strictly required for maintaining rapid proton uptake. Furthermore, despite the rapid proton uptake in the Asn-139 Thr/Asp-132-Asn mutant cytochrome c oxidase, proton pumping was impaired, which indicates that the segment around these residues is functionally linked to pumping. PMID- 23674680 TI - Distinct quaternary structures of the AAA+ Lon protease control substrate degradation. AB - Lon is an ATPase associated with cellular activities (AAA+) protease that controls cell division in response to stress and also degrades misfolded and damaged proteins. Subunits of Lon are known to assemble into ring-shaped homohexamers that enclose an internal degradation chamber. Here, we demonstrate that hexamers of Escherichia coli Lon also interact to form a dodecamer at physiological protein concentrations. Electron microscopy of this dodecamer reveals a prolate structure with the protease chambers at the distal ends and a matrix of N domains forming an equatorial hexamer-hexamer interface, with portals of ~45 A providing access to the enzyme lumen. Compared with hexamers, Lon dodecamers are much less active in degrading large substrates but equally active in degrading small substrates. Our results support a unique gating mechanism that allows the repertoire of Lon substrates to be tuned by its assembly state. PMID- 23674681 TI - Addressing uncertainty in adaptation planning for agriculture. AB - We present a framework for prioritizing adaptation approaches at a range of timeframes. The framework is illustrated by four case studies from developing countries, each with associated characterization of uncertainty. Two cases on near-term adaptation planning in Sri Lanka and on stakeholder scenario exercises in East Africa show how the relative utility of capacity vs. impact approaches to adaptation planning differ with level of uncertainty and associated lead time. An additional two cases demonstrate that it is possible to identify uncertainties that are relevant to decision making in specific timeframes and circumstances. The case on coffee in Latin America identifies altitudinal thresholds at which incremental vs. transformative adaptation pathways are robust options. The final case uses three crop-climate simulation studies to demonstrate how uncertainty can be characterized at different time horizons to discriminate where robust adaptation options are possible. We find that impact approaches, which use predictive models, are increasingly useful over longer lead times and at higher levels of greenhouse gas emissions. We also find that extreme events are important in determining predictability across a broad range of timescales. The results demonstrate the potential for robust knowledge and actions in the face of uncertainty. PMID- 23674682 TI - Direct interaction between the TnsA and TnsB subunits controls the heteromeric Tn7 transposase. AB - The transposon Tn7 transposase that recognizes the transposon ends and mediates breakage and joining is heteromeric. It contains the Tn7-encoded proteins TnsB, which binds specifically to the transposon ends and carries out breakage and joining at the 3' ends, and TnsA, which carries out breakage at the 5' ends of Tn7. TnsA apparently does not bind specifically to DNA, and we have hypothesized that it is recruited to the ends by interaction with TnsB. In this work, we show that TnsA and TnsB interact directly and identify several TnsA and TnsB amino acids involved in this interaction. We also show that TnsA can stimulate two key activities of TnsB, specific binding to the ends and pairing of the Tn7 ends. The ends of Tn7 are structurally asymmetric (i.e., contain different numbers of TnsB binding sites), and Tn7 also is functionally asymmetric, inserting into its specific target site, attachment site attTn7 (attTn7) in a single orientation. Moreover, Tn7 elements containing two Tn7 right ends can transpose, but elements with two Tn7 left ends cannot. We show here that TnsA + TnsB are unable to pair the ends of a Tn7 element containing two Tn7 left ends. This pairing defect likely contributes to the inability of Tn7 elements with two Tn7 left ends to transpose. PMID- 23674683 TI - Host and viral features of human dengue cases shape the population of infected and infectious Aedes aegypti mosquitoes. AB - Dengue is the most prevalent arboviral disease of humans. The host and virus variables associated with dengue virus (DENV) transmission from symptomatic dengue cases (n = 208) to Aedes aegypti mosquitoes during 407 independent exposure events was defined. The 50% mosquito infectious dose for each of DENV-1 4 ranged from 6.29 to 7.52 log10 RNA copies/mL of plasma. Increasing day of illness, declining viremia, and rising antibody titers were independently associated with reduced risk of DENV transmission. High early DENV plasma viremia levels in patients were a marker of the duration of human infectiousness, and blood meals containing high concentrations of DENV were positively associated with the prevalence of infectious mosquitoes 14 d after blood feeding. Ambulatory dengue cases had lower viremia levels compared with hospitalized dengue cases but nonetheless at levels predicted to be infectious to mosquitoes. These data define serotype-specific viremia levels that vaccines or drugs must inhibit to prevent DENV transmission. PMID- 23674684 TI - Rapid feedback regulation of synaptic efficacy during high-frequency activity at the Drosophila larval neuromuscular junction. AB - High-frequency firing of neurons depresses transmitter release at many synapses. At the glutamatergic synapse of the Drosophila larval neuromuscular junction, we find that presynaptic depression is modulated by postsynaptic ionotropic glutamate receptor (iGluR) activity. Although basal release at low frequency was insensitive to postsynaptic iGluR activity, recovery from depression elicited by high-frequency presynaptic trains decreased with partial block of native iGluRs. Moreover, recovery from depression increased with optical activation of the light gated mammalian iGluR6 (LiGluR) expressed postsynaptically. The enhancement of recovery from depression occurred within 2 min of optical activation of LiGluR and persisted for minutes after optical deactivation. This effect depended on cAMP-dependent presynaptic recruitment of vesicles from the reserve pool. Our findings reveal a unique dimension to postsynaptic iGluR activity: fast retrograde signaling that preserves transmission efficacy during high-frequency presynaptic firing. PMID- 23674685 TI - Cross-validation in cryo-EM-based structural modeling. AB - Single-particle cryo-EM is a powerful approach to determine the structure of large macromolecules and assemblies thereof in many cases at subnanometer resolution. It has become popular to refine or flexibly fit atomic models into density maps derived from cryo-EM experiments. These density maps are typically significantly lower in resolution than electron density maps obtained from X-ray diffraction experiments, such that the number of parameters that need to be determined is much larger than the number of experimental observables. Overfitting and misinterpretation of the density, thus, become a serious problem. For diffraction data, a cross-validation approach was introduced almost 20 y ago; however, no such approach has been described yet for structure refinement against cryo-EM density maps, although the overfitting problem is, because of the lower resolution, significantly larger. We present a cross-validation approach for real space refinement against cryo-EM density maps in analogy to cross-validation typically used in crystallography. Our approach is able to detect overfitting and allows for optimizing the choice of restraints used in the refinement. The approach is shown on three protein structures with simulated data and experimental data of the rotavirus double-layer particle. Because cross validation requires splitting the dataset into at least two independent sets, we further present an approach to quantify correlations between the structure factor sets. This analysis is also helpful for other cross-validation applications, such as refinements against diffraction data or 3D reconstructions of cryo-EM density maps. PMID- 23674686 TI - Role of a polymorphism in a Hox/Pax-responsive enhancer in the evolution of the vertebrate spine. AB - Patterning of the vertebrate skeleton requires the coordinated activity of Hox genes. In particular, Hox10 proteins are essential to set the transition from thoracic to lumbar vertebrae because of their rib-repressing activity. In snakes, however, the thoracic region extends well into Hox10-expressing areas of the embryo, suggesting that these proteins are unable to block rib formation. Here, we show that this is not a result of the loss of rib-repressing properties by the snake proteins, but rather to a single base pair change in a Hox/Paired box (Pax) responsive enhancer, which prevents the binding of Hox proteins. This polymorphism is also found in Paenungulata, such as elephants and manatees, which have extended rib cages. In vivo, this modified enhancer failed to respond to Hox10 activity, supporting its role in the extension of rib cages. In contrast, the enhancer could still interact with Hoxb6 and Pax3 to promote rib formation. These results suggest that a polymorphism in the Hox/Pax-responsive enhancer may have played a role in the evolution of the vertebrate spine by differently modulating its response to rib-suppressing and rib-promoting Hox proteins. PMID- 23674687 TI - LYM2-dependent chitin perception limits molecular flux via plasmodesmata. AB - Chitin acts as a pathogen-associated molecular pattern from fungal pathogens whose perception triggers a range of defense responses. We show that LYSIN MOTIF DOMAIN-CONTAINING GLYCOSYLPHOSPHATIDYLINOSITOL-ANCHORED PROTEIN 2 (LYM2), the Arabidopsis homolog of a rice chitin receptor-like protein, mediates a reduction in molecular flux via plasmodesmata in the presence of chitin. For this response, lym2-1 mutants are insensitive to the presence of chitin, but not to the flagellin derivative flg22. Surprisingly, the chitin-recognition receptor CHITIN ELCITOR RECEPTOR KINASE 1 (CERK1) is not required for chitin-induced changes to plasmodesmata flux, suggesting that there are at least two chitin-activated response pathways in Arabidopsis and that LYM2 is not required for CERK1-mediated chitin-triggered defense responses, indicating that these pathways are independent. In accordance with a role in the regulation of intercellular flux, LYM2 is resident at the plasma membrane and is enriched at plasmodesmata. Chitin triggered regulation of molecular flux between cells is required for defense responses against the fungal pathogen Botrytis cinerea, and thus we conclude that the regulation of symplastic continuity and molecular flux between cells is a vital component of chitin-triggered immunity in Arabidopsis. PMID- 23674688 TI - Tissue plasminogen activator regulates Purkinje neuron development and survival. AB - The cerebellar cortex is centrally involved in motor coordination and learning, and its sole output is provided by Purkinje neurons (PNs). Growth of PN dendrites and their major synaptic input from granule cell parallel fiber axons takes place almost entirely in the first several postnatal weeks. PNs are more vulnerable to cell death than most other neurons, but the mechanisms remain unclear. We find that the homozygous nervous (nr) mutant mouse's 10-fold-increased cerebellar tissue plasminogen activator (tPA), a part of the tPA/plasmin proteolytic system, influences several different molecular mechanisms, each regulating a key aspect of postnatal PN development, followed by selective PN necrosis, as follows. (i) Excess endogenous or exogenous tPA inhibits dendritic growth in vivo and in vitro by activating protein kinase Cgamma and phosphorylation of microtubule-associated protein 2. (ii) tPA/plasmin proteolysis impairs parallel fiber-PN synaptogenesis by blocking brain-derived neurotrophic factor/tyrosine kinase receptor B signaling. (iii) Voltage-dependent anion channel 1 (a mitochondrial and plasma membrane protein) bound with kringle 5 (a peptide derived from the excess plasminogen) promotes pathological enlargement and rounding of PN mitochondria, reduces mitochondrial membrane potential, and damages plasma membranes. These abnormalities culminate in young nr PN necrosis that can be mimicked in wild-type PNs by exogenous tPA injection into cerebellum or prevented by endogenous tPA deletion in nr:tPA-knockout double mutants. In sum, excess tPA/plasmin, through separate downstream molecular mechanisms, regulates postnatal PN dendritogenesis, synaptogenesis, mitochondrial structure and function, and selective PN viability. PMID- 23674689 TI - Mutant presenilin 1 expression in excitatory neurons impairs enrichment-mediated phenotypes of adult hippocampal progenitor cells. AB - Inheritance of mutant presenilin 1 genes (PSEN1) encoding presenilin 1 (PS1)variants causes autosomal dominant forms of familial Alzheimer's disease (FAD). We previously reported that ubiquitous expression of FAD-linked PS1 variants in mice impairs environmental enrichment (EE)-induced proliferation and neuronal commitment of adult hippocampal neural progenitor cells (AHNPCs). Notably, the self-renewal and differentiation properties of cultured AHNPCs expressing either human PS1 wild-type or PS1 variants were identical, suggesting that accessory cells within the hippocampal niche expressing PS1 variants may modulate AHNPC phenotypes in vivo. We now report that nontransgenic mouse AHNPCs transduced with retroviruses harboring cDNAs that encode either human PS1 wild type or FAD-linked PS1 variants show no differences in EE-mediated proliferation and neuronal differentiation. Moreover, conditional inactivation of a mutant PS1 transgene in type-1 primary progenitor cells failed to rescue impairments of EE induced proliferation, survival, or neurogenesis. In contrast, conditional inactivation of the mutant PS1 transgene in excitatory neurons of the mouse forebrain largely rescued the deficits in EE-induced proliferation and survival of AHNPCs, but not their differentiation into mature neuronal phenotypes. These results persuasively argue for a noncell autonomous effect of FAD-linked PS1 mutants on EE-mediated adult hippocampal neurogenesis. PMID- 23674690 TI - End-binding proteins sensitize microtubules to the action of microtubule targeting agents. AB - Microtubule-targeting agents (MTAs) are widely used for treatment of cancer and other diseases, and a detailed understanding of the mechanism of their action is important for the development of improved microtubule-directed therapies. Although there is a large body of data on the interactions of different MTAs with purified tubulin and microtubules, much less is known about how the effects of MTAs are modulated by microtubule-associated proteins. Among the regulatory factors with a potential to have a strong impact on MTA activity are the microtubule plus end-tracking proteins, which control multiple aspects of microtubule dynamic instability. Here, we reconstituted microtubule dynamics in vitro to investigate the influence of end-binding proteins (EBs), the core components of the microtubule plus end-tracking protein machinery, on the effects that MTAs exert on microtubule plus-end growth. We found that EBs promote microtubule catastrophe induction in the presence of all MTAs tested. Analysis of microtubule growth times supported the view that catastrophes are microtubule age dependent. This analysis indicated that MTAs affect microtubule aging in multiple ways: destabilizing MTAs, such as colchicine and vinblastine, accelerate aging in an EB-dependent manner, whereas stabilizing MTAs, such as paclitaxel and peloruside A, induce not only catastrophes but also rescues and can reverse the aging process. PMID- 23674693 TI - A Dutch regional trauma registry: quality check of the registered data. AB - BACKGROUND: Quality indicators have become increasingly important in the healthcare sector. Data from a trauma registry (TR) should be accurate and reliable as they are used to describe and evaluate (the quality of) trauma care. OBJECTIVE: To investigate the reliability of injury coding, injury severity scoring and survival status in a regional TR. The feasibility of the format that was developed for this study was also investigated. METHODS: A random sample, without replacement, was taken from the TR of a Dutch regional trauma care network. All 343 patients in the sample were then recoded by another trauma registrar (rater). Reliability was expressed in the percentage agreement between the raters. RESULTS: In the total study sample of 333 patients, the reliability of the number of Abbreviated Injury Scale (AIS) codes was substantial (intraclass correlation coefficient (ICC)=0.70); and the reliability of the Injury Severity Score (ISS) (ICC=0.84) and survival status were 'almost perfect' (Cohen's kappa=0.82). Both raters had given 129 patients one AIS code. The reliability of the body region of the AIS was 'almost perfect' (Cohen's kappa=0.91); and the reliability of the severity of the injury and the ISS were 'almost perfect' (weighted kappa=0.88 and ICC=0.90). The reliability of the ISS in the patients who were assigned at least two AIS codes (n=128) was 'almost perfect' (ICC=0.86). The reliability of the number of AIS codes and the number of body regions was 'moderate' (ICC=0.56 and Cohen's kappa=0.52). CONCLUSIONS: The reliability of injury coding in a regional trauma registry was 'substantial' and the reliability of the ISS and survival status was 'almost perfect'. The format and design of this study were feasible and could be used to investigate the quality of (trauma) registries. PMID- 23674692 TI - The Patient-Reported Incident in Hospital Instrument (PRIH-I): assessments of data quality, test-retest reliability and hospital-level reliability. AB - BACKGROUND: The objective of this study was to test the data quality, test-retest reliability and hospital-level reliability of the Patient-Reported Incident in Hospital Instrument (PRIH-I). METHODS: 13 incident questions were included in a national patient-experience survey in Norway during the spring of 2011. All questions and a composite incident index were assessed by calculating missing item rates, test-retest reliability and hospital-level reliability. A multivariate linear regression on a global item regarding incorrect treatment was used to assess the main sources of variation in patient-perceived incorrect treatment at hospitals. RESULTS: Five of the 13 patient-incident questions had a missing-item rate of >20%. Only one item met the criterion of 0.7 for test-retest reliability (wrong or delayed diagnosis), seven items had a score of >0.5, while the remainder had a reliability score of <0.5. However, the reliability was >0.7 for six of 10 items tested at the hospital level, and >0.6 for the remaining four items. A patient-incident index based on 12 of the incident items had no missing data, the test-retest reliability was 0.6 and the hospital-level reliability was 0.85. CONCLUSIONS: The PRIH-I comprises 13 questions about patient-perceived incidents in hospitals, and can be easily and cost-effectively included in national patient-experience surveys with an acceptable increase in respondent burden. Although the missing-item rate and test-retest reliability were poor for several items, the hospital-level reliability was satisfactory for most of the items. The incident items contribute to a patient-reported incident index, with excellent data quality and hospital-level reliability. PMID- 23674691 TI - ADAM-10 and -17 regulate endometriotic cell migration via concerted ligand and receptor shedding feedback on kinase signaling. AB - A Disintegrin and Metalloproteinases (ADAMs) are the principal enzymes for shedding receptor tyrosine kinase (RTK) ectodomains and ligands from the cell surface. Multiple layers of activity regulation, feedback, and catalytic promiscuity impede our understanding of context-dependent ADAM "sheddase" function and our ability to predictably target that function in disease. This study uses combined measurement and computational modeling to examine how various growth factor environments influence sheddase activity and cell migration in the invasive disease of endometriosis. We find that ADAM-10 and -17 dynamically integrate numerous signaling pathways to direct cell motility. Data-driven modeling reveals that induced cell migration is a quantitative function of positive feedback through EGF ligand release and negative feedback through RTK shedding. Although sheddase inhibition prevents autocrine ligand shedding and resultant EGF receptor transactivation, it also leads to an accumulation of phosphorylated receptors (HER2, HER4, and MET) on the cell surface, which subsequently enhances Jnk/p38 signaling. Jnk/p38 inhibition reduces cell migration by blocking sheddase activity while additionally preventing the compensatory signaling from accumulated RTKs. In contrast, Mek inhibition reduces ADAM-10 and -17 activities but fails to inhibit compensatory signaling from accumulated RTKs, which actually enhances cell motility in some contexts. Thus, here we present a sheddase-based mechanism of rapidly acquired resistance to Mek inhibition through reduced RTK shedding that can be overcome with rationally directed combination inhibitor treatment. We investigate the clinical relevance of these findings using targeted proteomics of peritoneal fluid from endometriosis patients and find growth-factor-driven ADAM-10 activity and MET shedding are jointly dysregulated with disease. PMID- 23674694 TI - Organising a manuscript reporting quality improvement or patient safety research. AB - BACKGROUND: Peer-reviewed publication plays important roles in disseminating research findings, developing generalisable knowledge and garnering recognition for authors and institutions. Nonetheless, many bemoan the whole manuscript writing process, intimidated by the arbitrary and somewhat opaque conventions. METHODS: This paper offers practical advice about organising and writing a manuscript reporting quality improvement or patient safety research for submission to a peer-reviewed journal. RESULTS: Each section of the paper discusses a specific manuscript component-from title, abstract and each section of the manuscript body, through to reference list and tables and figures explaining key principles, offering content organisation tips and providing an example of how this section may read. The paper also offers a checklist of common mistakes to avoid in a manuscript. PMID- 23674695 TI - Picasso, professionalism and plastic surgery: why privileging the patient's perspective is a moral imperative. PMID- 23674696 TI - Public confessions of a sinner: a healthy take on obesity? PMID- 23674697 TI - Therapeutic acts of witness: why writing poetry and prose has never been just for patients. PMID- 23674698 TI - Existential boredom: the experience of living on haemodialysis therapy. AB - Empathy is an essential component of professional nursing practice. In order to empathise appropriately with patients, it is crucial that nurses appreciate, understand and respond to their patients' experience of illness. This study sought to explore the experiences of 16 people with end stage renal disease on haemodialysis therapy in Ireland. A hermeneutical phenomenological methodology was employed incorporating qualitative interviews. The data were analysed using qualitative interpretive analysis. The experience of waiting was significant for the participants in the study. The experience of waiting was constituted by two themes labelled killing time and wasting time. It is suggested that the participants' experience of waiting is reminiscent of Heidegger's existential account of boredom. Moreover, the existential perspective of boredom contained within the participants' accounts is also depicted by Beckett in his play Waiting for Godot. Consequently, the literature of both existential writers is incorporated to provide a more in-depth description of the participants' experience of waiting. It is hoped that the insights provided in this paper will enable practitioners to gain a new awareness and understanding of patients' experiences of end stage renal disease and haemodialysis therapy. This would subsequently enable these professionals to empathise more effectively with their patients' situation and respond more appropriately to their care needs. PMID- 23674699 TI - Confessions of the flesh and biopedagogies: discursive constructions of obesity on Nip/Tuck. AB - Informed by the work of Michel Foucault, the authors discuss the Nip/Tuck episode entitled "Momma Boone" and how it discursively constructs "obesity". They show how this popular media text can be understood as a crystallisation of the dominant discourse surrounding fat bodies. In the process, how the episode can be seen as a "biopedagogy" that instructs its viewers in how to think and feel about the fat body is examined. Foucault's formulation of the confessional is seen to be useful to theorise the ways in which biopedagogy leads subjects to believe and ultimately take part in processes leading to salvation. It is argued that in this Nip/Tuck episode, biopedagogy functions in and through Momma Boone's "confessions of the flesh", that is, confessions aimed at revealing her obese body so that it can be rescued, rehabilitated and saved. Momma Boone's salvation is shown to require three stages: first, the "confession" of obesity; second, the conversion to the "truth" of the "dominant obesity discourse"; and third, the codification of a "new life" for the obese subject. In the end, it is argued that since it is represented as abject, monstrous and out of control, Momma Boone's body is made to inspire fear and panic in so far as it provides constructed "evidence" regarding the consequences of the obese subject's failure to convert to the truth of obesity discourse. PMID- 23674700 TI - A time like all others. PMID- 23674701 TI - Finding a voice: revisiting the history of therapeutic writing. AB - We review the history of therapeutic writing, focusing on the role of narrative competence and the use of writing therapy for stress, trauma and coping with chronic illness. After providing a historical overview of the evidence for writing's positive effects on health and the hypothesised mechanisms underlying this effect, we ask whether narrative competence can explain and improve writing's benefit. Narrative competence is defined across two dimensions: (1) Emplotment, or the ability to construct and comprehend goal-oriented connections among temporally situated events; and (2) Meaning, or the ability to understand and communicate contextual interpretations of ambiguous story structures. We suggest that the ability to construct well-organised and meaningful narratives is an important skill for successfully coping with life stressors and trauma, enabling individuals to create coherent stories from fractured memories and to facilitate cognitive processing of traumatic events. Given the positive effect of narrative competence on psycho-physical health, there is a need to broaden medical use of narrative competence therapies beyond the current interventions aimed at fostering empathy among healthcare providers, to include therapies for the patients themselves. Toward this end, we briefly explore one clinical model currently offered by Dr Allan Peterkin and colleagues at Mount Sinai Hospital providing group Narrative Competence Psychotherapy (NCP) for individuals living with HIV. PMID- 23674702 TI - Glancing light: three prose poems. PMID- 23674703 TI - Picasso's bodies: representations of modern society? AB - During the course of a long artistic career, the work of Pablo Picasso (1881 1973) passed through a number of stages. This article concentrates on his representation of the human body prior to the First World War. Three paintings are used to illustrate the transition from social realism to the Blue period and Cubism: Science and Charity (1897); Tragedy (1903); and Seated Nude (1909/10). They are interpreted through the lens of Arthur C Danto's concept of the "art world", which subsequent theorists have elaborated to capture the historical context as well as the aesthetic form and biographical detail that preoccupied traditional critics. Therefore, the analysis not only embraces colour, perspective and significant events in Picasso's life but also early 20th century politics and ideology, science and medicine. In this way, the synergies that exist between cultural artefacts and the body are demonstrated, and the interdisciplinary understanding of health and healthcare that medical humanities promote is endorsed. PMID- 23674704 TI - Performing the good death: the medieval Ars moriendi and contemporary doctors. AB - Death is inevitable, but dying well is not. Despite the role of medical professionals as overseers of dying in contemporary society, there is comparatively little discourse among doctors about the constituents of a good death. In the 15th century, by contrast, the Ars moriendi portrayed normative medieval ideas about good and bad deaths. At a time when dying could be viewed as a performed battle against damnation, the Ars moriendi codified a set of moral precepts that governed the expression of autonomy, relations between the dying and the living and orientation towards God. In these images, dying well is a moral activity that results from active decisions by the dying person to turn from earthly preoccupations to contemplation of, and submission to, the divine. It is likely in contemporary society that there is a range of understandings of the "good death". While attitudes to personal autonomy may differ, reflectiveness and dying at home in the presence of family (expressed in the Ars moriendi), remain part of many modern notions of the good death. We argue that medical institutions continue to construct death as a performed battle against physical debility, even when patients may have different views of their preferred deaths. The dialectic approach of the Ars moriendi may offer a way for contemporary doctors to reflect critically on the potential dissonance between their own approach to death and the variety of culturally valorised "good deaths". PMID- 23674705 TI - Jane Austen and Addison's disease: an unconvincing diagnosis. AB - Jane Austen's letters describe a two-year deterioration into bed-ridden exhaustion, with unusual colouring, bilious attacks and rheumatic pains. In 1964, Zachary Cope postulated tubercular Addison's to explain her symptoms and her relatively pain-free illness. Literary scholars later countered this posthumous diagnosis on grounds that are not well substantiated, while medical authors supported his conclusion. Important symptoms reported by contemporary Addison's patients-mental confusion, generalised pain and suffering, weight loss and anorexia-are absent from Jane Austen's letters. Thus, by listening to the patient's perspective, we can conclude it is unlikely that Addison's disease caused Jane Austen's demise. Disseminated bovine tuberculosis would offer a coherent explanation for her symptoms, so that Cope's original suggestion of infective tuberculosis as the cause of her illness may have been correct. PMID- 23674706 TI - What training do artists need to work in healthcare settings? AB - Given the increased attention paid to the development of arts in healthcare settings, the need for a formalised training framework to enable artists to work comfortably and safely in healthcare settings has become pressing. This paper sets out a review of literature and best practice regarding the training of professional artists wishing to work in healthcare settings. The authors' research confirms the gap in the arts sector with regard to such training. Very little formal training is currently available internationally for artists wishing to work in healthcare settings outside of the arts therapies professions. There is a need for the health sector to formalise a currently ad hoc approach to employing artists in healthcare settings. There are a number of best-practice models of arts and health practice from which we can learn but relatively scant literature on course development. The arts therapies are relatively expert in the domain of using the arts in healthcare and while there are different aims and intentions to this work, it is important that any establishment of arts and health training recognises the contribution and expertise of arts therapists in the healthcare arena. A culture of mutual learning between the arts therapies and the arts and health specialists is recommended. PMID- 23674708 TI - Hospital time. PMID- 23674707 TI - Opera and madness: Britten's Peter Grimes--a case study. AB - In this paper, Britten's opera Peter Grimes (1945) is used as an illustrative case study through which to examine the depiction of psychiatric disorders in opera. It is argued that Peter Grimes is a powerful example of how opera, in the hands of a great composer, can become an invaluable tool for examining subjective human experience. After a brief discussion of opera as a vehicle to express emotions, various operas are drawn upon to provide a historical perspective and to demonstrate the long interconnection existing between opera and madness. An in depth analysis of Peter Grimes, its background and central character, is then provided, in order to demonstrate how opera can elicit empathy for individuals affected by mental health problems. PMID- 23674709 TI - Challenges to UK community pharmacy: a bio-photographic study of workspace in relation to professional pharmacy practice. AB - This paper presents a novel, qualitative, bio-photographic study with intertextual analysis highlighting the relationship between community pharmacy workspace and practice. Sixteen pharmacists working across pharmacy types such as independent shops, large and small pharmacy chains and multiple pharmacies such as those in supermarkets participated in data capture and feedback consultation. Findings disclosed workspaces unfit for purpose and a workforce ill at ease with their new professional identity, involving increasingly complex tasks in health provision and retail. There was conflict between delegating to others and taking personal responsibility, and there were pressures from a demanding public within the context of a target-driven, litigious society. The study highlights that innovative, mixed methods in this context reveal nuanced, rich data. PMID- 23674710 TI - An immigrant's story. PMID- 23674711 TI - Using art and literature as educational resources in palliative care. AB - This case study outlines a staff seminar programme that used art and literature as vehicles to explore personal and professional dimensions of palliative care. Participating staff found the learning experience interesting and insightful. PMID- 23674712 TI - Using paintings to explore the medical humanities in a Nepalese medical school. PMID- 23674713 TI - Direct red: a surgeon's story. PMID- 23674714 TI - Cutting for stone. PMID- 23674716 TI - The body and the arts. PMID- 23674715 TI - Blue pills: a positive love story. PMID- 23674717 TI - The growth of British sex education films: negotiating what we shouldn't know. PMID- 23674718 TI - Nurse edith cavell. PMID- 23674719 TI - Exploitation, akrasia, and Goldilocks: how many pounds for flesh for medical uses? AB - Modest reforms to the present system of the giving of body parts for therapy and research are being put on the table (for example, by the Nuffield Council on Bioethics and the Human Fertilisation and Embryology Authority). These potentially presage a move to a system where (greater) material incentives could be offered in the future (and this is certainly how such initial reforms will be perceived by objectors). At present, however, the diverse rationales for constraints on both payments being offered in themselves, and to specific levels of payments, are both confused and consistently conflated. Greater clarity in the application of both concepts and terminology will provide a sounder foundation for deliberation of potential reforms in areas where demand is pressing and substantial suffering very real. PMID- 23674720 TI - Use of NP-59 SPECT/CT imaging in atypical primary aldosteronism. PMID- 23674721 TI - Diagnostic 20-min whole blood clotting test in Russell's viper envenoming delays antivenom administration. AB - BACKGROUND: The 20-min whole blood clotting test (WBCT20) is widely used for the identification of coagulopathy in snake envenoming, but its performance in practice has not been evaluated. AIM: We aimed to investigate the diagnostic utility of the WBCT20 for coagulopathy in Russell's viper envenoming. DESIGN: Prospective observational study. METHODS: Adult patients with snake envenoming were recruited. Age, sex, bite information, clinical effects, serial WBCT20 and antivenom treatment were recorded. Definite Russell's viper envenoming was confirmed with venom specific enzyme immunoassay. We assessed sensitivity of admission WBCT20 to coagulopathy (international normalized ratio, INR > 1.5) in Russell's viper envenoming, the specificity of negative WBCT20 in non-envenomed patients and directly compared paired WBCT20 and INR. RESULTS: Admission WBCT20 was done in 140 Russell's viper bites with coagulopathy and was positive in 56/140 [sensitivity 40% (95% confidence interval (CI): 32-49%)]. A negative WBCT20 led to delayed antivenom administration [WBCT20-ve tests: median delay, 1.78 h (interquartile range (IQR): 0.83-3.7 h) vs. WBCT20 + ve tests: median delay, 0.82 h (IQR: 0.58-1.48 h); P = 0.0007]. Delays to antivenom were largely a consequence of further WBCT20 being performed and more common if the first test was negative (41/84 vs. 12/56). Initial WBCT20 was negative in 9 non-envenomed patients and 48 non-venomous snakebites [specificity: 100% (95% CI: 94-100%)]. In 221 paired tests with INR > 1.5, the WBCT20 was positive in 91(41%). The proportion of positive WBCT20 only increased slightly with higher INR. CONCLUSION: In clinical practice, the WBCT20 has low sensitivity for detecting coagulopathy in snake envenoming and should not over-ride clinical assessment based decisions about antivenom administration. There is an urgent need to develop a simple bedside test for coagulopathy in snake envenoming. PMID- 23674722 TI - Unusual huge erythema annulare centrifugum presentation of second syphilis. PMID- 23674723 TI - eComment. Is the sternal closure technique using titanium hooks and wires cost effective? PMID- 23674724 TI - eComment. Multiple approaches for sternal dehiscence. PMID- 23674725 TI - eComment. Extended utilization of axillary cannulation as arterial access for cardiopulmonary bypass. PMID- 23674726 TI - eComment. Coronary anastomosis simulation: assessing surgical dexterity. PMID- 23674727 TI - eComment. The impact of blood conservation on outcomes in adult cardiac surgery. PMID- 23674728 TI - eComment. Is retrograde autologous priming effective on cerebral functions and haematocrit levels? PMID- 23674730 TI - eComment. The definition of neuroendocrine tumour and sublobar resection. PMID- 23674731 TI - eComment. Surgical management of carcinoid tumours of the lung: sublobar resection versus lobectomy. PMID- 23674732 TI - eComment. Pectus excavatum surgical repair improves cardiopulmonary function in adults. PMID- 23674733 TI - eComment. Aorto-right atrial fistula in type A aortic dissection. PMID- 23674734 TI - eComment. Fistulous complications of acute dissection of the ascending aorta. PMID- 23674735 TI - eComment. Endovascular ascending aortic aneurysm repair: an effective alternative to open repair? PMID- 23674736 TI - Commentary: 'On the cards': collective investigation of disease and medical life histories in the nineteenth century. PMID- 23674738 TI - Dr Bruno Sachs addresses an audience of first year medical students: an extract from the writing of Martin Winckler, French doctor and writer. AB - One of the authors of this paper (DJ) has been impressed by the work of the second author (MW) for some time. On reading one of his works, Les Trois Medecins, DJ was so struck by a particular passage that he attempted a translation. He received not only permission from Winckler to seek publication but also help with the translation. Along with that translation, which forms the body of this article, the passage has been set in context by MW, who also provides some explanation of it. It is DJ's hope that the article will prove stimulating in its own right, and also lead some readers at least to seek out more of Winckler's work. PMID- 23674739 TI - "I am living in my own corpse"--the experience of tuberculosis in poems by A B Simic. AB - This paper focuses on seven poems dealing with various aspects of his experience of tuberculosis and uncovers different shades of poetic self within his verses: the notions of self transforming from a helpless child to a ghostly, transparent creature in the secluded world of a hospital ward, and to decaying flesh and "living in a cadaver" are pinpointed. Poetry as creation is the opposite of physical demise; in poetry Simic finds escape not from the inevitable end, but from suffering. These poems are not confessions of a sick young man; they are relevant works of art touching readers' sensitivity and imagination. They may be relevant for medical professionals in enabling them to view disease-in this case tuberculosis-in a wider context and to be open to the many and different ways in which the experience of illness can be expressed. PMID- 23674740 TI - Sickness, healing, and opera: Wagner's Parsifal. AB - Richard Wagner's opera Parsifal is examined as a study in illness, pain and healing. Wagner's intention was to communicate directly to the audience the "emotional content" of the suffering of the character Amfortas. This presentation of suffering allows us to take from the opera some general ideas about the nature of illness and healing and their metaphorical representation in art. Further insights can be gained from the genre of classical tragic drama, of which Parsifal is a modern example. PMID- 23674741 TI - Some perspectives on Chekhov's short story A Case History. AB - The Russian writer and physician Anton Chekhov (1860-1904) draws on his clinical experience in many of his stories. One of his later masterpieces entitled A Case History (1898) depicts a physician's visit to a small industrial community where a wealthy young woman is suffering from diffuse symptoms. The physician, Dr Koryolov, meets the patient and makes a diagnosis. While staying on the estate overnight he also analyses the patient's relation to her living conditions. PMID- 23674742 TI - Creativity, self creation, and the treatment of mental illness. AB - This paper examines how an understanding of systematic findings about creative processes involved in art, literature, and science can be applied to the effective treatment of mental illness. These findings and applications are illustrated by particular reference to the work of the poet Sylvia Plath and the treatment of a patient who aspired to become a writer. PMID- 23674743 TI - Motherhood versus patienthood: a conflict of identities. AB - This paper examines a thread that runs through my memoir of illness: the "shock" of becoming a patient and finding that this new identity, "patienthood", conflicts with the specific, culturally defined role of mother that I idealise as "motherhood". I have taken four excerpts from my memoir and discuss them in relation to the way I constructed my intersectional and conflicting identities as mother and patient, both during the initial phase of my illness and in the act of writing about them afterwards. My conclusions echo those of many theorists: while there may be no elusive core self, we are each made up of many identities, many stories, all provisional on factors such as ethnicity, gender, or race, and all in a state of continuous flux in response to changing contexts over time. Furthermore, our identities are often shaped by, and are also shaping, that ethical question: how to lead the "good life". It is all these dimensions that constitute the richness of individual "selfhood". PMID- 23674744 TI - Body and self: a phenomenological study on the ageing body and identity. AB - The aim of the study was to investigate how older people (60+) experience the ageing body and how these experiences affect aged peoples' sense of identity. Explorative, open ended, interviews were conducted with 13 respondents between the ages of 63 and 82, recruited from a retired peoples' organisation, Church organisations, and from the working population. The qualitative data was analysed with a phenomenological method, the so called EPP method, the empirical phenomenological psychological method. The results showed that generally the experience of the ageing body has to do with a changed life world, reactions to this change in terms of body and self, and finding ways to feel at home in this changed situation. Results are presented as three typologies, reflecting the different ways in which the respondents described this general experience: existential awakening, making it good enough, and new possibilities. The results give support to the research that points out the importance of activity for the self esteem of the elderly. According to this study, however, the meaning of "activity" can vary and can have different sources of motivation. Respondents in only one typology expressed frustration over limitations of the ageing body. Respondents exhibited entirely different ways of relating to the fact that death was approaching, which raises questions about how the elderly experience this impending horizon. Finally, the gender differences in this small study were quite clear: all the male respondents belonged to the typology "New possibilities", raising questions about gender aspects concerning the meaning of freedom, appearance, activity, and self esteem. PMID- 23674746 TI - Mister doctor batley. PMID- 23674745 TI - Stories for change. PMID- 23674747 TI - Going to the DOCS. PMID- 23674748 TI - The voyage. PMID- 23674749 TI - Being the monster: women's narratives of body and self after treatment for breast cancer. AB - Serious illness and its treatment frequently changes a woman's sense of herself and her body. Narrative medicine posits that individuals permitted to tell their stories regain control over the plotline of the illness, reclaim the central role as protagonist, and thus diminish the sense of helplessness, marginalisation, and isolation that are inevitable aspects of serious disease. The women presented here speak about losses that occur during treatment for advanced cancer. These losses include: loss of the former body; loss of one or both breasts; loss of hair; loss of fertility, and changes in weight, energy, and sexuality. This paper will not review the medical literature on the psychological aspects of change in appearance secondary to disease and/or treatment. As a way of broadening our understanding of what women attempt to communicate to their care providers about who they are and who they are becoming through the experience of illness, this paper will present brief excerpts from the interviews of four women talking about issues of identity and bodily change, using concepts of feminine identity developed by the French psychoanalytic theorist Helene Cixous in her essay, The laugh of the Medusa. PMID- 23674750 TI - "Stepford doctors": an allegory. AB - The Stepford Wives, a novel by Ira Levin, provides the theme for this allegory. The men of Stepford belong to the Men's Association. Their wives are "perfect", in that they do nothing other than clean, cook, preen, and provide satisfaction without argument for their husbands. They are, furthermore, content with their lot, and believe that their previous interests and freedoms were self indulgent. Levin never informs his readers how the men came to obtain total mastery over their "Stepford wives", although there is the suggestion that the real wives have been replaced by robotic lookalikes. PMID- 23674751 TI - Evaluating a poetry workshop in medical education. AB - This study aimed at evaluating how doing poetry could affect students' understanding of medical practice and at assessing the effectiveness of the evaluation method used. Qualitative research was carried out on the experiences of medical students participating in a poetry workshop, followed by some quantitative analysis. The study was conducted at Peninsula Medical School and St Ives, Cornwall, UK, with three medical students, a poet and a pathologist as participants. Data were collected by interviews, observation and web access. "Doing poetry" with a professional poet was found to assist communication between doctors and patients as it enhanced skills of observation, heightened awareness of the effect of language and fostered deep reflection. Poetry was also found to offer an outlet for medics and patients. The voluntary workshop attracted three participants; however, it might have had an effect on the wider student community because the poetry website received 493 hits in four months. Qualitative methods worked well as a tool for evaluation. "Doing poetry for poetry's sake" seemed to foster the development of skills related to empathy. The opportunity to do poetry should be made available to medical students as part of a wider arts and humanities programme. PMID- 23674752 TI - Mycologic catastrophe. PMID- 23674753 TI - What types of Candida infections should be included when evaluating breakthrough infections during posaconazole prophylaxis? PMID- 23674754 TI - Reply to "What types of Candida infections should be included when evaluating breakthrough infections during posaconazole prophylaxis?". PMID- 23674756 TI - Foreign body reaction in glaucoma drainage implant surgery. AB - PURPOSE: To investigate the histopathology of the foreign body reaction (FBR) and the effect of aqueous humor on it in glaucoma drainage implant surgery. METHODS: A glaucoma drainage device was implanted into 20 New Zealand white rabbits. We monitored the histopathology of blebs at microscopic levels from 3 days to 8 weeks postoperatively. Hematoxylin and eosin staining, Masson's trichrome staining, anti-actin and alpha-smooth muscle immunofluorescence staining, and antiproliferating cell nuclear antigen immunohistochemistry were performed. To observe effects of aqueous humor on FBR, we designed two implant models. One group received a plate with a tube placed in the anterior chamber (experimental group), whereas the other received the plate cut from the tube (control group). RESULTS: Foreign body giant cells were found along the inner border of blebs, and the innermost layer of blebs demonstrated a densely packed collagenous stratum in both groups. The number of foreign body giant cells was suppressed in the experimental group compared with the control group (P < 0.001). Fibroblast division was more active in the experimental group than that in the control group. Masson's trichrome staining demonstrated that the innermost avascular collagenous layer was much thicker in the experimental group than that in the control group (P = 0.021). The extent of alpha-SMA staining was greater in the experimental group than that in the control group. CONCLUSIONS: In the aqueous humor environment, wound healing around a glaucoma drainage implant revealed a unique FBR with the relatively small number of foreign body giant cells and reinforced fibrotic encapsulation. PMID- 23674758 TI - Analysis of saccades and peak velocity to symmetrical convergence stimuli: binocularly normal controls compared to convergence insufficiency patients. AB - PURPOSE: To assess the potential peak velocity asymmetry between the left-eye and right-eye movement responses stimulated by symmetrical vergence steps in those with normal binocular vision and those with convergence insufficiency (CI) before and after vergence training. This study also evaluated whether vergence training influenced convergence peak velocity and the prevalence of saccades within the first second of the response. METHODS: The peak velocities of the left-eye, right eye, and combined vergence response evoked from symmetrical 2 degrees , 4 degrees , and 6 degrees convergence step stimuli were assessed in 10 controls and 7 CI subjects. Four of the CI subjects participated in vergence training. An asymmetry ratio was calculated as the peak velocity of the slower eye movement response divided by the peak velocity of the faster eye movement response. RESULTS: Controls were significantly more symmetrical (left-eye peak velocity was approximately equal to right-eye peak velocity) compared to CI subjects (P < 0.001). After vergence training, the CI subjects' left-eye and right-eye movements became significantly more symmetrical, convergence peak velocity increased, and the prevalence of saccades within the first 1 second decreased (P < 0.01). Peak convergence velocity was significantly correlated to the prevalence of saccades observed within the first second of the response (r = 0.8; P < 0.05). CONCLUSIONS: Data suggest that vergence training improves the symmetry between the left-eye and right-eye movements, increases convergence peak velocity, and decreases the prevalence of saccades within the first second of the response, which facilitates binocular coordination in CI patients. Saccades may be a compensatory mechanism used by CI subjects when convergence peak velocity is reduced. PMID- 23674757 TI - STAT3 activates miR-155 in Th17 cells and acts in concert to promote experimental autoimmune uveitis. AB - PURPOSE: MicroRNA-155 (miR-155) and STAT3 are implicated in uveitis and pathogenic mechanisms of CNS autoimmune diseases. In our study, we used miR-155( /-) mice and mice with targeted STAT3 deletion in T cells (CD4-STAT3KO) to investigate roles of miR-155 and STAT3 in the development of experimental autoimmune uveitis (EAU), a mouse model of human uveitis. METHODS: We induced EAU in WT, miR-155(-/-), or CD4-STAT3KO mice by immunization with interphotoreceptor retinoid-binding protein/complete Freund's adjuvant (IRBP/CFA) or adoptive transfer of T cells. EAU was assessed by funduscopy and histology. RNA expression was analyzed by quantitative PCR (qPCR), while cytokine production was assessed by fluorescence-activated cell sorting (FACS). RESULTS: We used a combination of genomic and genetic tools to provide the first evidence that STAT3 binds directly to the miR-155 locus and that STAT3 is required for miR-155 expression. Furthermore, STAT3-dependent increase in miR-155 expression in vivo correlated temporally with onset of EAU, and miR-155(-/-) or CD4-STAT3KO mice did not suffer EAU. CD4(+) lymph node cells from IRBP-immunized WT mice transferred EAU to naive wild-type (WT) and miR-155(-/-) mice, while miR-155(-/-) IRBP-specific T cells did not. CONCLUSIONS: Although miR-155 and STAT3 have been implicated in the etiology of multiple sclerosis (MS), uveitis, or rheumatoid arthritis, their exact roles in these diseases are unclear. We show here for the first time to our knowledge that STAT3 regulates miR-155 expression in Th17 cells. We show further that STAT3 and miR-155 form an axis that promotes the expansion of pathogenic Th17 cells that mediate uveitis. Thus, STAT3 and miR-155 may be therapeutic targets for treating uveitis and other Th17-mediated inflammatory disorders. PMID- 23674759 TI - Analysis of ethanol effects on corneal epithelium. AB - PURPOSE: Ethanol is widely used in ocular surface surgeries and for the treatment of corneal diseases. However, ethanol is a toxic agent that is related to the development of a number of alcohol-related diseases. Despite the common use of ethanol for therapeutic purposes in ophthalmology, effects of ethanol on the ocular surface have been poorly defined. Hence, we performed this study to investigate effects of ethanol on corneal epithelium from various aspects. METHODS: We exposed corneal epithelial cells in culture to different concentrations of ethanol for 30 seconds and evaluated the cells for toxicity, survival, and expression of cell-specific markers and inflammatory cytokines at 24, 48, and 72 hours after ethanol exposure. RESULTS: We found that ethanol markedly decreased the viability of cells in a concentration-dependent manner by causing cell lysis, suppressing proliferation, and inducing apoptosis. Also, expression of corneal epithelial cell-specific markers, both stem cell and differentiation markers, was significantly reduced by ethanol exposure. Expression of proinflammatory cytokines and chemokines was highly increased in corneal epithelial and stromal cells that were exposed to ethanol. CONCLUSIONS: Together, data suggest that brief exposure of the corneal surface to ethanol may have long-term effects by disrupting the integrity of corneal epithelium and generating inflammation, both of which are precursors to a number of ocular surface diseases. PMID- 23674760 TI - Levels of erythropoietin and vascular endothelial growth factor in surgery required advanced neovascular glaucoma eyes before and after intravitreal injection of bevacizumab. AB - PURPOSE: To evaluate changes of levels of erythropoietin (EPO) and VEGF in aqueous humor before and after an intravitreal injection of bevacizumab (IVB) and determine the underlying correlation between them. METHODS: This prospective study involved 21 eyes of 21 patients with surgery-required advanced neovascular glaucoma (NVG) and 20 control subjects from October 2011 through November 2012. The NVG eyes received the IVB treatment before antiglaucomatous surgery. Aqueous humor was collected at the time of the IVB injection (pre-IVB) and at the time of antiglaucomatous surgery (post-IVB). Aqueous humor and plasma VEGF and EPO levels were measured with ELISA and chemiluminescence methods, respectively. RESULTS: The mean aqueous humor EPO and VEGF concentrations in pre-ivb eyes were significantly higher than those of the control subjects (p 0.001), whereas plasma levels showed no significant difference. There was a statistically significant correlation between the aqueous humor epo and the VEGF concentration (R = 0.612; P = 0.003). The mean aqueous humor VEGF in post-ivb eyes dramatically decreased from 1704.83 757.82 TO 19.02 14.65 PG/ML (P 0.001). However, EPO remained almost the same: 326.60 +/- 104.28 compared with 312.67 +/- 103.23 mU/mL (P = 0.675). CONCLUSIONS: The NVG eyes showed high aqueous EPO and VEGF levels, and there was a positive correlation between them. However, levels of EPO did not change after post-IVB, whereas those of VEGF decreased. PMID- 23674761 TI - Haplogroup heterogeneity of LHON patients carrying the m.14484T>C mutation in India. AB - PURPOSE: To investigate the clinical and mitochondrial DNA (mtDNA) haplogroup background of Indian Leber hereditary optic neuropathy (LHON) patients carrying the m.14484T>C mutation. METHODS: Detailed clinical investigation and complete mtDNA sequencing analysis was carried out for eight Indian LHON families with the m.14484T>C mutation. Haplogroup was constructed based on the evolutionarily important mtDNA variants. RESULTS: In the present study, we characterized eight unrelated probands selected from 187 LHON cases. The overall penetrance of the disease was estimated to be 19.75% (16/81) in eight pedigrees with the m.14484T>C mutation and showed substantially higher sex bias (male: female = 13:3). The mtDNA haplogrouping revealed that they belong to diverse haplogroups; i.e., F1c1, M31a, U2a, M*, I1, M6, M3a1, and R30a. Interestingly, we did not find an association of the m.14484T>C mutation with any specific haplogroup within the Indian population. We also did not find any secondary mutation(s) in these pedigrees, which might affect the clinical expression of LHON. CONCLUSIONS: Contrary to earlier reports showing preferential association of the m.14484T>C mutation with western Eurasian haplogroup J and increased clinical penetrance when present in J1 subhaplogroup background, the present study shows that m.14484T>C arose independently in a different mtDNA haplogroup and ethnic background in India, which may influence the clinical expression of the disease. PMID- 23674763 TI - Spread of NDM-2-producing Acinetobacter baumannii in the Middle East. PMID- 23674762 TI - Travel-associated faecal colonization with ESBL-producing Enterobacteriaceae: incidence and risk factors. AB - OBJECTIVES: To study the acquisition of extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBL-PE) among the faecal flora during travel, with a focus on risk factors, antibiotic susceptibility and ESBL-encoding genes. METHODS: An observational prospective multicentre cohort study of individuals attending vaccination clinics in south-east Sweden was performed, in which the submission of faecal samples and questionnaires before and after travelling outside Scandinavia was requested. Faecal samples were screened for ESBL-PE by culturing on ChromID ESBL and an in-house method. ESBL-PE was confirmed by phenotypic and genotypic methods. Susceptibility testing was performed with the Etest. Individuals who acquired ESBL-PE during travel (travel-associated carriers) were compared with non-carriers regarding risk factors, and unadjusted and adjusted ORs after manual stepwise elimination were calculated using logistic regression. RESULTS: Of 262 enrolled individuals, 2.4% were colonized before travel. Among 226 evaluable participants, ESBL-PE was detected in the post-travel samples from 68 (30%) travellers. The most important risk factor in the final model was the geographic area visited: Indian subcontinent (OR 24.8, P < 0.001), Asia (OR 8.63, P < 0.001) and Africa north of the equator (OR 4.94, P = 0.002). Age and gastrointestinal symptoms also affected the risk significantly. Multiresistance was seen in 77 (66%) of the ESBL-PE isolates, predominantly a combination of reduced susceptibility to third-generation cephalosporins, trimethoprim/sulfamethoxazole and aminoglycosides. The most common species and ESBL-encoding gene were Escherichia coli (90%) and CTX-M (73%), respectively. CONCLUSION: Acquisition of multiresistant ESBL-PE among the faecal flora during international travel is common. The geographical area visited has the highest impact on ESBL-PE acquisition. PMID- 23674764 TI - Characterization of methicillin-resistant Staphylococcus spp. carrying the mecC gene, isolated from wildlife. AB - OBJECTIVES: A recently identified mecA homologue, mecC, in methicillin-resistant Staphylococcus aureus (MRSA) has been isolated from humans and different animal hosts. The aim of this study was to determine antimicrobial resistance and provide molecular characterization of MRSA and methicillin-resistant non Staphylococcus aureus staphylococci (MRnSA) isolated from wildlife that carried the gene mecC. METHODS: Five S. aureus and one coagulase-negative Staphylococcus isolate displaying phenotypic oxacillin resistance, but not recognized with conventional PCR for mecA, were further characterized by a polyphasic approach. The presence of mecC in all isolates was determined using specific PCR. PCR targeting Panton-Valentine leucocidin (PVL) genes of MRSA was performed. MRSA isolates were genotyped by spa typing and multilocus sequence typing. All isolates were genotyped by staphylococcal cassette chromosome mec (SCCmec) typing. 16S rDNA sequence analysis for MRnSA identification was performed. Antimicrobial susceptibility testing was performed for all isolates. RESULTS: All five MRSA isolates contained the mecC gene, were PVL negative, carried SCCmec type XI and belonged to ST130 (where ST stands for sequence type), with spa types t843, t10513 or t3256, or to ST2620, with spa type t4335. The MRnSA isolate, most closely related to Staphylococcus stepanovicii, carried mecA and blaZ genes related to SCCmec XI. MRSA isolates exhibited resistance to the beta-lactams only. CONCLUSIONS: The MRSA isolates described in this study represent the first detection of mecC-positive MRSA in a European otter (Lutra lutra) and a European brown hare (Lepus europaeus). The MRnSA isolate represents the first isolation of MRnSA from a Eurasian lynx (Lynx lynx). PMID- 23674765 TI - Presence of beta-lactamases in extended-spectrum-cephalosporin-resistant Salmonella enterica of 30 different serovars in Germany 2005-11. AB - OBJECTIVES: Between 20 000 and 35 000 cases of salmonellosis are detected annually in Germany, but only a few Salmonella are resistant to third-generation cephalosporins. The German National Reference Centre for Salmonella and other Enterics obtained 150 Salmonella enterica isolates from human infections between 2005 and 2011. In the present study we identified the beta-lactamase genes causing resistance to third-generation cephalosporins in these isolates. METHODS: For all isolates serotyping and antimicrobial susceptibility testing were performed. The presence of beta-lactamase genes was detected by PCR amplification and sequencing. Isolates with identical serovar and beta-lactamase genes were typed by XbaI macrorestriction followed by PFGE. Broth mate conjugation assays and plasmid analysis using S1 nuclease restriction of genomic DNA and subsequent PFGE as well as PCR-based replicon typing were performed for selected isolates. RESULTS: The 150 isolates were assigned to 30 different serovars, with S. enterica serovar Typhimurium (n = 73; 48.7%) as the most prevalent. Two different AmpC beta-lactamase genes (blaCMY-2, n = 8; blaACC-1, n = 6) and various extended spectrum beta-lactamase (ESBL) genes were identified. The majority harboured the blaCTX-M-1 gene (n = 91; 60.7%) followed by blaCTX-M-14 (n = 12; 8.0%) and blaSHV 12 (n = 11; 7.3%). Typing of strains and subsequent comparison with selected Salmonella isolates from livestock revealed the presence of several clones in both humans and livestock. CONCLUSIONS: The wide spread of ESBL and AmpC genes in Salmonella of various serovars is most probably due to transfer of conjugative plasmids. Furthermore, our data indicate the clonal spread of distinct cephalosporin-resistant Salmonella strains from livestock to humans. PMID- 23674766 TI - Influence of the MBC/MIC ratio on the antibacterial activity of vancomycin versus linezolid against methicillin-resistant Staphylococcus aureus isolates in a pharmacodynamic model simulating serum and soft tissue interstitial fluid concentrations reported in diabetic patients. AB - OBJECTIVES: To explore serum and tissue pharmacodynamics of linezolid versus vancomycin against methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates with different MBC/MIC ratios. METHODS: Five strains (vancomycin MIC/MBCs, mg/L) were used: TOL-1 (2/>=64), TOL-2 (1/16), LT-1 and LT-2 (1/8) and NT (1/2). The linezolid MIC/MBC for all strains was 2/>=64 mg/L. A two compartment dynamic computerized device was used (inocula 10(7) cfu/mL). Free concentrations obtained in serum and interstitial fluid with twice-daily regimens of 1 g of vancomycin or 600 mg of linezolid were simulated over 48 h. ABBCs (differences between control growth curves and killing curves of bacteria exposed to antibiotics; log10 cfu * h/mL) and log10 reductions in initial inocula were calculated. RESULTS: In serum simulations, vancomycin (AUC0-24/MIC = 251.8 for TOL-1 and 503.6 for the remaining strains) was bacteriostatic against strains with MBC/MIC >=8, but bactericidal against NT. In interstitial fluid simulations (AUC0-24/MIC = 54.6 for TOL-1 and 109.2 for the remaining strains), initial inocula grew in all cases. Linezolid, both in serum (AUC0-24/MIC = 87.0) and in interstitial fluid (AUC0-24/MIC = 130.6) simulations, reduced initial inocula >=2.2 log10 for all strains (apart from LT-1 in serum simulations that showed a bacteriostatic profile). ABBCs were similar in serum and interstitial fluid with linezolid, but significantly lower in interstitial fluid simulations with vancomycin. CONCLUSIONS: From the pharmacodynamic perspective (serum concentrations), vancomycin tolerance should include MBC/MIC >=8 since strains exhibiting this ratio showed bacteriostatic profiles similar to those obtained with isolates with MBC/MIC ratios of 16 or 32. Insufficient concentrations of vancomycin at the simulated infected site were linked to bacteriological failure. Free concentrations of linezolid at the infection site pharmacodynamically covered MRSA. PMID- 23674767 TI - Imaging of vascular complications and their consequences following transplantation in the abdomen. AB - Transplantation is the surgical treatment of choice for end-stage organ failure. Transplantation procedures performed in the abdomen include liver, renal, pancreas, islet, intestinal, and multivisceral transplantations. Imaging plays a pivotal role in the posttransplantation setting for monitoring the transplant allograft and screening for complications. Knowledge of the surgical techniques employed in abdominal transplantation is essential because it facilitates radiologic understanding and interpretation of the posttransplantation anatomy. This article includes a basic description of the standard surgical techniques performed in the abdomen, with emphasis on the relevant vascular anastomotic reconstructions used. Posttransplantation complications can be broadly classified as vascular or nonvascular in origin. Many of these complications can be accurately depicted and characterized at imaging and dealt with definitively by using interventional radiology techniques, which can be graft- and life-saving and can obviate further complex surgical intervention. The article discusses imaging appearances of vascular complications and their consequences after transplantation in the abdomen. These vascular complications include arterial thrombosis, arterial stenosis, venous thrombosis and stenosis, arteriovenous fistula formation, and pseudoaneurysm formation. The relevant predisposing factors, clinical features, imaging appearances, and potential treatment options for vascular complications of various types of transplantation are presented in a logical and integrated fashion. Knowledge and imaging recognition of the posttransplantation vascular complications discussed in this article will aid radiologists in accurate imaging characterization and thereby facilitate appropriate clinical management and therapy. PMID- 23674768 TI - Diffusion-weighted MR imaging of the gastrointestinal tract: technique, indications, and imaging findings. AB - Diffusion-weighted magnetic resonance (MR) imaging has emerged as an important tool in the diagnostic work-up of patients with bowel cancer and inflammatory conditions of the gastrointestinal tract. It functions on the basis of the microscopic motion of water molecules in a cellular environment and provides functional information about the water in body tissues. Diffusion-weighted imaging serves to complement conventional MR imaging, and its use may improve the accuracy of tumor detection and staging. It does not rely on the use of intravenous contrast material and may be performed in patients with renal impairment. Because it provides quantitative information about tissue cellularity, diffusion-weighted imaging may be used to distinguish between tissues with altered cellularity (eg, tumors and metastases) and normal tissues. Data from diffusion-weighted MR images enable the calculation of apparent diffusion coefficient (ADC) values, which provide useful information about response to treatment. Malignant gastrointestinal tract tumors have low ADC values, which increase after successful therapy. Diffusion-weighted imaging also plays a role in the evaluation of patients with inflammatory bowel disease and may help assess inflammation and complications, such as abscesses and fistulas. Quantitative measurements of signal intensity at diffusion-weighted imaging may help differentiate actively inflamed bowel from normal bowel, and ADC values provide useful information about disease activity and response to treatment. PMID- 23674769 TI - Current MR imaging lipid detection techniques for diagnosis of lesions in the abdomen and pelvis. AB - One application of the unique capability of magnetic resonance (MR) imaging for characterizing soft tissues is in the specific detection of lipid. Adipose tissue may be abundant in the body, but its presence in a lesion can greatly limit differential diagnostic considerations. This article reviews MR imaging fat detection techniques and discusses lesions in the abdomen and pelvis that can be readily diagnosed by using these techniques. Traditional fat detection methods include inversion-recovery and chemically selective fat-suppression pulse sequences, with the former being less sensitive to field heterogeneity and less tissue specific than the latter. Chemical shift-based sequences, which exploit the inherent resonance frequency difference between lipid and water to depict intracytoplasmic fat, have great utility for evaluating hepatic steatosis and lesions such as adrenal and hepatic adenomas, hepatocellular carcinoma, focal lipomatosis of the pancreas, and adrenal cortical carcinoma. The signal from large amounts of fat can be suppressed by using a narrow radiofrequency pulse for selective excitation of fat protons (ie, fat saturation imaging), a technique that increases image contrast resolution and highlights lesions such as contrast enhancing tissue, edema, and blood products. This technique is especially useful for evaluating renal angiomyolipomas, adrenal myelolipomas, ovarian teratomas, and liposarcomas. MR spectroscopy is a promising method for quantifying absolute liver fat concentration and changes in hepatic triglyceride content during treatment. New and evolving techniques include magnetization transfer and modified Dixon sequences. A solid understanding of these techniques will help improve the interpretation of abdominal and pelvic imaging studies. PMID- 23674770 TI - Abdominal MR imaging in children: motion compensation, sequence optimization, and protocol organization. AB - Familiarity with basic sequence properties and their trade-offs is necessary for radiologists performing abdominal magnetic resonance (MR) imaging. Acquiring diagnostic-quality MR images in the pediatric abdomen is challenging due to motion, inability to breath hold, varying patient size, and artifacts. Motion compensation techniques (eg, respiratory gating, signal averaging, suppression of signal from moving tissue, swapping phase- and frequency-encoding directions, use of faster sequences with breath holding, parallel imaging, and radial k-space filling) can improve image quality. Each of these techniques is more suitable for use with certain sequences and acquisition planes and in specific situations and age groups. Different T1- and T2-weighted sequences work better in different age groups and with differing acquisition planes and have specific advantages and disadvantages. Dynamic imaging should be performed differently in younger children than in older children. In younger children, the sequence and the timing of dynamic phases need to be adjusted. Different sequences work better in smaller children and in older children because of differing breath-holding ability, breathing patterns, field of view, and use of sedation. Hence, specific protocols should be maintained for younger children and older children. Combining longer higher-resolution sequences and faster-lower-resolution sequences helps acquire diagnostic-quality images in a reasonable time. PMID- 23674771 TI - Imaging of penile and scrotal emergencies. AB - Penile and scrotal emergencies are uncommon, but when they do occur, urgent or emergent diagnosis and treatment are necessary. Emergent conditions of the male genitalia are primarily infectious, traumatic, or vascular. Infectious conditions, such as epididymitis and epididymo-orchitis, are well evaluated at ultrasonography (US), and their key findings include heterogeneity and hyperemia. Pyocele and abscess may also be seen at US. Fournier gangrene is best evaluated at computed tomography, which depicts subcutaneous gas. Vascular conditions, such as testicular torsion, infarction, penile Mondor disease, and priapism, are well evaluated at duplex Doppler US. The key imaging finding of testicular torsion and infarction is a lack of blood flow in the testicle or a portion of the testicle. Penile Mondor disease is characterized by a lack of flow to and noncompressibility of the superficial dorsal vein of the penis. Clinical examination and history are usually adequate for diagnosis of priapism, but Doppler US may help confirm the diagnosis. Traumatic injuries of the penis and scrotum are initially imaged with US, which depicts whether the penile corpora and testicular seminiferous tubules are contained by the tunicae albuginea; herniation of contents and discontinuity of the tunica albuginea indicate rupture. In some cases, magnetic resonance imaging may be performed because of its ability to directly depict discontinuity of the tunica albuginea. Radiologists must closely collaborate with emergency physicians, surgeons, and urologists to quickly and efficiently diagnose or rule out emergent conditions of the male genitalia to facilitate prompt and appropriate treatment. PMID- 23674772 TI - MR imaging of prostate cancer in radiation oncology: what radiologists need to know. AB - Radiation therapy (RT) is one of the principal treatment modalities for localized or locally advanced prostate cancer. The two major forms of RT for prostate cancer are external-beam RT (EBRT) with a photon or proton beam and brachytherapy. With modern conformal techniques for EBRT (three-dimensional conformal RT, intensity-modulated RT, and image-guided RT) and advanced computer based planning systems for brachytherapy, the dose can be more precisely delivered to the prostate while reducing unnecessary radiation to normal tissue. The dominant intraprostatic tumor can be targeted with a higher dose, so-called dose painting. Magnetic resonance (MR) imaging plays a pivotal role in pretreatment assessment of prostate cancer. Multiparametric MR imaging, a combination of anatomic and functional MR imaging techniques (diffusion-weighted imaging, dynamic contrast material-enhanced imaging, and MR spectroscopy), significantly improves the accuracy of tumor localization and local staging. For pretreatment planning, anatomic MR imaging provides highly accurate local staging information, particularly about extraprostatic extension and seminal vesicle invasion. The dominant intraprostatic tumor and local recurrence in the prostatectomy bed can be better localized with multiparametric MR imaging for dose painting. MR imaging allows excellent delineation of the contours of the prostate and surrounding structures. It can also be used in early posttreatment evaluation after brachytherapy. PMID- 23674773 TI - Male breast disease: pictorial review with radiologic-pathologic correlation. AB - The male breast is susceptible to many of the same pathologic processes as the female breast. Many of these conditions have mammographic, ultrasonographic (US), and magnetic resonance imaging findings that allow differentiation between clearly benign conditions and those that require biopsy. Gynecomastia is the most common abnormality of the male breast and has characteristic imaging features that usually allow differentiation from malignancy. Mammography is the initial imaging modality for a clinically suspicious mass. A palpable mass that is occult or incompletely imaged at mammography mandates targeted US. Suspicious or indeterminate masses require biopsy, which can usually be performed with US guidance. Approximately 0.7% of breast cancers occur in men. Men with breast cancer often present at a more advanced stage than do women owing to a delay in diagnosis. Benign breast neoplasms that may occur in men include angiolipoma, schwannoma, intraductal papilloma, and lipoma. Benign nonneoplastic entities that may occur in the male breast include intramammary lymph node, sebaceous cyst, diabetic mastopathy, hematoma, fat necrosis, subareolar abscess, breast augmentation, venous malformation, secondary syphilis, and nodular fasciitis. Familiarity with the salient features of the classic benign male breast conditions will allow accurate imaging interpretation and avoid unnecessary and often invasive treatment. (c) RSNA, 2013. PMID- 23674774 TI - Physiologic, histologic, and imaging features of retained products of conception. AB - Retained products of conception (RPOC) are a common and treatable complication after delivery or termination of pregnancy. The pathologic diagnosis of RPOC is made based on the presence of chorionic villi, which indicates persistent placental or trophoblastic tissue. In the setting of postpartum hemorrhage, however, distinguishing RPOC from bleeding related to normal postpartum lochia or uterine atony can be clinically challenging. Ultrasonographic (US) evaluation can be particularly helpful in these patients, and a thickened endometrial echo complex (EEC) or a discrete mass in the uterine cavity is a helpful gray-scale US finding that suggests RPOC. However, gray-scale US findings alone are inadequate for accurate diagnosis. Detection of vascularity in a thickened EEC or an endometrial mass at color or power Doppler US increases the positive predictive value for the diagnosis of RPOC. Computed tomography or magnetic resonance imaging may be helpful when US findings are equivocal and typically demonstrates an enhancing intracavitary mass in patients with RPOC. Diagnostic pitfalls are rare but may include highly vascular RPOC, which can be mistaken for a uterine arteriovenous malformation; true arteriovenous malformations of the uterus; invasive moles; blood clot; and subinvolution of the placental implantation site. PMID- 23674775 TI - AIRP best cases in radiologic-pathologic correlation: mediastinal mature cystic teratoma. PMID- 23674776 TI - From the radiologic pathology archives: ewing sarcoma family of tumors: radiologic-pathologic correlation. AB - The Ewing sarcoma family of tumors includes osseous Ewing sarcoma, extraskeletal Ewing sarcoma, primitive neuroectodermal tumor, and Askin tumor. They share a karyotype abnormality with translocation involving chromosomes 11 and 22. Histologically, these lesions demonstrate crowded sheets of small round blue cells. Imaging features of osseous Ewing sarcoma often suggest the diagnosis, with aggressive long-bone destruction in the metadiaphysis of an adolescent or young adult and an associated soft-tissue mass. Focal areas of cortical destruction are frequent, allowing continuity between the intraosseous and extraosseous components. This continuity is also commonly seen as subtle channels extending through the cortex at computed tomography or magnetic resonance (MR) imaging, a finding that reflects the underlying pathologic appearance. Extraskeletal Ewing sarcoma commonly demonstrates a nonspecific radiologic appearance of a large soft-tissue mass affecting the paraspinal region or lower extremity. Askin tumor represents extraskeletal Ewing sarcoma involving the chest wall. Imaging typically reveals a large pleural-based mass and associated pleural effusion. Treatment of these tumors is usually a combination of neoadjuvant chemotherapy followed by surgical resection, which may be supplemented with radiation therapy. Imaging, particularly MR, is also vital to evaluate response to neoadjuvant therapy, direct surgical resection, and detect local recurrence or metastatic disease. PMID- 23674777 TI - MR imaging in the evaluation of cystic-appearing soft-tissue masses of the extremities. AB - Cystic-appearing lesions are commonly seen in clinical practice at imaging of the extremities. However, only some of these lesions are truly cystic lesions (eg, ganglia or synovial cysts, bursae) and may be managed conservatively. Fluid filled lesions usually have homogeneous high T2 signal at magnetic resonance (MR) imaging. A broad array of solid benign masses (eg, myxomas, peripheral nerve sheath tumors [PNSTs], certain vascular lesions, glomus tumors) and malignant solid masses (including undifferentiated pleomorphic sarcomas, myxofibrosarcomas, myxoid liposarcomas, synovial sarcomas, extraskeletal myxoid chondrosarcomas, and, less frequently, soft-tissue metastases) may also exhibit bright T2 signal at MR imaging, thereby simulating a cyst. On the other hand, fluid-filled lesions with associated complications (eg, bleeding or inflammatory changes) may have a more complex appearance. MR imaging plays a major role in distinguishing truly cystic lesions from solid lesions. If a cystic-appearing lesion demonstrates wall thickening or internal complexity (heterogeneous signal, nodules, or thick septa), evaluation with contrast material enhancement is mandatory, and a solid lesion must be suspected if any internal enhancement is present. In addition to categorizing the lesions as truly cystic or solid, the differential diagnosis may be further narrowed by considering the anatomic location of the lesion or characteristic imaging features (eg, internal linear or patchy enhancement at contrast-enhanced MR imaging and an intramuscular location in myxomas; the "split fat sign," "string sign," and "target sign" in PNSTs; tiny foci of fat in myxoid liposarcomas). In most cases, however, histologic analysis is required to achieve a definitive diagnosis. PMID- 23674778 TI - Can big data lead us to big savings? PMID- 23674779 TI - AIRP Best Cases in Radiologic-Pathologic Correlation: Maffucci Syndrome. PMID- 23674780 TI - Traumatic elbow injuries: what the orthopedic surgeon wants to know. AB - Traumatic elbow injuries are commonly encountered in the emergency department setting, but their complexity and clinical significance often go unrecognized at the initial evaluation. Initial imaging in patients with elbow trauma should not only help identify major injuries that require immediate intervention but also allow detection of other, often more subtle injuries that may lead to instability or poor functional outcomes if appropriate treatment is delayed. Awareness and detection of these injuries may be improved by a better-developed and more intuitive understanding of the mechanisms that underlie the most common injury patterns. Ideally, such understanding should prompt appropriate early use of advanced imaging techniques. Traumatic elbow injuries should be described in the radiology report within the context of their clinical significance and their implications for management, information that is often best captured by the injury grading and classification systems used by the orthopedic surgery community. This article reviews the relevant anatomy and functional stability of the elbow and discusses common traumatic elbow injury patterns, including elbow dislocations as well as fractures of the distal humerus, radial head and neck, coronoid process, and olecranon. Less commonly encountered injury constellations that are clinically significant are also described. Injury patterns are explained in the context of the responsible force mechanism by using three-dimensional modeling and animation, with emphasis on the functional impact of associated secondary bone and soft-tissue injuries. The utility of cross-sectional imaging modalities such as computed tomography and magnetic resonance imaging in the acute care setting is discussed, and specific imaging guidelines are provided. Supplemental material available at http://radiographics.rsna.org/lookup/suppl/doi:10.1148/rg.333125176/-/DC1. PMID- 23674781 TI - Application of basic principles of physics to head and neck MR angiography: troubleshooting for artifacts. AB - Neurovascular imaging studies are routinely used for the assessment of headaches and changes in mental status, stroke workup, and evaluation of the arteriovenous structures of the head and neck. These imaging studies are being performed with greater frequency as the aging population continues to increase. Magnetic resonance (MR) angiographic imaging techniques are helpful in this setting. However, mastering these techniques requires an in-depth understanding of the basic principles of physics, complex flow patterns, and the correlation of MR angiographic findings with conventional MR imaging findings. More than one imaging technique may be used to solve difficult cases, with each technique contributing unique information. Unfortunately, incorporating findings obtained with multiple imaging modalities may add to the diagnostic challenge. To ensure diagnostic accuracy, it is essential that the radiologist carefully evaluate the details provided by these modalities in light of basic physics principles, the fundamentals of various imaging techniques, and common neurovascular imaging pitfalls. PMID- 23674782 TI - Abdominal and pelvic aneurysms and pseudoaneurysms: imaging review with clinical, radiologic, and treatment correlation. AB - Abnormally enlarged visceral arteries in the abdomen and pelvis must be recognized radiologically because early treatment can improve the quality of life and prevent life-threatening complications. These lesions, typically classified as aneurysms and pseudoaneurysms, are being detected more frequently with increased utilization of imaging and have various causes (eg, atherosclerosis, trauma, infection) and complications that may be identified radiologically. Ultrasonography, computed tomography, and magnetic resonance imaging often enable detection of visceral vascular lesions, but angiography is important for further diagnosis and treatment. Endovascular treatment is often the first-line therapy. Endovascular intervention or open surgical repair is necessary for all visceral pseudoaneurysms and is likely indicated for visceral aneurysms 2 cm or more in diameter. Endovascular exclusion of flow can be achieved with coils, stents, and injectable liquids. Techniques include embolization ("sandwich" or "sac-packing" technique), exclusion of flow with luminal stents, and stent-assisted coil embolization. Management often depends on the location and technical feasibility of endovascular repair. Embolization is usually preferred for aneurysms or pseudoaneurysms within solid organs, and the sandwich technique is often used when collateral flow is present. Covered stent placement may be preferred to preserve the parent artery when main visceral vessels are being treated. It is usually tailored to lesion location, and a cure can often be effected while preserving end-organ arterial flow. Posttreatment follow-up is usually based on treatment location, modality accuracy, and potential consequences of treatment failure. Follow-up imaging may help identify vessel recanalization, unintended thrombosis of an artery or end organ, or sequelae of nontarget embolization. Retreatment is usually warranted if the clinical risks for which embolization was performed are still present. PMID- 23674783 TI - Demystifying radial imaging of the hip. AB - The hip joint poses unique challenges at magnetic resonance (MR) imaging because of its shape and anatomic position. When conventional imaging planes are used, partial-volume averaging effects may substantially hamper the depiction of cartilage and labral damage at MR imaging. Such effects are most prevalent when the imaging plane is not perpendicular to the curvature of the joint and result in images that poorly depict or fail to depict cartilage and labral conditions. Partial-volume averaging, along with the inherently thin and closely apposed articular cartilage, may be partly to blame for the seemingly disparate reported sensitivities of MR imaging for depicting cartilage damage in the literature, which vary widely depending on whether arthrography was used. Fortunately, the multiplanar capability of MR imaging is not limited to standard anatomic planes. Radial sections, which are obtained perpendicular to the surfaces of the hip joint, provide a true cross section of the cartilage and labrum that conventional planes do not. Radial imaging is a reproducible technique that enhances the morphologic assessment of the articular cartilage and labrum. The additional information it provides is important because early damage occurs in the anterosuperior region of the hip in patients with femoroacetabular impingement. PMID- 23674784 TI - Digital compared with screen-film mammography: performance measures in concurrent cohorts within an organized breast screening program. AB - PURPOSE: To evaluate the performance of digital direct radiography (DR) and computed radiography (CR) compared with that of screen-film mammography (SFM) in large concurrent cohorts. MATERIALS AND METHODS: This study was approved by the University of Toronto Research Ethics Board and did not require informed consent. Concurrent cohorts of women aged 50-74 years screened with DR (n = 220 520), CR (n = 64 210), or SFM (n = 403 688) between 2008 and 2009 were identified and followed for 12 months. Performance was compared between cohorts, with SFM as the referent cohort. Associations were examined by using mixed-effect logistic regression. RESULTS: The cancer detection rate was similar for DR (4.9 per 1000; 95% confidence interval [CI]: 4.7, 5.2) and SFM (4.8 per 1000; 95% CI: 4.7, 5.0); however, the rate was significantly lower for CR (3.4 per 1000; 95% CI: 3.0, 3.9) (odds ratio, 0.79; 95% CI: 0.68, 0.93). Recall rates were higher for DR (7.7%; 95% CI: 7.6%, 7.8%) and lower for CR (6.6%; 95% CI: 6.5%, 6.7%) than for SFM (7.4%; 95% CI: 7.3%, 7.5%). Positive predictive value was lower for CR (5.2%; 95% CI: 4.7%, 5.8%) than for SFM (6.6%; 95% CI: 6.4%, 6.8%); however, the adjusted odds were not significant. CONCLUSION: Although DR is equivalent to SFM for breast screening among women aged 50-74 years, the cancer detection rate was lower for CR. Screening programs should monitor the performance of CR separately and may consider informing women of the potentially lower cancer detection rates. PMID- 23674785 TI - Measurement of Tissue interstitial volume in healthy patients and those with amyloidosis with equilibrium contrast-enhanced MR imaging. AB - PURPOSE: To investigate equilibrium contrast material-enhanced magnetic resonance (MR) imaging measurement of extracellular volume (ECV) fraction within healthy abdominal tissues and to test the hypotheses that tissue ECV in systemic amyloid light-chain (AL) amyloidosis is greater than in healthy patients and show that this increase correlates with organ amyloid burden. MATERIALS AND METHODS: A local ethics committee approved the study and all patients gave written informed consent. Forty healthy volunteers (18 men, 22 women; median age, 43 years; age range, 24-88 years) and 67 patients with AL amyloidosis (43 men, 24 women; median age, 65 years; age range, 38-81 years) underwent equilibrium MR imaging of the upper abdomen. ECV was measured in the liver, spleen, and paravertebral muscle. Patients with amyloidosis also underwent serum amyloid P (SAP) component scintigraphy so that specific organ involvement by amyloid could be scored. Variation in ECV between tissues was assessed by using a Friedman Test. Tissue ECV in healthy and amyloidosis groups were compared by using a Mann-Whitney U test. Spearman correlation was used to test for an association between the organ SAP score and ECV. RESULTS: ECV measured at equilibrium MR imaging varied significantly between organs in healthy volunteers (chi(2) = 31.0; P < .001). ECV was highest in the spleen (0.34), followed by liver (0.29) and muscle (0.09). ECVs measured within the spleen (0.39; P< .001), liver (0.31; P = .005), and muscle (0.16; P< .001) were significantly higher in patients with amyloidosis than in healthy control subjects. ECV measured in the liver and spleen showed increasing organ amyloid burden assessed at SAP scintigraphy (liver, rs = 0.54; spleen, rs = 0.57). CONCLUSION: Equilibrium MR imaging can be used to define ECV within healthy tissues. ECV is increased in amyloidosis compared with healthy tissues, and this increase correlates with rising tissue amyloid burden. PMID- 23674786 TI - Improved subthalamic nucleus depiction with quantitative susceptibility mapping. AB - PURPOSE: To assess quantitative susceptibility mapping (QSM) in the depiction of the subthalamic nucleus (STN) by using 3-T magnetic resonance (MR) imaging. MATERIALS AND METHODS: This study was HIPAA compliant and institutional review board approved. Ten healthy subjects (five men, five women; mean age, 24 years +/ 3 [standard deviation]; age range, 21-33 years) and eight patients with Parkinson disease (five men, three women; mean age, 57 years +/- 14; age range, 25-69 years) who were referred by neurologists for preoperative navigation MR imaging prior to deep brain stimulator placement were included in this study. T2 weighted (T2w), T2*-weighted (T2*w), R2* mapping (R2*), phase, susceptibility weighted (SW), and QSM images were reconstructed for STN depiction. Qualitative visualization scores of STN and internal globus pallidus (GPi) were recorded by two neuroradiologists on all images. Contrast-to-noise ratios (CNRs) of the STN and GPi were also measured. Measurement differences were assessed by using the Wilcoxon rank sum test and the signed rank test. RESULTS: Qualitative scores were significantly higher on QSM images than on T2w, T2*w, R2*, phase, or SW images (P < .05) for STN and GPi visualization. Median CNR was 6.4 and 10.7 times higher on QSM images than on T2w images for differentiation of STN from the zona incerta and substantia nigra, respectively, and was 22.7 and 9.1 times higher on QSM images than on T2w images for differentiation of GPi from the internal capsule and external globus pallidus, respectively. CNR differences between QSM images and all other images were significant (P < .01). CONCLUSION: QSM at 3-T MR imaging performs significantly better than current standard-of-care sequences in the depiction of the STN. PMID- 23674787 TI - Coronary stenosis: Morphologic index characterized by using CT angiography correlates with fractional flow reserve and is associated with hemodynamic status. AB - PURPOSE: To study the diagnostic performance of the ratio of lesion length (LL) to the fourth power of minimal lumen diameter (MLD) (MLD(4)) at coronary computed tomographic (CT) angiography for differentiating between hemodynamically significant and nonsignificant lesions, with correlation with fractional flow reserve (FFR). MATERIALS AND METHODS: This retrospective study had institutional review board approval, and the need to obtain informed consent was waived. Sixty one patients (mean age, 65.3 years +/- 8.8 [standard deviation]; range, 43-82 years; 43 men and 18 women; P = .019 for age) who underwent both coronary CT angiography and FFR measurement at conventional coronary angiography within 2 weeks were retrospectively included in this study. LL/MLD(4) ratio, along with other parameters, including minimal luminal area (MLA), stenosis diameter, stenosis area, plaque burden, remodeling index, and Agatston score of lesions, were recorded. Lesions with FFRs of less than 0.8 were considered to be functionally significant. Univariate and multivariate statistical tests were performed to identify variables associated with hemodynamically significant lesions. RESULTS: Sixty-one patients with 85 lesions were ultimately included for analysis. LL, stenosis diameter, stenosis area, and plaque burden were longer or larger in the group with FFRs of less than 0.8 (P < .001 for all), while smaller MLA and MLD were also noted (P < .001). Mean LL/MLD(4) ratio was significantly larger in the group with FFRs of less than 0.8 than in the group with FFRs of 0.8 or greater (9.7 +/- 7.5 vs 3.1 +/- 3.6, P < .001). Rest myocardial perfusion defect was recorded in five lesions with FFRs of less than 0.8 (P = .006). LL/MLD(4) ratio proved at multivariate analysis to be the only independent predictor of hemodynamically significant stenosis (odds ratio = 1.44; P = .043). When 3.86 was used as the cutoff value for LL/MLD(4) ratio, the sensitivity and specificity for diagnosing hemodynamically significant lesions were 82.9% (29 of 35) and 82% (41 of 50), respectively. CONCLUSION: The LL/MLD(4) ratio, as characterized by using coronary CT angiography, correlates inversely with FFR measurements and is associated with the hemodynamic status of coronary stenoses. Online supplemental material is available for this article. PMID- 23674788 TI - Ischemic stroke: measurement of intracranial artery calcifications can improve prediction of asymptomatic coronary artery disease. AB - PURPOSE: To examine the associations between intracranial artery calcifications (IACs) and coronary artery calcifications (CACs) in patients with ischemic stroke and to assess the predictive value of IAC for asymptomatic coronary artery disease (CAD). MATERIALS AND METHODS: This retrospective study, approved by an institutional review board that waived the need for informed consent, included 314 consecutive patients who had acute ischemic stroke and who underwent both brain and coronary computed tomography (CT) within 1 month of stroke. IAC was quantified semiautomatically by calculating both Agatston scores (area of calcification multiplied by a weighted value assigned to its highest Hounsfield unit) and volumes on thin-section unenhanced images and was correlated with coronary calcium scores and volumes. Quartiles were created for IAC scores and were used for logistic regression analysis. An optimal IAC score cutoff value was determined and used to predict the presence of asymptomatic CAD. Independent factors for asymptomatic CAD were assessed by using multiple logistic regression analysis. Receiver operating characteristic curve analysis was performed to evaluate the added value of IAC scores for prediction of asymptomatic CAD. RESULTS: IAC and CAC were significantly correlated for both Agatston scores and volumes (R = 0.665 and 0.663, respectively; P < .001). A graded association was found between IAC scores and presence of asymptomatic CAD. Both IAC scores of 120.11 or greater (odds ratio [OR], 2.57; 95% confidence interval [CI]: 1.45, 4.55) and diabetes mellitus (OR, 4.23; 95% CI: 2.42, 7.4) were independent predictors for asymptomatic CAD. Adding the IAC score to analytic models significantly improved the ability to predict asymptomatic CAD. CONCLUSION: The IAC scores quantified by using unenhanced CT correlate significantly with coronary calcium scores and may serve as an independent predictor of asymptomatic CAD in patients with ischemic stroke. PMID- 23674789 TI - Osteochondral repair: evaluation with sweep imaging with fourier transform in an equine model. AB - PURPOSE: To evaluate the status of articular cartilage and bone in an equine model of spontaneous repair by using the sweep imaging with Fourier transform (SWIFT) magnetic resonance (MR) imaging technique. MATERIALS AND METHODS: Experiments were approved by the Utrecht University Animal Ethics Committee. Six millimeter-diameter chondral (n = 5) and osteochondral (n = 5, 3-4 mm deep into subchondral bone) defects were created in the intercarpal joints of seven 2-year old horses and examined with SWIFT at 9.4 T after spontaneous healing for 12 months. Conventional T2 maps and gradient-echo images were obtained for comparison, and histologic assessment of cartilage and micro-computed tomography (CT) of bone were performed for reference. Signal-to-noise ratio (SNR) analysis was performed, and a radiologist evaluated the MR images. Structural bone parameters were derived from SWIFT and micro-CT datasets. Significance of differences was investigated with the Wilcoxon signed rank test and Pearson correlation analysis. RESULTS: SWIFT was able to depict the different outcomes of spontaneous healing of focal chondral versus osteochondral defects. SWIFT produced constant signal intensity throughout cartilage, whereas T2 mapping showed elevated T2 values (P = .06) in repair tissue (mean T2 in superficial region of interest in an osteochondral lesion = 50.0 msec +/- 10.2) in comparison to adjacent intact cartilage (mean T2 = 32.7 msec +/- 4.2). The relative SNR in the subchondral plate with SWIFT (0.91) was more than four times higher than that with conventional fast spin-echo (0.12) and gradient-echo (0.19) MR imaging. The correlation between bone volume-to-tissue volume fractions determined with SWIFT and micro-CT was significant (r = 0.83, P < .01). CONCLUSION: SWIFT enabled assessment of spontaneous osteochondral repair in an equine model. PMID- 23674790 TI - Penetrating diaphragmatic injury: accuracy of 64-section multidetector CT with trajectography. AB - PURPOSE: To (a) determine the diagnostic performance of 64-section multidetector computed tomography (CT) trajectography for penetrating diaphragmatic injury (PDI), (b) determine the diagnostic performance of classic signs of diaphragmatic injury at 64-section multidetector CT, and (c) compare the performance of these signs with that of trajectography. MATERIALS AND METHODS: This HIPAA-compliant retrospective study had institutional review board approval, with a waiver of the informed consent requirement. All patients who had experienced penetrating thoracoabdominal trauma, who had undergone preoperative 64-section multidetector CT of the chest and abdomen, and who had surgical confirmation of findings during a 2.5-year period were included in this study (25 male patients, two female patients; mean age, 32.6 years). After a training session, four trauma radiologists unaware of the surgical outcome independently reviewed all CT studies and scored the probability of PDI on a six-point scale. Collar sign, dependent viscera sign, herniation, contiguous injury on both sides of the diaphragm, discontinuous diaphragm sign, and transdiaphragmatic trajectory were evaluated for sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV). Accuracies were determined and receiver operating characteristic curves were analyzed. RESULTS: Sensitivities for detection of PDI by using 64-section multidetector CT with postprocessing software ranged from 73% to 100%, specificities ranged from 50% to 92%, NPVs ranged from 71% to 100%, PPVs ranged from 68% to 92%, and accuracies ranged from 70% to 89%. Discontinuous diaphragm, herniation, collar, and dependent viscera signs were highly specific (92%-100%) but nonsensitive (0%-60%). Contiguous injury was generally more sensitive (80%-93% vs 73%-100%) but less specific (50% 67% vs 83%-92%) than transdiaphragmatic trajectory when patients with multiple entry wounds were included in the analysis. Transdiaphragmatic trajectory was a much more sensitive sign of PDI than previously reported (73%-100% vs 36%), with NPVs ranging from 71% to 100% and PPVs ranging from 85% to 92%. CONCLUSION: Sixty four-section multidetector CT trajectography facilitates the identification of transdiaphragmatic trajectory, which accurately rules in PDI when identified. Contiguous injury remains a highly sensitive sign, even when patients with multiple injuries are considered, and is useful for excluding PDI. PMID- 23674791 TI - Split-bolus spectral multidetector CT of the pancreas: assessment of radiation dose and tumor conspicuity. AB - PURPOSE: To assess tumor conspicuity and radiation dose with a new multidetector computed tomography (CT) protocol for pancreatic imaging that combines spectral CT and split-bolus injection. MATERIALS AND METHODS: This study was approved by the institutional review board and compliant with HIPAA. The requirement for informed consent was waived. One hundred sixty-three consecutive patients referred for possible pancreatic mass underwent CT with either a standard or split-bolus spectral CT protocol depending on scanner availability. Split-bolus spectral CT (CT unit with spectral imaging) combines pancreatic and portal venous phases in a single scan: 70 seconds before CT, 100 mL of contrast material is injected for the portal venous phase followed approximately 35 seconds later by injection of 40 mL of contrast material to boost the pancreatic phase. Bolus tracking after the second bolus initiates scanning 15 seconds after aorta enhancement reaches 280 HU. Images were reconstructed at 60 and 77 keV. The standard protocol (64-detector row unit) included unenhanced and pancreatic and portal venous phase imaging, with a single contrast material injection timed with bolus tracking 15 seconds after aortic enhancement of 300 HU for the pancreatic phase and 32 seconds later for the portal venous phase. Tumor conspicuity (difference in attenuation between tumor and pancreatic parenchyma) and contrast to-noise ratio (CNR) were determined. Attenuation of aorta, main portal vein, and liver were measured. Patient size and per-examination radiation dose were recorded. The heteroscedastic t test, Fisher exact test, and Mann-Whitney test were used for statistical analysis. RESULTS: There were no significant differences in age, weight, and body mass index between patients in the standard CT (46 of 80 patients had lesions) and split-bolus spectral CT (39 of 83 patients had lesions) groups; however, there were significantly more women in the split bolus group (P = .02). Tumor conspicuity and CNR were higher with the 60-keV split-bolus protocol (89.1 HU +/- 56.6 and 8.8 +/- 6.2, respectively) than with the pancreatic or portal venous phase of the standard protocol (43.5 HU +/- 28.4 and 4.5 +/- 3.0, and 51.5 HU +/- 30.3 and 5.6 +/- 4.0, respectively; P < .01 for all comparisons). Dose-length product was 1112 mGy . cm +/- 437 with the standard protocol and 633 mGy . cm +/- 105 with the split-bolus protocol (P < .001). CONCLUSION: Split-bolus spectral multidetector CT resulted in vascular, liver, and pancreatic attenuation and tumor conspicuity equal to or greater than that with multiphase CT, with a 43% reduction in radiation dose. PMID- 23674792 TI - Nutritional interventions to alleviate the negative consequences of heat stress. AB - Energy metabolism is a highly coordinated process, and preferred fuel(s) differ among tissues. The hierarchy of substrate use can be affected by physiological status and environmental factors including high ambient temperature. Unabated heat eventually overwhelms homeothermic mechanisms resulting in heat stress, which compromises animal health, farm animal production, and human performance. Various aspects of heat stress physiology have been extensively studied, yet a clear understanding of the metabolic changes occurring at the cellular, tissue, and whole-body levels in response to an environmental heat load remains ill defined. For reasons not yet clarified, circulating nonesterified fatty acid levels are reduced during heat stress, even in the presence of elevated stress hormones (epinephrine, glucagon, and cortisol), and heat-stressed animals often have a blunted lipolytic response to catabolic signals. Either directly because of or in coordination with this, animals experiencing environmental hyperthermia exhibit a shift toward carbohydrate use. These metabolic alterations occur coincident with increased circulating basal and stimulated plasma insulin concentrations. Limited data indicate that proper insulin action is necessary to effectively mount a response to heat stress and minimize heat-induced damage. Consistent with this idea, nutritional interventions targeting increased insulin action may improve tolerance and productivity during heat stress. Further research is warranted to uncover the effects of heat on parameters associated with energy metabolism so that more appropriate and effective treatment methodologies can be designed. PMID- 23674793 TI - Chronic illness and disordered eating: a discussion of the literature. AB - This paper describes the prevalence of eating disorders and disordered eating behaviors, the reasons why these practices are endorsed, and the potential consequences in youths and young adults with selected diet-related chronic health conditions (DRCHCs) and provides recommendations for eating disorder prevention interventions and research efforts. Although it remains unclear whether the prevalence of eating disorders is higher in those with DRCHCs compared with the general population, overall findings suggest that young people with DRCHCs may be at risk of endorsing disordered eating behaviors that may lead to diagnosis of an eating disorder and other health problems over the course of their treatment. Thus, health care providers should be aware that young people with DRCHCs may be at risk of eating disorders and carefully monitor psychological changes and the use of unhealthy weight control methods. It is also important to develop and evaluate theory-based interventions and disease-specific eating disorder risk screening tools that are effective in halting the progression of eating disorders and negative health outcomes in young people with chronic health conditions. PMID- 23674794 TI - Impaired calcium entry into cells is associated with pathological signs of zinc deficiency. AB - Zinc is an essential trace element whose deficiency gives rise to specific pathological signs. These signs occur because an essential metabolic function is impaired as the result of failure to form or maintain a specific metal-ion protein complex. Although zinc is a component of many essential metalloenzymes and transcription factors, few of these have been identified with a specific sign of incipient zinc deficiency. Zinc also functions as a structural component of other essential proteins. Recent research with Swiss murine fibroblasts, 3T3 cells, has shown that zinc deficiency impairs calcium entry into cells, a process essential for many cell functions, including proliferation, maturation, contraction, and immunity. Impairment of calcium entry and the subsequent failure of cell proliferation could explain the growth failure associated with zinc deficiency. Defective calcium uptake is associated with impaired nerve transmission and pathology of the peripheral nervous system, as well as the failure of platelet aggregation and the bleeding tendency of zinc deficiency. There is a strong analogy between the pathology of genetic diseases that result in impaired calcium entry and other signs of zinc deficiency, such as decreased and cyclic food intake, taste abnormalities, abnormal water balance, skin lesions, impaired reproduction, depressed immunity, and teratogenesis. This analogy suggests that failure of calcium entry is involved in these signs of zinc deficiency as well. PMID- 23674795 TI - Dietary fats and health: dietary recommendations in the context of scientific evidence. AB - Although early studies showed that saturated fat diets with very low levels of PUFAs increase serum cholesterol, whereas other studies showed high serum cholesterol increased the risk of coronary artery disease (CAD), the evidence of dietary saturated fats increasing CAD or causing premature death was weak. Over the years, data revealed that dietary saturated fatty acids (SFAs) are not associated with CAD and other adverse health effects or at worst are weakly associated in some analyses when other contributing factors may be overlooked. Several recent analyses indicate that SFAs, particularly in dairy products and coconut oil, can improve health. The evidence of omega6 polyunsaturated fatty acids (PUFAs) promoting inflammation and augmenting many diseases continues to grow, whereas omega3 PUFAs seem to counter these adverse effects. The replacement of saturated fats in the diet with carbohydrates, especially sugars, has resulted in increased obesity and its associated health complications. Well-established mechanisms have been proposed for the adverse health effects of some alternative or replacement nutrients, such as simple carbohydrates and PUFAs. The focus on dietary manipulation of serum cholesterol may be moot in view of numerous other factors that increase the risk of heart disease. The adverse health effects that have been associated with saturated fats in the past are most likely due to factors other than SFAs, which are discussed here. This review calls for a rational reevaluation of existing dietary recommendations that focus on minimizing dietary SFAs, for which mechanisms for adverse health effects are lacking. PMID- 23674797 TI - Linoleic acid. PMID- 23674796 TI - A novel approach localizes the association of vitamin D status with insulin resistance to one region of the 25-hydroxyvitamin D continuum. AB - Vitamin D status has been implicated in insulin resistance, type 2 diabetes mellitus, and hypertension, but the range of vitamin D status values over which the association can be found is unknown. Our objective was to define this range in a cohort of nondiabetic adult Canadians. We used a regression modeling strategy, first adjusting insulin-response variables and systolic and diastolic blood pressure for BMI, waist circumference, weight, age, and sex. The resulting residuals were regressed against serum 25-hydroxyvitamin D [25(OH)D] concentration using successive 40% data blocks ranging from the 0th to the 60th percentile of 25(OH)D values. All of the predictor variables were significantly associated with each of the dependent variables, with BMI and waist circumference accounting for >98% of the explained variance. The vitamin D association was localized to the serum 25(OH)D range extending from ~40 to ~90 nmol/L (16-36 MUg/L). We conclude that vitamin D status is inversely associated with insulin responsiveness and blood pressure. Consistent with the threshold response characteristic typical of nutrients, the association was strongest in a circumscribed region of the range of 25(OH)D values. There was no association at 25(OH)D values >80-90 nmol/L (32-36 MUg/L), indicating that the vitamin D association applied principally to values below that level. The differences observed, if they can be further confirmed in prospective studies, are of a magnitude that would be clinically important. PMID- 23674798 TI - Centers for Disease Control and Prevention. 2013. Vital signs: binge drinking among women and high school girls--United States, 2011. PMID- 23674800 TI - White vegetables: a forgotten source of nutrients: Purdue roundtable executive summary. AB - Purdue University convened a scientific roundtable, "White Vegetables: A Forgotten Source of Nutrients," in Chicago, IL, June 18-19, 2012, to bring together experts to address the contributions of white vegetables, including potatoes, as sources of key nutrients and other microconstituents within a dietary pattern supporting health and wellness. This paper summarizes the meeting and supplement papers, including discussion among participants. The group of researchers identified areas of ambiguity regarding classification of vegetables for research and dietary guidance, future research needs, and the imperative to draw on that research to enhance evidence-based dietary guidance about white vegetables, including potatoes. U.S. dietary guidance encourages consumption of a variety of fruits and vegetables, including at least 1 serving of a dark green and 1 orange vegetable daily. However, no such recommendation exists for white vegetables, such as potatoes, cauliflowers, turnips, onions, parsnips, mushrooms, corn, and kohlrabi. Vegetable subgrouping approaches need to be considered in the context of nutrients of concern and low fruits and vegetable consumption. This Roundtable and supplement provide a substantial body of evidence to demonstrate how the inclusion of white vegetables, such as potatoes, can increase shortfall nutrients, notably fiber, potassium, and magnesium, as well as help increase overall vegetable consumption among children, teens, and adults in the United States. In so doing, these increases can help consumers to effectively and economically meet the recommended 2010 Dietary Guidelines for Americans vegetable servings and improve nutrient intake for all age and sex categories. Although inclusion of many types of vegetables in the diet improves nutritional adequacy, a priority public health message is to increase vegetable consumption. Potatoes appear to be a pathway to increased vegetable consumption, thereby helping to meet the recommended 2010 Dietary Guidelines for Americans servings for vegetables provided the forms served limit the amount of added salt and fat. Potatoes, in all forms, when consumed in MyPlate serving sizes, can be part of health-promoting dietary patterns. More research is needed to determine the health contributions of white vegetables as a source of nutrients and bioactive constituents and their bioavailability beyond the isolated components. PMID- 23674801 TI - In nutrition, can we "see" what is good for us? AB - The selection of foods to eat is a complex interplay of vision, taste, smell, and texture. In addition to micro- and macronutrients, plant-based foods also contain several classes of phytochemicals. In many cases, the phytochemicals account for the various colors of foods. Although aesthetically pleasing, the color of foods may mislead consumers as to their phytochemical content, which is particularly true with regard to polyphenols. Polyphenols are a broad class of compounds with antioxidant and other health benefits. Human vision is limited to a small window (390-765 nm) of the electromagnetic spectrum. Many important phytochemicals (e.g., vitamin C) have no absorbance in this range. Therefore, the human eye cannot directly judge the vitamin C content of foods. Being able to see in the ultraviolet range allows bees to locate the pollen-rich region of flowers, whereas pit vipers locate their prey by being able to "see" them in the infrared range. Assessing the impact of phytochemicals on human health depends on several factors. Colorless phytochemicals in unprocessed foods may be lost during the cooking process because no visual guide exists to ensure their retention. The molecular structures of phytochemicals influence the extent to which they are altered by cooking processes and the methods by which they are absorbed from the gastrointestinal tract. Extensive metabolism by phase I/II enzymes and by the gut microbiome may also create compounds that the eye is never allowed to appreciate. PMID- 23674802 TI - Contributions of white vegetables to nutrient intake: NHANES 2009-2010. AB - Vegetables, especially white potatoes, provide significant levels of key nutrients of concern, such as potassium and dietary fiber. Per capita availability (PCA) data for vegetables-often used as a proxy for vegetable consumption-show that vegetable consumption, including consumption of white potatoes, declined in the past decade. Using dietary data for participants in the NHANES 2009-2010, we examined total vegetable, white potato, and French-fried potato consumption among all age-gender groups as well as mean energy, potassium, and dietary fiber intakes. Mean total energy intake for the US population (>=2 y old) was 2080 kcal/d, with white potatoes and French-fried potatoes providing ~4% and ~2% of total energy, respectively. Individuals who consumed white potatoes had significantly higher total vegetable and potassium intakes than did nonconsumers. In addition, the proportion of potassium and dietary fiber contributed by white potatoes was higher than the proportion that they contributed to total energy. Among white potato consumers aged 14-18 y, white potatoes provided ~23% of dietary fiber and ~20% of potassium but only ~11% of total energy in the diet. The nutrient-dense white potato may be an effective way to increase total vegetable consumption and potassium and dietary fiber intake. PMID- 23674803 TI - Innovations in food chemistry and processing to enhance the nutrient profile of the white potato in all forms. AB - Potatoes can be an important part of a balanced diet because they are an excellent source of many nutrients, including nutrients that are commonly underconsumed (dietary fiber and potassium). Despite the existence of many positive nutrients in potatoes, the popular press has recently aligned potatoes, and particularly fried potatoes, with an unhealthy diet. This article examines the nutritional content of potatoes and how these nutrients are affected by cooking and other food-processing operations. In addition, it examines how the nutritional content of potatoes is altered by cooking methods and how fried potatoes can have wide variations in fat content depending on the cooking method. Finally, the potential of new food-processing technologies to improve the nutritional content of cooked potatoes is evaluated. PMID- 23674804 TI - Carbohydrates, dietary fiber, and resistant starch in white vegetables: links to health outcomes. AB - Vegetables are universally promoted as healthy. Dietary Guidelines for Americans 2010 recommend that you make half of your plate fruits and vegetables. Vegetables are diverse plants that vary greatly in energy content and nutrients. Vegetables supply carbohydrates, dietary fiber, and resistant starch in the diet, all of which have been linked to positive health outcomes. Fiber lowers the incidence of cardiovascular disease and obesity. In this paper, the important role of white vegetables in the human diet is described, with a focus on the dietary fiber and resistant starch content of white vegetables. Misguided efforts to reduce consumption of white vegetables will lower intakes of dietary fiber and resistant starch, nutrients already in short supply in our diets. PMID- 23674805 TI - White vegetables: glycemia and satiety. AB - The objective of this review is to discuss the effect of white vegetable consumption on glycemia, satiety, and food intake. White vegetables is a term used to refer to vegetables that are white or near white in color and include potatoes, cauliflowers, turnips, onions, parsnips, white corn, kohlrabi, and mushrooms (technically fungi but generally considered a vegetable). They vary greatly in their contribution to the energy and nutrient content of the diet and glycemia and satiety. As with other foods, the glycemic effect of many white vegetables has been measured. The results illustrate that interpretation of the semiquantitative comparative ratings of white vegetables as derived by the glycemic index must be context dependent. As illustrated by using the potato as an example, the glycemic index of white vegetables can be misleading if not interpreted in the context of the overall contribution that the white vegetable makes to the carbohydrate and nutrient composition of the diet and their functionality in satiety and metabolic control within usual meals. It is concluded that application of the glycemic index in isolation to judge the role of white vegetables in the diet and, specifically in the case of potato as consumed in ad libitum meals, has led to premature and possibly counterproductive dietary guidance. PMID- 23674807 TI - Magnesium in disease prevention and overall health. AB - Magnesium is the fourth most abundant mineral and the second most abundant intracellular divalent cation and has been recognized as a cofactor for >300 metabolic reactions in the body. Some of the processes in which magnesium is a cofactor include, but are not limited to, protein synthesis, cellular energy production and storage, reproduction, DNA and RNA synthesis, and stabilizing mitochondrial membranes. Magnesium also plays a critical role in nerve transmission, cardiac excitability, neuromuscular conduction, muscular contraction, vasomotor tone, blood pressure, and glucose and insulin metabolism. Because of magnesium's many functions within the body, it plays a major role in disease prevention and overall health. Low levels of magnesium have been associated with a number of chronic diseases including migraine headaches, Alzheimer's disease, cerebrovascular accident (stroke), hypertension, cardiovascular disease, and type 2 diabetes mellitus. Good food sources of magnesium include unrefined (whole) grains, spinach, nuts, legumes, and white potatoes (tubers). This review presents recent research in the areas of magnesium and chronic disease, with the goal of emphasizing magnesium's role in disease prevention and overall health. PMID- 23674806 TI - Potassium and health. AB - Potassium was identified as a shortfall nutrient by the Dietary Guidelines for Americans 2010 Advisory Committee. The committee concluded that there was a moderate body of evidence of the association between potassium intake and blood pressure reduction in adults, which in turn influences the risk of stroke and coronary heart disease. Evidence is also accumulating of the protective effect of adequate dietary potassium on age-related bone loss and reduction of kidney stones. These benefits depend on organic anions associated with potassium as occurs in foods such as fruits and vegetables, in contrast to similar blood pressure-lowering benefits of potassium chloride. Benefits to blood pressure and bone health may occur at levels below current recommendations for potassium intake, especially from diet, but dose-response trials are needed to confirm this. Nevertheless, intakes considerably above current levels are needed for optimal health, and studies evaluating small increases in fruit and vegetable intake on bone and heart outcomes for short periods have had disappointing results. In modern societies, Western diets have led to a decrease in potassium intake with reduced consumption of fruits and vegetables with a concomitant increase in sodium consumption through increased consumption of processed foods. Consumption of white vegetables is associated with decreased risk of stroke, possibly related to their high potassium content. Potatoes are the highest source of dietary potassium, but the addition of salt should be limited. Low potassium to-sodium intake ratios are more strongly related to cardiovascular disease risk than either nutrient alone. This relationship deserves further attention for multiple target tissue endpoints. PMID- 23674809 TI - White potatoes, human health, and dietary guidance. AB - The white potato is a concentrated source of carbohydrate, dietary fiber, and resistant starch and continues to be the staple food of choice for many cultures. The white potato is also a concentrated source of vitamin C and potassium. Two of the nutrients in white potatoes, dietary fiber and potassium, have been designated as nutrients of concern in the 2010 Dietary Guidelines for Americans. Potatoes are often maligned in nutrition circles because of their suspected link to obesity, and popular potato foods often contain more fat calories than carbohydrate calories. Some food guides do not include potatoes in the vegetable group because of their association with high-fat diets. However, potatoes should be included in the vegetable group because they contribute critical nutrients. All white vegetables, including white potatoes, provide nutrients needed in the diet and deserve a prominent position in food guides. PMID- 23674808 TI - Health-promoting components of fruits and vegetables in the diet. AB - Regular consumption of fruits, vegetables, whole grains, and other plant foods has been negatively correlated with the risk of the development of chronic diseases. There is a huge gap between the average consumption of fruits and vegetables in Americans and the amount recommended by the 2010 Dietary Guidelines for Americans. The key is to encourage consumers to increase the total amount to 9 to 13 servings of fruits and vegetables in all forms available. Fresh, processed fruits and vegetables including frozen and canned, cooked, 100% fruit juices and 100% vegetable juices, as well as dry fruits are all considered as servings of fruits and vegetables per day. A wide variety of fruits, vegetables, whole grains, and other plant foods provide a range of nutrients and different bioactive compounds including phytochemicals, vitamins, minerals, and fibers. Potatoes serve as one of the low-fat foods with unique nutrients and phytochemical profiles, particularly rich in vitamin C, vitamin B-6, potassium, manganese, and dietary fibers. Potatoes provide 25% of vegetable phenolics in the American diet, the largest contributors among the 27 vegetables commonly consumed in the United States, including flavonoids (quercetin and kaempferol), phenolic acids (chlorogenic acid and caffeic acid), and carotenoids (lutein and zeaxanthin). More and more evidence suggests that the health benefits of fruits, vegetables, whole grains, and other plant foods are attributed to the synergy or interactions of bioactive compounds and other nutrients in whole foods. Therefore, consumers should obtain their nutrients, antioxidants, bioactive compounds, and phytochemicals from a balanced diet with a wide variety of fruits, vegetables, whole grains, and other plant foods for optimal nutrition, health, and well-being, not from dietary supplements. PMID- 23674810 TI - Nebulized albuterol delivery in a model of spontaneously breathing children with tracheostomy. AB - BACKGROUND: Nebulized therapy is commonly used in spontaneously breathing tracheostomized patients, despite a lack of recommended devices and techniques. I compared albuterol dose delivered to a model of spontaneously breathing children with tracheostomy, using different nebulizers, tracheostomy tube sizes, inhalation techniques, and breathing patterns. METHODS: A tracheostomy model was connected in series to a breathing simulator, with a filter interposed. I simulated the breathing patterns of a 16-month-old child and 12-year-old child, and tested tracheostomy tubes with internal diameters of 3.5 mm and 5.5 mm. Albuterol nebulizer solution (2.5 mg/3 mL) was used. A breath-enhanced nebulizer (Pari LC Plus), a breath-actuated nebulizer (AeroEclipse), and a nebulizer that continuously delivers aerosol (Up-Draft II Opti-Neb) were operated for 5 min at 6 L/min with wall air. The Up-Draft II was tested with T-piece and mask interfaces, with an extension tube, and with and without assisted breathing (every breath and every other breath). The amount of albuterol delivered was analyzed via spectrophotometry. Particle size distribution was measured with a cascade impactor. RESULTS: The Pari LC Plus was more efficient than the Up-Draft II or AeroEclipse. Assisted breathing with the Up-Draft II with extension increased albuterol delivery with every other breath (second best device/configuration), being superior to every breath technique. Adding an extension tube increased delivered albuterol. T-piece was more efficient than mask. Breathing patterns with larger tidal volume increased albuterol delivery. Tracheostomy size had less impact on drug delivery. Mass median aerodynamic diameter decreased by 48-74% when passing through the tracheostomy tubes, and 0.8% of the nominal dose was deposited in the tracheostomy tube. CONCLUSIONS: Albuterol delivery in a model of spontaneously breathing children with tracheostomy is influenced by type of device and configuration, use of assisted breathing, breathing pattern, and tracheostomy tube size. Mass median aerodynamic diameter significantly decreases during passage through a tracheostomy tube. PMID- 23674811 TI - The influence of purulence on ciliary and cough transport in bronchiectasis. AB - BACKGROUND: Individuals with bronchiectasis exhibit colonization and infection of the respiratory system, with a consequent alteration of the macroscopic appearance of secretions, which ranges from mucoid to purulent. Purulence is related to the structural conformation, rheological profile, and transport indexes of mucus. We analyzed and compared the transport properties of respiratory secretions with mucoid appearance versus those with purulent appearance in patients with bronchiectasis and in subjects without lung disease. METHODS: In a simulated cough machine we assessed the mucociliary transport and contact angle of 32 mucoid and 19 purulent samples from subjects with bronchiectasis, and 21 samples from subjects without lung disease. RESULTS: Mucociliary transport was lower in the mucoid samples (0.78 +/- 0.22) and in the purulent samples (0.73 +/- 0.22) than in the samples from subjects without lung disease (1 +/- 0.19). The purulent samples had less displacement in the simulated cough machine (7.57 +/- 3 cm) than did the mucoid samples (23 +/- 15 cm) or the samples from subjects without lung disease (34 +/- 8.4 cm), as did the mucoid samples compared to the samples from subjects without lung disease. The purulent samples had a higher contact angle (25 +/- 6.1 degrees ) than the mucoid samples (17 +/- 7.8 degrees ) or the samples from subjects without lung disease (10 +/- 2.5 degrees ), as did the mucoid samples compared to the samples from subjects without lung disease. CONCLUSIONS: Respiratory secretions in individuals with bronchiectasis have poor transport properties, which manifest as reduced mucociliary transport, reduced mucus transport by cough, and higher contact angle. These features were more accentuated in the purulent samples. This simple classification can be used by therapists to plan treatments, and by researchers to obtain more homogeneity between groups of subjects. PMID- 23674812 TI - In vitro evaluation of heat and moisture exchangers designed for spontaneously breathing tracheostomized patients. AB - BACKGROUND: Heat and moisture exchangers (HMEs) are commonly used in chronically tracheostomized spontaneously breathing patients, to condition inhaled air, maintain lower airway function, and minimize the viscosity of secretions. Supplemental oxygen (O2) can be added to most HMEs designed for spontaneously breathing tracheostomized patients. We tested the efficiency of 7 HMEs designed for spontaneously breathing tracheostomized patients, in a normothermic model, at different minute ventilations (VE) and supplemental O2 flows. METHODS: HME efficiency was evaluated using an in vitro lung model at 2 VE (5 and 15 L/min) and 4 supplemental O2 flows (0, 3, 6, and 12 L/min). Wet and dry temperatures of the inspiratory flow were measured, and absolute humidity was calculated. In addition, HME efficiency at 0, 12, and 24 h use was evaluated, as well as resistance to flow at 0 and 24 h. RESULTS: The progressive increase in O2 flow from 0 to 12 L/min was associated with a reduction in temperature and absolute humidity. Under the same conditions, this effect was greater at lower VE. The HME with the best performance provided an absolute humidity of 26 mg H2O/L and a temperature of 27.8 degrees C. No significant changes in efficiency or resistance were detected during the 24 h evaluation. CONCLUSIONS: The efficiency of HMEs in terms of temperature and absolute humidity is significantly affected by O2 supplementation and V(E). PMID- 23674813 TI - Non-cardiogenic pulmonary edema and life-threatening shock due to calcium channel blocker overdose: a case report and clinical review. AB - Calcium channel blockers (CCBs) overdose can be life-threatening when manifest as catastrophic shock and non-cardiogenic pulmonary edema. We describe a case of massive overdose of multiple medications, including sustained-release verapamil, which was resistant to conventional support. Initial treatment for CCB overdose is primarily supportive, and includes fluid resuscitation. The mechanism of non cardiogenic pulmonary edema is not well known, and reported cases have been successfully treated with mechanical ventilation. Circulatory shock may fail to respond to atropine, glucagon, and calcium in severely poisoned patients, and vasopressors are usually required. Attempting to overcome calcium-channel antagonism with the supra-therapeutic doses of calcium salts is clinically indicated to reverse hypotension and bradycardia. There is evidence that hyperinsulinemia-euglycemia therapy is superior to other therapies for CCB poisoning, and the mechanism is thought to be the insulin-mediated active transport of glucose into the cells, which counters the CCB-induced intra cellular carbohydrate-deficient state. Conventional decontamination measures are ineffective in accelerating clearance of CCB. Experience with intravenous lipid emulsion for lipophilic drug overdose, such as verapamil, is limited, but has been proposed as a rescue therapy and might improve cardiac inotropy through intravascular sequestration of the lipophilic CCB. PMID- 23674814 TI - Chest wall mobility is related to respiratory muscle strength and lung volumes in healthy subjects. AB - BACKGROUND: Chest wall mobility is often measured in clinical practice, but the correlations between chest wall mobility and respiratory muscle strength and lung volumes are unknown. We investigate the associations between chest wall mobility, axillary and thoracic cirtometry values, respiratory muscle strength (maximum inspiratory pressure and maximum expiratory pressure), and lung volumes (expiratory reserve volume, FEV(1), inspiratory capacity, FEV(1)/FVC), and the determinants of chest mobility in healthy subjects. METHODS: In 64 healthy subjects we measured inspiratory capacity, FVC, FEV(1), expiratory reserve volume, maximum inspiratory pressure, and maximum expiratory pressure, and chest wall mobility via axillary and thoracic cirtometry. We used linear regression to evaluate the influence of the measured variables on chest wall mobility. RESULTS: The subjects' mean +/- SD values were: age 24 +/- 3 years, axillary cirtometry 6.3 +/- 2.0 cm, thoracic cirtometry 7.5 +/- 2.3 cm; maximum inspiratory pressure 90.4 +/- 10.6% of predicted, maximum expiratory pressure 92.8 +/- 13.5% of predicted, inspiratory capacity 99.7 +/- 8.6% of predicted, FVC 101.9 +/- 10.6% of predicted, FEV(1) 98.2 +/- 10.3% of predicted, expiratory reserve volume 90.9 +/- 19.9% of predicted. There were significant correlations between axillary cirtometry and FVC (r = 0.32), FEV(1) (r = 0.30), maximum inspiratory pressure (r = 0.48), maximum expiratory pressure (r = 0.25), and inspiratory capacity (r = 0.24), and between thoracic cirtometry and FVC (r = 0.50), FEV(1) (r = 0.48), maximum inspiratory pressure (r = 0.46), maximum expiratory pressure (r = 0.37), inspiratory capacity (r = 0.39), and expiratory reserve volume (r = 0.47). In multiple regression analysis the variable that best explained the axillary cirtometry variation was maximum inspiratory pressure (R(2) 0.23), and for thoracic cirtometry it was FVC and maximum inspiratory pressure (R(2) 0.32). CONCLUSIONS: Chest mobility in healthy subjects is related to respiratory muscle strength and lung function; the higher the axillary cirtometry and thoracic cirtometry values, the greater the maximum inspiratory pressure, maximum expiratory pressure, and lung volumes in healthy subjects. PMID- 23674816 TI - Clinical implication of FDG-PET/CT in monitoring disease activity in IgG4-related disease. PMID- 23674815 TI - Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer. AB - In human cancers, loss of PTEN, stabilization of hypoxia inducible factor-1alpha, and activation of Ras and AKT converge to increase the activity of a key regulator of glycolysis, 6-phosphofructo-2-kinase (PFKFB3). This enzyme synthesizes fructose 2,6-bisphosphate (F26BP), which is an activator of 6 phosphofructo-1-kinase, a key step of glycolysis. Previously, a weak competitive inhibitor of PFKFB3, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), was found to reduce the glucose metabolism and proliferation of cancer cells. We have synthesized 73 derivatives of 3PO and screened each compound for activity against recombinant PFKFB3. One small molecule, 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen 1-one (PFK15), was selected for further preclinical evaluation of its pharmacokinetic, antimetabolic, and antineoplastic properties in vitro and in vivo. We found that PFK15 causes a rapid induction of apoptosis in transformed cells, has adequate pharmacokinetic properties, suppresses the glucose uptake and growth of Lewis lung carcinomas in syngeneic mice, and yields antitumor effects in three human xenograft models of cancer in athymic mice that are comparable to U.S. Food and Drug Administration-approved chemotherapeutic agents. As a result of this study, a synthetic derivative and formulation of PFK15 has undergone investigational new drug (IND)-enabling toxicology and safety studies. A phase I clinical trial of its efficacy in advanced cancer patients will initiate in 2013 and we anticipate that this new class of antimetabolic agents will yield acceptable therapeutic indices and prove to be synergistic with agents that disrupt neoplastic signaling. PMID- 23674817 TI - Expression of cathepsin K and tartrate-resistant acid phosphatase is not confined to osteoclasts but is a general feature of multinucleated giant cells: systematic analysis. AB - OBJECTIVE: Cathepsin K and tartrate-resistant acid phosphatase (TRAP) are two proteins expressed in osteoclastic giant cells. Recently we showed that lesional multinucleated giant cells (MNGs) in pulmonary granulomatosis with polyangiitis expressed these proteins. We aimed to clarify whether the expression of these two proteins has any specificity or is a general feature of MNGs associated with multiple types of granulomatous inflammation. METHODS: In total, 7 Crohn's disease (CD), 5 GCA, 5 giant cell myocarditis (GCM), 11 sarcoidosis and 6 tuberculosis cases were examined for expression of cathepsin K and TRAP using immunohistochemistry (IHC). Protein expression was semi-quantitatively classified as none, weak, moderate or strong. In addition, tissue TRAP activity was examined using an enzymatic reaction. RESULTS: The expression of cathepsin K was robust in >95% of MNGs of all examined disease groups, whereas TRAP expression varied; CD, GCA and tuberculosis showed strong TRAP expression. TRAP expression in sarcoidosis and GCM was weaker (CD vs GCM, P = 0.04; CD vs sarcoidosis, P = 0.06). Compared with IHC, TRAP detection using an enzymatic colour reaction had limited sensitivity. CONCLUSION: Expression of TRAP and cathepsin K is a general feature of MNGs and their expression might be related to histopathological pattern. PMID- 23674818 TI - Characterization of a new regulatory CD4+ T cell subset in primary Sjogren's syndrome. AB - OBJECTIVE: CD4(+)CD25(low)GITR(+) T lymphocytes expressing FoxP3 and showing regulatory function have been recently described in healthy donors (HD). The objective of the study was to investigate their presence and role in patients with primary SS (pSS). METHODS: CD4(+)CD25(low)GITR(+) cells circulating in peripheral blood (PB) of patients with pSS were isolated by MACS technique, their phenotype was studied by flow cytometry and real-time PCR, and their function was studied by in vitro co-culture. CD4(+)CD25(low)GITR(+) cells infiltrating salivary glands (SGs) were revealed by immunohistochemistry. RESULTS: Results indicated that conventional CD4(+)CD25(high) regulatory T cells (Tregs) are decreased, whereas CD4(+)CD25(low)GITR(+) cells are expanded in the PB of pSS as compared with HD. Phenotypic analysis demonstrated that CD4(+)CD25(low)GITR(+) cells display Treg markers, including FoxP3, TGF-beta and IL-10, and functional experiments demonstrated that they exert a strong inhibitory activity against autologous effector cells. CD4(+)CD25(low)GITR(+) cells were detectable in great number in the SG inflammatory infiltrate. Interestingly, PB CD4(+)CD25(low)GITR(+) cell expansion was evident only in patients with inactive disease, while conventional CD4(+)CD25(high) Treg number was not associated with disease activity. CONCLUSION: The present data demonstrate that circulating CD4(+) cells expressing GITR, but with low levels of CD25 (CD4(+)CD25(low)GITR(+)), are detectable in pSS patients. These cells, displaying Treg phenotype and function, are present in SG inflamed tissues and are expanded in the PB of subjects with inactive disease. Data suggest that the expansion of CD4(+)CD25(low)GITR(+) cells in pSS may represent a counter-regulatory attempt against autoimmune-driven inflammation and may provide a new target for future treatment strategies. PMID- 23674819 TI - Lack of use in the literature from the last 20 years supports dropping traditional schizophrenia subtypes from DSM-5 and ICD-11. AB - The diagnoses of paranoia, catatonia, and hebephrenia preceded the use of dementia praecox and Bleuler's subsequent recognition of a heterogenous "Group of Schizophrenias." With some modification, traditional schizophrenia subtypes have been formalized for many years in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD) classification systems. While widely used in the past, it is not clear that the schizophrenia subtypes remain in wide use or are influential in 21st-century research and clinical practice, and especially in the scientific literature. A review of published articles reveals over the last 20 years (1990, 2000, 2010) the use of traditional subtypes in the literature has fallen from 27.7% to 9.8% to 6.5%. Thus, by 2010, the use of subtypes in the leading literature venues declined to <10%. These facts strongly support DSM-5 and ICD-11 proposed elimination of traditional schizophrenia subtypes from a research and evolving knowledge perspective because traditional subtypes are simply no longer being used much in the scientific literature. PMID- 23674821 TI - A role for Hipk in the Hippo pathway. AB - Since characterization of the Hippo pathway as a major regulator of growth control and organ size, major efforts to unravel the molecular mechanisms that regulate this pathway have been undertaken. These investigations have led to the discovery of diverse upstream regulators of Hippo signaling, the majority of which function to activate the Hippo kinase cascade and thereby restrict the transcriptional output of the downstream targets, Yorkie (Yki) in flies and TAZ and YAP in mammals, collectively Yki/TAZ/YAP. Two studies have delineated a role for HIPK (homeodomain-interacting protein kinase) in promoting Yki/TAZ/YAP transcriptional activity. PMID- 23674822 TI - An increase in synaptic NMDA receptors in the insular cortex contributes to neuropathic pain. AB - Neurons in the insular cortex are activated by acute and chronic pain, and inhibition of neuronal activity in the insular cortex has analgesic effects. We found that in a mouse model in which peripheral nerve injury leads to the development of neuropathic pain, the insular cortex showed changes in synaptic plasticity, which were associated with a long-term increase in the amount of synaptic N-methyl-d-aspartate receptors (NMDARs), but not that of extrasynaptic NMDARs. Activation of cyclic adenosine monophosphate (cAMP)-dependent signaling enhanced the amount of synaptic NMDARs in acutely isolated insular cortical slices and increased the surface localization of NMDARs in cultured cortical neurons. We found that the increase in the amount of NMDARs required phosphorylation of the NMDAR subunit GluN2B at Tyr(1472) by a pathway involving adenylyl cyclase subtype 1 (AC1), protein kinase A (PKA), and Src family kinases. Finally, injecting NMDAR or GluN2B-specific antagonists into the insular cortex reduced behavioral responses to normally nonnoxious stimuli in the mouse model of neuropathic pain. Our results suggest that activity-dependent plasticity takes place in the insular cortex after nerve injury and that inhibiting the increase in NMDAR function may help to prevent or treat neuropathic pain. PMID- 23674824 TI - Elucidating human phosphatase-substrate networks. AB - Phosphatases are crucially involved in cellular processes by dephosphorylating cellular components. We describe a structure-based classification scheme for all active human phosphatases that reveals previously unrecognized relationships between them. By collating protein and nonprotein substrates and integrating colocalization and coexpression data, we generated a human phosphatase-substrate network. Analysis of the protein sequences surrounding sites of dephosphorylation suggested that common recognition mechanisms may apply to both kinases and a subset of phosphatases. Analysis of three-dimensional substrate recognition by protein phosphatases revealed preferred domains in the substrates. We identified phosphatases with highly specific substrates and those with less specificity by examining the relationship between phosphatases, kinases, and their shared substrates and showed how this analysis can be used to generate testable hypotheses about phosphatase biological function. DEPOD (human DEPhOsphorylation Database, version 1.0, http://www.DEPOD.org) is an online resource with information about active human phosphatases, their substrates, and the pathways in which they function. The database includes links to kinases and chemical modulators of phosphatase activity and contains a sequence similarity search function for identifying related proteins in other species. PMID- 23674823 TI - Ubiquitin-specific protease 25 regulates TLR4-dependent innate immune responses through deubiquitination of the adaptor protein TRAF3. AB - Protein ubiquitination plays a critical role in Toll-like receptor (TLR) signaling and innate immunity. Although several E3 ubiquitin ligases have been identified downstream of TLRs, the regulation of protein deubiquitination in TLR triggered innate immune responses is poorly understood. We identified ubiquitin specific protease 25 (USP25) as a regulator of TLR signaling. USP25 was recruited to the TLR4 signaling complex, and it associated with the adaptor proteins tumor necrosis factor receptor-associated factor 3 (TRAF3) and TRAF6 after stimulation of TLR4 with its ligand lipopolysaccharide (LPS). USP25 specifically reversed the Lys(48)-linked ubiquitination of TRAF3 that was mediated by the E3 ubiquitin ligase cIAP2 (cellular inhibitor of apoptosis 2). Deficiency in USP25 enhanced the extent of ubiquitination of TRAF3 and accelerated its degradation after TLR4 activation, which potentiated TLR4-induced activation of NF-kappaB (nuclear factor kappaB) and MAPK (mitogen-activated protein kinase) signaling, but inhibited activation of the transcription factor IRF3 (interferon regulatory factor 3). USP25-deficient mice exhibited increased susceptibility to LPS-induced septic shock compared to their wild-type counterparts, which was associated with enhanced production of proinflammatory cytokines and decreased production of interferon-alpha. Thus, by inhibiting the degradation of TRAF3 during TLR4 activation, USP25 enables a balanced innate immune response. PMID- 23674825 TI - The current situation of voluntary vaccination and the factors influencing its coverage among children in Takatsuki, Japan: focus on Hib and pneumococcal vaccines. AB - This study aimed to understand the current scenario of voluntary vaccination and the factors influencing its coverage among 18-month-old children of Takatsuki City, Japan. Based on 1167 parents responses, we found that voluntary vaccination coverage rates were low when compared with routine vaccination rates. The children who were not the first born of the family and who had young and poorly educated parents were less likely to receive voluntary vaccination. Japanese government-supported vaccines, such as Haemophilus influenzae type b and pneumococcal vaccine, had a higher coverage than the vaccines for which parents had to bear the entire vaccination cost. Furthermore, it was found that mass communication media and family pediatricians were effective means to disseminate voluntary vaccination-related information. We envisage that an active participation of medical professionals, easy access to vaccinations, and mass awareness programs will increase voluntary vaccination coverage in Takatsuki. PMID- 23674826 TI - A qualitative study of risk factors related to child malnutrition in Aileu District, Timor-Leste. AB - Improvement in child nutritional status is one of the major health priorities in Timor-Leste. A qualitative study was conducted in Aileu District, adjacent to the capital of Timor-Leste, Dili, in September 2010 to determine the possible risk factors associated with the high prevalence of child malnutrition. In-depth interviews were conducted to 32 guardians of children aged younger than 5 years. It was observed that early termination of exclusive breast-feeding and a short lactation period along with an unsanitary living environment were associated with the nutritional status of children in the study area. Although previous surveys have reported poor food security conditions in the country, no statements from the subjects supported this contention. The identified possible risk factors for child malnutrition were closely linked to each other and were mostly modifiable. PMID- 23674827 TI - The relationship between changes in employment status and mortality risk based on the Korea Labor and Income Panel Study (2003-2008). AB - The aim of this study was to analyze the relationship between the mortality rate and changes in employment status. This study used mortality data from the Korean Labor and Income Panel Study. To analyze the relationship between the mortality rate and changes in employment status, the population was classified into employed, unemployed, or economically inactive. Demographic and socioeconomic variables such as gender, age, educational level, annual household income, marital status, and self-rated health status were controlled. In this study, the generalized estimating equations were used to analyze the relationship between the morality rate and the changes in employment status. The mortality rate was higher (odds ratio = 4.31) among the population that experienced a change in economic status from employed to unemployed than those who maintained employment. The mortality rate for the population who became unemployed or economically inactive was higher (odds ratio = 5.05) in cases of death by disease. PMID- 23674828 TI - Glutamate oxaloacetate transaminase: a new key in the dysregulation of glutamate in migraine patients. AB - OBJECTIVE: Based on the capacity of the blood-resident enzyme glutamate oxaloacetate transaminase (GOT) to metabolize blood glutamate, our aim was to study the association of GOT activity with serum glutamate levels and clinical parameters in patients with migraine. METHODS: This case-control study included 45 episodic migraine patients (IHS 2004 criteria) and 16 control subjects. We analyzed glutamate and GOT activity in peripheral blood samples obtained during interictal periods and migraine attacks ( N = 15). Frequency, severity, and duration of attacks and time of evolution were also recorded. RESULTS: Migraine patients showed lower GOT activity than controls (15.2 +/- 2.9 vs. 18.7 +/- 3.8 U/l) and higher levels of glutamate (153.7 +/- 68.6 vs. 121.5 +/- 59.2 MUM) (all P < 0.05). A negative correlation was found between GOT activity and glutamate levels ( R = -0.493; P < 0.0001) in interictal periods; however, this negative correlation was lost during attacks ( R = -0.026; P = 0.925). During attacks, we found a positive correlation between the time elapsed from attack onset and glutamate levels ( R = 0.738; P < 0.0001), but not for GOT activity ( R = 0.075; P = 0.809). CONCLUSIONS: Migraine patients showed reduced GOT activity and increased levels of blood glutamate levels as compared to control subjects. Furthermore, a negative correlation was found between GOT activity and glutamate levels in interictal periods. PMID- 23674829 TI - Transient unilateral spatial neglect during aura in a woman with sporadic hemiplegic migraine. AB - BACKGROUND: Hemiplegic migraine is a rare form of migraine with aura characterized by motor aura. Although auras in hemiplegic migraine are typically complex with two or more aura symptoms, neglect has been rarely described. CASE REPORT: We report the case of a 20-year-old woman with sporadic hemiplegic migraine that was investigated for the presence of unilateral spatial neglect (USN) during aura in one of her migraine attacks. Transient hemispatial neglect was observed during a right-sided migraine attack with left sensory-motor hemisyndrome; after migraine resolution there was a total recovery. CONCLUSIONS: Our case demonstrates that USN may be a symptom of aura. To our knowledge, this is the first report of USN during aura in an adult with sporadic hemiplegic migraine. PMID- 23674830 TI - Association of oestrogen-receptor gene (ESR1) polymorphisms with migraine in the large Norfolk Island pedigree. AB - BACKGROUND: Oestrogen receptor 1 ( ESR1) is located in region 6q25.1 and encodes a ligand-activated transcription factor composed of several domains important for hormone binding and transcription activation. Progesterone receptor ( PGR) is located in 11q22-23 and mediates the role of progesterone interacting with different transcriptional co-regulators. ESR1 and PGR have previously been implicated in migraine susceptibility. Here, we report the results of an association study of these genes in a migraine pedigree from the genetic isolate of Norfolk Island, a population descended from a small number of Isle of Man "Bounty Mutineer" and Tahitian founders. METHODS: A significant number of molecular markers in the ESR1 (143) and PGR (43) genes were evaluated in a sample of 285 related individuals (135 males; 150 females). A pedigree-based analysis in the GenABEL package was used to analyse the results. RESULTS AND CONCLUSIONS: A total of 10 markers in the ESR1 gene showed association with migraine ( P < 0.05) in the Norfolk Island population. No association was detected with PGR . Three haplotypes in ESR1 were found to be associated with migraine ( P = 0.004, 0.03, 0.005). Future genetic studies in larger populations and expression analysis are required to clarify the role of ESR1 in migraine susceptibility. PMID- 23674831 TI - Lacrimal neuralgia: so far, a missing cranial neuralgia. AB - BACKGROUND: The lacrimal nerve supplies the lacrimal gland, the lateral upper eyelid, and a small cutaneous area adjacent to the external CANTHUS . First division trigeminal neuralgia, supraorbital/supratrochlear neuralgia, and infraorbital neuralgia have been acknowledged as neuralgic causes of pain in the forehead and periorbit. However, the lacrimal nerve has never been identified as a source of facial pain. Here we report two cases of lacrimal neuralgia. CASE REPORTS: A 66-year-old woman had continuous pain in the lateral aspect of her left superior eyelid and an adjacent area of the temple since age 64. A 33-year old woman suffered from continuous pain in a small area next to the lateral CANTHUS of her left eye since age 25. In both patients the superoexternal edge of the orbit was tender. In addition, sensory dysfunction could be demonstrated within the painful area. Anaesthetic blockades of the lacrimal nerve with lidocaine 2% resulted in complete but short-lasting relief. Pregabalin provided a complete response in the first patient. The second patient was refractory to various oral and topical drugs and different radiofrequency procedures, but she eventually obtained partial relief with pregabalin. CONCLUSIONS: Lacrimal neuralgia should be considered among the neuralgic causes of orbital and periorbital pain. PMID- 23674832 TI - Rocking dizziness and headache: a two-way street. AB - BACKGROUND: Chronic rocking dizziness, often described as the feeling of being on a boat, is classically triggered by prolonged exposure to passive motion. Patients with this motion-triggered sensation of rocking, which is also known as MAL DE DEBARQUEMENT SYNDROME , often develop new onset headaches along with the dizziness. Chronic rocking dizziness has also been noted in vestibular migraine, occurring without a motion trigger. We sought to clarify the association between both motion-triggered (MT) and non-motion-triggered (non-MT) chronic rocking dizziness and headache history. METHODS: Our methods included questionnaire and interview study of subjects with either MT or non-MT chronic rocking dizziness. RESULTS: Onset of headaches was earlier in patients with non-MT rocking dizziness (median 26 years: MT; 16 years: non-MT). In MT subjects, there was a bimodal peak of age of onset of headache (20-29 years and 40-49 years). Most headache met criteria for migraine in both groups. By the time that chronic dizziness occurred, both groups had a comparable prevalence of migraine headache (41%: MT; 46%: non-MT). Pre-existing headache usually worsened after the onset of dizziness. DISCUSSION: Though rocking dizziness does not meet current criteria for vestibular migraine, migraine physiology may predispose to, develop in, or worsen with the onset of chronic rocking dizziness. PMID- 23674833 TI - Predicting risk of coronary events and all-cause mortality: role of B-type natriuretic peptide above traditional risk factors and coronary artery calcium scoring in the general population: the Heinz Nixdorf Recall Study. AB - AIMS: Several biomarkers including B-type natriuretic peptide (BNP) have been suggested to improve prediction of coronary events and all-cause mortality. Moreover, coronary artery calcium (CAC) as marker of subclinical atherosclerosis is a strong predictor for cardiovascular mortality and morbidity. We aimed to evaluate the predictive ability of BNP and CAC for all-cause mortality and coronary events above traditional cardiovascular risk factors (TRF) in the general population. METHODS: We followed 3782 participants of the population based Heinz Nixdorf Recall cohort study without coronary artery disease at baseline for 7.3 +/- 1.3 years. Associations of BNP and CAC with incident coronary events and all-cause mortality were assessed using Cox regression, Harrell's c, and time-dependent integrated discrimination improvement (IDI(t), increase in explained variance). RESULTS: Subjects with high BNP levels had increased frequency of coronary events and death (coronary events/mortality: 14.1/28.2% for BNP >=100 pg/ml vs. 2.7/5.5% for BNP < 100 pg/ml, respectively). Subjects with a BNP >=100 pg/ml had increased incidence of hard endpoints sustaining adjustment for CAC and TRF (for coronary events: hazard ratio (HR) (95% confidence interval (CI)) 3.41(1.78-6.53); for all-cause mortality: HR 3.35(2.15-5.23)). Adding BNP to TRF and CAC increased measures of predictive ability: coronary events (Harrell's c, for coronary events, 0.775-0.784, p = 0.09; for all-cause mortality 0.733-0.740, p = 0.04; and IDI(t) (95% CI), for coronary events: 2.79% (0.33-5.65%) and for all-cause mortality 1.78% (0.73 3.10%). CONCLUSIONS: Elevated levels of BNP are associated with excess incident coronary events and all-cause mortality rates, with BNP and CAC significantly and complementary improving prediction of risk in the general population above TRF. PMID- 23674834 TI - Spleen IL-10, a key player in obesity-driven renal risk. PMID- 23674835 TI - Recurrent IgA nephropathy in the renal allograft: not a benign condition. PMID- 23674837 TI - Retraction of "Enhanced expression of coproporphyrinogen oxidase in malignant brain tumors: CPOX expression and 5-ALA-induced fluorescence". Neuro-Oncology 13(11):1234-1243. PMID- 23674838 TI - Stability of the nicotine metabolite ratio in smokers of progressively reduced nicotine content cigarettes. AB - INTRODUCTION: The nicotine metabolite ratio (NMR), the ratio of trans-3' hydroxycotinine (3-HC) to cotinine, has been used as a biomarker of the rate of CYP2A6-mediated nicotine metabolism. While stable in smokers who maintain constant smoking consumption, since smoking has been shown to inhibit nicotine metabolism and this inhibition could be mediated by the nicotine in the smoke, NMR could change during nicotine reduction. The objective of this study was to determine the reproducibility (or stability) of plasma NMR in smokers of progressively reduced nicotine content (RNC) cigarettes. METHODS: We analyzed data from subjects in a clinical trial of smoking progressively RNC cigarettes. Plasma NMR in 30 smokers whose plasma cotinine levels had decreased by at least 50% from the use of the first test cigarette (12mg nicotine content) to the final test cigarette (1mg nicotine content) was measured on 4 occasions over a period of 24 weeks. RESULTS: Plasma cotinine and 3-HC decreased by an average of 85% and 84%, respectively, following the use of the first type of RNC cigarette to the last type. Plasma NMR had an average absolute change of 28.5% over the same period. Using repeated measures analysis, changes in plasma NMR over time were not significant with or without controlling for the effects of age, body mass index, gender, and race (p = .24 and p = .23, respectively). The reliability coefficient for repeated measurements of plasma NMR was .72. The average within subject coefficient of variation for plasma NMR was 21.6% (SD = 12.0%). CONCLUSION: The plasma NMR is relatively stable over time as nicotine levels decline in smokers of progressively RNC cigarettes. PMID- 23674839 TI - Beliefs and perceptions toward quitting waterpipe smoking among cafe waterpipe tobacco smokers in Bahrain. AB - INTRODUCTION: There is a rising prevalence of waterpipe smoking worldwide, but still a paucity of information on perceptions toward quitting waterpipe use. We set out to establish the beliefs and perceptions of cafe waterpipe smokers toward quitting waterpipe smoking in the Kingdom of Bahrain. METHODS: A cross-sectional study. A random sample of 20 of 91 cafes serving waterpipe tobacco in Bahrain was taken. A questionnaire was administered in each cafe to 20 participants aged 18 and above. RESULTS: Three hundred eighty participants completed questionnaires from waterpipe smokers. Eighty-four percent of participants were Bahraini and 71% had a university degree. Mean age was 28.9 years. Average age of waterpipe smoking initiation was 20.3 years. The majority of waterpipe users chose flavored tobacco. Sixty-one percent smoked waterpipe tobacco daily with a mean smoking time of 2.6hr/day. Seventy-two percent considered waterpipe tobacco as harmful as or more harmful than cigarettes, but 67% considered cigarettes as more addictive. Eighty-two percent stated that they could quit waterpipe at any time, but only 40% were interested in quitting. Interest in quitting smoking was related to 4 variables: a physician mentioning the need to quit smoking, being non-Bahraini, having a family with a hostile attitude toward waterpipe smoking, and not considering oneself "hooked" on waterpipe tobacco. CONCLUSIONS: Waterpipe smokers in Bahrain cafes are frequent and high users. Health professionals must consider waterpipe smoking in all consultations and health promotion messages. A partnership between health professionals and disapproving members of families may be an effective strategy in encouraging waterpipe smokers to quit. PMID- 23674840 TI - To what extent does adding tobacco to cannabis expose young users to nicotine? AB - INTRODUCTION: To determine if mulling, the process of adding tobacco to cannabis for its consumption, exposes young cannabis users to significant levels of nicotine. METHODS: This observational study performed in 2009-2010 among Swiss youths aged 16-25 years involved the completion of a self-administrated questionnaire and the collection of a urine sample on the same day. Measures of urinary cotinine were blindly performed using liquid chromatography coupled-mass spectrometry. A total of 197 eligible participants were divided in 3 groups based on their consumption profile in the past 5 days: 70 abstainers (ABS) not having used cigarettes or cannabis, 57 cannabis users adding tobacco to the cannabis they smoke (MUL) but not having smoked cigarettes, and 70 cigarette smokers (CIG) not having smoked cannabis. RESULTS: Exposure to nicotine was at its lowest among ABS with a mean (SE) cotinine level of 3.2 (1.4) ng/ml compared, respectively, with 214.6 (43.8) and 397.9 (57.4) for MUL and CIG (p < .001). While consumption profile appeared as the only significant factor of influence when examining nicotine exposure from the ABS and MUL participants on multivariate analysis, it did not result in substantial differences among MUL and CIG groups. CONCLUSIONS: Urinary cotinine levels found among MUL are high enough to indicate a significant exposure to nicotine originating from the mulling process. In line with our results, health professionals should pay attention to mulling as it is likely to influence cannabis and cigarette use as well as the efficacy of cessation interventions. PMID- 23674841 TI - Effect of weather and environmental factors on the clinical course of psoriasis. PMID- 23674842 TI - Phytochemical genomics on the way. PMID- 23674843 TI - The effect of carrier gas flow rate and source cell temperature on low pressure organic vapor phase deposition simulation by direct simulation Monte Carlo method. AB - The process of low pressure organic vapor phase deposition (LP-OVPD) controls the growth of amorphous organic thin films, where the source gases (Alq3 molecule, etc.) are introduced into a hot wall reactor via an injection barrel using an inert carrier gas (N2 molecule). It is possible to control well the following substrate properties such as dopant concentration, deposition rate, and thickness uniformity of the thin film. In this paper, we present LP-OVPD simulation results using direct simulation Monte Carlo-Neutrals (Particle-PLUS neutral module) which is commercial software adopting direct simulation Monte Carlo method. By estimating properly the evaporation rate with experimental vaporization enthalpies, the calculated deposition rates on the substrate agree well with the experimental results that depend on carrier gas flow rate and source cell temperature. PMID- 23674844 TI - Surgery for inflammatory bowel disease in the era of laparoscopy. AB - During the course of inflammatory bowel disease (IBD), surgery may be needed. Approximately 20% of patients with ulcerative colitis (UC) will require surgery, whereas up to 80% of Crohn's disease (CD) patients will undergo an operation during their lifetime. For UC patients requiring surgery, total proctocolectomy and ileoanal pouch anastomosis (IPAA) is the operation of choice as it provides a permanent cure and good quality of life. Nevertheless a permanent stoma is a good option in selected patients, especially the elderly. Minimally invasive surgery has replaced the conventional open approach in many specialized centres worldwide. Laparoscopic colectomy and restorative IPAA is rapidly becoming the standard of care in the treatment of UC requiring surgery, whilst laparoscopic ileo-cecal resection is already the new gold standard in the treatment of complicated CD of terminal ileum. Short term advantages of laparoscopic surgery includes faster recovery time and reduced requirement for analgesics. It is, however, in the long term that minimally invasive surgery has demonstrated its superiority over the open approach. A better cosmesis, a reduced number of incisional hernias and fewer adhesions are the long term advantages of laparoscopy in IBD surgery. A reduction in abdominal adhesions is of great benefit when a second operation is needed in CD and this influences positively the pregnancy rate in young women undergoing restorative IPAA. In developing the therapeutic plan for IBD patients it should be recognized that the surgical approach to the abdomen has changed and that surgical treatment of complicated IBD can be safely performed with a true minimally invasive approach with great patient satisfaction. PMID- 23674845 TI - Genetic association of interleukin-6 polymorphism (-174 G/C) with chronic liver diseases and hepatocellular carcinoma. AB - Interleukin-6 (IL-6) is a pleiotropic cytokine which is expressed in many inflammatory cells in response to different types of stimuli, regulating a number of biological processes. The IL-6 gene is polymorphic in both the 5' and 3' flanking regions and more than 150 single nucleotide polymorphisms have been identified so far. Genetic polymorphisms of IL-6 may affect the outcomes of several diseases, where the presence of high levels of circulating IL-6 have been correlated to the stage and/or the progression of the disease itself. The -174 G/C polymorphism is a frequent polymorphism, that is located in the upstream regulatory region of the IL-6 gene and affects IL-6 production. However, the data in the literature on the genetic association between the -174 G/C polymorphism and some specific liver diseases characterized by different etiologies are still controversial. In particular, most of the studies are quite unanimous in describing a correlation between the presence of the high-producer genotype and a worse evolution of the chronic liver disease. This is valid for patients with hepatitis C virus (HCV)-related chronic hepatitis and liver cirrhosis and hepatocellular carcinoma (HCC) whatever the etiology. Studies in hepatitis B virus-related chronic liver diseases are not conclusive, while specific populations like non alcoholic fatty liver disease/non-alcoholic steatohepatitis, autoimmune and human immunodeficiency virus/HCV co-infected patients show a higher prevalence of the low-producer genotype, probably due to the complexity of these clinical pictures. In this direction, a systematic revision of these data should shed more light on the role of this polymorphism in chronic liver diseases and HCC. PMID- 23674846 TI - Annexin A1: A new immunohistological marker of cholangiocarcinoma. AB - AIM: To evaluate a new immunohistological marker, annexin A1 (ANXA1), in cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC). METHODS: Expression of ANXA1 protein was investigated in liver tissues from patients with CCA and HCC by immunohistochemistry. Its expression on differences stages of tumor development was investigated in hamster CCA tissues induced by Opisthorchis viverrini and N-nitrosodimethylamine. Moreover, mRNA expression of ANXA1 was assessed in CCA cell lines by quantitative real-time polymerase chain reaction and silencing of ANXA1 gene expression using small interfering RNA. RESULTS: In human CCA tissue arrays, immunohistochemical analysis revealed that the positive expression of ANXA1 was 94.1% (64/68 cases) consisting of a high expression (66.2%, 45/68 cases) and a low expression (33.8%, 23/68 cases). However, expression of ANXA1 protein was negative in all histologic patterns for HCC (46/46 cases) and healthy individuals (6/6 cases). In hamster with opisthorchiasis-associated CCA, the expression of ANXA1 was observed in the cytoplasm of inflammatory cells, bile duct epithelia and tumor cells. Grading scores of ANXA1 expression were significantly increased with tumor progression. In addition, mRNA expression of ANXA1 significantly increased in all of the various CCA cell lines tested compared to an immortalized human cholangiocyte cell line (MMNK1). Suppressing the ANXA1 gene significantly reduced the matrix metalloproteinase (MMP) 2 and MMP9, and transforming growth factor-beta genes, but increased nuclear factor-kappaB gene expression. CONCLUSION: ANXA1 is highly expressed in CCA, but low in HCC, suggesting it may serve as a new immunohistochemical marker of CCA. ANXA1 may play a role in opisthorchiasis associated cholangiocarcinogenesis. PMID- 23674847 TI - Hepatocellular carcinoma in patients with chronic kidney disease. AB - AIM: To investigate outcomes of hepatocellular carcinomas (HCCs) in patients with chronic kidney disease (CKD). METHODS: Four hundred and forty patients referred between 2000 and 2002 for management of HCCs were categorized according to their CKD stage, i.e., estimated glomerular filtration rate (eGFR) > 90 (stage 1), 60 90 (stage 2), 30-60 (stage 3), 15-30 (stage 4), and < 15 (stage 5) mL/min per 1.73 m2, respectively. Demographic, clinical and laboratory data were collected and mortality rates and cause of mortality were analyzed. The mortality data were examined with Kaplan-meier method and the significance was tested using a log rank test. An initial univariate Cox regression analysis was performed to compare the frequency of possible risk factors associated with mortality. To control for possible confounding factors, a multivariate Cox regression analysis (stepwise backward approach) was performed to analyze those factors that were significant in univariate models (P < 0.05) and met the assumptions of a proportional hazard model. RESULTS: Most HCC patients with CKD were elderly, with mean age of diagnosis of 60.6 +/- 11.9 years, and mostly male (74.8%). Hepatitis B, C and B and C co-infection virus were positive in 61.6%, 45.7% and 14.1% of the patients, respectively. It was found that patients with stages 4 and 5 CKD were not only older (P = 0.001), but also had higher hepatitis C virus carrier rate (P = 0.001), lower serum albumin level (P = 0.001), lower platelet count (P = 0.037), longer prothrombin time (P = 0.001) as well as higher proportions of advanced cirrhosis (P = 0.002) and HCCs (P = 0.001) than patients with stages 1 and 2 CKD. At the end of analysis, 162 (36.9%) patients had died. Kaplan-Meier analysis revealed that patients with stages 4 and 5 CKD suffered lower cumulative survival than stages 1 and 2 CKD (log-rank test, chi2 = 11.764, P = 0.003). In a multivariate Cox-regression model, it was confirmed that CKD stage [odds ratio (OR) = 1.988, 95%CI: 1.012-3.906, P = 0.046)], liver cirrhosis stage (OR = 3.571, 95%CI: 1.590-8.000, P = 0.002) and serum albumin level (OR = 0.657, 95%CI: 0.491 0.878, P = 0.005) were significant predictors for mortality in this population. CONCLUSION: HCC patients with stages 4 and 5 CKD had inferior survival than stages 1 and 2 CKD. This warrants further studies. PMID- 23674848 TI - Overexpression of carbonic anhydrase II and Ki-67 proteins in prognosis of gastrointestinal stromal tumors. AB - AIM: To investigate the expression and prognostic value of carbonic anhydrase II (CA II) and Ki-67 in gastrointestinal stromal tumors (GISTs). METHODS: One hundred and thirteen GIST patients admitted to Chinese People's Liberation Army General Hospital from January 2004 to December 2010 were retrospectively followed up, and immunohistochemistry was used to detect CA II, Ki-67 and CD117 expression in tumor samples. The survival rates of the patients were analyzed using the Kaplan-Meier method. Log-rank test, chi2 test and Cox proportional hazards model were used to determine the relationships between CA II, Ki-67 and CD117 expression and prognostic value in GISTs. RESULTS: The survival rates at 1, 3 and 5 years were 90.0%, 82.0% and 72.0% in all patients. However, in patients with positive CA II or Ki-67, the survival rates were 92.0%, 83.0% and 77.0% or 83.0%, 66.6% and 53.0%, respectively. Compared with the negative groups, the survival rates in the positive groups were significantly lower (CA II log-rank P = 0.000; Ki-67 log-rank P = 0.004). Multivariate Cox analysis revealed that CA II, CD117 and Ki-67 were considerable immune factors in prognosis of GIST patients (CA II P = 0.043; CD117 P = 0.042; Ki-67 P = 0.007). Besides, tumor diameter, mitotic rate, tumor site, depth of invasion, complete resection, intraoperative rupture, and adjuvant therapy were important prognosis predictive factors. Our study indicated that CA II had strong expression in GISTs and the prognosis of GISTs with high CA II expression was better than that of GISTs with low or no expression, suggesting that CA II is both a diagnostic and prognostic biomarker for GIST. CONCLUSION: CA II and Ki-67 are significant prognostic factors for GISTs. CA II associated with neovascular endothelia could serve as a potential target for cancer therapy. PMID- 23674849 TI - Emodin regulating excision repair cross-complementation group 1 through fibroblast growth factor receptor 2 signaling. AB - AIM: To investigate the molecular mechanisms underlying the reversal effect of emodin on platinum resistance in hepatocellular carcinoma. METHODS: After the addition of 10 MUmol/L emodin to HepG2/oxaliplatin (OXA) cells, the inhibition rate (IR), 50% inhibitory concentration (IC50) and reversal index (IC50 in experimental group/IC50 in control group) were calculated. For HepG2, HepG2/OXA, HepG2/OXA/T, each cell line was divided into a control group, OXA group, OXA + fibroblast growth factor 7 (FGF7) group and OXA + emodin group, and the final concentrations of FGF7, emodin and OXA in each group were 5 ng/mL, 10 MUg/mL and 10 MUmol/L, respectively. Single-cell gel electrophoresis was conducted to detect DNA damage, and the fibroblast growth factor receptor 2 (FGFR2), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2) and excision repair cross complementing gene 1 (ERCC1) protein expression levels in each group were examined by Western blotting. RESULTS: Compared with the IC50 of 120.78 MUmol/L in HepG2/OXA cells, the IC50 decreased to 39.65 MUmol/L after treatment with 10 MUmol/L emodin; thus, the reversal index was 3.05. Compared with the control group, the tail length and Olive tail length in the OXA group, OXA + FGF7 group and OXA + emodin group were significantly increased, and the differences were statistically significant (P < 0.01). The tail length and Olive tail length were lower in the OXA + FGF7 group than in the OXA group, and this difference was also statistically significant. Compared with the OXA + FGF7 group, the tail extent, the Olive tail moment and the percentage of tail DNA were significantly increased in the OXA + emodin group, and these differences were statistically significant (P < 0.01). In comparison with its parental cell line HepG2, the HepG2/OXA cells demonstrated significantly increased FGFR2, p-ERK1/2 and ERCC1 expression levels, whereas the expression of all three molecules was significantly inhibited in HepG2/OXA/T cells, in which FGFR2 was silenced by FGFR2 shRNA. In the examined HepG2 cells, the FGFR2, p-ERK1/2 and ERCC1 expression levels demonstrated increasing trends in the OXA group and OXA + FGF7 group. Compared with the OXA group and OXA + FGF7 group, the FGFR2, p-ERK1/2, and ERCC1 expression levels were significantly lower in the OXA + emodin group, and these differences were statistically significant. In the HepG2/OXA/T cell line that was transfected with FGFR2 shRNA, the FGFR2, p-ERK1/2 and ERCC1 expression levels were significantly inhibited, but there were no significant differences in these expression levels among the OXA, OXA + FGF7 and OXA + emodin groups. CONCLUSION: Emodin markedly reversed OXA resistance by enhancing OXA DNA damage in HepG2/OXA cells, and the molecular mechanism was related to the inhibitory effect on ERCC1 expression being mediated by the FGFR2/ERK1/2 signaling pathway. PMID- 23674850 TI - Correlation of fibrinogen-like protein 2 with progression of acute pancreatitis in rats. AB - AIM: To examine fibrinogen-like protein 2 (fgl2) expression during taurocholate induced acute pancreatitis progression in rats and its correlation with pancreatic injury severity. METHODS: Forty-eight male Sprague-Dawley rats were randomly divided into the severe acute pancreatitis (SAP) group (n = 24) and the sham operation (SO) group (n = 24). Sodium taurocholate (4% at doses of 1 mL/kg body weight) was retrogradely injected into the biliopancreatic ducts of the rats to induce SAP. Pancreatic tissues were prepared immediately after sacrifice. At the time of sacrifice, blood was obtained for determination of serum amylase activity and isolation of peripheral blood mononuclear cells (PBMCs). Pancreatic tissue specimens were obtained for routine light microscopy including hematoxylin and eosin staining, and the severity of pancreatic injury was evaluated 1, 4 and 8 h after induction. Expression of fgl2 mRNA was measured in the pancreas and PBMCs using reverse transcription polymerase chain reaction. Expression of fgl2 protein was evaluated in pancreatic tissues using Western blotting and immunohistochemical staining. Masson staining was also performed to observe microthrombosis. RESULTS: At each time point, levels of fgl2 mRNAs in pancreatic tissues and PBMCs were higher (P < 0.05) in the SAP group than in the SO group. For pancreatic tissue in SAP vs SO, the levels were: after 1 h, 3.911 +/- 1.277 vs 1.000 +/- 0.673; after 4 h, 9.850 +/- 3.095 vs 1.136 +/- 0.609; and after 8 h, 12.870 +/- 3.046 vs 1.177 +/- 0.458. For PBMCs in SAP vs SO, the levels were: after 1 h, 2.678 +/- 1.509 vs 1.000 +/- 0.965; after 4 h, 6.922 +/- 1.984 vs 1.051 +/- 0.781; and after 8 h, 13.533 +/- 6.575 vs 1.306 +/- 1.179. Levels of fgl2 protein expression as determined by Western blotting and immunohistochemical staining were markedly up-regulated (P < 0.001) in the SAP group compared with those in the SO group. For Western blotting in SAP vs SO, the results were: after 1 h, 2.183 +/- 0.115 vs 1.110 +/- 0.158; after 4 h, 2.697 +/- 0.090 vs 0.947 +/- 0.361; and after 8 h, 3.258 +/- 0.094 vs 1.208 +/- 0.082. For immunohistochemical staining in SAP vs SO, the results were: after 1 h, 1.793 +/- 0.463 vs 0.808 +/- 0.252; after 4 h, 4.535 +/- 0.550 vs 0.871 +/- 0.318; and after 8 h, 6.071 +/- 0.941 vs 1.020 +/- 0.406. Moreover, we observed a positive correlation in the pancreas (r = 0.852, P < 0.001) and PBMCs (r = 0.735, P < 0.001) between fgl2 expression and the severity of pancreatic injury. Masson staining showed that microthrombosis (%) in rats with SAP was increased (P < 0.001) compared with that in the SO group and it was closely correlated with fgl2 expression in the pancreas (r = 0.842, P < 0.001). For Masson staining in SAP vs SO, the results were: after 1 h, 26.880 +/- 9.031 vs 8.630 +/- 3.739; after 4 h, 53.750 +/- 19.039 vs 8.500 +/- 4.472; and after 8 h, 80.250 +/- 12.915 vs 10.630 +/- 7.003. CONCLUSION: Microthrombosis due to fgl2 overexpression contributes to pancreatic impairment in rats with SAP, and fgl2 level may serve as a biomarker during early stages of disease. PMID- 23674851 TI - How do we manage post-OLT redundant bile duct? AB - AIM: To address endoscopic outcomes of post-Orthotopic liver transplantation (OLT) patients diagnosed with a "redundant bile duct" (RBD). METHODS: Medical records of patients who underwent OLT at the Liver Transplant Center, University Texas Health Science Center at San Antonio Texas were retrospectively analyzed. Patients with suspected biliary tract complications (BTC) underwent endoscopic retrograde cholangiopancreatography (ERCP). All ERCP were performed by experienced biliary endoscopist. RBD was defined as a looped, sigmoid-shaped bile duct on cholangiogram with associated cholestatic liver biomarkers. Patients with biliary T-tube placement, biliary anastomotic strictures, bile leaks, bile-duct stones-sludge and suspected sphincter of oddi dysfunction were excluded. Therapy included single or multiple biliary stents with or without sphincterotomy. The incidence of RBD, the number of ERCP corrective sessions, and the type of endoscopic interventions were recorded. Successful response to endoscopic therapy was defined as resolution of RBD with normalization of associated cholestasis. Laboratory data and pertinent radiographic imaging noted included the pre-ERCP period and a follow up period of 6-12 mo after the last ERCP intervention. RESULTS: One thousand two hundred and eighty-two patient records who received OLT from 1992 through 2011 were reviewed. Two hundred and twenty-four patients underwent ERCP for suspected BTC. RBD was reported in each of the initial cholangiograms. Twenty-one out of 1282 (1.6%) were identified as having RBD. There were 12 men and 9 women, average age of 59.6 years. Primary indication for ERCP was cholestatic pattern of liver associated biomarkers. Nineteen out of 21 patients underwent endoscopic therapy and 2/21 required immediate surgical intervention. In the endoscopically managed group: 65 ERCP procedures were performed with an average of 3.4 per patient and 1.1 stent per session. Fifteen out of 19 (78.9%) patients were successfully managed with biliary stenting. All stents were plastic. Selection of stent size and length were based upon endoscopist preference. Stent size ranged from 7 to 11.5 Fr (average stent size 10 Fr); Stent length ranged from 6 to 15 cm (average length 9 cm). Concurrent biliary sphincterotomy was performed in 10/19 patients. Single ERCP session was sufficient in 6/15 (40.0%) patients, whereas 4/15 (26.7%) patients needed two ERCP sessions and 5/15 (33.3%) patients required more than two (average of 5.4 ERCP procedures). Single biliary stent was sufficient in 5 patients; the remaining patients required an average of 4.9 stents. Four out of 19 (21.1%) patients failed endotherapy (lack of resolution of RBD and recurrent cholestasis in the absence of biliary stent) and required either choledocojejunostomy (2/4) or percutaneous biliary drainage (2/4). Endoscopic complications included: 2/65 (3%) post-ERCP pancreatitis and 2/10 (20%) non-complicated post-sphincterotomy bleeding. No endoscopic related mortality was found. The medical records of the 15 successful endoscopically managed patients were reviewed for a period of one year after removal of all biliary stents. Eleven patients had continued resolution of cholestatic biomarkers (73%). One patient had recurrent hepatitis C, 2 patients suffered septic shock which was not associated with ERCP and 1 patient was transferred care to an outside provider and records were not available for our review. CONCLUSION: Although surgical biliary reconstruction techniques have improved, RBD represents a post-OLT complication. This entity is rare however, endoscopic management of RBD represents a reasonable initial approach. PMID- 23674852 TI - Human leukocyte antigen DQ2/8 prevalence in non-celiac patients with gastrointestinal diseases. AB - AIM: To investigate the prevalence of human leukocyte antigen (HLA) DQ2/8 alleles in Southern Italians with liver and gastrointestinal (GI) diseases outside of celiac disease. METHODS: HLA DQ2/8 status was assessed in 443 patients from three ambulatory gastroenterology clinics in Southern Italy (University of Federico II, Naples, Loreto Crispi Hospital, Ruggi D'Aragona Hospital, Salerno). Patients were grouped based on disease status [pre-post transplant liver disease, esophageal/gastric organic and functional diseases, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD)] and DQ2/8 alleles, which correspond to a celiac disease genetic risk gradient. Subject allele frequencies were compared to healthy Italian controls. RESULTS: One hundred and ninety-six out of four hundred and forty-three (44.2%) subjects, median age 56 years and 42.6% female, were DQ2/8 positive. When stratifying by disease we found that 86/188 (45.7%) patients with liver disease were HLA DQ2/8 positive, 39/73 (53.4%) with functional upper GI diseases and 19/41 (46.3%) with organic upper GI diseases were positive. Furthermore, 38/105 (36.2%) patients with IBS and 14/36 (38.9%) with IBD were HLA DQ2/8 positive (P = 0.21). Compared to healthy controls those with functional upper GI diseases disorders had a 1.8 times higher odds of DQ2/8 positivity. Those with liver disease had 1.3 times the odds, albeit not statistically significant, of DQ2/8 positivity. Both those with IBS and IBD had a lower odds of DQ2/8 positivity compared to healthy controls. CONCLUSION: The proportion of individuals HLA DQ2/8 positive is higher in those with liver/upper functional GI disease and lower in IBS/IBD as compared to general population estimates. PMID- 23674853 TI - Gastroesophageal reflux disease after diagnostic endoscopy in the clinical setting. AB - AIM: To investigate the outcome of patients with symptoms of gastroesophageal reflux disease (GERD) referred for endoscopy at 2 and 6 mo post endoscopy. METHODS: Consecutive patients referred for upper endoscopy for assessment of GERD symptoms at two large metropolitan hospitals were invited to participate in a 6 mo non-interventional (observational) study. The two institutions are situated in geographically and socially disparate areas. Data collection was by self completion of questionnaires including the patient assessment of upper gastrointestinal disorders symptoms severity and from hospital records. Endoscopic finding using the Los-Angeles classification, symptom severity and it's clinically relevant improvement as change of at least 25%, therapy and socio demographic factors were assessed. RESULTS: Baseline data were available for 266 patients and 2-mo and 6-mo follow-up data for 128 and 108 patients respectively. At baseline, 128 patients had erosive and 138 non-erosive reflux disease. Allmost all patient had proton pump inhibitor (PPI) therapy in the past. Overall, patients with non-erosive GERD at the index endoscopy had significantly more severe symptoms as compared to patients with erosive or even complicated GERD while there was no difference with regard to medication. After 2 and 6 mo there was a small, but statistically significant improvement in symptom severity (7.02 +/- 5.5 vs 5.9 +/- 5.4 and 5.5 +/- 5.4 respectively); however, the majority of patients continued to have symptoms (i.e., after 6 mo 81% with GERD symptoms). Advantaged socioeconomic status as well as being unemployed was associated with greater improvement. CONCLUSION: The majority of GORD patients receive PPI therapy before being referred for endoscopy even though many have symptoms that do not sufficiently respond to PPI therapy. PMID- 23674854 TI - Trans-arterial chemo-embolization is safe and effective for very elderly patients with hepatocellular carcinoma. AB - AIM: To assess the safety and efficacy of trans-arterial chemo-embolization (TACE) in very elderly patients. METHODS: A prospective cohort study, from 2001 to 2010, compared clinical outcomes following TACE between patients >= 75 years old and younger patients (aged between 65 and 75 years and younger than 65 years) with hepatocellular carcinoma (HCC), diagnosed according to the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases criteria. The decision that patients were not candidates for curative therapy was made by a multidisciplinary HCC team. Data collected included demographics, co-morbidities, liver disease etiology, liver disease severity and the number of procedures. The primary outcome was mortality; secondary outcomes included post-embolization syndrome (nausea, fever, abdominal right upper quadrant pain, increase in liver enzymes with no evidence of sepsis and with a clinical course limited to 3-4 d post procedure) and 30-d complications. Additionally, changes in liver enzyme measurements were assessed [alanine and aspartate aminotransferase (ALT and AST), gamma-glutamyl transpeptidase and alkaline phosphatase] in the week following TACE. Analysis employed both univariate and multivariate methods (Cox regression models). RESULTS: Of 102 patients who underwent TACE as sole treatment, 10 patients (9.8%) were > 80 years old at diagnosis; 13 (12.7%) were between 75 and 80 years, 45 (44.1%) were between 65 and 75 years and 34 (33.3%) were younger than 65 years. Survival analysis demonstrated similar survival patterns between the elderly patients and younger patients. Age was also not associated with the adverse event rate. Survival rates at 1, 2 and 3 years from diagnosis were 74%, 37% and 31% among patients < 65 years; 83%, 66% and 48% among patients aged 65 to 75 years; and 86%, 41% and 23% among patients >= 75 years. There were no differences between the age groups in the pre-procedural care, including preventive treatment for contrast nephropathy and prophylactic antibiotics. Multivariate survival analysis, controlling for disease stage at diagnosis with the Barcelona Clinic Liver Cancer score, number of TACE procedures, sex and alpha-fetoprotein level at the time of diagnosis, found no significant difference in the mortality hazard for elderly vs younger patients, and there were no differences in post-procedural complications. Serum creatinine levels did not change after 55% of the procedures, in all age groups. In 42% of all procedures, serum creatinine levels increased by no more than 25% above the baseline levels prior to TACE. Overall, there were 69 post-embolization events (23%). Hepatocellular enzymes often increased following TACE, with no association with prognosis. In 40% of the procedures, ALT and AST levels rose by at least 100%. The increases in hepatocellular enzymes occurred similarly in all age groups. CONCLUSION: TACE is safe and effective in very elderly patients with HCC, and is not associated with decreased survival or increased complication rates. PMID- 23674855 TI - Effects of Nigella sativa on outcome of hepatitis C in Egypt. AB - AIM: To evaluate the safety, efficacy and tolerability of Nigella sativa (N. sativa) in patients with hepatitis C not eligible for interferon (IFN)-alpha. METHODS: Thirty patients with hepatitis C virus (HCV) infection, who were not eligible for IFN/ribavirin therapy, were included in the present study. Inclusion criteria included: patients with HCV with or without cirrhosis, who had a contraindication to IFN-alpha therapy, or had refused or had a financial constraint to IFN-alpha therapy. Exclusion criteria included: patients on IFN alpha therapy, infection with hepatitis B or hepatitis I virus, hepatocellular carcinoma, other malignancies, major severe illness, or treatment non-compliance. Various parameters, including clinical parameters, complete blood count, liver function, renal function, plasma glucose, total antioxidant capacity (TAC), and polymerase chain reaction, were all assessed at baseline and at the end of the study. Clinical assessment included: hepato and/or splenomegaly, jaundice, palmar erythema, flapping tremors, spider naevi, lower-limb edema, and ascites. N. sativa was administered for three successive months at a dose of (450 mg three times daily). Clinical response and incidence of adverse drug reactions were assessed initially, periodically, and at the end of the study. RESULTS: N. sativa administration significantly improved HCV viral load (380808.7 +/- 610937 vs 147028.2 +/- 475225.6, P = 0.001) and TAC (1.35 +/- 0.5 vs 1.612 +/- 0.56, P = 0.001). After N. sativa administration, the following laboratory parameters improved: total protein (7.1 +/- 0.7 vs 7.5 +/- 0.8, P = 0.001), albumin (3.5 +/- 0.87 vs 3.69 +/- 0.91, P = 0.008), red blood cell count (4.13 +/- 0.9 vs 4.3 +/- 0.9, P = 0.001), and platelet count (167.7 +/- 91.2 vs 198.5 +/- 103, P = 0.004). Fasting blood glucose (104.03 +/- 43.42 vs 92.1 +/- 31.34, P = 0.001) and postprandial blood glucose (143.67 +/- 72.56 vs 112.1 +/- 42.9, P = 0.001) were significantly decreased in both diabetic and non-diabetic HCV patients. Patients with lower-limb edema decreased significantly from baseline compared with after treatment [16 (53.30%) vs 7 (23.30%), P = 0.004]. Adverse drug reactions were unremarkable except for a few cases of epigastric pain and hypoglycemia that did not affect patient compliance. CONCLUSION: N. sativa administration in patients with HCV was tolerable, safe, decreased viral load, and improved oxidative stress, clinical condition and glycemic control in diabetic patients. PMID- 23674856 TI - ABO blood type, long-standing diabetes, and the risk of pancreatic cancer. AB - AIM: To retrospectively study pancreatic cancer patients with respect to their ABO blood type and diabetes. METHODS: Our analysis included a cohort of 1017 patients with pancreatic ductal cancer diagnosed at our hospital in Tokyo. They were divided into two groups: 114 patients with long-standing type 2 diabetes (DM group, defined as diabetes lasting for at least three years before the diagnosis of pancreatic cancer) and 903 patients without diabetes (non-DM group). Multivariate analysis was performed to identify factors that are associated with long-standing diabetes. The DM group was further divided into three subgroups according to the duration of diabetes (3-5 years, 5.1-14.9 years, and 15 years or more) and univariate analyses were performed. RESULTS: Of the 883 pancreatic cancer patients with serologically assessed ABO blood type, 217 (24.6%) had blood type O. Compared with the non-DM group, the DM group had a higher frequency of blood type B [odds ratio (OR) = 2.61, 95%CI: 1.24-5.47; reference group: blood type A]. Moreover, male (OR = 3.17, 95%CI: 1.67-6.06), older than 70 years of age (OR = 2.19, 95%CI: 1.20-3.98) and presence of a family history of diabetes (OR = 6.21, 95%CI: 3.38-11.36) were associated with long-standing type 2 diabetes. The mean ages were 64.8 +/- 9.2 years, 67.1 +/- 9.8 years, and 71.7 +/- 7.0 years in the subgroups with the duration of diabetes, 3-5 years, 5.1-14.9 years, and 15 years or more, respectively (P = 0.007). A comparison of ABO blood type distribution among the subgroups also showed a significant difference (P = 0.03). CONCLUSION: The association of pancreatic cancer with blood type and duration of diabetes needs to be further examined in prospective studies. PMID- 23674857 TI - Computed tomography findings for predicting severe acute hepatitis with prolonged cholestasis. AB - AIM: To evaluate the significance of computed tomography (CT) findings in relation to liver chemistry and the clinical course of acute hepatitis. METHODS: Four hundred and twelve patients with acute hepatitis who underwent enhanced CT scanning were enrolled retrospectively. Imaging findings were analyzed for the following variables: gallbladder wall thickness (GWT), arterial heterogeneity, periportal tracking, number and maximum size of lymph nodes, presence of ascites, and size of spleen. The serum levels of alanine aminotransferase, alkaline phosphatase, bilirubin, albumin, and prothrombin time were measured on the day of admission and CT scan, and laboratory data were evaluated every 2-4 d for all subjects during hospitalization. RESULTS: The mean age of patients was 34.4 years, and the most common cause of hepatitis was hepatitis A virus (77.4%). The mean GWT was 5.2 mm. The number of patients who had findings of arterial heterogeneity, periportal tracking, lymph node enlargement > 7 mm, and ascites was 294 (80.1%), 348 (84.7%), 346 (84.5%), and 56 (13.6%), respectively. On multivariate logistic regression, male gender [odds ratio (OR) = 2.569, 95%CI: 1.477-4.469, P = 0.001], toxic hepatitis (OR = 3.531, 95%CI: 1.444-8.635, P = 0.006), level of albumin (OR = 2.154, 95%CI: 1.279-3.629, P = 0.004), and GWT (OR = 1.061, 95%CI: 1.015-1.110, P = 0.009) were independent predictive factors for severe hepatitis. The level of bilirubin (OR = 1.628, 95%CI: 1.331-1.991, P < 0.001) and GWT (OR = 1.172, 95%CI: 1.024-1.342, P = 0.021) were independent factors for prolonged cholestasis in multivariate analysis. CONCLUSION: In patients with acute hepatitis, GWT on CT scan was an independent predictor of severe hepatitis and prolonged cholestasis. PMID- 23674858 TI - New-style laparoscopic and endoscopic cooperative surgery for gastric stromal tumors. AB - AIM: To evaluate the feasibility and safety of a new style of laparoscopic and endoscopic cooperative surgery (LECS), an improved method of laparoscopic intragastric surgery (LIGS) for the treatment of gastric stromal tumors (GSTs). METHODS: Six patients were treated with the new-style LECS. Surgery was performed according to the following procedures: (1) Exposing and confirming the location of the tumor with gastroscopy; (2) A laparoscopy light was placed in the cavity using the trocar at the navel, and the other two trocars penetrated both the abdominal and stomach walls; (3) With gastroscopy monitoring, the operation was carried out in the gastric lumen using laparoscopic instruments and the tumor was resected; and (4) The tumor tissue was removed orally using a gastroscopy basket, and puncture holes and perforations were sutured using titanium clips. RESULTS: Tumor size ranged from 2.0 to 4.5 cm (average 3.50 +/- 0.84 cm). The operative time ranged from 60 to 130 min (average 83.33 +/- 26.58 min). Blood loss was less than 20 mL and hospital stay ranged from 6 to 8 d (average 6.67 +/- 0.82 d). The patients were allowed out of bed 12 h later. A stomach tube was inserted for 72 h after surgery, and a liquid diet was then taken. All cases had single tumors which were completely resected using the new-style LECS. No postoperative complications occurred. Pathology of all resected specimens showed GST: no cases of implantation or metastasis were found. CONCLUSION: New-style LECS for GSTs is a quick, optimized, fast recovery, safe and effective therapy. PMID- 23674859 TI - Endoscopic mucosal resection for rectal carcinoids under micro-probe ultrasound guidance. AB - AIM: To assess the therapeutic value of endoscopic mucosal resection (EMR) under micro-probe ultrasound guidance for rectal carcinoids less than 1 cm in diameter. METHODS: Twenty-one patients pathologically diagnosed with rectal carcinoids following colonoscopy in our hospital from January 2007 to November 2012 were included in this study. The patients consisted of 14 men and 7 women, with a mean age of 52.3 +/- 12.2 years (range: 36-72 years). The patients with submucosal tumors less than 1 cm in diameter arising from the rectal and muscularis mucosa detected by micro-probe ultrasound were treated with EMR and followed up with conventional endoscopy and micro-probe ultrasound. RESULTS: All of the 21 tumors were confirmed by micro-probe ultrasound as uniform hypoechoic masses originating from the rectal and muscularis mucosa, without invasion of muscularis propria and vessels, and less than 1 cm in diameter. EMR was successfully completed without bleeding, perforation or other complications. The resected specimens were immunohistochemically confirmed to be carcinoids. Patients were followed up for one to two years, and no tumor recurrence was reported. CONCLUSION: EMR is a safe and effective treatment for rectal carcinoids less than 1 cm in diameter. PMID- 23674860 TI - Acid suppressive drugs and gastric cancer: a meta-analysis of observational studies. AB - AIM: To evaluate the association between acid suppressive drug use and the development of gastric cancer. METHODS: A systematic search of relevant studies that were published through June 2012 was conducted using the MEDLINE (PubMed), EMBASE, and Cochrane Library databases. The search included observational studies on the use of histamine 2-receptor antagonists (H2RAs) or proton pump inhibitors and the associated risk of gastric cancer, which was measured using the adjusted odds ratio (OR) or the relative risk and 95%CI. An independent extraction was performed by two of the authors, and a consensus was reached. RESULTS: Of 4595 screened articles, 11 observational studies (n = 94558) with 5980 gastric cancer patients were included in the final analyses. When all the studies were pooled, acid suppressive drug use was associated with an increased risk of gastric cancer risk (adjusted OR = 1.42; 95%CI: 1.29-1.56, I2 = 48.9%, P = 0.034). The overall risk of gastric cancer increased among H2RA users (adjusted OR = 1.40; 95%CI: 1.24-1.59, I2 = 59.5%, P = 0.008) and PPI users (adjusted OR = 1.39; 95%CI: 1.19 1.64, I2 = 0.0%, P = 0.377). CONCLUSION: Acid suppressive drugs are associated with an increased risk of gastric cancer. Further studies are needed to test the effect of acid suppressive drugs on gastric cancer. PMID- 23674861 TI - Portal vein stenosis after pancreatectomy following neoadjuvant chemoradiation therapy for pancreatic cancer. AB - Extrahepatic portal vein (PV) stenosis has various causes, such as tumor encasement, pancreatitis and as a post-surgical complication. With regard to post pancreaticoduodenectomy, intraoperative radiation therapy with/without PV resection is reported to be associated with PV stenosis. However, there has been no report of PV stenosis after pancreatectomy following neoadjuvant chemoradiation therapy (NACRT). Here we report the cases of three patients with PV stenosis after pancreatectomy and PV resection following gemcitabine-based NACRT for pancreatic cancer and their successful treatment with stent placement. We have performed NACRT in 18 patients with borderline resectable pancreatic cancer since 2005. Of the 15 patients who completed NACRT, nine had undergone pancreatectomy. Combined portal resection was performed in eight of the nine patients. We report here three patients with PV stenosis, and thus the ratio of post-operative PV stenosis in patients with PV resection following NACRT is 37.5% in this series. We encountered no case of PV stenosis among 22 patients operated with PV resection for pancreatobiliary cancer without NACRT during the same period. A relationship between PV stenosis and NACRT is suspected, but further investigation is required to determine whether NACRT has relevance to PV stenosis. PMID- 23674862 TI - Henoch-Schonlein purpura with intestinal perforation and cerebral hemorrhage: a case report. AB - Henoch-Schonlein purpura (HSP) with intestinal perforation and cerebral hemorrhage is a very rare clinical condition. There has been no report of HSP complicated with both intestinal perforation and cerebral hemorrhage until October 2012. Here we describe a case of HSP with intestinal perforation and cerebral hemorrhage in a 5-year-old girl. Plain abdominal radiograph in the erect position showed heavy gas in the right subphrenic space with an elevated diaphragm. Partial resection of the small intestine was performed, and pathological analysis suggested chronic suppurative inflammation in all layers of the ileal wall and mesentery. Seventeen days after surgery, cerebral hemorrhage developed and the patient died. PMID- 23674863 TI - Surgical treatment of a patient with peliosis hepatis: a case report. AB - This report describes a case of a space-occupying lesion in the right liver in a 38-year-old man who was found to have peliosis hepatis. Clinical data of this patient were presented, including medical history, laboratory test and imaging results, and postoperative pathological findings (hematoxylin and eosin staining). Review of his medical history showed that the patient had been bitten by a dog three years earlier. B-mode ultrasonography revealed an uneven echo mass in the right hemiliver, and magnetic resonance imaging scans also showed a mass in the anterior segment of the right liver. Upon surgical removal, the mass was found to be 4.0 cm * 3.8 cm * 3.8 cm in size and located in segment VI. The mass had a dark and soft appearance, with an irregular edge on intraoperative ultrasonography. Postoperative pathological findings revealed many small capsules filled with blood cells. The patient was diagnosed with peliosis hepatis based on his medical history of having been bitten by a dog, presence of mild anemia, and lack of characteristic symptoms, including fever of unknown origin, abdominal pain, and hepatosplenomegaly, combined with intraoperative and postoperative pathologic findings. The operation was successful, and after being treated with anti-infection agents, the patient had a good recovery. PMID- 23674864 TI - Role of molecular analysis in the adjuvant treatment of gastrointestinal stromal tumours: it is time to define it. AB - Sendur et al pointed out the attention on the importance of mutational analysis for adjuvant treatment of gastrointestinal stromal tumor (GIST) in an article published in World Journal of Gastroenterology. In particular, they suggested that the optimal dose and duration of adjuvant therapy could be defined by the mutational status of the primary disease. This comment would underline the importance of centralised laboratories, given the increasingly important role of molecular analysis in the work-flow of all GIST, and the need of retrospective analyses for subgroups population stratified for the mutational status from the available studies in the adjuvant setting, in order to define the role of mutational analysis in choosing the optimal dose and duration of adjuvant therapy. PMID- 23674865 TI - Mycotoxins are conventional and novel risk biomarkers for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a common malignant disease with poor prognosis. To improve the clinical outcome, early diagnosis of HCC arising from nonviral agents and hepatitis virus is important. Among several etiological factors, mycotoxins defined as carcinogens by the International Agency for Research in Cancer (IARC) might be one of the critical risk factors for nonviral HCC. Aflatoxin B1 is the most well-known carcinogenic mycotoxin for HCC, but the role of the other types of mycotoxin remains unclear. Several studies have reported that a chromatographic separation technique based on high-performance liquid chromatography can successfully detect the concentration of mycotoxins in plasma. Recently, serum level of ochratoxin A (OTA), a widely distributed mycotoxin classified as Group 2B by IARC, was evaluated in HCC patients in Egypt. The results suggested that serum OTA levels might be a good biomarker for HCC. In this article, we review recent studies of OTA, and discuss its possible significance as a biomarker of HCC. PMID- 23674866 TI - Tumor necrosis factor-alpha inhibitor therapy and fetal risk: a systematic literature review. AB - Tumor necrosis factor-alpha inhibitors (anti-TNFs) are effective in the treatment of inflammatory bowel disease (IBD) recalcitrant to conventional medical therapy. As the peak incidence of IBD overlaps with the prime reproductive years, it is crucial to establish pharmacologic regimens for women of childbearing age that achieve effective disease control without posing significant fetal harm. A systematic literature review was performed to identify all human studies with birth outcomes data after maternal exposure to infliximab, adalimumab, or certolizumab pegol within 3 mo of conception or during any trimester of pregnancy. Live births, spontaneous abortions or stillbirths, preterm or premature births, low birth weight or small for gestational age infants, and congenital abnormalities were recorded. Fifty selected references identified 472 pregnancy exposures. The subsequent review includes general information regarding anti-TNF therapy in pregnancy followed by a summary of our findings. The benefits of biologic modalities in optimizing disease control during pregnancy must be weighed against the potential toxicity of drug exposure on the developing fetus. Although promising overall, there is insufficient evidence to prove absolute safety for use of anti-TNFs during pregnancy given the limitations of available data and lack of controlled trials. PMID- 23674867 TI - CD133: a cancer stem cells marker, is used in colorectal cancers. AB - Colorectal cancer is one of the most common malignant tumors worldwide. A model of cancer development involving cancer stem cells has been put forward because it provides a possible explanation of tumor hierarchy. Cancer stem cells are characterized by their proliferation, tumorigenesis, differentiation, and self renewal capacities, and chemoradiotherapy resistance. Due to the role of cancer stem cells in tumor initiation and treatment failure, studies of cancer stem cell markers, such as CD133, have been of great interest. CD133, a five-transmembrane glycoprotein, is widely used as a marker to identify and isolate colorectal cancer stem cells. This marker has been investigated to better understand the characteristics and functions of cancer stem cells. Moreover, it can also be used to predict tumor progression, patient survival, chemoradiotherapy resistance and other clinical parameters. In this review, we discuss the use of CD133 in the identification of colorectal cancer stem cell, which is currently controversial. Although the function of CD133 is as yet unclear, we have discussed several possible functions and associated mechanisms that may partially explain the role of CD133 in colorectal cancers. In addition, we focus on the prognostic value of CD133 in colorectal cancers. Finally, we predict that CD133 may be used as a possible target for colorectal cancer treatment. PMID- 23674868 TI - Prevalence of celiac disease in Germany: a prospective follow-up study. AB - AIM: To determine the prevalence of celiac disease in a randomly selected population sample. METHODS: A total of 2157 subjects (1036 males; 1121 females) participating in a population-based cross-sectional study underwent laboratory testing for tissue transglutaminase and antibodies to immunoglobulin A, endomysium and antigliadin. In a second step, all subjects who had been examined serologically were surveyed using a questionnaire that included questions specific to celiac disease. Subjects with positive antibody titers and those with histories positive for celiac disease then underwent biopsy. At the first follow up, antibody titers were again determined in these subjects and subjects were questioned regarding symptoms specific for celiac disease and disorders associated with celiac disease. The second follow up consisted of a telephone interview with subjects positive for celiac disease. RESULTS: Antibody tests consistent with celiac disease were reported in eight subjects, corresponding to an overall prevalence of 1:270 (8/2157). The prevalence among women was 1:224 and 1:518 in men. Classical symptoms were observed in 62.5% of subjects. Atypical celiac disease was present in 25.0%, and transient celiac disease in 12.5%. False negative test results were returned in three subjects. This yields a sensitivity and specificity of 62.5% and 50.0%, respectively, for tissue transglutaminase immunoglobulin-A antibody; of 62.5% and 71.4% respectively, for endomysium antibody; and of 62.5% and 71.4%, respectively, for antigliadin antibody. CONCLUSION: The prevalence rate in our collective lies within the middle tertile of comparable studies in Europe. The use of a single antibody test for screening purposes must be called into question. PMID- 23674869 TI - CYP24A1 inhibition facilitates the anti-tumor effect of vitamin D3 on colorectal cancer cells. AB - AIM: The effects of vitamin D3 have been investigated on various tumors, including colorectal cancer (CRC). 25-hydroxyvitamin-D3-24-hydroxylase (CYP24A1), the enzyme that inactivates the active vitamin D3 metabolite 1,25 dihydroxyvitamin D3 (1,25-D3), is considered to be the main enzyme determining the biological half-life of 1,25-D3. During colorectal carcinogenesis, the expression and concentration of CYP24A1 increases significantly, suggesting that this phenomenon could be responsible for the proposed efficacy of 1,25-D3 in the treatment of CRC. The aim of this study was to investigate the anti-tumor effects of vitamin D3 on the human CRC cell line Caco-2 after inhibition of the cytochrome P450 component of CYP24A1 activity. METHODS: We examined the expression of CYP24A1 mRNA and the effects of 1,25-D3 on the cell line Caco-2 after inhibition of CYP24A1. Cell viability and proliferation were determined by means of sulforhodamine-B staining and bromodeoxyuridine incorporation, respectively, while cytotoxicity was estimated via the lactate dehydrogenase content of the cell culture supernatant. CYP24A1 expression was measured by real time reverse transcription polymerase chain reaction. A number of tetralone compounds were synthesized to investigate their CP24A1 inhibitory activity. RESULTS: In response to 1,25-D3, CYP24A1 mRNA expression was enhanced significantly, in a time- and dose-dependent manner. Caco-2 cell viability and proliferation were not influenced by the administration of 1,25-D3 alone, but were markedly reduced by co-administration of 1,25-D3 and KD-35, a CYP24A1 inhibiting tetralone. Our data suggest that the mechanism of action of co administered KD-35 and 1,25-D3 does not involve a direct cytotoxic effect, but rather the inhibition of cell proliferation. CONCLUSION: These findings demonstrate that the selective inhibition of CYP24A1 by compounds such as KD-35 may be a new approach for enhancement of the anti-tumor effect of 1,25-D3 on CRC. PMID- 23674870 TI - Establishment of mouse intestinal myofibroblast cell lines. AB - AIM: To establish novel intestinal myofibroblast (IMF) cell lines from mouse colonic mucosa and investigate their biological characters. METHODS: Primary IMFs were isolated from mucosal tissues of mouse colon that was denuded of epithelial cells and smooth muscle layer. For immortalization, primary IMFs were transfected with simian virus 40 large T antigen (designated as LmcMF). We also isolated some primary IMFs that spontaneously became immortalized without transfection (designated as SmcMF). To check immortality and normality of these cells, we examined their proliferative ability and contact inhibition. Moreover, the expression levels of proteins characterizing IMFs [including alpha-smooth muscle actin (alpha-SMA), vimentin, desmin, and type I collagen] and proteins associated with the immune response [such as toll-like receptor 4 (TLR-4), CD14, MD2, IkappaBalpha, and p-p38] were determined by Western blotting. The localization of several myofibroblast protein markers was also detected by immunofluorescence staining. RESULTS: The cell growth assay results show that both LmcMF and SmcMF cells proliferated logarithmically at least up to passage 20. In addition, the contact inhibition assays show that LmcMF and SmcMF stopped growing after the cells reached confluence. These data suggest that these 2 types of cells were immortalized without losing contact inhibition of growth. Moreover, both LmcMF and SmcMF, like primary IMFs, showed spindle-shaped appearance. The expression levels of key myofibroblast protein markers, including alpha-SMA, vimentin, and desmin, were also examined by the Western blotting and immunofluorescence analyses. Our results show that these cells were positive for alpha-SMA and vimentin, but not desmin, as well as that both LmcMF and SmcMF expressed type I collagen at a lower level than primary IMFs. Finally, we investigated the expression level of lipopolysaccharide (LPS) receptor-related proteins, as well as the response of the cells to LPS treatment. We found that the TLR4, CD14, and MD-2 proteins were present in LmcMF and SmcMF, as well as in primary IMFs, and that all these cells responded to LPS. CONCLUSION: We established 2 novel IMF cell lines from mouse colonic mucosa, namely, LmcMF and SmcMF, both of which were able to respond to LPS. PMID- 23674871 TI - Expression of interleukin-22/STAT3 signaling pathway in ulcerative colitis and related carcinogenesis. AB - AIM: To investigate the expression of interleukin (IL)-22 and its related proteins in biopsy specimens from patients with ulcerative colitis (UC) and UC related carcinogenesis. METHODS: Biopsy specimens were obtained from patients with inactive (n = 10), mild-to-moderately active (n = 30), severely active (n = 34), initial (n = 30), and chronic UC (n = 44), as well as UC patients with dysplasia (n = 10). Specimens from patients without colonic abnormalities (n = 20) served as controls. Chronic colitis in experimental mice was induced by 2.5% dextran sodium sulfate. The expression levels of IL-22, IL-23, IL-22R1 and phosphorylated STAT3 (p-STAT3) were determined by immunohistochemistry. Bcl-2, cyclin D1 and survivin expression was detected by Western blotting. RESULTS: Patients with active UC had significantly more IL-22, IL-23, IL-22R1 and p-STAT3 positive cells than the patients with inactive UC and normal controls. Furthermore, IL-22 and related proteins were closely related to the severity of the colitis. The expression of IL-22 and IL-22R1 in the tissue of initial UC was stronger than in that of chronic UC, whereas the expression of p-STAT3 was significantly increased in chronic UC tissues. In dysplasia tissues, the expression level of IL-22 and related proteins was higher compared with controls. Mouse colitis model showed that expression of IL-22, IL-22R1 and IL-23 was increased with time, p-STAT3 and the downstream gene were also remarkably upregulated. CONCLUSION: IL-22/STAT3 signaling pathway may be related to UC and UC-induced carcinogenesis and IL-22 can be used as a biomarker in judging the severity of UC. PMID- 23674872 TI - Prognostic and survival analysis of 837 Chinese colorectal cancer patients. AB - AIM: To develop a prognostic model to predict survival of patients with colorectal cancer (CRC). METHODS: Survival data of 837 CRC patients undergoing surgery between 1996 and 2006 were collected and analyzed by univariate analysis and Cox proportional hazard regression model to reveal the prognostic factors for CRC. All data were recorded using a standard data form and analyzed using SPSS version 18.0 (SPSS, Chicago, IL, United States). Survival curves were calculated by the Kaplan-Meier method. The log rank test was used to assess differences in survival. Univariate hazard ratios and significant and independent predictors of disease-specific survival and were identified by Cox proportional hazard analysis. The stepwise procedure was set to a threshold of 0.05. Statistical significance was defined as P < 0.05. RESULTS: The survival rate was 74% at 3 years and 68% at 5 years. The results of univariate analysis suggested age, preoperative obstruction, serum carcinoembryonic antigen level at diagnosis, status of resection, tumor size, histological grade, pathological type, lymphovascular invasion, invasion of adjacent organs, and tumor node metastasis (TNM) staging were positive prognostic factors (P < 0.05). Lymph node ratio (LNR) was also a strong prognostic factor in stage III CRC (P < 0.0001). We divided 341 stage III patients into three groups according to LNR values (LNR1, LNR <= 0.33, n = 211; LNR2, LNR 0.34-0.66, n = 76; and LNR3, LNR >= 0.67, n = 54). Univariate analysis showed a significant statistical difference in 3-year survival among these groups: LNR1, 73%; LNR2, 55%; and LNR3, 42% (P < 0.0001). The multivariate analysis results showed that histological grade, depth of bowel wall invasion, and number of metastatic lymph nodes were the most important prognostic factors for CRC if we did not consider the interaction of the TNM staging system (P < 0.05). When the TNM staging was taken into account, histological grade lost its statistical significance, while the specific TNM staging system showed a statistically significant difference (P < 0.0001). CONCLUSION: The overall survival of CRC patients has improved between 1996 and 2006. LNR is a powerful factor for estimating the survival of stage III CRC patients. PMID- 23674873 TI - Short- and long-term efficacy of endoscopic balloon dilation in Crohn's disease strictures. AB - AIM: To evaluate short- and long-term efficacy of endoscopic balloon dilation in a cohort of consecutive patients with symptomatic Crohn's disease (CD)-related strictures. METHODS: Twenty-six CD patients (11 men; median age 36.8 year, range 11-65 years) with 27 symptomatic strictures underwent endoscopic balloon dilation (EBD). Both naive and post-operative strictures, of any length and diameter, with or without associated fistula were included. After a clinical and radiological assessment, EBD was performed with a Microvasive Rigiflex through the scope balloon system. The procedure was considered successful if no symptom reoccurred in the following 6 mo. The long-term clinical outcome was to avoid surgery. RESULTS: The mean follow-up time was 40.7 +/- 5.7 mo (range 10-94 mo). In this period, forty-six EBD were performed with a technical success of 100%. No procedure-related complication was reported. Surgery was avoided in 92.6% of the patients during the entire follow-up. Two patients, both presenting ileocecal strictures associated with fistula, failed to respond to the treatment and underwent surgical strictures resection. Of the 24 patients who did not undergo surgery, 11 patients received 1 EBD, and 13 required further dilations over time for the treatment of relapsing strictures (7 patients underwent 2 dilations, 5 patients 3 dilations, and 1 patient 4 dilations). Overall, the EBD success rate after the first dilation was 81.5%. No difference was observed between the EBD success rate for naive (n = 12) and post-operative (n = 15) CD related strictures (P > 0.05). CONCLUSION: EBD appears to be a safe and effective procedure in the therapeutic management of CD-related strictures of any origin and dimension in order to prevent surgery. PMID- 23674874 TI - Narrow-band imaging with magnifying endoscopy is accurate for detecting gastric intestinal metaplasia. AB - AIM: To investigate the predictive value of narrow-band imaging with magnifying endoscopy (NBI-ME) for identifying gastric intestinal metaplasia (GIM) in unselected patients. METHODS: We prospectively evaluated consecutive patients undergoing upper endoscopy for various indications, such as epigastric discomfort/pain, anaemia, gastro-oesophageal reflux disease, suspicion of peptic ulcer disease, or chronic liver diseases. Patients underwent NBI-ME, which was performed by three blinded, experienced endoscopists. In addition, five biopsies (2 antrum, 1 angulus, and 2 corpus) were taken and examined by two pathologists unaware of the endoscopic findings to determine the presence or absence of GIM. The correlation between light blue crest (LBC) appearance and histology was measured. Moreover, we quantified the degree of LBC appearance as less than 20% (+), 20%-80% (++) and more than 80% (+++) of an image field, and the semiquantitative evaluation of LBC appearance was correlated with IM percentage from the histological findings. RESULTS: We enrolled 100 (58 F/42 M) patients who were mainly referred for gastro-esophageal reflux disease/dyspepsia (46%), cancer screening/anaemia (34%), chronic liver disease (9%), and suspected celiac disease (6%); the remaining patients were referred for other indications. The prevalence of Helicobacter pylori (H. pylori) infection detected from the biopsies was 31%, while 67% of the patients used proton pump inhibitors. LBCs were found in the antrum of 33 patients (33%); 20 of the cases were classified as LBC+, 9 as LBC++, and 4 as LBC+++. LBCs were found in the gastric body of 6 patients (6%), with 5 of them also having LBCs in the antrum. The correlation between the appearance of LBCs and histological GIM was good, with a sensitivity of 80% (95%CI: 67-92), a specificity of 96% (95%CI: 93-99), a positive predictive value of 84% (95%CI: 73 96), a negative predictive value of 95% (95%CI: 92-98), and an accuracy of 93% (95%CI: 90-97). The NBI-ME examination overlooked GIM in 8 cases, but the GIM was less than 5% in 7 of the cases. Moreover, in the 6 false positive cases, the histological examination showed the presence of reactive gastropathy (4 cases) or H. pylori active chronic gastritis (2 cases). The semiquantitative correlation between the rate of LBC appearance and the percentage of GIM was 79% (P < 0.01). CONCLUSION: NBI-ME achieved good sensitivity and specificity in recognising GIM in an unselected population. In routine clinical practice, this technique can reliably target gastric biopsies. PMID- 23674875 TI - Clinical effects of adalimumab treatment with concomitant azathioprine in Japanese Crohn's disease patients. AB - AIM: To assess adalimumab's efficacy with concomitant azathioprine (AZA) for induction and maintenance of clinical remission in Japanese Crohn's disease (CD) patients. METHODS: This retrospective, observational, single-center study enrolled 28 consecutive CD patients treated with adalimumab (ADA). Mean age and mean disease duration were 38.1 +/- 11.8 years and 11.8 +/- 10.1 years, respectively. The baseline mean Crohn's disease activity index (CDAI) and C reactive protein were 177.8 +/- 82.0 and 0.70 +/- 0.83 mg/dL, respectively. Twelve of these patients also received a concomitant stable dose of AZA. ADA was subcutaneously administered: 160 mg at week 0, 80 mg at week 2, followed by 40 mg every other week. Clinical response and remission rates were assessed via CDAI and C-reactive protein for 24 wk. RESULTS: The mean CDAI at weeks 2, 4, 8, and 24 was 124.4, 120.2, 123.6, and 135.1, respectively. The CDAI was significantly decreased at weeks 2 and 4 with ADA and was significantly suppressed at 24 wk with ADA/AZA. Overall clinical remission rates at weeks 4 and 24 were 66.7% and 63.2%, respectively. Although no statistically significant difference in C reactive protein was demonstrated, ADA with AZA resulted in a greater statistically significant improvement in CDAI at 24 wk, compared to ADA alone. CONCLUSION: Scheduled ADA with concomitant AZA may be more effective for clinical remission achievement at 24 wk in Japanese Crohn's disease patients. PMID- 23674876 TI - Dietary polyphenols and colorectal cancer risk: the Fukuoka colorectal cancer study. AB - AIM: To investigate the associations between dietary intake of polyphenols and colorectal cancer. METHODS: The study subjects were derived from the Fukuoka colorectal cancer study, a community-based case-control study. The study subjects were 816 cases of colorectal cancer and 815 community-based controls. The consumption of 148 food items was assessed by a computer-assisted interview. We used the consumption of 97 food items to estimate dietary intakes of total, tea and coffee polyphenols. The Phenol-Explorer database was used for 92 food items. Of the 5 foods which were not listed in the Phenol-Explorer Database, polyphenol contents of 3 foods (sweet potatoes, satoimo and daikon) were based on a Japanese study and 2 foods (soybeans and fried potatoes) were estimated by ORAC-based polyphenol contents in the United States Department of Agriculture Database. Odds ratios (OR) and 95%CI of colorectal cancer risk according to quintile categories of intake were obtained by using logistic regression models with adjustment for age, sex, residential area, parental history of colorectal cancer, smoking, alcohol consumption, body mass index 10 years before, type of job, leisure-time physical activity and dietary intakes of calcium and n-3 polyunsaturated fatty acids. RESULTS: There was no measurable difference in total or tea polyphenol intake between cases and controls, but intake of coffee polyphenols was lower in cases than in controls. The multivariate-adjusted OR of colorectal cancer according to quintile categories of coffee polyphenols (from the first to top quintile) were 1.00 (referent), 0.81 (95%CI: 0.60-1.10), 0.65 (95%CI: 0.47-0.89), 0.65 (95%CI: 0.46-0.89) and 0.82 (95%CI: 0.60-1.10), respectively (P trend = 0.07). Similar, but less pronounced, decreases in the OR were also noted for the third and fourth quintiles of total polyphenol intake. Tea polyphenols and non coffee polyphenols showed no association with colorectal cancer risk. The site specific analysis, based on 463 colon cancer cases and 340 rectal cancer cases, showed an inverse association between coffee polyphenols and colon cancer. The multivariate-adjusted OR of colon cancer for the first to top quintiles of coffee polyphenols were 1.00 (referent), 0.92 (95%CI: 0.64-1.31), 0.75 (95%CI: 0.52 1.08), 0.69 (95%CI: 0.47-1.01), and 0.68 (95%CI: 0.46-1.00), respectively (P trend = 0.02). Distal colon cancer showed a more evident inverse association with coffee polyphenols than proximal colon cancer. The association between coffee polyphenols and rectal cancer risk was U-shaped, with significant decreases in the OR at the second to fourth quintile categories. There was also a tendency that the OR of colon and rectal cancer decreased in the intermediate categories of total polyphenols. The decrease in the OR in the intermediate categories of total polyphenols was most pronounced for distal colon cancer. Intake of tea polyphenols was not associated with either colon or rectal cancer. The associations of coffee consumption with colorectal, colon and rectal cancers were almost the same as observed for coffee polyphenols. The trend of the association between coffee consumption and colorectal cancer was statistically significant. CONCLUSION: The present findings suggest a decreased risk of colorectal cancer associated with coffee consumption. PMID- 23674877 TI - Coinfection with hepatitis C virus and schistosomiasis: fibrosis and treatment response. AB - AIM: To assess whether schistosomiasis coinfection with chronic hepatitis C virus (HCV) influences hepatic fibrosis and pegylated-interferon/ribavirin (PEG IFN/RIB) therapy response. METHODS: This study was designed as a retrospective analysis of 3596 chronic HCV patients enrolled in the Egyptian National Program for HCV treatment with PEG-IFN/RIB. All patients underwent liver biopsy and anti schistosomal antibodies testing prior to HCV treatment. The serology results were used to categorize the patients into group A (positive schistosomal serology) or group B (negative schistosomal serology). Patients in group A were given oral antischistosomal treatment (praziquantel, single dose) at four weeks prior to PEG IFN/RIB. All patients received a 48-wk course of PEG-IFN (PEG-IFNalpha2a or PEG IFNalpha2b)/RIB therapy. Clinical and laboratory follow-up examinations were carried out for 24 wk after cessation of therapy (to week 72). Correlations of positive schistosomal serology with fibrosis and treatment response were assessed by multiple regression analysis. RESULTS: Schistosomal antibody was positive in 27.3% of patients (15.9% females and 84.1% males). The patients in group A were older (P = 0.008) and had a higher proportion of males (P = 0.002) than the patients in group B. There was no significant association between fibrosis stage and positive schistosomal serology (P = 0.703). Early virological response was achieved in significantly more patients in group B than in group A (89.4% vs 86.5%, P = 0.015). However, significantly more patients in group A experienced breakthrough at week 24 than patients in group B (36.3% vs 32.3%, P = 0.024). End of treatment response was achieved in more patients in group B than in group A (62.0% vs 59.1%) but the difference did not reach statistical significance (P = 0.108). Sustained virological response occurred in significantly more patients in group B than in group A (37.6% vs 27.7%, P = 0.000). Multivariate logistic regression analysis of patient data at treatment weeks 48 and 72 showed that positive schistosomal serology was associated with failure of response to treatment at week 48 (OR = 1.3, P = 0.02) and at week 72 (OR = 1.7, P < 0.01). CONCLUSION: Positive schistosomal serology has no effect on fibrosis staging but is significantly associated with failure of response to HCV treatment despite antischistosomal therapy. PMID- 23674878 TI - Increased expression of DLX2 correlates with advanced stage of gastric adenocarcinoma. AB - AIM: To investigate the expression of distal-less homeobox 2 (DLX2) in gastric adenocarcinoma and its clinicopathological significance. METHODS: Gastric adenocarcinoma tissues were obtained from gastrectomy specimens of 129 patients from the Department of Surgery and Pathology, the Second Affiliated Hospital of Kunming Medical University. Sixty cases of normal gastric tissues were collected from gastrectomy specimens of adjacent gastric cancer margins greater than 5 cm. Patient diagnosis was established pathologically, and no patient had received chemotherapy or radiotherapy before surgery. All tissue specimens were formalin fixed and paraffin-embedded. Immunohistochemistry was carried out to investigate the expression of DLX2 in 129 gastric adenocarcinoma tissues and 60 adjacent normal tissues. The immunostaining reaction was semiquantitatively evaluated based on the proportion of positive cells and the median staining intensity in normal gastric epithelial cells or tumor cells. All patients had follow-up records for more than 5 years. Correlations of DLX2 expression with clinicopathological features and prognosis of patients with gastric adenocarcinoma were analyzed. All statistical analyses were performed using the SPSS 17.0 software. RESULTS: The positive expression of DLX2 was detected in 68 (52.7%) cases of 129 gastric adenocarcinoma tissues and 14 (23.3%) cases of 60 adjacent normal tissues. The difference in DLX2 expression between gastric adenocarcinoma tissues and adjacent normal tissues was statistically significant (chi2 = 14.391, P < 0.001). Moreover, high expression of DLX2 was detected in 48 (37.2%) cases of 129 human gastric cancer tissues, but not in adjacent normal tissues. The expression of DLX2 correlated with the size of tumor (P = 0.001), depth of invasion (P = 0.008), lymph node metastasis (P = 0.023) and tumor-node metastasis stages (P = 0.020), but was not correlated with age, gender, histological differentiation and distant metastasis. The Kaplan-Meier survival analysis revealed that survival time of patients with high DLX2 expression was significantly shorter than that with low DLX2 expression. However, the multivariate analysis showed that invasion depth (P < 0.001), lymph nodes metastasis (P = 0.001) and distant metastasis (P < 0.001) were independent prognostic factors for patients with gastric adenocarcinoma, but DLX2 expression, tumor location and tumor size were not. CONCLUSION: These results suggest that increased expression of DLX2 may correlate with the advanced stage of gastric adenocarcinoma, and it may contribute to tumor development. PMID- 23674879 TI - Effects of medical adhesives in prevention of complications after endoscopic submucosal dissection. AB - AIM: To evaluate the use of medical adhesive spray in endoscopic submucosal dissection (ESD). METHODS: Patients who underwent ESD between January 2009 and June 2012 (n = 173) were enrolled in the prospective randomized study. Two patients undergoing surgery due to severe intraoperative hemorrhage and failed hemostasis were excluded, and the remaining 171 patients were randomly divided into two groups: group A (medical adhesive group, n = 89) and group B (control group, n = 82). In group A, a medical adhesive spray was evenly applied after routine electrocoagulation and hemostasis using hemostatic clip after ESD. Patients in group B only treated with routine wound management. Intraoperative and postoperative data were collected and compared. RESULTS: In all 171 patients, ESD was successfully completed. There was no significant difference in the average treatment time between groups A and B (59.4 min vs 55.0 min, respectively). The average length of hospital stay was significantly different between group A and B (8.89 d vs 9.90 d, respectively). The incidence of intraoperative perforation was 10.1% in group A and 9.8% in group B, and was not significantly different between the two groups. In all cases, perforations were successfully managed endoscopically and with conservative treatment. The incidence of postoperative delayed bleeding in group A was significantly lower than that in group B (0.00% vs 4.88%, respectively). CONCLUSION: ESD is an effective minimally invasive treatment for gastrointestinal precancerous lesions or early-stage gastrointestinal cancer. Medical adhesive spray is effective in preventing delayed bleeding after ESD, and can thus reduce the average length of hospital stay. PMID- 23674880 TI - Difference in DRB1* gene polymorphisms between Han and Uyghur ulcerative colitis patients in China. AB - AIM: To evaluate the association between HLA-DRB1 alleles and Han and Uyghur ulcerative colitis (UC) patients residing in the Xinjiang Uyghur Autonomous Region of China. METHODS: In this study, 102 UC patients (53 Han including 22 men and 31 women, and 49 Uyghur patients including 25 men and 24 women; aged 48.07 +/ 15.83 years) and 310 age- and sex-matched healthy controls were enrolled in the Department of Gastroenterology, Xinjiang People's Hospital of China from January 2010 to May 2011. UC was diagnosed based on the clinical, endoscopic and histological findings following Lennard-Jones criteria. Blood samples were collected and genomic DNA was extracted by routine laboratory methods, and both polymerase chain reaction and gene sequencing were used to identify HLA-DRB1 allele variants. The potential association between genetic variation and UC in Han and Uyghur patients was examined. There were no statistical differences in HLA-DRB1 allele frequencies in Han UC patients. RESULTS: There was no significant difference in the sex ratio between the controls and UC patients (P = 0.740). In Han patients with UC (n = 53), HLA-DRB1 *03, *13 allele frequencies were lower than in healthy controls (n = 161), but not statistically significant, and HLA DRB1*04*11*14 allele frequencies were higher than in healthy controls, but without statistical significance. Differences between Uyghur UC patients and the control group were observed for HLA-DRB1*04 and HLA-DRB1*13, both showed a greater frequency in UC patients (10.21% vs 2.69%, P = 0.043; 14.29% vs 4.03%, P = 0.019). HLA-DRB1*14 also showed a greater frequency in UC patients (14.29% vs 2.69%, P = 0.006). The frequencies of DRB1*04, *13*14 alleles were increased in Uyghur UC patients compared with normal controls. The frequency of DRB1 * 08 was decreased in Uyghur UC patients compared with normal controls. HLA-DRB1 alleles showed no association with UC in Han patients. There were no statistical differences in HLA-DRB1 allele frequencies in Han UC patients. The frequencies of DRB1*04, *13*14 alleles were increased in Uyghur UC patients compared with normal controls. The frequency of DRB1*08 was decreased in Uyghur UC patients compared with normal controls. Polymorphism of the HLA-DRB1 gene may contribute to the clinical heterogeneity of UC between Han and Uyghur UC patients in China. CONCLUSION: HLA-DRB1*04*13*14 and DRB1*08 may contribute to the clinical heterogeneity of UC between Han and Uyghur UC patients. PMID- 23674881 TI - Isolated arterioportal fistula presenting with variceal hemorrhage. AB - We report a case of life-threatening hematemesis due to portal hypertension caused by an isolated arterioportal fistula (APF). Intrahepatic APFs are extremely rare and are a cause of presinusoidal portal hypertension. Etiologies for APFs are comprised of precipitating trauma, malignancy, and hereditary hemorrhagic telangiectasia, but these were not the case in our patient. Idiopathic APFs are usually due to congenital vascular abnormalities and thus usually present in the pediatric setting. This is one of the first cases of adult onset isolated APF who presented with portal hypertension and was successfully managed through endoscopic hemostasis and subsequent interventional radiological embolization. PMID- 23674883 TI - Accurate hemostasis with a new endoscopic overtube for emergency endoscopy. AB - Endoscopic hemostasis performed in the emergency room is difficult due to the presence of blood clots and food residue that makes obtaining a clear view of the bleeding vessel difficult. We experienced the efficacy of a newly developed inverted overtube to shorten the hemostatic time and obtain a clear endoscopic view with upper gastrointestinal bleeding patient who were transferred by ambulance car and required emergency endoscopy. The technique improved the endoscopic views and enabled us to perform the hemostatic procedures from the conventional standing position while freely and easily changing the patient's position. The presence of blood clots and food residue in the gastric fornix or upper gastric body makes identifying a bleeding exposed vessel impossible. This set-up significantly shortened the procedure time. The inverted overtube helped us obtain a clear view in patients who were laid in the right lateral position. Rapid identification of exposed vessels resulted in success of hemostasis. PMID- 23674882 TI - Therapeutic efficacy of the Qing Dai in patients with intractable ulcerative colitis. AB - Ulcerative colitis (UC) is a chronic inflammatory bowel disease that may become intractable when treated with conventional medications such as aminosalicylates, corticosteroids, and azathioprine. The herbal medicine Qing Dai has traditionally been used in Chinese medicine to treat UC patients, but there is a lack of published data on the efficacy of Qing Dai in UC treatment. We report several cases of patients with intractable UC who take Qing Dai in a retrospective observational study. Furthermore, we explore the mechanisms of action of Qing Dai. Nine patients with active UC who received conventional medications but wished to receive Qing Dai as an alternative medication were included in our analysis. The UC severity level was determined based on the clinical activity index (CAI). Additionally, 5 of the 9 patients were endoscopically evaluated according to the Matts grading system. Each patient received 2 g/d of Qing Dai orally and continued taking other medications for UC as prescribed. Electron spin resonance was applied to explore the mechanisms of action of Qing Dai. After 4 mo of treatment with Qing Dai, the CAI score decreased from 8.3 +/- 2.4 to 2.4 +/- 3.4 (mean +/- SD; P < 0.001). Similarly, the endoscopic Matts grade decreased from 3.4 +/- 0.5 to 2.2 +/- 0.8 (P = 0.02). Six of 7 patients who were on prednisolone upon enrollment in the study were able to discontinue this corticosteroid. Electron spin resonance revealed that Qing Dai possesses strong hydroxyl radical scavenging activity. Qing Dai showed significant clinical and endoscopic efficacy in patients who failed to respond to conventional medications. Scavenging of hydroxyl radicals appears to be a potential mechanism through which Qing Dai acts, but the significance of the scavenging ability of Qing Dai with respect to the anti-inflammatory effect in UC patients warrants further investigation. PMID- 23674884 TI - Meckel's diverticulum bleeding diagnosed with magnetic resonance enterography: a case report. AB - Although the introduction of double-balloon enteroscopy has greatly improved the diagnostic rate, definite diagnosis of Meckel's diverticulum far from the ileocecal valve is still impossible in most cases. We explored the role of magnetic resonance (MR) enterography in detecting bleeding from Meckel's diverticulum that can not be confirmed via double-balloon enteroscopy. This study describes a case of male patient with bleeding from Meckel's diverticulum diagnosed with MR enterography of the small intestine. No bleeding lesion was found via colonoscopy, anal enteroscopy, or oral colonoscopy. MR enterography of the small intestine revealed an occupying lesion of 3.0 cm in the lower segment of the ileum. The patient was transferred to the Department of Abdominal Surgery of our hospital for surgical treatment. During surgery, a mass of 3 cm * 2 cm was found 150 cm from the ileocecal valve, in conjunction with congestion and edema of the corresponding mesangium. Intraoperative diagnosis was small bowel diverticulum with bleeding. The patient underwent partial resection of the small intestine. Postoperative pathology showed Meckel's diverticulum containing pancreatic tissues. He was cured and discharged 7 d after operation. We conclude that MR enterography of the small intestine has greatly improved the diagnosis rate of Meckel's diverticulum, particularly in those patients with the disease which can not be confirmed via double-balloon enteroscopy. PMID- 23674885 TI - Correlation between risk factors during the neonatal period and appearance of retinopathy of prematurity in preterm infants in neonatal intensive care units in Alexandria, Egypt. AB - BACKGROUND: This study aimed to identify the main risk factors for development of retinopathy of prematurity (ROP) in neonatal intensive care units in Alexandria, Egypt, from January 2010 to January 2012. METHODS: A prospective cohort study was undertaken in infants weighing < 1250 g and maternal postmenstrual age < 32 weeks if there was concern about prolonged exposure to oxygen. The main clinical outcomes were occurrence of any stage of ROP and in particular severe ROP. Perinatal variables considered were: birth weight, gestational age, gender, method of ventilation (nasal continuous airway pressure or intermittent mechanical ventilation), packed red blood cell and/or plasma transfusion, occurrence of sepsis, neonatal indirect hyperbilirubinemia, intraventricular hemorrhage, and patent ductus arteriosus. After obtaining informed consent from the parents, infants at risk were examined for ROP using indirect ophthalmoscopy, ie, RetCam II fundus photography. RESULTS: The study included 152 infants of mean gestational age 31.02 weeks and mean birth weight 1.229 kg. Seventy-two cases (47.5%) were male and 80 cases (52.5%) were female. Of the cases screened, 100 (65.6%) had no ROP, 52 had ROP of any stage (34.4%), and 27 (18%) had stage 1, five (3.3%) had stage 2, 17 (11.5%) had stage 3, and three (1.6%) had stage 4 disease. No infants had stage 5 ROP. Of all our cases with ROP, 15 (28.6%) had prethreshold disease type 1 that required treatment, comprising 9.8% of all cases screened for ROP. Using stepwise logistic regression analysis, all risk factors studied were found to be significantly associated with the development of ROP, except for neonatal indirect hyperbilirubinemia. Severity of ROP was inversely proportional to birth weight and gestational age. CONCLUSION: ROP occurred in 34.4% of all infants screened in the neonatal intensive care units at three obstetric hospitals in Alexandria. The main risk factors for development of threshold ROP by regression analysis were low birth weight, gestational age, method of ventilation, need for packed red blood cell and/or plasma transfusion, occurrence of sepsis, intraventricular hemorrhage, and patent ductus arteriosus but not neonatal indirect hyperbilirubinemia. We suggest that both immaturity and compromised pulmonary function are both important etiological factors in the development of ROP. PMID- 23674886 TI - Rapid anterior capsular contraction after phacoemulsification surgery in a patient with retinitis pigmentosa. AB - A decrease in the anterior capsule opening after cataract surgery has been observed in eyes with weakened lens zonules. It commonly occurs in diabetes mellitus, uveitis, pseudoexfoliation syndrome, high myopia, and elderly patients. Herein, we report the case of a middle-aged man with advanced retinitis pigmentosa who developed a rapid contraction of the anterior capsule after an uneventful phacoemulsification surgery that resulted in severe visual loss during the early postoperative period. PMID- 23674887 TI - Bosutinib in the management of chronic myelogenous leukemia. AB - Bosutinib (SKI-606) is an orally available, once-daily dual Src and Abl kinase inhibitor, approved by the US Food and Drug Administration for the treatment of adults with chronic, accelerated, or blast-phase Philadelphia chromosome-positive chronic myelogenous leukemia who are intolerant of or resistant to first- or second-generation tyrosine kinase inhibitors. Bosutinib effectively overcomes the majority of imatinib-resistance-conferring BCR-ABL mutations except V299L and T315I. In the Bosutinib Efficacy and Safety in chronic myeloid LeukemiA (BELA) trial, bosutinib attained a faster and deeper molecular response than imatinib in newly diagnosed chronic-phase chronic myelogenous leukemia patients. Treatment emergent adverse events are usually very manageable. Low grade, mostly self limiting diarrhea represents the most frequently observed toxicity of bosutinib. Anti-diarrheal drugs, antiemetic agents, and/or fluid replacement should be used to treat these patients. The improved hematological toxicity of bosutinib compared with other tyrosine kinase inhibitors has been ascribed to its minimal activity against platelet-derived growth factor receptor and KIT. In this review, we give an overview on the profile of bosutinib, the clinical potential and treatment-emergent adverse events. PMID- 23674888 TI - Ambrisentan for the treatment of pulmonary arterial hypertension: improving outcomes. AB - Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature that is associated with severe functional impairment and a poor prognosis. Ambrisentan is a selective endothelin type A receptor antagonist approved for the treatment of patients with PAH World Health Organization group 1. The efficacy and safety of ambrisentan has been evaluated in the ARIES series (Ambrisentan for the Treatment of Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies), which has established its use as both monotherapy or in conjunction with other PAH therapies. Specifically, ambrisentan is effective at increasing exercise tolerance, decreasing the risk of functional class deterioration, and prolonging time to clinical worsening. Further, ambrisentan has a favorable effect on mortality, with an 88% patient survival rate after two years of therapy compared with a 61% survival rate as estimated by the National Institute of Health Registry. Ambrisentan is generally well tolerated in all patient groups, with the main side effects of peripheral edema, sinusitis, flushing, and nasal congestion considered to be mild to moderate in nature. Ambrisentan has several favorable qualities that potentially make it more acceptable to patients, including once daily administration, limited adverse drug reactions and drug-drug interactions, and minimal risk of liver enzyme elevation. Because of the potential risk of teratogenicity associated with ambrisentan, it is only available through a limited distribution program, ie, LEAP (the Letairis Education and Access Program). Ongoing clinical trials will help to clarify the role of ambrisentan in the treatment of PAH. PMID- 23674889 TI - Response to Alzheimer's research paper. PMID- 23674891 TI - Nanostructured magnesium has fewer detrimental effects on osteoblast function. AB - Efforts have been made recently to implement nanoscale surface features on magnesium, a biodegradable metal, to increase bone formation. Compared with normal magnesium, nanostructured magnesium has unique characteristics, including increased grain boundary properties, surface to volume ratio, surface roughness, and surface energy, which may influence the initial adsorption of proteins known to promote the function of osteoblasts (bone-forming cells). Previous studies have shown that one way to increase nanosurface roughness on magnesium is to soak the metal in NaOH. However, it has not been determined if degradation of magnesium is altered by creating nanoscale features on its surface to influence osteoblast density. The aim of the present in vitro study was to determine the influence of degradation of nanostructured magnesium, created by soaking in NaOH, on osteoblast density. Our results showed a less detrimental effect of magnesium degradation on osteoblast density when magnesium was treated with NaOH to create nanoscale surface features. The detrimental degradation products of magnesium are of significant concern when considering use of magnesium as an orthopedic implant material, and this study identified a surface treatment, ie, soaking in NaOH to create nanoscale features for magnesium that can improve its use in numerous orthopedic applications. PMID- 23674890 TI - Liposomes functionalized to overcome the blood-brain barrier and to target amyloid-beta peptide: the chemical design affects the permeability across an in vitro model. AB - PURPOSE: We investigated the ability of amyloid-beta-targeting liposomes, decorated with an anti-transferrin receptor antibody, to cross the blood-brain barrier (BBB), comparing two antibody ligation techniques. METHODS: Fluorescent or radiolabeled liposomes composed of sphingomyelin/cholesterol and containing phosphatidic acid, known to bind amyloid-beta, were further functionalized with the anti-transferrin receptor antibody RI7217. Two different techniques were used to attach RI7217 to the liposomes surface: biotin/streptavidin linkage or thiol maleimide covalent ligation. Surface plasmon resonance (SPR) and immunoblotting were employed to assess the nanoparticles' binding performances. Confocal microscopy and radiochemical techniques were used for uptake and permeability studies on an in vitro BBB model made of human brain capillary endothelial cells hCMEC/D3. RESULTS: Immunoblotting experiments showed that RI7217-functionalized liposomes bind to transferrin receptor independently of the procedure employed to ligate their surface with the antibody, while SPR experiments showed a slightly higher affinity for covalently functionalized nanoliposomes. The functionalization with RI7217 did not affect the liposomes' affinity for amyloid beta. The functionalization of liposomes with RI7217, independently of the ligation procedure, gave higher values of uptake and permeability across the barrier model in comparison to the nondecorated ones, without cell monolayer alterations. Of note, the best performing particles were those covalently coupled with the antibody. The ratios of the two radiolabeled lipids ((3)H-sphingomyelin and (14)C-phosphatidic acid) present in the liposome bilayer were found to be similar in the apical and in the basolateral compartments of the barrier model, suggesting that liposomes were transported intact across the cell monolayer. Confocal experiments showed no co-localization of RI7217-liposomes with early/late endosomes or early lysosomes. CONCLUSION: Our results suggest that RI7217 promotes the in vitro barrier crossing of liposomes containing phosphatidic acid, targeting the Alzheimer's disease amyloid-beta peptide. Moreover, for the first time, we prove herein the superior efficiency of covalent coupling of RI7217 versus biotin/streptavidin ligation to facilitate liposomes in overcoming the BBB in vitro. PMID- 23674892 TI - Chitosan-coated boron nitride nanospheres enhance delivery of CpG oligodeoxynucleotides and induction of cytokines. AB - BACKGROUND: Cytosine-phosphate-guanine (CpG) oligodeoxynucleotides activate Toll like receptor 9, leading to induction of proinflammatory cytokines, which play an important role in induction and maintenance of innate and adaptive immune responses. Previously, we have used boron nitride nanospheres (BNNS) as a carrier for delivery of unmodified CpG oligodeoxynucleotides to activate Toll-like receptor 9. However, because CpG oligodeoxynucleotides and BNNS are both negatively charged, electrostatic repulsion between them is likely to reduce the loading of CpG oligodeoxynucleotides onto BNNS. Therefore, the efficiency of uptake of CpG oligodeoxynucleotides is also limited and does not result in induction of a robust cytokine response. To ameliorate these problems, we developed a CpG oligodeoxynucleotide delivery system using chitosan-coated BNNS as a carrier. METHODS: To facilitate attachment of CpG oligodeoxynucleotides onto the BNNS and improve their loading capacity, we prepared positively charged BNNS by coating them with chitosan preparations of three different molecular weights and used them as carriers for delivery of CpG oligodeoxynucleotides. RESULTS: The zeta potentials of the BNNS-CS complexes were positive, and chitosan coating improved their dispersity and stability in aqueous solution compared with BNNS. The positive charge of the BNNS-CS complexes greatly improved the loading capacity and cellular uptake efficiency of CpG oligodeoxynucleotides. The loading capacity of the CpG oligodeoxynucleotides depended on the molecular weight of chitosan, which affected the positive charge density on the surface of the BNNS. CpG oligodeoxynucleotides loaded onto BNNS-CS complexes significantly enhanced production of interleukin-6 and tumor necrosis factor-alpha by peripheral blood mononuclear cells compared with CpG oligodeoxynucleotides directly loaded onto BNNS, or when LipofectamineTM 2000 was used as the carrier. The molecular weight of the chitosan used to coat the BNNS affected the magnitude of cytokine induction by varying the strength of condensation of the CpG oligodeoxynucleotides. CONCLUSION: Although the loading capacity of BNNS coated with low molecular weight chitosan preparations was the lowest of all the preparations, they induced the highest levels of cytokines. PMID- 23674893 TI - Application of the central composite design to optimize the preparation of novel micelles of harmine. AB - Lactose-palmitoyl-trimethyl-chitosan (Lac-TPCS), a novel amphipathic self assembled polymer, was synthesized for administration of insoluble drugs to reduce their adverse effects. The central composite design was used to study the preparation technique of harmine (HM)-loaded self-assembled micelles based on Lac TPCS (Lac-TPCS/HM). Three preparation methods and single factors were screened, including solvent type, HM amount, hydration volume, and temperature. The optimal preparation technique was identified after investigating the influence of two independent factors, namely, HM amount and hydration volume, on four indexes, ie, encapsulation efficiency (EE), drug-loading amount (LD), particle size, and polydispersity index (PDI). Analysis of variance showed a high coefficient of determination of 0.916 to 0.994, thus ensuring a satisfactory adjustment of the predicted prescription. The maximum predicted values of the optimal prescription were 91.62%, 14.20%, 183.3 nm, and 0.214 for EE, LD, size, and PDI, respectively, when HM amount was 1.8 mg and hydration volume was 9.6 mL. HM-loaded micelles were successfully characterized by Fourier-transform infrared spectroscopy, differential scanning calorimetry, X-ray diffraction, and a fluorescence quenching experiment. Sustained release of Lac-TPCS/HM reached 65.3% in 72 hours at pH 7.4, while free HM released about 99.7% under the same conditions. PMID- 23674894 TI - Cellular uptake mechanism and intracellular fate of hydrophobically modified pullulan nanoparticles. AB - The cellular uptake mechanism and intracellular fate of self-assembled nanoparticles (NPs) of cholesterol-modified pullulan (CHSP) by human hepatocellular carcinoma (HepG2) cells were investigated. Covalent conjugation with fluorescein isothiocyanate (FITC) yielded stably labeled CHSP (FITC-CHSP), which was successfully formulated into NPs (mean particle size 63.0 +/- 1.9 nm) by dialysis. A cytotoxicity assay clearly indicated that the CHSP NPs did not show significant toxicity in HepG2 cells. The effects of NP concentration, incubation time, and temperature on the cellular uptake of the NPs were systematically evaluated by fluorometry, and the results suggested that cellular uptake of the NPs was concentration-,time-, and temperature-dependent. In vitro experiments with endocytic inhibitors revealed that clathrin-mediated endocytosis and macropinocytosis were involved in the internalization of CHSP NPs. The intracellular trafficking study demonstrated that CHSP NPs were entrapped in the lysosomes at 1 hour after incubation; colocalization of NPs with either the Golgi apparatus or the endoplasmic reticula was not observed during the entire course of the study. These results suggested that the CHSP NPs may serve as a versatile carrier for intracellular delivery of therapeutic agents. PMID- 23674895 TI - The synergistic effect and mechanism of doxorubicin-ZnO nanocomplexes as a multimodal agent integrating diverse anticancer therapeutics. AB - BACKGROUND: Nanomaterials have emerged as ideal multimodal nanomedicine platforms, each one combining different designs and therapeutic approaches in a single system against cancer. The aim of the current study was to explore the synergistic effect and mechanism of a doxorubicin (Dox)-ZnO nanocomplex as a multimodal drug delivery system, integrating Dox chemotherapy and ZnO-mediated photodynamic therapy, in anticancer therapeutics. METHODS: Dox was loaded onto ZnO nanomaterials, forming complexes with the transition metal Zn to yield the Dox-ZnO nanocomplexes. After culture with SMMC-7721 hepatocarcinoma cells, the cellular uptake was quantitatively detected by flow cytometry and visualized by fluorescence microscopy. The synergistic effects of the different anticancer therapeutic modalities on the proliferation of SMMC-7721 hepatocarcinoma cells were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The expression of B-cell lymphoma 2 protein (Bcl-2), Bcl-2 associated X protein (Bax), caspase 9, and caspase 3 were examined by Western blot, to elucidate the possible molecular mechanisms involved. RESULTS: Our observations demonstrated that Dox-ZnO nanocomplexes could act as an efficient drug delivery system for importing Dox into SMMC-7721 cells, enhancing its potential chemotherapy efficiency by increasing the intracellular concentration of Dox. With the addition of ultraviolet (UV) illumination, the ZnO nanomaterials showed excellent photodynamic therapeutic properties, attacking the cancer cells further. Thus the caspase-dependent apoptosis was synergistically induced, resulting in distinct improvement in anticancer activity. CONCLUSION: The Dox-ZnO nanocomplex presents a promising multimodal agent for comprehensive cancer treatment. PMID- 23674897 TI - PIK3CA gene mutation associated with poor prognosis of lung adenocarcinoma. AB - PURPOSE: PIK3CA gene mutations have been detected in many malignancies, but the frequency of different mutations and their role in the carcinogenesis of lung adenocarcinoma are still unclear. The purpose of this study was to explore the clinical pathological impact and prognostic implications of PIK3CA mutations in lung adenocarcinoma. METHODS: Five common PIK3CA mutations (E542K, E545K, and E545D mutation in exon 9, H1047R and H1047L mutation in exon 20) were detected by amplification refractory mutation system (ARMS) allele-specific polymerase chain reaction (PCR), in 122 patients with lung adenocarcinoma. The relationships were studied between these mutations and various clinicopathologic variables (age, lymph node status, distant metastasis, clinicopathologic stage, smoking status, and progression-free survival). RESULTS: In total, 25 mutations were identified, of which 24 mutations were clustered in exon 20, and one mutation in exon 9. The most common mutations were H1047R (18 out of the 122 patients, 14.8%) in exon 20. PIK3CA-mutated tumors were more frequently found in patients with lymph node positive metastasis status (P < 0.05). There was no significant association between PIK3CA mutations and age, distant metastasis, smoking status, or clinicopathologic stage. However, mutations were found less frequently in the early clinicopathologic stage patients (six in 50 cases, 12%) than in advanced stage (19 in 72 cases, 26.4%). Higher frequency of H1047R mutations was associated with poor prognosis, and this association reached statistical significance (P < 0.05). CONCLUSION: Our data indicate that the PIK3CA mutations H1047R and H1047L are significant genetic alterations in lung adenocarcinoma. Among lung adenocarcinoma patients who underwent curative resection, PIK3CA mutations were associated with shorter progression-free survival. Our findings demonstrated a significant role of PIK3CA in lung adenocarcinoma. PMID- 23674896 TI - Potential role of new anticoagulants for prevention and treatment of venous thromboembolism in cancer patients. AB - Venous thromboembolism (VTE), encompassing deep vein thrombosis and pulmonary embolism, represents a major cause of morbidity and mortality in patients with cancer. Low molecular weight heparins are the preferred option for anticoagulation in cancer patients according to current clinical practice guidelines. Fondaparinux may also have a place in prevention of VTE in hospitalized cancer patients with additional risk factors and for initial treatment of VTE. Although low molecular weight heparins and fondaparinux are effective and safe, they require daily subcutaneous administration, which may be problematic for many patients, particularly if long-term treatment is needed. Studying anticoagulant therapy in oncology patients is challenging because this patient group has an increased risk of VTE and bleeding during anticoagulant therapy compared with the population without cancer. Risk factors for increased VTE and bleeding risk in these patients include concomitant treatments (surgery, chemotherapy, placement of central venous catheters, radiotherapy, hormonal therapy, angiogenesis inhibitors, antiplatelet drugs), supportive therapies (ie, steroids, blood transfusion, white blood cell growth factors, and erythropoiesis stimulating agents), and tumor-related factors (local vessel damage and invasion, abnormalities in platelet function, and number). New anticoagulants in development for prophylaxis and treatment of VTE include parenteral compounds for once-daily administration (ie, semuloparin) or once-weekly dosing (ie, idraparinux and idrabiotaparinux), as well as orally active compounds (ie, dabigatran, rivaroxaban, apixaban, edoxaban, betrixaban). In the present review, we discuss the pharmacology of the new anticoagulants, the results of clinical trials testing these new compounds in VTE, with special emphasis on studies that included cancer patients, and their potential advantages and drawbacks compared with existing therapies. PMID- 23674898 TI - Recovery of putative pathogens from paper point sampling at different depths of periodontal lesions. AB - BACKGROUND: The aim of this study was to compare the recovery of three putative periodontal pathogens from periodontal lesions in samples using paper points inserted to different depths of the lesions. METHODS: Twenty 6-8 mm deep periodontal lesions with bleeding on probing were studied. Microbial samples were obtained using paper points inserted to three different depths of the lesions: orifice of lesion; 2 mm into the lesion; and to the base of lesion. Culturing was used for recovery and identification of Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, and Prevotella intermedia. RESULTS: The recovery of each of the three putative periodontal pathogens was similar following sampling at the various depths of the lesions. CONCLUSIONS: The findings may be explained by the fact that the paper points become saturated as they pass through the orifice of the lesion. Absorption of microorganisms will therefore primarily occur at the orifice. It is also conceivable that the pathogens may be present in similar proportions throughout the various depths of the periodontal lesions. PMID- 23674899 TI - Bone resorption in incompletely impacted mandibular third molars and acute pericoronitis. AB - Acute pericoronitis (AP) arises frequently in incompletely impacted mandibular third molars, but it remains unknown whether bone resorption in aging is associated with acute inflammation of the third molar. We conducted an experiment to compare the ratio of bone resorption to root length in the distal surface of the second molar (A), the proximal surface (B), and distal surface (C) in mesio angular, incompletely impacted third molars in 27 young and 58 older adults with AP and 77 young and 79 older adults without a history of AP. Bone resorption in A, B, and C in older adults with AP demonstrated a significantly higher ratio when compared to those without AP, whereas there was no difference between those with and without AP in young adults except for B in women. However, there were no differences between bone resorption in B with AP in young and older women, and between bone resorption in C with AP in young and older adults. These indicate that AP and bone resorption are associated with incompletely impacted mandibular third molars in older adults. PMID- 23674900 TI - Periosteoplasty for covering gingival recessions: Clinical results. AB - This is a case series in which a new technique for the surgical treatment of periodontal recessions is presented along with the results of the first clinical trial. A new technique of periodontal flap surgery was performed on 30 patients with severe periodontal recessions of the upper or lower front teeth. Root and soft tissue scaling was carried out with an open approach, then the periosteum was incised and mobilized at the apical part of the mucoperiosteum flap to cover the defect before the mucoperiosteum was reattached and fixed by sutures. Sulcus bleeding, periodontal probing depths, attachment loss and the length of the attached gingiva of the affected teeth were recorded preoperatively and at 3, 6, and 12 months postoperatively. Every clinical parameter was improved by surgery. No sulcus bleeding was observed at any time during the postoperative follow-up. A mean reattachment of 5.5 mm was noticed 12 months postoperatively at a mean probing depth of 0.3 mm. The mean height of the attached gingiva was 0 mm before surgery, 2.3 mm at three and six months postoperatively, and 2.2 mm at 12 months. The periosteum eversion technique is suitable for the treatment of gingival recessions resulting in good gingival function and a clear improvement in aesthetics. PMID- 23674901 TI - Influence of light curing and sample thickness on microhardness of a composite resin. AB - The aim of this in vitro study was to evaluate the influence of light-curing units and different sample thicknesses on the microhardness of a composite resin. Composite resin specimens were randomly prepared and assigned to nine experimental groups (n = 5): considering three light-curing units (conventional quartz tungsten halogen [QTH]: 550 mW/cm(2) - 20 s; high irradiance QTH: 1160 mW/cm(2) - 10 s; and light-emitting diode [LED]: 360 mW/cm(2) - 40 s) and three sample thicknesses (0.5 mm, 1 mm, and 2 mm). All samples were polymerized with the light tip 8 mm away from the specimen. Knoop microhardness was then measured on the top and bottom surfaces of each sample. The top surfaces, with some exceptions, were almost similar; however, in relation to the bottom surfaces, statistical differences were found between curing units and thicknesses. In all experimental groups, the 0.5-mm-thick increments showed microhardness values statistically higher than those observed for 1- and -2-mm increments. The conventional and LED units showed higher hardness mean values and were statistically different from the high irradiance unit. In all experimental groups, microhardness mean values obtained for the top surface were higher than those observed for the bottom surface. In conclusion, higher levels of irradiance or thinner increments would help improve hybrid composite resin polymerization. PMID- 23674903 TI - Root coverage of a previously restored tooth. A case report with a 7-year follow up. AB - This case report describes the treatment of a maxillary canine that had 4 mm of marginal gingival recession. The exposed root had been previously restored with a composite class 5 restoration. The restoration was removed and the root planed and demineralized. The root was then covered by a subepithelial connective tissue graft harvested from the palate. The flap was coronally positioned to completely cover the graft and exposed root. The healing was photographed post-operatively at one month, six months, and seven years. Root coverage increased to 100% after seven years. The zone of attached gingiva also increased. PMID- 23674902 TI - Radiolucency below the crown of mandibular horizontal incompletely impacted third molars and acute inflammation in men with diabetes. AB - Although mandibular third molar has a high risk of infection extending any complications, the influence of diabetes on radiolucency and acute inflammation in pericoronitis remains unclear. The present study was to evaluate whether radiolucency below the crown is related to acute inflammation in mandibular horizontal incompletely impacted third molars and to review the records of 140 men more than 45 years with and without diabetes. The odds ratio of exhibiting acute inflammation was 3.38 (95% CI: 1.13-10.16, p < 0.05) and that of exhibiting severe acute inflammation was 15.38 (95% CI: 3.56-66.49, p < 0.0001), indicating an association of acute pericoronitis in diabetes. The frequency of radiolucency below the crown and below the root in diabetics was similar to that in nondiabetics. However, the odds ratio of exhibiting both radiolucency below the crown and acute inflammation under the diabetic condition was 4.85 (95% CI: 1.60 14.73, p < 0.01), whereas that of diabetics showing both radiolucency below the root and acute inflammation was 0.46 (95% CI: 0.06-3.74, p = 0.74). Radiolucency below the crown and acute inflammation were associated with diabetes, but that below root and acute inflammation were not associated with diabetes, indicating that the region below the crown carries susceptibility to acute pericoronitis, whereas the periodontium shows a protective effect against acute pericoronitis. PMID- 23674904 TI - Evolution of photography in maxillofacial surgery: from analog to 3D photography an overview. AB - In maxillofacial surgery, digital photographic documentation plays a crucial role in clinical routine. This paper gives an overview of the evolution from analog to digital in photography and highlights the integration of digital photography into daily medical routine. The digital workflow is described and we show that image quality is improved by systematic use of photographic equipment and post processing of digital photographs. One of the advantages of digital photography is the possibility of immediate reappraisal of the photographs for alignment, brightness, positioning, and other photographic settings, which aids in avoiding errors and allows the instant repetition of photographs if necessary. Options for avoiding common mistakes in clinical photography are also described and recommendations made for post-processing of pictures, data storage, and data management systems. The new field of 3D digital photography is described in the context of cranial measurements. PMID- 23674906 TI - Cleft deformities in adults and children aged over six years in Nigeria: Reasons for late presentation and management challenges. AB - In developing countries, untreated cleft lips and palates are found with increasing frequency and patients often present to the surgeon far past the optimal time for closure of the cleft deformities. A prospective study was conducted between March 2007 and September 2009, to identify the reasons and treatment challenges of delayed presentation of cleft lip and palate deformities at the Lagos University Teaching Hospital, Nigeria. Out of a total of 150 patients with cleft defects during the period, 43 (28.7%) were adults and children aged over six years. The mean age of these patients at the time of presentation was 17.3 years. The most common reasons for late presentation were lack of money (56.7%), lack of health care services nearby (18.4%), and lack of awareness of treatment availability (13.3%). Common challenges in these patients included surgical, orthodontic, speech, anesthetic, and psychological. Although adult clefts were significantly enlarged in three dimensions the anatomic landmarks were easier to discern than in an infant. However, extensive soft tissue dissection in adult cleft lip repair resulted in significant postoperative edema. Closure of wide palatal cleft often required the use of adjunct intraoral flaps. Despite late presentation, surgical outcome of these patients was satisfactory and comparable to cleft repair in infants. PMID- 23674905 TI - Current practicality of nanotechnology in dentistry. Part 1: Focus on nanocomposite restoratives and biomimetics. AB - First described in 1959 by physicist Richard P Feynman, who saw it as an unavoidable development in the progress of science, nanotechnology has been part of mainstream scientific theory with potential medical and dental applications since the early 1990s. Nanoparticles, nanospheres, nanorods, nanotubes, nanofibers, dendrimers and other nanostructures have been studied for various applications to biologic tissues and systems. While many layers of nanotechnologic capability have been envisioned for oral health in the last decade (eg, oral hygiene maintenance, local anesthesia, even whole-tooth replacement), few of these applications have been developed. Part 1 of a three part series reviews the current clinical utility of nanotechnology's most tangible contribution to dentistry to date: the restoration of tooth structure with nanocomposites. Characterized by filler-particle sizes of <=100 nm, these materials can offer esthetic and strength advantages over conventional microfilled and hybrid resin-based composite (RBC) systems, primarily in terms of smoothness, polishability and precision of shade characterization, plus flexural strength and microhardness similar to those of the better-performing posterior RBCs. Available comparative data for nanocomposites and organically-modified ceramic (Ormocer((r))) restoratives are also reviewed. Finally, plausible "next phase" trends in current nanorestorative research are judiciously examined, including 1) calcium-, phosphate-, and fluoride-ion-releasing nanocomposites for anticaries applications and 2) restorative systems based on biomimetic emulation of the nanomolecular assembly processes inherent in dental enamel formation using nanorods, nanospheres, and recombinant amelogenins. PMID- 23674907 TI - Temporomandibular joint sounds and disc dislocations incidence after orotracheal intubation. AB - The aim of this study was to analyze the temporomandibular joint (TMJ) disc displacement and articular sounds incidence after orotracheal intubation. A prospective cohort study was conducted in the Hospital Universitario do Oeste do Parana (HUOP), in Cascavel, Brazil. 100 patients (aged 14-74 years, mean 44 years), 34 male and 66 female, in need of surgical procedure with orotracheal intubation were evaluated. The anterior disc displacement with reduction incidence and the nonclassifiable sounds incidence by the Research Diagnostic Criteria Axis I was evaluated in all patients after orotracheal intubation. The patients was evaluated one day before and until two days after the procedure. Eight percent present with anterior disc displacement with reduction and 10% presented nonclassifiable sounds after the orotracheal intubation. There was no correlation of any kind regarding gender related influence in the incidence of disc dislocations (P = 0.2591) and TMJ sounds (P = 0.487). Although anterior disc dislocations and TMJ sounds after anesthetic with orotracheal intubation presented a low incidence (8%-10%), it is recommended that the evaluation of TMJ signs and symptoms be done before the anesthetic procedure to take care with susceptible patients manipulation. PMID- 23674908 TI - Oxidized galectin-1 reduces lipopolysaccharide-induced increase of proinflammatory cytokine mRNA in cultured macrophages. AB - BACKGROUND: Periodontitis is prevalent in older humans. Limiting the inflammation associated with periodontitis may provide a therapy for this condition, because Gram-negative bacteria expressing lipopolysaccharide (LPS) have a key role in initiation of inflammation by activating macrophage functions. Because oxidized galectin-1 regulates macrophage functions in other systems, we sought to establish whether this galectin-1 mRNA is expressed in the oral cavity, and whether it could dampen LPS-induced macrophage activation in vitro. METHODS: Using the reverse transcriptase polymerase chain reaction (RT-PCR), we measured galectin-1 mRNA expression to clarify its localization to rat gingival tissues and studied the effect of Porphyromonas gingivalis challenge on galectin-1 expression. Next, we tested the effects of adding oxidized galectin-1 to cultured LPS-activated peritoneal macrophages on mRNA expression of proinflammatory factors by RT-PCR and real-time RT-PCR. RESULTS: We established that galectin-1 mRNA is expressed in gingival tissues and also showed that galectin-1 mRNA was significantly increased by challenge with P. gingivalis, indicating that galectin 1 may regulate oral inflammation. On the other hand, LPS 100 ng/mL in serum containing medium induced macrophages to upregulate mRNA associated with a proinflammatory response, ie, interleukins 1beta and 6, and inducible nitric oxide synthase. We showed that application of 0.1-10 ng/mL of oxidized galectin-1 to LPS-treated macrophages reduced the intense LPS- induced increase by serum in proinflammatory mRNA expression in a concentration-dependent manner. Furthermore, application of oxidized galectin-1 10 ng/mL to LPS-treated macrophages in serum free medium also showed a similar effect on LPS activity. CONCLUSION: Oxidized galectin-1 restricts the proinflammatory actions of LPS, and this protein could limit the negative effects of inflammation. PMID- 23674909 TI - Microscope-controlled glass bead blasting: a new technique. AB - OBJECTIVE: The aim of periodontal therapy is the healing of periodontal inflammation; the protection of the attachment and the alveolar bone; and the regeneration of the periodontal structures. In the therapy of periodontitis, supra- and subgingival scaling and root planing plays a main role. The procedure described combines perfect root cleaning without scaling and root planing and minimal invasive periodontal surgery without a scalpel. MATERIAL AND METHODS: Glass beads of 90 MUm were used with the kinetic preparation unit PrepStart((r)) under a pressure of 0.5-5 bar. This technique was practised only under visual control using the OPMI((r)) PRO Magis microscope. Seven examinations were carried out at baseline after 3, 6, 12, 18, 24, and 36 months. RESULTS: Time shows a statistically significant influence on all of the considered target variables (P < 0.0001 for all). As the according estimate is negative, probing depth decreases over time. The major decrease seems to be during the first 6 months. Considering probing depth, plaque on the main effect root shows significant influence (again, P < 0.0001 for all). Observations with high probing depth at the beginning were faster than those with low probing depth. The same characteristic appears by attachment level. Patients with more loss of attachment show more gain. CONCLUSIONS: Using microscope-controlled glass bead blasting results in a perfectly clean root surface using visual control (magnification 20*). Microscope controlled glass bead blasting is therefore a good alternative to periodontal surgery. PMID- 23674910 TI - Treatment of nonsyndromic dentigerous cysts in primary dentition. AB - OBJECTIVE: Dentigerous cysts are benign odontogenic cysts that are associated with the crowns of permanent teeth. They usually occur singly and are located in the mandible. Nonsyndromic bilateral dentigerous cysts (NSBDC) are rarely seen during childhood. The aim of this study was to determine the long-term effects of the marsupialization technique in growing children with NSBDC. STUDY DESIGN: Seven patients with NSBDC (4 female, 3 male) ranging in age from 7 to 9 years (mean 8.35 years) were involved in the study. All the individuals were treated by marsupialization. Space-maintaining appliances were applied during permanent teeth eruption. Intraoral photographs, and panoramic and periapical films were taken before surgery and during healing. RESULTS: The NSBDC were successfully treated by the marsupialization technique and rapid healing period was observed in the growing patients, without any loss of permanent teeth. No recurrence was seen in the long-term follow-up period (3-10 years). CONCLUSION: Our clinical and radiological results revealed that using the marsupialization technique in children with NSBDC provided safe healing of permanent teeth around the dentigerous cysts in a short period. However, treatment planning and regular clinical follow-ups are necessary to ensure clinical success. PMID- 23674911 TI - New phosphated poly(methyl methacrylate) polymers for the prevention of denture induced microbial infection: an in vitro study. AB - PURPOSE: Poly(methyl methacrylate) (PMMA) has been widely used as a denture-base acrylic resin due to its excellent physical and mechanical properties. However, the material is highly prone to microbial fouling that often leads to Candida associated denture stomatitis. Incorporation of phosphate groups into PMMA could facilitate adsorption of salivary antimicrobials and inhibit microbial adherence on the polymer surface. An in vitro study evaluated PMMA polymers containing varying amounts of phosphate group for their efficacy to inhibit Candida albicans adhesion, adsorb salivary histatin 5, and exhibit candidacidal activity. METHODS: Six PMMA polymers containing 0%, 5%, 15%, 10%, 20%, and 25% of phosphate group were synthesized by bead (suspension) polymerization technique using mixtures of methyl methacrylate and methallyl phosphate as monomers. The efficacy of the polymers to inhibit the adherence of C. albicans was examined by using human saliva-coated polymer beads and radio-labeled C. albicans cells, as compared with that of PMMA. The potency of the phosphated PMMA polymers to adsorb histatin 5 was determined by measuring the radioactivity of the adsorbed labeled-peptide on the polymer surface. The candidacidal activity of the histatin 5-adsorbed polymers was assessed by using the fluorescence technique. The percent release of the fluorescent probe calcein from the C. albicans membrane caused by the disruption of the cell membrane was determined. The data were analyzed statistically by one-way ANOVA followed by Scheffe's test (alpha = 0.05 and n = 6). RESULTS: The presence of >=15% phosphate content in PMMA significantly reduced the saliva-mediated adhesion of C. albicans. Phosphated PMMA polymers showed significantly enhanced adsorption of histatin 5 in a phosphate density dependent manner. The candidacidal activity of the histatin 5-bound polymers increased significantly with the increase in the phosphate content of the polymer. CONCLUSION: Phosphated PMMA polymers have the potential to serve as novel denture-base resins, which may reduce C. albicans colonization and prevent denture stomatitis. PMID- 23674912 TI - Use of Artelon((r)) Cosmetic in soft tissue augmentation in dentistry. AB - BACKGROUND: Soft tissue augmentation is a widely used procedure in partially and fully edentulous patients to increase soft tissue volume. Polyurethanes have been used for scaffolds in a variety of implantable devices. Artelon((r)) is a degradable polyurethane that has been manufactured as fibers, films, and porous scaffolds to be used for various purposes. In this review, the characteristics of Artelon are described, and its clinical applications in orthopedics, dermatology, cardiovascular medicine, and dentistry are also discussed. METHODS: A Medline (PubMed) search was conducted, and articles published in English were included. Keywords, including "Artelon", "polyurethanes", "soft tissue augmentation", "biocompatibility", "resorption", "mechanical stability", and "complications" were used in different combinations. Titles and abstracts were screened, and full text article analyses were performed. RESULTS: Most of the studies reported orthopedic, dermal, and myocardial applications. There were only a few reports related to dental and implant applications. Artelon has been successfully used for reinforcement of soft tissues, including the rotator cuff, Achilles, patellar, biceps, and quadriceps tendons in orthopedic surgery, and is used clinically for the treatment of osteoarthritis in the hand, wrist, and foot. One type of Artelon material, Artelon Cosmetic, has been used in the dental field to increase soft tissue volume, and stable results are achieved for up to 6 months. This material is reported to be easily handled when cut to the desired shape, with little additional time needed for manipulation during surgery, eliminates the need for connective tissue autografts, and thereby decreases patient morbidity and postoperative discomfort, with increased likelihood of a positive subjective outcome. CONCLUSION: Artelon may be applied in the dental field to increase soft tissue volume. Further studies of various applications in dentistry with long-term results are needed to confirm the safety and efficacy of this material before it can be used on a routine basis in dentistry. PMID- 23674913 TI - Bond strength comparison of color-change adhesives for orthodontic bonding using a self-etching primer. AB - BACKGROUND: The purpose of this study was to compare the shear bond strengths of two color-change adhesives with a commonly used conventional light-cure adhesive while using a self-etching primer, and to compare any changes in shear bond strengths over time. METHODS: One hundred and eighty extracted bovine incisors were randomly divided into nine groups of 20 teeth each. The teeth were prepared with a self-etching primer (TransbondTM Plus) Metal lower incisor brackets were bonded directly to each tooth with two different color-change adhesives (TransbondPlus and GrenglooTM) and a control (Transbond XT). The teeth were debonded at three different time points (15 minutes, 24 hours, 1 week) using an Instron at 1.0 mm/min. The teeth that were to be debonded at 24 hours and 1 week were stored in distilled water at 37 degrees C to simulate the oral environment. The data were analyzed by two-way analysis of variance and with Fisher's protected least-significant difference multiple comparisons test at the P < 0.05 level of significance. Adhesive remnant index (ARI) scores were calculated for each debonded tooth. RESULTS: Transbond Plus at 1 week had the highest mean shear bond strength (14.7 mPa). Grengloo tested at 24 hours had the lowest mean shear bond strength (11.3 mPa). The mean shear bond strengths for the remaining seven groups had a range of 12-14.5 mPa. Grengloo had >80% samples presenting with an ARI score of 1 at all times. Interestingly, both Transbond groups had ARI scores of 3 in more than 50% of their samples. CONCLUSION: Time had no significant effect on the mean shear bond strength of Transbond XT, Grengloo, or Transbond Plus adhesive. PMID- 23674914 TI - Erosion and abrasion on dental structures undergoing at-home bleaching. AB - This review investigates erosion and abrasion in dental structures undergoing at- home bleaching. Dental erosion is a multifactorial condition that may be idiopathic or caused by a known acid source. Some bleaching agents have a pH lower than the critical level, which can cause changes in the enamel mineral content. Investigations have shown that at-home tooth bleaching with low concentrations of hydrogen or carbamide peroxide have no significant damaging effects on enamel and dentin surface properties. Most studies where erosion was observed were in vitro. Even though the treatment may cause side effects like sensitivity and gingival irritation, these usually disappear at the end of treatment. Considering the literature reviewed, we conclude that tooth bleaching agents based on hydrogen or carbamide peroxide have no clinically significant influence on enamel/dentin mineral loss caused by erosion or abrasion. Furthermore, the treatment is tolerable and safe, and any adverse effects can be easily reversed and controlled. PMID- 23674915 TI - Effects of myrrh on intra-oral mucosal wounds compared with tetracycline- and chlorhexidine-based mouthwashes. AB - AIM: To evaluate the effect of myrrh compared with chlorhexidine gluconate- and tetracycline-containing mouthwashes on wound healing over time in an animal model. METHODS: A unilateral incision on the right buccal mucosa was made, and the wound was irrigated with myrrh-, chlorhexidine gluconate-, or tetracycline based mouthwashes at various time intervals. Clinical and histological examination was performed for all the groups. RESULTS: It was found that the myrrh suspension promotes healing and repair of damaged tissue when used over a short period of time (less than 2 weeks) and in a low-concentration suspension; however, it can have harmful effects if used in excess or over a long period of time. CONCLUSION: Further studies will also be required to study these effects and their mechanism of action in detail. PMID- 23674916 TI - Current knowledge about the hydrophilic and nanostructured SLActive surface. AB - This review summarizes the present documentation for the SLActive surface, a hydrophilic and nanostructured surface produced by Straumann Company in Switzerland, and covers the results from 15 in vitro, 17 in vivo, and 16 clinical studies. The SLActive surface is a development of the large grit-blasted and acid etched SLA surface, and is further processed to a high degree of hydrophilicity. In general, the in vitro and in vivo studies of the SLActive surface demonstrate a stronger cell and bone tissue response than for the predecessor, the SLA surface, produced by the same company. However, in most studies, this difference disappears after 6-8 weeks. In the clinical studies, a stronger bone response was reported for the SLActive surface during the early healing phase when compared with the SLA surface. However, the later biological response was quite similar for the two surfaces and both demonstrated very good clinical results. PMID- 23674917 TI - The comparative effectiveness of demineralized bone matrix, beta-tricalcium phosphate, and bovine-derived anorganic bone matrix on inflammation and bone formation using a paired calvarial defect model in rats. AB - BACKGROUND: In this study, the effectiveness of Iranian Tissue Bank-produced demineralized bone matrix (ITB-DBM), beta-tricalcium phosphate (betaTCP), and Bio Oss((r)) (Geistlich Pharma AG, Wolhusen, Switzerland) were evaluated and compared with double controls. The main goal was to measure the amount of new bone formation in the center of defects created in rat calvaria. Another goal was to compare the controls and evaluate the effects of each treatment material on their adjacent untreated (control) defects. METHODS: In this study, 40 male Wistar rats were selected and divided into four groups, In each group, there were ten rats with two defects in their calvarias; one of them is considered as control and the other one was treated with ITB-DBM (group 1), BIO-OSS (group2), and betaTCP (group 3), respectively. But in group 4, both defects were considered as control. The amount of inflammation and new bone formation were evaluated at 4 and 10 weeks. In the first group, one defect was filled with ITB-DBM; in the second group, one defect was filled with Bio-Oss; in the third group, one defect was filled with betaTCP; and in the fourth group, both defects were left unfilled. Zeiss microscope (Carl Zeiss AG, Oberkochen, Germany) and Image Tool((r)) (version 3.0; University of Texas Health Science Center at San Antonio, San Antonio, TX) software were used for evaluation. SPSS Statistics (IBM Corp, Somers, NY) was used for statistical analysis. RESULTS: Maximum bone formation at 4 and 10 weeks were observed in the ITB-DBM group (46.960% +/- 4.366%, 94.970% +/ 0.323%), which had significant difference compared with the other groups (P < 0.001). Ranking second was the Bio-Oss group and third, the betaTCP group. Bone formation in the group with two unfilled defects was much more significant than in the other controls beside the Bio-Oss and betaTCP after 10 weeks (29.1 +/- 2.065, 29.05 +/- 1.649), while this group had the least bone formation compared with the other controls at week 4 (2.100% +/- 0.758%, 1.630% +/- 0.668%, P < 0.001). CONCLUSION: Overall, the ITB-DBM group showed the best results, although the results for other experimental groups were unfavorable. The authors conclude that human DBM (ITB-DBM) should be offered as an alternative for bone regeneration in animals, such as horses, as well as in humans, especially for jaw reconstruction. In relation to bone regeneration in control defects, the effect of experimental material on controls was apparent during the initial weeks. PMID- 23674919 TI - Patient characteristics and trends in nontraumatic dental condition visits to emergency departments in the United States. AB - OBJECTIVE: We examined trends and patient characteristics for non-traumatic dental condition (NTDC) visits to emergency departments (EDs), and compared them to other ED visit types, specifically non-dental ambulatory care sensitive conditions (non-dental ACSCs) and non-ambulatory care sensitive conditions (non ACSCs) in the United States. METHODS: We analyzed data from the National Hospital Ambulatory Medical Care survey (NHAMCS) for 1997 to 2007. We performed descriptive statistics and used a multivariate multinomial logistic regression to examine the odds of one of the three visit types occurring at an ED. All analyses were adjusted for the survey design. RESULTS: NTDC visits accounted for 1.4% of all ED visits with a 4% annual rate of increase (from 1.0% in 1997 to 1.7% in 2007). Self-pay patients (32%) and Medicaid enrollees (27%) were over-represented among NTDC visits compared to non-dental ACSC and non-ACSC visits (P < 0.0001). Females consistently accounted for over 50% of all types of ED visits examined. Compared to whites, Hispanics had significantly lower odds of an NDTC visit versus other visit types (P < 0.0001). Blacks had significantly lower odds of making NDTC visits when compared to non-dental ACSC visits only (P < 0.0001). Compared to private insurance enrollees, Medicaid and self-pay patients had 2-3 times the odds of making NTDC visits compared to other visit types. CONCLUSION: Nationally, NTDC visits to emergency departments increased over time. Medicaid and self-pay patients had significantly higher odds of making NDTC visits. PMID- 23674918 TI - Enamel matrix protein derivatives: role in periodontal regeneration. AB - The role of regenerative periodontal therapy is the reconstitution of lost periodontal structures, ie, new formation of root cementum, periodontal ligament, and alveolar bone. The outcome of basic research has pointed to the important role of enamel matrix protein derivative (EMD) in periodontal wound healing. Histologic results from animal and human studies have shown that treatment with EMD promotes periodontal regeneration. Moreover, clinical studies have indicated that treatment with EMD positively influences periodontal wound healing in humans. The goal of this paper is to review the existing literature on EMD. PMID- 23674920 TI - Advances in dental veneers: materials, applications, and techniques. AB - Laminate veneers are a conservative treatment of unaesthetic anterior teeth. The continued development of dental ceramics offers clinicians many options for creating highly aesthetic and functional porcelain veneers. This evolution of materials, ceramics, and adhesive systems permits improvement of the aesthetic of the smile and the self-esteem of the patient. Clinicians should understand the latest ceramic materials in order to be able to recommend them and their applications and techniques, and to ensure the success of the clinical case. The current literature was reviewed to search for the most important parameters determining the long-term success, correct application, and clinical limitations of porcelain veneers. PMID- 23674921 TI - Gillies fan flap for the reconstruction of an upper lip defect caused by noma: case presentation. AB - The case of a 65-year-old noma patient with a defect involving her upper lip is presented. The defect also included missing teeth numbers eleven, twelve, 21, and 22 and the adjoining alveolus. One-stage lip reconstruction was carried out with Gillies fan flap followed by vestibuloplasty and commissuroplasty. An acrylic partial denture was subsequently fabricated to replace the missing teeth and thereby restore function. Even though the incidence of cancrum oris has reduced worldwide, cases are still being reported in Africa and can leave behind a significant facial defect. Whereas most cases of lip defects reported from the Western world are due to cancer, cancrum oris could be the cause of lip defects in sub-Saharan Africa. Gillies fan flap could be employed for the reconstruction of a relatively large defect of the lip and the disadvantage of microstomia could be minimized for the restoration of articulation, speech, and masticatory functions of the lip. PMID- 23674922 TI - Myofibroblasts and their resistance to apoptosis: a possible mechanism of osteoradionecrosis. AB - Osteoradionecrosis (ORN) in the head and neck area is the most devastating long term complication of radiotherapy, with slow progression and inability to heal spontaneously. ORN can lead to intolerable pain, fractures, and sequestration of devitalized bone and fistulae, making oral feeding impossible and causing facial deformation. In spite of its notorious reputation over at least 90 years, the precise pathogenesis of ORN has not been fully clarified, which has led to obstacles in the management of the disease. Several theories about its pathogenesis have been formulated, and radiation-induced fibrosis is the newest one. According to this theory, ORN is essentially a type of fibrosis induced by radiotherapy, and antifibrosis therapy has been shown to be effective in its treatment. We assumed that ORN, like fibrosis in other organs, is the result of a process of fibrogenesis in which myofibroblasts are the key effector cells. The uninterrupted accumulation of myofibroblasts and consequent persistent excess production of collagenous extracellular matrix and tensile force result in loss of normal function and ultimately radiation-induced fibrosis. During this process, myofibroblasts may be protected from apoptosis by acquiring an immune privileged capacity, which allows continuous matrix synthesis. If this hypothesis proves to be correct, it would enable better understanding of the cellular and molecular mechanisms underlying the pathogenesis and progression of ORN, and would help improve our ability to prevent occurrence of ORN, give an earlier diagnosis, and treat it more effectively. PMID- 23674923 TI - The effect of steam sterilization on the accuracy of spring-style mechanical torque devices for dental implants. AB - BACKGROUND: Mechanical torque devices (MTDs) are one of the most commonly recommended devices used to deliver optimal torque to the screw of dental implants. Recently, high variability has been reported about the accuracy of spring-style mechanical torque devices (S-S MTDs). Joint stability and survival rate of fixed implant supported prosthesis depends on the accuracy of these devices. Currently, there is limited information on the steam sterilization influence on the accuracy of MTDs. The purpose of this study was to assess the effect of steam sterilization on the accuracy (+/-10% of the target torque) of spring-style mechanical torque devices for dental implants. MATERIALS AND METHODS: Fifteen new S-S MTDs and their appropriate drivers from three different manufacturers (Nobel Biocare, Straumann [ITI], and Biomet 3i [3i]) were selected. Peak torque of devices (5 in each subgroup) was measured before and after autoclaving using a Tohnichi torque gauge. Descriptive statistical analysis was used and a repeated-measures ANOVA with type of device as a between-subject comparison was performed to assess the difference in accuracy among the three groups of spring-style mechanical torque devices after sterilization. A Bonferroni post hoc test was used to assess pairwise comparisons. RESULTS: Before steam sterilization, all the tested devices stayed within 10% of their target values. After 100 sterilization cycles, results didn't show any significant difference between raw and absolute error values in the Nobel Biocare and ITI devices; however the results demonstrated an increase of error values in the 3i group (P < 0.05). Raw error values increased with a predictable pattern in 3i devices and showed more than a 10% difference from target torque values (maximum difference of 14% from target torque was seen in 17% of peak torque measurements). CONCLUSION: Within the limitation of this study, steam sterilization did not affect the accuracy (+/-10% of the target torque) of the Nobel Biocare and ITI MTDs. Raw error values increased with a predictable pattern in 3i devices and showed more than 10% difference from target torque values. Before expanding upon the clinical implications, the controlled and combined effect of aging (frequency of use) and steam sterilization needs more investigation. PMID- 23674924 TI - Prosthetic reconstruction using gingiva-colored ceramic agent in fixed partial restoration in a 24-year old patient. AB - Achieving an optimal esthetic result when replacing missing anterior teeth with a fixed partial denture can be a challenge. This is especially true when interdisciplinary treatment is needed and the patient refuses this for personal or financial reasons. Here we report a clinical case where a fixed partial denture was used to change the incisor relationship and to restore the normal tooth and gingival tissue shape, morphology, and relationship by including artificial gingiva within the fixed partial denture when the patient refused lengthy and costly multispecialty treatment options. PMID- 23674925 TI - The relationship between smile attractiveness and esthetic parameters of patients with lateral agenesis treated with tooth recontouring or implants. AB - BACKGROUND: The purpose of this study was to associate smile esthetic judgment with dentofacial attributes of patients with unilateral and bilateral agenesis of maxillary lateral incisors treated with recontouring of canines or implants and patients with no agenesis (control). MATERIAL AND METHODS: Forty-six participants were divided into two groups: those treated with recontouring (N = 26) and those treated with implants (N = 20). The participants in the control group (N = 22) were selected among dentistry students at the State University of Maringa, Brazil. Photographs of posed smiles (17 cm * 10 cm) were evaluated with a 100-mm Visual Analog Scale. Smile attractiveness was judged by two groups: laypersons and dentists (N = 20 in each group). Judgment was classified into Unpleasant and Pleasant. Measurements of 11 smile attributes were done with ImageTool Version 3.0. These measurements were correlated with the type of judgment using the Pearson correlation coefficient. RESULTS: The two groups of evaluators showed no rating difference (analysis of variance, P = 0.64), thus they were placed into a single group. No significant correlation was found between esthetic judgment and six smile attributes (incisor exposure, interlabial gap, width 3 to 3, smile index, right buccal corridor, and buccal corridor ratio). The control group showed more correlations with the unpleasant judgment type than the other groups. CONCLUSION: Some correlations between smile attributes and esthetic judgment were found, but other features of smiles not evaluated in this study may interfere in smile attractiveness. PMID- 23674927 TI - A comparison of the efficacy of powered and manual toothbrushes in controlling plaque and gingivitis: a clinical study. AB - BACKGROUND: Plaque is intimately related to the production and progress of dental caries and inflammatory gingival and periodontal diseases. Good plaque control facilitates the return to health for patients with gingival and periodontal diseases. Daily use of a toothbrush and other oral hygiene aids is the most dependable way to achieve oral health benefits for all patients. METHODS: A randomized clinical trial was conducted to compare the efficacy of a powered toothbrush with a manual toothbrush in controlling plaque and gingivitis over a 6 week period. The sample consisted of 60 dental students of both sexes, with ages ranging from 18 to 28 years. The samples were stratified and randomly divided into two groups of 30 by a second examiner using the coin toss method; one group used a manual toothbrush and the other group used a powered toothbrush. Each participant's gingival index, plaque index and oral hygiene index were assessed on the seventh, 14th, and 45th days on the basis of the assigned toothbrush. Collected data were analyzed and different subgroups were compared using Student's t-test. RESULTS: A paired t-test revealed a highly significant reduction in the gingival, plaque, and oral hygiene index scores of the manual and powered groups at the first, second, and sixth weeks (P-value < 0.0001). An unpaired t-test revealed a significant reduction between the plaque index scores of the manual and powered groups at the second week (P-value < 0.05). Another unpaired t-test revealed a highly significant reduction between the plaque index scores of the manual and powered groups at the sixth week (P-value < 0.0001). CONCLUSION: The subject group using the powered toothbrush demonstrated clinical and statistical improvement in overall plaque scores. Powered toothbrushes offer an individual the ability to brush the teeth in a way that is optimal in terms of removing plaque and improving gingival health, conferring good brushing technique on all who use them, irrespective of manual dexterity or training. PMID- 23674928 TI - Oral biofilms: molecular analysis, challenges, and future prospects in dental diagnostics. AB - Oral biofilms are functionally and structurally organized polymicrobial communities that are embedded in an extracellular matrix of exopolymers on mucosal and dental surfaces. These biofilms are found naturally in health, and provide benefits to the host. However, this relationship can break down, and disease can occur; disease is associated with a shift in the balance of the species within these biofilms. Simple diagnostic tests have been developed that involve the culture of selected bacteria, eg, those implicated in dental caries, facilitating an assessment of risk of further disease in individual patients. However, oral diseases have a complex etiology, and because only around 50% of oral biofilm can be grown at present, culture-independent molecular-based approaches are being developed that give a more comprehensive assessment of the presence of a range of putative pathogens in samples. The diversity of these biofilms creates challenges in the interpretation of findings, and future work is investigating the ability of novel techniques to detect biological activity and function in oral biofilms, rather than simply providing a catalogue of microbial names. PMID- 23674929 TI - Assessing population aging and disability in sub-Saharan Africa: lessons from Malawi? PMID- 23674930 TI - Obstructive sleep apnea and the subsequent risk of depressive disorder: a population-based follow-up study. AB - STUDY OBJECTIVES: Empirical findings on the prospective link between obstructive sleep apnea (OSA) and subsequent depression are mixed. This nationwide, population-based study thus aimed at assessing the risk of depressive disorder within the first year following a diagnosis with OSA. Gender effects were further examined. DESIGN: Cohort study. SETTING: Taiwan. PATIENTS: This study used data from the Longitudinal Health Insurance Database 2000. A total of 2,818 patients diagnosed with OSA between 2002 and 2008 were evaluated, and 14,090 matched non OSA enrollees used as a comparison cohort. MEASUREMENTS AND RESULTS: Each patient was followed for one year to identify subsequent depressive disorder. We found that during the one-year follow-up, the incidence of depressive disorder per thousand person-years was about twice as high among patients with OSA (18.10, 95% CI = 13.62-23.61) as those without OSA (8.23, 95% CI = 6.83-9.84). The Cox proportional hazards model revealed that patients with OSA were independently associated with a 2.18 times (95% CI = 1.55-3.08) increased risk of subsequent depressive disorder within a year, compared to those without OSA. As epidemiological studies have consistently documented an increased risk for depression in women, we hypothesized and confirmed higher risks of depressive disorder among female patients with OSA (2.72, 95% CI = 1.68-4.40) than their male counterparts (1.81, 95% CI = 1.09-3.01). CONCLUSION: A prospective link between OSA and subsequent depressive disorder within one year was confirmed by the current study. The risk was particularly evident among women. Regular psychiatric screening among patients with OSA is suggested to prompt the timely detection of depression. COMMENTARY: A commentary on this article appears in this issue on page 425. PMID- 23674931 TI - The link between OSA and depression: another reason for integrative sleep medicine teams. PMID- 23674932 TI - Obstructive sleep apnea after weight loss: a clinical trial comparing gastric bypass and intensive lifestyle intervention. AB - INTRODUCTION: Few studies have compared the effect of surgical and conservative weight loss strategies on obstructive sleep apnea (OSA). We hypothesized that Roux-en-Y gastric bypass (RYGB) would be more effective than intensive lifestyle intervention (ILI) at reducing the prevalence and severity of OSA (apnea-hypopnea index [AHI] >= 5 events/hour). METHODS: A total of 133 morbidly obese subjects (93 females) were treated with either a 1-year ILI-program (n = 59) or RYGB (n = 74) and underwent repeated sleep recordings with a portable somnograph (Embletta). RESULTS: Participants had a mean (SD) age of 44.7(10.8) years, BMI 45.1(5.7) kg/m(2), and AHI 17.1(21.4) events/hour. Eighty-four patients (63%) had OSA. The average weight loss was 8% in the ILI-group and 30% in the RYGB-group (p < 0.001). The mean (95%CI) AHI reduced in both treatment groups, although significantly more in the RYGB-group (AHI change -6.0 [ILI] vs -13.1 [RYGB]), between group difference 7.2 (1.3, 13.0), p = 0.017. Twenty-nine RYGB-patients (66%) had remission of OSA, compared to 16 ILI-patients (40%), p = 0.028. At follow-up, after adjusting for age, gender, and baseline AHI, the RYGB-patients had significantly lower adjusted odds for OSA than the ILI-patients-OR (95% CI) 0.33 (0.14, 0.81), p = 0.015. After further adjustment for BMI change, treatment group difference was no longer statistically significant-OR (95% CI) 1.31 (0.32, 5.35), p = 0.709. CONCLUSION: Our study demonstrates that RYGB was more effective than ILI at reducing the prevalence and severity of OSA. However, our analysis also suggests that weight loss, rather than the surgical procedure per se, explains the beneficial effects. PMID- 23674933 TI - Evaluation of drug-induced sleep endoscopy as a patient selection tool for implanted upper airway stimulation for obstructive sleep apnea. AB - STUDY OBJECTIVES: To study the possible predictive value of drug-induced sleep endoscopy (DISE) in assessing therapeutic response to implanted upper airway stimulation (UAS) for obstructive sleep apnea (OSA). METHODS: During DISE, artificial sleep is induced by midazolam and/or propofol, and the pharyngeal collapse patterns are visualized using a flexible fiberoptic nasopharyngoscope. The level (palate, oropharynx, tongue base, hypopharynx/epiglottis), the direction (anteroposterior, concentric, lateral), and the degree of collapse (none, partial, or complete) were scored in a standard fashion. RESULTS: We report on the correlation between DISE results and therapy response in 21 OSA patients (apnea-hypopnea index [AHI] 38.5 +/- 11.8/h; body mass index [BMI] 28 +/ 2 kg/m(2), age 55 +/- 11 y, 20 male/1 female) who underwent DISE before implantation of a UAS system. Statistical analysis revealed a significantly better outcome with UAS in patients (n = 16) without palatal complete concentric collapse (CCC), reducing AHI from 37.6 +/- 11.4/h at baseline to 11.1 +/- 12.0/h with UAS (p < 0.001). No statistical difference was noted in AHI or BMI at baseline between the patients with and without palatal CCC. In addition, no predictive value was found for the other DISE collapse patterns documented. CONCLUSIONS: The absence of palatal CCC during DISE may predict therapeutic success with implanted UAS therapy. DISE can be recommended as a patient selection tool for implanted UAS to treat OSA. PMID- 23674934 TI - Impact of zaleplon on continuous positive airway pressure therapy compliance. AB - STUDY OBJECTIVE: To determine whether pretreatment with zaleplon immediately before CPAP titration improves 1-month CPAP adherence in subjects newly diagnosed with OSA. METHODS: Prospective, randomized, double-blinded, placebo-controlled trial of a single dose of zaleplon 10 mg or matching placebo at the start of CPAP titration during laboratory-based, split-night polysomnography (PSG). Baseline sleep symptoms were assessed with the Functional Outcomes of Sleep Questionnaire (FOSQ) and Epworth Sleepiness Scale (ESS). CPAP usage and change in symptom questionnaire responses were assessed at 1-month follow-up. RESULTS: One hundred thirty-four newly diagnosed OSA patients undergoing their initial split-night PSG (49.8 +/- 11.3 years old with an apnea-hypopnea index of 16.5 (7, 32) [median (interquartile range)] were randomized to zaleplon (n = 73) or placebo (n = 63). Complete follow-up data were available in 83 subjects (44 zaleplon group; 39 placebo group). CPAP was used for 6.5 (5, 7) h/day with zaleplon versus 6.5 (5, 8) h/ day with placebo (p = 0.64). Improvements in FOSQ and ESS scores did not differ between the two groups. CONCLUSION: A single dose of zaleplon at the start of a split-night CPAP titration does not result in superior CPAP adherence or improvement in symptoms at 1-month compared to placebo. Our data show that zaleplon is safe and is associated with shorter sleep latency during CPAP titration, but it does not translate into improved short-term CPAP adherence. PMID- 23674935 TI - Effects of armodafinil on simulated driving and self-report measures in obstructive sleep apnea patients prior to treatment with continuous positive airway pressure. AB - STUDY OBJECTIVES: Obstructive sleep apnea (OSA) has been associated with an increased risk of motor vehicle crashes. This driving risk can be reduced (>= 50%) by treatment with continuous positive airway pressure (CPAP). However residual excessive daytime sleepiness (EDS) can persist for some patients who regularly use CPAP. The current study was designed to assess the effect of armodafinil on simulated driving performance and subsequent CPAP treatment compliance in newly diagnosed OSA patients with EDS during a 2-week "waiting period" prior to initiation of CPAP. METHODS: Sixty-nine newly diagnosed OSA patients, awaiting CPAP therapy, were randomized (1:1) to placebo or armodafinil (150 mg/day) treatment. Simulated driving tests and self-report measures were completed at baseline, after 2 weeks of drug treatment, and following 6 weeks of CPAP treatment. CPAP compliance was evaluated at the end of 6 weeks of CPAP. RESULTS: Compared to placebo, armodafinil improved simulated driving safety performance in OSA patients awaiting CPAP therapy (p = 0.03). Improvement was seen in lane position deviation (p = 0.002) and number of lane excursions (p = 0.02). Improvement was also observed on measures of sleepiness using the Epworth Sleepiness Scale (ESS) and sleep related quality of life. Following 6 weeks of CPAP, there was also significant improvement observed on multiple measures of simulated driving performance. CPAP compliance did not differ between armodafinil treated and placebo-treated patients (p = 0.80). CONCLUSIONS: Armodafinil was found to improve simulated driving performance in OSA patients with EDS prior to initiation of CPAP. Treatment with armodafinil showed no effect on subsequent CPAP compliance. PMID- 23674936 TI - The prevalence of restless legs syndrome across the full spectrum of kidney disease. AB - STUDY OBJECTIVES: Although restless legs syndrome (RLS) is common and well recognized as an important and potentially treatable cause of sleep disruption in end-stage renal disease (ESRD), few studies have evaluated the prevalence of RLS and its impact on sleep in the non-dialysis-dependent chronic kidney disease (CKD) population. The objectives of the study were to determine the prevalence of RLS across the full spectrum of kidney disease and to assess the impact of RLS on sleep quality and daytime function. METHODS: Five hundred patients were recruited from nephrology clinics and were stratified according to estimated glomerular filtration rate (EGFR): eGFR >= 60 mL/min/1.73m(2) (n = 127), CKD (eGFR < 60, not on dialysis, n = 242), and ESRD (on hemodialysis, n = 131). All subjects completed a sleep and medical history questionnaire, an RLS questionnaire, the Pittsburgh Sleep Quality Index (PSQI), and the Epworth Sleepiness Scale (ESS). RESULTS: The prevalence of RLS did not differ among the three groups (18.9% [eGFR >= 60], 26% (CKD), and 26% (ESRD) p = 0.27). However, many symptoms of sleep disruption were more common in patients with RLS, and RLS was independently correlated with the PSQI score both in the full cohort (OR = 2.63, CI = 1.60 4.00, p < 0.001) and the CKD group (OR = 2.39, CI = 1.20-4.79, p = 0.014). CONCLUSIONS: RLS is common in non-dialysis-dependent CKD patients and is an important source of sleep disruption. PMID- 23674937 TI - Is nocturnal panic a distinct disease category? Comparison of clinical characteristics among patients with primary nocturnal panic, daytime panic, and coexistence of nocturnal and daytime panic. AB - OBJECTIVE: Many patients with panic disorder (PD) experience nocturnal panic attacks. We investigated the differences in demographic variables and symptom characteristics as well as response to treatment among patients with primary day panic (DP), primary nocturnal panic (NP), and the coexistence of DP and NP (DP/NP), and discuss whether NP is a distinct disease category. METHOD: One hundred one consecutive untreated patients with PD were enrolled and subsequently divided into the NP, DP, and DP/NP groups. The presence of 13 panic attack symptom items as well as scores on the Panic Disorder Severity Scale (PDSS) and the Pittsburgh Sleep Quality Index (PSQI) were compared among the groups. After 3 months of regular treatment, PDSS scores were assessed again to evaluate treatment response. RESULTS: Nocturnal panic attacks of the participants were mostly reported to occur in the first tertile of nocturnal sleep. The number of males, onset age, and presence of choking sensation were significantly higher, and the PDSS score was significantly lower in the NP group compared with the other groups. The DP/NP group showed the highest PDSS score, and participants in this group were prescribed the highest doses of medication among all groups. Only diagnostic sub-category was significantly associated with treatment response. The total score for PDSS and PSQI correlated significantly only in the NP group. CONCLUSIONS: DP/NP could be a severe form of PD, while primary NP could be a relatively mild subcategory that may partially share common pathophysiology with adult type night terror. PMID- 23674938 TI - A multi-step pathway connecting short sleep duration to daytime somnolence, reduced attention, and poor academic performance: an exploratory cross-sectional study in teenagers. AB - BACKGROUND: A multi-step causality pathway connecting short sleep duration to daytime somnolence and sleepiness leading to reduced attention and poor academic performance as the final result can be envisaged. However this hypothesis has never been explored. OBJECTIVE: To explore consecutive correlations between sleep duration, daytime somnolence, attention levels, and academic performance in a sample of school-aged teenagers. METHODS: We carried out a survey assessing sleep duration and daytime somnolence using the Pediatric Daytime Sleepiness Scale (PDSS). Sleep duration variables included week-days' total sleep time, usual bedtimes, and absolute weekday to-weekend sleep time difference. Attention was assessed by d2 test and by the coding subtest from the WISC-IV scale. Academic performance was obtained from literature and math grades. Structural equation modeling was used to assess the independent relationships between these variables, while controlling for confounding effects of other variables, in one single model. Standardized regression weights (SWR) for relationships between these variables are reported. RESULTS: Study sample included 1,194 teenagers (mean age: 15 years; range: 13-17 y). Sleep duration was inversely associated with daytime somnolence (SWR = -0.36, p < 0.01) while sleepiness was negatively associated with attention (SWR = -0.13, p < 0.01). Attention scores correlated positively with academic results (SWR = 0.18, p < 0.01). Daytime somnolence correlated negatively with academic achievements (SWR = -0.16, p < 0.01). The model offered an acceptable fit according to usual measures (RMSEA = 0.0548, CFI = 0.874, NFI = 0.838). A Sobel test confirmed that short sleep duration influenced attention through daytime somnolence (p < 0.02), which in turn influenced academic achievements through reduced attention (p < 0.002). CONCLUSIONS: Poor academic achievements correlated with reduced attention, which in turn was related to daytime somnolence. Somnolence correlated with short sleep duration. PMID- 23674940 TI - Sensitivity and specificity of polysomnographic criteria for defining insomnia. AB - STUDY OBJECTIVES: In recent years, polysomnography-based eligibility criteria have been increasingly used to identify candidates for insomnia research, and this has been particularly true of studies evaluating pharmacologic therapy for primary insomnia. However, the sensitivity and specificity of PSG for identifying individuals with insomnia is unknown, and there is no consensus on the criteria sets which should be used for participant selection. In the current study, an archival data set was used to test the sensitivity and specificity of PSG measures for identifying individuals with primary insomnia in both home and lab settings. We then evaluated the sensitivity and specificity of the eligibility criteria employed in a number of recent insomnia trials for identifying primary insomnia sufferers in our sample. DESIGN: Archival data analysis. SETTINGS: Study participants' homes and a clinical sleep laboratory. PARTICIPANTS: ADULTS: 76 with primary insomnia and 78 non-complaining normal sleepers. MEASUREMENTS AND RESULTS: ROC and cross-tabs analyses were used to evaluate the sensitivity and specificity of PSG-derived total sleep time, latency to persistent sleep, wake after sleep onset, and sleep efficiency for discriminating adults with primary insomnia from normal sleepers. None of the individual criteria accurately discriminated PI from normal sleepers, and none of the criteria sets used in recent trials demonstrated acceptable sensitivity and specificity for identifying primary insomnia. CONCLUSIONS: The use of quantitative PSG-based selection criteria in insomnia research may exclude many who meet current diagnostic criteria for an insomnia disorder. PMID- 23674939 TI - Validation of the Mayo Sleep Questionnaire to screen for REM sleep behavior disorder in a community-based sample. AB - OBJECTIVE: To validate a questionnaire focused on REM sleep behavior disorder (RBD) in a community-based sample. BACKGROUND: RBD is a parasomnia manifested by recurrent dream enactment behavior during REM sleep. While confirmation of RBD requires the presence of REM sleep without atonia on polysomnography (PSG), a screening measure for RBD validated in older adults would be desirable for clinical and research purposes. METHODS: We had previously developed the Mayo Sleep Questionnaire (MSQ) to screen for the presence of RBD and other sleep disorders. We assessed the validity of the MSQ by comparing the responses of subjects' bed partners with the findings on PSG. All subjects recruited from 10/04 to 12/08 in the Mayo Clinic Study of Aging--a population-based study of aging in Olmsted County, Minnesota--who had also undergone a previous PSG were the focus of this analysis. RESULTS: The study sample included 128 subjects (104 male; median age 77 years [range 67-90]), with the following clinical diagnoses at baseline assessment: normal (n = 95), mild cognitive impairment (n = 30), and mild Alzheimer disease (n = 3). Nine (5%) subjects had RBD based on history and PSG evidence of REM sleep without atonia. The core question on recurrent dream enactment behavior yielded sensitivity (SN) of 100% and specificity (SP) of 95% for the diagnosis of RBD. The profile of responses on four additional subquestions on RBD improved specificity. CONCLUSIONS: These data suggest that the MSQ has adequate SN and SP for the diagnosis of RBD among elderly subjects in a community-based sample. PMID- 23674941 TI - C-reactive protein and carotid intima-media thickness in children with sleep disordered breathing. AB - STUDY OBJECTIVES: Obesity is a risk factor for sleep disordered breathing (SDB) in children. Plasma levels of high-sensitivity C-reactive protein (Hs-CRP) are predictive of cardiovascular morbidity in adults, and CRP levels are associated with over-weight. Increased carotid intima-media thickness (IMT) is associated with several cardiovascular risk factors. We evaluated the effect of SDB on CRP levels and IMT in lean and obese children not selected for snoring. METHODS: 101 children (age 5-15 years) attending a weight clinic or scheduled for routine visit. IMT was measured with quantitative B-mode ultrasound scans. The apnea hypopnea index (AHI) was measured overnight: AHI < 1 defined controls, AHI >= 1 to < 5 = mild SDB, and AHI >= 5 = obstructive sleep apnea (OSA). RESULTS: AHI was significantly associated with Hs-CRP concentration (r = 0.32, p = 0.002) in all 101 children irrespective of age and sex. Body mass index (BMI) was higher in OSA children than controls (25.5 +/- 7.0 vs 22.1 +/- 6.9, p = 0.05). Obese children had 3.3 times more probability of having OSA (HR 3.3, 95% CI 1.2-9.3, p = 0.02) than lean children. Hs-CRP values were significantly higher in children with OSA than in children without (p = 0.011), but not when BMI z-score was added as covariate. IMT was not associated with AHI or SDB. CONCLUSIONS: The results of this study suggest an association between OSA and Hs-CRP concentrations (mainly mediated by overweight and obesity), but not between OSA and subclinical atherosclerosis. There is scope for prevention in childhood before OSA syndrome causes the irreversible damage to arteries observed in adult patients. PMID- 23674942 TI - Nocturnal temazepam in the treatment of narcolepsy. AB - Narcolepsy is characterized by fragmented nighttime sleep and frequent arousals. One treatment approach to improve daytime symptoms is to consolidate nighttime sleep through decreasing arousals. Sodium oxybate is the first FDA-approved medication that follows this approach. Benzodiazepines are known to also decrease arousals at night and have been proposed to help with sleep fragmentation. In one report, clonazepam was shown to improve cataplexy in 10 of 14 patients with narcolepsy although no improvement in daytime sleepiness was reported. The purpose of this case review was to share our experience of nocturnal temazepam on daytime sleepiness in patients with narcolepsy as measured by the Epworth Sleepiness Scale (ESS). PMID- 23674944 TI - Normal ferritin in a patient with iron deficiency and RLS. PMID- 23674945 TI - CPAP and Cognition in OSA (APPLES). PMID- 23674943 TI - Sleep disturbance in pediatric PTSD: current findings and future directions. AB - Many studies have provided strong evidence of a fundamental and complex role for sleep disturbances in adult posttraumatic stress disorder (PTSD). Investigations of adult PTSD using subjective and objective measures document sleep architecture abnormalities and high prevalence of sleep disordered breathing, periodic limb movement disorder, nightmares, and insomnia. PTSD treatment methods do appear to significantly improve sleep disturbance, and also studies suggest that treatments for sleep disorders often result in improvements in PTSD symptoms. Further, the most recent evidence suggests sleep abnormalities may precede the development of PTSD. Given the importance of sleep disorders to the onset, course, and treatment of adult PTSD, examination of sleep disturbances far earlier in the life course is imperative. Here we review the literature on what we know about sleep disturbances and disorders in pediatric PTSD. Our review indicates that the extant, empirical data examining sleep disturbance and disorders in pediatric PTSD is limited. Yet, this literature suggests there are significantly higher reports of sleep disturbances and nightmares in children and adolescents exposed to trauma and/or diagnosed with PTSD than in non-trauma-exposed samples. Sleep questionnaires are predominantly employed to assess sleep disorders in pediatric PTSD, with few studies utilizing objective measures. Given the important, complex relationship being uncovered between adult PTSD and sleep, this review calls for further research of sleep in children with PTSD using more specific subjective measures and also objective measures, such as polysomnography and eventually treatment trial studies. PMID- 23674946 TI - Vitamin D deficiency, excessive daytime sleepiness: an epiphenomenon or a "chicken or an egg-which came first" issue? PMID- 23674947 TI - We've only just begun: a conversation started shouldn't be mistaken for the last word. PMID- 23674948 TI - 5S rRNA: Structure and Function from Head to Toe. AB - 5S rRNA is uniquely positioned so as to link together all of the functional centers of the ribosome. Previous studies have supported the hypothesis that 5S rRNA acts as a physical transducer of information, facilitating communication between the different functional centers and coordinating of the multiple events catalyzed by the ribosome. Here, we present a synthesis of both structural and genetic information to construct a more detailed picture of how 5S rRNA may act to transmit and coordinate all of the functional centers of the ribosome. PMID- 23674949 TI - Effect of TGF-beta1 Stimulation on the Smad Signal Transduction Pathway of Human Peritoneal Mesothelial Cells. AB - OBJECTIVE: To prove whether the SMAD signal transduction pathway in human peritoneal mesothelial cells (HPMCs) influenced the process of human peritoneal fibrosis stimulated by TGF-beta1. METHODS: HPMCs were isolated from normal human omentum and the third generation cells were stimulated by 5 ng/ml TGF-beta1. Immunohistochemistry, Western blotting, ELISA and RT-PCR were employed to investigate the protein expression of p-Smad2/3 and the protein and mRNA expressions of SMAD 7, fibronectin (FN) and collagen-I (COL1). RESULTS: The protein expression of p-Smad2/3 in HPMCs was remarkably increased 15 min (29% p Smad2/3-positive cells) after TGF-beta1 stimulation, peaking from 30 min (81%) to 1 h (84%) and dropping after 2 h (37%); Meanwhile, p-Smad2/3 mainly distributed in cytoplasm at 15 min, concentrated in cell nucleus and peri-nucleus from 30 min to 1 h, and distributed in cytoplasm again at 2 h. The protein expression of SMAD 7 in cells was obviously increased 24 h after TGF-beta1 stimulation, peaking at 48 h. The mRNA expression of SMAD7 was time-dependently increased. The expressions of extracellular FN protein, intracellular FN mRNA, as well as intracellular COL1 protein and mRNA were significantly increased and all of them displayed time dependency. CONCLUSIONS: The SMAD signal transduction pathway of HPMCs can be specifically activated by TGF-beta1 and influence the process of human peritoneal fibrosis. The protein and mRNA expression of SMAD 7 (an inhibitor of SMAD pathway) are significantly increased as a result of feedback. PMID- 23674950 TI - Association study: the aminopeptidase a gene and essential hypertension. AB - Aminopeptidase A (APA) cleaves the N-terminal aspartyl acid residue of angiotensin II (Ang II) to produce angiotensin III (Ang III). It has been reported that the APA knockout mouse exhibits elevated blood pressure. Therefore, the APA gene is thought to be a susceptibility gene for essential hypertension (EH). However, extensive studies have yet to define the relationship between the APA gene and EH. The aims of this study were to genotype some of the single nucleotide polymorphisms (SNPs) for the human APA gene and to perform a haplotype based case-control study to further assess the association between and the APA gene and EH. We performed a genetic association study using SNPs in 227 EH patients and 221 age-matched normotensive (NT) individuals. Although the overall distribution of the genotype did not significantly differ between the EH and NT groups when the entire group of subjects were evaluated, the frequency of rs2290105 did differ between the two when just women were included in the analysis. The haplotype-based case-control analysis also revealed a significant difference between the women of the EH and NT groups. The A-T-A-C haplotype was significantly higher in the EH versus the NT group. These results suggest that rs2290105 and the A-T-A-C haplotype of the APA gene are genetic markers for EH, and that APA or a neighboring gene might be a susceptibility gene for EH. PMID- 23674951 TI - The Effects of Rheum Tanguticum Polysaccharide on the Polarization of Th1 and Th2 Cells in TNBS-Induced Colitis in Murine. AB - Inflammatory bowel diseases (IBDs) are chronic inflammatory intestinal disorders that are characterized by thickened colon walls, colon ulcerations, including two forms of ulcerative colitis (UC) and Crohn's disease (CD). UC and CD share some similar clinico-pathological characteristics but their causes are opposite. The imbalance in cytokinesis produced by Th1 and Th2 cells, the subunit of CD4(+) T cells, plays a key role in the development of IBDs. Although traditional treatment for IBDs is effective to some patients, it has numerous adverse-effects such as immuno-depression. In our previous study we found some therapeutic effects of Rheum tanguticum polysaccharide (RTP) on CD. Our present investigation focuses on the comparison of the effects of RTP (200 mg.kg(-1), once a day for five days) on UC induced by trinitrobenzene sulfonic acid (TNBS)/ethanol in BALB/c mice and CD induced by TNBS in SD rats. The mechanism of RTP was investigated by using immuno-histochemistry, Elisa assay, flow cytometry and western-blot analysis. Our results showed that RTP had significant therapeutic effects on both UC and CD. The ulcerative index and colon weight were significantly attenuated after RTP treatment while MPO activity in RTP-treated animals was markedly lower than that in the animals of TNBS administration (P<0.05, P<0.01). RTP also showed significant inhibitory effects on the expansion of CD4+T cells simultaneously improving the imbalance of Th1 and Th2 polarization (P<0.01). In conclusion, RTP appears to poses all the pre-requisites to be applied in therapeutic intervention, thus, offering a hope for effective treatment for IBDs. PMID- 23674952 TI - Use of gelatinized maca (lepidium peruvianum) in early postmenopausal women. AB - OBJECTIVE: This double-blind, placebo-corrected clinical pilot study was aimed at assessing the use of hypocotyls of cruciferous Andean plant Maca (Lepidium peruvianum Chacon), in alleviating symptoms of menopausal discomfort experienced by women in early post menopause as measured by profiles of serum hormones: Luteinizing Hormone (LH), Follicle-stimulating Hormone (FSH), Estrogen (E2) and Progesterone (PG) and as assessed by Greene's Menopausal Index. DESIGN: Study was conducted on 20 Caucasian healthy early-postmenopausal women volunteers during the three months period (Trial I) and on eight women during nine months period (Trial II). Hormone levels were determined in blood with a simultaneous assessment of menopausal index at the start of study, after one month use of placebo, and after two and eight months administration of 2g gelatinized Maca root powder (Maca-GO) in the form of two 500mg hard gel capsules, twice daily. RESULTS: In comparison to placebo, after both, two and eight months administration of Maca-GO capsules to EPMW, level of FSH significantly (P<0.05) decreased with a simultaneous significant (P<0.05) increase in the LH level, resulting in significant (P<0.05) increase in both E2 and PG, after eight months of Maca-GO treatment only. There was a significant (P<0.05) placebo effect resulting in an elevated PG level after one month administration of placebo capsules. Changes in hormone levels was accompanied by substantially-reduced feeling of discomfort associated with menopause, although, there was a distinctive, positive placebo effect as judged by responses to Greene's questionnaire. CONCLUSIONS: It is reasonable to suggest that Maca-GO when used in EPMW, depending on the length of use, was acting as a toner of hormonal processes as reflected by decrease in FSH and increased LH secretion, which stimulated production of both ovarian hormones, E2 and PG and resulted in a substantial reduction of menopausal discomfort felt by women participating in the study, with a distinctive placebo effect, thus, fully justifying further, more complex study on effectiveness of Maca-GO as a reliable alternative to HRT program. PMID- 23674953 TI - Influence of pro- and anti-inflammatory cytokines in Th1 polarization after allogeneic stimulation. AB - The exogenous cytokine milieu can influence Th1/Th2 polarization. Besides the differential functional properties, T lymphocytes also acquire distinct profiles of chemokine receptors. Human Th1 lymphocytes preferentially express CCR5 and CXCR3 while Th2 lymphocytes express CCR3, CCR4 and CCR8. After their polarization into Th1 cells, grafted T lymphocytes mediate the development of graft-vs-host disease, the major complication after bone marrow transplantation. We performed mixed lymphocyte cultures for ten days, with and without addition of IL-2, IL-4, IL-10, IL-12 and IL-18 at the third and sixth day of cultures. The expression of CXCR3 and CCR5, in CD4(+) and CD8(+) T lymphocytes was evaluated by flow cytometry, before and after ten days of culture. The exogenous addition of IL-2 or IL-12 favoured the Th1/Tc1 phenotype and IL-4 was also capable of inducing Th1 polarization. In opposition to IL-12, IL-18 didn't induce a significant polarization into Th1 phenotype, an effect more similar to that induced by IL-10. This action could explain, at least in part, its possible protective effect in the incidence of acute and chronic graft-versus-host disease after allogeneic stem cell transplantation. PMID- 23674954 TI - Effect of Bizhongxiao Decotion (BZXD) on Some Cytokines in Plasma of Rats with CII-induced Rheumatoid Arthritis. AB - OBJECTIVE: To investigate the influence of bizhongxiao decoction (BZXD) which is a Traditional Chinese medicine for RA including, on the plasma TNF-alpha and IL 1beta in rats with CII-induced arthritis (CIA) and explore the protective mechanism of BZXD in the treatment of rheumatoid arthritis. METHODS: 75 SD rats were divided into four groups randomly. Normal control group (n=5) not be treated any more. The CIA rat was established by subcutaneous injection with bovine II collagen (B II C) and complete Freund, s adjuvant (CFA) after 7d breeding. The CIA rats were divided into the CIA group (n=16), BZXD group (n=29) treated with BZXD and the MTX group (n=25) treated with methotrexate. All rats were killed after various intervals (25, 30, 35, 40, or 45d). At the end of each time interval, we collected the blood of each rat. To detect TNF-alpha and IL-1beta in plasma with radio-immunity kit. RESULTS: BIIC and CFA can be used to copying CIA model. The incidence of arthritis was 88%. The plasma TNF-alpha and IL-1beta levels of CIA group, BZXD group and MTX group were notably higher than those of normal control group (p<0.05), moreover, the CIA group was higher than those of the MTX group and BZXD group at various interval (p<0.01). TNF-alpha and IL-1beta rose step by step in CIA group but decreased in BZXD group and MTX group gradually. Moreover, in BZXD group were lower than those in MTX group (p<0.05). CONCLUSION: TNF-alpha and IL-1beta play a very important role in the formation and development of RA. BZXD can notably decrease the plasma TNF-alpha and IL 1beta levels, which was better than MTX. PMID- 23674955 TI - Body mass index reference curves for children aged 0-18 years in shaanxi, china. AB - OBJECTIVES: Health care professionals have recommended the use of age-related body mass index (BMI) to evaluate obesity in children. Until now, no age-related reference curves for BMI have been reported in China. Presented here are age related BMI percentile curves for children aged 0~18 years in Shaanxi, China, 1995. METHODS: The Third Nationwide Growth Survey was performed in 1995 and from this survey, data of the Shaanxi population were retrieved to construct the age related BMI percentile curves. A total of 27,200 healthy children aged 0~18 years were examined for height and weight, using the standardized methods. The lambda median-coefficient of variation (LMS) method was used for curve fitting; all analyses were carried out on the basis of different sexes and areas through a special program for LMS method. RESULTS: Median BMI increased steeply in early life, with a peak at 8 months, then declined, and then leveled off at about 6 years. The age of adiposity rebound for urban children was about two years earlier than that for rural children and one year earlier for boys than for girls. After adiposity rebound, BMI increased more rapidly in girls than in boys, and the increase in urban children was more rapid than that in rural children. As the onset of puberty, female BMI became higher than that of males, and the difference between boys and girls was larger for rural children than for urban children. The 95th, 50th and 5th percentiles for Shaanxi children were lower than those of comparable American children. Cut-off points for obesity was lower than those of international averages, suggesting the nutrition status of Shaanxi children is lower than that of children in developed countries, and has not reached the international average level. CONCLUSIONS: Using the LMS method, we constructed age-related BMI percentile curves for Shaanxi children aged 0~18 years, the first for Chinese children. Percentile curves and cut-off points for obesity can be used as a reference for assessing the nutrition status of Shaanxi children aged 0~18 years. The identified gender and residency differences may serve as guides to an understanding of the cause and prevention of obesity. PMID- 23674956 TI - Changes of noradrenaline in brain homogenate of rats with brain injury secondary to intracerebral hemorrhage: a study of the mechanism. AB - OBJECTIVE: To observe the changes of noradrenaline (NE) content dynamically in the homogenate of rat brain tissues during experimental intracerebral hemorrhage (ICH), so as to understand the role of NE in secondary brain injury. METHODS: Seventy Wistar rats were randomly assigned into sham operation group and ICH group, each group subdivided into different time phase points as pre-operation, 0.5, 6, 12, 24, 48 and 72 h post-operation groups (n=5). ICH model was established by injection of collagenase and heparin into rat caudate nucleus, and the changes of NE content in the peripheral tissues of the hematoma, hypothalamus and brainstem were observed respectively at following time points as before operation and 0.5, 6, 12, 48 and 72 h after the operation. NE was determined by high-performance liquid chromatography. RESULTS: NE activities in the peripheral tissues of the hematoma, hypothalamus and brainstem increased synchronously 0.5 h after operation, peaked at 24 h, and then began to decline at 48 h. At the same time, the neurobehavioral score varied synchronously together with NE. CONCLUSION: NE is involved in the pathogenesis of secondary damage of the brain during ICH. PMID- 23674957 TI - Seroepidemiological Study on SARS-CoV IgG Antibodies of Different Populations from Several Areas. AB - OBJECTIVE: In order to investigate the clinical and epidemiological rules of severe acute respiratory syndrome (SARS), rates and levels SARS coronavirus (SARS CoV) IgG antibodies of the patients and community populations from several areas were detected. METHODS: Indirect immunofluorescent assay (IFA) and double-antigen sandwich enzyme-linked immunosorbent assay (ELISA) were used to detect the SARS coronavirus-specific IgG antibodies in sera of 1700, including 1453 general populations from Hongkong, Marco, Guangzhou and Peking and 257 SARS patients from Guangzhou and Peking. The dynamics of the serum antibodies of SARS patients were observed from 3 to 360 days after onset of symptoms. RESULTS: 90% of 257 patient serum specimens after 20 days of disease onset showed positive SARS-CoV IgG either using ELISA or IFA. 257 SARS patients, antibodies titers increased steadily in early 4 to 6 months after onset of SARS. The titers of most cases came to the peak in the 6th month. then antibodies titers declined rapidly in some cases. However, all specimens still were positive for SARS-CoV IgG in the 48th month. CONCLUSIONS: This study suggest that few inapparent infectious patients exist during SARS epidemic. Serum IgG antibodies has diagnostic value for SARS in the late course of disease and the antibodies present more than 48 months. PMID- 23674958 TI - Effects of resveratrol on bone mineral density in ovarectomized rats. AB - Hormone replacement therapy (HRT) has been used to prevent osteoporosis in postmenopausal women. However, HRT is not for everyone, due to concerns of side effects as well as increased risk of breast and possibly uterine cancer. Therefore, Dietary alternatives are considered, which include Trans-3,5,4' Trihydroxystilbene (trans-resveratrol), a phytoestrogen naturally found in grapes, peanuts and wine with beneficial effects in both cardioprotective and chemopreventive. The purpose of this study was to evaluate the effects of trans resveratrol on the bone metabolism in ovariectomized rats. 48 Rats were assigned to the following groups: sham surgery + normal diet; ovariectomy (Ovx) + normal diet; Ovx + diethylstilbestrol 0.03 mg * kgbw(-1) * d(-1);Ovx +Trans-Resveratrol 5 mg * kgbw(-1) * d(-1); Ovx + Trans-Resveratrol 15 mg * kgbw(-1) * d(-1); Trans Resveratrol 45 mg * kgbw(-1) * d(-1). The rats were fed for 90 days. In the 90th day, OVX + Trans-Resveratrol 45 mg/(kgbw(-1).d) group had a greater bone mineral density (BMD) than other groups. In the OVX + Trans-Resveratrol 45 mg/(kgbw( 1).d), indices of endocortical bone formation (ALP 37.90 +/- 2.96U/100ml, BGP 1.27 +/- 0.10 ng/ml) were greater than those of the other groups, while the index of endocortical bone absorption (TRAP 10.35 +/- 1.72 U/L) were lower than those of the other groups. Histopathological examination showed that resveratrol had no endometrial hyperplasia adverse effect. All of these support that resveratroal may have positive effect on postmenopausal osteoporosis prevention. PMID- 23674959 TI - Principles and practice of epidemiology avoid statistical esotericism. PMID- 23674960 TI - Ecoepidemiological and Social Factors Related to Rabies Incidence in Venezuela during 2002-2004. AB - Rabies in Venezuela has been important in last years, affecting dogs, cats, and human, among other animals, being a reportable disease. In Zulia state, it is considered a major public health concern. Recently, a considerable increase in the incidence of rabies has been occurring, involving many epidemiological but also ecoepidemiological and social factors. These factors are analyzed in this report. During 2002-2004, 416 rabies cases were recorded. Incidence has been increasingly significantly, affecting mainly dogs (88.94%). Given this epidemiology we associated ecoepidemiological and social factors with rabies incidence in the most affected state, Zulia. In this period 411 rabies cases were recorded. Zulia has varied environmental conditions. It is composed mostly of lowlands bordered in the west by mountain system and in the south by the Andes. The mean is temperature 27.8 degrees C, and mean yearly rainfall is 750 mm. Climatologically, 2002 corresponded with El Nino (drought), middle 2003 evolved to a Neutral period, and 2004 corresponded to La Nina (rainy); this change may have affected many diseases, including rabies. Ecological analysis showed that most cases occurred in lowland area of the state and during rainy season (p<0.05). Additionally, there is an important social problem due to educational deficiencies in the native population. Many ethnic groups live un Zulia, many myths about rabies are in circulation, and the importance of the disease is not widely realized. The full scale of the rabies burden is unknown, owing to inadequate disease surveillance. Although there have been important advances in our knowledge and ability to diagnose and prevent it, enormous challenges remain in animal rabies control and provision of accessible-appropriate human prophylaxis worldwide. Human and animal surveillance including ecological and social factors is needed. PMID- 23674961 TI - ABCC6 Mutation in Patients with Angioid Streaks. AB - Angioid streaks (AS) are hereditary eye conditions caused by breaks in the elastic layer of Bruch's membrane. Patients with AS are also frequently affected with pseudoxanthoma elasticum (PXE). The locus of PXE has been reported to exist in chromosome 16p13.1, and the ABCC6 gene in this locus has been identified as the causal gene of PXE. In this study we investigated the association of the ABCC6 gene and AS. Elucidation of the causal gene of AS will be useful for gene diagnosis in the future. Many mutations in patients with PXE are found in exons 24 and 27 of the ABCC6 gene in previous reports. Therefore, we examined exons 24 and 27 of the ABCC6 gene using the single-strand conformation polymorphism technique. There was no mutation or polymorphism in exon 24. The base substitution of G3803A was identified in exon 27, with a change in the amino acid from CGG to CAG (R1268Q). The genotype frequencies in patients with AS were G/G 52% (23/44), G/A 32% (14/44) and A/A 16% (14/44). In control subjects, the genotype frequencies were G/G 69% (107/154), G/A 29% (44/154) and A/A 2% (3/154). Highly significant differences were observed in both genotype and allele frequencies of R1268Q between patients with AS and control subjects (p<0.001, p<0.002; chi-square test). In conclusion, the missense mutation R1268Q in the ABCC6 gene is not a specific marker of PXE, but is associated with the disease state of AS. PMID- 23674962 TI - Short and long-term physiological responses of male and female rats to two dietary levels of pre-gelatinized maca (lepidium peruvianum chacon). AB - OBJECTIVE: The aim of this study is to identify physiological responses of male and female rats to either a short- or long-term administration of two doses of Maca (Lepidium peruvianum) and observe relationships which may exist between groups of hormones and effects mediated by them. DESIGN: The effect of pre gelatinized (extruded) organic Maca powder (Maca-GO) was studied on Sprague Dowley male and female rats (1:1 ratio) receiving two dietary levels of Maca-GO (0.75 g/kg and 7.5 g/kg body weight) and assessed against control during 28 and 90 day laboratory trials on 30 and 60 rats respectively. Blood morphology, biochemistry (hormones, lipids and minerals) and histology of internal organs were determined. Homogenates of skeletal muscles and bones of rats were also analyzed. RESULTS: Maca-GO has low toxicity (LD=7.5 g/kg) and appears to be safe for short-term and extended use as dietary supplement or as a component of functional dietary and therapeutic preparations. There were different responses of male and female rats to different levels of Maca-GO administered during a short- and a longer-term periodl. When administered at higher dose for extended period of time (90 days), Maca-GO acted as a toner of hormonal processes in adult female rats at increased progesterone and a steady estradiol level, without affecting levels of blood FSH, LH and TSH. CONCLUSIONS: Obtained results justify further clinical research on use of Maca-GO in sportsmen, physically-active people of both sexes and peri-menopausal women to clarify mechanisms underlaying physiological mode of action of Maca-GO validaet in clinical study on humans. Substantial decrease in blood cortisol levels in a short- and longer-term trial and simultaneous tendency to lower blood ACTH, may indicate antidepressive effect of Maca-GO, which together with reduction in body weight, lowering triglycerides in blood plasma and increasing calcium and phosphorus deposition in bone and muscle tissues is worthy consideration in potential application to women at both, pre- and postmenopausal stage. PMID- 23674963 TI - Enhanced Enzymatic Activity of Yeast-like Fungi Responsible for Onychomycosis in Renal Transplant Recipients. AB - BACKGROUND: Renal transplant recipients (RTR) are regarded as a group especially predisposed to onychomycosis. The exact mechanism of increased frequency of onychomycosis in RTR is however not fully understood. OBJECTIVES: This study was undertaken to evaluate activity of hydrolitic enzymes of fungi most commonly causing fungal nail infections in RTR and to compare it with enzymatic activity of the same fungi isolated from lesional nails in immunocompetent patients. MATERIAL AND METHODS: 28 strains of yeast-like fungi cultured from lesional nails in RTR and 25 strains of yeasts isolated from changed nails in immunocompetent patients were included into the study. All fungi were identified on the basis of routine mycological procedures. Activity of 19 hydrolytic enzymes was assessed by API ZYMO test (bioMerieux). RESULTS: Fungi cultured from RTR showed activity of 16 out of 19 enzymes, whereas fungi isolated from immunocompetent patients only 11 out of 19 enzymes. Moreover, yeast-like fungi isolated from RTR showed higher generally higher activity of detected enzymes compared to yeast strains obtained from the lesional nails of immunocompetent patients. CONCLUSIONS: This study shows for the first time enhanced enzymatic activity of yeast-like fungi isolated from lesional nails in RTR in comparison to fungi cultured from changed nails in immunocompetent patients. It is hypothesized that this enhanced enzymatic activity may be responsible for higher incidence of onychomycosis in RTR. PMID- 23674965 TI - Effect of 3'-Azido-3'-Deoxythymidine (AZT) on Telomerase Activity and Proliferation of HO-8910 Cell Line of Ovarian Cancer. PMID- 23674964 TI - Effect of 3'-Azido-3'-Deoxythymidine (AZT) on Telomerase Activity and Proliferation of HO-8910 Cell Line of Ovarian Cancer. AB - OBJECTIVE: To study the effect of 3'-azido-3'-deoxythymidine (AZT) on telomerase activity and the proliferation of ovarian cancer cells in vitro. METHODS: Telomerase activity was detected by enzyme linked immunosorbent assay (ELISA) in treated and untreated HO-8910 cells by AZT. The detection of cell viability was performed with 3-(4,5-dimethylthiazol-2-yl)-2,5-Diphenyl tetrazolium bromide (MTT) assay and the ultrastructure of the cells was observed by electron microscopy. The apoptotic rate of the cells was measured by flow cytometry. RESULTS: AZT significantly inhibited telomerase activity of HO-8910 cells, and the effect was both time- and dose-dependent. The HO-8910 cells treated at different concentrations of AZT showed a significant reduction of cell viability and morphological changes of apoptosis. The apoptotic peak was detected in the AZT treated cells and the apoptotic rate was 14.2%. CONCLUSION: AZT can effectively inhibit both telomerase activity and proliferation of human ovarian cancer HO-8910 cells in vitro, suggesting that AZT may be used in the clinic treatment of ovarian cancer. PMID- 23674966 TI - A Study of the Relationships between Serum Calcitonin Gene-Related Peptide, Sex Hormone, Homocysteine and Coronary Heart Disease in Postmenopausal Women. AB - OBJECTIVE: To investigate the relationships among serum calcitonin gene-related peptide (CGRP), homocysteine (Hcy), female hormone, and coronary arteriopathy in postmenopausal women. METHOD: In a cross-sectional study, serum CGRP, estrodiol (E2), progesterone (P) and Hcy levels of 144 postmenopausal women with coronary heart disease (CHD) and non-coronary heart disease (NCHD) were measured. RESULTS: The mean serum CGRP level was significantly lower in CHD patients than in NCHD subjects. The mean serum E2 and P level were significantly lower in CHD patients than in NCHD subjects. The mean serum Hcy level was significantly higher in CHD patients than in NCHD subjects. By multivariate logistic regression, the OR of high Hcy level >=1, p<0.01, which suggests that Hcy is an independent risk factor in the development of coronary arteriopathy. The OR of CGRP, E2, and P are all<=1, indicating that CGRP, E2 and P are independent protective factor. CONCLUSION: The results of our study show that Hcy is an independent risk factor in the development of arteriopathy. CGRP and endogenous E2 are independent protective factors in the development of coronary arteriopathy. There are no relationships between Hcy, CGRP, and endogenous E2. PMID- 23674967 TI - Anti-Neutrophil Cytoplasmic Antibody in Behcet's Disease. AB - Anti neutrophil cytoplasmic antibody (ANCA) is strongly associated with some vasculitic disorders. Behcet's disease (BD) is a systemic vasculitis of unknown etiology. In this study, ANCA was found to be positive in 8 out of 66 patients (10.2%) with BD by combination testing consisting of immunofluorescence and ELISA [one patient showed an atypical pattern by indirect immunofloresence techique, 6 patients were reactive to bacterial-permeability increasing protein (BPI) and one patient was reactive to Cathepsin G in ELISA]. There were no vascular manifestations such as veneous or arterial thrombosis and arterial aneurysms in ANCA-positive patients with BD. The results suggest that ANCA may be found in a minority of BD as those in previous published studies. PMID- 23674968 TI - Design of cocaethylene and cocaine conjugates to produce highly selective polyclonal antibodies. AB - With the aim to obtain specific anti-cocaine antibodies directed against cocaine and active metabolites for use in immunotherapy, a series of six haptens were prepared, based on the structure of cocaine. The haptens differed by 3 positions of linkers: nitrogen, carboxyl group, and aromatic nucleus. The haptens were grafted onto 3 carrier proteins: bovine serum albumin, tetanus toxoid or keyhole limpet hemocyanin according to different methods of coupling: carbodiimide or mixed anhydride techniques. The immuno-conjugates were administered to rabbits and the antisera elicited were analyzed in term of titer, affinity and specificity. Variation in antisera properties were observed and attributed to the site of coupling the hapten, to the carrier proteins, and to the method of coupling. Antisera titers were in the range of 1/1 (no significant response) to 1/12,832, with antisera affinity up to 5.9 * 10(11) M-1. This strategy allowed the selection of a new hapten, which after coupling on carrier proteins, led to the production of antisera with a high specificity toward cocaine and cocaethylene, but exclude the inactive metabolites of cocaine. PMID- 23674969 TI - Research on hereditability of gastric cancer in wuwei city. AB - AIM: To explore hereditability of gastric cancer in Wuwei city. METHODS: A case control study was used to investigate 251 gastric cancer families located in Wuwei city. Li-Mantel-Gan and Falconer regression methods were used to calculate segregation ratios and hereditability. RESULTS: The segregation ratio in Wuwei families was 0.0774, the hereditability of class I kinfolks and class II kinfolks were respectively 22.91% and 20.07%. CONCLUSION: The segregation ratio of gastric cancer in Wuwei was significantly lower than for mono-genetic diseases (0.25), corresponding better with a model of polygenetic diseases. The genetic susceptibility factor accounted for about 1/5-1/4 in the formation of gastric cancer familial aggregation. Mi DH, Chen XP, Luo HZ Research on hereditability of gastric cancer in Wuwei city. PMID- 23674970 TI - Suppressive effects of intrathecal application of diazepam on visceral pain and hyperalgesia induced by intracolonic instillation of formalin. AB - Using an animal model of colonic inflammation, the effects of intrathecal (i.t.) diazepam (0.02 mg/kg, 0.08 mg/kg and 0.15 mg/kg) on visceral pain-related behaviors and hyperalgesia associated with colonic inflammation were investigated. In this visceral pain model, acute visceral pain response was induced by intracolonic (i.c.) injection of 0.5 ml of dilute formalin (2%, 5% and 10%) in rats, and the peak pain behavioral response and hyperalgesia were evoked by i.c. 5% formalin. I.t. diazepam (0.02 mg/kg, 0.08 mg/kg and 0.15 mg/kg) followed 10 min later by i.c. injection of 5% formalin, attenuated the visceral pain behaviors induced by 5% formalin in a dose dependent manner. Of the three doses tested, the duration of the suppressive effect of 0.15 mg/kg diazepam on visceral pain was the longest, which is 60 min compared with 45 min at other two doses. Moreover, i.t. pretreatment with 0.08 mg/kg diazepam attenuated the hyperalgesia induced by i.c. injection of 5% formalin. The findings in our studies shown that i.t. diazepam had a suppressive effect on visceral pain associated with noxious stimulation of colon, and provided evidence that diazepam may be used as an analgesic drug in the future. PMID- 23674971 TI - Chiral drugs: an overview. AB - About more than half of the drugs currently in use are chiral compounds and near 90% of the last ones are marketed as racemates consisting of an equimolar mixture of two enantiomers. Although they have the same chemical structure, most isomers of chiral drugs exhibit marked differences in biological activities such as pharmacology, toxicology, pharmacokinetics, metabolism etc. Some mechanisms of these properties are also explained. Therefore, it is important to promote the chiral separation and analysis of racemic drugs in pharmaceutical industry as well as in clinic in order to eliminate the unwanted isomer from the preparation and to find an optimal treatment and a right therapeutic control for the patient. In this article, we review the nomenclature, pharmacology, toxicology, pharmacokinetics, metabolism etc of some usual chiral drugs as well as their mechanisms. Different techniques used for the chiral separation in pharmaceutical industry as well as in clinical analyses are also examined. PMID- 23674973 TI - Immunomodulation of fucosyl-lactose and lacto-N-fucopentaose on mononuclear cells from multiple sclerosis and healthy subjects. AB - The 1,2-fucosyl-oligosaccharides, and among these the 2'-fucosyl-lactose (2'-FL) and lacto-N-fucopentaose (LNFP)-I, are quantitatively the most represented oligosaccharides of human milk. They are also seen to represent an important immune device to prevent nursing infants from severe infectious diarrhoea. Recent evidences show that the appearance of 2'-FL and LNFP-I in human colostrums is synchronised with the macrophage inhibition and that LNFP-III induces a Th2 response from the mouse peripheral immune system. Since mannosyl-fucosyl receptors are described on the macrophage surface, all these evidences allow us to investigate on the possible immune function of human 2'-FL and LNFP-I in vitro on LPS-activated mononuclear cells (MNC) from 12 patients with multiple sclerosis (MS) and 20 matched health controls (HC). We found that 2'-FL and LNFP-I significantly decrease, to a different extent, the MNC proliferation from both HC and MS patients, in a linear and dose-dependent manner. 2'-FL and LNFP-I also reduce the production of IL-12 and IFN-gamma, particularly in MS patients as compared to HC (p=0.01 and p<0.001, respectively), while increasing that of IL 10. The overall immunomodulatory effect of 2'-FL and LNFP I here presented may represent a future therapeutic option for the abnormal immune response found in some monocyte-mediated diseases. PMID- 23674972 TI - Virus-associated lymphomagenesis. AB - At least 2 billion people are affected by viral infections worldwide. The infections induce a lot of various human diseases and are one of the main causes of human mortality. In particular, they can lead to development of various human cancers. Up to 15-20% of human cancer incidence can be attributed to viruses. Although viral infections are very common in the general population, only few of them result in clinically relevant lesions. Certain associations between virus infections and malignancy are strong and irrefutable, the others are still speculative. The criteria most often used for determining the causality are the consistence of the association, either epidemiologic or at the molecular level, and oncogenicity of viruses or particular viral genes in animal models or cell cultures. Due to some ambiguity of such a determination, it is instructive to consider by specific cases what evidence is generally accepted as sufficient to establish a causal relation between virus and cancer. Lymphomas are one of the best studied cancer types closely associated with a small but definite range of viruses. Numerous data show a close interrelation between lymphomagenesis and infection by such viruses as Kaposi's sarcoma herpesvirus (KSHV), Epstein-Barr virus (EBV), hepatitis C virus (HCV), human T-cell leukemia virus (HTLV), and human immunodeficiency virus (HIV). For instance, experiments on monkeys artificially infected with viruses and data on anti-cancer effect of specific antiviral preparations strongly suggest the involvement of viruses in lymphoma development. The present review is devoted to the association of different viruses with human lymphomas and to viral genes potentially involved in the neoplastic process. The recognition of virus involvement in lymphomagenesis may facilitate new strategies for cancer therapy, diagnosis and screening and can lead to a reduction in the number of individuals at risk of disease. PMID- 23674974 TI - Effects of Reactive Oxygen Species on in vitro Filtration of Water and Albumin across Glomerular Basement Membrane. AB - Most of the interest in the glomerular basement membrane (GBM) stems from the observation that it undergoes morphological changes in renal disease. Studies on persistent proteinuria in experimental animal models have shown that the permeability properties of the GBM have been altered as a result of protein degradation and cross-linking of type IV collagen via its NC1 domains promoted by reactive oxygen species (ROS) and extrusion of tubular cell contents. We used the in vitro ultrafiltration technique to assess permeability properties of bare isolated GBM films to water and albumin in the Munich Wistar Fromter rat model of glomerular injury. Hydraulic permeability for water and albumin solutions and albumin fractional clearances were measured for rats treated with lisinopril [an angiotensin converting enzyme (ACE) inhibitor] and were compared with those measured for rats treated with dimethylthiouria (an ROS scavenger) and their control groups, at four pressure levels (50, 100, 200, and 300 mmHg). The ACE inhibitors and ROS scavengers treatment regimens for studied rats in addition to significantly lowering their systolic blood pressure and urinary protein excretion values to normal levels, have significantly increased their in vitro hydraulic and Darcy permeability, which is a measure of the intrinsic hydraulic conductance of the GBM, either in the absence or presence of albumin; in comparison with control animals. We believe that these favorable effects may derive from ROS scavenging beneficial effects that preserve the GBM protein structure by reducing entactin and laminin degradation and type IV collagen cross linking. PMID- 23674975 TI - Endogenous Estradiol and Testosterone may Predispose toward Atherogenic Lipid Profile, but Higher Blood Level of Testosterone is Associated with Lower Number of Stenoses in the Coronary Arteries of Men with Coronary Disease. AB - OBJECTIVES: To assess the correlations between blood levels of sex steroid hormones and blood lipid profile or the degree of coronary artery stenosis in men with coronary artery disease (CAD). METHODS: 111 men with stable CAD, aged 36-73 yrs, unselected for the coexisting clinical coronary risk factors were prospectively studied. Degree of coronary stenosis was assessed angiographically using different indices. Total cholesterol (T-Ch), high density lipoproteins cholesterol (HDL-Ch), low density lipoproteins cholesterol (LDL-Ch), triglicerydes (TG), testosterone, estradiol, dehydroepiandrosterone sulfate (DHEA S), and sex hormone binding globulin (SHBG) were measured in the blood. Free testosterone index (FTI) was calculated. RESULTS: A positive, significant correlations were found between blood concentrations of estradiol and T-Ch (r=0.29, p<0.01) or LDL-Ch (r=0.34, p<0.005) as well as between FTI and blood LDL Ch (r=0.23, p<0.05). Blood level of estradiol negatively correlated with HDL-Ch/T Ch ratio (r=-0.21, p<0.05). While blood levels of T-Ch correlated positively with 3 out of 5 applied here indices of coronary stenosis, blood LDL-Ch with two of them. In turn, blood level of testosterone negatively correlated with one index of coronary stenosis (r=-0.26, p<0.05). CONCLUSION: In men with CAD, plasma estradiol concentrations are predictive for T-Ch, LDL-Ch and HDL-Ch/TCh ratio, and FTI for LDL-Ch. Regression analyses indicated that while sex steroid hormones may predispose toward atherogenic lipid profile and are predictive for the number and degree of coronary artery stenosis, higher blood level of total testosterone was associated with the lower number of stenosis in the coronary arteries. Hence, endogenous testosterone may have beneficial effect on coronary arteries. PMID- 23674976 TI - Therapeutic Effects of Pre-Gelatinized Maca (Lepidium Peruvianum Chacon) used as a Non-Hormonal Alternative to HRT in Perimenopausal Women - Clinical Pilot Study. AB - BACKGROUND: Roots of cruciferous plant Lepidium peruvianum Chacon cultivated in high plateaus of Andes and known under its common name Maca, have been traditionally-used as an energizing vegetable with therapeutic properties for both men and women. Maca has been recognized by natives of Peru as herbal remedy helping to treat conditions affecting menopausal women. OBJECTIVE: The effects of Pre-Gelatinized Organic Maca (Maca-GO) on quantitative physiological responses and alleviation of symptoms contributing to menopausal discomfort in perimenopausal women was examined. METHODS: IN THIS, FOUR MONTHS, DOUBLE BLIND, CROSSOVER, RANDOMIZED PILOT TRIAL, MONTHLY MEASUREMENTS OF THE FOLLOWING BLOOD SERUM CONSTITUENTS WERE TAKEN: Estrogen (E2), Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH) and Progesterone (PGS), Cortisol (CT), Adrenocorticotropic Hormone (ACTH), Thyroid Hormones (TSH, T3, T4), minerals (Ca, K, Fe) and lipid profile (Triglicerides, Total Cholesterol, LDL, HDL). In monthly interviews conducted by gynecologist, body weight and blood pressure were registered and Menopausal Index according to Kupperman's was determined. Toxicity of Maca -GO determined on rats showed its safe use at the level of 7.5mg/kg body weight. A group of 20 women (aged 41-50 years), who fulfilled criteria of being in perimenopausal stage (E2 above 40pg/ml and FSH below 30IU/ml), were randomly allocated to two even groups, one receiving for two months Maca-GO and the other Placebo capsules followed by a crossover with treatment change for another two months period. All participants signed informed consent to participate. Two 500mg hard capsules with Maca-GO or Placebo were self-administered by participants twice daily with meals (total 2g/day). RESULTS: Two months administration of Maca GO significantly alleviated symptoms of discomfort observed in majority of women involved in the study (74%-87%) as assessed by Kupperman's Menopausal index. This was associated with significant increase in E2 and FSH, Progesterone and ACTH levels, and reduction in blood pressure, body weight, Triglycerides and Cholesterol levels. There was a distinctive placebo effect observed at the beginning of the study. CONCLUSIONS: The results showed that in addition to reduction in body weight, blood pressure and increasing serum HDL and Iron, pre gelatinized Maca-GO may be a valuable non-hormonal plant preparation for balancing levels of hormones (FSH, E2, PG and ACTH) and alleviating negative physiological and psychological symptoms (frequency of hot flushes, incidence in night sweating, interrupted sleep pattern, nervousness, depression and heart palpitations) experienced by women in perimenopausal stage. It appears that Maca GO may act as a toner of hormonal processes, leading to alleviation of discomfort felt by perimenopausal women, hence, its potential use as non-hormonal alternative to HRT program. PMID- 23674977 TI - Molecular analysis for differential diagnosis of small bowel obstruction: expression of proinflammatory cytokines and diamine oxidase activity. AB - BACKGROUND: A small bowel obstruction is classified as simple (nonstrangulated) or strangulated. The early recognition with correct diagnosis of small bowel obstruction is a critical issue as the release from strangulation requires surgical emergency. METHODS: To evaluate the physiological effect on small bowel obstruction, a metallic ring was put in the small intestine (simple ileus) and a loop obstruction was made with keeping the blood flow (strangulated obstruction). Serum level of cytokines, IL-6, TNF-alpha, and IL-1beta as well as endotoxin and seromuscular enzymes, CPK and LDH, were serially analyzed. Serum and mucosal DAO activity were also assessed. RESULTS: Endotoxin was increased at 18 h through 48 h in strangulated obstruction, but not detected in the simple ileus. Early proinflammatory cytokines were significantly elevated in strangulated obstruction. High expression of IL-6 prolonged after 12h. Transiently expressed IL-1beta peaked at 12h, TNF-alpha was increased at 18 h. In simple ileus, these expressions of cytokines were low and slow. LDH and CPK were significantly elevated at 48h, but there were no difference between simple ileus and strangulated obstruction. Serum DAO activity was significantly increased in simple ileus, but gradually decreased in strangulated obstruction, while mucosal DAO activity was decreased in both groups. CONCLUSIONS: High level of serum IL-6 is an early marker for strangulated obstruction. The pattern of serum DAO activity, decrease in strangulated obstruction and increase in simple ileus, might be useful molecular parameter in the early and proper diagnosis of small bowel obstruction. PMID- 23674978 TI - Haplotype Based Association Study between t-PA Gene and Essential Hypertension. AB - Several previous studies have shown that essential hypertension (EH) is associated with fibrinolysis. Tissue plasminogen activator (t-PA) plays a key role in fibrinolysis. Thus, it is possible that the t-PA gene is a susceptibility gene of EH. However, there have been no reported studies of association between EH and the t-PA gene using single nucleotide polymorphisms (SNPs). The aim of the present haplotype-based case-control study was to investigate whether SNPs in the human t-PA gene are associated with EH. We performed a genetic association study using 3 SNPs (rs7007329, rs8178750, rs4471024). The subjects were 276 EH patients and 283 age-matched normotensive (NT) individuals. There were no significant differences in overall distribution of genotypes or alleles between EH patients and NT subjects. Also, there were no significant differences in the haplotype based case-control study. The present results do not indicate an association between the t-PA gene and EH. PMID- 23674979 TI - Cortical Spreading Depression Elicited in Rat Brain after Exposure to Microwave from GSM Mobile Phone. AB - The aim of the present work is to evaluate possibility of microwave emitted by cellular phone that can elicit cortical spreading depression (CSD) in rat brain and studying the characteristics of the evoked signals. (CSD) was elicited in cerebral cortex of anesthetized rats after exposure to microwave irradiation (935.2-960.2 MHz) from Global System for Mobile communications (GSM) mobile phone. With the microwave output of about 8.5 mW at the antenna - tissue surface (4mm in diameter), CSD was elicited after 50 sec irradiation from the beginning of a received signal to the mobile and after 35 sec irradiation from the beginning of a transmitted signal from the mobile. CSD was elicited in about 90% of experiments after irradiation by both types of signal exposure. The results have shown that slow potential change (SPC) has an amplitude of 4.5 +/- 0.75 mV, duration of 1.5 +/- 0.5 min and propagated speed of 3 mm/min on the average. The amplitude, duration and behaviour of SPC of the evoked spreading depression were found to be affected by irradiation time and the method of exposure. PMID- 23674980 TI - Human Milk, Environmental Toxins and Pollution of Our Infants: Disturbing Findings during the First Six Months of Life. AB - BACKGROUND: Toxic organochlorine compounds (OC) are transmitted from mother to infant during lactation. OC are ingested by and stored in their offspring. Different harmful effects later in life have been attributed to the body pollution with these OC, although these findings are still discussed in an argumentative manner, since first other investigators could demonstrate beneficial effects of breast-feeding despite elevated OC concentrations, and second the benefits of breast-feeding are an unchallenged fact, especially in those countries, where infant formulas are not available. It was the aim of the present study to determine the lactational uptake of different OC (polychlorinated biphenyls (PCB), hexachlorobenzene (HCB), and DDE) in breast-fed vs. bottle-fed infants up to six months of age. METHODS: With the written informed consent of the parents, blood samples were taken from each ten breast fed and bottle-fed infants, respectively. The specimens were immediately centrifuged, and serum was stored in glass tubes without an anticoagulant up to analysis. Three higher-chlorinated PCB congeners (IUPAC Nos. 138, 153, and 180), HCB, and DDE, the main metabolite of DDT in mammals, were determined with capillary gas chromatography with electron capture detection. In addition, reliability was tested with gas chromatography-mass spectrometry. Possible correlations of OC with personal data were tested with a standard multivariate regression model. Differences between study groups were tested on mean differences with Wilcoxons test for independent samples. RESULTS: We could demonstrate that breast-fed infants have significantly (p<0.0001) elevated serum concentrations of all OC as early as at the age of six weeks (90%), which over and above nearly doubled further until the age of six months. (Median (MUg/L); A=six weeks; B=six months): PCB 138, A: 0.40 vs. 0.09; B: 0.72 vs. 0.07; PCB 153, A: 0.57 vs. 0.11; B: 0.99 vs. 0.09; PCB 180, A: 0.33 vs. 0.04; B: 0.58 vs. 0.02; PCB (sum of the three PCB congeners), A: 1.19 vs. 0.29; B: 2.28 vs. 0.18; HCB, A: 0.13 vs. 0.04; B: 0.43 vs. 0.07; DDE, A: 1.05 vs. 0.18; B: 1.90 vs. 0.19. CONCLUSIONS: The discussion about the benefits of breast-feeding should be reconsidered again, with special emphasis on the question, whether the recommendations for breast-feeding can unreservedly be maintained for the future throughout the world, especially in face of the availability of infant formulas in industrialized vs. Third World countries, respectively. PMID- 23674981 TI - Umbilical cord segmental hemorrhage and fetal distress. AB - We describe an unexplained case of umbilical cord segmental hemorrhage linked with meconium-stained amniotic fluid. A severely asphyxiated infant was delivered at term by Caesarean section. There were poor prognostic signs on fetal cardiotocography with rupture of membranes with meconium-stained amniotic fluid. The pathophysiologic mechanism in this case is still unknown, even if we argued a possible role of the umbilical cord shortness. PMID- 23674983 TI - Alois Alzheimer: a hundred years after the discovery of the eponymous disorder. AB - The familiar term "Alzheimer's disease" was coined by Emil Kraepelin to honour his pupil, Alois Alzheimer. However, little is known about the life of the man after whom this important and well-known disease was termed. On the centennial of the discovery of Alzheimer's disease, it is appropriate to report some aspects of the life and scientific work of Alois Alzheimer. The authors contacted all the libraries of the Universities where Alzheimer studied and/or worked to receive any original material regarding Alois Alzheimer. This review is based for a most part on an original biography written by Konrad and Urlike Maurer after the interviews to Alzheimer's nieces, Hildegard Koeppen, Ilse Lieblein, Barbel Lippert, Karin Weibeta, and his nephew, Rupert Finsterwalder. The authors obtained this biography from the Central Library of Medicine in Koeln. PMID- 23674982 TI - Saving Implants BMP-2 Application in Revision Total Hip Surgery. AB - OBJECTIVE: Besides others, there are two major problems in total hip replacement surgery which result in implant failure. First there is aseptic loosening due to a lack of implant biocompatibility or micromovements and second periimplant wear debris induced osteolysis which limits the survival rate of an implant. Regarding to recent data there are only limited therapeutic strategies to heal these bony defects without arthroplasty revision surgery. Since the investigation and characterization of adult mesenchymal stem cells (MSCs) from bone marrow, a cell and tissue engineering based therapy might be a promising solution to heal endoprosthesis associated bony defects. Moreover the application of growth factors in bone reconstructive surgery is another treatment concept to promote local bone regeneration. PATIENT AND METHODS: We report about a 73-year old patient with a painful weight bearing and a large, wear debris induced pelvic osteolysis after total hip arthroplasty. To prevent from salvage surgical procedures and preserve bone, a healing attempted was performed by filling the critical bony defect zone with a BMP-2/MSC composit. RESULTS: Clinical and radiological follow-ups showed a progressive bony healing of the critical size defect area without any complications. Fifteen months after application the patient is still pain free, has no limitations in daily life or sport activities. CONCLUSION: The case embarks on a strategy of non-embryonic stem cell and growth factor application to heal bony defects at patients with total hip endoprosthesis. PMID- 23674984 TI - New advance in caspase-independent programmed cell death and its potential in cancer therapy. AB - Caspase activation has been frequently viewed as synonymous with programmed cell death (PCcD); however, accumulating evidence showed that there existing caspase independent PCcD pathways displaying morphologies that are not fully consistent with classical apoptosis. In this article, we will focus on the most recent progresses of different models of PCcD independent of caspases activity. Since some tumor cells can unexpectedly survive the activation of caspases, and tumor suppressor proteins that activate caspase-independent PCcD are commonly mutated in human cancer, the alternative cell death pathways are gaining increasing interest among cancer researchers. Though the mechanism of this cell death pathway is poorly understood, it is clear that a full understanding of the regulation of caspase-independent PCcD could provide new means of improving current diagnosis and promoting conceptual advances for the design of new therapeutic strategies for cancer therapy. PMID- 23674986 TI - Endocrine function in thalassemia intermedia. AB - Thalassemias are the most common genetic disorder on a wordwide basis. beta thalassemia is a severe hemolytic anemia which results from genetic defects in the synthesis of the hemoglobin beta-chain. Various endocrine abnormalities have been described in patients with thalassemia major. Endocrine disturbances have also been observed in patients with thalassemia intermedia (TI). In this study endocrine functions were investigated in TI and here the frequency of different abnormalities is reported. Ninety-three patients (40 males, 53 females) with thalassemia intermedia, 11-40 years old (mean 19.4 yr) were studied. Medical history was obtained and a complete physical examination was done for each patient. The age, sex, weight, height and serum ferritin levels were recorded using a questionnaire. Growth Hormone (GH) secretion, thyrotropin (TSH), T(4), parathyroid hormone (PTH) and cortisole levels were determined in these patients. The mean +/- Standard Deviation (SD) serum ferritin level was 452.4 +/- 312.60 MUg/L. Mean +/- SD hemoglobin concentration was 9 +/- 1 g/dl. Short stature was present in 46% of patients. Growth hormone deficiency was one of the most frequent (31%) endocrine abnormalities in these patients. Primary hypothyroidism was observed in 21.5% of patients. Hypoparathyroidism was found in one patient (1%). Failure of puberty was present in 2% of patients, secondary ammenorrhea was observed in 6.4% of patients and diabetes mellitus (DM) in 2% of patients. CONCLUSION: Growth retardation and GH deficiency should be considered as common finding in TI. Therefore endocrine evaluation of these patients is suggested to prevent complications and to improve the overall quality of life. PMID- 23674987 TI - Metacarpal Index Estimated by Digital X-ray Radiogrammetry as a Tool for Differentiating Rheumatoid Arthritis Related Periarticular Osteopenia. AB - To investigate Metacarpal Index (MCI) and Bone Mineral Density (BMD) estimated by Digital X-ray Radiogrammetry (DXR) with respect to its ability to quantify severity-dependent variations of bone mineralisation in patients with early rheumatoid arthritis compared to Dual Energy X-ray Absorptiometry (DXA), 122 patients underwent a prospective analysis of BMD and MCI by DXR, whereas both DXR parameters were estimated from plain radiographs of the non-dominant hand. In comparison DXA measured BMD on total femur and lumbar spine (L2-L4). Additionally Steinbrocker Stage was assessed to differentiate the severity of rheumatoid arthritis (RA). Disease activity of RA was estimated by C-reactive Protein (CRP; in mg/l), Erythrocyte Sedimentation Rate (ESR in mm/1st hour) and by the disease activity score with 28-joint count (DAS 28). In consequence, The DXR-parameters, in particular DXR-MCI, revealed significant associations to age, Body Mass Index, CRP, DAS 28 and Steinbrocker graduation; no significant associations could be verified between DXA-parameters and all characteristics of disease activity and severity of RA. The highest correlation was found between DXR-MCI and DXR-BMD with R=0.89 (independent from severity of RA). In all patients DXR-MCI significantly decreased (-14.3%) from 0.42 +/- 0.09 (stage 1) to 0.36 +/- 0.07 (stage 2) dependent on severity of RA. The comparable relative reduction of DXR BMD was -11.1%. The group of patients with minor disease activity (DAS 28>5.1) showed a significant flattened reduction (-11.4%) for DXR-MCI from 0.44 +/- 0.08 (stage 1) to 0.39 +/- 0.08 (stage 2). For accentuated disease activity (DAS 28>5.1) the DXR-MCI revealed a pronounced reduction (-23.1 %). No significant declines were observed for DXA-BMD of the lumbar spine and total femur in all patients as well as dependent on disease activity. CONCLUSION: DXR can exactly quantify cortical thinning of the metacarpal bones and can identify cortical demineralisation in patients suffering from early rheumatoid arthritis surpassing DXA-measurements at axial bone sites. In this context DXR-MCI seems to be the most sensitive parameter for differentiation of patients with minor or accentuated disease activity following severity-dependent cortical bone loss. PMID- 23674985 TI - Immunoassay Methods and their Applications in Pharmaceutical Analysis: Basic Methodology and Recent Advances. AB - Immunoassays are bioanalytical methods in which the quantitation of the analyte depends on the reaction of an antigen (analyte) and an antibody. Immunoassays have been widely used in many important areas of pharmaceutical analysis such as diagnosis of diseases, therapeutic drug monitoring, clinical pharmacokinetic and bioequivalence studies in drug discovery and pharmaceutical industries. The importance and widespread of immunoassay methods in pharmaceutical analysis are attributed to their inherent specificity, high-throughput, and high sensitivity for the analysis of wide range of analytes in biological samples. Recently, marked improvements were achieved in the field of immunoassay development for the purposes of pharmaceutical analysis. These improvements involved the preparation of the unique immunoanalytical reagents, analysis of new categories of compounds, methodology, and instrumentation. The basic methodologies and recent advances in immunoassay methods applied in different fields of pharmaceutical analysis have been reviewed. PMID- 23674988 TI - Expression, Purification and Characterization of a Recombinant Plasmodium Vivax Thrombospondin Related Adhesive Protein (PvTRAP). AB - Thrombospondin Related Adhesive Protein (TRAP) is a transmembrane parasite molecule responsible in sporozoite-host interactions. This molecule is one of the most promising vaccine candidates against the pre-erythrocytic forms of malaria. In the present study, a gene encoding the Plasmodium vivax TRAP (PvTRAP) was expressed in Escherichia coli (M15 strain) using the expression plasmid pQE30. The expressed recombinant protein PvTRAP of about 70kDa was achieved, purified and refolded according to the standardized refolding procedure. This refolded protein (PvTRAP) showed a single band monomeric form with SDS-PAGE and blot analysis. In reduced and alkylated form, PvTRAP showed less binding to hepatoma (HepG2) liver cells, when compared to the normal purified and refolded form. Purified and refolded recombinant PvTRAP bound Duffy-positive human erythrocytes, while no binding was observed with Duffy-negative erythrocytes. Our report on PvTRAP is currently documented for the first time and it has been able to provide an experimental evidence of the biochemical and binding properties of PvTRAP in the invasion of hepatocytes and interaction with Duffy-positive and Duffy negative human erythrocytes. In conclusion, our findings have been able to demonstrate the potential of PvTRAP as a promising target for vivax malaria vaccine candidate. PMID- 23674989 TI - Hormone-Balancing Effect of Pre-Gelatinized Organic Maca (Lepidium peruvianum Chacon): (I) Biochemical and Pharmacodynamic Study on Maca using Clinical Laboratory Model on Ovariectomized Rats. AB - Ovariectomized rats were used in a model laboratory study to examine biochemical and pharmacodynamic effects of pre-gelatinized organic preparation of Lepidium peruvianum Chacon (Maca-GO). Biochemical and Pharmacodynamic effects of Maca-GO (250 mg Maca-GO per kg body weight (bw) administered by intubation twice daily) were assessed in a 28 day model laboratory study on ovariectomized (by laparoscopy) Wistar rats with pharmacodynamic tests performed at the conclusion of the trial followed by blood collection for morphology and biochemical tests. Toxicity of Maca-GO used in the study was determined in bioassay on mice and rats. Anti-depressive function (Porsolt's test) and anxiolytic sedative and cognitive effects (using elevated-plus maze, locomotor activity and passive avoidance tests) were assessed against control (laparotomized female rats with intact ovaries). In addition to blood morphology, the following blood serum constituents were analyzed: Estrogen (E2), Progesterone (PGS), Cortisol (CT), Adrenocorticotropic Hormone (ACTH), Thyroid Hormones (TSH, T3, and T4), Iron (Fe) and lipid profile (Triglycerides, Total Cholesterol, LDL, HDL). Analytically determined non-toxic status of Maca-GO was confirmed in bioassays when applied to mice and rats at levels of 0.5 and up to 15mg/kg bw which shows it safe use in humans with the LD50>15 mg/kg bw. Maca-GO showed a distinctive, (P<0.05) antidepressant-like and sedative effect in ovariectomized rats only, while there was no anxiolytic activity nor disturbance of cognitive function observed in both, test and control animals. Observed in this study balancing effect of Maca GO on sex hormone levels show its potential as a safe preparation for use in correcting physiological symptoms characteristic in postmenopausal stage with an indication of potentially even more value for its use in pre-menopausal women. PMID- 23674990 TI - Spectrophotometric Determination of Alfuzosin HCl in Pharmaceutical Formulations with some Sulphonephthalein Dyes. AB - Bromocresol purple (BCP), bromophenol blue (BPB) and bromothymol blue (BTB) were used to determine alfuzosin hydrochloride either in pure form or in pharmaceutical formulations. Alfuzosin was extracted as an ion-pair complex from sample solution containing KCl-HCl buffer pH2.2, 2.4 and 2.6 into CHCl3 and the absorbance was measured at 407, 413 and 412nm with use of the cited reagents, respectively. The analytical parameters and their effects on the reported systems are investigated. The reactions were extremely rapid at room temperature and the absorbance values remains unchanged up to 24 h. Beer's law was obeyed in the concentration ranges 1.20-38.3, 0.85-46.0 and 0.63-34.0 MUg/ml and detection limits were 0.28, 0.24 and 0.18 MUg/ml with BCP, BPB and BTB, respectively. Recoveries were 98.80-101.33%. Interferences of the other ingredients and excipients were not observed. The proposed method is simple, fast and sensitive, and the first reported extractive method for the determination of alfuzosin in commercial tablets. PMID- 23674991 TI - Effects of Hypoxia on Nitric Oxide (NO) in Skin Gas and Exhaled Air. AB - This study confirmed the effects of hypoxia on nitric oxide (NO) concentrations in skin gas and exhaled air. NO concentrations in skin gas and exhaled air were measured by a chemiluminescence analyzer. Arterial oxygen saturation (SpO2) of the right forefinger was determined using an oxygen saturation monitor. The M +/- SEM of NO concentrations in skin gas at 20.93% (control), 15.1% and 14.8% oxygen concentrations were 23.7 +/- 3.6, 32.3 +/- 4.7 and 36.2 +/- 5.2 ppb, respectively. M +/- SEM of NO concentrations in exhaled air at 20.93% (control), 15.1%, and 14.8% were 25.0 +/- 5.1, 35.01 +/- 5.6 and 44.9 +/- 7.2 ppb, respectively. There was no significant difference in NO concentration at the absolute value of skin gas and exhaled air between normoxia and hypoxia. But significant increase was found at relative changes in skin gas at 15.1% (p<0.01) and 14.8% (p<0.01) oxygen content compared with control. Significant increase was also found at relative changes in exhaled air at 15.1% (p<0.01) and 14.8% (p<0.01) oxygen content compared with control. In conclusion, we confirmed that exposure to hypoxia elicits an increase in NO concentrations at relative changes of skin gas and exhaled air compared to normoxia. PMID- 23674992 TI - Neuroprotective effects of sesamin and sesamolin on gerbil brain in cerebral ischemia. AB - Sesamin and sesamolin, abundant lignans found in sesame oil, have been demonstrated to possess several bioactivities beneficial for human health. Excess generation of nitric oxide in lipopolysaccharide-stimulated rat primary microglia cells was significantly attenuated when they were pretreated with sesamin or sesamolin. The neuroprotective effect of sesamin and sesamolin was also observed in vivo using gerbils subjected to a focal cerebral ischemia induced by occlusion of the right common carotid artery and the right middle cerebral artery. Repeated treatment of sesamin or a crude sesame oil extract containing both sesamin and sesamolin significantly reduced the infarct size, visualized via 2,3,5 triphenyltetrazolium chloride staining, by approximately 50% when compared with the control group. These results suggest that sesamin and sesamolin exert effective neuroprotection against cerbral ischemia. PMID- 23674993 TI - Ocular lesions in the inmates of leprosy rehabilitation centre. AB - A detailed eye examination of 145 inmates of a leprosy rehabilitation centre was done to determine the prevalence of ocular involvement. Age, gender of patients, type and duration of leprosy, systemic disabilities were noted. The mean age of patients was 45.8 years (range 19-70 years); 72.4% were males; 55.2% were suffering from paucibacillary leprosy. The mean duration of leprosy was 18.2 years in multibacillary type and 13.1 years in paucibacillary type. Ocular lesions related to leprosy were seen in 85.5% of patients; more often in multibacillary leprosy (92.3%). Corneal changes (80.7%) were the most frequently observed lesions followed by eye lid lesions (48.2%). Potentially sight threatening lesions such as lagophthalmos (23.4%), cornealanaesthesia (43.4%), and iridocyclitis (8.9%) were seen in both types of leprosy. Nine out of 26 (34.6%) patients with history of erythema nodosum leprosum reaction showed eye changes related to this reaction. Blindness in one eye due to lesions related to leprosy was seen in 2.7% of eyes. Age related cataract was the most common cause of blindness in patients of leprosy. The prevalence of ocular lesions was found to be high in the inmates of leprosy rehabilitation centre, and they were seen more frequently in patients with longer duration of the disease. Potentially sight threatening lesions were more often associated with systemic disabilities in these patients. PMID- 23674994 TI - Oxidative hemolysis of erythrocytes induced by various vitamins. AB - Hemolytic effect of some water-soluble vitamins (niacin B5, pyridoxine B6, thiamine B1 and ascorbic and acid C) on erythrocytes was studied spectrophotometrically at relatively high concentration. The oxidation mechanism of hemoglobin was the same for the used vitamins. Vitamin C was the strongest hemolytic agent in comparison with the other vitamins, while vitamin B1 is the weakest one. The results were confirmed by studying the variation in conductivity of erythrocytes with temperature in the range 20-40 degrees C for the used vitamins at a concentration of 2 mM and after two hours from adding each vitamin to the erythrocytes suspension. The conductivity measurements show that the conductivity for the used vitamins is lower than that for control (without adding vitamin) due to hemoglobin oxidation, also may be due to the electrical reorganization of the erythrocyte membrane after the interaction of the used vitamin with it. The obtained results insure the oxidizing effect of the used vitamins on hemoglobin and consequently their hemolytic effect on erythrocytes. PMID- 23674995 TI - Sterile Corneal Ulcer and Sjogren's Syndrome Associated with Long-Term Interferon alpha-2b Treatment in a Case of Multiple Myeloma. AB - A 71-year-old Chinese male was referred for severe dry eyes who suffered from multiple corneal melting ulcers and underwent a long-term and high-dosage interferon alpha-2b (INFalpha-2b) treatment for multiple myeloma (MM). The patient was diagnosed to have MM 12 years ago, and since then INFalpha-2b (3 million units, intramuscularly, three times a week) was prescribed until the present. Two years ago, diffuse superficial punctuate epithelial defects, filaments and multiple melting ulcers in his cornea were noted. Sjogren's syndrome was diagnosed after the salivary gland biopsy. In addition to preservative-free topical lubricants, bilateral permanent punctal occlusion and tarsorraphy were performed but in vain. Topical and systemic immunosuppressants including corticosteroids, cyclosporin and methotrexate improved his corneal condition successfully. The present case suggests a relationship between INFalpha 2b and Sjogren's syndrome. Long-term use of INFalpha-2b may impair tear functions and complicate corneal melting ulcers. Immunosuppressants play a role in treatment of INFalpha-2b associated keratopathy. PMID- 23674996 TI - Detection of varicella-zoster virus DNA in the iris of a zoster sine herpete patient. AB - A 55-year-old man presented with unilateral iridocyclitis and elevated intraocular pressure (IOP) in his right eye. Varicella-zoster virus (VZV) DNA was detected by polymerase chain reaction (PCR) in the iris of a patient of Zoster Sine Herpete. No symptoms or signs of herpes zoster like neuralgia or cutaneous eruptions on forehead were noted. His iridocyclitis was treated and responded well with systemic and topical acyclovior as well as topical steroid. However, the marked elevated IOP could not be controlled by maximal dosage of anti glaucomatous medicine. The patient underwent trabeculectomy to control his IOP. Samples of aqueous humor and iris tissue were obtained and VZV was checked by PCR. VZV virus DNA was detected from samples of the aqueous humor and iris tissue patient of Zoster Sine Herpete by PCR analysis. PMID- 23674997 TI - Estriol and progesterone: a new role for sex hormones. AB - The physiological states pregnancy and parturition are undoubtedly associated with clinical changes of most of the autoimmune diseases. An altered Th1/Th2 balance has been proposed as an underlying mechanism. A pregnancy has protective effect on Th1-mediated autoimmune diseases, and a deteriorative effect on Th2 mediated autoimmune diseases. Numerous studies, both experimental and clinical, imply that estriol and progesterone, at high doses (such as those achieved during pregnancy), have potent anti-inflammatory and neuroprotective roles. These studies, as well as a further investigation of pregnancy-associated immunomodulation, can be used to advance and develop a new therapy approaches. PMID- 23674998 TI - Peroxisomes and disease - an overview. AB - Peroxisomes are indispensable for human health and development. They represent ubiquitous subcellular organelles which compartmentalize enzymes responsible for several crucial metabolic processes such as beta-oxidation of specific fatty acids, biosynthesis of ether phospholipids and metabolism of reactive oxygen species. Peroxisomes are highly flexible organelles that rapidly assemble, multiply and degrade in response to metabolic needs. Basic research on the biogenesis of peroxisomes and their metabolic functions have improved our knowledge about their crucial role in several inherited disorders and in other pathophysiological conditions. The goal of this review is to give a comprehensive overview of the role of peroxisomes in disease. Besides the genetic peroxisomal disorders in humans, the role of peroxisomes in carcinogenesis and in situations related to oxidative stress such as inflammation, ischemia-reperfusion, and diabetes will be addressed. PMID- 23674999 TI - Regulation of prion protein expression: a potential site for therapeutic intervention in the transmissible spongiform encephalopathies. AB - The Transmissible Spongiform Encephalopathies (TSEs) are a group of rare neurodegenerative diseases, which can be transmitted between members of the same species and possibly across different species. The link between the emergence of Bovine Spongiform Encephalopathy (BSE) and the new variant form of Creutzfedlt Jakob Disease (vCJD) has been the cause of much public concern. vCJD is the most widely known of the human TSEs but by no means the most common; inherited and sporadic forms are much more prevalent. The agent responsible for these diseases is a conformationally altered form of a normal cell surface glycoprotein, called the prion protein (PrP). The normal isoform must be present for the disease to progress, and disease incubation time decreases with increased PrP expression. There is still no cure for any of these diseases but recent advances in the understanding of how prion protein expression is regulated at the genetic level, and of exogenous factors modulating expression levels, may provide new insights into potential therapeutic targets for disease management by down regulation of cellular PrP levels. PMID- 23675000 TI - Induction of Constitutive High-Level Expression of c-Myc in 32D Cells by Mycoplasmas is Associated with their Ability to Prevent Apoptosis and Induce Malignant Transformation. AB - Our previous studies showed that mycoplasmas prevented apoptosis and induced the malignant transformation of mammalian cells. Other studies indicate that c-Myc plays an important role in promoting apoptosis and malignant transformation of cells. To understand the role of c-Myc in the mycoplasma induced apoptosis prevention and malignant cell transformation, 32D cells, an IL-3 dependent cell line, were infected and transformed by different species of mycoplasmas. The expression of Myc and ras gene families, apoptosis and the cell cycle during the infection and transformation were examined. Results showed that c-Myc expression was significantly increased in mycoplasma transformed 32D cells. Withdrawal of IL 3 substantially decreased c-Myc expression and led to cell cycle arrest at the G1 phase followed by rapid apoptosis. Infection by M. fermentans or M. penetrans not only alleviated the sharp decrease of c-Myc expression, rescued 32D cells from cell-cycle arrest and prevented apoptosis in IL-3-free culture, but also induced autonomous growth of 32D cells. Although M. hominis and M. salivarium had the ability neither to prevent apoptosis nor to induce malignant transformation, they were still able to rescue the cells from cell cycle arrest. The expression of ras family did not change significantly during the infection and transformation. These results suggest that constitutive expression of c-Myc appears to be associated with the continuous growth and malignant transformation of 32D cells induced by M. fermentans and M. penetrans, but not with rescuing the cell cycle arrest by the mycoplasmas. PMID- 23675001 TI - An Angiotensin II (Ang II) Type 1 Receptor Blocker, Telmisartan, Improves Insulin Resistance in KK-A(y) Diabetic Mice. AB - Metabolic syndrome is strongly associated with insulin resistance and consists of a constellation of factors such as hypertension and hyperlipidemia that raise the risk for cardiovascular diseases and diabetes mellitus. The renin-angiotensin system (RAS) plays a pivotal role in the pathogenesis of diabetes and cardiovascular disease (CVD) in hypertensive patients. Further, recently, the interruption of the RAS has been shown to prevent the onset of diabetes in hypertensive patients. However, whether telmisartan, an angiotensin II type 1 receptor blocker (ARB) with selective peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonistic property could improve insulin sensitivity is not fully understood. In this study, we studied the effects of telmisartan on insulin sensitivity in KK-A(y) mice, an obese type 2 diabetic animal. Although there was no significant difference in body weight, food consumption, and glucose levels between the two groups, plasma insulin, triglycerides and non-esterified fatty acid levels were significantly decreased in telmisartan-treated KK-A(y) mice, compared with control KK-A(y) mice. The present findings suggest that telmisartan could exert a beneficial effect on insulin sensitivity in diabetic animals. Inhibition of the RAS by telmisartan, a selective agonist of PPAR-gamma, may become a promising strategy for the treatment of hypertensive patients with metabolic syndrome and/or insulin resistance. PMID- 23675002 TI - Introduction of sustained release opipramol dihydrochloride matrix tablets as a new approach in the treatment of depressive disorders. AB - Opipramol 2-HCl (OP) is used for therapy of general somatoform and anxiety disorders. Conventional tablets in the market contain 50 mg OP to be used once or up to three times a day in effective treatment of depression in mild. In case of serious depressive disorders, OP may be administired up to 300 mg a day. Decrease in frequency of high dose administration via sustained drug release would reduce incidence of symptoms of intoxication in long-term use of OP. With this aim, OP matrix tablets containing 100 mg were prepared by direct compression method to be used once a day to provide patient compliance and constant blood level, consequently to decrease side effects. Two concentrations of polymers (10% and 20%): hydroxypropylcellulose (HPC) and hydroxypropyl methylcellulose (HPMC), sodium alginate (NaAlg), xanthan gum (XG) and Carbopol((r))941 (C941) were used in preparation of matrix tablets. Drug release study were performed in distilled water, pH1.2 HCl buffer and pH7.4 phosphate buffer solutions according to the Method II in USP 29. Two commercial tablets containing 50 mg OP available in Turkish market were used for comparison. Kinetic models of release patterns from tablets were evaluated. Drug release was displayed slower to faster pattern in order of formulations containing C941, HPMC and HPC. Drug release was significantly faster in tablets of 10% polymers than those of 20%. NaAlg and XG were insufficient to sustain drug release. The most sustaining drug release effect at the lowest polymer concentration was obtained with C941. Drug release from matrix tablets containing 10% C941 was determined as 58.2%, 52.4 and 57.0% in related dissolution mediums above after 8 hours, respectively. However, HPMC and HPC sustained drug release at 20% concentration. As a result, Carbopol(r) 941, HPMC and HPC can be suggested as suitable to prepare matrix tablets of OP. PMID- 23675003 TI - Phospholipid-Nucleic Acid Complexation: Biomolecular Energetics of DNA-Mg(2+) Phosphatidylcholine Ternary Complex Formation, Compaction and Relevance as Lipoplex Formulation. AB - Thermodynamic features related to preparation and use of self-assemblies formed between multilamellar and unilamellar zwitterionic liposomes and polynucleotides with various conformation and sizes are presented. The divalent metal cation induced adsorption, aggregation and adhesion between single- and double-stranded polyribonucleotides and phosphatidylcholine vesicles was followed by differential adiabatic scanning microcalorimetry. Nucleic acid condensation and compaction mediated by Mg(2+) was followed, with regard to interfacial interaction with unilamellar vesicles. Microcalorimetric measurements of synthetic phospholipid vesicles and poly(ribo) nucleotides and their ternary complexes with inorganic cations were used to build the thermodynamic model of their structural transitions. The increased thermal stability of the phospholipid bilayers is achieved by affecting their melting transition temperature by nucleic acid induced electrostatic charge screening. Measurements give evidence for the stabilization of polynucleotide helices upon their association with liposomes in presence of divalent metal cations. Such an induced aggregation vesicles either leads to heterogeneous multilamellar DNA-lipid arrangements, or to DNA-induced bilayer destabilization and lipid fusion. The further employment of these polyelectrolyte nanostructures as an improved formulations in therapeutic gene delivery trials, as well as in DNA chromatography is discussed. PMID- 23675004 TI - Dietary Supplementation of Vitamin E and alpha-Lipoic Acid Upregulates Cell Growth and Signaling Genes in Rat Myocardium. AB - The efficacy of antioxidant supplementation in the prevention of cardiovascular disease appears equivocal, however the use of more potent antioxidant combinations than those traditionally used may exert a more positive effect. We have shown previously that supplementation of vitamin E and alpha-lipoic acid increases cardiac performance during post-ischemia reperfusion in older rats and increases Bcl-2 levels in endothelial cells. The purpose of this study was to examine the effects of vitamin E and alpha-lipoic acid supplementation on myocardial gene expression with a view to determine their mechanism of action. Young male rats received either a control (n=7) or vitamin E and alpha-lipoic acid supplemented diet (n=8) for 14 weeks. RNA from myocardial tissue was then amplified and samples were pooled within groups and competitively hybridized to 8.5K oligonucleotide rat microarrays. The relative expression of each gene was then compared to the control sample. Animals that received the antioxidant supplemented diet exhibited upregulation (>1.5*) of 13 genes in the myocardium with 2 genes downregulated. Upregulated genes include those involved in cell growth and maintenance (LynB, Csf1r, Akt2, Tp53), cell signaling (LynB, Csf1r) and signal transduction (Pacsin2, Csf1r). Downregulated genes encode thyroid (Thrsp) and F-actin binding proteins (Nexilin). PMID- 23675005 TI - Hormone-Balancing Effect of Pre-Gelatinized Organic Maca (Lepidium peruvianum Chacon): (II) Physiological and Symptomatic Responses of Early-Postmenopausal Women to Standardized doses of Maca in Double Blind, Randomized, Placebo Controlled, Multi-Centre Clinical Study. AB - This was a double-blind, randomized, placebo-corrected, outpatient, multi-centre (five sites) clinical study, in which a total of 168 Caucasian early postmenopausal women volunteers (age>49 years) participated after fulfilling the criteria: follicle stimulating hormone (FSH) >30 IU/ml and estrogen (E2) <40 pg/ml levels at admission. They were randomly allocated to Placebo and Pre Gelatinized Organic Maca (Maca-GO) treatment, according to different monthly treatment sequences scheduled for each site. Two 500 mg vegetable hard gel capsules with Maca-GO or Placebo powder were self-administered twice daily with meals (total 2 g/day) during three (Trial I; n=102) or four (Trial II; n=66) months study periods. At the baseline and follow- up monthly intervals, blood levels of FSH, E2, progesterone (PRG) and lutinizing hormone (LH), as well as serum cholesterol (CHOL), triglycerides (TRG), high- and low density lipoproteins (HDL and LDL) were measured. Menopausal symptoms were assessed according to Greene's Score (GMS) and Kupperman's Index (KMI). Data were analyzed using multivariate technique on blocs of monthly results in one model and Maca versus Placebo contrast in another model. A total of 124 women concluded the study. Maca GO significantly stimulated production of E2 (P<0.001) with a simultaneous suppression (P<0.05) of blood FSH, increase (P<0.05) in HDL. Maca-GO significantly reduced both frequency and severity of individual menopausal symptoms (hot flushes and night sweating in particular) resulting in significant (P<0.001) alleviation of KMI (from 22 to 10), thus, offering an attractive non hormonal addition to the choices available to early-postmenopausal women in the form of a natural plant alternative to Hormone Replacement Therapy (HRT) - hence, reducing dependence on hormone therapy programs. PMID- 23675006 TI - Hormone-Balancing Effect of Pre-Gelatinized Organic Maca (Lepidium peruvianum Chacon): (III) Clinical responses of early-postmenopausal women to Maca in double blind, randomized, Placebo-controlled, crossover configuration, outpatient study. AB - This is the second, conclusive part of the clinical study on clinical responses of early-postmenopausal women to standardized doses of pre-Gelatinized Organic Maca (Maca-GO). Total of 34 Caucasian women volunteers participated in a double blind, randomized, four months outpatient crossover configuration Trial. After fulfilling the criteria of being early-postmenopausal: blood Estrogen (E2<40 pg/ml) and Follicle Stimulating Hormone (FSH>30 IU/ml) at admission, they were randomly allocated to Placebo (P) and Maca-GO (M) treatments (2 groups of 11 participants each). Two 500 mg vegetable hard gel capsules with Maca-GO or Placebo powder were self-administered twice daily with meals (total 2 g/day). At admission and follow-up monthly intervals, body mass index (BMI), blood pressure, levels of gonadal, pituitary, thyroid and adrenal hormones, lipids and key minerals were measured. Bone markers were determined after four months M and P use in 12 participants. Menopausal symptoms were assessed according to Greene's Score (GMS) and Kupperman's Index (KMI). Data were analyzed using multivariate technique on blocs of monthly. Results and canonical variate technique was applied to GMS and KMI matrices. Two months application of Maca-GO stimulated (P<0.05) production of E2, suppressed (P<0.05) blood FSH, Thyroid (T3) and Adrenocorticotropic hormones, Cortisol, and BMI, increased (P<0.05) low density lipoproteins, blood Iron and alleviated (P<0.001) menopausal symptoms. Maca-GO noticeably increased bone density markers. In conclusion, Maca-GO applied to early-postmenopausal women (i) acted as a toner of hormonal processes along the Hypothalamus-Pituitary-Ovarian axis, (ii) balanced hormone levels and (iii) relieved symptoms of menopausal discomfort, (hot flushes and night sweating in particular), thus, (iv) exhibited a distinctive function peculiar to adaptogens, providing an alternative non-hormonal plant option to reduce dependence on hormone therapy programs (HRT). PMID- 23675007 TI - Gossypol-Induced Differentiation in Human Leukemia HL-60 Cells. AB - The main treatment of leukemia is traditional radiochemotherapy, which is associated with serious side effects. In the past twenty years, differentiation was found as an important effective measure to treat leukemia with fewer side effects. Gossypol, a natural compound which has been used as an effective contraceptive drug, has been proposed to be a potent drug to treat leukemia, but the differentiation effect has not been studied. In the present study, we investigated the pro-differentiated effects, in vitro, of gossypol on the classic human myeloid leukemia HL-60 cell line. The effects of gossypol were investigated by using morphological changes, nitroblue tetrazolium (NBT) reduction, surface markers, cell-cycle analysis and Western blot analysis, etc. When HL-60 cells were incubated with low concentrations of gossypol (2-5MUM) for 48hr, a prominent G0/G1 arrest was observed. At 96 hr of treatment, 90% of HL-60 cells differentiated, as evidenced by morphological changes, NBT reduction, and increase in cell surface expression of some molecules were detected. This study is the first to identify gossypol's pro-differentiated effects on the leukemia cell line, and it induced differentiation through the PBK (PDZ-binding kinase)/TOPK (T-LAKcell-originated protein kinase) (PBK/TOPK) pathway. It is concluded that gossypol could induce differentiation in the leukemia HL-60 cells, and it may be a potential therapeutic agent, chemoprevention or chemotherapeutic adjuvant especially in combination drug therapy for leukemia. PMID- 23675008 TI - Lifespan extension by the antioxidant curcumin in Drosophila melanogaster. AB - The interest in health benefits associated with consumption of anti-oxidants has led to investigations examining the possibility that diets rich in anti-oxidants promote lifespan extension. Studies using the standard fruit fly (Drosophila melanogaster) model of longevity have shown that the antioxidants vitamin E and N acetyl cysteine prolong lifespan. Turmeric is a spice which has been consumed and used for medicinal purposes for many centuries in Asia. Interestingly, turmeric contains the powerful antioxidant, curcumin. To test the hypothesis that dietary curcumin prolongs lifespan, groups of 30 male D. melanogaster were cultured on media containing 1) no additive; 2) 0.5 mg of curcumin/gram of media; 3) 1.0 mg of curumin/gram of media; 4) 1.0MUg of the superoxide dismutase inhibitor, disulfiram/gram of media; 5) 10 g of disulfiram/gram of media; 6) 0.5 mg curcumin and 1.0 g disulfiram/ gram of media; 7) 1.0 mg curcumin and 1.0 g disulfiram/ gram of media; 8) 0.5 mg curcumin and 10 g disulfiram/gram of media; or 9) 1.0 mg curcumin and 10 g disulfiram/gram of media. The number of live fruitflies was noted daily and mean lifespan determined for each treatment group. A significant (P<=0.05) increase in mean lifespan was noted only for the fruitflies maintained on 1.0 mg of curcumin/gram of media; this effect was reversed by addition of disulfiram. These results demonstrate that dietary curcumin prolongs lifespan and that this effect is associated with enhanced superoxide dismutase activity. PMID- 23675009 TI - Kinetic spectrophotometric method for the determination of ketoprofen in pharmaceuticals and biological fluids. AB - A simple and sensitive kinetic method is described for the determination of ketoprofen in pure form, pharmaceuticals and biological fluids. The method utilizes an oxidative- coupling reaction based upon oxidation of 3-methyl-2-benzo thiazolinone hydrazone hydrochloride (MBTH) with Ce(IV) in presence of HCl, where an electrophilic intermediate (diazonium salt of the reagent) is produced, then couples with ketoprofen yielding a highly colored condensation product. The absorbance is measured after 20 min at 605 nm. Calibration graph was linear over the concentration range of 1-8MUg/mL with a minimum detection limit of 0.07 MUg/mL. The proposed method was applied successfully to the determination of Ketoprofen in pharmaceutical preparations, plasma and urine. The % recoveries were 100.11 for pure form, 100.10 for tablets and gel, 100.0 for suspension and suppositories, 100.2 for capsules and ampoules and 99.79, 99.9 for plasma and urine. The results obtained were in good agreement with those obtained using reference methods for comparison. PMID- 23675010 TI - Intraoperative ethanol treatment as an adjuvant therapy of pterygium excision. AB - Recurrence of pterygium is the main concern for ophthalmic surgeons after the excision of pterygium. To evaluate the efficacy and safety of ethanol treatment during pterygium excision in preventing the recurrence of pterygia. A prospective randomized study was performed of 78 eyes in primary pterygium patients treated by excision. Primary pterygium patients were randomly assigned to ethanol group (38 eyes given intraoperative ethanol) or mitomycin-c (MMC) group (40 eyes given intraoperative MMC). Ethanol (20%) was applied for 60 seconds to the pterygial and its adjacent corneal surfaces before pterygium excision. After excision, the excised site of sclera was soaked with 20% Ethanol for 60 seconds. In group 2, MMC (0.25 mg/ml) was applied for 60 seconds to the bare sclera after pterygium excision. The outcomes were followed for more than one year. Pterygium recurred in 2 (5.3%) of 38 eyes in ethanol group and 4 (10.0%) of 40 eyes in MMC group. Final appearance of the pterygium excision area was satisfactory in 73.6% of group1 and 67.5% of group 4. No patients experienced severe complications postoperatively. In comparison with MMC treatment, intraoperative ethanol is more efficacious in preventing recurrence of pterygium and causes fewer complications. It suggests this regimen as an alternative for the treatment of pterygium, especially for those patients of high risk group for MMC treatment complications. PMID- 23675011 TI - Cervical Cancer Screening for the Reluctant - HPV Testing of Air-Dried Vaginal Discharge. AB - Despite the availability of the PAP test, cervical cancer continues to cause considerable morbidity and mortality. Many women default cervical cytology for a variety of reasons. This demands the development of alternative screening strategies, such as HPV testing on self-procured cervical-vaginal specimens in order to capture this group of women. We investigated the self-procured air-dried vaginal discharge for HPV testing. We recruited 82 patients with HPV-associated cervical lesions and 36 patients with normal cervical pathology. Participants were briefed and informed consents obtained. Each was then given a kit containing written instructions, a slim napkin, an empty zip-lock plastic bag for soiled napkin specimen, and a return envelope. After wearing the napkin for the day, the patient removes it, dries it, and returns the specimen by mail. Specimens were batched and a 0.5 cm area of each stained napkin was tested for HPV by PCR. Specimens from all 26 patients with high-grade (CIN 2 or above) HPV-induced cervical lesions and 4 of 36 normal subjects tested positive for HPV, giving a sensitivity and specificity of 100% and 88.9%, respectively. We propose offering to women who refuse cervical cytology the alternative screening strategy of testing of self-procured air-dried vaginal discharge for HPV. This method of cervical cancer screening is also suitable for people living in remote regions of the world. PMID- 23675012 TI - Comparison of intraocular pressure fluctuations measured by goldmann applanation tonometer and pulsatile ocular blood flow analyser. AB - BACKGROUND: Intraocular pressure (IOP) is the major known risk factor in glaucoma and the primer mover of the functional damage in glaucomatous patients but it is not a unique determinant of glaucomatous damage. Clinical assessment of glaucoma patients may not be a true reflection of overall IOP control. Evaluation of the effect of glaucoma medication is restricted by measurement of IOP as a dynamic physiological parameter. PURPOSE: To compare IOP fluctuations over time using Goldmann applanation tonometry (IOPGAT) and pulsatile ocular blood flow analyzer (IOP-POBFA) under the Dorzolamide/timolol or latanoprost treatment regimes. DESIGN: Prospective 1 year follow-up study. PARTICIPANTS: 30 randomly chosen controlled open angle glaucoma patients (60 eyes): 16 patients (32 eyes) receiving Dorzolamide/timolol fixed combination (D/T) and 14 (28 eyes) latanoprost 0.005% treatment. MAIN OUTCOME MEASURES: Changes in IOP and perfusion pressure dynamics. RESULTS: THERE WAS NO STATISTICALLY SIGNIFICANT DIFFERENCE IN BASELINE IOP PARAMETERS BETWEEN STUDY GROUPS: 15.69 +/- 2.02 mmHg with D/T and 16.71 +/- 2.84 mmHg with latanoprost (p=0.314). Both treatment regimes were tolerated and patients were adherent to treatment. Determined a strong positive correlation between IOP-GAT and IOP-POBFA; verified over time period under particular treatment regime. After 1 year follow-up D/T and latanoprost results referred to statistically significant tachyphylaxis effect, i.e. IOP-GAT increased in 2.31mmHg with D/T (p=0.007) and 2.72 mmHg (p=0.004) with latanoprost and IOP-POBFA increased in 1.74 mmHg (p=0.026) and 3.13 mmHg (p=0.007) respectively. Multiple regression analysis revealed no important blood flow factors as predictors in the increase of IOP. CONCLUSIONS: Strong positive correlation was revealed between IOP-POBFA and IOP-GAT over a time period. Observed tachyphylaxis effects after 1 year under both treatment regimes should be assessed with respect to patient compliance and persistence to treatment. PMID- 23675013 TI - Antemortem diagnosis of new york human rabies case and review of u.s. Cases. AB - To help elucidate rabies disease patterns and control issues, a full assessment of a human case of dog-variant rabies was undertaken. In 2000, a 54-year-old man presented to a New York hospital with lower back discomfort four days after arrival from Africa. Rabies was first suspected 8 days after hospitalization based on clinical signs, specimens were collected on the same day, and rabies infection was confirmed the following day (fluorescence antibody testing on nuchal skin biopsy specimen). By the 12(th) day after illness onset, he was unresponsive, and life support was removed on day 15. Subsequently, an African dog variant was confirmed by nucleic acid sequence analysis of rabies viral RNA extracted and amplified from the patient's saliva. Management of human concerns about exposure to the patient kept the number of persons receiving postexposure prophylaxis to 26. With less than half of the U.S. human rabies cases being diagnosed antemortem, this case emphasizes the need to routinely include rabies in the differential diagnosis of any unexplained encephalitis to ensure early confirmation and triage of human contacts to reduce associated healthcare costs. PMID- 23675014 TI - Integrin-Linked Kinase: It's Role in the Vascular System. AB - Integrin-linked kinase (ILK) is an intracellular molecule that binds to the cytoplasmic domain of beta1 and beta3-integrin. It has been previously demonstrated in various epithelial cell lines to mediate the 'outside-in' signals into the cells and to control the survival of these cells by controlling the phosphorylation of various downstream proteins, such as protein kinase B/Akt (PKB/Akt). We now present in this review the important role of ILK in the vascular system with particular emphasis on its role in endothelial cells (ECs). The results presented here demonstrate that ILK is essential for the proper function, structure and survival of ECs and finally, for the process of neovascularization. PMID- 23675015 TI - Regulating inflammation in the heart. AB - Cardiovascular disease is the leading cause of death in the United States and estimated to be the leading cause of death worldwide by the year 2020. Many pathogens including bacteria, protozoa, and viruses are associated with inflammatory heart disease in patients, and can induce similar disease in animal models. Recognition of pathogens by the innate immune system leads to the release of proinflammatory cytokines that both reduce infection and increase inflammation in the heart. Signaling pathways that will eventually down-regulate cardiac inflammation, such as anti-inflammatory cytokines and regulatory T cells, are also initiated during the innate immune response. A careful balance between activation and regulation of the immune response to infection reduces the severity of inflammation in the heart, the leading cause of cardiovascular diseases such as atherosclerosis, myocarditis and dilated cardiomyopathy. PMID- 23675016 TI - Overlapping of genes in the human genome. AB - Overlapping genes are relatively common in DNA and RNA viruses. There are several examples in bacterial and eukaryotic genomes, but, in general, overlapping genes are quite rare in organisms other than viruses. There have been a few reports of overlapping genes in mammalian genomes. The present study identified all of the overlapping loci and overlapping exons in every chromosome of the human genome using a public database. The total number of overlapping loci on the same and opposite strands was 949 and 743, respectively. Similarly, in every chromosome, the instances in which two loci were located on the same strand was similar to the number of 2 genes observed on opposite strands, except for chromosome 5. The number of 2 exons located on the same strand was higher than that for 2 exons located on opposite strands, indicating the presence of many comprehensive-type overlaps. The mean percentage of overlapping exons on opposite strands in each chromosome was 3.3%, suggesting that parts of the nucleotide sequences of 26,501 exons are used to produce 2 transcribed products from each strand. The ratio of the number of overlapping regions to chromosomal length revealed that, on chromosomes 22, 17 and 19, ratios were high for both types of 2 loci, with exons located on the same and opposite strands. Ratios were low on chromosomes Y, 13 and 18. These results show that all overlapping types are distributed throughout the human genome, but that distributions differ for each chromosome. PMID- 23675017 TI - Kinetic determination of acarbose and miglitol in bulk and pharmaceutical formulations using alkaline potassium permanganate. AB - A simple and sensitive kinetic spectrophotometric method was established for the determination of acarbose and miglitol in bulk and in their pharmaceutical preparations using alkaline potassium permanganate as an oxidizing agent. The method involves determination of acarbose and miglitol by kinetic studies of their oxidation at room temperature for a fixed time of 15 minutes for acarbose and 25 minutes for miglitol. The absorbance of the colored manganate ion was measured at 610 nm. Alternatively, the kinetic decrease in the absorbance of permanganate upon addition of the studied drugs at 525 nm was also used. The absorbance concentration plot was rectilinear over the concentration range of 4 20 and 1-10 MUg/ml for acarbose and miglitol, respectively. The detection limits were 0.189 and 0.089 MUg/ml at 610 nm and 0.081 and 0.179 MUg/ml at 525 nm for acarbose and miglitol respectively. The method was successfully applied for the determination of these drugs in their dosage forms. The results obtained were in good agreement with those obtained with the reference methods. PMID- 23675018 TI - Panretinal-Photocoagulation before Pars Plana Vitrectomy Influences Vitreous Level of Interleukin-6 but not of Vascular Endothelial Growth Factor in Patients with Diabetic Retinopathy. AB - For eyes with diabetic retinopathy which require vitreous surgery and pan-retinal photocoagulation (PRP), pre-treatment of PRP before vitreous surgery reduce the activity of diabetic retinopathy, however sometimes cause macular edema leading to visual disturbance. Some cytokines in the vitreous increase in eyes with diabetic macular edema, thus the relationship between PRP and vitreous cytokines is to be investigated. In this study, 72 eligible eyes of 65 patients were recruited, and 36 eyes had pre-treatment of PRP before vitreous surgery. The other 36 eyes were served as control which had PRP not before but under surgery. There was no statistical significant difference of systemic conditions between two groups. All eyes had pars plana vitrectomy, and 1 ml of vitreous sample was obtained under the surgery. Vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) in the vitreous sample were measured in each case. After the completion of pre-treatment of PRP, macular edema defined as increase of foveal thickness was prominently worsened, and the vitreous level of IL-6 in PRP pre treated group showed statistically higher than that in control. In contrast, there was no significant difference of VEGF level between two groups. While, vitreous level of VEGF in control group was strongly correlated with grade of retinopathy and duration of diabetes. In conclusion, PRP influenced vitreous level of IL-6 but not VEGF, leading to macular edema, which suggests that IL-6 plays critical roles of PRP induced macular edema. PMID- 23675019 TI - Urotensin-II Immunoreactivity in Normolipidemic and Hyperlipidemic New Zealand White Rabbits Following Balloon Angioplasty and Stenting. AB - Treatment for symptomatic atherosclerosis is being carried out by balloon mediated angioplasty, with or without stent implantation, more and more frequently. Although advances with the development of drug eluting stents have improved prognosis, restenosis is still the most limiting factor for this treatment modality. Urotensin-II (UII), a small pleiotropic vasoactive peptide is increasingly being recognized as a contributory factor in cardiovascular diseases. We qualitatively evaluated UII immunoreactivity (IR) in three models of balloon angioplasty mediated restenosis. Specifically, we performed balloon angioplasty in the ilio-femoral arteries of New Zealand White Rabbits (NZWR) fed either a normal chow or high fat diet. In addition, UIIIR was also assessed in stent implanted abdominal aortae of NZWR fed a high fat diet. UII was constitutively expressed in the endothelium of all arterial segments evaluated. Abundant expression of UII was associated with lesion progression, particularly in myointimal cells, and less so in medial smooth muscle cells (SMC). The strongest UII-IR was observed in foam cells of animals fed a high fat diet. We demonstrate abundant expression of UII in regenerating endothelial cells and myointimal cells in vascular lesions following balloon mediated angioplasty and stent implantation in both animals fed a normal chow and high fat diet. PMID- 23675020 TI - Expression of Retinoic Acid Receptor (RAR) alpha Protein in the Synovial Membrane from Patients with Osteoarthritis and Rheumatoid Arthritis. AB - Retinoic acid receptors (RAR) are expressed in inflammatory cells and, through ligand binding, play an important role in cell proliferation and differentiation, as well as in regulation of cytokine and matrix metalloproteinase (MMP) production. Inflammatory cytokines and MMPs play a significant role in cartilage destruction in osteoarthritis (OA) and in joint destruction in rheumatoid arthritis (RA), the prototype of inflammatory arthritis. To determine if RARalpha is expressed in the synovial membrane (SM) of patients with OA and compare it with RA, SM biopsy samples were used in this study which were from 31 patients with late OA and 14 patients with late RA. Cryostat sections were studied by immunochemistry using a RARalpha-specific antibody. All SM samples from OA and RA patients exhibited cellular localization for RARalpha. Immunoreactivity was present in mononuclear inflammatory cells, endothelial cells, synovial lining cells, and fibroblasts. Inflammatory infiltrates were interstitial and nodular. Roughly one half of mononuclear cells in the inflammatory nodules in OA and RA were positive for RARalpha. The conclusion is that the presence of RARalpha in SM of patients with OA and RA suggests that RARs may play a role in the immunomodulation of synovial inflammation and therefore can be a potential target of therapeutic intervention in these arthritides. PMID- 23675021 TI - Spectrophotometric Determination of Diazepam in Pure form, Tablets and Ampoules. AB - The interaction of diazepam with picric acid (I), 3,5-dinitrobenzoic acid (II) and 2,4-dinitrobenzoic acid (III) was found to be useful for its spectrophotometric determination. The quantitation was carried out at 475, 500, and 500 nm for the reaction with (I), (II) and (III), respectively. The effect of several variables on the coloring process was studied. The proposed methods have been applied successfully for the determination of diazepam in pure samples and in its pharmaceutical preparations with good accuracy and precision. The results were compared to those obtained by the pharmacopoeial methods. The linear ranges for obedience of Beer's law are up to 85.6, 180.2, and 128.6 ug/ml, Ringbom ranges are 10.0-79.0, 15.2-177.8, 17.0-83.0 ug/ml, and RSD 0.048, 0.028, and 0.026% for reaction of diazepam with I, II, and III, respectively. PMID- 23675023 TI - Synthesis and antitumor activity of substituted succinamides using a potato disc tumor induction assay. AB - In view of potential biological activities of some succinic acid derivatives, we synthesized some novel N-[4-(4-morpholinosulfonyl)-phenyl]-succinamides (6a, c; 7a, c) and N-[4-(benzylaminosulfonyl) phenyl]-succinamides (6b, d; 7b, d) derivatives as antitumor agents. The antitumor activity of compounds was studied using the potato disk bioassay technique. Vincristine at 0.25 mg/ml was employed as positive control and caused -67.24% inhibitions. Compound 7b at 1 mg/ml caused -80.50% tumor inhibitions with highest activity among compounds tested. PMID- 23675022 TI - Argon laser: a modality of treatment for trichiasis. AB - The purpose of this study is to evaluate the success rate and safety of argon laser photocoagulation as a modality of treatment for symptomatic trichiasis in a Middle Eastern country (Jordan). This simple descriptive study included 54 patients (68 lids) with symptomatic trichiasis. They were treated with argon laser and followed over 8 month period. After topical and infiltration anaesthesia, 30-40 shots of blue-argon laser were directed to the lash root to a depth of 2-3mm. Laser beam variables were: 50-100 MUm spot size, 0.3 second duration and 0.50 Watt power. The maximum number of treated lashes per lid was five. Recurrence was defined as regrowth of one or more trichiatic lash. Up to two additional applications with the same laser parameters were done for recurrent trichiasis. The success rate after one treatment session was 61.1% and with up to a total of three sessions, it was 85.2%. The complication rate was 20.6% (14 lids) in the form of mild hypopigmentation in 8 lids and notching in 6 lids. The complication rate was higher among patients treated previously with cryotheray or lid surgery. Argon laser photocoagulation is a safe and effective office procedure for treatment of symptomatic trichiasis. PMID- 23675024 TI - Kinetic determination of ribavirin in drug formulations. AB - Two simple and sensitive kinetic methods were developed for the determination of ribavirin in bulk and in its pharmaceutical preparations using alkaline potassium permanganate as an oxidizing agent. The methods are based upon a kinetic investigation of the oxidation reaction of the drug at room temperature for fixed times of 20 and 30 minutes. In the first method, the absorbance of the colored manganate ion was measured at 610 nm, while in second method the reduction in the absorbance of permanganate was measured at 525 nm. The absorbance concentration plots were linear over the range of 3-15 MUg/ml with detection limits of 0.028 MUg/ml in the first method and 0.229 MUg/ml for the second method. The proposed methods were applied successfully for the determination of the drug in its pharmaceutical formulations, the percentage recoveries were 100.15 +/- 1.34, 100.06 +/- 0.86 in the first method, and 99.60 +/- 0.54, 100.43 +/- 0.82 in the second method. The results obtained were compared statistically with those obtained by the official method and showed no significant differences regarding accuracy and precision. PMID- 23675025 TI - Identification of HPV-16 in Borderline Mucinous Cystic Neoplasm of Pancreas. AB - Pancreatic mucinous cystic neoplasms (PMCN) predominantly affect women in the reproductive age, are located in the body and tail of the pancreas, and share morphological features with similar tumors of the ovary. We report the detection of human papillomavirus (HPV) using several different PCR protocols in a borderline PMCN from a female patient. Type-specific PCR demonstrated the HPV to be type 16. If confirmed by others, this group of neoplasms might become preventable by HPV vaccination. PMID- 23675026 TI - The immune properties of mesenchymal stem cells. AB - The goal of this review is to summarize current knowledge on the immune properties of mesenchymal stem cells (MSCs) and to discuss how these properties might affect clinical applications, in particular tissue regeneration. Mesenchymal Stem Cells (MSCs) are pluripotent cells with unique immune properties. They show immunoenhancing as well as immunosuppressive properties. It is the latter property that makes them stem cells of interest by scientists since they could be ideal for tissue regeneration, across allogeneic barrier. MSCs can transdifferentiate and differentiate into specialized cells. Although found mostly in the adult bone marrow, MSCs also reside in a variety of fetal tissues. In the adult bone marrow they act as "gatekeeper" cells regulating traffic in and out to the peripheral circulation and lymphatics. Their location within the vicinity of the bone marrow and periphery allows the MSCs, through their immune suppressor ability and antigen presenting property (APC) to maintain homeostasis in bone marrow function. There is potential for clinical therapy with MSCs. They have the potential to facilitate bone marrow transplantation by reducing graft versus-host disease (GVHD). In addition, their immunosuppressive properties show promise for cell therapy across allogeneic barrier. Their role in the bone marrow, as it relates to hematological disorder is discussed. PMID- 23675027 TI - Using discounting biases, risk characteristics, and perceived control improves preventive programs. AB - Health promotion often works toward remote goals with a trade-off between costs today and benefits in the future. However, for individuals using a positive discount rate for health outcomes a healthy state many years ahead has such a small value that it is difficult to motivate them to engage in preventive behaviors. The framework of time and risk for analysis can perform a useful role in health education and information where the framing of different features of risk might diminish discounting and increase motivation to change behavior. Personal versus general risk and perceived control related to preventive programs are discussed. A summary of valuation factors in preventive programs based on literature review is presented: (a) long-term decisions are sensitive to discount rates; (b) discount rates vary by level of uncertainty, individuals, and contexts; (c) personal risks from adverse health behaviors are judged as smaller than the same risks for people in general; (d) probability discounting is used, if the risk is perceived as controllable; (e) people's tendency to discount future consequences might be suppressed by lowering the amount of perceived control. PMID- 23675028 TI - Dual Role of CXCL10 as Conductor of Cellular Trafficking during Type 1 Diabetes. AB - One possible way of how autoimmune disease can be initiated is by infection with a foreign pathogen. Especially viruses are thought to act as triggering factors, inducing a detrimental attack against 'self' by the immune system of a susceptible host because of two major reasons. First, viruses cause a massive inflammation of the infected tissue and therefore initiate the infiltration of a broad variety of leukocytes, including potentially 'self'-reactive lymphocytes. Second, some viruses have been demonstrated to bear molecules with a strong structural similarity to host components. The existence of such a 'molecular mimicry' may elicit an immune response, which is initially generated in defense against the invading pathogen but in a second wave targets similar structures of the host. In the present review we will reflect on the dual role of inflammatory factors during this process and discuss possibilities of how such a detrimental second wave of the immune system can be blocked. Most of the presented data have been obtained from animal models that integrate the concept of molecular mimicry. They use transgenic mice expressing a defined model protein specifically in a target tissue and a virus containing either an identical or a similar protein as a triggering factor. PMID- 23675029 TI - Sildenafil inhibits the proliferation of cultured human endothelial cells. AB - The proliferation of endothelial cells plays a crucial role in the development of intraplaque angiogenesis (IPA). IPA is a major source of intraplaque hemorrhage and therefore contributes to the destabilization of atherosclerotic plaques. Therefore, the aim of the present study was to examine, whether sildenafil inhibits endothelial cell growth. The proliferation of human endothelial cells derived from umbilical cord veins (HUVEC) was examined on DNA level by measurements of ((3)H)-thymidine incorporation. Cell viability was analyzed using trypan blue staining. The proliferation of cultured human endothelial cells was significantly decreased by 1 MUmol/l (-48.4%) and 10 MUmol/l (-89.6%) sildenafil (n=10, p<0.05). This was not a cytotoxic effect, because cell viability was only reduced at sildenafil concentrations of 50 MUmol/l or greater. In addition sildenafil significantly reduced endothelial proliferation induced by bFGF (n=10, p<0.05). The presented results demonstrate an antiangiogenic effect of sildenafil that might be useful in the prevention of atherosclerotic plaque vascularization. PMID- 23675030 TI - EMRSA-15 Bacteremia is not Associated with a Worse Outcome Compared with Bacteremia Caused by Multidrug-Resistant MRSA. AB - EMRSA-15 (ST22-MRSA-IV) is rapidly replacing the endemic ST239 health care associated methicillin-resistant Staphylococcus aureus clone in Singapore. A one year single-centre cohort study of inpatients with MRSA bacteremia was performed to determine if bacteremia caused by EMRSA-15 was associated with worse outcomes compared to bacteremia caused by the endemic ST239 strain. Strains were identified by antibiotypes, and subsequent validation was performed on a selected sample of MRSA strains via pulsed-field gel electrophoresis and staphylococcal chromosome cassette mec typing. Two hundred and twenty-eight patients with MRSA bacteremia were studied; Seventy-three were infected with EMRSA-15. EMRSA-15 and ST239-infected patients were similar regarding gender, frequencies of most co morbidities, and risk factors for adverse outcomes. Similar numbers of EMRSA-15 infected and ST239-infected patients died (24.7% vs 27.1%, P=0.70) or developed complicated infections (41.1% vs 40.0%, P=0.88). After multivariate analysis, EMRSA-15 as a cause of bacteremia was not significantly associated with either death or development of complicated infections, although inappropriate therapy (5.45-fold, P<0.01) and a respiratory source of bacteremia (4.69, P<0.01) were independently associated with subsequent mortality. The increased propensity of EMRSA-15 for dissemination was not associated with increased virulence in our patients. Further work in determining the mechanisms by which highly transmissible MRSA spreads rapidly is required to better target infection control approaches at these important emerging MRSA clones. PMID- 23675031 TI - Suramin increased telomerase activity in the c6 glioma/wistar experimental brain tumor model. AB - Glioblastoma multiforme (GBM) is the most treatment-resistant glioma variant. Significant roles for telomerase in etiology, recurrence and drug resistance of GBM have been highlighted. Suramin (Bayer, Leverkusen, Germany) is an antineoplastic agent that affects many cellular mechanisms including growth factor, purinergic receptor, cytokine and key cellular enzymes signaling. The aim of this study was to investigate whether suramin, 40 mg/kg, i.p., inhibits telomerase activity in a subcutaneous C6 glioma/Wistar experimental brain tumor model using PCR based telomeric repeat amplification assay. In comparison to the control group, suramin increased tumor volume and telomerase activity. We also used transmission electron microscopy to evaluate the alterations of cell morphology. Apoptosis was seen markedly in electron micrographs of the control group and anti-apoptotic activity of telomerase was verified in the electron micrographs of suramin-applied group. The in vitro inhibitory effects of suramin on telomerase activity in several cell lines except for brain tumors have been reported. Contrary to in vitro reports, our results were the first to demonstrate that suramin increased telomerase activity in a C6 glioma/Wistar experimental brain tumor. Large numbers of drugs exhibited apparent hormetic effects on cultured cancer cells and in vivo cancer growth. Several drug examples for their hormetic effects in vivo were listed as resveratrol, suramin, and tamoxifen. The action of suramin in the present study could be evaluated as one of the hormetic examples of suramin in vivo. PMID- 23675032 TI - Antibacterial activity of synthetic precursors of podophyllotoxin. AB - Precursors of podophyllotoxin were synthesized and screened for their antibacterial activity. The results proved that ethyl-2-(3'-methyl-4' methoxybenzoyl)-3-(4" methoxyphenol)-cyclopropane-1-carboxylic acid and Ethyl-2 (3'-methyl-4'-methoxybenzyol-3-1 3", 4"-dimethoxyphenyl)-cyclopropane-carboxylic acid have significant antibacterial activity against Citrobacter sp., Escherchia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella typhi, Shigella sonnei and Streptococcus faecalis. The activity is lower than Ciprofloxacin and equal to Gentamicin and more than Penicillin and Streptomycin. PMID- 23675033 TI - Medial Expression of TNF-alpha and TNF Receptors Precedes the Development of Atherosclerotic Lesions in Apolipoprotein E/LDL Receptor Double Knockout Mice. AB - TNF-alpha is present in atherosclerotic lesions, activates endothelial adhesion molecule expression, stimulates the release of proinflammatory cytokines and matrix metalloproteinases and promotes smooth muscle cell proliferation and migration. Taken together these observations suggest that TNF-alpha may be functionally involved in early atherosclerosis development. To further evaluate this hypothesis we compared vascular TNF-alpha and TNF receptor expression in atherosclerosis-susceptible apoE(-/-)/LDL receptor(-/-) mice and control C57BL/6 mice. The aortas of 8 week old apoE(-/-)/LDLreceptor(-/-) mice displayed immunoreactivity for TNF-alpha as well as TNF p55 and p75 receptors (2.1 +/- 1.6%, 5.6 +/- 1.5% and 3.6 +/- 1.3% of total media area, respectively), but did not have any detectable lesions. A marginal increase in TNF-alpha and TNF receptor immunoreactivity was observed at 12 weeks and atherosclerotic plaques were detected in 1 out of 5 animals. At 16 weeks TNF-alpha expression in the media was increased more than four-fold as compared with 8 week old mice, and atherosclerosis was widespread. TNF-alpha immunoreactivity was also observed in all plaques. In addition, at the same age a tendency towards increased TNF-alpha mRNA levels was detected in the double knockout mice compared to age-matched controls. A further increase in TNF-alpha and TNF receptor immunoreactivity as well as plaque size was observed at 20 weeks. With only a few exceptions, no TNF alpha or TNF receptor immunoreactivity was detected in C57BL/6 control mice. These findings demonstrate that medial TNF-alpha and TNF receptor expression precedes lesion formation in apoE(-/-)/LDL receptor(-/-) mice. PMID- 23675034 TI - Sensitive indirect spectrophotometric method for determination of h2-receptor antagonists in pharmaceutical formulations. AB - A simple, accurate and sensitive spectrophotometric method has been developed and validated for determination of H2-receptor antagonists: cimetidine, famotidine, nizatidine, and ranitidine hydrochloride. The method was based on the oxidation of these drugs with cerium (IV) in presence of perchloric acid and subsequent measurement of the excess Ce (IV) by its reaction with p dimethylaminocinnamaldehyde to give a red colored product (lambdamax at 464 nm). The decrease in the absorption intensity (DeltaA) of the colored product, due to the presence of the drug was correlated with its concentration in the sample solution. Different variables affecting the reaction were carefully studied and optimized. Under the optimum conditions, linear relationships with good correlation coefficients (0.9985-0.9994) were found between DeltaA values and the concentrations of the drugs in a concentration range of 1-16 ug ml(-1). The assay limits of detection and quantitation were 0.12-0.44 and 0.37-1.33 ug ml(-1), respectively. The method was validated, in terms of accuracy, precision, ruggedness, and robustness; the results were satisfactory. The proposed method was successfully applied to the analysis of the investigated drugs in their pure and pharmaceutical dosage forms (recovery was 98.8-102.5 +/- 0.79-1.72%) without interference from the common excipients. The results obtained by the proposed method were comparable with those obtained by the official methods. PMID- 23675035 TI - Sensitive assay for carvedilol in tablets and spiked human plasma using a flow injection chemiluminometric method. AB - A simple and sensitive chemiluminometric method using flow injection (FI) is developed for the determination of carvedilol, based on the reaction of carvedilol with tris (2, 2'-bipyridyl) ruthenium (II), and KMnO4 in sulfuric acid medium. Under the optimum conditions; the chemiluminescence (CL) intensity is a linear function of carvedilol concentration over the range of 0.04-1.0 ug ml(-1) (9.8 * 10(-8) - 2.5 * 10(-6) mol L(-1)) with a detection limit (S/N=3) of 0.025 ugml(-1) (6.2 * 10(-8) mol L(-1)). The relative standard deviation of the proposed method calculated from 10 replicate injections of 0.4 ug ml(-1) carvedilol is 0.95%. The sample throughput is 90 samples h(-1). The method is applied successfully to the determination of carvedilol in tablets dosage form and spiked human plasma. PMID- 23675036 TI - Biological and Molecular Properties of Dengue 2 Strains Isolated during the DHF/DSS Cuban Epidemic, 1981. AB - To study some biological and molecular properties of nine DENV-2 strains isolated during the 1981 Cuban epidemic, temperature sensitivity, viral plaque size, the kinetic of virus replication in newborn mice inoculated by intracerebral route, the influence of pH medium on virus-cell attachment phase and the restriction enzyme pattern were studied. Strains were classified in two patterns according to temperature sensitivity, plaque size, and virus replication in mouse brain and cell culture and restriction enzymatic pattern the changes observed differentiate clearly the strains isolated at the beginning and at the end of the epidemic suggesting that viruses with different characteristics circulated. PMID- 23675037 TI - Clinical features and laboratory diagnosis of infection with the potential bioterrorism agents burkholderia mallei and burkholderia pseudomallei. AB - Burkholderia mallei and Burkholderia pseudomallei are the causative organisms of Glanders and Melioidosis, respectively. Although now rare in Western countries, both organisms have recently gained much interest because of their unique potential as bioterrorism agents. These organisms are less familiar to medical and laboratory personnel than other select bioterrorism bacterial agents and thus heightened awareness of Glanders and Melioidosis is crucial in order to enable adequate emergency preparedness and response to deliberate release of B. mallei and B. pseudomallei. The microbiological diagnosis of both species in the clinical laboratory is complicated. This paper reviews the various challenges and pitfalls associated with the diagnosis of Melioidosis and Glanders in the clinical setting, with emphasis on the role of sentinel laboratories. PMID- 23675038 TI - Recent progress in therapeutic angiogenesis. AB - Coronary artery disease and peripheral arterial disease are devastating status of acute vessel occlusion in diseased vessels that are already narrowed enough by atherosclerotic process. People are now focused on therapeutic angiogenesis against the ischemic diseases, to supply and growth of new vessels into the ischemic tissue. Recently, we and others performed autologous transplantation of bone marrow mononuclear cell or endothelial progenitor cell and gene therapy using hepatocyte growth factor (HGF) in clinical trials. Autologous implantation of bone marrow mononuclear cells or endothelial progenitor cells in ischemic limb or heart may induce blood flow and improve function in several pilot clinical studies. The regenerative potential of bone-marrow cells can be explained by any of four mechanisms, transdiffentiaion, cytokine-induced growth, stimulation of endogenous stem cells, and induction of cell fusion. Transdifferentiaion has been described by previous investigators and the concept has been called into question by recent experimental studies. In the pilot clinical study, similar improvements were seen in gene therapy using HGF in peripheral arterial diseases which might be more noninvasive. The clinical significance of the novel therapeutic approach might embrace the large number of patients with peripheral arterial diseases and with chronic coronary artery disease. And we need to figure out the strong angiogenic factor or specific differentiated progenitor cells for therapeutic angiogenesis in the study of bone marrow cell therapy. For the patients, we need to constitute a safe and effective strategy for achievement of therapeutic angiogenesis. PMID- 23675039 TI - Role of monocyte chemoattractant protein-1 in myocardial infarction. AB - Myocardial infarction (MI) is accompanied by inflammatory responses that lead to the recruitment of leukocytes and subsequent myocardial damage, healing, and scar formation. Chemokines are a family of potent chemoattractant cytokines that regulate the leukocyte trafficking in basal levels and inflammatory processes; however, it has been recently recognized that chemokines are expressed by non hematopoietic cells such as endothelial cells, smooth muscle cells, and cardiomyocytes, and their function extends far beyond leukocyte migration and activation. Many experimental and clinical studies have demonstrated that chemokines play an important role in the pathophysiology of MI. In particular, the CC chemokine - monocyte chemoattractant protein-1 (MCP-1/CCL2) - is one of the most frequently investigated, and it is believed to play an important role in the pathophysiology of MI. This review will focus on the role of MCP-1 in the pathophysiology of MI and discuss its potential as a therapeutic target in this condition. PMID- 23675040 TI - Thrombophilias and pregnancy complications: a case-control study. AB - Inherited thrombophilia is believed to be a multiple gene disease with more than one defect. We wanted to determine the association between single thrombophilic patterns and a variety of pregnancy diseases. 301 pregnant women were recruited for the present case-control study and were divided into two groups: A group (176 controls) and B group (125 cases). Patients belonging to the B group had one of the following: severe preeclampsia, HELLP syndrome, gestational hypertension, fetal growth restriction (FGR), intrauterine death, abruptio placentae, placenta previa, disseminated intravascular coagulopathy (DIC) and preterm labour. To detect MTHFR A1298C, MTHFR C677T, Factor V Leiden, PAI-1, Mutant Prothrombin G20210A, an inverse hybridization technology was used. Plasma homocysteine, Antithrombin III and protein levels S were determined. A modified functional activated protein C resistance was assayed. MTHFR C677T and hyperhomocysteinemia were more numerous than other thrombophilias. Deficiency in AT III was significantly linked with preeclampsia (Pearson Index and p value: 0.131 and 0.022, respectively) and disseminated intravascular coagulopathy (Pearson Index and p value: 0.138 and 0.016 respectively). Activated Protein C resistance was related to abruptio placentae (Pearson Index and p value: 0.159 and 0.005 respectively). Apart from the linkage between AT III deficiency and the occurrence of preeclampsia and disseminated intravascular coagulopathy, we obtained findings in contrast to some literature. In our case series, no association of preeclampsia with Factor V Leiden or with prothrombin gene mutation was found. PMID- 23675041 TI - Celecoxib Enhances the Chemotherapeutic Response of Cisplatin and TNF-alpha in SiHa Cells through Reactive Oxygen Species-Mediated Mitochondrial Pathway. AB - Recently, many studies have shown that celecoxib induces apoptosis in various cancer cells by different mechanisms depending on the cell type. This study examined the effect of the selective COX-2 inhibitor celecoxib on cisplatin and TNF-alpha cytotoxicity and studied the role of mitochondria in the induction of apoptosis in the human cervical carcinoma SiHa cells. Apoptosis was detected by flow cytometry. The protein expression of Bcl-2, Bcl-XL, Bax, cytochrome c and AIF was analyzed by Western Blotting. The mRNA level of anti-oxidant enzymes was quantitated by RT-PCR. Priming SiHa cells with celecoxib increased the cisplatin induced apoptosis by 20.56% and priming with celecoxib increased the TNF-alpha induced apoptosis by 22.07%. This was accompanied by downregulation of Bcl-XL and Bcl-2 and upregulation of Bax. Cytosolic cytochrome c increased by 43.0% with celecoxib and TNF-alpha treatment but was not significant with celecoxib and cisplatin treatment. Nuclear AIF increased by 21.0% with celecoxib and cisplatin treatment whereas it was not significant with celecoxib and TNF-alpha treatment. The mRNA level of Mn-Superoxide dismutase, CuZn-Superoxide dismutase, Glutathione peroxidase and Catalase decreased significantly on priming with celecoxib and then treating with cisplatin or TNF-alpha. There was no significant increase in the activity of caspase-3 with either celecoxib or TNF-alpha treatment or with celecoxib and cisplatin treatment. The findings suggest that priming with celecoxib induces the TNF-alpha and cisplatin-mediated apoptosis in SiHa cells perhaps through ROS-mediated mitochondrial pathway. PMID- 23675042 TI - Antibodies against M. Bovis 65 KDa Heat Shock Protein and Its P180-188 Epitope in Sera of Patients with Juvenile Idiopathic Arthritis. AB - We screened the levels of antibodies to M. bovis hsp65 and the 180-188 epitope by using ELISA in a cohort of 72 juvenile idiopathic arthritis (JIA) patients and 38 healthy controls. We analysed an association between antibody levels and rheumatoid factor, antinuclear antibodies, human leukocyte antigen B27 and the severity and the duration of the disease. The majority of anti-hsp65 antibodies in a cohort of JIA patients were of the IgG isotype (54.2%) with IgM (13.9%) antibodies increased to a lesser degree. IgG antibodies to M. bovis hsp65 (P<0.001) and the 180-188 epitope (P<0.001) were significantly increased in all of three disease onset types when compared with healthy controls. The highest levels of IgG antibodies to M. bovis hsp65 and its P180-188 epitope were observed in oligoarthritis and in patients with no X-ray changes and functional limitation, while the lowest antibody levels were detected in patients with the most severe stage of articular damage. When antibody levels to M. bovis hsp65 and the 180-188 epitope were examined within patient and control populations, significantly higher levels of IgG and IgM antibodies to M. bovis hsp65 were observed in both JIA (P<0.001) and healthy control (P<0.001) cohorts. These findings may suggest that the high levels of IgG antibodies to M. bovis hsp65 and its P180-188 epitope would reflect the least serious cases of JIA. Since IgM antibodies to M. bovis hsp65 and P180-188 M. bovis hsp65 epitope exceeded the control level in a few patients with JIA we believe they are not of concern. PMID- 23675043 TI - Evaluation of cytotoxic potential of newly synthesized antiviral aminopyrazoloquinoline derivatives. AB - In the present study, we screened newly synthesized antiviral aminopyrazoloquinoline derivatives for cytotoxic potential in human normal and breast cancer cell lines using apoptosis as biomarker. These derivatives and the well known antiviral drug, acyclovir, were incubated with the normal (MCF-10A, MCF-12A) and cancer (MCF-7, MDA-MB-231) cell lines at 10, 50 and 100 MUM for 72 h at 37 degrees C. Both the parent compounds and their sugar derivatives were found to be differentially cytotoxic in various cell lines. MCF-7 cells were more or less completely resistant to all these compounds while MDA-MB-231 cells were significantly killed by apoptosis. The methoxy derivative of aminopyrazoloquinoline (compound 3) was found to be the most cytotoxic in the normal breast epithelial cell lines (MCF-10A and MCF-12A) and MDA-MB-231 cell lines at 100 MUM killing over 90% of the cells with up to 80% apoptosis. Interestingly MCF-7 cells showed only up to 50% killing at 100 MUM dose with less than 20% apoptosis. Acyclovir did not cause any cytotoxicity, apoptosis or cell cycle arrest in any of the cells lines at the doses tested. Our results suggest that the newly synthesized antiviral compounds have an associated risk of being cytotoxic compared to the acyclovir. PMID- 23675044 TI - Advanced antigen delivery of murine survivin: chimeric virus-like particles in cancer vaccine research. AB - Success in cancer immunotherapy depends on the identification and efficient targeting of specific tumor-associated antigens. Two pivotal strategies to prime patients' immune system against malignant cells are tumor-specific adoptive T cell therapy and tumor-specific vaccination. Here, we will focus on immunotherapeutic vaccination and discuss the advantages and disadvantages of different strategies to deliver tumor-specific T-cell epitopes. A particular focus will be put on virus-like particles (VLPs) as vehicle to deliver tumor specific epitopes in the context of full-length proteins, as multi-epitope constructs or as individual tumor-associated T-cell epitopes. VLPs represent non infectious and non-replicating antigen delivery systems devoid of any nucleic acid. They constitute innovative immunotherapeutic agents against cancer due to their superior, adjuvant-like antigenicity. We will present various tumor associated antigens currently in different stages of development including survivin, as promising candidates for targeted tumor therapies. PMID- 23675045 TI - Heterogeneity of 3'-Untraslated Region of Genome RNA of the Tick-Borne Encephalitis Virus (TBEV) Strains Isolated from Ticks in the Western Siberia, Russia. AB - The tick-borne encephalitis virus (TBEV) strains have been isolated from unfed adult ticks Ixodes persulcatus Schulze in Novosibirsk region (South-Western Siberia, Russia) beginning from 1980 till 2006. The TBEV 3'-untraslated region (3'UTR) variable fragment was amplified with primers corresponding to conserved flanking areas. The RT-PCR product lengths varied in range from 100 to 400 bp. Comparative analysis of 3'UTR nucleotide sequences revealed a few groups of the TBEV strains within Siberian genetic subtype with significant intra-group homology and essential differences between groups. Correlation between lengths of the 3'UTR fragments and hemagglutination (HA) titers for subsequent passages of the TBEV strains was not found. However, for the viral strains with shorter 3'UTR (less than 200 nucleotides) incubation period for suckling mice was longer than 5 days. It might be resulted from decreased RNA synthesis or reduced neuroinvasiveness. PMID- 23675046 TI - An investigation on the solid dispersions of chlordiazepoxide. AB - The aim of this study was to prepare solid dispersions of chlordiazepoxide techniques to improve its dissolution rate. To this end, three techniques namely, two solvent methods and co-grinding technique were used. Solid dispersions of chlordiazepoxide in polyvinylpyrrolidone (PVP), Eudragit E100, Mannitol and Sorbitol with two different ratios of drug to carrier (5:5 and 1:9) were prepared. These solid dispersions were evaluated using dissolution tester to monitor dissolution behaviour and Fourier-transform infrared spectroscopy to investigate interaction between the drug and carriers in solid dispersion samples. Solid dispersion of chlordiazepoxide with all three carriers (PVP, mannitol and eudragit E) prepared by solvent method showed considerable increase in the dissolution rate of chlordiazepoxide in comparison with physical mixture and pure drug at different pH values. According to the results of this investigation cogrinding technique yields solid dispersions with a less improved dissolution rate than does the solvent deposition technique. Infrared studies showed no interaction between chlordiazepoxide and carriers in solid dispersions in solid state. PMID- 23675047 TI - Genetic studies of bone diseases: evidence for involvement of DNA damage response proteins in bone remodeling. AB - Bone remodeling is carried out by bone marrow mesenchymal stem cell derived osteoblasts, which form the bones, and hematopoeitic stem cell derived osteoclasts, which absorb the bones. Their actions are coordinated in two ways: osteoblasts and their precursors synthesize and secrete cytokines such as RANKL and M-CSF to regulate osteoclastogenesis; bone resorption releases matrix associated TGF-beta and BMPs to stimulate bone formation at the same sites. Recent studies on transgenic mouse models revealed that several proteins involved in the DNA damage response play important roles in bone remodeling. DNA damage response is triggered by double stranded DNA breaks, single stranded DNA breaks as well as other types of lesions, which recruit and activate Ser/Thr kinases such as Atm to the damaged sites, where Atm activates p53 to promote apoptosis, cell cycle arrest, and DNA repair. Atm also activates c-Abl, a non-receptor tyrosine kinase, to promote apoptosis. Studies from our and other laboratories have shown that c-Abl and Atm positively regulate osteoblast differentiation and bone formation and mice deficient for either of them show osteoporosis, whereas p53 negatively regulates osteoblast proliferation/differentiation and bone formation and the knockout mouse shows osteosclerosis. These three proteins have osteoblast autonomous effect without directly affecting osteoclast differentiation or resorption activity. Furthermore, they appear to regulate osteoblast differentiation through controlling the expression of osterix, an osteoblast specific transcription factor essential for osteoblast differentiation. These results establish a functional link between osteoblast differentiation and DNA damage response. PMID- 23675048 TI - Identification of biomarkers for type 2 diabetes and its complications: a bioinformatic approach. AB - The long asymptomatic period before the onset of chronic diseases presents opportunities for disease prevention. Many chronic diseases like type 2 diabetes and its complications may be preventable by avoiding factors that trigger the disease process (primary prevention) or by use of therapies that modulate the disease process before the onset of clinical symptoms (secondary prevention). Accurate prediction and identification using biomarkers will be useful for disease prevention and initiation of proactive therapies to those individuals who are most likely to develop the disease. Recent technological advances in genetics, genomics, proteomics, and bioinformatics offer great opportunities for biomarker discovery. In this review, type 2 diabetes and its complications are used as examples discuss pertinent issues related to high throughput biomarker discovery using bioinformatic pathways. PMID- 23675050 TI - From folklore to scientific evidence: breast-feeding and wet-nursing in islam and the case of non-puerperal lactation. AB - Breast-feeding practice has an important medical and socio-cultural role. It has many anthropological aspects concerning the "power structures" that find their expression in breast-feeding and the practices that formed around it, both socially, scientifically, and legally-speaking. Breast-feeding has been given much attention by religions and taboos, folklore, and misconception abound around it making it a topic of genuine curiosity. This paper aims at expanding the spectrum of folklore associated with breast-feeding. The paper deals with historical, religious, and folkloristic aspects of breast-feeding, especially wet nursing, in Islam and focuses on an intriguing Islamic tale on breast-feeding - lactation by non-pregnant women (or non-puerperal lactation). Apparently, accounts of non-puerperal lactation are not restricted to Islam but have been documented in various societies and religions throughout centuries. Two medical situations - hyperprolactinemia and induced lactation, appear as possible explanations for this phenomenon. This serves as an excellent example for the value of utilizing contemporary scientific knowledge in order to elucidate the origin, anthropology and evolvement of ancient myth and superstition. PMID- 23675051 TI - Photodynamic Therapy of the Murine LM3 Tumor Using Meso-Tetra (4-N,N,N Trimethylanilinium) Porphine. AB - Photodynamic therapy (PDT) of cancer is based on the cytotoxicity induced by a photosensitizer in the presence of oxygen and visible light, resulting in cell death and tumor regression. This work describes the response of the murine LM3 tumor to PDT using meso-tetra (4-N,N,N-trimethylanilinium) porphine (TMAP). BALB/c mice with intradermal LM3 tumors were subjected to intravenous injection of TMAP (4 mg/kg) followed 24 h later by blue-red light irradiation (lambdamax: 419, 457, 650 nm) for 60 min (total dose: 290 J/cm(2)) on depilated and glycerol covered skin over the tumor of anesthetized animals. Control (drug alone, light alone) and PDT treatments (drug + light) were performed once and repeated 48 h later. No significant differences were found between untreated tumors and tumors only treated with TMAP or light. PDT-treated tumors showed almost total but transitory tumor regression (from 3 mm to less than 1 mm) in 8/9 animals, whereas no regression was found in 1/9. PDT response was heterogeneous and each tumor showed different regression and growth delay. The survival of PDT-treated animals was significantly higher than that of TMAP and light controls, showing a lower number of lung metastasis but increased tumor-draining lymph node metastasis. Repeated treatment and reduction of tissue light scattering by glycerol could be useful approaches in studies on PDT of cancer. PMID- 23675049 TI - Post-operative capsular opacification: a review. AB - Post-operative capsular opacification is a multifactorial physiological consequence of cataract surgery. Opacification involving the central posterior capsule has a significant impact on high and low contrast acuity and low contrast sensitivity. The assessment of Posterior Capsule Opacification (PCO) on cadaver eyes, experimental studies, culture models and in clinical studies has provided an understanding of its pathogenesis. The proliferation, migration and abnormal differentiation of residual lens epithelial cells and fibers in the capsular bag have been implicated in the pathogenesis of PCO. The incidence and severity of PCO correlates to the meticulous use of surgical techniques, IOL optic edge designs and IOL materials. This article summarizes the clinical studies with recommendations for retarding the development of central PCO. It discusses experiments with pharmacological agents broadly categorized as anti-inflammatory, immuno-modulating, antiproliferative, antiadhering, antitransdifferentiating agents for the prevention of PCO. These studies will remain critical for future endeavors undertaken for eradication of PCO. PMID- 23675052 TI - Sirolimus-Eluting Stents vs Uncoated Stents for the Treatment of Proximal Left Anterior Descending Coronary Artery Stenosis. AB - Sirolimus-eluting stents (SES) have demonstrated low incidence of target vessel revascularizations in several anatomic scenarios, including proximal left anterior descending coronary artery (pLAD) lesions. The aim of present study was to compare the efficacy of SES with bare metal stents (BMS) for the treatment of such lesions. 96 patients with severe pLAD stenosis treated with SES were included. Clinical follow-up were performed during a 24 month period. A 98 patient sample with pLAD lesions treated with BMS was taken as control group. Death, angiographic restenosis, new target lesion revascularization (TLR) and target vessel failure (TVF) were registered. Clinical, angiographic and procedural variables were analysed to identify predictors of TVF and TLR. Angiographic procedural success was 100% in SES group vs 99% in BMS group (p=1.0). At 2.5 years, the cumulative rate of TVF was 9.4% in SES group vs 16.3% in BMS group (p=0.15), and the rate of TLR was 5.2% in SES group vs 12.2% in control group (p=0.08). The probabilities of cumulative TVF and TLR free survival were in BMS group 83.7% and 87.8%, and in SES group 90.6% and 94.8%, respectively. After multivariate analysis only SES utilization was found as independent protective factor against TVF and TLR (HR 0.38, 95%CI [0.15-0.94] p=0.037 and HR 0.21, 95%CI [0.06-0.66] p=0.008, respectively), and diabetes as independent predictor of TFV and TLR (HR 2.37, 95%CI [1.07-5.24] p=0.034 and HR 3.57, 95%CI [1.29-9.87] p=0.014, respectively). This study demonstrates that SES utilization is safe and effective in the tretament of pLAD lesions with a better clinical outcome than BMS in a long-term follow-up. PMID- 23675053 TI - Phytochemical and Antimicrobial Studies of Methyl Angolensate and Luteolin-7-O glucoside Isolated from Callus Cultures of Soymida febrifuga. AB - Soymida febrifuga (Roxb.) A. Juss. is an indigenous lofty deciduous medicinal tree, monotypic genus endemic to India. Hexane, ethyl acetate and methanol extracts of Soymida febrifuga root callus were tested for their phytochemical constituents and antimicrobial activity. Among them, ethyl acetate extract was found to be most effective, which on subjection to silica gel column chromatography led to the separation and isolation of methyl angolensate and luteolin-7-O-glucoside. Structures were determined by Nuclear Magnetic Resonance and Liquid Chromatographic Mass Spectroscopic methods. Further studies indicated that methyl angolensate and luteolin-7-O-glucoside had an anti-bacterial effect against Bacillus subtilis and Salmonella typhimurium, respectively. In addition to that methyl angolensate had an anti-fungal activity against Aspergillus niger while luteolin-7-O-glucoside inhibited Alternaria alternata. PMID- 23675054 TI - Evidence for the Effects of Xanthohumol in Disrupting Angiogenic, but not Stable Vessels. AB - Angiogenesis is a complex multistep process that comprises proliferation, migration, and anastomosis of endothelial cells, followed by stabilization of the newly formed vessel through the attachment of support cells. This process is imbalanced in a large number of disorders, including cardiovascular disease, diabetes and cancer. Evidence indicates that xanthohumol (XN), a prenylated chalcone present in beer, exerts anti-angiogenic properties. However, its precise effect within the angiogenic steps is not accurately established. The purpose of the present study was to examine which features of the angiogenic process can be disturbed by XN. Human umbilical vein endothelial cells (HUVEC) and human fetal aortic smooth muscle cells (SMC) were incubated with xanthohumol at 5 and 10 MUM, and cell viability, apoptosis, invasion and capillary-like structures formation were examined. Treatment with 10 MUM XN significantly decreased viability and invasion capacity and increased apoptosis in both cell types as assessed by MTT, double-chamber assay and TUNEL assay respectively. The two concentrations of XN further led to a significant reduction in the number of capillary-like structures, when HUVEC were cultured on growth factor reduced-Matrigel-coated plates. Interestingly, XN exhibited the opposite effect when HUVEC were co cultured with SMC, leading to an increase in the number of cord structures. In addition, incubation of both types of cells with XN resulted in reduced activity of NFkappaB, a transcription factor implicated in these cell fates. Given the absence of adverse effects in mature vasculature by XN, these findings emphasize the potential use of XN against pathological situations where angiogenesis is stimulated. PMID- 23675055 TI - Quantitative analysis of the p65 gene expression in patients with coloroctal cancer. AB - P65 gene expression level was determined in colon cancer cases by means of real time PCR. 51 cases of colorectal carcinomas showing positive RT-PCR signals for P65 gene expression selected from 109 frozen samples were further investigated by quantitative real-time PCR. P65 levels were higher in cancer with metastases to lymph nodes and distant metastases. Higher levels were observed in more advanced cases classified as III and IV according to pTNM classification. In two groups of patients with vessel invasion and absence of lymphocytes in tumour tissue, the presence of P65 expression correlated with shorter survival time. Quantitative results confirmed that P65 gene expression in colon cancer is engaged in the process of metastasis formation and could be correlated with worse prognosis for the patients. PMID- 23675056 TI - Multiple Sclerosis and HERV-W/MSRV: A Multicentric Study. AB - We designed a large multicentric study to analyse the presence of MSRV particles in blood and CSF of a large cohort of patients and controls from different European areas. 149 MS patients and 153 neurological and healthy controls were selected from Sardinia, Spain, Northern-Italy and Sweden. To avoid biological and inter-assay variability MSRV was detected within a single laboratory through nested and real-time PCR assays specific for pol and env genes. MSRV detection in blood and CSF of MS patients and controls in populations of different ethnicity gave significant differences (p<0.05 compared to neurological controls and <0.001 compared to healthy controls). The presence and viral load of MSRV are significantly associated with MS as compared to neurological and healthy controls in all ethnic groups. PMID- 23675057 TI - Quality assurance and commissioning of an infrared marker-based patient positioning system for frameless extracranial stereotactic radiotherapy. AB - Rapid advancements in imaging technology have led to remarkable improvements in identification and localization of tumors, ushering the era of high-precision techniques in contemporary radiotherapy practice. However, uncertainties in patient set-up and organ motion during a course of fractionated radiotherapy can compromise precision of radiation therapy. Excellent accuracy has been achieved with invasive and non-invasive fixation systems for stereotactic radiotherapy. This report describes the commissioning procedure and Quality Assurance studies done to evaluate the accuracy of isocenter localization by an infrared marker based positioning system (ExacTrac). The ExacTrac has two infrared cameras that emit and detect infrared rays from reflective markers and construct three dimensional coordinates of each marker. It detects the difference of the actual isocenter position from the planned isocenter coordinates in three translational (lateral, longitudinal, vertical, or x,y,z axes) and three rotational axes (six degree of freedom). This study performed on a flat and static phantom shows excellent accuracy achieved by the ExacTrac system. The positioning accuracy of ExacTrac (+/- 1 mm translational displacement and +/- 1 degrees rotational errors) can be a valuable tool in implementing frameless extracranial stereotactic radiotherapy. Nevertheless, it needs to be further evaluated on patients with inherent motion and greater positional uncertainty before being adopted in clinical practice. PMID- 23675058 TI - Atypical small hemangiomas of the liver: hypervascular hemangiomas. AB - Hyperdynamic hemangiomas (HH) are atypical hepatic hemangiomas with an incidence of approximately 16% of all hemangiomas in the liver. We report a case of HH in a 47-year-old woman. Multiphase helical CT scan, MRI appearances and differential diagnoses are discussed. PMID- 23675059 TI - Adult neural stem cells: redefining the physio- and pathology of the CNS. AB - Stem cells are the "building blocks" of the body; they are self-renewing undifferentiated cells that give rise to the specialized cells of the tissues. In adult, stem cells are multipotent, they contribute to homeostasis of the tissues and regeneration after injury. Until recently, it was believed that the adult brain was devoid of stem cells, hence unable to make new neurons and regenerate. The recent confirmation that neurogenesis occurs in the adult brain and neural stem cells (NSCs) reside in the adult central nervous system (CNS) suggests that the adult brain has the potential to regenerate and may be amenable to repair. The advent of adult neurogenesis and NSC research will redefine our understanding of the physio- and pathology of the nervous system, and provide new avenues and opportunities to treat a broad range of neurological diseases, disorders and injuries. Adult NSC-based therapies will involve cellular therapy, but also pharmacology. PMID- 23675060 TI - Synergistic effect of various regulatory factors in TH1/TH2 balance; immunotherapeutic approaches in asthma. AB - The immune balance controlled by T helper 1 (Th1) and T helper 2 (Th2) is crucial for immunoregulation and its imbalance causes various immune diseases including allergic asthma. Therefore, diagnosis of Th1/Th2 balance in autoimmune diseases including asthma is essential for the application of immune balance regulating drugs. Th1/Th2 balance is not only controlled by Th1 cells and Th2 cells, but also by various regulatory factors including regulatory T cells, sexual factor, chemokines, transcription factors, signal transduction pathway (STAT6) etc. From that point of view, conception of "Th1/Th2 balance" resembles the balance of yin and yang which is main concept of Korean traditional medicine for treatment diseases. This article discusses various regulatory factors that influence Th1/Th2. Current research strategies seek to exploit these observations to improve the generation of novel targets for regulating Th1/Th2 balance. The Th1/Th2 balance could be influenced by imunomodulatory drugs (including herbs, prescription and its main components) but this way of therapy needs further evaluation focused on this various factors and synergistic effect. PMID- 23675061 TI - Experimental Studies on the Differentiation of Fibroblasts into Myoblasts induced by MyoD Genes in vitro. AB - To evaluate the biological functions of myogenic regulatory factors, we have examined the effects of ectopic expression of MyoD and Cx43 genes in the fibroblasts on the differentiation of myoblast in vitro. The expression of MyoD and Cx43 in the transfectants was confirmed by RT-PCR and Western blot. More than 50% of fibroblasts transfected with MyoD or both MyoD and Cx43 genes displayed typical morphological features of myoblast-like cells at 20 days following gene transfection, including cell elongation, cytoplasm enrichment and granule manifold. Moreover, these myoblast-like cells also expressed both desmin and alpha-actin. These results demonstrate that direct exogenous expression of the myogenic regulatory factors is sufficient to induce transdifferentiation of fibroblasts into a myoblast-like lineage and provide new insights into the trauma repair after myocardial infraction. PMID- 23675062 TI - Role of raf-1 kinase in diabetes-induced accelerated apoptosis of retinal capillary cells. AB - Small molecular weight G-proteins serve as fundamental signaling switches that regulate cell fates by coupling receptor activation to downstream effector pathways. H-Ras, a small molecular weight G-protein, in its active form, recruits Raf. Activated Raf via a signaling transduction pathway regulates apoptosis. Our previous studies have shown that H-Ras has an important role in the loss of retinal capillary cells in diabetes. The purpose of this study is to investigate the role of Raf-1 in the development of diabetic retinopathy. Bovine retinal endothelial cells were incubated in 5 mM or 20 mM glucose in the presence of Raf 1 kinase inhibitor (10MUM of GW5074), activator (200MUM of ZM336374) or mitogen activated protein kinase inhibitor (30MUM of PD098059) for five days. Apoptosis of endothelial cells was analyzed by ELISA and activation of Raf-1 and its downstream signaling proteins by determining genes and protein expressions. Inhibition of Raf-1 kinase repressed glucose-induced apoptosis of the cells by 75%, and this was accompanied by attenuation of activation of MAP kinase, ERK-1, nuclear transcriptional factor and caspase-3. In contrast, ZM336374 further increased glucose-induced apoptosis by 50%, and activated the signaling molecules and caspase 3 by over 30%. Further, PD098059 alone also attenuated glucose induced apoptosis of retinal endothelial cells. These findings demonstrate that accelerated loss of retinal capillary cells in diabetes is mediated via Raf-1 kinase activation. Modulation of Raf-1 kinase activity could, in part, regulate apoptosis of retinal endothelial cells, which may ultimately contribute to the development of diabetic retinopathy. PMID- 23675063 TI - Different Effects of Regulatory Genes (tat, nef) of Human Immunodeficiency Virus Type 1 (HIV-1) on the Proliferation and Differentiation of Mouse Embryonic Stem Cells in vitro. AB - To examine the effects of the tat and nef regulatory genes of human immunodeficiency virus (HIV-1) on cell differentiation we used the mouse embryonic stem cells (ESC) as a model. Proliferation, embryoid bodies (EB) formation and subsequent differentiation into cardiomyocytes, glial and neuronal cells were investigated in ESC lines transfected with these genes. It has been shown that the transfection of ESC by the tat gene increased their proliferating activity, whereas the nef gene transfected ESC showed its decrease. The number of embryoid bodies formed was higher in the cultures of ESC transfected by the nef and lower in the cells transfected by the tat in comparison with controls. The percentage of embryoid bodies with contracting cardiomyocytes was higher against control in the nef transfected cells and lower in ESC transfected with the tat. There were no reliable differences in the appearance of glial cells between control and the nef and tat transfected cell lines. Spontaneous differentiation of ESC into neuronal cells was almost not observed in the nef transfected cells, in contrast to control and the tat transfected cells. However, addition of retinoic acid (RA) to the nef transfected cells caused even a slight increase in neuron formation as compared to control ESC treated with RA. Thus, for the first time we have shown that the tat and nef regulatory genes of HIV-1 had a visible effect on proliferation of ESC and some first steps of their differentiation. In general, the reverse correlation between the effects of these two viral genes on ESC proliferation and differentiation were observed. PMID- 23675064 TI - A novel technique of total laparoscopic hysterectomy for routine use: evaluation of 140 cases. AB - Hysterectomy is one of the most commonly performed gynecological procedures. Although the first laparoscopic hysterectomy was performed in 1989, this technique accounts for only a few of all hysterectomies performed today. To assess the safety of total laparoscopic hysterectomy through a novel technique that we have evolved, a retrospective analysis of 140 patients with benign uterine pathologies operated at our institute between 2004 and 2007 was performed. All patients underwent total laparoscopic hysterectomy (TLH) using a simple technique. The highlight of this technique was the omission of any vaginal manipulator. The mean operation time was 88.75 +/- 52.72 minutes, the mean blood loss 53.80 +/- 35.94 ml and the mean hospital stay 2.21 +/- 1.12 days. No conversion to open surgery was necessary. Iatrogenic complications were bowel injury (n=1) and vaginal tears (n=3) and were managed laparoscopically. The new method of TLH proved to be reproducible and safe with decreased morbidity and operation time. This can be attributed to the performance of the same standardized steps each time. Our technique provides a safe procedure suitable for routine use in gynecological surgery. PMID- 23675065 TI - Pilot study to assess isoflavone intake in middle-aged italian subjects. AB - Knowledge of isoflavone (IF) intake in Western populations is scarce, primarily because data about the content of these compounds in non-soy derived foods are incomplete or unavailable. The aims of this study were 1) to enrich the data available in literature about the IF content in traditional Italian foods, 2) to estimate daidzein (D) and genistein (G) intake in an Italian population sample. Eighteen Italian foods have been selected and analysed for IF content by GC-MS; the assessment of IF intake was performed in sixty healthy middle-aged Italian subjects after investigation of their dietary habits by food frequency questionnaire (FFQ). The mean IF intake was 171 +/- 261 MUg/die (26-1415 MUg/die). The mean G intake was greater than D (98 +/- 131 MUg/die vs 76 +/- 131 MUg/die). As expected, soy products, even though poorly consumed (27%), resulted the main contributor to IF intake (IF intake was 473.4 +/- 440 MUg/die vs 75 +/- 38 MUg/die in soy consumers and non soy consumers respectively p<0.001). Among Mediterranean foods, the main contributor resulted fresh bread that is widely consumed (97%). The percentage contribution of the cereal group to mean IF intake was 91%; the legume, fruit and vegetables groups brought a low contribution (3%, 2% and 4% respectively). The total daily IF intake found was low and probably not sufficient to produce biological effects. However more studies are necessary to investigate whether low exposure to IF for a long time could have positive effects on human health. PMID- 23675066 TI - Neutralization of IL-4 and IFN-gamma Facilitates inducing TGF-beta-induced CD4(+)Foxp3(+) Regulatory Cells. AB - It has been well recognized that TGF-beta is able to induce CD4(+)CD25(+)Foxp3(+) suppressor/regulatory T (iTreg) cells and IL-2 facilitates iTreg induction and expansion, however, only half of TGF-beta-induced CD4(+)CD25(+) cells express Foxp3 and remaining CD4(+)CD25(+)Foxp3- cells may represent effector cells. Whether other factor(s) can increase Foxp3 expression by CD4(+)CD25(+) cells induced with TGF-beta is still unclear. Here we show that addition of exogenous IFN-gamma or IL-4 diminished the ability of TGF-beta to induce Foxp3 expression and IL-2 failed to rescue this decreased Foxp3 expression. Conversely, neutralization of IFN-gamma and IL-4 significantly enhanced the ability of TGF beta to induce Foxp3 and develop the suppressive activity, indicating that different cytokine profiles affect the differentiation of CD4(+)CD25(+)Foxp3(+) subset induced by TGF-beta. These results show that combination of antibodies against IFN-gamma and IL-4 and TGF-beta enhances the efficacy of generation and function of iTreg cells and may therefore provide a novel therapeutic strategy for the treatment of autoimmune and other chronic inflammatory diseases. PMID- 23675067 TI - Clinicopathological Significance of VEGF-C, VEGFR-3 and Cyclooxygenase-2 in Early Stage Cervical Cancer. AB - To investigate the roles of VEGF-C, VEGFR-3 and cyclooxygenase-2 (COX-2) in tumor progression and lymph node metastasis. The expression of VEGF-C, VEGFR-3 and COX 2 were examined in 93 cases of surgical speciments of cervical diseases by immunohistochemical staining. The correlation between expression of these factors and tumor aggressiveness was evaluated. The expression levels of VEGF-C and COX-2 were much higher in cervical cancer than in cervical intraepithelial neoplasia (CIN) and in chronic cervicitis. VEGF-C expression correlated with lymph node metastases (P<0.01). Multivariate analysis indicated that lymph vessel density (LVD) was associated with the coexpression of VEGF-C and COX-2. Expression of VEGF-C and VEGFR-3 were both in coincidence with lymph node metastasis. VEGF-C and COX-2 may promote the canceration of cervical cancer and that VEGF-C/ VEGFR-3 system had a significant association with the lymphagiogenesis and lymph node metastasis. PMID- 23675068 TI - Inter- and intra-observer concordance of cyberpathology in twenty-five cases. AB - To study the feasibility of anatomical pathology consultation in cyberspace (cyberpathology) and to determine inter- and intra-observer concordance. Twenty five consecutive cytology and histopathology cases are photographed using a digital camera placed against the eyepiece, and uploaded to an image-server in the Internet. Participants view the images, rate their confidence, and provide a diagnosis. They then view the original glass slides and provide a final diagnosis. The diagnoses are compared for inter- and intra-observer concordance. Participants are confident of their diagnoses based on viewing images on the Internet. The intra-observer concordance exceeds 95% individually, and 96% overall. Inter-observer concordance was 100% in a subset of cases. Cyberpathology as described is both available and affordable and is a valid alternative to slide based anatomic pathology consultation. PMID- 23675069 TI - Bioinformatic analysis of functional proteins involved in obesity associated with diabetes. AB - The twin epidemic of diabetes and obesity pose daunting challenges worldwide. The dramatic rise in obesity-associated diabetes resulted in an alarming increase in the incidence and prevalence of obesity an important complication of diabetes. Differences among individuals in their susceptibility to both these conditions probably reflect their genetic constitutions. The dramatic improvements in genomic and bioinformatic resources are accelerating the pace of gene discovery. It is tempting to speculate the key susceptible genes/proteins that bridges diabetes mellitus and obesity. In this regard, we evaluated the role of several genes/proteins that are believed to be involved in the evolution of obesity associated diabetes by employing multiple sequence alignment using ClustalW tool and constructed a phylogram tree using functional protein sequences extracted from NCBI. Phylogram was constructed using Neighbor-Joining Algorithm a bioinformatic tool. Our bioinformatic analysis reports resistin gene as ominous link with obesity associated diabetes. This bioinformatic study will be useful for future studies towards therapeutic inventions of obesity associated type 2 diabetes. PMID- 23675070 TI - Early onset of metastatic gestational trophoblastic disease after full-term pregnancy. AB - Choriocarcinoma is a curable malignancy that occurred approximately 50% after term pregnancies, and prognosis in this form of gestational trophoblastic Disease (GTD) is Poor. The earliest onset choriocarcinoma after term pregnancy in one study was reported 3 weeks after delivery, but in current study, choriocarcinoma was diagnosed 2 weeks after delivery. 28 years-old women gravidity 2, parity 2 delivered a healthy infant at term. Frequent episodes of vaginal bleeding occurred after 10 days of delivery. On admission to hospital, she had lesions in the lungs. The pretreatment human chorionic gonadotropin (HCG) level was 84,000 mIU/ml and her FIGO risk factor score was 8 (high risk group). The EMA/CO regimen was administered as first line chemotherapy and the patient achieved complete remission after 7 courses. Although early onset postpartum hemorrhage is due to complication of delivery, but gestational trophoblastic disease (GTD) may be occurred and assessment of human chorionic gonadotropin could be help to early diagnose of GTD. PMID- 23675071 TI - Retroperitoneal hemorrhage from adrenocortical carcinoma as a poor prognostic factor. AB - In most patients, adrenocortical carcinoma is diagnosed at an advanced stage of the disease. A sudden retroperitoneal hemorrhage may sometimes be the first symptom of the adrenal cancer. We describe four patients with adrenocortical carcinoma diagnosed during a retroperitoneal hemorrhage. A clinical analysis suggests that such a complication is a poor prognostic factor. PMID- 23675072 TI - Overcoming hurdles in hepatitis C virus research: efficient production of infectious virus in cell culture. AB - Hepatitis C virus is a flavivirus that infects nearly 2% of the world population. There is no vaccine available and current therapy with interferon and ribavirin is expensive, not well tolerated and effective in only 60% of patients. HCV research has been hampered by the lack of a robust tissue culture system, but recent advances have made virus growth in culture possible. Here we review the current state-of-the-art and the molecular hurdles that have been met and those that still need to be overcome. PMID- 23675073 TI - Free radicals, antioxidants in disease and health. AB - Free radicals and oxidants play a dual role as both toxic and beneficial compounds, since they can be either harmful or helpful to the body. They are produced either from normal cell metabolisms in situ or from external sources (pollution, cigarette smoke, radiation, medication). When an overload of free radicals cannot gradually be destroyed, their accumulation in the body generates a phenomenon called oxidative stress. This process plays a major part in the development of chronic and degenerative illness such as cancer, autoimmune disorders, aging, cataract, rheumatoid arthritis, cardiovascular and neurodegenerative diseases. The human body has several mechanisms to counteract oxidative stress by producing antioxidants, which are either naturally produced in situ, or externally supplied through foods and/or supplements. This mini review deals with the taxonomy, the mechanisms of formation and catabolism of the free radicals, it examines their beneficial and deleterious effects on cellular activities, it highlights the potential role of the antioxidants in preventing and repairing damages caused by oxidative stress, and it discusses the antioxidant supplementation in health maintenance. PMID- 23675074 TI - Analysis of Peptidases in Non-Infected and Trypanosoma cruzi-Infected Mouse Embryo Hepatocyte Cells. AB - Cellular and extracellular peptidase profiles from non-infected and Trypanosoma cruzi-infected hepatocyte cell cultures were characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) containing different copolymerized proteins as substrates. A 100 kDa metallopeptidase activity was detected in the cellular extracts and in the culture supernatant fluids of both systems, had the ability to exclusively degrade gelatin. However, non-infected hepatocytes produced an additional extracellular metallopeptidase of 85 kDa. In the non-infected and in the infected hepatocytes, a cysteine peptidase migrating in gelatin-SDS-PAGE at 60 kDa presented the broadest specificity, since it was also able to hydrolyze casein and hemoglobin. The 100 kDa component was only detected at alkaline pH and predominantly expressed in non-infected hepatocytes. Conversely, the 60 kDa cysteine peptidase was only observed in acidic condition and its production was robustly augmented in T. cruzi-infected cells, probably due to the cysteine peptidase synthesized by the parasites, as corroborated by immunoblotting assay using anti-cruzipain antibody. Collectively, these results suggest that peptidases may be involved in the interaction process between T. cruzi and hepatocytes in vitro. PMID- 23675075 TI - Inhibition of endotoxin-induced hepatotoxicity by melatonin in rats. AB - Bacterial endotoxin or lipopolysaccharide causes extensive damage to various organs including the liver. This is due to an increased production of tumor necrosis factor alpha induced- reactive intermediates. These intermediates are known to cause extensive damage to a variety of cellular biomolecules leading to oxidative stress. In the present study, the role of the pineal hormone melatonin was evaluated as an antioxidant against endotoxin induced- hepatotoxicity using Wistar rats. Bacterial endotoxin was injected (i.v) and animals were sacrificed 8h post-challenge. Endotoxemia was associated with a statistically significant rise in the serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and also caused histopathological changes. Administration of melatonin could significantly attenuate these enzymatic and associated histological alterations. Melatonin was administered (i.p) pre and/or post endotoxin challenge. A significant reduction in the levels of malondialdehyde and tumor necrosis factor-alpha in the hepatic tissue was also observed with melatonin supplementation. Reduction in the levels of endogenous antioxidants such as superoxide dismutase, catalase and reduced glutathione after endotoxin challenge was effectively attenuated by the administration of melatonin. Endotoxin challenge caused a marked increases in the levels of nitrite, and this was significantly lowered by melatonin administration. The above mentioned changes might have resulted in endotoxin associated hepatocellular necrosis which was minimized by melatonin supplementation in the present study. PMID- 23675076 TI - Dicom Color Medical Image Compression using 3D-SPIHT for Pacs Application. AB - The proposed algorithm presents an application of 3D-SPIHT algorithm to color volumetric dicom medical images using 3D wavelet decomposition and a 3D spatial dependence tree. The wavelet decomposition is accomplished with biorthogonal 9/7 filters. 3D-SPIHT is the modern-day benchmark for three dimensional image compressions. The three-dimensional coding is based on the observation that the sequences of images are contiguous in the temporal axis and there is no motion between slices. Therefore, the 3D discrete wavelet transform can fully exploit the inter-slices correlations. The set partitioning techniques involve a progressive coding of the wavelet coefficients. The 3D-SPIHT is implemented and the Rate-distortion (Peak Signal-to-Noise Ratio (PSNR) vs. bit rate) performances are presented for volumetric medical datasets by using biorthogonal 9/7. The results are compared with the previous results of JPEG 2000 standards. Results show that 3D-SPIHT method exploits the color space relationships as well as maintaining the full embeddedness required by color image sequences compression and gives better performance in terms of the PSNR and compression ratio than the JPEG 2000. The results suggest an effective practical implementation for PACS applications. PMID- 23675077 TI - Bone densitometric analysis in egyptian hemodialysis patients. AB - End-stage renal failure (ESRF) is the ultimate consequence of chronic renal failure, and in such cases dialysis is generally required. Almost all dialysed patients have abnormal bone histology and lower values of glomerular filtration rate have been associated with lower bone mineral density (BMD) at all sites. The objective of the present study was to investigate the effect of hemodialysis (HD) on body-composition (BC), specially segmental and total BMD in Egyptian ESRF patients. Forty ESRF patients (20 male/20 female; age range: 21.00-74.00 yr) undergoing regular HD 3 times/week (duration range: 0.08-20.00 yr) using bicarbonate dialysis and polysulphon membrane were matched with 40 healthy controls for age, height, and sex. Blood samples were obtained and serum levels of calcium (Ca), inorganic phosphate (P), osteocalcin (OC), and parathyroid hormone (PTH) were monitored for all participants. BC was evaluated by dual X-ray absorptiometry. HD patients manifested lower segmental and total BMD values in comparison with age-matched healthy controls (Z-score: -0.17 +/- 1.12) due to significantly higher levels of P (4.04 +/- 1.33 vs. 3.39 +/- 0.51 mg/dl, p<0.001), PTH (538.17 +/- 363.99 vs. 48.86 +/- 19.64 ng/L, p<0.0001), and OC (50.39 +/- 34.91 vs. 16.32 +/- 5.37 MUg/L, p<0.0001). Pelvis, lumbar spine, and total BMD (g/cm(2)) for HD patients were significantly correlated with HD duration (yr) (R=0.94, 80, and 92, respectively; p<0.0001). Thus, BC analysis is of utmost importance for efficiently providing tailored individual mineral supplementation to HD patients. PMID- 23675078 TI - Is There a Correlation between Vitamin C Status and Catecholamines Concentrations in Hemodialysis Patients? AB - It is well established that there is a high incidence of cardiovascular diseases in hemodialysis patients, and involvement of oxidative stress has been hypothesised in these phenomena. Plasma norepinephrine is an independent predictor of many causes of mortality in general, and high norepinephrine levels predict cardiovascular complications in end stage renal disease. The aim of our study was to evaluate the potential link between vitamin C status, a marker of oxidative stress, and catecholamine concentrations before and after hemodialysis sessions. In a prospective study of 16 chronic hemodialysis patients, ascorbyl free radical levels were directly measured using electron spin resonance spectroscopy. These values were expressed with respect to vitamin C concentrations to obtain a direct index of oxidative stress. Vitamin C, epinephrine and norepinephrine were measured by high performance liquid chromatography. The data were examined for correlations between these compounds and clinical parameters including blood pressure and heart rates. In hemodialysis patients, ascorbyl free radical/vitamin C ratios increased significantly after dialysis. No differences were observed for catecholamine concentrations during hemodialysis sessions. In multivariate analysis, the ascorbyl free radical/vitamin C ratio did not correlate with epinephrine or norepinephrine levels. In our study, plasma norepinephrine and ascorbyl free radical/vitamin C ratios were not related among patients with end-stage renal disease. From these findings, we conclude that although these two factors are likely to be involved in the same causal pathway leading to cardiovascular events, it is likely that they seem to be independent. PMID- 23675079 TI - Changes in Mice Brain Spontaneous Electrical Activity during Cortical Spreading Depression due to Mobile Phone Radiation. AB - The objective of the present study was to investigate changes in spontaneous EEG activity during cortical spreading depression (CSD) in mice brain. The cortical region of anaesthetized mice were exposed to the electromagnetic fields (EMFs) emitted from a mobile phone (MP, 935.2-960.2 MHz, 41.8 mW/cm(2)). The effect of EMFs on EEG was investigated before and after exposure to different stimuli (MP, 2% KCl, and MP & 2% KCl). The records of brain spontaneous EEG activity, slow potential changes (SPC), and spindle shaped firings were obtained through an interfaced computer. The results showed increases in the amplitude of evoked spindles by about 87%, 17%, and 226% for MP, 2% KCl, and MP & 2% KCl; respectively, as compared to values for the control group. These results showed that the evoked spindle is a more sensitive indicator of the effect of exposure to EMFs from MP. PMID- 23675080 TI - Quantitative determination of pravastatin in pharmaceutical dosage forms by high performance liquid chromatography with ultraviolet detection. AB - A simple, sensitive and precise high-performance liquid chromatographic formulations assay for pravastatin (PVS) is described. Good chromatographic separation was achieved using a Teknokroma C8 (5 MUm, 25cm * 4.6mm) column and a mobile phase consisting of 10mM ammonium acetate: methanol: triethylamine (40:60:0.17 v/v/v) while at a flow-rate of 1.0 mL min(-1). PVS was detected at 239 nm and was eluted 2.15 min after injection. No endogenous substances were found to interfere. No internal standard was required. Linearity range for PVS was 0.4-1000 MUg mL(-1). The determination of intra- and inter-day precision (RSD) was less than 2.94 and 2.97%, at all concentration levels. Statistical treatment of the experimental results indicates that the method is precise and accurate. The proposed method was applied to the determination of the component in commercial tablets with no interference from the excipients. A comparative study between the suggested procedure and the pharmacopoeial method for this compound in the tablets showed no significant difference between the two methods. PMID- 23675081 TI - Spectrofluorimetric determination of labetalol hydrochloride in pharmaceutical preparations and urine samples. AB - Two simple and sensitive spectrofluorimetric methods have been developed for the determination of labetalol (LBT). In method A, the native fluorescence was measured at 432 nm after excitation at 312 nm. The second method (method B) is based on the formation of a ternary complex between zinc (II), eosin and LBT. The fluorescence intensity of the ternary complex was measured at 452 nm after excitation at 317 nm. Optimum conditions for the determination were also investigated. The linear range and detection limit for method A and B were found to be 1.25-30 ug/ml; 0.24 ug/ml and 0.5-4 ug/ml; 0.08 ug/ml, respectively. The proposed methods are simple, practical and relatively free of interference from coexisting substances. The methods have been applied to assess LBT in commercial tablets and human urine samples with good precision and accuracy. PMID- 23675082 TI - Novel Spectrophotometric Method for the Assay of Captopril in Dosage Forms using 2,6-Dichloroquinone-4-Chlorimide. AB - A simple spectrophotometric method was developed for the determination of captopril (CPL) in pharmaceutical preparations. The method is based on coupling captopril with 2,6-dichloroquinone-4-chlorimide (DCQ) in dimethylsulphoxide. The yellow reaction product was measured at 443 nm. The absorbance-concentration plot was rectilinear over the range of 10-50 MUg/mL with minimum detection limit (LOD) of 0.66 MUg/mL and a quantification limit (LOQ) of 2.0 MUg/mL. The different experimental parameters affecting the development and stability of the color were carefully studied and optimized. The proposed method was successfully applied to the analysis of commercial tablets and the results were in good agreement with those obtained using official and reference spectrophotometric methods. Hydrochlorothiazide which is frequently co-formulated with CPL did not interfere with the assay. A proposal of the reaction pathway was presented. PMID- 23675083 TI - Quantitative thin-layer chromatographic method for determination of amantadine hydrochloride. AB - A simple and accurate thin-layer chromatographic (TLC) method for quantitative determination of amantadine hydrochloride (AMD) was developed and validated. The method employed TLC aluminum plates pre-coated with silica gel 60F-254 as a stationary phase. The solvent system used for development consisted of n-hexane methanol-diethylamine (80: 40: 5, v/v/v). The separated spots were visualized as brown spots after spraying with modified Dragendorff's reagent solution. Amantadine hydrochloride was subjected to accelerated stress conditions: boiling, acid and alkaline hydrolysis, oxidation, and irradiation with ultraviolet light. The drug was found to be stable under all the investigated stress conditions. The method was validated for linearity, limits of detection (LOD) and quantitation (LOQ), precision, robustness, selectivity and accuracy. The optical densities of the separated spots were found to be linear with the amount of AMD in the range of 5-40 ug/spot with good correlation coefficient (r=0.9994). The LOD and LOQ values were 0.72 and 2.38 ug/spot, respectively. Statistical analysis proved that the method is repeatable and accurate for the determination of AMD. The method, in terms of its sensitivity, accuracy, precision, and robustness met the International Conference of Harmonization/Federal Drug Administration regulatory requirements. The proposed TLC method was successfully applied for the determination of AMD in bulk and capsules with good accuracy and precision; the label claim percentages were 99.0 +/- 1.0%. The results obtained by the proposed TLC method were comparable with those obtained by the official method. The proposed method is more advantageous than the previously published chromatographic methods as it involved the most simple chromatographic technique; TLC. In addition, method relies on the use of inexpensive equipment, a scanner and software, and not critical derivatizing reagent, thus maximizing the ability of laboratories worldwide to analyze samples of AMD. PMID- 23675084 TI - Detection of Hemizygous Chromosomal Copy Number Variants in Williams-Beuren Syndrome (WBS) by Duplex Quantitative PCR Array: An Unusual Type of WBS Genetic Defect. AB - We have developed a dual probe quantitative PCR (qPCR) mini array enabling a more accurate analysis of the relationship between copy number variants (CNVs) and other genomic features in specific areas. We used it to map hemizygous microdeletion on human chromosome 7 around the elastin gene (ELN), which is the molecular basis of the Williams-Beuren syndrome (WBS). In two WBS patients, the haploid content of the elastin gene was ascertained previously by the fluorescence in-situ hybridization (FISH). Our dual-color qPCR assay used this information to normalize for DNA content in all tests. We mapped the extent of the deleted area using 10 loci spanning over 4 Mb. A border region containing the GTF2I gene, usually deleted in most cases, was found about 10 times amplified in both patients, suggesting an unusual type of the WBS genetic defect. This 10-WBS loci-specific qPCR assay could be an affirmative diagnostic tool alternative to FISH. Due to low cost, it could be used as a screening test that would not only facilitate research on CNVs, but also allow early diagnosis of the disease, as well-timed diagnosis would benefit WBS children with earlier proper health-care measures. PMID- 23675085 TI - Effect of glutathione depletion on Ifosfamide nephrotoxicity in rats. AB - Kidney injury is an important side effect of the chemotherapeutic agent ifosfamide in humans. Previous studies have shown that treatment with ifosfamide reduces kidney glutathione and that the toxicity of ifosfamide is enhanced in glutathione-depleted renal tubule cells in vitro. In this study, we examined the effect of glutathione depletion on ifosfamide nephrotoxicity in vivo using rats treated with the glutathione-depleting agent buthionine sulfoximine. Animals received 80 mg/kg ifosfamide intraperitoneally daily for three days with or without buthionine sulfoximine in drinking water. Buthionine sulfoximine produced a significant fall in renal glutathione content but did not affect kidney function. Ifosfamide-treated rats developed low-grade glucosuria, phosphaturia and proteinuria that worsened with concomitant buthionine sulfoximine therapy. These findings indicate that glutathione depletion exacerbates ifosfamide nephrotoxicity in rats and suggest that pharmacological methods for replenishing intracellular glutathione may be effective in ameliorating ifosfamide-induced renal injury. PMID- 23675086 TI - Increased Prevalence of Glycoprotein IIb/IIIa Leu 33 Pro Polymorphism in End Stage Renal Disease Patients on Hemodialysis. AB - Traditional atherosclerosis risk factors cannot elucidate the increased prevalence of cardiovascular events in end stage renal disease (ESRD) patients on hemodialysis. A previous study has indicated a strong association of the PI(A1/A2) polymorphism with myocardial infarction, diabetes and renal allograft rejection. In this investigation, we determined the prevalence of the PI(A1/A2) polymorphism of platelet glycoprotein (GP) IIb/IIIa in ESRD patients on hemodialysis in the Eastern Province of Saudi Arabia. The PI(A1/A2) polymorphism was determined in 42 ESRD patients receiving hemodialysis and in 49 subjects without current or past history of renal disease. Genotypes were determined by a reverse-hybridization assay and were confirmed by restriction fragment length polymorphism procedures. The PI(A2) allele frequency among the control sample was 28.6% (2 were homozygous for PI(A2), 23 were homozygous for PI(A1), and 24 were heterozygous PI(A1/A2)). The PI(A2) allele frequency among the hemodialysis sample was 50% (2 were homozygous for PI(A2), 2 were homozygous for PI(A1) and 38 were heterozygous for PI(A1/A2)). The PI(A2) allele frequency among the hemodialysis patients was significantly higher than that in the control group [Odds ratios 2.5 (1.35-4.61), p<0.003; Adjusted odds ratios of 2.21 (1.05-4.65), p<0.036 after adjustment for the presence of diabetes; Simultaneously adjusting the odds ratios for the presence of standard risk factors (diabetes and hypertension) gave an adjusted OR of 6.87 (1.54-30.71), p=0.064]. These results suggest that the PI(A2) polymorphism may contribute toward the etiology of cardiovascular diseases in ESRD patients. A further study with a larger sample size is needed to confirm above results. PMID- 23675087 TI - Detection and characterization of nocardia from patients diagnosed as tuberculosis in egypt. AB - Pulmonary tuberculosis and pulmonary nocardiosis are similar in most clinical symptoms and radiological manifestation. In the developing countries like Egypt where tuberculosis is very common, anti-tuberculosis drugs are started on basis of radiology and clinical symptoms. This study included 600 sputum specimens collected from 200 patients diagnosed as pulmonary tuberculosis from three chest hospitals in Egypt. IS6110 specific primer were selected for PCR to identify the Mycobacterium tuberculosis and hsp65 gene specific primers were used for PCR and sequencing for the identification of Mycobacterium and Nocardial species. The region of the gene coding for 16S rRNA in Nocardia species were selected as genus specific primer sequences for a PCR and Real Time PCR assays. Our result confirmed that four whole DNA samples, extracted from sputum specimen from the pulmonary tuberculosis patients on anti-tuberculosis treatment, were Nocardia species. Three of them matched (99% homology) with Nocardia farcinica (formerly Nocardia asteroid type V) and one match (83% homology) with Nocardia pneumonia. Molecular methods such as PCR and real-time PCR for identification of Nocardia are rapid and accurate methods. No cross-reactions were observed using Real Time PCR specific for Nocordia with other closely related genera. PMID- 23675088 TI - Association between Interleukin-10 Gene Promoter Haplotype and Schizophrenia in a Han-Chinese Study. AB - Schizophrenia is a multi-factorial genetic disease, and it is caused by a combination of different gene polymorphisms and not individual ones, however, its pathogenesis is still unclear. The purpose of this study was explored the association between the -1082G/A, -819T/C, and -592C/A polymorphisms of interleukin-10 (IL-10) in schizophrenia. A total of 659 schizophrenics were recruited from a teaching hospital, whereas 411 healthy non-schizophrenic individuals were recruited from community in the same geographical area. The 1082G/A, -819T/C and -592C/A polymorphisms were genotyped by using PCR-RFLP, direct sequencing and TaqMan((r)) SNP assay. Both maximum likelihood method of UNPHASED program and Bayesian method of PHASE software were utilized for haplotypic analysis. An allelic frequency difference was found between the schizophrenics and community controls at -1082G/A polymorphism of IL-10 promoter (chi(2) =4.678, P=0.031). A haplotype of ACA was observed to be associated with schizophrenia after performing UNPHASED, PHASE and multivariate logistic regression analysis (P<0.001; P=0.001). In addition, the persons who carry haplotype ACA of IL-10 promoter SNPs were estimated for 5.789 fold higher risk to develop schizophrenia than controls. We postulated this haplotype association might due to variant-specific effect on IL-10 gene regulation, which leads to imbalance secretion of Th1/Th2 cytokines. Nevertheless, more detailed mechanism needs to be elucidated in further investigations in order to confirm this hypothesis. PMID- 23675089 TI - HIV/AIDS Knowledge, Attitudes, and Behaviors of Construction Workers in China. AB - The objective of the study was to describe HIV/AIDS knowledge, attitudes, risk behaviors, and sources of information among construction workers in China. A cross-sectional survey of 458 construction workers was conducted among 4 construction sites in Shenyang city in 2006. All 458 participants were individually interviewed in a private setting by a trained team of medical researchers using a structured questionnaire, which included questions on general personal information and the knowledge, attitudes, practice questions and the favorable mode of health education. A total of 428 valid questionnaires were collected. Data entry and statistical analyses were performed using the SPSS 13.0. Our results indicated that the majority of construction workers in China are sexually active youths and adults with limited education and poor knowledge of HIV/AIDS. The proportions of correct answers to questions about HIV/AIDS ranged from 4.9% to 70.7%. The score was significantly different by education level (chi(2)=47.51, p<0.01), and marrital status (chi(2)=16.48, p<0.01). More than 60% of the construction workers had a negative attitude toward HIV/AIDS infected individuals. The source of workers' knowledge toward HIV/AIDS mainly came from TV (35.8%), newspaper (14.3%), family and friend (13.1%) and others (28.2%). Chinese migrant workers in general lack knowledge about HIV/AIDS. Our study suggests prevention programs should be encouraged and these may have the potential role to limit the emergence of China's HIV/AIDS epidemic. PMID- 23675090 TI - A novel terpenoid from elephantopus scaber - antibacterial activity on Staphylococcus aureus: a substantiate computational approach. AB - Staphylococcus aureus has gained much attention in the last decade as it is a major cause of the Urinary Tract Infection in Diabetic patients. The Extended Spectrum beta-Lactamases (ESbetaL) producers are highly resistant to several conventional antibiotics. This limits the therapeutic options.Hence efforts are now taken to screen few medicinal plants, which are both economic and less toxic. Among the several plants screened, we have chosen the acetone extract of Elephantopus scaber from which we purified a new terpenoid for our study. Its structure was generated using CHEMSKETCH software and the activity prediction was done using PASS PREDICTION software. We have confirmed the mechanism of anti bacterial effect of terpenoid using Computer - Aided Drug Design (CADD) with computational methods to simulate drug - receptor interactions. The Protein Ligand interaction plays a significant role in the structural based drug designing. In this present study we have taken the Autolysin, the bacteriolytic enzyme, that digest the cell wall peptidoglycon. The autolysin and terpenoid were docked using HEX docking software and the docking score with minimum energy value of -209.54 was calculated. It infers that the terpenoid can inhibit the activity of autolysin by forming a strong atomic interaction with the active site residues. Hence the terpenoid can act as a drug for bacterial infections. Further investigations can be carried out to predict the activity of terpeniod on other targets. PMID- 23675091 TI - Increase in Levels of BDNF is Associated with Inflammation and Oxidative Stress during Cardiopulmonary Bypass. AB - Cardiopulmonary Bypass (CPB) is thought to generate reactive oxygen species associated with a systemic inflammation and neurotrophins seem to be involved in cardiovascular inflammatory reactions. The aim of this study was to determine the impact of CPB on plasma neurotrophins levels and to appreciate the links existing between inflammation, oxidative stress and neurotrophins. Blood samples were taken from 27 patients undergoing cardiac surgery: before CPB, during ischemia and at reperfusion under CPB. Oxidative stress was evaluated using an Electron Spin Resonance technique by superoxide detection, and antioxidant defences by measurement of Endogenous Peroxidase Activity (EPA). The evolution of two neurotrophins: Brain Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF) was assessed with an ELISA method. An inflammatory index was determined by a multiplex flow cytometry method. The inflammatory index showed that MCP-1, P selectin, t-PA and interleukins 6, 8 and 10 levels increased during CPB (p<0.05). Superoxide production and EPA were higher during ischemia and reperfusion than before CPB (p<0.05). BDNF plasma levels were higher at reperfusion (p<0.05). NGF levels did not change. Our study shows an increase of BDNF levels, associated with an inflammatory phenomenon and a redox modification, in the plasma of patients undergoing cardiac surgery under CPB. The role played by this neurotrophin in this complex situation still needs to be elucidated, in particular its cellular origin. It is also necessary to understand whether BDNF has a beneficial or deleterious effect during CPB. PMID- 23675092 TI - Improved localization of coronary stents based on image enhancement. AB - Stent thrombosis remains a life threatening complication of percutaneous coronary interventions. The angiographic result of stent implantation is a high predictive factor of stent thrombosis. Nevertheless accurate placement of stents is hindered by the fact that most stents are only slightly radiopaque and hence difficult to see in typical coronary X-ray images. In this work, we propose a simple image guidance approach, making it easier to achieve optimum and complete intracoronary stent deployment. The main idea is to enhance the visibility of stents using an iterative landmark-based registration. After frame averaging over the series of registered frames, the resultant stent image is post processed to increase the contrast visibility. Preliminary simulation results show that despite its low computational cost, our method significantly improves the visibility of stent edge struts. PMID- 23675093 TI - Utility of vascular endothelial specific peptides for enhancement of adeno associated virus-mediated gene transfer. AB - Vascular endothelial cells (EC) have been targeted for the treatment of pathological conditions such as atherosclerosis, hypercholesterolemia, post angioplasty restenosis and hypertension. Non-pathogenic adeno-associated virus (AAV) has been shown as a good gene delivery tool in a variety of cell lines as well as in animal models. However, AAV has been reported to induce less endothelial cell transduction. AAV vector alone transduced HUVEC much lower than other cell lines including Hela, PAC1, and C2C12. Preincubation of AAV vector with EC membrane specific peptides markedly increased AAV transduction of HUVEC. On the contrary, those peptides did not affect AAV expression in other cell types. These EC-specific peptides may be a strategy for enhancement of AAV mediated-gene expression. PMID- 23675094 TI - Chitosan-alginate nanoparticles as a novel drug delivery system for nifedipine. AB - Chitosan-alginate (CS/ALG) nanoparticles were prepared by ionotropic pre-gelation of an alginate core followed by chitosan polyelectrolyte complexation, nifedipine was chosen as a model drug. Morphology and structure characterization of nanoparticles were investigated by transmission electron microscope (TEM) and Fourier transform infrared spectra (FTIR), respectively. The diameter of the nanoparticles was about 20-50 nm, suitable for uptake within the gastrointestinal tract due to their nanosize range and mucoadhesive properties. A reversed-phase high-performance liquid chromatographic (HPLC) method has been developed and validated for the determination of nifedipine in nanoparticulate dosage forms. In addition, the delivery behavior of nifedipine from nanoparticles was studied. Nifedipine released from chitosan-alginate nanoparticles was 26.52% at pH1.5, 69.69% at pH6.8 and 56.50% at pH7.4 within 24hour. This suggests that the release of nifedipine from nanoparticles was pH-responsive. Quick release occurred in simulated intestinal fluid (SIF, pH6.8) and phosphate buffer solution (pH7.4), while the release was slow in simulated gastric fluid (SGF, pH1.5). The release profile was characterized by an initial burst effect in three media, followed by a continuous and controlled release phase, the drug release mechanism from polymer was due to Fickian diffusion. PMID- 23675095 TI - Cannabinoid receptor activation in the nucleus tractus solitaries produces baroreflex-like responses in the rat. AB - The effects of cannabinoids on the baroreflex have been investigated in the nucleus tractus solitarii (NTS). In urethane-anesthetized rats, microinjection of the cannabinoid (CB) receptor agonist WIN 55212-2 (100 mM) into the NTS produced a short lasting decrease in arterial pressure (from 95.2 +/- 2.9 to 76.2 +/- 1.5, n=5, P<0.05) but no change in the heart rate. Another cannabinoid agonist, CP 55940 (100 mM) also caused hypotensive responses (from 90.2 +/- 11.3 to 66.4 +/- 12.3 mmHg, n=5, P<0.05). Simultaneous sympathetic nerve discharge recordings showed suppression prior to the arterial pressure lowering effect of these agonists. Microinjection of the cannabinoid receptor antagonist, AM 281 (70 mM) did not cause any significant change in arterial pressure (from 100.8 +/- 12 mmHg to 108.1 +/- 12.8 mmHg, n=5, P>0.05) though it inhibited the agonist-induced responses. The non-NMDA receptor antagonist, DNQX (4 mM) microinjections antagonized the actions of CB agonist WIN 55212-2. Furthermore, sinoaortic denervation attenuated the responses to CB agonists suggesting an intact baroreflex arc is necessary to elicit CB-mediated effects. Neither WIN 55212-2 nor AM 281, altered baroreceptor reflex activation by bolus phenylephrine (25 microg//kg) injections. These data suggest that cannabinoid receptors in the NTS are not involved in the tonic regulation of the arterial pressure but may have a modulatory role in the baroreceptor reflex integration. PMID- 23675096 TI - Kinetic spectrophotometric determination of biotin in pharmaceutical preparations. AB - A simple accurate kinetic spectrophotometric method was developed for the determination of biotin in pure form and pharmaceutical preparations. The proposed method is based on a catalytic acceleration of biotin on the reaction between sodium azide and tri-iodide in an aqueous solution. Concentration range of 4-16 MUg/mL for biotin was determined by measuring the decrease in the absorbance of tri-iodide at 348 nm by a fixed time method. The decrease in absorbance after 14 min from the initiation of the reaction was markedly correlated to the concentration with correlation coefficient of 0.9999. The detection limit (LOD) of biotin was 0.18 MUg/mL while quantitation limit (LOQ) was 0.54 MUg/mL. The percentage recovery of the spiked samples was 100.08 +/- 0.761. The proposed procedure was successfully applied for the determination of biotin in its pharmaceutical preparations with mean recoveries of 101.17 +/- 2.05 and 97.87 +/- 1.50 for biotin ampoules and capsules, respectively. The results obtained were in good agreement with those obtained using official method. PMID- 23675097 TI - Lower-Dose and Long-Term Intermittent Interferon Therapy for Hepatitis C Genotype 2a may be a Possibility. AB - We report two recent, successful cases in treating active chronic hepatitis C patients (genotype 2a) with a lower-dose and long-term intermittent interferon therapy. Case 1: A 67-year-old female received IFN-alpha 3 MU twice a week. Biochemical and virological remissions were achieved after 4 weeks and 14 months, respectively. We changed the IFN to pegylated-interferon alpha-2a (P-IFN) 45 MUg once a week. After which, we successfully reduced the frequency of injections to once a month while maintaining both remissions. Case 2: A 61-year-old male had received a conventional genetical recombination interferon therapy. However, the hepatitis recurred. He was given IFN-alpha 3 MU once a week. A biochemical remission was achieved after 3 months. After 7 months, we changed the IFN to P IFN 90 MUg once a week, and a virological remission soon occurred. Then, we also could reduce the frequency to once every two months. Our novel strategy using P IFN is safe and economic. PMID- 23675098 TI - TP53 codon 72 Gene Polymorphism Paradox in Associated with Various Carcinoma Incidences, Invasiveness and Chemotherapy Responses. AB - TP53 is the most common mutated gene in human cancers. Approximately half of all human malignancies exhibit TP53 mutations. The TP53 codon 72 polymorphism is a single-nucleotide polymorphism (SNP) in exon 4, resulting in the expression of either arginine (CGC) or proline (CCC) residues. In this article, we review literatures published in MEDLINE, and attempt to describe how these two polymorphic variants of TP53 are functionally distinct, and how they influence cancer vulnerability and response to chemotherapy. The Arg72 variant has been shown to be more likely to induce apoptosis than the Pro72 variant, due to its ability to localize itself to mitochondria and trigger the release of cytochrome c into the cytosol. However, the influence of the TP53 codon 72 polymorphism on the risk of developing various cancers, and their progression remains inconclusive because there has been no sustained evidence supporting a crucial role for the codon 72 variant in cancer therapy till now. We hypothesize that TP53 gene might not only be involved in cell cycle control and the apoptosis induction response to DNA damage, but may also modulate individual cancer risk, and that this may correlate with the biofunctions of the two codon 72 variants. Additionally, latent factors might function synergistically with codon 72 variants to confer susceptibility to cancer development, progression, prognosis, and therapeutic responsiveness. Further etiological investigations are essential to reveal the association of and interaction between genetic and environmental factors in relation to carcinogenesis. PMID- 23675099 TI - Forgotten radicals in biology. AB - Redox reactions play key roles in intra- and inter-cellular signaling, and in adaptative processes of tissues towards stress. Among the major free radicals with essential functions in cells are reactive oxygen species (ROS) including superoxide anion (O2 (*-)), hydroxyl radical ((*)OH) and reactive nitrogen species (RNS) such as nitric oxide ((*)NO). In this article, we review the forgotten and new radicals with potential relevance to cardiovascular pathophysiology. Approximately 0.3% of O2 (*-) present in cytosol exists in its protonated form: hydroperoxyl radical (HO2 (*)). Water (H2O) can be split into two free radicals: (*)OH and hydrogen radical (H(*)). Several free radicals, including thiyl radicals (RS(*)) and nitrogen dioxide (NO2 (*)) are known to isomerize double bonds. In the omega-6 series of poly-unsaturated fatty acids (PUFAs), cis-trans isomerization of gamma-linolenate and arachidonate catalyzed by RS(*) has been investigated. Evidence is emerging that hydrogen disulphide (H2S) is a signaling molecule in vivo which can be a source of free radicals. The Cu-Zn superoxide dismutase (SOD) enzyme can oxidize the ionized form of H2S to hydro-sulphide radical: HS(*). Recent studies suggest that H2S plays an important function in cardiovascular functions. Carbonate radical, which can be formed when (*)OH reacts with carbonate or bicarbonate ions, is also involved in the activity of Cu-Zn-SOD. Recently, it has been reported that carbonate anion were potentially relevant oxidants of nucleic acids in physiological environments. In conclusion, there is solid evidence supporting the formation of many free radicals by cells leading which may play an important role in their homeostasis. PMID- 23675100 TI - QSAR Study on a Series of Protein Tyrosine Phosphatase 1B Inhibitors. AB - As a therapeutic target, protein tyrosine phosphatase 1B (PTP1B) has received considerable attention for the treatment of diabetes mellitus. A QSAR study using substituted monocyclic and polycyclic thiophene derivatives, recently reported as potent PTP1B inhibitors, was carried out. More than 60 physicochemical descriptors were calculated which underwent rational selection before their use in derivation of QSAR models. Statistically significant equations were generated using multiple linear regression analysis. External validation of the derived models with test set compounds proved good predictability of the models. Interpretation of the results revealed lipophilicity as a key regulatory feature which affects PTP1B inhibition along with several electronic and steric parameters. The study provides an important platform upon which novel rationally designed molecules can be synthesized with cautious optimism. PMID- 23675101 TI - Spectrophotometric Determination of Pipazethate HCl and Dextromethorphan HBr using Potassium Permanganate. AB - Rapid, simple and sensitive validated spectrophotometric methods have been described for the assay of pipazethate HCl (PiCl) and dextromethorphan HBr (DEX) either in pure form or in pharmaceutical formulations. The proposed methods were based on the oxidation of the studied drugs by a known excess of potassium permanganate in acidic medium and estimating the unreacted permanganate with amaranth dye (method A), acid orange II (method B), indigocarmine (method C) and methylene blue (method D), in the same acid medium at a suitable lambdamax=521, 485, 610 and 664 nm, respectively. Beer's law is obeyed in the concentration range of 2.0-16 and 2.0-15 MUg mL(-1) for PiCl and DEX, respectively with correlation coefficient (n=6) >= 0.9993. The apparent molar absorptivity and sandell sensitivity values are in the range 1.062-1.484 * 10(4), 3.35-4.51 * 10(4) L mol(-1) cm(-1) and 29.36-41.03, 8.21-11.06 ng cm(-2) for PiCl and DEX, respectively. Different variables affecting the reaction were studied and optimized. The proposed methods were applied successfully to the determination of the examined drugs either in a pure or pharmaceutical dosage forms with good accuracy and precision. No interferences were observed from excipients and the results obtained were in good agreement with those obtained using the official methods. PMID- 23675102 TI - Spectrophotometric Determination of Risedronate in Pharmaceutical Formulations via Complex Formation with Cu (II) Ions: Application to Content Uniformity Testing. AB - A simple, sensitive, rapid and accurate spectrophotometric method was developed for the determination of risedronate, a bisphosphonate drug important for the treatment of a variety of bone diseases, in raw material and pharmaceutical formulations. The proposed method is based on complex formation between risedronate and Cu (II) ions in acetate buffer of pH5.5. The optimum conditions for this reaction were ascertained and a spectrophotometric method was developed for the determination of risedronate in concentration range of 2-40 MUg/mL with detection limit of 0.03 MUg/mL (9.51 * 10(-8) mol/L). The molar absorbtivity was 8.00 * 10(3) l/mol/cm. The method was successfully applied for the determination of risedronate in tablet dosage form with mean percentage recovery of 101.04 +/- 0.32. The results obtained were favorably compared with those obtained by the comparison method. Furthermore, the proposed method was applied for content uniformity testing of risedronate tablets. PMID- 23675103 TI - A Validated Adsorptive Stripping Voltammetric Determination of Antidiabetic Agent Pioglitazone HCl in Tablets and Biological Fluids. AB - Square-wave adsorptive cathodic stripping voltammetry was used to determine pioglitazone HCl in Britton Robinson buffer of pH5. The adsorptive cathodic peak was observed at -1.5 V vs. Ag/AgCl. The peak response was characterized with respect to pH, supporting electrolyte, frequency, scan increment, pulse amplitude, accumulation potential and pre-concentration time. Under optimal conditions, the peak current is proportional to the concentration of pioglitazone HCl, and a linear calibration graphs were obtained within the concentration levels of 10(-8) and 10(-4) M following different accumulation time periods (0 300 s). The obtained results were analyzed and the statistical parameters were calculated. The detection limit is 8.08 * 10(-9) M (3.17 ng ml(-1)) using 300 s pre-concentration time, whereas the quantitative limit is 2.45 * 10(-8) M (9.63 ng ml(-1)). The proposed method was applied to assay the drug in pharmaceutical formulations and biological fluids. The pharmacokinetic parameters of drug in human plasma were estimated as: C max=785.8 ng ml(-1), t max=1.5 h, K e=0.125 h( 1) and t 1/2=8 h which are favorably compared with those reported in literature. PMID- 23675104 TI - Antilisterial Activity of Plantaricin UG1 during Manufacture of Zabady and Kareesh Cheese: Two Arabian Dairy Products. AB - Here, plantaricin UG1 was shown to inhibit Listeria monocytogenes LMG10470 (L. monocytogenes) cells. The inhibition was not caused by lactic acid produced by the bacteriocin producing strain Lactobacillus plantarum UG1 (Lact. plantarum). Partially purified plantaricin UG1 had a higher antilisterial activity than Lact. plantarum cells in both Zabady and Kareesh cheese samples during their maturation. Compared to the antilisterial activity in Kareesh cheese, plantaricin UG1 showed a faster effect during Zabady manufacture. PMID- 23675105 TI - Physical parameters of blood as a non - newtonian fluid. AB - Do increasing doses of electromagnetic fields (EMFs) increase the hazards effect on blood? Studies on the blood of rats provide guidance for the assessment of occupational and public health significance of exposure to EMFs. Here, apparent additive viscosity of animal blood after exposing to EMFs (3,5 and 10 gauss) is examined. The results indicate that hematocrite (HCT) increased as EMF increases while the viscocity decreased with the increase of EMF. Red blood cell permeability, deformability and the electrical properties of hemoglobin (conductivity and relaxation time) were also examined. The results show that EMF produces pronounced changes in the molecular structure of hemoglobin and induced force acting on the charged particle of charge q which may activate Rouleau formation of red blood cells (RBCs). PMID- 23675106 TI - Pseudomonas aeruginosa endocarditis in acute myeloid leukemia: a rare complication. AB - Infectious endocarditis is a rarely encountered complication among leukemia patient during induction therapy. We describe a young patient who developed prolonged high fever after aggressive chemotherapy for Acute Myeloid Leukemia. Pseudomonas Aeruginosa endocarditis was found to be the etiology for the febrile state. Our purpose is to emphasize the need for an early diagnosis of this rare, albeit treatable complication. PMID- 23675108 TI - The Contractility of Isolated Rat Atrial Tissue during Hypoxia is Better Preserved in a High- or Zero-Glucose Environment than in a Normal Glucose Environment. AB - AIM: Hyperglycemia is known to be associated with an increase in mortality in myocardial infarction and intensive care patients despite the fact that glucose metabolism plays a central role in myocardial protection. We studied the effect of different glucose levels (22 mM L(-1); 5.5 mM L(-1); and 0 mM L(-1)) on the contractile reserve of isolated rat atrial myocardium during and after hypoxia. METHODS: We observed the contraction of isolated rat atrium strips caused by electrical-field stimulation in a modified Krebs-Henseleit Buffer (KHB) organ bath oxygenated with 95% O2 + 5% CO2 at 37 degrees C. We applied two periods of hypoxia and two periods of reoxygenation. Three glucose concentrations were used in the buffer to study the effect of glucose (high- n=6; normal- n=7; and zero glucose n=6). The effect of isoproterenol 1 MUM L(-1) was tested during the second ischemic period. RESULTS: The main finding was that both a zero-glucose (27.8 +/- 5.9 vs. 14.7 +/- 3 % of baseline tension) and a high-glucose environment (38.5 +/- 14 vs. 14.7 +/- 3 % of baseline tension) had a positive effect in terms of better contractility than the normal-glucose buffer during both the first (p=0.00062) and the second ischemic period (31.2 +/- 5.9 % zero glucose vs. 14.7 +/- 4.2 normal-glucose vs. 35.3 +/- 15.9% high-glucose p=0.0038). CONCLUSION: Both zero-glucose and high-glucose environments resulted in a better contractile reserve in isolated rat atrial myocardium during hypoxia than in a normal one. The exact clinical relevance of this observation is, at present, unclear. PMID- 23675109 TI - Stretching the Limits of Laparoscopy in Gynecological Oncology: Technical Feasibility of doing a Laparoscopic Total Pelvic Exenteration for Palliation in advanced Cervical Cancer. AB - INTRODUCTION: Improving quality of life and supportive care are of paramount importance in helping patients of advanced cervical cancer. Pelvic exenteration has both palliative and curative role in the management of cervical cancer. We aim to demonstrate the feasibility of performing laparoscopic total pelvic exenteration in advanced carcinoma of the cervix and to evaluate the immediate morbidity associated with it. METHODS: We performed laparoscopic total pelvic exenteration in 7 patients of advanced cervical cancer at Galaxy Laparoscopy Institute from August 2005 to December 2007. All patients underwent a diagnostic laparoscopy for assessment of resectibility of the tumor followed by pelvic exenteration in the same operative procedure. The purpose of this procedure was palliation. RESULTS: The mean operative time was 230 +/- 15 min and mean blood loss was 250 +/- 50 ml. Five patients received intra-operative blood transfusions. All patients tolerated the procedure well. No patients required conversion to open surgery. The mean postoperative hospital stay was 8 (7-21) days. The mean follow up was 11 (4-24) months and mean symptom free period was 8 (3-24) months. There was no major and unanticipated post-operative morbidity. There was no immediate post-operative mortality in the present study. DISCUSSION: Laparoscopic total pelvic exenteration is technically feasible and can be offered to carefully selected patients with advanced carcinoma of the cervix. The feasibility of this procedure defines newer limits for the use of laparoscopy in gynecological cancers. PMID- 23675107 TI - Overview of major classes of plant-derived anticancer drugs. AB - Cancer is the second leading cause of death worldwide. Conventional cancer therapies cause serious side effects and, at best, merely extend the patient's lifespan by a few years. Cancer control may therefore benefit from the potential that resides in alternative therapies. The demand to utilize alternative concepts or approaches to the treatment of cancer is therefore escalating. There is compelling evidence from epidemiological and experimental studies that highlight the importance of compounds derived from plants "phytochemicals" to reduce the risk of colon cancer and inhibit the development and spread of tumors in experimental animals. More than 25% of drugs used during the last 20 years are directly derived from plants, while the other 25% are chemically altered natural products. Still, only 5-15% of the approximately 250,000 higher plants have ever been investigated for bioactive compounds. The advantage of using such compounds for cancer treatment is their relatively non-toxic nature and availability in an ingestive form. An ideal phytochemical is one that possesses anti-tumor properties with minimal toxicity and has a defined mechanism of action. As compounds that target specific signaling pathways are identified, researchers can envisage novel therapeutic approaches as well as a better understanding of the pathways involved in disease progression. Here, we focus on 4 classes of natural anticancer drugs: methyltransferase inhibitors, DNA damaging/pro-oxidant drugs, HDAC inhibitors (HDACi), and mitotic disrupters, and we will focus on the mode of action for one promising example per group. PMID- 23675110 TI - The Relationship between Exercise Intensity and Lactate Concentration on the Skin Surface. AB - We examined the relationship between skin surface lactate concentration on working muscle and heart rate during continuous graded cycling exercise. Sixteen healthy male volunteers participated in this study. A plastic container with 100 MUl 1% ethanol was put on the skin surface on the belly of rectus femoris muscle. The workloads were 300, 600, 900 and 1080 (or 990) kpm/min, and each stage was 5 min in duration. Sample collections were performed at rest, during exercise, and recovery. The lactate concentration during exercise significantly increased compared to the basal level (p<0.05 or p<0.001). Skin surface lactate concentration was found to correlate significantly with heart rate at the exercise intensity of 360 kpm/min (r=-0.52, p<0.05), 720 kpm/min (r=-0.74, p<0.01) and 900 kpm (r=-0.53, p<0.05). This study confirmed that 1) the increase in lactate concentration on the skin surface on working muscle is associated with increase in exercise intensity (heart rate), and 2) the skin surface lactate concentration on the working muscle can be used as a parameter of exercise intensity in each subject. PMID- 23675111 TI - The Comparison of the Podocyte Expression of Synaptopodin, CR1 and Neprilysin in Human Glomerulonephritis: Could the Expression of CR1 be Clinically Relevant? AB - Podocytes are considered as the most important cells that determine loss of structure and function of the glomerular filter. We compared the expression of three podocyte markers, i.e.: synaptopodin (SYN), CR1 and neprilysin (NEP) in 107 patients with different forms of glomerulonephritis (GN) and 5 normal kidneys (NK). A quantitative immunohistochemistry was applied to evaluate the expression of podocyte proteins. The results were related with serum creatinine (Scr), estimated glomerular filtration rate (eGFR) and urinary protein. We observed the reduction in the podocyte expression of NEP, SYN and CR1 in proliferative and non proliferative forms of GN. Interestingly, in mesangial proliferative GN (MesPGN), the expression of SYN and CR1 was lower in IgA-MesPGN than in non-IgA-MesPGN (p<0.005 and p<0.02, respectively). In all the patients, the expression of NEP and SYN was positively related (r=0.53, p=0.02) as that of NEP and CR1 (r=0.39, p=0.04). Yet, clinical correlations with Scr (r=-0.33, p=0.03) and eGFR (r=0.26, p=0.05) were obtained only with respect to CR1. In conclusion, SYN, CR1 and NEP may be used as markers of podocyte loss in patients with GN. However, in agreement with previous studies, the clinical relevance draws a special attention to the expression of CR1. PMID- 23675112 TI - A novel high performance liquid chromatographic method for simultaneous determination of ceftriaxone and sulbactam in sulbactomax. AB - An isocratic liquid chromatographic method with UV detection at 220 nm is described for simultaneous determination of ceftriaxone sodium and sulbactam sodium in Sulbactomax. Chromatographic separation of two drugs was achieved on a Hypersil ODS C-18 column using a mobile phase consisting of a binary mixture of acetonitrile and tetrabutyl ammonium hydroxide adjusted to pH7.0 with orthophosphoric acid in ratio 70:30. The developed Liquid Chromatographic method offers symmetric peak shape, good resolution and reasonable retention time for both drugs. Linearity, accuracy and precision were found to be acceptable over the concentration range of 125-750 ppm for ceftriaxone sodium and 62.5-375 ppm for sulbactam sodium. The LC method can be used for the quality control of formulated products containing ceftriaxone and sulbactam. PMID- 23675113 TI - Annual International Geographic Medicine Congress Meetings in Shiraz, Iran: Publication Rates during 1999-2006. AB - The present study aimed to examine which portion of abstracts presented between 1999 to 2006 at Annual International Geographic Medicine Congress meetings in Shiraz, Iran, were published during 1999-2006, and to identify factors affecting publication rate of those abstracts. Two hundred fifty abstracts were reviewed and categorized according to the type of presentation, study design, sample size, main findings, source of funding, and statistical significance of the results. Principal investigators of those abstracts were provided with a questionnaire inquiring whether their abstracts lead to full-length publications in peer reviewed journals indexed under PubMed. One hundred twenty five authors responded to the questionnaire. The publication rate of the meeting presentations was found 27.2%. Statistically significant associations were found between publication rate and certain characteristics of the presentations including type of the study, achieving positive results, and conducting multi-center trial funded by a sponsor. Insufficient fluency in English, insufficient time to prepare the manuscript, and assuming journals are unlikely to accept those studies were most common reasons for not preparing or submitting the manuscripts. The publication rate of research studies presented in this annual scientific meeting in Shiraz, Iran, is lower than many similar meetings in other countries. PMID- 23675114 TI - Comparison of the vertical and the highest point of shoulder methods in brachial plexus block. AB - BACKGROUND AND AIM: Brachial plexus block by the highest point of the shoulder method may decrease the rate of complication in comparing with the vertical method because the needle is more lateral in the former. We aimed to investigate the highest point of the shoulder block technique against the vertical infraclavicular plexus method regarding the success rates and complications. PATIENTS AND METHODS: Thirty patients with ASA I-III undergoing elective surgery were included in this study. Patients were divided into two groups, randomly. Group 1 was the highest point of the shoulder method (n of 15), and goup 2 was the vertical approach technique (n of 15). The extensor motor response of hand, wrist and elbow (The target nerves in the operation area: n. medianus, n. ulnaris, n. radialis and n. musculocutanaeus) was obtained by neurostimulation technique. Then, 30 ml bupivacaine (0.5%) was used for the initial block. Spread of analgesia and sensory and motor blocks were evaluated every 5 minutes by an anesthesiologist who was blind to the block techniques. STATISTICAL ANALYSIS: T test and Mann-Whitney U test were used. RESULTS: Successful block was achieved in all patients in both groups. There was no difference among the groups for the onset of block and the duration of block (both sensory and motor), the number of attempt, and the depth of the neddle. One patient developed pneumothorax in group 2. Procedure time of the block was longer in group 2 than in group 1 (p<0.05). CONCLUSIONS: The highest point of shoulder method with a less complication rate and shorter procedure time has a comparable success rate to vertical approach technique. PMID- 23675115 TI - Adsorptive stripping anodic voltammetric determination of thioctic Acid in bulk and pharmaceutical formulations. AB - The electrochemical behavior of thioctic acid at the hanging mercury drop electrode was studied in different supporting electrolytes. In Britton - Robinson buffer pH 3.29, the square - wave adsorptive anodic stripping voltammogram of thioctic acid exhibited a single well - defined anodic peak at about -0.21 V vs Ag/AgCl. The peak response was characterized with respect to pH, preconcentration time, accumulation potential, supporting electrolytes, frequency, scan increment and pulse amplitude. Under the optimized conditions, a fully validated, simple, high sensitive, precise and inexpensive square - wave adsorptive anodic stripping voltammetric procedure was described for determination of thioctic acid in bulk form and tablets. The obtained results were in good agreement with those obtained with the reference method. The calibration graph was linear over the range 5 * 10(-8) - 9 * 10(-7) M (r=0.9997) with accumulation for 60 s at -0.4 V vs Ag/AgCl and the detection limit was ca. 1.2 * 10(-8) M. PMID- 23675116 TI - The Effects of Meperidine Analgesia during Labor on Fetal Heart Rate. AB - To estimate the effects of intramuscular meperidine analgesia on fetal heart rate (FHR) patterns compared with placebo. In a prospective randomized study, 150 healthy women with singleton term pregnancy requesting analgesia during active labor were planned to receive either intramuscular meperidin 50 mg (meperidin group) or normal saline (control group) when they requested analgesia. Fetal heart rate patterns occurring within 40 minutes of initiation of labor analgesia were retrospectively read by maternal fetal medicine specialist who was blind to type of labor analgesia. Meperidine, compared with placebo, was associated with statistically significantly less beat to beat variability (absent or less than 5 beats per minute) (28% versus 5% of fetuses, P<0.05), lower proportion of accelerations (37.3% versus 17.3% P<0.05) and of the FHR. Also FHR deceleration was significantly more than control group (25.5% versus 4%, P<0.05). Meperidine has deleterious effects on FHR. PMID- 23675117 TI - Development and validation of a new HPLC method for the determination of gabapentin. AB - A simple HPLC method was developed and validated for quantitation of gabapentin in pure form. The HPLC separation was achieved on a C18 5 MUm Waters column (150 mm * 4.6 mm) using a mobile phase of methanol - potassium dihydrogen orthophosphate solution (20:80, v/v) containing 10% NaOH to adjust pH6.2 at a flow rate of 1.0 ml/min. The UV detector was operated at 275 nm. The method was validated for specificity, linearity, precision, accuracy, robustness and limit of quantitation. The degree of linearity of the calibration curves, the percent recoveries, limit of detection and quantitation for the HPLC method were determined. The method was found to be simple, specific, precise, accurate, and reproducible. PMID- 23675118 TI - Evaluation of Hypolipidaemic Activity of Capparis decidua. AB - BACKGROUND: The effect of various extracts (50% ethanolic) of Capparis decidua on lipid profile of streptozotocin diabetic rats was studied. PROCEDURE: The extract was administered to the diabetic models for 30days. FINDINGS: The extract produced a significant (p<0.05) dose-dependent decrease in the levels of total cholesterol (TC), Triacylglycerol (TG), low-density lipoprotein-cholesterol (LDL cholesterol), with a significant increase in the level High-density lipoprotein cholesterol (HDL-C). CONCLUSION: The extracts of Capparis decidua prove to have a hypolipidemic potential. PMID- 23675119 TI - Clinical Outcome of High Risk Gastrointestinal Stromal Tumor in a Meckel's Diverticulum. AB - We describe a seven years follow-up of a high risk gastrointestinal stromal tumor in a Meckel's diverticulum in a 68-year-old man with abdominal pain and vomiting. The patient was operated in emergency for peritonitis due to perforation of small intestine and treated with imatinib mesylate. The metastatic progression of the disease demonstrated the value of prognostic indicators (mitotic rate >10/50 high power field, necrosis and 8 cm in maximum diameter) for assessing risk of aggressive behaviour. Computed tomography was a valuable procedure for detection of local recurrence, the distant metastases and for surveillance after surgery in the follow-up. The review of the literature shows that this case has the longest follow up and consents the comparisons of the same neoplasm in other sites most frequent and better described than Meckel's diverticulum. PMID- 23675120 TI - Idiopathic Benign Hyper-CK-Emia. AB - It is not uncommon for a rheumatologist to get a request for evaluating a patient with persistent elevation of serum creatine (phospho) kinase (CK) level (hyper-CK emia) especially if this laboratory abnormality is persistent. We present a descriptive analysis of 16 consecutive adult patients seen with a condition called idiopathic benign hyper-CK-emia at a tertiary care Rheumatology Clinic in Bismarck, North Dakota. This condition is well described in the medical literature but unfortunately is not recognized very often by the primary care physicians especially its benign course. A short review of literature is also presented. To the best of our knowledge this is the first such report on this condition from the state of North Dakota. PMID- 23675121 TI - Endovascular Treatment of a Ruptured Splenic Artery Aneurysm using Amplatzer((r)) Vascular Plug. AB - Splenic Artery Aneurysms are commonly detected incidentally and can present acutely as a source of intra-abdominal catastrophe. Management options include both surgical and endovascular repair. The role of endovascular repair in an haemodynamically stable acute rupture is undefined and the use of Amplatzer((r)) Vascular Plug has not to our knowledge been reported. PMID- 23675122 TI - Primary tumors of the spleen. AB - Tumors of the spleen are rare compared to the incidence of such tumors in other parenchymatous organs. Their classification has varied with both time and author. They can be divided into two main categories: nonlymphoid and lymphoid. The most common nonlymphoid tumors are the vascular tumors which include benign and malignant haemangiomas, littoral cell angiomas, lymphangiomas and haemangioendotheliomas. The remaining nonlymphoid tumors, such as fibrosarcoma, neurinoma, and lipoma are very uncommon. The lymphoid tumors include Hodgkin's and non Hodgkin's lymphoma, histiocytic lymphoma and plasmacytoma. Metastatic tumors to the spleen mainly originate from melanoma, breast and lung lesions. However, metastases to the spleen are rare compared to those of other parenchymatous organs. PMID- 23675123 TI - Relationship between NK Cell Activation and Clinical Response in Rheumatoid Arthritis Treated with Rituximab. AB - INTRODUCTION: We investigated the relationship between the anti CD20 therapy and the NK cell phenotype in patients with Rheumatoid Arthritis (RA). METHODS: patients with seropositive RA according to the ACR criteria that was refractory to conventional and anti TNF alpha agents were studied. All patients were treated with Rituximab (1.0 g at days 1 and 15). At baseline and day 30 were collected: absolute counts of B cells (CD19+), total T cells (CD3+), helper (CD3+CD4+), cytotoxic (CD3+CD8+) and NK (CD16+CD56+). As NK activation marker was used CD54bright expression. Disease activity was primarily assessed using the the Clinical Disease Activity Index (CDAI); in addition, we calculated the Disease Activity Score 28-joint assessment (DAS28). RESULTS: 18 patients were enrolled (mean age +/- SD 58.6 +/- 2.8 years old). After the rituximab course, as expected CD19+ cells were not detectable, the cytotoxic lymphocytes and CD56+CD16+ cells downregulated (283 +/- 34 and 85 +/- 15 respectively), instead an up regulation of CD56+CD16+CD54bright was observed (187 +/- 43). The dynamic of NK cells activation was significantly associated with clinical variables (r=0.811, p<0.001). CONCLUSIONS: our data suggest a role of rituximab therapy in varying NK phenotype in patients with RA and show that NK cells activation correlates with clinical response. PMID- 23675124 TI - Mycobacterium xenopi: Evidence for Increased Rate of Clinical Isolation. AB - In light of recent reports of increased isolation of M. xenopi, we reviewed the number of M. xenopi isolates in a hospital setting over five years. A total of 133 isolates from 100 patients were reported, of these isolates, 8 were reported over the first two years, 21 isolates in the third year, 47 isolates in year four and 57 isolates in year five. The specimen sources were mainly respiratory specimens; however a few specimens were isolated from other sources. Clinical data on 12 patients with repeated isolates are presented. Patient conditions upon admission and previous medical histories are shown and compared to earlier reports. An increased awareness of the presence of this organism is necessary since the clinical presentation of patients with M. xenopi can be confused with tuberculosis. PMID- 23675125 TI - Pneumococcal serotypes recovered from health children and their possible association with risk factor in istanbul, Turkey. AB - Streptococcus pneumonia is an increasing problem worldwide and nasopharyngeal colonization plays an important role in pneumococcal infections. The aims of this study were to assess the nasopharyngeal colonization rate, investigate the risk factors for nasopharyngeal colonization with S. pneumonia, serogroup and penicillin susceptibility patterns of Streptococcus pneumoniae strains isolated from healthy children. A single swab was obtained over the nasopharyngeal walls of the 500 healthy children, of which 25 (5%) were found to be carriers. The carrier rate was significantly higher in the seven-nine years-old age group. Upper respiratory tract infection within the last month (OR=1.1, p>0.001), day care attendance (OR=3.1, p: 0.02), and the presence of more than five people living in the house of the child (OR=0.2, p: 0.003) have been determined to be risk factors for S. pneumoniae carriage. The most prevalent serogroups in descending order were 9, 19, 23, 6, 10 and 18 and these are in accordance with conjugated pneumococcal vaccine (PCV7). No penicillin-resistant S. pneumoniae were obtained. CONCLUSION: after conjugated vaccine we have seen benefits of vaccine in especially colonization rate and penicillin-resistance. PMID- 23675126 TI - Dyslipidaemia and Intima-Media Thickness of Carotid Arteries in Thirty-Five HIV/AIDS Patients Receiving Highly Active Antiretroviral Therapy. AB - OBJECTIVES: Highly active antiretroviral therapy (HAART) has being impacted significantly therapies for natural human immunodeficiency virus (HIV) infection, which leads to a remarkable decrease in its morbidity and mortality but it is frequently associated with metabolic complications such as dyslipidaemia and cardiovascular complications. HIV reverse transcriptase (RT) inhibitors can be classified into nucleoside and non-nucleoside types. Mitochondrial dysfunction due to the depletion of mt-DNA is partly responsible for various nucleoside RT inhibitors-associated adverse effects including dyslipidaemia. Efavirenz (EFV) is metabolized primarily by cytochrome P450 2B6 (CYP2B6) and the metabolic effects of EFV have been described previously. All patients in this study received the same HAART treatment regime (Stavudine (d4T) + Lamivudine (3TC) + Efavirenz (EFV)). This study aims to assess incidences for dyslipidaemia and atherosclerosis. METHODS: This retrospective study was conducted within outpatients of Shanghai Public Health Center. We selected thirty-five HIV-1 infected patients who receiving highly active antiretroviral therapy. Their mean CD4 cell count was 69.5 (+/-34.6) copies per micro liter before therapy. Fasting total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol values were respectively compared among patients at present and before therapy. Then the data was statistically analyzed. Twenty-two patients had the intima-media thickness (IMT) of their carotid arteries measured by Philips 5000 Color-Doppler ultrasound tests. RESULTS: After therapy, patients achieved significant changes in levels of triglycerides (1.44 +/- 0.35mmol/L Vs. 2.07 +/- 0.54mmol/L) (P<0.001), total cholesterol (4.96 +/- 0.46 mmol/L Vs. 6.15 +/- 0.83mmol/L) (P<0.001) and LDL cholesterol (2.29 +/- 0.33 Vs. 3.11 +/- 0.29 mmol/L) (P<0.001). In contrast, the level of HDL cholesterol did not significantly change (1.06 +/- 0.01 mmol/L Vs. 1.04 +/- 0.01 mmol/L) (P>0.5). The mean IMT of twenty-two patients was (0.86 +/- 0.14) mm after HAART, which is higher than the norm age-matched value of (0.7 +/- 0.2) mm (P<0.05). RESULTS: After therapy, patients achieved significant changes in levels of triglycerides (1.44 +/- 0.35mmol/L Vs. 2.07 +/- 0.54mmol/L) (P<0.001), total cholesterol (4.96 +/- 0.46 mmol/L Vs. 6.15 +/- 0.83mmol/L) (P<0.001) and LDL cholesterol (2.29 +/- 0.33 Vs. 3.11 +/- 0.29 mmol/L) (P<0.001). In contrast, the level of HDL cholesterol did not significantly change (1.06 +/- 0.01 mmol/L Vs. 1.04 +/- 0.01 mmol/L) (P>0.5). The mean IMT of twenty-two patients was (0.86 +/- 0.14) mm after HAART, which is higher than the norm age-matched value of (0.7 +/- 0.2) mm (P<0.05). CONCLUSION: These data suggest that HAART is potentially dangerous for hyperlipidaemia and maybe an increase in atherosclerosis. PMID- 23675127 TI - Myeloperoxidase to risk stratify emergency department patients with chest pain. AB - Previous studies suggest that serum myeloperoxidase (MPO) is a potentially useful biomarker to risk stratify troponin-negative patients with suspected myocardial ischemia. We hypothesized that the relationship between initial serum MPO levels would correlate with 30-day adverse cardiac outcomes for low risk emergency department (ED) patients with suspected myocardial ischemia. This prospective cohort study enrolled ED patients with chest pain or suspected myocardial ischemia, non-diagnostic ECG, and initially negative cardiac troponin I. We defined 30-day adverse cardiac events as death, myocardial infarction, or coronary revascularization. We calculated summary statistics, standard deviation (SD), odds ratios (OR), 95% confidence intervals (CI), and receiver operating characteristics (ROC). We enrolled 159 patients who had a mean age of 55 +/- 13, were 56% female, of whom 5.2% suffered at least one adverse cardiac event. MPO test characteristics were poor, with an ROC area of only 0.47 (CI 0.23-0.71). MPO levels were not associated with adverse events (OR 0.99, CI 0.98-1.01, p=0.62). The optimal ROC cutpoint to predict adverse cardiac events had poor sensitivity and specificity (57% and 52%, respectively). Mean MPO concentrations in the event group did not differ from the non-event group. In this limited cohort of low risk ED patients with chest pain, we were unable to demonstrate utility of MPO for risk stratification. If confirmed in larger studies, these findings may call into question the routine use of MPO for low-risk chest pain. PMID- 23675128 TI - Second derivative synchronous fluorescence spectroscopy for the simultaneous determination of chlorzoxazone and Ibuprofen in pharmaceutical preparations and biological fluids. AB - A rapid, simple and highly sensitive second derivative synchronous fluorometric method has been developed for the simultaneous analysis of binary mixture of chlorzoxazone (CLZ) and ibuprofen (IP). The method is based upon measurement of the synchronous fluorescence intensity of these drugs at Deltalambda=60 nm in methanol. The different experimental parameters affecting the fluorescence of the two drugs were carefully studied and optimized. The fluorescence-concentration plots were rectilinear over the range of 0.2-4 MUg/mL and 0.1-1.6 MUg/mL for CLZ and IP, respectively with lower detection limits (LOD) of 0.028 and 8.3 * 10(-3) MUg/mL and quantification limits (LOQ) of 0.086 and 0.03 MUg/mL for CLZ and IP, respectively. The proposed method was successfully applied for the determination of the two compounds in synthetic mixtures and in commercial capsules. The high sensitivity attained by the proposed method allowed the determination of both drugs and real human plasma samples. The mean % recoveries in real human plasma (n=3) were 87.69 +/- 6.15 and 92.57 +/- 4.39 for each of CLZ and IP respectively. PMID- 23675129 TI - Kinetic Spectrofluorometric Determination of Certain Calcium Channel Blockers via Oxidation with Cerium (IV) in Pharmaceutical Preparations. AB - A simple and sensitive kinetic spectrofluorometric method was developed for the determination of some calcium channel blockers namely, verapamil hydrochloride, diltiazem hydrochloride, nicardipine hydrochloride and flunarizine. The method is based upon oxidation of the studied drugs with cerium (IV) ammonium sulphate in acidic medium. The fluorescence of the produced Ce (III) was measured at 365 nm after excitation at 255 nm. The different experimental parameters affecting the development and stability of the reaction product were carefully studied and optimized. The fluorescence-concentration plots were rectilinear for all the studied compounds over the concentration range of 0.01 to 0.12 MUg mL(-1). The limits of detections for the studied compounds ranged from 2.93 * 10(-3) to 0.012 MUg mL(-1) and limits of quantification from 9.76 * 10(-3) to 0.04 MUg mL(-1) were obtained. The method was successfully applied to the analysis of commercial tablets. The results obtained were in good agreement with those obtained with reference methods. PMID- 23675130 TI - Spectrofluorimetric Determination of Famotidine in Pharmaceutical Preparations and Biological Fluids through Ternary Complex Formation with Some Lanthanide Ions: Application to Stability Studies. AB - A simple, sensitive and specific method was developed for the determination of famotidine (FMT) in pharmaceutical preparations and biological fluids. The proposed method is based on ternary complex formation of famotidine (FMT) with EDTA and terbium chloride TbCl3 in acetate buffer of pH 4. Alternatively, the complex is formed via the reaction with hexamine and either lanthanum chloride LaCl3, or cerous chloride CeCl3 in borate buffer of pH6.2 and 7.2 respectively. In all cases, the relative fluorescence intensity of the formed complexes was measured at 580 nm after excitation at 290 nm. The fluorescence intensity - concentration plots were rectilinear over the concentration range of 10-100, 5 70, and 5-60 ng/ml, with minimum quantification limits (LOQ) of 2.4, 2.2, and 5.2 ng/ml, and minimum limits of detection (LOD) of 0.79, 0.74, and 1.7 ng/ml upon using TbCl3, LaCl3, and CeCl3 respectively. The proposed method was applied successfully for the analysis of famotidine in dosage forms and in human plasma. The kinetics of both alkaline and oxidative induced degradation of the drug was studied using the proposed method. The apparent first order rate constant and half life time were calculated. A proposal of the reaction pathways is presented. PMID- 23675131 TI - A Validated Method without Derivatization for the Determination of Gabapentin in Bulk, Pharmaceutical Formulation and Human Urine Samples. AB - A rapid, sensitive and accurate high performance liquid chromatography with UV detection method was developed and validated for the quantification of gabapentin in bulk, pharmaceutical formulation and human urine samples. Most of the published methods for analysis of gabapentin used derivatization with reagent. The present paper however describes the analysis of gabapentin without any derivatization. The chromatographic separation was carried out on a Waters C18 5 MUm column (150 mm * 4.6 mm) using a mixture of methanol - acetonitrile - potassium dihydrogen orthophosphate (pH5.2; 0.028 M) (25:10:65) as a mobile phase with UV detection at 210 nm. The method was linear over the range of 0.1-3.8 mg/ml of gabapentin. The within day and between day precision values are very good. PMID- 23675132 TI - Development and Validation of Pregabalin in Bulk, Pharmaceutical Formulations and in Human Urine Samples by UV Spectrophotometry. AB - A simple and sensitive UV spectrophotometric method was developed and validated for the determination of pregabalin in bulk, pharmaceutical formulations and in human urine samples. The method was linear in the range of 0.5-5.0 MUg/ml. There is no generally accepted method for the determination of pregabalin. The absorbance was measured at 210 nm. The method was validated with respect to accuracy, precision, specificity, ruggedness, and robustness, limit of detection and limit of quantitation. This method was used successfully for the quality assessment of five pregabalin drug products and in human urine samples with good precision and accuracy. This is found to be simple, specific, precise, accurate, reproducible and low cost UV Spectrophotometric method. PMID- 23675133 TI - Investigating the Icr Effect in a Zhadin's Cell. AB - Investigations into the ion cyclotronic resonance (ICR) in living matter confront the so called Zhadin effect (12), whose explanation is not fully achieved. Several attempts have been done to explain this phenomenon, the most interesting of which is based on Quantum Electrodynamics (18): the molecules of water, the ions and the biomolecules form extended mesoscopic regions, called Coherence Domains (CD), where they oscillate in unison between two selected levels of their spectra in tune with a self-produced coherent E.M. field having a well defined frequency, dynamically trapped within the CD. Moreover, it is possible, to induce, by an external applied field (either hydrodynamical or EM) or also by a chemical stimulation, coherent excitations of CD's that give rise to electric currents circulating without friction within the CD's: as a consequence magnetic fields are produced. A resonating magnetic field thus is able to extract the ions from the orbit and push them in the flowing current. Electrochemical investigation of the system suggested that the observed phenomenon involves the transitory activation of the anode due to ICR, followed by anode passivation due to the adsorption of amino acid and its oxidation products (18). This hypothesis induced us to investigate an alternate configuration of the experiment, removing the electrolytic cell and submitting a flask containing the solution into a condenser to be exposed to the proper ICR. Temperature and variable parameters involved in the effect have been investigated in order to overcome the randomness of the effect. PMID- 23675134 TI - Thrombelastography guides transfusion strategy. AB - During surgery for an abdominal aortic aneurysm, coagulation may be impaired and the use of thrombelastography (TEG) is described in six patients with a perioperative blood loss of 3L. During surgery blood products were infused but not platelets. When the patients were admitted to the intensive care unit, the TEG report demonstrated a lowered MA value indicating impaired function of platelets. The use of TEG may guide transfusion strategy. PMID- 23675135 TI - Diabetic ketoacidosis precipitated by henoch-schonlein purpura. AB - Numerous investigations have been devoted to the search for environmental factors controlling the onset of autoimmune diseases. Pancreatic involvement, a rare complication of Henoch-Schonlein purpura, has been found mainly in adults, and it has not been reported in children. We present a case of a severe diabetic ketoacidosis in a child, a 7-year-old boy, following a typical clinical picture of Henoch-Schonlein purpura. Therapy with intravenous insulin resulted in resolution of the diabetic ketoacidosis and resolved the petechial rash of both legs. PMID- 23675136 TI - The potential effects of a biofeedback writing exercise on radial artery blood flow and neck mobility. AB - BACKGROUND: It has been suggested that sustained contraction of the deep neck muscles may reduce axial cervical range of motion (CROM) and radial artery blood flow velocity (vrad.art.mean). No studies have reported both phenomena in relation to acute hand, shoulder or neck trauma. PROCEDURES: The CROM and vrad.art.mean were measured in 20 police officers prior to and immediately after a 2-hours drive on a motorcycle and immediately after a 1-minute writing exercise using biofeedback. The CROM was measured using separate inclinometers and the vrad.art.mean was measured in both arms just proximal to the wrist using echo Doppler. FINDINGS: During the study, one officer had a motorcycle accident resulting in acute symptoms of neck trauma. His vrad.art.mean was acutely reduced by 73% (right arm) and 45% (left arm). Writing with biofeedback increased his vrad.art.mean by 150% (right arm) and 80% (left arm). In the remaining 19 officers, the CROM to the right was significantly increased after the 2-hours driving task (p<0.05; paired subject t-test). Writing with biofeedback increased their CROM in both directions and vrad.art.mean in both arms (p<001). CONCLUSIONS: A 2-hours drive showed modest physical changes in the upper extremities. Biofeedback in writing tasks might relate to the influence of relaxation and diverting attention for neck mobility and arterial blood flow improvement. PMID- 23675137 TI - Idiopathic gingival hyperplasia. AB - Gingival hyperplasia is a rare condition but it is important for cosmetic and mechanic reasons and because of its potential as an indicator of systemic disease. Gingival fibromatosis may exist as an isolated abnormality or as part of a syndrome. In this article a case that was diagnosed clinically and histologically as idiopathic gingival fibromatosis is presented. Patient with gingival hyperplasia should be examined to exclude other reasons to determine the idiopathic gingival fibromatosis or not. Treatment is not required in all cases of idiopathic gingival hyperplasia. Surgical excision is indicated if mechanical problems exist. Recurrence has not been reported. PMID- 23675138 TI - Robot-assisted laparoscopic radical prostatectomy: technique and outcomes of 700 cases. AB - BACKGROUND: Robotic prostatectomy techniques are evolving rapidly as the procedure gains popularity and continues to be compared to the gold standard of open retropubic radical prostatectomy. Our objective is to report the operative technique and outcomes of 700 consecutive robotic radical prostatectomies performed by a single surgeon at Mount Sinai Medical Center between May 2007 and October 2008. Data was prospectively collected in an Internal Review Board (IRB) approved database. SURGICAL PROCEDURE: Key aspects of our technique include 1) dissection of the bladder neck first; 2) minimal to no use of cautery from posterior bladder neck dissection onward; 3) leaving endopelvic fascia intact until after neurovascular bundles dissected; 4) preservation of a wide margin of endopelvic fascia; 5) posterior dissection and nerve-sparing in a medial to lateral direction; 6) cold transection of the dorsal venous complex without prior ligation; and 7) posterior bladder neck reconstruction. RESULTS: Mean OR time from skin incision to skin closure was 124 minutes [48-266]; mean robotic time was 88 minutes [36-190]. Mean EBL was 69.3ml [5-400]. Mean and median length of stay was 1 day. Overall complication rate was 3.3% with no mortalities and no conversions to open or laparoscopic approaches. The overall positive margin rate (PMR) was 11.9%. PMR was 1.4% for pT2a, 0% for pT2b, 8.3% for pT2c, 39.7% for pT3a, and 56.7% for pT3b. Biochemical recurrence rate at one year was 1.7%. Continence rate by 12 months was 94%. Potency rate by 12 months was 83%. CONCLUSIONS: Both perioperative and postoperative outcomes of our series of robotic prostatectomies performed by a single surgeon at Mount Sinai Medical Center demonstrate the superb outcomes that can be achieved through this modality of treatment. PMID- 23675139 TI - Trends in Outcomes and Hospitalization Charges among Mechanically Ventilated Patients with Myasthenia Gravis in the United States. AB - INTRODUCTION: To assess the impact of new therapeutic strategies on outcome and cost of hospitalization among patients with myasthenia gravis (MG) who are mechanically ventilated in United States. METHODS: Using a retrospective analysis of cross sectional survey, we determined the rates of occurrence, in-hospital outcomes, and mean hospital charges for patients hospitalized with MG requiring mechanical ventilation in 1991-1992 using the Nationwide Inpatient Survey (NIS) and compared these outcomes with homologous data from 2001-2002. NIS is the largest all-payer inpatient care database in the United States. RESULTS: When comparing data from 2001-2002 with data from 1991-1992, we found a higher number of admissions for MG that required mechanical ventilation (994 vs. 652). The proportion of women was similar (53% vs. 60%). The average age (in years +/- standard deviation) was significantly higher (65 +/- 17 vs. 58 +/- 18, p=0.0002). The length of hospitalization (in days +/- standard deviation) was not different (22 +/- 19 vs. 21 +/- 16). Discharge to home occurred less frequently (29% vs. 60%, p=0.0001) and in hospital mortality minimally lower (13% vs. 15%). There was a significant increase in mean hospital charges ($118,000 vs. $84,100 adjusted for inflation, p=0.0001). In hospital mortality was higher among urban teaching hospitals compared with urban non teaching hospitals in 2001-2002. CONCLUSIONS: Despite improvement in therapeutic strategies from 1991 to 2002, there was only a modest reduction in mortality and no substantial reduction of length of hospitalization for patients with MG requiring mechanical ventilation. PMID- 23675140 TI - The role of lithium carbonate and lithium citrate in regulating urinary citrate level and preventing nephrolithiasis. AB - BACKGROUND AND PURPOSE: Urinary Citrate is an inhibitor of Calcium oxalate stone formation. It is reabsorbed in the proximal kidney through sodium dicarboxylate co-transporters (NaDC-1, NaDC-3) present in the renal tubular epithelium. Lithium (Li) is a known potent inhibitor of these transporters. We investigated the effect of lithium carbonate (LiC) and lithium citrate (LiCit) in regulating urinary citrate levels and preventing nephrolithiasis (NL) in the rat model. EXPERIMENTAL APPROACH: We took 220 Wistar rats and induced nephrolithiasis in 130 of them by administering high doses of 5% ammonium oxalate (AmOx) for seven days and labeled them as Group B. Rest were labeled as Group A. Each group was then divided into 3 subgroups. First sub-group acted as control while other two were treated with either lithium carbonate (LiC) or lithium citrate (LiCit) for 21 days. Ten rats from each of the six sub-groups were randomly selected for sacrifice on 3(rd), 7(th) and 14(th) day and additional 10(th) and 21(st) day from Li treated groups. Blood and urine samples were collected and analyzed on these days. The kidneys of the sacrificed rats were dissected and studied under light microscopy for crystal deposition (left kidney) and histological changes (right kidney). KEY RESULTS: Urinary citrate levels were significantly increased in response to either LiC (p<0.001) or LiCit (p<0.001). Increased urinary citrate levels resulted in the reduction of calcium oxalate (CaOx) crystal deposition, kidney tubular dilatation and infiltration of inflammatory cell in the tubulo interstitium. CONCLUSIONS AND IMPLICATIONS: Use of lithium salts might be a potentially useful approach in the prevention of recurrent NL. PMID- 23675141 TI - Kinetics of BCR-ABL Transcripts in Imatinib Mesylate treated Chronic Phase CML (CPCML), A Predictor of Response and Progression Free Survival. AB - PURPOSE: To assess the kinetics of molecular response to Imatinib Mesylate (IM) therapy in predicting progression free survival (PFS), sustained hematological, and cytogenetic responses in CPCML. METHODS: Ninety five newly diagnosed CPCML Egyptian patients were treated with IM 400 mg daily dose. Cytogenetic analysis was performed at diagnosis and every 6 months. Molecular monitoring by RT-QPCR was performed at diagnosis and every 3 months during a median follow-up period (FUp) of 26 months. Mutation detection of ABL domain was performed by ASO-PCR. RESULTS: Hematological response was 98% after three months of IM therapy. Out of 95 patients 59 showed 2 log reduction of BCR-ABL/ABL ratio after 6 months of whom 49 (83%) had complete cytogenetic response (CCyR) and 42 (71%) had major molecular response (MMR) at 12 months. BCR-ABL transcripts remained undetectable in 22 patients (39%) at 26 months. Among the remaining 34 patients not achieving 2 log reduction at 6 months only 5 (15%) had CCyR and MMR by 12 months. ABL domain mutations were detected in 11/15 (73%) resistant and suboptimal responding patients. Achieving 2 log reduction after 6 months of IM therapy significantly correlated with sustained cytogenetic and molecular responses (p<0.0001), with PFS at 2 years (p<0.03) and inversely with ABL gene mutations (p<0.001). DISCUSSION: These data demonstrated the predictive value of early molecular response to IM in CPCML regarding disease course and PFS. A 2 log reduction at 6 months of IM treatment could be a cut off level predicting resistance, CCyR, or suggesting IM dose modification. PMID- 23675142 TI - Evaluation of ginkgo biloba extract on hematological changes affected with hazards of electromagnetic field exposure. AB - The aim of the present work is to study if the GBE 761 (Ginkgo biloba leaves extract) which is beneficial in arterial disease owing to its vasodilator and blood flow acts against the hazards of exposure to electromagnetic field. Here, the GBE was used in two ways either as a protector or for treating the hazards due to exposure to electromagnetic field (EMF). For this purpose, albino rats were grouped into six groups and blood samples were collected from eye vein of the animals from all groups at the end of the experiment. This study concentrates on the cellular membrane and function of the RBCs and focuses on the rheological and physical measurements for blood and hemoglobin molecule because the RBCs membranes play an essential role in the blood flow rate. The changes in its biophysical properties of RBCs membrane will affect its capability for carrying on its metabolic functions. Furthermore, the molecular diameter of hemoglobin, its relaxation time and conductivity were calculated from the dielectric relaxation data. The results indicate that the administration of GBE led to the decrease of RBCs membrane elasticity will lead to the increase of the blood viscosity. Results suggest that GBE may be not of clinical value as anti-oxidant drug for such diseases occurred due to to EMF exposure for long time. It may be conclude that through treatment with those extract some physical measurements like "viscosity of blood, Osmotic fragility to measure the hemolysis rat of RBCs, the radius and the conductivity of hemoglobin molecule" should be considered during the time of treatment. Overall, these leaves (GBE) need more study and there is a recommendation to put the physical parameters parallel to the clinical study. PMID- 23675143 TI - Engineered FADD Induces Apoptosis via an Artificial Death-Inducing Signaling Complex (DISC). AB - An engineered Fas-associated death domain protein (FADD), 2DEDplusE-made previously by fusing the tandem DEDs of FADD to the E protein of lambda phage greatly enhances apoptosis-inducing activity in adherent cells in vitro. To investigate the mechanism of apoptosis-inducing activity of this engineered FADD, we compared the apoptosis-inducing activity of various other engineered FADDs. The tandem DED of 2DEDplusE contributed most to the enhancement of apoptosis, and the E protein contributed moderately. The engineered factor produced artificial death-inducing signaling complex (DISC)-like signals in the cytoplasm that appear as grains under fluorescence microscopy. Membrane blebbing associated with apoptosis was observed just after formation of grain-like signals. Immunoprecipitation analysis demonstrated that 2DEDplusE-FLAG can bind p43/p41 forms of caspase 8 but E protein-FLAG cannot. Gel filtration analysis demonstrated that 2DEDplusE forms a large complex containing partially cleaved procaspase 8 (p43/p41) in the cytoplasm; the size of this complex varies greatly. In the absence of an extrinsic signal, the engineered FADD formed artificial DISC in the cytoplasm, and then its tandem DED activated procaspase 8, which in turn executed apoptosis. The engineered FADD complex closely mimicked intrinsic DISC and increased apoptosis-inducing activity. PMID- 23675144 TI - Role of Calcium Signals on Hydrogen Peroxide-Induced Apoptosis in Human Myeloid HL-60 Cells. AB - The present study is aimed to determine the role of calcium signaling evoked by the oxygen radical, hydrogen peroxide (H2O2) and the specific inhibitor of calcium reuptake thapsigargin on apoptosis in the human leukemia cell line HL-60. Our results show that treatment of HL-60 cells with 100 uM H2O2 and 1 uM thapsigargin induced a transient increase in cytosolic free calcium concentration ([Ca(2+)]c) due to calcium release from internal stores. These stimulatory effects on calcium signals were followed by activation of the mitochondrial permeability transition pore (mPTP), as well as a time-dependent increase in caspase-9 and -3 activities. Our results also show that H2O2 and thapsigargin were able to increase the relative content of fragmented DNA and phosphatidylserine externalization, as detected by double-staining with propidium iodide (PI) and annexin-V-FITC, respectively. Treatment of cells with H2O2 or thapsigargin resulted in activation of the proapoptotic protein Bid. Furthermore, coimmunoprecipitation experiments showed active Bax was bound to Bid, which regulates Bid activity and promotes apoptosis. Our findings suggest that H2O2(-) and thapsigargin-induced apoptosis is dependent on rises in [Ca(2+)]c in human myeloid HL-60 cells. PMID- 23675145 TI - Cord plasma concentrations of visfatin, adiponectin and insulin in healthy term neonates: positive correlation with birthweight. AB - OBJECTIVE: The aims of this study were to examine the relationships between adiponectin, insulin, visfatin and weight at birth in healthy term infants. DESIGN AND METHODS: Anthropometric parameters including weight, length were measured and plasma lipid profiles, insulin, visfatin and adiponectin concentrations in cord blood samples from 50 LGA and 50 AGA singleton infants born at term after uncomplicated pregnancies were assayed. RESULTS: Mean visfatin and adiponectin levels were significantly higher in the LGA group than AGA group (11.8 +/- 8 vs. 6.3 +/- 5.5 ng/ml, p<0.001; 28.4 +/- 3.9 vs. 25.7 +/- 3.6 MUg/ml, p=0.001; respectively). Insulin, triglyceride, total cholesterol, HDL-cholesterol and LDL-cholesterol levels did not differ significantly between LGA and AGA infants. Cord plasma adiponectin, visfatin and insulin levels correlated significantly and positively with birthweight (p=0.01, p<0.001, p<0.001; respectively) and with birthlength (p=0.01, p<0.001, p=0.01; respectively). Cord plasma adiponectin concentration correlated positively with visfatin level (p=0.005), but not with insulin level (p=0.8), and cord plasma visfatin concentration correlated positively with insulin level (p<0.001). CONCLUSION: High adiponectin and visfatin levels are present in the cord blood in LGA group. Cord plasma adiponectin and visfatin levels are positively correlated with birthweight. This suggests that adiponectin and visfatin may be involved in regulating fetal growth. PMID- 23675146 TI - Spectrophotometric determination of labetalol and lercanidipine in pure form and in pharmaceutical preparations using ferric-1,10-phenanthroline. AB - A simple and sensitive spectrophotometric method was developed for the determination of labetalol HCl (LBT) and lercanidipine HCl (LER) in pure form and in dosage forms. The method was based upon oxidation of the LBT and LER with Fe(+3) and the estimation of the produced Fe(+2) with 1,10-phenanthroline. The absorbance of the tris(1,10-phenanthroline) Fe(+2) complex was measured at 510 nm. Reaction conditions were optimized to obtain colored complex of higher sensitivity and longer stability. The absorbance concentration plots were rectilinear over the concentration rang of 5-90 and 1-20 MUg/mL with lower detection limits of 0.74 and 0.01 MUg/mL and quantification limits of 2.26 and 0.02 MUg/mL for LBT and LER, respectively. The developed method was successfully applied for the determination of LBT and LER in bulk drugs and dosage forms. The common excipients and additives did not interfere in their determinations. There was no significant difference between the results obtained by the proposed and the reference methods regarding Student t-test and the variance ratio F-test. PMID- 23675147 TI - Spectrophotometric methods for the determination of cefprozil in bulk and dosage form. AB - Two simple spectrophotometric methods were developed for the determination of cefprozil in pure bulk and in tablets forms. The first is a colorimetric method based on the coupling of cefprozil, after being hydrolyzed by sodium hydroxide (0.1N), with ascorbic acid as a chromogen (method A). It has been established that cefprozil reacts with ascorbic acid to form a 1:1 water soluble colored product with maximum absorbance (lambdamax) at 408 nm and molar absorptivity of 7.2 * 10(3)L mol(-1) cm(-1). The second method (Method B) utilizes a direct reaction between cefprozil and sodium hydroxide (1N). A colored product with lambdamax at 486 nm and molar absorptivity of 7.4 * 10(3) L mol(-1) cm(-1) is formed after heating cefprozil with sodium hydroxide (1N). The absorbance concentration plot was rectilinear over the range 5-25 ug/ml in both methods with correlation coefficient values not less than 0.999. The detection limits (L.O.D.) were 0.96 ug/ml and 0.93 ug/ml for method A and method B respectively. The methods were validated using the USP liquid chromatography method for cefprozil assay. The results obtained by the USP liquid chromatography method for the tablets dosage form were statistically compared with those of the developed methods and evaluated at 95% confidence limits. PMID- 23675148 TI - The effect of bone morphogenetic protein 4 on the differentiation of mouse embryonic stem cell to erythroid lineage in serum free and serum supplemented media. AB - This study was done to compare the effects of bone morphogenetic protein-4 (BMP 4) on mouse embryonic stem cells (ESC) differentiation to erythroid lineage in serum free and serum supplemented media. The embryoid bodies (EBs) cells were seeded in semisolid serum free and serum supplemented media in the presence of different concentrations of BMP-4. The erythroid colonies were assessed morphologically, ultrastructurally and by benzidine staining. The expression of the epsilon (epsilon), betaH1 and betamajor globins, Runx1 and beta2m genes was evaluated by Real time PCR. The colony size and the percent of benzidine-positive colonies increased in both BMP-4 supplementd groups but the number of colonies were lower in these groups than control. Erythropoiesis related genes were expressed in both serum free and serum supplemented groups. There were not significant differences between the ratios of genes expression to beta2m in these groups except the ratio of Runx1 was significantly higher in serum free group (P<0.05). The ratio of epsilon and betaH1 to beta2m in EBs was higher than both BMP-4 containing groups (P<0.05) and betamajor was not expressed in EB cells. These findings showed in serum free condition the effects of BMP-4 on the erythroid differentiation was prominent than serum supplemented group. PMID- 23675149 TI - Spectrophotometric, spectrofluorimetric and voltammetric analyses of naftidrofuryl oxalate in its tablets. AB - THIS WORK DEALS WITH SEVERAL DIRECT AND INDIRECT SPECTROPHOTOMETRIC, SPECTROFLUORIMETRIC AND VOLTAMMETRIC ANALYSES OF THE VASODILATOR DRUG: naftidrofuryl oxalate (NF). For the derivative spectrophotometric measurement, NF was determined by measuring the peak to peak amplitude of (1)D263-299 and (2)D282 311 or the absolute peak height of (1)D237 and (2)D241, while its reaction product with concentrated sulfuric acid was determined by measuring the peak to peak amplitude of (2)D248-263 or the absolute peak height of (1)D275. For the spectrofluorimetric measurement, native NF fluorescence was measured in Britton Robinson buffer (pH 5) at lambdaem = 331 nm (lambdaex = 277 nm), while the reaction product was measured in aqueous solution at lambdaem = 385 nm (lambdaex = 258 nm). All factors affecting these analyses were studied and optimized. This work also describes a differential pulse cathodic voltammetric determination of the NF reaction product with concentrated sulfuric acid at the hanging mercury drop electrode (HMDE) where the experimental conditions affecting analysis including buffer pH, pulse amplitude and scan rate were examined and optimized. The chemical structure of the reaction product with concentrated sulfuric acid was investigated using several spectroscopic methods. All the developed procedures were validated and satisfactorily applied for the determination of NF in its pharmaceutical tablets. PMID- 23675150 TI - A simple stabilization method of reduced albumin in blood and plasma for the reduced/oxidized albumin ratio measurement. AB - Albumin (Alb) is mixture of reduced and oxidized forms. It is physiologically significant to determine Alb(red)%, which is the proportion of reduced Alb in the sum of Alb. However, reduced Alb in both blood and plasma samples is easily converted to oxidized Alb. Accordingly, the stabilization of Alb in samples is necessary to determine precise Alb(red)% values. Alb stabilization in blood or plasma was achieved by pH control and buffer dilution. At least a 50-fold dilution with 50 mmol/l phosphate buffer (pH 6.0) was required for human plasma. For human blood, a 10-fold dilution with 0.5 mol/l sodium citrate buffer (pH 4.3) was required. To measure Alb(red)%, treated samples were applied to HPLC or LC ESI-TOFMS. We also developed a "pre-incubation method", to accelerate the oxidative reaction in plasma by heating at 37 degrees C. Alb(red)% values were maintained around the initial value for 48 h after stabilizing human plasma and 72 h after stabilizing human blood. Accelerating the oxidative reaction in plasma produced large differences in the Alb(red)% values between normal and model disease samples. Precise Alb(red)% values were routinely obtained under the stabilization control. Additionally, pre-incubation of the plasma before measurement is useful to enhance the difference between normal and disease samples. PMID- 23675151 TI - Omental Well-Differentiated Liposarcoma: US, CT and MR Findings. AB - Liposarcomas are the most common of sarcoma tumours, they are usually located in the lower limbs, retroperitoneum, or abdominal cavity; up to date, only a few cases of omental liposarcoma with different histotype have been described. We present a case of omental well-differentiated liposarcoma and discuss imaging findings on ultrasound, computed tomography, and magnetic resonance to differentiate omental liposarcomas from other abdominal tumour entities. PMID- 23675153 TI - A corpus-based study of cohesion in english medical texts and its chinese translation. AB - Cohesion as an indispensable linguistic feature in discourse analysis and translation has aroused many researchers' interest. To explore the regularity in shifting cohesive devices from English into Chinese our study was designed to analyze the similarities and differences of cohesive devices between English medical texts (EMTs) and their Chinese translation texts (CTTs). A parallel corpus consisting of 15 EMTs and 15 CTTs was established, each type of cohesive devices was identified, and paired t-test was run for statistic analysis. We have revealed that both EMTs and CTTS share more similarities than differences in the use of cohesive devices; the differences between them only exist in the employment of reference in terms of occurrence frequencies; the majority of cohesive devices are maintained in Chinese translation for precision, clarity and logicality. Our study will not only help medical students and medical workers but also shed light on EMP teaching and research. PMID- 23675152 TI - A Common Polymorphism of Upstream Transcription Factor 1 Gene is associated with Lipid Profile: A Study in Chinese Type 2 Diabetes Families. AB - Upstream transcription factor 1 (USF1) is capable of controlling various members in glucose and lipid metabolism pathways. Much evidence suggests that the rs3737787 polymorphism in the USF1 gene may lead to alteration of lipid metabolism. The objective of this study was to test the association between rs3737787 and type 2 diabetes mellitus (T2DM) and its related lipid metabolic traits in the Chinese population. A total of 287 eligible T2DM families were chosen in Beijing. A set of questionnaires was administered to obtain information on demographic characteristics. Physical measurements were recorded. DNA was extracted from blood samples and genotyped using PCR-RFLP method. Statistical analyses including linkage analysis and family-based association test were performed to detect the relationship between rs3737787 and T2DM related traits. In the non-parametric linkage analysis, it was observed that rs3737787 is potentially linked with triglyceride and apolipoprotein E levels, where the logarithm of the odds scores were 0.87 (p=0.02) and 1.96 (p=0.001), respectively. Similar results were obtained in the multi-factorial generalized estimating equation analysis. Using different statistical approaches, in this study, we have confirmed that the single nucleotide polymorphism rs3737787 is related to triglyceride and apolipoprotein E levels in type 2 diabetes mellitus families. PMID- 23675154 TI - Clinical analysis and management of gestational trophoblastic diseases: a 90 cases study. AB - OBJECTIVE: The aim of the study was to identify the incidence, diagnosis, therapeutic and histological particularities of molar pregnancies and to evaluate our management of gestational trophoblastic tumors (GTT) according to the recommendations of FIGO. METHODS: This was a retrospective study of 90 patients who were diagnosed with molar pregnancy from January 1991 to December 2007. After remission, post molar pregnancy surveillance was continued for one year. Patients whose condition required chemotherapy for GTT were attributed a FIGO/WHO score. RESULTS: Molar pregnancy occurred in 90 women. The frequency of molar pregnancy was 1 per 1124 pregnancies. The mean age was 32.21 years. Molar pregnancies were more frequent in pauciparous patients (52.24%). At diagnosis, the median gestational age was 13 weeks. The main presenting symptom was metrorrhagia (90%). Treatment consisted in uterine evacuation by suction curettage. Histological findings were complete mole in 66.66% of the cases and partial mole in 33.33% of the cases. 81 patients (90%) achieved remission without chemotherapy and 9 patients (10%) had FIGO stage I GTT. They achieved remission with a monochemotherapy. CONCLUSION: The practice of ultrasonography in the first trimester of pregnancy allows an early diagnosis of molar pregnancy and an adequate treatment and follow-up. PMID- 23675155 TI - Characterization of Molecular Evolution in Multi-Drug Resistant of Mycobacterium tuberculosis by rpoB Gene in Patient with Active Pulmonary Tuberculosis from Iranian Isolates. AB - This is the first genetic biodiversity study of Mycobacterium tuberculosis in Iran. Thus, we investigated the genetic patterns of strains isolated in the first survey of anti-tuberculosis drug-resistance by rpoB gene as part of the Global Project of Anti-tuberculosis Drug Resistance Surveillance (IAU, Iran). A 411-bp fragment of the rpoB gene, containing the sequence of the 81-bp rpoB fragment, was amplified by PCR and the rpoB gene fragments of tuberculosis strains were sequenced using the Amersham auto sequencer. For analysing tree evolution used method UPGMA and Neighbour-Joining. Clinical isolates (34/163) were analyzed by using sequencing gene rpoB and genotyped by program MEGA. The results were compared with the international database. Multi-drug resistant (MDR) was 14% in never treated patients and 8% in previously treated patients. Mutations in rpoB gene and katG genes were detected in 95% and 84% of the MDR strains, respectively. Two clusters were found to be identical by the four different analysis methods, presumably representing cases of recent transmission of MDR tuberculosis. The other strains are divided into 2 groups: group A - similar to the standard and Eastern strains (China, Taiwan) and group B - strains of another genotype. They are grouped separately on the dendrogram and became prevalent in Iran (they are called Iranian residential strains). This study gives a first overview of the M. tuberculosis strains circulating in Iran during the first survey of anti-tuberculosis drug-resistance. It may aid in the creation of a national database that will be a valuable support for further studies. PMID- 23675156 TI - Inhibition of IgE Activity to Bind its High Affinity Receptor (FcepsilonRIalpha) by Mouse Anti-IgE Cepsilon3~4 Monoclonal Antibody (QME5). AB - Using computer-guided homology modeling method, the 3-D structure of the Fv fragment of a functional anti-IgE antibody (MAE11) was constructed and the spatial structure of E24-MAE11 complex was modeled based on the crystal structure of IgE-Fc (abbr. E24) and molecular docking method. Then the identified epitope of IgE was determined theoretically, which showed the key role of IgE-CE3 in interacting with both FcERIalpha and MAE11. By normal protocols, we immunized mice with purified protein E34 and screened six anti-E34 monoclonal antibodies. Purified antibodies could identify E34 by Western blot; furthermore, all of them could bind IgE by ELISA, in which QME5 seemed to be the best. Flow cytometry analysis displayed that only QME5 could bind membrane IgE and it could compete with membrane FcERIalpha to bind soluble IgE. Meanwhile, QME5 couldn't bind FcERIalpha-attached IgE, which suggested no hypersensitivity in triggering the target cells (mast cells or basophils) by crosslinking or inducing the release of a variety of chemical mediators. PMID- 23675157 TI - Pamidronate alters the growth plate in the oim mouse model for osteogenesis imperfecta. AB - Bisphosphonates alleviate bone pain and fractures associated with osteogenesis imperfecta (OI). Using the oim mouse model to simulate variations in OI severity, the effect of pamidronate on bone growth was assessed. Homozygous (oim/oim) and heterozygous (oim/wt) mice from 4 to 12 weeks of age were given pamidronate at 0 mg/kg/wk (control), 1.25 mg/kg/wk (low) and 2.5 mg/kg/wk (high). Humerus and ulna lengths were reduced in oim/oim mice relative to those of the oim/wt. Further, the oim/oim genotype exhibited a 23.5% prevalence of fractures in these bones as compared to the 2.8% prevalence observed in the oim/wt mice. Pamidronate tended to reduce fracture prevalence in a dose dependent manner for the oim/oim genotype (p<0.08) but had no effect on the low fracture prevalence in oim/wtmice. The high dose of pamidronate reduced bone length in females of both genotypes but not males when compared to control (p<0.01). Pamidronate increased growth plate area (p<0.05) by increasing growth plate height, particularly the proliferative and hypertrophic zones, in both genotypes indicating reduced growth plate cell turnover. The increased area coincided with increased osteoclast numbers in the metaphyseal region (p<0.05) though when corrected for the greater mineralized surface area that accompanies bisphosphonate treatment, osteoclasts per surface area were reduced indicating reduced resorptive capacity. This study demonstrated that the effects of pamidronate were independent of the degree of collagen deficit and fracture prevalence was improved in the most severe OI model, the oim/oim genotype. PMID- 23675158 TI - Long Term Persistence of IgE Anti-Varicella Zoster Virus in Pediatric and Adult Serum Post Chicken Pox Infection and after Vaccination with Varicella Virus Vaccine. AB - The production of IgE specific to different viruses (HIV-1, Parvovirus B19, RSV), and the ability for IgE anti-HIV-1 to suppress HIV-1 production in vitro, strongly suggest an important role for IgE and/or anti viral specific IgE in viral pathogenesis. Previous studies in our laboratory were the first to report the presence of IgE anti-varicella zoster virus (VZV) in an adolescent patient with shingles. However, the presence and long term persistence of IgE anti VZV antibodies has not been studied in adults. The presence of serum IgE in addition to IgE and IgG anti-VZV antibody in sera were studied in children (N=12) (0-16 y/o) and adults (N=9) (32-76 y/o) with either a past history of (wild type) chicken pox (N=7 children, 9 adults) or 5 years after vaccination with varicella zoster (N=2 children) (Varicella virus vaccine live, Oka/Merck), as well as in non-infected subjects (N=3 children). Of the patients who had a positive history of chicken pox 13 of 16 (81%) contained IgE anti-VZV antibodies; they were both serum IgEHi (>100 IU/ml) and IgELo (<100 IU/ml). Of the patients who were vaccinated, IgE anti-VZV antibodies were undetected. In contrast, serum from the patients without a history of chicken pox or vaccination did not make either IgE or IgG anti-VZV antibodies. This is the first demonstration of the existence of IgE anti-VZV antibodies, and its long-term persistence in serum of previously infected subjects. Future studies regarding the functional role of anti-viral IgE and its relationship to VZV are warranted. PMID- 23675159 TI - Antioxidant and Antimicrobial Activity of 5-methyl-2-(5-methyl-1,3-diphenyl-1H pyrazole-4-carbonyl)-2,4-dihydro-pyrazol-3-one. AB - Cycloaddition of nitrile imines 4 generated in situ by the catalytic dehydrogenation of diphenyl hydrazones 3 using Chloramine-T (CAT) as oxidant in glacial acetic acid with enolic form of ethyl acetoacetate 5 afforded Ethyl 3 aryl-5-methyl-1-phenyl-1H-pyrazol-4-carboxylate 6 in 80% yield. The said pyrazoles 6 refluxed with 80% hydrazine hydrate using absolute alcohol as solvent for about 2-3 hours to produce the respective 5-methyl-1,3-diphenyl-1H-pyrazole-4 carboxylic acid hydrazide 7. The alcoholic solution of pyrazole acid hydrazides on heating with ethyl acetoacetate 5 to give the 5-methyl-2-(5-methyl-1,3 diphenyl-1H-pyrazole-4-carbonyl)-2,4-dihydro-pyrazol-3-one 8. The synthesized compounds were found to exhibit good antimicrobial and antioxidant activity as evaluated by 1,1-diphenyl-2-picryl Hydrazyl (DPPH) radical scavenging, reducing power and DNA protection assays. PMID- 23675160 TI - Mortality pattern in children: a hospital based study in Nigeria. AB - BACKGROUND: Hospital based data on mortality pattern is a reflection of what is obtainable in a community at large. Therefore, data obtained from such review is usually beneficial in re-evaluating existing services and in improving facilities and patient care. The aim of this study was to evaluate the mortality pattern of children admitted into the children medical wards of the University of Port Harcourt Teaching Hospital from Jan 2007 to December 2008. MATERIALS AND METHODS: This was a retrospective study. The case files of all patients aged one month to 16 years, admitted into the paediatric wards of University of Port-Harcourt Teaching Hospital, Port-Harcourt, Nigeria over a 2 year period were reviewed. Neonatal and surgical cases were excluded. RESULTS: There were 2,174 admissions during the study period. Sixty one of the total number of admissions died in the children medical wards giving a mortality rate of 2.8%. The youngest child was 2 months and the oldest 10 years. Fifty two (80.3%) were under 5 years. There was male preponderance. Most of the deaths occurred between April and September. The commonest causes of death were HIV/AIDS and bronchopneumonia in the under five age group; while in those above 5 years of age malignancies and HIV/AIDS were the predominant causes. CONCLUSION: Effective HIV/AIDS control measures will significantly reduce child mortality in our community. Also there is need to have a closer look at the potential risk for malignancies. Health intervention programmes such as integrated management of childhood illnesses and primary health care, which have been shown to reduce childhood deaths significantly, need to be intensified in order to achieve the MDG 4 by 2015. PMID- 23675161 TI - A novel spectrophotometric method for the determination oxacillin sodium. AB - A simple and sensitive spectrophotometric method was developed for the determination of Oxacillin sodium. The method was based on charge transfer complexation reaction of the drug with iodine in methanol - dichloromethane medium. The absorbance was measured at 365 nm against the reagent blank. Under optimized experimental conditions, Beer's law is obeyed in the concentration ranges 2-8 MUg/ml for Oxacillin Sodium. The method was validated for specificity, linearity, precision, accuracy, limit of quantitation, robustness and ruggedness. The LOD and LOQ value were 0.39 and 1.18 MUg/ml respectively. The method was successfully applied to the analysis of Oxacillin sodium in Human Urine samples with good accuracy and precision. PMID- 23675162 TI - In Vitro Effects of PDGF Isoforms (AA, BB, AB and CC) on Migration and Proliferation of SaOS-2 Osteoblasts and on Migration of Human Osteoblasts. AB - PDGF is a major constituent of platelet rich plasma (PRP), responsible of chemotactic and possibly of mitogenic effects of PRP on osteoblasts. PDGF family includes 5 isoforms: PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC and PDGF-DD, all expressed in platelets except PDGF-DD. Aim of this study was to analyze the effect of recombinant hPDGF-A, -AB, -B and -C, on migration and proliferation of a human osteoblastic cell line, SaOS-2. Preliminary observations on cell migration were also done in primary cultures of human osteoblasts. In vitro microchemotaxis and (3)H-thymidine mitogenic assays were used. While PDGF-AB is active at concentrations present in PRP, PDGF-AA and BB are chemotactic only at much higher doses. PDGF-C is totally inactive alone or together with the active isoforms. PDGF-AA, PDGF-BB and PDGF-C stimulate SaOS-2 proliferation only at the highest dose tested, while PDGF-AB is ineffective. Primary osteoblasts are less sensitive than SaOS-2 and progressively lose responsiveness with increasing passages in culture, in line with loss of cell differentiation. The different PDGF isoforms act differentially on osteoblasts, the-AB isoform appearing the major responsible of the PRP chemiotaxis. PDGF, at the concentrations present in PRP, does not affect cell proliferation. PMID- 23675163 TI - Perinatal outcome of babies delivered to eclamptic mothers: a prospective study from a nigerian tertiary hospital. AB - BACKGROUND: Eclampsia is a leading cause of maternal and perinatal mortality in Nigeria. Preventive and interventional measures have been shown to reduce maternal mortality and morbidity with no significant beneficial effect on neonatal outcomes. The aim of this study is to assess the perinatal outcome of eclampsia at the University of Port-Harcourt Teaching Hospital (UPTH). MATERIALS AND METHODS: This prospective, cross-sectional study was conducted on 88 consecutive patients presenting with antepartum eclampsia at the UPTH between 1(st) January 2007 and 31(st) December 2008. A protocol was developed and used to collect information about socio-demographic characteristics, mode of delivery, perinatal complications and outcome. Data collected was entered into a spread sheet using SPSS 15.0 for Windows((r)) statistical software which was also used for analysis. Chi square was used to test relationship between variables. P value<0.05 was considered statistically significant. RESULTS: There were a total of 5488 deliveries at the University of Port-Harcourt Teaching Hospital from January 2007 to December 2008. Of these, 5,310 were live births while 404 were perinatal deaths giving perinatal mortality rate of 73.6 per 1000 live births. Eighty eight (1.6%) of the mothers were eclamptic. Eight (9.1%) were booked, 80 (90.1%) were unbooked. The mean gestational age at delivery was 35.1 +/- 4.2 weeks. The main mode of delivery was by emergency caesarian section in 49 (55.7%) of the patients. Others were spontaneous vertex delivery (34.1%), assisted vaginal breech delivery (6.8%) and instrumental vaginal delivery (3.4%). Fifty four babies (61.4%) were admitted into the Special Care Baby Unit. Indications for admission include prematurity (n=23), low birth weight (n=10), severe birth asphyxia (n=12), neonatal jaundice (n=4) and neonatal sepsis (n=5). There were 37 perinatal deaths giving a perinatal mortality rate of 411 per 1000 live births. Of the mortalities, 19 were intrauterine foetal deaths, while 18 were early neonatal deaths. Causes of death include severe birth asphyxia (n=6), respiratory distress syndrome (n=4), prematurity (n=4), neonatal jaundice (n=1) and sepsis (n=3). CONCLUSION: Eclampsia is a major contributor of perinatal mortality and morbidity in Nigeria. Detection and appropriate management of preeclampsia is critical to reduce the risk of eclampsia. PMID- 23675164 TI - Dopamine-beta-Hydroxylase (DBH), Its Cofactors and Other Biochemical Parameters in the Serum of Neurological Patients in Bangladesh. AB - Dopamine-beta-hydroxylase (DBH) is a neurotransmitter synthesizing enzyme which catalyzes the formation of norepinephrine from dopamine. In this study, we measured the level of DBH activity in the serum of patients of three different age groups (8-14 yrs, 20-40 yrs and 45-60 yrs) suffering from neurological diseases. Serum DBH activity was measured in 38 neurological patients and 38 normal individuals in order to determine significant variables for its potential use to diagnose the neurological patients. It was found that the DBH activity decreased in the patients of all age groups. A considerable decrease in activity was observed in the patients of 8-14 yrs age group (14.2 nmoles/min/ml in patients compared to the normal value of 22.6). A significant decrease in activity was found in the 20-40 yrs age group (23.4 nmoles/min/ml in patients compared to the normal value of 33.0). The decrease in DBH activity was also found in the patients of 45-60 yrs age group but to a lesser extent (26.4 nmoles/min/ml in the patients compared to the normal value of 30.2). The kinetic studies of DBH exhibited an increase of Km value and a decrease in Vmax in the neurological patients. Serum copper and ascorbic acid levels (cofactors of DBH) were found to be decreased in neurological patients and hence are in agreement with the decrease in DBH activity in these patients. Other parameters such as glucose and cholesterol levels increased, protein and zinc levels decreased and ALT, AST, creatinine and urea content remained nearly unchanged in the patients' serum. PMID- 23675165 TI - Standardization of a method to evaluate the antioxidant capacity of high-density lipoproteins. AB - BACKGROUND: A method to evaluate the antioxidant capacity of high-density lipoprotein (HDL) was developed and standardized. METHODS: This method measure conjugated diene (CD) formation and electrophoretic mobility of low-density lipoprotein (LDL) in agarose gels in the presence and absence of HDL. HDL was isolated from 1 mL of plasma within 24 hours and oxidation assays were performed within 6 hours. Oxidation was induced by adding CuSO4. The lag phase increase in CD kinetics and the inhibition of electrophoretic mobility were defined as the HDL antioxidant capacity. RESULTS: The optimal conditions for the CD assay were 2.5 MUM CuSO4, LDL at 0.1 g apoB/L, HDL at 0.1 g apoA-I/L, at 37 degrees C and for 3h 50 min. Agarose electrophoresis at 100 V, at 4 degrees C for 50 min was then performed immediately. CD formation variability was 21.1% for inter-assay CV and 12.7% for intra-assay CV. Electrophoretic mobility was 26.5% for inter-assay CV and 2.4% for intra-assay CV. Correlation analysis showed a significant association between the antioxidant capacity of HDL and its neutral/polar lipid ratio. CONCLUSIONS: The method herein described measures of the HDL antioxidant capacity in a reproducible and rapid manner that can be applied to a relatively high number of samples. PMID- 23675167 TI - A sensitive spectrophotometric method for the determination of pregabalin in bulk, pharmaceutical formulations and in human urine samples. AB - A simple and sensitive spectrophotometric method was developed and validated for the determination of pregabalin in bulk, pharmaceutical formulations and in human urine samples. The method was based on the reaction of drug with the mixture of potassium iodate and potassium iodide. The method was linear in the range of 0.5 3.5 MUg/ml. There is no official method for the determination of pregabalin. The absorbance was measured at 353 nm. The method was validated with respect to accuracy, precision, specificity, ruggedness, robustness, limit of detection and limit of quantitation. This method was used successfully for the quality assessment of five pregabalin drug products and in human urine samples with good precision and accuracy. PMID- 23675166 TI - Statins inhibit the proliferation and induce cell death of human papilloma virus positive and negative cervical cancer cells. AB - Statins, competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase, have anti-tumoral effects on multiple cancer types; however, little is known about their effect on cervical cancer. We evaluated the effect on proliferation, cell cycle, oxidative stress and cell death of three statins on CaSki, HeLa (HPV(+)) and ViBo (HPV(-)) cervical cancer cell lines. Cell proliferation was assayed by crystal violet staining, cell cycle by flow cytometry and cell death by annexin-V staining. Reactive oxygen species (ROS) production was evaluated by the oxidation of 2,7-dichlorofluorescein diacetate and nitrite concentration (an indirect measure of nitric oxide (NO) production), by the Griess reaction. Inhibition of cell proliferation by atorvastatin, fluvastatin and simvastatin was dose-dependent. ViBo cells were the most responsive. Statins did not affect the cell cycle, instead they induced cell death. The antiproliferative effect in ViBo cells was completely inhibited with mevalonate, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) treatments. In contrast, cell proliferation of CaSki and HeLa cells was partially (33%) rescued with these intermediates. The three statins increased ROS and nitrite production, mainly in the ViBo cell line. These results suggest that statins exert anti-tumoral effects on cervical cancer through inhibition of cell proliferation and induction of cell death and oxidative stress. Statins could be an aid in the treatment of cervical cancer, especially in HPV(-) tumors. PMID- 23675168 TI - A 28-days sub-acute toxicity study in swiss albino mice to evaluate toxicity profile of neurotol plus (mannitol and glycerol combination). AB - Osmotic agents are still the most common treatment options available for controlling intracranial pressure (ICP). Combining Mannitol and Glycerol provides a better alternative and is currently available as best therapy used for increased ICP. The aim of this work was to study the effects of repeated dosing (28 days) of Mannitol 20% and Glycerol 10% combined formulation, Neurotol plus on safety profile. A twenty eight days sub-acute toxicity study was conducted at three different dose levels of 5ml/kg, 10 ml/kg and 20 ml/kg. Mice were randomly divided into four groups of six animals each. Physical parameters, biochemical parameters related to liver toxicity & nephrotoxicity and hematological parameters were studied as end point of evaluation. We also carried out histopathlogical studies to assess any organ specific toxicity. The present study demonstrated that there were either no or very minimal changes (at high dose) were observed on various physical, biochemical and hematological parameters between Neurotol plus and control group. In conclusion the data of present study suggest that the combination of Mannitol and Glycerol is not associated with any serious adverse effects and is safe therapeutic choice for ICP reduction. PMID- 23675169 TI - A pilot study for inducing chronic heart failure in calves by means of oral monensin. AB - INTRODUCTION: Heart failure remains a major cause of mortality in the United States, despite advancing technologies, newer methods of treatment, and novel devices. To evaluate such novel devices, a large-animal model of chronic heart failure is critical in carrying out preclinical animal studies. METHODS: We evaluated the efficacy of oral monensin in inducing stable heart failure in five Jersey calves. Various doses of monensin were administered. Hemodynamics, pressure-volume loops, echocardiographic measurements, extent of tissue perfusion, and histopathologic data were recorded before and after induction of heart failure. RESULTS: Responses were variable in the animals. One experiment showed a significant decrease in cardiac output within one week, associated with simultaneous increases in left atrial pressure, central venous pressure, and mean pulmonary artery pressure. Left ventricular pressure-volume loops showed that the slope of the end-systolic pressure-volume relation decreased markedly between the baseline and terminal study, suggesting a decrease in contractility. Echocardiographic studies indicated a decrease in ejection fraction. Histopathologic analysis in cardiac tissue showed extensive fibrosis and necrosis. CONCLUSION: We demonstrated the feasibility of inducing and maintaining severe yet stable heart failure for up to 3 weeks in a calf model by administration of oral monensin. PMID- 23675170 TI - Is there a role of early neonatal events in susceptibility to allergy? AB - BACKGROUND: Several studies suggest a protective role of bilirubin against oxidative damage during the neonatal period. ADA1*2 allele has been found associated with higher bilirubin levels in newborns and with a protective action against bronchial asthma. Thus the relation between ADA1 and asthma could be mediated by events occurring during the early extrauterine life. Moreover the increased prevalence of allergic diseases in western populations parallels the widespread practice of phototherapy during the neonatal period. These observations prompted us to reevaluate our previous data and show new observations. METHODS: Data from 2729 previously studied subjects, from 53 subjects studied at birth and after 30 years and from a survey of phototherapy frequency in four Italian Hospital including 7392 newborns are reported. RESULTS: ADA1*2 allele carriers are less represented among asthmatic subjects than in controls (p=0.0004). ADA1*2 allele carriers among newborns undergoing phototherapy for hyperbilirubinemia is higher when compared to newborns not undergoing this treatment (p=0.006). In infants treated by phototherapy, the maximum bilirubin level attained during the first few days of life positively correlated with the ADA1*2 allele dose (p=0.001). Among subjects studied at birth, allergic rhinitis and/or conjunctivitis are more frequent among those treated with phototherapy than among those not treated (p=0.046). CONCLUSIONS: These observations support our hypothesis that ADA1*2 allele through an increase of bilirubin level in the neonatal period protects infants from oxidative stress and favours Th2->Th1 switching thus preventing allergic manifestations in later periods of life. PMID- 23675171 TI - Simultaneous Determination of Miconazole Nitrate and Metronidazole in Different Pharmaceutical Dosage Forms by Gas Chromatography and Flame Ionization Detector (GC-FID). AB - A simple, rapid and precise gas chromatographic method has been developed for the simultaneous determination of miconazole nitrate (MIZ) and metronidazole (MNZ) in tablets and ovules, using a capillary column AE.SE-54 (15 m * 0.53 mm, i.d.) and nitrogen as a carrier gas at a flow rate of 9 mL min(-1). The oven temperature was programmed at 140 degrees C for 3 min, with a rise of 40 degrees C min(-1) up to 180 degrees C (held for 2 min) and then increased to a final temperature of 250 degrees C. The injector and detector port temperatures were maintained at 260 degrees C. Detection was carried out using flame ionization detector. Results of assay and recovery studies were statistically evaluated for its accuracy and precision. The retention times were about 3.50 and 12.90 min for MNZ and MIZ, respectively. Linearity ranges were 50.0-6030.0 and 62.5-2000.0 MUg mL(-1) for MNZ and MIZ, with limit of detection values of 2.5 and 3.1 MUg mL(-1), respectively. Correlation coefficients (R(2)) of the regression equations were greater than 0.999 in all cases. No interference from any components of pharmaceutical dosage forms or degradation products was observed. According to the validation results, the proposed method was found to be specific, accurate, precise and could be applied to the simultaneous quantitative analysis of MIZ and MNZ in tablets and ovules. PMID- 23675172 TI - Kinetic spectrophotometric determination of fluvastatin in pharmaceutical preparations. AB - Simple, accurate and reliable kinetic spectrophotometric method for the determination of fluvastatin sodium (FVS) in pure form and pharmaceutical formulations has been described. The method is based on the formation of colored product between FVS and 4-chloro-7-nitrobenzofurazan (NBD-Cl) in acetone medium at 55 +/- 2oC. The reaction is followed spectrophotometrically by measuring the increase in absorbance at 462 nm as a function of time. The rate data and fixed time methods were adopted for constructing the calibration curves. The linearity ranges were found to be 15.0-50.0 and 10.0-90.0 MUg mL(-1) for rate data and fixed time methods, respectively. The limit of detection for rate data and fixed time methods is 0.017 and 0.134 MUg mL(-1), respectively. The proposed methods have been successfully applied to the determination of fluvastatin sodium in pharmaceutical dosage forms with no interference from the excipients. Statistical comparison of the results shows that there is no significant difference between the proposed and official methods. PMID- 23675173 TI - Emergence of dendritic cells in the myocardium after acute myocardial infarction implications for inflammatory myocardial damage. AB - Dendritic cells (DC) are crucial for T cell mediated immune responses. Recently, we observed a significant decrease in circulating myeloid DC precursors in patients with acute myocardial infarction (AMI). The aim of the present study was to investigate whether myeloid DC are present in infarcted myocardium. Myocardial specimens of 10 patients with AMI and 7 accident victims (controls) were collected after autopsy. In immunostainings the presence of DC (CD209(+), fascin(+)), T cells (CD3(+)), macrophages (CD68(+)), and HLA-DR expression was analyzed. Significantly higher numbers of CD209(+)-DC (97 vs. 44 cells/0.25 mm(2), p=0.03), fascin(+)-DC (54 vs. 8 cells/0.25 mm(2), p=0.02), T cells (27 vs. 6 cells/0.25 mm(2), p=0.02), and macrophages (44 vs. 6 cells/0.25 mm(2), p=0.01) associated with high HLA-DR expression were detected in infarcted myocardium. Frequent colocalizations of DC and T cells were observed. In occluded coronary arteries numerous DC, T cells, macrophages and high HLA-DR expression were found. We show that DC are present in infarcted myocardium after AMI. High HLA-DR expression and the colocalization with T cells suggest that they might trigger an immune response leading to further myocardial damage. PMID- 23675174 TI - Ghrelin Protection against Cytotoxic Effect of Ethanol on Rat Salivary Mucin Synthesis involves Cytosolic Phospholipase A2 Activation through S-Nitrosylation. AB - Recent advances in identifying the salivary constituents of significance to the maintenance of soft oral tissue integrity have brought to focus the importance of a 28-amino acid peptide hormone, ghrelin. Here, we report on the role of ghrelin in countering the disturbances in salivary mucin synthesis caused by ethanol cytotoxicity in rat sublingual gland acinar cells. We show that the countering effect of ghrelin on mucin synthesis was associated with the increase in NO and PGE2 production, and the enhancement in cytosolic phospholipase A2 (cPLA2) activity. The ghrelin-induced up-regulation in mucin synthesis, like that of cPLA2 activity, was subject to suppression by Src inhibitor, PP2, ERK inhibitor, PD98059, as well as Akt inhibitor, SH-5 and ascorbate. Moreover, the loss in countering effect of ghrelin on the ethanol cytotoxicity and mucin synthesis was attained with cNOS inhibitor, L-NAME as well as COX-1 inhibitor, SC-560. Furthermore, while the effect of L-NAME was also reflected in the inhibition of the acinar cell capacity for NO and PGE2 generation, and cPLA2 S-nitrosylation, the COX-1 inhibitor caused the inhibition in PGE2 only. Our findings demonstrate that ghrelin protection of the acinar cells against ethanol cytotoxicity and the impairment in salivary mucin synthesis involves Src kinase activation of the Akt/cNOS pathway that leads to up-regulation in cNOS activity. We also show that cNOS-derived NO induction of the cPLA2 activation through S-nitrosylation, for the increase in PGE2 generation, is an essential element of the protective mechanism of ghrelin action. PMID- 23675175 TI - Synthesis of Some New 3, 5-Bis (substituted) Pyrazoles and Isoxazoles Based on (N'(1)E, N'(3)E)- N'(1), N'(3)-Bis (3, 4, 5-substitutedbenzlidene) Malonohydrazide under Solvothermal Conditions. AB - The new 3,5-(substituted) pyrazoles and isoxazoles were prepared by reaction of (N'(1)E, N'(3)E)- N'(1), N'(3)-bis (3,4,5-substitutedbenzylidene)malonohydrazide with hydrazine hydrate and hydroxylamine hydrochloride respectively under solvothermal conditions involving an ecofriendly method without any environmental pollution, the yield are in the range of 75-96%. The structure of the new compounds were established using elemental analysis, IR, (1)H NMR, (13)C NMR. PMID- 23675177 TI - Synthesis and Evaluation of Benzophenone-N-ethyl Morpholine Ethers as Anti inflammatory Agents. AB - The synthesis of hydroxy benzophenones and benzophenone-N-ethyl morpholine ethers and the results of anti-inflammatory activity in vivo are described. The structures of the compounds were elucidated by IR, (1)H-NMR, mass spectroscopy and the elementary analysis. The anti-inflammatory activity of the synthesized compounds were determined by carrageenan-induced hind paw oedema test in rats. Most of the tested compounds exhibited anti-inflammatory activity and some of them were more active than standard drugs. In addition ulcerogenic and cyclooxygenase activities are also described. PMID- 23675176 TI - Prox1 Facilitates Transfected CHO Cell Proliferation through Activation of the AKT Signaling Pathway. AB - The homeobox transcription factor Prox1 plays an important role in the development of many embryonic organs. Previous studies indicated that Prox1 facilitates hepatic progenitor-cells proliferation. However, the underlying mechanism of Prox1 in tumor genesis, formation, and progression are poorly understood and need to be exploited. Herein, Chinese Hamster Ovary (CHO) cells were transfected and over-expressed human recombinant Prox1 gene, and developed several stable cell lines of Prox1-CHO after screening. The results indicated that over expression of Prox1 increased CHO cell proliferation in comparison to GFP-CHO and parental CHO cells, and Prox1 increased AKT phosphorylation and up regulated PI3 Kinase expression. An AKT specific inhibitor-AKTi-X (5 MUM) and a PI3 K inhibitor-LY294002 (5 MUM) were able to reverse AKT phosphorylation and PI3 K expression induced by Prox1, respectively. Furthermore, AKTi-X but LY-294002 decreased Prox1-CHO cell proliferations at 48 and 72 h. Our results suggest that over expression of Prox1 facilitates CHO cell proliferation via activation of the AKT signaling pathway. This finding provides new insights into the mechanism of Prox1 mediated tumor growth and metastasis where Prox1 is rich. PMID- 23675178 TI - Metastatic male ductal breast cancer mimicking obstructing primary colon cancer. AB - Male breast cancer comprises only about 1% of all breast cancers. Commonly, sites of metastases include the central nervous system, lungs, bones, and even liver. In females, extrahepatic gastrointestinal metastases are unusual but have been reported with various clinical presentations. We are reporting the first case of a male patient with a history of ductal breast carcinoma that developed colonic metastasis and presented with mechanical large bowel obstruction masquerading as primary colon cancer. PMID- 23675179 TI - Non-Markovian Population Dynamics: Does it Help to Optimize the Chemotherapeutic Strategy? AB - A non-Markovian theory of population dynamics is to simulate the anti-cancer drug distribution between malignant and the hosting normal cell pools. The model takes into account both the cell life span and the proliferation rate differences. This new simulation approach looks promising for its potential to optimize a chemotherapeutic strategy by choosing the scheme with a higher degree of the drug tumor selectivity. The pre-test designed simulation mode fits nicely the experimental data on Porphylleren-MC16 (PMC16) pharmacokinetics patterns including the allometric plots revealed for this novel medicinal nanoparticle possessing some anti-cancer potential and intervening into the oxygen-independent ATP production mechanisms. PMID- 23675180 TI - The post-antibiotic era: promising developments in the therapy of infectious diseases. AB - An overview of investigational antibiotics highlights that antimicrobial drug development is slower than the emergence and spread of resistant strains. In the last three decades only two antibiotics belonging to truly new classes have been introduced into the market, i.e. linezolid and daptomycin. This situation is fostering a huge amount of research aimed at the development of novel molecules and novel antibacterial approaches. The present review details the state of the art research in the fields of antimicrobial peptides, antivirulence factors, bacteriophages, and antibodies as possible replacements or enhancers of classic antibiotics. If the number of new antibacterials in phase II or III of clinical trials remains disappointing, it seems nonetheless reasonable to expect major breakthroughs, made possible by the synergistic use of computational methods and chemical and biological research. PMID- 23675181 TI - Evolution in the management of acute myocardial infarction in the autonomous community of valencia (Spain): ten years of the primvac registry (1995-2004). AB - INTRODUCTION AND OBJECTIVES: Several registries of acute myocardial infarction (AMI) have been carried out in Spain, but few remain active. This work analyses the evolution of the characteristics and control of patients with AMI during the first 10 years of the PRIMVAC registry, initiated in 1995. METHODS: The demographical and clinical characteristics, therapeutic-diagnostic procedures and pharmacological treatment of patients admitted with AMI between January 1995 and December 2004, were analysed in 17 coronary centres in the Autonomous Community of Valencia (South eastern Spain). RESULTS: The mean age of the 19,719 patients recruited was of 65. The percentage of women, hypertension, hypercholestrolemia and diabetes increased during registry period. The median time of symptoms onset hospital arrival was 151 minutes, without a decrease over the time, and the delay of thrombolysis fell from 200 to 154 minutes (p<0.01). Percentage of thrombolytic treatment oscillated between 39% and 48%. The mortality in the coronary units decreased (14.1% vs. 8.9%; p<0.001). The number of coronary angiography and percutaneous revascularisation performed increased up to 61% and 32%, respectively, of patients included. On discharge, the use of beta-blockers (29.3% vs. 66.7%), angiotensin-converting enzyme (ACE) inhibitors (41.7% vs. 57.9%) and statins (29.3% vs. 71%) went up. CONCLUSIONS: Overall mortality in the coronary unit decreased, without any variation in the incidence of serious complications. Time to thrombolysis was reduced over the time, with no significant increment in its use. The performance of coronary angiography and percutaneous revascularisation increased, with a low use of primary angioplasty. The use of beta-blockers, ACE inhibitors and statins increased at discharge. PMID- 23675182 TI - Claudin 1 and Claudin 7 Gene Polymorphisms and Protein Derangement are Unrelated to the Growth Pattern and Tumor Volume of Colon Carcinoma. AB - Tight junctions together with adherens junctions are important for preserving tissue integrity. In tumors the normal tissue structure is lost which results in a disorganization and change of phenotype. In this study we assessed the complexity of the invasive front of colon carcinoma using an objective morphometrical technique based on the estimation of fractal dimension and number of free tumor cell clusters. The complexity of the invasive front was correlated to Claudin 1 and Claudin 7 protein expression as well as genetic polymorphisms of their genes. Thirty-three colon carcinomas were used. Images from the invasive front of the tumors were captured and used to calculate a complexity index of the invasive front. The tight junction proteins Claudin 1 and Claudin 7 were stained immunohistochemically in the tumor and in the surrounding normal mucosa. Screening of their genes was performed using DNA sequencing. A significant aberration of protein expression was seen for both Claudin 1 and Claudin 7 compared to normal mucosa. Both homozygous and heterozygous polymorphisms in exon 2 of claudin 1 were found. In claudin 7 a homozygous polymorphism was seen in exon 4. All individuals with tumors that showed either of these polymorphisms also showed the same polymorphism in the adjacent normal mucosa. A significant correlation was found between polymorphisms in CLDN 7 and tumor differentiation p<0.02. However no correlations were found to Complexity Index, tumor size, localization or tumor stage (pT and pN). The results show that there is a perturbed expression of claudin 1 and claudin 7 proteins in colon tumors compared to normal mucosa. A high incidence of polymorphisms was found in normal tissue and tumors. It remains to be shown if these polymorphisms are coupled to the occurrence of colon carcinomas. PMID- 23675183 TI - Histomorphometric Evaluation of Cartilage Degradation using Rabbit Articular Chondrocytes Cultured in Alginate Beads - Effects of Hyaluronan. AB - OBJECTIVE: A 3-dimensional alginate bead culturing method using rabbit articular chondrocytes was studied for the screening of the effectiveness of drugs for articular diseases. DESIGN: The beads cultured with IL-1beta, TGF-beta, and Hyaluronan (HA) were evaluated histochemically with Alecian blue and immunohistochemically with CS-56 antibody. Chondrocytes in alginate beads were arbitrarily classified into four groups: 1) chodrocyte surrounded with cell associated matrix (CAM) in which proteoglycan (PG) was positively stained (PG possitive chondrocyte); 2) chondrocyte with PG-negative CAM; 3) PG-positive CAM alone, and 4) PG-negative CAM alone. Total sulfated GAG concentrations in the culture media were quantitated by dimethylmethylene blue (DMMB) assay. ProMMP-3, TIMP-1 and -2 concentrations in the culture media were determined by sandwich enzyme immunoassays. RESULTS: Significant increase of PG-nagative cells were immunohistochemically found by IL-1beta stimulation. The pretreatment with TGF beta almost fully suppressed those increase of PG-negative cells by IL-1beta. Both GAG and proMMP-3 concentrations in the culture media were significantly increased after IL-1beta stimulation. There were no significant differences in both TIMP-1 and TIMP-2 concentrations in the culture media with or without IL 1beta stimulation. 800-kDa HA reduced significantly the number of PG-negative cells and proMMP-3 concentration in the culture media, but showed no effects on the concentrations of both TIMPs. CONCLUSIONS: Because this 3-dimensional chondrocyte culture in alginate beads is close to in vivo conditions, this method can be used for evaluation of the effectiveness of novel drugs for articular diseases. PMID- 23675184 TI - Diethylcarbamazine and non-diethylcarbamazine related bancroftian granuloma: an immunohistochemical study of eosinophil toxic proteins. AB - It has been suggested, mostly using in vitro experiments, that defenses against parasites involve mainly activated eosinophils and their toxic proteins, such as major basic protein (MBP), eosinophil cationic protein (ECP) and eosinophil peroxidase (EPO). Eosinophil degranulation has been described around degenerating onchocercal microfilariae in patients treated with diethylcarbamazine (DEC). In bancroftian filariasis, traditional histopathologic studies have shown remarkable numbers of eosinophils in granulomatous lesions associated with both DEC-induced and spontaneous death of adult Wuchereria bancrofti parasites. No immunohistochemical study targeting eosinophil degranulation has been previously performed in these granulomas, which are found mainly within intrascrotal lymphatic vessels. This investigation was undertaken in 22 (12 DEC-treated and 10 untreated) male patients in order to determine the immunohistochemical expressions of MBP, EPO and ECP in bancofitian granulomas, using the indirect method. Stained intact esosinophils, as well as granular, extra-cellular material positive for all three proteins, were found in all granulomas. The immunohistochemical patterns were similar in both DEC-treated and untreated cases, irrespective of microfilaremia, blood eosinophilia, and granuloma age. Positive intact cells were observed mostly at the periphery of the granulomas, whereas granular material predominated in central areas around dead or degenerating parasites. These results indicate that eosinophils accumulate in the granulomas and degranulate preferentially in close proximity to degenerating or dead adult parasites. In bancroftian granulomas, influx and degranulation of eosinophils are considered a consequence of parasite death, rather than its cause. PMID- 23675185 TI - Determination of Azelastine in Human Plasma by Validated Liquid Chromatography Coupled to Tandom Mass Spectrometry (LC-ESI/MS/MS) for the Clinical Studies. AB - A liquid chromatography coupled to tandem mass spectrometry (LC-ESI/MS/MS) was validated to determine azelastine in human plasma. Azelastine and internal standard (IS, clomipramine) were separated using a mobile phase of acetonitrile:(5 mM)-ammonium acetate solution (70:30, v/v, pH=6.4) with flow rate of 0.25 mL/min over YMC C8 column. One mL of plasma was extracted by n-hexane: 2 propanol (97:3, v/v) and then injected into HPLC system after reconstitution by acetonitrile: (5 mM)-ammonium acetate (1:1, v/v) solution. Detection was carried out on API5000 MS system by multiple reactions monitoring mode. The ionization was optimized using ESI (+) and selectivity was achieved at m/z 382.2->112.2 for azelastine and m/z 315.3->228.0 for IS. Total run-time (<2.0 min) and linearity (10 (LLOQ) ~5000 pg/mL) were good. No endogenous compounds were found around the retention time. The inter- and intra-day precision and accuracy were 4.13~17.91% and 87.57~109.70%, respectively. This validated method was successfully applied to a bioequivalence study in 23 healthy Korean male volunteers from the blood samples taken up to 96 h after orally administered 2 tablets of 1 mg of reference and test formulations of azelastine in a double-blind, randomized, cross-over design. The mean peak plasma concentrations (Cmax +/- SD) of 1.02 +/- 0.37 and 1.10 +/- 0.43 ng/mL were reached at 5.9 and 5.6 h for reference and test azelastine, respectively. The mean total area under the curve (AUC0-infinity) were 25.96 +/- 10.84 and 28.24 +/- 11.09 ng.h/mL for reference and test formulations, respectively. The reference and test azelastine formulations can be considered bioequivalent from the obtained pharmacokinetics by LC-ESI/MS/MS. PMID- 23675186 TI - Voltammetric determination of cyproterone acetate in pharmaceutical preparations. AB - The voltammetric behaviour of cyproterone acetate (CPA) was studied using direct current (DCt) and differential pulse polarography (DPP). The drug manifests cathodic waves over the pH range of 4-11.8. In Britton-Robinson buffer (BRb) of pH 10, the diffusion current-concentration relationship was found to be rectilinear over the range 3.2-32 MUg/mL and 0.5-14 MUg/mL using DCt and DPP modes, respectively, with minimum limits of detection (LOD) of 0.13 MUg/mL using the DDP. The diffusion-current constant (Id) was 9.29 +/- 0.046 (n=9). The proposed method was successfully applied to the determination of the studied compound in its formulations. The mean percentage recoveries in tablets were 99.48 +/- 1.25 and 100.01 +/- 1.07 (n=4) using DCt and DPP modes, respectively. The results obtained were in agreement with those of the reference method. A proposal for the electrode reaction was postulated. PMID- 23675187 TI - IL-6 Induction by TNFalpha and IL-1beta in an Osteoblast-Like Cell Line. AB - Stress cytokines tumor necrosis factor alpha, interleukin-1 beta and interleukin 6 modulate the activity of a variety of cell types including osteoblasts, and are involved in the pathogenesis of several rheumatic diseases associated with systemic bone loss. We have studied the expression of interleukin-6 induced by interleukin-1 beta and tumor necrosis factor alpha in the osteoblast-like cell line MG-63, derived from a human osteosarcoma. We have observed marked differences in the regulation of interleukin-6 gene expression by tumor necrosis factor alpha or interleukin-1 beta, at the level of mRNA steady state and stability and cytokine secretion. In addition, N-acetyl cysteine, a scavenger of reactive oxygen species, inhibits activation of NF-kappaB and induction of interleukin-6 by tumor necrosis factor alpha, being ineffective on interleukin-1 beta activity. These data illustrate the action of stress cytokines on a cell line widely used in in vitro studies as a reliable model of osteoblast response to cytokines involved in bone resorbing diseases, an important issue for developing new strategies for treatments of bone diseases. PMID- 23675188 TI - Validated Stability indicating Spectrophotometric Method for the Determination of Acetazolamide in Dosage Forms through Complex Formation with Palladium (II). AB - A simple and sensitive spectrophotometric method was developed for the determination of acetazolamide (ACM) in pure form and pharmaceutical preparations. The proposed method is based on the complex formation of acetazolamide with Palladium (II) chloride in acetate buffer pH5.4 and measuring the absorbance at 308 nm. The absorbance- concentration plot was rectilinear over the concentration range of 5-70 MUg/ml with a minimum detection limit (LOD) of 0.98 MUg/ml, limit of quantification (LOQ) of 2.96 MUg/ml, and a molar absorptivity zeta=2.7 * 10(3) L/mol.cm. The factors affecting the absorbance of the formed complex were carefully studied and optimized. The composition of the complex as well as its stability constant was also investigated. The proposed method was applied for the determination of acetazolamide in its tablets and the results obtained were favorably compared with those obtained using the official method. A proposal of the reaction pathway was postulated. PMID- 23675189 TI - A New Spectrophotometric Method for Determination of Phenylpropanolamine HCl in its Pharmaceutical Formulations via Reaction with 2,3,5,6-tetrachloro-1,4 benzoquinone. AB - A selective and simple spectrophotometric method has been developed for the determination of phenylpropanolamine HCl (PPA) in its dosage forms. The method was based on the formation of a colored N-vinyl chlorobenzoquinone derivative of PPA through its reaction with 2,3,5,6-tetrachloro-1,4-benzoquinone in presence of acetaldehyde. The colored product exhibits maximum absorbance at 650 nm. Different experimental parameters affecting formation and stability of the product were carefully studied and optimized. The stoichiometry of the reaction was determined, and the reaction pathway was postulated. The absorbance concentration plot was rectilinear over the range of 5-100 MUg/mL with Limit of Detection (LOD) and Limit of Quantitation (LOQ) of 0.244 MUg/mL and 0.74 MUg/mL respectively. The analytical performance of the method was fully validated, and the results were satisfactory. The proposed method was successfully applied to the determination of PPA in its commercial dosage forms including tablets, capsules and syrups with good recoveries. Statistical comparison of the results with those of the comparison method showed good agreement and proved that there was no significant difference in the accuracy and precision between the reference and the proposed methods. The mechanism of the reaction pathway was postulated. PMID- 23675191 TI - In vitro and in vivo studies on the effects of bone morphogenetic protein-7 on human kidney and lung tumor cells. AB - Breast, kidney, lung, and prostate cancers are among the human cancers that show high propensity to form bone metastasis. Bone morphogenetic protein (BMP) -2 and 7 are two members of the BMP superfamily which show the most potent biological activity in stimulating bone differentiation and repair. These proteins have been used in clinical treatment of orthopedic diseases and have also been studied in different types of cancer. We report here detection of mRNA coding for three type I and one type II BMP receptors in G-402 kidney tumor cells and A-549 lung tumor cells, suggesting that these cells are responsive to BMPs. We then observed that BMP-7 inhibited cell proliferation of both cell lines in a protein concentration dependent manner in vitro. Additionally, when BMP-7-treated cells were implanted into the flank region of male nude mice, smaller tumors, compared to those formed with the untreated cells, were observed. Histological analysis showed that the masses formed at the site of implantation displayed significantly less number of tumors than the control and exhibited significant ectopic bone formation. These findings raise the possibility of BMP-7 as a therapeutic agent for kidney and lung cancers. PMID- 23675190 TI - Heterogeneity of glucocorticoid resistance in patients with bronchial asthma. AB - Bronchial asthma is assumed to be the result of excessive inflammation driven by an aberrant T-helper-2 (Th2) response. Recently, it has begun to be recognized that asthma is a heterogeneous disorder. Glucocorticoids (GCs) are effective treatment for bronchial asthma; however, the inflammation in bronchial asthma cannot always be fully controlled. A recent study demonstrated a new underlying mechanism of glucocorticoid resistance that acts in a Th2-independent manner. Thus, responses to GCs are highly heterogeneous. PMID- 23675192 TI - Methyl angolensate from callus of Indian redwood induces cytotoxicity in human breast cancer cells. AB - AIM: Natural products discovered from medicinal plants have played an important role in the treatment of cancer. Methyl angolensate (MA), a tetranortriterpenoid obtained from the root callus of Indian Redwood tree, Soymida febrifuga Roxb. (A.Juss) was tested for its anticancer properties on breast cancer cells. METHODS: Cell viability was tested using trypan blue, MTT and LDH assays. Tritiated thymidine assay and flowcytometry were used to study effect of MA on cell proliferation. The activation of apoptosis was checked by annexin V and JC-1 staining followed by FACS analysis. Immunoblotting analysis was used for studying expression of apoptotic and DNA double strand break repair proteins. RESULTS: We find that MA inhibited the growth of breast cancer cell line, T47D in a time- and dose-dependent manner. MA treatment led to the inhibition of cell proliferation as detected by tritiated thymidine assay and flowcytometry. Further, MA treated cells exhibited typical apoptotic morphological changes and led to the accumulation of subG1 peak in cell cycle distribution. The induction of apoptosis was further confirmed both by annexin V staining and JC1 staining. We also find that MA activates MAP kinase pathway to induce apoptosis. Besides, we find a time dependent activation followed by degradation of DNA double-strand break repair proteins upon treatment with MA. CONCLUSION: These results suggest that MA induces cytotoxicity in breast cancer cells. Further, the altered expression of DSB repair proteins in MA treated cells may control the induction of apoptosis in these cancer cells. PMID- 23675193 TI - Hospital Bed Occupancy and HIV/AIDS in three Major Public Hospitals of Addis Ababa, Ethiopia. AB - BACKGROUND: In countries like Ethiopia where the spread of HIV infection is extensive, health services are faced with an increased demand for care. The most obvious reflection of this increased demand is through patient load, longer bed occupancy perhaps to the exclusion of patients with other ailments. OBJECTIVE: The purpose of this study was to describe the bed occupancy rate and the average length of stay of HIV/AIDS inpatients of three major public hospitals. METHODS: A Retrospective Cross-sectional study was conducted in three major hospitals of Addis Ababa namely Zewditu Memorial Hospital, Tikure Anbessa Hospital and Saint Paul's Hospital from February to March 2004. RESULTS: Of the total 453 sampled inpatients, 293 (65 %) were HIV positives. Over half (55.0%) were Males. The most affected age group was between 24 and 56 years. The majority (85.8%) were from Addis Ababa and over half (57.7%) was married. Housewives constituted about a quarter (26.3%) of all the admitted cases. The most common co-morbidities resulted in admission to the medical wards among the HIV-positive cases were Tuberculosis (73.0%) and jirovicii pneumonia (70.3%), and their occurrence was significantly higher among HIV+ than their counter parts (p=0.001). Although numbers of patients admitted in Tikur Anbesa hospital was more than Saint Paul's and Zewditu Memorial hospitals (ZMH), the proportion of HIV positive cases admitted to ZMH however was higher (49.0%) than Tikur Anbessa (14.0%) and Saint Paul's hospitals (18.0%). Likewise the number of inpatient days was also higher in ZMH (n=7765) than the other hospitals. The bed occupancy rate was however, higher in ZMH (53.0%) than Tikur Anbessa (12.0%) and Saint Paul's (12.0%) hospitals. CONCLUSION: One of the most obvious consequences of HIV/AIDS patients are the increased occupancy of hospitals beds suggesting that only 81.1 % of the beds are for all other afflictions in the hospitals. It appears that there is a lot of concern that patients with HIV are competing with the non-HIV infected patients in a resource limited areas. Home based care with community involvement and greater use made of existing community resources might be a response to the limitations of curative hospital-based care and treatment needs of many HIV/AIDS patients. PMID- 23675194 TI - HPLC Method for the Simultaneous Determination of Ten Annonaceous Acetogenins after Supercritical Fluid CO2 Extraction. AB - Annonaceous acetogenins (ACGs) isolated from Annonaceae plants exhibited a broad range of biological bioactivities such as cytotoxic, antitumoral, antiparasitic, pesticidal and immunosuppresive activities. However, their structures were liable to change at more than 60 degrees C and their extraction yields were low using traditional organic solvent extraction. In the present study, all samples from Annona genus plant seeds were extracted by supercritical carbon dioxide under optimized conditions and a high-performance liquid chromatography (HPLC) method was established for simultaneously determining ten ACGs. All of the ten compounds were simultaneously separated on reversed-phase C18 column (250 mm * 4.6 mm, 5 MUm) with the column temperature at 30 degrees C. The mobile phase was composed of (A) methanol and (B) distilled water, the flow rate was 1.0 ml/min and the detection wavelength was set at 220 nm. All calibration curves showed good linear regression (gamma>0.9995) within the test range. The established method showed good precision and accuracy with overall intra-day and inter-day variations of 0.99-2.56% and 1.93-3.65%, respectively, and overall recoveries of 95.16-105.01% for the ten compounds analyzed. The established method can be applied to evaluate the intrinsic quality of Annonaceae plant seeds. The determination results recover the content-variation regularities of various ACGs in different species, which are helpful to choose the good-quality Annonaceae plant seeds for anticancer lead compound discovery. PMID- 23675195 TI - Effects of life table models on the evaluation of excess mortality. AB - BACKGROUND: Northern regions of Iran have been encountered to dominate malignancies of gastrointestinal (GI) tract. We aimed to examine the excess mortality due to the GI tract cancer in Mazandaran province. METHODS: Socio demographic and clinical data of 484 patients with GI cancer collected during the years 1990-1991 were available from Babol Cancer Registry Center in Iran. Patients were followed-up for a maximum period of 15 years by the year 2006. The Coale-Demeny life tables were established for each combination of birth cohort and sex of patients, and were considered as the reference population in estimating excess mortality rates. The relative and additive mortality models for excess mortality estimation were used. RESULTS: The sample of subjects encompassed 66.3% men and 33.7% women, with mean age 58.26 +/- 10.90 years. Esophageal cancer appeared to be the most common one, and endoscopy was the general method for cancer detection. Survival rate in 15 years following diagnosis was nearly 6%. Excess mortality estimated by each of the relative and additive models reached the most value in the first two years of observation in both genders and according to each of the Coale-Demeny regional patterns. CONCLUSION: considering individuals in a population come from different cohorts with different mortality patterns, it might be recommended to construct distinct life tables for different birth cohorts when estimating excess hazard. The West model as a general pattern is recommended to represent mortality patterns in countries whose registration systems either do not exist or are so affected by omission and other errors. PMID- 23675196 TI - Cyclic peptidomimetic lead compounds to reduce neurotoxicity and associated oxidative stress in Alzheimer's disease. AB - Cyclic peptidomimetic compounds have been investigated utilizing ab initio Hartree Fock molecular orbital calculations. Prospective use of these ionophores as curative drugs for Alzheimer's disease has been investigated by considering their metal toxicity removal efficiency. A (2,4,2,4) system that is, ((gly-et) (ala-gly-gly-et))2 with CH2NH backbone is predicted to undergo low conformational reorganization in presence of Zn(2+) ion with moderate electrostatic stabilization of ion. Conformation of this system and molecular weight render it suitable to be a lead compound for metal toxicity removal drugs required in AD. PMID- 23675197 TI - Feasibility Evaluation of Detecting Hydroxymethylphosphine Oxide In Vivo by (31)P MRS. AB - Application of organophosphorus compounds in biomedicine is attractive because the (31)P nucleus is very amenable to study by nuclear magnetic resonance (NMR) techniques, particularly, by in vivo (31)P magnetic resonance spectroscopy ((31)P MRS). The water-soluble organophosphorus compounds that are non-toxic, exhibit metabolic stability, and show a unique resonance peak in (31)P NMR spectroscopy, which could be ideal to be used as probes for (31)P-MRS. Here we evaluated the in vivo feasibility of potentially using a hydroxymethylphosphine oxide as a novel probe for (31)P-MRS studies using tris (hydroxymethyl) phosphine oxide (THPO) as an example. THPO was synthesized, injected in the normal CF1 mice, and (31)P spectra were acquired before and after injection with the coil located on the regions of interest. The NMR signal from the region of interest appeared within one minute of THPO injection. The compound was stable in vivo as no metabolites of THPO were observed. No toxicity was observed after THPO injection in mice. The peak concentrations of THPO in liver and kidney were reached within 15 min and 60 min respectively. THPO was excreted exclusively in urine without undergoing any metabolism indicating that it is very stable under in vivo conditions. These initial studies in normal CF1 mice clearly demonstrate that THPO possess the essential characteristics required for a potential MRS probe. Based on the current preliminary results, we suggest that HMPs, when incorporated into targeted drugs (peptides, proteins, antibodies, etc.), may serve as novel (31)P probes for monitoring the drug distribution in vivo by MRS. PMID- 23675198 TI - Hypolipidemic and renal functionality potentials of the hexane extract fractions of elephantopus scaber linn. AB - BACKGROUND: Abnormalities in lipid profile are one of the most common complications in diabetes mellitus. In STZ-induced diabetic rats, the rise in blood glucose is accompanied by a disturbance in lipid profile. Further still is the disturbance in the renal functions which includes abnormality in the serum urea,protein and creatinine levels The aim of the present study is to prove the hypolipidemic and the renal functionality effect of the root of Elephantopus scaber Linn. PROCEDURE: Fractions obtained from crude extracts of hexane prepared from the root of Elephantopus scaber Linn. were administered to white albino rats at a dose of 0.15 g/Kg bwt for a period of 30 days to prove its hypolipidemic effect on a long term basis which is proved to be irreversible as the plant is reported to have regenerative property. FINDINGS: The extract produced a significant (p<0.001) dose-dependent decrease in the levels of total cholesterol (TC), Triacylglycerol (TG), low-density lipoprotein-cholesterol (LDL cholesterol), with a significant increase in the level High-density lipoprotein cholesterol (HDL) and reporting the restoration in renal functions back to near normal. CONCLUSION: The fractions of Elephantopus scaber Linn. hexane extract are confirmed to have a hypolipidemic potential and a re-establishment of renal functions. PMID- 23675199 TI - Anxiety Disorder amongst Secondary School Children in an Urban City in Nigeria. AB - Anxiety is a source of concern to the clinicians as it is co morbid with other mental disorders, particularly depression and learning disabilities, and it causes low self-esteem. The aim of this research was to evaluate the prevalence of anxiety disorder amongst secondary school children in Port Harcourt. A two staged stratified sampling method was used to select the schools. Structured questionnaire based on Vanderbilt ADHD Diagnostic Teacher Rating Scale for anxiety and depression symptoms was used in evaluating the students. The questionnaires administered to the students were filled with the assistance of the researchers and the classroom teachers. Direct verbal interview was conducted for those noted to have symptoms of any of the various types of anxiety disorders and fears. Out of 885 students, 91 met the criteria for the diagnosis of anxiety/ depression disorder; prevalence was 10.28%, age range was 9-18 years. There were 37 males and 54 females giving a male: female ratio of 0.69:1. Majority 52 (57.14%) of the children lived with their parents, 28 (30.77%) of them lived with family relations and 11 (12.09%) of them were working as house helps to other families. The reasons given for being anxious were poor self image, fear of death, repeated physical and sexual abuses by their care givers and other adults. Learning disability was the major associated co morbid disorder (18.68%). Generalized anxiety was the most common type of anxiety disorder identified (32.97%). Anxiety disorders are debilitating chronic conditions. When it affects school aged children it contributes significantly to poor academic performance. PMID- 23675200 TI - Spectrophotometric Determination of the Antidepressants Sertraline and Paroxetine HCl using 2,4-Dinitrofluorobenzene. AB - A simple and sensitive spectrophotometric method was developed for the determination of each of sertraline (SER) and paroxetine HCl (PXT) in dosage forms. The method is based upon reaction of PXT and SER with 2,4 dinitrofluorobenzene (DNFB) to form colored products. The absorbance of the products were measured at 375and 390 nm for SER and PXT respectively. The absorbance concentration plots were rectilinear over the concentration rang of 1 10 and 2-20 MUg/mL with lower detection limits (LOD) of 0.11 and 0.28 MUg/mL and quantification limits (LOQ) of 0.32 and 0.85 MUg/mL for SER and PXT, respectively. The developed method was successfully applied for the determination of SER and PXT in dosage forms. The common excipients and additives did not interfere in their determinations. There was no significant difference between the results obtained by the proposed and the reference methods regarding Student t-test and the variance ratio F-test respectively. A proposal of the reaction pathway was postulated. PMID- 23675201 TI - Spectrofluorimetric and spectrophotometric determination of pregabalin in capsules and urine samples. AB - Three new, simple, sensitive and selective spectrofluorimetric and spectrophotometric methods were developed for the determination of the gamma amino-n-butyric acid derivative, pregabalin. Pregabalin as a primary amine reacts with fluorescamine to yield a fluorescent product (Method I), with 2,4 dinitrofluorobenzene (Method II) and 2,3,5,6-tetrachloro-1,4-benzoquinone (Method III) in aqueous alkaline buffered media to form colored products which could be measured spectrophotometrically. The optimum conditions for each reaction were ascertained and the methods were applied for the determination of pregabalin over the concentration range of 20-280 ng mL(-1) and 1-7 MUg mL(-1) for spectrofluorimetry and spectrophotometry, respectively with good correlation (>=0.999). The limits of assays detection ranged from 9.6 * 10(-4) MUg mL(-1) to 0.42 MUg mL(-1) for spectrofluorimetry and spectrophotometry, respectively. The suggested methods were applied to the determination of the drug in capsules. No interference could be observed from the additives listed to be in capsules. Furthermore, the spectrofluorimetric method was extended to the in-vitro determination of pregabalin in spiked urine, interference from endogenous amino acids could be eliminated through selective complexation with copper acetate; the percentage recovery was found to be 98% +/- 1.42 (n=6). Co- administered drugs such as chlordiazepoxide, clonazepam, diazepam, nitrazepam and lamotrigine did not interfere with the assay. The methods were validated with respect to linearity, accuracy, precision and robustness. The results obtained were determined to be in good agreement with those obtained using a previously reported method. PMID- 23675202 TI - Development and Validation of Spectrofluorimetric Method for Determination of Biotin in Bulk and Pharmaceutical Preparations via its Oxidation with Cerium (IV). AB - A simple and sensitive spectrofluorimetric method was developed for the determination of biotin in pure form and in pharmaceutical preparations. The proposed method is based on the oxidation of the drug with cerium (IV) ammonium sulfate in acidic medium. The fluorescence of the produced Cerium (III) was measured at 365 nm after excitation at 255 nm. The different experimental parameters affecting the development and stability of the reaction were carefully studied and optimized. The method is applicable over the concentration range of 30-120 ng/mL with correlation coefficient of 0.9998. The detection limit (LOD) of biotin was 2.41 ng/mL while quantitation limit (LOQ) was 7.29 ng/mL. The proposed procedure was successfully applied for the determination of biotin in pharmaceutical preparations with mean recoveries of 99.55 +/- 0.83 and 101.67 +/- 1.53 for biotin ampoules and capsules, respectively. The results obtained were in good agreement with those obtained using the official method. PMID- 23675205 TI - Extracellular superoxide dismutase activity and plasma malondialdehyde in human immunodeficiency virus subjects of kano state as surrogate markers of CD4 status. AB - This study looked at the profile of plasma extracellular superoxide dismutase (SOD3) activity, malondialdehyde (MDA) vis-a-vis that of CD4 counts in human immunodeficiency virus subjects in Kano State, Nigeria. The subjects for this study comprised twenty (20) non-HIV infected volunteers as control and one hundred (100) HIV infected subjects. Forty nine (49) infected patients have not been on treatment, while fifty one (51) were at various stages of treatment. There was a negative correlation between the serum malondialdehyde concentration and CD4 count (Pearson r=-0.68, p<0.01). There was also a negative correlation between serum malondialdehyde concentration and extracellular superoxide dismutase activity ((Pearson r=-0.71, p<0.01) and Vitamin A concentration (Pearson r=-0.75; p<0.01). Conversely a positive correlation was observed between the CD4 counts in HIV infected patients and activity of extracellular superoxide dismutase (Pearson r=0.86, p<0.01). Similarly there was a positive correlation between CD4 count and serum vitamin A concentration (Pearson r=0.89 p<0.01). The possibility remains for using these indicators to monitor HIV patients not eligible for therapy in resource constrained facilities of our rural areas. PMID- 23675204 TI - Transforming Growth Factor-beta1 and Laminin-111 Cooperate in the Regulation of Expression of Interleukin-6 and Interleukin-8 in Synovial Fibroblasts. AB - In a recent study we showed that binding of synovial fibroblasts (SF) to laminin 111 (LM-111) in the presence of TGF-beta1 induced a significant production of IL 16. Here we go on to investigate the regulation of IL-6 and IL-8 in SF by LM-111 and TGF-beta1. Changes in steady state mRNA levels encoding the interleukins were investigated by quantitative RT-PCR. We screened for interleukin production by a multiplexed immunoarray and quantified it with ELISA. The biological activity of IL-6 and IL-8 was corroborated by B-lymphocyte proliferation and cell migration assays, respectively. Growth of SF on LM-111 in presence of TGF-beta1 induced significant mRNA responses for IL-6 (mean 3.72-fold increase, +/- 1.6, p<0.003) and IL-8 (mean 4.5-fold increase, +/- 1.6, p<0.001). In the supernatants significantly elevated concentrations of IL-6 (mean 7.9 +/- 5 ng/mL, p<0.005) and IL-8 (mean 73.0 ng/mL +/- 51, p<0.05) were detected, and they were shown to be biologically active. Binding to LM-111 in the presence of TGF-beta1 activates SF for expression of IL-6 and IL-8 and thus may contribute to synovial inflammation and to infiltration of leukocytes. PMID- 23675206 TI - Downregulation of Signaling-active IGF-1 by Dipeptidyl Peptidase IV (DPP-IV). AB - Functioning as an extracellular protease, dipeptidyl peptidase IV (DPP-IV) preferentially cleaves the peptide bond after the penultimate proline residue. We report here that DPP-IV cleaves the first two amino acids from insulin-like growth factor 1 (IGF-1), revealed by mass spectrometry. The kinetic parameters of the proteolytic cleavage indicate that this reaction is physiologically relevant. Interestingly, truncated IGF-1 is less potent than the full-length protein in activating the IGF-1R, but binds more readily to IGF-binding protein 3 (IGFBP3). Quantitative RT-PCR showed that the level of DPP-IV mRNA is dramatically lower in lung squamous cell carcinoma tissues than in adjacent nonneoplastic lung tissues. However, this reduction was not observed in lung adenocarcinoma tissues. Our study suggests a possible link between IGF-1 and DPP-IV in cancer development in a specific tumor niche. A DPP-IV-related pathway may be important in mitigating IGF-1 signaling. Consequently, a robust IGF signaling pathway may accelerate early carcinogenesis in environments lacking DPP-IV. PMID- 23675207 TI - Application of spatially distributed field of electric impulses for correction of angiogenesis in ischemic muscular tissue. AB - Influence of spatially distributed field of electric impulses in a projection to cervical ganglions of the sympathetic nervous system on angiogenesis in ischemic muscular tissue of a rat's shin has been studied. It is revealed that blood supply of animals, influenced by the field, is restored through increase in quantity of capillaries in ischemic tissues, and number of products of endogenous intoxication is reduced. PMID- 23675203 TI - The efferent system or olivocochlear function bundle - fine regulator and protector of hearing perception. AB - The efferent system of the ear possesses several distinct functions, in particular noise protection, mediation of selective attention and improvement of signal to noise ratio. It also supports adaptation and frequency selectivity by modification of the micromechanical properties of outer hair cells. There are many differences in anatomy and physiology between the medial and lateral olivocochlear system suggesting that they are functionally separate systems. The efferent system is affected by inner ear stressors, e.g. noise, ototoxic drugs, and might play a key role in tinnitus generation and maintenance. The anatomy, physiology and its realtionships to inner ear pathologies are discussed in this review article. PMID- 23675208 TI - Treatment of the Posterolateral Tibial Plateau Fractures using the Anterior Surgical Approach. AB - BACKGROUND: Fracture of the posterolateral tibial plateau is relatively uncommon. While surgical treatment by the posterior approach is theoretically ideal, this approach is associated with numerous complications. We describe a series of fractures of the posterolateral tibial plateau treated by the anterior surgical approach. METHODS: Fifteen patients with posterolateral tibial plateau fractures were included in this study. All patients were treated operatively using the anterior approach. The quality of fracture reduction was evaluated and functional results were estimated by the Hospital for Special Surgery knee scoring system. RESULTS: The most common cause of fracture was a motor scooter accident (86%, 13 of 15 patients), which may have resulted in the protective front plate of the scooter hitting the knee in the flexion position, causing an axial compression and valgus force, resulting in the fracture of the posterolateral tibial plateau. The average knee motion after surgery was 0-124 degrees of flexion and 14 out of 15 patients (93%) experienced satisfactory articular reduction. There were no postoperative neural or vascular injuries and no wound complications. The average Hospital for Special Surgery knee score was 92 (range, 74-98). CONCLUSIONS: In our series, with careful preoperative planning, the anterior approach for the surgical treatment of posterolateral tibial plateau fractures had no complications and was associated with satisfactory outcomes. PMID- 23675209 TI - Socioeconomic and Demographic Factors Affecting Body Mass Index of Adolescents Students Aged 10-19 in Ambo (a Rural Town) in Ethiopia. AB - BACKGROUND: Body mass index (BMI) is a commonly used anthropometric measurement to estimate the level of nutritional indices (underweight/overweight) of adolescents and adults. Knowledge of the factors affecting BMI is essential for developing intervention programs. This study was conducted to measure BMI and determine the socioeconomic and demographic factors affecting the relative weight of adolescents living in rural districts in Ethiopia. METHODS: A randomized cross sectional study of 425 adolescent students living in the Ambo region of Ethiopia was conducted. A pre-tested questionnaire was used to collect the socioeconomic and demographic status of the participants. BMI (weight/height(2), kg/m(2)) was measured and used as index of relative weight. Data were analyzed using SPSS version 15. A stepwise backward logistic regression analysis was applied to identify the major determinant abnormal weight of the adolescents while controlling for co-linearity. RESULTS: The prevalence of underweight was 27.2% with male preponderance. The proportion of normal weight females was higher than that of males. There was no significant difference in the proportion of overweight males and females. Age, number of meals, parental education level, source of food, and number of cattle owned were correlated with being underweight. After adjusting for confounding variables only being a member of the younger age group (AOR=1.99; 95% CI=1.01 to 3.57), source of food (AOR=2.4; 95% CI=1.24 to 4.74), and a greater number of cattle owned (AOR=4.9; 95% CI=1.27 to 19.28 were positively correlated with being underweight. CONCLUSION: Younger age adolescents, those who come from homes with no or few cattle, and their parents purchased food were likely to be underweight. This study will help local governments, educators and community groups develop programs to assist underweight adolescents attending schools. PMID- 23675210 TI - Spectrophotometric and Spectrofluorimetric Methods for the Determination of Dothiepin Hydrochloride in its Pure and Dosage Forms using Eosin. AB - Spectrophotometric and spectrofluorimetric methods were developed for the determination of dothiepin hydrochloride (DOP) in different dosage forms. The spectrophotometric method (Method I) is based on formation of a binary complex with eosin at 540 nm in acetate buffer of pH3.7. The absorbance-concentration plot is rectilinear over the range 1-10 MUg/mL with LOD of 0.18 MUg/mL and LOQ of 0.54 MUg/mL. The spectroflurimetric method (Method II) is based on the quantitative quenching effect of Dothiepin on the native fluorescence of eosin at the same pH. The quenching of the fluorescence of eosin was measured at 543 nm after excitation at 304 nm. The fluorescence-concentration plot is rectilinear over the range 0.3-8 MUg/ mL with LOD of 0.11 MUg/mL and LOQ of 0.34 MUg/mL. The proposed methods were successfully applied to the analysis of commercial tablets and capsules containing the drug. Statistical comparison of the results with those of the reference method revealed good agreement and proved that there were no significant differences in the accuracy and precision between the two methods respectively. PMID- 23675211 TI - Simultaneous Determination of Potassium Clavulanate and Amoxicillin Trihydrate in Bulk, Pharmaceutical Formulations and in Human Urine Samples by UV Spectrophotometry. AB - A simple and sensitive UV spectrophotometric method was developed and validated for the simultaneous determination of Potassium Clavulanate (PC) and Amoxicillin Trihydrate (AT) in bulk, pharmaceutical formulations and in human urine samples. The method was linear in the range of 0.2-8.5 MUg/ml for PC and 6.4-33.6 MUg/ml for AT. The absorbance was measured at 205 and 271 nm for PC and AT respectively. The method was validated with respect to accuracy, precision, specificity, ruggedness, robustness, limit of detection and limit of quantitation. This method was used successfully for the quality assessment of four PC and AT drug products and in human urine samples with good precision and accuracy. This is found to be simple, specific, precise, accurate, reproducible and low cost UV Spectrophotometric method. PMID- 23675212 TI - Lexis in Chinese-English Translation of Drug Package Inserts: Corpus-based Error Analysis and Its Translation Strategies. AB - Error analysis (EA) has been broadly applied to the researches of writing, speaking, second language acquisition (SLA) and translation. This study was carried out based on Carl James' error taxonomy to investigate the distribution of lexical errors in Chinese-English (C-E) translation of drug package inserts (DPIs)(1), explore the underlying causes and propose some translation strategies for correction and reduction of lexical errors in DPIs. A translation corpus consisting of 25 DPIs translated from Chinese into English was established. Lexical errors in the corpus and the error causes were analyzed qualitatively and quantitatively. Some examples were used to analyze the lexical errors and their causes, and some strategies for translating vocabulary in DPIs were proposed according to Eugene Nida's translation theory. This study will not only help translators and medical workers reduce errors in C-E translation of vocabulary in DPIs and other types of medical texts but also shed light on the learning and teaching of C-E translation of medical texts. PMID- 23675213 TI - Brain CT-Scan Findings in Unconscious Patients after Poisoning. AB - The aim of this study was to identify and describe brain CT findings in patients with poisoning or drug overdose and altered mental status. In this study, 403 patients with some degree of loss of consciousness who referred due to poisoning or drug overdose were evaluated by brain CT. The most common cause of intoxication was suicide. Intoxication status was determined by the physician and was mainly based on a history of intoxication, positive toxicologic screen result, or physical evidence suggesting intoxication. Among 403 unconscious patients, 229 patients who were ingested or inhaled Benzodiazepine, Carbamazepine, Carbon Monoxide, Ethanol, Methanol, Opium, Tricyclic antidepressants, and Tramadol included in the study. Others had used multiple drugs and/or toxins, or their intoxication was unknown. Mean age of patients was 37.6 +/- 17.7 years (14-95). Among them, 181 (79%) were male. Among all patients, 92 had consumed opium (40.2%), 47 had consumed Benzodiazepines (20.5%) and other patients had been overdosed by other drugs or exposed to other poisonous agents. Totally 38 (16.5%) patients had abnormal CT findings. These included 10 cases of infarction, four cases of hemorrhage, two cases of herniation, 13 cases of edema, and 10 cases of basal ganglia changes (including 9 cases of hypodensity and one case of hypodensity with hemorrhage). A good knowledge of the CT findings in unconscious patients due to poisoning or drug overdose seems to be necessary for radiologists and clinicians. This study is unique in that it reported most of the radiological findings in these patients. PMID- 23675214 TI - Correlation of oxidative stress parameters and inflammatory markers in tunisian coronary artery disease patients. AB - INTRODUCTION: Oxidative stress is now recognized as being the cause and the consequence of cardiovascular diseases. OBJECTIVE: The role that oxidative stress parameters and inflammatory markers may play in diabetes and related cardiovascular disease (CVD) among Tunisian coronary diabetic patients. PATIENTS AND METHODS: We measured the erythrocyte glutathione peroxidase (GPX), the superoxide dismutase (SOD) activities and the plasmatic total antioxidant status (TAS) concentration by colorimetric methods, the hs-CRP by immunonephelometry assays. RESULTS: TAS and GPX were significantly decreased among patients compared to the controls (1.14 +/- 0.28 mmol/l vs 1.55 +/- 0.35 mmol/l; 59.32 +/- 10.72 U/gHb vs 149.19 +/- 30.95 U/gHb). For the diabetic patients, TAS is correlated positively with hs-CRP (r=0.01, p<10(-3)). At the not diabetic subjects, TAS is correlated negatively with the hsCRP. CONCLUSION: Determination of antioxidative defense markers contributes to understanding the effect of stress oxidative on the development and the prevention of cardiovascular disease. PMID- 23675215 TI - Reversibility of hepatic histological damage after surgical temporary obstruction of the common bile duct in a murine model. AB - The reversibility of hepatic histological damage after restoring bile flow in a murine model was assessed. 25 male Balb C mice (25-35 g, age 6 weeks) were divided into 5 groups and their common bile duct (CBD) fastened to obstruct the release of gall bladder and liver contents. Group I, CBD untied at day 10, group II at day 15, and groups III and IV at days 20 and 30, respectively. Hematoxilin eosin stained liver slices were analysed 0, 5, 10 and 20 days after restoring bile flow. Group I showed slight histological lesions (second stage), as cholangiolar bile pigment concretion, pericholangiolar and portal collagen accumulation; group II, mild lesions (third stage), as cholangiolar hamartomatous proliferation and bile duct portal fibrosis; group III showed severe lesions (fourth stage), as loss of functional parenchyma, and also the second and first stage lesions. Group IV died before 30 days. First stage corresponds to absent lesions (control group). Group I recovered totally, group II recovered only from slight lesions and group III had irreversible damage. Severity of lesions increased gradually and accumulatively, irreversible hepatic damage was achieved at 20 days and is deadly at 30 days. Our model of temporary CBD obstruction was suitable to assess reversibility of hepatic histological damage. PMID- 23675217 TI - Orthodontic molar brackets: the effect of three different base designs on shear bond strength. AB - The purpose of the study was to assess the relative base designs of three different maxillary molar stainless steel brackets with reference to the shear bond strength of three different adhesive resins. The molar brackets used were Victory series (3M Unitek), Upper Molar (GAC) and Optimesh XRT (Ormco). The adhesives used were Transbond XT (3M Unitek), Enlight (Ormco) and Sure Ortho Light Bond (Sure Orthodontics). The human enamel specimens (144) were randomly divided into nine groups and each group (n=16) was allocated to a bracket/adhesive combination. The contact surface of each of the bracket bases was measured three dimensionally using a reflex microscope. The base designs were also subjected to further microscopic investigations. The brackets were bonded to the enamel, temperature cycled and the shear bond strength was measured. The size and design of each of the brackets was different. The base size, surface treatment, mesh strand diameter and aperture size of the bracket base mesh have a significant effect on the shear bond strength at the bracket/adhesive interface. The shear bond strengths of all three Ormco bracket/adhesive resin combinations (5.8-6.8 MPa) were significantly lower (p<0.05; Kruskal-Wallis) than the other six bracket/adhesive combinations (9.4-12.1 MPa). The different adhesive types (3 types) could not be mainly responsible for the low shear bond values found for the Ormco bracket. The 3M Unitek combination of the Victory series bracket and Transbond XT adhesive proved to have a high shear bond strength without enamel damage. PMID- 23675216 TI - MafA is a Key Molecule in Glucose and Energy Balance in the Central Nervous System and Peripheral Organs. AB - MafA is a strong transactivator of insulin in pancreatic beta cells. Elucidating the profile of MafA action in organs other than the pancreas is essential. We established an mRNA interference technique that modifies the level of target mRNAs in mice in vivo. After rapidly injecting MafA-siRNA, the resulting changes in the gene profile were analyzed using a microarray system. Significant suppression of the MafA mRNA levels was observed in the pancreas, liver, adipose tissue, and brain of siRNA-injected mice. As we reported previously, the down regulation of insulin mRNA and adipocytokines was observed in the pancreas, and MafA siRNA caused alterations in the expressions of genes related to lipid metabolism and cell growth in the liver, and the attenuation of cell differentiation in cultured adipocytes. In addition to the effects on these organs, MafA expression was immunohistochemically detected in the brain in our preliminary data, and the expression level in siRNA-treated mice was significantly suppressed. The expressions of the affected genes were distinct, including growth hormone, vasopressin, hypocretin, and pro-melanin-concentrating hormone, were almost completely down-regulated (to ~1/100). These results suggested that MafA is likely involved in the regulation of hormonal systems related to glucose metabolism, and MafA is likely positioned near the beginning of the cascade or may influence the expressions of the above-mentioned genes in coordination with other factors in brain tissue. Taken together, the findings in this study suggested that MafA functions as a transcription factor with distinct activities in each organ and is cross-linked in several organs. PMID- 23675218 TI - Statistical analysis of pseudoexfoliation syndrome prevalence, glaucoma and coronary artery disease of the patients with cataract. AB - Cataract is a common disease of the eye and cataract development is usually a very gradual process of normal aging. Many people with cataract disease can also have pseudoexfoliation (PEX) syndrome, glaucoma and coronary artery disease (CHD). We use the data from the Department of Ophthalmology, Medical School of the University of Patras, Greece. These data contains 2140 Greek patients from the southwestern Greece with cataract disease. In order to investigate the association between any two variables statistical analysis were studied. Considering the binary behavior of the response we decide to use non parametric analysis in this study to deal with the testing the populations mean with different distributions. PMID- 23675219 TI - In silico design of a peptidomimetic carrier for levodopa. AB - Ab initio molecular orbital calculations at the Hartree Fock level utilizing 6 31G basis set have been performed on small cyclic peptides and peptidomimetic compounds to explore their utility as carriers of levodopa (L-3,4 dihydroxyphenylalanine) to enhance its brain bioavailability. A cyclic peptidomimetic compound with hydrophobic CH2NH backbone is suggested as possible carrier. This carrier is predicted to efficiently carry Levodopa held by non covalent interactions encompassed in its cyclic backbone without chances of expulsion before delivery inside brain. Carrier is expected to undergo passive diffusion alongwith the drug held inside. Once inside the brain, drug may be delivered enzymatically or non enzymatically. PMID- 23675220 TI - Aerobic Fitness and Cognitive Functions in Economically Underprivileged Children Aged 7-9 Years: A preliminary Study from South India. AB - This study examined the relationship between aerobic fitness and cognitive functions in 7-9 year old school going children hailing from a socio-economically disadvantaged background in Bangalore, India. Ninety eight children (51% boys and 49% girls) were assessed on height, weight, BMI, aerobic fitness (multistage 20 m shuttle test) and cognitive functions (verbal tests: comprehension, arithmetic, vocabulary, analogies; performance tests: block design, object assembly and coding). Number of shuttles was significantly positively correlated with two of the cognitive tests: comprehension (p=0.01) and block design (p=0.005). Multiple linear regression analysis showed that the number of shuttles emerged as an independent predictor of tests of comprehension and block design after adjusting for BMI and gender. The above findings provide preliminary evidence for the association between aerobic fitness and cognitive functions in children from poor socio-economic background. PMID- 23675221 TI - Spectrophotometric methods for the determination of sitagliptin and vildagliptin in bulk and dosage forms. AB - Simple, accurate and precise spectrophotometric methods have been developed for the determination of sitagliptin and vildagliptin in bulk and dosage forms. The proposed methods are based on the charge transfer complexes of sitagliptin phosphate and vildagliptin with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), 7,7,8,8-tetracyanoquinodimethane (TCNQ) and tetrachloro-1,4-benzoquinone (p chloranil). All the variables were studied to optimize the reactions conditions. For sitagliptin, Beer's law was obeyed in the concentration ranges of 50-300 MUg/ml, 20-120 MUg/ml and 100-900 MUg/ml with DDQ, TCNQ and p-chloranil, respectively. For vildagliptin, Beer's law was obeyed in the concentration ranges of 50-300 MUg/ml, 10-85 MUg/ml and 50-350 MUg/ml with DDQ, TCNQ and p-chloranil, respectively. The developed methods were validated and proved to be specific and accurate for the quality control of the cited drugs in pharmaceutical dosage forms. PMID- 23675222 TI - Spectroflourometric and spectrophotometric methods for the determination of sitagliptin in binary mixture with metformin and ternary mixture with metformin and sitagliptin alkaline degradation product. AB - Simple, accurate and precise spectroflourometric and spectrophotometric methods have been developed and validated for the determination of sitagliptin phosphate monohydrate (STG) and metformin HCL (MET). Zero order, first derivative, ratio derivative spectrophotometric methods and flourometric methods have been developed. The zero order spectrophotometric method was used for the determination of STG in the range of 50-300 MUg mL(-1). The first derivative spectrophotometric method was used for the determination of MET in the range of 2 12 MUg mL(-1) and STG in the range of 50-300 MUg mL(-1) by measuring the peak amplitude at 246.5 nm and 275 nm, respectively. The first derivative of ratio spectra spectrophotometric method used the peak amplitudes at 232 nm and 239 nm for the determination of MET in the range of 2-12 MUg mL(-1). The flourometric method was used for the determination of STG in the range of 0.25-110 MUg mL(-1). The proposed methods used to determine each drug in binary mixture with metformin and ternary mixture with metformin and sitagliptin alkaline degradation product that is obtained after alkaline hydrolysis of sitagliptin. The results were statistically compared using one-way analysis of variance (ANOVA). The methods developed were satisfactorily applied to the analysis of the pharmaceutical formulations and proved to be specific and accurate for the quality control of the cited drugs in pharmaceutical dosage forms. PMID- 23675223 TI - Statistical modeling of lung cancer: answering relative questions. AB - THE OBJECTIVE OF THIS PAPER IS TO PERFORM PARAMETRIC AND NONPARAMETRIC ANALYSIS TO ADDRESS SOME VERY IMPORTANT QUESTIONS CONCERNING LUNG CANCER UTILIZING REAL LUNG CANCER DATA: What is the probabilistic nature of mortality time in ex-smoker lung cancer patients and non-smoker lung cancer patients, for female, male, and the totality of female and male patients? Is there significant difference of mortality time between ex-smoker and non-smoker patients? For ex-smokers, are there any differences with respect to the key variables such as mortality time, cigarettes per day (CPD), and duration of smoking between female and male patients? For non-smokers, can we notice a difference in mortality time between female and male patients? Can we accurately predict mortality time given information on CPD, starting time and quitting time for a specific lung cancer patient who smokes? Thus best fitting probability distributions are identified and their parameters are estimated. Mean mortality times are compared between non smokers and ex-smokers, female non-smokers and male non-smokers, and female ex smokers and male ex-smokers. Important entities related to lung cancer mortality time, such as cigarettes per day (CPD), and duration of smoking (DUR), are compared between female and male ex-smoker lung cancer patients. Finally, a model is developed to predict the mortality time of ex-smokers with a high degree of accuracy. PMID- 23675224 TI - Penetrated arrow shot injury in anterior neck. AB - BACKGROUND: Although gunshot injuries are the most common penetrating anterior neck injuries in the developed world, this finding is not the case in the developing world, where knives, spears, arrows, and machetes are the preferred weapons, particularly in tribal societies. AIM: To present the case report of a patient with arrow shot injury to the anterior neck. METHOD: A 48 year old cattle rearer in a village in northern part of Nigeria presented with 3 hr history of an arrow shot in anterior part of the neck which he sustained the while trying to prevent some armed robbers from stealing his cow. There was scanty bleeding from the site with the arrow in-situ sealing the wound. RESULT: The entrance point of the arrow, about 1 cm in diameter, was just at the anterior border of the right sternocleidomastoid muscle; about 4 cm above the medial end of the right clavicle. There was a small skin bruise with slight swelling and tenderness around the opening but no active bleeding and no crepitus. CONCLUSION: Penetrating neck trauma from arrow shot may lead to potentially life-threatening injuries. A prompt diagnosis, a systematic treatment protocol, and an experienced trauma team are necessary to prevent a potential catastroph. PMID- 23675225 TI - Biomaterials in maxillofacial surgery: membranes and grafts. AB - Today, significant differences in the use of biomaterials (membranes and grafts) of animal or synthetic origin have yet to be reported. Nevertheless, some evidences suggest that synthetic materials have a lower risk of disease transmission. This review aims to assess the available informations on regenerative bone technique using reasorbable membranes and bone grafts. In particular, biocompatibility, immunological response, tissue reaction, reabsorption time and histological features of materials daily use in dentistry and in maxillofacial surgery were emphasized. PMID- 23675226 TI - Lipid Profile in Relation to Anthropometric Measurements among College Male Students in Riyadh, Saudi Arabia: A Cross-Sectional Study. AB - BACKGROUND: Anthropometric measurements can easily reflect any changes in the lipid concentration in the human body. OBJECTIVES: The present work is aimed at studying lipid profile and its relation to anthropometric measurements in college males from Riyadh, Saudi Arabia. SUBJECTS AND METHODS: This study was conducted from September 2006 to December 2008. 333 students aged 18-35 years of Riyadh College of Health Science - male section - participated in the study. Anthropometric measurements including weight, height, waist and hip circumferences were measured. Body Mass Index (BMI) was calculated. Fasting blood sugar and lipid profile including total cholesterol (TC), Low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL) and triglycerides (TG) were estimated. Socio-demographic data were collected from a questionnaire. RESULTS: Mean TC level was 4.227 +/- 0.869 mmol/l, while for LDL, HDL and TG were 2.57 +/- 0.724, 1.360 +/- 0.545 and 1.385 +/- 0.731 mmol/l, respectively. Mean TC level did not differ significantly across weight groups except among obese patients. Mean HDL, LDL and TG did not differ significantly among different groups at 5% level of significance. There was positive, statistically non significant correlation between age and BMI. The correlation between age and all lipid parameters were statistically non-significant. There was positive correlation between BMI and TC and LDL, while there was a negative correlation between BMI and HDL. There was no correlation between BMI and triglycerides. CONCLUSION: BMI, waist and hip circumferences all increase with age. The level of TC, LDL and TG go high with increase in age and BMI. PMID- 23675227 TI - The prevalence of serum immunoglobulin g antibody to Chlamydia trachomatis in subfertile women presenting at the university of port harcourt teaching hospital, Nigeria. AB - OBJECTIVES: This study was undertaken to assess the prevalence of IgG antibody to Chlamydia trachomatis in subfertile patients at the University of Port Harcourt Teaching Hospital and to determine associated factors between this and infertility. STUDY DESIGN: This case controlled study was conducted among 100 women presenting for infertility consultation at the University of Port Harcourt Teaching Hospital. One hundred women with normal intrauterine pregnancies attending the antenatal clinic were used as controls. A questionnaire was used to obtain information on their socio-demographic data, sexual and obstetric history administered to them. 2mls of venous blood was collected, labelled and sent to the laboratory. The presence of IgG antibody to Chlamydia trachomatis was determined. Hysterosalpingography was performed on all infertile women to assess tubal patency. Data management was with SPSS 15.0 for Windows((r)) statistical software. RESULTS: The mean age of the subjects was 30 +/- 3.1 years, median parity 0.5 and average life time sexual partner 3.7 +/- 2.8. All the participants in the study were married. 62% of subjects had tertiary education. The Chlamydia trachomatis IgG antibody prevalence in the subfertile population was 74% and 51% in the control group, P<0.001. Tubal occlusion occurred in 58 (78.4%) of cases positive for chlamydia antibody. Pelvic inflammatory disease and mucopurulent discharge were the most common presentating symptoms among Chlamydia antigen positive infertile women, P<0.001. There was an association between subfertility and the number of life time sexual partners. There was an association between subfertility and non usage of condoms. CONCLUSION: The prevalence IgG antibody to Chlamydia trachomatis was significantly higher in women with subfertility compared to women with proven fertility. There was a strong association between Chlamydia antibody positivity and tubal occlusion. In a resource-poor country such as Nigeria, enzyme immunosorbent assay for chlamydial IgG antibodies may be substituted for HSG for the detection of tubal occlusion. PMID- 23675228 TI - In-hospital death caused by pancreatic cancer in Spain: application with a bayesian network. AB - Pancreatic cancer is one of the least common tumors (2.1%), but it remains one of the most lethal. This lethality is primarily due to late stage diagnosis in the vast majority of patients. Here we demonstrate, using a Bayesian network, that we can determine a posteriori, with a high probability of success, the probability of in-hospital death of pancreatic cancer in hospitals across Spain with information related to the type of admission, the type of procedure, the primary diagnosis or the Charlson co-morbidity index. The advantages of using a Bayesian network are that it allows us to examine multiple hypotheses and to measure the effect of the introduction of variables on our hypotheses. Being able to determine deceases in the probability of survival based on hospital admission data, such as the diagnosis resulting in the present admission or the presence of co-morbidities, could facilitate the detection of deficiencies in the patient treatment and improve hospital management. Moreover, the control of related co morbidities may have an impact on the in-hospital deaths of these patients. PMID- 23675229 TI - Herbal extract of gynostemma pentaphyllum decreases hepatic glucose output in type 2 diabetic goto-kakizaki rats. AB - The aim of the study was to explore the effect of Gynostemma pentaphyllum (GP) extract on hepatic glucose output (HGO) in spontaneously type 2 diabetic Goto Kakizaki (GK) rats treated orally with GP or placebo extract 1600 mg/kg daily, during three days or three weeks. The three-week treatment of GP, but not three day treatment, significantly reduced plasma glucose (PG) levels from 9.8 +/- 0.6 to 6.8 +/- 0.4 mmol/L (p=0.027) in GK rats, whereas PG levels were not significantly decreased in the placebo rats. Glucose tolerance assessed by an intra-peritoneal glucose tolerance test was significantly improved in GP treated compared to placebo treated group (areas under the glucose curves, AUCs, from 0 to 120 min were 1150 +/- 200 vs. 1761 +/- 87 mmol/L; p=0.013). The glucose response in an intra-peritoneal pyruvate tolerance test from minute 15 to minute 120, the AUC (15-120) was significantly lower in the GP group (415.5 +/- 68.0 vs. 641.5 +/- 41.8 mmol/L; p<0.05). In liver perfusions, the AUCs for HGO during 18 min (0-18 min) were significantly decreased in GP treated rats compared with control rats (302.8 +/- 36.5 vs. 423.5 +/- 44.7 MUmol, p<0.05). The three-week GP treatment significantly reduced the hepatic glycogen content, but not glycogen synthase activity compared to placebo group (p<0.007). In conclusion, three-week treatment of GP extract exerted anti-diabetic effect in GK rats, reducing plasma glucose levels and HGO, suggesting that GP improves the hepatic insulin sensitivity by suppressing gluconeogenesis. PMID- 23675230 TI - Simultaneous determination of norfloxacin and tinidazole binary mixture by difference spectroscopy. AB - A simple and rapid difference spectroscopic method was developed for the simultaneous determination of binary mixture of norfloxacin (NF) and tinidazole (TZ) without prior separation. The proposed method depends upon measuring the absorbance of NF at 291.6 nm which is the zero crossing point on the difference spectra of TZ in 0.1 N NaOH vs. 0.1 N HCl. Similarly, the absorbance of TZ was measured at 344.4 nm which is the zero crossing point on the difference spectra of NF. Beer's law was obeyed in the concentration range of 2-20 and 5-50 MUg/mL for NF and TZ, respectively. The lower limits of detection (LOD) of NF and TZ are 0.23 and 0.36 MUg/mL, respectively, while the lower limits of quantification (LOQ) of NF and TZ were 0.70 and 1.08 MUg/mL, respectively. The precision of the method was satisfactory; the maximum value of relative standard deviations did not exceed 1.5% (n=10). The accuracy, expressed as recovery is between 98.25 and 101.8% with relative error of 0.29 and 0.23 for NF and TZ, respectively. The proposed method was successfully applied for the determination of both drugs in bulk powder, laboratory prepared mixture and commercial dosage forms such as tablets without interference from the commonly encountered excipients and additives. The results obtained are in good agreement with those obtained by the reference methods. PMID- 23675231 TI - Pattern of paediatric neurological disorders in port harcourt, Nigeria. AB - BACKGROUND: Paediatric Neurological disorders in developing countries are very challenging. This is due to its chronicity, late presentation and unavailability of modern diagnostic facilities in developing countries like Nigeria. Lack of these modern technology and manpower contribute significantly to increased morbidity and mortality. This study demonstrates the pattern of neurological disorders and the challenges in management in a developing country. MATERIALS AND METHOD: This was a retrospective hospital based analysis of neurological disorders seen in the Paediatric neurology unit of the University of Port Harcourt Teaching hospital, Nigeria from January 2004 to December 2009. Descriptive statistics was used to present the result. RESULT: A total of 35,473 patients were seen in the Paediatric unit. Of these 2,379 had neurological disorders. This gave a prevalence of 6.7% of Paediatric neurological disorders. There were 1,431 males and 948 females (male: female ratio of 1.51:1.0). The age ranged from 3 months to 15 years. The age group 1->5 years accounted for the most affected age group constituting 87.7%. The most frequent Paediatric neurological disorders were epilepsy (24.6%), cerebral palsy (15.4%), and central nervous system infections (9.5%). CONCLUSIONSRECOMMENDATION: Wide spectrum of neurological disorders occur in our environment. The high incidence of epilepsy and cerebral palsy suggests that effort should be geared towards educating the populace about early diagnosis and prompt management. PMID- 23675232 TI - High Prevalence of Iron Deficiency among Educated Hospital Employees in Switzerland. AB - Iron deficiency is known to cause symptoms such as fatigue, depression and restless legs syndrome resulting in impaired quality of life and working capacity. We sought to examine the iron status of reportedly healthy individuals by a framed study design in 58 highly educated Swiss hospital employees and to compare the use of non invasive tests for assessing iron deficiency (ID). A structured interview was used to assess health status, nutritional intake and potential blood loss, blood counts as well as parameters proposed to diagnose iron deficiency were determined. All subjects felt well and were working at their maximum capacity. The male subjects were neither anaemic nor had decreased iron parameters however 50% (23/46) of the women had a serum ferritin of below 22 MUg/L, still 33% (15/46) of the women had a ferritin value below the more stringent cut off value of 15 MUg/L. In 15% (7/46) of the women we diagnosed iron deficient anaemia. Red meat consumption correlated with ferritin values as did the menstrual blood loss which was estimated by asking the amount of tampons used. Of the additionally analysed iron parameters only the percentage of hypochromic erythrocytes, soluble transferrin receptor and transferrin values were significantly correlated with ferritin and reached an AUCROC of >=0.7 indicating good predictive tests. Nevertheless neither soluble transferrin receptor nor transferrin showed diagnostic advantages for the diagnosis of ID compared to ferritin alone or together with erythrocyte parameters. Working in a hospital environment and having access to health education does not seem to correlate with prevention of ID or ID anaemia in female hospital employees. PMID- 23675234 TI - Comparison of Two Methods for Detecting Alternative Splice Variants Using GeneChip((r)) Exon Arrays. AB - The Affymetrix GeneChip Exon Array can be used to detect alternative splice variants. Microarray Detection of Alternative Splicing (MIDAS) and Partek((r)) Genomics Suite (Partek((r)) GS) are among the most popular analytical methods used to analyze exon array data. While both methods utilize statistical significance for testing, MIDAS and Partek((r)) GS could produce somewhat different results due to different underlying assumptions. Comparing MIDAS and Partek((r)) GS is quite difficult due to their substantially different mathematical formulations and assumptions regarding alternative splice variants. For meaningful comparison, we have used the previously published generalized probe model (GPM) which encompasses both MIDAS and Partek((r)) GS under different assumptions. We analyzed a colon cancer exon array data set using MIDAS, Partek((r)) GS and GPM. MIDAS and Partek((r)) GS produced quite different sets of genes that are considered to have alternative splice variants. Further, we found that GPM produced results similar to MIDAS as well as to Partek((r)) GS under their respective assumptions. Within the GPM, we show how discoveries relating to alternative variants can be quite different due to different assumptions. MIDAS focuses on relative changes in expression values across different exons within genes and tends to be robust but less efficient. Partek((r)) GS, however, uses absolute expression values of individual exons within genes and tends to be more efficient but more sensitive to the presence of outliers. From our observations, we conclude that MIDAS and Partek((r)) GS produce complementary results, and discoveries from both analyses should be considered. PMID- 23675235 TI - Interleukin-2 Functions in Anaplastic Large Cell Lymphoma Cells through Augmentation of Extracellular Signal-Regulated Kinases 1/2 Activation. AB - In addition to intrinsic genetic alterations, the effects of the extrinsic microenvironment also play a pathological role in cancer development. Altered chemokine/cytokine networks in the tumor microenvironment may contribute to the dysregulation of cellular functions in cancer cells. Anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma caused by abnormal expression of anaplastic lymphoma kinase due to a chromosomal translocation. Notably, ALCL cells are also characterized by high-level expression of the high-affinity IL-2 receptor subunit CD25 on the cell surface. However, whether the IL-2/IL-2 receptor functions in ALCL cells and how this signaling affects the tumor remain unclear. In this study, we treated cultured ALCL cells with exogenous IL-2 and examined changes in cellular function and signaling pathways. IL-2 stimulated cell growth and augmented activation of the extracellular signal-regulated kinases 1/2 (ERK1/2) pathway. Additionally, IL-2 enhanced lymphoma cell survival by overcoming kinase inhibitor U0126-induced growth arrest and apoptosis. Subsequently, to identify the potential source of IL-2 for lymphoma cells in vivo, we performed gene expression and immunochemical analyses. RT-PCR revealed no IL-2 gene expression in cultured ALCL cells and ruled out the possibility of an IL-2 autocrine loop. Interestingly, immunostaining of lymphoma tumor tissues showed IL-2 protein expression in background cells within tumor tissue, but not in ALCL cells. Our findings demonstrate that IL-2 signaling plays a functional role in ALCL cells, and enhances lymphoma cell survival by increasing activation of the ERK1/2 pathway. PMID- 23675236 TI - Clinical study of advanced glycation end products in egyptian diabetic obese and non-obese patients. AB - Advanced glycation end products (AGEs) are complex, heterogenous molecules generated by glycation and oxidation of proteins in vivo, which are thought to markedly increase in diabetic patients. One of the recently identified AGEs is carboxy methyl lysine (CML), which is the main ligand of receptors for advanced glycation end products (RAGE). The present study aimed to assess the effect of obesity on such pathways in presence and absence of Type 2 diabetes mellitus. CML, soluble receptors for advanced glycation end products (sRAGE), HbA1C, lipid profile, liver function tests and kidney function tests were determined in 29 diabetic obese, 29 diabetic non-obese, 15 non-diabetic obese and 15 non-diabetic non-obese subjects. The study compared obese and non-obese subjects in presence and absence of type 2 diabetes. The results showed a significant increase in CML and a significant decrease in sRAGE in each of the diabetic obese group when compared with the diabetic non-obese group and the non-diabetic obese group when compared with the non-diabetic non-obese group. A significant positive correlation was found between CML and markers of obesity (body mass index and waist/hip ratio). These results suggest that obesity can increase CML independent of diabetes and support the reports that CML could be generated from both sugars and lipids. The present study suggests that treatment using glycation inhibitors like aminoguanidine or recombinant sRAGE will not only retard the diabetic complications, but may also have a prophylactic effect. PMID- 23675233 TI - Genetic variation and its role in malignancy. AB - Genetic variation has long been thought associated with common complex disease and has therefore been widely studied. Genetic variation in the human genome is present in many forms and have been summarised in this review. The potential role of DNA damage, DNA repair and environmental influence on genetic variation in the development of cancer will be discussed, before significant genome projects are reviewed. All the various forms of genetic variation have been associated with malignancies and have been extensively studied and this is a review of the state of the field. We also discuss the road ahead in fulfilling the ultimate goal in all cancer genetic studies, which is decreasing deaths caused by cancer. PMID- 23675237 TI - Liquid chromatographic methods for the determination of vildagliptin in the presence of its synthetic intermediate and the simultaneous determination of pioglitazone hydrochloride and metformin hydrochloride. AB - Two reversed-phase liquid chromatographic (RP-LC) methods are described for the determination of two binary mixtures of hypoglycemic agents. In the first method, vildagliptin (VDG) was determined in the presence of 3-amino-1-adamantanol (AAD), a synthetic intermediate and impurity of VDG. In the second method, pioglitazone hydrochloride (PGZ) and metformin hydrochloride (MET) were simultaneously determined in their binary mixture. Chromatographic separation in the two methods was achieved on a Symmetry((r)) Waters C18 column (150 mm * 4.6 mm, 5 MUm). In the first mixture, isocratic elution using a mobile phase of potassium dihydrogen phosphate buffer pH (4.6) - acetonitrile - methanol (30:50:20, v/v/v) at a flow rate of 1 mL min(-1) with UV detection at 220 nm was performed. In the second method, isocratic elution based on potassium dihydrogen phosphate buffer pH (4.6) - acetonitrile (60:40, v/v) at a flow rate of 1 mL min(-1) with UV detection at 210 nm was performed. Linearity, accuracy and precision were found to be acceptable over the concentration ranges of 5-200 MUg mL(-1), 0.5-3 MUg mL(-1) and 10-150 MUg mL(-1) for VDG, PGZ and MET, respectively. The optimized methods were validated and proved to be specific, robust, precise and accurate for the quality control of the drugs in their pharmaceutical preparations. PMID- 23675238 TI - Maternal Gestational Dietary Fat has Minimal Effects on Serum Lipid Profiles and Hepatic Glucose Transporter 2 and No Effect on Glucokinase Expression in Neonatal Wistar Rat Offspring. AB - The study investigated the effects of maternal diets, varying in fat content, on lipid profiles and the expression of hepatic glucose transporter 2 (GLUT2) and glucokinase (GK) in neonatal Wistar rat offspring. Dams were maintained on diets of 10% (control), 20% (20F), 30% (30F) and 40% (40F) fat as energy throughout gestation; daily food intakes and weekly body weights were measured. Circulating fasting glucose, insulin and glucagon concentrations were determined in dams and their neonatal offspring. In neonates, total serum triglyceride, total and individual serum fatty acid concentrations, hepatic GLUT2 and GK mRNA and protein expression were determined. In dams, overall food intake of 20F (645.50 +/- 25.26 g) and 40F (716.30 +/- 14.15 g) dams was reduced compared to control (1007.00 +/- 44.83 g) and 30F (924.50 +/- 21.16 g) dams. The 20F neonates displayed elevated blood glucose concentrations (4.63 +/- 0.153 mmol/l) compared to control neonates (4.14 +/- 0.112 mmol/l). In 30F neonates, serum palmitoleic acid was reduced (1.63 +/- 0.21% vs. 3.56 +/- 0.38%) whereas stearic acid was elevated (10.05 +/- 0.40% vs. 7.40 +/- 0.72%) compared to control neonates. Further, the palmitoleic acid/palmitic acid ratio was reduced in 30F neonates (0.085 +/- 0.009% vs. 0.165 +/- 0.020% in control neonates). The 40F neonates displayed elevated GLUT2 immunoreactivity (22.86 +/- 0.760%) compared to 20F (11.46 +/- 2.701%) and 30F (6.45 +/- 1.759%) neonates. Gestational programming with different dietary fat proportions minimally affects lipid profiles and hepatic GLUT2 immunoreactivity in neonatal offspring. PMID- 23675239 TI - Audit of Pediatric ENT Injuries. AB - BACKGROUND: Ear, Nose and throat (ENT) injuries are relatively common in children. Sometimes they may result in disfigurement or dysfunction of the affected parts. This study was aimed at the pattern and mechanisms of ENT injuries encountered by children in Ilorin located in north central Nigeria. It is therefore our hope that the information will go a long way to assist other African countries as well in health care plans for children. OBJECTIVES: The study was aimed at determining the pattern and causes of ENT injuries in children in Ilorin. METHODOLOGY: This was a descriptive cross sectional, prospective study of all pediatrics patients aged 15 years and below who were managed between January 2005 and December 2009 (a period of 5 years) for ENT trauma in the accident & emergency unit, wards and clinics of University of Ilorin Teaching Hospital. Most of them were treated as out-patients; a few of them needed admission for some procedures. Patients with injuries to other areas than ENT were not included in this study. The data that were analyzed included the age, sex, presenting complaints, duration of symptoms prior to presentation, diagnoses, treatments and complications. RESULTS: Two hundred and seventy-one children were studied, of which 168 (62.0%) were males and 103 (38.0%) were females. Most of the children, 97 (35.8%), were between age group of 6-10 years, 81 (29.9%) aged 5 years and below, while the rest were 11-15 years of age. Injuries due to foreign bodies in Ear, Nose and Throat accounted for 80 (29.5%) of the causes. Falls accounted for 60 (24.4%) of cases while Road Traffic Injuries (RTI), 42 (15.5%) of cases. Bleeding was the commonest presenting symptom. Most of the children, 97 (35.8%) presented within 1 hour of injury while the least, 45 (16.6%), presented more than 8 hours after the injury. 132 (48.7%) had injuries in the Ear, 117 (43.2%) in the Nose and 22 (8.1%) in the Throat. CONCLUSION: ENT injuries in pediatrics are relatively common in our environment with injuries from FB insertion/ingestion being the commonest. This is closely followed by falls. Several disabilities and morbidity may result from the trauma like anosmia, facial palsy and permanently depressed nose. These have impact on psychology of the child. For these reason close monitoring of children by parents and care-givers cannot be overemphasized. Also these injuries are avoidable causes of death and disability in children. PMID- 23675240 TI - Comparison of the anti-inflammatory and analgesic effects in rats of diclofenac sodium, felbinac and indomethacin patches. AB - BACKGROUND: Topically applied nonsteroidal anti-inflammatory drugs (NSAIDs) are used widely for the treatment of pain and inflammation in musculoskeletal disorders. This study compared the analgesic and anti-inflammatory effects of patches of 1% diclofenac-sodium, 3.5% and 0.5% felbinac and 3.75% indomethacin in rats using the carrageenan-induced paw pad edema model and the brewer's yeast induced hyper algesia model. Two studies were conducted: in the preliminary study, the patch was removed at 2 or 24 hrs after application, and in the main study the patch was removed at 2 hrs. The volume of the right hind paw and the pain threshold were assessed at 1, 3, 5, and 7 hrs after induction of inflammation in both studies. RESULTS: In the main study, the edema ratio in the 1% diclofenac group at 5 hrs after induction of inflammation and the AUEC (Area Under the Effect Curve) were significantly lower than in the control animals (p=0.009). The edema suppression rate in the 1% diclofenac group (12.1-33.2%) was higher than in the 3.5% and 0.5% felbinac and 3.75% indomethacin groups. The pain threshold ratio did not decrease in the 1% diclofenac group and it was significantly higher than in the control group at 3 (p=0.0004) and 5 hrs (p=0.029). The 1/AUEC was significantly lower than that in the control group (p=0.004) and the lowest among all the NSAID groups. CONCLUSIONS: This study demonstrated that the analgesic and anti-inflammatory effects of the 1% diclofenac sodium patch in a rat model may be exerted more promptly and persistently than with the 3.5% and 0.5% felbinac and 3.75% indomethacin patches. PMID- 23675241 TI - Gene Encoding Chitinase 3-Like 1 Protein (CHI3L1) is a Putative Oncogene. AB - An important task in understanding oncogenesis is the identification of those genes whose copy number and expression increase during tumorigenesis. Previously, in an effort to identify genes which could be used as molecular markers for glial tumors, we compared gene expression in glioblastoma to the normal brain cells. Among the genes with the most pronounced increased expression in tumors there was CHI3L1, encoding the secreted chitinase 3-like 1 protein (also known as HC gp-39 or YKL-40). Expression of CHI3L1 was found increased significantly in various tumors in comparison with corresponding normal tissues. Here we show that CHI3L1 can decrease the doubling time of 293 cells. We have also demonstrated that CHI3L1 allows the anchorage-independent growth in soft agar and, in addition, stable CHI3L1 expression made 293 cells tumorigenic: these cells stimulate the initiation of tumors after their xenograft transplantation into the Wistar rat brains. Thus, the overexpression of CHI3L1 is likely to be critical in the development of some tumors and when we gain more information about mechanisms of CHI3L1 oncogenicity, it could be used as one of the potential targets for anticancer therapy. PMID- 23675243 TI - A join point survival model for brain tumor patients. AB - To investigate the relationship between medical improvements and the survival experienced by the patient population, it would be useful to find out when and how much the cancer treatment breakthroughs and early diagnosis have significantly improved the prognosis of brain cancer patients. A join point model facilitates the identification of trends with significant change-points in survival; the main goal of such a model would be to find out when cancer survival starts exhibiting a pattern of improvement. The model will be applied to grouped relative survival data for major cancer sites from the 'Surveillance, epidemiology and end results' program of the National Cancer Institute. PMID- 23675244 TI - Artificial Neural Network Modeling of Quality of Life of Cancer Patients: Relationships between Quality of Life Assessments, as Evaluated by Patients, Pharmacists, and Nurses. AB - AIM: The purpose of this study was to investigate the difference between the professional perspectives of pharmacists and nurses in Japan with regard to evaluation of the quality of life (QOL) of cancer patients. METHODS: A group of cancer hospital inpatients (n=15) were asked to rate the condition of their health and their QOL by filling in a questionnaire. On the same day, a group of pharmacists (n=8) and nurses (n=18) also evaluated patient QOL. Three-layered artificial neural network (ANN) architecture was used to model the relationship between the different QOL evaluations made by patients, pharmacists, and nurses. RESULTS: Although there was no statistical difference between the QOL scores obtained from pharmacists and nurses, the correlation between these scores was weak (0.1188). These results suggest that pharmacists and nurses evaluate the QOL of their patients from different perspectives, based on their respective profession. QOL parameters were modeled with an ANN using the scores, given by patients in answer to questions regarding health-related QOL as input variables. Both the predictive performance of the ANN and the robustness of the optimized model were acceptable. The response surfaces calculated by ANN modeling showed that pharmacists and nurses evaluate patient's QOL using different information and reasoning, which is likely related to the nature of their contact with the patients. CONCLUSION: Health professionals evaluate patient QOL from different perspectives, depending on their profession. PMID- 23675242 TI - Role of genetic changes in the progression of cardiovascular diseases. AB - This review aims to investigate the role of genetic changes in the development of cardiovascular diseases [CVD]. Oxidation of Low density Lipoprotein (LDL) and mutations in LDL receptors gene are a trigger for numerous of atherogenic events. Also, endothelial nitric oxide synthase (eNOS) plays an important role in vasodilatation of blood vessels through synthesis of nitric oxide. Three single base pair changes, 786T/C, 922A/G, and 1468T/A, have been identified in the promoter region of the eNOS gene and are associated with coronary spasm. Moreover, two distinct variable nucleotide tandem repeats (VNTRs) in introns 4 and 13 have been detected. The presence of a minimum of 38 CA repeats in intron 13 has been associated with an independent 2.2-fold increase in the risk of coronary artery disease [CAD]. Plasma glutathione peroxidase (GPx-3) maintains the vascular bioavailability of nitric oxide (NO), through depletion of reactive oxygen species. Mutation(s) or polymorphism(s) in the plasma GPx-3 gene promoter may predispose to a thrombotic disorder, and constitute a genetic risk factor for thrombotic cerebrovascular disease. Hyperhomocysteinemia is another independent risk factor for atherosclerosis and arterial thrombosis. Severe hyperhomocysteinemia could be caused by cystathionine-beta-synthase enzyme deficiency but it could be due to homozygosity of a common 677C/T point mutation in the coding region of the methylenetetrahydrofolate reductase (MTHFR) gene as a 3-fold increase in risk of CAD is associated with the MTHFR 677TT genotype. A second common variant in MTHFR 1298A/C is associated with decreased enzyme activity in vitro and in vivo, especially when occurring simultaneously with the 677 C/T polymorphism. Elevated fibrinogen, an essential component of the coagulation system, has been most consistently associated with arterial thrombotic disorders. Several polymorphisms (148C/T, 455G/A, and -854G/A) have been identified in the genes encoding the 3 pairs of fibrinogen polypeptide chains. The -455G/A, and -854G/A substitutions are the most physiologically relevant mutations. In addition the -455A allele has been associated with the progression of atheroma, and also with a 2.5-fold increase in risk of multiple lacunar infarcts in a cohort of elderly patients with stroke. It is concluded that genetic changes in the previously mentioned genes could play a significant role in the initiation and progression of CVD. This review provides useful information for both physicians and medical students whom are interested in human genetics which is related to cardiovascular diseases. PMID- 23675245 TI - Mutagenic and genotoxic effect of hydroxyurea. AB - The hydroxyurea, a cytotoxic drug, is the mainly available therapeutical strategy for the treatment of sickle cell disease. This study aimed to evaluate the mutagenic and genotoxic potential of the hydroxyurea through the Salmonella/Microsome assay and micronucleus test in peripheral blood of mice. The doses were evaluated at 29.25-468 MUmol/plate in Salmonella/Microsome assay in presence and absence of metabolic activation the drug. In the micronucleus test the doses were evaluated at 12.5; 25; 50; 75 and 100 mg/kg. The results show that hydroxyurea present mutagenic activity in TA98 and TA100 in doses above 117 MUmol/plate and 234 MUmol/plate respectively. The drug induced a significant increase in the frequency of micronuclei in reticulocytes of mice at concentrations of 50, 75 and 100 mg/kg, compared to negative control (water). These results demonstrated the mutagenic and genotoxic potential of hydroxyurea. PMID- 23675246 TI - Epidemilogical profile of speech and language disorder in north central Nigeria. AB - BACKGROUND: Speech-language pathologists/Otolaryngologists recognize high prevalence of speech and language disorder among children. The aim of the study is to find out the epidemiological profile of speech and language disorder in north central Nigeria. METHOD: A five year retrospective review of all referral to speech and language therapy unit ENT Department between January 2005 and December 2009. Information retrieved and analysed included bio-data, clinical presentation and diagnosis of the patients. Descriptive analysis of these data were done. RESULTS: A total of 146 patients were seen out of which 89 (61%) were under five, 32 (21.9%) were between 5-10 years, 20 (13.7%) in the range of 11-20 yrs and 2 (1.4%) were between 21-34 yrs. None was observed in the elderly. Male preponderance was noted with male to female ratio of 1.9:1.0. The commonest diagnosis was deaf-mutism in 84 (57.5%) followed by delayed speech development in 31(21.2%) patients. The least diagnosis was aphasia in 2 (1.4%) patients. CONCLUSION: Speech and language disorder was commonest among the under five's with non in the elderly, There was a higher prevalence amongst males and deaf mutism was the commonest observed. PMID- 23675247 TI - Relevant Networks involving the p53 Signalling Pathway in Renal Cell Carcinoma. AB - INTRODUCTION: Renal cell carcinoma is the most common type of kidney cancer. A better understanding of the critical pathways and interactions associated with alterations in renal function and renal tumour properties is required. Our final goal is to combine the knowledge provided by a regulatory network with experimental observations provided by the dataset. METHODS: In this study, a systems biology approach was used, integrating immunohistochemistry protein expression profiles and protein interaction information with the STRING and MeV bioinformatics tools. A group consisting of 80 patients with renal cell carcinoma was studied. The expression of selected markers was assessed using tissue microarray technology on immunohistochemically stained slides. The immunohistochemical data of the molecular factors studied were analysed using a parametric statistical test, Pearson's correlation coefficient test. RESULTS: Bioinformatics analysis of tumour samples resulted in 2 protein networks. The first network consists of proteins involved in the angiogenesis pathway and the apoptosis suppressor, BCL2, and includes both positive and negative correlations. The second network shows a negative interaction between the p53 tumour suppressor protein and the glucose transporter type 4. CONCLUSION: The comprehensive pathway network will help us to realise the cooperative behaviours among pathways. Regulation of metabolic pathways is an important role of p53. The pathway involving the tumour suppressor gene p53 could regulate tumour angiogenesis. Further investigation of the proteins that interact with this pathway in this type of tumour may provide new strategies for cancer therapies to specifically inhibit the molecules that play crucial roles in tumour progression. PMID- 23675248 TI - Validated high-performance liquid chromatographic method for the estimation of rosuvastatin calcium in bulk and pharmaceutical formulations. AB - A reversed-phase high-performance liquid chromatographic method was developed and validated for the determination of rosuvastatin calcium in pharmaceutical dosage forms. The determination was performed on a Nucleodur column C8 (250 * 4.6 mm i.d., 5 MUm particle size); the mobile phase consisted of a mixture of 0.1M formic acid and methanol (25:75, v/v), pumped at a flow rate 1.0 mL min(-1). The photodiode array detector was operated at 280 nm. The retention times for rosuvastatin and fluvastatin, which was used as internal standard, were 3.98 and 7.78 min, respectively. Linearity range (r (2) better than 0.999, n=6) was 3.0 1602.0 MUg mL(-1) with limit of detection value of 0.12 MUg mL(-1). The precision of the method was demonstrated using intra- and inter-day assay RSD% values which were less than 2.40%, while the recovery was 99.86-102.86%. The method was applied in the quality control of commercial tablets and content uniformity test and proved to be suitable for rapid and reliable quality control. PMID- 23675249 TI - Spectrophotometric Determination of Captopril and Penicillamine through the Use of Ligand Exchange Complexation Reactions. AB - Two spectrophotmetric methods based on combined redox - ligand exchange reactions were developed for the determination of captopril and penicillamine in pure form and in their dosage forms. The first method is based on attenuating the absorbance of a ternary complex: silver (I) - bromopyrogallol red - phenanthroline in a buffer solution of pH6-8. The method has the concentration ranges 2-10 MUg mL(-1) and 0.5-1.75 MUg mL(-1) for captopril and penicillamine respectively, and the detection limits 7.1 * 10(-2) and 5.7 * 10(-2) MUg mL(-1) for captopril and penicillamine respectively. The second method is based on decreasing the absorbance of a chloroformic solution of copper (II) - oxine chelate when shaken with the drug solution in buffer medium of pH 8. The drugs were determined in the concentrations 30-90 MUg mL(-1) and 30-100 MUg mL(-1) for captopril and penicillamine respectively, and the detection limits 0.94 and 1.76 MUg mL(-1) for captopril and penicillamine respectively. The proposed methods were applied in the analysis of both compounds in their pharmaceutical preparations, and results were favorably compared with reference spectrophotometric methods regarding accuracy and precision. PMID- 23675250 TI - HIV-Related Sexual Behaviors among Migrants and Non-migrants in Rural Ethiopia: Role of Rural to Urban Migration in HIV Transmission. AB - OBJECTIVE: To compare HIV-related sexual risk behavior among temporary rural to urban migrants and non-migrants and to explore the role of migration in HIV transmission in a rural area of Ethiopia. METHODS: A cross-sectional comparative study was conducted in Bure Woreda, West Gojam, Amhara Region, Ethiopia. A total of 1,310 male subjects (655 rural to urban migrants and 655 non-migrants) were selected randomly and were assessed, analyzed using SPSS version 17 software for their HIV related sexual risk behaviours including the role of migration in HIV transmission in a rural Ethiopia. Two parts of questionnaires were prepared and used for comparing the above groups. The first part of the questionnaires included non-sensitive questions such as demographics and HIV knowledge while the second part comprised sensitive questions related to sexual behaviors. RESULTS: When multiple sexual partners, sex with commercial sex workers, sexual transmitted infections and premarital sex compared between the two groups, the proportions of rural to urban migrants Vs non- migrants who had multiple sexual partners (31.4 % Vs 7.4 %), sex with commercial sex workers (22.3% Vs 13.3%), sexual transmitted infections (11.7% Vs 3.2%) and premarital sex (20.8% Vs 14.2 %) were significantly higher in rural to urban migrants than non-migrants. Among those who had multiple sexual partners, only 12.7 % of, rural to urban migrants and 9.8 % of non-migrants reported consistent condom use with sexual partners other than their spouse. CONCLUSIONS: As both rural to urban migrants and non migrants are at risk for HIV infection, intervention programmes targeting both groups are recommended. However, in order to contain the bridging effect on HIV transmission from urban to rural areas particular attention should be given for the rural to urban migrant population. PMID- 23675251 TI - Identification of Novel Variant of EML4-ALK Fusion Gene in NSCLC: Potential Benefits of the RT-PCR Method. AB - BACKGROUND: The discovery of the transforming fusion gene of the anaplastic lymphoma kinase (ALK) with the echinoderm microtubule-associated protein like 4 (EML4) as an oncogene in 2007 has led to its validation as a clinical target in NSCLC patients in a short period of time. The inhibition of the anaplastic lymphoma receptor tyrosine kinase has demonstrated to prolong progression-free survival compared to the standard of care chemotherapy in patients with advanced NSCLC that are ALK positive. However, the clinical implications of the 15 different variants of the EML4-ALK transforming gene described so far are currently not defined. Here we present a novel variant of the EML4-ALK fusion gene which we named variant 3c. METHODS: RNA extracted from formalin fixed paraffin embedded (FFPE) specimens from patients with advanced and metastatic NSCLC was amplified, using primers and probes designed to detect specific EML4 ALK fusion gene fragments. Gel electrophoresis showed a different band for the new variant 3c compared to the known bands of positive cell lines for variant 3a and 3b. These findings were further investigated by dye-terminator Sequencing and FISH. RESULTS: The novel variant, detected in two NSCLC specimens, is longer than v3a and shorter than v3b, representing an 18 base pair insertion of intron 19 of ALK between exon 6 of EML4 and exon 20 of ALK. All of the two samples showed exactly the same sequencing result. One of the samples was negative for FISH break apart testing and the other one showed a positive result, defined by >=15% split nuclei as indicative of an ALK rearrangement. CONCLUSIONS: Compared to FISH technology, RT-PCR enables the detection of different isoforms of the EML4-ALK transforming gene, which can be validated by sequencing. Only one out of two samples that were positive for the new variant by RT-PCR could be confirmed by FISH. The clinical significance of the different variants, notably to resistance and response to ALK-Inhibitors and the concordance and sensitivity of FISH and RT PCR should be subject to further investigations. PMID- 23675252 TI - Comparative study on the efficiency of using pulsed and direct current electrochemotherapy in treating ehrlich tumor. AB - The Electrochemotherapy (ECT) is an effective treatment of cutaneous and subcutaneous solid tumors. Electric field is applied to tumor nodules to enhance the delivery/distribution of a non-permeable or poorly permeable chemotherapeutic agent into the tumor cells thereby increasing local concentration of anticancer drugs. The aim of this study was to evaluate the effectiveness of using two types of electric fields in ECT, pulsed sine waves and direct current (DC) application in addition to intra-tumoral injection of bleomycin (BLM), a cytotoxic drug for treating Ehrlich tumor. The electric fields were delivered through six stainless steel needle electrodes inserted into the tumor. Tumor volume, tumor mass, percentage of fragmented DNA in the tumor tissue, relative spleen mass/total body mass, mortality rate, histological and ultrastructural examinations were investigated in each group. There were 40% complete response (CR) and 60% partial response (PR) in the group treated with DC as the electric field source of ECT, while 0% (CR) and only 25% (PR) were found in the group treated with pulsed sine wave ECT. We concluded that the utilization of low dose DC for ECT gives better results than the low voltage pulsed sine waves in treating Ehrlich tumor which may be due to the dual effects of electrochemical reactions evoked by DC application and the anti-cancer activity of BLM. PMID- 23675253 TI - Reconstruction and visualization of human gastrointestinal tract. AB - BACKGROUND: Converting the two-dimensional (2D) cross-sectional photographs into an intuitive three-dimensional (3D) model is a basic task for medical imaging data for auxiliary disease-linked diagnosis purpose. METHODS: Reconstruction and visualization process of gastrointestinal cross-sectional photographs includes image preparation, image registration, image segmentation, 3D surface-rendering reconstruction, and implementation of 3D digital visualization. RESULTS: Using the visualization toolkit (VTK), we implemented 3D digital reconstruction and visualization of gastrointestinal tract, whose visualized model can be zoomed, paned, and rotated, including the stomach, the small intestine, and the large intestine. PMID- 23675254 TI - Tetrandrine combined with gemcitabine and Cisplatin for patients with advanced non-small cell lung cancer improve efficacy. AB - Lung cancer has the highest morbidity and mortality of any malignant tumor. To improve efficacy and reduce toxicity in patients with advanced non-small cell lung cancer (NSCLC), it is important to integrate traditional and conventional medicine. Two hundred and forty patients with advanced NSCLC were randomized to tetrandrine plus GP or GP only. We infused gemcitabine on days 1 and 8; cisplatin on day 1. The tetrandrine group received continuous i.v. infusion for 10 days, with treatment repeated every 21 days. After 2 consecutive treatment cycles, we used RECIST criteria to evaluate short-term efficacy. Quality of life (QOL) was assessed according to Karnofsky score (KPS) and body weight change. We used NCI CTC 3.0 to evaluate treatment toxicity. The short-term objective response rate was 36.1% in the tetrandrine group and 24.3% in the controls (P=0.057). The short term disease control rate was 63.9% in the tetrandrine group and 52.3% in the controls (P=0.081). The 1-year survival rates were 45.7% and 31.3%, respectively (P=0.059). KPS scores improved by 49.1% and 32.4%, respectively (P=0.012). Body weight increased by 28.7% in the tetrandrine group and 16.2% in the controls (P=0.027). The incidence of grade 2-4 leukopenia, thrombocytopenia, nausea, and vomiting in the tetrandrine group was 38.0%, 19.4%, 46.3%, and 16.7%, respectively; the control group figures were 53.2%, 34.2%, 63.0% and 27.9% (P<0.05). Tetrandrine may improve short-term efficacy and survival in patients with advanced NSCLC. Tetrandrine may also mitigate adverse reactions to chemotherapy and improve QOL for patients with NSCLC. PMID- 23675255 TI - Association between XmnI Polymorphism and HbF Level in Sickle Cell Disease Patients from Chhattisgarh. AB - The gamma(G)-158 (C->T) polymorphism plays important function in the disease severity of sickle cell anemia. The XmnI restriction site at -158 position of the gamma(G)-gene is associated with increased expression of the gamma(G)-globin gene and higher production of HbF. This study aims to determine the frequency of the different genotypes of the gamma(G) Xmn I polymorphism in sickle cell anemia and sickle cell trait patients in Chhattisgarh and its association with high HbF level. The Xmn1 polymorphic site was determined by PCR-RFLP procedure. XmnI polymorphism were studied in 100 sickle cell patients (SS), 50 sickle cell trait (AS) and 50 controls individuals (AA). The presence of XmnI (+/+) site in SS and AS patients associated with the increase of HbF (P<0.0001) synthesis. we also find that presence of one XmnI (+/-) site in SS patients compared with XmnI-/- site had not shows difference in HbF level. Polymorphic association is found between presence and absence of XmnI site with HbF level, in AS and AA individuals. PMID- 23675256 TI - Validated Densitometric TLC-Method for the Simultaneous Analysis of (R)- and (S) Citalopram and its Related Substances Using Macrocyclic Antibiotic as a Chiral Selector: Application to the Determination of Enantiomeric Purity of Escitalopram. AB - A novel economic procedure for the simultaneous stereospecific separation and analysis of (R)- and (S)-citalopram and its related substances or impurities has been developed and validated. Chromatography was performed on silica gel 60 F254 plates with acetonitrile: methanol: water (15:2.5:2.5: v/v/v) as a mobile phase containing 1.5 mM norvancomycin or 2.5 mM vancomycin as a selector at ambient temperature. (R)- and (S)-citalopram enantiomers in presence of its related substances; citalopram citadiol and citalopram N-oxide were well separated with significant Rf values of 0.33 +/- 0.02, 0.85 +/- 0.02, 0.45 +/- 0.02 and 0.22 +/- 0.02, respectively. The spots were detected with either iodine vapor, or by use of a UV lamp followed by densitometric measurement at 239 nm. All variables affecting the resolution, such as concentration of chiral selectors, mobile phase system at different temperatures and pH-values were investigated and the conditions were optimized. Calibration plots for analysis of (R)- and (S) enantiomers were linear in the range of 0.2-16.8 MUg/10 MUl (R>=0.9994, n=6) with acceptable precision (%RSD<2.0) and accuracy (99.70 +/- 0.85% and 99.51 +/- 0.61% for (S)-citalopram and escitalopram, respectively). The limit of detection and quantification were 0.08 MUg/10 MUl and 0.25 MUg/10 MUl, respectively, for (R)- and (S)-citalopram. The proposed method is simple, selective, and robust and can be applied for quantitative determination of enantiomeric purity of (R)- and (S) citalopram (escitalopram) as well as the related impurities in drug substances and pharmaceutical preparations. The method can be useful to investigate adulteration of pure isomer with the cheep racemic form. PMID- 23675257 TI - The Predominant Proteins that React to the MC-20 Estrogen Receptor Alpha Antibody Differ in Molecular Weight between the Mammary Gland and Uterus in the Mouse and Rat. AB - There are many estrogen receptor alpha (ERalpha) antibodies available but few of them target a rodent ERalpha. Using the MC-20 antibody raised against the C terminus of mouse ERalpha, we show in this communication that in the mammary gland of female mice and rats, the wild type (wt) ERalpha was detected on immunoblots as a dominant protein only during lactation, and the protein was lactating specific as it migrated slightly faster than the 67-kD wt ERalpha in the uterus, likely due to a different phosphorylation status. In contrast, in the nulliparous, pregnant, involuting and involuted mammary glands, the dominant protein recognized by MC-20 was about 61-kD, which is dubbed herein as "MC-20 reactive protein" or MC20RP in abbreviation as its identity is unknown. Our results showed that it was not derived from proteolysis or de-phosphorylation of the 67-kD ERalpha and was unlikely to be translated from an ERalpha mRNA variant. Ovariectomy decreased the lactating specific wt ERalpha but increased the 61-kD MC20RP in the mammary tumors from MMTV-c-myc transgenic mice but these two proteins in the uterus were unaffected. The 61-kD MC20RP was decreased in the mammary tumors, compared with proliferating mammary glands, in estrogen-treated ACI rats. These results suggest that while the lactating specific wt ERalpha alone or together with the MC20RP may sustain lactation, the MC20RP may support proliferation of the mammary gland and some mammary tumors. PMID- 23675258 TI - Effects of Gametophytes of Ecklonia Kurome on the Levels of Glucose and Triacylglycerol in db/db, Prediabetic C57BL/6J and IFN-gamma KO Mice. AB - We have studied edible algae that have the potential to down-regulate blood glucose. In Japan, Ecklonia species have been believed to improve the circulation of blood. In this study, we used leptin receptor deficient type 2 diabetes model mice (db/db) and prediabetic C57BL/6J mice. We also focused on the role of IFN gamma in the control of blood levels of triacylglycerol and glucose, because it is reportedly engaged in the regulation of energy consumption together with leptin. We report that gametophytes of Ecklonia kurome down-regulate the blood level of glucose and serum level of triacylglycerol in db/db. We also report that gametophytes of Ecklonia kurome down-regulate the level of glucose but not the level of triacylglycerol in prediabetic C57BL/6J mice induced by a high fat diet. They increased the level of triacylglycerol compared to that of control group in C57BL/6J, but not in IFN-gamma KO mice. Gametophytes of Ecklonia kurome were administered orally to prediabetic C57BL/6J and IFN-gamma KO mice and oral glucose tolerance tests were performed to evaluate the effects of algae. During the administration of the normal diet, we found a higher level of blood glucose in a glucose tolerance test of IFN-gamma KO mice compared with that of C57BL/6J. Although a high fat diet induced a higher level of blood glucose compared with a normal diet group in a glucose tolerance test of C57BL/6J mice, this effect of high fat diet was not observed clearly at first but appeared three hours after glucose administration in IFN-gamma KO mice. Gametophytes of Ecklonia kurome down regulated the level of blood glucose in both C57BL/6J and IFN-gamma KO mice, when administered a normal diet after making them prediabetic. These results suggest that Ecklonia kurome are effective to down-regulate the blood glucose and IFN gamma is involved in the regulation of blood glucose and triacylglycerol. PMID- 23675259 TI - Comparison of Cytotoxic Activity of Anticancer Drugs against Various Human Tumor Cell Lines Using In Vitro Cell-Based Approach. AB - Chemotherapy is the main treatment modality for certain types of cancer. It is important to monitor and ensure that these chemotherapeutic drugs are potent and effective prior to patient administration. The objective of the study is to evaluate the cytotoxic activity and potency of selected commercially available generic anticancer drugs in comparison with originator using various human cancer cell lines in an in vitro cell-based assay. Half-maximal inhibitory concentration (IC50) of the different chemotherapeutic agents was obtained from an experimentally derived dose-response curve. Relative potency of the drugs was estimated according to Parallel Line assay. This study demonstrated that the selected generic oncology products tested had similar efficacy compared with the originator. Both products showed comparable results as shown both in vitro cytotoxicity assay and statistical analysis. In vitro cell-based cytotoxicity assay promises to be a useful, reliable and rapid method for demonstrating chemotherapeutic drug activity. PMID- 23675260 TI - Hydrogen sulfide: potent regulator of vascular tone and stimulator of angiogenesis. AB - Hydrogen sulfide is the "third" gasotransmitter on the rise in cardiovascular research. Recent studies show that hydrogen sulfide has a great potential in the regulation of vascular tone of systemic arteries and many molecular targets are discussed. However, the complex mechanism of vascular tone regulation by hydrogen sulfide is only incompletely understood. It seems that a potent interaction of hydrogen sulfide with vascular endothelial growth factor (VEGF) becomes important in angiogenesis, in the process of wound healing, but also in tumor angiogenesis. Hydrogen sulfide exerts anti-inflammatory effects and it could be a pharmacological target in vascular dysfunction in association with obesity related hypertension as well as in tumor development and progression. However, the underlying molecular pathways still need to be revealed. This review primarily focuses on the regulatory role of hydrogen sulfide in controlling vascular tone. We attempt to provide recent insights into mechanisms by which CSE dependent hydrogen sulfide plays a role in the regulation of vascular tone by perivascular adipose tissue. The role of KCNQ channels and other ionic permeation pathways as key targets will be discussed. Recent findings which are summarized in this paper provide new insights into molecular mechanisms of hydrogen sulfide that are crucial for understanding vascular dysfunction in cardiovascular disease and possibly angiogenesis. Future research will be extended to investigate the therapeutic potential of hydrogen sulfide and their targets such as KCNQ channels in cardiovascular diseases, angiogenesis and tumor genesis. PMID- 23675261 TI - The Excellent Anti-Tumour Strategy (CTGVT, OV-gene) and the Excellent Anti-Tumor Gene (IL-24). PMID- 23675262 TI - In Vitro and In Vivo (1)H-MR Spectroscopic Examination of the Renal Cell Carcinoma. AB - BACKGROUND: Paraneoplastic effects are some of the major side effects of advanced renal cell carcinoma (RCC). Magnetic resonance spectroscopy (MRS) is known as a powerful tool to study cancer cell metabolism and cancer cell - host interactions. Aim of this study was to assess tumor cell metabolism and systemic effects using (1)H-MRS. METHODS: Spectroscopic analysis of 10 patients with RCC was compared with those of 15 healthy volunteers. Local tumor metabolism was assessed using image-guided (1)H-in-vivo-spectroscopy in a 1.5 Tesla MR whole body tomograph. Systemic effects of RCC were measured using (1)H-High-Resolution (HR) spectra of blood plasma samples in a 500 MHz Bruker DRX 500 spectrometer. RESULTS: In-vivo-spectroscopy can significantly differentiate tumor tissue from healthy renal tissue by comparing their lipid composition. Moreover after detailed assignment of the various metabolites in blood plasma in the in-vitro-HR spectra significant systemic alterations could be identified in patients with RCC especially regarding lipid and amino acid metabolism. CONCLUSION: This work indicates that using (1)H-MRS both changes in tumor metabolism and resulting systemic/paraneoplastic effects can be assessed in patients with RCC. This approach therefore offers scope for diagnosis and therapy evaluation. PMID- 23675263 TI - Electrical Field Stimulation with a Novel Platform: Effect on Cardiomyocyte Gene Expression but not on Orientation. AB - Electrical field stimulation has been shown to improve cardiac cell alignment and functional properties. In this study, neonatal rat cardiomyocytes were exposed to both long-term and short-term stimulation with the goal of investigating whether it is possible to achieve cell orientation and the maturation of cardiomyocytes with a novel, microelectrode array (MEA)-compatible electrical stimulation platform. Cells were viable after electrical stimulation, but no orientation or other morphological changes were observed. However, the electrode wires in MEA dishes affected the cell orientation. Cell contractions synchronized with pacing, but settled back to their original frequency in the absence of stimulation. The expression of genes encoding a gap junction protein connexin-43 (Cx-43), and contractile cardiac protein beta myosin heavy chain 7, was stronger in stimulated cells than in controls (p<0.05). In summary, the surface topography influenced to cardiomyocyte orientation, suggesting that the micro architecture of the biomaterials should be carefully designed for cell applications. However, as electrical stimulation and its duration affected gene expression of some main cardiac proteins, the stimulation system may prove useful to enhance the cardiac differentiation of stem cells. PMID- 23675265 TI - The "Cross Talk" between the Receptors of Insulin, Estrogen and Progesterone in Neutrophils in the Synthesis of Maspin through Nitric Oxide in Breast Cancer. AB - PURPOSE: The binding of either insulin, or estrogen or progesterone to their specific receptors on neutrophils has been reported to stimulate nitric oxide (NO) induced maspin synthesis in these cells. Experiments were carried out to determine the role of insulin receptor interaction in the nitric oxide induced maspin synthesis in neutrophils that was effected by estrogen or progesterone. METHODS: Estrogen receptor positive (ER+) and progesterone receptor positive (PR+) neutrophils were isolated from the blood cancer subjects. Maspin was determined by enzyme linked immunosorbent assay after in vitro translation of maspin mRNA. NO was determined by methemoglobin method. RESULTS: It was found that pre incubation of normal neutrophils with insulin to reach equilibrium binding decreased both ER and PR numbers by ~50% without changing the dissociation constants of the steroids binding. The reduction of ER or PR numbers on neutrophils due to the pretreatment with insulin resulted in the decreased NO induced maspin synthesis from 2.383 +/- 0.014 nM to 1.454 +/- 0.004 nM in the case of estrogen and in the decrease of maspin synthesis from 2.329 +/- 0.012 nM to 1.410 +/- 0.002 nM in the case of progesterone. The incubation of ER+ neutrophils or PR+ neutrophils with insulin further decreased the maspin synthesis from 1.422 +/- 0.029 nM to 0.790 +/- 0.004 nM in the case of estrogen, and from 1.138 +/- 0.024 nM to 0.555 +/- 0.003 nM maspin in the case of progesterone respectively compared to normal control. CONCLUSION: These results suggested that a "cross-talk" between the insulin receptors and the steroid receptors down regulated maspin synthesis in normal and in breast cancer neutrophils. PMID- 23675264 TI - A Single Nucleotide Polymorphism in the Phospholipase D1 Gene is Associated with Risk of Non-Small Cell Lung Cancer. AB - Phospholipase D (PLD) has an important role in various biological functions including vesicular transport, endocytosis, exocytosis, cell migration, and mitosis. These cellular biological processes are deregulated in the development of various human tumors. In order to explore the relationship between the PLD1 gene and risk of non-small cell lung cancer (NSCLC), single nucleotide polymorphisms (SNP) in the PLD1 exon region were surveyed in 211 NSCLC patients and 205 normal controls. In this study, we identified six SNPs at exon 23 in the PLD1 gene. Among the six SNPs, the most notable was a heterozygous A to C transition at nucleotide 2698 (A2698C, p<0.001). In addition, the genotype frequencies of A2744C (AC+CC) and A2756C (AC+CC) were associated with gender (female, A2744C and A2756C: p=0.071) in NSCLC patients. Interestingly, although the SNP A2698C did not cause change in amino acid, correlation between odd ratio of NSCLC patients and the SNP A2698C was observed to be statistically significant. PMID- 23675266 TI - Reliability of the Mid Upper Arm Circumference for the Assessment of Wasting among Children Aged 12-59 Months in Urban Ibadan, Nigeria. AB - Although the mid upper arm circumference (MUAC) is used as a proxy to assess wasting in children, its validity abounds in controversies. This study therefore assessed the validity of MUAC as a measure of nutritional status among children aged 12-59 months in urban setting in western Nigeria. A cross sectional study of children aged 12-59 months in selected nursery schools in Moniya, Akinyele local government area, Oyo state was carried out between February to April 2010. The age, weight, length and MUAC, were obtained from the school children who were selected through total sampling. The sensitivity, specificity, positive predictive value, and negative predictive values of the MUAC were determined using weight for age as gold standard (underweight). Z-Scores for anthropometric indicators were calculated using EPI-NUT programme. Receivers operating curve was prepared to determine the optimal cut off of MUAC for the sensitivity and specificity. The overall prevalence of under nutrition among the respondents was 5.6%. The mean mid upper arm circumference was 15.47 +/- 1.4 cm and appears to increase with age from 11.49 +/- 3.0 at 12-23 months and peaks at age five with a value of 18.05 +/- 3.5. At 13.5 cm cut off, the sensitivity of MUAC is 20%, and the specificity is 95.3%, with a Kappa of 16.7%. The receivers operating curve reveals an optimum cut off of 15.5 cm with optimal but improved MUAC sensitivity of 80% and specificity of 53.5%. Thus MUAC was a poorly sensitive indicator of under nutrition at a cut-off below 13.5 cm but highly sensitive at 15.5 cm. A higher cut off value is therefore for recommended for screening for acute malnutrition among under five children. PMID- 23675268 TI - Histological and Demographic Characteristics of the Distribution of Brain and Central Nervous System Tumors' Sizes: Results from SEER Registries Using Statistical Methods. AB - The examination of brain tumor growth and its variability among cancer patients is an important aspect of epidemiologic and medical data. Several studies for tumors of brain interpreted descriptive data, in this study we perform inference in the extent possible, suggesting possible explanations for the differentiation in the survival rates apparent in the epidemiologic data. Population based information from nine registries in the USA are classified with respect to age, gender, race and tumor histology to study tumor size variation. The Weibull and Dagum distributions are fitted to the highly skewed tumor sizes distributions, the parametric analysis of the tumor sizes showed significant differentiation between sexes, increased skewness for both the male and female populations, as well as decreased kurtosis for the black female population. The effect of population characteristics on the distribution of tumor sizes is estimated by quantile regression model and then compared with the ordinary least squares results. The higher quantiles of the distribution of tumor sizes for whites are significantly higher than those of other races. Our model predicted that the effect of age in the lower quantiles of the tumor sizes distribution is negative given the variables race and sex. We apply probability and regression models to explore the effects of demographic and histology types and observe significant racial and gender differences in the form of the distributions. Efforts are made to link tumor size data with available survival rates in relation to other prognostic variables. PMID- 23675267 TI - Simultaneous determination of metformin, nateglinide and gliclazide in pharmaceutical preparations using micellar liquid chromatography. AB - A micellar chromatographic method has been developed and validated for simultaneous separation and determination of metformin(MF), nateglinide (NT) and gliclazide (GL). The separation was carried out using a Nucleosil C18 column, 150 mm * 4.6 mm i.d., 5 MUm particle size, using micellar mobile phase consisting of sodium dodecyl sulphate (SDS), n-propanol with UV detection. The optimum conditions for the simultaneous separation of the three drugs were 0.12 M SDS, 10% (v/v) n-popanol, 0.3% triethylamine adjusted to pH5.6 with a flow rate of 1 ml.min(-1) and detection at 254 nm. The limit of detection (LOD) of MF, NT, GL were 0.047, 0.00115, 0.036 MUg.mL(-1) respectively. The method showed good linearity in the ranges of 0.4-16 MUg.mL(-1), (r(2)=0.999), 0.8-16 MUg.ml(-1) (r(2)=0.999) and 1-40 MUg.ml(-1) (r(2)=0.999) for MF, NT, GL respectively. The suggested method was successfully applied for the analysis of the three antidiabetic drugs in pharmaceutical preparations with average recoveries of 99.66%, 100.08% and 100.31% for MT, NT and GL respectively. The results obtained were in good agreement with those obtained from comparison methods. The method was validated regarding accuracy and precision. PMID- 23675269 TI - Salivary ceruloplasmin ferroxidase & oxidase activities in celiac patients. AB - The aim of the current study was to evaluate salivary ferroxidase ceruloplasmin activities in celiac patients with different histopathological severity. This study included 75 celiac patients with different mean age (18.68 +/- 11.13) year, who had positive screen for celiac antibodies, and who had gastrointestinal symptoms. In order to simplify the comparison with the healthy control group, celiac patients were divided into two groups according to their histopathological severity: severe (marsh IIIa, b, c) & less severe (marsh 0, I). All these patients have been evaluating for salivary ceruloplasmin (Cp) concentration and Cp ferroxidase activities. To confirm the presence of the enzymatic activity of this protein, polyacrylamide gel electrophoresis was carried out and then stained for Cp ferroxidase, as well as for Cp oxidase activity. Furthermore, the concentrations of salivary total protein, albumin, and globulin were measured in the studied groups. A significant increase (p<0.05) in salivary concentration of ceruloplasmin was found in all above mentioned patients groups in comparison to that of the control group, except for total villous atrophy (marsh IIIc) patients subgroup. Salivary Cp ferroxidase activity revealed statistically significant decrease among the patient groups as well as between them and the control group. The result of salivary total protein and globulin showed presence a significant increase (p<0.05) in comparison to that of the control group. Meanwhile albumin levels was found to increase non-significantly (p=0.186). PMID- 23675270 TI - The Control of Stress Induced Type I Diabetes Mellitus in Humans through the Hepatic Synthesis of Insulin by the Stimulation of Nitric Oxide Production. AB - The role of stress induced development of Type-1 diabetes mellitus (T1DM) as opposed to autoimmunity remains obscure. It has been reported that a stress induced protein, identified to be dermcidin isoform 2 (dermcidin) inhibited insulin synthesis in both the pancreatic beta cells and the hepatic cells. As dermcidin effect could be neutralized by the increased production of systemic nitric oxide (NO), investigations were carried out to determine the feasibility of controlling stress induced T1DM through the neutralization of dermcidin by systemic increase of NO. To determine the role of plasma dermcidin level in T1DM subjects (n=45), if any, when the plasma dermcidin level were determined, it was found that the protein level was increased in 65% of the participating volunteers. Efforts were made to normalize the plasma glucose level (median=175 mg/dL) in these T1DM subjects by systemic increase of NO by applying a cotton pad containing 0.28mmol sodium nitroprusside on the abdominal skin. It was found that the systemic increase of NO level decreased the blood glucose level of 275 mg/dL (median) to 115 mg/dL (median) in these volunteers within 24 h with concomitant increase of plasma insulin level from 7.5 MUunits/dL to 101 MUunits/dL at the same time. The increase of plasma insulin level was accompanied by the decrease of dermcidin level of 124.5 nM to 18 nM with increase of NO from 0.43 +/- 0.19 nM to 4.1 +/- 1.56 nM. The results suggested that the stress induced T1DM by dermcidin could be controlled by the systemic increase of NO which in consequence led to increased synthesis of insulin. PMID- 23675271 TI - Health related quality of life of stroke survivors: experience of a stroke unit. AB - BACKGROUND: Stroke has a major impact on survivors including Health related Quality of life (HRQoL). HRQoL measurements are potentially more relevant to patients than measurements of impairments or disability and are an important index of outcome after stroke that can facilitate a broader description of disease and outcome. This study examined the factors associated with HRQoL of stroke survivors. METHODS: In a cross-sectional and descriptive correlational design, 62 patients were prospectively enrolled and interviewed 3 months post stroke in neurology out-patient clinic. After case identification, functional status (handicap) was determined using the Modified Rankin Scale (MRS), while Zung Depression Self-Rating Scale (ZDS) was used to determine presence of depression. HRQoL was assessed using the Stroke Impact Scale-16 (SIS-16). Age, sex, duration of formal education, depression and degree of disability were correlated with HRQoL in multiple logistic regressions. RESULTS: The mean age of patients was 54.4 +/- 9.9 years. Mean duration of formal education was significantly higher in males than females (p value=0.007). About one third (29%) of the stroke survivors were depressed and more than half (54.8%) had good recovery. Function status measured by modified Rankin Scale and depression were independent determinants of poor HRQoL. CONCLUSION: Functional status and depression were identified as independent factors affecting HRQoL of stroke survivors. PMID- 23675272 TI - Effects of aspirin on rheological properties of erythrocytes in vitro. AB - Aspirin is of proven value as an antithrombotic drug. In unstable angina it reduces the risk of death and myocardial infarction by half. Most studies on the mechanism of action of aspirin have concentrated on the effect of aspirin on platelets. In the present study we have tried to prove that there is another biophysical mechanism of aspirin, and that is through the effect of aspirin on erythrocytes. In this study ten blood samples were incubated with aspirin at different concentrations. The fractal dimension of erythrocytes subjected to shear rates from 5 s(-1) to 30 s(-1), in a cone and plate device designed and constructed in our lab, was calculated by processing the images of the erythrocyte. At each shear rate, the fractal dimensions of the erythrocytes were found to be strongly correlated with aspirin concentration. It is suggested that further studies using different biophysical methods must be carried out to detect the other mechanisms underlying the effect of aspirin on different blood cells. PMID- 23675273 TI - Developmental Changes of Catecholamine-mediating Enzyme - Dopamine-beta- Hydroxylase and Its Cofactors in Central and Peripheral Tissues and Serum of Long Evans Rats. AB - Dopoamine-beta-hydroxylase (DBH) is a catecholamine-synthesizing enzyme which catalyzes the formation of norepinephrine from dopamine. Fifty nine Long-Evans rats of 1 week-old were used to grow on normal diets in 7 different developmental stages, viz., 15 rats in 1 week-old group, 9 rats in 2 weeks-old group, and the remaining 35 rats were divided equally into five groups, 7 rats in each group of 5-, 8-, 12-, 15- and 27-weeks old for systematic developmental studies of DBH. At the end of each developmental period, weights of rats were recorded for that specific group and they were sacrificed. The brain tissues (caudate nucleus, hypothalamus, brain stem, colliculi, cerebral cortex and cerebellum) and peripheral tissues (liver, heart, kidney, adrenal, spleen, pancreas, lung and small intestine) and serum were collected. The brain tissues had the highest activity (expressed as nmole/min/g of wet weight tissue) of DBH at 5 weeks of age. The hypothalamus had the highest activities (11.5 +/- 2.2) and the lowest activities were found in the cerebellum (5.7 +/- 0.9). The peripheral tissues also showed the peak DBH activities at 5 weeks of age and adrenals had the highest activities (59.2 +/- 7.0) among the central and peripheral tissues. The serum DBH activities were relatively low (1.3 +/- 0.2) as compared to those in all other tissues. The highest serum DBH activities (1.28 +/- 21 nmole/min/ml of serum) were also found in the 5- weeks-old rats. The specific activities of DBH were also measured in various developmental stages and the results were found to be in agreement with the DBH activities expressed in terms of gram of tissues or milliliter of serum. The Km and Vmax values for DBH were measured in the serum samples of each group and the highest Vmax values (78.3 +/- 21.2 pmol/min/mg protein) were obtained at 5 weeks of age; while the lowest Km values (0.52 +/- 0.04 mM) were obtained at this stage of age. PMID- 23675274 TI - Spectrophotometric methods based on charge transfer complexation reactions for the determination of saxagliptin in bulk and pharmaceutical preparation. AB - Simple, accurate and precise spectrophotometric methods have been developed for the determination of saxagliptin in bulk and dosage forms. The proposed methods are based on the charge transfer complexes of saxagliptin with 2,3-dichloro-5,6 dicyano-1,4-benzoquinone (DDQ) and 7,7,8,8-tetracyanoquinodimethane (TCNQ). All the variables were studied to optimize the reactions' conditions. Beer's law was obeyed in the concentration ranges of 50-300 MUg/ml and 10-110 MUg/ml with DDQ and TCNQ, respectively. The developed methods were validated and proved to be precise and accurate for the quality control of the saxagliptinin its pharmaceutical dosage form. PMID- 23675275 TI - Liquid chromatographic determination of linagliptin in bulk, in plasma and in its pharmaceutical preparation. AB - In this work, two reversed-phase liquid chromatographic (RP-LC) methods have been developed for the determination of linagliptin (LNG) based on isocratic elution using a mobile phase consisting of potassium dihydrogen phosphate buffer pH (4.6) acetonitrile(20:80, v/v) at a flow rate of 1 mL min(-1). Two detection techniques have been applied either UV detection at 299 nm in the first method or fluorometric detection at 239 nm for excitation and 355 nm for emission in the second method. Chromatographic separation in the two methods was achieved on a Symmetry((r)) cyanide column (150 mm * 4.6 mm, 5 MUm). Linearity, accuracy and precision were found to be acceptable over the concentration ranges of 2.5-80 MUg mL(-1) for LNG in bulk and 2.5-15 MUg mL(-1) for LNG in plasma with the first method and 5-160 MUg mL(-1) for LNG in bulk with the second method. The optimized methods were validated and proved to be specific, robust and accurate for the quality control of the cited drug in its pharmaceutical preparation. PMID- 23675276 TI - Liquid chromatographic determination of alogliptin in bulk and in its pharmaceutical preparation. AB - In this work, a reversed-phase liquid chromatographic (RP-LC) method has been developed for the determination of alogliptin (ALG) based on isocratic elution using a mobile phase consisting of potassium dihydrogen phosphate buffer pH (4.6) acetonitrile (20:80, v/v) at a flow rate of 1 mL min(-1) with UV detection at 215 nm. Chromatographic separation was achieved on a Symmetry((r)) cyanide column (150 mm * 4.6 mm, 5 MUm). Linearity, accuracy and precision were found to be acceptable over the concentration range of 5-160 MUg mL(-1) for ALG in bulk. The optimized method was validated and proved to be specific, robust and accurate for the quality control of ALG in pharmaceutical preparations. PMID- 23675277 TI - Multiple Sites of Type II Site Ligand (Luteolin and BMHPC) Regulation of Gene Expression in PC-3 Cells. AB - Type II [(3)H]estradiol binding site ligands including luteolin (a naturally occurring bioflavonoid) and synthetic compounds such as 2,6-bis((3-methoxy-4 hydroxyphenyl)methylene)cyclohexanone (BMHPC) inhibit normal and malignant prostate cell (PC-3, LNCaP, DU-145) proliferation in vitro and in vivo. Type II sites represent a binding domain on histone H4 possibly involved in an epigenetic mechanism for controlling gene transcription. Treatment of PC-3 human prostate cancer cells with luteolin or BMHPC modulated the expression of a number of genes in the epidermal growth factor receptor signaling pathway (EGFRSP) and cell cycle pathway (CCP). Pronounced stimulation (400-2000% of control) of c-FOS and p21 RNA expression was observed, suggesting that these were primary sites of action. Both compounds also caused irreversible G2/M arrest (p<0.001). siRNA's for c-FOS or p21 reduced the RNA expression of their respective targets by 85-95%, with minimal effects on cell proliferation. Furthermore, neither siRNA alone (single knockdown), or in combination (double knockdown), blocked luteolin or BMHPC inhibition of PC-3 cell proliferation. Thus, although c-FOS and p21 are known to modulate the expression of genes in the ESGRSP (EGFR, SOS, GRB2, JNK1, MKK4, RasGAP) and CCP (CCNA2, CCNE2, CDC25A, CDKN1A, CDKN1B, p27, PLK1) involved in the regulation of cell proliferation by luteolin and BMHPC, the c-FOS and p21 siRNA knockdown studies reported here suggest that c-FOS and p21 may be secondary bystanders in the overall response to these ligands in the regulation of PC-3 cell proliferation. PMID- 23675278 TI - New view on the initial development site and radiographic classification system of osteoarthritis of the knee based on radiographic analysis. AB - INTRODUCTION: Radiographic pathology of severe osteoarthritis of the knee (OAK) such as severe osteophyte at tibial spine (TS), compartment narrowing, marginal osteophyte, and subchondral sclerosis is well known. Kellgren-Lawrence grading system, which is widely used to diagnose OAK, describes narrowing-marginal osteophyte in 4-grades but uses osteophyte at TS only as evidence of OAK without detailed-grading. However, kinematically the knee employs medial TS as an axis while medial and lateral compartments carry the load, suggesting that early OAK would occur sooner at TS than at compartment. Then, Kellgren-Lawrence system may be inadequate to diagnose early-stage OAK manifested as a subtle osteophyte at TS without narrowing-marginal osteophyte. This undiagnosed-OAK will deteriorate becoming a contributing factor in an increasing incidence of OAK. METHODS: This study developed a radiographic OAK-marker based on both osteophyte at TS and compartment narrowing-marginal osteophyte and graded as normal, mild, moderate, and severe. With this marker, both knee radiographs of 1,728 patients with knee pain were analyzed. RESULTS: Among 611 early-stage mild OAK, 562 or 92% started at TS and 49 or 8% at compartment. It suggests the initial development site of OAK, helping develop new site-specific radiographic classification system of OAK accurately to diagnose all severity of OAK at early, intermediate, or late-stage. It showed that Kellgren-Lawrence system missed 92.0% of early-stage mild OAK from diagnosis. CONCLUSIONS: A subtle osteophyte at TS is the earliest radiographic sign of OAK. A new radiographic classification system of OAK was suggested for accurate diagnosis of all OAK in severity and at stage. PMID- 23675279 TI - Acute myeloid leukaemia of donor cell origin developing 17 years after allogenic hematopoietic cell transplantation for acute promyelocytic leukaemia. AB - Donor cell leukaemia (DCL) is a rare complication of allogenic hematopoietic cell transplantation (HCT). We report the case of a female patient with acute promyelocytic leukaemia (APL), FAB type M3, who developed acute myeloid leukaemia (AML) type M5 of donor origin 17 years after allogenic bone marrow transplantation (BMT) from her HLA-matched sister. Morphology and immunophenotyping showed differences with the initial leukaemia, and short tandem repeat (STR) analysis confirmed donor-type haematopoiesis. Interphase fluorescence in situ hybridisation (FISH) showed an 11q23 deletion. Given that the latency period between transplant and development of leukaemia was the longest reported to date, we discuss the mechanisms underlying delayed leukaemia onset. PMID- 23675280 TI - An in vitro model of cartilage degradation by chondrocytes in a three-dimensional culture system. AB - OBJECTIVE: Using the alginate bead three-dimensional culturing method, which is considered to be advantageous for the in vitro study of chondrocytes, we confirmed earlier reports concerning the inhibitory effect of TGF-beta on IL 1beta-induced cartilage destruction and serially evaluated changes in proteinases and their inhibitors in cartilage destruction. METHODS: Chondrocytes were cultured on alginate beads with IL-1beta or TGF-beta alone or both. The glycosaminoglycan (GAG) concentration in the culture medium was determined by use of the DMMB assay; and the levels of TIMP-1, -2 and proMMP-3 were measured with their respective sandwich EIAs. Sections of the beads were prepared and stained with toluidine blue or anti-TIMP-1 -2, -3 antibodies. The numbers of chondrocytes negative for pericellular proteoglycan staining and TIMP-positive chondrocytes were counted, and positive staining for TIMP-3 in the extracellular matrix was examined. RT-PCR was performed to evaluate the gene expression of TIMP-1, -2, -3, and MMP-3. RESULTS: The number of TIMP-1(+)chondrocytes, TIMP-1 concentration in the culture medium, and TIMP-1-gene expression all increased maximally as early as 6 hours after IL-1beta stimulation, and then gradually decreased. However, the number of cells immunopositive for TIMP-3 increased somewhat later. GAG and proMMP-3 concentrations in the culture medium increased gradually with time. The number of TIMP-3(+)chondrocytes and positive staining for TIMP-3 in the extracellular matrix significantly increased in the TGF-beta group compared with the values for the IL-1beta group. The proMMP-3 concentration in the culture medium of TGF-beta-treated cells was significantly decreased compared with that for the IL-1beta-treated ones at all times examined. DISCUSSION: We suggest that TIMP-1 plays a primary role in the prevention of articular cartilage destruction in its early stage but that TIMP-3 gradually takes over this role. Also, TGF-beta was shown to regulate these TIMPs and act as a suppressor of articular cartilage destruction. These results suggest that TIMP-1 and TIMP-3 are closely involved in preventing the progression of joint disorders such as OA. PMID- 23675281 TI - (31)P and (1)h nuclear magnetic resonance spectroscopy of blood plasma in female patients with preeclampsia. AB - OBJECTIVE: Using (31)P and (1)H magnetic resonance spectroscopy to measure phosphorus- and hydrogen-containing metabolites, this study aimes to investigate whether or not women with preeclampsia have detectable systemic abnormalities concerning certain components of the blood plasma. METHODS: PLASMA WAS OBTAINED FROM TWO GROUPS OF WOMEN: Group 1 with preeclampsia (n=10) and Group 2, as a control group with no complications during pregnancy (n=10). Plasma analysis were performed using in-vitro (31)P and (1)H nuclear magnetic resonance spectroscopy. RESULTS: (31)P nuclear magnetic resonance (NMR) spectra showed significantly higher levels of lysophosphatidylcholine 1 in the plasma of the patients in Group 1, along with significantly decreased levels of lysophosphatidylcholine 2 and phosphatidylinositol. However, the total amount of phospholipids did not differ significantly between the groups. In addition, the (1)H NMR spectra showed a significantly lower level of HDL in samples from Group 1, and a trend towards higher plasma levels of VLDL 2 and LDL 2 in the same group. CONCLUSION: This study supports the theory that preeclampsia is a disorder in phospholipid metabolism in which malfunctioning of cellular membranes seems to play a major pathogenic role. PMID- 23675282 TI - Biomedical and social aspects of spondyloepiphyseal dysplasia tarda cases from bengkulu district of indonesia. AB - BACKGROUND: Although short stature male (SSM) cases are often found in South Bengkulu, no management reports about their existence are available. This paper summarizes the researches of biomedical and social aspects for the human genetic disorders. CASE PRESENTATION: Field survey results indicated that SSM community was located in Kedurang area, and 67 persons with SSM were successfully sampled from a population of 17,357 persons (one of 260). Anthropometric comparative studies, history of the pattern of X-linked inheritance, as well as the study of anatomy through radiology and ultrasound confirmed that SSM is spondyloepiphyseal dysplasia tarda (SEDT). Genomic studies through characterisation of mutations of the SEDL gene revealed that point mutations on SEDT Kedurang are different from the results of previous similar studies, and these people are predicted to come from the same ancestors. It is necessary to notice that persons with SEDT have normal intellectual ability, but the physical conditions make their socio economic competitiveness very low. Furthermore premature joint pains make persons with SEDT become old faster than the ordinary people by the age of 40 years. Realizing that they are marginalized, some of them try to come together to establish a foundation designed to make a better life. CONCLUSION: It can be concluded that the appropriate management of SEDT should be done by integrating to improve their nutritional status, reduce the suffering of joint pain, develop labelled molecular markers for early detection, and increase their socio-economic competitiveness. PMID- 23675283 TI - The biology of the glutamatergic system and potential role in migraine. AB - Migraine is a common genetically linked neurovascular disorder. Approximately ~12% of the Caucasian population are affected including 18% of adult women and 6% of adult men (1, 2). A notable female bias is observed in migraine prevalence studies with females affected ~3 times more than males and is credited to differences in hormone levels arising from reproductive achievements. Migraine is extremely debilitating with wide-ranging socioeconomic impact significantly affecting people's health and quality of life. A number of neurotransmitter systems have been implicated in migraine, the most studied include the serotonergic and dopaminergic systems. Extensive genetic research has been carried out to identify genetic variants that may alter the activity of a number of genes involved in synthesis and transport of neurotransmitters of these systems. The biology of the Glutamatergic system in migraine is the least studied however there is mounting evidence that its constituents could contribute to migraine. The discovery of antagonists that selectively block glutamate receptors has enabled studies on the physiologic role of glutamate, on one hand, and opened new perspectives pertaining to the potential therapeutic applications of glutamate receptor antagonists in diverse neurologic diseases. In this brief review, we discuss the biology of the Glutamatergic system in migraine outlining recent findings that support a role for altered Glutamatergic neurotransmission from biochemical and genetic studies in the manifestation of migraine and the implications of this on migraine treatment. PMID- 23675284 TI - Proposed Technique for Accurate Detection/Segmentation of Lung Nodules using Spline Wavelet Techniques. AB - In this paper we are going to discuss and analyze the different methods which are developed to detect the Lung nodules which cause the lung cancer. At the end of analyzing different methods, the new methodology of detecting the lung nodules using Spline Wavelet technique has been proposed in this paper. Continuous modeling of data often required in medical imaging, Polynomial Splines are especially useful to consider image data as continuum rather than discrete array of pixels. The multi resolution property of Splines makes them prime candidates for constructing wavelet bases. Wavelet tool also let us to compress the original CT image to greater factor without any sacrifice in accuracy of nodule detection. Different Algorithms for segmentation/ detection of lung nodules from CT image is discussed in this paper. PMID- 23675285 TI - Role of DNA Repair Pathways in Response to Zidovudine-induced DNA Damage in Immortalized Human Liver THLE2 Cells. AB - The nucleoside reverse transcriptase inhibitor zidovudine (3'-azido-3' dexoythymidine, AZT) can be incorporated into DNA and cause DNA damage. Previously, we determined that the human hepatocellular carcinoma HepG2 cells are more susceptible to AZT-induced toxicities than the immortalized normal human liver THLE2 cells and the nucleotide excision repair (NER) pathway plays an essential role in the response to AZT-induced DNA damage. We have now investigated if the effects of AZT treatment on the expression levels of genes related to DNA damage and repair pathways contribute to the differences in sensitivity to AZT treatment between HepG2 cells and THLE2 cells. Of total 84 genes related to DNA damage and repair, two, five, and six genes were up regulated more than 1.5-fold at 50, 500, and 2,500 uM AZT groups compared with that of control THLE2 cells. Seven genes showed a decreased expression of more than 1.5-fold following the 2,500 uM AZT treatment. Two-sided multivariate analysis of variance indicated that the change in expression of genes involved in apoptosis, cell cycle, and DNA repair pathways was significant only at 2,500 uM AZT. Statistically significant dose-related increases were identified in XPC gene expression and GTF2H1 protein level after the AZT treatments, which implicated the NER pathway in response to the DNA damage induced by AZT. In contrast, AZT treatment did not alter significantly the expression of the APE1 gene or the levels of APE1 protein. These results indicate that the NER repair pathway is involved in AZT-induced DNA damage response in immortalized human hepatic THLE2 cells. PMID- 23675286 TI - Cytogenetic Profile of de novo Acute Myeloid Leukemia Patients in Malaysia. AB - Acute myeloid leukemia (AML) is a heterogeneous disease in terms of cytogenetics and molecular genetics. AML is the most common acute leukemia in adults and its incidence increases with age. Diagnostic cytogenetics is an important prognostic indicator for predicting outcome of AML. We examined the karyotypic patterns of 480 patients with de novo AML seen at government hospitals throughout the country and evaluated the association of chromosome aberrations with the age of patient. Chromosome abnormalities were detected in 146 (30.4%) patients. The most common cytogenetic abnormality was balanced translocation t (8; 21), followed by trisomy 8 (as sole abnormality) and t (15; 17). The age of our Malaysian patients at diagnosis ranged from four months to 81 years, with a median age of 39 years. The normal karyotype was found mainly in patients aged 15-30 years. About 75% of patients with t (8; 21) were below 40 years of age, and the complex karyotype was found with the highest frequently (34.3%) in elderly patients (age above 60 years). More than half of the patients with complex karyotype were above 50 years of age. The deletion 5q was detected only in patients aged above 50 years. Different cytogenetic abnormalities in AML show different frequencies with increasing age. Probably different genetic mechanisms are involved in the pathogenesis of AML and these mechanisms might occur at different frequencies over lifetime. PMID- 23675287 TI - The ethnobotanical, phytochemical and mineral analyses of phragmanthera incana (klotzsch), a species of mistletoe growing on three plant hosts in South-Western Nigeria. AB - Mistletoe is collected wildly on various plants and Phragmanthera incana is noted to grow on different plant hosts. This study was designed to carry out the ethnobotanical survey, phytochemical and mineral analyses of Phragmanthera incana, a species of mistletoe growing on three plant hosts namely Cocoa (Theobroma cacao), Kolanut (Cola nitida) and Bush mango (Irvingia gabonensis). Mistletoe samples were identified at the Forestry Research Institute of Nigeria Herbarium. Phragmanthera incana was screened for its phytochemical constituents and mineral cations along its hosts following standard methods and to confirm if the mistletoe species is host specific. The powdered samples of the mistletoe species (Phragmanthera incana) was used for both the phytochemical screening and the cation mineral analysis. The uses and the harvesting methods of mistletoe were also reviewed extensively in this paper. PMID- 23675288 TI - Spectrophotometric Methods for the Determination of Linagliptin in Binary Mixture with Metformin Hydrochloride and Simultaneous Determination of Linagliptin and Metformin Hydrochloride using High Performance Liquid Chromatography. AB - Simple, accurate and precise Zero order, first derivative spectrophotometric and chromatographic methods have been developed and validated for the determination of linagliptin (LNG) and metformin HCl (MET). The zero order and first derivative spectrophotometric methods were used for the determination of LNG in the range of 5-30 MUg mL(-1) by measuring the absorbance at 299 nm and 311 respectively. Besides, a reversed-phase liquid chromatographic (RP-LC) method is described for the simultaneous determination of LNG and MET. Chromatographic separation was achieved on a Symmetry((r)) Waters C18 column (150 mm * 4.6 mm, 5 MUm). Isocratic elution based on potassium dihydrogen phosphate buffer pH (4.6) - methanol (30:70, v/v) at a flow rate of 1 mLmin(-1) with UV detection at 260 nm was performed. Linearity, accuracy and precision were found to be acceptable over the concentration ranges of 0.125-4 MUg mL(-1) and 20-800 MUg mL(-1) for LNG and MET, respectively. The results were statistically compared using one-way analysis of variance (ANOVA). The optimized methods were validated and proved to be specific, robust, precise and accurate for the quality control of the drugs in their pharmaceutical preparation. PMID- 23675289 TI - Predictive Value of Pretreatment BCR-ABL(IS) Transcript level on Response to Imatinib Therapy in Egyptian Patients with Chronic Phase Chronic Myeloid Leukemia (CPCML). AB - BACKGROUND: A wide range of responses of patients with CPCML to IM has been reported. Several factors were proposed to predict response including molecular response at 3 and 6 months. PURPOSE: To study the impact of pretreatment BCR-ABL transcript level on molecular response to IM, and to assess the value of the milestone ; <=10% transcript at 3 months on PFS and OS. PATIENTS AND METHODS: Fifty five adult CP-CML patients receiving daily dose of 400 mg IM were subjected to molecular and cytogenetic analysis at diagnosis and at regular time intervals. Median follow up period was 36 months (15-48). Hematologic, cytogenetic, and molecular responses were rated according to ELN. RESULTS: Two Patient groups were distinguished regarding response to IM therapy. A group of 22/55 patients (40%) having pretreatment BCR-ABL(IS) level <=200% and a second patient group 33/55 (60%) having transcript level >200%. The <=10% milestone was achieved by 15/22 patients (68%) versus 7/33 patients (21%), p=0.04 in favor of the first group. Optimal responders in first group were 14/22 (64%) compared to 13/33 (39%) in second group, p=0.02. Achievement of 10% transcript level significantly correlated with longer PFS. The median BCR-ABL(IS) transcripts levels in optimal responders at 3, 6 and 18 months was 10%, 2% and 0.1%, respectively compared to 100%, 65% and 10%, in suboptimal/resistant patients p=0.001. Resistance in 11 patients was correlated with identifiable ABL Kinase mutations. CONCLUSIONS: The Pretreatment 200% cutoff and the 3 month BCR-ABL(IS) <=10% transcript levels proved strong predictors of response to IM and significantly correlated with probability of CCyR, MMR and PFS. PMID- 23675291 TI - Host resistance, population structure and the long-term persistence of bubonic plague: contributions of a modelling approach in the Malagasy focus. AB - Although bubonic plague is an endemic zoonosis in many countries around the world, the factors responsible for the persistence of this highly virulent disease remain poorly known. Classically, the endemic persistence of plague is suspected to be due to the coexistence of plague resistant and plague susceptible rodents in natural foci, and/or to a metapopulation structure of reservoirs. Here, we test separately the effect of each of these factors on the long-term persistence of plague. We analyse the dynamics and equilibria of a model of plague propagation, consistent with plague ecology in Madagascar, a major focus where this disease is endemic since the 1920s in central highlands. By combining deterministic and stochastic analyses of this model, and including sensitivity analyses, we show that (i) endemicity is favoured by intermediate host population sizes, (ii) in large host populations, the presence of resistant rats is sufficient to explain long-term persistence of plague, and (iii) the metapopulation structure of susceptible host populations alone can also account for plague endemicity, thanks to both subdivision and the subsequent reduction in the size of subpopulations, and extinction-recolonization dynamics of the disease. In the light of these results, we suggest scenarios to explain the localized presence of plague in Madagascar. PMID- 23675290 TI - Sparse coding can predict primary visual cortex receptive field changes induced by abnormal visual input. AB - Receptive fields acquired through unsupervised learning of sparse representations of natural scenes have similar properties to primary visual cortex (V1) simple cell receptive fields. However, what drives in vivo development of receptive fields remains controversial. The strongest evidence for the importance of sensory experience in visual development comes from receptive field changes in animals reared with abnormal visual input. However, most sparse coding accounts have considered only normal visual input and the development of monocular receptive fields. Here, we applied three sparse coding models to binocular receptive field development across six abnormal rearing conditions. In every condition, the changes in receptive field properties previously observed experimentally were matched to a similar and highly faithful degree by all the models, suggesting that early sensory development can indeed be understood in terms of an impetus towards sparsity. As previously predicted in the literature, we found that asymmetries in inter-ocular correlation across orientations lead to orientation-specific binocular receptive fields. Finally we used our models to design a novel stimulus that, if present during rearing, is predicted by the sparsity principle to lead robustly to radically abnormal receptive fields. PMID- 23675292 TI - STL-based analysis of TRAIL-induced apoptosis challenges the notion of type I/type II cell line classification. AB - Extrinsic apoptosis is a programmed cell death triggered by external ligands, such as the TNF-related apoptosis inducing ligand (TRAIL). Depending on the cell line, the specific molecular mechanisms leading to cell death may significantly differ. Precise characterization of these differences is crucial for understanding and exploiting extrinsic apoptosis. Cells show distinct behaviors on several aspects of apoptosis, including (i) the relative order of caspases activation, (ii) the necessity of mitochondria outer membrane permeabilization (MOMP) for effector caspase activation, and (iii) the survival of cell lines overexpressing Bcl2. These differences are attributed to the activation of one of two pathways, leading to classification of cell lines into two groups: type I and type II. In this work we challenge this type I/type II cell line classification. We encode the three aforementioned distinguishing behaviors in a formal language, called signal temporal logic (STL), and use it to extensively test the validity of a previously-proposed model of TRAIL-induced apoptosis with respect to experimental observations made on different cell lines. After having solved a few inconsistencies using STL-guided parameter search, we show that these three criteria do not define consistent cell line classifications in type I or type II, and suggest mutants that are predicted to exhibit ambivalent behaviors. In particular, this finding sheds light on the role of a feedback loop between caspases, and reconciliates two apparently-conflicting views regarding the importance of either upstream or downstream processes for cell-type determination. More generally, our work suggests that these three distinguishing behaviors should be merely considered as type I/II features rather than cell-type defining criteria. On the methodological side, this work illustrates the biological relevance of STL-diagrams, STL population data, and STL-guided parameter search implemented in the tool Breach. Such tools are well-adapted to the ever-increasing availability of heterogeneous knowledge on complex signal transduction pathways. PMID- 23675294 TI - Identification of targets of CD8+ T cell responses to malaria liver stages by genome-wide epitope profiling. AB - CD8+ T cells mediate immunity against Plasmodium liver stages. However, the paucity of parasite-specific epitopes of CD8+ T cells has limited our current understanding of the mechanisms influencing the generation, maintenance and efficiency of these responses. To identify antigenic epitopes in a stringent murine malaria immunisation model, we performed a systematic profiling of H(2b) restricted peptides predicted from genome-wide analysis. We describe the identification of Plasmodium berghei (Pb) sporozoite-specific gene 20 (S20)- and thrombospondin-related adhesive protein (TRAP)-derived peptides, termed PbS20318 and PbTRAP130 respectively, as targets of CD8+ T cells from C57BL/6 mice vaccinated by whole parasite strategies known to protect against sporozoite challenge. While both PbS20318 and PbTRAP130 elicit effector and effector memory phenotypes in both the spleens and livers of immunised mice, only PbTRAP130 specific CD8+ T cells exhibit in vivo cytotoxicity. Moreover, PbTRAP130-specific, but not PbS20318-specific, CD8+ T cells significantly contribute to inhibition of parasite development. Prime/boost vaccination with PbTRAP demonstrates CD8+ T cell-dependent efficacy against sporozoite challenge. We conclude that PbTRAP is an immunodominant antigen during liver-stage infection. Together, our results underscore the presence of CD8+ T cells with divergent potencies against distinct Plasmodium liver-stage epitopes. Our identification of antigen-specific CD8+ T cells will allow interrogation of the development of immune responses against malaria liver stages. PMID- 23675295 TI - Volatile metabolites of pathogens: a systematic review. AB - Ideally, invading bacteria are detected as early as possible in critically ill patients: the strain of morbific pathogens is identified rapidly, and antimicrobial sensitivity is known well before the start of new antimicrobial therapy. Bacteria have a distinct metabolism, part of which results in the production of bacteria-specific volatile organic compounds (VOCs), which might be used for diagnostic purposes. Volatile metabolites can be investigated directly in exhaled air, allowing for noninvasive monitoring. The aim of this review is to provide an overview of VOCs produced by the six most abundant and pathogenic bacteria in sepsis, including Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli. Such VOCs could be used as biological markers in the diagnostic approach of critically ill patients. A systematic review of existing literature revealed 31 articles. All six bacteria of interest produce isopentanol, formaldehyde, methyl mercaptan, and trimethylamine. Since humans do not produce these VOCs, they could serve as biological markers for presence of these pathogens. The following volatile biomarkers were found for identification of specific strains: isovaleric acid and 2-methyl-butanal for Staphylococcus aureus; 1-undecene, 2,4-dimethyl-1-heptane, 2-butanone, 4-methyl-quinazoline, hydrogen cyanide, and methyl thiocyanide for Pseudomonas aeruginosa; and methanol, pentanol, ethyl acetate, and indole for Escherichia coli. Notably, several factors that may effect VOC production were not controlled for, including used culture media, bacterial growth phase, and genomic variation within bacterial strains. In conclusion, VOCs produced by bacteria may serve as biological markers for their presence. Goal-targeted studies should be performed to identify potential sets of volatile biological markers and evaluate the diagnostic accuracy of these markers in critically ill patients. PMID- 23675296 TI - Persistently active microbial molecules prolong innate immune tolerance in vivo. AB - Measures that bolster the resolution phase of infectious diseases may offer new opportunities for improving outcome. Here we show that inactivation of microbial lipopolysaccharides (LPS) can be required for animals to recover from the innate immune tolerance that follows exposure to Gram-negative bacteria. When wildtype mice are exposed to small parenteral doses of LPS or Gram-negative bacteria, their macrophages become reprogrammed (tolerant) for a few days before they resume normal function. Mice that are unable to inactivate LPS, in contrast, remain tolerant for several months; during this time they respond sluggishly to Gram-negative bacterial challenge, with high mortality. We show here that prolonged macrophage reprogramming is maintained in vivo by the persistence of stimulatory LPS molecules within the cells' in vivo environment, where naive cells can acquire LPS via cell-cell contact or from the extracellular fluid. The findings provide strong evidence that inactivation of a stimulatory microbial molecule can be required for animals to regain immune homeostasis following parenteral exposure to bacteria. Measures that disable microbial molecules might enhance resolution of tissue inflammation and help restore innate defenses in individuals recovering from many different infectious diseases. PMID- 23675297 TI - Malaria parasite cGMP-dependent protein kinase regulates blood stage merozoite secretory organelle discharge and egress. AB - The malaria parasite replicates within an intraerythrocytic parasitophorous vacuole (PV). Eventually, in a tightly regulated process called egress, proteins of the PV and intracellular merozoite surface are modified by an essential parasite serine protease called PfSUB1, whilst the enclosing PV and erythrocyte membranes rupture, releasing merozoites to invade fresh erythrocytes. Inhibition of the Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) prevents egress, but the underlying mechanism is unknown. Here we show that PfPKG activity is required for PfSUB1 discharge into the PV, as well as for release of distinct merozoite organelles called micronemes. Stimulation of PfPKG by inhibiting parasite phosphodiesterase activity induces premature PfSUB1 discharge and egress of developmentally immature, non-invasive parasites. Our findings identify the signalling pathway that regulates PfSUB1 function and egress, and raise the possibility of targeting PfPKG or parasite phosphodiesterases in therapeutic approaches to dysregulate critical protease-mediated steps in the parasite life cycle. PMID- 23675298 TI - Recruitment of EB1, a master regulator of microtubule dynamics, to the surface of the Theileria annulata schizont. AB - The apicomplexan parasite Theileria annulata transforms infected host cells, inducing uncontrolled proliferation and clonal expansion of the parasitized cell population. Shortly after sporozoite entry into the target cell, the surrounding host cell membrane is dissolved and an array of host cell microtubules (MTs) surrounds the parasite, which develops into the transforming schizont. The latter does not egress to invade and transform other cells. Instead, it remains tethered to host cell MTs and, during mitosis and cytokinesis, engages the cell's astral and central spindle MTs to secure its distribution between the two daughter cells. The molecular mechanism by which the schizont recruits and stabilizes host cell MTs is not known. MT minus ends are mostly anchored in the MT organizing center, while the plus ends explore the cellular space, switching constantly between phases of growth and shrinkage (called dynamic instability). Assuming the plus ends of growing MTs provide the first point of contact with the parasite, we focused on the complex protein machinery associated with these structures. We now report how the schizont recruits end-binding protein 1 (EB1), a central component of the MT plus end protein interaction network and key regulator of host cell MT dynamics. Using a range of in vitro experiments, we demonstrate that T. annulata p104, a polymorphic antigen expressed on the schizont surface, functions as a genuine EB1-binding protein and can recruit EB1 in the absence of any other parasite proteins. Binding strictly depends on a consensus SxIP motif located in a highly disordered C-terminal region of p104. We further show that parasite interaction with host cell EB1 is cell cycle regulated. This is the first description of a pathogen-encoded protein to interact with EB1 via a bona-fide SxIP motif. Our findings provide important new insight into the mode of interaction between Theileria and the host cell cytoskeleton. PMID- 23675299 TI - NOD2-mediated suppression of CD55 on neutrophils enhances C5a generation during polymicrobial sepsis. AB - Nucleotide-binding oligomerization domain (NOD) 2 is a cytosolic protein that plays a defensive role in bacterial infection by sensing peptidoglycans. C5a, which has harmful effects in sepsis, interacts with innate proteins. However, whether NOD2 regulates C5a generation during sepsis remains to be determined. To address this issue, cecal ligation & puncture (CLP)-induced sepsis was compared in wild type and Nod2-/- mice. Nod2-/- mice showed lower levels of C5a, IL-10, and IL-1beta in serum and peritoneum, but higher survival rate during CLP-induced sepsis compared to wild type mice. Injection of recombinant C5a decreased survival rates of Nod2-/- mice rate during sepsis, whereas it did not alter those in wild type mice. These findings suggest a novel provocative role for NOD2 in sepsis, in contrast to its protective role during bacterial infection. Furthermore, we found that NOD2-mediated IL-10 production by neutrophils enhanced C5a generation by suppressing CD55 expression on neutrophils in IL-1beta dependent and/or IL-1beta-independent manners, thereby aggravating CLP-induced sepsis. SB203580, a receptor-interacting protein 2 (RIP2) inhibitor downstream of NOD2, reduced C5a generation by enhancing CD55 expression on neutrophils, resulting in attenuation of polymicrobial sepsis. Therefore, we propose a novel NOD2-mediated complement cascade regulatory pathway in sepsis, which may be a useful therapeutic target. PMID- 23675300 TI - Gain-of-sensitivity mutations in a Trim5-resistant primary isolate of pathogenic SIV identify two independent conserved determinants of Trim5alpha specificity. AB - Retroviral capsid recognition by Trim5 blocks productive infection. Rhesus macaques harbor three functionally distinct Trim5 alleles: Trim5alpha(Q) , Trim5alpha(TFP) and Trim5(CypA) . Despite the high degree of amino acid identity between Trim5alpha(Q) and Trim5alpha(TFP) alleles, the Q/TFP polymorphism results in the differential restriction of some primate lentiviruses, suggesting these alleles differ in how they engage these capsids. Simian immunodeficiency virus of rhesus macaques (SIVmac) evolved to resist all three alleles. Thus, SIVmac provides a unique opportunity to study a virus in the context of the Trim5 repertoire that drove its evolution in vivo. We exploited the evolved rhesus Trim5alpha resistance of this capsid to identify gain-of-sensitivity mutations that distinguish targets between the Trim5alpha(Q) and Trim5alpha(TFP) alleles. While both alleles recognize the capsid surface, Trim5alpha(Q) and Trim5alpha(TFP) alleles differed in their ability to restrict a panel of capsid chimeras and single amino acid substitutions. When mapped onto the structure of the SIVmac239 capsid N-terminal domain, single amino acid substitutions affecting both alleles mapped to the beta-hairpin. Given that none of the substitutions affected Trim5alpha(Q) alone, and the fact that the beta-hairpin is conserved among retroviral capsids, we propose that the beta-hairpin is a molecular pattern widely exploited by Trim5alpha proteins. Mutations specifically affecting rhesus Trim5alpha(TFP) (without affecting Trim5alpha(Q) ) surround a site of conservation unique to primate lentiviruses, overlapping the CPSF6 binding site. We believe targeting this site is an evolutionary innovation driven specifically by the emergence of primate lentiviruses in Africa during the last 12 million years. This modularity in targeting may be a general feature of Trim5 evolution, permitting different regions of the PRYSPRY domain to evolve independent interactions with capsid. PMID- 23675301 TI - Bile acid recognition by the Clostridium difficile germinant receptor, CspC, is important for establishing infection. AB - Clostridium difficile spores must germinate in vivo to become actively growing bacteria in order to produce the toxins that are necessary for disease. C. difficile spores germinate in vitro in response to certain bile acids and glycine. In other sporulating bacteria, proteins embedded within the inner membrane of the spore sense the presence of germinants and trigger the release of Ca++-dipicolinic acid (Ca++-DPA) from the spore core and subsequent hydrolysis of the spore cortex, a specialized peptidoglycan. Based upon homology searches of known germinant receptors from other spore-forming bacteria, C. difficile likely uses unique mechanisms to recognize germinants. Here, we identify the germination specific protease, CspC, as the C. difficile bile acid germinant receptor and show that bile acid-mediated germination is important for establishing C. difficile disease in the hamster model of infection. These results highlight the importance of bile acids in triggering in vivo germination and provide the first description of a C. difficile spore germinant receptor. Blocking the interaction of bile acids with the C. difficile spore may represent an attractive target for novel therapeutics. PMID- 23675302 TI - LAB/NTAL facilitates fungal/PAMP-induced IL-12 and IFN-gamma production by repressing beta-catenin activation in dendritic cells. AB - Fungal pathogens elicit cytokine responses downstream of immunoreceptor tyrosine based activation motif (ITAM)-coupled or hemiITAM-containing receptors and TLRs. The Linker for Activation of B cells/Non-T cell Activating Linker (LAB/NTAL) encoded by Lat2, is a known regulator of ITAM-coupled receptors and TLR associated cytokine responses. Here we demonstrate that LAB is involved in anti fungal immunity. We show that Lat2-/- mice are more susceptible to C. albicans infection than wild type (WT) mice. Dendritic cells (DCs) express LAB and we show that it is basally phosphorylated by the growth factor M-CSF or following engagement of Dectin-2, but not Dectin-1. Our data revealed a unique mechanism whereby LAB controls basal and fungal/pathogen-associated molecular patterns (PAMP)-induced nuclear beta-catenin levels. This in turn is important for controlling fungal/PAMP-induced cytokine production in DCs. C. albicans- and LPS induced IL-12 and IL-23 production was blunted in Lat2-/- DCs. Accordingly, Lat2 /- DCs directed reduced Th1 polarization in vitro and Lat2-/- mice displayed reduced Natural Killer (NK) and T cell-mediated IFN-gamma production in vivo/ex vivo. Thus our data define a novel link between LAB and beta-catenin nuclear accumulation in DCs that facilitates IFN-gamma responses during anti-fungal immunity. In addition, these findings are likely to be relevant to other infectious diseases that require IL-12 family cytokines and an IFN-gamma response for pathogen clearance. PMID- 23675303 TI - The lipid kinase phosphatidylinositol-4 kinase III alpha regulates the phosphorylation status of hepatitis C virus NS5A. AB - The lipid kinase phosphatidylinositol 4-kinase III alpha (PI4KIIIalpha) is an essential host factor of hepatitis C virus (HCV) replication. PI4KIIIalpha catalyzes the synthesis of phosphatidylinositol 4-phosphate (PI4P) accumulating in HCV replicating cells due to enzyme activation resulting from its interaction with nonstructural protein 5A (NS5A). This study describes the interaction between PI4KIIIalpha and NS5A and its mechanistic role in viral RNA replication. We mapped the NS5A sequence involved in PI4KIIIalpha interaction to the carboxyterminal end of domain 1 and identified a highly conserved PI4KIIIalpha functional interaction site (PFIS) encompassing seven amino acids, which are essential for viral RNA replication. Mutations within this region were also impaired in NS5A-PI4KIIIalpha binding, reduced PI4P levels and altered the morphology of viral replication sites, reminiscent to the phenotype observed by silencing of PI4KIIIalpha. Interestingly, abrogation of RNA replication caused by mutations in the PFIS correlated with increased levels of hyperphosphorylated NS5A (p58), indicating that PI4KIIIalpha affects the phosphorylation status of NS5A. RNAi-mediated knockdown of PI4KIIIalpha or pharmacological ablation of kinase activity led to a relative increase of p58. In contrast, overexpression of enzymatically active PI4KIIIalpha increased relative abundance of basally phosphorylated NS5A (p56). PI4KIIIalpha therefore regulates the phosphorylation status of NS5A and viral RNA replication by favoring p56 or repressing p58 synthesis. Replication deficiencies of PFIS mutants in NS5A could not be rescued by increasing PI4P levels, but by supplying functional NS5A, supporting an essential role of PI4KIIIalpha in HCV replication regulating NS5A phosphorylation, thereby modulating the morphology of viral replication sites. In conclusion, we demonstrate that PI4KIIIalpha activity affects the NS5A phosphorylation status. Our results highlight the importance of PI4KIIIalpha in the morphogenesis of viral replication sites and its regulation by facilitating p56 synthesis. PMID- 23675304 TI - T-Cell tropism of simian varicella virus during primary infection. AB - Varicella-zoster virus (VZV) causes varicella, establishes a life-long latent infection of ganglia and reactivates to cause herpes zoster. The cell types that transport VZV from the respiratory tract to skin and ganglia during primary infection are unknown. Clinical, pathological, virological and immunological features of simian varicella virus (SVV) infection of non-human primates parallel those of primary VZV infection in humans. To identify the host cell types involved in virus dissemination and pathology, we infected African green monkeys intratracheally with recombinant SVV expressing enhanced green fluorescent protein (SVV-EGFP) and with wild-type SVV (SVV-wt) as a control. The SVV-infected cell types and virus kinetics were determined by flow cytometry and immunohistochemistry, and virus culture and SVV-specific real-time PCR, respectively. All monkeys developed fever and skin rash. Except for pneumonitis, pathology produced by SVV-EGFP was less compared to SVV-wt. In lungs, SVV infected alveolar myeloid cells and T-cells. During viremia the virus preferentially infected memory T-cells, initially central memory T-cells and subsequently effector memory T-cells. In early non-vesicular stages of varicella, SVV was seen mainly in perivascular skin infiltrates composed of macrophages, dendritic cells, dendrocytes and memory T-cells, implicating hematogenous spread. In ganglia, SVV was found primarily in neurons and occasionally in memory T-cells adjacent to neurons. In conclusion, the data suggest the role of memory T-cells in disseminating SVV to its target organs during primary infection of its natural and immunocompetent host. PMID- 23675305 TI - A unique spumavirus Gag N-terminal domain with functional properties of orthoretroviral matrix and capsid. AB - The Spumaretrovirinae, or foamyviruses (FVs) are complex retroviruses that infect many species of monkey and ape. Although FV infection is apparently benign, trans species zoonosis is commonplace and has resulted in the isolation of the Prototypic Foamy Virus (PFV) from human sources and the potential for germ-line transmission. Despite little sequence homology, FV and orthoretroviral Gag proteins perform equivalent functions, including genome packaging, virion assembly, trafficking and membrane targeting. In addition, PFV Gag interacts with the FV Envelope (Env) protein to facilitate budding of infectious particles. Presently, there is a paucity of structural information with regards FVs and it is unclear how disparate FV and orthoretroviral Gag molecules share the same function. Therefore, in order to probe the functional overlap of FV and orthoretroviral Gag and learn more about FV egress and replication we have undertaken a structural, biophysical and virological study of PFV-Gag. We present the crystal structure of a dimeric amino terminal domain from PFV, Gag-NtD, both free and in complex with the leader peptide of PFV Env. The structure comprises a head domain together with a coiled coil that forms the dimer interface and despite the shared function it is entirely unrelated to either the capsid or matrix of Gag from other retroviruses. Furthermore, we present structural, biochemical and virological data that reveal the molecular details of the essential Gag-Env interaction and in addition we also examine the specificity of Trim5alpha restriction of PFV. These data provide the first information with regards to FV structural proteins and suggest a model for convergent evolution of gag genes where structurally unrelated molecules have become functionally equivalent. PMID- 23675306 TI - Duplication and retention biases of essential and non-essential genes revealed by systematic knockdown analyses. AB - When a duplicate gene has no apparent loss-of-function phenotype, it is commonly considered that the phenotype has been masked as a result of functional redundancy with the remaining paralog. This is supported by indirect evidence showing that multi-copy genes show loss-of-function phenotypes less often than single-copy genes and by direct tests of phenotype masking using select gene sets. Here we take a systematic genome-wide RNA interference approach to assess phenotype masking in paralog pairs in the Caenorhabditis elegans genome. Remarkably, in contrast to expectations, we find that phenotype masking makes only a minor contribution to the low knockdown phenotype rate for duplicate genes. Instead, we find that non-essential genes are highly over-represented among duplicates, leading to a low observed loss-of-function phenotype rate. We further find that duplicate pairs derived from essential and non-essential genes have contrasting evolutionary dynamics: whereas non-essential genes are both more often successfully duplicated (fixed) and lost, essential genes are less often duplicated but upon successful duplication are maintained over longer periods. We expect the fundamental evolutionary duplication dynamics presented here to be broadly applicable. PMID- 23675307 TI - Liver x receptors protect from development of prostatic intra-epithelial neoplasia in mice. AB - LXR (Liver X Receptors) act as "sensor" proteins that regulate cholesterol uptake, storage, and efflux. LXR signaling is known to influence proliferation of different cell types including human prostatic carcinoma (PCa) cell lines. This study shows that deletion of LXR in mouse fed a high-cholesterol diet recapitulates initial steps of PCa development. Elevation of circulating cholesterol in Lxralphabeta-/- double knockout mice results in aberrant cholesterol ester accumulation and prostatic intra-epithelial neoplasia. This phenotype is linked to increased expression of the histone methyl transferase EZH2 (Enhancer of Zeste Homolog 2), which results in the down-regulation of the tumor suppressors Msmb and Nkx3.1 through increased methylation of lysine 27 of histone H3 (H3K27) on their promoter regions. Altogether, our data provide a novel link between LXR, cholesterol homeostasis, and epigenetic control of tumor suppressor gene expression. PMID- 23675308 TI - From mouse to human: evolutionary genomics analysis of human orthologs of essential genes. AB - Understanding the core set of genes that are necessary for basic developmental functions is one of the central goals in biology. Studies in model organisms identified a significant fraction of essential genes through the analysis of null mutations that lead to lethality. Recent large-scale next-generation sequencing efforts have provided unprecedented data on genetic variation in human. However, evolutionary and genomic characteristics of human essential genes have never been directly studied on a genome-wide scale. Here we use detailed phenotypic resources available for the mouse and deep genomics sequencing data from human populations to characterize patterns of genetic variation and mutational burden in a set of 2,472 human orthologs of known essential genes in the mouse. Consistent with the action of strong, purifying selection, these genes exhibit comparatively reduced levels of sequence variation, skew in allele frequency towards more rare, and exhibit increased conservation across the primate and rodent lineages relative to the remainder of genes in the genome. In individual genomes we observed ~12 rare mutations within essential genes predicted to be damaging. Consistent with the hypothesis that mutations in essential genes are risk factors for neurodevelopmental disease, we show that de novo variants in patients with Autism Spectrum Disorder are more likely to occur in this collection of genes. While incomplete, our set of human orthologs shows characteristics fully consistent with essential function in human and thus provides a resource to inform and facilitate interpretation of sequence data in studies of human disease. PMID- 23675309 TI - Genome-wide identification of regulatory RNAs in the human pathogen Clostridium difficile. AB - Clostridium difficile is an emergent pathogen, and the most common cause of nosocomial diarrhea. In an effort to understand the role of small noncoding RNAs (sRNAs) in C. difficile physiology and pathogenesis, we used an in silico approach to identify 511 sRNA candidates in both intergenic and coding regions. In parallel, RNA-seq and differential 5'-end RNA-seq were used for global identification of C. difficile sRNAs and their transcriptional start sites at three different growth conditions (exponential growth phase, stationary phase, and starvation). This global experimental approach identified 251 putative regulatory sRNAs including 94 potential trans riboregulators located in intergenic regions, 91 cis-antisense RNAs, and 66 riboswitches. Expression of 35 sRNAs was confirmed by gene-specific experimental approaches. Some sRNAs, including an antisense RNA that may be involved in control of C. difficile autolytic activity, showed growth phase-dependent expression profiles. Expression of each of 16 predicted c-di-GMP-responsive riboswitches was observed, and experimental evidence for their regulatory role in coordinated control of motility and biofilm formation was obtained. Finally, we detected abundant sRNAs encoded by multiple C. difficile CRISPR loci. These RNAs may be important for C. difficile survival in bacteriophage-rich gut communities. Altogether, this first experimental genome-wide identification of C. difficile sRNAs provides a firm basis for future RNome characterization and identification of molecular mechanisms of sRNA-based regulation of gene expression in this emergent enteropathogen. PMID- 23675310 TI - The specificity and flexibility of l1 reverse transcription priming at imperfect T-tracts. AB - L1 retrotransposons have a prominent role in reshaping mammalian genomes. To replicate, the L1 ribonucleoprotein particle (RNP) first uses its endonuclease (EN) to nick the genomic DNA. The newly generated DNA end is subsequently used as a primer to initiate reverse transcription within the L1 RNA poly(A) tail, a process known as target-primed reverse transcription (TPRT). Prior studies demonstrated that most L1 insertions occur into sequences related to the L1 EN consensus sequence (degenerate 5'-TTTT/A-3' sites) and frequently preceded by imperfect T-tracts. However, it is currently unclear whether--and to which degree -the liberated 3'-hydroxyl extremity on the genomic DNA needs to be accessible and complementary to the poly(A) tail of the L1 RNA for efficient priming of reverse transcription. Here, we employed a direct assay for the initiation of L1 reverse transcription to define the molecular rules that guide this process. First, efficient priming is detected with as few as 4 matching nucleotides at the primer 3' end. Second, L1 RNP can tolerate terminal mismatches if they are compensated within the 10 last bases of the primer by an increased number of matching nucleotides. All terminal mismatches are not equally detrimental to DNA extension, a C being extended at higher levels than an A or a G. Third, efficient priming in the context of duplex DNA requires a 3' overhang. This suggests the possible existence of additional DNA processing steps, which generate a single stranded 3' end to allow L1 reverse transcription. Based on these data we propose that the specificity of L1 reverse transcription initiation contributes, together with the specificity of the initial EN cleavage, to the distribution of new L1 insertions within the human genome. PMID- 23675311 TI - The majority of primate-specific regulatory sequences are derived from transposable elements. AB - Although emerging evidence suggests that transposable elements (TEs) have contributed novel regulatory elements to the human genome, their global impact on transcriptional networks remains largely uncharacterized. Here we show that TEs have contributed to the human genome nearly half of its active elements. Using DNase I hypersensitivity data sets from ENCODE in normal, embryonic, and cancer cells, we found that 44% of open chromatin regions were in TEs and that this proportion reached 63% for primate-specific regions. We also showed that distinct subfamilies of endogenous retroviruses (ERVs) contributed significantly more accessible regions than expected by chance, with up to 80% of their instances in open chromatin. Based on these results, we further characterized 2,150 TE subfamily-transcription factor pairs that were bound in vivo or enriched for specific binding motifs, and observed that TEs contributing to open chromatin had higher levels of sequence conservation. We also showed that thousands of ERV derived sequences were activated in a cell type-specific manner, especially in embryonic and cancer cells, and we demonstrated that this activity was associated with cell type-specific expression of neighboring genes. Taken together, these results demonstrate that TEs, and in particular ERVs, have contributed hundreds of thousands of novel regulatory elements to the primate lineage and reshaped the human transcriptional landscape. PMID- 23675313 TI - Revisiting the Ventral Medial Nucleus of the Hypothalamus: The Roles of SF-1 Neurons in Energy Homeostasis. AB - Obesity, diabetes, and other metabolic complications are growing concerns for public health and could lead to detrimental life-threatening conditions. Neurons whose activities are required for energy and glucose homeostasis are found in a number of hypothalamic nuclei. In the early twentieth century, the ventral medial nucleus of the hypothalamus (VMH) was the first site reported to play a prominent role in the regulation of energy homeostasis through control of food intake and energy expenditure. Recent studies using sophisticated genetic tools have further highlighted the importance of the VMH and have extended our understanding of the physiological role of the nucleus in regulation of energy homeostasis. These genetic studies were preceded by the identification of steroidogenic factor-1 (SF 1) as a marker of the VMH. This review focuses on the emerging homeostatic roles of the SF-1 neurons in the VMH discovered through the use of genetic models, particularly highlighting the control of energy, and glucose homeostasis. PMID- 23675312 TI - Bck2 acts through the MADS box protein Mcm1 to activate cell-cycle-regulated genes in budding yeast. AB - The Bck2 protein is a potent genetic regulator of cell-cycle-dependent gene expression in budding yeast. To date, most experiments have focused on assessing a potential role for Bck2 in activation of the G1/S-specific transcription factors SBF (Swi4, Swi6) and MBF (Mbp1, Swi6), yet the mechanism of gene activation by Bck2 has remained obscure. We performed a yeast two-hybrid screen using a truncated version of Bck2 and discovered six novel Bck2-binding partners including Mcm1, an essential protein that binds to and activates M/G1 promoters through Early Cell cycle Box (ECB) elements as well as to G2/M promoters. At M/G1 promoters Mcm1 is inhibited by association with two repressors, Yox1 or Yhp1, and gene activation ensues once repression is relieved by an unknown activating signal. Here, we show that Bck2 interacts physically with Mcm1 to activate genes during G1 phase. We used chromatin immunoprecipitation (ChIP) experiments to show that Bck2 localizes to the promoters of M/G1-specific genes, in a manner dependent on functional ECB elements, as well as to the promoters of G1/S and G2/M genes. The Bck2-Mcm1 interaction requires valine 69 on Mcm1, a residue known to be required for interaction with Yox1. Overexpression of BCK2 decreases Yox1 localization to the early G1-specific CLN3 promoter and rescues the lethality caused by overexpression of YOX1. Our data suggest that Yox1 and Bck2 may compete for access to the Mcm1-ECB scaffold to ensure appropriate activation of the initial suite of genes required for cell cycle commitment. PMID- 23675314 TI - Adaptive cluster analysis approach for functional localization using magnetoencephalography. AB - In this paper we propose an agglomerative hierarchical clustering Ward's algorithm in tandem with the Affinity Propagation algorithm to reliably localize active brain regions from magnetoencephalography (MEG) brain signals. Reliable localization of brain areas with MEG has been difficult due to variations in signal strength, and the spatial extent of the reconstructed activity. The proposed approach to resolve this difficulty is based on adaptive clustering on reconstructed beamformer images to find locations that are consistently active across different participants and experimental conditions with high spatial resolution. Using data from a human reaching task, we show that the method allows more accurate and reliable localization from MEG data alone without using functional magnetic resonance imaging (fMRI) or any other imaging techniques. PMID- 23675315 TI - Impact of structural aberrancy of polysialic acid and its synthetic enzyme ST8SIA2 in schizophrenia. AB - Psychiatric disorders are a group of human diseases that impair higher cognitive functions. Whole-genomic analyses have recently identified susceptibility genes for several psychiatric disorders, including schizophrenia. Among the genes reported to be involved in psychiatric disorders, a gene encoding a polysialyltransferase involved in the biosynthesis of polysialic acid (polySia or PSA) on cell surfaces has attracted attention for its potential role in emotion, learning, memory, circadian rhythm, and behaviors. PolySia is a unique polymer that spatio-temporally modifies neural cell adhesion molecule (NCAM) and is predominantly found in embryonic brains, although it persists in areas of the adult brain where neural plasticity, remodeling of neural connections, or neural generation is ongoing, such as the hippocampus, subventricular zone (SVZ), thalamus, prefrontal cortex, and amygdala. PolySia is thought to be involved in the regulation of cell-cell interactions; however, recent evidence suggests that it is also involved in the functional regulation of ion channels and neurologically active molecules, such as Brain-derived neurotrophic factor (BDNF), FGF2, and dopamine (DA) that are deeply involved in psychiatric disorders. In this review, the possible involvement of polysialyltransferase (ST8SIA2/ST8SiaII/STX/Siat8B) and its enzymatic product, polySia, in schizophrenia is discussed. PMID- 23675316 TI - A novel DNA-binding feature of MeCP2 contributes to Rett syndrome. PMID- 23675317 TI - Long-term fluoxetine treatment induces input-specific LTP and LTD impairment and structural plasticity in the CA1 hippocampal subfield. AB - Antidepressant drugs are usually administered for several weeks for the treatment of major depressive disorder. However, they are also prescribed in several additional psychiatric conditions as well as during long-term maintenance treatments. Antidepressants induce adaptive changes in several forebrain structures which include modifications at glutamatergic synapses. We recently found that repetitive administration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine to naive adult male rats induced an increase of mature, mushroom-type dendritic spines in several forebrain regions. This was associated with an increase of GluA2-containing alpha-amino-3-hydroxy-5 methylisoxazole-4-propionate receptors (AMPA-Rs) in telencephalic postsynaptic densities. To unravel the functional significance of such a synaptic re arrangement, we focused on glutamate neurotransmission in the hippocampus. We evaluated the effect of four weeks of 0.7 mg/kg fluoxetine on long-term potentiation (LTP) and long-term depression (LTD) in the CA1 hippocampal subfield. Recordings in hippocampal slices revealed profound deficits in LTP and LTD at Schaffer collateral-CA1 synapses associated to increased spine density and enhanced presence of mushroom-type spines, as revealed by Golgi staining. However, the same treatment had neither an effect on spine morphology, nor on LTP and LTD at perforant path-CA1 synapses. Cobalt staining and immunohistochemical experiments revealed decreased AMPA-R Ca(2+) permeability in the stratum radiatum (s.r.) together with increased GluA2-containing Ca(2+) impermeable AMPA-Rs. Therefore, 4 weeks of fluoxetine treatment promoted structural and functional adaptations in CA1 neurons in a pathway-specific manner that were selectively associated with impairment of activity-dependent plasticity at Schaffer collateral-CA1 synapses. PMID- 23675318 TI - Neonatal citalopram exposure decreases serotonergic fiber density in the olfactory bulb of male but not female adult rats. AB - Manipulation of serotonin (5HT) during early development has been shown to induce long-lasting morphological changes within the raphe nuclear complex and serotonergic circuitry throughout the brain. Recent studies have demonstrated altered raphe-derived 5HT transporter (SERT) immunoreactive axonal expression in several cortical target sites after brief perinatal exposure to selective 5HT reuptake inhibitors such as citalopram (CTM). Since the serotonergic raphe nuclear complex projects to the olfactory bulb (OB) and perinatal 5HT disruption has been shown to disrupt olfactory behaviors, the goal of this study was to further investigate such developmental effects in the OB of CTM exposed animals. Male and female rat pups were exposed to CTM from postnatal day 8-21. After animals reach adulthood (>90 days), OB tissue sections were processed immunohistochemically for SERT antiserum. Our data revealed that the density of the SERT immunoreactive fibers decreased ~40% in the OB of CTM exposed male rats, but not female rats. Our findings support a broad and long-lasting change throughout most of the 5HT system, including the OB, after early manipulation of 5HT. Because dysfunction of the early 5HT system has been implicated in the etiology of neurodevelopmental disorders such as autism spectrum disorders (ASDs), these new findings may offer insight into the abnormal olfactory perception often noted in patients with ASD. PMID- 23675320 TI - Supraphysiological doses of performance enhancing anabolic-androgenic steroids exert direct toxic effects on neuron-like cells. AB - Anabolic-androgenic steroids (AAS) are lipophilic hormones often taken in excessive quantities by athletes and bodybuilders to enhance performance and increase muscle mass. AAS exert well known toxic effects on specific cell and tissue types and organ systems. The attention that androgen abuse has received lately should be used as an opportunity to educate both athletes and the general population regarding their adverse effects. Among numerous commercially available steroid hormones, very few have been specifically tested for direct neurotoxicity. We evaluated the effects of supraphysiological doses of methandienone and 17-alpha-methyltestosterone on sympathetic-like neuron cells. Vitality and apoptotic effects were analyzed, and immunofluorescence staining and western blot performed. In this study, we demonstrate that exposure of supraphysiological doses of methandienone and 17-alpha-methyltestosterone are toxic to the neuron-like differentiated pheochromocytoma cell line PC12, as confirmed by toxicity on neurite networks responding to nerve growth factor and the modulation of the survival and apoptosis-related proteins ERK, caspase-3, poly (ADP-ribose) polymerase and heat-shock protein 90. We observe, in contrast to some previous reports but in accordance with others, expression of the androgen receptor (AR) in neuron-like cells, which when inhibited mitigated the toxic effects of AAS tested, suggesting that the AR could be binding these steroid hormones to induce genomic effects. We also note elevated transcription of neuritin in treated cells, a neurotropic factor likely expressed in an attempt to resist neurotoxicity. Taken together, these results demonstrate that supraphysiological exposure to the AAS methandienone and 17-alpha methyltestosterone exert neurotoxic effects by an increase in the activity of the intrinsic apoptotic pathway and alterations in neurite networks. PMID- 23675319 TI - Interplay between pro-inflammatory cytokines and growth factors in depressive illnesses. AB - The development of depressive disorders had long been attributed to monoamine variations, and pharmacological treatment strategies likewise focused on methods of altering monoamine availability. However, the limited success achieved by treatments that altered these processes spurred the search for alternative mechanisms and treatments. Here we provide a brief overview concerning a possible role for pro-inflammatory cytokines and growth factors in major depression, as well as the possibility of targeting these factors in treating this disorder. The data suggest that focusing on one or another cytokine or growth factor might be counterproductive, especially as these factors may act sequentially or in parallel in affecting depressive disorders. It is also suggested that cytokines and growth factors might be useful biomarkers for individualized treatments of depressive illnesses. PMID- 23675322 TI - Visually driven chaining of elementary swim patterns into a goal-directed motor sequence: a virtual reality study of zebrafish prey capture. AB - Prey capture behavior critically depends on rapid processing of sensory input in order to track, approach, and catch the target. When using vision, the nervous system faces the problem of extracting relevant information from a continuous stream of input in order to detect and categorize visible objects as potential prey and to select appropriate motor patterns for approach. For prey capture, many vertebrates exhibit intermittent locomotion, in which discrete motor patterns are chained into a sequence, interrupted by short periods of rest. Here, using high-speed recordings of full-length prey capture sequences performed by freely swimming zebrafish larvae in the presence of a single paramecium, we provide a detailed kinematic analysis of first and subsequent swim bouts during prey capture. Using Fourier analysis, we show that individual swim bouts represent an elementary motor pattern. Changes in orientation are directed toward the target on a graded scale and are implemented by an asymmetric tail bend component superimposed on this basic motor pattern. To further investigate the role of visual feedback on the efficiency and speed of this complex behavior, we developed a closed-loop virtual reality setup in which minimally restrained larvae recapitulated interconnected swim patterns closely resembling those observed during prey capture in freely moving fish. Systematic variation of stimulus properties showed that prey capture is initiated within a narrow range of stimulus size and velocity. Furthermore, variations in the delay and location of swim triggered visual feedback showed that the reaction time of secondary and later swims is shorter for stimuli that appear within a narrow spatio-temporal window following a swim. This suggests that the larva may generate an expectation of stimulus position, which enables accelerated motor sequencing if the expectation is met by appropriate visual feedback. PMID- 23675321 TI - Contextual behavior and neural circuits. AB - Animals including humans engage in goal-directed behavior flexibly in response to items and their background, which is called contextual behavior in this review. Although the concept of context has long been studied, there are differences among researchers in defining and experimenting with the concept. The current review aims to provide a categorical framework within which not only the neural mechanisms of contextual information processing but also the contextual behavior can be studied in more concrete ways. For this purpose, we categorize contextual behavior into three subcategories as follows by considering the types of interactions among context, item, and response: contextual response selection, contextual item selection, and contextual item-response selection. Contextual response selection refers to the animal emitting different types of responses to the same item depending on the context in the background. Contextual item selection occurs when there are multiple items that need to be chosen in a contextual manner. Finally, when multiple items and multiple contexts are involved, contextual item-response selection takes place whereby the animal either chooses an item or inhibits such a response depending on item-context paired association. The literature suggests that the rhinal cortical regions and the hippocampal formation play key roles in mnemonically categorizing and recognizing contextual representations and the associated items. In addition, it appears that the fronto-striatal cortical loops in connection with the contextual information-processing areas critically control the flexible deployment of adaptive action sets and motor responses for maximizing goals. We suggest that contextual information processing should be investigated in experimental settings where contextual stimuli and resulting behaviors are clearly defined and measurable, considering the dynamic top-down and bottom-up interactions among the neural systems for contextual behavior. PMID- 23675323 TI - Frequency response areas in the inferior colliculus: nonlinearity and binaural interaction. AB - The tuning, binaural properties, and encoding characteristics of neurons in the central nucleus of the inferior colliculus (CNIC) were investigated to shed light on nonlinearities in the responses of these neurons. Results were analyzed for three types of neurons (I, O, and V) in the CNIC of decerebrate cats. Rate responses to binaural stimuli were characterized using a 1st- plus 2nd-order spectral integration model. Parameters of the model were derived using broadband stimuli with random spectral shapes (RSS). This method revealed four characteristics of CNIC neurons: (1) Tuning curves derived from broadband stimuli have fixed (i. e., level tolerant) bandwidths across a 50-60 dB range of sound levels; (2) 1st-order contralateral weights (particularly for type I and O neurons) were usually larger in magnitude than corresponding ipsilateral weights; (3) contralateral weights were more important than ipsilateral weights when using the model to predict responses to untrained noise stimuli; and (4) 2nd-order weight functions demonstrate frequency selectivity different from that of 1st order weight functions. Furthermore, while the inclusion of 2nd-order terms in the model usually improved response predictions related to untrained RSS stimuli, they had limited impact on predictions related to other forms of filtered broadband noise [e. g., virtual-space stimuli (VS)]. The accuracy of the predictions varied considerably by response type. Predictions were most accurate for I neurons, and less accurate for O and V neurons, except at the lowest stimulus levels. These differences in prediction performance support the idea that type I, O, and V neurons encode different aspects of the stimulus: while type I neurons are most capable of producing linear representations of spectral shape, type O and V neurons may encode spectral features or temporal stimulus properties in a manner not easily explained with the low-order model. Supported by NIH grant DC00115. PMID- 23675324 TI - Broca's area and its striatal and thalamic connections: a diffusion-MRI tractography study. AB - In the recent decades structural connectivity between Broca's area and the basal ganglia has been postulated in the literature, though no direct evidence of this connectivity has yet been presented. The current study investigates this connectivity using a novel diffusion-weighted imaging (DWI) fiber tracking method in humans in vivo. Our findings suggest direct connections between sub-regions of Broca's area and the anterior one-third of the putamen, as well as the ventral anterior nucleus of the thalamus. Thus, we are the first to provide a detailed account of inferred circuitry involving basal ganglia, thalamus, and Broca's area, which would be a prerequisite to substantiate their support of language processing. PMID- 23675325 TI - Postnatal development of cerebellar zones revealed by neurofilament heavy chain protein expression. AB - The cerebellum is organized into parasagittal zones that control sensory-motor behavior. Although the architecture of adult zones is well understood, very little is known about how zones emerge during development. Understanding the process of zone formation is an essential step toward unraveling how circuits are constructed to support specific behaviors. Therefore, we focused this study on postnatal development to determine the spatial and temporal changes that establish zonal patterns during circuit formation. We used a combination of wholemount and tissue section immunohistochemistry in mice to show that the cytoskeletal protein neurofilament heavy chain (NFH) is a robust marker for postnatal cerebellar zonal patterning. The patterned expression of NFH is initiated shortly after birth, and compared to the domains of several known zonal markers such as zebrin II, HSP25, neurogranin, and phospholipase Cbeta4 (PLCbeta4), NFH does not exhibit transient expression patterns that are typically remodeled between stages, and the adult zones do not emerge after a period of uniform expression in all lobules. Instead, we found that throughout postnatal development NFH gradually reveals distinct zones in each cerebellar lobule. The boundaries of individual NFH zones sharpen over time, as zones are refined during the second and third weeks after birth. Double labeling with neurogranin and PLCbeta4 further revealed that although the postnatal expression of NFH is spatially and temporally unique, its pattern of zones respects a fundamental and well-known molecular topography in the cerebellum. The dynamics of NFH expression support the hypothesis that adult circuits are derived from an embryonic map that is refined into zones during the first 3-weeks of life. PMID- 23675326 TI - Relationship between postural control and restricted, repetitive behaviors in autism spectrum disorders. AB - Restricted, repetitive behaviors (RRBs) are one of the core diagnostic criteria of autism spectrum disorders (ASD), and include simple repetitive motor behaviors and more complex cognitive behaviors, such as compulsions and restricted interests. In addition to the core symptoms, impaired movement is often observed in ASD. Research suggests that the postural system in individuals with ASD is immature and may never reach adult levels. RRBs have been related to postural sway in individuals with mental retardation. Our goals were to determine whether subjects with ASD had greater postural sway and whether RBS-R scores were related to the magnitude of postural sway. We compared the center of pressure (COP) sway area during quiet stance with scores on the Repetitive Behavior Scale-Revised (RBS-R) in children with ASD and typically developing (TD) controls ages 3-16. All subjects had Non-verbal IQ > 70. Subjects performed four quiet stance trials at a self-selected stance width for 20 s. Subjects with ASD had greater postural sway area compared to controls. Not surprisingly, subjects with ASD exhibited greater frequencies and intensities of RRBs overall and on all six subscales. Further, there was a positive correlation between postural sway area and presence of RRBs. Interestingly, results of the postural sway area for the ASD group suggests that roughly half of the ASD subjects scored comparable to TD controls, whereas the other half scored >2 SD worse. Motor impaired children did not have significantly worse IQ scores, but were younger and had more RRBs. Results support previous findings of relationships between RRBs and postural control. It appears that motor control impairments may characterize a subset of individuals with ASD. Better delineation of motor control abilities in individuals with ASD will be important to help explain variations of abilities in ASD, inform treatment, and guide examination of underlying neural involvement in this very diverse disorder. PMID- 23675328 TI - Cognitive functions of the posterior parietal cortex. PMID- 23675327 TI - Using diffusion anisotropy to characterize neuronal morphology in gray matter: the orientation distribution of axons and dendrites in the NeuroMorpho.org database. AB - Accurate mathematical modeling is integral to the ability to interpret diffusion magnetic resonance (MR) imaging data in terms of cellular structure in brain gray matter (GM). In previous work, we derived expressions to facilitate the determination of the orientation distribution of axonal and dendritic processes from diffusion MR data. Here we utilize neuron reconstructions available in the NeuroMorpho database (www.neuromorpho.org) to assess the validity of the model we proposed by comparing morphological properties of the neurons to predictions based on diffusion MR simulations using the reconstructed neuron models. Initially, the method for directly determining neurite orientation distributions is shown to not depend on the line length used to quantify cylindrical elements. Further variability in neuron morphology is characterized relative to neuron type, species, and laboratory of origin. Subsequently, diffusion MR signals are simulated based on human neocortical neuron reconstructions. This reveals a bias in which diffusion MR data predict neuron orientation distributions to have artificially low anisotropy. This bias is shown to arise from shortcomings (already at relatively low diffusion weighting) in the Gaussian approximation of diffusion, in the presence of restrictive barriers, and data analysis methods involving higher moments of the cumulant expansion are shown to be capable of reducing the magnitude of the observed bias. PMID- 23675329 TI - Altered anxiety-related and abnormal social behaviors in rats exposed to early life seizures. AB - Neonatal seizures are the most common manifestation of neurological dysfunction in the neonate. The prognosis of neonatal seizures is highly variable, and the controversy remains whether the severity, duration, or frequency of seizures may contribute to brain damage independently of its etiology. Animal data indicates that seizures during development are associated with a high probability of long term adverse effects such as learning and memory impairment, behavioral changes and even epilepsy, which is strongly age dependent, as well as the severity, duration, and frequency of seizures. In preliminary studies, we demonstrated that adolescent male rats exposed to one-single neonatal status epilepticus (SE) episode showed social behavior impairment, and we proposed the model as relevant for studies of developmental disorders. Based on these facts, the goal of this study was to verify the existence of a persistent deficit and if the anxiety related behavior could be associated with that impairment. To do so, male Wistar rats at 9 days postnatal were submitted to a single episode of SE by pilocarpine injection (380 mg/kg, i.p.) and control animals received saline (0.9%, 0.1 mL/10 g). It was possible to demonstrate that in adulthood, animals exposed to neonatal SE displayed low preference for social novelty, anxiety-related behavior, and increased stereotyped behavior in anxiogenic environment with no locomotor activity changes. On the balance, these data suggests that neonatal SE in rodents leads to altered anxiety-related and abnormal social behaviors. PMID- 23675331 TI - Contagious scratching: shared feelings but not shared body locations. PMID- 23675330 TI - Neuroimaging resilience to stress: a review. AB - There is a high degree of intra-individual variation in how individuals respond to stress. This becomes evident when exploring the development of posttraumatic symptoms or stress-related disorders after exposure to trauma. Whether or not an individual develops posttraumatic symptoms after experiencing a traumatic event is partly dependent on a person's resilience. Resilience can be broadly defined as the dynamic process encompassing positive adaptation within the context of significant adversity. Even though research into the neurobiological basis of resilience is still in its early stages, these insights can have important implications for the prevention and treatment of stress-related disorders. Neuroimaging studies contribute to our knowledge of intra-individual variability in resilience and the development of posttraumatic symptoms or other stress related disorders. This review provides an overview of neuroimaging findings related to resilience. Structural, resting-state, and task-related neuroimaging results associated with resilience are discussed. There are a limited number of studies available and neuroimaging research of resilience is still in its infancy. The available studies point at brain circuitries involved in stress and emotion regulation, with more efficient processing and regulation associated with resilience. PMID- 23675332 TI - Spatial compression impairs prism adaptation in healthy individuals. AB - Neglect patients typically present with gross inattention to one side of space following damage to the contralateral hemisphere. While prism-adaptation (PA) is effective in ameliorating some neglect behaviors, the mechanisms involved and their relationship to neglect remain unclear. Recent studies have shown that conscious strategic control (SC) processes in PA may be impaired in neglect patients, who are also reported to show extraordinarily long aftereffects compared to healthy participants. Determining the underlying cause of these effects may be the key to understanding therapeutic benefits. Alternative accounts suggest that reduced SC might result from a failure to detect prism induced reaching errors properly either because (a) the size of the error is underestimated in compressed visual space or (b) pathologically increased error detection thresholds reduce the requirement for error correction. The purpose of this study was to model these two alternatives in healthy participants and to examine whether SC and subsequent aftereffects were abnormal compared to standard PA. Each participant completed three PA procedures within a MIRAGE mediated reality environment with direction errors recorded before, during and after adaptation. During PA, visual feedback of the reach could be compressed, perturbed by noise, or represented veridically. Compressed visual space significantly reduced SC and aftereffects compared to control and noise conditions. These results support recent observations in neglect patients, suggesting that a distortion of spatial representation may successfully model neglect and explain neglect performance while adapting to prisms. PMID- 23675333 TI - Psychosocial deprivation, executive functions, and the emergence of socio emotional behavior problems. AB - Early psychosocial deprivation can negatively impact the development of executive functions (EFs). Here we explore the impact of early psychosocial deprivation on behavioral and physiological measures (i.e., event-related potentials; ERPs) of two facets of EF, inhibitory control and response monitoring, and their associations with internalizing and externalizing outcomes in the Bucharest Early Intervention Project (BEIP; Zeanah et al., 2003). This project focuses on two groups of children placed in institutions shortly after birth and then randomly assigned in infancy to either a foster care intervention or to remain in their current institutional setting. A group of community controls was recruited for comparison. The current study assesses these children at 8-years of age examining the effects of early adversity, the potential effects of the intervention on EF and the role of EF skills in socio-emotional outcomes. Results reveal exposure to early psychosocial deprivation was associated with impaired inhibitory control on a flanker task. Children in the foster care intervention exhibited better response monitoring compared to children who remained in the institution on the error-related positivity (Pe). Moreover, among children in the foster care intervention those who exhibited larger error-related negativity (ERN) responses had lower levels of socio-emotional behavior problems. Overall, these data identify specific aspects of EF that contribute to adaptive and maladaptive socio emotional outcomes among children experiencing early psychosocial deprivation. PMID- 23675336 TI - Predicting functional outcome after stroke: the influence of neglect on basic activities in daily living. AB - One prominent deficit resulting from stroke is visuo-spatial neglect, which has been associated with slower and more attenuated recovery patterns of sensory motor impairment as well as limitations in activities of daily living (ADL). The aim of the current study was to further specify the relationship between neglect and recovery of different domains of ADL. One hundred eighty four patients were assessed with the Functional Independence Measure in the first week of inpatient rehabilitation, and again at 6, 12, and 36 months post-stroke. On average, neglect patients scored significantly lower on Self-care, Transfers, and Locomotion compared to non-neglect patients, but these differences became smaller with progress of time. Overall, no differences between groups were found for Sphincter control and Cognition. Patients with more severe neglect scored significantly lower on Self-care and Transfers compared to patients with mild neglect. During rehabilitation, it would be of importance to test for independence in ADL domains in neglect in order to define realistic treatment goals. The current findings could be taken into account in early multidisciplinary intervention planning in the sub-acute phase, to optimize regaining ADL. PMID- 23675334 TI - Structural basis of empathy and the domain general region in the anterior insular cortex. AB - Empathy is key for healthy social functioning and individual differences in empathy have strong implications for manifold domains of social behavior. Empathy comprises of emotional and cognitive components and may also be closely linked to sensorimotor processes, which go along with the motivation and behavior to respond compassionately to another person's feelings. There is growing evidence for local plastic change in the structure of the healthy adult human brain in response to environmental demands or intrinsic factors. Here we have investigated changes in brain structure resulting from or predisposing to empathy. Structural MRI data of 101 healthy adult females was analyzed. Empathy in fictitious as well as real-life situations was assessed using a validated self-evaluation measure. Furthermore, empathy-related structural effects were also put into the context of a functional map of the anterior insular cortex (AIC) determined by activation likelihood estimate (ALE) meta-analysis of previous functional imaging studies. We found that gray matter (GM) density in the left dorsal AIC correlates with empathy and that this area overlaps with the domain general region (DGR) of the anterior insula that is situated in-between functional systems involved in emotion-cognition, pain, and motor tasks as determined by our meta-analysis. Thus, we propose that this insular region where we find structural differences depending on individual empathy may play a crucial role in modulating the efficiency of neural integration underlying emotional, cognitive, and sensorimotor information which is essential for global empathy. PMID- 23675335 TI - What can we learn about emotion by studying psychopathy? AB - Psychopathy is a developmental disorder associated with core affective traits, such as low empathy, guilt, and remorse, and with antisocial and aggressive behaviors. Recent neurocognitive and neuroimaging studies of psychopathy in both institutionalized and community samples have begun to illuminate the basis of this condition, in particular the ways that psychopathy affects the experience and recognition of fear. In this review, I will consider how understanding emotional processes in psychopathy can shed light on the three questions central to the study of emotion: (1) Are emotions discrete, qualitatively distinct phenomena, or quantitatively varying phenomena best described in terms of dimensions like arousal and valence? (2) What are the brain structures involved in generating specific emotions like fear, if any? And (3) how do our own experiences of emotion pertain to our perceptions of and responses to others' emotion? I conclude that insights afforded by the study of psychopathy may provide better understanding of not only fundamental social phenomena like empathy and aggression, but of the basic emotional processes that motivate these behaviors. PMID- 23675337 TI - A Comparison between Uni- and Bilateral tDCS Effects on Functional Connectivity of the Human Motor Cortex. AB - Transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) has been shown to induce changes in motor performance and learning. Recent studies indicate that tDCS is capable of modulating widespread neural network properties within the brain. However the temporal evolution of online- and after effects of tDCS on functional connectivity (FC) within and across the stimulated motor cortices (M1) still remain elusive. In the present study, two different tDCS setups were investigated: (i) unilateral M1 tDCS (anode over right M1, cathode over the contralateral supraorbital region) and (ii) bilateral M1 tDCS (anode over right M1, cathode over left M1). In a randomized single-blinded cross over design, 12 healthy subjects underwent functional magnetic resonance imaging at rest before, during and after 20 min of either bi-, unilateral, or sham M1 tDCS. Seed-based FC analysis was used to investigate tDCS-induced changes across and within M1. We found that bilateral M1 tDCS induced (a) a decrease in interhemispheric FC during stimulation and (b) an increase in intracortical FC within right M1 after termination of the intervention. While unilateral M1 tDCS also resulted in similar effects during stimulation, no such changes could be observed after termination of tDCS. Our results provide evidence that depending on the electrode montage, tDCS acts upon a modulation of either intracortical and/or interhemispheric processing of M1. PMID- 23675340 TI - Biophysically based computational models of astrocyte ~ neuron coupling and their functional significance. PMID- 23675339 TI - Rehabilitation Interventions for Unilateral Neglect after Stroke: A Systematic Review from 1997 through 2012. AB - A systematic review of the effectiveness of rehabilitation for persons with unilateral neglect (UN) after stroke was conducted by searching the computerized databases from 1997 through 2012. Randomized controlled trials (RCTs) of neglect treatment strategies for stroke patients which used the Behavioral Inattention Test (BIT) as the primary outcome measure were eligible for inclusion. Out of 201 studies initially identified, 12 RCTs covering 277 participants were selected for analysis. All had the same weakness of low power with smaller samples and limitation in the blinding of the design. Prism Adaptation (PA) was the most commonly used intervention while continuous Theta-burst stimulation (cTBS) appeared to be a new approach. Meta-analysis showed that for immediate effects, the BIT conventional subscore had a significant and large mean effect size (ES = 0.76; 95% CI 0.28-1.23; p = 0.002) whereas the BIT total score showed a modestly significant mean ES (ES = 0.55; 95% CI 0.16-0.94; p = 0.006). No significant mean ES in sensitivity analysis was found for long-lasting effects across all BIT outcomes. PA appeared to be the most effective intervention based on the results of pooled analysis. More rigorous studies should be done on repetitive transcranial magnetic stimulation (rTMS) before it can be concluded that it is a promising treatment for UN. PMID- 23675341 TI - Distinguishing synchronous and time-varying synergies using point process interval statistics: motor primitives in frog and rat. AB - We present and apply a method that uses point process statistics to discriminate the forms of synergies in motor pattern data, prior to explicit synergy extraction. The method uses electromyogram (EMG) pulse peak timing or onset timing. Peak timing is preferable in complex patterns where pulse onsets may be overlapping. An interval statistic derived from the point processes of EMG peak timings distinguishes time-varying synergies from synchronous synergies (SS). Model data shows that the statistic is robust for most conditions. Its application to both frog hindlimb EMG and rat locomotion hindlimb EMG show data from these preparations is clearly most consistent with synchronous synergy models (p < 0.001). Additional direct tests of pulse and interval relations in frog data further bolster the support for synchronous synergy mechanisms in these data. Our method and analyses support separated control of rhythm and pattern of motor primitives, with the low level execution primitives comprising pulsed SS in both frog and rat, and both episodic and rhythmic behaviors. PMID- 23675338 TI - Vicarious motor activation during action perception: beyond correlational evidence. AB - Neurophysiological and imaging studies have shown that seeing the actions of other individuals brings about the vicarious activation of motor regions involved in performing the same actions. While this suggests a simulative mechanism mediating the perception of others' actions, one cannot use such evidence to make inferences about the functional significance of vicarious activations. Indeed, a central aim in social neuroscience is to comprehend how vicarious activations allow the understanding of other people's behavior, and this requires to use stimulation or lesion methods to establish causal links from brain activity to cognitive functions. In the present work, we review studies investigating the effects of transient manipulations of brain activity or stable lesions in the motor system on individuals' ability to perceive and understand the actions of others. We conclude there is now compelling evidence that neural activity in the motor system is critical for such cognitive ability. More research using causal methods, however, is needed in order to disclose the limits and the conditions under which vicarious activations are required to perceive and understand actions of others as well as their emotions and somatic feelings. PMID- 23675342 TI - Interfacing sensory input with motor output: does the control architecture converge to a serial process along a single channel? AB - Modular organization in control architecture may underlie the versatility of human motor control; but the nature of the interface relating sensory input through task-selection in the space of performance variables to control actions in the space of the elemental variables is currently unknown. Our central question is whether the control architecture converges to a serial process along a single channel? In discrete reaction time experiments, psychologists have firmly associated a serial single channel hypothesis with refractoriness and response selection [psychological refractory period (PRP)]. Recently, we developed a methodology and evidence identifying refractoriness in sustained control of an external single degree-of-freedom system. We hypothesize that multi segmental whole-body control also shows refractoriness. Eight participants controlled their whole body to ensure a head marker tracked a target as fast and accurately as possible. Analysis showed enhanced delays in response to stimuli with close temporal proximity to the preceding stimulus. Consistent with our preceding work, this evidence is incompatible with control as a linear time invariant process. This evidence is consistent with a single-channel serial ballistic process within the intermittent control paradigm with an intermittent interval of around 0.5 s. A control architecture reproducing intentional human movement control must reproduce refractoriness. Intermittent control is designed to provide computational time for an online optimization process and is appropriate for flexible adaptive control. For human motor control we suggest that parallel sensory input converges to a serial, single channel process involving planning, selection, and temporal inhibition of alternative responses prior to low dimensional motor output. Such design could aid robots to reproduce the flexibility of human control. PMID- 23675343 TI - Mathematical analysis and algorithms for efficiently and accurately implementing stochastic simulations of short-term synaptic depression and facilitation. AB - The release of neurotransmitter vesicles after arrival of a pre-synaptic action potential (AP) at cortical synapses is known to be a stochastic process, as is the availability of vesicles for release. These processes are known to also depend on the recent history of AP arrivals, and this can be described in terms of time-varying probabilities of vesicle release. Mathematical models of such synaptic dynamics frequently are based only on the mean number of vesicles released by each pre-synaptic AP, since if it is assumed there are sufficiently many vesicle sites, then variance is small. However, it has been shown recently that variance across sites can be significant for neuron and network dynamics, and this suggests the potential importance of studying short-term plasticity using simulations that do generate trial-to-trial variability. Therefore, in this paper we study several well-known conceptual models for stochastic availability and release. We state explicitly the random variables that these models describe and propose efficient algorithms for accurately implementing stochastic simulations of these random variables in software or hardware. Our results are complemented by mathematical analysis and statement of pseudo-code algorithms. PMID- 23675344 TI - Stimulus number, duration and intensity encoding in randomly connected attractor networks with synaptic depression. AB - Randomly connected recurrent networks of excitatory groups of neurons can possess a multitude of attractor states. When the internal excitatory synapses of these networks are depressing, the attractor states can be destabilized with increasing input. This leads to an itinerancy, where with either repeated transient stimuli, or increasing duration of a single stimulus, the network activity advances through sequences of attractor states. We find that the resulting network state, which persists beyond stimulus offset, can encode the number of stimuli presented via a distributed representation of neural activity with non-monotonic tuning curves for most neurons. Increased duration of a single stimulus is encoded via different distributed representations, so unlike an integrator, the network distinguishes separate successive presentations of a short stimulus from a single presentation of a longer stimulus with equal total duration. Moreover, different amplitudes of stimulus cause new, distinct activity patterns, such that changes in stimulus number, duration and amplitude can be distinguished from each other. These properties of the network depend on dynamic depressing synapses, as they disappear if synapses are static. Thus, short-term synaptic depression allows a network to store separately the different dynamic properties of a spatially constant stimulus. PMID- 23675345 TI - Humanoids Learning to Walk: A Natural CPG-Actor-Critic Architecture. AB - The identification of learning mechanisms for locomotion has been the subject of much research for some time but many challenges remain. Dynamic systems theory (DST) offers a novel approach to humanoid learning through environmental interaction. Reinforcement learning (RL) has offered a promising method to adaptively link the dynamic system to the environment it interacts with via a reward-based value system. In this paper, we propose a model that integrates the above perspectives and applies it to the case of a humanoid (NAO) robot learning to walk the ability of which emerges from its value-based interaction with the environment. In the model, a simplified central pattern generator (CPG) architecture inspired by neuroscientific research and DST is integrated with an actor-critic approach to RL (cpg-actor-critic). In the cpg-actor-critic architecture, least-square-temporal-difference based learning converges to the optimal solution quickly by using natural gradient learning and balancing exploration and exploitation. Futhermore, rather than using a traditional (designer-specified) reward it uses a dynamic value function as a stability indicator that adapts to the environment. The results obtained are analyzed using a novel DST-based embodied cognition approach. Learning to walk, from this perspective, is a process of integrating levels of sensorimotor activity and value. PMID- 23675346 TI - Thrombin, a mediator of cerebrovascular inflammation in AD and hypoxia. AB - Considerable evidence implicates hypoxia and vascular inflammation in Alzheimer's disease (AD). Thrombin, a multifunctional inflammatory mediator, is demonstrable in the brains of AD patients both in the vessel walls and senile plaques. Hypoxia inducible factor 1alpha (HIF-1alpha), a key regulator of the cellular response to hypoxia, is also upregulated in the vasculature of human AD brains. The objective of this study is to investigate inflammatory protein expression in the cerebrovasculature of transgenic AD mice and to explore the role of thrombin as a mediator of cerebrovascular inflammation and oxidative stress in AD and in hypoxia-induced changes in brain endothelial cells. Immunofluorescent analysis of the cerebrovasculature in AD mice demonstrates significant (p < 0.01-0.001) increases in thrombin, HIF-1alpha, interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinases (MMPs), and reactive oxygen species (ROS) compared to controls. Administration of the thrombin inhibitor dabigatran (100 mg/kg) to AD mice for 34 weeks significantly decreases expression of inflammatory proteins and ROS. Exposure of cultured brain endothelial cells to hypoxia for 6 h causes an upregulation of thrombin, HIF-1alpha, MCP-1, IL-6, and MMP2 and ROS. Treatment of endothelial cells with the dabigatran (1 nM) reduces ROS generation and inflammatory protein expression (p < 0.01-0.001). The data demonstrate that inhibition of thrombin in culture blocks the increase in inflammatory protein expression and ROS generation evoked by hypoxia. Also, administration of dabigatran to transgenic AD mice diminishes ROS levels in brain and reduces cerebrovascular expression of inflammatory proteins. Taken together, these results suggest that inhibiting thrombin generation could have therapeutic value in AD and other disorders where hypoxia, inflammation, and oxidative stress are involved. PMID- 23675347 TI - Insights into the Molecular Mechanisms Underlying Mammalian P2X7 Receptor Functions and Contributions in Diseases, Revealed by Structural Modeling and Single Nucleotide Polymorphisms. AB - The mammalian P2X7 receptors (P2X7Rs), a member of the ionotropic P2X receptor family with distinctive functional properties, play an important part in mediating extracellular ATP signaling in health and disease. A clear delineation of the molecular mechanisms underlying the key receptor properties, such as ATP binding, ion permeation, and large pore formation of the mammalian P2X7Rs, is still lacking, but such knowledge is crucial for a better understanding of their physiological functions and contributions in diseases and for development of therapeutics. The recent breakthroughs in determining the atomic structures of the zebrafish P2X4.1R in the closed and ATP-bound open states have provided the long-awaited structural information. The human P2RX7 gene is abundant with non synonymous single nucleotide polymorphisms (NS-SNPs), which generate a repertoire of human P2X7Rs with point mutations. Characterizations of the NS-SNPs identified in patients of various disease conditions and the resulting mutations have informed previously unknown molecular mechanisms determining the mammalian P2X7R functions and diseases. In this review, we will discuss the new insights into such mechanisms provided by structural modeling and recent functional and genetic linkage studies of NS-SNPs. PMID- 23675348 TI - Systemic cancer therapy: achievements and challenges that lie ahead. AB - In the last half of the century, advances in the systemic therapy of cancer, including chemotherapy, hormonal therapy, targeted therapy, and immunotherapy have been responsible for improvements in cancer related mortality in developed countries even as the population continues to age. Although such advancements have yet to benefit all cancer types, systemic therapies have led to an improvement in overall survival in both the adjuvant and metastatic setting for many cancers. With the pressure to make therapies available as soon as possible, the side-effects of systemic therapies, in particular long-term side-effects are not very well characterized and understood. Increasingly, a number of cancer types are requiring long-term and even lifelong systemic therapy. This is true for both younger and older patients with cancer and has important implications for each subset. Younger patients have an overall greater expected life-span, and as a result may suffer a greater variety of treatment related complications in the long-term, whereas older patients may develop earlier side-effects as a result of their frailty. Because the incidence of cancer in the world will increase over the next several decades and there will be more people living with cancer, it is important to have an understanding of the potential side-effects of new systemic therapies. As an introductory article, in this review series, we begin by describing some of the major advances made in systemic cancer therapy along with some of their known side-effects and we also make an attempt to describe the future of systemic cancer therapy. PMID- 23675349 TI - Therapy's Shadow: A Short History of the Study of Resistance to Cancer Chemotherapy. AB - This article traces the history of research on resistance to drug therapy in oncology using scientometric techniques and qualitative analysis. Using co citation analysis, we generate maps to visualize subdomains in resistance research in two time periods, 1975-1990 and 1995-2010. These maps reveal two historical trends in resistance research: first, a shift in focus from generic mechanisms of resistance to chemotherapy to a focus on resistance to targeted therapies and molecular mechanisms of oncogenesis; and second, a movement away from an almost exclusive reliance on animal and cell models and toward the generation of knowledge about resistance through clinical trial work. A close reading of highly cited articles within each subdomain cluster reveals specific points of transition from one regime to the other, in particular the failure of several promising theories of resistance to be translated into clinical insights and the emergence of interest in resistance to a new generation of targeted agents such as imatinib and trastuzumab. We argue that the study of resistance in the oncology field has thus become more integrated with research into cancer therapy - rather than constituting it as a separate domain of study, as it has done in the past, contemporary research treats resistance as the flip side to treatment, as therapy's shadow. PMID- 23675350 TI - Promises and pitfalls of a Pannexin1 transgenic mouse line. AB - Gene targeting strategies have become a powerful technology for elucidating mammalian gene function. The recently generated knockout (KO)-first strategy produces a KO at the RNA processing level and also allows for the generation of conditional KO alleles by combining FLP/FRT and Cre/loxP systems, thereby providing high flexibility in gene manipulation. However, this multipurpose KO first cassette might produce hypomorphic rather than complete KOs if the RNA processing module is bypassed. Moreover, the generation of a conditional phenotype is also dependent on specific activity of Cre recombinase. Here, we report the use of an efficient molecular biological approach to test pannexin1 (Panx1) mRNA expression in global and conditional Panx1 KO mice derived from the KO-first mouse line, Panx1(tm1a(KOMP)Wtsi). Using qRT-PCR, we demonstrate that tissues from wild-type (WT) mice show a range of Panx1 mRNA expression levels, with highest expression in trigeminal ganglia, bladder and spleen. Unexpectedly, we found that in mice homozygous for the KO-first allele, Panx1 mRNA expression is not abolished but reduced by 70% compared to that of WT tissues. Thus, Panx1 KO-first mice present a hypomorphic phenotype. Crosses of Panx1 KO-first with FLP deleter mice generated Panx1(f/f) mice. Further crosses of the latter mice with mGFAP-Cre or NFH-Cre mice were used to generate astrocyte- and neuron-specific Panx1 deletions, respectively. A high incidence of ectopic Cre expression was found in offspring of both types of conditional Panx1 KO mice. Our study demonstrates that Panx1 expression levels in the global and conditional Panx1 KO mice derived from KO-first mouse lines must be carefully characterized to ensure modulation of Panx1 gene expression. The precise quantitation of Panx1 expression and its relation to function is expected to provide a foundation for future efforts aimed at deciphering the role of Panx1 under physiological and pathological conditions. PMID- 23675352 TI - Flexible echolocation behavior of trawling bats during approach of continuous or transient prey cues. AB - Trawling bats use echolocation not only to detect and classify acoustically continuous cues originated from insects at and above water surfaces, but also to detect small water-dwelling prey items breaking the water surface for a very short time, producing only transient cues to be perceived acoustically. Generally, bats need to adjust their echolocation behavior to the specific task on hand, and because of the diversity of prey cues they use in hunting, trawling bats should be highly flexible in their echolocation behavior. We studied the adaptations in the behavior of Noctilio leporinus when approaching either a continuous cue or a transient cue that disappeared during the approach of the bat. Normally the bats reacted by dipping their feet in the water at the cue location. We found that the bats typically started to adapt their calling behavior at approximately 410 ms before prey contact in continuous cue trials, but were also able to adapt their approach behavior to stimuli onsets as short as 177 ms before contact, within a minimum reaction time of 50.9 ms in response to transient cues. In both tasks the approach phase ended between 32 and 53 ms before prey contact. Call emission always continued after the end of the approach phase until around prey contact. In some failed capture attempts, call emission did not cease at all after prey contact. Probably bats used spatial memory to dip at the original location of the transient cue after its disappearance. The duration of the pointed dips was significantly longer in transient cue trials than in continuous cue trials. Our results suggest that trawling bats possess the ability to modify their generally rather stereotyped echolocation behavior during approaches within very short reaction times depending on the sensory information available. PMID- 23675353 TI - Cold exposure enhances fat utilization but not non-esterified fatty acids, glycerol or catecholamines availability during submaximal walking and running. AB - Cold exposure modulates the use of carbohydrates (CHOs) and fat during exercise. This phenomenon has mostly been observed in controlled cycling studies, but not during walking and running when core temperature and oxygen consumption are controlled, as both may alter energy metabolism. This study aimed at examining energy substrate availability and utilization during walking and running in the cold when core temperature and oxygen consumption are maintained. Ten lightly clothed male subjects walked or ran for 60-min, at 50% and 70% of maximal oxygen consumption, respectively, in a climatic chamber set at 0 degrees C or 22 degrees C. Thermal, cardiovascular, and oxidative responses were measured every 15-min during exercise. Blood samples for serum non-esterified fatty acids (NEFAs), glycerol, glucose, beta-hydroxybutyrate (BHB), plasma catecholamines, and serum lipids were collected immediately prior, and at 30- and 60-min of exercise. Skin temperature strongly decreased while core temperature did not change during cold trials. Heart rate (HR) was also lower in cold trials. A rise in fat utilization in the cold was seen through lower respiratory quotient (RQ) (-0.03 +/- 0.02), greater fat oxidation (+0.14 +/- 0.13 g . min(-1)) and contribution of fat to total energy expenditure (+1.62 +/- 1.99 kcal . min(-1)). No differences from cold exposure were observed in blood parameters. During submaximal walking and running, a greater reliance on derived fat sources occurs in the cold, despite the absence of concurrent alterations in NEFAs, glycerol, or catecholamine concentrations. This disparity may suggest a greater reliance on intra-muscular energy sources such as triglycerides during both walking and running. PMID- 23675351 TI - The mitochondrial permeability transition pore: a mystery solved? AB - The permeability transition (PT) denotes an increase of the mitochondrial inner membrane permeability to solutes with molecular masses up to about 1500 Da. It is presumed to be mediated by opening of a channel, the permeability transition pore (PTP), whose molecular nature remains a mystery. Here I briefly review the history of the PTP, discuss existing models, and present our new results indicating that reconstituted dimers of the FOF1 ATP synthase form a channel with properties identical to those of the mitochondrial megachannel (MMC), the electrophysiological equivalent of the PTP. Open questions remain, but there is now promise that the PTP can be studied by genetic methods to solve the large number of outstanding problems. PMID- 23675355 TI - Issues in the management of acute agitation: how much current guidelines consider safety? AB - Agitated behavior constitutes up to 10% of emergency psychiatric interventions. Pharmacological tranquilization is often used as a valid treatment for agitation but a strong evidence base does not underpin it. Available literature shows different recommendations, supported by research data, theoretical considerations, or clinical experience. Rapid tranquilization (RT) is mainly based on parenteral drug treatment and the few existing guidelines on this topic, when suggesting the use of first generation antipsychotics and benzodiazepines, include drugs with questionable tolerability profile such as chlorpromazine, haloperidol, midazolam, and lorazepam. In order to systematically evaluate safety concerns related to the adoption of such guidelines, we reviewed them independently from principal diagnosis while examining tolerability data for suggested treatments. There is a growing evidence about safety profile of second generation antipsychotics for RT but further controlled studies providing definitive data in this area are urgently needed. PMID- 23675356 TI - Addiction, the concept of disorder, and pathways to harm: comment on levy. PMID- 23675354 TI - Mitochondrial dynamics in the adult cardiomyocytes: which roles for a highly specialized cell? AB - Mitochondrial dynamics is a recent topic of research in the field of cardiac physiology. The study of mechanisms involved in the morphological changes and in the mobility of mitochondria is legitimate since the adult cardiomyocytes possess numerous mitochondria which occupy at least 30% of cell volume. However, architectural constraints exist in the cardiomyocyte that limit mitochondrial movements and communication between adjacent mitochondria. Still, the proteins involved in mitochondrial fusion and fission are highly expressed in these cells and could be involved in different processes important for the cardiac function. For example, they are required for mitochondrial biogenesis to synthesize new mitochondria and for the quality-control of the organelles. They are also involved in inner membrane organization and may play a role in apoptosis. More generally, change in mitochondrial morphology can have consequences in the functioning of the respiratory chain, in the regulation of the mitochondrial permeability transition pore (MPTP), and in the interactions with other organelles. Furthermore, the proteins involved in fusion and fission of mitochondria are altered in cardiac pathologies such as ischemia/reperfusion or heart failure (HF), and appear to be valuable targets for pharmacological therapies. Thus, mitochondrial dynamics deserves particular attention in cardiac research. The present review draws up a report of our knowledge on these phenomena. PMID- 23675357 TI - Some Preliminary Notes on an Empirical Test of Freud's Theory on Depression. AB - A review of the literature indicates that empirical researchers have difficulty translating Freud's theory on depression into appropriate research questions and hypotheses. In their attempt to do so, the level of complexity in Freud's work is often lost. As a result, what is empirically tested is no more than a caricature of the original theory. To help researchers avoid such problems, this study presents a conceptual analysis of Freud's theory of depression as it is presented in Mourning and Melancholia (Freud, 1917). In analyzing Freud's theory on the etiology of depression, it is essential to differentiate between (1) an identification with the satisfying and frustrating aspects of the love object, (2) the inter- and an intrapersonal loss of the love object, and (3) conscious and unconscious dynamics. A schematic representation of the mechanism of depression is put forward and a research design by which this schema can be empirically investigated is outlined. PMID- 23675358 TI - Expressing and amplifying positive emotions facilitate goal attainment in workplace interactions. AB - Expressing emotions has social functions; it provides information, affects social interactions, and shapes relationships with others. Expressing positive emotions could be a strategic tool for improving goal attainment during social interactions at work. Such effects have been found in research on social contagion, impression management, and emotion work. However, expressing emotions one does not feel entails the risk of being perceived as inauthentic. This risk may well be worth taking when the emotions felt are negative, as expressing negative emotions usually has negative effects. When experiencing positive emotions, however, expressing them authentically promises benefits, and the advantage of amplifying them is not so obvious. We postulated that expressing, and amplifying, positive emotions would foster goal attainment in social interactions at work, particularly when dealing with superiors. Analyses are based on 494 interactions involving the pursuit of a goal by 113 employes. Multilevel analyses, including polynomial analyses, show that authentic display of positive emotions supported goal attainment throughout. However, amplifying felt positive emotions promoted goal attainment only in interactions with superiors, but not with colleagues. Results are discussed with regard to the importance of hierarchy for detecting, and interpreting, signs of strategic display of positive emotions. PMID- 23675359 TI - Contextual modulation of physiological and psychological responses triggered by emotional stimuli. AB - A series of emotional events successively occur in temporal context. The present study investigated how physiological and psychological responses are modulated by emotional context. Skin conductance response (SCR), heart rate, corrugator activity, zygomatic activity, and subjective feelings during emotional picture viewing were measured. To create an emotional context, a unpleasant or pleasant picture was preceded by three types of pictures, i.e., unpleasant, pleasant, and neutral pictures, resulting in six pairings. The results showed that viewing an unpleasant picture attenuated pleasant feelings induced by the following pleasant picture. On the other hand, preceding pleasant pictures decreased SCR to the following pictures. The effects of contextual modulation on emotional responses might be due to the informative function of pre-existing feelings; unpleasant feelings signal a threatening environment, whereas pleasant feelings signal a benign environment. With respect to facial muscle activities, viewing a pleasant picture decreased corrugator activity in response to the preceding picture. These findings suggest several types of contextual modulation effects on psychological, autonomic, and somatic responses to emotional stimuli. PMID- 23675360 TI - Prediction, postdiction, and perceptual length contraction: a bayesian low-speed prior captures the cutaneous rabbit and related illusions. AB - Illusions provide a window into the brain's perceptual strategies. In certain illusions, an ostensibly task-irrelevant variable influences perception. For example, in touch as in audition and vision, the perceived distance between successive punctate stimuli reflects not only the actual distance but curiously the inter-stimulus time. Stimuli presented at different positions in rapid succession are drawn perceptually toward one another. This effect manifests in several illusions, among them the startling cutaneous rabbit, in which taps delivered to as few as two skin positions appear to hop progressively from one position to the next, landing in the process on intervening areas that were never stimulated. Here we provide an accessible step-by-step exposition of a Bayesian perceptual model that replicates the rabbit and related illusions. The Bayesian observer optimally joins uncertain estimates of spatial location with the expectation that stimuli tend to move slowly. We speculate that this expectation a Bayesian prior - represents the statistics of naturally occurring stimuli, learned by humans through sensory experience. In its simplest form, the model contains a single free parameter, tau: a time constant for space perception. We show that the Bayesian observer incorporates both pre- and post-dictive inference. Directed spatial attention affects the prediction-postdiction balance, shifting the model's percept toward the attended location, as observed experimentally in humans. Applying the model to the perception of multi-tap sequences, we show that the low-speed prior fits perception better than an alternative, low-acceleration prior. We discuss the applicability of our model to related tactile, visual, and auditory illusions. To facilitate future model driven experimental studies, we present a convenient freeware computer program that implements the Bayesian observer; we invite investigators to use this program to create their own testable predictions. PMID- 23675362 TI - Working memory capacity: the need for process task-analysis. PMID- 23675361 TI - How Task Goals Mediate the Interplay between Perception and Action. AB - Theories of embodied cognition suppose that perception, action, and cognition are tightly intertwined and share common representations and processes. Indeed, numerous empirical studies demonstrate interaction between stimulus perception, response planning, and response execution. In this paper, we present an experiment and a connectionist model that show how the Simon effect, a canonical example of perception-action congruency, can be moderated by the (cognitive representation of the) task instruction. To date, no representational account of this influence exists. In the experiment, a two-dimensional Simon task was used, with critical stimuli being colored arrows pointing in one of four directions (backward, forward, left, or right). Participants stood on a Wii balance board, oriented diagonally toward the screen displaying the stimuli. They were either instructed to imagine standing on a snowboard or on a pair of skis and to respond to the stimulus color by leaning toward either the left or right foot. We expected that participants in the snowboard condition would encode these movements as forward or backward, resulting in a Simon effect on this dimension. This was confirmed by the results. The left-right congruency effect was larger in the ski condition, whereas the forward-backward congruency effect appeared only in the snowboard condition. The results can be readily accounted for by HiTEC, a connectionist model that aims at capturing the interaction between perception and action at the level of representations, and the way this interaction is mediated by cognitive control. Together, the empirical work and the connectionist model contribute to a better understanding of the complex interaction between perception, cognition, and action. PMID- 23675363 TI - Talking about Emotion: Prosody and Skin Conductance Indicate Emotion Regulation. AB - Talking about emotion and putting feelings into words has been hypothesized to regulate emotion in psychotherapy as well as in everyday conversation. However, the exact dynamics of how different strategies of verbalization regulate emotion and how these strategies are reflected in characteristics of the voice has received little scientific attention. In the present study, we showed emotional pictures to 30 participants and asked them to verbally admit or deny an emotional experience or a neutral fact concerning the picture in a simulated conversation. We used a 2 * 2 factorial design manipulating the focus (on emotion or facts) as well as the congruency (admitting or denying) of the verbal expression. Analyses of skin conductance response (SCR) and voice during the verbalization conditions revealed a main effect of the factor focus. SCR and pitch of the voice were lower during emotion compared to fact verbalization, indicating lower autonomic arousal. In contradiction to these physiological parameters, participants reported that fact verbalization was more effective in down-regulating their emotion than emotion verbalization. These subjective ratings, however, were in line with voice parameters associated with emotional valence. That is, voice intensity showed that fact verbalization reduced negative valence more than emotion verbalization. In sum, the results of our study provide evidence that emotion verbalization as compared to fact verbalization is an effective emotion regulation strategy. Moreover, based on the results of our study we propose that different verbalization strategies influence valence and arousal aspects of emotion selectively. PMID- 23675365 TI - Transient global amnesia and neurological events: the framingham heart study. AB - BACKGROUND/OBJECTIVE: Transient global amnesia (TGA) is a temporary amnestic syndrome characterized by lack of other focal neurological deficits. Cerebrovascular disease, migraine and seizures have been suggested as underlying mechanisms. TGA may be a risk factor for cerebrovascular or other neurological events. We studied the relation of TGA, vascular risk factors, brain magnetic resonance imaging (MRI) indices of subclinical ischemia and neurological events in a community-based sample. DESIGN/SETTING: A total of 12 TGA cases were ascertained using standard criteria by experienced neurologists, and matched to 41 stroke- and seizure-free controls. Vascular risk factors, brain MRI findings, and subsequent cerebrovascular or seizure events were compared in cases and controls. PARTICIPANTS: Framingham Heart Study (FHS) original and offspring cohort participants were included. RESULTS: No significant differences between the groups were observed in the prevalence of vascular risk factors, or brain MRI measures. Few incident stroke/transient ischemic attacks (TIA) (one event among the cases and four in controls) or subsequent seizures occurred in either group. Head CT during the acute event (n = 11) and brain MRI (n = 7) were negative for acute abnormalities. Electroencephalograms (EEG) (n = 5) were negative for epileptiform activity. Extracranial vascular studies were negative for significant stenosis in all cases. CONCLUSION: In our community-based study TGA was not related to traditional vascular risk factors, or cerebrovascular disease. However, our study is limited by small sample size and power, and larger studies are required to exclude an association. PMID- 23675364 TI - Training to improve language outcomes in cochlear implant recipients. AB - Cochlear implants (CI) have brought with them hearing ability for many prelingually deafened children. Advances in CI technology have brought not only hearing ability but speech perception to these same children. Concurrent with the development of speech perception has come spoken language development, and one goal now is that prelingually deafened CI recipient children will develop spoken language capabilities on par with those of normal hearing (NH) children. This goal has not been met purely on the basis of the technology, and many CI recipient children lag behind their NH peers with large variability in outcomes, requiring further behavioral intervention. It is likely that CI recipient children struggle to develop spoken language at NH-like levels because they have deficits in both auditory and cognitive skills that underlie the development of language. Fortunately, both the auditory and cognitive training literature indicate an improvement of auditory and cognitive functioning following training. It therefore stands to reason that if training improves the auditory and cognitive skills that support language learning, language development itself should also improve. In the present manuscript we will review the auditory and cognitive training and their potential impact on speech outcomes with an emphasis on the speech perception literature. PMID- 23675366 TI - Clinical and Demographic Features of Vertigo: Findings from the REVERT Registry. AB - INTRODUCTION: Despite being a common disease, data on vertigo management in a real-world setting are scarce. AIMS: To provide information on the vertigo and its management in a real-world setting. METHODS: Data were collected from 4,294 patients with vertigo in 13 countries over 28 months via a multi-national, non interventional observational study (the so-called REVERT registry). Data included medical history and details of anti-vertigo therapy. "Clinical global impression" (CGI) of severity (CGI-S) was assessed at baseline (V1) and then at 6 months follow-up (V2) along with CGI change (CGI-C). All variables were analyzed descriptively. RESULTS: The majority of patients were female, >40 years of age, and almost half had co-morbid cardio-vascular disease. Diagnoses were split into four categories: 37.2% "other vertigo of peripheral vestibular origin," 26.9% benign paroxysmal positional vertigo (BPPV), 20.5% "peripheral vestibular vertigo of unknown origin," and 15.4% Meniere's disease (MD). Betahistine was the most commonly prescribed therapy prior to and after enrollment, and was followed by piracetam, ginkgo biloba, and diuretics. MD had the highest proportion of betahistine treated patients. Almost half of patients were "moderately ill" at V1 based on CGI-S. At V2, patient distribution moved toward "less severe illness" (91.0% improved). The greatest improvements were in the more severely ill, and those with BPPV or "other vertigo of peripheral origin." CONCLUSION: There was a reduction in illness severity over the course of the study, some of which is likely to be due to pharmacological intervention. Further studies are needed to confirm these results. PMID- 23675367 TI - Focal Peak Activities in Spread of Interictal-Ictal Discharges in Epilepsy with Beamformer MEG: Evidence for an Epileptic Network? AB - Non-invasive studies to predict regions of seizure onset are important for planning intracranial grid locations for invasive cortical recordings prior to resective surgery for patients with medically intractable epilepsy. The neurosurgeon needs to know both the seizure onset zone (SOZ) and the region of immediate cortical spread to determine the epileptogenic zone to be resected. The immediate zone of spread may be immediately adjacent, on a nearby gyrus, in a different lobe, and sometimes even in the contralateral cerebral hemisphere. We reviewed consecutive simultaneous EEG/MEG recordings on 162 children with medically intractable epilepsy. We analyzed the MEG signals in the bandwidth 20 70 Hz with a beamformer algorithm, synthetic aperture magnetometry, at a 2.5 mm voxel spacing throughout the brain (virtual sensor locations, VSLs) with the kurtosis statistic (g 2) to determine presence of excess kurtosis (gamma2) consistent with intermittent increased high frequency spikiness of the background. The MEG time series was reconstructed (virtual sensor signals) at each of these VSLs. The VS signals were further examined with a relative peak amplitude spike detection algorithm. The time of VS spike detection was compared to the simultaneous EEG and MEG sensor signals for presence of conventional epileptiform spike morphology in the latter signals. The time of VS spike detection was compared across VSLs to determine earliest and last VSL to show a VS spike. Seven subjects showed delay in activation across VS locations detectable on visual examination. We compared the VS locations that showed earliest and later VS spikes with the locations on intracranial grid locations by electrocorticography (ECoG) that showed spikes and both onset and spread of seizures. We compared completeness of resection of VS locations to postoperative outcome. The VS locations for spike onset and spread were similar to locations for ictal onset and spread by ECoG. PMID- 23675369 TI - Activation of PAC1 Receptors in Rat Cerebellar Granule Cells Stimulates Both Calcium Mobilization from Intracellular Stores and Calcium Influx through N-Type Calcium Channels. AB - High concentrations of pituitary adenylate cyclase-activating polypeptide (PACAP) and a high density of PACAP binding sites have been detected in the developing rat cerebellum. In particular, PACAP receptors are actively expressed in immature granule cells, where they activate both adenylyl cyclase and phospholipase C. The aim of the present study was to investigate the ability of PACAP to induce calcium mobilization in cerebellar granule neurons. Administration of PACAP induced a transient, rapid, and monophasic rise of the cytosolic calcium concentration ([Ca(2+)]i), while vasoactive intestinal peptide was devoid of effect, indicating the involvement of the PAC1 receptor in the Ca(2+) response. Preincubation of granule cells with the Ca(2+) ATPase inhibitor, thapsigargin, or the d-myo-inositol 1,4,5-trisphosphate (IP3) receptor antagonist, 2 aminoethoxydiphenyl borate, markedly reduced the stimulatory effect of PACAP on [Ca(2+)]i. Furthermore, addition of the calcium chelator, EGTA, or exposure of cells to the non-selective Ca(2+) channel blocker, NiCl2, significantly attenuated the PACAP-evoked [Ca(2+)]i increase. Preincubation of granule neurons with the N-type Ca(2+) channel blocker, omega-conotoxin GVIA, decreased the PACAP induced [Ca(2+)]i response, whereas the L-type Ca(2+) channel blocker, nifedipine, and the P- and Q-type Ca(2+) channel blocker, omega-conotoxin MVIIC, had no effect. Altogether, these findings indicate that PACAP, acting through PAC1 receptors, provokes an increase in [Ca(2+)]i in granule neurons, which is mediated by both mobilization of calcium from IP3-sensitive intracellular stores and activation of N-type Ca(2+) channel. Some of the activities of PACAP on proliferation, survival, migration, and differentiation of cerebellar granule cells could thus be mediated, at least in part, through these intracellular and/or extracellular calcium fluxes. PMID- 23675370 TI - Abnormal fermentations in table-olive processing: microbial origin and sensory evaluation. AB - The process of transformation of table olives from tree to table is the result of complex biochemical reactions that are determined by the interactions between the indigenous microflora of the olives, together with a variety of contaminating microrganisms from different sources [fiber-glass fermenters, polyvinyl chloride (PVC) tanks, pipelines, pumps, and water], with the compositional characteristics of the fruit. One of the most important aspects of improving the quality of table olives is the use of selected microorganisms to drive the fermentation. These can supplant the indigenous microflora and, in particular, the complementary microflora that are responsible for spoilage of canned olives. In this context, from a technological point of view, a well-characterized collection of microrganisms (lactic acid bacteria, yeast) that can be isolated from the matrix to be processed (the olive fruit) will provide the basis for the development of starter culture systems. These cultures can be fully compatible with the typical products and will guarantee high quality standards. Inoculation of the brine with such selected starter cultures will reduce the probability of spoilage, and help to achieve an improved and more predictable fermentation process. Control of the fermentation processes can thus occur through chemical, chemico-physical and microbiological approaches, and since 2008, also through organoleptic evaluation (COI/OT/MO/Doc. No 1. Method for the sensory analysis of table olives). This last has established the necessary criteria and procedures for sensory analysis of the negative, gustatory and kinaesthetic sensations of table olives, which can also be attributed to abnormal proliferation of microrganisms. It also sets out the system for commercial classification, through assessment of the median of the defect predominantly perceived. PMID- 23675372 TI - Links between metabolic plasticity and functional redundancy in freshwater bacterioplankton communities. AB - Metabolic plasticity and functional redundancy are fundamental properties of microbial communities, which shape their response to environmental forcing, and also mediate the relationship between community composition and function. Yet, the actual quantification of these emergent community properties has been elusive, and we thus do not know how they vary across bacterial communities, and their relationship to environmental gradients and to each other. Here we present an experimental framework that allows us to simultaneously quantify metabolic plasticity and functional redundancy in freshwater bacterioplankton communities, and to explore connections that may exists between them. We define metabolic plasticity as the rate of change in single-cell properties (cell wall integrity, cell size, single-cell activity) relative to changes in community composition. Likewise, we define functional redundancy as the rate of change in carbon substrate uptake capacities relative to changes in community composition. We assessed these two key community attributes in transplant experiments where bacterioplankton from various aquatic habitats within the same watershed were transplanted from their original water to waters from other systems that differ in their main resources. Our results show that metabolic plasticity is an intrinsic property of bacterial communities, whereas the expression of functional redundancy appears to be more dependent on environmental factors. Furthermore, there was an overall strong positive relationship between the level of functional redundancy and of metabolic plasticity, suggesting no trade-offs between these community attributes but rather a possible co-selection. The apparent continuum in the expression of both functional redundancy and plasticity among bacterial communities and the link between them, in turn suggest that the link between community diversity and function may also vary along a continuum, from being very tight, to being weak, or absent. PMID- 23675368 TI - Mechanisms of obesity-induced inflammation and insulin resistance: insights into the emerging role of nutritional strategies. AB - Obesity and associated chronic inflammation initiate a state of insulin resistance (IR). The secretion of chemoattractants such as MCP-1 and MIF and of cytokines IL-6, TNF-alpha, and IL-1beta, draw immune cells including dendritic cells, T cells, and macrophages into adipose tissue (AT). Dysfunctional AT lipid metabolism leads to increased circulating free fatty acids, initiating inflammatory signaling cascades in the population of infiltrating cells. A feedback loop of pro-inflammatory cytokines exacerbates this pathological state, driving further immune cell infiltration and cytokine secretion and disrupts the insulin signaling cascade. Disruption of normal AT function is causative of defects in hepatic and skeletal muscle glucose homeostasis, resulting in systemic IR and ultimately the development of type 2 diabetes. Pharmaceutical strategies that target the inflammatory milieu may have some potential; however there are a number of safety concerns surrounding such pharmaceutical approaches. Nutritional anti-inflammatory interventions could offer a more suitable long-term alternative; whilst they may be less potent than some pharmaceutical anti inflammatory agents, this may be advantageous for long-term therapy. This review will investigate obese AT biology, initiation of the inflammatory, and insulin resistant environment; and the mechanisms through which dietary anti-inflammatory components/functional nutrients may be beneficial. PMID- 23675373 TI - Molecular determinants of regulatory T cell development: the essential roles of epigenetic changes. AB - Regulatory T (Treg) cells constitute a distinct T cell subset, which plays a key role in immune tolerance and homeostasis. The transcription factor Foxp3 controls a substantial part of Treg cell development and function. Yet its expression alone is insufficient for conferring developmental and functional characteristics of Treg cells. There is accumulating evidence that concurrent induction of Treg specific epigenetic changes and Foxp3 expression is crucial for lineage specification and functional stability of Treg cells. This review discusses recent progress in our understanding of molecular features of Treg cells, in particular, the molecular basis of how a population of developing T cells is driven to the Treg cell lineage and how its function is stably maintained. PMID- 23675371 TI - A brief multi-disciplinary review on antimicrobial resistance in medicine and its linkage to the global environmental microbiota. AB - The discovery and introduction of antimicrobial agents to clinical medicine was one of the greatest medical triumphs of the 20th century that revolutionized the treatment of bacterial infections. However, the gradual emergence of populations of antimicrobial-resistant pathogenic bacteria resulting from use, misuse, and abuse of antimicrobials has today become a major global health concern. Antimicrobial resistance (AMR) genes have been suggested to originate from environmental bacteria, as clinically relevant resistance genes have been detected on the chromosome of environmental bacteria. As only a few new antimicrobials have been developed in the last decade, the further evolution of resistance poses a serious threat to public health. Urgent measures are required not only to minimize the use of antimicrobials for prophylactic and therapeutic purposes but also to look for alternative strategies for the control of bacterial infections. This review examines the global picture of antimicrobial resistance, factors that favor its spread, strategies, and limitations for its control and the need for continuous training of all stake-holders i.e., medical, veterinary, public health, and other relevant professionals as well as human consumers, in the appropriate use of antimicrobial drugs. PMID- 23675375 TI - Lectin receptor kinases in plant innate immunity. AB - A key feature of innate immunity is the ability to recognize and respond to potential pathogens in a highly sensitive and specific manner. In plants, the first layer of defense is induced after recognition by pattern recognition receptors of microbe-associated molecular patterns. This recognition elicits a defense program known as pattern-triggered immunity. Pathogen entry into host tissue is a critical early step in causing infection. For foliar bacterial pathogens, natural surface openings such as stomata, are important entry sites. Stomata in contact with bacteria rapidly close and can thus restrict bacterial entry into leaves. The molecular mechanisms regulating stomatal closure upon pathogen perception are not yet well-understood. Plant lectin receptor kinases are thought to play crucial roles during development and in the adaptive response to various stresses. Although the function of most plant lectin receptor kinases is still not clear, a role for this kinase family in plant innate immunity is emerging. Here, we summarize recent progresses in the identification of lectin receptor kinases involved in plant innate immunity. We also discuss the role of lectin receptor kinases in stomatal innate immunity signaling. PMID- 23675374 TI - When Aging Reaches CD4+ T-Cells: Phenotypic and Functional Changes. AB - Beyond midlife, the immune system shows aging features and its defensive capability becomes impaired, by a process known as immunosenescence that involves many changes in the innate and adaptive responses. Innate immunity seems to be better preserved globally, while the adaptive immune response exhibits profound age-dependent modifications. Elderly people display a decline in numbers of naive T-cells in peripheral blood and lymphoid tissues, while, in contrast, their proportion of highly differentiated effector and memory T-cells, such as the CD28(null) T-cells, increases markedly. Naive and memory CD4+ T-cells constitute a highly dynamic system with constant homeostatic and antigen-driven proliferation, influx, and loss of T-cells. Thymic activity dwindles with age and essentially ceases in the later decades of life, severely constraining the generation of new T-cells. Homeostatic control mechanisms are very effective at maintaining a large and diverse subset of naive CD4+ T-cells throughout life, but although later than in CD8 + T-cell compartment, these mechanisms ultimately fail with age. PMID- 23675376 TI - Mitochondrial Genome Sequence of the Legume Vicia faba. AB - The number of plant mitochondrial genomes sequenced exceeds two dozen. However, for a detailed comparative study of different phylogenetic branches more plant mitochondrial genomes should be sequenced. This article presents sequencing data and comparative analysis of mitochondrial DNA (mtDNA) of the legume Vicia faba. The size of the V. faba circular mitochondrial master chromosome of cultivar Broad Windsor was estimated as 588,000 bp with a genome complexity of 387,745 bp and 52 conservative mitochondrial genes; 32 of them encoding proteins, 3 rRNA, and 17 tRNA genes. Six tRNA genes were highly homologous to chloroplast genome sequences. In addition to the 52 conservative genes, 114 unique open reading frames (ORFs) were found, 36 without significant homology to any known proteins and 29 with homology to the Medicago truncatula nuclear genome and to other plant mitochondrial ORFs, 49 ORFs were not homologous to M. truncatula but possessed sequences with significant homology to other plant mitochondrial or nuclear ORFs. In general, the unique ORFs revealed very low homology to known closely related legumes, but several sequence homologies were found between V. faba, Beta vulgaris, Nicotiana tabacum, Vitis vinifera, and even the monocots Oryza sativa and Zea mays. Most likely these ORFs arose independently during angiosperm evolution (Kubo and Mikami, 2007; Kubo and Newton, 2008). Computational analysis revealed in total about 45% of V. faba mtDNA sequence being homologous to the Medicago truncatula nuclear genome (more than to any sequenced plant mitochondrial genome), and 35% of this homology ranging from a few dozen to 12,806 bp are located on chromosome 1. Apparently, mitochondrial rrn5, rrn18, rps10, ATP synthase subunit alpha, cox2, and tRNA sequences are part of transcribed nuclear mosaic ORFs. PMID- 23675377 TI - Conserved Non-Coding Sequences are Associated with Rates of mRNA Decay in Arabidopsis. AB - Steady-state mRNA levels are tightly regulated through a combination of transcriptional and post-transcriptional control mechanisms. The discovery of cis acting DNA elements that encode these control mechanisms is of high importance. We have investigated the influence of conserved non-coding sequences (CNSs), DNA patterns retained after an ancient whole genome duplication event, on the breadth of gene expression and the rates of mRNA decay in Arabidopsis thaliana. The absence of CNSs near alpha duplicate genes was associated with a decrease in breadth of gene expression and slower mRNA decay rates while the presence CNSs near alpha duplicates was associated with an increase in breadth of gene expression and faster mRNA decay rates. The observed difference in mRNA decay rate was fastest in genes with CNSs in both non-transcribed and transcribed regions, albeit through an unknown mechanism. This study supports the notion that some Arabidopsis CNSs regulate the steady-state mRNA levels through post transcriptional control mechanisms and that CNSs also play a role in controlling the breadth of gene expression. PMID- 23675378 TI - Phloem RNA-binding proteins as potential components of the long-distance RNA transport system. AB - RNA-binding proteins (RBPs) govern a myriad of different essential processes in eukaryotic cells. Recent evidence reveals that apart from playing critical roles in RNA metabolism and RNA transport, RBPs perform a key function in plant adaptation to various environmental conditions. Long-distance RNA transport occurs in land plants through the phloem, a conducting tissue that integrates the wide range of signaling pathways required to regulate plant development and response to stress processes. The macromolecules in the phloem pathway vary greatly and include defense proteins, transcription factors, chaperones acting in long-distance trafficking, and RNAs (mRNAs, siRNAs, and miRNAs). How these RNA molecules translocate through the phloem is not well understood, but recent evidence indicates the presence of translocatable RBPs in the phloem, which act as potential components of long-distance RNA transport system. This review updates our knowledge on the characteristics and functions of RBPs present in the phloem. PMID- 23675379 TI - Iron-biofortification in rice by the introduction of three barley genes participated in mugineic acid biosynthesis with soybean ferritin gene. AB - Iron deficiency is a serious problem around the world, especially in developing countries. The production of iron-biofortified rice will help ameliorate this problem. Previously, expression of the iron storage protein, ferritin, in rice using an endosperm-specific promoter resulted in a two-fold increase in iron concentration in the resultant transgenic seeds. However, further over expression of ferritin did not produce an additional increase in the seed iron concentration, and symptoms of iron deficiency were noted in the leaves of the transgenic plants. In the present study, we aimed to further increase the iron concentration in rice seeds without increasing the sensitivity to iron deficiency by enhancing the uptake and transport of iron via a ferric iron chelator, mugineic acid. To this end, we introduced the soybean ferritin gene (SoyferH2) driven by two endosperm-specific promoters, along with the barley nicotianamine synthase gene (HvNAS1), two nicotianamine aminotransferase genes (HvNAAT-A and B), and a mugineic acid synthase gene (IDS3) to enhance mugineic acid production in rice plants. A marker-free vector was utilized as a means of increasing public acceptance. Representative lines were selected from 102 transformants based on the iron concentration in polished seeds and ferritin accumulation in the seeds. These lines were grown in both commercially supplied soil (iron-sufficient conditions) and calcareous soil (iron-deficient conditions). Lines expressing both ferritin and mugineic acid biosynthetic genes showed signs of iron deficiency tolerance in calcareous soil. The iron concentration in polished T3 seeds was increased by 4 and 2.5 times, as compared to that in non-transgenic lines grown in normal and calcareous soil, respectively. These results indicate that the concomitant introduction of the ferritin gene and mugineic acid biosynthetic genes effectively increased the seed iron level without causing iron sensitivity under iron-limited conditions. PMID- 23675380 TI - Application of laser microdissection to identify the mycorrhizal fungi that establish arbuscules inside root cells. AB - Obligate symbiotic fungi that form arbuscular mycorrhizae (AMF; belonging to the Glomeromycota phylum) are some of the most important soil microorganisms. AMFs facilitate mineral nutrient uptake from the soil, in exchange for plant assimilated carbon, and promote water-stress tolerance and resistance to certain diseases. AMFs colonize the root by producing inter- and intra-cellular hyphae. When the fungus penetrates the inner cortical cells, it produces a complex ramified structure called arbuscule, which is considered the preferential site for nutrient exchange. Direct DNA extraction from the whole root and sequencing of ribosomal gene regions are commonly carried out to investigate intraradical AMF communities. Nevertheless, this protocol cannot discriminate between the AMFs that actively produce arbuscules and those that do not. To solve this issue, the authors have characterized the AMF community of arbusculated cells (AC) through a laser microdissection (LMD) approach, combined with sequencing-based taxa identification. The results were then compared with the AMF community that was found from whole root DNA extraction. The AMF communities originating from the LMD samples and the whole root samples differed remarkably. Five taxa were involved in the production of arbuscules, while two taxa were retrieved inside the root but not in the AC. Unexpectedly, one taxon was found in the AC, but its detection was not possible when extracting from the whole root. Thus, the LMD technique can be considered a powerful tool to obtain more precise knowledge on the symbiotically active intraradical AMF community. PMID- 23675381 TI - The determination of genetic markers of age-related cancer pathologies in populations from Kazakhstan. AB - Aging associates with a variety of pathological conditions such as cancer, cardiovascular, neurodegenerative, autoimmune diseases, and metabolic disorders. The oncogenic alterations overlap frequently with the genes linked to aging. Here, we show that several aging related genes may serve as the genetic risk factors for cervical and esophagus cancers. In our study, we analyzed samples obtained from 115 patients with esophageal and 207 patients with cervical cancer. The control groups were selected to match the ethnicity and age of cancer patients. We examined the genes involved in the processes of xenobiotics detoxification (GSTM1 and GSTT1), DNA repair (XRCC1 and XRCC3), and cell cycle regulation and apoptosis (CCND1 and TP53). Our study revealed that deletions of GSTT1 and GSTM1 genes or the distinct point mutations of XRCC1 gene are associated with cervical and esophageal cancers. These results will lead to development of screening for detection of individuals susceptible to esophageal and cervical cancers. Introduction of the screening programs will allow the early and effective preventive measures that will reduce cancer incidence and mortality in Kazakhstan. PMID- 23675383 TI - Genome-Wide Association Identifies TBX5 as Candidate Gene for Osteochondrosis Providing a Functional Link to Cartilage Perfusion as Initial Factor. AB - Osteochondrosis (OC) is an orthopedic syndrome of the joints that occurs in children and adolescents and domestic animals, particularly pigs, horses, and dogs. OC is the most frequent cause of leg weakness in rapidly growing pigs causing animal welfare issues and economic losses. In this study, a genome-wide association study (GWAS) was performed using the Porcine 60k SNPChip in animals of the breed Large White (n = 298) to identify chromosome regions and candidate genes associated with OC lesion scores. A total of 19 SNPs on chromosomes (SSC) 3, 5, 8, 10, 14, and 18 were significantly associated with OC lesion scores (p values <= 10(-5)). The SNPs MARC0098684, MARC00840086, MARC0093124, and ASGA0062794 at SSC14 36.1-38.2 Mb encompass a region of six linkage disequilibrium (LD) blocks. The most significant SNP ASGA0062794 is located in a LD block spanning 465 kb and covering the gene encoding T-box transcription factor 5 (TBX5). A SNP (c.54T > C) identified in TBX5 was significantly associated with OC lesion scores in a single-marker analysis. TBX5 c.54T > C showed highest LD with ASGA00627974 (r (2) = 0.96) and superior association with OC lesion scores over other SNPs when included in the genome scan, whereas its treatment as an additional fixed effect in the GWAS statistical model led to a drop of significance of nearby markers. Moreover, real-time PCR showed different transcript abundance of TBX5 in healthy and defect cartilage. The results imply that the association signal obtained on SCC14 is largely attributable to TBX5 c.54T > C likely to be in LD with a regulatory polymorphism of TBX5. The transcription factor TBX5 interacts with GJA5 and MEF2C both being involved in vascularization. This study provides evidence for epistatic interaction of TBX5 and MEF2C, thus supporting deficiency of blood supply to growth cartilage as being fundamental for the initiation of OC. PMID- 23675382 TI - Major channels involved in neuropsychiatric disorders and therapeutic perspectives. AB - Voltage-gated ion channels are important mediators of physiological functions in the central nervous system. The cyclic activation of these channels influences neurotransmitter release, neuron excitability, gene transcription, and plasticity, providing distinct brain areas with unique physiological and pharmacological response. A growing body of data has implicated ion channels in the susceptibility or pathogenesis of psychiatric diseases. Indeed, population studies support the association of polymorphisms in calcium and potassium channels with the genetic risk for bipolar disorders (BPDs) or schizophrenia. Moreover, point mutations in calcium, sodium, and potassium channel genes have been identified in some childhood developmental disorders. Finally, antibodies against potassium channel complexes occur in a series of autoimmune psychiatric diseases. Here we report recent studies assessing the role of calcium, sodium, and potassium channels in BPD, schizophrenia, and autism spectrum disorders, and briefly summarize promising pharmacological strategies targeted on ion channels for the therapy of mental illness and related genetic tests. PMID- 23675385 TI - Controversial report regarding seroprevalence of hepatitis B and C viruses among hemodialysis patients in kerman province, South-East iran. PMID- 23675384 TI - Hepatitis B viral DNA among HBs antigen negative healthy blood donors. AB - BACKGROUND: Presence of occult hepatitis B infection (OBI) renders HBs antigen (HBsAg) undetectable by ELISA. Therefore it is valuable to evaluate the frequency of OBI among healthy blood donors to improve and perhaps change the strategies of blood screening to reduce the risk of HBV transmission. OBJECTIVES: The aim of this study was to determine the presence of HBcAb and HBV DNA among Iranian HBsAg negative healthy blood donors who donated their blood to the Tehran Blood Transfusion Center during 2011. PATIENTS AND METHODS: 1000 serum specimens negative for HBsAg, HCV antibody and HIV antibody were collected from healthy blood donors and tested for HBcAb. Presence of hepatitis B viral DNA was checked in HBcAb positive samples by nested PCR with two sets of primers to amplify part of HBV S gene. RESULTS: There were 64 women and 936 men in the population under study. The mean +/- SD age of the donors was 38 +/- 11 years. 80 out of 1000 samples (8%) were found to be positive for HBcAb. HBV DNA was detected in 50% of HBcAb positive specimens. The mean +/- SD age of donors without HBV DNA was 37.7 +/- 10.5 years and for donors with HBV DNA was 40.9 +/- 11.2 years (P = 0.05). CONCLUSIONS: OBI was prevalent among 50% of HBcAb positive healthy blood donors. The frequency of positive HBcAb among healthy HBsAg negative blood donors was comparable to previous studies reported from Iran. On the other hand, the frequency of HBV DNA in HBsAg negative blood donors was higher than previous reports. PMID- 23675386 TI - Do we have to shift three doses of hepatitis B vaccine instead of four doses in chronic renal failure: think before action. PMID- 23675387 TI - Influence of droplet size, pH and ionic strength on endotoxin-triggered ordering transitions in liquid crystalline droplets. AB - We report an investigation of ordering transitions that are induced in water dispersed, micrometer-sized droplets of a thermotropic liquid crystal (LC) by the bacterial lipopolysaccharide endotoxin. We reveal that the ordering transitions induced by endotoxin - from a bipolar state of the droplets to a radial state - are strongly dependent on the size of the LC droplets. Specifically, as the diameters of the LC droplets increase from 2 MUm to above 10 MUm (in phosphate buffered saline with an ionic strength of 90 mM and a pH of 7.2), we measured the percentage of droplets exhibiting a radial configuration in the presence of 100 pg/mL endotoxin to decrease from 98 +/- 1 % to 3 +/- 2 %. In addition, we measured a decrease in either the ionic strength or pH of the aqueous phase to reduce the percentage of droplets exhibiting a radial configuration in the presence of endotoxin. These results, when interpreted within the context of a simple thermodynamic model that incorporates the contributions of elasticity and surface anchoring to the free energies of the LC droplets, lead us to conclude that (i) the elastic constant K24 plays a central role in determining the size dependent response of the LC droplets to endotoxin, and (ii) endotoxin-triggered ordering transitions occur only under solution conditions (pH, ionic strength) where the combined contributions of elasticity and surface anchoring to the free energies of the bipolar and radial configurations of the LC droplets are similar in magnitude. Our analysis also suggests that the presence of endotoxin perturbs the free energies of the LC droplets by ~10-17 J/droplet, which is comparable to the standard free energy of self-association of ~103 endotoxin molecules. These results, when combined with prior reports of localization of endotoxin at the center of LC droplets, are consistent with the hypothesis that self-assembly of endotoxin within micrometer-sized LC droplets provides the driving force for the ordering transitions. Overall, these results advance our understanding of ordering transitions triggered by the interactions of analytes with LC droplets and, more broadly, provide guidance to the design of LC droplet systems as the basis of stimuli-responsive soft materials. PMID- 23675405 TI - Ventral hippocampal kappa opioid receptors mediate the renewal of fear following extinction in the rat. AB - The hippocampus is part of a neural network which regulates the renewal of fear following extinction. Both the ventral (VH) and dorsal (DH) hippocampus have been shown to be necessary for renewal, however the critical receptors and neurotransmitters mediating these contributions are poorly understood. One candidate mechanism is the kappa opioid receptor (KOR) system, which has been implicated in fear learning and anxiety. Here we examined the effect of the KOR antagonist norbinaltorphamine hydrochloride (norBNI), infused into either the VH or DH, on the renewal of extinguished fear. We found that an infusion of norBNI into the VH significantly reduced the relapse of fear on test compared to that seen in saline controls (Experiment 1), while similar infusions of norBNI into the DH had no effect on renewal (Experiment 2). These findings show that hippocampal KORs are involved in fear renewal and also identify a dissociation in the contribution of VH and DH KORs to the expression of renewed fear. PMID- 23675406 TI - Intraoperative cryoprecipitate transfusion and its association with the incidence of biliary complications after liver transplantation--a retrospective cohort study. AB - BACKGROUND: Cryoprecipitate is largely used for acquired hypofibrinogenemia in the setting of massive hemorrhage in liver transplantation (LT). However, the influence of intraoperative cryoprecipitate transfusion on biliary complications (BC) after LT has not been studied in detail. STUDY DESIGN AND METHODS: In a series of 356 adult patients who received their first LT, the causes of BC were retrospectively studied by multivariate logistic regression analysis. The clinical relationship between intraoperative cryoprecipitate transfusion and BC occurrence was studied through a retrospective cohort study in patients. All patients received follow-ups for one year, and, during the follow-up period, the time of BC occurrence and liver biopsies were recorded. RESULTS: Intraoperative cryoprecipitate transfusion (RR = 3.46, 95% CI [1.72-6.97], P<0.001), cold ischemia time >8 h (RR = 4.24, 95% CI [2.28-7.92], P<0.01), and high-level Child Pugh ( RR = 1.71, 95% CI [1.11-2.63], P = 0.014) are independent risk factors to predict BC after LT according to time-to-event analysis. One year BC-free survival probability of patients received intraoperative cryoprecipitate transfusions was significantly lower when compared to the group that received no cryoprecipitate(P<0.001). Moreover, BC patients in the cryoprecipitate transfusion group owned different liver pathological feature, pathological micro thrombus formation and cholestasis were seen more often (41.4% vs 0%, 62.1% vs 12.5%, respectively) than no cryoprecipitate transfusion group. CONCLUSION: These findings suggested that intraoperative cryoprecipitate transfusion was associated with BC after LT. The mechanism of BC occurrence might involve micro-thrombus formation and immune rejection. PMID- 23675407 TI - Upregulation of miR-150* and miR-630 induces apoptosis in pancreatic cancer cells by targeting IGF-1R. AB - MicroRNAs have been implicated in many critical cellular processes including apoptosis. We have previously found that apoptosis in pancreatic cancer cells was induced by adamantyl retinoid-related (ARR) molecule 3-Cl-AHPC. Here we report that 3-Cl-AHPC-dependent apoptosis involves regulating a number of microRNAs including miR-150* and miR-630. 3-Cl-AHPC stimulated miR-150* expression and caused decreased expression of c-Myb and IGF-1R in the pancreatic cancer cells. 3 Cl-AHPC-mediated reduction of c-Myb resulted in diminished binding of c-Myb with IGF-1R and Bcl-2 promoters, thereby causing repression of their transcription and protein expression. Over-expression of miR-150* also resulted in diminished levels of c-Myb and Bcl-2 proteins. Furthermore, the addition of the miRNA inhibitor 2'-O-methylated miR-150 blocked 3-Cl-AHPC-mediated increase in miR-150* levels and abrogated loss of c-Myb protein. Knockdown of c-Myb in PANC-1 cells resulted in enhanced apoptosis both in the presence or absence of 3-Cl-AHPC confirming the anti-apoptotic property of c-Myb. Overexpression of miR-630 also induced apoptosis in the pancreatic cancer cells and inhibited target protein IGF 1R mRNA and protein expression. Together these results implicate key roles for miR-150* and miR-630 and their targeting of IGF-1R to promote apoptosis in pancreatic cancer cells. PMID- 23675408 TI - Neural basis of impaired cognitive flexibility in patients with anorexia nervosa. AB - BACKGROUND: Impaired cognitive flexibility in anorexia nervosa (AN) causes clinical problems and makes the disease hard to treat, but its neural basis has yet to be fully elucidated. The purpose of this study was to evaluate the brain activity of individuals with AN while performing a task requiring cognitive flexibility on the Wisconsin Card Sorting Test (WCST), which is one of the most frequently used neurocognitive measures of cognitive flexibility and problem solving ability. METHODS: Participants were 15 female AN patients and 15 age- and intelligence quotient-matched healthy control women. Participants completed the WCST while their brain activity was measured by functional magnetic resonance imaging during the task. Brain activation in response to set shifting error feedback and the correlation between such brain activity and set shifting performance were analyzed. RESULTS: The correct rate on the WCST was significantly poorer for AN patients than for controls. Patients showed poorer activity in the right ventrolateral prefrontal cortex and bilateral parahippocampal cortex on set shifting than controls. Controls showed a positive correlation between correct rate and ventrolateral prefrontal activity in response to set shifting whereas patients did not. CONCLUSION: These findings suggest dysfunction of the ventrolateral prefrontal cortex and parahippocampal cortex as a cause of impaired cognitive flexibility in AN patients. PMID- 23675409 TI - Habitat-associations of turban snails on intertidal and subtidal rocky reefs. AB - Patchiness of habitat has important influences on distributions and abundances of organisms. Given the increasing threat of loss and alteration of habitats due to pressures associated with humans, there is a need for ecologists to understand species' requirements for habitat and to predict changes to taxa under various future environmental conditions. This study tested hypotheses about the generality of patterns described for one species of marine intertidal turban snail for a different, yet closely-related species in subtidal habitats along the coast of New South Wales, Australia. These two closely-related species live in similar habitats, yet under quite different conditions, which provided an opportunity to investigate how similar types of habitats influence patterns of distribution, abundance and size-structure in intertidal versus subtidal environments. For each species, there were similar associations between biogenically structured habitat and densities. The intertidal species, Turbo undulates, were more abundant, with greater proportions of small individuals in habitats formed by the canopy-forming alga, Hormosira banksii, the solitary ascidian, Pyura stolonifera or the turfing red alga, Corallina officinalis compared to simple habitat (bare rock). Similarly, more Turbo torquatus were found in biogenically structured subtidal habitat, i.e. canopy-forming algae, Ecklonia radiata, mixed algal communities ('fringe'), or turfing red algae (Corallina officinalis and Amphiroa aniceps) than where habitat is simple (barrens). Small T. torquatus were more abundant in areas of turf and 'fringe', while large snails were more abundant in areas of kelp and barrens. These patterns were found at each location sampled (i.e. eight intertidal and two subtidal rocky reefs) and at all times of sampling, across each environment. This study highlighted the consistent influence of biogenically structured habitats on the distribution, abundance and size-structure of intertidal and subtidal turban snails and forms a basis for increasing the understanding of the potential underlying processes causing such patterns. PMID- 23675410 TI - An exploratory case control study of risk factors for hepatitis E in rural Bangladesh. AB - Hepatitis E virus (HEV) is the major cause of epidemic and sporadic hepatitis globally. Outbreaks are associated with fecal contamination of drinking water, yet the environmental reservoir of HEV between epidemics remains unclear. In contrast to neighboring countries, where epidemics and sporadic disease co-occur, HEV-endemic communities in rural Bangladesh seldom report outbreaks; sporadic hepatitis E is reported from urban and rural areas of the country. Besides typical enteric risk factors, other routes for HEV infection and disease are unclear. We conducted monthly household surveillance of a southern Bangladeshi community of 23,500 people to find incident cases of acute hepatitis E over a 22 month period. An algorithm was used to capture 279 candidate cases, of which 46 were confirmed acute HEV infections. An exploratory case-control study was conducted to identify putative risk factors for disease. Nearly 70% of cases were over 15 years old. Female gender seemed protective (OR:0.34) against hepatitis E in this conservative setting, as was the use of sanitary latrines (OR:0.28). Socioeconomic status or animal exposures were not significant predictors of disease, although outdoor employment and recent urban travel were. Unexpectedly, recent contact with a "jaundiced" patient and a history of injection exposure in the 3 months prior to disease (OR:15.50) were significant. Susceptible individuals from "endemic" communities share similar enteric exposure risks to those commonly associated with tourists from non-endemic countries. This study also raises the novel possibility of parenteral and person-to-person transmission of HEV in non-epidemic, sporadic disease settings. PMID- 23675411 TI - Diagnosis and interim treatment outcomes from the first cohort of multidrug resistant tuberculosis patients in Tanzania. AB - SETTING: Kibong'oto National Tuberculosis Hospital (KNTH), Kilimanjaro, Tanzania. OBJECTIVE: Characterize the diagnostic process and interim treatment outcomes from patients treated for multidrug-resistant tuberculosis (MDR-TB) in Tanzania. DESIGN: A retrospective cohort study was performed among all patients treated at KNTH for pulmonary MDR-TB between November 2009 and September 2011. RESULTS: Sixty-one culture-positive MDR-TB patients initiated therapy, 60 (98%) with a prior history of TB treatment. Forty-one (67%) were male and 9 (14%) were HIV infected with a mean CD4 count of 424 (+/-106) cells/ul. The median time from specimen collection to MDR-TB diagnosis and from diagnosis to initiation of MDR TB treatment was 138 days (IQR 101-159) and 131 days (IQR 32-233), respectively. Following treatment initiation four (7%) patients died (all HIV negative), 3 (5%) defaulted, and the remaining 54 (89%) completed the intensive phase. Most adverse drug reactions were mild to moderate and did not require discontinuation of treatment. Median time to culture conversion was 2 months (IQR 1-3) and did not vary by HIV status. In 28 isolates available for additional second-line drug susceptibility testing, fluoroquinolone, aminoglycoside and para-aminosalicylic acid resistance was rare yet ethionamide resistance was present in 9 (32%). CONCLUSION: The majority of MDR-TB patients from this cohort had survived a prolonged referral process, had multiple episodes of prior TB treatment, but did not have advanced AIDS and converted to culture negative early while completing an intensive inpatient regimen without serious adverse event. Further study is required to determine the clinical impact of second-line drug susceptibility testing and the feasibility of alternatives to prolonged hospitalization. PMID- 23675412 TI - A cryptic targeting signal creates a mitochondrial FEN1 isoform with tailed R Loop binding properties. AB - A growing number of DNA transacting proteins is found in the nucleus and in mitochondria, including the DNA repair and replication protein Flap endonuclease 1, FEN1. Here we show a truncated FEN1 isoform is generated by alternative translation initiation, exposing a mitochondrial targeting signal. The shortened form of FEN1, which we term FENMIT, localizes to mitochondria, based on import into isolated organelles, immunocytochemistry and subcellular fractionation. In vitro FENMIT binds to flap structures containing a 5' RNA flap, and prefers such substrates to single-stranded RNA. FENMIT can also bind to R-loops, and to a lesser extent to D-loops. Exposing human cells to ethidium bromide results in the generation of RNA/DNA hybrids near the origin of mitochondrial DNA replication. FENMIT is recruited to the DNA under these conditions, and is released by RNase treatment. Moreover, high levels of recombinant FENMIT expression inhibit mtDNA replication, following ethidium bromide treatment. These findings suggest FENMIT interacts with RNA/DNA hybrids in mitochondrial DNA, such as those found at the origin of replication. PMID- 23675413 TI - Stromal Claudin14-heterozygosity, but not deletion, increases tumour blood leakage without affecting tumour growth. AB - The maintenance of endothelial cell-cell junctions is vital for the control of blood vessel leakage and is known to be important in the growth and maturation of new blood vessels during angiogenesis. Here we have investigated the role of a tight junction molecule, Claudin 14, in tumour blood vessel leakage, angiogenesis and tumour growth. Using syngeneic tumour models our results showed that genetic ablation of Claudin 14 was not sufficient to affect tumour blood vessel morphology or function. However, and surprisingly, Claudin 14-heterozygous mice displayed several blood vessel-related phenotypes including: disruption of ZO-1 positive cell-cell junctions in tumour blood vessels; abnormal distribution of basement membrane laminin around tumour blood vessels; increased intratumoural leakage and decreased intratumoural hypoxia. Additionally, although total numbers of tumour blood vessels were increased in Claudin 14-heterozygous mice, and in VEGF-stimulated angiogenesis ex vivo, the number of lumenated vessels was not changed between genotypes and this correlated with no difference in syngeneic tumour growth between wild-type, Claudin 14-heterozygous and Claudin 14-null mice. Lastly, Claudin 14-heterozygosity, but not complete deficiency, also enhanced endothelial cell proliferation significantly. These data establish a new role for Claudin 14 in the regulation of tumour blood vessel integrity and angiogenesis that is evident only after the partial loss of this molecule in Claudin 14-heterozyous mice but not in Claudin 14-null mice. PMID- 23675414 TI - Rapid catalytic template searching as an enzyme function prediction procedure. AB - We present an enzyme protein function identification algorithm, Catalytic Site Identification (CatSId), based on identification of catalytic residues. The method is optimized for highly accurate template identification across a diverse template library and is also very efficient in regards to time and scalability of comparisons. The algorithm matches three-dimensional residue arrangements in a query protein to a library of manually annotated, catalytic residues--The Catalytic Site Atlas (CSA). Two main processes are involved. The first process is a rapid protein-to-template matching algorithm that scales quadratically with target protein size and linearly with template size. The second process incorporates a number of physical descriptors, including binding site predictions, in a logistic scoring procedure to re-score matches found in Process 1. This approach shows very good performance overall, with a Receiver-Operator Characteristic Area Under Curve (AUC) of 0.971 for the training set evaluated. The procedure is able to process cofactors, ions, nonstandard residues, and point substitutions for residues and ions in a robust and integrated fashion. Sites with only two critical (catalytic) residues are challenging cases, resulting in AUCs of 0.9411 and 0.5413 for the training and test sets, respectively. The remaining sites show excellent performance with AUCs greater than 0.90 for both the training and test data on templates of size greater than two critical (catalytic) residues. The procedure has considerable promise for larger scale searches. PMID- 23675415 TI - Enhanced dentin-like mineralized tissue formation by AdShh-transfected human dental pulp cells and porous calcium phosphate cement. AB - The aim of the present study was to investigate the effect of Sonic hedgehog (Shh) on human dental pulp cells (hDPCs) and the potential of complexes with Shh gene modified hDPCs and porous calcium phosphate cement (CPC) for mineralized tissue formation. hDPCs were cultured and transfected with adenoviral mediated human Shh gene (AdShh). Overexpression of Shh and cell proliferation was tested by real-time PCR analysis, western blotting analysis, and MTT analysis, respectively. The odontoblastic differentiation was assessed by alkaline phosphatase (ALP) activity and real-time PCR analysis on markers of Patched-1 (Ptc-1), Smoothened (Smo), Gli 1, Gli 2, Gli 3, osteocalcin (OCN), dentin matrix protein-1 (DMP-1), and dentin sialophosphoprotein (DSPP). Finally, AdShh transfected hDPCs were combined with porous CPC and placed subcutaneously in nude mice for 8 and 12 weeks, while AdEGFP-transfected and untransfected hDPCs were treated as control groups. Results indicated that Shh could promote proliferation and odontoblastic differentiation of hDPCs, while Shh/Gli 1 signaling pathway played a key role in this process. Importantly, more mineralized tissue formation was observed in combination with AdShh transfected hDPCs and porous CPC, moreover, the mineralized tissue exhibited dentin-like features such as structures similar to dentin-pulp complex and the positive staining for DSPP protein similar to the tooth tissue. These results suggested that the constructs with AdShh-transfected hDPCs and porous CPC might be a better alternative for dental tissue regeneration. PMID- 23675416 TI - Worldwide spread of Dengue virus type 1. AB - BACKGROUND: DENV-1 is one of the four viral serotypes that causes Dengue, the most common mosquito-borne viral disease of humans. The prevalence of these viruses has grown in recent decades and is now present in more than 100 countries. Limited studies document the spread of DENV-1 over the world despite its importance for human health. METHODOLOGY/PRINCIPAL FINDINGS: We used representative DENV-1 envelope gene sequences to unravel the dynamics of viral diffusion under a Bayesian phylogeographic approach. Data included strains from 45 distinct geographic locations isolated from 1944 to 2009. The estimated mean rate of nucleotide substitution was 6.56 * 10-4 substitutions/site/year. The larger genotypes (I, IV and V) had a distinctive phylogenetic structure and since 1990 they experienced effective population size oscillations. Thailand and Indonesia represented the main sources of strains for neighboring countries. Besides, Asia broadcast lineages into the Americas and the Pacific region that diverged in isolation. Also, a transmission network analysis revealed the pivotal role of Indochina in the global diffusion of DENV-1 and of the Caribbean in the diffusion over the Americas. CONCLUSIONS/SIGNIFICANCE: The study summarizes the spatiotemporal DENV-1 worldwide spread that may help disease control. PMID- 23675417 TI - Basolateral BMP signaling in polarized epithelial cells. AB - Bone morphogenetic proteins (BMPs) regulate various biological processes, mostly mediated by cells of mesenchymal origin. However, the roles of BMPs in epithelial cells are poorly understood. Here, we demonstrate that, in polarized epithelial cells, BMP signals are transmitted from BMP receptor complexes exclusively localized at the basolateral surface of the cell membrane. In addition, basolateral stimulation with BMP increased expression of components of tight junctions and enhanced the transepithelial resistance (TER), counteracting reduction of TER by treatment with TGF-beta or an anti-tumor drug. We conclude that BMPs maintain epithelial polarity via intracellular signaling from basolaterally localized BMP receptors. PMID- 23675418 TI - Dissecting the mechanisms of left ventricular diastolic dysfunction and inflammation in peritoneal dialysis patients. AB - OBJECTIVE: Patients with symptoms of heart failure and preserved left ventricular (LV) systolic function are commonly encountered in clinical practice especially in peritoneal dialysis (PD) patients. We hypothesized that adiposity might influence LV diastolic function through systemic inflammation in this specific group. METHODS: We designed a cross-sectional study in 173 prevalent PD patients. LV diastolic dysfunction was diagnosed by echocardiography. PD patient without LV diastolic dysfunction served as the control group. Serum inflammatory biomarkers were examined including tissue necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6). The location and amount of adipose tissue were assessed by computerized tomography (CT) at the level of the fourth lumbar vertebra. RESULTS: Subjects with LV diastolic dysfunction had higher levels of the pro-inflammation cytokines and more visceral and peritoneal fat (all P<0.001) than control subjects. A significant correlation was found between visceral adipose tissue and pro inflammatory cytokines (r = 0.70; P<0.001). Multivariable regression analysis found that the relationship between visceral adipose tissue and LV diastolic dysfunction became insignificant when either TNF-alpha or IL-6 were introduced into the model, although TNF-alpha and IL-6 were both significantly associated with LV diastolic dysfunction even after adjusting for visceral fat (OR = 1.51; 95% CI = 1.09-2.02; P = 0.033 and OR = 1.62; 95% CI = 1.09-1.82; P = 0.031, respectively). CONCLUSIONS: Larger amounts of adipose tissue were associated with higher serum pro-inflammatory levels in PD patients, which might be related to the development of LV diastolic dysfunction. Modulating inflammatory reactions in PD patients can be a useful therapeutic approach for managing LV diastolic dysfunction. PMID- 23675419 TI - Color Doppler imaging analysis of retrobulbar blood flow velocities in primary open-angle glaucomatous eyes: a meta-analysis. AB - BACKGROUND: To analyze the diagnostic value of color Doppler imaging (CDI) of blood flow in the retrobulbar vessels of eyes with primary open-angle glaucoma (POAG). METHODS: Pertinent publications were retrieved from the Cochrane Central Register of Controlled Trials, PubMed and the ISI Web of Knowledge up to October 2012. Changes in peak systolic velocity (PSV), end diastolic velocity (EDV) and resistive index (RI) of the ophthalmic artery (OA), central retinal artery (CRA) and short posterior ciliary artery (SPCA) of POAG eyes and normal controls were evaluated by CDI. Subgroup analyses were conducted according to whether patients received IOP-lowering drugs treatment and were defined as treated and untreated. RESULTS: PSV and EDV were statistically significantly reduced in the OA of POAG eyes (P = 0.0002; P<0.00001; respectively), with significant heterogeneity (P(heterogeneity)<0.00001, I2 = 94%; P(heterogeneity)<0.00001, I2 = 85%; respectively). Similar results were demonstrated for the CRA (P<0.00001; respectively) and SPCA (P = 0.005; P<0.00001; respectively), with significant heterogeneities for both the CRA (P(heterogeneity)<0.00001, I2 = 81%; P(heterogeneity)<0.00001, I2 = 98%; respectively) and the SPCA (P(heterogeneity)<0.00001, I2 = 96%; P(heterogeneity)<0.00001, I2 = 93%; respectively). Significant increases in RI were found in all retrobulbar vessels (P<0.00001; respectively), with significant heterogeneities (P(heterogeneity)<0.00001, I2 = 95%; P(heterogeneity)<0.00001, I2 = 94%; P(heterogeneity)<0.00001, I2 = 97%; respectively). CONCLUSIONS: This meta analysis suggests that CDI is a potential diagnostic tool for POAG. PMID- 23675420 TI - Dispec: a novel peptide scoring algorithm based on peptide matching discriminability. AB - Identifying peptides from the fragmentation spectra is a fundamental step in mass spectrometry (MS) data processing. The significance (discriminability) of every peak varies, providing additional information for potentially enhancing the identification sensitivity and the correct match rate. However this important information was not considered in previous algorithms. Here we presented a novel method based on Peptide Matching Discriminability (PMD), in which the PMD information of every peak reflects the discriminability of candidate peptides. In addition, we developed a novel peptide scoring algorithm Dispec based on PMD, by taking three aspects of discriminability into consideration: PMD, intensity discriminability and m/z error discriminability. Compared with Mascot and Sequest, Dispec identified remarkably more peptides from three experimental datasets with the same confidence at 1% PSM-level FDR. Dispec is also robust and versatile for various datasets obtained on different instruments. The concept of discriminability enhances the peptide identification and thus may contribute largely to the proteome studies. As an open-source program, Dispec is freely available at http://bioinformatics.jnu.edu.cn/software/dispec/. PMID- 23675421 TI - Xuezhikang, extract of red yeast rice, improved abnormal hemorheology, suppressed caveolin-1 and increased eNOS expression in atherosclerotic rats. AB - BACKGROUND: Xuezhikang is the extract of red yeast rice, which has been widely used for the management of atherosclerotic disease, but the molecular basis of its antiatherosclerotic effects has not yet been fully identified. Here we investigated the changes of eNOS in vascular endothelia and RBCs, eNOS regulatory factor Caveolin-1 in endothelia, and hemorheological parameters in atherosclerotic rats to explore the protective effects of Xuezhikang. METHODOLOGY/PRINCIPAL FINDINGS: Wistar rats were divided into 4 groups (n = 12/group) group C, controls; group M, high-cholesterol diet (HCD) induced atherosclerotic models; group X, HCD+Xuezhikang; and group L, HCD +Lovastatin. In group X, Xuezhikang inhibited oxidative stress, down-regulated caveolin-1 in aorta wall (P<0.05), up-regulated eNOS expression in vascular endothelia and erythrocytes (P<0.05), increased NOx (nitrite and nitrate) in plasma and cGMP in erythrocyte plasma and aorta wall (P<0.05), increased erythrocyte deformation index (EDI), and decreased whole blood viscosity and plasma viscosity (P<0.05), with the improvement of arterial pathology. CONCLUSIONS/SIGNIFICANCE: Xuezhikang up-regulated eNOS expression in vascular endothelia and RBCs, increased plasma NOx and improved abnormal hemorheology in high cholesterol diet induced atherosclerotic rats. The elevated eNOS/NO and improved hemorheology may be beneficial to atherosclerotic disease. PMID- 23675422 TI - The safety and short-term efficacy of aliskiren in the treatment of immunoglobulin a nephropathy--a randomized cross-over study. AB - BACKGROUND: Laboratory research and previous study suggest that aliskiren, a direct renin inhibitor, has anti-proteinuric effects. We conducted a randomized crossover study to evaluate the anti-proteinuric effect of aliskiren in patients with immunoglobulin A (IgA) nephropathy. METHODS: We studied 22 patients with biopsy-proven IgA nephropathy and persistent proteinuria despite angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). Patients were randomized to either oral aliskiren 300 mg/day or placebo for 16 weeks and then crossed over to the other treatment arm after a washout period. Proteinuria, estimated glomerular filtration rate (eGFR), blood pressure, and serum potassium were monitored. RESULTS: After aliskiren treatment, there was a significant reduction in proteinuria in 4 weeks (1.76+/-0.95 to 1.03+/-0.69 g:g-Cr, p<0.0001), which remained at a low level throughout the treatment period. There was a significant difference in proteinuria between the aliskiren and placebo groups from 4 to 16 weeks after treatment (p<0.01 for all comparisons). After aliskiren treatment, there were modest but statistically significant reductions in eGFR (57.2+/-29.1 to 54.8+/-29.3 ml/min/1.73 m(2), p = 0.013) and diastolic blood pressure (72.6+/-12.3 to 66.2+/-11.2 mmHg, p<0.0001). None of the patient developed severe hyperkalemia (serum potassium >=6.0 mmol/l) during the study period. CONCLUSIONS: Aliskiren has anti-proteinuric effect in patients with IgA nephropathy and persistent proteinuria despite ACE inhibitor or ARB. Further studies are needed to confirm the renal protecting effect of direct renin inhibition in chronic proteinuric kidney diseases. TRIAL REGISTRATION: ClinicalTrials.gov NCT00870493. PMID- 23675423 TI - Efficacy of mitomycin C in endoscopic dacryocystorhinostomy: a systematic review and meta-analysis. AB - BACKGROUND: A number of published comparative studies have been conducted to evaluate the efficacy and safety of intraoperative mitomycin C (MMC) in endoscopic dacryocystorhinostomy (EN-DCR). However, results have not always been consistent. Therefore, we carried out a meta-analysis to compare the clinical results of EN-DCR with and without MMC. METHODS AND FINDINGS: A comprehensive literature search of Cochrane Library, PubMed and EMBASE to identify relevant trials comparing EN-DCR with and without MMC. Eleven studies including 574 eyes were included in this meta-analysis. The success was defined as patency of the nasolacrimal canal and symptomatic improvement. There was significantly higher success rate in the MMC group in comparison with control group [RR = 1.12, 95% CI (1.04, 1.20), P = 0.004]. A sensitivity analysis after the non-randomized controlled trials were excluded from the meta-analysis demonstrated no differences compared with the overall results. Subgroup analyses showed that MMC group had a significantly higher success rate than control group in primary and revision EN-DCR, and EN-DCR without silicone intubation, but no difference in the subgroup of with silicone intubation. The size of the osteotomy site was bigger in the MMC group compared to the control group at 3 months [WMD = 7.65, 95% CI (0.33, 14.98), P = 0.041] and 6 months [WMD = 9.28, 95% CI (2.45, 16.11), P = 0.008] after surgery. However, there was statistically significant difference in the osteotomy surface area between the two groups at 12 months after surgery [WMD = 11.63, 95% CI (-1.04, 24.29), P = 0.072]. CONCLUSION: Intraoperative MMC application seems to be a safe adjuvant that could reduce the closure rate of the osteotomy and enhance the success rate after both primary and revision EN-DCR. TRIAL REGISTRATION: ClinicalTrials.gov NCT01772277. PMID- 23675424 TI - Molecular analysis of Staphylococcus epidermidis strains isolated from community and hospital environments in China. AB - BACKGROUND: Staphylococcus epidermidis is a common cause of nosocomial infections worldwide. This study analyzed the differences in genetic endowment and clonal lineages with pathogenesis and resistance traits of S. epidermidis isolates collected from community and hospital environments (patients and healthcare staff) of the same ecological niche, time period, and geographical location in China. METHODOLOGY/PRINCIPAL FINDINGS: Molecular epidemiology and population analysis showed that nasal colonization rates of S. epidermidis in the community of Shanghai area of China and in healthcare personnel were 44.8% (methicillin resistant S. epidermidis, MRSE: 17.2%) and 61.3% (MRSE: 30.0%), respectively. 86.7% of clinical isolates were MRSE. Among the strains studied, 44 sequence types (STs) were identified with 91.7% belonging to clonal complex 2 (CC2). Only 40.8% isolates from patients were also found in healthy individuals. MRSE-ST2 SCCmecIII was the predominant clone in clinical isolates, almost resistant to all antibiotics tested. Biofilm-related genes IS256 and icaA were detected in majority of the predominant clinical MRSE-ST2 clone with a 40.5% biofilm-positive rate. No ST2 isolate was found in community setting. We found a high prevalence of arginine catabolic mobile element (ACME) (74.1%). The prevalence of ACME-arc and ACME-opp3 clusters was 71.6% and 32.4%, respectively. Methicillin-sensitive S. epidermidis (MSSE) isolates harbored more ACME (83.3%) than MRSE isolates (67.7%), and there was no association between ACME and SCCmec types. An association was found between low-level ACME presence and invasive infections. CONCLUSIONS/SIGNIFICANCE: We observed a high level of diversity within S. epidermidis in this study, with CC2 as the dominant clonal complex in both community and hospital settings. Only 40.8% of the isolates from patients were also found in healthy individuals. Contrary to that biofilm formation and multiple antibiotic resistance were associated closely with pathogenicity of S. epidermidis, ACME was more likely to be an indicator for colonization rather than a virulence factor. PMID- 23675425 TI - A hybrid CPU-GPU accelerated framework for fast mapping of high-resolution human brain connectome. AB - Recently, a combination of non-invasive neuroimaging techniques and graph theoretical approaches has provided a unique opportunity for understanding the patterns of the structural and functional connectivity of the human brain (referred to as the human brain connectome). Currently, there is a very large amount of brain imaging data that have been collected, and there are very high requirements for the computational capabilities that are used in high-resolution connectome research. In this paper, we propose a hybrid CPU-GPU framework to accelerate the computation of the human brain connectome. We applied this framework to a publicly available resting-state functional MRI dataset from 197 participants. For each subject, we first computed Pearson's Correlation coefficient between any pairs of the time series of gray-matter voxels, and then we constructed unweighted undirected brain networks with 58 k nodes and a sparsity range from 0.02% to 0.17%. Next, graphic properties of the functional brain networks were quantified, analyzed and compared with those of 15 corresponding random networks. With our proposed accelerating framework, the above process for each network cost 80~150 minutes, depending on the network sparsity. Further analyses revealed that high-resolution functional brain networks have efficient small-world properties, significant modular structure, a power law degree distribution and highly connected nodes in the medial frontal and parietal cortical regions. These results are largely compatible with previous human brain network studies. Taken together, our proposed framework can substantially enhance the applicability and efficacy of high-resolution (voxel based) brain network analysis, and have the potential to accelerate the mapping of the human brain connectome in normal and disease states. PMID- 23675427 TI - Site fidelity in space use by spider monkeys (Ateles geoffroyi) in the Yucatan peninsula, Mexico. AB - Animal home ranges may vary little in their size and location in the short term but nevertheless show more variability in the long term. We evaluated the degree of site fidelity of two groups of spider monkeys (Ateles geoffroyi) over a 10- and 13-year period, respectively, in the northeastern Yucatan peninsula, Mexico. We used the Local Convex Hull method to estimate yearly home ranges and core areas (defined as the 60% probability contour) for the two groups. Home ranges varied from 7.7 to 49.6 ha and core areas varied from 3.1 to 9.2 ha. We evaluated the degree of site fidelity by quantifying the number of years in which different areas were used as either home ranges or core areas. Large tracts were used only as home ranges and only for a few years, whereas small areas were used as either core area or home range for the duration of the study. The sum of the yearly core areas coincided partially with the yearly home ranges, indicating that home ranges contain areas used intermittently. Home ranges, and especially core areas, contained a higher proportion of mature forest than the larger study site as a whole. Across years and only in one group, the size of core areas was positively correlated with the proportion of adult males in the group, while the size of home ranges was positively correlated with both the proportion of males and the number of tree species included in the diet. Our findings suggest that spider monkey home ranges are the result of a combination of long-term site fidelity and year-to-year use variation to enable exploration of new resources. PMID- 23675426 TI - Inhibiting HER3-mediated tumor cell growth with affibody molecules engineered to low picomolar affinity by position-directed error-prone PCR-like diversification. AB - The HER3 receptor is implicated in the progression of various cancers as well as in resistance to several currently used drugs, and is hence a potential target for development of new therapies. We have previously generated Affibody molecules that inhibit heregulin-induced signaling of the HER3 pathways. The aim of this study was to improve the affinity of the binders to hopefully increase receptor inhibition efficacy and enable a high receptor-mediated uptake in tumors. We explored a novel strategy for affinity maturation of Affibody molecules that is based on alanine scanning followed by design of library diversification to mimic the result from an error-prone PCR reaction, but with full control over mutated positions and thus less biases. Using bacterial surface display and flow cytometric sorting of the maturation library, the affinity for HER3 was improved more than 30-fold down to 21 pM. The affinity is among the higher that has been reported for Affibody molecules and we believe that the maturation strategy should be generally applicable for improvement of affinity proteins. The new binders also demonstrated an improved thermal stability as well as complete refolding after denaturation. Moreover, inhibition of ligand-induced proliferation of HER3-positive breast cancer cells was improved more than two orders of magnitude compared to the previously best-performing clone. Radiolabeled Affibody molecules showed specific targeting of a number of HER3 positive cell lines in vitro as well as targeting of HER3 in in vivo mouse models and represent promising candidates for future development of targeted therapies and diagnostics. PMID- 23675428 TI - Population dynamics of bacterial persistence. AB - Persistence is a prime example of phenotypic heterogeneity, where a microbial population splits into two distinct subpopulations with different growth and survival properties as a result of reversible phenotype switching. Specifically, persister cells grow more slowly than normal cells under unstressed growth conditions, but survive longer under stress conditions such as the treatment with bactericidal antibiotics. We analyze the population dynamics of such a population for several typical experimental scenarios, namely a constant environment, shifts between growth and stress conditions, and periodically switching environments. We use an approximation scheme that allows us to map the dynamics to a logistic equation for the subpopulation ratio and derive explicit analytical expressions for observable quantities that can be used to extract underlying dynamic parameters from experimental data. Our results provide a theoretical underpinning for the study of phenotypic switching, in particular for organisms where detailed mechanistic knowledge is scarce. PMID- 23675429 TI - The impact of genetic susceptibility to systemic lupus erythematosus on placental malaria in mice. AB - Severe malaria, including cerebral malaria (CM) and placental malaria (PM), have been recognized to have many of the features of uncontrolled inflammation. We recently showed that in mice genetic susceptibility to the lethal inflammatory autoimmune disease, systemic lupus erythematosus (SLE), conferred resistance to CM. Protection appeared to be mediated by immune mechanisms that allowed SLE prone mice, prior to the onset of overt SLE symptoms, to better control their inflammatory response to Plasmodium infection. Here we extend these findings to ask does SLE susceptibility have 1) a cost to reproductive fitness and/or 2) an effect on PM in mice? The rates of conception for WT and SLE susceptible (SLE(s)) mice were similar as were the number and viability of fetuses in pregnant WT and SLE(s) mice indicating that SLE susceptibility does not have a reproductive cost. We found that Plasmodium chabaudi AS (Pc) infection disrupted early stages of pregnancy before the placenta was completely formed resulting in massive decidual necrosis 8 days after conception. Pc-infected pregnant SLE(s) mice had significantly more fetuses (~1.8 fold) but SLE did not significantly affect fetal viability in infected animals. This was despite the fact that Pc-infected pregnant SLE(s) mice had more severe symptoms of malaria as compared to Pc infected pregnant WT mice. Thus, although SLE susceptibility was not protective in PM in mice it also did not have a negative impact on reproductive fitness. PMID- 23675430 TI - Antithrombin regulates matriptase activity involved in plasmin generation, syndecan shedding, and HGF activation in keratinocytes. AB - Matriptase, a membrane-associated serine protease, plays an essential role in epidermal barrier function through activation of the glycosylphosphatidylinositol (GPI)-anchored serine protease prostasin. The matriptase-prostasin proteolytic cascade is tightly regulated by hepatocyte growth factor activator inhibitor (HAI)-1 such that matriptase autoactivation and prostasin activation occur simultaneously and are followed immediately by the inhibition of both enzymes by HAI-1. However, the mechanisms whereby matriptase acts on extracellular substrates remain elusive. Here we report that some active matriptase can escape HAI-1 inhibition by being rapidly shed from the cell surface. In the pericellular environment, shed active matriptase is able to activate hepatocyte growth factor (HGF), accelerate plasminogen activation, and shed syndecan 1. The amount of active matriptase shed is inversely correlated with the amount of antithrombin (AT) bound to the surface of the keratinocytes. Binding of AT to the surface of keratinocytes is dependent on a functional heparin binding site, Lys-125, and that the N-glycosylation site Asn-135 be unglycosylated. This suggests that beta AT, and not alpha-AT, is responsible for regulation of pericellular matriptase activity in keratinocytes. Keratinocytes appear to rely on AT to regulate the level of pericellular active matriptase much more than breast and prostate epithelial cells in which AT regulation of matriptase activity occurs at much lower levels than keratinocytes. These results suggest that keratinocytes employ two distinct serine protease inhibitors to control the activation and processing of two different sets of matriptase substrates leading to different biological events: 1) HAI-1 for prostasin activation/inhibition, and 2) AT for the pericellular proteolysis involved in HGF activation, accelerating plasminogen activation, and shedding of syndecans. PMID- 23675431 TI - Efficacy of individual computer-based auditory training for people with hearing loss: a systematic review of the evidence. AB - BACKGROUND: Auditory training involves active listening to auditory stimuli and aims to improve performance in auditory tasks. As such, auditory training is a potential intervention for the management of people with hearing loss. OBJECTIVE: This systematic review (PROSPERO 2011: CRD42011001406) evaluated the published evidence-base for the efficacy of individual computer-based auditory training to improve speech intelligibility, cognition and communication abilities in adults with hearing loss, with or without hearing aids or cochlear implants. METHODS: A systematic search of eight databases and key journals identified 229 articles published since 1996, 13 of which met the inclusion criteria. Data were independently extracted and reviewed by the two authors. Study quality was assessed using ten pre-defined scientific and intervention-specific measures. RESULTS: Auditory training resulted in improved performance for trained tasks in 9/10 articles that reported on-task outcomes. Although significant generalisation of learning was shown to untrained measures of speech intelligibility (11/13 articles), cognition (1/1 articles) and self-reported hearing abilities (1/2 articles), improvements were small and not robust. Where reported, compliance with computer-based auditory training was high, and retention of learning was shown at post-training follow-ups. Published evidence was of very-low to moderate study quality. CONCLUSIONS: Our findings demonstrate that published evidence for the efficacy of individual computer-based auditory training for adults with hearing loss is not robust and therefore cannot be reliably used to guide intervention at this time. We identify a need for high-quality evidence to further examine the efficacy of computer-based auditory training for people with hearing loss. PMID- 23675432 TI - Effect of intra- and interspecific competition on the performance of native and invasive species of Impatiens under varying levels of shade and moisture. AB - Many alien plants are thought to be invasive because of unique traits and greater phenotypic plasticity relative to resident species. However, many studies of invasive species are unable to quantify the importance of particular traits and phenotypic plasticity in conferring invasive behavior because traits used in comparative studies are often measured in a single environment and by using plants from a single population. To obtain a deeper insight into the role of environmental factors, local differences and competition in plant invasions, we compared species of Impatiens (Balsaminaceae) of different origin and invasion status that occur in central Europe: native I. noli-tangere and three alien species (highly invasive I. glandulifera, less invasive I. parviflora and potentially invasive I. capensis). In two experiments we harvested late-stage reproductive plants to estimate performance. The first experiment quantified how populations differed in performance under varying light and moisture levels in the absence of competition. The second experiment quantified performance across these environments in the presence of intra- and inter-specific competition. The highly invasive I. glandulifera was the strongest competitor, was the tallest and produced the greatest biomass. Small size and high plasticity were characteristic for I. parviflora. This species appeared to be the second strongest competitor, especially under low soil moisture. The performance of I. capensis was within the range of the other Impatiens species studied, but sometimes limited by alien competitors. Our results suggest that invasion success within the genus Impatiens depends on the ability to grow large under a range of environmental conditions, including competition. The invasive species also exhibited greater phenotypic plasticity across environmental conditions than the native species. Finally, the decreased performance of the native I. noli-tangere in competition with other species studied indicates that this species may be possibly excluded from its sites by invading congeners. PMID- 23675433 TI - The use of sub-mental ultrasonography for identifying patients with severe obstructive sleep apnea. AB - OBJECTIVE: This study aimed to explore the association between obstructive sleep apnea (OSA) severity and pharyngeal parameters using sub-mental ultrasonography (US), and investigate the accuracy of US for identifying severe OSA patients. METHODS: One hundred and five consecutive referrals for suspected OSA were enrolled. The diameters of the retro-glossal (RG) and retro-palatal (RP) regions were measured via sub-mental US upon expiration during tidal breathing, forced inspiration, and Muller maneuver (MM). Independent factors associated with severe OSA identified from two-thirds of randomly-selected patients (model-development group) were used to construct a model for predicting severe OSA. The accuracy of the model was validated in the remaining one-third of patients (validation group). RESULTS: Fifty severe OSA patients, 30 with mild-moderate OSA, and 25 without OSA were enrolled. Compared to non-OSA and mild-moderate OSA patients, those with severe OSA had narrower RP diameter in all three maneuvers. Using the prediction model constructed with changes of RP diameters at MM and neck circumference, the independent predictors of severe OSA in the model-development group had 100% sensitivity and 65% specificity. CONCLUSION: Sub-mental US can accurately discriminate the severity of OSA and be used to identify patients with severe OSA. TRIAL REGISTRATION: ClinicalTrials.gov NCT00674076. PMID- 23675435 TI - Pathogenicity of Nosema sp. (Microsporidia) in the diamondback moth, Plutella xylostella (Lepidoptera: Plutellidae). AB - Biological control using pathogenic microsporidia could be an alternative to chemical control of the diamondback moth (DBM) Plutella xylostella (Lepidoptera: Plutellidae). The microsporidium Nosema bombycis (NB) is one of the numerous pathogens that can be used in the Integrated Pest Management (IPM) of DBM. However, its pathogenicity or effectiveness can be influenced by various factors, particularly temperature. This study was therefore conducted to investigate the effect of temperature on NB infection of DBM larvae. Second-instar larvae at different doses (spore concentration: 0, 1*102,1*103,1*104, and 1*105) at 15 degrees , 20 degrees , 25 degrees , 30 degrees and 35 degrees C and a relative humidity(RH) of 65% and light dark cycle (L:D) of 12?12. Larval mortality was recorded at 24 h intervals until the larvae had either died or pupated. The results showed that the spore concentration had a significant negative effect on larval survival at all temperatures, although this effect was more pronounced (92%) at 35 degrees C compared with that at 20 and 30 degrees C (?50%) and 25 degrees C (26%). Histological observations showed that Nosema preferentially infected the adipose tissue and epithelial cells of the midgut, resulting in marked vacuolization of the cytoplasm. These findings suggest that Nosema damaged the midgut epithelial cells. Our results suggest that Nosema had a direct adverse effect on DBM, and could be utilized as an important biopesticide alternative to chemical insecticides in IPM. PMID- 23675434 TI - New insights into FoxE1 functions: identification of direct FoxE1 targets in thyroid cells. AB - BACKGROUND: FoxE1 is a thyroid-specific forkhead transcription factor essential for thyroid gland development, as well as for the maintenance of the thyroid differentiated state in adults. FoxE1 recognizes and binds to a short DNA sequence present in thyroglobulin (Tg) and thyroperoxidase (Tpo) promoters, but FoxE1 binding to regulatory regions other than Tg and Tpo promoters remains almost unexplored. Improving knowledge of the regulatory functions of FoxE1 is necessary to clarify its role in endocrine syndromes and cancer susceptibility. METHODOLOGY/PRINCIPAL FINDING: In order to further investigate downstream FoxE1 targets, we performed a genome-wide expression screening after knocking-down FoxE1 and obtained new insights into FoxE1 transcriptional networks in thyroid follicular cells. After validation, we confirmed Adamts9, Cdh1, Duox2 and S100a4 as upregulated genes and Casp4, Creld2, Dusp5, Etv5, Hsp5a, Nr4a2 and Tm4sf1 as downregulated genes when FoxE1 was silenced. In promoter regions of putative FoxE1-regulated genes and also in the promoters of the classical thyroid genes Nis, Pax8 and Titf1, we performed an in silico search of the FoxE1 binding motif that was in close proximity to the NF1/CTF binding sequence, as previously described for other forkhead factors. Using chromatin immunoprecipitation we detected specific in vivo FoxE1 binding to novel regulatory regions in two relevant thyroid genes, Nis and Duox2. Moreover, we demonstrated simultaneous binding of FoxE1 and NF1/CTF to the Nis upstream enhancer region, as well as a clear functional activation of the Nis promoter by both transcription factors. CONCLUSIONS/SIGNIFICANCE: In search for potential downstream mediators of FoxE1 function in thyroid cells, we identified two novel direct FoxE1 target genes. To our knowledge, this is the first evidence regarding the implication of Nis and Duox2 in executing the transcriptional program triggered by FoxE1. Furthermore, this study points out the important role of FoxE1 in the regulation of a large number of genes in thyroid cells. PMID- 23675436 TI - Validation of the Simple Shoulder Test in a Portuguese-Brazilian population. Is the latent variable structure and validation of the Simple Shoulder Test Stable across cultures? AB - BACKGROUND: The validation of widely used scales facilitates the comparison across international patient samples. The objective of this study was to translate, culturally adapt and validate the Simple Shoulder Test into Brazilian Portuguese. Also we test the stability of factor analysis across different cultures. OBJECTIVE: The objective of this study was to translate, culturally adapt and validate the Simple Shoulder Test into Brazilian Portuguese. Also we test the stability of factor analysis across different cultures. METHODS: The Simple Shoulder Test was translated from English into Brazilian Portuguese, translated back into English, and evaluated for accuracy by an expert committee. It was then administered to 100 patients with shoulder conditions. Psychometric properties were analyzed including factor analysis, internal reliability, test retest reliability at seven days, and construct validity in relation to the Short Form 36 health survey (SF-36). RESULTS: Factor analysis demonstrated a three factor solution. Cronbach's alpha was 0.82. Test-retest reliability index as measured by intra-class correlation coefficient (ICC) was 0.84. Associations were observed in the hypothesized direction with all subscales of SF-36 questionnaire. CONCLUSION: The Simple Shoulder Test translation and cultural adaptation to Brazilian-Portuguese demonstrated adequate factor structure, internal reliability, and validity, ultimately allowing for its use in the comparison with international patient samples. PMID- 23675437 TI - Stable isotopes of C and N reveal habitat dependent dietary overlap between native and introduced turtles Pseudemys rubriventris and Trachemys scripta. AB - Habitat degradation and species introductions are two of the leading causes of species declines on a global scale. Invasive species negatively impact native species through predation and competition for limited resources. The impacts of invasive species may be increased in habitats where habitat degradation is higher due to reductions of prey abundance and distribution. Using stable isotope analyses and extensive measurements of resource availability we determined how resource availability impacts the long term carbon and nitrogen assimilation of the invasive red-eared slider turtle (Trachemys scripta elegans) and a native, threatened species, the red-bellied turtle (Pseudemys rubriventris) at two different freshwater wetland complexes in Pennsylvania, USA. At a larger wetland complex with greater vegetative species richness and diversity, our stable isotope analyses showed dietary niche partitioning between species, whereas analyses from a smaller wetland complex with lower vegetative species richness and diversity showed significant dietary niche overlap. Determining the potential for competition between these two turtle species is important to understanding the ecological impacts of red-eared slider turtles in wetland habitats. In smaller wetlands with increased potential for competition between native turtles and invasive red-eared slider turtles we expect that when shared resources become limited, red-eared slider turtles will negatively impact native turtle species leading to long term population declines. Protection of intact wetland complexes and the reduction of introduced species populations are paramount to preserving populations of native species. PMID- 23675438 TI - Targeting caspase-3 as dual therapeutic benefits by RNAi facilitating brain targeted nanoparticles in a rat model of Parkinson's disease. AB - The activation of caspase-3 is an important hallmark in Parkinson's disease. It could induce neuron death by apoptosis and microglia activation by inflammation. As a result, inhibition the activation of caspase-3 would exert synergistic dual effect in brain in order to prevent the progress of Parkinson's disease. Silencing caspase-3 genes by RNA interference could inhibit the activation of caspase-3. We developed a brain-targeted gene delivery system based on non-viral gene vector, dendrigraft poly-L-lysines. A rabies virus glycoprotein peptide with 29 amino-acid linked to dendrigraft poly-L-lysines could render gene vectors the ability to get across the blood brain barrier by specific receptor mediated transcytosis. The resultant brain-targeted vector was complexed with caspase-3 short hairpin RNA coding plasmid DNA, yielding nanoparticles. In vivo imaging analysis indicated the targeted nanoparticles could accumulate in brain more efficiently than non-targeted ones. A multiple dosing regimen by weekly intravenous administration of the nanoparticles could reduce activated casapse-3 levels, significantly improve locomotor activity and rescue dopaminergic neuronal loss and in Parkinson's disease rats' brain. These results indicated the rabies virus glycoprotein peptide modified brain-targeted nanoparticles were promising gene delivery system for RNA interference to achieve anti-apoptotic and anti inflammation synergistic therapeutic effects by down-regulation the expression and activation of caspase-3. PMID- 23675439 TI - Integrating murine gene expression studies to understand obstructive lung disease due to chronic inhaled endotoxin. AB - RATIONALE: Endotoxin is a near ubiquitous environmental exposure that that has been associated with both asthma and chronic obstructive pulmonary disease (COPD). These obstructive lung diseases have a complex pathophysiology, making them difficult to study comprehensively in the context of endotoxin. Genome-wide gene expression studies have been used to identify a molecular snapshot of the response to environmental exposures. Identification of differentially expressed genes shared across all published murine models of chronic inhaled endotoxin will provide insight into the biology underlying endotoxin-associated lung disease. METHODS: We identified three published murine models with gene expression profiling after repeated low-dose inhaled endotoxin. All array data from these experiments were re-analyzed, annotated consistently, and tested for shared genes found to be differentially expressed. Additional functional comparison was conducted by testing for significant enrichment of differentially expressed genes in known pathways. The importance of this gene signature in smoking-related lung disease was assessed using hierarchical clustering in an independent experiment where mice were exposed to endotoxin, smoke, and endotoxin plus smoke. RESULTS: A 101-gene signature was detected in three murine models, more than expected by chance. The three model systems exhibit additional similarity beyond shared genes when compared at the pathway level, with increasing enrichment of inflammatory pathways associated with longer duration of endotoxin exposure. Genes and pathways important in both asthma and COPD were shared across all endotoxin models. Mice exposed to endotoxin, smoke, and smoke plus endotoxin were accurately classified with the endotoxin gene signature. CONCLUSIONS: Despite the differences in laboratory, duration of exposure, and strain of mouse used in three experimental models of chronic inhaled endotoxin, surprising similarities in gene expression were observed. The endotoxin component of tobacco smoke may play an important role in disease development. PMID- 23675440 TI - A soft coral-derived compound, 11-epi-sinulariolide acetate suppresses inflammatory response and bone destruction in adjuvant-induced arthritis. AB - In recent years, a significant number of metabolites with potent anti inflammatory properties have been discovered from marine organisms, and several of these compounds are now under clinical trials. In the present study, we isolated 11-epi-sinulariolide acetate (Ya-s11), a cembrane-type compound with anti-inflammatory effects, from the Formosa soft coral Sinularia querciformis. Preliminary screening revealed that Ya-s11 significantly inhibited the expression of the proinflammatory proteins induced nitric oxide synthase and cyclooxygenase 2 in lipopolysaccharide-stimulated murine macrophages. We also examined the therapeutic effects of Ya-s11 on adjuvant-induced arthritis (AIA) in female Lewis rats, which demonstrate features similar to human rheumatoid arthritis (RA). Animal experiments revealed that Ya-s11 (subcutaneously 9 mg/kg once every 2 days from day 7 to day 28 postimmunization) significantly inhibited AIA characteristics. Moreover, Ya-s11 also attenuated protein expression of cathepsin K, matrix metalloproteinases-9 (MMP-9), tartrate-resistant acid phosphatase (TRAP), and tumor necrosis factor-alpha (TNF-alpha) in ankle tissues of AIA-rats. Based on its attenuation of the expression of proinflammatory proteins and disease progression in AIA rats, the marine-derived compound Ya-s11 may serve as a useful therapeutic agent for the treatment of RA. PMID- 23675441 TI - Genomic and proteomic analyses of the terminally redundant genome of the Pseudomonas aeruginosa phage PaP1: establishment of genus PaP1-like phages. AB - We isolated and characterized a new Pseudomonas aeruginosa myovirus named PaP1. The morphology of this phage was visualized by electron microscopy and its genome sequence and ends were determined. Finally, genomic and proteomic analyses were performed. PaP1 has an icosahedral head with an apex diameter of 68-70 nm and a contractile tail with a length of 138-140 nm. The PaP1 genome is a linear dsDNA molecule containing 91,715 base pairs (bp) with a G+C content of 49.36% and 12 tRNA genes. A strategy to identify the genome ends of PaP1 was designed. The genome has a 1190 bp terminal redundancy. PaP1 has 157 open reading frames (ORFs). Of these, 143 proteins are homologs of known proteins, but only 38 could be functionally identified. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and high-performance liquid chromatography-mass spectrometry allowed identification of 12 ORFs as structural protein coding genes within the PaP1 genome. Comparative genomic analysis indicated that the Pseudomonas aeruginosa phage PaP1, JG004, PAK_P1 and vB_PaeM_C2-10_Ab1 share great similarity. Besides their similar biological characteristics, the phages contain 123 core genes and have very close phylogenetic relationships, which distinguish them from other known phage genera. We therefore propose that these four phages be classified as PaP1-like phages, a new phage genus of Myoviridae that infects Pseudomonas aeruginosa. PMID- 23675443 TI - Effects of food availability on yolk androgen deposition in the black-legged kittiwake (Rissa tridactyla), a seabird with facultative brood reduction. AB - In birds with facultative brood reduction, survival of the junior chick is thought to be regulated primarily by food availability. In black-legged kittiwakes (Rissa tridactyla) where parents and chicks are provided with unlimited access to supplemental food during the breeding season, brood reduction still occurs and varies interannually. Survival of the junior chick is therefore affected by factors in addition to the amount of food directly available to them. Maternally deposited yolk androgens affect competitive dynamics within a brood, and may be one of the mechanisms by which mothers mediate brood reduction in response to a suite of environmental and physiological cues. The goal of this study was to determine whether food supplementation during the pre-lay period affected patterns of yolk androgen deposition in free-living kittiwakes in two years (2003 and 2004) that varied in natural food availability. Chick survival was measured concurrently in other nests where eggs were not collected. In both years, supplemental feeding increased female investment in eggs by increasing egg mass. First-laid ("A") eggs were heavier but contained less testosterone and androstenedione than second-laid ("B") eggs across years and treatments. Yolk testosterone was higher in 2003 (the year with higher B chick survival) across treatments. The difference in yolk testosterone levels between eggs within a clutch varied among years and treatments such that it was relatively small when B chick experienced the lowest and the highest survival probabilities, and increased with intermediate B chick survival probabilities. The magnitude of testosterone asymmetry in a clutch may allow females to optimize fitness by either predisposing a brood for reduction or facilitating survival of younger chicks. PMID- 23675442 TI - Long-term effects of chronic intermittent ethanol exposure in adolescent and adult rats: radial-arm maze performance and operant food reinforced responding. AB - BACKGROUND: Adolescence is not only a critical period of late-stage neurological development in humans, but is also a period in which ethanol consumption is often at its highest. Given the prevalence of ethanol use during this vulnerable developmental period we assessed the long-term effects of chronic intermittent ethanol (CIE) exposure during adolescence, compared to adulthood, on performance in the radial-arm maze (RAM) and operant food-reinforced responding in male rats. METHODOLOGY/PRINCIPAL FINDINGS: Male Sprague Dawley rats were exposed to CIE (or saline) and then allowed to recover. Animals were then trained in either the RAM task or an operant task using fixed- and progressive- ratio schedules. After baseline testing was completed all animals received an acute ethanol challenge while blood ethanol levels (BECs) were monitored in a subset of animals. CIE exposure during adolescence, but not adulthood decreased the amount of time that animals spent in the open portions of the RAM arms (reminiscent of deficits in risk-reward integration) and rendered animals more susceptible to the acute effects of an ethanol challenge on working memory tasks. The operant food reinforced task showed that these effects were not due to altered food motivation or to differential sensitivity to the nonspecific performance-disrupting effects of ethanol. However, CIE pre-treated animals had lower BEC levels than controls during the acute ethanol challenges indicating persistent pharmacokinetic tolerance to ethanol after the CIE treatment. There was little evidence of enduring effects of CIE alone on traditional measures of spatial and working memory. CONCLUSIONS/SIGNIFICANCE: These effects indicate that adolescence is a time of selective vulnerability to the long-term effects of repeated ethanol exposure on neurobehavioral function and acute ethanol sensitivity. The positive and negative findings reported here help to further define the nature and extent of the impairments observed after adolescent CIE and provide direction for future research. PMID- 23675444 TI - The association of retinoic acid receptor beta2(RARbeta2) methylation status and prostate cancer risk: a systematic review and meta-analysis. AB - The retinoic acid receptor beta2(RARbeta2) is a type of nuclear receptor that is activated by both all-trans retinoic acid and 9-cis retinoic acid, which has been shown to function as a tumor suppressor gene in different types of human tumors. Previous reports demonstrated that the frequency of RARbeta2 methylation was significantly higher in prostate cancer patients compared with controls, but the relationship between RARbeta2 promoter methylation and pathological stage or Gleason score of prostate cancer remained controversial. Therefore, a meta analysis of published studies investigating the effects of RARbeta2 methylation status in prostate cancer occurrence and association with both pathological stage and Gleason score in prostate cancer was performed in the study. A total of 12 eligible studies involving 777 cases and 404 controls were included in the pooled analyses. Under the random-effects model, the pooled OR of RARbeta2 methylation in prostate cancer patients, compared to non-cancer controls, was 17.62 with 95%CI = 6.30-49.28. The pooled OR with the fixed-effects model of pathological stage in RASSF1A methylated patients, compared to unmethylated patients, was 0.67 (95%CI = 0.40-1.09) and the pooled OR of low-GS in RARbeta2 methylated patients by the random-effect model, compared to high-GS RARbeta2 methylated patients, was 0.54 (95%CI = 0.28-1.04). This study showed that RARbeta2 might be a potential biomarker in prostate cancer prevention and diagnosis. The detection of RARbeta2 methylation in urine or serum is a potential non-invasive diagnostic tool in prostate cancer. The present findings also require confirmation through adequately designed prospective studies. PMID- 23675445 TI - Inhibitor discovery of full-length New Delhi metallo-beta-lactamase-1 (NDM-1). AB - New Delhi metallo-beta-lactmase-1 (NDM-1) has recently attracted extensive attention for its biological activities to catalyze the hydrolysis of almost all of beta-lactam antibiotics. To study the catalytic property of NDM-1, the steady kinetic parameters of NDM-1 toward several kinds of beta-lactam antibiotics have been detected. It could effectively hydrolyze most beta-lactams (k cat/K m ratios between 0.03 to 1.28 umol-1.s-1), except aztreonam. We also found that thiophene carboxylic acid derivatives could inhibit NDM-1 and have shown synergistic antibacterial activity in combination with meropenem. Flexible docking and quantum mechanics (QM) study revealed electrostatic interactions between the sulfur atom of thiophene-carboxylic acid derivatives and the zinc ion of NDM-1, along with hydrogen bond between inhibitor and His189 of NDM-1. The interaction models proposed here can be used in rational design of NDM-1 inhibitors. PMID- 23675446 TI - Notch signaling maintains neural rosette polarity. AB - Formation of the metazoan body plan requires a complex interplay of morphological changes and patterning, and central to these processes is the establishment of apical/basal cell polarity. In the developing nervous system, apical/basal cell polarity is essential for neural tube closure and maintenance of the neural stem cell population. In this report we explore how a signaling pathway important for nervous system development, Notch signaling, impacts on apical/basal cell polarity in neural differentiation. CSL(-/-) mouse embryos, which are devoid of canonical Notch signaling, demonstrated a neural tube phenotype consistent with cell polarity and convergent extension defects, including deficiencies in the restricted expression of apical polarity markers in the neuroepithelium. CSL(-/-) mouse embryonic stem (ES) cells, cultured at low density, behaved as wild-type in the establishment of neural progenitors and apical specification, though progression through rosette formation, an in vitro correlate of neurulation, required CSL for correct maintenance of rosette structure and regulation of neuronal differentiation. Similarly, acute pharmacological inhibition of Notch signaling led to the breakdown of neural rosettes and accelerated neuronal differentiation. In addition to functional Notch signaling, rosette integrity was found to require actin polymerization and Rho kinase (ROCK) activity. Disruption of rosettes through inhibition of actin polymerization or ROCK activity, however, had no effect on neuronal differentiation, indicating that rosette maintenance is not a prerequisite for normal neuronal differentiation. In conclusion, our data indicate that Notch signaling plays a role not only in differentiation, but also in organization and maintenance of polarity during development of the early nervous system. PMID- 23675447 TI - High-throughput identification of promoters and screening of highly active promoter-5'-UTR DNA region with different characteristics from Bacillus thuringiensis. AB - In bacteria, both promoters and 5'-untranslated regions (5'-UTRs) of mRNAs play vital regulatory roles in gene expression. In this study, we identified 1203 active promoter candidates in Bacillus thuringiensis through analysis of the genome-wide TSSs based on the transcriptome data. There were 11 types of sigma factor and 34 types of transcription factor binding sites found in 723 and 1097 active promoter candidates, respectively. Moreover, within the 1203 transcriptional units (TUs), most (52%) of the 5'-UTRs were 10-50 nucleotides in length, 12.8% of the TUs had a long 5'-UTR greater than 100 nucleotides in length, and 16.3% of the TUs were leaderless. We then selected 20 active promoter candidates combined with the corresponding 5'-UTR DNA regions to screen the highly active promoter-5'-UTR DNA region complexes with different characteristics. Our results demonstrate that among the 20 selected complexes, six were able to exert their functions throughout the life cycle, six were specifically induced during the early-stationary phase, and four were specifically activated during the mid-stationary phase. We found a direct corresponding relationship between sigma-factor-recognized consensus sequences and complex activity features: the great majority of complexes acting throughout the life cycle possess sigma(A)-like consensus sequences; the maximum activities of the sigma(F)-, sigma(E)-, sigma(G)-, and sigma(K)-dependent complexes appeared at 10, 14, 16, and 22 h under our experimental conditions, respectively. In particular, complex Phj3 exhibited the strongest activity. Several lines of evidence showed that complex Phj3 possessed three independent promoter regions located at -251~-98, -113~-31, and -54~+14, and that the 5'-UTR +1~+118 DNA region might be particularly beneficial to both the stability and translation of its downstream mRNA. Moreover, Phj3 successfully overexpressed the active beta galactosidase and turbo-RFP, indicating that Phj3 could be a proper regulatory element for overexpression of proteins in B. thuringiensis. Therefore, our efforts contribute to molecular biology research and the biotechnological application of B. thuringiensis. PMID- 23675448 TI - The coexistence of asthma and chronic obstructive pulmonary disease (COPD): prevalence and risk factors in young, middle-aged and elderly people from the general population. AB - BACKGROUND: The joint distribution of asthma and chronic obstructive pulmonary disease (COPD) has not been well described. This study aims at determining the prevalence of self-reported physician diagnoses of asthma, COPD and of the asthma COPD overlap syndrome and to assess whether these conditions share a common set of risk factors. METHODS: A screening questionnaire on respiratory symptoms, diagnoses and risk factors was administered by mail or phone to random samples of the general Italian population aged 20-44 (n = 5163) 45-64 (n = 2167) and 65-84 (n = 1030) in the frame of the multicentre Gene Environment Interactions in Respiratory Diseases (GEIRD) study. RESULTS: A physician diagnosis of asthma or COPD (emphysema/chronic bronchitis/COPD) was reported by 13% and 21% of subjects aged <65 and 65-84 years respectively. Aging was associated with a marked decrease in the prevalence of diagnosed asthma (from 8.2% to 1.6%) and with a marked increase in the prevalence of diagnosed COPD (from 3.3% to 13.3%). The prevalence of the overlap of asthma and COPD was 1.6% (1.3%-2.0%), 2.1% (1.5% 2.8%) and 4.5% (3.2%-5.9%) in the 20-44, 45-64 and 65-84 age groups. Subjects with both asthma and COPD diagnoses were more likely to have respiratory symptoms, physical impairment, and to report hospital admissions compared to asthma or COPD alone (p<0.01). Age, sex, education and smoking showed different and sometimes opposite associations with the three conditions. CONCLUSION: Asthma and COPD are common in the general population, and they coexist in a substantial proportion of subjects. The asthma-COPD overlap syndrome represents an important clinical phenotype that deserves more medical attention and further research. PMID- 23675449 TI - Cross-language distributions of high frequency and phonetically similar cognates. AB - The coinciding form and meaning similarity of cognates, e.g. 'flamme' (French), 'Flamme' (German), 'vlam' (Dutch), meaning 'flame' in English, facilitates learning of additional languages. The cross-language frequency and similarity distributions of cognates vary according to evolutionary change and language contact. We compare frequency and orthographic (O), phonetic (P), and semantic similarity of cognates, automatically identified in semi-complete lexicons of six widely spoken languages. Comparisons of P and O similarity reveal inconsistent mappings in language pairs with deep orthographies. The frequency distributions show that cognate frequency is reduced in less closely related language pairs as compared to more closely related languages (e.g., French-English vs. German English). These frequency and similarity patterns may support a better understanding of cognate processing in natural and experimental settings. The automatically identified cognates are available in the supplementary materials, including the frequency and similarity measurements. PMID- 23675450 TI - In vivo measurement of oxygenation changes after stroke using susceptibility weighted imaging filtered phase data. AB - BACKGROUND AND PURPOSE: Cerebral blood oxygenation level is critical for following the evolution of stroke patients. The purpose of this study was to investigate the feasibility of measuring changes in blood oxygen levels for patients with acute stroke using SWI and to compare these changes with the patient's recovery over time. MATERIALS AND METHODS: A total 30 MRI scans was performed on 10 acute ischemic stroke patients. Every patient was followed at three time points: less than 24 hours; 2-3 weeks after stroke and 2 months after stroke. Both MRI scan and NIH stroke scale (NIHSS) were acquired for each patient at all three time points. Oxygen saturation changes were derived from phase values differences (Deltaphi) measured over 10 veins from each hemisphere for all 10 patients over 3 time points. The correlation of oxygen saturation and NIHSS was further evaluated. RESULTS: The stroke affected side of the brain showed moderate (r = -0.62) to strong (r = -0.70) correlation between the oxygenation change and NIHSS change. The oxygen saturation change from the normal side of the brain had essentially no association with recovery (r = -0.02 and-0.31). The results suggest that increases in oxygen saturation correspond to improved outcome and reductions in oxygen saturation correspond to worse outcome. CONCLUSION: High resolution SWI provided a novel method to measure changes in oxygenation change of the human brain in vivo. By using the phase values from the veins, both spatial and temporal information can be found that relates to patient outcome post stroke. PMID- 23675451 TI - Adaptive mutations and replacements of virulence traits in the Escherichia coli O104:H4 outbreak population. AB - The sequencing of highly virulent Escherichia coli O104:H4 strains isolated during the outbreak of bloody diarrhea and hemolytic uremic syndrome in Europe in 2011 revealed a genome that contained a Shiga toxin encoding prophage and a plasmid encoding enteroaggregative fimbriae. Here, we present the draft genome sequence of a strain isolated in Sweden from a patient who had travelled to Tunisia in 2010 (E112/10) and was found to differ from the outbreak strains by only 38 SNPs in non-repetitive regions, 16 of which were mapped to the branch to the outbreak strain. We identified putatively adaptive mutations in genes for transporters, outer surface proteins and enzymes involved in the metabolism of carbohydrates. A comparative analysis with other historical strains showed that E112/10 contained Shiga toxin prophage genes of the same genotype as the outbreak strain, while these genes have been replaced by a different genotype in two otherwise very closely related strains isolated in the Republic of Georgia in 2009. We also present the genome sequences of two enteroaggregative E. coli strains affiliated with phylogroup A (C43/90 and C48/93) that contain the agg genes for the AAF/I-type fimbriae characteristic of the outbreak population. Interestingly, C43/90 also contained a tet/mer antibiotic resistance island that was nearly identical in sequence to that of the outbreak strain, while the corresponding island in the Georgian strains was most similar to E. coli strains of other serotypes. We conclude that the pan-genome of the outbreak population is shared with strains of the A phylogroup and that its evolutionary history is littered with gene replacement events, including most recently independent acquisitions of antibiotic resistance genes in the outbreak strains and its nearest neighbors. The results are summarized in a refined evolutionary model for the emergence of the O104:H4 outbreak population. PMID- 23675452 TI - N-terminal helix-cap in alpha-helix 2 modulates beta-state misfolding in rabbit and hamster prion proteins. AB - Susceptibility of a particular species to prion disease is affected by small differences in the sequence of PrP and correlates with the propensity of its PrP to assume the beta-state. A helix-cap motif in the beta2-alpha2-loop of native alpha-helical rabbit PrP, a resistant species, contains sequence differences that influence intra- and interspecies transmission. To determine the effect the helix cap motif on beta-state refolding propensity, we mutated S170N, S174N, and S170N/S174N of the rabbit PrP helix-cap to resemble that of hamster PrP and conversely, N170S, N174S, and N170S/N174S of hamster PrP to resemble the helix cap of rabbit PrP. High-resolution crystal structures (1.45-1.6 A) revealed that these mutations ablate hydrogen-bonding interactions within the helix-cap motif in rabbit PrP(C). They also alter the beta-state-misfolding propensity of PrP; the serine mutations in hamster PrP decrease the propensity up to 35%, whereas the asparagine mutations in rabbit PrP increase it up to 42%. Rapid dilution of rabbit and hamster into beta-state buffer conditions causes quick conversion to beta-state monomers. Kinetic monitoring using size-exclusion chromatography showed that the monomer population decreases exponentially mirrored by an increase in an octameric species. The monomer-octamer transition rates are faster for hamster than for rabbit PrP. The N170S/N174S mutant of hamster PrP has a smaller octamer component at the endpoint compared to the wild-type, whereas the kinetics of octamer formation in mutant and wild-type rabbit PrP are comparable. These findings demonstrate that the sequence of the beta2-alpha2 helix-cap affects refolding to the beta-state and subsequently, may influence susceptibility to prion disease. PMID- 23675453 TI - Tumor environmental factors glucose deprivation and lactic acidosis induce mitotic chromosomal instability--an implication in aneuploid human tumors. AB - Mitotic chromosomal instability (CIN) plays important roles in tumor progression, but what causes CIN is incompletely understood. In general, tumor CIN arises from abnormal mitosis, which is caused by either intrinsic or extrinsic factors. While intrinsic factors such as mitotic checkpoint genes have been intensively studied, the impact of tumor microenvironmental factors on tumor CIN is largely unknown. We investigate if glucose deprivation and lactic acidosis--two tumor microenvironmental factors--could induce cancer cell CIN. We show that glucose deprivation with lactic acidosis significantly increases CIN in 4T1, MCF-7 and HCT116 scored by micronuclei, or aneuploidy, or abnormal mitosis, potentially via damaging DNA, up-regulating mitotic checkpoint genes, and/or amplifying centrosome. Of note, the feature of CIN induced by glucose deprivation with lactic acidosis is similar to that of aneuploid human tumors. We conclude that tumor environmental factors glucose deprivation and lactic acidosis can induce tumor CIN and propose that they are potentially responsible for human tumor aneuploidy. PMID- 23675454 TI - Tumor burden talks in cancer treatment with PEGylated liposomal drugs. AB - PURPOSE: PEGylated liposomes are important drug carriers that can passively target tumor by enhanced permeability and retention (EPR) effect in neoplasm lesions. This study demonstrated that tumor burden determines the tumor uptake, and also the tumor response, in cancer treatment with PEGylated liposomal drugs in a C26/tk-luc colon carcinoma-bearing mouse model. METHODS: Empty PEGylated liposomes (NanoX) and those encapsulated with VNB (NanoVNB) were labeled with In 111 to obtain InNanoX and InVNBL in high labeling yield and radiochemical purity (all >90%). BALB/c mice bearing either small (58.4+/-8.0 mm(3)) or large (102.4+/ 22.0 mm(3)) C26/tk-luc tumors in the right dorsal flank were intravenously administered with NanoVNB, InNanoX, InVNBL, or NanoX as a control, every 7 days for 3 times. The therapeutic efficacy was evaluated by body weight loss, tumor growth inhibition (using calipers and bioluminescence imaging) and survival fraction. The scintigraphic imaging of tumor mouse was performed during and after treatment. RESULTS: The biodistribution study of InVNBL revealed a clear inverse correlation (r (2) = 0.9336) between the tumor uptake and the tumor mass ranged from 27.6 to 623.9 mg. All three liposomal drugs showed better therapeutic efficacy in small-tumor mice than in large-tumor mice. Tumor-bearing mice treated with InVNBL (a combination drug) showed the highest tumor growth inhibition rate and survival fraction compared to those treated with NanoVNB (chemodrug only) and InNanoX (radionuclide only). Specific tumor targeting and significantly increased tumor uptake after periodical treatment with InVNBL were evidenced by scintigraphic imaging, especially in mice bearing small tumors. CONCLUSION: The significant differences in the outcomes of cancer treatment and molecular imaging between animals bearing small and large tumors revealed that tumor burden is a critical and discriminative factor in cancer therapy using PEGylated liposomal drugs. PMID- 23675455 TI - A human anti-c-Met Fab fragment conjugated with doxorubicin as targeted chemotherapy for hepatocellular carcinoma. AB - c-Met is over-expressed in hepatocellular carcinoma(HCC) but is absent or expressed at low levels in normal tissues. Therefore we generated a novel conjugate of a human anti-c-Met Fab fragment (MetFab) with doxorubicin (DOX) and assessed whether it had targeted antitumor activity against HCC and reduced the side-effects of DOX. The MetFab was screened from human phage library, conjugated with DOX via chemical synthesis, and the conjugation MetFab-DOX was confirmed by HPLC. The drug release patterns, the binding efficacy, and cellular distribution of MetFab-DOX were assessed. MetFab-DOX was stable at pH7.2 PBS while release doxorubicin quickly at pH4.0, the binding efficacy of MetFab-DOX was similarly as MetFab, and the cellular distribution of the MetFab-DOX is distinct from free DOX. The cytotoxicity of MetFab-DOX was analyzed by the MTT method and the nude mouse HCC model. The MetFab-DOX demonstrated cytotoxic effects on c-Met expressing-tumor cells, but not on the cells without c-Met expression. MetFab-DOX exerted anti-tumor effect and significantly reduced the side effect of free DOX in mice model. Furthermore, the localization of conjugate was confirmed by immunofluorescence staining of tumor tissue sections and optical tumor imaging, respectively, and the tissue-distribution of drug was compared between free DOX and MetFab-DOX treatment by spectrofluorometer. MetFab-DOX can localize to the tumor tissue, and the concentration of doxorubicin in the tumor was higher after MetFab-DOX administration than after DOX administration. In summary, MetFab-DOX can target c-Met expressing HCC cells effectively and have obvious antitumor activity with decreased side-effects in preclinical models of HCC. PMID- 23675456 TI - Altered modular organization of structural cortical networks in children with autism. AB - Autism is a complex developmental disability that characterized by deficits in social interaction, language skills, repetitive stereotyped behaviors and restricted interests. Although great heterogeneity exists, previous findings suggest that autism has atypical brain connectivity patterns and disrupted small world network properties. However, the organizational alterations in the autistic brain network are still poorly understood. We explored possible organizational alterations of 49 autistic children and 51 typically developing controls, by investigating their brain network metrics that are constructed upon cortical thickness correlations. Three modules were identified in controls, including cortical regions associated with brain functions of executive strategic, spatial/auditory/visual, and self-reference/episodic memory. There are also three modules found in autistic children with similar patterns. Compared with controls, autism demonstrates significantly reduced gross network modularity, and a larger number of inter-module connections. However, the autistic brain network demonstrates increased intra- and inter-module connectivity in brain regions including middle frontal gyrus, inferior parietal gyrus, and cingulate, suggesting one underlying compensatory mechanism associated with brain functions of self-reference and episodic memory. Results also show that there is increased correlation strength between regions inside frontal lobe, as well as impaired correlation strength between frontotemporal and frontoparietal regions. This alteration of correlation strength may contribute to the organization alteration of network structures in autistic brains. PMID- 23675457 TI - Enhanced responses to angiogenic cues underlie the pathogenesis of hereditary hemorrhagic telangiectasia 2. AB - Hereditary Hemorrhagic Telangiectasia (HHT) is a genetic vascular disease in which arteriovenous malformations (AVMs) manifest in skin and multiple visceral organs. HHT is caused by heterozygous mutations in endoglin (ENG), activin receptor-like kinase 1 (ALK1), or SMAD4. ALK1 regulates angiogenesis, but the precise function of ALK1 in endothelial cells (ECs) remains elusive. Since most blood vessels of HHT patients do not produce pathological vascular lesions, ALK1 heterozygous ECs may be normal unless additional genetic or environmental stresses are imposed. To investigate the cellular and biochemical phenotypes of Alk1-null versus Alk1-heterozygous ECs, we have generated pulmonary EC lines in which a genotype switch from the Alk1-conditional allele (Alk1 (2f)) to the Alk1 null allele (Alk1 (1f)) can be induced by tamoxifen treatment. Alk1-null (1 f/1 f) ECs displayed increased migratory properties in vitro in response to bFGF compared with Alk1-het (2 f/1 f) ECs. The 1 f/1 f-ECs formed a denser and more persistent tubular network as compared with their parental 2 f/1 f-ECs. Interestingly, the response to BMP-9 on SMAD1/5 phosphorylation was impaired in both 2 f/1 f- and 1 f/1 f-ECs at a comparable manner, suggesting that other factors in addition to SMADs may play a crucial role for enhanced angiogenic activity in 1 f/1 f-ECs. We also demonstrated in vivo that Alk1-deficient ECs exhibited high migratory and invasive properties. Taken together, these data suggest that enhanced responses to angiogenic cues in ALK1-deficient ECs underlie the pathogenesis of HHT2. PMID- 23675458 TI - Structural and functional connectivity changes in the brain associated with shyness but not with social anxiety. AB - Shyness and social anxiety are correlated to some extent and both are associated with hyper-responsivity to social stimuli in the frontal cortex and limbic system. However to date no studies have investigated whether common structural and functional connectivity differences in the brain may contribute to these traits. We addressed this issue in a cohort of 61 healthy adult subjects. Subjects were first assessed for their levels of shyness (Cheek and Buss Shyness scale) and social anxiety (Liebowitz Social Anxiety scale) and trait anxiety. They were then given MRI scans and voxel-based morphometry and seed-based, resting-state functional connectivity analysis investigated correlations with shyness and anxiety scores. Shyness scores were positively correlated with gray matter density in the cerebellum, bilateral superior temporal gyri and parahippocampal gyri and right insula. Functional connectivity correlations with shyness were found between the superior temporal gyrus, parahippocampal gyrus and the frontal gyri, between the insula and precentral gyrus and inferior parietal lobule, and between the cerebellum and precuneus. Additional correlations were found for amygdala connectivity with the medial frontal gyrus, superior frontal gyrus and inferior parietal lobule, despite the absence of any structural correlation. By contrast no structural or functional connectivity measures correlated with social or trait anxiety. Our findings show that shyness is specifically associated with structural and functional connectivity changes in cortical and limbic regions involved with processing social stimuli. These associations are not found with social or trait anxiety in healthy subjects despite some behavioral correlations with shyness. PMID- 23675459 TI - Activating mutations in protein tyrosine phosphatase Ptpn11 (Shp2) enhance reactive oxygen species production that contributes to myeloproliferative disorder. AB - Gain of function (GOF) mutations in protein tyrosine phosphatase Ptpn11 have been identified in childhood leukemias, and these mutations are sufficient to drive the development of myeloproliferative disorder and malignant leukemias in mice. However, the molecular mechanisms by which Ptpn11 mutations induce these malignancies are not completely understood. Here we report that Ptpn11 GOF mutations cause cytokine hypersensitivity in hematopoietic cells partly by enhancing the production of reactive oxygen species (ROS). GOF mutations D61G or E76K in Ptpn11 increased ROS levels in myeloid progenitors but not in hematopoietic stem cells. Increased ROS enhanced cellular responses to cytokines by promoting cytokine signaling. Treatment with an antioxidant partially corrected cytokine hypersensitivity in Ptpn11 mutant progenitors. Further analyses demonstrated that Ptpn11 mutations increased mitochondrial aerobic metabolism by interacting with a novel substrate in the mitochondria. This study provides new insights into the pathogenic effects of GOF mutations of Ptpn11 and implies that antioxidants may have a therapeutic benefit for the leukemic patients with these mutations. PMID- 23675460 TI - Orthostatic hypotension and the risk of congestive heart failure: a meta-analysis of prospective cohort studies. AB - BACKGROUND: Orthostatic hypotension (OH) has been related to the increased risk of future congestive heart failure (CHF) events. However, the overall quantitative estimate of predictive ability of OH for CHF has not been determined. We therefore performed a meta-analysis to investigate the association between OH and incident CHF. METHODS: Prospective cohort studies relevant to the aim of the study were identified by searching of Medline and Embase databases up to December 25, 2012 without restrictions and by reviewing the reference lists from retrieved articles. RESULTS: A total of 51270 subjects and 3603 incident CHF cases from 4 prospective cohorts were included in the meta-analysis. Using random effect model, the pooled result indicated that presence of OH at baseline was significantly associated with an increased risk for future CHF outcomes (adjusted hazard ratio: 1.30, 95% confidence interval 1.09-1.55; p = 0.004). Results of stratified analysis suggested that the association between OH and CHF incidence seemed to be significant in middle-age subjects, or the individuals with hypertension and diabetes at baseline, but did not significant in the elderly subjects or those without hypertension or diabetes. CONCLUSIONS: Our meta analysis confirmed that presence of OH is related to a significant increased risk for development of CHF in the future. Studies are needed to explore the potential mechanisms underlying this association. More importantly, screen for OH may be of great clinical significance for the early identification of subjects at higher risk for development of CHF. PMID- 23675461 TI - Separation, immobilization, and biocatalytic utilization of proteins by a supramolecular membrane. AB - Membrane separation of biomolecules and their application in biocatalysis is becoming increasingly important for biotechnology, demanding the development of new biocompatible materials with novel properties. In the present study, an entirely noncovalent water-based material is used as a membrane for size selective separation, immobilization, and biocatalytic utilization of proteins. The membrane shows stable performance under physiological conditions, allowing filtration of protein mixtures with a 150 kDa molecular weight cutoff (~8 nm hydrodynamic diameter cutoff). Due to the biocompatibility of the membrane, filtered proteins stay functionally active and retained proteins can be partially recovered. Upon filtration, large enzymes become immobilized within the membrane. They exhibit stable activity when subjected to a constant flux of substrates for prolonged periods of time, which can be used to carry out heterogeneous biocatalysis. The noncovalent membrane material can be easily disassembled, purified, reassembled, and reused, showing reproducible performance after recycling. The robustness, recyclability, versatility, and biocompatibility of the supramolecular membrane may open new avenues for manipulating biological systems. PMID- 23675463 TI - Image texture predicts avian density and species richness. AB - For decades, ecologists have measured habitat attributes in the field to understand and predict patterns of animal distribution and abundance. However, the scale of inference possible from field measured data is typically limited because large-scale data collection is rarely feasible. This is problematic given that conservation and management typical require data that are fine grained yet broad in extent. Recent advances in remote sensing methodology offer alternative tools for efficiently characterizing wildlife habitat across broad areas. We explored the use of remotely sensed image texture, which is a surrogate for vegetation structure, calculated from both an air photo and from a Landsat TM satellite image, compared with field-measured vegetation structure, characterized by foliage-height diversity and horizontal vegetation structure, to predict avian density and species richness within grassland, savanna, and woodland habitats at Fort McCoy Military Installation, Wisconsin, USA. Image texture calculated from the air photo best predicted density of a grassland associated species, grasshopper sparrow (Ammodramus savannarum), within grassland habitat (R(2) = 0.52, p-value <0.001), and avian species richness among habitats (R(2)= 0.54, p value <0.001). Density of field sparrow (Spizella pusilla), a savanna associated species, was not particularly well captured by either field-measured or remotely sensed vegetation structure variables, but was best predicted by air photo image texture (R(2)= 0.13, p-value = 0.002). Density of ovenbird (Seiurus aurocapillus), a woodland associated species, was best predicted by pixel-level satellite data (mean NDVI, R(2)= 0.54, p-value <0.001). Surprisingly and interestingly, remotely sensed vegetation structure measures (i.e., image texture) were often better predictors of avian density and species richness than field-measured vegetation structure, and thus show promise as a valuable tool for mapping habitat quality and characterizing biodiversity across broad areas. PMID- 23675462 TI - Mitogen- and stress-activated protein kinases 1 and 2 are required for maximal trefoil factor 1 induction. AB - Mitogen- and stress-activated protein kinases 1 and 2 (MSK1 and MSK2), activated downstream of the ERK- and p38-mitogen-activated protein kinase pathways are involved in cell survival, proliferation and differentiation. Following mitogenic or stress stimuli, they mediate the nucleosomal response, which includes phosphorylation of histone H3 at serine 10 (H3S10ph) coupled with transcriptional activation of immediate-early genes. While MSK1 and MSK2 are closely related, their relative roles may vary with cellular context and/or stimuli. However, our knowledge of MSK2 recruitment to immediate-early genes is limited, as research has primarily focused on MSK1. Here, we demonstrate that both MSK1 and MSK2, regulate the phorbol ester 12-O-tetradecanoylphorbol-13-acetate induced expression of the breast cancer marker gene, trefoil factor 1 (TFF1), by phosphorylating H3S10 at its 5' regulatory regions. The MSK-mediated phosphorylation of H3S10 promotes the recruitment of 14-3-3 isoforms and BRG1, the ATPase subunit of the BAF/PBAF remodeling complex, to the enhancer and upstream promoter elements of TFF1. The recruited chromatin remodeling activity leads to the RNA polymerase II carboxy-terminal domain phosphorylation at the TFF1 promoter, initiating TFF1 expression in MCF-7 breast cancer cells. Moreover, we show that MSK1 or MSK2 is recruited to TFF1 regulatory regions, but as components of different multiprotein complexes. PMID- 23675464 TI - Population trends and variation in body mass index from 1971 to 2008 in the Framingham Heart Study Offspring Cohort. AB - OBJECTIVE: We examined body mass index (BMI) across place and time to determine the pattern of BMI mean and standard deviation trajectories. METHODS: We included participants in the Framingham Heart Study (FHS) Offspring Cohort over eight waves of follow-up, from 1971 to 2008. After exclusions, the final sample size was 4569 subjects with 28,625 observations. We used multi-level models to examine population means and variation at the individual and neighborhood (census tracts) levels across time with measured BMI as the outcome, controlling for individual demographics and behaviors and neighborhood poverty. Because neighborhoods accounted for limited BMI variance, we removed this level as a source of variation in final models. We examined sex-stratified models with all subjects and models stratified by sex and baseline weight classification. RESULTS: Mean BMI increased from 24.0 kg/m(2) at Wave 1 to 27.7 at Wave 8 for women and from 26.6 kg/m(2) to 29.0 for men. In final models, BMI variation also increased from Waves 1 to 8, with the standard deviation increasing from 4.18 kg/m(2) to 6.15 for women and 3.31 kg/m(2) to 4.73 for men. BMI means increased in parallel across most baseline BMI weight classifications, except for more rapid increases through middle-age for obese women followed by declines in the last wave. BMI standard deviations also increased in parallel across baseline BMI classifications for women, with greater divergence of BMI variance for obese men compared to other weight classifications. CONCLUSION: Over nearly 40 years, BMI mean and variation increased in parallel across most baseline weight classifications in our sample. Individual-level characteristics, especially baseline BMI, were the primary factors in rising BMI. These findings have important implications not only for understanding the sources of the obesity epidemic in the United States but also for the targeting of interventions to address the epidemic. PMID- 23675465 TI - Prescription pattern and its influencing factors in Chinese county hospitals: a retrospective cross-sectional study. AB - OBJECTIVE: This study aimed to investigate prescription patterns and influencing factors in Chinese county hospitals. METHODS: Prescription quality was evaluated by five indicators proposed by WHO/INRUD. A questionnaire for doctors was designed by our research group. All internists, surgeons, obstetricians, gynecologists and pediatricians from 10 county hospitals in Anhui province were asked to fill the questionnaire. Their prescriptions from May 2011 to April 2012 were analyzed. RESULTS: Three-hundred and thirty-seven doctors completed valid questionnaires, and 5099 prescriptions were analyzed. The average number of drugs per prescription was 3.52+/-2.31; the average percentage of generic drugs, antibiotic usage, injection drug usage, and drugs prescribed from the national essential drug list were 96.12%, 29.90%, 20.02% and 48.85%, respectively. Differences in final academic degree and specialty led to differences in all of the five prescription quality indicators. The older doctors tended to use more antibiotics. Doctors with more education, more training on rational drug use, and better acquisition of medicine knowledge prescribe a lower percentage of generic drugs. Moreover, the more supportive the doctor's attitude to national essential medicine policy, the higher the percentage of generic drugs were prescribed. A higher level of medical knowledge was associated with a higher percentage of drugs prescribed from the essential drugs list. CONCLUSIONS: Promoting the education of medical knowledge on doctors, reinforcing the publicity of rational drug use to doctors, and initiating the performance evaluation for doctors are effective ways for improving prescription quality in Chinese county hospitals. PMID- 23675466 TI - Speciation on oceanic islands: rapid adaptive divergence vs. cryptic speciation in a Guadalupe Island songbird (Aves: Junco). AB - The evolutionary divergence of island populations, and in particular the tempo and relative importance of neutral and selective factors, is of central interest to the study of speciation. The rate of phenotypic evolution upon island colonization can vary greatly among taxa, and cases of convergent evolution can further confound the inference of correct evolutionary histories. Given the potential lability of phenotypic characters, molecular dating of insular lineages analyzed in a phylogenetic framework provides a critical tool to test hypotheses of phenotypic divergence since colonization. The Guadalupe junco is the only insular form of the polymorphic dark-eyed junco (Junco hyemalis), and shares eye and plumage color with continental morphs, yet presents an enlarged bill and reduced body size. Here we use variation in mtDNA sequence, morphological traits and song variables to test whether the Guadalupe junco evolved rapidly following a recent colonization by a mainland form of the dark-eyed junco, or instead represents a well-differentiated "cryptic" lineage adapted to the insular environment through long-term isolation, with plumage coloration a result of evolutionary convergence. We found high mtDNA divergence of the island lineage with respect to both continental J. hyemalis and J. phaeonotus, representing a history of isolation of about 600,000 years. The island lineage was also significantly differentiated in morphological and male song variables. Moreover, and contrary to predictions regarding diversity loss on small oceanic islands, we document relatively high levels of both haplotypic and song-unit diversity on Guadalupe Island despite long-term isolation in a very small geographic area. In contrast to prevailing taxonomy, the Guadalupe junco is an old, well differentiated evolutionary lineage, whose similarity to mainland juncos in plumage and eye color is due to evolutionary convergence. Our findings confirm the role of remote islands in driving divergence and speciation, but also their potential role as repositories of ancestral diversity. PMID- 23675467 TI - TRIM11 negatively regulates IFNbeta production and antiviral activity by targeting TBK1. AB - The innate immune response is a host defense mechanism against infection by viruses and bacteria. Type I interferons (IFNalpha/beta) play a crucial role in innate immunity. If not tightly regulated under normal conditions and during immune responses, IFN production can become aberrant, leading to inflammatory and autoimmune diseases. In this study, we identified TRIM11 (tripartite motif containing 11) as a novel negative regulator of IFNbeta production. Ectopic expression of TRIM11 decreased IFNbeta promoter activity induced by poly (I:C) stimulation or overexpression of RIG-I (retinoic acid-inducible gene-I) signaling cascade components RIG-IN (constitutively active form of RIG-I), MAVS (mitochondrial antiviral signaling protein), or TBK1 (TANK-binding kinase-1). Conversely, TRIM11 knockdown enhanced IFNbeta promoter activity induced by these stimuli. Moreover, TRIM11 overexpression inhibited the phosphorylation and dimerization of IRF3 and expression of IFNbeta mRNA. By contrast, TRIM11 knockdown increased the IRF3 phosphorylation and IFNbeta mRNA expression. We also found that TRIM11 and TBK1, a key kinase that phosphorylates IRF3 in the RIG-I pathway, interacted with each other through CC and CC2 domain, respectively. This interaction was enhanced in the presence of the TBK1 adaptor proteins, NAP1 (NF kappaB activating kinase-associated protein-1), SINTBAD (similar to NAP1 TBK1 adaptor) or TANK (TRAF family member-associated NF-kappaB activator). Consistent with its inhibitory role in RIG-I-mediated IFNbeta signaling, TRIM11 overexpression enhanced viral infectivity, whereas TRIM11 knockdown produced the opposite effect. Collectively, our results suggest that TRIM11 inhibits RIG-I mediated IFNbeta production by targeting the TBK1 signaling complex. PMID- 23675468 TI - Impact of hepatitis C virus infection on bone mineral density in renal transplant recipients. AB - BACKGROUND: The average prevalence of hepatitis C virus (HCV) infection in renal transplant recipients is 10%. Studies of these patients with HCV infection usually focuses on long-term graft survival and patient survival. Studies of the correlation between HCV infection and bone mineral density (BMD) in renal transplant patients are limited. The aim of this study was to investigate whether HCV infection is a risk factor for BMD change during a short follow-up period. METHODS: Seventy-six renal transplant recipients underwent 2 separate dual-energy X-ray absorptiometry (DXA) scans during a mean period of 14 months. Fifteen patients were HCV infection. First bone mineral density (BMD) at the lumbar spine, hip, and femoral neck was determined using dual-energy X-ray absorptiometry (DXA) between September 2008 and March 2009. After that, 34 patients took alendronate sodium 70 mg per week. Subgroups risk factors analysis was also performed into with or without alendronate. Immunosuppressive agents, bisphosphonates, patient characteristics, and biochemical factors were analyzed to identify associations with BMD. RESULTS: After 14 months, in 76 patients, BMD of the lumbar spine had significantly increased (from 0.9 g/cm2 to 0.92 g/cm2, p<0.001), whereas BMD of the hip and femoral neck had not. Multiple linear regression analysis showed that HCV infection was negatively associated with BMD change in the lumbar spine ( beta: -0.247, 95% CI, -0.035 to -0.002; p = 0.028). Moreover, in subgroup analysis, among 42 patients without alendronate, multiple linear regression analysis showed HCV infection was a risk factor for adverse BMD change of the lumbar spine ( beta: -0.371, 95% CI, -0.043 to -0.003; p = 0.023). CONCLUSION: HCV infection in renal transplant recipients was a negative risk factor for BMD change in the lumbar spine. Moreover, alendronate may be able to reverse the negative effect of HCV infection on bone in renal transplant recipients. PMID- 23675469 TI - The redox state of cytochrome c modulates resistance to methotrexate in human MCF7 breast cancer cells. AB - BACKGROUND: Methotrexate is a chemotherapeutic agent used to treat a variety of cancers. However, the occurrence of resistance limits its effectiveness. Cytochrome c in its reduced state is less capable of triggering the apoptotic cascade. Thus, we set up to study the relationship among redox state of cytochrome c, apoptosis and the development of resistance to methotrexate in MCF7 human breast cancer cells. RESULTS: Cell incubation with cytochrome c-reducing agents, such as tetramethylphenylenediamine, ascorbate or reduced glutathione, decreased the mortality and apoptosis triggered by methotrexate. Conversely, depletion of glutathione increased the apoptotic action of methotrexate, showing an involvement of cytochrome c redox state in methotrexate-induced apoptosis. Methotrexate-resistant MCF7 cells showed increased levels of endogenous reduced glutathione and a higher capability to reduce exogenous cytochrome c. Using functional genomics we detected the overexpression of GSTM1 and GSTM4 in methotrexate-resistant MCF7 breast cancer cells, and determined that methotrexate was susceptible of glutathionylation by GSTs. The inhibition of these GSTM isoforms caused an increase in methotrexate cytotoxicity in sensitive and resistant cells. CONCLUSIONS: We conclude that overexpression of specific GSTMs, GSTM1 and GSTM4, together with increased endogenous reduced glutathione levels help to maintain a more reduced state of cytochrome c which, in turn, would decrease apoptosis, thus contributing to methotrexate resistance in human MCF7 breast cancer cells. PMID- 23675470 TI - Fine-mapping and genetic analysis of the loci affecting hepatic iron overload in mice. AB - The liver, as the major organ for iron storage and production of hepcidin, plays pivotal roles in maintaining mammalian iron homeostasis. A previous study showed that Quantitative Trait Loci (QTLs) on chromosome 7 (Chr7) and 16 (Chr16) may control hepatic non-heme iron overload in an F2 intercross derived from C57BL/6J (B6) and SWR/J (SWR) mice. In this study, we aimed to validate the existence of these loci and identify the genes responsible for the phenotypic variations by generating congenic mice carrying SWR chromosome segments expanding these QTLs (D7Mit68-D7Mit71 and D16Mit125-D16Mit185, respectively). We excluded involvement of Chr7 based on the lack of iron accumulation in congenic mice. In contrast, liver iron accumulation was observed in Chr16 congenic mice. Through use of a series of subcongenic murine lines the interval on Chr16 was further fine-mapped to a 0.8 Mb segment spanning 11 genes. We found that the mRNA expression pattern in the liver remained unchanged for all 11 genes tested. Most importantly, we detected 4 missense mutations in 3 candidate genes including Sidt1 (P172R), Spice1(R708S), Boc (Q1051R) and Boc (S450-insertion in B6 allele) in the liver of SWR homozygous congenic mice. To further delineate potential modifier gene(s), we reconstituted seven candidate genes, Sidt1, Boc, Zdhhc23, Gramd1c, Atp6v1a, Naa50 and Gtpbp8, in mouse liver through hydrodynamic transfection. However, we were unable to detect significant changes in liver iron levels upon reconstitution of these candidate genes. Taken together, our work provides strong genetic evidence of the existence of iron modifiers on Chr16. Moreover, we were able to delineate the phenotypically responsible region to a 0.8 Mb region containing 11 coding genes, 3 of which harbor missense mutations, using a series of congenic mice. PMID- 23675471 TI - A cocoa peptide protects Caenorhabditis elegans from oxidative stress and beta amyloid peptide toxicity. AB - BACKGROUND: Cocoa and cocoa-based products contain different compounds with beneficial properties for human health. Polyphenols are the most frequently studied, and display antioxidant properties. Moreover, protein content is a very interesting source of antioxidant bioactive peptides, which can be used therapeutically for the prevention of age-related diseases. METHODOLOGY/PRINCIPAL FINDINGS: A bioactive peptide, 13L (DNYDNSAGKWWVT), was obtained from a hydrolyzed cocoa by-product by chromatography. The in vitro inhibition of prolyl endopeptidase (PEP) was used as screening method to select the suitable fraction for peptide identification. Functional analysis of 13L peptide was achieved using the transgenic Caenorhabditis elegans strain CL4176 expressing the human Abeta1 42 peptide as a pre-clinical in vivo model for Alzheimer's disease. Among the peptides isolated, peptide 13L (1 ug/mL) showed the highest antioxidant activity (P<=0.001) in the wild-type strain (N2). Furthermore, 13L produced a significant delay in body paralysis in strain CL4176, especially in the 24-47 h period after Abeta1-42 peptide induction (P<=0.0001). This observation is in accordance with the reduction of Abeta deposits in CL4176 by western blot. Finally, transcriptomic analysis in wild-type nematodes treated with 13L revealed modulation of the proteosomal and synaptic functions as the main metabolic targets of the peptide. CONCLUSIONS/SIGNIFICANCE: These findings suggest that the cocoa 13L peptide has antioxidant activity and may reduce Abeta deposition in a C. elegans model of Alzheimer's disease; and therefore has a putative therapeutic potential for prevention of age-related diseases. Further studies in murine models and humans will be essential to analyze the effectiveness of the 13L peptide in higher animals. PMID- 23675472 TI - Rotating shift-work as an independent risk factor for overweight Italian workers: a cross-sectional study. AB - BACKGROUND: A job-related factor is attracting a growing interest as a possible determinant of body weight gain in shift-workers. OBJECTIVE: The aim of the study was to reinvestigate the issue of overweight between rotating shift workers and daytime workers, taking into consideration possible confounding covariate factors. METHODS: This is a cross-sectional study, conducted by reviewing data from subjects participating in an occupational surveillance program in 2008. Participants answered a self-administered questionnaire to retrieve information about socio-demographic factors and working conditions (job schedule type, job related physical activity, time in job), subjective health status, health care visits during the previous year, and lifestyle factors (dietary habits, leisure time physical activity, alcohol consumption). Participants underwent a medical examination for measurement of BMI, and acquisition of medical history. RESULTS: Compared to daytime workers (N = 229), rotating shift workers (N = 110) displayed higher BMI (mean BMI was 27.6+/-3.9 and 26.7+/-3.6 for shift workers, and daytime workers, respectively; p<0.05). Logistic regression analysis allowed to highlight the role of rotating shift-work as an independent risk factor for increased body weight (OR 1.93, 95%CI 1.01-3.71), being aged between 35 and 54 years was a major determinant of increased BMI (OR 2.39, 95%CI 1.14-5.00). In addition, family history of obesity was the strongest determinant of overweight/obesity (OR 9.79, 95%CI 1.28-74.74). Interestingly, no significant association was found between overweight and other potentially relevant factors, such as diet quality and food choices, alcohol consumption, levels of occupational and leisure-time physical activity. CONCLUSIONS: Present findings seem to support the notion that rotating shift work is an independent risk factor for overweight, regardless of workers' dietary habits and physical activity levels. PMID- 23675473 TI - Gaseous hydrogen sulfide protects against myocardial ischemia-reperfusion injury in mice partially independent from hypometabolism. AB - BACKGROUND: Ischemia-reperfusion injury (IRI) is a major cause of cardiac damage following various pathological processes. Gaseous hydrogen sulfide (H2S) is protective during IRI by inducing a hypometabolic state in mice which is associated with anti-apoptotic, anti-inflammatory and antioxidant properties. We investigated whether gaseous H2S administration is protective in cardiac IRI and whether non-hypometabolic concentrations of H2S have similar protective properties. METHODS: Male C57BL/6 mice received a 0, 10, or 100 ppm H2S-N2 mixture starting 30 minutes prior to ischemia until 5 minutes pre-reperfusion. IRI was inflicted by temporary ligation of the left coronary artery for 30 minutes. High-resolution respirometry equipment was used to assess CO2-production and blood pressure was measured using internal transmitters. The effects of H2S were assessed by histological and molecular analysis. RESULTS: Treatment with 100 ppm H2S decreased CO2-production by 72%, blood pressure by 14% and heart rate by 25%, while treatment with 10 ppm H2S had no effects. At day 1 of reperfusion 10 ppm H2S showed no effect on necrosis, while treatment with 100 ppm H2S reduced necrosis by 62% (p<0.05). Seven days post-reperfusion, both 10 ppm (p<0.01) and 100 ppm (p<0.05) H2S showed a reduction in fibrosis compared to IRI animals. Both 10 ppm and 100 ppm H2S reduced granulocyte-influx by 43% (p<0.05) and 60% (p<0.001), respectively. At 7 days post-reperfusion both 10 and 100 ppm H2S reduced expression of fibronectin by 63% (p<0.05) and 67% (p<0.01) and ANP by 84% and 63% (p<0.05), respectively. CONCLUSIONS: Gaseous administration of H2S is protective when administered during a cardiac ischemic insult. Although hypometabolism is restricted to small animals, we now showed that low non hypometabolic concentrations of H2S also have protective properties in IRI. Since IRI is a frequent cause of myocardial damage during percutaneous coronary intervention and cardiac transplantation, H2S treatment might lead to novel therapeutical modalities. PMID- 23675475 TI - A DTI-based template-free cortical connectome study of brain maturation. AB - Improved understanding of how the human brain is "wired" on a macroscale may now be possible due to the emerging field of MRI connectomics. However, mapping the rapidly developing infant brain networks poses challenges. In this study, we applied an automated template-free "baby connectome" framework using diffusion MRI to non-invasively map the structural brain networks in subjects of different ages, including premature neonates, term-born neonates, six-month-old infants, and adults. We observed increasing brain network integration and decreasing segregation with age in term-born subjects. We also explored how the equal area nodes can be grouped into modules without any prior anatomical information--an important step toward a fully network-driven registration and analysis of brain connectivity. PMID- 23675474 TI - Regulation of IDO activity by oxygen supply: inhibitory effects on antimicrobial and immunoregulatory functions. AB - Tryptophan is an essential amino acid for human beings as well as for some microorganisms. In human cells the interferon-gamma (IFN-gamma) inducible enzyme indoleamine 2,3-dioxygenase (IDO) reduces local tryptophan levels and is therefore able to mediate broad-spectrum effector functions: IDO activity restricts the growth of various clinically relevant pathogens such as bacteria, parasites and viruses. On the other hand, it has been observed that IDO has immunoregulatory functions as it efficiently controls the activation and survival of T-cells. Although these important effects have been analysed in much detail, they have been observed in vitro using cells cultured in the presence of 20% O2 (normoxia). Such high oxygen concentrations are not present in vivo especially within infected and inflamed tissues. We therefore analysed IDO-mediated effects under lower oxygen concentrations in vitro and observed that the function of IDO is substantially impaired in tumour cells as well as in native cells. Hypoxia led to reduced IDO expression and as a result to reduced production of kynurenine, the downstream product of tryptophan degradation. Consequently, effector functions of IDO were abrogated under hypoxic conditions: in different human cell lines such as tumour cells (glioblastoma, HeLa) but also in native cells (human foreskin fibroblasts; HFF) IDO lost the capacity to inhibit the growth of bacteria (Staphylococcus aureus), parasites (Toxoplasma gondii) or viruses (herpes simplex virus type 1). Additionally, IDO could no longer efficiently control the proliferation of T-cells that have been co-cultured with IDO expressing HFF cells in vitro. In conclusion, the potent antimicrobial as well as immunoregulatory functions of IDO were substantially impaired under hypoxic conditions that pathophysiologically occurs in vivo. PMID- 23675476 TI - Antibiofilm properties of silver and gold incorporated PU, PCLm, PC and PMMA nanocomposites under two shear conditions. AB - Silver and gold nanoparticles (of average size ~20-27 nm) were incorporated in PU (Polyurethane), PCLm (Polycaprolactam), PC (polycarbonate) and PMMA (Polymethylmethaacrylate) by swelling and casting methods under ambient conditions. In the latter method the nanoparticle would be present not only on the surface, but also inside the polymer. These nanoparticles were prepared initially by using a cosolvent, THF. PU and PCLm were dissolved and swollen with THF. PC and PMMA were dissolved in CHCl3 and here the cosolvent, THF, acted as an intermediate between water and CHCl3. FTIR indicated that the interaction between the polymer and the nanoparticle was through the functional group in the polymer. The formation of E.coli biofilm on these nanocomposites under low (in a Drip flow biofilm reactor) and high shear (in a Shaker) conditions indicated that the biofilm growth was higher (twice) in the former than in the latter (ratio of shear force = 15). A positive correlation between the contact angle (of the virgin surface) and the number of colonies, carbohydrate and protein attached on it were observed. Ag nanocomposites exhibited better antibiofilm properties than Au. Bacterial attachment was highest on PC and least on PU nanocomposite. Casting method appeared to be better than swelling method in reducing the attachment (by a factor of 2). Composites reduced growth of organisms by six orders of magnitude, and protein and carbohydrate by 2-5 times. This study indicates that these nanocomposites may be suitable for implant applications. PMID- 23675477 TI - The global burden of visual difficulty in low, middle, and high income countries. AB - PURPOSE: Using a world-wide, population-based dataset of adults, we sought to determine the frequency of far visual difficulty and its associated risk factors. METHODS: The World Health Survey (WHS) was conducted in 70 countries throughout the world in 2003 using a random, multi-stage, stratified, cluster sampling design of adults ages 18 years and older. Far vision was assessed by asking "In the last 30 days, how much difficulty did you have in seeing and recognizing a person you know across the road (i.e. from a distance of about 20 meters)?". Responses included none, mild, moderate, severe, or extreme/unable. The income status of countries was estimated using gross national income per capita data from 2003 from the World Bank. Prevalence and regression estimates were adjusted to account for the complex sample design. RESULTS: 21% of adults reported any visual difficulty. The rate varied by the income status of the country with the percentage who had any visual difficulty being 24%, 23%, and 13% in low, middle, and high income countries, respectively. Five percent of people reported severe or extreme visual difficulty with rates in low, middle, and high income countries of 6%, 5%, and 2% respectively. Risk factors for visual difficulty included older age, female sex, poorer socioeconomic status, little to no formal education, and diabetes (P<0.05). CONCLUSIONS: One out of five adults in the WHS reported some degree of far visual difficulty. Given the importance of vision to living an independent life, better access to quality eye care services and life course factors affecting vision health (e.g. repeated eye infections, diet lacking vitamin A) must receive adequate attention and resources, especially in low and middle income countries. PMID- 23675478 TI - Reversed scototaxis during withdrawal after daily-moderate, but not weekly-binge, administration of ethanol in zebrafish. AB - Alcohol abuse can lead to severe psychological and physiological damage. Little is known, however, about the relative impact of a small, daily dose of alcohol (daily-moderate schedule) versus a large, once per week dose (weekly-binge schedule). In this study, we examined the effect of each of these schedules on behavioural measures of anxiety in zebrafish (Danio rerio). Adult wild-type zebrafish were administered either 0.2% ethanol on a daily-moderate schedule or 1.4% ethanol on a weekly-binge schedule for a period of 21 days, and then tested for scototaxis (preference for darkness) during withdrawal. Compared to a control group with no alcohol exposure, the daily-moderate group spent significantly more time on the light side of the arena (indicative of decreased anxiety) on day two of withdrawal, but not day 9 of withdrawal. The weekly-binge group was not significantly different from the control group on either day of withdrawal and showed no preference for either the light or dark zones. Our results indicate that even a small dose of alcohol on a daily basis can cause significant, though reversible, changes in behaviour. PMID- 23675479 TI - Lrp5 and Lrp6 exert overlapping functions in osteoblasts during postnatal bone acquisition. AB - The canonical Wnt signaling pathway is critical for skeletal development and maintenance, but the precise roles of the individual Wnt co-receptors, Lrp5 and Lrp6, that enable Wnt signals to be transmitted in osteoblasts remain controversial. In these studies, we used Cre-loxP recombination, in which Cre expression is driven by the human osteocalcin promoter, to determine the individual contributions of Lrp5 and Lrp6 in postnatal bone acquisition and osteoblast function. Mice selectively lacking either Lrp5 or Lrp6 in mature osteoblasts were born at the expected Mendelian frequency but demonstrated significant reductions in whole-body bone mineral density. Bone architecture measured by microCT revealed that Lrp6 mutant mice failed to accumulate normal amounts of trabecular bone. By contrast, Lrp5 mutants had normal trabecular bone volume at 8 weeks of age, but with age, these mice also exhibited trabecular bone loss. Both mutants also exhibited significant alterations in cortical bone structure. In vitro differentiation was impaired in both Lrp5 and Lrp6 null osteoblasts as indexed by alkaline phosphatase and Alizarin red staining, but the defect was more pronounced in Lrp6 mutant cells. Mice lacking both Wnt co receptors developed severe osteopenia similar to that observed previously in mice lacking beta-catenin in osteoblasts. Likewise, calvarial cells doubly deficient for Lrp5 and Lrp6 failed to form osteoblasts when cultured in osteogenic media, but instead attained a chondrocyte-like phenotype. These results indicate that expression of both Lrp5 and Lrp6 are required within mature osteoblasts for normal postnatal bone development. PMID- 23675480 TI - Malonate inhibits virulence gene expression in Vibrio cholerae. AB - We previously found that inhibition of the TCA cycle, either through mutations or chemical inhibition, increased toxT transcription in Vibrio cholerae. In this study, we found that the addition of malonate, an inhibitor of succinate dehydrogenase (SDH), decreased toxT transcription in V. cholerae, an observation inconsistent with the previous pattern observed. Unlike another SDH inhibitor, 2 thenoyltrifluoroacetone (TTFA), which increased toxT transcription and slightly inhibited V. cholerae growth, malonate inhibited toxT transcription in both the wild-type strain and TCA cycle mutants, suggesting malonate-mediated inhibition of virulence gene expression is independent to TCA cycle activity. Addition of malonate also inhibited ctxB and tcpA expressions but did not affect aphA, aphB, tcpP and toxR expressions. Malonate inhibited cholera toxin (CT) production in both V. cholerae classical biotype strains O395N1 and CA401, and El Tor biotype strain, N16961. Consistent with previous reports, we confirmed that these strains of V. cholerae did not utilize malonate as a primary carbon source. However, we found that the addition of malonate to the growth medium stimulated V. cholerae growth. All together, these results suggest that metabolizing malonate as a nutrient source negatively affects virulence gene expression in V. cholerae. PMID- 23675481 TI - Thymidylate synthase expression determines pemetrexed targets and resistance development in tumour cells. AB - Although treatment options for cancer patients are increasing every year, the drug resistance problem remains very present. It is very difficult to find a drug that acts equally on tumours of the same histology as the individual's genetic characteristics often determine the response to treatment. Furthermore, tumours that initially respond to anti-tumour therapy are able to adapt and develop resistance to the drug, while others do not. In addition, this usually implies resistance development to agents to which the cells have not been exposed, a phenomenon called cross-resistance or multidrug resistance. Given this situation, it has been suggested that the most appropriate treatment would be able to act in parallel on multiple pathways constitutively altered in tumour cells. Pemetrexed is a multitargeted antifolate that exerts its activity against folate-dependent enzymes involved in de novo pyrimidine and purine synthesis. It is currently in use in combination with cisplatin against malignant pleural mesothelioma and non squamous non-small cell lung cancer with favourable results. By real-time RT-PCR gene expression assays and restoration viability assays we demonstrated that Pemetrexed targets folate-dependent enzymes involved in de novo biosynthesis of purines differently depending on the intrinsic genetic characteristics of the tumour. These differences did not, however, interfere either with the initial response to the drug or with the activation of apoptotic pathways. In addition, these genetic fingerprints can differentiate two groups of tumours: those capable of developing resistance to antifolate, and not capable. These results may be useful to employ targets gene expression as resistance markers, a valuable tool for identifying patients likely to receive combination therapy to prevent the development of resistance. PMID- 23675482 TI - Mucosal and systemic immune responses to Mycobacterium tuberculosis antigen 85A following its co-delivery with CpG, MPLA or LTB to the lungs in mice. AB - Pulmonary vaccination is a promising route for immunization against tuberculosis because the lung is the natural site of infection with Mycobacterium tuberculosis. Yet, adjuvants with a suitable safety profile need to be found to enhance mucosal immunity to recombinant antigens. The aim of this study was to evaluate the immunogenicity, the safety and the protective efficacy of a subunit vaccine composed of the immunodominant mycolyl-transferase antigen 85A (Ag85A) and one of three powerful mucosal adjuvants: the oligodeoxynucleotide containing unmethylated cytosine-phosphate-guanine motifs (CpG), the monophosphoryl lipid A of Salmonella minnesota (MPLA) or the B subunit of heat-labile enterotoxin of Escherichia coli (LTB). BALB/c mice were vaccinated in the deep lungs. Our results showed that lung administration of these adjuvants could specifically induce different types of T cell immunity. Both CpG and MPLA induced a Th-1 type immune response with significant antigen-specific IFN-gamma production by spleen mononuclear cells in vitro and a tendency of increased IFN-gamma in the lungs. Moreover, MPLA triggered a Th-17 response reflected by high IL-17A levels in the spleen and lungs. By contrast, LTB promoted a Th-2 biased immune response, with a production of IL-5 but not IFN-gamma by spleen mononuclear cells in vitro. CpG did not induce inflammation in the lungs while LTB and MPLA showed a transient inflammation including a neutrophil influx one day after pulmonary administration. Pulmonary vaccination with Ag85A without or with MPLA or LTB tended to decrease bacterial counts in the spleen and lungs following a virulent challenge with M. tuberculosis H37Rv. In conclusion, CpG and MPLA were found to be potential adjuvants for pulmonary vaccination against tuberculosis, providing Th-1 and Th-17 immune responses and a good safety profile. PMID- 23675483 TI - Improvement of intestinal absorption of forsythoside A and chlorogenic acid by different carboxymethyl chitosan and chito-oligosaccharide, application to Flos Lonicerae-Fructus Forsythiae herb couple preparations. AB - The current study aims to investigate the effect of chitosan derivatives on the intestinal absorption and bioavailabilities of forsythoside A (FTA) and Chlorogenic acid (CHA), the major active components in Flos Lonicerae-Fructus Forsythiae herb couple. Biopharmaceutics and pharmacokinetics properties of the two compounds have been characterized in vitro, in situ as well as in rats. Based on the identified biopharmaceutics characteristics of the two compounds, the effect of chitosan derivatives as an absorption enhancer on the intestinal absorption and pharmacokinetics of FTA and CHA in pure compound form as well as extract form were investigated in vitro, in situ and in vivo. Both FTA and CHA demonstrated very limited intestinal permeabilities, leading to oral bioavailabilities being only 0.50% and 0.13% in rats, respectively. Results from both in vitro, in situ as well as in vivo studies consistently indicated that Chito-oligosaccharide (COS) at dosage of 25 mg/kg could enhance intestinal permeabilities significantly as well as the in vivo bioavailabilities of both FTA and CHA than CMCs in Flos Lonicerae-Fructus Forsythiae herb couple preparations, and was safe for gastrointestine from morphological observation. Besides, treatment with Flos Lonicerae-Fructus Forsythiae herb couple preparations with COS at the dosage of 25 mg/kg prevented MDCK damage after influenza virus propagation, which was significantly better than control. The current findings not only identified the usefulness of COS for the improved delivery of Flos Lonicerae-Fructus Forsythiae preparations but also demonstrated the importance of biopharmaceutical characterization in the dosage form development of traditional Chinese medicine. PMID- 23675484 TI - Blood cholesterol trends 2001-2011 in the United States: analysis of 105 million patient records. AB - OBJECTIVES: We report annual trends in low density lipoprotein cholesterol (LDL C) from an in-care patient population of nearly 105 million adults across the United States (U.S.), from 2001 through 2011. BACKGROUND: Average blood cholesterol values have declined in the U.S. since at least 1960. The National Health and Nutrition Examination Survey (NHANES) reported declining blood cholesterol values from 1999 through 2010. In the absence of more recent published data, we examined LDL-C values from a single clinical laboratory database to determine whether these values continued to decline through 2011. METHODS AND RESULTS: We extracted almost 247 million LDL-C results from nearly 105 million adults who received diagnostic testing from a single national clinical laboratory. Annual age-adjusted mean LDL-C values were calculated, and analyzed by gender. Piecewise regression analysis of the total study population indicates a breakpoint, or change in slope, in the years following 2008 (F = 163.13; p<0.05). Between 2001 and 2008, the average rate of annual decline was 2.05 mg/dL (95% CI [-2.35, -1.75]). After 2008, mean LDL-C levels flattened out, with a slope not statistically different from zero (slope = -0.10 mg/dL/year; 95% CI [-1.46, 1.26]). This stabilization was observed in both genders and all age ranges, and was also reflected in the percentage of results in low- and high-risk categories. CONCLUSIONS: The trends reported suggest historical progress in decreasing LDL-C levels, observed from 2001-2008, may have stalled in recent years. Further research is needed to determine the cause of the observed trends and develop new strategies to reduce lipid-based cardiovascular risk further. PMID- 23675485 TI - Overexpression of EGFR in head and neck squamous cell carcinoma is associated with inactivation of SH3GL2 and CDC25A genes. AB - The aim of this study is to understand the mechanism of EGFR overexpression in head and neck squamous cell carcinoma (HNSCC). For this reason, expression/mutation of EGFR were analyzed in 30 dysplastic head and neck lesions and 148 HNSCC samples of Indian patients along with 3 HNSCC cell lines. In addition, deletion/methylation/mutation/expression of SH3GL2 (associated with EGFR degradation) and CDC25A (associated with dephosphorylation of EGFR) were analyzed in the same set of samples. Our study revealed high frequency of EGFR overexpression (66-84%), low frequency of gene amplification (10-32.5%) and absence of functional mutation in the dysplastic lesions and HNSCC samples. No correlation was found between protein overexpression and mRNA expression/gene amplification status of EGFR. On the other hand, frequent alterations (deletion/methylation) of SH3GL2 (63-77%) and CDC25A (37-64%) were seen in the dysplastic and HNSCC samples. Two novel single nucleotide polymorphism (SNPs) were found in the promoter region of SH3GL2. Reduced expression of these genes showed concordance with their alterations. Overexpression of EGFR and p-EGFR were significantly associated with reduced expression and alterations of SH3GL2 and CDC25A respectively. In-vitro demethylation experiment by 5-aza-2'-deoxycytidine (5-aza-dC) showed upregulation of SH3GL2 and CDC25A and downregulation of EGFR expression in Hep2 cell line. Poor patient outcome was predicted in the cases with alterations of SH3GL2 and CDC25A in presence of human papilloma virus (HPV) infection. Also, low SH3GL2 and high EGFR expression was a predictor of poor patient survival. Thus, our data suggests that overexpression of EGFR due to its reduced degradation and dephosphorylation is needed for development of HNSCC. PMID- 23675486 TI - Lipopolysaccharide induces endoplasmic store Ca2+-dependent inflammatory responses in lung microvessels. AB - The pulmonary microvasculature plays a critical role in endotoxin-induced acute lung injury. However, the relevant signaling remain unclear. Specifically the role of endothelial Ca(2+) in the induction of endotoxin-mediated responses in lung microvessels remains undefined. Toward elucidating this, we used the isolated blood-perfused rat lung preparation. We loaded microvessels with the Ca(2+) indicator, Fura 2 AM and then determined Ca(2+) responses to infusions of lipopolysaccharide (LPS) into the microvessels. LPS induced a more than two-fold increase in the amplitude of cytosolic Ca(2+) oscillations. Inhibiting inositol 1,4,5 trisphosphate receptors on endoplasmic reticulum (ER) Ca(2+) stores with Xestospongin C (XeC), blocked the LPS-induced increase in the Ca(2+) oscillation amplitude. However, XeC did not affect entry of external Ca(2+) via plasma membrane Ca(2+) channels in lung microvascular endothelial cells. This suggested that LPS augmented the oscillations via release of Ca(2+) from ER stores. In addition, XeC also blocked LPS-mediated activation and nuclear translocation of nuclear factor-kappa B in lung microvessels. Further, inhibiting ER Ca(2+) release blunted increases in intercellular adhesion molecule-1 expression and retention of naive leukocytes in LPS-treated microvessels. Taken together, the data suggest that LPS-mediated Ca(2+) release from ER stores underlies nuclear factor-kappa B activation and downstream inflammatory signaling in lung microvessels. Thus, we show for the first time a role for inositol 1,4,5 trisphosphate-mediated ER Ca(2+) release in the induction of LPS responses in pulmonary microvascular endothelium. Mechanisms that blunt this signaling may mitigate endotoxin-induced morbidity. PMID- 23675487 TI - Reduce manual curation by combining gene predictions from multiple annotation engines, a case study of start codon prediction. AB - Nowadays, prokaryotic genomes are sequenced faster than the capacity to manually curate gene annotations. Automated genome annotation engines provide users a straight-forward and complete solution for predicting ORF coordinates and function. For many labs, the use of AGEs is therefore essential to decrease the time necessary for annotating a given prokaryotic genome. However, it is not uncommon for AGEs to provide different and sometimes conflicting predictions. Combining multiple AGEs might allow for more accurate predictions. Here we analyzed the ab initio open reading frame (ORF) calling performance of different AGEs based on curated genome annotations of eight strains from different bacterial species with GC% ranging from 35-52%. We present a case study which demonstrates a novel way of comparative genome annotation, using combinations of AGEs in a pre-defined order (or path) to predict ORF start codons. The order of AGE combinations is from high to low specificity, where the specificity is based on the eight genome annotations. For each AGE combination we are able to derive a so-called projected confidence value, which is the average specificity of ORF start codon prediction based on the eight genomes. The projected confidence enables estimating likeliness of a correct prediction for a particular ORF start codon by a particular AGE combination, pinpointing ORFs notoriously difficult to predict start codons. We correctly predict start codons for 90.5+/-4.8% of the genes in a genome (based on the eight genomes) with an accuracy of 81.1+/-7.6%. Our consensus-path methodology allows a marked improvement over majority voting (9.7+/-4.4%) and with an optimal path ORF start prediction sensitivity is gained while maintaining a high specificity. PMID- 23675488 TI - Blood-brain barrier alterations provide evidence of subacute diaschisis in an ischemic stroke rat model. AB - BACKGROUND: Comprehensive stroke studies reveal diaschisis, a loss of function due to pathological deficits in brain areas remote from initial ischemic lesion. However, blood-brain barrier (BBB) competence in subacute diaschisis is uncertain. The present study investigated subacute diaschisis in a focal ischemic stroke rat model. Specific focuses were BBB integrity and related pathogenic processes in contralateral brain areas. METHODOLOGY/PRINCIPAL FINDINGS: In ipsilateral hemisphere 7 days after transient middle cerebral artery occlusion (tMCAO), significant BBB alterations characterized by large Evans Blue (EB) parenchymal extravasation, autophagosome accumulation, increased reactive astrocytes and activated microglia, demyelinization, and neuronal damage were detected in the striatum, motor and somatosensory cortices. Vascular damage identified by ultrastuctural and immunohistochemical analyses also occurred in the contralateral hemisphere. In contralateral striatum and motor cortex, major ultrastructural BBB changes included: swollen and vacuolated endothelial cells containing numerous autophagosomes, pericyte degeneration, and perivascular edema. Additionally, prominent EB extravasation, increased endothelial autophagosome formation, rampant astrogliosis, activated microglia, widespread neuronal pyknosis and decreased myelin were observed in contralateral striatum, and motor and somatosensory cortices. CONCLUSIONS/SIGNIFICANCE: These results demonstrate focal ischemic stroke-induced pathological disturbances in ipsilateral, as well as in contralateral brain areas, which were shown to be closely associated with BBB breakdown in remote brain microvessels and endothelial autophagosome accumulation. This microvascular damage in subacute phase likely revealed ischemic diaschisis and should be considered in development of treatment strategies for stroke. PMID- 23675489 TI - Increased long-flight activity triggered in beet armyworm by larval feeding on diet containing Cry1Ac protoxin. AB - Evaluating ecological safety and conducting pest risk analysis for transgenic crops are vitally important before their commercial planting. The beet armyworm, Spodoptera exigua, a long-distance migratory insect pest, is not a direct target of transgenic Cry1Ac-expressing cotton in China, but nevertheless it has recently become an important pest. Migrants leaving their natal field arrive in other appropriate habitat far away in a short time, often followed by larval outbreaks. S. exigua has low susceptibility to Cry1Ac. However, our results from laboratory experiments identified (i) sublethal effects of Cry1Ac protoxin on larval development rate, larval and pupal weight, and adult lifetime fecundity, and (ii) increased long-flight behavior triggered by Cry1Ac which may contribute to larval outbreaks elsewhere. No significant differences in larval mortality, pupation rate, adult emergence rate, longevity, pre-oviposition period, or oviposition period were observed between controls and larvae fed on artificial diet incorporating a low concentration of Cry1Ac protoxin. The negative sublethal effects on some developmental and reproductive traits and lack of effect on others suggest they do not contribute to the observed severity of S. exigua outbreaks after feeding on Cry1Ac cotton. Interestingly, the percentage of long fliers increased significantly when larvae were reared on diet containing either of two low-dose treatments of Cry1Ac, suggesting a possible increased propensity to disperse long distances triggered by Cry1Ac. We hypothesize that negative effects on development and reproduction caused by Cry1Ac in the diet are offset by increased flight propensity triggered by the poor food conditions, thereby improving the chances of escaping adverse local conditions before oviposition. Increased long-flight propensity in turn may amplify the area damaged by outbreak populations. This phenomenon might be common in other migratory insect pests receiving sublethal doses of Bt toxins and warrants further study. PMID- 23675490 TI - Completely anonymous multi-recipient signcryption scheme with public verification. AB - Most of the existing multi-recipient signcryption schemes do not take the anonymity of recipients into consideration because the list of the identities of all recipients must be included in the ciphertext as a necessary element for decryption. Although the signer's anonymity has been taken into account in several alternative schemes, these schemes often suffer from the cross-comparison attack and joint conspiracy attack. That is to say, there are few schemes that can achieve complete anonymity for both the signer and the recipient. However, in many practical applications, such as network conference, both the signer's and the recipient's anonymity should be considered carefully. Motivated by these concerns, we propose a novel multi-recipient signcryption scheme with complete anonymity. The new scheme can achieve both the signer's and the recipient's anonymity at the same time. Each recipient can easily judge whether the received ciphertext is from an authorized source, but cannot determine the real identity of the sender, and at the same time, each participant can easily check decryption permission, but cannot determine the identity of any other recipient. The scheme also provides a public verification method which enables anyone to publicly verify the validity of the ciphertext. Analyses show that the proposed scheme is more efficient in terms of computation complexity and ciphertext length and possesses more advantages than existing schemes, which makes it suitable for practical applications. The proposed scheme could be used for network conferences, paid-TV or DVD broadcasting applications to solve the secure communication problem without violating the privacy of each participant. PMID- 23675491 TI - Pin1 null mice exhibit low bone mass and attenuation of BMP signaling. AB - Bone is constantly formed and resorbed throughout life by coordinated actions of osteoblasts and osteoclasts. However, the molecular mechanisms involved in osteoblast function remain incompletely understood. Here we show, for the first time, that the peptidyl-prolyl isomerase PIN1 controls the osteogenic activity of osteoblasts. Pin1 null mice exhibited an age-dependent decrease in bone mineral density and trabecular bone formation without alteration in cortical bone. Further analysis identified a defect in BMP signaling in Pin1 null osteoblasts but normal osteoclast function. PIN1 interacted with SMAD5 and was required for the expression by primary osteoblasts of osteoblast specific transcription factors (CBFA1 and OSX), ECM (collagen I and OCN) and the formation of bone nodules. Our results thus uncover a novel aspect of the molecular underpinning of osteoblast function and identify a new therapeutic target for bone diseases. PMID- 23675492 TI - Lactobacillus decelerates cervical epithelial cell cycle progression. AB - We investigated cell cycle progression in epithelial cervical ME-180 cells during colonization of three different Lactobacillus species utilizing live cell microscopy, bromodeoxyuridine incorporation assays, and flow cytometry. The colonization of these ME-180 cells by L. rhamnosus and L. reuteri, originating from human gastric epithelia and saliva, respectively, was shown to reduce cell cycle progression and to cause host cells to accumulate in the G1 phase of the cell cycle. The G1 phase accumulation in L. rhamnosus-colonized cells was accompanied by the up-regulation and nuclear accumulation of p21. By contrast, the vaginal isolate L. crispatus did not affect cell cycle progression. Furthermore, both the supernatants from the lactic acid-producing L. rhamnosus colonies and lactic acid added to cell culture media were able to reduce the proliferation of ME-180 cells. In this study, we reveal the diversity of the Lactobacillus species to affect host cell cycle progression and demonstrate that L. rhamnosus and L. reuteri exert anti-proliferative effects on human cervical carcinoma cells. PMID- 23675493 TI - The fusion protein signal-peptide-coding region of canine distemper virus: a useful tool for phylogenetic reconstruction and lineage identification. AB - Canine distemper virus (CDV; Paramyxoviridae, Morbillivirus) is the etiologic agent of a multisystemic infectious disease affecting all terrestrial carnivore families with high incidence and mortality in domestic dogs. Sequence analysis of the hemagglutinin (H) gene has been widely employed to characterize field strains, permitting the identification of nine CDV lineages worldwide. Recently, it has been established that the sequences of the fusion protein signal-peptide (Fsp) coding region are extremely variable, suggesting that analysis of its sequence might be useful for strain characterization studies. However, the divergence of Fsp sequences among worldwide strains and its phylogenetic resolution has not yet been evaluated. We constructed datasets containing the Fsp coding region and H gene sequences of the same strains belonging to eight CDV lineages. Both datasets were used to evaluate their phylogenetic resolution. The phylogenetic analysis revealed that both datasets clustered the same strains into eight different branches, corresponding to CDV lineages. The inter-lineage amino acid divergence was fourfold greater for the Fsp peptide than for the H protein. The likelihood mapping revealed that both datasets display strong phylogenetic signals in the region of well-resolved topologies. These features indicate that Fsp-coding region sequence analysis is suitable for evolutionary studies as it allows for straightforward identification of CDV lineages. PMID- 23675494 TI - Senescent fibroblasts enhance early skin carcinogenic events via a paracrine MMP PAR-1 axis. AB - The incidence of carcinoma increases greatly with aging, but the cellular and molecular mechanisms underlying this correlation are only partly known. It is established that senescent fibroblasts promote the malignant progression of already-transformed cells through secretion of inflammatory mediators. We investigated here whether the senescent fibroblast secretome might have an impact on the very first stages of carcinogenesis. We chose the cultured normal primary human epidermal keratinocyte model, because after these cells reach the senescence plateau, cells with transformed and tumorigenic properties systematically and spontaneously emerge from the plateau. In the presence of medium conditioned by autologous senescent dermal fibroblasts, a higher frequency of post-senescence emergence was observed and the post-senescence emergent cells showed enhanced migratory properties and a more marked epithelial-mesenchymal transition. Using pharmacological inhibitors, siRNAs, and blocking antibodies, we demonstrated that the MMP-1 and MMP-2 matrix metalloproteinases, known to participate in late stages of cancer invasion and metastasis, are responsible for this enhancement of early migratory capacity. We present evidence that MMPs act by activating the protease-activated receptor 1 (PAR-1), whose expression is specifically increased in post-senescence emergent keratinocytes. The physiopathological relevance of these results was tested by analyzing MMP activity and PAR-1 expression in skin sections. Both were higher in skin sections from aged subjects than in ones from young subjects. Altogether, our results suggest that during aging, the dermal and epidermal skin compartments might be activated coordinately for initiation of skin carcinoma, via a paracrine axis in which MMPs secreted by senescent fibroblasts promote very early epithelial mesenchymal transition of keratinocytes undergoing transformation and oversynthesizing the MMP-activatable receptor PAR-1. PMID- 23675495 TI - HIF-1alpha transgenic bone marrow cells can promote tissue repair in cases of corticosteroid-induced osteonecrosis of the femoral head in rabbits. AB - Although corticosteroid-induced osteonecrosis of the femoral head (ONFH) is common, the treatment for it remains limited and largely ineffective. We examined whether implantation of hypoxia inducible factor-1alpha (HIF-1alpha) transgenic bone marrow cells (BMCs) can promote the repair of the necrotic area of corticosteroid-induced ONFH. In this study, we confirmed that HIF-1alpha gene transfection could enhance mRNA expression of osteogenic genes in BMCs in vitro. Alkaline phosphatase activity assay and alizarin red-S staining indicated HIF 1alpha transgenic BMCs had enhanced osteogenic differentiation capacity in vitro. Furthermore, enzyme linked immunosorbent assay (ELISA) for VEGF revealed HIF 1alpha transgenic BMCs secreted more VEGF as compared to normal BMCs. An experimental rabbit model of early-stage corticosteroid-induced ONFH was established and used for an evaluation of cytotherapy. Transplantation of HIF 1alpha transgenic BMCs dramatically improved the bone regeneration of the necrotic area of the femoral head. The number and volume of blood vessel were significantly increased in the necrotic area of the femoral head compared to the control groups. These results support HIF-1alpha transgenic BMCs have enhanced osteogenic and angiogenic activity in vitro and in vivo. Transplantation of HIF 1alpha transgenic BMCs can potentially promote the repair of the necrotic area of corticosteroid-induced ONFH. PMID- 23675496 TI - The effects of exercise under hypoxia on cognitive function. AB - Increasing evidence suggests that cognitive function improves during a single bout of moderate exercise. In contrast, exercise under hypoxia may compromise the availability of oxygen. Given that brain function and tissue integrity are dependent on a continuous and sufficient oxygen supply, exercise under hypoxia may impair cognitive function. However, it remains unclear how exercise under hypoxia affects cognitive function. The purpose of this study was to examine the effects of exercise under different levels of hypoxia on cognitive function. Twelve participants performed a cognitive task at rest and during exercise at various fractions of inspired oxygen (FIO2: 0.209, 0.18, and 0.15). Exercise intensity corresponded to 60% of peak oxygen uptake under normoxia. The participants performed a Go/No-Go task requiring executive control. Cognitive function was evaluated using the speed of response (reaction time) and response accuracy. We monitored pulse oximetric saturation (SpO2) and cerebral oxygenation to assess oxygen availability. SpO2 and cerebral oxygenation progressively decreased during exercise as the FIO2 level decreased. Nevertheless, the reaction time in the Go-trial significantly decreased during moderate exercise. Hypoxia did not affect reaction time. Neither exercise nor difference in FIO2 level affected response accuracy. An additional experiment indicated that cognitive function was not altered without exercise. These results suggest that the improvement in cognitive function is attributable to exercise, and that hypoxia has no effects on cognitive function at least under the present experimental condition. Exercise-cognition interaction should be further investigated under various environmental and exercise conditions. PMID- 23675498 TI - Corticosterone facilitates fluoxetine-induced neuronal plasticity in the hippocampus. AB - The hippocampal dentate gyrus has been implicated in a neuronal basis of antidepressant action. We have recently shown a distinct form of neuronal plasticity induced by the serotonergic antidepressant fluoxetine, that is, a reversal of maturation of the dentate granule cells in adult mice. This "dematuration" is induced in a large population of dentate neurons and maintained for at least one month after withdrawal of fluoxetine, suggesting long-lasting strong influence of dematuration on brain functioning. However, reliable induction of dematuration required doses of fluoxetine higher than suggested optimal doses for mice (10 to 18 mg/kg/day), which casts doubt on the clinical relevance of this effect. Since our previous studies were performed in naive mice, in the present study, we reexamined effects of fluoxetine using mice treated with chronic corticosterone that model neuroendocrine pathophysiology associated with depression. In corticosterone-treated mice, fluoxetine at 10 mg/kg/day downregulated expression of mature granule cell markers and attenuated strong frequency facilitation at the synapse formed by the granule cell axon mossy fiber, suggesting the induction of granule cell dematuration. In addition, fluoxetine caused marked enhancement of dopaminergic modulation at the mossy fiber synapse. In vehicle-treated mice, however, fluoxetine at this dose had no significant effects. The plasma level of fluoxetine was comparable to that in patients taking chronic fluoxetine, and corticosterone did not affect it. These results indicate that corticosterone facilitates fluoxetine-induced plastic changes in the dentate granule cells. Our finding may provide insight into neuronal mechanisms underlying enhanced responsiveness to antidepressant medication in certain pathological conditions. PMID- 23675497 TI - Actin microfilament mediates osteoblast Cbfa1 responsiveness to BMP2 under simulated microgravity. AB - Microgravity decreases osteoblastic activity, induces actin microfilament disruption and inhibits the responsiveness of osteoblast to cytokines, but the mechanisms remains enigmatic. The F-actin cytoskeleton has previously been implicated in manifold changes of cell shape, function and signaling observed under microgravity. Here we investigate the involvement of microfilament in mediating the effects of microgravity and BMP2 induction on Cbfa1 activity. For this purpose we constructed a fluorescent reporter cell line (OSE-MG63) of Cbfa1 activity by stably transfecting MG63 cells with a reporter consisting of six tandem copies of OSE2 and a minimal mOG2 promoter upstream of enhanced green fluorescent protein (EGFP). The fluorescence intensity of OSE-MG63 showed responsiveness to bone-related cytokines (IGF-I, vitamin D3 and BMP2) and presented an accordant tendency with alkaline phosphatase (ALP) activity. Using OSE-MG63 reporter fluorescence, we performed a semi-quantitative analysis of Cbfa1 activity after treatment with simulated microgravity, microfilament disrupting agent (cytochalasin B, CB), microfilament-stabilizing agent (Jasplakinolide, JAS) or any combination thereof. In parallel, ALP activity, DNA binding activity of Cbfa1 to OSE2 (ChIP), F-actin structure (immunofluorescence) and EGFP mRNA expression (RT-qPCR) were analyzed. Simulated microgravity inhibited Cbfa1 activity, affected the responsiveness of Cbfa1 to cytokine BMP2, and caused a thinning and dispersed distribution of microfilament. Under normal gravity, CB significantly attenuated BMP2 induction to Cbfa1 activity as well as DNA binding activity of Cbfa1 to OSE2. The addition of JAS reversed the inhibitory effects of microgravity on the responsiveness of Cbfa1 to BMP2. Our study demonstrates that disrupting the microfilament organization by CB or simulated microgravity attenuates the responsiveness of Cbfa1 to BMP2. A stabilization of the microfilament organization by JAS reverses this inhibition. Taken together, these results suggest that actin microfilament participates in BMP2's induction to Cbfa1 activity and that their disruption might be an important contributor to microgravity's inhibition on BMP2's osteogenic induction. PMID- 23675500 TI - Toward trait-based mortality models for tropical forests. AB - Tree mortality in tropical forests is a complex ecological process for which modelling approaches need to be improved to better understand, and then predict, the evolution of tree mortality in response to global change. The mortality model introduced here computes an individual probability of dying for each tree in a community. The mortality model uses the ontogenetic stage of the tree because youngest and oldest trees are more likely to die. Functional traits are integrated as proxies of the ecological strategies of the trees to permit generalization among all species in the community. Data used to parametrize the model were collected at Paracou study site, a tropical rain forest in French Guiana, where 20,408 trees have been censused for 18 years. A Bayesian framework was used to select useful covariates and to estimate the model parameters. This framework was developed to deal with sources of uncertainty, including the complexity of the mortality process itself and the field data, especially historical data for which taxonomic determinations were uncertain. Uncertainty about the functional traits was also considered, to maximize the information they contain. Four functional traits were strong predictors of tree mortality: wood density, maximum height, laminar toughness and stem and branch orientation, which together distinguished the light-demanding, fast-growing trees from slow-growing trees with lower mortality rates. Our modelling approach formalizes a complex ecological problem and offers a relevant mathematical framework for tropical ecologists to process similar uncertain data at the community level. PMID- 23675499 TI - Engineering Pseudomonas protegens Pf-5 for nitrogen fixation and its application to improve plant growth under nitrogen-deficient conditions. AB - Nitrogen is the second most critical factor for crop production after water. In this study, the beneficial rhizobacterium Pseudomonas protegens Pf-5 was genetically modified to fix nitrogen using the genes encoding the nitrogenase of Pseudomonas stutzeri A1501 via the X940 cosmid. Pf-5 X940 was able to grow in L medium without nitrogen, displayed high nitrogenase activity and released significant quantities of ammonium to the medium. Pf-5 X940 also showed constitutive expression and enzymatic activity of nitrogenase in ammonium medium or in nitrogen-free medium, suggesting a constitutive nitrogen fixation. Similar to Pseudomonas protegens Pf-5, Pseudomonas putida, Pseudomonas veronii and Pseudomonas taetrolens but not Pseudomonas balearica and Pseudomonas stutzeri transformed with cosmid X940 showed constitutive nitrogenase activity and high ammonium production, suggesting that this phenotype depends on the genome context and that this technology to obtain nitrogen-fixing bacteria is not restricted to Pf-5. Interestingly, inoculation of Arabidopsis, alfalfa, tall fescue and maize with Pf-5 X940 increased the ammonium concentration in soil and plant productivity under nitrogen-deficient conditions. In conclusion, these results open the way to the production of effective recombinant inoculants for nitrogen fixation on a wide range of crops. PMID- 23675501 TI - Primary treatment results of Nasopharyngeal Carcinoma (NPC) in Yogyakarta, Indonesia. AB - INTRODUCTION: Nasopharyngeal Carcinoma (NPC) is a major health problem in southern and eastern Asia. In Indonesia NPC is the most frequent cancer in the head and neck area. NPC is very sensitive to radiotherapy resulting in 3-year disease-free and overall survival of approximately 70% and 80%, respectively. Here we present routine treatment results in a prospective study on NPC in a top referral; university hospital in Indonesia. METHODS: All NPC patients presenting from September 2008 till January 2011 at the ear, nose and throat (ENT) department of the Dr. Sardjito General Hospital, Universitas Gadjah Mada, Yogyakarta, Indonesia, were possible candidates. Patients were included if the biopsy was a histological proven NPC without distant metastasis and were assessed during counselling sessions prior to treatment, as being able to complete the entire treatment. RESULTS: In total 78 patients were included for treatment analysis. The median time between diagnosis and start of radiotherapy is 120 days. Forty-eight (62%) patients eventually finished all fractions of radiotherapy. The median duration of the radiotherapy is 62 days for 66 Gy. Median overall survival is 21 months (95% CI 18-35) from day of diagnosis. CONCLUSION: The results presented here reveal that currently the treatment of NPC at an Indonesian hospital is not sufficient and cannot be compared to the treatment results in literature. Main reasons for these poor treatment results are (1) a long waiting time prior to the start of radiotherapy, (2) the extended overall duration of radiotherapy and (3) the advanced stage of disease at presentation. PMID- 23675502 TI - Characterization of the metabolic requirements in yeast meiosis. AB - The diploid yeast Saccharomyces cerevisiae undergoes mitosis in glucose-rich medium but enters meiosis in acetate sporulation medium. The transition from mitosis to meiosis involves a remarkable adaptation of the metabolic machinery to the changing environment to meet new energy and biosynthesis requirements. Biochemical studies indicate that five metabolic pathways are active at different stages of sporulation: glutamate formation, tricarboxylic acid cycle, glyoxylate cycle, gluconeogenesis, and glycogenolysis. A dynamic synthesis of macromolecules, including nucleotides, amino acids, and lipids, is also observed. However, the metabolic requirements of sporulating cells are poorly understood. In this study, we apply flux balance analyses to uncover optimal principles driving the operation of metabolic networks over the entire period of sporulation. A meiosis-specific metabolic network is constructed, and flux distribution is simulated using ten objective functions combined with time-course expression-based reaction constraints. By systematically evaluating the correlation between computational and experimental fluxes on pathways and macromolecule syntheses, the metabolic requirements of cells are determined: sporulation requires maximization of ATP production and macromolecule syntheses in the early phase followed by maximization of carbohydrate breakdown and minimization of ATP production in the middle and late stages. Our computational models are validated by in silico deletion of enzymes known to be essential for sporulation. Finally, the models are used to predict novel metabolic genes required for sporulation. This study indicates that yeast cells have distinct metabolic requirements at different phases of meiosis, which may reflect regulation that realizes the optimal outcome of sporulation. Our meiosis-specific network models provide a framework for an in-depth understanding of the roles of enzymes and reactions, and may open new avenues for engineering metabolic pathways to improve sporulation efficiency. PMID- 23675503 TI - Selective homocysteine lowering gene transfer improves infarct healing, attenuates remodelling, and enhances diastolic function after myocardial infarction in mice. AB - BACKGROUND AND AIMS: Homocysteine levels predict heart failure incidence in prospective epidemiological studies and correlate with severity of heart failure in cross-sectional surveys. The objective of this study was to evaluate whether a selective homocysteine lowering intervention beneficially affects cardiac remodelling and cardiac function after myocardial infarction (MI) in a murine model of combined hypercholesterolemia and hyperhomocysteinemia. METHODOLOGY AND PRINCIPAL FINDINGS: A selective homocysteine lowering gene transfer strategy was evaluated in female C57BL/6 low density lipoprotein receptor (Ldlr)-/- cystathionine-beta-synthase (Cbs)+/- deficient mice fed a hyperhomocysteinemic and high saturated fat/high cholesterol diet using an E1E3E4-deleted hepatocyte specific adenoviral vector expressing Cbs (AdCBS). MI was induced by permanent ligation of the left anterior descending coronary artery 14 days after saline injection or gene transfer. AdCBS gene transfer resulted in a persistent more than 5-fold (p<0.01) decrease of plasma homocysteine levels and significantly improved endothelial progenitor cell function. Selective homocysteine lowering enhanced infarct healing as indicated by a 21% (p<0.01) reduction of infarct length at day 28 after MI and by an increased number of capillaries and increased collagen content in the infarct zone. Adverse remodelling was attenuated in AdCBS MI mice as evidenced by a 29% (p<0.05) reduction of left ventricular cavity area at day 28, by an increased capillary density in the remote myocardium, and by reduced interstitial collagen. The peak rate of isovolumetric relaxation was increased by 19% (p<0.05) and the time constant of left ventricular relaxation was reduced by 21% (p<0.05) in AdCBS MI mice compared to control MI mice, indicating improved diastolic function. CONCLUSION/SIGNIFICANCE: Selective homocysteine lowering gene transfer improves infarct healing, attenuates remodelling, and significantly enhances diastolic function post-MI in female C57BL/6 Ldlr-/- Cbs+/- mice. The current study corroborates the view that hyperhomocysteinemia exerts direct effects on the myocardium and may potentiate the development of heart failure. PMID- 23675504 TI - Hypoxic tumor kinase signaling mediated by STAT5A in development of castration resistant prostate cancer. AB - In this study, we hypothesized that androgen-deprivation therapy (ADT) in prostate cancer, although initially efficient, induces changes in the tumor kinome, which subsequently promote development of castration-resistant (CR) disease. Recognizing the correlation between tumor hypoxia and poor prognosis in prostate cancer, we further hypothesized that such changes might be influenced by hypoxia. Microarrays with 144 kinase peptide substrates were applied to analyze CWR22 prostate carcinoma xenograft samples from ADT-naive, androgen-deprived (AD), long-term AD (ADL), and CR disease stages. The impact of hypoxia was assessed by matching the xenograft kinase activity profiles with those acquired from hypoxic and normoxic prostate carcinoma cell cultures, whereas the clinical relevance was evaluated by analyzing prostatectomy tumor samples from patients with locally advanced disease, either in ADT-naive or early CR disease stages. By using this novel peptide substrate microarray method we revealed high kinase activity mediated by signal transducer and activator of transcription 5A (STAT5A) in CR prostate cancer. Additionally, we uncovered high STAT5A kinase activity already in regressing ADL xenografts, before renewed CR growth was evidenced. Finally, since increased STAT5A kinase activity also was detected after exposing prostate carcinoma cells to hypoxia, we propose long-term ADT to induce tumor hypoxia and stimulate STAT5A kinase activity, subsequently leading to renewed CR tumor growth. Hence, the study detected STAT5A as a candidate to be further investigated for its potential as marker of advanced prostate cancer and as possible therapeutic target protein. PMID- 23675505 TI - Expression analysis of Lrrk1, Lrrk2 and Lrrk2 splice variants in mice. AB - Missense mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are linked to autosomal dominant forms of Parkinson's disease (PD). In order to get insights into the physiological role of Lrrk2, we examined the distribution of Lrrk2 mRNA and different splice variants in the developing murine embryo and the adult brain of Mus musculus. To analyse if the Lrrk2-paralog, Lrrk1, may have redundant functions in PD-development, we also compared Lrrk1 and Lrrk2 expression in the same tissues. Using radioactive in situ hybridization, we found ubiquitous expression of both genes at low level from embryonic stage E9.5 onward, which progressively increased up until birth. The developing central nervous system (CNS) displayed no prominent Lrrk2 mRNA signals at these time-points. However, in the entire postnatal brain Lrrk2 became detectable, showing strongest level in the striatum and the cortex of adult mice; Lrrk1 was only detectable in the mitral cell layer of the olfactory bulb. Thus, due to the non-overlapping expression patterns, a redundant function of Lrrk2 and Lrrk1 in the pathogenesis of PD seems to be unlikely. Quantification of Lrrk2 mRNA and protein level in several brain regions by real-time PCR and Western blot verified the striatum and cortex as hotspots of postnatal Lrrk2 expression. Strong expression of Lrrk2 is mainly found in neurons, specifically in the dopamine receptor 1 (DRD1a) and 2 (DRD2)-positive subpopulations of the striatal medium spiny neurons. Finally, we identified 2 new splice-variants of Lrrk2 in RNA-samples from various adult brain regions and organs: a variant with a skipped exon 5 and a truncated variant terminating in an alternative exon 42a. In order to identify the origin of these two splice variants, we also analysed primary neural cultures independently and found cell-specific expression patterns for these variants in microglia and astrocytes. PMID- 23675506 TI - Targeted ANP32E mutant mice do not demonstrate obvious movement defects. AB - BACKGROUND: The ANP32 family of proteins have been implicated in neuronal function through biochemical and cellular biology studies in neurons, as well as by recent behavioural studies of a gene-trapped loss-of-function mutation of Anp32e in mice, particularly with respect to fine motor function. A second targeted allele of the Anp32e, however, did not appear to demonstrate neurological phenotypes. METHODOLOGY/PRINCIPAL FINDINGS: Using a stringently controlled cohort of ten-generation backcrossed, co-caged, sex-matched, littermate pairs, we assayed for potential motor defects in the targeted ANP32E deficient mice. We found no phenotypic difference in any assays. CONCLUSION: Since it is unlikely that the gene-trap is a more complete loss-of-function, our results suggest that ANP32E has no appreciable effect on motor functions and that genetic background differences most likely account for the gene-trap phenomena. PMID- 23675507 TI - Taxonomic status of the Bemisia tabaci complex (Hemiptera: Aleyrodidae) and reassessment of the number of its constituent species. AB - Bemisia tabaci (Hemiptera: Aleyrodidae) is one of the most important insect pests in the world. In the present study, the taxonomic status of B. tabaci and the number of species composing the B. tabaci complex were determined based on 1059 COI sequences of B. tabaci and 509 COI sequences of 153 hemipteran species. The genetic divergence within B. tabaci was conspicuously higher (on average, 11.1%) than interspecific genetic divergence within the respective genera of the 153 species (on average, 6.5%). This result indicates that B. tabaci is composed of multiple species that may belong to different genera or subfamilies. A phylogenetic tree constructed based on 212 COI sequences without duplications revealed that the B. tabaci complex is composed of a total of 31 putative species, including a new species, JpL. However, genetic divergence within six species (Asia II 1, Asia II 7, Australia, Mediterranean, New World, and Sub Saharan Africa 1) was higher than 3.5%, which has been used as a threshold of species boundaries within the B. tabaci complex. These results suggest that it is necessary to increase the threshold for species boundaries up to 4% to distinguish the constituent species in the B. tabaci complex. PMID- 23675508 TI - Sodium alginate microneedle arrays mediate the transdermal delivery of bovine serum albumin. AB - BACKGROUND: The "poke and release" strategy for the delivery of macromolecules using polymeric microneedle (MN) is of great importance because it eliminates microneedle reuse, the risks of biohazardous sharps and cross contamination, and it requires no special disposal mechanism. The main objective of this study was the determination of the stability and delivery of bovine serum albumin (BSA) that was transported across human skin via sodium alginate (SA) microneedle arrays (MNs) and SA needle free patches using two different analytical methods. METHODOLOGY AND FINDINGS: The capability of two analytical methods, the bicinchoninic acid (BCA) assay and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), to precisely detect and quantify BSA within different types of polymeric MNs was assessed. The ex vivo protein release of BSA across dermatomed human abdominal skin from 10 w/w SA MNs was compared to that from needle-free patches using Franz diffusion cells. The developed applicator was mechanically characterized using a Texture Analyzer. The patch mold and its components were fabricated using a rapid prototyping machine. CONCLUSIONS/SIGNIFICANCE: The BCA method was able to precisely detect BSA that had been loaded into SA MNs. However, the use of SDS-PAGE as the analytical method resulted in significantly different amounts of BSA recovered from differently conditioned polymeric MNs. The permeation of BSA across dermatomed human abdominal skin by SA MNs, which were composed of 100 pyramidal needles, increased by approximately 15.4 fold compared to the permeation obtained with SA needle-free patches. The ease of use of the applicator during the release studies was also demonstrated, as was its mechanical characterization. PMID- 23675509 TI - Deficiency of insulin-like growth factor-1 receptor confers resistance to oxidative stress in C2C12 myoblasts. AB - IGF-1 receptor (IGF-1R) signaling regulates cell growth, transformation and survival. Haploinsufficiency of the IGF-1R is reported to paradoxically confer resistance to oxidative stress in vivo and in cells cultured from Igf1r(+/-) mice. In order to determine whether IGF-1R deficiency directly confers resistance to oxidative stress in specific cell types, an siRNA-mediated approach was applied to reduce IGF-1R in C2C12 myoblasts, NIH3T3 fibroblasts and MC3T3-E1 osteoblasts. Treating the IGF-1R deficient myoblasts with H2O2 resulted in significantly higher phosphorylation of Akt as compared to cells having normal expression of IGF-1R. Similar results were obtained with UV treatment, another inducer of oxidative stress. This enhanced activation of Akt was associated with reduced level of cleaved caspase-3 and PARP. Moreover, in the IGF-1R knockdown myoblasts, phosphorylation of the Akt substrate Bad was enhanced after peroxide treatment. However, in NIH-3T3 fibroblasts and MC3T3-E1 osteoblasts, the loss of IGF-1R by siRNA directed knockdown was associated with reduced levels of phosphorylated Akt on treatment with H2O2 or UV as compared to control cells and these cells showed more apoptosis. These results suggest a novel mechanism of cell type specific differential regulation of resistance to oxidative stress induced apoptosis by reduced levels of IGF-1R. PMID- 23675510 TI - Calcium channel-dependent molecular maturation of photoreceptor synapses. AB - Several studies have shown the importance of calcium channels in the development and/or maturation of synapses. The Ca(V)1.4(alpha(1F)) knockout mouse is a unique model to study the role of calcium channels in photoreceptor synapse formation. It features abnormal ribbon synapses and aberrant cone morphology. We investigated the expression and targeting of several key elements of ribbon synapses and analyzed the cone morphology in the Ca(V)1.4(alpha(1F)) knockout retina. Our data demonstrate that most abnormalities occur after eye opening. Indeed, scaffolding proteins such as Bassoon and RIM2 are properly targeted at first, but their expression and localization are not maintained in adulthood. This indicates that either calcium or the Ca(V)1.4 channel, or both are necessary for the maintenance of their normal expression and distribution in photoreceptors. Other proteins, such as Veli3 and PSD-95, also display abnormal expression in rods prior to eye opening. Conversely, vesicle related proteins appear normal. Our data demonstrate that the Ca(V)1.4 channel is important for maintaining scaffolding proteins in the ribbon synapse but less vital for proteins related to vesicular release. This study also confirms that in adult retinae, cones show developmental features such as sprouting and synaptogenesis. Overall we present evidence that in the absence of the Ca(V)1.4 channel, photoreceptor synapses remain immature and are unable to stabilize. PMID- 23675511 TI - Mice lacking pten in osteoblasts have improved intramembranous and late endochondral fracture healing. AB - The failure of an osseous fracture to heal (development of a non-union) is a common and debilitating clinical problem. Mice lacking the tumor suppressor Pten in osteoblasts have dramatic and progressive increases in bone volume and density throughout life. Since fracture healing is a recapitulation of bone development, we investigated the process of fracture healing in mice lacking Pten in osteoblasts (Ocn-cre(tg/+;)Pten(flox/flox) ). Mid-diaphyseal femoral fractures induced in wild-type and Ocn-cre(tg/+;)Pten(flox/flox) mice were studied via micro-computed tomography (uCT) scans, biomechanical testing, histological and histomorphometric analysis, and protein expression analysis. Ocn cre(tg/+;)Pten(flox/flox) mice had significantly stiffer and stronger intact bones relative to controls in all cohorts. They also had significantly stiffer healing bones at day 28 post-fracture (PF) and significantly stronger healing bones at days 14, 21, and 28 PF. At day 7 PF, the proximal and distal ends of the Pten mutant calluses were more ossified. By day 28 PF, Pten mutants had larger and more mineralized calluses. Pten mutants had improved intramembranous bone formation during healing originating from the periosteum. They also had improved endochondral bone formation later in the healing process, after mature osteoblasts are present in the callus. Our results indicate that the inhibition of Pten can improve fracture healing and that the local or short-term use of commercially available Pten-inhibiting agents may have clinical application for enhancing fracture healing. PMID- 23675512 TI - Evolutionary, molecular and genetic analyses of Tic22 homologues in Arabidopsis thaliana chloroplasts. AB - The Tic22 protein was previously identified in pea as a putative component of the chloroplast protein import apparatus. It is a peripheral protein of the inner envelope membrane, residing in the intermembrane space. In Arabidopsis, there are two Tic22 homologues, termed atTic22-III and atTic22-IV, both of which are predicted to localize in chloroplasts. These two proteins defined clades that are conserved in all land plants, which appear to have evolved at a similar rates since their separation >400 million years ago, suggesting functional conservation. The atTIC22-IV gene was expressed several-fold more highly than atTIC22-III, but the genes exhibited similar expression profiles and were expressed throughout development. Knockout mutants lacking atTic22-IV were visibly normal, whereas those lacking atTic22-III exhibited moderate chlorosis. Double mutants lacking both isoforms were more strongly chlorotic, particularly during early development, but were viable and fertile. Double-mutant chloroplasts were small and under-developed relative to those in wild type, and displayed inefficient import of precursor proteins. The data indicate that the two Tic22 isoforms act redundantly in chloroplast protein import, and that their function is non-essential but nonetheless required for normal chloroplast biogenesis, particularly during early plant development. PMID- 23675513 TI - Acetylcholineestarase-inhibiting alkaloids from Lycoris radiata delay paralysis of amyloid beta-expressing transgenic C. elegans CL4176. AB - The limited symptom relief and side effects of current Alzheimer's disease (AD) medications warrant urgent discovery and study of new anti-AD agents. The "cholinergic hypothesis" of AD prompts us to search for plant-derived acetylcholineesterase (AChE) inhibitors such as galanthamine that has been licensed in Europe for AD treatment. We used the unique amyloid beta-expressing transgenic C. elegans CL4176, which exhibits paralysis when human Abeta1-42 is induced, to study two natural benzylphenethylamine alkaloids isolated from Lycoris radiata (L' Her.) Herb, galanthamine and haemanthidine, and their synthetic derivatives 1,2-Di-O-acetyllycorine and 1-O-acetyllycorine for their anti-paralysis effects. Our data indicate that these Lycoris compounds effectively delay the paralysis of CL4176 worms upon temperature up-shift, and prolong the lives of these transgenic worms. Lycoris compounds were shown to significantly inhibit the gene expression of ace-1 and ace-2. Additionally, the Lycoris compounds may modulate inflammatory and stress-related gene expressions to combat the Abeta-toxicity in C. elegans. PMID- 23675514 TI - Impact of shocks on mortality in patients with ischemic or dilated cardiomyopathy and defibrillators implanted for primary prevention. AB - BACKGROUND: Emerging interest is seen in the paradox of defibrillator shocks for ventricular tachyarrhythmia and increased mortality risk. Particularly in patients with dilated cardiomyopathy (DCM), the prognostic importance of shocks is unclear. The purpose of this study was to compare the outcome after shocks in patients with ischemic cardiomyopathy (ICM) or DCM and defibrillators (ICD) implanted for primary prevention. METHODS AND RESULTS: Data of 561 patients were analyzed (mean age 68.6+/-10.6 years, mean left ventricular ejection fraction 28.6+/-7.3%). During a median follow-up of 49.3 months, occurrence of device therapies and all-cause mortality were recorded. 74 out of 561 patients (13.2%) experienced >=1 appropriate and 51 out of 561 patients (9.1%) >=1 inappropriate shock. All-cause mortality was 24.2% (136 out of 561 subjects). Appropriate shock was associated with a trend to higher mortality in the overall patient population (HR 1.48, 95% CI 0.96-2.28, log rank p = 0.072). The effect was significant in ICM patients (HR 1.61, 95% CI 1.00-2.59, log rank p = 0.049) but not in DCM patients (HR 1.03, 95% CI 0.36-2.96, log rank p = 0.96). Appropriate shocks occurring before the median follow-up revealed a much stronger impact on mortality (HR for the overall patient population 2.12, 95% CI 1.24-3.63, p = 0.005). The effect was driven by ICM patients (HR 2.48, 95% CI 1.41-4.37, p = 0.001), as appropriate shocks again did not influence survival of DCM patients (HR 0.63, 95% CI 0.083-4.75, p = 0.65). Appropriate shocks occurring after the median follow-up and inappropriate shocks occurring at any time revealed no impact on survival in any of the groups (p = ns). CONCLUSION: Appropriate shocks are associated with reduced survival in patients with ICM but not in patients with DCM and ICDs implanted for primary prevention. Furthermore, the negative effect of appropriate shocks on survival in ICM patients is only evident within the first 4 years after device implantation. PMID- 23675515 TI - Incidence and risk factors for tuberculosis in people living with HIV: cohort from HIV referral health centers in Recife, Brazil. AB - OBJECTIVE: To identify the incidence of and risk factors for tuberculosis in people living with HIV (PLHIV). DESIGN: Observational, prospective cohort study. METHODS: A total of 2069 HIV-infected patients was observed between July 2007 and December 2010. The Kaplan-Meier method was used to estimate the probability of survival free of tuberculosis, and Cox regression analysis to identify risk factors associated with the development of tuberculosis. RESULTS: Survival free of tuberculosis (TB) was 91%. The incidence rate of tuberculosis was 2.8 per 100 persons/years. Incidence of tuberculosis was higher when subjects had CD4 cell count <200 cells/mm(3); were not on antiretroviral therapy; in those who had, a body mass index <18.5 kg/m(2), anemia (or were not tested for it), were illiterate or referred previous tuberculosis treatment at entry into the cohort. Those not treated for latent TB infection had a much higher risk (HR = 7.9) of tuberculosis than those with a negative tuberculin skin test (TST). Having a TST>=5 mm but not being treated for latent TB infection increased the risk of incident tuberculosis even in those with a history of previous tuberculosis. CONCLUSIONS: Preventive actions to reduce the risk of TB in people living with HIV should include an appropriate HAART and treatment for latent TB infection in those with TST>=5 mm. The actions towards enabling rigorous implementation of treatment of latent TB infection and targeting of PLHIV drug users both at the individual and in public health level can reduce substantially the incidence of TB in PLHIV. PMID- 23675516 TI - Health-related behavior, profile of health locus of control and acceptance of illness in patients suffering from chronic somatic diseases. AB - PURPOSE: The purpose of the study was to determine health-related behaviors, profile of health locus of control (HLC), and to assess the relationships between these constructs among patients suffering from chronic somatic diseases. MATERIAL AND METHODS: Three-hundred adult patients suffering from various chronic diseases participated in the study. The patients' mean age was 54.6 years (SD = 17.57). RESULTS: No statistically significant differences were found between the different clinical groups in health-related behavior, acceptance of illness, internal HLC or chance HLC. Patients with neurologic conditions showed slightly lower powerful others HLC than did some other clinical groups. Health-related behavior was significantly positively related to all three categories of HLC, with most prominent associations observed with powerful others HLC. Only one type of health-related behavior--preventive behavior--correlated significantly and negatively with acceptance of illness. Differences in the frequency of health related behavior were also found due to gender (women showing more healthy nutritional habits than men), age (older subjects showing more frequent health promoting behavior), education (higher education was associated with less frequent health-promoting behavior) and marital status (widowed subjects reporting more frequent health-promoting behavior). CONCLUSIONS: Health-related behavior in patients with chronic diseases seems to be unrelated to a specific diagnosis; however it shows associations with both internal and external HLC. Sociodemographic factors are also crucial factors determining frequency of health related behavior in such patients. PMID- 23675517 TI - Interaction of osteopontin with IL-18 in obese individuals: implications for insulin resistance. AB - BACKGROUND/OBJECTIVE: Osteopontin (OPN) and IL-18 are known inflammatory mediators and both participate in a wide range of biological processes linked to immunological disorders. Since an interaction between OPN and IL-18 has not been studied in obesity, we investigated whether: (i) their levels were simultaneously elevated in obese individuals; (ii) OPN was associated with IL-18 in obese individuals and (iii) their levels associated with fasting blood glucose (FBG) and BMI. SUBJECTS AND METHODS: PBMCs and plasma samples were isolated from 60 individuals including lean as well as overweight and obese individuals. Subcutaneous adipose tissue samples were obtained. OPN and IL-18 were measured by ELISA. OPN and IL-18 mRNA expression was quantified by real time quantitative RT PCR. RESULTS: Obese individuals exhibited significantly increased circulating OPN levels as compared with lean individuals (obese 2865+/-101; lean 1681+/-116 pg/ml; P<0.0001). IL-18 levels were also high in obese individuals (obese 491+/ 39, lean 301+/-26 pg/ml; P = 0.0009). OPN and IL-18 expression were simultaneously up-regulated (OPN: 5.4-Fold; IL-18: 8.9-Fold; P<0.05) in PBMCs from obese individuals compared to lean group. Adipose tissue from obese individuals had high expression of OPN (7.3-Fold) and IL-18 (9.6-Fold). Plasma OPN levels correlated positively with FBG levels (r = 0.32, P = 0.02). Similarly, IL-18 correlated positively with FBG levels (r = 0.406, P = 0.0042). Stepwise multiple regression analysis showed an independent association of BMI with OPN and IL-18. Interestingly, OPN levels increased progressively with an increase in IL-18 levels (r = 0.52, P = 0.0004). We also examined the regulatory role of IL 18 in OPN secretion from PBMCs. Neutralizing anti-IL-18Ralpha mAb reduced OPN secretion. CONCLUSION: These findings represent the first observation that plasma, PBMC and adipose tissue OPN and IL-18 are simultaneously increased and correlate with each other in overweight/obese individuals which may trigger the development of obesity-associated insulin resistance. Moreover, these results provide the direct evidence that IL-18 regulates OPN production in PBMCs. PMID- 23675518 TI - Construction of new ligation-independent cloning vectors for the expression and purification of recombinant proteins in silkworms using BmNPV bacmid system. AB - A ligation independent cloning (LIC) system has been developed to facilitate the rapid and high-efficiency cloning of genes in a Bombyx mori expression system. This system was confirmed by the expression of human microsomal triglyceride transfer protein (hMTP) fused with EGFP in silkworm larvae and pupae. Moreover, hMTP and human protein disulfide isomerase (hPDI) genes were inserted into two LIC vectors harboring gcLINK sequences and were combined by using the LIC through gcLINK sequences. The constructed vector was incorporated into the Bombyx mori nucleopolyhedrovirus (BmNPV) bacmid, and injected into silkworm larvae. The expressed hMTP-hPDI complex was purified from the fat bodies of silkworm larvae. This LIC vector system was applied to express the E1, E2, and E3 subunits of human alpha-ketoglutarate dehydrogenase (KGDH) in silkworm larvae. The expressed proteins were purified easily from fat bodies using three different affinity chromatography steps. The LIC vectors constructed as described in this report allow for the rapid expression and purification of recombinant proteins or their complexes by using the BmNPV bacmid system. PMID- 23675519 TI - Peroxisome proliferator-activated receptor (PPAR) gamma and PPARalpha agonists modulate mitochondrial fusion-fission dynamics: relevance to reactive oxygen species (ROS)-related neurodegenerative disorders? AB - Recent studies showed that the activation of the retinoid X receptor, which dimerizes with peroxisome proliferator-activated receptors (PPARs), leads to an enhanced clearance of Abeta from the brain of transgenic mice model of Alzheimer's disease (AD), because an increased expression of apolipoprotein E and it main transporters. However, the effects observed must involve additional underlying mechanisms that have not been yet explored. Several studies conducted in our laboratory suggest that part of the effects observed for the PPARs agonist might involves mitochondrial function and, particularly, mitochondrial dynamics. In the present study we assessed the effects of oxidative stress challenge on mitochondrial morphology and mitochondrial dynamics-related proteins in hippocampal neurons. Using immunofluorescence, we evaluated the PPARgamma co activator 1alpha (PGC-1alpha), dynamin related protein 1 (DRP1), mitochondrial fission protein 1 (FIS1), and mitochondrial length, in order to determine if PPARs agonist pre-treatment is able to protect mitochondrial population from hippocampal neurons through modulation of the mitochondrial fusion-fission events. Our results suggest that both a PPARgamma agonist (ciglitazone) and a PPARalpha agonist (WY 14.643) are able to protect neurons by modulating mitochondrial fusion and fission, leading to a better response of neurons to oxidative stress, suggesting that a PPAR based therapy could acts simultaneously in different cellular components. Additionally, our results suggest that PGC 1alpha and mitochondrial dynamics should be further studied in future therapy research oriented to ameliorate neurodegenerative disorders, such as AD. PMID- 23675520 TI - Mechanisms of color production in a highly variable shield-back stinkbug, Tectocoris diophthalmus [corrected] (Heteroptera: Scutelleridae), and why it matters. AB - Theory suggests that aposematism, specifically the learned avoidance of unprofitable prey via memorable color patterns, should result in selection for pattern uniformity. However, many examples to the contrary are seen in nature. Conversely, honest sexual signals are likely to exhibit greater variation because they reflect underlying variation in mate quality. Here we aim to characterize and quantify the mechanistic causes of color in Tectocoris diophthalmus [corrected] to shed light on the costs of color production, and thus the potential information content of its color signals. We use Tectocoris diophthalmus [corrected] because it is a weakly-defended stinkbug, and presents elements that have classically been studied in the context of aposematism (red coloring), and sexual selection (sexual dichromatism and iridescent coloring). Pigment analysis reveals that variation in orange coloration is due to the amount of erythropterin pigment, stored in intracellular granules. This pigment is common in Heteroptera, and as an endogenously produced excretory byproduct is unlikely to reflect mate quality or variation in unprofitability of the bug. Electron microscopy reveals the iridescent patches are caused by an epicuticular multilayer reflector, and the hue and patch size are directly related to the layer widths and extent of coverage of this layering. Furthermore, we identified melanin as an essential component of the multilayer reflector system; therefore, the quality of the iridescent patches may be affected by aspects of rearing environment and immunocompetence. We posit that T. diophthalmus [corrected] has co-opted the melanic patches of a 'typical' red and black aposematic signal, transforming it into a complex and variable iridescent signal that may enhance its capacity to display individual quality. PMID- 23675521 TI - Retinal pigmented epithelial cells cytotoxicity and apoptosis through activation of the mitochondrial intrinsic pathway: role of indocyanine green, brilliant blue and implications for chromovitrectomy. AB - PURPOSE: To investigate the in vitro effect of four vital dyes on toxicity and apoptosis in a human retinal pigment epithelial (RPE) cell line. METHODS: ARPE-19 cells were exposed to brilliant blue (BriB), methyl blue (MetB), acid violet (AcV) and indocyanine green (ICG). Balanced salt solution was used as control. Five different concentrations of each dye (1, 0.5, 0.25, 0.05 and 0.005 mg/mL) and two exposure times (3 and 30 min) were tested. Cell viability was determined by cell count and MTS assay and cell toxicity by LDH assay. Real-time PCR and Western blotting were used to access the apoptosis process. RESULTS: ICG significantly reduced cell viability after 3 minutes of exposure at all concentrations (p<0.01). BriB was safe at concentrations up to 0.25 mg/mL and MetB at concentrations up to 0.5 mg/mL, while AcV was safe up to 0.05 mg/ml, after 3 minutes of exposure. Toxicity was higher, when the cells were treated for 30 minutes. Expression of Bax, cytochrome c and caspase-9 was upregulated at the mRNA and protein level after ICG exposure, while Bcl-2 was downregulated. AcV and MetB were similar to control. However, BriB resulted in upregulation of Bcl-2, an antiapoptotic protein. CONCLUSIONS: The safest dye used on RPE cells was MetB followed by BriB and AcV. ICG was toxic at all concentrations and exposure times tested. Moreover, ICG was the only dye that induced apoptosis in ARPE-19 cells. BriB significantly increased Bcl-2 protein levels, which might protect against the apoptosis process. PMID- 23675522 TI - Diapause prevention effect of Bombyx mori by dimethyl sulfoxide. AB - HCl treatment has been, for about 80 years, the primary method for the prevention of entry into embryonic diapauses of Bombyx mori. This is because no method is as effective as the HCl treatment. In this study, we discovered that dimethyl sulfoxide (DMSO) prevented entry into the diapause of the silkworm, Bombyx mori. The effect of diapause prevention was 78% as a result of treatment with 100% DMSO concentration, and the effect was comparable to that of the HCl treatment. In contrast, in the case of non-diapause eggs, hatchability was decreased by DMSO in a concentration-dependent manner. The effect of DMSO was restricted within 24 hours after oviposition of diapause eggs, and the critical period was slightly shorter than the effective period of the HCl treatment. DMSO analogs, such as dimethyl formamide (DMF) and dimethyl sulfide (DMS), did little preventive effect against the diapause. Furthermore, we also investigated the permeation effects of chemical compounds by DMSO. When treated with an inhibitor of protein kinase CK2 (CK2) dissolved in DMSO, the prevention rate of the diapause was less than 40%. This means that the inhibition effect by the CK2 inhibitor was the inhibition of embryonic development after diapause prevention by DMSO. These data suggest that DMSO has the effects of preventing from entering into the diapause and permeation of chemicals into diapause eggs. PMID- 23675523 TI - Perinatal bisphenol A exposure and adult glucose homeostasis: identifying critical windows of exposure. AB - Bisphenol A (BPA) is a widespread endocrine-disrupting chemical used as the building block for polycarbonate plastics. Epidemiological evidence has correlated BPA exposure with higher risk of heart disease and type 2 diabetes. However, it remains unknown whether there are critical windows of susceptibility to BPA exposure on the development of dysglycemia. This study was an attempt to investigate the critical windows and the long-term consequences of perinatal exposure to BPA on glucose homeostasis. Pregnant mice were given either vehicle or BPA (100 ug/kg/day) at different time of perinatal stage: 1) on days 1-6 of pregnancy (P1-P6, preimplantation exposure); 2) from day 6 of pregnancy until postnatal day (PND) 0 (P6-PND0, fetal exposure); 3) from lactation until weaning (PND0-PND21, neonatal exposure); and 4) from day 6 of gestation until weaning (P6 PND21, fetal and neonatal exposure). At 3, 6 and 8 months of age, offspring in each group were challenged with glucose and insulin tolerance tests. Then islet morphometry and beta-cell function were measured. The glucose homeostasis was impaired in P6-PND0 mice from 3 to 6 months of age, and this continued to 8 months in males, but not females. While in PND0-PND21 and P6-PND21 BPA-treated groups, only the 3-month-old male offspring developed glucose intolerance. Moreover, at the age of 3 months, perinatal exposure to BPA resulted in the increase of beta-cell mass mainly due to the coordinate changes in cell replication, neogenesis, and apoptosis. The alterations of insulin secretion and insulin sensitivity, rather than beta-cell mass, were consistent with the development of glucose intolerance. Our findings suggest that BPA may contribute to metabolic disorders relevant to glucose homeostasis and the effects of BPA were dose, sex, and time-dependent. Fetal development stage may be the critical window of susceptibility to BPA exposure. PMID- 23675524 TI - Generation and characterization of an Nxf7 knockout mouse to study NXF5 deficiency in a patient with intellectual disability. AB - Members of the Nuclear eXport Factor (NXF) family are involved in the export of mRNA from the nucleus to the cytoplasm, or hypothesized to play a role in transport of cytoplasmic mRNA. We previously reported on the loss of NXF5 in a male patient with a syndromic form of intellectual disability. To study the functional role of NXF5 we identified the mouse counterpart. Based on synteny, mouse Nxf2 is the ortholog of human NXF5. However, we provide several lines of evidence that mouse Nxf7 is the actual functional equivalent of NXF5. Both Nxf7 and NXF5 are predominantly expressed in the brain, show cytoplasmic localization, and present as granules in neuronal dendrites suggesting a role in cytoplasmic mRNA metabolism in neurons. Nxf7 was primarily detected in the pyramidal cells of the hippocampus and in layer V of the cortex. Similar to human NXF2, mouse Nxf2 is highly expressed in testis and shows a nuclear localization. Interestingly, these findings point to a different evolutionary path for both NXF genes in human and mouse. We thus generated and validated Nxf7 knockout mice, which were fertile and did not present any gross anatomical or morphological abnormalities. Expression profiling in the hippocampus and the cortex did not reveal significant changes between wild-type and Nxf7 knockout mice. However, impaired spatial memory was observed in these KO mice when evaluated in the Morris water maze test. In conclusion, our findings provide strong evidence that mouse Nxf7 is the functional counterpart of human NXF5, which might play a critical role in mRNA metabolism in the brain. PMID- 23675526 TI - Water-deficit inducible expression of a cytokinin biosynthetic gene IPT improves drought tolerance in cotton. AB - Water-deficit stress is a major environmental factor that limits agricultural productivity worldwide. Recent episodes of extreme drought have severely affected cotton production in the Southwestern USA. There is a pressing need to develop cotton varieties with improved tolerance to water-deficit stress for sustainable production in water-limited regions. One approach to engineer drought tolerance is by delaying drought-induced senescence via up-regulation of cytokinin biosynthesis. The isopentenyltransferase gene (IPT) that encodes a rate limiting enzyme in cytokinin biosynthesis, under the control of a water-deficit responsive and maturation specific promoter P(SARK) was introduced into cotton and the performance of the P(SARK)::IPT transgenic cotton plants was analyzed in the greenhouse and growth chamber conditions. The data indicate that P(SARK)::IPT transgenic cotton plants displayed delayed senescence under water deficit conditions in the greenhouse. These plants produced more root and shoot biomass, dropped fewer flowers, maintained higher chlorophyll content, and higher photosynthetic rates under reduced irrigation conditions in comparison to wild type and segregated non-transgenic lines. Furthermore, P(SARK)::IPT-transgenic cotton plants grown in growth chamber condition also displayed greater drought tolerance. These results indicate that water-deficit induced expression of an isopentenyltransferase gene in cotton could significantly improve drought tolerance. PMID- 23675525 TI - Proprotein convertase subtilisin/kexin type 9 (PCSK9) can mediate degradation of the low density lipoprotein receptor-related protein 1 (LRP-1). AB - Elevated LDL-cholesterol (LDLc) levels are a major risk factor for cardiovascular disease and atherosclerosis. LDLc is cleared from circulation by the LDL receptor (LDLR). Proprotein convertase subtilisin/kexin 9 (PCSK9) enhances the degradation of the LDLR in endosomes/lysosomes, resulting in increased circulating LDLc. PCSK9 can also mediate the degradation of LDLR lacking its cytosolic tail, suggesting the presence of as yet undefined lysosomal-targeting factor(s). Herein, we confirm this, and also eliminate a role for the transmembrane-domain of the LDLR in mediating its PCSK9-induced internalization and degradation. Recent findings from our laboratory also suggest a role for PCSK9 in enhancing tumor metastasis. We show herein that while the LDLR is insensitive to PCSK9 in murine B16F1 melanoma cells, PCSK9 is able to induce degradation of the low density lipoprotein receptor-related protein 1 (LRP-1), suggesting distinct targeting mechanisms for these receptors. Furthermore, PCSK9 is still capable of acting upon the LDLR in CHO 13-5-1 cells lacking LRP-1. Conversely, PCSK9 also acts on LRP-1 in the absence of the LDLR in CHO-A7 cells, where re-introduction of the LDLR leads to reduced PCSK9-mediated degradation of LRP-1. Thus, while PCSK9 is capable of inducing degradation of LRP-1, the latter is not an essential factor for LDLR regulation, but the LDLR effectively competes with LRP-1 for PCSK9 activity. Identification of PCSK9 targets should allow a better understanding of the consequences of PCSK9 inhibition for lowering LDLc and tumor metastasis. PMID- 23675527 TI - The association of common SNPs and haplotypes in CETP gene with HDL cholesterol levels in Latvian population. AB - The heritability of high-density lipoprotein cholesterol (HDL-C) level is estimated at approximately 50%. Recent genome-wide association studies have identified genes involved in regulation of high-density lipoprotein cholesterol (HDL-C) levels. The precise genetic profile determining heritability of HDL-C however are far from complete and there is substantial room for further characterization of genetic profiles influencing blood lipid levels. Here we report an association study comparing the distribution of 139 SNPs from more than 30 genes between groups that represent extreme ends of HDL-C distribution. We genotyped 704 individuals that were selected from Genome Database of Latvian Population. 10 SNPs from CETP gene showed convincing association with low HDL-C levels (rs1800775, rs3764261, rs173539, rs9939224, rs711752, rs708272, rs7203984, rs7205804, rs11076175 and rs9929488) while 34 SNPs from 10 genes were nominally associated (p<0.05) with HDL-C levels. We have also identified haplotypes from CETP with distinct effects on determination of HDL-C levels. Our conclusion: So far the SNPs in CETP gene are identified as the most common genetic factor influencing HDL-C levels in the representative sample from Latvian population. PMID- 23675528 TI - Minor ailments in pregnancy are not a minor concern for pregnant women: a morbidity assessment survey in rural Sri Lanka. AB - BACKGROUND: Although maternal mortality has become a major focus on global public health agenda, maternal morbidity is a neglected area of research. The purpose of this paper is to present the burden of acute maternal illness during pregnancy. METHODS: A cross sectional study was carried out in Anuradhapura district, Sri Lanka. Pregnant women residing in the Anuradhapura district with a gestational age more than 24 weeks through 36 weeks were recruited to the study using a two stage cluster sampling technique. All pregnant women who consented participated in a detailed interview using a structured questionnaire. Self reported episodes of acute illness during pregnancy were the main outcome measures. Secondary outcomes were utilization of medical services and frequency of hospitalizations. RESULTS: Nausea and vomiting during pregnancy (NVP) was experienced by 325 (69.7%) of the 466 pregnant women studied. Other common symptoms were backache (152, 32.6%), dizziness (112, 24.0%) and heartburn/regurgitation (107, 23.0%). Of the 421 pregnant women who reported ill health conditions 260 (61.8%) women sought medical treatment for these illnesses. Total number of episodes that needed treatment seeking were 373. Hospitalizations were reported by 83 (17.8%) pregnant women and the total number of hospitalizations was 109. The leading cause of hospitalization was NVP which accounted for 43.1% of total admissions and 49.1% of total days spent in hospitals. CONCLUSIONS: Minor maternal ill health conditions affecting day-to-day life have a major burden on pregnancy period. Evidence based management guidelines and health promotion strategies are needed to control and prevent these conditions, in order to provide comprehensive, good quality maternal health care. PMID- 23675529 TI - Increased leptin response and inhibition of apoptosis in thymocytes of young rats offspring from protein deprived dams during lactation. AB - We investigated the consequences of mild maternal malnutrition in rat dams, in terms of thymocyte responses and the putative role of leptin. The young progeny of dams submitted to protein deprivation (PD) during lactation showed at 30 days of age lower body and thymus weights, significant alterations in CD4/CD8-defined T cell subsets without modifications in total thymocyte number as well as in proliferative response. Despite, the rats from PD group did not present alterations in leptin circulating levels, the expression of leptin receptor ObRb was enhanced in their thymocytes. This change was accompanied by an increase in leptin signaling response of thymocytes from PD rats, with an increase in JAK2 and STAT3 phosphorylation after leptin stimulation. Thymocytes from PD rats also presented a decreased rate of spontaneous apoptosis when compared to controls. Accordingly, higher expression of anti-apoptotic protein Bcl-2, and lower of pro apoptotic protein Bax, with no change of pro-apoptotic Bad, and higher pro caspase 3 content were detected in PD thymocytes. Moreover, thymocytes from PD group exhibited a constitutive higher nuclear content of p65 NF-kB associated to a lower IkB content in the cytoplasm. Finally, although there was no change in ob gene expression in PD thymocytes, a higher mRNA expression for the Ob gene was observed in the thymic microenvironment from PD animals. Taken together, the results show that mild maternal protein deprivation during lactation affects thymic homeostasis, enhancing leptin activity, which in turn protects thymocytes from apoptosis in the young progeny, with possible consequences upon the immune response of these animals in adult life. PMID- 23675531 TI - DDRGK1 regulates NF-kappaB activity by modulating IkappaBalpha stability. AB - NF-kappaB is a ubiquitously expressed transcription factor that regulates a large number of genes in response to diverse physiological and pathological stimuli. The regulation of the transcriptional activity of NF-kappaB is often dependent on its interaction with IkappaBalpha. Proteins that bind to IkappaBalpha are critical regulators of NF-kappaB activity. DDRGK1 is a member of the DDRGK domain containing protein family with unknown function. In this study, we showed that the depletion of DDRGK1 inhibits cell proliferation and invasion. Microarray analysis indicated that the expression of NF-kappaB target genes showed the most significant decrease after depleting of DDRGK1, suggesting that DDRGK1 may play an important role in the NF-kappaB signaling pathway. We further demonstrated that DDRGK1 interacts with IkappaBalpha and regulates its stability, thereby regulates the NF-kappaB transcriptional activity. Our findings identify DDRGK1 as an important regulator of the NF-kappaB pathway. PMID- 23675530 TI - Probiotic yeast inhibits VEGFR signaling and angiogenesis in intestinal inflammation. AB - BACKGROUND AND AIMS: Saccharomyces boulardii (Sb) can protect against intestinal injury and tumor formation, but how this probiotic yeast controls protective mucosal host responses is unclear. Angiogenesis is an integral process of inflammatory responses in inflammatory bowel diseases (IBD) and required for mucosal remodeling during restitution. The aim of this study was to determine whether Sb alters VEGFR (vascular endothelial growth factor receptor) signaling, a central regulator of angiogenesis. METHODS: HUVEC were used to examine the effects of Sb on signaling and on capillary tube formation (using the ECMatrixTM system). The effects of Sb on VEGF-mediated angiogenesis were examined in vivo using an adenovirus expressing VEGF-A(164) in the ears of adult nude mice (NuNu). The effects of Sb on blood vessel volume branching and density in DSS-induced colitis was quantified using VESsel GENeration (VESGEN) software. RESULTS: 1) Sb treatment attenuated weight-loss (p<0.01) and histological damage (p<0.01) in DSS colitis. VESGEN analysis of angiogenesis showed significantly increased blood vessel density and volume in DSS-treated mice compared to control. Sb treatment significantly reduced the neo-vascularization associated with acute DSS colitis and accelerated mucosal recovery restoration of the lamina propria capillary network to a normal morphology. 2) Sb inhibited VEGF-induced angiogenesis in vivo in the mouse ear model. 3) Sb also significantly inhibited angiogenesis in vitro in the capillary tube assay in a dose-dependent manner (p<0.01). 4) In HUVEC, Sb reduced basal VEGFR-2 phosphorylation, VEGFR-2 phosphorylation in response to VEGF as well as activation of the downstream kinases PLCgamma and Erk1/2. CONCLUSIONS: Our findings indicate that the probiotic yeast S boulardii can modulate angiogenesis to limit intestinal inflammation and promote mucosal tissue repair by regulating VEGFR signaling. PMID- 23675532 TI - Differential cytotoxic activity of a novel palladium-based compound on prostate cell lines, primary prostate epithelial cells and prostate stem cells. AB - The outcome for patients with advanced metastatic and recurrent prostate cancer is still poor. Therefore, new chemotherapeutics are required, especially for killing cancer stem cells that are thought to be responsible for disease recurrence. In this study, we screened the effect of a novel palladium-based anticancer agent (Pd complex) against six different prostate cancer cell lines, and primary cultures from seven Gleason 6/7 prostate cancer, three Gleason 8/9 prostate cancer and four benign prostate hyperplasia patient samples, as well as cancer stem cells selected from primary cultures. MTT and ATP viability assays were used to assess cell growth and flow cytometry to assess cell cycle status. In addition, immunofluorescence was used to detect gammaH2AX nuclear foci, indicative of DNA damage, and Western blotting to assess the induction of apoptosis and autophagy. The Pd complex showed a powerful growth-inhibitory effect against both cell lines and primary cultures. More importantly, it successfully reduced the viability of cancer stem cells as first reported in this study. The Pd complex induced DNA damage and differentially induced evidence of cell death, as well as autophagy. In conclusion, this novel agent may be promising for use against the bulk of the tumour cell population as well as the prostate cancer stem cells, which are thought to be responsible for the resistance of metastatic prostate cancer to chemotherapy. This study also indicates that the combined use of the Pd complex with an autophagy modulator may be a more promising approach to treat prostate cancer. In addition, the differential effects observed between cell lines and primary cells emphasise the importance of the model used to test novel drugs including its genetic background, and indeed the necessity of using cells cultured from patient samples. PMID- 23675533 TI - The role of Pfmdr1 and Pfcrt in changing chloroquine, amodiaquine, mefloquine and lumefantrine susceptibility in western-Kenya P. falciparum samples during 2008 2011. AB - Single Nucleotide Polymorphisms (SNPs) in the Pfmdr1, and Pfcrt, genes of Plasmodium falciparum may confer resistance to a number of anti-malaria drugs. Pfmdr1 86Y and haplotypes at Pfcrt 72-76 have been linked to chloroquine (CQ) as well as amodiaquine (AQ) resistance. mefloquine (MQ) and lumefantrine (LU) sensitivities are linked to Pfmdr1 86Y. Additionally, Pfcrt K76 allele carrying parasites have shown tolerance to LU. We investigated the association between Pfmdr1 86/Pfcrt 72-76 and P. falciparum resistance to CQ, AQ, MQ and LU using field samples collected during 2008-2011 from malaria endemic sites in western Kenya. Genomic DNA from these samples was genotyped to examine SNPs and haplotypes in Pfmdr1 and Pfcrt respectively. Additionally, immediate ex vivo and in vitro drug sensitivity profiles were assessed using the malaria SYBR Green I fluorescence-based assay. We observed a rapid but steady percent increase in wild type parasites with regard to both Pfmdr1 and Pfcrt between 2008 and 2011 (p<0.0001). Equally, a significant reciprocate decrease in AQ and CQ median IC50 values occurred (p<0.0001) during the same period. Thus, the data in this study point to a significantly rapid change in parasite response to AQ and CQ in the study period. This may be due to releasing of drug pressure on the parasite from reduced use of AQ in the face of increased Artemisinin (ART) Combination Therapy (ACT) administration following the intervention of the Global Fund in 2008. LU has been shown to select for 76K genotypes, thus the observed increase in 76K genotypes coupled with significant cross resistance between LU and MQ, may herald emergence of tolerance against both drugs in future. PMID- 23675534 TI - Regulatory T cells are protective in systemic inflammation response syndrome induced by zymosan in mice. AB - Systemic inflammation response syndrome (SIRS) is a key and mainly detrimental process in the pathophysiology of multiple organ dysfunction syndrome. The balance of pro-inflammation and anti-inflammation controls the initiation and development of SIRS. However, the endogenous counterregulatory immune mechanisms that are involved in the development of SIRS are not well understood. CD4(+)CD25(+)Foxp3 (forkhead box P3)(+) regulatory T lymphocytes (Treg cells) play a key role in the immunological balance of the body. Thus, our aim was to investigate the contribution of these key immunomodulators (Treg cells) to the immune dysfunction that is observed in zymosan-induced SIRS in mice. We first evaluated the level of Treg cells in the lung of mice 6 h, 1 d, 2 d, 3 d, 5 d, and 7 d after the injection of zymosan or normal saline by western blot, real time PCR and flow cytometry. We found that the number of Treg cells and the levels of the Treg cell-related transcription factor (Foxp3) and cytokines (IL 10) in the zymosan-treated group significantly decreased on day 1 and day 2 and significantly increased on day 5 compared with the NS-treated group. In the next experiment, the mice were injected with 200 MUg of anti-CD25 mAb (clone PC61) to deplete the Treg cells and then injected with zymosan 2 days later. The number of Treg cells decreased by more than 50% after the injection of the PC61 mAb. In addition, the expression of the anti-inflammatory cytokine IL-10 also decreased. Moreover, the depletion of the Treg cells profoundly increased the mice'mortality and the degree of lung tissue injury. In conclusion, Treg cells tend to play a protective role in pathogenesis of the zymosan-induced generalized inflammation, and IL-10 signaling is associated with their immunomodulatory effect. PMID- 23675535 TI - Genomic approach to identify factors that drive the formation of three dimensional structures by EA.hy926 endothelial cells. AB - Understanding the mechanisms responsible for tube formation by endothelial cells (ECs) is of major interest and importance in medicine and tissue engineering. Endothelial cells of the human cell line EA.hy926 behave ambivalently when cultured on a random positioning machine (RPM) simulating microgravity. Some cells form tube-like three-dimensional (3D) aggregates, while other cells (AD) continue to grow adherently. Between the fifth and seventh day of culturing, the two types of cell growth achieve the greatest balance. We harvested ECs that grew either adherently or as 3D aggregates separately after five and seven days of incubation on the RPM, and applied gene array analysis and PCR techniques to investigate their gene expression profiles in comparison to ECs growing adherently under normal static 1 g laboratory conditions for equal periods of time. Using gene arrays, 1,625 differentially expressed genes were identified. A strong overrepresentation of transient expression differences was found in the five-day, RPM-treated samples, where the number of genes being differentially expressed in comparison to 1 g cells was highest as well as the degree of alteration regarding distinct genes. We found 27 genes whose levels of expression were changed at least 4-fold in RPM-treated cells as compared to 1 g controls. These genes code for signal transduction and angiogenic factors, cell adhesion, membrane transport proteins or enzymes involved in serine biosynthesis. Fifteen of them, with IL8 (interleukin 8) and VWF (von Willebrand factor) the most prominently affected, showed linkages to genes of another 20 proteins that are important in cell structure maintenance and angiogenesis and extended their network of interaction. Thus, the study reveals numerous genes, which mutually influence each other during initiation of 3D growth of endothelial cells. PMID- 23675536 TI - Protective effect of pregnancy in rural South Africa: questioning the concept of "indirect cause" of maternal death. AB - BACKGROUND: Measurement of the level and composition of maternal mortality depends on the definition used, with inconsistencies leading to inflated rates and invalid comparisons across settings. This study investigates the differences in risk of death for women in their reproductive years during and outside the maternal risk period (pregnancy, delivery, puerperium), focusing on specific causes of infectious, non-communicable and external causes of death after separating out direct obstetrical causes. METHODS: Data on all deaths of women aged 15-49 years that occurred in the Agincourt sub-district between 1992 and 2010 were obtained from the Agincourt health and socio-demographic surveillance system (HDSS) located in rural South Africa. Causes of death were assessed using a validated verbal autopsy instrument. Analysis included 2170 deaths, of which 137 occurred during the maternal risk period. FINDINGS: Overall, women had significantly lower mortality during the maternal risk period than outside it (age-standardized RR = 0.75; 95% CI = 0.63-0.89). This was true in most age groups with the exception of adolescents aged 15-19 years where the risk of death was higher. Mortality from most causes, other than obstetric causes, was lower during the maternal risk period except for malaria, cardiovascular diseases and violence where there were no differences. Lower mortality was significant for HIV/AIDS (RR = 0.29, P<0.0001), cancers (RR = 0.10, P<0.023), and accidents (RR = 0, P<0.0001). INTERPRETATION: In this rural setting typical of much of Southern Africa, pregnancy was largely protective against the risk of death, most likely because of a strong selection effect amongst those women who conceived successfully. The concept of indirect cause of maternal death needs to be re examined. PMID- 23675537 TI - Gateway vectors for efficient artificial gene assembly in vitro and expression in yeast Saccharomyces cerevisiae. AB - Construction of synthetic genetic networks requires the assembly of DNA fragments encoding functional biological parts in a defined order. Yet this may become a time-consuming procedure. To address this technical bottleneck, we have created a series of Gateway shuttle vectors and an integration vector, which facilitate the assembly of artificial genes and their expression in the budding yeast Saccharomyces cerevisiae. Our method enables the rapid construction of an artificial gene from a promoter and an open reading frame (ORF) cassette by one step recombination reaction in vitro. Furthermore, the plasmid thus created can readily be introduced into yeast cells to test the assembled gene's functionality. As flexible regulatory components of a synthetic genetic network, we also created new versions of the tetracycline-regulated transactivators tTA and rtTA by fusing them to the auxin-inducible degron (AID). Using our gene assembly approach, we made yeast expression vectors of these engineered transactivators, AIDtTA and AIDrtTA and then tested their functions in yeast. We showed that these factors can be regulated by doxycycline and degraded rapidly after addition of auxin to the medium. Taken together, the method for combinatorial gene assembly described here is versatile and would be a valuable tool for yeast synthetic biology. PMID- 23675538 TI - Generation of murine sympathoadrenergic progenitor-like cells from embryonic stem cells and postnatal adrenal glands. AB - Sympathoadrenergic progenitor cells (SAPs) of the peripheral nervous system (PNS) are important for normal development of the sympathetic PNS and for the genesis of neuroblastoma, the most common and often lethal extracranial solid tumor in childhood. However, it remains difficult to isolate sufficient numbers of SAPs for investigations. We therefore set out to improve generation of SAPs by using two complementary approaches, differentiation from murine embryonic stem cells (ESCs) and isolation from postnatal murine adrenal glands. We provide evidence that selecting for GD2 expression enriches for ESC-derived SAP-like cells and that proliferating SAP-like cells can be isolated from postnatal adrenal glands of mice. These advances may facilitate investigations about the development and malignant transformation of the sympathetic PNS. PMID- 23675539 TI - A mode-of-action approach for the identification of genotoxic carcinogens. AB - Distinguishing between clastogens and aneugens is vital in cancer risk assessment because the default assumption is that clastogens and aneugens have linear and non-linear dose-response curves, respectively. Any observed non-linearity must be supported by mode of action (MOA) analyses where biological mechanisms are linked with dose-response evaluations. For aneugens, the MOA has been well characterised as disruptors of mitotic machinery where chromosome loss via micronuclei (MN) formation is an accepted endpoint used in risk assessment. In this study we performed the cytokinesis-block micronucleus assay and immunofluorescence mitotic machinery visualisation in human lymphoblastoid (AHH-1) and Chinese Hamster fibroblast (V79) cell lines after treatment with the aneugen 17-beta-oestradiol (E2). Results were compared to previously published data on bisphenol-A (BPA) and Rotenone data. Two concentration-response approaches (the threshold-[Td] and benchmark-dose [BMD] approaches) were applied to derive a point of departure (POD) for in vitro MN induction. BMDs were also derived from the most sensitive carcinogenic endpoint. Ranking comparisons of the PODs from the in vitro MN and the carcinogenicity studies demonstrated a link between these two endpoints for BPA, E2 and Rotenone. This analysis was extended to include 5 additional aneugens, 5 clastogens and 3 mutagens and further concentration and dose-response correlations were observed between PODs from the in vitro MN and carcinogenicity. This approach is promising and may be further extended to other genotoxic carcinogens, where MOA and quantitative information from the in vitro MN studies could be used in a quantitative manner to further inform cancer risk assessment. PMID- 23675540 TI - Costs of suppressing emotional sound and countereffects of a mindfulness induction: an experimental analog of tinnitus impact. AB - Tinnitus is the experience of sounds without an appropriate external auditory source. These auditory sensations are intertwined with emotional and attentional processing. Drawing on theories of mental control, we predicted that suppressing an affectively negative sound mimicking the psychoacoustic features of tinnitus would result in decreased persistence in a mentally challenging task (mental arithmetic) that required participants to ignore the same sound, but that receiving a mindfulness exercise would reduce this effect. Normal hearing participants (N = 119) were instructed to suppress an affectively negative sound under cognitive load or were given no such instructions. Next, participants received either a mindfulness induction or an attention control task. Finally, all participants worked with mental arithmetic while exposed to the same sound. The length of time participants could persist in the second task served as the dependent variable. As hypothesized, results indicated that an auditory suppression rationale reduced time of persistence relative to no such rationale, and that a mindfulness induction counteracted this detrimental effect. The study may offer new insights into the mechanisms involved in the development of tinnitus interference. Implications are also discussed in the broader context of attention control strategies and the effects of emotional sound on task performance. The ironic processes of mental control may have an analog in the experience of sounds. PMID- 23675541 TI - A public health response against Strongyloides stercoralis: time to look at soil transmitted helminthiasis in full. AB - Strongyloides stercoralis infections have a worldwide distribution with a global burden in terms of prevalence and morbidity that is largely ignored. A public health response against soil-transmitted helminth (STH) infections should broaden the strategy to include S. stercoralis and overcome the epidemiological, diagnostic, and therapeutic challenges that this parasite poses in comparison to Ascaris lumbricoides, Trichuris trichiura, and hookworms. The relatively poor sensitivity of single stool evaluations, which is further lowered when quantitative techniques aimed at detecting eggs are used, also complicates morbidity evaluations and adequate drug efficacy measurements, since S. stercoralis is eliminated in stools in a larval stage. Specific stool techniques for the detection of larvae of S. stercoralis, like Baermann's and Koga's agar plate, despite superiority over direct techniques are still suboptimal. New serologies using recombinant antigens and molecular-based techniques offer new hopes in those areas. The use of ivermectin rather than benzimidazoles for its treatment and the need to have curative regimens rather than lowering the parasite burden are also unique for S. stercoralis in comparison to the other STH due to its life cycle, which allows reproduction and amplification of the worm burden within the human host. The potential impact on STH of the benzimidazoles/ivermectin combinations, already used for control/elimination of lymphatic filariasis, should be further evaluated in public health settings. While waiting for more effective single-dose drug regimens and new sensitive diagnostics, the evidence and the tools already available warrant the planning of a common platform for STH and S. stercoralis control. PMID- 23675542 TI - IRES-driven expression of the capsid protein of the Venezuelan equine encephalitis virus TC-83 vaccine strain increases its attenuation and safety. AB - The live-attenuated TC-83 strain is the only licensed veterinary vaccine available to protect equids against Venezuelan equine encephalitis virus (VEEV) and to protect humans indirectly by preventing equine amplification. However, TC 83 is reactogenic due to its reliance on only two attenuating point mutations and has infected mosquitoes following equine vaccination. To increase its stability and safety, a recombinant TC-83 was previously engineered by placing the expression of the viral structural proteins under the control of the Internal Ribosome Entry Site (IRES) of encephalomyocarditis virus (EMCV), which drives translation inefficiently in insect cells. However, this vaccine candidate was poorly immunogenic. Here we describe a second generation of the recombinant TC-83 in which the subgenomic promoter is maintained and only the capsid protein gene is translated from the IRES. This VEEV/IRES/C vaccine candidate did not infect mosquitoes, was stable in its attenuation phenotype after serial murine passages, and was more attenuated in newborn mice but still as protective as TC-83 against VEEV challenge. Thus, by using the IRES to modulate TC-83 capsid protein expression, we generated a vaccine candidate that combines efficient immunogenicity and efficacy with lower virulence and a reduced potential for spread in nature. PMID- 23675543 TI - A real-time ITS1-PCR based method in the diagnosis and species identification of Leishmania parasite from human and dog clinical samples in Turkey. AB - Human visceral leishmaniasis (VL) caused by L. infantum and cutaneous leishmaniasis (CL) caused by L. tropica and L. infantum have been reported in Turkey. L. infantum is also responsible for canine leishmaniasis (CanL) and it is widely common in the country. The main aim of the present study was to design a real-time PCR method based on the internal transcribed spacer 1 (ITS1) region in the diagnosis of all clinical forms of leishmaniasis in Mediterranean, and to identify the species directly from clinical samples. Totally, 315 clinical specimens, human/canine visceral (blood, bone marrow, lymph node) and cutaneous (lesion aspiration) samples, and 51 Turkish Leishmania isolates typed by isoenzymatic method were included in the study. For optimization, DNA samples of the 34 strains were amplified by conventional ITS1-PCR and then sequenced for designing the primers and probes, allowing the species identification. Following the validation with the isolates, the test was applied on clinical samples and melting temperatures were used for genotyping. A group of PCR products were further sequenced for confirmation and assigning the inter- and intraspecies heterogeneity. The diagnosis of leishmaniasis is successfully achieved by the new real-time PCR method, and the test identified 80.43% of human and canine VL samples as L.infantum and 6.52% as L.tropica; 52.46% of CL samples as L. infantum and 26.90% as L. tropica. In 13.04% of visceral and 20.62% of cutaneous samples, two peaks were observed. However, the higher peak was found to be concordant with the sequencing results in 96.96%, in terms of species identification. The real time ITS1 PCR assay clearly identified the leishmanial species in 81.58% of all clinical samples. Genotypic variations of Leishmania parasites in Turkey within species and intraspecies were observed, and L. tropica is also found as causative agent of human and canine VL in Turkey. PMID- 23675544 TI - Post-exposure therapeutic efficacy of COX-2 inhibition against Burkholderia pseudomallei. AB - Burkholderia pseudomallei is a Gram-negative, facultative intracellular bacillus and the etiologic agent of melioidosis, a severe disease in Southeast Asia and Northern Australia. Like other multidrug-resistant pathogens, the inherent antibiotic resistance of B. pseudomallei impedes treatment and highlights the need for alternative therapeutic strategies that can circumvent antimicrobial resistance mechanisms. In this work, we demonstrate that host prostaglandin E2 (PGE2) production plays a regulatory role in the pathogenesis of B. pseudomallei. PGE2 promotes B. pseudomallei intracellular survival within macrophages and bacterial virulence in a mouse model of pneumonic melioidosis. PGE2-mediated immunosuppression of macrophage bactericidal effector functions is associated with increased arginase 2 (Arg2) expression and decreased nitric oxide (NO) production. Treatment with a commercially-available COX-2 inhibitor suppresses the growth of B. pseudomallei in macrophages and affords significant protection against rapidly lethal pneumonic melioidosis when administered post-exposure to B. pseudomallei-infected mice. COX-2 inhibition may represent a novel immunotherapeutic strategy to control infection with B. pseudomallei and other intracellular pathogens. PMID- 23675545 TI - Bayesian geostatistical modeling of leishmaniasis incidence in Brazil. AB - BACKGROUND: Leishmaniasis is endemic in 98 countries with an estimated 350 million people at risk and approximately 2 million cases annually. Brazil is one of the most severely affected countries. METHODOLOGY: We applied Bayesian geostatistical negative binomial models to analyze reported incidence data of cutaneous and visceral leishmaniasis in Brazil covering a 10-year period (2001 2010). Particular emphasis was placed on spatial and temporal patterns. The models were fitted using integrated nested Laplace approximations to perform fast approximate Bayesian inference. Bayesian variable selection was employed to determine the most important climatic, environmental, and socioeconomic predictors of cutaneous and visceral leishmaniasis. PRINCIPAL FINDINGS: For both types of leishmaniasis, precipitation and socioeconomic proxies were identified as important risk factors. The predicted number of cases in 2010 were 30,189 (standard deviation [SD]: 7,676) for cutaneous leishmaniasis and 4,889 (SD: 288) for visceral leishmaniasis. Our risk maps predicted the highest numbers of infected people in the states of Minas Gerais and Para for visceral and cutaneous leishmaniasis, respectively. CONCLUSIONS/SIGNIFICANCE: Our spatially explicit, high-resolution incidence maps identified priority areas where leishmaniasis control efforts should be targeted with the ultimate goal to reduce disease incidence. PMID- 23675546 TI - Strongyloides stercoralis: a plea for action. PMID- 23675547 TI - Incidence of rabies in humans and domestic animals and people's awareness in North Gondar Zone, Ethiopia. AB - BACKGROUND: Rabies is a zoonotic disease that has been prevalent in humans and animals for centuries in Ethiopia and it is often dealt with using traditional practices. There is lack of accurate quantitative information on rabies both in humans and animals in Ethiopia and little is known about the awareness of the people about the disease. In this study, we estimated the incidence of rabies in humans and domestic animals, and assessed the people's awareness about the disease in North Gondar zone, Ethiopia. METHODOLOGY/PRINCIPAL FINDINGS: The incidence of rabies in humans and domestic animals was prospectively followed up for one year period based on clinical observation. A questionnaire was also administered to 120 randomly selected dog owners and 5 traditional healers to assess the knowledge and practices about the disease. We found an annual estimated rabies incidence of 2.33 cases per 100,000 in humans, 412.83 cases per 100,000 in dogs, 19.89 cases per 100,000 in cattle, 67.68 cases per 100,000 in equines, and 14.45 cases per 100,000 in goats. Dog bite was the source of infection for all fatal rabies cases. Ninety eight percent of the questionnaire respondents were familiar with rabies and mentioned dog bite as a means of transmission. But discordant with current scientific knowledge, 84% and 32% of the respondents respectively mentioned any type of contact (irrespective of skin condition) with saliva, and inhalation as a means of transmission of rabies. Eighty four percent of the respondents relied on traditional healers for management of rabies. CONCLUSIONS: The study shows high canine rabies burden, and lack of sufficient awareness about the disease and high reliance on traditional treatment that interfere with timely post exposure management. Vaccination of dogs, proper post exposure management, and increasing the awareness of the community are suggested to reduce the disease burden. PMID- 23675548 TI - Is pregnancy associated with severe dengue? A review of data from the Rio de Janeiro surveillance information system. AB - BACKGROUND: Dengue is a reportable disease in Brazil; however, pregnancy has been included in the application form of the Brazilian notification information system only after 2006. To estimate the severity of maternal dengue infection, the available data that were compiled from January 2007 to December 2008 by the official surveillance information system of the city of Rio de Janeiro were reviewed. METHODS AND PRINCIPAL FINDINGS: During the study period, 151,604 cases of suspected dengue infection were reported. Five hundred sixty-one women in their reproductive age (15-49 years) presented with dengue infection; 99 (18.1%) pregnant and 447 (81.9%) non-pregnant women were analyzed. Dengue cases were categorized using the 1997 WHO classification system, and DHF/DSS were considered severe disease. The Mann-Whitney test was used to compare maternal age, according to gestational period, and severity of disease. A chi-square test was utilized to evaluate the differences in the proportion of dengue severity between pregnant and non-pregnant women. Univariate analysis was performed to compare outcome variables (severe dengue and non-severe dengue) and explanatory variables (pregnancy, gestational age and trimester) using the Wald test. A multivariate analysis was performed to assess the independence of statistically significant variables in the univariate analysis. A p-value<0.05 was considered statistically significant. A higher percentage of severe dengue infection among pregnant women was found, p = 0.0001. Final analysis demonstrated that pregnant women are 3.4 times more prone to developing severe dengue (OR: 3.38; CI: 2.10-5.42). Mortality among pregnant women was superior to non-pregnant women. CONCLUSION: Pregnant women have an increased risk of developing severe dengue infection and dying of dengue. PMID- 23675549 TI - A cluster randomized study of the safety of integrated treatment of trachoma and lymphatic filariasis in children and adults in Sikasso, Mali. AB - BACKGROUND: Neglected tropical diseases are co-endemic in many areas of the world, including sub Saharan Africa. Currently lymphatic filariasis (albendazole/ivermectin) and trachoma (azithromycin) are treated separately. Consequently, financial and logistical benefit can be gained from integration of preventive chemotherapy programs in such areas. METHODOLOGY/FINDINGS: 4 villages in two co-endemic districts (Kolondieba and Bougouni) of Sikasso, Mali, were randomly assigned to coadministered treatment (ivermectin/albendazole/azithromycin) or standard therapy (ivermectin/albendazole with azithromycin 1 week later). These villages had previously undergone 4 annual MDA campaigns with ivermectin/albendazole and 2 with azithromycin. One village was randomly assigned to each treatment arm in each district. There were 7515 eligible individuals in the 4 villages, 3011(40.1%) of whom participated in the study. No serious adverse events occurred, and the majority of adverse events were mild in intensity (mainly headache, abdominal pain, diarrhoea and "other signs/symptoms"). The median time to the onset of the first event, of any type, was later (8 days) in the two standard treatment villages than in the co administration villages. Overall the number of subjects reporting any event was similar in the co-administration group compared to the standard treatment group [18.7% (281/1501) vs. 15.8% (239/1510)]. However, the event frequency was higher in the coadministration group (30.4%) than in the standard treatment group (11.0%) in Kolondieba, while the opposite was observed in Bougouni (7.1% and 20.9% respectively). Additionally, the overall frequency of adverse events in the co-administration group (18.7%) was comparable to or lower than published frequencies for ivermectin+albendazole alone. CONCLUSIONS: These data suggest that co-administration of ivermectin+albendazole and azithromycin is safe; however the small number of villages studied and the large differences between them resulted in an inability to calculate a meaningful overall estimate of the difference in adverse event rates between the regimens. Further work is therefore needed before co-administration can be definitively recommended. TRIAL REGISTRATION: ClinicalTrials.gov; NCT01586169. PMID- 23675550 TI - Leishmania mexicana infection induces IgG to parasite surface glycoinositol phospholipids that can induce IL-10 in mice and humans. AB - Infection with the intracellular protozoan parasite Leishmania mexicana causes chronic disease in C57BL/6 mice, in which cutaneous lesions persist for many months with high parasite burdens (10(7)-10(8) parasites). This chronic disease process requires host IL-10 and FcgammaRIII. When Leishmania amastigotes are released from cells, surface-bound IgG can induce IL-10 and suppress IL-12 production from macrophages. These changes decrease IFN-gamma from T cells and nitric oxide production in infected cells, which are both required for Leishmania control. However, antibodies targets and the kinetics of antibody production are unknown. Several groups have been unsuccessful in identifying amastigote surface proteins that bind IgG. We now show that glycoinositol phospholipids (GIPLs) of L. mexicana are recognized by mouse IgG1 by 6 weeks of infection, with a rapid increase between 12 and 16 weeks, consistent with the timing of chronic disease in C57BL/6 mice vs. healing in FcgammaRIII-deficient mice. A single prominent spot on TLC is recognized by IgG, and the glycolipid is a glycosyl phosphatidylinositol containing a branched mannose structure. We show that the lipid structure of the GIPL (the sn-2 fatty acid) is required for antibody recognition. This GIPL is abundant in L. mexicana amastigotes, rare in stationary phase promastigotes, and absent in L. major, consistent with a role for antibodies to GIPLs in chronic disease. A mouse monoclonal anti-GIPL IgG recognizes GIPLs on the parasite surface, and induces IL-10 from macrophages. The current work also extends this mouse analysis to humans, finding that L. mexicana infected humans with localized and diffuse cutaneous leishmaniasis have antibodies that recognize GIPLs, can bind to the surface of amastigotes, and can induce IL-10 from human monocytes. Further characterization of the target glycolipids will have important implications for drug and vaccine development and will elucidate the poorly understood role of glycolipids in the immunology of infections. PMID- 23675551 TI - Prospective study on the incidence and progression of clinical signs in naive dogs naturally infected by Leishmania infantum. AB - The incidence of clinical and clinicopathological signs associated with the progression of infection was evaluated prospectively in 329 naive young dogs exposed to Leishmania infantum transmission and examined periodically during 22 months (M). The dogs were part of Leishmania vaccine investigations performed under natural conditions. Vaccinated groups were considered in the evaluation when the vaccine resulted non-protective and the appearance and progression of signs did not differ statistically from controls at each time point, otherwise only control groups were included. 115 beagles were part of 3 studies (A to C) performed in the same kennel; 214 owned dogs (29 breeds, 2.3% beagles) were included in a study (D) performed in 45 endemic sites. At M22 the prevalence of any Leishmania infection stage classified as subpatent, active asymptomatic, or symptomatic was 59.8% in studies A-C and 29.2% in study D. Despite different breed composition and infection incidence, the relative proportion of active infections and the progression and type of clinical and clinicopathological signs have been similar in both study sets. All asymptomatic active infections recorded have invariably progressed to full-blown disease, resulting in 56 sick dogs at M22. In these dogs, lymph nodes enlargement and weight loss--recorded from M12- were the most common signs. Cutaneous signs were seen late (M18) and less frequently. Ocular signs appeared even later, being sporadically recorded at M22. Most clinicopathological alterations became evident from M12, although a few cases of thrombocytopenia or mild non-regenerative anemia were already observed at M6. Albumin/globulin inversions were recorded from M12 and urea/creatinine increase appeared mostly from M18. Altogether our findings indicate that any susceptible young dogs naturally infected by L. infantum present a common pattern of progression of signs during 2 years post infection, providing clues for medical and epidemiological applied aspects. PMID- 23675552 TI - From the epicardial adipose tissue to vulnerable coronary plaques. AB - Thin cap fibroatheromas (TCFAs) are thought to be the most common underlying substrate in patients suffering acute coronary thrombotic events. Recently, an interesting association between TCFAs and a particular depot of visceral fat called epicardial adipose tissue (EAT) has been suggested. In this article, we discuss some basic and clinical aspects of this association and then briefly review some of the pathophysiological characteristics attributed to EAT that explain why this particular depot of fat has been attracting the attention of the cardiological scientific community in recent years. Finally we discuss the value of optical coherence tomography in the diagnosis of TCFAs and the role of multislice computed tomography to assess EAT. PMID- 23675553 TI - Sphingolipids in cardiovascular and cerebrovascular systems: Pathological implications and potential therapeutic targets. AB - The sphingolipid metabolites ceramide, sphingosine, and sphingosine-1-phosphate (S1P) and its enzyme sphingosine kinase (SphK) play an important role in the regulation of cell proliferation, survival, inflammation, and cell death. Ceramide and sphingosine usually inhibit proliferation and promote apoptosis, while its metabolite S1P phosphorylated by SphK stimulates growth and suppresses apoptosis. Because these metabolites are interconvertible, it has been proposed that it is not the absolute amounts of these metabolites but rather their relative levels that determine cell fate. The relevance of this "sphingolipid rheostat" and its role in regulating cell fate has been borne out by work in many labs using many different cell types and experimental manipulations. A central finding of these studies is that SphK is a critical regulator of the sphingolipid rheostat, as it not only produces the pro-growth, anti-apoptotic messenger S1P, but also decreases levels of pro-apoptotic ceramide and sphingosine. Activation of bioactive sphingolipid S1P signaling has emerged as a critical protective pathway in response to acute ischemic injury in both cardiac and cerebrovascular disease, and these observations have considerable relevance for future potential therapeutic targets. PMID- 23675554 TI - Drugs to be avoided in patients with long QT syndrome: Focus on the anaesthesiological management. AB - Long QT syndrome incidence is increasing in general population. A careful pre-, peri- and post-operative management is needed for patients with this syndrome because of the risk of Torsades de Pointes and malignant arrhythmias. The available data regarding prevention of lethal Torsades de Pointes during anesthesia in patients with long QT syndrome is scant and conflicting: only case reports and small case series with different outcomes have been published. Actually, there are no definitive guidelines on pre-, peri- and post-operative anesthetic management of congenital long QT syndrome. Our review focuses on anesthetic recommendations for patients diagnosed with congenital long QT syndrome furnishing some key points for preoperative optimization, intraoperative anesthetic agents and postoperative care plan, which could be the best for patients with c-long QT syndrome who undergo surgery. PMID- 23675556 TI - Papillary fibroelastoma of the aortic valve: An unusual cause of angina. AB - Papillary fibroelastoma of the aortic valve is an uncommon benign tumor of the heart that can present with embolic events. We report a case of 54-year-old lady with exertional chest pain and prior history of ST segment elevation myocardial infarction who was subsequently found to have a fibroelastoma of the aortic valve. The absence of angiographically significant coronary artery disease and resolution of anginal symptoms post-surgery in our patient points to the possibility of fibroelastoma causing these anginal symptoms. Although uncommon, fibroelastoma are being recognized more frequently with the help of transesophageal echocardiography. Hence, in the absence of significant coronary artery disease, we emphasize the importance of consideration of papillary fibroelastoma of the aortic valve as a cause of angina. We also discuss the key aspects of the fibroelastoma including presentation, diagnostic modalities and treatment options. PMID- 23675557 TI - Concept of defibrillation vector in the management of high defibrillation threshold. AB - We present a case where defibrillation threshold was dangerously elevated to the point that the patient had no safety margin, and his implantable cardioverter defibrillator generator was discovered to have migrated. Generator migration reduces the distance between the can and the coil, effectively creating a smaller bipolar current and sparing the left ventricle from the current needed for defibrillation. This case underscores the importance of securing the generator in place, as this patient would have been spared multiple shocks and an invasive medical procedure had his generator been better secured. PMID- 23675555 TI - Renal sympathetic denervation in resistant hypertension. AB - Resistant hypertension remains a major clinical problem despite the available multidrug therapy. Over the next decades, its incidence will likely increase given that it is strongly associated with older age and obesity. Resistant hypertension patients have an increased cardiovascular risk, thus effective antihypertensive treatment will provide substantial health benefits. The crosstalk between sympathetic nervous system and kidneys plays a crucial role in hypertension. It influences several pathophysiological mechanisms such as the central sympathetic tone, the sodium balance and the systemic neurohumoral activation. In fact, studies using several animal models demonstrated that the renal denervation prevented and attenuated hypertension in multiple species. Large reductions in blood pressure were also observed in malignant hypertension patients submitted to sympathectomy surgeries. However, these approaches had an unacceptably high rates of periprocedural complications and disabling adverse events. Recently, an innovative non-pharmacological therapy that modulates sympathetic activation has been successfully developed. Renal sympathetic percutaneous denervation is an endovascular procedure that uses radiofrequency energy to destroy the autonomic renal nerves running inside the adventitia of renal arteries. This method represents a promising new approach to the strategy of inhibiting the sympathetic nervous system. The aim of this review is to examine the background knowledge that resulted in the development of this hypertension treatment and to critically appraise the available clinical evidence. PMID- 23675558 TI - Transvenous defibrillator implantation in a patient with persistent left superior vena cava. AB - Persistent left superior vena cava (LSVC) can be incidentally detected during pacemaker implantation through left pectoral side. There is technical difficulty of optimal site pacing and lead stability for right ventricle lead in such situation. We hereby report a case of successful single-chamber implantable cardioverter defibrillator (ICD) implantation in a 50 years-old male with LSVC. The practical issues related with right ventricle lead implantation and pacing/defibrillation parameters for ICD device are discussed. PMID- 23675559 TI - A case of type I variant Kounis syndrome with Samter-Beer triad. AB - Kounis syndrome is defined as the coexistence of acute coronary syndromes with situations associated with allergy or hypersensitivity, as well as anaphylactic or anaphylactoid reactions, to a variety of medical conditions, environmental and medication exposures. We report a case of Kounis-Zavras syndrome type I variant in the setting of aspirin-induced asthma, or the Samter-Beer triad of asthma, nasal polyps and aspirin allergy. When there is a young individual with no predisposing factors of atherosclerosis and apparent coronary lesion, with or without electrocardiography and biochemical markers of infarction, the possibility of Kounis syndrome should be kept in mind. PMID- 23675560 TI - Evaluation of myocardial infarction patients after coronary revasculation by dual phase multi-detector computed tomography: Now and in future. AB - Multidetector-row computed tomography (MDCT) has become one of the major tools in diagnosing and evaluating patients with coronary artery disease in recent years. In selected patients, MDCT has been shown to provide more reliable accuracy in detection of stent patency than invasive coronary angiography. Chiou et al reported a delicate infarcted myocardium at-risk score. According to their results, the MDCT-based myocardium at-risk score had a good correlation with the thallium 201 ST-segment elevation myocardial infarction-based summed difference score (r = 0.841, P < 0.001). They claimed that dual-phase MDCT is useful in detecting different patterns of obstructive lesions and the extent of myocardium at risk. In this commentary, we discuss the current status of the clinical application of MDCT in patients with myocardial infarction in relation to evaluating the myocardial perfusion defect, detecting reversible myocardial ischemia, assessing myocardial viability, estimating target lesion restenosis, and calculating of fractional flow reserve from MDCT. PMID- 23675562 TI - Understanding basic steps to hematopoietic stem cell transplantation evaluation. AB - We are celebrating one millionth transplant in year 2013! With continued improvement in hematopoietic cell transplantation (HCT) outcome, the indications for HCT continue to grow. Furthermore the sources of stem cells and the number of suitable matches are expanding. At the same time, modified transplantation regimens have facilitated safer procedures despite increase in patient's age and comorbidies. In the current era, any patient indicated for HCT has a stem cell source and therefore steps to HCT and coordinated pre-transplant care is an integral part of management to improve transplant outcome. This review discusses our approach to the transplant evaluation process and this article will serve as a valuable tool for primary care physicians and referring hematologists/oncologists. PMID- 23675561 TI - Immune surveillance and lymphoid malignancy in immunocompromised host. AB - Immune surveillance is a dynamic process that involves an intact immune system to identify and protect the host against tumor development. The increased understanding of the genetics, infections and hematological malignancies in congenital immune deficiency states supports the concept that impaired T cells and Natural-killer/T cells leads to B-cell lymphoma. Furthermore, severe combined immunodeficient mice are prone to spontaneous tumor development and therefore serve as experimental models. Here we discuss the acquired conditions and mechanisms involved in dysregulation of the immune system that lead to lymphoma. Preemptive strategies to improve immune regulation and response and restore a competent immune system may lead to a decrease in lymphoid malignancies. PMID- 23675563 TI - Aging- and activation-induced platelet microparticles suppress apoptosis in monocytic cells and differentially signal to proinflammatory mediator release. AB - BACKGROUND: Platelet microparticles (PM) are the most abundant cell-derived microparticles in the blood, and accumulate in thrombo-inflammatory diseases. Platelets produce PM upon aging via an apoptosis-like process and by activation with strong agonists. We previously showed that long-term treatment of monocytic cells with apoptosis-induced PM (PMap) promotes their differentiation into resident macrophages. Here we investigated shorter term effects of various types of PM on monocyte signalling and function. METHODS AND RESULTS: Flow cytometry and scanning electron microscopy revealed that PM formed upon platelet aging (PMap) or ultra-sonication (PMsonic) expressed activated alphaIIbbeta3 integrins and tended to assemble into aggregates. In contrast, PM formed upon platelet activation with thrombin (PMthr) or Ca(2+) ionophore (PMiono) had mostly non activated alphaIIbbeta3 and little aggregate formation, but had increased CD63 expression. PM from activated and sonicated platelets expressed phosphatidylserine at their surface, while only the latter were enriched in the receptors CD40L and CX3CR1. All PM types expressed P-selectin, interacted with monocytic cells via this receptor, and were internalised into these cells. The various PM types promoted actin cytoskeletal rearrangements and hydrogen peroxide production by monocytic cells. Markedly, both aging- and activation-induced PM types stimulated the phosphoinositide 3-kinase/Akt pathway, suppressing apoptosis induced by several agonists, in a P-selectin-dependent manner. On the other hand, the PM types differentially influenced monocyte signalling in eliciting Ca(2+) fluxes (particularly PMap) and in releasing secondary mediators (complement factor C5a with PMap, and pro-inflammatory tumour necrosis factor-alpha with PMthr). CONCLUSIONS: In spite of their common anti-apoptotic potential via Akt activation, aging- and activation-induced PM cause different Ca(2+) signalling events and mediator release in monocytic cells. By implication, aging and activated platelets may modulate monocyte function in different way by the shedding of different PM types. PMID- 23675564 TI - MyD88 is involved in myeloid as well as lymphoid hematopoiesis independent of the presence of a pathogen. AB - MyD88 was originally described as a primary response gene up-regulated during myeloid differentiation after IL-6 induction. Later, MyD88 was shown to be a key molecule necessary for IL1, IL18 and Toll-like receptor signaling. Since these receptors recognize abundantly produced cytokines during infection or molecular patterns of pathogens, MyD88 itself was suggested to be an important regulator of the first line of defense against invading pathogens, including the differentiation and maturation of myeloid cells. Here we describe that MyD88 is important for early and late hematopoietic events that occur independently of antigen under steady-state conditions. In MyD88-deficient mice the earliest alteration in hematopoiesis was found at the level of long-term hematopoietic stem cells. Moreover, we found that MyD88 influences not only the development of the myeloid lineage but also the differentiation of B cells. The B cell defect observed in Btk-deficient mice is further enhanced when both molecules, Btk and MyD88, are not expressed. Therefore, MyD88 affects myeloid as well as lymphoid hematopoiesis. Since Btk and MyD88 deficiencies influence differentially myeloid and lymphoid development, both molecules seem to act in different signaling pathways important for appropriate developmental events during myelo- and lymphopoiesis. PMID- 23675566 TI - Refinement of IKZF1 recombination hotspots in pediatric BCP-ALL patients. AB - Chromosomal translocations resulting in chimeric fusion genes are prototypic for pediatric leukemia patients. The most known fusions are ETV6-RUNX1 or BCR-ABL1 in B-cell progenitor (BCP)-ALL, and rearrangements of MLL in pediatric ALL and AML. Genome-wide sequencing projects have revealed additional, recurrent gene mutations in B cell malignancies. One of these mutations comprises the IKZF1 gene, encoding the IKAROS transcription factor which is one of the essential transcription factors driving lymphoid development. IKZF1 deletions were first identified by SNP arrays in ALL patients, and later identified with a high prevalence in BCR-ABL1(+) patients. IKZF1 deletions turned out to be an independent prognostic marker associated with a poor outcome. Here, we characterized IKZF1 deletions in pediatric BCP-ALL patients by combining MLPA mapping experiments with long distance inverse PCR. The aim of our study was also to compare existing methods with our approach. Our attempt confirmed many of the existing data but revealed a more complex pattern of recombination sites, including a total of 4 recombination hotspots. This extended knowledge was translated into a novel, multiplex PCR assay that allows to perform IKZF1 deletion analyses by using a 2-tube PCR approach. PMID- 23675565 TI - Treatment of older patients with acute myeloid leukemia (AML): a Canadian consensus. AB - Patients over age 60 comprise the majority of those diagnosed with acute myeloid leukemia (AML), but treatment approaches in this population are variable, with many uncertainties and controversies. Our group conducted a literature review to summarize the latest information and to develop a consensus document with practical treatment recommendations. We addressed five key questions: selection criteria for patients to receive intensive induction chemotherapy; optimal induction and post-remission regimens; allogeneic hematopoietic stem cell transplantation (HSCT); treatment of patients not suitable for induction chemotherapy; and treatment of patients with prior hematological disorders or therapy-related AML. Relevant literature was identified through a PubMed search of publications from 1991 to 2012. Key findings included the recognition that cytogenetics and molecular markers are major biologic determinants of treatment outcomes in the older population, both during induction therapy and following HSCT. Although disease-specific and patient-specific risk factors for poor outcomes are more common in the older population, age is not in itself sufficient grounds for withholding established treatments, including induction and consolidation chemotherapy. The role of HSCT and use of hypomethylating agents are discussed. Finally, suggested treatment algorithms are outlined, based on these recommendations. PMID- 23675567 TI - Guidelines and diagnostic algorithm for patients with suspected systemic mastocytosis: a proposal of the Austrian competence network (AUCNM). AB - Systemic mastocytosis (SM) is a hematopoietic neoplasm characterized by pathologic expansion of tissue mast cells in one or more extracutaneous organs. In most children and most adult patients, skin involvement is found. Childhood patients frequently suffer from cutaneous mastocytosis without systemic involvement, whereas most adult patients are diagnosed as suffering from SM. In a smaller subset of patients, SM without skin lesions develops which is a diagnostic challenge. In the current article, a diagnostic algorithm for patients with suspected SM is proposed. In adult patients with skin lesions and histologically confirmed mastocytosis in the skin (MIS), a bone marrow biopsy is recommended regardless of the serum tryptase level. In adult patients without skin lesions who are suffering from typical mediator-related symptoms, the basal serum tryptase level is an important diagnostic parameter. In those with slightly elevated tryptase (15-30 ng/ml), additional non-invasive investigations, including a KIT mutation analysis of peripheral blood cells and sonographic analysis, is performed. In adult patients in whom i) KIT D816V is detected or/and ii) the basal serum tryptase level is clearly elevated (> 30 ng/ml) or/and iii) other clinical or laboratory features are suggesting the presence of occult mastocytosis, a bone marrow biopsy should be performed. In the absence of KIT D816V and other indications of mastocytosis, no bone marrow investigation is required, but the patient's course and the serum tryptase levels are examined in the follow-up. PMID- 23675568 TI - Absence of BRAF exon 15 mutations in multiple myeloma and Waldenstrom's macroglobulinemia questions its validity as a therapeutic target in plasma cell neoplasias. AB - PURPOSE: Recent whole genome and/or exome sequencing in a cohort of 32 Multiple Myeloma (MMU) patients reported the incidence of BRAF mutations at 4%, while in another exome sequencing study, BRAF mutations were reported in up to 13% of cases tested. We ran a confirmatory study by using High Resolution Melting Analysis (HRMA), which is a low-cost, straightforward and sensitive screening test for detection of BRAF exon 15 mutations in MM and Waldenstrom's macroglobulinemia (WM) patients, in order to investigate their incidence in every day clinical practice. We considered this investigation to be of clinical relevance following the recent emergence of potent anti-BRAF compounds. PATIENTS AND METHODS: We used genomic DNA isolated from 31 bone marrow aspirates obtained from 25 MM patients and 3 patients with WM (14 female; 14 male) who signed an informed consent. Patients' median age was 69 years (range 43-86) and median follow-up time was 45 months. Myeloma subtypes were as follows: 7 IgGkappa, 6 IgGlambda, 7 IgAlambda, 4 IgAlambda and 1 non-secretory. The bone marrow plasma cells ranged from 12 to 100% (mean/median value 45%). By International Staging System (ISS) 9/25 patients were stage Iota, 6/25 stage IotaIota, 7/25 stage IotaIotaIota, while in 3 cases staging information was missing. In 3 MM cases matched paired samples at diagnosis and at relapse were also available. DNA samples were screened using HRMA. HRMA results were confirmed by subsequent ds-bi directional sequencing (Sanger method) for somatic mutations in exon 15 of BRAF. RESULTS: At a limit of detection >=2.5% mutant allelic content by HRMA, we did not detect any BRAF mutations in exon 15 in any of our 31 samples. CONCLUSIONS: By using HRMA we do not confirm previously reported results. Lack of detection of BRAF exon 15 mutations in our MM and WM series may be related to different sensitivity of the assays used and/or the relatively small sample size. In any case, we consider that existing data should be taken into account when considering the clinical development of BRAF inhibitors in plasma cell neoplasms. PMID- 23675569 TI - A rare der(Y)t(Y;1)(q12;q12) in a patient with post-polycythemic myelofibrosis: a case report. AB - We describe a case of post-polycythemic myelofibrosis harboring der(Y)t(Y;1)(q12;q12). The patient was a 69-year-old man and was initially diagnosed with polycythemia vera. During the clinical course of his condition, the polycythemia developed into myelofibrosis. Chromosome analysis detected der(Y)t(Y;1)(q12;q12). We discuss the association between der(Y)t(Y;1)(q11~12;q12~21) and tumorigenesis along with a review of literature. PMID- 23675570 TI - A hybrid model of the role of VEGF binding in endothelial cell migration and capillary formation. AB - Vascular endothelial growth factor (VEGF) is the most studied family of soluble, secreted mediators of endothelial cell migration, survival, and proliferation. VEGF exerts its function by binding to specific tyrosine kinase receptors on the cell surface and transducing the effect through downstream signaling. In order to study the influence of VEGF binding on endothelial cell motion, we develop a hybrid model of VEGF-induced angiogenesis, based on the theory of reinforced random walks. The model includes the chemotactic response of endothelial cells to angiogenic factors bound to cell-surface receptors, rather than approximating this as a function of extracellular chemical concentrations. This allows us to capture biologically observed phenomena such as activation and polarization of endothelial cells in response to VEGF gradients across their lengths, as opposed to extracellular gradients throughout the tissue. We also propose a novel and more biologically reasonable functional form for the chemotactic sensitivity of endothelial cells, which is also governed by activated cell-surface receptors. This model is able to predict the threshold level of VEGF required to activate a cell to move in a directed fashion as well as an optimal VEGF concentration for motion. Model validation is achieved by comparison of simulation results directly with experimental data. PMID- 23675571 TI - Organization and Evolution of Drosophila Terminin: Similarities and Differences between Drosophila and Human Telomeres. AB - Drosophila lacks telomerase and fly telomeres are elongated by occasional transposition of three specialized retroelements. Drosophila telomeres do not terminate with GC-rich repeats and are assembled independently of the sequence of chromosome ends. Recent work has shown that Drosophila telomeres are capped by the terminin complex, which includes the fast-evolving proteins HOAP, HipHop, Moi, and Ver. These proteins, which are not conserved outside Drosophilidae and closely related Diptera, localize and function exclusively at telomeres, protecting them from fusion events. Other proteins required to prevent end-to-end fusion in flies include HP1, Eff/UbcD1, ATM, the components of the Mre11-Rad50 Nbs (MRN) complex, and the Woc transcription factor. These proteins do not share the terminin properties; they are evolutionarily conserved non-fast-evolving proteins that do not accumulate only at telomeres and do not serve telomere specific functions. We propose that following telomerase loss, Drosophila rapidly evolved terminin to bind chromosome ends in a sequence-independent manner. This hypothesis suggests that terminin is the functional analog of the shelterin complex that protects human telomeres. The non-terminin proteins are instead likely to correspond to ancestral telomere-associated proteins that did not evolve as rapidly as terminin because of the functional constraints imposed by their involvement in diverse cellular processes. Thus, it appears that the main difference between Drosophila and human telomeres is in the protective complexes that specifically associate with the DNA termini. We believe that Drosophila telomeres offer excellent opportunities for investigations on human telomere biology. The identification of additional Drosophila genes encoding non-terminin proteins involved in telomere protection might lead to the discovery of novel components of human telomeres. PMID- 23675574 TI - Tailoring DNA Vaccines: Designing Strategies Against HER2-Positive Cancers. AB - The crucial role of HER2 in epithelial transformation and its selective overexpression on cancer tissues makes it an ideal target for cancer immunotherapies such as passive immunotherapy with Trastuzumab. There are, however, a number of concerns regarding the use of monoclonal antibodies which include resistance, repeated treatments, considerable costs, and side effects that make active immunotherapies against HER2 desirable alternative approaches. The efficacy of anti-HER2 DNA vaccination has been widely demonstrated in transgenic cancer-prone mice, which recapitulate several features of human breast cancers. Nonetheless, the rational design of a cancer vaccine able to trigger a long-lasting immunity, and thus prevent tumor recurrence in patients, would require the understanding of how tolerance and immunosuppression regulate antitumor immune responses and, at the same time, the identification of the most immunogenic portions of the target protein. We herein retrace the findings that led to our most promising DNA vaccines that, by encoding human/rat chimeric forms of HER2, are able to circumvent peripheral tolerance. Preclinical data obtained with these chimeric DNA vaccines have provided the rationale for their use in an ongoing Phase I clinical trial (EudraCT 2011-001104-34). PMID- 23675579 TI - A new dimension for cell identification by FTIR spectroscopy: depth profiling in attenuated total reflection. AB - The multiresistant phenotype is an important problem in cancer chemotherapy. It is characterized by cell resistance to multiple and structurally unrelated drugs. We have shown previously that K562 multiresistant leukemia cells could be differentiated from their sensitive counterparts (wild-type K562 cells) on the basis of their infrared spectrum. In ATR FTIR mode, the penetration depth is controlled by both the wavelength and the incident angle, allowing depth profiling of samples. In this paper we took advantage of the ATR capability to modulate the penetration depth of the infrared wave into the cell, by modulating the incident angle, to investigate the differences between K562 multiresistant cells and their sensitive counterparts (wild-type K562 cells) as a function of this penetration depth. It is shown that focusing the IR beam on the most discriminant depth allows improvement of the discrimination between multiresistant and sensitive K562 cells. It is suggested that the depth profile of the difference spectra could allow a more precise localization of the biochemical modifications arising within the multidrug resistance phenotype. PMID- 23675580 TI - In situ analysis of corrosion inhibitors using a portable mass spectrometer with paper spray ionization. AB - Paper spray (PS) ambient ionization is implemented using a portable mass spectrometer and applied to the detection of alkyl quaternary ammonium salts in a complex oil matrix. These salts are commonly used as active components in the formulation of corrosion inhibitors. They were identified in oil and confirmed by their fragmentation patterns recorded using tandem mass spectrometry (MS/MS). The cations of alkyl and benzyl-substituted quaternary ammonium salts showed characteristic neutral losses of CnH2n (n carbon number of the longest chain) and C7H8, respectively. Individual quaternary ammonium compounds were detected at low concentrations (<1 ng MUL(-1)) and over a dynamic range of ~5 pg MUL(-1) to 500 pg MUL(-1) (ppb). Direct detection of these compounds in complex oil samples without prior sample preparation or pre-concentration was also demonstrated using a home-built miniature mass spectrometer at levels below 1 ng MUL(-1). PMID- 23675572 TI - DNA double-strand break repair as determinant of cellular radiosensitivity to killing and target in radiation therapy. AB - Radiation therapy plays an important role in the management of a wide range of cancers. Besides innovations in the physical application of radiation dose, radiation therapy is likely to benefit from novel approaches exploiting differences in radiation response between normal and tumor cells. While ionizing radiation induces a variety of DNA lesions, including base damages and single strand breaks, the DNA double-strand break (DSB) is widely considered as the lesion responsible not only for the aimed cell killing of tumor cells, but also for the general genomic instability that leads to the development of secondary cancers among normal cells. Homologous recombination repair (HRR), non-homologous end-joining (NHEJ), and alternative NHEJ, operating as a backup, are the major pathways utilized by cells for the processing of DSBs. Therefore, their function represents a major mechanism of radiation resistance in tumor cells. HRR is also required to overcome replication stress - a potent contributor to genomic instability that fuels cancer development. HRR and alternative NHEJ show strong cell-cycle dependency and are likely to benefit from radiation therapy mediated redistribution of tumor cells throughout the cell-cycle. Moreover, the synthetic lethality phenotype documented between HRR deficiency and PARP inhibition has opened new avenues for targeted therapies. These observations make HRR a particularly intriguing target for treatments aiming to improve the efficacy of radiation therapy. Here, we briefly describe the major pathways of DSB repair and review their possible contribution to cancer cell radioresistance. Finally, we discuss promising alternatives for targeting DSB repair to improve radiation therapy and cancer treatment. PMID- 23675581 TI - Use of a large Stokes-shift fluorophore to increase the multiplexing capacity of a point-of-care DNA diagnostic device. AB - The intense demand for fluorescence-based point of care (POC) DNA diagnostics is driving developments to reduce the size of instrumentation, imposing limitations on the optical hardware that can be included. Here we describe a combination of instrumentation and fluorogenic probes to detect three fluorophores using two excitation and two detection channels. PMID- 23675582 TI - Introduction to analyzing the solidification of multifunctional acrylic esters by ESR. AB - Published approaches to analyze the kinetics of radical photo-polymerization are mainly based on in situ IR or Raman measurements. But these techniques only monitor the monomer decay. Additional information particularly about solidification cannot be obtained with these methods. Electron spin resonance, ESR, spectroscopy allows monitoring of radicals. The presented investigation gives an introduction to additional applications of ESR to monitor the solidification of multifunctional acrylic esters by successive in situ irradiation. This general approach to monitor the termination rate of the midchain radical which is not involved in propagation but whose lifetime is correlated via mobility with the solidification which is demonstrated with a set of commercially available multifunctional resins without an initiator. A detailed analysis of ESR signals is required to prove that the presented method is applicable for acrylic esters and to clarify published contradictory statements. The properties and the curing of the resins are characterized by additional methods, such as UV-Vis and Raman spectroscopy. The first results based on this innovative technique indicate that the functionality of the ester group has a significant and, most of all, measurable effect on the mobility of the small reactive molecules within the cured(-ing) polymer. PMID- 23675583 TI - Dramatic tuning of ligand donor properties in (Ttz)CuCO through remote binding of H+ (Ttz = hydrotris(triazolyl)borate). AB - Complexes with bulky hydrotris(triazolyl)borate (Ttz) ligands, TtzCuCO, were used to probe how acids change the donor properties of Ttz ligands. (Ttz(tBu,Me))CuCO shows four distinct protonation states and a gradual increase in the CO stretch. The increased electrophilic nature of the Cu center upon protonation leads to enhanced C-H activation catalysis. PMID- 23675573 TI - Identifying molecular targets of lifestyle modifications in colon cancer prevention. AB - One in four deaths in the United States is cancer-related, and colorectal cancer (CRC) is the second leading cause of cancer-associated deaths. Screening strategies are utilized but have not reduced disease incidence or mortality. In this regard, there is an interest in cancer preventive strategies focusing on lifestyle intervention, where specific etiologic factors involved in cancer initiation, promotion, and progression could be targeted. For example, exposure to dietary carcinogens, such as nitrosamines and polycyclic aromatic hydrocarbons influences colon carcinogenesis. Furthermore, dietary deficiencies could alter sensitivity to genetic damage and influence carcinogen metabolism contributing to CRC. High alcohol consumption increases the risk of mutations including the fact that acetaldehyde, an ethanol metabolite, is classified as a group 1 carcinogen. Tobacco smoke exposure is also a risk factor for cancer development; approximately 20% of CRCs are associated with smoking. Additionally, obese patients have a higher risk of cancer development, which is further supported by the fact that physical activity decreases CRC risk by 55%. Similarly, chronic inflammatory conditions also increase the risk of CRC development. Moreover, the circadian clock alters digestion and regulates other biochemical, physiological, and behavioral processes that could influence CRC. Taken together, colon carcinogenesis involves a number of etiological factors, and therefore, to create effective preventive strategies, molecular targets need to be identified and beleaguered prior to disease progression. With this in mind, the following is a comprehensive review identifying downstream target proteins of the above lifestyle risk factors, which are modulated during colon carcinogenesis and could be targeted for CRC prevention by novel agents including phytochemicals. PMID- 23675584 TI - Dioxygen mediated conversion of {Fe(NO)2}9 dinitrosyl iron complexes to Roussin's red esters. AB - The reactivity of a series of {Fe(NO)2}(9) dinitrosyl iron complexes bearing thiolate ligands with molecular oxygen is reported. These reactions result in the formation of the corresponding Roussin's red esters along with thiolate oxidation. This reactivity is contrasted with that previously reported for {Fe(NO)2}(10) complexes. PMID- 23675586 TI - Proceedings of the 11th European Conference on Computational Biology, ECCB 2012, September 9-12, 2012, Basal, Switzerland. PMID- 23675585 TI - Protecting the patient-physician relationship in Florida. PMID- 23675587 TI - Special Issue on A Clinical and Molecular Immunology Symposium in Honour of Dr DC Kilpatrick. PMID- 23675588 TI - Reply to Huang et al.: Slow proton exchange can duplicate the number of species observed in single-molecule experiments of protein folding. PMID- 23675590 TI - Retraction. Short interfering RNA (siRNA) as a novel therapeutic. PMID- 23675589 TI - Reply to Campos and Munoz: Why phosphate is a bad buffer for guanidinium chloride titrations. PMID- 23675591 TI - [Proceedings of the 10th National Congress on Transfusion Safety and Hemovigilance, November 14-18, 2012, Nantes, France]. PMID- 23675592 TI - Proceedings of the Fourth ESWI Influenza Conference, September 11-14, 2011, Malta. PMID- 23675593 TI - Proceedings of the International Workshop on Neural Coding, 29 October - 3 November 2010, Limassol, Cyprus. PMID- 23675594 TI - Proceedings of the XXV National Congress of the Italian Society of Geriatric Surgery, May 10-11, 2012, Padova, Italy. PMID- 23675596 TI - The proceedings of the 6th International Meeting on Rickettsiae and Rickettsial Diseases (IMRRD), June 5-7, 2011, Crete, Greece. PMID- 23675595 TI - Characterization of prescription opioid abuse in the United States: focus on route of administration. AB - Prescription opioids are prescribed increasingly for the management of chronic pain, and this has been accompanied by a dramatic rise in opioid-related abuse, addiction, and overdose deaths. Reports of abuse involving nonoral administration (e.g., snorting, injecting) of prescription opioids are increasing, although the epidemiology of oral versus nonoral abuse is not well understood. Available data indicate that oral abuse is far more common,with 72% to 97% of opioid abusers perferring oral administration. Factors associated with nonoral administration include longer duration of opioid abuse, male gender, and rural setting. Extended release opioids, because of their relatively high drug load, may be attractive to experienced abusers seeking to manipulate the formulation to facilitate a rapid onset of effect. Putative abuse-deterrent formulations have been developed to decrease the likelihood or consequences of nonoral abuse. In addition, Risk Evaluation and Mitigation Strategies (REMS) are now required for prescribed extended-release/long-acting opioids by the US Food and Drug Administration, although their effectiveness in reducing the risk of abuse, addiction, and overdose has not been evaluated. Physicians should remain vigilant when prescribing opioids and should exercise appropriate patient selection, perform risk analysis and stratification, and maintain continuous patient monitoring to ensure the benefits outweigh these important risks. PMID- 23675597 TI - Close encounters of the 3D kind - exploiting high dimensionality in molecular semiconductors. PMID- 23675598 TI - The essentials and importance of good communication between the surgeon and his or her patient. Opening the 2012 Annual Scientific Meeting of General Surgeons of Australia. PMID- 23675599 TI - Manpower and economic issues in post-mastectomy breast reconstruction. PMID- 23675600 TI - Is "informed consent" a deceptive notion with negligible protection value for doctors? PMID- 23675601 TI - [Epilepsy in Africa]. PMID- 23675602 TI - Benjamin D. McCallister, MD, MACC (1932-2012). PMID- 23675603 TI - [Compensatory mechanisms in multiple sclerosis(review)]. AB - Neuroprotective mechanisms of delay of neurodegeneration and recovery of function in multiple sclerosis are reviewed. Different adaptive reactions(neuroprotective autoimmunity, neuroplasticity, sodium channels expression and function changes, remyelination) are described. The possibility of neurogenesis, axonal regeneration and synaptic changes is discussed. Understanding the compensatory mechanisms in multiple sclerosis is fundamental basis for the development of new therapeutic approaches. PMID- 23675604 TI - Physician, study thyself. PMID- 23675605 TI - [Characteristics of coping strategies in patients with multiple sclerosis(review)]. AB - Adaptation of patients with multiple sclerosis (MS) to their condition is an actual problem especially due to the implementation of treatment with disease modifying drugs (DMT). Coping is the unique way of controlling the situation. Relationship between environmental conditions and resources available to respond to these conditions is a basis of coping; stable patterns of copings form so called coping strategies. The predominance of one or another type of coping strategies of the patient can determine adherence to treatment with DMT as well as to predict the further course of disease. Own data on the characteristics of coping strategies in MS are also analyzed. PMID- 23675606 TI - [Alemtuzumab is a new drug based on monoclonal antibodies for treatment multiple sclerosis: treatment possibilities and risks(review)]. AB - Recently published results of II and II phase clinical trials of alemtuzumab in relapsing-remitting multiple sclerosis (MS) are reviewed. This drug has an immunosuppressive mechanism of action with an anti-inflammatory effect higher than that of high-dose beta-interferon. Its neuroprotective activity and possible side-effects are discussed. PMID- 23675607 TI - [Laquinimod is an oral drug with a marked neuroprotective effect for pathogenetic treatment of multiple sclerosis(review)]. AB - New oral therapies of MS cause great attention. This review includes data on the II and III phase clinical studies of laquinimod (LAQ) - a new oral therapy for MS with immunoregulatory, anti inflammatory and neuroprotective action. LAQ has no immunosuppressive effects and has a very good safety and tolerability profile. Data of phase III studies including 2437 MS patients confirmed positive effect of LAQ on relapse rate and disability progression. These clinical results were supported by the MRI data, showing also a significant slowing of the brain atrophy. Russian neurological clinics actively participated in all LAQ clinical trials: 241 MS patients from 11 centers from Russia took part in the phase II trials. The data in this subgroup confirm all changes, registered in the whole group of patients. PMID- 23675608 TI - Durable plasmonic cap arrays on flexible substrate with real-time optical tunability for high-fidelity SERS devices. AB - Active tunable plasmonic cap arrays were fabricated on a flexible stretchable substrate using a combination of colloidal lithography, lift-up soft lithography, and subsequent electrostatic assembly of gold nanoparticles. The arrangement of the plasmonic caps could be tuned under external strain to deform the substrate in reversible. Real-time variation in the arrangement could be used to tune the optical properties and the electromagnetic field enhancement, thereby a proving a promising mechanism for optimizing the SERS sensitivity. PMID- 23675609 TI - Full-scale characterization of UVLED Al(x)Ga(1-x)N nanowires via advanced electron microscopy. AB - III-Nitride semiconductor heterostructures continue to attract a great deal of attention due to the wide range of wavelengths at which they can emit light, and the subsequent desire to employ them in optoelectronic applications. Recently, a new type of pn-junction which relies on polarization-induced doping has shown promise for use as an ultraviolet light emitting diode (UVLED); nanowire growth of this device has been successfully demonstrated. However, as these devices are still in their infancy, in order to more fully understand their physical and electronic properties, they require a multitude of characterization techniques. Specifically, the present contribution will discuss the application of advanced scanning transmission electron microscopy (STEM) to AlxGa1-xN UVLED nanowires. In addition to structural data, chemical and electronic properties will also be probed through various spectroscopy techniques, with the focus remaining on practically applying the knowledge gained via STEM to the growth procedures in order to optimize device peformance. PMID- 23675611 TI - Identification of seafood as an important dietary source of heterocyclic amines by chemometry and chromatography-mass spectrometry. AB - Heterocyclic amines (HCAs), which are formed during the cooking of protein-rich foods, are potent mutagens and a risk factor for human cancers. Levels of HCAs have been extensively investigated in meat products but not in fish products. Here, we report levels of HCAs in fried salmon, tuna, hake, sardine, angler fish, cod, sole, swordfish, squid, and cuttlefish. The HCA levels of some of these foods have not been previously analyzed. We employed multivariate factor-analysis tools, including principal components analysis (PCA) and partial least-squares (PLS) regression, to study the effects of cooking weight loss and levels of creatine, glucose, and free amino acids on HCA levels. The highest concentrations of mutagenic HCAs, 159.3 ng.g(-1) total, where 2-amino-1-methyl-6 phenylimidazo[4,5-b]pyridine (PhIP) accounted for 121 ng.g(-1), were found in fried swordfish (cooking loss of 51.8%). These levels are higher than those generally found in fried chicken, which is typically cited as the most contaminated food item. Thus, swordfish is among the richest known sources of HCAs. The other cooked seafood items contained from 0.4 to 35.4 ng.g(-1) HCAs, comparable to concentrations typically reported for meat. Chemometric analysis showed that the fish species is the most influential parameter on the formation of HCAs such as DMIP, PhIP, and norharman. Concentrations of histidine, lysine, creatine, and glucose, as well as weight loss, also influence the yield of HCAs. These results suggest that seafood is an important dietary source of HCAs. The formation of HCAs in fish is influenced by multiple factors, some of which remain unknown. PMID- 23675610 TI - Mitochondrial-targeted protective properties of isolated diterpenoids from sideritis spp. in response to the deleterious changes induced by H2O2. AB - Mitochondrial impairment and oxidative stress are considered widely to be central events in many forms of neurodegenerative disease. The current study has evaluated for the first time the potential protective role of three diterpenoids [andalusol (1), conchitriol (2), and lagascatriol (3)] in response to the deleterious H2O2-induced changes on mitochondrial function. U373-MG human astrocytoma cells and PC12 rat adrenal pheochromocytoma cells were used as models for evaluating the cytoprotective potential of these compounds. In the absence of diterpenoids 1-3, H2O2 compromised mitochondrial function, decreasing mitochondrial membrane potential and ATP levels, increasing caspase-3 activity, and disrupting cytosolic and mitochondrial calcium homeostasis. However, treatment with the diterpenoids, prior to H2O2, prevented these mitochondrial perturbations. In particular, 1 and 3 were the most effective compounds in protecting mitochondrial function against H2O2-induced oxidative stress in U373 MG, whereas all three diterpenoids studied were significantly active against PC12 cells. Since consistent evidence has demonstrated the contribution of H2O2 on both progression and pathological development of several human diseases associated with mitochondrial function and oxidative stress responses, compounds 1-3 are worthy of further investigation. PMID- 23675612 TI - Mohs surgery in metastatic cancer: renal cell carcinoma solitary cutaneous metastasis and visceral tumor metastases to skin treated with microscopically controlled surgical excision. AB - BACKGROUND: Mohs micrographic surgery is the reference standard treatment for primary cutaneous malignancies. OBJECTIVES: The purpose of this case study is to demonstrate that Mohs surgery may be considered as a possible treatment for a solitary metastatic tumor under the appropriate circumstances. METHODS: We report a patient in whom a solitary cutaneous metastasis of renal cell carcinoma (RCC) was successfully treated with microscopically controlled surgical excision, and cite instances of the successful management of cutaneous metastases using the Mohs surgical technique in oncology patients reported in the literature. Patient reports and previous reviews of the subject were critically assessed. Salient features are presented. RESULTS: Metastases to the skin are rare in RCC. Albeit rarely, surgical excision, particularly Mohs micrographic surgery, has been used for the removal of isolated RCC cutaneous metastases. In the present patient with metastatic RCC, a solitary cutaneous metastasis on the occipital scalp was successfully treated with Mohs micrographic surgery. There was no recurrence of the lesion after two years of follow-up; however, the patient eventually succumbed to progressive disease. CONCLUSIONS: We suggest that, in the appropriate setting, surgical excision of isolated cutaneous metastases using microscopically controlled margins at the time of surgery should be added to the indications for Mohs surgery. PMID- 23675613 TI - The stochastic silencing phenotype of Arabidopsis morc6 mutants reveals a role in efficient RNA-directed DNA methylation. AB - The RNA-directed DNA methylation (RdDM) pathway is of central importance to the initiation and maintenance of transcriptional gene silencing in plants. DNA methylation is directed to target sequences by a mechanism that involves production of small RNAs by RNA polymerase IV and long non-coding RNAs by RNA polymerase V. DNA methylation then leads to recruitment of histone-modifying enzymes, followed by establishment of a silenced chromatin state. Recently MORC6, a member of the microrchidia (MORC) family of adenosine triphosphatases (ATPases), has been shown to be involved in transcriptional gene silencing. However, reports differ regarding whether MORC6 is involved in RdDM itself or acts downstream of DNA methylation to enable formation of higher-order chromatin structure. Here we demonstrate that MORC6 is required for efficient RdDM at some target loci, and, using a GFP reporter system, we found that morc6 mutants show a stochastic silencing phenotype. By using cell sorting to separate silenced and unsilenced cells, we show that release of silencing at this locus is associated with a loss of DNA methylation. Thus our data support a view that MORC6 influences RdDM and that it is not acting downstream of DNA methylation. For some loci, efficient initiation or maintenance of DNA methylation may depend on the ability to form higher-order chromatin structure. PMID- 23675614 TI - Effects of electromagnetic fields on biological systems. PMID- 23675615 TI - Nonthermal electromagnetic fields: from first messenger to therapeutic applications. AB - Nonthermal pulsed electromagnetic fields, from low frequency to pulse-modulated radio frequency, have been successfully employed as adjunctive therapy for the treatment of delayed and non-union fractures, fresh fractures and chronic wounds. Recent increased understanding of the mechanism of action of electromagnetic fields (EMF) has permitted technologic advances allowing the development of EMF devices which are portable and disposable, can be incorporated into dressings, supports and casts, and can be used over clothing. This broadens the use of non pharmacological, non-invasive EMF therapy to the treatment of postoperative pain and edema to enhance surgical recovery. EMF therapy is rapidly becoming a standard part of surgical care, and new, more significant, clinical applications for osteoarthritis, brain and cardiac ischemia and traumatic brain injury are in the pipeline. This study reviews recent evidence which suggests that calmodulin (CaM)-dependent nitric oxide signaling is involved in cell and tissue response to weak nonthermal EMF signals. There is abundant evidence that EMF signals can be configured a priori to increase the rate of CaM activation, which, in turn, can modulate the biochemical cascades living cells and tissues employ in response to external insult. Successful applications in pilot clinical trials, coupled with evidence at the cellular and animal levels, provide support that EMF is a first messenger that can modulate the response of challenged biological systems. PMID- 23675616 TI - Possible mechanisms of synaptic plasticity modulation by extremely low-frequency magnetic fields. AB - Understanding the biological mechanisms by which extremely low-frequency (ELF, < 300 Hz) magnetic fields (MFs) interact with human brain activity is an active field of research. Such knowledge is required by international agencies providing guidelines for general public and workers exposure to ELF MFs (such as ICNIRP, the International Commission on Non-Ionizing Radiation Protection). The identification of these interaction mechanisms is extremely challenging, since the effects of ELF MF exposure need to be monitored and understood at very different spatial (from micrometers to centimeters) and temporal (from milliseconds to minutes) scales. One possibility to overcome these issues is to develop biophysical models, based on the systems of mathematical equations describing the electric or metabolic activity of the brain tissue. Biophysical models of the brain activity offer the possibility to simulate how the brain tissue interacts with ELF MFs, in order to gain new insights into experimental data, and to test novel hypotheses regarding interaction mechanisms. This paper presents novel hypotheses regarding the effects of power line (60 Hz in North America) MFs on human brain activity, with arguments from biophysical models. We suggest a hypothetic chain of events that could bridge MF exposure with detectable effects on human neurophysiology. We also suggest novel directions of research in order to reach a convergence of biophysical models of brain activity and corresponding experimental data to identify interaction mechanisms. PMID- 23675617 TI - Electromagnetic field occupational exposure: non-thermal vs. thermal effects. AB - There are a variety of definitions for "non-thermal effects" included in different international standards. They start by the simple description that they are "effects of electromagnetic energy on a body that are not heat-related effects", passing through the very general definition related to low-level effects: "biological effects ascribed to exposure to low-level electric, magnetic and electromagnetic fields, i.e. at or below the corresponding dosimetric reference levels in the frequency range covered in this standard (0 Hz-300 GHz)", and going to the concrete definition of "the stimulation of muscles, nerves, or sensory organs, vertigo or phosfenes". Here, we discuss what kind of effect does the non-thermal one has on human body and give data of measurements in different occupations with low-frequency sources of electromagnetic field such as electric power distribution systems, transformers, MRI systems and : video display units (VDUs), whereas thermal effects should not be expected. In some of these workplaces, values above the exposure limits could be found, nevertheless that they are in the term "non-thermal effects" on human body. Examples are workplaces in MRI, also in some power plants. Here, we will not comment on non-thermal effects as a result of RF or microwave exposure because there are not proven evidence about the existance of such effects and mechanisms for them are not clear. PMID- 23675618 TI - The effects of 15 Hz trans-spinal magnetic stimulation on locomotor control in mice with chronic contusive spinal cord injury. AB - The effects of repetitive trans-spinal magnetic stimulation (rTSMS), combined with acrobatic exercise on functional locomotor recovery in chronic spinal contused mice were tested. The exposure to magnetic stimulation was initiated 3 weeks after injury, when the animals entered chronic stage. The rTSMS was applied for a total of 4 weeks over a 9-week duration trial. Seventeen mice with the spinal cord contusion injured at level T13 were separated into two groups. While one group consisting of 10 animals was exposed to rTSMS (15 Hz), the other seven animals served as controls. Functional recovery measured with Basso mouse scale and horizontal ladder scale showed significantly better functional recovery in rTSMS-treated animals. The progress in recovery continued even after cessation of magnetic stimulation. In vitro experiments revealed that the release of glutamate analog, radioactive D-aspartate from the segments of the spinal cord exposed to rTSMS was significantly elevated. In conclusion, the exposure to rTSMS, applied to injured spinal cord during chronic post-surgery stage remarkably improves the functional recovery. This recovery may be correlated by magnetically induced elevation in the release of major excitatory neurotransmitter, glutamate from injured tissue. PMID- 23675619 TI - Influence of pulsing electromagnetic field therapy on resting blood pressure in aging adults. AB - This double-blind study tested the effects of pulsating electromagnetic field (PEMF) therapy sessions on the changes in peripheral cardiovascular function in a group of aging adults after 12 weeks of treatment. Each therapy session involved 15 min of exposure to low-frequency PEMF with asymmetrical waveforms emitted by the ImpulserTM Pro mattress. The treatment was provided 5 days per week for a total of 60 sessions. Resting blood pressure and arterial stiffness index were determined for peripheral cardiovascular function. Fifty-four older men and women (mean age 59.8 +/- 3.5 yrs) completed the entire protocol involving either the PEMF or a sham treatment. The results include statistically significant reductions in systolic and pulse blood pressure, while no significant difference in diastolic pressure or the index of arterial stiffness was observed. These findings suggest that the PEMF treatment might be linked to improvements in peripheral resistance or circulation. PMID- 23675620 TI - Nonlinear heart rate variability measures under electromagnetic fields produced by GSM cellular phones. AB - This study was designed to assess the nonlinear dynamics of heart rate variability (HRV) during exposure to low-intensity EMFs. Twenty-six healthy young volunteers were subjected to a rest-to-stand protocol to evaluate autonomic nervous system in quiet condition (rest, vagal prevalence) and after a sympathetic activation (stand). The procedure was conducted twice in a double blind design: once with a genuine EMFs exposure (GSM cellular phone at 900 MHz, 2 W) and once with a sham exposure (at least 24 h apart). During each session, three-lead electrocardiograms were recorded and RR series extracted off-line. The RR series were analyzed by nonlinear deterministic techniques in every phase of the protocol and during the different exposures. The analysis of the data shows there was no statistically significant effect due to GSM exposure on the nonlinear dynamics of HRV. PMID- 23675621 TI - The pattern of exposure to static magnetic field of nurses involved in activities related to contrast administration into patients diagnosed in 1.5 T MRI scanners. AB - Static magnetic fields (SMFs) and time-varying electromagnetic fields exposure is necessary to obtain the diagnostic information regarding the structure of patient's tissues, by the use of magnetic resonance imaging (MRI) scanners. A diagnostic procedure may also include the administration of pharmaceuticals called contrast, which are to be applied to a patient during the examination. The nurses involved in administering contrast into a patient during the pause in examination are approaching permanently active magnets of MRI scanners and are exposed to SMF. There were performed measurements of spatial distribution of SMF in the vicinity of MRI magnets and parameters of personal exposure of nurses (i.e. individual exposimetric profiles of variability in time of SMF affecting the nurse who is performing tasks in the vicinity of magnet, characterized by statistical parameters of recorded magnetic flux density affecting the nurse). The SMF exposure in the vicinity of various MRI magnets depends on both magnetic flux density of the main field B 0 (applicable to a patient) and the construction of the scanner, but the most important factor determining the workers' exposure is the work practice. In the course of a patient's routine examination in scanners of B0 = 1.5 T, the nurses are present over ~0.4-2.9 min in SMF exceeding 0.03% of B0 (i.e. 0.5 mT), but only sometimes they are present in SMF exceeding 5% of B 0 (i.e. 75 mT). When patients need more attention because of their health status/condition, the nurses' exposure may be significantly longer--it may even exceed 10 min and 30% of B 0 (i.e. 500 mT). We have found that the level of exposure of nurses to SMF may vary from < 5% of the main field (a median value: 0.5-1.5%; inter-quartile range: 0.04-8.8%; max value: 1.3-12% of B0) when a patient is moved from the magnets bore before contrast administration, up to the main field level (B0) when a patient stays in the magnets bore and nurse is crawling into the bore. PMID- 23675622 TI - Biosomatic effects of the electromagnetic fields on view of the physiotherapy personnel health. AB - The effects of electromagnetic fields (EMFs) in physiotherapy have been discussed mainly with regard to the patient's safety, while the operator's safety is neglected. This paper presents the medical assessment and specific tendencies in the health status of personnel in physical therapy wards--where the EMFs are everyday background factor. This paper summarizes the somatic part of results from the study among physiotherapy personnel from facilities with different equipment and work load by using survey card designed by us for health status screening in somatic and neurobehavioral aspects. The main specific somatic findings and complaints in investigated group include parodontosis--42%; cardiovascular disorders--41.6%; allergic conditions with skin or systemic manifestation--40.8%; photosensibilization-- 34.1%; skin diseases--31.5%; musculoskeletal disorders--30.0% and neoplasm disorders--7.5%. Keeping in mind that better part of the personnel in the physical therapy units is female, a special attention was paid to the pathology of the reproductive system; menstrual disturbances are observed in 20.0%. These findings are collected in complex for the first time in physiotherapy personnel, and when data were available from other professional groups, we found a good correlation. PMID- 23675623 TI - Wi-Fi technology--an uncontrolled global experiment on the health of mankind. AB - The twenty-first century is marked with exponentially increasing development of technologies that provide wireless communications. To the pollution of the atmosphere with radio and TV signals, not only satellite communications but also any varieties of the Wi-Fi networks are added. By 2010 in the USA, 285 million mobile phone subscribers have been registered (for a little bit more than 300 million inhabitants). The estimate for the world is more than 5 billion mobile phone users at approximately 7 billion people living on this planet. Approximately 2 years ago, the International Agency of Research on Cancer (IARC) classified the electromagnetic fields used in mobile communication as a possible cancerogene. This paper discusses the potential health hazard and lack of scientific assessment and regulatory actions in protection of the life on the planet. PMID- 23675624 TI - Pilot study of extremely low frequency magnetic fields emitted by transformers in dwellings. Social aspects. AB - A large number of epidemiologic studies examining the potential effect of residential exposure to extremely-low frequency (ELF) magnetic fields and childhood leukemia have been published. Two pooled analyses [Ahlbom A, Day N, Feychting M, Roman E, Skinner J, Dockerty J, Linet M, et al. (2000). A pooled analysis of magnetic fields and childhood leukaemia. Br J Cancer. 83(5):692-698; Greenland S, Sheppard AR, Kaune WT, Poole C, Kelsh AM (2000). A pooled analysis of magnetic fields, wire codes, and childhood leukemia. Epidemiology. 11(6):624 634], which included the major epidemiologic studies on ELF magnetic fields and childhood leukemia showed twofold increase in childhood leukemia risk in association with residential ELF exposure above 0.3-0.4 MUT. Based on "limited" epidemiologic evidence linking ELF exposure to childhood leukemia and "inadequate evidence" for carcinogenicity of ELF in rodent bioassays, the International Agency for Research on Cancer (IARC) classified ELF magnetic fields as a possible human carcinogen (2B classification) [International Agency for Research on Cancer (IARC) (2002). Non-ionizing radiation, Part 1: Static and extremely low-frequency (ELF) electric and magnetic fields. IARC monographs on the evaluation of carcinogenic risks to humans. Vol. 80. IARC Press: Lyon], confirmed by WHO on the basis of studies published after 2000 [World Health Organization. Extremely low frequency fields. In: 238 Environmental health criteria, Geneva: WHO; 2007]. The analysis of more recent studies of ELF magnetic fields and childhood leukemia had small findings and propose methodological improvements concerning the uncertainties in epidemiological approaches and exposure assessment, bias in selection of controls [Kheifets L, Oksuzyan S (2008). Exposure assessment and other challenges in non-ionizing radiation studies of childhood leukaemia. Radiat Prot Dosimetry. 132(2):139-147]. By the end of 2010, 37 countries had been identified for possible participation in the International study TRANSEXPO. The pilot work has been completed in five countries (Finland, Hungary, Israel, Switzerland and Bulgaria). In 2008, Bulgaria through the National Centre of Public Health Protection joined with pilot study in TRANSEXPO Project. At this first stage of the project our investigation was directed to performing measurements in dwellings with built-in transformer stations, collecting data of population and cancer registry and choosing the epidemiology design feasible for continuing the project. Taking into account the available sources of information in Bulgaria (different registers of the population) needed for epidemiological approach, it was found that the most appropriate epidemiology design would be the nested case-control study. Control group could be collected in accordance with the international requirements for such epidemiological studies. This approach could be modified in the course of the further study in order to ensure achievement of the purposes of the main international requirements of the study. PMID- 23675625 TI - Tuning, coupling and matching of a resonant cavity in microwave exposure system for biological objects. AB - A new microwave exposure system for biological experiments with well-defined exposure conditions and improved control of the exposure parameters consisting of variable frequency power source, coaxial to waveguide transition, matching network and single-mode resonant cavity with movable shorting plunger was fabricated and characterized. The introduction of a biological sample into a resonant cavity has a large impact on its field configuration and port impedance. As such, the properties, geometry and position of the biological sample become a part of the electrical properties of the microwave circuit. With that change, the electrical properties of the resonant cavity, such as impedance, quality factor and resonant frequency, also change. In this study, an appropriate coupling system with effective power transfer and an algorithm to tuning and coupling of resonant cavity in resonance before and after the introduction of biological sample have been proposed. This procedure will lead to a known dose distribution within the biological sample and allow a better comparison with other studies. Coupling of the electromagnetic energy into a resonant cavity was experimentally investigated. Graphical representation of cavity impedance in case of undercoupled, critically coupled and overcoupled cavity has been presented. Critical coupling of an empty resonant cavity has been accomplished at voltage standing wave ratio (VSWR) 1.01, at resonance frequencies 900 and 947.5 MHz. Critical coupling with the introduction of a biological sample has been accomplished at VSWR <= 1.07 for frequency bandwidth 1 MHz and VSWR <= 1.5 for frequency bandwidth up to 5 MHz with central frequency 947.5 MHz. PMID- 23675626 TI - The properties of human body phantoms used in calculations of electromagnetic fields exposure by wireless communication handsets or hand-operated industrial devices. AB - According to international guidelines, the assessment of biophysical effects of exposure to electromagnetic fields (EMF) generated by hand-operated sources needs the evaluation of induced electric field (E(in)) or specific energy absorption rate (SAR) caused by EMF inside a worker's body and is usually done by the numerical simulations with different protocols applied to these two exposure cases. The crucial element of these simulations is the numerical phantom of the human body. Procedures of E(in) and SAR evaluation due to compliance analysis with exposure limits have been defined in Institute of Electrical and Electronics Engineers standards and International Commission on Non-Ionizing Radiation Protection guidelines, but a detailed specification of human body phantoms has not been described. An analysis of the properties of over 30 human body numerical phantoms was performed which has been used in recently published investigations related to the assessment of EMF exposure by various sources. The differences in applicability of these phantoms in the evaluation of E(in) and SAR while operating industrial devices and SAR while using mobile communication handsets are discussed. The whole human body numerical phantom dimensions, posture, spatial resolution and electric contact with the ground constitute the key parameters in modeling the exposure related to industrial devices, while modeling the exposure from mobile communication handsets, which needs only to represent the exposed part of the human body nearest to the handset, mainly depends on spatial resolution of the phantom. The specification and standardization of these parameters of numerical human body phantoms are key requirements to achieve comparable and reliable results from numerical simulations carried out for compliance analysis against exposure limits or within the exposure assessment in EMF-related epidemiological studies. PMID- 23675627 TI - Parametric study of radiofrequency ablation in the clinical practice with the use of two-compartment numerical models. AB - The objective of the current work was to simulate radiofrequency ablation (RFA) with theoretical and realistic computational models, which correspond to single compartment models and clinical scenarios. A 3D model in a cubic region of 12 cm edge was studied representing either a homogeneous model or real clinical scenarios in three human tissues, i.e., liver, lung and kidney. An active electrode was placed at the center of the model. Various tumor sizes (1-3 cm) and source voltages (10-30 V) were investigated for the second case of a two compartment model. In the case of a 3-cm tumor in diameter, the electrical and thermal problems (at steady state) were solved to calculate the temperature distribution within the tumor and tissue. Lesion volume was quantified using the Arrhenius equation and the isothermals of 50 and 60 degrees C. The physical properties of all materials were constant during the simulations, i.e., no changes with temperature were considered. It was found that tumor conductivity was low to achieve significant damage in the tumor; in all clinical scenarios, saline-enhanced RFA was necessary and led to a more efficient tumor destruction. It was also shown that highly perfused tissues, such as liver and kidney, block the energy deposition within them, in contrast to lung, and, thus, require a further saline enhancement. Finally, the effect of perfusion on lesion size was studied, and it was concluded that tumor perfusion was more significant than surrounding tissue perfusion. PMID- 23675628 TI - Dielectric properties of muscle and liver from 500 MHz-40 GHz. AB - Dielectric properties are the most important parameters determining energy deposition when biological tissues are exposed to radio frequency and microwave fields. Energy absorption is determined by the specific absorption rate (SAR). SAR distributions can be computed accurately only if the complex relative permittivity of the target tissue is known to a sufficiently high accuracy, and currently there is a lack of data on the dielectric properties of biological tissues at high frequencies. In this study, tissue dielectric properties are measured using an open-ended coaxial probe technique from 500 MHz up to 40 GHz. We present dielectric data for ex vivo bovine and porcine muscle and liver tissues at 37 degrees C. One-pole Cole-Cole model is used to fit the measured data as a function of frequency and the dispersion parameters are presented. This data is supported by an accurate study on reference liquids such as methanol and ethanediol. PMID- 23675629 TI - Replication of heart rate variability provocation study with 2.4-GHz cordless phone confirms original findings. AB - This is a replication of a study that we previously conducted in Colorado with 25 subjects designed to test the effect of electromagnetic radiation generated by the base station of a cordless phone on heart rate variability (HRV). In this study, we analyzed the response of 69 subjects between the ages of 26 and 80 in both Canada and the USA. Subjects were exposed to radiation for 3-min intervals generated by a 2.4-GHz cordless phone base station (3-8 MUW/cm2). A few participants had a severe reaction to the radiation with an increase in heart rate and altered HRV indicative of an alarm response to stress. Based on the HRV analyses of the 69 subjects, 7% were classified as being "moderately to very" sensitive, 29% were "little to moderately" sensitive, 30% were "not to little" sensitive and 6% were "unknown". These results are not psychosomatic and are not due to electromagnetic interference. Twenty-five percent of the subjects' self proclaimed sensitivity corresponded to that based on the HRV analysis, while 32% overestimated their sensitivity and 42% did not know whether or not they were electrically sensitive. Of the 39 participants who claimed to experience some electrical hypersensitivity, 36% claimed they also reacted to a cordless phone and experienced heart symptoms and, of these, 64% were classified as having some degree of electrohypersensitivity (EHS) based on their HRV response. Novel findings include documentation of a delayed response to radiation. Orthostatic HRV testing combined with provocation testing may provide a diagnostic tool for some sufferers of EHS when they are exposed to electromagnetic emitting devices. The protocol used underestimates reaction to electromagnetic radiation for those who have a delayed autonomic nervous system reaction and it may under diagnose those who have adrenal exhaustion as their ability to mount a response to a stressor is diminished. PMID- 23675630 TI - Excessive magnetic field flux density distribution from overhead isolated powerline conductors due to neutral line current. AB - Overhead isolated powerline conductors (hereinafter: "OIPLC") are the most compact form for distributing low voltage currents. From the known physics of magnetic field emission from 3-phase power lines, it is expected that excellent symmetry of the 120 degrees shifted phase currents and where compact configuration of the 3-phase+neutral line exist, the phase current vectorial summation of the magnetic field flux density (MFFD) is expected to be extremely low. However, despite this estimation, an unexpectedly very high MFFD was found in at least three towns in Israel. This paper explains the reasons leading to high MFFD emissions from compact OIPLC and the proper technique to fix it. Analysis and measurement results had led to the failure hypothsis of neutral line poor connection design and poor grounding design of the HV-LV utility transformers. The paper elaborates on the low MFFD exposure level setup by the Israeli Environmental Protection Office which adopted a rather conservative precaution principal exposure level (2 mG averaged over 24 h). PMID- 23675632 TI - A prospective two-year assessment of miconazole resistance in Candida spp. With repeated treatment with 0.25% miconazole nitrate ointment in neonates and infants with moderate to severe diaper dermatitis complicated by cutaneous candidiasis. AB - A petrolatum and zinc oxide-based ointment containing 0.25% miconazole nitrate is reported to be effective and well tolerated in the treatment of diaper dermatitis complicated by cutaneous candidiasis (DDCC). This prospective, multicenter, open label, long-term, phase IV study investigated the potential resistance of Candida spp. to repeated topical use of 0.25% miconazole nitrate in infants age 15 months and younger with moderate to severe DDCC. For initial and recurring episodes of DDCC over the 2-year study period, subjects were treated with a 7-day course of 0.25% miconazole nitrate ointment (active components: miconazole nitrate 0.25%, zinc oxide 15%, and white petrolatum 81.35%) with a 7-day follow-up. Clinical and mycologic evaluations were conducted before treatment (day 0) and 7 days after treatment (day 14). Potential resistance to miconazole was defined using an arbitrary breakpoint of minimum inhibitory concentration of 2 MUg/mL. There was no evidence of resistance to miconazole in Candida spp. after single or repeated treatment courses of 0.25% miconazole nitrate ointment. For the initial episode of DDCC, 83 of 168 subjects (49.4%) achieved a clinical cure, 77 (45.8%) achieved a mycologic cure, and 49 (29.2%) achieved an overall cure (clinical and mycologic). The overall cure rate for recurrent episodes of DDCC was similar to or numerically greater than rates observed for the initial episode. Treatment of DDCC with 0.25% miconazole nitrate ointment was effective and generally well tolerated. No evidence of the development of resistance to miconazole in Candida spp. was observed. PMID- 23675633 TI - Support interventions for caregivers of physically disabled adults: a systematic review. AB - In developing countries family caregivers are an important community-based resource who provide care for physically disabled adults. Substantial caregiving commitment is known to adversely affect caregiver health and thereby their capacity to provide ongoing care. This systematic review focused on support interventions for caregivers using Thailand as an example. From 1964 to 2011 international and Thai electronic databases and relevant grey literature were searched. Six English papers and 34 Thai papers published between 1990 and 2010 were found. The Critical Appraisal Skills Programme (CASP) tool was modified to appraise methodological quality. All nurse-led interventions mainly focused on improving caregiving capacity; nearly half considered caregiver health. Only 15 interventions were community-based. Despite variable research quality all studies showed benefits for caregivers, care recipients, and healthcare services. In developing countries without healthy caregivers physically disabled adults would not receive care. There is an urgent need for further investment in community based research to develop effective interventions designed to promote caregiver health and help them maintain their role. PMID- 23675634 TI - Pattern of oral-maxillofacial trauma stemming from interpersonal physical violence and determinant factors. AB - BACKGROUND/AIM: Facial trauma is among the most common types of injury. The aim of the present study was to assess the prevalence and pattern of oral maxillofacial trauma stemming from interpersonal physical violence (IPV) and determine whether IPV is factor associated with oral-maxillofacial trauma. MATERIALS AND METHODS: A retrospective analysis was conducted of 790 complete patient charts for data on the type of IPV for the gender, area of residence (urban or rural), age and type of trauma. Statistical analysis involved the chi squared test (P < 0.05), univariate/multivariate Poisson, and logistic regression (P < 0.20). Type of oral-maxillofacial trauma was the dependent variable. Socio demographic status and type of IPV were the independent variables. RESULTS: One hundred forty (17.7%) individuals had oral-maxillofacial injuries stemming from IPV [80 (10.1%) due to urban violence (UV) and 42 (5.3%) due to domestic violence (DV)]. DV was more prevalent among females (69%), and UV was more prevalent among males (67.5%). The most common types of trauma were facial contusion and laceration, dental concussion, and mandibular fracture. Age and UV were explanatory factors for mandibular fracture. Females from rural areas and who suffered DV were more likely to exhibit facial contusion and dental concussion. CONCLUSIONS: Interpersonal physical violence was identified as a factor associated with oral-maxillofacial trauma, specifically mandibular fracture, facial contusion, and dental concussion. PMID- 23675635 TI - Beach nourishment impacts on bacteriological water quality and phytoplankton bloom dynamics. AB - A beach nourishment with approximately 1/3 fine-grained sediment (fines; particle diameter <63 MUm) by mass was performed at Southern California's Border Fields State Park (BFSP). The nourishment was found to briefly (<1 day) increase concentrations of surf-zone fecal indicator bacteria (FIB) above single-sample public health standards [104 most probable number (MPN).(100 mL)(-1)] but had no effect on phytoplankton. Contamination was constrained to the nourishment site: waters 300 m north or south of the nourishment were always below single-sample and geometric mean [<= 35 MPN . (100 mL)(-1)] standards. Nourishment fines were identified as a source of the fecal indicator Enterococcus ; correlations between fines and enterococci were significant (p < 0.01), and generalized linear model analysis identified fines as the single best predictor of enterococci. Microcosm experiments and field sampling suggest that the short surf-zone residence times observed for enterococci (e-folding time 4 h) resulted from both rapid, postplacement FIB inactivation and mixing/transport by waves and alongshore currents. Nourishment fines were phosphate-rich/nitrogen-poor and were not correlated with surf-zone phytoplankton concentrations, which may have been nitrogen-limited. PMID- 23675636 TI - Reconstruction of functional ocular surface by acellular porcine cornea matrix scaffold and limbal stem cells derived from human embryonic stem cells. AB - Limbal stem cells (LSCs) derived from human embryonic stem cells (hESCs) hold great potential for cell-based therapies for ocular surface diseases. The cell based therapies mainly depend on an appropriate differentiation proposal with a high efficiency and on a suitable scaffold. In this study, we aimed to establish a feasible and efficient strategy for inducing hESCs into LSC-like cells by the LSC conditioned medium. The induced cells possessed the similar morphologic characteristics and expression of normal LSCs and showed a strong clonogenic and proliferative capacity in vitro. To construct a tissue-engineering corneal graft, these differentiated cells were seeded on an acelluar porcine corneal matrix (APCM), which maintained the corneal basement membrane in vitro. After 14 days culture, these induced cells gave rise to stratified epithelial cell sheets on the APCM and the basal cells still kept LSC characteristics. In rabbit total limbal stem cell deficiency (LSCD) models, the tissue-engineering graft had the potential to reconstruct the damaged ocular surface and alleviated the invasion of corneal neovascularization. These findings indicated that the engraftment constructed with the APCM scaffold and hESC-derived LSCs might be a potential therapy option for ocular surface regeneration in LSCD cases. PMID- 23675637 TI - Depression as a risk factor for adverse outcomes in coronary heart disease. AB - BACKGROUND: Depression is firmly established as an independent predictor of mortality and cardiac morbidity in patients with coronary heart disease (CHD). However, it has been difficult to determine whether it is a causal risk factor, and whether treatment of depression can improve cardiac outcomes. In addition, research on biobehavioral mechanisms has not yet produced a definitive causal model of the relationship between depression and cardiac outcomes. DISCUSSION: Key challenges in this line of research concern the measurement of depression, the definition and relevance of certain subtypes of depression, the temporal relationship between depression and CHD, underlying biobehavioral mechanisms, and depression treatment efficacy. SUMMARY: This article examines some of the methodological challenges that will have to be overcome in order to determine whether depression should be regarded as a key target of secondary prevention in CHD. PMID- 23675638 TI - DSM-5 and autism spectrum disorders (ASDs): an opportunity for identifying ASD subtypes. AB - The heterogeneous clinical presentations of individuals with autism spectrum disorders (ASDs) poses a significant challenge for sample characterization and limits the interpretability and replicability of research studies. The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) diagnostic criteria for ASD, with its dimensional approach, may be a useful framework to increase the homogeneity of research samples. In this review, we summarize the revisions to the diagnostic criteria for ASD, briefly highlight the literature supporting these changes, and illustrate how DSM-5 can improve sample characterization and provide opportunities for researchers to identify possible subtypes within ASD. PMID- 23675639 TI - Sebaceous carcinoma in the clinical setting of non-Hodgkin lymphoma: the Mayo Clinic experience. AB - OBJECTIVES: Non-Hodgkin lymphoma is a hematologic malignancy associated with the more aggressive behavior of some forms of skin cancer. An association between sebaceous carcinoma and immunosuppression has been identified, but the behavior of sebaceous carcinoma in the setting of non-Hodgkin lymphoma has not been studied. This study aimed to increase understanding of the behavior of sebaceous carcinoma in patients with concomitant non-Hodgkin lymphoma. METHODS: Six patients diagnosed with sebaceous carcinoma and non-Hodgkin lymphoma from 1976 to 2008 were identified at the Mayo Clinic in Rochester, Minnesota. Their charts were reviewed retrospectively. RESULTS: All six patients were male and White and presented with sebaceous carcinoma on non-eyelid regions of the head and neck. Two patients had Muir-Torre syndrome; four had secondary cancers that included colon, prostate, transitional cell, and urothelial cancers. Skin cancers other than sebaceous carcinoma included basal cell carcinoma and squamous cell carcinoma. Three patients died of causes unrelated to sebaceous carcinoma; one died of an unknown cause and two were alive at the time of the study. CONCLUSIONS: Sebaceous carcinoma does not appear to behave more aggressively in the setting of non-Hodgkin lymphoma. Larger studies are needed to definitively understand how sebaceous carcinoma behaves in patients with lymphoma. PMID- 23675641 TI - Peripheral and total parenteral nutrition as the strongest risk factors for nosocomial candidemia in elderly patients: a matched case-control study. AB - Candidemia is an important cause of morbidity and mortality in the healthcare setting. However, there is limited information about risk factors for such infection among elderly patients. A case-control study was conducted during the period 2008-2011. For each case, two controls were selected among patients admitted to the same hospital, and individually matched by sex, age, time of admission, hospital ward and hospitalisation duration. The adjusted odds ratio (OR) was calculated using multiple conditional logistic regression. We identified 145 episodes of candidemia occurring in 140 patients with a median age of 80 years. Candida albicans caused 55% of all candidemia episodes. After adjustment, candidemia was strongly associated with duration of total [duration > 7 days: OR = 20.09; 95% confidence interval (CI): 3.44-117.52] and peripheral parenteral nutrition (duration > 7 days: OR = 26.83; 95% CI: 6.54-110.17), other central vascular catheters (OR = 5.17; 95% CI: 1.24-23.54) and glycopeptide antibiotics (OR = 6.45; 95% CI: 1.90-21.91). Duration of peripheral and total parenteral nutrition and antibiotics predicted over 50% of all candidemias. Intervention studies should be planned to evaluate effectiveness of candidemia prevention by restricting parenteral nutrition, prompting earlier enteral feeding, and reducing use of antibiotics, especially glycopeptides, in elderly patients. PMID- 23675640 TI - New frontier in regenerative medicine: site-specific gene correction in patient specific induced pluripotent stem cells. AB - Advances in cell and gene therapy are opening up new avenues for regenerative medicine. Because of their acquired pluripotency, human induced pluripotent stem cells (hiPSCs) are a promising source of autologous cells for regenerative medicine. They show unlimited self-renewal while retaining the ability, in principle, to differentiate into any cell type of the human body. Since Yamanaka and colleagues first reported the generation of hiPSCs in 2007, significant efforts have been made to understand the reprogramming process and to generate hiPSCs with potential for clinical use. On the other hand, the development of gene-editing platforms to increase homologous recombination efficiency, namely DNA nucleases (zinc finger nucleases, TAL effector nucleases, and meganucleases), is making the application of locus-specific gene therapy in human cells an achievable goal. The generation of patient-specific hiPSC, together with gene correction by homologous recombination, will potentially allow for their clinical application in the near future. In fact, reports have shown targeted gene correction through DNA-Nucleases in patient-specific hiPSCs. Various technologies have been described to reprogram patient cells and to correct these patient hiPSCs. However, no approach has been clearly more efficient and safer than the others. In addition, there are still significant challenges for the clinical application of these technologies, such as inefficient differentiation protocols, genetic instability resulting from the reprogramming process and hiPSC culture itself, the efficacy and specificity of the engineered DNA nucleases, and the overall homologous recombination efficiency. To summarize advances in the generation of gene corrected patient-specific hiPSCs, this review focuses on the available technological platforms, including their strengths and limitations regarding future therapeutic use of gene-corrected hiPSCs. PMID- 23675642 TI - The role of the NIH in nurturing clinician-scientists. PMID- 23675644 TI - In-home fall risk assessment and detection sensor system. AB - Falls are a major problem in older adults. A continuous, unobtrusive, environmentally mounted (i.e., embedded into the environment and not worn by the individual), in-home monitoring system that automatically detects when falls have occurred or when the risk of falling is increasing could alert health care providers and family members to intervene to improve physical function or manage illnesses that may precipitate falls. Researchers at the University of Missouri Center for Eldercare and Rehabilitation Technology are testing such sensor systems for fall risk assessment (FRA) and detection in older adults' apartments in a senior living community. Initial results comparing ground truth (validated measures) of FRA data and GAITRite System parameters with data captured from Microsoft((r)) Kinect and pulse-Doppler radar are reported. PMID- 23675645 TI - Clinical and transitional care: considerations to optimize functional recovery following hip fracture. AB - Between 30% and 40% of community-dwelling older adults in the United States fall at least once each year, and approximately 10% of these falls are associated with a major injury such as a hip fracture. Return to maximum level of functional status following surgery requires individualized rehabilitation programs and may involve multiple care transitions. Using an individual example, this article provides context for meeting rehabilitation goals during transitional care following hip fractures. Understanding recommended clinical management strategies during the acute perioperative period and the rationale for postsurgical rehabilitation decisions based on clinical assessment, program eligibility, and Medicare coverage will allow all health professionals to provide optimal guidance and maximize functional recovery for older adults with hip fractures. PMID- 23675643 TI - Equol enhances tamoxifen's anti-tumor activity by induction of caspase-mediated apoptosis in MCF-7 breast cancer cells. AB - BACKGROUND: Soy phytoestrogens, such as daidzein and its metabolite equol, have been proposed to be responsible for the low breast cancer rate in Asian women. Since the majority of estrogen receptor positive breast cancer patients are treated with tamoxifen, the basic objective of this study is to determine whether equol enhances tamoxifen's anti-tumor effect, and to identify the molecular mechanisms involved. METHODS: For this purpose, we examined the individual and combined effects of equol and tamoxifen on the estrogen-dependent MCF-7 breast cancer cells using viability assays, annexin-V/PI staining, cell cycle and western blot analysis. RESULTS: We found that equol (>50 MUM) and 4-hydroxy tamoxifen (4-OHT; >100 nM) significantly reduced the MCF-7 cell viability. Furthermore, the combination of equol (100 MUM) and 4-OHT (10 MUM) induced apoptosis more effectively than each compound alone. Subsequent treatment of MCF 7 cells with the pan-caspase inhibitor Z-VAD-FMK inhibited equol- and 4-OHT mediated apoptosis, which was accompanied by PARP and alpha-fodrin cleavage, indicating that apoptosis is mainly caspase-mediated. These compounds also induced a marked reduction in the bcl-2:bax ratio, which was accompanied by caspase-9 and caspase-7 activation and cytochrome-c release to the cytosol. Taken together, these data support the notion that the combination of equol and tamoxifen activates the intrinsic apoptotic pathway more efficiently than each compound alone. CONCLUSIONS: Consequently, equol may be used therapeutically in combination treatments and clinical studies to enhance tamoxifen's effect by providing additional protection against estrogen-responsive breast cancers. PMID- 23675646 TI - Predicting project environmental performance under market uncertainties: case study of oil sands coke. AB - A method combining life cycle assessment (LCA) and real options analyses is developed to predict project environmental and financial performance over time, under market uncertainties and decision-making flexibility. The method is applied to examine alternative uses for oil sands coke, a carbonaceous byproduct of processing the unconventional petroleum found in northern Alberta, Canada. Under uncertainties in natural gas price and the imposition of a carbon price, our method identifies that selling the coke to China for electricity generation by integrated gasification combined cycle is likely to be financially preferred initially, but eventually hydrogen production in Alberta is likely to be preferred. Compared to the results of a previous study that used life cycle costing to identify the financially preferred alternative, the inclusion of real options analysis adds value as it accounts for flexibility in decision-making (e.g., to delay investment), increasing the project's expected net present value by 25% and decreasing the expected life cycle greenhouse gas emissions by 11%. Different formulations of the carbon pricing policy or changes to the natural gas price forecast alter these findings. The combined LCA/real options method provides researchers and decision-makers with more comprehensive information than can be provided by either technique alone. PMID- 23675647 TI - Gene therapy briefs. PMID- 23675648 TI - Antisense oligonucleotides for therapeutic interventions in neuromuscular diseases. PMID- 23675649 TI - Study of nonadiabatic effects in low-lying electronic states of HCNH with implication in its dissociation to HCN and HNC. AB - Abnormal abundance of HNC in interstellar spaces has been the motivation of many experimental as well as theoretical studies of the branching ratio [HNC]/[HCN] in the dissociation of HCNH, right after its formation from electron capture by HCNH(+), available in the upper atmosphere. In the present work we were interested in nonadiabatic studies involving the dissociation channel of HCNH leading to the formation of HNC. This study reports for the first time that the conical intersection (CI) between the states 1(2)Sigma(+) and 2(2)Sigma(+) exists only in some bent geometry (and not in the collinear geometry) where both of these states have A' symmetry. This finding is important as this CI is crucial in the dissociation of HCNH. We further report that these two states strongly couple with 1(2)Pi, the lowest electronic state of collinear HCNH. Hence we construct a three-state Hilbert subspace (HSS), comprising of the states 1(2)Pi, 1(2)Sigma(+), and 2(2)Sigma(+), in a configuration space where these states interact very strongly and the adiabatic-to-diabatic transformation angles (mixing angle) yield meaningful values of topological (Berry) phase. This leads to the construction of the corresponding three-state diabatic potentials. We advocate that these diabatic potentials, considering both the linear as well as bent configurations, nicely elucidate the formation of the HNC molecule by the CH bond dissociation of HCNH molecule. PMID- 23675650 TI - In situ synthesis of high density sub-50 nm ZnO nanopatterned arrays using diblock copolymer templates. AB - Fabrication of high density (~155 Gbit in(-2)) ZnO nanopatterns through in situ decomposition of Zn precursors inside diblock copolymer templates and their application as charge storage centers in nonvolatile memory devices is described. The fabrication is performed in a highly controlled fashion with the resulting ZnO nanopatterned arrays exhibiting diameters of 38 nm and heights of 14 nm offering sub-50 nm feature resolutions. The ZnO nanopatterns are naturally n-type due to the presence of zinc interstitials and oxygen vacancies that act as defect levels in trapping charge carriers. Test capacitors (metal-oxide-semiconductor, MOS) constructed using nanopatterns formed on p-Si exhibited a large flatband voltage shift of about ~2.2 V for a low operating voltage of 10 V. A high charge trap density of 3.47 * 10(18) cm(-3) combined with a good retention capacity is observed with low tunneling oxide (thermally grown) thickness of 3 nm. This demonstrates the significant promise of the ZnO nanopatterned arrays to act as charge storage centers for potential application in nonvolatile flash memory devices. The charge trapping characteristics, the capacitance-voltage measurements, and the potential of ZnO nanopatterns as charge storage centers in fabricating nonvolatile memory devices are discussed. PMID- 23675651 TI - Hydrolyzable tannins of tamaricaceous plants. V. Structures of monomeric-trimeric tannins and cytotoxicity of macrocyclic-type tannins isolated from Tamarix nilotica (1). AB - Three new ellagitannin monomers, nilotinins M5-M7 (1-3), a dimer, nilotinin D10 (4), and a trimer, nilotinin T1 (5), together with three known dimers, hirtellin D (7) and tamarixinins B (8) and C (9), and a trimer, hirtellin T2 (6), were isolated from Tamarix nilotica dried leaves. The structures of the tannins were elucidated by intensive spectroscopic methods and chemical conversions into known tannins. The new trimer (5) is a unique macrocyclic type whose monomeric units are linked together by an isodehydrodigalloyl and two dehydrodigalloyl moieties. Additionally, dimeric and trimeric macrocyclic-type tannins isolated from T. nilotica in this study were assessed for possible cytotoxic activity against four human tumor cell lines. Tumor-selective cytotoxicities of the tested compounds were higher than those of synthetic and natural potent cytotoxic compounds, including polyphenols, and comparable with those of 5-fluorouracil and melphalan. PMID- 23675652 TI - Camelid single-domain antibody-fragment engineering for (pre)clinical in vivo molecular imaging applications: adjusting the bullet to its target. AB - INTRODUCTION: Molecular imaging is a fast developing field and there is a growing need for specific imaging tracers in the clinic. Camelid single-domain antibody fragments (sdAbs) recently emerged as a new class of molecular imaging tracers. AREAS COVERED: We review the importance of molecular imaging in the clinic and the use of camelid sdAbs as in vivo molecular imaging tracers. Interest in imaging tracers based on antibody fragments or man-made protein scaffolds expanded over the last years. Camelid sdAbs are small, monomeric binding fragments that are derived from unique heavy-chain-only antibodies. In vivo imaging studies with sdAbs targeting various cell membrane receptors in different disease models have been reported and more sdAb imaging tracers are under development. The first clinical trial with a camelid sdAb as a molecular imaging tracer targeting the breast cancer marker Human Epidermal growth factor Receptor 2 is currently ongoing. EXPERT OPINION: We expect that the development and use of sdAbs as tracers for both preclinical and clinical molecular imaging applications will become widespread. PMID- 23675653 TI - Differential regulation of host genes including hepatic fatty acid synthase in HBV-transgenic mice. AB - Hepatitis B virus (HBV) is the most common of the hepatitis viruses that cause chronic liver infections in humans, and it is considered to be a major global health problem. To gain a better understanding of HBV pathogenesis, and identify novel putative targets for anti-HBV therapy, this study was designed to elucidate the differential expression of host proteins in liver tissue from HBV-transgenic mice. Liver samples from two groups, (1) HBV-transgenic (Tg) mice, (2) corresponding background normal mice, wild-type (WT) mice, were collected and subjected to iTRAQ and mass spectrometry analysis. In total, 1950 unique proteins were identified, and 68 proteins were found to be differentially expressed in HBV Tg mice as compared with that in WT mice. Several differentially expressed proteins were further validated by real-time quantitative RT-PCR, Western blot and immunohistochemical analysis. Furthermore, the association of HBV replication with fatty acid synthase (FASN), one of the highly expressed proteins in HBV-Tg mice, was verified. Silencing of FASN expression in HepG2.2.15 cells suppressed viral replication through the IFN signaling pathway, and some downstream antiviral effectors. The implicated role of FASN in HBV replication provides an opportunity to test existing compounds against FASN for adjuvant therapy and/or treatment of HBV replication. PMID- 23675654 TI - Mapping molecular orientation with phase sensitive vibrationally resonant sum frequency generation microscopy. AB - We demonstrate a phase sensitive, vibrationally resonant sum-frequency generation (PSVR-SFG) microscope that combines high resolution, fast image acquisition speed, chemical selectivity, and phase sensitivity. Using the PSVR-SFG microscope, we generate amplitude and phase images of the second-order susceptibility of collagen I fibers in rat tail tendon tissue on resonance with the methylene vibrations of the protein. We find that the phase of the second order susceptibility shows dependence on the effective polarity of the fibril bundles, revealing fibrous collagen domains of opposite orientations within the tissue. The presence of collagen microdomains in tendon tissue may have implications for the interpretation of the mechanical properties of the tissue. PMID- 23675655 TI - Short communication: High prevalence of vitamin D deficiency in HIV-infected and HIV-uninfected pregnant women. AB - Vitamin D deficiency is common in HIV-infected populations. In resource-limited settings, vitamin D deficiency has been shown to affect HIV disease progression and mortality in pregnant women, and also increases mother-to-child HIV transmission and mortality in their infants. This study sought to investigate vitamin D status in HIV-infected women compared to healthy controls in a high income country setting and determine variables associated with vitamin D deficiency. We prospectively enrolled 40 women/infant pairs (16 HIV-infected women/HIV-exposed infant pairs and 24 uninfected/unexposed pairs). In serum cord blood, 25-hydroxyvitamin D [25(OH)D] concentrations were suboptimal (<30 ng/ml) in 100% of subjects from both groups. White race, non-Hispanic ethnicity was the only variable associated with higher serum 25(OH)D concentrations. This high prevalence of vitamin D deficiency, especially among HIV-infected women and their infants, deserves further investigation, as it may have a negative impact on maternal and infant health. PMID- 23675656 TI - Intracellular organic matter from cyanobacteria as a precursor for carbonaceous and nitrogenous disinfection byproducts. AB - The formation of total organic halogen (TOX), carbonaceous disinfection byproducts (DBPs) (trihalomethanes (THMs) and haloacetic acids (HAAs)), and nitrogenous DBPs (trichloronitromethane (TCNM) or chloropicrin, haloacetonitriles (HANs), and nitrosamines) was examined during the chlorination or chloramination of intracellular organic matter (IOM) extracted from Microcystis aeruginosa, Oscillatoria sp. (OSC), and Lyngbya sp. (LYN). The percentage of unknown TOX (22 38%) during chlorination indicated that the majority of DBPs were identified among THMs, HAAs, TCNM, and HANs. Bromide was readily incorporated into DBPs with speciation shifting slightly from dihalogenated species to trihalogenated species. During formation potential testing with chloramines, nitrosamine yields from IOM were measured for N-nitrosodimethylamine (NDMA, 10-52 ng/mgC), N nitrosopyrrolidine (NPYR, 14 ng/mgC), N-nitrosopiperidine (NPIP, 3.7-5.5 ng/mgC), and N-nitrosomethylethylamine (NMEA, 2.1-2.6 ng/mgC). When IOM was added to a natural water matrix, the nitrosamine yields were not realized likely due to competition from natural organic matter. Ozonation increased NDMA and NMEA formation and reduced NPYR and NPIP formation during subsequent chloramination. In addition, ozone oxidation of IOM formed detectable concentrations of aldehydes, which may contribute to DBP formation. Finally, bioluminescence-based test results showed that >99% of the IOM extracted from OSC and LYN was biodegradable. Therefore, a biological treatment process could minimize this source of DBP precursor material during drinking water treatment. PMID- 23675657 TI - Hepatitis C in the United States. PMID- 23675658 TI - Perspectives of physicians and nurse practitioners on primary care practice. AB - BACKGROUND: The U.S. health care system is at a critical juncture in health care workforce planning. The nation has a shortage of primary care physicians. Policy analysts have proposed expanding the supply and scope of practice of nurse practitioners to address increased demand for primary care providers. These proposals are controversial. METHODS: From November 23, 2011, to April 9, 2012, we conducted a national postal-mail survey of 972 clinicians (505 physicians and 467 nurse practitioners) in primary care practice. Questionnaire domains included scope of work, practice characteristics, and attitudes about the effect of expanding the role of nurse practitioners in primary care. The response rate was 61.2%. RESULTS: Physicians reported working longer hours, seeing more patients, and earning higher incomes than did nurse practitioners. A total of 80.9% of nurse practitioners reported working in a practice with a physician, as compared with 41.4% of physicians who reported working with a nurse practitioner. Nurse practitioners were more likely than physicians to believe that they should lead medical homes, be allowed hospital admitting privileges, and be paid equally for the same clinical services. When asked whether they agreed with the statement that physicians provide a higher-quality examination and consultation than do nurse practitioners during the same type of primary care visit, 66.1% of physicians agreed and 75.3% of nurse practitioners disagreed. CONCLUSIONS: Current policy recommendations that are aimed at expanding the supply and scope of practice of primary care nurse practitioners are controversial. Physicians and nurse practitioners do not agree about their respective roles in the delivery of primary care. (Funded by the Gordon and Betty Moore Foundation and others.). PMID- 23675660 TI - Images in clinical medicine. Pyostomatitis vegetans. PMID- 23675661 TI - Case records of the Massachusetts General Hospital. Case 15-2013. A 76-year-old man with fever, worsening renal function, and altered mental status. PMID- 23675662 TI - Putting aside preconceptions--time for dialogue among primary care clinicians. PMID- 23675659 TI - Current and future therapies for hepatitis C virus infection. PMID- 23675663 TI - Expanding the role of advanced nurse practitioners--risks and rewards. PMID- 23675664 TI - Tumor-stromal interactions in medulloblastoma. PMID- 23675665 TI - Rivaroxaban for thromboprophylaxis in acutely ill medical patients. PMID- 23675666 TI - Rivaroxaban for thromboprophylaxis in acutely ill medical patients. PMID- 23675667 TI - Rivaroxaban for thromboprophylaxis in acutely ill medical patients. PMID- 23675668 TI - Rivaroxaban for thromboprophylaxis in acutely ill medical patients. PMID- 23675669 TI - More on confusion of drug names. PMID- 23675670 TI - More on confusion of drug names. PMID- 23675671 TI - Ondansetron for diarrhea associated with neuroendocrine tumors. PMID- 23675672 TI - Public funding of and access to in vitro fertilization. PMID- 23675673 TI - Images in clinical medicine. Persistent hemichorea. PMID- 23675674 TI - Newcomers' cognitive development of social identification: a cross-sectional and longitudinal analysis of self-anchoring and self-stereotyping. AB - Upon joining a new social category, group members strive to establish and maintain high social identification. Thus far, we know relatively little about the cognitive underpinnings of social identification when developing from a new to a well-established group member. This research investigates the differential impact of newcomers' self-stereotyping (i.e., assimilation of the self to group stereotypes) and self-anchoring (i.e., projection of self-attributes onto the ingroup) on the development of social identification over time. Across two time points during the academic year, first year psychology students (N = 123) filled in a questionnaire on their perceptions about the self, psychology students, and social identification. Cross-sectional and longitudinal analyses confirmed our hypotheses that self-anchoring instigated new group members' social identification, while self-stereotyping instigated social identification once group membership was more well-established. This research emphasizes the interactive role of the personal and social self in the development of social identification. PMID- 23675675 TI - Hepatitis C virus genotypes among patients with lichen planus in the Kingdom of Saudi Arabia. AB - OBJECTIVES: This study aimed to determine the prevalence of anti-hepatitis C virus (HCV) antibodies and HCV genotypes/subtypes among patients with lichen planus (LP) in Saudi Arabia. METHODS: Fifty patients with LP and 50 healthy blood donors were recruited from dermatology outpatient clinics, and blood samples along with demographic and clinical data were collected. Sera were analyzed for aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, bilirubin, hepatitis B virus surface antigen, anti-HCV antibodies, and HCV-RNA. Patients with anti-HCV-positive LP were genotyped and subtyped. RESULTS: Clinical examination revealed that 26 (55.3%) of our patients had cutaneous LP, and 10 (21.30%) presented with oral LP. Eleven (23.4%) patients with LP had cutaneous as well as oral infection. Twenty-eight (59.6%) of our patients with LP were exposed to a variety of HCV risk factors, including history of intramuscular injections (nine of 47; 19%), blood transfusion (seven of 47; 15%), and exposure to family member with HCV infection (five of 47; 10.6%). Of the 47 patients with LP, six (12.76%) tested positive for anti-HCV antibodies, with two of six (33.33%) being HCV-RNA positive showing HCV genotypes 1b and 4a, respectively. Mean +/- SD serum levels of ALT and AST among patients with anti-HCV-positive LP (n = 6) were slightly higher as compared with patients with anti-HCV-negative LP. None of the 50 healthy blood donors tested positive for anti-HCV antibodies, and their liver function test profiles were within normal reference range. CONCLUSION: Our findings are in agreement with earlier reports that HCV infection is associated with LP and recommend the screening of patients with LP for ALT, AST, and anti HCV antibodies for early diagnosis of HCV infection. PMID- 23675676 TI - The influence of physical activity on vascular complications and mortality in patients with type 2 diabetes mellitus. AB - AIMS: There is limited evidence regarding the association between physical activity and vascular complications, particularly microvascular disease, in patients with type 2 diabetes. METHODS: From the 11 140 patients in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron modified release Controlled Evaluation) trial, the effect of physical activity, categorized as none, mild, moderate or vigorous, and the number of sessions within a week, was examined in multivariable regression models adjusted for potential confounders. The study end-points were major cardiovascular events, microvascular complications and all-cause mortality. RESULTS: Forty-six percent of participants reported undertaking moderate to vigorous physical activity for >15 min at least once in the previous week. During a median of 5 years of follow-up, 1031 patients died, 1147 experienced a major cardiovascular event and 1136 a microvascular event. Compared to patients who undertook no or mild physical activity, those reporting moderate to vigorous activity had a decreased risk of cardiovascular events (HR: 0.78, 95% CI: 0.69-0.88, p < 0.0001), microvascular events (HR: 0.85, 95% CI: 0.76-0.96, p = 0.010) and all-cause mortality (HR: 0.83, 95% CI: 0.73 0.94, p = 0.0044). CONCLUSIONS: Moderate to vigorous, but not mild, physical activity is associated with a reduced incidence of cardiovascular events, microvascular complications and all-cause mortality in patients with type 2 diabetes. PMID- 23675677 TI - Nutritional status, gender and marital status in patients with chronic obstructive pulmonary disease. AB - AIM AND OBJECTIVES: To describe and compare nutritional status, pulmonary function, gender and marital status in patients with chronic obstructive pulmonary disease. BACKGROUND: Chronic obstructive pulmonary disease is a chronic illness that can lead to poor nutritional status due to an increased energy requirements related to laboured breathing. Inadequate nutritional intake has often been described in this patient group. Nutritional support for patients with chronic obstructive pulmonary disease who suffer from nutritional problems is essential, both for their sense of well-being and for their survival with chronic obstructive pulmonary disease. DESIGN: The study design was descriptive and comparative. METHODS: Quantitative data collection was carried out among 81 patients with chronic obstructive pulmonary disease (47 women and 34 men) with an average age of 65 years (SD 3.5). The Mini Nutritional Assessment was used to assess nutritional status. RESULTS: Participants who lived alone had worse nutritional status than those who did not live alone, and female participants had worse nutritional status than their male counterparts. No significant correlation was found between pulmonary function and nutritional status. CONCLUSIONS: This study contributes knowledge of a potential correlation between nutritional status, gender and marital status in patients with chronic obstructive pulmonary disease. Women with chronic obstructive pulmonary disease may be at an increased risk of malnutrition. Despite the previous results showing malnutrition and underweight to be common, the present study found that many of the participants were overweight, which may reflect a global health trend regardless of disease. RELEVANCE TO CLINICAL PRACTICE: Early identification of patients at risk of malnutrition is important. Registered nurses should be aware that patients with chronic obstructive pulmonary disease who are female or who live alone may be at an increased risk of nutritional problems. Patients with chronic obstructive pulmonary disease must be offered information and support for individually adapted measures at an early stage in order to avoid nutritional problems, regardless of under- and overweight. PMID- 23675678 TI - The politics of combating the organ trade: lessons from the Israeli and Pakistani experience. AB - Israel and Pakistan--two major participants in the global organ trade--enacted legislative prohibitions on the trade at roughly the same time. The article highlights three influences that brought about this change of policy in both countries: advocacy by local physicians coupled with media coverage and reinforced by the international medical community. The analysis also explains why the two countries have differed with respect to the enforcement of the organ trade prohibition. The insights from the Israeli and Pakistani cases will be of use for the transplant community's efforts against organ trafficking. PMID- 23675679 TI - Surgical repair of coronary artery fistula combined with coronary artery ectasia in adults. AB - OBJECTIVES: Coronary artery fistula (CAF) is rare in patients undergoing coronary angiography. Coronary artery ectasia (CAE) is found in 1.2% to 4.9% of patients at autopsy or during angiographic studies. CAF combined with CAE is a extremely rare clinical condition. This study aimed to summarize a treatment strategy for this complex disorder. METHODS: Ten consecutive patients who underwent surgical repair of CAF combined with CAE between 2000 and 2012 are reported. The main outcome measure was death. Secondary outcome measures included surgical technique, the extracorporeal circulation time, intubation duration, the intensive care unit stay period and discharge period. RESULTS: The mean extracorporeal circulation period was 103.8 W 25.7 minutes. The mean intubation duration was 10.5 W 3.2 hours. The mean intensive care unit stay period was 2.0 W 0.8 days and the mean discharge period was 11.4 W 2.6 days two patients were lost to follow-up. The other eight patients were asymptomatic and there were no deaths during the follow-up period. CONCLUSIONS: Surgical repair for CAF combined with CAE is effective with satisfactory results in adults. PMID- 23675681 TI - Primary cardiac paraganglioma arising from interatrial septum. PMID- 23675680 TI - Innominate artery as an alternative site for proximal anastomoses in patients with a severely calcified aorta. AB - BACKGROUND: Atheromatous plaques of the ascending aorta are one of the most important risk factors for postoperative mortality and morbidity in coronary artery bypass grafting (CABG). We have retrospectively analyzed the results of proximal anastomoses constructed on the innominate artery in patients with calcific atheromatous plaques (CAP) in their ascending aorta detected intraoperatively. PATIENTS AND METHODS: This study is a retrospective review of 16 consecutive patients who underwent CABG operations and had CAP on their ascending aorta between November 2006 and June 2009. The atheromatous lesions were detected intraoperatively and the operation plan was changed to off-pump surgery. All the proximal anastomoses were made on the innominate artery, left internal thoracic artery (LITA) or the other saphenous vein grafts (SVG). Thirteen patients were male and three were female with a mean age of 63.7 +/- 5.3 (ranged, 53-71) years. RESULTS: A total of 56 distal anastomoses (3.5 per patient) and 25 proximal anastomoses on the innominate artery were performed. Of the 16 patients, seven (43.7%) had received a sequential SVG; two (12.5%) patients, sequential LITA graft; and one (6.25%) patient sequential SVG and LITA graft. One of the proximal anastomoses was performed on the SVG in four patients (25%) and on the LITA graft in one patient (6.2%). One patient (6.2%) died due to cerebrovascular morbidity. No other complications were observed. CONCLUSIONS: The innominate artery is an alternative site for proximal anastomoses in patients with calcific atheromatous aorta. PMID- 23675682 TI - Concomitant replacement of the dilated ascending aorta during aortic valve replacement; does it increase the perioperative morbidity and mortality risks? AB - BACKGROUND: Concerns of increased surgical risks with ascending aortic replacement have led surgeons to manage post-stenotic aortic dilatation more conservatively during aortic valve replacement (AVR). The present study aimed to assess the prognostic implications and surgical risks of replacing the dilated aorta during AVR. METHODS: Between January 1999 and March 2010, 134 patients who received surgery for aortic stenosis and post-stenotic dilatation (aorta size >=40 mm) were included in the present study. AVR was performed in 92 patients (AVR group) while aortic valve and ascending aorta replacement (AVR + aorta group) were performed in 42 patients. Overall survival was compared between the two groups using Cox proportional hazard model after adjustment with inverse probability-of-treatment weighting. RESULTS: The mean follow-up duration was 3.5 +/- 3 years. There were no significant differences in the operative mortality and morbidity between the two groups. The late cardiac deaths were also not significantly different between the two groups (p = 1.00). In the AVR group, the ascending aortic expansion rate which was 0.18 mm/year over a mean follow-up duration of 2.3 +/- 2.2 years by echocardiography showed a positive correlation with time (r = 0.3, p = 0.08). A relatively greater aortic expansion rate was identified as a risk factor for late mortality (p = 0.015, HR 1.08 (CI: 1.02 to 1.15). CONCLUSIONS: Concomitant replacement of the dilated ascending aorta during AVR did not increase the immediate postoperative morbidity or mortality risks and tended to exert a long-term beneficial effect on the risk of late mortality. PMID- 23675683 TI - Surgical management of apical muscular ventricular septal defects using the sandwich technique. AB - OBJECTIVE: We performed closure of apical muscular ventricular septal defects (VSDs) using the sandwich technique and assessed its role in the treatment of the defects. METHODS: Twenty-one patients (nine males and 12 females) underwent VSD closure at a mean age of 15.4 months (range, 1 month to 6 years) and a mean weight of 8.3 kg (range, 4 to 20 kg). Associated cardiac malformations were present in all of the patients. VSDs were exposed through the tricuspid valve and also from the left ventricular (LV) side through a coexisting large perimembranous VSD or through the mitral valve through an interatrial septostomy. All the apical muscular VSDs were closed using the sandwich technique. RESULTS: There were no hospital deaths, and the postoperative course was uneventful in all patients. There was no residual shunt in 13 patients, and a minimal residual shunt (diameter <=2 mm) was observed in four patients. Mild residual shunt (diameter <=4 mm) was observed in two patients. At the latest follow-up, all the residual shunts had disappeared except in one patient. The wall motion of the interventricular septum and cardiac function were normal in all the patients one month after surgery. All patients were free of cardiac medications. CONCLUSIONS: We conclude that the sandwich technique is safe and reliable. Even in cases when a residual shunt is present, the shunt tends to decrease with time. Further experience and longer follow-up of these patients are necessary to conclude whether this technique is applicable to neonates and young infants. PMID- 23675684 TI - Exploring the segregating and mineralization-inducing capacities of cationic hydrophilic polymers for preparation of robust, multifunctional mesoporous hybrid microcapsules. AB - A facile approach to preparing mesoporous hybrid microcapsules is developed by exploring the segregating and mineralization-inducing capacities of cationic hydrophilic polymer. The preparation process contains four steps: segregation of cationic hydrophilic polymer during template formation, cross-linking of the segregated polymer, biomimetic mineralization within cross-linked polymer network, and removal of template to simultaneously generate capsule lumen and mesopores on the capsule wall. Poly(allylamine hydrochloride) (PAH) is chosen as the model polymer, its hydrophilicity renders the segregating capacity and spontaneous enrichment in the near-surface region of CaCO3 microspheres; its biopolyamine-mimic structure renders the mineralization-inducing capacity to produce titania from the water-soluble titanium(IV) precursor. Meanwhile, CaCO3 microspheres serve the dual templating functions in the formation of hollow lumen and mesoporous wall. The thickness of capsule wall can be controlled by changing the polymer segregating and cross-linking conditions, while the pore size on the capsule wall can be tuned by changing the template synthesizing conditions. The robust hybrid microcapsules exhibit desirable efficiency in enzymatic catalysis, wastewater treatment and drug delivery. This approach may open facile, generic, and efficient pathway to designing and preparing a variety of hybrid microcapsules with high and tunable permeability, good stability and multiple functionalities for a broad range of applications. PMID- 23675685 TI - Exposure to HIV prevention programmes associated with improved condom use and uptake of HIV testing by female sex workers in Nagaland, Northeast India. AB - BACKGROUND: There a concentrated HIV epidemic among female sex workers (FSWs) in the state of Nagaland, located in the north-east of India. Local non-government organisations (NGOs) are supported by the National State AIDS Control Society (NSACS) and the Avahan-funded Project ORCHID (Avahan is the India AIDS initiative of Bill & Melinda Gates Foundation in India) to deliver a range of interventions to FSWs including safe sex promotion, condom distribution, and testing and treatment of sexually transmitted infections (STIs). The commercial hub of Nagaland, Dimapur, is an important transportation node, and hosts a concentration of FSWs. This paper reports on comparative analysis of Integrated Behavioural and Biological Assessment (IBBA) data collected from FSWs in Dimapur in 2006 and 2009 to assess changes in condom use, HIV testing, and exposure to interventions. METHODS: Two IBBA cross-sectional surveys were undertaken among FSWs in Dimapur in 2006 (Round 1) and 2009 (Round 2) using an interviewer-administered questionnaire and the collection of blood and urine samples. Respondent-driven sampling (RDS), a sampling technique for use among hidden populations, was used to recruit the samples. RESULTS: When round 1 is compared with round 2, there was a marked and statistically significant improvement in the use of condoms at last sex with both occasional (35.2% to 72.4%) and regular (25.8% to 57.7%) clients, and an increase in the proportion having ever had an HIV test (8.9% to 29.1%). There was no evidence of an improvement in the proportional coverage of the HIV prevention services delivered to FSWs in Dimapur between round 1 and round 2. In round 2, FSWs exposed to the programme were more than twice (OR=2.27) as likely to consistently use condoms with occasional clients, four times (OR: 4.11) more likely to use condoms consistently with regular clients and nine times (OR: 9.08) more likely to have ever had an HIV test. CONCLUSIONS: We found evidence of an increase in condom use and HIV testing, and a strong and consistent association between programme exposure and condom use and HIV testing indicating that NGO HIV prevention programmes have been making a substantial contribution to HIV prevention among FSWs in Dimapur. However, there was no evidence of improved coverage of HIV prevention services, and there is a clear need to expand the reach of services in order for them to have an impact on a larger pool of FSWs. PMID- 23675686 TI - Early necrotizing fasciitis following initiation of mycophenolate mofetil in two patients with bullous pemphigoid. PMID- 23675687 TI - Educational session as a tool to increase patient satisfaction of switching etanercept from the prefilled syringe to the autoinjection pen. AB - OBJECTIVE: To assess patients' acceptability of switching etanercept from the prefilled syringe to the autoinjection pen in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis patients. METHODS: A two-phase cross sectional study was designed. First phase: consisted of a 2 h information/education session to present the pen and learning its use. At the end of the session, patients completed a self-administered questionnaire regarding the meeting usefulness. Second phase: eight single-use prefilled Enbrel(r) Pen Myclic were provided. RESULTS: The number of patients included were 104 (rheumatoid arthritis 58, psoriatic arthritis 31, ankylosing spondylitis 15). Attendees showed a high satisfaction degree with the meeting. A high percentage of patients (74.4 - 95.1%) rated the items of the questionnaire as 'very much'. Patients reported > 95% adherence to etanercept autoinjection pen. The percentage of patients self-administering etanercept increased from 66 to 94% and the percentage of those attending primary care for injection decreased from 23 to 2%. It produced important cost savings, in our study represents > 22.000 euros/year. Pain at the injection site was significantly reduced with the use of autoinjection pen. Ninty seven (93%) patients considered that the use of the autoinjection pen was easier than the syringe and 94.2% chose the pen as their preferred delivery system. CONCLUSIONS: The autoinjection pen is an advantageous delivery option for etanercept. This study provides further evidence to support that the education strategy is a valid method for switching anti-TNF-alpha drugs from syringe to pen in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. PMID- 23675688 TI - Autism in DSM-5: progress and challenges. AB - BACKGROUND: Since Kanner's first description of autism there have been a number of changes in approaches to diagnosis with certain key continuities . Since the Fourth edition of the Diagnostic and Statistical Manual (DSM-IV) appeared in 1994 there has been an explosion in research publications. The advent of changes in DSM-5 presents some important moves forward as well as some potential challenges. METHODS: The various relevant studies are summarized. RESULTS: If research diagnostic instruments are available, many (but not all) cases with a DSM-IV diagnosis of autism continue to have this diagnosis. The overall efficiency of this system falls if only one source of information is available and, particularly, if the criteria are used outside the research context. The impact is probably greatest among the most cognitively able cases and those with less classic autism presentations. CONCLUSIONS: Significant discontinuities in diagnostic practice raise significant problems for both research and clinical services. For DSM-5, the impact of these changes remains unclear. PMID- 23675689 TI - Slower immune system aging in women versus men in the Japanese population. AB - BACKGROUND: Gender-related differences in humans are commonly observed in behaviour, physical activity, disease, and lifespan. However, the notion that age related changes in the immune system differ between men and women remains controversial. To elucidate the relationship between immunological changes and lifespan, peripheral blood mononuclear cells from healthy Japanese subjects (age range: 20-90 years; N = 356) were analysed by using three-colour flow cytometry. The proliferative activities and cytokine-producing capacities of T cells in response to anti-CD3 monoclonal antibody stimulation were also assessed. RESULTS: An age-related decline in the number of T cells, certain subpopulations of T cells (including CD8+ T cells, CD4+CDRA+ T cells, and CD8+CD28+ T cells), and B cells, and in the proliferative capacity of T cells was noted. The rate of decline in these immunological parameters, except for the number of CD8+ T cells, was greater in men than in women (p < 0.05). We observed an age-related increase or increasing trend in the number of CD4+ T cells, CD4+CDRO+ T cells, and natural killer (CD56+CD16+) cells, as well as in the CD4+ T cell/CD8+ T cell ratio. The rate of increase of these immunological parameters was greater in women than in men (p < 0.05). T cell proliferation index (TCPI) was calculated from the T cell proliferative activity and the number of T cells; it showed an age-related decline that was greater in men than in women (p < 0.05). T cell immune score, which was calculated using 5 T cell parameters, also showed an age-related decline that was greater in men than in women (p < 0.05). Moreover, a trend of age-related decreases was observed in IFNgamma, IL-2, IL-6, and IL-10 production, when lymphocytes were cultured with anti-CD3 monoclonal antibody stimulation. The rate of decline in IL-6 and IL-10 production was greater in men than in women (p < 0.05). CONCLUSION: Age-related changes in various immunological parameters differ between men and women. Our findings indicate that the slower rate of decline in these immunological parameters in women than that in men is consistent with the fact that women live longer than do men. PMID- 23675691 TI - Development of an oligopeptide functionalized surface plasmon resonance biosensor for online detection of glyphosate. AB - We report a surface plasmon resonance (SPR) biosensor for online detection of glyphosate. The surface of the sensing element is decorated with an oligopeptide, TPFDLRPSSDTR, which is identified by using phage display library. This oligopeptide shows high binding specificity for glyphosate (KD = 8.6 MUM), probably because of the presence of R and D in the oligopeptide. To detect glyphosate in buffer solution, an SPR gold sensor chip is modified by using the oligopeptide with a surface density of 0.6 1/nm(2). The sensitivity of this oligopeptide-functionalized SPR biosensor is 1.02 RU/MUM whereas the limit of detection (LOD) is 0.58 MUM. This oligopeptide functionalized SPR biosensor also shows good specificity against other analytes such as glycine, thiacloprid, and imidacloprid. PMID- 23675690 TI - Alterations of histone H1 phosphorylation during bladder carcinogenesis. AB - There is a crucial need for development of prognostic and predictive biomarkers in human bladder carcinogenesis in order to personalize preventive and therapeutic strategies and improve outcomes. Epigenetic alterations, such as histone modifications, are implicated in the genetic dysregulation that is fundamental to carcinogenesis. Here we focus on profiling the histone modifications during the progression of bladder cancer. Histones were extracted from normal human bladder epithelial cells, an immortalized human bladder epithelial cell line (hTERT), and four human bladder cancer cell lines (RT4, J82, T24, and UMUC3) ranging from superficial low-grade to invasive high-grade cancers. Liquid chromatography-mass spectrometry (LC-MS) profiling revealed a statistically significant increase in phosphorylation of H1 linker histones from normal human bladder epithelial cells to low-grade superficial to high-grade invasive bladder cancer cells. This finding was further validated by immunohistochemical staining of the normal epithelium and transitional cell cancer from human bladders. Cell cycle analysis of histone H1 phosphorylation by Western blotting showed an increase of phosphorylation from G0/G1 phase to M phase, again supporting this as a proliferative marker. Changes in histone H1 phosphorylation status may further clarify epigenetic changes during bladder carcinogenesis and provide diagnostic and prognostic biomarkers or targets for future therapeutic interventions. PMID- 23675692 TI - The crystal structure of Mycobacterium tuberculosis NrdH at 0.87 A suggests a possible mode of its activity. AB - Members of the NrdH family of redox proteins, which consists of small glutaredoxin-like proteins with thioredoxin-like activity, serve as the reducing partners of class Ib ribonucleotide reductases. Here, we report the crystal structure of NrdH from Mycobacterium tuberculosis, refined to a crystallographic R factor of 14.02% (Rfree = 15.53%) at 0.87 A resolution. The tertiary structure of M. tuberculosis NrdH has a typical thioredoxin fold as expected. The extremely high resolution of the structure allows us to dissect the functionality of the protein in great depth. Structural superimposition of M. tuberculosis NrdH and thioredoxin reductase over the Escherichia coli thioredoxin reductase-thioredoxin complex suggests the ability of NrdH to accept electrons from M. tuberculosis thioredoxin reductase. This raises the important question of why glutaredoxins are unable to accept electrons from thioredoxin reductases and why thioredoxins are unable to reduce ribonucleotide reductases. Furthermore, forms of NrdH from other organisms have been shown to be a specific reductant of class Ib ribonucleotide reductases. We attempt to explain this substrate specificity by modeling the C-terminal peptide of a ribunucleotide subunit, NrdE, in the active site of NrdH using the already available Grx-NrdA-Cter-peptide structure. Statistical coupling analysis of NrdH, glutaredoxins, and thioredoxins reveals different sets of co-evolving contiguous clusters of amino acid residues, which might explain the differences in the biochemical properties of these structurally similar yet functionally distinct subclasses of proteins. PMID- 23675693 TI - Senile gluteal dermatosis: a clinical study of 137 cases. AB - BACKGROUND: Senile gluteal dermatosis (SGD) is a common genital dermatosis but has gained little attention before. A large-scale clinical study of this disease is lacking. MATERIALS AND METHODS: We examined 162 consecutive outpatients with gluteal skin diseases of different causes. Fourteen skin biopsies were performed. Patient's age, gender, body mass index (BMI), way of sitting or lying, treatment response, and underlying systemic diseases were recorded. RESULTS: About 137 (85%) patients could be defined as SGD. These patients, with a mean age of 79.4 +/- 40.7 years and a mean BMI of 21.7 +/- 10.8, presented with either partial (n = 43, 31%) or full-blown (n = 94, 69%) SGD lesions characterized by the sign of so-called "three corners of a triangle": brownish plaques on the gluteal cleft and each side of the buttocks. Male/female ratio was 130/7. Itching or pain of varying intensity was reported by 50 patients (36%) and 14 patients (10%), respectively. Eighty-six patients (53%) presented with horizontal hyperkeratotic ridges, a characteristic sign of SGD. Most patients spent most of the day sitting but reported no special way of sitting or lying. More than half of patients with SGD claimed no response to topical steroids and/or keratolytics. In comparison with patients with SGD, SGD-free patients were younger (61.3 +/- 36 years, P = 0.0005) and heavier (BMI 26.2 +/- 15.6, P < 0.0001) but showed no significant difference in the frequency of underlying systemic diseases. CONCLUSIONS: SGD is a common dermatosis, mostly affecting the thinner elderly. Friction, pressures and long hours sitting seemed to be important factors to trigger this dermatosis. PMID- 23675694 TI - Bond strength to radicular dentin and sealing ability of AH Plus in combination with a bonding agent. AB - OBJECTIVE: To evaluate the sealing ability and bond strength of AH Plus sealer associated with the hybridization protocol of radicular dentin with Scotchbond Multi Purpose (SB). MATERIALS AND METHODS: Ninety palatal roots of maxillary molars were selected and divided into three groups (n = 30) according to filling protocol (G1, AH Plus/Resilon; G2, SB/AH Plus/Resilon; and G3, AH Plus/Gutta Percha). In groups in which AH Plus + resin cones were used, dentin was hybridized before applying sealing material. For the bond strength test, 60 roots of bovine teeth were selected. Six holes were made in each root, two in the cervical, middle and apical third of the root. The roles were filled with AH Plus sealer with or without an adhesive system and submitted to push out test and the fracture mode was examined using a stereomicroscope (*32). RESULTS: Statistical analysis showed that ScotchBond Multi Purpose (SB) + Resilon cone + AH Plus group promoted higher sealing ability than the gutta-percha + AH Plus group (p < 0.05). Bond strength was lower with SB application than without it (p < 0.05). A reverse correlation was found between bond strength and sealing ability. The fracture mode methodology revealed 22.77% of adhesive, 11.67% of cohesive and 65.55% of mixture fractures for SBMP/AH Plus protocol, whereas the AH Plus protocol indicated 86.11% of cohesive and 13.89% of mixed fractures. CONCLUSION: It was concluded that the use of the adhesive system Scotchbond Multi Purpose improved coronal sealing ability of AH Plus, but bond strength of sealer was reduced when adhesive was applied. PMID- 23675695 TI - Socio-cultural aspects of oral health among the Fulani in Ferlo (Senegal): a qualitative study. AB - OBJECTIVES: Health is a subjective concept that considers the social, cultural, environmental and behavioural problems of the individual. This study was conducted with the objective of better understanding the sociocultural aspects related to the oral health of the Fulani populations of Ferlo, Senegal. METHODS: The study was qualitative and based in the area of the Great Green Wall (GGW) in the region known as Ferlo, northern Senegal. Data were collected by semi structured interviews in a sample of the population and through discussions with a focus group. It concerned health and aesthetics of the teeth, care and traditional herbal recipes, teeth and superstitions. RESULTS: It appears that people were using the toothpick, the chewing stick and/or charcoal to clean their teeth. Confusion persisted with respect to the types of food consumed that were implicated in the occurrence of dental caries: tea, rice, 'jumbo' (a seasoning spice) and tobacco. 'Borom bop', which means 'master of the head', was the most commonly reported cause of caries. Healthy, beautiful teeth were attributes of beauty and elegance, enhanced by tattoos and crafted crowns in the Fulani. Their health problems were generally managed by healers or traditional practitioners who based their practices on empirical and 'handed down' knowledge. Socio anthropological meanings were given to children with neonatal teeth. CONCLUSIONS: It is therefore important to consider the sociocultural aspects in oral health projects and programmes; the place of herbal medicine in dentistry should be recognized and maybe researched in the region of the Great Green Wall. PMID- 23675696 TI - Sorafenib for ovarian cancer. AB - INTRODUCTION: Sorafenib is an unselective inhibitor of multiple kinases which has demonstrated clinical advantage in renal cancer and hepatocellular carcinoma. It inhibits tumor proliferation by targeting receptor accessory factor (Raf) kinase isoforms, inhibiting receptor tyrosine kinases of a variety of pro-angiogenic factors and of several receptor tyrosine kinases involved in neovascularization and tumor development. AREAS COVERED: This review offers an explanation of the mechanism of action and of the pharmacokinetics of sorafenib, and gives readers a complete overview of Phase I and II studies on the clinical efficacy, tolerability and safety of this agent in the setting of ovarian cancer (OC) treatment. EXPERT OPINION: The available results from the studies which investigated the use of sorafenib for OC treatment demonstrated poor clinical benefit either as single agent or in combination therapy. The most promising results have been achieved combining sorafenib with bevacizumab, although overlapping and cumulative toxicities should be taken in consideration. Research should focus its attention to the development of reliable predictive biomarkers to assess response and direct therapy in order to allow patient selection and improving treatment schedules maximizing the clinical benefit and simultaneously minimizing the toxicity related to the chemotherapy. Further studies are needed to evaluate the role of sorafenib in the primary treatment of OC. PMID- 23675697 TI - The efficacy and safety of gamma-linolenic acid for the treatment of acne vulgaris. PMID- 23675698 TI - Evaluation of the heats of formation of corannulene and C60 by means of inexpensive theoretical procedures. AB - Inexpensive ab initio procedures that employ homologous sequences of isodesmic reactions for the calculation of enthalpies of formation of moderate-sized organic molecules were tested with benzene, naphthalene, phenanthrene, and triphenylene. Two size-consistent adjustable parameters were found to bring the calculated values within the uncertainty of the experimental values. These procedures were then applied to C20H10 (corannulene) and C60 (buckminsterfullerene). The results, specifically, Delta(f)H(298)(0)(C20H10) = 484 +/- 4 kJ mol(-1) and Delta(f)H(298)(0)(C60) = 2531 +/- 15 kJ mol(-1), are in excellent agreement with both the recent definitive W1h calculations of Karton et al. for corannulene [Delta(f)H(298)(0)(C20H10) = 485.2 +/- 7.9 kJ mol(-1)] and their estimated value for buckminsterfullerene [Delta(f)H(298)(0)(C60) = 2521.6 +/- 13.6 kJ mol(-1)] ( J. Phys. Chem. A 2013, 117, 1834-1842). We support their conclusion that the experimental values should be reexamined. PMID- 23675699 TI - Recent graduate nurse views of nursing, work and leadership. AB - AIMS AND OBJECTIVES: To assess recent nurse graduates of a large university and seeks their views of university preparation, requisite nursing skills and qualities, workplace transition, supports received, nurse leadership and role models, and career development and retention. BACKGROUND: Concern about attracting and retaining registered nurses is a continuing workforce issue in parts of Asia and throughout the world. DESIGN: Qualitative interviews with recent nursing graduates. METHODS: Seventeen face-to-face interviews took place using a structured schedule of 23 questions. Data were coded and analysed by hand to determine clusters of interest and develop themes. RESULTS: Four broad topics emerged: (1) skills and qualities graduates consider central to nursing; (2) the support they received during the transition from graduate to novice practitioner and that which continues; (3) elements they value in nursing role models and leaders; and (4) the ward characteristics that will encourage them to remain in nursing and develop a career. Interviewees expressed concerns about retention related issues, making suggestions for improvements. Unique findings focus on the blaming culture that many respondents consider they are working in, and the system whereby they are not free to access postgraduate studies until a specific time frame has elapsed, and when they do pursue further studies, they are bonded to the auspicing hospital/health service. CONCLUSIONS: Responses unique to this research are the explicit concerns about a blaming culture, and complaints about rigid rules (bonding system) that virtually prevent an individual from accessing postgraduate studies independent of the hospital system. Interviewees strongly resent the bonding system that indentures them to that place of work. RELEVANCE TO CLINICAL PRACTICE: Quality health care is dependent on a well-educated, sustainable and skilled nursing workforce. Recognition of the concerns of newly graduated nurses in relation to nursing skill acquisition, workplace support issues and career concerns can assist in ensuring these issues are adequately addressed and in turn contribute to a stronger, more stable and competent nursing workforce. PMID- 23675700 TI - Generation and properties of antibacterial coatings based on electrostatic attachment of silver nanoparticles to protein-coated polypropylene fibers. AB - We present a simple method for attaching silver nanoparticles to polypropylene (PP) fibers in a two-step process to impart antibacterial properties. Specifically, PP fibers are pretreated by the adsorption from an aqueous solution of heat-denatured lysozyme (LYS) followed by LYS cross-linking using glutaraldehyde and sodium borohydride. At neutral pH, the surface of the adsorbed LYS layer is enriched with numerous positive charges. Silver nanoparticles (AgNPs) capped with trisodium citrate are subsequently deposited onto the protein coated PP. Nanoparticle binding is mediated by electrostatic interactions between the positively charged LYS layer and the negatively charged AgNPs. The density of AgNPs deposited on PP depends on the amount of protein adsorbed on the surface. UV-vis spectroscopy, transmission electron microscopy, Fourier transform infrared spectroscopy, and scanning electron microscopy are employed to follow all preparation steps and to characterize the resulting functional surfaces. The antibacterial activity of the modified surfaces is tested against gram negative bacteria Escherichia coli (E. coli). Overall, our results show that PP surfaces coated with AgNPs exhibit excellent antibacterial activity with 100% removal efficiency. PMID- 23675701 TI - Chondrosarcoma presenting as a saddle tumor pulmonary embolism. AB - This is a case of an 18-year-old male who presented with hip pain, shortness of breath, and respiratory failure and was found to have a large saddle pulmonary embolus involving the pulmonary artery bifurcation, which extended into the main right and left pulmonary arteries, as well as the lobar branches bilaterally. The patient was taken to the operating room for an emergent pulmonary embolectomy where a significant amount of tumor was removed through an incision in the main pulmonary artery with pathology consistent with metastatic chondrosarcoma. PMID- 23675702 TI - Establishment of a promising human nucleus pulposus cell line for intervertebral disc tissue engineering. AB - Low-back pain caused by intervertebral disc degeneration could be recovered by the regeneration of the nucleus pulposus (NP). This study aimed to establish a chondrogenic recovery model with promising a human NP (hNP) cell line, an immortalized hNP (ihNP), which could be a screening platform to identify regenerative drugs. The ihNP cells were created from primary human NP cells transfected with a retroviral vector-driven HPV16 E6/E7. Growth properties and characteristics of ihNP were evaluated by comparing with parental NP cells. Successful immortalization of ihNP cells stably expressed HPV 16 E6/E7 mRNA. The doubling time of ihNP was shortened to 53.16+/-2.63 h compared with parental hNP P1. Cell cycle regulators, including p53, p21, and pRB were downregulated compared to parental hNP-P1. The in vivo neoplastic forming assay also demonstrated that the ihNP was nontumorigenic. After 25 generations of cell cultures, the ihNP cells, yet stably expressed chondrogenic genes, including (SOX9), type II collagen (Col II), aggrecan, decorin, biglycan, and versican. Higher expressions of chondrogenic proteins, including Col II, phosphorylated SOX9 (p-SOX9), and CD44 were also determined. Under the stressful inflammatory conditions induced by lipopolysaccharides (LPS), the regenerative and anti inflammatory potentials of ihNP in two-dimensional culture with the presence of platelet-rich plasma (PRP) were evaluated by reverse transcriptase polymerase chain reaction. PRP showed significant effects on restoring diminished chondrogenic markers and deleterious inflammatory responses induced by LPS in ihNP. The therapeutic potentials of ihNP in three-dimensional neocartilage model could also be exerted by PRP using histological evaluation and immunological staining. Hence, the established ihNP cells can provide a chondrogenic recovery model as a regenerative drug screening tool for further regenerative drug discovery and development. PMID- 23675703 TI - The impact of vascular anastomosis time on early kidney transplant outcomes. AB - BACKGROUND: Most studies have found cold ischemic time to be an important predictor of delayed graft function in kidney transplantation. Relatively less is known about the warm time associated with vascular anastomosis and early outcomes. METHODS: A retrospective cohort of 298 consecutive solitary deceased donor kidney recipients from January 2006 to August 2012 was analyzed to examine the association between anastomosis time and delayed graft function (need for dialysis) and length of hospital stay. RESULTS: Delayed graft function (DGF) was observed in 56 patients (18.8%). The median anastomosis time was 30 minutes (interquartile range 24, 45 minutes). Anastomosis time was independently associated with DGF in a multivariable, binary logistic regression analysis (odds Ratio (OR) 1.037 per minute, 95% CI 1.016, 1.057, P = 0.001). An anastomosis time >29 minutes was also associated with a 3.5 fold higher (OR 3.5, 95% CI 1.6, 7.3, P = 0.001) risk of DGF. Median days in hospital was 9 (interquartile range 7, 14 days). Every 5 minutes of longer anastomosis time (0.20 days per minute, 95% CI 0.13, 0.27, P <0.001) was associated with 1 extra day in hospital in a multivariable linear regression model. An anastomosis time >29 minutes was associated with 3.8 (95% CI 1.6, 6.0, P <0.001) more days in hospital. CONCLUSION: Anastomosis time may be an underappreciated but modifiable variable in dictating use of hospital resources. The impact of anastomosis time on longer term outcomes deserves further study. PMID- 23675704 TI - Na(1.4)InTe(3.6)O(9.4): new variant of a hexagonal tungsten oxide (HTO)-like layered framework containing both a main-group cation, In3+, and a lone-pair cation, Te4+. AB - A novel hexagonal tungsten oxide (HTO)-like layered framework containing a main group cation, In(3+), and a lone-pair cation, Te(4+), is reported. Na(1.4)InTe(3.6)O(9.4) exhibits a layered structure consisting of InO6, TeO3, and TeO4 polyhedra. The synthesis, crystal structure determination, characterization, and reactivity of the material will be presented. PMID- 23675705 TI - Can social dancing prevent falls in older adults? a protocol of the Dance, Aging, Cognition, Economics (DAnCE) fall prevention randomised controlled trial. AB - BACKGROUND: Falls are one of the most common health problems among older people and pose a major economic burden on health care systems. Exercise is an accepted stand-alone fall prevention strategy particularly if it is balance training or regular participation in Tai chi. Dance shares the 'holistic' approach of practices such as Tai chi. It is a complex sensorimotor rhythmic activity integrating multiple physical, cognitive and social elements. Small-scale randomised controlled trials have indicated that diverse dance styles can improve measures of balance and mobility in older people, but none of these studies has examined the effect of dance on falls or cognition. This study aims to determine whether participation in social dancing: i) reduces the number of falls; and ii) improves cognitive functions associated with fall risk in older people. METHODS/DESIGN: A single-blind, cluster randomised controlled trial of 12 months duration will be conducted. Approximately 450 participants will be recruited from 24 self-care retirement villages that house at least 60 residents each in Sydney, Australia. Village residents without cognitive impairment and obtain medical clearance will be eligible. After comprehensive baseline measurements including physiological and cognitive tests and self-completed questionnaires, villages will be randomised to intervention sites (ballroom or folk dance) or to a wait listed control using a computer randomisation method that minimises imbalances between villages based on two baseline fall risk measures. Main outcome measures are falls, prospectively measured, and the Trail Making cognitive function test. Cost-effectiveness and cost-utility analyses will be performed. DISCUSSION: This study offers a novel approach to balance training for older people. As a community-based approach to fall prevention, dance offers older people an opportunity for greater social engagement, thereby making a major contribution to healthy ageing. Providing diversity in exercise programs targeting seniors recognises the heterogeneity of multicultural populations and may further increase the number of taking part in exercise. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000889853The trial is now in progress with 12 villages already have been randomised. PMID- 23675707 TI - Global Initiative on Obstructive Lung Disease revised: what constitutes a guideline? PMID- 23675706 TI - Cotton GhBAK1 mediates Verticillium wilt resistance and cell death. AB - Virus-induced gene silencing (VIGS) offers a powerful approach for functional analysis of individual genes by knocking down their expression. We have adopted this approach to dissect gene functions in cotton resistant to Verticillium wilt, one of the most devastating diseases worldwide. We showed here that highly efficient VIGS was obtained in a cotton breeding line (CA4002) with partial resistance to Verticillium wilt, and GhMKK2 and GhVe1 are required for its resistance to Verticillium wilt. Arabidopsis AtBAK1/SERK3, a central regulator in plant disease resistance, belongs to a subfamily of somatic embryogenesis receptor kinases (SERKs) with five members, AtSERK1 to AtSERK5. Two BAK1 orthologs and one SERK1 ortholog were identified in the cotton genome. Importantly, GhBAK1 is required for CA4002 resistance to Verticillium wilt. Surprisingly, silencing of GhBAK1 is sufficient to trigger cell death accompanied with production of reactive oxygen species in cotton. This result is distinct from Arabidopsis in which AtBAK1 and AtSERK4 play redundant functions in cell death control. Apparently, cotton has only evolved SERK1 and BAK1 whereas AtSERK4/5 are newly evolved genes in Arabidopsis. Our studies indicate the functional importance of BAK1 in Verticillium wilt resistance and suggest the dynamic evolution of SERK family members in different plant species. PMID- 23675708 TI - What is chronic obstructive pulmonary disease anyway?: Continua, categories, cut points, and moving beyond spirometry. PMID- 23675709 TI - Quality measurement in the Affordable Care Act: a reaffirmed commitment to value in health care. PMID- 23675710 TI - Glucocorticoids and airway smooth muscle: some answers, more questions. PMID- 23675711 TI - Recombinant human activated protein C as a therapy for severe sepsis: lessons learned? PMID- 23675712 TI - Good news for lung repair in preterm infants. PMID- 23675713 TI - Microbes in bronchiectasis: the forest or the trees? PMID- 23675714 TI - Update in sleep medicine 2012. PMID- 23675715 TI - Update in pulmonary infections 2012. PMID- 23675716 TI - A watery mediastinal mass. PMID- 23675717 TI - Endobronchial epinephrine: confusion is in the air. PMID- 23675718 TI - The renin-angiotensin system in pulmonary hypertension. PMID- 23675719 TI - Reply: Endobronchial epinephrine: confusion is in the air. PMID- 23675720 TI - Reply: The renin-angiotensin system in pulmonary hypertension. PMID- 23675721 TI - Reply: Risk of tuberculosis among QuantiFERON converters and nonconverters. PMID- 23675722 TI - Risk of tuberculosis among QuantiFERON converters and nonconverters. PMID- 23675723 TI - Pulmonary venous thromboembolism due to extreme video gaming. PMID- 23675724 TI - Severe toxoplasmosis in immunocompetent hosts: be aware of atypical strains. PMID- 23675725 TI - Life-saving closure of a pulmonary cavity by endobronchial valve placement. PMID- 23675726 TI - Protein identification of two allergens of Boletus edulis causing occupational asthma. PMID- 23675727 TI - Effects of acute intermittent hypoxia on working memory in young healthy adults. PMID- 23675728 TI - Acute respiratory distress syndrome: the prognostic value of ventilatory ratio--a simple bedside tool to monitor ventilatory efficiency. PMID- 23675731 TI - The value of video polysomnography in the assessment of intermittent obstructive sleep apnea. PMID- 23675732 TI - Denoising peptide tandem mass spectra for spectral libraries: a Bayesian approach. AB - With the rapid accumulation of data from shotgun proteomics experiments, it has become feasible to build comprehensive and high-quality spectral libraries of tandem mass spectra of peptides. A spectral library condenses experimental data into a retrievable format and can be used to aid peptide identification by spectral library searching. A key step in spectral library building is spectrum denoising, which is best accomplished by merging multiple replicates of the same peptide ion into a consensus spectrum. However, this approach cannot be applied to "singleton spectra," for which only one observed spectrum is available for the peptide ion. We developed a method, based on a Bayesian classifier, for denoising peptide tandem mass spectra. The classifier accounts for relationships between peaks, and can be trained on the fly from consensus spectra and immediately applied to denoise singleton spectra, without hard-coded knowledge about peptide fragmentation. A linear regression model was also trained to predict the number of useful "signal" peaks in a spectrum, thereby obviating the need for arbitrary thresholds for peak filtering. This Bayesian approach accumulates weak evidence systematically to boost the discrimination power between signal and noise peaks, and produces readily interpretable conditional probabilities that offer valuable insights into peptide fragmentation behaviors. By cross validation, spectra denoised by this method were shown to retain more signal peaks, and have higher spectral similarities to replicates, than those filtered by intensity only. PMID- 23675734 TI - Self-care practices and experiences of people living with HIV not receiving antiretroviral therapy in an urban community of Lusaka, Zambia: implications for HIV treatment programmes. AB - BACKGROUND: Despite the increasingly wider availability of antiretroviral therapy (ART), some people living with HIV (PLHIV) and eligible for treatment have opted to adopt self-care practices thereby risking early AIDS-related mortality. METHODS: A qualitative study was conducted in urban Zambia to gain insights into PLHIV self-care practices and experiences and explore the implications for successful delivery of ART care. Between March 2010 and September 2011, in-depth interviews were conducted with PLHIV who had dropped out of treatment (n=25) and those that had opted not to initiate medication (n=37). Data was entered into and managed using Atlas ti, and analysed inductively using latent content analysis. RESULTS: PHIV used therapeutic and physical health maintenance, psychological well-being and healthy lifestyle self-care practices to maintain physical health and mitigate HIV-related symptoms. Herbal remedies, faith healing and self prescription of antibiotics and other conventional medicines to treat HIV-related ailments were used for therapeutic and physical health maintenance purposes. Psychological well-being self-care practices used were religiosity/spirituality and positive attitudes towards HIV infection. These practices were modulated by close social network relationships with other PLHIV, family members and peers, who acted as sources of emotional, material and financial support. Cessations of sexual relationships, adoption of safe sex to avoid re-infections and uptake of nutritional supplements were the commonly used risk reduction and healthy lifestyle practices respectively. CONCLUSIONS: While these self-care practices may promote physical and psychosocial well-being and mitigate AIDS-related symptoms, at least in the short term, they however undermine PLHIV access to ART care thereby putting PLHIV at risk of early AIDS-related mortality. The use of scientifically unproven herbal remedies raises health and safety concerns; faith healing may create fatalism and resignation with death while the reported self prescription of antibiotics to treat HIV-related infections raises concerns about future development of microbial drug resistance amongst PLHIV. Collectively, these self-care practices undermine efforts to effectively abate the spread and burden of HIV and reduce AIDS-related mortality. Therefore, there is need for sensitization campaigns on the benefits of ART and the risks associated with widespread self-prescription of antibiotics and use of scientifically unproven herbal remedies. PMID- 23675735 TI - Both human ferredoxins equally efficiently rescue ferredoxin deficiency in Trypanosoma brucei. AB - Ferredoxins are highly conserved proteins that function universally as electron transporters. They not only require Fe-S clusters for their own activity, but are also involved in Fe-S formation itself. We identified two homologues of ferredoxin in the genome of the parasitic protist Trypanosoma brucei and named them TbFdxA and TbFdxB. TbFdxA protein, which is homologous to other eukaryotic mitochondrial ferredoxins, is essential in both the procyclic (= insect transmitted) and bloodstream (mammalian) stage, but is more abundant in the active mitochondrion of the former stage. Depletion of TbFdxA caused disruption of Fe-S cluster biogenesis and lowered the level of intracellular haem. However, TbFdxB, which is present exclusively within kinetoplastid flagellates, was non essential for the procyclic stage, and double knock-down with TbFdxA showed this was not due to functional redundancy between the two homologues. Heterologous expressions of human orthologues HsFdx1 and HsFdx2 fully rescued the growth and Fe-S-dependent enzymatic activities of TbFdxA knock-down. In both cases, the genuine human import signals allowed efficient import into the T. brucei mitochondrion. Given the huge evolutionary distance between trypanosomes and humans, ferredoxins clearly have ancestral and highly conserved function in eukaryotes and both human orthologues have retained the capacity to participate in Fe-S cluster assembly. PMID- 23675736 TI - Hand-foot syndrome induced by erlotinib (Tarceva(R) ). PMID- 23675737 TI - Abstracts of the 36th Annual Scientific Meeting of the Research Society on Alcoholism. June 22-26, 2013. Orlando, Florida, USA. PMID- 23675738 TI - Luminescent core-shell imprinted nanoparticles engineered for targeted Forster resonance energy transfer-based sensing. AB - Red-luminescent 200 nm silica nanoparticles have been designed and prepared as a versatile platform for developing FRET (Forster resonance energy transfer) biomimetic assays. Ru(phen)32+ dye molecules embedded off-center in the silica core provide the long-lived donor emission, and a near-infrared labeled analyte serves as fluorescent acceptor (the measured R0 of this D-A pair is 4.3 nm). A thin surface-grafted molecularly imprinted polymer (MIP) shell intervenes as selective enrofloxacin-binding element. These nanoparticles have been tested for photochemical detection of enrofloxacin by using a competitive scheme that can be readily performed in MeCN-HEPES (pH 7.5) 7:3 (v/v) mixtures and allows for the antibiotic detection in the MUM range (LOD = 2 MUM) without optimization of the assay. Given the well-known difficulties of coupling the target-binding-to-MIP and the transducing events, the novel photochemical approach tuned up here will be valuable in future developments of MIP-based assays and optosensors that capitalize also on the advantages of nanomaterials for (bio)analysis. PMID- 23675739 TI - Lymph node retrieval in pancreaticoduodenectomy specimens: does educating the pathologist matter? AB - BACKGROUND: Many previous studies have suggested that the number of lymph nodes retrieved should serve as a benchmark for assessing the adequacy of the resection. The aim was to retrospectively observe the impact of nodal retrieval after educating the pathologist. METHODS: Patients undergoing a pancreaticoduodenectomy (PD) between September 2005 and March 2009 were included in the study. The PDs performed between September 2005 and March 2008 were designated as Group A. The pathologists were educated regarding the importance of nodal counts in PD by the surgeon on the 1st April 2008. PDs performed between April 2008 and March 2009 were designated as Group B. RESULTS: Ninety-eight PDs performed by a single surgeon (D.R.J.) for peri-ampullary malignancy were evaluated. The median number of lymph nodes retrieved in Group A was 11(3-32) nodes. The median number of lymph nodes retrieved in Group B was 22 (10-29) nodes (P < 0.001).The lymph node ratio (positive/total nodes), median number of positive nodes retrieved, and the node positivity (node positive compared to node negative) rate did not change. DISCUSSION: A single intervention with the pathologists did impact the number of lymph nodes retrieved from PD specimens. However, the lymph node ratio and lymph node positivity rate remained unchanged. The pathologist is critical to nodal retrieval in PD, but the use of this lymph node number for benchmark of surgical adequacy may be simplistic. PMID- 23675740 TI - A simplified clinical technique for a routine indirect restoration impression on a challenging patient using a dry field illuminator. AB - Detailed and accurate impressions are made when the oral environment is dry during the impression process. Maintaining a dry field on medically, physically, or emotionally compromised patients can be very challenging. If not achieved, it may compromise dental care and accurate outcomes. This article describes a technique that can be used to make a final impression for an indirect restoration in a protected, isolated, and dry environment, using a dry field illuminator. PMID- 23675741 TI - Influence of chlorhexidine and/or ethanol treatment on bond strength of an etch and-rinse adhesive to dentin: an in vitro and in situ study. AB - The aim of this study was to evaluate the effect of a chlorhexidine and/or ethanol application on the bond strength of an etch-and-rinse, hydrophobic adhesive system either under in vitro aging or in situ cariogenic challenge. The dentin surface of 36 human third molars were flattened and allocated into four groups to be treated with chlorhexidine, ethanol, or chlorhexidine + ethanol or left unexposed to any solution (control) (n=9). Then, a resin composite restoration was made on the dentin surface and longitudinal sticks were obtained. Sticks from each tooth were assigned to three test conditions: stored in water in vitro for 24 hours, stored in water in vitro for 6 months, or worn in situ for 14 days. During in situ wear time, a high-cariogenic challenge condition was simulated. Specimens were tested for microtensile bond strength (MUTBS). Multivariate analysis of variance and Tukey's test showed that chlorhexidine, ethanol, or chlorhexidine + ethanol did not affect the MUTBS. The in vitro MUTBS values were significantly lower for the specimens stored for 6 months than for those stored for 24 hours. Intermediate MUTBS values were shown by the specimens worn in situ. Thus, use of chlorhexidine and/or ethanol was incapable of containing the degradation at the bond interface in the in vitro model. The in situ model was capable of reducing bond strength similarly to the in vitro/6 months model. Despite this, the in situ bond strength was still similar to that of the in vitro/24-hour model. PMID- 23675742 TI - The incidence of type 2 diabetes in the United Kingdom from 1991 to 2010. AB - AIMS: To characterize the incidence of type 2 diabetes in the UK over the previous 20 years; and determine if there has been an increase in people aged 40 years or less at diagnosis. METHODS: For this retrospective cohort study, patients newly diagnosed with type 2 diabetes between 1991 and 2010 were identified from the UK Clinical Practice Research Datalink (CPRD). Patient data were grouped into 5-year intervals by year of diagnosis and age at diagnosis. A standardized incidence ratio (SIR) was determined (1991-1995 = 100). The percentage of newly diagnosed patients for each age group and aged <=40 years was calculated for each 5-year calendar period. The incidence rate by age and 5-year calendar period was also determined. RESULTS: In 2010, the crude incidence rate of type 2 diabetes was 515 per 100,000 population. The overall SIR increased to 158 (95% CI 157-160, p < 0.001), 237 (235-238, p < 0.001) and 275 (273-276, p < 0.001) for 1996-2000, 2001-2005 and 2006-2010, respectively. For those <=40, the respective values were 217 (209-226, p < 0.001), 327 (320-335, p < 0.001) and 598 (589-608, p < 0.001). An increase in incidence occurred with increasing 5-year calendar period. The incidence of type 2 diabetes was higher for males after the age of 40 and higher for females aged <=40. The percentage of patients aged <=40 years at diagnosis increased with each increasing 5-year calendar period (5.9, 8.4, 8.5 and 12.4%, respectively). CONCLUSIONS: There was a significant increase in the incidence of diagnosed type 2 diabetes between 1991 and 2010 and the proportion of people diagnosed at a relatively early age has increased markedly. PMID- 23675743 TI - Acanthosis nigricans, tripe palms, and sign of Leser-Trelat in a patient with gastric adenocarcinoma: case report and literature review in China. PMID- 23675744 TI - Band alignment in partial and complete ZnO/ZnS/CdS/CuSCN extremely thin absorber cells: an X-ray photoelectron spectroscopy study. AB - In all solar cells, and especially in extremely thin absorber (ETA) solar cells, proper energy band alignment is crucial for efficient photovoltaic conversion. However, available tabulated data usually do not agree with actual results, and in most cases, Voc values lower than expected are achieved. In fact, ETA cells suffer from a very low Voc/Egap ratio, such as in ZnO/CdS/CuSCN cells. Here, we investigate limiting factors of ZnO/CdS/CuSCN ETA cells, applying X-ray photoelectron spectroscopy (XPS), chemically resolved electrical measurement (CREM), Kelvin probe, and I-V characterization. We show that electric fields are gradually developed in the cell upon increased absorber thickness. Moreover, an accumulation layer, unfavorable for the solar cell function, has been revealed at the oxide-absorber interface An effective chemical treatment to prevent formation of this accumulation layer is demonstrated. PMID- 23675745 TI - Emerging anti-inflammatory drugs for atherosclerosis. AB - INTRODUCTION: Cardiovascular disease is the most common cause of morbidity and mortality worldwide. Inflammation is responsible for initiation and progression of atherosclerosis, and leads to plaque vulnerability. Evidence-based therapies reduce the risk of initial and recurrent cardiovascular events but many patients experience recurrent events due to the failure of conventional therapies to adequately address inflammation. AREAS COVERED: Statins were originally developed for their LDL cholesterol-lowering effects, but are now thought to improve cardiovascular morbidity and mortality through anti-inflammatory effects as well. Drugs that inhibit the various inflammatory pathways responsible for atherosclerosis are the subject of current research. These include antioxidants, phospholipase A(2) inhibitors, leukotriene pathway inhibitors, CCL2-CCR2 pathway inhibitors, non-specific anti-inflammatory drugs (i.e., methotrexate), IL-1 inhibitors and p-selectin inhibitors. EXPERT OPINION: Currently, only three anti inflammatory drugs (methotrexate, darapladib and canakinumab) are being investigated in Phase III clinical trials of atherosclerosis. The development of cardiovascular drugs requires long, expensive Phase III trials to demonstrate incremental improvement in cardiovascular events. Imaging end points and soluble biomarkers accelerate Phase II development, but further validation is needed before these can be used as surrogate end points in the large trials leading to drug approval. Improved access to currently available therapies like statins would decrease the burden of cardiovascular disease worldwide. PMID- 23675746 TI - The association between functional movement and overweight and obesity in British primary school children. AB - BACKGROUND: The purpose of this study was to examine the association between functional movement and overweight and obesity in British children. METHODS: Data were obtained from 90, 7-10 year old children (38 boys and 52 girls). Body mass (kg) and height (m) were assessed from which body mass index (BMI) was determined and children were classified as normal weight, overweight or obese according to international cut offs. Functional movement was assessed using the functional movement screen. RESULTS: Total functional movement score was significantly, negatively correlated with BMI (P = .0001). Functional movement scores were also significantly higher for normal weight children compared to obese children (P = .0001). Normal weight children performed significantly better on all individual tests within the functional movement screen compared to their obese peers (P <0.05) and significantly better than overweight children for the deep squat (P = .0001) and shoulder mobility tests (P = .04). Overweight children scored significantly better than obese in the hurdle step (P = .0001), in line lunge (P = .05), shoulder mobility (P = .04) and active straight leg raise (P = .016). Functional movement scores were not significantly different between boys and girls (P > .05) when considered as total scores. However, girls performed significantly better than boys on the hurdle step (P = .03) and straight leg raise (P = .004) but poorer than boys on the trunk stability push-up (P = .014). CONCLUSIONS: This study highlights that overweight and obesity are significantly associated with poorer functional movement in children and that girls outperform boys in functional movements. PMID- 23675747 TI - Rattling motion of alkali metal ions through the cavities of model compounds of graphyne and graphdiyne. AB - We study the passage of the alkali metal ions (Li(+), Na(+), and K(+)) through some conjugated carbon-based ring systems, starting from C12H6 and C24H12 (tribenzocyclyne; TBC), which serve as model compounds for graphyne to some of the higher analogues, C26H12, C28H12, and C30H12, the model systems for graphdiyne. The motion of the ions through cyclic carbon clusters, C12 and C14, is also investigated. The potential for the motion of the ions from one side of the ring to the other through the cavities of the molecules is a symmetric double well in most cases, while it is a rather flat potential in others, arising due to the free motion of the ions through the cavities. Electrostatic potential (ESP) analyses reveal that the ions bind to the ring systems at the most negative regions of ESP. The estimated energy barriers for the motion of Li(+) through C12H6 and C24H12 are 4.7 and 4.3 kcal mol(-1), respectively, and are comparable to the barrier for the classic case of umbrella-like inversion in ammonia. Transmission of Li(+) through C26H12, C28H12, C30H12, C12, and C14 rings is barrierless. We predict that the rattling motion of Li(+) through the model compounds of graphyne and graphdiyne should be experimentally observable. We also model the effectively one-dimensional motion of the ions through the rings using discrete variable representation (DVR) and calculate the energy levels of the complexes in the symmetric double well potentials. The molecular orbital analyses and the nuclear independent chemical shift (NICS) values for the rings suggest distinct trends based on the (4n + 2/4n) pi electron count, leading us to propose two neutral complexes, (C12H6)Li2 and (C24H12)Li2, that are highly stable with binding energies of 400 and 356 kcal mol(-1), respectively. PMID- 23675748 TI - Mechanism elucidation of the cis-trans isomerization of an azole ruthenium nitrosyl complex and its osmium counterpart. AB - Synthesis and X-ray diffraction structures of cis and trans isomers of ruthenium and osmium metal complexes of general formulas (nBu4N)[cis-MCl4(NO)(Hind)], where M = Ru (1) and Os (3), and (nBu4N)[trans-MCl4(NO)(Hind)], where M = Ru (2) and Os (4) and Hind = 1H-indazole are reported. Interconversion between cis and trans isomers at high temperatures (80-130 degrees C) has been observed and studied by NMR spectroscopy. Kinetic data indicate that isomerizations correspond to reversible first order reactions. The rates of isomerization reactions even at 110 degrees C are very low with rate constants of 10(-5) s(-1) and 10(-6) s(-1) for ruthenium and osmium complexes, respectively, and the estimated rate constants of isomerization at room temperature are of ca. 10(-10) s(-1). The activation parameters, which have been obtained from fitting the reaction rates at different temperatures to the Eyring equation for ruthenium [DeltaH(cis trans)? = 122.8 +/- 1.3; DeltaH(trans-cis)? = 138.8 +/- 1.0 kJ/mol; DeltaS(cis trans)? = -18.7 +/- 3.6; DeltaS(trans-cis)? = 31.8 +/- 2.7 J/(mol.K)] and osmium [DeltaH(cis-trans)? = 200.7 +/- 0.7; DeltaH(trans-cis)? = 168.2 +/- 0.6 kJ/mol; DeltaS(cis-trans)? = 142.7 +/- 8.9; DeltaS(trans-cis)? = 85.9 +/- 3.9 J/(mol.K)] reflect the inertness of these systems. The entropy of activation for the osmium complexes is highly positive and suggests the dissociative mechanism of isomerization. In the case of ruthenium, the activation entropy for the cis to trans isomerization is negative [-18.6 J/(mol.K)], while being positive [31.0 J/(mol.K)] for the trans to cis conversion. The thermodynamic parameters for cis to trans isomerization of [RuCl4(NO)(Hind)]-, viz. DeltaH degrees = 13.5 +/- 1.5 kJ/mol and DeltaS degrees = -5.2 +/- 3.4 J/(mol.K) indicate the low difference between the energies of cis and trans isomers. The theoretical calculation has been carried out on isomerization of ruthenium complexes with DFT methods. The dissociative, associative, and intramolecular twist isomerization mechanisms have been considered. The value for the activation energy found for the dissociative mechanism is in good agreement with experimental activation enthalpy. Electrochemical investigation provides further evidence for higher reactivity of ruthenium complexes compared to that of osmium counterparts and shows that intramolecular electron transfer reactions do not affect the isomerization process. A dissociative mechanism of cis<->trans isomerization has been proposed for both ruthenium and osmium complexes. PMID- 23675749 TI - Insertion of an Abiomed Impella(r) left ventricular assist device following bioprosthetic aortic valve placement. AB - BACKGROUND: Post-cardiotomy cardiogenic shock is an infrequent devastating complication with few options for support. MATERIALS AND METHODS: We present a case highlighting use of the Impella 5.0 (ABIOMED; Danvers, MA) for postcardiotomy cardiogenic shock after coronary artery bypass and bioprosthetic aortic valve replacement. RESULTS: Support was maintained for 7 days before being successfully weaned with myocardial recovery and no damage to the bioprosthetic aortic valve. CONCLUSIONS: This is the first published report of successful use of an Impella 5.0 (ABIOMED; Danvers, MA) for post-cardiotomy cardiogenic shock through a new implanted bioprosthetic aortic valve. PMID- 23675750 TI - Vitamin D and insulin resistance in non-diabetic women's interagency HIV study participants. AB - We explored the relationship between vitamin D levels and insulin resistance (IR) among 1082 nondiabetic (754 HIV-infected) women enrolled in the Women's Interagency HIV study (WIHS), a large and well-established cohort of HIV infected and uninfected women in the US. Vitamin D levels 20-29 ng/mL were considered insufficient and <20 ng/mL deficient. IR was estimated using the homeostasis model assessment (HOMA) and a clinically significant cut-off >=2.6 was used for HOMA-IR. In the unadjusted analysis, women who were vitamin D insufficient or deficient were 1.62 (95% CI: 1.01-2.61, p=0.05) and 1.70 (95% CI: 1.11-2.60, p=0.02) times more likely to have HOMA values>=2.6 compared to women with sufficient vitamin D. The association did not remain significant after adjustment for factors associated with IR. Among the 754 HIV-infected women, current PI use (OR 1.61, 95% CI: 1.13-2.28, p=0.008) remained independently associated with HOMA >=2.6 while vitamin D insufficiency (OR 1.80, 95% CI: 0.99-3.27, p=0.05) was marginally associated with HOMA >=2.6 after adjustment. Ethnicity, body mass index, smoking status, and hepatitis C status were independently associated with insulin resistance in HIV-infected and uninfected women. We found a marginally significant association between vitamin D insufficiency and insulin resistance among nondiabetic HIV-infected WIHS women. PMID- 23675752 TI - Inpatient dermatology: profile of patients and characteristics of admissions to a tertiary dermatology inpatient unit in Sao Paulo, Brazil. AB - BACKGROUND: Dermatology is primarily an outpatient clinical and surgical specialty, but substantial numbers of patients are admitted to hospital for inpatient treatment in dermatology wards. METHODS: We performed a retrospective study of patients admitted to dermatology beds between September 1, 2002, and September 30, 2010. Patient data were analyzed for age, gender, ethnicity, length of stay (LoS), dermatologic disease, comorbidities, hospital-acquired infection (HAI), transfer to the intensive care unit (ICU), and mortality. RESULTS: A total of 3308 patients admitted during this 8-year period were identified for analysis. The most frequent admissions were for eczema/dermatitis (17.5%) and cutaneous infections (15.9%). The mean LoS was 13.0 days. The mean +/- standard deviation (SD) number of comorbidities per patient was 1.0 +/- 1.2, among the most frequent of which were hypertension and diabetes mellitus. The rate of HAI was 6.2%; bloodstream infection was regarded as the most commonly acquired type and Staphylococcus aureus as the infectious agent most commonly found in culture. Of the patients admitted, 3.7% were transferred to the ICU and 2.5% died. In these latter two groups, the most common dermatologic diagnoses were immunobullous diseases, and the mean hospital LoS and rate of HAI were higher than in the total admissions cohort. CONCLUSIONS: Higher value should be placed on dermatology inpatient services in order to expand the availability of dermatology beds, mainly in tertiary hospitals, in view of the potentially high severity of the dermatologic diseases found in many patients referred to this type of service. PMID- 23675751 TI - Hormonal regulation of epithelial organization in a three-dimensional breast tissue culture model. AB - The establishment of hormone target breast cells in the 1970's resulted in suitable models for the study of hormone control of cell proliferation and gene expression using two-dimensional (2D) cultures. However, to study mammogenesis and breast tumor development in vitro, cells must be able to organize in three dimensional (3D) structures like in the tissue. We now report the development of a hormone-sensitive 3D culture model for the study of mammogenesis and neoplastic development. Hormone-sensitive T47D breast cancer cells respond to estradiol in a dose-dependent manner by forming complex epithelial structures. Treatment with the synthetic progestagen promegestone, in the presence of estradiol, results in flat epithelial structures that display cytoplasmic projections, a phenomenon reported to precede side-branching. Additionally, as in the mammary gland, treatment with prolactin in the presence of estradiol induces budding structures. These changes in epithelial organization are accompanied by collagen remodeling. Collagen is the major acellular component of the breast stroma and an important player in tumor development and progression. Quantitative analysis of second harmonic generation of collagen fibers revealed that collagen density was more variable surrounding budding and irregularly shaped structures when compared to more regular structures; suggesting that fiber organization in the former is more anisotropic than in the latter. In sum, this new 3D model recapitulates morphogenetic events modulated by mammogenic hormones in the breast, and is suitable for the evaluation of therapeutic agents. PMID- 23675753 TI - Discrete interactions between bacteriophage T7 primase-helicase and DNA polymerase drive the formation of a priming complex containing two copies of DNA polymerase. AB - Replisomes are multiprotein complexes that coordinate the synthesis of leading and lagging DNA strands to increase the replication efficiency and reduce DNA strand breaks caused by stalling of replication forks. The bacteriophage T7 replisome is an economical machine that requires only four proteins for processive, coupled synthesis of two DNA strands. Here we characterize a complex between T7 primase-helicase and DNA polymerase on DNA that was trapped during the initiation of Okazaki fragment synthesis from an RNA primer. This priming complex consists of two DNA polymerases and a primase-helicase hexamer that assemble on the DNA template in an RNA-dependent manner. The zinc binding domain of the primase-helicase is essential for trapping the RNA primer in complex with the polymerase, and a unique loop located on the thumb of the polymerase also stabilizes this primer extension complex. Whereas one of the polymerases engages the primase-helicase and RNA primer on the lagging strand of a model replication fork, the second polymerase in the complex is also functional and can bind a primed template DNA. These results indicate that the T7 primase-helicase specifically engages two copies of DNA polymerase, which would allow the coordination of leading and lagging strand synthesis at a replication fork. Assembly of the T7 replisome is driven by intimate interactions between the DNA polymerase and multiple subunits of the primase-helicase hexamer. PMID- 23675754 TI - Metabonomics identifies serum metabolite markers of colorectal cancer. AB - Recent studies suggest that biofluid-based metabonomics may identify metabolite markers promising for colorectal cancer (CRC) diagnosis. We report here a follow up replication study, after a previous CRC metabonomics study, aiming to identify a distinct serum metabolic signature of CRC with diagnostic potential. Serum metabolites from newly diagnosed CRC patients (N = 101) and healthy subjects (N = 102) were profiled using gas chromatography time-of-flight mass spectrometry (GC TOFMS) and ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS). Differential metabolites were identified with statistical tests of orthogonal partial least-squares-discriminant analysis (VIP > 1) and the Mann-Whitney U test (p < 0.05). With a total of 249 annotated serum metabolites, we were able to differentiate CRC patients from the healthy controls using an orthogonal partial least-squares-discriminant analysis (OPLS-DA) in a learning sample set of 62 CRC patients and 62 matched healthy controls. This established model was able to correctly assign the rest of the samples to the CRC or control groups in a validation set of 39 CRC patients and 40 healthy controls. Consistent with our findings from the previous study, we observed a distinct metabolic signature in CRC patients including tricarboxylic acid (TCA) cycle, urea cycle, glutamine, fatty acids, and gut flora metabolism. Our results demonstrated that a panel of serum metabolite markers is of great potential as a noninvasive diagnostic method for the detection of CRC. PMID- 23675756 TI - Cultural and climatic changes shape the evolutionary history of the Uralic languages. AB - Quantitative phylogenetic methods have been used to study the evolutionary relationships and divergence times of biological species, and recently, these have also been applied to linguistic data to elucidate the evolutionary history of language families. In biology, the factors driving macroevolutionary processes are assumed to be either mainly biotic (the Red Queen model) or mainly abiotic (the Court Jester model) or a combination of both. The applicability of these models is assumed to depend on the temporal and spatial scale observed as biotic factors act on species divergence faster and in smaller spatial scale than the abiotic factors. Here, we used the Uralic language family to investigate whether both 'biotic' interactions (i.e. cultural interactions) and abiotic changes (i.e. climatic fluctuations) are also connected to language diversification. We estimated the times of divergence using Bayesian phylogenetics with a relaxed clock method and related our results to climatic, historical and archaeological information. Our timing results paralleled the previous linguistic studies but suggested a later divergence of Finno-Ugric, Finnic and Saami languages. Some of the divergences co-occurred with climatic fluctuation and some with cultural interaction and migrations of populations. Thus, we suggest that both 'biotic' and abiotic factors contribute either directly or indirectly to the diversification of languages and that both models can be applied when studying language evolution. PMID- 23675755 TI - Expression of thyroid transcription factor-1 is associated with a basal-like phenotype in breast carcinomas. AB - BACKGROUND: The differential diagnosis between primary and secondary breast cancers might be difficult, especially in poorly differentiated tumors. Thyroid Transcription Factor-1 (TTF-1) has been regarded as a reliable marker for lung or thyroid origin, with only occasional positive staining in other tumors. However, positive cases have recently been reported among primary breast carcinomas. METHODS AND RESULTS: Here, we analyzed expression of TTF-1 protein (clone SPT24) by immunohistochemical staining of sections from paraffin embedded tumor samples in 247 primary breast cancers from the population-based Norwegian Breast Cancer Screening Program. Positive staining (weak or strong) was observed in 7 cases (2,8%). As novel observations, positivity was demonstrated more frequently in estrogen receptor negative cases (14,0% vs. 1,4%; p = 0,004), highly proliferative tumors (8,8% vs. 1,1%; p = 0,008), tumors with a basal-like phenotype by showing expression of CK5/6 and/or P-cadherin (11,1% vs. 1,4%; p = 0,01), and tumors with blood vessel invasion (9,7% vs. 1,9%; p = 0,04). Also, TTF 1 was associated with histological grade 3 tumors compared with grade 1 or 2 tumors (7,7% vs. 1,5%; p = 0,04) as well as lymph node positive cases (5,2% vs. 1,8%; p = 0,03). CONCLUSIONS: Our population-based findings indicate that TTF-1 may be positive in approximately 3% of primary breast cancers, and positivity indicates an association with adverse prognostic factors. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8313753509421182. PMID- 23675757 TI - Adsorption and desorption of plasticizers with humic-fraction-immobilized silica gel in hexane: a facile approach to pre-concentration. AB - Humic fraction (HF) collected under acidic conditions and used as an adsorbent for various phosphate-based plasticizers in hexane is immobilized on silica gel. Most plasticizer analytes examined in this study under the same conditions achieved adsorption percentages above 90% in 1 h based on the difference in peak area. The Fourier transform infrared (FTIR) spectroscopy results indicate that the interaction leading to the adsorptions between the functional moieties of the analyte and HF (e.g., the carboxylate group of analyte against the carboxyl group of HF) is specific, reversible, and dipole-dipole-oriented. Moreover, it is significantly enhanced by hexane. However, the pi-pi interaction (even hydrogen bonding in all cases) was either not as significant or absent in hexane and, therefore, contributed little or nothing to the percentage of adsorption. The interaction is highly affected by the acidic or basic origin of the additive introduced to the liquid phase of the matrix, and it is subject to the steric hindrance effect caused by the bulky alkyl groups attached to ether linkages and the relative position of the two ether bonds on the aromatic moiety of the analyte. The pre-concentration of the analyte and, thus, the recycle of the adsorbent can be achieved by adsorbing and, subsequently, desorbing it in a different solvent, such as acetonitrile. Furthermore, the adsorption process is surface-oriented because of its dependence upon both time and the amount of adsorbent. PMID- 23675758 TI - Strong two-photon-induced fluorescence from photostable, biocompatible nitrogen doped graphene quantum dots for cellular and deep-tissue imaging. AB - Bright two-photon fluorescent probes are highly desirable to be able to optically probe biological activities deep inside living organisms with larger imaging depth, minor autofluorescence background, and less photodamage. In this study, we report the biocompatible nitrogen-doped graphene quantum dots (N-GQDs) as efficient two-photon fluorescent probes for cellular and deep-tissue imaging. The N-GQD was prepared by a facile solvothermal method using dimethylformamide as a solvent and nitrogen source. The two-photon absorption cross-section of N-GQD reaches 48,000 Goppert-Mayer units, which far surpasses that of the organic dyes and is comparable to that of the high performance semiconductor QDs, achieving the highest value ever reported for carbon-based nanomaterials. More importantly, a study of penetration depth in tissue phantom demonstrates that the N-GQD can achieve a large imaging depth of 1800 MUm, significantly extending the fundamental two-photon imaging depth limit. In addition, the N-GQD is nontoxic to living cells and exhibits super photostability under repeated laser irradiation. The high two-photon absorption cross-section, large imaging depth, good biocompatibility, and extraordinary photostability render the N-GQD an attractive alternative probe for efficient two-photon imaging in biological and biomedical applications. PMID- 23675759 TI - Effects of short-term disability awareness training on attitudes of adolescent schoolboys toward persons with a disability. AB - BACKGROUND: Schoolboys (N = 156, M age = 13 years) participated in a disability awareness training program that included guest speakers (athletes from the Paralympics and the Special Olympics), a documentary about people with a disability, a disability simulation activity, and factual information about different disabilities. METHOD: Participants were allocated to a training program or a control condition. Subsequently, control participants completed the training program. Attitudes toward disability were measured by the Chedoke-McMaster Attitudes Towards Children With Handicaps (CATCH) Scale and the scale from the "Just Like You" disability awareness intervention, before and after training. Results Training improved attitude scores, and gains were retained at one-month follow-up. CONCLUSIONS: Disability awareness training that delivered relevant information by involving guest speakers with a disability, included documentary evidence about the lives of people with a disability, and included interactive discussion, was successful. CATCH and "Just Like You" are useful tools for measuring self-reported attitudes about disability. PMID- 23675760 TI - High-purity hydrogen via the sorption-enhanced steam methane reforming reaction over a synthetic CaO-based sorbent and a Ni catalyst. AB - Sorbent-enhanced steam methane reforming (SE-SMR) is an emerging technology for the production of high-purity hydrogen from hydrocarbons with in situ CO2 capture. Here, SE-SMR was studied using a mixture containing a Ni-hydrotalcite derived catalyst and a synthetic, Ca-based, calcium aluminate supported CO2 sorbent. The fresh and cycled materials were characterized using N2 physisorption, X-ray diffraction, and scanning and transmission electron microscopy. The combination of a Ni-hydrotalcite catalyst and the synthetic CO2 sorbent produced a stream of high-purity hydrogen, that is, 99 vol % (H2O- and N2 free basis). The CaO conversion of the synthetic CO2 sorbent was 0.58 mol CO2/mol CaO after 10 cycles, which was more than double the value achieved by limestone. The favorable CO2 capture characteristics of the synthetic CO2 sorbent were attributed to the uniform dispersion of CaO on a stable nanosized mayenite framework, thus retarding thermal sintering of the material. On the other hand, the cycled limestone lost its nanostructured morphology completely over 10 SE-SMR cycles due to its intrinsic lack of a support component. PMID- 23675761 TI - FePt alloy nanoparticles for biosensing: enhancement of vitamin C sensor performance and selectivity by nanoalloying. AB - Electrocatalytic activity of supported FePt alloy nanoparticles (NPs) with different compositions (Fe25Pt75, Fe30Pt70, Fe35Pt65) for the electro-oxidation of vitamin C is investigated. These spherical FePt NPs with nanocrystallite size of 7-9 nm are found to consist of a nanoalloy core with a more Pt-rich shell. The FePt alloy NPs are superior catalysts than Pt NPs for vitamin C electro oxidation, with a linear concentration range of 0.01-1 mM, a high sensitivity of 4.347 mA cm(-2) mM(-1), and a low detection limit of 0.1 MUM (S/N = 3). By effectively reducing the overpotential for the electro-oxidation, these alloy NPs are significantly more selective to the detection of vitamin C against other common interference species, including dopamine, citric acid, uric acid, glucose, and NaCl. Enhancement in sensor performance can be attributed to the increase in surface area due to reduction of nanocrystallite size and to modification in the Pt electronic structure as a result of nanoalloying. These are supported by the X ray diffraction data and binding energy shifts as observed by X-ray photoelectron spectroscopy, respectively. Alloying therefore represents a powerful approach to introduce synergetic properties for new biosensor applications. PMID- 23675762 TI - Peginesatide as a new approach for treating anemia of CKD patient: is it like a falling star? AB - Any scientific innovation needs to translate into a significant benefit. Peginesatide is noninferior to other erythropoiesis stimulating agents (ESAs) in terms of efficacy, and it shares the advantages of other long-acting ESAs: delayed administration frequency and no changes in dose needs according to the administration route. The molecular structure of peginesatide does not require the use of recombinant DNA technology during the manufacturing process, making its synthesis simpler and likely economically cheaper. During clinical development, its safety profile seemed to be safe, excepting the potential increase in the risk of safety end-point events in nondialysis CKD patients. However postmarketing serious hypersensitivity reactions have completely changed the scenario and urgently needs in-depth clarification. This promising drug seems to have prematurely finished its prospects. PMID- 23675763 TI - An immunocytochemical-derived correlate for evaluating the bridging of heteromeric mu-delta opioid protomers by bivalent ligands. AB - Bivalent ligands that contain two pharmacophores linked by a spacer are promising tools to investigate the pharmacology of opioid receptor heteromers. Evidence for occupation of neighboring protomers by two phamacophores of a single bivalent ligand (bridging) has relied mainly on pharmacological data. In the present study, we have employed an immunocytochemical correlate to support in vivo biological studies that are consistent with bridging. We show that a bivalent mu agonist/delta antagonist (MDAN-21) that is devoid of tolerance due to possible bridging of mu and delta protomers prevents endocytosis of the heteromeric receptors in HEK-293 cells. Conversely, a bivalent ligand (MDAN-16) with a short spacer or monovalent mu agonist give rise to robust internalization. The data suggest that the immobilization of proximal mu and delta protomers is due to bridging by MDAN-21. The finding that MDAN-21 and its shorter spacer homologue MDAN-16 possess equivalent activity in HEK-293 cells, but produce dramatically divergent internalization of mu-delta heteromer, is relevant to the role of internalization and tolerance. PMID- 23675765 TI - Out of Africa: Miocene dispersal, vicariance, and extinction within Hyacinthaceae subfamily Urgineoideae. AB - Disjunct distribution patterns in plant lineages are usually explained according to three hypotheses: vicariance, geodispersal, and long-distance dispersal. The role of these hypotheses is tested in Urgineoideae (Hyacinthaceae), a subfamily disjunctly distributed in Africa, Madagascar, India, and the Mediterranean region. The potential ancestral range, dispersal routes, and factors responsible for the current distribution in Urgineoideae are investigated using divergence time estimations. Urgineoideae originated in Southern Africa approximately 48.9 Mya. Two independent dispersal events in the Western Mediterranean region possibly occurred during Early Oligocene and Miocene (29.9-8.5 Mya) via Eastern and Northwestern Africa. A dispersal from Northwestern Africa to India could have occurred between 16.3 and 7.6 Mya. Vicariance and extinction events occurred approximately 21.6 Mya. Colonization of Madagascar occurred between 30.6 and 16.6 Mya, after a single transoceanic dispersal event from Southern Africa. The current disjunct distributions of Urgineoideae are not satisfactorily explained by Gondwana fragmentation or dispersal via boreotropical forests, due to the younger divergence time estimates. The flattened winged seeds of Urgineoideae could have played an important role in long-distance dispersal by strong winds and big storms, whereas geodispersal could have also occurred from Southern Africa to Asia and the Mediterranean region via the so-called arid and high altitude corridors. PMID- 23675766 TI - The role of infrared thermography in evaluation of proliferative infantile hemangiomas. Results of a pilot study. PMID- 23675767 TI - Cutaneous sarcoidosis in a chronic hepatitis C patient receiving pegylated interferon and ribavirin therapy. AB - A 61-year-old Japanese woman suffered from a small, painful, subcutaneous nodule on the sole of her foot that was 10 mm across in diameter during pegylated interferon (PEG IFN) and ribavirin (RBV) combination therapy for chronic hepatitis C. Skin biopsy revealed multiple non-caseating granulomas composed of epithelioid histiocytes with multinucleate giant cells, which was consistent with sarcoidosis. Ophthalmologic examination revealed uveitis. Thoracic computed tomography (CT) showed multiple bilateral hilar lymphadenopathies and a diffuse micronodular interstitial pattern of the lungs. Genetic analysis indicated a probable homozygous haplotype of A*02:01-C*15:02-B*51:01-DRB1*16:02-DQB1*05:02 in human leukocyte antigen regions. The patient was observed carefully without any additional medication because no significant systemic symptoms were noted. Combination therapy was continued for 2 months afterwards. She was asymptomatic for over 3 years of follow up, and repeated hematological and biological investigations and chest CT showed improvement. In conclusion, clinicians should bear sarcoidosis in mind as a complication during PEG IFN and RBV combination therapy. They should also be aware of the usually good prognosis of PEG IFN induced cutaneous sarcoidosis in order not to prematurely discontinue a treatment necessary for liver disease; maintenance of PEG IFN treatment may be advised with careful follow up. PMID- 23675768 TI - Implantation site-dependent differences for tracheal regeneration with induced pluripotent stem cells (iPS cells). AB - CONCLUSION: The histological findings and quantitative measurements demonstrated that there were differences in teratoma formation according to the site of implantation. Elucidating the mechanisms of the teratoma formation caused by the site of implantation moves the field another step closer to clinical use of induced pluripotent stem (iPS) cells for tracheal regeneration. OBJECTIVES: Our previous study demonstrated the potential for iPS cells to be used as a new cell source for tracheal regeneration. However, teratoma formation remains a major problem. Implantation site-dependent differences in teratoma formation have been reported. In this study, the teratoma-forming propensity after implantation into tracheal defects and abdominal subcutaneous tissue was examined histologically and quantitatively. METHODS: Mouse iPS cells were cultured in artificial material under various conditions. After cultivation in vitro, artificial materials with cultured iPS cells were then implanted into cervical tissue around tracheal defects and into abdominal subcutaneous tissue in nude rats. Teratoma formation was evaluated histologically and quantitatively with measurement of maximum diameter (MD). RESULTS: Teratoma was observed in 10 of 11 rats with cervical tissue around tracheal defects and in 3 of 11 rats with abdominal subcutaneous tissue implants. The average MD was 5.36 mm in the trachea and 0.97 mm in the abdomen. PMID- 23675769 TI - Optic chiasm B-cell lymphoma in a 20-month-old Mastiff dog. AB - A 20-month-old intact female Mastiff dog presented for evaluation of acute blindness. Computed tomography confirmed a tumor involved the optic chiasm and optic nerves. A B-cell lymphoma was confirmed with postmortem examinations. This case report documents a central nervous system neoplasm in a young dog. PMID- 23675770 TI - An efficient indirect mechanism for the ultrafast intersystem crossing in copper porphyrins. AB - The ultrafast dynamics of copper tetraphenylporphyrin (CuTPP), copper octaethylporphyrin (CuOEP), and of the free base tetraphenylporphyrin (H2TPP), excited in the S2 state have been investigated in the gas phase by femtosecond pump/probe experiments. The porphyrins were excited in the Soret band at 400 nm. Strikingly, the S2-S1 internal conversion in H2TPP is very rapid (110 fs), as compared to that of ZnTPP (600 fs), previously observed. In turn, CuTPP and CuOEP, excited in S2, follow an efficient and different relaxation pathway from that of other open-shell metalloporphyrins. These two molecules exhibit a sequential four-step decay ending on a slow evolution in the nanosecond range (2)S2 -> (2)CT -> (2)T -> (2)Ground State. This latter evolution is linked to the formation of the (2)T, tripdoublet state in CuTPP, observed in the condensed phase. It is shown that an intermediate charge transfer state plays a crucial role in linking the porphyrin centered (1)pipi* and (3)pipi* configurations. A simple model is presented that allows a rapid evolution between these two configurations, via coupling of the porphyrin pi system with the free d electron on the copper. The mechanism obviates the need for the spin orbit coupling within the porphyrin. The result is that these copper porphyrins can exhibit an ultrafast apparent intersystem crossing, unprecedented for organic molecules. PMID- 23675771 TI - Interactions between cytochromes P450 2B4 (CYP2B4) and 1A2 (CYP1A2) lead to alterations in toluene disposition and P450 uncoupling. AB - The goal of this study was to characterize the effects of CYP1A2.CYP2B4 complex formation on the rates and efficiency of toluene metabolism by comparing the results from simple reconstituted systems containing P450 reductase (CPR) and a single P450 to those using a mixed system containing CPR and both P450s. In the mixed system, the rates of formation of CYP2B4-specific benzyl alcohol and p cresol were inhibited, whereas that of CYP1A2-specific o-cresol was increased, results consistent with the formation of a CYP1A2.CYP2B4 complex in which the CYP1A2 moiety has a higher affinity for CPR binding. Comparison of the rates of NADPH oxidation and production of hydrogen peroxide and excess water by the simple and mixed systems indicated that excess water formed at a much lower rate in the mixed system. The commensurate increase in the rate of CYP1A2-specific product formation suggested the P450.P450 interaction increased the rate of the putative rate-limiting step of CYP1A2 catalysis, abstraction of a hydrogen radical from the substrate. Cumene hydroperoxide-supported metabolism was measured to determine whether the effects of the P450.P450 interaction required the presence of CPR. Peroxidative metabolism was not affected by the interaction of the two P450s, even with CPR present. However, CPR did stimulate peroxidative metabolism by the simple system containing CYP1A2. These results suggest the major functional effects of the P450.P450 interaction are mediated by changes in the relative abilities of the P450s to receive electrons from CPR. Furthermore, CPR may play an effector role by causing a conformational change in CYP1A2 that makes its metabolism more efficient. PMID- 23675773 TI - Hypothesis-based weight-of-evidence evaluation of the human carcinogenicity of toluene diisocyanate. AB - Humans are exposed to toluene diisocyanate (TDI) primarily through inhalation in workplaces where TDI is produced or used. It is classified as a possible human carcinogen, based primarily on increased tumor incidences in rodents treated with TDI by oral gavage. We used the hypothesis-based weight-of-evidence (HBWoE) method to evaluate whether the available data support the hypothesis that TDI is a human carcinogen. The epidemiology data are not sufficiently robust to support TDI as a human carcinogen; the few positive associations are more likely attributable to alternative explanations than causation. The experimental animal studies indicate that inhalation exposure to TDI does not induce tumors in rats or mice. Tumors observed after oral gavage exposure are most likely due to the conversion of approximately 5% of the administered TDI to toluene diamine (TDA), a known rodent tumorigen. This contention is supported by the observations that TDA is rapidly formed from TDI during in vitro genotoxicity assays, the spectra of responses to TDA and TDI in these assays and in oral bioassays are essentially the same, and TDI is not genotoxic in rodents or humans in vivo after inhalation exposure, when TDA is not formed to a biologically significant degree. We conclude that the weight of the evidence indicates that the conversion of TDI to TDA does not occur in mammalian species under physiological exposure conditions (i.e. inhalation), but is necessary for carcinogenesis to occur. Thus, a causal association between TDI exposure and carcinogenic effects is not plausible in humans. PMID- 23675772 TI - Helical ambivalency induced by point mutations. AB - BACKGROUND: Mutation of amino acid sequences in a protein may have diverse effects on its structure and function. Point mutations of even a single amino acid residue in the helices of the non-redundant database may lead to sequentially identical peptides which adopt different secondary structures in different proteins. However, various physico-chemical factors which govern the formation of these ambivalent helices generated by point mutations of a sequence are not clearly known. RESULTS: Sequences generated by point mutations of helices are mapped on to their non-helical counterparts in the SCOP database. The results show that short helices are prone to transform into non-helical conformations upon point mutations. Mutation of amino acid residues by helix breakers preferentially yield non-helical conformations, while mutation with residues of intermediate helix propensity display least preferences for non-helical conformations. Differences in the solvent accessibility of the mutating/mutated residues are found to be a major criteria for these sequences to conform to non helical conformations. Even with minimal differences in the amino acid distributions of the sequences flanking the helical and non-helical conformations, helix-flanking sequences are found be more solvent accessible. CONCLUSIONS: All types of mutations from helical to non-helical conformations are investigated. The primary factors attributing such changes in conformation can be: i) type/propensity of the mutating and mutant residues ii) solvent accessibility of the residue at the mutation site iii) context/environment dependence of the flanking sequences. The results from the present study may be used to design de novo proteins via point mutations. PMID- 23675774 TI - The association of skin conditions with housing conditions among North Carolina Latino migrant farm workers. AB - BACKGROUND: Skin conditions are common among Latino migrant farm workers. Although many skin conditions are related to occupational exposures, poor housing conditions may also contribute to skin ailments in migrant farm workers. OBJECTIVES: To evaluate the association between housing conditions and skin conditions among Latino migrant farm workers. MATERIALS AND METHODS: A cross sectional study design using interview questionnaires, home inspections, and environmental sampling was implemented to document housing quality of farm worker camps/homes and the prevalence of self-reported skin conditions in Latino migrant farm workers. Interviews were completed with 371 farm workers residing in 186 of the 226 camps (camp response rate 82.3%). RESULTS: Self-reported pruritus (31%), rash (25%), scaling (12%), blisters (11%), and ingrown nails (10%) were common among the participants. Pruritus was more likely to be reported by farm workers living in dwellings without air-conditioning (P < 0.05). Rash was associated with dwellings reported to have a low humidity (P < 0.05). Scaling was more likely to be reported by farm workers living in dwellings with indoor temperatures in the thermal discomfort range (P < 0.05). No statistically significant associations were detected for indoor allergens and self-reported skin ailments among migrant farm workers. CONCLUSIONS: Skin conditions are common among migrant farm workers in North Carolina. The quality of housing conditions, particularly hot, dry indoor thermal environment, demonstrated significant associations with pruritus, rash, and scaling. The impact of housing characteristics on pruritus and blisters was greatest in new migrant farm workers. Further research is needed to delineate additional housing factors that could cause or exacerbate skin diseases in farm workers. PMID- 23675776 TI - Influence of anions and alkyl chain lengths of N-alkyl-n-(R)-12-hydroxyoctadecyl ammonium salts on their hydrogels and organogels. AB - The self-assembly and gelating characteristics of a set of N-alkyl-(R)-12 hydroxyoctadecylammonium salts (n-HOA-X, where n = 0-6, 18 is the length of the alkyl chain on nitrogen, X = Cl, n = 3, and X = Br, NO3, and BF4) are described. Solid-solid phase transitions were observed for powders of n-HOA-Cl, and orthorhombic-type crystal packing arrangements and lattice spacings were calculated from X-ray diffractograms at 22 degrees C. The diffractogram of 3-HOA Br indicates the presence of more than one morph at room temperature, and that of 3-HOA-I corresponds to a lamellar packing arrangement. Differences in the molecular packing arrangements of 3-HOA-X are reflected in their gelation abilities. The melting temperatures (T(gel)) of the hydrogels of 3-HOA-Br are higher than those of 3-HOA-Cl at the same concentrations, and 3-HOA-I failed to gelate any of the investigated liquids. 3-HOA-NO3 gelated only water and CCl4 and 3-HOA-BF4 formed only hydrogels. Plots of changes in conductivities of the 3-HOA X salts (where X = Cl, Br, NO3 and BF4) as a function of temperature were used to calculate the critical aggregation concentrations (CGCs). Because the CGCs from the 'falling drop' method are nearly the same as those from the conductivity measurements, aggregation, nucleation, and gelation must occur within a very narrow 3-HOA-X concentration range. T(gel) values of 2 wt % 3-HOA-Cl hydrogels (prepared by fast cooling of the sol phase) increased upon adding KCl up to 0.1 M. The effects can be attributed principally to the chloride anion rather than its cation partners. The properties of the hydrogels of 3-HOA-X do not follow the Hofmeister ranking rule. The variations in the counterions afford detailed insight into the behavior of 3-HOA-X in their neat solids and assemblies in gels as well as the processes accompanying gel formation in water and organic liquids. PMID- 23675775 TI - Identification of alverine and benfluorex as HNF4alpha activators. AB - The principal finding of this study is that two drugs, alverine and benfluorex, used in vastly different clinical settings, activated the nuclear receptor transcription factor HNF4alpha. Both were hits in a high-throughput screen for compounds that reversed the inhibitory effect of the fatty acid palmitate on human insulin promoter activity. Alverine is used in the treatment of irritable bowel syndrome, while benfluorex (Mediator) was used to treat hyperlipidemia and type II diabetes. Benfluorex was withdrawn from the market recently because of serious cardiovascular side effects related to fenfluramine-like activity. Strikingly, alverine and benfluorex have a previously unrecognized structural similarity, consistent with a common mechanism of action. Gene expression and biochemical studies revealed that they both activate HNF4alpha. This novel mechanism of action should lead to a reinterpretation of previous studies with these drugs and suggests a path toward the development of therapies for diseases such as inflammatory bowel and diabetes that may respond to HNF4alpha activators. PMID- 23675777 TI - Regulation of myocardial interleukin-6 expression by p53 and STAT1. AB - Cardiovascular diseases are a major cause of morbidity and mortality worldwide. The interferon inducible transcriptional activator signal transducer and activator of transcription-1 (STAT1) and p53 are two critical transcriptional factors that have pivotal roles in cardiac biology and pathology. Here we describe a novel interplay between these two key players that critically regulate the levels of the pleiotropic interleukin 6 (IL6) in the heart. We provide in vivo evidence to demonstrate that, in cardiac tissues, STAT1 is a positive regulator of IL6 expression and it competes with the suppressive effect of p53 to sustain basal IL6 levels. Induction of IL6 expression in response to interferon gamma (IFNgamma), a well-characterized activator of STAT1, parallels that of STAT1 phosphorylation and induction of STAT1 target genes, such as the interferon regulatory factor-1 (IRF-1), major histocompatibility complex class II transactivator (C2ta), and beta2-microglobulin (B2m). Furthermore, hearts from STAT1 knockout mice fail to induce IL6 expression in response to IFNgamma. More importantly, we showed that this regulatory system is not functional in mouse embryonic fibroblasts, suggesting that activation of IL6 expression by STAT1 may be tissue specific. IL6 is a major effector of inflammation and cardiac hypertrophy, two major processes involved in heart failure, and therefore, understanding the molecular mechanisms regulating IL6 expression will enable better therapies and treatments for cardiovascular disease patients. PMID- 23675779 TI - Type I and type II interferons inhibit both basal and tumor necrosis factor-alpha induced CXCL8 secretion in primary cultures of human thyrocytes. AB - Interferons (IFNs) and tumor necrosis factor-alpha (TNF-alpha) cooperate in activating several inflammation-related genes, which sustain chronic inflammation in autoimmune thyroid disease (AITD). Much is known about the positive signaling of IFNs to activate gene expression in AITD, while the mechanisms by which IFNs negatively regulate genes remain less studied. While IFNs inhibit CXCL8 secretion in several human cell types, their effects on thyroid cells were not evaluated. Our aim was to study the interplay between TNF-alpha and type I or type II IFNs on CXCL8 secretion by human thyroid cells. CXCL8 was measured in supernatants of primary cultures of thyroid cells basally and after a 24-h incubation with TNF alpha. CXCL8 was detected in thyroid cell supernatants in basal conditions (96.2+/-23.5 pg/mL) being significantly increased (784.7+/-217.3 pg/mL; P<0.0001 vs. basal) by TNF-alpha. Twenty-four hour incubation with IFN-gamma or IFN-beta or IFN-alpha dose dependently and significantly inhibited both basal and TNF alpha-induced CXCL8 secretion. The degree of the inhibitory effect was IFN gamma>IFN-beta>IFN-alpha. This study demonstrates that type I and type II IFNs downregulate both basal and TNF-alpha-induced CXCL8 secretion by human thyrocytes, IFN-gamma being the most powerful inhibitor. Future studies aimed at a better comprehension of the interplay between CXCL8 and thyroid diseases appear worthwhile. PMID- 23675780 TI - An update on pharmacological treatment of erectile dysfunction with phosphodiesterase type 5 inhibitors. AB - INTRODUCTION: Phosphodiesterase type 5 inhibitors (PDE5-i) are used for the oral treatment of erectile dysfunction (ED). Since the launch of sildenafil more than 15 years ago, new molecules have become available. At present, in addition to tadalafil and vardenafil, there are three other drugs, udenafil, avanafil and mirodenafil, marketed in some countries which appear to be promising. AREAS COVERED: The clinical pharmacological differences in dosage and side effects of all PDE5-i are evaluated. EXPERT OPINION: All PDE5-i are equally effective and safe for the treatment of ED. On-demand use of any PDE5-i is also safe for patients with comorbid conditions. Tadalafil seems to be the preferred drug by patients and physicians, probably due to its peculiar pharmacological profile that makes sexual intercourse more spontaneous for the patients. Preliminary data suggest that the use of vardenafil may also be beneficial in cases of ED associated with premature ejaculation. Daily treatment is another option in men with ED and documented vascular or prostate disease. In geriatric or in difficult to-treat populations, the evaluation of testosterone plasma levels will help to predict the efficacy of any PDE5-i. Remarkably, when such drugs are withdrawn for any reason, ED most often continues to occur because of the presence of an underlying disease. PMID- 23675781 TI - Transcatheter aortic valve insertion catastrophe in inoperable patients: should aortic valve replacement be denied? AB - This paper reports the outcomes of patients initially deemed inoperable for standard aortic valve replacement who received transcatheter aortic valve insertion. Each patient experienced a transcatheter valve insertion complication and was then subsequently reconsidered for urgent standard valve replacement. We review the outcomes of these inoperable patients and discuss recommendations for managing this complication. PMID- 23675782 TI - New type of single chain magnet: pseudo-one-dimensional chain of high-spin Co(II) exhibiting ferromagnetic intrachain interactions. AB - Two new six-coordinated high-spin Co(II) complexes have been synthesized through the reactions of Co(II) salts with dipyridylamine (dpamH) and 5-nitro salicylaldehyde (5-NO2-saloH) or 3-methoxy-salicylaldehyde (3-OCH3-saloH) under argon atmosphere: [Co(dpamH)2(5-NO2-salo)]NO3 (1) and [Co(dpamH)2(3-OCH3 salo)]NO3.1.3 EtOH.0.4H2O (2). According to the crystal packing of compound 1, two coordination cations are linked with two nitrate anions into a cyclic dimeric arrangement via N-H...O and C-H...O hydrogen bonds. In turn, these dimers are assembled into (100) layers through pi-pi stacking interactions between inversion center related pyridine rings of the dpamH ligands. The crystal packing of compound 2 reveals a 1D assembly consisting solely from the coordination cations, which is formed by pi-pi stacking interactions between pyridine rings of one of the dpamH along the [010] and another 1D assembly of the coordination cations and nitrate anions through the N-H...O hydrogen-bonding interactions along the [001] direction. All complexes were magnetically characterized, and a new approximation method was used to fit the magnetic susceptibility data in the whole temperature range 2-300 K on the basis of an empirical expression which allows the treatment of each cobalt(II) ion in axial symmetry as an effective spin S(eff) = 1/2. In zero-field, dynamic magnetic susceptibility measurements show slow magnetic relaxation below 5.5 K for compound 2. The slow dynamics may originate from the motion of broad domain walls and is characterized by an Arrhenius law with a single energy barrier Deltar/k(B) = 55(1) K for the [10-1488 Hz] frequency range. In order to reveal the importance of the crystal packing in the SCM behavior, a gentle heating process to 180 degrees C was carried out to remove the solvent molecules. The system, after heating, undergoes a major but not complete collapse of the network retaining to a small percentage its SCM character. PMID- 23675778 TI - Toll-like receptor polymorphisms, inflammatory and infectious diseases, allergies, and cancer. AB - Toll-like receptors (TLRs) are germ-line-encoded innate immune sensors that recognize conserved microbial structures and host alarmins and signal expression of MHC proteins, costimulatory molecules, and inflammatory mediators by macrophages, neutrophils, dendritic cells, and other cell types. These processes activate immediate and early mechanisms of innate host defense, as well as initiate and orchestrate adaptive immune responses. Several single-nucleotide polymorphisms (SNPs) within the TLR genes have been associated with altered susceptibility to infectious, inflammatory, and allergic diseases, and have been found to play a role in tumorigenesis. Critical advances in our understanding of innate immune functions and genome-wide association studies (GWAS) have uncovered complex interactions of genetic polymorphisms within TLRs and environmental factors. However, conclusions obtained in the course of such analyses are restricted by limited power of many studies that is likely to explain controversial findings. Further, linkages to certain ethnic backgrounds, gender, and the presence of multigenic effects further complicate the interpretations of how the TLR SNPs affect immune responses. For many TLRs, the molecular mechanisms by which SNPs impact receptor functions remain unknown. In this review, I have summarized current knowledge about the TLR polymorphisms, their impact on TLR signaling, and associations with various inflammatory, infectious, allergic diseases and cancers, and discussed the directions of future scientific research. PMID- 23675783 TI - Identification of an abundant 56 kDa protein implicated in food allergy as granule-bound starch synthase. AB - Rice, the staple food of south and east Asian counties, is considered to be hypoallergenic. However, several clinical studies have documented rice-induced allergy in sensitive patients. Rice proteins with molecular weights of 14-16, 26, 33, and 56 kDa have been identified as allergens. Recently, it was documented that the 56 kDa rice allergen was responsible for rice-induced anaphylaxis. The 14-16 kDa allergens have been identified as alpha-amylase inhibitors; the 26 kDa protein has been identified as alpha-globulin; and the 33 kDa protein has been identified as glyoxalase I. However, the identity of the 56 kDa rice allergen has not yet been determined. In this study, we demonstrate that serum from patients allergic to maize shows IgE binding to a 56 kDa protein that was present in both maize and rice but not in the oil seeds soybean and peanut. The 56 kDa IgE binding protein was abundant in the rice endosperm. We have purified this protein from rice endosperm and demonstrated its reactivity to IgE antibodies from the serum of maize-allergic patients. The purified protein was subjected to matrix assisted laser desorption ionization-time of flight-tandem mass spectrometry analysis, resulting in identification of this rice allergen as granule-bound starch synthase, a product of the Waxy gene. Immunoblot analysis using protein extracts from a waxy mutant of rice revealed the absence of the 56 kDa IgE binding protein. Our results demonstrate that the 56 kDa rice allergen is granule bound starch synthase and raise the possibility of using waxy mutants of rice as a potential source of the hypoallergenic diet for patients sensitized to the 56 kDa rice allergen. PMID- 23675784 TI - Using genome-referenced expressed sequence tag assembly to analyze the origin and expression patterns of Gossypium hirsutum transcripts. AB - We assembled a total of 297,239 Gossypium hirsutum (Gh, a tetraploid cotton, AADD) expressed sequence tag (EST) sequences that were available in the National Center for Biotechnology Information database, with reference to the recently published G. raimondii (Gr, a diploid cotton, DD) genome, and obtained 49,125 UniGenes. The average lengths of the UniGenes were increased from 804 and 791 bp in two previous EST assemblies to 1,019 bp in the current analysis. The number of putative cotton UniGenes with lengths of 3 kb or more increased from 25 or 34 to 1,223. As a result, thousands of originally independent G. hirsutum ESTs were aligned to produce large contigs encoding transcripts with very long open reading frames, indicating that the G. raimondii genome sequence provided remarkable advantages to assemble the tetraploid cotton transcriptome. Significant different distribution patterns within several GO terms, including transcription factor activity, were observed between D- and A-derived assemblies. Transcriptome analysis showed that, in a tetraploid cotton cell, 29,547 UniGenes were possibly derived from the D subgenome while another 19,578 may come from the A subgenome. Finally, some of the in silico data were confirmed by reverse transcription polymerase chain reaction experiments to show the changes in transcript levels for several gene families known to play key role in cotton fiber development. We believe that our work provides a useful platform for functional and evolutionary genomic studies in cotton. PMID- 23675785 TI - Overview of skin diseases linked to connexin gene mutations. AB - Mutations in skin-expressed connexin genes, such as connexins 26, 30, 30.3, 31, and 43, have been linked to several human hereditary diseases with multiple organ involvement. Mutations in connexin 26 are linked to diseases including Vohwinkel syndrome, keratitis-ichthyosis deafness, and hystrix-like ichthyosis deafness syndromes, palmoplantar keratoderma with deafness, deafness with Clouston-like phenotype, and Bart-Pumphrey syndrome. Mutations in connexin 30 are correlated with Clouston syndrome. Connexin 30.3 and 31 mutations lead to erythrokeratoderma variabilis, and mutations in connexin 43 are correlated with oculodentodigital dysplasia. Provided is a review of these mutations and related skin disorders. PMID- 23675786 TI - The effect of RHIZOMA COPTIDIS and COPTIS CHINENSIS aqueous extract on radiation induced skin injury in a rat model. AB - BACKGROUND: Radiation-induced skin injury is a common complication of radiotherapy. The RHIZOMA COPTIDIS and COPTIS CHINENSIS aqueous extract (RCE) can ameliorate radiation-induced skin injury in our clinical observation. But, the protective mechanism of RHIZOMA COPTIDIS and COPTIS CHINENSIS in radiation induced skin injury remains unclear. METHODS: In this experiment, we developed a radiation-induced skin injury rat model to study the mechanism. The animals were randomly divided into control group, treatment group, radiation group, and treatment and radiation group. 5 rats in each group were separately executed on 2 d and 49 d post-radiation. The semi-quantitative skin injury score was used to measure skin reactions by unblinded observers, and hematoxylin and eosin staining was used to evaluate the damage areas by irradiation. The MDA content, SOD activity of skin and serum were measured to detect the oxidative stress. RESULTS: Acute skin reactions were caused by a single dose of 45 Gy of beta-ray irradiation, and the skin injury could be found in all rats receiving irradiation based on the observation of HE staining of skin at different time-points, while RCE could significantly ameliorate those changes. The MDA content in serum and skin of control rats was 4.13+/-0.12 mmol/ml and 4.95+/-0.35 mmol/mgprot on 2 d post-radiation. The rats receiving radiation showed an increased content of MDA (5.54+/-0.21 mmol/ml and 7.10+/-0.32 mmol/mgprot), while it was 4.57+/-0.21 mmol/ml and 5.95+/-0.24 mmol/mgprot after treated with RCE (p<0.05). Similar changes of the MDA content could be seen on 49 d post-radiation. However, the SOD activity of rats receiving radiation decreased compared with control group on both time-points, which was inhibited by RCE (p<0.05). Meanwhile, no valuable changes could be found between control group and treatment group on 2 d and 49 d. CONCLUSIONS: Our study provides evidences for the radioprotective role of RCE against radiation-induced skin damage in rats by modulating oxidative stress in skin, which may be a useful therapy for radiation-induced skin injury. PMID- 23675788 TI - A 3-month jump-landing training program: a feasibility study using the RE-AIM framework. AB - CONTEXT: Evaluating the translatability and feasibility of an intervention program has become as important as determining the effectiveness of the intervention. OBJECTIVE: To evaluate the applicability of a 3-month jump-landing training program in basketball players, using the RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework. DESIGN: Randomized controlled trial. SETTING: National and regional basketball teams. PATIENTS OR OTHER PARTICIPANTS: Twenty-four teams of the second highest national division and regional basketball divisions in Flanders, Belgium, were randomly assigned (1:1) to a control group and intervention group. A total of 243 athletes (control group = 129, intervention group = 114), ages 15 to 41 years, volunteered. INTERVENTION(S): All exercises in the intervention program followed a progressive development, emphasizing lower extremity alignment during jump-landing activities. MAIN OUTCOME MEASURE(S): The results of the process evaluation of the intervention program were based on the 5 dimensions of the RE-AIM framework. The injury incidence density, hazard ratios, and 95% confidence intervals were determined. RESULTS: The participation rate of the total sample was 100% (reach). The hazard ratio was different between the intervention group and the control group (0.40 [95% confidence interval = 0.16, 0.99]; effectiveness). Of the 12 teams in the intervention group, 8 teams (66.7%) agreed to participate in the study (adoption). Eight of the participating coaches (66.7%) felt positively about the intervention program and stated that they had implemented the training sessions of the program as intended (implementation). All coaches except 1 (87.5%) intended to continue the intervention program the next season (maintenance). CONCLUSIONS: Compliance of the coaches in this coach-supervised jump-landing training program was high. In addition, the program was effective in preventing lower extremity injuries. PMID- 23675789 TI - Changes in lower extremity biomechanics due to a short-term fatigue protocol. AB - CONTEXT: Noncontact anterior cruciate ligament injury has been reported to occur during the later stages of a game when fatigue is most likely present. Few researchers have focused on progressive changes in lower extremity biomechanics that occur throughout fatiguing. OBJECTIVE: To evaluate the effects of a sequential fatigue protocol on lower extremity biomechanics during a sidestep cutting task (SS). DESIGN: Controlled laboratory study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Eighteen uninjured female collegiate soccer players (age = 19.2 +/- 0.9 years, height = 1.66 +/- 0.5 m, mass = 61.6 +/- 5.1 kg) volunteered. INTERVENTION(S): The independent variable was fatigue level, with 3 levels (prefatigue, 50% fatigue, and 100% fatigue). Using 3-dimensional motion capture, we assessed lower extremity biomechanics during the SS. Participants alternated between a fatigue protocol that solicited different muscle groups and mimicked actual sport situations and unanticipated SS trials. The process was repeated until fatigue was attained. MAIN OUTCOME MEASURE(S): Dependent variables were hip- and knee-flexion and abduction angles and internal moments measured at initial contact and peak stance and defined as measures obtained between 0% and 50% of stance phase. RESULTS: Knee-flexion angle decreased from prefatigue (-17 degrees +/- 5 degrees ) to 50% fatigue (-16 degrees +/- 6 degrees ) and to 100% fatigue (-14 degrees +/- 4 degrees ) (F2,34 = 5.112, P = .004). Knee flexion at peak stance increased from prefatigue (-52.9 degrees +/- 5.6 degrees ) to 50% fatigue (-56.1 degrees +/- 7.2 degrees ) but decreased from 50% to 100% fatigue (-50.5 degrees +/- 7.1 degrees ) (F2,34 = 8.282, P = 001). Knee-adduction moment at peak stance increased from prefatigue (0.49 +/- 0.23 Nm/kgm) to 50% fatigue (0.55 +/- 0.25 Nm/kgm) but decreased from 50% to 100% fatigue (0.37 +/- 0.24) (F2,34 = 3.755, P = 03). Hip-flexion angle increased from prefatigue (45.4 degrees +/- 10.9 degrees ) to 50% fatigue (46.2 degrees +/- 11.2 degrees ) but decreased from 50% to 100% fatigue (40.9 degrees +/- 11.3 degrees ) (F2,34 = 6.542, P = .004). Hip flexion at peak stance increased from prefatigue (49.8 degrees +/- 9.9 degrees ) to 50% fatigue (52.9 degrees +/- 12.1 degrees ) but decreased from 50% to 100% fatigue (46.3 degrees +/- 12.9 degrees ) (F2,34 = 8.639, P = 001). Hip-abduction angle at initial contact decreased from prefatigue (-13.8 degrees +/- 6.6 degrees ) to 50% fatigue (-9.1 degrees +/- 6.5 degrees ) and to 100% fatigue (-7.8 degrees +/- 6.5 degrees ) (F2,34 = 11.228, P < .001). Hip-adduction moment decreased from prefatigue (0.14 +/- 0.13 Nm/kgm) to 50% fatigue (0.08 +/- 0.13 Nm/kgm) and to 100% fatigue (0.06 +/- 0.05 Nm/kg) (F2,34 = 5.767, P = .007). CONCLUSIONS: The detrimental effects of fatigue on sagittal and frontal mechanics of the hip and knee were visible at 50% of the participants' maximal fatigue and became more marked at 100% fatigue. Anterior cruciate ligament injury-prevention programs should emphasize feedback on proper mechanics throughout an entire practice and not only at the beginning of practice. PMID- 23675790 TI - Exergaming and static postural control in individuals with a history of lower limb injury. AB - CONTEXT: Therapeutic exercise programs that incorporate real-time feedback have been reported to enhance outcomes in patients with lower extremity joint injuries. The Wii Fit has been purported to improve balance, strength, flexibility, and fitness. OBJECTIVE: To determine the effects of Wii Fit rehabilitation on postural control and self-reported function in patients with a history of lower limb injury. DESIGN: Single-blinded, randomized controlled trial. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Twenty-eight physically active participants with a history of lower limb injuries were randomly assigned to 1 of 3 groups (9 Wii Fit, 10 traditional, 9 control). INTERVENTION(S): Intervention groups performed supervised rehabilitation 3 d/wk for a total of 12 sessions. MAIN OUTCOME MEASURE(S): Time to boundary (TTB) and the Star Excursion Balance Test (SEBT) were conducted at baseline, 2 weeks, and 4 weeks. Self-reported function was measured at baseline and 4-week follow-up. Between-groups differences were compared using repeated-measures multivariate analysis of variance. RESULTS: With the eyes open, both intervention groups improved (P < .05) in the mean and the SD of the TTB anterior-posterior minima. In the eyes-closed condition, a time main effect (P < .05) for absolute TTB medial-lateral minima was observed. A time main effect was also noted in the posteromedial and posterolateral reach directions of the SEBT. When the scores for each group were pooled, improvement (P < .05) in self-reported function was demonstrated at 4-week follow-up. CONCLUSIONS: Rehabilitation using the Wii Fit and traditional exercises improved static postural control in patients with a history of lower extremity injury. PMID- 23675791 TI - Foot structure and muscle reaction time to a simulated ankle sprain. AB - CONTEXT: Foot structure has been shown to affect aspects of neuromuscular control, including postural stability and proprioception. However, despite an association between pronated and supinated foot structures and the incidence of lateral ankle sprains, no one to our knowledge has measured muscle reaction time to a simulated ankle-sprain mechanism in participants with different foot structures. OBJECTIVE: To determine whether pronated or supinated foot structures contribute to neuromuscular deficits as measured by muscle reaction time to a simulated ankle-sprain mechanism. DESIGN: Cross-sectional study. SETTING: University biomechanics laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirty volunteers were categorized into 3 groups according to navicular-drop-height measures. Ten participants (4 men, 6 women) had neutral feet (navicular-drop height = 5-9 mm), 10 participants (4 men, 6 women) had pronated feet (navicular drop height >= 10 mm), and 10 participants (4 men, 6 women) had supinated feet (navicular-drop height <= 4 mm). INTERVENTION(S): Three perturbations on a standing tilt platform simulating the mechanics of an inversion and plantar flexion ankle sprain. MAIN OUTCOME MEASURE(S): Muscle reaction time in milliseconds of the peroneus longus, tibialis anterior, and gluteus medius to the tilt-platform perturbation. RESULTS: Participants with pronated or supinated foot structures had slower peroneus longus reaction times than participants with neutral feet (P = .01 and P = .04, respectively). We found no differences for the tibialis anterior or gluteus medius. CONCLUSIONS: Foot structure influenced peroneus longus reaction time. Further research is required to establish the consequences of slower peroneal reaction times in pronated and supinated foot structures. Researchers investigating lower limb muscle reaction time should control for foot structure because it may influence results. PMID- 23675792 TI - Test-retest and interrater reliability of the functional movement screen. AB - CONTEXT: The Functional Movement Screen (FMS) is a popular test to evaluate the degree of painful, dysfunctional, and asymmetric movement patterns. Despite great interest in the FMS, test-retest reliability data have not been published. OBJECTIVE: To assess the test-retest and interrater reliability of the FMS and to compare the scoring by 1 rater during a live session and the same session on video. DESIGN: Cross-sectional study. SETTING: Human performance laboratory in the sports medicine center. PATIENTS OR OTHER PARTICIPANTS: A total of 21 female (age = 19.6 +/- 1.5 years, height = 1.7 +/- 0.1 m, mass = 64.4 +/- 5.1 kg) and 18 male (age = 19.7 +/- 1.0 years, height = 1.9 +/- 0.1 m, mass = 80.1 +/- 9.9 kg) National Collegiate Athletic Association Division IA varsity athletes volunteered. INTERVENTION(S): Each athlete was tested and retested 1 week later by the same rater who also scored the athlete's first session from a video recording. Five other raters scored the video from the first session. MAIN OUTCOME MEASURE(S): The Krippendorff alpha (K alpha) was used to assess the interrater reliability, whereas intraclass correlation coefficients (ICCs) were used to assess the test-retest reliability and reliability of live-versus-video scoring. RESULTS: Good reliability was found for the test-retest (ICC = 0.6), and excellent reliability was found for the live-versus-video sessions (ICC = 0.92). Poor reliability was found for the interrater reliability (K alpha = .38). CONCLUSIONS: The good test-retest and high live-versus-video session reliability show that the FMS is a usable tool within 1 rater. However, the low interrater K alpha values suggest that the FMS within the limits of generalization should not be used indiscriminately to detect deficiencies that place the athlete at greater risk for injury. The FMS interrater reliability may be improved with better training for the rater. PMID- 23675793 TI - A novel experimental knee-pain model affects perceived pain and movement biomechanics. AB - CONTEXT: Knee injuries are prevalent, and the associated knee pain is linked to disability. The influence of knee pain on movement biomechanics, independent of other factors related to knee injuries, is difficult to study and unclear. OBJECTIVE: (1) To evaluate a novel experimental knee-pain model and (2) better understand the independent effects of knee pain on walking and running biomechanics. DESIGN: Crossover study. SETTING: Biomechanics laboratory. PATIENTS OR OTHER PARTICIPANTS: Twelve able-bodied volunteers (age = 23 +/- 3 years, height = 1.73 +/- 0.09 m, mass = 75 +/- 14 kg). INTERVENTION(S): Participants walked and ran at 3 time intervals (preinfusion, infusion, and postinfusion) for 3 experimental conditions (control, sham, and pain). During the infusion time interval for the pain and sham conditions, hypertonic or isotonic saline, respectively, was continuously infused into the right infrapatellar fat pad for 22 minutes. MAIN OUTCOME MEASURE(S): We used repeated-measures analyses of variance to evaluate the effects of time and condition on (1) perceived knee pain and (2) key biomechanical characteristics (ground reaction forces, and joint kinematics and kinetics) of walking and running (P < .05). RESULTS: The hypertonic saline infusion (1) increased perceived knee pain throughout the infusion and (2) reduced discrete characteristics of each component of the walking ground reaction force, walking peak plantar-flexion angle (range = 62 degrees -67 degrees ), walking peak plantar-flexion moment (range = 95-104 N.m), walking peak knee-extension moment (range = 36-49 N.m), walking peak hip abduction moment (range = 62-73 N.m), walking peak support moment (range = 178 207 N.m), running peak plantar-flexion angle (range = 38 degrees -77 degrees ), and running peak hip-adduction angle (range = 5-21 degrees ). CONCLUSIONS: This novel experimental knee pain model consistently increased perceived pain during various human movements and produced altered running and walking biomechanics that may cause abnormal knee joint-loading patterns. PMID- 23675794 TI - Selective activation of the infraspinatus muscle. AB - CONTEXT: To improve selective infraspinatus muscle strength and endurance, researchers have recommended selective shoulder external-rotation exercise during rehabilitation or athletic conditioning programs. Although selective strengthening of the infraspinatus muscle is recommended for therapy and training, limited information is available to help clinicians design a selective strengthening program. OBJECTIVE: To determine the most effective of 4 shoulder external-rotation exercises for selectively stimulating infraspinatus muscle activity while minimizing the use of the middle trapezius and posterior deltoid muscles. DESIGN: Cross-sectional study. SETTING: University research laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 30 healthy participants (24 men, 6 women; age = 22.6 +/- 1.7 years, height = 176.2 +/- 4.5 cm, mass = 65.6 +/- 7.4 kg) from a university population. INTERVENTION(S): The participants were instructed to perform 4 exercises: (1) prone horizontal abduction with external rotation (PER), (2) side-lying wiper exercise (SWE), (3) side-lying external rotation (SER), and (4) standing external-rotation exercise (STER). MAIN OUTCOME MEASURE(S): Surface electromyography signals were recorded from the infraspinatus, middle trapezius, and posterior deltoid muscles. Differences among the exercise positions were tested using a 1-way repeated-measures analysis of variance with Bonferroni adjustment. RESULTS: The infraspinatus muscle activity was greater in the SWE (55.98% +/- 18.79%) than in the PER (46.14% +/- 15.65%), SER (43.38% +/- 22.26%), and STER (26.11% +/- 15.00%) (F3,87 = 19.97, P < .001). Furthermore, the SWE elicited the least amount of activity in the middle trapezius muscle (F3,87 = 20.15, P < .001). Posterior deltoid muscle activity was similar in the SWE and SER but less than that measured in the PER and STER (F3,87 = 25.10, P < .001). CONCLUSIONS: The SWE was superior to the PER, SER, and STER in maximizing infraspinatus activity with the least amount of middle trapezius and posterior deltoid activity. These findings may help clinicians design effective exercise programs. PMID- 23675795 TI - Intramuscular heating through fluidotherapy and heat shock protein response. AB - CONTEXT: Therapeutic modalities that can increase intramuscular temperature commonly are used to treat injuries in the clinical setting. Researchers recently have suggested that the physiologic changes occurring during an increase in temperature also could provide a cytoprotective effect for exercise-induced muscle damage. OBJECTIVE(S): To determine if the Fluidotherapy treatment increases the inducible expression of heat shock protein (HSP), to identify the rate of heating that occurs in the lower extremity with Fluidotherapy treatment, and to evaluate the relationship between the inducible expression of HSP and temperature. DESIGN: Controlled laboratory study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Six male (age = 21.67 +/- 1.63 years, height = 180.09 +/- 4.83 cm, mass = 87.60 +/- 10.51 kg) and 6 female (age = 24.60 +/- 4.59 years, height = 151.05 +/- 35.76 cm, mass = 55.59 +/- 14.58 kg) college-aged students. INTERVENTION(S): One lower extremity was randomly selected to receive the heat treatment, and the other extremity received no treatment. MAIN OUTCOME MEASURE(S): We measured intramuscular temperature every 10 minutes, determining peak intramuscular temperature by 2 identical sequential measurements, and we analyzed the time to peak temperature. We analyzed the amount of HSP70 expression and HSP27P:T (ratio of HSP27 to the total HSP27 expression) in the gastrocnemius and soleus muscles and measured baseline skinfold thickness and estradiol levels. RESULTS: Fluidotherapy increased intramuscular temperature by 5.66 +/- 0.78 degrees C (t11 = 25.67, P < .001) compared with baseline temperature, with a peak temperature of 39.08 degrees C +/- 0.39 degrees C occurring at 84.17 +/- 6.69 minutes. We did not find a heat treatment effect for HSP70 or HSP27P:T in the gastrocnemius or soleus muscles (P > .05). Peak temperature and the percentage change of HSP70 were positively correlated for the gastrocnemius and soleus muscles (P < .05). We found no other correlations for skinfold thickness, sex, or estradiol levels (P > .05). No effect of sex for skinfold thickness or estradiol levels at baseline was discovered (P > .05). CONCLUSIONS: This Fluidotherapy protocol increased the intramuscular temperature to a therapeutic level; however, it did not stimulate inducible HSP70 or HSP27P:T in the soleus and gastrocnemius muscles regardless of sex or skinfold thickness. These data confirmed that Fluidotherapy is an effective heating modality but suggested it is not an effective method for stimulating an HSP response in the lower limb. PMID- 23675796 TI - A learner-centered technique and clinical reasoning, reflection, and case presentation attributes in athletic training students. AB - CONTEXT: Providing opportunities to develop clinical decision-making skills, including clinical reasoning, is an important aspect of clinical education. The learner-centered technique of summarizing the history and findings, narrowing the differential, analyzing the differential, probing the instructor about uncertainties, plan management, and selecting an issue for self-directed study (SNAPPS) is used in medicine to express clinical reasoning. OBJECTIVE: To investigate the effects of SNAPPS on the clinical reasoning, reflection, and 4 case presentation attributes (length, conciseness, case summary, and expression of clinical reasoning) in athletic training students. DESIGN: Randomized controlled clinical trial. SETTING: Three undergraduate programs accredited by the Commission on Accreditation of Athletic Training Education. PATIENTS OR OTHER PARTICIPANTS: We randomly assigned 38 athletic training students (17 men, 21 women; age = 21.53 +/- 1.18 years, grade point average = 3.25 +/- 0.31) who had completed at least 1 year of clinical education and all orthopaedic evaluation coursework to the SNAPPS group or the usual and customary group using a stratification scheme. INTERVENTION(S): The SNAPPS group completed four 45-minute clinical reasoning and case presentation learning modules led by an investigator to learn the SNAPPS technique, whereas the usual and customary group received no formal instruction. Both groups audio recorded all injury evaluations performed over a 2-week period. MAIN OUTCOME MEASURES: Participants completed the Diagnostic Thinking Inventory and Reflection in Learning Scale twice. Case presentations were analyzed for 4 attributes: length, conciseness, case summary, and expression of clinical reasoning. RESULTS: Case presentations were longer (t18.806 = -5.862, P < .001) but were more concise (t32 = 11.297, P < .001) for the SNAPPS group than for the usual and customary group. The SNAPPS group performed better on both the case summary subscale (t32 = 2.857, P = .007) and the clinical reasoning subscale (t25.773 = -14.162, P < .001) than the other group. We found a time effect for Diagnostic Thinking Inventory scores (F1,34 = 6.230, P = .02) but observed no group effects (F1,34 = 0.698, P = .41) or time-by group interaction (F1,34 = 1.050, P = .31). The Reflection in Learning Scale scores analysis revealed no group-by-time interaction (F1,34 = 1.470, P = .23) and no group (F1,34 = 3.751, P = .06) or time (F1,34 = 0.835, P = .37) effects. CONCLUSIONS: The SNAPPS is an effective and feasible clinical education technique for case presentations. This learner-centered technique provides the opportunity for the expression of clinical reasoning skills. PMID- 23675797 TI - Injury rehabilitation overadherence: preliminary scale validation and relationships with athletic identity and self-presentation concerns. AB - CONTEXT: Evidence suggests that nonadherence to rehabilitation protocols may be associated with worse clinical and functional rehabilitation outcomes. Recently, it has been recognized that nonadherence may not only reflect a lack of rehabilitation engagement but that some athletes may "overadhere" to their injury rehabilitation regimen or risk a premature return to sport. Presently, no measure of overadherence exists, and correlates of overadherence and risking a premature return to sport remain uncertain. OBJECTIVE: To provide initial validation of a novel injury-rehabilitation overadherence measure (study 1) and to examine correlates of overadherence and risking a premature return to sport (study 2). DESIGN: Cross-sectional study. SETTING: High school athletes (study 1) and collegiate athletes (study 2). PATIENTS OR OTHER PARTICIPANTS: In study 1, 118 currently injured US adolescent athletes competing in a range of high school sports participated. In study 2, 105 currently injured collegiate athletes (National Collegiate Athletic Association Divisions I-III) volunteered. MAIN OUTCOME MEASURE(S): The Rehabilitation Overadherence Questionnaire was a novel instrument developed to assess injured athletes' tendency toward overadherence behaviors and beliefs. We used an adapted version of the Injury Psychological Readiness to Return to Sport Scale to assess the tendency to risk a premature return to sport. RESULTS: In study 1, the construct validity of the overadherence measure was supported using principal axis factoring. Moreover, bivariate correlation and regression analyses indicated that self-presentation concerns and athletic identity were positive predictors of adolescent rehabilitation overadherence and a premature return to sport. Study 2 provided support for the 2 factor structure of the overadherence measure found in study 1 via confirmatory factor analysis. Further support for the relationship among self-presentation concerns, athletic identity, and rehabilitation overadherence was also noted. CONCLUSIONS: The Rehabilitation Overadherence Questionnaire is a valid and reliable measure of overadherence. PMID- 23675798 TI - Perceptions of approved clinical instructors: barriers in the implementation of evidence-based practice. AB - CONTEXT: As evidence-based practice (EBP) becomes prevalent in athletic training education, the barriers that Approved Clinical Instructors (ACIs) experience in implementing it with students need to be understood. OBJECTIVE: To investigate barriers ACIs face when implementing EBP concepts in clinical practice and in teaching EBP to professional athletic training students and to investigate the educational emphases to improve the barriers. DESIGN: Qualitative study. SETTING: Telephone interviews. PATIENTS OR OTHER PARTICIPANTS: Sixteen ACIs (11 men, 5 women; experience as an athletic trainer = 10 +/- 4.7 years, experience as an ACI = 6.81 +/- 3.9 years) were interviewed. DATA COLLECTION AND ANALYSIS: We interviewed each participant by telephone. Interview data were analyzed and coded for common themes and subthemes regarding barriers and educational emphases. Themes were triangulated through multiple-analyst triangulation and interpretive verification. RESULTS: Barriers to EBP incorporation and educational emphasis placed on EBP were the main themes reported. Resources, personnel, and student characteristics were subthemes identified as barriers. Resource barriers included time, equipment, access to current literature, and knowledge. Coworkers, clinicians, and coaches who were unwilling to accept evidence regarding advancements in treatment were identified as personnel barriers. Programmatic improvement and communication improvement were subthemes of the educational emphasis placed on EBP theme. The ACIs reported the need for better integration between the clinical setting and the classroom and expressed the need for EBP to be integrated throughout the athletic training education program. CONCLUSIONS: Integration of the classroom and clinical experience is important in advancing ACIs' use of EBP with their students. Collaborative efforts within the clinical and academic program could help address the barriers ACIs face when implementing EBP. This collaboration could positively affect the ability of ACIs to implement EBP within their clinical practices. PMID- 23675799 TI - Use of evidence-based practice among athletic training educators, clinicians, and students, part 1: perceived importance, knowledge, and confidence. AB - CONTEXT: Although evidence-based practice (EBP) has become more prevalent, athletic trainers' perceptions of importance and knowledge of these concepts and their confidence in EBP are largely unknown. OBJECTIVE: To assess perceived importance and knowledge of and confidence in EBP concepts in athletic trainers in various roles and with different degree levels. DESIGN: Cross-sectional study. SETTING: Online survey instrument. PATIENTS OR OTHER PARTICIPANTS: The survey was sent to 6702 athletic training educators, clinicians, and postprofessional students. A total of 1209 completed the survey, for a response rate of 18.04%. MAIN OUTCOME MEASURE(S): Demographic information and perceived importance and knowledge of and confidence in the steps of EBP were obtained. One-way analysis of variance, a Kruskal-Wallis test, and an independent-samples t test were used to determine differences in scores among the demographic variables. RESULTS: Athletic trainers demonstrated low knowledge scores (64.2% +/- 1.29%) and mild to moderate confidence (2.71 +/- 0.55 out of 4.0). They valued EBP as moderately to extremely important (3.49 +/- 0.41 out of 4.0). Perceived importance scores differed among roles (clinicians unaffiliated with an education program scored lower than postprofessional educators, P = .001) and highest educational degree attained (athletic trainers with terminal degrees scored higher than those with bachelor's or master's degrees, P < .001). Postprofessional athletic training students demonstrated the highest total EBP knowledge scores (4.65 +/- 0.91), whereas clinicians demonstrated the lowest scores (3.62 +/- 1.35). Individuals with terminal degrees had higher (P < .001) total knowledge scores (4.31 +/- 1.24) than those with bachelor's (3.78 +/- 1.2) or master's degrees (3.76 +/- 1.35). Postprofessional educators demonstrated greater confidence in knowledge scores (3.36 +/- 0.40 out of 4.0) than did those in all other athletic training roles (P < .001). CONCLUSIONS: Overall knowledge of the basic EBP steps remained low across the various athletic trainers' roles. The higher level of importance indicated that athletic trainers valued EBP, but this value was not reflected in the knowledge of EBP concepts. Individuals with a terminal degree possessed higher knowledge scores than those with other educational preparations; however, EBP knowledge needs to increase across all demographics of the profession. PMID- 23675800 TI - Use of evidence-based practice among athletic training educators, clinicians, and students, part 2: attitudes, beliefs, accessibility, and barriers. AB - CONTEXT: Successful implementation of evidence-based practice (EBP) within athletic training is contingent upon understanding the attitudes and beliefs and perceived barriers toward EBP as well as the accessibility to EBP resources of athletic training educators, clinicians, and students. OBJECTIVE: To assess the attitudes, beliefs, and perceived barriers toward EBP and accessibility to EBP resources among athletic training educators, clinicians, and students. DESIGN: Cross-sectional study. SETTING: Online survey instrument. PATIENTS OR OTHER PARTICIPANTS: A total of 1209 athletic trainers participated: professional athletic training education program directors (n = 132), clinical preceptors (n = 266), clinicians (n = 716), postprofessional athletic training educators (n = 24) and postprofessional students (n = 71). MAIN OUTCOME MEASURE(S): Likert-scale items (1 = strongly disagree, 4 = strongly agree) assessed attitudes and beliefs and perceived barriers, whereas multipart questions assessed accessibility to resources. Kruskal-Wallis H tests (P <= .05) and Mann-Whitney U tests with a Bonferroni adjustment (P <= .01) were used to determine differences among groups. RESULTS: Athletic trainers agreed (3.27 +/- 0.39 out of 4.0) that EBP has various benefits to clinical practice and disagreed (2.23 +/- 0.42 out of 4.0) that negative perceptions are associated with EBP. Benefits to practice scores (P = .002) and negative perception scores (P < .001) differed among groups. With respect to perceived barriers, athletic trainers disagreed that personal skills and attributes (2.29 +/- 0.52 out of 4.0) as well as support and accessibility to resources (2.40 +/- 0.40 out of 4.0) were barriers to EBP implementation. Differences were found among groups for personal skills and attributes scores (P < .001) and support and accessibility to resources scores (P < .001). Time (76.6%) and availability of EBP mentors (69.6%) were the 2 most prevalent barriers reported. Of the resources assessed, participants were most unfamiliar with clinical prediction rules (37.6%) and Cochrane databases (52.5%); direct access to these 2 resources varied among participants. CONCLUSIONS: Athletic trainers had positive attitudes toward the implementation of EBP within didactic education and clinical practice. However, accessibility and resource use remained low for some EBP-related resources. Although the perceived barriers to implementation are minimal, effective integration of EBP within athletic training will present challenges until these barriers dissolve. PMID- 23675801 TI - Athletic trainer perceptions of life-work balance and parenting concerns. AB - CONTEXT: Life-work balance may be one reason for retention concerns among athletic trainers (ATs), yet evidence does not exist to support the supposition. OBJECTIVE: To assess the perceptions of ATs regarding life-work balance, specifically on parenting issues. DESIGN: Survey. SETTING: Online survey at www.surveymonkey.com . PATIENTS OR OTHER PARTICIPANTS: A random sample of National Athletic Trainers' Association members (N = 9516) received the survey; 20.6% (n = 1962; male = 954, female = 816; age = 37 +/- 10 years, experience = 13 +/- 9 years) completed any portion of the survey. Most respondents worked in the college/university (34.5%, n = 657 of 1908) and secondary school settings (25.9%, n = 476 of 1908). A majority of participants (50.7%, n = 898 of 1770) were parents. INTERVENTION(S): We calculated frequencies and percentages and used Mann Whitney U tests and Kruskal-Wallis tests to identify the differences between sexes and among job settings on life-work balance measures among parents. MAIN OUTCOME MEASURES: The questionnaire included 8 life-work balance items, 7 parenting challenge items, and 3 nonparent items. RESULTS: The results indicate that sex and setting significantly affected perceptions about parenting. Males articulated a stronger sense of difficulty in finding balance as a working parent (P < .001; 1.95 +/- 1.98). Females felt more strongly than males that managing work and family was stressful (P = .04; 3.86 +/- 1.13) and caused burnout (P = .004; 3.50 +/- 1.24), and that their energy tended to fall short of their needs (P < .001; 3.74 +/- 1.15). The decision not to have children was strongly affected by the work setting (P = .014; 3.37 +/- 1.42). Both college/university (4.14 +/- 0.85) and secondary school (4.03 +/- 0.90) ATs would prefer to spend more time at home, as compared with ATs in other settings (P < .001). College/university ATs (P = .025; 3.17 +/- 1.23) felt most strongly that their families were neglected because of work. In none of the settings did ATs feel that their employment settings were particularly tolerant of their parenting responsibilities (P = .027; 1.72 +/- 1.97). CONCLUSIONS: Male and female employees had similar perceptions of life-work balance, but occupational setting may affect these perceptions. PMID- 23675802 TI - Perceptions of wellness and burnout among certified athletic trainers: sex differences. AB - CONTEXT: Athletic trainers are exposed to various stressors, increasing the potential for burnout and decreasing perceived wellness. Burnout and decreased perceived wellness can result from many factors: years of experience, hours per week worked, or decreased levels of physical activity. Another factor that accounts for a portion of the variance is sex differences. OBJECTIVE: To determine the differences in burnout, physical activity, and perceived wellness scores relating to sex in District 9 of the National Athletic Trainers' Association (NATA). DESIGN: Cross-sectional study. SETTING: Web-based questionnaire. PATIENTS OR OTHER PARTICIPANTS: Athletic trainers who were included in the e-mail directory of NATA District 9 (men = 232, women = 158). INTERVENTION(S): A 19-item questionnaire for burnout, a 36-item questionnaire for perceived wellness, and a 16-item activity questionnaire for physical activity and demographics. MAIN OUTCOME MEASURE(S): The variables included demographics (hours per week worked, years of experience, sex), Copenhagen Burnout Inventory (CBI; scores range from 0-100, and higher scores represent a higher level of burnout), Perceived Wellness Survey (PWS; scores range from 1-36, and scores close to 29 are considered healthy), and Baecke Physical Activity Questionnaire (BPAQ; scores range from 1-15, and higher scores represent more physical activity). RESULTS: Of the 1560 members contacted, 390 responded (response rate = 25%), and 59.5% (n = 232) were male. The mean scores were 38.73 +/- 16.9 for men and 46.2 +/- 17.1 for women for the CBI, 16.68 +/- 2.76 for men and 16.41 +/- 2.81 for women for the PWS, and 8.42 +/- 1.32 for men and 8.77 +/- 1.36 for women for the BPAQ. Men and women worked an average of 55.60 +/- 26.03 and 47.86 +/- 20.57 hours per week, respectively, and had a mean experience of 14.79 +/- 9.86 and 8.92 +/- 6.51 years, respectively. Women reported a higher level of burnout (t388 = -4.255, P = .001) and greater levels of physical activity (t388 = -2.52, P = .01) than men. Men reported working more hours (t388 = 3.131, P = .002) and having more years of experience (t388 = 6.568, P = .001) than women. Perceived wellness was not different between sexes (t388 = 0.958, P = .34). CONCLUSIONS: Our results suggest that women experienced moderate to high burnout and men experienced moderate burnout. Interestingly, men reported lower levels of burnout but worked more hours than women. Future researchers should focus on why women experience higher levels of burnout but work fewer hours. These findings may lead to educational interventions that might reduce burnout and increase professional longevity and quality of work. PMID- 23675803 TI - Factor V leiden thrombophilia in a female collegiate soccer athlete: a case report. AB - OBJECTIVE: To raise awareness among health care providers caring for an active population to an uncommon genetic mutation that increases the risk for a potentially fatal venous thromboembolism. BACKGROUND: A 19-year-old previously healthy female collegiate soccer athlete complained of coughing and progressively decreased exercise tolerance, which were attributed to a recent illness and lack of sleep. Later that evening, she complained of dyspnea and pleuritic pain and was referred to the emergency department. Bilateral pulmonary emboli were identified with computed tomography, and a hypercoagulable panel revealed that the patient was heterozygous for the factor V Leiden mutation. DIFFERENTIAL DIAGNOSIS: Pneumonia, pneumothorax, pericarditis, pleuritis, gastroesophageal reflux disease, pulmonary embolism. TREATMENT: Intravenous heparin therapy was initiated immediately in the emergency department. This was followed by inpatient anticoagulant therapy for 5 days and outpatient anticoagulant therapy for an additional 12 months. During this time, the patient was unable to participate in soccer drills or return to competition and was limited to conditioning activities due to the risk of increased bleeding time. UNIQUENESS: Documented cases of pulmonary embolism in a young athletic population are rare and are usually associated with genetic risk factors. Factor V Leiden is a relatively uncommon genetic mutation that dramatically increases the risk for venous thromboembolism. Although the fatality rate in this population is low, fatality is preventable if the condition is recognized early and managed properly. CONCLUSIONS: Athletes should be encouraged to communicate with their athletic trainers regarding any changes in health status or medication usage. When an athlete presents with nonspecific symptoms such as dyspnea and chest pain, athletic trainers should consider the possibility of pulmonary embolism. A high degree of suspicion results in early diagnosis and treatment and may prevent a fatal event. PMID- 23675805 TI - Two cases with hepatic amyloidosis suspected of having primary sclerosing cholangitis. AB - Sclerogenic biliary changes in hepatic amyloidosis are seldom observed. Here, we report two recent cases initially suspected as primary sclerosing cholangitis (PSC), which were later diagnosed as hepatic amyloidosis (AL type). Case 1: On the basis of magnetic resonance cholangiopancreatography (MRCP) findings, PSC was suspected in a 41-year-old woman with jaundice. Computed tomography (CT) showed nodular pulmonary lesions and swollen cervical, mediastinal and para-aortic lymph nodes, the cause of which was unknown despite detailed examinations. Because of rapid deterioration in the patient's liver function, living donor liver transplantation was performed. She was then diagnosed with hepatic amyloidosis, but died of heart failure due to cardiac amyloidosis 74 days after surgery. Case 2: On the basis of MRCP findings, PSC was suspected in a 49-year-old woman with jaundice. CT showed multiple cystic pulmonary lesions, and hypogammaglobulinemia was also observed (immunoglobulin G, 481 mg/dL). After a biliary plastic stent was placed, liver and lung biopsy confirmed the presence of amyloid deposition. These two cases indicate that it is important to consider hepatic amyloidosis as a differential diagnosis of PSC. The presence of atypical extrahepatic lesions may be useful clues for confirming the diagnosis. PMID- 23675804 TI - De novo CD5-positive diffuse large B-cell lymphomas show high specificity for cyclin D2 expression. AB - D cyclins positively regulate the cell cycle and mediate the pathogenesis of some lymphomas. Cyclin D1 overexpression is the hallmark of mantle cell lymphoma, whereas cyclins D2 and D3 are reportedly not as specific to certain lymphomas as cyclin D1. In this study, cyclin D2 was found to be overexpressed in 98% of de novo CD5-positive diffuse large B-cell lymphomas (DLBCLs) (50/51) and in 28% of CD5-negative DLBCLs (14/51). A statistically significant difference was observed between these two groups (p<0.0001). In contrast, no statistical difference was found in the cyclin D3 expression between CD5-positive (18/51) and CD5-negative (24/51) DLBCLs (p=0.23). Based on these findings, cyclin D2 is therefore considered to be closely associated with de novo CD5-positive DLBCLs. This insight may be useful for overcoming the inferior survival of this aggressive lymphoma. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1382856320966453. PMID- 23675806 TI - Doses of erythemal ultraviolet radiation observed in Brazil. AB - Non-melanoma skin cancer represents a quarter of the new cancer cases detected in Brazil. Despite the importance of this issue to public health, there are deficits in knowledge on the local UV radiation levels among physicians. In this work, we evaluate a set of daily erythemal UV doses measured in different Brazilian locations. Very high erythemal UV doses that often exceeded safe amounts were observed over almost the whole year, even during the time interval usually recommended as safe (before 10:00 h and after 16:00 h). These findings will hopefully enable foreign tourists, dermatologists, and decision-makers to implement new measures for solar protection according to South American standards. PMID- 23675807 TI - Optimization and automation of quantitative NMR data extraction. AB - NMR is routinely used to quantitate chemical species. The necessary experimental procedures to acquire quantitative data are well-known, but relatively little attention has been applied to data processing and analysis. We describe here a robust expert system that can be used to automatically choose the best signals in a sample for overall concentration determination and determine analyte concentration using all accepted methods. The algorithm is based on the complete deconvolution of the spectrum which makes it tolerant of cases where signals are very close to one another and includes robust methods for the automatic classification of NMR resonances and molecule-to-spectrum multiplets assignments. With the functionality in place and optimized, it is then a relatively simple matter to apply the same workflow to data in a fully automatic way. The procedure is desirable for both its inherent performance and applicability to NMR data acquired for very large sample sets. PMID- 23675808 TI - Non-echo planar diffusion-weighted MRI increases follow-up accuracy after one step step canal wall-down obliteration surgery for cholesteatoma. AB - CONCLUSION: Non-echo planar (non-EPI) diffusion-weighted (DW) magnetic resonance imaging (MRI) increases the number of detected cholesteatoma after one-step canal wall-down (CWD) obliteration surgery for cholesteatoma compared with clinical evaluation alone. OBJECTIVE: To evaluate the use of DW-MRI for detection of cholesteatoma after surgical treatment using a CWD obliteration technique. METHODS: Thirty-eight adult patients (41 ears) treated with an identical one-step CWD obliteration surgical technique were included in a prospective and blinded study. All patients were investigated with non-EPI and EPI DW-MRI 1-9 months after the clinical examination. Follow-up time after primary surgery varied between 10 and 234 months. DW-MRI was assessed by two neuroradiologists and compared with clinical results. Inter-rater agreement was calculated. Positive non-EPI DW-MRI cases underwent revision surgery within 18-159 days after imaging. RESULTS: Seven of 41 cases were evaluated as positive for cholesteatoma on non EPI DW-MRI. Since one patient refused surgery six of these seven cases underwent surgical revision and all were verified. There was agreement between clinical and non-EPI findings in five of eight cases. EPI findings correlated poorly with non EPI and clinical findings. Inter-rater agreement (Cohen's kappa) was 0.91 for non EPI DW-MRI (p < 0.001) and -0.062 for EPI DW-MRI (p = 0.43). PMID- 23675809 TI - Psychological condition in patients with intractable Meniere's disease. AB - CONCLUSIONS: Physicians should consider additional treatment strategies for Meniere's disease patients with a long history of disease and hearing loss in the secondary affected ear and also provide psychological support regarding future progressive bilateral hearing loss. OBJECTIVES: To treat intractable Meniere's disease patients effectively, we need to understand the psychological condition of each patient. We examined the state of neurosis and depression in patients and correlated this with demographic and background information. METHODS: Between 1998 and 2009, we enrolled 207 patients with intractable Meniere's disease in this prospective study. We used the Cornell Medical Index and the Self-rating Depression Scale to evaluate their psychological condition. We also obtained demographic and background information relating to sex, age, duration of disease, vertigo frequency, hearing level in bilateral sides, and plasma vasopressin level. RESULTS: Neurosis and depression was diagnosed in 40.1% and 60.4%, respectively, of patients with intractable Meniere's disease. Our results showed that surgical treatment significantly improved vertigo and hearing ability in patients with no psychological symptoms compared with those exhibiting psychological symptoms. Patients with a longer duration and worse hearing level in the secondary affected ear had a significantly higher incidence of mental illness than those with a shorter duration and better level of hearing. PMID- 23675810 TI - Pseudo-anterior canalolithiasis. AB - CONCLUSION: Because nystagmus induced by ampullopetal inhibition of the posterior semicircular canal (PSCC) rotates around the axis perpendicular to the plane of the anterior semicircular canal (ASCC) of the other side, when free-floating debris is initially located at the distal portion of the PSCC, a patient showing positional nystagmus appears to have the ASCC type of benign paroxysmal positional nystagmus. We name this 'pseudo-anterior canalolithiasis'. OBJECTIVE: We report on pseudo-anterior canalolithiasis originating in the PSCC and discuss the differential findings between pseudo-anterior and true anterior canalolithiasis by means of three-dimensional (3D) analysis of the positional nystagmus. METHODS: We performed 3D analysis of the positional nystagmus in a patient with true anterior canalolithiasis and in another patient with pseudo anterior canalolithiasis. RESULTS: In the patient with true anterior canalolithiasis, the direction of positional nystagmus during reverse Epley maneuver was constant and its axis was perpendicular to the plane of the right ASCC three-dimensionally. In contrast, in the patient with pseudo-anterior canalolithiasis, the first positional nystagmus of which the axis was perpendicular to the plane of the left ASCC became a second positional nystagmus of which the axis was perpendicular to the plane of the right PSCC during the reverse Epley maneuver. PMID- 23675811 TI - Changes in brainstem auditory response threshold in preterm babies from birth to late term. AB - CONCLUSION: The hearing threshold in preterm infants was 23 dB above adult hearing level at 30 weeks gestation, and decreased to around 13 dB at term date. There was no major difference in the threshold for infants born at different gestations. At term, 9% had hearing threshold elevation. OBJECTIVE: To examine changes in hearing threshold from preterm to term in infants born at 30-36 weeks gestation and to detect the prevalence of threshold elevation. METHODS: The threshold in brainstem auditory evoked response (BAER) was obtained 656 times from postconceptional age (PCA) 30 to 42 weeks in 268 infants born at 30-36 weeks gestation. RESULTS: The BAER threshold was 23 dB nHL at the youngest age (PCA 30 weeks), and then decreased to around 13 dB nHL at later preterm and term dates (PCA 35-42 weeks). The threshold was decreased with increasing age at a rate of 1.24 dB per week from PCA 30 to 36 weeks and 0.65 dB per week from PCA 30 to 42 weeks. At PCA 33-42 weeks, there were no significant differences in BAER threshold between the infants born at gestational age (GA) 30-32 weeks and those at GA 33-36 weeks. At term, 9% had threshold elevation (>20 dB nHL). PMID- 23675812 TI - Active middle ear implants: VibroplastyTM in children and adolescents with acquired or congenital middle ear disorders. AB - CONCLUSION: Active middle ear implant (AMEI) implantation in children and adolescents is safe and provides improved hearing results. No statistical difference in hearing outcomes was shown in the group of patients affected by chronic middle ear diseases versus aural atresia. Also, the transducer location (round window versus oval window placement) did not lead to different outcomes in hearing abilities. OBJECTIVES: (1) To assess the hearing outcomes with the active implant Vibrant Soundbridge (VSB) in children and adolescents. (2) To evaluate whether functional results of the subjects in the study could depend on the hearing loss etiology (chronic middle ear diseases versus aural atresia) or on transducer location (round window versus oval window placement). METHODS: The study was carried out with a retrospective, single-subject, repeated measures design, and included 22 children and adolescents with conductive or mixed hearing loss due to aural atresia or chronic middle ear diseases. Preoperative and postoperative pure tone air conduction (AC) and bone conduction (BC) thresholds were measured to demonstrate implantation safety. Free-field warble tone and speech audiometry were performed to assess postoperative hearing abilities with and without the VSB. RESULTS: No significant changes in mean BC or AC thresholds between preoperative and postoperative conditions were seen in the 22 patients. Mean PTA4 functional gain was 30.7 dB. Averaged over all 22 patients, word recognition at 65 dB SPL changed from an average of 19% in the unaided postoperative condition to 97% in the VSB-aided condition. Functional results were independent of hearing loss etiology and transducer location. PMID- 23675813 TI - Influence of facial paresis on ocular vestibular-evoked myogenic potentials. AB - CONCLUSION: The ocular vestibular-evoked myogenic potential (oVEMP) test with eyes up condition may help differentiate facial paresis with and without vestibular nerve deficit, while the oVEMP test with the eyes closed condition is not reliable for testing patients with facial paresis. OBJECTIVE: This study investigated the influence of facial paresis on oVEMPs via the eyes up versus eyes closed conditions. METHODS: Twenty patients with unilateral facial paresis underwent a battery of audiovestibular function tests. The oVEMP test was performed via bone-conducted vibration stimuli with the eyes up and eyes closed conditions used in a randomized order. RESULTS: Under the eyes up condition, the rate of abnormal oVEMP tests in the lesion ear was 30%, significantly higher than the 0% in the opposite healthy ear, indicating that the lesion ear not the recorded eye is responsible for abnormal oVEMPs. However, abnormal oVEMP test results of lesion ears under the eyes closed condition did not significantly differ from those of opposite healthy ears. Analysis of caloric and oVEMP test results indicated that both tests obtained normal responses from 10 ears, and abnormal responses from 5 ears. The caloric and oVEMP test results were significantly correlated. PMID- 23675814 TI - Validation of a Swedish version of the Facial Disability Index (FDI) and the Facial Clinimetric Evaluation (FaCE) scale. AB - CONCLUSION: Swedish versions of the Facial Disability Index (FDI) and Facial Clinimetric Evaluation (FaCE) scale are psychometrically valid. Both questionnaires can be used for clinical studies on peripheral facial palsy patients, and provide important information on quality of life. OBJECTIVES: To translate and validate Swedish versions of the FDI and FaCE scale in patients with peripheral facial palsy. METHODS: Translation of the original questionnaires followed international guidelines. Internal consistency and test-retest stability were assessed in adult patients with stable peripheral facial palsy. Facial function was examined with the Sunnybrook and House-Brackmann scales. Subjects answered the questionnaires twice with a 2-week interval. Validity was assessed by comparing FDI and FaCE scale scores to SF-36 and Sunnybrook/House-Brackmann scores. RESULTS: Ninety-three patients were included, 53% women and 47% men, mean age 56.9 years and mean duration of palsy 51.9 months. The questionnaires showed good/excellent psychometric properties with Cronbach's alpha scores between 0.76 and 0.92. In the test-retest analysis, intra-class correlation coefficients were very good for both questionnaires with scores of 0.83-0.97. Both questionnaires showed good sensitivity to discriminate between patients with varying degrees of facial dysfunction. Moderate to strong correlation was found between the social domains in the questionnaires when compared with the equivalent domains in SF-36. PMID- 23675816 TI - Periorbital adenocarcinoma in a bearded dragon (Pogona vitticeps). AB - A 4.5-year-old female bearded dragon (Pogona vitticeps) presented for periorbital swelling affecting the left eye. A well-organized, hypoechoic mass was noted ventral and medial to the globe on ocular ultrasound. The mass continued to grow despite antibiotic therapy, and an exenteration was performed. The mass was diagnosed via histopathology and immunohistochemical staining as a probable lacrimal gland carcinoma, although a Harderian gland origin could not definitively be ruled out. The tumor recurred following removal, and the lizard died 2 months postoperatively. PMID- 23675819 TI - Repetition priming effects dissociate between miniature eye movements and induced gamma-band responses in the human electroencephalogram. AB - The role of induced gamma-band responses (iGBRs) in the human electroencephalogram (EEG) is a controversial topic. On the one hand, iGBRs have been associated with neuronal activity reflecting the (re-)activation of cortical object representations. On the other hand, it was shown that miniature saccades (MSs) lead to high-frequency artifacts in the EEG that can mimic cortical iGBRs. We recorded EEG and eye movements simultaneously while participants were engaged in a combined repetition priming and object recognition experiment. MS rates were mainly modulated by object familiarity in a time window from 100 to 300 ms after stimulus onset. In contrast, artifact-corrected iGBRs were sensitive to object repetition and object familiarity in a prolonged time window. EEG source analyses revealed that stimulus repetitions modulated iGBRs in temporal and occipital cortex regions while familiarity was associated with activity in parieto occipital regions. These results are in line with neuroimaging studies employing functional magnetic resonance imaging or magnetoencephalography. We conclude that MSs reflect early mechanisms of visual perception while iGBRs mirror the activation of cortical networks representing a perceived object. PMID- 23675818 TI - Molecular detection of Rickettsia felis and Candidatus Rickettsia asemboensis in fleas from human habitats, Asembo, Kenya. AB - The flea-borne rickettsioses murine typhus (Rickettsia typhi) and flea-borne spotted fever (FBSF) (Rickettsia felis) are febrile diseases distributed among humans worldwide. Murine typhus has been known to be endemic to Kenya since the 1950s, but FBSF was only recently documented in northeastern (2010) and western (2012) Kenya. To characterize the potential exposure of humans in Kenya to flea borne rickettsioses, a total of 330 fleas (134 pools) including 5 species (Xenopsylla cheopis, Ctenocephalides felis, Ctenocephalides canis, Pulex irritans, and Echidnophaga gallinacea) were collected from domestic and peridomestic animals and from human dwellings within Asembo, western Kenya. DNA was extracted from the 134 pooled flea samples and 89 (66.4%) pools tested positively for rickettsial DNA by 2 genus-specific quantitative real-time PCR (qPCR) assays based upon the citrate synthase (gltA) and 17-kD antigen genes and the Rfelis qPCR assay. Sequences from the 17-kD antigen gene, the outer membrane protein (omp)B, and 2 R. felis plasmid genes (pRF and pRFd) of 12 selected rickettsia-positive samples revealed a unique Rickettsia sp. (n=11) and R. felis (n=1). Depiction of the new rickettsia by multilocus sequence typing (MLST) targeting the 16S rRNA (rrs), 17-kD antigen gene, gltA, ompA, ompB, and surface cell antigen 4 (sca4), shows that it is most closely related to R. felis but genetically dissimilar enough to be considered a separate species provisionally named Candidatus Rickettsia asemboensis. Subsequently, 81 of the 134 (60.4%) flea pools tested positively for Candidatus Rickettsia asemboensis by a newly developed agent-specific qPCR assay, Rasemb. R. felis was identified in 9 of the 134 (6.7%) flea pools, and R. typhi the causative agent of murine typhus was not detected in any of 78 rickettsia-positive pools assessed using a species-specific qPCR assay, Rtyph. Two pools were found to contain both R. felis and Candidatus Rickettsia asemboensis DNA and 1 pool contained an agent, which is potentially new. PMID- 23675820 TI - The evolution of mammal body sizes: responses to Cenozoic climate change in North American mammals. AB - Explanations for the evolution of body size in mammals have remained surprisingly elusive despite the central importance of body size in evolutionary biology. Here, we present a model which argues that the body sizes of Nearctic mammals were moulded by Cenozoic climate and vegetation changes. Following the early Eocene Climate Optimum, forests retreated and gave way to open woodland and savannah landscapes, followed later by grasslands. Many herbivores that radiated in these new landscapes underwent a switch from browsing to grazing associated with increased unguligrade cursoriality and body size, the latter driven by the energetics and constraints of cellulose digestion (fermentation). Carnivores also increased in size and digitigrade, cursorial capacity to occupy a size distribution allowing the capture of prey of the widest range of body sizes. With the emergence of larger, faster carnivores, plantigrade mammals were constrained from evolving to large body sizes and most remained smaller than 1 kg throughout the middle Cenozoic. We find no consistent support for either Cope's Rule or Bergmann's Rule in plantigrade mammals, the largest locomotor guild (n = 1186, 59% of species in the database). Some cold-specialist plantigrade mammals, such as beavers and marmots, showed dramatic increases in body mass following the Miocene Climate Optimum which may, however, be partially explained by Bergmann's rule. This study reemphasizes the necessity of considering the evolutionary history and resultant form and function of mammalian morphotypes when attempting to understand contemporary mammalian body size distributions. PMID- 23675817 TI - DNA A-tracts are not curved in solutions containing high concentrations of monovalent cations. AB - The intrinsic curvature of seven 98 bp DNA molecules containing up to four centrally located A6-tracts has been measured by gel and capillary electrophoresis as a function of the number and arrangement of the A-tracts. At low cation concentrations, the electrophoretic mobility observed in polyacrylamide gels and in free solution decreases progressively with the increasing number of phased A-tracts, as expected for DNA molecules with increasingly curved backbone structures. Anomalously slow electrophoretic mobilities are also observed for DNA molecules containing two pairs of phased A tracts that are out of phase with each other, suggesting that out-of-phase distortions of the helix backbone do not cancel each other out. The mobility decreases observed for the A-tract samples are due to curvature, not cation binding in the A-tract minor groove, because identical free solution mobilities are observed for a molecule with four out-of-phase A-tracts and one with no A tracts. Surprisingly, the curvature of DNA A-tracts is gradually lost when the monovalent cation concentration is increased to ~200 mM, regardless of whether the cation is a hydrophilic ion like Na+, NH4+, or Tris+ or a hydrophobic ion like tetrabutylammonium. The decrease in A-tract curvature with increasing ionic strength, along with the known decrease in A-tract curvature with increasing temperature, suggests that DNA A-tracts are not significantly curved under physiological conditions. PMID- 23675821 TI - Conformational analysis of octopamine and synephrine in the gas phase. AB - Four and six conformers of the neurotransmitters octopamine and synephrine, respectively, have been identified in the gas phase using a laser ablation device in combination with a molecular-beam Fourier transform microwave spectrometer operating in the 4-10 GHz frequency range. The identification of all of the conformers was based on a comparison of the experimental rotational and (14)N quadrupole coupling constants with those predicted by ab initio calculations, as well as the relative values of their electric dipole moment components. The conformational preferences have been rationalized in terms of the various intramolecular forces operating in the different conformers of the studied molecules. All observed species are characterized by an intramolecular hydrogen bond of the type O-H...N established in the side chain of the neurotransmitters, which adopts an extended disposition in their most stable forms. For conformers with a folded side chain, an extra N-H...pi hydrogen-bond-type interaction is established between the amino group and the pi system of the aromatic ring. PMID- 23675822 TI - Boltzmann's H-function and diffusion processes. AB - There exists a generalization of Boltzmann's H-function that allows for nonuniformly populated stationary states, which may exist far from thermodynamic equilibrium. Here we describe a method for obtaining a generalized or collective diffusion coefficient D directly from this H-function, the only constraints being that the relaxation process is Markov (short memory), continuous in the reaction coordinate, and local in the sense of a flux/force relationship. As an application of this H-function method, we simulate the self-consistent extraction of D via Langevin/Fokker-Planck (L/FP) dynamics on various potential energy landscapes. We observe that the initial epoch of relaxation, which is far removed from the stationary state, provides the most reliable estimates of D. The construction of an H-function that guarantees conformity with the second law of thermodynamics has been generalized to allow for diffusion coefficients that may depend on both the reaction coordinate and time, and the extension to an arbitrary number of reaction coordinates is straightforward. For this multidimensional case, the diffusion tensor must be positive definite in the sense that its eigenvalues must be real and positive. To illustrate the behavior of the proposed collective diffusion coefficient, we simulate the H-function for a variety of Langevin systems. In particular, the impacts on H and D of landscape shape, sample size, selection of an initial distribution, finite dynamic observation range, stochastic correlations, and short/long-term memory effects are examined. PMID- 23675823 TI - Chemical modification of polymer brushes via nitroxide photoclick trapping. AB - The preparation of polymer brushes (PBs) bearing alpha-hydroxyalkylphenylketone (2-hydroxy-2-methyl-1-phenylpropan-1-one) moieties as photoreactive polymer backbone substituents is presented. Photoreactive polymer brushes with defined thicknesses (up to 60 nm) and high grafting densities are readily prepared by surface initiated nitroxide mediated radical polymerization (SINMP). The photoactive moieties can be transformed via Norrish-type I photoreaction to surface-bound acyl radicals. Photolysis in the presence of a persistent nitroxide leads to chemically modified PBs bearing acylalkoxyamine moieties as side chains resulting from trapping of the photogenerated acyl radicals with nitroxides. Application of functionalized nitroxides to the photochemical PB postmodification provides functionalized PBs bearing cyano, polyethylene glycol (PEG), perfluoroalkyl, and biotin moieties. As shown for one case, photochemical postfunctionalization of the PB through a mask using a biotin-conjugated nitroxide as the trapping reagent leads to the corresponding site-selective chemically modified PB, which is successfully used for site-specific streptavidin immobilization. Surface analysis of PBs was performed by contact angle (CA) measurements, X-ray photoelectron spectroscopy (XPS), attenuated total reflection (ATR), fourier transform infrared (FTIR) spectroscopy, and fluorescence microscopy. PMID- 23675824 TI - A study of regional variation in the inpatient cost of lower extremity amputation among patients with diabetes in the United States. AB - OBJECTIVE: Understanding of the effects of providers' cost on regional variation in healthcare spending is still very limited. The objective of this study is to assess cross-state and cross-region variations in inpatient cost of lower extremity amputation among diabetic patients (DLEA) in relation to patient, hospital, and state factors. METHODS: Patient and hospital level data were obtained from the 2007 US Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project (HCUP). State level data were obtained from the US Census Bureau and the Kaiser Family Foundation websites. Regression models were implemented to analyze the association between in-patient cost and variables at patient, hospital, and state levels. RESULTS: This study analyzed data on 9066 DLEA hospitalizations from 39 states. The mean cost per in-patient stay was $17,103. Four out of the five most costly states were located on the East and West coasts (NY and NJ, CA and OR). Age, race, length of stay, level of amputation, in-patient mortality, primary payer, co-morbidities, and type of hospital were significantly correlated with in-patient costs and explained 55.3% of the cost variance. Based on the means of costs unexplained by those factors, the three West coast states had the highest costs, followed by five Midwestern states, and four Southern states, and Kansas were the least costly. CONCLUSIONS: Over 40% of the variations in DLEA hospital costs could not be explained by major patient-, hospital-, and state-level variables. Further research is needed to examine whether similar patterns exist for other costly surgical procedures among diabetic patients. PMID- 23675825 TI - Bilastine for the treatment of urticaria. AB - INTRODUCTION: Urticaria is a highly prevalent disease among people. First-choice treatment continues to be centred on the second-generation H1 antihistamines, including a wide group of drugs with a better therapeutic index (or risk:benefit ratio) than the classic ones, even in the high, off-label dosage occasionally required in chronic urticaria. Bilastine is a newly registered H1-antihistamine for treatment of allergic rhinoconjunctivitis and urticaria. With established antihistaminic and antiallergic properties, it is widely reviewed in the medical literature; however, to our knowledge, a specific review of bilastine's role in the treatment of urticaria was lacking. AREAS COVERED: This article reviews the medical literature on the effectiveness and safety of bilastine in urticarial syndromes, either spontaneous or inducible, by means of a Medline search from 1990 to present, completed with some nonpublished data provided by the manufacturer. EXPERT OPINION: Once-daily treatment with bilastine 20 mg is effective in managing symptoms and improving patient's quality of life in chronic urticaria, with at least comparable efficacy to levocetirizine. As far as studies in healthy volunteers, clinical assays, and recent clinical experience can establish, bilastine's safety profile is adequate, appearing to be entirely free from cardiovascular effects, and not impairing psychomotor performance or actual driving, even at twice the therapeutic dose. PMID- 23675826 TI - Uptake of di(2-ethylhexyl) phthalate (DEHP) by the plant Benincasa hispida and its use for lowering DEHP content of intercropped vegetables. AB - Uptake of di(2-ethylhexyl) phthalate (DEHP) by the plant Benincasa hispida and its use for topical phytoremediation were investigated by cultivation of plants in DEHP-contaminated environments. The results showed that major plant organs of B. hispida , including leaves, stems, and fruits, readily absorbed DEHP from the air. The amount of DEHP that accumulated in leaves, stems, and fruits was mainly dependent upon exposure time, and most DEHP accumulated in their inner tissues. A single plant of B. hispida with a gourd was able to absorb more than 700 mg of DEHP when it was exposed to DEHP-contaminated air for 6 week. B. hispida reduced air DEHP concentration by 65-76% as the air DEHP concentration ranged from 2351 to 3955 MUg/m3 (high DEHP level) and 85-92% as the air DEHP concentration ranged from 35.1 to 65.3 MUg/m3 (low DEHP level) in greenhouse experiments. When intercropping of B. hispida and Brassica chinensis or Brassica campestris , B. hispida reduced more than 87% of DEHP accumulation in the latter, which indicates that B. hispida has excellent use potential for lowering the DEHP content of intercropped vegetables. PMID- 23675827 TI - Delayed diagnosis of pericardial hematoma compressing the right ventricle after blunt chest trauma. PMID- 23675828 TI - Afro-Caribbean pemphigus: epidemiological data from a 5-year prospective study on the island of Guadeloupe (French West Indies). AB - BACKGROUND: There are no reported epidemiological data regarding autoimmune pemphigus in the Afro-Caribbean population. OBJECTIVES: To present the epidemiology of autoimmune pemphigus on the island of Guadeloupe (French West Indies, 400,736 inhabitants, mostly black Caribbean of African European descent). MATERIALS AND METHODS: Five-year prospective study. Inclusion of the incident cases when directly referred to the Dermatology Department or secondarily referred by their private practice dermatologist once identified by the computerized databases of the Guadeloupian pathology laboratories. RESULTS: World population-standardized incidence was 6.96 (95% CI: 3.41-10.52) for pemphigus vulgaris and 3.75 (95% CI: 1.12-6.39) for pemphigus foliaceus. Patients usually live in the rural countryside, whereas 75% of the population of Guadeloupe Island live in an urban environment. CONCLUSION: We report a high incidence of autoimmune pemphigus in Guadeloupe, especially for the foliaceus type, and the existence of particular epidemiological features such as the rural countryside habitat. PMID- 23675829 TI - Plasma uric acid and tumor volume are highly predictive of outcome in nasopharyngeal carcinoma patients receiving intensity modulated radiotherapy. AB - BACKGROUND: The combined predictive value of plasma uric acid and primary tumor volume in nasopharyngeal carcinoma (NPC) patients receiving intensity modulated radiation therapy (IMRT) has not yet been determined. METHODS: In this retrospective study, plasma uric acid level was measured after treatment in 130 histologically-proven NPC patients treated with IMRT. Tumor volume was calculated from treatment planning CT scans. Overall (OS), progression-free (PFS) and distant metastasis-free (DMFS) survival were compared using Kaplan-Meier analysis and the log rank test, and Cox multivariate and univariate regression models were created. RESULTS: Patients with a small tumor volume (<27 mL) had a significantly better DMFS, PFS and OS than patients with a large tumor volume. Patients with a high post-treatment plasma uric acid level (>301 MUmol/L) had a better DMFS, PFS and OS than patients with a low post-treatment plasma uric acid level. Patients with a small tumor volume and high post-treatment plasma uric acid level had a favorable prognosis compared to patients with a large tumor volume and low post treatment plasma uric acid level (7-year overall OS, 100% vs. 48.7%, P <0.001 and PFS, 100% vs. 69.5%, P <0.001). CONCLUSIONS: Post-treatment plasma uric acid level and pre-treatment tumor volume have predictive value for outcome in NPC patients receiving IMRT. NPC patients with a large tumor volume and low post treatment plasma uric acid level may benefit from additional aggressive treatment after IMRT. PMID- 23675830 TI - Muscle and nerve biopsy for the neurosurgical trainee. AB - BACKGROUND: Nerve and muscle biopsy are common procedures often performed by junior surgical trainees. This educational review article describes the operative details of performing biopsies of muscle and nerve. Indications, pre-operative investigations and complication rates are described to aid in proper patient selection. METHODS: A systematic literature review was performed to identify the indications, surgical techniques and results for nerve and muscle biopsy. RESULTS: The most commonly described techniques involve vastus lateralis muscle, distal sural nerve, median sural nerve/gastrocnemius muscle, superficial peroneal nerve/peroneus brevis muscle and superficial radial nerve. Each technique has its own relative merits and intra-operative anatomical nuances. The yield from each of the techniques varies with the indications and patient selection. Complication rates are low but do vary between the techniques. CONCLUSIONS: Judicious use of pre-operative investigations is required to select out patients whose nerve and muscle biopsy justifies the risk of complications. A thorough knowledge of relevant surgical anatomy and correct specimen handling is paramount to achieving optimal results while avoiding complications. PMID- 23675831 TI - Spinal epidural haematoma; factors influencing outcome. AB - OBJECTIVE: Spinal epidural haematoma (SEH) causing spinal cord compression is potentially a cause of long-term neurological disability. We reviewed the relevant literature with the intention of establishing the factors that influence long-term outcome and the timeframe within which operative intervention must be undertaken for optimal results. METHODS: A total of 1177 papers were identified using PubMed among which 31 papers were selected and analysed. The grades of neurological deficit, pre- and post-operatively, were classified according to the Frankel grade. The timing of surgery was from the onset of first symptoms of incomplete cord lesions and the onset of paraplegia with complete lesions. RESULTS: The two main factors that determine long-term outcome were the degree of neurological deficit at the time of treatment and the timing of surgical intervention. Fifty-six per cent of patients who had 'incomplete SCI' made a full neurological recovery as compared to 27% when the initial injury was 'complete SCI' (Chi square, p < 0.001). Operative intervention within 12 h of onset of symptoms gave the best chance of recovery to 'normal' (Frankel E), even in patients who were paraplegic (Frankel A) pre-operatively. CONCLUSION: Recovery to 'normal', or 'incomplete SCI', is possible with surgical decompression if performed within 12 h, even if the patient is paraplegic pre-operatively. If the diagnosis is suspected, immediate investigations must be undertaken and/or arrangements for appropriate referral must be made urgently to ensure diagnosis and treatment in the tertiary centre within the 12 h window. PMID- 23675832 TI - Universal microfluidic automaton for autonomous sample processing: application to the Mars Organic Analyzer. AB - A fully integrated multilayer microfluidic chemical analyzer for automated sample processing and labeling, as well as analysis using capillary zone electrophoresis is developed and characterized. Using lifting gate microfluidic control valve technology, a microfluidic automaton consisting of a two-dimensional microvalve cellular array is fabricated with soft lithography in a format that enables facile integration with a microfluidic capillary electrophoresis device. The programmable sample processor performs precise mixing, metering, and routing operations that can be combined to achieve automation of complex and diverse assay protocols. Sample labeling protocols for amino acid, aldehyde/ketone and carboxylic acid analysis are performed automatically followed by automated transfer and analysis by the integrated microfluidic capillary electrophoresis chip. Equivalent performance to off-chip sample processing is demonstrated for each compound class; the automated analysis resulted in a limit of detection of ~16 nM for amino acids. Our microfluidic automaton provides a fully automated, portable microfluidic analysis system capable of autonomous analysis of diverse compound classes in challenging environments. PMID- 23675833 TI - Teaching and learning the Hodgkin-Huxley model based on software developed in NEURON's programming language hoc. AB - BACKGROUND: We present a software tool called SENB, which allows the geometric and biophysical neuronal properties in a simple computational model of a Hodgkin Huxley (HH) axon to be changed. The aim of this work is to develop a didactic and easy-to-use computational tool in the NEURON simulation environment, which allows graphical visualization of both the passive and active conduction parameters and the geometric characteristics of a cylindrical axon with HH properties. RESULTS: The SENB software offers several advantages for teaching and learning electrophysiology. First, SENB offers ease and flexibility in determining the number of stimuli. Second, SENB allows immediate and simultaneous visualization, in the same window and time frame, of the evolution of the electrophysiological variables. Third, SENB calculates parameters such as time and space constants, stimuli frequency, cellular area and volume, sodium and potassium equilibrium potentials, and propagation velocity of the action potentials. Furthermore, it allows the user to see all this information immediately in the main window. Finally, with just one click SENB can save an image of the main window as evidence. CONCLUSIONS: The SENB software is didactic and versatile, and can be used to improve and facilitate the teaching and learning of the underlying mechanisms in the electrical activity of an axon using the biophysical properties of the squid giant axon. PMID- 23675834 TI - Ancillary ligand effects upon dithiolene redox noninnocence in tungsten bis(dithiolene) complexes. AB - An expanded set of compounds of the type [W(S2C2Me2)2L1L2](n) (n = 0: L1 = L2 = CO, 1; L1 = L2 = CN(t)Bu, 2; L1 = CO, L2 = carbene, 3; L1 = CO, L2 = phosphine, 4; L1 = L2 = phosphine, 5. n = 2-: L1 = L2 = CN(-), [6](2-)) has been synthesized and characterized. Despite isoelectronic formulations, the compound set reveals gradations in the dithiolene ligand redox level as revealed by intraligand bond lengths, upsilon(CCchelate), and rising edge energies in the sulfur K-edge X-ray absorption spectra (XAS). Differences among the terminal series members, 1 and [6](2-), are comparable to differences seen in homoleptic dithiolene complexes related by full electron transfer to/from a dithiolene-based MO. The key feature governing these differences is the favorable energy of the CO pi* orbitals, which are suitably positioned to overlap with tungsten d orbitals and exert an oxidizing effect on both metal and dithiolene ligand via pi-backbonding. The CN( ) pi* orbitals are too high in energy to mix effectively with tungsten and thus leave the filled dithiolene pi* orbitals unperturbed. This work shows how, and the degree to which, the redox level of a noninnocent ligand can be modulated by the choice of ancillary ligands(s). PMID- 23675835 TI - Transient access to the protein interior: simulation versus NMR. AB - Many proteins rely on rare structural fluctuations for their function, whereby solvent and other small molecules gain transient access to internal cavities. In magnetic relaxation dispersion (MRD) experiments, water molecules buried in such cavities are used as intrinsic probes of the intermittent protein motions that govern their exchange with external solvent. While this has allowed a detailed characterization of exchange kinetics for several proteins, little is known about the exchange mechanism. Here, we use a millisecond all-atom MD trajectory produced by Shaw et al. (Science2010, 330, 341) to characterize water exchange from the four internal hydration sites in the protein bovine pancreatic trypsin inhibitor. Using a recently developed stochastic point process approach, we compute the survival correlation function probed by MRD experiments as well as other quantities designed to validate the exchange-mediated orientational randomization (EMOR) model used to interpret the MRD data. The EMOR model is found to be quantitatively accurate, and the simulation reproduces the experimental mean survival times for all four sites with activation energy discrepancies in the range 0-3 kBT. On the other hand, the simulated hydration sites are somewhat too flexible, and the water flip barrier is underestimated by up to 6 kBT. The simulation reveals that water molecules gain access to the internal sites by a transient aqueduct mechanism, migrating as single-file water chains through transient (<5 ns) tunnels or pores. The present study illustrates the power of state-of-the-art molecular dynamics simulations in validating and extending experimental results. PMID- 23675836 TI - Antimicrobial activities of some mushrooms in Turkey. AB - CONTEXT: Terfezia boudieri Chatin (Pezizaceae), Agaricus brunnescens Peck (Agaricaceae) and Lactarius vellereus (Fr.) Fr. (Russulaceae) are well-known species in Turkey, and are used both for food and traditional medicine. OBJECTIVE: The powdered fruit bodies of T. boudieri, A. brunnescens and L. vellereus were used to evaluate the antimicrobial activities. MATERIALS AND METHODS: Chloroform, acetone and methanol extracts of T. boudieri, A. brunnescens and L. vellereus were tested for their antimicrobial activities against four Gram positive bacteria, five Gram-negative bacteria and yeast using a micro-dilution method. RESULTS: The strongest minimum inhibitory concentration (MIC) value observed against the test microorganisms was with the chloroform extract of T. boudieri (MIC 2.4 ug/mL) against Streptococcus pyogenes. Maximum antimicrobial effects were observed with the acetone extracts of T. boudieri and L. vellereus (MIC 4.8 ug/mL) against Bacillus subtilis. The strongest antifungal activity was observed with the acetone extracts of T. boudieri (MIC 2.4 ug/mL) and A. brunnescens (MIC 19.5 ug/mL) against Candida albicans. The strongest MIC values for all fungal extracts were observed between 78 and 2.4 ug/mL. DISCUSSION AND CONCLUSION: Present results demonstrated that these three mushroom species have excellent antimicrobial and antifungal activities, and thus have great potential as a source for natural health products. PMID- 23675837 TI - Anti-arthritic activity of ethanol extract of Fagopyrum cymosum with adjuvant induced arthritis in rats. AB - CONTEXT: Fagopyrum cymosum (Trey.) Meisn (Polygonaceae) (EFC) has long been used as a folk medicine to treat various ailments of the lung, dysentery and rheumatism in China. OBJECTIVE: The present study evaluated the anti-arthritic effect of 95% ethanol extract of EFC (extract of Fagopyrum cymosum). MATERIALS AND METHODS: The anti-arthritic activity was investigated by adjuvant arthritic (AA) rat model induced by Freund's complete adjuvant (FCA). The AA rats were randomly separated into different groups and then treated with EFC (40, 80 and 160 mg/kg) from day 7 to day 28 after immunization. Arthritis was evaluated by hind paw swelling, polyarthritis index, body weight and index of immune organs. In addition, the severity of arthritis in the knee joints was evaluated by histopathological and hemorheological examination. The levels of interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) in the serum were assessed by ELISA. RESULTS: The high dose level of EFC (160 mg/kg) significantly suppressed the swelling of hind paw of AA rats (p < 0.01) and inhibited their body weight loss (p < 0.01). Based on histopathological examination, all EFC groups showed great amelioration compared with the model group. EFC (80 and 160 mg/kg) also decreased the plasma viscosity in different shear rates (p < 0.01). Moreover, EFC significantly reduced the production of IL-1 and TNF-alpha in the serum of AA (p < 0.01). DISCUSSION AND CONCLUSION: This study provides a scientific basis for the claims that F. cymosum is effective in preventing and suppressing the development and progression of experimental arthritis, with reductions in inflammatory response. PMID- 23675838 TI - Antinociceptive activity and chemical composition of Wei-Chang-An-Wan extracts. AB - CONTEXT: Currently, famous traditional Chinese medicine formulas have undergone re-evaluation and development in China. Wei-Chang-An-Wan (WCAW) as one of them has been used for treating various gastrointestinal diseases for several decades. The secondary development of WCAW is in progress so as to interpret the effective material basis or find new pharmacological activity. OBJECTIVE: To evaluate the antinociceptive effect of methanol extract of WCAW (ME) as well as four fractions (P.E., EtOAc, n-BuOH, H2O) and obtain information on the correlation between the contents of the fractions and antinociceptive effect. MATERIALS AND METHODS: ME was divided into four parts extracted by petroleum ether, ethyl acetate and n butanol. Antinociceptive activity was evaluated by three models of acetic acid induced writhing, formalin and hot-plate test in mice after repetitive administration of ME at 200, 400 or 800 mg/kg, P.E. 132 mg/kg, EtOAc 106 mg/kg, n BuOH 176 mg/kg and H2O 176 mg/kg for six days. The chemical compounds were analyzed by HPLC-ESI-MS. RESULTS: ME at 800 mg/kg inhibited acid-induced writhing by 84.69%, and reduced the licking time of second phase in formalin test by 53.23%. The inhibition rates in acid-induced writhing of P.E., EtOAc, n-BuOH and H2O were 27.79, 33.85, 38.97 and 37.69%, respectively, and in formalin test about 50%. They had no effect on the hot-plate test. HPLC-ESI-MS analysis showed that 68 chemical compounds were detected and 41 compounds were identified from ME. DISCUSSION AND CONCLUSION: The results obtained herein indicate that WCAW possesses the antinociceptive activity that provides a new aspect in clinical application. PMID- 23675839 TI - Therapeutic potential of octyl gallate isolated from fruits of Terminalia bellerica in streptozotocin-induced diabetic rats. AB - CONTEXT: Medicinal plants are a potential source of antidiabetic drugs. Terminalia bellerica Roxb. (Combretaceae) is used in Indian traditional systems of medicine to treat diabetes mellitus. OBJECTIVE: The aim of this study was to isolate and identify antihyperglycemic principle(s) from the fruits of T. bellerica and assess the bioactivity in streptozotocin (STZ)-induced diabetic rats. MATERIALS AND METHODS: Bioassay-guided fractionation was followed to isolate the active compound(s), structure was elucidated using (1)H and (13)C NMR, IR and mass spectrometry and administered intragastrically to diabetic Wistar rats at different doses (5, 10 and 20 mg/kg, body weight) for 28 d. Plasma glucose, insulin, C-peptide and other biochemical parameters were studied. RESULTS: Octyl gallate (OG) isolated first time from the fruit rind of T. bellerica significantly (p < 0.05) reduced plasma glucose to near normal values (108.47 +/- 6.9 mg/dl) after 14 d at the dose of 20 mg/kg. In addition, OG significantly increased plasma insulin, C-peptide, total protein, albumin, tissue glycogen, body weight and markedly decreased serum total cholesterol, triglyceride, LDL-cholesterol, urea, uric acid and creatinine in diabetic rats. Also OG restored the altered regulatory enzymes of carbohydrate metabolism. DISCUSSION AND CONCLUSION: OG might have augmented the secretion of insulin by the modulation of cAMP and intracellular calcium levels in the beta cells of the pancreas. Our findings indicate that OG isolated first time from the fruit rind of T. bellerica has potential antidiabetic effect as it augments insulin secretion and normalizes the altered biochemical parameters in experimental diabetic rat models. PMID- 23675840 TI - Modulation of cyclophosphamide-induced early lung injury by allicin. AB - CONTEXT: Cyclophosphamide (CP) causes lung injury in rats through its ability to generate free radicals with subsequent epithelial and endothelial cell damage. OBJECTIVE: This study was conducted to assess whether allicin can ameliorate CP induced early lung injury in rats. MATERIALS AND METHODS: Male Sprague Dawely rats were divided into four groups. Group I was the control group. Group II received allicin (50 mg/kg/d, p.o.) for 14 consecutive days. Group III was injected once with CP (150 mg/kg, i.p.). Group IV received allicin for seven consecutive days, before and after CP injection (150 mg/kg, i.p.). The parameters of study were serum biomarkers, lung tissue antioxidant profile and histopathological changes in lung tissue. RESULTS: A single intraperitoneal injection of CP markedly altered the levels of several biomarkers in lung homogenates. Significant increases in lung content of lipid hydroperoxides were seen that paralleled the decreased levels of total reduced glutathione. Superoxide dismutase activity (SOD) was significantly increased. CP increased the level of serum biomarkers; total protein, lactate dehydrogenase (LDH) and tumor necrosis factor-alpha (TNF-alpha). Pretreatment of rats daily with oral allicin seven days prior to and seven days after CP inject significantly inhibited the development of lung injury, prevented the alterations in lung and serum biomarkers associated with inflammatory reactions, with less lipid peroxidation (LP) and restoration of antioxidants. Moreover, allicin attenuated the secretion of proinflammatory cytokine, TNF-alpha expression in rat serum. In addition, allicin effectively blunted CP-induced histopathological changes in lung tissue. DISCUSSION AND CONCLUSION: Our results suggest that allicin is efficient in blunting CP-induced pulmonary damage. PMID- 23675841 TI - Case of idiopathic portal hypertension complicated with autoimmune hepatitis. AB - We report a case of idiopathic portal hypertension (IPH) complicated with autoimmune hepatitis. A 60-year-old woman was admitted to our hospital with esophageal and gastric varices in February 2010. Abdominal ultrasonography and computed tomography showed splenomegaly and collateral veins without evidence of liver cirrhosis. Laboratory examinations and liver biopsy indicated that the esophageal and gastric varices were caused by IPH. She underwent endoscopic injection sclerotherapy and partial splenic embolization. Two years after these therapies, laboratory examinations showed liver dysfunction with elevated levels of aspartate aminotransferase (180 IU/L), alanine aminotransferase (190 IU/L), gamma-glutamyl transpeptidase (159 IU/L) and immunoglobulin G (2609 mg/dL). The titer of antinuclear antibodies was 1:320 and its pattern was homogeneous and speckled. Histological examination revealed plasma cell/lymphocyte infiltration and interface hepatitis in the portal tract. Based on these findings, a diagnosis of autoimmune hepatitis accompanied by IPH was made. After treatment with prednisolone (20 mg/day), liver functions were normalized immediately. Overlapping of IPH and AIH is extremely rare, but the present case is interesting considering the etiology of IPH because an autoimmune mechanism is thought to be involved in the pathogenesis of IPH. PMID- 23675842 TI - Mental health nurses and consumers of mental health services: shared challenges. PMID- 23675845 TI - Thinking outside the illness. PMID- 23675849 TI - Dispersion stability and electrokinetic properties of intrinsic plutonium colloids: implications for subsurface transport. AB - Subsurface transport of plutonium (Pu) may be facilitated by the formation of intrinsic Pu colloids. While this colloid-facilitated transport is largely governed by the electrokinetic properties and dispersion stability (resistance to aggregation) of the colloids, reported experimental data is scarce. Here, we quantify the dependence of zeta-potential of intrinsic Pu(IV) colloids on pH and their aggregation rate on ionic strength. Results indicate an isoelectric point of pH 8.6 and a critical coagulation concentration of 0.1 M of 1:1 electrolyte at pH 11.4. The zeta-potential/pH dependence of the Pu(IV) colloids is similar to that of goethite and hematite colloids. Colloid interaction energy calculations using these values reveal an effective Hamaker constant of the intrinsic Pu(IV) colloids in water of 1.85 * 10(-19) J, corresponding to a relative permittivity of 6.21 and refractive index of 2.33, in agreement with first principles calculations. This relatively high Hamaker constant combined with the positive charge of Pu(IV) colloids under typical groundwater aquifer conditions led to two contradicting hypotheses: (a) the Pu(IV) colloids will exhibit significant aggregation and deposition, leading to a negligible subsurface transport or (b) the Pu(IV) colloids will associate with the relatively stable native groundwater colloids, leading to a considerable subsurface transport. Packed column transport experiments supported the second hypothesis. PMID- 23675850 TI - Microsaccade and drift dynamics reflect mental fatigue. AB - Our eyes are always in motion. Even during periods of relative fixation we produce so-called 'fixational eye movements', which include microsaccades, drift and tremor. Mental fatigue can modulate saccade dynamics, but its effects on microsaccades and drift are unknown. Here we asked human subjects to perform a prolonged and demanding visual search task (a simplified air traffic control task), with two difficulty levels, under both free-viewing and fixation conditions. Saccadic and microsaccadic velocity decreased with time-on-task whereas drift velocity increased, suggesting that ocular instability increases with mental fatigue. Task difficulty did not influence eye movements despite affecting reaction times, performance errors and subjective complexity ratings. We propose that variations in eye movement dynamics with time-on-task are consistent with the activation of the brain's sleep centers in correlation with mental fatigue. Covariation of saccadic and microsaccadic parameters moreover supports the hypothesis of a common generator for microsaccades and saccades. We conclude that changes in fixational and saccadic dynamics can indicate mental fatigue due to time-on-task, irrespective of task complexity. These findings suggest that fixational eye movement dynamics have the potential to signal the nervous system's activation state. PMID- 23675851 TI - Practical pearls in phototherapy. AB - The following tips are suggested for phototherapy: (i) calibrate the unit with a radiometer every 2-4 weeks; (ii) change all bulbs at the same time every 8-10 months for regularly used machines or when the UV meter shows that the power has reached 3 or 4 mW/cm(2) ; (iii) avoid phototherapy sessions on consecutive days to prevent burn on burn; (iv) in the event of a burn, reduce the last PUVA or UVB dose by 50%, reinitiating when erythema has fully disappeared, which might take two days to two weeks; (v) nausea from oral psoralens can be avoided by taking it with a fixed amount of milk or food, taking an antiemetic with this meal prior to dosing, taking five ginger tablets 15 minutes before dosing, or dividing the dosage; (vi) to achieve 0.03% concentration of 8-methoxypsoralen for hand and foot soak PUVA, dissolve a 10-mg tablet or 1.0 cc of Oxsoralen((r)) solution 1% in 3 l of water; and (vii) to achieve 0.000075% concentration of 8 methoxypsoralen for full-body soak PUVA, dissolve 60 mg 8-methoxypsoralen in 80 l of water (i.e. a bath tub). PMID- 23675852 TI - Grapevine bunch rots: impacts on wine composition, quality, and potential procedures for the removal of wine faults. AB - Bunch rot of grape berries causes economic loss to grape and wine production worldwide. The organisms responsible are largely filamentous fungi, the most common of these being Botrytis cinerea (gray mold); however, there are a range of other fungi responsible for the rotting of grapes such as Aspergillus spp., Penicillium spp., and fungi found in subtropical climates (e.g., Colletotrichum spp. (ripe rot) and Greeneria uvicola (bitter rot)). A further group more commonly associated with diseases of the vegetative tissues of the vine can also infect grape berries (e.g., Botryosphaeriaceae, Phomopsis viticola ). The impact these fungi have on wine quality is poorly understood as are remedial practices in the winery to minimize wine faults. Compounds found in bunch rot affected grapes and wine are typically described as having mushroom, earthy odors and include geosmin, 2-methylisoborneol, 1-octen-3-ol, 2-octen-1-ol, fenchol, and fenchone. This review examines the current state of knowledge about bunch rot of grapes and how this plant disease complex affects wine chemistry. Current wine industry practices to minimize wine faults and gaps in our understanding of how grape bunch rot diseases affect wine production and quality are also identified. PMID- 23675853 TI - Reactive scattering for different isotopologues of the H3(-) system: comparison of different potential energy surfaces. AB - Reaction probabilities and cross sections for the ion-neutral molecule collision H(-) + H2 and its different isotopologues are presented. Quasi-classical trajectory, time-independent, and time-dependent quantum calculations are compared with experimental results. In the calculations, three different ab initio potentials have been used to clarify their applicability. PMID- 23675854 TI - Long-term follow-up of children exposed intrauterine to maternal thiopurine therapy during pregnancy in females with inflammatory bowel disease. AB - BACKGROUND: Inflammatory bowel disease (IBD) affects a substantial number of female patients in their reproductive years. Therefore, many physicians face the dilemma whether thiopurines, prescribed to maintain remission, can be taken safely during pregnancy. Data on long-term development outcome of children exposed to maternal thiopurine therapy are very limited. AIM: To assess the long term effects of in utero exposure to thiopurines during pregnancy on infant health status. METHODS: A prospective multicentre follow-up study was performed in children exposed intrauterine to maternal thiopurine therapy. Physical, cognitive and social aspects of infant health status were assessed with the 43 item TNO-AZL Preschool Children Quality of Life Questionnaire (TAPQOL). Furthermore, information on visits to general practitioner and medical specialists, and physician's advice regarding lactation was evaluated. Data were compared with normative data from a control group consisting of 340 children. RESULTS: Thirty children were included in this study [median 3.8 years (IQR 2.9 4.7)]. No differences on global medical and psychosocial health status were found between children exposed to intrauterine thiopurines and the reference group. Exposure to intrauterine thiopurines was not associated with increased susceptibility to infection or immunodeficiency in childhood. Twenty-one of 30 children were exclusively formula-fed based on a negative advice of medical specialists directed at thiopurine use during lactation. CONCLUSIONS: Thiopurine use during pregnancy did not affect long-term development or immune function of children up to 6 years of age. Our results underscore the present notion that mothers, even those using thiopurines, should be encouraged to breastfeed their infants. PMID- 23675855 TI - Primary primitive neuroectodermal tumors of the retina and ciliary body in dogs. AB - We describe the clinical, histological, and immunohistochemical features of primary intraocular primitive neuroectodermal tumors in eight dogs. Four of eight tumors exhibited histological features similar to human retinoblastomas characterized by Flexner-Wintersteiner rosettes, and fleurettes, and demonstrated variable immunoreactivity for retinal markers opsin, S-antigen (S-Ag) and interphotoreceptor retinoid-binding protein (IRBP). All dogs with tumors displaying histological and immunohistochemical features of retinal differentiation were <=2 years of age. All tumors diagnosed as medulloepitheliomas (n = 4) did not display histological and immunohistochemical features of retinal differentiation and were present in dogs 7 years or older. Age of onset, in conjunction with immunohistochemistry for opsin, S-Ag, and IRBP, is an important aid in the differentiation of primary, primitive neuroectodermal tumors arising within the canine ciliary body, retina, and optic papilla. PMID- 23675856 TI - Evaluation of in vitro metabolic systems for common drugs of abuse. 1. Cocaine. AB - This study examined the efficacy of four common in vitro assay systems in producing metabolic profiles consistent with in vivo data for drugs of abuse. Cocaine (COC) was selected for this study because of its complex biotransformation pathways, diverse metabolic processes and because extensive Phase I and Phase II metabolomic examination of COC has not yet been reported by means of in vitro assay. COC metabolism was assessed with a series of common in vitro assay systems (human liver microsomes, cytosol and human liver S9 fraction and horseradish peroxidase) using liquid chromatography-tandem mass spectrometry with multiple reaction monitoring. Qualitative and quantitative differences in analyte production were noted among the various active Phase I and Phase II metabolic systems. Assay incubation time was found to be a determining factor in metabolic profile, specifically with primary versus secondary metabolite formation. Regioselective arene hydroxylation of COC was conclusively documented in human hepatic metabolic models, while peroxidase-based assay systems displayed less selectivity in oxidative aryl biotransformation. Results demonstrate the applicability of in vitro systems in studying COC metabolite production and the impact of assay selection and variation in method parameters on metabolite profiles for this important drug of abuse. PMID- 23675857 TI - Direct imaging of 3D atomic-scale dopant-defect clustering processes in ion implanted silicon. AB - The fabrication of nanoscale semiconductor devices for use in future electronics, energy, and health is among others based on the precise placement of dopant atoms into the crystal lattice of semiconductors and their concurrent or subsequent electrical activation. Dopants are built into the lattice by fabrication processes like ion implantation, plasma-based doping, and thermal annealing. Throughout the fabrication processes fundamental phenomena like dopant diffusion, activation, and clustering occur concurrently with damaging and subsequently recovering the crystal lattice. These processes are described by atomic-scale mechanisms of ion-host atom interaction and have an immense impact on the electrical performance of the resulting devices. Insight in their fundamental nature is of utmost importance for optimizing the performance of nanoscale technologies. In this paper, we demonstrate direct three-dimensional imaging of boron clusters and atoms in crystal defects using field ion microscopy. Our approach allows for the first time the complete characterization of the size and crystallographic orientation of boron-decorated crystal defects. This new method opens a path to image a wide variety of dopant-cluster forms and hence to study the formation and dissolution of boron clusters in silicon on the atomic scale. PMID- 23675858 TI - The costs of being dark: the genetic basis of melanism and its association with fitness-related traits in the sand cricket. AB - Melanism is an important component of insect cuticle and serves numerous functions that enhance fitness. Despite its importance, there is little information on its genetic basis or its phenotypic and genetic correlation with fitness-related traits. Here, we examine the heritability of melanism in the wing dimorphic sand cricket and determine its phenotypic and genetic correlation with wing morphology, gonad mass and size of the dorso-longitudinal muscles (the principle flight muscles). Previously demonstrated trade-offs among these traits are significant factors in the evolution of life history variation. Using path analysis, we show that melanization is causally related to gonad mass, but not flight muscle mass. Averaged over the sexes, the heritability of melanism was 0.61, the genetic correlation with gonad mass was -0.36 and with wing morph was 0.51. The path model correctly predicted the ranking of melanization score in lines selected for increased ovary mass, increased flight muscle mass, an index that increased both traits and an unselected control. Our results support the general hypothesis that melanization is costly for insects and negatively impacts investment in early reproduction. PMID- 23675859 TI - Expression patterns of Phf5a/PHF5A and Gja1/GJA1 in rat and human endometrial cancer. AB - Endometrial adenocarcinoma is the most frequently diagnosed cancer of the female genital tract in the western world. Studies of complex diseases can be difficult to perform on human tumor samples due to the high genetic heterogeneity in human. The use of rat models is preferable since rat has similarities in pathogenesis and histopathological properties to that of human.A genomic region including the highly conserved Phf5a gene associated to development of EAC has previously been identified in an association study. PHF5A has been suggested to acts as a transcription factor or cofactor in the up regulation of expression of Gja1 gene in the presence of estrogen. It has earlier been shown that the Phf5a gene is down regulated in rat EAC derived cell lines by means of expression microarrays.We analyzed the expression of Phf5a and Gja1 by qPCR, and potential relations between the two genes in EAC tumors and non-malignant cell lines derived from the BDII rat model. In addition, the expression pattern of these genes was compared in rat and human EAC tumor samples.Changes in expression for Phf5a/PHF5A were found in tumors from both rat and human even though the observed pattern was not completely consistent between the two species. By separating rat EAC cell lines according to the genetic background, a significant lower expression of Phf5a in one of the two cross backgrounds was revealed, but not for the other. In contrast to other studies, Phf5a/PHF5A regulation of Gja1/GJA1 was not revealed in this study. PMID- 23675860 TI - Reduced WWOX protein expression in human astrocytoma. AB - The WW domain-containing oxidoreductase (WWOX) functions as a tumor suppressor by interacting with various proteins in numerous important signaling pathways. WWOX silencing via homozygous deletion of its locus and/or promoter hypermethylation has been observed in various human cancers. However, the relationship between WWOX and tumors in the central nervous system has not been fully explored. In this study, the expression levels of WWOX protein in astrocytomas from 38 patients with different tumor grades were retrospectively analyzed by immunohistochemical staining. The results showed that 19 (50.0%) samples had highly reduced WWOX protein expression when compared with normal controls, while 14 (36.8%) and five (13.2%) cases exhibited moderate and mild decreases in WWOX expression, respectively. Reduction of the expression of WWOX protein correlated with patient age, supra-tentorial localization of the tumor and severity of the symptoms. Furthermore, loss of WWOX expression inversely correlated with survival time. No significant correlation was observed between the loss of WWOX expression and the gender of patients or the difference in pre-operative and post-operative karnofsky performance status scores. Surprisingly, there was no significant correlation between the loss of WWOX protein expression and overall tumor grades. Nevertheless, it was found that 63.6% (7/11) of the grade II astrocytomas had highly reduced WWOX expression and 36.4% (4/11) showed moderately reduced WWOX expression, while none of the samples exhibited mild reductions. Similar results were also found in grade III astrocytomas. The results from this small-size sample pilot study suggest that the loss of WWOX expression may be an early event in the pathogenesis of human astrocytoma. PMID- 23675861 TI - Small pH and salt variations radically alter the thermal stability of metal binding domains in the copper transporter, Wilson disease protein. AB - Although strictly regulated, pH and solute concentrations in cells may exhibit temporal and spatial fluctuations. Here we study the effect of such changes on the stability, structure, and dynamics in vitro and in silico of a two-domain construct (WD56) of the fifth and sixth metal-binding domains of the copper transport protein, ATP7B (Wilson disease protein). We find that the thermal stability of WD56 is increased by 40 degrees C when increasing the pH from 5.0 to 7.5. In contrast, addition of salt at pH 7.2 decreases WD56 stability by up to 30 degrees C. In agreement with domain-domain coupling, fractional copper loading increases the stability of both domains. HSQC chemical shift changes demonstrate that, upon lowering the pH from 7.2 to 6, both His in WD6 as well as the second Cys of the copper site in each domain become protonated. MD simulations reveal increased domain-domain fluctuations at pH 6 and in the presence of high salt concentration, as compared to at pH 7 and low salt concentration. Thus, the surface charge distribution at high pH contributes favorably to overall WD56 stability. By introducing more positive charges by lowering the pH, or by diminishing charge-charge interactions by salt, fluctuations among the domains are increased and thereby overall stability is reduced. Copper transfer activity also depends on pH: delivery of copper from chaperone Atox1 to WD56 is more efficient at pH 7.2 than at pH 6 by a factor of 30. It appears that WD56 is an example where the free energy landscapes for folding and function are linked via structural stability. PMID- 23675862 TI - Treatment options for esophageal squamous cell carcinoma. AB - INTRODUCTION: The treatment for esophageal squamous cell carcinoma (SCC) depends on its etiology. For mucosal cancer, endoscopic resection is standard; while for locally advanced cancer, esophagectomy is the main treatment. When the tumor is more advanced, neoadjuvant or adjuvant therapy is added. For unresectable cancer, concurrent chemoradiotherapy is the standard therapy. AREAS COVERED: The standard chemotherapy for esophageal SCC is a cisplatin- and 5-fluorouracil (CF)-based regimen. Chemoradiotherapy (CRT) is the standard treatment for unresectable esophageal SCC and is also an option for resectable tumors. For patients who are inoperable, concurrent CRT should be the standard of care. Docetaxel, cisplatin and 5-fluorouracil (DCF) therapy is a promising candidate for chemotherapy with or without radiotherapy because an excellent local control rate and pathological remission rate have been reported. Although salvage surgery after definitive CRT is a practical treatment, judicious patient selection is crucial. EXPERT OPINION: Presently, the standard regimen for esophageal SCC is CF. DCF is expected to be the next standard regimen. In the near future, some new therapeutic options, such as molecular targeted therapy or particle beam therapy, may confer further advantages. A thorough understanding of these therapeutic modalities is important to achieve this endeavor. PMID- 23675863 TI - Synthesis of benzidine derivatives via FeCl3.6H2O-promoted oxidative coupling of anilines. AB - Under open-flask conditions in the presence of commercially available FeCl3.6H2O, N,N-disubstituted anilines can be converted into diversely functionalized benzidines with yields of up to 99%. Oxidative coupling was extended to N monosubstituted anilines, and the method was applied to the efficient preparation of 6,6'-biquinoline. Mechanistic investigations have also been performed to explain the observed reactivities. PMID- 23675864 TI - New Ag(I)-iminophosphorane coordination polymers as efficient catalysts precursors for the MW-assisted Meyer-Schuster rearrangement of propargylic alcohols in water. AB - Treatment of the N-thiophosphorylated iminophosphorane ligands (PTA)?NP(?S)(OR)2 [PTA = 1,3,5-triaza-7-phosphaadamantane, 3a and 3b] and (DAPTA)?NP(?S)(OR)2 [DAPTA = 3,7-diacetyl-1,3,7-triaza-5-bicyclo[3.3.1]nonane, 4a and 4b] with an equimolecular amount of AgSbF6 leads to high-yield formation of the new one dimensional coordination polymers [Ag{MU(2)-N,S-(PTA)?NP(?S)(OR)2}]x[SbF6]x (5a and 5b) and [Ag{MU(2)-O,S-(DAPTA)?NP(?S)(OR)2}]x[SbF6]x (6a and 6b), respectively. These new (iminophosphorane)silver(I) coordination polymers are efficient catalyst precursors for the Meyer-Schuster isomerization of both terminal and internal alkynols. Reactions proceeded in water, under aerobic conditions and using microwave irradiation as heating source, to afford the corresponding alpha,beta-unsaturated carbonyl compounds in excellent yields, without the addition of any cocatalyst. Remarkably, it should be noted that this catalytic system can be recycled up to 10 consecutive runs (1st cycle 45 min, 99%; 10th cycle 6 h, 97%). ESI-MS analysis of 5a in water has been carried out providing valuable insight into the monomeric active species responsible for catalytic activity in water. PMID- 23675865 TI - Penile preservation surgery in a case of erythroplasia of Queyrat involving the glans penis and distal urethra. PMID- 23675866 TI - Extraction and neoformation of antioxidant compounds by pressurized hot water extraction from apple byproducts. AB - There is a great interest in searching for new environmentally sustainable techniques to enhance the use of agricultural byproducts. In this work, a response surface methodology was used to study the influence of the two independent variables, temperature (25-200 degrees C) and extraction time (3-17 min), in the extraction of antioxidants by pressurized hot water extraction (PHWE) from industrial apple byproducts. The optimized extraction method for determination of flavonols was at 120 degrees C and 3 min, giving a predicted total yield of flavonols of 1.3 MUmol/g dry apple byproduct. Results obtained suggest that new antioxidant compounds were formed at the higher extraction temperatures. A desirability function response surface, considering maximum antioxidant capacity and minimal formation of brown color, was calculated and gave an optimum of 125 degrees C and 3 min. This latter PHWE method correlates well with the obtained results for flavonols; thus, a desirability function is a simpler alternative method for finding optimal conditions. PMID- 23675867 TI - Alcohol use in pregnancy: prevalence and predictors in the Longitudinal Study of Australian Children. AB - INTRODUCTION AND AIMS: This study aimed to estimate the prevalence and describe the patterns of alcohol use during pregnancy among Australian mothers. The study also aimed to examine the characteristics associated with alcohol use in pregnancy. DESIGN AND METHODS: Data comprised two representative samples of families (infant cohort = 5107 parents of 0- to 1-year-olds; child cohort = 4983 parents of 4- to 5-year-olds) from the 2005 Longitudinal Study of Australian Children. RESULTS: Alcohol use in pregnancy was reported by 37.6% of mothers of infants aged 0-1 years and 27.6% of mothers of children aged 4-5 years. The majority of women reported low level/occasional use of alcohol but, when extrapolated to population level, this equates to 131,250 children in these two age groups exposed to alcohol in utero, with over 1000 children exposed to alcohol most days and an estimated 671 infants exposed to three or more drinks per occasion. Among mothers of infants, alcohol use in pregnancy was associated with increasing maternal age, higher education, greater economic advantage and fewer physical health problems in pregnancy. Among mothers of children, maternal drinking in pregnancy was associated with increasing maternal age and smoking in pregnancy. DISCUSSION AND CONCLUSIONS: Alcohol use during pregnancy is common with around one-third of all mothers reporting use. Most women reported only occasional use, and among those who were asked, consumed one standard drink on average per occasion. Significant numbers were exposed to three or more drinks on one occasion or to alcohol most days while in utero. National guidelines recommend abstinence as no 'safe' threshold has been determined. Public health campaigns are needed to educate pregnant women regarding national guidelines. PMID- 23675868 TI - Living related liver transplantation in an adult patient with hepatocellular adenoma and carcinoma 13 years after bone marrow transplantation for Fanconi anemia: A case report. AB - Fanconi anemia (FA) is an inherited bone marrow failure syndrome due to defective DNA inter-strand cross-link repair. Hematopoietic stem cell transplantation (HSCT) is curative for pancytopenia, but may not prevent the development of non hematological malignancies. We describe a 26-year-old male patient with FA and Marfan syndrome who in 1994 underwent successful HSCT with bone marrow stem cells from his human leukocyte antigen (HLA)-identical sister. In 2006, three lesions in the liver were detected and resected. The three lesions all showed activation of the beta-catenin pathway and were histologically characterized by a highly differentiated steatotic hepatocellular carcinoma (HCC) with remnants of the underlying adenoma from which it arose, a hepatocellular adenoma with foci of well-differentiated HCC, and a cholestatic adenoma. Risk factors for the emergence of HCC included FA itself, the use of androgens for a period of 3 years preceding HSCT and toxicity of the conditioning regimen. Because of the danger of developing additional HCC, liver transplantation was proposed, taking into consideration that immunosuppression would increase the risk of other malignancies. By using part of the liver of the sister, who already acted as bone marrow donor 13 years earlier, immunosuppression could be avoided. Liver transplantation was performed in 2007 without complication. Five years after liver transplantation the patient is doing well. This case is twofold special being the first case reporting FA co-occurring with Marfan syndrome and being the first reported case of FA treated for HCC by liver transplantation from a HLA identical sibling donor without the use of immunosuppression. PMID- 23675869 TI - Attomolar detection of influenza A virus hemagglutinin human H1 and avian H5 using glycan-blotted field effect transistor biosensor. AB - Influenza virus, through cell invasion and propagation with the interaction between hemagglutinin (HA) present on its surface and glycans on the host cell, causes a rapidly spreading infection throughout the world. In the present investigation, we succeeded for the first time in the attomolar-level sensing and discrimination of influenza A viral HA molecules H1 and H5 by using a glycan immobilized field effect transistor (FET) biosensor. The small ligand glycans immobilized on the FET device, which make effective use of the charge-detectable region for FET-based detection in terms of Debye length, gave an advantage in the highly sensitive detection of the proteins. Two kinds of trisaccharides receptors terminating in sialic acid-alpha2,6-galactose (6'-sialyllactose) and in sialic acid-alpha2,3-galactose (3'-sialyllactose) were conjugated directly with the SiO2 surface of FET devices by a simple glycoblotting method using the self-assembled monolayer (SAM) of aminooxy terminated silane-coupling reagent, 3 aminooxypropyltriethoxysilane. Furthermore, it was demonstrated that the FETs with densely immobilized glycans, which possess the high capture ability by achieving the glycoside cluster effect, clearly distinguish HA molecules between their subtypes H1 (human) and H5 (avian) at the attomolar level, while the conventional method based on HA antibodies achieves only picomolar-level detection. Our findings indicate that the glycan-immobilized FET is a promising device to detect various pathogenic bacteria and viruses through glycan-protein interaction found ubiquitously in many infectious diseases. PMID- 23675870 TI - Synthesis of telechelic olefin polymers via catalyzed chain growth on multinuclear alkylene zinc compounds. AB - Multinuclear alkylene zinc (MAZ) compounds of the type EtZn-(R"-Zn)n-Et (R" = ethyl and propyl branched alkylene groups) were synthesized by a simple one-step procedure in nonpolar hydrocarbon solvents from alpha,omega-dienes (e.g., 1,7 octadiene or 1,9-decadiene) and diethylzinc using a bis(salicylaldiminato)Zr(IV) complex, [(2-methylcyclohexyl)N?CH(2-O-C6H3-3,5-di-tert-butyl)]2ZrMe2, as a catalyst. The MAZ serves as a divalent reversible chain-transfer agent for olefin polymerization, resulting in telechelic Zn-metalated polyolefins whose molecular weights are controllable over a wide range. The Zn-terminated telechelics serve as a polymer precursor for further reactions and can be converted into a variety of telechelic functionalized polyolefins in high yield. PMID- 23675871 TI - Enhanced periodontal tissue regeneration by periodontal cell implantation. AB - AIM: Due to a lack of regenerative potential, current treatments for periodontal defects do not always provide satisfactory clinical results. Previously, the implantation of a biomaterial scaffold-cell construct has been suggested as a clinically achievable approach. In this study, it was aimed to investigate the contribution of implanted periodontal ligament (PDL) cells to periodontal tissue regeneration. MATERIALS & METHODS: Gelatin sponges were seeded with green fluorescent protein (GFP) transfected PDL or gingival fibroblasts (GF) cells, and implanted into a surgically created rat intrabony periodontal defect model. After six weeks, decalcified maxillae were used for histomorphometrical and immunohistochemical analyses. RESULTS: After six weeks, animals that had received the PDL cells exhibited significantly more functional bone and ligament. Furthermore, there were remarkable differences in the distribution of the transplanted cells. Periodontal ligament cells were always located directly lining the newly regenerated areas. In contrast, GF cells dispersed over the whole defect area, and did not provide a favourable effect on the regeneration of the periodontal tissues. CONCLUSION: We concluded that PDL cells transplanted into a periodontal defect survive and favour regeneration of periodontium, possibly in a paracrine manner. PMID- 23675872 TI - Experimental demonstration of continuous electronic structure tuning via strain in atomically thin MoS2. AB - We demonstrate the continuous tuning of the electronic structure of atomically thin MoS2 on flexible substrates by applying a uniaxial tensile strain. A redshift at a rate of ~70 meV per percent applied strain for direct gap transitions, and at a rate 1.6 times larger for indirect gap transitions, has been determined by absorption and photoluminescence spectroscopy. Our result, in excellent agreement with first principles calculations, demonstrates the potential of two-dimensional crystals for applications in flexible electronics and optoelectronics. PMID- 23675873 TI - Analytical study of superaromaticity in cycloarenes and related coronoid hydrocarbons. AB - Recently synthesized septulene is a unique cycloarene molecule in that no macrocyclic conjugation circuits can be chosen from the pi-system. This molecule has essentially no superaromatic stabilization energy (SSE) and can be viewed as an ideal nonsuperaromatic macrocycle. SSEs for kekulene and other cycloarenes are also very small. In these hydrocarbons, a macrocycle formed by fused benzene rings effectively suppresses not only the aromaticity inherent in macrocyclic (4n+2)-site conjugation circuits but also the antiaromaticity inherent in macrocyclic (4n+/-1)-site circuits. Comparative study of superaromaticity in multilayered coronoid hydrocarbons revealed that not only SSE but also the HOMO contribution to SSE is minimized in odd-layered coronoids. PMID- 23675874 TI - The State of Climate Negotiations: a personal scientific commentary. AB - Humanity seems unable to rein in its CO2 emissions, and yet the author finds reasons for hope. PMID- 23675875 TI - Intraocular myelolipoma in a dog. AB - An 8-year-old Scottish terrier was presented with a red and painful right eye. Slitlamp biomicroscopy and ocular ultrasound demonstrated the presence of a large mass in the anterior chamber. Enucleation was performed one week after initial presentation. Histological examination of the eye revealed a relatively well delineated mass distorting the dorsal iris and occupying most of the anterior chamber. The tumor was composed of fully differentiated adipose tissue and normal hematopoietic cells of the three major blood-forming elements. These findings were most consistent with the diagnosis of an anterior chamber myelolipoma distorting the iris. To the author's knowledge, this is the first report of an intraocular myelolipoma in any species. PMID- 23675876 TI - Potential of patient-reported outcomes as nonprimary endpoints in clinical trials. AB - BACKGROUND: The purpose of this research was to fully explore the impact of endpoint type (primary vs. nonprimary) on decisions related to patient-reported outcome (PRO) labeling claims supported by PRO measures and to determine if nonprimary PRO endpoints are being fully optimized.This review examines the use of PROs as both primary and nonprimary endpoints in support of demonstration of treatment benefit of new molecular entities (NMEs) and biologic license applications (BLAs) in the United States in the years 2000 to 2012. METHODS: All NMEs and BLAs approved by the Food and Drug Administration (FDA) between January 2000 and June 2012 were identified using the FDA Drug Approval Reports Web page. Generic products granted tentative approvals were excluded. For all identified products, medical review sections from publicly available drug approval packages were reviewed to identify PRO endpoint status. Product labels (indication, clinical trials sections) were reviewed to determine the number and type of PRO claim. RESULTS: A total of 308 NMEs/BLAs were identified. Of these, 70 NMEs/BLAs (23%) were granted PRO claims. The majority of product claims were for disease- or condition-specific signs and symptoms. Of the 70 products with PRO claims, a PRO was a primary endpoint for the vast majority (57 [81%]). A total of 19 of the 70 products were granted a PRO claim based on a nonprimary endpoint. While nonprimary endpoints were used most often to support claims of improved signs or symptoms, nonprimary endpoints were much more likely to support claims of higher order impacts. CONCLUSIONS: Successful PRO labeling claims are typically based on primary endpoints assessing signs and symptoms. Based on this research, studies with PROs as primary endpoints are far more likely to facilitate positive regulatory review and acceptance of PROs in support of labeling claims. Although inclusion of PROs as nonprimary endpoints in clinical trials has its challenges, recent PRO labels granted by the FDA show that they can indeed be candidates for PRO labeling claims as long as they are supported by evidence. PMID- 23675877 TI - Effect of ionic aqueous environments on the structure and dynamics of the Abeta(21-30) fragment: a molecular-dynamics study. AB - The amyloid beta-protein (Abeta) has been implicated in the pathogenesis of Alzheimer's disease. The role of the structure and dynamics of the central Abeta21-30 decapeptide region of the full-length Abeta is considered crucial in the aggregation pathway of Abeta. Here we report results of isobaric-isothermal (NPT) all-atom explicit water molecular dynamics simulations of the monomeric form of the wild-type Abeta21-30 fragment in aqueous salt environments formed by neurobiologically important group IA (NaCl, KCl) and group IIA (CaCl2, MgCl2) salts. Our simulations reveal the existence of salt-specific changes to secondary structure propensities, lifetimes, hydrogen bonding, salt-bridge formation, and decapeptide-ion contacts of this decapeptide. These results suggest that aqueous environments with the CaCl2 salt, and to a much lesser extent the MgCl2 salt, have profound effects by increasing random coil structure propensities and lifetimes and diminishing intrapeptide hydrogen bonding. These effects are rationalized in terms of direct cation-decapeptide contacts and changes to the hydration-shell water molecules. On the other side of the spectrum, environments with the NaCl and KCl salts have little influence on the decapeptide's secondary structure despite increasing hydrogen bonding, salt-bridge formation, and lifetime of turn structures. The observed enhancement of open structures by group IIA may be of importance in the folding and aggregation pathway of the full length Abeta. PMID- 23675878 TI - Differentiating microbial forensic qPCR target and control products by electrospray ionization mass spectrometry. AB - Molecular bioforensic research is dependent on rapid and sensitive methods such as real-time PCR (qPCR) for the identification of microorganisms. The use of synthetic positive control templates containing small modifications outside the primer and probe regions is essential to ensure all aspects of the assay are functioning properly, including the primers and probes. However, a typical qPCR or reverse transcriptase qPCR (qRT-PCR) assay is limited in differentiating products generated from positive controls and biological samples because the fluorescent probe signals generated from each type of amplicon are indistinguishable. Additional methods used to differentiate amplicons, including melt curves, secondary probes, and amplicon sequencing, require significant time to implement and validate and present technical challenges that limit their use for microbial forensic applications. To solve this problem, we have developed a novel application of electrospray ionization mass spectrometry (ESI-MS) to rapidly differentiate qPCR amplicons generated with positive biological samples from those generated with synthetic positive controls. The method has sensitivity equivalent to qPCR and supports the confident and timely determination of the presence of a biothreat agent that is crucial for policymakers and law enforcement. Additionally, it eliminates the need for time-consuming methods to confirm qPCR results, including development and validation of secondary probes or sequencing of small amplicons. In this study, we demonstrate the effectiveness of this approach with microbial forensic qPCR assays targeting multiple biodefense agents (bacterial, viral, and toxin) for the ability to rapidly discriminate between a positive control and a positive sample. PMID- 23675879 TI - Mating strategies in dominant meerkats: evidence for extra-pair paternity in relation to genetic relatedness between pair mates. AB - Rates of extra-pair paternity (EPP) have frequently been associated with genetic relatedness between social mates in socially monogamous birds. However, evidence is limited in mammals. Here, we investigate whether dominant females use divorce or extra-pair paternity as a strategy to avoid the negative effects of inbreeding when paired with a related male in meerkats Suricata suricatta, a species where inbreeding depression is evident for several traits. We show that dominant breeding pairs seldom divorce, but that rates of EPP are associated with genetic similarity between mates. Although extra-pair males are no more distantly related to the female than social males, they are more heterozygous. Nevertheless, extra pair pups are not more heterozygous than within-pair pups. Whether females benefit from EPP in terms of increased fitness of the offspring, such as enhanced survival or growth, requires further investigations. PMID- 23675880 TI - Giant digital fibrokeratoma of the finger. PMID- 23675881 TI - Signal transduction in human cutaneous melanoma and target drugs. AB - Malignant melanoma is an extremely aggressive and metastatic cancer, highly resistant to conventional treatment modalities. Understanding of fundamental mechanisms responsible for its genesis and progression is critical for development of successful chemotherapeutic treatment. It is becoming clear that melanoma results from complex changes in multiple signaling pathways that control cell proliferation and ability to evade the cell death processes. Impairment or hyper-activation of some components of these pathways may lead to malignant transformation and cancer development. In the present review we consider the current data on involvement of such signaling pathways as cyclin/CDK, Ras/Raf/MEK/MAPK, JNK/c-Jun/AP-1, PI3K/Akt/PTEN/mTOR, IKK/I-kappaB/NF-kappaB, Wnt/beta-catenin, Notch, Jak/STAT, MITF and some growth factors in regulation of the cell cycle progression, apoptosis and development of human cutaneous melanoma. Understanding of molecular aberrations that underlie melanoma oncogenesis is essential for improvement of diagnosis, accurate prognosis assessment, and rational design of effective therapeutics. Inhibitors of these pathways may serve as promising tools for anti-melanoma targeted therapy. Some novel anti-melanoma target drugs are characterized. PMID- 23675882 TI - Unmet needs in ovarian cancer: dividing histologic subtypes to exploit novel targets and pathways. AB - Ovarian cancer (OC) carries a poor prognosis; however, accumulating molecular data for the major histologic subtypes may lead to subtype-specific treatment paradigms. The present review discusses what is currently understood about the major molecular and histologic subgroups of OC. Areas specifically addressed include hormonal pathways, tumor protein p53 (TP53) and AT rich interactive domain 1A (SWI-like; ARID1A) mutation, and the breast cancer 1/2, early onset (BRCA1/2) mutation/poly (ADP-ribose) polymerase 1 (PARP1), phosphatidylinositol 4,5-bisphosphate 3- kinase, catalytic subunit alpha (PI3KCA)/v-akt murine thymoma viral oncogene homolog 1 (AKT1)/mechanistic target of rapamycin (MTOR), and mitogen-activated protein kinase kinase 1 and 2 (MAP2K1/2) pathways. This molecular characterization only very recently has impacted clinical research efforts to develop targeted therapies for both common and rare OC subtypes. This targeted strategy is illustrated by ongoing low-grade serous, clear-cell, and mucinous subtypeexclusive clinical trials evaluating agents based on common molecular abnormalities among patients (i.e., PARP1 inhibitors for BRCA1/2 mutation-positive OC). This report also reviews the published clinical trial efficacy data for investigational therapies within specific subgroups, and summarizes the currently active clinical trials evaluating these agents (e.g., temsirolimus, sunitinib, TP53 immunotherapy, olaparib, iniparib, veliparib). Available data suggest that histologic profiles and molecular tumor markers are valuable resources for identifying patients who may benefit from these specific agents, and future research should focus on targeting molecules and signaling pathways that are most commonly altered in each subtype. PMID- 23675883 TI - Targeted therapy with kinase inhibitors in aggressive endocrine tumors. AB - INTRODUCTION: Kinase inhibitors (KIs) are a class of anticancer drugs that inhibit activity of the enzymes protein kinases, which regulate crucial cellular processes and have a demonstrated role in human oncogenesis. Treatment of advanced forms of endocrine cancer which are not responsive to cytotoxic chemotherapies is challenging and use of KIs is gaining a growing role in this field. AREAS COVERED: The authors summarize the main genetic alterations known to be linked to endocrine tumors, indicating the rationale for utilizing KIs. Furthermore, they present an updated analysis of clinical trials available on PubMed Central, which were pertinent to the activities of KIs in aggressive endocrine cancer. The authors also discuss the adverse effects of KIs and summarize likely involved underlying mechanisms. EXPERT OPINION: KIs are effective in obtaining a radiological disease control and an improvement of progression-free survival in several forms of endocrine cancer but will never deliver a knockout blow of the disease, due to mechanisms of adaptation to circumvent the specific molecular blockade. The new frontier of KIs treatment is to identify agents that could synergize activity of KIs. The true goal will be to perform an overall genotyping of each tumor, thus predicting the impact of combined targeted therapies in the context of a particular constellation of mutant genes. PMID- 23675885 TI - Comprehensive experimental study of N-heterocyclic pi-stacking interactions of neutral and cationic pyridines. AB - A comprehensive experimental study was carried out by measuring the relative strengths of parallel pi-stacking interactions of N-heterocycles with nonheterocycles. A versatile and rigid model system was developed, which was in equilibrium between a "closed" conformation that forms an intramolecular pi stacking interaction and an "open" conformation that cannot form the interaction. First, the formation and geometries of the intramolecular N-heterocyclic pi stacking interactions were verified by X-ray crystallography. Next, the closed/open ratios were measured in solution via integration of the (1)H NMR spectra, providing an accurate comparison of the N-heterocyclic pi-stacking interactions. The synthetic versatility of this model system enabled the systematic and comprehensive comparison of the influences of position, charge, and substituent effects of the nitrogen atom of the N-heterocycles within a single model system. The pi-stacking interactions of the neutral N-heterocyclic rings were slightly stronger than that of nonheterocyclic rings. Cationic N heterocycles formed significantly stronger pi-stacking interactions than neutral N-heterocycles. The position of the nitrogen atom also had a strong influence on the stability of N-heterocyclic pi-stacking complexes. Interestingly, opposite stability trends were observed for neutral and cationic N-heterocycles. For neural N-heterocycles, geometries with the nitrogen away from the pi-face of the opposing ring were the more stable. For cationic N-heterocycles, geometries with the nitrogen close to the pi-face of the opposing ring were the more stable. Finally, N-methylated heterocycles consistently formed stronger pi-stacking interactions than N-protonated heterocycles. PMID- 23675886 TI - Nanoelectrospray ionization mass spectrometric study of Mycobacterium tuberculosis CYP121-ligand interactions. AB - Nondenaturing nanoelectrospray ionization mass spectrometry (nanoESI MS) of intact protein complexes was used to study CYP121, one of the 20 cytochrome P450s in Mycobacterium tuberculosis (Mtb) and an enzyme that is essential for bacterial viability. The results shed new light on both ligand-free and ligand-bound states of CYP121. Isolated unbound CYP121 is a predominantly dimeric protein, with a minor monomeric form present. High affinity azoles cause the dissociation of dimeric CYP121 into monomer, whereas weaker azole binders induce partial dimer dissociation or do not significantly destabilize the dimer. Complexes of CYP121 with azoles were poorly detected by nanoESI MS, indicating kinetically labile complexes that are easily prone to gas-phase dissociation. Unlike with the azoles, CYP121 forms a stable complex with its natural substrate cYY that does not undergo gas-phase dissociation. In addition, a series of potential ligands from fragment-based studies were used as a test for nanoESI MS work against CYP121. Most of these ligands formed stable complexes with CYP121, and their binding did not promote dimer dissociation. On the basis of binding to the monomer and/or CYP121 dimer it was possible to determine the relative order of their CYP121 binding affinities. The top nanoESI MS screening hit was confirmed by heme absorbance shift assay to have a Kd of 40 MUM. PMID- 23675887 TI - Antimony tartrate transition-metal-oxo chiral clusters. AB - A chiral precursor K2Sb2(L-tartrate)2 was used for the assembly of three homochiral heterometallic antimony(III)-tartrate transition-metal-oxo clusters: Mn(H2O)6[Fe4Mn4Sb6(MU4-O)6(MU3-O)2(l-tartrate)6(H2O)8].10.5H2O (1), [V4Mn5Sb6(MU4 O)6(MU3-O)2(L-tartrate)6(H2O)13].9.5H2O (2), and (H3O)[Ni(H2O)6]2[NiCrSb12(MU3 O)8(MU4-O)3(l-tartrate)6].6H2O (3). In 1 and 2, the antimony tartrate dimer precursor decomposes and recombines to form Sb3(MU3-O)(L-tartrate)3 chiral trimers, which act as scaffolds to construct negative-charged [Fe4Mn4Sb6(MU4 O)6(MU3-O)2(L-tartrate)6](2-) in 1 and neutral [V4Mn5Sb6(MU4-O)6(MU3-O)2(L tartrate)6] in 2. The scaffold is flexible and accommodates different types of transition-metal-oxo clusters due to the different possible coordination modes of the L-tartrate ligand. In 3, a two-level chiral scaffold Sb3(MU3-O)(L tartrate)3Sb3 is formed from the precursor. Two such scaffolds are linked by three bridging oxygen atoms to form a cavity occupied by one Cr(3+) ion and one Ni(2+) ion disordered over two positions. Cr(3+) and Ni(2+) ions are located in two face-shared MO6 octahedra at the center of a negatively charged [NiCrSb12(MU3 O)8(MU4-O)3(L-tartrate)6](3-) cluster. PMID- 23675889 TI - On the calculation of resonances in pre-Born-Oppenheimer molecular structure theory. AB - The main motivation for this work is the exploration of rotational-vibrational states corresponding to electronic excitations in a pre-Born-Oppenheimer quantum theory of molecules. These states are often embedded in the continuum of the lower-lying dissociation channel of the same symmetry and thus are thought to be resonances. To calculate rovibronic resonances, the pre-Born-Oppenheimer variational approach of [J. Chem. Phys. 2012, 137, 024104], based on the usage of explicitly correlated Gaussian functions and the global vector representation, is extended with the complex coordinate rotation method. The developed computer program is used to calculate resonance energies and widths for the three-particle positronium anion, Ps(-), and the four-particle positronium molecule, Ps(2). Furthermore, the excited bound and resonance rovibronic states of the four particle H2 molecule are also considered. Resonance energies and widths are estimated for the lowest-energy resonances of H(2) beyond the b (3)?(u)(+) continuum. PMID- 23675888 TI - Editorial comment to regenerative medicine as a new therapeutic strategy for lower urinary tract dysfunction. PMID- 23675890 TI - Electron-deficient poly(p-phenylene vinylene) provides electron mobility over 1 cm2 V(-1) s(-1) under ambient conditions. AB - Poly(p-phenylene vinylene) derivatives (PPVs) are one of the most widely investigated p-type polymers in organic electronics. PPVs generally exhibit electron mobilities lower than 10(-4) cm(2) V(-1) s(-1), thus hindering their applications in high-performance polymer field-effect transistors and organic photovoltaics. Herein, we design and synthesize a novel electron-deficient PPV derivative, benzodifurandione-based PPV (BDPPV). This new PPV derivative displays high electron mobilities up to 1.1 cm(2) V(-1) s(-1) under ambient conditions (4 orders of magnitude higher than those of other PPVs), because it overcomes common defects in PPVs, such as conformational disorder, weak interchain interaction, and a high LUMO level. BDPPV represents the first polymer that can transport electrons over 1 cm(2) V(-1) s(-1) under ambient conditions. PMID- 23675891 TI - Seroprevalence of bovine ephemeral fever virus in domesticated and wildlife species during epidemic and inter-epidemic periods (2000-2009) in Israel. AB - Bovine ephemeral fever (BEF) is an economically important vector-borne viral disease of cattle and buffalo. It has been reported from most of the world's tropical and subtropical regions. In the last few decades, outbreaks of BEF have occurred in Israel almost every other year. Several serological studies have demonstrated a wide range of wild animal species that are positive for BEF virus (BEFV) antibodies. However, the question of whether wild animals and domesticated species other than cattle also play an important role in the maintenance and transmission of BEFV in Israel remains. Here, we examined the prevalence of anti BEFV antibodies in 942 samples collected from various wild, semi-captive and domesticated animal species during the years 2000-2009 using the serum neutralization (SN) method. SN test revealed the presence of BEFV-neutralizing antibodies in nine samples (0.96%), from three species: Bubalus bubalis (4/29, 13.79%), Gazella g. gazella (3/68, 4.44%) and Dama d. mesopotamica (2/296, 0.68%). All positive samples were collected in areas of earlier outbreaks. The low prevalence of positive animals and the solid correlation with prior outbreaks indicate that the tested species probably do not serve as virus reservoirs and may play only a minor role in the maintenance of BEFV in the Middle East. PMID- 23675892 TI - Effects of the bolus volume on hyoid movements in normal individuals. AB - The hyoid bone moves during swallowing due to contraction of suprahyoid muscles, which are critical components of normal swallowing function. It has been reported that the muscle force and shortening velocity decline gradually with age. Reduced hyoid velocities may delay the sealing of the laryngeal vestibule and opening of the cricopharyngeal muscle. We hypothesised that the hyoid velocity could be a factor influencing aspiration. This study evaluated effects of bolus volume changes on the hyoid distance and velocity in normal swallowing. The subjects were 21 healthy young adults. Lateral projection videofluorography was recorded while each subject swallowed 2.5, 5.0, 10 and 20 mL of liquid barium. We evaluated the maximum hyoid distance (Max d), anterior and superior distance (Max ad, Max sd). And, we evaluated the maximum velocity (Max v), anterior and superior velocity (Max av, Max sv). Two-way anova test revealed that Max d, Max ad and Max sd for different bolus volumes are not significantly different. But, two-way anova test showed statistically significant difference in Max v, Max av and Max sv among different bolus volume (P < 0.01). Tukey's test showed that there are significant differences in Max v between 2.5 and 20 mL, 5.0 and 20 mL, 10 and 20 mL, and 2.5 and 10 mL swallowing. And, Tukey's test showed significant differences in Max av and Max sv between 2.5 and 20 mL, 5.0 and 20 mL, and 10 and 20 mL swallowing. It is possible that a larger bolus volume requires greater maximum hyoid velocity. We plan to study hyoid velocity in elderly subjects and in those with dysphagia. PMID- 23675893 TI - Sharing stories: indigenous alcohol and other drug workers' well-being, stress and burnout. AB - BACKGROUND: Indigenous alcohol and other drug (AOD) workers' roles are often exhausting, poorly paid and under-recognised. There has been relatively little examination of work-related stressors on their health and well-being. This national study identified Indigenous AOD workers' experiences and perspectives on well-being, stress and burnout along with strategies to improve worker well being. METHODS: Focus groups were conducted with 121 participants (70 Indigenous, 20 non-Indigenous, 31 unspecified) from metropolitan, rural and remote locations around Australia, selected via a purposive sampling strategy. Audio files and interview notes were analysed to identify key themes. RESULTS: Main themes identified included excessive workloads, extensive demands and expectations, workers' proximity to communities, loss and grief issues, lack of recognition, inadequate rewards, stigma and racism, and Indigenous ways of working. Stressors were compounded by workers' complex personal circumstances, profound levels of loss and grief, and lack of culturally safe working environments. DISCUSSION AND CONCLUSION: Indigenous workers' stress was exacerbated by close links and responsibilities to their communities and a 'dual accountability', being constantly on call, playing multiple roles, complex personal and professional lives, and needing to interact with multiple agencies. Many Indigenous AOD workers had developed mechanisms to deal with work-related pressures and received valued support from their communities. The study identified the importance of workforce strategies to improve Indigenous workers' well-being and reduce stress, including: mutual support networks, training in assertiveness and boundary setting, workloads that take account of Indigenous ways of working, adequate remuneration, supervision and mentorship, and cultural sensitivity training for non-Indigenous workers. PMID- 23675894 TI - Hepatoportal sclerosis (obliterative portal venopathy) and nodular regenerative hyperplasia in a patient with myasthenia gravis: A case report and review of the published work. AB - Nodular regenerative hyperplasia (NRH) and hepatoportal sclerosis, also known as obliterative portal venopathy (OPV), are two causes of non-cirrhotic portal hypertension (NCPH). NCPH is an increasingly recognized entity that can be seen in association with collagen vascular diseases and with the use of medications such as azathioprine and didanosine, but oftentimes the etiology remains unidentified. We herein report a case of NCPH occurring due to OPV and NRH in a 64-year-old woman with myasthenia gravis (MG), status post-thymectomy. Portal hypertension was diagnosed incidentally on computed tomography in the absence of predisposing factors. Extensive work-up to determine the etiology of any underlying liver disease was unrevealing. NRH and OPV were identified on liver biopsy. Subsequently, the patient had variceal bleeding that necessitated transjugular intrahepatic portosystemic shunt placement. A few similar cases of NCPH occurring in the setting of MG have been previously reported, suggesting that the immunological mechanisms involved in the pathogenesis of myasthenia may also have contributed to the development of NCPH. PMID- 23675895 TI - Transgenic resistance to Bamboo mosaic virus by expression of interfering satellite RNA. AB - Plant genetic engineering has broadened the options for plant virus resistance and is mostly based on pathogen-derived resistance. Previously, we have shown that interfering satellite RNA (satRNA) of Bamboo mosaic virus (satBaMV) greatly reduces Bamboo mosaic virus (BaMV) accumulation and BaMV-induced symptoms in co inoculated plants. Here, we generated a nonviral source of virus-resistant transgenic Nicotiana benthamiana and Arabidopsis thaliana by introducing interfering satBaMV. Asymptomatic transgenic N. benthamiana lines were highly resistant to BaMV virion and viral RNA infection, and the expression of the transgene BSL6 was higher in asymptomatic than mildly symptomatic lines. In addition, BaMV- and satBaMV-specific small RNAs were detectable only after BaMV challenge, and their levels were associated with genomic viral RNA or satRNA levels. By transcriptomic analysis, the salicylic acid (SA) signalling pathway was not induced in satBaMV transgenic A. thaliana in mock conditions, suggesting that two major antiviral mechanisms, RNA silencing and SA-mediated resistance, are not involved directly in transgenic satBaMV-mediated BaMV interference. In contrast, resistance is associated with the level of the interfering satBaMV transgene. We propose satBaMV-mediated BaMV interference in transgenic plants by competition for replicase with BaMV. PMID- 23675897 TI - Inhibition of hedgehog/Gli signaling by botanicals: a review of compounds with potential hedgehog pathway inhibitory activities. AB - The hedgehog (Hh) signaling pathway is an important therapeutic target in cancer; involvement of the Hh pathway has been shown in a variety of cancers including basal cell carcinoma, medulloblastoma, leukemia, and gastrointestinal, breast, prostate, lung, and pancreatic cancers [1-10]. Currently, several Hh pathway inhibitory drugs are in clinical development, and the FDA recently approved Erivedge (vismodegib) from Curis/Genentech [11-15]. These new drugs are effective in many, but not all patients [16]. In fact there are documented reports of tumors developing mutations that confer resistance to the drugs [14, 17-19]. This highlights the importance of finding second generation drugs that can be used on cancers that develop resistance to the first generation Hh inhibitors. Botanicals may serve as the backbone for such research. The gold-standard pathway inhibitor, cyclopamine, is itself a naturally occurring alkaloid found in Veratrum californicum [20]. In this review we will summarize the available literature on botanical compounds in Hh-related studies. In particular we will look at curcumin, genistein, EGCG, resveratrol, quercetin, baicalen, and apigenin along with novel compounds isolated from Southeast Asian plants, such as the potent sub micromolar gitoxigenin derivatives. Due to the nature of the pathway, most of the research published has focused on functional Gli-transcriptional assays, which we will describe and summarize. PMID- 23675898 TI - Expansion of orifices of open C60 derivatives and formation of an open C59S derivative by reaction with sulfur. AB - The reaction of a tetraketo-open-cage C60 derivative with elemental sulfur in the presence of tetrakis(dimethylamino)ethylene afforded novel open C60 derivatives containing sulfur atom(s) in the rim of the orifice and the first example of an open C59S derivative. The single crystal X-ray analyses clearly determined these structures and demonstrated that a water molecule was encapsulated inside the cages. The orifice sizes and electronic properties of these fullerene derivatives were revealed. PMID- 23675896 TI - Stat and interferon genes identified by network analysis differentially regulate primitive and definitive erythropoiesis. AB - BACKGROUND: Hematopoietic ontogeny is characterized by overlapping waves of primitive, fetal definitive, and adult definitive erythroid lineages. Our aim is to identify differences in the transcriptional control of these distinct erythroid cell maturation pathways by inferring and analyzing gene-interaction networks from lineage-specific expression datasets. Inferred networks are strongly connected and do not fit a scale-free model, making it difficult to identify essential regulators using the hub-essentiality standard. RESULTS: We employed a semi-supervised machine learning approach to integrate measures of network topology with expression data to score gene essentiality. The algorithm was trained and tested on the adult and fetal definitive erythroid lineages. When applied to the primitive erythroid lineage, 144 high scoring transcription factors were found to be differentially expressed between the primitive and adult definitive erythroid lineages, including all expressed STAT-family members. Differential responses of primitive and definitive erythroblasts to a Stat3 inhibitor and IFNgamma in vitro supported the results of the computational analysis. Further investigation of the original expression data revealed a striking signature of Stat1-related genes in the adult definitive erythroid network. Among the potential pathways known to utilize Stat1, interferon (IFN) signaling-related genes were expressed almost exclusively within the adult definitive erythroid network. CONCLUSIONS: In vitro results support the computational prediction that differential regulation and downstream effectors of STAT signaling are key factors that distinguish the transcriptional control of primitive and definitive erythroid cell maturation. PMID- 23675899 TI - Analysis of biomolecular solvation sites by 3D-RISM theory. AB - We derive, implement, and apply equilibrium solvation site analysis for biomolecules. Our method utilizes 3D-RISM calculations to quickly obtain equilibrium solvent distributions without either necessity of simulation or limits of solvent sampling. Our analysis of these distributions extracts highest likelihood poses of solvent as well as localized entropies, enthalpies, and solvation free energies. We demonstrate our method on a structure of HIV-1 protease where excellent structural and thermodynamic data are available for comparison. Our results, obtained within minutes, show systematic agreement with available experimental data. Further, our results are in good agreement with established simulation-based solvent analysis methods. This method can be used not only for visual analysis of active site solvation but also for virtual screening methods and experimental refinement. PMID- 23675900 TI - Consistency of compliance with nutrition-related regulations among Delaware child care centers. AB - BACKGROUND: As more calls are made in the literature for nutrition interventions to be delivered in child care settings, research on the implementation of these interventions becomes more important. This study examined compliance with Delaware's regulations related to nutrition in child care settings, which are designed to improve the nutrition-related environment in these settings. METHODS: A stratified random sample of licensed child care centers (n=233) was created from the total population of eligible centers in Delaware (N=450). Study staff visited each center and distributed self-administered surveys to the director and two randomly selected teachers. Surveys contained items about classroom-level compliance with the regulations along with center-level characteristics. Bivariate analyses were conducted to explore relationships between consistent compliance with each regulation component and center-level characteristics. RESULTS: A total of 179 of the 233 centers in the selected sample participated in the study. Compliance with the regulations varied within centers and across components; the highest levels of consistent compliance were reported for juice type (88.3%) and the lowest levels for whole grains (18.6%). Center characteristics, such as participation in the Child and Adult Care Food Program, were associated with consistent compliance for certain regulations components. CONCLUSIONS: Our results suggest that these types of regulations can be implemented across a diversity of centers, but that certain components (e.g., those relating to whole grains and water) may need further clarification. Our results also suggest that there are certain types of centers on which to focus training efforts to maximize compliance. PMID- 23675901 TI - Copper(I)-catalyzed synthesis of 5-arylindazolo[3,2-b]quinazolin-7(5H)-one via Ullmann-type reaction. AB - The treatment of 2-amino-N'-arylbenzohydrazide and o-halogenated benzaldehyde in the presence of CuBr and Cs2CO3 gave 5-arylindazolo[3,2-b]quinazolin-7(5H)-one in high yields. This procedure contains an Ullmann-type reaction and provides an efficient method to construct fused tetracyclic heterocycles. PMID- 23675902 TI - Lepromatous leprosy treated with combined chemotherapy and immunotherapy (injection BCG): three case reports. AB - BACKGROUND: Lepromatous leprosy is associated with suppressed cell-mediated immunity (CMI). This results in failure of the body to mount an efficient immune response and may render chemotherapy ineffective. The lack of sufficient response may mimic drug resistance. Three case reports in which the immunity was stimulated by administering Injection BCG are presented. All three patients were initially anergic and showed no reaction at the Mantoux testing site, showing an inability to mount type IV hypersensitivity and characterized by live bacilli in smears. Following 1-4 doses of Injection BCG, all three showed dead bacilli in smears. CASE REPORTS: The first case, a 61-year-old man with lepromatous leprosy who continued to show live bacilli in smears after prolonged chemotherapy, was administered a total of four BCG injections, following which he achieved clearance. The second, a 40-year-old man with borderline lepromatous leprosy and severe type 2 reactions, achieved bacterial clearance and control of severe reactions following a single injection. The third, a 67-year-old man with histoid leprosy, achieved effective bacterial killing with a single dose of Injection BCG. RESULTS: All three patients achieved good results when chemotherapy was combined with Injection BCG. Following Injection BCG, all three showed a reaction at the Mantoux testing site. CONCLUSIONS: Suppressed CMI may be responsible for the lack of response in recalcitrant cases of lepromatous leprosy. These case reports would lead to the trend in combination therapy (immunotherapy combined with chemotherapy) for such cases, and help lower the tendency for inappropriate diagnosis of drug-resistant leprosy. PMID- 23675903 TI - Clinical analysis of the PADUA and the RENAL scoring systems for renal neoplasms: a retrospective study of 245 patients undergoing laparoscopic partial nephrectomy. AB - OBJECTIVE: To investigate the clinical significance of preoperative aspects and dimensions used for anatomic (PADUA) and radius exophytic/endophytic nearness anterior/posterior location (RENAL) scoring systems for renal neoplasms in patients undergoing laparoscopic partial nephrectomy. METHODS: A retrospective analysis was carried out on clinical data of 245 Chinese patients with renal neoplasms undergoing laparoscopic partial nephrectomy from June 2008 to June 2012. The perioperative complications and variables, as well as PADUA and RENAL score, were compared. RESULTS: The PADUA and RENAL scoring systems were significantly associated with percent change in estimated glomerular filtration rate (P = 0.032 and P = 0.026 respectively), whereas the RENAL scoring system was also significantly associated with warm ischemia time (P = 0.032). On multivariate analysis, both scores were able to predict percent change in estimated glomerular filtration rate (PADUA, P = 0.011; RENAL, P = 0.028). There were no significant associations between the two scoring systems assessed and the occurrence of complications or tumor stage. The correlation between PADUA classification and RENAL nephrometry score was significant (P < 0.0001). Fleiss' generalized kappa was 0.69-0.89 for the various components of the PADUA score and 0.67-0.89 for the RENAL nephrometry components. CONCLUSIONS: The PADUA classification and RENAL nephrometry score are comprehensive assessment tools for delineating renal tumor anatomy. The reproducibility of the PADUA and RENAL scores is substantial, but further research is required to evaluate its performance in more accurately predicting operative and patient-related outcomes. PMID- 23675904 TI - Synchrotron-based mass spectrometry to investigate the molecular properties of mineral-organic associations. AB - Soil organic matter (SOM) is important because its decay drives life processes in the biosphere. Analysis of organic compounds in geological systems is difficult because of their intimate association with mineral surfaces. To date there is no procedure capable of quantitatively separating organic from mineral phases without creating artifacts or mass loss. Therefore, analytical techniques that can (a) generate information about both organic and mineral phases simultaneously and (b) allow the examination of predetermined high-interest regions of the sample as opposed to conventional bulk analytical techniques are valuable. Laser desorption synchrotron postionization (synchrotron-LDPI) mass spectrometry is introduced as a novel analytical tool to characterize the molecular properties of organic compounds in mineral-organic samples from terrestrial systems, and it is demonstrated that, when combined with secondary ion mass spectrometry (SIMS), it can provide complementary information on mineral composition. Mass spectrometry along a decomposition gradient in density fractions verifies the consistency of our results with bulk analytical techniques. We further demonstrate that, by changing laser and photoionization energies, variations in molecular stability of organic compounds associated with mineral surfaces can be determined. The combination of synchrotron-LDPI and SIMS shows that the energetic conditions involved in desorption and ionization of organic matter may be a greater determinant of mass spectral signatures than the inherent molecular structure of the organic compounds investigated. The latter has implications for molecular models of natural organic matter that are based on mass spectrometric information. PMID- 23675905 TI - Thermodynamics of tetravalent thorium and uranium complexes from first-principles calculations. AB - Enthalpies of formation for the ThX4 and UX4 (X = F, Cl, OH) species have been investigated with density functional theory and coupled-cluster methods. ThX4 molecules are all confirmed as tetrahedral, while all UX4 molecules are predicted to adopt D2d symmetry using density functional theory. Multireference coupled cluster approaches confirm the D2d symmetry for UF4. The bonding is mostly ionic, and predicted formation energies for the halogen species show good agreement with experiment. Our calculated hydration energy of UF4 (-54.0 kcal/mol) is in very good agreement with the experimental data (-54.8 kcal/mol). We predict CCSD(T) formation energies of DeltafG[U(OH)4(g)] = -286.3 kcal/mol and DeltafG[U(OH)4(aq)] = -318.7 kcal/mol. DeltafG[U(OH)4(aq)] is 21 kcal/mol less stable than the established experimental thermodynamic data. PMID- 23675906 TI - Atomic-scale surface roughness of rutile and implications for organic molecule adsorption. AB - Crystal surfaces provide physical interfaces between the geosphere and biosphere. It follows that the arrangement of atoms at the surfaces of crystals profoundly influences biological components at many levels, from cells through biopolymers to single organic molecules. Many studies have focused on the crystal-molecule interface in water using large, flat single crystals. However, little is known about atomic-scale surface structures of the nanometer- to micrometer-sized crystals of simple metal oxides typically used in batch adsorption experiments under conditions relevant to biogeochemistry and the origins of life. Here, we present atomic-resolution microscopy data with unprecedented detail of the circumferences of nanosized rutile (alpha-TiO2) crystals previously used in studies of the adsorption of protons, cations, and amino acids. The data suggest that one-third of the {110} faces, the largest faces on individual crystals, consist of steps at the atomic scale. The steps have the orientation to provide undercoordinated Ti atoms of the type and abundance for adsorption of amino acids as inferred from previous surface complexation modeling of batch adsorption data. A remarkably uniform pattern of step proportions emerges: the step proportions are independent of surface roughness and reflect their relative surface energies. Consequently, the external morphology of rutile nanometer- to micrometer-sized crystals imaged at the coarse scale of scanning electron microscope images is not an accurate indicator of the atomic smoothness or of the proportions of the steps present. Overall, our data strongly suggest that amino acids attach at these steps on the {110} surfaces of rutile. PMID- 23675907 TI - Expression analysis of MND1/GAJ, SPATA22, GAPDHS and ACR genes in testicular biopsies from non-obstructive azoospermia (NOA) patients. AB - BACKGROUND: High-throughput studies provide a wide spectrum of genes for use as predictive markers during testicular sperm extraction (TESE) in combination with ICSI. In this work, we used the specimens from testicular biopsies of men with non-obstructive azoospermia who underwent TESE to investigate the expression of spermatogenesis-related genes MND1, SPATA22, GAPDHS and ACR. METHODS: Testicular biopsy specimens were subdivided into three groups: hypospermatogenesis (HS); maturation arrest (MA); and Sertoli cell-only syndrome (SCO). The levels of expression of the spermatogenesis-related genes MND1, SPATA22, GAPDHS and ACR in the testes were compared among these three groups using the reverse transcription polymerase chain reaction (RT-PCR) technique. RESULTS: Analysis of the expression of spermatogenic genes in human testes with abnormal spermatogenesis showed different expression patterns in patients from different groups. Fertilization rate for studied set of patients was 66% and pregnancy rate 29%. For HS group fertilization rate was 72% and pregnancy rate 32%, while for MA group fertilization and pregnancy rates were 54% and 26%, respectively. Fertilization rates in relation to the studied genes were uniformly around 70%, pregnancy rates for ACR and GAPDHS genes were surprisingly low at 6% and 8% correspondingly. CONCLUSIONS: Analysis of the expression of genes involved in spermatogenesis can be a fast additional test for the level of spermatogenesis in testicular samples. PMID- 23675908 TI - Cooperative self-assembly of discoid dimers: hierarchical formation of nanostructures with a pH switch. AB - Derivatives of the self-complementary 2-guanidiniocarbonyl pyrrole 5-carboxylate zwitterion (1) (previously reported by us to dimerize to 1*1 with an aggregation constant of ca. >10(10) M(-l) in DMSO) aggregate in a diverse manner depending on, e.g., variation of concentration or its protonation state. The mode of aggregation was analyzed by spectroscopic (NMR, UV) and microscopic (AFM, SEM, HIM, and TEM) methods. Aggregation of dimers of these zwitterions to higher supramolecular structures was achieved by introduction of sec-amide substituents at the 3-position, i.e., at the rearward periphery of the parent binding motif. A butyl amide substituent as in 2b enables the discoid dimers to further aggregate into one-dimensional (rod-like) stacks. Quantitative UV dilution studies showed that this aggregation is strongly cooperative following a nucleation elongation mechanism. The amide hydrogen seems to be essential for this rod-like aggregation, as neither 1 nor a corresponding tert-amide congener 2a form comparable structures. Therefore, a hydrogen bond-assisted pi-pi-interaction of the dimeric zwitterions is suggested to promote this aggregation mode, which is further affected by the nature of the amide substituent (e.g., steric demand), enabling the formation of bundles of strands or even two-dimensional sheets. By exploiting the zwitterionic nature of the aggregating discoid dimers, a reversible pH switch was realized: dimerization of all compounds is suppressed by protonation of the carboxylate moiety, converting the zwitterions into typical cationic amphiphiles. Accordingly, typical nanostructures like vesicles, tubes, and flat sheets are formed reversibly under acidic conditions, which reassemble into the original rod-like aggregates upon readjustment to neutral pH. PMID- 23675909 TI - Effects of experimental occlusal interference on body posture: an optoelectronic stereophotogrammetric analysis. AB - In recent years, there has been increasing interest in the relationship between dental occlusion and body posture both among people and in scientific literature. The aim of the present longitudinal study is to investigate the effects of an experimental occlusal interference on body posture by means of a force platform and an optoelectronic stereophotogrammetric analysis. An occlusal interference of a 0- to 2-mm-thick glass composite was prepared to disturb the intercuspal position while not creating interference during lateral or protrusive mandibular excursions. Frontal and sagittal kinematic parameters, dynamic gait measurements and superficial electromyographic (SEMG) activity of head and neck muscles were performed on 12 healthy subjects. Measurements were taken 10 days before the application of the occlusal interference, and then immediately before the application, the day after it, and at a distance of 7 and 14 days under four different exteroceptive conditions. The outcomes of this study show that an occlusal interference does not modify significantly over time static and dynamic parameters of body posture under different exteroceptive conditions. It has a minimal influence only on the frontal kinematic parameters related to mandibular position, and it induces a transient increase of the activity of masticatory muscles. In this study, the experimental occlusal interference did not significantly influence the body posture during a 14-day follow-up period. PMID- 23675910 TI - Cyclometalated iridium complexes of bis(aryl) phosphine ligands: catalytic C-H/C D exchanges and C-C coupling reactions. AB - This work details the synthesis and structural identification of a series of complexes of the (eta(5)-C5Me5)Ir(III) unit coordinated to cyclometalated bis(aryl)phosphine ligands, PR'(Ar)2, for R' = Me and Ar = 2,4,6-Me3C6H2, 1b; 2,6 Me2-4-OMe-C6H2, 1c; 2,6-Me2-4-F-C6H2, 1d; R' = Et, Ar = 2,6-Me2C6H3, 1e. Both chloride- and hydride-containing compounds, 2b-2e and 3b-3e, respectively, are described. Reactions of chlorides 2 with NaBArF (BArF = B(3,5-C6H3(CF3)2)4) in the presence of CO form cationic carbonyl complexes, 4(+), with nu(CO) values in the narrow interval 2030-2040 cm(-1), indicating similar pi-basicity of the Ir(III) center of these complexes. In the absence of CO, NaBArF forces kappa(4) P,C,C',C" coordination of the metalated arm (studied for the selected complexes 5b, 5d, and 5e), a binding mode so far encountered only when the phosphine contains two benzylic groups. A base-catalyzed intramolecular, dehydrogenative, C C coupling reaction converts the kappa(4) species 5d and 5e into the corresponding hydrido phosphepine complexes 6d and 6e. Using CD3OD as the source of deuterium, the chlorides 2 undergo deuteration of their 11 benzylic positions whereas hydrides 3 experience only D incorporation into the Ir-H and Ir-CH2 sites. Mechanistic schemes that explain this diversity have come to light thanks to experimental and theoretical DFT studies that are also reported. PMID- 23675911 TI - New substituted benzimidazole derivatives: a patent review (2010 - 2012). AB - INTRODUCTION: Benzimidazole is a heterocyclic aromatic system, which is part of some natural and many synthetic compounds. A large number of benzimidazoles and its derivatives are found to be biologically active against many diseases. Researchers around the world are paying greater attention to and showing increasing interests in this field. AREAS COVERED: Areas covered in this paper include a review of the synthesis, biological effects and mechanisms of benzimidazole derivatives in the past 2 years, based on literature and patents. The patent databases SciFinder and esp@cenet were used to locate patent applications that were published between 2010 to present. Information from articles published is also included. The current state and problems are also discussed. EXPERT OPINION: Benzimidazole derivatives possess a broad spectrum of biological activities, whose scopes of treatment ranging from ordinary antimicrobial activities to world's most deadly diseases. However, challenges such as drug resistance, relatively little knowledge of structure of receptors and rare convenient methods for synthesis of benzimidazoles still exist. PMID- 23675912 TI - Reproductive and post-reproductive life history of wild-caught Drosophila melanogaster under laboratory conditions. AB - The life history of the fruit fly (Drosophila melanogaster) is well understood, but fitness components are rarely measured by following single individuals over their lifetime, thereby limiting insights into lifetime reproductive success, reproductive senescence and post-reproductive lifespan. Moreover, most studies have examined long-established laboratory strains rather than freshly caught individuals and may thus be confounded by adaptation to laboratory culture, inbreeding or mutation accumulation. Here, we have followed the life histories of individual females from three recently caught, non-laboratory-adapted wild populations of D. melanogaster. Populations varied in a number of life-history traits, including ovariole number, fecundity, hatchability and lifespan. To describe individual patterns of age-specific fecundity, we developed a new model that allowed us to distinguish four phases during a female's life: a phase of reproductive maturation, followed by a period of linear and then exponential decline in fecundity and, finally, a post-ovipository period. Individual females exhibited clear-cut fecundity peaks, which contrasts with previous analyses, and post-peak levels of fecundity declined independently of how long females lived. Notably, females had a pronounced post-reproductive lifespan, which on average made up 40% of total lifespan. Post-reproductive lifespan did not differ among populations and was not correlated with reproductive fitness components, supporting the hypothesis that this period is a highly variable, random 'add-on' at the end of reproductive life rather than a correlate of selection on reproductive fitness. Most life-history traits were positively correlated, a pattern that might be due to genotype by environment interactions when wild flies are brought into a novel laboratory environment but that is unlikely explained by inbreeding or positive mutational covariance caused by mutation accumulation. PMID- 23675913 TI - Oral bioavailability and stability study of a self-emulsifying drug delivery system (SEDDS) of amphotericin B. AB - Amphotericin B (AmB) is a poorly water soluble polyene antifungal antibiotic which is negligibly absorbed from the gastro intestinal tract after oral administration. The objective of this research work was to study the oral bioavailability and stability of a self-emulsifying drug delivery system (SEDDS) of amphotericin B (AmB). The SEDDS formulation consisted of glyceryl monooleate, tween 80, polyethylene glycol 400 (PEG 400) and propylene glycol and had AmB content of about 8 mg per ml. The stability of the SEDDS formulation was studied in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) in comparison to pure drug. Oral bioavailability of the SEDDS formulation was studied in rats in comparison to the pure drug. The formulation was filled in two different types of capsule shell, namely HPMC capsule and hard gelatin capsule and stability of the formulation was studied for 3 months. The SEDDS formulation resulted in a mean AUC value of 40.57ug/ml.hr with mean peak plasma concentration of 6.17ug/ml reached after 2 hours after oral administration in rats, whereas concentration of AmB in plasma was not detectable after administration of the pure drug. The formulation filled in hard gelatin capsule shell was physically and chemically stable for more than 3 months under refrigeration (4 degrees C). The study demonstrates that SEDDS approach can be successfully utilized for oral delivery of AmB. PMID- 23675915 TI - Sub-diffusion decays in fluorescence correlation spectroscopy: dye photophysics or protein dynamics? AB - Transitions between bright and dark fluorescent states of several rhodamine dyes were investigated by fluorescence correlation spectroscopy. We resolved two sub diffusion exponential decays for free rhodamines in aqueous solutions, of which the slower component scales linearly with the viscosity of the solution. Correlation data for proteins and DNA labeled with tetramethylrhodamine were fitted with three to four exponential decays describing flickering dynamics on a time scale between 0.5 and 100 MUs. We investigated the nature of these processes by performing experiments under different experimental conditions and for different samples. On the basis of how their population and lifetime change with viscosity, the oxygen content of the solution, the laser irradiance, and the detection geometry, we assigned these states, in the order of increasing lifetimes, to a triplet state, a hybrid between twisted-intramolecular-charge transfer state and a ground state lactonic state, a lactonic state, and a photoionized state, respectively. Our data suggests that none of the observed sub diffusion correlation decays can be directly assigned to the intramolecular dynamics of the labeled biomolecules. However, we found evidence that the intrinsic conformational dynamics of the biomolecule appears in the correlation curves as a modulation of the photophysics of the dye label. This shows the importance of accurate control measurements and appropriate modeling of the dye photophysics in fluorescence correlation studies, and it cautions against direct assignments of dark-state relaxation times to folding kinetics in proteins and nucleic acids. PMID- 23675916 TI - Ionization behavior of chitosan and chitosan-DNA polyplexes indicate that chitosan has a similar capability to induce a proton-sponge effect as PEI. AB - Polycations having a high buffering capacity in the endosomal pH range, such as polyethylenimine (PEI), are known to be efficient at delivering nucleic acids by overcoming lysosomal sequestration possibly through the proton sponge effect, although other mechanisms such as membrane disruption arising from an interaction between the polycation and the endosome/lysosome membrane, have been proposed. Chitosan is an efficient delivery vehicle for nucleic acids, yet its buffering capacity has been thought to be significantly lower than that of PEI, suggesting that the molecular mechanism responsible for endolysosomal escape was not proton sponge based. However, previous comparisons of PEI and chitosan buffering capacity were performed on a mass concentration basis instead of a charge concentration basis, the latter being the most relevant comparison basis because polycation-DNA complexes form at ratios of charge groups (amine to phosphate), rather than according to mass. We hypothesized that chitosan has a high buffering capacity when compared to PEI on a molar basis and could therefore possibly mediate endolysosomal release through the proton sponge effect. In this study, we examined the ionization behavior of chitosan and chitosan-DNA complexes and compared to that of PEI and polylysine on a charge concentration basis. A mean field theory based on the use of the Poisson-Boltzmann equation and an Ising model were also applied to model ionization behavior of chitosan and PEI, respectively. We found that chitosan has a higher buffering capacity than PEI in the endolysosomal pH range, while the formation of chitosan-DNA complexes reduces chitosan buffering capacity because of the negative electrostatic environment of nucleic acids that facilitates chitosan ionization. These data suggest that chitosans have a similar capacity as PEI to mediate endosomal escape through the proton sponge effect, possibly in a manner which depends on the presence of excess chitosan. PMID- 23675914 TI - Epidemiology, molecular virology and diagnostics of Schmallenberg virus, an emerging orthobunyavirus in Europe. AB - After the unexpected emergence of Bluetongue virus serotype 8 (BTV-8) in northern Europe in 2006, another arbovirus, Schmallenberg virus (SBV), emerged in Europe in 2011 causing a new economically important disease in ruminants. The virus, belonging to the Orthobunyavirus genus in the Bunyaviridae family, was first detected in Germany, in The Netherlands and in Belgium in 2011 and soon after in the United Kingdom, France, Italy, Luxembourg, Spain, Denmark and Switzerland. This review describes the current knowledge on the emergence, epidemiology, clinical signs, molecular virology and diagnosis of SBV infection. PMID- 23675917 TI - Degradation of progestagens by oxidation with potassium permanganate in wastewater effluents. AB - BACKGROUND: This study investigated the oxidation of selected progestagenic steroid hormones by potassium permanganate at pH 6.0 and 8.0 in ultrapure water and wastewater effluents, using bench-scale assays. Second order rate constants for the reaction of potassium permanganate with progestagens (levonorgestrel, medroxyprogesterone, norethindrone and progesterone) was determined as a function of pH, presence of natural organic matter and temperature. This work also illustrates the advantages of using a novel analytical method, the laser diode thermal desorption (LDTD-APCI) interface coupled to tandem mass spectrometry apparatus, allowing for the quick determination of oxidation rate constants and increasing sample throughput. RESULTS: The second-order rate constants for progestagens with permanganate determined in bench-scale experiments ranged from 23 to 368 M(-1) sec(-1) in both wastewater and ultrapure waters with pH values of 6.0 and 8.0. Two pairs of progestagens exhibited similar reaction rate constants, i.e. progesterone and medroxyprogesterone (23 to 80 M(-1) sec(-1) in ultrapure water and 26 to 149 M(-1) sec(-1) in wastewaters, at pH 6.0 and 8.0) and levonorgestrel and norethindrone (179 to 224 M(-1) sec(-1) in ultrapure water and 180 to 368 M(-1) sec(-1) in wastewaters, at pH 6.0 and 8.0). The presence of dissolved natural organic matter and the pH conditions improved the oxidation rate constants for progestagens with potassium permanganate only at alkaline pH. Reaction rates measured in Milli-Q water could therefore be used to provide conservative estimates for the oxidation rates of the four selected progestagens in wastewaters when exposed to potassium permanganate. The progestagen removal efficiencies was lower for progesterone and medroxyprogesterone (48 to 87 %) than for levonorgestrel and norethindrone (78 to 97%) in Milli-Q and wastewaters at pH 6.0-8.2 using potassium permanganate dosages of 1 to 5 mg L(-1) after contact times of 10 to 60 min. CONCLUSION: This work presents the first results on the permanganate-promoted oxidation of progestagens, as a function of pH, temperature as well as NOM. Progestagen concentrations used to determine rate constants were analyzed using an ultrafast laser diode thermal desorption interface coupled to tandem mass spectrometry for the analysis of water sample for progestagens. PMID- 23675918 TI - Cleavage of carbon-carbon triple bond: direct transformation of alkynes to nitriles. AB - A new cleavage reaction of carbon-carbon triple bonds proceeds efficiently with NIS and TMSN3, giving the corresponding nitriles in moderate to good yields. PMID- 23675919 TI - An annular patch of the scalp reveals tertiary syphilis. PMID- 23675920 TI - 'Oseltamivir hot topic issue': a one-stop shop for oseltamivir. PMID- 23675921 TI - Oseltamivir pharmacology in young children: a commentary. AB - Oseltamivir is listed by the World Health Organization as an essential drug for the treatment and prophylaxis of both seasonal and pandemic influenza. Since influenza mortality is highest in neonates and infants, optimal dosing of oseltamivir in this high risk population is of utmost public health concern. To date, only two major clinical trials have been conducted investigating oselatmivir exposure and exposure/response in neonates and infants. The first study was a prospective, open label pharmacokinetic/pharmacodynamic and safety evaluation of oseltamivir in a total of 87 young children less than 2 years of age and was conducted by the National Institute of Allergy and Infectious Diseases (NIAID) Collaborative Antiviral Study Group (CASG). The second Roche sponsored study was also an open label, prospective, pharmacokinetic/ pharmacodynamic and safety evaluation of oseltamivir in the treatment of 65 children less than 12 months of age. A recent supplemental new drug application (sNDA) was submitted to the Food and Drug Administration (FDA) on the basis of these two studies which resulted in oseltamivir becoming the first and so far only neuraminidase inhibitor to gain FDA approval for treatment of influenza in neonates and infants less than 1 year of age. The two review articles in this volume discuss the complex pharmacokinetics of oseltamivir and its active metabolite oseltamivir carboxylate from different perspectives while attempting to contrast and critique different literature views of the optimal dose in neonates, infants and young children. The articles also offer suggestions to generate more robust pediatric PKPD data and mend current gaps in knowledge. PMID- 23675922 TI - Pharmacokinetics and pharmacodynamics of oseltamivir in neonates, infants and children. AB - Pharmacokinetic-pharmacodynamic (PKPD) studies have the potential to yield useful information on whether and how a drug works, and what dose to use. This approach is often best suited to situations where dose-response relationships need to be elucidated and where randomisation is not feasible. Children make up around one third of cases during influenza outbreaks, and are more susceptible to certain complications such as otitis media. Despite this, high-quality randomised controlled trials (RCT) of antiviral therapies such as oseltamivir have not been performed, leaving open the question of whether and at what dose to use. This review therefore focusses on the available PKPD data in children. Oseltamivir has complex PK which requires modelling to properly understand the relationship between dose and concentration with time, and there is a lack of clarity on appropriate pharmacodynamic endpoints. Following a general overview of oseltamivir PKPD, this review seeks to summarise the available paediatric PKPD data, identify gaps in our knowledge and priorities for future research. PMID- 23675923 TI - Oseltamivir in neonates, infants and young children: a focus on clinical pharmacology. AB - Influenza is a cause of significant morbidity and mortality in young children. It is associated with high annual attack rates as well as being responsible for frequent outpatient visits and hospitalisations. Children aged <2 years are at the highest risk for serious illness or death during the influenza season. The neuraminidase inhibitor oseltamivir has been proven to reduce the duration and severity of illness when treatment is commenced within 48 hours of symptom onset. The H1N1 pandemic of 2009 prompted temporary emergency authorisation of oseltamivir use in infants aged <1 year in the USA. In December 2012, Food and Drug Administration (FDA) reinstated approval of oseltamivir to treat children younger than 1 year old including neonates who have shown symptoms of influenza for less than 48 hours. Current data on the use of oseltamivir in neonates and infants are limited. In this review, we evaluated accumulated data on oseltamivir use in newborns, infants and young children with a special focus on pharmacokinetics, efficacy and safety. PMID- 23675925 TI - Emergence of oseltamivir resistance: control and management of influenza before, during and after the pandemic. AB - Neuraminidase inhibitors (NAIs), such as oseltamivir and zanamivir, are the medicines of choice against influenza A or B. Oseltamivir resistance can be conferred by a single point missense mutation from histidine to tyrosine at position 275 (H275Y) of the neuraminidase gene. Oseltamivir resistance in seasonal influenza A/H1N1 strains rose markedly during the 2007-2008 season. Furthermore, oseltamivir resistant (OsR) strains of pandemic influenza A/H1N1 2009 (influenza A(H1N1)pdm09) have been increasingly isolated, although the majority remain sensitive. These OsR strains retain virulence, replicative fitness and transmissibility from person to person, with outbreaks reported. Treatment options in those at risk of severe or complicated disease are limited to zanamivir which is only licenced in those over the age of 5 years; of further concern, strains demonstrating low level resistance to both oseltamivir and zanamivir have been reported. Strategies to reduce emergence of resistant strains, such as higher dose oseltamivir regimens, need further examination. PMID- 23675924 TI - Towards a personalised approach to managing influenza infections in infants and children - food for thought and a note on oseltamivir. AB - Acute respiratory infections represent common diseases in childhood and a challenge to infection control, public heath, and the clinical management of patients and their families. Children are avid spreaders of respiratory viruses, and seasonal outbreaks of influenza create additional disease burden and healthcare cost. Infants under the age of two and children with chronic conditions are at high risk. The absence of pre-defined risk factors however, does not protect from serious disease. Immunisation rates remain low, and physical interventions are of limited value in young children. Children with influenza may be contagious prior to the onset of symptoms, and school closures have been shown to have a temporary effect at most. The timely detection of influenza in at-risk patients is important to prevent hospital-based transmission and influenza-associated morbidity and mortality. Guidelines issued by professional associations and public health agencies need to be translated into everyday clinical practice. Antiviral therapy should be initiated early and monitored closely, including virologic and clinical outcomes. The duration of treatment and the decision to readmit children to schools and kindergartens should be adjusted to the individual child patient using evidence-based clinical and virologic criteria. This article presents lessons learnt from a quality management program for infants and children with influenza-like illness at the Charite Department of Paediatrics in collaboration with the National Reference Centre for Influenza at the Robert Koch Institute, in Berlin, Germany. The Charite Influenza-Like Disease (ChILD) Cohort was established during the 2009 influenza pandemic and encompasses nearly 4000 disease episodes to date. PMID- 23675926 TI - Oseltamivir for control of influenza at mass gatherings. AB - The use of oseltamivir at mass gatherings (MGs) or other crowded settings has not previously been systematically examined to synthesise the evidence of its usefulness. Here we have evaluated its effectiveness by reviewing the published literature. The effectiveness of oseltamivir at MGs is controversial because published clinical trials evaluating this are lacking. Its use, to date, has been predominantly therapeutic, i.e. to treat patients with confirmed or suspected influenza. There are some examples of its use in mass prophylaxis at MGs and other crowded settings like schools and camps, and closed settings such as prisons and aged care facilities. Most of the available studies indicate that oseltamivir use, whether therapeutic or prophylactic, is effective in containing influenza outbreaks in those settings though there are some reports of moderately high side effects, particularly among young children. Targeted prophylaxis of oseltamivir seems to help contain an outbreak of influenza at MG. A combination of 'treatment of cases' and 'ring prophylaxis of contacts' appears to be a feasible and economically sustainable strategy. Further research needs to be directed to uncertainties (e.g. how, when and for whom oseltamivir should be used) over oseltamivir's place in influenza control at mass gatherings. PMID- 23675927 TI - Oseltamivir use in adolescents and adults: clinical and economic considerations. AB - Influenza remains an important cause of morbidity and mortality, and incurs substantial economic costs (mainly due to hospitalisation) especially for the elderly aged 65 years or more, and among those with high-risk medical conditions. Influenza vaccination is the most effective control measure for both healthy populations and the chronically ill in whom complications of influenza cluster. Unfortunately, vaccination is less effective in the elderly and immunocompromised persons. Additional benefit may accrue from other health care interventions including antiviral therapy. Oseltamivir, a neuraminidase inhibitor, has become a drug of public health importance since it was included in influenza pandemic management plans. Many systematic reviews and meta-analyses of oseltamivir treatment and prophylaxis trials have been published. We provide a summary of the conclusions and review the various findings of economic analyses. Future randomised controlled trials should focus upon costly outcomes such as hospital admissions and should be conducted in populations at high risk of complications from influenza. Future economic analyses need to address variation in (1) willing to-pay value, (2) annual attack rate of influenza, and (3) influenza vaccination effectiveness and uptake rates. PMID- 23675928 TI - On contigs and coverage. AB - This work revisits the classic problem of coverage in genomic shotgun assembly (the "Lander-Waterman statistics"). A novel formulation, based on the analysis of an autonomous Markov automaton, is presented, and two main conclusions are derived. The first is an evaluation of the minimum multiplicity ("coverage") required to achieve uninterrupted covering (one single contig) with a prescribed confidence level. The second is a detailed analysis of the effect of replacing the hypothesis of fixed-length genomic fragments with that of an arbitrary distribution of lengths over a finite interval. PMID- 23675929 TI - CORaL: comparison of ranked lists for analysis of gene expression data. AB - Because a very large number of gene expression data sets are currently publicly available, comparisons across experiments between different laboratories have become a common task. However, most existing methods of comparing gene expression data sets require setting arbitrary cutoffs (e.g., for statistical significance or fold change), which could select genes according to different criteria because of differences in experimental protocols and statistical analysis in different data sets. A new method is proposed for comparing expression profiles across experiments by using the rank of genes in the different datasets. We introduce a maximization statistic, which can be calculated recursively and allows for efficient searches on a large space (paths on a grid). We apply our method to both simulated and real datasets and show that it outperforms other existing rank based algorithms. CORaL is a novel method for comparison of gene expression data that performs well on simulated and real data. It has the potential for wide and effective use in computational biology. PMID- 23675930 TI - Editorial comment to "Anti-oxidant activity and attenuation of bladder hyperactivity by the flavonoid compound kaempferol". PMID- 23675931 TI - Outcome after severe multiple trauma: a retrospective analysis. AB - BACKGROUND: Aim of this study was to evaluate prognosis of severely injured patients. METHODS: All severely injured patients with an Injury Severity Score (ISS) >= 50 were identified in a 6-year-period between 2000 and 2005 in German Level 1 Trauma Center Murnau. Data was evaluated from German Trauma Registry and Polytrauma Outcome Chart of the German Society for Trauma Surgery and a personal interview to assess working ability and disability and are presented as average. RESULTS: 88 out of 1435 evaluated patients after severe polytrauma demonstrated an ISS >= 50 (6.5%), among them 23% women and 77% men. 66 patients (75%) had an ISS of 50-60, 14 (16%) 61-70, and 8 (9%) >= 70. In 27% of patients trauma was caused by motor bike accidents. 3.6 body regions were involved. Patients had to be operated 5.3 times and were treated 23 days in the ICU and stayed 73 days in hospital. Mortality rate was 36% and rate of multi-organ failure 28%. 15% of patients demonstrated severe senso-motoric dysfunction as well as residues of severe head injury. 25% recovered well or at least moderately. 29 out of 56 survivors answered the POLO-chart. A personal interview was performed with 13 patients. The state of health was at least moderate in 72% of patients. In 48% interpersonal problems and in 41% severe pain was observed. In 57% of patients problems with working ability regarding duration, as well as quantitative and qualitative performance were observed. Symptoms of post-traumatic stress disorder were found in 41%. The more distal the lesions were located (foot/ankle) the more functional disability affected daily life. In only 15%, working ability was not impaired. 8 out of 13 interviewed patients demonstrated complete work disability. CONCLUSIONS: Even severely injured patients after multiple trauma have a good prognosis. The ISS is an established tool to assess severity and prognosis of trauma, whereas prediction of clinical outcome cannot be deducted from this score. PMID- 23675932 TI - Experimentally created unilateral anterior crossbite induces a degenerative ossification phenotype in mandibular condyle of growing Sprague-Dawley rats. AB - The effect of unilateral anterior crossbite on the remodelling of mandibular condyle needs to be investigated. This study aimed to investigate the effects of experimentally created unilateral anterior crossbite on the remodelling of mandibular condyle and explore the changes in the expression of relevant transcription factors and growth factors. The experimental unilateral anterior crossbite was created in 6-week-old female growing rats by bonding metal tubes to the left pairs of incisors. Remodelings of mandibular condylar cartilage was assessed histologically at 2, 4 and 8 weeks. Protein and mRNA levels of Sox9, runt-related transcription factor 2 (Runx2), Osterix (Osx), transforming growth factor beta 1 (TGFbeta1), transforming growth factor beta receptor 2 (TGFbetar2) and type X collagen (ColX) were investigated by immunohistochemistry and real time PCR, while alkaline phosphatise (ALP) by histochemistry and real-time PCR. Decreased ratio of hypertrophic cartilage layer was noticed in the 4w experimental group versus controls. At all the time points, the expression of Sox9 and ALP increased but that of TGFbeta1 and TGFbetar2 decreased in experimental groups (P < 0.05). The expression of Runx2, Osx and Col X increased at 2w, but decrease at 4w (P < 0.05). The results that obvious cartilage degradation and altered expression of related transcription factors and growth factors were detected in the mandibular condyles of the experimental group suggested that the present unilateral anterior crossbite plays an adverse role in the TMJ, and thus leading to the degenerative endochondral ossification. PMID- 23675933 TI - ADME and toxicity in early drug discovery. PMID- 23675934 TI - A perspective on quantum mechanics calculations in ADMET predictions. AB - Understanding the molecular basis of drug action has been an important objective for pharmaceutical scientists. With the increasing speed of computers and the implementation of quantum chemistry methodologies, pharmacodynamic and pharmacokinetic problems have become more computationally tractable. Historically the former has been the focus of drug design, but within the last two decades efforts to understand the latter have increased. It takes about fifteen years and over $1 billion dollars for a drug to go from laboratory hit, through lead optimization, to final approval by the U.S. Food and Drug Administration. While the costs have increased substantially, the overall clinical success rate for a compound to emerge from clinical trials is approximately 10%. Most of the attrition rate can be traced to ADMET (absorption, distribution, metabolism, excretion, and toxicity) problems, which is a powerful impetus to study these issues at an earlier stage in drug discovery. Quantum mechanics offers pharmaceutical scientists the opportunity to investigate pharmacokinetic problems at the molecular level prior to laboratory preparation and testing. This review will provide a perspective on the use of quantum mechanics or a combination of quantum mechanics coupled with other classical methods in the pharmacokinetic phase of drug discovery. A brief overview of the essential features of theory will be discussed, and a few carefully selected examples will be given to highlight the computational methods. PMID- 23675935 TI - In silico ADMET prediction: recent advances, current challenges and future trends. AB - There are numerous small molecular compounds around us to affect our health, such as drugs, pesticides, food additives, industrial chemicals, and environmental pollutants. Over decades, properties related to absorption, distribution, metabolism, excretion, and toxicity (ADMET) have become one of the most important issues to assess the effects or risks of these compounds on human body. Recent high-rate drug withdrawals increase the pressure on regulators and pharmaceutical industry to improve preclinical safety testing. Since in vivo and in vitro evaluations are costly and laborious, in silico techniques have been widely used to estimate these properties. In this review, we would briefly describe the recent advances of in silico ADMET prediction, with emphasis on substructure pattern recognition method that we developed recently. Challenges and limitations in the area of in silico ADMET prediction were further discussed, such as application domain of models, models validation techniques, and global versus local models. At last, several new promising research directions were provided, such as computational systems toxicology (toxicogenomics), data-integration and meta-decision making systems, which could be used for systemic in silico ADMET prediction in drug discovery and hazard risk assessment. PMID- 23675936 TI - Understanding the molecular properties and metabolism of top prescribed drugs. AB - Molecular properties such as the molecular weight, hydrophobicity parameter logP, and the total polar surface area (TPSA) have been used extensively in modern drug discovery. We investigated these properties and ADMET scores of the top 200 therapeutic drugs by the U.S. retail sales (2010) and classified them according to the clinical indications and/or routes of administration. This list of drugs provides ample information of these molecular descriptors for successfully approved drugs. The mean logP for oral drugs is 2.5 while the logP for injectable drugs seems to be smaller. Among different types of clinical indications, drugs used for anti-HIV, and antibiotics tend to have lower logP. The molecular weights of anti-HIV drugs, antihypertensives and antibiotics appear to be larger. The ADMET scores, derived from a combination of molecular weights and logP, are consistent for oral drugs, with a mean score of 1.5 and a standard deviation of 1.0. Many clinical drugs that violate Lipinski's rule of five criteria can still exhibit ADMET scores that are very close to the mean value for oral drugs (1.5) and lie within the acceptable standard deviation. The molecular properties of MW, logP, and TPSA appear to vary according to their clinical indications. Many drugs form salts or cocrystals with acids or solvents that increase their solubility. Our data show that addition of hydrochloride is the most common method to increase solubility of drug ingredients. Cytochrome P450 isozymes 3A4, 2D6, 2C9, 2C8 and 3C5 are the top five proteins that metabolize the 200 most prescribed drugs. Drugs metabolized by 3A4 appear to have larger molecular weights and those metabolized by 2D6 have lower molecular weights. CYP2C8-metabolized drugs appear to be most hydrophilic, with the smallest logP and the largest polar surface areas. PMID- 23675937 TI - Permeability diagnosis model in drug discovery: a diagnostic tool to identify the most influencing properties for gastrointestinal permeability. AB - Permeability is important in governing the ability of drug substances to transport across gastrointestinal membrane and also crucial for proper drug distribution to pharmacological target organs and cells, and is therefore frequently utilized in drug discovery and development. In this report, we have performed a systematic analysis, using principal component analysis on the historically measured permeability data from in-house Caco-2 and parallel artificial membrane permeability assays on discovery new chemical entities from multiple projects. This work allows for establishment of a permeability diagnosis model by purposefully identifying most influencing physicochemical properties of the permeability issues, including polarity-lipophilicity line contributed primarily by polar surface area and LogP, number of rotation bond, fractional ionization at neutral pH and efflux ratio. A number of cases were also shown to demonstrate the applicability of the current model. The analysis of the model over internal drug discovery compounds exhibited promising diagnostic and predictive power of the model. The advantages and limitation of the model as well as the integral strategy to apply it in drug discovery to guide projects for permeability-related optimization were also presented. PMID- 23675938 TI - Recent developments in computational prediction of HERG blockage. AB - The blockage of the voltage dependent ion channel encoded by human ether-a-go-go related gene (hERG) may lead to drug-induced QT interval prolongation, which is a critical side-effect of non-cardiovasular therapeutic agents. Therefore, identification of potential hERG channel blockers at the early stage of drug discovery process will decrease the risk of cardiotoxicity-related attritions in the later and more expensive development stage. Computational approaches provide economic and efficient ways to evaluate the hERG liability for large-scale compound libraries. In this review, the structure of the hERG channel is briefly outlined first. Then, the latest developments in the computational predictions of hERG channel blockers and the theoretical studies on modeling hERG-blocker interactions are summarized. Finally, the challenges of developing reliable prediction models of hERG blockers, as well as the strategies for surmounting these challenges, are discussed. PMID- 23675939 TI - Pharmacophore modeling for ADME. AB - One of the major reasons for late-stage failure of drug candidates is due to problems uncovered in pharmacokinetics during clinical trials. There is now a general consensus for earlier consideration of these effects in the drug discovery process. Computer-aided design technology provides us with tools to develop predictive models for such pharmacokinetic properties. Among these tools, we focus on pharmacophore modeling techniques in this article. Pharmacophore models that are reported for various cytochrome P450 (CYP) enzymes are reviewed for the isoenzymes CYP1A2, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4. In addition pharmacophore models for related metabolic processes through CYP19 (aromatase), CYP51 (14.alpha-lanosterol demethylase), PXR (pregnane X-receptor), and finally for human intrinsic clearance are also reviewed. The models reported by various scientists are schematically represented in the figures in order to visually demonstrate their similarities and differences. The models developed by different researchers or sometimes even by the same research group for different sets of ligands, provide a clear picture of the challenges in coming up with a single model with good predictive values. One of the main reasons for this challenge is related to relatively large size of the active sites and flexibility of the CYP isoenzymes, which results in multiple binding sites. We propose development of multiple- diverse pharmacophore models for each binding mode (as opposed to a single predictive model for each CYP isoenzyme). After scoring and prioritization of the models, we propose the use of a battery of pharmacophore models for each CYP isoenzyme binding mode to computationally obtain a P450 interaction profile for drug candidates early in the drug development cycle, when decisions on their fate can be made before incurring the costs of synthesis and testing. PMID- 23675940 TI - Quantitative prediction of glucuronidation in humans using the in vitro- in vivo extrapolation approach. AB - Glucuronidation has been recognized as an important clearance mechanism in humans. Therefore, knowledge about the contribution of glucuronidation to clearance of drug candidates is of great value in early drug development. In this article, we discuss the recent progress made to predict in vivo glucuronidation parameters (e.g., hepatic clearance, and intestinal availability) using in vitro data, which are readily obtained using microsomes and hepatocytes, so called "in vitro- in vivo extrapolation" (IVIVE). Of note the intrinsic clearances obtained from microsomal incubations in the presence of bovine serum albumin (BSA) provide accurate predictions of the in vivo clearances in addition to those from hepatocytes. Further, we describe the lack of correlation between cellular and microsomal production of glucuronide and provide possible reasons. Due to the high prediction accuracy, those who study in vitro glucuronidation are encouraged to map their data to in vivo using IVIVE strategy for more informative data interpretation. PMID- 23675942 TI - Conversion of bilayers of PS-b-PDMS block copolymer into closely packed, aligned silica nanopatterns. AB - Block copolymer (BCP) self-assembly is an effective and versatile approach for the production of complex nanopatterned interfaces. Monolayers of BCP films can be harnessed to produce a variety of different patterns, including lines, with specific spacings and order. In this work, bilayers of cylinder-forming polystyrene-block-polydimethylsiloxane block copolymer (PS-b-PDMS) were transformed into arrays of silica lines with half the pitch normally attained for conventional monolayers, with the PDMS acting as the source for the SiOx. The primary hurdle was ensuring the bilayer silica lines were distinctly separate; to attain the control necessary to prevent overlap, a number of variables related to the materials and self-assembly process were investigated in detail. Developing a detailed understanding of BCP film swelling during solvent annealing, blending of the PS-b-PDMS with PS homopolymer, utilization of a surface brush layer, and adjustment of the plasma exposure conditions, distinct and separate silica lines were prepared. On the microscale, the sample coverage of PS-b-PDMS bilayers was investigated and maximized to attain >95% bilayers under defined conditions. The bilayer BCP structures were also amenable to graphoepitaxy, and thus, dense and highly ordered arrays of silica line patterns with tightly controlled width and pitch were fabricated and distributed uniformly across a Si surface. PMID- 23675941 TI - Predictive in silico studies of human 5-hydroxytryptamine receptor subtype 2B (5 HT2B) and valvular heart disease. AB - Serotonin (5-hydroxytryptamine, 5-HT) receptors are neuromodulator neurotransmitter receptors which when activated trigger a signal transduction cascade within cells resulting in cell-cell communication. 5-hydroxytryptamine receptor 2B (5-HT2B) is a subtype of the seven members of 5-hydroxytrytamine receptors family which is the largest member of the super family of 7 transmembrane G-protein coupled receptors (GPCRs). Not only do 5-HT receptors play physiological roles in the cardiovascular system, gastrointestinal and endocrine function as well as the central nervous system, but they also play a role in behavioral functions. In particular 5-HT2B receptor is widely spread with regards to its distribution throughout bodily tissues and is expressed at high levels in the lungs, peripheral tissues, liver, kidneys and prostate, just to name a few. Hence 5-HT2B participates in multiple biological functions including CNS regulation, regulation of gastrointestinal motality, cardiovascular regulation and 5-HT transport system regulation. While 5-HT2B is a viable drug target and has therapeutic indications for treating obesity, psychosis, Parkinson's disease etc. there is a growing concern regarding adverse drug reactions, specifically valvulopathy associated with 5-HT2B agonists. Due to the sequence homology experienced by 5-HT2 subtypes there is also a concern regarding the off-target effects of 5-HT2A and 5-HT2C agonists. The concepts of sensitivity and subtype selectivity are of paramount importance and now can be tackled with the aid of in silico studies, especially cheminformatics, to develop models to predict valvulopathy associated toxicity of drug candidates prior to clinical trials. This review has highlighted three in silico approaches thus far that have been successful in either predicting 5-HT2B toxicity of molecules or identifying important interactions between 5-HT2B and drug molecules that bring about valvulopathy related toxicities. PMID- 23675943 TI - Acral localized acquired cutis laxa. PMID- 23675944 TI - How should parents adjust the size of their young in response to local environmental cues? AB - Models of parental investment typically assume that populations are well mixed and homogeneous and have devoted little attention to the impact of spatial variation in the local environment. Here, in a patch-structured model with limited dispersal, we assess to what extent resource-rich and resource-poor mothers should alter the size of their young in response to the local environment in their patch. We show that limited dispersal leads to a correlation between maternal and offspring environments, which favours plastic adjustment of offspring size in response to local survival risk. Strikingly, however, resource poor mothers are predicted to respond more strongly to local survival risk, whereas resource-rich mothers are predicted to respond less strongly. This lack of sensitivity on the part of resource-rich mothers is favoured because they accrue much of their fitness through dispersing young. By contrast, resource-poor mothers accrue a larger fraction of their fitness through philopatric young and should therefore respond more strongly to local risk. Mothers with more resources gain a larger share of their fitness through dispersing young partly because their fitness in the local patch is constrained by the limited number of local breeding spots. In addition, when resource variation occurs at the patch level, the philopatric offspring of resource-rich mothers face stronger competition from the offspring of other local mothers, who also enjoy abundant resources. The effect of limited local breeding opportunities becomes less pronounced as patch size increases, but the impact of patch-level variation in resources holds up even with many breeders per patch. PMID- 23675945 TI - Aromaticity of closed-shell charged polybenzenoid hydrocarbons. AB - The aromatic stabilization of closed-shell charged polybenzenoid hydrocarbons (PBHs) has been scrutinized by means of energetic and magnetic aromaticity criteria and by direct measures of electron delocalization. Thus, topological resonance energies and their circuit contributions, ring current maps, and multicenter delocalization indices have been calculated for a series of 18 polybenzenoid cations containing from 3 to 10 benzene rings. All calculations indicate that the closed-shell cations have a similar degree of aromaticity compared to that of the corresponding closed-shell neutral PBHs. All cations investigated display a large degree of electronic delocalization in the ring, accompanied by significant aromatic stabilization and a strong diatropic peripheral electron current. Graph theoretical models describe perfectly the aromatic features of these hydrocarbon fragments, showing how they can be understood as a superposition of specific neutral PBHs. The large aromatic character of these systems suggests they may be relatively stable upon formation at combustion conditions, like those given in the interstellar medium. It has been postulated that closed-shell fragments of PBHs may play an important role in the photoluminescent phenomenon known as extended red emission. PMID- 23675946 TI - Hydrogen bonds in cocrystals and salts of 2-amino-4,6-dimethylpyrimidine and carboxylic acids studied by nuclear quadrupole resonance. AB - (14)N and (17)O nuclear quadrupole resonance frequencies have been measured in 1:1 cocrystals and salts of 2-amino-4,6-dimethylpyrimidine and several carboxylic acids. A systematic decrease of the (17)O quadrupole coupling constant on increasing strength of the hydrogen bond is observed in cocrystals bound by O H...N hydrogen bonds. The O-H distances deduced from the line widths of the (17)O NQR lines show that the hydrogen atom is in a hydrogen bond formed by a carboxylic groups for about 0.01 nm displaced from the oxygen atom toward the center of the hydrogen bond. In the O-H...N hydrogen bond formed by the hydroxyl group, which is only slightly longer than the hydrogen bonds formed by the carboxyl group, the hydrogen atom is much less displaced. A linear relation between the (14)N quadrupole coupling constant and the sum of the inverse third powers of the H...A (A = O or N) distances is deduced for the amino group. A linear correlation of the principal values of the (14)N quadrupole coupling tensor in -NH2, as observed in the solid phase and in the gas phase, is analyzed in a simple model assuming a displacement of the electron charge in the N-H sigma bond and simultaneous deformation of the nitrogen lone pair electron orbital. At the ring nitrogen position, hydrogen bonding and proton transfer produce a large decrease of the (14)N quadrupole coupling constant. A linear correlation of the principal values of the (14)N quadrupole coupling tensor is observed in cocrystals and salts of 2-amino-4,6-dimethylpyrimidine. This correlation differs from the correlation observed in substituted pyrimidine, where the hydrogen atoms are replaced by other atoms or functional groups. The difference is analyzed in a model, which assumes that the hydrogen bonding and substituents affect the nitrogen lone pair and pi electron orbitals. The analysis shows that the two effects are nearly independent. PMID- 23675948 TI - Hypervalent iodine(III)-mediated benzannulation of enamines with alkynes for the synthesis of polysubstituted naphthalene derivatives. AB - A series of functionalized 1-amino-2-naphthalenecarboxylic acid derivatives were synthesized from enamines and alkynes via a benzannulation strategy mediated by iodosylbenzene and BF3.Et2O. The advantages of this novel benzannulation process include broad substrate scope, good functional group tolerance, and mild reaction conditions without the use of heavy metals. PMID- 23675947 TI - Persistent infections after natural transmission of bovine viral diarrhoea virus from cattle to goats and among goats. AB - Bovine viral diarrhoea virus (BVDV) is an economically important pathogen of cattle worldwide. Infection of a pregnant animal may lead to persistent infection of the foetus and birth of a persistently infected (PI) calf that sheds the virus throughout its life. However, BVD viruses are not strictly species specific. BVDV has been isolated from many domesticated and wild ruminants. This is of practical importance as virus reservoirs in non-bovine hosts may hamper BVDV control in cattle. A goat given as a social companion to a BVDV PI calf gave birth to a PI goat kid. In order to test if goat to goat infections were possible, seronegative pregnant goats were exposed to the PI goat. In parallel, seronegative pregnant goats were kept together with the PI calf. Only the goat to goat transmission resulted in the birth of a next generation of BVDV PI kids whereas all goats kept together with the PI calf aborted. To our knowledge, this is the first report which shows that a PI goat cannot only transmit BVD virus to other goats but that such transmission may indeed lead to the birth of a second generation of PI goats. Genetic analyses indicated that establishment in the new host species may be associated with step-wise adaptations in the viral genome. Thus, goats have the potential to be a reservoir for BVDV. However, the PI goats showed growth retardation and anaemia and their survival under natural conditions remains questionable. PMID- 23675951 TI - Successive regioselective metalations of fused heterocycles: synthesis of polyfunctionalized furo[3,2-b]pyridines. AB - The furopyridine framework was chosen as a target for a lithiation study, in order to define the most effective conditions leading to the total functionalization of the heterocycle. Consequently, a detailed procedure for successive regioselective lithiations/electrophilic trapping of furo[3,2 b]pyridines is described and afforded several polyfunctionalized derivatives in good overall yields. A Pd-catalyzed cross-coupling reaction is also described and easily yielded the 7,7'-bifuro[3,2-b]pyridine. PMID- 23675949 TI - Collagen loaded nano-sized surfactant based dispersion for topical application: formulation development, characterization and safety study. AB - Collagen, a high molecular weight, hydrophilic and highly abundant protein is known to have anti-ageing, anti-wrinkle, anti-acne, anti-scar and wound healing properties. High molecular weight and hydrophilic nature hinder its effective topical delivery. So, the objective of present study was to develop effective topical nano-surfactant dispersion (NSD) for collagen delivery. NSD was prepared from sorbitan monostearate (Span60) and cholesterol using ethanol injection method followed by probe sonication. NSD was characterized for entrapment efficiency (%EE), size and size distribution (Z-avg and polydispersity index (PDI)), shape, zeta-potential (zeta), in vitro drug release, skin hydration and skin irritation test and histopathological examination. Optimized NSD (NSD3) had %EE, z-avg, PDI and zeta-potential of 77.56% +/- 1.09%, 158.1 +/- 2.31 nm, 0.211 and -17.2 +/- 0.64 mV, respectively. In in vivo skin hydration test, NSD treatment showed nearly 2.5-fold and 3-fold increase in the thickness of stratum corneum (SC) as compared to the collagen gel treated and untreated skin, respectively. The mean scores of skin irritation test in two animal species, rats and rabbits, were found to be 1.42 +/- 1.01 and 1.71 +/- 0.29, respectively, indicating the non-irritant nature of collagen loaded NSD. Histopathology of the skin after application of developed NSD showed non-significant changes in skin anatomy indicating its safe nature. PMID- 23675950 TI - Intraovarian regulation of gonadotropin-dependent folliculogenesis depends on notch receptor signaling pathways not involving Delta-like ligand 4 (Dll4). AB - BACKGROUND: In-situ hybridisation studies demonstrate that Notch receptors and ligands are expressed in granulosa cells (GCs) and in the theca layer vasculature of growing follicles. Notch signaling involves cell-to-cell interaction mediated by transmembrane receptors and ligands. This signaling pathway may represent a novel intraovarian regulator of gonadotropin-dependent follicular development to the preovulatory stage. We hypothesized that blocking Notch pathways would disrupt follicular maturation in the mouse ovary. METHODS: Hypophysectomized CD21 female mice were administered pregnant mare serum gonadotropin (PMSG) for 3 days to stimulate follicular development. In one experiment, a pan-notch inhibitor, compound E, was initiated 2 days prior to and throughout stimulation (n = 10), while in a second experiment, a humanized phage Dll4 blocking antibody, YW152F, was used (n = 5). After sacrifice, ovarian histology, serum estradiol levels and uterine weights were compared to controls. The ovarian morphology was evaluated with hematoxylin/eosin staining and immunohistochemistry was performed for Notch1, Notch2, Notch3, Notch4, Jagged1, Dll4, platelet endothelial cell adhesion molecule (PECAM) and alpha-smooth muscle actin (alpha-SMA) detection. RESULTS: We localized specific Notch ligands and receptors in the following structures: Dll4 is specific to theca layer endothelial cells (ECs); Notch1/Notch4 and Jagged1 are expressed in theca layer ECs and vascular smooth muscle cells (VSMCs), whereas Notch3 is restricted to VSMCs; Notch2 is expressed mostly on GCs of small follicles. Administration of a pan-Notch inhibitor, compound E, inhibits follicular development to the preovulatory stage (8.5 preovulatory follicles in treatment vs. 3.4 preovulatory follicles in control, p < 0.01; average number per ovary) with significant secondary effects on ovarian and uterine weight and estradiol secretion in a setting of uninhibited vascular proliferation, but disorganized appearance of ECs and VSMCs. Inhibition of endothelial Notch1 function through the inactivation of its ligand Dll4 with the blocking antibody YW152F induces mild disorganisation of follicular vasculature, but has no significant effect on gonadotropin-dependent folliculogenesis. CONCLUSIONS: Our experiments suggest that the complete blockage of the Notch signaling pathway with compound E impairs folliculogenesis and induces disruption of gonadotropin stimulated angiogenesis. It seems the mechanism involves Notch1 and Notch3, specifically, causing the improper assembly of ECs and VSMCs in the theca layer, although the potential role of non-angiogenic Notch signaling, such as Jagged2 to Notch2 in GCs, remains to be elucidated. PMID- 23675953 TI - Speed of spinal vs general anaesthesia for category-1 caesarean section: a simulation and clinical observation-based study. AB - Controversy exists as to whether effective spinal anaesthesia can be achieved as quickly as general anaesthesia for a category-1 caesarean section. Sixteen consultants and three fellows in obstetric anaesthesia were timed performing spinal and general anaesthesia for category-1 caesarean section on a simulator. The simulation time commenced upon entry of the anaesthetist into the operating theatre and finished for the spinal anaesthetic at the end of intrathecal injection and for the general anaesthetic when the anaesthetist was happy for surgery to start. In the second clinical part of the study, the time from intrathecal administration to 'adequate surgical anaesthesia' (defined as adequate for start of a category-1 caesarean section) was estimated in 100 elective (category-4) caesarean sections. The median (IQR [range]) times (min:s) for spinal procedure, onset of spinal block and general anaesthesia were 2:56 (2:32-3:32 [1:22-3:50]), 5:56 (4:23-7:39 [2:9-13:32]) and 1:56 (1:39-2:9 [1:13 3:12]), respectively. The limiting factor in urgent spinal anaesthesia is the unpredictable time needed for adequate surgical block to develop. PMID- 23675952 TI - Periodontopathogen and Epstein-Barr virus-associated periapical periodontitis may be the source of retrograde infectious peri-implantitis. AB - BACKGROUND: Herpesviral-bacterial synergism may play a role in periodontitis and peri-implantitis etiopathogenesis. Periapical periodontitis (PP) lesions can predict future apical peri-implantitis complications. PURPOSE: This pilot study aimed to substantiate herpesviral-bacterial coinfection in symptomatic (SP) and asymptomatic (AP) PP and assess associations with periodontopathogen salivary contamination in patients receiving implants. MATERIALS AND METHODS: Polymerase chain reaction (PCR)-based identification was performed on PP granulation tissue (GT) from 33 SP and AP patients and compared with unstimulated whole saliva. Quantitative PCR evaluated Epstein-Barr virus (EBV) and cytomegalovirus copy counts. RESULTS: SP GT had higher proportions of periodontopathogens. Symptomatic patients were 3.7 times more likely to be infected with EBV than AP (p = .07; 95% CI: 0.8-16.2). SP were 2.9, 2.1, 3.6, and 1.6 times more likely to be infected with Treponema denticola, Prevotella intermedia, Aggregatibacter actinomycetemcomitans, and Porphyromonas gingivalis, respectively. The odds ratio of EBV infecting PP lesions was two times higher in those positive for the virus in saliva. Saliva Tannerella forsythia-positive patients were 15 times more likely to present this pathogen in PP lesions (p = .038). Saliva EBV-positive individuals were 7 and 3.5 times more likely to yield GT contamination with T. forsythia and T. denticola, respectively. EBV copy counts were significantly higher in SP (p < .01). CONCLUSIONS: A causal association between EBV, specific bacterial anaerobic infection, and symptomatic PP is likely. EBV high prevalence underscores the viral etiological importance. Salivary EBV contamination is likely to be associated with viral and bacterial GT infection. Saliva PCR analysis can be a good predictor of GT specific infection and help establish antimicrobial therapy. If confirmed by prospective longitudinal clinical trials, antiviral therapy could possibly benefit SP and nonresponsive to treatment individuals and help prevent potential peri-implant infectious complications. PMID- 23675954 TI - Comparison of the efficacies of intermittent and continuous low-dose isotretinoin regimens in the treatment of moderate acne vulgaris. AB - BACKGROUND: Acne vulgaris is a chronic inflammatory disease that usually requires systemic treatment for severe forms. Isotretinoin is the most effective drug in the treatment of acne vulgaris. In this study, we aimed to compare the efficacies of intermittent and continuous low-dose isotretinoin regimens in the treatment of moderate acne vulgaris. METHODS: Sixty patients with moderate acne were included. They were divided into two groups to receive either intermittent or continuous low-dose isotretinoin. All patients were followed up monthly during the treatment period and for at least six months after completion of therapy. RESULTS: There were no statistically significant differences between the two groups regarding improvement rates at the end of treatments. However, reduction rates in mean acne scores at post-treatment controls were in favor of the continuous low-dose group. During the post-treatment follow-up period, three patients in the intermittent group relapsed, while no relapses were observed in the low-dose group. No significant side effects were observed in any groups. CONCLUSIONS: Both intermittent and continuous low-dose isotretinoin regimens are very well tolerated and effective as classical regimens in the treatment of moderate acne vulgaris. However, a continuous low-dose regimen seems to be slightly superior in terms of patients' compliance to the treatment and lower risk of relapse. PMID- 23675956 TI - Lymphoproliferative response to the 30-kDa protein and a crude lysate from Salmonella typhimurium in patients with ankylosing spondylitis. AB - OBJECTIVES: To determine the lymphoproliferative response to the 30-kDa protein (p30) of Salmonella typhimurium in patients with ankylosing spondylitis (AS). METHOD: Lymphoproliferative response was determined in peripheral blood mononuclear cells (PBMCs) from 30 patients with AS and 40 healthy subjects. Cells were cultured with concanavalin A (Con A), a crude lysate of S. typhimurium (StCL), or p30. Lymphoproliferation was measured by the MTT assay. RESULTS: Our data show that the mitogenic response to Con A was similar in both groups studied; however, the lymphoproliferative response to StCL and p30 was statistically higher in AS patients than in healthy subjects. CONCLUSIONS: Our data strongly suggest that S. typhimurium, and particularly p30, are associated with AS. PMID- 23675955 TI - Two-dimensional isoelectric focusing OFFGEL and microfluidic lab-on-chip electrophoresis for assessing dissolved proteins in seawater. AB - Dissolved proteins were assessed in surface and deep seawater by two-dimensional isoelectric focusing (IEF) OFFGEL-lab-on-chip (LOC) electrophoresis after tangential flow ultrafiltration followed by centrifugal ultrafiltration (preconcentration factor of 3000). Dissolved protein isolation was performed by treating the ultrafiltrated retentate with cold acetone and also with chloroform as precipitating reagents. The best electrophoretic behavior of the isolated proteins was obtained after protein precipitation with chloroform before different rinsing stages for removing methanol and water interferences. Metals bound to proteins in the different OFFGEL fractions were assessed by inductively coupled plasma-optical emission spectrometry and electrothermal atomic absorption spectrometry, under optimized operating conditions. Experiments regarding stability of the metal-binding proteins [superoxide dismutase (SOD) and alcohol dehydrogenase (ADH) as protein models] showed the integrity of the Zn-binding SOD/ADH under the OFFGEL electrophoretic conditions. However, stability of Cu bound to SOD is not guaranteed. The first electrophoretic dimension (IEF OFFGEL) showed that dissolved proteins in surface seawater exhibit alkaline isoelectric points (pIs of 8.10 and 8.37) and also acid Ips (4.82, 5.13, 5.43, and 5.73), while LOC showed that the isolated proteins exhibit a spread molecular weight range (within 15 - 63 kDa); although, high molecular weights were the most commonly found. Regarding deep seawater, isolated proteins were of acid Ips (from 3.30 to 4.22) and low molecular weight (within the 21-24 kDa range). Elements such as Cd, Cu, Mn, and Ni were mainly associated with dissolved proteins of alkaline pIs in surface seawater, while Zn was mainly associated to proteins of acid pIs. However, only Cu and Mn were found to be bound to dissolved proteins of higher Ips in deep seawater, and the amount of Mn (from 68 to 84 MUg L(-1)) was higher than that found in dissolved proteins in surface seawater (22.4 MUg L( 1)). PMID- 23675957 TI - Provisional classification and in silico study of biopharmaceutical system based on caco-2 cell permeability and dose number. AB - Today, early characterization of drug properties by the Biopharmaceutics Classification System (BCS) has attracted significant attention in pharmaceutical discovery and development. In this direction, the present report provides a systematic study of the development of a BCS-based provisional classification (PBC) for a set of 322 oral drugs. This classification, based on the revised aqueous solubility and the apparent permeability across Caco-2 cell monolayers, displays a high correlation (overall 76%) with the provisional BCS classification published by World Health Organization (WHO). Current database contains 91 (28.3%) PBC class I drugs, 76 (23.6%) class II drugs, 97 (31.1%) class III drugs, and 58 (18.0%) class IV drugs. Other approaches for provisional classification of drugs have been surveyed. The use of a calculated polar surface area with a labetalol value as a high permeable cutoff limit and aqueous solubility higher than 0.1 mg/mL could be used as alternative criteria for provisionally classifying BCS permeability and solubility in early drug discovery. To develop QSPR models that allow screening PBC and BCS classes of new molecular entities (NMEs), 18 statistical linear and nonlinear models have been constructed based on 803 0-2D Dragon and 126 Volsurf+ molecular descriptors to classify the PBC solubility and permeability. The voting consensus model of solubility (VoteS) showed a high accuracy of 88.7% in training and 92.3% in the test set. Likewise, for the permeability model (VoteP), accuracy was 85.3% in training and 96.9% in the test set. A combination of VoteS and VoteP appropriately predicts the PBC class of drugs (overall 73% with class I precision of 77.2%). This consensus system predicts an external set of 57 WHO BCS classified drugs with 87.5% of accuracy. Interestingly, computational assignments of the PBC class reasonably correspond to the Biopharmaceutics Drug Disposition Classification System (BDDCS) allocations of drugs (accuracy of 63.3-69.8%). A screening assay has been simulated using a large data set of compounds in different drug development phases (1, 2, 3, and launched) and NMEs. Distributions of PBC forecasts illustrate the current status in drug discovery and development. It is anticipated that a combination of the QSPR approach and well-validated in vitro experimentations could offer the best estimation of BCS for NMEs in the early stages of drug discovery. PMID- 23675958 TI - Site-specific growth of Au-Pd alloy horns on Au nanorods: a platform for highly sensitive monitoring of catalytic reactions by surface enhancement Raman spectroscopy. AB - Surface-enhanced Raman scattering (SERS) is a highly sensitive probe for molecular detection. The aim of this study was to develop an efficient platform for investigating the kinetics of catalytic reactions with SERS. To achieve this, we synthesized a novel Au-Pd bimetallic nanostructure (HIF-AuNR@AuPd) through site-specific epitaxial growth of Au-Pd alloy horns as catalytic sites at the ends of Au nanorods. Using high-resolution electron microscopy and tomography, we successfully reconstructed the complex three-dimensional morphology of HIF AuNR@AuPd and identified that the horns are bound with high-index {11l} (0.25 < l < 0.43) facets. With an electron beam probe, we visualized the distribution of surface plasmon over the HIF-AuNR@AuPd nanorods, finding that strong longitudinal surface plasmon resonance concentrated at the rod ends. This unique crystal morphology led to the coupling of high catalytic activity with a strong SERS effect at the rod ends, making HIF-AuNR@AuPd an excellent bifunctional platform for in situ monitoring of surface catalytic reactions. Using the hydrogenation of 4-nitrothiophenol as a model reaction, we demonstrated that its first-order reaction kinetics could be accurately determined from this platform. Moreover, we clearly identified the superior catalytic activity of the rod ends relative to that of the rod bodies, owing to the different SERS activities at the two positions. In comparison with other reported Au-Pd bimetallic nanostructures, HIF AuNR@AuPd offered both higher catalytic activity and greater detection sensitivity. PMID- 23675959 TI - Cu(II) and Cu(I) coordination complexes involving two tetrathiafulvalene-1,3 benzothiazole hybrid ligands and their radical cation salts. AB - Preparations, crystal structure analyses, and magnetic property investigations on a new Cu(II)(hfac)2 complex coordinated with two TTF-CH?CH-BTA ligands, where hfac is hexafluoroacetylacetonate, TTF is tetrathiafulvalene, and BTA is 1,3 benzothiazole, are reported together with those of its dicationic AsF6(-) salt, [Cu(hfac)2(TTF-CH?CH-BTA)2](AsF6)2, in which each TTF part is in a radical cation state. In these Cu(II)(hfac)2 complexes, two ligands are bonded to the central Cu atom of the Cu(hfac)2 part through the nitrogen atom of the 1,3-benzothiazole ring and occupy the two apical positions of the Cu(hfac)2 complex with an elongated octahedral geometry. These two ligands are located parallelly in a transverse head-to-tail manner, and the Cu(hfac)2 moiety is closely sandwiched by these two ligands. In the AsF6(-) salt of the Cu(hfac)2 complex, each TTF dimer is separated by the AsF6(-) anions and has no overlap with each other within the one-dimensional arrays, resulting in an insulating behavior. Both Cu(hfac)2 complexes showed the simple Curie-like temperature dependence of paramagnetic susceptibilities (chiM), indicating that no interaction exists between the paramagnetic Cu(II) d spins. Furthermore, crystal structure analysis and magnetic/conducting properties of a radical cation ReO4(-) salt of the Cu(I) complex with two TTF-CH?CH-BTA ligands, [Cu(TTF-CH?CH-BTA)2](ReO4)2, are also described. Two nitrogen atoms of the ligands are connected to the central Cu(I) in a linear dicoordination with a Cu-N bond length of 1.879(9) A. Two TTF parts of the neighboring complexes form a dimerized structure, and such a TTF dimer forms a one-dimensional uniform array along the a direction with a short S-S contact of 3.88 A. Magnetic property measurement suggested the existence of a strongly antiferromagnetic one-dimensional uniform chain of S = 1/2 spins that originate from the radical cation states of the TTF dimers. Due to the construction of the one-dimensional uniform array of the radical cation state of the TTF dimer along the a axis, a semiconducting behavior is observed with sigma(rt) = of 6 * 10(-5) S cm(-1) and an activation energy of E(a) = 0.16 eV. PMID- 23675960 TI - Senescent case of cholesterol ester storage disease that progressed to liver cirrhosis with a novel mutation (N250H) of lysosomal acid lipase gene. AB - The patient, a 69-year-old man, had a chief complaint of hepatomegaly. The liver was palpated four fingerbreadths below the costal margin, and the spleen was three fingerbreadths below the costal margin. There were no other abnormal findings. Laparoscopy showed that the liver resembled an orange-yellow crayon in appearance and was nodular. The pathological findings of the liver biopsy tissue were consistent with liver cirrhosis. Inside the fibrous septum was an apparent aggregation of enlarged macrophages that phagocytosed lipid components, as well as enlarged Kupffer cells that phagocytosed lipid droplets. Electron microscopy showed the lipid droplets to have a moth-eaten appearance. Using monocytes extracted from the peripheral blood, acid lipase activity was measured by fluorescence spectrometry using 4-methylumbelliferone palmitate as a substrate. This patient's human lysosomal acid lipase activity was 0.020 nM/min per 10(6) cells, corresponding to 5.9% of that in healthy subjects (0.332 +/- 0.066 nM/min per 10(6) cells). Cholesterol ester storage disease was therefore diagnosed. The acid lipase A base sequence obtained from leukocytes by direct sequencing was compared with a library. This patient had a point mutation of N250H/N250H in exon 7, a novel gene abnormality that has not previously been reported. PMID- 23675961 TI - Inside-out versus outside-in transobturator tension-free vaginal tape: a 5-year prospective comparative study. AB - OBJECTIVE: To compare the 1-year and 5-year outcomes of transobturator tension free vaginal tape with outside-in and inside-out approaches in women with urinary stress incontinence, and to identify risk factors for treatment failure at 5 years. METHOD: A prospective observational study was carried out for women with urinary stress incontinence who underwent transobturator tension-free vaginal tape from September 2004 to March 2008 in a tertiary urogynecology center. Women (n = 213) had either an outside-in (n = 124) or inside-out (n = 89) procedure. They were followed up annually until 5 years after the operation. Subjective cure was defined as women not experiencing any urine loss on physical activity. Objective cure was defined as no urine leak at cough during a standard urodynamic study. RESULTS: At a mean follow up of 59.2 months, the subjective cure rates were 81.7% and 84.1%; the objective cure rate were 82.6% and 82.5% for the outside-in and inside-out approach, respectively. There was no statistically significant difference between the procedures. De novo overactive bladder syndrome (10.6% in outside-in and 14.6% in inside-out approach; P = 0.40) and de novo detrusor overactivity (5.8% in outside-in and 15% in inside-out approach; P = 0.11) was also comparable between the two groups. Complications at the fifth year were low and not significantly different among both methods. CONCLUSION: The outside-in approach and inside-out approach are both safe and effective in treating women with urinary stress incontinence up to 5 years. PMID- 23675962 TI - Covalent core-shell architecture of hemoglobin and human serum albumin as an artificial O2 carrier. AB - Covalent core-shell structured protein clusters of hemoglobin (Hb) and human serum albumin (HSA) (HbX-HSAm) (m = 2, 3) with novel physiological properties were generated by linkage of Hb surface lysins to HSA cysteine-34 via an alpha succinimidyl-epsilon-maleimide cross-linker (X: 1 or 2). The isoelectric points of HbX-HSAm (pI = 5.0-5.2) were markedly lower than that of Hb and almost identical to that of HSA. AFM and TEM measurements revealed a triangular Hb1-HSA3 cluster in aqueous medium. The complete 3D structure of Hb1-HSA3 based on TEM data was reconstructed, revealing two possible conformer variants. All HbX-HSAm clusters showed a moderately higher O2 affinity than the native Hb. Furthermore, the exterior HSA units possess a remarkable ability to bind lumiflavin (LF). The addition of NADH to an aqueous solution of the met-Hb2-(HSA-LF)3 cluster reduced the inactive ferric Hb center to the functional ferrous Hb. This O2-carrying hemoprotein cluster with strongly negative surface net charge, high O2 affinity, and NADH-dependent reductase unit can support a new generation of molecular architecture for red blood cell substitutes. PMID- 23675963 TI - Gastric emptying rate in subjects with malocclusion examined by [(13) C] breath test. AB - Masticatory function is significantly lower in individuals with malocclusion than in those with normal occlusion. Although several studies suggest that masticatory function influences gastrointestinal digestive function, the relationship between malocclusion and gastrointestinal symptoms has not been studied extensively. We hypothesised that insufficient masticatory function would increase the functional burden of the stomach and have some influence on the gastrointestinal system. The purpose of this study was to investigate masticatory function and gastric emptying rate in subjects with malocclusion. Eleven healthy dentate female volunteers and eleven female patients with maloc-clusion underwent a (13) C acetate breath test with a liquid meal. Maximum (13) CO2 exhalation time (Tmax ) was compared statistically between both groups. Masticatory function was assessed by colour-changeable chewing gum. In addition, the frequency scale for the symptoms of gastroeso-phageal reflux disease (FSSG) and questionnaires on food intake were given to both groups. The mean Tmax of the malocclusion group was significantly longer than that of the normal occlusion group (P = 0.007). Masticatory performance, measured by colour-changeable gum and questionnaires, was significantly lower in the malocclusion group than in the normal occlusion group (P = 0.023, P = 0.003). There was no significant difference in the FSSG results between the two groups (P = 0.262). This study suggested that there was a correlation between malocclusion and gastric emptying function in women. PMID- 23675964 TI - Immunotherapy with dendritic cells as a cancer treatment: perspectives and therapeutic potential. AB - The immune system, which is indispensible for controlling neoplasias, relies on its innate and acquired immunity components to mount an effective response against tumors. In this context, dendritic cells (DCs) are seen as the best antigen-presenting cells because of their capacity for cross-presentation, which can activate both T-helper and cytotoxic lymphocytes. Thus immunotherapy with DCs is considered promising, especially for early-stage cancers. This article provides a clarifying review of recent perspectives on the development of cancer immunotherapy, which has a wide potential for therapeutic applications, and of patents related to immunotherapy with DCs. PMID- 23675965 TI - Synthesis and pharmacological characterization of 4-substituted-2 aminobicyclo[3.1.0]hexane-2,6-dicarboxylates: identification of new potent and selective metabotropic glutamate 2/3 receptor agonists. AB - As part of our ongoing interest in identifying novel agonists acting at metabotropic glutamate (mGlu) 2/3 receptors, we have explored the effect of structural modifications of 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6 dicarboxylate (LY354740), a potent and pharmacologically balanced mGlu2/3 receptor agonist. Incorporation of relatively small substituents (e.g., F, O) at the C4 position of this molecule resulted in additional highly potent mGlu2/3 agonists that demonstrate excellent selectivity over the other mGlu receptor subtypes, while addition of larger C4-substituents (e.g., SPh) led to a loss of agonist potency and/or the appearance of weak mGlu2/3 receptor antagonist activity. Further characterization of the alpha-fluoro-substituted analogue (LY459477) in vivo revealed that this molecule possesses good oral bioavailability in rats and effectively suppresses phencyclidine-evoked locomotor activity at doses that do not impair neuromuscular coordination. This molecule therefore represents a valuable new addition to the arsenal of pharmacological tools competent to investigate mGlu2/3 receptor function both in vitro and in vivo. PMID- 23675966 TI - A comparative study of urea-induced aggregation of collapsed poly(N isopropylacrylamide) and poly(N,N-diethylacrylamide) chains in aqueous solutions. AB - The urea-induced aggregation of poly(N-isopropylacrylamide) (PNIPAM) and poly(N,N diethylacrylamide) (PDEAM) globules was studied by using a combination of static and dynamic light scattering. Our results have revealed that urea acting as a cross-linker via formation of two hydrogen bonds with the amide groups of PNIPAM and PDEAM in different globules causes the aggregation, and the aggregation of PNIPAM and PDEAM globules is a reaction-limited cluster-cluster aggregation (RLCA) process. The aggregates have a uniform sphere structure that may be due to the restructuring of the aggregates. The aggregation rate of PNIPAM globules is slower than that of PDEAM, which might mainly contribute to the reasons that the amides groups of PNIPAM have more chance to be inside the globules because of the formation of intra- and inter-hydrogen bonds and the smaller number density of the PNIPAM aggregates at the original time. When the aqueous urea solutions were cooled and reheated to 40 degrees C, the aggregation became faster than the first heating process, indicating that the urea molecules have replaced some water molecules binding to the amide groups at high temperature and some of the urea molecules remain interacting with the polymers even at the temperature lower than the cloud point temperature. PMID- 23675968 TI - Post-kala-azar dermal leishmaniasis caused by Leishmania infantum in an immunocompetent patient. PMID- 23675967 TI - Targeting self-renewal pathways in myeloid malignancies. AB - A fundamental property of hematopoietic stem cells (HSCs) is the ability to self renew. This is a complex process involving multiple signal transduction cascades which control the fine balance between self-renewal and differentiation through transcriptional networks. Key activators/regulators of self-renewal include chemokines, cytokines and morphogens which are expressed in the bone marrow niche, either in a paracrine or autocrine fashion, and modulate stem cell behaviour. Increasing evidence suggests that the downstream signaling pathways induced by these ligands converge at multiple levels providing a degree of redundancy in steady state hematopoiesis. Here we will focus on how these pathways cross-talk to regulate HSC self-renewal highlighting potential therapeutic windows which could be targeted to prevent leukemic stem cell self renewal in myeloid malignancies. PMID- 23675969 TI - Long-term results after subcrestal or crestal placement of delayed loaded implants. AB - PURPOSE: Prevention of peri-implant bone loss is essential for achieving long term implant success, but few studies have evaluated the impact of placement depth on long-term bone loss. The aim of this retrospective study was to evaluate outcomes for platform-shifted implants placed at different depths relative to the bone crest. MATERIALS AND METHODS: The mesial and distal shoulders of 228 delayed loaded Ankylos(r) (Dentsply Implants Manufacturing GmbH, Mannheim, Germany) implants placed in 85 patients were divided retrospectively into two groups based on the implant shoulder position on the day of placement surgery as follows: subcrestal group A (n = 197; 0.5 mm or more below the crestal bone level) or crestal group B (n = 65; within 0.5 mm or less of the crestal bone level). The remaining sites (n = 194; more than 0.5 mm above the crestal bone level) were supracrestal and were excluded from this analysis. Mesial and distal bone loss was evaluated under 5* magnification and analyzed, along with Periotest values. RESULTS: Mean Periotest values were -1.77 (+/-3.57) for Group A and -1.77 (+/ 3.26) for Group B. For Group A, mean mesial (m) bone loss was 1.84 (+/-1.49 mm) and mean distal (d) bone loss was 1.73 (+/-1.31 mm). For Group B, the bone loss values were m: 1.41 (+/-1.65 mm) and d: 1.34 (+/-1.60 mm). No statistically significant differences were found for the Periotest values (p = .521) or bone level values for the two groups (m: p = .130; d: p = .153). CONCLUSION: Within the limitations of this study, subcrestal or crestal implant placement in combination with delayed loading was associated with similar initial implant stability and subsequent crestal bone loss. PMID- 23675970 TI - Altered expression of miRNAs in a dihydrotestosterone-induced rat PCOS model. AB - BACKGROUND: The polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine condition characterized by hyperandrogenism, hyperinsulinemia, insulin resistance and chronic anovulation. Regulation and interaction of a multitude of genes required for follicular development are found to be altered in PCOS. MicroRNAs (miRNAs) mediate posttranscriptional gene regulation by binding to the 3' untranslated region of mRNAs to either inhibit or enhance translation. However, the extent and regulation of miRNA expression in PCOS is poorly understood and the current study is the first to describe altered expression of miRNAs in PCOS. METHODS: A chronically androgenized [5alpha-dihydrotestosterone (DHT)-treated] rat model which recapitulates many of the phenotypes of human PCOS, and miRNA PCR array was used to investigate the expression of 349 miRNAs in DHT treated rat ovaries. The ovarian expression of several selected miRNAs was also analyzed by in situ localization experiment. RESULTS: DHT-treated rats exhibit increased body weight, disrupted estrus cyclicity, decreased insulin sensitivity and decreased ovarian weight, with the latter phenomenon readily rescued by gonadotropin treatment in vivo. In general, 24% of the 349 miRNAs investigated were found to be differentially expressed between DHT-treated and control rats. Most of the differentially expressed miRNAs were found to be predominantly localized in the theca cells of the follicles. In silico analysis of the potential target genes of dysregulated miRNAs revealed their possible involvement in various pathways in the regulation of ovarian function. CONCLUSION: Our current findings suggest that miRNAs are differentially regulated in hyperandrogenism, a condition possibly involved in the dysregulation of steroid hormone receptors and intra-ovarian factors, and that miRNAs may be involved in the etiology of PCOS. PMID- 23675971 TI - Integration of the mammalian shoulder girdle within populations and over evolutionary time. AB - Morphological integration has the potential to link morphological variation within populations with morphological evolution among species. This study begins to investigate this link by comparing integration among shoulder girdle elements (e.g. scapular blade, glenoid, coracoid, etc.) during the origin and evolution of therian mammals, and within modern bat, opossum and mouse populations. In this study, correlations among skeletal elements and patterns of allometry are used as proxies for integration. Results suggest that shoulder girdle elements tended to vary and evolve independently during the origin of mammals and subsequent radiation of placentals, consistent with the elements' distinct developmental and evolutionary origins. This finding suggests that skeletal element correlations, and therefore integration, can be conserved over large taxonomic and temporal scales. However, marsupials display a different pattern in which shoulder girdle elements tend to be more integrated, with the exception of the coracoid. This finding is consistent with a shift in the pattern of skeletal element integration coincident with the appearance of the marsupial mode of reproduction. This finding provides further evidence that development can play a significant role in the establishment of patterns of skeletal element correlation and that patterns of skeletal element correlation can themselves evolve when faced with sufficient selective pressures. PMID- 23675972 TI - Mycobacterium marinum infection in a case of psoriasis treated with antitumor necrosis factor alpha antibody detected by QuantiFERON((r)) -TB test. PMID- 23675973 TI - Energetics and electronic structure of encapsulated graphene nanoribbons in carbon nanotube. AB - We report results of our total energy electronic structure calculation of encapsulation of graphene nanoribbon (GNR) in the carbon nanotube (CNT). The encapsulation of both coronene and perylene based graphene nanoribbons in zigzag (n,0) carbon nanotubes (where n ranges from 14 to 18 for perylene based nanoribbon and from 16 to 20 for coronene based nanoribbons) is an exothermic process. Our study shows that in certain cases arm-chair GNR (aGNR) encapsulated CNT results in type II band alignment and may be useful in the application in solar cells. We have also studied the potential of this composites for hydrogen storage. We found that the encapsulated GNR composite systems have higher hydrogen adsorption energies than the individual components of either GNR and CNT. The hydrogen molecules oriented perpendicular to GNR are found to be more stable as compared to hydrogen molecules parallel to GNR. PMID- 23675974 TI - Expression of pigment epithelium-derived factor in human cutaneous appendages. AB - BACKGROUND: Pigment epithelium-derived factor (PEDF), a 50-kDa glycoprotein and a member of the serine protease inhibitor gene family, is well known as a potent endogenous inhibitor of angiogenesis. However, the expression of PEDF in human cutaneous appendages has not yet been determined. AIM: To investigate the expression of PEDF in human cutaneous appendages. METHODS: Immunohistochemical staining was used to detect the expression of PEDF in human cutaneous appendages. Reverse transcriptase PCR, western blotting and indirect immunofluorescence were used to determine the mRNA and protein expression of PEDF on cells of the outer root sheath (ORS). A wound-healing assay was used to determine the effect of different concentrations of PEDF on the migration of ORS cells. RESULTS: PEDF was expressed in the hair follicle (including epidermal matrix, inner root sheath, ORS and fibrous root sheath), sebaceous glands and eccrine sweat glands. Both protein and RNA expression of PEDF was detected, and expression was localized to both cytoplasm and nucleus of ORS cells. Both interleukin (IL)-4 and IL-17 at 25 ng/mL upregulated the expression of PEDF of ORS cells, with IL-4 having the greater effect. PEDF 50 ng/mL decreased migration of ORS cells. CONCLUSIONS: PEDF is expressed in human cutaneous appendages and may play a modulatory role in the physiology of ORS cells. PMID- 23675975 TI - Atopic dermatitis burden scale: creation of a specific burden questionnaire for families. AB - BACKGROUND: The notion of individual burden, associated with a disease, has been introduced to determine the 'disability' in the broadest sense (psychological, social, economic and physical). Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases with an estimated prevalence of 5%-30% in children. OBJECTIVE: To develop and validate a specific questionnaire which assess the burden of families of children with AD: the Atopic dermatitis Burden Scale (ABS). METHODS: Items for inclusion in ABS were initially generated from a literature review and a verbatim report from parents whose child had AD. ABS was refined via item reduction according to interquestion correlations, consensus among experts and exploratory factor analysis. Internal consistency was determined by calculating the Cronbach's alpha, concurrent validity by calculating the correlation between ABS and the Short-Form 12 items. Discriminant validity was analysed according to the severity degrees of AD assessed by Patient Oriented SCORing index of Atopic Dermatitis (PO-SCORAD). RESULTS: From an initial list of 29 items, ABS was reduced to a 14-item questionnaire, grouped into four dimensions based on the exploratory factor analysis. Construct validity was demonstrated and ABS showed good internal coherence (Cronbach's alpha: 0.78). ABS was significantly correlated to the mental dimension of Short-Form 12 (r = 0.49), but it was not correlated to the physical dimension (r = 0.04). ABS scores were significantly different according to the severity degrees of AD, with higher ABS score in parents whose child had severe AD. CONCLUSION: The ABS questionnaire is a validated tool for assessing the burden of families of children with AD. An implementation of a prospective study is planned to estimate sensitivity to change and to confirm its domain structure in larger samples. PMID- 23675976 TI - Synthesis and application of palladium precatalysts that accommodate extremely bulky di-tert-butylphosphino biaryl ligands. AB - A series of palladacyclic precatalysts that incorporate electron-rich di-tert butylphosphino biaryl ligands is reported. These precatalysts are easily prepared, and their use provides a general means of employing bulky ligands in palladium-catalyzed cross-coupling reactions. The application of these palladium sources to various C-N and C-O bond-forming processes is also described. PMID- 23675977 TI - Evaluation of the role of heterogeneities on transverse mixing in bench-scale tank experiments by numerical modeling. AB - In this work, numerical modeling is used to evaluate and interpret a series of detailed and well-controlled two-dimensional bench-scale conservative tracer tank experiments performed to investigate transverse mixing in porous media. The porous medium used consists of a fine matrix and a more permeable lens vertically aligned with the tracer source and the flow direction. A sensitivity analysis shows that the tracer distribution after passing the lens is only slightly sensitive to variations in transverse dispersivity, but strongly sensitive to the contrast of hydraulic conductivities. A unique parameter set could be calibrated to closely fit the experimental observations. On the basis of calibrated and validated model, synthetic experiments with different contrasts in hydraulic conductivity and more complex setups were performed and the efficiency of mixing evaluated. Flux-related dilution indices derived from these simulations show that the contrasts in hydraulic conductivity between matrix and high-permeable lenses as well as the spatial configuration of tracer plumes and lenses dominate mixing, rather than the actual pore scale dispersivities. These results indicate that local material distributions, the magnitude of permeability contrasts, and their spatial and scale relation to solute plumes are more important for macro-scale transverse dispersion than the micro-scale dispersivities of individual materials. Local material characterization by thorough site investigation hence is of utmost importance for the evaluation of mixing-influenced or -governed problems in groundwater, such as tracer test evaluation or an assessment of contaminant natural attenuation. PMID- 23675978 TI - QSAR and docking based semi-synthesis and in vitro evaluation of 18 beta glycyrrhetinic acid derivatives against human lung cancer cell line A-549. AB - For the prediction of anticancer activity of glycyrrhetinic acid (GA-1) analogs against the human lung cancer cell line (A-549), a QSAR model was developed by forward stepwise multiple linear regression methodology. The regression coefficient (r(2)) and prediction accuracy (rCV(2)) of the QSAR model were taken 0.94 and 0.82, respectively in terms of correlation. The QSAR study indicates that the dipole moments, size of smallest ring, amine counts, hydroxyl and nitro functional groups are correlated well with cytotoxic activity. The docking studies showed high binding affinity of the predicted active compounds against the lung cancer target EGFR. These active glycyrrhetinic acid derivatives were then semi-synthesized, characterized and in-vitro tested for anticancer activity. The experimental results were in agreement with the predicted values and the ethyl oxalyl derivative of GA-1 (GA-3) showed equal cytotoxic activity to that of standard anticancer drug paclitaxel. PMID- 23675979 TI - Hepatic failure in pregnancy successfully treated by online hemodiafiltration: Chronic hepatitis B virus infection without viral genome mutation. AB - A 23-year-old nulliparous woman, a hepatitis B virus (HBV) carrier with stable liver functions, presented with exacerbation of viral replication (HBV DNA level >9.0 log copies/mL) in gestational week 26. During the subsequent follow up without antiviral therapy, she was hospitalized with progression to hepatic failure in gestational week 35. Following initiation of antiviral therapy with lamivudine, emergent cesarean delivery was conducted for fetal safety. Liver atrophy and persistent hepatic encephalopathy (stage 2) necessitated artificial liver support (ALS) involving online hemodiafiltration (HDF) and plasma exchange. She regained full consciousness after the sixth online HDF session. ALS was terminated after the seventh online HDF session. On day 33 of hospitalization, she was discharged home without sequelae. Genetic analysis of the HBV strain isolated from her serum showed that this strain had genotype C. Direct full length sequencing identified no known mutations associated with fulminant hepatitis B. HBV-related hepatic failure observed in the present case might have been related to perinatal changes in the host immune response. PMID- 23675980 TI - Ultrasound-modulated shape memory and payload release effects in a biodegradable cylindrical rod made of chitosan-functionalized PLGA microspheres. AB - Minimally invasive implants and/or scaffolds integrated with multiple functionalities are of interest in the clinical settings. In this paper, chitosan (CTS) functionalized poly(lactic-co-glycolic acid) (PLGA) microspheres containing a model payload, lysozyme (Lyz), were prepared by a water-in-oil-in-water emulsion method, from which cylindrical shaped rod (5 mm in diameter) was fabricated by sintering the composite microspheres in a mold. High-intensity focused ultrasound (HIFU) was then employed as a unique technique to enable shape memory and payload release effects of the three-dimensional (3-D) structure. It was found that incorporation of CTS into PLGA microspheres could regulate the transition temperature Ttrans of the microsphere from 45 to 50 degrees C and affect shape memory ratio of the fabricated cylindrical rod to some extent. Shape memory test and drug release assay proved that HIFU could modulate the shape recovery process and synchronize the release kinetics of the encapsulated Lyz in the rod in a switchable manner. Moreover, the two processes could be manipulated by varying the acoustic power and insonation duration. Mechanical tests of the microspheres-based rod before and after ultrasound irradiation revealed its compressive properties in the range of trabecular bone. Examination of the degradation behavior indicated that the introduction of CTS into the PLGA microspheres also alleviated acidic degradation characteristic of the PLGA dominant cylindrical rod. With HIFU, this study thus demonstrated the desired capabilities of shape recovery and payload release effects integrated in one microspheres-based biodegradable cylindrical structure. PMID- 23675982 TI - Irinotecan delivery by microbubble-assisted ultrasound: in vitro validation and a pilot preclinical study. AB - Irinotecan is a powerful anticancer drug with severe systemic side effects that limit its clinical application. Drug-targeted delivery with noninvasive methods is required to enhance the drug concentration locally and to reduce these undesirable events. Microbubble-assisted ultrasound has become a promising method for noninvasive targeted drug delivery. The aim of this study is to evaluate the therapeutic effectiveness of in vitro and in vivo irinotecan delivery based on the combination of ultrasound and microbubbles. In the present study, in vitro results showed that the irinotecan treatment with microbubble-assisted ultrasound induced a significant decrease in cell viability of human glioblastoma cells. Moreover, using subcutaneous glioblastoma xenografts, the in vivo preclinical study in nude mice demonstrated that this therapeutic protocol led to a decrease in tumor growth and perfusion and an increase of tumor necrosis. The conclusions drawn from this study demonstrate the promising potential of this therapeutic approach for the anticancer targeted therapy. PMID- 23675981 TI - Impact of genotype 1 and 2 of porcine reproductive and respiratory syndrome viruses on interferon-alpha responses by plasmacytoid dendritic cells. AB - Porcine reproductive and respiratory syndrome (PRRS) virus (PRRSV) infections are characterized by prolonged viremia and viral shedding consistent with incomplete immunity. Type I interferons (IFN) are essential for mounting efficient antiviral innate and adaptive immune responses, but in a recent study, North American PRRSV genotype 2 isolates did not induce, or even strongly inhibited, IFN-alpha in plasmacytoid dendritic cells (pDC), representing "professional IFN-alpha producing cells". Since inhibition of IFN-alpha expression might initiate PRRSV pathogenesis, we further characterized PRRSV effects and host modifying factors on IFN-alpha responses of pDC. Surprisingly, a variety of type 1 and type 2 PRRSV directly stimulated IFN-alpha secretion by pDC. The effect did not require live virus and was mediated through the TLR7 pathway. Furthermore, both IFN-gamma and IL-4 significantly enhanced the pDC production of IFN-alpha in response to PRRSV exposure. PRRSV inhibition of IFN-alpha responses from enriched pDC stimulated by CpG oligodeoxynucleotides was weak or absent. VR-2332, the prototype genotype 2 PRRSV, only suppressed the responses by 34%, and the highest level of suppression (51%) was induced by a Chinese highly pathogenic PRRSV isolate. Taken together, these findings demonstrate that pDC respond to PRRSV and suggest that suppressive activities on pDC, if any, are moderate and strain-dependent. Thus, pDC may be a source of systemic IFN-alpha responses reported in PRRSV-infected animals, further contributing to the puzzling immunopathogenesis of PRRS. PMID- 23675983 TI - Growth intermediates for CVD graphene on Cu(111): carbon clusters and defective graphene. AB - Graphene growth on metal films via chemical vapor deposition (CVD) represents one of the most promising methods for graphene production. The realization of the wafer scale production of single crystalline graphene films requires an atomic scale understanding of the growth mechanism and the growth intermediates of CVD graphene on metal films. Here, we use in situ low-temperature scanning tunneling microscopy (LT-STM) to reveal the graphene growth intermediates at different stages via thermal decomposition of methane on Cu(111). We clearly demonstrate that various carbon clusters, including carbon dimers, carbon rectangles, and 'zigzag' and 'armchair'-like carbon chains, are the actual growth intermediates prior to the graphene formation. Upon the saturation of these carbon clusters, they can transform into defective graphene possessing pseudoperiodic corrugations and vacancies. These vacancy-defects can only be effectively healed in the presence of methane via high temperature annealing at 800 degrees C and result in the formation of vacancy-free monolayer graphene on Cu(111). PMID- 23675984 TI - Long-term safety of low-level laser therapy at different power densities and single or multiple applications to the bone marrow in mice. AB - OBJECTIVE: The purpose of this study was to determine the long-term safety effect of low-level laser therapy (LLLT) to the bone marrow (BM) in mice. BACKGROUND DATA: LLLT has been shown to have a photobiostimulatory effect on various cellular processes and on stem cells. It was recently shown that applying LLLT to BM in rats post-myocardial infarction caused a marked reduction of scar tissue formation in the heart. METHODS: Eighty-three mice were divided into five groups: control sham-treated and laser-treated at measured density of either 4, 10, 18, or 40 mW/cm(2) at the BM level. The laser was applied to the exposed flat medial part of the tibia 8 mm from the knee joint for 100 sec. Mice were monitored for 8 months and then killed, and histopathology was performed on various organs. RESULTS: No histological differences were observed in the liver, kidneys, brain or BM of the laser-treated mice as compared with the sham-treated, control mice. Moreover, no neoplasmic response in the tissues was observed in the laser-treated groups as compared with the control, sham-treated mice. There were no significant histopathological differences among the same organs under different laser treatment regimes in response to the BM-derived mesenchymal stem cell proliferation following LLLT to the BM. CONCLUSIONS: LLLT applied multiple times either at the optimal dose (which induces photobiostimulation of stem cells in the BM), or at a higher dose (such as five times the optimal dose), does not cause histopathological changes or neoplasmic response in various organs in mice, as examined over a period of 8 months. PMID- 23675985 TI - Immediate and short-term effects of in-office desensitizing treatments for dentinal tubule occlusion. AB - OBJECTIVE: The objective of this in vitro study was to evaluate the immediate and short-term effects of laser neodymium-doped yttrium aluminum garnet (Nd:YAG) irradiation and in-office desensitizing treatment on dentin tubule occlusion. BACKGROUND DATA: Literature shows a lack of long-lasting treatments for dentin hypersensitivity. METHODS: Forty-eight dentin slabs (4*4*2 mm) were ground flat, polished, and treated with 27% ethylenediaminetetraacetic acid (EDTA) to open the dentinal tubules. Specimens were randomly divided into the following experimental groups (n=12): Group 1: Control (no treatment); Group 2: Nd:YAG laser irradiation (100 mJ, 85 J/cm(2) per pulse with a quartz fiber of 400 MUm, in scanning movements); Group 3: In-office prophylaxis with pumice; Group 4: In-office Colgate Sensitive Pro-ReliefTM Desensitizing Paste. Treatments were performed according to the manufacturer's instructions. After treatment, the specimens were submitted to a sequence of erosive and abrasive challenges, twice a day for 5 days. The specimens were qualitatively and quantitatively evaluated by scanning electron microscopy immediately after treatment and after 4 and 5 days. The response variable was the amount of occluded dentin tubules per area, determined by three different examiners with the use of visual criteria, with a standardized grade created in the PowerPoint program. Data were compared with ANOVA and Tukey's test, considering a 5% significance level. RESULTS: Immediately after treatment, a reduction in the number of opened dentin tubules was observed for the laser group when compared with the control group (p<0.05). After the experimental procedures, there were no quantitative differences between the amount of opened dentin tubules for all groups; however, micrographs showed some qualitative tubule occlusion for the laser group after the erosive/abrasive challenge. CONCLUSIONS: only laser irradiation was capable of immediately sealing the dentinal tubules; however, none of the treatments showed efficacy in maintaining tubule occlusion after the chemical and mechanical challenges. PMID- 23675986 TI - Association between NFKB1 -94 insertion/deletion ATTG polymorphism and risk of intracranial aneurysm. AB - OBJECTIVE: Growing evidence indicates that vascular inflammation is a common phenomenon in the pathogenesis of intracranial aneurysms (IAs). Nuclear factor kappa B is a key molecule that is involved in the vascular inflammation of IA. We hypothesized that an insertion/deletion (ins/del) ATTG polymorphism located between two putative key promoter regulatory elements in the NFKB1 gene may be related to the risk of IA. METHODS: We performed a case-control study, including 164 patients with IA and 525 healthy controls in a Chinese population using a polymerase chain reaction-polyacrylamide gel electrophoresis assay. RESULTS: A significantly decreased risk of IA was observed in the ATTG1/ATTG2 and ATTG2/ATTG2 genotypes compared with the ATTG1/ATTG1 genotype (ATTG1/ATTG2 vs. ATTG1/ATTG1: odds ratio [OR]=0.58, 95% confidence interval [95% CI]=0.39-0.87, p=0.007; ATTG2/ATTG2 vs. ATTG1/ATTG1: OR=0.12, 95% CI=0.06-0.23, p<0.001), and also the ATTG2 allele (ATTG2 vs. ATTG1: OR=0.41, 95% CI=0.32-0.54, p<0.001). CONCLUSION: These findings suggest that the NFKB1 -94ins/del ATTG polymorphism may contribute to the risk of IA. PMID- 23675987 TI - A haplotype of the GOSR2 gene is associated with myocardial infarction in Japanese men. AB - AIMS: The Golgi SNAP Receptor Complex Member 2 (GOSR2) gene is a Golgi-associated soluble factor attachment receptor (SNARE) protein. Some single-nucleotide polymorphisms (SNPs) in the GOSR2 gene have been found to be associated with myocardial infarction (MI). The aim of the present study was to assess the association between the human GOSR2 gene and MI using a haplotype-based case control study. METHODS: A total of 238 MI patients and 284 controls were genotyped for the five SNPs used as genetic markers for the human GOSR2 gene (rs197932, rs3785889, rs197922, rs17608766, and rs16941382). Data were analyzed for three separate groups: the total subjects, men, and women. RESULTS: The overall distribution of the haplotypes in the total subjects and the men was significantly different between the MI patients and the control subjects (p=0.001, p=0.005, respectively). Additionally, the frequency of the T-G-G haplotype (rs197932-rs3785889-rs197922) for men was significantly lower in the MI patients than in the control subjects (p=0.040). Multiple logistic regression analysis also revealed that the frequency of the subjects with the T-G-G haplotype (homozygous and heterozygous diplotypes) was significantly lower compared with subjects without this haplotype in men after adjustment for the major confounding factors (odds ratio=0.455, p=0.041). CONCLUSIONS: The results of this study indicate that the T-G-G haplotype may be a protective genetic marker for MI in Japanese men. PMID- 23675989 TI - Hydrogen production in aromatic and aliphatic ionic liquids. AB - The radiolytic production of molecular hydrogen in the ionic liquids N-trimethyl N-butylammonium bis(trifluoromethanesulfonyl)imide ([N1114][Tf2N]) and 1-ethyl-3 methylimidazolium bis(trifluoromethylsulfonyl)imide ([emim][Tf2N]) has been examined with gamma-rays, 2-10 MeV protons, and 5-20 MeV helium ions to determine the functional dependence of the yield on particle track structure. Molecular hydrogen is the dominant gaseous radiolysis product from these ionic liquids, and the yields with gamma-rays are 0.73 and 0.098 molecules per 100 eV of energy absorbed for [N1114][Tf2N] and [emim][Tf2N], respectively. These low yields are consistent with the relative insensitivity of most aromatic compounds to radiation. However, the molecular hydrogen yields increase considerably on going from gamma-rays to protons to helium ions with [emim][Tf2N] while they remain essentially constant for [N1114][Tf2N]. FTIR and UV-vis spectroscopic studies show slight degradation of the ionic liquids with radiation. PMID- 23675988 TI - Associations between eating meals, watching TV while eating meals and weight status among children, ages 10-12 years in eight European countries: the ENERGY cross-sectional study. AB - BACKGROUND: To assess the association of eating meals, and never watching TV while eating meals, with weight status among children, ages 10-12 years across Europe. METHODS: 7915 children (mean age: 11.5 years) in eight European countries (Belgium, Greece, Hungary, the Netherlands, Norway, Slovenia, Spain and Switzerland) completed a questionnaire at school. Data on meals eaten the day before questionnaire administration and the frequency of eating meals while watching TV were collected. Height and weight of the children were objectively assessed. Multinomial and binary regression analyses were conducted to test associations of eating meals (adjusted for gender and ethnicity) and never watching TV while eating meals (adjusted for gender, ethnicity and total TV time) with overweight/obesity, and to test for country- and socio-demographic differences. RESULTS: The proportions of children reporting eating breakfast, lunch and dinner were 85%, 96%, and 93% respectively, and 55%, 46% and 32% reported to never watch TV at breakfast, lunch and dinner respectively. The children who ate breakfast (OR = 0.6 (95% CI 0.5-0.7)) and dinner (OR = 0.4 (95% CI 0.3-0.5)), had lower odds of being overweight compared to those who did not. The children who never watched TV at lunch (OR = 0.7 (95% CI 0.7-0.8)) and dinner (OR = 0.8 (95% CI 0.7-0.9)) had lower odds of being overweight compared to those who watched TV at the respective meals. CONCLUSIONS: The odds of being overweight was lower for children who ate breakfast and dinner compared to those who did not eat the respective meals. The odds of being overweight was lower for children who reported to never watch TV at lunch and dinner compared to those who did. A focus towards meal frequency and watching TV during meals in longitudinal and interventions studies in prevention of overweight and obesity, may contribute to a better understanding of causality. PMID- 23675990 TI - Diabetes-ameliorating effects of fermented red ginseng and causal effects on hormonal interactions: testing the hypothesis by multiple group path analysis. AB - Although diagnostic criteria for metabolic syndrome (MtS) vary among various health professionals and organizations, blood glucose dysregulation and insulin resistance are common to all definitions. Red ginseng is beneficial for glucose regulation and insulin sensitivity but the mechanism is not yet elucidated. Ginsenosides Rh1 and Rg3 act as ligands of the estrogen receptor, and Rh2 and compound K act as ligands of the glucocorticoid receptors, which may influence the diabetes markers. The objective of this study was to test the hypothesis that there are significant causal relationships among diabetes-related markers and several hormones, and assess whether or not the consumption of fermented red ginseng (FRG) influences these causal relationships by multiple group path analysis and conventional statistical analyses. The 93 postmenopausal women were randomly divided into two groups for a double-blind trial. FRG powder and placebo were provided for 2 weeks. The data were analyzed by multiple group path analysis and the mean between groups were compared. The model's goodness of fit was excellent, with a root mean square error of approximation of 0.00, and comparative fit index of 1.00. The FRG group exhibited significantly increased levels of dehydroepiandrosterone sulfate (DHEAS), growth hormone (GH), and estradiol (E2), and they exhibited decreased levels of glycosylated hemoglobin (HbA1c), insulin, and homeostatic model assessment of insulin resistance. With regard to the hypothesis, the blood glucose lowering effects of FRG were due to the negative effects of aldosterone and increased GH, which was associated with DHEAS and E2. Even though the differences of variables between both groups were small, the total effects of these variables may indicate beneficial changes for the prevention of diabetes in healthy postmenopausal women. PMID- 23675991 TI - Can mass education and a television campaign change the attitudes towards cardiopulmonary resuscitation in a rural community? AB - BACKGROUND: Survival after out-of-hospital cardiac arrest (OHCA) is improved when bystanders provide Basic Life Support (BLS). However, bystander BLS does not occur frequently. The aim of this study was to assess the effects on attitudes regarding different aspects of resuscitation of a one-year targeted media campaign and widespread education in a rural Danish community. Specifically, we investigated if the proportion willing to provide BLS and deploy an automated external defibrillator (AED) increased. METHODS: BLS and AED courses were offered and the local television station had broadcasts about resuscitation in this study community. A telephone enquiry assessed the attitudes towards different aspects of resuscitation among randomly selected citizens before (2008) and after the project (2009). RESULTS: For responses from 2008 (n = 824) to 2009 (n = 815), there was a significant increase in the proportions who had participated in a BLS course within the past 5 years, from 34% to 49% (p = 0.0001), the number willing to use an AED on a stranger (p < 0.0001), confident at providing chest compressions (p = 0.03), and confident at providing mouth-to-mouth ventilations (MMV) (p = 0.048). There was no significant change in the proportions willing to provide chest compressions (p = 0.15), MMV (p = 0.23) or confident at recognizing a cardiac arrest (p = 0.09). The most frequently reported reason for not being willing to provide chest compressions, MMV and use an AED was insecurity about how to perform the task. CONCLUSION: A targeted media campaign and widespread education can significantly increase the willingness to use an AED, and the confidence in providing chest compressions and MMV. The willingness to provide chest compressions and MMV may be less influenced by a targeted campaign. PMID- 23675992 TI - Vertical osteoconductive characteristics of titanium implants with calcium phosphate-coated surfaces - a pilot study in rabbits. AB - INTRODUCTION: Osteoconductive characteristics of different implant surface coatings are in the focus of current interest. The aim of the present study was to compare the vertical osteoconductivity at the implant shoulder of supracrestal inserted calcium-phosphate coated implants (SLA-CaP) with conventional sand blasted/acid-etched (SLA) implants in a rabbit model. MATERIALS AND METHODS: SLA CaP and SLA implants were inserted bilaterally in the mandible of four rabbits in a split-mouth design. The implants were placed 2 mm supracrestal. After 3 weeks, at the left and right implant shoulder, the percentage of linear bone fill (PLF) as well as bone-implant contact (BIC-D) were determined. RESULTS: After 3 weeks, newly formed woven bone could be found at the shoulder of the most of both surface-treated implants (75%). PLF was significantly higher in SLA-CaP implants (11.2% vs. 46.5%; n = 8, p = .008). BIC-D was significantly increased in the SLA CaP implants (13.0% vs. 71.4%; n = 8, p < .001) as well. CONCLUSION: The results of this study show for the first time that calcium-phosphate coated surfaces on supracrestal inserted implants have vertical osteoconductive characteristics and increase the bone-implant contact at the implant shoulder significantly in a rabbit model. In clinical long-term settings, these implants may contribute to a better vertical bone height. PMID- 23675993 TI - Synthesis and biological investigation of coumarin piperazine (piperidine) derivatives as potential multireceptor atypical antipsychotics. AB - The discovery and synthesis of potential and novel antipsychotic coumarin derivatives, associated with potent dopamine D2, D3, and serotonin 5-HT1A and 5 HT2A receptor properties, are the focus of the present article. The most promising derivative was 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1 yl)butoxy)-4-methyl-8-chloro-2H-chromen-2-one (17m). This derivative possesses unique pharmacological features, including high affinity for dopamine D2 and D3 and serotonin 5-HT1A and 5-HT2A receptors. Moreover, it possesses low affinity for 5-HT2C and H1 receptors (to reduce the risk of obesity associated with chronic treatment) and hERG channels (to reduce the incidence of torsade des pointes). In animal models, compound 17m inhibited apomorphine-induced climbing behavior, MK-801-induced hyperactivity, and the conditioned avoidance response without observable catalepsy at the highest dose tested. Further, fewer preclinical adverse events were noted with 17m compared with risperidone in assays that measured prolactin secretion and weight gain. Acceptable pharmacokinetic properties were also noted with 17m. Taken together, 17m may constitute a novel class of drugs for the treatment of schizophrenia. PMID- 23675994 TI - A rare case of acquired partial lipodystrophy (Barraquer-Simons syndrome) with localized scleroderma. PMID- 23675995 TI - Comparing first and second generation digital natives' Internet use, Internet anxiety, and Internet identification. AB - The aim of the study was to compare first and second generation Digital Natives' attitudes toward and use of the Internet. The sample of first generation Digital Natives consisted of 558 students who we surveyed in 2002 and who were born after 1980. The sample of second generation Digital Natives consisted of a sample of 458 students who we surveyed in 2012 and were born after 1993. They completed a questionnaire in the first semester of their first academic year, which consisted of a measure of Internet experience, an Internet anxiety scale, and an Internet identification scale. Second generation Digital Natives had more positive attitudes toward the Internet than first generation Digital Natives. They had higher scores on the Internet identification scale and lower scores on the Internet anxiety scale compared with first generation Digital Natives. Furthermore, we found that second generation Digital Natives used the Internet more than first generation Digital Natives. E-mail was the most popular activity for both generations, although second generation Digital Natives used it significantly more than first generation Digital Natives. Social networking sites emerged as very popular for second generation Digital Natives. Both generations reported low use of Web 2.0 technologies. PMID- 23675996 TI - Understanding differences in sexting behaviors across gender, relationship status, and sexual identity, and the role of expectancies in sexting. AB - Sexting, or the exchange of sexually explicit material via Internet social networking site or mobile phone, is an increasingly prevalent behavior. The study sought to (1) identify expectancies regarding sexting behaviors, (2) examine how demographics (i.e., gender, sexual identity, relationship status) might be differentially related to sexting expectancies and behaviors, and (3) examine whether these concurrent relationships are consistent with a theoretical causal model in which sexting expectancies influence sexting behaviors. The sample consisted of 278 undergraduate students (mean age=21.0 years, SD=4.56; 53.8% female; 76.3% caucasian). Factor analyses supported the validity and reliability of the Sextpectancies Measure (alpha=0.85-0.93 across subscales) and indicated two expectancy domains each for both sending and receiving sexts: positive expectancies (sexual-related and affect-related) and negative expectancies. Males reported stronger positive expectancies (F=4.64, p=0.03) while females reported stronger negative expectancies (F=6.11, p=0.01) about receiving sexts. There were also differences across relationship status regarding negative expectancies (F=2.25, p=0.05 for sending; F=4.24, p=0.002 for receiving). There were also significant effects of positive (F=45.98, p<0.001 for sending, F=22.42, p<0.001 for receiving) and negative expectancies (F=36.65, p=0.02 sending, F=14.41, p<0.001 receiving) on sexting behaviors (eta(2) from 0.04-0.13). College students reported both positive and negative sextpectancies, although sextpectancies and sexting varied significantly across gender, race, sexual identity, and relationship status. Concurrent relationships were consistent with the causal model of sextpectancies influencing sexting behaviors, and this study serves as the first test of this model, which could inform future prevention strategies to mitigate sexting risks. PMID- 23675997 TI - Clinical and histopathological characteristics of a family with R1141X mutation of pseudoxanthoma elasticum - presymptomatic testing and lack of carrier phenotypes. AB - BACKGROUND: Pseudoxanthoma elasticum (PXE) is a heritable ectopic mineralization disorder affecting cutaneous, ocular, and cardiovascular systems, caused by mutations in the ABCC6 gene. PXE presents with a marked clinical and genetic heterogeneity. Furthermore, heterozygous carriers may present with limited histopathological features. This study was conducted to investigate a patient with PXE and her family members clinically, histopathologically, and genetically. METHODS: Clinical and histopathological examinations and mutation analyses of ABCC6 gene were performed. RESULTS: Lesional skin biopsy of the patient with PXE demonstrated clumping and fragmentation of elastic fibers, and calcification in the dermis. Non-lesional axillary skin samples of the husband, daughter, and older son were histopathologically normal. The skin from a similar region of a younger son revealed elastic fibers with some fragmentation and clumping but no mineralization. The patient with PXE was homozygous for the R1141X mutation in the ABCC6 gene. The husband had wild-type alleles, while all children were heterozygous carriers. Daily treatment of antioxidant therapy with tocopherol acetate and ascorbic acid was prescribed to the patient with PXE. After one year, both clinical and histopathological regression of the lesions was observed; however, lesions began to progress during the additional 6-month period of treatment. CONCLUSION: The mutation analyses of ABCC6 gene are important to determine the genotype of both patients with PXE and putative heterozygous carriers, as histopathological features of carriers may differ even in the same family. The role of antioxidant therapy for PXE is unclear, and there is a need for controlled clinical trials. PMID- 23675998 TI - Bone morphogenetic protein receptor type 2 mutations, clinical phenotypes and outcomes of Japanese patients with sporadic or familial pulmonary hypertension. AB - BACKGROUND AND OBJECTIVE: Mutation of bone morphogenetic protein receptor type 2 (BMPR2) is a cause of pulmonary arterial hypertension (PAH). We measured the prevalence of this mutation and its impact on the phenotypes and long-term clinical outcomes in Japanese patients. METHODS: Between 1999 and 2007, we consecutively enrolled and, until March 2012, followed 49 Japanese patients with PAH, including nine familial cases from seven families. We genotyped BMPR2, using direct sequencing and multiplex ligation-dependent probe amplification, to examine (i) the prevalence of BMPR2 mutations and gene rearrangement, (ii) the relationship between BMPR2 genotype and clinical phenotypes, and (iii) the long term clinical outcomes of mutation carriers versus non-carriers under state-of the-art medical therapy. RESULTS: BMPR2 mutations were present in four of the seven families (57%) and in 14 of the 40 patients (35%) with sporadic PAH. The mean age at onset of PAH was 37.4 years in BMPR2 carriers, versus 25.9 years in non-carriers (P = 0.0025). The gender distribution and hemodynamic status at time of diagnosis were similar regardless of the mutation status. The 5-year survival rate after diagnosis of PAH was 88.5% in BMPR2 mutation carriers versus 80.9% in non-carriers (ns). CONCLUSIONS: The prevalence of BMPR2 mutations in Japanese with PAH was similar to that reported in other populations. At onset of PAH, BMPR2 mutation non-carriers were, on average, younger than carriers, possibly due to the heterogeneity of this subpopulation. With state-of-the-art therapy, the long-term survival of patients with PAH was high, regardless of the mutation status. PMID- 23676000 TI - Autocatalytic chemiluminescence sheds new light on the classic permanganate oxalate reaction. AB - The emission of light from the permanganate-oxalate reaction enables monitoring of intermediates not accessible through traditional spectrophotometric interrogation. Despite the inherent complexity of the underlying chemical reactions and equilibria, the emission intensity-time profile was characterized by a simple model combining previously independent minimalistic descriptions of chemiluminescence and autocatalysis. The generation of the electronically excited [Mn(II)]* emitter and the acceleration of the reaction even in the presence of high initial concentrations of Mn(II) (under conditions that preclude accumulation of colloidal Mn(IV)) provide new evidence for the reduction of manganese species by a reactive radical intermediate as a supplementary positive feedback loop to the formation of Mn(II). PMID- 23675999 TI - Effects of Y27632 on keratinocyte procurement and wound healing. AB - A number of Rho-kinase inhibitors have been developed for various clinical applications. We examined the effects of the Rho-kinase inhibitor Y27632 on keratinocyte proliferation and migration, and found that it promoted primary human keratinocyte proliferation and migration in both monolayer and skin explant cultures. In addition, topical application of Y27632 enhanced cutaneous wound closure in the majority of wounds in mice. The growth and migration effects of Y27632 appeared to be specific to keratinocytes compared with dermal fibroblasts, and required intact Jun kinase function. Y27632 seems to be a promising agent for keratinocyte procurement and wounding healing. PMID- 23676001 TI - Low prevalence of positive skin pathergy testing in Danish patients with Behcet's disease. PMID- 23676002 TI - Kinetic resolution of racemic carboxylic acids through asymmetric protolactonization promoted by chiral phosphonous acid diester. AB - Chiral phosphonium salts induce the kinetic resolution of racemic alpha substituted unsaturated carboxylic acids through asymmetric protolactonization. Both the lactones and the recovered carboxylic acids are obtained with high enantioselectivities and high S (= kfast/kslow) values. Asymmetric protolactonization also leads to the desymmetrization of achiral carboxylic acids. Notably, chiral phosphonous acid diester not only induced the enantioselectivity but also promoted protolactonization. PMID- 23676003 TI - Comparison of interictal vestibular function in vestibular migraine vs migraine without vertigo. AB - BACKGROUND: Patients with vestibular migraine (VM) suffer attacks of vertigo that often occur in isolation from headache attacks. We aimed to assess and compare vestibular function interictally in patients with VM and patients with migraine without vertigo (M). METHODS: Thirty-eight patients diagnosed with definite VM according to the Neuhauser criteria, and 32 patients diagnosed with M according to the International Headache Society criteria were examined between attacks using a broad battery of bedside vestibular tests, a caloric test, and videonystagmography. RESULTS: Overall, 70% of the VM patients and 34% of the M patients showed abnormalities on one or more of the 14 performed vestibular tests (P = .006). Abnormal findings were more frequent in VM than in M patients on Romberg's test, test for voluntary fixation suppression of the vestibular ocular reflex and test for static positional nystagmus (P = .03, .01 and .04, respectively). There were no differences in the distribution of central and peripheral vestibular signs between VM and M patients. CONCLUSIONS: Vestibular abnormalities were present interictally among both VM and M patients, but were found about twice as frequently among VM patients. This may indicate that subclinical vestibular dysfunction is an integral part of migraine pathology in general, and not solely in VM. PMID- 23676004 TI - Structure of clean and adsorbate-covered single-crystal rutile TiO2 surfaces. PMID- 23676006 TI - States modulation in graphene nanoribbons through metal contacts. AB - We are reporting the results of density functional calculations of the electronic structure of finite graphene nanoribbons adsorbed on Au, Pd, and Ti electrodes. While the interaction of nanoribbons with the Au contact is more characteristic of a physisorbed state, the adsorption of Pd and Ti involves much stronger state mixing as in chemisorption. Metal-induced gap states, which can potentially short circuit the device, are clearly revealed for the first time, allowing us to evaluate their penetration length. The evanescence of MIGS is primarily governed by the band gap of the nanoribbon, and we can estimate an acceptable minimal length for an effective transport channel to a few nanometers. Different impacts of the presence of metal-induced gap states on the properties of graphene nanoribbons are discussed in terms of charge transfer and electrostatics. PMID- 23676005 TI - Systemic inflammation, depression and obstructive pulmonary function: a population-based study. AB - BACKGROUND: Levels of Interleukin-6 (IL-6) and C-creative protein (CRP) indicating systemic inflammation are known to be elevated in chronic diseases including chronic obstructive pulmonary disease (COPD) and depression. Comorbid depression is common in patients with COPD, but no studies have investigated whether proinflammatory cytokines mediate the association between pulmonary function and depressive symptoms in healthy individuals with no known history of obstructive pulmonary diseases. METHODS: In a population-based sample (n = 2077) of individuals aged 55 and above with no known history of obstructive pulmonary disease in the Singapore Longitudinal Ageing Study (SLAS), we analyzed the relationships between IL-6 and CRP, depressive symptoms (GDS-15 >=5) and obstructive pulmonary function (FEV1% predicted and FEV1/FVC% predicted). RESULTS: High serum levels of IL-6 and CRP were associated with greater prevalence of depressive symptoms (p < 0.05). High IL-6, high CRP and depressive symptoms were independently associated with decreased FEV1% predicted and FEV1/FVC% predicted after adjusting for smoking status, BMI and number of chronic inflammatory diseases. Increasing grades of combination of inflammatory markers and/or depressive symptoms was associated with progressive increases in pulmonary obstruction. In hierarchical models, the significant association of depressive symptoms with pulmonary obstruction was reduced by the presence of IL-6 and CRP. CONCLUSIONS: This study found for the first time an association of depressive symptoms and pulmonary function in older adults which appeared to be partly mediated by proinflammatory cytokines. Further studies should be conducted to investigate proinflammatory immune markers and depressive symptoms as potential phenotypic indicators for chronic obstructive airway disorders in older adults. PMID- 23676007 TI - Single-antibody, targeted nanoparticle delivery of camptothecin. AB - We have developed a new method for assembling targeted nanoparticles that utilizes the complexation between targeting agents that contain boronic acids and polymer-drug conjugates that possess diols. Here, we report the first in vivo, antitumor results of a nanoparticle formed via this new assembly methodology. A nanoparticle consisting of a mucic acid polymer conjugate of camptothecin (CPT), MAP-CPT, and containing on average one Herceptin antibody is investigated in nude mice bearing HER2 overexpressing BT-474 human breast cancer tumors. Nontargeted MAP-CPT and antibody-containing MAP-CPT nanoparticles of ca. 30-40 nm diameter and slightly negative zeta potential show prolonged in vivo circulation and similar biodistributions after intravenous tail vein injections in mice. The maximum tolerated dose (MTD) of the nontargeted and Herceptin-containing MAP-CPT nanoparticles is found to be 10 and 8 mg of CPT/kg, respectively, in mice. Mice bearing BT-474 human breast tumors treated with nontargeted MAP-CPT nanoparticles at 8 mg of CPT/kg show significant tumor growth inhibition (mean tumor volume of 63 mm(3)) when compared to irinotecan at 80 mg/kg (mean tumor volume of 575 mm(3)) and CPT at 8 mg/kg (mean tumor volume of 808 mm(3)) at the end of the study. Herceptin antibody treatment at 5.9 mg/kg results in complete tumor regressions in 5 out of 8 mice, with a mean tumor volume of 60 mm(3) at the end of the study. Mice treated with MAP-CPT nanoparticles at 1 mg of CPT/kg do not show tumor inhibition. However, all mice receiving administrations of MAP-CPT nanoparticles (1 mg of CPT/kg) that contain on average a single Herceptin molecule per nanoparticle (5.9 mg of Herceptin equivalent/kg) show complete tumor regression by the end of the study. These results demonstrate that the antitumor efficacy of nanoparticles carrying anticancer drugs can be enhanced by incorporating on average a single antibody. PMID- 23676008 TI - Stimuli responsive hybrid magnets: tuning the photoinduced spin-crossover in Fe(III) complexes inserted into layered magnets. AB - The insertion of a [Fe(sal2-trien)](+) complex cation into a 2D oxalate network in the presence of different solvents results in a family of hybrid magnets with coexistence of magnetic ordering and photoinduced spin-crossover (LIESST effect) in compounds [Fe(III)(sal2-trien)][Mn(II)Cr(III)(ox)3].CHCl3 (1.CHCl3), [Fe(III)(sal2-trien)][Mn(II)Cr(III)(ox)3].CHBr3 (1.CHBr3), and [Fe(III)(sal2 trien)][Mn(II)Cr(III)(ox)3].CH2Br2 (1.CH2Br2). The three compounds crystallize in a 2D honeycomb anionic layer formed by Mn(II) and Cr(III) ions linked through oxalate ligands and a layer of [Fe(sal2-trien)](+) complexes and solvent molecules (CHCl3, CHBr3, or CH2Br2) intercalated between the 2D oxalate network. The magnetic properties and Mossbauer spectroscopy indicate that they undergo long-range ferromagnetic ordering at 5.6 K and a spin crossover of the intercalated [Fe(sal2-trien)](+) complexes at different temperatures T1/2. The three compounds present a LIESST effect with a relaxation temperature TLIESST inversely proportional to T1/2. The isostructural paramagnetic compound, [Fe(III)(sal2-trien)][Zn(II)Cr(III)(ox)3].CH2Cl2 (2.CH2Cl2) was also prepared. This compound presents a partial spin crossover of the inserted Fe(III) complex as well as a LIESST effect. Finally, spectroscopic characterization of the Fe(III) doped compound [Ga0.99Fe0.01(sal2trien)][Mn(II)Cr(III)(ox)3].CH2Cl2 (3.CH2Cl2) shows a gradual and complete thermal spin crossover and a LIESST effect on the isolated Fe(III) complexes. This result confirms that cooperativity is not a necessary condition to observe the LIESST effect in an Fe(III) compound. PMID- 23676009 TI - Design, synthesis and biological evaluation of novel non-peptide boronic acid derivatives as proteasome inhibitors. AB - A series of novel non-peptide boronic acid derivatives were designed and synthesized via rational drug design principles. All target compounds were screened for the proteasome inhibitory activities in vitro. Selected compounds (6a and 7j) were evaluated for their cytotoxic activities in vitro. Among these tested compounds, two (6a, 7j) displayed better proteasome inhibitory activities than that of the lead compound PI-083, and compound 6a was the most potent one with IC50 value of 161.90+/-29.46 nM. However, both of the two compounds (6a, 7j) exhibited weak cytotoxic activities, the discrepancy may lie in the compensatory pathways of the ubiquitin-proteasome pathway that promote tumor cell survival. PMID- 23676010 TI - Chemometric studies on potential larvicidal compounds against Aedes aegypti. AB - The mosquito Aedes aegypti (Diptera, Culicidae) is the vector of yellow and dengue fever. In this study, chemometric tools, such as, Principal Component Analysis (PCA), Consensus PCA (CPCA), and Partial Least Squares Regression (PLS), were applied to a set of fifty five active compounds against Ae. aegypti larvae, which includes terpenes, cyclic alcohols, phenolic compounds, and their synthetic derivatives. The calculations were performed using the VolSurf+ program. CPCA analysis suggests that the higher weight blocks of descriptors were SIZE/SHAPE, DRY, and H2O. The PCA was generated with 48 descriptors selected from the previous blocks. The scores plot showed good separation between more and less potent compounds. The first two PCs accounted for over 60% of the data variance. The best model obtained in PLS, after validation leave-one-out, exhibited q(2) = 0.679 and r(2) = 0.714. External prediction model was R(2) = 0.623. The independent variables having a hydrophobic profile were strongly correlated to the biological data. The interaction maps generated with the GRID force field showed that the most active compounds exhibit more interaction with the DRY probe. PMID- 23676011 TI - Study of continuous irrigation negative-pressure treatment using an original ulceration model. AB - A continuous irrigation with intermittent aspiration (CIIA) method has previously been developed in the treatment of infected expander sites. For the purpose of treatment of infected wounds, a new intermittent negative pressure irrigation treatment (INPIT) has been developed that is a combination of CIIA with topical negative-pressure therapy. This study aims to investigate the efficacy of INPIT. The efficacy of irrigation was investigated by changing the conditions including the location and the number of irrigation tubes, flow volume, and the timetable of negative-pressure application using original ulcer models. Although the presence of side holes and increase in the number of tubes or flow volume improved the irrigation efficacy, non-washed-out areas remained. On the other hand, INPIT allowed more uniform and wide area washing even at low flow volume. The results suggest that INPIT is superior to general conventional continuous irrigation treatment in irrigation efficiency. PMID- 23676012 TI - Surgical treatment of spontaneous anterior interosseous nerve palsy: a comparison between minimal incision surgery and wide incision surgery. AB - Recent reports have suggested that fascicular constriction located proximal to the elbow may be the primary aetiology of spontaneous anterior interosseous nerve palsy (sAINP), and recommended interfascicular neurolysis ranging from the proximal forearm to distal upper arm (wide incision surgery: WIS) for its treatment. On the basis of these reports, it was hypothesised that, if the aetiology of sAINP was fascicular constriction, neurolysis limited proximal to the elbow (minimal incision surgery: MIS) should have similar results to those of WIS. Twenty-five surgically treated sAINP cases were retrospectively evaluated. The mean age of onset was 42.8 years, the mean preoperative period was 5.3 months, and mean follow-up period after operation was 31 months. Eleven patients underwent MIS, while 14 underwent WIS according to the patient's intention (intention-to-treat). Twenty-one patients had fascicular constriction, and no entrapment neuropathy was seen in this series. At the latest follow-up, 82% of the patients had British Medical Research Council grade of >=4 in flexor-pollicis longus, while 80% had grade of >=4 in flexor-digitorum-profundus-of-the-index finger. There were no significant differences between the results of either group. These result suggested that the aetiology of sAINP may not be external compression, but fascicular constriction, and MIS may be its favourable surgical treatment. PMID- 23676013 TI - Barrenness vanquished: the legacy of Lesley Brown. AB - Prior to 1978, the therapeutic offerings available to couples afflicted with infertility were painfully limited. Indeed, there was precious little one could offer Lesley and John Brown in their desperation. Anovulatory infertility was managed with ovulation induction using Clomiphene Citrate and Human Menopausal Gonadotropins. Anatomic infertility was addressed by increasingly sophisticated if marginally effective microsurgical approaches. The therapy of male infertility, still in its infancy, was commonly handled through cervical or intrauterine insemination including the use of donor sperm. The road traveled by Mrs. Brown radically altered this hope-limited landscape. A trailblazer to the millions who followed, Mrs. Brown played a key role in the abolition of the scourge of infertility. In this communication we trace in some detail the singular story of Mrs. Lesley Brown and the all-important legacy thereof. In doing so, we wish to pay tribute to this remarkable individual and her contributions to one of the most compelling scientific and medical breakthroughs of the 20th century. PMID- 23676014 TI - Update on the Kelch-like (KLHL) gene family. AB - The Kelch-like (KLHL) gene family encodes a group of proteins that generally possess a BTB/POZ domain, a BACK domain, and five to six Kelch motifs. BTB domains facilitate protein binding and dimerization. The BACK domain has no known function yet is of functional importance since mutations in this domain are associated with disease. Kelch domains form a tertiary structure of beta propellers that have a role in extracellular functions, morphology, and binding to other proteins. Presently, 42 KLHL genes have been classified by the HUGO Gene Nomenclature Committee (HGNC), and they are found across multiple human chromosomes. The KLHL family is conserved throughout evolution. Phylogenetic analysis of KLHL family members suggests that it can be subdivided into three subgroups with KLHL11 as the oldest member and KLHL9 as the youngest. Several KLHL proteins bind to the E3 ligase cullin 3 and are known to be involved in ubiquitination. KLHL genes are responsible for several Mendelian diseases and have been associated with cancer. Further investigation of this family of proteins will likely provide valuable insights into basic biology and human disease. PMID- 23676015 TI - Time delays and capability of elderly to activate speaker function for continuous telephone CPR. AB - BACKGROUND: Telephone-CPR (T-CPR) can increase rate of bystander CPR as well as CPR quality. Instructions for T-CPR were developed when most callers used a land line. Telephones today are often wireless and can be brought to the patient. They often have speaker function which further allows the rescuer to receive instructions while performing CPR.We wanted to measure adult lay people's ability to activate the speaker function on their own mobile phone. METHODS: Elderly lay people, previously trained in CPR, were contacted by telephone. Participants with speaker function experience were asked to activate this without further instructions, while participants with no experience were given instructions on how to activate it. Participants were divided in three groups; Group 1: Can activate the speaker function without instruction, Group 2: Can activate the speaker function with instruction, and Group 3: Unable to activate the speaker function. Time to activation for group 1 and 2 was compared using Mann-Whitney U test. RESULTS: Seventy-two elderly lay people, mean age 68 +/- 6 years participated in the study. Thirty-five (35)% of the participants were able to activate the speaker function without instructions, 29% with instructions and 36% were unable to activate the speaker function. The median time to activate the speaker function was 8s and 93s, with and without instructions, respectively (p < 0.01). CONCLUSION: One-third of the elderly could activate speaker function quickly, and two-third either used a long time or could not activate the function. PMID- 23676016 TI - Pyoderma gangrenosum--a review of 24 cases observed over 10 years. AB - BACKGROUND AND OBJECTIVES: Pyoderma gangrenosum (PG) is a disorder, included in the spectrum of neutrophilic and auto-inflammatory dermatoses, whose clinical aspects and outcome we intend to characterize. MATERIALS AND METHODS: In a retrospective study based on files of patients diagnosed during a 10-year period (2000-2009), we evaluated demographic data, anatomic locations, number of lesions, clinical variants, associated diseases, treatment regimens, healing time, and recurrence. RESULTS: A total of 24 patients were included, 19 women and five men (F/M = 3.8/1), aged between 17 and 89 years (mean 58.3 +/- 24.6 years) with a diagnosis of PG. Lesions, single in 15 patients (62.5%) and multiple in nine (37.5%), were localized in the lower limbs in 19 patients (79.2%), upper limbs (4), abdomen (4), face (2) and genital area (1). Clinical variants observed were ulcerative (17 patients), pustular (4), bullous (2) and superficial granulomatous (1). Associated systemic diseases were observed in 18 patients (75%), gastrointestinal in seven patients (29.2%), hematological in seven (25%), autoimmune inflammatory in three (12%), and solid tumors in two (8.3%). Systemic steroids were used in the treatment, either alone in 10 patients (41.7%) or combined with cyclosporine in eight (33.3%). Complete healing was achieved in 20 patients, on average five months after diagnosis, but lesions recurred one or more times in four patients (16.7%). CONCLUSIONS: As reported in the literature, PG is a rare disorder, more common in females, frequently associated with systemic disease, which compromises the prognosis. PMID- 23676017 TI - Communication: overtone (2NH) spectroscopy of NH3-Ar. AB - The Pi (1(1)) <- Sigma (0(0)) 2NH (nu1+nu3) band of the NH3-Ar van der Waals complex formed in a supersonic jet expansion, with origin at 6628 cm(-1) was recorded at high-resolution using cavity ring down spectroscopy. The analysis leads to upper state rotational constants and J-dependent predissociation lifetimes estimated from linewidth analysis, with a mean value about 0.6 ns. PMID- 23676018 TI - Communication: electronic structure of the solvated chloride anion from first principles molecular dynamics. AB - We present first principles molecular dynamics simulations of the chloride anion in liquid water performed using gradient-corrected and hybrid density functionals. We show that it is necessary to use hybrid functionals both for the generation of molecular dynamics trajectories and for the calculation of electronic states in order to obtain a qualitatively correct description of the electronic properties of the solution. In particular, it is only with hybrid functionals that the highest occupied molecular orbital of the anion is found above the valence band maximum of water, consistent with photoelectron detachment measurements. Similar results were obtained using many body perturbation theory within the G0W0 approximation. PMID- 23676020 TI - Communication: explicitly-correlated second-order correction to the correlation energy in the random-phase approximation. AB - Within the framework of density-functional theory, the basis-set convergence of energies obtained from the random-phase approximation to the correlation energy is equally slow as in wavefunction theory, as for example in coupled-cluster or many-body perturbation theory. Fortunately, the slow basis-set convergence of correlation energies obtained in the random-phase approximation can be accelerated in exactly the same manner as in wavefunction theory, namely by using explicitly correlated two-electron basis functions that are functions of the interelectronic distances. This is demonstrated in the present work. PMID- 23676019 TI - Communication: excitation band modulation with high-order photonic band gap in PMMA:Eu(TTA)3(TPPO)2 opals. AB - Changes in the excitation spectra of luminescent species inserted in photorefractive crystals as a function of changes in the high-order photonic band gap (PBG) have not been previously observed. In this communication, we present our results monitoring the excitation band of Eu(TTA)3(TPPO)2 inserted in the PMMA opal photonic crystals as a function of the changes in the high-order PBG of the crystals. We find shifts in the complex excitation band and changes in the integrated emission intensity that correlates with shifts in the high-order PBG through coupling to the excitation transition. PMID- 23676021 TI - Communication: dynamical embedding: correct quantum response from coupling TDDFT for a small cluster with classical near-field electrodynamics for an extended region. AB - We show how to obtain the correct electronic response of a large system by embedding; a small region is propagated by TDDFT (time-dependent density functional theory) simultaneously with a classical electrodynamics evolution using the Near-Field method over a larger external region. The propagations are coupled through a combined time-dependent density yielding a common Coulomb potential. We show that the embedding correctly describes the plasmonic response of a Mg(0001) slab and its influence on the dynamical charge transfer between an adsorbed H2O molecule and the substrate, giving the same spectral shape as full TDDFT (similar plasmon peak and molecular-dependent differential spectra) with much less computational effort. The results demonstrate that atomistic embedding electrodynamics is promising for nanoplasmonics and nanopolaritonics. PMID- 23676022 TI - Communication: a case where the hard/soft acid/base principle holds regardless of acid/base strength. AB - We show that the hard/soft acid/base principle holds when electron-transfer effects are dominant and the weaker acid and stronger base are harder than the other acidic and basic reagents. In this case the preference of strong acids for strong bases and weak acids for weak bases reinforces the preference of hard acids for hard bases and soft acids for soft bases. PMID- 23676023 TI - On the origin and convergence of a Post-Quantization Constrained propagator for path integral simulations of rigid bodies. AB - We present a new methodological procedure, based on Post-Quantization Constraints (PQC), to obtain approximate density matrices and energy estimators for use in path integral molecular dynamics and Monte Carlo simulations. The approach serves as a justification of the use of "RATTLE & SHAKE" type methods for path integrals. A thorough discussion of the underlying geometrical concepts is given. Two standard model systems, the particle on a ring and the three-dimensional linear rotor, are used to illustrate and benchmark the approach. In these two cases, matrix elements of the newly defined propagator are explicitly computed in both "angular coordinate" and "angular momentum" bases. A detailed analysis of the convergence properties of the density matrix, and energy estimator with respect to their "exact" counterparts, is presented along with numerical illustrations. We conclude that the use of a PQC-type propagator is justified and practical. PMID- 23676024 TI - Growing string method with interpolation and optimization in internal coordinates: method and examples. AB - The growing string method (GSM) has proven especially useful for locating chemical reaction paths at low computational cost. While many string methods use Cartesian coordinates, these methods can be substantially improved by changes in the coordinate system used for interpolation and optimization steps. The quality of the interpolation scheme is especially important because it determines how close the initial path is to the optimized reaction path, and this strongly affects the rate of convergence. In this article, a detailed description of the generation of internal coordinates (ICs) suitable for use in GSM as reactive tangents and in string optimization is given. Convergence of reaction paths is smooth because the IC tangent and orthogonal directions are better representations of chemical bonding compared to Cartesian coordinates. This is not only important quantitatively for reducing computational cost but also allows reaction paths to be described with smoothly varying chemically relevant coordinates. Benchmark computations with challenging reactions are compared to previous versions of GSM and show significant speedups. Finally, a climbing image scheme is included to improve the quality of the transition state approximation, ensuring high reliability of the method. PMID- 23676025 TI - Analytic energy gradients for the orbital-optimized second-order Moller-Plesset perturbation theory. AB - Analytic energy gradients for the orbital-optimized second-order Moller-Plesset perturbation theory (OMP2) are presented. The OMP2 method is applied to difficult chemical systems, including those where spatial or spin symmetry-breaking instabilities are observed. The performance of the OMP2 method is compared with that of second-order Moller-Plesset perturbation theory (MP2) for investigating geometries and vibrational frequencies of the cis-HOOH(+), trans-HOOH(+), LiO2, C3(+), and NO2 molecules. For harmonic vibrational frequencies, the OMP2 method eliminates the singularities arising from the abnormal response contributions observed for MP2 in case of symmetry-breaking problems, and provides significantly improved vibrational frequencies for the above molecules. We also consider the hydrogen transfer reactions between several free radicals, for which MP2 provides poor reaction energies. The OMP2 method again exhibits a considerably better performance than MP2, providing a mean absolute error of 2.3 kcal mol(-1), which is more than 5 times lower than that of MP2 (13.2 kcal mol( 1)). Overall, the OMP2 method seems quite helpful for electronically challenging chemical systems such as symmetry-breaking molecules, hydrogen transfer reactions, or other cases where standard MP2 proves unreliable. For such systems, we recommend using OMP2 instead of MP2 as a more robust method with the same computational scaling. PMID- 23676026 TI - Polaron dynamics in a two-dimensional Holstein-Peierls system. AB - A semiclassical model for studying charge transport in a two-dimensional molecular lattice is presented and applied to both a well ordered system and a system with disorder. The model includes both intra- and inter-molecular electron lattice interactions and the focus of the studies is to describe the dynamics of a charge carrier in the system. In particular, we study the dynamics of the system in which the polaron solution is dynamically stable. It is found that the parameter space for which the polaron is moving through the system is quite restricted and that the polaron is immobile for large electron-phonon coupling and weak intermolecular electron interactions and dynamically unstable and disassociates into a delocalized electronic state decoupled from the lattice for small electron-phonon coupling and strong intermolecular electron interactions. Disorder further limits the parameter space in which the polaron is mobile. PMID- 23676027 TI - An efficient implementation of two-component relativistic exact-decoupling methods for large molecules. AB - We present an efficient algorithm for one- and two-component relativistic exact decoupling calculations. Spin-orbit coupling is thus taken into account for the evaluation of relativistically transformed (one-electron) Hamiltonian. As the relativistic decoupling transformation has to be evaluated with primitive functions, the construction of the relativistic one-electron Hamiltonian becomes the bottleneck of the whole calculation for large molecules. For the established exact-decoupling protocols, a minimal matrix operation count is established and discussed in detail. Furthermore, we apply our recently developed local DLU scheme [D. Peng and M. Reiher, J. Chem. Phys. 136, 244108 (2012)] to accelerate this step. With our new implementation two-component relativistic density functional calculations can be performed invoking the resolution-of-identity density-fitting approximation and (Abelian as well as non-Abelian) point group symmetry to accelerate both the exact-decoupling and the two-electron part. The capability of our implementation is illustrated at the example of silver clusters with up to 309 atoms, for which the cohesive energy is calculated and extrapolated to the bulk. PMID- 23676028 TI - A virtual-system coupled multicanonical molecular dynamics simulation: principles and applications to free-energy landscape of protein-protein interaction with an all-atom model in explicit solvent. AB - We propose a novel generalized ensemble method, a virtual-system coupled multicanonical molecular dynamics (V-McMD), to enhance conformational sampling of biomolecules expressed by an all-atom model in an explicit solvent. In this method, a virtual system, of which physical quantities can be set arbitrarily, is coupled with the biomolecular system, which is the target to be studied. This method was applied to a system of an Endothelin-1 derivative, KR-CSH-ET1, known to form an antisymmetric homodimer at room temperature. V-McMD was performed starting from a configuration in which two KR-CSH-ET1 molecules were mutually distant in an explicit solvent. The lowest free-energy state (the most thermally stable state) at room temperature coincides with the experimentally determined native complex structure. This state was separated to other non-native minor clusters by a free-energy barrier, although the barrier disappeared with elevated temperature. V-McMD produced a canonical ensemble faster than a conventional McMD method. PMID- 23676029 TI - An analytical continuation approach for evaluating emission lineshapes of molecular aggregates and the adequacy of multichromophoric Forster theory. AB - In large photosynthetic chromophore-protein complexes not all chromophores are coupled strongly, and thus the situation is well described by formation of delocalized states in certain domains of strongly coupled chromophores. In order to describe excitation energy transfer among different domains without performing extensive numerical calculations, one of the most popular techniques is a generalization of Forster theory to multichromophoric aggregates (generalized Forster theory) proposed by Sumi [J. Phys. Chem. B 103, 252 (1999)] and Scholes and Fleming [J. Phys. Chem. B 104, 1854 (2000)]. The aim of this paper is twofold. In the first place, by means of analytic continuation and a time convolutionless quantum master equation approach, a theory of emission lineshape of multichromophoric systems or molecular aggregates is proposed. In the second place, a comprehensive framework that allows for a clear, compact, and effective study of the multichromophoric approach in the full general version proposed by Jang, Newton, and Silbey [Phys. Rev. Lett. 92, 218301 (2004)] is developed. We apply the present theory to simple paradigmatic systems and we show on one hand the effectiveness of time-convolutionless techniques in deriving lineshape operators and on the other hand we show how the multichromophoric approach can give significant improvements in the determination of energy transfer rates in particular when the systems under study are not the purely Forster regime. The presented scheme allows for an effective implementation of the multichromophoric Forster approach which may be of use for simulating energy transfer dynamics in large photosynthetic aggregates, for which massive computational resources are usually required. Furthermore, our method allows for a systematic comparison of multichromophoric Foster and generalized Forster theories and for a clear understanding of their respective limits of validity. PMID- 23676030 TI - Fukui function and response function for nonlocal and fractional systems. AB - We present extensions to our previous work on Fukui functions and linear-response functions [W. Yang, A. J. Cohen, F. D. Proft, and P. Geerlings, J. Chem. Phys. 136, 144110 (2012)]. Viewed as energy derivatives with respect to the number of electrons and the external potential, all second-order derivatives (the linear response function, the Fukui function, and the chemical hardness) are extended to fractional systems, and all third-order derivatives (the second-order response function, the Fukui response function, the dual descriptor, and the hyperhardness) for integer systems are also obtained. These analytical derivatives are verified by finite difference numerical derivatives. In the context of the exact linearity condition and the constancy condition, these analytical derivatives enrich greatly the information of the exact conditions on the energy functional through establishing real-space dependency. The introduction of an external nonlocal potential defines the nonlocal Fukui function and the nonlocal linear-response function. The nonlocal linear-response function so defined also provides the precise meaning for the time-dependent linear-response density-functional theory calculations with generalized Kohn-Sham functionals. These extensions will be useful to conceptual density-functional theory and density functional development. PMID- 23676031 TI - Steady-state simulation of metastable stochastic chemical systems. AB - We address the problem of steady-state simulation for metastable continuous-time Markov chains with application to stochastic chemical kinetics. Such systems are characterized by the existence of two or more pseudo-equilibrium states and very slow convergence towards global equilibrium. Approximation of the stationary distribution of these systems by direct application of the Stochastic Simulation Algorithm (SSA) is known to be very inefficient. In this paper, we propose a new method for steady-state simulation of metastable Markov chains that is centered around the concept of stochastic complementation. The use of this mathematical device along with SSA results in an algorithm with much better convergence properties, that facilitates the analysis of rarely switching stochastic biochemical systems. The efficiency of our method is demonstrated by its application to two genetic toggle switch models. PMID- 23676032 TI - Interpreting medium ring canonical conformers by a triangular plane tessellation of the macrocycle. AB - Cyclic conformational coordinates are essential for the distinction of molecular ring conformers as the use of Cremer-Pople coordinates have illustrated for five- and six-membered rings. Here, by tessellating medium rings into triangular planes and using the relative angles made between triangular planes we are able to assign macrocyclic pucker conformations into canonical pucker conformers such as chairs, boats, etc. We show that the definition is straightforward compared with other methods popularly used for small rings and that it is computationally simple to implement for complex macrocyclic rings. These cyclic conformational coordinates directly couple to the motion of individual nodes of a ring. Therefore, they are useful for correlating the physical properties of macrocycles with their ring pucker and measuring the dynamic ring conformational behavior. We illustrate the triangular tessellation, assignment, and pucker analysis on 7- and 8-membered rings. Sets of canonical states are given for cycloheptane and cyclooctane that have been previously experimentally analysed. PMID- 23676033 TI - A maximum entropy thermodynamics of small systems. AB - We present a maximum entropy approach to analyze the state space of a small system in contact with a large bath, e.g., a solvated macromolecular system. For the solute, the fluctuations around the mean values of observables are not negligible and the probability distribution P(r) of the state space depends on the intricate details of the interaction of the solute with the solvent. Here, we employ a superstatistical approach: P(r) is expressed as a marginal distribution summed over the variation in beta, the inverse temperature of the solute. The joint distribution P(beta, r) is estimated by maximizing its entropy. We also calculate the first order system-size corrections to the canonical ensemble description of the state space. We test the development on a simple harmonic oscillator interacting with two baths with very different chemical identities, viz., (a) Lennard-Jones particles and (b) water molecules. In both cases, our method captures the state space of the oscillator sufficiently well. Future directions and connections with traditional statistical mechanics are discussed. PMID- 23676034 TI - On trajectory-based nonadiabatic dynamics: Bohmian dynamics versus trajectory surface hopping. AB - In this work, we present a complete derivation of the NonAdiabatic Bohmian DYnamics (NABDY) equations of motion. This approach naturally emerges from a transformation of the molecular time-dependent Schrodinger equation in the adiabatic representation of the electronic states. The numerical implementation of the method is discussed while simple nonadiabatic models are employed to address the accuracy of NABDY and to reveal its ability to capture nuclear quantum effects that are missed in trajectory surface hopping (TSH) due to the independent trajectory approximation. A careful comparison of the correlated, NABDY, and the uncorrelated, TSH, propagation is also given together with a description of the main approximations and assumptions underlying the "derivation" of a nonadiabatic molecular dynamics scheme based on classical trajectories. PMID- 23676035 TI - Including nuclear quantum effects into highly correlated electronic structure calculations of weakly bound systems. AB - An interface between the APMO code and the electronic structure package MOLPRO is presented. The any particle molecular orbital APMO code [Gonzalez et al., Int. J. Quantum Chem. 108, 1742 (2008)] implements the model where electrons and light nuclei are treated simultaneously at Hartree-Fock or second-order Moller-Plesset levels of theory. The APMO-MOLPRO interface allows to include high-level electronic correlation as implemented in the MOLPRO package and to describe nuclear quantum effects at Hartree-Fock level of theory with the APMO code. Different model systems illustrate the implementation: (4)He2 dimer as a protype of a weakly bound van der Waals system; isotopomers of [He-H-He](+) molecule as an example of a hydrogen bonded system; and molecular hydrogen to compare with very accurate non-Born-Oppenheimer calculations. The possible improvements and future developments are outlined. PMID- 23676036 TI - Orphan spin operators enable the acquisition of multiple 2D and 3D magic angle spinning solid-state NMR spectra. AB - We propose a general method that enables the acquisition of multiple 2D and 3D solid-state NMR spectra for U-(13)C, (15)N-labeled proteins. This method, called MEIOSIS (Multiple ExperIments via Orphan SpIn operatorS), makes it possible to detect four coherence transfer pathways simultaneously, utilizing orphan (i.e., neglected) spin operators of nuclear spin polarization generated during (15)N (13)C cross polarization (CP). In the MEIOSIS experiments, two phase-encoded free induction decays are decoded into independent nuclear polarization pathways using Hadamard transformations. As a proof of principle, we show the acquisition of multiple 2D and 3D spectra of U-(13)C, (15)N-labeled microcrystalline ubiquitin. Hadamard decoding of CP coherences into multiple independent spin operators is a new concept in solid-state NMR and is extendable to many other multidimensional experiments. The MEIOSIS method will increase the throughput of solid-state NMR techniques for microcrystalline proteins, membrane proteins, and protein fibrils. PMID- 23676037 TI - Multiplets at zero magnetic field: the geometry of zero-field NMR. AB - For liquid samples at Earth's field or below, nuclear-spin motion within scalar coupled networks yields multiplets as a spectroscopic signature. In weak fields, the structure of the multiplets depends on the magnitude of the Zeeman interaction relative to the scalar couplings; in Earth's field, for example, heteronuclear couplings are truncated by fast precession at distinct Larmor frequencies. At zero field, weak scalar couplings are truncated by the relatively fast evolution associated with strong scalar couplings, and the truncated interactions can be described geometrically. When the spin system contains a strongly coupled subsystem A, an average over the fast evolution occurring within the subsystem projects each strongly coupled spin onto FA, the summed angular momentum of the spins in A. Weakly coupled spins effectively interact with FA, and the coupling constants for the truncated interactions are found by evaluating projections. We provide a formal description of zero-field spin systems with truncated scalar couplings while also emphasizing visualization based on a geometric model. The theoretical results are in good agreement with experimental spectra that exhibit second-order shifts and splittings. PMID- 23676038 TI - Structures of protonated methanol clusters and temperature effects. AB - The accurate evaluation of pKa's, or solvation energies of the proton in methanol at a given temperature is subject to the determination of the most favored structures of various isomers of protonated (H(+)(MeOH)n) and neutral ((MeOH)n) methanol clusters in the gas phase and in methanol at that temperature. Solvation energies of the proton in a given medium, at a given temperature may help in the determination of proton affinities and proton dissociation energies related to the deprotonation process in that medium and at that temperature. pKa's are related to numerous properties of drugs. In this work, we were interested in the determination of the most favored structures of various isomers of protonated methanol clusters in the gas phase and in methanol, at a given temperature. For this aim, the M062X/6-31++G(d,p) and B3LYP/6-31++G(d,p) levels of theory were used to perform geometries optimizations and frequency calculations on various isomers of (H(+)(MeOH)n) in both phases. Thermal effects were retrieved using our homemade FORTRAN code. Thus, we accessed the relative populations of various isomers of protonated methanol clusters, in both phases for temperatures ranging from 0 to 400 K. As results, in the gas phase, linear structures are entropically more favorable at high temperatures, while more compact ones are energetically more favorable at lower temperatures. The trend is somewhat different when bulk effects are taken into account. At high temperatures, the linear structure only dominates the population for n <= 6, while it is dominated by the cyclic structure for larger cluster sizes. At lower temperatures, compact structures still dominate the population, but with an order different from the one established in the gas phase. Hence, temperature effects dominate solvent effects in small cluster sizes (n <= 6), while the reverse trend is noted for larger cluster sizes. PMID- 23676039 TI - Selecting boron fullerenes by cage-doping mechanisms. AB - So far, no boron fullerenes were synthesized: more compact sp(3)-bonded clusters are energetically preferred. To circumvent this, metallic clusters have been suggested by Pochet et al. [Phys. Rev. B 83, 081403(R) (2011)] as "seeds" for a possible synthesis which would topologically protect the sp(2) sector of the configuration space. In this paper, we identify a basic pentagonal unit which allows a balance between the release of strain and the self-doping rule. We formulate a guiding principle for the stability of boron fullerenes, which takes the form of an isolated filled pentagon rule (IFPR). The role of metallic clusters is then reexamined. It is shown that the interplay of the IFPR and the seed-induced doping breaks polymorphism and its related problems: it can effectively select between different isomers and reduce the reactivity of the boron shells. The balance between self and exterior doping represents the best strategy for boron buckyball synthesis. PMID- 23676040 TI - Resonant two-photon ionization spectroscopy of jet-cooled UN: determination of the ground state. AB - The optical transitions of supersonically cooled uranium nitride (UN) have been investigated in the range from 19,200 to 23,900 cm(-1) using resonant two-photon ionization spectroscopy. A large number of bands have been observed, of which seven have been rotationally resolved and analyzed. All are found to arise from the same state, which is presumably the ground state of the molecule. From the analysis of the bands, the ground state has Omega = 3.5, with a bond length of 1.7650(12) A. Comparisons to the known isovalent molecules are made, and the variations in ground state configuration are explained in terms of the configurational reordering that occurs with changes in the nuclear and ligand charges. It is concluded that the UN molecule is best considered as a U(3+)N(3-) species in which the closed shell nitride ligand interacts with a U(3+) ion. The ground state of the molecule derives from a U(3+) ion in its 7s(1)5f 2) atomic configuration. PMID- 23676041 TI - High resolution photoelectron imaging of Au2(-). AB - We report high resolution photoelectron spectra of Au2(-) using a newly built photoelectron imaging apparatus. Vibrationally resolved photoelectron images are obtained for the ground state detachment transition of Au2(-) at various photon energies (442.80-670.18 nm) at a resolution of 3 cm(-1) for low energy electrons. Franck-Condon simulations yield the vibrational temperature of Au2(-) and the high resolution data yield accurate spectroscopic constants for the ground states of Au2 and Au2(-). The electron affinity of Au2 is measured to be 1.9393 +/- 0.0006 eV. A more precise value for the Au2(-) dissociation energy is also obtained as 1.937 +/- 0.005 eV. PMID- 23676042 TI - Hirshfeld density partitioning technique: a first application to the transition metal compounds, HScO, TiO, VO. AB - We apply a variant of the Hirshfeld density partitioning technique, HI, to calculate the atomic charges and decompose the dipole moments into the part due to the charges and the induced dipoles developed on each atom for three different transition metal (TM) containing molecules. Additionally, the alpha and beta spin densities are treated separately developing a new variant (spin-adapted HI) of the fractional occupation HI version proposed recently. We also study the dependence of HI charges on the atomic state of the TM employed in the promolecule. The VO case exhibits a strong dependence of the atomic charge on the V or V(+) state used. Although the bonding in the ground high spin electronic state and the first excited low spin state in TiO and VO is essentially identical, the dipole moments differ significantly and we find that this is due entirely to the sigma electron distribution localized on the transition metal. Finally, the mechanism for the rapid change of the dipole moment of HScO upon bending is confirmed to occur mainly due to the induced atomic charges. PMID- 23676043 TI - Quantum-mechanical predictions of electron-induced ionization cross sections of DNA components. AB - Ionization of biomolecules remains still today rarely investigated on both the experimental and the theoretical sides. In this context, the present work appears as one of the first quantum mechanical approaches providing a multi-differential description of the electron-induced ionization process of the main DNA components for impact energies ranging from the target ionization threshold up to about 10 keV. The cross section calculations are here performed within the 1st Born approximation framework in which the ejected electron is described by a Coulomb wave whereas the incident and the scattered electrons are both described by a plane wave. The biological targets of interest, namely, the DNA nucleobases and the sugar-phosphate backbone, are here described by means of the GAUSSIAN 09 system using the restricted Hartree-Fock method with geometry optimization. The theoretical predictions also obtained have shown a reasonable agreement with the experimental total ionization cross sections while huge discrepancies have been pointed out with existing theoretical models, mainly developed within a semi classical framework. PMID- 23676044 TI - Temperature dependence on the structure of Zundel cation and its isotopomers. AB - Temperature dependence on the structural fluctuations of Zundel cation, H5O2(+), and its isotopomers, D5O2(+) and T5O2(+), have been studied using path integral molecular dynamics simulations in which nuclear quantum effect is fully taken into account. It has been found that the fluctuations of hydrogen-oxygen and oxygen-oxygen distances, which are relevant to the hydrogen bonded structure, grow drastically as the temperature increases within the range of investigation between 100 K and 900 K. The fluctuation with respect to the position of non bonded hydrogen also increases substantially as the temperature increases. The temperature dependence on the fluctuation is greater for D5O2(+) or T5O2(+) than that of H5O2(+), since the zero-point effect of the former is less than the latter. PMID- 23676046 TI - Electron ionisation of sulfur dioxide. AB - Relative precursor-specific partial ionisation cross sections for the fragment ions formed following electron ionisation of sulfur dioxide (SO2) have been measured for the first time, from 30 to 200 eV, using time-of-flight mass spectrometry coupled with two-dimensional ion coincidence detection. These data quantify the yields of O(2+), O(+), SO(2+), S(+), O2(+), and SO(+) ions, relative to the formation of SO2(+), via single, double, and triple electron ionisation of SO2. Formation of O(2+), following electron-SO2 collisions, has been quantified for the first time. The data allow a first experimental estimate of the triple ionisation potential of SO2 (69.0 +/- 3.6 eV), an energy in good agreement with a value derived in this study via computational chemistry. The triple ion combination S(+) + O(+) + O(+) is clearly detected following electron collisions with SO2 at electron energies markedly below the vertical energy for forming SO2(3 +). This observation is accounted for by the operation of a stepwise pathway to the formation of S(+) + 2O(+) which does not involve the formation of a molecular trication. PMID- 23676045 TI - Mode specificity in the H + H2O -> H2 + OH reaction: a full-dimensional quantum dynamics study. AB - The initial state-selected time-dependent wave packet approach to an atom-triatom reaction is employed to study the H + H2O -> H2 + OH reaction without the centrifugal sudden approximation. The total reaction probabilities and integral cross sections, which are the exact coupled-channel results, are calculated for the H2O reactant initially in the ground and several vibrationally excited states, including bending excited states, first and second stretching excited states, and simultaneous excitations of both bending and stretching modes. The reactivity enhancements from different initial states of the H2O reagent are presented and discussed in detail. The thermal rate constant for the title reaction and the contributions to this coefficient from individual vibrational states of H2O are also obtained and compared with the previous theoretical and experimental data. PMID- 23676047 TI - Experimental study of the reactive processes in the gas phase K(+) + i-C3H7Cl collisions: a comparison with Li and Na ions. AB - Reactive collisions between alkali ions (Li(+), Na(+), and K(+)) and halogenated hydrocarbon molecules have been studied recently in our research group. In this paper, we have reported on the K(+) + i-C3H7Cl system in the 0.20-14.00 eV center of-mass energy range using a radio frequency guided-ion beam apparatus developed in our laboratory. Aiming at increasing our knowledge about this kind of reactions, we compare our latest results for K(+) with those obtained previously for Li(+) and Na(+). While the reaction channels are the same in all three cases, their energy profiles, reactivity, measured reactive cross-section energy dependences, and even their reaction mechanisms, differ widely. By comparing experimentally measured reactive cross-sections as a function of the collision energy with the ab initio calculations for the different potential energy surfaces, a qualitative interpretation of the dynamics of the three reactive systems is presented in the present work. PMID- 23676048 TI - Vibronic effects on the low-lying electronic excitations in CO2 induced by electron impact. AB - We report an angle-resolved electron energy loss spectroscopy (EELS) study on the valence-shell electronic excitations of CO2. Experimentally, momentum-transfer dependent generalized oscillator strengths (GOSs) or GOS profiles for low-lying electronic excitations have been derived from EELS spectra measured at incident electron energy of 3 keV. Theoretically, we have calculated GOS profiles using wave functions at the equation-of-motion coupled-cluster singles and doubles level. In the calculation, vibronic effects are taken into account by evaluating the electronic transition amplitudes along the individual normal coordinates. The calculation satisfactorily reproduces the experiment for the (1)Pig and (1)Deltau transitions and reveals prominent roles of strong coupling between the associated mixed-Rydberg-valence and valence excited states through the bending vibration of CO2. Vibronic effects on GOS profiles have also been examined for the (1)Sigmau (+), (1)Piu, and 2(1)Pig transitions. PMID- 23676049 TI - Variation of droplet acidity during evaporation. AB - Variation of acidity and associated chemical changes of macromolecules in evaporating droplets is of central importance in electrosprayed aerosols. We study changes in acidity during evolution of a droplet that is composed of solvent and a charge binding macromolecule. We analyze the acidity of the droplet using analytical theory and stochastic modeling. We derive a universal relation for the minimum pH of a droplet in the presence of a protein and the results are confirmed by the stochastic modeling of ubiquitin and lysozyme at varying values of pH. We establish that in acidic droplets, once the number of solvated charges reaches the macroion charge, the further droplet evaporation, counter intuitively, reduces the number of charges on the macromolecule and increases the droplet pH. PMID- 23676050 TI - Transient behavior of a model fluid under applied shear. AB - We study the transient behavior of a model fluid composed by soft repulsive spheres subjected to a planar uniform shear. To this aim, we use a dynamical non equilibrium molecular dynamics method originally developed by Ciccotti and Jacucci [Phys. Rev. Lett. 35, 789 (1975)] and recently applied to the study of the transient regimes in various fluid systems. We show that the dynamical method allows one to study the transient behavior of the viscous time-dependent response over a wide range of applied shear rates, provided that a temperature control is enforced on the system. In this study, we adopt in particular the configurational thermostat of Braga and Travis [J. Chem. Phys. 123, 134101 (2005)]. The initial behavior of the dynamical response to a theta-like perturbation is characterized by a rapid increase, culminating in a pronounced peak, later relaxing to a plateau value. The latter positively reproduces the values of the viscosity observed in standard steady-state non-equilibrium molecular dynamics. PMID- 23676051 TI - An analysis of fluctuations in supercooled TIP4P/2005 water. AB - Large-scale, long-time molecular dynamics simulations are used to investigate fluctuations in the TIP4P/2005 water model in the supercooled region (240-190 K). Particular attention is focused in the vicinity of a previously reported liquid liquid critical point [J. L. F. Abascal and C. Vega, J. Chem. Phys. 133, 234502 (2010)]. Water is viewed as an equimolar binary mixture with "species" defined based on a local tetrahedral order parameter. A Bhatia-Thornton fluctuation analysis is used to show that species concentration fluctuations couple to density fluctuations and completely account for the anomalous increase in the structure factor at small wave number observed under supercooled conditions. Although we find that both concentration and density fluctuations increase with decreasing temperature along the proposed critical isochore, we cannot confirm the existence of a liquid-liquid critical point. Our simulations suggest that the parameters previously reported are not a true liquid-liquid critical point and we find no evidence of two-phase coexistence in its vicinity. It is shown that very long simulations (on the order of 8 MUs for 500 molecules) are necessary to obtain well converged density distributions for deeply supercooled water and this is especially important if one is seeking direct evidence of a two-phase region. PMID- 23676052 TI - Structure and dynamics in yttrium-based molten rare earth alkali fluorides. AB - The transport properties of molten LiF-YF3 mixtures have been studied by pulsed field gradient nuclear magnetic resonance spectroscopy, potentiometric experiments, and molecular dynamics simulations. The calculated diffusion coefficients and electric conductivities compare very well with the measurements across a wide composition range. We then extract static (radial distribution functions, coordination numbers distributions) and dynamic (cage correlation functions) quantities from the simulations. Then, we discuss the interplay between the microscopic structure of the molten salts and their dynamic properties. It is often considered that variations in the diffusion coefficient of the anions are mainly driven by the evolution of its coordination with the metallic ion (Y(3+) here). We compare this system with fluorozirconate melts and demonstrate that the coordination number is a poor indicator of the evolution of the diffusion coefficient. Instead, we propose to use the ionic bonds lifetime. We show that the weak Y-F ionic bonds in LiF-YF3 do not induce the expected tendency of the fluoride diffusion coefficient to converge toward one of the yttrium cation when the content in YF3 increases. Implications on the validity of the Nernst-Einstein relation for estimating the electrical conductivity are discussed. PMID- 23676053 TI - Volume crossover in deeply supercooled water adiabatically freezing under isobaric conditions. AB - The irreversible return of a supercooled liquid to stable thermodynamic equilibrium often begins as a fast process which adiabatically drives the system to solid-liquid coexistence. Only at a later stage will solidification proceed with the expected exchange of thermal energy with the external bath. In this paper we discuss some aspects of the adiabatic freezing of metastable water at constant pressure. In particular, we investigated the thermal behavior of the isobaric gap between the molar volume of supercooled water and that of the warmer ice-water mixture which eventually forms at equilibrium. The available experimental data at ambient pressure, extrapolated into the metastable region within the scheme provided by the reference IAPWS-95 formulation, show that water ordinarily expands upon (partially) freezing under isenthalpic conditions. However, the same scheme also suggests that, for increasing undercoolings, the volume gap is gradually reduced and eventually vanishes at a temperature close to the currently estimated homogeneous ice nucleation temperature. This behavior is contrasted with that of substances which do not display a volumetric anomaly. The effect of increasing pressures on the alleged volume crossover from an expanded to a contracted ice-water mixture is also discussed. PMID- 23676054 TI - Si isotopic structure of the infrared absorption of the fully hydrogenated vacancy in silicon. AB - An infrared absorption spectrum consisting in three lines observed around 2223 cm(-1) at liquid helium temperature characterizes a defect common in silicon crystals containing hydrogen. Several investigations of this spectrum have converged towards its assignment to a fully hydrogenated lattice vacancy defect V(Si-H)4. However, the fact that the ratios of the intensities of the three lines have been reported to be proportional to the natural abundances of the three silicon isotopes suggests that only one Si atom is involved in the defect, apparently contradicting the above assignment. In this paper, the spectroscopic investigation of this defect is revisited and the Si-related isotopic structures of V(Si-H)4 and V(Si-D)4 defects are modeled. It is shown that the near proportionalities observed between the intensities of these lines and the abundances of the Si isotopes are fortuitous. Our analysis of the isotope dependence of the 2223 cm(-1) line finds the V(Si-H)4 model to be correct and that the model of a single interstitial Si atom complexed with H can be rejected. The investigation is extended to the analysis of tetra-hydrogenated vacancy trapped by a carbon atom. PMID- 23676055 TI - Conformational isomerisms and nano-aggregation in substituted alkylammonium nitrates ionic liquids: an x-ray and computational study of 2 methoxyethylammonium nitrate. AB - In this study, we discuss, using molecular dynamics simulations and energy dispersive x-ray diffraction data, how a conformational isomerism can dramatically alter the nanosegregation phenomena that take place in a prototypical ionic liquid. The diffraction patterns of liquid 2 methoxyethylammonium nitrate are compared with the results from molecular dynamics simulations. The simulations conditions and force field parameters have been varied producing different charge models and different populations of conformers of the cation. We show that, while the short range structure is relatively unchanged in the models, the long range aggregation phenomena deemed responsible for the appearance of low Q peaks in the X-ray patterns strongly depend on the choice of the charge model. In the title compound, the best agreement with the experiment, where no low Q peaks appear, occurs if the point charges are calculated using the gauche conformation of the cation, which is characterized by an intramolecular hydrogen bond between ammonium and ether groups. PMID- 23676056 TI - Anisotropy induced crossover from weakly to strongly first order melting of two dimensional solids. AB - Melting and freezing transitions in two dimensional (2D) systems are known to show highly unusual characteristics. Most of the earlier studies considered atomic systems: the melting of 2D molecular solids is still largely unexplored. In order to understand the role of anisotropy as well as multiple energy and length scales present in molecular systems, here we report computer simulation studies of melting of 2D molecular systems. We computed a limited portion of the solid-liquid phase diagram. We find that the interplay between the strength of isotropic and anisotropic interactions can give rise to rich phase diagram consisting of isotropic liquid and two crystalline phases-honeycomb and oblique. The nature of the transition depends on the relative strength of the anisotropic interaction and a strongly first order melting turns into a weakly first order transition on increasing the strength of the isotropic interaction. This crossover can be attributed to an increase in stiffness of the solid phase free energy minimum on increasing the strength of the anisotropic interaction. The defects involved in melting of molecular systems are quite different from those known for the atomic systems. PMID- 23676057 TI - Two-photon-induced singlet fission in rubrene single crystal. AB - The two-photon-induced singlet fission was observed in rubrene single crystal and studied by use of femtosecond pump-probe spectroscopy. The location of two-photon excited states was obtained from the nondegenerate two-photon absorption (TPA) spectrum. Time evolution of the two-photon-induced transient absorption spectra reveals the direct singlet fission from the two-photon excited states. The TPA absorption coefficient of rubrene single crystal is 52 cm/GW at 740 nm, as obtained from Z-scan measurements. Quantum chemical calculations based on time dependent density functional theory support our experimental data. PMID- 23676059 TI - Characterizing heterogeneous dynamics at hydrated electrode surfaces. AB - In models of Pt 111 and Pt 100 surfaces in water, motions of molecules in the first hydration layer are spatially and temporally correlated. To interpret these collective motions, we apply quantitative measures of dynamic heterogeneity that are standard tools for considering glassy systems. Specifically, we carry out an analysis in terms of mobility fields and distributions of persistence times and exchange times. In so doing, we show that dynamics in these systems is facilitated by transient disorder in frustrated two-dimensional hydrogen bonding networks. The frustration is the result of unfavorable geometry imposed by strong metal-water bonding. The geometry depends upon the structure of the underlying metal surface. Dynamic heterogeneity of water on the Pt 111 surface is therefore qualitatively different than that for water on the Pt 100 surface. In both cases, statistics of this ad-layer dynamic heterogeneity responds asymmetrically to applied voltage. PMID- 23676058 TI - Density functional study of methanol decomposition on clean and O or OH adsorbed PdZn(111). AB - Methanol is the future and clean fuel, and its chemistry on metal surfaces has received much attention. In this paper we explore methanol dissociation on the clean and O or OH covered PdZn(111) that mimics Pd/ZnO catalyst studied as a promising catalyst for methanol steam reforming, using density functional theory at PW91 level and slab model. Our study demonstrates that unlike the situation on Pd (111), methanol preferentially undergoes the O-H bond scission on the PdZn (111). The presence of O and OH species hinders the C-H bond dissociation, but significantly reduces the O-H bond-breaking barrier. The present results indicate that in the course of methanol steam reforming, methanol first loses the hydrogen atom of the hydroxyl group, forming methoxy. This step is greatly enhanced when there are O and/or OH species (i.e., after water dissociation happens). Analyses reveal that CH2O is formed mainly from CH3O, not from CH2OH. PMID- 23676060 TI - Insights into hydrogen bond dynamics at the interface of the charged monolayer protected Au nanoparticle from molecular dynamics simulation. AB - The structure and dynamics properties of water molecules at the interface of the charged monolayer-protected Au nanoparticle (MPAN) have been investigated in detail by using classical molecular dynamics simulation. The simulation results demonstrated clearly that a well-defined hydration layer is formed at the interface of MPAN and a stable "ion wall" consisting of terminal NH3 (+) groups and Cl(-) counterions exists at the outmost region of self-assembled monolayer (SAM) where the translational and rotational motions of water molecules slow considerably down compared to those in the bulk owing to the presence of SAM and ion wall. Furthermore, we found that the translational motions of interfacial water molecules display a subdiffusive behavior while their rotational motions exhibit a nonexponential feature. The unique behavior of interfacial water molecules around the MPAN can be attributed to the interfacial hydrogen bond (HB) dynamics. By comparison, the lifetime of NH3 (+)-Cl(-) HBs was found to be the longest, favoring the stability of ion wall. Meanwhile, the lifetime of H2O-H2O HBs shows an obvious increase when the water molecules approach the Au core, suggesting the enhanced H2O-H2O HBs around the charged MPAN, which is contrary to the weaken H2O-H2O HBs around the neutral MPAN. Moreover, the HB lifetimes between water molecules and the ion wall (i.e., the Cl(-)-H2O and NH3 (+)-H2O HBs) are much longer than that of interfacial H2O-H2O HBs, which leads to the increasing rotational relaxation time and residence time of water molecules surrounding the ion wall. In addition, the corresponding binding energies for different HB types obtained from the precise density functional theory are in excellent accordance with above simulation results. The detailed HB dynamics studied in this work provides insights into the unique behavior of water molecules at the interface of charged self-assemblies of nanoparticles as well as proteins. PMID- 23676061 TI - Visualization of hydration layers on muscovite mica in aqueous solution by frequency-modulation atomic force microscopy. AB - A three-dimensional interaction force mapping experiment was carried out on a muscovite mica surface in an aqueous solution using a high-resolution and low thermal drift frequency-modulation atomic force microscope. By collecting oscillatory frequency shift versus distance curves at the mica/solution interface, complicated hydration structures on the mica surface were visualized. Reconstructed two-dimensional frequency shift maps showed dot-like or honeycomb like patterns at different tip-sample distances with a separation of 0.2 nm with each other, which agree well to the water molecule density maps predicted by a statistical-mechanical theory. Moreover, site-specific force versus distance curves showed a good agreement with theoretically calculated site-specific force curves by a molecular dynamics simulation. It is found that the first and second hydration layers give honeycomb-like and dot-like patterns in the two-dimensional frequency shift images, respectively, corresponding to the lateral distribution function in each layer. PMID- 23676062 TI - A DFT study on structural, vibrational properties, and quasiparticle band structure of solid nitromethane. AB - We report a detailed theoretical study of the structural and vibrational properties of solid nitromethane using first principles density functional calculations. The ground state properties were calculated using a plane wave pseudopotential code with either the local density approximation, the generalized gradient approximation, or with a correction to include van der Waals interactions. Our calculated equilibrium lattice parameters and volume using a dispersion correction are found to be in reasonable agreement with the experimental results. Also, our calculations reproduce the experimental trends in the structural properties at high pressure. We found a discontinuity in the bond length, bond angles, and also a weakening of hydrogen bond strength in the pressure range from 10 to 12 GPa, picturing the structural transition from phase I to phase II. Moreover, we predict the elastic constants of solid nitromethane and find that the corresponding bulk modulus is in good agreement with experiments. The calculated elastic constants show an order of C11> C22 > C33, indicating that the material is more compressible along the c-axis. We also calculated the zone center vibrational frequencies and discuss the internal and external modes of this material under pressure. From this, we found the softening of lattice modes around 8-11 GPa. We have also attempted the quasiparticle band structure of solid nitromethane with the G0W0 approximation and found that nitromethane is an indirect band gap insulator with a value of the band gap of about 7.8 eV with G0W0 approximation. Finally, the optical properties of this material, namely the absorptive and dispersive part of the dielectric function, and the refractive index and absorption spectra are calculated and the contribution of different transition peaks of the absorption spectra are analyzed. The static dielectric constant and refractive indices along the three inequivalent crystallographic directions indicate that this material has a considerable optical anisotropy. PMID- 23676063 TI - Long-range specific ion-ion interactions in hydrogen-bonded liquid films. AB - Anions populate fluid interfaces specifically. Here, we report experiments showing that on hydrogen-bonded interfaces anions interact specifically over unexpectedly long distances. The composition of binary electrolyte (Na(+), X( )/Y(-)) films was investigated as a function of solvent, film thickness, and third ion additions in free-standing films produced by blowing up drops with a high-speed gas. These films soon fragment into charged sub-micrometer droplets carrying excess anions detectable in situ by online electrospray ionization mass spectrometry. We found that (1) the larger anions are enriched in the thinner (nanoscopic air-liquid-air) films produced at higher gas velocities in all (water, methanol, 2-propanol, and acetonitrile) tested solvents, (2) third ions (beginning at sub-MUM levels) specifically perturb X(-)/Y(-) ratios in water and methanol but have no effect in acetonitrile or 2-propanol. Thus, among these polar organic liquids (of similar viscosities but much smaller surface tensions and dielectric permittivities than water) only on methanol do anions interact specifically over long, viz.: /nm = 150 (c/MUM)(-1/3), distances. Our findings point to the extended hydrogen-bond networks of water and methanol as likely conduits for such interactions. PMID- 23676064 TI - Ag-Cu catalysts for ethylene epoxidation: selectivity and activity descriptors. AB - Ag-Cu alloy catalysts for ethylene epoxidation have been shown to yield higher selectivity towards ethylene oxide compared to pure Ag, the unique catalyst employed in the industrial process. Previous studies showed that under oxidizing conditions Cu forms oxide layers on top of Ag. Using first-principles atomistic simulations based on density functional theory, we investigate the reaction mechanism on the thin oxide layer structures and establish the reasons for the improved selectivity. We extend the range of applicability of the selectivity descriptor proposed by Kokalj et al. [J. Catal. 254, 304 (2008)], based on binding energies of reactants, intermediates, and products, by refitting its parameters so as to include thin oxide layer catalysts. We show that the selectivity is mainly controlled by the relative strength of the metal-carbon vs. metal-oxygen bonds, while the height of the reaction barriers mostly depend on the binding energy of the common oxametallacycle intermediate. PMID- 23676065 TI - Photoinduced electron transfer at a Si(111) nanostructured surface: effect of varying light wavelength, temperature, and structural parameters. AB - We treat electronic dynamics at surfaces of nanostructured semiconductors induced by absorption of visible light using reduced density matrices and properties obtained from ab initio electronic structure calculations, to focus on two non adiabatic phenomena: (a) how active electrons interacting non-adiabatically with atoms at the surface undergo electronic transitions and (b) how active electrons interacting by exchanging energy with excitons in the medium undergo a dissipative non-adiabatic dynamics. We test the effects on charge separation from varying oscillator strengths, non-adiabatic momentum couplings, the rates of relaxation of excited states coupled to the medium, temperature, and light wavelength. Varying the oscillator strength displays the interplay between competing relaxation and charge transfer dynamics. Varying the non-adiabatic momentum coupling between excited and final states demonstrates the importance of including enough vibrational levels to model the full dynamics of the system and further shows the interplay of relaxation and charge transfer from the final state to the excited state. Larger electron transfer probabilities and longer lasting charge separation occur when oscillator strength into the intermediate state decreases, or when it increases into the final state, and when temperature increases. Longer lasting charge separation also occurs when the non-adiabatic momentum coupling decreases, a somewhat unexpected result which is due to the combined effect of population relaxation and transitions among many vibronic states. PMID- 23676066 TI - Transient photocurrent in molecular junctions: singlet switching on and triplet blocking. AB - The kinetic approach adapted to describe charge transmission in molecular junctions, is used for the analysis of the photocurrent under conditions of moderate light intensity of the photochromic molecule. In the framework of the HOMO-LUMO model for the single electron molecular states, the analytic expressions describing the temporary behavior of the transient and steady state sequential (hopping) as well as direct (tunnel) current components have been derived. The conditions at which the current components achieve their maximal values are indicated. It is shown that if the rates of charge transmission in the unbiased molecular diode are much lower than the intramolecular singlet-singlet excitation/de-excitation rate, and the threefold degenerated triplet excited state of the molecule behaves like a trap blocking the charge transmission, a possibility of a large peak-like transient switch-on photocurrent arises. PMID- 23676067 TI - Adsorption and diffusion of the Rh and Au adatom on graphene moire/Ru(0001). AB - Detailed density functional theory calculations have been performed to investigate the adsorption and diffusion of the Rh and Au adatom on the graphene moire superstructure on Ru(0001). The adsorption energies of each adatom in all of the non-equivalent C-top and C6 ring center sites on the graphene moire have been calculated. The resulting potential energy surfaces encompass the entire graphene moire unit cell and shows that the adsorption of both Rh1 and Au1 is most stable in the fcc region on the graphene moire. The minimum-energy diffusion path between adjacent moire cells is identified to run mostly directly between the fcc and hcp regions for Au1, but deviates toward the mound region for Rh1. The global diffusion barrier is estimated to be 0.53 eV for Rh1 and 0.71 eV for Au1, corresponding to a hopping rate between adjacent moire cells of ~10(3) s(-1) and ~1 s(-1) at 298 K, respectively. The consequences of different hopping rates to cluster nucleation have been explored by performing Monte Carlo-based statistical analysis, which suggests that diffusing species other than adatoms need to be taken into account to develop an accurate description of cluster nucleation and growth on this surface. PMID- 23676068 TI - Structure factor and rheology of chain molecules from molecular dynamics. AB - Equilibrium and non-equilibrium molecular dynamics were performed to determine the relationship between the static structure factor, the molecular conformation, and the rheological properties of chain molecules. A spring-monomer model with Finitely Extensible Nonlinear Elastic and Lennard-Jones force field potentials was used to describe chain molecules. The equations of motion were solved for shear flow with SLLOD equations of motion integrated with Verlet's algorithm. A multiple time scale algorithm extended to non-equilibrium situations was used as the integration method. Concentric circular patterns in the structure factor were obtained, indicating an isotropic Newtonian behavior. Under simple shear flow, some peaks in the structure factor were emerged corresponding to an anisotropic pattern as chains aligned along the flow direction. Pure chain molecules and chain molecules in solution displayed shear-thinning regions. Power-law and Carreau-Yasuda models were used to adjust the generated data. Results are in qualitative agreement with rheological and light scattering experiments. PMID- 23676069 TI - Differentiating bonding and caging in a charged colloid system through rheological measurements. AB - The linear and nonlinear rheological measurements were utilized to study the mechanical response of concentrated mixtures of colloidal particles with opposite charges. The particle volume fraction (Phi) spans the region from low volume fraction (Phi = 0.18) gel to high volume fraction (Phi = 0.53) glass. In the linear viscoelastic region, the storage moduli G' exhibits deferent Phi dependence at low and high Phi's. It follows a power law relationship as G' ~ Phi(6.2+/-0.2) for Phi < 0.46, and follows an exponential relationship as G' ~ exp[(13.8 +/- 0.6)Phi] for Phi >= 0.46. The difference can be taken as a distinction between a colloidal gel and an attractive glass (or dense gel) for the present system. The loss moduli G" is almost frequency independent within the whole experimental frequency range (10(-1)-10(2) rad/s) for colloidal gel, and G" exhibits a weak minimum for attractive glass. In the nonlinear large amplitude rheological measurement, samples with Phi < 0.46 show one-step yielding, and samples with Phi >= 0.46 exhibit two-step yielding which is in agreement with numerous experiments in attractive glassy systems. The first yielding is due to the breaking of short range interactions which bond the interconnected clusters or local clusters, while the second yielding is attributed to the breaking of long range interaction, normally the caging forming or glass forming interactions. The qualitative distinction between attractive glass and gel in terms of their yielding behavior is consistent with the linear rheological results. The particle-particle interactions were modulated by salt concentration. It was found that, when the attraction interaction is enhanced, both yielding points in attractive glass shift to higher strain amplitude and the gap between the two yielding points become more separated. PMID- 23676070 TI - Dynamical simulation of dipolar Janus colloids: dynamical properties. AB - The dynamical properties of dipolar Janus particles are studied through simulation using our previously-developed detailed pointwise (PW) model and an isotropically coarse-grained (CG) model [M. C. Hagy and R. Hernandez, J. Chem. Phys. 137, 044505 (2012)]. The CG model is found to have accelerated dynamics relative to the PW model over a range of conditions for which both models have near identical static equilibrium properties. Physically, this suggests dipolar Janus particles have slower transport properties (such as diffusion) in comparison to isotropically attractive particles. Time rescaling and damping with Langevin friction are explored to map the dynamics of the CG model to that of the PW model. Both methods map the diffusion constant successfully and improve the velocity autocorrelation function and the mean squared displacement of the CG model. Neither method improves the distribution of reversible bond durations f(tb) observed in the CG model, which is found to lack the longer duration reversible bonds observed in the PW model. We attribute these differences in f(tb) to changes in the energetics of multiple rearrangement mechanisms. This suggests a need for new methods that map the coarse-grained dynamics of such systems to the true time scale. PMID- 23676071 TI - Segregation of semiflexible macromolecules in nanochannel. AB - Investigation of segregation of polymer coils in open channel was extended relative to previous studies from flexible chains to semiflexible chains. Our results are based on simulation of confinement free energy of a chain in channel and on direct simulation of coil segregation process. For confinement free energy, we confirm the predicted opposite trend with increasing chain stiffness for the weak and for strong confinement regimes. Results of two different approaches are consistent, in agreement with theoretical analysis and indicate a stronger segregation tendency of flexible chains in channel relative to semiflexible chains both in its extent and dynamics. PMID- 23676072 TI - Velocity relaxation of a particle in a confined compressible fluid. AB - The velocity relaxation of an impulsively forced spherical particle in a fluid confined by two parallel plane walls is studied using a direct numerical simulation approach. During the relaxation process, the momentum of the particle is transmitted in the ambient fluid by viscous diffusion and sound wave propagation, and the fluid flow accompanied by each mechanism has a different character and affects the particle motion differently. Because of the bounding walls, viscous diffusion is hampered, and the accompanying shear flow is gradually diminished. However, the sound wave is repeatedly reflected and spreads diffusely. As a result, the particle motion is governed by the sound wave and backtracks differently in a bulk fluid. The time when the backtracking of the particle occurs changes non-monotonically with respect to the compressibility factor epsilon = nu/ac and is minimized at the characteristic compressibility factor. This factor depends on the wall spacing, and the dependence is different at small and large wall spacing regions based on the different mechanisms causing the backtracking. PMID- 23676073 TI - Dual effect of crowders on fibrillation kinetics of polypeptide chains revealed by lattice models. AB - We have developed the lattice model for describing polypeptide chains in the presence of crowders. The influence of crowding confinement on the fibrillation kinetics of polypeptide chains is studied using this model. We observed the non trivial behavior of the fibril formation time taufib that it decreases with the concentration of crowders if crowder sizes are large enough, but the growth is observed for crowders of small sizes. This allows us to explain the recent experimental observation on the dual effect of crowding particles on fibril growth of proteins that for a fixed crowder concentration the fibrillation kinetics is fastest at intermediate values of total surface of crowders. It becomes slow at either small or large coverages of cosolutes. It is shown that due to competition between the energetics and entropic effects, the dependence of taufib on the size of confined space is described by a parabolic function. PMID- 23676075 TI - Note: slowing-down of diffusion-controlled reactions in dense liquid matter. PMID- 23676074 TI - Kinetic theory of amyloid fibril templating. AB - The growth of amyloid fibrils requires a disordered or partially unfolded protein to bind to the fibril and adapt the same conformation and alignment established by the fibril template. Since the H-bonds stabilizing the fibril are interchangeable, it is inevitable that H-bonds form between incorrect pairs of amino acids which are either incorporated into the fibril as defects or must be broken before the correct alignment can be found. This process is modeled by mapping the formation and breakage of H-bonds to a one-dimensional random walk. The resulting microscopic model of fibril growth is governed by two timescales: the diffusion time of the monomeric proteins, and the time required for incorrectly bound proteins to unbind from the fibril. The theory predicts that the Arrhenius behavior observed in experiments is due to off-pathway states rather than an on-pathway transition state. The predicted growth rates are in qualitative agreement with experiments on insulin fibril growth rates as a function of protein concentration, denaturant concentration, and temperature. These results suggest a templating mechanism where steric clashes due to a single mis-aligned molecule prevent the binding of additional molecules. PMID- 23676079 TI - Therapeutic approaches of melatonin in microwave radiations-induced oxidative stress-mediated toxicity on male fertility pattern of Wistar rats. AB - Microwave (MW) radiation produced by wireless telecommunications and a number of electrical devices used in household or in healthcare institutions may adversely affects the reproductive pattern. Present study aimed to investigate the protective effects of melatonin (is well known antioxidant that protects DNA, lipids and proteins from free radical damage) against oxidative stress-mediated testicular impairment due to long-term exposure of MWs. For this, 70-day-old male Wistar rats were divided into four groups (n = 6/group): Sham exposed, Melatonin (Mel) treated (2 mg/kg), 2.45 GHz MWs exposed and MWs + Mel treated. Exposure took place in Plexiglas cages for 2 h a day for 45 days where, power density (0.21 mW/cm(2)) and specific absorption rate (SAR 0.14 W/Kg) were estimated. After the completion of exposure period, rats were sacrificed and various stress related parameters, that is LDH-X (lactate dehydrogenase isoenzyme) activity, xanthine oxidase (XO), ROS (reactive oxygen species), protein carbonyl content, DNA damage and MDA (malondialdehyde) were performed. Result shows that melatonin prevent oxidative damage biochemically by significant increase (p < 0.001) in the levels of testicular LDH-X, decreased (p < 0.001) levels of MDA and ROS in testis (p < 0.01). Meanwhile, it reversed the effects of MWs on XO, protein carbonyl content, sperm count, testosterone level and DNA fragmentation in testicular cells. These results concluded that the melatonin has strong antioxidative potential against MW induced oxidative stress mediated DNA damage in testicular cells. PMID- 23676078 TI - Differential transcript isoform usage pre- and post-zygotic genome activation in zebrafish. AB - BACKGROUND: Zebrafish embryos are transcriptionally silent until activation of the zygotic genome during the 10th cell cycle. Onset of transcription is followed by cellular and morphological changes involving cell speciation and gastrulation. Previous genome-wide surveys of transcriptional changes only assessed gene expression levels; however, recent studies have shown the necessity to map isoform-specific transcriptional changes. Here, we perform isoform discovery and quantification on transcriptome sequences from before and after zebrafish zygotic genome activation (ZGA). RESULTS: We identify novel isoforms and isoform switches during ZGA for genes related to cell adhesion, pluripotency and DNA methylation. Isoform switching events include alternative splicing and changes in transcriptional start sites and in 3' untranslated regions. New isoforms are identified even for well-characterized genes such as pou5f1, sall4 and dnmt1. Genes involved in cell-cell interactions such as f11r and magi1 display isoform switches with alterations of coding sequences. We also detect over 1000 transcripts that acquire a longer 3' terminal exon when transcribed by the zygote compared to their maternal transcript counterparts. ChIP-sequencing data mapped onto skipped exon events reveal a correlation between histone H3K36 trimethylation peaks and skipped exons, suggesting epigenetic marks being part of alternative splicing regulation. CONCLUSIONS: The novel isoforms and isoform switches reported here include regulators of transcriptional, cellular and morphological changes taking place around ZGA. Our data display an array of isoform-related functional changes and represent a valuable resource complementary to existing early embryo transcriptomes. PMID- 23676080 TI - Object orientation affects spatial language comprehension. AB - Typical spatial descriptions, such as "The car is in front of the house," describe the position of a located object (LO; e.g., the car) in space relative to a reference object (RO) whose location is known (e.g., the house). The orientation of the RO affects spatial language comprehension via the reference frame selection process. However, the effects of the LO's orientation on spatial language have not received great attention. This study explores whether the pure geometric information of the LO (e.g., its orientation) affects spatial language comprehension using placing and production tasks. Our results suggest that the orientation of the LO influences spatial language comprehension even in the absence of functional relationships. PMID- 23676081 TI - Translation cost, quality, and adequacy. AB - PURPOSE: Although the inclusion of non-native-speaking participants in nursing research is important in every country where nursing research takes place, the literature contains little on the method of achieving quality translation while simultaneously addressing cost containment. We describe a process for evaluating translation adequacy and demonstrate its use in comparing procedures for translating data from non-native-speaking interviews. ORGANIZING CONSTRUCT: This work demonstrates a process for establishing, evaluating, and achieving translation adequacy when conducting qualitative research for cross-cultural comparisons. METHODS: In an ethnographic investigation of disability in Mexican American women, we describe a process for obtaining translation adequacy, defined here as the methodological goal whereby the quality of the translated text meets the needs of the specified study. Using a subset of responses transcribed from Spanish audiotapes into Spanish text, the text was subjected to two separate translation processes, which were compared for adequacy based on error rates and accuracy of meaning, as well as for cost. FINDINGS: The process for discriminating translation adequacy was sensitive to differences in certified versus noncertified translators. While the noncertified translation initially appeared to be seven times less expensive than the certified process, auditing and correcting errors in noncertified translations substantially increased cost. No errors were found with the certified translations. CONCLUSIONS: The level of translation adequacy needed for any qualitative study should be considered before beginning the study itself. Based on a predetermined level, translation choices can be assessed using specified methods, which can also lead to greater transparency in the research process. CLINICAL RELEVANCE: An ongoing process to verify translation outcomes including cost, a component minimally discussed in the current literature, is relevant to nurses worldwide. Awareness of expense and quality issues makes greater methodological transparency possible in the design of translation projects and research studies. PMID- 23676082 TI - UV resonance Raman and DFT studies of arginine side chains in peptides: insights into arginine hydration. AB - We examined the UV resonance Raman (UVRR) spectra of four models of the Arg side chain, guanidinium (Gdn), ethylguanidinium (EG), arginine (Arg), and Ac-Arg-OMe (AAO) in H2O and D2O, in order to identify spectral markers that report on the environment of the Arg side chain. To elucidate the resonance Raman enhancement mechanism of the Arg side chain, we used density functional theory (DFT) to calculate the equilibrium geometries of the electronic ground state and the first excited state. We determined the vibrational mode frequencies of the ground state and the first derivative of the first electronic excited state potential energy with respect to each vibrational normal mode of the electronic ground state at the electronic ground state equilibrium geometry. The DFT calculations and the potential energy distributions reveal that, in addition to the Gdn group C-N stretching vibrations, the C-N bond stretching vibration of the Gdn group methylene linkage is also strongly resonance-enhanced in EG, Arg, and AAO. From the UVRR spectra, we find that the Raman cross section and frequency of the ~1170 cm(-1) vibration of the Arg side chain depends on its hydration state and can be used to determine the hydration state of the Arg side chain in peptides and proteins. We examined the hydration of the Arg side chain in two polyAla peptides and found that in the alpha-helical conformation the Arg side chain in the AEP peptide (sequence: A9RA3EA4RA2) is less hydrated than that in the AP peptide (sequence: A8RA4RA4RA2). PMID- 23676084 TI - Scattering of graphene plasmons by defects in the graphene sheet. AB - A theoretical study is presented on the scattering of graphene surface plasmons (GSPs) by defects in the graphene sheet they propagate in. These defects can be either natural (as domain boundaries, ripples, and cracks, among others) or induced by an external gate. The scattering is shown to be governed by an integral equation, derived from a plane wave expansion of the fields, which in general must be solved numerically, but it provides useful analytical results for small defects. Two main cases are considered: smooth variations of the graphene conductivity (characterized by a Gaussian conductivity profile) and sharp variations (represented by islands with different conductivity). In general, reflection largely dominates over radiation out of the graphene sheet. However, in the case of sharply defined conductivity islands, there are some values of island size and frequency where the reflectance vanishes and, correspondingly, the radiation out-of-plane is the main scattering process. For smooth defects, the reflectance spectra present a single maximum at the condition k(p)a ~ ?2, where k(p) is the GSP wavevector and a is the spatial width of the defect. In contrast, the reflectance spectra of sharp defects present periodic oscillations with period k(p)'a, where k(p)' is the GSP wavelength inside the defect. Finally, the case of cracks (gaps in the graphene conductivity) is considered, showing that the reflectance is practically unity for gap widths larger than one-tenth of the GSP wavelength. PMID- 23676083 TI - Temporomandibular disorders and chronic daily headaches in the community and in specialty care. AB - BACKGROUND: Chronic daily headaches (CDHs) are often associated with temporomandibular disorders (TMDs). However, large studies assessing the relationship were conducted in general, and not clinical, populations. Thus, clinical exams were not completed. Clinic-based studies with expert diagnosis are, in turn, often small and may not be representative. OBJECTIVE: To contrast the demographic and clinical symptoms of CDH and TMD in participants within the general population relative to patients seen in a headache clinic. METHODS: All inhabitants 10 years and older of a small city in Brazil were interviewed. Those with more than 15 days of headache per month were examined by a team consisting of a neurologist, a dentist, and a physical therapist. Headaches were classified as per the Second Edition of the International Classification of Headache Disorders and TMD as per the Research Diagnostic Criteria. The procedure was repeated (by the same team) with CDH sufferers consecutively seen in a headache center. RESULTS: Of 1605 inhabitants interviewed, 57 (3.6%) had CDH, and 43 completed all physical assessments. For specialty care group, of 289 patients, 92 had CDH, and 85 completed all assessments. No significant differences were seen for gender and age, but education level was significantly higher among those recruited at specialty care. Muscular TMD happened in 30.2% of CDH patients from the community vs 55.3% in the headache center (difference of -25.1%, 95% confidence interval of difference=-40.8% to -9.4%). No TMD happened in 41.9% of those recruited from the population relative to 20% of those in the headache center (21.9%, 95% confidence interval=6.7-37.1%). CONCLUSION: Individuals with CDH recruited from the general population are significantly less likely to have CDH relative to those selected from the headache center. Issues of generalizability are of concern when conducting clinic-based studies on the topic. PMID- 23676085 TI - Skin cancer screening campaigns in a Bucharest dermatology clinic. PMID- 23676086 TI - Identification of M. tuberculosis thioredoxin reductase inhibitors based on high throughput docking using constraints. AB - A virtual screening campaign is presented that led to small molecule inhibitors of thioredoxin reductase of Mycobacterium tuberculosis (MtTrxR) that target the protein-protein interaction site for the substrate thioredoxin (Trx). MtTrxR is a promising drug target because it dominates the Trx-dependent hydroperoxide metabolism and the reduction of ribonucleotides, thus facilitating survival and proliferation of M. tuberculosis. Moreover, MtTrxR sufficiently differs from its human homologs to suggest the possibility of selective inhibition if the MtTrxR Trx interaction site is targeted. To this end, high-throughput docking of 6.5 million virtual compounds to the thioredoxin binding site of MtTrxR combined with constraints as filtering steps was applied. A total of 170 high-scoring compounds yielded 18 compounds that inhibited MtTrxR with IC50 values up to the low micromolar range, thus revealing that the protein-protein interaction site of MtTrxR is indeed druggable. Most importantly, selectivity toward MtTrxR in comparison to human TrxR (HsTrxR) is also demonstrated. PMID- 23676087 TI - Visualization of 'Candidatus Liberibacter asiaticus' cells in the vascular bundle of citrus seed coats with fluorescence in situ hybridization and transmission electron microscopy. AB - 'Candidatus Liberibacter asiaticus' is the bacterium implicated as a causal agent of the economically damaging disease of citrus called huanglongbing (HLB). Vertical transmission of the organism through seed to the seedling has not been demonstrated. Previous studies using real-time polymerase chain reaction assays indicated abundant bacterial 16S rRNA sequences in seed coats of citrus seed but the presence of intact bacterial cells was not demonstrated. We used microscopy to verify that intact bacterial cells were present in citrus seed coats. Bacterial cells with the morphology and physical dimensions appropriate for 'Ca. L. asiaticus' were seen in phloem sieve elements in the vascular bundle of grapefruit seed coats using transmission electron microscopy (TEM). Fluorescence in situ hybridization (FISH) analyses utilizing probes complementary to the 'Ca. L. asiaticus' 16S rRNA gene revealed bacterial cells in the vascular tissue of intact seed coats of grapefruit and pummelo and in fragmented vascular bundles excised from grapefruit seed coats. The physical measurements and the morphology of individual bacterial cells were consistent with those ascribed in the literature to 'Ca. L. asiaticus'. No bacterial cells were observed in preparations of seed from fruit from noninfected trees. A small library of clones amplified from seed coats from a noninfected tree using degenerate primers targeting prokaryote 16S rRNA gene sequences contained no 'Ca. L. asiaticus' sequences, whereas 95% of the sequences in a similar library from DNA from seed coats from an infected tree were identified as 'Ca. L. asiaticus', providing molecular genetic corroboration that the bacterial cells observed by TEM and FISH in seed coats from infected trees were 'Ca. L. asiaticus'. PMID- 23676088 TI - Identification and molecular mapping of a wheat gene for resistance to an unadapted isolate of Colletotrichum cereale. AB - To elucidate genetic mechanisms of host species specificity between graminicolous anthracnose fungi and gramineous plants, infection assays were performed with a Sorghum isolate (Colletotrichum sublineolum), a Digitaria isolate (C. hanaui), a Polypogon isolate (C. cereale), and an Avena isolate (C. cereale). They were specifically virulent on the plants from which they were isolated. When 72 wheat lines were inoculated with an unadapted isolate from Asia Minor bluegrass (Cgp29), however, some exceptional cultivars were recognized. Although most cultivars were resistant to Cgp29, 'Hope' was susceptible. In F2 populations derived from crosses between three resistant cultivars-'Norin 4' (N4), 'Chinese Spring' (CS), and 'Shin-chunaga' (Sch)-and the susceptible Hope, resistant and susceptible seedlings segregated in a 3:1 ratio, suggesting that a major gene is involved in the resistance of each cultivar to Cgp29. In F2 populations derived from crosses between the three resistant cultivars, all seedlings were resistant, suggesting that these three cultivars carry the same gene. This resistance gene was designated as "resistance to Colletotrichum cereale 1" (Rcc1). Analysis with the CS-Hope chromosome substitution lines and molecular mapping revealed that Rcc1 was located on the long arm of chromosome 5A. Cytologically, Rcc1 was mainly associated with hypersensitive reaction. These results suggest that major genes similar to those controlling cultivar specificity are involved in the resistance of wheat against the unadapted isolate of C. cereale. PMID- 23676089 TI - Gene expression profiling of a compatible interaction between Douglas-Fir and the root rot fungal pathogen Phellinus sulphurascens. AB - Douglas-fir (DF) (Pseudotsuga menziesii) is one of the largest and most economically important coniferous species in western North America. Its productivity is greatly affected by the root rot fungus Phellinus sulphurascens Pilat. Evidence of resistance by DF to fungal root pathogens such as P. sulphurascens has been reported but mechanisms of resistance in this compatible pathosystem are not yet known. To better understand the DF-P. sulphurascens interaction, especially at the molecular level, we selected 12 diverse plant genes already identified as defense-related from a cDNA library constructed using root tissues from P. sulphurascens-infected DF seedlings. Using quantitative reverse-transcriptase polymerase chain reaction on infected DF root samples collected at five different time points after inoculation, we found that P. sulphurascens infection significantly elevated expression of the 12 selected genes. In most cases the highest expression level was recorded within 2 to 3 days after inoculation. The constructed cDNA library, which is enriched with defense related host genes and a number of fungal genes, will continue to serve as a useful resource for future larger-scale gene discovery and functional research on the P. sulphurascens and DF pathosystem. PMID- 23676090 TI - Nontoxic and neuroprotective beta-naphthotacrines for Alzheimer's disease. AB - The synthesis, toxicity, neuroprotection, and human acetylcholinesterase (hAChE)/ human butyrylcholinesterase (hBuChE) inhibition properties of beta naphthotacrines1-14 as new drugs for Alzheimer's disease (AD) potential treatment, are reported. beta-Naphthotacrines1-14 showed lower toxicity than tacrine; moreover, at the highest concentration assayed (300 MUM) compounds 7, 10 and 11 displayed 2.25-2.01-fold higher cell viability than tacrine in HepG2 cells. A neuroprotective effect was observed for compounds 10 and 11 in a neuronal cortical culture exposed to a combination of oligomycin A/rotenone. An efficient and selective inhibition of hAChE, was only observed for the beta naphthotacrines bearing electron-donating substituents at the aromatic ring, beta naphthotacrine10 being the most potent (hAChE: IC50 = 0.083 +/- 0.024 MUM). Kinetic inhibition analysis clearly demonstrated that beta-naphthotacrine10 behaves as a mixed-type inhibitor (Ki2= 0.72 +/- 0.06 MUM) at high substrate concentrations (0.5-10 MUM), while at low concentrations (0.01-0.1 MUM) it behaves as a hAChE competitive inhibitor (Ki1= 0.007 +/- 0.001 MUM). These findings identified beta-naphthotacrine10 as a potent and selective hAChE inhibitor in a nanomolar range, with toxicity lower than that of tacrine both in human hepatocytes and rat cortical neurons, with a potent neuroprotective activity and, consequently, an attractive multipotent active molecule of potential application in AD treatment. PMID- 23676091 TI - Two routes to expertise in mental rotation. AB - The ability to imagine objects undergoing rotation (mental rotation) improves markedly with practice, but an explanation of this plasticity remains controversial. Some researchers propose that practice speeds up the rate of a general-purpose rotation algorithm. Others maintain that performance improvements arise through the adoption of a new cognitive strategy-repeated exposure leads to rapid retrieval from memory of the required response to familiar mental rotation stimuli. In two experiments we provide support for an integrated explanation of practice effects in mental rotation by combining behavioral and EEG measures in a way that provides more rigorous inference than is available from either measure alone. Before practice, participants displayed two well-established signatures of mental rotation: Both response time and EEG negativity increased linearly with rotation angle. After extensive practice with a small set of stimuli, both signatures of mental rotation had all but disappeared. In contrast, after the same amount of practice with a much larger set both signatures remained, even though performance improved markedly. Taken together, these results constitute a reversed association, which cannot arise from variation in a single cause, and so they provide compelling evidence for the existence of two routes to expertise in mental rotation. We also found novel evidence that practice with the large but not the small stimulus set increased the magnitude of an early visual evoked potential, suggesting increased rotation speed is enabled by improved efficiency in extracting three-dimensional information from two-dimensional stimuli. PMID- 23676092 TI - Multiple squamous cell carcinomas following treatment with sorafenib for renal cell carcinoma. PMID- 23676094 TI - Early admission to community-based palliative care reduces use of emergency departments in the ninety days before death. AB - BACKGROUND: Overcrowded emergency departments (EDs) and the staff within them are often not able to address the complex physical and psychosocial needs of people at the end of life. While some studies have suggested that the ED environment should be adapted and staff trained to address this issue, there are no previous studies which have investigated whether the provision of timely palliative care services could prevent people with palliative care needs from attending EDs. OBJECTIVE: This study investigates whether early admission to community-based palliative care reduces ED admissions in the last 90 days of life for patients with cancer. METHODS: The study was a retrospective, cross-sectional study using death registrations and hospital morbidity data for 746 Western Australian adults who died of cancer and where palliative care may have been a viable and appropriate option for care. RESULTS: In their final 90 days before death, 31.3% of decedents who had early access to palliative care and 52.0% of those who did not have early access to palliative care visited an ED (OR=2.86; 95% CI, 1.91, 4.30). Early admission to community-based palliative care reduces the use of EDs by cancer patients in the 90 days before death. CONCLUSIONS: Proactive care in the form of timely community-based palliative care assists in preventing vulnerable people at the end of life from being exposed to the stressful ED environment and decreases the pressure on EDs. PMID- 23676095 TI - Case report: long-term mood response to repeat dose intramuscular ketamine in a depressed patient with advanced cancer. PMID- 23676096 TI - A nationwide study comparing end-of-life care for men and women veterans. AB - BACKGROUND: The quality of end-of-life (EOL) care at Veterans Affairs Medical Centers (VAMC) has improved. To date, however, the quality and outcomes of end-of life care delivered to women veterans have not been examined. OBJECTIVE: The goal of this study was to evaluate gender differences in the quality of EOL care received by patients in VAMCs nationwide. DESIGN: The study was conducted via retrospective medical chart review and telephone survey with next of kin of recently deceased inpatients. SETTING/SUBJECTS: The chart review included records for all patients who died in acute and long-term care units in 145 VAMCs nationwide (n=36,618). For the survey, the documented next of kin were invited to respond on behalf of the deceased veteran; a total of 25,638 next of kin completed the survey. MEASUREMENTS: Chart review measures included five indicators of optimal end-of-life care. Bereaved family survey items included one global and nine specific items (e.g., bereavement care, pain management) describing care in the last month of life. RESULTS: Receipt of optimal end-of life care did not differ significantly between women and men with respect to frequency of discussion of treatment goals with a family member, receipt of palliative consult, bereavement contact, and chaplain contact with a family member. Family members of women were more likely than those of men to report that the overall care provided to the veteran had been "excellent" (adjusted proportions: 63% versus 56%; odds ratio (OR)=1.33; 95% confidence interval (CI) 1.10-1.61; p=0.003). CONCLUSIONS: In this nationwide study of all inpatient deaths in VAMCs, women received comparable and on some metrics better quality EOL care than that received by male patients. PMID- 23676093 TI - Structural and functional annotation of the porcine immunome. AB - BACKGROUND: The domestic pig is known as an excellent model for human immunology and the two species share many pathogens. Susceptibility to infectious disease is one of the major constraints on swine performance, yet the structure and function of genes comprising the pig immunome are not well-characterized. The completion of the pig genome provides the opportunity to annotate the pig immunome, and compare and contrast pig and human immune systems. RESULTS: The Immune Response Annotation Group (IRAG) used computational curation and manual annotation of the swine genome assembly 10.2 (Sscrofa10.2) to refine the currently available automated annotation of 1,369 immunity-related genes through sequence-based comparison to genes in other species. Within these genes, we annotated 3,472 transcripts. Annotation provided evidence for gene expansions in several immune response families, and identified artiodactyl-specific expansions in the cathelicidin and type 1 Interferon families. We found gene duplications for 18 genes, including 13 immune response genes and five non-immune response genes discovered in the annotation process. Manual annotation provided evidence for many new alternative splice variants and 8 gene duplications. Over 1,100 transcripts without porcine sequence evidence were detected using cross-species annotation. We used a functional approach to discover and accurately annotate porcine immune response genes. A co-expression clustering analysis of transcriptomic data from selected experimental infections or immune stimulations of blood, macrophages or lymph nodes identified a large cluster of genes that exhibited a correlated positive response upon infection across multiple pathogens or immune stimuli. Interestingly, this gene cluster (cluster 4) is enriched for known general human immune response genes, yet contains many un-annotated porcine genes. A phylogenetic analysis of the encoded proteins of cluster 4 genes showed that 15% exhibited an accelerated evolution as compared to 4.1% across the entire genome. CONCLUSIONS: This extensive annotation dramatically extends the genome based knowledge of the molecular genetics and structure of a major portion of the porcine immunome. Our complementary functional approach using co-expression during immune response has provided new putative immune response annotation for over 500 porcine genes. Our phylogenetic analysis of this core immunome cluster confirms rapid evolutionary change in this set of genes, and that, as in other species, such genes are important components of the pig's adaptation to pathogen challenge over evolutionary time. These comprehensive and integrated analyses increase the value of the porcine genome sequence and provide important tools for global analyses and data-mining of the porcine immune response. PMID- 23676097 TI - Creating a climate for healing: a visual model for goals of care discussions. PMID- 23676099 TI - The ambiguities of free-standing pediatric hospices. PMID- 23676100 TI - Regulation of DNA transposition by CpG methylation and chromatin structure in human cells. AB - BACKGROUND: The activity of transposable elements can be regulated by different means. DNA CpG methylation is known to decrease or inhibit transpositional activity of diverse transposons. However, very surprisingly, it was previously shown that CpG methylation of the Sleeping Beauty (SB) transposon significantly enhanced transposition in mouse embryonic stem cells. RESULTS: In order to investigate the unexpected response of SB transposition to CpG methylation, related transposons from the Tc1/mariner superfamily, that is, Tc1, Himar1, Hsmar1, Frog Prince (FP) and Minos were tested to see how transposition was affected by CpG methylation. A significant increase of >20-fold in transposition of SB, FP and Minos was seen, whereas Tc1, Himar1 and Hsmar1 showed no difference in transposition upon CpG-methylation. The terminal inverted repeats (TIRs) of the SB, FP and Minos elements share a common structure, in which each TIR contains two functionally important binding sites for the transposase (termed the IR/DR structure). The group of IR/DR elements showed increased excision after CpG methylation compared to untreated transposon donor plasmids. We found that de novo CpG methylation is not required for transposition. A mutated FP donor plasmid with depleted CpG sites in both TIRs was as efficient in transposition as the wild-type transposon, indicating that CpG sites inside the TIRs are not responsible for altered binding of factors potentially modulating transposition. By using an in vivo one-hybrid DNA-binding assay in cultured human cells we found that CpG methylation had no appreciable effect on the affinity of SB transposase to its binding sites. However, chromatin immunoprecipitation indicated that CpG methylated transposon donor plasmids are associated with a condensed chromatin structure characterized by trimethylated histone H3K9. Finally, DNA compaction by protamine was found to enhance SB transposition. CONCLUSIONS: We have shown that DNA CpG methylation upregulates transposition of IR/DR elements in the Tc1/mariner superfamily. CpG methylation provokes the formation of a tight chromatin structure at the transposon DNA, likely aiding the formation of a catalytically active complex by facilitating synapsis of sites bound by the transposase. PMID- 23676101 TI - Effects of motivational interviewing intervention on blackouts among college freshmen. AB - PURPOSE: Alcohol and illicit drug abuse is a serious public health issue facing college students. This study examined the impact of motivational interviewing (MI) as an intervention on the rate of blackouts among freshmen who engaged in high-risk drinking and illicit drug use. DESIGN: A sample of 188 volunteer freshmen from a university were administered the Daily Drinking Questionnaire, the Rutgers Alcohol Problem Index, and the Government Performance and Results Act at baseline and again at 6 months postintervention. MI was applied at baseline and then again at 2 weeks, 3 months, and 6 months. METHODS: Generalized estimated equations and logistic regression models were used to determine associations between the rate of blackouts and time, ethnicity, gender, illicit drug use, and alcohol consumption. FINDINGS: At 6 months, the rate of blackouts decreased from 40% at baseline to 16% (p < .0001). The average number, time, and days of drinking and frequency of drug use also decreased significantly (p < .0001). An association between rate of blackouts and gender was observed, but not with ethnicity. CONCLUSIONS: MI had an impact on reducing alcohol consumption and the rate of blackouts among college freshmen who were engaging in high-risk drinking and illicit drug use. CLINICAL RELEVANCE: The findings support the importance of using MI with freshmen college students to decrease drinking and the associated negative consequences, including blackouts, which has particular relevance for advanced practice registered nurses, physicians, and community health nurses who conduct MI as an intervention with college students. PMID- 23676102 TI - Insights into the catalytic mechanism of coral allene oxide synthase: a dispersion corrected density functional theory study. AB - In this present work the mechanism by which cAOS catalyzes the formation of allene oxide from its hydroperoxy substrate was computationally investigated by using a DFT-chemical cluster approach. In particular, the effects of dispersion interactions and DFT functional choice (M06, B3LYP, B3LYP*, and BP86), as well as the roles of multistate reactivity and the tyrosyl proximal ligand, were examined. It is observed that the computed relative free energies of stationary points along the overall pathway are sensitive to the choice of DFT functional, while the mechanism obtained is generally not. Large reductions in relative free energies for stationary points along the pathway (compared to the initial reactant complex) of on average 46.3 and 97.3 kJ mol(-1) for the doublet and quartet states, respectively, are observed upon going from the M06 to BP86 functional. From results obtained by using the B3LYP* method, well-tested previously on heme-containing systems, the mechanism of cAOS appears to occur with considerably higher Gibbs free energies than that for the analogous pathway in pAOS, possibly due to the presence of a ligating tyrosyl residue in cAOS. Furthermore, at the IEFPCM-B3LYP*/6-311+G(2df,p)//B3LYP/BS1 level of theory the inclusion of dispersion effects leads to the suggestion that the overall mechanism of cAOS could occur without the need for spin inversion. PMID- 23676103 TI - Generation of high photocurrent in three-dimensional silicon quantum dot superlattice fabricated by combining bio-template and neutral beam etching for quantum dot solar cells. AB - We fabricated a three-dimensional (3D) stacked Si nanodisk (Si-ND) array with a high aspect ratio and uniform size by using our advanced top-down technology consisting of bio-template and neutral beam etching processes. We found from conductive atomic microscope measurements that conductivity became higher as the arrangement was changed from a single Si-ND to two-dimensional (2D) and 3D arrays with the same matrix of SiC, i.e., the coupling of wave functions was changed. Moreover, our theoretical calculations suggested that the formation of minibands enhanced tunneling current, which well supported our experimental results. Further analysis indicated that four or more Si-NDs basically maximized the advantage of minibands in our structure. However, it appeared that differences in miniband widths between 2D and 3D Si-ND arrays did not affect the enhancement of the optical absorption coefficient. Hence, high photocurrent could be observed in our Si-ND array with high photoabsorption and carrier conductivity due to the formation of 3D minibands. PMID- 23676105 TI - Graphene oxide nanosheet with high proton conductivity. AB - We measured the proton conductivity of bulk graphite oxide (GO'), a graphene oxide/proton hybrid (GO-H), and a graphene oxide (GO) nanosheet for the first time. GO is a well-known electronic insulator, but for proton conduction we observed the reverse trend, as it exhibited superionic conductivity. The hydrophilic sites present in GO as -O-, -OH, and -COOH functional groups attract the protons, which propagate through hydrogen-bonding networks along the adsorbed water film. The proton conductivities of GO' and GO-H at 100% humidity were ~10( 4) and ~10(-5) S cm(-1), respectively, whereas that for GO was amazingly high, nearly 10(-2) S cm(-1). This finding indicates the possibility of GO-based perfect two-dimensional proton-conductive materials for applications in fuel cells, sensors, and so on. PMID- 23676104 TI - Application of nanotechnology in the treatment and diagnosis of gastrointestinal cancers: review of recent patents. AB - Gastrointestinal cancers remain one of the main causes of death in developed countries. The main obstacles to combating these diseases are the limitations of current diagnostic techniques and the low stability, availability, and/or specificity of pharmacological treatment. In recent years, nanotechnology has revolutionized many fields of medicine, including oncology. The association of chemotherapeutic agents with nanoparticles offers improvement in the solubility and stability of antitumor agents, avoidance of drug degradation, and reductions in therapeutic dose and toxicity, increasing drug levels in tumor tissue and decreasing them in healthy tissue. The use of specific molecules that drive nanoparticles to the tumor tissue represents a major advance in therapeutic specificity. In addition, the use of nanotechnology in contrast agents has yielded improvements in the diagnosis and the follow-up of tumors. These nanotechnologies have all been applied in gastrointestinal cancer treatment, first in vitro, and subsequently in vivo, with promising results reported in some clinical trials. A large number of patents have been generated by nanotechnology research over recent years. The objective of this paper is to review patents on the clinical use of nanoparticles for gastrointestinal cancer diagnosis and therapy and to offer an overview of the impact of nanotechnology on the management of this disease. PMID- 23676106 TI - Effectiveness of abdominal acupuncture for patients with obesity-type polycystic ovary syndrome: a randomized controlled trial. AB - OBJECTIVE: To assess the effectiveness of abdominal acupuncture at the endocrine and metabolic level in patients with obesity-type polycystic ovary syndrome (PCOS). METHODS: Eighty-six women from the First Affiliated Hospital of Guangzhou Medical College with a diagnosis of PCOS (body-mass index [BMI] >=25 kg/m(2)) were randomly assigned to receive 6 months of abdominal acupuncture (once a day) or oral metformin (250 mg three times daily in the first week, followed by 500 mg three times daily thereafter). BMI, waist-to-hip ratio (WHR), ovarian volume, menstrual frequency, homeostasis model assessment for insulin resistance (HOMA IR), and Ferriman-Gallwey score were measured at the beginning of the study and after 6 months of treatment. Luteotrophic hormone (LH), testosterone, follicle stimulating hormone (FSH), fasting blood glucose, 2-hour Postprandial blood glucose, fasting insulin, 2-hour postprandial blood insulin, total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were also assessed. RESULTS: According to the results at baseline and 6 months, BMI, WHR, Ferriman-Gallwey score, ovarian volume, luteotrophic hormone, ratio of luteotrophic hormone to follicle stimulating hormone, testosterone, LDL-C, triglycerides, total cholesterol, fasting blood glucose, 2-hour postprandial blood glucose, fasting insulin, 2-hour postprandial blood insulin, and HOMA-IR were reduced significantly in the two groups (p<0.05). Menstrual frequency and HDL-C (p<0.05) increased significantly in both groups; follicle-stimulating hormone also increased in both groups, but the change was not significant (p>0.05). The acupuncture group showed considerable advantages over the metformin group in terms of reduced BMI and WHR and increases in menstrual frequency (p<0.05). CONCLUSION: Abdominal acupuncture and metformin improved the endocrine and metabolic function of patients with obesity-type PCOS. Abdominal acupuncture may be more effective in improving menstrual frequency, BMI, and WHR, with few adverse effects. PMID- 23676108 TI - Abstracts Submitted for Presentation at the 2013 APS-MSA Joint Meeting. PMID- 23676109 TI - Abstracts of Special Session Presentations at the 2013 APS-MSA Joint Meeting. PMID- 23676107 TI - Effects of dietary beta-(1,3)(1,6)-D-glucan supplementation on growth performance, intestinal morphology and haemato-immunological profile of mirror carp (Cyprinus carpio L.). AB - In recent years, aquaculture research has focused on probiotics, prebiotics, and beta-glucans, in order to improve health status and growth performance. Information regarding the effects of beta-glucan on growth performance and intestinal immunity of mirror carp (Cyprinus carpio L.) is scarce. An experiment was therefore conducted to investigate the effects of a yeast beta-glucan preparation (MacroGard((r)) ) on growth performance, intestinal morphology and haemato-immunological indices of mirror carp. Carp (initial weight 11.1 +/- 0.0 g) were fed highly purified diets supplemented with 0% (control), 0.1%, 1% or 2% MacroGard((r)) for 8 weeks. Fish fed diets containing 1% and 2% MacroGard((r)) showed significant improvements in weight gain, specific growth rate and feed conversion ratio compared to fish fed both the control and the 0.1% MacroGard((r)) containing diet. Histological appraisal of the intestine showed a significantly higher infiltration of leucocytes into the epithelial layer of fish fed diets supplemented with 1% and 2% MacroGard((r)) in the anterior intestine compared to fish fed the control and 0.1% MacroGard((r)) diet. This effect was not observed in the posterior intestine. There were no significant differences in the intestinal absorptive surface area and number of goblet cells in either intestinal region. At the end of the experiment, the haematological status of the fish was examined. Compared to control fed fish, the haematocrit value was significantly elevated in fish fed the 2% MacroGard((r)) diet. Furthermore, the blood monocyte fraction was significantly higher in fish fed the 1% and 2% MacroGard((r)) diets. No significant changes were observed in the other blood parameters assessed. The present study shows that high dietary beta-glucan inclusion increases growth performance without detrimental effects on the health indicators assessed. Increased intraepithelial leucocytes in the anterior intestine may indicate a localized immune response; no detrimental effects on intestinal morphology were observed. PMID- 23676110 TI - Localized calcific hematoma of the scalp presenting as a nummular-like headache: a case report. PMID- 23676111 TI - Long-term operation of microbial electrosynthesis systems improves acetate production by autotrophic microbiomes. AB - Microbial electrosynthesis is the biocathode-driven production of chemicals from CO2 and has the promise to be a sustainable, carbon-consuming technology. To date, microbial electrosynthesis of acetate, the first step in order to generate liquid fuels from CO2, has been characterized by low rates and yields. To improve performance, a previously established acetogenic biocathode was operated in semi batch mode at a poised potential of -590 mV vs SHE for over 150 days beyond its initial development. Rates of acetate production reached a maximum of 17.25 mM day(-1) (1.04 g L(-1) d(-1)) with accumulation to 175 mM (10.5 g L(-1)) over 20 days. Hydrogen was also produced at high rates by the biocathode, reaching 100 mM d(-1) (0.2 g L(-1) d(-1)) and a total accumulation of 1164 mM (2.4 g L(-1)) over 20 days. Phylogenetic analysis of the active electrosynthetic microbiome revealed a similar community structure to what was observed during an earlier stage of development of the electroacetogenic microbiome. Acetobacterium spp. dominated the active microbial population on the cathodes. Also prevalent were Sulfurospirillum spp. and an unclassified Rhodobacteraceae. Taken together, these results demonstrate the stability, resilience, and improved performance of electrosynthetic biocathodes following long-term operation. Furthermore, sustained product formation at faster rates by a carbon-capturing microbiome is a key milestone addressed in this study that advances microbial electrosynthesis systems toward commercialization. PMID- 23676113 TI - A highly diastereo- and enantioselective synthesis of tetrahydroquinolines: quaternary stereogenic center inversion and functionalization. AB - Tetrahydroquinolines containing two quaternary stereogenic centers were synthesized with excellent ee and dr via a four-component cyclization reaction catalyzed by a chiral phosphoric acid. High chemoselectivity was achieved by differentiating anilines with similar reactivities to yield diverse "hybrid" products. The chirality of the quaternary C4 atom of the 4 aminotetrahydroquinoline products was found to undergo highly stereoselective inversion, enabling facile functionalization using a wide range of nucleophiles (C, O, N, and S). PMID- 23676112 TI - Mesenchymal stromal cell characteristics vary depending on their origin. AB - Mesenchymal stromal cells (MSCs) are rare progenitor cells that can be isolated from various tissues. They exhibit multilineage differentiation potential, support regenerative processes, and interact with various immune cells. Therefore, MSCs represent a promising tool for regenerative medicine. However, source-dependent and donor-dependent differences of MSC properties, including implications on their clinical application are still largely unknown. We evaluated MSCs derived from perinatal tissues umbilical cord (UC) and amniotic membrane (AM) in comparison to adult MSCs from bone marrow (BM), which were used as gold standard. We found genetic background-independent differences between MSCs from UC and AM. While AM- and UC-MSCs were closer to each other than to BM MSCs, they also exhibited differences between each other. AM-MSCs from different donors but not UC-MSCs displayed high interdonor variability. In addition, we show that although all MSCs expressed similar surface markers, MSC populations from UC and AM showed differential profiles of gene expression and paracrine factor secretion to BM-derived MSCs. Notably, pathway analysis of gene expression data revealed intriguing differences between MSCs suggesting that MSCs from UC and AM possess in general a higher potential of immunomodulatory capacity, whereas BM-MSCs showed a higher potential of supporting regenerative processes as exemplified by neuronal differentiation and development. These differences between perinatal and BM-derived MSCs may be relevant for clinical applications. PMID- 23676115 TI - A systematic review of social networking sites: innovative platforms for health research targeting adolescents and young adults. AB - PURPOSE: To review the evidence to determine if social networking sites (SNS) are effective tools for health research in the adolescent and young adult populations. DESIGN: Systematic review of published research articles focused on use of SNS for youth health research. METHODS: Seventeen articles were selected that met the following criteria: used SNS at any stage of study, participants between 13 and 25 years of age, English language, and both international and national studies. Reviewers categorized selected studies based on the way SNS were used. FINDINGS: Utilization of SNS for effectively implementing research with adolescents and young adults include (a) recruitment, (b) intervention, and (c) measurement. Four findings about advantages of using SNS apparent in this review are (a) ease of access to youth, (b) cost effectiveness in recruitment, (c) ease of intervention, and (d) reliable screening venue of mental status and high-risk behaviors. CONCLUSIONS: Although this literature review showed relatively minimal research to date on the use of SNS for research targeting adolescents and young adults, the impact of using SNS for health research is of considerable importance for researchers as well as participants. With careful focus, SNS can become a valuable platform to access, recruit, and deliver health interventions in a cost-effective manner to youth populations as well as hard-to reach minority or underserved populations. CLINICAL RELEVANCE: The evidence demonstrates the usefulness of SNS as innovative platforms for health promotion among adolescents and young adults. PMID- 23676114 TI - Intravenous anidulafungin followed optionally by oral voriconazole for the treatment of candidemia in Asian patients: results from an open-label Phase III trial. AB - BACKGROUND: Candidemia is a significant cause of morbidity and mortality in hospitalized patients, particularly in Asia. Anidulafungin has been reported to be an effective treatment for candidemia in Western populations, but little is known about its efficacy in Asian patients, where the clinical presentation and epidemiology may be different. METHODS: An open-label study of anidulafungin for the treatment of candidemia was recently conducted in several Asian countries. Treatment was initiated with intravenous anidulafungin, given for at least 5 days, with the option to complete treatment with oral voriconazole. The primary endpoint was global (clinical and microbiological) response, and the primary analysis was the proportion of patients in the modified intent-to-treat population with successful global response at the end of therapy. Secondary analyses included proportion with successful global response in clinically relevant patient subgroups. The safety and tolerability profile of anidulafungin and voriconazole in this population was also investigated. RESULTS: Forty-three patients were studied, including 42 in the modified intent-to-treat population. Eighteen patients were > 65 years, the largest age subgroup, and 21 had central venous catheters. The most common Candida species causing infection were C. tropicalis (n = 18) and C. albicans (n = 10). In the primary analysis, 73.8% had a successful global response at end of therapy. Success rates in subgroups were: 72.2% for C. tropicalis and 71.4% for C. albicans infection, 58.8% for patients > 65 years, and 81.0% for patients with central venous catheters. Safety and tolerability were comparable with the known profiles for anidulafungin (and voriconazole). CONCLUSIONS: Although the epidemiology of Candida infections was different in this open-label study, the efficacy of anidulafungin in Asian patients with documented candidemia was consistent with previous studies in Western populations. No new safety concerns were identified. TRIAL REGISTRATION: http://www.clinicaltrials.gov identifier NCT00537329. PMID- 23676116 TI - Voltage-driven translocation behaviors of IgG molecule through nanopore arrays. AB - Nanopore-based biosensing has attracted more and more interests in the past years, which is also regarded as an emerging field with major impact on bio analysis and fundamental understanding of nanoscale interactions down to single molecule level. In this work, the voltage-driven translocation properties of goat antibody to human immunoglobulin G (IgG) are investigated using nanopore arrays in polycarbonate membranes. Obviously, the background ionic currents are modulated by IgG molecules for their physical place-holding effect. However, the detected ionic currents do 'not' continuously decrease as conceived; the currents first decrease, then increase, and finally stabilize with increasing IgG concentration. To understand this phenomenon, a simplified model is suggested, and the calculated results contribute to the understanding of the abnormal phenomenon in the actual ionic current changing tendency. PMID- 23676117 TI - The structure and function of quinones in biological solar energy transduction: a cyclic voltammetry, EPR, and hyperfine sub-level correlation (HYSCORE) spectroscopy study of model naphthoquinones. AB - Quinones function as electron transport cofactors in photosynthesis and cellular respiration. The versatility and functional diversity of quinones is primarily due to the diverse midpoint potentials that are tuned by the substituent effects and interactions with surrounding amino acid residues in the binding site in the protein. In the present study, a library of substituted 1,4-naphthoquinones are analyzed by cyclic voltammetry in both protic and aprotic solvents to determine effects of substituent groups and hydrogen bonds on the midpoint potential. We use continuous-wave electron paramagnetic resonance (EPR) spectroscopy to determine the influence of substituent groups on the electronic properties of the 1,4-naphthoquinone models in an aprotic solvent. The results establish a correlation between the presence of substituent group(s) and the modification of electronic properties and a corresponding shift in the midpoint potential of the naphthoquinone models. Further, we use pulsed EPR spectroscopy to determine the effect of substituent groups on the strength and planarity of the hydrogen bonds of naphthoquinone models in a protic solvent. This study provides support for the tuning of the electronic properties of quinone cofactors by the influence of substituent groups and hydrogen bonding interactions. PMID- 23676118 TI - Alternative in vitro approach for assessing AHR-mediated CYP1A induction by dioxins in wild cormorant (Phalacrocorax carbo) population. AB - Our line of papers revealed that the common (great) cormorant (Phalacrocorax carbo) possesses two isoforms of the aryl hydrocarbon receptor (ccAHR1 and ccAHR2). This paper addresses in vitro tests of the ccAHR signaling pathways to solve two questions: (1) whether there are functional differences in the two ccAHR isoforms, and (2) whether a molecular perturbation, cytochrome P450 1A (ccCYP1A) induction, in the population-level can be predicted from the in vitro tests. The transactivation potencies mediated by ccAHR1 and ccAHR2 were measured in COS-7 cells treated with 15 selected dioxins and related compounds (DRCs), where ccAHR1 or ccAHR2 expression plasmid and ccCYP1A5 promoter/enhancer-linked luciferase reporter plasmid were transfected. For congeners that exhibited dose dependent luciferase activities, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) relative potencies (REPs) and induction equivalency factors (IEFs) were estimated. ccAHR1-IEF profile was similar to WHO avian TCDD toxic equivalency factor (TEF) profile except for dioxin-like polychlorinated biphenyls that showed lower IEFs in ccAHR1-driven reporter assay. ccAHR2-IEF profile was different from WHO TEFs and ccAHR1-IEFs. Notably, 2,3,4,7,8-PeCDF was more potent than TCDD for ccAHR2-mediated response. Using ccAHR1- and ccAHR2-IEFs and hepatic DRC concentrations in the Lake Biwa cormorant population, total TCDD induction equivalents (IEQs) were calculated for each ccAHR-mediated response. Nonlinear regression analyses provided significant sigmoidal relationships of ccAHR1- and ccAHR2-derived IEQs with hepatic ccCYP1A5 mRNA levels, supporting the results of in vitro ccAHR-mediated TCDD dose-response curves. Collectively, our in vitro AHR reporter assay potentially could be an alternative to molecular epidemiology of the species of concern regarding CYP1A induction by AHR ligands. PMID- 23676119 TI - How well can parametrized and parameter-free double-hybrid approximations predict response properties of hydrogen-bonded systems? Dipole polarizabilities of water nanoclusters as a working model. AB - The development of double-hybrid (DH) density functional approximations has been a crucial ingredient in the success of density functional theory (DFT). To further extend the range of applicability of these approximations, their suitability for investigating the response of hydrogen-bonded systems to external static electric fields is explored here. As a case study, we focus on the performance of parametrized and parameter-free DH density functionals for calculations of isotropic and anisotropic dipole polarizabilities of water nanoclusters. The functionals considered in our study are B2GP-PLYP, B2-PLYP, mPW2-PLYP, and SD-PBEP86 as parametrized functionals, and PBE0-DH and PBE0-2 as parameter-free models. The second-order Moller-Plesset perturbation theory (MP2) as a wave function theory (WFT) based method is also included for the sake of comparison. As a reference for methods benchmarking, the results of coupled cluster method with single and double excitations (CCSD) are used. Scrutinizing the role of exchange, correlation, and their contributions in the functionals reveals that PBE0-DH is the best method that predicts the most accurate isotropic polarizabilities by a large margin with respect to other tested functionals. Moreover, we found that the PBE0-DH has a smaller mean absolute deviation than MP2. On the other hand, our results show that PBE0-2 outperforms other methods for anisotropic polarizabilities of clusters studied. On the whole, among all the tested DH density functionals for dipole polarizabilities of water clusters, the parameter-free PBE-based models are found to offer the best overall performance. PMID- 23676120 TI - Abdominal wall thickness: is it associated with superficial and deep incisional surgical site infection after colorectal surgery? AB - BACKGROUND: Colorectal surgical procedures have a high rate of surgical site infection (SSI), and obesity has been implicated as a predictor of such infection. We hypothesized that abdominal wall thickness (AWT), as a metric of obesity, would predict postoperative superficial and deep incisional SSI after colorectal surgery, and conducted a study to assess superficial and deep incisional SSI and its relationship to abdominal wall thickness. METHODS: To measure pre-operative AWT through cross-sectional imaging, and to analyze its relationship to SSI, we conducted a retrospective study at a single academic medical center of patients who had had colorectal resection for any indication in 2008 and 2009. RESULTS: We identified 143 patients for inclusion in the study. Superficial or deep incisional SSI occurred in 43 patients (30%). Abdominal wall thickness at the midpoint between the umbilicus and pubis was associated with SSI (OR 1.03; p=0.014). Body-mass index (BMI) was also significantly associated with SSI (OR 1.08; p=0.014). Other significant (p<0.05) predictors of SSI by univariate analysis included a history of soft tissue infection, a surgical wound classification of 3 or 4, and lack of compliance with perioperative antibiotic guidelines. In a multivariable analysis of factors that were statistically significantly associated with SSI in univariate comparisons, lack of appropriate preoperative antibiotic administration independently predicted SSI (OR 4.33; 95% CI 1.08-17.40), but AWT and BMI were not significantly associated with SSI. CONCLUSIONS: Surgical site infection is common after colorectal surgery. Increased AWT predicts SSI by univariate analysis. Our findings could guide further studies of interventions that may decrease the risk of SSIs in patients with a thick abdominal wall. PMID- 23676121 TI - Malnutrition in the twenty-first century: an epidemic affecting surgical outcome. PMID- 23676122 TI - Advancing bodies of evidence for population-based health promotion programs: randomized controlled trials and case studies. AB - This study provides a demonstration of how published intervention outcomes can be used to create benchmarks for wellness programs for comparison of a case study. Case study results can then be applied by decision makers to adopt and evaluate the relative effectiveness of wellness programs. This case study assessed outcomes from Transtheoretical Model (TTM) computer-tailored interventions (CTIs) on 6 behaviors over a 5-year period. Results were compared with outcomes from a series of TTM randomized controlled trials and a representative review of workplace wellness interventions. The case study included 6544 employees, their spouses, and adult dependents who participated in a multicomponent CTI that assessed health risks and provided tailored feedback. Case study results were compared with 26 outcomes from 14 randomized controlled TTM-based CTIs, and with results from a published review of worksite-based wellness programs. The outcomes of the dissemination study were comparable to the average results of the TTM based randomized controlled trials on stress and depression but exceeded the averages on smoking, healthy eating, fruit and vegetable consumption, and exercise by 16.4% to 44.8%. The dissemination study also exceeded by 89.3% to 7 times the average results of the workplace wellness interventions. The comparisons applied in this project represent a demanding test of the effectiveness of case studies. Length of treatment and choice of treatments are factors that may have contributed to above-average outcomes. PMID- 23676123 TI - Provision of health promotion programmes to people with serious mental illness: a mapping exercise of four South London boroughs. AB - ACCESSIBLE SUMMARY: BACKGROUND: People with serious mental illness (SMI) are at increased risk of developing various physical health diseases, contributing to significantly reduced life expectancies compared with the general population. In light of this, the Department of Health have set the physical health of people with mental health problems as a priority for improvement. Additionally, the UK government encourages the NHS and local authorities to develop health promotion programmes (HPPs) for people with SMI. AIMS: To document how many and what types of HPPs were available to people with SMI across four South London boroughs, UK. RESULTS: We found 145 HPPs were available to people with SMI across the four boroughs, but with an inequitable distribution. We also found that certain HPPs set admission criteria that were likely to act as a barrier to improving health. CONCLUSIONS: A more integrated approach of documenting and providing information regarding the provision of HPPs for or inclusive of people with SMI is needed. ABSTRACT: People with serious mental illness (SMI) such as schizophrenia, schizoaffective disorders and bipolar disorder are at increased risk of developing diabetes, cardiovascular disease and respiratory disease, contributing to significantly reduced life expectancies. As a result, emphasis has been placed on developing Health Promotion Programmes (HPPs) to modify the risk of poor physical health in SMI. We examined how many and what types of HPPs are available for or inclusive of people with SMI across four borough in South London, UK. A cross-sectional mapping study was carried out to identify the number of HPPs available to people with SMI. We found 145 HPPs available to people with SMI existed across the four boroughs but with an inequitable distribution, which in some boroughs we anticipate may not meet need. In some cases, HPPs set admission conditions which were likely to further impede access. We recommend that accurate and readily available information on the provision of HPPs for or inclusive of people with SMI is needed. PMID- 23676124 TI - Increased incidence of herpes zoster in the setting of cytomegalovirus preemptive therapy after kidney transplantation. AB - BACKGROUND: Herpes zoster (HZ) is a common infectious disease after kidney transplantation (KT). The incidence of HZ may increase during cytomegalovirus (CMV) preemptive therapy. We therefore evaluated the incidence, risk factors, and clinical outcomes of HZ after KT, according to the type of CMV prophylaxis used. METHODS: We retrospectively established a cohort of KT recipients who underwent transplantation from June 2008 to May 2010. Patients were categorized into 3 groups according to CMV prophylaxis regimen: Group A (preemptive therapy), Group B (universal prophylaxis <3 months), and Group C (universal prophylaxis >3 months). The incidence rate of HZ was compared in each group, and risk factors for HZ were identified. RESULTS: The incidence rate of HZ was 46.6 (95% confidence interval [CI] 31.4-66.5) per 1000 person-years. The incidence rate was higher in Group A than in Group C (80.0 vs. 13.0 per 1000 person-years; P = 0.001). Median onset time of HZ after KT was shorter in Group A than in Group B (0.9 vs. 9.9 months; P < 0.001) and Group C (0.9 vs. 14.8 months; P = 0.008). Post-herpetic neuralgia occurred in 7 patients (23%). No visceral involvement or death was related to HZ. By multivariate analysis, only female gender (corrected relative risk 1.59; 95% CI 1.09-2.00) was independently associated with HZ development. CONCLUSIONS: In the setting of CMV preemptive therapy, a differentiated varicella zoster virus-specific prophylaxis might be necessary for patients with HZ risk factors. PMID- 23676125 TI - Biogenic trypanocidal sesquiterpenes: lead compounds to design future trypanocidal drugs - a mini review. AB - Human trypanosomiasis is a parasitic disease among poor people in Africa and Latin America. Therapy against African and American trypanosomiasis is based on a few drugs that often cause severe side-effects. Therefore, it is essential to develop drug discovery especially from natural origins. Sesquiterpenes, a diverse group of natural terpenoids, are found in essential oils of many plants and show a broad range of bioactivities. They act through multiple mechanisms in the chemotherapy of trypanosomiasis. Some of these active compounds contain hydroperoxides, aldehydes, alcohols, alpha,beta-unsaturated gamma-lactone and even halogenated moieties. Among the compounds reported, sesquiterpene lactones showed a potent anti-trypanosoma effect comparable with commercial trypanocidal drugs. Trypanocidal activity of sesquiterpene lactones mostly depends on the reaction between gamma-lactone moieties and nucleophile groups of trypanithione, which is essential for Trypanosoma defense against the oxidative stresses. Elatol is a sesquiterpenoid from marine algae, with a different structure and considerable trypanocidal activity which could be an interesting candidate for further antiprotozoal investigations. To develop novel drugs with higher efficacy and lower toxicity from natural products, this review summarizes the more recent information on trypanocidal activities of various sesquiterpenes. PMID- 23676127 TI - [A man with colorectal signet ring cell carcinoma: which therapy is required?]. AB - BACKGROUND: Primary colorectal signet ring cell carcinoma (SRCC) is rare and often affects younger patients. It demonstrates a different biological behaviour and has a less favourable prognosis than the more conventional colorectal adenocarcinoma. CASE DESCRIPTION: Patient A, a 65-year-old man, presented with a change in bowel habit. Colonoscopy showed a stenosis with signs of a nonspecific inflammation. However, laparoscopy revealed a primary colorectal SRCC with diffuse peritoneal metastases. Standard chemotherapy was unsuccessful. Patient A died 13 months after diagnosis. CONCLUSION: Based on clinical and molecular differences, SRCC can be recognized as a separate subtype of colorectal cancer. The case description illustrates that this group of patients may benefit from a different management strategy than the usual therapy. A greater understanding of the characteristics of this specific malignancy is needed. PMID- 23676126 TI - [Brown adipose tissue: the body's own weapon against obesity?]. AB - Brown adipose tissue (BAT) dissipates energy stored in triglycerides as heat via the uncoupling protein UCP1. It has recently been discovered that BAT is present and active in adults. BAT is situated predominantly around the aorta and in the supraclavicular area. BAT volume and activity are lower in individuals who are obese. This suggests that BAT significantly contributes to total energy expenditure. Several pathological conditions that are accompanied by activation of BAT, such as hyperthyroidism and phaeochromocytoma, result in the increased expenditure of energy and in weight loss. Various ways in which BAT can be manipulated to increase the expenditure of energy have been identified, e.g. exposure to cold, the use of so-called uncoupling agents or the administration of the hormone irisin. The activation of BAT could potentially be used to induce weight loss. PMID- 23676128 TI - [Cerebellar dysfunction due to pneumonia caused by Legionella pneumophila]. AB - BACKGROUND: Legionnaires' disease is frequently complicated by extrapulmonary symptoms such as neurological abnormalities. Cerebellar disorders are rare, but can be long-lasting and disabling. CASE DESCRIPTION: A 57-year-old male developed severe cerebellar disorders such as dysarthria and ataxia after being hospitalized for pneumonia. Despite an extensive diagnostic work-up, no explanation for the cerebellar symptoms could be found. The patient was transferred to a rehabilitation facility. Repeated serological tests revealed infection with Legionella, which was most probably the cause of the cerebellar dysfunction. CONCLUSION: Cerebellar disorders are a rare complication of Legionnaires' disease. The pathogenesis is unknown. There is no diagnostic test that proves or excludes cerebellar involvement in an infection caused by Legionella. The treatment is supportive and recovery can take months or even years. PMID- 23676129 TI - [A kickboxer with a painful wrist]. AB - We report a case of a female kickboxer who presented to the emergency department with an isolated volar dislocation of the ulnar at the distal radioulnar joint. Familiarity with this type of lesion is essential for establishing the correct diagnosis. PMID- 23676130 TI - [European practice guidelines for the treatment of inguinal hernia: a summary]. AB - The European best practice guidelines on the treatment of inguinal hernia were published in 2009. Publications on this subject in international journals were updated in 2012. In patients with asymptomatic inguinal hernia or with minimal symptoms, conservative treatment is safe, but they do need to be informed that the risk for undergoing surgery increases by nearly 10% a year. Conservative treatment is less useful in younger patients. All adult men with symptomatic inguinal hernia need to undergo surgery. They should be treated with a technique in which a synthetic prosthesis (mesh) is used. The Lichtenstein technique is advised for the open treatment of inguinal hernia, since this is the most thoroughly evaluated technique. For endoscopic treatment, the European best practice guidelines advise the total extra-peritoneal technique. Nowadays the focus in complications is on the prevention of postoperative chronic pain. PMID- 23676132 TI - [Severe abdominal pain after colostomy]. AB - A 57-year-old man with a history of laparoscopic loop colostomy presented with acute abdominal pain. An abdominal CT-scan demonstrated a closed-loop bowel obstruction. On exploratory laparotomy, we encountered an ischemic small bowel segment herniating through a mesocolic defect. After reposition, the bowel appeared viable. Internal herniation is a rare cause of small bowel obstruction and has a high mortality rate due to strangulation and bowel ischemia. PMID- 23676131 TI - [Asymptomatic myocardial infarction after non-cardiac surgery; importance of routine testing of troponin concentration]. AB - Perioperative myocardial infarction (PMI) is associated with a high mortality rate. Detection of PMI, however, is difficult due to a lack of typical anginal symptoms associated with the use of strong analgesics. Also, characteristic changes on the electrocardiogram may be minimal and/or transient. Recent studies have shown that postoperative troponin elevation is a strong, independent predictor of short- and intermediate-term mortality. In this article, we illustrate the importance of routine troponin measurements after major non cardiac surgery with two patient cases. Moreover, we provide a brief overview of current evidence on perioperative myocardial infarction, and highlight current and future perspectives of troponin measurements. PMID- 23676133 TI - [Cardiovascular disease: big problems require big solutions]. AB - At the age of 45, the lifetime risk of developing cardiovascular disease has been shown to be 60% in men and 55% in women in an analysis which included over 900,000 individuals in 5 prospective cohort studies in the United States. Only 4% of the men and 8% of the women had an optimal risk profile. The benefits of being at low risk were great: 14 more healthy years in those without risk factors. Identifying middle-aged individuals at high risk will prevent only a minority of clinical events. There are two alternatives that can be considered; the first one being the 'polypill' approach in which multiple generic drugs are started by every individual at a certain age, e.g., 55 years. This could prove to be an affordable and effective approach for the entire population. Alternatively, fundamental changes in society aimed at improving lifestyle and dietary habits could be implemented. PMID- 23676134 TI - [Stump problems after a lower limb amputation]. AB - Problems in the amputation stump occur frequently in lower limb amputees. These problems can range from skin defects to serious vascular insufficiency and have a major impact on the amputee's quality of life. We illustrate this with 2 patients aged 20 and 65. The first patient developed a Candida skin infection of the stump skin as a result of silicone liner use. She was successfully treated with miconazole/hydrocortisone and hygiene measures. The second patient developed progressive lower limb ischemia that resulted in a stump wound and claudication. He was treated with vascular surgery. Patients with stump problems should be referred to a rehabilitation physician for thorough examination of the stump in determining the cause of the symptoms and subsequent instalment of adequate treatment. PMID- 23676135 TI - [Transfusions in the acutely bleeding patient: the borders between too little too late and too much too early]. AB - A restrictive regime regarding the initiation of blood transfusions was found to be safe in a Spanish study that included 921 patients with upper gastrointestinal bleeding. Survival after 6 weeks was higher (95 vs. 91%) in the restrictive group (Hb 4.3 mmol/l) than in the liberal group (Hb 5.6 mmol/l). The restrictive regimen was found favourable in patients with cirrhosis (class Child-Pugh A and B). In the Netherlands, guidelines prescribe the use of the 4-5-6 rule for initiating blood transfusions, depending on comorbidity (according to ASA classification) for patients who are haemodynamically stable and an aggressive regime when unstable. Starting blood transfusions can be lifesaving and must not be withheld in those who are haemodynamically unstable, but when stable, nuance is needed. In conclusion, the right balance needs to be found between too little too late and too much too early. PMID- 23676136 TI - [High time for cerebral rehabilitation following stroke: discrepancies between guidelines and practice]. AB - Cardiac rehabilitation programmes reduce mortality in patients following myocardial infarction. Patients with a history of transient ischaemic attack (TIA) or ischemic stroke have a high risk of recurrent stroke or other cardiovascular events, comparable with the risk that myocardial infarction patients show for recurrence. Evidence for the effectiveness of secondary prevention strategies following TIA and ischemic stroke is compelling. Despite this convincing evidence, secondary prevention in the routine practice of stroke care is suboptimal. Improving adherence to guidelines and cardiovascular lifestyle changes by standardized post-stroke care, mirroring practice in cardiac rehabilitation programmes, could be a promising method for increasing effectiveness of secondary stroke prevention. PMID- 23676137 TI - Effects of lactulose supplementation on performance, blood profiles, excreta microbial shedding of Lactobacillus and Escherichia coli, relative organ weight and excreta noxious gas contents in broilers. AB - This study was to evaluate the effects of lactulose supplementation on performance, blood profiles, excreta microbial shedding of Lactobacillus and Escherichia coli, relative organ weight and excreta noxious gas contents in broilers. A total of 720 ROSS 308 broilers with a body weight of 46 +/- 0.1 g (1 day of age) were used in a 28-d experiment. Broilers were randomly allotted to 4 experiment diets with 12 replicate pens and 15 birds per pen. Dietary treatments were as follows: NC, negative control (without antibiotic); PC, NC + 0.1% tiamulin; L1, NC + 0.1% lactulose; and L2, NC + 0.2% lactulose. Broilers were fed with phase 1 (1-8 day), phase 2 (9-18 day) and phase 3 (19-28 day) diets in the form of mash. During day 1-8, broilers fed the PC and L2 diets had higher (p < 0.05) body weight gain than those fed the NC diet. During day 19-28, broilers fed the L1 and L2 diets had lower (p < 0.05) feed intake than those fed the NC diet. The feed conversion ratio (FCR) was decreased (p < 0.05) in L1 treatment compared with NC treatment. Overall, the FCR was improved (p < 0.05) in all supplementation treatments compared with NC treatment. The apparently metabolizable nitrogen in L1 treatment was higher (p < 0.05) than that in NC treatment at day 28. The excreta Lactobacillus was increased and E. coli was decreased in PC and L2 treatments compared with NC treatment at day 28 (p < 0.05). The excreta NH3, H2S and acetic acid contents were decreased (p < 0.05) in L1 and L2 treatments compared with NC treatment. The relative weight of abdominal fat of broilers fed the PC diet was lowest (p < 0.05) compared with other treatments. In conclusion, this study indicated that dietary supplementation of 0.1% or 0.2% lactulose could improve growth performance, decrease excreta E. coli and excreta NH3 and H2S contents. PMID- 23676139 TI - May editorial. PMID- 23676138 TI - Research opportunities in optimizing storage of red blood cell products. PMID- 23676140 TI - Function of the diiron cluster of Escherichia coli class Ia ribonucleotide reductase in proton-coupled electron transfer. AB - The class Ia ribonucleotide reductase (RNR) from Escherichia coli employs a free radical mechanism, which involves bidirectional translocation of a radical equivalent or "hole" over a distance of ~35 A from the stable diferric/tyrosyl radical (Y122(*)) cofactor in the beta subunit to cysteine 439 (C439) in the active site of the alpha subunit. This long-range, intersubunit electron transfer occurs by a multistep "hopping" mechanism via formation of transient amino acid radicals along a specific pathway and is thought to be conformationally gated and coupled to local proton transfers. Whereas constituent amino acids of the hopping pathway have been identified, details of the proton-transfer steps and conformational gating within the beta sununit have remained obscure; specific proton couples have been proposed, but no direct evidence has been provided. In the key first step, the reduction of Y122(*) by the first residue in the hopping pathway, a water ligand to Fe1 of the diferric cluster was suggested to donate a proton to yield the neutral Y122. Here we show that forward radical translocation is associated with perturbation of the Mossbauer spectrum of the diferric cluster, especially the quadrupole doublet associated with Fe1. Density functional theory (DFT) calculations verify the consistency of the experimentally observed perturbation with that expected for deprotonation of the Fe1-coordinated water ligand. The results thus provide the first evidence that the diiron cluster of this prototypical class Ia RNR functions not only in its well-known role as generator of the enzyme's essential Y122(*), but also directly in catalysis. PMID- 23676141 TI - Genetic characterization of Clupisoma garua (Hamilton 1822) from six Indian populations using mtDNA cytochrome b gene. AB - Clupisoma garua (Hamilton, 1822) is a commercially important freshwater fish and a potential candidate species for aquaculture. This study investigates the genetic diversity and population structure of six Indian populations of C. garua using cytochrome b (cyt b) sequences of mitochondrial DNA (mtDNA). We sequenced cyt b gene of 64 individuals collected from five distant rivers: Ganga, Gomti, Betwa, Gandak and Brahmaputra. Sequencing of 1054 bp cyt b mtDNA fragment revealed the presence of 19 haplotypes with a haplotype diversity value of 1.000 and a nucleotide diversity value of 0.0258 +/- 0.00164. The Gandak river fish population showed highest nucleotide diversity. The fixation index analysis indicated significant genetic divergence among populations from different geographical areas. Both the neighbor-joining tree and median-joining network analysis of the haplotype data showed distinct patterns of phylo-geographic structure. The hierarchical analysis of molecular variance revealed that intra group variation among populations was highly significant. The results of this study suggest that C. garua populations, especially geographically isolated groups, have developed significant genetic structures within the population. In addition, tests of neutrality suggest that C. garua may have experienced a population expansion. The study results establish cyt b as polymorphic and a potential marker to determine the population structure of C. garua. Information of genetic variation and population structure generated from this study would be useful for planning effective strategies for the conservation and rehabilitation of Schilibid cat fishes. PMID- 23676142 TI - Complete mitochondrial genome of dotted grouper Epinephelus epistictus (Serranidae: Epinephelinae). AB - The complete mitochondrial genome of Epinephelus epistictus was first presented in this study. It was 16,920 bp in length, consisted of 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes and 1 putative control region (D-loop). Overall nucleotide base composition was 28.78% A, 28.5% C, 16.12% G and 26.6% T. The COI gene started with GTG codon and the ATP6 gene started with CTG codon. The tRNA Ser2 lacked the dihydrouridine (DHU) arm and formed one loop. The origin of L strand replication (OL) was identified between tRNA-Asn and tRNA-Cys genes. The control region was rich in A + T (69.93%) and poor in G (12.80%). Two tandem repeat motifs were found in the control region with one nucleotide different. PMID- 23676143 TI - Evaluation of the IL2/IL21, IL2RA and IL2RB genetic variants influence on the endogenous non-anterior uveitis genetic predisposition. AB - BACKGROUND: Recently, different genetic variants located within the IL2/IL21 genetic region as well as within both IL2RA and IL2RB loci have been associated to multiple autoimmune disorders. We aimed to investigate for the first time the potential influence of the IL2/IL21, IL2RA and IL2RB most associated polymorphisms with autoimmunity on the endogenous non-anterior uveitis genetic predisposition. METHODS: A total of 196 patients with endogenous non-anterior uveitis and 760 healthy controls, all of them from Caucasian population, were included in the current study. The IL2/IL21 (rs2069762, rs6822844 and rs907715), IL2RA (2104286, rs11594656 and rs12722495) and IL2RB (rs743777) genetic variants were genotyped using TaqMan(r) allelic discrimination assays. RESULTS: A statistically significant difference was found for the rs6822844 (IL2/IL21 region) minor allele frequency in the group of uveitis patients compared with controls (P(-value)=0.02, OR=0.64 CI 95%=0.43-0.94) although the significance was lost after multiple testing correction. Furthermore, no evidence of association with uveitis was detected for the analyzed genetic variants of the IL2RA or IL2RB loci. CONCLUSION: Our results indicate that analyzed IL2/IL21, IL2RA and IL2RB polymorphisms do not seem to play a significant role on the non-anterior uveitis genetic predisposition although further studies are needed in order to clear up the influence of these loci on the non-anterior uveitis susceptibility. PMID- 23676144 TI - Depression as a non-causal variable risk marker in coronary heart disease. AB - BACKGROUND: After decades of investigations, explanations for the prospective association between depression and coronary heart disease (CHD) are still incomplete. DISCUSSION: Depression is often suggested to be causally related to CHD. Based on the available literature, we would rather argue that depression can best be regarded as a variable risk marker, that is, a variable that fluctuates together with mechanisms leading to poor cardiovascular fitness. Despite numerous efforts, no evidence is found that manipulation of depression alters cardiovascular outcomes--a key premise for determining causality. To explain the concept of a variable risk marker, we discuss several studies on the heterogeneity of depression suggesting that depression is particularly harmful for the course of cardiovascular disease when it appears to be a physiological consequence of the cardiovascular disease itself. SUMMARY: We conclude that instead of depression being a causal risk factor for CHD, the association between depression and CHD is likely confounded, at least by the cardiac disease itself. PMID- 23676145 TI - Aspergillosis after liver transplantation in the context of common variable immunodeficiency: case report. AB - Common variable immunodeficiency (CVID) is the most common primary immune defect, resulting in hypogammaglobulinemia as well as deficits in cell-mediated immunity. Although it mainly manifests in immunodeficiency and related infection, CVID can also be associated with autoimmune phenomena such as immune thrombocytopenic purpura, hemolytic anemia, rheumatoid arthritis, lupus, primary biliary cirrhosis, and autoimmune hepatitis (AIH). AIH is a less common but serious complication of CVID, which can result in early cirrhosis, ascites, and even hepatocellular carcinoma. Here, we discuss a recent case of transplantation for cirrhosis secondary to AIH in the context of CVID. Although the patient's surgery occurred without complication, he rapidly developed fulminant alveolar hemorrhage and seizures, and died secondary to disseminated neuroaspergillosis. PMID- 23676146 TI - Destruction of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) by ball milling. AB - Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) have received high concerns due to their extreme persistence, and very few technologies have been reported for their complete destruction. For sound PFCs wastes disposal, mechanochemical method was employed using a planetary ball mill. Potassium hydroxide (KOH) was identified as the best comilling reagent and nearly complete destruction of both PFOS and PFOA was realized. The measured water-soluble fluoride accounted for most of the organic fluorine. The final products of PFOS after treatment were shown to be KF and K2SO4 by XRD analysis. The mass ratio between PFOS and KOH significantly affected the fluoride recovery but not for PFOS destruction and the sulfate recovery. The gradual formation of sulfate and fluoride reveals that the degradation of PFOS is initiated with the dissociation of the sulfonate group. FTIR spectra further showed the disappearance of the -CF3 and -CF2- groups with the generation of sulfate. The cleavage of C-F bonds in PFOS and the formation of fluoride ion were also identified by XPS spectra. On the basis of these results, possible reaction pathways were proposed. The approach was also successfully applied for the destruction of PFOS and PFOA homologues with different chain lengths. PMID- 23676147 TI - Tandem antioxidant enzymes confer synergistic protective responses in experimental filariasis. AB - Helminth parasites use antioxidant defence strategies for survival during oxidative stress due to free radicals in the host. Accordingly, tissue-dwelling filarial parasites counteract host responses by releasing a number of antioxidants. Targeting these redox regulation proteins together, would facilitate effective parasite clearance. Here, we report the combined effect of protective immune responses trigged by recombinant Wuchereria bancrofti thioredoxin (WbTRX) and thioredoxin peroxidase (WbTPX) in an experimental filarial model. The expression of WbTRX and WbTPX in different stages of the parasite and their cross-reactivity were analysed by enzyme-linked immunosorbent assay (ELISA). The immunogenicity of recombinant proteins and their protective efficacy were studied in animal models when immunized in single or cocktail mode. The antigens showed cross-reactive epitopes and induced high humoral and cellular immune responses in mice. Further, parasite challenge against Brugia malayi L3 larvae in Mastomys coucha conferred significant protection of 57% and 62% against WbTRX and WbTPX respectively. The efficacy of L3 clearance was significantly higher (71%) (P < 0.001) when the antigens were immunized together, showing a synergistic effect in multiple-mode vaccination. Hence, the study suggests WbTRX and WbTPX to be attractive vaccine candidates when immunized together and provides a tandem block for parasite elimination in the control of lymphatic filariasis. PMID- 23676148 TI - Cutaneous metastasis of papillary thyroid carcinoma to the thyroidectomy scar. PMID- 23676149 TI - The perihematomal glutamate level is associated with the outcome of patients with basal ganglia hematomas treated by minimally invasive procedures. AB - INTRODUCTION: The purpose of this study was to provide pathophysiological evidence for the time window of minimally invasive (MI) procedures for evacuating intracerebral hematoma by observing the perihematomal glutamate level and its correlation with the outcome of the patients treated with MI surgery. METHODS: One hundred consecutive patients with intracerebral hemorrhage (ICH) in the basal ganglia were assigned to either a medical treatment group (MT group, 20 patients) or a minimally invasive treatment group (MI group, 80 patients). The intracerebral hematoma was evacuated using stereotactic MI surgery within 6 hours, 12 hours, 18 hours, or 24 hours of symptom onset based on the interval between the initial hemorrhage to the patients' arrival at the hospital. Perihematomal glutamate levels and brain water content were measured in 10 randomly selected patients in each MI subgroup. The outcome of the patients was determined by the National Institute of Health Stroke Scale (NIHSS) and Modified Ranking Scale (MRS) within 6 months after admission. RESULTS: The perihematomal glutamate levels and brain water content increased gradually as the intervals from symptom onset to surgery were prolonged. Minimally invasive surgery at all the investigated time points could improve the neurological functions. Performing the MI procedures in 6 hours showed the most remarkable decrease of NIHSS and MRS, and secondarily in 12 hours. CONCLUSIONS: Minimally invasive surgery could be effective in the treatment of patients with ICH. The optimal time window for MI surgery may be within 6-12 hours of symptom onset. PMID- 23676150 TI - The effect of donor variation and senescence on endothelial differentiation of human mesenchymal stromal cells. AB - Application of autologous cells is considered for a broad range of regenerative therapies because it is not surrounded by the immunological and ethical issues of allo- or xenogenic cells. However, isolation, expansion, and application of autologous cells do suffer from variability in therapeutic efficacy due to donor to donor differences and due to prolonged culture. One important source of autologous cells is mesenchymal stromal cells (MSCs), which can differentiate toward endothelial-like cells, thus making them an ideal candidate as cell source for tissue vascularization. Here we screened MSCs from 20 donors for their endothelial differentiation capacity and correlated it with the gene expression profile of the whole genome in the undifferentiated state. Cells of all donors were able to form tubes on Matrigel and induced the expression of endothelial genes, although with quantitative differences. In addition, we analyzed the effect of prolonged in vitro expansion on the multipotency of human MSCs and found that endothelial differentiation is only mildly sensitive to expansion induced loss of differentiation as compared to osteogenic and adipogenic differentiation. Our results show the robustness of the endothelial differentiation protocol and the gene expression data give insight in the differences in endothelial differentiation between donors. PMID- 23676151 TI - Drug-resistant tuberculosis: how are we doing? PMID- 23676152 TI - Are we ready to shorten the treatment duration for non-cavitary pulmonary tuberculosis? PMID- 23676153 TI - Epidemiology of pulmonary non-tuberculous mycobacterial infections: need to identify environmental sources. PMID- 23676154 TI - 2012: the year in review. Part 1: Tuberculosis. PMID- 23676155 TI - First national tuberculin survey in Viet Nam: characteristics and association with tuberculosis prevalence. AB - OBJECTIVES: To estimate the prevalence of infection with Mycobacterium tuberculosis and the annual risk of tuberculous infection (ARTI) and to compare this with the prevalence of tuberculosis (TB) over study clusters and households. METHODS: A nationwide, stratified cluster sample survey was carried out in 2006 2007 in Viet Nam to assess the prevalence of infection with M. tuberculosis. A representative sample of children aged 6-14 years underwent a tuberculin skin test (TST) using the Mantoux method. RESULTS: Of 23,160 children registered, 21,487 (92.8%) were tested and read and available for analysis. Using a cut-off point of 10 mm, the estimated prevalence of TST positivity was 16.7%, and the ARTI was 1.7% (95%CI 1.5-1.8). Higher infection rates were found in urban than in rural and remote areas, and infection rates increased with age. There was significant association between the prevalence of TB disease and infection at the cluster level (regression coefficient 0.54, 95%CI 0.06-1.01, P = 0.027, correlation coefficient R(2) 0.120). Children with a (recent) case of TB in the household were 1.6 times more likely to be TST-positive than children in households with no recent cases (P < 0.05). CONCLUSION: The estimated nationwide ARTI was 1.7%. TST positivity was associated with the presence of a TB case in the household. PMID- 23676156 TI - Spatio-temporal analysis of tuberculosis in Spain, 2008-2010. AB - BACKGROUND: The characteristics of respiratory tuberculosis (TB) favour the appearance of clusters of cases in space and time. It is important for public health authorities to know which clusters occur randomly and which merit further investigation. OBJECTIVE: To detect spatial and spatio-temporal clusters of respiratory TB in Spain during the period from 1 January 2008 to 31 December 2010. MATERIALS AND METHODS: Retrospective spatio-temporal study of respiratory TB cases reported to Spain's National Epidemiological Surveillance Network from 2008 to 2010, at a municipal level. We used the purely spatial and space-time Scan statistic estimators. All analyses were adjusted for age and sex. RESULTS: The spatial cluster analysis detected 28 significant clusters and the spatio temporal cluster analysis detected 20 significant clusters. The most likely spatial cluster comprised seven municipalities in the Greater Barcelona Area. Most space-time clusters were situated in the same area, and were detected between 1 April 2008 and 31 March 2009. CONCLUSION: The distribution of TB clusters as shown by the proposed models furnishes a spatial pattern of the distribution of the disease. The two methods used can be a useful tool for analysing the distribution of respiratory TB in Spain. PMID- 23676157 TI - Epidemiology and control of tuberculosis in Victoria, a low-burden state in south eastern Australia, 2005-2010. AB - SETTING: Victoria, Australia. OBJECTIVE: To describe the epidemiology and control of tuberculosis (TB) in Victoria, 2005-2010. DESIGN: Retrospective review of laboratory-confirmed TB in Victoria, 2005-2010. State TB reference laboratory records were matched with Department of Health notification records to obtain laboratory, demographic, clinical and treatment data. RESULTS: The incidence of TB fell in the Australian-born population but increased overall, reflecting an increase in the proportion of overseas-born cases from 88.9% to 95.8% between 2005 and 2010 (P = 0.03). Patients from India and Viet Nam accounted for over one third of all cases. For overseas-born cases, the median time between arrival and diagnosis was 4 years. Half of all diagnoses were pulmonary disease, of which 45.4% were Ziehl-Neelsen smear-positive. Treatment was most commonly self administered (76.9%), and very few patients defaulted or failed treatment (1.1%). Only 4.1% of cases were linked to another laboratory-confirmed case. Multidrug resistant TB remained uncommon (1.7% of cases). CONCLUSIONS: TB in Victoria remains low by global standards and continues to overwhelmingly affect the overseas-born population. Current TB control strategies in Victoria are effective, but strengthened control in high-burden countries will also improve TB control locally. PMID- 23676158 TI - Public health costs for tuberculosis suspects in Wake County, North Carolina, United States. AB - SETTING: As the incidence of tuberculosis (TB) declines in high-income countries, resources to control TB are also declining. A portion of these resources are utilized for the evaluation and treatment of persons initially suspected of, but who do not actually have, TB (TB suspects). OBJECTIVE: To describe the cost of TB suspects to public health departments, and determine whether part of this cost can be averted using improved diagnostic tools. DESIGN: We evaluated resource utilization for all TB suspects as well as a random sample of TB cases managed at the Wake County public health clinic during 2008-2010. The proportion of total health department costs attributable to TB suspects was estimated. A sensitivity analysis assessed the potential impact of a rapid, accurate diagnostic test to avert suspect-associated costs. RESULTS: Of 135 patients evaluated for TB, 36 (27%) were suspects, accounting for 14% (US5,885) of the total estimated costs for managing all patients. A perfect diagnostic test with a 3-day turnaround would have averted US27,975 (53%) of the costs attributable to suspects. CONCLUSION: A substantial proportion of public health resources is utilized to manage persons whose final diagnosis is not TB. Efficient implementation of novel rapid tests could avert substantial public health costs. PMID- 23676160 TI - Smoking in tuberculosis patients increases the risk of infection in their contacts. AB - OBJECTIVE: To determine the risk of latent tuberculous infection (LTBI) among contacts of smokers with tuberculosis (TB). METHODS: A study was conducted to determine the prevalence of LTBI among contacts of TB cases aged >14 years in Catalonia, Spain. A survey was carried out for each TB case and their contacts. LTBI was diagnosed using the tuberculin skin test (>=5 mm). The risk of LTBI associated with smoking was determined by multi-variate logistic regression analysis, with adjusted odds ratio (aOR) and their 95% confidence intervals (CI). RESULTS: The smoking prevalence among TB cases was 40.7% (439/1079). The prevalence of LTBI among their contacts was 29.7% (2281/7673). It was higher among contacts of smoking index cases (35.3%) than among those of non-smokers (25.7%). Smoking was independently associated with an increased risk of LTBI among contacts (aOR 1.5, 95%CI 1.3-1.7), and was estimated to be responsible for 12.8% of infections. CONCLUSIONS: Index case smoking increases the risk of LTBI and should be systematically investigated. A reduction in smoking could lower the risk of infection substantially. PMID- 23676159 TI - Household ventilation and tuberculosis transmission in Kampala, Uganda. AB - OBJECTIVE: To test the feasibility of measuring household ventilation and evaluate whether ventilation is associated with tuberculosis (TB) in household contacts in Kampala, Uganda. DESIGN: Adults with pulmonary TB and their household contacts received home visits to ascertain social and structural household characteristics. Ventilation was measured in air changes per hour (ACH) in each room by raising carbon dioxide (CO2) levels using dry ice, removing the dry ice, and measuring changes in the natural log of CO2 (lnCO2) over time. Ventilation was compared in homes with and without co-prevalent TB. RESULTS: Members of 61 of 66 (92%) households approached were enrolled. Households averaged 5.4 residents/home, with a median of one room/home. Twelve homes (20%) reported co prevalent TB in household contacts. Median ventilation for all rooms was 14 ACH (interquartile range [IQR] 10-18). Median ventilation was 12 vs. 15 ACH in index cases' sleeping rooms in households with vs. those without co-prevalent TB (P = 0.12). Among smear-positive indexes not infected by the human immunodeficiency virus (HIV), median ventilation was 11 vs. 17 ACH in index cases' sleeping rooms in homes with vs. those without co-prevalent TB (P = 0.1). CONCLUSION: Our findings provide evidence that a simple CO2 decay method used to measure ventilation in clinical settings can be adapted to homes, adding a novel tool and a neglected variable, ventilation, to the study of household TB transmission. PMID- 23676161 TI - Incidence of and risk factors for active tuberculosis in human immunodeficiency virus-infected patients in South Korea. AB - BACKGROUND: In South Korea, a high-income country with an intermediate tuberculosis (TB) burden and low human immunodeficiency virus (HIV) prevalence, studies on incidence and risk factors of TB in HIV-infected persons have rarely been reported. OBJECTIVE: To investigate the incidence of and risk factors for active TB in HIV-infected persons in South Korea. METHODS: A retrospective analysis was conducted of 1265 HIV-1 infected patients who visited four hospitals in South Korea between 1985 and 2012. We analysed the incidence of TB during the follow-up period. To investigate risk factors associated with active TB, we conducted a 1:2 matched case-control study of HIV-infected patients with newly active TB and controls without active TB who had similar CD4(+) T-cell counts and dates of first visit. RESULTS: Over a total of 4457 person-years (py), 185 (14.6%) subjects were diagnosed with active TB; the incidence was 4.2 cases/100 py. In multivariate analysis, low body mass index (P = 0.033) and current smoking (P = 0.003) were independent risk factors for TB in HIV-infected patients. CONCLUSION: Further strategies on prevention and treatment of active TB among HIV infected patients should be implemented in South Korea. Encouraging smoking cessation and supporting good nutrition may be ways to reduce the incidence of active TB in HIV-infected patients. PMID- 23676162 TI - Contribution of the Ogawa-Kudoh swab culture method to the diagnosis of pulmonary tuberculosis in Brazil. AB - OBJECTIVE: To analyse the contribution of the Ogawa-Kudoh (O-K) swab culture method to the diagnosis of pulmonary tuberculosis (PTB) in four different regions of Brazil. DESIGN: This study was carried out in two phases. Phase 1 was designed to compare the direct swab culture method (O-K) with the culture concentrated method (N-acetyl-L-cysteine-sodium hydroxide [NALC-NaOH]); for this purpose, 569 sputum samples were cultured by both methods. Phase 2 was carried out to assess the contribution of the O-K method to the diagnosis of PTB in four different regions in Brazil, based on the evaluation of 19,163 sputum samples. RESULTS: In the first phase of the study, O-K culture had a sensitivity of 94.8% and specificity of 99.8% in cases confirmed by NALC-NaOH/Lowenstein-Jensen (LJ) culture. In the second phase of the study, the overall contribution of O-K culture compared to acid-fast bacilli (AFB) examination (AFB-/culture+) to the diagnosis of PTB was 29.8%. CONCLUSION: O-K culture contributes significantly to the diagnosis of smear-negative PTB. Importantly, this method allows the recovery of clinical isolates in areas where use of the standard culture centrifuge is impossible, indicating that the O-K swab culture method should become a standard method for TB diagnosis in these regions. PMID- 23676163 TI - Can tuberculous pleural effusions be diagnosed by pleural fluid analysis alone? AB - OBJECTIVE: To assess whether pleural fluid analysis (PFA) can confidently diagnose tuberculous pleural effusion (TPE). METHODS: PFA of 548 TPEs was performed between January 1991 and December 2011. The control group consisted of patients with malignant PE (MPE), complicated parapneumonic/empyema (infectious) PE (IPE), miscellaneous PE (MisPE) and transudative PE (TrPE). RESULTS: The PFA of 548 histologically or culture-positive consecutive cases of TPE was compared with that of 158 consecutive cases of MPE, 113 cases of IPE, 37 cases of MisPE and 115 cases of TrPE. Statistically significant differences were noted in pleural fluid glucose, pH, cholesterol, triglycerides, adenosine deaminase (ADA), and total percentages of lymphocytes, neutrophils and macrophages when TPEs were compared to all other groups. Of the TPEs, 99.1% were exudates. Pleural fluid protein >= 5.0 g/dl, lymphocytes > 80% and ADA > 45 U/l were diagnostic of TPE, with a specificity of 100%, a sensitivity of 34.9% and an area under the curve of 0.975. CONCLUSION: PFA alone was diagnostic in one third of the TPE cases, with a high probability in nearly 60%. PMID- 23676164 TI - Requirements for the clinical evaluation of new anti-tuberculosis agents in children. AB - The ultimate goal of evidence-based drug treatment is to produce a desired pharmacological response in a predictable manner and also to minimise adverse effects. This goal requires not only an increased awareness of the need to provide specific dosing recommendations aimed at specific patient groups, but also the implementation of a consistent integrative approach to recognise all factors contributing to the within- and between-subject variability in drug disposition and response. The assessment of new anti-tuberculosis agents and regimens in children requires a specific programme of investigation, and should be included early in human drug evaluation programmes. Appreciation of this principle is an important step forward towards the full integration of children into the tuberculosis research agenda and control programmes. The development of anti-tuberculosis drug formulations and regimens tailored to the requirements of children needs to consider physiological age-related differences for pharmacokinetics and toxicity between adults and children. Research based on these principles will create an evidence base that will inform the appropriate treatment of children with novel agents and regimens and will also inform future research, including the use of chemoprophylaxis and treatment-shortening strategies in children. PMID- 23676165 TI - Age, nutritional status and INH acetylator status affect pharmacokinetics of anti tuberculosis drugs in children. AB - SETTING: The currently recommended dosages of rifampicin (RMP), isoniazid (INH), pyrazinamide (PZA) and ethambutol in children are extrapolated from adult pharmacokinetic studies, and have not been adequately evaluated in children. OBJECTIVE: To describe the pharmacokinetics of RMP, INH and PZA given thrice weekly in children with tuberculosis (TB), and to relate pharmacokinetics to treatment outcomes. METHODS: Eighty-four human immunodeficiency virus negative children with TB aged 1-12 years in Chennai and Madurai, India, were recruited. Phenotypic INH acetylator status was determined. Nutritional status was assessed using Z scores. During the intensive phase of anti-tuberculosis treatment, a complete pharmacokinetic study was performed after directly observed administration of drugs. At 2 and 6 months, drug levels were measured 2 h post dose. Drug concentrations were measured using high performance liquid chromatography and pharmacokinetic variables were calculated. Multivariable regression analysis was performed to explore factors impacting drug levels and treatment outcomes. RESULTS AND CONCLUSIONS: Children aged <3 years had significantly lower RMP, INH and PZA concentrations than older children, and 90% of all children had sub-therapeutic RMP Cmax (<8 MUg/ml). Age, nutritional status and INH acetylator status influenced drug levels. Peak RMP and INH concentrations were important determinants of treatment outcome. Recommendations for anti tuberculosis treatment in children should take these factors into consideration. PMID- 23676166 TI - Is a 4-month regimen adequate to cure patients with non-cavitary tuberculosis and negative cultures at 2 months? AB - A recent trial evaluating a 4-month regimen of standard drugs in adults with non cavitary tuberculosis (TB) and negative cultures at 2 months failed to demonstrate equivalence compared to the same regimen given for 6 months. To contribute further evidence, data from two trials conducted by the British Medical Research Council (BMRC) comparing 4 and 6 month regimens were re analysed. The results from the BMRC trials in patients with non-cavitary TB and negative cultures at 2 months were consistent with those from the recent trial. However, given that there was no acquired drug resistance, the estimated 6.6% relapse rate (95%CI 4.3-10.1) across all three trials might be considered acceptable for a 4-month regimen in patients with non-cavitary pulmonary TB. PMID- 23676167 TI - Pulmonary tuberculosis: the day after. AB - BACKGROUND: Tuberculosis (TB) is a widespread disease, and in spite of timely diagnosis and treatment it can permanently compromise lung function. OBJECTIVE: To study the prevalence of pulmonary impairment in cured adult pulmonary TB (PTB) patients. MATERIALS AND METHODS: Adult cured PTB patients were included in the study; those with any other condition or disease affecting lung function were excluded. After detailed history taking and examination, all patients underwent chest X-ray (CXR) and spirometry; 76 patients were investigated for pulmonary hypertension using electrocardiogram and two-dimensional echocardiogram. RESULTS AND DISCUSSION: A total of 264 patients were enrolled in the study. The majority were male and aged between 40 and 50 years. The most common complaint was cough with expectoration. CXR showed varying degrees of lung destruction, with 38% of the patients having Wilcox Grade II involvement. Spirometry was normal in 34 cases, while in the remaining cases varying degrees of obstructive airway disease with restrictive pattern and reversibility were observed. Seventy-two patients had evidence of pulmonary hypertension. These findings are comparable to those reported in the literature. CONCLUSION: PTB patients need long-term follow-up to diagnose and treat functional impairment after cure. PMID- 23676168 TI - Drug resistance among new smear-positive pulmonary tuberculosis cases in Thailand. AB - SETTING: A 1200-bed hospital in Bangkok, Thailand. OBJECTIVE: To describe pre treatment drug susceptibility patterns and determine factors predicting drug resistance in new sputum-smear positive tuberculosis (TB) patients in Thailand. DESIGN: In a retrospective cohort study from October 2007 to September 2010, clinical data on all new sputum-smear positive pulmonary TB (PTB) patients were reviewed. The pre-treatment drug susceptibility patterns and statistically significant differences in variables between groups of patients were described. RESULTS: A total of 769 new smear-positive PTB patients were included in the study. Overall rates of pre-treatment isoniazid resistance and multidrug resistant TB were respectively 11.8% and 2.5%. TB patients co-infected with the human immunodeficiency virus (HIV) had a four times greater risk of pre-treatment drug resistance than non-HIV-infected patients. No other groups of patients that needed to be prioritised for drug susceptibility testing (DST) were identified. CONCLUSION: Groups of patients to be prioritised for DST other than those with HIV infection could not be identified. PMID- 23676169 TI - Immunogenicity of dormancy-related antigens in individuals infected with Mycobacterium tuberculosis in Japan. AB - SETTING: DosR regulon genes are considered essential for Mycobacterium tuberculosis dormancy, and their products are demonstrated to have immunogenicity in M. tuberculosis-infected individuals, suggesting that DosR regulon-encoded proteins are suitable targets for vaccines to control the reactivation of dormant M. tuberculosis. OBJECTIVE: Prospective analysis of T-cell and antibody responses against DosR regulon-encoded antigens in M. tuberculosis-infected individuals in Japan to identify effective vaccine targets. DESIGN: T-cell responses against 33 DosR regulon-encoded antigens were investigated in 26 consecutive M. tuberculosis infected individuals--14 with latent tuberculosis infection (LTBI) and 12 with active pulmonary tuberculosis (PTB)--using enzyme-linked immunosorbent spot assay, and antibody responses in 42 consecutive individuals, 14 with LTBI and 28 with PTB. RESULT: Six antigens (Rv0570, Rv1996, Rv2004c, Rv2028c, Rv2029c and Rv3133c) induced stronger T-cell responses in LTBI than in PTB, In contrast, antigen-specific antibody responses to five antigens (Rv0080, Rv1738, Rv2007c, Rv2031c and Rv2032) were found to be stronger in PTB than in LTBI cases. CONCLUSION: T-cell responses to six antigens might contribute to natural protection against dormant M. tuberculosis. These antigens are therefore considered to be potential targets of novel vaccines to control M. tuberculosis reactivation in the Japanese population. PMID- 23676170 TI - Lymphocyte subpopulations in active tuberculosis: association with disease severity and the QFT-GIT assay. AB - Cell-mediated immune response plays an essential role in the pathogenesis of tuberculosis (TB). We retrospectively evaluated lymphocyte subpopulations in 177 active TB patients compared to 93 healthy controls, finding a relevant decrease in total lymphocytes and CD8+ cells. Conversely, activated human leukocyte antigen (HLA-DR+) and CD4+CD57+ cells were higher in the TB group. B-1a (CD5+CD19+) lymphocytes were reduced in TB subjects, particularly those with extended and cavitary pulmonary forms, suggesting increased compartmentalisation at the infection site. QuantiFERON-TB Gold In-Tube positive results were associated with higher HLA-DR+CD4+ and CD4+CD57+ cells, while interferon-gamma response and total lymphocyte levels were lower in advanced pulmonary TB cases. PMID- 23676171 TI - High-resolution computed tomography and health-related quality of life in Mycobacterium avium complex disease. AB - SETTING: Kyoto, Japan. OBJECTIVE: To validate the St George's Respiratory Questionnaire (SGRQ) in pulmonary Mycobacterium avium-intracellulare complex disease and to analyse the significance of high-resolution computed tomography (HRCT) findings as determinants of health-related quality of life (HRQoL) after adjusting for clinical and physiological parameters. DESIGN: Eighty-five patients completed the SGRQ, pulmonary function tests and other patient-reported measurements. HRCT findings were assessed using an established computed tomography (CT) scoring method. RESULTS: The SGRQ was validated with good internal consistency, test-retest reliability and significant correlations with most physiological variables and other patient-reported measurements. White blood cell counts, C-reactive protein levels, sputum culture results, treatment history, total CT scores, and consolidation, cavity and lobar volume-decrease CT component scores were significantly correlated with the SGRQ total and component scores. Stepwise multiple regression analyses revealed that the consolidation, cavity and lobar volume-decrease component scores were correlated with the SGRQ total and/or component scores. The total CT scores had the strongest relationships with the SGRQ total scores among the various clinical parameters tested, including microbiological, radiological, physiological and laboratory findings (32.8% of variance). CONCLUSION: HRCT findings, particularly consolidation, cavity and lobar volume-decreases, were the most significant clinical parameters related to patient HRQoL. PMID- 23676172 TI - Geographical distribution and clinical relevance of non-tuberculous mycobacteria in Croatia. AB - SETTING: The clinical relevance of non-tuberculous mycobacteria (NTM) in Croatia is unknown. OBJECTIVE: To estimate the isolation rate of NTM, record geographical differences and assess the burden of pulmonary NTM disease in Croatia. DESIGN: Nationwide retrospective cohort study of all Croatian residents with NTM isolated by culture in the period from 2006 to 2010. Microbiological criteria of the American Thoracic Society were used to establish a laboratory-based case definition of possible and probable NTM disease. RESULTS: Of 1187 individuals with pulmonary NTM isolates, 8.6% met the possible and 5.5% met the probable disease criteria. We estimated an annual incidence of probable pulmonary NTM disease of 0.23 per 100,000 population. This estimated annual incidence was 0.35/100,000 in the coastal region and 0.17/100,000 in the continental region. Species distribution differed between coastal and continental Croatia. NTM isolation frequency increased over the study period. CONCLUSION: Geography plays an important role in NTM species distribution and possible disease. The overall burden of NTM pulmonary disease in Croatia is still low compared to that of tuberculosis, but it is higher in the coastal region compared to the continental region. PMID- 23676173 TI - Czech adolescent smokers: unhappy to smoke but unable to quit. AB - OBJECTIVE: To assess the prevalence of tobacco dependence among adolescents in the Czech Republic in 2010, their willingness to quit and knowledge about quitting options. METHODS: Primary, intermediate and secondary school students completed an anonymous questionnaire on tobacco use during a smoking prevention class, with a response rate of 100%. RESULTS: Of 1420 anonymous questionnaires analysed, 66.8% (n = 949) of respondents had ever tried smoking. More were from smoking (50.4%) than non-smoking (49.6%) families; there were no differences in sex. Most student smokers had experimented with cigarettes (94.6%), cigars (8%), marihuana cigarettes (4.6%) and water pipes (1.9%). At the time of the survey, 52.9% (520/949) of those who had ever tried smoking were current smokers, 30.3% smoked daily, 18.3% weekly and 4.2% less frequently. Only 20.5% of smokers had not considered quitting, and 66.9% had tried unsuccessfully to quit. Withdrawal symptoms were experienced by 24.5% (123/502) of the current smokers, indicating a high level of nicotine dependence in this age group. The majority (346/467, 74.1%) of the current smokers said they would stop smoking immediately on their own. Only a few would seek help at a pharmacy (4.9%), 3.4% would ask their doctor and 1.7% their parents. CONCLUSIONS: Tobacco dependence is prevalent among Czech adolescents. The majority of smokers wanted to stop, but knowledge about smoking cessation and quitting assistance offered to smokers was low. PMID- 23676174 TI - Current epidemiology of childhood tuberculous meningitis in Greece: a 10-year population-based study. PMID- 23676175 TI - Pulmonary tuberculosis in a 4-month-old twin: hereditary versus environmental factors. PMID- 23676176 TI - Detection of and treatment protocol for rifampicin-monoresistant tuberculosis: what is the role of isoniazid? PMID- 23676177 TI - Improvement in tubercular cavities following adjuvant treatment with endobronchial valves: a case report. PMID- 23676178 TI - Evidence for wave heating in the solar corona. AB - The temperature of the Sun increases over a short distance from a few thousand degrees in the photosphere to over a million degrees in the corona. To understand coronal heating is one of the major problems in astrophysics. There is general agreement that the energy source is convective motion in and below the photosphere. It remains to determine how this mechanical energy is transported outward into the corona and then deposited as heat. Two classes of models have been proposed, namely those that rely on magnetic reconnection and those that rely on waves, particularly Alfven waves. There is increasing evidence that waves are ubiquitous in the corona. However, a difficulty for wave-driven models has been that most theories predict Alfven waves to be undamped in the corona, and therefore they cannot dissipate their energy into heat. Our research has shown unambiguous observational evidence that the waves do damp at sufficiently low heights in the corona to be important for coronal heating. PMID- 23676179 TI - Frameworks for learner assessment in medicine: AMEE Guide No. 78. AB - In any evaluation system of medical trainees there is an underlying set of assumptions about what is to be evaluated (i.e., which goals reflect the values of the system or institution), what kind of observations or assessments are useful to allow judgments 1 ; and how these are to be analyzed and compared to a standard of what is to be achieved by the learner. These assumptions can be conventionalized into a framework for evaluation. Frameworks encompass, or "frame," a group of ideas or categories to reflect the educational goals against which a trainee's level of competence or progress is gauged. Different frameworks provide different ways of looking at the practice of medicine and have different purposes. In the first place, frameworks should enable educators to determine to what extent trainees are ready for advancement, that is, whether the desired competence has been attained. They should provide both a valid mental model of competence and also terms to describe successful performance, either at the end of training or as milestones during the curriculum. Consequently, such frameworks drive learning by providing learners with a guide for what is expected. Frameworks should also enhance consistency and reliability of ratings across staff and settings. Finally, they determine the content of, and resources needed for, rater training to achieve consistency of use. This is especially important in clinical rotations, in which reliable assessments have been most difficult to achieve. Because the limitations of workplace-based assessment have persisted despite the use of traditional frameworks (such as those based on knowledge, skills, and attitudes), this Guide will explore the assumptions and characteristics of traditional and newer frameworks. In this AMEE Guide, we make a distinction between analytic, synthetic, and developmental frameworks. Analytic frameworks deconstruct competence into individual pieces, to evaluate each separately. Synthetic frameworks attempt to view competence holistically, focusing evaluation on the performance in real-world activities. Developmental frameworks focus on stages of, or milestones, in the progression toward competence. Most frameworks have one predominant perspective; some have a hybrid nature. PMID- 23676180 TI - Empathy amongst medical students. PMID- 23676181 TI - DSM-5: the debate continues. AB - We are fortunate to have invited commentaries from the laboratories of Dr Cathy Lord and Dr Fred Volkmar offering their perspectives on the new Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria for the autism spectrum. Both commentaries note how DSM-5 collapses the earlier diagnostic categories of the pervasive developmental disorders into a single category of autism spectrum disorder. In addition, DSM-5 collapses social and communication domains into a single combined domain. The commentaries go on to discuss the positive aspects of these changes and raise some areas of potential concern. We support the evidence based changes to autism diagnosis found in DSM-5, and look forward to further studies on the autism phenotype as this has implications for diagnosis and treatment. As our mechanistic understanding of autism improves, diagnoses based on behavioral parameters will continue to provide opportunities for interventions targeting the behaviors, while etiological diagnoses will provide opportunities for interventions tailored to etiology. PMID- 23676182 TI - Gas purification by nonthermal plasma: a case study of ethylene. AB - The destruction of ethylene in a dielectric barrier discharge plasma is investigated by the combination of kinetic modeling and experiments, as a case study for plasma-based gas purification. The influence of the specific energy deposition on the removal efficiency and the selectivity toward CO and CO2 is studied for different concentrations of ethylene. The model allows the identification of the destruction pathway in dry and humid air. The latter is found to be mainly initiated by metastable N2 molecules, but the further destruction steps are dominated by O atoms and OH radicals. Upon increasing air humidity, the removal efficiency drops by +/- 15% (from 85% to 70%), but the selectivity toward CO and CO2 stays more or less constant at 60% and 22%, respectively. Beside CO and CO2, we also identified acetylene, formaldehyde, and water as byproducts of the destruction process, with concentrations of 1606 ppm, 15033 ppm, and 185 ppm in humid air (with 20% RH), respectively. Finally, we investigated the byproducts generated by the humid air discharge itself, which are the greenhouse gases O3, N2O, and the toxic gas NO2. PMID- 23676183 TI - Effects of high-density lipoprotein elevation with cholesteryl ester transfer protein inhibition on insulin secretion. AB - RATIONALE: High-density lipoprotein cholesterol elevation via cholesteryl ester transfer protein (CETP) inhibition represents a novel therapy for atherosclerosis, which also may have relevance for type 2 diabetes mellitus. OBJECTIVE: The current study assessed the effects of a CETP inhibitor on postprandial insulin, ex vivo insulin secretion, and cholesterol efflux from pancreatic beta-cells. METHODS AND RESULTS: Healthy participants received a daily dose of CETP inhibitor (n=10) or placebo (n=15) for 14 days in a randomized double-blind study. Insulin secretion and cholesterol efflux from MIN6N8 beta cells were determined after incubation with treated plasma. CETP inhibition increased plasma high-density lipoprotein cholesterol, apolipoprotein AI, and postprandial insulin. MIN6N8 beta-cells incubated with plasma from CETP inhibitor treated individuals (compared with placebo) exhibited an increase in both glucose stimulated insulin secretion and cholesterol efflux over the 14-day treatment period. CONCLUSIONS: CETP inhibition increased postprandial insulin and promoted ex vivo beta-cell glucose-stimulated insulin secretion, potentially via enhanced beta-cell cholesterol efflux. PMID- 23676184 TI - Link between relationship violence and depression works both ways. PMID- 23676185 TI - Confirmatory factor analysis of the Behavior Rating Inventory of Executive Function-Adult version in healthy adults and application to attention deficit/hyperactivity disorder. AB - The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) is a questionnaire measure designed to assess executive functioning in everyday life. Analysis of data from the BRIEF-A standardization sample yielded a two-factor solution (labeled Behavioral Regulation and Metacognition). The present investigation employed confirmatory factor analysis (CFA) to evaluate four alternative models of the factor structure of the BRIEF-A self-report form in a sample of 524 healthy young adults. Results indicated that a three-factor model best fits the data: a Metacognition factor, a Behavioral Regulation factor consisting of the Inhibit and Self-Monitor scales, and an Emotional Regulation factor composed of the Emotional Control and Shift scales. The three factors contributed 14%, 19%, and 24% of unique variance to the model, respectively, and a second-order general factor accounted for 41% of variance overall. This three factor solution is consistent with recent CFAs of the Parent report form of the BRIEF. Furthermore, although the Behavioral Regulation factor score in the two factor model did not differ between adults with attention-deficit/hyperactivity disorder and a matched healthy comparison group, greater impairment on the Behavioral Regulation factor but not the Emotional Regulation factor was found using the three-factor model. Together, these findings support the multidimensional nature of executive function and the clinical relevance of a three-factor model of the BRIEF-A. PMID- 23676186 TI - Effect of a clinical pathway on length of stay and cost of pediatric inpatient asthma admissions: an integrative review. AB - Asthma is the leading cause of pediatric hospital admissions in the United States. In response to the high prevalence of asthma and the variations in care, clinical practice guidelines have been developed and recommend the use of a clinical pathway for inpatient management. This review will examine the effects of a pediatric asthma clinical pathway on inpatient stays, specifically the length of stay (LOS) and cost of inpatient admissions. A literature review was performed to identify original research projects examining the effects of an asthma clinical pathway on inpatient pediatric admissions. Nine studies were found to fit the criteria and are included in this review. These nine studies found consistent evidence that the use of an asthma clinical pathway for inpatient asthma admissions resulted in reduced LOS and cost. PMID- 23676187 TI - Women who sexually offend display three main offense styles: a reexamination of the descriptive model of female sexual offending. AB - This study examined a theory constructed to describe the offense process of women who sexually offend-the Descriptive Model of Female Sexual Offending (DMFSO). In particular, this report sets out to establish whether the original three pathways (or offending styles) identified within United Kingdom convicted female sexual offenders and described within the DMFSO (i.e., Explicit-Approach, Directed Avoidant, Implicit-Disorganized) were applicable to a small sample (N = 36) of North American women convicted of sexual offending. Two independent raters examined the offense narratives of the sample and-using the DMFSO-coded each script according to whether it fitted one of the three original pathways. Results suggested that the three existing pathways of the DMFSO represented a reasonable description of offense pathways for a sample of North American women convicted of sexual offending. No new pathways were identified. A new "Offense Pathway Checklist" devised to aid raters' decision making is described and future research and treatment implications explored. PMID- 23676188 TI - Ethosomes in hair dye products as carriers of the major compounds of black tea extracts. AB - OBJECTIVES: This study describes a novel carrier, the ethosome-based system, which is composed of non-ionic surfactants, ethanol, and water. METHODS: Brij((r)) 52 (non-ionic surfactants), soya phosphatidylcholine (PC), cholesterol, and the major compounds (caffeine and gallic acid) of black tea extracts were dissolved in the ethanolic phase. The aqueous phase containing Paragon III was heated to 60 degrees C and mixed with the previous solution. Finally, 3.4 ml NaOH (6.5 N) was added to adjust the pH level to 4.05. The mixture was centrifuged at 2000 g for two minutes, and the precipitate was taken as the end product. Black tea extracts were applied in ethosome-based formulations, and the efficacy of these formulations in penetrating nude mouse skin and in dyeing white hairs was investigated. RESULTS: Compared with an ethanolic solution and black tea extracts, the non-ionic ethosomal delivery system dramatically enhanced the adsorption of black tea extracts onto hair surfaces in vitro. The non-ionic ethosomal system was much more efficient in delivering and facilitating the adsorption of black tea extracts to the hair surface than hydroalcoholic black tea extracts. CONCLUSIONS: This formulation may have potential for development as a hair dye and protective agent. PMID- 23676189 TI - Exploration of the mechanisms by which 3,4-benzopyrene promotes angiotensin II induced abdominal aortic aneurysm formation in mice. AB - OBJECTIVE: This study examined the influence of 3,4-benzopyrene (BaP), a compound found in cigarette smoke, on the formation of angiotensin II (Ang II)-induced abdominal aortic aneurysm (AAA) formation in mice and the underlying mechanisms. METHODS: C57/B6n mice were divided into four groups. The control group received a weekly intraperitoneal injection of medium-chain triglycerides. The Ang II group received a daily Ang II infusion (0.72 mg/kg) and a weekly intraperitoneal injection of medium-chain triglycerides. The Ang II/BaP group received a daily Ang II infusion (0.72 mg/kg) and a weekly intraperitoneal BaP injection (10 mg/kg, dissolved in medium-chain triglycerides). The BaP group received a weekly intraperitoneal BaP injection (10 mg/kg). After 5 weeks, abdominal aortic diameter was determined. Aortic tissues underwent hematoxylin and eosin, Masson, and immunochemistry staining for evaluation of vascular wall structure, collagen, macrophage infiltration, matrix metalloproteinases (MMPs), and apoptosis. RESULTS: The Ang II infusion and BaP injection induced AAAs in 41.67% of mice vs 25% in the Ang II group (P < .05). The average aortic diameter increased in the Ang II/BaP group compared with the Ang II group (1.40 +/- 0.25 vs 1.2 +/- 0.23 mm; P < .05). Average aortic muscular cell apoptosis was higher in the Ang II/BaP group (31% +/- 12%) than in the Ang II (19% +/- 5%; P < .05) or BaP groups (23% +/- 4%; P < .05). Aortic macrophage infiltration and expression of MMP-2, MMP-9, MMP-12, and nuclear factor-kappaB increased (0.56 +/- 0.12, 0.47 +/- 0.13, 0.49 +/- 0.14, 0.49 +/- 0.11, and 0.42 +/- 0.12, respectively) in the Ang II/BaP group compared with the Ang II group (0.27 +/- 0.08, 0.25 +/- 0.06, 0.24 +/- 0.09, 0.24 +/- 0.09, and 0.23 +/- 0.06, respectively; P < .05 for all). CONCLUSIONS: BaP promotes Ang II-induced AAA formation in mice via elevating infiltration of macrophages, activating nuclear factor-kappaB, upregulating the expression of MMP 2, MMP-9, and MMP-12, and increasing the apoptosis of vascular muscle cells in its synergistic effect with Ang II in aortic wall. PMID- 23676190 TI - Development of a risk index for prediction of mortality after open aortic aneurysm repair. AB - OBJECTIVE: Open infrarenal abdominal aortic aneurysm (oAAA) repair is associated with significant morbidity and mortality. Although there has been a shift toward endovascular repair, many patients continue to undergo an open repair due to anatomic considerations. Tools currently existing for estimation of periprocedural risk in patients undergoing open aortic surgery have certain limitations. The objective of this study was to develop a risk index to estimate the risk of 30-day perioperative mortality after elective oAAA repair. METHODS: Patients who underwent elective oAAA repair (n = 2845) were identified from the American College of Surgeons' 2007 to 2009 National Surgical Quality Improvement Program (NSQIP), a prospective database maintained at >250 centers. Univariable and multivariable analyses were performed to evaluate risk factors associated with 30-day mortality after oAAA repair and a risk index was developed. RESULTS: The 30-day mortality after oAAA repair was 3.3%. Multivariable analysis identified six preoperative predictors of mortality, and a risk index was created by assigning weighted points to each predictor using the beta-coefficients from the regression analysis. The predictors included dyspnea (at rest: 8 points; on moderate exertion: 2 points; none: 0 points), history of peripheral arterial disease requiring revascularization or amputation (3 points), age >65 years (3 points), preoperative creatinine >1.5 mg/dL (2 points), female gender (2 points), and platelets <150,000/mm(3) or >350,000/mm(3) (2 points). Patients were classified as low (<7%), intermediate (7%-15%), and high (>15%) risk for 30-day mortality based on a total point score of <8, 8 to 11, and >11, respectively. There were 2508 patients (88.2%) patients in the low-risk category, 278 (9.8%) in the intermediate-risk category, and 59 (2.1%) in the high-risk category. CONCLUSIONS: This risk index has excellent predictive ability for mortality after oAAA repair and awaits validation in subsequent studies. It is anticipated to aid patients and surgeons in informed patient consent, preoperative risk assessment, and optimization. PMID- 23676191 TI - Three-year results of the VIBRANT trial of VIABAHN endoprosthesis versus bare nitinol stent implantation for complex superficial femoral artery occlusive disease. AB - OBJECTIVE: The predominant mode of bare nitinol stent failure is diffuse in-stent restenosis, and failure rates correlate to the length and complexity of the treated lesion. Addition of an expanded polytetrafluoroethylene lining to a nitinol stent frame, as found in the VIABAHN endoprosthesis, mitigates the ingrowth of intimal hyperplasia. We compared the long-term outcomes of complex superficial femoral artery disease intervention using the VIABAHN endoprosthesis to those obtained with bare nitinol stent implantation. METHODS: One hundred forty-eight patients with symptomatic complex superficial femoral artery disease (TransAtlantic Inter-Society Consensus I class C and D lesions, accompanied by intermittent claudication or ischemic rest pain) were randomized to endovascular intervention using either bare nitinol stent implantation (76 patients) or nonheparin-bonded VIABAHN endoprosthesis deployment (72 patients). Patency, limb hemodynamics, and quality of life were evaluated at 1, 6, 12, 24, and 36 months following intervention. RESULTS: The average treated lesion measured 18 +/- 8 cm in length, and 58.8% of lesions displayed segmental or complete occlusion. At 3 years, primary patency rates (defined by peak systolic velocity ratio <= 2.0 and no target lesion revascularization) did not significantly differ between patients treated with the VIABAHN stent graft and those who received a bare nitinol stent (24.2% vs 25.9%; P = .392). Stent fractures were significantly more common in bare nitinol stents (50.0%) than in the VIABAHN endoprostheses (2.6%). Primary assisted patency rates were higher in those receiving bare nitinol stents than the VIABAHN stent graft (88.8% vs 69.8%; P = .04), although secondary patency rates did not differ between bare nitinol stent and stent graft recipients (89.3% vs 79.5%; P = .304). There were no instances of procedure-related mortality or amputation. The hemodynamic improvement and quality measures improved equally in both groups. CONCLUSIONS: The long-term outcomes of complex superficial femoral artery disease intervention using the VIABAHN endograft and bare nitinol stents are similar. Although primary patency rates are low in both study arms, excellent primary-assisted and secondary patency rates were achieved, with sustained augmentation of limb perfusion and quality-of-life measures. Patency rates diminish most rapidly in the first year after device implantation. PMID- 23676192 TI - Dance recognition system using lower body movement. AB - The current means of locating specific movements in film necessitate hours of viewing, making the task of conducting research into movement characteristics and patterns tedious and difficult. This is particularly problematic for the research and analysis of complex movement systems such as sports and dance. While some systems have been developed to manually annotate film, to date no automated way of identifying complex, full body movement exists. With pattern recognition technology and knowledge of joint locations, automatically describing filmed movement using computer software is possible. This study used various forms of lower body kinematic analysis to identify codified dance movements. We created an algorithm that compares an unknown move with a specified start and stop against known dance moves. Our recognition method consists of classification and template correlation using a database of model moves. This system was optimized to include nearly 90 dance and Tai Chi Chuan movements, producing accurate name identification in over 97% of trials. In addition, the program had the capability to provide a kinematic description of either matched or unmatched moves obtained from classification recognition. PMID- 23676194 TI - A model for multiphoton absorption in dielectric materials induced by short laser pulses at moderate intensities. AB - We present a semi-analytical model for free electron production induced by multiphoton ionization in dielectric materials for short laser pulses at moderate intensities. Within this approach, the laser-induced absorption is described through the Bloch-Volkov formalism, and the electronic structure of materials is evaluated through first-principles calculations. Results obtained for NaCl and KDP (KH2PO4) materials show that significant deviations from the parabolic band approximation may occur. When the laser intensity increases, high multiphotonic orders may become the predominant mechanisms outside the centre of the Brillouin zone. PMID- 23676193 TI - Functional genomics lead to new therapies in follicular lymphoma. AB - Recent technological advances allow analysis of genomic changes in cancer in unprecedented detail. The next challenge is to prioritize the multitude of genetic aberrations found and identify therapeutic opportunities. We recently completed a study that illustrates the use of unbiased genetic screens and murine cancer models to find therapeutic targets among complex genomic data. We genetically dissected the common deletion of chromosome 6q and identified the ephrin receptor A7 (EPHA7) as a tumor suppressor in lymphoma. Notably, EPHA7 encodes a soluble splice variant that acts as an extrinsic tumor suppressor. Accordingly, we developed an antibody-based strategy to specifically deliver EPHA7 back to tumors that have lost this gene. Recent sequencing studies have implicated EPHA7 in lung cancer and other tumors, suggesting a broader therapeutic potential for antibody-mediated delivery of this tumor suppressor for cancer therapy. Together, our comprehensive approach provides new insights into cancer biology and may directly lead to the development of new cancer therapies. PMID- 23676195 TI - Strategies for specifically directing metal functionalization of protein nanotubes: constructing protein coated silver nanowires. AB - Biological molecules that self-assemble in the nanoscale range are useful multifunctional materials. Rotavirus VP6 protein self-assembles into tubular structures in the absence of other rotavirus proteins. Here, we present strategies for selectively directing metal functionalization to the lumen of VP6 nanotubes. The specific in situ metal reduction in the inner surface of nanotube walls was achieved by the simple modification of a method previously reported to functionalize the nanotube outer surface. Silver nanorods and nanowires as long as 1.5 MUm were formed inside the nanotubes by coalescence of nanoparticles. Such one-dimensional structures were longer than others previously obtained using bioscaffolds. The interactions between silver ions and the nanotube were simulated to understand the conditions that allowed nanowire formation. Molecular docking showed that a naturally occurring arrangement of aspartate residues enabled the stabilization of silver ions on the internal surface of the VP6 nanotubes. This is the first time that such a spatial arrangement has been proposed for the nucleation of silver nanoparticles, opening the possibility of using such an array to direct functionalization of other biomolecules. These results demonstrate the natural capabilities of VP6 nanotubes to function as a versatile biotemplate for nanomaterials. PMID- 23676196 TI - Naturalistic outcomes of community treatment orders: antipsychotic long-acting injections versus oral medication. AB - BACKGROUND: Community treatment orders (CTOs) are initiated to compel the patient in the community to take part in a management plan, of which medication is often a part. CTOs were introduced in 2008, in England and Wales. We evaluated naturalistic outcomes of CTOs, according to the antipsychotic formulation prescribed at CTO initiation. METHODS: A cohort study with prospective consecutive sampling and 1-year follow-up was conducted in a large mental health trust in South London. Measures included: demographics, psychotropics and CTO outcomes. Comparison groups were long-acting injection (LAI) versus oral formulations only, for the primary outcomes of time to CTO cessation in days and time to first hospital admission in days, whilst the CTO remained active. RESULTS: For the 188 included patients, the CTO ceased within 1 year, either due to revocation (22.3%), discharge (28.1%) or lapse (19.7%). The CTO was renewed at 6 months for 92 (48.9%) patients, and then 56 (29.8%) were renewed again at 12 months. The antipsychotic formulation at CTO initiation was more likely to be LAI (60.6%) than oral (39.4%). Time to CTO cessation was longer for LAI than oral (median 251 versus 182 days, p = 0.030). A total of 54 patients experienced at least one admission; there was no difference between groups by drug formulation (oral 28.4% versus LAI 28.9%, p = 0.933). The mean time to first admission was 147.1 days and did not differ by formulation. CONCLUSIONS: CTO duration was longer for those prescribed an antipsychotic LAI at CTO initiation, although the time to first admission and number of admissions did not differ between groups. CTOs not only compel treatment, but bind services to the patient, resulting in more intensive follow up. Whether enhanced treatment, via oral or LAI and enabled by the CTO, translates into improved clinical outcomes is yet to be determined. PMID- 23676197 TI - Quantitative damage-benefit evaluation of drug effects: major discrepancies between the general population, users and experts. AB - AIMS: This study sought to quantify the perceptions of damage and benefit, for users and society, associated with five addictive substances (alcohol, tobacco, cannabis, cocaine and heroin) and one addictive behavior (gambling), in a large sample representative of the French population. We compared with expert assessments and investigated the effects of substance consumption on these perceptions. FINDINGS: The ranking of substances by the lay public is very divergent from that of experts. The public overestimates damage to users and to society and underestimates the benefit, in comparison with experts, for all substances. Alcohol is the only exception, with damage and benefit perceptions similar to those of experts. Heroin and cocaine are perceived as the two most dangerous substances. The damage of cannabis and alcohol are judged to be equivalent. The three legal substances are associated with the highest overall benefit, although cannabis has the highest perceived benefit for users. Substances with the highest perceived benefit tend to be associated with perception of lower levels of damage. Individuals with an history of substance use have a perception of the damage and the benefit for that substance which is more congruent with experts, including a similar ranking of substances. CONCLUSIONS: Prevention campaigns focused on perceptions of damage alone have reached their limits. The perception of benefit should be taken into account in early interventions with illegal substance users. PMID- 23676198 TI - Two cases of delayed-onset suicidal ideation, dysphoria and anxiety after ketamine infusion in patients with obsessive-compulsive disorder and a history of major depressive disorder. AB - Ketamine is a non-competitive N-methyl-D-aspartate receptor antagonist that is Food and Drug Administration-approved in the United States for anesthesia due to its sedative effects with low risk of severe respiratory depression. Subanesthetic dose intravenous ketamine has rapidly acting antidepressant effects in treatment-resistant unipolar and bipolar depression. We recently reported an open-label trial of ketamine in 10 subjects with treatment-refractory obsessive compulsive disorder, seven of whom had active comorbid depression. Although ketamine had no sustained anti-obsessive effect, four of the seven subjects with comorbid depression experienced an acute antidepressant effect. However, we unexpectedly observed delayed-onset dysphoria, worsening anxiety and suicidal thinking in two of the three subjects with obsessive-compulsive disorder and extensive psychiatric comorbidity but minimal depressive symptoms at the start of infusion. The implications of these adverse neuropsychiatric effects in two patients with similar psychiatric comorbidity are discussed. We conclude that there remains insufficient data on therapeutic ketamine in the presence of comorbid psychiatric disorders to promote its off-label use in a non-research milieu. PMID- 23676199 TI - Computational simulation of convection-enhanced drug delivery in the non-human primate brainstem: a simple model predicting the drug distribution. AB - OBJECTIVES: Convection-enhanced delivery (CED) is a technique that delivers therapeutic agents directly and effectively into the brain parenchyma. Application of CED is now under investigation as a new treatment for various diseases. Diffuse brainstem glioma is one of the important candidates that could be targeted with CED. Especially when targeting brainstem lesions, prediction of drug distribution prior to CED will be necessary. This study evaluated the computational simulation of CED in the primate brainstem using a simplified model. METHODS: Three in vivo experiments infusing gadolinium solution into the non-human primate brainstem were analyzed. T1-weighted magnetic resonance (MR) images were acquired during infusion of a total of 300 MUl gadolinium solution. Computational simulation reconstructed the surface geometry of the brainstem from the MR images. The volume of the whole structure was meshed by grid generating software. Under the assumptions that the brainstem surface was rigid and the interior was filled with cerebrospinal fluid, the equations of continuity and Darcy's law were solved within a computational fluid dynamics package using a finite volume method. The results of computational simulations were compared with those of the in vivo experiments. RESULTS: The distribution volume (Vd) in the simulations corresponded well with the in vivo experiments. Under the condition without massive 'catheter back flow', computational simulations predicted almost 70% of the Vd of the in vivo experiments. CONCLUSIONS: The simplified computational simulations were consistent with the experiments in vivo. The methodology used in this study can be applied to predict convective drug distribution in the primate brainstem. PMID- 23676200 TI - NR2A- and NR2B-containing NMDA receptors in the prelimbic medial prefrontal cortex differentially mediate trace, delay, and contextual fear conditioning. AB - Activation of N-methyl-D-aspartate receptors (NMDAR) in the prelimbic medial prefrontal cortex (PL mPFC) is necessary for the acquisition of both trace and contextual fear memories, but it is not known how specific NR2 subunits support each association. The NR2B subunit confers unique properties to the NMDAR and may differentially regulate these two fear memories. Here we show that NR2A containing NMDARs mediate trace, delay, and contextual fear memories, but NR2B containing NMDARs are required only for trace conditioning, consistent with a role for PL mPFC in working memory. PMID- 23676201 TI - Differential recruitment of distinct amygdalar nuclei across appetitive associative learning. AB - The amygdala is important for reward-associated learning, but how distinct cell groups within this heterogeneous structure are recruited during appetitive learning is unclear. Here we used Fos induction to map the functional amygdalar circuitry recruited during early and late training sessions of Pavlovian appetitive conditioning. We found that a number of distinct amygdalar nuclei were differentially recruited by tone-food pairings during the early and late stages of training, suggesting evidence of learning-induced plasticity. Notably, these selectively activated nuclei belong to dissociable subsystems that are well placed to simultaneously inform cortical (cognitive) processing and behavioral control during tone-food learning. PMID- 23676202 TI - 17beta-estradiol is necessary for extinction of cocaine seeking in female rats. AB - Human and preclinical models of addiction demonstrate that gonadal hormones modulate acquisition of drug seeking. Little is known, however, about the effects of these hormones on extinction of drug-seeking behavior. Here, we investigated how 17beta-estradiol (E2) affects expression and extinction of cocaine seeking in female rats. Using a conditioned place preference (CPP) paradigm, ovariectomized rats were maintained throughout conditioning with 2 d of E2 treatment followed by 2 d of vehicle treatment, or were injected with E2 daily. Hormone injections were paired or explicitly unpaired with place conditioning sessions. Expression of a cocaine CPP was of equal magnitude regardless of conditioning protocol, suggesting that E2 levels during conditioning did not affect subsequent CPP expression. During extinction, daily E2 administration initially enhanced expression of the cocaine CPP, but resulted in significantly faster extinction compared to controls. Whereas E2-treated rats were extinguished within 8 d, vehicle-treated rats maintained CPP expression for more than a month, indicative of perseveration. To determine whether E2 could rescue extinction in these rats, half were given daily E2 treatment and half were given vehicle. E2-treated rats showed rapid extinction, whereas vehicle-treated rats continued to perseverate. These data demonstrate for the first time that E2 is necessary for extinction of cocaine seeking in female rats, and that it promotes rapid extinction when administered daily. Clinically, these findings suggest that monitoring and maintaining optimal E2 levels during exposure therapy would facilitate therapeutic interventions for female cocaine addicts. PMID- 23676203 TI - Effects of the updated national emission regulation in China on circulating fluidized bed boilers and the solutions to meet them. AB - The advantage of circulating fluidized bed (CFB) boilers in China is their ability to utilize low rank coal with low cost emission control. However, the new National Emission Regulation (NER) issued in early 2012 brings much more stringent challenges on the CFB industries, which also causes much attention from other countries. Based on the principle of a CFB boiler and previous operating experience, it is possible for the CFB boilers to meet the new NER and maintain the advantage of low cost emission control, while, more influences should be considered in their design and operation. To meet the requirement of the new NER, the fly ash collector should adopt a bag house or combination of electrostatic precipitator and bag filter to ensure dust emissions of less than 30 mg . Nm(-3). For SO2 emission control, the bed temperature should be strictly lower than 900 degrees C to maintain high reactivity and pores. The limestone particle size distribution should be ranged within a special scope to optimize the residence time and gas-solid reaction. At the same time, the injecting point should be optimized to ensure fast contact of lime with oxygen. In such conditions, the desulfurization efficiency could be increased more than 90%. For lower sulfur content fuels (<1.5%, referred value based on the heating value of standard coal of China), increasing Ca/S enough could decrease SO2 emissions lower than that of the new NER, 100 mg . Nm(-3). For fuels with sulfur content higher than 1.5%, some simplified systems for flue gas desulfurization, such as flash dryer absorber (FDA), are needed. And the NOx emissions of a CFB can be controlled to less than 100 mg . Nm(-3) without any equipment at a bed temperature lower than 900 degrees C for fuels with low volatiles content (<12%), while for fuels with high volatiles, selective non-catalytic reduction (SNCR) should be considered. Due to the unique temperature in CFB as well as the circulating ash, the efficiency of SNCR could reach as high as 70%. The Hg emission of CFB is very low for the new NER due to its innate property. PMID- 23676204 TI - Concentration and excitation effects on the exciton dynamics of poly(3 hexylthiophene)/PbS quantum dot blend films. AB - The dynamics of photoexcitations in hybrid blends of poly(3-hexylthiophene) (P3HT) conjugated polymer donor and oleic-acid capped lead sulfide (PbS) quantum dot (QD) acceptors of different concentrations-for light harvesting applications were investigated using time-resolved transmission and photoluminescence spectroscopies. Following excitation at 400 nm and probing in the 500-1000 nm region, we find that geminate excitation recombination in the blend of P3HT/PbS QDs dominates the transient decays at sub-ns times while intermaterial interactions such as charge transfer processes appear at longer times in the 1-50 ns regime. For the hybrid blend films with lower QD concentrations (<67% wt), polymer exciton recombination dominates the overall transient absorption signal. For higher QD contents, QD state relaxation effects become visible. Excitation density studies reveal the presence of linear exciton relaxation effects in the P3HT region while carrier decay for films with high PbS QD concentration is influenced by QD Auger recombination. Time-resolved luminescence shows that electron transfer from the P3HT/PbS QDs appears relatively inefficient in comparison to the geminate recombination, while hole transfer competes favorably to intrinsic QD recombination. PMID- 23676206 TI - Competing exchanges and spin-phonon coupling in Eu(1-x)R(x)MnO3 (R=Y, Lu). AB - This work is focused on the phase diagrams and physical properties of Y-doped and Lu-doped EuMnO3. The differences in the corresponding phase boundaries in the (x,T) phase diagram could be overcome by considering a scaling of the Y(3+) and Lu(3+) concentrations to the tolerance factor. This outcome evidences that the tolerance factor is in fact a more reliable representative of the lattice deformation induced by doping. The normalization of the phase boundaries using the tolerance factor corroborates previous theoretical outcomes regarding the key role of competitive FM and AFM exchanges in determining the phase diagrams of manganite perovskites. However, significant differences in the nature and number of phases at low temperatures and concentrations could not be explained by just considering the normalization to the tolerance factor. The vertical phase boundary observed just for Lu-doped EuMnO3, close to 10% Lu, is understood by considering a low temperature Peierls-type spin-phonon coupling, which stabilizes the AFM-4 phase in Lu-doped EuMnO3. PMID- 23676205 TI - Improving the pharmacokinetic properties of biologics by fusion to an anti-HSA shark VNAR domain. AB - Advances in recombinant antibody technology and protein engineering have provided the opportunity to reduce antibodies to their smallest binding domain components and have concomitantly driven the requirement for devising strategies to increase serum half-life to optimise drug exposure, thereby increasing therapeutic efficacy. In this study, we adopted an immunization route to raise picomolar affinity shark immunoglobulin new antigen receptors (IgNARs) to target human serum albumin (HSA). From our model shark species, Squalus acanthias, a phage display library encompassing the variable binding domain of IgNAR (VNAR) was constructed, screened against target, and positive clones were characterized for affinity and specificity. N-terminal and C-terminal molecular fusions of our lead hit in complex with a naive VNAR domain were expressed, purified and exhibited the retention of high affinity binding to HSA, but also cross-selectivity to mouse, rat and monkey serum albumin both in vitro and in vivo. Furthermore, the naive VNAR had enhanced pharmacokinetic (PK) characteristics in both N- and C terminal orientations and when tested as a three domain construct with naive VNAR flanking the HSA binding domain at both the N and C termini. Molecules derived from this platform technology also demonstrated the potential for clinical utility by being available via the subcutaneous route of delivery. This study thus demonstrates the first in vivo functional efficacy of a VNAR binding domain with the ability to enhance PK properties and support delivery of multifunctional therapies. PMID- 23676207 TI - Associations of prenatal maternal smoking with offspring hyperactivity: causal or confounded? AB - BACKGROUND: The relationship between prenatal tobacco exposure and hyperactivity remains controversial. To mitigate limitations of prior studies, we used a strategy involving comparison of maternal and paternal smoking reports in a historical sample where smoking during pregnancy was common. METHOD: Data were drawn from a longitudinally followed subsample of the Child Health and Development Study (n = 1752), a population-based pregnancy cohort ascertained in 1961-1963 in California. Maternal prenatal smoking was common (33.4%). Maternal and paternal smoking patterns were assessed at three time points by mother report. Hyperactivity was assessed at the mean of age of 10 years based on mother report to a personality inventory. RESULTS: Unadjusted, maternal smoking during pregnancy was associated with offspring hyperactivity [beta = 0.22, 95% confidence interval (CI) 0.11-0.33] and, to a similar degree, when the father smoked (beta = 0.18, 95% CI 0.07-0.30). After adjustment, maternal smoking remained robustly predictive of offspring hyperactivity (beta = 0.25, 95% CI 0.09 0.40) but father smoking was not (beta = 0.02, 95% CI -0.20 to 0.24). When examined among the pairs matched on propensity score, mother smoking was robustly related to offspring hyperactivity whether the father smoked (beta = 0.26, 95% CI 0.03-0.49) or did not smoke (beta = 0.30, 95% CI 0.04-0.57). By number of cigarettes, associations with hyperactivity were present for 10-19 and 20+ cigarettes per day among mothers. CONCLUSIONS: In a pregnancy cohort recruited in a time period in which smoking during pregnancy was common, we document associations between prenatal smoking exposure and offspring hyperactivity. Novel approaches to inferring causality continue to be necessary in describing the potential adverse consequences of prenatal smoking exposure later in life. PMID- 23676208 TI - Increased aortic pulse wave velocity as measured by echocardiography is strongly associated with poor prognosis in patients with heart failure. AB - BACKGROUND: An increased aortic pulse wave velocity (PWV), a marker of arterial stiffness, is associated with poor prognosis in various diseases. In patients with heart failure (HF), an increased aortic PWV is associated with low peak exercise oxygen consumption, which is a strong risk factor of adverse clinical outcomes. However, it remains unknown if an increased aortic PWV predicts poor prognosis in patients with HF, independent of peak exercise oxygen consumption. METHODS AND RESULTS: We enrolled 156 patients with HF and left ventricular ejection fraction <45%, who were followed up for a mean (SD) period of 36 +/- 19 months. At baseline, all the patients underwent a complete echocardiography with aortic PWV as measured by Doppler ultrasonography and peak exercise oxygen consumption as measured by bicycle exercise testing with expiratory gas exchange monitoring. During the follow-up period, 20 patients (12.8%) died and 15 patients (9.6%) were hospitalized for worsening HF. In the Kaplan-Meier analysis, patients in the first tertile of aortic PWV had a lower risk of developing cardiac death or hospitalization (combined end point) than those in the second and third tertile combined (P < .001). In Cox regression analysis, increased aortic PWV (both as a continuous and categorical variable) was significantly associated with an increased risk of adverse clinical outcomes after adjustment for peak exercise oxygen consumption and other clinical risk factors (P < .05). CONCLUSIONS: Increased aortic PWV, as measured by echocardiography, independently predicted adverse clinical outcomes (cardiac death or hospitalization) among patients with HF. PMID- 23676210 TI - Chronic contact eczema on the hand related to PlayStation((r)) controller use. PMID- 23676211 TI - Use of an aortic stent graft extension for the treatment of urethral stricture in a dog. AB - A 2-year-old male mixed dog was referred to us for further evaluation and treatment of a 4-week-history of oliguria and abdominal distension after a surgical repair of urethral injury. To relieve the urethral stricture, we placed a self-expanding aortic stent graft extension with a partial coverage with an expanded polytetrafluoroethylene (ePTFE). After the placement of the stent, the dog presented with a normal urinary voiding, despite the presence of urinary incontinence. The current case indicates that the ePTFE-covered, self-expanding ASGE is an effective intervention for the treatment of severe urethral stricture in the dog. PMID- 23676212 TI - Evidence of the clinical effectiveness of cognitive pharmaceutical services for aged patients. AB - BACKGROUND: cognitive pharmaceutical services (CPSs) encompass a variety of pharmacists' interventions to optimise pharmacotherapy. The clinical effectiveness of CPSs for aged patients remains controversial. OBJECTIVE: to analyse and describe the evidence of the clinical effectiveness of CPSs in aged patients by means of performing a systematic review of systematic reviews. METHODS: using the recommended methodology by Cochrane, a search was undertaken for systematic reviews of the clinical effectiveness of CPSs in MEDLINE, EMBASE, DOAJ, SCIELO and COCHRANE LIBRARY. Reviews were assessed using the Assessment of Multiple Systematic Reviews (AMSTAR) instrument. Quality of the evidence in the reviews was ranked using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: a total of 14 systematic reviews and one meta-analysis were analysed. The overall quality of the reviews was moderate. High and moderate strength of evidence was found for the positive effect of certain CPSs on reducing the number and improving the appropriateness of medicines. There was conflicting evidence of the effect on adherence. There was limited evidence of high and moderate strength on clinical outcomes. No positive evidence was found on mortality, hospitalisations, functional capacity and cognitive function. No systematic reviews reported the effect on the level of control of health problems. CONCLUSIONS: certain types of CPSs reduce the number of medicines and improve the appropriateness of prescriptions. Longer follow-up periods and/or the use of surrogate clinical variables measuring the short-term impact are required to demonstrate the effect on clinical outcomes. PMID- 23676214 TI - Spatial recognition of defects and tube type in carbon nanotube field effect transistors using electrostatic force microscopy. AB - The exceedingly high current capacity of single wall carbon nanotubes (SWCNTs) and the high currents that SWCNT thin films can sustain are driving significant efforts to fabricate high quality horizontally aligned SWCNTs. Dielectrophoresis is being increasingly used to prepare aligned nanotubes. However, the aligned nanotubes are generally of low quality since the processing involved can introduce defects. In addition, in arrays of tubes, tube-tube contact resistance can be high. Electrostatic force microscopy is a technique similar to atomic force microscopy, but in this case a bias voltage between the conductive tip and sample enables one to probe the long range electrostatic force. In this study we confirm that the technique can be successfully used to spatially determine defects, crossover points between tubes and nanotube electronic type. PMID- 23676213 TI - Postnatal ablation of POMC neurons induces an obese phenotype characterized by decreased food intake and enhanced anxiety-like behavior. AB - Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus are central components of systems regulating appetite and energy homeostasis. Here we report on the establishment of a mouse model in which the ribonuclease III ribonuclease Dicer-1 has been specifically deleted from POMC-expressing neurons (POMC(DeltaDCR)), leading to postnatal cell death. Mice are born phenotypically normal, at the expected genetic ratio and with normal hypothalamic POMC-mRNA levels. At 6 weeks of age, no POMC neurons/cells could be detected either in the arcuate nucleus or in the pituitary of POMC(DeltaDCR) mice. POMC(DeltaDCR) develop progressive obesity secondary to decreased energy expenditure but unrelated to food intake, which was surprisingly lower than in control mice. Reduced expression of AgRP and ghrelin receptor in the hypothalamus and reduced uncoupling protein 1 expression in brown adipose tissue can potentially explain the decreased food intake and decreased heat production, respectively, in these mice. Fasting glucose levels were dramatically elevated in POMC(DeltaDCR) mice and the glucose tolerance test revealed marked glucose intolerance in these mice. Secondary to corticotrope ablation, basal and stress-induced corticosterone levels were undetectable in POMC(DeltaDCR) mice. Despite this lack of activation of the neuroendocrine stress response, POMC(DeltaDCR) mice exhibited an anxiogenic phenotype, which was accompanied with elevated levels of hypothalamic corticotropin-releasing factor and arginine-vasopressin transcripts. In conclusion, postnatal ablation of POMC neurons leads to enhanced anxiety and the development of obesity despite decreased food intake and glucocorticoid deficiency. PMID- 23676215 TI - INK4a/ARF limits the expansion of cells suffering from replication stress. AB - Replication stress (RS) is a source of DNA damage that has been linked to cancer and aging, which is suppressed by the ATR kinase. In mice, reduced ATR levels in a model of the ATR-Seckel syndrome lead to RS and accelerated aging. Similarly, ATR-Seckel embryonic fibroblasts (MEF) accumulate RS and undergo cellular senescence. We previously showed that senescence of ATR-Seckel MEF cannot be rescued by p53-deletion. Here, we show that the genetic ablation of the INK4a/Arf locus fully rescues senescence on ATR mutant MEF, but also that induced by other conditions that generate RS such as low doses of hydroxyurea or ATR inhibitors. In addition, we show that a persistent exposure to RS leads to increased levels of INK4a/Arf products, revealing that INK4a/ARF behaves as a bona fide RS checkpoint. Our data reveal an unknown role for INK4a/ARF in limiting the expansion of cells suffering from persistent replication stress, linking this well-known tumor suppressor to the maintenance of genomic integrity. PMID- 23676216 TI - Tight correlation of 5-hydroxymethylcytosine and Polycomb marks in health and disease. AB - Modifications to DNA and histone tails represent key epigenetic marks involved in establishing and maintaining cell identity and can be dysregulated in human diseases, including cancer. Two such modifications, tri-methylation of lysine-27 on histone H3 (H3K27me3) mediated by the Polycomb complex and hydroxymethylation of cytosines on DNA, have recently been shown to be dynamically regulated during differentiation. Here, we show that global levels of 5-hydroxymethylcytosine (5hmC) and H3K27me3 are highly correlated across a variety of somatic tissues. In multiple hierarchically organized tissues, both marks showed almost identical cell-by-cell distribution patterns that exhibited a tight association with differentiation. In particular, tissue stem cell compartments were characterized by low levels of both marks, whereas differentiated cell compartments exhibited high levels of 5hmC and H3K27me3. This pattern of correlation between the two marks could be recapitulated in an in vitro model system of induced differentiation in prostate epithelial cells. While the correlation between 5hmC and H3K27me3 levels is also maintained in human cancers, the degree of correlation is reduced. These findings suggest a previously unappreciated link between 5hmC and H3K27me3 regulation that should be explored in future mechanistic studies. PMID- 23676218 TI - Enforcing the pause: transcription factor Sp3 limits productive elongation by RNA polymerase II. AB - The transition of paused RNA polymerase II into productive elongation is a highly dynamic process that serves to fine-tune gene expression in response to changing cellular environments. We have recently reported that the transcription factor Sp3 inhibits the transition of paused RNA Pol II to productive elongation at the promoter of the cyclin-dependent kinase inhibitor p21(CIP1) and other Sp3 repressed genes. Our studies support the view that Sp3 has three modes of action: activation, SUMO-Sp3-mediated heterochromatin silencing and SUMO-independent inhibition of elongation. At the p21(CIP1) promoter, binding of the positive elongation factor P-TEFb kinase was not affected by Sp3. In contrast, Sp3 promoted binding of the protein phosphatase PP1 to the p21(CIP1) promoter, suggesting that Sp3-dependent regulation of the local balance between kinase and phosphatase activities may contribute to gene expression. Our findings show that the transition of paused RNA Pol II to productive elongation is an important step regulated by both promoter-specific activators and repressors to finely modulate mRNA expression levels. PMID- 23676217 TI - STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma. AB - The pathogenesis of cutaneous T-cell lymphoma (CTCL) remains elusive. Recent discoveries indicate that the oncogenic microRNA miR-155 is overexpressed in affected skin from CTCL patients. Here, we address what drives the expression of miR-155 and investigate its role in the pathogenesis of CTCL. We show that malignant T cells constitutively express high levels of miR-155 and its host gene BIC (B cell integration cluster). Using ChIP-seq, we identify BIC as a target of transcription factor STAT5, which is aberrantly activated in malignant T cells and induced by IL-2/IL-15 in non-malignant T cells. Incubation with JAK inhibitor or siRNA-mediated knockdown of STAT5 decreases BIC/miR-155 expression, whereas IL 2 and IL-15 increase their expression in cell lines and primary cells. In contrast, knockdown of STAT3 has no effect, and BIC is not a transcriptional target of STAT3, indicating that regulation of BIC/miR-155 expression by STAT5 is highly specific. Malignant proliferation is significantly inhibited by an antisense-miR-155 as well as by knockdown of STAT5 and BIC. In conclusion, we provide the first evidence that STAT5 drives expression of oncogenic BIC/miR-155 in cancer. Moreover, our data indicate that the STAT5/BIC/miR-155 pathway promotes proliferation of malignant T cells, and therefore is a putative target for therapy in CTCL. PMID- 23676219 TI - HIPK1 drives p53 activation to limit colorectal cancer cell growth. AB - HIPK1 (homeodomain interacting protein kinase 1) is a serine/threonine kinase that belongs to the CMGC superfamily. Emerging data point to the role of HIPK1 in cancer, but it is still not clear whether it acts as a tumor suppressor or promoter. Here we identified HIPK1 as a kinase that is significantly overexpressed in colorectal cancer (CRC) and whose expression is stage-dependent. Being abundantly expressed at the onset of the disease, the HIPK1 level gradually decreased as tumor stage progressed. To further uncover how this factor regulates tumorigenesis and establish whether it constitutes an early factor necessary for neoplastic transformation or for cellular defense, we studied the effect of its overexpression in vitro by investigating various cancer-related signaling cascades. We found that HIPK1 mostly regulates the p53 signaling pathway both in HCT116 and HeLa cells. By phosphorylating p53 on its serine-15, HIPK1 favored its transactivation potential, which led to a rise in p21 protein level and a decline in cell proliferation. Assuming that HIPK1 could impede CRC growth by turning on the p53/p21 pathway, we then checked p21 mRNA levels in patients. Interestingly, p21 transcripts were only increased in a subset of patients expressing high levels of HIPK1. Unlike the rest of the cohort, the majority of these patients hosted a native p53 protein, meaning that such a pro-survival pathway (HIPK1+ > p53 > p21) is active in patients, and that HIPK1 acts rather as a tumor suppressor. PMID- 23676220 TI - Induction of prolonged early G1 arrest by CDK4/CDK6 inhibition reprograms lymphoma cells for durable PI3Kdelta inhibition through PIK3IP1. AB - Phosphatidylinositol-3-kinase (PI3K) signaling is constitutive in most human cancers. Selective inhibition of PI3Kdelta (p110delta) by GS-1101 has emerged as a promising therapy in chronic lymphocytic leukemia and indolent lymphomas. In aggressive non-Hodgkin lymphomas such as mantle cell lymphoma (MCL), however, efficacy has been observed, but the extent and duration of tumor control is modest. To determine if tumor killing by GS-1101 is cell cycle-dependent, we show in primary MCL cells by whole-transcriptome sequencing that, despite aberrant expression and recurrent mutations in Cyclin D1, mutations are rare in coding regions of CDK4, RB1 and other genes that control G1-S cell cycle progression or PI3K/AKT signaling. PI3Kdelta is the predominant PI3K catalytic subunit expressed, and inhibition by GS-1101 transiently inhibits AKT phosphorylation but not proliferation in MCL cells. Induction of prolonged early G1-arrest (pG1) by selective inhibition of CDK4/CDK6 with PD 0332991 amplifies and sustains PI3Kdelta inhibition, which leads to robust apoptosis. Accordingly, inhibition of PI3Kdelta induces apoptosis of primary MCL tumor cells once they have ceased to cycle ex vivo, and this killing is enhanced by PD 0332991 inhibition of CDK4/CDK6. PIK3IP1, a negative PI3K regulator, appears to mediate pG1 sensitization to PI3K inhibition; it is markedly reduced in MCL tumor cells compared with normal peripheral B cells, profoundly induced in pG1 and required for pG1 sensitization to GS-1101. Thus, the magnitude and duration of PI3K inhibition and tumor killing by GS-1101 is pG1-dependent, suggesting induction of pG1 by CDK4/CDK6 inhibition as a strategy to sensitize proliferating lymphoma cells to PI3K inhibition. PMID- 23676221 TI - Current concepts in managing wet AMD suboptimally responsive to anti-VEGF therapy. PMID- 23676222 TI - Anchoring the market position of retina practices through customer service, branding, and relationship building. PMID- 23676223 TI - Surgery for retinal detachment in patients with giant retinal tear: etiologies, management strategies, and outcomes. AB - BACKGROUND AND OBJECTIVE: To evaluate etiologies, management, and outcomes for patients with giant retinal tears undergoing initial surgery at a single institution. PATIENTS AND METHODS: Noncomparative, retrospective, consecutive case series at a university referral center including 79 eyes of 77 patients. RESULTS: Blunt trauma constituted 22% of cases. All patients underwent pars plana vitrectomy with gas or silicone oil tamponade. Eighty-five percent (67 eyes) underwent an encircling scleral buckle. Perfluorocarbon liquids were used in 71% (61 eyes). Eighteen percent (14 eyes) underwent re-operation for recurrent retinal detachment. Ninety-two percent (73 eyes) achieved anatomic success with one or more surgical procedures. Visual acuity at last follow-up was at least 20/400 in 84.9% of patients (28 of 33) with 3 clock hours compared to 65.2% (30 of 46) with tears greater than 3 clock hours. CONCLUSION: Patients with giant retinal tear undergoing surgery achieved high rates of anatomic success, but re operations were frequent. Better visual outcomes were associated with smaller circumferential dimensions in the giant retinal tears. PMID- 23676224 TI - The role of ILM peeling in vitreous surgery for proliferative diabetic retinopathy complications. AB - BACKGROUND AND OBJECTIVE: To evaluate the influence of pars plana vitrectomy (PPV) with or without internal limiting membrane (ILM) peeling on spectral-domain optical coherence tomography (SD-OCT) in vitreous hemorrhage and tractional retinal detachment as a complication of diabetic retinopathy. PATIENTS AND METHODS: Retrospective study of PPV in patients with diabetic retinopathy complications. Group A (53 patients) had PPV with ILM peeling, and group B (59 patients) had PPV without ILM peeling. SD-OCT imaging and fluorescein angiography were performed postoperatively. RESULTS: Preoperative visual acuity was 0.04 and final postoperative visual acuity was 0.27 in both groups (23.4 months in group A, 60 months in group B). Postoperative central retinal thickness was 193 MUm (group A) and 258.6 MUm (group B). Epiretinal membranes were observed less frequently in group A than in group B (24% vs 49%). Repeated surgeries were performed in 38 cases in group A and in 51 cases in group B. CONCLUSION: Fewer cases of epiretinal membranes and macular edema are observed postoperatively with ILM peeling. Visual acuity is similar in both groups, but additional surgeries are fewer with ILM peeling. PMID- 23676225 TI - Endocyclophotocoagulation as an adjuvant to vitreoretinal surgery in cases with concomitant glaucoma. AB - BACKGROUND AND OBJECTIVE: To evaluate the efficacy of endocyclophotocoagulation (ECP) in patients undergoing pars plana vitrectomy for vitreoretinal disease with medically uncontrolled glaucoma. PATIENTS AND METHODS: This is a retrospective review of 12 patients who underwent 270 degrees ECP following vitrectomy. RESULTS: Ten of the 12 patients had excellent intraocular pressure (IOP) control postoperatively, without medication in four patients and with reduced medication in six patients. IOP decreased from 26.3 +/- 12.9 to 17.9 +/- 6.0 at 1 month (P = .03) and 16.9 +/- 4.4 at 3 months postoperatively (P = .02). Best corrected visual acuity was improved by 1 month postoperatively. The number of glaucoma agents decreased from 2.7 +/- 1.1 to 1.3 +/- 1.3 (P = .03). One patient with neovascular glaucoma developed hypotony. Postoperative inflammation or discomfort did not exceed what was expected for a standard vitrectomy in any patient. CONCLUSION: ECP can be effectively combined with vitrectomy; however, ECP produced unpredictable results in the two patients with neovascular glaucoma. PMID- 23676226 TI - Recurrent leakage after Visudyne photodynamic therapy for the treatment of circumscribed choroidal hemangioma. AB - BACKGROUND: To report on the recurrence of serous retinal detachment following verteporfin photodynamic therapy for circumscribed choroidal hemangioma. PATIENTS AND METHODS: A single-center chart review was performed for patients with circumscribed choroidal hemangioma (CCH) treated with Visudyne (verteporfin injection; QLT Ophthalmics, Menlo Park, CA) photodynamic therapy (PDT). Initial and post-treatment visual acuity, ultrasound and ocular coherence tomography were evaluated. RESULTS: Four patients who were treated with PDT for symptomatic serous retinal detachment secondary to CCH were managed for recurrent leakage and followed for an average of 47.5 months. Two patients required three re-treatments and two required four re-treatments for recurrent detachment. Average time to re treatment was 23.4 months, with successive re-treatment intervals decreasing to 13 months, then 9.5 months, and finally 3.5 months. CONCLUSION: Visudyne PDT is a successful initial treatment modality for CCH with serous retinal detachment; however, those patients who require multiple re-treatments may experience recurrent leakage at more frequent intervals. PMID- 23676227 TI - Analysis of the morphology and vascular layers of the choroid in retinitis pigmentosa using spectral-domain OCT. AB - BACKGROUND AND OBJECTIVE: To analyze choroidal morphology and vascular layers in eyes with retinitis pigmentosa (RP) using spectral-domain optical coherence tomography. PATIENTS AND METHODS: Cross-sectional, retrospective analysis of 14 patients (14 eyes) with RP and 33 healthy subjects (33 eyes) who underwent high definition one-line raster scanning at a single center. Two independent raters evaluated the morphology, thickness, and vascular layers of the choroid in both groups. RESULTS: The choroid had an irregular shape in 11 of 14 eyes (79%) with RP. The thickest point of choroid was not subfoveal as in healthy eyes, and exaggerated nasal thinning of the choroid was observed in nine of 14 eyes (65%) with RP. Mean subfoveal total choroidal thickness and large choroidal vessel layer thickness were significantly lower in eyes with RP (P = .04 and P = .02, respectively) than in healthy eyes. CONCLUSION: Choroidal morphology is altered and an exaggerated thinning of the large choroidal vessel layer is observed in eyes with RP. Further studies involving correlation of disease stage and severity with choroidal changes may provide further insight into the involvement of choroid in RP and other inherited retinal dystrophies. PMID- 23676228 TI - Macular pigment optical density in a Central European population. AB - BACKGROUND AND OBJECTIVE: The purpose of this study is to measure the macular pigment optical density and study its spatial profile as well as identify its determinant factors in a Central European population. PATIENTS AND METHODS: The macular pigment optical density (MPOD) and its distribution were assessed in 228 eyes of 129 subjects using fundus reflectometry with the Visucam 500 (Carl Zeiss Meditec, Jena, Germany). RESULTS: A statistically significant positive association between a diet rich in xanthophylls and all MPOD values was found. A positive monotonic relationship was demonstrated between an increasing degree in pigment distribution eccentricity and age, as well as all MPOD values except for area. CONCLUSION: Assuming that macular pigment is protective against age-related macular degeneration, our study highlights the role of nutritional counseling and intervention in preventing this disease. Furthermore, MPOD appears to increase with age, and the distribution of macular pigment appears to form more eccentric profiles. PMID- 23676229 TI - Evaluation of the ability of a photocoagulator to rupture the retinal vein and Bruch's membrane for potential vein bypass in retinal vein occlusion. AB - BACKGROUND AND OBJECTIVE: To evaluate the laser power required to rupture both the retinal vein and Bruch's membrane in a porcine model using a new laser system for treatment of retinal vein occlusion. MATERIALS AND METHODS: The retina was treated in areas with and without an overlying vein. Sections through the laser sites were stained for light and transmission electron microscopy. The percentage of the laser sites with rupture of the retinal vein and Bruch's membrane, the degree of tissue damage, and the diameter of the rupture in Bruch's membrane were determined. RESULTS: The rate of vein rupture was 75% at 3 W, and rupture of Bruch's membrane was achieved at all powers tested. The mean diameter of the rupture in Bruch's membrane increased with laser power. CONCLUSION: The Integre Duo laser system (Ellex Medical Lasers, Adelaide, Australia) is capable of rupturing the retinal vein and Bruch's membrane at lower powers than prior laser systems. PMID- 23676230 TI - A novel technique for choroidal fluid drainage in uveal effusion syndrome. AB - BACKGROUND AND OBJECTIVE: Uveal effusion syndrome (UES) is a rare disorder associated with thickening of the choroid and secondary retinal detachment as a possible serious complication. UES occurs in hypermetropic or nanophthalmic eyes or can be idiopathic and is a diagnosis of exclusion. Vortex vein decompression, sclerectomy or sclerotomy, and drainage of choroidal fluid are surgical treatment options. PATIENTS AND METHODS: The authors describe a novel surgical technique for drainage of serous choroidal detachment using a penetrating diathermy probe in two patients with UES. The procedure involves drainage of choroidal fluid by using a penetrating diathermy probe (2 mm tip length) after placing a 20-gauge infusion line in the anterior chamber. RESULTS: Choroidal fluid drainage was successful in both patients, with satisfactory outcome on follow-up. CONCLUSION: The proposed simple and feasible surgical drainage technique may improve the management of patients with UES. PMID- 23676231 TI - Transvitreal endoresection of refractory retinal capillary hemangioblastoma after feeder vessel ligation. AB - BACKGROUND AND OBJECTIVE: Retinal capillary hemangioma (RCH) is a developmental vascular tumor occurring sporadically or associated with Von Hippel-Lindau syndrome. Treatment for large solitary RCH is challenging. Laser, cryotherapy, radiotherapy, photodynamic therapy, and en bloc resection for advanced cases have been described in the literature without consensus on standard management. MATERIALS AND METHODS: A novel technique of 20-gauge transvitreal endoresection of solitary peripheral RCH after ligating the feeder vessels is described. RESULTS: Tumors were successfully resected after ligating the feeder vessels bimanually in a closed and more controlled ocular environment. Feeder vessel ligation is intended to compensate for the involution time of the caliber of feeder vessels, when postoperative hemorrhage is more likely to occur. Another advantage of ligating the blood vessels is to secure hemostasis without using heavy endocautery. Postoperatively, proliferative vitreoretinopathy remains a concern. CONCLUSION: Pending a larger randomized trial, performing endoresection in RCH that is large and unresponsive to conventional treatment is an acceptable option. PMID- 23676232 TI - Hypopyon and pseudoendophthalmitis 1 month after vitrectomy for retinal detachment with subretinal hemorrhage. AB - The presence of postoperative hypopyon warrants consideration of the diagnosis of infectious endophthalmitis, but other etiologies may mimic a hypopyon. The differential diagnosis of a postoperative hypopyon must include causes of pseudoendophthalmitis to avoid unnecessary and invasive interventions. The context and clinical presentation are the most important factors allowing such a distinction. A patient with a hypopyon and elevated intraocular pressure presented 1 month after pars plana vitrectomy for a hemorrhagic retinal detachment. Slit lamp examination disclosed khaki-colored cells layered in the anterior chamber, and a diagnosis of pseudoendophthalmitis was made. The hypopyon resolved without intervention. PMID- 23676233 TI - Suprachoroidal silicone oil migration following retinal detachment repair. AB - Silicone oil is a commonly used tamponade agent. We report the rare complication of a patient who presented with silicone oil in the suprachoroidal space following retinal detachment repair. The silicone oil was subsequently removed without any long-term complications. PMID- 23676234 TI - Resolution of serous retinal detachment following partial sclerectomy with mitomycin C in nanophthalmos. AB - The authors report the results of partial-thickness sclerectomy combined with mitomycin C in a nanophthalmic eye with serous retinal detachment. Partial sclerectomy in two quadrants with adjuvant use of mitomycin C without drainage of subretinal fluid was performed. The patient was monitored with serial fundus photographs and spectral-domain optical coherence tomography (SD-OCT) for up to 16 weeks postoperatively. Best corrected visual acuity improved from counting fingers at 1 meter preoperatively to 6/60 at final follow-up. There was gradual but complete resolution of serous retinal detachment both clinically and on SD OCT. Partial-thickness sclerectomy with mitomycin C is an effective and safe procedure in the management of nanophthalmic eyes with uveal effusion. PMID- 23676235 TI - Paraneoplastic vitelliform retinopathy following ciliochoroidal melanoma. AB - A case of a paraneoplastic vitelliform retinopathy is described in the fellow eye of a 40-year-old woman 4 years after enucleation of her left eye for a ciliochoroidal melanoma. There were multiple yellow subretinal vitelliform-like lesions at the posterior pole, which were hyperautofluorescent and hypofluorescent on fluorescein and indocyanine green angiographies. Spectral domain optical coherence tomography showed hyperreflective material between the retinal pigment epithelium and the photoreceptor layer. Paraneoplastic vitelliform retinopathy may appear concomitantly with the development of distant metastases years after treatment of a ciliochoroidal melanoma and may present with symptoms resembling melanoma-associated retinopathy and electroretinogram findings. However, unlike with melanoma-associated retinopathy, the retinal lesions are located between the retinal pigment epithelium and the photoreceptor layer. PMID- 23676236 TI - Ultra-widefield imaging of Duchenne muscular dystrophy-associated proliferative retinal vasculopathy improved with panretinal laser photocoagulation alone. AB - Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder whose ophthalmic associations most commonly consist of pigmentary fundus changes and scotopic electroretinogram abnormalities. A 23-year-old man with advanced DMD and associated cardiopulmonary compromise complaining of floaters presented with a striking retinal vasculopathy characterized by vitreous hemorrhage, neovascularization, capillary drop-out, and prominent saccular venular aneurysms diffusely throughout the fundus of both eyes. This vasculopathy was promptly treated with panretinal phocoagulation with marked improvement to at least 1 year. This report suggests that early identification and prompt treatment of DMD may be important in managing this condition. PMID- 23676237 TI - High-resolution multimodal imaging of multiple evanescent white dot syndrome. AB - The integrity of macular morphology was examined in a patient with multiple evanescent white dot syndrome (MEWDS) diagnosed through clinical and investigational adaptive optics (AO) retinal imaging techniques. Imaging was performed during the acute and recovery phases to examine changes in retinal morphology, revealing characteristic small multifocal white dots in the perifoveal region and a granular appearance in the fovea. Fluorescein angiography revealed early and intermediate hyperfluorescence, and regions of decreased fundus autofluorescence were observed. Photoreceptor disruption was apparent during the acute phase and recurrence. Conventional multimodal imaging combined with AO imaging offers more insight into the pathology of MEWDS by providing complementary views of the retina throughout the acute phase, recovery, and recurrence. PMID- 23676238 TI - Congenital hypertrophy of the retinal pigment epithelium: choroidal cavitation demonstrated on spectral-domain OCT. AB - A patient with solitary congenital hypertrophy of the retinal pigment epithelium demonstrated a striking choroidal cavitation on spectral-domain optical coherence tomography (OCT). Although photoreceptor atrophy overlying congenital hypertrophy of the retinal pigment epithelium has been described on time-domain OCT, this patient manifested a previously unrecognized tomographic feature. PMID- 23676239 TI - Traumatic macular hole from intentional basketball overinflation. AB - We report a new mechanism of ocular trauma. A basketball was intentionally overinflated until it exploded, resulting in corneal edema, hyphema, iritis, vitreous hemorrhage, commotio retinae, and a macular hole. The macular hole did not close after observation and subsequent pars plana vitrectomy with posterior hyaloid removal, but a repeat vitrectomy with internal limiting membrane peeling resulted in hole closure. Basketball overinflation to the point of explosion is a potentially blinding practice of which the public and manufacturers should be made aware. PMID- 23676240 TI - Eight questions with Dr. Puliafito. PMID- 23676241 TI - Adrenomedullin concentration in the cerebrospinal fluid is related to appetite loss and delayed ischemic neurological deficits after subarachnoid hemorrhage. AB - OBJECTIVE: Adrenomedullin (AM) is secreted into the cerebrospinal fluid (CSF) from the choroid plexus and regulates appetite. Adrenomedullin concentration in the CSF is elevated 7-10 days after the onset of aneurysmal subarachnoid hemorrhage (SAH). The aim of the present study was to determine whether CSF AM concentration is related to appetite and delayed ischemic neurological deficits (DIND) after SAH. METHODS: Adrenomedullin concentration in the CSF, blood plasma profile, and appetite status were measured in 22 patients with SAH who underwent aneurysmal clipping within 48 hours of SAH onset. Appetite status was measured using dietary oral calorie intake and self-reported appetite level. All outcome variables were measured at an early (Day 3) and late (Day 8) time point after SAH onset (Day 0). RESULTS: Dietary oral calorie intake (P = 0.02), self-reported appetite level (P = 0.03), hemoglobin (P = 0.01), albumin (P = 0.03), glucose (P = 0.01), and insulin (P = 0.03) levels were lower at the late time point than at the early time point. Cerebrospinal fluid adrenomedullin concentration was higher at the late time point than at the early time point (P = 0.0007). There was a significant negative correlation between AM concentration and dietary oral calorie intake (r = -0.478, P = 0.024) and self-reported appetite level (r = 0.454, P = 0.033) at the late time point. Six patients (27%) developed DIND. Adrenomedullin concentration at the late time point was significantly higher in patients who developed DIND than in patients who did not (P = 0.02). CONCLUSIONS: Cerebrospinal fluid adrenomedullin concentration 8 days after SAH onset is related to appetite loss and DIND. PMID- 23676242 TI - High temperature far-infrared dynamics of orthorhombic NdMnO3: emissivity and reflectivity. AB - We report on near normal far- and mid-infrared emission and reflectivity of NdMnO3 perovskite from room temperature to sample decomposition above 1800 K. At 300 K the number of infrared active phonons is in close agreement with the 25 calculated for the orthorhombic D(2h)(16)-Pbnm (Z = 4) space group. Their number gradually decreases as we approach the temperature of orbital disorder at ~1023 K where the orthorhombic O' lower temperature cooperative phase coexists with the cubic orthorhombic O. At above ~1200 K, the three infrared active phonons coincide with that expected for cubic Pm-3m (Z = 1) in the high temperature insulating regime. Heating samples in dry air triggers double exchange conductivity by Mn(3+) and Mn(4+) ions and a small polaron mid-infrared band. Fits to the optical conductivity single out the octahedral antisymmetric and symmetric vibrational modes as the main phonons in the electron-phonon interactions at 875 K. For 1745 K, it is enough to consider the symmetric stretching internal mode. An overdamped defect induced Drude component is clearly outlined at the highest temperatures. We conclude that rare earth manganite eg electrons are prone to spin, charge, orbital, and lattice couplings in an intrinsic orbital distorted perovskite lattice, favoring embryonic low energy collective excitations. PMID- 23676243 TI - Patient-provider communication and trust in relation to use of an online patient portal among diabetes patients: The Diabetes and Aging Study. AB - Patient-provider relationships influence diabetes care; less is known about their impact on online patient portal use. Diabetes patients rated provider communication and trust. In this study, we linked responses to electronic medical record data on being a registered portal user and using secure messaging (SM). We specified regression models to evaluate main effects on portal use, and subgroup analyses by race/ethnicity and age. 52% of subjects were registered users; among those, 36% used SM. Those reporting greater trust were more likely to be registered users (relative risk (RR)=1.14) or SM users (RR=1.29). In subgroup analyses, increased trust was associated with being a registered user among white, Latino, and older patients, as well as SM use among white patients. Better communication ratings were also related to being a registered user among older patients. Since increased trust and communication were associated with portal use within subgroups, this suggests that patient-provider relationships encourage portal engagement. PMID- 23676244 TI - In-home monitoring of older adults with vision impairment: exploring patients', caregivers' and professionals' views. AB - OBJECTIVE: To develop a conceptual framework for the design of an in-home monitoring system (IMS) based on the requirements of older adults with vision impairment (VI), informal caregivers and eye-care rehabilitation professionals. MATERIALS AND METHODS: Concept mapping, a mixed-methods statistical research tool, was used in the construction of the framework. Overall, 40 participants brainstormed or sorted and rated 83 statements concerning an IMS for older adults with VI. Multidimensional scaling and hierarchical cluster analysis were employed to construct the framework. A questionnaire yielded further insights into the views of a wider sample of older adults with VI (n=78) and caregivers (n=25) regarding IMS. RESULTS: Concept mapping revealed a nine-cluster model of IMS related aspects including affordability, awareness of system capabilities, simplicity of installation, operation and maintenance, system integrity and reliability, fall detection and safe movement, user customization, user preferences regarding information delivery, and safety alerts for patients and caregivers. From the questionnaire, independence, safety and fall detection were the most commonly reported reasons for older adults and caregivers to accept an IMS. Concerns included cost, privacy, security of the information obtained through monitoring, system accuracy, and ease of use. DISCUSSION: Older adults with VI, caregivers and professionals are receptive to in-home monitoring, mainly for fall detection and safety monitoring, but have concerns that must be addressed when developing an IMS. CONCLUSION: Our study provides a novel conceptual framework for the design of an IMS that will be maximally acceptable and beneficial to our ageing and vision-impaired population. PMID- 23676245 TI - Temporal reasoning over clinical text: the state of the art. AB - OBJECTIVES: To provide an overview of the problem of temporal reasoning over clinical text and to summarize the state of the art in clinical natural language processing for this task. TARGET AUDIENCE: This overview targets medical informatics researchers who are unfamiliar with the problems and applications of temporal reasoning over clinical text. SCOPE: We review the major applications of text-based temporal reasoning, describe the challenges for software systems handling temporal information in clinical text, and give an overview of the state of the art. Finally, we present some perspectives on future research directions that emerged during the recent community-wide challenge on text-based temporal reasoning in the clinical domain. PMID- 23676246 TI - Improvement in the workflow efficiency of treating non-emergency outpatients by using a WLAN-based real-time location system in a level I trauma center. AB - BACKGROUND: Patient localization can improve workflow in outpatient settings, which might lead to lower costs. The existing wireless local area network (WLAN) architecture in many hospitals opens up the possibility of adopting real-time patient tracking systems for capturing and processing position data; once captured, these data can be linked with clinical patient data. OBJECTIVE: To analyze the effect of a WLAN-based real-time patient localization system for tracking outpatients in our level I trauma center. METHODS: Outpatients from April to August 2009 were included in the study, which was performed in two different stages. In phase I, patient tracking was performed with the real-time location system, but acquired data were not displayed to the personnel. In phase II tracking, the acquired data were automatically collected and displayed. Total treatment time was the primary outcome parameter. Statistical analysis was performed using multiple linear regression, with the significance level set at 0.05. Covariates included sex, age, type of encounter, prioritization, treatment team, number of residents, and radiographic imaging. RESULTS/DISCUSSION: 1045 patients were included in our study (540 in phase I and 505 in phase 2). An overall improvement of efficiency, as determined by a significantly decreased total treatment time (23.7%) from phase I to phase II, was noted. Additionally, significantly lower treatment times were noted for phase II patients even when other factors were considered (increased numbers of residents, the addition of imaging diagnostics, and comparison among various localization zones). CONCLUSIONS: WLAN-based real-time patient localization systems can reduce process inefficiencies associated with manual patient identification and tracking. PMID- 23676248 TI - Poor long term outcomes after prolapse surgery. PMID- 23676247 TI - A corpus-based approach for automated LOINC mapping. AB - OBJECTIVE: To determine whether the knowledge contained in a rich corpus of local terms mapped to LOINC (Logical Observation Identifiers Names and Codes) could be leveraged to help map local terms from other institutions. METHODS: We developed two models to test our hypothesis. The first based on supervised machine learning was created using Apache's OpenNLP Maxent and the second based on information retrieval was created using Apache's Lucene. The models were validated by a random subsampling method that was repeated 20 times and that used 80/20 splits for training and testing, respectively. We also evaluated the performance of these models on all laboratory terms from three test institutions. RESULTS: For the 20 iterations used for validation of our 80/20 splits Maxent and Lucene ranked the correct LOINC code first for between 70.5% and 71.4% and between 63.7% and 65.0% of local terms, respectively. For all laboratory terms from the three test institutions Maxent ranked the correct LOINC code first for between 73.5% and 84.6% (mean 78.9%) of local terms, whereas Lucene's performance was between 66.5% and 76.6% (mean 71.9%). Using a cut-off score of 0.46 Maxent always ranked the correct LOINC code first for over 57% of local terms. CONCLUSIONS: This study showed that a rich corpus of local terms mapped to LOINC contains collective knowledge that can help map terms from other institutions. Using freely available software tools, we developed a data-driven automated approach that operates on term descriptions from existing mappings in the corpus. Accurate and efficient automated mapping methods can help to accelerate adoption of vocabulary standards and promote widespread health information exchange. PMID- 23676249 TI - Subsyndromal delirium and its determinants in elderly patients hospitalized for acute medical illness. AB - BACKGROUND: In older individuals, acute medical illnesses and admission to hospital are often associated with a deterioration of cognitive status, also in the absence of dementia and full-blown delirium. We evaluated the prevalence of subsyndromal delirium (SSD) and its correlates in a sample of elderly medical inpatients. METHODS: From 763 consecutive inpatients, 325 participants with known dementia or delirium were excluded, whereas 438 (mean age: 80.6 years; female participants: 60.1%) were enrolled. SSD was diagnosed within 48 hour from admission, when at least two DSM-IV delirium criteria including disorientation, attention or memory deficit, altered level of consciousness, or perceptual disturbances were present. Cognitive performance was evaluated by Mini Mental Status Examination (MMSE). General, clinical, and laboratory parameters were also registered. RESULTS: One hundred and sixty-six patients (37%) had SSD. Compared with controls, SSD patients were older individuals, had less formal education, higher comorbidity, lower hemoglobin/lymphocytes counts, and higher creatinine levels. A trend toward higher prevalence of previous stroke and widowhood was observed. A MMSE score of less than 24/30 identified SSD with 88% sensitivity and 78% specificity. In SSD patients, MMSE independently correlated with years of education, high-sensitivity C reactive protein levels, and O2 arterial saturation (model adjusted r (2) = 0.30, p = .001); conversely, only years of education were associated with MMSE in controls (adjusted r (2) = 0.06, p = .01). CONCLUSIONS: Our data suggest that SSD is common in hospitalized older medical inpatients, and low MMSE score might be useful for identification of participants at risk of SSD. Current inflammatory response and reduced O2 arterial saturation were the only independent determinants of cognitive performance in SSD patients. PMID- 23676250 TI - Longitudinal decline of neuromuscular activation and power in healthy older adults. AB - BACKGROUND: Weakness contributes to the decline of physical function that occurs with aging. Contradictory findings have been reported as to whether neuromuscular activation is impaired with aging, and the extent to which it contributes to weakness. The present study uses a longitudinal design to assess how potential age-related change of neuromuscular activation affects strength, power, and mobility function. METHODS: Participants included 16 healthy older adults who were healthy and high functioning at baseline. Strength was measured by leg press one repetition maximum. Power production was measured during a maximal effort rapid leg press movement with resistance set to 70% of the one repetition maximum. During the same movement, neuromuscular activation was quantified as the rate of rise of the quadriceps surface electromyogram (rate of electromyogram rise). Thigh muscle cross-sectional area was measured by computed tomography. Mobility function was assessed by the Short Physical Performance Battery. RESULTS: The time between baseline and follow-up testing was almost 3 years. Between these time points, rate of electromyogram rise decreased 28% (p = .004) and power decreased 16.5% (p = .01). There was a trend for reduced anterior thigh muscle cross-sectional area (3%, p = .05), but no change in posterior thigh muscle cross-sectional area (p = .84), one repetition maximum strength (p = .72), or Short Physical Performance Battery score (p = .17). Loss of power was strongly associated with reduction in the rate of electromyogram rise (R (2) = .61, p < .001), but not with reduction of anterior thigh muscle cross-sectional area (p = .83). CONCLUSIONS: The present findings suggest that voluntary neuromuscular activation declines with advancing age, contributes to a reduction in power production, and precedes the decline of mobility function. PMID- 23676251 TI - Pioglitazone enhances the blood pressure-lowering effect of losartan via synergistic attenuation of angiotensin II-induced vasoconstriction. AB - INTRODUCTION: This study was designed to investigate the underlying mechanisms of synergistic antihypertensive effect produced by combination therapy of losartan and pioglitazone in metabolic syndrome (MS) rats. MATERIALS AND METHODS: An MS model was induced by feeding rats a high-fat, high-sodium diet and 20% sucrose solution. Losartan (20 mg/kg/day), pioglitazone (10 mg/kg/day), and their combination were orally administered for eight consecutive weeks. Systolic blood pressure (SBP) and mean arterial pressure (MAP) were measured using the tail-cuff method and carotid arterial catheterization, respectively. The aortas were isolated and in vitro vascular reactivity studies were performed. The protein expression of angiotensin type 1 receptor (AT1), endothelial nitric oxide synthase (eNOS), phosphorylated eNOS and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47(phox), level of nitrotyrosine as well as activity of eNOS and NADPH oxidase in aortas of MS rats were detected. RESULTS: After eight weeks of treatment, the SBP and MAP in the losartan (115 +/- 5 and 106 +/- 6 mmHg), pioglitazone (130 +/- 6 and 118 +/- 6 mmHg), and combination therapy (105 +/- 6 and 98 +/- 5 mmHg) groups were lower than those in the model group (150 +/- 8 and 136 +/- 9 mmHg). Combination therapy of losartan and pioglitazone reduced BP more than either monotherapy, and showed additive effects on improving endothelial dysfunction and abolishing the increased vascular responsiveness to angiotensin II. These synergistic effects were associated with further reductions in protein expression of p47(phox) and AT1, NADPH oxidase activity, and nitrotyrosine level. CONCLUSIONS: Our data indicate that combined treatment exerts more beneficial effects on lowering BP and improving vascular lesions. PMID- 23676252 TI - Associations between the angiotensin-converting enzyme insertion/deletion polymorphism and susceptibility to sarcoidosis: A meta-analysis. AB - INTRODUCTION: The purpose of this study was to examine whether the insertion (I) or deletion (D) of angiotensin-converting enzyme (ACE) polymorphism confers susceptibility to sarcoidosis. METHODS: A meta-analysis on the associations between the ACE I/D polymorphism and sarcoidosis was conducted. RESULTS: Seventeen comparison studies consisting of 1556 cases and 2381 controls were available for the meta-analysis. Meta-analysis revealed a significant association between the D allele and sarcoidosis (OR 1.206, 95% CI 1.049-1.386, p = 0.009). An ethnicity-specific meta-analysis of the DD+ID genotype showed an association with sarcoidosis in East Asians (OR 1.342, 95% CI 1.041-1.729, p = 0.023). An association was found between the DD genotype of the ACE I/D polymorphism and sarcoidosis (OR 1.251, 95% CI 1.070-1.463, p = 0.005). Furthermore, stratification by ethnicity indicated an association between the DD genotype and sarcoidosis in Europeans (OR = 1.215, 95% CI = 1.010-1.462, p = 0.039). CONCLUSIONS: Our meta-analysis demonstrates that the ACE I/D polymorphism is associated with susceptibility to sarcoidosis in European and East Asian populations. PMID- 23676253 TI - Effects of single dose intranasal oxytocin on social cognition in schizophrenia. AB - Deficits in social cognition are common in schizophrenia and predict poor community functioning. Given the current limitations of psychosocial treatments and the lack of pharmacological treatments for social cognitive deficits, the development of novel therapeutic agents could greatly enhance functional recovery in schizophrenia. This study evaluated whether a single dose of intranasal oxytocin acutely improves social cognitive functioning in schizophrenia. Twenty three male veterans with schizophrenia completed baseline assessments of social cognition that were divided into lower-level (facial affect perception, social perception, detection of lies) and higher-level (detection of sarcasm and deception, empathy) processes. One week later, patients received the same battery after being randomized to a single dose of 40 IU intranasal oxytocin or placebo. Though the groups did not differ significantly on the social cognition composite score, oxytocin improved performance for the higher-level social cognitive tasks (Cohen's d=1.0, p=0.045). Subjects were unable to accurately guess which treatment they had received. The improvements found in higher-level social cognition encourage further studies into the therapeutic potential of oxytocin in schizophrenia. PMID- 23676254 TI - Total and high molecular weight adiponectin levels and risk of cardiovascular disease in individuals with high blood glucose levels. AB - OBJECTIVE: The association of adiponectin levels with cardiovascular disease (CVD) may vary by age and health condition. It is unknown whether adiponectin predicts CVD events among individuals with high blood glucose levels. METHODS: We conducted a nested case-control study among 15,566 men and women aged 40-85 years from four communities, who were free of CVD at baseline. During 192,181 person years of follow-up, 117 individuals subsequently developed coronary heart disease or ischemic stroke and had high plasma glucose concentrations (fasting/nonfasting >= 5.6/7.2 mmol/L or treated) at baseline. Controls were randomly selected at a 2:1 ratio and matched for sex, age, blood glucose, year of survey, fasting conditions, and community (n = 234). Baseline total and high molecular weight (HMW) adiponectin and their ratio were examined for total subjects and the association with CVD was compared between ages of 40-69 and 70-85 years. RESULTS: After adjustment for matched variables and traditional risk factors, total and HMW adiponectin and their ratio were not associated with overall risk of CVD. However, significant interactions of the associations between the age groups were found. The highest quartile for HMW adiponectin and HMW/total adiponectin ratio decreased risk of CVD compared with the lowest quartile among middle-aged individuals (multivariable-adjusted odds ratio = 0.33 [95%CI, 0.13-0.83] and 0.47 [0.22-0.98], respectively), while this association was not seen among the elderly. CONCLUSIONS: High HMW adiponectin levels may decrease the risk of CVD in middle-aged adults with high blood glucose. PMID- 23676256 TI - Self-reported learning difficulties and dietary intake in Norwegian adolescents. AB - AIM: The academic performance of children impacts future educational attainment which may increase socioeconomic status which again influences their health. One of several factors that might affect academic performance is the diet. The aim of this study was to investigate the cross sectional relation between diet and self reported reading-, writing-, and mathematical difficulties in Norwegian adolescents. METHODS: In total, 475 ninth- and tenth-grade students out of 625 eligible ones from four different secondary schools in three different municipalities in Vest-Agder County, Norway, participated, giving a participation rate of 77%. The students filled in a questionnaire with food frequency questions of selected healthy and unhealthy food items, questions of meal frequency and different learning difficulties. RESULTS: Regular breakfast was significantly associated with decreased odds of both writing and reading difficulties (OR: 0.44 (0.2-0.8), p = 0.01) and mathematical difficulties (OR: 0.33 (0.2-0.6), p <= 0.001). In addition, having lunch, dinner and supper regularly were associated with decreased odds of mathematical difficulties. Further, a high intake of foods representing a poor diet (sugar-sweetened soft drinks, sweets, chocolate, savory snacks, pizza and hot dogs) was significantly associated with increased odds of mathematical difficulties. CONCLUSIONS: Having a less-frequent intake of unhealthy foods and not skipping meals are associated with decreased odds of self reported learning difficulties in Norwegian adolescents in this study. The results of this study support the need for a larger study with a more representative sample. PMID- 23676255 TI - TLR3 deficiency protects against collagen degradation and medial destruction in murine atherosclerotic plaques. AB - OBJECTIVE: Inflammatory cell activation plays a key role in atherosclerotic plaque growth and acute complications. While secretion of proteases and inflammatory cytokines are likely involved in the development of plaque instability, the precise mechanistic pathways are not well understood. METHODS AND RESULTS: Based on our previous study, we crossed Toll-like receptor 3 (Tlr3)( /-) mice with a unique BALB-Apoe(-/-)Npc1(-/-) plaque complication-susceptible mouse model, as well as the widely-used B6-Ldlr(-/-) atherosclerosis model, to test the role of TLR3 signaling in the development of plaque instability. TLR3 deficient mice showed no change in aortic root lesion area, but displayed a marked increase in collagen and smooth muscle cell (SMC) content of lesions. Notably, Apoe(-/-)Npc1(-/-)Tlr3(-/-) mice exhibited a 50% reduction in the incidence of medial destruction, a precursor to aortic aneurysm formation. MMP-2 activity was markedly reduced in aortic extracts from Apoe(-/-)Npc1(-/-)Tlr3(-/-) compared to controls, while both MMP-2 and -9 activities were reduced in Ldlr(-/ )Tlr3(-/-) extracts. Consistent with the in vivo data, TLR3 deficiency suppressed MMP-2 activity induced by TNF-alpha or polyinosine-polycytidylic acid in macrophages from Apoe(-/-)Npc1(-/-) mice. CONCLUSIONS: TLR3 plays a critical role in regulating the degradation of extracellular matrix in lesions, in part by modulation of macrophage MMP-2 and -9 activities. PMID- 23676257 TI - Determinants for employer-paid health insurance coverage: a population-based study of the Danish labour force. AB - AIM: In 2002, the Danish tax law was changed, giving employees a tax exemption on supplemental, employer-paid health insurance. This might have conflicted with one of the key foundations of the healthcare system, namely equal access for equal needs. The aim of this study was to investigate determinants for employer-paid health insurance coverage. Because the policy change affected only people who were part of the labour force and because the public sector at that time had no tradition of providing fringe benefits, the analysis was restricted to the private labour force. METHOD: The analysis was based on data from a range of Danish person-level and company-level registers (explanatory variables). These data were combined with information on insurance status obtained from the trade organisation for insurance (dependent variable). A logistic regression was performed to estimate the odds of having employer-paid health insurance coverage. RESULTS: The individuals who were most likely to be insured were those employed in foreign companies as mid-level managers within the field of building and construction. Other important variables were the number of persons employed in a company, gender, ethnicity, region of residence, years of education, and annual income. CONCLUSIONS: Both company and individual characteristics were found to be important and significant predictors for employer-paid health insurance coverage. The Danish tax exemption on private health insurance in the years 2002-12 thus seems to have led to inequality in employer-paid health insurance coverage. PMID- 23676258 TI - Seasonal dynamics of tuberculosis epidemics and implications for multidrug resistant infection risk assessment. AB - Understanding how seasonality shapes the dynamics of tuberculosis (TB) is essential in determining risks of transmission and drug resistance in (sub)tropical regions. We developed a relative fitness-based multidrug-resistant (MDR) TB model incorporated with seasonality and a probabilistic assessment model to assess infection risk in Taiwan regions. The model accurately captures the seasonal transmission and population dynamics of TB incidence during 2006-2008 and MDR TB in high TB burden areas during 2006-2010 in Taiwan. There is ~3% probability of having exceeded 50% of the population infected attributed to MDR TB. Our model not only provides insight into the understanding of the interactions between seasonal dynamics of TB and environmental factors but is also capable of predicting the seasonal patterns of TB incidence associated with MDR TB infection risk. A better understanding of the mechanisms of TB seasonality will be critical in predicting the impact of public control programmes. PMID- 23676259 TI - A locking contoured plate for distal fibular fractures: mechanical evaluation in an osteoporotic bone model using screws of different length. AB - Osteoporotic bone with poor mechanical capacity provides limited stability after fixation of ankle fractures. Stabilization with an implant providing increased fixation strength in osteoporotic bone could reduce failure rates of fixation and allow a more functional treatment. The purpose of this study was to evaluate a locking contoured plate for fixation of distal fibular fractures in comparison with a conventional contoured plate in an osteoporotic bone model. Eighty cylinders of osteoporotic bone surrogates were fixed with the two plates. We performed torque-to-failure and cyclic testing experiments using screws of different length with a Zwick/Roell testing machine. The locking system showed higher torque-to-failure and maximum torque levels as compared with the conventional plate in torque-to-failure experiments and torsional cyclic testing. The locking contoured plate provides improved fixation strength in the osteoporotic bone model. The locking system may be appropriate for fixation of distal fibular fractures, especially in osteoporotic bone with poor mechanical capacity. PMID- 23676260 TI - Early parental death and risk of hospitalization for affective disorder in adulthood. AB - BACKGROUND: Early parental death is one of the most stressful childhood life events and may influence subsequent psychological health. We investigated the association between early parental loss and risk of hospitalization for an affective disorder in adulthood. METHODS: Our nationwide register-based cohort study comprises 1,225,660 people born in Denmark in 1970-1990, of whom 138,893 experienced the death of a parent before the age of 30 years. Follow-up for hospitalization for an affective disorder in the period 1990-2009 yielded 15,261,058 person-years and 19,867 hospitalizations for affective disorder (bereaved n = 2,644; nonbereaved n = 17,223). A Cox proportional hazards model was used to assess hazard ratios (HRs) for hospitalization with an affective disorder according to early parental death. RESULTS: People who experienced early parental death had an increased risk of hospitalization for a unipolar disorder (men: HR= 1.33; 95% confidence interval [CI] = 1.23-1.44; women: 1.23; 1.17 1.30). Stronger associations were observed for parental death caused by suicide than for other causes. For bipolar affective disorder, an increased risk of hospitalization was observed only after suicide. CONCLUSIONS: People who had lost a parent had an increased risk of hospitalization for unipolar affective disorder. Although this was particularly true for bereavement due to parental suicide, it was also found for parental death from other causes. In contrast, an increased risk of hospitalization for bipolar affective disorder was observed only after parental suicide. PMID- 23676261 TI - Investigations of gene-disease associations: costs and benefits of environmental data. AB - Environmental exposure data may improve statistical power in genetic studies when gene-environment interaction is present. However, resources invested in obtaining exposure data could instead be applied to measure disease status and genotype on more subjects. In a cohort-study setting, we consider the tradeoff between measuring only disease status and genotype for a larger study sample and measuring disease status, genotype, and environmental exposure for a smaller sample, under the gene-environment independence assumption in the study population. We focus on the power of tests for gene-disease association, applied in situations where a gene modifies risk of disease due to environmental exposure. Our results are equally applicable to exploratory genome-wide association studies and to more hypothesis-driven candidate gene investigations. We further consider the impact of misclassification for environmental exposures. We identify circumstances under which higher power is achieved via the larger study sample without measurements of environmental exposure. PMID- 23676262 TI - Long-term residential exposure to air pollution and lung cancer risk. AB - BACKGROUND: There is accumulating evidence that air pollution causes lung cancer. Still, questions remain about exposure misclassification, the components of air pollution responsible, and the histological subtypes of lung cancer that might be produced. METHODS: We investigated lung cancer incidence in relation to long-term exposure to three ambient air pollutants and proximity to major roads, using a Canadian population-based case-control study. We compared 2,390 incident, histologically confirmed lung cancer cases with 3,507 population controls in eight Canadian provinces from 1994 to 1997. We developed spatiotemporal models for the whole country to estimate annual residential exposure to fine particulate matter (PM2.5), nitrogen dioxide (NO2), and ozone (O3) over a 20-year exposure period. We carried out a subanalysis in urban centers, using exposures derived from fixed-site air pollution monitors, and also examined traffic proximity measures. Hierarchical logistic regression models incorporated a comprehensive set of individual and geographic covariates. RESULTS: The increase in lung cancer incidence (expressed as fully adjusted odds ratios [ORs]) was 1.29 (95% confidence interval = 0.95-1.76) with a ten-unit increase in PM2.5 (MUg/m), 1.11 (1.00-1.24) with a ten-unit increase in NO2 (ppb), and 1.09 (0.85-1.39) with a ten-unit increase in O3 (ppb). The urban monitor-based subanalyses generally supported the national results, with larger associations for NO2 (OR = 1.34; 1.07 1.69) per 10 ppb increase. No dose-response trends were observed, and no clear relationships were found for specific histological cancer subtypes. There was the suggestion of increased risk among those living within 100 m of highways, but not among those living near major roads. CONCLUSIONS: Lung cancer incidence in this Canadian study was increased most strongly with NO2 and PM2.5 exposure. Further investigation is needed into possible effects of O3 on development of lung cancer. PMID- 23676263 TI - Does ambient air pollution trigger stillbirth? AB - OBJECTIVE: We previously reported an increased risk of stillbirth associated with increases in trimester-specific ambient air pollutant concentrations. Here, we consider whether sudden increase in the mean ambient air pollutant concentration immediately before delivery triggers stillbirth. METHODS: We used New Jersey linked fetal death and hospital discharge data and hourly ambient air pollution measurements from particulate matter <= 2.5 mm (PM2.5), carbon monoxide (CO), nitrogen dioxide (NO2), and sulfur dioxide (SO2) monitors across New Jersey for the years 1998-2004. For each stillbirth, we assigned the concentration of air pollutants from the closest monitoring site within 10 km of the maternal residence. Using a time-stratified case-crossover design and conditional logistic regression, we estimated the relative odds of stillbirth associated with interquartile range (IQR) increases in the mean pollutant concentrations on lag day 2 and lag days 2 through 6 before delivery, and whether these associations were modified by maternal risk factors. RESULTS: The relative odds of stillbirth increased with IQR increases in the mean concentrations of CO (odds ratio [OR] = 1.20, 95% confidence interval [CI] = 1.05-1.37), SO2 (OR = 1.11, 95% CI = 1.02 1.22), NO2 (OR = 1.11, 95% CI = 0.97-1.26), and PM2.5 (OR = 1.07, 95% CI = 0.93 1.22) 2 days before delivery. We found similar associations with increases in pollutants 2 through 6 days before delivery. These associations were not modified by maternal risk factors. CONCLUSION: Short-term increases in ambient air pollutant concentrations immediately before delivery may trigger stillbirth. PMID- 23676264 TI - Mediterranean diet and cognitive function in older age. AB - BACKGROUND: Adherence to a Mediterranean diet may help prevent cognitive decline in older age, but studies are limited. We examined the association of adherence to the Mediterranean diet with cognitive function and decline. METHODS: We included 6174 participants, aged 65+ years, from the cognitive substudy of the Women's Health Study. Women provided dietary information in 1998 and completed a cognitive battery 5 years later, followed by two assessments at 2-year intervals. The primary outcomes were composite scores of global cognition and verbal memory. The alternate Mediterranean diet adherence nine-point score was constructed based on intakes of vegetables, fruits, legumes, whole grains, nuts, fish, red and processed meats, moderate alcohol, and the ratio of monounsaturated-to-saturated fats. RESULTS: After multivariable adjustment, the alternate Mediterranean diet score was not associated with trajectories of repeated cognitive scores (P for score quintiles medians-x-time interaction = 0.26 for global cognition and 0.40 for verbal memory), nor with overall global cognition and verbal memory at older ages, assessed by averaging the three cognitive measures (P trend = 0.63 and 0.44, respectively). Among alternate Mediterranean diet components, a higher monounsaturated-to-saturated fats ratio was associated with more favorable cognitive trajectories (P for ratio quintiles medians-x-time = 0.03 for global cognition and 0.05 for verbal memory). Greater whole grain intake was not associated with cognitive trajectories but was related to better averaged global cognition (P trend = 0.02). CONCLUSIONS: In this large study of older women, we observed no association of the Mediterranean diet with cognitive decline. Relations between individual Mediterranean diet components, particularly whole grains, and cognitive function merit further study. PMID- 23676265 TI - Competition between Streptococcus pneumoniae strains: implications for vaccine induced replacement in colonization and disease. AB - BACKGROUND: Vaccine-induced replacement by nonvaccine serotypes in pneumococcal colonization and disease poses a threat to the long-term effectiveness of pneumococcal vaccination. One of the main drivers for serotype replacement is likely to be the competitive interactions between pneumococcal serotypes. METHODS: We used longitudinal datasets of pneumococcal colonization among infants (American Indian and The Gambia) and toddlers (Denmark) to study the strength and mechanism of competition between pneumococcal serotypes. We characterized the strength of competition as the relative reduction in the expected time spent colonized with two serotypes (double colonization) as compared with colonization with no competition. We also assessed the mechanism of competition, that is, whether reduction in double colonization is due to reduced rate of acquisition or enhanced clearance of colonization. The three datasets were analyzed assuming both perfect (100%) and imperfect (50%) sensitivity in detection of double colonization. RESULTS: Each dataset showed strong between-serotype competition, and competition in acquisition was clearly identified. These findings remained in the secondary analysis assuming only 50% sensitivity to detect double colonization. Inferences about enhanced clearance due to competition were susceptible to the assumed sensitivity of detection. CONCLUSIONS: Strong competition between pneumococcal serotypes can explain the prompt replacement by the nonvaccine serotypes in vaccinated persons and populations. The main mechanism of between-serotype interaction was identified as competition in acquisition, which suggests that replacement in pneumococcal disease depends largely on propensities of the replacing serotypes to cause disease through acquisition of colonization. PMID- 23676266 TI - Long- and short-term exposure to PM2.5 and mortality: using novel exposure models. AB - BACKGROUND: Many studies have reported associations between ambient particulate matter (PM) and adverse health effects, focused on either short-term (acute) or long-term (chronic) PM exposures. For chronic effects, the studied cohorts have rarely been representative of the population. We present a novel exposure model combining satellite aerosol optical depth and land-use data to investigate both the long- and short-term effects of PM2.5 exposures on population mortality in Massachusetts, United States, for the years 2000-2008. METHODS: All deaths were geocoded. We performed two separate analyses: a time-series analysis (for short term exposure) where counts in each geographic grid cell were regressed against cell-specific short-term PM2.5 exposure, temperature, socioeconomic data, lung cancer rates (as a surrogate for smoking), and a spline of time (to control for season and trends). In addition, for long-term exposure, we performed a relative incidence analysis using two long-term exposure metrics: regional 10 * 10 km PM2.5 predictions and local deviations from the cell average based on land use within 50 m of the residence. We tested whether these predicted the proportion of deaths from PM-related causes (cardiovascular and respiratory diseases). RESULTS: For short-term exposure, we found that for every 10-ug/m increase in PM 2.5 exposure there was a 2.8% increase in PM-related mortality (95% confidence interval [CI] = 2.0-3.5). For the long-term exposure at the grid cell level, we found an odds ratio (OR) for every 10-ug/m increase in long-term PM2.5 exposure of 1.6 (CI = 1.5-1.8) for particle-related diseases. Local PM2.5 had an OR of 1.4 (CI = 1.3-1.5), which was independent of and additive to the grid cell effect. CONCLUSIONS: We have developed a novel PM2.5 exposure model based on remote sensing data to assess both short- and long-term human exposures. Our approach allows us to gain spatial resolution in acute effects and an assessment of long term effects in the entire population rather than a selective sample from urban locations. PMID- 23676267 TI - Risk factors for falls with use of acid-suppressive drugs. AB - BACKGROUND: Some recent reports suggest an increased risk of fractures with use of proton pump inhibitors (PPIs) and histamine type 2 receptor antagonists (H2RAs), although results are inconsistent and a causal relationship has yet to be proven. As these acid-suppressive drugs may have uncommon adverse effects on the central nervous system (CNS), such as dizziness, we investigated whether their use is associated with falls as a possible mechanism for increasing fracture risk. METHODS: A cohort study with nested case-control analysis and two validation strategies was performed using data from UK patients (aged 40-89 years) included in The Health Improvement Network database (2000-2008). Due to the large number of falls, a random sample of 20,000 cases was used for the analysis. RESULTS: The overall incidence of falls per 1000 person-years was 13.0 (95% confidence interval [CI] = 12.9-13.1). After adjustment for potential confounders, there was no relationship between falls and current use of single PPIs (odds ratio [OR] = 0.95; 95% CI = 0.89-1.02) or H2RAs (OR = 1.01; 95% CI = 0.90-1.14); there was no relationship with dose or duration of treatment. Falls were associated with CNS disorders and treatment with various pharmacological agents including antiparkinson drugs (OR = 2.7; 95% CI = 2.2-3.3) and antiepileptics (OR = 2.1; 95% CI = 1.8-2.3). CONCLUSIONS: There was no association between falls and use of PPIs or H2RAs. Any potential increase in the risk of fractures proposed to be associated with the use of acid-suppressive drugs is not via an increased risk of falls. PMID- 23676268 TI - Hyperuricemia after exposure to polychlorinated dibenzo-p-dioxins and dibenzofurans near a highly contaminated area. AB - BACKGROUND: Hyperuricemia (too much uric acid in the blood) is the predisposing condition for gout and is associated with hypertriglyceridemia, diabetes mellitus, and coronary artery disease. Polychlorinated dibenzo-p-dioxins and dibenzo-furans (PCDD/Fs) cause renal toxicity and elevate uric acid. The aim of this analysis was to investigate and clarify the effect of moderate-to-high PCDD/F exposure on hyperuricemia risk. METHODS: In this cross-sectional study, we recruited 1531 healthy participants living near a deserted pentachlorophenol factory. We measured serum levels of 17 2,3,7,8-substituted PCDD/Fs, and then examined associations between the main predictor variable, serum TEQ(DF-2005) (total PCDD/Fs 2005 World Health Organization [WHO] toxic equivalency [TEQ]), and dependent variables such as uric acid, glomerular filtration rates, and hyperuricemia risk. RESULTS: We observed a strong monotonic inverse relationship between serum TEQ(DF-2005) quartiles and the estimated glomerular filtration rate after adjusting for confounding factors (Men: beta were 0, -4.7, -6.2, and -14.8; Women: beta were 0, -6.7, -12.9, and -21.5). In addition, we observed a suggestive positive trend between serum TEQDF-2005 quartiles and uric acid only in men after adjusting for confounding factors (Men: beta were 0, 0.40, 0.36, and 0.59; P for trend <0.05). Men with serum TEQ(DF-2005) higher than the reference group's (<7.4 pg WHO(2005)-TEQ(DF/g) lipid) had a higher hyperuricemia risk after adjusting for confounding factors (25th to <50th percentile, adjusted odds ratio [AOR] = 2.20 [95% confidence interval {CI} = 1.30-3.73]; 50th to <75th percentile, AOR = 1.86 [95% CI = 1.08-3.22]; >= 75th percentile, AOR = 3.00 [95% CI = 1.69-5.31]). CONCLUSIONS: We conclude that serum TEQ(DF-2005) is an important determinant of serum uric acid levels and heightens the risk of hyperuricemia in general populations. PMID- 23676269 TI - Short-term effects of air pollution on hospital admissions in Korea. AB - BACKGROUND: Numerous studies have identified short-term effects of air pollution on morbidity in North America and Europe. The effects of air pollution may differ by region of the world. Evidence on air pollution and morbidity in Asia is limited. METHODS: We investigated associations between ambient air pollution and hospital admissions in eight Korean cities for 2003-2008. We applied a two-stage Bayesian hierarchical model to estimate city-specific effects and the overall effects across the cities. We considered lagged effects of pollutants by cause (allergic disease, asthma, selected respiratory disease, and cardiovascular disease), sex, and age (0-14, 15-64, 65-74, and >= 75 years). RESULTS: We found evidence of associations between hospital admissions and short-term exposure to air pollution. An interquartile range (IQR) increase in PM10 (30.7 ug/m) was associated with an overall increase of 2.2% (95% posterior interval = 0.5%-3.9%), 2.8% (1.3%-4.4%), 1.7% (0.9%-2.6%), and 0.7% (0.0%-1.4%) in allergic, asthma, selected respiratory, and cardiovascular admissions, respectively. For NO2 (IQR 12.2 ppb), the corresponding figures were 2.3% (0.6%-4.0%), 2.2% (0.3%-4.1%), 2.2% (0.6%-3.7%), and 2.2% (1.1%-3.4%). For O3, we found positive associations for all the studied diagnoses except cardiovascular disease. SO2 was associated with hospital admissions for selected respiratory or cardiovascular causes, whereas O3 was negatively associated with cardiovascular admissions. We found suggestive evidence for stronger associations in younger and older age groups. Associations were similar for men and women. CONCLUSIONS: Ambient air pollution was associated with increased risk of hospital admissions in Korea. Results suggest increased susceptibility among the young or the elderly for pollution effects on specific diseases. PMID- 23676270 TI - Coupled Ca2+/H+ transport by cytoplasmic buffers regulates local Ca2+ and H+ ion signaling. AB - Ca(2+) signaling regulates cell function. This is subject to modulation by H(+) ions that are universal end-products of metabolism. Due to slow diffusion and common buffers, changes in cytoplasmic [Ca(2+)] ([Ca(2+)]i) or [H(+)] ([H(+)]i) can become compartmentalized, leading potentially to complex spatial Ca(2+)/H(+) coupling. This was studied by fluorescence imaging of cardiac myocytes. An increase in [H(+)]i, produced by superfusion of acetate (salt of membrane permeant weak acid), evoked a [Ca(2+)]i rise, independent of sarcolemmal Ca(2+) influx or release from mitochondria, sarcoplasmic reticulum, or acidic stores. Photolytic H(+) uncaging from 2-nitrobenzaldehyde also raised [Ca(2+)]i, and the yield was reduced following inhibition of glycolysis or mitochondrial respiration. H(+) uncaging into buffer mixtures in vitro demonstrated that Ca(2+) unloading from proteins, histidyl dipeptides (HDPs; e.g., carnosine), and ATP can underlie the H(+)-evoked [Ca(2+)]i rise. Raising [H(+)]i tonically at one end of a myocyte evoked a local [Ca(2+)]i rise in the acidic microdomain, which did not dissipate. The result is consistent with uphill Ca(2+) transport into the acidic zone via Ca(2+)/H(+) exchange on diffusible HDPs and ATP molecules, energized by the [H(+)]i gradient. Ca(2+) recruitment to a localized acid microdomain was greatly reduced during intracellular Mg(2+) overload or by ATP depletion, maneuvers that reduce the Ca(2+)-carrying capacity of HDPs. Cytoplasmic HDPs and ATP underlie spatial Ca(2+)/H(+) coupling in the cardiac myocyte by providing ion exchange and transport on common buffer sites. Given the abundance of cellular HDPs and ATP, spatial Ca(2+)/H(+) coupling is likely to be of general importance in cell signaling. PMID- 23676271 TI - Notch2 regulates BMP signaling and epithelial morphogenesis in the ciliary body of the mouse eye. AB - The ciliary body (CB) of the mammalian eye is responsible for secreting aqueous humor to maintain intraocular pressure, which is elevated in the eyes of glaucoma patients. It contains a folded two-layered epithelial structure comprising the nonpigmented inner ciliary epithelium (ICE), the pigmented outer ciliary epithelium (OCE), and the underlying stroma. Although the CB has an important function in the eye, its morphogenesis remains poorly studied. In this study, we show that conditional inactivation of the Jagged 1 (Jag1)-Notch2 signaling pathway in the developing CB abolishes its morphogenesis. Notch2 is expressed in the OCE of the CB, whereas Jag1 is expressed in the ICE. Conditional inactivation of Jag1 in the ICE or Notch2 in the OCE disrupts CB morphogenesis, but neither affects the specification of the CB region. Notch2 signaling in the OCE is required for promoting cell proliferation and maintaining bone morphogenetic protein (BMP) signaling, both of which have been suggested to be important for CB morphogenesis. Although Notch and BMP signaling pathways are known to cross-talk via the interaction between their downstream transcriptional factors, this study suggests that Notch2 maintains BMP signaling in the OCE possibly by repressing expression of secreted BMP inhibitors. Based on our findings, we propose that Jag1-Notch2 signaling controls CB morphogenesis at least in part by regulating cell proliferation and BMP signaling. PMID- 23676272 TI - Arid5a controls IL-6 mRNA stability, which contributes to elevation of IL-6 level in vivo. AB - Posttranscriptional regulation of IL-6 has been largely uncharacterized, with the exception of the ribonuclease Regnase-1, which prevents autoimmunity by destabilizing IL-6 mRNA. Here, we identified AT-rich interactive domain containing protein 5A (Arid5a) as a unique RNA binding protein, which stabilizes IL-6 but not TNF-alpha mRNA through binding to the 3' untranslated region of IL-6 mRNA. Arid5a was enhanced in macrophages in response to LPS, IL-1beta, and IL-6. Arid5a deficiency inhibited elevation of IL-6 serum level in LPS-treated mice and suppressed IL-6 levels and the development of T(H)17 cells in experimental autoimmune encephalomyelitis. Importantly, Arid5a inhibited the destabilizing effect of Regnase-1 on IL-6 mRNA. These results indicate that Arid5a plays an important role in promotion of inflammatory processes and autoimmune diseases. PMID- 23676273 TI - Prefrontal microcircuit underlies contextual learning after hippocampal loss. AB - Specific brain circuits have been classically linked to dedicated functions. However, compensation following brain damage suggests that these circuits are capable of dynamic adaptation. Such compensation is exemplified by Pavlovian fear conditioning following damage to the dorsal hippocampus (DH). Although the DH normally underlies contextual fear and fear renewal after extinction, both can be learned in the absence of the DH, although the mechanisms and nature of this compensation are currently unknown. Here, we report that recruitment of alternate structures, specifically the infralimbic and prelimbic prefrontal cortices, is required for compensation following damage to the hippocampus. Disconnection of these cortices in DH-compromised animals and immediate early gene induction profiles for amygdala-projecting prefrontal cells revealed that communication and dynamic rebalancing within this prefrontal microcircuit is critical. Additionally, the infralimbic cortex normally plays a role in limiting generalization of contextual fear. These discoveries reveal that plasticity through recruitment of alternate circuits allows the brain to compensate following damage, offering promise for targeted treatment of memory disorders. PMID- 23676274 TI - Interaction of 14-3-3 proteins with the estrogen receptor alpha F domain provides a drug target interface. AB - Estrogen receptor alpha (ERalpha) is involved in numerous physiological and pathological processes, including breast cancer. Breast cancer therapy is therefore currently directed at inhibiting the transcriptional potency of ERalpha, either by blocking estrogen production through aromatase inhibitors or antiestrogens that compete for hormone binding. Due to resistance, new treatment modalities are needed and as ERalpha dimerization is essential for its activity, interference with receptor dimerization offers a new opportunity to exploit in drug design. Here we describe a unique mechanism of how ERalpha dimerization is negatively controlled by interaction with 14-3-3 proteins at the extreme C terminus of the receptor. Moreover, the small-molecule fusicoccin (FC) stabilizes this ERalpha/14-3-3 interaction. Cocrystallization of the trimeric ERalpha/14-3 3/FC complex provides the structural basis for this stabilization and shows the importance of phosphorylation of the penultimate Threonine (ERalpha-T(594)) for high-affinity interaction. We confirm that T(594) is a distinct ERalpha phosphorylation site in the breast cancer cell line MCF-7 using a phospho-T(594) specific antibody and by mass spectrometry. In line with its ERalpha/14-3-3 interaction stabilizing effect, fusicoccin reduces the estradiol-stimulated ERalpha dimerization, inhibits ERalpha/chromatin interactions and downstream gene expression, resulting in decreased cell proliferation. Herewith, a unique functional phosphosite and an alternative regulation mechanism of ERalpha are provided, together with a small molecule that selectively targets this ERalpha/14 3-3 interface. PMID- 23676275 TI - Sequestration of a highly reactive intermediate in an evolving pathway for degradation of pentachlorophenol. AB - Microbes in contaminated environments often evolve new metabolic pathways for detoxification or degradation of pollutants. In some cases, intermediates in newly evolved pathways are more toxic than the initial compound. The initial step in the degradation of pentachlorophenol by Sphingobium chlorophenolicum generates a particularly reactive intermediate; tetrachlorobenzoquinone (TCBQ) is a potent alkylating agent that reacts with cellular thiols at a diffusion-controlled rate. TCBQ reductase (PcpD), an FMN- and NADH-dependent reductase, catalyzes the reduction of TCBQ to tetrachlorohydroquinone. In the presence of PcpD, TCBQ formed by pentachlorophenol hydroxylase (PcpB) is sequestered until it is reduced to the less toxic tetrachlorohydroquinone, protecting the bacterium from the toxic effects of TCBQ and maintaining flux through the pathway. The toxicity of TCBQ may have exerted selective pressure to maintain slow turnover of PcpB (0.02 s(-1)) so that a transient interaction between PcpB and PcpD can occur before TCBQ is released from the active site of PcpB. PMID- 23676276 TI - A unified selection signal for attention and reward in primary visual cortex. AB - Stimuli associated with high rewards evoke stronger neuronal activity than stimuli associated with lower rewards in many brain regions. It is not well understood how these reward effects influence activity in sensory cortices that represent low-level stimulus features. Here, we investigated the effects of reward information in the primary visual cortex (area V1) of monkeys. We found that the reward value of a stimulus relative to the value of other stimuli is a good predictor of V1 activity. Relative value biases the competition between stimuli, just as has been shown for selective attention. The neuronal latency of this reward value effect in V1 was similar to the latency of attentional influences. Moreover, V1 neurons with a strong value effect also exhibited a strong attention effect, which implies that relative value and top-down attention engage overlapping, if not identical, neuronal selection mechanisms. Our findings demonstrate that the effects of reward value reach down to the earliest sensory processing levels of the cerebral cortex and imply that theories about the effects of reward coding and top-down attention on visual representations should be unified. PMID- 23676277 TI - STED super-resolution microscopy reveals an array of MINOS clusters along human mitochondria. AB - The mitochondrial inner membrane organizing system (MINOS) is a conserved large hetero-oligomeric protein complex in the mitochondrial inner membrane, crucial for the maintenance of cristae morphology. MINOS has been suggested to represent the core of an extended protein network that controls mitochondrial function and structure, and has been linked to several human diseases. The spatial arrangement of MINOS within mitochondria is ill-defined, however. Using super-resolution stimulated emission depletion (STED) microscopy and immunogold electron microscopy, we determined the distribution of three known human MINOS subunits (mitofilin, MINOS1, and CHCHD3) in mammalian cells. Super-resolution microscopy revealed that all three subunits form similar clusters within mitochondria, and that MINOS is more abundant in mitochondria around the nucleus than in peripheral mitochondria. At the submitochondrial level, mitofilin, a core MINOS subunit, is preferentially localized at cristae junctions. In primary human fibroblasts, mitofilin labeling uncovered a regularly spaced pattern of clusters arranged in parallel to the cell growth surfaces. We suggest that this array of MINOS complexes might explain the observed phenomenon of largely horizontally arranged cristae junctions that connect the inner boundary membrane to lamellar cristae. The super-resolution images demonstrate an unexpectedly high level of regularity in the nanoscale distribution of the MINOS complex in human mitochondria, supporting an integrating role of MINOS in the structural organization of the organelle. PMID- 23676279 TI - Coexistence of spiral magnetic state and weak ferromagnetism in a multiferroic, cross-controlled by external magnetic and electric fields. AB - The influence of external magnetic and electric fields on the properties of a multiferroic with a helical magnetic structure is described. Thermodynamics of the phase transition from the antiferromagnetic ferroelectric to the new magnetic state is described for a multiferroic with a perovskite-type structure. In this magnetic state a spiral spin structure and weak ferromagnetism can exist simultaneously. Such a state is a result of the first-order phase transition at a certain temperature below T(N) when, due to the Dzyaloshinskii-Moriya effect, a helical magnetic structure occurs. In this state the vectors of electrical polarization and the helicoid of magnetic moments in perovskites are mutually perpendicular and lie in the basic (ab) plane perpendicular to the main c axis. In this case an additional electrical polarization proportional to the square of magnetization appears in the (ab) plane which reduces the common polarization of the ferroelectric. It is shown that a weak ferromagnetic moment m occurs along the c axis in an applied magnetic field in addition to a modulated magnetic structure appearing in the (ab) plane. The dependence of these phenomena on the applied electric field is considered. It is shown that a sign-alternating electric field causes a linear-in-the-field variation of the magnetic moment opposite in sign to the electric field variation (i.e., the greater is the electric field, the smaller is the magnetic moment m). The observed hysteresis phenomena determining the temperature ranges of overheating and overcooling of each phase under applied magnetic and electrical fields are explained. PMID- 23676278 TI - Effect of chronic hemoplasma infection on cattle productivity. AB - The present study evaluated the effect of hemoplasmosis on cattle productivity. Prevalence of bovine hemoplasma was examined by polymerase chain reaction (PCR) using whole blood samples collected from 93 breeding cows and their 71 calves in Hokkaido, Japan. Monthly milk production records and other clinical data were compared between Mycoplasma wenyonii (Mw)-infected, "Candidatus Mycoplasma haemobos" (CMh)-infected, co-infected and PCR-negative groups. Blood chemical parameters were obtained from the 93 cows and 64 calves. PCR results showed that 89.2% (83/93) of cows and 14.1% (10/71) of calves were positive for bovine hemoplasma. Based on productivity data obtained from the 93 cows, Mw-infected, CMh-infected and co-infected cows had significantly lower monthly milk yield compared to PCR-negative cows. Furthermore, decline in milk yield was prolonged in CMh-infected and co-infected groups. No significant differences were found for other clinical findings among the four groups. Calf birth weight tended to be lower for Mw-infected, CMh-infected and co-infected groups compared to the PCR negative group. There were no significant differences in all blood parameters of cows and calves among the four groups. In addition, no significant differences were found in any parameter between hemoplasma-infected and PCR-negative calves. PMID- 23676280 TI - Field potential recording from rat hippocampus provides a functional evaluation method for assessing demyelination and myelin repair. AB - OBJECTIVES: In multiple sclerosis (MS) demyelination occurs in both white and gray matter. Here we introduce an electrophysiological approach for studying functional demyelination and myelin repair in rat hippocampus, a gray matter structure, which is frequently affected in patients suffering from MS. METHODS: Using a stereotaxic approach, bipolar stimulating and monopolar recording electrodes were respectively implanted into the perforant path and the dentate gyrus of the hippocampus of the adult male Sprague-Dawley rats weighing 280-320 g. Animals received intra-hippocampal injections of saline or lysolecithin (LPC) and afterward, changes in the parameters of field potentials recorded from the dentate gyrus granular cells in response to electrical stimulation of perforant path were investigated on days 7, 14, and 28, post-lesion. Changes in the electrophysiological parameters were compared with changes in the molecular markers of myelination (myelin basic protein, MBP) and repairing cells (Olig2). RESULTS: On day 2, a significant decrease in the slope of the population excitatory postsynaptic potential (pEPSP) and the amplitude of population spike (PS) was observed. However, during days 7-28, these parameters were increased toward control. Decreased expression of MBP and increased expression of Olig2 were observed on days 2 and 7 while the expression levels were partially reversed toward control on day 28. DISCUSSION: Our data showed the efficacy of field potential recording for studying demyelination and endogenous myelin repair in hippocampus. Changes in electrophysiological parameters were concomitant with the level of molecular markers. This recording method provides an opportunity for functional evaluation of myelin loss and repair and the effect of potential therapies. PMID- 23676281 TI - Substrate-attached materials are enriched with tetraspanins and are analogous to the structures associated with rear-end retraction in migrating cells. AB - Substrate-attached materials (SAMs) are cellular feet that remain on substrates after the treatment of adherent cells with EGTA. SAMs are thought to contain cell adhesion machineries, but their biochemical properties have not been addressed in detail. To gain insight into the molecular mechanisms operating in cell adhesions, we comprehensively identified the protein components of SAMs by liquid chromatography coupled with tandem mass spectrometry, followed by immunoblot analysis. We found that the tetraspanins CD9, CD81, and CD151 were enriched in SAMs along with other transmembrane proteins that are known to associate with tetraspanins. Notably, integrins were detected in SAMs, but the components of focal adhesions were scarcely detected. These observations are reminiscent of the "footprints" that remain on substrates when the retraction fibers at the rear of migrating cells are released, because such footprints have been reported to contain tetraspanins and integrins but not focal adhesion proteins. In support of this hypothesis, the formation of SAMs was attenuated by inhibitors of ROCK, myosin II and dynamin, all of which are known to participate in rear-end retraction in migrating cells. Furthermore, SAMs left on collagen-coated substrates were found by electron microscopy to be fewer and thinner than those on laminin-coated substrates, reflecting the thin and fragile retraction fibers of cells migrating on collagen. Collectively, these results indicate that SAMs closely resemble the footprints and retraction fibers of migrating cells in their protein components, and that they are yielded by similar mechanisms. PMID- 23676284 TI - The impact of the condenser on cytogenetic image quality in digital microscope system. AB - BACKGROUND: Optimizing operational parameters of the digital microscope system is an important technique to acquire high quality cytogenetic images and facilitate the process of karyotyping so that the efficiency and accuracy of diagnosis can be improved. OBJECTIVE: This study investigated the impact of the condenser on cytogenetic image quality and system working performance using a prototype digital microscope image scanning system. METHODS: Both theoretical analysis and experimental validations through objectively evaluating a resolution test chart and subjectively observing large numbers of specimen were conducted. RESULTS: The results show that the optimal image quality and large depth of field (DOF) are simultaneously obtained when the numerical aperture of condenser is set as 60% 70% of the corresponding objective. Under this condition, more analyzable chromosomes and diagnostic information are obtained. As a result, the system shows higher working stability and less restriction for the implementation of algorithms such as autofocusing especially when the system is designed to achieve high throughput continuous image scanning. CONCLUSIONS: Although the above quantitative results were obtained using a specific prototype system under the experimental conditions reported in this paper, the presented evaluation methodologies can provide valuable guidelines for optimizing operational parameters in cytogenetic imaging using the high throughput continuous scanning microscopes in clinical practice. PMID- 23676282 TI - Environmental exposure to metals and children's growth to age 5 years: a prospective cohort study. AB - In this prospective cohort study, based on 1,505 mother-infant pairs in rural Bangladesh, we evaluated the associations between early-life exposure to arsenic, cadmium, and lead, assessed via concentrations in maternal and child urine, and children's weights and heights up to age 5 years, during the period 2001-2009. Concurrent and prenatal exposures were evaluated using linear regression analysis, while longitudinal exposure was assessed using mixed-effects linear regression. An inverse association was found between children's weight and height, age-adjusted z scores, and growth velocity at age 5 years and concurrent exposure to cadmium and arsenic. In the longitudinal analysis, multivariable adjusted attributable differences in children's weight at age 5 years were -0.33 kg (95% confidence interval (CI): -0.60, -0.06) for high (>=95th percentile) arsenic exposure and -0.57 kg (95% CI: -0.88, -0.26) for high cadmium exposure, in comparison with children with the lowest exposure (<=5th percentile). Multivariable-adjusted attributable differences in height were -0.50 cm (95% CI: 1.20, 0.21) for high arsenic exposure and -1.6 cm (95% CI: -2.4, -0.77) for high cadmium exposure. The associations were apparent primarily among girls. The negative effects on children's growth at age 5 years attributable to arsenic and cadmium were of similar magnitude to the difference between girls and boys in terms of weight (-0.67 kg, 95% CI: -0.82, -0.53) and height (-1.3 cm, 95% CI: 1.7, -0.89). PMID- 23676285 TI - Effects of hypothetical type 2 diabetes genetic testing on parents' efforts to prevent diabetes in children. AB - OBJECTIVE: To examine the effect of hypothetical genetic susceptibility test results on diabetic parents' intention to prevent type 2 diabetes (T2D) in their children. METHODS: Parents with T2D indicated their intention to prevent T2D in their youngest child at baseline and after a hypothetical positive and negative T2D genetic test result. We calculated mean/median "preventive intention scores" for each scenario and examined the association between parents' score change and parent/child characteristics. RESULTS: A total of 63% of parents reported that their child had "almost no risk" or "slight risk" of developing T2D. Parents' median baseline preventive intention score was 8. It increased to 10 after a positive test result and decreased to 5 after a negative test result. CONCLUSIONS: Negative T2D genetic susceptibility test results may decrease diabetic parents' intentions to prevent T2D for their children. Future research studies in a real-life clinical context should examine this phenomenon. PMID- 23676286 TI - Sensitivity and specificity of obesity diagnosis in pediatric ambulatory care in the United States. AB - OBJECTIVE: We examined the sensitivity and specificity of an obesity diagnosis in a nationally representative sample of pediatric outpatient visits. METHODS: We used the 2005 to 2009 National Ambulatory Medical Care and National Hospital Ambulatory Medical Care surveys. We included visits with children 2 to 18 years, yielding a sample of 48 145 database visits. We determined 3 methods of identifying obesity: documented body mass index (BMI) >=95th percentile; International Classification of Diseases, Ninth Revision (ICD-9) code; and positive answer to the question, "Does the patient now have obesity?" Using BMI as the gold standard, we calculated the sensitivity and specificity of a clinical obesity diagnosis. RESULTS: Among the 19.5% of children who were obese by BMI, 7.0% had an ICD-9 code and 15.2% had a positive response to questioning. The sensitivity of an obesity diagnosis was 15.4%, and the specificity was 99.2%. CONCLUSIONS: The sensitivity of the obesity diagnosis in pediatric ambulatory visits is low. Efforts are needed to increase identification of obese children. PMID- 23676287 TI - Canadian pediatricians' prescribing practices for community-acquired pneumonia. PMID- 23676288 TI - An after-hours rapid access pediatric weight management clinic increases show rate. PMID- 23676289 TI - Obesity outcomes in children with a history of failure to thrive. PMID- 23676290 TI - Reference point indentation study of age-related changes in porcine femoral cortical bone. AB - The reference point indentation (RPI) method is a microindentation technique involving successive indentation cycles. We employed RPI to measure average stiffness (Ave US), indentation distance increase (IDI), total indentation distance (TID), average energy dissipated (Ave ED), and creep indentation distance (CID) of swine femoral cortical bone (mid-diaphysis) as a function of age (1, 3.5, 6, 14.5, 24, and 48 months) and loading directions (longitudinal and transverse). The Ave US increases with animal age, while the IDI, TID, Ave ED, and CID decrease with age, for both longitudinal (transverse surface) and transverse (periosteal surface) loading directions. Longitudinal measurements generally give higher Ave US and lower IDI and TID values compared to transverse measurements. The RPI measurements show similar trends to those obtained using nanoindentation test, and ash and water content tests. PMID- 23676291 TI - Apical contractility in growing epithelium supports robust maintenance of smooth curvatures against cell-division-induced mechanical disturbance. AB - In general, a rapidly growing epithelial sheet during tissue morphogenesis shows a smooth and continuous curvature on both inner cavity (apical) and basement membrane (basal) sides. For instance, epithelia of the neural tube and optic vesicle in the early embryo maintain continuous curvatures in their local domains, even during their rapid growth. However, given that cell divisions, which substantially perturb the local force balance, frequently and successively occur in an uncoordinated manner, it is not self-evident to explain how the tissue keeps a continuous curvature at large. In the majority of developing embryonic epithelia with smooth surfaces, their curvatures are apically concave, because of the presence of strong tangential contractile force on the apical side. In this numerical study, we demonstrate that tangential contractile forces on the apical surface play a critical role in the maintenance of smooth curvatures in the epithelium and reduce irregular undulations caused by uncoordinated generation of local pushing force. Using a reversible network reconnection (RNR) model, which we previously developed to make numerical analyses highly reproducible even under rapid tissue-growth conditions, we performed simulations for morphodynamics to examine the effect of apical contractile forces on the continuity of curvatures. Interestingly, the presence of apical contractile forces suppressed irregular undulations not only on the apical side but also on the basal surface. These results indicate that cellular contractile forces on the apical surface control not only the shape at a single cell level but also at a tissue level as a result of emergent mechanical coordination. PMID- 23676292 TI - Commentary on "Cognition in schizophrenia". PMID- 23676293 TI - P2Y12 receptor blockade augments glycoprotein IIb-IIIa antagonist inhibition of platelet activation, aggregation, and procoagulant activity. AB - BACKGROUND: New antiplatelet agents that provide greater, more consistent inhibition of the platelet ADP receptor P2Y12 may be used in combination with glycoprotein (GP) IIb-IIIa antagonists, but their combined effect on platelet function and procoagulant activity is not well studied. Therefore, the objective of this study was to evaluate the independent and complementary effects of P2Y12 and GPIIb-IIIa inhibition on platelet function and procoagulant activity. METHODS AND RESULTS: Healthy donor blood was treated with the active metabolite of prasugrel (R-138727 5 MUmol/L), GPIIb-IIIa antagonists (abciximab 3 MUg/mL or eptifibatide 0.9 MUg/mL), and combinations thereof, exposed to physiologically relevant agonists (collagen and ADP) and then evaluated for markers of platelet activation and procoagulant activity. Significant interactions between R-138727 and GPIIb-IIIa antagonists were observed. R-138727 and the GPIIb-IIIa antagonists had additive inhibitory effects on collagen-stimulated platelet aggregation and on the collagen plus ADP-stimulated level of activated platelet surface GPIIb IIIa. R-138727 and abciximab each inhibited collagen plus ADP-stimulated platelet phosphatidylserine expression and prothrombin cleavage, and the combination produced greater inhibition than achieved with abciximab alone. In contrast, eptifibatide did not inhibit, but instead enhanced, collagen plus ADP-stimulated prothrombin cleavage. Addition of R-138727 reduced prothrombin cleavage in eptifibatide-treated samples, suggesting a novel mechanism for potential benefit from combined prasugrel and eptifibatide treatment. CONCLUSIONS: The complementary effects of abciximab and R-138727 on platelet activation, aggregation, and procoagulant activity suggest their combined use may, to a greater degree than with either agent alone, reduce thrombus formation in vivo. PMID- 23676295 TI - No cardiovascular benefit from fish oil for high risk adults. PMID- 23676294 TI - Improved survival after heart failure: a community-based perspective. AB - BACKGROUND: Heart failure is a highly prevalent, morbid, and costly disease with a poor long-term prognosis. Evidence-based therapies utilized over the past 2 decades hold the promise of improved outcomes, yet few contemporary studies have examined survival trends in patients with acute heart failure. The primary objective of this population-based study was to describe trends in short- and long-term survival in patients hospitalized with acute decompensated heart failure (ADHF). A secondary objective was to examine patient characteristics associated with decreased long-term survival. METHODS AND RESULTS: We reviewed the medical records of 9748 patients hospitalized with ADHF at all 11 medical centers in central Massachusetts during 1995, 2000, 2002, and 2004. Patients hospitalized with ADHF were more likely to be elderly and to have been diagnosed with multiple comorbidities in 2004 compared with 1995. Over this period, survival was significantly improved in-hospital, and at 1, 2, and 5 years postdischarge. Five-year survival rates increased from 20% in 1995 to 29% in 2004. Although survival improved substantially over time, older patients and patients with chronic kidney disease, chronic obstructive pulmonary disease, anemia, low body mass index, and low blood pressures had consistently lower postdischarge survival rates than patients without these comorbidities. CONCLUSION: Between 1995 and 2004, patients hospitalized with ADHF have become older and increasingly comorbid. Although there has been a significant improvement in survival among these patients, their long-term prognosis remains poor, as fewer than 1 in 3 patients hospitalized with ADHF in 2004 survived more than 5 years. PMID- 23676296 TI - Family caregiving at the intersection of private care by migrant home care workers and public care by nursing staff. AB - BACKGROUND: This study evaluated private family caregiving at the intersection of private migrant home care and public nursing care on the hospitalization of an older patient. METHODS: Seventy-three individuals were interviewed, including older hospitalized patients, their family members, accompanying migrant home care workers, and nursing personnel. RESULTS: There was no clear consensus concerning the role of family members. Although family members emphasized care management as their main role, the other three groups emphasized that the family members' mere physical presence was their main role. All four groups identified potential barriers to family caregiving, rather than motives for family caregiving, hence pointing to a potential discrepancy between expected and performed family caregiving roles. CONCLUSIONS: An indication of the lack of clarity concerning family caregiving roles stems from the finding that family members were frequently viewed as unengaged and neglectful, yet at times they were criticized for being overly involved in patient care. Implications for the care of hospitalized older adults are discussed. PMID- 23676297 TI - Expert approaches to promote adolescent physical activity in Iran: development of the promoting strategies using the Nominal Group Technique meeting. AB - BACKGROUND: Several studies have shown that physical activity decreases as the age increases. This study was for evaluating the perspectives of health sciences specialists or informants on the strategies for increasing physical activity among Iranian adolescents using Nominal Group Technique (NGT). METHODS: a semiquantitative/qualitative methodology research using NGT for prioritizing the strategies for alleviating the physical activities among Iranian adolescents based on the opinions of health sciences experts. This study conducted in Tehran, Iran, 2011. RESULTS: Overall, 16 items received scores from 2-29 and were further listed as the accepted strategies for promoting physical activity among adolescents. The most and least recommended strategies were respectively in the categories of school, neighborhood and family. This study findings show 'the constructionist activities or strategies (eg, claim-making, image-making, myth constructing and framing) among adolescents using main claim-makers of Iranian society, including the state-sponsored media.,' received the highest score by all the participants of NGT. CONCLUSIONS: The interesting finding of this study is the special view point of the specialists to role of socioecological factors in promoting physical activity in the context of Iranian society. PMID- 23676298 TI - Colloid transport in dual-permeability media. AB - It has been widely reported that colloids can travel faster and over longer distances in natural structured porous media than in uniform structureless media used in laboratory studies. The presence of preferential pathways for colloids in the subsurface environment is of concern because of the increased risks for disease caused by microorganisms and colloid-associated contaminants. This study presents a model for colloid transport in dual-permeability media that includes reversible and irreversible retention of colloids and first-order exchange between the aqueous phases of the two regions. The model may also be used to describe transport of other reactive solutes in dual-permeability media. Analytical solutions for colloid concentrations in aqueous and solid phases were obtained using Laplace transformation and matrix decomposition. The solutions proved convenient to assess the effect of model parameters on the colloid distribution. The analytical model was used to describe effluent concentrations for a bromide tracer and 3.2- or 1-MUm-colloids that were observed after transport through a composite 10-cm long porous medium made up of a cylindrical lens or core of sand and a surrounding matrix with sand of a different grain size. The tracer data were described very well and realistic estimates were obtained for the pore-water velocity in the two flow domains. An accurate description was also achieved for most colloid breakthrough curves. Dispersivity and retention parameters were typically greater for the larger 3.2-MUm-colloids while both reversible and irreversible retention rates tended to be higher for the finer sands than the coarser sand. The relatively small sample size and the complex flow pattern in the composite medium made it difficult to reach definitive conclusions regarding transport parameters for colloid transport. PMID- 23676299 TI - Generalized alopecia with vasculitis-like changes in a dog with babesiosis. AB - A locally bred, 12-year-old, intact female Satsuma dog presented with generalized alopecia. Erythema, crusts and desquamation were observed primarily on the truck. Papules and erosions were present in the pinnae, and there were multiple areas of skin necrosis on the right forelimb. The cutaneous lesions had not responded to treatment with systemic antibiotics and prednisolone. The dog also had progressive anemia. Babesia gibsoni was detected in the blood, and the dog was treated with antiprotozoal agents. The skin lesions and anemia improved, but relapsed after the treatment was discontinued. Histopathological examination of skin biopsies revealed findings suggestive of early leukocytoclastic vasculitis or ischemic vasculopathy. PMID- 23676300 TI - Microscopic distribution of metal dopants and anion vacancies in Fe-doped BaTiO(3 delta) single crystals. AB - A detailed microscopic structural study on two single crystalline dilute magnetic oxides, BaTi0.95Fe0.05O(3-delta) with and without perceptible delta, has been carried out. Although it has been reported earlier that varying delta significantly affects high temperature ferromagnetism, the real distribution/redistribution of vacancies and dopant Fe ions inside the 6H hexagonal structure was never probed. This study reveals that oxygen vacancies reduce the dopant Fe(3+) ions to Fe(2+) and mostly accumulate around these Fe(2+) ions. Another distinct trend is the tendency of the dopant Fe ions to get closer instead of being distributed randomly, thereby creating Fe2(2+)O(9-delta') like dimers within the 6H hexagonal unit cell. This experimental observation definitively confirms previous hypotheses based on theoretical models. PMID- 23676302 TI - American indians and spiritual needs during hospitalization: developing a model of spiritual care. AB - PURPOSE: Although spirituality is typically intertwined with health in Native cultures, little research has examined the relationship between American Indians' spiritual needs and overall satisfaction with service provision during hospitalization. This study examined this relationship, in tandem with the effects of 8 potential mediators, to develop a model of spiritual care for older hospitalized American Indians. DESIGN AND METHODS: Structural equation modeling was used with a sample of American Indians (N = 860), aged 50 and older, who were consecutively discharged from hospitals across the United States over a 12-month period. RESULTS: As posited, addressing spiritual needs was positively associated with overall satisfaction with service provision. The relationship between spiritual needs and satisfaction was fully mediated by 4 variables: nursing staff, the discharge process, physicians, and visitors. IMPLICATIONS: As the first study to develop and test a model of spiritual care for older hospitalized American Indians, this study provides practitioners with the information to provide more effective, culturally relevant services to older American Indians. PMID- 23676301 TI - Positive affect is associated with fewer sleep problems in older caregivers but not noncaregivers. AB - PURPOSE OF THE STUDY: Older adults who are depressed or are caregivers experience more sleep problems, whereas recent studies suggest that adults with high positive affect (PA) have fewer sleep problems. This study examined whether the associations of PA and depressive symptoms with sleep problems differed between caregivers and noncaregivers. DESIGN AND METHODS: Face-to-face interviews were conducted with 92 caregivers to a relative or friend with Alzheimer's disease or Parkinson's disease, and 137 noncaregivers aged 60 years and older (mean 73.8+/ 7.9 years) from the Boston, Massachusetts, metropolitan area. Sleep problems were assessed using the Pittsburgh Sleep Quality Index (PSQI). Respondents were categorized as high PA (n = 122), low PA (n = 69), and depressive symptoms (n = 38) based on the Center for Epidemiologic Studies-Depression scale. RESULTS: The mean PSQI score was 5.19 (SD = 3.26) and did not differ by caregiving status. In multivariable linear regression analyses among caregivers, those with high PA had significantly fewer sleep problems than their counterparts with low PA (adjusted mean PSQI score was 4.16 [SE = 0.50] vs. 5.69 [SE = 0.58], p = .05), whereas caregivers with depressive symptoms reported slightly more problems (adjusted mean 6.92 [SE = 0.80], p = .22). High PA and depressive symptoms were not associated with sleep problems among noncaregivers (adjusted mean PSQI scores were 4.88 [SE = 0.35], 5.38 [SE = 0.51], and 5.99 [SE = 0.73], respectively). Similar associations were found with PSQI scale components. IMPLICATIONS: Results suggest that routine screening and interventions to increase PA may reduce sleep problems among older caregivers. PMID- 23676303 TI - Parvovirus evades interferon-dependent viral control in primary mouse embryonic fibroblasts. AB - Engagement of innate viral sensors elicits a robust antiviral program via the induction of type I interferons (IFNs). Innate defense mechanisms against ssDNA viruses are not well defined. Here, we examine type I IFN induction and effectiveness in controlling a ssDNA virus. Using mouse embryonic fibroblasts (MEFs), we found that a murine parvovirus, minute virus of mice (MVMp), induced a delayed but significant IFN response. MEFs deficient in mitochondrial antiviral signaling protein (MAVS) mounted a wild-type IFN response to MVMp infection, indicating that RIG-I-dependent RNA intermediate recognition is not required for innate sensing of this virus. However, MVMp-induced IFNs, as well recombinant type I IFNs, were unable to inhibit viral replication. Finally, MVMp infected cells became unresponsive to Poly (I:C) stimulation. Together, these data suggest that the MVMp efficiently evades antiviral immune mechanisms imposed by type I IFNs, which may in part explain their efficient transmission between mice. PMID- 23676304 TI - Variations in radiotherapy delivery in England - evidence from the national radiotherapy dataset. AB - AIMS, MATERIALS AND METHOD: Data in the national radiotherapy dataset for England for 2009-2011 is based upon downloads of activity from every linear accelerator in the country through its oncology management system linked to the local patient administration system to give a full overview of each patient episode. RESULTS: An analysis of this dataset shows that there is still a considerable variation in radiotherapy activity across the country, with a two-fold variation between the most and least active networks. Lower activity is seen in London and the southeast compared with the rest of the country, but when the data are split between the north and south of the country, no such variation is seen. Activity is higher in smaller centres and non-teaching centres. About half of all treatment is palliative and this proportion does not vary with geography, although there is considerable variation between individual centres in the proportion of radical radiotherapy given. There is a trend towards less use of radiotherapy, both radical and palliative, in the more deprived population groups, although no change in the relative use of palliative and radical treatment. CONCLUSION: It is important to emphasise that these data currently reflect activity patterns only and do not reflect quality of care or treatment outcomes, which will be achieved by linkage with cancer registry data in the future. PMID- 23676305 TI - Multilevel correlates of physical activity for early, mid, and late adolescent girls. AB - BACKGROUND: We examined associations among multilevel variables and girls' physical activity to determine whether they vary at different adolescent ages. METHODS: All field sites of the Trial of Activity for Adolescent Girls contributed participants from 6th (n = 1576) and 8th grades (n = 3085). The Maryland site contributed an 11th grade sample (n = 589). Questionnaires were used to obtain demographic and psychosocial information (individual- and social level variables); height, weight, and triceps skinfold to assess body composition; interviews and surveys for school-level data; and geographical information systems and self-report for neighborhood-level variables. Moderate to vigorous physical activity minutes (MVPA) were assessed from accelerometers. Mixed models (13 individual, 5 social, 15 school, 12 neighborhood variables) were used to determine multilevel associations. RESULTS: Variables at individual, social, school, and neighborhood levels were associated with MVPA, but differed across grades. Lower percent body fat, higher social support from friends, and lower school math scores were associated with higher MVPA at 6th and 8th grade. Higher physical activity self-efficacy was associated with higher MVPA at 11th grade. Only lower physical activity barriers were associated with higher MVPA at all grades. CONCLUSION: MVPA is a complex behavior with fluid, multilevel correlates that differ among girls across middle and high school. PMID- 23676306 TI - Imaging in epilepsy. AB - This is a review of the use of neuroimaging in epilepsy outlining the imaging strategy for new onset seizures and also those with intractable focal seizures being investigated as potential epilepsy surgery candidates. The review describes the radiological features of conditions which may be encountered in each clinical context, together with advice on the optimum imaging protocols to detect epileptogenic lesions. The review also presents the role of imaging in presurgical planning, the demonstration of eloquent function, grid placement and postoperative assessment. PMID- 23676307 TI - Augmentation of GABAergic neurotransmission by novel N-(substituted)-2-[4 (substituted)benzylidene]hydrazinecarbothioamides-a potential anticonvulsant approach. AB - New N-(substituted)-2-[4-(substituted)benzylidene]hydrazinecarbothioamides were designed, synthesized and evaluated for anticonvulsant activity and neurotoxicity. The anticonvulsant activity was established in three seizure models i.e. MES, scMET and 6 Hz model. The most active compound was N-(4 methoxyphenyl)-2-[4-(4-methylphenoxy) benzylidene]hydrazinecarbothioamide PT 30 which showed 100% protection in both MES and 6 Hz test. Compound PT 30 showed protection at three different time points in 6 Hz test at a dose of 100 mg/kg. Compound 2-[4-(4-Chlorophenoxy)benzylidene]-N-cyclohexylhydrazine carbothioamide PT 4 was also found to be active in both MES and 6 Hz test. Titled compounds exhibited good binding properties with epilepsy molecular targets GABA (A) delta and GABA (A) alpha-1 receptors, in LGA based flexible docking studies. Compounds PT 30 and PT 4 were found to elevate gamma-aminobutyric acid (GABA) levels in the midbrain and medulla oblongata regions of rat brain. A computational study was carried out for calculation of pharmacophore pattern and prediction of pharmacokinetic properties. PMID- 23676308 TI - Initial neuropsychological profile of a series of 20 patients with logopenic variant of primary progressive aphasia. AB - BACKGROUND: Logopenic variant of primary progressive aphasia (LPPA) is classically considered as an isolated language disorder, but verbal short-term memory deficit induces difficulties in neuropsychological tests that are not intended to evaluate language. OBJECTIVE: The aim of this study is to describe the initial symptoms and neuropsychological profiles of LPPA. METHODS: A retrospective study was conducted with a series of 20 consecutive patients diagnosed with LPPA. Clinical, neuroimaging, neuropsychological, and linguistic examinations are reported. The first neuropsychological examinations (mean time between neuropsychological assessment and diagnosis: 11 months) were then compared to 20 patients with mild cognitive impairment (MCI) and 20 patients with Alzheimer's disease (AD) matched by age, gender, and education level. RESULTS: A recent onset or aggravation of anxiety disorders was frequently reported. An unusual neuropsychological profile, different from that of AD or MCI, was observed: dissociation between verbal and visual memory performances, poor encoding performances on verbal memory tests, and preserved orientation to time, difficulties with mental calculation and fluency tasks. Biparetal abnormality and left hippocampal diaschisis was frequently observed. Asymptomatic dopaminergic depletion was observed in four patients. CONCLUSION: Our study identifies that de novo or recently worsening anxiety and specific neuropsychological profiles call for screening for LPPA, including a linguistic examination. Sometimes, there may be a continuum between LPPA and corticobasal syndrome. PMID- 23676309 TI - Effect of minocycline on carotid atherosclerotic plaques. AB - OBJECTIVES: To investigate whether minocycline could attenuate the expression of extracellular matrix metalloproteinase inducer (CD147) and matrix metalloproteinase (MMP)-9 and enhance stability of atherosclerotic plaques. METHODS: Twenty-four New Zealand rabbits underwent balloon-induced endothelial injury of right carotid artery and were fed 1% cholesterol diet for 16 weeks. From week 12 to week 16, the animals were intervened with minocycline (2.5 mg kg( 1) d(-1), group A), atorvastatin (2.5 mg kg(-1) d(-1), group B) or were not treated with drugs (group C). After 16 weeks, all the rabbits were sacrificed by Chinese Russell's viper venom and histamine injection, then serum and right common carotid arteries were collected for biochemical, histological, and reverse transcription polymerase chain reaction (RT-PCR) analysis. RESULTS: A rabbit model of atherosclerotic vulnerable plaques was established. Minocycline significantly increased the thickness of the plaque fibrous caps and decreased the positive staining area of macrophages in group A. When compared with group C, CD147, and MMP-9 expression in both mRNA and protein level were remarkably reduced in group A and B (P < 0.05). However, there was no significant difference between group A and B. Serum TC and low-density lipoprotein cholesterol (LDL-C) levels were decreased in the Atorvastatin group (P < 0.05), while minocycline had no obvious influence on the serum lipid levels. The incidence of plaque ruptures in group A (14.3%) and group B (14.3%) was lower than that in group C (66.7%, P < 0.05). CONCLUSIONS: Minocycline intervention significantly reduced the activity of CD147, MMP in plaque and histologically enhanced plaque stabilization. Minocycline was equally effective as Atorvastatin. PMID- 23676310 TI - Oligosaccharide analysis in urine by maldi-tof mass spectrometry for the diagnosis of lysosomal storage diseases. AB - BACKGROUND: There are 45 known genetic diseases that impair the lysosomal degradation of macromolecules. The loss of a single lysosomal hydrolase leads to the accumulation of its undegraded substrates in tissues and increases of related glycoconjugates in urine, some of which can be detected by screening of free oligosaccharides (FOS) in urine. Traditional 1-dimensional TLC for urine oligosaccharide analysis has limited analytical specificity and sensitivity. We developed fast and robust urinary FOS and glycoaminoacid analyses by MALDI-time of-flight/time-of-flight (MALDI-TOF/TOF) mass spectrometry for the diagnosis of oligosaccharidoses and other lysosomal storage diseases. METHODS: The FOS in urine equivalent to 0.09 mg creatinine were purified through sequential passage over a Sep-Pak C18 column and a carbograph column and were then permethylated. MALDI-TOF/TOF was used to analyze the permethylated FOS. We studied urine samples from individuals in 7 different age groups ranging from 0-1 months to >= 17 years as well as urine from known patients with different lysosomal storage diseases. RESULTS: We identified diagnostic urinary FOS patterns for alpha-mannosidosis, galactosialidosis, mucolipidosis type II/III, sialidosis, alpha-fucosidosis, aspartylglucosaminuria (AGU), Pompe disease, Gaucher disease, and GM1 and GM2 gangliosidosis. Interestingly, the increase in urinary FOS characteristic of lysosomal storage diseases relative to normal FOS appeared to correlate with the disease severity. CONCLUSIONS: The analysis of urinary FOS by MALDI-TOF/TOF is a powerful tool for first-tier screening of oligosaccharidoses and lysosomal storage diseases. PMID- 23676311 TI - Exercise throughout pregnancy does not cause preterm delivery: a randomized, controlled trial. AB - BACKGROUND: In spite of an extensive knowledge of the physiologic features of exercise during pregnancy, we still lack a comprehensive understanding of the effects of different types, intensities and duration of exercise throughout pregnancy on maternal and fetal well being. The aim of the current study was to examine the influence of an aerobic exercise program throughout pregnancy on gestational age at the moment of delivery. METHODS: This study was a randomized controlled trial. Three hundred and twenty Caucasian (Spanish) healthy pregnant women with singleton gestation were randomly assigned to either an exercise (n = 160) or a control (n = 160) group. Gestational age (weeks) and other outcomes were measured. The exercise program included 85 sessions (general fitness class, 3 times/week, 55-60 min/session from weeks 8-10 to weeks 38-39 of pregnancy). RESULTS: Two hundred and ninety women were analyzed (exercise group EG, n = 138, control group CG, n = 152). The mean gestational age did not differ between groups (EG= 39.7 +/- 1.3 vs CG= 39.6 +/- 1.1 weeks, P = .81). Relative to preterm deliveries in EG we found 6 (4.3%) and 11 (7.2%) in CG, (P = .73). CONCLUSIONS: A supervised program of moderate exercise performed throughout pregnancy is not a risk of preterm delivery for healthy pregnant women. PMID- 23676312 TI - Effects of the chemical chaperone 4-phenylbutylate on the function of the serotonin transporter (SERT) expressed in COS-7 cells. AB - The serotonin transporter (SERT) is involved in various psychiatric disorders, including depression and autism. Recently, chemical chaperones have been focused as potential therapeutic drugs that can improve endoplasmic reticulum (ER) stress related pathology. In this study, we used SERTtransfected COS-7 cells to investigate whether 4-phenylbutylate (4-PBA), a chemical chaperone, affects the membrane trafficking and uptake activity of SERT. Treatment with 4-PBA for 24 h dose-dependently increased the uptake activity of SERT. In accordance with increased SERT activity, the expression of maturely glycosylated SERT was increased, while the expression of immaturely glycosylated SERT was decreased. This finding suggests that 4-PBA increased the functional SERT with mature glycosylation via accelerating its folding and trafficking. 4-PBA also increased the activity of the C-terminus-deleted mutant SERT (SERTDeltaCT), which was stacked in the ER, and decreased SERTDeltaCT-induced ER stress, further supporting the idea that 4-PBA acts as a chemical chaperone for SERT. Imaging studies showed that fluorescence-labeled SERT was gradually and significantly translocated to the plasma membrane by 4-PBA. These results suggest that 4-PBA and related drugs can potentially affect serotonergic neural transmission by functioning as chaperones, thereby providing a novel therapeutic approach for SERT-related diseases. PMID- 23676313 TI - Acceleration of reflex maturation and physical development in suckling rats: effects of a maternal diet containing lipids from goat milk. AB - OBJECTIVE: To investigate the effects of lipids from goat milk containing conjugated linoleic acids on body weight and reflex ontogeny of neonatal rats treated during the prenatal and suckling periods. METHODS: Three groups were studied: soybean oil (S), coconut oil (C), and goat milk lipids (GM). Reflex maturation (palm grasp, righting reflex, cliff avoidance, vibrissae placing, negative geotaxis, auditory startle, and free-fall righting) as well as body weight evolution were recorded during lactation. RESULTS: Data demonstrated that the lipids from goat milk accelerated body weight evolution as well as all the reflex maturation investigated (P < 0.05). DISCUSSION: The supply of goat's milk offered to Wistar rats during pregnancy and lactation provided a variety of fatty acids necessary to accelerate the development of offspring. PMID- 23676314 TI - A cluster-glass magnetic state in R5Pd2 (R = Ho, Tb) compounds evidenced by AC susceptibility and neutron scattering measurements. AB - AC- and DC-susceptibility, high-field magnetization and neutron diffraction measurements have been performed in order to study the magnetic state of R5Pd2 (R = Ho, Tb) compounds. The results show that both compounds undergo cluster-glass freezing upon cooling below Tf. According to the neutron diffraction a long-range magnetic order is absent down to 2 K and magnetic clusters with short-range incommensurate antiferromagnetic correlations exist not only below Tf but also in a wide temperature range above the freezing temperature (at least up to 2Tf). A complex cluster-glass magnetic state existing in Ho5Pd2 and Tb5Pd2 down to low temperatures results in rather complicated magnetization behavior in DC and AC magnetic fields. Such an unusual magnetic state in compounds with a high rare earth concentration may be associated with the layered type of their crystal structure and with substantial atomic disorder, which results in frustrations in the magnetic subsystem. PMID- 23676315 TI - Improvement in myocardial function by Terminalia arjuna in streptozotocin-induced diabetic rats: possible mechanisms. AB - Vascular complications are a leading cause of mortality and morbidity in diabetic patients. Herbal drugs are increasingly being used in the treatment of cardiovascular disorders. The present study was designed to examine the therapeutic potential of Terminalia arjuna bark extract in improving myocardial function in streptozotocin (STZ)-induced diabetic rats. After 8 weeks of STZ administration, rats showed a decline in left ventricular pressure (LVP), maximal rate of rise and fall in LVP (LV [dP/dt] max and LV [dP/dt] min), cardiac contractility index (LV [dP/dt] max/LVP), and rise in LV end-diastolic pressure. Altered lipid profile, oxidative stress, and increased levels of endothelin 1 (ET 1), tumor necrosis factor-alpha (TNF-alpha), and interleukin 6 (IL-6) along with histological changes in heart and pancreas were observed in diabetic rats. T arjuna significantly attenuated cardiac dysfunction and myocardial injury in diabetic rats. It also reduced oxidative stress, ET-1, and inflammatory cytokine levels. The decreased body weight, heart rate blood pressure, and raised blood sugar in diabetic rats did not improve after T arjuna therapy. Results suggest that T arjuna bark extract improves the altered myocardial function in diabetic rats possibly through maintaining endogenous antioxidant enzyme activities, decreasing ET-1 and cytokine levels. PMID- 23676316 TI - Eat out, gain weight. PMID- 23676317 TI - Eruptive poromatosis following radiotherapy. PMID- 23676318 TI - Hybrid peripheral nerve sheath tumors, including a malignant variant in type 1 neurofibromatosis. AB - The authors report a small case series of hybrid nerve sheath tumors occurring in the setting of type 1 neurofibromatosis. Four lesions were benign and consisted of plexiform neurofibromas with considerable areas of perineuriomatous differentiation in patients with type 1 neurofibromatosis. In these lesions, biphasic (Schwannian and perineuriomatous) differentiation was apparent on immunohistochemistry, with the perineuriomatous areas staining for epithelial membrane antigen, glut-1, and claudin-1 and being negative for S-100 protein. Three patients were members of a single family, with a history of various malignant neoplasms. Included in the series is 1 hybrid lesion in which neurofibromatous and perineuriomatous areas were clearly visible on hematoxylin- and eosin-stained slides. The lesion was unique in that it manifested malignant change in the S-100 protein-positive component, which was classified as malignant peripheral nerve sheath tumor. The malignant component showed areas with an epithelioid cell morphology. PMID- 23676319 TI - Pseudoherpetic grover disease: report of 2 cases and review of the literature. AB - Two cases of a pseudoherpetic variant of Grover disease are presented. The first patient was a 60-year-old woman who had high fevers in combination with right lower lobe pneumonia. She developed an itchy papulovesicular rash on her back and upper abdomen. The second patient was a 68-year-old woman who while bedridden developed an itchy papulovesicular rash on her back. Vesiculobullous forms of dermatitis were clinically suspected in both cases, and herpetic vesicles were the lead diagnosis in one case. Pathologically, lesions from both patients revealed intraepidermal fluid-filled vesicles that at scanning magnification raised the suspicion of herpetic lesions. At higher magnification, acantholytic cells, some seemingly multinucleated, could be ppreciated. However, immunohistochemistry for herpes simplex virus and varicella zoster virus antigens proved negative. Moreover, some of the lesional cells revealed dyskeratosis more typical of the spongiotic/vesicular variant of Grover disease, and accordingly, this diagnosis was eventually established in both patients. Recognition of the pseudoherpetic variant of spongiotic/vesicular Grover disease is important in determining correct treatment, and therefore, subtle clues to its diagnosis should be sought in evaluation of such lesions. PMID- 23676320 TI - Verruciform xanthoma developing in recessive dystrophic epidermolysis bullosa: A sheep in wolf's clothing. AB - A 23-year-old male affected of recessive dystrophic epidermolysis bullosa presented with a 2-month history of a growing verrucous plaque on the right flank. The clinical features and evolution suggested the diagnosis of cutaneous squamous cell carcinoma. Histopathological examination showed hyperkeratosis, parakeratossis, and verrucous acanthosis and numerous large xanthoma cells in the papillary dermis. Reflectance confocal microscopy disclosed the absence of epidermal atypia and the presence of aggregates of reflecting cells at dermal epidermal junction and upper dermis. These cells were ultrastructurally characterized and corresponded to foamy histiocytes. Verruciform xanthoma is a benign reactive lesion that has occasionally been reported to develop in chronically eroded areas in patients with recessive dystrophic epidermolysis bullosa. In this group of patients, verruciform xanthoma may clinically mimic cutaneous squamous cell carcinoma and a correct diagnosis is crucial to avoid inappropriate aggressive therapeutic approaches. In vivo noninvasive image technologies such as reflectance confocal microscopy may be helpful diagnostic tools in this clinical setting. PMID- 23676321 TI - Follicular induction in a case of molluscum contagiosum: possible link with secondary anetoderma-like changes? AB - Molluscum contagiosum (MC) can rarely show follicular neogenesis as a result of proliferation of virus-infected basal cells. We report a case of molluscum contagiosum showing multifocal areas of primitive follicular induction involving the adjacent surface epidermis. The underlying dermis showed histological features suggestive of secondary anetoderma. The pathogenetic mechanisms behind development of these microscopic features and the putative link between follicular induction and secondary anetoderma are explored. Awareness of this unusual phenomenon will be helpful in avoiding a misdiagnosis of a superficial basal cell (trichoblastic) carcinoma in such cases. PMID- 23676322 TI - Bioavailability of long-chain omega-3 fatty acids. AB - Supplements have reached a prominent role in improving the supply of long-chain omega-3 fatty acids, such as Eicosapentaenoic acid (EPA 20:5n-3) and Docosahexaenoic acid (DHA 22:6n-3). Similar to other nutrients, the availability of omega-3 fatty acids is highly variable and determined by numerous factors. However, the question of omega-3 fatty acids bioavailability has long been disregarded, which may have contributed to the neutral or negative results concerning their effects in several studies. This review provides an overview of the influence of chemical binding form (free fatty acids bound in ethylesters, triacylglycerides or phospholipids), matrix effects (capsule ingestion with concomitant intake of food, fat content in food) or galenic form (i.e. microencapsulation, emulsification) on the bioavailability of omega-3 fatty acids. There is a need to systematically investigate the bioavailability of omega 3 fatty acids formulations, which might be a key to designing more effective studies in the future. PMID- 23676323 TI - Comprehensive review of the limitations of relative value unit measurements of productivity in academic departments. AB - Measuring radiologist, especially sonologist, productivity has never been of greater interest than now, as radiology has moved from its historical status as a cost center to the largest revenue generator in most institutions. With more local institutional and federal oversight and regulation into the reimbursement and valuation of imaging procedures, including emphasis on outsourcing, overvalued procedures, and bundling, the ability to measure productivity and to draw meaningful conclusions from the data becomes increasingly imperative if we as radiologists and sonologists expect to contribute meaningfully to the process. This article presents a history of the "relative value unit" and discusses the valuation of radiologist/sonologist productivity in this era of ubiquitous high technology implementation. PMID- 23676324 TI - Does Daylight Savings Time encourage physical activity? AB - BACKGROUND: Extending Daylight Savings Time (DST) has been identified as a policy intervention that may encourage physical activity. However, there has been little research on the question of if DST encourages adults to be more physically active. METHODS: Data from residents of Arizona, Colorado, New Mexico, and Utah ages 18-64 who participated in the 2003-2009 American Time Use Survey are used to assess whether DST is associated with increased time spent in moderate-to vigorous physical activity (MVPA). The analysis capitalizes on the natural experiment created because Arizona does not observe DST. RESULTS: Both bivariate and multivariate analyses indicate that shifting 1 hour of daylight from morning to evening does not impact MVPA of Americans living in the southwest. CONCLUSIONS: While DST may affect the choices people make about the timing and location of their sports/recreational activities, the potential for DST to serve as a broad-based intervention that encourages greater sports/recreation participation is not supported by this analysis. Whether this null effect would persist in other climate situations is an open question. PMID- 23676326 TI - Work. From the editor. PMID- 23676325 TI - Influence of organic matter type and medium composition on the sorption affinity of C12-benzalkonium cation. AB - We used the 7-MUm polyacrylate ion-exchange SPME fibers to investigate C12 benzalkonium sorption to 10 mg/L natural organic matter at concentrations well below the cation-exchange capacity. C12-BAC sorption at constant medium conditions differed within 0.4 log units for two humic acids (Aldrich, Leonardite) and peat (Sphagnum, Pahokee), with similar nonlinear sorption isotherms (KF ~ 0.8). Sorption to the SPME fibers and Aldrich humic acid (AHA) was reduced at both low pH and high electrolyte concentration, and reduced more strongly by Ca2+ compared with Na+ at similar concentrations. Sorption isotherms for AHA (5-50-500 mM Na+, pH 6) was modeled successfully by the NICA-Donnan approach, resulting in an intrinsic sorption coefficient of 5.35 (Caq = 1 nM). The NICA-Donnan model further explained the stronger specific binding of Ca2+ compared to Na+ by differences in Boltzmann factors. This study provides relevant information to interpret bioavailability of quaternary ammonium compounds, and possibly for other organic cations. PMID- 23676327 TI - A method to improve the accuracy of pair-wise combinations of anthropometric elements when only limited data are available. AB - BACKGROUND: Designers and ergonomists occasionally must produce anthropometric models of workstations with only summary percentile data available regarding the intended users. Until now the only option available was adding or subtracting percentiles of the anthropometric elements, e.g. heights and widths, used in the model, despite the known resultant errors in the estimate of the percent of users accommodated. This paper introduces a new method, the Median Correlation Method (MCM) that reduces the error. OBJECTIVE: Compare the relative accuracy of MCM to combining percentiles for anthropometric models comprised of all possible pairs of five anthropometric elements. Describe the mathematical basis of the greater accuracy of MCM. METHODS: MCM is described. 95th percentile accommodation percentiles are calculated for the sums and differences of all combinations of five anthropometric elements by combining percentiles and using MCM. The resulting estimates are compared with empirical values of the 95th percentiles, and the relative errors are reported. RESULTS: The MCM method is shown to be significantly more accurate than adding percentiles. MCM is demonstrated to have a mathematical advantage estimating accommodation relative to adding or subtracting percentiles. CONCLUSIONS: The MCM method should be used in preference to adding or subtracting percentiles when limited data prevent more sophisticated anthropometric models. PMID- 23676328 TI - Cognitive work hardening: a return-to-work intervention for people with depression. AB - Mental health claims in the workplace are rising, particularly those due to depression. Associated with this is an increase in disability costs for the employer and the disability insurer, but even more important is the human suffering that results. While treatments are available for the depression there is a gap in interventions that specifically target return-to-work preparation. This paper presents cognitive work hardening, a treatment intervention that can bridge this gap by addressing the unique functional issues inherent in depression with a view to increasing return-to-work success. Cognitive work hardening applies the proven principles of classical work hardening (which has typically been applied to people with physical injuries) to the mental health domain. This paper explains how the occupational therapy principle of occupation and the core competency, enablement, are utilized and applied in cognitive work hardening. Key skills of the occupational therapist are also discussed. In addition, the paper considers the relationship of cognitive work hardening to recovery and mental illness, and the role it plays among workplace-based return-to-work interventions in the current movement toward non-clinical return-to-work interventions. PMID- 23676329 TI - Individual features, working conditions and work injuries are associated with work ability among nursing professionals. AB - OBJECTIVE: To investigate factors associated with work ability among nursing professionals. PARTICIPANTS: They comprised 514 nursing professionals (83.8% of the total number of workers) from a hospital in Sao Paulo, Brazil. METHODS: In 2009, we conducted a cross-sectional study that was a part of a 5-year planned cohort study initiated in 2008. We administered a comprehensive questionnaire to the participants in order to obtain data on their sociodemographic characteristics, lifestyles, and working conditions. The questionnaire also contained the Brazilian versions of the following: the Job Stress Scale (JSS), Effort-Reward Imbalance (ERI) Questionnaire, Work-Related Activities That May Contribute To Job-Related Pain and/or Injury (WRAPI), and Work Ability Index (WAI). The results were analyzed using descriptive, bivariate, and multivariate linear regression analyses. RESULTS: On the WAI, 74.9% of the workers obtained a score of over 40 points (score range 7-49); the mean score was 42.3 points (SD=4.5). The final multivariate model showed that lower WAI scores were related to the work-related outcome, which was work injury, and the following individual characteristics and working conditions: body mass index (p=0.001), sex (female; p=0.002), sedentariness (p < 0.001), time in the profession (p=0.005), social support at work (p=0.003), effort-reward ratio (p=0.001), violence at work (p=0.005), WRAPI score (p < 0.001), and work injuries (yes; p=0.001). CONCLUSIONS: Various factors were associated with work ability. The results showed that a number of variables should be considered when planning and implementing actions to maintain or improve work ability among nursing professionals. PMID- 23676330 TI - Impact of conflict and violence on workers in a hospital emergency room. AB - BACKGROUND: Emergency room (ER) work includes dealing with situations of conflict and aggression. The diversity and unpredictability of these situations and the lack of pre-established procedures to guide workers in dealing with these phenomena affect and weaken their physical and mental health. OBJECTIVE: The purpose of the article is to learn about conflict and aggression at work and its impact on the workers in a hospital emergency room. METHOD: The method is a transversal, exploratory, descriptive and observational study, carried out from September to November 2008, using direct observation procedures and interviews. PARTICIPANTS: Two hundred and eighty emergency room workers participated in the observations and eleven interviews were carried out with workers from several professional categories. RESULTS: The work process is marked by overload, individualization of responsibilities, time pressures and deadlines for making decision, little space for exchange and sharing, lack of support or guidance. The strong pressure to provide care quickly causes conflict and aggression among users and the different professional teams. These situations arise from problems in work organization and users in excess of the ER service capacity. CONCLUSION: The article recommends changes in the work process that can simultaneously improve both the quality of care for patients and provide protective measures for workers. PMID- 23676331 TI - Work as a therapeutic resource: case study of a rehabilitation community for persons with chemical dependency. AB - BACKGROUND: Studies involving the therapeutic nature of the work done by chemically dependent individuals undergoing treatment in therapeutic communities are scarce, not only in Brazil, but also in the international literature. OBJECTIVE: To clarify the role played by work as a therapeutic element for patients who are undergoing treatment in a drug-free therapeutic community setting in Brazil. Clients are free to choose their occupations during treatment, that exercise their creativity and their responsability for their recovery. METHOD: The Biographical Method was employed in two case studies. CONCLUSIONS: The approach adopted by the community enabled clients to recognize how they became chemically dependent, as well as their possibilities for recovery. Clients expanded their interests and their daily activities that were once exclusively directed towards the consumption of drugs. Their personal development improved through their contact with reality through work activities, in the context of a therapeutic community. From there, clients were increasingly able to plan and execute life projects aimed at their full recovery. PMID- 23676332 TI - People with disabilities in the labor market: facilitators and barriers. AB - BACKGROUND: Participation in the workforce is one of the main social evaluations all individuals are subject to in modern society. Public policies supporting social justice for persons with disabilities have gained prominence in several nations in the last decades and it is critical to ensure that those who want to work are afforded the opportunity to do so. Meanwhile they remain under represented in the labor market within the contemporary world. OBJECTIVE: The purpose of this study was to identify facilitators or barriers faced by people with disability within the workforce. PARTICIPANTS: Ten workers with disabilities from various companies and performing diverse professional job functions participated in semi-structured interviews. METHOD: The Discourse of the Collective Subject method was employed as a means to organize and analyze qualitative data of a verbal nature. RESULTS: Reasonable work conditions, adjustments, and accommodations facilitate performance and job retention. Social participation through employment leads to social recognition and the feeling of citizenship. On the other hand prejudice, unequal opportunities, workers' low educational attainment, and lack of training opportunities lead to employment exclusion. CONCLUSION: To include people with disabilities in the workforce, it is necessary to focus on attaining equal levels of education, an unbiased and inclusive process for entering the labor market, and continued management of disability issues within the workplace. Together, these elements create equal opportunities for workers with disabilities to advance in their careers, which in turn enables participation, social recognition and guaranties their rights as citizens. PMID- 23676333 TI - Work reality perceived by individuals with impairments: a biopsychosocial experience. AB - BACKGROUND: Individuals with different impairments are working in the formal and/or informal market despite physical and attitudinal barriers. To date, few studies have addressed this situation from the perspective of the individuals. OBJECTIVE: Apprehend factors that restrict work performance in the perspective of workers with impairments and identify the strategies employed and the difficulties faced. PARTICIPANTS: Individuals with impairment who exercised paid activities. METHODS: Thirty semi-structured interviews and eleven observations of individuals in work activities. RESULTS: Limitations stemming from participants' disability and health status had an influence over their execution of tasks, but did not compromise work performance. Environmental factors that impacted as facilitators or barriers were: lack of preparation of colleagues, employers, education and rehabilitation systems; attitudes and coexistence; accessibility, implementation of land use policies, urban structures and transportation; products and technology; and distributive policies. Personal factors (upbringing, self-esteem, good mood, outgoingness, communicability, willpower, age and how the disability was acquired) also influenced participation at work. Important strategies included recognizing and sharing capabilities and needs, which minimized or eliminated difficulties at work. CONCLUSIONS: Workers with impairments developed effective strategies for dealing with adverse situations, which remained in the individual realm. Working with impairments is a complex experience that demands overcoming old paradigms. PMID- 23676334 TI - Xi'an making history in vascular biology. PMID- 23676335 TI - Hydrogen sulfide suppresses high glucose-induced expression of intercellular adhesion molecule-1 in endothelial cells. AB - Hydrogen sulfide (H2S) is a newly identified endogenous gasotransmitter that has been implicated in the pathophysiology of several biologic systems. However, the role of H2S in the pathogenesis of diabetic vascular injury remains unclear. The aims of this study were to determine the effect of H2S on the high glucose (HG) induced expression of intercellular adhesion molecule-1 (ICAM-1) in human umbilical vein endothelial cells and to explore the possible underlying mechanisms. Human umbilical vein endothelial cells were exposed either to a normal concentration of D-glucose (5.5 mmol/L) or to HG (16.7 mmol/L) in the absence or presence of NaHS for the indicated periods. The ICAM-1 protein and messenger RNA (mRNA) levels were analyzed by Western blotting and real-time reverse transcriptase-polymerase chain reaction, respectively. Exposure to HG for 48 or 72 hours significantly increased ICAM-1 expression at both the protein and mRNA levels, and these increases correlated with increases in both the production of intracellular reactive oxygen species and the activation of nuclear factor kappaB. Pretreatment with NaHS inhibited HG-induced ICAM-1 expression at both the protein and mRNA levels and resulted in a reduction in the intracellular reactive oxygen species level and the suppression of nuclear factor-kappaB activity. NaHS also inhibited tumor necrosis factor-alpha-induced ICAM-1 protein expression, which was similar to the effect of antioxidant N-acetyl-L-cysteine. These findings indicate that H2S might protect against HG-induced vascular damage by down-regulating ICAM-1 expression in endothelial cells. PMID- 23676337 TI - Psychosocial determinants and perceived environmental barriers as mediators of the effectiveness of a web-based tailored intervention promoting physical activity in adolescents: the HELENA Activ-O-Meter. AB - BACKGROUND: The aim was to examine if psychosocial determinants (attitudes, self efficacy, social support from a sports partner) and perceived environmental barriers (PEB) of physical activity (PA) mediated the effect of a 3-month Internet-based intervention on PA in European adolescents. METHODS: A sample of 536 adolescents (51% boys) aged 12-17 years were randomly assigned to intervention or control condition. Questionnaires were used to assess different PA behaviors, psychosocial determinants and PEB at baseline and at 3-month follow up. Mediating effects were assessed with the bootstrapping method. RESULTS: PEB regarding neighborhood safety mediated the effect of the intervention on all PA indices. PEB regarding sports facilities availability at neighborhood and PEB regarding sport-related facilities availability at school mediated the effect of the intervention on moderate to vigorous PA (MVPA) and moderate PA (in leisure time and at school, respectively). Social support from a sports partner suppressed the effect of the intervention on vigorous PA and MVPA. No other factor had a mediation effect. CONCLUSIONS: All PEB measures appear to mediate PA behaviors of different intensities and in different contexts. Interventions promoting PA in adolescents should also focus on improving the targeted PEB as mediators of engagement in PA to bring the desired effects in actual behaviors. PMID- 23676338 TI - Photoneutron spectrum measured with a Bonner sphere spectrometer in planetary method mode. AB - The spectrum of photoneutrons produced by a 15 MV VARIAN iX linac working in Bremsstrahlung mode was measured a 100 cm from the IC located 5 cm-depth of a solid water phantom. The spectrum was measured with a Bonner spheres spectrometer with pairs of TLDs as thermal neutron detector. The measurements were carried out using the spectrometer in planetary method mode where a single shoot of the LINAC was required. PMID- 23676339 TI - Heat transfer monitoring by means of the hot wire technique and finite element analysis software. AB - It is reported the study of the radial heat transfer in a homogeneous and isotropic substance with a heat linear source in its axial axis. For this purpose, the hot wire characterization technique has been used, in order to obtain the temperature distribution as a function of radial distance from the axial axis and time exposure. Also, the solution of the transient heat transport equation for this problem was obtained under appropriate boundary conditions, by means of finite element technique. A comparison between experimental, conventional theoretical model and numerical simulated results is done to demonstrate the utility of the finite element analysis simulation methodology in the investigation of the thermal response of substances. PMID- 23676336 TI - Anti-inflammatory effects of omega-3 polyunsaturated fatty acids and soluble epoxide hydrolase inhibitors in angiotensin-II-dependent hypertension. AB - The mechanisms underlying the anti-inflammatory and antihypertensive effects of long-chain omega-3 polyunsaturated fatty acids (omega-3 PUFAs) are still unclear. The epoxides of an omega-6 fatty acid, arachidonic acid epoxyeicosatrienoic acids also exhibit antihypertensive and anti-inflammatory effects. Thus, we hypothesized that the major omega-3 PUFAs, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may lower the blood pressure and attenuate renal markers of inflammation through their epoxide metabolites. Here, we supplemented mice with an omega-3 rich diet for 3 weeks in a murine model of angiotensin-II dependent hypertension. Also, because EPA and DHA epoxides are metabolized by soluble epoxide hydrolase (sEH), we tested the combination of an sEH inhibitor and the omega-3 rich diet. Our results show that omega-3 rich diet in combination with the sEH inhibitor lowered Ang-II, increased the blood pressure, further increased the renal levels of EPA and DHA epoxides, reduced renal markers of inflammation (ie, prostaglandins and MCP-1), downregulated an epithelial sodium channel, and upregulated angiotensin-converting enzyme-2 message and significantly modulated cyclooxygenase and lipoxygenase metabolic pathways. Overall, our findings suggest that epoxides of the omega-3 PUFAs contribute to lowering systolic blood pressure and attenuating inflammation in part by reduced prostaglandins and MCP-1 and by upregulation of angiotensin-converting enzyme-2 in angiotensin-II-dependent hypertension. PMID- 23676340 TI - Progression of Alzheimer's disease during a three-year follow-up using the CERAD NB total score: Kuopio ALSOVA study. AB - BACKGROUND: We studied the suitability of The Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery (CERAD-NB) total score for monitoring Alzheimer's disease (AD) progression in early-diagnosed medicated patients. We also investigated possible differences in progression between patients with very mild or mild baseline AD. METHODS: In this three-year follow up of 115 ALSOVA study patients with clinical dementia ratings (CDR) of very mild (0.5) or mild (1) AD, we analyzed total CERAD-NB, Mini-Mental State Examination (MMSE), Neuropsychiatric Inventory (NPI), The Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory, and Clinical Dementia Rating Sum of Boxes scores. Correlations were identified with efficacy parameters. RESULTS: Over three years, total CERAD-NB declined significantly in both groups. Annual change rates of total CERAD-NB were also significant. Total CERAD-NB revealed annual differences in cognition between study groups, while MMSE did not. Total CERAD-NB correlated well with other cognitive and global measures, but not with NPI. For almost two years, the CDR-0.5 group maintained a higher activities of daily living than the CDR-1 group exhibited at baseline. Furthermore, the CDR-0.5 group showed milder neuropsychiatric symptoms at the end of follow-up than the CDR-1 group showed at baseline. CONCLUSIONS: The CERAD total score is a suitable and sensitive follow-up tool in longitudinal AD trials. Cognition progression rates did not significantly differ between study groups; however, patients with very mild AD at baseline had milder neuropsychiatric symptoms after long-term follow-up. This emphasizes the importance of early diagnosis and assessment of neuropsychiatric symptoms at the diagnostic visit and during follow-up. PMID- 23676341 TI - Correlations between the level of high-sensitivity C-reactive protein and cardiovascular risk factors in Korean adults with cardiovascular disease or diabetes mellitus: the CALLISTO study. AB - AIM: We assessed the relationship between the level of high-sensitivity C reactive protein (hsCRP) and cardiovascular risk factors in Korean adults. METHODS: We reviewed 1,561 patients with cardiovascular disease or diabetes mellitus with hsCRP levels measured within the past year. Four cardiovascular risk groups were determined: low (<10%, 0-1 risk), moderate (<10%, >2 risk), high (10-20%) and very high (>20%) risk, according to the number of risk factors and the Framingham/NCEP ATP III risk score. The correlations between the hsCRP level and cardiovascular risk factors (age, smoking, hypertension, lipid profiles and familial history of premature coronary heart disease) were investigated. RESULTS: The mean and median hsCRP (mg/L) levels were 1.32 +/- 9.69 and 0.29 (range: 0.01 7.48), respectively. Men had a higher median level of hsCRP than women (p<0.001). The levels of hs CRP significantly increased from the low to the very high risk group (0.15, 0.23, 0.27 and 0.47, respectively) and were significantly correlated with age, the level of glycosylated hemoglobin, body mass index (BMI), the level of high-density lipoprotein cholesterol (HDL-C), the low-density lipoprotein cholesterol (LDL-C)/HDL-C ratio, the LDL-C/total cholesterol (TC) ratio, the HDL C/TC ratio, the HDL-C/triglyceride (TG) ratio and the TC/TG ratio. Neither smoking, the LDL-C level nor the TG level affected the hsCRP level. In a multivariate regression analysis, age, the HDL-C level, the LDL-C/TC ratio and BMI were found to be independently correlated with the hsCRP level. CONCLUSIONS: There is a significant relationship between the degree of cardiovascular risk and the hsCRP level in Korean adults with cardiovascular disease or diabetes mellitus. Assessing the hsCRP levels may thus provide additive value in predicting cardiovascular risks. PMID- 23676342 TI - Cardiovascular toxicity and sorafenib: a case report. AB - We report a case of a 55-year-old male with chronic hepatitis C virus infection and compensated liver disease treated with sorafenib for advanced hepatocarcinoma (Barcelona Clinic Liver Cancer stage C). At follow-up, the patient developed hypertension, which was well controlled with beta-blocker medication, and an aortic dilation detected by abdominal computerized tomography and echocardiography. There are some reports of the side effects of sorafenib on the cardiovascular system. The patient had no cardiac or aortic pathology before the start of this palliative chemotherapy. There is an article that describes the development of an aortic aneurysm in a patient with uncontrolled hypertension, who received treatment with sorafenib for renal carcinoma. However, our patient had a good control of blood pressure. The adverse vascular effects of Sorafenib may be due to the inhibition of the proliferation of vascular endothelial muscle cells. We believe that this case illustrates a probable relationship between sorafenib and aortic dilatation according to the Karch and Lasagna causality algorithm. PMID- 23676343 TI - Prediction of drug concentration-time profiles in children from adults: an allometric approach. AB - The main objective of this work was to evaluate 2 methods to predict concentration-time profiles of drugs in children (aged 5 years or older) from adult pharmacokinetic (PK) parameters. Five drugs from the literature were chosen for this study, and all these 5 drugs were described by a 2-compartment model in both adults and children. PK parameters (CL, Vc, Vss, and Vbeta) were allometrically predicted in children from adults. PK constants such as A, B, alpha, and beta were also predicted in children from adults as described in . Using predicted PK parameters and constants, concentration-time profiles of 5 drugs were predicted in children and compared with the observed profiles. Both methods of predictions provided fairly good prediction of concentration-time profiles in children. The predicted concentration-time profiles in children were comparable with the observed profiles and can be used to design first-in-children clinical trials. PMID- 23676344 TI - A case of fibrolamellar cancer with a palliative response and minor radiographic regression with erlotinib and bevacizumab combination therapy. AB - Fibrolamellar cancer (FLC) is a rare primary hepatic malignancy with no established standard systemic treatments. Case reports and subgroup analyses from larger liver cancer studies suggest possible activity for fluoropyrimidines, platinum agents, and interferon-alpha. However, randomized studies are lacking, and the merits of any particular regimen in FLC are still largely unsubstantiated. We report the outcome of a case of metastatic FLC with previous progressive disease on 5-FU plus interferon-alpha and FOLFOX regimens that was treated with bevacizumab and erlotinib. The patient derived a prompt palliative response with complete resolution of cancer-related pain 2 weeks after initiation of erlotinib. Computed tomography after 2 months of treatment showed disease regression in distant lymphadenopathy. Molecular testing failed to confirm any evidence of epidermal growth factor receptor (EGFR) mutation, whereas immunohistochemistry showed 2 to 3+ staining for EGFR expression. To our knowledge, this is the first case report of a clinical benefit for FLC in association with erlotinib and bevacizumab treatment. FLC overexpresses EGFR in comparison to hepatocellular cancer, suggesting that EGFR targeting may be an interesting therapeutic approach in this rare malignancy. PMID- 23676345 TI - Low-dose manic switch and high-dose antimanic effect and extrapyramidal symptoms by aripiprazole in a single bipolar patient. AB - A case report of an adult female patient with bipolar depression who developed mania after short-term administration of low-dose aripiprazole (2 mg daily) is reported. Later, the author rechallenged with high-dose aripiprazole (22 mg) for treating mania, but there was no manic switch, unlike when using low-dose aripiprazole. A 1-month follow-up revealed no further symptoms of mania or depression, except dyskinesia and sialorrhea. Clinicians should therefore carefully and vigilantly monitor for both the induction of mania and extrapyramidal symptoms according to the aripiprazole dose. PMID- 23676346 TI - Elemental Impurities in Nigerian Pediatric Syrups: Mercury in Violation of Standard Guidelines. AB - Studies on the human exposure to elemental impurities like antimony, tin, and mercury pharmaceutical products in the African environment are scarce and limited. In this study, we determined the concentrations of these elemental impurities in 28 different brands of commonly used pediatric syrups, purchased randomly from patent medicine retail outlets in Port Harcourt, Rivers State, Nigeria. The aim of this study was to compare the antimony, tin, and mercury levels in these pediatric syrups with the recommended limits of United States Pharmacopeia. Twenty-eight different pediatric syrups were randomly sampled and purchased using the market basket protocol from pharmacy shops in Port Harcourt, Rivers State, Nigeria in December 2010. Syrups were ashed before digestion using concentrated aqua regia, HCl: HNO3 (3:1), and antimony, tin, and mercury were analyzed using Unicam Atomic Absorption Spectrophotometer (AAS) Model 929. The ranges of heavy metal content in these pediatric syrups were 0.54-1.27, 0.86 2.56, and 0.97-5.13 MUg/g for antimony, tin, and mercury, respectively. About 75% of the syrups exceeded the United States Pharmacopeia mercury limit of 1.5 MUg/g. The estimated or calculated amounts of antimony, tin, and mercury in the 3 most likely administered syrups were 17.15, 64.20, and 34.60 MUg of antimony, tin, and mercury, respectively. The daily intake or estimated amount from the ingestion of syrups excluding background exposure (MUg metal.kg body weight.d) for a 15-kg child were 1.17, 2.31, and 4.28 for antimony, tin, and mercury, respectively. Mercury content in pediatric syrups may constitute a significant source of heavy metal exposure to children and may be of public health importance in Nigeria. PMID- 23676347 TI - Endotracheal Administration of Sufentanil and Tetracaine During Awake Fiberoptic Intubation. AB - Combined use of local anesthetics and low-dose opioids enhances the effects of local anesthetics. This study aimed to evaluate the efficacy of combined administration of sufentanil and tetracaine through the cricothyroid membrane during awake nasal intubation using fiberoptic bronchoscopy in patients with difficult airways. Forty patients were divided into 2 groups: group A received endotracheal administration of 25 MUg of sufentanil and 2 mL of 1% tetracaine mixture; group B received endotracheal administration of 2 mL 1% tetracaine and routine local anesthetic sprays followed by slow intravenous injection of 25 MUg of sufentanil. The results showed that endotracheal intubation was safely completed in all patients and vital signs including blood pressure, heart rate, and pulse oxygen saturation were not significantly different between groups A and B. However, time required for local anesthesia to take effect, time required to complete intubation, cough reflex, patient tolerance during intubation, and hemodynamic indices were significantly better in group A than in group B. In conclusion, our results suggest that endotracheal administration of sufentanil combined with tetracaine is safe, effective, and feasible in the context of awake nasal intubation using fiberoptic bronchoscopy. PMID- 23676349 TI - A study of CT dose distribution in an elliptical phantom and the influence of automatic tube current modulation in the x-y plane. AB - Computed tomography (CT) performance assessments relating to patient dose to the body are made conventionally in 320 mm diameter cylindrical acrylic phantoms. The cross section of the human trunk is closer to an ellipse and automatic tube current modulation (ATCM) systems adjust the exposure level with orientation in the x-y plane, changing the dose distribution within the body. This study has investigated differences in the distributions of dose within a standard cylindrical body phantom and an elliptical dosimetry phantom for Toshiba, General Electric and Philips CT scanners, and recorded changes with the application of the ATCM. Single slice dose profiles have been recorded within the phantoms using Gafchromic film. CT dose indices along 100 mm lengths have been calculated and data sets combined to simulate helical scans, from which values for cumulative doses have been derived. The doses in the centre of the elliptical phantom are 70 100% larger than for the cylindrical one and in the anterior are around 20-40% larger, while the doses in the lateral positions are similar for the two phantom shapes. The differences between the anterior and lateral doses were larger for the Toshiba scanner and this is thought to be linked to the narrower profile of the beam produced by the bow-tie filter. When the ATCM mode for the Toshiba scanner is implemented, the doses in the anterior and posterior positions are reduced preferentially, bringing them closer to the doses in the lateral positions. PMID- 23676348 TI - Superficial vein thrombosis, thrombin generation and activated protein C resistance as predictors of thromboembolic events in lupus and antiphospholipid patients. A prospective cohort study. AB - INTRODUCTION: Predicting thrombosis in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibodies (aPL) is still challenging. Our objective was to determine risk factors for thrombotic events including activated protein C (APC) resistance proven by a thrombin generation (TG) assay in patients with SLE and/or aPL. MATERIALS AND METHODS: We performed a prospective cohort study in a French University Hospital and tertiary care center. Ninety-two consecutive patients with SLE and/or aPL without ongoing anticoagulant treatment were enrolled. The outcome was time to thrombotic event. We evaluated clinical and laboratory variables including APC sensitivity ratio (APCsr) determined by TG. An APCsr>90th percentile of a control population indicated APC resistance. RESULTS: Patients were followed-up for a median duration of 35 months (inter quartile range: 26 to 62; 320 patient-years). Thrombosis during follow-up occurred in 18 patients. In univariate analysis, together with history of hypertension, superficial vein thrombosis (SVT) and arterial thrombosis, patients with both aPL and APC resistance had an increased risk for incident thromboembolic events (HR, 3.67 [95% confidence interval, 1.31 to 10.31]). In multivariate analysis, only history of hypertension (HR, 10.77 [95% confidence interval, 3.15 to 36.83]), SVT (HR, 7.45 [95% confidence interval, 2.25 to 24.66]) and arterial thrombosis (HR, 3.31 [95% confidence interval, 1.14 to 9.55]) remained independent risk factors. CONCLUSIONS: History of thrombosis including seemingly benign SVT have a higher predictive value for incident thrombotic events in SLE or aPL patients than APC resistance proven by TG. PMID- 23676350 TI - Mutations in GBA and risk of Parkinson's disease: a meta-analysis based on 25 case-control studies. AB - The association between glucocerebrosidase (GBA) mutations and Parkinson's disease (PD) is attracting increased attention worldwide. Results from previous studies on the association of GBA mutations with PD in different ethnicities remain contradictory. In order to derive a more comprehensive understanding of the relationship between the most common GBA mutations, L444P and N370S and PD susceptibility, an updated meta-analysis was performed by searching PUBMED, EMBASE, MEDLINE, and EBSCO databases. Twenty five studies including 9, 599 cases and 13, 541 controls were collected in the end. The summary of odds ratios (OR) and corresponding 95% confidence intervals (CI) were estimated using fixed- and random-effects models, when appropriate. Overall, our meta-analysis provided evidence that both were risk factors associated with increased PD susceptibility. When stratified by ethnicities, the associations varied among different ethnical origins. PMID- 23676351 TI - Utilitarian cycling in Belgium: a cross-sectional study in a sample of regular cyclists. AB - BACKGROUND: For an accurate estimation of health benefits and hazards of utilitarian cycling, a prospective collection of bicycle usage data (exposure) is fundamental. Individual and environmental correlates are necessary to guide health promotion and traffic safety issues. Firstly, this study aims to report on utilitarian bicycle usage in Belgium, using a prospective data collection in regular adult commuter cyclists. Secondly, the association is explored between the individual variation in bicycle usage and individual and environmental correlates. METHODS: 1187 regular adult cyclists filled out travel diaries prospectively. Multivariate linear regression with Stepwise selection (SMLR) models studied the association between exposure and individual and environmental correlates. RESULTS: Higher age and availability of cycle paths have a positive association with bicycle usage to work. Women cycle significant less compared with men, and so do cyclists with 'poor' or 'average' health. Living in an urban crown (opposed to city center) and living in Flanders (opposed to Brussels or Wallonia) is associated with significantly more cycling. CONCLUSIONS: Utilitarian cycling is related to regional differences, level of urbanization of the place of residence, availability of bicycle paths, and gender. These findings are useful in estimating health benefits and hazards of utilitarian cycling among regular Belgian cyclists. PMID- 23676352 TI - Oxidative and molecular responses in Capsicum annuum L. after hydrogen peroxide, salicylic acid and chitosan foliar applications. AB - Hydrogen peroxide (H2O2) is an important ROS molecule (Reactive oxygen species) that serves as a signal of oxidative stress and activation of signaling cascades as a result of the early response of the plant to biotic stress. This response can also be generated with the application of elicitors, stable molecules that induce the activation of transduction cascades and hormonal pathways, which trigger induced resistance to environmental stress. In this work, we evaluated the endogenous H2O2 production caused by salicylic acid (SA), chitosan (QN), and H2O2 elicitors in Capsicum annuum L. Hydrogen peroxide production after elicitation, catalase (CAT) and phenylalanine ammonia lyase (PAL) activities, as well as gene expression analysis of cat1, pal, and pathogenesis-related protein 1 (pr1) were determined. Our results displayed that 6.7 and 10 mM SA concentrations, and, 14 and 18 mM H2O2 concentrations, induced an endogenous H2O2 and gene expression. QN treatments induced the same responses in lesser proportion than the other two elicitors. Endogenous H2O2 production monitored during several days, showed results that could be an indicator for determining application opportunity uses in agriculture for maintaining plant alert systems against a stress. PMID- 23676353 TI - Bioavailability of heavy metals in soil: impact on microbial biodegradation of organic compounds and possible improvement strategies. AB - Co-contamination of the environment with toxic chlorinated organic and heavy metal pollutants is one of the major problems facing industrialized nations today. Heavy metals may inhibit biodegradation of chlorinated organics by interacting with enzymes directly involved in biodegradation or those involved in general metabolism. Predictions of metal toxicity effects on organic pollutant biodegradation in co-contaminated soil and water environments is difficult since heavy metals may be present in a variety of chemical and physical forms. Recent advances in bioremediation of co-contaminated environments have focussed on the use of metal-resistant bacteria (cell and gene bioaugmentation), treatment amendments, clay minerals and chelating agents to reduce bioavailable heavy metal concentrations. Phytoremediation has also shown promise as an emerging alternative clean-up technology for co-contaminated environments. However, despite various investigations, in both aerobic and anaerobic systems, demonstrating that metal toxicity hampers the biodegradation of the organic component, a paucity of information exists in this area of research. Therefore, in this review, we discuss the problems associated with the degradation of chlorinated organics in co-contaminated environments, owing to metal toxicity and shed light on possible improvement strategies for effective bioremediation of sites co-contaminated with chlorinated organic compounds and heavy metals. PMID- 23676354 TI - Molecular cloning and characterization of the first caspase in the Striped Stem Borer, Chilo suppressalis. AB - Apoptosis is executed through the activity of the caspases that are aspartyl specific proteases. In this study, we isolated the caspase gene (Cscaspase-1) of Chilo suppressalis (one of the leading pests responsible for destruction of rice crops). It possesses the open reading frame (ORF) of 295 amino acids including prodomain, large subunit and small subunits, and two cleavage sites (Asp23 and Asp194) were found to be located among them. In addition to these profiles, Cscaspase-1 contains two active sites (His134 and Cys176). Genomic analysis demonstrated there was no intron in the genome of Cscaspase-1. The Cscaspase-1 transcripts were found in all tissues of the fifth instar larvae, and higher levels were found in the midgut, hindgut and Malpighian tubules. Examination of Cscaspase-1 expression in different developmental stages indicated low constitutive levels in the eggs and early larvae stages, and higher abundances were exhibited in the last larvae and pupae stages. The relative mRNA levels of Cscaspase-1 were induced by heat and cold temperatures. For example, the highest increase of Cscaspase-1 transcription was at -3 degrees C and 36 degrees C respectively. In a word, Cscaspase-1 plays a role of effector in the apoptosis of C. suppressalis. It also correlates with development, metamorphosis and thermotolerance of C. suppreassalis. PMID- 23676356 TI - Neural correlates of the components of the clock drawing test. AB - BACKGROUND: The aim of this study was to identify the neural correlates of each component of the clock drawing test (CDT) in drug-naive patients with Alzheimer's disease (AD) using single photon emission computed tomography. METHODS: The participants were 95 drug-naive patients with AD. The Rouleau CDT was used to score the clock drawings. The score for the Rouleau CDT (R total) is separated into three components: the scores for the clock face (R1), the numbers (R2), and the hands (R3). A multiple regression analysis was performed to examine the relationship of each score (i.e. R total, R1, R2, and R3) with regional cerebral blood flow (rCBF). Age, gender, and education were included as covariates. The statistical threshold was set to a family-wise error (FWE)-corrected p value of 0.05 at the voxel level. RESULTS: The R total score was positively correlated with rCBF in the bilateral parietal and posterior temporal lobes and the right middle frontal gyrus. R1 was not significantly positively correlated with rCBF, R2 was significantly positively correlated with rCBF in the right posterior temporal lobe and the left posterior middle temporal lobe, and R3 was significantly positively correlated with rCBF in the bilateral parietal lobes, the right posterior temporal lobe, the right middle frontal gyrus, and the right occipital lobe. CONCLUSIONS: Various brain regions were associated with each component of the CDT. These results suggest that an assessment of these components is useful for the detection of localization of brain damage. PMID- 23676355 TI - Soda and other beverages and the risk of kidney stones. AB - BACKGROUND AND OBJECTIVES: Not all fluids may be equally beneficial for reducing the risk of kidney stones. In particular, it is not clear whether sugar and artificially sweetened soda increase the risk. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We prospectively analyzed the association between intake of several types of beverages and incidence of kidney stones in three large ongoing cohort studies. Information on consumption of beverages and development of kidney stones was collected by validated questionnaires. RESULTS: The analysis involved 194,095 participants; over a median follow-up of more than 8 years, 4462 incident cases occurred. There was a 23% higher risk of developing kidney stones in the highest category of consumption of sugar-sweetened cola compared with the lowest category (P for trend=0.02) and a 33% higher risk of developing kidney stones for sugar sweetened noncola (P for trend=0.003); there was a marginally significant higher risk of developing kidney stones for artificially sweetened noncola (P for trend=0.05). Also, there was an 18% higher risk for punch (P for trend=0.04) and lower risks of 26% for caffeinated coffee (P for trend<0.001), 16% for decaffeinated coffee (P for trend=0.01), 11% for tea (P for trend=0.02), 31%-33% for wine (P for trend<0.005), 41% for beer (P for trend<0.001), and 12% for orange juice (P for trend=0.004). CONCLUSIONS: Consumption of sugar-sweetened soda and punch is associated with a higher risk of stone formation, whereas consumption of coffee, tea, beer, wine, and orange juice is associated with a lower risk. PMID- 23676357 TI - Comparison of transrectal and transvaginal hybrid natural orifice transluminal endoscopic surgery partial nephrectomy in the porcine model. AB - OBJECTIVE: To compare the feasibility of porcine transrectal (TR) and transvaginal (TV) hybrid natural orifice transluminal endoscopic surgery (NOTES) partial nephrectomy (PN), as NOTES nephrectomy has recently been performed in the porcine model. MATERIALS AND METHODS: A total of 10 female pigs (weight 45 kg) underwent TR (n = 5) or TV (n = 5) NOTES PN. The pneumoperitoneum was created by a periumbilical 12-mm trocar, through which a laparoscope was advanced for intra abdominal visualization. For TV-NOTES PN, a gastroscope was used to obtain TV peritoneal access. For TR-NOTES PN, a horizontal incision was made 2 cm above the dentate line, and a submucosal tunnel was created in the posterior rectal wall. The gastroscope was advanced through the submucosal tunnel and retroperitoneum to the kidney, and a peritoneal window was created. For both TR- and TV-NOTES PN, the gastroscope was exchanged for the SPIDER Surgical System. Flexible dissecting instruments and hook cautery introduced through the SPIDER Surgical System were used to mobilize the kidney. A harmonic scalpel introduced periumbilically was used to excise a portion of the lower pole. LAPRA-TY-secured sutured renorrhaphy was performed, followed by TR or TV specimen extraction. RESULTS: TR- and TV NOTES PN was successfully performed in all 10 pigs. A comparison of TR- and TV NOTES PN revealed no significant differences in the mean access time (29.2 vs 29.6 minutes, P = .944), operative time (196.0 vs 183.0 minutes, P = .631), and estimated blood loss (59.0 vs 54.0 mL, P = .861). Necropsy did not demonstrate abdominal injuries. CONCLUSION: We have demonstrated proof-of-principle for TR and TV-NOTES PN in swine, with comparable perioperative parameters. Preclinical survival studies are requisite to assess the potential of TR-NOTES as an alternative to TV-NOTES. PMID- 23676358 TI - Who should we trust in screening for lower urinary tract dysfunction in children: the parents or the child? AB - OBJECTIVE: To investigate whether the child's and the parents' reports about lower urinary tract symptoms (LUTS) are reliable and correlate with each other. MATERIALS AND METHODS: A validated questionnaire, the International Consultation on Incontinence Questionnaire Pediatric Lower Urinary Tract Symptoms, including both children and parent versions, was completed by children (age 5-18 years) with and without LUTS (control) and their parents without assistance. All children were investigated with detailed history, bladder diary, urinalysis, and flowmetry with postvoid residual urine volume measurement. The data were stratified into 3 age groups (5-9, 10-13, and 14-18 years). The reliability of both versions was evaluated using Cronbach's alpha and >=0.7 indicated acceptability. The correlation between the children's and parents' reports for each question was evaluated using Spearman correlation coefficients. The receiver operating characteristic curve was used to define the cutoff points, and the sensitivity and specificity were calculated. The principal component analysis method was used to explain the construct validity. RESULTS: A total of 272 children (147 with and 125 without LUTS) and their parents completed the questionnaire. The children and parent versions of the questionnaire were both reliable (Cronbach's alpha 0.709 and 0.710, respectively). The sensitivity and specificity was 82.4% and 80.0% for the children version and 87.8% and 78.4% for the parent version, respectively. The reliability and acceptability of the children's reports were insufficient for the 5-9 year age group, and the parents' answers were unreliable for the 10-13 year age group. The correlation between the parent and children reports was the lowest for the 10-13 year age group. CONCLUSION: The alteration in the reliability in the different age groups suggests that the combination of the parent and children versions is most appropriate for screening children with LUTS. PMID- 23676359 TI - The prevalence and predictors of androgen deficiency in Taiwanese men with type 2 diabetes. AB - OBJECTIVE: To evaluate the prevalence and predictors of androgen deficiency (AD) in Taiwanese men with type 2 diabetes mellitus (T2DM). METHODS: A recent hospital based series of Western populations showed that 30%-50% of men with T2DM have low testosterone, and AD links to DM and obesity bidirectionally. However, data of AD from other ethnicities with character of less obesity are rarely reported. AD was defined as having a total testosterone level less than 300 ng/dL. The clinical variables and diabetes-associated complications of the risk of AD were evaluated. RESULTS: Of 766 consecutive subjects (mean age 62.2 years, mean body mass index [BMI] 26.0) attending out-patient diabetic clinics, 32.5% have AD. The AD group was older, had higher BMI, waist circumference, higher proportion of metabolic syndrome and stroke, higher levels of triglyceride, high sensitivity C-reactive protein (hsCRP), uric acid, and lower levels of total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) than the normal testosterone group. After age adjustment, AD was positively associated with metabolic syndrome (odds ratio [OR] = 2.142), serum high sensitivity C-reactive protein (OR = 1.120), uric acid (OR = 1.118), BMI (OR = 1.083), waist circumference (OR = 1.038), triglyceride (OR = 1.028), and inversely associated with serum low density lipoprotein (OR = 0.931) and high-density lipoprotein (OR = 0.826) in logistic regression analysis. There were no significant differences in retinopathy, neuropathy, nephropathy, or coronary artery disease between patients with or without AD. CONCLUSION: One third of Taiwanese men with T2DM have AD. The major predictors of AD are linked to obesity, which is a potentially modifiable risk factor, and may represent an important avenue for intervention. PMID- 23676360 TI - Urologist attitudes toward end-of-life care. AB - OBJECTIVE: To examine urology trainees' views about the quality and current practices of end-of-life care and to explore strategies for improving integration and quality of care. METHODS: We conducted semi-structured interviews with 20 trainees from 4 institutions in different regions of the United States. Open ended questions allowed participants to express themselves independently, and follow-up discussions explored their perception of current end-of-life practices, as well as avenues for future integration and improvement. We analyzed transcripts using a multistage, cutting-and-sorting technique in an inductive approach based on grounded theory analysis. RESULTS: Clinicians agreed that their patients do not currently receive ideal care and were interested in joining a team geared towards improving care at the end of life. They expressed a preference for a multidisciplinary team, although the precise role each wanted to play within the team varied. Better identification of depression, pain, and patient-centered goals to allow value-congruent care were high in priorities for improvement. Trainees cited the lack of an educational curriculum on end-of-life care as a barrier to improving care and expressed a desire for formal education on this topic. CONCLUSION: Urology trainees believe that end-of-life care can be improved and are interested in participating as part of a multidisciplinary team to better care for these individuals. There was consensus that end-of-life care should be formally taught to all intern and resident physicians and care at the end of life should be integrated to pursue value-congruent care for each patient. PMID- 23676361 TI - The relationships between renal compensatory hypertrophy etiologic factors and anthropometric development in the pediatric age group. AB - OBJECTIVE: To evaluate the factors associated with compensatory hypertrophy in the functional kidneys of children. METHODS: The medical files of patients with a solitary functional kidney were reviewed retrospectively. Data regarding anthropometric measurements, functional renal length, functional renal length of standard deviation score (SDS) of functional kidney at diagnosis, and end of follow-up were obtained. Patients were divided into 2 groups, those with a unilateral kidney function of <10% (hypoplasia, dysplasia, and atrophy, group 1) and those with a solitary kidney (agenesis, and multicystic dysplastic kidney, group 2). RESULTS: A total of 126 patients (70 boys) were evaluated. Both the sizes of the functional kidney and functional kidney SDS values at diagnosis were greater in group 1 relative to group 2. At the end of the follow-up period, anthropometric values including functional kidney size were higher in group 2. Functional kidney size of 2 SDS above the normal was mostly predictive at age 17.5 months (odds ratio [OR] 5.06) and at a body height of 82 cm (OR 5.57). CONCLUSION: The most determining factors for renal length SDS values were age and height. Solitary kidneys complete compensatory hypertrophy by 17.5 months of age, and after that their growth continues in parallel to normal growth. PMID- 23676362 TI - Comparative characterization of proteins secreted by Neurospora sitophila in solid-state and submerged fermentation. AB - Although submerged fermentation (SmF) accounts for most of current enzyme industries, it has been reported that solid-state fermentation (SSF) can produce higher enzyme yields in laboratory scale. In order to understand the reasons contributing to high enzyme production in SSF, this study compared the cellulase activities and secretomes of Neurospora sitophila cultured in SSF and SmF using steam exploded wheat straw as carbon source and enzyme inducer. The total amounts of protein and biomass (glucosamine content) in SSF were respectively 30 and 2.8 times of those in SmF. The CMCase, FPA and beta-glucoside activities in SSF were 53-181 times of those in SmF. Both in SSF and SmF, N. sitophila secreted the most critical cellulases and hemicellulases known for Trichoderma reesei, although a beta-xylosidase was exclusively identified in SSF. Six endoglucanases were identified in N. sitophila secretion with the high CMCase activity. The non enzyme proteins in SSF were involved in fungal mycelia growth and conidiation; while those in SmF were more related to glycometabolism and stress tolerance. This revealed that SSF more likely serves as a natural habitat for filamentous fungi to facilitate the enzyme secretion. PMID- 23676363 TI - Stretching exercises enhance vascular endothelial function and improve peripheral circulation in patients with acute myocardial infarction. AB - The purpose of this study was to clarify the acute effects of a single session of stretching exercises on vascular endothelial function and peripheral circulation in patients with acute myocardial infarction. This study evaluated 32 patients (mean age, 66 +/- 9 years) who received phase I cardiac rehabilitation after acute myocardial infarction. Five types of stretching exercises were performed on the floor: wrist dorsiflexion, close-legged trunk flexion, open-legged trunk flexion, open-legged lateral trunk bending, and cross-legged trunk flexion. Each exercise entailed a 30-second stretching followed by a 30-second relaxation, and was repeated twice. Low- and high-frequency components (LF and HF) of heart rate variability (LF, 0.04-0.15 Hz; HF, 0.15-0.40 Hz) were analyzed, and HF and LF/HF were used as indices of parasympathetic and sympathetic nervous activities, respectively. Reactive hyperemia peripheral arterial tonometry (RH-PAT) index was measured and used as a parameter for vascular endothelial function. Transcutaneous oxygen pressure (tcPO2) on the right foot and chest was also measured, and the Foot-tcPO2/Chest-tcPO2 ratio was used as a parameter for peripheral circulation. The HF, RH-PAT index, and Foot-tcPO2/Chest-tcPO2 ratio were significantly higher after the exercises than before (P < 0.05, P < 0.01, and P < 0.05, respectively). There was no significant difference in the LF/HF ratio measured before and after stretching exercises. These findings demonstrate that stretching exercises improve vascular endothelial function and peripheral circulation in patients with acute myocardial infarction. PMID- 23676364 TI - Inter-scan reproducibility of geometric coronary artery measurements using frequency-domain optical coherence tomography. AB - Frequency-domain optical coherence tomography (FD-OCT) is a novel technology which provides high-resolution cross-sectional images of coronary arteries. The aim of this study was to evaluate the inter-scan reproducibility of geometric FD OCT measurements in the clinical setting. We examined 20 coronary lesions using FD-OCT. Following the FD-OCT image acquisition (1st pullback), and after the disengagement and re-engagement of the guiding catheter, an additional acquisition (2nd pullback) was performed using a new FD-OCT catheter. There was excellent correlation for minimum lumen area (r = 0.99, P < 0.001), lesion length (r = 0.99, P < 0.001) and lumen volume (r = 0.99, P < 0.001) between the 1st pullback and the 2nd pullback. The Bland-Altman test demonstrated good agreement between the 1st pullback and the 2nd pullback: the mean difference for minimum lumen area, lesion length, and lumen volume was 0.05 mm(2), 0.03 mm, and 0.70 mm(3), respectively; and the lower and upper limit of agreement for minimum lumen area, lesion length, and lumen volume was -0.58 and 0.48, -0.36 and 0.42, and 13.4 and 12.1, respectively. FD-OCT showed an excellent inter-scan reproducibility for the geometric coronary artery measurements. Our findings emphasize the value of FD-OCT as a tool for clinical longitudinal studies of coronary artery disease. PMID- 23676365 TI - Molecular imaging of apolipoprotein B-100 in human coronary plaques by color fluorescent angioscopy and microscopy. AB - Apolipoprotein B-100 (ApoB-100) is an important risk factor for coronary artery disease. However, its localization in human coronary plaques is not well understood. The present study was performed to visualize ApoB-100 in human coronary artery wall. Deposition of native ApoB-100 in excised human coronary plaques and normal segments classified by conventional angioscopy was investigated by color fluorescent angioscopy (CFA) and microscopy (CFM) using Nile blue dye (NB) which elicits a golden fluorescence characteristic of ApoB-100 as a biomarker. By CFA, the % incidence of ApoB-100 was 20 in 40 normal segments, 38 in 42 white, and 11 in 35 yellow plaques (P < 0.05 versus white plaques). There was no significant difference in detection sensitivity between CFA and luminal surface scan by CFM. By CFM transected surface scan, ApoB-100 deposited in superficial, deep, and/or in both layers. Deposition in both layers was frequently observed in white plaques and yellow plaques without necrotic core (NC), less frequently in normal segments, and rarely in yellow plaques with NC. (1) Taking into consideration the well known process of plaque growth, the results suggest that ApoB-100 begins to deposit before plaque formation, increasingly deposits with plaque growth, and disappears after necrotic core formation. (2) CFA is feasible for imaging of ApoB-100 in human coronary artery wall. PMID- 23676366 TI - Efficacy and limitations of oral inotropic agents for the treatment of chronic heart failure. AB - The heart failure guideline in Japan has stated the necessity of investigating the role of oral inotropic agents in patients with chronic heart failure (CHF), which are clinically available only in Japan. A total of 1,846 consecutive patients with heart failure (mean: 69.5 years old, 1,279 males) treated at our institute from November 2009 to August 2010 were investigated retrospectively. Thirty-one patients (1.84%) who had taken oral inotropic agents (pimobendan 27, docarpamine 6, and denopamine 4) were extracted for this study, and the efficacy and limitations of the treatments were analyzed. Following the oral inotropic treatment, the NYHA functional class (P = 0.017), cardiothoracic ratio (P = 0.002) and B-type natriuretic peptide levels (P = 0.011) were significantly improved, and the number of emergency room (ER) visits (P < 0.001) and hospitalizations (P < 0.001) were significantly reduced. The nonsurviving patients (n = 7/31, 22.6%) were significantly older (P = 0.02) and tended to have a larger cardiothoracic ratio (P = 0.084) compared with the survivors. An absence of concomitant beta-blocker therapy was significantly associated with a worse prognosis (oneyear mortality 2/21 versus 5/10, log rank, P = 0.011). Oral inotropic agents brought about improvements in the clinical parameters of CHF and a reduction in ER visits and hospitalizations. However, concomitant beta-blocker therapy should be considered for patients receiving oral inotropic treatment. PMID- 23676367 TI - Left ventricular hypertrophy, diastolic dysfunction, pulse pressure, and plasma ET-1 in marathon runners with exaggerated blood pressure response. AB - This study was conducted to study left ventricular hypertrophy (LVH), diastolic dysfunction, pulse pressure (PP), and plasma endothelin (ET)-1 level in amateur marathon runners with an exaggerated blood pressure response (EBPR) to exercise. The study participants included normotensive marathon runners (NM, n = 15), EBPR marathon runners (EBPR, n = 17), normotensive sedentary individuals (CON, n = 13), and hypertensive patients (HTN, n = 14). An integrated M-mode/2-dimensional echocardiographic analysis was performed. Plasma ET-1 levels at resting were measured using a commercial ELISA kit. LV wall thickness and end-diastolic dimensions as well as LV mass index (LVMI) were higher in EBPR than in CON. There were no differences in systolic function among the groups. Analysis of diastolic function, such as lower Em and higher E/Em ratio on TDI, showed a worse relaxation pattern in EBPR. Despite LVH, NM subjects showed no abnormality of LV diastolic dysfunction. HTN subjects in the early stage of their disease showed a slightly modified LV structural and diastolic function, but there was no statistical difference compared with CON. The E/Em ratio was significantly correlated with PP and LVMI. LVMI was significantly correlated with PP. There was a significant difference in plasma ET-1 concentration between marathon runners and hypertensive subjects. We demonstrated that marathon runners with EBPR showed an increase in LVMI and diastolic dysfunction more than HTN subjects in the early stage. PP was significantly related to these two variables. Caution should be exercised when connecting LVH and diastolic dysfunction with plasma ET-1 concentration in all marathon runners. PMID- 23676368 TI - Effectiveness of the direct renin inhibitor, aliskiren, in patients with resistant hypertension. AB - Currently there is no consensus regarding which add-on therapy to use in resistant hypertension. We have conducted an open observational study of the use of aliskiren in resistant hypertensive patients. Forty-three patients with resistant hypertension were included in the study. The inclusion criteria were as follows: 1) office blood pressure (BP) > 140/90 mmHg despite treatment with at least three or more antihypertensive drugs; 2) no prior therapy with aliskiren; and 3) no renal insufficiency. Follow-up BP was determined at 1 and 3 months. Baseline BP was 153 +/- 12/79 +/- 12 mmHg. After 3 months, systolic BP (SBP) and diastolic BP (DBP) dropped significantly: 140 +/- 19/73 +/- 13 mmHg (P < 0.0001). Twenty-one patients (49%) had an office BP < 140/90 mmHg, and these patients were assigned to the good BP control group. Another 22 were placed into the poor BP control group. BP reductions from baseline in the good BP control group (SBP/ DBP: 19 +/- 11/8 +/- 7 mmHg) were larger than those in the poor BP control group (5 +/- 15/3 +/- 9 mmHg, P < 0.05). Mean BP (MBP) values at baseline, 1, and 3 months were higher in the poor BP control group. There was no significant difference in pulse pressure at baseline between the 2 groups. In multivariate analysis, only MBP at baseline correlated with lack of BP control. Aliskiren administration to resistant hypertensive patients was effective in reducing BP. The present findings suggest aliskiren may be useful as a fourth-line or fifth line treatment added to other drugs in the treatment of resistant hypertension. PMID- 23676369 TI - Trends in antidiabetic prescription patterns in Japan from 2005 to 2011. AB - There have been few reports concerning the trends in antidiabetic drug use in Japan. In 2009, a dipeptidyl peptidase-4 inhibitor (DPP4I), an antidiabetic with a new mechanism of action, was made available. This study was conducted to analyze the antidiabetic prescription trends in Japan in recent years and the influence of DPP4Is on those trends. We used monthly claims data obtained from a database company. Data from patients 20 years of age or older and who were prescribed antidiabetics were extracted and analyzed. A total of 18,457 patients were prescribed antidiabetics (mean age, 53.6 +/- 11.0). The sulfonylurea prescription rate decreased while that of biguanides increased. After the introduction of DPP4Is, use of these agents rapidly increased and the rate further increased one year after DPP4I introduction. DP-P4Is also became the most prescribed antidiabetics for those prescribed antidiabetics for the first time. The decrease in the use of sulfonylureas and the increase in the use of biguanides are in accordance with trends observed in the United States and Europe, and probably reflect Japanese physicians' awareness of cumulating evidence gained from studies such as the UK Prospective Diabetes Study (UKPDS). The rapid increase in the DPP4I prescription rate might be the result of several factors including their safety profiles, which were highlighted in clinical studies published just prior to the drugs becoming available. However, there is little data regarding the efficacy of DPP4Is in reducing diabetes related complications, which should be determined in future studies. PMID- 23676370 TI - Renoprotective effect of vasopressin v2 receptor antagonist tolvaptan in Dahl rats with end-stage heart failure. AB - Tolvaptan is a highly selective and orally effective arginine vasopressin V2 receptor antagonist, and is potentially useful for the treatment of heart failure (HF) patients. However, the renoprotective effect of long-term tolvaptan therapy and its underlying mechanisms remain unknown. We evaluated the effects of chronic treatment with tolvaptan on renal dysfunction, podocyte injury, inflammation, oxidative stress, Rho-kinase, epithelial-mesenchymal transition (EMT), and the extracellular signal-regulated protein kinase (ERK1/2) pathway in the renal cortex of Dahl salt-sensitive hypertensive (DS) rats with end-stage severe HF. DS and Dahl salt-resistant rats were fed a high-salt diet at 6 weeks of age. DS rats were treated with vehicle and tolvaptan (0.05% concentration in diet) from the age of 11 to 18 weeks. Vehicle-treated DS rats developed proteinuria, renal dysfunction, glomerulosclerosis, and interstitial fibrosis, which were ameliorated by tolvaptan without changing blood pressure. Decreased expression of nephrin and podocin and increased desmin-positive area in failing rats were restored by tolvaptan. Upregulation of NAD(P)H oxidase p22(phox), p47(phox), and gp91(phox), EMT markers such as transforming growth factor-beta1, vimentin, and fibronectin expression, and Rho-kinase and ERK1/2 phosphorylation in DS rats were significantly suppressed by tolvaptan. Tolvaptan administration resulted in significant inhibition of tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression, and nuclear factor-kappaB phosphorylation. We concluded that long-term tolvaptan therapy may improve renal dysfunction, glomerulosclerosis, podocyte injury, and inflammation associated with oxidative stress, as well as EMT, ERK, and the Rho-kinase pathway in the failing heart of DS rats. Thus, tolvaptan may be a therapeutic strategy for end-stage severe HF. PMID- 23676371 TI - Cardiac symptoms related to paroxysmal atrial fibrillation varied with menstrual cycle in a premenopausal woman. AB - Atrial fibrillation, an arrhythmia observed more frequently in men than women, is induced by both sympathetic and parasympathetic autonomic nerve activations. The menstrual cycle in premenopausal women has been reported to modulate the autonomic nervous system: parasympathetic activity is dominant in the follicular phase and sympathetic activity is dominant in the luteal phase. However, the relationship between atrial fibrillation and the menstrual cycle has not yet been reported, because this arrhythmia is very rarely detected in premenopausal women. We experienced a 38 year-old woman with paroxysmal atrial fibrillation. Her menstrual cycle was 30.4 +/- 0.5 days and the menstrual period was 3.9 +/- 0.2 days for 22 cycles. Although she had taken flecainide 200 mg/day, bepridil 200 mg/day, and propranolol 20 mg/day, she sometimes experienced mild palpitations. QTc intervals measured at her visits to our clinic were 440 +/- 3 msec in the follicular phase and 425 +/- 2 msec in the luteal phase (P = 0.01). These changes in QTc intervals during the menstrual cycle are compatible with earlier reports. During the 22 menstrual cycles, she felt palpitations on 3.2 +/- 0.7 days in the menstrual period, 6.4 +/- 0.3 days in the follicular phase, and 4.1 +/- 0.4 days in the luteal phase (P = 0.01). Afterward, the medication was changed from daily to periodic administration for one week beginning a couple of days before the expected menstrual time, and she did not feel symptomatic variation in her menstrual cycle. These data suggest that her symptoms related to atrial fibrillation might have been dependent on parasympathetic activity. PMID- 23676372 TI - Radiofrequency catheter ablation of the accessory pathway adversely affected the left ventricular outflow tract pressure gradient in a patient with hypertrophic obstructive cardiomyopathy. AB - Although hypertrophic cardiomyopathy (HCM) with an accessory pathway is encountered in clinical practice, there is little evidence of a coherent strategy for ablation of the accessory pathway in patients with HCM. We present the case of a 61-year-old man who had type B Wolff-Parkinson-White (WPW) syndrome with hypertrophic obstructive cardiomyopathy (HOCM). Due to paroxysmal atrial fibrillation, he underwent radiofrequency catheter ablation of the accessory pathway located in the right postero-lateral wall to prevent secondary symptomatic events. His LV dyssynchrony improved after the procedure, but the degree of the LV outflow tract (LVOT) pressure gradient was increased. To stabilize the LVOT pressure gradient, he needed additional medications. This case shows that patients with HOCM should be carefully evaluated before making a decision concerning ablation of the accessory pathway. PMID- 23676373 TI - A case with recovery of response to tolvaptan associated with remission of acute kidney injury and increased urine osmolality. AB - Tolvaptan (TLV), a vasopressin type 2 receptor antagonist, has been demonstrated to be effective in patients with decompensated heart failure (HF) refractory to incremental doses of diuretics, but the responsiveness has not always been predictable. We have recently proposed that urine osmolality (U-OSM) is a valuable parameter for the prediction of responses to TLV, because U-OSM reflects the activity of the collecting ducts, where TLV plays its unique role. Acute kidney injury (AKI) is often associated with severe tubular dysfunction, including the collecting ducts, and in such cases a response to TLV may not be expected. We here experienced a patient with HF and AKI in whom TLV was not effective during AKI. We also observed recovery of responsiveness to TLV along with remission of AKI as well as increased U-OSM later on. We believe that this is the first report on the reversibility of the TLV response in relation to U OSM. PMID- 23676374 TI - Cardiac magnetic resonance imaging in a patient with amniotic fluid embolism associated with severe cardiopulmonary complications. AB - Amniotic fluid embolism (AFE) is a rare but devastating complication of pregnancy. Acute circulatory failure and obstetric disseminated intravascular coagulopathy are often associated with AFE and lead to poor prognosis of this syndrome. Although many reports of AFE and its cardiopulmonary complications exist, their etiology remains unknown. Classically, it was believed that the fatal cardiopulmonary complication in AFE is due to acute and severe pulmonary hypertension caused by critical obstruction of the pulmonary vessels by embolized amniotic fluid. However, recent hypotheses are suggesting that anaphylactic reaction or a cytokine effect induced by amniotic fluid is the main pathophysiological mechanism. We report a case in which cardiac magnetic resonance imaging was performed at the chronic stage of AFE. Late gadolinium enhancement (LGE) was detected at the mid-wall of the left ventricle with no evidence of pulmonary hypertension. This finding suggests that the pathophysiological mechanism of severe cardiac complications in AFE may include direct left ventricular myocardial injury through an immune reaction or cytokine release, rather than pulmonary embolism. PMID- 23676375 TI - Oxytocin pretreatment attenuates oxytocin-induced contractions in human myometrium in vitro. AB - BACKGROUND: Oxytocin receptor desensitization has been shown to occur in humans at biomolecular level and in isolated rat myometrium; however, its effect on human myometrial contractility has not been demonstrated. The objective of this in vitro study was to investigate the contractile response of human pregnant myometrium to oxytocin after pretreatment with different concentrations of oxytocin for variable durations. METHODS: Myometrial samples were obtained from 62 women undergoing elective cesarean deliveries under regional anesthesia. The strips were pretreated with oxytocin 10, 10, 10 M, or physiological salt solution (control) for 2, 4, 6, or 12 h, followed by a dose-response testing with oxytocin 10 to 10 M. Amplitude and frequency of contractions, motility index, and area under the curve during the dose-response period were recorded, analyzed with linear regression models, and compared among groups. RESULTS: Pretreatment with oxytocin 10 and 10 M significantly reduced motility index (estimate [standard error]: -0.771 [0.270] square root units, P = 0.005 and -0.697 [0.293], P = 0.02, respectively) and area under the curve (-3.947 [1.909], P = 0.04 and -4.241 [2.189], P = 0.05, respectively) compared with control group, whereas pretreatment with oxytocin 10 M did not significantly attenuate contractions. Increase in duration of oxytocin pretreatment from 2 to 12 h significantly decreased amplitude (type 3 generalized estimating equation analysis: chi-square = 14.0; df = 3; P = 0.003), motility index (chi-square = 9.3; df = 3; P = 0.03), and area under the curve (chi-square = 10.5; df = 3; P = 0.02), but not the frequency of oxytocin-induced contractions. CONCLUSION: Pretreatment with oxytocin decreases oxytocin-induced myometrial contractions in a concentration and time-dependent manner, likely as a function of the oxytocin receptor desensitization phenomenon. PMID- 23676376 TI - Response surface methodology (RSM) analysis of photodegradation of sulfonated diazo dye Reactive Green 19 by UV/H2O2 process. AB - A central composite design was used to investigate the influence of the main process parameters on the degradation of Reactive Green 19 (RG19) azo dye by the UV/H2O2 treatment. The combined use of UV radiation and H2O2 resulted in the decolorization and dearomatization of the dye. They were monitored by measuring the spectral changes occurring, respectively, in the visible and UV regions of the dye spectrum. RG19 degradation was found to be practically complete over a time of 15-60 min, for decolorization, and 50-200 min, for dearomatization, depending on the applied conditions. Both processes followed apparent first-order kinetics. The associated rate constants were used as the response variables and their dependence on initial dye and H2O2 concentrations, pH and reaction time was investigated by the response surface methodology. Response surface plots for the decolorization and dearomatization processes were very similar in shape. For both processes, the initial dye and H2O2 concentrations were the key factors controlling dye degradation. PMID- 23676377 TI - Clustering of risk factors for noncommunicable diseases in Brazilian adolescents: prevalence and correlates. AB - BACKGROUND: Few studies have investigated the prevalence and correlates of risk factors for noncommunicable diseases among Brazilian adolescents. We evaluated the clustering of risk factors and their associations with sociodemographic variables. METHODS: We used a cross-sectional study carried out in 2011 comprising 1132 students aged 14-19 years from Santa Maria, Brazil. The cluster index was created as the sum of the risk factors. For the correlates analysis, a multinomial logistic regression was used. Furthermore, the observed/expected ratio was calculated. RESULTS: Prevalence of individual risk factors studied was as follows: 85.8% unhealthy diets, 53.5% physical inactivity, 31.3% elevated blood pressure, 23.9% overweight, 22.3% excessive drinking alcohol, and 8.6% smoking. Only 2.8% of the adolescents did not present any risk factor, while 21.7%, 40.9%, 23.1%, and 11.5% presented 1, 2, 3, and 4 or more risk factors, respectively. The most prevalent combination was between unhealthy diets and physical inactivity (observed/expected ratio =1.32; 95% CI: 1.16-1.49). Clustering of risk factors was directly associated with age and inversely associated with socioeconomic status. CONCLUSIONS: Clustering of risk factors for noncommunicable diseases is high in Brazilian adolescents. Preventive strategies are more likely to be successful if focusing on multiple risk factors, instead of a single one. PMID- 23676378 TI - Relationship between EEG beta power abnormality and early diagnosis of cognitive impairment post cerebral hemorrhage. AB - Cerebral hemorrhage is a common disease of older adults, which could increase the risk of cognitive impairment. Electroencephalogram (EEG) characteristics can be analyzed to investigate the applied value in the assessment of cognitive impairment of the patients with cerebral hemorrhage. One hundred eighty-two patients (including patients with cognitive impairment [CHCI] and patients with cognitive normality [CHNC] with cerebral hemorrhage, and 120 normal healthy persons [control; CN]) were recruited between July 2008 to March 2012 at the department of neurology. All patients were analyzed by EEG, and analysis results were compared to the Montreal Cognitive Assessment (MoCA) scale, using the methods of correlation analysis, clustering analysis, and concordance analysis. The results indicated that patients with CHCI had significantly lower EEG beta power (0.814 +/- 0.113 mcV(2)) relative to CHNC (1.601 +/- 0.186 mcV(2), P < .01) or CN group (1.713 +/- 0.201 mcV(2), P < .01). Significant negative correlation was found between the beta power and hemorrhage region, age, hemorrhage size, hemorrhage amount (r 1 = -.92223, r 2 = -.81084, r 3 = -.79258, r 4 = -.84961, respectively, all P < .001). There was good concordance between K-means clustering algorithm calculating the beta power and MoCA scoring (Kappa = 0.899, P < .001). In conclusion, the preliminary findings suggest that the recognition techniques of EEG hold considerable promise for the assessment of cognitive impairment post cerebral hemorrhage, which negatively related to the hemorrhage region, hemorrhage size, hemorrhage amount, and age. PMID- 23676379 TI - Are constructed treatment wetlands sustainable sanitation solutions? AB - The main objective of sanitation systems is to protect and promote human health by providing a clean environment and breaking the cycle of disease. In order to be sustainable, a sanitation system has to be not only economically viable, socially acceptable and technically and institutionally appropriate, but it should also protect the environment and the natural resources. 'Resources oriented sanitation' describes the approach in which human excreta and water from households are recognized as resource made available for reuse. Nowadays, 'resources-oriented sanitation' is understood in the same way as 'ecological sanitation'. For resources-oriented sanitation systems to be truly sustainable they have to comply with the definition of sustainable sanitation as given by the Sustainable Sanitation Alliance (SuSanA, www.susana.org). Constructed treatment wetlands meet the basic criteria of sustainable sanitation systems by preventing diseases, protecting the environment, and being an affordable, acceptable, and simple technology. Additionally, constructed treatment wetlands produce treated wastewater of high quality, which is fostering reuse, which in turn makes them applicable in resources-oriented sanitation systems. The paper discusses the features that make constructed treatment wetlands a suitable solution in sustainable resources-oriented sanitation systems, the importance of system thinking for sustainability, as well as key factors for sustainable implementation of constructed wetland systems. PMID- 23676380 TI - Photo-degradation of butyl parahydroxybenzoate by using TiO2-supported catalyst. AB - The present work evaluates the potential of the photocatalysis (PC) process for the degradation of butylparaben (BPB). Relatively high treatment efficiency was achieved by comparison to photochemical process. Prior to photocatalytic degradation, adsorption (AD) of BPB occurred on the titanium dioxide (TiO2) supported catalyst. AD was described by Langmuir isotherm (KL = 0.085 L g(-1), qm = 4.77 mg g(-1)). The influence of angle of inclination of the reactor, pH, recirculation flow rate and initial concentration of BPB were investigated. The PC process applied under optimal operating conditions (recirculation flow rate of 0.15 L min(-1), angle of inclination of 15 degrees , pH = 7 and 5 mg L(-1) of BPB) is able to oxidize 84.9-96.6% of BPB and to ensure around 38.7% of mineralization. The Langmuir-Hinshelwood kinetic model described well the photocatalytic oxidation of BPB (k = 7.02 mg L(-1) h(-1), K = 0.364 L mg(-1)). PMID- 23676381 TI - Collaboration essential for an energy neutral urban water cycle. AB - Two Dutch water boards prepared a Master Plan with measures to substantially reduce their energy use by 2027. In total, more than 100 measures were identified such as bubble aeration and heat recovery from effluent. Together these measures result in a 90-95% reduction in energy use at the water boards. However, for the whole urban water cycle, thus including the energy required for warm water use in households, the total energy reduction from these measures at the water boards is only 5-6%. To attain the objective to have an energy neutral urban water cycle, collaboration with other sectors such as housing, energy, agriculture and industry will be essential. Active collaboration of the water boards through the incorporation of energy efficient water measures as part of the carbon neutral effort of cities is recognized to be a promising strategy. PMID- 23676382 TI - Micellar-enhanced ultrafiltration of copper ions using sodium dodecyl sulfate and its mixture with Brij 35, Tween 80 and Triton X-100. AB - The performance of copper ion removal using sodium dodecyl sulfate (SDS) and its mixtures with Brij 35, Tween 80 (TW80) and Triton X-100 (TX100) by micellar enhanced ultrafiltration (MEUF) was investigated. The effects of the molar ratio of nonionic surfactant to SDS on the critical micelle concentration (CMC) of SDS/Brij 35, SDS/TW80 and SDS/TX100, the removal efficiency of Cu(2+), the residual concentration of SDS in the permeate solution and the permeate flux were tested. The results showed that the CMCs of the mixed surfactants were sharply less than that of pure SDS. The removal efficiencies of Cu(2+) were up to the maximum values 98.3 and 95.8% when the molar ratios of Brij 35 and TW80 to SDS were 0.3, and it was 93.5% given 0.7 molar ratio of TX100 to SDS. The concentration of SDS in the permeate decreased dramatically with the addition of nonionic surfactant, and the permeate flux decreased slightly as the molar ratio increased. Compared with the performance by single SDS, the mixed SDS/Brij 35, SDS/TW80 and SDS/TX100 at an optimum composition could result in not only higher rejection of Cu(2+) but also much less dosage of surfactant and concentration of SDS in the permeate. PMID- 23676383 TI - Water scarcity and institutional change: lessons in adaptive governance from the drought experience of Perth, Western Australia. AB - Urban water systems will be increasingly challenged under future climates and global pressures. Meeting challenges by reconfiguring water systems to integrate supplies and deliver multifunctional uses is technically well described. Adjusting the institutions that frame the management of these systems is not well operationalized in practice or conceptualized in theory. This study seeks to address this gap through an institutional analysis of Perth, Australia, a city where drought crisis has put under pressure both management practices and the institutional setting that underlies them. The study found that while trusted practices moderated water scarcity, the stability of the institutional setting may not facilitate a shift toward adaptable institutional configurations suited to future conditions. The results identified three key ingredients for a flexible institutional setting: (i) feedbacks in the system through better information management, (ii) reflexive dialogue and strategic use of projects to generate greater learning opportunities, and (iii) policy level support for sector-wide collaboration through progressive agendas, incentives for innovation and capacity building in stakeholder and community engagement. Further, the results suggest that a deeper understanding of institutional dynamics is needed to enable adaptive governance. The paper provides an analytical framework for diagnosing how greater adaptive capacity might be mobilized through influencing these dynamics. PMID- 23676384 TI - Aeration tank settling and real time control as a tool to improve the hydraulic capacity and treatment efficiency during wet weather: results from 7 years' full scale operational data. AB - This paper investigates the aeration tank settling (ATS) operation in combination with real time control (RTC) as a tool for increasing the hydraulic capacity and improving the treatment efficiency of a wastewater treatment plant (WWTP) during wet weather flows. Results from 7 years' full-scale operational data at the Avedore WWTP, Denmark, show that ATS operation in combination with RTC increases the hydraulic capacity of the treatment plant with up to 150 and 67% of the design capacity during winter and summer respectively. Compared to the conventional wet weather operation, the ATS in combination with RTC operation resulted in lower effluent concentrations for total phosphate (40-50%), suspended solids (30-60%) and chemical oxygen demand (30-50%), whereas no significant effect was observed on total nitrogen. Apart from the reduced effluent concentrations, the RTC resulted in economic savings in the form of reduced costs for electricity and green taxes. However, in very few cases the ATS operation in combination with RTC was not able to handle design capacity, and some overflows occurred at flows below the design capacity. The frequency of these overflows may increase in the future due to increased rain intensity resulting in shorter prediction time available for ATS. PMID- 23676385 TI - Electrochemical degradation of 2,5-dichloro-1,4-phenylenediamine by anodic oxidation. AB - Electrochemical degradation of 2,5-dichloro-1,4-phenylenediamine (DP) in aqueous solution by anodic oxidation was investigated. Linear sweep voltammograms and cyclic voltammograms were studied. The influence of operating parameters on electrochemical oxidation of DP was studied as a function of the current density, initial pH, and initial concentration of DP. The degradation kinetics analysis indicated that the electrochemical degradation of DP followed a first-order reaction. The degradation intermediates during electrochemical oxidation were analyzed by UV-vis spectrophotometer, ionic chromatograph (IC), and gas chromatography/mass spectrometry (GC/MS). The combustion efficiency of DP at the anode was also estimated. The electrochemical oxidation of DP resulted in the release of NH4(+) and Cl(-). Based on these results, a degradation mechanism for electrochemical degradation of DP by anodic oxidation was proposed. PMID- 23676386 TI - Ferrate(VI): a novel oxidant for degradation of cationic surfactant - cetylpyridinium bromide. AB - Ferrate(VI) is an efficient multi-functional water treatment reagent that has several novel properties, such as strong oxidation, absorption, flocculation, disinfection and deodorization. The removal of cationic surfactants based on ferrate (K2FeO4) was performed in the case of cetylpyridinium bromide (CPB). The influence of operating variables on the mineralization efficiency was studied as a function of ferrate dosage, initial pH and reaction time. Total organic carbon (TOC), UV and infrared spectra were performed to gain a better understanding of the degradation process. Results show that the optimal treatment conditions are as follows, solution initial pH is over 5, oxidation time is 5 min and ferrate dosage is 1.5 times that of CPB. The removal efficiency of CPB above 99% and TOC removal percentage of 91.3% can be achieved in minutes. The reaction of CPB with K2FeO4 responds to a second-order kinetic law. PMID- 23676387 TI - Degradation and toxicity change of 4-chlorophenol in aqueous solution during CGDE treatment. AB - This study focused on the degradation and toxicity change of 4-chlorophenol (4 CP) in aqueous solution by contact glow discharge electrolysis (CGDE) with and without Fe(2+). It was found that the addition of Fe(2+) increased the degradation rate of 4-CP and decreased the toxicity of the solution. After 90 min CGDE treatment, only 28.0% 4-CP was removed and EC50 increased from 33.8 to 63.1 mg/L. With 25.0 mg/L Fe(2+) in solution, the degradation rate of 4-CP reached 93.3% and EC50 changed from 35.9 to 93.9 mg/L after 90 min CGDE treatment. PMID- 23676388 TI - Investigation of chemical-free nutrient removal and recovery from CO2-rich wastewater. AB - The feasibility of a bench-scale system for removal and recovery of phosphorus (P) as struvite from CO2-rich wastewater was tested. A continuous 12 L reactor system combining a fluidized seedbed and aeration for pH increase was developed and tested using synthetic feed. For a 100 mL min(-1) influent rate, an aeration and recycle rate combination of 7 L min(-1) and 700 mL min(-1) was sufficient for increasing and maintaining the reactor pH from 6.7 to between 7.6 and 8.0. Significant P removal was achieved in 6 h runs without a seedbed (91-92%), while neither the struvite nor sand seedbeds improved P removal (91-96%). Struvite was recovered in all runs, with additional calcium (Ca) precipitation in the seedbed runs. Reactor operation was possible for an extended period of time, up to 46 h without any major adjustment during long-term run. The average P removal was 88%, and precipitate collected after 24 h was found to be mainly struvite, while the final precipitate had a Ca: total phosphorus molar ratio of 0.56 and also contained calcite. This study has demonstrated the technical feasibility of an aerated crystallization reactor system for chemical-free struvite removal and recovery from CO2-rich wastewater such as stored livestock manure. PMID- 23676389 TI - The dye or humic acid water treatment and membrane fouling by polyaluminum chloride composited with sodium alginate in coagulation-ultrafiltration process. AB - Composite flocculants have been extensively studied and applied in recent years in order to improve the water treatment efficiency. In this study, a new composite flocculant prepared by polyaluminum chloride (PAC) and sodium alginate (SA) was used to treat dye and humic acid water in the coagulation ultrafiltration process. The subsequent effects of PAC/SA on ultrafiltration membrane fouling were investigated by calculating the Modified Fouling Index (MFI). The results showed that the application of PAC/SA could not only restrict the membrane fouling but also improve the removal efficiency of the coagulation ultrafiltration process. MFI of PAC/SA was the lowest, followed by PAC and the raw water for coagulated effluents filtered by ultrafiltration membrane. For example, MFI of PAC/SA was 0.40 s mL(-2) for reactive blue KGL (denoted as RB KGL) treatment, while that of PAC was 2.26 s mL(-2). The removal efficiencies were improved as coagulation was used as pretreatment of ultrafiltration membrane. And PAC/SA could form the higher removal efficiency than PAC, especially for RB-KGL. The color removal efficiency of PAC/SA was 96.36% for RB KGL treated by coagulation-ultrafiltration process, which was higher than that of PAC (85.62%). PMID- 23676390 TI - Dynamic coupling of near field and far field models for simulating effluent discharges. AB - In many cases, (processed) wastewater or thermal effluents are discharged into the marine environment, rivers or lakes. To accurately determine the dispersion, recirculation and environmental impacts of outfall plumes, it is important to be able to model the different characteristics of the outfall plume in detail - from the near field (metres around the outfall) to the far field (up to kilometres away). The solution for engineering practice is to combine different types of models (near and far field models) that each focus on specific scales, with corresponding optimised resolutions and processes. However, to adequately describe the hydrodynamic processes on these different scales, it is essential to couple these models in a dynamic and comprehensive way. To achieve this, a dynamic coupling between the open-source Delft3D-FLOW far field model and the CORMIX near field expert system is proposed. This coupled modelling system is able to use the computed far field ambient conditions in the near field computations and, conversely, to use the initial near field dilution and mixing behaviour in the far field model. Preliminary results are presented to provide a first indication of the potential of the method for modelling the complete trajectory of effluent outfall plumes, allowing an accurate assessment of the environmental effects and the design of possible mitigating measures. PMID- 23676391 TI - Ecotoxicity comparison of organic contaminants and heavy metals using Vibrio qinghaiensis sp.-Q67. AB - By using the Vibrio-qinghaiensis sp.-Q67 test, the concentration-inhibition relationships were established for comparing the ecotoxicity of selected organic compounds and heavy metals. The toxicity indices for the four organic compounds were 11-628 mg/L in terms of EC50,TOC (EC: effective concentration, TOC: total organic carbon), with the toxicity in an order of linear alkylbenzene sulfonate > ciprofloxacin > phenol > acetaminophene, while that for the six heavy metals were 0.40-2.74 mg/L in terms of EC50,metal with the toxicity in an order of Cd > Hg > Zn > Pb > Cr > Cu. Through extracting organic matter from the raw sewage and secondary effluent of a wastewater treatment plant (WWTP), their EC50,TOC was measured as 94.5 and 125.2 mg/L, respectively, indicating that WWTP reduced not only the organic concentration but also the ecotoxicity of the wastewater. By analyzing the organic and heavy metal contents and the ecotoxicity of five typical industrial wastewaters, it was identified that the coking wastewater had the highest ecotoxicity (toxicity index as EC50,% = 0.18%), which might be mainly caused by organic contaminants, while the ecotoxicity of the electroplating wastewater (EC50,% = 6.08%) would be mainly caused by heavy metals. The ecotoxicity on Q67 could provide a comprehensive evaluation of the wastewater without knowing exactly the contaminants composition. PMID- 23676392 TI - Advanced characterization of algogenic organic matter, bacterial organic matter, humic acids and fulvic acids. AB - Advanced characterization techniques of organic matter, including bulk organic characterization, size-exclusion chromatography, three-dimensional excitation emission matrix, Fourier transform infrared spectroscopy, and fractionations using Amberlite XAD-8/4 resins, were used to investigate differences and similarities in the physicochemical properties of four different organic matter, namely algogenic organic matter (AOM), bacterial organic matter (BOM), Suwanee River humic acids (SRHA) and Suwanee River fulvic acids (SRFA). From the comparison of characteristics of the AOM, BOM, SRHA, and SRFA, it was identified that the specific UV absorbance, molar ratio of organic nitrogen to organic carbon, molecular weight, fluorescence characteristics, functional group compositions, and relative hydrophobicity/hydrophilicity of all the tested organic matter were considerably different from their sources. The SRHA and SRFA were mainly composed of hydrophobic fractions while the AOM and BOM included more hydrophilic fractions than the SRHA and SRFA due to the alcohol and amide functional groups. This indicated that the origin of organic matter in natural waters can be predicted by their physicochemical characteristics, and the source identification of organic matter provides a better understanding of the interactions between the origin of organic matter and water treatment processes (e.g., coagulation and membrane filtration). PMID- 23676393 TI - A new approach for evaluating the infectivity of noncultivatable enteric viruses without cell culture. AB - This study developed a novel approach for evaluating the infectivity of enteric viruses without cell culture. Cumulative carbonyl groups on the viral capsid protein were labeled using biotin hydrazide, and the biotinylated virions were separated using a spin column filled with avidin-immobilized gel. Rotavirus was treated with free chlorine at an initial concentration of 0.3 mg/L for 3 min, and the log reduction in the infectious titer was 0.19 log (standard deviation, SD = 0.05). The log reduction of rotavirus treated with free chlorine at an initial concentration of 0.6 mg/L for 3 min was 2.6 log (SD = 0.37). No significant reductions in the amplicon copy numbers were observed in these free chlorine treated samples. The recovery levels of intact virions in the first three fractions after biotin-avidin affinity chromatography were 76, 21, and 2.8%, while those of virions treated with free chlorine at an initial concentration of 0.3 mg/L for 3 min were 70, 23, and 5.6%. These results showed that the proposed approach could discriminate a 0.19 log infectivity-reduced population from an intact population, although no reduction in the amplicon copy number was observed. This novel method could be applied to noncultivatable enteric viruses such as human norovirus and sapovirus, and it could be very helpful for evaluating the viral inactivation efficiencies of intervention measures. PMID- 23676394 TI - Influence of temperature and pH on nitrogen removal in a series of maturation ponds treating anaerobic effluent. AB - This paper presents an evaluation of the influence of pH and temperature on nitrogen removal in a series of three shallow maturation ponds serving as post treatment of upflow anaerobic sludge blanket (UASB) reactor effluent (approximately 200 population equivalent). Monitoring was from January 2007 to May 2009. Throughout this period, the ponds maintained relatively stable operational conditions in terms of depth and hydraulic retention time, thus enabling the evaluation of the influence of variations in temperature and pH on the performance in terms of nitrogen removal. In general, as expected, the removal of nitrogen was more effective when the temperature and pH of the ponds were higher, implying that these variables are relevant in the removal of nitrogen. Due to the fact that these parameters are included in the prediction equations for effluent ammonia and total nitrogen found in traditional models from the literature, fitting of the models to the experimental data was investigated. The models gave acceptable fittings in the estimation of effluent concentrations of ammonia and total nitrogen from maturation ponds treating UASB reactor effluent. PMID- 23676395 TI - Numerical prediction of the performance of horizontal sand filters as the pitch of the spiral protrusion changes. AB - The height of vertical sand filters are limited due to their structural cost. A horizontal sand filter may offer a better alternative; however, flow channels to the least resistance zone generated at the top of the filter as the sand gets wet and settles. A horizontal sand filter, internally baffled with spiral protrusion, is numerically modelled to study the effect of these spirals in reducing the channelling and enhancing the filter's effectiveness. Three different spiral pitches, 1.0, 0.75, and 0.5 m have been numerically modelled using Ansys FLUENT software. The parameters investigated were the power needed to run a flow rate through the horizontal filter and the residence time. The results show that as the spiral pitch decreases, the channelling reduces while the power increases. The power needed to pump a given flow rate of water in a 10 m long horizontal filter in all three cases investigated was less than the power needed to pump the same flow rate to the top of a 10 m long vertically standing sand filter. Results also showed that the time required for the flow to traverse through the sand filter increases in a nonlinear fashion as the pitch size decreases; however, the effectiveness of the filter increases. PMID- 23676396 TI - Retention and distribution of Cu, Pb, Cr, and Zn in a full-scale hybrid constructed wetland receiving municipal sewage. AB - This study was conducted to investigate the retention and distribution of Cu, Pb, Cr, and Zn in a hybrid constructed wetland (CW) that consists of both vertical baffled flow wetlands (VBFWs) and horizontal subsurface flow wetlands (HSSFs) with unique flow regimes and oxygen distribution. The heavy metal concentrations in water, sediments, and plant tissues in the hybrid CW were analysed. The removal of heavy metals from the water stream in the monitoring period was not statistically significant. Metal concentrations in the sediments generally decreased along the wastewater treatment process. The reductive anaerobic condition in the VBFW may promote the sulphate reduction and form highly insoluble Cu, Pb, and Zn sulphides, resulting in the higher concentration of the bivalent cations in the VBFW sediments than the corresponding values in the HSSF; however, the aerobic and anoxic environments in the HSSF enhanced the removal of Cr with the co-precipitation of iron and manganese oxides, and their hydroxides. Metal concentrations in plant tissues were not significantly influenced by the concentrations in sediments, while roots contained statistically higher metal concentrations than stems and leaves. The sediments stored 94.01, 86.31, 95.85, and 89.51% of the total Cu, Pb, Cr, and Zn retained in the hybrid CW system, respectively, while only small fractions (<10%) were accumulated in the harvestable macrophyte tissues. It is important to clean not only the accessible sediments in free water surface tank and ponds but also the embedded sediments in vegetated beds for the sustainable removal of heavy metals. PMID- 23676397 TI - Study of oyster shell as a potential substrate for constructed wetlands. AB - We tested the suitability of oyster shell (OS) as a substrate for phosphorus removal in constructed wetlands (CWs) treating swine wastewater. OS is proven to have a significant phosphorus adsorption capacity; significant phosphorus removal was achieved in vertical subsurface flow constructed wetlands (VSSFs) that were filled with OS and used to treat swine wastewater. In the VSSF system, OS adsorption and precipitation played the greatest role in phosphorus removal, and the phosphorus distribution in the substrate layers was attributed to the vertical flow state of wastewater in the system. Ca-P was the predominant form of phosphorus in the system. Overall, the study results showed that OS could be used for phosphorus removal in CWs. OS also allowed for reuse of a waste substance, making the overall system more environmentally friendly. PMID- 23676398 TI - Enhanced nitrogen removal in trickling filter plants. AB - The Beaudesert Sewage Treatment Plant (STP), originally built in 1966 and augmented in 1977, is a typical biological trickling filter (TF) STP comprising primary sedimentation tanks (PSTs), TFs and humus tanks. The plant, despite not originally being designed for nitrogen removal, has been consistently achieving over 60% total nitrogen reduction and low effluent ammonium concentration of less than 5 mg NH3-N/L. Through the return of a NO3(-)-rich stream from the humus tanks to the PSTs and maintaining an adequate sludge age within the PSTs, the current plant is achieving a substantial degree of denitrification. Further enhanced denitrification has been achieved by raising the recycle flows and maintaining an adequate solids retention time (SRT) within the PSTs. This paper describes the approach to operating a TF plant to achieve a high degree of nitrification and denitrification. The effectiveness of this approach is demonstrated through the pilot plant trial. The results from the pilot trial demonstrate a significant improvement in nitrogen removal performance whilst maximising the asset life of the existing infrastructure. This shows great potential as a retrofit option for small and rural communities with pre-existing TFs that require improvements in terms of nitrogen removal. PMID- 23676399 TI - Catalytic wet air oxidation of high concentration pharmaceutical wastewater. AB - In this study, we investigated the pretreatment of a high concentration pharmaceutical wastewater by catalytic wet air oxidation (CWAO) process. Different experiments were conducted to investigate the effects of the catalyst type, operating temperature, initial system pH, and oxygen partial pressure on the oxidation of the wastewater. Results show that the catalysts prepared by the co-precipitation method have better catalytic activity compared to others. Chemical oxygen demand (COD) conversion increased with the increase in temperature from 160 to 220 degrees C and decreased with the increase in pH. Moreover, the effect of the oxygen partial pressure on the COD conversion was significant only during the first 20 min of the reaction. Furthermore, the biodegradability of the wastewater improved greatly after CWAO, the ratio of BOD5/COD increased less than 0.1-0.75 when treated at 220 degrees C (BOD: biochemical oxygen demand). PMID- 23676400 TI - Laccase immobilized onto poly(GMA-MAA) microspheres for p-benzenediol removal from wastewater. AB - Enzymes have already been extensively applied to degrade various organic pollutants in industrial wastewater, and how to improve the stability and reusability of the enzymes is critical to their practical application. In this study, poly(glycidyl methacrylate-methacrylic acid), poly(GMA-MAA), microspheres were prepared by suspension polymerization, and were used as a new support to immobilize Trametes versicolor laccase. The maximum loading capacity to immobilize enzyme reached as high as 44.78 mg protein/g support. The stability and reusability of laccase were greatly improved after immobilization on the microspheres. While the immobilized laccase was used as catalyst to remove p benzenediol from wastewater, the removal efficiency reached 88.5%. PMID- 23676401 TI - Working with energy and mass balances: a conceptual framework to understand the limits of municipal wastewater treatment. AB - At present all municipal waste water treatment plants (WWTPs) are energy consumers. Electrical energy requirements for oxygen transfer are large in secondary biological systems. Nevertheless, from a thermodynamic point of view chemical oxygen demand (COD) is an energy source. Combustion of every kilogram of COD releases 3.86 kWh of energy. In this manuscript some measures are presented, from a conceptual point of view, in order to convert the actual concept of wastewater treatment as an 'energy sink' to an 'energy source' concept. In this sense, electrical self-sufficiency in carbon removal WWTPs could be obtained by increasing the sludge load to the anaerobic sludge digester. Nitrogen removal increases the energy requirements of WWTPs. The use of a combined two-stage biological treatment, using a high loaded first stage for carbon removal and a second stage combined nitrification-anammox process for nitrogen removal in the water line, offers a way to recover self-sufficiency. This is not a proven technology at ambient temperature, but its development offers an opportunity to reduce the energy demand of WWTPs. PMID- 23676402 TI - Sensitive nanosilver-based spectrophotometric determination of Brilliant Blue FCF in surface water samples. AB - An accurate method was developed for the determination of Brilliant Blue FCF, a synthetic soluble colorant, in environmental samples. The method is based on the catalytic effect of silver nanoparticles (AgNPs) on the oxidation of Brilliant Blue FCF by hexacyanoferrate(III) in acetate-acetic acid medium at room temperature. Linearity of around four orders in the magnitude of concentration was generally obtained. Detection and quantification limits of the investigated dye, which was evaluated at a signal-to-noise ratio of 3 for detection limit and quantification limit, were 0.1 and 0.6-130.0 ng/mL, respectively. The recoveries of the synthetic colorant Brilliant Blue FCF in environmental matrices (surface water) ranged from 95.0 to 101.0%. Relative standard deviation of less than 3.1% was also achieved. This method has been applied successfully in the determination of water-soluble colorant Brilliant Blue FCF in surface water samples. PMID- 23676403 TI - Highly effective permeability and antifouling performances of polypropylene non woven fabric membranes modified with graphene oxide by inkjet printing and immersion coating methods. AB - In the current study, graphene oxide (GO)-modified polypropylene non-woven fabric (PP-NWF) membranes were prepared via inkjet printing and immersion coating methods. Scanning electron microscopy, Fourier transform infrared spectroscopy, contact angle measurements, pure water permeation (JPWP) and protein adsorption were tested to evaluate the impact of the GO nanosheet on the characteristics and performance of modified PP-NWF membranes. The results showed that the exfoliated GO nanosheets uniformly deposited on the membrane surface and firmly embedded into the interlaced fibers, resulting in the improvement of membrane hydrophilicity, permeability and antifouling properties comparing with original PP-NWF membranes. The GO-printed and GO-coated membranes had 113 and 188% higher fluxes, and 70.95 and 75.74% lower protein adsorptions than the original PP-NWF membranes, respectively. After cross-linked treatment, ultrasound processing was conducted to evaluate the stability of the modified PP-NWF membranes. The results demonstrated that there was almost no decrease in permeation after ultrasonic treatment indicating that the cross-linking treatment could enhance the immobilization of the GO nanosheets on and into the modified membranes. PMID- 23676404 TI - Adaptive optimal control for a wastewater treatment plant based on a data-driven method. AB - In order to optimize the operating points of the dissolved oxygen concentration and the nitrate level in a wastewater treatment plant (WWTP) benchmark, a data driven adaptive optimal controller (DDAOC) based on adaptive dynamical programming is proposed. This DDAOC consists of an evaluation module and an optimization module. When a certain group of operating points is given, first the evaluation module estimates the energy consumption and the effluent quality in the future under this policy, and then the optimization module adjusts the operating points according to the evaluation result generated by the evaluation module. The optimal operating points will be found gradually as this process continues repeatedly. During the optimization, only the input-output data measured from the plant are needed, while a mechanistic model is unnecessary. The DDAOC is tested and evaluated on BSM1 (Benchmark Simulation Model No.1), and its performance is compared to the performance of a proportional-integral-derivative (PID) controller with fixed operating points under the full range of operating conditions. The results show that DDAOC can reduce the energy consumption significantly. PMID- 23676405 TI - Biological Cr(VI) immobilisation in saturated aquifer zone using culture inoculated soil columns. AB - Remediation of Cr(VI) requires the reduction of the mobile state [Cr(VI)], which exists in the natural environment as the oxyanionic species (CrxOy(z)(-)), to the less mobile trivalent state [Cr(III)], which readily forms the hydroxide precipitate [Cr(OH)3(s)] under natural pH conditions. In this study, Cr(VI) reduction is investigated using inoculated microcosm aquifer systems operated as fully submerged plug flow systems. The system was design to simulate the operation of a microbial contaminant barrier in the saturated zone of an open aquifer system. No organic carbon sources and no air was introduced to simulate Cr(VI) reduction under oxygen free conditions. The inoculated microcosm column operated at influent feed concentrations of 10, 20, and 40 mg/L, and a hydraulic retention time of 12 hours achieved complete removal of Cr(VI) over a 90 cm distance. Steady-state conditions were obtained in less than 48 hours under feed concentrations of 10 and 20 mg/L. Very little Cr(VI) reduction was observed in non-inoculated microcosm controls operated under identical conditions. PMID- 23676406 TI - Distribution and characterization of anammox in a swine wastewater activated sludge facility. AB - Anaerobic ammonium oxidation (anammox) is a novel biological nitrogen removal process that oxidizes NH4(+) to N2 with NO2(-) as an electron acceptor. The purpose of this study was to examine the potential activity and characteristics of anammox in a conventional swine wastewater treatment facility, which uses an activated sludge system consisting of three cascade aeration tanks equipped with ceramic support material. Anammox activity was estimated by a (15)N tracer assay method and was detected in all the sludge and biofilm samples in each aeration tank. Biofilm taken from the third aeration tank, in which the dissolved oxygen concentration was 7.5 mg/L and the wastewater included a high concentration of NO3(-), showed by far the highest anammox activity. A clone library analysis showed the existence of anammox bacteria closely related to 'Candidatus Jettenia asiatica' and 'Ca. Brocadia caroliniensis'. The optimum conditions for anammox activity were a pH of 6.7-7.2, a temperature of 35 degrees C, a NO2(-) concentration of 10 mmol/L or less, and an NH4(+) concentration of 32 mmol/L or less. PMID- 23676407 TI - Experiences with pre-precipitation of phosphorus in a vertical flow constructed wetland in Austria. AB - Using constructed wetlands (CWs) with vertical flow and intermittent loading, high organic matter and ammonium removal can be achieved. In the case of additional requirements for phosphorus removal, which in Austria often occurs if the treated wastewater is discharged into small sensitive receiving waters, additional measures have to be taken. The objective of this work was to investigate the applicability of conventional phosphorus pre-precipitation with sodium aluminate for a CW system. The experiment was carried out at a full-scale CW in Oberwindhag in Lower Austria, a two-stage vertical flow CW with intermittent loading designed for a size of 60 person equivalents (PE). The goal was to reach the required value of 1.6 mg/L PO4-P for the effluent of the system. Prior to the experiments the plant was in operation for 3 years without measures for phosphorus removal. After pre-precipitation with sodium aluminate was activated, three different dosages were investigated. Satisfying results in the preliminary treatment chambers were not obtained until a high dosage (beta = 3.5, i.e. 3.5 times the dose required from stoichiometry) was applied. After an adaptation time of several months the required effluent concentration of 1.6 mg PO4-P/L could be reached and maintained. However, the additional phosphorus pre precipitation increases the yearly operating costs of a vertical flow CW system significantly, e.g. for 60 and 25 PE, by 15 and 38%, respectively, thus indicating the need for optimizing the dosing of the chemical. PMID- 23676408 TI - Distribution of sterols and the sources of pollution in surface sediments of Ulungur lake, Xinjiang. AB - Domestic sewage discharged into lakes brings great pressure to the ecological environment. This study selected sediment from an inland lake as a research object to evaluate pollution of the environment. Eight sterols were used to evaluate the content of pollutants, while the ratios of sterols were used as the index to analyze the sources of pollution. The correlations were analyzed between sterols and total organic carbon (TOC), salinity and particle size. The distribution and composition of sterol compounds were determined in 12 surface sediment samples collected from Ulungur lake. The total concentrations of detected sterols in the sediments ranged from 1.3 to 36.3 MUg/g.dw. The most abundant sterol detected was beta-sitosterol (STI) with average concentrations of 2.6 MUg/g.dw, followed by cholesterol (CHOE), stigmasterol (STIG) and stigmastanol (STAN). The concentration of coprostanol (COP) was between 0.03 and 1.66 MUg/g.dw. Through correlation analysis, it was found that there was a significant correlation between fecal sterols and plant sterols. So the plant sterols shall not be neglected in evaluating the sources of pollution for their impact to identify the fecal sources. The study suggests that the composition and distribution of sterols in surface sediment provide useful information for environmental contamination monitoring and assessment in the inland lake. PMID- 23676409 TI - Methane and nitrous oxide emissions from municipal wastewater treatment - results from a long-term study. AB - Methane and nitrous oxide emissions from a fully covered municipal wastewater treatment plant were measured on-line during 16 months. At the plant under study, nitrous oxide contributed three-quarters to the plant's carbon footprint, while the methane emission was slightly larger than the indirect carbon dioxide emission related to the plant's electricity and natural gas consumption. This contrasted with two other wastewater treatment plants, where more than 80% of the carbon footprint came from the indirect carbon dioxide emission. The nitrous oxide emission exhibited a seasonal dynamic, of which the cause remains unclear. Three types of air filter were investigated with regard to their effectiveness to remove methane from the off-gas. PMID- 23676410 TI - Nitrogen removal in micro-polluted surface water by the combined process of bio filter and ecological gravel bed. AB - Nitrogen removal in micro-polluted surface water by the combined process of a bio filter and an ecological gravel bed was studied. Sodium acetate was added into micro-polluted surface water as carbon source and the nitrogen removal under different C/N ratio, hydraulic load and temperature were investigated. The results showed that the variations in C/N ratio, hydraulic load and temperature have significant influence on nitrogen removal in bio-filter. It was found that the denitrification rate was above 90% when C/N ratio reached 10; also, the denitrification was inhibited at low water temperature (2-10 degrees C); at the condition of water temperature above 20 degrees C, C/N ratio 10, hydraulic load 8 m(3)/(m(2) h), the combined process obtained the nitrogen removal of more than 90%, and the residual organics could be removed in ecological gravel bed. PMID- 23676412 TI - The societal cost of schizophrenia in Sweden. AB - BACKGROUND: Schizophrenia is a disabling psychiatric disorder that has severe consequences for patients and their families. Moreover, the expensive treatment of schizophrenia imposes a burden on health care providers and the wider society. Existing cost estimates for Sweden, however, are based on relatively small patient populations and need to be confirmed in a large register-based study. AIMS OF THE STUDY: To investigate the health care resource utilization and cost of-illness in patients with schizophrenia in Sweden and to relate the costs to hospitalizations and global assessment of functioning (GAF). METHODS: Hospital based registry data were combined with national registry data from a large patient population to get reliable estimates of the costs of schizophrenia in Sweden. Schizophrenia was defined by ICD-10 codes F20; F21; F23.1,2,8,9; F25.1,8,9. Registry data on socio-demographics and disease-related healthcare resource use in outpatient and inpatient care were obtained from Northern Stockholm Psychiatry. Data on pharmaceuticals were obtained from the National Board of Health and Welfare, and data on sick leave and early retirement were obtained from the Swedish Social Insurance Agency. Costs for community mental health care were not available at the individual level, but were estimated based on previous studies and aggregate cost data from Stockholm. Resource use data from the registries were combined with unit costs from publicly available sources. The study was conducted from a societal perspective, with indirect costs valued according to the human capital method. RESULTS: The average annual psychiatric cost per patient with schizophrenia in 2008 was EUR 42700 (95% CI: EUR 41500-44000), based on a sample of 2161 patients. To this should be added costs for community mental health care of EUR 12400 per patient, giving a total cost of EUR 55100 per patient. The two largest cost items in the total costs were indirect costs due to lost productivity (60%) and community mental health care (22% of the total cost). Patients who were hospitalized in 2008 had greater psychiatric costs than those who were not, EUR 71700 vs. EUR 37700 (p<0.0001). Psychiatric costs were significantly and negatively correlated with GAF (p<0.001). DISCUSSION: The major strengths of the study are the relatively large sample, and the linkage of patient-level clinical data on inpatient and outpatient care with national registry data on prescription pharmaceuticals, and days on social insurance. A limitation was that costs for informal care and primary care were not included in the data, but previous studies suggest that these costs items are small compared to other costs for schizophrenia. IMPLICATIONS FOR HEALTH POLICIES AND FUTURE RESEARCH: Costs were strongly related to hospitalization and GAF, suggesting that attempts to improve global functioning and avoid hospitalizations by means of effective treatment and rehabilitation might not only decrease suffering for patients and relatives, but also reduce the societal cost of schizophrenia. A detailed knowledge of the societal costs can also be helpful in evaluating the cost-effectiveness of new treatment strategies to improve the care for patients with schizophrenia. PMID- 23676411 TI - Measuring disparities across the distribution of mental health care expenditures. AB - BACKGROUND: Previous mental health care disparities studies predominantly compare mean mental health care use across racial/ethnic groups, leaving policymakers with little information on disparities among those with a higher level of expenditures. AIMS OF THE STUDY: To identify racial/ethnic disparities among individuals at varying quantiles of mental health care expenditures. To assess whether disparities in the upper quantiles of expenditure differ by insurance status, income and education. METHODS: Data were analyzed from a nationally representative sample of white, black and Latino adults 18 years and older (n=83,878). Our dependent variable was total mental health care expenditure. We measured disparities in any mental health care expenditures, disparities in mental health care expenditure at the 95th, 97.5 th, and 99 th expenditure quantiles of the full population using quantile regression, and at the 50 th, 75 th, and 95 th quantiles for positive users. In the full population, we tested interaction coefficients between race/ethnicity and income, insurance, and education levels to determine whether racial/ethnic disparities in the upper quantiles differed by income, insurance and education. RESULTS: Significant Black white and Latino-white disparities were identified in any mental health care expenditures. In the full population, moving up the quantiles of mental health care expenditures, Black-White and Latino-White disparities were reduced but remained statistically significant. No statistically significant disparities were found in analyses of positive users only. The magnitude of black-white disparities was smaller among those enrolled in public insurance programs compared to the privately insured and uninsured in the 97.5 th and 99 th quantiles. Disparities persist in the upper quantiles among those in higher income categories and after excluding psychiatric inpatient and emergency department (ED) visits. DISCUSSION: Disparities exist in any mental health care and among those that use the most mental health care resources, but much of disparities seem to be driven by lack of access. The data do not allow us to disentangle whether disparities were related to white respondent's overuse or underuse as compared to minority groups. The cross-sectional data allow us to make only associational claims about the role of insurance, income, and education in disparities. With these limitations in mind, we identified a persistence of disparities in overall expenditures even among those in the highest income categories, after controlling for mental health status and observable sociodemographic characteristics. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: Interventions are needed to equalize resource allocation to racial/ethnic minority patients regardless of their income, with emphasis on outreach interventions to address the disparities in access that are responsible for the no/low expenditures for even Latinos at higher levels of illness severity. IMPLICATIONS FOR HEALTH POLICIES: Increased policy efforts are needed to reduce the gap in health insurance for Latinos and improve outreach programs to enroll those in need into mental health care services. IMPLICATIONS FOR FURTHER RESEARCH: Future studies that conclusively disentangle overuse and appropriate use in these populations are warranted. PMID- 23676413 TI - The fiscal consequences of ADHD in Germany: a quantitative analysis based on differences in educational attainment and lifetime earnings. AB - OBJECTIVE: To estimate the long-term fiscal consequences of attention deficit hyperactivity disorder (ADHD) on the German government and social insurance system based on differences in educational attainment and the resulting differences in lifetime earnings compared with non-ADHD cohorts. METHODS: Differences in educational attainment between ADHD and non-ADHD cohorts were linked to education-specific earnings data. Direct and indirect tax rates and social insurance contributions were linked to differences in lifetime, education specific earnings to derive lost tax revenue in Germany associated with ADHD. For ADHD and non-ADHD cohorts we derived the age-specific discounted net taxes paid by deducting lifetime transfers from lifetime gross taxes paid. RESULTS: The lifetime net tax revenue for a non-ADHD individual was approximately EUR 80,000 higher compared to an untreated ADHD individual. The fiscal burden of untreated ADHD, based on a cohort of n=31,844 born in 2010, was estimated at EUR 2.5 billion in net tax revenue losses compared with an equally-sized non-ADHD cohort. ADHD interventions providing a small improvement in educational attainment resulted in fiscal benefits from increases in lifetime tax gains. CONCLUSIONS: ADHD results in long-term financial loss due to lower education attainment and lifetime reduced earnings and resulting lifetime taxes and social contributions paid. Investments in ADHD interventions allowing more children to achieve their educational potential may offer fiscal benefits generating a positive rate of return. PMID- 23676414 TI - The impact of retirement on mental health in Canada. AB - BACKGROUND: Like most of other developed countries, Canada experienced baby boom in the 20 years after World War II. With the eldest baby turned 65 in 2011, it is expected that a considerable number of people will retire in coming years and consequently, retired people will soon constitute a significant part of Canadian population. In this context, an interesting question would be how retirement impacts mental health. This question is related to the well-being of the retired population as well as to over all health care expenditures. AIMS: The major objective of this study is to examine the impact of retirement on mental health as measured by the Short Form Depression Scale. This study further conducts separate analyses to examine whether the impact of retirement on mental health differs between males and females, and among different education and income groups. METHODS: This study uses large scale Canadian National Population Heath Survey (Longitudinal Component) data and adopts fixed effect method and fixed effect instrumental variable method to deal with possible endogeneity problem. RESULTS: After controlling for unobserved individual specific heterogeneity, the study found that retirement has an insignificant impact on depression. As a robustness check, the study utilizes logit, conditional fixed effect logit, and fixed effect instrumental variable regression on a dichotomous variable representing depression and found that retirement has an insignificant impact on depression. The study further examined this issue using different subgroups based on gender, education and marital status, and again found that impacts of retirement on depression are not statistically significant. IMPLICATIONS FOR POLICY: Though the coefficients are statistically insignificant, however, most of the results are economically meaningful since the magnitudes are relatively large, implying very large effects. The effects of retirement on mental health appear to be complex and multidimensional; however, based on the FE-IV models, most of the effects seem to suggest that there may be some increase in depression symptoms. The findings of this study will have important policy implications. If retirement worsens mental health, then policy encouraging retirement may actually increase health care expenditures. On the other hand, if retirement improves mental health, then such policy will likely to decrease health care expenditure. Studies based on data from Canada and other OECD countries suggest that the provisions of social security programs themselves often provide strong incentive to leave the labor force early. The finding of this study that retirement has negative impact on mental health in Canada will imply that current Canadian policy of encouraging early retirement is likely to increase mental health care expenditure. IMPLICATIONS FOR FURTHER RESEARCH: There are a number of ways to extend this study. Depending on the availability of data, future studies can focus on sub populations: voluntary retiree/ involuntary retirement, early retiree/ late retiree and complete retiree/ partial retiree. Future study can also conduct more detailed analysis by including variables such as previous job characteristics, voluntary activity during retirement and family characteristics. PMID- 23676415 TI - The survival of patients with not-for-resuscitation orders. AB - BACKGROUND: Studies have shown higher in-hospital mortality rates in patients with not-for-resuscitation (NFR) decisions. Long-term survival of these patients after their discharge from acute care is largely unknown as is communication of such decisions to primary care givers through letters or discharge summaries. AIM: To evaluate the in-hospital mortality and post-discharge survival of general medical patients with documented resuscitation decisions as well as the prevalence of these decisions being communicated to primary health care providers through discharge summaries. DESIGN: Retrospective cross-sectional study. METHODS: The medical records of 618 general medical patients admitted to an Australian tertiary referral teaching hospital between January and December 2007 were reviewed to determine the documentation of resuscitation decisions. Mortality rates in-hospital and up to 5 years post-discharge were assessed in relation to the nature of any resuscitation decisions. Communication of these decisions in the discharge summaries was also evaluated. RESULTS: One hundred and thirty-six (22%) patients had resuscitation decisions documented of whom 91 (67%) did not want resuscitation (NFR). For this NFR group, the in-hospital mortality rate was 20%, and their cumulative 1- and 5-year mortality rates were 53 and 85%, respectively. Of the 112 patients with resuscitation decisions who survived to discharge, 104 of them (93%) had discharge summaries completed but only 9 (8.4%) had resuscitation decisions documented in those discharge summaries. CONCLUSION: Many general medical patients with a documented NFR decision survive beyond 1 year after their index admission. The rate of communication of resuscitation decisions in hospital discharge summaries is low. PMID- 23676416 TI - What is Connected Health and why will it change your practice? AB - As a society we have to re-imagine our health and social care models to meet the challenge of an ageing population with greater levels of chronic disease. The digital revolution offers us the potential to leverage technological innovations to develop proactive 'connected' health and social care models that are built around the patient's needs to facilitate efficient management of wellness and health throughout their lifespan. However, efforts to utilize technological innovations for this purpose have not been universally successful to date, indicating that technology itself is only part of the solution. To achieve a truly connected, technology enabled, health and social care model we need to overcome some key challenges; first, we need to optimize the process of sensing data from end users in the home and community such that monitoring protocols are built around the person and designed with respect to their needs to provide for accurate and reliable harvesting of target data. We then need to gather and mine large datasets from the home and community to analyse the complex relationships between home and community acquired data and health status. Only then can we begin to design, implement and evaluate new models of care that leverage technology platforms. In meeting this challenge we can leverage technology to transform the way in which we promote and manage wellness and health throughout the lifespan. PMID- 23676417 TI - Influence of environmental factors on the paralytic shellfish toxin content and profile of Alexandrium catenella (Dinophyceae) isolated from the Mediterranean Sea. AB - Laboratory experiments were designed to study the toxin content and profile of the Alexandrium catenella strain ACT03 (isolated from Thau Lagoon, French Mediterranean) in response to abiotic environmental factors under nutrient replete conditions. This dinoflagellate can produce various paralytic shellfish toxins with concentrations ranging from 2.9 to 50.3 fmol/cell. The toxin profile was characterized by carbamate toxins (GTX3, GTX4 and GTX5) and N-sulfocarbamoyl toxins (C1, C2, C3 and C4). C2 dominated at 12-18 degrees C, but only for salinities ranging from 10 to 25 psu, whereas GTX5 became dominant at temperatures ranging from 21 to 30 degrees C at almost all salinities. There was no significant variation in the cellular toxin amount from 18 degrees C to 27 degrees C for salinities ranging between 30 and 40 psu. At salinities of 10 to 25 psu, the toxin concentrations always remained below 20 fmol/cell. Toxin content was stable for irradiance ranging from 10 to 70 MUmol photons/m2/s then slightly increased. Overall, the toxin profile was more stable than the toxin content (fmol/cell), except for temperature and/or salinity values different from those recorded during Alexandrium blooms in Thau Lagoon. PMID- 23676418 TI - Tumor marker and measurement fluctuations may not reflect treatment efficacy in patients with medullary thyroid carcinoma on long-term RET inhibitor therapy. AB - BACKGROUND: RET kinase inhibitors have significant activity in patients with medullary thyroid carcinoma (MTC). PATIENTS AND METHODS: We retrospectively reviewed the electronic medical record for patterns of calcitonin, carcinoembryonic antigen (CEA) and tumor measurement responses in consecutive patients with MTC who received treatment with a RET inhibitor for at least 6 months. RESULTS: Twenty-six patients who received RET kinase inhibitors for at least 6 months were included. All patients experienced an initial decline in calcitonin; 20 (77%) demonstrated later fluctuations in calcitonin, which spiked above baseline levels in 9 individuals (35%). Twenty of the 22 patients (91%) with elevated CEA experienced a decline with treatment, with 11 individuals (50%) later demonstrating transient fluctuations in CEA, including spikes above baseline in 7 patients (32%). Ten of the 26 patients (38%) also demonstrated short-lived fluctuations in RECIST measurements, including changes of over 20% from nadir values. Vacillations in calcitonin, CEA and measurements often occurred repeatedly in individual patients and did not regularly correlate with each other. CONCLUSIONS: Repeated transient fluctuations in tumor markers and measurements are a characteristic of patients with MTC receiving treatment with RET inhibitors, and such short-term vacillations may not reflect responsiveness over the long term. CLINICAL TRIALS INCLUDED: NCT00215605; NCT00244972; NCT00121680; NCT00495872. PMID- 23676419 TI - Prevalence and risk factors of extrapancreatic malignancies in a large cohort of patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas. AB - BACKGROUND: The objectives of this study are to estimate prevalence and incidence of extrapancreatic malignancies (EPMs) among intraductal papillary mucinous neoplasms (IPMNs) of the pancreas, and to identify risk factors for their occurrence. PATIENTS AND METHODS: We conducted multicentric cohort study in Italy from January 2010 to January 2011 including 390 IPMN cases. EPMs were grouped as previous, synchronous (both prevalent) and metachronous (incident). We calculated the observed/expected (O/E) ratio of prevalent EPMs, and compared the distribution of demographic, medical history and lifestyle habits. RESULTS: Ninety-seven EPMs were diagnosed in 92 patients (23.6%), among them 78 (80.4%) were previous, 14 (14.4%) were synchronous and 5 (5.2%) were metachronous. O/E ratios for prevalent EPMs were significantly increased for colorectal carcinoma (2.26; CI 95% 1.17-3.96), renal cell carcinoma (6.00; CI 95% 2.74-11.39) and thyroid carcinoma (5.56; CI 95% 1.80-12.96). Increased age, heavy cigarette smoking, alcohol consumption and first-degree family history of gastric cancer are significant risk factors for EPMs, while first-degree family history of colorectal carcinoma was borderline. CONCLUSION: We report an increased prevalence of EPMs in Italian patients with IPMN, especially for colorectal carcinoma, renal cell and thyroid cancers. A systematic surveillance of IPMN cases for such cancer types would be advised. PMID- 23676420 TI - Circulating tumor cells in locally advanced pancreatic adenocarcinoma: the ancillary CirCe 07 study to the LAP 07 trial. AB - BACKGROUND: Pancreatic carcinoma is one of the leading causes of cancer-related mortality. At the time of diagnosis, 30% of patients present with a locally advanced pancreatic carcinoma (LAPC). As circulating tumor cells (CTCs) count may be a surrogate of the cancer metastatic abilities, CTC detection rates and prognostic value were studied in a prospective cohort of LAPC patients. PATIENTS AND METHODS: An LAP07 international multicenter randomized study assesses in patients whose LAPC is controlled after 4 months of chemotherapy whether chemoradiotherapy could increase survival versus continuation of chemotherapy. A subgroup of patients included in the LAP07 trial was screened for CTCs (CellSearch(r)) before the start of the chemotherapy and after 2 months of treatment. Patient characteristics and survival were obtained prospectively and were correlated with CTC detection. RESULTS: Seventy-nine patients were included. One or more CTCs/7.5 ml were detected in 5% of patients before treatment and in 9% of patients after 2 months of treatment (overall detection rate: 11% of patients). CTC positivity was associated with poor tumor differentiation (P = 0.04), and with shorter overall survival (OS) in multivariable analysis (RR = 2.5, P = 0.01), together with anemia. CONCLUSIONS: The evaluation of micrometastatic disease using CTC detection appears as a promising prognostic tool in LAPC patients. PMID- 23676421 TI - Dietary sodium intake is associated with total fluid and sugar-sweetened beverage consumption in US children and adolescents aged 2-18 y: NHANES 2005-2008. AB - BACKGROUND: Increasing dietary sodium drives the thirst response. Because sugar sweetened beverages (SSBs) are frequently consumed by children, sodium intake may drive greater consumption of SSBs and contribute to obesity risk. OBJECTIVE: We examined the association between dietary sodium, total fluid, and SSB consumption in a nationally representative sample of US children and adolescents aged 2-18 y. DESIGN: We analyzed cross-sectional data from NHANES 2005-2008. Dietary sodium, fluid, and SSB intakes were assessed with a 24-h dietary recall. Multiple regression analysis was used to assess associations between sodium, fluid, and SSBs adjusted for age, sex, race-ethnic group, body mass index (BMI), socioeconomic status (SES), and energy intake. RESULTS: Of 6400 participants, 51.3% (n = 3230) were males, and the average (+/-SEM) age was 10.1 +/- 0.1 y. The average sodium intake was 3056 +/- 48 mg/d (equivalent to 7.8 +/- 0.1 g salt/d). Dietary sodium intake was positively associated with fluid consumption (r = 0.42, P < 0.001). After adjustment for age, sex, race-ethnic group, SES, and BMI, each additional 390 mg Na/d (1 g salt/d) was associated with a 74-g/d greater intake of fluid (P < 0.001). In consumers of SSBs (n = 4443; 64%), each additional 390 mg Na/d (1 g salt/d) was associated with a 32-g/d higher intake of SSBs (P < 0.001) adjusted for age, sex, race-ethnic group, SES, and energy intake. CONCLUSIONS: Dietary sodium is positively associated with fluid consumption and predicted SSB consumption in consumers of SSBs. The high dietary sodium intake of US children and adolescents may contribute to a greater consumption of SSBs, identifying a possible link between dietary sodium intake and excess energy intake. PMID- 23676422 TI - Effect of serum folate status on total folate and 5-methyltetrahydrofolate in human skin. AB - BACKGROUND: It has been suggested that human skin color adapts to balance the need for vitamin D synthesis in comparison with the protection of DNA and folate from photodegradation. However, the folate content of human skin is unknown and may affect the effectiveness of the antifolate methotrexate for the treatment of psoriasis. OBJECTIVES: We examined whether total folate and 5-methyl-(6S) tetrahydrofolate (5-MTHF) in human skin can be predicted by serum concentrations and whether there are differences in the proportion of 5-MTHF in dermis compared with epidermis. DESIGN: Total folate (by using a microbiological assay) and 5 MTHF (by using high-pressure liquid chromatography) were measured in fasting serum and fresh skin obtained at surgery by using a recovery validated extraction method. RESULTS: Total folate in human epidermis was shown to be low compared with in many other tissues, and dermal folate was an order-of-magnitude even lower. These concentrations were directly and linearly linked to serum folate status. Although the percentage of 5-MTHF of the total in the dermis was similar to that in other organs, it was especially high in the epidermis and increased to >65% as serum folate decreased. CONCLUSIONS: The high proportion of 5-MTHF in the epidermis, which is further emphasized in subjects with a lower (10-20-nmol/L) serum folate status, points to a special role for this form of folate in skin, perhaps as a protectant from ultraviolet-induced photosensitization reactions. 5 MTHF may also maintain methylation reactions that influence the proliferative activity. These results may help to individualize the treatment of psoriasis patients with methotrexate and folate. PMID- 23676423 TI - Egg consumption in relation to risk of cardiovascular disease and diabetes: a systematic review and meta-analysis. AB - BACKGROUND: The associations of egg consumption with cardiovascular disease (CVD) and diabetes are still unclear. OBJECTIVE: We aimed to quantitatively summarize the literature on egg consumption and risk of CVD, cardiac mortality, and type 2 diabetes by conducting a meta-analysis of prospective cohort studies. DESIGN: A systematic literature review was conducted for published studies in PubMed and EMBASE through March 2012. Additional information was retrieved through Google or a hand review of the reference from relevant articles. Studies were included if they had a prospective study design, were published in English-language journals, and provided HRs and 95% CIs for the associations of interest. Data were independently extracted by 2 investigators, and the weighted HRs and 95% CIs for the associations of interest were estimated by using a random-effects model. RESULTS: A total of 22 independent cohorts from 16 studies were identified, including participants ranging in number from 1600 to 90,735 and in follow-up time from 5.8 to 20.0 y. Comparison of the highest category (>=1 egg/d) of egg consumption with the lowest (<1 egg/wk or never) resulted in a pooled HR (95% CI) of 0.96 (0.88, 1.05) for overall CVD, 0.97 (0.86, 1.09) for ischemic heart disease, 0.93 (0.81, 1.07) for stroke, 0.98 (0.77, 1.24) for ischemic heart disease mortality, 0.92 (0.56, 1.50) for stroke mortality, and 1.42 (1.09, 1.86) for type 2 diabetes. Of the studies conducted in diabetic patients, the pooled HR (95% CI) was 1.69 (1.09, 2.62) for overall CVD. CONCLUSIONS: This meta-analysis suggests that egg consumption is not associated with the risk of CVD and cardiac mortality in the general population. However, egg consumption may be associated with an increased incidence of type 2 diabetes among the general population and CVD comorbidity among diabetic patients. PMID- 23676424 TI - Trends in sugar-sweetened beverage consumption among youth and adults in the United States: 1999-2010. AB - BACKGROUND: Reducing sugar-sweetened beverage (SSB) consumption is a recommended strategy to promote optimal health. OBJECTIVE: The objective was to describe trends in SSB consumption among youth and adults in the United States. DESIGN: We analyzed energy intake from SSBs among 22,367 youth aged 2-19 y and 29,133 adults aged >=20 y who participated in a 24-h dietary recall as part of NHANES, a nationally representative sample of the US population with a cross-sectional design, between 1999 and 2010. SSBs included soda, fruit drinks, sports and energy drinks, sweetened coffee and tea, and other sweetened beverages. Patterns of SSB consumption, including location of consumption and meal occasion associated with consumption, were also examined. RESULTS: In 2009-2010, youth consumed a mean (+/-SE) of 155 +/- 7 kcal/d from SSBs, and adults consumed an age adjusted mean (+/-SE) of 151 +/- 5 kcal/d from SSBs--a decrease from 1999 to 2000 of 68 kcal/d and 45 kcal/d, respectively (P-trend < 0.001 for each). In 2009 2010, SSBs contributed 8.0% +/- 0.4% and 6.9% +/- 0.2% of daily energy intake among youth and adults, respectively, which reflected a decrease compared with 1999-2000 (P-trend < 0.001 for both). Decreases in SSB consumption, both in the home and away from home and also with both meals and snacks, occurred over the 12 y study duration (P-trend < 0.01 for each). CONCLUSION: A decrease in SSB consumption among youth and adults in the United States was observed between 1999 and 2010. PMID- 23676425 TI - War of the words. PMID- 23676426 TI - Plain cigarette packets could reduce nicotine addiction. PMID- 23676427 TI - The big four diarrhoeal pathogens. PMID- 23676428 TI - Introduce standard cigarette packets now. PMID- 23676429 TI - Antireflection effects at nanostructured material interfaces and the suppression of thin-film interference. AB - Thin-film interference is a well-known effect, and it is commonly observed in the colored appearance of many natural phenomena. Caused by the interference of light reflected from the interfaces of thin material layers, such interference effects can lead to wavelength and angle-selective behavior in thin-film devices. In this work, we describe the use of interfacial nanostructures to eliminate interference effects in thin films. Using the same principle inspired by moth-eye structures, this approach creates an effective medium where the index is gradually varying between the neighboring materials. We present the fabrication process for such nanostructures at a polymer-silicon interface, and experimentally demonstrate its effectiveness in suppressing thin-film interference. The principle demonstrated in this work can lead to enhanced efficiency and reduce wavelength/angle sensitivity in multilayer optoelectronic devices. PMID- 23676430 TI - Escitalopram for antipsychotic nonresponsive visual hallucinosis: eight patients suffering from Charles Bonnet syndrome. AB - BACKGROUND: The Charles Bonnet syndrome (CBS) is characterized by distinct visual hallucinations and ocularpathology causing visual impairment in patients with insight and the absence of psychiatric comorbidity. The number of reported cases of CBS is expanding as the population ages and the prevalence of vision disorders increases. Antipsychotic medications are often prescribed. However, their efficacy in CBS has been based on sketchy evidence. The use of serotonin selective reuptake inhibitor (SSRI) for CBS was anecdotally reported. We herein describe effectiveness of escitalopram in a series of patients suffering from CBS who were unresponsive to antipsychotic treatment. METHODS: Eight consecutive patients suffering from CBS who did not respond to standard antipsychotic treatment were switched to escitalopram. CBS severity prior to escitalopram treatment was quantified using the Clinical Global Impression (CGI) scale and again after eight weeks of treatment. All had undergone brain CT and cognitive assessment. Brain CT imaging was normal except for an incidental finding of a small frontal meningioma in one patient. All had Mini-Mental Status Examination scores of >= 27/30. RESULTS: There were four men and four women, with a mean age of 81.7 +/- 7.3 years. Previous antipsychotic treatment was mostly with risperidone, 1.0 to 3.0 mg/daily. Mean CGI-severity upon switching to escitalopram treatment was 5.7. This was significantly reduced to 1.8 (p < 0.001) after eight weeks of escitalopram treatment (mean dose: 11.8 mg/daily). There were no side effects, nor any adverse events were reported. CONCLUSIONS: This is the first case-series to show that SSRI is an effective and well-tolerated treatment for visual hallucinations associated with vision impairment such as in CBS. PMID- 23676431 TI - Role of (p)ppGpp in biofilm formation and expression of filamentous structures in Bordetella pertussis. AB - Bordetella pertussis, the causative agent of whooping cough, is highly adapted to cause human infection. The production of virulence factors, such as adhesins and toxins, is just part of an array of mechanisms by which B. pertussis causes infection. The stringent response is a global bacterial response to nutritional limitation that is mediated by the accumulation of cellular ppGpp and pppGpp [termed together as (p)ppGpp]. Here, we demonstrate that production of (p)ppGpp was controlled by RelA and SpoT proteins in B. pertussis, and that mutation induced loss of both proteins together caused deficiencies in (p)ppGpp production. The (p)ppGpp-deficient mutants also exhibited defects in growth regulation, decreases in viability under nutritionally limited conditions, increases in susceptibility to oxidative stress and defects in biofilm formation. Analysis of the secreted proteins and the respective transcripts showed that lack of (p)ppGpp led to decreased expression of fim3 and bsp22, which encode a fimbrial subunit and the self-polymerizing type III secretion system tip protein, respectively. Moreover, electron microscopic analysis also indicated that (p)ppGpp regulated the formation of filamentous structures. Most virulence genes including fim3 and bsp22 - were expressed in the Bvg(+) phase during which the BvgAS two-component system was activated. Although fim3 and bsp22 were downregulated in a (p)ppGpp-deficient mutant, normal expression of fhaB, cyaA and ptxA persisted. Lack of coherence between virulence gene expression and (p)ppGpp production indicated that (p)ppGpp did not modulate the Bvg phase. Taken together, our data indicate that (p)ppGpp may govern an as-yet-unrecognized system that influences B. pertussis pathogenicity. PMID- 23676432 TI - Characterization of genes required for the pathogenicity of Pectobacterium carotovorum subsp. carotovorum Pcc21 in Chinese cabbage. AB - Pectobacterium carotovorum subsp. carotovorum is a well-known plant pathogen that causes severe soft rot disease in various crops, resulting in considerable economic loss. To identify pathogenicity-related factors, Chinese cabbage was inoculated with 5314 transposon mutants of P. carotovorum subsp. carotovorum Pcc21 derived using Tn5 transposon mutagenesis. A total of 35 reduced-virulence or avirulent mutants were isolated, and 14 loci were identified. The 14 loci could be functionally grouped into nutrient utilization (pyrD, purH, purD, leuA and serB), production of plant cell-wall-degrading enzymes (PCWDEs) (expI, expR and PCC21_023220), motility (flgA, fliA and flhB), biofilm formation (expI, expR and qseC), susceptibility to antibacterial plant chemicals (tolC) and unknown function (ECA2640). Among the 14 genes identified, qseC, tolC and PCC21_023220 are novel pathogenicity factors of P. carotovorum subsp. carotovorum involved in biofilm formation, phytochemical resistance and PCWDE production, respectively. PMID- 23676433 TI - Mechanisms of intrinsic resistance to antimicrobial peptides of Edwardsiella ictaluri and its influence on fish gut inflammation and virulence. AB - The genus Edwardsiella comprises a genetically distinct taxon related to other members of the family Enterobacteriaceae. It consists of bacteria differing strongly in their biochemical and physiological features, natural habitats, and pathogenic properties. Intrinsic resistance to cationic antimicrobial peptides (CAMPs) is a specific property of the genus Edwardsiella. In particular, Edwardsiella ictaluri, an important pathogen of the catfish (Ictalurus punctatus) aquaculture and the causative agent of a fatal systemic infection, is highly resistant to CAMPs. E. ictaluri mechanisms of resistance to CAMPs are unknown. We hypothesized that E. ictaluri lipopolysaccharide (LPS) plays a role in both virulence and resistance to CAMPs. The putative genes related to LPS oligo polysaccharide (O-PS) synthesis were in-frame deleted. Individual deletions of wibT, gne and ugd eliminated synthesis of the O-PS, causing auto-agglutination, rough colonies, biofilm-like formation and motility defects. Deletion of ugd, the gene that encodes the UDP-glucose dehydrogenase enzyme responsible for synthesis of UDP-glucuronic acid, causes sensitivity to CAMPs, indicating that UDP glucuronic acid and its derivatives are related to CAMP intrinsic resistance. E. ictaluri OP-S mutants showed different levels of attenuation, colonization of lymphoid tissues and immune protection in zebrafish (Danio rerio) and catfish. Orally inoculated catfish with O-PS mutant strains presented different degrees of gut inflammation and colonization of lymphoid tissues. Here we conclude that intrinsic resistance to CAMPs is mediated by Ugd enzyme, which has a pleiotropic effect in E. ictaluri influencing LPS synthesis, motility, agglutination, fish gut inflammation and virulence. PMID- 23676434 TI - Isolation, characterization and complete genome sequence of PhaxI: a phage of Escherichia coli O157 : H7. AB - Bacteriophages are considered as promising biological agents for the control of infectious diseases. Sequencing of their genomes can ascertain the absence of antibiotic resistance, toxin or virulence genes. The anti-O157 : H7 coliphage, PhaxI, was isolated from a sewage sample in Iran. Morphological studies by transmission electron microscopy showed that it has an icosahedral capsid of 85 86 nm and a contractile tail of 115*15 nm. PhaxI contains dsDNA composed of 156 628 nt with a G+C content of 44.5 mol% that encodes 209 putative proteins. In MS analysis of phage particles, 92 structural proteins were identified. PhaxI lyses Escherichia coli O157 : H7 in Luria-Bertani medium and milk, has an eclipse period of 20 min and a latent period of 40 min, and has a burst size of about 420 particles per cell. PhaxI is a member of the genus 'Viunalikevirus' of the family Myoviridae and is specific for E. coli O157 : H7. PMID- 23676435 TI - Synthetic riboswitches for the conditional control of gene expression in Streptomyces coelicolor. AB - We have demonstrated the portability of theophylline-dependent synthetic riboswitches for the conditional control of gene expression in Streptomyces coelicolor. The riboswitches mediate dose-dependent, up to 260-fold activation of reporter gene expression. Riboswitch regulation is a simple method requiring a sequence of only ~85 nt to be inserted between a transcriptional start site and the start codon; no additional auxiliary factors are necessary. The promoters galP2, ermEp1 and SF14 worked well in concert with the riboswitches. They allowed theophylline-dependent expression of not only the heterologous beta-glucuronidase reporter gene but also dagA, an endogenous agarase gene. The successful combination of all tested promoters with the riboswitches underlines the orthogonality of riboswitch regulation. We anticipate that any additional natural or synthetic promoters can be combined with the riboswitch. PMID- 23676436 TI - ClpP deletion causes attenuation of Salmonella Typhimurium virulence through mis regulation of RpoS and indirect control of CsrA and the SPI genes. AB - Salmonella enterica serovar Typhimurium requires the type III secretion system encoded by Salmonella pathogenicity island 1 (SPI1) and controlled by the master regulator, HilA, to penetrate the intestinal epithelium. Numerous regulators affect virulence through influence on this system, including the proteolytic component ClpP, the stationary phase regulator RpoS and the carbon-storage regulator CsrA. However, the mechanism behind the ClpP regulation is not fully understood. To elucidate this we examined differentially expressed genes in a DeltaclpP mutant compared with WT using global transcriptomic analysis. SPI1 and SPI4 virulence genes were significantly downregulated in the DeltaclpP mutant, whereas several RpoS-dependent genes and the fliC gene encoding flagellin were upregulated. While the DeltaclpP mutant was attenuated in cell invasion, this attenuation was not present in a DeltaclpP/rpoS : : amp double mutant, suggesting the repression of invasion was directed through RpoS. The expression of the csrA virulence regulator was increased in the DeltaclpP mutant and decreased in the rpoS : : amp and DeltaclpP/rpoS : : amp mutants, indicating that ClpP affects the csrA expression level as well. Thus, this study suggests that ClpP affects SPI1 expression and thereby virulence indirectly through its regulation of both RpoS and CsrA. PMID- 23676437 TI - Genomic and expression analysis of the vanG-like gene cluster of Clostridium difficile. AB - Primary antibiotic treatment of Clostridium difficile intestinal diseases requires metronidazole or vancomycin therapy. A cluster of genes homologous to enterococcal glycopeptides resistance vanG genes was found in the genome of C. difficile 630, although this strain remains sensitive to vancomycin. This vanG like gene cluster was found to consist of five ORFs: the regulatory region consisting of vanR and vanS and the effector region consisting of vanG, vanXY and vanT. We found that 57 out of 83 C. difficile strains, representative of the main lineages of the species, harbour this vanG-like cluster. The cluster is expressed as an operon and, when present, is found at the same genomic location in all strains. The vanG, vanXY and vanT homologues in C. difficile 630 are co transcribed and expressed to a low level throughout the growth phases in the absence of vancomycin. Conversely, the expression of these genes is strongly induced in the presence of subinhibitory concentrations of vancomycin, indicating that the vanG-like operon is functional at the transcriptional level in C. difficile. Hydrophilic interaction liquid chromatography (HILIC-HPLC) and MS analysis of cytoplasmic peptidoglycan precursors of C. difficile 630 grown without vancomycin revealed the exclusive presence of a UDP-MurNAc-pentapeptide with an alanine at the C terminus. UDP-MurNAc-pentapeptide [d-Ala] was also the only peptidoglycan precursor detected in C. difficile grown in the presence of vancomycin, corroborating the lack of vancomycin resistance. Peptidoglycan structures of a vanG-like mutant strain and of a strain lacking the vanG-like cluster did not differ from the C. difficile 630 strain, indicating that the vanG like cluster also has no impact on cell-wall composition. PMID- 23676438 TI - Characterization of two resuscitation promoting factors of Listeria monocytogenes. AB - In actinobacteria, resuscitation promoting factor (Rpf) proteins have been described as having the ability to increase the viable count of dormant cultures and stimulate growth of vegetative cells through lag phase reduction. Recently, it was suggested that proteins Lmo0186 and Lmo2522 of Listeria monocytogenes are equivalent to Rpf proteins based on their genomic context and conserved domain architecture. It was proposed that they have evolved through non-orthologous displacement of the Rpf domain found in actinobacteria. Here we present biological and biochemical data supporting a function of Lmo0186 and Lmo2522 as Rpfs. These proteins are collectively dispensable for growth but a lmo0186 lmo2522 double mutant exhibits an extended lag phase when diluted in minimal medium. This phenotype could be partially complemented by medium supplementation with fM to nM concentrations of purified hexahistidine-tagged versions of Lmo0186 and Lmo2522, showing that these proteins can stimulate growth. Gel filtration analysis and cross-linking experiments suggest that the recombinant proteins in solution are elongated monomers. Both proteins display muralytic activity against crude cell wall preparations and are active against an artificial lysozyme substrate. Our study thus supports the hypothesis that Lmo0186 and Lmo2522 are functional equivalents of actinobacteria Rpf proteins and represents the first characterization of two Rpf homologues from firmicutes. PMID- 23676439 TI - Investigation of the atypical FBXW7 mutation spectrum in human tumours by conditional expression of a heterozygous propellor tip missense allele in the mouse intestines. AB - OBJECTIVE: FBXW7 encodes the substrate recognition component of a ubiquitin ligase that degrades targets such as Notch1, c-Jun, c-Myc and cyclin E. FBXW7 mutations occur in several tumour types, including colorectal cancers. The FBXW7 mutation spectrum in cancers is unusual. Some tumours have biallelic loss of function mutations but most have monoallelic missense mutations involving specific arginine residues at beta-propellor tips involved in substrate recognition. DESIGN: FBXW7 functional studies have generally used null systems. In order to analyse the most common mutations in human tumours, we created a Fbxw7(fl(R482Q))(/+) mouse and conditionally expressed this mutation in the intestines using Vill-Cre. We compared these mice with heterozygous null (Fbxw7(+/-)) mutants. RESULTS: A few sizeable intestinal adenomas occurred in approximately 30% of R482Q/+ and Fbxw7(+/-) mice at age >300 days. Breeding the R482Q allele onto Apc mutant backgrounds led to accelerated morbidity and increased polyp numbers and size. Within the small bowel, polyp distribution was shifted proximally. Elevated levels of two particular Fbxw7 substrates, Klf5 and Tgif1, were found in normal intestine and adenomas of R482Q/+, R482Q/R482Q and Fbxw7(-/-) mice, but not Fbxw7(+/-) animals. On the Apc mutant background, Fbxw7(+/-) mutants had a phenotype intermediate between Fbxw7 wild-type and R482Q/+ mice. CONCLUSIONS: Heterozygous Fbxw7 propellor tip (R482Q) mutations promote intestinal tumorigenesis on an Apc mutant background. Klf5 and Tgif1 are strong candidates for mediating this effect. Although heterozygous null Fbxw7 mutations also promote tumour growth, these have a weaker effect than R482Q. These findings explain the FBXW7 mutation spectrum found in human cancers, and emphasise the need for animal models faithfully to reflect human disease. PMID- 23676440 TI - Treatment of patients with dual hepatitis C and B by peginterferon alpha and ribavirin reduced risk of hepatocellular carcinoma and mortality. AB - OBJECTIVE: Whether peginterferon alpha and ribavirin combination therapy reduces risk of hepatocellular carcinoma (HCC) or improves survival in patients dual infected with hepatitis C virus (HCV) and hepatitis B virus (HBV) is unknown. Since it is ethically impossible to conduct a randomised trial to learn the long term efficacy, we rely upon the large database to explore the effectiveness of combination therapy among dual-infected patients. DESIGN: Data for this population-based retrospective cohort study were obtained from the treatment programme, Cancer Registry, National Health Insurance and death certification. We examined the risk of HCC, mortality and adverse events in 1096 treated and 18 988 untreated HCV-HBV dually-infected patients. Outcomes were analysed using the bias corrected inverse probability weighting (IPW) by propensity scores. Outcomes of HCV-HBV dually-infected and HCV mono-infected patients receiving the same treatment were compared using new user design with IPW estimators to adjust for confounding. RESULTS: After adjustment, combination therapy significantly reduced the risk of HCC (HR 0.76, 95% CI 0.59 to 0.97), liver-related mortality (HR 0.47, 95% CI 0.37 to 0.6) and all-cause mortality (HR 0.42, 95% CI 0.34 to 0.52). Nevertheless, the underlying HBV infection was still a risk factor for HCC and mortality after treatment. Treatment was associated with an increase in the incidence of thyroid dysfunction (HR 1.9, p<0.001) and mood disorders (HR 1.81, p=0.005). CONCLUSIONS: This is the first evidence showing that combination therapy decreased the risk of HCC and improved survival in HCV-HBV dually infected patients despite a slight increase in the incidence of thyroid and mood disorders. PMID- 23676442 TI - Measuring vaccine confidence: analysis of data obtained by a media surveillance system used to analyse public concerns about vaccines. AB - BACKGROUND: The intensity, spread, and effects of public opinion about vaccines are growing as new modes of communication speed up information sharing, contributing to vaccine hesitancy, refusals, and disease outbreaks. We aimed to develop a new application of existing surveillance systems to detect and characterise early signs of vaccine issues. We also aimed to develop a typology of concerns and a way to assess the priority of each concern. METHODS: Following preliminary research by The Vaccine Confidence Project, media reports (eg, online articles, blogs, government reports) were obtained using the HealthMap automated data collection system, adapted to monitor online reports about vaccines, vaccination programmes, and vaccine-preventable diseases. Any reports that did not meet the inclusion criteria--any reference to a human vaccine or vaccination campaign or programme that was accessible online--were removed from analysis. Reports were manually analysed for content and categorised by concerns, vaccine, disease, location, and source of report, and overall positive or negative sentiment towards vaccines. They were then given a priority level depending on the seriousness of the reported event and time of event occurrence. We used descriptive statistics to analyse the data collected during a period of 1 year, after refinements to the search terms and processes had been made. FINDINGS: We analysed data from 10,380 reports (from 144 countries) obtained between May 1, 2011, and April 30, 2012. 7171 (69%) contained positive or neutral content and 3209 (31%) contained negative content. Of the negative reports, 1977 (24%) were associated with impacts on vaccine programmes and disease outbreaks; 1726 (21%) with beliefs, awareness, and perceptions; 1371 (16%) with vaccine safety; and 1336 (16%) with vaccine delivery programmes. We were able to disaggregate the data by country and vaccine type, and monitor evolution of events over time and location in specific regions where vaccine concerns were high. INTERPRETATION: Real-time monitoring and analysis of vaccine concerns over time and location could help immunisation programmes to tailor more effective and timely strategies to address specific public concerns. FUNDING: Bill & Melinda Gates Foundation. PMID- 23676441 TI - Nrf2 deficiency impairs the barrier function of mouse oesophageal epithelium. AB - OBJECTIVE: As a major cellular defence mechanism, the Nrf2/Keap1 pathway regulates expression of genes involved in detoxification and stress response. Here we hypothesise that Nrf2 is involved in oesophageal barrier function and plays a protective role against gastro-oesophageal reflux disease (GERD). DESIGN: Human oesophageal biopsy samples, mouse surgical models and Nrf2(-/-) mice were used to assess the role of the Nrf2/Keap1 pathway in oesophageal barrier function. Trans-epithelial electrical resistance (TEER) was measured with mini Ussing chambers. HE staining and transmission electron microscopy were used to examine tissue morphology, while gene microarray, immunohistochemistry, western blotting and chromatin immunoprecipitation (ChIP) analysis were used to assess gene expression. RESULTS: Nrf2 was expressed in normal oesophageal epithelium and activated in GERD of both humans and mice. Nrf2 deficiency and gastro-oesophageal reflux in mice, alone or in combination, reduced TEER and increased intercellular space in oesophageal epithelium. Nrf2 target genes and gene sets associated with oxidoreductase activity, mitochondrial biogenesis and energy production were downregulated in the oesophageal epithelium of Nrf2(-/-) mice. Consistent with the antioxidative function of Nrf2, a DNA oxidative damage marker (8OHdG) dramatically increased in oesophageal epithelial cells of Nrf2(-/-) mice compared with those of wild-type mice. Interestingly, ATP biogenesis, Cox IV (a mitochondrial protein) and Claudin 4 (Cldn4) expression were downregulated in the oesophageal epithelium of Nrf2(-/-) mice, suggesting that energy-dependent tight junction integrity was subject to Nrf2 regulation. ChIP analysis confirmed the binding of Nrf2 to Cldn4 promoter. CONCLUSIONS: Nrf2 deficiency impairs oesophageal barrier function through disrupting energy-dependent tight junction. PMID- 23676443 TI - Inoculating communities against vaccine scare stories. PMID- 23676444 TI - More on lymphoproliferative disorders associated with crohn disease treatments. PMID- 23676445 TI - Validation of the modified Vesikari score in children with gastroenteritis in 5 US emergency departments. AB - OBJECTIVES: The burden of acute gastroenteritis (AGE) in US children is substantial. Research into outpatient treatment strategies has been hampered by the lack of easily used and validated gastroenteritis severity scales relevant to the populations studied. We sought to evaluate, in a US cohort, the reliability, construct validity, and generalizability of a gastroenteritis severity scale previously derived in a Canadian population, the modified Vesikari score (MVS). METHODS: We conducted a prospective, cohort, clinical observational study of children 3 to 48 months of age with acute gastroenteritis presenting to 5 US emergency departments. A baseline MVS score was determined in the emergency department, and telephone follow-up 14 days after presentation was used to assign the follow-up MVS. We determined reliability using inter-item correlations; construct validity via principal component factor analysis; cross-sectional construct validity via correlations with the presence of dehydration, hospitalization, and day care and parental work absenteeism; and generalizability via score distribution among sites. RESULTS: Two hundred eighteen of 274 patients (80%) were successfully contacted for follow-up. Cronbach alpha was 0.63, indicating expectedly low internal reliability because of the multidimensional properties of the MVS. Factor analysis supported the appropriateness of retaining all variables in the score. Disease severity correlated with dehydration (P < 0.001), hospitalization (P < 0.001), and subsequent day care (P = 0.01) and work (P < 0.001) absenteeism. The MVS was normally distributed, and scores did not differ among sites. CONCLUSIONS: The MVS effectively measures global severity of disease and performs similarly in varying populations within the US health care system. Its characteristics support its use in multisite outpatient clinical trials. PMID- 23676446 TI - Femicide and colonization: between the politics of exclusion and the culture of control. AB - This article explores the murder of women and girls, which we name it Femicide, among the Palestinian community living in Israel. Specifically, it analyzes how the dialectic interrelationship between informal and formal legal-social systems constructs the murders of Palestinian women. The data revealed that femicide is a crime empowered by the wider context of colonization and the increasing spatial segregation of Palestinian communities. The study confirms the need to move beyond simplistic "cultural" explanations of femicide, and pay closer attention to the ways in which the structure, politics and economy of death function in colonized spaces and contexts. PMID- 23676447 TI - Violence against women in the context of war: experiences of Shi'i women and Palestinian refugee women in Lebanon. AB - In times of war, women are likely to experience, in addition to the "normal" violence of peacetime, random cruelties perpetrated by the enemy against all members of the community. During research conducted with Palestinian refugees and Shi'i Muslims in Lebanon, women described various forms of violence and, in this article, I examine violence suffered by women in the context of conflict from three perspectives: victimization, trauma, and resistance. I argue that traumatic events have the effect of obliterating identity, but they can also strengthen the resolve to resist. PMID- 23676448 TI - Women's shelters in Turkey: a qualitative study on shortcomings of policy making and implementation. AB - Despite a long history of women's movements and policy-making efforts to ameliorate women's status in Turkey, the number and quality of women's shelters are far from sufficient. This article aims to reveal the shortcomings of shelter policy through the lens of those "at work" on this important social issue using a qualitative research design. Forty semistructured in-depth interviews were conducted with municipal administrative officials, state social workers, and employees of civil society organizations that run shelters. The research findings reveal that there is a lack of effective authority that has the willpower to combat violence against women, and that it is difficult to keep shelters secure in a patriarchal society away from the male gaze. Furthermore, results indicate that there has been an erosion of social services provided by the state. PMID- 23676449 TI - Attitudes of Palestinian physicians toward wife abuse: their definitions, perceptions of causes, and perceptions of appropriate interventions. AB - The article presents results from a larger survey, which examined the attitudes and perceptions of Palestinian physicians (N = 396) toward wife abuse. The instrument was a self-administered questionnaire, with open-ended questions in which participants expressed their definitions of wife abuse, their perceptions of the causes of wife abuse, and their perceptions of appropriate interventions with wife abuse. The relevance of the sociocultural contexts of Palestinian society in particular and Arab societies in general to the participants' responses is highlighted in the article. The limitations of the study as well as implications for theory development, future research, and professional training are discussed. PMID- 23676450 TI - Gender-based violence in Egypt: analyzing impacts of political reforms, social, and demographic change. AB - Over recent decades, Egypt has witnessed developments in gender equality. This article discusses recent changes relating to violence against women within this context. Statistical data from the Egyptian DHS surveys is used to describe trends in reported violence and in attitudes toward marital abuse, as well as to examine the survey tools used to measure violence. While findings reflect a growing awareness regarding the issue, the number of women reporting spousal violence remained stable during the study period. The results are contextualized within the political and social debate in which NGO's and women's rights activists play a central role. PMID- 23676452 TI - XEDS STEM tomography for 3D chemical characterization of nanoscale particles. AB - We present a tomography technique which couples scanning transmission electron microscopy (STEM) and X-ray energy dispersive spectrometry (XEDS) to resolve 3D distribution of elements in nanoscale materials. STEM imaging when combined with XEDS mapping using a symmetrically arranged XEDS detector design around the specimen overcomes many of the obstacles in 3D chemical imaging of nanoscale materials and successfully elucidates the 3D chemical information in a large field of view of the transmission electron microscopy (TEM) sample. We employed this technique to investigate 3D distribution of Nickel (Ni), Manganese (Mn) and Oxygen (O) in a Li1.2Ni0.2Mn0.6O2 (LNMO) nanoparticle used as a cathode material in Lithium (Li) ion batteries. For this purpose, 2D elemental maps were acquired for a range of tilt angles and reconstructed to obtain 3D elemental distribution in an isolated LNMO nanoparticle. The results highlight the strength of this technique in 3D chemical analysis of nanoscale materials by successfully resolving Ni, Mn and O elemental distributions in 3D and discovering the new phenomenon of Ni surface segregation in this material. Furthermore, the comparison of simultaneously acquired high angle annular dark field (HAADF) STEM and XEDS STEM tomography results shows that XEDS STEM tomography provides additional 3D chemical information of the material especially when there is low atomic number (Z) contrast in the material of interest. PMID- 23676451 TI - Validity and reliability of the Self-Reported Physical Fitness (SRFit) survey. AB - BACKGROUND: An accurate physical fitness survey could be useful in research and clinical care. PURPOSE: To estimate the validity and reliability of a Self Reported Fitness (SRFit) survey; an instrument that estimates muscular fitness, flexibility, cardiovascular endurance, BMI, and body composition (BC) in adults >= 40 years of age. METHODS: 201 participants completed the SF-36 Physical Function Subscale, International Physical Activity Questionnaire (IPAQ), Older Adults' Desire for Physical Competence Scale (Rejeski), the SRFit survey, and the Rikli and Jones Senior Fitness Test. BC, height and weight were measured. SRFit survey items described BC, BMI, and Senior Fitness Test movements. Correlations between the Senior Fitness Test and the SRFit survey assessed concurrent validity. Cronbach's Alpha measured internal consistency within each SRFit domain. SRFit domain scores were compared with SF-36, IPAQ, and Rejeski survey scores to assess construct validity. Intraclass correlations evaluated test retest reliability. RESULTS: Correlations between SRFit and the Senior Fitness Test domains ranged from 0.35 to 0.79. Cronbach's Alpha scores were .75 to .85. Correlations between SRFit and other survey scores were -0.23 to 0.72 and in the expected direction. Intraclass correlation coefficients were 0.79 to 0.93. All P values were 0.001. CONCLUSION: Initial evaluation supports the SRFit survey's validity and reliability. PMID- 23676453 TI - Limits of simulation based high resolution EBSD. AB - High resolution electron backscattered diffraction (HREBSD) is a novel technique for a relative determination of both orientation and stress state in crystals through digital image correlation techniques. Recent works have tried to use simulated EBSD patterns as reference patterns to achieve the absolute orientation and stress state of crystals. However, a precise calibration of the pattern centre location is needed to avoid the occurrence of phantom stresses. A careful analysis of the projective transformation involved in the formation of EBSD patterns has permitted to understand these phantom stresses. This geometrical analysis has been confirmed by numerical simulations. The results indicate that certain combinations of crystal strain states and sample locations (pattern centre locations) lead to virtually identical EBSD patterns. This ambiguity makes the problem of solving the absolute stress state of a crystal unfeasible in a single-detector configuration. PMID- 23676454 TI - The use of the mechanical microenvironment of phospholipid polymer hydrogels to control cell behavior. AB - We considered that properties of the microenvironment surrounding cells are important for the control of the cell functions. Cytocompatible polymer hydrogels are good candidates to study such microenvironment. Here, we prepared spontaneously forming hydrogels composed of two polymer systems, namely poly(2 methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate-co-p vinylphenylboronic acid) (PMBV) and poly(vinyl alcohol) (PVA). The PMBV/PVA hydrogels could be reversibly dissociated by the addition of d-sorbitol. The storage modulus was measured for evaluating the mechanical properties of the PMBV/PVA hydrogels. The storage modulus could be controlled in the range 0.30-2.5 kPa by changing the cross-linking density of the hydrogels. After pluripotent stem cells were encapsulated within the PMBV/PVA hydrogels during the preparation of the hydrogel under normal cell-culturing conditions, the proliferation rate and the cell cycle of the encapsulated cells were observed. Cells lived for more than three days in every PMBV/PVA hydrogel. However, the proliferation significantly depended on the storage modulus of the hydrogels. Although the cell cycle of the initial cells was heterogenous, it developed uniformity toward the G1 phase when the cells were encapsulated within the PMBV/PVA hydrogel with a storage modulus of 1.1 kPa for three days. That is, the mechanical properties of the PMBV/PVA environment influenced the biological functions of the cells encapsulated in the hydrogels. From these results, we conclude that PMBV/PVA hydrogels are useful for adjusting cell cycles and proliferation, thus providing uniform cells for applications in the field of cell engineering. PMID- 23676455 TI - Patient satisfaction with anesthesia: beauty is in the eye of the consumer. PMID- 23676456 TI - The accumulation of the glycoxidation product N(epsilon)-carboxymethyllysine in cardiac tissues with age, diabetes mellitus and coronary heart disease. AB - Heart disease is one of the most important causes of death in developed countries. N(epsilon)-carboxymethyllysine (CML) is a major advanced glycation end product formed by combined reactions of non-enzymatic glycation and oxidation (glycoxidation), and it represents a general marker of oxidative stress. CML has been suggested to be involved in the pathogenesis of heart disease. Plasma CML is elevated in aging, atherosclerosis and/or diabetes. In this study, we measured cardiac CML levels to elucidate its role in the pathogenesis of heart disease. Cardiac tissues were collected from 105 patients (55.6 +/- 17.0 years old: age range, 1-78 years) undergoing cardiac surgery. The diseases comprised coronary heart disease (CHD), CHD associated with diabetes mellitus (DM), valvular heart disease and congenital heart disease. The concentration of CML in cardiac tissues of each group was 4.31 +/- 0.66, 5.29 +/- 0.59, 2.74 +/- 1.05 and 1.75 +/- 1.16 MUg/g, respectively. ELISA was used for measuring cardiac and plasma CML concentrations. Multiple linear regression analysis showed a significant positive correlation of CML concentrations with age (r = 0.803, p < 0.001), DM (r = 0.567, p < 0.001) and CHD (r = 0.523 p < 0.001). R(2) was 0.872 (p < 0.001); the three independent variables could explain 87.2% variation of CML concentrations. Cardiac CML concentrations exhibited a significant positive correlation with plasma CML (r = 0.983, p < 0.001). Our data indicate that cardiac CML concentrations increase with age, DM and/or CHD, and exhibit a positive correlation with plasma CML concentrations. PMID- 23676457 TI - Transplant rejection and paradigms lost. AB - During transplant rejection, migrating T cells infiltrate the grafted organ, but the signals that direct this migration are incompletely understood. In this issue of the JCI, Walch et al. debunk two classical paradigms concerning transplant rejection, with important consequences for the design of antirejection therapeutics. PMID- 23676458 TI - Blazing a new TRAIL in hematopoietic cell transplantation. AB - There is a ying/yang to most biological therapies, and the balance of efficacy versus toxicity is delicate and sometimes difficult to achieve in favor of the patients. When the therapeutic window is wide, these therapies can be used in the majority of patients, but when the therapeutic window is narrow, the decision to proceed must be carefully balanced with a thoughtful risk-benefit analysis. In this issue of the JCI, Ghosh et al. tackle one of the major obstacles in hematopoietic cell transplantation (HCT) technology: balancing the beneficial antitumor effect with the harmful anti-host effect. PMID- 23676459 TI - Cognate antigen directs CD8+ T cell migration to vascularized transplants. AB - The migration of effector or memory T cells to the graft is a critical event in the rejection of transplanted organs. The prevailing view is that the key steps involved in T cell migration - integrin-mediated firm adhesion followed by transendothelial migration - are dependent on the activation of Galphai-coupled chemokine receptors on T cells. In contrast to this view, we demonstrated in vivo that cognate antigen was necessary for the firm adhesion and transendothelial migration of CD8+ effector T cells specific to graft antigens and that both steps occurred independent of Galphai signaling. Presentation of cognate antigen by either graft endothelial cells or bone marrow-derived APCs that extend into the capillary lumen was sufficient for T cell migration. The adhesion and transmigration of antigen-nonspecific (bystander) effector T cells, on the other hand, remained dependent on Galphai, but required the presence of antigen specific effector T cells. These findings underscore the primary role of cognate antigen presented by either endothelial cells or bone marrow-derived APCs in the migration of T cells across endothelial barriers and have important implications for the prevention and treatment of graft rejection. PMID- 23676460 TI - The genomic landscape of small intestine neuroendocrine tumors. AB - Small intestine neuroendocrine tumors (SI-NETs) are the most common malignancy of the small bowel. Several clinical trials target PI3K/Akt/mTOR signaling; however, it is unknown whether these or other genes are genetically altered in these tumors. To address the underlying genetics, we analyzed 48 SI-NETs by massively parallel exome sequencing. We detected an average of 0.1 somatic single nucleotide variants (SNVs) per 106 nucleotides (range, 0-0.59), mostly transitions (C>T and A>G), which suggests that SI-NETs are stable cancers. 197 protein-altering somatic SNVs affected a preponderance of cancer genes, including FGFR2, MEN1, HOOK3, EZH2, MLF1, CARD11, VHL, NONO, and SMAD1. Integrative analysis of SNVs and somatic copy number variations identified recurrently altered mechanisms of carcinogenesis: chromatin remodeling, DNA damage, apoptosis, RAS signaling, and axon guidance. Candidate therapeutically relevant alterations were found in 35 patients, including SRC, SMAD family genes, AURKA, EGFR, HSP90, and PDGFR. Mutually exclusive amplification of AKT1 or AKT2 was the most common event in the 16 patients with alterations of PI3K/Akt/mTOR signaling. We conclude that sequencing-based analysis may provide provisional grouping of SI NETs by therapeutic targets or deregulated pathways. PMID- 23676461 TI - Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity. AB - Current strategies to suppress graft-versus-host disease (GVHD) also compromise graft-versus-tumor (GVT) responses. Furthermore, most experimental strategies to separate GVHD and GVT responses merely spare GVT function without actually enhancing it. We have previously shown that endogenously expressed TNF-related apoptosis-inducing ligand (TRAIL) is required for optimal GVT activity against certain malignancies in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to model a donor-derived cellular therapy, we genetically engineered T cells to overexpress TRAIL and adoptively transferred donor-type unsorted TRAIL+ T cells into mouse models of allo-HSCT. We found that murine TRAIL+ T cells induced apoptosis of alloreactive T cells, thereby reducing GVHD in a DR5-dependent manner. Furthermore, murine TRAIL+ T cells mediated enhanced in vitro and in vivo antilymphoma GVT response. Moreover, human TRAIL+ T cells mediated enhanced in vitro cytotoxicity against both human leukemia cell lines and against freshly isolated chronic lymphocytic leukemia (CLL) cells. Finally, as a model of off-the-shelf, donor-unrestricted antitumor cellular therapy, in vitro-generated TRAIL+ precursor T cells from third-party donors also mediated enhanced GVT response in the absence of GVHD. These data indicate that TRAIL-overexpressing donor T cells could potentially enhance the curative potential of allo-HSCT by increasing GVT response and suppressing GVHD. PMID- 23676463 TI - Specific peripheral B cell tolerance defects in patients with multiple sclerosis. AB - Multiple sclerosis (MS) is a genetically mediated autoimmune disease of the central nervous system. B cells have recently emerged as major contributors to disease pathogenesis, but the mechanisms responsible for the loss of B cell tolerance in patients with MS are largely unknown. In healthy individuals, developing autoreactive B cells are removed from the repertoire at 2 tolerance checkpoints during early B cell development. Both of these central and peripheral B cell tolerance checkpoints are defective in patients with rheumatoid arthritis (RA) and type 1 diabetes (T1D). Here, we found that only the peripheral, but not the central, B cell tolerance checkpoint is defective in patients with MS. We show that this specific defect is accompanied by increased activation and homeostatic proliferation of mature naive B cells. Interestingly, all of these MS features parallel defects observed in FOXP3-deficient IPEX patients, who harbor nonfunctional Tregs. We demonstrate that in contrast to patients with RA or T1D, bone marrow central B cell selection in MS appears normal in most patients. In contrast, patients with MS suffer from a specific peripheral B cell tolerance defect that is potentially attributable to impaired Treg function and that leads to the accumulation of autoreactive B cell clones in their blood. PMID- 23676462 TI - PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells. AB - The inhibitory receptor programmed cell death 1 (PD-1) plays a major role in functional exhaustion of T cells during chronic infections and cancer, and recent clinical data suggest that blockade of the PD-1 pathway is an effective immunotherapy in treating certain cancers. Thus, it is important to define combinatorial approaches that increase the efficacy of PD-1 blockade. To address this issue, we examined the effect of IL-2 and PD-1 ligand 1 (PD-L1) blockade in the mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection. We found that low-dose IL-2 administration alone enhanced CD8+ T cell responses in chronically infected mice. IL-2 treatment also decreased inhibitory receptor levels on virus-specific CD8+ T cells and increased expression of CD127 and CD44, resulting in a phenotype resembling that of memory T cells. Surprisingly, IL-2 therapy had only a minimal effect on reducing viral load. However, combining IL-2 treatment with blockade of the PD-1 inhibitory pathway had striking synergistic effects in enhancing virus-specific CD8+ T cell responses and decreasing viral load. Interestingly, this reduction in viral load occurred despite increased numbers of Tregs. These results suggest that combined IL-2 therapy and PD-L1 blockade merits consideration as a regimen for treating human chronic infections and cancer. PMID- 23676464 TI - Lamin B1 mediates cell-autonomous neuropathology in a leukodystrophy mouse model. AB - Adult-onset autosomal-dominant leukodystrophy (ADLD) is a progressive and fatal neurological disorder characterized by early autonomic dysfunction, cognitive impairment, pyramidal tract and cerebellar dysfunction, and white matter loss in the central nervous system. ADLD is caused by duplication of the LMNB1 gene, which results in increased lamin B1 transcripts and protein expression. How duplication of LMNB1 leads to myelin defects is unknown. To address this question, we developed a mouse model of ADLD that overexpresses lamin B1. These mice exhibited cognitive impairment and epilepsy, followed by age-dependent motor deficits. Selective overexpression of lamin B1 in oligodendrocytes also resulted in marked motor deficits and myelin defects, suggesting these deficits are cell autonomous. Proteomic and genome-wide transcriptome studies indicated that lamin B1 overexpression is associated with downregulation of proteolipid protein, a highly abundant myelin sheath component that was previously linked to another myelin-related disorder, Pelizaeus-Merzbacher disease. Furthermore, we found that lamin B1 overexpression leads to reduced occupancy of Yin Yang 1 transcription factor at the promoter region of proteolipid protein. These studies identify a mechanism by which lamin B1 overexpression mediates oligodendrocyte cell autonomous neuropathology in ADLD and implicate lamin B1 as an important regulator of myelin formation and maintenance during aging. PMID- 23676466 TI - Insights into the concept and measurement of health literacy from a study of shared decision-making in a low literacy population. AB - This article explores the concept and measurement of health literacy in the context of shared health decision-making. It draws upon a series of qualitative and quantitative studies undertaken in the development and evaluation of a bowel cancer screening decision aid for low literacy populations. The findings indicate that different types of health literacy (functional, interactive and critical) are required in decision-making and present a set of instruments to assess and discriminate between higher level health literacy skills required for engagement in decision-making. It concludes that greater sophistication in both the definition and measurement of health literacy in research is needed. PMID- 23676465 TI - Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium. AB - TNF has remarkable antitumor activities; however, therapeutic applications have not been possible because of the systemic and lethal proinflammatory effects induced by TNF. Both the antitumor and inflammatory effects of TNF are mediated by the TNF receptor p55 (p55TNFR) (encoded by the Tnfrsf1a gene). The antitumor effect stems from an induction of cell death in tumor endothelium, but the cell type that initiates the lethal inflammatory cascade has been unclear. Using conditional Tnfrsf1a knockout or reactivation mice, we found that the expression level of p55TNFR in intestinal epithelial cells (IECs) is a crucial determinant in TNF-induced lethal inflammation. Remarkably, tumor endothelium and IECs exhibited differential sensitivities to TNF when p55TNFR levels were reduced. Tumor-bearing Tnfrsf1a++/- or IEC-specific p55TNFR-deficient mice showed resistance to TNF-induced lethality, while the tumor endothelium remained fully responsive to TNF-induced apoptosis and tumors regressed. We demonstrate proof of principle for clinical application of this approach using neutralizing anti-human p55TNFR antibodies in human TNFRSF1A knockin mice. Our results uncover an important cellular basis of TNF toxicity and reveal that IEC-specific or systemic reduction of p55TNFR mitigates TNF toxicity without loss of antitumor efficacy. PMID- 23676467 TI - FAM83B-mediated activation of PI3K/AKT and MAPK signaling cooperates to promote epithelial cell transformation and resistance to targeted therapies. AB - Therapies targeting MAPK and AKT/mTOR signaling are currently being evaluated in clinical trials for several tumor types. However, recent studies suggest that these therapies may be limited due to acquired cancer cell resistance and a small therapeutic index between normal and cancer cells. The identification of novel proteins that are involved in MAPK or AKT/mTOR signaling and differentially expressed between normal and cancer cells will provide mechanistically distinct therapeutic targets with the potential to inhibit these key cancer-associated pathways. We recently identified FAM83B as a novel, previously uncharacterized oncogene capable of hyperactivating MAPK and mTOR signaling and driving the tumorigenicity of immortalized human mammary epithelial cells (HMEC). We show here that elevated FAM83B expression also activates the PI3K/AKT signaling pathway and confers a decreased sensitivity to PI3K, AKT, and mTOR inhibitors. FAM83B co-precipitated with the p85alpha and p110alpha subunits of PI3K, as well as AKT, and increased p110alpha and AKT membrane localization, consistent with elevated PI3K/AKT signaling. In tumor-derived cells harboring elevated FAM83B expression, ablation of FAM83B decreased p110alpha and AKT membrane localization, suppressed AKT phosphorylation, and diminished proliferation, AIG, and tumorigenicity in vivo. We propose that the level of FAM83B expression may be an important factor to consider when combined therapies targeting MAPK and AKT/mTOR signaling are used. Moreover, the identification of FAM83B as a novel oncogene and its integral involvement in activating PI3K/AKT and MAPK provides a foundation for future therapies aimed at targeting FAM83B in order to suppress the growth of PI3K/AKT- and MAPK-driven cancers. PMID- 23676468 TI - Oxidative stress and immune related gene expression following exposure to di-n butyl phthalate and diethyl phthalate in zebrafish embryos. AB - In the present study, we analyzed the oxidative stress related indices and immune related gene expression of zebrafish embryos after a short-term exposure to various concentrations of di-n-butyl phthalate (DBP), diethyl phthalate (DEP) and their mixture (DBP-DEP) from 4h post-fertilization (hpf) to 96hpf. Exposure to the chemicals was found to enhance the production of reactive oxygen species (ROS) and lipid peroxidation (LPO) in a concentration-dependent manner. Simultaneously, adaptive responses to DBP/DEP-induced oxidative stress were observed. The activity of antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were all increased in a concentration-dependent manner. The transcription of innate immune related genes including interferon gamma (IFNgamma), interleukin-1beta (IL1beta), Myxovirus resistance (Mx), tumor necrosis factor alpha (TNFalpha), CC-chemokine, CXCL-clc, lysozyme (Lyz) and complement factor C3B (C3) were up-regulated upon DBP, DEP and their mixture exposure, suggesting the induction of immune response. In addition, co-exposure to DBP-DEP also induced antioxidant defense and immune response in zebrafish embryo. The results demonstrat that DBP/DEP exposure could induce the antioxidant and immune responses in zebrafish embryos. PMID- 23676469 TI - Hexachlorocyclotriphosphazene (HCCP)-mediated direct formation of thioethers and ethers from quinazolin-4(3H)-ones. AB - A hexachlorocyclotriphosphazene (HCCP)-mediated direct formation of quinazoline (thio)ethers from quinazolin-4(3H)-ones has been developed. Treatment of quinazolin-4(3H)-ones with HCCP, diisopropylethylamine (DIPEA), and thiophenols resulted in formation of the corresponding 4-arylthioquinazoline derivatives in moderate to excellent yields. This method has also been utilized to prepare 4 aryloxyquinazoline and 4-alkoxyquinazoline derivatives using phenols and sodium alkoxides as the nucleophiles. PMID- 23676470 TI - Development of a new positron emission tomography tracer for targeting tumor angiogenesis: synthesis, small animal imaging, and radiation dosimetry. AB - Angiogenesis plays a key role in cancer progression and correlates with disease aggressiveness and poor clinical outcomes. Affinity ligands discovered by screening phage display random peptide libraries can be engineered to molecularly target tumor blood vessels for noninvasive imaging and early detection of tumor aggressiveness. In this study, we tested the ability of a phage-display-selected peptide sequence recognizing specifically bone marrow- derived pro-angiogenic tumor-homing cells, the QFP-peptide, radiolabeled with 64Cu radioisotope to selectively image tumor vasculature in vivo by positron emission tomography (PET). To prepare the targeted PET tracer we modified QFP-phage with the DOTA chelator and radiolabeled the purified QFP-phage-DOTA intermediate with 64Cu to obtain QFP-targeted radioconjugate with high radiopharmaceutical yield and specific activity. We evaluated the new PET tracer in vivo in a subcutaneous (s.c.) Lewis lung carcinoma (LLC) mouse model and conducted tissue distribution, small animal PET/CT imaging study, autoradiography, histology, fluorescence imaging, and dosimetry assessments. The results from this study show that, in the context of the s.c. LLC immunocompetent mouse model, the QFP-tracer can target tumor blood vessels selectively. However, further optimization of the biodistribution and dosimetry profile of the tracer is necessary to ensure efficient radiopharmaceutical applications enabled by the biological specificity of the QFP-peptide. PMID- 23676471 TI - Chitosan for gene delivery and orthopedic tissue engineering applications. AB - Gene therapy involves the introduction of foreign genetic material into cells in order exert a therapeutic effect. The application of gene therapy to the field of orthopaedic tissue engineering is extremely promising as the controlled release of therapeutic proteins such as bone morphogenetic proteins have been shown to stimulate bone repair. However, there are a number of drawbacks associated with viral and synthetic non-viral gene delivery approaches. One natural polymer which has generated interest as a gene delivery vector is chitosan. Chitosan is biodegradable, biocompatible and non-toxic. Much of the appeal of chitosan is due to the presence of primary amine groups in its repeating units which become protonated in acidic conditions. This property makes it a promising candidate for non-viral gene delivery. Chitosan-based vectors have been shown to transfect a number of cell types including human embryonic kidney cells (HEK293) and human cervical cancer cells (HeLa). Aside from its use in gene delivery, chitosan possesses a range of properties that show promise in tissue engineering applications; it is biodegradable, biocompatible, has anti-bacterial activity, and, its cationic nature allows for electrostatic interaction with glycosaminoglycans and other proteoglycans. It can be used to make nano- and microparticles, sponges, gels, membranes and porous scaffolds. Chitosan has also been shown to enhance mineral deposition during osteogenic differentiation of MSCs in vitro. The purpose of this review is to critically discuss the use of chitosan as a gene delivery vector with emphasis on its application in orthopedic tissue engineering. PMID- 23676472 TI - Photophysical studies of a new water soluble indocarbocyanine dye adsorbed onto microcrystalline cellulose and beta-cyclodextrin. AB - A water-soluble indocarbocyanine dye was synthesized and its photophysics were studied for the first time on two solid hosts, microcrystalline cellulose and b cyclodextrin, as well as in homogeneous media. The inclusion of the indocarbocyanine moiety onto microcrystalline cellulose increased the dye aggregation with both H and J aggregates being formed. Adsorption on b cyclodextrin enhanced aggregation in a similar way. The fluorescence quantum yields were determined for the powdered samples of the cyanine dye on the two hosts and a significant increase was observed relative to homogeneous solution. A remarkable concentration dependence was also detected in both cases. A lifetime distribution analysis has shown that the indocarbocyanine dye mainly occupies the amorphous part of cellulose and is not entrapped in the crystalline part of this host. In the b-CD case, the adsorption occurs outside the host cavity. In both hosts a strong concentration quenching effect is observed and only monomers emit. Both adsorptions may be explained by stereochemical constraints imposed by the two long sulphoethyl tails linked to nitrogen atoms of the indocarbocyanine dye. PMID- 23676473 TI - Effects of chirality on the antifungal potency of methylated succinimides obtained by Aspergillus fumigatus biotransformations. comparison with racemic ones. AB - Eighteen (3R) and (3R,4R)-N-phenyl-, N-phenylalkyl and N-arylsuccinimides were prepared with high enantioselectivity by biotransformation of maleimides with A. fumigatus. This environmentally friendly, clean and economical procedure was performed by the whole-cell fungal bioconversion methodology. Their corresponding eighteen racemic succinimides were prepared instead by synthetic methods. Both, the racemic and the chiral succinimides were tested simultaneously by the microbroth dilution method of CLSI against a panel of human opportunistic pathogenic fungi of clinical importance. Chiral succinimides showed higher antifungal activity than the corresponding racemic ones and the differences in activity were established by statistical methods. The bottlenecks for developing chiral drugs are how to obtain them through a low-cost procedure and with high enantiomeric excess. Results presented here accomplish both these objectives, opening an avenue for the development of asymmetric succinimides as new antifungal drugs for pharmaceutical use. PMID- 23676474 TI - Identification of insecticidal constituents of the essential oil of Acorus calamus rhizomes against Liposcelis bostrychophila Badonnel. AB - The aim of this research was to determine the chemical composition of the essential oil of Acorus calamus rhizomes, its insecticidal activity against the booklouse, (Liposcelis bostrychophila) and to isolate any insecticidal constituents from the essential oil. The essential oil of A. calamus rhizomes was obtained by hydrodistillation and analyzed by GC-FID and GC-MS. A total of 32 components of the essential oil of A. calamus rhizomes was identified and the principal compounds in the essential oil were determined to be alpha-asarone (50.09%), (E)-methylisoeugenol (14.01%), and methyleugenol (8.59%), followed by beta-asarone (3.51%), alpha-cedrene (3.09%) and camphor (2.42%). Based on bioactivity-guided fractionation, the three active constituents were isolated from the essential oil and identified as methyleugenol, (E)-methylisoeugenol and alpha-asarone. The essential oil exhibited contact toxicity against L. bostrychophila with an LD50 value of 100.21 ug/cm2 while three constituent compounds, alpha-asarone, methyleugenol, and (E)-methylisoeugenol had LD50 values of 125.73 ug/cm2, 103.22 ug/cm2 and 55.32 ug/cm2, respectively. Methyleugenol and (E)-methylisoeugenol possessed fumigant toxicity against L. bostrychophila adults with LC50 values of 92.21 MUg/L air and 143.43 MUg/L air, respectively, while the crude essential oil showed an LC50 value of 392.13 MUg/L air. The results indicate that the essential oil of A. calamus rhizomes and its constituent compounds have potential for development into natural fumigants/insecticides for control of the booklice. PMID- 23676475 TI - Correlates of isolated nocturnal hypertension and target organ damage in a population-based cohort of African Americans: the Jackson Heart Study. AB - BACKGROUND: African Americans have higher rates of nocturnal hypertension and less nocturnal blood pressure (BP) dipping compared with whites. Although nocturnal hypertension is associated with increased cardiovascular morbidity and mortality, its clinical significance among those with normal daytime BP is unclear. This paper reports the prevalence and correlates of isolated nocturnal hypertension (INH) in a population-based cohort of African Americans enrolled in the Jackson Heart Study (JHS). METHODS: The study sample included 425 untreated, normotensive and hypertensive JHS participants who underwent 24-hour ambulatory BP monitoring (ABPM), echocardiography, and 24-hour urine collection. Multiple logistic regression and 1-way analysis of variance models were used to test the hypothesis that those with INH have worse target organ damage reflected by greater left ventricular (LV) mass and proteinuria compared with normotensive participants. RESULTS: Based on 24-hour ABP profiles, 19.1% of participants had INH. In age and sex-adjusted models, participants with INH had greater LV mass compared with those who were normotensive (P = 0.02), as well as about 3 times the odds of LV hypertrophy and proteinuria (Ps < 0.10). However, multivariable adjustment reduced the magnitude and statistical significance of each of these differences. CONCLUSIONS: INH was associated with increased LV mass compared with normo tension in a population-based cohort of African Americans enrolled in the JHS. There were trends toward a greater likelihood of LV hyper trophy and proteinuria among participants with INH vs. those who were normotensive. The clinical significance of the noted target organ damage should be explored in this population. PMID- 23676476 TI - Effects of a policy-level intervention on children's pedometer-determined physical activity: preliminary findings from Movin' Afterschool. AB - OBJECTIVES: Although evidence supports the benefits of incorporating physical activity (PA) after school and standards for quality after-school programs (ASPs) include PA, evaluation of policies to increase PA after school is nonexistent. The purpose of this study was to examine the effect of an evidence-informed policy-level ASP intervention on youth pedometer-determined PA. DESIGN: This study was a quasi-experimental community-based intervention (Movin' Afterschool), with a pre-/posttest design, without a control. SETTING: Movin' Afterschool took place in the after-school setting. PARTICIPANTS: Participants were children (5-12 years old) attending 1 of 12 ASPs in Nebraska during the fall and spring of 2010 2011. INTERVENTION: Movin' Afterschool was an evidence-informed policy-level intervention. MAIN OUTCOME MEASURES: Physical activity was measured using pedometers. RESULTS: Children averaged 3145 steps per day at baseline and 3042 steps per day at postassessment. There were no effects of sex, body mass index percentile, age, or the interaction of these covariates on steps. Three ASPs experienced substantial declines in PA compared with the remaining 9 ASPs. Excluding these 3 sites, there was an average increase in steps per day in the remaining 9 sites. No significant contribution was observed with the covariates. CONCLUSION: This was the first study to provide evidence for the initial effectiveness of a policy-level intervention on youth PA participation while attending an ASP despite the failed attempt by some ASPs to improve PA. Further research may help determine the following: (1) the amount of support necessary to help ASPs modify their planning to meet policies, and (2) strategies that should be emphasized during staff training to ensure that staff are able to implement PA policies. PMID- 23676477 TI - Physician awareness of enhanced prenatal services for medicaid-insured pregnant women. AB - CONTEXT: Medicaid enhanced prenatal service (EPS) programs, including care coordination, were developed to improve birth outcomes for low-income pregnant women. In Michigan, less than a third of eligible pregnant women are enrolled in services. Physician or medical clinics provide referrals to community-based EPS. OBJECTIVE: The objective of this study was to examine physician knowledge and perceptions of EPS. DESIGN: A cross-sectional survey of obstetric providers was conducted in 2009. A questionnaire was created to assess understanding of the EPS program. SETTING: The study was conducted in an urban Michigan community. PARTICIPANTS: Participants included a convenience sample (N = 56) of community Obstetrics and Gynecology attending physicians and resident physicians within a single, large health system. MAIN OUTCOME MEASURES: Outcome measures included knowledge of the program and patient participation, referral practices, perceptions of the program, value for patients and providers, appropriateness of physicians to provide program referrals, and barriers to referring. RESULTS: Findings indicated that most physicians (84%) had little familiarity with EPS, 60% did not personally refer to EPS, 54% did not know whether other office staff referred to EPS, and 65% were unaware whether their patients received EPS. Yet, more than 90% of physicians reported that EPS would benefit their patients and believed that it was appropriate for them to refer all their eligible patients. CONCLUSION: Further efforts should be made to better understand how physicians and EPS providers could function together on behalf of patients. Statewide Medicaid-sponsored EPS programs could serve as a valuable patient and physician resource for psychosocial risk screening, care management, education, and referral support if better utilized. PMID- 23676478 TI - Long-range air-hole assisted subwavelength waveguides. AB - A novel air-hole assisted metal-dielectric-metal (MDM) waveguide is proposed and demonstrated. The configuration can be considered as a hybrid waveguide combining an MDM waveguide with a photonic crystal waveguide. The results reveal that the figure of merit of the proposed waveguide is as high as 6 * 10(8), the propagation length is 15.2 mm with the lateral mode width between 511.3 and 564.3 nm, and the waveguide isolation is over 36 dB with tiny center-to-center separation at the wavelength of 1.55 MUm. In addition, we also demonstrate its broad optical bandwidth, highly efficient 90 degrees and 120 degrees direct bends, and low radiation loss of the metallic gaps. The above excellent features show that the proposed waveguide could be an ideal candidate for high-density photonic integrations, compared to long-range surface plasmon polariton waveguides and TE-mode MDM waveguides. PMID- 23676479 TI - Surgical treatment of larynx T1N0M0 cancer - partial laryngectomy modified Majer Piquet's intervention. AB - The increase of general radiation background in Georgia and some national characteristics such as spicy dishes, high level of alcohol and cigarette consumption, emotional, loud way of speaking result in a high percentage of people suffering from larynx malignant tumor. As generally known, the majority of larynx cancer cases represent surgical indications and only a small percentage submit to radio or chemotherapy. Since the beginning of the previous century, laryngologists have been intensely thinking about maintaining the larynx itself when giving surgical treatment. With this article we aim to introduce you to one of surgical techniques often applied in France. The method is Pr. B. Guerrier's modification of Majer-Piquet's cricohyoidoepiglotopexy, which is very popular in Europe. This consists in reconstructive operation maintaining cricoid cartilage and epiglottis with larynx's pexy when resecting partially. In cases of exact indications the, Majet-Piquet's modified operation provides a perfect: opportunity both to achieve the desirable outcome and maintain the main functions of larynx vocal, swallowing and breathing with a relatively less invasive surgical interference. PMID- 23676480 TI - [The problem of early detection cervical cancer in republic of Kazakhstan]. AB - Cervical cancer (CC) is the 2nd malignant tumor in Republic of Kazakhstan (RK). The quantity of late stage CC diagnoses remains high. Annual reports (2011-2012) of 19 cytology laboratories were analyzed. Study of the incidences and detection of early forms of cervical cancer screening was conducted. The investigation showed incomplete screening coverage of the female population in Kazakhstan, and a shortage of specialists (Cytopathologists, cytotechnicians). The peculiarities of CC during formal and informal screening were detected. Measures to increase female screening coverage are proposed. Among them creation of a reference laboratory at the national level, adoption of the training methods of the International Academy of Cytology (IAC), periodic testing of cytopathologists, training by specialists from Kazakhstan and experts from IAC. PMID- 23676481 TI - Changes in sex and non-sex hormones and distribution of erythrocyte antigens in reproductive age women with tumors of body of uterus in Adjara. AB - The aim the research was to study the hormonal state of reproductive age women with tumors of body of uterus. The quantitative changes of sex steroid hormones: progesterone (P), estradiol (E), testosterone (T), gonadotropine -Luteinizing hormone (LH) and Follicle-stimulating hormone (FSH) were investigated. Distribution of ABO blood group antigens and Rh-Hr systems genetic variants in the blood of women living in Adjara Region was also studied. For study was used reproductive age women's blood with benign (fibromioma) and malignant (endometrial cancer) tumors of body of uterus (the middle age was 20-45 years). The determination of hormones was made by the enzymatic analysis method (ELAIZA). For the research of blood groups, were used the immunoserologic methods. The study have revealed that in blood of reproductive age women with benign and malignant tumors of body of uterus, level of estradiol was increased while levels of progesterone and testosterone were sharply reduced. Amount of Follicle stimulating hormone and Luteinizing hormone were also increased. It's significant that, both hormones were sharply increased in case of cancer of body of uterus, in comparison with control group and benign tumor. According to distribution of ABO blood group phenotypes - O (I) phenotypic group of ABO system has its highest frequency in blood of women with cancer of body of uterus. Cancer of body of uterus is associated with O (I) phenotypic groups; benign tumor of body of uterus - with A(II) and AB(IV) phenotypic groups. Women with cc and EE genetic variants of Rh-Hr system have sensitivity to the development of benign and malignant tumors of body of uterus; women with ee genetic variant have lower sensitivity towards body of uterus cancer and sharply expressed sensitivity to uterus benign tumors. In women with malignant tumors of body of uterus the frequency of distribution of Rh-Hr system CC genetic variant was sharply reduced. PMID- 23676482 TI - Cytologic, colposcopic and histopathologic correlations of LSIL and HSIL in reproductive and menopausal patients with hyperkeratosis. AB - The significance of hyperkeratotic cells in Pap smear is not yet fully understood. Hyperkeratosis represents benign structural change of cervical squamous epithelium, which may mask displastic lesions and make an accurate colpo cytological examination difficult. We investigated the cytologic, colposcopic and histopathologic correlations of low grade squamous intraepithelial lesion (LSIL) and high grade squamous intraepithelial lesion (HSIL) in hyperkeratotic patients, in order to estimate the influence of hyperkeratosis on the accuracy of cyto colposcopic examination. We examined conventional Pap smears of 766 reproductive and 384 menopausal women. Patients with hyperkeratotic cells in Pap smear were subsequently investigated by colposcopy and in case of colposcopically proved hyperkeratosis, direct biopsy with subsequent histopathological examination of H&E stained sections were performed. LSIL was found in 2,74% and 1,08% of Pap smears, whilst CIN1 was detected in 6,46% and 4,85% of biopsy specimens inreproductive and menopausal women respectively. ASC-H/HSIL were found in 2,74% and 2,71% of Pap smears and CIN2/3 in 4,18% and 7,76% of biopsy specimens in reproductive and menopausal women respectively. The reliability of Pap test significantly decreases under the presence of hyperkeratosis and it must be an indication for colposcopy. In cases of colposcopically proved hyperkeratosis direct biopsy with subsequent histopathological examination must be performed. PMID- 23676483 TI - [Post-operational acute inflammation of an eye in patients with cataracts]. AB - Despite the implementation of the newest highly efficient equipment into the practice of modern clinical ophthalmology, improvement of technical skills of ophthalmologist surgeons, the cases of post-operational acute endophthalmitis development, toxic syndrome of anterior segment of an eye, reactive aseptic inflammatory process are rather negatively reflected in the course of a post operational process of rehabilitation. Under our supervision there were 1100 patients with the senile and complicated cataracts, who underwent operational intervention microcoaxial phacoemulsification. Differential diagnostics was carried out on the basis of the standard objective and subjective methods of research accepted in ophthalmology. On the basis of obtained data is found that clinical symptomatology of autoimmune aseptic anterior uveitis, in particular, the eye inflammation associated with the broken syndrome of an eye anterior chamber-associated immune deviation (ACAID), considerably differs from clinical implications of acute endophthalmitis and a toxic syndrome of the anterior chamber of an eye. In overwhelming majority of cases under the complicated cataracts, precisely the autoimmune aseptic inflammatory process, which originated due to withdrawal of regional immune reactions responsible for ACAID, was observed in postoperative period. PMID- 23676484 TI - [Post-operational acute iridocyclitis and immune shifts in intraocular humor of patients with cataracts]. AB - The negative tendency of cataracts growth, which is a consequence of various diseases of the organism including those of eyes, combined in the concept "the complicated cataract" is clearly traced now. In the concept of such a complication of cataracts as the acute autoimmune iridocyclitis, the important role, in our opinion, should be given to regional immunopathological disorders, which testify to the withdrawal of the known phenomenon underlying in the immunological tolerance of post-barrier eye membrane "a syndrome of eye anterior chamber-associated immune deviation (ACAID). Microcoaxial phacoemulsification was carried in three hundred patients with senile and complicated cataracts. The intraocular humor of the operated patients was subjected to immune-enzyme immunomorphological analysis for SD4, SD8, IgG and B-lymphocytic populations. On the base of performed clinical-laboratory research we found that the gravest inflammatory process in eye tissues manifested in the form of autoimmune aseptic iridocyclitis was observed particularly in patients with complicated cataracts, proceeding on the background of glaucoma, diabetes and the previous trauma of an eye. The high indicators of IgG, SD4 were registered on the background of low SD8 indicators in the intraocular humour at these patients. The revealed regional inflammatory reaction in eye tissues testifies, in our opinion, in favour of in situ withdrawal of ACAID; this latter brings to origination of acute aseptic autoimmune iridocyclitis in the early post-operational course of the complicated cataracts. PMID- 23676485 TI - [Expression of parodontal tissue matrix metalloproteinases-1,2 in adolescent and their role in gingival pathology]. AB - Expression of matrix mettaloproteinases-1,2 were determine immunohistochemistry in gingival mucosa cells in Adolescent groups aged 9-13 and 14-17 years. The material was collected in cohort group of 50 persons. Relative data base - stomatological status in 618 school children aged 9-17 years (304 girls and 314 boys). The MMP-1,2 levels were statistically higher in epitheliocytes, macrophages and capillaries endotheliocytes in all instances not depend on the sex and correlate with mucosa disease activity. It was found that MMP-1,2 expression were higher in prepubertal group. Activity of MMP-1, 2 in gingival mucosa was significantly elevated in female 14-17 years group, than those associated with group 9-13 years. PMID- 23676486 TI - [Role of autoimmune disorders in development of extrahepatic implications of chronic hepatitis C]. AB - The materials received in the course of inspection of 104 patients with chronic hepatitis S are presented in article. In work it is shown that at patients with chronic hepatitis C the wide range of the autoantibodies which frequency of identification and expansion of their range is combined with emergence of biochemical signs and the subsequent clinical manifestation of the admixed cryoglobulinemia, and also accession of other extrahepatic implications is registered. The highest maintenance of the admixed cryoglobulins, rhematoid factor of IgM, circulating immune complexes in blood serum is registered at patients with existence of cliniko-biochemical signs of the HCV associated admixed cryoglobulinemia in combination with other extrahepatic implications. PMID- 23676487 TI - [Prospects of stem cells application in patients with ischemic heart disease (review)]. AB - Coronary heart disease (CHD) is the most common cause of human mortality. Despite of recent advances in the management of CHD (drug treatment, coronary angioplasty and stenting, coronary artery bypass surgery) prognostic estimation of this kind of mortality threatens to increase to the year 2030. Major cause of adversity of CHD is decrease in myocardial contractility which leads to heart failure (HF). HF occurs as a result of myocardial cell ischemic injury or infarction. There is general assumption that recovery of myocardial contractility after tissue injury is not available. This dogma has been changed for the last decade with the introduction of stem cell (SC) therapy in cardiology. Research in this detection (nowadays the phase I-II of research is going on) proved SC therapy safety for human body (no risk of oncogenesis, heart attack or ventricular tachycardia, there is no heart remodeling and no need of coronary revascularization) and efficacy in myocardial contractility improvement (increase of left ventricular ejection fraction). Such positive results were obtained with the use of high dose SC therapy (10 8 cell) and its application the first week of acute myocardial infarction. PMID- 23676488 TI - Subdural empyema due to Escherichia coli and Neisseria meningitides in an immunocompetent infant (a case report). AB - Subdural empyema (SDE) is a focal accumulation of pus between the arachnoid and dura matter. In infants and young children, it is usually attributed to meningitis complications. SDE is considered a serious neurological condition and the culprit is usually a single organism. In rare occasions, polymicrobial is the cause and the organisms involved are, usually streptococci and anaerobe bacteria. A search of the PubMed database was carried out, using a combination of the following terms: subdural empyema , infant, and meningitis. The majority studies conducted on infants mentioned one single organism as the cause of subdural empyema. We are presenting a rare, if not unique, case of subdural empyema in an immunocompetent infant due to an unusual combination of Escherichia coli and Neisseria meningitides. Meningitis is a dynamic disease, and its detrimental consequences could be avoided if diagnosed early. It will be crucial to re-sample the CSF looking for additional organism if a patient with meningitis continues to be febrile, despite antibiotics therapy. Although CSF culture is considered the gold standard in identifying the organism in meningitis, it could be missed due to different reasons including technical flaws. Latex bacterial antigen test could be an indispensable ancillary technique in the diagnosis of meningitis and hence treatment. PMID- 23676489 TI - Inclusion of zinc fortified tea into the children's diet and its hygienicassessment. AB - Micronutrients are nutrients required by humans throughout life in small quantities to orchestrate a whole range of physiological functions, but which the human body itself cannot produce. The most important micronutrients are iron, zinc and iodine. Microelements are essential part of nutrition. Among them particular importance is attached to those micro elements that are comparatively in low quantity in the food (such as iron, iodine), Accordingly occurrence of the iodine deficiency, iron deficiency in adolescents requires particular attention so that they are duly prevented. Monitoring of the nutrition of adolescents in the present none stable economic conditions is absolutely necessary. We have studied the ration of the nutrition of the adolescents and conducted its analysis. The research was conducted in the boarding house among the adolescents (between the ages 11 and 13) in which 36 adolescents participated (22 girls and 14 boys). The results are compared to the norms of physiological requirements of the adolescents taking into account the major substances and energy. Besides that, biochemical monitoring of the Zn requirement in the adolescents has been conducted. Thus results of the clinical assessment of implementing zinc fortified tea in children's diet show convincing amount of zinc statistics in urine analysis and hair. This confirms the efficiency of zinc usage for the correction of its deficiency and convinces us that this product is recommendable for the children's diet. PMID- 23676490 TI - [Pathogenesis of periodontal cell DNA damage during periodontitis]. AB - Objective of our work: To carry out a comparative assessment of the expression level p53 protein and associate it with the degree of DNA damage in inflammation of periodontal disease. The research was conducted on periodontal tissue with signs of inflammation taken from dead patients of Sumy Regional Hospital. The materials were investigated using immunohistochemistry and DNA comet assay. It was established that acute inflammation in the periodontal tissues develop changes leading to DNA damage Acute inflammation is characterized by high levels of p53 Considerable damage to the nuclear DNA is called p53. p53 in apoptosis may include inability to repair. PMID- 23676491 TI - [Study on the separation process of pharmacological active total alkaloids from Chelidonium majus L. growing in Georgia]. AB - In present article was studied the separation process of pharmacological active total alkaloids from Chelidonium majus L. growing in Georgia. Alkaloids were extracted from medicinal herbal material and separated by liquid extraction, diluents gas and a microfiltration through membrane equipment. The obtained A1, A2, A3 fractions were analyzed by GC/MS method; in all cases separation proceeds by the principle of extraction of the target alkaloids. It was concluded that the A1 is enriched with alpha and beta cryptopins, and protopin, but homochelidonine and chelidonine are in low contents. As accompanying alkaloid is identified dihydrosanguinarine as an artifact; the A2 is enriched with the maximum contents of stylopine and protopin, but the poor contents of chelidonine and homochelidonine; the A3 is enriched with alpha and beta cryptopins and maximum content of chelidonine. Extraction of alkaloids from Chelidonium majus L. proceeds selectively, but depending on a way of separation of the total alkaloids allows varying qualitative and quantitative consistence of the final product. PMID- 23676492 TI - [Identification of originality of constituents of the tablets containing medical herbs]. AB - In the article are shown the results of development of methods for identification of originality of aqueous extract s obtained from herbs with medical properties ingressed in multicomponent phyto preparations. During provided research were developed different methods of evaluation of identity of herbal aqueous extracts with poorly known structure in complex tablets. These methods could be introduced in practice for reliable evaluation of qualitative composition of multicomponent phyto preparations, containing aqueous extract s of herbs studded in this work. Monitoring of qualitative composition of phyto preparations during production and in the phase of marketing will promote further rise of efficacy and safety of remedy. We demonstrate the results of the work aimed to develop the methods for identification of originality of aqueous extracts obtained from herbs with medical properties ingressed in multicomponent phyto preparations. PMID- 23676493 TI - [Development of technology, of rheological and biopharmaceutical properties of new gel]. AB - The purpose of this research is the development of technology for preparation of hydrogel Glysotrical and study its rheological and biopharmaceutical characteristics. Based on gel-forming chitosan, PEG-400, glycerol and Tween-80 a new composition of hydrogel - Glysotrical was developed. Rheological properties of Glysotrical, as well as biopharmaceutical properties of artificial (cellophane) and natural membrane (chicken and pork skin) were investigated by dialysis. Rheological properties of different concentrations of chitosan solution and gel Glysotrical prepared on their basis were studied. It was determined that gel derived from the 5% solution of chitosan meets the technological requirements (pH-5,5-6,0, melting point-75,0+/-1,07 degrees C, dynamic viscosity - 890,6 +/- 3,57 cps). Rheological properties of the hydrogel Glysotrical, prepared on the basis of a multi-component composition in different temperatures (20, 40, 60 degrees C) were identified. It was found that shear of helium drug (458 H/m2, 355 H/m2) at 20 degrees and 40 degrees C is lower, and the value of dynamic viscosity (912spz, 602spz) higher than that of chitosan gel; the hydrogel is stable at 20 degrees and 40 degrees C. High kinetic activity of hydrogel with Tween-80 is observed. During 5 hours membrane maximum quantity of routine diffusion from helium mass into dialysate in cellophane is 57,54 +/-0,51%; in normal skin chicken - 20,04+/-0,55%; in the skin of chicken treated with 2% citric acid - 23,14+/-0,45%; normal pig skin - 12,64+/-0,09%; in the skin of pigs, treated with acid - 15,08+/- 0,11%. The study showed that the gel Glysotrical at 10-22 degrees C is maintained for 2 years. Physico-chemical, rheological, technological and biopharmaceutical research showed that 4% gel Glysotrical was good in treatment of dermatological diseases. PMID- 23676494 TI - The etymological role of the main atmosphere pollutants in development of human diseases. AB - The aim of research was monitoring of the main atmospheric air pollutants concentration on Adjara Autonomous Republic territory in order to determine their role in causing different diseases. The following atmospheric air pollutants have been determined in Batumi: dust, carbon monoxide, sulfur and nitrogen dioxide. The number of diseases registered in Adjara Autonomous Republic, which may be linked to the air pollution, has been studied. These are the following: chronic and nonspecific bronchitis, asthma and asthma status diseases, allergic rhinitis, trachea-, bronchi- and lung malignant tumor. In order to reduce the number of risk-factors significant attention should be paid to the proper functionality of the vehicles and systematic observations should continue on the chemical pollution of the air to make proper decisions to reduce the number of diseases. PMID- 23676495 TI - Apolipoproteins E and AV mediate lipoprotein clearance by hepatic proteoglycans. AB - The heparan sulfate proteoglycan (HSPG) syndecan-1 (SDC1) acts as a major receptor for triglyceride-rich lipoprotein (TRL) clearance in the liver. We sought to identify the relevant apolipoproteins on TRLs that mediate binding to SDC1 and determine their clinical relevance. Evidence supporting ApoE as a major determinant arose from its enrichment in TRLs from mice defective in hepatic heparan sulfate (Ndst1f/fAlbCre+ mice), decreased binding of ApoE-deficient TRLs to HSPGs on human hepatoma cells, and decreased clearance of ApoE-deficient [3H]TRLs in vivo. Evidence for a second ligand was suggested by the faster clearance of ApoE-deficient TRLs after injection into WT Ndst1f/fAlbCre- versus mutant Ndst1f/fAlbCre+ mice and elevated fasting and postprandial plasma triglycerides in compound Apoe-/-Ndst1f/fAlbCre+ mice compared with either single mutant. ApoAV emerged as a candidate based on 6-fold enrichment of ApoAV in TRLs accumulating in Ndst1f/fAlbCre+ mice, decreased binding of TRLs to proteoglycans after depletion of ApoAV or addition of anti-ApoAV mAb, and decreased heparan sulfate-dependent binding of ApoAV-deficient particles to hepatocytes. Importantly, disruption of hepatic heparan sulfate-mediated clearance increased atherosclerosis. We conclude that clearance of TRLs by hepatic HSPGs is atheroprotective and mediated by multivalent binding to ApoE and ApoAV. PMID- 23676496 TI - Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism. AB - The mechanisms involved in the coordinate regulation of the metabolic and structural programs controlling muscle fitness and endurance are unknown. Recently, the nuclear receptor PPARbeta/delta was shown to activate muscle endurance programs in transgenic mice. In contrast, muscle-specific transgenic overexpression of the related nuclear receptor, PPARalpha, results in reduced capacity for endurance exercise. We took advantage of the divergent actions of PPARbeta/delta and PPARalpha to explore the downstream regulatory circuitry that orchestrates the programs linking muscle fiber type with energy metabolism. Our results indicate that, in addition to the well-established role in transcriptional control of muscle metabolic genes, PPARbeta/delta and PPARalpha participate in programs that exert opposing actions upon the type I fiber program through a distinct muscle microRNA (miRNA) network, dependent on the actions of another nuclear receptor, estrogen-related receptor gamma (ERRgamma). Gain-of function and loss-of-function strategies in mice, together with assessment of muscle biopsies from humans, demonstrated that type I muscle fiber proportion is increased via the stimulatory actions of ERRgamma on the expression of miR-499 and miR-208b. This nuclear receptor/miRNA regulatory circuit shows promise for the identification of therapeutic targets aimed at maintaining muscle fitness in a variety of chronic disease states, such as obesity, skeletal myopathies, and heart failure. PMID- 23676497 TI - Endocytosis of synaptic ADAM10 in neuronal plasticity and Alzheimer's disease. AB - A disintegrin and metalloproteinase 10 (ADAM10), a disintegrin and metalloproteinase that resides in the postsynaptic densities (PSDs) of excitatory synapses, has previously been shown to limit beta-amyloid peptide (Abeta) formation in Alzheimer's disease (AD). ADAM10 also plays a critical role in regulating functional membrane proteins at the synapse. Using human hippocampal homogenates, we found that ADAM10 removal from the plasma membrane was mediated by clathrin-dependent endocytosis. Additionally, we identified the clathrin adaptor AP2 as an interacting partner of a previously uncharacterized atypical binding motif in the ADAM10 C-terminal domain. This domain was required for ADAM10 endocytosis and modulation of its plasma membrane levels. We found that the ADAM10/AP2 association was increased in the hippocampi of AD patients compared with healthy controls. Long-term potentiation (LTP) in hippocampal neuronal cultures induced ADAM10 endocytosis through AP2 association and decreased surface ADAM10 levels and activity. Conversely, long-term depression (LTD) promoted ADAM10 synaptic membrane insertion and stimulated its activity. ADAM10 interaction with the synapse-associated protein-97 (SAP97) was necessary for LTD-induced ADAM10 trafficking and required for LTD maintenance and LTD induced changes in spine morphogenesis. These data identify and characterize a mechanism controlling ADAM10 localization and activity at excitatory synapses that is relevant to AD pathogenesis. PMID- 23676499 TI - Acylglycerol kinase augments JAK2/STAT3 signaling in esophageal squamous cells. AB - JAK2 activity is tightly controlled through a self-inhibitory effect via its JAK homology domain 2 (JH2), which restricts the strength and duration of JAK2/STAT3 signaling under physiological conditions. Although multiple mutations within JAK2, which abrogate the function of JH2 and sustain JAK2 activation, are widely observed in hematological malignancies, comparable mutations have not been detected in solid tumors. How solid tumor cells override the autoinhibitory effect of the JH2 domain to maintain constitutive activation of JAK2/STAT3 signaling remains puzzling. Herein, we demonstrate that AGK directly interacted with the JH2 domain to relieve inhibition of JAK2 and activate JAK2/STAT3 signaling. Overexpression of AGK sustained constitutive JAK2/STAT3 activation, consequently promoting the cancer stem cell population and augmenting the tumorigenicity of esophageal squamous cell carcinoma (ESCC) cells both in vivo and in vitro. Furthermore, AGK levels significantly correlated with increased STAT3 phosphorylation, poorer disease-free survival, and shorter overall survival in primary ESCC. More importantly, AGK expression was significantly correlated with JAK2/STAT3 hyperactivation in ESCC, as well as in lung and breast cancer. These findings uncover a mechanism for constitutive activation of JAK2/STAT3 signaling in solid tumors and may represent a prognostic biomarker and therapeutic target. PMID- 23676498 TI - BMPR2 is required for postimplantation uterine function and pregnancy maintenance. AB - Abnormalities in cell-cell communication and growth factor signaling pathways can lead to defects in maternal-fetal interactions during pregnancy, including immunologic rejection of the fetal/placental unit. In this study, we discovered that bone morphogenetic protein receptor type 2 (BMPR2) is essential for postimplantation physiology and fertility. Despite normal implantation and early placental/fetal development, deletion of Bmpr2 in the uterine deciduae of mice triggered midgestation abnormalities in decidualization that resulted in abnormal vascular development, trophoblast defects, and a deficiency of uterine natural killer cells. Absence of BMPR2 signaling in the uterine decidua consequently suppressed IL-15, VEGF, angiopoietin, and corin signaling. Disruption of these pathways collectively lead to placental abruption, fetal demise, and female sterility, thereby placing BMPR2 at a central point in the regulation of several physiologic signaling pathways and events at the maternal-fetal interface. Since trophoblast invasion and uterine vascular modification are implicated in normal placentation and fetal growth in humans, our findings suggest that abnormalities in uterine BMPR2-mediated signaling pathways can have catastrophic consequences in women for the maintenance of pregnancy. PMID- 23676500 TI - Endothelin-2 deficiency causes growth retardation, hypothermia, and emphysema in mice. AB - To explore the physiological functions of endothelin-2 (ET-2), we generated gene targeted mouse models. Global Et2 knockout mice exhibited severe growth retardation and juvenile lethality. Despite normal milk intake, they suffered from internal starvation characterized by hypoglycemia, ketonemia, and increased levels of starvation-induced genes. Although ET-2 is abundantly expressed in the gastrointestinal tract, the intestine was morphologically and functionally normal. Moreover, intestinal epithelium-specific Et2 knockout mice showed no abnormalities in growth and survival. Global Et2 knockout mice were also profoundly hypothermic. Housing Et2 knockout mice in a warm environment significantly extended their median lifespan. However, neuron-specific Et2 knockout mice displayed a normal core body temperature. Low levels of Et2 mRNA were also detected in the lung, with transient increases soon after birth. The lungs of Et2 knockout mice showed emphysematous structural changes with an increase in total lung capacity, resulting in chronic hypoxemia, hypercapnia, and increased erythropoietin synthesis. Finally, systemically inducible ET-2 deficiency in neonatal and adult mice fully reproduced the phenotype previously observed in global Et2 knockout mice. Together, these findings reveal that ET-2 is critical for the growth and survival of postnatal mice and plays important roles in energy homeostasis, thermoregulation, and the maintenance of lung morphology and function. PMID- 23676503 TI - Analysis of axial prestretch in the abdominal aorta with reference to post mortem interval and degree of atherosclerosis. AB - It is a well-known fact that the length of an artery in situ and the length of an excised artery differs. Retraction of blood vessels is usually observed. This prestretch plays an important role in arterial physiology. We have recently determined that the decrease of axial prestretch in the human abdominal aorta is so closely correlated with age that it is suitable for forensic applications (estimation of the age at time of death for cadavers of unknown identity). Since post mortem autolysis may affect the reliability of an estimate based on axial prestretch, the present study aims to detail analysis of the effect of post mortem time. The abdominal aorta is a prominent site of atherosclerotic changes (ATH), which may potentially affect longitudinal prestretch. Thus ATH was also involved in the analysis. Axial prestretch in the human abdominal aorta, post mortem interval (PMI), and the degree of ATH were documented in 365 regular autopsies. The data was first age adjusted to remove any supposed correlation with age. After the age adjustment of the sample, the correlation analysis showed no significant PMI effects on the prestretch in non-putrefied bodies. Analysis of the prestretch variance with respect to ATH suggested that ATH is not a suitable factor to explain the prestretch variability remaining after the age adjustment. It was concluded that, although atherosclerotic plaques may certainly change the biomechanics of arteries, they do not significantly affect the longitudinal prestretch in the human abdominal aorta. PMID- 23676501 TI - Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs. AB - Cystic fibrosis (CF) pigs develop disease with features remarkably similar to those in people with CF, including exocrine pancreatic destruction, focal biliary cirrhosis, micro-gallbladder, vas deferens loss, airway disease, and meconium ileus. Whereas meconium ileus occurs in 15% of babies with CF, the penetrance is 100% in newborn CF pigs. We hypothesized that transgenic expression of porcine CF transmembrane conductance regulator (pCFTR) cDNA under control of the intestinal fatty acid-binding protein (iFABP) promoter would alleviate the meconium ileus. We produced 5 CFTR-/-;TgFABP>pCFTR lines. In 3 lines, intestinal expression of CFTR at least partially restored CFTR-mediated anion transport and improved the intestinal phenotype. In contrast, these pigs still had pancreatic destruction, liver disease, and reduced weight gain, and within weeks of birth, they developed sinus and lung disease, the severity of which varied over time. These data indicate that expressing CFTR in intestine without pancreatic or hepatic correction is sufficient to rescue meconium ileus. Comparing CFTR expression in different lines revealed that approximately 20% of wild-type CFTR mRNA largely prevented meconium ileus. This model may be of value for understanding CF pathophysiology and testing new preventions and therapies. PMID- 23676504 TI - Integrins-FAK-Rho GTPases pathway in endothelial cells sense and response to surface wettability of plasma nanocoatings. AB - Vascular endothelial cell (EC) adhesion and migration are essential processes in re-endothelialization of implanted biomaterials, which are affected by surface properties of implanted materials such as surface wettability. Our previous study demonstrated that, as model substrates, EC adhesion/migration showed an opposite behavior on the hydrophobic and hydrophilic surfaces of plasma SiOx:H nanocoatings. Extending our previous works, the expression and distribution of crucial proteins in integrins-FAK-Rho GTPases signaling pathways were examined, respectively. The results showed that a hydrophilic surface could enhance the expression of focal adhesion protein associated with cell adhesion; however, the hydrophobic surface could improve the expression of Rho GTPases associated with cell migration and phosphorylation level of FAK, revealing the potential reason of surface wettability mediating different cells' adhesion/migration behaviors. These findings reveal the relationship and molecular mechanism of endothelial cell adhesion/migration, which was expected to guide the surface modification of implants for accelerating endothelialization. PMID- 23676502 TI - CXCR4 downregulation of let-7a drives chemoresistance in acute myeloid leukemia. AB - We examined the role of microRNAs (miRNAs) in targeting the stromal-derived factor 1alpha/CXCR4 (SDF-1alpha/CXCR4) axis to overcome chemoresistance of AML cells. Microarray analysis of OCI-AML3 cells revealed that the miRNA let-7a was downregulated by SDF-1alpha-mediated CXCR4 activation and increased by CXCR4 inhibition. Overexpression of let-7a in AML cell lines was associated with decreased c-Myc and BCL-XL protein expression and enhanced chemosensitivity, both in vitro and in vivo. We identified the transcription factor Yin Yang 1 (YY1) as a link between SDF-1alpha/CXCR4 signaling and let-7a, as YY1 was upregulated by SDF-1alpha and downregulated by treatment with a CXCR4 antagonist. ChIP assay confirmed the binding of YY1 to unprocessed let-7a DNA fragments, and treatment with YY1 shRNA increased let-7a expression. In primary human AML samples, high CXCR4 expression was associated with low let-7a levels. Xenografts of primary human AML cells engineered to overexpress let-7a exhibited enhanced sensitivity to cytarabine, resulting in greatly extended survival of immunodeficient mice. Based on these data, we propose that CXCR4 induces chemoresistance by downregulating let-7a to promote YY1-mediated transcriptional activation of MYC and BCLXL in AML cells. PMID- 23676505 TI - Methotrexate therapy leading to a rapid progression of a previously indolent prostate cancer: is immunosuppression to blame? AB - Methotrexate therapy has been associated with occurrence and/or accelerated progression of malignancies. We describe a patient who developed widespread bone metastases of a previously confined to the prostate gland prostate cancer shortly after starting methotrexate therapy for rheumatoid arthritis and large granular lymphocyte leukemia. We believe an immunosuppressive milieu brought on by the methotrexate use in this case is responsible for the rapid progression of prostate cancer leading to the patient's demise. To the best of our knowledge, no association has been made to date between the therapy with methotrexate and a fulminant course of a previously indolent prostate cancer. Given its utilization in a variety of benign and malignant conditions and the ageing population, caution is advised with the use of this agent, especially in the presence of an underlying malignancy. PMID- 23676506 TI - GCSF with or without chemotherapy compared to Plerixafor with GCSF as salvage mobilization regimen in patients with multiple myeloma and lymphoma: collection effectiveness and cost effectiveness analysis. AB - INTRODUCTION: Plerixafor is a novel mobilizing agent of peripheral blood stem cells (PBSCs) in lymphoma and multiple myeloma (MM) patients whose cells mobilize poorly. Due to the substantial cost associated with its use, we aimed to compare the effectiveness and cost effectiveness of Plerixafor + GCSF (PG) versus GCSF +/ Chemotherapy (GC) as salvage mobilization regimens. METHODS: The charts of consecutive lymphoma and MM patients who had undergone at least one previous attempt of PBSCs mobilization that failed or resulted in an insufficient cell dose for transplant between 2007 and 2010 were retrospectively reviewed. Patients identified received salvage mobilization with GC (prior to 2009) or PG after Plerixafor's FDA approval. Data collected included demographics, medical histories, apheresis yields and transplant outcome. The cost effectiveness analysis was from the perspective of the Jordanian Ministry of Health. The incremental cost effectiveness ratio (ICER) was calculated by dividing the difference in cost by the difference in effectiveness for the two regimens. RESULTS: Five patients received GC and twelve received PG. A minimum CD34+ cell dose of 2 * 10(6) cells/kg was collected from 8 patients (67%) in the PG group compared to 3 (60%) in the GC group (p=0.79). The average costs were US$8570 and US$25,700 for the GC group and the PG group, respectively. The ICER was US$244,714 per successful stem cell collection. CONCLUSION: Salvage Plerixafor use showed a non-significant improvement in PBSCs collection with a significant increase in cost. Prospective comparative effectiveness studies are warranted to inform the optimal salvage mobilization regimen. To our knowledge, this is the first study from the Middle East to describe the effectiveness and cost effectiveness of Plerixafor. PMID- 23676507 TI - Isotretinoin maintenance therapy for glioblastoma: a retrospective review. AB - OBJECTIVES: The current standard treatment of glioblastoma includes maximal safe surgical resection, radiation, and temozolomide. Although isotretinoin has been used for maintenance therapy to delay tumor recurrence, this approach has not been proven to be effective. The objectives of the study are to compare the overall survival, progression-free survival and tolerability of isotretinoin maintenance therapy in patients who received isotretinoin maintenance therapy to patients who did not receive this treatment. METHODS: This study is a retrospective review of adult patients with glioblastoma treated at MD Anderson Cancer Center from 2004 to 2009. Patients who underwent surgical resection, radiation with concurrent temozolomide, and adjuvant treatment with temozolomide were included in the control group, and compared to similarly treated patients who received isotretinoin maintenance following adjuvant temozolomide. RESULTS: Eighteen patients who received isotretinoin maintenance therapy and 70 control patients were included in the analysis. Progression-free survival was 25.3 months with maintenance therapy versus 8.3 months for those not receiving maintenance (p = 0.04). There was no difference in the 2-year or 3-year overall survival estimates (p = 0.11). The common toxicities of isotretinoin included dermatologic , metabolic-, and psychiatric-related adverse effects. CONCLUSIONS: Isotretinoin maintenance therapy was associated with increased progression-free survival, but did not increase the overall survival in this retrospective review. The potential benefit of maintenance therapy should be weighed against toxicities and negative impact on quality of life in this patient population. PMID- 23676508 TI - Complete response and long-term remission to anti-HER2 combined therapy in a patient with breast cancer presented with bone marrow metastases. AB - Presentation with bone marrow metastasis at diagnosis is a rare event in breast carcinoma. Here, we report a rare presentation of metastatic breast cancer patient with bone marrow metastases, who was successfully treated with trastuzumab combined chemotherapy. The regimens initially applied for bone marrow metastasis were docetaxel/adriamycin, gemcitabine/vinorelbine, epirubicin/cyclophosphamide, capecitabine, docetaxel, gemcitabine, and paclitaxel. But, the best response to these regimens was not satisfactory. Our patient was completely treated with etoposide-cisplatin and trastuzumab combination. She is still on remission after five years of metastatic breast cancer diagnosis using letrozole and trastuzumab without complication. Physicians should be careful in treating bone marrow metastases in breast cancer, since patients can show improved marrow function after chemotherapy and long-lasting survival is possible. PMID- 23676509 TI - Soft tissue calcification secondary to imatinib mesylate in a patient with gastrointestinal stromal tumor. AB - Imatinib mesylate has been associated with the changes in bone turnover. We report a case of the development of tissue calcification in a patient on long term therapy with this drug. A 48-year-old male patient with gastrointestinal stromal tumor and liver metastasis complained of abdominal pain. His treatment included hepatic artery chemoembolization and partial hepatectomy in addition to chronic imatinib mesylate for 4 years. On physical examination, he had a peritoneal mass just beneath the laparotomy incision scar that, after resection, was found to be dystrophic bone formation. Based on the previous studies suggesting bone changes due to chronic therapy with imatinib mesylate, we believe that the patient's new bone formation was causally related to the use of this drug. To our knowledge, there are no similar reported cases in the literature. PMID- 23676510 TI - Pilot study to assess toxicity and pharmacokinetics of docetaxel in patients with metastatic breast cancer and impaired liver function secondary to hepatic metastases. AB - BACKGROUND: Limited clinical data are available regarding the safety of docetaxel in metastatic breast cancer patients with liver dysfunction. METHODS: Eligible patients had breast cancer with impaired liver function secondary to hepatic metastases and were candidates for docetaxel therapy. They were assigned to one of five groups on the basis of total bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase levels. All other causes of liver dysfunction were excluded, and bile duct obstruction was corrected, if possible, prior to study entry. Patients received docetaxel every three weeks. The chemotherapy dose was chosen on the basis of the patient's level of hepatic dysfunction and escalated as tolerated. The primary outcome of this study was safety. The secondary outcomes were pharmacokinetic data and efficacy in terms of time to disease progression. RESULTS: Twenty-three patients were enrolled. No unexpected toxicities occurred. Grade 3/4 fatigue (65%), neutropenia (30%), myalgias (26%), neutropenic fever (26%), vomiting (9%), and rash (9%) were the most common serious adverse events. The median time to progression was three months (range 1-18 months). Pharmacokinetic results indicated that patients with more severe hepatic dysfunction may have been underdosed based on our conservative dosing strategy. CONCLUSIONS: Docetaxel can be administered to patients with metastatic breast cancer and liver dysfunction after dose attenuation. However, because of a narrow therapeutic index in this clinical setting, therapy should be closely monitored with subsequent dose escalation when possible. PMID- 23676511 TI - Determination of the external contamination and cross-contamination by cytotoxic drugs on the surfaces of vials available on the Swiss market. AB - INTRODUCTION: The external contamination and cross-contamination by cytotoxic drugs on the surface (outside and septum) of 133 vials from various manufacturers and available on the Swiss market were evaluated. All of the tested vials contained one of the following active ingredients: cyclophosphamide, cytarabine, doxorubicin, epirubicin, etoposide phosphate, gemcitabine, ifosfamide, irinotecan, methotrexate or vincristine. METHODS AND MATERIALS: The validated wiping liquid chromatography-mass spectrometry method used in this study allowed for the simultaneous determination of these 10 cytotoxic drugs in less than 30 min. RESULTS: External contamination by cytotoxic drugs was detected on 63% of tested vials (outside and septum). The highest contamination level was observed on etoposide phosphate vials with 1896.66 ng of active ingredient on the outside of the vial. Approximately 20% of the contaminated vials had greater than 10 ng of cytotoxic drugs. Chemical contamination on the septum was detected on 38% of the vials. No contamination or very low levels of cytotoxic drugs, less than 1 ng per vial, were detected on the vials protected by plastic shrink-wrap. Traces of cytotoxic drugs different from the active ingredient were detected on 35% of the tested vials. CONCLUSION: Handling cytotoxic vials with gloves and having a procedure for the decontamination of vials are of the utmost importance for reducing exposure to cytotoxic drugs. Moreover, manufacturers must improve their procedures to provide products free from any contamination. PMID- 23676512 TI - Cutaneous leukocytoclastic vasculitis associated with letrozole. AB - Aromatase inhibitors are increasingly used in the treatment of early and metastatic breast cancer. They can produce various skin adverse effects but are only rarely associated with cutaneous vasculitis. We report the first case of cutaneous vasculitis clearly associated with the use of aromatase inhibitor letrozole. PMID- 23676513 TI - Physical and chemical stability of reconstituted and diluted dexrazoxane infusion solutions. AB - BACKGROUND AND PURPOSE: Dexrazoxane is used clinically to prevent anthracycline associated cardiotoxicity. Hydrolysis of dexrazoxane prior to reaching the cardiac membranes severely hampers its mode of action; therefore, degradation during the preparation and administration of intravenous dexrazoxane admixtures demands special attention. Moreover, the ongoing national shortage of one dexrazoxane formulation in the United States has forced pharmacies to dispense other commercially available dexrazoxane products. However, the manufacturers' limited stability data restrict the flexibility of dexrazoxane usage in clinical practice. The aims of this study are to determine the physical and chemical stability of reconstituted and diluted solutions of two commercially available dexrazoxane formulations. METHODS: The stability of two dexrazoxane products, brand and generic name, in reconstituted and intravenous solutions stored at room temperature without light protection in polyvinyl chloride bags was determined. The concentrations of dexrazoxane were measured at predetermined time points up to 24 h using a validated reversed phase high-performance liquid chromatography with ultraviolet detection assay. RESULTS: Brand (B-) and generic (G-) dexrazoxane products, reconstituted in either sterile water or 0.167 M sodium lactate (final concentration of 10 mg/mL), were found stable for at least to 8 h. Infusion solutions of B-dexrazoxane, prepared according to each manufacturer's directions, were stable for at least 24 h and 8 h at 1 mg/mL and 3 mg/mL, respectively. Infusion solutions of G-dexrazoxane, prepared in either 5% dextrose or 0.9% sodium chloride following the manufacturer's guidelines, were also stable for at least 24 h and 8 h at 1 mg/mL and 3 mg/mL, respectively. All tested solutions were found physically stable up to 24 h at room temperature. CONCLUSION: The stability of dexrazoxane infusion solutions reported herein permits advance preparation of dexrazoxane intravenous admixtures, facilitating pharmacy workflow and clinical operations. However, due to the potential risks of fluid overload when these intravenous solutions are administered to patients, caution is advised to ensure patient safety. PMID- 23676514 TI - Three mini-incision double-eyelid blepharoplasty. AB - Although there are many procedures reported in the literature regarding the partial incision double-eyelid blepharoplasty, the current methods still have potential problems such as unstable and limitation of application. In this study, the authors developed a 3-mini-incision technique that minimizes tissue injury and provides a tough connection between the levator aponeurosis and skin. With this method, 3 minute incisions (3-4 mm) are made in the upper eyelid. Through these incisions, the whole strip of pretarsal orbicularis oculi muscle under the inferior incision line and the excessive fat can be removed. This technique gives a stable and natural-looking supratarsal fold, with invisible scar, minimal complications, and a short recovery period; and can be applied to patients with fatty eyelids. This method has the benefits of both nonincisional and full incisional techniques, and avoids the disadvantages of the current partial incisional methods. PMID- 23676515 TI - Equine pericardium membrane to prevent dorsal irregularities in rhinoplasty. AB - Even after a well-executed rhinoplasty, small dorsal irregularities are not uncommon. Many materials have been used for camouflage, including autologous, homologous, and alloplastic materials. We used an equine pericardium membrane in 33 postrhinoplasty patients to prevent or correct nasal dorsal irregularities. The membrane promotes a local fibrous reaction, which leaves a uniform connective layer. In our hands, equine pericardium membrane seems to be a useful material for rhinoplasty refinements. PMID- 23676517 TI - Long-term outcomes of failed prosthetic breast reconstruction. AB - INTRODUCTION: For patients undergoing prosthetic breast reconstruction whose device was removed because of infection or exposure, there is no published information examining long-term outcomes. Despite initial failure, many patients want to pursue breast reconstruction. METHODS: A retrospective review was performed of immediate prosthetic breast reconstruction failures during a 5-year period. RESULTS: A total of 26 patients (29 breasts) were identified who failed primary prosthetic 2-stage reconstruction. On average, the device was removed 262 days from the initial expander placement. Of these breasts, 19 were removed for infection, 7 for exposure, and 3 for a combination of both. Of these 29 failures, secondary reconstruction was attempted in 20 (69%). Among secondary reconstructions, 13 were with a device and 7 with autologous tissue. Of the 13 (92.3%) secondary device reconstructions, 12 were successful.Those in whom secondary reconstruction was attempted were younger at initial reconstruction (48 vs 57 years; P = 0.038), had lower body mass indexes (BMIs) (26.0 vs 29.4; P = 0.27), and smaller breasts (650 vs 979 g; P = 0.23) than those who did not attempt secondary reconstruction.Of the nipple-sparing mastectomy patients, 100% underwent secondary reconstruction, whereas only 61% of skin-sparing mastectomy patients underwent secondary reconstruction (P = 0.14).For patients undergoing secondary reconstruction, those receiving a second device reconstruction had lower BMIs (24.7 vs 28.5; P = 0.18) and smaller breasts (489 vs 946 g; P = 0.08) than those with autologous reconstructions; 15% of secondary implant reconstructions underwent irradiation versus 43% of the secondary autologous reconstructions (P = 0.29). CONCLUSIONS: After failed prosthetic breast reconstruction, a second attempt with an implant in properly selected patients has a high success rate (92.3%). PMID- 23676519 TI - Parry-Romberg reconstruction: beneficial results despite poorer fat take. AB - OBJECTIVE: For the treatment of Parry-Romberg syndrome or progressive hemifacial atrophy, we studied the volume retention and skin changes after autologous fat grafts within diseased regions. SUMMARY BACKGROUND DATA: The long-term survival and volume retention of fat grafts used in soft tissue reconstruction of Parry Romberg syndrome is still unknown, as are skin changes after fat grafting. METHODS: Sex, age, severity of deformity, number of procedures, operative times, and augmentation volumes were recorded. Preoperative/postoperative 3-dimensional computed tomographic scans were also reviewed. A digital 3-dimensional photogrammetry system was used to determine "final fat take" and symmetry. Romberg fat grafting volumes were compared to nonaffected, cosmetic fat-grafted patients. For skin changes, a spectrophotometer was used to quantify percent improvement in melanin index. Physician and patient satisfaction surveys (5-point scale) were elicited, including overall outcome and skin color/texture. RESULTS: The mean number of procedures correlated to the severity of deformity: mild, 1.8 procedures; moderate, 3.4; and severe, 5.2. With Romberg patients, fat grafting injected: per case, 48 mL; total, 188 mL; and final measured volume, 101 mL. Romberg patients had less "fat take" than nonaffected grafted patients (final take, 41% vs 81%). Skin color/texture showed 3-fold improvement after fat grafting procedures. The mean melanin index improvement seen in the diseased regions of Romberg patients after fat grafting was 42% (+3%). Skin color and texture improvement was also shown in patient surveys (preoperative = 2.4 + 0.06 to follow-up = 3.4 + 0.09) and physician (preoperatively = 2.1 + 0.1 to follow-up = 3.6 + 0.1). CONCLUSIONS: Despite poorer fat graft take within the disease region of Romberg patients, fat grafting resulted in long-term improvement in hypoplasia and skin hyperpigmentation. PMID- 23676520 TI - Latissimus dorsi donor-site morbidity: the combination of quilting and fibrin sealant reduce length of drain placement and seroma rate. PMID- 23676521 TI - Do patients with Pierre Robin sequence have worse outcomes after cleft palate surgery? AB - BACKGROUND: Pierre Robin sequence (PRS) is a congenital condition characterized by micrognathia, glossoptosis, airway obstruction, and often clefting of the soft and hard palate. The purpose of this study was to compare oronasal fistula rates, long-term speech outcomes, and rates of secondary surgery for velopharyngeal insufficiency (VPI) after primary cleft palate repair using the modified Furlow technique between nonsyndromic patients with and without PRS. This study also sought to determine if type of airway management in infancy correlated with speech outcomes in patients with PRS. METHODS: A retrospective review was performed of all nonsyndromic patients with clefts of the palate only who underwent repair between 1981 and 2006 at The Children's Hospital of Philadelphia using the modified Furlow technique. Patient outcomes were evaluated by the rate of postoperative oronasal fistula, speech scores at a minimum of age 5 years using the Pittsburgh Weighted Values for Speech Symptoms Associated with VPI, and the need for secondary pharyngeal surgery for VPI. RESULTS: Fifty-five patients with PRS and 129 without PRS were included in this study. There was no significant difference in oronasal fistula rate between groups. Speech outcomes were worse in patients with PRS with 52.7% demonstrating a competent velopharyngeal mechanism, and 30.9% a borderline mechanism, compared to 72.1% and 19.4% in the non-PRS group, respectively (P = 0.035). In addition, only 76.3% of patients with PRS had no or mild hypernasality compared to 91.5% of patients without PRS (P = 0.01). The rates of nasal emission, articulation errors associated with VPI, and secondary surgery for VPI did not differ between groups. Of the patients with PRS, 36 were managed in infancy with positioning alone and 15 underwent surgical intervention for airway obstruction, and there were no significant differences in speech scores or rates of secondary surgery for VPI between these subgroups. CONCLUSIONS: Nonsyndromic patients with PRS had worse speech outcomes after modified Furlow cleft palate repair, but no significant differences were seen in the rates of secondary surgery for VPI or postoperative oronasal fistula. In addition, initial airway management in patients with PRS did not correlate with speech outcomes. PMID- 23676522 TI - Hair transplantation on a free microvascular latissimus dorsi flap: case report. AB - Large scalp defects can present as a challenging clinical problem for a reconstructive surgeon. We present a patient with a large scalp defect following an infection after neurosurgical treatment. Reconstruction of a defect was performed using a free latissimus dorsi flap with split-thickness skin graft. For achieving good aesthetic result, we transplanted 1000 minigrafts in 3 sessions on the latissimus dorsi flap. In our opinion, hair transplantation on a free microvascular flap is a viable and easy procedure with good aesthetic outcome for treating residual alopecia after reconstructing large scalp defects. PMID- 23676524 TI - Catastrophic antiphospholipid syndrome and pregnancy: an experience of 13 cases. AB - OBJECTIVE: Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening disease caused by the onset of rapidly progressive and widespread small-vessel thromboses in the presence of aPLs. The aim of this study was to examine pregnancy-related CAPS. METHODS: Retrospective series of 13 patients with pregnancy-related CAPS with special focus on the follow-up. RESULTS; Eleven patients had known APS and had been treated with low-molecular-weight heparin (n = 10), aspirin (n = 8), oral anticoagulants (n = 1), HCQ (n = 3) and/or steroids (n = 1) during pregnancy. The most frequent manifestations of CAPS were cutaneous (n = 11), hepatic (n = 11), renal (n = 10), cardiac (n = 8) and neurological (n = 5). CAPS usually followed haemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome (n = 12), which was associated with pre-eclampsia (n = 6) or with eclampsia (n = 3). No maternal death was observed. The perinatal mortality of 54% was related to prematurity with a mean gestational age of 26.6 weeks at onset of CAPS or HELLP syndrome. During a mean follow-up of 4.8 years (range 2-8 years), seven new pregnancies occurred in five patients and led to one miscarriage, four successful pregnancies and two HELLP syndrome with pre eclampsia or eclampsia that occurred at 28 weeks gestation in both cases despite optimal treatment. No relapse of CAPS was observed. Two mothers suddenly died 2.5 and 6 years after CAPS. CONCLUSION: The occurrence of HELLP syndrome in a patient with APS should raise the suspicion of CAPS in the following days, and anticoagulation should be maintained post-partum or post-abortum. Subsequent pregnancies are at very high risk. PMID- 23676526 TI - [Reliability and validity of the Japanese version of the Mentoring Functions Questionnaire 9-item version]. AB - PURPOSE: Mentoring is defined as a supporting behavior whereby a knowledgeable and experienced person (mentor) supports an inexperienced person (mentee) in order to develop his/her career and psychosocial aspects. Empirical studies on mentoring in the U.S. and Europe have shown that a high level of mentoring support is associated with greater career success among mentored individuals, such as job satisfaction and organizational commitment, better mental health as well as work life conflict. We translated a 9-item version of Mentoring Functions Questionnaire (MFQ-9, Castro et al. 2004), one of the most frequently used mentoring measures, and examined the internal consistency, reliability, and factor-based and concurrent validities of this measure. METHOD: In January 2012, we conducted a web survey of internet survey monitors working as employees of private companies and analyzed the data of 357 respondents without missing answers. The questionnaire included the Japanese MFQ-9, job satisfaction, and organizational commitment as well as demographic variables. RESULTS: Cronbach alpha coefficients of MFQ-9 and its three subscales were all above 0.7 (0.75 0.77). The hypothesized three factors (career support, psychosocial support, and role modeling) were extracted by factor analysis. In the confirmatory factor analysis, assuming that there were three factors, fit indices were 0.96, 0.94, 0.97, and 0.05 for GFI, AGFI, CFI, and RMSEA respectively. Concurrent validity was supported by expected correlations of MFQ-9 with job satisfaction (r=0.20, p<0.01) and organizational commitment (r=0.17, p<0.01). As for subscales, career support and role modeling correlated with job satisfaction (r=0.14 and 0.15, respectively; both p<0.01) and commitment (r=0.17 and 0.14, respectively; both p<0.01), while psychosocial support was correlated only with job satisfaction (r=0.14, p<0.01). CONCLUSIONS: While issues such as the relationship between psychosocial support with organizational commitment will be a topic for further research, this study has shown that the Japanese version of MFQ-9 has an acceptable level of reliability and validity. PMID- 23676525 TI - Physical activity, measures of obesity, and cardiometabolic risk: the Multi Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: The influence of higher physical activity on the relationship between adiposity and cardiometabolic risk is not completely understood. METHODS: Between 2000-2002, data were collected on 6795 Multi-Ethnic Study of Atherosclerosis (MESA) participants. Self-reported intentional physical activity in the lowest quartile (0-105 MET-minutes/week) was categorized as inactive and the upper three quartiles (123-37,260 MET-minutes/week) as active. Associations of body mass index (BMI) and waist circumference categories, stratified by physical activity status (inactive or active) with cardiometabolic risk factors (dyslipidemia, hypertension, upper quartile of homeostasis model assessment of insulin resistance [HOMA-IR] for population, and impaired fasting glucose or diabetes) were assessed using logistic regression analysis adjusting for age, gender, race/ethnicity, and current smoking. RESULTS: Among obese participants, those who were physically active had reduced odds of insulin resistance (47% lower; P < .001) and impaired fasting glucose/diabetes (23% lower; P = .04). These associations were weaker for central obesity. However, among participants with a normal waist circumference, those who were inactive were 63% more likely to have insulin resistance (OR [95% CI] 1.63 [1.24-2.15]) compared with the active reference group. CONCLUSIONS: Physical activity was inversely related to the cardiometabolic risk associated with obesity and central obesity. PMID- 23676527 TI - [Assessment of the risk of ischemic heart disease and its relevant factors among Japanese police officers]. AB - OBJECTIVES: Compared to other public employees, police officers have higher absence rates due to heart diseases, and ischemic heart disease (IHD) is one of the most frequent causes of death in their occupational life. The aim of this study was to investigate the prevalence of the risk factors for IHD among police officers and to examine its association with working conditions and lifestyles. METHODS: First, 58 male police officers who developed IHD from 1996 to 2011 and 116 age- and rank-matched controls who were free from cerebro- and cardiovascular diseases were compared with respect to the prevalence of traditional risk factors five years before the onset of IHD. Then, the prevalence of IHD risk factors, and the frequency of metabolic syndrome (MetS) by age group, working condition and lifestyle were investigated in a cross-sectional survey of data of 1,539 male police officers and 153 male office workers in a prefectural police force. RESULTS: In the case control study, the IHD cases had significantly higher prevalences of hypertension (p<0.001), hyper-LDL-cholesterolemia (p<0.05), glucose intolerance (p<0.05), and hyperuricemia (p<0.05) before the onset of IHD. Multiple logistic regression analysis revealed that hypertension (odds ratio [95% confidence interval] : 3.96 [1.82-8.59]), glucose intolerance (3.28 [1.34-8.03]), hypo-HDL-cholesterolemia (2.26 [1.03-4.97]), and hyper-LDL-cholesterolemia (2.18 [1.03-4.61]) were independently associated with the development of IHD (model chi square, p<0.001; correct classification rate, 77.0%). In the cross sectional analyses, among the police officers, abdominal obesity (waist circumference of >= 85 cm) was significantly more frequent (57.3% vs. 35.3%, p<0.001) and the prevalence of dyslipidemia and glucose intolerance increased with age more remarkably than in the general office workers. In the age-group of 45-59 years, the clustering number of risk factors in individuals (1.8 vs. 1.4, p<0.01) and the frequency of MetS (25.0 vs. 15.5, p<0.1) were greater in the police officers than the office workers. Among the police officers, subjects with MetS had significantly higher rates of shift work (33.6% vs. 25.4%, p<0.01), lack of sound sleep (42.5% vs. 33.7%, p<0.01), and heavy drinking (12.8 vs. 6.3%, p<0.01) than those without MetS. CONCLUSIONS: In this study, the development of IHD in police officers was significantly associated with traditional risk factors, especially with hypertension, dyslipidemia and glucose intolerance. The increase with age of the prevalence of IHD risk factors and the frequency of MetS were greater in police officers than office workers. Irregular working conditions, such as shift work, long working time, and unfavorable lifestyles, e.g. alcohol drinking and poor sleeping conditions, may influence the higher prevalence of risk factors for IHD in police officers. PMID- 23676528 TI - Air leaks and pulmonary emphysema in infants: selective bronchial intubation or balloon occlusion? PMID- 23676529 TI - Rate of improvement during and across three treatments for panic disorder with or without agoraphobia: cognitive behavioral therapy, selective serotonin reuptake inhibitor or both combined. AB - BACKGROUND: Existing literature on panic disorder (PD) yields no data regarding the differential rates of improvement during Cognitive Behavioral Therapy (CBT), Selective Serotonin Reuptake Inhibitor (SSRI) or both combined (CBT+SSRI). METHOD: Patients were randomized to CBT, SSRI or CBT+SSRI which each lasted one year including three months of medication taper. Participating patients kept record of the frequency of panic attacks throughout the full year of treatment. Rate of improvement on panic frequency and the relationship between rate of improvement and baseline agoraphobia (AG) were examined. RESULTS: A significant decline in frequency of panic attacks was observed for each treatment modality. SSRI and CBT+SSRI were associated with a significant faster rate of improvement as compared to CBT. Gains were maintained after tapering medication. For patients with moderate or severe AG, CBT+SSRI was associated with a more rapid improvement on panic frequency as compared to patients receiving either mono-treatment. LIMITATIONS: Frequency of panic attacks was not assessed beyond the full year of treatment. Second, only one process variable was used. CONCLUSIONS: Patients with PD respond well to each treatment as indicated by a significant decline in panic attacks. CBT is associated with a slower rate of improvement as compared to SSRI and CBT+SSRI. Discontinuation of SSRI treatment does not result in a revival of frequency of panic attacks. Our data suggest that for patients without or with only mild AG, SSRI-only will suffice. For patients with moderate or severe AG, the combined CBT+SSRI treatment is recommended. PMID- 23676530 TI - Teachers' perceptions of promoting sign language phonological awareness in an ASL/English bilingual program. AB - The National Reading Panel emphasizes that spoken language phonological awareness (PA) developed at home and school can lead to improvements in reading performance in young children. However, research indicates that many deaf children are good readers even though they have limited spoken language PA. Is it possible that some deaf students benefit from teachers who promote sign language PA instead? The purpose of this qualitative study is to examine teachers' beliefs and instructional practices related to sign language PA. A thematic analysis is conducted on 10 participant interviews at an ASL/English bilingual school for the deaf to understand their views and instructional practices. The findings reveal that the participants had strong beliefs in developing students' structural knowledge of signs and used a variety of instructional strategies to build students' knowledge of sign structures in order to promote their language and literacy skills. PMID- 23676531 TI - Washington State cancer patients found to be at greater risk for bankruptcy than people without a cancer diagnosis. AB - Much has been written about the relationship between high medical expenses and the likelihood of filing for bankruptcy, but the relationship between receiving a cancer diagnosis and filing for bankruptcy is less well understood. We estimated the incidence and relative risk of bankruptcy for people age twenty-one or older diagnosed with cancer compared to people the same age without cancer by conducting a retrospective cohort analysis that used a variety of medical, personal, legal, and bankruptcy sources covering the Western District of Washington State in US Bankruptcy Court for the period 1995-2009. We found that cancer patients were 2.65 times more likely to go bankrupt than people without cancer. Younger cancer patients had 2-5 times higher rates of bankruptcy than cancer patients age sixty-five or older, which indicates that Medicare and Social Security may mitigate bankruptcy risk for the older group. The findings suggest that employers and governments may have a policy role to play in creating programs and incentives that could help people cover expenses in the first year following a cancer diagnosis. PMID- 23676532 TI - Size-dependent properties of single InAs quantum dots grown in nanoimprint lithography patterned GaAs pits. AB - We report on the structural and optical properties of single InAs quantum dots (QDs) formed in etched GaAs pits with different dimensions. The site-controlled QDs were fabricated by molecular beam epitaxy on GaAs(001) surfaces patterned by nanoimprint lithography. We show that the properties of the QDs can be modified by varying the dimensions of the etched GaAs pits. Increasing the pit size resulted in larger QDs and thus in longer photoluminescence wavelengths. However, the fine structure splitting remained unaffected. A photoluminescence linewidth of 41 MUeV and average fine structure splitting of 15.7 MUeV were obtained for exciton recombination in the single site-controlled QDs. PMID- 23676534 TI - Health care reform: what went wrong. PMID- 23676533 TI - Acute kidney injury, renal function, and the elderly obese surgical patient: a matched case-control study. AB - OBJECTIVE: To investigate the association between obesity and perioperative acute kidney injury (AKI), controlling for preoperative kidney dysfunction. BACKGROUND: More than 30% of patients older than 60 years are obese and, therefore, at risk for kidney disease. Postoperative AKI is a significant problem. METHODS: We performed a matched case-control study of patients enrolled in the Obesity and Surgical Outcomes Study, using data of Medicare claims enriched with detailed chart review. Each AKI patient was matched with a non-AKI control similar in procedure type, age, sex, race, emergency status, transfer status, baseline estimated glomerular filtration rate, admission APACHE score, and the risk of death score with fine balance on hospitals. RESULTS: We identified 514 AKI cases and 694 control patients. Of the cases, 180 (35%) followed orthopedic procedures and 334 (65%) followed colon or thoracic surgery. After matching, obese patients undergoing a surgical procedure demonstrated a 65% increase in odds of AKI within 30 days from admission (odds ratio = 1.65, P < 0.005) when compared with the nonobese patients. After adjustment for potential confounders, the odds of postoperative AKI remained elevated in the elderly obese (odds ratio = 1.68, P = 0.01.) CONCLUSIONS: : Obesity is an independent risk factor for postoperative AKI in patients older than 65 years. Efforts to optimize kidney function preoperatively should be employed in this at-risk population along with keen monitoring and maintenance of intraoperative hemodynamics. When subtle reductions in urine output or a rising creatinine are observed postoperatively, timely clinical investigation is warranted to maximize renal recovery. PMID- 23676537 TI - Outcome of radical prostatectomy in patients meeting criteria for active surveillance. AB - OBJECTIVES: Advances in diagnosis of prostate cancer (PCa)have led to an increased detection of these tumors, some of them with low-risk of progression, with the consequent risk of overdiagnosis and overt treatment. In consequence, there is a tendency to offer alternatives to active therapy, like active surveillance (AS)however, some patients under AS need definitive therapy and after surgery it becomes evident that they are not "low-risk" patients. We retrospectively reviewed the data of patients who met criteria for low-risk tumors treated with radical prostatectomy. METHODS: We selected 21 out of 190 patients treated with radical prostatectomy from January 2004 to December 2008 who met Epstein's criteria for low-risk tumors. We analyzed the number of organ confined tumors,Gleason undergrading and understaging by biopsy, surgical margins and postoperative PSA. RESULTS: Mean age was 58.6 years; mean PSA was 6.6 ng/ml, predominant Gleason score was 6 (3+3), 76%were unilateral tumors and 90%were organ-confined, 10% had extracapsular extension, none had involvement of the seminal % vesicles, 15% of the patients had Gleason score >6 and surgical margins were positive in 30% of the specimens. Eighty five percent had their first postoperative PSA <0.10 ng/ml and 75% remain free of biochemical recurrence. According to the Johns Hopkins criteria for "incurable tumors ", our cohort had 28%. CONCLUSION: Patients with low-risk prostate cancer include cases that may have greater risk than estimated. In our series, we had 10% extracapsular disease, 15% understaging for Gleason score and 25% biochemical recurrence, which demonstrates that current criteria do not warrant good oncological results. Active surveillance offers good quality of life and acceptable oncological results, it can be proposed until definitive therapy, without seriously endangering the patient. Anyway, as a therapeutic tool, it still requires improvements. Technical advances are awaited so as to properly assess each patient's risk and to define the best therapeutic option for every case. PMID- 23676536 TI - A performance analysis of the presence of malignant circulating prostate cells as a predictive factor for the detection of prostate cancer in the first, second and third prostate biopsy. AB - OBJECTIVES: Serum prostate specific antigen and digital rectal examination are the tests used as screening tests to detect prostate cancer. However, only approximately 30% of men with suspicion of cancer have it confirmed on prostate biopsy, and not all of these need treatment. Detection of circulating tumor cells in localized prostate cancer has given variable results, but it could be a useful complementary screening tool to detect prostate cancer in men with abnormal screening tests before the evaluation with prostate biopsy. This may be more so in subsequent biopsies where serum PSA has a decreased diagnostic yield. To evaluate the diagnostic yield of the detection of CPCs as a complementary PC screening test in a population fulfilling criteria for an initial, second and third prostate biopsy for suspicion of PC. METHODS: A prospective screening study of consecutive patients aged 45-80 years presenting to the urologist for PC screening. Inclusion criteria were PSA >4.0 ng/ml, PSA velocity >0.35 ng/ml/year and/or DRE suspicious for cancer. Patients fulfilling inclusion criteria had blood taken for CPC detection and then underwent 12-core transrectal prostate biopsy. Double immune-his-tochemical staining with anti-PSA and anti-P504S was used to detect CPCs. Both cytologist and pathologist were blinded to the results of the biopsy, CPC results and clinical details. The diagnostic yield of the presence or absence of CPC was evaluated; the prostate biopsy was classified as cancer or no-cancer. RESULTS: 282 men participated, 83 undergoing of these undergoing a second and 38 a third biopsy, with a mean age of 66.2 +/- 8.9 years and a median serum PSA of 5.10 ng/ml, 5.45 ng/ml and 6.45 ng/ml for first, second and third biopsies. Cancer was detected in 33,6%, 10.8% and 29.0% of first, second and third biopsies respectively, CPCs were detected in 36.9%, 21.7% and 36.8% of the patients. Sensibility, specificity and negative predictive value were 86% ,91% and 94% for the first biopsy, 89%, 87% and 99% for the second and 100% , 89% and 100% for third biopsy respectively. All the CPC determinations were interpretable. There were 11 false negative cases, all with small low grade tumors. Of the 29 men with a false positive CPC, 8/10 had cancer detected in the subsequent biopsy. CONCLUSIONS: The use of CPC detection could be useful as a complementary prostate cancer screening test, especially for excluding cancer, and including patients with indications for repeat biopsies. Men with a false positive CPC detection had a high risk of detecting cancer in the succeeding biopsy. PMID- 23676538 TI - The role of ischemia in the deterioration of renal function after partial nephrectomy. AB - OBJECTIVES: Nephron-sparing surgery (NSS ) has been considered throughout history for patients with solitary kidney, bilateral renal tumors, impaired renal function (RF), and hereditary renal cancer. However, recently the indications for Partial Nephrectomy (PN ) have extended and include patients with a healthy contralateral kidney. NSS has evolved in a great way during the last decade, specifically in terms of oncological indications, and in the renal ischemia time used with the goal to maintain as much renal function as possible. This change is secondary to a better understanding of renal cancer histology, the equivalence in oncological outcomes between radical and PN, and finally the impact of chronic kidney disease (CKD ) as a cause of cardiovascular complications and mortality.The main purpose of our study is to review the role of ischemia in NSS. METHODS: A literature review was performed focusing on NSS, risk factors of renal damage, types of ischemia, as well as its effect on RF, and ischemia time. CONCLUSIONS: Renal ischemia has been considered for a long time as the main factor related with postoperative Renal Function (RF) in patients with NSS. Furthermore it is one of the few modifiable factors that directly depend on the surgeon. The ischemia time limit, both in warm and cold, is not well established and is a controversial issue that is still on debate till now. At this moment, there is evidence that considers the impact of ischemia only in acute or early stages. Also other factors have emerged and seem to have greater effect on RF, mainly in the long-term, leaving ischemia in second place. These factors are the quantity and quality of the remaining renal parenchyma. More studies are needed to support this rising concept and to clarify the real part that ischemia plays. PMID- 23676539 TI - Laparoscopic radical prostatectomy. Impact of the learning curve on positive surgical margins. AB - OBJECTIVES: The study was conducted to assess the incidence of positive surgical margins (PSMs ) in our series of laparoscopic radical prostatectomy (LRP ) performed by a fellowship trained surgeon in independent practice. METHODS: In this series, 300 patients underwent LRP by the same surgeon at our institution. The prospectively created records of all consecutive LRPs were reviewed. The patients were divided into three groups based on the time of surgery: group I included the first 100 cases;group II included the second 100 cases; and group III the last 100 cases. We compared the incidence rate and the location of PSMs among the groups. As additional variables, prostate-specific antigen (PSA ) level, biopsy/specimen Gleason score, clinical/pathological stage and pathologic tumor volume were also evaluated. RESULTS: Patient demographics and preoperative staging variables were comparable among the three groups, with no statistically significant differences among them. The PSM rates were 27%, 22% and 27% for groups I, II and III, respectively. The difference in overall PSM rates in the three groups was statistically insignificant (p: 0.966 ) . PSM rates decreased specifically at the posterolateral region and in pT3b stage with non/significant difference when comparing the first 100 patients to the last 100 patients. CONCLUSION: Pathologic surgical margin safety can be achieved with laparoscopic fellowship/training (LFT ) from the initial cases in independent practice. PMID- 23676540 TI - Editorial comment: Laparoscopic radical prostatectomy. Impact of the learning curve on positive surgical margins. PMID- 23676541 TI - Large-cell neuroendocrine carcinoma of prostate. Case report. AB - OBJECTIVE: To report a case of a neuroendocrine differentiation in a prostate cancer patient, a rare subtype. METHODS: We describe the case of a patient diagnosed with adenocarcinoma of the prostate initially, who presented hematuria due to disease progression with neuroendocrine differentiation despite androgen deprivation therapy (ADT ). DISCUSSION: Prostate cancer is the most common tumor in men. Histologically they are diagnosed as adenocarcinomas, which followed by ADT for a long time, develop neuroendocrine differentiation (NED ). CONCLUSIONS: The prognostic significance of NED remains controversial. We must think in neuroendocrine differentiation in ADT-treated patient with disease progression and low PSA. PMID- 23676542 TI - Testicular reconstruction after testicular rupture and review of the literature. AB - OBJECTIVE: To report a clinical case of testicular rupture and review of the literature published. METHOD: A 15 years old male with a testicular rupture after a sports injury was diagnosed by Doppler ultrasound. RESULTS: Surgical exploration was performed and the tear was repaired. He had a benign postoperative course. The patient presents a normal size testicle after a year of follow-up. CONCLUSIONS: Testicular rupture is an uncommon but important entity that may occur. It is essential early diagnosis and e management to avoid orchiectomy. PMID- 23676543 TI - Castleman's disease presented as a retroperitoneal mass. AB - OBJECTIVE: We report one case of Castleman's disease and review published literature. METHODS: We report the case of a 58 year old man who was referred to our institution because of lumbar pain. A computed tomography scan revealed a retroperitoneal mass. Open surgical exploration and excision were carried out. Finally pathological examination addressed the diagnosis. RESULTS: Pathological examination demonstrated findings characteristic of unicentric hyaline vascular type of Castleman's disease. After surgical excision and 12 months follow-up there is no evidence of recurrence disease. CONCLUSIONS: Castleman's disease is a rare lymphoproliferative disorder of uncertain etiology. Retroperitoneal localization is exceptional. PMID- 23676544 TI - Basaloid carcinoma of the prostate: an extremely rare tumor. AB - OBJECTIVE: The basaloid carcinoma of the prostate (BC) is a rare malignant neoplasm arising from the basal cells of prostatic ducts and acini. We report a case and review the literature. METHODS: A 76-year-old man presented with symptoms of lower obstructive uropathy, the IPSS score was 29 and prostate specific antigen (PSA)of 0,924 ng /ml. Transurethral resection of prostate (TURP) was performed in September 2008, histopathological diagnosis was BC. In February 2009 laparoscopic radical prostatectomy was performed. RESULTS: Histopathological examination revealed a BC with adenoid cystic growth pattern, perineural infiltration and focal involvement of the left seminal vesicle. Immunohistochemically, the cells were negative for PSA, stained and were strongly positive for specific monoclonal antibodies anti-cytokeratin 34betaE12, p63 and BCL-2. The patient has 23 months of follow-up, with complete continence and no evidence of tumor recurrence. CONCLUSIONS: The BC is an extremely rare subtype of malignant tumors of the prostate, where immunohistochemistry plays a fundamental role in diagnosis. PMID- 23676545 TI - Mesothelioma of the tunica vaginalis. Case report. AB - OBJECTIVE: To report a case of a mesothelioma of the tunica vaginalis and to review the published literature. METHODS / RESULTS: A 61-year-old patient complained of one-month increase of right scrotum size with pain. An ultrasound showed a right hydrocele with a mass attached to the tunica vaginalis. He didn't refer any urological history or known exposure to asbestos. Blood levels of tumor markers (alpha-fetoprotein and beta-HCG) were within normal limits. We performed a radical inguinal orchiectomy with an en-bloc resection of the tunica vaginalis. The pathology described a potentially malignant biphasic mesothelioma. The patient has remained asymptomatic with negative extension studies after 10 years of follow up. CONCLUSIONS: Paratesticular mesotheliomas are rare tumors (approximately 250 cases reported )with uncertain etiology (only 30-40% are associated with asbestos exposure). The age range is between 50-70 years. Its presentation is usually as a scrotal mass with recurrent reactive hydrocele, which may delay early diagnosis. During surgery, intraoperative biopsy is recommended. It is important to do a differential diagnosis with other benign diseases. Treatment is only curative in early stages with radical orchidectomy and resection in-block of the tunica vaginalis. Despite being multidisciplinary, it is not curative in most cases due to rapid local and distant spread. PMID- 23676546 TI - Asymptomatic left ureter inguinal hernia during valsalva maneuver in a patient with complete left pyelo ureteral system duplication. PMID- 23676547 TI - Congenital kidney and upper urinary tract fusion and rotation anomalies. PMID- 23676548 TI - Is dietitian use associated with celiac disease outcomes? AB - A gluten-free diet (GFD) is the treatment for celiac disease (CD), but due to its complexity, dietitian referral is uniformly recommended. We surveyed patients with CD to determine if dietitian use is associated with quality of life, symptom severity, or GFD adherence. The survey utilized three validated CD-specific instruments: the CD quality of life (CD-QOL), CD symptom index (CSI) and CD adherence test (CDAT). Four hundred and thirteen patients with biopsy-proven CD were eligible for inclusion. The majority (77%) were female and mean BMI was 24.1. Over three-quarters of patients (326, 79%) had seen a dietitian, however, 161 (39%) had seen a dietitian only once. Age, sex, and education level were not associated with dietitian use; nor was BMI (24.6 vs. 24.0, p = 0.45). On multivariate analysis, adjusting for age gender, education, duration of disease, and body mass index, dietitian use was not associated with CD-QOL, CSI, or CDAT scores. Our survey did not show an association between dietitian use and symptom severity, adherence, or quality of life. Delay in diagnosis was associated with poorer outcomes. This is a preliminary study with several limitations, and further prospective analysis is needed to evaluate the benefits and cost effectiveness of dietitian-referral in the care of celiac disease patients. PMID- 23676550 TI - Sources of vitamin A in the diets of pre-school children in the Avon Longitudinal Study of Parents and Children (ALSPAC). AB - Vitamin A is essential for growth and development. We investigated whether high consumption of energy-dense nutrient-poor foods in the diets of pre-school children is detrimental to diet quality with respect to vitamin A. Data were collected from 755 children at 18-months and 31/2-years, from the Avon Longitudinal Study of Parents and Children, using 3-day unweighed dietary records completed by parents in 1994 and 1996, respectively. Energy, carotene and retinol intakes were calculated. The quality of the diet declined from 18-months to 31/2 years with respect to vitamin A. Preformed retinol intakes decreased by -54 MUg/day on average (p = 0.003). Carotene intakes were similar at each age although there was a 23% increase in energy intake by 31/2-years. Longitudinally those in the highest quartile of intake at 18-months were twice as likely to remain in the highest quartile at 31/2-years for retinol (OR 2.21 (95% CI 1.48 3.28)) and carotene (OR 1.66 (95% CI 1.11-2.50)) than to change quartiles. Nutrient-rich core foods provided decreasing amounts of carotene and preformed retinol over time (both p < 0.001). Vegetables and milk contributed the highest proportion of carotene at both ages, but milk's contribution decreased over time. Milk and liver were the largest sources of retinol. Nutrient-poor foods provided an increased proportion of energy (p < 0.001) with low proportions of both nutrients; however fat spreads made an important contribution. It is recommended that pre-school children should take vitamin supplements; only 19% at 18-months did this, falling to 11% at 31/2-years. Care should be taken to choose nutrient rich foods and avoid energy-dense, nutrient-poor foods when feeding pre-school children. PMID- 23676549 TI - Iron deficiency and bariatric surgery. AB - It is estimated that the prevalence of anaemia in patients scheduled for bariatric surgery is higher than in the general population and the prevalence of iron deficiencies (with or without anaemia) may be higher as well. After surgery, iron deficiencies and anaemia may occur in a higher percentage of patients, mainly as a consequence of nutrient deficiencies. In addition, perioperative anaemia has been related with increased postoperative morbidity and mortality and poorer quality of life after bariatric surgery. The treatment of perioperative anaemia and nutrient deficiencies has been shown to improve patients' outcomes and quality of life. All patients should undergo an appropriate nutritional evaluation, including selective micronutrient measurements (e.g., iron), before any bariatric surgical procedure. In comparison with purely restrictive procedures, more extensive perioperative nutritional evaluations are required for malabsorptive procedures due to their nutritional consequences. The aim of this study was to review the current knowledge of nutritional deficits in obese patients and those that commonly appear after bariatric surgery, specifically iron deficiencies and their consequences. As a result, some recommendations for screening and supplementation are presented. PMID- 23676551 TI - Enhanced killing of ovarian carcinoma using oncolytic measles vaccine virus armed with a yeast cytosine deaminase and uracil phosphoribosyltransferase. AB - OBJECTIVE: To preclinical assess the feasibility of combining oncolytic measles vaccine virus (MeV) with suicide gene therapy for ovarian cancer treatment. METHODS: We genetically engineered a recombinant MeV armed with a yeast-derived bifunctional suicide gene that encodes for cytosine deaminase and uracil phosphoribosyltransferase (MeV-SCD). From this suicide gene, a chimeric protein is produced that converts the non-toxic prodrug 5-fluorocytosine (5-FC) into highly cytotoxic 5-fluorouracil (5-FU) and directly into 5-fluorouridine monophosphate (5-FUMP) thereby bypassing an important mechanism of chemoresistance to 5-FU. RESULTS: MeV-SCD was demonstrated to infect, replicate in and effectively lyse not only human ovarian cancer cell lines, but also primary tumor cells (albeit at lower efficiencies) that were derived from malignant ascites of ovarian cancer patients. Addition of the prodrug 5-FC significantly enhanced cell killing. Importantly, precision-cut tumor slices of human ovarian cancer patient specimens were efficiently infected with MeV-SCD. The prodrug-converting enzyme SCD was expressed by all infected tumor slices, thereby ensuring provision of the suicide gene arming function in patient-derived materials. CONCLUSIONS: With respect to safety and therapeutic impact, arming of oncolytic measles vaccine virus warrants further clinical investigation for ovarian cancer treatment. PMID- 23676552 TI - Phenotypic characteristics of hydrocephalus in stillborn Friesian foals. AB - Hydrocephalus is uncommon in horses. However, in recent years, it has become clear that the prevalence of hydrocephalus is greater in Friesian horses than in other breeds probably due to their limited gene pool. Before identification of candidate genes that predispose to the development of hydrocephalus in Friesian horses can be pursued, an in-depth, phenotypic, pathological description of the condition in Friesians would be of great benefit. Our study aimed to characterize the morphology of hydrocephalus in Friesian horses, to support further investigation of the genetic background of this condition. Four stillborn Friesian foals with hydrocephalus were examined macroscopically and microscopically and compared with 2 normal stillborn Friesian foals without hydrocephalus. In all clinical cases, tetraventricular and venous dilatations were observed, together with malformation of the petrosal bone and, as a result, narrowing of the jugular foramen. These observations suggest a communicative hydrocephalus with a diminished absorption of cerebrospinal fluid into the systemic circulation at the venous sinuses due to a distorted, nonfunctional jugular foramen. This type of hydrocephalus is also recognized in humans and dogs and has been linked genetically to chondrodysplasia; this has already been recognized in dwarfism, which is another monogenetic defect in Friesian horses. PMID- 23676553 TI - Internet-delivered cognitive therapy for social anxiety disorder: a development pilot series. AB - BACKGROUND: Randomized controlled trials have established that individual cognitive therapy based on the Clark and Wells (1995) model is an effective treatment for social anxiety disorder that is superior to a range of alternative psychological and pharmacological interventions. Normally the treatment involves up to 14 weekly face-to-face therapy sessions. AIM: To develop an internet based version of the treatment that requires less therapist time. METHOD: An internet delivered version of cognitive therapy (iCT) for social anxiety disorder is described. The internet-version implements all key features of the face-to-face treatment; including video feedback, attention training, behavioural experiments, and memory focused techniques. Therapist support is via a built-in secure messaging system and by brief telephone calls. A cohort of 11 patients meeting DSM-IV criteria for social anxiety disorder worked through the programme and were assessed at pretreatment and posttreatment. RESULTS: No patients dropped out. Improvements in social anxiety and related process variables were within the range of those observed in randomized controlled trials of face-to-face CT. Nine patients (82%) were classified as treatment responders and seven (64%) achieved remission status. Therapist time per patient was only 20% of that in face-to-face CT. CONCLUSIONS: iCT shows promise as a way of reducing therapist time without compromising efficacy. Further evaluation of iCT is ongoing. PMID- 23676556 TI - "When Roscius was an actor in Rome-" care for the elderly with N2-positive non small-cell lung cancer. PMID- 23676554 TI - Effect of epigallocatechin-3-gallate on graft-versus-host disease. AB - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often complicated by alloreactive donor T-cell-mediated graft-versus-host disease (GvHD). The major polyphenol of green tea, epigallocatechin-3-gallate (EGCG), is an inhibitor of both DNA methyltransferase 1 (DNMT1) and signal transducer and activator of transcription 1 (STAT1), which are essential for induction of GvHD. Thus, in this report, we examine if in vivo administration of EGCG mitigates GvHD in several different animal models. While we concede that refinement of EGCG treatment might result in GvHD prevention, our results suggest that EGCG treatment might not be an effective therapy against GvHD in the clinic. PMID- 23676557 TI - Interobserver agreement in the nuclear grading of primary pulmonary adenocarcinoma. AB - INTRODUCTION: Nuclear grading involves an evaluation of the size and shape of nuclei and the percentage of tumor cells that are in the mitotic phase. To estimate the degree of aggressiveness, this approach has been applied to various types of carcinomas, such as breast carcinoma and pulmonary adenocarcinoma (Nakazato et al.). In the present study, we estimated and evaluated the interobserver variability of nuclear grading in primary pulmonary adenocarcinomas. METHODS: We selected 122 primary pulmonary adenocarcinomas measuring 2 cm or less in diameter. Eight pathologists independently evaluated the nuclear factors, using the nuclear grading system reported previously by Nakazato et al. The same pathologists also used both the international multidisciplinary classification of pulmonary adenocarcinoma (2011 International Association for the Study of Lung Cancer classification) and Noguchi's classification, and assessed the extent of the lepidic pattern in the largest cut surface of the tumor. Interobserver agreement was evaluated using the kappa statistic. The disease-free survival curves of the patients were obtained using the Kaplan-Meier method and analyzed with the log-rank test. RESULTS: The mean (+/-SD) kappa values for the two histological classifications, the extent of the lepidic pattern, and nuclear grading were 0.46 +/- 0.09, 0.48 +/- 0.09, 0.45 +/- 0.16, and 0.58 +/- 0.09, respectively. The cases judged as negative on the basis of nuclear grading showed a significantly better prognosis (5-year disease-free survival rate; 91.8% +/- 2.7) than the positive cases did (68.6% +/- 3.1). CONCLUSION: : Nuclear grading is practical for prognostic evaluation of pulmonary adenocarcinoma. The interobserver agreement for nuclear grading is significantly higher than for histological classifications and the extent of the lepidic pattern. Nuclear grading is a reliable prognostic indicator for small adenocarcinomas. PMID- 23676558 TI - Sarcomatoid lung carcinomas show high levels of programmed death ligand-1 (PD L1). AB - Programmed death-1 (PD-1) is a coinhibitory inducible receptor present on T-cells and macrophages. Tumor cells with increased programmed death ligand-1 (PD-L1) are believed to escape immunity through activation of PD-1/PD-L1 pathway and suppression of effector-immune responses. Recent strategies targeting the PD-1/PD L1 axis have shown promising results in patients with several tumors types, including lung carcinomas. Preliminary data suggest that PD-L1 protein expression might have predictive response to such therapies. Sarcomatoid carcinomas (SCs) of the lung include rare subtypes of poorly differentiated non-small-cell lung carcinomas of high grade and aggressive behavior. The biology of these neoplasms is poorly understood and they frequently show increased local inflammatory and lymphocytic infiltration. Here, we report the expression of PD-L1 in 13 SCs from two large retrospective lung cancer cohorts. Using automated quantitative immunofluoresence and a mouse monoclonal antibody directed against the extracellular domain of PD-L1, we show that 9 of 13 patients (69.2%) with SCs are positive for PD-L1 and their levels are higher than in conventional non-small cell lung carcinoma. These results provide rationale for the potential use of targeted immunotherapy in lung SCs. PMID- 23676559 TI - FDG uptake in the chest wall of a patient with small-cell lung cancer. PMID- 23676560 TI - Biostatistics primer: what a clinician ought to know--prognostic and predictive factors. AB - Several prognostic factors in oncology have been established over the years, such as performance status, tumor size, and disease stage. The identification of prognostic and predictive factors is becoming increasingly important in medical research, particularly as scientific discoveries have led to better understanding of diseases and genetics, resulting in tailored therapy. Advances in drug discovery and better understanding of the mechanism of action, may also identify factors that may be prognostic and/or predictive. Prognostic or predictive factors may include patient characteristics such as age, ethnicity, sex, or smoking status, disease characteristics such as disease stage or nodal status, and molecular markers such as HER2 amplification and K ras mutation.It can be challenging to distinguish whether a factor is prognostic or predictive, based on what is reported in the literature. This article is intended to help the reader assess whether a factor is prognostic and/or predictive. PMID- 23676561 TI - Use of denosumab in a patient with non-small-cell lung cancer and severe renal function impairment. PMID- 23676562 TI - Benefit of a second opinion: intrapulmonary metastases or multiple primary tumors? PMID- 23676563 TI - Thymic neuroendocrine tumor presenting with the ectopic ACTH syndrome. PMID- 23676564 TI - Improved HPLC purification strategy for [11C]raclopride and [11C]DASB leading to high radiochemical yields and more practical high quality radiopharmaceutical formulations. AB - A downscaled analytical HPLC purification strategy for [(11)C]raclopride and [(11)C]DASB was proposed to obtain a straightforward produced injectable solution with a substantially reduced volume. Both tracers were radiosynthesized using [(11)C]methyl triflate, and several analytical columns, in combination with ethanol containing eluents, were examined to optimize the chromatographic resolution. This resulted in a 5 mL solution of [(11)C]raclopride, obtained after 6 min, and a 7 mL solution of [(11)C]DASB, obtained after 10 min, using a C16 alkylamide and CN column respectively. PMID- 23676565 TI - Determination of alpha activity in organic solvents using CR-39. AB - Solid State Nuclear Track Detector (SSNTD) like CR-39 offers a unique opportunity to measure alpha radiations in a complex matrix like high level nuclear waste due to its sensitivity to only alpha radiations in the presence of intense beta-gamma radiation field. There is however a concern about the lower sensitivity of SSNTD when the radiation source is present in solution vis-a-vis solid medium. The sensitivity of CR-39 toward detection of alpha particles homogenously distributed in n-hexane, n-dodecane and n-octanol has been investigated and was found to be better than that obtained in 3 M HNO3. PMID- 23676567 TI - For the patient! PMID- 23676566 TI - Physicochemical characterization of tretinoin tocoferil emulsion and povidone iodine sugar ointment blend developed for improved regulation of wound moisture. AB - Maintenance of proper moisture and regulation of infection are simultaneously required to promote healing of pressure ulcers. Continuous use of water-rich ointment may often lead to excess moisture and induce edematous granulation tissue. Use of water soluble ointment may excessively absorb exudates and induce dry granulation tissue. Selection of appropriate topical ointment is desired to avoid worse clinical outcomes. For adjustment of wound moisture a novel blended ointment (tretinoin tocoferil-povidone-iodine (TR-PI)) was developed consisting of emulsion base, tretinoin tocoferil oil-in-water (o/w) emulsion (TR-cream), and sugar base, povidone-iodine and sugar (PI-sugar). For the characterization of TR PI water absorption was tested using Franz diffusion cell with cellulose membrane. For rheological characteristics spreadability was tested using spread meter and yield value was calculated. Iodine permeation was tested using a permeation cell with silicon membrane. Water absorption rate constant of TR-PI with combination ratio of PI-sugar at 75% (TR-PI75, 18.5 mg cm(-2) min(-0.5)) was equivalent to that of TR-cream alone (16.4 mg cm(-2) min(-0.5)). The yield value of TR-PI75 (26.1 Pa) exhibited intermediate values as compared to those of TR-PI with combination ratio of PI-sugar at 50% (11.3 Pa) and TR-cream alone (46.8 Pa). The amount of released free-iodine from TR-PI75 was similar to that released from PI-sugar alone. TR-PI75 may have superior performance in keeping the moist environment in wounds and in preventing infection. TR-PI75 can be used to promote formation of favorable granulation tissue in pressure ulcers with moderate exudates. PMID- 23676568 TI - Oral and sublingual peanut immunotherapy is not ready for general use. AB - Food oral immunotherapy (OIT) is an investigational peanut allergy treatment aimed to achieve specific oral tolerance induction. Allergic children are given titrated oral (or sublingual) doses of their allergen on a daily basis, unlike in subcutaneous immunotherapy (SCIT). OIT is theorized to cause a shift from a Th2 to a Th1 regulatory environment, reflected by increases in food-specific IgG4/IgE, and the production of FoxP3. Peanut OIT holds special promise because peanut allergy has an unfavorable natural history and is rarely outgrown. A high percentage of the participants experience symptoms during peanut OIT, including anaphylaxis, warranting epinephrine and/or discontinuation of therapy. This is a concerning fact given that the studies have mostly targeted only older children, with less historical reactivity for enrollment. The handful of peanut OIT studies have shown that some participants can be desensitized to peanut, but none have shown that long-term tolerance can be reestablished. Factors predictive of which patients are most likely to succeed and become desensitized through OIT are unknown. Some private practices have begun offering peanut OIT as a therapy. Such practice is potentially dangerous given the safety and efficacy of OIT in randomized controlled clinical trials is still not well established. Therefore, until further investigation emerges that conclusively demonstrates OIT is safe, intermediate and long-term outcomes are better established, the number of participants that experience symptoms is reduced, and proof of concept established in patients of all ages, (irrespective of past reaction severity), OIT is not ready for use in the general allergy practice. PMID- 23676569 TI - Oral immunotherapy for peanut allergy in clinical practice is ready. AB - Oral immunotherapy (OIT) for peanut allergy is ready for clinical allergy practice. Some physicians, particularly at academic centers, believe that OIT is not ready for clinical practice. The shortcomings of the present general recommendations of food avoidance and provision of epinephrine autoinjectors for a select number of patients demand a different approach. In peanut-allergic patients, the rate of accidental reactions is ~10% annually. Between 1 and 2% of these reactions require epinephrine or emergency department visits. Food allergy and peanut allergy, specifically, have a large negative impact on the quality of life (QOL) for patients and their families, which can be psychosocially debilitating. These decreases in health-related QOL continue into adulthood. There is only an ~20% chance of spontaneous remission in peanut allergy. Given this climate, three private allergy practices have begun providing OIT to 150 patients with peanut anaphylaxis. One hundred eleven (74%) patients were able to tolerate eight peanuts (8 g, ~2 g of protein). During outpatient dosing, epinephrine was used at a rate of 8 per 10,000 doses. To date, there have been no long-term (>24-36 months) unexpected reactions. OIT decreases risk and in one study, conducted in a practice setting, it was shown to improve QOL. OIT is a meaningful clinical procedure that can help our patients. PMID- 23676570 TI - Biphasic reactions in children undergoing oral food challenges. AB - Literature regarding biphasic reactions in the pediatric population is sparse. We aimed to determine the prevalence of biphasic reactions in children with food allergies undergoing oral food challenges (OFCs) and examine whether any clinical or treatment factors are associated with biphasic reactions. A retrospective chart review of OFCs conducted between July 2007 and March 2011 was performed. Charts were reviewed from time of challenge to 48 hours after challenge to capture data on any biphasic reactions. Uniphasic and biphasic reactions were compared in terms of specific clinical features and treatments. Of 614 positive challenges, 9 resulted in a biphasic reaction (1.5%). Six of the biphasic reactions occurred in challenges where the initial reaction met anaphylaxis criteria. The biphasic reactions were to eggs (4), peanuts (3), and milk (2). The symptom-free interval ranged from 2 to 24 hours. There were no statistically significant differences in clinical features between uniphasic and biphasic reactions, but there appeared to be a higher percentage of initial reactions with multiple organ involvement and meeting anaphylaxis criteria in the biphasic group. Biphasic reactors were significantly more likely to have received steroids for their initial reaction. A higher percentage of biphasic reactors also appeared to have received epinephrine, multiple doses of epinephrine, and antihistamines for their initial reactions. Biphasic reactions are rare in children undergoing OFCs and may be associated with more severe allergic reactions. Children with severe reactions may benefit from a 24-hour period of observation. PMID- 23676571 TI - Relationship between treatment with antacid medication and the prevalence of food allergy in children. AB - Food allergy affects 8% of preschool children, but factors responsible for food allergy in children are poorly understood. Use of antacid medication may be a contributing factor. The purpose of this study was to determine if parent reported antacid medication use was associated with higher prevalence of food allergy in atopic children. In this cross-sectional study, parents of children with atopic diseases completed a questionnaire relating to a history of treatment with antacid medication and food allergy. Charts were independently reviewed for food-specific IgE and/or skin-prick test results. Food allergy was defined as a reaction to a food consistent with the anaphylaxis consensus statement and either an elevated food-specific IgE or a positive food skin-prick test. One hundred four questionnaires were completed. Mean age of the participating children was 7.0 +/- 4.3 years (range, 5 months to 18 years of age). Forty-seven (45%) individuals were reported to have taken an antacid medication in the past. History of taking antacid medication was associated with an increased prevalence (57% (27)/47 versus 32% (18)/57) and higher prevalence of food allergy of having food allergy (aPR, 1.7 [1.1-2.5]). Mean peanut food-specific IgE was higher in those with a history of taking antacid medication (11.0 +/- 5.0 versus 2.0 +/- 5.5.; p = 0.01). History of treatment with antacid medication is associated with an increased prevalence of having food allergy. PMID- 23676572 TI - Anaphylaxis in infancy compared with older children. AB - Although there has been increasing data on pediatric anaphylaxis, information about anaphylaxis in the 1st year of life is scarce. This study provides detailed information on clinical signs and symptoms of anaphylaxis in the 1st year of life. A retrospective review was performed of our pediatric allergy database between 2007 and 2011. Children who met the diagnostic criteria of anaphylaxis were included. They were categorized as "infant" if they were <=12 months of age at the time of anaphylactic reaction and "children" if >12 months. There were 104 patients (60 male and 44 female subjects) who met the diagnosis criteria of anaphylaxis. From the 104 cases of anaphylaxis, 23 (22.1%) were infants. Boys (p = 0.043), atopic eczema (p = 0.049), and history of food allergy (p < 0.001) were significantly higher in infants than in children with anaphylaxis. Severe anaphylaxis was less frequent in infants than in children (p = 0.04). There was no significant difference between infants and children considering cutaneous and respiratory symptoms (p > 0.05 for both) but persistent vomiting was (p = 0.023). Irritability, persistent crying, and somnolence are the signs which are difficult to interpret in infants with anaphylaxis. Within these signs, irritability, persistent crying, and somnolence were present in 69.6, 43.5, and 26.1% of infants, respectively. Blood pressure was measured in 5 infants (21.7%) compared with 44 children (54.3%; p = 0.005). Four children (4.9%) required more than one epinephrine treatment, but no infant did. Median observation periods were 4 hours in both groups (p = 0.087) and no biphasic reactions occurred in either. Food (p < 0.001) was significantly more and drugs (p = 0.015) were a less frequent cause of anaphylaxis in infants than in children. Anaphylaxis in infants is not rare but many signs of anaphylaxis are overlooked and still undertreated. PMID- 23676573 TI - Characteristics of anaphylaxis in children referred to a tertiary care center. AB - Anaphylaxis is a potentially life-threatening condition. There are limited data about the etiology and the clinical characteristics in developing countries. This study aimed to investigate the clinical characteristics of anaphylaxis patients attending our pediatric allergy clinic. We conducted a prospective analysis of patients who were admitted to our allergy clinic for anaphylaxis from 2010 to 2012. Ninety-six patients were evaluated during the study period. The mean age was 7.4 +/- 5.2 years. Venom, food, and drugs were the most common causative agents responsible for 31 (32.3%), 30 (31.3%), and 26 (27.1%) of the cases, respectively. Foods implicated most frequently were peanuts and nuts (n = 9; 30.0%), cow's milk (n = 7; 23.3%), and egg white (n = 6; 20.0%). The clinical manifestations during anaphylaxis in order of frequency were cutaneous (97.9%), respiratory (86.5%), gastrointestinal (42.7%), neurological (37.5%), and cardiovascular symptoms (30.2%). A biphasic course was noticed in five cases (5.2%). Of the 91 patients, 79 (86.8%) received H1-antihistamines, 73 (80.2%) received corticosteroids, 40 (44.4%) received adrenaline, 38 (41.8%) received fluid replacement therapy, 18 (19.8%) received beta2-mimetics, and 8 (8.8%) received H2-antihistamines. According to severity, 7.3% of patients had mild, 59.4% had moderate, and 33.3% had severe anaphylaxis. Food and bee venom allergy were the most common etiologies. Adrenaline, the first-line treatment of anaphylaxis, was administered in only 44.4% of our cases. PMID- 23676574 TI - Safety of multiple aeroallergen rush immunotherapy using a modified schedule. AB - Rush immunotherapy (RIT) accelerates the build-up phase of traditional IT. The biggest potential benefit of using RIT is decreased time to symptomatic improvement. However, aeroallergen RIT carries an increased risk of systemic reaction (SR) compared with traditional IT. This study was designed to assess the safety of a modified 1-day multiple aeroallergen RIT protocol. A retrospective chart review was performed of 138 patients from an outpatient, university-based allergy practice who underwent RIT between November 2007 and February 2011. The RIT protocol consisted of eight injections over 5 hours, and stopped at one 10 fold dilution below the maintenance vial. All patients were premedicated on the same day of RIT with prednisone and histamine 1 and 2 receptor blockers. Primary end point observed was rate of SR. One hundred thirty-eight patients received a total of 2911 RIT injections. Thirty- eight patients (28%) had SRs. The SR rate per injection was 1.3%. Most of the reactions (82%) occurred after the last dose of the protocol. No patients with SR had severe anaphylaxis requiring emergency department support or hospitalization. The post-RIT SR rate was within the range seen with traditional IT. Well-controlled asthmatic patients were not at increased risk of SR compared with nonasthmatic patients. Modification of RIT to end at one 10-fold dilution below the maintenance vial for multiple aeroallergen RIT did not significantly decrease the SR rate compared with other protocols that end at the maintenance vial. Unlike hymenoptera RIT, aeroallergen RIT continues to be associated with a high risk of SR compared with traditional IT. PMID- 23676575 TI - Signs and symptoms preceding acute attacks of hereditary angioedema: results of three recent surveys. AB - In patients with hereditary angioedema (HAE), premonitory symptoms ("prodromes") may appear hours to days before attack onset. It remains to be determined if prodromes could be useful indicators for early treatment initiation. Most published reports of prodromes have been limited to case reports or small case series. The common objective of several recent survey-based studies was to collect information relevant to prodromal patterns in patients with HAE. Three separate surveys solicited prodromal data from HAE patients. Although differences in survey methodologies permit only descriptive analysis of data, responses to the surveys provide the largest compilation of observational data on this topic to date. Prodromes were reported by 82.5-95.7% of patients surveyed. In one survey, about two-thirds of subjects reported experiencing prodromes before all or most acute HAE attacks, and only 6% of subjects noted the appearance of prodromes in <10% of all attacks. The most common types of prodromal symptoms were related to skin/soft tissue and gastrointestinal tract. Most prodromes were experienced hours to days before the onset of angioedema. A large percentage of surveyed subjects indicated being able to predict an impending HAE attack all or most of the time; <10% reported being rarely or never able to predict an attack. Although insufficient to establish the clinical role of prodromal symptoms, results of these surveys provide additional data on the scope of prodromes and could stimulate further research into the potential efficacy and cost effectiveness of HAE attack prediction and prodrome-triggered interventions. PMID- 23676576 TI - Factors associated with hospitalization of patients with angiotensin-converting enzyme inhibitor-induced angioedema. AB - Angiotensin-converting enzyme inhibitor (ACE-I)-induced angioedema can be life threatening without emergent intervention. The putative mediator is believed to be bradykinin, similar to hereditary angioedema, so these patients respond poorly to corticosteroids and antihistamines. This study was designed to determine characteristics and clinical outcomes of patients presenting to an emergency department (ED) with ACE-I angioedema. This was a retrospective chart review of 100 patients presenting to the ED from 2007 to 2008 with an ICD-9 code of 995.1 (angioedema) or 995.2 (drug-induced angioedema). Two hundred fifty-two patients with these ICD-9 codes were identified and placed in random order, and the first 100 meeting inclusion criteria were included. Statistical analysis was primarily descriptive. All 100 patients had an ICD-9 code of 995.1 (angioedema). Patients presented in every month, with spring months (April-June) having the most presentations (32%). The median age was 59 years, 75% were African American, and 66% were admitted to the hospital. Two patients (2%) required endotracheal intubation. Lisinopril was the most commonly prescribed ACE-I (84%). The most common symptom was moderate lip and tongue swelling (89%) followed by mild difficulty breathing (12%). Tongue swelling was significantly associated with admission. Time from symptom onset to ED presentation was not associated with need for admission. Concomitant medications did not differ between admitted and discharged patients. ACE-I angioedema is associated with significant morbidity and health care use because many patients require hospitalization, suggesting an unmet need for novel therapies targeted to treat this condition. PMID- 23676577 TI - Randomized controlled trial of desloratadine for persistent allergic rhinitis: correlations between symptom improvement and quality of life. AB - Allergic rhinitis (AR) symptoms can impart emotional, quality of life (QOL), and work productivity burdens, especially in persistent AR (PER). Desloratadine, an H1-receptor antagonist, has been shown to be effective against nasal and nonnasal AR symptoms and to improve QOL. Exploratory analyses were conducted to evaluate whether desloratadine-mediated symptom improvement correlated with improvements in QOL and productivity. The Aerius Control: Clinical and Evaluative Profile of Treatment 2 (NCT00405964) study was a 12-week, multinational, randomized, placebo controlled prospective study of once-daily desloratadine at 5 mg in subjects with moderate-to-severe PER. Assessments included twice-daily symptom severity ratings (0 = none to 3 = severe; total and individual symptoms), sleep interference (morning [A.M.]), interference with activities of daily living (ADL; evening [P.M.]), the Rhinoconjunctivitis Quality of Life Questionnaire-Standardized version (baseline and days 29 and 85), and the Work Productivity and Activity Impairment-Allergy-Specific questionnaire (baseline and weekly). Pearson product moment correlation statistics (r) were determined to assess correlations between symptom score improvements and QOL factors. All desloratadine-treated patients (n = 360) were included in this exploratory analysis. In the desloratadine-treated patients, all correlations tested were positive (all p < 0.0001). The highest coefficients were seen for the correlations between A.M./P.M. PRIOR total five symptom score and interference with ADL (r = 0.72) and between A.M. NOW congestion and ADL interference (r = 0.69). Continuous daily treatment of moderate-to-severe PER with desloratadine at 5 mg/day significantly improved symptoms, which correlated positively, albeit moderately, with QOL benefits and reversal of functional impairments caused by PER. PMID- 23676578 TI - An integrated analysis of the efficacy of fluticasone furoate nasal spray versus placebo on the nasal symptoms of perennial allergic rhinitis. AB - Intranasal corticosteroids are widely prescribed for the treatment of perennial allergic rhinitis (PAR). The aim of this analysis was to determine whether the beneficial effects of once-daily (q.d.) fluticasone furoate nasal spray (FFNS) effectively improved individual nasal symptoms of PAR. An integrated analysis was performed on data from three randomized, double-blind, placebo-controlled, parallel-group trials designed to evaluate the efficacy and safety of FFNS at 110 micrograms, q.d. in subjects with PAR. The analysis included 460 subjects who received FFNS and 459 who received placebo for 4 weeks. All subjects evaluated the severity of individual nasal symptoms of nasal congestion, nasal itching, rhinorrhea, and sneezing on a four-point categorical scale. The main efficacy measures included change from baseline in daily reflective total nasal symptom score (rTNSS), reflective daily scores for each individual symptom, and predose instantaneous TNSS (iTNSS). Over 4 weeks of treatment, FFNS significantly improved rTNSS, iTNSS, and the reflective scores for each individual symptom compared with placebo. The least squares (LS) mean treatment difference over weeks 1-4 between FFNS and placebo for rTNSS was -0.93, ranging from -0.20 to 0.28 for the individual nasal symptoms (p < 0.001 for all versus placebo). For the iTNSS, the LS mean treatment difference between FFNS and placebo over weeks 1 4 was -0.95 (95% CI,-1.24, -0.66; p < 0.001). FFNS at 110 micrograms q.d. effectively relieved all nasal symptoms of PAR including nasal congestion over a 24-hour period. PMID- 23676579 TI - Anosmia and an uncommon nonsteroidal anti-inflammatory drug reaction in a 38-year old man. AB - Anosmia with asthma and nasal polyposis raises suspicion for aspirin-exacerbated respiratory disease (AERD). Guidelines for desensitization of patients with AERD to prevent recurrent nasal polyposis and improve upper and lower respiratory symptoms are well established. We present a patient with an uncommon reaction to acetylsalicylic acid (ASA) and nonsteroidal anti-inflammatory drugs who required deviation from the standard ASA desensitization approach. PMID- 23676580 TI - For the patient. PMID- 23676581 TI - WSAAI 50th Annual Scientific Session, Kohala Coast, Hawaii, January 20-24, 2013. PMID- 23676582 TI - Caspase-1: the inflammasome and beyond. AB - Caspase-1 plays a fundamental role in innate immunity and in several important inflammatory diseases as the protease activates the pro-inflammatory cytokines proIL-1beta and proIL-18. Caspase-1 itself is activated in different inflammasome complexes, which assemble in response to a variety of exogenous and endogenous stressors. More recently, pyroptosis, a caspase-1-dependent type of programmed cell death, has been identified that is able to support secreted IL-1 and IL-18 in triggering an inflammatory response. Whereas these 'canonical' activities are well appreciated, this review also highlights less-known pathways and molecules activated by caspase-1. There is evidence that caspase-1 supports cell survival by activation of NF-kappaB, induction of membrane repair and regulation of unconventional secretion of certain proteins. The physiologic effects of processing of other downstream targets, such as proteins involved in glycolysis or activation of caspase-7, are less well understood. However, there is increasing evidence that caspase-1 contributes to innate and adaptive immunologic defense mechanisms, repair and pathologic conditions by the regulation of several different and partially opposing pathways. PMID- 23676583 TI - Durations and domains of daily aerobic activity: evidence from the 2010 Canadian time-use survey. AB - BACKGROUND: This study employs national time-diary data to evaluate how much aerobic activity Canadians engage in on a daily basis, how that activity is apportioned by activity domain, and how subgroups within the population vary in their aerobic attainment. METHODS: The study employs time-use data from the 2010 General Social Survey of Canada, for 15,390 respondents aged 15 and older. To estimate effort levels, the authors harmonized survey codes with those in the Compendium of Physical Activities. Aerobic activity was defined as moderate or vigorous effort at 3.5 Metabolic Equivalent of Task (MET) or higher. RESULTS: Among the 4 activity domains, aerobic participation is highest in leisure activities, followed by chores, paid work, and active transportation (AT). Only a minority (42%) of respondents recorded at least 20 mins/day of aerobic activity. Aerobic totals were particularly low for women and those in poor or fair health, and low for students, 15- to 24-year-olds, and those residing in Quebec, Ontario, and larger cities. CONCLUSIONS: The majority of Canadian adults are failing to meet recommended aerobic activity levels. However, there is considerable opportunity to increase aerobic participation for some groups, particularly women and young adults, especially in the leisure and AT domains. PMID- 23676584 TI - Mild renal dysfunction on admission is an important prognostic predictor in patients with infective endocarditis: a retrospective single-center study. AB - OBJECTIVE: Infective endocarditis (IE) continues to be associated with high mortality. The aim of the present study was to identify prognostic predictors for short-term mortality in patients with IE. METHODS: We conducted a retrospective study of 119 consecutive patients with IE (mean age 58+/-17). Prognostic predictors for mortality at the early phase of admission were determined using a multivariate regression analysis, and a receiver operating characteristic (ROC) analysis was carried out to evaluate the predictive ability. RESULTS: Eleven of 119 patients died during hospital admission. In this non-survivor group, the clinical parameters at the time of admission, including serum creatinine (Cr), the estimated glomerular filtration rate (eGFR), the red blood cell count, the white blood cell count, the serum CRP level and heart rate, differed significantly from those observed in the survivors (all; p<0.05). According to a logistic regression analysis, an increase in log-serum Cr per one standard deviation (odds ratio=2.18, 95%CI=1.08-4.41) and a decrease in log-eGFR per one standard deviation (odds ratio=0.51, 95%CI=0.26-0.98) were significantly associated with in-hospital death. The area under the ROC curve for serum Cr to predict the outcome was 0.80, the sensitivity was 64% and the specificity was 85% at a cut-off value of 1.16 mg/dL. For eGFR, the area under the ROC curve was 0.77, the sensitivity was 64% and the specificity was 86% at a cut-off value of 47.5 mL/min./1.73 m(2). CONCLUSION: Mild renal dysfunction at the time of admission is an important predictor of early phase mortality in patients with IE. PMID- 23676585 TI - An elevated ratio of placental growth factor to soluble fms-like tyrosine kinase 1 predicts adverse outcomes in patients with stable coronary artery disease. AB - OBJECTIVE: To investigate the predictive values of placental growth factor (PlGF) and its endogenous antagonist, soluble fms-like tyrosine kinase-1 (sFlt-1), for the long-term prognosis of patients with stable coronary artery disease (CAD). Both PlGF and sFlt-1 play important roles in the pathological mechanisms of atherosclerosis. We recently demonstrated that the plasma levels of these molecules are correlated with the severity of coronary atherosclerosis. METHODS: We enrolled 464 patients with stable CAD who consecutively underwent coronary angiography. Baseline blood samples were collected from the femoral artery immediately before coronary angiography (after the administration of 20 units of heparin), and the plasma levels of PlGF and sFlt-1 were measured. A Cox proportional hazard regression analysis was performed to evaluate the relationship between these parameters and the occurrence of all-cause death (ACD) and total cardiovascular events (TCVE) during a median follow-up of 3.3 years. RESULTS: A total of 31 ACDs and 51 TCVEs occurred. Patients with higher PlGF/sFlt 1 ratios (>4.22*10(-2)) had a significantly higher risk of both ACD and TCVE than patients with lower ratios (<4.22*10(-2)) (hazard ratio [HR]: 3.32, 95% confidence interval [CI]: 1.43 to 7.72, p=0.005, and HR: 2.23, 95% CI: 1.23 to 4.03, p=0.008, respectively). A multivariate analysis showed the PlGF/sFlt-1 ratio to be an independent predictor for ACD, but not TCVE. CONCLUSION: The baseline PlGF/sFlt-1 ratio is an independent predictor of long-term adverse outcomes in patients with stable CAD. PMID- 23676586 TI - Effects of liraglutide, a human glucagon-like peptide-1 analogue, on body weight, body fat area and body fat-related markers in patients with type 2 diabetes mellitus. AB - OBJECTIVE: To evaluate the effects of six-month liraglutide treatment on body weight, visceral and subcutaneous fat and related markers in Japanese type 2 diabetic patients. METHODS: A total of 59 patients with type 2 diabetes were treated with liraglutide (0.3 mg/day for >=1 week and then 0.6 mg/day for >=1 week, gradually increasing the dose to 0.9 mg/day) for six months. Changes in body weight, body mass index (BMI), HbA1c, the fasting blood glucose level, visceral and subcutaneous fat areas, hepatic and renal CT values and the associated markers proinsulin, adiponectin and pentraxin (PTX) 3 were measured. RESULTS: The study included one treatment-naive patient, 10 patients who were switched from oral antidiabetic drugs and 35 patients who were switched from insulin therapy. At six months after treatment, the preprandial blood glucose levels were higher (148.8+/-40.5 mg/dL) than the baseline values (130.8+/-36.7, p<0.05); however, body weight, BMI and abdominal circumference were lower, and the liver/kidney CT ratio improved significantly from 1.64+/-0.44 at baseline to 1.78+/-0.42. An analysis of the patients who were not pretreated with insulin resistance ameliorators showed that six months of liraglutide treatment significantly decreased the subcutaneous but not visceral fat areas, significantly decreased the serum adiponectin levels and significantly increased the serum PTX3 levels. CONCLUSION: In addition to its glucose-lowering effects, liraglutide exhibits weight loss promotion actions, reducing subcutaneous fat areas in particular. The weight and total fat area reduction properties of liraglutide are likely to be beneficial when this medication is used in combination with other oral antidiabetic drugs and insulin. PMID- 23676587 TI - Inhibition of calcium(2+)/calmodulin-dependent protein kinase type IV ameliorates experimental nephrotic syndrome. AB - OBJECTIVE: Evidence has demonstrated that Ca(2+)/calmodulin-dependent protein kinase type IV (CaMKIV) contributes to altered cytokine production by promoting the production of inflammatory cytokines. This study aimed to explore the protective role and underlying mechanisms of CaMKIV inhibition in experimental nephrotic syndrome. METHODS: BALB/c mice received single intravenous injections of adriamycin (10 mg/kg) then were sacrificed at two, four and six weeks. In the second study, treatment with KN-93, a CaMKIV inhibitor, or vehicle administered via intraperitoneal injection was started five days after adriamycin injection. Functional and pathologic parameters, the presence of inflammatory infiltration and the expressions of pro-inflammatory cytokines were assessed. RESULTS: The CaMKIV protein expression levels were upregulated in the mice with adriamycin nephropathy, which was significantly inhibited by KN-93 (p<0.01). As compared with the vehicle-treated controls, KN-93 treatment resulted in marked suppression of proteinuria and serum creatinine at week 6 (p<0.01), but not at two weeks after induction of the disease. KN-93 inhibited glomerulosclerosis and the development of tubulointerstitial lesions. The renal alpha-smooth muscle actin (alpha-SMA) expression was also significantly suppressed by KN-93 treatment at week 6 (p<0.01). Moreover, KN-93 inhibited the renal monocyte chemoattractant protein-1 (MCP-1) expression, paralleled by a reduction in the interstitial infiltration of macrophages and T-cells (p<0.01). CONCLUSION: Our findings suggest that activation of CaMKIV signaling is involved in the progression of glomerular diseases with a proteinuric state. Our data therefore justify the development of small molecule CaMKIV inhibitors for the treatment of clinical nephrotic syndrome. PMID- 23676588 TI - Dual antiplatelet therapy clopidogrel with low-dose cilostazol intensifies platelet inhibition in patients with ischemic stroke. AB - OBJECTIVE: We previously reported that the antiplatelet action is intensified with combined use of clopidogrel and cilostazol in ischemic stroke patients using the VerifyNow P2Y12 Assay. In this study, the relationship between the cilostazol dose and the platelet function achieved with combination therapy was investigated. METHODS: The subjects included 231 patients with noncardiogenic ischemic stroke treated at our hospital (18 patients treated with a combination of clopidogrel (75 mg) and cilostazol (100 mg), 52 patients treated with a combination of clopidogrel (75 mg) and cilostazol (200 mg), 126 patients treated with clopidogrel (75 mg) alone and 35 patients treated with cilostazol (200 mg) alone). The platelet function achieved with 20 MUM of adenosine diphosphate was measured using the VerifyNow P2Y12 Assay. Clopidogrel resistance was defined as P2Y12 Reaction Units (PRU) >230 and/or % inhibition <20%. Results The PRU was >230 in 32 patients (25.4%) receiving clopidogrel alone, one patient (5.6%) receiving combination therapy with cilostazol (100 mg) and one patient (1.9%) receiving combination therapy with cilostazol (200 mg). The rate of PRU >230 was significantly lower in both of the cilostazol combination groups than in the clopidogrel alone group. The percent inhibition was <20% in 41 patients (32.5%) receiving clopidogrel alone, one patient (5.6%) receiving a combination with cilostazol (100 mg) and one patient (1.9%) receiving a combination with cilostazol (200 mg). The rate of % inhibition <20% was significantly lower in both of the cilostazol combination groups than in the clopidogrel alone group. CONCLUSION: Clopidogrel resistance was clearly decreased with combination clopidogrel (75 mg) and low-dose (100 mg) cilostazol therapy. The use of combination therapy with clopidogrel and low-dose cilostazol may be one means of overcoming clopidogrel resistance. PMID- 23676589 TI - Maintenance of the remission stage of Crohn's disease with adalimumab therapy during pregnancy. AB - A 25-year-old pregnant woman complained of abdominal pain and diarrhea. Total colonoscopy provided a diagnosis of Crohn's disease (CD) of the large intestine (Crohn's colitis). Because the patient was allergic to mesalazine, adalimumab (ADA) was used as maintenance therapy during pregnancy, following prednisolone as remission induction therapy. Remission of the patient's CD was maintained with ADA, and the patient delivered a baby girl without any difficulties. Remission of the patient's CD continued to be maintained with the administration of ADA after childbirth. We believe that this is the first report of the use of ADA therapy in a pregnant CD patient in Japan. PMID- 23676590 TI - Portal biliopathy diagnosed using color Doppler and contrast-enhanced ultrasound. AB - Portal biliopathy is a morphological abnormality of the biliary ductal and gallbladder wall associated with portal hypertension. A patient with essential thrombocythemia was initially diagnosed with extrahepatic portal vein obstruction (EHPVO). The contrast-enhanced computed tomography (CT) findings were similar to those of cholangiocarcinoma or sclerosing cholangitis. However, color Doppler and contrast-enhanced ultrasound (US) were more specific. The paracholedocheal veins around the bile ducts appeared as beads soon after the injection of contrast medium, followed by linear enhancement of the epicholedochal veins and the gradual enhancement of the whole bile ducts. These findings led to a diagnosis of portal biliopathy, which prevented the patient from having to endure hazardous procedures such as bile duct biopsies. Color Doppler and contrast-enhanced US findings are useful for diagnosing or ruling out portal biliopathy in patients who present with EHPVO. PMID- 23676591 TI - Pulmonary hypertension and refractory heart failure in a patient with Crow-Fukase (POEMS) syndrome. AB - We experienced the case of a 67-year-old man with refractory heart failure. He presented with dyspnea and progressive pitting edema of the lower limbs. Diuretics were insufficient to improve his symptoms. Cardiac catheterization demonstrated pulmonary hypertension. Additional examinations confirmed polyneuropathy, organomegaly, endocrinopathy and monoclonal gammopathy. The plasma vascular endothelial growth factor (VEGF) level was 1,340 pg/mL. The patient was diagnosed with Crow-Fukase (POEMS) syndrome. Echocardiography detected left ventricular hypertrophy and diastolic dysfunction. Polysomnography demonstrated severe sleep-disordered breathing. We herein describe a case of pulmonary hypertension with Crow-Fukase syndrome accompanied by left ventricular diastolic dysfunction and sleep-disordered breathing. PMID- 23676592 TI - Dilated cardiomyopathy as a presenting feature of Cushing's syndrome. AB - Cardiovascular complications, including cardiomegaly, myocardial ischemia and left ventricular hypertrophy, are some of the major determinants of the mortality rate in patients with Cushing's syndrome. We herein report the case of a patient with Cushing's syndrome caused by an adrenal adenoma who presented with congestive heart failure secondary to dilated cardiomyopathy. Follow-up echocardiography showed a marked improvement in the left ventricular cardiac function, and the plasma B-type natriuretic peptide (BNP) levels regressed after successful treatment. "Reversible" dilated cardiomyopathy is rarely associated with Cushing's syndrome; however, it should be recognized. Administering appropriate treatment in a timely manner can reverse this cardiomyopathy along with the other symptoms of Cushing's syndrome. PMID- 23676593 TI - A marked difference in the vasopressin responsiveness between the adrenal glands in a patient with adrenocorticotropin-independent macronodular adrenal hyperplasia. AB - We herein present the case of a 53-year-old patient with adrenocorticotropin independent macronodular adrenocortical hyperplasia (AIMAH), which is a rare form of Cushing syndrome. He had hypercortisolemia and bilateral macronodular adrenal glands with a left side predominance. The administration of vasopressin significantly increased the plasma cortisol level (1.9-fold). Following left adrenalectomy, the patient's hypercortisolemia significantly improved and vasopressin responsiveness was lost, suggesting that the responsiveness originated from the resected left adrenal gland. The marked difference in vasopressin responsiveness between the adrenals corresponded with their asymmetrical size and function. Evaluating the differences in the vasopressin sensitivity may therefore be helpful for understanding the progression of AIMAH. PMID- 23676594 TI - Rituximab treatment for adult purpura nephritis with nephrotic syndrome. AB - The case of a 68-year-old woman with purpura nephritis associated with nephrotic syndrome is herein described. The patient's clinical course and the findings of a renal biopsy study revealed purpura nephritis. Following treatment with corticosteroids and intravenous cyclophosphamide accompanied by an angiotensin II type I receptor-blocker, an anti-platelet drug and an hydroxymethylglutaryl (HMG) CoA, the proteinuria mildly decreased. Additional rituximab therapy led to a complete remission. This report describes our successful experience using rituximab to treat refractory nephrotic syndrome of purpura nephritis. Further studies are required to confirm the efficacy of rituximab as an alternative therapy for nephrotic syndrome. PMID- 23676595 TI - Successful treatment with noninvasive positive-pressure ventilation based on the prediction of disease onset using CT and respiratory function tests in an elderly patient with relapsing polychondritis. AB - An 83-year-old man who had been receiving treatment for bronchial asthma since 62 years of age experienced difficulty breathing on exertion and was admitted to the hospital. On admission, computed tomography revealed tracheal wall thickening, while test results for antinuclear antibodies and anti-type II collagen antibodies were positive. Since a saddle nose deformity, malacia of the auricles and sensorineural deafness were also observed, relapsing polychondritis was diagnosed. Measuring the peak expiratory flow rate was useful in the early airway assessment. During the follow-up period, the patient's dyspnea worsened and noninvasive positive-pressure ventilation was introduced. As a result, the subjective symptoms improved. PMID- 23676596 TI - Hereditary hemorrhagic telangiectasia with pulmonary arteriovenous malformations and embolic strokes treated successfully with video-assisted thoracoscopic resection. AB - A 67-year-old hypoxic woman was admitted following two episodes of cerebral infarction. Based on the clinical presentation and radiological findings, a diagnosis of hereditary hemorrhagic telangiectasia was made and the cerebral ischemic complications were considered to have been caused by paradoxical embolizations related to pulmonary arteriovenous malformations (PAVMs). We performed video-assisted thoracoscopic surgery (VATS) and identified turbulent thrombi in one of the PAVMs that were capable of circulating systemically and inducing embolic strokes. The condition of the patient improved immediately following VATS. This case suggests that VATS may be a preferred therapeutic option in the treatment of patients with PAVM accompanying recurrent episodes of life-threatening complications such as strokes. PMID- 23676597 TI - Systemic vasculitis associated with anti-neutrophil cytoplasmic antibodies against bactericidal/permeability increasing protein. AB - Myeloperoxidase- and proteinase 3-anti-neutrophil cytoplasmic antibodies (ANCAs) are often negative in cases in which systemic vasculitis is highly suspected. We herein present a case of bactericidal/permeability increasing protein (BPI)-ANCA positive systemic vasculitis. This case highlights the possible role of BPI-ANCA in the pathogenesis of systemic vasculitis as well as the possible use of BPI as a diagnostic tool. The accumulation of further case-based reports is expected to shed some light on the pathogesis of systemic vasculitis. PMID- 23676598 TI - Therapeutic effects of lenalidomide on hemorrhagic intestinal myeloma-associated AL amyloidosis. AB - A 74-year-old woman with refractory IgG-kappa multiple myeloma developed massive melena caused by hemorrhagic submucosal tumors in the duodenum and middle jejunum. A biopsy revealed the tumor to be marked AL amyloid deposition. Treatment with bortezomib did not improve the melena or the underlying disease. The patient also developed multiple amyloidomas in the bilateral femoral heads, which caused a fracture in the left femoral head. Treatment with lenalidomide, as the final therapeutic option, resolved the intractable melena and improved both the intestinal lesions and myeloma. This case shows that successful treatment of multiple myeloma leads to marked improvement of accompanying AL amyloidosis. PMID- 23676599 TI - Central diabetes insipidus in an HHV6 encephalitis patient with a posterior pituitary lesion that developed after tandem cord blood transplantation. AB - A 60-year-old myelodysplastic syndrome patient underwent tandem cord blood transplantation. The primary cord blood graft was rejected, and human herpesvirus 6 (HHV6) encephalitis developed after engraftment of secondary cord blood. Polyuria and adipsic hypernatremia were observed during treatment of the encephalitis. The patient died of bacteremia caused by methicillin-resistant Streptococcus epidermis. HHV6 infection in the posterior pituitary was confirmed on autopsy, as was infection of the hippocampus, but not of the hypothalamus. This is the first case report of central diabetes insipidus caused by an HHV6 posterior pituitary infection demonstrated on a pathological examination. PMID- 23676601 TI - Opalski syndrome caused by vertebral artery compression of the lateral surface of the medulla oblongata. AB - A 55-year-old man presented with vertigo, nystagmus, and gait ataxia followed by left hemiparesis (Opalski syndrome). T2-weighted magnetic resonance imaging revealed vascular compression of the left lateral side of the medulla oblongata by the left vertebral artery. On diffusion tensor imaging, the level of fractional anisotropy (FA) in the left corticospinal fibers caudal to the pyramidal decussation was lower than that observed in the right corticospinal fibers. Opalski syndrome caused by vascular compression is very rare. This is the first reported case of Opalski syndrome that was imaged on FA. PMID- 23676600 TI - Drug-induced thrombotic thrombocytopenic purpura successfully treated with recombinant human soluble thrombomodulin. AB - A 61-year-old woman with recurrent non-small cell lung cancer presented with thrombocytopenia, microangiopathic hemolytic anemia, neurological abnormalities, renal failure and a fever that appeared during chemotherapy with gemcitabine and bevacizumab. She was diagnosed with drug-induced thrombotic thrombocytopenic purpura (TTP). After the discontinuation of chemotherapy, the administration of recombinant human soluble thrombomodulin and fresh-frozen plasma rapidly ameliorated the TTP. Hypertension preceded the onset of TTP and required the administration of quadruple therapy on admission. However, after three months, the hypertension was controllable without anti-hypertensive drugs. Twelve months later, the ninth course of vinorelbine was administered safely, preventing the patient's lung cancer from progressing. PMID- 23676602 TI - Tolosa-hunt syndrome associated with cytomegalovirus infection. AB - We herein present the case of a 38-year-old woman with left-sided oculomotor paralysis with ocular pain that developed after a respiratory infection. Her serum was positive for IgM against GM2 and GalNAc-GD1a gangliosides and cytomegalovirus. Thin-slice magnetic resonance imaging revealed enhanced abnormal tissue located primarily in the superolateral part of the left-sided cavernous sinus, which corticosteroids subsequently obscured with immediate resolution of the patient's ocular symptoms. These clinical features were consistent with those of Tolosa-Hunt syndrome (THS). Our findings in the present patient suggest that cytomegalovirus may provoke granuloma formation in the cavernous sinus, as reported in other various organs, thereby leading to the development of THS. PMID- 23676603 TI - Successful treatment of class IV+V lupus nephritis with combination therapy of high-dose corticosteroids, tacrolimus and intravenous cyclophosphamide. AB - A substantial number of patients with lupus nephritis (LN) are refractory to conventional glucocorticoid (GC) treatment. Although many of these patients respond to immunosuppressive drugs such as intravenous cyclophosphamide (IVCY), azathioprine (AZA), mizoribine, tacrolimus, cyclosporine A (CSA) and mycofenolate mofetil (MMF), some remain refractory to such therapies. Recent studies of multi target therapies have reported effective outcomes for immunosuppression following renal transplantation and refractory LN when therapy consists of two or more immunosuppressive drugs with different mechanisms of action. We herein report a case of LN unresponsive to IVCY that was successfully treated with the addition of tacrolimus and discuss the usefulness of multi-target therapy for LN. PMID- 23676604 TI - Infective endocarditis caused by Enterococcus faecalis treated with continuous infusion of ampicillin without adjunctive aminoglycosides. AB - Aminoglycosides are useful antimicrobial agents for treating infective endocarditis; however, they occasionally cause troublesome side effects, such as nephrotoxicity and ototoxicity. We herein report a case of infective endocarditis caused by Enterococcus faecalis that was treated successfully with continuous infusion of ampicillin without adjunctive aminoglycosides. The serum ampicillin concentrations were higher than the minimal inhibitory concentration for the target strain. Although the use of ampicillin monotherapy is currently avoided because double beta-lactam therapy is reportedly more effective, continuous penicillin administration remains an effective therapeutic choice for treating infective endocarditis. PMID- 23676605 TI - Incidental finding of the sternalis muscle on chest multidetector-row computed tomography (MDCT): the diagnostic value of additional postprocessed MDCT images for an uncommon muscular variant. AB - We herein report two cases of incidental finding of the sternalis muscle in the right anterior chest wall on multidetector-row computed tomography (MDCT). We emphasize the diagnostic utility and value of additional postprocessed MDCT images, which can be easily created using volume data sets of MDCT, in establishing an accurate diagnosis of the sternalis muscle, an uncommon muscular variant. PMID- 23676606 TI - Endoscopic diagnosis of appendicitis. PMID- 23676607 TI - Severe right coronary artery kinking treated with stent placement. PMID- 23676608 TI - Recurrent refractory arterial thromboembolism in a patient with anti-phospholipid antibody syndrome. PMID- 23676609 TI - Reversible splenial lesion associated with Staphylococcus aureus endocarditis. PMID- 23676610 TI - Pigmented villonodular synovitis of the ankle. PMID- 23676611 TI - Hypopharyngeal foreign body. PMID- 23676612 TI - Retraction: Use of non-benzodiazepine hypnotics is associated with decreased risk of coronary artery disease. PMID- 23676613 TI - Highly conductive and transparent Ag honeycomb mesh fabricated using a monolayer of polystyrene spheres. AB - We describe the design principles and fabrication of Ag honeycomb mesh as a transparent conductive electrode using a polystyrene (PS) sphere template. Monolayers of PS spheres with different diameters, such as 600 nm, 3 MUm, and 10 MUm, are studied as templates to form Ag mesh with high transmittance. Since the parasitic Ag islands degrade the transmittance, both heat pretreatment and wet etching are used to control the area covered by parasitic Ag islands. The trade off between transmittance and conductivity forces us to use larger diameter PS spheres. Ten-micron PS spheres are chosen as the template for the PS sphere monolayer, and heat pretreatment and Ag wet etching are used to demonstrate that the Ag honeycomb mesh transparent electrodes have high performance. The transmittance and the sheet resistance are 83% and 20 Omega/sq, which are comparable to commercial ITO electrodes. PMID- 23676614 TI - A blind re-analysis of the Iowa family study of obsessive-compulsive disorder. AB - We present results from a re-analysis of the Iowa family study of obsessive compulsive disorder (OCD) that previously concluded the disorder was not familial. These conclusions were based on Diagnostic Interview Schedule results of first-degree relatives (FDRs) and not a best estimate diagnosis (BED). For the re-analysis we reviewed raw data on OCD and control probands and their FDRs. Relatives had been assessed through structured interviews, validated questionnaires, family history, and medical records in some cases. BEDs were assigned through a blind consensus procedure employing DSM-IV criteria. The data were analyzed using logistic regression with generalized estimating equations to account for within family correlations. BEDs were assigned to 32 OCD probands, 31 control probands, and 352 FDRs, including 249 FDRs who were interviewed directly and 103 FDRs who were unavailable or deceased. Lifetime prevalence of definite/probable OCD was significantly higher in the FDRs of OCD probands than controls (10.7% vs. 3.8%, OR=3.04, p=0.026). FDRs of OCD probands had significantly higher rates of depressive illness than relatives of controls. Depression of any type in relatives was predicted by the proband's depression history. We conclude that OCD is familial. The re-analysis highlights the importance of the BED procedure in family studies. PMID- 23676615 TI - Visit-to-visit variability of blood pressure: current knowledge and future research directions. AB - Blood pressure (BP) is known to vary over time within individuals. Although variability between office visits has traditionally been regarded as a barrier to the accurate measurement of BP, several recent studies have reported strong associations between visit-to-visit variability (VVV) of BP and increased risk for cardiovascular outcomes. In this article, we review data on VVV of BP and outcomes, determinants of high VVV of BP including demographics, medical history, and antihypertensive medication classes and poor adherence. In addition, we will discuss methodological issues related to interpreting data from studies of VVV of BP and data on BP variability assessed outside of the office setting. In conclusion, we highlight pressing research needs related to VVV of BP including those aimed at determining the mechanism underlying high VVV of BP, assessing interventions that lower VVV of BP and the utility of quantifying VVV of BP using measurements obtained in routine clinical practice. PMID- 23676618 TI - Parental health information seeking and re-exploration of the 'digital divide'. AB - AIM: To describe patterns of 'online' and 'offline' health information seeking in families with children under five years of age and living in five socially, economically and culturally disparate local authority (LA) wards in one inner city area. BACKGROUND: Earlier work analysed data from the five LA wards merged as one data set. A 'digital divide' in health information seeking was identified between parents who actively sought information from both internet websites and from 14 other health information sources (online health information seekers), and those who acquired information from a more limited range of sources excluding the internet. Of the two groups, the online health information seekers had higher levels of computer ownership and, therefore, internet access within the home. METHOD: Re-analysis of data (questionnaires n = 224; five focus groups; two interviews with service providers; two opportunistic conversations with service providers). Additional data were retrieved after the original data analysis and between 2005 and 2007. These data were from service user-led discussions (n = 30) held with parents in child health clinics, informal interviews (n = 11) with health visitors and semi-structured interviews (n = 2) with health visitors. Information was also retrieved from the Office for National Statistics data set. In the re-analysis, data were disaggregated at LA ward level in order to explore local influences on patterns of health information seeking. RESULTS: Multiple layers of influence upon parental health information seeking emerged and revealed a non-digital second divide, which was independent of computer ownership and home internet access. This divide was based on preference for use of certain health information sources, which might be either 'online' or 'offline'. A spatial patterning of both digital and preferential divides was identified with an association between each of these and features of the physical, social, cultural and psychosocial environment, one of which was perceived access to primary health care. CONCLUSION: Complex patterns of health information seeking relate to each of the 'divides'--digital and preferential. Patterns of health information seeking reflect differing perceptions of information availability and usefulness as experienced by parents within their local physical, social, cultural and psychosocial worlds. Access to primary care services is a key component of this local environment. PMID- 23676617 TI - Whole-genome sequencing in health care: recommendations of the European Society of Human Genetics. PMID- 23676619 TI - Global detection and identification of developmental stage specific transcripts in mouse brain using subtractive cross-screening algorithm. AB - BACKGROUND: Pre-mRNA splicing is a crucial step for genetic regulation and accounts largely for downstream translational diversity. The current time of biological research is characterized by advances in functional genomics study and the understanding of the pre-mRNA splicing process has thus become a major portal for biologists to gain insights into the complex gene regulatory mechanism. The intranuclear alternative splicing process can form a variety of genomic transcripts that modulate the growth and development of an organism, particularly in the immune and neural systems. METHODS: In the current study, we investigated and identified alternative splicing transcripts at different stages of embryonic mouse brain morphogenesis using subtractive cross-screening algorithm. RESULTS: A total of 195 candidate transcripts were found during organogenesis; 1629 identified at fetus stage, 116 in juvenile and 148 transcripts from adulthood. To document our findings, we developed a database named DMBAS, which can be accessed through the link: http://173.234.48.5/DMBAS. We further investigated the alternative splicing products obtained in our experiment and noted the existence of chromosome preference between prenatal and postnatal transcripts. Additionally, the distribution of splicing sites and the splicing types were found to have distinct genomic features at varying stages of brain development. The majority of identified alternative splices (72.3%) at fetus stage were confirmed later using separate RNA-seq data sets. CONCLUSION: This study is a comprehensive profiling of alternative splicing transcripts of mouse brain morphogenesis using advanced computational algorithm. A series of developmental stage specific transcripts, as well as their splicing sites and chromosome preferences were revealed in the current study. Our findings and the related online database would form a solid foundation for studies of broader biological significance and paved the way for future investigations in relevant human brain diseases. PMID- 23676620 TI - An unusual burn. PMID- 23676621 TI - Obama vows to fully implement Affordable Care Act despite opposition. PMID- 23676622 TI - Challenge to research on heart disease patterns in India sparks controversy. PMID- 23676623 TI - Medicare fails to monitor questionable prescribing practices, investigation finds. PMID- 23676624 TI - Effect of nitrogen and fluorine on mechanical properties and bioactivity in two series of bioactive glasses. AB - Bioactive glasses are able to bond to bone through formation of carbonated hydroxyapatite in body fluids, and fluoride-releasing bioactive glasses are of interest for both orthopaedic and, in particular, dental applications for caries inhibition. However, because of their poor strength their use is restricted to non-load-bearing applications. In order to increase their mechanical properties, doping with nitrogen has been performed on two series of bioactive glasses: series (I) was a "bioglass" composition (without P2O5) within the quaternary system SiO2-Na2O-CaO-Si3N4 and series (II) was a simple substitution of CaF2 for CaO in series (I) glasses keeping the Na:Ca ratio constant. The objective of this work was to evaluate the effect of the variation in nitrogen and fluorine content on the properties of these glasses. The density, glass transition temperature, hardness and elastic modulus all increased linearly with nitrogen content which indicates that the incorporation of nitrogen stiffens the glass network because N is mainly in 3-fold coordination with Si atoms. Fluorine addition significantly decreases the thermal property values but the mechanical properties of these glasses remain unchanged with fluorine. The combination of both nitrogen and fluorine in oxyfluoronitride glasses gives better mechanical properties at much lower melting temperatures since fluorine reduces the melting point, allows higher solubility of nitrogen and does not affect the higher mechanical properties arising from incorporation of nitrogen. The characterization of these N and F substituted bioactive glasses using (29)Si MAS NMR has shown that the increase in rigidity of the glass network can be explained by the formation of SiO3N, SiO2N2 tetrahedra and Q(4) units with extra bridging anions at the expense of Q(3) units. Bioactivity of the glasses was investigated in vitro by examining apatite formation on the surface of glasses treated in acellular simulated body fluid (SBF) with ion concentrations similar to those in human blood plasma. Formation of a bioactive apatite layer on the samples treated in SBF was confirmed by grazing incidence X-ray diffraction and scanning electron microscopy (SEM) combined with energy dispersive X-ray spectroscopy (EDS). The crystallinity of this layer decreases with increasing N content suggesting that N may decrease bioactivity slightly. PMID- 23676625 TI - A novel power efficient location-based cooperative routing with transmission power-upper-limit for wireless sensor networks. AB - The extensive usage of wireless sensor networks (WSNs) has led to the development of many power- and energy-efficient routing protocols. Cooperative routing in WSNs can improve performance in these types of networks. In this paper we discuss the existing proposals and we propose a routing algorithm for wireless sensor networks called Power Efficient Location-based Cooperative Routing with Transmission Power-upper-limit (PELCR-TP). The algorithm is based on the principle of minimum link power and aims to take advantage of nodes cooperation to make the link work well in WSNs with a low transmission power. In the proposed scheme, with a determined transmission power upper limit, nodes find the most appropriate next nodes and single-relay nodes with the proposed algorithm. Moreover, this proposal subtly avoids non-working nodes, because we add a Bad nodes Avoidance Strategy (BAS). Simulation results show that the proposed algorithm with BAS can significantly improve the performance in reducing the overall link power, enhancing the transmission success rate and decreasing the retransmission rate. PMID- 23676626 TI - A longitudinal examination of the developmental executive function hierarchy in children with externalizing behavior problems. AB - OBJECTIVE: Using a 4-year longitudinal design, we evaluated two hypotheses based on developmental executive function (EF) hierarchy accounts in a sample of children with externalizing problems. METHOD: The participants performed EF tasks when they were between 8 and 12 years (M = 9.93), and again approximately 4 years later when they were between 12 and 15 years (M = 13.36). RESULTS: Inhibition in middle childhood predicted working memory (WM) 4 years later. Further, deficits in inhibition and sustained attention were more prominent in middle rather than late childhood, whereas poor WM was salient throughout these periods. CONCLUSIONS: These findings support the hypotheses that EFs develop hierarchically and that EF deficits in ADHD are more prominent in actively developing EFs. They also emphasize ADHD as a developmental disorder. PMID- 23676627 TI - Correlates of frailty among homeless adults. AB - Frailty, a relatively unexplored concept among vulnerable populations, may be a significant issue for homeless adults. This cross-sectional study assessed correlates of frailty among middle age and older homeless adults (N = 150, 40 73). A Pearson (r) bivariate correlation revealed a weak relationship between frailty and being female (r = .230, p < .01). Significant moderate negative correlations were found between frailty and resilience (r = -.395, p < .01), social support (r = -.377, p < .01), and nutrition (r = -.652, p < .01). Furthermore, Spearman's rho (r s) bivariate correlations revealed a moderate positive relationship between frailty and health care utilization (r(s) = .444, p < .01). A stepwise backward linear regression analysis was conducted and in the final model, age, gender, health care utilization, nutrition, and resilience were significantly related to frailty. Over the next two decades, there is an anticipated increase in the number of homeless adults which will necessitate a greater understanding of the needs of this hard-to-reach population. PMID- 23676628 TI - Synthesis and biopharmaceutical studies of JLTN as potential dasatinib prodrug. AB - Dasatinib was identified as a potent orally administered Src/Abl kinase inhibitor with excellent antiproliferative activity against Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase. The low bioavailability of Dasatinib may be due to both incomplete oral absorption and first-pass metabolism. A prodrug, JLTN, was synthesized to minimize the first-pass effect of Dasatinib and improve the oral bioavailability following oral administration via targeting intestinal peptide transporter and enhancing chemical stability. Biological evaluation data indicated that there was a 150%-fold increase in oral bioavailability of this prodrug compared to the parent drug Dasatinib in monkeys. PMID- 23676629 TI - Paracrine mechanisms of mesenchymal stem cell-based therapy: current status and perspectives. AB - Mesenchymal stem cells (MSCs) are one of a few stem cell types to be applied in clinical practice as therapeutic agents for immunomodulation and ischemic tissue repair. In addition to their multipotent differentiation potential, a strong paracrine capacity has been proposed as the principal mechanism that contributes to tissue repair. Apart from cytokine/chemokine secretion, MSCs also display a strong capacity for mitochondrial transfer and microvesicle (exosomes) secretion in response to injury with subsequent promotion of tissue regeneration. These unique properties of MSCs make them an invaluable cell type to repair damaged tissues/organs. Although MSCs offer great promise in the treatment of degenerative diseases and inflammatory disorders, there are still many challenges to overcome prior to their widespread clinical application. Particularly, their in-depth paracrine mechanisms remain a matter for debate and exploration. This review will highlight the discovery of the paracrine mechanism of MSCs, regulation of the paracrine biology of MSCs, important paracrine factors of MSCs in modulation of tissue repair, exosome and mitochondrial transfer for tissue repair, and the future perspective for MSC-based therapy. PMID- 23676630 TI - Estimation of abdominal fat mass: validity of abdominal bioelectrical impedance analysis and a new model based on anthropometry compared with dual-energy x-ray absorptiometry. AB - OBJECTIVE: Since abdominal adiposity has been associated with increased risk for chronic diseases, valid and low cost methods to estimate it are needed for clinical and research purposes. The aim of the current study was to develop and validate, using dual-energy x-ray absorptiometry (DXA) as reference method, a model that estimates abdominal fat mass percentage (AFM%) in white postmenopausal women based on simple and easy-to-apply anthropometric measurements. An additional aim was to validate an abdominal bioelectrical impedance analyzer (ViScan) for estimating waist circumference (WC) and AFM% in this group. METHODS: Ninety-one postmenopausal women (mean age, 61.5 y) with body mass index ranging from 20.9 to 42 kg/m2 were randomly divided into one training set (n = 60) and one testing set (n = 31) to develop and validate a model based on anthropometric measurements estimating abdominal fat mass. Furthermore, in all 91 participants, ViScan estimations of WC and AFM% were validated against tape measurement and DXA results. RESULTS: The model developed was AFM% = 4.496 + (0.318 * WC) + 0.342 * suprailiac skinfold (r = 0.834, P < 0.0001). The model had no significant bias (0.25%) and +/- 7.5% limits of agreement. ViScan significantly overestimated WC by 7.04 cm and estimated AFM% with no significant bias (-0.13%) and +/- 7.6% limits of agreement. CONCLUSIONS: Both the model and ViScan are equally valid against DXA in estimating AFM%. However, ViScan is not valid in estimating WC in white postmenopausal women. PMID- 23676631 TI - Postmenopausal dyspareunia: has the Food and Drug Administration really helped? PMID- 23676632 TI - Effects of acupuncture and Chinese herbal medicine (Zhi Mu 14) on hot flushes and quality of life in postmenopausal women: results of a four-arm randomized controlled pilot trial. AB - OBJECTIVE: The aim of this study was to evaluate the feasibility of a clinical trial investigating the effects of acupuncture (AP) and Chinese herbal medicine (CHM) on hot flushes and quality of life in postmenopausal women. METHODS: Forty postmenopausal women reporting at least 20 hot flushes per week were enrolled in a randomized controlled trial. They were randomly allocated to receive traditional Chinese medicine (TCM) AP, sham AP, verum CHM, or placebo CHM for 12 weeks. Follow-up assessment was conducted 12 weeks after intervention. Primary outcome measures included hot flush frequency and severity. As a secondary outcome measure, the severity of menopausal symptoms was assessed using the Menopause Rating Scale (MRS) II. RESULTS: TCM AP induced a significant decline in all outcome measures from pretreatment to posttreatment compared with sham AP (hot flush frequency, P = 0.016; hot flush severity, P = 0.013; MRS, P < 0.001). In the TCM AP group, a larger decrease in MRS scores persisted from pretreatment to follow-up (P = 0.048). No significant differences were noted between the verum CHM group and the placebo CHM group. Compared with the verum CHM group, there was a significant decrease in MRS scores (P = 0.002) and a trend toward a stronger decrease in hot flush severity (P = 0.06) in the TCM AP group from pretreatment to posttreatment. CONCLUSIONS: TCM AP is superior to sham AP and verum CHM in reducing menopausal symptoms, whereas verum CHM shows no significant improvements when compared with placebo CHM. PMID- 23676634 TI - Vulnerability to depression and cardiometabolic risk associated with early ovarian disruption. PMID- 23676633 TI - Objective cognitive performance is related to subjective memory complaints in midlife women with moderate to severe vasomotor symptoms. AB - OBJECTIVE: Memory complaints increase as women transition from the premenopausal stage to the postmenopausal stage. We explored the extent to which subjective memory complaints were associated with objective cognitive test performance, affective symptoms, and menopausal symptoms in midlife women with moderate to severe vasomotor symptoms. We predicted that subjective memory complaints would be related to affective symptoms and lower performance on tests of memory and attention. METHODS: Sixty-eight midlife women (mean age, 53 y; 54% African American) with at least 35 hot flashes per week completed the Memory Functioning Questionnaire, a battery of objective cognitive tests, a menopausal symptom inventory, and mood questionnaires. Linear regression analyses were conducted to examine predictors (symptoms and objective cognitive scores) of ratings on each of four Memory Functioning Questionnaire subscales and a validated single-item rating of current memory. RESULTS: Negative affect and delayed verbal memory predicted a single-item rating of current memory. Negative affect and poorer scores on tests of attention and working memory predicted Frequency of Forgetting. Lower positive affect, higher vasomotor symptoms, and increased age predicted lower Retrospective Memory Functioning. Increased age predicted Use of Mnemonics. CONCLUSIONS: These findings strengthen the growing body of evidence indicating that women with memory complaints during the menopausal transition have an accurate appraisal of their memory function and that their complaints relate to affect and, to a lesser extent, vasomotor symptoms. Given that cognitive performance is within the reference range, these findings suggest that women can detect subtle changes in memory performance during the menopausal transition. PMID- 23676635 TI - There is more to the relation between intraocular pressure and metabolic syndrome than meets the eye: a connection to estrogen deficiency. PMID- 23676636 TI - Influence of patient perceptions and preferences for osteoporosis medication on adherence behavior in the Denosumab Adherence Preference Satisfaction study. AB - OBJECTIVE: This study aims to evaluate patient perceptions of subcutaneous denosumab or oral alendronate in postmenopausal women with or at risk for osteoporosis and how these perceptions influence adherence. METHODS: Postmenopausal women with low bone mass were randomized to denosumab 60 mg every 6 months for 1 year (treatment period 1 [TP1]) followed by alendronate 70 mg once weekly for 1 year (treatment period 2 [TP2]), or vice versa. Beliefs about Medicines Questionnaire data were collected at baseline and at 6, 12, 18, and 24 months; a necessity-concerns differential (NCD) was calculated for each time point. Logistic regression analyses were performed to evaluate the influences of baseline characteristics on nonadherence. RESULTS: Participants included 250 women (alendronate/denosumab, n = 124; denosumab/alendronate, n = 126). During TP1, the NCD at month 6 was higher with denosumab than with alendronate (P = 0.0076). In TP2, the NCD was higher for women switched to denosumab than for women switched to alendronate at 6 months (P = 0.0126) and 12 months (P = 0.4605). Denosumab was preferred to alendronate regardless of treatment sequence (P < 0.0001). Covariate analysis revealed that higher TP2 baseline necessity scores were associated with lower odds of nonadherence (P = 0.0055), whereas higher concerns about medication scores were associated with higher odds of nonadherence (P = 0.0247). Higher NCD scores were also associated with lower odds of nonadherence (P = 0.0015). CONCLUSIONS: Participants preferred denosumab to alendronate while on treatment and had more positive perceptions of denosumab than alendronate. These perceptions were associated with better adherence. PMID- 23676637 TI - Localized brain metabolite changes during visual sexual stimulation in postmenopausal women: a pilot study using functional magnetic resonance spectroscopy. AB - OBJECTIVE: Functional magnetic resonance spectroscopy was used to compare brain metabolite changes between nonpostmenopausal and postmenopausal women exposed to visual sexual stimulation with erotic video clips. METHODS: Twenty nonpostmenopausal women and 20 postmenopausal women were enrolled in this study. Menopause was defined as continuous amenorrhea for more than 12 months and a follicle-stimulating hormone level higher than 40 mIU/mL. Brain metabolite concentrations were measured from a localized voxel on the anterior cingulate gyrus, one of the most important areas associated with sexual arousal. Subjective sexual arousal and attention to visual stimulation were assessed using a 5-point scale. Functional magnetic resonance spectroscopy data were acquired from nonpostmenopausal and postmenopausal women during rest and activation conditions. RESULTS: Compared with nonpostmenopausal women, postmenopausal women showed significantly lower levels of both betagamma-glutamate/glutamine and lipid during the "rest" period but had lower levels of betagamma-glutamate/glutamine only during the "activation" period (P < 0.05). CONCLUSIONS: This study finds differential brain metabolite changes during visual sexual arousal in nonpostmenopausal and postmenopausal women. These findings would be helpful in understanding the neural mechanism of visual sexual arousal in connection with brain metabolite changes after menopause. PMID- 23676639 TI - [Picture in clinical hematology no. 61]. PMID- 23676640 TI - [Analysis of thyroid lesions in childhood recipients after hematopoietic stem cell transplantation]. AB - We performed a physical examination and ultrasonography of the thyroid gland in 24 patients who had received hematopoietic stem cell transplantation with a total body irradiation (TBI)-containing regimen during childhood. When ultrasonography revealed thyroid nodules larger than 1 cm in diameter, fine-needle aspiration biopsies were performed. Of 5 patients with palpable masses and thyroid nodules larger than 1 cm, adenomatous goiter was diagnosed in 4 cases and thyroid cancer in 1. Of the remaining 19 patients in whom no palpable mass was detected in the physical examination, 5 had thyroid nodules (including 1 adenomatous goiter), 6 had cystic lesions, and 8 exhibited no abnormalities on ultrasonography. No significant differences in sex, age at transplantation, interval between transplantation and evaluation, primary disease, preconditioning regimen, status at transplantation, stem cell source, chronic graft-versus-host disease, hypogonadism, or hypothyroidism were observed between patients with and without nodules. Individuals who received hematopoietic stem cell transplantation with a TBI-containing regimen are at risk of secondary thyroid cancer due to radiotherapy and require regular clinical evaluations of the thyroid gland by palpation, and ultrasonography should be incorporated into these checkups. PMID- 23676638 TI - Effects of bazedoxifene, conjugated equine estrogens, and a tissue-selective estrogen complex containing both bazedoxifene and conjugated equine estrogens on cerebral artery atherosclerosis in postmenopausal monkeys. AB - OBJECTIVE: This study aims to evaluate the effects of a new selective estrogen receptor modulator (bazedoxifene acetate [BZA]) and a tissue-specific estrogen complex (BZA combined with conjugated equine estrogens [CEE]) on the extent and severity of cerebral artery atherosclerosis. METHODS: Ninety-eight surgically postmenopausal monkeys (Macaca fascicularis) were fed a moderately atherogenic diet and randomized to receive no treatment or women's equivalent doses of BZA (20 mg/d), CEE (0.45 mg/d), or BZA + CEE. After an experimental period of 20 months (approximately equivalent to 5 years of participant experience), the extent and severity of atherosclerosis in the common carotid artery, carotid bifurcation, internal carotid artery, and basilar artery were determined. Lesion severity was determined using the American Heart Association grading system (grades 0-V). RESULTS: BZA had no consistent adverse effects on the extent and severity of atherosclerosis in the cerebral arteries and did not attenuate the beneficial effects of CEE on the severity of common carotid artery atherosclerosis. Although CEE had only modest beneficial effects on the extent of carotid bifurcation atherosclerosis, the severity of lesions and the number of affected cases in the common carotid artery were reduced with CEE treatment. As reported previously, plasma lipid profiles did not differ among the treatment groups. CONCLUSIONS: In this long-term (equivalent to 5 human patient-years) nonhuman primate trial, BZA shows no consistent adverse effect on cerebral artery atherosclerosis and does not attenuate the modest beneficial effect of CEE on the common carotid artery. Furthermore, CEE inhibits the development of complicated plaques in the common carotid artery. PMID- 23676641 TI - [Development of syndrome of inappropriate secretion of ADH and reversible posterior leukoencephalopathy during initial rituximab-CHOP therapy in a patient with diffuse large B-cell lymphoma]. AB - A 61-year-old woman presented with a right mandibular tumor and was diagnosed with DLBCL clinical stage IIIA from the biopsy results of the tumor and CT examination. An initial rituximab was administrated a week after the first CHOP treatment. During the infusion of rituximab, she exhibited disorientation, seizure, and consciousness disturbance. Hyponatremia due to SIADH and hypertension were coincidentally observed. MRI revealed T2 and FLAIR hyperintense signals involving the bilateral occipital, parietal, frontal lobes and the cerebellum that were consistent with reversible posterior leukoencephalopathy syndrome (RPLS). Her consciousness level recovered in parallel with corrections in serum sodium levels and blood pressure. Although she presented with transient cortical blindness, all neurological abnormalities disappeared 40 hours after the occurrence of seizure. She received a further 7 cycles of CHOP followed by 7 cycles of rituximab treatment with no relapse of RPLS. After irradiation for a residual abdominal tumor, she has maintained complete remission for 2 years. Although RPLS is a rare complication of rituximab-CHOP chemotherapy, it should be considered in patients with DLBCL who present with acute neurological deterioration. PMID- 23676642 TI - [Recurrent pulmonary edema after umbilical cord blood transplantation in a patient with infant acute lymphoblastic leukemia]. AB - This report describes two infants with recurrent pulmonary edema after umbilical cord blood transplantation (CBT). A 3-month-old boy and a 7-month-old boy with infant acute lymphoblastic leukemia underwent CBT from an unrelated donor in the first complete remission. The conditioning regimen consisted of busulfan, etoposide, and cyclophosphamide. Tacrolimus and short-term methotrexate were administered for the prophylaxis of acute graft-versus-host disease (GVHD). Neutrophil engraftment was achieved on days 17 and 19, respectively. Neither infant developed acute GVHD. They both exhibited tachypnea and weight gain on days 25 and 30, respectively, which were diagnosed as pulmonary edema by chest X rays. The respiratory condition of the patients improved within a few days with the close monitoring of weight changes after the administration of diuretics. However, they suddenly developed dyspnea and pulmonary edema again on days 37 and 59, respectively. Steroid therapy was initiated for both patients. Their respiratory condition again improved quickly after the initiation of steroid therapy. Their symptoms and clinical courses may be classified as a new entity of idiopathic pneumonia syndrome (IPS). Therefore, these cases may represent a new unclassifiable IPS associated with either CBT or infants. PMID- 23676643 TI - [Sustained remission with allogeneic peripheral blood stem cell transplantation and subsequent maintenance therapy with dasatinib in a patient with myeloblastic crisis of imatinib-resistant CML]. AB - A 45-year-old man with chronic myelogenous leukemia (CML) in the chronic phase was treated with imatinib mesylate (IM). Although partial cytogenetic response (CyR) was obtained in 3 months, the patient exhibited back pain after treatment with IM for 5 months. He was diagnosed with myeloblastic crisis of CML with 30% blasts in the bone marrow. An extramedullary tumor with a diameter of 5-cm was found adjacent to the pancreatic head. Mutation analysis of the bcr/abl chimeric gene was negative. After the treatment with dasatinib (140 mg/day) for 40 days, complete CyR was obtained by bone marrow examination and the extramedullary tumor shrunk resulting in partial response on computed tomography. Allogeneic peripheral blood stem cell transplantation (allo-PBSCT) was performed from his HLA-DR one locus-mismatched sister. He has been in molecular remission for 24 months after allo-PBSCT and maintenance therapy with dasatinib has been administered. Dasatinib was tolerable without severe adverse events before and after allo-PBSCT in this case. PMID- 23676644 TI - [Splenic rupture associated with aggressive conversion of indolent T-cell prolymphocytic leukemia]. AB - A 65-year-old man was diagnosed with leukocytosis in a routine medical examination. Further laboratory examinations showed increased LDH and sIL-2R levels in the serum. There was no evidence of infiltrative lesions or organomegaly. Bone marrow aspiration revealed many atypical small-sized lymphocytes without apparent nucleoli. Flow cytometric analysis of atypical lymphocytes was positive for T-cell markers, and chromosome analysis showed a normal karyotype. He was diagnosed with the small cell variant of T-PLL. Approximately 34 months later, having received no treatment, his cervical lymph nodes increased in size and number, and his white blood cell count, LDH and sIL 2R levels also rapidly increased. He was then admitted to our hospital. Bone marrow aspiration and cervical lymph node biopsy revealed complex chromosome abnormalities including inv(14)(q11;q32). Computed tomography showed swollen lymph nodes all over his body and hepatosplenomegaly. On the fourth hospital day, spontaneous splenic rupture occurred. Transcatheter arterial embolization was unsuccessful and the patient died. We report this case with rare autopsy findings. PMID- 23676645 TI - [Extramedullary onset of mixed phenotype acute leukemia with MLL gene rearrangement]. AB - Rearrangements of the mixed lineage leukemia MLL gene at chromosome 11q23 are common chromosomal abnormalities in human leukemia. MLL fused with numerous partner genes causes different leukemia phenotypes that depend on the function of partner genes. MLLT3-MLL is generated by translocation t(9;11), which primarily induces acute myeloid leukemia in humans, whereas MLLT3-MLL induces ALL or biphenotypic leukemia in mice. The microenvironment that surrounds leukemia cells plays a central role in this process. We report a patient with mixed phenotype acute leukemia with MLLT3-MLL. This patient, a 44-year-old woman, initially exhibited extramedullary leukemia with multiple tumors and subsequently developed bone marrow disease. The leukemia cells exhibited myeloid (CD13 and MPO) and B cell (CD19 and CD79a) phenotypes. Chromosomal analysis and RT-PCR assay revealed tumor cells with the MLLT3-MLL fusion gene. We treated this patient with a drug regimen for AML (Ara-C plus anthracycline), and complete remission was obtained. This report describes the fourth case of mixed phenotypic leukemia with extramedullary disease. The extramedullary circumstance may underlie the biphenotypic features of these patients. PMID- 23676646 TI - [Progression of bone marrow fibrosis with reticulin and collagen hyperplasia during treatment with the thrombopoietin receptor agonist romiplostim in a patient with immune thrombocytopenia]. AB - Romiplostim is a thrombopoietin (TPO) receptor agonist that has attracted attention as a novel drug for the treatment of refractory immune thrombocytopenia (ITP). However, bone marrow reticulin and collagen fibrosis during the long-term use of romiplostim has recently become a concern. Here, we present a patient with ITP who exhibited bone marrow fibrosis after the completion of a Japanese phase III clinical trial and long-term extension study of romiplostim. The patient was a 64-year-old woman. She was diagnosed with refractory ITP and participated in a clinical trial of romiplostim. Myeloblasts were found in her peripheral blood in Week 116 of treatment with romiplostim in the long-term extension study, and romiplostim was discontinued. In Week 118, teardrop cells appeared and she underwent a bone marrow biopsy. Results showed reticulin and collagen fiber hyperplasia and her platelet count decreased markedly to 0.4*10(4)/MUl with macroscopic hematuria. Thereafter, a reduced dose of romiplostim was resumed. Approximately one year after the resumption of romiplostim, a bone marrow biopsy revealed a decrease in reticulin and collagen fibrosis. Although few patients exhibited bone marrow fibrosis with TPO and the event may be reversible, our observations indicate that careful monitoring is required for general clinical use. PMID- 23676647 TI - [Successful management of neurosurgical procedures with continuous infusion of recombinant factor IX in a child with hemophilia B]. AB - This report describes the successful management of neurosurgical procedures with continuous infusion of recombinant factor IX (rFIX). A 1-year-old boy with severe hemophilia B was administered prophylactic therapy with rFIX after intracranial bleeding. We found the enlargement of an arachnoid cyst in a follow-up CT scan. He underwent marsupialization of the cyst under the continuous infusion of rFIX. FIX levels were examined in our hospital and the rFIX infusion rate was adjusted in an attempt to keep FIX levels above 90% intraoperatively, and 70% until his 7th post-operative day. We studied the pharmacokinetic profile of rFIX and found a half-time of 25 hours and mean in vivo recovery of 0.69 IU/dl/IU/kg. Reconstituted rFIX also retained at least 95% activity after 72 hours at room temperature. This is the first report of the perioperative management of a child undergoing a neurosurgical procedure under the continuous infusion of rFIX in Japan. Further studies are required before the routine use of this product for continuous infusion. PMID- 23676648 TI - [Central intravenous catheter-related bacteremia due to Chryseobacterium indologenes after cord blood transplantation]. AB - A 3-year-old girl with acute myeloid leukemia underwent unrelated cord blood stem cell transplantation (UCBT) due to primary induction failure. Fourteen days after UCBT, she developed central venous catheter (CVC)-related bloodstream infection due to Chryseobacterium indologenes. Despite ciprofloxacin and minocycline being administered according to the results of susceptibility, a high grade fever recurred. Therefore, the CVC was removed 21 days after UCBT and symptoms related to CVC infection improved. Although C. indologenes is widely distributed in nature, it is a rare pathogen in humans. Most cases of C. indologenes bacteremia have been found in immunocompromised patients with malignancies and diabetes mellitus. C. indologenes exhibits specific characteristics, including the progression of resistance to antibiotics and the formation of a biofilm. Therefore, removal of the CVC appears to be the most reasonable treatment for CVC infection due to C. indologenes in patients undergoing hematopoietic stem cell transplantation if clinical symptoms do not improve after appropriate antibiotic therapy. PMID- 23676649 TI - [Fatal zygomycosis caused by Mucor indicus after haplo-identical stem cell transplantation]. AB - A 62-year-old woman with acute lymphoblastic leukemia in first complete remission was treated with unrelated cord blood transplantation, but exhibited primary graft failure. She then underwent HLA-haploidentical peripheral blood stem cell transplantation from her daughter. The conditioning regimen consisted of fludarabine 30 mg/m(2)/day for 6 days, intravenous busulfan 3.2 mg/kg/day for 2 days, and thymoglobulin 1 mg/kg/day for 2 days. Voriconazole was administered to prevent fungal infections. The patient achieved prompt hematopoietic recovery. Fever was observed 21 days after the second transplant, followed by sigmoid colon perforation and a liver space occupying lesion (SOL). A filamentous fungus was detected in a percutaneous biopsy of the liver SOL. In spite of changing the antifungal drug from voriconazole to liposomal amphotericin B, the patient died on day 41. The fungus was identified as Mucor indicus, a type of zygomycete. Although Mucor indicus inhabits soil, an infectious disease is extremely rare, and breakthrough infection after voriconazole prophylaxis had not been reported until now. It is mandatory to consider preventive antifungal treatment for drug resistant fungal infectious diseases in patients after neutrophilic recovery with a strongly immunocompromised state after a HLA-haploidentical transplant. PMID- 23676650 TI - [Current national and international status of supportive therapy for the coagulopathy associated with L-asparaginase containing regimen for acute lymphoblastic leukemia]. AB - We investigated supportive therapy against coagulopathy associated with L asparaginase treatment in patients with acute lymphoblastic leukemia who were enrolled in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG), Japan Adult Leukemia Study Group (JALSG), and foreign institutes. Fresh frozen plasma (FFP) was administered as a supplement in 46% patients in the JPLSG and 86% in the JALSG. The threshold level of FFP infusion was less than 100 mg/dl plasma fibrinogen in 70% of the JALSG and 20% of the JPLSG, while in another 20% of the JPLSG, FFP was administered when the fibrinogen level was less than 50 mg/dl. The preventive use of antithrombin products (AT) was prescribed in 93% of the JPLSG and 63% of the JALSG: The threshold level of AT supplementation was less than 70% of plasma antithrombin activity, which was similar in both groups. Most foreign institutes do not routinely use FFP or AT. PMID- 23676651 TI - Reply to Drs. Corrales and Rivero--Meta-analysis on fish consumption, omega-3 fatty acids and risk of heart failure. PMID- 23676652 TI - On validity and controls in animal personality research: a comment on Galhardo et al. (2012). PMID- 23676653 TI - A basal thunnosaurian from Iraq reveals disparate phylogenetic origins for Cretaceous ichthyosaurs. AB - Cretaceous ichthyosaurs have typically been considered a small, homogeneous assemblage sharing a common Late Jurassic ancestor. Their low diversity and disparity have been interpreted as indicative of a decline leading to their Cenomanian extinction. We describe the first post-Triassic ichthyosaur from the Middle East, Malawania anachronus gen. et sp. nov. from the Early Cretaceous of Iraq, and re-evaluate the evolutionary history of parvipelvian ichthyosaurs via phylogenetic and cladogenesis rate analyses. Malawania represents a basal grade in thunnosaurian evolution that arose during a major Late Triassic radiation event and was previously thought to have gone extinct during the Early Jurassic. Its pectoral morphology appears surprisingly archaic, retaining a forefin architecture similar to that of its Early Jurassic relatives. After the initial latest Triassic radiation of early thunnosaurians, two subsequent large radiations produced lineages with Cretaceous representatives, but the radiation events themselves are pre-Cretaceous. Cretaceous ichthyosaurs therefore include distantly related lineages, with contrasting evolutionary histories, and appear more diverse and disparate than previously supposed. PMID- 23676654 TI - Evolution of parental incubation behaviour in dinosaurs cannot be inferred from clutch mass in birds. AB - A recent study proposed that incubation behaviour (i.e. type of parental care) in theropod dinosaurs can be inferred from an allometric analysis of clutch volume in extant birds. However, the study in question failed to account for factors known to affect egg and clutch size in living bird species. A new scaling analysis of avian clutch mass demonstrates that type of parental care cannot be distinguished by conventional allometry because of the confounding effects of phylogeny and hatchling maturity. Precociality of young but not paternal care in the theropod ancestors of birds is consistent with the available data. PMID- 23676655 TI - Could brown bears (Ursus arctos) have survived in Ireland during the Last Glacial Maximum? AB - Brown bears are recorded from Ireland during both the Late Pleistocene and early mid Holocene. Although most of the Irish landmass was covered by an ice sheet during the Last Glacial Maximum (LGM), Irish brown bears are known to have hybridized with polar bears during the Late Pleistocene, and it is suggested that the Irish brown bear population did not become extinct but instead persisted in situ through the LGM in a southwestern ice-free refugium. We use historical population modelling to demonstrate that brown bears are highly unlikely to have survived through the LGM in Ireland under any combination of life-history parameters shown by living bear populations, but instead would have rapidly become extinct following advance of the British-Irish ice sheet, and probably recolonized Ireland during the end-Pleistocene Woodgrange Interstadial from a closely related nearby source population. The time available for brown bear-polar bear hybridization was therefore restricted to narrow periods at the beginning or end of the LGM. Brown bears would have been extremely vulnerable to extinction in Quaternary habitat refugia and required areas substantially larger than southwestern Ireland to survive adverse glacial conditions. PMID- 23676656 TI - Disparities in uptake pattern of (123)I-MIBG, (18)F-FDG, and (99m)Tc-MDP within the same primary neuroblastoma. AB - We report an unusual case of primary neuroblastoma in an 11-year-old girl. The superior portion of the tumor accumulated I-MIBG, Tc-MDP, and F-FDG. In contrast, the inferior portion of the tumor showed no abnormal F-FDG or Tc-MDP uptake, which usually indicates tumor necrosis. This inferior portion of the tumor, however, had intense I-MIBG activity, consistent with viable tumor rather than tumor necrosis. PMID- 23676657 TI - Incidentally detected arterial thrombosis in (99m)Tc-methylene diphosphonate skeletal scintigraphy: an atypical observation. AB - The association between cancer and venous thrombosis is well established. However, that between malignancy and arterial thrombosis is less well described. We herein report a 48-year-old male patient diagnosed with base of tongue carcinoma, referred for Tc-methylene diphosphonate (MDP) bone scan study to evaluate recently developed pain and numbness in his right leg while undergoing chemoradiation. Tc-MDP bone scan study revealed complete absence of radiotracer distribution in the right lower limb below the knee region. This finding was inferred to be due to avascularity in this region secondary to thrombo-embolism that was substantiated by color Doppler sonography. PMID- 23676658 TI - 18F-FDG uptake in intraductal tubulopapillary neoplasm of the pancreas. AB - We report a 74-year-old man with intraductal tubulopapillary neoplasm (ITPN), a rare primary intraductal neoplasm of the pancreas. Focal intense uptake of 18F FDG was seen on the initial PET, corresponding to a pancreatic mass. Although the patient had no treatment, the uptake was mild to moderate on a second PET performed about 1 month later. The tumor was resected, with the final diagnosis of ITPN with an associated invasive carcinoma. Clinicians should be aware that decreased uptake of FDG during the follow-up period without treatment can occur even in malignant tumors. PMID- 23676659 TI - Batch fabrication of gold-gold nanogaps by E-beam lithography and electrochemical deposition. AB - We report on the successful development of a well-controlled two-step batch nano fabrication process to achieve nanometer-size gaps at the wafer scale. The technique is based on an optimized electron-beam lithography process, which enables the fabrication of nanogaps in the range (15 +/- 4) nm. Following this first step, the feedback-controlled electrochemical deposition of gold from an aqueous HAuCl4-based electrolyte is applied to further reduce the size of the gap down to about 0.3-1.0 nm. This protocol was successfully demonstrated by fabricating more than 385 nanogaps on a 4 inch wafer. The reproducible fabrication of nanogaps in the range between 0.3 and 1.0 nm opens up new perspectives for addressing the electrical and reactivity properties of single molecules and clusters in confined space under well-controlled conditions. PMID- 23676660 TI - Physical activity, sedentary behavior, and body mass index in the Czech Republic: a nationally representative survey. AB - BACKGROUND: Post-communist countries have experienced rapid economic development and social changes, which have been accompanied by changes in health-related lifestyle behaviors, such as physical activity. The purpose of this study was to examine the associations of domain-specific physical activity and total sedentary time with BMI among adults in the Czech Republic. METHODS: We surveyed a nationally representative sample (n = 4097) of the Czech Republic in fall 2007 using the International Physical Activity Questionnaire (long form). Multiple linear regression analyses were used to examine associations of physical activity, sedentary time and sociodemographic characteristics with BMI. RESULTS: Older age, lower educational attainment, and lower levels of leisure-time physical activity were associated with higher BMI. Compared with those living in large cities, men living in small towns and women living in small villages had higher BMI. CONCLUSIONS: This study has identified correlates of BMI in the Czech Republic. Although more evidence from longitudinal studies is needed, findings from the current study can inform interventions to prevent the rising obesity epidemic. PMID- 23676661 TI - [On publication language and international publishing, success of Professor Ozaydin and Anatolian Journal of Cardiology, peer-review and academic depression]. PMID- 23676662 TI - SCD6 induces ribonucleoprotein granule formation in trypanosomes in a translation independent manner, regulated by its Lsm and RGG domains. AB - Ribonucleoprotein (RNP) granules are cytoplasmic, microscopically visible structures composed of RNA and protein with proposed functions in mRNA decay and storage. Trypanosomes have several types of RNP granules, but lack most of the granule core components identified in yeast and humans. The exception is SCD6/Rap55, which is essential for processing body (P-body) formation. In this study, we analyzed the role of trypanosome SCD6 in RNP granule formation. Upon overexpression, the majority of SCD6 aggregates to multiple granules enriched at the nuclear periphery that recruit both P-body and stress granule proteins, as well as mRNAs. Granule protein composition depends on granule distance to the nucleus. In contrast to findings in yeast and humans, granule formation does not correlate with translational repression and can also take place in the nucleus after nuclear targeting of SCD6. While the SCD6 Lsm domain alone is both necessary and sufficient for granule induction, the RGG motif determines granule type and number: the absence of an intact RGG motif results in the formation of fewer granules that resemble P-bodies. The differences in granule number remain after nuclear targeting, indicating translation-independent functions of the RGG domain. We propose that, in trypanosomes, a local increase in SCD6 concentration may be sufficient to induce granules by recruiting mRNA. Proteins that bind selectively to the RGG and/or Lsm domain of SCD6 could be responsible for regulating granule type and number. PMID- 23676663 TI - Instantaneous inactivation of cofilin reveals its function of F-actin disassembly in lamellipodia. AB - Cofilin is a key regulator of the actin cytoskeleton. It can sever actin filaments, accelerate filament disassembly, act as a nucleation factor, recruit or antagonize other actin regulators, and control the pool of polymerization competent actin monomers. In cells these actions have complex functional outputs. The timing and localization of cofilin activity are carefully regulated, and thus global, long-term perturbations may not be sufficient to probe its precise function. To better understand cofilin's spatiotemporal action in cells, we implemented chromophore-assisted laser inactivation (CALI) to instantly and specifically inactivate it. In addition to globally inhibiting actin turnover, CALI of cofilin generated several profound effects on the lamellipodia, including an increase of F-actin, a rearward expansion of the actin network, and a reduction in retrograde flow speed. These results support the hypothesis that the principal role of cofilin in lamellipodia at steady state is to break down F actin, control filament turnover, and regulate the rate of retrograde flow. PMID- 23676664 TI - Mice overexpressing CD97 in intestinal epithelial cells provide a unique model for mammalian postnatal intestinal cylindrical growth. AB - Postnatal enlargement of the mammalian intestine comprises cylindrical and luminal growth, associated with crypt fission and crypt/villus hyperplasia, respectively, which subsequently predominate before and after weaning. The bipartite adhesion G protein-coupled receptor CD97 shows an expression gradient along the crypt-villus axis in the normal human intestine. We here report that transgenic mice overexpressing CD97 in intestinal epithelial cells develop an upper megaintestine. Intestinal enlargement involves an increase in length and diameter but does not affect microscopic morphology, as typical for cylindrical growth. The megaintestine is acquired after birth and before weaning, independent of the genotype of the mother, excluding altered availability of milk constituents as driving factor. CD97 overexpression does not regulate intestinal growth factors, stem cell markers, and Wnt signaling, which contribute to epithelial differentiation and renewal, nor does it affect suckling-to-weaning transition. Consistent with augmented cylindrical growth, suckling but not adult transgenic mice show enlarged crypts and thus more crypt fissions caused by a transient increase of the crypt transit-amplifying zone. Intestinal enlargement by CD97 requires its seven-span transmembrane/cytoplasmic C-terminal fragment but not the N-terminal fragment binding partner CD55. In summary, ectopic expression of CD97 in intestinal epithelial cells provides a unique model for intestinal cylindrical growth occurring in breast-fed infants. PMID- 23676665 TI - Protein import and oxidative folding in the mitochondrial intermembrane space of intact mammalian cells. AB - Oxidation of cysteine residues to disulfides drives import of many proteins into the intermembrane space of mitochondria. Recent studies in yeast unraveled the basic principles of mitochondrial protein oxidation, but the kinetics under physiological conditions is unknown. We developed assays to follow protein oxidation in living mammalian cells, which reveal that import and oxidative folding of proteins are kinetically and functionally coupled and depend on the oxidoreductase Mia40, the sulfhydryl oxidase augmenter of liver regeneration (ALR), and the intracellular glutathione pool. Kinetics of substrate oxidation depends on the amount of Mia40 and requires tightly balanced amounts of ALR. Mia40-dependent import of Cox19 in human cells depends on the inner membrane potential. Our observations reveal considerable differences in the velocities of mitochondrial import pathways: whereas preproteins with bipartite targeting sequences are imported within seconds, substrates of Mia40 remain in the cytosol for several minutes and apparently escape premature degradation and oxidation. PMID- 23676667 TI - The small GTPase HRas shapes local PI3K signals through positive feedback and regulates persistent membrane extension in migrating fibroblasts. AB - Self-amplification of phosphoinositide 3-kinase (PI3K) signaling is believed to regulate asymmetric membrane extension and cell migration, but the molecular organization of the underlying feedback circuit is elusive. Here we use an inducible approach to synthetically activate PI3K and interrogate the feedback circuitry governing self-enhancement of 3'-phosphoinositide (3-PI) signals in NIH3T3 fibroblasts. Synthetic activation of PI3K initially leads to uniform production of 3-PIs at the plasma membrane, followed by the appearance of asymmetric and highly amplified 3-PI signals. A detailed spatiotemporal analysis shows that local self-amplifying 3-PI signals drive rapid membrane extension with remarkable directional persistence and initiate a robust migratory response. This positive feedback loop is critically dependent on the small GTPase HRas. Silencing of HRas abrogates local amplification of 3-PI signals upon synthetic PI3K activation and results in short-lived protrusion events that do not support cell migration. Finally, our data indicate that this feedback circuit is likely to operate during platelet-derived growth factor-induced random cell migration. We conclude that positive feedback between PI3K and HRas is essential for fibroblasts to spontaneously self-organize and generate a productive migratory response in the absence of spatial cues. PMID- 23676666 TI - The WASH complex, an endosomal Arp2/3 activator, interacts with the Hermansky Pudlak syndrome complex BLOC-1 and its cargo phosphatidylinositol-4-kinase type IIalpha. AB - Vesicle biogenesis machinery components such as coat proteins can interact with the actin cytoskeleton for cargo sorting into multiple pathways. It is unknown, however, whether these interactions are a general requirement for the diverse endosome traffic routes. In this study, we identify actin cytoskeleton regulators as previously unrecognized interactors of complexes associated with the Hermansky Pudlak syndrome. Two complexes mutated in the Hermansky-Pudlak syndrome, adaptor protein complex-3 and biogenesis of lysosome-related organelles complex-1 (BLOC 1), interact with and are regulated by the lipid kinase phosphatidylinositol-4 kinase type IIalpha (PI4KIIalpha). We therefore hypothesized that PI4KIIalpha interacts with novel regulators of these complexes. To test this hypothesis, we immunoaffinity purified PI4KIIalpha from isotope-labeled cell lysates to quantitatively identify interactors. Strikingly, PI4KIIalpha isolation preferentially coenriched proteins that regulate the actin cytoskeleton, including guanine exchange factors for Rho family GTPases such as RhoGEF1 and several subunits of the WASH complex. We biochemically confirmed several of these PI4KIIalpha interactions. Of importance, BLOC-1 complex, WASH complex, RhoGEF1, or PI4KIIalpha depletions altered the content and/or subcellular distribution of the BLOC-1-sensitive cargoes PI4KIIalpha, ATP7A, and VAMP7. We conclude that the Hermansky-Pudlak syndrome complex BLOC-1 and its cargo PI4KIIalpha interact with regulators of the actin cytoskeleton. PMID- 23676668 TI - Atazanavir pharmacokinetics, efficacy and safety in pregnancy: a systematic review. AB - BACKGROUND: For some antiretroviral therapies, drug concentrations are reduced during pregnancy, potentially compromising effective virological suppression. METHODS: Data on atazanavir boosted with ritonavir in pregnancy are reviewed. RESULTS: With standard atazanavir/ritonavir 300/100 mg once-daily dosing: atazanavir area-under-the-concentration-time curves were reduced during pregnancy in most studies, but overall interpretation differed according to the data used for comparison; atazanavir concentration 24 h post-dose was maintained >150 ng/ml in 97.6% of women; no instance of mother-to-child transmission occurred in treatment-adherent mothers; and infant hyperbilirubinaemia was not elevated beyond levels expected in the neonatal period. CONCLUSIONS: With concurrent medications that reduce atazanavir drug concentrations, optimal therapy during pregnancy may require once-daily atazanavir/ritonavir 400/100 mg; however, using this dose during the third trimester doubled maternal grade 3-4 hyperbilirubinaemia rates. PMID- 23676669 TI - Long-term warming restructures Arctic tundra without changing net soil carbon storage. AB - High latitudes contain nearly half of global soil carbon, prompting interest in understanding how the Arctic terrestrial carbon balance will respond to rising temperatures. Low temperatures suppress the activity of soil biota, retarding decomposition and nitrogen release, which limits plant and microbial growth. Warming initially accelerates decomposition, increasing nitrogen availability, productivity and woody-plant dominance. However, these responses may be transitory, because coupled abiotic-biotic feedback loops that alter soil temperature dynamics and change the structure and activity of soil communities, can develop. Here we report the results of a two-decade summer warming experiment in an Alaskan tundra ecosystem. Warming increased plant biomass and woody dominance, indirectly increased winter soil temperature, homogenized the soil trophic structure across horizons and suppressed surface-soil-decomposer activity, but did not change total soil carbon or nitrogen stocks, thereby increasing net ecosystem carbon storage. Notably, the strongest effects were in the mineral horizon, where warming increased decomposer activity and carbon stock: a 'biotic awakening' at depth. PMID- 23676671 TI - Biochemistry: The ylide has landed. PMID- 23676670 TI - Structure-guided discovery of the metabolite carboxy-SAM that modulates tRNA function. AB - The identification of novel metabolites and the characterization of their biological functions are major challenges in biology. X-ray crystallography can reveal unanticipated ligands that persist through purification and crystallization. These adventitious protein-ligand complexes provide insights into new activities, pathways and regulatory mechanisms. We describe a new metabolite, carboxy-S-adenosyl-l-methionine (Cx-SAM), its biosynthetic pathway and its role in transfer RNA modification. The structure of CmoA, a member of the SAM-dependent methyltransferase superfamily, revealed a ligand consistent with Cx SAM in the catalytic site. Mechanistic analyses showed an unprecedented role for prephenate as the carboxyl donor and the involvement of a unique ylide intermediate as the carboxyl acceptor in the CmoA-mediated conversion of SAM to Cx-SAM. A second member of the SAM-dependent methyltransferase superfamily, CmoB, recognizes Cx-SAM and acts as a carboxymethyltransferase to convert 5 hydroxyuridine into 5-oxyacetyl uridine at the wobble position of multiple tRNAs in Gram-negative bacteria, resulting in expanded codon-recognition properties. CmoA and CmoB represent the first documented synthase and transferase for Cx-SAM. These findings reveal new functional diversity in the SAM-dependent methyltransferase superfamily and expand the metabolic and biological contributions of SAM-based biochemistry. These discoveries highlight the value of structural genomics approaches in identifying ligands within the context of their physiologically relevant macromolecular binding partners, and in revealing their functions. PMID- 23676672 TI - Structural biology: tiny enzyme uses context to succeed. PMID- 23676673 TI - Hofstadter's butterfly and the fractal quantum Hall effect in moire superlattices. AB - Electrons moving through a spatially periodic lattice potential develop a quantized energy spectrum consisting of discrete Bloch bands. In two dimensions, electrons moving through a magnetic field also develop a quantized energy spectrum, consisting of highly degenerate Landau energy levels. When subject to both a magnetic field and a periodic electrostatic potential, two-dimensional systems of electrons exhibit a self-similar recursive energy spectrum. Known as Hofstadter's butterfly, this complex spectrum results from an interplay between the characteristic lengths associated with the two quantizing fields, and is one of the first quantum fractals discovered in physics. In the decades since its prediction, experimental attempts to study this effect have been limited by difficulties in reconciling the two length scales. Typical atomic lattices (with periodicities of less than one nanometre) require unfeasibly large magnetic fields to reach the commensurability condition, and in artificially engineered structures (with periodicities greater than about 100 nanometres) the corresponding fields are too small to overcome disorder completely. Here we demonstrate that moire superlattices arising in bilayer graphene coupled to hexagonal boron nitride provide a periodic modulation with ideal length scales of the order of ten nanometres, enabling unprecedented experimental access to the fractal spectrum. We confirm that quantum Hall features associated with the fractal gaps are described by two integer topological quantum numbers, and report evidence of their recursive structure. Observation of a Hofstadter spectrum in bilayer graphene means that it is possible to investigate emergent behaviour within a fractal energy landscape in a system with tunable internal degrees of freedom. PMID- 23676675 TI - Synthetic biology: It's an analog world. PMID- 23676674 TI - Variation and genetic control of protein abundance in humans. AB - Gene expression differs among individuals and populations and is thought to be a major determinant of phenotypic variation. Although variation and genetic loci responsible for RNA expression levels have been analysed extensively in human populations, our knowledge is limited regarding the differences in human protein abundance and the genetic basis for this difference. Variation in messenger RNA expression is not a perfect surrogate for protein expression because the latter is influenced by an array of post-transcriptional regulatory mechanisms, and, empirically, the correlation between protein and mRNA levels is generally modest. Here we used isobaric tag-based quantitative mass spectrometry to determine relative protein levels of 5,953 genes in lymphoblastoid cell lines from 95 diverse individuals genotyped in the HapMap Project. We found that protein levels are heritable molecular phenotypes that exhibit considerable variation between individuals, populations and sexes. Levels of specific sets of proteins involved in the same biological process covary among individuals, indicating that these processes are tightly regulated at the protein level. We identified cis-pQTLs (protein quantitative trait loci), including variants not detected by previous transcriptome studies. This study demonstrates the feasibility of high-throughput human proteome quantification that, when integrated with DNA variation and transcriptome information, adds a new dimension to the characterization of gene expression regulation. PMID- 23676676 TI - The rewards of restraint in the collective regulation of foraging by harvester ant colonies. AB - Collective behaviour, arising from local interactions, allows groups to respond to changing conditions. Long-term studies have shown that the traits of individual mammals and birds are associated with their reproductive success, but little is known about the evolutionary ecology of collective behaviour in natural populations. An ant colony operates without central control, regulating its activity through a network of local interactions. This work shows that variation among harvester ant (Pogonomyrmex barbatus) colonies in collective response to changing conditions is related to variation in colony lifetime reproductive success in the production of offspring colonies. Desiccation costs are high for harvester ants foraging in the desert. More successful colonies tend to forage less when conditions are dry, and show relatively stable foraging activity when conditions are more humid. Restraint from foraging does not compromise a colony's long-term survival; colonies that fail to forage at all on many days survive as long, over the colony's 20-30-year lifespan, as those that forage more regularly. Sensitivity to conditions in which to reduce foraging activity may be transmissible from parent to offspring colony. These results indicate that natural selection is shaping the collective behaviour that regulates foraging activity, and that the selection pressure, related to climate, may grow stronger if the current drought in their habitat persists. PMID- 23676678 TI - Cloning of Dirac fermions in graphene superlattices. AB - Superlattices have attracted great interest because their use may make it possible to modify the spectra of two-dimensional electron systems and, ultimately, create materials with tailored electronic properties. In previous studies (see, for example, refs 1-8), it proved difficult to realize superlattices with short periodicities and weak disorder, and most of their observed features could be explained in terms of cyclotron orbits commensurate with the superlattice. Evidence for the formation of superlattice minibands (forming a fractal spectrum known as Hofstadter's butterfly) has been limited to the observation of new low-field oscillations and an internal structure within Landau levels. Here we report transport properties of graphene placed on a boron nitride substrate and accurately aligned along its crystallographic directions. The substrate's moire potential acts as a superlattice and leads to profound changes in the graphene's electronic spectrum. Second-generation Dirac points appear as pronounced peaks in resistivity, accompanied by reversal of the Hall effect. The latter indicates that the effective sign of the charge carriers changes within graphene's conduction and valence bands. Strong magnetic fields lead to Zak-type cloning of the third generation of Dirac points, which are observed as numerous neutrality points in fields where a unit fraction of the flux quantum pierces the superlattice unit cell. Graphene superlattices such as this one provide a way of studying the rich physics expected in incommensurable quantum systems and illustrate the possibility of controllably modifying the electronic spectra of two-dimensional atomic crystals by varying their crystallographic alignment within van der Waals heterostuctures. PMID- 23676677 TI - Crystal structure of the integral membrane diacylglycerol kinase. AB - Diacylglycerol kinase catalyses the ATP-dependent phosphorylation of diacylglycerol to phosphatidic acid for use in shuttling water-soluble components to membrane-derived oligosaccharide and lipopolysaccharide in the cell envelope of Gram-negative bacteria. For half a century, this 121-residue kinase has served as a model for investigating membrane protein enzymology, folding, assembly and stability. Here we present crystal structures for three functional forms of this unique and paradigmatic kinase, one of which is wild type. These reveal a homo trimeric enzyme with three transmembrane helices and an amino-terminal amphiphilic helix per monomer. Bound lipid substrate and docked ATP identify the putative active site that is of the composite, shared site type. The crystal structures rationalize extensive biochemical and biophysical data on the enzyme. They are, however, at variance with a published solution NMR model in that domain swapping, a key feature of the solution form, is not observed in the crystal structures. PMID- 23676679 TI - Second sound and the superfluid fraction in a Fermi gas with resonant interactions. AB - Superfluidity is a macroscopic quantum phenomenon occurring in systems as diverse as liquid helium and neutron stars. It occurs below a critical temperature and leads to peculiar behaviour such as frictionless flow, the formation of quantized vortices and quenching of the moment of inertia. Ultracold atomic gases offer control of interactions and external confinement, providing unique opportunities to explore superfluid phenomena. Many such (finite-temperature) phenomena can be explained in terms of a two-fluid mixture comprising a normal component, which behaves like an ordinary fluid, and a superfluid component with zero viscosity and zero entropy. The two-component nature of a superfluid is manifest in 'second sound', an entropy wave in which the superfluid and the non-superfluid components oscillate with opposite phases (as opposed to ordinary 'first sound', where they oscillate in phase). Here we report the observation of second sound in an ultracold Fermi gas with resonant interactions. The speed of second sound depends explicitly on the value of the superfluid fraction, a quantity that is sensitive to the spectrum of elementary excitations. Our measurements allow us to extract the temperature dependence of the superfluid fraction, a previously inaccessible quantity that will provide a benchmark for theories of strongly interacting quantum gases. PMID- 23676680 TI - Palaeontological evidence for an Oligocene divergence between Old World monkeys and apes. AB - Apes and Old World monkeys are prominent components of modern African and Asian ecosystems, yet the earliest phases of their evolutionary history have remained largely undocumented. The absence of crown catarrhine fossils older than ~20 million years (Myr) has stood in stark contrast to molecular divergence estimates of ~25-30 Myr for the split between Cercopithecoidea (Old World monkeys) and Hominoidea (apes), implying long ghost lineages for both clades. Here we describe the oldest known fossil 'ape', represented by a partial mandible preserving dental features that place it with 'nyanzapithecine' stem hominoids. Additionally, we report the oldest stem member of the Old World monkey clade, represented by a lower third molar. Both specimens were recovered from a precisely dated 25.2-Myr-old stratum in the Rukwa Rift, a segment of the western branch of the East African Rift in Tanzania. These finds extend the fossil record of apes and Old World monkeys well into the Oligocene epoch of Africa, suggesting a possible link between diversification of crown catarrhines and changes in the African landscape brought about by previously unrecognized tectonic activity in the East African rift system. PMID- 23676681 TI - Synthetic analog computation in living cells. AB - A central goal of synthetic biology is to achieve multi-signal integration and processing in living cells for diagnostic, therapeutic and biotechnology applications. Digital logic has been used to build small-scale circuits, but other frameworks may be needed for efficient computation in the resource-limited environments of cells. Here we demonstrate that synthetic analog gene circuits can be engineered to execute sophisticated computational functions in living cells using just three transcription factors. Such synthetic analog gene circuits exploit feedback to implement logarithmically linear sensing, addition, ratiometric and power-law computations. The circuits exhibit Weber's law behaviour as in natural biological systems, operate over a wide dynamic range of up to four orders of magnitude and can be designed to have tunable transfer functions. Our circuits can be composed to implement higher-order functions that are well described by both intricate biochemical models and simple mathematical functions. By exploiting analog building-block functions that are already naturally present in cells, this approach efficiently implements arithmetic operations and complex functions in the logarithmic domain. Such circuits may lead to new applications for synthetic biology and biotechnology that require complex computations with limited parts, need wide-dynamic-range biosensing or would benefit from the fine control of gene expression. PMID- 23676682 TI - Long non-coding RNA GAS5 regulates apoptosis in prostate cancer cell lines. AB - While the role of small non-coding RNAs, such as miRNAs, in apoptosis control is well established, long non-coding RNAs (lncRNAs) have received less attention. Growth Arrest-Specific 5 (GAS5) encodes multiple snoRNAs within its introns, while exonic sequences produce lncRNA which can act as a riborepressor of the glucocorticoid and related receptors. GAS5 negatively regulates the survival of lymphoid and breast cells, and is aberrantly expressed in several cancers. Although cellular GAS5 levels decline as prostate cancer cells acquire castration resistance, the influence of GAS5 on prostate cell survival has not been determined. To address this question, prostate cell lines were transfected with GAS5-encoding plasmids or GAS5 siRNAs, and cell survival was assessed. Basal apoptosis increased, and cell survival decreased, after transfection of 22Rv1 cells with plasmids encoding GAS5 transcripts, including mature GAS5 lncRNA. Similar effects were observed in PC-3 cells. In stable clones of 22Rv1, cell death correlated strongly with cellular GAS5 levels. Induction of 22Rv1 cell death by UV-C irradiation and chemotherapeutic drugs was augmented in cells transiently transfected with GAS5 constructs, and attenuated following down regulation of GAS5 expression. Again, in these experiments, cell death was strongly correlated with cellular GAS5 levels. Thus, GAS5 promotes the apoptosis of prostate cells, and exonic sequence, i.e. GAS5 lncRNA, is sufficient to mediate this activity. Abnormally low levels of GAS5 expression may therefore reduce the effectiveness of chemotherapeutic agents. Although several lncRNAs have recently been shown to control cell survival, this is the first report of a death-promoting lncRNA in prostate cells. PMID- 23676683 TI - Cancer control and prevention: nutrition and epigenetics. AB - PURPOSE OF REVIEW: To evaluate recent developments in nutritional epigenomics and related challenges, opportunities, and implications for cancer control and prevention. RECENT FINDINGS: Cancer is one of the leading causes of death worldwide, and understanding the factors that contribute to cancer development may facilitate the development of strategies for cancer prevention and control. Cancer development involves genetic and epigenetic alterations. Genetic marks are permanent, whereas epigenetic marks are dynamic, change with age, and are influenced by the external environment. Thus, epigenetics provides a link between the environment, diet, and cancer development. Proper food selection is imperative for better health and to avoid cancer and other diseases. Nutrients either contribute directly to cancer prevention or support the repair of genomic and epigenomic damage caused by exposure to cancer-causing agents such as toxins, free radicals, radiation, and infectious agents. Nutritional epigenomics provides an opportunity for cancer prevention because selected nutrients have the potential to reverse cancer-associated epigenetic marks in different tumor types. A number of natural foods and their bioactive components have been shown to have methylation-inhibitory and deacetylation-inhibitory properties. SUMMARY: Natural foods and bioactive food components have characteristics and functions that are similar to epigenetic inhibitors and therefore have potential in cancer control and prevention. PMID- 23676684 TI - Common phenotypes and the developmental origins of disease. AB - PURPOSE OF REVIEW: The association between nutrition during pregnancy and the development of metabolic disease in the offspring has been well evidenced in humans and animals. Whilst evidence has accumulated to support various theories linking maternal diet to long-term health, the precise mechanisms of action remain poorly understood. This review summarizes recent advances within the field, focusing on the use of animal models to investigate common phenotypic outcomes. RECENT FINDINGS: Continued characterization of postnatal phenotypes has highlighted the importance of postnatal diet in unmasking programming effects of prenatal diet. Whilst common phenotypes are observed across models, differences in associated regulatory processes exist dependent upon the dietary exposure used and sex of the offspring. The use of unbiased techniques at developmental stages has identified gene pathways sensitive to maternal diet, potentially explaining the induction of a common phenotype by different nutritional interventions. Evidence has also grown to support the role of epigenetic modification, with an increasing range of targets identified as being sensitive. SUMMARY: A challenge remains in identifying the direct functional and long-term consequences of changes in gene expression or epigenetic status during development, and to translate these back to human populations. PMID- 23676685 TI - [Risks from hazardous chemicals in food]. PMID- 23676686 TI - [Risk communication about radionuclide contamination of food after the fukushima nuclear power plant accident]. PMID- 23676687 TI - [Standard limits for radionuclides in foods]. PMID- 23676688 TI - [Analysis and inspection of radioactive materials in foods]. PMID- 23676689 TI - [Determination of uranium in spinach]. AB - After the severe accident at the Fukushima-1 Nuclear Power Plant in March 2011, radioactive contamination of food has become a matter of serious concern in Japan. There is considerable information about radioactive iodine and cesium, but little is known about uranium contamination. We determined uranium content in spinach by the Japanese official method (Manual on Radiation Measurement of Food in Emergency Situations). In the preliminary study, we confirmed that the use of a microwave digestion system for preparing the test solution of spinach could shorten the testing time and give acceptable results. The manual recommends the use of two elements (Tl and Bi) as internal standards for measurement of uranium by ICP-MS. We found that Tl was more suitable than Bi to quantify trace amounts of uranium in spinach. However, it was necessary to determine Tl or Bi concentrations in the sample before analysis, since some samples of spinach contained significant amounts of these elements. The uranium contents of 9 spinach samples bought in April and May 2011 were less than 10 MUg/kg, which are very low compared to the provisional regulatory limit in Japan. PMID- 23676690 TI - [Radioactive cesium in total diet in Hokkaido (2011-2012)]. AB - The level of radioactive cesium (the sum of (134)cesium (Cs) and (137)Cs) was investigated in total diet samples collected from adults living in the Sapporo area, Hokkaido. They were ashed, and examined with a germanium semiconductor detector. The maximum and average radioactivities of cesium in an indivividual's daily food intake were as follows: 1.0 Bq and 0.24 Bq in July 2011, 1.3 Bq and 0.30 Bq in November 2011, 3.9 Bq and 1.0 Bq in February 2012, and 0.34 Bq and 0.12 Bq in July 2012, respectively. The committed effective dose would be 0.022 mSv/year in the case of continued intake of meals containing the maximum cesium concentration. PMID- 23676691 TI - [Concentration of natural radioactive nuclide (pb-214 and bi-214) in foods from Yamanashi]. AB - The concentrations of Pb-214 and Bi-214 in groundwaters and agricultural products from several geologically distinct parts of the Yamanashi region of Japan were measured and compared. The concentrations of Pb-214 and Bi-214 in groundwaters were well correlated with each other, and were consistent with the predominant geology in each area. The concentrations of both radio-nuclides in agricultural products were much lower than the levels in groundwaters, and did not appear to be related to local geology or habitat. Freshwater fish showed higher levels than agricultural products, though the levels were lower than those in groundwaters. Unexpectedly, wild mushrooms (but not cultivated mushrooms) showed relatively high levels of Bi-214, though their levels of Pb-214 were undetectable. Based on the levels of Pb-214 and Bi-214 detected here, annual internal radiation exposure of humans from these sources is considered to be extremely low. PMID- 23676692 TI - [Radiation screening test for commercial food products and foodstuffs for food services using NaI (Tl) scintillation survey meter]. AB - Screening tests were carried out for radioactive cesium in foods using a NaI (Tl) scintillation survey meter. The screening level was set at 250 Bq/kg, and specimens exceeding this level were scheduled to be sent to an external testing organization, which would conduct further tests using a germanium semiconductor detector. Some specimens that did not reach the screening level were also sent to the same organization. Foodstuffs used in commercial food products circulated in Chiba city were targeted, along with food services provided to schools and day care centers. In all, 495 specimens were tested; however, no specimens exceeded the screening level. The results of verification tests confirmed that no specimen exceeded the tentative regulatory limit. PMID- 23676693 TI - [Surveillance of radioactive cesium in foods]. AB - We surveyed foods on the market from areas that had been exposed to radioactive materials contamination following the Fukushima accident. We used a NaI (Tl) scintillation spectrometer for the screening tests and a germanium semiconductor detector for the final tests. Test results from 1,427 samples showed that 6 samples (0.4%) exceeded the regulatory limit of 500 Bq/kg. Considering the detection rate of radioactive cesium in each food category, we suggest that it is necessary to continue monitoring fruits such as chestnuts and ginkgo nuts, mushrooms (especially raw wood-shiitake), mountain vegetables, and sea fish. PMID- 23676694 TI - [Estimation of the intake of radioactive cesium based on analysis of total diet samples in Nagoya]. AB - Food samples were purchased in Nagoya based on daily intake in the Tokai region, and prepared as total diet samples according to the market basket method. The contents of radioactive cesium (Cs) were determined by using a gamma-ray spectrometer with a germanium semiconductor detector, and a committed effective dose was estimated. Radioactive Cs was not detected in samples collected in 2006 before the Fukushima nuclear plant accident. Radioactive Cs was detected in samples prepared in August, 2011, five months after the accident. The sources were sugar and confectioneries (3rd food group), other vegetables, seaweeds and mushrooms (8th food group) and fishes, shellfishes and processed seafoods (10th food group). Only Cs-137 was detected in samples prepared in August, 2012, one year and five months after the accident. The sources were the 8th and the 10th food groups. The estimated committed effective dose for radioactive Cs was 0.0015 mSv in 2011 and 0.00016 mSv in 2012. PMID- 23676695 TI - [Examination of radioactive contamination in foods]. AB - Following the Fukushima nuclear plant accident in Mar. 2011, the examination of radioactive contamination in foods is being carried out in Nagoya. During the period between 30 Mar. 2011 and 31 Oct. 2012, a total of 300 food samples were collected and the concentrations of radioactive nuclides were determined by means of gamma-ray spectrometry using a high-purity germanium semiconductor detector. The results of analysis indicate that the concentrations of radioactive iodine (I) and cesium (Cs) were below the regulatory limits. Radioactive I ((131)I) was detected in 7 samples which belonged to the categories of green and yellow vegetables and other vegetables. Radioactive Cs ((134)Cs and (137)Cs) was detected in 60 samples which belonged to the categories of rice and its processed products, potatoes and its processed products, nuts and seeds, green and yellow vegetables, other vegetables, fruits, mushrooms, fishes and shellfishes, processed sea foods, meat, milk and dairy products and other beverages. PMID- 23676696 TI - [Radioactive contamination of foods marketed in saitama prefecture]. AB - Up to October 31, 2012, a total of 170 food samples marketed in Saitama Prefecture were examined following the setting of provisional regulatory limits for radioactivity in drinking water and foodstuffs by the Ministry of Health, Labour and Welfare on 1 April 2012. No sample exceeded the regulatory limits as determined by gamma ray spectrometry with a germanium semiconductor detector. However the radioactive cesium concentrations of food samples such as raw wood shiitake and maccha (powdered green tea) produced in Saitama were nearly at the regulatory limits, being 74 Bq/kg and 84 Bq/kg, respectively. PMID- 23676699 TI - 'No more strangers': Investigating the experiences of women, midwives and others during the establishment of a new model of maternity care for remote dwelling aboriginal women in northern Australia. AB - OBJECTIVE: to describe the experiences of women, midwives and others during the establishment of a new model of maternity care for remote dwelling Aboriginal women transferred to a regional centre in northern Australia for maternity care and birth. DESIGN: a mixed method design within a Participatory Action Research approach was used. Qualitative findings are presented here. Data for this paper were collected from semi-structured interviews, field notes and observations and analysed thematically. SETTING: the 'top end' of the Northern Territory of Australia. PARTICIPANTS: a total of 66 participants included six MGP midwives, two Aboriginal Health Workers and one Senior Aboriginal Woman working in the new model; eight hospital midwives; 34 Department of Health staff, three staff from other agencies; and 12 remote dwelling Aboriginal women who used the service. FINDINGS: the study generated one overarching theme, it's not a perfect system but it's changing. This encompassed improvements to the services evident to all participants. Core themes related to the previous maternity service which was described as the arduous journey, the new model was seen as a new way of working and a resultant very different journey occurred for Aboriginal women using the service. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: there was a dissonance between the previous culture of maternity services and the woman centred focus of the new model. Over 12 months initial resistance to the new model diminished and it became highly valued. The transfer of information between the regional service and remote community health centres improved as did the safety and quality of care. Aboriginal women can access continuity of carer in the regional centre for the first time and reported a more positive experience with maternity services. The new model appears to have changed the cultural responsiveness of the regional maternity service; and care provided for remote dwelling women within this service. The qualitative findings inform others seeking to implement a similar model of care for remote dwelling women transferred to a regional centre for birth. PMID- 23676698 TI - Variations in the microcystin content of different fish species collected from a eutrophic lake. AB - Microcystins produced from cyanobacteria can accumulate in fish tissues. Liquid chromatography coupled with tandem quadrupole mass spectrometry (LC-MS/MS) is an attractive alternative to immunoassays for the determination of low concentrations of microcystins in tissues. Fish taken from Grand Lake St. Marys, a eutrophic lake in Ohio, USA, were analyzed for microcystin-LR in their fillets using LC-MS/MS. Of 129 fish tested for microcystins, only black crappie (Pomoxis nigromaculatus) and common carp (Cyprinus carpio) tested positive for microcystin LR. Less than 10% of Pomoxis and 7% of Cyprinus samples contained measurable levels of microcystin-LR. Statistical analysis yielded a p-value of 0.07 between Pomoxis and the pooled results of the other four fish species. However, this comparison was complicated by the large difference in sample size between species. Further sampling in Grand Lake St. Marys for microcystin-LR would help determine if microcystin-LR exposure occurs through foodweb transfer. PMID- 23676700 TI - Facile preparation of high-quality Pt/reduced graphene oxide nanoscrolls for methanol oxidation. AB - A simple and novel approach for the preparation of a Pt/reduced graphene oxide nanoscroll (Pt/RGOS) nanocatalyst is reported for the first time. The Pt/reduced graphene oxide (Pt/RGO) was fabricated by the co-reduction of GO and Pt salt using ethylene glycol under microwave irradiation, then the Pt/RGOSs were obtained by oxygen implosion in situ rolling up of the Pt/RGO using catalytic decomposition of Pt towards H2O2 under ultrasonication. Transmission electron microscopy shows that the Pt nanoparticles are uniformly dispersed on the reduced graphene oxide nanoscrolls with tubular structure, open edges and ends, and tubular diameter ranging from 10 to 100 nm. X-ray diffraction indicates that the crystal structure and diffraction intensity of the platinum practically remains unchanged, and the RGO has not been oxidized before or after rolling. Raman spectroscopy reveals that the Pt/RGOSs have a higher D/G ratio (1.2) than Pt/RGO (1.1). BET (Brunauer, Emmett and Teller) results exhibit that the Pt/RGOSs possess higher specific surface area and broader pore size range (188 m(2) g(-1), 25-45 nm) than Pt/RGO (122 m(2) g(-1), 30-38 nm). Additionally, the electrocatalytic performance of the Pt/RGOSs for methanol oxidation was evaluated, and the results show that the Pt/RGOSs possess significantly higher electrocatalytic activity and stability than Pt/RGO. PMID- 23676701 TI - Molecule-based water-oxidation catalysts (WOCs): cluster-size-dependent dye sensitized polyoxometalates for visible-light-driven O2 evolution. AB - From atomic level to understand the cluster-size-dependant behavior of dye sensitized photocatalysts is very important and helpful to design new photocatalytic materials. Although the relationship between the photocatalytic behaviors and particles' size/shape has been widely investigated by theoretical scientists, the experimental evidences are much less. In this manuscript, we successfully synthesized three new ruthenium dye-sensitized polyoxometalates (POM n, n relate to different size clusters) with different-sized POM clusters. Under visible-light illumination, all three complexes show the stable O2 evolution with the efficient order POM-3 > POM-2 > POM-1. This cluster-size-dependent catalytic behavior could be explained by the different numbers of M = Ot (terminal oxygen) bonds in each individual cluster because it is well-known that Mo = Ot groups are the catalytically active sites for photooxidation reaction. The proposed mechanism of water oxidation for the dye-sensitized POMs is radical reaction process. This research could open up new perspectives for developing new POM based WOCs. PMID- 23676702 TI - A novel dark-field microscopy technique coupled with capillary electrophoresis for visual analysis of single nanoparticles. AB - A system for interfacing dark field microscopy (DFM) with capillary electrophoresis (CE) was demonstrated and applied to investigate the movement of single gold nanoparticles (AuNPs) visually and in real time for the first time. When using ~60 nm cetyl trimethyl ammonium bromide (CTAB) and sodium dodecyl sulfate (SDS) capped AuNPs as target analytes, preliminary data indicated that differently charged AuNPs had different movement velocities (v). From the result of the effect of applied voltage and buffer pH value on the movement of single AuNPs, we could "image" that positively charged CTAB-capped AuNPs (red) moved faster than negatively charged SDS-capped AuNPs (green), and the former could catch up with and pass the latter. The results visually confirmed the separation rules and some fundamental theories of CE including the effect of buffer pH value on the electroosmotic flow (EOF) and the plug-like profile of EOF. This novel integration was successfully utilized to evaluate the size distribution and homogeneity of AuNPs, from which the results obtained were in accordance with transmission electron microscopy (TEM) results. The proposed system offers a new insight into CE analysis and has potential applications in many fields, such as the study of interaction between NPs and biomolecules in bioanalysis. PMID- 23676703 TI - Effect of extruded linseed supplementation on blood metabolic profile and milk performance of Saanen goats. AB - This study assessed the effects of dietary supplementation with extruded linseed on milk yield and composition, milk fatty acid (FA) profile and renal and hepatic metabolism of grazing goats in mid-lactation. Forty Saanen goats were divided into two isoproductive groups: one group was fed the control diet (CON) composed of hay and pelleted concentrate and the other group was supplemented with additional 180 g/day of extruded linseed (LIN; dry matter basis), which supplied 70 g/day of fat per head for 9 weeks. Animals grazed on pasture for ~3 h/day after the first of the 2 daily milkings. Milk samples were collected weekly and analyzed for fat, protein, lactose, milk urea nitrogen (MUN) and somatic cell count. Blood samples were collected every 2 weeks and analyzed for total bilirubin, creatinine, aspartate transaminase (AST), alanine transaminase (ALT), gamma glutamyl transpeptidase, alkaline phosphatase, total protein and urea nitrogen. Milk yield was higher in the LIN than in the CON group (2369 v. 2052 g/day). LIN group had higher milk fat (37.7 v. 33.4 g/kg) and protein (30.7 v. 29.1 g/kg) concentration and lower MUN (35.0 v. 43.3 mg/dl) than CON group. Goats fed LIN had greater proportions of 18:1 trans11, 18:2 cis9trans11 and total polyunsatured fatty acids n-3 in milk fat, because of higher 18:3n-3 and 20:5n-3 FA, and lower proportions of short- and medium-chain FAs than goats fed CON. All kidney and liver function biomarkers in serum did not differ between dietary groups, except for AST and ALT, which tended to differ. Extruded linseed supplementation to grazing mid-lactating goats for 2 months can enhance the milk performance and nutritional profile of milk lipids, without altering the general hepatic and renal metabolism. PMID- 23676704 TI - Transposable elements in eukaryotic genomes: epigenetic regulation by the host and functionalization for the host. PMID- 23676705 TI - Small RNAs and regulation of transposons in plants. AB - RNA interference is now a well-recognized post-transcriptional mechanism for regulation of gene expression in both animals and plants. In this process, microRNAs (miRNAs) direct silencing complexes to complementary RNA sequences, leading to either degradation or repression of translation. Plants also contain another type of small RNA, small interfering RNAs (siRNAs), that play a role in gene silencing by directing cytosine methylation activities of complementary DNA sequences and thus, differ from miRNAs. This nuclear regulation system is referred to as RNA-directed DNA methylation (RdDM). In plant genomes, transposable elements were initially thought to be regulated by DNA methylation alone. However, several recent reports have revealed that siRNAs and RdDM also play crucial roles in silencing of transposons and endogenous repeats. It is also becoming apparent that transposons are subjected to different levels of regulation in response to developmental and environmental cues. Transposons are tightly regulated in germ cells to protect the host genome from transgenerational mutagenic activity. In plants, transposons are also activated by biotic and abiotic stress. The regulation of transposons in these different situations has been associated with both the DNA methylation and siRNA-mediated regulation systems, suggesting that plants likely evolved "multi-lock" systems for transposon regulation to ensure tight control during the developmental phase and environmental changes. PMID- 23676706 TI - The epigenetic regulation of transposable elements by PIWI-interacting RNAs in Drosophila. AB - A mechanism is required to repress the expression and transposition of transposable elements (TEs) to ensure the stable inheritance of genomic information. Accumulating evidence indicates that small non-coding RNAs are important regulators of TEs. Among small non-coding RNAs, PIWI-interacting RNAs (piRNAs) serve as guide molecules for recognizing and silencing numerous TEs and work in collaboration with PIWI subfamily proteins in gonadal cells. Disruption of the piRNA pathway correlates with loss of proper genomic organization, gene expression control and fertility. Moreover, recent studies on the molecular mechanisms of piRNA biogenesis and on piRNA function have shown that piRNAs act as maternally inherited genic elements, transferring information about repressed TEs to progeny. These findings enable a molecular explanation of mysterious epigenetic phenomena, such as hybrid dysgenesis and TE adaptation with age. Here, I review our current knowledge of piRNAs derived from biochemical and genetic studies and discuss how small RNAs are utilized to maintain genome organization and to provide non-DNA genetic information. I mainly focus on Drosophila but also discuss comparisons with other species. PMID- 23676707 TI - Epigenetic regulation of transcription and possible functions of mammalian short interspersed elements, SINEs. AB - Short interspersed elements (SINEs) are a class of retrotransposons, which amplify their copy numbers in their host genomes by retrotransposition. More than a million copies of SINEs are present in a mammalian genome, constituting over 10% of the total genomic sequence. In contrast to the other two classes of retrotransposons, long interspersed elements (LINEs) and long terminal repeat (LTR) elements, SINEs are transcribed by RNA polymerase III. However, like LINEs and LTR elements, the SINE transcription is likely regulated by epigenetic mechanisms such as DNA methylation, at least for human Alu and mouse B1. Whereas SINEs and other transposable elements have long been thought as selfish or junk DNA, recent studies have revealed that they play functional roles at their genomic locations, for example, as distal enhancers, chromatin boundaries and binding sites of many transcription factors. These activities imply that SINE retrotransposition has shaped the regulatory network and chromatin landscape of their hosts. Whereas it is thought that the epigenetic mechanisms were originated as a host defense system against proliferation of parasitic elements, this review discusses a possibility that the same mechanisms are also used to regulate the SINE-derived functions. PMID- 23676708 TI - Retroelements: molecular features and implications for disease. AB - Eukaryotic genomes comprise numerous retroelements that have a major impact on the structure and regulation of gene function. Retroelements are regulated by epigenetic controls, and they generate multiple miRNAs that are involved in the induction and progression of genomic instability. Elucidation of the biological roles of retroelements deserves continuous investigation to better understand their evolutionary features and implications for disease. PMID- 23676709 TI - Loss- and gain-of-function analyses of vacuolar protein sorting 2 in Notch signaling of Drosophila melanogaster. AB - Notch signaling is an evolutionarily conserved mechanism that controls many cell fate specifications through local cell-cell interactions. The core mechanisms of Notch activation and its subsequent intracellular signaling are well understood. Various cellular functions are required for the activation and regulation of Notch signaling. Among them, the endocytosis of Notch and its ligands is important for the activation and suppression of Notch signaling. The endosomal sorting complex required for transport (ESCRT) proteins are required to sort ubiquitinated membrane proteins, such as Notch, into early endosomes. A loss-of function allele of vacuolar protein sorting 2 (vps2), which encodes a component of ESCRT-III, has been reported. However, this vps2 mutant still produces the N terminal half of the protein, and its phenotypes were studied in only a few organs. Here, we generated the first null mutant allele of Drosophila vps2, designated vps22, to better understand the function of this gene. In Drosophila wing imaginal discs homozygous for the vps22 allele, early endosomes and multivesicular bodies (MVBs) were enlarged, and Notch and Delta accumulated inside them. As reported for the previous vps2 mutant, the epithelium grew excessively under this condition. We further studied the roles of vps2 by RNA interference-knockdown. These experiments revealed that a partial reduction of vps2 attenuated Notch signaling; in contrast, the loss-of-function vps2 mutant is reported to up-regulate the Notch signaling in eye imaginal disc cells. These results suggest that Notch signaling can be up- or down-regulated, depending on the level of vps2 expression. Finally, we found that vps2 overexpression also resulted in early-endosome enlargement and the accumulation of Notch and Delta. In these cells, a portion of the Vps2 protein was detected in MVBs and colocalized with Notch. These data indicate that the expression of vps2 must be precisely regulated to maintain the normal structure of early endosomes. PMID- 23676710 TI - Mitochondrial genomes of Japanese Babina frogs (Ranidae, Anura): unique gene arrangements and the phylogenetic position of genus Babina. AB - Genus Babina is a member of Ranidae, a large family of frogs, currently comprising 10 species. Three of them are listed as endangered species. To identify mitochondrial (mt) genes suitable for future population genetic analyses for endangered species, we determined the complete nucleotide sequences of the mt genomes of 3 endangered Japanese Babina frogs, B. holsti, B. okinavana, and B. subaspera and 1 ranid frog Lithobates catesbeianus. The genes of NADH dehydrogenase subunit 5 (nad5) and the control region (CR) were found to have high sequence divergences and to be usable for population genetics studies. At present, no consensus on the phylogenetic position of genus Babina has been reached. To resolve this problem, we performed molecular phylogenetic analyses with the largest dataset used to date (11,345 bp from 2 ribosomal RNA- and 13 protein-encoding genes) in studies dealing with Babina phylogeny. These analyses revealed monophyly of Babina and Odorrana. It is well known that mt gene rearrangements of animals can provide usable phylogenetic information. Thus, we also compared the mt gene arrangements among Babina species and other related genera. Of the surveyed species, only L. catesbeianus manifested typical neobatrachian-type mt gene organization. In the B. okinavana, an additional pseudogene of tRNA-His (trnH) was observed in the CR downstream region. Furthermore, in the B. holsti and B. subaspera, the trnH/nad5 block was translocated from its typical position to the CR downstream region, and the translocated trnH became a pseudogene. The position of the trnH pseudogene is consistent with the translocated trnH position reported in Odorrana. Consequently, the trnH rearrangement seems to be a common ancestry characteristic (synapomorphy) of Babina and Odorrana. Based on the "duplication and deletion" gene rearrangement model, a single genomic duplication event can explain the order of derived mt genes found in Babina and Odorrana. PMID- 23676711 TI - Population genetic study of the raccoon dog (Nyctereutes procyonoides) in South Korea using newly developed 12 microsatellite markers. AB - The raccoon dog (Nyctereutes procyonoides) is distributed from southeastern Siberia to northern Vietnam, including Korea and Japan, as well as Europe. In Korea, most of its predators and competitors are extinct, which has resulted in rapid growth of the raccoon dog population. This population increase has raised concerns about its role in the ecosystem and the zoonotic transfer of various contagious diseases, and thus an effective method of raccoon dog population control in Korea is required. To investigate the genetic diversity and structure of raccoon dog populations, 12 polymorphic microsatellite loci were identified and characterized. These novel microsatellite markers were employed to obtain basic population genetic parameters for 104 N. procyonoides specimens from five locations in South Korea. The mean allele number of 12 loci across samples was 8.7, and the number of alleles per locus ranged 2-13. Mean expected and observed heterozygosities were 0.723 and 0.619, respectively. Genetic differentiation, estimated by pairwise FST, was significant for all population pairs excepting Seoul/Gyeonggi and Gangwon pair, with a moderate level of genetic differentiation for all the population pairs (mean FST = 0.054), but little differentiation between Seoul/Gyeonggi and Gangwon (FST = 0.024). Bayesian-based clustering analysis predicted that Korean raccoon dog population is composed of four distinct genetic subpopulations. These genetic information and structure of raccoon dog will be very useful to prevent spreading infectious diseases. PMID- 23676712 TI - Prevalence and correlates of disability in a late middle-aged population of women. AB - OBJECTIVE: This study estimates the prevalence of disability among late middle aged women and identifies important correlates of disability among this population. METHOD: Disability was assessed among 376 participants of the Michigan Study of Women's Health Across the Nation cohort at the 2011 follow-up using the World Health Organization Disability Assessment Schedule. Demographic and health measures were related to disability status using logistic regression models (none or mild vs. moderate, severe, or extreme disability). RESULTS: Nearly 25% of women reported moderate to extreme global disability. African American race/ethnicity, economic strain, peripheral neuropathy, and depressive symptomatology were associated with global disability. Obesity, knee osteoarthritis, and hypertension were only associated with disability for the mobility domain (getting around). DISCUSSION: The prevalence of disability is relatively high among this population of late middle-aged women. Efforts to prevent or forestall disability should be extended to include middle-aged populations as they may be most amenable to intervention. PMID- 23676713 TI - Day of the week is associated with meeting physical activity recommendations and engaging in excessive sedentary time in youth. AB - BACKGROUND: Most youth fail to achieve 60 minutes of moderate-to-vigorous physical activity (MVPA) daily while engaging in excessive amounts of sedentary behaviors. The objective of this investigation was to identify modifiable factors associated with meeting MVPA recommendations or engaging in greater than 55% of observed time sedentary. METHODS: Youth (N = 1005, 10.5 yrs, 52% girls) wore accelerometers with daily minutes of MVPA (>= 2296 counts . min(-1)) classified as >= 60 min s/d vs. < 60 min/d of MVPA. Sedentary behavior (< 100 counts . min( 1)) was classified as < 55% or >= 55% of total wear-time. Two-level random effects logit survival models for repeated events (days of monitoring) examined the association of psychosocial self-report measures and demographic characteristics to meeting the MVPA recommendation and spending >= 55% of time sedentary. RESULTS: Wednesdays, Thursdays, and Sundays were associated with a decreased likelihood of meeting MVPA recommendations relative to Mondays. Wednesday thru Sunday were associated with a decreased likelihood of spending >= 55% of time sedentary. Being a boy, receiving transportation, and fewer reported barriers to physical activity were associated with meeting MVPA recommendations. CONCLUSIONS: Relatively few youth are engaging in recommended levels of physical activity. Provision of transportation and reduction of barriers to physical activity are relevant targets for physical activity promotion. PMID- 23676714 TI - Evaluation of a Web-based social network electronic game in enhancing mental health literacy for young people. AB - BACKGROUND: Internet-based learning programs provide people with massive health care information and self-help guidelines on improving their health. The advent of Web 2.0 and social networks renders significant flexibility to embedding highly interactive components, such as games, to foster learning processes. The effectiveness of game-based learning on social networks has not yet been fully evaluated. OBJECTIVES: The aim of this study was to assess the effectiveness of a fully automated, Web-based, social network electronic game on enhancing mental health knowledge and problem-solving skills of young people. We investigated potential motivational constructs directly affecting the learning outcome. Gender differences in learning outcome and motivation were also examined. METHODS: A pre/posttest design was used to evaluate the fully automated Web-based intervention. Participants, recruited from a closed online user group, self assessed their mental health literacy and motivational constructs before and after completing the game within a 3-week period. The electronic game was designed according to cognitive-behavioral approaches. Completers and intent-to treat analyses, using multiple imputation for missing data, were performed. Regression analysis with backward selection was employed when examining the relationship between knowledge enhancement and motivational constructs. RESULTS: The sample included 73 undergraduates (42 females) for completers analysis. The gaming approach was effective in enhancing young people's mental health literacy (d=0.65). The finding was also consistent with the intent-to-treat analysis, which included 127 undergraduates (75 females). No gender differences were found in learning outcome (P=.97). Intrinsic goal orientation was the primary factor in learning motivation, whereas test anxiety was successfully alleviated in the game setting. No gender differences were found on any learning motivation subscales (P>.10). We also found that participants' self-efficacy for learning and performance, as well as test anxiety, significantly affected their learning outcomes, whereas other motivational subscales were statistically nonsignificant. CONCLUSIONS: Electronic games implemented through social networking sites appear to effectively enhance users' mental health literacy. PMID- 23676715 TI - An update on venom allergy. AB - PURPOSE OF REVIEW: Allergic reactions to stinging insects may be unexpected, frightening, and severe. A clear understanding of recent advances in the field facilitates appropriate care of children who experience severe reactions to hymenoptera stings. RECENT FINDINGS: Recent investigations have underscored the importance of appropriate patient selection for potentially life-saving venom immunotherapy. Venom immunotherapy is effective in preventing future anaphylaxis from hymenoptera stings. Immunotherapy is indicated for patients with a history of anaphylaxis. Children who develop large local swelling or strictly cutaneous systemic reactions generally do not require immunotherapy. Component resolved diagnostic testing has been investigated to clarify the possibility of multiple venom allergies in patients with sensitization to multiple venoms. SUMMARY: Rapid recognition and treatment of anaphylaxis are critical. Subsequent education about avoiding future stings and attention to emergency preparedness with appropriate prescription of self-injectable epinephrine is important. Referral of patients who have experienced venom-associated anaphylaxis for possible venom immunotherapy can prevent future severe episodes of anaphylaxis resulting from stings. PMID- 23676716 TI - Clinical factors predicting the response of acute graft-versus-host disease to corticosteroid therapy: an analysis from the GVHD Working Group of the Japan Society for Hematopoietic Cell Transplantation. AB - Systemic corticosteroid therapy is recommended as a first-line treatment for acute graft-versus-host disease (GVHD). We performed a retrospective study to identify the factors affecting the response of grade II to IV acute GVHD to systemic corticosteroid therapy using the Japanese national registry data for patients who received first allogeneic hematopoietic cell transplantation with bone marrow (BM) (n = 1955), peripheral blood stem cells (PBSCs) (n = 642), or umbilical cord blood (UCB) (n = 839). Of 3436 patients, 2190 (63.7%) showed improvement of acute GVHD to first-line therapy with corticosteroids. Various factors were identified to predict corticosteroid response. Interestingly, UCB (versus HLA-matched related BM) transplantation was significantly associated with a higher probability of improvement, whereas HLA-matched unrelated BM and HLA mismatched stem cell sources other than UCB were significantly associated with a lower probability of improvement. HLA-matched related PBSC transplantation was not significantly different from HLA-matched related BM transplantation. Patients without improvement from corticosteroid therapy had a 2.5-times higher nonrelapse mortality and a .6-times lower overall survival rate. The present study demonstrated, for the first time, a higher probability of improvement in grade II to IV acute GVHD with systemic corticosteroid therapy in patients after UCB transplantation than in those after BM and PBSC transplantation. A prospective study is warranted. PMID- 23676717 TI - Driving students into science is a fool's errand. PMID- 23676729 TI - Human stem cells created by cloning. PMID- 23676730 TI - Magnetar found at giant black hole. PMID- 23676731 TI - Chinese project probes the genetics of genius. PMID- 23676732 TI - Hawking decision fuels Israel debate. PMID- 23676733 TI - Meeting targets lab lapses. PMID- 23676735 TI - Neanderthal culture: old masters. PMID- 23676736 TI - Invasive species: the 18-km(2) rat trap. PMID- 23676737 TI - Lab life: don't bristle at blunders. PMID- 23676738 TI - Philanthropy: the difficult art of giving. PMID- 23676742 TI - Q&A: Elephant man. Interview by Laura Spinney. PMID- 23676743 TI - Astronomy: Japan's work on ALMA telescope. PMID- 23676744 TI - Policy: social responsibility for new technologies. PMID- 23676745 TI - Whales: no mass strandings since sonar ban. PMID- 23676746 TI - Archives: preserve our digital heritage. PMID- 23676747 TI - Pollution: an innovation prize for clean cookstoves. PMID- 23676748 TI - Robert Edwards (1925-2013). PMID- 23676749 TI - Fisheries: climate change at the dinner table. PMID- 23676750 TI - Planetary science: plumbing the depths of Uranus and Neptune. PMID- 23676751 TI - Atmospheric confinement of jet streams on Uranus and Neptune. AB - The observed cloud-level atmospheric circulation on the outer planets of the Solar System is dominated by strong east-west jet streams. The depth of these winds is a crucial unknown in constraining their overall dynamics, energetics and internal structures. There are two approaches to explaining the existence of these strong winds. The first suggests that the jets are driven by shallow atmospheric processes near the surface, whereas the second suggests that the atmospheric dynamics extend deeply into the planetary interiors. Here we report that on Uranus and Neptune the depth of the atmospheric dynamics can be revealed by the planets' respective gravity fields. We show that the measured fourth-order gravity harmonic, J4, constrains the dynamics to the outermost 0.15 per cent of the total mass of Uranus and the outermost 0.2 per cent of the total mass of Neptune. This provides a stronger limit to the depth of the dynamical atmosphere than previously suggested, and shows that the dynamics are confined to a thin weather layer no more than about 1,000 kilometres deep on both planets. PMID- 23676752 TI - An electrically pumped polariton laser. AB - Conventional semiconductor laser emission relies on stimulated emission of photons, which sets stringent requirements on the minimum amount of energy necessary for its operation. In comparison, exciton-polaritons in strongly coupled quantum well microcavities can undergo stimulated scattering that promises more energy-efficient generation of coherent light by 'polariton lasers'. Polariton laser operation has been demonstrated in optically pumped semiconductor microcavities at temperatures up to room temperature, and such lasers can outperform their weak-coupling counterparts in that they have a lower threshold density. Even though polariton diodes have been realized, electrically pumped polariton laser operation, which is essential for practical applications, has not been achieved until now. Here we present an electrically pumped polariton laser based on a microcavity containing multiple quantum wells. To prove polariton laser emission unambiguously, we apply a magnetic field and probe the hybrid light-matter nature of the polaritons. Our results represent an important step towards the practical implementation of polaritonic light sources and electrically injected condensates, and can be extended to room-temperature operation using wide-bandgap materials. PMID- 23676753 TI - Deep fracture fluids isolated in the crust since the Precambrian era. AB - Fluids trapped as inclusions within minerals can be billions of years old and preserve a record of the fluid chemistry and environment at the time of mineralization. Aqueous fluids that have had a similar residence time at mineral interfaces and in fractures (fracture fluids) have not been previously identified. Expulsion of fracture fluids from basement systems with low connectivity occurs through deformation and fracturing of the brittle crust. The fractal nature of this process must, at some scale, preserve pockets of interconnected fluid from the earliest crustal history. In one such system, 2.8 kilometres below the surface in a South African gold mine, extant chemoautotrophic microbes have been identified in fluids isolated from the photosphere on timescales of tens of millions of years. Deep fracture fluids with similar chemistry have been found in a mine in the Timmins, Ontario, area of the Canadian Precambrian Shield. Here we show that excesses of (124)Xe, (126)Xe and (128)Xe in the Timmins mine fluids can be linked to xenon isotope changes in the ancient atmosphere and used to calculate a minimum mean residence time for this fluid of about 1.5 billion years. Further evidence of an ancient fluid system is found in (129)Xe excesses that, owing to the absence of any identifiable mantle input, are probably sourced in sediments and extracted by fluid migration processes operating during or shortly after mineralization at around 2.64 billion years ago. We also provide closed-system radiogenic noble-gas ((4)He, (21)Ne, (40)Ar, (136)Xe) residence times. Together, the different noble gases show that ancient pockets of water can survive the crustal fracturing process and remain in the crust for billions of years. PMID- 23676754 TI - Signature of ocean warming in global fisheries catch. AB - Marine fishes and invertebrates respond to ocean warming through distribution shifts, generally to higher latitudes and deeper waters. Consequently, fisheries should be affected by 'tropicalization' of catch (increasing dominance of warm water species). However, a signature of such climate-change effects on global fisheries catch has so far not been detected. Here we report such an index, the mean temperature of the catch (MTC), that is calculated from the average inferred temperature preference of exploited species weighted by their annual catch. Our results show that, after accounting for the effects of fishing and large-scale oceanographic variability, global MTC increased at a rate of 0.19 degrees Celsius per decade between 1970 and 2006, and non-tropical MTC increased at a rate of 0.23 degrees Celsius per decade. In tropical areas, MTC increased initially because of the reduction in the proportion of subtropical species catches, but subsequently stabilized as scope for further tropicalization of communities became limited. Changes in MTC in 52 large marine ecosystems, covering the majority of the world's coastal and shelf areas, are significantly and positively related to regional changes in sea surface temperature. This study shows that ocean warming has already affected global fisheries in the past four decades, highlighting the immediate need to develop adaptation plans to minimize the effect of such warming on the economy and food security of coastal communities, particularly in tropical regions. PMID- 23676755 TI - X-ray phase-contrast in vivo microtomography probes new aspects of Xenopus gastrulation. AB - An ambitious goal in biology is to understand the behaviour of cells during development by imaging-in vivo and with subcellular resolution-changes of the embryonic structure. Important morphogenetic movements occur throughout embryogenesis, but in particular during gastrulation when a series of dramatic, coordinated cell movements drives the reorganization of a simple ball or sheet of cells into a complex multi-layered organism. In Xenopus laevis, the South African clawed frog and also in zebrafish, cell and tissue movements have been studied in explants, in fixed embryos, in vivo using fluorescence microscopy or microscopic magnetic resonance imaging. None of these methods allows cell behaviours to be observed with micrometre-scale resolution throughout the optically opaque, living embryo over developmental time. Here we use non-invasive in vivo, time-lapse X ray microtomography, based on single-distance phase contrast and combined with motion analysis, to examine the course of embryonic development. We demonstrate that this powerful four-dimensional imaging technique provides high-resolution views of gastrulation processes in wild-type X. laevis embryos, including vegetal endoderm rotation, archenteron formation, changes in the volumes of cavities within the porous interstitial tissue between archenteron and blastocoel, migration/confrontation of mesendoderm and closure of the blastopore. Differential flow analysis separates collective from relative cell motion to assign propulsion mechanisms. Moreover, digitally determined volume balances confirm that early archenteron inflation occurs through the uptake of external water. A transient ectodermal ridge, formed in association with the confrontation of ventral and head mesendoderm on the blastocoel roof, is identified. When combined with perturbation experiments to investigate molecular and biomechanical underpinnings of morphogenesis, our technique should help to advance our understanding of the fundamentals of development. PMID- 23676758 TI - Elderly in-hospital cardiac arrest patients who are resuscitated with neurological recovery experience favourable long-term survival similar to non arrest heart failure patients. PMID- 23676757 TI - Identification of biomarkers for Mycobacterium tuberculosis infection and disease in BCG-vaccinated young children in Southern India. AB - Pediatric tuberculosis (TB) often goes undiagnosed because of the lack of reliable diagnostic methods. With the aim of assessing biomarker(s) that can aid in the diagnosis of TB infection and disease, we investigated 746 Indian children with suspected TB. Whole-blood mRNA from 210 children was examined by dual-color Reverse-Transcriptase Multiple Ligation-dependent Probe-Amplification for the expression of 45 genes and a Bio-Plex assay for the expression of cytokines/chemokines in QuantiFERON supernatants. The study shows that transcription of SEC14L1, GUSB, BPI, CCR7 and TGFbeta-1 (all P <= 0.05) was downregulated in TB disease compared with uninfected controls, while transcription of RAB33A was downregulated in TB disease compared with both latent TB (P < 0.05) and controls (P < 0.01). The transcription of CD4, TGFbeta-1 (P < 0.01) and the expression of IL-2 (P < 0.01) and IL-13 (P < 0.05) was upregulated in latent TB compared with that in controls. Using the Least Absolute Shrinkage and Selection Operator (lasso) model, RAB33A alone discriminated between TB disease and latent TB (area under the curve (AUC) 77.5%), whereas a combination of RAB33A, CXCL10, SEC14L1, FOXP3 and TNFRSF1A was effective in discriminating between TB disease and controls (AUC 91.7%). A combination of 11 biomarkers predicted latent TB with moderate discriminatory power (AUC 72.2%). In conclusion, RAB33A is a potential biomarker for TB disease, whereas CD4, TGFbeta 1 and IL-2, IL-13 may identify latent TB in children. PMID- 23676759 TI - Hypertensive disorders of pregnancy predict chronic kidney disease and end-stage renal disease. PMID- 23676760 TI - Identifying hidden rate changes in the evolution of a binary morphological character: the evolution of plant habit in campanulid angiosperms. AB - The growth of phylogenetic trees in scope and in size is promising from the standpoint of understanding a wide variety of evolutionary patterns and processes. With trees comprised of larger, older, and globally distributed clades, it is likely that the lability of a binary character will differ significantly among lineages, which could lead to errors in estimating transition rates and the associated inference of ancestral states. Here we develop and implement a new method for identifying different rates of evolution in a binary character along different branches of a phylogeny. We illustrate this approach by exploring the evolution of growth habit in Campanulidae, a flowering plant clade containing some 35,000 species. The distribution of woody versus herbaceous species calls into question the use of traditional models of binary character evolution. The recognition and accommodation of changes in the rate of growth form evolution in different lineages demonstrates, for the first time, a robust picture of growth form evolution across a very large, very old, and very widespread flowering plant clade. PMID- 23676761 TI - Lateral cavoatriotomy for partial anomalous pulmonary venous connection to the superior vena cava. AB - PURPOSE: Surgical correction of the partial anomalous pulmonary venous connection (PAPVC) draining into the superior vena cava (SVC) has been associated with sinus node dysfunction and venous return obstruction, postoperatively. We present the results of our lateral cavoatriotomy approach with little modifications to avoid injury to the sinus node and its artery. METHODS: 32 patients who underwent surgical repair of PAPVC to SVC with modified lateral cavoatriotomy in our clinic between January 2003 and January 2009 were evaluated retrospectively. RESULTS: Median age was 6 years (2-32 years). The mean follow-up time was 65.8 +/- 23.7 months (36-111 months). There were no early or late deaths. No patients required reoperation. New onset of arrhythmia had developed in two patients and resolved before hospital discharge. Stenosis of the SVC in one patient had developed 11 months after the operation and was treated with balloon angioplasty, successfully. No sinus node dysfunction or venous return obstruction was detected in their last follow-up. CONCLUSION: Cavoatrial incision for repair of PAPVC to SVC may become a safer surgical technique with some modifications. PMID- 23676762 TI - Physiologically-relevant modes of membrane interactions by the human antimicrobial peptide, LL-37, revealed by SFG experiments. AB - Antimicrobial peptides (AMPs) could become the next generation antibiotic compounds which can overcome bacterial resistance by disrupting cell membranes and it is essential to determine the factors underlying its mechanism of action. Although high-resolution NMR and other biological studies have provided valuable insights, it has been a major challenge to follow the AMP-membrane interactions at physiologically-relevant low peptide concentrations. In this study, we demonstrate a novel approach to overcome this major limitation by performing Sum Frequency Generation (SFG) vibrational spectroscopic experiments on lipid bilayers containing an AMP, LL-37. Our results demonstrate the power of SFG to study non-linear helical peptides and also infer that lipid-peptide interaction and the peptide orientation depend on the lipid membrane composition. The observed SFG signal changes capture the aggregating process of LL-37 on membrane. In addition, our SFG results on cholesterol-containing lipid bilayers indicate the inhibition effect of cholesterol on peptide-induced membrane permeation process. PMID- 23676763 TI - Bloodstream infection rates in outpatient hemodialysis facilities participating in a collaborative prevention effort: a quality improvement report. AB - BACKGROUND: Bloodstream infections (BSIs) cause substantial morbidity in hemodialysis patients. In 2009, the US Centers for Disease Control and Prevention (CDC) sponsored a collaborative project to prevent BSIs in outpatient hemodialysis facilities. We sought to assess the impact of a set of interventions on BSI and access-related BSI rates in participating facilities using data reported to the CDC's National Healthcare Safety Network (NHSN). STUDY DESIGN: Quality improvement project. SETTING & PARTICIPANTS: Patients in 17 outpatient hemodialysis facilities that volunteered to participate. QUALITY IMPROVEMENT PLAN: Facilities reported monthly event and denominator data to NHSN, received guidance from the CDC, and implemented an evidence-based intervention package that included chlorhexidine use for catheter exit-site care, staff training and competency assessments focused on catheter care and aseptic technique, hand hygiene and vascular access care audits, and feedback of infection and adherence rates to staff. OUTCOMES: Crude and modeled BSI and access-related BSI rates. MEASUREMENTS: Up to 12 months of preintervention (January 2009 through December 2009) and 15 months of intervention period (January 2010 through March 2011) data from participating centers were analyzed. Segmented regression analysis was used to assess changes in BSI and access-related BSI rates during the preintervention and intervention periods. RESULTS: Most (65%) participating facilities were hospital based. Pooled mean BSI and access-related BSI rates were 1.09 and 0.73 events per 100 patient-months during the preintervention period and 0.89 and 0.42 events per 100 patient-months during the intervention period, respectively. Modeled rates decreased 32% (P = 0.01) for BSIs and 54% (P < 0.001) for access related BSIs at the start of the intervention period. LIMITATIONS: Participating facilities were not representative of all outpatient hemodialysis centers nationally. There was no control arm to this quality improvement project. CONCLUSIONS: Facilities participating in a collaborative successfully decreased their BSI and access-related BSI rates. The decreased rates appeared to be maintained in the intervention period. These findings suggest that improved implementation of recommended practices can reduce BSIs in hemodialysis centers. PMID- 23676764 TI - A turn-on fluorescent nanoprobe for selective determination of selenium(IV). AB - A turn-on fluorescent nanoprobe was developed for selective determination of selenium(IV). A trace amount of selenium, as an essential nutrient, plays an important role in human health. It has been proven that a selenium deficiency will result in serious health problems. The developed nanoprobe is capable of in situ detection of selenium with target-induced signaling, and no separation step is needed. The nanoprobe consists of a silica nanoparticle core and a coating layer containing selenium(IV)-induced fluorescent molecules, 3,3' diaminobenzidine (DAB). The nanoprobes have no fluorescence signals if they are not exposed to selenium(IV). However, the nanoprobes will be "turned on", with fluorescence, when they bind to the targets of selenium(IV). With this strategy, the selenium(IV) are first collected and enriched on a small domain of the nanoprobes. Then, with an excitation at 420 nm, the nanoprobes emit fluorescence signals at 530 nm. The fluorescence intensity is proportional to the selenium concentration. A fluorescence microscope was used to monitor the process of enriching and collecting of the selenium(IV) by the nanoprobes. The optimal conditions for the determination of selenium(IV) using the nanoprobe were investigated including pH, solvent, and linear range. The interference from common metal ions was studied as well. This study is expected to shed light on how to design turn-on fluorescent nanoprobes for in situ monitoring of a wide variety of targets in biological processes. PMID- 23676765 TI - What is the impact of electromagnetic waves on epileptic seizures? AB - BACKGROUND: The effects of electromagnetic waves (EMWs) on humans and their relationship with various disorders have been investigated. We aimed to investigate the effects of exposure to different frequencies of EMWs in various durations in a mouse epilepsy model induced by pentylenetetrazole (PTZ). MATERIAL AND METHODS: A total of 180 4-week-old male mice weighing 25-30 g were used in this study. Each experimental group consisted of 10 mice. They were exposed to 900, 700, 500, 300, and 100 MHz EMWs for 20 hours, 12 hours and 2 hours. Following electromagnetic radiation exposure, 60 mg/kg of PTZ was injected intraperitoneally to all mice. Each control was also injected with PTZ without any exposure to EMW. The latency of initial seizure and most severe seizure onset were compared with controls. RESULTS: The shortest initial seizure latency was noted in the 12-hour group, followed by the 700 MHz. The mean initial seizure latencies in the 2-hour EMW exposed group was significantly shorter compared to that in the 12- and 20-hour groups. There was no significant difference between 12- and 20-hour EMW exposed groups. There was a significant difference between control and 2- and 10-hour EMW exposed groups. No statistically significant differences were noted in mean latencies of the most severe seizure latency, following 20-, 12-, and 2- hour EMW exposed groups and control groups. CONCLUSIONS: Our findings suggest that acute exposure to EMW may facilitate epileptic seizures, which may be independent of EMW exposure time. This information might be important for patients with epilepsy. Further studies are needed. PMID- 23676767 TI - Realization of high performance silicon nanowire based solar cells with large size. AB - We report the realization of high performance silicon nanowire (SiNW) based solar cells with a conversion efficiency of 17.11% and a large size of 125 * 125 mm(2). The key factor for success lies in an efficient approach of dielectric passivation to greatly enhance the electrical properties while keeping the advantage of excellent light trapping of the SiNW structure. The suppression of carrier recombination has been demonstrated through the combination of the SiO2/SiNx stack, which exhibits a good passivation effect on heavily doped SiNWs via reducing both the Shockley-Read-Hall recombination and near surface Auger recombination. We have examined in detail the effects of different passivations and SiNW lengths on the effective minority carrier lifetime, reflectance and carrier recombination characteristics, as well as cell performance. The proposed passivation techniques can be easily adapted to conventional industrial manufacturing processes, providing a potential prospect of SiNW based solar cells in mass production. PMID- 23676766 TI - Preclinical study and phase I clinical safety evaluation of recombinant Mycobacterium tuberculosis ESAT6 protein. AB - BACKGROUND: To investigate the ability of rESAT6 to identify different mycobacteria-sensitized guinea pigs and its safety in preclinical and phase I clinical study. MATERIAL AND METHODS: Guinea pigs were sensitized with different Mycobacteria. After sensitization, all animals were intradermally injected with rESAT6 and either PPD or PPD-B. At 24 h after the injection, the erythema of the injection sites were measured using a double-blind method. For the preclinical safety study, different doses of rESAT6 and BSA were given 3 times intramuscularly to guinea pigs. On day 14 after the final immunization, the guinea pigs were intravenously injected with the same reagents in the hind legs and the allergic reactions were observed. A single-center, randomized, open phase I clinical trial was employed. The skin test was conducted in 32 healthy volunteers aged 19-65 years with 0.1 ug, 0.5 ug, and 1 ug rESAT6. Physical examination and laboratory tests were performed before and after the skin test and adverse reactions were monitored. The volunteers' local and systemic adverse reactions and adverse events were recorded for 7 days. RESULTS: Positive PPD or PPD-B skin tests were observed in all Mycobacteria-sensitized guinea pigs; the diameters of erythema were all >10 mm. The rESAT6 protein induced a positive skin test result in the guinea pigs sensitized with MTB, M. bovis, M. africanum and M. kansasii; the diameters of erythema were 14.7+/-2.0, 9.3+/-3.8, 18.7+/-2.4, and 14.8+/-4.2 mm, respectively. A negative skin test result was detected in BCG vaccinated and other NTM-sensitized guinea pigs. The rESAT6 caused no allergic symptoms, but many allergic reactions, such as cough, dyspnea, and even death, were observed in the guinea pigs who were administered BSA. During the phase I clinical trial, no adverse reactions were found in the 0.1 ug rESAT6 group, but in the 0.5 ug rESAT6 group 2 volunteers reported pain and 1 reported itching, and in the 1 ug rESAT6 group there was 1 case of pain, 1 case of itching, and 1 case of blister. No other local or systemic adverse reactions or events were reported. CONCLUSIONS: The rESAT6 can differentiate effectively among MTB infection, BCG vaccination, and NTM infection and is safe in healthy volunteers. PMID- 23676769 TI - Phylogenetic analysis of 47 chloroplast genomes clarifies the contribution of wild species to the domesticated apple maternal line. AB - Both the origin of domesticated apple and the overall phylogeny of the genus Malus are still not completely resolved. Having this as a target, we built a 134,553-position-long alignment including two previously published chloroplast DNAs (cpDNAs) and 45 de novo sequenced, fully colinear chloroplast genomes from cultivated apple varieties and wild apple species. The data produced are free from compositional heterogeneity and from substitutional saturation, which can adversely affect phylogeny reconstruction. Phylogenetic analyses based on this alignment recovered a branch, having the maximum bootstrap support, subtending a large group of the cultivated apple sorts together with all analyzed European wild apple (Malus sylvestris) accessions. One apple cultivar was embedded in a monophylum comprising wild M. sieversii accessions and other Asian apple species. The data demonstrate that M. sylvestris has contributed chloroplast genome to a substantial fraction of domesticated apple varieties, supporting the conclusion that different wild species should have contributed the organelle and nuclear genomes to the domesticated apple. PMID- 23676768 TI - Patterns of Epistasis between beneficial mutations in an antibiotic resistance gene. AB - Understanding epistasis is central to biology. For instance, epistatic interactions determine the topography of the fitness landscape and affect the dynamics and determinism of adaptation. However, few empirical data are available, and comparing results is complicated by confounding variation in the system and the type of mutations used. Here, we take a systematic approach by quantifying epistasis in two sets of four beneficial mutations in the antibiotic resistance enzyme TEM-1 beta-lactamase. Mutations in these sets have either large or small effects on cefotaxime resistance when present as single mutations. By quantifying the epistasis and ruggedness in both landscapes, we find two general patterns. First, resistance is maximal for combinations of two mutations in both fitness landscapes and declines when more mutations are added due to abundant sign epistasis and a pattern of diminishing returns with genotype resistance. Second, large-effect mutations interact more strongly than small-effect mutations, suggesting that the effect size of mutations may be an organizing principle in understanding patterns of epistasis. By fitting the data to simple phenotype resistance models, we show that this pattern may be explained by the nonlinear dependence of resistance on enzyme stability and an unknown phenotype when mutations have antagonistically pleiotropic effects. The comparison to a previously published set of mutations in the same gene with a joint benefit further shows that the enzyme's fitness landscape is locally rugged but does contain adaptive pathways that lead to high resistance. PMID- 23676770 TI - What is a factorial trial? AB - Randomized controlled trials (RCTs), typically, randomize participants to one of two intervention groups. It has been shown, however, that about 25% of RCTs published in the scientific literature randomize participants to three or more treatment groups. These studies are called 'multi-arm' trials: there may be, for instance, two or more experimental intervention groups with a common control group, or two control intervention groups such as a placebo group and a standard treatment group. A special case of multi-arm studies are factorial trials, which address two or more intervention comparisons carried out simultaneously, using four or more intervention groups. PMID- 23676771 TI - Should physical activity intervention efforts take a whole population, high-risk or middle road strategy? AB - PURPOSE: This study was designed to compare theoretical strategies for changing physical activity (PA) in terms of their potential to reduce the incidence of chronic conditions in midage women: (1) whole population: +30 minutes/week in all, (2) high-risk: +60 minutes/week in the lowest 25% of the PA distribution, and (3) middle road: shift all those not meeting guidelines to a level commensurate with meeting guidelines. METHODS: 10,854 participants (50-55 years in 2001) in the Australian Longitudinal Study of Women's Health completed mail surveys in 2001, 2004, 2007, and 2010. PA was calculated as MET . minutes/week spent in walking, moderate and vigorous PA in the previous week. Incidence rates per 1000 person-years for diabetes, heart disease, hypertension, cancer, and depression were calculated for the actual distribution and after modeled shifts in PA. RESULTS: The incidence rates were 10.6 for diabetes, 7.0 for heart disease, 30.7 for hypertension, 8.0 for cancer, and 28.4 for depression. Greater reductions in incidence were found for the middle road strategy than for the whole population and high-risk strategies, with reductions ranging from -6.3% for cancer to -12.3% for diabetes. DISCUSSION: This theoretical modeling showed that a middle road strategy to increasing PA was superior to the whole population and high-risk strategies, in terms of reducing incidence rates of chronic conditions in middle-aged women. PMID- 23676772 TI - Short-term intermittent administration of CXCR4 antagonist AMD3100 facilitates myocardial repair in experimental myocardial infarction. AB - The binding of the stromal cell-derived factor-1alpha (SDF-1alpha) to the cysteine (C)-X-C motif chemokine receptor 4 (CXCR4) has emerged as a key signal for stem and progenitor cells trafficking to the circulation from the bone marrow. Our aim was to investigate the role of daily intermittent administration of AMD3100 (a specific reversible CXCR4 receptor antagonist) during the healing process after myocardial infarction (MI). Wistar rats were subjected to MI and AMD3100 was injected intraperitoneally after surgery. SDF-1alpha mRNA expression was measured by real-time polymerase chain reaction. Histology changes were analyzed with immunofluorescence, Masson's trichrome staining, and wheat germ agglutinin. The number of leukocytes in peripheral blood was measured by complete blood cell count analysis. The activities of matrix metalloproteinase-2/9 (MMP 2/9) were determined by gelatin zymography. The expression level of SDF-1alpha mRNA in the infarcted tissue was enhanced rapidly (6 h), peaked at 24 h, and then declined to the normal level at 7 days post-MI. AMD3100 further enhanced the increase of SDF-1alpha in infarct area. Increased leukocytes were observed in AMD3100-treated groups. The mobilization of c-kit(+) stem/progenitor cells and enhanced neovascularization were augmented by AMD3100. Additionally, AMD3100 improved ventricular remodeling, which was revealed by the decrease of infarct size, viable cardiomyocyte cross-sectional area and left ventricle (LV) expansion index, and the increase of LV free wall thickness. The activities of MMP-2/9 were up-regulated by AMD3100. In conclusion, short-term intermittent administration of AMD3100 could accelerate the wound healing process in experimental MI and be a potential therapy for the treatment of MI. PMID- 23676773 TI - Immunoreactive endothelin-1 and endothelin a receptor in basilar artery perivascular nerves of young and adult capybaras. AB - The purpose of this qualitative morphological study was the immunocytochemical and ultrastructural comparison of perivascular nerves of the basilar artery (BA) of young (6-month-old) and adult (12-month-old) capybaras - adult capybaras showed regression of the internal carotid artery (ICA). The study focused on immunolabeling for the vasoactive peptide endothelin-1 (ET-1) and endothelin A receptor (ETA) as well as for the synapse marker synaptophysin (SYP). In the BA of young capybaras, immunoreactivity for ET-1, ETA receptor and SYP was detected in perivascular nerve varicosities and/or intervaricosities. Immunoreactivity for ET-1 and ETA receptor was also displayed by some Schwann cells, which accompanied perivascular nerves. In addition to the presence of the above-described perivascular nerve characteristics, the BA of adult animals also revealed structurally altered perivascular nerves, where axon profiles were irregular in shape with dense axoplasm, while the cytoplasm of Schwann cells was vacuolated and contained myelin-like figures. These structurally altered perivascular nerves displayed immunoreactivity for ET-1, ETA receptor and SYP. These results show that the ET-1 system is present in some of the BA perivascular nerves and it is likely that this system is affected during animal maturation when ICA regression takes place. The role of ET-1 in cerebrovascular nerves is still unclear but its involvement in neural (sensory) control of cerebral blood flow and nerve function is possible. PMID- 23676774 TI - Does elastic therapeutic tape reduce postoperative swelling, pain, and trismus after open reduction and internal fixation of mandibular fractures? AB - PURPOSE: The aim of the present study was to investigate whether the application of elastic therapeutic tape (Kinesio Tape [KT]) prevents or decreases swelling, pain, and trismus after open reduction and internal fixation of mandibular fracture, thus improving patients' postoperative morbidity. MATERIALS AND METHODS: To address the research purpose, the investigators designed and implemented an open-label, monocentric, parallel-group, randomized clinical trial. Patients were prospectively assigned for treatment of unilateral mandibular fractures and randomly allocated to receive treatment with or without KT application. KT was applied directly after surgery and maintained for 5 days postoperatively. Facial swelling was quantified using a 5-line measurement at 6 specific time points. Pain score was assessed using a 10-level visual analog scale; mouth opening was measured. In addition, all patients were asked to evaluate overall satisfaction and swelling (2 groups) and the effect of the tape on movement and comfort (KT group only). RESULTS: The study included 26 patients (11 female and 15 male; mean age, 43 yr; standard deviation, 18.5 yr). Application of KT after surgery for mandibular fracture had a statistically significant influence on tissue reaction and swelling, decreasing the incidence of swelling and turgidity by more than 60% during the first 2 days after surgery. Although KT had no significant influence on pain control, patients in the KT group perceived significantly lower morbidity. CONCLUSION: The present results showed that KT after open reduction and internal fixation of mandibular fracture is a promising, simple, less traumatic, and economical approach for managing postoperative swelling that is free from systemic adverse reactions, thus improving patients' quality of life. PMID- 23676775 TI - Effects of allogenous periosteal-derived cells transfected with adenovirus mediated BMP-2 on repairing defects of the mandible in rabbits. AB - PURPOSE: This report describes the effect of periosteal-derived cells transfected with adenovirus-mediated bone morphogenetic protein-2 (BMP-2) on the repair of mandibular defects in rabbits. MATERIALS AND METHODS: Periosteal-derived cells were transfected with a replication-defective adenoviral vector encoding BMP-2, and the expression of BMP-2 was examined in transfected cells using in situ hybridization and enzyme-linked immunosorbent assay. In addition, the proliferation ability and activity of alkaline phosphatase of transfected cells were examined using the 3-[4,5-dimethylthiazol-2-Yl]-2,5-diphenyltetrazolium bromide method and enzymology, respectively. In vitro critical-size defects (about 10 * 6 mm) were made bilaterally in each rabbit mandible, and individual sites were implanted with tissue-engineered bone modified with an adenovirus construct encoding the recombinant human BMP-2 gene (Ad-BMP-2), tissue-engineered bone without modification, single bioactive glass ceramic, or no implants (control). New bone formation was evaluated by histochemical stain. RESULTS: BMP 2 expression in the supernate of infected cells was detected from the first day after Ad-BMP-2 transfection and remained at a high level for at least 2 weeks. Alkaline phosphatase expression in transfected cells was significantly greater than in uninfected cells. The group of Ad-BMP-2-modified periosteal-derived cells formed more new bone than the other group at any time point. CONCLUSION: Gene modified tissue-engineered bone grafts have greater osteogenic potential than single tissue-engineered bone and single bioactive glass ceramic graft. Ex vivo Ad-BMP-2 transfer to periosteal-derived cells can increase bone formation in critical-size bone defects. Further studies are needed to determine if modified engineered cells can be developed for safe and effective clinical applications. PMID- 23676776 TI - Single-step resection and reconstruction using patient-specific implants in the treatment of benign cranio-orbital tumors. AB - PURPOSE: The aim of this study was to evaluate surgical outcomes using patient specific prostheses produced by computer-aided design and manufacturing for primary reconstruction in patients with benign cranio-orbital tumors. Polyetheretherketone was used to manufacture the implants. MATERIALS AND METHODS: The present study included 3 patients who underwent fronto-orbito-pterional craniotomy using individual custom-made surgical guides. Patient-specific polyetheretherketone prostheses were used for reconstruction during the same surgery. All patients underwent esthetic examination (facial and orbital symmetry, globe projection and position), ophthalmologic examination (diplopia with the Hess-Lancaster test, visual field and acuity), and radiologic evaluations (computed tomography and magnetic resonance imaging) during the preoperative and follow-up periods. Operating time and short- and long-term complications were recorded. RESULTS: The immediate and long-term morphologic results were satisfactory; in particular, ocular globe position and projection were correct. After 25 to 31 months, none of the patients developed implant related complications, such as infection, extrusion, or malposition. Two-year postoperative computed tomograms and magnetic resonance images showed no recurrences. CONCLUSION: Single-step resection and reconstruction with computer aided designed and manufactured implants is a challenging new technique that decreases operative time and morbidity. The implants adequately restore an anatomically complex area with satisfactory cosmetic results. PMID- 23676777 TI - Correlated Raman micro-spectroscopy and scanning electron microscopy analyses of flame retardants in environmental samples: a micro-analytical tool for probing chemical composition, origin and spatial distribution. AB - We present correlated application of two micro-analytical techniques: scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDS) and Raman micro-spectroscopy (RMS) for the non-invasive characterization and molecular identification of flame retardants (FRs) in environmental dusts and consumer products. The SEM/EDS-RMS technique offers correlated, morphological, molecular, spatial distribution and semi-quantitative elemental concentration information at the individual particle level with micrometer spatial resolution and minimal sample preparation. The presented methodology uses SEM/EDS analyses for rapid detection of particles containing FR specific elements as potential indicators of FR presence in a sample followed by correlated RMS analyses of the same particles for characterization of the FR sub-regions and surrounding matrices. The spatially resolved characterization enabled by this approach provides insights into the distributional heterogeneity as well as potential transfer and exposure mechanisms for FRs in the environment that is typically not available through traditional FR analysis. We have used this methodology to reveal a heterogeneous distribution of highly concentrated deca-BDE particles in environmental dust, sometimes in association with identifiable consumer materials. The observed coexistence of deca-BDE with consumer material in dust is strongly indicative of its release into the environment via weathering/abrasion of consumer products. Ingestion of such enriched FR particles in dust represents a potential for instantaneous exposure to high FR concentrations. Therefore, correlated SEM/RMS analysis offers a novel investigative tool for addressing an area of important environmental concern. PMID- 23676778 TI - Thermosensitive micelles formed from a small-molecule amphiphile: switchable LCST and potential application in cloud point separation. AB - Thermosensitive micelles are prepared through self-assembly of a small-molecule amphiphile. The micelles exhibit a lower critical solution temperature (LCST) of 34 degrees C in aqueous solution, which can be switched simply by bubbling CO2. Moreover, thermally induced aggregation of the micelles can facilitate the separation of hydrophobic pollutants from water. PMID- 23676779 TI - Can we identify source lithology of basalt? AB - The nature of source rocks of basaltic magmas plays a fundamental role in understanding the composition, structure and evolution of the solid earth. However, identification of source lithology of basalts remains uncertainty. Using a parameterization of multi-decadal melting experiments on a variety of peridotite and pyroxenite, we show here that a parameter called FC3MS value (FeO/CaO-3*MgO/SiO2, all in wt%) can identify most pyroxenite-derived basalts. The continental oceanic island basalt-like volcanic rocks (MgO>7.5%) (C-OIB) in eastern China and Mongolia are too high in the FC3MS value to be derived from peridotite source. The majority of the C-OIB in phase diagrams are equilibrium with garnet and clinopyroxene, indicating that garnet pyroxenite is the dominant source lithology. Our results demonstrate that many reputed evolved low magnesian C-OIBs in fact represent primary pyroxenite melts, suggesting that many previous geological and petrological interpretations of basalts based on the single peridotite model need to be reconsidered. PMID- 23676780 TI - Polarity and air-stability transitions in field-effect transistors based on fullerenes with different solubilizing groups. AB - A series of o-xylene and indene fullerene derivatives with varying frontier molecular orbital energy levels were utilized for assessing the impact of the number of solubilizing groups on the electrical performance of fullerene-based organic-field-effect transistors (OFETs). The charge-carrier polarity was found to be strongly dependent upon the energy levels of fullerene derivatives. The o xylene C60 monoadduct (OXCMA) and indene C60 monoadduct (ICMA) exhibited unipolar n-channel behaviors with high electron mobilities, whereas the bis- and trisadducts of indene and o-xylene C60 derivatives showed ambipolar charge transport. The OXCMA OFETs fabricated by solution shearing and molecular n-type doping showed an electron mobility of up to 2.28 cm(2) V(-1) s(-1), which is one of the highest electron mobilities obtained from solution-processed fullerene thin-film devices. Our findings systematically demonstrate the relationship between the energy level and charge-carrier polarity and provide insight into molecular design and processing strategies toward high-performance fullerene based OFETs. PMID- 23676781 TI - Eye banking and corneal transplantation communicable adverse incidents: current status and project NOTIFY. AB - PURPOSE: Evidence of the transmission of disease via donor ocular tissue has been demonstrated for adenocarcinoma, rabies, hepatitis B virus, cytomegalovirus, herpes simplex virus, Creutzfeldt-Jakob disease, and a variety of bacterial and fungal infections. METHODS: Although there is no evidence to date of disease transmission for HIV infection, syphilis, hepatitis C, hepatitis A, tuberculosis, HTLV-1 and -2 infection, active leprosy, active typhoid, smallpox, and active malaria, these entities remain contraindications for transplantation for all eye banks nationally and internationally. The potential sources of contamination include infected donors, during the process of removing tissue from cadaveric donors, the processing environment, and contaminated supplies and reagents used during processing. The transmissions of Herpes simplex virus and HSV via corneal graft have been shown to be responsible for primary graft failure. HSV-1 may also be an important cause of PFG. RESULTS: The long latency period of some diseases, the emergence of new infectious disease, and the reemergence of others emphasize the need for long-term record maintenance and effective tracing capabilities. CONCLUSIONS: The standardization of definitions for adverse events and reactions will be necessary to support the prevention and transmission of disease. International classification of a unique identification system for donors will be increasingly important for vigilance and traceability in cross-national exportation of human cells, tissues, and cellular- and tissue-based products. Opportunities for continuous improvement exist as does the need for constant vigilance and surveillance. PMID- 23676782 TI - Tear cytokine levels in vernal keratoconjunctivitis: the effect of topical 0.05% cyclosporine a therapy. AB - PURPOSE: The aims of this study were to evaluate the efficacy of topical 0.05% cyclosporine A on clinical signs and symptoms of vernal keratoconjunctivitis (VKC) and to examine its effect on tear cytokine levels. METHODS: Twenty-one patients with active VKC and 15 healthy volunteers were included. Patients were treated with topical 0.05% cyclosporine A. Symptoms and signs were scored on the day of enrollment and at the end of month 1 and month 3. Tear and serum samples were collected before and on the third month of treatment. Interleukin (IL)-2, soluble IL-2 receptor (sIL-2R), IL-3, IL-4, IL-5, IL-6, IL-9, IL-13, IL-17, eotaxin, tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN gamma) in cell-free tear and serum supernatants were measured by multiplex bead analysis. RESULTS: At the end of month 1 and month 3 with topical 0.05% cyclosporine A treatment, statistically a significant decrease was observed in sign and symptom scores of the patients (P < 0.0001). Tear IL-2, sIL-2R, IL-9, IL 17, IFN-gamma, and eotaxin levels in VKC patients were significantly higher than those in controls (P < 0.05). IL-3, IL-4, IL-5, and TNFalpha levels tended to be higher in VKC patients. There was also statistically significant reduction from before 0.05% cyclosporine A treatment to after treatment in tear levels of IL-4, IL-5, IL-17A, TNFalpha, IFN-gamma, and eotaxin (P < 0.05). IL-2 and sIL-2R levels tended to be lower than pretreatment levels. CONCLUSIONS: Topical 0.05% cyclosporine A is effective in alleviating signs and symptoms of VKC patients and shows its effect probably by decreasing the local production of some inflammatory mediators in tears. PMID- 23676783 TI - Toxic corneal epitheliopathy after intravitreal methotrexate and its treatment with oral folic acid. AB - PURPOSE: To determine whether oral folic acid can ameliorate an iatrogenic, visually significant corneal epitheliopathy, which commonly occurs with intravitreal injections of methotrexate for the treatment of intraocular lymphoma. METHODS: We report 2 cases of visually significant corneal epitheliopathy occurring after intravitreal injections of methotrexate for intraocular lymphoma. The first patient did not receive any treatment for the corneal disease, and the second patient with bilateral intraocular lymphoma received 1 mg of oral folic acid daily, a commonly used dosage for patients on systemic methotrexate. RESULTS: In the first patient without treatment, there was a complete regression of the corneal epithelial disease only when the frequency of intravitreal methotrexate was reduced from weekly to monthly as per a commonly used dosage regimen for methotrexate. In the second patient, the corneal disease improved 80% within 1 week of initiating oral folic acid for her eye already experiencing severe epitheliopathy during her weekly dosing regimen of methotrexate and also had significantly decreased epithelial disease in her second eye that started weekly intravitreal methotrexate several weeks after beginning oral folic acid. CONCLUSIONS: Currently, oral folic acid supplements are recommended for patients using systemic methotrexate to minimize drug toxicity. We suggest a similar use in patients undergoing intravitreal methotrexate injections to decrease toxic effects on the corneal epithelium. PMID- 23676784 TI - Biopsy of an anterior episcleral nodule as an aid in managing a ciliary body melanocytic tumor. AB - PURPOSE: To demonstrate the value of a diagnostic biopsy of a fixed episcleral nodule overlying a uveal mass. METHOD: Clinicopathologic report with immunohistochemical investigations. RESULTS: B-scan ultrasonographic biomicroscopy disclosed in a 67-year-old man an asymptomatic placoid ciliary body tumor measuring 1.28 mm in thickness underlying a poorly pigmented, fixed episcleral nodule 0.56 mm in thickness. Biopsy of the episcleral nodule displayed benign nevus-type spindle cells with small nuclei, punctate nucleoli, no mitoses, and scattered melanophages. Immunohistochemistry demonstrated that the tumor cells were Ki67 negative (proliferation index, 0) and MART-1, HMB-45, and microphthalmia-associated transcription factor positive, all melanocytic markers. The melanophages but not the tumor cells were CD68 positive, a histiocytic marker. CONCLUSIONS: The results from biopsying an episcleral nodule can help to select among therapeutic options in managing an associated ciliary body tumor. A 1-year follow-up study and 3 sequential ultrasonographic studies in the current patient have failed to document the growth of the intraocular tumor, further confirming that it is a nevus. The excised epibulbar tumor has not recurred. PMID- 23676785 TI - Deep anterior lamellar keratoplasty for the treatment of stromal corneal dystrophies. PMID- 23676786 TI - Effect of rebamipide ophthalmic suspension on optical quality in the short break up time type of dry eye. AB - PURPOSE: To determine the effect of rebamipide ophthalmic suspension on optical quality in patients with dry eye with short break-up time (BUT) of the tear film. METHODS: Twenty-six eyes of 16 patients with the short BUT type of dry eye were enrolled and treated with 2% rebamipide ophthalmic suspension. At baseline and at 2 and 4 weeks after initiating the treatment, the serial corneal higher-order aberrations (HOAs), BUT, fluorescein staining, and Schirmer test were measured. Patients were asked to complete questionnaires about the changes in dry eye related ocular symptoms after the treatment. RESULTS: Before the treatment, the pattern of postblink corneal HOAs for 10 seconds showed a sawtooth pattern, with a marked upward curve that increased after blinking. Treatment with rebamipide for 4 weeks significantly (P < 0.05) improved the postblink corneal HOAs and stabilized the pattern of the corneal HOAs. Significant increases in the tear film BUT were seen 2 and 4 weeks after the treatment (P < 0.001 for both comparisons). CONCLUSIONS: Rebamipide administered to treat the short BUT type of dry eye significantly improved optical quality because of the improvement in tear stability. PMID- 23676787 TI - Hepatitis B DNA vaccine-polycation nano-complexes enhancing immune response by percutaneous administration with microneedle. AB - Percutaneous immune method is becoming an attractive alternative for DNA vaccine as a lot of antigen presenting cells are existed in the viable epidermis. However, due to the barrier function of stratum corneum, it would be hard for DNA vaccine to reach the viable epidermis of the skin. In order to deliver the DNA vaccine successfully cross the stratum corneum, pentagram silicon microneedle array was prepared in this study, and fluorescently labeled nanoparticle was taken as the model to observe the situation inside the skin processed by microneedle. Via microneedle nanoparticles could enter the skin through the micro channel (diameter about 20-30 um) and its amount is greatly larger than that enter though the hair follicle of intact skin. A new type of gene vector Pluronic P123-modified polyethyleneimine (P123-PEI) was synthesized by high molecular weight polyethylenimine and Pluronic P123 with the molar ratio of 1 : 1 to take the advantage of P123-PEI as low cytotoxicity and high transfection efficiency. Mice were immunized percutaneously with Hepatitis B DNA vaccine/P123-PEI nano complexes by microneedle. The humoral and cellular immunity generated in percutaneously immunized mice through microneedle array by Hepatitis B DNA vaccine/P123-PEI nano-complex was significantly higher than that of DNA vaccine intramuscular administration. PMID- 23676788 TI - Effectiveness of sirolimus in combination with cyclosporine against chronic rejection in a pediatric liver transplant patient. AB - The patient is a 3-year-old boy who received living-donor liver transplantation (LDLT) for hepatoblastoma, with his mother as the donor. Oral tacrolimus was started at a dose of 0.3 mg every 12 h from day 1, with the dosage adjusted on the basis of trough concentrations. The levels of aspartate aminotransferase (AST), alanine transferase (ALT), and total bilirubin (T-bil) were 110 U/L, 182 U/L, and 12.6 mg/dL, respectively, when chronic rejection (CR) was pathologically diagnosed. Then, sirolimus at a dose of 1.0 mg/d was added to the tacrolimus based regimen. The T-bil level rapidly decreased to 5.4 mg/dL, without changes in AST and ALT. Because the intracellular receptor of sirolimus and tacrolimus is FK506-binding protein 12, we switched tacrolimus to cyclosporine at a dose of 60 mg/d to avoid competitive inhibition between these 2 drugs. The target trough concentration of sirolimus and cyclosporine was set to around 15 ng/mL and 180 ng/mL, respectively. The concentration/dose ratio of sirolimus was significantly correlated with the blood cyclosporine level (r=0.5293, p<0.05), suggesting the pharmacokinetic interaction between these 2 drugs. Thereafter, the levels of AST and ALT as well as the T-bil were successfully decreased to 73 U/L, 83 U/L, and 3.0 mg/dL, respectively. These results suggest that sirolimus therapy in combination with cyclosporine may be an effective treatment against CR after liver transplantation. PMID- 23676789 TI - Role of cysteine residues in thermal inactivation of fungal Cel6A cellobiohydrolases. AB - Numerous protein engineering studies have focused on increasing the thermostability of fungal cellulases to improve production of fuels and chemicals from lignocellulosic feedstocks. However, the engineered enzymes still undergo thermal inactivation at temperatures well below the inactivation temperatures of hyperthermophilic cellulases. In this report, we investigated the role of free cysteines in the thermal inactivation of wild-type and engineered fungal family 6 cellobiohydrolases (Cel6A). The mechanism of thermal inactivation of Cel6A is consistent with disulfide bond degradation and thiol-disulfide exchange. Circular dichroism spectroscopy revealed that a thermostable variant lacking free cysteines refolds to a native-like structure and retains activity after heat treatment over the pH range 5-9. Whereas conserved disulfide bonds are essential for retaining activity after heat treatment, free cysteines contribute to irreversible thermal inactivation in engineered thermostable Cel6A as well as Cel6A from Hypocrea jecorina and Humicola insolens. PMID- 23676790 TI - Detection of BCR-ABL kinase domain mutations in patients with chronic myeloid leukemia on imatinib. AB - BCR-ABL tyrosine kinase domain mutations are the most important factor contributing to imatinib-resistance in patients with chronic myeloid leukemia. We used a semi-nested reverse transcriptase-polymerase chain reaction followed by bidirectional sequencing to detect mutations in a cohort of 110 chronic myeloid leukemia patients. In total, 34 mutations in 19 distinct codons were identified in 32 patients, of which D276N and E279A were novel. The most commonly mutated region was drug-binding site (29%) followed by P-loop region (26%) and most patients bearing them were in accelerated phase and blastic phase. This report expands the spectrum of BCR-ABL mutations and stresses the use of mutation testing in imatinib-resistant patients for continuation of treatment procedure. PMID- 23676791 TI - Acute prosocial effects of oxytocin and vasopressin when given alone or in combination with 3,4-methylenedioxymethamphetamine in rats: involvement of the V1A receptor. AB - The neuropeptides oxytocin (OT) and vasopressin (AVP) are recognized for their modulation of social processes in humans when delivered peripherally. However, there is surprisingly little evidence for acute social effects of peripherally administered OT or AVP in animal models. On the other hand, the party drug 3,4 methylenedioxymethamphetamine (MDMA, 'Ecstasy') has powerful prosocial effects in rats that appear to occur through stimulation of central OT release. Here, we directly compared the social effects of peripherally administered OT and AVP with those of MDMA, and examined a possible role for the vasopressin 1A receptor (V1AR) in the observed prosocial effects. Adult male Long-Evans rats were tested in a social interaction paradigm after OT (0.1, 0.25, 0.5, and 1 mg/kg, intraperitoneal (IP)), AVP (0.001, 0.0025, 0.005, 0.01, and 0.1 mg/kg, IP), and MDMA (2.5, 5 mg/kg, IP), or combined low doses of OT and MDMA, or AVP and MDMA. The effects of pretreatment with the non-peptide OT receptor antagonist compound 25 (C25; 5 mg/kg, IP) and the V1AR antagonist SR49059 (1 mg/kg, IP) were also examined. OT (0.5 mg/kg), AVP (0.01 mg/kg), and MDMA (5 mg/kg) potently increased 'adjacent lying', where rats meeting for the first time lie passively next to each other. C25 did not inhibit adjacent lying induced by OT, whereas SR49059 inhibited adjacent lying induced by MDMA (5 mg/kg), OT (0.5 mg/kg), and AVP (0.01 mg/kg). Interestingly, when ineffective doses of OT and MDMA, or AVP and MDMA, were combined, a robust increase in adjacent lying was observed. These results show for the first time acute prosocial effects of peripherally injected OT and AVP in laboratory rats, and suggest a commonality of action of OT, AVP, and MDMA in stimulating social behavior that involves V1ARs. PMID- 23676793 TI - Free radicals and endothelial dysfunction: potential positive effects of TNF alpha inhibitors. AB - OBJECTIVES: During the last decade many new biological immune modulators have entered the market as new therapeutic principles. Tumor necrosis factor (TNF) alpha is a pro-inflammatory cytokine known to a have a key role in the pathogenic mechanisms of various immune-mediated or inflammatory diseases. However, TNF alpha also plays a key role in endothelial dysfunction and, thus, in the development and progression of atherosclerosis. What, then, is the potential therapeutic role of TNF-alpha inhibitors? METHODS: We analysed the current literature concerning the administration of TNF-alpha inhibitors and their potential benefits upon endothelial function. RESULTS: TNF-alpha inhibitors decrease the serum levels of inflammatory markers such as TNF-alpha itself, CRP, IL-6, and increased the tissue expression of endothelial NO synthase and the vasodilatory response to bradykinin. DISCUSSION: TNF-alpha inhibitors may change the progression of endothelial dysfunction and, thus, slow down the atherosclerotic process. PMID- 23676792 TI - Neuroplasticity in depressed individuals compared with healthy controls. AB - Several lines of evidence suggest that neuroplasticity is impaired in depression. This study aimed to compare neuroplasticity in 23 subjects with DSM-IV major depressive episode and 23 age- and gender-matched healthy controls, using an objective test that is independent of subject effort and motivation. Neuroplasticity was assessed in the motor cortex using a brain stimulation paradigm known as paired associative stimulation (PAS), which induces transient changes in motor cortical function. Motor cortical excitability was assessed before and after PAS using single-pulse transcranial magnetic stimulation (TMS) to induce motor evoked potentials (MEPs) in a hand muscle. After PAS, MEP amplitudes significantly increased in healthy controls compared with depressed subjects (P=0.002). The functional significance of motor cortical changes was assessed using a motor learning task-a computerized version of the rotor pursuit task. Healthy controls also performed better on motor learning (P=0.02). BDNF blood levels and genotype were assayed to determine any relationship with motor cortical plasticity. However, PAS results did not correlate with motor learning, nor appear to be related to BDNF measures. The significance of these findings is that it provides one of the first direct demonstrations of reduced neuroplasticity in depressed subjects, using an objective test. PMID- 23676794 TI - Facile and green synthesis of silver nanoparticles in quaternized carboxymethyl chitosan solution. AB - A facile and green method to synthesize stable Ag nanoparticles (Ag NPs) with a narrow size distribution in water is reported. Water-soluble quaternized carboxymethyl chitosan (QCMC) with a surfactant-like structure was used as both a reducing and stabilizing agent under microwave irradiation via the modified Tollens reaction. In order to study the preparation mechanism, carboxymethyl chitosan (CMC) and quaternized chitosan (QCS) were compared as both reducing and stabilizing agents. Full characterization was performed using UV-vis, XRD, TEM, AAS, FT-IR, NMR and TGA. The results revealed that the prepared Ag NPs were mostly spherical with a small proportion being cylinders or cuboids; they were stable due to the package of the macromolecules; the diameters were 10.24 +/- 3.13 nm. The Tollens reaction followed first order kinetics, and the Ea was 102.4 kJ mol(-1) for QCMC/Ag NP composite. During the growth of the Ag NPs, some quaternary ammonium groups and carboxymethyl groups were respectively oxidized to -CH2COCH3 and -CH3 groups, and the quaternary ammonium groups were more helpful for the growth of Ag NPs than the carboxymethyl groups. In addition, QCMC/Ag NP composite had much higher thermal stability than QCMC. PMID- 23676795 TI - Placing clinical variables on a common linear scale of empirically based risk as a step towards construction of a general patient acuity score from the electronic health record: a modelling study. AB - OBJECTIVE: To explore the hypothesis that placing clinical variables of differing metrics on a common linear scale of all-cause postdischarge mortality provides risk functions that are directly correlated with in-hospital mortality risk. DESIGN: Modelling study. SETTING: An 805-bed community hospital in the southeastern USA. PARTICIPANTS: 42302 inpatients admitted for any reason, excluding obstetrics, paediatric and psychiatric patients. OUTCOME MEASURES: All cause in-hospital and postdischarge mortalities, and associated correlations. RESULTS: Pearson correlation coefficients comparing in-hospital risks with postdischarge risks for creatinine, heart rate and a set of 12 nursing assessments are 0.920, 0.922 and 0.892, respectively. Correlation between postdischarge risk heart rate and the Modified Early Warning System (MEWS) component for heart rate is 0.855. The minimal excess risk values for creatinine and heart rate roughly correspond to the normal reference ranges. We also provide the risks for values outside that range, independent of expert opinion or a regression model. By summing risk functions, a first-approximation patient risk score is created, which correctly ranks 6 discharge categories by average mortality with p<0.001 for differences in category means, and Tukey's Honestly Significant Difference Test confirmed that the means were all different at the 95% confidence level. CONCLUSIONS: Quantitative or categorical clinical variables can be transformed into risk functions that correlate well with in-hospital risk. This methodology provides an empirical way to assess inpatient risk from data available in the Electronic Health Record. With just the variables in this paper, we achieve a risk score that correlates with discharge disposition. This is the first step towards creation of a universal measure of patient condition that reflects a generally applicable set of health-related risks. More importantly, we believe that our approach opens the door to a way of exploring and resolving many issues in patient assessment. PMID- 23676796 TI - Predictive models to assess risk of type 2 diabetes, hypertension and comorbidity: machine-learning algorithms and validation using national health data from Kuwait--a cohort study. AB - OBJECTIVE: We build classification models and risk assessment tools for diabetes, hypertension and comorbidity using machine-learning algorithms on data from Kuwait. We model the increased proneness in diabetic patients to develop hypertension and vice versa. We ascertain the importance of ethnicity (and natives vs expatriate migrants) and of using regional data in risk assessment. DESIGN: Retrospective cohort study. Four machine-learning techniques were used: logistic regression, k-nearest neighbours (k-NN), multifactor dimensionality reduction and support vector machines. The study uses fivefold cross validation to obtain generalisation accuracies and errors. SETTING: Kuwait Health Network (KHN) that integrates data from primary health centres and hospitals in Kuwait. PARTICIPANTS: 270 172 hospital visitors (of which, 89 858 are diabetic, 58 745 hypertensive and 30 522 comorbid) comprising Kuwaiti natives, Asian and Arab expatriates. OUTCOME MEASURES: Incident type 2 diabetes, hypertension and comorbidity. RESULTS: Classification accuracies of >85% (for diabetes) and >90% (for hypertension) are achieved using only simple non-laboratory-based parameters. Risk assessment tools based on k-NN classification models are able to assign 'high' risk to 75% of diabetic patients and to 94% of hypertensive patients. Only 5% of diabetic patients are seen assigned 'low' risk. Asian specific models and assessments perform even better. Pathological conditions of diabetes in the general population or in hypertensive population and those of hypertension are modelled. Two-stage aggregate classification models and risk assessment tools, built combining both the component models on diabetes (or on hypertension), perform better than individual models. CONCLUSIONS: Data on diabetes, hypertension and comorbidity from the cosmopolitan State of Kuwait are available for the first time. This enabled us to apply four different case control models to assess risks. These tools aid in the preliminary non-intrusive assessment of the population. Ethnicity is seen significant to the predictive models. Risk assessments need to be developed using regional data as we demonstrate the applicability of the American Diabetes Association online calculator on data from Kuwait. PMID- 23676797 TI - Cardiac arrest management in general practice in Ireland: a 5-year cross sectional study. AB - OBJECTIVE: To document the involvement of general practitioners (GPs) in cardiac arrests with resuscitation attempts (CARAs) and to describe the outcomes. DESIGN: A 5-year prospective cross-sectional study of GPs in Ireland equipped with automated external defibrillators (AEDs) and immediate care training by the MERIT Project, with data collection every 3 months over the 5-year period. Practices reported CARAs by quarterly survey with an 89% mean response rate (81-97% for the period). SETTING: General practices throughout Ireland. PARTICIPANTS: 495 GP participated: 168 (33.9%) urban, 163 (32.9%) rural and 164 (33.1%) mixed. INTERVENTIONS: All participating practices received a standard AED and basic life support kit. Training in immediate care was provided for at least one GP in the practice. MAIN OUTCOME MEASURES: Incidence of CARA in participating practices. Return of spontaneous circulation (ROSC) and discharge alive from hospital. RESULTS: 36% of practices were involved in a CARA during the 5-year period and 13% were involved in more than one CARA. Of the 272 CARAs reported, ROSC occurred in 32% (87/272) and discharge from hospital in 18.7% (49/262). In 45% of cases, the first AED was brought by the GP and in 65%, the GP arrived before the ambulance service. More cases occurred in rural and mixed settings than urban ones, but the survival rates did not differ between areas. In 65% of cases, the GP was on duty at the time of the incident and 47% of cases occurred in the patient's home. CONCLUSIONS: These outcomes are comparable with more highly structured components of the emergency response system and indicate that GPs have an important role to play in the care of patients in their own communities. GPs experience cardiac arrest cases during the course of their daily work and provide prompt care which results in successful outcomes in urban, mixed and rural settings. PMID- 23676798 TI - Physical activity and self-reported health status among adolescents: a cross sectional population-based study. AB - OBJECTIVES: Little is known about the dose-response relationship between physical activity and health benefits among young people. Our objective was to analyse the association between the frequency of undertaking moderate-to-vigorous physical activity (MVPA) and the self-reported health status of the adolescent population. DESIGN: Cross-sectional study. SETTING: All regions of Spain. PARTICIPANTS: Students aged 11-18 years participating in the Spanish Health Behaviour in School aged Children survey 2006. A total of 375 schools and 21 188 students were selected. MAIN OUTCOMES: The frequency of undertaking MVPA was measured by a questionnaire, with the following four health indicators: self-rated health, health complaints, satisfaction with life and health-related quality of life. Linear and logistic regression models were used to analyse the association, adjusting for potential confounding variables and the modelling of the dose response relationship. RESULTS: As the frequency of MVPA increased, the association with health benefits was stronger. A linear trend (p<0.05) was found for self-rated health and health complaints in males and females and for satisfaction with life among females; for health-related quality of life this relationship was quadratic for both sexes (p<0.05). For self-reported health and health complaints, the effect was found to be of greater magnitude in males than in females and, in all scales, the benefits were observed from the lowest frequencies of MVPA, especially in males. CONCLUSIONS: A protective effect of MVPA was found in both sexes for the four health indicators studied, and this activity had a gradient effect. Among males, health benefits were detected from very low levels of physical activity and the magnitude of the relationship was greater than that for females. PMID- 23676799 TI - Individual empowerment in overweight and obese patients: a study protocol. AB - INTRODUCTION: Obesity is a growing health problem in Europe and it causes many diseases. Many weight-reducing methods are reported in medical literature, but none of them proved to be effective in maintaining the results achieved over time. Self-empowerment can be an important innovative method, but an effectiveness study is necessary. In order to standardise the procedures for a randomised controlled study, a pilot study will be run to observe, measure and evaluate the effects of a period of self-empowerment group treatment on overweight/obese patients. METHODS: and analysis Non-controlled, experimental, pilot study. A selected group of patients with body mass index >25, with no severe psychiatric disorders, with no aesthetic or therapeutic motivation will be included in the study. A set of quantitative and qualitative measures will be utilised to evaluate the effects of a self-empowerment course in a 12 month time. Group therapy and medical examinations will also complete this observational phase. At the end of this pilot study, a set of appropriate measures and procedures to determine the effectiveness of individual empowerment will be identified and agreed among the different professional figures. Results will be recorded and analysed to start a randomised controlled trial to evaluate the effectiveness of the proposed methodology. ETHICS AND DISSEMINATION: This protocol was approved by the local Ethics Committee of Udine in March 2012. The findings of the trial will be disseminated through peer-reviewed journals, national and international conference presentations and public events involving the local administrations of the towns where the trial participants are resident. TRIAL REGISTRATION: http://www.clinicalstrials.gov identifier NCT01644708. PMID- 23676800 TI - Considering sport participation as a source for physical activity among adolescents. AB - BACKGROUND: Studies have shown participation in sport is lower among girls than boys, decreases as students matriculate through high school, is lowest among Black and Hispanic girls and has a positive relationship with SES. With sport recognized as a contributor to physical activity and health in adolescents, consideration of diminishing rates of participation appears warranted. The purpose of this study was to identify patterns related to differences in self reported sport participation between genders, ethnic groups, grades and SES. METHODS: This study was a cross-sectional, secondary analysis of data collected for a sport interest survey. All students in grades 8-11 attending middle and high schools were provided an opportunity to participate in the survey. Data from 49,832 students were analyzed. RESULTS: Among the participants, Black girls participated more and White girls participated less than expected. Black boys participated more while White and Asian boys participated less than expected. Reported sport participation was high compared with national data when analyzed by gender and ethnic group. Sport participation was higher in low SES schools compared with high SES schools. CONCLUSION: The importance of sport as a source of physical activity in underserved groups is significant. PMID- 23676801 TI - Fluorescence quenching in luminescent porous silicon nanoparticles for the detection of intracellular Cu2+. AB - After microwave-induced hydrosilylation reaction with 10-undecenoic acid, luminescent porous silicon nanoparticles (LPSiNPs) showed excellent fluorescence stability under physiological conditions. Fluorescence quenching in as-prepared LPSiNPs was highly sensitive with the concentration of Cu(2+) at MUmol L(-1) level, which could be further applied to the detection of intracellular Cu(2+). PMID- 23676802 TI - Appendicitis in a Spigelian hernia: an unusual cause for a tender right iliac fossa mass. AB - Spigelian hernias are a rare type of hernia through the Spigelian aponeurosis, whose contents commonly include omentum or small bowel. In the absence of incarceration or strangulation, they can be difficult to diagnose clinically. In the emergency setting, they can present rarely as a painful abdominal mass and computed tomography provides a reliable diagnostic imaging modality. We report an emergency presentation of a Spigelian hernia containing the appendix. PMID- 23676803 TI - A concealed small bowel perforation in an adult secondary to bicycle handlebar trauma. AB - Traumatic abdominal wall hernia (TAWH) secondary to bicycle handlebar is a rare injury. The majority of the literature describes abdominal wall herniation in children. We present a rare case of TAWH in an adult with a concealed small bowel perforation. Although clinical examination in conjunction with computed tomography can exclude the majority of solid organ injuries, small bowel injuries can often be missed. Our case initially revealed a serosal tear in the small bowel but, on close inspection, a separate 3mm perforation was identified, hidden in the small bowel mesentery. We strongly support a low threshold for operative intervention if there is any suspicion. Moreover, we stress the importance of meticulous examination during laparotomy as this injury could have been easily missed, resulting in potential morbidity or mortality in a patient sustaining such an injury. PMID- 23676804 TI - A case report of an intracaval extrathoracic solitary fibrous tumour. AB - Solitary fibrous tumours are infrequent neoplasms based in the pleura that are predominantly benign with malignant pathology and behaviour described in 10-36% of cases. Extrathoracic solitary fibrous tumours (ESFTs) have been considered separately to their intrathoracic counterparts and comprise a third of all solitary fibrous tumours. The extrathoracic location was identified as an adverse prognostic factor for local recurrence but not for metastatic disease. So far, there have not been any reports of solitary fibrous tumours demonstrating caval infiltration. We present a case of a benign ESFT infiltrating into the perirenal inferior vena cava. Together with extrauterine leiomyomas, ESFTs should also be considered as a differential diagnosis for the rare benign lesions invading the inferior vena cava. PMID- 23676805 TI - Novel xylan-controlled delivery of therapeutic proteins to inflamed colon by the human anaerobic commensal bacterium. AB - INTRODUCTION: Growth factors such as keratinocyte growth factor-2 (KGF-2) and transforming growth factor-beta (TGF-beta) are important immunoregulatory and epithelial growth factors. They are also potential therapeutic proteins for inflammatory bowel disease. However, owing to protein instability in the upper gastrointestinal tract, it is difficult to achieve therapeutic levels of these proteins in the injured colon when given orally. Furthermore, the short half-life necessitates repeated dosage with large amounts of the growth factor, which may have dangerous side effects, hence the importance of temporal and spatial control of growth factor delivery. METHODS: The human commensal gut bacterium, Bacteroides ovatus, was genetically engineered to produce human KGF-2 or TGF beta1 (BO-KGF or BO-TGF) in a regulated manner in response to the dietary polysaccharide, xylan. The successful application of BO-KGF or BO-TGF in the prevention of dextran sodium sulphate induced murine colitis is presented here. RESULTS: This novel drug delivery system had a significant prophylactic effect, limiting the development of intestinal inflammation both clinically and histopathologically. The ability to regulate heterologous protein production by B ovatus using xylan is both unique and an important safety feature of this drug delivery system. CONCLUSIONS: The use of genetically engineered B ovatus for the controlled and localised delivery of epithelial growth promoting and immunomodulatory proteins has potential clinical applications for the treatment of various diseases targeting the colon. PMID- 23676806 TI - Pancreatic trauma. AB - INTRODUCTION: Pancreatic trauma occurs in approximately 4% of all patients sustaining abdominal injuries. The pancreas has an intimate relationship with the major upper abdominal vessels, and there is significant morbidity and mortality associated with severe pancreatic injury. Immediate resuscitation and investigations are essential to delineate the nature of the injury, and to plan further management. If main pancreatic duct injuries are identified, specialised input from a tertiary hepatopancreaticobiliary (HPB) team is advised. METHODS: A comprehensive online literature search was performed using PubMed. Relevant articles from international journals were selected. The search terms used were: 'pancreatic trauma', 'pancreatic duct injury', 'radiology AND pancreas injury', 'diagnosis of pancreatic trauma', and 'management AND surgery'. Articles that were not published in English were excluded. All articles used were selected on relevance to this review and read by both authors. RESULTS: Pancreatic trauma is rare and associated with injury to other upper abdominal viscera. Patients present with non-specific abdominal findings and serum amylase is of little use in diagnosis. Computed tomography is effective in diagnosing pancreatic injury but not duct disruption, which is most easily seen on endoscopic retrograde cholangiopancreaticography or operative pancreatography. If pancreatic injury is suspected, inspection of the entire pancreas and duodenum is required to ensure full evaluation at laparotomy. The operative management of pancreatic injury depends on the grade of injury found at laparotomy. The most important prognostic factor is main duct disruption and, if found, reconstructive options should be determined by an experienced HPB surgeon. CONCLUSIONS: The diagnosis of pancreatic trauma requires a high index of suspicion and detailed imaging studies. Grading pancreatic injury is important to guide operative management. The most important prognostic factor is pancreatic duct disruption and in these cases, experienced HPB surgeons should be involved. Complications following pancreatic trauma are common and the majority can be managed without further surgery. PMID- 23676807 TI - Transanal haemorrhoidal dearterialisation with mucopexy versus stapler haemorrhoidopexy: a randomised trial with long-term follow-up. AB - INTRODUCTION: The present study aimed to compare the long-term results of transanal haemorrhoidal dearterialisation (THD) with mucopexy and stapler haemorrhoidopexy (SH) in treatment of grade III and IV haemorrhoids. METHODS: One hundred and twenty-four patients with grade III and IV haemorrhoids were randomised to receive THD with mucopexy (n=63) or SH (n=61). A telephone interview with a structured questionnaire was performed at a median follow-up of 42 months. The primary outcome was the occurrence of recurrent prolapse. Patients, investigators and those assessing the outcomes were blinded to group assignment. RESULTS: Recurrence was present in 21 patients (16.9%). It occurred in 16 (25.4%) in the THD group and 5 (8.2%) in the SH group (p=0.021). A second surgical procedure was performed in eight patients (6.4%). Reoperation was open haemorrhoidectomy in seven cases and SH in one case. Five patients out of six in the THD group and both patients in the SH group requiring repeat surgery presented with grade IV haemorrhoids. No significant difference was found between the two groups with respect to symptom control. Patient satisfaction for the procedure was 73.0% after THD and 85.2% after SH (p=0.705). Postoperative pain, return to normal activities and complications were similar. CONCLUSIONS: The recurrence rate after THD with mucopexy is significantly higher than after SH at long-term follow-up although results are similar with respect to symptom control and patient satisfaction. A definite risk of repeat surgery is present when both procedures are performed, especially for grade IV haemorrhoids. PMID- 23676808 TI - Factors affecting the healing of the perineum following surgery. AB - INTRODUCTION: The aim of this study was to establish patient and procedural factors associated with the development of an unhealed perineum in patients undergoing a proctectomy or excision of an ileoanal pouch. METHODS: A review of 194 case notes for procedures performed between 1997 and 2009 was carried out. All patients had at least 12 months' follow-up. Univariate and multivariate analyses were performed in 16 parameters. For those patients who developed an unhealed perineum, Cox regression analysis was performed to establish healing over a 12-month period. RESULTS: Two hundred patients were included in the study, of which six had unknown wound status and were subsequently excluded. This left 194 study patients. Of these, 86 (44%) achieved primary wound healing with a fully healed perineum and 108 (56%) experienced primary wound failure. With reference to the latter, 63 (58%) healed by 12 months. Comparing patients with an initially intact perineum with those with initial wound failure showed pre existing sepsis was highly relevant (odds ratio: 4.32, 95% confidence interval [CI]: 2.16-8.62, p<0.001). In patients who had an unhealed perineum initially, perineal sepsis and surgical treatment were both significantly associated with time to healing (hazard ratio [HR]: 0.54, 95% CI: 0.31-0.93, p=0.03; and HR: 0.42, 95% CI: 0.21-0.84, p=0.01). CONCLUSIONS: The presence of pre-existing perineal sepsis is associated with an unhealed perineum following proctectomy in inflammatory bowel disease (IBD) and non-IBD surgery. Further studies are indicated to establish perineal sepsis as a causative factor. PMID- 23676809 TI - The diagnostic value of fine needle aspiration in parotid lumps. AB - INTRODUCTION: Fine needle aspiration (FNA) is a safe and quick method of diagnosing superficial lumps, which aids preoperative planning. However, FNA of the parotid gland has not gained the widespread acceptance noted in other head and neck lumps. The aim of this study was to determine the ability of FNA of the parotid gland to differentiate benign and malignant disease, and to determine the impact on surgical outcome. METHODS: A retrospective analysis of 201 consecutive parotid operations with preoperative FNA in a large district hospital in the UK was performed. The diagnostic characteristics were calculated for benign and malignant disease, and the impact on surgical procedure was determined. RESULTS: In identifying benign disease, FNA has a sensitivity of 85% and a specificity of 76%. In detecting malignant disease, FNA has a sensitivity and specificity of 52% and 92% respectively. A false positive on FNA was associated with a higher incidence of neck dissection. CONCLUSIONS: FNA is a useful diagnostic test. However, owing to low sensitivity, it is necessary to interpret it in the context of all other clinical information. PMID- 23676810 TI - A decade of experience of thyroglossal cyst excision. AB - INTRODUCTION: We report our ten-year experience of thyroglossal cyst excision at Queen's Medical Centre, Nottingham, comparing outcomes, practice and technique. METHODS: Retrospective case note analysis was conducted alongside surgical histopathology review for all thyroglossal cyst excisions performed between 2000 and 2010. This yielded 108 patients with histopathology results confirming a thyroglossal cyst. RESULTS: The mean patient age was 21 years (range: 1 week - 76 years). Over half the patients (n=59, 55%) were less than 18 years of age. Fifty five patients (51%) were male and fifty-three (49%) were female. Seventy cases (63%) were operated on by ear, nose and throat (ENT) surgeons. The rest were performed by paediatric surgeons (n=35, 32%), maxillofacial surgeons (n=2, 2%) and general surgeons (n=1, 1%). Paediatric surgeons undertook 35 (69%) of the 59 paediatric cases, with ENT surgeons operating on the rest (n=24, 41%). The primary surgeon was a consultant in 59 operations (55%) while in 49 cases (45%) it was a registrar. Thyroglossal cysts were ruptured in 21 operations (19%) during removal. The central portion of the hyoid bone was not excised in seven cases (6%). Twelve patients (11%) suffered postoperative complications, six of which were recurrences. CONCLUSIONS: There was a combined recurrence rate of 6% across all specialties for the Sistrunk procedure. This is in keeping with commonly reported recurrence rates. However, we found that central compartment neck dissection, as a modification of the original Sistrunk procedure, provides a highly effective method for permanently excising a thyroglossal cyst and, in our experience, it eliminates recurrence. PMID- 23676811 TI - Bearing exchange in the management of pseudotumours. AB - INTRODUCTION: Soft tissue reactions following metal-on-metal (MoM) arthroplasty of the hip have been under considerable discussion. These reactions are seen following both hip resurfacing and MoM total hip arthroplasty (THA). The phenomenon may arise owing to shedding of metal particles in high wear states, hypersensitivity with normal metal wear rates or a combination of the two. METHODS: Three patients were identified who had developed a soft tissue reaction (pseudotumour) following MoM hip resurfacing procedures. The prostheses were revised to ceramic-on-ceramic (CoC) THA with only minimal debridement of the pseudotumour. Pre and postoperative magnetic resonance imaging was performed to assess the size of the lesions. RESULTS: Progressive and satisfactory resolution of the associated pseudotumours was identified following revision of the prostheses to CoC THA. CONCLUSIONS: In the early stages of pseudotumour formation following MoM hip resurfacing, this potentially devastating condition can be managed adequately with revision to a CoC bearing THA with minimal soft tissue excision. PMID- 23676812 TI - Complications following hemiarthroplasty for displaced intracapsular femoral neck fractures in the absence of routine follow-up. AB - INTRODUCTION: Hemiarthroplasty is the most commonly performed surgery for displaced intracapsular femoral neck fractures. At present, it is not routine practice to follow up these patients despite the risk of all the complications associated with arthroplasty. This study aimed to determine the prevalence and nature of complications occurring following hemiarthroplasty that re-presented to this centre in the absence of routine postoperative follow-up. METHODS: Consecutive patients undergoing uncemented hip hemiarthroplasty for displaced intracapsular femoral neck fractures at a district general hospital between 2004 and 2009 were identified. Data were collected from the hospital database on all complications relating to the index procedure, further surgery performed and mortality. RESULTS: There were 490 hemiarthroplasties performed in 477 patients (mean age: 80 years, 75% female). Of these, 110 (22%) were referred postoperatively for specialist orthopaedic review. The prevalence of any complication following hemiarthroplasty was 12% (n=59) and the prevalence of hemiarthroplasty failure was 8% (n=40). The most common indications for failure were periprosthetic fracture (28%), aseptic femoral loosening (25%) and unexplained pain (25%). Persistent hip pain and poor mobility accounted for most complications not requiring further surgery (n=15). The mortality rate within 30 days and 1 year of hemiarthroplasty was 6% (n=31) and 29% (n=146) respectively. CONCLUSIONS: In the absence of routine follow-up, complications were encountered frequently in patients undergoing hip hemiarthroplasty, with most requiring further surgery. Appropriate services should be implemented to allow timely referral for orthopaedic assessment, and enable the early identification and treatment of postoperative complications. PMID- 23676813 TI - Diabetes is predictive of longer hospital stay and increased rate of complications in spinal surgery in the UK. AB - INTRODUCTION: Diabetes is a common co-morbidity of patients undergoing spinal surgery in the UK but there are no published studies from the UK, particularly with respect to length of hospital stay and complications. The aims of this study were to identify complications and length of hospital stay in patients with diabetes undergoing spinal surgery. METHODS: Data were collected retrospectively for 111 consecutive patients with diabetes (and 97 age and sex matched control patients, identified using computer records) who underwent spinal surgery between 2004 and 2010 in a single centre. The data collected included operative time, blood loss, details of surgery, Clavien complications and length of hospital stay. RESULTS: No significant differences were found by group in operative time, blood loss, instrumentation, use of graft or revision surgery. Overall complication rates were higher in the patients with diabetes than in the controls (28.8% vs 15.5%). The mean hospital stay was significantly longer for patients with diabetes than for control patients (4.6 vs 3.2 days, p<0.001). CONCLUSIONS: This study identified a significantly higher Clavien grade I complication rate and length of hospital stay in patients with diabetes undergoing spinal surgery than control patients (p=0.02). This has resulted in a predictive model being generated. Of note, no infections were seen in patients with diabetes, suggesting that infection rates in this particular group of patients undergoing spinal surgery might not be as high as considered previously. PMID- 23676814 TI - The cost effectiveness of early management of acute appendicitis underlies the importance of curative surgical services to a primary healthcare programme. AB - INTRODUCTION: Appendicitis in the developing world is a cause of significant preventable morbidity. This prospective study from a regional hospital in South Africa constructs a robust cost model that demonstrates the cost effectiveness of an efficient curative surgical service in a primary healthcare-orientated system. METHODS: A prospective audit of all patients with acute appendicitis admitted to Edendale Hospital was undertaken from September 2010 to September 2011. A microcosting approach was used to construct a cost model based on the estimated cost of operative and perioperative interventions together with the associated hospital stay. For cost analysis, patients were divided into the following cohorts: uncomplicated appendicitis, complicated appendicitis with localised intra-abdominal sepsis, complicated appendicitis with generalised intra-abdominal sepsis, with and without intensive care unit admission. RESULTS: Two hundred patients were operated on for acute appendicitis. Of these, 36% (71/200) had uncomplicated appendicitis and 57% (114/200) had perforation. Pathologies other than appendicitis were present in 8% (15/200) and these patients were excluded. Of the perforated appendices, 45% (51/114) had intra-abdominal contamination that was localised while 55% (63/114) generalised sepsis. The mean cost for each patient was: 6,578 ZAR (L566) for uncomplicated appendicitis; 14,791 ZAR (L1,272) for perforation with localised intra-abdominal sepsis and 34,773 ZAR (L2,990) for perforation with generalised intra-abdominal sepsis without intensive care admission. With intensive care admission it was 77,816 ZAR (L6,692). The total cost of managing acute appendicitis was 4,272,871 ZAR (L367,467). Almost 90% of this total cost was owing to advanced disease with abdominal sepsis and therefore potentially preventable. CONCLUSIONS: Early uncomplicated appendicitis treated appropriately carries little morbidity and is relatively inexpensive to treat. As the pathology progresses, the cost rises exponentially. An efficient curative surgical service must be regarded as a cost effective component of a primary healthcare orientated system. PMID- 23676815 TI - Operative and non-operative management of endoscopic retrograde cholangiopancreatography-associated duodenal injuries. AB - INTRODUCTION: Endoscopic retrograde cholangiopancreatography (ERCP) is indispensable in everyday surgical practice. Despite this, as an invasive procedure, it has its own mortality and morbidity, the most feared of which is periduodenal perforations. Our experience with ERCP related periduodenal perforations and its treatment strategies are presented. Additionally, a rarely encountered subtype is highlighted. METHODS: Patients who underwent ERCP and sustained a periduodenal perforation between August 2008 and October 2011 were reviewed. RESULTS: During the period from August 2008 to October 2011, 597 ERCP procedures were performed in our hospital. Ten of these patients (3 male, 7 female) had a perforation. The mean patient age was 56.6 years. During the procedure, injury was suspected in four patients; it passed unnoticed in the remaining six. The decision to operate or follow a conservative policy was based on a combination of clinical and radiological findings. Operative intervention was required in three patients, with one mortality, while conservative treatment was followed in the remaining seven. A laparotomy was performed early in two patients whereas it was performed after an initial period of conservative treatment in one. The presence of periduodenal fluid collection, contrast extravasation or free intraperitoneal air were decisive factors for performing laparotomy. CONCLUSIONS: ERCP-related periduodenal perforations include different categories. Certain types require operative repair while others should be treated conservatively. The choice of the management approach should be individualised, depending on the clinical picture and radiological findings. Although rare, these are potentially serious complications that may end fatally. Early recognition and appropriate intervention is the only way to avert a fatal outcome. PMID- 23676817 TI - A simple and cost-effective method in delivery of bone graft in lumbar spine posterolateral fusion. PMID- 23676816 TI - Topical steroids for chronic wounds displaying abnormal inflammation. AB - INTRODUCTION: Chronic, non-healing wounds are often characterised by an excessive, and detrimental, inflammatory response. We review our experience of using a combined topical steroid, antibiotic and antifungal preparation in the treatment of chronic wounds displaying abnormal and excessive inflammation. METHODS: A retrospective review was undertaken of all patients being treated with a topical preparation containing a steroid (clobetasone butyrate 0.05%), antibiotic and antifungal at a tertiary wound healing centre over a ten-year period. Patients were selected as the primary treating physician felt the wounds were displaying excessive inflammation. Healing rates were calculated for before and during this treatment period for each patient. Changes in symptom burden (pain, odour and exudate levels) following topical application were also calculated. RESULTS: Overall, 34 ulcers were identified from 25 individual patients (mean age: 65 years, range: 37-97 years) and 331 clinic visits were analysed, spanning a total time of 14,670 days (7,721 days 'before treatment' time, 6,949 days 'during treatment' time). Following treatment, 24 ulcers demonstrated faster rates of healing, 3 ulcers showed no significant change in healing rates and 7 were healing more slowly (p=0.0006). Treatment generally reduced the burden of pain and exudate, without affecting odour. CONCLUSIONS: In normal wound healing, inflammation represents a transient but essential phase of tissue repair. In selected cases, direct application of a steroid containing agent has been shown to improve healing rates, presumably by curtailing this phase. Further evaluation is required to establish the role of preparations containing topical steroids without antimicrobials in the management of chronic wounds. PMID- 23676818 TI - Simple design for an aeroplane plaster of Paris splint in the immobilisation of axillary skin grafts. PMID- 23676819 TI - Portal vein occlusion following pancreatico-duodenectomy and portal vein resection: treatment by percutaneous portal vein stent. PMID- 23676820 TI - Difficult urethral catheterisation made easy: validation and the new application of the established technique. PMID- 23676821 TI - Posterolateral fibula preserving approach to the peroneal artery. PMID- 23676822 TI - NICE embracing digital technology. PMID- 23676826 TI - Comparison of femoral stem alignment in primary total hip replacement by transtrochanteric and posterior approach. AB - BACKGROUND: In this study we have compared the femoral component alignment in primary cemented THR performed by a single surgeon using the same implant by trochanteric osteotomy and posterior approach in 50 consecutive cases. MATERIAL AND METHODS: The femoral component was compared in sagital and coronal planes on plane X-rays. The femoral stem position was classified as neutral, varus or valgus in the sagital plane. In the coronal plane the femoral stem was graded as neutral, stem pointing anteriorly or stems pointing posteriorly. Chi square test was used for the statistical significance of the findings. RESULTS: The number of stems in neutral position in AP radiograph (coronal plane) was 36 and 42 respectively in osteotomy and posterior approach. 6 stems were in varus/valgus angle of >=5 degrees in osteotomy group and 1 stem in the posterior approach group had a varus/valgus angle of >=5 degrees (p value 0.05). In the lateral radiograph (sagital plane) 45 and 43 stems respectively in osteotomy and posterior approach were in neutral position (p value 0.37). CONCLUSIONS: There is no statistically significant difference in the positioning of the femoral stem in the sagital plane by either trochanteric osteotomy or posterior approach to the hip. The positioning of the femoral stem in the coronal plane is better with the posterior approach as compared to trochanteric osteotomy PMID- 23676827 TI - Orientation control of liquid crystals using carbon-nanotube-magnetic particle hybrid materials. AB - We have developed a simple yet versatile method for aligning liquid crystals (LCs) by using magnetic-field oriented single-walled carbon nanotubes (SWNTs) that were modified with magnetic particles. A high degree of homeotropic/planar LC alignment was achieved by SWNTs being exposed to a very low strength magnetic field, combined with strong pi-pi interactions between the biphenyl group in the LCs and the wall of the SWNTs. PMID- 23676825 TI - Structure-activity relationship of memapsin 2: implications on physiological functions and Alzheimer's disease. AB - Memapsin 2 (BACE1, beta-secretase), a membrane aspartic protease, functions in the cleavage of the type I transmembrane protein, beta-amyloid precursor protein (APP), leading to the production of amyloid beta (Abeta) in the brain. Since Abeta is closely associated with the pathogenesis of Alzheimer's disease, understanding the biological function, particularly the catalytic activities of memapsin 2, would assist in a better understanding of the disease and the development of its inhibitors. The transmembrane and cytosolic domains of memapsin 2 function in cellular transport and localization, which are important regulatory mechanisms for its activity. The catalytic ectodomain contains a long substrate cleft that is responsible for substrate recognition, specificity, and peptide bond hydrolysis. The substrate cleft accommodates 11 residues of the substrate in separate binding subsites. Besides APP, a number of membrane proteins have been reported to be substrates of memapsin 2. The elucidation for the specificity of these subsites and the amino acid sequences surrounding the memapsin 2 cleavage site in these proteins has led to the establishment of a predictive model that can quantitatively estimate the efficiency of cleavage for any potential substrates. Such tools may be employed for future studies of memapsin 2 about its biological function. Herein, we review the current knowledge on the structure-function relationship of memapsin 2 and its relationship in the biological function. PMID- 23676828 TI - Clinical potentials of adsorptive dialysis membranes. PMID- 23676829 TI - The double polymethylmethacrylate filter (DELETE system) in the removal of light chains in chronic dialysis patients with multiple myeloma. AB - Multiple myeloma (MM) is still one of the most common haematological diseases and is associated with a poor prognosis. It is frequently worsened by acute kidney failure that, in turn, aggravates the risk of death. In the past few years, the idea has made headway that the removal of free light chains (FLC) by means of extracorporeal blood purification systems may facilitate the recovery of renal function. Up to now, many different extracorporeal techniques have been put forward in FLC removal, such as plasma exchange, dialysis with super-flux filters, and adsorption by means of cartridge of resins. In this paper, we illustrate the use of polymethylmethacrylate (PMMA) dialysis membranes with a high adsorptive capacity (Toray BK-F; Toray Industries, Inc., Tokyo, Japan). We have evaluated light chain removal by means of an original dialysis procedure using a double-filter circuit made of PMMA working in sequential dialysis (DELETE system). The system provides satisfactory results in terms of FLC removal and, at the same time, ensures an adequate dialysis treatment (Kt/V >1.5) with significant reduction in urea, creatinine, and beta2-microglobulin. The dual PMMA filter system combines an acceptable cost/efficiency ratio when compared with other methods and constitutes a concrete prospect in FLC removal. Its preferential setting of use is in patients with MM or with monoclonal gammopathies, who are on chronic dialysis and maintain high circulating levels of FLC. PMID- 23676830 TI - Natural killer cell dysfunction in uremia: the role of oxidative stress and the effects of dialysis. AB - Immune deficiency is one of the numerous consequences of chronic renal failure. We can hypothesize that an abnormal natural killer (NK) cell response is present in patients with end-stage renal disease (ESRD). To characterize the immune defect in ESRD patients, we performed a NK cell subset analysis in 66 patients with ESRD treated by hemodialysis or peritoneal dialysis. Compared with healthy blood donors, patients undergoing chronic dialysis showed a profound decrease in NKG2D(+) cells within both CD8(+) T cell (58 vs. 67%, p = 0.03) and NK cell (39 vs. 56%, p = 0.002) populations. We further studied NK cell subsets in 55 hemodialysis patients and 17 patients treated by peritoneal dialysis. As compared to healthy donors, all these patients had significantly decreased NKG2D-positive NK cells. Patients using PMMA membranes (BK-F) or Helixone-FX membranes had a smaller decrease in NKG2D-positive NK cells when compared to patients treated with Nephral membranes. The expression of MICA on the cell surface of monocytes, which is a marker of inflammation induced by cellular stress, was also lower in patients using BK-F membranes. In conclusion, these data suggest that a subpopulation of NK cells is decreased in patients with ESRD. This decrease is associated with high circulating levels of the HLA-related molecule MICA. The dialysis membrane can influence the modulation of both the phenotype of NK cells and MICA overexpression. PMID- 23676831 TI - Removal of protein-bound uraemic toxins by haemodialysis. AB - Accumulating evidence suggests that protein-bound uraemic toxins play an important role in uraemic complications, especially in cardiovascular disease. Notably, protein-bound uraemic toxins such as indoxyl sulphate, p-cresyl sulphate, and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF) have emerged as important targets of therapeutic removal. Indoxyl sulphate stimulates reactive oxygen species production in human umbilical vein endothelial cells (HUVEC) most intensely, followed by CMPF. Indoxyl sulphate and CMPF inhibit cell growth of HUVEC. Haemodialysis (HD) even with a high-flux membrane cannot efficiently remove the protein-bound uraemic toxins because of their high albumin binding property. Especially, indoxyl sulphate, p-cresyl sulphate, and CMPF showed high protein-binding ratios (more than 95%) and low reduction rates by HD (less than 35%). Removal of indoxyl sulphate and p-cresyl sulphate can be improved to some extent by increasing the diffusion of the free forms with super flux membrane HD, increasing the dialyzer mass transfer area coefficient and dialysate flow, haemodiafiltration, daily HD, and addition of a sorbent to dialysate. However, CMPF is more strongly bound to albumin (with a binding ratio of 99-100%) than indoxyl sulphate and p-cresyl sulphate, and cannot be removed at all by conventional HD. Uraemic toxins strongly or covalently bound to albumin such that CMPF can be removed by protein-leaking HD. Protein-leaking HD with a polymethylmethacrylate membrane BK-F dialyzer can reduce serum levels of CMPF with improvement of anaemia as well as reduce plasma levels of homocysteine, pentosidine, and inflammatory cytokines. PMID- 23676832 TI - Prurigo nodularis and dialyzer membrane. AB - Prurigo nodularis is a skin disease with unknown origin which is frequent in patients on maintenance renal replacement therapy. Here, we report a patient who was dialyzed for more than 10 years with different dialyzers using different dialyzer membranes. Each time when the patient was switched to a polymethylmethacrylate membrane (Filtryzer BK-1.6P), itching and skin lesions disappeared completely. This effect could be verified three times. PMID- 23676833 TI - New insights in end-stage renal disease therapies: from dialysis to apheresis by means of membrane characteristics. PMID- 23676834 TI - Nondialyzable uremic toxins. AB - Nondialyzable uremic toxins can be defined as solutes producing adverse biological effects that consequently to peculiar physicochemical features (mainly their large size and hydrophobic character) cannot leave the blood stream through a dialysis membrane. These are the subject of great interest for the scientific community, in that emerging evidence suggests that such uremic retention solutes may contribute a main role to the complex inflammatory and vascular comorbidity of the uremic syndrome. Treatments based on most efficient diffusive or convective protocols of dialysis and pharmacological therapies cannot prevent nor correct such clinical symptoms. Protein-bound solutes and other proteinaceous components present in excess in the uremic milieu are thus natural candidates for explaining the resistance of uremic toxicity to current regimens of therapy. Intense research is in progress to identify molecular species and mechanisms of toxicity, but the real challenge of our times is to develop innovative clinical protocols that may remove or prevent the formation/toxicity of nondialyzable uremic solutes. These include high-efficacy protein-leaking dialyzers, adsorption techniques, frequent dialysis, and pharmacological therapies. These aspects are examined in this review paper, paying particular attention to covalent posttranslational modifications of plasma proteins produced as a consequence of oxidative, nitrosative and carbonyl stress. These represent an emerging trait in the pathobiology of inflammatory and age-related disorders, deserving further consideration in chronic kidney disease. PMID- 23676835 TI - Adsorption dialysis: from physical principles to clinical applications. AB - The uremic syndrome is characterized by the retention of various solutes that would normally be excreted by the kidneys. The substances that interact negatively with biologic functions are called uremic toxins. Over the past five decades, the membranes used for the treatment of chronic kidney disease have continuously evolved. The exposure of blood to any extracorporeal artificial surface results in the activation of several pathways within the body, including those involving coagulation and complement activation. One of the by-products of this generalized activation process is protein adsorption to the membrane surface, another phenomenon which can have a significant impact on solute removal. In fact, an array of studies showed that with increasing size of middle sized proteins and other compounds, relatively more clearance is achieved by membrane adsorption compared with loss into the dialysate. A high adsorptive capacity, one of the main features of polymethylmethacrylate (PMMA) membranes, is very helpful and may both increase the total amount of solutes removed and remove different kinds of solutes. In this setting, a few studies have shown a variety of efficient clinical implications for adsorption hemodialysis, such as uremic pruritus, anemia, carpal tunnel syndrome and renal amyloidosis, immune dysfunction and improved response to vaccination. In addition, nutrition and survival were also improved using PMMA membranes. PMID- 23676836 TI - Adsorption techniques: dialysis sorbents and membranes. AB - Adsorption is based on the attraction between the sorbent and the solute through hydrophobic interactions, ionic or electrostatic forces, hydrogen bonding or van der Waals forces. Adsorption is the adherence of molecules by the above-mentioned forces not only to the surface of the membrane but also to its interior. Since polymethylmethacrylate membranes have a much higher inside effective exchange surface than polysulfone membranes, these membranes are able to ensure a high level of adsorption, and therefore reduce the concentration of high-molecular weight molecules and protein-bound uremic toxins. PMID- 23676840 TI - Prospective evaluation of qualitative and quantitative 18F-FDG PET-CT parameters for predicting survival in recurrent carcinoma of the cervix. AB - OBJECTIVE: The aim of this study was to evaluate the prognostic significance of qualitative and quantitative F-fluorodeoxyglucose (F-FDG) PET-computed tomography (PET-CT) parameters in patients with recurrent cervical carcinoma. METHODS: Twenty-six patients (age: 44 +/- 10.1 years) with histologically proven recurrent carcinoma of the cervix (squamous, 21; adenocarcinoma, five) were prospectively enrolled and they underwent F-FDG PET-CT before salvage therapy. The qualitative parameters included for analysis were vaginal involvement, regional nodal metastasis, and distant metastasis on PET-CT. The quantitative PET-CT parameters included were standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Cutoff values were determined using receiver operating characteristic curve analysis. A Kaplan-Meier analysis was carried out to compare survival among groups. Impact of PET-CT parameters on progression-free survival (PFS) and overall survival (OS) was evaluated using Cox proportional hazard regression. RESULTS: On PET-CT, vaginal involvement was seen in 16 patients, regional nodal metastasis in 12 patients, and distant metastasis (node and lung) in 11 patients. The mean SUVmax was 6.8 +/- 4, MTV was 8.2 +/- 12.8 ml, and TLG was 49.6 +/- 108.4 ml. On multivariate analysis, SUVmax of up to 4.9 [hazard ratio (HR): 0.026, confidence interval (CI): 0.002-0.268, P=0.002] and distant metastasis (HR: 18.88, CI: 2.14-166.24, P=0.008) were independent predictors of PFS. On multivariate analysis, SUVmax greater than 9 (HR: 19.25, CI: 2.15-172.17, P=0.008) and distant metastasis (HR: 33.88, CI: 2.17-526.61, P=0.012) were also independent predictors of OS. MTV, TLG, and regional node involvement evaluated using PET-CT were found to be significant on univariate analysis but not on multivariate analysis. CONCLUSION: SUVmax and the presence of distant metastasis on F-FDG PET-CT are independent predictors of PFS and OS in patients with recurrent cervical carcinoma. PMID- 23676837 TI - Polymethylmethacrylate membrane and serum free light chain removal: enhancing adsorption properties. AB - INTRODUCTION: Polymethylmethacrylate (PMMA) membranes can adsorb a wide variety of uremic toxins including serum free light chains (sFLC). However, limited data are available regarding the clinical use of PMMA in multiple myeloma patients and its maximum adsorption capacity in this setting. AIM: This study aimed to measure the capacity of PMMA to adsorb sFLC and identify strategies to improve its efficiency in clinical practice. METHODS: Ten patients with dialysis-dependent renal failure and high levels of sFLC were included in the study. Five patients received standard PMMA hemodialysis (HD; n = 18), while in the other 5 patients a new technique called enhanced adsorption dialysis (EAD) was used, which involves PMMA dialyzer replacement after 2 h (n = 19). In all patients, sFLC were measured at the beginning and at the end of each dialysis session to calculate the difference between start and end of treatment and the percentage removal. RESULTS: PMMA membranes reduced sFLC in both the PMMA HD and EAD groups. PMMA HD showed similar efficiency on kappa and lambda percentage removal (22.3 and 21.0%, respectively, n.s.) but, in contrast, had a significantly greater effect on the delta of sFLC in kappa [1,555 mg/l (-511 to +6,027)] versus lambda [390 mg/l (120 650)] treatments (p = 0.007). EAD treatments only partially increased percentage removal of kappa sFLC (22.3-31.0%, p = 0.38), while they had a significantly great effect on lambda (21.0-53.1%, p = 0.003). A positive linear correlation was found between delta sFLC and pre-HD sFLC concentrations in PMMA HD kappa treatments (r = 0.68, p < 0.02) but not for lambda treatments (r = 0.54, p = 0.21), while the analysis of patients receiving EAD demonstrated a strong positive correlation for both kappa and lambda subtypes (r = 0.81 and r = 0.85, respectively, p < 0.008). In EAD sessions, a positive linear correlation was shown between blood flow during treatment and percentage removal of sFLC (r = 0.58, p = 0.02); however, with PMMA HD such a correlation was not observed (r = 0.28, p = 0.25). CONCLUSIONS: PMMA membranes can efficiently adsorb sFLC, but the process is limited by membrane saturation and is different between kappa and lambda sFLC. The new EAD technique can greatly improve lambda removal but only partially act on kappa sFLC. Therefore, EAD should be considered a valid economic treatment option without side effects in particular subsets of patients for the removal of sFLC. PMID- 23676841 TI - Plasmonic nanofocusing with a metallic pyramid and an integrated C-shaped aperture. AB - We demonstrate the design, fabrication and characterization of a near-field plasmonic nanofocusing probe with a hybrid tip-plus-aperture design. By combining template stripping with focused ion beam lithography, a variety of aperture-based near-field probes can be fabricated with high optical performance. In particular, the combination of large transmission through a C-shaped aperture aligned to the sharp apex (<10 nm radius) of a template-stripped metallic pyramid allows the efficient delivery of light--via the C-shaped aperture--while providing a nanometric hotspot determined by the sharpness of the tip itself. PMID- 23676842 TI - Preparation of well-dispersed gold/magnetite nanoparticles embedded on cellulose nanocrystals for efficient immobilization of papain enzyme. AB - A nanocomposite consisting of magnetite nanoparticles (Fe3O4NPs) and Au nanoparticles (AuNPs) embedded on cellulose nanocrystals (CNCs) was used as a magnetic support for the covalent conjugation of papain and facilitated recovery of this immobilized enzyme. Fe3O4NPs (10-20 nm in diameter) and AuNPs (3-7 nm in diameter) were stable and well-dispersed on the CNC surface. Energy-dispersive spectroscopy, X-ray diffraction, and Fourier transform infrared spectroscopy were used to evaluate the surface composition and structure of CNC/Fe3O4NPs/AuNPs. The nanocomposite was successfully used for the immobilization and separation of papain from the reaction mixture. The optimal enzyme loading was 186 mg protein/g CNC/Fe3O4NPs/AuNPs, significantly higher than the value reported in the literature. The activity of immobilized papain was studied by electrochemical detection of its specific binding to the Thc-Fca-Gly-Gly-Tyr-Arg inhibitory sequence bound to an Au electrode. The immobilized enzyme retained 95% of its initial activity after 35 days of storage at 4 degrees C, compared to 41% for its free form counterpart. PMID- 23676843 TI - A differential equation for the Generalized Born radii. AB - The Generalized Born (GB) model offers a convenient way of representing electrostatics in complex macromolecules like proteins or nucleic acids. The computation of atomic GB radii is currently performed by different non-local approaches involving volume or surface integrals. Here we obtain a non-linear second-order partial differential equation for the Generalized Born radius, which may be solved using local iterative algorithms. The equation is derived under the assumption that the usual GB approximation to the reaction field obeys Laplace's equation. The equation admits as particular solutions the correct GB radii for the sphere and the plane. The tests performed on a set of 55 different proteins show an overall agreement with other reference GB models and "perfect" Poisson Boltzmann based values. PMID- 23676844 TI - Guidelines for the clinical application of bypass grafts and the surgical techniques (JCS 2011) published in 2012--digest version. PMID- 23676845 TI - A comprehensive strategy to identify stoichiometric membrane protein interactomes. AB - There are numerous experimental approaches to identify the interaction networks of soluble proteins, but strategies for the identification of membrane protein interactomes remain limited. We discuss in detail the logic of an experimental design that led us to identify the interactome of a membrane protein of complex membrane topology, the calcium activated chloride channel Anoctamin 1/Tmem16a (Ano1). We used covalent chemical stabilizers of protein-protein interactions combined with magnetic bead immuno-affinity chromatography, quantitative SILAC mass-spectrometry and in silico network construction. This strategy led us to define a putative Ano1 interactome from which we selected key components for functional testing. We propose a combination of procedures to narrow down candidate proteins interacting with a membrane protein of interest for further functional studies. PMID- 23676846 TI - Unraveling the internal dynamics of the benzene dimer: a combined theoretical and microwave spectroscopy study. AB - We report a combined theoretical and microwave spectroscopy study of the internal dynamics of the benzene dimer, a benchmark system for dispersion forces. Although the extensive ab initio calculations and experimental work on the equilibrium geometry of this dimer have converged to a tilted T-shaped structure, the rich internal dynamics due to low barriers for internal rotation have remained largely unexplored. We present new microwave spectroscopy data for both the normal (C6H6)2 and partially deuterated (C6D6)(C6H6) dimers. The splitting patterns obtained for both species are unraveled and understood using a reduced dimensionality theoretical approach. The hindered sixfold rotation of the stem can explain the observed characteristic 1 : 2 : 1 tunneling splitting pattern, but only the concerted stem rotation and tilt tunneling motion, accompanied by overall rotation of the dimer, yield the correct magnitude of the splittings and their strong dependence on the dimer angular momentum J that is essential to explain the experimental data. Also the surprising observation that the splittings are reduced by 30% for the mixed (C6D6)(C)(C6H6)(S) dimer in which only the cap (C) in the T-shaped structure is deuterated, while the rotating stem (S) monomer is the same as in the homodimer, is understood using this approach. Stark shift measurements allowed us to determine the dipole moment of the benzene dimer, MU = 0.58 +/- 0.051 D. The assumption that this dipole moment is the vector sum of the dipole moments induced in the monomers by the electric field of the quadrupole on the other monomer yields a calculated value of MU = 0.63 D. Furthermore, the observed Stark behavior is typical for a symmetric top, another confirmation of our analysis. PMID- 23676848 TI - Level of serum antibody against a periodontal pathogen is associated with atherosclerosis and hypertension. AB - Inflammation has a role in the pathogenesis of atherosclerosis, which causes hypertension. Results from some studies have suggested links between periodontal disease and atherosclerosis, but links between periodontal disease and hypertension have been seldom studied. We investigated whether periodontal disease and serum antibody level were associated with hypertension. We studied 127 patients (93 men and 34 women, mean age 68+/-9 years) who were admitted with ischemic heart disease to our institution. A composite periodontal risk score was calculated from five periodontal vector scores. The levels of serum antibody against Porphyromonas gingivalis (Pg) were measured. Pulse pressure, mean blood pressure (BP) and pulse wave velocity were used as indices of atherosclerosis. We divided patients into two groups according to the levels of serum antibody against Pg: higher or equal to the median (high Pg antibody group) and lower than the median (low Pg antibody group).There was no difference in the use of antihypertensive agents between the two groups. The composite periodontal risk score (P=0.0003), systolic BP (P=0.030), diastolic BP (P=0.038), pulse pressure (P=0.050) and mean BP (P=0.055) were higher in the high Pg antibody group than in the low Pg antibody group. The composite periodontal risk score (r=0.320, P=0.0003), systolic BP (r=0.212, P=0.017), diastolic BP (r=0.188, P=0.035) and mean BP (r=0.225, P=0.011) correlated with the level of serum antibody against Pg, even after adjustment for age. An elevated antibody level against Pg indicates advanced periodontal disease and suggests advancement of atherosclerosis and hypertension. PMID- 23676847 TI - Non-invasive assessment of cardiac function in a mouse model of renovascular hypertension. AB - Hypertension continues to be a significant cause of morbidity and mortality, underscoring the need to better understand its early effects on the myocardium. The aim of this study is to determine the feasibility of in vivo longitudinal assessment of cardiac function, particularly diastolic function, in a mouse model of renovascular hypertension. Renovascular hypertension (RVH) was induced in 129S1/SvImJ male mice (n=9). To assess left ventricular (LV) systolic and diastolic function, M-mode echocardiography, pulsed-wave Doppler echocardiography and tissue Doppler imaging were performed at baseline, 2 and 4 weeks after the induction of renal artery stenosis. Myocardial tissue was collected to assess cellular morphology, fibrosis, extracellular matrix remodeling and inflammation ex vivo. RVH led to a significant increase in systolic blood pressure after 2 and 4 weeks (baseline: 99.26+/-1.09 mm Hg; 2 weeks: 140.90+/-7.64 mm Hg; 4 weeks: 147.52+/-5.91 mm Hg, P<0.05), resulting in a significant decrease in LV end diastolic volume, associated with a significant elevation in ejection fraction and preserved cardiac output. Furthermore, the animals developed an abnormal diastolic function profile, with a shortening in the E velocity deceleration time as well as increases in the E/e' and the E/A ratio. The ex vivo analysis revealed a significant increase in myocyte size and deposition of extracellular matrix. Non-invasive high-resolution ultrasonography allowed assessment of the diastolic function profile in a small animal model of renovascular hypertension. PMID- 23676849 TI - Therapeutics: blocking RAS effects. PMID- 23676850 TI - The hen as a model of ovarian cancer. AB - The domestic laying hen is the only non-human animal that spontaneously develops ovarian cancer with a high prevalence. Hens ovulate prolifically, and this has made the hen intuitively appealing as a model of this disease in light of epidemiological evidence that ovulation rate is highly correlated with the risk of human ovarian cancer. As in women, ovarian cancer in the hen is age-related and it is also grossly and histologically similar to that in humans. In both women and hens, the cancer metastasizes to similar tissues with an accumulation of ascites fluid. Some aggressive ovarian cancers in women arise from cells in the oviduct; this is intriguing because ovarian cancers in the hen express an oviductal protein that is normally absent in the ovary. PMID- 23676851 TI - MicroRNA: lacking in maturity. PMID- 23676852 TI - Ultra-rapid colorimetric assay for protease detection using magnetic nanoparticle based biosensors. AB - Sensitive protease detection methods often require time-consuming techniques and expensive instrumentation. To overcome this limitation, a novel, simple, sensitive and selective colorimetric detection approach was developed. This biosensing configuration was validated by the use of prostate specific antigen (PSA) protease as a model target. In this method, proteolytically active PSA capable of cleaving PSA substrates caused the release of black-colored magnetic carrier complexes, exposing the gold color sensor surface visible to the naked eye. The assay showed excellent sensitivity as well as specificity, capable of discriminating between different types of protease targets. The biosensor was able to quantitatively detect different PSA concentrations with a detection limit as low as 10 ng mL(-1). The sensor offers the possibility of developing a wash less and cost-effective point-of-care device due to the simplicity of the probe immobilization process and the elimination of labeling and reporter molecules during the biosensing step. PMID- 23676853 TI - Cerebrorenal interaction and stroke. AB - Beyond the original meaning of chronic kidney disease (CKD) as high-risk state for future dialysis, CKD is now known as an established risk factor for cardiovascular diseases. Stroke is a major player of cardiovascular disease and has deep two-way relationships with CKD. CKD is an evident risk factor for stroke. Meta-analyses of cohort studies and trials indicate that proteinuria/albuminuria increases the risk of stroke by 71-92%, and reduced glomerular filtration rate increases the risk by 43%. In addition, CKD has a strong relationship with subclinical brain damage including white matter changes, microbleeds, cognitive impairment, and carotid atherosclerosis. CKD is prevalent in acute stroke patients; patients with estimated glomerular filtration rate <60 ml/min/1.73 m(2) or proteinuria amounted to 46% of total ischemic stroke patients and 39% of total intracerebral hemorrhage patients in our institute. Acute and chronic management of stroke are influenced by CKD. Therapeutic effects of several antithrombotic and thrombolytic agents, including recently-developed novel oral anticoagulants, are affected by renal function. Moreover, reduced glomerular filtration rate is independently associated with increased 1- and 10 year mortalities in the end. Stroke also has deep relationships with end-stage kidney disease. Stroke occurs much more commonly in dialysis patients than general population or CKD patients without need for dialysis. The triggers of ischemic and hemorrhagic stroke in patients with end-stage kidney disease include special characteristics unique to dialysis, such as drastic hemodynamic change, dialysate and anticoagulants, and vascular calcification. As cohorts of dialysis patients become older, more hypertensive, and more diabetic than before, stroke become more prevalent and more serious events in dialysis clinics. Now, clinicians should have much interest in the association between CKD and cerebrovascular diseases, so-called the cerebro-renal interaction. PMID- 23676854 TI - Roles of the hepcidin-ferroportin axis and iron in cancer. AB - Hepcidin is a low-molecular-weight hepatic peptide that regulates iron homeostasis, and acts by causing the degradation of its receptor, the cellular iron exporter ferroportin. On the basis of the major role of the hepcidin ferroportin axis in iron regulation, recently several studies have discussed its expression and influence on the development and prognosis of cancer. Iron plays a pivotal role in homeostasis. However, insights into the mechanisms of normal iron regulation have provided a new perspective on the basic mechanisms, biological rationale, and pathophysiologic implications of changes in iron metabolism in cancer. Besides being a crucial stimulus for cancer, iron dysfunction also causes cancer-related anemia. In this review, we discuss aspects of the hepcidin ferroportin axis and iron regulation, as well as the inherent connections between them in cancer. We also attempt to consider the possibility in theory of novel targets for further individualized therapy. However, many molecular mechanisms and functions of these regulators remain unclear. PMID- 23676855 TI - Tailoring the electrical properties of graphene layers by molecular doping. AB - It is an essential issue in graphene-based nanoelectronic and optoelectronic devices to tune the electrical properties of graphene layers, while preserving its unique band structure. Here, we report the tuning of electronic properties of single-, bi-, and trilayer mechanically exfoliated graphenes by p-toluenesulfonic acid (PTSA) molecular doping. Raman spectroscopy and charge transport measurements revealed that PTSA molecule imposes n-doping to single-, bi-, and trilayer graphenes. The shift of G and 2D peak frequencies and intensity ratio of single-, bi-, and trilayer graphenes are analyzed as a function of reaction time. The Dirac point is also analyzed as a function of reaction time indicates the n type doping effect for all single-, bi-, and trilayer graphenes. Our study demonstrates that chemical modification is a simple approach to tailor the electrical properties of single-, bi-, and trilayer graphenes, while maintaining the important electrical assets. PMID- 23676856 TI - Population pharmacokinetic-pharmacodynamic target attainment analysis of imipenem plasma and urine data in neonates and children. AB - BACKGROUND: Population pharmacokinetic (PK)-pharmacodynamic target attainment analysis of imipenem was performed to elucidate the PK properties in neonates and children and to rationalize and optimize dosing regimens. METHODS: Population PK models were separately developed in neonates and children by simultaneously fitting plasma and urine data from 60 neonates and 39 children. The newly developed models were then used to estimate the probability of attaining the pharmacodynamic target (40% of the time above the minimum inhibitory concentration) against clinical isolates of common bacteria in pediatric patients. RESULTS: The data were best described by a 1-compartment model in neonates and a 2-compartment model in children, respectively. Renal clearance in children (0.187 L/h/kg) was double that of neonates (0.0783 L/h/kg), whereas the volume of distribution at steady-state was approximately 1.8-fold larger in neonates (0.466 L/kg) than in children (0.260 L/kg). Age was not a statistically significant covariate in the PK of both groups. Infusions (0.5 h) of 15 mg/kg every 8 h (45 mg/kg/day) and 25 mg/kg every 12 h (50 mg/kg/day) were shown to be sufficient against common bacterial isolates in both patient populations. However, 1.5-h infusions of 25 mg/kg every 8 h (75 mg/kg/day) in neonates and 25 mg/kg every 6 h (100 mg/kg/day) in children were required to be effective against Pseudomonas aeruginosa (minimum inhibitory concentration for 90% of the isolates=16 MUg/mL). CONCLUSIONS: These results explain the changes in imipenem PK properties during the human growth process and provide guidance for tailoring dosing regimens in each pediatric age group. PMID- 23676857 TI - Supportive environments for physical activity, community action, and policy in 8 European Union Member States: comparative analysis and specificities of context. AB - BACKGROUND: A multilevel theoretical framework of physical activity (PA) promotion that addresses supportive environments, PA behavior, community action, and PA promoting policies is related to research and development in an international comparative study. METHODS: Most-different and most-similar case selection was applied to data from 8 European Union Member States. Data from semistructured key informant qualitative interviews, focus group interviews with experts and policy-makers, as well as document analysis were linked to corresponding Eurobarometer data. RESULTS: The framework on the interplay of environment, PA behavior, community action and policies appears to be working across most different countries. Comprehensive systems of PA infrastructures are interlinked with relatively high levels of PA prevalence. These countries implement comprehensive national policies on PA promotion and show a positive perception of related local governments' engagement. Less comprehensive systems of infrastructures interplay with lower levels of PA prevalence, less community action and fewer policies. Differences between similar cases are linked to country-specific contexts. CONCLUSIONS: Framework application and comparative analysis indicates how to relate theory to empirical research and complex data sets. In-depth analysis of country-specific contexts and longitudinal observation on changes within and between countries might advise on how to integrate the framework into intervention research. PMID- 23676858 TI - Stereotactic radiosurgery for spinal neoplasms: current status and future perspective. AB - Stereotactic radiosurgery (SRS) is increasingly utilized for the treatment of primary and metastatic spinal tumors. SRS implies high dose per fraction radiation (typically >5 Gy per fraction) is delivered to an image-guided target in 1 to 5 fractions by using conformal radiation techniques. Its use is based on the radiobiological superiority of hypofractionated high dose radiation and precision of radiation delivery using real time image-guidance facilities. Spine SRS devices can be classified into two groups according to the type of treatment unit: Cyberknife (Accuray, Inc., Sunnyvale, CA, USA) and multileaf collimation (MLC) linear accelerator (LINAC) systems. The major indications for the use of SRS include primary and metastatic spine tumors. In spine metastasis, SRS was reported to be highly effective at decreasing pain, regardless of prior radiation, with an overall pain improvement rate of 85% and local control rate of approximately 90%. Improved local control could lead to more effective palliation and potentially longer survival. Some of benign spinal disease such as schwannoma, neurofibroma, meningioma, hemangioblastoma and vascular malformations were also treated. Complications associated with spinal SRS have been rarely reported, myelopathy risk is estimated to be 0.4% of treated patients. We believe that SRS is an established treatment for patients with spinal tumors, which is both safe and highly effective. The purpose of this review is to introduce principles of spinal SRS and summarize the literature regarding the usefulness of SRS for treatment of spinal neoplasms. PMID- 23676859 TI - The current management of lumbar spondylolisthesis. AB - Lumbar spondylolisthesis can lead to disabling low back pain and neurological deficits. This review details the clinical history, neurological examination, clinical presentation, imaging modalities, and current management standards for lumbar spondylolisthesis. Based on the available clinical trials, there is evidence that, compared with nonsurgical care, the surgical treatment of symptomatic spondylolisthesis offers a significant clinical benefit in the presence of progressive neurological deficits; cauda equina syndrome; failure of an adequate response to conservative therapy: radiographic instability with neurological symptoms; radiographic progression of subluxation to greater than grade II; symptomatic grades III, II, or spondyloptosis; and unremitting pain that affects the quality of life. Optimizing the diagnostic paths and surgical indications and standardizing both the surgical procedures as well as the outcome measurements with validated instruments should assist the spine care community in acquiring data that are essential for providing the best evidence-based treatment while reducing or eliminating procedures that lack evidence of either efficacy or value. PMID- 23676860 TI - Thoracolumbar spine trauma: review of the evidence. AB - AIM: The aim of this paper was to provide a comprehensive review of literature regarding the classification systems and surgical management of thoracolumbar spine trauma. METHODS: A Pubmed search of "thoracolumbar", "spine", "fracture" was used on January 05, 2013. Exclusionary criteria included non-Human studies, case reports, and non-clinical papers. RESULTS. One thousand five hundred twenty manuscripts were initially returned for the combined search string; 150 were carefully reviewed, and 48 manuscripts were included in the review. DISCUSSION: Traumatic spinal cord injury (SCI) has a high prevalence in North America. The thoracolumbar junction is a point of high kinetic energy transfer and often results in thoracolumbar fractures. New classification systems for thoracolumbar spine fractures are being developed in an attempt to standardize evaluation, diagnosis, and treatment as well as reporting in the literature. Earlier classifications such as the Denis "3-column model" emphasized anatomic divisions to guide surgical planning. More modern classification systems such as the Thoracolumbar injury classification system (TLICS) emphasize initial neurologic status and structural integrity of the posterior ligamentous complex as a guide for surgical decision making and have demonstrated a high intra- and interobserver reliability. Other systems such as the Load-Sharing Classification aid as a useful tool in planning the extent of instrumentation and fusion. CONCLUSION: There is still much controversy over the surgical management of various thoracolumbar fractures. Level I data exists supporting the nonsurgical management of thoracolumbar burst fractures without neurologic compromise. However, for the majority of fracture types in this region, more randomized controlled trials are necessary to establish standards of care. PMID- 23676861 TI - Minimally invasive transmuscular approach for the treatment of lumbar herniated disc: far lateral lumbar disc herniation: a clinical study. Applications for cervical and thoracic disc herniation. AB - AIM: In this study, we are using a recently developed method: a minimally invasive retractor system and an operating microscope to treat far lateral lumbar herniated disc. This method decreases tissue dissection and blood loss, and improves postoperative recovery. METHODS: This is a retrospective study of 46 patients, there was 25 female and 21 male. They all underwent minimal invasive surgery. The average age was 56 years old (19-83 years). Lumbar disc herniation is a common pathology. Far lateral disc herniation accounts for 2.6% to 11.2% of all lumbar disc herniation. A few surgical techniques have been describes to treat this type of disc pathology. All patients were operated under general anesthesia. The fluoroscopic guidance was absolutely necessary. A 12-15 mm skin incision was made on the side of the disc herniation (30 mm from the midline). Then, we inserted a tubular retractor system (muscle splitting approach) followed by a 14 mm diameter-working channel. Under operating microscope the pars interarticularis was dreamed to expose the nerve root and the disc. After removing the intertransverse ligament, we removed the herniated disc. RESULTS: The average time of surgery was 55 min. The operating time decreased with the experience of the surgical team. Postoperatively the radicular pain was around 2 (using an analogical visual scale), over 7 preoperatively. The length of hospitalization was 3 days. There were no complications in our study. The average follow-up was 2 years (6-36 months). There was no complication, no postoperative infection. CONCLUSION: This technique combines the advantages of endoscopic surgery and microscope guided surgery (3D vision) and provides good functional results in this study. PMID- 23676862 TI - An evidence-based analysis of vertebroplasty and kyphoplasty. AB - There is a vast array of literature comparing treatment modalities for vertebral augmentation, which includes balloon kyphoplasty (BKP); vertebroplasty (VP); and non-surgical management (NSM). This has produced differing and sometimes contradictory conclusions in determining the efficacy of these procedures, which prompts further investigation into the design and outcome measures of these studies. This review examines the recent literature on the management of vertebral compression fractures and offers insight on the Level I and Level II trials comparing these treatment modalities, with specific focus on design, endpoints, and outcome measurements. The review emphasizes the idea that no one study can be held as gospel, and further studies with standardized methods of inclusion and measuring outcome are necessary to determine which patients will enjoy the greatest benefit from each treatment modality. PMID- 23676863 TI - Correlation between preoperative imaging features and intraoperative blood loss of meningioma: a new scoring system for predicting intraoperative blood loss. AB - AIM: The aim of this paper was to analyze the correlation between preoperative imaging features and intraoperative blood loss and transfusion of meningioma in order to explore the possibility of reasonable blood preparation based on the preoperative images. METHODS: The data of 93 adults with meningioma having undergone microsurgical operations was retrospectively analyzed. The intraoperative blood loss of meningioma was evaluated with "estimated blood loss (EBL)". The preoperative imaging features including volume, origin, peritumoral edema, invasive behavior, calcification, dural tail sign, adjacent bone involvement, blood vessel or venous sinus involvement were reviewed. Logistic regression analysis was used to determine the correlations between the imaging factors and the EBL or blood requirement. RESULTS: Origin, volume, and blood vessel or venous sinus involvement of meningioma affected its EBL statistically. Calcification, invasive behaviors, dural tail sign, peritumoral edema and adjacent bone involvement did not influence EBL statistically. Origin and volume were independent risk factors for the high intraoperative blood loss. Origin, volume and blood vessel or venous sinus involvement were independent risk factors for the intraoperative red blood cell transfusion requirement. A scoring method was proposed to predict the intraoperative blood loss and transfusion of meningioma based on preoperative images. CONCLUSION: It is feasible to predict the intraoperative blood loss and transfusion of meningioma surgery according to the preoperative images. PMID- 23676864 TI - Role of radiotherapy for high grade gliomas management. AB - We have analyzed the therapeutic standard options for high grade gliomas, with particular attention to the different radiation therapy modalities and techniques and their application considering the natural history of the disease. Of the several therapeutic options, surgical resection remains the initial treatment of choice for patients with high grade glioma; of all adjuvant treatments tested, radiotherapy offers the greatest magnitude of survival benefit, so radiotherapy, which must be started within 6 weeks of surgery, is mandatory for practically all patients with high grade gliomas. In this paper we perform an overview considering the integration between the different therapeutic modalities, with particular attention to the radiation therapy role in the management of high grade gliomas. PMID- 23676865 TI - Use of dexmedetomidine for postoperative analgesia in spine patients. AB - AIM: Postoperative spinal patients remain a challenge for provision of postoperative analgesia. They often exhibit tolerance to narcotics, which requires alternative agents. Our institution has an experience with the use of dexmedetomidine for postoperative analgesia in spine patients. METHODS: This was conducted as a retrospective chart review of spine patients that received dexmedetomidine during an entire calendar year, and we excluded any patients that were mechanically ventilated or received other sedation agents. RESULTS: Twenty nine patients were identified that received the dexmedetomidine for a mean of 31.3 hours, at a mean rate of 0.5 mcg/kg/hour. Their mean pain score went from 7.1 to 1.6 (P<0.001) within 4 hours of starting the drug. Both the heart rate, and systolic blood pressure decreased by approximately 10% after starting the dexmedetomidine. In 4 patients (13.8%) the dexmedetomidine had to be stopped early on due to bradycardia or hypotension. CONCLUSION: Dexmedetomidine represents an important agent for the treatment of severe postoperative spinal pain as a supplemental agent with patients that do not achieve adequate analgesia from narcotics. PMID- 23676866 TI - Electronic structure and morphology of dark oxides on zinc generated by electrochemical treatment. AB - Oxides formed by electrochemical treatment of metals frequently have properties and structures very different from the respective bulk oxides. Here, electronic structure and chemical composition were investigated for the oxide formed on polycrystalline zinc after electrochemical oxidation, and after subsequent reduction, in a Na2CO3 electrolyte. Photoluminescence and spectroscopic ellipsometry show the presence of states deep in the ZnO band gap in the oxidized sample, which consists of a highly disordered oxide. These states determine the absorption of light in the visible spectral range. After reduction, the characteristics of the ZnO electronic structure have disappeared, leaving a defect-dominated material with a band gap of ~1.8 eV. Complementary detailed analysis of the morphology of the resulting surfaces shows hexagon-shaped metallic Zn-"nanoplates" to be formed in the reduction step. The optical appearance of the surfaces is dark, because of their efficient extinction of light over a large part of the visible spectrum. The optical appearance is a result of changed surface morphology and electronic structure of the oxide film. Such materials may possess interesting applications in photocatalysis or photoelectrochemistry. PMID- 23676867 TI - Integration in medical education: what do we mean? PMID- 23676868 TI - Expanding the horizons of practice-based small-group learning: what are we learning? PMID- 23676869 TI - Quality criteria for general practice teaching. PMID- 23676870 TI - Integrating postgraduate and undergraduate general practice education: qualitative study. AB - BACKGROUND: Educational activity in general practice has increased considerably in the past 20 years. Vertical integration, whereby practices support students and trainees at different stages, may enhance general practices' capacity to fulfil this role. AIMS: To explore the potential for vertical integration in undergraduate and postgraduate education in general practice, by describing the experience of (and attitudes towards) 'vertical integration in general practice education' among key stakeholder groups. METHODS: Qualitative study of GPs, practice staff, GPs-in-training and medical students involving focus groups which were thematically analysed. RESULTS: We identified four overarching themes: (1) Important practical features of vertical integration are interaction between learners at different stages, active involvement in clinical teams and interagency collaboration; (2) Vertical integration may benefit GPs/practices, students and patients through improved practice systems, exposure to team-working and multi-morbidity and opportunistic health promotion, respectively; (3) Capacity issues may challenge its implementation; (4) Strategies such as recognising and addressing diverse learner needs and inter-agency collaboration can promote vertical integration. CONCLUSIONS: Vertical integration, whereby practices support students and trainees at different stages, may enhance general practices' teaching capacity. Recognising the diverse educational needs of learners at different stages and collaboration between agencies responsible for the planning and delivery of specialist training and medical degree programmes would appear to be important. PMID- 23676871 TI - Evaluating a community-engaged vertically integrated teaching and learning pilot project. AB - OBJECTIVE: To evaluate a community engaged vertically integrated teaching and learning pilot project. METHOD: Thematic analysis of focus group interviews was used to examine 27 general practitioners' (GPs'), registrars' and medical students' perceptions of a vertically integrated workshop in adolescent health and subsequent small group health education sessions at two secondary schools. Pre- and postintervention surveys were used to measure changes to participants' knowledge, confidence, and attitudes towards registrars and students teaching in general practice. RESULTS: Knowledge scores (7.46 +/- 1.17 vs 9.54 +/- 1.17; t = 9.6, P <0.001), and scores on the Confidence to Teach (3.34 +/- 0.51 vs 4.09 +/- 0.33; t = -6.61, P <0.001), and Vertically Integrated Teaching (4.01 +/- 0.40 vs 4.30 +/- 0.42; t = -3.45, P <0.05) scales increased significantly following the intervention. Scale reliability ranged from 0.74 to 0.87. Participants enjoyed the collegiality of learning together in a vertically integrated model. The experience stimulated self-reflection on teaching skills and a desire for peer review of teaching. Suggestions for improving the intervention included building a clearer link between the facilitation skills learnt in the school setting and how to implement them in general practice, and providing more targeted support for GPs on facilitating sessions with multiple levels of learner involved. CONCLUSIONS: A community-engaged vertically integrated teaching and learning model has the potential to increase participants' confidence to teach in small groups, and create a more positive perception of registrars and students teaching in general practice. The concept would benefit from further longitudinal research with a wider sample. PMID- 23676872 TI - Practice-based small group learning (PBSGL) for CPD: a pilot with general practice trainees to support the transition to independent practice. AB - The paper describes a small-scale enquiry with UK-based general practice specialty trainees (GPSTs) at the time of transition from training to independent practice. It aimed to identify whether they were supported in making this transition through attending practice-based small group learning (PBSGL) sessions. Participants in the study reported that the sessions helped them to consolidate their learning from their third year of training (GPST3), improved their ability to identify and use evidence in practice, and shifted the focus of their learning needs away from the two UK general practice postgraduate exams (applied Knowledge Test or aKT; and Clinical Skills assessment or CSa) and towards 'real world' practice. The two pilot groups have become established as means of peer support and continue to meet, with small changes in composition. The work has led to the wider roll out of PBSGL for newly qualified GPs across Wessex. PMID- 23676873 TI - Supporting educational supervisor development at the interface: evaluation of a pilot of PBSGL for faculty development. AB - Practice-based small group learning (PBSGL) is an established approach for continuing professional development (CPD) for GPs in Scotland. This paper describes an extension of the PBSGL approach to support the learning and development of educational supervisors from both hospital and general practice, working together in peer-facilitated small groups to address topic-specific, evidence-based educational modules. Four groups met on three occasions each and qualitative data were gathered from interviews with the facilitators and the participants. This was supplemented with observational data of the group process and function. Both GPs and consultants enjoyed the format and were very positive about the experience of working together in this way. Commitment to change educational practice and reported actual changes in practice were evident. PMID- 23676874 TI - GP tutor opinions on quality criteria generated for undergraduate education in primary care: a practice-based educational evaluation. AB - This study explores GP tutor views of a nationally derived list of quality criteria for undergraduate and postgraduate practice-based teaching. Whilst these published criteria provided a means of benchmarking locally, an evaluation of utility in practice required further exploration. This educational evaluation was conducted within a West Yorkshire locality as a means of supporting their practice-based primary care education. A survey approach using an online Likert scaled questionnaire was distributed to all GP tutors with an additional opportunity for free text qualitative comments. Data were analysed using an online reporting package for survey results (MarketSight) and thematic analysis of qualitative data. Key findings were that in general all the criteria were rated having a high level of importance with 83% of GPs claiming they would find such a list important in directing their learning and teaching approach. The opinions on out-of-hours experiences for medical students were also interesting as they differed greatly. These findings will be of interest to those involved in the organisation and delivery of medical education within primary care as the list of criteria could act as a structural guide for directing medical student teaching, learning and its quality assurance. Implications for further research include the utility of core criteria and the exploration of out-of-hours experience for medical student education. PMID- 23676875 TI - Medical student perspectives of what makes a high-quality teaching practice. AB - Primary care has seen increasing involvement in undergraduate medical education following recommendation from the GMC in Tomorrow's Doctors. This is also influenced by an increasing number of medical students and changing patterns of health care. The variety of practices involved in delivering undergraduate primary care placements poses a challenge for the quality of these placements. The variety of learners in primary care may also affect this. To reflect this, Cotton et al in 2009 produced a national consensus list of quality criteria for community-based education using a variety of medical education stakeholders. This paper seeks to explore the medical student perspective of what makes a high quality teaching practice. This study uses focus group interviewing to explore student perspectives of the range of factors that can contribute towards the quality of a primary care placement. Previous research into student perspectives of teaching in primary care has revealed a strong focus on tutor quality. Students in this study again highlighted the important of good GP tutors and organisation of placements. However, one novel finding was the emphasis that students placed on involving patients in teaching and the vital role that they play in this. PMID- 23676876 TI - Quality of report writing falls off during GPST training. PMID- 23676877 TI - A national primary care curriculum for medical students: Is this another quest for the Holy Grail? PMID- 23676878 TI - Consultation skills teaching in primary care. PMID- 23676879 TI - Interactive, interesting and inexpensive: using the three I(s) to bring the classroom to life. PMID- 23676880 TI - Exploring art with foundation doctors: reflecting on clinical experience. PMID- 23676881 TI - Not enough evidence' is a symptom not a conclusion: why trainees fail to engage with their e-portfolio. PMID- 23676882 TI - A sustainability scholarship programme in the Severn Deanery's school of primary care: a case study. PMID- 23676883 TI - Development of educational podcasts for GPs. PMID- 23676884 TI - Zm908p11, encoded by a short open reading frame (sORF) gene, functions in pollen tube growth as a profilin ligand in maize. AB - Double fertilization of flowering plants depends on the targeted transportation of sperm to the embryo sac by the pollen tube. Currently, little is known about the underlying molecular mechanisms that regulate pollen germination and pollen tube growth in maize (Zea mays). Here, a maize pollen-predominant gene Zm908, with several putative short open reading frames (sORFs), was isolated and characterized. The longest ORF of Zm908 encodes a small protein of 97 amino acids. This was designated as Zm908p11 and is distributed throughout the maize pollen tube. Western blot detected the small peptide in mature pollen. Quantitative reverse transcription-PCR and northern blot analysis revealed that Zm908p11 was expressed predominantly in mature pollen grains. Ectopic overexpression of full-length Zm908 and Zm908p11 in tobacco resulted in defective pollen, while transgenic tobacco plants with a site-specific mutation or a frameshift mutation of Zm908p11 showed normal pollen development. Overexpression of Zm908p11 in maize decreased pollen germination efficiency. Maize pollen cDNA library screening and protein-protein interaction assays demonstrated that Zm908p11 interacts with maize profilin 1 (ZmPRO1). A microarray analysis identified 273 up-regulated and 203 down-regulated genes in the overexpressing transgenic Zm908p11 pollen. Taken together, these results indicate that Zm908 functions as Zm908p11, and binds to profilins as a novel ligand, with a required role during pollen tube growth in maize. Accordingly, a model is proposed for the role of Zm908p11 during pollen tube growth in maize. PMID- 23676885 TI - Preeclampsia: are platelet count and indices useful for its prognostic? AB - INTRODUCTION: Preeclampsia (PE) is characterized by hypertension and proteinuria after the 20th week gestation. The aim of this study was to investigate whether platelet count (PC) and platelet indices (mean platelet volume (MPV), platelet distribution width (PDW), and plateletcrit (PCT)) could predict severe form of preeclampsia (sPE). METHODS: Three groups were evaluated; G1-pregnant with sPE (N = 29); G2-normotensive pregnant (N = 28) and Group 3: non-pregnant women (N = 30). Platelet parameters were obtained using the same automatic blood cells count. Statistical analysis was performed by analysis of variance, t-test, and receiver operating characteristic (ROC) curve. P <= 0.05 was considered significant. RESULTS: Lower PC and PCT were observed in sPE comparing to normal pregnant (P = 0.031 and 0.035, respectively) and to non-pregnant women (P < 0.001 and 0.004, respectively). PDW was higher in sPE comparing to normotensive pregnant (P = 0.028) and to non-pregnant women (P < 0.001). MPV was higher in sPE comparing to normotensive pregnant and non-pregnant women (P = 0.05 and P < 0.001, respectively). Analysis from the ROC curve and its areas for each variable showed that the parameters have regular diagnostic significance, except for PCT, considered as not good for this purpose. CONCLUSION: PC emerges as a good candidate for sPE diagnosis, since it is a simple and habitually done method, with lower cost and greater accessibility in the clinical laboratory. Further studies evaluating sequential PC and platelet indices throughout pregnancy are necessary to clarify the role of platelet parameters in PE development and severity. PMID- 23676886 TI - Anticoagulation management in the perioperative phase of implantable cardioverter defibrillator implantation. AB - BACKGROUND: According to the current guidelines, substitution of warfarin with heparin is recommended as perioperative management in patients with high risk of thromboembolism. Optimal management of oral anticoagulation in patients undergoing implantable cardioverter defibrillator (ICD) implantation, however, remains controversial. METHODS AND RESULTS: Bleeding complications among 273 consecutive patients undergoing initial ICD implantation were retrospectively analyzed. Patients were grouped according to medication at the time of device implantation: neither antiplatelet nor anticoagulation (N group, n=121); antiplatelet only (AP group, n=59); warfarin (W group, n=59); and heparin bridging (H group, n=34). The rate of the major bleeding complications, defined as hematoma requiring reoperation, cardiac tamponade, and pericardial effusion requiring additional hospital stay, was 1.7% in the N group, 0% in the AP group, 5.1% in the W group, and 17.6% in the H group (P<0.001, N group vs. H group). After multivariate adjustment, heparin bridging was a significant predictor of major bleeding complications (odds ratio, 7.44; 95% confidence interval: 2.06 26.89; P=0.0022). The international normalized ratio of 3 patients in the W group with major bleeding complications was 1.98 +/- 0.10, and was significantly higher than in patients without them (1.31 +/- 0.05, n=26, P<0.001). CONCLUSIONS: Heparin bridging increased the risk of bleeding complications at the time of ICD implantation. PMID- 23676887 TI - Do semi-rigid prosthetic rings affect left ventricular function after mitral valve repair? AB - BACKGROUND: After reports of cardiac impairment caused by mitral annuloplasty with rigid rings, several prosthetic rings with semi-rigidity were introduced. The influence of semi-rigid rings on postoperative cardiac function remains unknown. This study compared postoperative cardiac function between patients receiving a semi-rigid prosthetic ring and those receiving a flexible ring or band. METHODS AND RESULTS: Transthoracic echocardiographic data of 305 patients who underwent mitral valve repair for degenerative mitral regurgitation (227 patients receiving a semi-rigid ring and 78 receiving a flexible ring or band) were retrospectively reviewed. The imbalance in the preoperative characteristics between groups was adjusted with propensity score matching. Left ventricular ejection fraction, end-diastolic dimension, and end-systolic dimension were compared at 1 week, 6 months, and 1 year after surgery. Propensity score matching yielded 68 matched pairs of patients for whom there were few group differences in preoperative covariates. Between patients receiving a semi-rigid ring and those receiving a flexible ring or band in the propensity-matched cohorts, there were no significant differences in ejection fraction (P=0.322), end-diastolic dimension (P=0.576), or end-systolic dimension (P=0.567). CONCLUSIONS: There was little difference in the influence on postoperative cardiac function between semi rigid rings and flexible rings or bands. PMID- 23676888 TI - Comparison of febuxostat and allopurinol for hyperuricemia in cardiac surgery patients (NU-FLASH Trial). AB - BACKGROUND: Febuxostat has been reported to have a stronger effect on hyperuricemia than allopurinol. METHODS AND RESULTS: Cardiac surgery patients with hyperuricemia (n=141) were randomized to a febuxostat group or an allopurinol group. The study was single-blind, so the treatment was not known by the investigators. The primary endpoint was serum uric acid (UA) level. Secondary endpoints included serum creatinine, urinary albumin, cystatin-C, oxidized low density lipoprotein (LDL), eicosapentaenoic acid/arachidonic acid ratio, total cholesterol, triglycerides, LDL, high-density lipoprotein, high-sensitivity C reactive protein, blood pressure, heart rate, pulse wave velocity (PWV), ejection fraction, left ventricular mass index (LVMI), and adverse reactions. UA level was significantly lower in the febuxostat group than the allopurinol group from 1 month of treatment onward. Serum creatinine, urinary albumin, cystatin-C and oxidized LDL were also significantly lower in the febuxostat group. There were no significant changes in systolic blood pressure, PWV, and LVMI in the allopurinol group, but these parameters all had a significant decrease in the febuxostat group. CONCLUSIONS: Febuxostat was effective for high-risk cardiac surgery patients with hyperuricemia because it reduced UA more markedly than allopurinol. Febuxostat also had a renoprotective effect, inhibited oxidative stress, showed anti-atherogenic activity, reduced blood pressure, and decreased PWV and LVMI. PMID- 23676889 TI - Does vaginal delivery affect postnatal coitus? AB - The concern that vaginal birth will result in loose vagina and negatively affect their postnatal sexual life is one of the main reasons that many women choose cesarean section. Here we aimed to implement a new device to measure and compare the intra-vaginal pressures between women who gave vaginal birth and those who had cesarean section, and to evaluate the relationship between sexual function and type of delivery by Female Sexual Function Index (FSFI). A total of 165 women including 88 in the vaginal-delivery group and 77 in the cesarean-delivery group were recruited in the study. Significant differences in intra-vaginal pressures were found between the two groups, and intra-vaginal pressures of vaginal delivery group were lower than those of cesarean-delivery group. Significant difference was also found in coitus time. However, no significant difference was found regarding sexual satisfaction and sexual function indicated by the FSFI. We concluded that vaginal delivery indeed may result in loose vagina compared with cesarean delivery. However, it did not negatively affect the postnatal sexual function. Therefore, women should be assured that their sexual functions won't be affected by the types of delivery. PMID- 23676890 TI - Incorporation of the factor IX Padua mutation into FIX-Triple improves clotting activity in vitro and in vivo. AB - Using gain-of-function factor IX (FIX) for replacement therapy for haemophilia B (HB) is an attractive strategy. We previously reported a high-activity FIX, FIX Triple (FIX-V86A/E277A/R338A) as a good substitute for FIX-WT (wild-type) in protein replacement therapy, gene therapy, and cell therapy. Here we generated a new recombinant FIX-TripleL (FIX-V86A/E277A/R338L) by replacing the alanine at residue 338 of FIX-Triple with leucine as in FIX-Padua (FIX-R338L). Purified FIX TripleL exhibited 22-fold higher specific clotting activity and 15-fold increased binding affinity to activated FVIII compared to FIX-WT. FIX-TripleL increased the therapeutic potential of FIX-Triple by nearly 100% as demonstrated with calibrated automated thrombogram and thromboelastography. FIX-TripleL demonstrated a normal clearance rate in HB mice. The clotting activity of FIX TripleL was consistently 2- to 3-fold higher in these mice than that of FIX Triple or FIX-R338L. Gene delivery of adeno-associated virus (AAV) in HB mice showed that FIX-TripleL had 15-fold higher specific clotting activity than FIX WT, and this activity was significantly better than FIX-Triple (10-fold) or FIX R338L (6-fold). At a lower viral dose, FIX-TripleL improved FIX activity from sub therapeutic to therapeutic levels. Under physiological conditions, no signs of adverse thrombotic events were observed in long-term AAV-FIX-treated C57Bl/6 mice. Hepatocellular adenomas were observed in the high- but not the medium- or the low-dose AAV-treated mice expressing FIX-WT or FIX-Triple, indicating the advantages of using hyperfunctional FIX variants to reduce viral doses while maintaining therapeutic clotting activity. Thus, incorporation of the FIX Padua mutation significantly improves the clotting function of FIX-Triple so as to optimise protein replacement therapy and gene therapy. PMID- 23676891 TI - Hetero-oligonucleotide nanoscale tiles capable of two-dimensional lattice formation as testbeds for a rapid, affordable purification methodology. AB - New nanoscale hetero-oligonucleotide tiles are assembled from DNA, RNA and morpholino oligos and purified using size exclusion filtration. Homo oligonucleotide tiles assembled from RP-cartridge processed DNA oligos are purified by nondenaturing gel electrophoresis. These tiles' purity and homogeneity are demonstrated by gel electrophoresis and their incorporation into two-dimensional arrays visualized by AFM. This purification methodology increases throughput and decreases costs for researchers who wish to screen multiple tiles for utilization in structural or analytical studies. PMID- 23676892 TI - Effects of the infectious period distribution on predicted transitions in childhood disease dynamics. AB - The population dynamics of infectious diseases occasionally undergo rapid qualitative changes, such as transitions from annual to biennial cycles or to irregular dynamics. Previous work, based on the standard seasonally forced 'susceptible-exposed-infectious-removed' (SEIR) model has found that transitions in the dynamics of many childhood diseases result from bifurcations induced by slow changes in birth and vaccination rates. However, the standard SEIR formulation assumes that the stage durations (latent and infectious periods) are exponentially distributed, whereas real distributions are narrower and centred around the mean. Much recent work has indicated that realistically distributed stage durations strongly affect the dynamical structure of seasonally forced epidemic models. We investigate whether inferences drawn from previous analyses of transitions in patterns of measles dynamics are robust to the shapes of the stage duration distributions. As an illustrative example, we analyse measles dynamics in New York City from 1928 to 1972. We find that with a fixed mean infectious period in the susceptible-infectious-removed (SIR) model, the dynamical structure and predicted transitions vary substantially as a function of the shape of the infectious period distribution. By contrast, with fixed mean latent and infectious periods in the SEIR model, the shapes of the stage duration distributions have a less dramatic effect on model dynamical structure and predicted transitions. All these results can be understood more easily by considering the distribution of the disease generation time as opposed to the distributions of individual disease stages. Numerical bifurcation analysis reveals that for a given mean generation time the dynamics of the SIR and SEIR models for measles are nearly equivalent and are insensitive to the shapes of the disease stage distributions. PMID- 23676893 TI - Computational fluid dynamic simulations of image-based stented coronary bifurcation models. AB - One of the relevant phenomenon associated with in-stent restenosis in coronary arteries is an altered haemodynamics in the stented region. Computational fluid dynamics (CFD) offers the possibility to investigate the haemodynamics at a level of detail not always accessible within experimental techniques. CFD can quantify and correlate the local haemodynamics structures which might lead to in-stent restenosis. The aim of this work is to study the fluid dynamics of realistic stented coronary artery models which replicate the complete clinical procedure of stent implantation. Two cases of pathologic left anterior descending coronary arteries with their bifurcations are reconstructed from computed tomography angiography and conventional coronary angiography images. Results of wall shear stress and relative residence time show that the wall regions more prone to the risk of restenosis are located next to stent struts, to the bifurcations and to the stent overlapping zone for both investigated cases. Considering a bulk flow analysis, helical flow structures are generated by the curvature of the zone upstream from the stent and by the bifurcation regions. Helical recirculating microstructures are also visible downstream from the stent struts. This study demonstrates the feasibility to virtually investigate the haemodynamics of patient-specific coronary bifurcation geometries. PMID- 23676894 TI - Directed evolution of bacteriorhodopsin for applications in bioelectronics. AB - In nature, biological systems gradually evolve through complex, algorithmic processes involving mutation and differential selection. Evolution has optimized biological macromolecules for a variety of functions to provide a comparative advantage. However, nature does not optimize molecules for use in human-made devices, as it would gain no survival advantage in such cooperation. Recent advancements in genetic engineering, most notably directed evolution, have allowed for the stepwise manipulation of the properties of living organisms, promoting the expansion of protein-based devices in nanotechnology. In this review, we highlight the use of directed evolution to optimize photoactive proteins, with an emphasis on bacteriorhodopsin (BR), for device applications. BR, a highly stable light-activated proton pump, has shown great promise in three dimensional optical memories, real-time holographic processors and artificial retinas. PMID- 23676896 TI - Joint kinematics and kinetics of overground accelerated running versus running on an accelerated treadmill. AB - Literature shows that running on an accelerated motorized treadmill is mechanically different from accelerated running overground. Overground, the subject has to enlarge the net anterior-posterior force impulse proportional to acceleration in order to overcome linear whole body inertia, whereas on a treadmill, this force impulse remains zero, regardless of belt acceleration. Therefore, it can be expected that changes in kinematics and joint kinetics of the human body also are proportional to acceleration overground, whereas no changes according to belt acceleration are expected on a treadmill. This study documents kinematics and joint kinetics of accelerated running overground and running on an accelerated motorized treadmill belt for 10 young healthy subjects. When accelerating overground, ground reaction forces are characterized by less braking and more propulsion, generating a more forward-oriented ground reaction force vector and a more forwardly inclined body compared with steady-state running. This change in body orientation as such is partly responsible for the changed force direction. Besides this, more pronounced hip and knee flexion at initial contact, a larger hip extension velocity, smaller knee flexion velocity and smaller initial plantarflexion velocity are associated with less braking. A larger knee extension and plantarflexion velocity result in larger propulsion. Altogether, during stance, joint moments are not significantly influenced by acceleration overground. Therefore, we suggest that the overall behaviour of the musculoskeletal system (in terms of kinematics and joint moments) during acceleration at a certain speed remains essentially identical to steady-state running at the same speed, yet acting in a different orientation. However, because acceleration implies extra mechanical work to increase the running speed, muscular effort done (in terms of power output) must be larger. This is confirmed by larger joint power generation at the level of the hip and lower power absorption at the knee as the result of subtle differences in joint velocity. On a treadmill, ground reaction forces are not influenced by acceleration and, compared with overground, virtually no kinesiological adaptations to an accelerating belt are observed. Consequently, adaptations to acceleration during running differ from treadmill to overground and should be studied in the condition of interest. PMID- 23676895 TI - Genetic redundancy strengthens the circadian clock leading to a narrow entrainment range. AB - Circadian clocks are internal timekeepers present in almost all organisms. Driven by a genetic network of highly conserved structure, they generate self-sustained oscillations that entrain to periodic external signals such as the 24 h light dark cycle. Vertebrates possess multiple, functionally overlapping homologues of the core clock genes. Furthermore, vertebrate clocks entrain to a range of periods three times as narrow as that of other organisms. We asked whether genetic redundancies play a role in governing entrainment properties and analysed locomotor activity rhythms of genetically modified mice lacking one set of clock homologues. Exposing them to non-24 h light-dark cycles, we found that the mutant mice have a wider entrainment range than the wild types. Spectral analysis furthermore revealed nonlinear phenomena of periodically forced self-sustained oscillators for which the entrainment range relates inversely to oscillator amplitude. Using the forced oscillator model to explain the observed differences in entrainment range between mutant and wild-type mice, we sought to quantify the overall oscillator amplitude of their clocks from the activity rhythms and found that mutant mice have weaker circadian clocks than wild types. Our results suggest that genetic redundancy strengthens the circadian clock leading to a narrow entrainment range in vertebrates. PMID- 23676897 TI - Built for rowing: frog muscle is tuned to limb morphology to power swimming. AB - Rowing is demanding, in part, because drag on the oars increases as the square of their speed. Hence, as muscles shorten faster, their force capacity falls, whereas drag rises. How do frogs resolve this dilemma to swim rapidly? We predicted that shortening velocity cannot exceed a terminal velocity where muscle and fluid torques balance. This terminal velocity, which is below Vmax, depends on gear ratio (GR = outlever/inlever) and webbed foot area. Perhaps such properties of swimmers are 'tuned', enabling shortening speeds of approximately 0.3Vmax for maximal power. Predictions were tested using a 'musculo-robotic' Xenopus laevis foot driven either by a living in vitro or computational in silico plantaris longus muscle. Experiments verified predictions. Our principle finding is that GR ranges from 11.5 to 20 near the predicted optimum for rowing (GR ~ 11). However, gearing influences muscle power more strongly than foot area. No single morphology is optimal for producing muscle power. Rather, the 'optimal' GR decreases with foot size, implying that rowing ability need not compromise jumping (and vice versa). Thus, despite our neglect of additional forces (e.g. added mass), our model predicts pairings of physiological and morphological properties to confer effective rowing. Beyond frogs, the model may apply across a range of size and complexity from aquatic insects to human-powered rowing. PMID- 23676898 TI - Relevance for food sciences of quantitative spatially resolved element profile investigations in wheat (Triticum aestivum) grain. AB - Bulk element concentrations of whole grain and element spatial distributions at the tissue level were investigated in wheat (Triticum aestivum) grain grown in Zn enriched soil. Inductively coupled plasma mass spectrometry and inductively coupled plasma optical emission spectrometry were used for bulk analysis, whereas micro-proton-induced X-ray emission was used to resolve the two-dimensional localization of the elements. Soil Zn application did not significantly affect the grain yield, but did significantly increase the grain Ca, Fe and Zn concentrations, and decrease the grain Na, P and Mo concentrations; bulk Mg, S, K, Mn, Cu, Cd and Pb concentrations remained unchanged. These changes observed in bulk element concentrations are the reflection of tissue-specific variations within the grain, revealing that Zn application to soil can lead to considerable alterations in the element distributions within the grain, which might ultimately influence the quality of the milling fractions. Spatially resolved investigations into the partitioning of the element concentrations identified the tissues with the highest element concentrations, which is of utmost importance for accurate prediction of element losses during the grain milling and polishing processes. PMID- 23676899 TI - Modelling seasonal influenza: the role of weather and punctuated antigenic drift. AB - Seasonal influenza appears as annual oscillations in temperate regions of the world, yet little is known as to what drives these annual outbreaks and what factors are responsible for their inter-annual variability. Recent studies suggest that weather variables, such as absolute humidity, are the key drivers of annual influenza outbreaks. The rapid, punctuated, antigenic evolution of the influenza virus is another major factor. We present a new framework for modelling seasonal influenza based on a discrete-time, age-of-infection, epidemic model, which allows the calculation of the model's likelihood function in closed form. This framework may be used to perform model inference and parameter estimation rigorously. The modelling approach allows us to fit 11 years of Israeli influenza data, with the best models fitting the data with unusually high correlations in which r > 0.9. We show that using actual weather to modulate influenza transmission rate gives better results than using the inter-annual means of the weather variables, providing strong support for the role of weather in shaping the dynamics of influenza. This conclusion remains valid even when incorporating a more realistic depiction of the decay of immunity at the population level, which allows for discrete changes in immunity from year to year. PMID- 23676900 TI - Metamorphosis revealed: time-lapse three-dimensional imaging inside a living chrysalis. AB - Studies of model insects have greatly increased our understanding of animal development. Yet, they are limited in scope to this small pool of model species: a small number of representatives for a hyperdiverse group with highly varied developmental processes. One factor behind this narrow scope is the challenging nature of traditional methods of study, such as histology and dissection, which can preclude quantitative analysis and do not allow the development of a single individual to be followed. Here, we use high-resolution X-ray computed tomography (CT) to overcome these issues, and three-dimensionally image numerous lepidopteran pupae throughout their development. The resulting models are presented in the electronic supplementary material, as are figures and videos, documenting a single individual throughout development. They provide new insight and details of lepidopteran metamorphosis, and allow the measurement of tracheal and gut volume. Furthermore, this study demonstrates early and rapid development of the tracheae, which become visible in scans just 12 h after pupation. This suggests that there is less remodelling of the tracheal system than previously expected, and is methodologically important because the tracheal system is an often-understudied character system in development. In the future, this form of time-lapse CT-scanning could allow faster and more detailed developmental studies on a wider range of taxa than is presently possible. PMID- 23676901 TI - Event-related desynchronization and synchronization quantification in motor related EEG by Kolmogorov entropy. AB - OBJECTIVE: Various approaches have been applied for the quantification of event related desynchronization/synchronization (ERD/ERS) in EEG/MEG data analysis, but most of them are based on band power analysis. In this paper, we sought a novel method using a nonlinear measurement to quantify the ERD/ERS time course of motor related EEG. APPROACH: We applied Kolmogorov entropy to quantify the ERD/ERS time course of motor-related EEG in relation to hand movement imagination and execution for the first time. To further test the validity of the Kolmogorov entropy measure, we tested it on five human subjects for feature extraction to classify the left and right hand motor tasks. MAIN RESULTS: The results show that the relative increase and decrease of Kolmogorov entropy indicates the ERD and ERS respectively. An average classification accuracy of 87.3% was obtained for five subjects. SIGNIFICANCE: The results prove that Kolmogorov entropy can effectively quantify the dynamic process of event-related EEG, and it also provides a novel method of classifying motor imagery tasks from scalp EEG by Kolmogorov entropy measurement with promising classification accuracy. PMID- 23676902 TI - Ln[N(SiMe3)2]3-catalyzed cycloaddition of terminal alkynes to azides leading to 1,5-disubstituted 1,2,3-triazoles: new mechanistic features. AB - The first example of rare earth metal-catalyzed cycloaddition of terminal alkynes to azides resulting in the formation of 1,5-disubstituted 1,2,3-triazoles is described. Preliminary studies revealed that the present cycloaddition shows unprecedented mechanistic features involving a tandem anionic cascade cyclization and anti-addition across the C=C triple bond. PMID- 23676903 TI - Fabrication of poly(gamma-glutamic acid) monolith by thermally induced phase separation and its application. AB - Monoliths are functional porous materials with a three-dimensional continuous interconnected pore structure in a single piece. A monolith with uniform shape based on poly(gamma-glutamic acid) (PGA) has been prepared via a thermally induced phase separation technique using a mixture of dimethyl sulfoxide, water, and ethanol as solvent. The morphology of the obtained monolith was observed by scanning electron microscopy and the surface area of the monolith was evaluated by the Brunauer Emmett Teller method. The effects of fabrication parameters such as the concentration and molecular mass of PGA and the solvent composition have been systematically investigated. The PGA monolith was cross-linked with hexamethylene diisocyanate to produce the water-insoluble monolith. The addition of sodium chloride to the phase separation solvent affected the properties of the cross-linked monolith. The swelling ratio of the cross-linked monolith toward aqueous solutions depended on the buffer pH as well as the monolith fabrication condition. Copper(II) ion was efficiently adsorbed on the cross-linked PGA monolith, and the obtained copper-immobilized monolith showed strong antibacterial activity for Escherichia coli. By combination of the characteristic properties of PGA (e.g., high biocompatibility and biodegradability) and the unique features of monoliths (e.g., through-pore structure, large surface area, and high porosity with small pore size), the PGA monolith possesses large potentials for various industrial applications in the biomedical, environmental, analytical, and separation fields. PMID- 23676904 TI - Engineering the cellular protein secretory pathway for enhancement of recombinant tissue plasminogen activator expression in Chinese hamster ovary cells: effects of CERT and XBP1s genes. AB - Cell line development is the most critical and also the most time-consuming step in the production of recombinant therapeutic proteins. In this regard, a variety of vector and cell engineering strategies have been developed for generating high producing mammalian cells; however, the cell line engineering approach seems to show various results on different recombinant protein producer cells. In order to improve the secretory capacity of a recombinant tissue plasminogen activator (t PA)-producing Chinese hamster ovary (CHO) cell line, we developed cell line engineering approaches based on the ceramide transfer protein (CERT) and X-box binding protein 1 (XBP1) genes. For this purpose, CERT S132A, a mutant form of CERT that is resistant to phosphorylation, and XBP1s were overexpressed in a recombinant t-PA-producing CHO cell line. Overexpression of CERT S132A increased the specific productivity of t-PA-producing CHO cells up to 35%. In contrast, the heterologous expression of XBP1s did not affect the t-PA expression rate. Our results suggest that CERTS132A- based secretion engineering could be an effective strategy for enhancing recombinant t- PA production in CHO cells. PMID- 23676905 TI - Statistical optimization of medium components for milk-clotting enzyme production by Bacillus amyloliquefaciens D4 using wheat Bran-an agro-industry waste. AB - In this paper, two statistical methods were applied to optimize medium components to improve the production of the milk-clotting enzyme by Bacillus amyloliquefaciens D4. First, wheat bran juice, skim milk powder, and Na2HPO4 were shown to have significant effects on D4 enzyme production using the Plackett Burman experimental design. Subsequently, an optimal medium was obtained using the Box-Behnken method, which consisted of 3.31 g/l of skim milk powder, 5.0 g/l of sucrose, 0.1 g/l of FeSO4.7H2O, 0.1 g/l of MgSO4.7H2O, 0.1 g/l of MnSO4.2H2O, 0.1 g/l of ZnSO4.7H2O, 1.52 g/l of Na2HPO4, and 172.45 g/l of wheat bran juice. With this optimal medium, the milk-clotting enzyme production was remarkably enhanced. The milk-clotting enzyme activity reached 3,326.7 SU/ml after incubation of 48 h, which was 1.76-fold higher than that of the basic medium, showing that the Plackett-Burman design and Box-Behnken response surface method are effective to optimize medium components, and B. amyloliquefaciens D4 possessed a high rennet-producing capacity in the optimal medium. PMID- 23676906 TI - Isolation and characterization of a cryptic plasmid, pMBLR00, from Leuconostoc mesenteroides subsp. mesenteroides KCTC 3733. AB - A cryptic plasmid, pMBLR00, from Leuconostoc mesenteroides subsp. mesenteroides KCTC 3733 was isolated, characterized, and used for the construction of a cloning vector to engineer Leuconostoc species. pMBLR00 is a rolling circle replication plasmid, containing 3,370 base pairs. Sequence analysis revealed that pMBLR00 has 3 open reading frames: Cop (copy number control protein), Rep (replication protein), and Mob (mobilization protein). pMBLR00 replicates by rolling circle replication, which was confirmed by the presence of a conserved double-stranded origin and single-stranded DNA intermediates. An Escherichia coli-Leuconostoc shuttle vector, pMBLR02, was constructed and was able to replicate in Leuconostoc citreum 95. pMBLR02 could be a useful genetic tool for metabolic engineering and the genetic study of Leuconostoc species. PMID- 23676907 TI - Purification and characterization of an alkaliphilic alginate lyase AlgMytC from Saccharophagus sp. Myt-1. AB - In a previous study, we isolated and reported a second species of the Saccharophagus genus, Saccharophagus sp. strain Myt-1. In the present study, an alginate lyase gene (algMytC) from the genomic DNA of Myt-1 was cloned and characterized. The DNA sequence fragment obtained contained an open reading frame of 1,032 bp that encoded a protein of 343 amino acids with an estimated molecular mass of 37.6 kDa and a pI of 6.60. The deduced protein, AlgMytC, had the conserved amino acid sequences (RTELREM, QIH, YFKAGVYNQ) of the polysaccharide lyase family 7. A BLAST homology search indicated that AlgMytC shared an amino acid sequence identity of 95.9% with alg7A of S. degradans 2-40. The cloned and purified AlgMytC protein showed optimal activity at 40 degrees C, and retained more than 90% of its total activity even after treatment at 25 degrees C for 24 h. AlgMytC was very alkaliphilic with an optimal pH of 9.0, and more than 90% of its activity was retained in the pH range 8.5-10.0. Moreover, AlgMytC was stable over a wide pH range. The activity of AlgMytC was also stable in the presence of various detergents. PMID- 23676908 TI - The developmental regulators, FlbB and FlbE, are involved in the virulence of Aspergillus fumigatus. AB - Several upstream activators required for proper activation of brlA are involved in the development, vegetative growth, toxin production, and pathogenesis of Aspergillus fumigatus. In this study, we characterized the roles of two upstream developmental regulators, A. fumigatus flbB (AfuflbB) and flbE (AfuflbE), in toxin production and virulence. The deletion of AfuflbB and AfuflbE resulted in reduction of the expression of AfulaeA. Moreover, only about 8% to 10% of fumagillin was produced in the two mutants compared with that of wild type, and DeltaAfuflbB strain produced 85% of gliotoxin compared with wild type, whereas none was produced by DeltaAfuflbE. Flow-cytometric analysis revealed decreased necrotic and apoptotic polymorphonuclear leukocytes cell death after exposure to supernatants from DeltaAfuflbB and DeltaAfuflbE strains compared with the wild type. These results indicate that FlbB and FlbE are necessary for the proper laeA expression, toxin production, and virulence of A. fumigatus. PMID- 23676909 TI - Production of a recombinant laccase from Pichia pastoris and biodegradation of chlorpyrifos in a laccase/vanillin system. AB - The recombinant strain P. pastoris GS115-lccC was used to produce laccase with high activity. Factors influencing laccase expression, such as pH, methanol concentration, copper concentration, peptone concentration, shaker rotate speed, and medium volume were investigated. Under the optimal conditions, laccase activity reached 12,344 U/L on day 15. The recombinant enzyme was purified by precipitating and dialyzing to electrophoretic homogeneity, and was estimated to have a molecular mass of about 58 kDa. When guaiacol was the substrate, the laccase showed the highest activity at pH 5.0 and was stable when the pH was 4.5~6.0. The optimal temperature for the laccase to oxidize guaiacol was 60 degrees C, but it was not stable at high temperature. The enzyme could remain stable at 30 degrees C for 5 days. The recombinant laccase was used to degrade chlorpyrifos in several laccase/mediator systems. Among three synthetic mediators (ABTS, HBT, VA) and three natural mediators (vanillin, 2,6-DMP, and guaiacol), vanillin showed the most enhancement on degradation of chlorpyrifos. Both laccase and vanillin were responsible for the degradation of chlorpyrifos. A higher dosage of vanillin may promote a higher level of degradation of chlorpyrifos, and the 2-step addition of vanillin led to 98% chlorpyrifos degradation. The degradation of chlorpyrifos was faster in the L/V system (kobs = 0.151) than that in the buffer solution (kobs = 0.028). PMID- 23676911 TI - In vitro selection of RNA aptamer specific to Salmonella typhimurium. AB - Salmonella is a major foodborne pathogen that causes a variety of human diseases. Development of ligands directly and specifically binding to the Salmonella will be crucial for the rapid detection of, and thus for efficient protection from, the virulent bacteria. In this study, we identified a RNA aptamer-based ligand that can specifically recognize Salmonella Typhimurium through SELEX technology. To this end, we isolated and characterized an RNase-resistant RNA aptamer that bound to the OmpC protein of Salmonella Typhimurium with high specificity and affinity (Kd ~ 20 nM). Of note, the selected aptamer was found to specifically bind to Salmonella Typhimurium, but neither to Gram-positive bacteria (Staphylococcus aureus) nor to other Gram-negative bacteria (Escherichia coli O157:H7). This was evinced by aptamer-immobilized ELISA and aptamer-linked precipitation experiments. This Salmonella species-specific aptamer could be useful as a diagnostic ligand against pathogen-caused foodborne sickness. PMID- 23676910 TI - Functional characterization of the alpha- and beta-subunits of a group II chaperonin from Aeropyrum pernix K1. AB - We isolated and functionally characterized the alpha- and beta- subunits (ApCpnA and ApCpnB) of a chaperonin from Aeropyrum pernix K1. The constructed vectors pET3d- ApCpnA and pET21a-ApCpnB were transformed into E. coli Rosetta (DE3), BL21 (DE3), or CodonPlus (DE3) cells. The expression of ApCpnA (60.7 kDa) and ApCpnB (61.2 kDa) was confirmed by SDS-PAGE analysis. Recombinant ApCpnA and ApCpnB were purified by heat-shock treatment and anion-exchange chromatography. ApCpnA and ApCpnB were able to hydrolyze not only ATP, but also CTP, GTP, and UTP, albeit with different efficacies. Purified ApCpnA and ApCpnB showed the highest ATPase, CTPase, UTPase, and GTPase activities at 80 degrees C. Furthermore, the addition of ApCpnA and ApCpnB effectively protected citrate synthase (CS) and alcohol dehydrogenase (ADH) from thermal aggregation and inactivation at 43 degrees C and 50 degrees C, respectively. In particular, the addition of ATP or CTP to ApCpnA and ApCpnB resulted in the most effective prevention of thermal aggregation and inactivation of CS and ADH. The ATPase activity of the two chaperonin subunits was dependent on the salt concentration. Among the ions we examined, potassium ions were the most effective at enhancing the ATP hydrolysis activity of ApCpnA and ApCpnB. PMID- 23676912 TI - Characterization of a squalene synthase from the thraustochytrid microalga Aurantiochytrium sp. KRS101. AB - The gene encoding squalene synthase (SQS) of the lipidproducing heterotrophic microalga Aurantiochytrium sp. KRS101 was cloned and characterized. The krsSQS gene is 1,551 bp in length and has two exons and one intron. The open reading frame of the gene is 1,164 bp in length, yielding a polypeptide of 387 predicted amino acid residues with a molecular mass of 42.7 kDa. The deduced krsSQS sequence shares at least four conserved regions known to be required for SQS enzymatic activity in other species. The protein, tagged with His6, was expressed into soluble form in Escherichia coli. The purified protein catalyzed the conversion of farnesyl diphosphate to squalene in the presence of NADPH and Mg(2+). This is the first report on the characterization of an SQS from a Thraustochytrid microalga. PMID- 23676913 TI - Decolorization of dyehouse effluent and biodegradation of Congo red by Bacillus thuringiensis RUN1. AB - A dye-decolorizing bacterium was isolated from a soil sample and identified as Bacillus thuringiensis using 16S rRNA sequencing. The bacterium was able to decolorize three different textile dyes, namely, Reactive blue 13, Reactive red 58, and Reactive yellow 42, and a real dyehouse effluent up to 80-95% within 6 h. Some non-textile industrially important dyes were also decolorized to different extents. Fourier transform infrared spectroscopy and gas chromatography-mass spectrometer analysis of the ethyl acetate extract of Congo red dye and its metabolites showed that the bacterium could degrade it by the asymmetric cleavage of the azo bonds to yield sodium (4- amino-3-diazenylnaphthalene-1-sulfonate) and phenylbenzene. Sodium (4-amino-3-diazenylnaphthalene-1-sulfonate) was further oxidized by the ortho-cleavage pathway to yield 2- (1-amino-2-diazenyl-2 formylvinyl) benzoic acid. There was induction of the activities of laccase and azoreductase during the decolorization of Congo red, which suggests their probable role in the biodegradation. B. thuringiensis was found to be versatile and could be used for industrial effluent biodegradation. PMID- 23676914 TI - Enhancement of supercritical CO2 inactivation of spores of Penicillium oxalicum by ethanol cosolvent. AB - The inactivation of spores of Penicillium oxalicum by supercritical carbon dioxide (SC-CO2) was optimized by response surface methodology. The optimal inactivation conditions of 16.8 MPa, 49 degrees C, and 20 min were determined using ridge analysis, at which the predicted and experimental log10 reductions were obtained as 5.74 and 6.12, respectively. The synergistic effect of a cosolvent (ethanol), which was used to modify SC-CO2, on the inactivation of the fungal spores was investigated. At less severe conditions of 10 MPa and 40 degrees C, P. oxalicum spores of 10(7) CFU/ml were completely inactivated within 45 min by SC-CO2 modified with ethanol. PMID- 23676915 TI - High-molecular-weight poly-gamma-glutamate protects against hypertriglyceridemic effects of a high-fructose diet in rat. AB - We studied the effects of 2 different dosages of highmolecular- weight poly-gamma glutamic acid (hm gamma-PGA) derived from Bacillus subtilis chungkookjang on lipid metabolism in a high-fructose diet-induced hypertriglyceridemic animal model. For 4 weeks, rats were fed either AIN-93 diet (normal control, NC; n = 10) or modified AIN-93 diet in which cornstarch was substituted with 63% fructose (n = 30) to induce hypertriglyceridemia. After 4 weeks, the hypertriglyceridemic rats were treated with daily oral doses of 0 mg (hypertriglyceridemic control, HC), 2.5 mg (hypertriglyceridemic, low hm gamma-PGA, HL), or 5 mg.kg.bw(-1).d(-1) (hypertriglyceridemic, high hm gamma-PGA, HH) hm gamma-PGA for 4 weeks. The HL and HH groups exhibited significantly lower levels of serum triglyceride, total cholesterol, LDL cholesterol, and free fatty acids than the HC group. The administration of hm gamma-PGA reduced serum ALT and AST levels. The activities of lipogenic enzymes such as hepatic malic enzyme and glucose-6-phosphate dehydrogenase as well as glucose-6-phosphate dehydrogenase mRNA expression were significantly decreased by hm gamma-PGA administration (p < 0.05). These results indicate that hm gamma- PGA has an anti-hypertriglyceridemic effect in highfructose diet-induced hypertriglyceridemic rats. PMID- 23676916 TI - Submerged culture conditions for the production of alternative natural colorants by a new isolated Penicillium purpurogenum DPUA 1275. AB - This work aims at investigating the production of yellow, orange, and red natural colorants in a submerged culture of Penicillium purpurogenum DPUA 1275. For this purpose, different experimental conditions evaluating the effect of incubation time, type and size of inoculum, and different carbon and nitrogen sources were performed. Furthermore, the growth kinetics were obtained in the conditions of 10(8) spores/ml and 5 mycelia agar discs during 360 h. These experiments showed that 5 mycelia agar discs and 336 h promoted the highest yellow (3.08 UA400nm), orange (1.44 UA470nm), and red (2.27 UA490nm) colorants production. Moreover, sucrose and yeast extract were the most suitable carbon and nitrogen sources for natural colorants production. Thus, the present study shows a new source of natural colorants, which can be used as an alternative to others available in the market after toxicological studies. PMID- 23676917 TI - Production of chlorphenesin galactoside by whole cells of beta-galactosidase containing Escherichia coli. AB - We investigated the transgalactosylation reaction of chlorphenesin (CPN) using beta-galactosidase (beta-gal)-containing Escherichia coli (E. coli) cells, in which galactose from lactose was transferred to CPN. The optimal CPN concentration for CPN galactoside (CPN-G) synthesis was observed at 40 mM under the conditions that lactose and beta-gal (as E. coli cells) were 400 g/l and 4.8 U/ml, respectively, and the pH and temperature were 7.0 and 40oC, respectively. The time-course profile of CPN-G synthesis under these optimal conditions showed that CPN-G synthesis from 40 mM CPN reached a maximum of about 27 mM at 12 h. This value corresponded to an about 67% conversion of CPN to CPN-G, which was 4.47-5.36-fold higher than values in previous reports. In addition, we demonstrated by thin-layer chromatography to detect the sugar moiety that galactose was mainly transferred from lactose to CPN. Liquid chromatography-mass spectrometry revealed that CPN-G and CPN-GG (CPN galactoside, which accepted two galactose molecules) were definitively identified as the synthesized products using beta-gal-containing E. coli cells. In particular, because we did not use purified beta-gal, our beta-gal-containing E. coli cells might be practical and cost-effective for enzymatically synthesizing CPN-G. It is expected that the use of beta-gal-containing E. coli will be extended to galactose derivatization of other drugs to improve their functionality. PMID- 23676918 TI - Production and characterization of ethanol- and protease-tolerant and xylooligosaccharides-producing endoxylanase from Humicola sp. Ly01. AB - This paper reports the production and characterization of crude xylanase from the newly isolated Humicola sp. Ly01. The highest (41.8 U/ml) production of the crude xylanase was obtained under the optimized conditions (w/v): 0.5% wheat bran, 0.2% KH2PO4, and 0.5% peptone; initial pH 7.0; incubation time 72 h; 30 degrees C; and 150 rpm. A considerable amount of the crude xylanase was induced using hulless barley bran or soybean meal as the carbon source, but a small amount of the enzyme was produced when supplementary urea was used as the nitrogen source to wheat bran. The crude xylanase showed apparent optimal cellulase-free xylanase activity at 60 degrees C and pH 6.0, more than 71.8% of the maximum xylanase activity in 3.0-30.0% (v/v) ethanol and more than 82.3% of the initial xylanase activity after incubation in 3.0-30.0% (v/v) ethanol at 30 degrees C for 2 h. The crude xylanase was moderately resistant to both acid and neutral protease digestion, and released 7.9 and 10.9 MUmol/ml reducing sugar from xylan in the simulated gastric and intestinal fluids, respectively. The xylooligosaccharides were the main products of the hydrolysis of xylan by the crude xylanase. These properties suggested the potential of the crude enzyme for being applied in the animal feed industry, xylooligosaccharides production, and high-alcohol conditions such as ethanol production and brewing. PMID- 23676919 TI - In vitro and in vivo anti-tobacco mosaic virus activities of essential oils and individual compounds. AB - Essential oils are increasingly of interest for use as novel drugs acting as antimicrobial and antiviral agents. In the present study, we report the in vitro antiviral activities of 29 essential oils, extracted from Chinese indigenous aromatic plants, against the tobacco mosaic virus (TMV). Of these essential oils, those oils from ginger, lemon, tea tree, tangerine peel, artemisia, and lemongrass effected a more than 50% inhibition of TMV at 100 MUg/ml. In addition, the mode of antiviral action of the active essential oils was also determined. Essential oils isolated from artemisia and lemongrass possessed potent inactivation and curative effects in vivo and had a directly passivating effect on TMV infection in a dose-dependent manner. However, all other active essential oils exhibited a moderate protective effect in vivo. The chemical constitutions of the essential oils from ginger, lemon, tea tree, tangerine peel, artemisia, and lemongrass were identified by gas chromatography and gas chromatography-mass spectrometry. The major components of these essential oils were alpha-zingiberene (35.21%), limonene (76.25%), terpinen-4-ol (41.20%), limonene (80.95%), 1,8 cineole (27.45%), and terpinolene (10.67%). The curative effects of 10 individual compounds from the active essential oils on TMV infection were also examined in vivo. The compounds from citronellal, limonene, 1,8-cineole, and alpha zingiberene effected a more than 40% inhibition rate for TMV infection, and the other compounds demonstrated moderate activities at 320 MUg/ml in vivo. There results indicate that the essential oils isolated from artemisia and lemongrass, and the individual compound citronellal, have the potential to be used as an effective alternative for the treatment of tobacco plants infected with TMV under greenhouse conditions. PMID- 23676920 TI - Proteomic analysis of the oxidative stress response induced by low-dose hydrogen peroxide in Bacillus anthracis. AB - Anthrax is a bacterial disease caused by the aerobic sporeforming bacterium Bacillus anthracis, which is an important pathogen owing to its ability to be used as a terror agent. B. anthracis spores can escape phagocytosis and initiate the germination process even in antimicrobial conditions, such as oxidative stress. To analyze the oxidative stress response in B. anthracis and thereby learn how to prevent antimicrobial resistance, we performed protein expression profiling of B. anthracis strain HY1 treated with 0.3 mM hydrogen peroxide using a comparative proteomics-based approach. The results showed a total of 60 differentially expressed proteins; among them, 17 showed differences in expression over time. We observed time-dependent changes in the production of metabolic and repair/protection signaling proteins. These results will be useful for uncovering the metabolic pathways and protection mechanisms of the oxidative response in B. anthracis. PMID- 23676922 TI - Chemogenomics profiling of drug targets of peptidoglycan biosynthesis pathway in Leptospira interrogans by virtual screening approaches. AB - Leptospirosis is a worldwide zoonosis of global concern caused by Leptospira interrogans. The availability of ligand libraries has facilitated the search for novel drug targets using chemogenomics approaches, compared with the traditional method of drug discovery, which is time consuming and yields few leads with little intracellular information for guiding target selection. Recent subtractive genomics studies have revealed the putative drug targets in peptidoglycan biosynthesis pathways in Leptospira interrogans. Aligand library for the murD ligase enzyme in the peptidoglycan pathway has also been identified. Our approach in this research involves screening of the pre-existing ligand library of murD with related protein family members in the putative drug target assembly in the peptidoglycan biosynthesis pathway. A chemogenomics approach has been implemented here, which involves screening of known ligands of a protein family having analogous domain architecture for identification of leads for existing druggable protein family members. By means of this approach, one murC and one murF inhibitor were identified, providing a platform for developing an antileptospirosis drug targeting the peptidoglycan biosynthesis pathway. Given that the peptidoglycan biosynthesis pathway is exclusive to bacteria, the in silico identified mur ligase inhibitors are expected to be broad-spectrum Gram negative inhibitors if synthesized and tested in in vitro and in vivo assays. PMID- 23676921 TI - IAA-producing Penicillium sp. NICS01 triggers plant growth and suppresses Fusarium sp.-induced oxidative stress in sesame (Sesamum indicum L.). AB - Application of rhizospheric fungi is an effective and environmentally friendly method of improving plant growth and controlling many plant diseases. The current study was aimed to identify phytohormone-producing fungi from soil, to understand their roles in sesame plant growth, and to control Fusarium disease. Three predominant fungi (PNF1, PNF2, and PNF3) isolated from the rhizospheric soil of peanut plants were screened for their growth-promoting efficiency on sesame seedlings. Among these isolates, PNF2 significantly increased the shoot length and fresh weight of seedlings compared with controls. Analysis of the fungal culture filtrate showed a higher concentration of indole acetic acid in PNF2 than in the other isolates. PNF2 was identified as Penicillium sp. on the basis of phylogenetic analysis of ITS sequence similarity. The in vitro biocontrol activity of Penicillium sp. against Fusarium sp. was exhibited by a 49% inhibition of mycelial growth in a dual culture bioassay and by hyphal injuries as observed by scanning electron microscopy. In addition, greenhouse experiments revealed that Fusarium inhibited growth in sesame plants by damaging lipid membranes and reducing protein content. Co-cultivation with Penicillium sp. mitigated Fusarium-induced oxidative stress in sesame plants by limiting membrane lipid peroxidation, and by increasing the protein concentration, levels of antioxidants such as total polyphenols, and peroxidase and polyphenoloxidase activities. Thus, our findings suggest that Penicillium sp. is a potent plant growthpromoting fungus that has the ability to ameliorate damage caused by Fusarium infection in sesame cultivation. PMID- 23676923 TI - Probing of potential luminous bacteria in bay of bengal and its enzyme characterization. AB - The present study dealt with the isolation, identification and enzyme characterization of potential luminous bacteria from water, sediment, squid, and cuttle fish samples of the Karaikal coast, Bay of Bengal, India during the study period September 2007 - August 2008. Bioluminescent strains were screened in SWC agar and identified using biochemical tests. As Shewanella henadai was found to be the most common and abundant species with maximum light emission [69,702,240 photons per second (pps)], the optimum ranges of various physicochemical parameters that enhance the luciferase activity in Shewanella hanedai were worked out. The maximum luciferase activity was observed at the temperature of 25 degrees C (69,674,387 pps), pH of 8.0 (70,523,671 pps), salinity of 20 ppt (71,674,387 pps), incubation period of 16 h (69,895,714 pps), 4% peptone (70,895,152 pps) as nitrogen source, 0.9% glycerol (71,625,196 pps), and the ionic supplements of 0.3% CaCO3 (73,991,591 pps), 0.3% K2HPO4 (73,919,915 pps), and 0.2% MgSO4 (72,161,155 pps). Shewanella hanedai was cultured at optimum ranges for luciferase enzyme characterization. From the centrifuged supernatant, the proteins were precipitated with 60% ammonium sulfate, dialyzed, and purified using anionexchange chromatography, and then luciferase was eluted with 500 mM phosphate of pH 7.0. The purified luciferase enzyme was subjected to SDS-PAGE and the molecular mass was determined as 78 kDa. PMID- 23676924 TI - Bacillus subtilis as a tool for screening soil metagenomic libraries for antimicrobial activities. AB - Finding new antimicrobial activities by functional metagenomics has been shown to depend on the heterologous host used to express the foreign DNA. Therefore, efforts are devoted to developing new tools for constructing metagenomic libraries in shuttle vectors replicatable in phylogenetically distinct hosts. Here we evaluated the use of the Escherichia coli-Bacillus subtilis shuttle vector pHT01 to construct a forest-soil metagenomic library. This library was screened in both hosts for antimicrobial activities against four opportunistic bacteria: Proteus vulgaris, Bacillus cereus, Staphylococcus epidermidis, and Micrococcus luteus. A new antibacterial activity against B. cereus was found upon screening in B. subtilis. The new antimicrobial agent, sensitive to proteinase K, was not active when the corresponding DNA fragment was expressed in E. coli. Our results validate the use of pHT01 as a shuttle vector and B. subtilis as a host to isolate new activities by functional metagenomics. PMID- 23676925 TI - Seasonal and spatial diversity of picocyanobacteria community in the Great Mazurian Lakes derived from DGGE analyses of ITS region of rDNA and cpcBAIGS [corrected] markers. AB - The seasonal and spatial diversity of picocyanobacteria (Pcy) in lakes of the Great Mazurian Lakes (GLM) system was examined by DGGE analysis of molecular markers derived from the 16S-23S internal transcribed spacer (ITS) of the ribosomal operon and the phycocyanin operon (cpcBA-IGS). The study of nine lakes, ranging from mesotrophy to hypereutrophy, demonstrated seasonal variance of Pcy. The richness and Shannon diversity index calculated on the basis of both markers were higher in spring and lower in early and late summer. No statistically significant relationships were found between the markers and trophic status of the studied lakes or Pcy abundance. There were, however, statistically significant relationships between the diversity indices and sampling time. The analysis pointed to a different distribution of the two markers. The ITS marker exhibited more unique sequences in time and space, whereas a greater role for common and ubiquitous sequences was indicated by the cpcBA-IGS data. Examination of the Pcy community structure demonstrated that communities were grouped in highly similar clusters according to sampling season/time rather than to the trophic status of the lake. Our results suggest that time is more important than trophic status in shaping the diversity and structure of Pcy communities. The seasonal changes in picocyanobacteria and differences in diversity and community structures are discussed in the context of well-established ecological hypotheses: the PEG model, intermediate disturbance hypothesis (IDH), and horizontal gene transfer (HGT). PMID- 23676926 TI - Deactivation of gold(I) catalysts in the presence of thiols and amines- characterisation and catalysis. AB - Thiols and amines, which are common heteroatom nucleophiles in gold-catalysed reactions, are known to dampen the reactivity of gold catalysts. In this article, the identity and activity of gold(I) catalysts in the presence of thiols and amines is investigated. In the presence of thioacid, thiophenol and thiol, digold with bridging thiolate complexes [{Au(L)}2(MU-SR)][SbF6] are formed and have been fully characterised by NMR and X-ray crystallography. In the presence of amines and anilines, complexes [LAu-NH2R][SbF6] are formed instead. All new isolated gold complexes were investigated for their catalytic activity in order to compare the level of deactivation in each species. PMID- 23676927 TI - Industrial microbiology: Designer biofuels? PMID- 23676928 TI - Hydroxyl radical oxidation of phospholipid-coated NaCl particles. AB - Biological organic compounds mixed with NaCl and other inorganic compounds in sea salt aerosol particles react in air with oxidants such as ozone and hydroxyl (OH) radicals. Laboratory studies of model systems can provide insight into these reactions. We report here studies of the kinetics and mechanism of oxidation of unsaturated 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) on NaCl by gas phase OH in air at room temperature and 1 atm pressure using diffuse reflection infrared Fourier transform spectrometry (DRIFTS) and matrix-assisted laser desorption/ionization-time-of-flight-mass spectrometry (MALDI-TOF-MS) to identify possible structures of surface-bound reaction products. For comparison, some studies were also carried out on the saturated 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC) on NaCl. The calculated concentration of hydroxyl radicals, generated by photolysis of isopropyl nitrite, was (1.6-6.4) * 10(8) radicals cm( 3). Surface-bound aldehydes, ketones, organic nitrates and nitrate ions were identified as products of these reactions and structures of potential products were proposed based on mechanistic considerations combined with the MALDI-TOF-MS and DRIFTS spectra. The loss rate of vinyl hydrogen, =C-H, at 3008 cm(-1) was used to obtain a lower limit for the rate constant (k1) for addition of OH to the double bond, k1 > (3 +/- 1) * 10(-13) cm(3) molecule(-1) s(-1) (1s), corresponding to a reaction probability of gamma(add) > (4 +/- 1) * 10(-3) (1s). Assuming that abstraction from -CH2- groups in POPC is the same as for DPPC, the percentage of the reaction that occurs by addition is ~80%. This is similar to the percent addition predicted using structure-reactivity relationships for gas phase reactions. Decreasing the amount of POPC relative to NaCl resulted in more nitrate ion formation and less relative loss of POPC, and increasing the OH concentration resulted in a more rapid loss of POPC and faster product formation. These studies suggest that under atmospheric conditions with an OH concentration of 5 * 10(6) radicals cm(-3), the lifetime of POPC with respect to OH is <6 days. PMID- 23676929 TI - [Relationship between degree of white matter damage and EEG changes in premature infants early after birth]. AB - OBJECTIVE: To study the relationship between the degree of white matter damage and changes in brain function in premature infants early after birth according to amplitude-integrated electroencephalogram (aEEG) and raw EEG (with burst suppression patterns). METHODS: Thirty-eight premature infants of less than 32 weeks' gestational age and with white matter damage, including 20 cases of mild white matter damage and 18 cases of severe white matter damage, were included in the study. Forty-two premature infants without white matter damage were selected as a control group. After birth, they were examined using aEEG and brain ultrasound once a week until four weeks after birth or a corrected gestational age of 32 weeks. The white matter damage and control groups were compared in terms of aEEG patterns and amplitudes and burst suppression ratio (BSR) on EEG. RESULTS: The white matter damage and control groups had highly discontinuous patterns and had no complete sleep cycles. The lower amplitude was significantly smaller in the severe white matter damage subgroup than in the mild white matter damage subgroup and control group. There was alternating burst-suppression activity on the raw EEG in the white matter damage and control groups; and the severe white matter damage subgroup had a significantly longer suppression time and a significantly higher BSR on EEG compared with the mild white matter damage subgroup and control group. CONCLUSIONS: Brain function monitoring should be performed in premature infants with white matter damage early after birth so as to detect cases of severe white matter damage in time. PMID- 23676930 TI - [Therapeutic effect of Ommaya reservoir implantation on hydrocephalus in premature infants following intraventricular hemorrhage and factors associted with the therapeutic effect]. AB - OBJECTIVE: To observe the therapeutic effect of Ommaya reservoir implantation on hydrocephalus in premature infants following intraventricular hemorrhage (IVH) and to investigate factors influencing the therapeutic effect. METHODS: An ambispective cohort study was conducted on the clinical and follow-up data of 20 premature infants (gestational age <32 weeks, birth weight <1500 g) who received Ommaya reservoir implantation because of hydrocephalus following IVH. The therapeutic effect of Ommaya reservoir implantation was observed. These patients were divided into cure and treatment failure groups according to their treatment outcomes. The factors influencing therapeutic effects were investigated by univariate analysis. RESULTS: Hydrocephalus was relieved significantly at 30 days after Ommaya reservoir implantation. However, some patients showed significantly decreased therapeutic effects since 3 months after operation: during 3-6 months after operation, 7 cases underwent ventriculoperitoneal shunt, 4 cases discontinued treatment because of economic reasons, and 1 case underwent endoscopic third ventriculostomy due to scalp hematoma with skin necrosis. The ventricles of the remaining 8 cases returned to normal size at 12-18 months after operation. As for postoperative complications, secondary IVH was seen in 8 cases, intracranial infection in 2 cases, and scalp hematoma with skin necrosis in 1 case. The univariate analysis revealed significant differences in gestational age, birth weight and duration of hydrocephalus before Ommaya reservoir implantation between the cure and the treatment failure groups (P<0.05). CONCLUSIONS: Ommaya reservoir implantation has a remarkable short-term therapeutic effect on hydrocephalus in premature infants following IVH, but later the effect decreases in some patients. Low gestational age, low birth weight and long duration of hydrocephalus may be the main factors influencing therapeutic effects of Ommaya reservoir implantation. PMID- 23676931 TI - [Relationship of B/A ratio and acidosis with abnormal brainstem auditory evoked potentials in neonates with severe hyperbilirubinemia]. AB - OBJECTIVE: To investigate the relationship of bilirubin/albumin (B/A) ratio and acidosis with abnormal brainstem auditory evoked potentials (BAEPs) in neonates with severe hyperbilirubinemia and its clinical significance. METHODS: A total of 967 neonates with severe hyperbilirubinemia between November 2008 and October 2009 were enrolled in the study. They were divided into two groups according to their BAEPs: normal BAEP group (n=799) and abnormal BAEP group (n=168). Univariate analysis and age-stratified Chi-square test were used to determine the relationship of B/A ratio and acidosis with BAEP. RESULTS: The univariate analysis showed that the abnormal BAEP group had significantly lower pH and base excess values and a significantly higher B/A ratio compared with the normal BAEP group (P<0.05). The age-stratified Chi-square test showed that neonates with acidosis or with a B/A ratio greater than 1.0 had a significantly higher incidence of abnormal BAEPs than those without acidosis or with a B/A ratio less than 1.0 in any age (days) group of neonates with severe hyperbilirubinemia (P<0.05). CONCLUSIONS: High B/A ratio and acidosis are the risk factors for abnormal BAEPs in neonates with severe hyperbilirubinemia, which is the case for those in any age group. In order to reduce the incidence of hearing loss in any age group of neonates with severe hyperbilirubinemia, we should correct the acidosis and lower the B/A ratio as soon as possible. PMID- 23676932 TI - [Pathological changes in the epileptogenic foci of children with intractable epilepsy]. AB - OBJECTIVE: To investigate pathological changes in the epileptogenic foci of children with intractable epilepsy and their clinical significance. METHODS: Thirty children with intractable epilepsy were included in the study. The epileptogenic foci were surgically resected and pathological changes in the obtained specimens were observed under a light microscope (LM) and a transmission electron microscope (TEM). RESULTS: Under the LM, cortical dysplasia was found in 14 cases (47%), hippocampal sclerosis in 11 cases (37%), dysembryoplastic neuroepithelial tumor in 1 case (3%), ganglioglioma in 1 case (3%), and encephalomalacia in 3 cases (10%). The TEM observation revealed pathological changes in the ultrastructure of the hippocampus and extra-hippocampal cortex, such as changes in the number of synapses and synaptic structure, decrease in neurons and karyopyknosis, swelling and degeneration of astrocytes, and changes in mitochondrial structures. CONCLUSIONS: Pathological changes in the hippocampus and extra-hippocampal cortex, especially synaptic remodeling, may be the morphological basis for spontaneous recurrent seizures in children with intractable epilepsy. The pathological changes and epileptiform activity are related to an imbalance between excitatory and inhibitory neurotransmission. PMID- 23676933 TI - [Clinical efficacy of oxcarbazepine suspension in children with focal epilepsy]. AB - OBJECTIVE: To investigate the clinical efficacy and safety of oxcarbazepine (OXC) suspension in children with focal epilepsy. METHODS: A total of 118 children aged 2-14 years, who were newly diagnosed with focal epilepsy between October 2009 and December 2011, were randomly divided into experimental group (n=60) and control group (n=58). The experimental group was treated with an orally suspension of OXC and the control group was orally administered with carbamazepine (CBZ) tablets. The two treatment regimens were compared in terms of clinical efficacy and safety. RESULTS: After 13 and 26 weeks of treatment, the experimental group had response rates of 75% and 72% respectively and seizure-free rates of 53% and 50%, and the control group had response rates of 71% and 66% and seizure-free rates of 50% and 43% respectively. There were no significant differences in the clinical efficacy between the two groups (P>0.05). After 26 weeks of treatment, the adverse event rates of the experimental and control groups were 18% and 40% respectively, with a significant difference between the two groups (P<0.05). CONCLUSIONS: OXC suspension has a comparable clinical efficacy to that of CBZ tablets in children aged 2-14 years who are newly diagnosed with focal epilepsy, but OXC suspension causes fewer adverse events and has higher safety. PMID- 23676934 TI - [Influential factors for methylphenidate treatment compliance in children with attention deficit hyperactivity disorder]. AB - OBJECTIVE: To investigate influential factors for the tendency to medicate and medication compliance in children with attention deficit hyperactivity disorder (ADHD). METHODS: A total of 188 children aged from 5 to 16 years, who were initially diagnosed with ADHD according to DSM-IV criteria, were included in the study. They underwent symptom assessment and cognitive function test. The compliance of methylphenidate treatment was evaluated. RESULTS: Patients with better emotional state, and fewer oppositional and hyperactive behaviors and those who had a family history of psychiatric diseases and who obtained lower scores in the number cancellation test (NCT), were more prone to medication and/or exhibited better medication compliance. Logistic regression analysis showed that fewer oppositional and hyperactive behaviors and lower NCT scores were the predictive factors for a higher tendency to medicate, and a better emotional state was the predictive factor for better medication compliance. Patients of predominantly inattentive type were more prone to medication and showed better medication compliance, as compared with those of combined type. Gender, age and symptom severity were not associated with the tendency to medicate and/or medication compliance. CONCLUSIONS: There is a need to enhance medication compliance in children with ADHD who have hyperactive, impulsive and oppositional behaviors, and to improve their long-term social functions. PMID- 23676935 TI - [Diagnostic value of Vanderbilt ADHD Parent Rating Scale in attention deficit hyperactivity disorder]. AB - OBJECTIVE: To study the value of the Vanderbilt ADHD Parent Rating Scale (VADPRS) in the diagnosis of attention deficit hyperactivity disorder (ADHD). METHODS: VADPRS were completed by parents of 319 children with suspected ADHD. The children were then evaluated by a specialist based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) and 196 of them were diagnosed with ADHD. The value of VADPRS in the diagnosis of attention deficit and hyperactivity was evaluated using ROC curves. Diagnostic evaluation indexes at best operating point were calculated. Kappa values were calculated to explore the consistency of items in VADPRS and corresponding items in the DSM-IV criteria. RESULTS: The area under the ROC curve for the diagnosis of attention deficit by VADPRS was 0.791. At the best operating point, its sensitivity was 0.83, specificity was 0.63, positive predictive value was 0.69 and negative predictive value was 0.79. The area under the ROC curve for the diagnosis of hyperactivity by VADPRS was 0.855. At the best operating point, its sensitivity was 0.82, specificity was 0.76, positive predictive value was 0.65, and negative predictive value was 0.88. The negative predictive value of VADPRS in general population screen was 0.99, based on the results of this study. The consistency of items in the VADPRS and corresponding items in DSM-IV criteria was poor, with the Kappa value of most items being less than 0.40. CONCLUSIONS: VADPRS is suitable for a general population screen for ADHD and it is helpful in the clinical diagnosis of ADHD, but its results can be influenced by parents' awareness and perception of children's behavior, and cannot replace the interview and judgment of professionals. PMID- 23676936 TI - [Application of umbilical venous catheter combined with peripherally inserted central catheter in very low birth weight infants]. AB - OBJECTIVE: To study the application of umbilical venous catheter (UVC) combined with peripherally inserted central catheter (PICC) in very low birth weight infants (VLBWIs). METHODS: A retrospective analysis was performed on the VLBWIs in the neonatal intensive care unit who received UVC combined with PICC (catheter group, n=63) or did not receive the catheter treatment (non-catheter group, n=38) to compare the differences in nosocomial infection, weight gain, and length of hospital stay between the two groups. RESULTS: The rate of nosocomial infection was 17% in the catheter group and 24% in the non-catheter group (P>0.05). Compared with the non-catheter group, the catheter group had a significantly higher weight gain (11.7+/-2.0 g/kg*d vs 10.6+/-2.3 g/kg*d; P<0.05) and a significantly shorter length of hospital stay (40+/-11 days vs 45+/-14 days; P<0.05). There was no significant difference in the incidence of complications between the two groups. CONCLUSIONS: Compared with those not receiving catheter treatment, the VLBWIs receiving UVC combined with PICC have a markedly higher weight gain and a markedly shorter length of hospital stay and show a declining trend in the rate of nosocomial infection. PMID- 23676937 TI - [Non-high-density-cholesterol as a predictor of non-lipid cardiovascular disease risk factors in obese children]. AB - OBJECTIVE: To investigate the role of non-high density lipoprotein cholesterol (non-HDL-C) in the assessment of cardiovascular disease (CVD) risk factors such as hypertension, pre-diabetes and diabetes in obese children. METHODS: According to the presence of complications (hypertension, pre-diabetes and diabetes), 810 children with central obesity were divided into two groups: one group with complications (n=499) and one group without complications (n=311). One hundred and sixty-four age- and sex-matched children served as the control group. Logistic regression analysis and receiver operating characteristic (ROC) curves were used to analyze the detection of non-lipid CVD risk factors by seven lipid markers. RESULTS: The prevalence rates of hypertension and pre-diabetes were significantly higher in obese children with high non-HDL-C concentrations (>=3.76 mmol/L). After adjusting for waist circumference Z-scores, the area under the ROC curve for non-HDL-C was 0.680 to detect non-lipid CVD risk factors, while the areas for low-density lipoprotein cholesterol, total cholesterol and apoprotein B were 0.659, 0.669 and 0.647 respectively. CONCLUSIONS: Compared with the other lipid markers, non-HDL-C is a better predictor for non-lipid CVD risk factors in obese children. Measurement of non-HDL-C concentations is recommended for obese children. PMID- 23676938 TI - [Effect of eating behavior intervention on infants in the urban area of Chongqing, China]. AB - OBJECTIVE: To investigate how to establish good eating behavior and correct bad eating habits in infants by means of the child health care outpatient clinic and to promote the growth and development of infants. METHODS: Infants aged 0-3 months, who were randomly selected from the urban area of Chongqing, were divided into intervention and control groups. The infants in the intervention group received all intervention measures in the study, while those in the control group received conventional health care. Both groups were subjected to regular monitoring of eating behavior indices including time of introduction of foods, frequency of adding complementary foods and intake frequency of unhealthy foods to analyze the effect of intervention. RESULTS: In the intervention group, foods were introduced at a reasonable time (P<0.01). Compared with those in the control group, the children aged 9 and 12 months in the intervention group had a significantly higher intake frequency of meat, vegetables and fruits (P<0.01) and a significantly lower intake frequency of sweet drinks (P<0.05), children aged 18 and 24 months in the intervention group had a significantly lower intake frequency of sweet drinks (P<0.01), and the children aged 24 months in the intervention group had a significantly lower intake frequency of ice cream (P<0.01). CONCLUSIONS: Eating behavior intervention can promote the proper introduction of foods and regular addition of supplementary foods, as well as decrease the intake frequency of unhealthy foods such as sweet drinks and ice cream, thus improving the eating behavior of infants. PMID- 23676939 TI - [Risk factors for asthma in children in Hefei, China]. AB - OBJECTIVE: To investigate the risk factors for asthma in children in Hefei, China and to provide a strategy for asthma control in this region. METHODS: A total of 400 children with a confirmed diagnosis of asthma, as well as 400 children of comparable age, sex, living environment, and family background, who had no respiratory diseases, were selected for a case-control study. A survey questionnaire survey was completed for all children. The obtained data were subjected to univariate and multivariate logistic regression analysis to determine the risk factors for asthma. RESULTS: The logistic regression analysis showed that a family history of allergy, allergic rhinitis, infantile eczema, no breastfeeding, air-conditioning and passive smoking were the risk factors for asthma in children, with odds ratios of 9.63, 7.56, 4.58, 2.16, 1.73, and 1.55 respectively. CONCLUSIONS: In order to reduce the incidence of asthma, we should advocate breast feeding, promote outdoor activities, keep ventilation natural, prevent passive smoking and cure allergic rhinitis. PMID- 23676940 TI - [Therapeutic efficacy of 3-year subcutaneous immunotherapy in asthmatic children allergic to mite]. AB - OBJECTIVE: To evaluate the therapeutic efficacy of 3-year subcutaneous immunotherapy (SCIT) in asthmatic children allergic to mite. METHODS: Ninety asthmatic children allergic to house dust mite (with or without allergic rhinitis) and aged 5-14 years were randomized into SCIT treatment group (n=45) and control group (n=45). The SCIT treatment group received SCIT combined with standardized treatment for asthma, while the control group received the standardized treatment alone. The therapeutic effects were assessed based on the daytime and nighttime symptom scores, mean daily doses of inhaled corticosteroids (ICS), skin prick test results, peak expiratory flows and total serum IgE at baseline and in the 3-year treatment. RESULTS: In both groups, the daytime and nighttime symptom scores in the first, second, and third years of treatment were significantly lower than the baseline values (P<0.01), and the scores decreased year by year during the 3-year treatment (P<0.01). Also, the mean daily doses of ICS in the first, second, and third years of treatment were significantly lower than the baseline values (P<0.01), and the doses decreased year by year during the 3-year treatment (P<0.01). The mean daily dose was significantly lower in the SCIT treatment group than in the control group in the second and third years of treatment (P<0.05). After 3-year treatment, the SCIT treatment group had a significantly higher proportion of children who discontinued use of ICS due to remission of symptoms compared with the control group (29% vs 20%, P<0.05). At the end of the 3-year treatment, the total serum IgE was significantly lower than the baseline value in the SCIT treatment group (P<0.01), and it was significantly lower in the SCIT treatment group than in the control group (P<0.05). CONCLUSIONS: Three-year SCIT is effective in asthmatic children allergic to house dust mite and allows reduction in the dosage of ICS. PMID- 23676941 TI - [Status of enterovirus infection in children with acute lower respiratory tract infection]. AB - OBJECTIVE: To investigate the status of enterovirus (EV) infection in children with acute lower respiratory tract infection (ALRTI). METHODS: A total of 404 samples (with odd numbers) of nasopharyngeal aspirates were collected from the children who were hospitalized in the Children's Medical Center, Hunan Provincial People's Hospital due to ALRTI between September 2007 and April 2008. The conserved sequence in the 5'-noncoding region of EV was used to design the primer, and nested RT-PCR was performed to detect EV in the samples. RESULTS: Of the 404 samples, 19 (4.7%) were EV-positive, and mostly taken from children under 3 years of age (95%); there was no significant difference in the detection rate between male and female children. Of the EV-positive children, 13 (68%) were clinically diagnosed with bronchial pneumonia, and 6 (32%) with bronchiolitis; 90% of them showed symptoms of fever, 84% had a cough, 63% had asthma, and 63% had complications mainly including diarrhea (6 cases), granulocytopenia (4 cases), and acute respiratory distress syndrome (2 cases). In addition, 26% of the EV-positive children had leukocyte disorder, more than half had liver dysfunction, and a few had myocardial involvement. CONCLUSIONS: EV is a pathogen that should not be neglected in children with ALRTI. For these children, close attention should be paid to the epidemiological status and clinical features of EV infection, and blood routine examination, liver function test and myocardial enzyme assay should be carried out periodically to improve prognosis. PMID- 23676942 TI - [Mixed infection and risk factors in children with severe adenovirus pneumonia]. AB - OBJECTIVE: To investigate the mixed infection and analyze risk factors in children with severe adenovirus pneumonia. METHODS: A retrospective analysis was performed on the clinical data of 756 children with adenovirus pneumonia between June 2009 and June 2011. Pathogens and risk factors were studied in 216 severe cases. RESULTS: Of the 216 severe cases, 138 (63.9%) were aged from 6 months to 2 years, and 161 (74.5%) developed the disease in the winter and spring; 177 (81.9%) were affected by 1-4 pathogens besides adenovirus, including 74 cases (34.3%) infected with one pathogen as an addition. A total of 334 pathogen strains were identified from the respiratory secretions and sera of the 216 cases. Of them, 163 (48.8%) were bacterial strains, dominated by Gram-negative bacteria (124 strains), 108 (32.3%) were viral strains, and 40 (12.0%) were fungal strains. Multivariate logistic regression analysis indicated that congenital heart disease, congenital airway abnormalities, nutritional anemia, recurrent pulmonary infection, and surgical history were the independent risk factors for severe adenovirus pneumonia in children, with odds ratios of 3.3, 11.1, 7.2, 14.3 and 12.9 respectively (P<0.05). CONCLUSIONS: Severe adenovirus pneumonia is mostly seen in children aged from 6 months to 2 years and occurs frequently in the winter and spring. Many cases are also infected with other pathogens, most commonly Gram-negative bacteria. Congenital heart disease, congenital airway abnormalities, nutritional anemia, recurrent pulmonary infection and surgical history are the independent risk factors for severe adenovirus pneumonia in children. PMID- 23676943 TI - [Clinical characteristics and antibiotic resistance in children with invasive Acinetobacter baumannii infection]. AB - OBJECTIVE: To analyze the clinical characteristics and antibiotic resistance in children with invasive Acinetobacter baumannii infection (IABI). METHODS: A retrospective analysis was performed on the clinical and drug sensitivity data of 52 children with IABI between January 2004 and December 2011. RESULTS: Of the 52 children with IABI, 35 (67%) were less than one year old and 35 (67%) had IABI in the summer and autumn, 19 (37%) of these children were clinically diagnosed with septicemia, 16 (31%) with urinary tract infection, and 12 (23%) with skin and soft tissue infection, and 38 (73%) of them suffered from underlying diseases. The incidence rates of hospital-acquired and community-acquired IABIs were 90% and 10% respectively; 44 cases (85%) were cured or showed improvement in symptoms, and 8 cases (15%) died. All the IAB strains isolated from these children were sensitive to amikacin, 82% of them were sensitive to imipenem, more than 70% were sensitive to fluoroquinolone and to cefoperazone/sulbactam, 13% were sensitive to cefoperazone, 8% were sensitive to aztreonam, 21% developed multi?drug resistance, and 17% developed pan-drug resistance. CONCLUSIONS: IABI occurs more frequently in children under one year of age, and most children with IABI have underlying diseases. IABI mainly results in septicemia, urinary tract infection and skin and soft tissue infection and is mostly hospital-acquired. Multi-drug resistance and pan-drug resistance are severe in IAB strains. PMID- 23676944 TI - [Expression of P38 MAPK and MMP-2 mRNA in neonatal rats with hyperoxia-induced lung injury]. AB - OBJECTIVE: To observe P38 mitogen-activated protein kinase (P38 MAPK) and matrix metalloproteinase-2 (MMP-2) mRNA expression level changes in neonatal rats with hyperoxia-induced lung injury,and to investigate the influence of P38 MAPK activation on MMP-2 mRNA expression. METHODS: Thirty-six Sprague-Dawley (SD) rats were randomly divided into three groups: air control, hyperoxia and SB203580 treated hyperoxia (n=12). The rats were sacrificed on the 3rd and 7th days and the lungs were removed. Hematoxylin-eosine staining was used to observe the pathological changes in lung tissues. RESULTS: Compared with the air and SB203580 treated groups, levels of P38 MAPK and MMP-2 mRNA significantly increased in the hyperoxia group (P<0.01). CONCLUSIONS: Expression of P38 MAPK increases in neonatal rats with hyperoxia-induced acute lung injury and this may play a role in control of the expression of MMP-2 mRNA. PMID- 23676945 TI - [Role of spinal MAPK-ERK signal pathway in myocardial ischemia-reperfusion injury]. AB - OBJECTIVE: To explore the role of spinal MAPK-ERK signal pathway in myocardial ischemia-reperfusion (I/R) injury. METHODS: Sixty male Sprague-Dawley(SD) rats (80-100 g) were randomly divided into 3 groups: sham (n=10), PD98059 (n=25) and I/R groups (n=25). Three days after successful intrathecal implantation, 5 MUg DMSO was injected intrathecally into the sham group, and then the left coronary arteries were separated without being tied. Rats in the I/R and PD98059 groups were injected with 5 MUL DMSO and PD98059 (5 MUg) 30 minutes before thoractomy respectively. Then the left coronary artery was tied for 30 minutes followed by 120 minutes of reperfusion. After the experiments, the ERK phosphorylation condition of T1-T4 spinal cord segments was detected with immunofluorescence; the myocardiac apoptosic index and infarct size were measured. RESULTS: Expression of p-ERK in the I/R group was significantly higher than in the sham and PD98059 groups (P<0.05). Myocardial apoptotic index and infarct size in the PD98059 group were significantly lower than in the I/R group (P<0.05), but higher in the PD98059 group than in the sham group (P<0.05). CONCLUSIONS: The MAPK-ERK pathway in the superior thorathic spinal cord can be activated by myocardial ischemia reperfusion and inhibition of the pathway can play a protective role in myocardial ischemia-reperfusion injury. PMID- 23676946 TI - [Treatment of congenital hyperinsulinism with octreotide: a case report]. PMID- 23676947 TI - [Trisomy 18 syndrome in a test-tube Amerasian infant]. PMID- 23676949 TI - Tuning the Forster overlap integral: energy transfer over 20 Angstroms from a pyrene-based donor to borondipyrromethene (Bodipy). AB - A linear molecular dyad was synthesised comprising a pyrene-thiophene energy donor linked via a triazole unit to a borondipyrromethene (Bodipy) energy acceptor. The donor to acceptor separation distance is around 20 A. Emission from the donor originates from a mixed pi-pi* and partial charge-transfer state and overlaps favourably with the absorption profile for the acceptor. The level of spectral overlap is dependent on the solvent polarity. Rates for electronic energy transfer were measured by transient absorption spectroscopy in solvents of varying polarity and refractive index. The measured rates for Forster energy transfer (k(EET)) correlate fairly well with the calculated overlap integrals (J(F)). A sigmoidal relationship is observed between k(EET) and the solvent polarity function DeltaF. PMID- 23676948 TI - [Research progress on periventricular white matter damage pathogenesis in preterm infants]. AB - Periventricular white matter damage is one of the characteristics of brain damage in preterm infants, and it is the most important type of encephalopathy. The pathological changes including the white matter of coagulation necrosis, oligodendrocyte damage, myelin damage, axonal injury and reactive gliosis and microglia infiltration in necrotic areas. All of these lesions are closely related to the nervous system sequelae in later-neonatal period. The pathogenesis of periventricular leukomalacia in premature infants are mainly cause by its immature brain vascular, and precursor oligodendrocytes of the attack of hypoxia, ischemia, infection, oxygen free radicals, inflammatory cytokines, increasing glutamate, and other high-risk factors. In this paper, an overview of progress in the study of the pathogenesis of periventricular white matter damage in premature infants through literature review to provide a theoretical support for clinical prevention, diagnosis and treatment. PMID- 23676950 TI - Protein-coding genes and long noncoding RNAs are differentially expressed in dasatinib-treated chronic myeloid leukemia patients with resistance to imatinib. AB - Dasatinib has demonstrated efficacy in patients with chronic-phase chronic myeloid leukemia (CML) who had resistance or intolerance to imatinib. However, some patients also develop resistance or intolerance to dasatinib. To identify potential molecular pathways involved in primary resistance to dasatinib in CML, we analyzed gene expression profiles of mononuclear cells of 7 imatinib-resistant patients, collected before and after 1-year dasatinib treatment. Large-scale gene expression was measured with Agilent microarrays covering protein-coding genes and long (>200 nt) noncoding RNAs (lncRNAs). Sets of genes and lncRNAs significantly differentially expressed (>1.5 fold-change; q value <=10%) were identified. Ingenuity Pathway Analysis pointed to a number of functions, canonical pathways and gene networks that were significantly enriched with differentially expressed genes. In addition to protein-coding genes, lncRNAs have been recently implicated in pathways leading to tumorigenesis. Our data point to new possible regulatory elements involved in dasatinib resistance in CML. PMID- 23676951 TI - Expanding the 2,2'-bipyrimidine bridged 1D homonuclear coordination polymers family: [M(II)(bpym)Cl2] (M = Fe, Co) magnetic and structural characterization. AB - One pot reaction of hydrated chloride salts of Fe(II) and Co(II) with stoichiometric amounts of 2,2'-bipyrimidine (bpym) in a methanol-acetonitrile mixture afforded the corresponding 1D homonuclear coordination polymers, [MU (bpym)MCl2]n. Crystal structures of both complexes are isomorphous in the highly symmetric orthorhombic space group Fddd. The 1D coordination polymers are composed of almost orthogonal alternating bipyrimidine bridges linking the {MCl2} units. The magnetic behaviour of the Fe(II) compound can be well understood as a uniform S = 2 chain with an antiferromagnetic exchange interaction between metal ion sites. In the case of the Co(II) ion, also an antiferromagnetic interaction is operative along the uniform chain, while at low temperatures a long range ordering is observed due to spin canting originating from the anisotropic behaviour of the Co(II) lowest energy Kramers doublets. PMID- 23676952 TI - Partnering to increase access to community exercise programs for people with stroke, acquired brain injury, and multiple sclerosis. AB - BACKGROUND: The purpose of this article is to describe the development and evaluation of a task-oriented group exercise program, delivered through a municipal recreation program, for community-dwelling people with neurological conditions. METHODS: Physical therapists (PTs) at a rehabilitation hospital partnered with a municipal recreation provider to develop and evaluate a 12-week exercise program for people with stroke, acquired brain injury, and multiple sclerosis at 2 community centers. Fitness instructors who were trained and supported by PTs taught 1-hour exercise classes twice a week. In a program evaluation of the safety, feasibility and effects of the program, standardized measures of physical function were administered before and after the program. RESULTS: Fourteen individuals (mean age: 63 years) participated and attended 92% of exercise classes, on average. Two minor adverse events occurred during 293 attendances. Improvement in mean score on all measures was observed. In people with stroke, a statistically significant improvement in mean Berg Balance Scale (mean +/- SD change = 3 +/- 2 points, P = .016, n = 7) and 6-minute walk test scores (change = 26 +/- 26 m, P = .017, n = 9) was observed. CONCLUSIONS: This model of exercise delivery provides people with neurological conditions with access to a safe, feasible and potentially beneficial exercise program in the community. PMID- 23676953 TI - An update on idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressively fibrotic disease with a median survival of 3-5 years. Despite recent advances the pathophysiology of the disease remains not fully understood. However, injury of type II alveolar epithelial cells is considered the key event for the initiation of the development of fibrosis. An accurate diagnosis is imperative because commencing treatment at an early stage may reduce disease progression. In this regard, the multidisciplinary disease meeting between pulmonologists, radiologists and pathologists has definitely improved the diagnostic confidence. Importantly, a milestone has been recently reached as the first IPF-specific drug namely pirfenidone has been licensed in Europe, Japan and Asia. PMID- 23676954 TI - Interventional pulmonology procedures: an update. AB - Bronchoscopy is the most important tool in diagnosis of respiratory diseases, but also provides therapeutic options in various disorders. Besides hemoptysis, airway stenoses are a frequent indication for therapeutic bronchoscopy interventions. Thereby, a broad spectrum of endoscopic techniques including electrocautery, argon plasma coagulation, laser treatment, cryosurgery and stent implantation is available. In the last decade, development of new endoscopic modalities provides also treatment of patients with chronic obstructive pulmonary disease and uncontrolled asthma. PMID- 23676955 TI - Transthoracic ultrasonography in respiratory medicine. AB - Transthoracic ultrasonography (US) has become an essential modality for the evaluation of a wide range of thoracic pathologies by respiratory, emergency and critical care physicians. It can be performed with entry-level equipment and by personnel with minimal training. Its advantages include low cost, lack of radiation and immediate application at the point of care. The main indications for transthoracic US are the qualitative and quantitative assessment of pleural effusions, pleural thickening, diaphragmatic pathology, and chest wall and pleural tumours. US may also be used to visualise pulmonary pathologies that abutt the pleura, including consolidation and the interstitial syndrome. Transthoracic US is at least as sensitive as chest radiographs in the detection of pneumothoraces, and is useful in diagnosing skeletal abnormalities like rib fractures. It is the ideal tool to guide transthoracic procedures, including thoracocentesis and pleural biopsy. Moreover, US-assisted procedures can be performed by a single clinician with no sedation and minimal monitoring. US assisted fine needle aspiration and/or cutting needle biopsy of extrathoracic lymph nodes, lesions arising from the chest wall, pleura, peripheral lung and mediastinum are safe and have a high yield in the of hands of clinicians. US can potentially also guide aspiration and biopsy of diffuse pulmonary infiltrates, consolidations and lung abscesses. Transthoracic US may also be used for the detection of pulmonary embolism. PMID- 23676956 TI - Current issues in the management of tuberculosis in Europe. AB - Tuberculosis is a rare disease in Europe, so that most medical doctors never see a case and, although they know that the disease exists, they usually do not include it among the differential diagnosis of many respiratory or general disorders. Why is it, therefore, still important to speak about TB? This paper analysis some reasons: 1) TB is rare but has not disappeared. In Europe, some 400,000 cases are registered each year, with a slight decreasing tendency over the last few years but great disparities between countries and regions; 2) TB is more frequent in some risk groups, particularly among patients born in a country with a high incidence of disease or in persons exposed to the contact with TB, like close relatives of infectious patients. In EU/EEA, the majority of TB cases are observed among foreign-born persons; 3) if infected, some persons have a higher risk to develop TB. Small children and persons with viral or drug-induced immunosuppression (for instance anti-TNF) must be screened and protected if infected; 4) cases of TB among migrants generally occur after the entry in the country, from reactivation of latent TB acquired before. The border screening does not offer a garantee that the disease has been detected. Due attention to incurring symptoms and easy access to care must be maintained during the whole stay in the country for all foreign-born persons; 5) one of the major threats for the future is the progressive increase in the number of cases resistant to first line drugs (Multidrug-resistant TB or MDR-TB) in several regions of the world, particularly in Eastern Europe; 6) due to decreasing knowledge and experience with the diagnosis and management of TB, many cases are diagnosed at a late stage. Medical doctors are encouraged to share their questions with experts and refer to existing Guidelines. PMID- 23676957 TI - Management of malignant pleural mesothelioma: have we made any progress? AB - As the incidence of malignant pleural mesothelioma (MPM) is increasing in the next decades, treatment is a challenge. The past 2 years have seen a number of promising achievements in the management of patients with MPM. Treatment of a symptomatic malignant pleural effusion through indwelling pleural catheter (IPC) may allow for an individualized treatment. Advances in the systemic treatment with targeted agents will undoubtedly gain by the discovery of a driver mutation which may be selectively targeted. In the meantime, the addition of monoclonal antibodies to a standard chemotherapy backbone might result in a modest improvement in outcome in patients selected for the presence of the ligand. New techniques in radiation therapy, pleural intensity-modulated radiotherapy, helical tomography and proton-therapy are exciting advances in multimodality treatment enhancing local control and therefore improving overall survival. The role of surgery remains controversial and should be further explored. Surgical procedures consist of extrapleural pneumonectomy or lung sparing operations like debulking of the parietal and visceral pleura by (extended) pleurectomy/decortication. Where the treatment in multimodality therapy may lead to improved disease-free survival and overall survival, the type of cyto reductive procedure should be selected on institutional and surgeon's experience. The increase in mesothelioma incidence is matched only by the increasing number of researchers and studies. It is up to the clinicians to support these efforts by stimulating their patients to participate in this clinical research. PMID- 23676958 TI - Treatment of sarcoidosis. AB - The treatment of pulmonary sarcoidosis is based on several factors. These include changes in pulmonary physiology, presence of extra-pulmonary disease, and symptoms. Several immunosuppressive agents have been studied and recommendations regarding the utility of these different agents have evolved. While glucocorticoids remain the most commonly used agent, other drugs have been used as steroid sparing and for those patients who progress despite routine treatment. Non immunosuppressive agents also play a role in the therapy of pulmonary sarcoidosis patients. These include treatments for pulmonary hypertension, infection, and fatigue. PMID- 23676959 TI - Obstructive sleep apnea/hypopnea syndrome. AB - Obstructive sleep apnea/hypopnea syndrome (OSAHS) is characterized by recurrent episodes of partial or complete upper airway collapse during sleep that is highlighted by a reduction in, or complete cessation of, airflow despite documented on going inspiratory efforts. Due to the lack of adequate alveolar ventilation that results from the upper airway narrowing, oxygen saturation may drop and partial pressure of CO2 may occasionally increase. The events are mostly terminated by arousals. Clinical consequences are excessive daytime sleepiness related to the sleep disruption. Minimal diagnostic criteria have been defined for OSAHS. Patients should have excessive daytime sleepiness that can not be better explained by other factors, or experience two or more of the following symptoms, again that are not better explained by other factors: choking or gasping during sleep; recurrent awakenings from sleep; un-refreshing sleep; daytime fatigue; and impaired concentration. All patients should have more than five obstructed breathing events per hour during sleep. An obstructive apnea or hypopnoea can be defined as an event that lasts for >= 10 s and is characterized by an absence or a decrease from baseline in the amplitude of a valid measure of breathing during sleep that either reaches >50% with an oxygen desaturation of 3% or an arousal (alternatively a 30% reduction with 4% desaturation). The American Academy of Sleep Medicine (AASM) recommends these definitions. The Task Force of the AASM also states that there are common pathogenic mechanisms for obstructive apnea syndrome, central apnea syndrome, sleep hypoventilation syndrome and Cheyne Stokes breathing. It was more preferable to discuss each of these separately; although, they could be placed under the common denominator of "sleep-disordered breathing syndrome". The definition of OSAHS using two components, daytime symptoms and breathing pattern disturbances during sleep, may suggest that there is a tight correlation between the two. However, unfortunately this is not the case. The breathing pattern abnormalities, mostly described by an Apnea/Hypopnoea Index (AHI), only weakly correlate with quantified measures of sleepiness, such as the Epworth Sleepiness Scale (ESS). This probably means that interindividual sensitivity, with some individuals coping better with sleep fragmentation than others, does compromise the relationship between the AHI and daytime sleepiness scores. In addition, epidemiological studies show a broad range of sleepiness in the general population. Obviously, epidemiological studies investigating the prevalence of OSAHS are all biased by the lack of a uniform definition. The prevalence of an AHI of >5 events . h-1 in a general population (without taking into account symptoms of sleepiness) has previously been estimated to be 24% in a male population. When symptoms of sleepiness were also taken into account, the prevalence decreased to 4% in males and 2% in females. PMID- 23676960 TI - Physiotherapy and rehabilitative interventions in patients with chronic respiratory diseases: exercise and non-exercise treatment. AB - AIM: The aim of this literature review was to describe and discuss the available evidence about different modalities of physical therapy treatment and pulmonary rehabilitation (PR) involving exercise training in patients with chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis and interstitial lung disease (ILD). METHODS: The search was performed by using the Cochrane Library and PubMed databases. We selected studies published between 2001 and 2012 which involved physiotherapy treatment and included patients with COPD, asthma, bronchiectasis or ILD, aged 18 years or more, in stable or unstable disease condition. RESULTS AND CONCLUSION: PR involving exercise training was effective in improving exercise capacity, muscle force, quality of life and reducing symptoms in patients with COPD and asthma. Although there are few studies published about exercise training in patients with bronchiectasis, improvement in exercise capacity and quality of life in those patients was also observed. Patients with ILD also respond to exercise training; however, the response is less pronounced than in COPD and they lose the gains more quickly. Non-exercise based interventions, such as bronchial hygiene techniques and inspiratory muscle training, also present positive results when applied to patients with COPD, asthma and bronchiectasis. In some cases it is recommended that these interventions are combined with exercise training. Studies about non-exercise based interventions applied to patients with ILD are still necessary. PMID- 23676961 TI - Result of a randomized clinical trial comparing different types of anesthesia on the immune function of patients with osteosarcoma undergoing radical resection. AB - AIM: The purpose of this article was to explore the effects of different anesthesia drugs and techniques on the immune function of patients with osteosarcoma around the knee undergoing radical resection. METHODS: Forty-five ASA (American Society of Anesthesiologists) I-II patients were randomized and divided into three groups: the epidural anesthesia group (Group A), the general anesthesia group (Group B), and the combination of epidural anesthesia and general anesthesia group (Group C). The populations of T lymphocyte subsets (CD3+, CD4+, CD8+, CD4+/CD8+) and a possible association between these variables were investigated 2 h before anesthesia, before and after skin incision, and on the 1st, 3rd and 5th days after operation. RESULTS: The serum sIL-2 levels and T lymphocyte subset populations did not show significant differences among the three groups before anesthesia and skin incision. Serum sIL-2R increased 2 h after skin incision and on the 1st and 3rd day after operation in groups A and B (P < 0.01), and was higher than that of group C 2 h after skin incision and on the 1st day after operation (P < 0.01). Serum sIL-2R increased on the 1st postoperative day in group C. The CD3+, CD4+ and CD4+/CD8+ populations decreased significantly in all groups 2 h after skin incision, and on the 1st and 3rd days after operation (P < 0.05). However, in group C, CD4+/CD8+ levels had almost returned to baseline values on the 3rd day after operation (P > 0.05), and were significantly higher than those of groups A and B (P < 0.05). On the 5th day after operation, CD3+, CD4+ and CD4+/CD8+ levels had returned to baseline values before anesthesia in group C (P > 0.05), and were significantly higher than those of groups A and B (P < 0.05). CONCLUSION: Epidural anesthesia combined with general anesthesia might reduce the stress reaction and the effect of anesthetic drugs on sIL-2 levels and T lymphocyte subsets, contributing to the restoration of immune function in cancer patients. PMID- 23676962 TI - Polymorphisms of alpha-actinin-3 and ciliary neurotrophic factor in national level Italian athletes. AB - AIM: The R577X polymorphism of the alpha-actinin-3 (ACTN3) gene and the IVS1-6G>A polymorphism of the ciliary neurotrophic factor (CNTF) gene have been associated with a favourable muscle phenotype (more muscle fibres with high glycolytic activity), reduced predisposition for congenital dystrophy and resistance to sarcopenia in old age. The aim of this study was to look for evidence of selective pressure towards genotypes favourable for strong muscle activity in a sample of national-level Italian athletes. METHODS: We analysed two stop codon polymorphisms in the DNA of 50 Italian athletes, specialised in power or endurance sports, and compared their genotypic distribution with those of a population of 50 controls. In a representative sub-group of athletes (N.=42) we then compared the genetic data with anaerobic threshold, assessed by an incremental exercise test up to exhaustion. RESULTS: The athlete group showed an allelic distribution of ACTN3 (R/R:64%, R/X:16%, X/X:20%) and CNTF (G/G:72%, G/A:26%, A/A:2%), significantly imbalanced towards alleles R/R and G/G, respectively, compared to controls (ACTN3=R/R:40% R/X:22% X/X:38% and CNTF=G/G:52%, G/A:24%, A/A:24%) (p=0.0024 and p=0.0001, respectively). Only the ACTN3 577X/X polymorphism showed a significant association with the anaerobic threshold of athletes (F-ratio= 4.037; p=0.025). Factorial ANOVA demonstrated a non significant interaction between favourable allelic patterns of ACTN3 and CNTF genes on aerobic performance in the athlete group. CONCLUSION: The relationship found between favourable muscle phenotype and this genetic profile may have interesting implications in sport performance and training, athlete selection and different clinical activities, such as physical rehabilitation and modifying phenotypes associated with neuromuscular diseases. PMID- 23676963 TI - Focal epilepsies associated with glioneuronal tumors: review article. AB - Glioneuronal tumors (GNTs) are an increasingly recognized cause of focal epilepsies, particularly in children and young adults. GNTs consist of a mixture of glial and neuronal elements and most commonly arise in the temporal lobe, particularly in the temporo-anterior-basal mesial site. They are often associated with cortical dysplasia or other neuronal migration abnormalities. Epilepsy associated with GNT is poorly controlled by antiepileptic drugs in many cases; but, it is extremely responsive to surgical treatment. However, the best management strategy of tumor-related focal epilepsies remains controversial and still remain one of the contemporary issues in epilepsy surgery. Temporo-mesial GNT are associated with a widespread epileptic network, defining, therefore, a distinct anatomo-clinico-pathological group with complex epileptogenic mechanisms. By using an epilepsy surgery oriented strategy GNT associated with focal epilepsies may have an excellent seizure outcome and, therefore, surgical treatment can be offered early to avoid both the consequences of uncontrolled seizures as well as the side effects of prolonged pharmacological therapy and the rare risk of tumor growth or malignant transformation. PMID- 23676964 TI - The effects of postmastectomy adjuvant radiotherapy on immediate two-stage prosthetic breast reconstruction: a systematic review. AB - BACKGROUND: The authors performed a systematic review of the literature on the outcome of therapy for patients with breast cancer who underwent adjuvant radiotherapy after an immediate two-stage prosthetic breast reconstruction, either following tissue expansion (stage 1) or after removal of the tissue expander and insertion of a final breast implant (stage 2). Their outcomes were compared to those of patients who had reconstruction without postmastectomy irradiation. METHODS: Electronic database searches were supplemented by a full text review of possible relevant articles on two-stage prosthetic immediate breast reconstruction and radiotherapy. Delayed or one-stage prosthetic or nonprosthetic breast reconstruction studies were excluded. The primary outcome measured was the reconstruction failure rate with prosthesis loss. Secondary endpoints were capsular contracture and aesthetic outcome. RESULTS: No randomized controlled trials were identified, and only one prospective, nonrandomized, multicenter trial was found. Reports with more than 15 patients were included; 12 studies had a total of 1853 patients (715 irradiated and 1138 nonirradiated). Adjuvant radiotherapy resulted in a significantly higher reconstruction failure rate in immediate two-stage prosthetic breast reconstruction compared with controls (18.6 percent versus 3.1 percent, p < 0.00001). Radiotherapy particularly increased the failure rate when given after stage 1 (expander) (29.7 percent versus 5 percent, p < 0.00001) but also stage 2 (permanent implant) (7.7 percent versus 1.5 percent, p = 0.0003). There was also an increase in severe capsular contractures and an inferior cosmetic result in the irradiated patients. CONCLUSION: Nonrandomized studies suggest that adjuvant radiotherapy results in a higher risk of reconstruction failure. PMID- 23676965 TI - Factors associated with readmission following plastic surgery: a review of 10,669 procedures from the 2011 American College of Surgeons National Surgical Quality Improvement Program data set. AB - BACKGROUND: This study explored factors associated with readmission following plastic surgery using a prospective, validated, national database. METHODS: Patients who underwent primary plastic surgery procedures (n = 10,669) were identified from the 2011 American College of Surgeons National Surgical Quality Improvement Program databases. Those who were readmitted were compared with those who were not. Preoperative patient comorbidities, laboratory values, and intraoperative details derived from the data set were analyzed, and multivariate regression analysis was used to identify predictors of readmission. RESULTS: A total of 10,669 patients were included, with a 4.5 percent readmission rate. Their average age was 49.5 years, 32.2 percent were obese, 15.2 percent were smokers, and 81.7 percent were women. The most commonly performed procedures included elective/cosmetic breast (23.4 percent), implant breast reconstruction (16.5 percent), revision breast procedures (14.9 percent), hand operations (9.7 percent), and body contouring (5.9 percent). The wound complication rate was 4.6 percent and the medical complication rate was 4.9 percent. The overall incidence of any postoperative complication was 10.9 percent, of which 4.8 percent were defined as major surgical complications. Independent risk factors associated with readmission included procedure type (p = 0.029); obesity (p = 0.011); anemia (p = 0.003); and medical (p < 0.001), major surgical (p < 0.001), and wound (p < 0.001) complications. CONCLUSIONS: The most significant predictor of readmission was postoperative complications. Patients experiencing postoperative surgical complications were six times more likely to be readmitted. These findings can assist surgeons and health systems to better tailor preoperative risk counseling, resource allocation, and postoperative discharge services. PMID- 23676966 TI - Mechanisms of action of external volume expansion devices. AB - BACKGROUND: External volume expansion by suction has been proposed to improve the survival of fat grafting by preparing the recipient site. In previous experimental work, external volume expansion demonstrated the capacity to stimulate cell proliferation, vessel remodeling, and adipogenesis. This study investigated possible mechanisms underlying these observed changes. METHODS: A miniaturized external volume expansion device was applied to the dorsum of mice for 2 hours. Hypoxia during stimulation was assessed with pimonidazole hydrochloride, and tissue perfusion was measured for up to 2 days using hyperspectral imaging. Treated tissues were evaluated by microscopy for edema, inflammation, and the effects on cell proliferation and vessel remodeling. RESULTS: External volume expansion-treated tissues were grossly expanded with 2 hours of stimulation, developing a macroscopic swelling that regressed slowly over the course of hours following stimulus cessation. This gross swelling was reflective of histologic signs of intense edema, persistent for at least 1 hour after external volume expansion. Tissues were hypoxic during stimulation, and hyperspectral imaging demonstrated decreased tissue content of both oxygenated and deoxygenated hemoglobin in the first hour after external volume expansion release. The onset of inflammation was already apparent by the end of stimulation and remained elevated through 2 days after external volume expansion. At this time point, epidermal and dermal cell proliferation and vascular density were significantly increased. CONCLUSION: External volume expansion sets in motion various mechanisms, including mechanical stimulation, edema, ischemia, and inflammation, that over distinct time periods maintain an environment conducive to cell proliferation and angiogenesis, which can be elicited even by a single 2 hour external volume expansion cycle. PMID- 23676967 TI - Vascular bone transfer options in the foot and ankle: a retrospective review and update on strategies. AB - BACKGROUND: The foot and ankle area has a tenuous blood supply that can easily be damaged with trauma or open exposures. The navicular and talus are susceptible to avascular necrosis, making arthrodesis difficult. In addition, in this region, large bone gaps occur as a result of avascular necrosis, trauma, or infection. Often, vascularized bone flaps are required for reconstruction or salvage. METHODS: A retrospective review of all vascularized bone flaps to the foot and ankle performed by the senior surgeon (L.S.L) from July of 2006 to July of 2012 was performed. Twelve cases were identified (seven fibula flaps and five medial femoral condyle flaps). Indications included talus avascular necrosis with tibiotalar and subtalar arthritis (n = 8), talus avascular necrosis with tibiotalar arthritis (n = 1), navicular avascular necrosis (n = 1), talus persistent nonunion (n = 1), and a traumatic bone defect (n = 1). RESULTS: There were no flap failures or thrombotic events. Ankle stabilization was performed with plates (n = 5), compression screws (n = 2), external fixator (n = 4), and a cast (n = 1). There were three complications requiring return to the operating room. All patients ultimately obtained union, and full weight bearing was allowed at 18.7 +/- 13.6 weeks after surgery. CONCLUSIONS: The authors have successfully used the medial femoral condyle flap and fibula flap for tibiotalar arthrodesis, pantalar arthrodesis, navicular revascularization, and persistent nonunion of the talus. The medial femoral condyle is ideal when a small segment of vascularized bone is required, but when structural support is necessary, the fibula offers a larger cortical surface area, providing more rigidity. Both flaps are valid options for foot and ankle reconstruction and salvage. PMID- 23676968 TI - Timing of traumatic upper extremity free flap reconstruction: a systematic review and progress report. AB - BACKGROUND: The recommendations on the timing of microsurgical extremity reconstruction are as variable and numerous as the flaps described for such reconstruction. Original articles suggested that reconstruction should take place within 72 hours of injury. However, significant changes in perioperative and intraoperative management have occurred in this field, which may allow for more flexibility in the timing of reconstruction. This article aims to review current literature on timing of upper extremity reconstruction to provide the microsurgeon with up-to-date recommendations. METHODS: A structured literature search including Spanish and English language articles published between January of 1995 and December of 2011 was performed using the MEDLINE and Scopus databases. The search strategy was conducted using groups of key words, and articles were subsequently reviewed for relevance. Bibliographies of selected articles were further reviewed for additional relevant publications. Rates of total flap loss, infection, hospital stay, and bony nonunion were recorded and analyzed according to emergent (<24 hours), early (<5 days), primary (6 to 21 days), or delayed (>21 days) reconstruction. RESULTS: Fifteen articles met inclusion criteria. There was no significant association between timing of reconstruction and rates of flap loss, infection, or bony nonunion. Linear regression analysis displayed a significant association between length of hospital stay and timing of reconstruction. CONCLUSIONS: No conclusive evidence exists to suggest that emergent, early, primary, or delayed reconstruction will eliminate or decrease complications associated with posttraumatic upper extremity reconstruction. Earlier reconstruction may decrease length of hospital stay and limit associated medical costs. PMID- 23676969 TI - The Children's Hospital of Philadelphia modification of the Furlow double opposing Z-palatoplasty: 30-year experience and long-term speech outcomes. AB - BACKGROUND: The purpose of this study was to evaluate the long-term outcomes following modified Furlow palatoplasty over a 30-year experience at a single institution. METHODS: A retrospective review was performed of all nonsyndromic patients undergoing primary modified Furlow palatoplasty at The Children's Hospital of Philadelphia between 1980 and 2011. Surgical success was evaluated by the rate of postoperative oronasal fistula, speech outcomes assessed at a minimum of age 5 years, and the need for secondary surgery for velopharyngeal dysfunction. Results were analyzed by surgeon, Veau cleft type, age at repair, and over time. RESULTS: Eight hundred sixty-nine patients who underwent modified Furlow repair were included in this study. The mean age at palatoplasty was 1.1 years, and the mean length of follow-up was 6.7 years. Repairs were performed by 11 surgeons, with 44.3 percent performed by a single surgeon. The overall oronasal fistula rate was 5.2 percent, and this improved significantly over the 30-year period (p = 0.003). Speech results at age 5 or older were available for 559 patients. Of these 559 patients, 72.4 percent had a competent velopharyngeal mechanism, and 21.5 percent had a borderline mechanism consistent with socially acceptable speech. Secondary pharyngeal surgery was indicated in 8.1 percent of patients. Speech results were stable (p = 0.10), and rates of secondary surgery for velopharyngeal dysfunction declined significantly over the study period (p = 0.005). CONCLUSIONS: The authors' 30-year experience with the modified Furlow palatoplasty shows stable speech results, decreasing rates of secondary surgery, and an acceptable rate of postoperative oronasal fistula. PMID- 23676970 TI - Fixing the match: a survey of resident behaviors. AB - BACKGROUND: The authors studied residency applicant attitudes toward rank list creation, communication with programs, and the impact of these factors on their performance in the Match. METHODS: An anonymous, 26-question, multiple-choice, online survey was distributed to the program coordinators of every Accreditation Council for Graduate Medical Education-accredited program participating in the National Resident Matching Program for whom e-mail addresses were available. The survey addressed five areas: (1) demographics and interview characteristics, (2) preinterview and interview factors, (3) postinterview contact, (4) importance of various factors in rank list creation, and (5) Match outcome. Survey responses were analyzed with Microsoft Excel. RESULTS: A total of 1179 responses were received. It was not possible to calculate a response rate, because the number of residents receiving the survey was not known. The majority of respondents (78 percent) reported postinterview contact with a program. A large portion of respondents (42 percent) considered such contact to be important in the creation of their rank lists. Half of all respondents admitted to exaggerating their interest in a program during or after an interview. The majority of respondents (87.5 percent) received no assistance in covering the costs of "second-look" visits to programs. CONCLUSIONS: Applicants may be modifying their rank lists in response to post-interview contact from programs; furthermore, they usually have no assistance in paying for the cost of second looks. To level the playing field for students and programs alike, the authors propose that the National Resident Matching Program modify residency interview rules to (1) disallow any postinterview contact between programs and students, and (2) disallow second looks. PMID- 23676971 TI - The open approach in secondary rhinoplasty: choosing an incision regardless of prior placement. AB - BACKGROUND: Secondary open rhinoplasty is a complex topic with many hazards. Although there has been much discussion in the literature about what transcolumellar scar design creates the best aesthetic result, placement of the scar in a previously opened nose has not been widely discussed. In light of the outstanding blood supply to the nose, and often the desire to reposition the transcolumellar scar, the senior surgeon (R.J.R.) has ignored prior incisions in the columella and has chosen to place the incision in the best location for the current operative plan. METHODS: This article retrospectively reviewed 100 secondary rhinoplasty patients who had undergone two open procedures with different transcolumellar incisions performed by the senior surgeon from 2000 to 2010. Scar quality was graded preoperatively and postoperatively by three reviewers on a four-point scale from imperceptible to poor scar. RESULTS: Scar quality averaged 1.68 preoperatively and 1.61 postoperatively, indicating scar quality between imperceptible and barely perceptible. There was no skin bridge necrosis in the series, no infection, and no wound breakdown. Patient satisfaction was noted to be high overall. CONCLUSIONS: Anatomical studies have previously shown the safety of the transcolumellar incision in rhinoplasty. This article has shown the safety of ignoring prior incisions in the columella and basing the new scar location solely on where the surgeon feels is ideal. Although caution should always be used when creating possibly devitalized skin bridges, this study lends weight to the argument that one can safely ignore prior incision patterns in this aesthetically important and well-vascularized area. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23676972 TI - Options for configuring the scapular free flap in maxillary, mandibular, and calvarial reconstruction. AB - BACKGROUND: A number of microvascular free-flap tissue transfer techniques exist for reconstruction of head and neck defects. The scapular free flap is a versatile option that can be used for a wide variety of defects in this complex region. METHODS: A series of 42 free flaps from 41 patients was retrospectively identified from the senior author's (J.R.C.) [corrected] database between 2006 and 2012. Information regarding patient demographics, indication for surgery, type of flap, reconstructive methods, complications, and prosthodontic outcome were reviewed and have been described. RESULT: A wide range of defects were reconstructed using the scapular free flap. Of the 42 reconstructions, 24 were for mandibular, 13 were for maxillary, and five were for calvarial reconstruction. The patients' ages ranged from 28 to 82 years, with a median of 70 years. Dental restoration was achieved in eight patients with maxillary reconstruction and two patients with mandibular reconstruction. There were 11 major complications, including two total flap failures. CONCLUSIONS: The authors have found the scapular free flap to be a reliable, robust, and versatile flap that provides an unparalleled range of reconstructive options, with minimal donor site morbidity. Thus, the authors believe that the scapular free flap is a valuable reconstructive option for patients with complex head and neck defects and in patients in whom comorbid disease contraindicates the use of the fibular free flap. PMID- 23676973 TI - Oral administration of a novel long-acting prostacyclin agonist with thromboxane synthase inhibitory activity for pulmonary arterial hypertension. AB - BACKGROUND: Continuous administration of prostacyclin has improved the survival of patients with pulmonary arterial hypertension (PAH). However, this treatment has some problems, including its short duration of activity and difficult delivery. Therefore, we developed ONO-1301, an orally active, long-acting prostacyclin agonist with thromboxane synthase inhibitory activity. METHODS AND RESULTS: We investigated whether oral administration of ONO-1301 can both prevent and reverse monocrotaline (MCT)-induced PAH in rats. Rats were randomly assigned to receive repeated oral administration of ONO-1301 twice daily beginning either 1 or 8 days after subcutaneous injection of MCT. A control group received oral saline, and a sham group received a subcutaneous injection of saline instead of MCT. MCT-treated controls developed significant pulmonary hypertension. Treatment with ONO-1301 from day 1 or 8 significantly attenuated the increases in right ventricular systolic pressure and the increase in medial wall thickness of pulmonary arterioles. Kaplan-Meier survival curves demonstrated that the effect of ONO-1301 was equivalent to that of an endothelin receptor antagonist and a phosphodiesterase-5 inhibitor. A single oral dose of ONO-1301 increased plasma cAMP levels for up to 6h. Treatment with ONO-1301 significantly decreased urinary 11-dehydro-thromboxane B2 and increased the plasma hepatocyte growth factor concentration. CONCLUSIONS: Oral administration of ONO-1301 ameliorated PAH in rats, an effect that may occur through cAMP and hepatocyte growth factor. PMID- 23676974 TI - Microvascular dysfunction: clinically relevant but still difficult to detect. PMID- 23676975 TI - Low high-density lipoprotein cholesterol and low/normal body mass index are associated with increased mortality in coronary artery disease patients in Taiwan. AB - BACKGROUND: Among patients with coronary artery disease (CAD), high-density lipoprotein cholesterol (HDL-C) is a cardiac protective factor. In contrast, body mass index (BMI) is inversely related to mortality, and this is known as the obesity-mortality paradox. The relationship of HDL-C and BMI to mortality, however, has not been clarified well. The aim of this study was to evaluate the impact of HDL-C and BMI on mortality among CAD patients. METHODS AND RESULTS: A cohort of 1,114 angiographic CAD patients from the ET-CHD registry during 1997 2003 in Taiwan was studied. The subjects were categorized into 4 groups according to BMI >= 25 kg/m(2) (overweight/obese) or BMI <25 kg/m(2) (normal/underweight), and HDL-C higher or lower than the median of 40 mg/dl in men and 45 mg/dl in women. At a mean follow-up of 5.3 years, cardiac and all-cause death were the primary endpoints. On multivariate analysis, low HDL-C predicted higher cardiac and all-cause mortality in normal/underweight patients (hazard ratio [HR], 1.59; 95% confidence interval [CI]: 1.08-2.33; and 1.65, 95% CI: 1.25-2.19, respectively). In contrast, high BMI predicted lower cardiac and all-cause mortality in patients with low HDL-C (HR, 0.78; 95% CI: 0.54-1.14; and 0.66, 95% CI: 0.49-0.88, respectively). CONCLUSIONS: Among CAD patients in Taiwan, those with low HDL-C and normal/underweight had higher risk of mortality. PMID- 23676976 TI - Post stimulus effects of high frequency biphasic electrical current on a fibre's conductibility in isolated frog nerves. AB - OBJECTIVE: High frequency biphasic (HFB) electrical currents are widely used in nerve blocking studies. Their safety margins largely remain unknown and need to be investigated. APPROACH: This study, exploring the post stimulus effects of HFB electrical currents on a nerve's conductibility, was performed on bullfrog sciatic nerves. Both compound action potentials (CAPs) and differential CAPs (DCAPs, i.e. control CAPs subtracted by CAPs following HFB currents) were obtained, and N1 and N2 components, which were the first and second upward components of DCAPs, were used for analyses of the effects introduced by HFB electrical stimulation. MAIN RESULTS: First, HFB currents of 10 kHz at a completely blocking threshold were applied for 5 s. The maximum amplitudes and conducting velocities of the CAPs were significantly (P < 0.02) decreased within the observed period (60 s) following HFB currents. The DCAPs displayed clear N1 and N2 components, demonstrating respectively the losses of the fibres' normal conductibility and the appearances of new delayed conductions. Decreases of N1 amplitudes along time, regarded as the recovery of the nerve's conductibility, exhibited two distinct phases: a fast one lasting several seconds and a slow one lasting longer than 5 min. Further tests showed a linear relationship between the HFB stimulation durations and recovering periods of N1 amplitudes. Supra threshold blocking did not cause higher N1 amplitudes. SIGNIFICANCE: This study indicates that HFB electrical currents lead to long lasting post stimulus reduction of a nerve's conductibility, which might relate to potential nerve injuries. A possible mechanism, focusing on changes in intracellular and periaxonal ionic concentrations, was proposed to underlie the reduction of the nerve's conductibility and potential nerve injuries. Greater caution and stimulation protocols with greater safety margins should be explored when utilizing HFB electrical current to block nerve conductions. PMID- 23676977 TI - [alpha-Enolase (ENO1) inhibits epithelial-mesenchymal transition in the A549 cell line?by suppressing ERK1/2 phosphorylation]. AB - BACKGROUND AND OBJECTIVE: It has been proven that epithelial-mesenchymal transition (EMT) is a critical process which is precisely regulated by multiple signaling pathways during the progression and metastasis of non-small cell lung cancer (NSCLC). Canonical MAPK signaling is essential to transforming growth factor beta (TGFbeta)-induced EMT. Using the NSCLC cell line A549 as a model, the aim of this study is to explore the molecular mechanism of ENO1 affecting EMT. METHODS: We established an A549 strain stably overexpressing ENO1. Cell mobility was measured by the wound-healing assay. EMT-related molecular alterations were detected by Western blot analysis. The effect of ENO1 on EMT was also detected by TGFbeta-1-inducing assay. EGF-stimulating assay was performed to illustrate ERK1/2 phosphorylation changes resulting from ENO1 overexpression. RESULTS: Overexpressed ENO1 inhibited the mobility of A549 (P<0.05), as well as the expression of the mesenchymal markers N-cadherin and vimentin, but upregulated the epithelial marker E-cadherin. TGFbeta-inducing assay also showed that the negative effect of ENO1 on EMT. ERK1/2 phosphorylation was also obviously suppressed by ENO1 in the EGF-stimulating assay. CONCLUSIONS: In NSCLC cells, ENO1 overexpression can inhibit EMT in vitro by suppressing ERK1/2 phosphorylation. PMID- 23676978 TI - [Association of mutation and methylation in the promoter region of TIF1gamma with non-small cell lung cancer]. AB - BACKGROUND AND OBJECTIVE: TIF1gamma (transcription intermediary factor 1 gamma), which belongs to transcription intermediary factor 1 family, is an inhibitor of the TGF-beta/Smad signaling pathway and could inhibit the signal transduction mediated by TGF-beta. The deficiency of TIF1gamma expression in a variety of tumor cells suggests that TIF1gamma may play as a tumor suppressor gene in cancer development. The aim of this study is to confirm the relationship between TIF1gamma and non-small cell lung cancer (NSCLC) through exploring the expression of TIF1gamma in NSCLC cells and tissues, and investigate the regulation mechanism of TIF1gamma expression in NSCLC cells. METHODS: Thirteen NSCLC and the paired corresponding para-cancerous lung tissue samples and three cell lines (a normal bronchial epithelial cell line HBE and two NSCLC cell lines A549 and 95C) were selected. The quantitative real-time PCR and Western blotting were used to determine the expression of TIF1gamma, and ImageJ was used to evaluate the relative expression of TIF1gamma. Direct sequencing was performed to detect mutations within the promoter region of the TIF1gamma gene and then Bisulfite sequencing PCR (BSP) and cloning sequencing were carried out to test the methylation status of the promoter region of TIF1gamma gene in the selected cell lines. RESULTS: Both mRNA and protein expression of TIF1gamma were found significantly decreased in A549 and 95C compared with those in HBE (P<0.05). And in 9 pairs (69.2%) of tissues among the 13 pairs, the mRNA expression of TIF1gamma gene was lower in the cancer tissues than that in the paired paracancerous lung tissues (P<0.05). No abnormal mutation was found in the -287 to -5 region of the promoter of TIF1gamma gene in the three cell lines. Moreover, five CpG sites (including -214 bp,-128 bp,-124 bp, -65 bp and -55 bp) were detected in the promoter of TIF1gamma gene by using BSP, and the methylation profiles in these CpG sites showed similar pattern between NSCLC cells and HBE cells. CONCLUSIONS: TIF1gamma may play a tumor suppressor role in the progression of NSCLC. No mutation was found in the -287- -5 region of the promoter of TIF1gamma gene in a normal bronchial epithelial cell line and two NSCLC cell lines. But there are five CpG sites which can be methylated located in this region. PMID- 23676979 TI - [Preliminary study of MALDI-TOF mass spectrometry-based screening of patients with the NSCLC serum-specific peptides]. AB - BACKGROUND AND OBJECTIVE: The improved survival of patients with lung cancer depends on early diagnosis of lung cancer. However, the traditional diagnostic techniques have several limitations. Mass spectrometry (MS) has been applied as a core technology for cancer diagnosis in preliminary proteomic studies. The aim of this study is to explore the differences in the serum peptide levels of patients with non-small cell lung cancer (NSCLC) and healthy individuals using matrix assisted laser desorption/ionization (MALDI)-time-of-flight (TOF)-MS. A NSCLC serum classification model was then established. METHODS: One hundred and thirty three cases of patients with NSCLC serum specimens and 132 cases of healthy human serum specimens were randomly divided into two groups in accordance with the ratio of three to one without age and gender differences. The training group was used to establish the classification model, this group included serum samples from 100 NSCLC cases and 100 healthy individuals. The test group for validating the proposed model was composed of the remaining serum samples from 33 NSCLC cases and 32 healthy individuals. Peptides were extracted from the samples using magnetic beads--immobilized metal affinity capture--copper, and their mass spectra were obtained using an automated MALDI-TOF-MS system. The MS data from the training group was analyzed using the ClinproToolTM software to identify the individual peptide fragments and establish the classification model. The sensitivity and specificity of the model were verified by blind testing with the test group. RESULTS: Among the 131 different peptide peaks, ranging from m/z 1,000 Da to 10,000 Da, 14 peaks were significantly different in the NSCLC samples of the training group, as compared with the controls (P<0.000,001; AUC>=0.9); these included 2 higher peaks and 12 lower peaks. The classification model was established, and the test group was verified for only 3 peptide peaks (7,478.59, 2,271.44 and 4,468.38 Da), which were selected by the statistical software. Blind testing revealed that the proposed method had 100% sensitivity, 96.9% specificity and 98.5% accuracy. CONCLUSIONS: Our results showed that the serum peptide levels were significantly different between NSCLC patients and healthy individuals. A serum peptide-based classification of NSCLC patients was established using an automated MALDI-TOF-MS system. This method demonstrated high sensitivity and specificity in a small-scale test. Future studies should test the proposed model through mass validation. The model could be compared or combined with traditional diagnostic methods to establish novel techniques for the early diagnosis of patients with NSCLC. PMID- 23676980 TI - [Clinical effects for patients with recurrent advanced non-small cell lung cancer treated with icotinib hydrochloride]. AB - BACKGROUND AND OBJECTIVE: Icotinib hydrochloride is the third single target EGFR TKI used in clinical treatment of advanced non-small cell lung cancer (NSCLC). Clinical research reports on its efficacy and survival in patients with Recurrent Advanced NSCLC are still little.The aim of this study is to evaluate the efficacy and survival of Icotinib hydrochloride for patients with advanced non-small cell lung cancer who failed to previous chemotherapy and explore the association of clinical features with the efficacy and survival. METHODS: The clinical data of 60 NSCLC patients referred to the Beijing Chest Hospital, Capital Medical University from March 2009 to July 2012 were retrospectively analyzed. RESULTS: The overall response rate (ORR) was 45.0% and the disease control rate (DCR) was 80.0%. The median progression-free survival (PFS) time was 6.7 months. RR and PFS in female were superior to male (P=0.014, 0.013, respectively). RR, DCR in 2nd line subgroup were superior to >=3rd-line subgroup (P=0.020, 0.024, respectively). RR, DCR and PFS in EGFR mutation carriers were significantly superior to wild-type patients (P=0.006, <0.001, 0.002, respectively). There was no statistical difference in RR and PFS between those age<65 and >=65 or PS<2 and PS>=2. There was no statistical difference in RR and DCR between exon 19 deletion and exon 21 mutations, while the former had much longer PFS (P=0.020). EGFR mutation and exon 19 deletion are the independent prognostic factors to significantly improve the PFS (P=0.009, 0.012, respectively). The side effects were generally mild and consisted of rash and diarrhea. CONCLUSIONS: Icotinib hydrochloride is effective especially in EGFR mutation carriers and well tolerated in patients with recurrent advanced non-small-cell lung cancer. PMID- 23676981 TI - [Pathological characteristic and clinical management of pulmonary carcinoid]. AB - BACKGROUND AND OBJECTIVE: Treatment of pulmonary carcinoid is a comprehensive modality focusing on surgery. Thus, accurate and timely preoperative and intraoperative pathological diagnoses are very crucial. The aim of this study is to retrospectively analyze the pathological characteristics of pulmonary carcinoid, its natural history, and patterns of disease progression to obtain evidence for clinical decision making. METHODS: Clinical and pathological data of 32 patients with pulmonary carcinoid were retrieved and retrospectively analyzed. The pathological characteristics and their relationship with clinical diagnosis and treatment effect were systematically studied. RESULTS: Among the 32 patients, 18 had typical carcinoid and 14 had atypical carcinoid. The male-to-female ratio was 2.2:1, and the average age was (44+/-15) years. Almost half of the patients were discovered by accident. The average maximum diameter was (3.1+/-1.3) cm. About 27 of all 32 cases (84.4%) were stage I, 2 were stage IIa, 2 were stage IIIa, and 1 was stage IV. The follow-up time was 5.2-9.7 years. The 5-year progression free survival of 15 typical carcinoid patients and 12 atypical carcinoid patients were 100% and 92.9%, respectively. The characteristic neuroendocrine morphology and variable expression levels of cytokeratin, chromogranin A, synaptophysin, CD56, and index of Ki-67 were important factors that differentiated pulmonary carcinoid from other tumors. CONCLUSIONS: Pathological diagnosis of pulmonary carcinoid must combine morphology with immunohistochemistry. Early-stage patients can also achieve good effect after surgery. PMID- 23676982 TI - [Dosimetric comparing between protons beam and photons beam?for lung cancer radiotherapy: a meta-analysis]. AB - BACKGROUND AND OBJECTIVE: The clinical evidences are not sufficient on the proton beam therapy of lung cancer for lacking of the RCTs on the comparing the proton with the photon beam in lung cancer radiotherapy. The aim of this study is to evaluate the dosimetry superiority of the proton beam and provide more valuable evidences to the clinical researches. METHODS: Clinical trails of dosimetric comparing between protons beam and photons beam for lung cancer radiotherapy were obtained from the Cochrane library, Pubmed, EMbase, CBM, CNKI, VIP, and Wan Fang databases. The data included in the study were evaluated and analyzed using the Cochrane Collaboration's RevMan 5.2 software. RESULTS: Six trails were included. Compared to photon therapy (three-dimensional conformal photon radiotherapy, 3D CRT), the proton therapy had a significantly lower total lung Dmean (MD=-4.15, 95%CI: -5.56--2.74, P<0.001) and V20, V10, V5 (MD=-10.92, 95%CI: -13.23--8.62, P<0.001); The V20, V10, V5 significantly decreased in proton therapy group. Compared to photon therapy (intensity-modulated photon radiotherapy, IMRT), V20, V10, V5 were also significantly lowered in proton therapy group (MD=-3.70, 95%CI: -5.31--2.10, P<0.001; MD=-8.86, 95%CI: -10.74--6.98, P<0.001; MD=-20.13, 95%CI: 27.11--13.14, P<0.001); The esophagus Dmean was not lowered, while the heart Dmean decreased in proton therapy group. CONCLUSIONS: Comparing to photon beam radiotherapy (3D-CRT and IMRT), proton beam therapy is advantageous in dosimetry of the lung cancer radiotherapy and recommended for clinical applying. PMID- 23676983 TI - [Research progress of treatment strategy for pulmonary nodule]. PMID- 23676984 TI - [Interstitial lung disease associated with lung cancer treatment]. AB - Interstitial lung disease is one of the most serious side effects caused by lung cancer treatment. Due to the complexity diagnosis and variability of the disease, it is often not diagnosied and treated in time, even endanger the patient's life and affect the patient's prognosis. The mechanism of interstitial pneumonia caused by radiotherapy, chemotherapy and targeted therapy is still not fully known. Therefore, it become a problem that how to early detection, diagnosis and treat the interstitial lung disease caused by lung cancer treatment and it should not be ignored in the future. PMID- 23676985 TI - [Giant primitive nuroectodermal tumor of mediastinum: a case report with literature review]. PMID- 23676987 TI - Repetitive traumatic brain injury, psychological symptoms, and suicide risk in a clinical sample of deployed military personnel. AB - IMPORTANCE: Traumatic brain injury (TBI) is believed to be one factor contributing to rising suicide rates among military personnel and veterans. This study investigated the association of cumulative TBIs with suicide risk in a clinical sample of deployed military personnel referred for a TBI evaluation. OBJECTIVE: To determine whether suicide risk is more frequent and heightened among military personnel with multiple lifetime TBIs than among those with no TBIs or a single TBI. DESIGN: Patients completed standardized self-report measures of depression, posttraumatic stress disorder (PTSD), and suicidal thoughts and behaviors; clinical interview; and physical examination. Group comparisons of symptom scores according to number of lifetime TBIs were made, and generalized regression analyses were used to determine the association of cumulative TBIs with suicide risk. PARTICIPANTS: Patients included 161 military personnel referred for evaluation and treatment of suspected head injury at a military hospital's TBI clinic in Iraq. MAIN OUTCOMES AND MEASURES: Behavioral Health Measure depression subscale, PTSD Checklist-Military Version, concussion symptoms, and Suicide Behaviors Questionnaire-Revised. RESULTS: Depression, PTSD, and TBI symptom severity significantly increased with the number of TBIs. An increased incidence of lifetime suicidal thoughts or behaviors was associated with the number of TBIs (no TBIs, 0%; single TBI, 6.9%; and multiple TBIs, 21.7%; P = .009), as was suicidal ideation within the past year (0%, 3.4%, and 12.0%, respectively; P = .04). The number of TBIs was associated with greater suicide risk (beta [SE] = .214 [.098]; P = .03) when the effects of depression, PTSD, and TBI symptom severity were controlled for. A significant interaction between depression and cumulative TBIs was also found (beta = .580 [.283]; P = .04). CONCLUSIONS AND RELEVANCE: Suicide risk is higher among military personnel with more lifetime TBIs, even after controlling for clinical symptom severity. Results suggest that multiple TBIs, which are common among military personnel, may contribute to increased risk for suicide. PMID- 23676988 TI - Hemorrhagic bullae in a 73-year-old man. Bullous hemorrhagic dermatosis related to enoxaparin use. PMID- 23676986 TI - Role of plasma kallikrein in diabetes and metabolism. AB - Plasma kallikrein (PK) is a serine protease generated from plasma prekallikrein, an abundant circulating zymogen expressed by the Klkb1 gene. The physiological actions of PK have been primarily attributed to its production of bradykinin and activation of coagulation factor XII, which promotes inflammation and the intrinsic coagulation pathway. Recent genetic, molecular, and pharmacological studies of PK have provided further insight into its role in physiology and disease. Genetic analyses have revealed common Klkb1 variants that are association with blood metabolite levels, hypertension, and coagulation. Characterisation of animal models with Klkb1 deficiency and PK inhibition have demonstrated effects on inflammation, vascular function, blood pressure regulation, thrombosis, haemostasis, and metabolism. These reports have also identified a host of PK substrates and interactions, which suggest an expanded physiological role for this protease beyond the bradykinin system and coagulation. The review summarises the mechanisms that contribute to PK activation and its emerging role in diabetes and metabolism. PMID- 23676989 TI - Selective synthesis of the [Ni36Co8C8(CO)48]6- octa-carbide carbonyl cluster by thermal decomposition of the [H2Ni22Co6C6(CO)36]4- hexa-carbide. AB - The thermal decomposition in thf solution of [H2Ni22Co6C6(CO)36](4-) results in the new [HNi36Co8C8(CO)48](5-) bimetallic Ni-Co octa-carbide, which can be converted into the closely related [H6-nNi36Co8C8(CO)48](n-) (n = 3-6) polyhydrides by means of acid-base reactions. The structure of the [Ni36Co8C8(CO)48](6-) hexa-anion has been established via X-ray crystallography, showing that the eight interstitial carbide atoms are lodged within different metal cages. Thus, two C-atoms are enclosed within regular square anti-prismatic Ni8C cages, four within irregular Ni8C square anti-prismatic cages, and the last two within mono-capped trigonal prismatic Ni5Co2C cages. The structure of [Ni36Co8C8(CO)48](6-) is non-compact and closely related to [Ni32C6(CO)38](6-) and [HNi38C6(CO)44](5-). [Ni36Co8C8(CO)48](6-) approaches the nanosize regime and the whole molecular ion has a diameter (measured from the outer oxygen atoms) of ca. 1.61 nm. PMID- 23676990 TI - Cross metathesis of allyl alcohols: how to suppress and how to promote double bond isomerization. AB - Under standard conditions the cross metathesis of allyl alcohols and methyl acrylate is accompanied by the formation of ketones, resulting from uncontrolled and undesired double bond isomerization. By conducting the CM in the presence of phenol, the catalyst loading and the reaction time required for quantiative conversion can be reduced, and isomerization can be suppressed. On the other hand, consecutive isomerization can be deliberately promoted by evaporating excess methyl acrylate after completing cross metathesis and by adding a base or silane as chemical triggers. PMID- 23676991 TI - The binding and fluorescence quenching efficiency of nitroaromatic (explosive) vapors in fluorescent carbazole dendrimer thin films. AB - We present a study on three generations of fluorescent carbazole dendrimers that exhibit strong binding with nitroaromatic compounds accompanied by photoluminescence (PL) quenching, making them attractive sensing materials for the detection of explosives such as 2,4,6-trinitrotoluene (TNT). The absorption and release of vapors of the (deuterated) TNT analogue 4-nitrotoluene (pNT) from thin films of the dendrimers were studied with a combination of time-correlated neutron reflectometry and PL spectroscopy. When saturated with pNT the PL of the films was fully quenched and could not be recovered with flowing nitrogen at room temperature but only upon heating to 40-80 degrees C. Although the majority of the absorbed pNT could be removed with this method the recovered films were found to still contain a residual pNT concentration of ~0.1 molecules per cubic nanometer. However, the proportion of the PL recovered increased with generation with the third generation dendrimer exhibiting close to full recovery despite the presence of residual pNT. This result is attributed to a combination of two effects. First, the dendrimer films present a range of binding sites for nitroaromatic molecules with the stronger binding sites surviving the thermal recovery process. Second, there is a large decrease of the exciton diffusion coefficient with dendrimer generation, preventing migration of the excitation to the remaining bound pNT. PMID- 23676992 TI - The heat capacity of matter beyond the Dulong-Petit value. AB - We propose a simple new way to evaluate the effect of anharmonicity on a system's thermodynamic functions, such as heat capacity. In this approach, the contribution of all the potentially complicated anharmonic effects to the constant-volume heat capacity is evaluated using one parameter only: the coefficient of thermal expansion. Importantly, this approach is applicable not only to crystals, but also to glasses and viscous liquids. To support this proposal, we perform molecular dynamics simulations of several crystalline and amorphous solids as well as liquids, and find a good agreement between the results from theory and simulations. We observe an interesting non-monotonic behavior of the liquid heat capacity with a maximum, and explain this effect as being a result of competition between anharmonicity at low temperature and decreasing number of transverse modes at high temperature. PMID- 23676993 TI - Outer retinal tubulation in degenerative retinal disorders. AB - PURPOSE: To demonstrate outer retinal tubulation (ORT) in various degenerative retinal disorders. METHODS: This was a retrospective review of the multimodal imaging of 29 eyes of 15 patients with various retinal dystrophies and inflammatory maculopathies manifesting ORT. The morphologic features of ORT and its evolution over time were analyzed using spectral-domain optical coherence tomography data. RESULTS: Outer retinal tubulation was identified as round or ovoid structures with hyperreflective borders in pattern dystrophy (six eyes), acute zonal occult outer retinopathy (five eyes), retinitis pigmentosa (four eyes), Stargardt disease (four eyes), gyrate atrophy (two eyes), choroideremia (two eyes), and various other degenerative conditions. These structures appeared to develop from the invagination of photoreceptors at the junction of intact and atrophic outer retina. During follow-up, the number and distribution of ORT largely remained stable. As zones of atrophy enlarged, the frequency of ORT appeared to increase. The ORT structures were found in <10% of patients with retinitis pigmentosa, Stargardt disease, or pattern dystrophy. CONCLUSION: Outer retinal tubulation is found in various degenerative retinal disorders that share in common damage to the outer retina and/or retinal pigment epithelium. The presence of ORT may be an indicator of underlying disease stage and severity. PMID- 23676994 TI - Electron spin resonance studies of trityl OX063 at a concentration optimal for DNP. AB - We have performed temperature-dependent electron spin resonance (ESR) measurements of the stable free radical trityl OX063, an efficient polarizing agent for dissolution dynamic nuclear polarization (DNP), at the optimum DNP concentration (15 mM). We have found that (i) when compared to the W-band electron spin-lattice relaxation rate T1e(-1) of other free radicals used in DNP at the same concentration, trityl OX063 has slower T1e(-1) than BDPA and 4-oxo TEMPO. At T > 20 K, the T1e(-1)vs. T data of trityl OX063 appears to follow a power law dependence close to the Raman process prediction whereas at T < 10 K, electronic relaxation slows and approaches the direct process behaviour. (ii) Gd(3+) doping, a factor known to enhance DNP, of trityl OX063 samples measured at W-band resulted in monotonic increases of T1e(-1) especially at temperatures below 20-40 K while the ESR lineshapes remained essentially unchanged. (iii) The high frequency ESR spectrum can be fitted with an axial g-tensor with a slight g anisotropy: g(x) = g(y) = 2.00319(3) and g(z) = 2.00258(3). Although the ESR linewidth D monotonically increases with field, the temperature-dependent T1e(-1) is almost unchanged as the ESR frequency is increased from 9.5 GHz to 95 GHz, but becomes faster at 240 GHz and 336 GHz. The ESR properties of trityl OX063 reported here may provide insights into the efficiency of DNP of low-gamma nuclei performed at various magnetic fields, from 0.35 T to 12 T. PMID- 23676996 TI - Use of musculoskeletal ultrasound in clinical studies in physiatry: the "stethoscope" is also becoming the "pen". PMID- 23676995 TI - The dark face of AMPK as an essential tumor promoter. AB - Numerous studies have shown that supraphysiological activation of AMPK could inhibit tumor growth. On the other hand, accumulating data also suggest that AMPK activity is required for tumor growth and migration. These findings suggest that physiological activation of AMPK is critical for tumor growth/migration, possibly through maintenance of ATP levels. Our recent study provides the first evidence that the maintenance of cellular NADPH homeostasis is the predominant mechanism by which AMPK promotes tumor cell survival and solid tumor formation. We showed that AMPK activation is required to maintain intracellular NADPH levels through the activation of fatty acid oxidation (FAO) or the inhibition of fatty acid synthesis (FAS) during glucose deprivation or matrix detachment respectively. Through these processes AMPK activation inhibits the rise in reactive oxygen species (ROS) levels and promotes metabolic adaptation in response to metabolic stress. This finding also provides a new therapeutic opportunity through targeting metabolic adaptation of cancer cells, either alone or in combination with conventional anti-cancer drugs that cause metabolic stress. PMID- 23676997 TI - [Proteomics and translational medicine: molecular biomarkers for cancer diagnosis, prognosis and prediction of therapy outcome]. PMID- 23676998 TI - [Promises and challenges in developing MiRNA as a molecular diagnostic tool for lung cancer]. PMID- 23676999 TI - [Proteome profiling for the identification of lung cancer signatures]. PMID- 23677000 TI - [Targeting the signaling pathways in cancer therapy]. PMID- 23677001 TI - [Great potential of miRNAs as predictive and prognostic markers for cancer]. PMID- 23677002 TI - [Advance in lung cancer surgery]. PMID- 23677003 TI - Angular dependence of the exchange interaction in fluoride-bridged Gd(III) Cr(III) complexes. AB - The observed angular variation of the magnetic exchange coupling parameter in a series of fluoride-bridged chromium(III)-gadolinium(III) complexes is explained by DFT calculations. PMID- 23677005 TI - Aerobic oxidation of indole carbinols using Fe(NO3)3.9H2O/TEMPO/NaCl as catalysts. AB - A practical aerobic oxidation of indole carbinols using Fe(NO3)3.9H2O/TEMPO/NaCl in DCE at room temperature and atmospheric pressure of oxygen affording aldehydes or ketones in good to excellent yields was developed. Furthermore, when using the industrially favored solvent toluene instead of DCE and air instead of pure oxygen, this protocol also works smoothly, demonstrating its high potential for possible industrial application. PMID- 23677006 TI - The missense Thr211Pro mutation in the factor X activation peptide of a bleeding patient causes molecular defect in the clotting cascade. AB - Factor X (FX) is a vitamin K-dependent coagulation zymogen, which upon activation to factor Xa assembles into the prothrombinase complex to activate prothrombin to thrombin. FX can be activated by either factor VIIa-tissue factor or factor IXa factor VIIIa in extrinsic and intrinsic pathways, respectively. In this study, we identified a bleeding patient with moderate FX deficiency who exhibits a clotting defect only in the intrinsic pathway. Exome sequencing revealed that the patient carries a novel homozygous missense mutation that results in substitution of Thr211 with Pro in the activation peptide of FX. Thr211 is the site of an O linked glycosylation in the activation peptide of FX. We postulated that the lack of this post-translational modification specifically impacts the activation of FX by intrinsic Xase, thereby impairing thrombin generation in the subject. To test this hypothesis, we expressed both wild-type FX and FX containing this mutation in mammalian cells and following the purification of the zymogens to homogeneity characterized their properties in both purified and plasma-based assay systems. Analysis of the results suggests that Thr211 to Pro substitution renders the FX mutant a poor substrate for both physiological activators, however, at physiological concentration of the substrate, the clotting defect manifest itself only in the intrinsic pathway, thus explaining the bleeding phenotype for the patient carrying this mutation. PMID- 23677007 TI - Behavioral and neurophysiological correlates of autobiographical memory deficits in patients with depression and individuals at high risk for depression. AB - IMPORTANCE: Individuals with major depressive disorder (MDD) compared with healthy control subjects (HCs) consistently recall fewer specific and more categorical autobiographical memories (AMs). This effect is most pronounced for positive AMs and persists into remission. OBJECTIVES: To determine whether individuals at high familial risk for developing MDD (HR group) also show an AM overgenerality bias and to use functional magnetic resonance imaging to assess differences in functional correlates of AM recall across HR, currently depressed MDD, and HC groups. DESIGN: While recalling AMs in response to emotionally valenced cue words, study participants underwent functional magnetic resonance imaging. Control tasks involved generating examples from a given category and counting the number of risers in a letter string. SETTING: Testing was conducted at the Laureate Institute for Brain Research, Tulsa, Oklahoma. PARTICIPANTS: Participants included 16 unmedicated patients with MDD, 16 HR participants, and 16 HCs. MAIN OUTCOMES AND MEASURES: Percentage of specific and categorical AMs recalled and brain regions in which hemodynamic activity changed during specific and positive AM recall compared with example generation. RESULTS: Both the MDD and HR groups generated fewer specific, more categorical, and fewer positive AMs than the HC group (P <= .02 for all). During specific AM recall compared with example generation, neuroimaging results showed between-group differences in the left cuneus (Talairach space coordinates x, y, z = -7, -71, 18; F = 7.55), right medial frontal cortex (x, y, z = 7, 59, 12; F = 8.53), right frontal operculum (x, y, z = 23, 23, 12; F = 8.25), and right and left pregenual anterior cingulate cortex (x, y, z = 9, 37, 10 and x, y, z = -3, 43, 6; F = 6.84 and F = 7.13, respectively). CONCLUSIONS AND RELEVANCE: Autobiographic memory deficits exist in HR individuals, suggesting that these impairments constitute traitlike abnormalities in MDD. We also found distinct patterns of hemodynamic activity for each group as they recalled specific AMs. Specifically, the HR and MDD groups showed differential hemodynamic activity from HCs in medial prefrontal and occipital regions, suggesting that these groups may use different self referential focus during successful retrieval of specific memories. PMID- 23677008 TI - Dysbiosis in inflammatory bowel diseases: the oxygen hypothesis. AB - The healthy intestine is characterized by a low level of oxygen and by the presence of large bacterial communities of obligate anaerobes. Dysbiosis of the gut microbiota has been reported in patients suffering from inflammatory bowel diseases (IBDs), but the mechanisms causing this imbalance remain unknown. Observations have included a decrease in obligate anaerobes of the phylum Firmicutes and an increase in facultative anaerobes, including members of the family Enterobacteriaceae. The shift of bacterial communities from obligate to facultative anaerobes strongly suggests a disruption in anaerobiosis and points to a role for oxygen in intestinal dysbiosis. Proposals to evaluate this hypothesis of a role for oxygen in IBD dysbiosis are provided. If this hypothesis is confirmed, decreasing oxygen in the intestine could open novel means to rebalance the microbiota and could provide novel preventative or therapeutic strategies for IBD patients in whom current treatments are ineffective. PMID- 23677009 TI - Insights from quantitative metaproteomics and protein-stable isotope probing into microbial ecology. AB - The recent development of metaproteomics has enabled the direct identification and quantification of expressed proteins from microbial communities in situ, without the need for microbial enrichment. This became possible by (1) significant increases in quality and quantity of metagenome data and by improvements of (2) accuracy and (3) sensitivity of modern mass spectrometers (MS). The identification of physiologically relevant enzymes can help to understand the role of specific species within a community or an ecological niche. Beside identification, relative and absolute quantitation is also crucial. We will review label-free and label-based methods of quantitation in MS-based proteome analysis and the contribution of quantitative proteome data to microbial ecology. Additionally, approaches of protein-based stable isotope probing (protein-SIP) for deciphering community structures are reviewed. Information on the species-specific metabolic activity can be obtained when substrates or nutrients are labeled with stable isotopes in a protein-SIP approach. The stable isotopes ((13)C, (15)N, (36)S) are incorporated into proteins and the rate of incorporation can be used for assessing the metabolic activity of the corresponding species. We will focus on the relevance of the metabolic and phylogenetic information retrieved with protein-SIP studies and for detecting and quantifying the carbon flux within microbial consortia. Furthermore, the combination of protein-SIP with established tools in microbial ecology such as other stable isotope probing techniques are discussed. PMID- 23677011 TI - Using high resolution electronic spectroscopy to probe the effects of ring twist on charge transfer in 2-phenylindole and N-phenylcarbazole. AB - High resolution electronic spectra of 2-phenylindole (PI) and N-phenylcarbazole (PC) have been recorded in the collision-free environment of a molecular beam. Inertial defects determined from fits of the spectra were used to determine the twist angles between the two chromophores and their attached benzene rings in the ground (S0) and excited (S1) electronic states. PI was found to be significantly more planar than PC, especially in the S1 state. Stark-effect measurements of the permanent electric dipole moments of both molecules in both states show that significantly more charge is transferred from the phenyl group to the chromophore in PI (0.13e) than in PC (0.076e) when the photon is absorbed. Thereby demonstrated for the first time is a direct connection between photo-induced geometry change and charge transfer on excitation of an isolated molecule by light. PMID- 23677010 TI - A design-constraint trade-off underpins the diversity in ecologically important traits in species Escherichia coli. AB - Bacterial species are internally diverse in genomic and multi-locus gene comparisons. The ecological causes of phenotypic and genotypic diversity within species are far less well understood. Here, we focus on the competitive fitness for growth on nutrients within Escherichia coli, an internally rich species. Competition experiments in nutrient-limited chemostats revealed that members of the ECOR collection exhibited a wide continuum of competitive abilities, with some fitter and some less fit than the lab strain MG1655. We observed an inverse relationship between competitiveness and the resistance of strains to detergent and antibiotic, consistent with the notion that membrane permeability and competitive fitness are linked by a trade-off between self-preservation and nutritional competence (SPANC); high permeability has a postulated cost in antibacterial sensitivity whereas a low permeability has a cost in nutrient affinity. Isolates moved along the markedly nonlinear trade-off curve by mutational adaptation; an ECOR strain sensitive to antibacterials and a good competitor was easily converted by mutation into a mutant with higher resistance but poorer competition in the presence of low antibiotic concentrations. Conversely, a resistant ECOR strain changed into a better competitor after a short period of selection under nutrient limitation. In both directions, mutations can affect porin proteins and outer membrane permeability, as indicated by protein analysis, gene sequencing and an independent assay of outer membrane permeability. The extensive, species-wide diversity of E. coli in ecologically important traits can thus be explained as an evolutionary consequence of a SPANC trade-off driven by antagonistic pleiotropy. PMID- 23677012 TI - Calculation of arrangement of oxygen ions and vacancies in double perovskite GdBaCo2O(5+delta) by first-principles DFT with Monte Carlo simulations. AB - The configurations of oxygen ions and vacancies at various oxygen stoichiometries and temperatures in double perovskite oxides (GdBaCo2O(5+delta), 0 <= delta <= 1) have been determined by density functional theory (DFT) combined with Monte Carlo (MC) simulations. The MC simulations confirmed the existence of a superstructure at delta = 0.5, showing alternating linear ordering of oxygen ions and vacancies along the b-axis in the GdO layer. This structure is identical to that reported experimentally. Increasing the temperature up to 1200 K induces a phase transition manifested in the breaking of the oxygen/vacancy arrangement at around delta = 0.5. In the high-temperature phase, vacancies are distributed in the GdO and CoO2 layers, whereas there are no vacancies in the BaO layer. In addition, the characteristic linear arrangement is partly preserved even in the disordered high-temperature phase. Consequently, oxygen ions can migrate between the GdO and CoO2 layers, as reported in previous classical molecular dynamics simulation studies. PMID- 23677013 TI - Spins on a curved surface: an Fe(III)14 ferracalixarene. AB - The synthesis of the high-nuclearity Fe(III)14 coordination cluster [Fe14(MU3 O)6(MU3-OH)4(MU-OH)3Cl11(dea)4(Hdea)3]Cl.H2O.27MeCN (1) is reported (in which deaH2 = diethanolamine). X-ray crystallographic analysis revealed that compound 1 crystallises in the cubic space group Im3 with Z = 24 and 8 independent Fe centres. Unusually for an Fe(III) coordination cluster, the Fe(III) centres in 1 adopt a range of 4, 5 and 6 coordinate geometries. Complex 1 presents a ferracalixarene topology which can be described in terms of a "half tennis ball" structure and binds a chloride anion guest via multiple hydrogen bonds. The curvature in the structure induced by this topology affects the overall spin structure. A ground spin state of S = 7 is proposed using a combination of magnetic susceptibility data and density functional theory (DFT) calculations. PMID- 23677014 TI - Electron-ion coupling effects on radiation damage in cubic silicon carbide. AB - A two-temperature model has been used to investigate the effects of electron-ion coupling on defect formation and evolution in irradiated cubic silicon carbide. By simulating 10 keV displacement cascades under identical primary knock-on atom conditions, we find that the final displacement and the kinetic energy of the primary knock-on atom decrease rapidly with increasing electron-ion coupling strength. Moreover, by analyzing the number of peak defects, atomic and electronic temperatures, it is found that a higher number of peak defects is created for intermediate coupling strength due to the electronic temperature making a contribution to the disorder. Strong electron-ion coupling rapidly removes energy from the cascade, thus the number of peak defects is lower. Meanwhile, there is a non-monotonic trend in the relationship between the coupling strength and the time at which the temperature of atoms reaches the minimum. Furthermore, we discuss the mechanisms involved. PMID- 23677016 TI - Residential segregation and gonorrhea rates in US metropolitan statistical areas, 2005-2009. AB - BACKGROUND: The residential segregation of black populations, often in areas of high-economic disadvantage and low social status, may play a crucial role in the observed racial inequities in sexually transmitted disease rates. METHODS: An ecological analysis of 2005 to 2009 average gonorrhea rates was performed across 277 US metropolitan statistical areas (MSAs). The black isolation index and Gini index of income inequality were used as proxy measures for racial and economic residential segregation respectively, derived from 2005 to 2009 US Census estimates. We used logistic regression modeling to produce estimates of odds ratios (ORs) and 95% confidence intervals (CIs) for the association between the segregation indices, both independently and in combination, on gonorrhea rates in MSAs. Effect measure modification was assessed by calculating the relative excess risk due to interaction between the 2 indices. RESULTS: Compared with MSAs with low levels of racial segregation, MSAs with high levels of racial segregation had increased odds of high gonorrhea rates (adjusted OR, 3.37; 95% CI, 1.23-9.21). Similarly, higher levels of income inequality predicted higher gonorrhea rates, although this association did not persist after adjustment for potential confounders (adjusted OR, 1.54; 95% CI, 0.74-3.24). In combined models, the influence of racial residential segregation on gonorrhea rates was stronger than that of income inequality-based segregation; there was no evidence of additivity or a multiplicative interaction. CONCLUSIONS: Residential segregation by race or income equality may be a key component in the perpetuation of high rates of gonorrhea and other sexually transmitted diseases among black populations in the United States. PMID- 23677015 TI - HIV, rectal chlamydia, and rectal gonorrhea in men who have sex with men attending a sexually transmitted disease clinic in a midwestern US city. AB - BACKGROUND: Men who have sex with men (MSM) who report receptive anal intercourse (RAI) are currently recommended to undergo at least annual screening for rectal Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) infection. METHODS: Using standard culture methods, we assessed the prevalence of rectal GC/CT among MSM who reported RAI in the last year (n = 326) at an urban sexually transmitted disease (STD) clinic in a midwestern US city. A subset (n = 125) also underwent rectal GC/CT screening via nucleic acid amplification testing. We examined the associations between HIV status and prevalence of rectal GC and rectal CT using unadjusted and adjusted logistic regression models. RESULTS: The prevalence of rectal GC, rectal CT, and either rectal infection was 9%, 9%, and 15% by culture and 24%, 23%, and 38% by nucleic acid amplification testing, respectively. HIV was not associated with rectal GC prevalence in unadjusted or adjusted analyses. HIV-positive status was significantly associated with increased rectal CT prevalence in unadjusted models (odds ratio, 2.18; 95% confidence interval, 1.04 4.60); this association increased after multivariable adjustment (odds ratio, 3.14; 95% confidence interval, 1.37-7.19). CONCLUSIONS: Men who have sex with men reporting RAI had a high prevalence of rectal GC and rectal CT. HIV-positive status was significantly associated with prevalent rectal CT but not with prevalent rectal GC. PMID- 23677017 TI - Residential racial segregation and disparities in sexually transmitted disease risk in the United States: the growing evidence. PMID- 23677018 TI - Biological markers of sexual activity: tools for improving measurement in HIV/sexually transmitted infection prevention research. AB - Research on interventions to prevent HIV and other sexually transmitted infections (STIs) is heavily influenced by participant reporting of sexual behavior, despite uncertainty about its validity. Exclusive reliance on participant self-report often is based, overtly or by implication, on 4 assumptions: (1) no feasible alternatives exist; (2) misreporting can be minimized to levels that can be disregarded; (3) misreporting tends to underreport sensitive behaviors; and (4) misreporting tends to be nondifferential with respect to the groups being compared. The objective of this review are to evaluate these assumptions, including a review of studies using semen biomarkers to evaluate the validity of self-reported data, and to make recommendations for applying biological markers of semen exposure detectable in women to further strengthen research on HIV/STI prevention. Increasing evidence shows that semen biomarkers provide an important means of assessing and augmenting the validity of studies on HIV/STI prevention. Additional biomarkers are needed to assess male exposure to vaginal sex and both male and female exposure to anal sex. Methods and study designs that incorporate biomarkers into studies collecting self reported behavioral data should be considered where possible. PMID- 23677020 TI - Sociostructural 2-mode network analysis: critical connections for HIV transmission elimination. PMID- 23677019 TI - Venue-based affiliation networks and HIV risk-taking behavior among male sex workers. AB - BACKGROUND: This study examined venue-based networks constituted by affiliation with gay bars and street intersections where male sex workers (MSWs) congregate to find their sexual/drug-sharing partners and network influence on risky sexual behavior (e.g., unprotected anal intercourse [UAI]) and HIV infection. METHODS: Data collected in 2003 to 2004 in Houston, Texas, consists of 208 MSWs affiliated with 15 gay bars and 51 street intersections. Two-mode network analysis was conducted to examine structural characteristics in affiliation networks, as well as venue-based network influence on UAI and HIV infection. RESULTS: Centralized affiliation patterns were found where only a few venues were popular among MSWs, and these were highly interdependent. Distinctive structural patterns of venue based clustering were associated with UAI and infection. Individuals who shared venue affiliation with MSWs who engage in UAI were less likely to have UAI themselves. This suggests a downhill effect; that is, individuals compensate for their risk of infection by adjusting their own risk-taking behavior, based on their perceptions of their venue affiliates. CONCLUSIONS: Venue-based HIV/AIDs interventions could be tailored to specific venues so as to target specific clusters that are more likely to engage in risky sexual behavior. PMID- 23677021 TI - A randomized, comparative safety study of a prefilled plastic and user-filled paper applicator with candidate microbicide tenofovir 1% gel. AB - BACKGROUND: A bridging study was performed to compare the safety, dose delivery, and acceptability of a prefilled plastic and user-filled paper applicator to assess whether a low-cost, user-filled, paper applicator could serve as a delivery option for tenofovir (TFV) 1% vaginal microbicide gel. METHODS: The study used a randomized crossover design with 25 healthy women randomized to begin with the prefilled or user-filled applicator. Within each study arm, participants delivered two 4.0-mL doses of TFV 1% gel vaginally for 7 days, with one dose delivered at the clinic each morning and a second dose delivered at home each evening. To assess the primary objective, applicator safety, colposcopy examinations were performed at 2 time points in each study arm. RESULTS: There were no colposcopic findings or adverse events attributable to either applicator. One case of vulvovaginal candidiasis was considered possibly related to gel use. On average, the user-filled applicator delivered 96% of the target dose, with 85% of doses falling within +/- 10% of the average dose volume. Participants found both applicators comparable for ease of use, insertion, and dispensing gel, with 60% of participants preferring the user-filled applicator. CONCLUSIONS: This study suggests that both applicators are safe, and most women delivered TFV with the user-filled applicator as directed. Participants found both applicators acceptable, with a slight majority preferring the user-filled applicator. Incorporating a low-cost, user-filled, paper applicator to deliver TFV could help reduce costs and improve access to TFV 1% gel, especially in resource-limited settings heavily impacted by HIV. PMID- 23677022 TI - A cross-sectional study of sexually transmitted pathogen prevalence and condom use with commercial and noncommercial sex partners among clients of female sex workers in southern India. AB - BACKGROUND: Clients of female sex workers (FSWs) are an important bridging population for HIV and other sexually transmitted infections. However, the extent of risk to female noncommercial partners (NCPs) of clients has not been explored. METHODS: Data originated from a cross-sectional behavioral and biological survey of FSW clients from 5 districts in Karnataka state, southern India. Clients were classified into 3 groups: married, single with at least 1 NCP, and single without an NCP. Bivariate and multivariable logistic regression models were constructed to examine the association between group membership and condom use patterns with FSWs and, where applicable, NCPs. HIV, herpes simplex virus type 2 (HSV-2), and other sexually transmitted infections were examined. Normalized weights were used to account for a complex sampling design. RESULTS: Most respondents in our sample (n = 2328) were married (61%). Compared with single respondents without an NCP, married clients were more likely to never use condoms with both occasional (adjusted odds ratio [AOR], 1.8; 95% confidence interval [CI], 1.3-2.5; P < 0.0001) and regular (AOR, 1.7; 95% CI, 1.1-2.6; P = 0.015) FSWs. Among clients with an NCP, married clients were at higher odds of never using a condom with their NCP (AOR, 5.5; 95% CI, 3.7-8.1; P < 0.0001). Overall prevalence for HIV, HSV-2, syphilis, and chlamydia or gonorrhea infection was 5.7%, 28.3%, 3.6%, and 2.1%, respectively. The prevalence of HSV-2 was 37%, 16%, and 19% among those who were married, those single without an NCP, and those single with an NCP, respectively. CONCLUSIONS: Married respondents were least likely to use condoms with both commercial and noncommercial sexual partners, while also having the highest prevalence of HSV-2. These results illustrate the risk posed to both commercial partners and NCPs of married clients. PMID- 23677023 TI - A prospective cohort study comparing the effect of single-dose 2 g metronidazole on Trichomonas vaginalis infection in HIV-seropositive versus HIV-seronegative women. AB - BACKGROUND: This analysis compared the frequency of persistent Trichomonas vaginalis (TV) among HIV-seropositive and HIV-seronegative women. METHODS: Data were obtained from women enrolled in an open cohort study of sex workers in Kenya. Participants were examined monthly, and those diagnosed as having TV by saline microscopy were treated with single-dose 2 g oral metronidazole. All women on antiretroviral therapy (ART) used nevirapine-based regimens. Generalized estimating equations with a logit link were used to compare the frequency of persistent TV (defined as the presence of motile trichomonads by saline microscopy at the next examination visit within 60 days) by HIV status. RESULTS: Three-hundred sixty participants contributed 570 infections to the analysis (282 HIV-seropositive and 288 HIV-seronegative). There were 42 (15%) persistent infections among HIV-seropositive participants versus 35 (12%) among HIV seronegative participants (adjusted odds ratio, 1.14; 95% confidence interval [CI], 0.70-1.87). Persistent TV was highest among HIV-seropositive women using ART (21/64 [33%]) compared with HIV-seropositive women not using ART (21/217 [10%]). Concurrent bacterial vaginosis (BV) at TV diagnosis was associated with an increased likelihood of persistent TV (adjusted odds ratio, 1.90; 95% confidence interval, 1.16-3.09). CONCLUSIONS: The frequency of persistent TV infection after treatment with single-dose 2 g oral metronidazole was similar by HIV status. Alternative regimens including multiday antibiotic treatment may be necessary to improve cure rates for women using nevirapine-based ART and women with TV and concurrent BV. PMID- 23677024 TI - Does Antiretroviral Therapy Interfere With the Treatment of Trichomonas vaginalis Among HIV+ Women? PMID- 23677025 TI - Where are we with partner treatment in bacterial vaginosis? A critical appraisal of the latest systematic review. PMID- 23677026 TI - Response to Madhivanan et al. PMID- 23677027 TI - Cell viability, collagen synthesis and cytokine expression in human osteoblasts following incubation with generated wear particles using different bone cements. AB - In total hip arthroplasty, wear particles generated at articulating surfaces and interfaces between bone, cement and implants have a negative impact on osteoblasts, leading to osteolysis and implant loosening. The aim of this experimental study was to determine the effects of particulate wear debris generated at the interface between straight stainless steel hip stems (Exeter((r))) and three different bone cements (Palacos((r)) R, SimplexTM P and Cemex((r)) Genta) on cell viability, collagen synthesis and cytokine expression in human osteoblasts. Primary osteoblasts were treated with various concentrations of wear particles. The synthesis of procollagen type I and different cytokines was analysed, and markers for apoptosis and necrosis were also detected. The cytokine synthesis rates in the osteoblasts were initially increased and varied, depending on incubation time and particle concentration. Specific differences in the synthesis rates of interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF) and monocyte chemotactic protein-1 (MCP-1) were observed with the different bone cements examined. The negative effect of the particles on the synthesis of procollagen type I and increased rates of cell apoptosis and necrosis were observed with all three cements analysed. Our present data suggest that wear particles from the interface between the total hip stem and bone cement have a significant effect on viability, cytokine expression and collagen synthesis in human osteoblasts, depending on the bone cement used. PMID- 23677028 TI - Actions of oestradiol and progesterone on the prostate in female gerbils: reversal of the histological effects of castration. AB - The female prostate is a functionally active gland in several mammalian species, including humans and rodents. Investigations of prostate morphophysiology during the phases of the oestrous cycle have shown that the female prostate is influenced by fluctuations in serum concentrations of oestradiol (E2) and progesterone (P4). The aim of the present study was to evaluate the effect of combined prolonged administration of E2 and P4 on the prostate in ovariectomised female gerbils. Ovariectomy caused atrophy and decreased glandular secretory activity. Administration of E2 and P4 (0.1mgkg(-1) diluted in 0.1mL of mineral oil, every 48h over 30 days) resulted in a recovery of overall prostate structure, as evidenced by increased epithelial height, mass and prostatic secretory activity, without leading the appearance of significant lesions. Evaluation of androgen receptor (AR) expression revealed increased immunoreactivity in the E2+P4-treated group. Immunostaining for oestrogen receptor (ER) alpha was decreased in the castrated groups, but increased in the group subjected to hormone treatment. There were no significant differences in ERbeta immunoreactivity among the groups. Assessment of cell proliferation revealed greater immunoreactivity in the treated group. Together, the results indicate that the interaction between E2 and P4 may be responsible for maintaining female prostate gland histophysiology. PMID- 23677029 TI - Antibiotically active metabolites from Talaromyces wortmannii, an endophyte of Aloe vera. PMID- 23677030 TI - A new pseudodepsidone from the Antarctic lichen Stereocaulon alpinum and its antioxidant, antibacterial activity. PMID- 23677031 TI - Micromonospora spongicola sp. nov., an actinomycete isolated from a marine sponge in the Gulf of Thailand. AB - An actinomycete strain, S3-1(T), was isolated from marine sponge sample collected from the Gulf of Thailand. The strain is aerobic, Gram-positive and produced single spores at the tip of the substrate mycelium. Strain S3-1(T) contained meso diaminopimelic acid in the peptidoglycan, whole-cell sugars were arabinose, galactose, glucose, rhamnose, ribose and xylose. The polar lipid profile of strain S3-1(T) consisted of phosphatidylethanolamine, phosphatidylmethylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannosides, phosphoglycolipid and unknown polar lipids. Morphological and chemotaxonomic characteristics of the strain were identified as a member of the genus Micromonospora. Phylogenetic analysis based on 16S rRNA gene sequence analysis of the strain showed similarity to Micromonospora nigra DSM 43818(T) (98.8%), Micromonospora yangpuensis FXJ6.011(T) (98.7%) and Micromonospora narathiwatensis BTG4-1(T) (98.6%). The DNA G+C content was 72.7 mol%. The phenotypic characteristics and DNA-DNA relatedness values supported that the classification of this strain as a novel species in the genus Micromonospora, for which the name Micromonospora spongicola sp. nov. (type strain S3-1(T) =BCC 45595(T)=NBRC 108779(T)) is proposed. PMID- 23677032 TI - Pulmonary disposition of vancomycin nebulized as lipid vesicles in rats. AB - Formulation of antibiotics as inhalable products is proposed to improve their therapeutic index when intended for the treatment of pulmonary infections; as vancomycin shows reduced values of lung partition coefficient, pulmonary administration might be an interesting alternative to conventional administration routes. An experimental study has been performed to compare the pulmonary disposition of vancomycin after inhalation of the drug formulated as a solution and as lipid vesicles (conventional liposomes or liposomes modified with chitosan). Vancomycin concentrations were determined in bronchoalveolar fluid, pulmonary tissue and blood samples from 27 Wistar rats distributed in three groups subjected to nebulisation of the drug formulated as a solution, conventional liposomes or chitosomes. Statistically significant differences between the mean drug concentrations in bronchoalveolar lavage (BALF) and lung tissue were found upon comparing the solution to lipid vesicles (116.95 MUg ml( 1)+/-62.13 versus 68.34 MUg ml(-1)+/-28.90 for liposomes and 65.36+/-22.11 MUg g( 1) for chitosomes in BALF; 222.74+/-37.15 MUg g(-1) versus 357.17+/-65.37 MUg g( 1) for liposomes and 378.83+/-85.87 MUg g(-1) for chitosomes in pulmonary tissue). The amount of available drug estimated by mass balance reached the highest values for chitosomes followed by liposomes (24289.66+/-4795.48 MUg and 20207.91+/-5318.29 MUg, respectively) and the lowest for the solution (18971.64+/ 4765.38 MUg). The drug transport and tissue uptake processes showed to be dependent on the nebulized formulation, being facilitated by the lipid vesicles that improved drug passage from the airway space to the pulmonary tissue and systemic circulation. PMID- 23677033 TI - Diorcinols B-E, new prenylated diphenyl ethers from the marine-derived fungus Aspergillus versicolor ZLN-60. AB - Four new prenylated diphenyl ethers (1-4), diorcinols B-E, together with one known diorcinol (5), were obtained from the marine-derived fungus Aspergillus versicolor. Their structures were established on the basis of chemical and spectroscopic data. The absolute configurations of compounds 1 and 2 were determined by Mosher's ester and specific rotation analysis. Their cytotoxicities were evaluated using A-549, Hela, BEL-7402 and K562 cell lines. Compound 3 exhibited moderate cytotoxicities against the Hela and K562 cell lines with the IC50 values of 31.5 and 48.9 MUM, respectively, and compound 4 exhibited moderate cytotoxicity only against the Hela cell line with the IC50 value of 36.5 MUM. PMID- 23677034 TI - Identification of micromonolactam, a new polyene macrocyclic lactam from two marine Micromonospora strains using chemical and molecular methods: clarification of the biosynthetic pathway from a glutamate starter unit. AB - Through a combination of chemical and molecular analysis, a new polyene macrolactam named micromonolactam was obtained from two marine-derived Micromonospora species. This new polyene metabolite is a constitutional isomer of salinilactam A but contains a different polyene pattern and one cis double bond, in contrast to the all trans structure reported for salinilactam A. The molecular analysis data also established that micromonolactam is a hybrid polyketide derived from 11 polyketide units and a modified glutamate starter unit. PMID- 23677035 TI - First studies directed towards the diastereoselective synthesis of the BCD tricyclic core of brownin F. AB - The BCD tricyclic core of brownin F was prepared in eight synthetic operations for the first time. Our synthesis features a diastereo-, chemo- and regioselective intramolecular [3 + 2] cycloaddition between a cyclic carbonyl ylide and a gamma-alkylidenebutenolide. PMID- 23677036 TI - Multiple slowly growing nodular lesions on the lower legs in a 78-year-old obese woman. Nodular obesity-associated lymphedematous mucinosis. PMID- 23677037 TI - Ru(II)-catalyzed intermolecular C-H amidation of weakly coordinating ketones. AB - An efficient Ru(II)-catalyzed intermolecular amidation of weakly coordinating ketones with sulfonyl azides via C-H bond activation is described. The reaction proceeds with high functional group tolerance, providing a novel approach to practical ketone-directed intermolecular C-N bond formation in the absence of an additional oxidant. PMID- 23677038 TI - Structural changes within the alkaline earth uranyl phosphites. AB - Three new alkaline earth (AE) uranyl phosphites and one barium uranium(IV) phosphate were synthesized under hydrothermal conditions. The carbonate salts of the AE's were employed both as cation sources and as pH regulators. Despite having very similar formulas and uranyl building units, the Ca(2+), Sr(2+) and Ba(2+) uranyl phosphites have three different extended networks. The calcium compound also contains a Ca(2+)/UO2(2+) mixed cation position. The four structure types will be presented herein with the AE cations generating distinct structural transformations. PMID- 23677039 TI - Radially aligned microchannels prepared from ordered arrays of cracks on colloidal films. AB - Arrayed microchannels with dimensions of tens to hundreds of micrometres show great potential for application in microfluidics, microreactor devices and other areas. In this work, we report the formation of ordered arrays of cracks on solution-cast colloidal films, and the preparation of radially aligned microchannels. The polymer film coating enables the colloidal film to be detached from the substrate, retaining the crack patterns on the bottom side. The subsequent chemical corrosion converts the cracks into microchannels. Crack patterned colloidal films are also used as structured substrates for the preparation of honeycomb films by the breath figure method. Hierarchical honeycomb structures are obtained, giving rise to improved support for colloidal films. PMID- 23677042 TI - TB-402 for the prevention of venous thromboembolism in orthopaedic surgery: something new and promising, or not? PMID- 23677041 TI - Global trends in the incidence and prevalence of type 2 diabetes in children and adolescents: a systematic review and evaluation of methodological approaches. AB - AIMS/HYPOTHESIS: This study aimed to systematically review what has been reported on the incidence and prevalence of type 2 diabetes in children and adolescents, to scrutinise the methodological issues observed in the included studies and to prepare recommendations for future research and surveillances. METHODS: PubMed, the Cochrane Database of Systematic Reviews, Scopus, EMBASE and Web of Science were searched from inception to February 2013. Population-based studies on incidence and prevalence of type 2 diabetes in children and adolescents were summarised and methodologically evaluated. Owing to substantial methodological heterogeneity and considerable differences in study populations a quantitative meta-analysis was not performed. RESULTS: Among 145 potentially relevant studies, 37 population-based studies met the inclusion criteria. Variations in the incidence and prevalence rates of type 2 diabetes in children and adolescents were mainly related to age of the study population, calendar time, geographical regions and ethnicity, resulting in a range of 0-330 per 100,000 person-years for incidence rates, and 0-5,300 per 100,000 population for prevalence rates. Furthermore, a substantial variation in the methodological characteristics was observed for response rates (60-96%), ascertainment rates (53-99%), diagnostic tests and criteria used to diagnose type 2 diabetes. CONCLUSIONS/INTERPRETATION: Worldwide incidence and prevalence of type 2 diabetes in children and adolescents vary substantially among countries, age categories and ethnic groups and this can be explained by variations in population characteristics and methodological dissimilarities between studies. PMID- 23677043 TI - High performance PbS Quantum Dot Sensitized Solar Cells exceeding 4% efficiency: the role of metal precursors in the electron injection and charge separation. AB - Here we report the preparation of high performance Quantum Dot Sensitized Solar Cells (QDSCs) based on PbS-CdS co-sensitized nanoporous TiO2 electrodes. QDs were directly grown on the TiO2 mesostructure by the Successive Ionic Layer Absorption and Reaction (SILAR) technique. This method is characterized by a fast deposition rate which involves random crystal growth and poor control of the defect states and lattice mismatch in the QDs limiting the quality of the electrodes for photovoltaic applications. In this work we demonstrate that the nature of the metallic precursor selected for SILAR has an active role in both the QD's deposition rate and the defect's distribution in the material, with important consequences for the final photovoltaic performance of the device. For this purpose, acetate and nitrate salts were selected as metallic precursors for the SILAR deposition and films with similar absorption properties and consequently with similar density of photogenerated carriers were studied. Under these conditions, ultrafast carrier dynamics and surface photovoltage spectroscopy reveal that the use of acetate precursors leads to higher injection efficiency and lower internal recombination due to contribution from defect states. This was corroborated in a complete cell configuration with films sensitized with acetate precursors, achieving unprecedented photocurrents of ~22 mA cm(-2) and high power conversion efficiency exceeding 4%, under full 1 sun illumination. PMID- 23677044 TI - Spinal and paraspinal infections associated with contaminated methylprednisolone acetate injections - Michigan, 2012-2013. AB - As of May 6, 2013, Michigan had reported 167 (52%) of the 320 paraspinal or spinal infections without meningitis associated with the 2012-2013 fungal meningitis outbreak nationally. Although the index patient had a laboratory confirmed Aspergillus fumigatus infection, the fungus most often identified, including in unopened vials of methylprednisolone acetate (MPA), remains Exserohilum rostratum, a common black mold found on plants and in soil. Exposures have occurred through epidural, paraspinal, peripheral nerve, and intra-articular injection with MPA from contaminated lots compounded by the New England Compounding Center in Framingham, Massachusetts. The Michigan Department of Community Health and CDC conducted case ascertainment to describe epidemiologic and clinical characteristics of Michigan patients and to determine factors that might have contributed to the high percentage of spinal and paraspinal infections reported from Michigan. A distinct epidemiologic or clinical difference was not observed between patients with paraspinal or spinal infection with and without meningitis. Lengthy periods (range: 12-121 days) were observed from date of last injection with contaminated MPA to date of first magnetic resonance imaging (MRI) finding indicative of infection. Clinicians should continue to maintain a higher index of suspicion for patients who received injections with contaminated MPA but have not developed infection. PMID- 23677045 TI - Assessment of risk for exposure to bats in sleeping quarters before and during remediation - Kentucky, 2012. AB - Bats are a reservoir for rabies viruses and have been identified as the most common source of human rabies infections acquired in the United States. The last human rabies fatality from a bat exposure reported in a Kentucky resident occurred in 1996. In July 2012, the Kentucky Department for Public Health (KDPH) was advised of multiple potential bat exposures following efforts to eliminate a bat colony from a volunteer facility. Bats had routinely been sighted in a brick building in eastern Kentucky that had been used as sleeping quarters by an organization that, since 1999, had hosted thousands of children and adults who performed stints of volunteer work over the course of several days. To assess the risk for bat exposure, KDPH and CDC interviewed 257 (94%) of the 273 volunteers and staff members who had slept in the facility in 2012. As a result of that assessment, 48 (19%) persons were identified as potentially exposed, and 16 (33%) of the 48 were recommended to receive rabies postexposure prophylaxis (PEP), including three persons categorized as at high risk and 13 as at moderate risk for exposure. This report highlights the need for guidelines for appropriate remediation of bat infestation and public health investigations of potential mass bat contacts. PMID- 23677046 TI - Microbes in pool filter backwash as evidence of the need for improved swimmer hygiene - metro-Atlanta, Georgia, 2012. AB - Filters physically remove contaminants, including microbes, from water in treated recreational water venues, such as pools. Because contaminants accumulate in filters, filter concentrates typically have a higher density of contamination than pool water. During the 2012 summer swimming season, filter concentrate samples were collected at metro-Atlanta public pools. Quantitative polymerase chain reaction (qPCR) assays were conducted to detect microbial nucleic acid. Pseudomonas aeruginosa was detected in 95 (59%) of 161 samples; detection indicates contamination from the environment (e.g., dirt), swimmers, or fomites (e.g., kickboards). P. aeruginosa detection underscores the need for vigilant pool cleaning, scrubbing, and water quality maintenance (e.g., disinfectant level and pH) to ensure that concentrations do not reach levels that negatively impact swimmer health. Escherichia coli, a fecal indicator, was detected in 93 (58%) samples; detection signifies that swimmers introduced fecal material into pool water. Fecal material can be introduced when it washes off of swimmers' bodies or through a formed or diarrheal fecal incident in the water. The risk for pathogen transmission increases if swimmers introduce diarrheal feces. Although this study focused on microbial DNA in filters (not on illnesses), these findings indicate the need for swimmers to help prevent introduction of pathogens (e.g., taking a pre-swim shower and not swimming when ill with diarrhea), aquatics staff to maintain disinfectant level and pH according to public health standards to inactivate pathogens, and state and local environmental health specialists to enforce such standards. PMID- 23677047 TI - Notes from the field: transmission of HBV among assisted-living-facility residents - Virginia, 2012. AB - On June 29, 2012, the Rappahannock Area Health District in northwestern Virginia received a report of an acute hepatitis B virus (HBV) infection in an elderly resident of an assisted-living facility (ALF). The resident reported no risk factors for HBV infection except assisted monitoring of blood glucose (AMBG), which has been implicated in the transmission of HBV in ALFs and other long-term care facilities. Rappahannock Area Health District investigated the source of the infection and the scope of transmission. Investigators observed facility infection control practices and procedures and conducted staff interviews. The facility was scheduled to close July 31, 2012, necessitating prompt response before residents were transferred. PMID- 23677049 TI - Hmgb1-TLR4-IL-23-IL-17A axis promote ischemia-reperfusion injury in a cardiac transplantation model. AB - BACKGROUND: Cardiac transplantation is the last resort for patients with end stage heart failure. Ischemia-reperfusion (IR) injury is a major issue in cardiac transplantation. Inflammatory processes play a major role in myocardial IR injury. However, the cellular and molecular immune mechanisms of myocardial IR injury remain elusive. METHODS: Hearts of C57BL/6 mice were flushed and stored in cold Bretschneider solution for 8 hr and then transplanted into syngeneic recipient. The involvement of high-mobility group box 1 (Hmgb1) and interleukin (IL)-17A was assessed in functional assays by neutralizing Hmgb1 or IL-17A. RESULTS: IL-17A was elevated after myocardial IR injury in cardiac transplantation. IL-17A was predominantly produced by gammadeltaT cells rather than CD4 or CD8 T cells infiltrated into the cardiac isografts. Neutralizing antibody against IL-17A or gammadeltaTCR attenuated cardiomyocyte apoptosis and neutrophil recruitment. Furthermore, a neutralizing IL-23p19 antibody decreased the level of IL-17A and neutrophil infiltration. Importantly, IL-23 and IL-17A were reduced after inhibition of macrophages and could not be induced in TLR4 mice after IR injury. Meanwhile, Hmgb1 increased after IR injury and the Hmgb1 inhibitor glycyrrhizin markedly reduced the production of IL-23 and IL-17A and ameliorated myocardial IR injury. CONCLUSION: The Hmgb1-TLR4-IL-23-IL-17A axis contributes to cardiomyocyte apoptosis, neutrophil accumulation and IR injury in cardiac transplantation. PMID- 23677050 TI - Usefulness of Oxford classification in assessing immunoglobulin A nephropathy after transplantation. AB - BACKGROUND: We explored the efficacy of the Oxford classification for assessing native immunoglobulin A nephropathy (IgAN) in posttransplantation patients compared with the glomerular injury score and Haas classification. METHODS: A total of 125 renal allograft biopsies obtained from 114 patients diagnosed with IgAN regardless of original disease were assessed. RESULTS: The average time to biopsy was 70.5+/-45.3 months after transplantation. Glomeruli showed normal histology in 18.4%. Mesangial hypercellularity (M1), endocapillary hypercellularity (E1), segmental glomerulosclerosis (S1), and tubulointerstitial fibrosis (T1-2) were present in 12.8%, 6.4%, 45.6%, and 20.8% of the samples, respectively. There was a significant correlation between Oxford-MEST scores and glomerular injury score or Haas subclass. S1 and T1-2 were correlated with elevated serum creatinine level, proteinuria, and decreased estimated glomerular filtration rate, and E1 was correlated with decreased estimated glomerular filtration rate at the time of biopsy. The 10- and 15-year graft survival rates were 62.9% and 34.3%, respectively. The graft survival rate was significantly lower in the presence of S1 and T1-2. Endocapillary hypercellularity, segmental sclerosis, and tubulointerstitial fibrosis predicted graft survival and endocapillary hypercellularity and tubulointerstitial fibrosis also predicted serum creatinine doubling. CONCLUSIONS: The Oxford classification scheme is useful for evaluating chronic graft dysfunction in patients with posttransplantation IgAN. In addition to tubulointerstitial fibrosis, the presence of endocapillary hypercellularity and segmental sclerosis should be included in the pathology report. PMID- 23677051 TI - Public awareness and attitudes to living organ donation: systematic review and integrative synthesis. AB - BACKGROUND: The deceased-donor organ shortage has driven widespread adoption of living-donor transplantation. Yet, public views on living donation are not well understood. This study aims to synthesize studies on public awareness and attitudes toward living organ donation. METHODS: Electronic databases and reference lists were searched to September 2012. Summary estimates from survey data were obtained by random effects meta-analysis. Qualitative descriptive synthesis of each study was performed. RESULTS: Forty-seven studies involving 34,610 respondents were included. The proportion of respondents aware of living organ donation was 76.7% (4 studies, n=3248; 95% confidence interval, 46.2% 97.0%; I=99.7%). The majority were in favor of living directed donation (85.5% (11 studies, n=15,836; 95% confidence interval, 81.6%-89.6%; I=98%), with recipient and community benefit as the rationale provided. However, barriers included fear of surgical and health risks, lack of knowledge, respect for cultural norms, financial loss, distrust in hospitals, and avoiding recipient indebtedness. The public voiced concern about possible risks or an obligatory pressure exerted on the donor. Many supported reimbursement for out-of-pocket expenses, paid leave, wait-listing priority, health insurance, and donor acknowledgment. There was strong opposition to financial incentives, which they believed risked exploitation and inequity and diminished voluntary altruistic donation. CONCLUSIONS: The public is generally supportive of living donation and articulated important equity and ethical considerations for protecting the health and safety of living donors. This supports increased public engagement and strengthening of a shared view among professionals and the public in living donation practice and policy. PMID- 23677052 TI - Factors affecting transplant outcomes in diabetic nude mice receiving human, porcine, and nonhuman primate islets: analysis of 335 transplantations. AB - BACKGROUND: In the absence of a reliable islet potency assay, nude mice (NM) transplantation is the criterion standard to assess islet quality for clinical transplantation. There are factors other than islet quality that affect the transplant outcome. METHODS: Here, we analyzed the transplant outcomes in 335 NM receiving islets from human (n=103), porcine (n=205), and nonhuman primate (NHP; n=27) donors. The islets (750, 1000, and 2000 islet equivalents [IEQ]) were transplanted under the kidney capsule of streptozotocin-induced diabetic NM. RESULTS: The proportion of mice that achieved normoglycemia was significantly higher in the group implanted with 2000 IEQ of human, porcine, or NHP islets (75% normoglycemic) versus groups that were implanted with 750 IEQ (7% normoglycemic) and 1000 IEQ (30% normoglycemic). In this study, we observed that the purity of porcine islet preparations (P<=0.001), islet pellet size in porcine preparations (P<= 0.01), and mice recipient body weight for human islet preparations (P=0.013) were independently associated with successful transplant outcome. NHP islets of 1000 IEQ were sufficient to achieve normoglycemic condition (83%). An islet mass of 2000 IEQ, high islet purity, increased recipient body weight, and high islet pellet volume increased the likelihood of successful reversal of diabetes in transplanted mice. Also, higher insulin secretory status of islets at basal stimulus was associated with a reduced mouse cure rate. The cumulative incidence of graft failure was significantly greater in human islets (56.12%) compared with porcine islets (35.57%; P<=0.001). CONCLUSION: Factors affecting NM bioassay were identified (islet mass, islet purity, pellet size, in vitro insulin secretory capability, and mouse recipient body weight) and should be considered when evaluating islet function. PMID- 23677053 TI - Use of pharmacogenetics for predicting cancer prognosis and treatment exposure, response and toxicity. AB - Cancer treatment is complicated because of a multitude of treatment options and little patient-specific information to help clinicians choose appropriate therapy. There are two genomes relevant in cancer treatment: the tumor (somatic) and the patient (germline). Together, these two genomes dictate treatment outcome through four processes: the somatic genome primarily determines tumor prognosis and response while the germline genome modulates treatment exposure and toxicity. In this review, we describe the influence of these genomes on treatment outcomes by highlighting examples of genetic variation that are predictors of each of these four factors, prognosis, response, toxicity and exposure, and discuss the translation and clinical implementation of each. Use of pre-treatment pharmacogenetic testing will someday enable clinicians to make individualized therapy decisions about aggressiveness, drug selection and dose, improving treatment outcomes for cancer patients. PMID- 23677054 TI - Analysis of genetic variants of dyslexia candidate genes KIAA0319 and DCDC2 in Indian population. AB - Developmental dyslexia (DD) is a heritable, complex genetic disorder associated with impairment in reading and writing skills despite having normal intellectual ability and appropriate educational opportunities. Chromosome 6p23-21.3 at DYX2 locus has showed the most consistent evidence of linkage for DD and two susceptible genes KIAA0319 and DCDC2 for DD at DYX2 locus showed significant association. Specific candidate gene-association studies have identified variants, risk haplotypes and microsatellites of KIAA0319 and DCDC2 correlated with wide range of reading-related traits. In this study, we used a case-control approach for analyzing single-nucleotide polymorphisms (SNPs) in KIAA0319 and DCDC2. Our study demonstrated the association of DD with SNP rs4504469 of KIAA0319 and not with any SNPs of DCDC2. PMID- 23677055 TI - Family-based genome-wide copy number scan identifies five new genes of dyslexia involved in dendritic spinal plasticity. AB - Genome-wide screening for copy number variations (CNVs) in ten Indian dyslexic families revealed the presence of five de novo CNVs in regions harboring GABARAP, NEGR1, ACCN1, DCDC5, and one in already known candidate gene CNTNAP2. These genes are located on regions of chromosomes 17p13.1, 1p31.1, 17q11.21, 11p14.1 and 7q35, respectively, and are implicated in learning, cognition and memory processes through dendritic spinal plasticity, though not formally associated with dyslexia. Molecular network analysis of these and other dyslexia-related module genes suggests them to be associated with synaptic transmission, axon guidance and cell adhesion. Thus, we suggest that dyslexia may also be caused by neuronal disconnection in addition to the earlier view that it is due to neuronal migrational disorder. PMID- 23677057 TI - Identification of KCNN2 as a susceptibility locus for coronary artery aneurysms in Kawasaki disease using genome-wide association analysis. AB - Kawasaki disease (KD) is often complicated by coronary artery lesions (CALs), including aneurysms. Because of the complications associated with KD, this disorder is the leading cause of acquired heart disease in children from developed countries. To identify genetic loci that confer a higher risk of developing CALs, we performed a case-control association study using previous genome-wide association study data for samples from KD cases only (n=186) by grouping KD patients without CALs (control: n=123) vs KD patients with extremely large aneurysms (diameter>5 mm) (case: n=17). Twelve loci with one or more sequence variants were found to be significantly associated with CALs (P<1 * 10( 5)). Of these, an SNP (rs17136627) in the potassium intermediate/small conductance calcium-activated channel, subfamily N, member 2 (KCNN2) at 5q22.3 was validated in 32 KD patients with large aneurysms (diameter>5 mm) and 191 KD patients without CALs (odds ratio (OR)=12.6, P(combined)=1.96 * 10(-8)). This result indicates that the KCNN2 gene can have an important role in the development of coronary artery aneurysms in KD. PMID- 23677056 TI - Epigenomic strategies at the interface of genetic and environmental risk factors for autism. AB - Autism spectrum disorders (ASD) have been increasing in prevalence over the last two decades, primarily because of increased awareness and diagnosis. However, autism is clearly a complex human genetic disorder that involves interactions between genes and environment. Epigenetic mechanisms, such as DNA methylation, act at the interface of genetic and environmental risk and protective factors. Advancements in genome-wide sequencing has broadened the view of the human methylome and revealed the organization of the human genome into large-scale methylation domains that footprint over neurologically important genes involved in embryonic development. Future integrative epigenomic analyses of genetic risk factors with environmental exposures and methylome analyses are expected to be important for understanding the complex etiology of ASD. PMID- 23677059 TI - Newborn screening for Fabry disease in Japan: prevalence and genotypes of Fabry disease in a pilot study. AB - Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency of alpha-galactosidase A (GLA) activity. Enzyme replacement therapy (ERT) for FD is available, and newborn mass screening for FD is being implemented. Here, we undertook a pilot study of newborn mass screening for FD in Japan. GLA activity in dried blood spots was measured using a fluorescence assay and confirmed by measurement of GLA activity in white blood cells (WBCs) in infants with abnormally low GLA activity. This was followed up by genetic testing. A total of 21 170 neonates were enrolled in the study. Of these, seven (five boys, two girls) had low GLA activities, which were verified by the WBC GLA activity assay. Thus, the initial fluorescence assay was suitable for newborn mass screening for FD. Pathogenic mutations of the GLA gene, that is, V199M and IVS4+919G>A, were found in two boys and one boy, respectively. Functional mutations, E66Q and c.-10C>T: g.1170C>T, were found in two boys and one girl, respectively. The prevalence of test-positive newborns was 1/3024, while that of those with a pathogenic mutation was 1/7057. The numbers are higher than those previously anticipated. Standardized management for FD found during newborn mass screening, including an ERT regimen, remains to be established. PMID- 23677058 TI - Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a clinically heterogeneous disease, with a 5-year disease-free survival (DFS) ranging from under 10% to over 70% for distinct groups of patients. At our institution, cytarabine, etoposide and busulfan are used in first or second remission patients treated with a two-step approach to autologous stem cell transplantation (ASCT). In this study, we tested the hypothesis that polymorphisms in the pharmacokinetic and pharmacodynamic pathway genes of these drugs are associated with DFS in AML patients. A total of 1659 variants in 42 genes were analyzed for their association with DFS using a Cox proportional hazards model. One hundred and fifty-four genetically European patients were used for the primary analysis. An intronic single nucleotide polymorphism (SNP) in ABCC3 (rs4148405) was associated with a significantly shorter DFS (hazard ratios (HR)=3.2, P=5.6 * 10(-6)) in our primary cohort. In addition, a SNP in the GSTM1-GSTM5 locus, rs3754446, was significantly associated with a shorter DFS in all patients (HR=1.8, P=0.001 for 154 European ancestry; HR=1.7, P=0.028 for 125 non-European patients). Thus, for the first time, genetic variants in drug pathway genes are shown to be associated with DFS in AML patients treated with chemotherapy-based autologous ASCT. PMID- 23677060 TI - Exome sequencing as a diagnostic tool to identify a causal mutation in genetically highly heterogeneous limb-girdle muscular dystrophy. PMID- 23677061 TI - miR-129-2 suppresses proliferation and migration of esophageal carcinoma cells through downregulation of SOX4 expression. AB - We report the emerging role of microRNA (miRNA) deregulation associated with activation of an oncogene SOX4 (a member of the SRY-related HMG-box) in esophageal carcinoma. Paired esophageal cancer and adjacent non-tumor tissues were obtained from 42 patients who underwent primary surgical resection for esophageal cancer. Experiments such as real-time PCR, western blot analysis, luciferase-reporter assay, cell proliferation and colony formation assays, in vitro migration and invasion assays, and a wound-healing assay were performed to determine the effects of miR-129-2. We found that SOX4 expression was elevated (P<0.005) in esophageal tumors (n=42) when compared with its expression in the controls (n=42). Compared with the normal esophageal tissues, the expression of miR-129-2 was downregulated in 27 of 31 primary esophageal tumors, while the expression of SOX4 was upregulated (P<0.001). Restoration of miR-129-2 by transfection with an miRNA expression plasmid led to a decrease in SOX4 expression, which was accompanied by reduced migration and proliferation of the cancer cells. These results suggest that aberrant expression of SOX4 is associated with repression of miR-129-2, and restoration of miR-129-2 suppresses the migration and proliferation of esophageal cancer cells. Our results demonstrated that the deregulation of miR-129-2 leads to aberrant SOX4 expression, presenting a new paradigm in which the restoration of miRNA suppresses its oncogenic target in esophageal cancer. PMID- 23677062 TI - Photothermal release of singlet oxygen from gold nanoparticles. AB - Anthracene endoperoxide ligands anchored to the surfaces of gold nanoparticles undergo bond breaking and release singlet oxygen when the nanoparticles convert 532 nm laser light to heat localized near their surfaces. PMID- 23677063 TI - Iridium-catalyzed triple C(sp3)-H borylations: construction of triborylated sp3 carbon centers. AB - An unprecedented catalytic C(sp(3))-H triborylation at a single carbon was developed with the assistance of a nitrogen directing group. PMID- 23677064 TI - Impact of obesity on ventricular size and function in children, adolescents and adults with Tetralogy of Fallot after initial repair. AB - Obesity is epidemic in congenital heart disease, with reported rates of 16% to 26% in children and 54% in adults. The aim of this study was to evaluate the impact of obesity on ventricular function and size in patients after initial repair for tetralogy of Fallot (TOF). Cardiac magnetic resonance studies in normal-weight (body mass index percentile <85th) and obese (body mass index percentile >=95th) children and adults with repaired tetralogy of Fallot were reviewed. The left ventricular ejection fraction, the right ventricular ejection fraction, left and right ventricular end-diastolic volumes indexed to actual body surface area, to height, and to body surface area using ideal body weight were evaluated in 36 obese patients and 72 age-matched normal-weight patients. Compared with normal-weight patients, obese patients had lower right ventricular ejection fractions (mean 46 +/- 9% vs 51 +/- 7%, p = 0.003) and left ventricular ejection fractions (mean 57 +/- 9% vs 61 +/- 6%, p = 0.017), higher right ventricular end-diastolic volumes indexed to height (mean 160 +/- 59 vs 135 +/- 41 ml/m, p = 0.015) and left ventricular end-diastolic volumes indexed to height (mean 86 +/- 25 vs 70 +/- 20 ml/m, p = 0.001), and higher right ventricular end diastolic volumes indexed to ideal body weight (mean 166 +/- 55 vs 144 +/- 38 ml/m2, p = 0.020) and left ventricular end-diastolic volumes indexed to ideal body weight (mean 90 +/- 22 vs 75 +/- 15 ml/m2, p <0.001). In conclusion, obesity is a modifiable risk factor associated with worsened biventricular systolic function and biventricular dilation in patients with repaired tetralogy of Fallot. The standard method of indexing ventricular volumes using actual body surface area may underestimate volume load in obese patients. PMID- 23677066 TI - Luminescence and photometric characterization of K+ compensated CaMoO4:Dy3+ nanophosphors. AB - A series of CaMoO4 phosphors doped with trivalent dysprosium (Dy(3+)) and codoped with potassium (K(+)) ions were prepared by hydrothermal method. The nanostructures of the as-synthesized phosphors were investigated by X-ray diffraction (XRD). The results reveal that the obtained powder phosphors are single-phase scheelite structure with tetragonal symmetry and the crystallite size is in the range of 10-60 nm. The emission spectra show a bright yellow emission at 576 nm and blue emission at 487 nm. As a charge compensator, K(+) ions were incorporated into CaMoO4:Dy(3+) phosphors, which enhance the PL intensities depending on the doping concentration of K(+). The CIE parameters such as colour coordinates, colour correlated temperature and luminous efficacy of radiation were calculated using spectral energy distribution functions and McCamy's empirical formula. Photometric characterization indicates the suitability of K(+) compensated CaMoO4:Dy(3+) phosphor for white LED applications. PMID- 23677065 TI - Formation of cyclobutane pyrimidine dimers at dipyrimidines containing 5 hydroxymethylcytosine. AB - Much of the cancer-causing effects of ultraviolet radiation from the sun have been linked to the formation of dimerized DNA bases. These dimeric DNA photoproducts include the cyclobutane pyrimidine dimers (CPDs) and the pyrimidine(6-4)pyrimidone photoproducts [(6-4)PPs]. CPDs are highly mutagenic and are produced in substantial quantities by UVB radiation. These dimers can form between any two adjacent pyrimidines and can involve thymine, cytosine, or 5 methylcytosine. Very recently, a sixth DNA base, 5-hydroxymethylcytosine (5hmC) has been identified and characterized as a normal component of mammalian DNA. Here, we investigated the formation of CPDs at different DNA sequences containing 5hmC following irradiation with UVA, UVB, or UVC light sources. We show that the formation of CPDs at dipyrimidines containing 5hmC occurs at different DNA sequences but is not enhanced relative to cytosine or 5-methylcytosines at the same sequence positions. In fact, in some sequence contexts, CPDs containing 5hmC are formed at very low levels. Nonetheless, CPD formation at 5hmC pyrimidines is expected to be biologically relevant since three types of human skin-derived cells, fibroblasts, keratinocytes and melanocytes, all contain detectable levels of this modified base. PMID- 23677068 TI - Molecular pathogenesis of malignant mesothelioma. AB - Malignant mesothelioma (MM) is an aggressive tumor arising primarily from the pleural or peritoneal cavities. It develops by asbestos exposure after a long latency, which is characterized by insidious growth and clinical presentation at an advanced stage of disease. MM is highly refractory to conventional therapies even with a combination of aggressive surgical intervention and multimodality strategies, with cure remaining elusive. Molecular genetic analysis has revealed several key genetic alterations, which are responsible for the development and progression of MM. The cyclin-dependent kinase inhibitor 2A/alternative reading frame (CDKN2A/ARF), neurofibromatosis type 2 (NF2) and BRCA1-associated protein-1 (BAP1) genes are the most frequently mutated tumor suppressor genes detected in MM cells; the alterations of the latter two are relatively characteristic of MM. Merlin, which is encoded by NF2, regulates multiple cell signaling cascades including the Hippo and mammalian target of rapamycin pathways, which regulate cell proliferation and growth. BAP1 is involved in histone modification and its inactivation induces the disturbance of global gene expression profiling. The discovery of a new familial cancer syndrome with germline mutation of BAP1 also indicates the importance of genetic factors in MM susceptibility. Meanwhile, although frequent expression and functional activations of oncogene products such as receptor tyrosine kinases are observed in MM cells, activating mutations of these genes are rare. With further comprehensive genome analyses, new genetic and epigenetic alterations in MM cells are expected to be revealed more precisely, and the new knowledge based on them will be applied for developing new diagnostic tools and new target therapies against MMs. PMID- 23677067 TI - FEZF2, a novel 3p14 tumor suppressor gene, represses oncogene EZH2 and MDM2 expression and is frequently methylated in nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated tumor prevalent in southern China and southeast Asia, with the 3p14-p12 locus reported as a critical tumor suppressor gene (TSG) region during its pathogenesis. We identified a novel 3p14.2 TSG, FEZF2 (FEZ family zinc finger 2), for NPC. FEZF2 is readily expressed in normal tissues including upper respiratory epithelium, testis, brain and ovary tissues, as well as in immortalized nasopharyngeal epithelial cell line NP69, but it is completely silenced in NPC cell lines due to CpG methylation of its promoter, although no homozygous deletion of FEZF2 was detected. 5-Aza-2'-deoxycytidine treatment restored FEZF2 expression in NPC cell lines along with its promoter demethylation. FEZF2 was frequently downregulated in NPC tumors, with promoter methylation detected in 75.5% of tumors, but only in 7.1% of normal nasopharyngeal tissues. Restored FEZF2 expression suppressed NPC cell clonogenicity through inducing G2/M cell cycle arrest and apoptosis and also inhibited NPC cell migration and stemness. FEZF2 acted as a histone deacetylase associated repressor downregulating multiple oncogenes including EZH2 and MDM2, through direct binding to their promoters. Concomitantly, overexpression of EZH2 was frequently detected in NPC tumors. Thus, we have identified FEZF2 as a novel 3p14.2 TSG frequently inactivated by promoter methylation in NPC, which functions as a repressor downregulating multiple oncogene expression. PMID- 23677069 TI - Critical role of the WASF3 gene in JAK2/STAT3 regulation of cancer cell motility. AB - WASF3 has been shown to be required for invasion and metastasis in different cancer cell types and knockdown of WASF3 leads to suppression of invasion/metastasis. Aberrant signaling through the interleukin 6/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) axis in cancer cells has emerged as a major mechanism for cancer progression. In this study, we demonstrate that interleukin 6 induces both WASF3 expression and phosphoactivation in breast and prostate cancer cell lines through the JAK2/STAT3 pathway in two different ways. First, we show that STAT3 binds directly to the WASF3 promoter and increases transcription levels, which correlates with increased migration potential. Inactivation of STAT3 with short hairpin RNA, dominant negative constructs or S3I-201 leads to reduced WASF3 levels and reduced migration. Second, we have shown that JAK2, while activating STAT3, also interacts with and activates WASF3. Inhibition of JAK2 with short hairpin RNA or AG490 leads to loss of migration due to reduced WASF3 activation levels and prevention of its membrane localization. Together, these results define a novel signaling network whereby JAK2/STAT3 signaling creates a feed-forward loop to raise activated WASF3 levels that promote cancer cell motility. PMID- 23677070 TI - An insulin-like growth factor-II intronic variant affects local DNA conformation and ovarian cancer survival. AB - Insulin-like growth factor-II (IGF-II) may be a prognostic marker in ovarian cancer, and its intronic single nucleotide polymorphism (SNP) rs4320932 has been associated with risk of the disease. We determined whether rs4320932 is associated with IGF-II expression and patient survival in ovarian cancer, and explored whether the SNP variation affects DNA conformation both in the absence of and presence of carboplatin. IGF-II genotype (rs4320932) and phenotype were analyzed in 212 primary invasive epithelial ovarian cancer tissue samples with Taqman(r) SNP genotyping assays, quantitative reverse transcription-polymerase chain reaction and commercial enzyme-linked immunosorbent assay. DNA conformation was evaluated by circular dichroism (CD) spectra. Kaplan-Meier survival curves and Cox proportional hazard regression models were used to analyze the SNP associations with patient survival. The C allele of rs4320932, previously associated with decreased risk of ovarian cancer development, was here associated with significantly elevated risks of relapse (Ptrend = 0.0002) and death (Ptrend = 0.0006), remaining significant in multivariate analyses. The adjusted hazard ratios were 3.05 (95% confidence interval [CI]: 1.47-6.37) for relapse and 3.28 (95% CI: 1.64-6.57) for death, respectively. The variant was also significantly associated with chemotherapy response, but not with other clinicopathologic variables or with IGF-II expression. DNA with genotypes TT and CC had distinct CD spectra in both the absence of and presence of carboplatin. These findings suggest that the intronic SNP rs4320932 affects patient survival and chemotherapy response via alteration of DNA conformation, but not through regulation of IGF-II expression. This novel finding may have implications in individualized medicine for the design of specific molecules targeting DNA of specific conformations. PMID- 23677071 TI - Common and distinct mechanisms of activation of rhodopsin and other G protein coupled receptors. AB - Detailed and systematic examination of high-resolution structural data is a rational strategy for understanding the function of biological macromolecules. G protein-coupled receptors (GPCRs) are an exceptionally valuable superfamily of proteins for such analysis. The most intriguing question is how a variety of extracellular stimuli evoke structural changes in the intracellular surface of the receptors. The recent active-like crystal structures of GPCRs provide information for uncovering common and distinct mechanisms of light-induced and ligand-induced activation. Based on systematic structural alignment, we have analyzed 3 receptors (rhodopsin, beta2 adrenergic receptor, adenosine A2A receptor) and demonstrate that the extracellular movement of helix VI is significantly different between rhodopsin and the other 2 receptors, and that the extracellular side of helix III exhibits distinct features in the 3 receptors. These findings not only emphasize the specialization of rhodopsin as a photoreceptor but also provide insights into the mechanism leading to rearrangement of helix VI. PMID- 23677074 TI - The American Suntanning Association: a "science-first organization" with a biased scientific agenda. PMID- 23677076 TI - "Granulomatosis with polyangiitis (Wegener's)" for "Wegener granulomatosis": dermatology journals should also adopt the alternative name. PMID- 23677077 TI - A female pioneer--doubly recognized. PMID- 23677079 TI - Factors predictive of recurrence and death from cutaneous squamous cell carcinoma: a 10-year, single-institution cohort study. AB - IMPORTANCE: Although most cases of cutaneous squamous cell carcinoma (CSCC) are easily cured with surgery or ablation, a subset of these tumors recur, metastasize, and cause death. We conducted the largest study of CSCC outcomes since 1968. OBJECTIVE: To identify risk factors independently associated with poor outcomes in primary CSCC. DESIGN: A 10-year retrospective cohort study. SETTING: An academic hospital in Boston. PARTICIPANTS: Nine hundred eighty-five patients with 1832 tumors. MAIN OUTCOMES AND MEASURES: Subhazard ratios for local recurrence, nodal metastasis, disease-specific death, and all-cause death adjusted for presence of known prognostic risk factors. RESULTS: The median follow-up was 50 (range, 2-142) months. Local recurrence occurred in 45 patients (4.6%) during the study period; 36 (3.7%) developed nodal metastases; and 21 (2.1%) died of CSCC. In multivariate competing risk analyses, independent predictors for nodal metastasis and disease-specific death were a tumor diameter of at least 2 cm (subhazard ratios, 7.0 [95% CI, 2.2-21.6] and 15.9 [4.8-52.3], respectively), poor differentiation (6.1 [2.5-14.9] and 6.7 [2.7-16.5], respectively), invasion beyond fat (9.3 [2.8-31.1] and 13.0 [4.3-40.0], respectively), and ear or temple location (3.8 [1.1-13.4] and 5.9 [1.3-26.7], respectively). Perineural invasion was also associated with disease-specific death (subhazard ratio, 3.6 [95% CI, 1.1-12.0]), as was anogenital location, but few cases were anogenital. Overall death was associated with poor differentiation (subhazard ratio, 1.3 [95% CI, 1.1-1.6]) and invasion beyond fat (1.7 [1.1-2.8]). CONCLUSIONS AND RELEVANCE: Cutaneous squamous cell carcinoma carries a low but significant risk of metastasis and death. In this study, patients with CSCC had a 3.7% risk of metastasis and 2.1% risk of disease-specific death. Tumor diameter of at least 2 cm, invasion beyond fat, poor differentiation, perineural invasion, and ear, temple, or anogenital location were risk factors associated with poor outcomes. Accurate risk estimation of outcomes from population-based data and clinical trials proving the utility of disease-staging modalities and adjuvant therapy is needed. PMID- 23677080 TI - Practice gaps. Toward a better definition of high-risk cutaneous squamous cell carcinoma: comment on "Factors predictive of recurrence and death from cutaneous squamous cell carcinoma". PMID- 23677082 TI - Facial stigmata and their powerful effects in literature and life. PMID- 23677081 TI - Reliability and convergent validity of the cutaneous sarcoidosis activity and morphology instrument for assessing cutaneous sarcoidosis. AB - IMPORTANCE: A validated scoring system is essential to assess the effect of therapeutic interventions on a disease. The instrument introduced here captures sarcoidosis disease activity in a reliable, reproducible manner, which will help standardize clinical trial outcomes and allow comparative efficacy studies in the future and may help lead to more robust data regarding the effect of different treatments on cutaneous sarcoidosis. OBJECTIVE: To assess the reliability and convergent validity of the Cutaneous Sarcoidosis Activity and Morphology Instrument (CSAMI) and Sarcoidosis Activity and Severity Index (SASI) for evaluating cutaneous sarcoidosis outcomes. DESIGN AND SETTING: Cross-sectional study evaluating cutaneous sarcoidosis disease severity using CSAMI, SASI, and Physician's Global Assessment (PGA) as reference in the dedicated cutaneous sarcoidosis clinic of a teaching hospital. PARTICIPANTS: Eight dermatologists evaluating cutaneous sarcoidosis in 11 patients. INTERVENTION: Evaluation using the study instruments. MAIN OUTCOMES AND MEASURES: Primary outcomes included interrater and intrarater reliability and convergent validity; secondary outcomes, correlation with quality-of-life measures and time required for completion. RESULTS: All instruments demonstrated good to excellent intrarater reliability. Interrater reliability was excellent for CSAMI Activity scores (intraclass correlation coefficient, 0.82 [95% CI, 0.66-0.94]) and fair to poor for CSAMI Damage scores (0.42 [0.21-0.72]), modified Facial SASI (0.40 [0.17 0.72]), and PGA scores (0.40 [0.18-0.70]). CSAMI Activity and Damage scores and modified Facial SASI all demonstrated convergent validity with statistically significant correlations with PGA scores. Trends for correlations were seen between CSAMI scores and specific Skindex-29 quality-of-life domains. Although CSAMI required longer time to complete than SASI, both were scored within adequate time for use in clinical trials. CONCLUSIONS AND RELEVANCE: CSAMI appears to be a reliable and valid outcome instrument to measure cutaneous sarcoidosis and may capture a wide range of body surface and cutaneous morphologic types. This instrument can be adopted into clinical practice and clinical trials to allow physicians to assess the intensity of their patients' cutaneous sarcoidosis disease activity. Widespread use of one metric for disease severity assessment can help standardize the evaluation of the effect of various treatments on the disease. Future research is necessary to demonstrate its sensitivity to change and to confirm its correlation with quality-of-life measures. PMID- 23677083 TI - Medicamina faciei femineae: Roman skin care. PMID- 23677084 TI - Neutrophilic dermatosis after azathioprine exposure. AB - IMPORTANCE: Azathioprine hypersensitivity syndrome can present clinically and histopathologically like Sweet syndrome. Shared clinical features include fever, constitutional symptoms, prompt response to systemic corticosteroid therapy, neutrophilia, and abrupt onset of erythematous cutaneous lesions. Histologically, both azathioprine hypersensitivity syndrome and Sweet syndrome are rich in neutrophils. OBSERVATIONS: An 81-year-old woman with Crohn disease presented with fever and an acute eruption of plaques on her extremities within 2 weeks of starting treatment with azathioprine. Laboratory evaluation was notable for leukocytosis and neutrophilia. Skin biopsy of an erythematous plaque on the thigh demonstrated a suppurative folliculitis. Azathioprine treatment was discontinued resulting in resolution of the clinical lesions within 5 days. Our case was compared with 18 cases with similar clinical features. CONCLUSIONS AND RELEVANCE: We report a case of azathioprine hypersensitivity syndrome and review the literature on azathioprine-induced eruptions with features of Sweet syndrome. Our patient's distribution of lesions on the extremities and the finding of suppurative folliculitis on histopathology were not classical for Sweet syndrome. Azathioprine hypersensitivity syndrome seems to be a neutrophil-driven dermatosis; therefore, many overlapping features with Sweet syndrome are not surprising. Due to the potential for anaphylaxis with azathioprine rechallenge, a better term for a Sweetlike presentation in the setting of azathioprine administration is azathioprine hypersensitivity syndrome. PMID- 23677085 TI - President Kennedy's White House tan. PMID- 23677086 TI - Topical tazarotene for the treatment of ectropion in ichthyosis. AB - IMPORTANCE: Ectropion is a complication of certain subtypes of ichthyosis and is often associated with substantial medical and cosmetic consequences. At present there is no standard of care for the treatment of ectropion in this population. Retinoids cause dyshesion and thinning of stratum corneum, thereby reducing hyperkeratosis that likely underlies ectropion in patients with ichthyosis. As such, retinoids provide a potential effective treatment for ectropion in this group of patients. OBSERVATION: We describe a patient with recessive ichthyosis for whom daily application of topical tazarotene produced rapid and persistent improvement of bilateral lower eyelid ectropion without adverse effects. CONCLUSIONS AND RELEVANCE: Additional studies will be necessary to more fully and systematically address the safety and efficacy of topical retinoids for the treatment of ectropion in patients with ichthyosis; however, this case illustrates that topical tazarotene and other retinoids provide a potential treatment option for ectropion in this population. We encourage clinicians to explore medical therapies as alternatives to surgical intervention for the treatment of ectropion in patients with ichthyosis. PMID- 23677087 TI - Association of androgenetic alopecia with mortality from diabetes mellitus and heart disease. AB - IMPORTANCE: Identifying predictors of mortality from diabetes mellitus (DM) and heart disease can help shape treatment strategies. Presence of androgenetic alopecia (AGA) might be such a predictor. OBJECTIVE: To determine whether the presence of AGA is associated with an elevated rate of mortality from DM and heart disease in both sexes after adjustment for potential confounders. DESIGN: A population-based prospective cohort study. SETTING: Community-based integrated screening in Taiwan. PARTICIPANTS: A total of 7252 subjects aged 30 to 95 years participated in the baseline AGA survey using the Norwood and Ludwig classifications between April and June 2005. Baseline information on metabolic syndrome (MetS) and other possible risk factors was also collected. We then followed this cohort over time to ascertain death and cause of death until December 2010. INTERVENTIONS OR EXPOSURES: Application of Norwood and Ludwig ALA classifications to study population. MAIN OUTCOMES AND MEASURES: Deaths from DM and heart disease. RESULTS: Among the 7126 subjects (2429 men and 4697 women) who provided complete data, there were 70 deaths from DM and heart disease during the 57-month follow-up period. Subjects with moderate to severe AGA vs normal or mild AGA had a significantly higher risk of mortality from DM (adjusted hazard ratio [HR], 2.97; 95% CI, 1.26-7.01) (P = .01) and heart disease (adjusted HR, 2.28; 95% CI, 1.00-5.23) (P = .05) after adjusting for age, family history of DM or heart disease, and MetS. CONCLUSIONS AND RELEVANCE: AGA is an independent predictor of mortality from DM and heart disease in both sexes. This finding may have significant implications for the identification of risk factors for DM and heart disease in patients with moderate or severe AGA, regardless of whether MetS is present. PMID- 23677088 TI - Harnessing hedgehog for the treatment of basal cell carcinoma. PMID- 23677089 TI - Solitary cerebriform nodule. Sclerotic granular cell tumor. PMID- 23677091 TI - Solitary, enlarging painful violaceous tumor on the cheek of a 10-year. Cutaneous precursor B-cell acute lymphoblastic leukemia (pre-B ALL). PMID- 23677093 TI - A palpable erythematous cord over the trunk in a patient with systemic lupus erythematosus. Interstitial granulomatous dermatitis (IGD). PMID- 23677095 TI - A rapidly enlarging nodule on the dorsal aspect of the nose. Adult nasal dermoid sinus cyst (NDSC). PMID- 23677097 TI - Update on metastatic basal cell carcinoma: a summary of published cases from 1981 through 2011. PMID- 23677098 TI - Rerecurrence 5 years after treatment of recurrent cutaneous basal cell and squamous cell carcinoma. PMID- 23677099 TI - Nonmelanoma skin cancer in organ transplant recipients: increase without delay after transplant and subsequent acceleration. PMID- 23677100 TI - Perspectives on acne: what Twitter can teach health care providers. PMID- 23677101 TI - On the comparison of diagnosis and management of melanoma between dermatologists and MelaFind. PMID- 23677102 TI - Immediate successful treatment of argyria with a single pass of multiple Q switched laser wavelengths. PMID- 23677103 TI - Eruptive melanocytic nevi in a patient undergoing treatment with sunitinib. PMID- 23677104 TI - Ustekinumab therapy for severe interstitial granulomatous dermatitis with arthritis. PMID- 23677105 TI - The use of aprepitant in brachioradial pruritus. PMID- 23677106 TI - A maroon plaque in an infant. PMID- 23677107 TI - Pseudoepitheliomatous hyperplasia: an unusual tattoo reaction. PMID- 23677109 TI - Tick removal with liquid nitrogen. PMID- 23677108 TI - Foreign-body reaction to Wound Seal. PMID- 23677110 TI - Hereditary benign telangiectasia: punctate telangiectasia surrounded by anemic halo. PMID- 23677111 TI - Use of sunlight to treat dyshidrotic eczema. PMID- 23677112 TI - Flexural agminated eruptive nevi in Langerhans cell histiocytosis. PMID- 23677113 TI - Dasatinib-induced leukotrichia in a patient with chronic myelogenous leukemia. PMID- 23677114 TI - Surgical excision after neoadjuvant therapy with vismodegib for a locally advanced basal cell carcinoma and resistant basal carcinomas in Gorlin syndrome. PMID- 23677115 TI - Diffuse umbilicated vesicles in a critically ill child. PMID- 23677116 TI - Successful treatment with vemurafenib in BRAF V600K-positive cerebral melanoma metastasis. PMID- 23677117 TI - Counting the costs of multiple stressors: is the whole greater than the sum of the parts? PMID- 23677118 TI - Industrial-age changes in atmospheric [CO2] and temperature differentially alter responses of faster- and slower-growing Eucalyptus seedlings to short-term drought. AB - Climate change may alter forest composition by differentially affecting the responses of faster- and slower-growing tree species to drought. However, the combined effects of rising atmospheric CO2 concentration ([CO2]) and temperature on drought responses of trees are poorly understood. Here, we examined interactive effects of temperature (ambient, ambient + degrees C) and [CO2] (290, 400 and 650mu;l l(-1)) on drought responses of Eucalyptus saligna Sm. (faster-growing) and E. sideroxylon A. Cunn. ex Woolls (slower-growing) seedlings. Drought was imposed via a controlled reduction in soil water over 1-2 weeks, re-watering seedlings when leaves visibly wilted. In ambient temperature, the effect of drought on the light-saturated net photosynthetic rate (Asat) in E. saligna decreased as [CO2] increased from pre-industrial to future concentrations, but rising [CO2] did not affect the response in Eucalyptus sideroxylon. In contrast, elevated temperature exacerbated the effect of drought in reducing Asat in both species. The drought response of Asat reflected changes in stomatal conductance (gs) associated with species and treatment differences in (i) utilization of soil moisture and (ii) leaf area ratio (leaf area per unit plant dry mass). Across [CO2] and temperature treatments, E. saligna wilted at higher soil water potentials compared with E. sideroxylon. Photosynthetic recovery from drought was 90% complete 2 days following re-watering across all species and treatments. Our results suggest that E. saligna (faster-growing) seedlings are more susceptible to drought than E. sideroxylon (slower-growing) seedlings. The greater susceptibility to drought of E. saligna reflected faster drawdown of soil moisture, associated with more leaf area and leaf area ratio, and the ability of E. sideroxylon to maintain higher gs at a given soil moisture. Inclusion of a pre-industrial [CO2] treatment allowed us to conclude that susceptibility of these species to short-term drought under past and future climates may be regulated by the same mechanisms. Further, the beneficial effects of rising [CO2] and deleterious effects of elevated temperature on seedling response to drought were generally offsetting, suggesting susceptibility of seedlings of these species to short-term drought in future climates that is similar to pre-industrial and current climate conditions. PMID- 23677119 TI - Immunolocalization of IAA and ABA in roots and needles of radiata pine (Pinus radiata) during drought and rewatering. AB - Anatomical, physiological and phytohormonal changes involved in drought tolerance were examined in different Pinus radiata D. Don breeds subjected to soil drying and rewatering. Breeds with the smallest stomatal chamber size had the lowest transpiration rate and the highest intrinsic water-use efficiency. Xylem cell size was positively correlated with leaf hydraulic conductance and needle indole 3-acetic acid (IAA) concentrations, whereas transpiration rate was negatively correlated with needle abscisic acid (ABA) levels. Since these two phytohormones seem important in regulating the P. radiata drought response, they were simultaneously immunolocalized in roots and needles of the most tolerant breed (P. radiata var. radiata * var. cedrosensis) during two sequential drought cycles and after rewatering. During drought, IAA was unequally distributed into the pointed area of the needle cross-section and mainly located in mesophyll and vascular tissue cells of needles, possibly inducing needle epinasty, whereas ABA was principally located in guard cells, presumably to elicit stomata closure. In the roots, at the end of the first drought cycle, while strong IAA accumulation was observed in the cortex, ABA levels decreased probably due to translocation to the leaves. Rewatering modified the distribution of both IAA and ABA in the needles, causing an accumulation principally in vascular tissue, with residual concentrations in mesophyll, likely favouring the acclimatization of the plants for further drought cycles. Contrarily, in the roots IAA and ABA were located in the exodermis, a natural barrier that regulates the phytohormone translocation to other plant tissues and hormone losses to the soil solution after rewatering. These results confirm that immunolocalization is an efficient tool to understand the translocation of IAA and ABA in plants subjected to different water stress situations, and clarify their role in regulating physiological responses such as stomata closure and epinasty in needles and root development. PMID- 23677120 TI - Comparison of the axial stiffness of carbon composite and aluminium alloy circular external skeletal fixator rings. AB - OBJECTIVES: The purpose of this study was to compare the axial stiffness of aluminium alloy and carbon composite single-ring constructs. METHODS: Single-ring constructs were made with rings of different material compositions (aluminium alloy and carbon composite), diameters (55 mm, 85 mm, and 115 mm), and thicknesses (6 mm for the single-ring, 12 mm for the double-ring) with all other components remaining constant. Stiffness of each construct was determined under loading in axial compression with a materials testing machine. The axial stiffness of each group was compared using a three-factor factorial analysis of variance investigating all main effects and interactions between ring diameter, ring thickness, and ring material composition; p <0.05 was considered significant. RESULTS: Carbon composite constructs were 16-55% as stiff as corresponding aluminium alloy constructs. Within each combination of ring material composition and ring diameter, stiffness did not significantly increase when the ring thickness was doubled. Within each combination of ring material composition and ring thickness, stiffness significantly decreased with increased ring diameter. CLINICAL SIGNIFICANCE: Aluminium alloy rings were found to be significantly stiffer than carbon composite rings. Although the carbon composite rings were considerably less stiff, clinical recommendations cannot be made from a single-ring in vitro analysis. Further studies are needed to evaluate the behaviour of these rings in vivo. PMID- 23677121 TI - The effect of screw angulation and insertion torque on the push-out strength of polyaxial locking screws and the single cycle to failure in bending of polyaxial locking plates. AB - OBJECTIVE: To evaluate the mechanical properties of the Polyaxial Advanced Locking System (PAX) in screw push-out and four-point bending. MATERIALS AND METHODS: Screw push-out: PAX locking screws were applied to first generation PAX plates at three different insertion angles with two different insertion torques. A load was applied parallel to the screw axis, and screw push-out force was measured. Four-point bending: PAX plates were applied to a bone model and a fracture gap was simulated. Bending stiffness, bending strength, and bending structural stiffness were evaluated and compared to published data. RESULTS: Screw push-out forces were significantly higher at 0 and 5 degree insertion angles when compared with an insertion angle of 10 degrees. An insertion torque of 3.5 Nm also produced significantly higher push-out forces compared to 2.5 Nm. Four-point bending: Qualitative comparison of the data gained in this study with previously published data suggests that the PAX system bending stiffness and bending structural stiffness seems to be higher than that of other veterinary orthopaedic implants, but the bending strength was similar. CLINICAL RELEVANCE: The PAX locking system offers the benefit of polyaxial screw insertion while maintaining comparable biomechanical properties to other currently available orthopaedic implants. PMID- 23677122 TI - Magnetic resonance imaging of plantar soft tissue structures of the tarsus and proximal metatarsus in foals and adult horses. AB - OBJECTIVES: The object of this study was to describe previously defined soft tissue structures by using spin and gradient sequences in a 0.5 Tesla magnetic resonance system in order to improve the characterisation of tendon and ligaments at the plantar region of the equine tarsus and metatarsus while considering possible age-related variations. METHODS: Cadaveric hindlimbs from twenty-two Warmblood horses with an age range from one month to twenty-five years were examined in spin and gradient echoes. The proximal suspensory ligament from six limbs was dissected to assign the signal intensities histologically. For statistical analysis, horses were divided into two groups (<=3 years and >3 years) for evaluating signal intensity and homogeneity of the plantar tendons and ligaments. RESULTS: Focal increase of the signal intensity within the deep digital flexor tendon was significantly more present in horses older than three years. Signal alterations of the long plantar ligament were seen without a significant dependency to age. The accessory ligament of the deep digital flexor tendon could not be visualized on all images within the region of interest. The morphology of the proximal suspensory ligament was not affected by age-related changes. CLINICAL RELEVANCE: Spin and gradient echoes in MRI were suitable to identify and assess soft tissue structures at the plantar aspect of the equine tarsus and proximal metatarsus. Age-related appearance must be considered when interpreting magnetic resonance images. PMID- 23677123 TI - Biomechanical strength of two laparoscopic herniorrhaphy techniques in a cadaveric diaphragm and in a neoprene model. AB - OBJECTIVES: Our objectives were to 1) Biomechanically compare two laparoscopic repair techniques; an automated suturing device and a stapling device to conventional open suturing, and 2) Evaluate a model for canine diaphragmatic tissue by comparisons to similar constructs in fresh diaphragms. We hypothesized that automated suturing is biomechanically superior to laparoscopic stapling in dogs, and that neoprene defect repair is an acceptable model for experimental cadaveric diaphragm herniorrhaphy. MATERIALS AND METHODS: Samples of diaphragm pars costalis were prepared with defects mimicking radial muscular tears. Defects were repaired using conventional open suturing, laparoscopic automated suturing, and laparoscopic stapling techniques. Similar defects were created in 6.35 mm thick single-sided neoprene. Samples were biomechanically tested across a biaxial loading machine. Site and mode of failure were noted for all samples. RESULTS: In both the diaphragm muscle and neoprene, the laparoscopic stapling technique was significantly weaker. The neoprene model showed a similar failure load as the diaphragm in both laparoscopic techniques, and a similar stiffness in an open sutured and stapled diaphragm compared to the neoprene samples. Site and mode of failure in neoprene were similar to cadaveric diaphragmatic tissue, but the overall median load-to-failure was higher for the neoprene. CONCLUSION: The strength of laparoscopically repaired simulated diaphragmatic hernias was higher with an automated suture technique than with a stapling technique. Neoprene defect repair is an acceptable model of canine diaphragmatic herniorrhaphy for biomechanical testing. PMID- 23677124 TI - Radiographic changes of the pelvis in Labrador and Golden Retrievers after juvenile pubic symphysiodesis: objective and subjective evaluation. AB - OBJECTIVES: The hypothesis of this study was that juvenile pubic symphysiodesis (JPS) results in pelvic changes that can be identified radiographically in adult dogs. METHODS: The medical records at the Clinica Veterinaria Vezzoni were searched for standard ventro-dorsal views of the pelvis of adult Labrador and Golden Retrievers that had undergone JPS or had not undergone surgery. The objective assessment of radiographs included the analysis of various pelvic measurements. Subjective evaluation of radiographs was undertaken by 18 specialists and 21 general practitioners and was based on five criteria relating to 1) the acetabular fossae, 2) the pubic symphysis, 3) the margin of the cranial pubic area, 4) the pubic rami, and 5) the obturator foramen. RESULTS: The radiographs of 42 Labrador Retrievers and 16 Golden Retrievers were evaluated. The most useful criteria were the radiographic measurement of the shape of the obturator foramen and two different ratios of length to width of the pubic rami; these values were significantly smaller in dogs after JPS. The pelvic canal width was the same in both groups. All objective measurements were repeatable within and between evaluators. The most reliable subjective criterion was number 4, followed by number 5 in Golden Retrievers and by 2 in Labrador Retrievers. CONCLUSION: Our objective and subjective evaluations were simple and yielded useful and repeatable results. There was no significant difference between general practitioners and specialists with regard to subjective evaluation, which indicates that these evaluation criteria can be used by small animal clinicians after minimal training. PMID- 23677125 TI - Use of Y-shaped TPLO plates for the stabilization of supracotyloid ilial fractures in four dogs and one cat. AB - OBJECTIVES: To describe the use of Y-shaped tibia plateau levelling osteotomy (TPLO) plates for the stabilization of supracotyloid ilial fracture in four dogs and one cat. METHODS: Clinical cases with supracotyloid ilial fracture that were repaired with a Y-shaped TPLO plate were retrospectively reviewed. Fracture type, concurrent injuries, fracture management, radiographic outcome and clinical recovery were documented. RESULTS: All fractures were reduced and a Y-shaped TPLO plate was applied with one short-term complication. Four fractures healed in original alignment. Screw loosening and malunion was documented in one patient at the six week follow-up examination. All patients had good to excellent limb function in the long-term follow-up. CLINICAL SIGNIFICANCE: The use of TPLO Y shaped plates for supracotyloid ilial fractures allows good fracture reduction and fixation with a minimal approach and few postoperative complications. PMID- 23677126 TI - Avulsion fragmentation of the tibial tuberosity apophysis and associated patellar tendon enthesopathy in a skeletally immature dog. AB - A 9.5-month-old, female entire, 31.3 kg crossbred dog was presented with a 12 week history of moderate weight-bearing right pelvic limb lameness. Radiographic, computed tomographic, and ultrasonographic imaging revealed progressive avulsion fragmentation of the right tibial tuberosity apophysis and a patellar tendon insertional enthesopathy without physeal involvement. Conservative management was successful in achieving a good clinical outcome. A progressive avulsion of the contralateral proximal tibial physes that occurred concurrently resulted in development of an excessive tibial plateau slope angle. The additional development of a moderate left distal femoral varus deformity was surgically corrected. This is the first report of a progressive, traction injury to the tibial tuberosity apophysis in a dog that appears clinically and radiographically very similar to Osgood-Schlatter disease in humans. PMID- 23677127 TI - Animal-induced injuries of humans. PMID- 23677128 TI - Acute lymphoblastic leukemia in first complete remission: temporal trend of outcomes in studies comparing allogeneic transplant with autologous transplant or chemotherapy. AB - In patients with acute lymphoblastic leukemia in first complete remission, several studies have compared allogeneic transplant with autologous transplant or chemotherapy. This material can be the basis for analyzing the temporal trend of outcomes. Our study was designed as a meta-regression focused on temporal trends and based on the endpoint of 5-year leukemia-free survival (5yLFS). Studies in which 5yLFS was determined in a patient group subjected to allogeneic transplant and in a control group (treated with autologous transplant and/or chemotherapy) were eligible for our meta-analysis. A standard literature search was carried out to identify pertinent studies. The results of included studies were submitted to an observational meta-analysis and to a meta-regression focused on two covariates (calendar year in which the study was conducted; percentage of high-risk patients). The endpoint of 5yLFS was separately assessed between allogeneic transplant and autologous transplant or chemotherapy. Our analysis included 14 studies that covered a period (1983 to 1999) in which patients were conditioned only with myeloablative conditioning and not with non-myeloablative ones. In the risk ratio (RR) analysis, the pooled outcome showed a significantly better profile for allogeneic transplantation (RR = 1.42; 95 % confidence interval (CI), 1.22 to 1.65). Separate analysis of the two treatment options found a pooled 5yLFS of 45 % (95 % CI, 38 to 51 %) for allogeneic transplant vs 30 % (95 % CI, 23 to 37 %) for the controls. In meta-regression, the temporal trend analysis revealed that, in patients subjected to allogeneic transplant, the values of 5yLFS showed no significant change over the 16-year interval (p = 0.720); the same stability over time was found in the control group (p = 0.489). On the other hand, the percentage of high-risk patients influenced outcomes in both patient groups at levels of statistical significance (p = 0.014 and p = 0.045 in the allotransplant group and in the controls, respectively). Our results can represent a reference point for future analyses focused on patients treated in more recent years. PMID- 23677129 TI - Nanopore-type black silicon anti-reflection layers fabricated by a one-step silver-assisted chemical etching. AB - An effective and economical fabrication process for the synthesis of nanopore type "black silicon", that significantly decreases reflectivity of silicon wafer surfaces, is reported using a room temperature one-step Ag-assisted chemical etching method. The effects on the surface morphology and the corresponding surface reflectivity of the concentration of the silver catalyst (500, 50, and 5 MUM), the HF and H2O2 concentration in the silicon etchant, the HF : H2O2 ratio, and etching time have been investigated. Lower reflectivity is a balance between sufficient silver catalyst to create large numbers of nanopores on a silicon surface and excessive silver that brings deeply etched channels that would potentially short-circuit a solar cell junction. The lowest relative effective reflectivity (0.17% over a range of 300-1000 nm) occurs with a silver ion concentration of 50 MUM, however, with the silver ion concentration decreases to 5 MUM surfaces with a low relative effective reflectivity (2.60%) and a short nanopore length (<250 nm) can be obtained with 10 minute etching time, indicating that this method can be used as a simple (one-pot), low cost (low silver concentration), energy efficient (room temperature), method for the synthesis of anti-reflection layers for silicon-based solar cell applications. PMID- 23677130 TI - Mental health surveillance among children--United States, 2005-2011. AB - Mental disorders among children are described as "serious deviations from expected cognitive, social, and emotional development" (US Department of Health and Human Services Health Resources and Services Administration, Maternal and Child Health Bureau. Mental health: A report of the Surgeon General. Rockville, MD: US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Mental Health Services, and National Institutes of Health, National Institute of Mental Health; 1999). These disorders are an important public health issue in the United States because of their prevalence, early onset, and impact on the child, family, and community, with an estimated total annual cost of $247 billion. A total of 13%-20% of children living in the United States experience a mental disorder in a given year, and surveillance during 1994-2011 has shown the prevalence of these conditions to be increasing. Suicide, which can result from the interaction of mental disorders and other factors, was the second leading cause of death among children aged 12 17 years in 2010. Surveillance efforts are critical for documenting the impact of mental disorders and for informing policy, prevention, and resource allocation. This report summarizes information about ongoing federal surveillance systems that can provide estimates of the prevalence of mental disorders and indicators of mental health among children living in the United States, presents estimates of childhood mental disorders and indicators from these systems during 2005-2011, explains limitations, and identifies gaps in information while presenting strategies to bridge those gaps. PMID- 23677132 TI - Identification of APN/CD13 as the target antigen of FU3, a human monoclonal antibody that recognizes malignant fibrous histiocytoma. AB - Malignant fibrous histiocytoma (MFH), a high-grade, undifferentiated sarcoma, is highly aggressive, resistant to radiochemotherapy and associated with poor prognosis. There are no specific immunohistochemical markers for its diagnosis. The MFH cell line SFT7913 served as and immunogen for the generation of the FU3 monoclonal antibody in our laboratory. FU3 reacted strongly with MFH cells and with perivascular mesenchymal cells. In this study, we demonstrated that the antigen recognized by FU3 was identical to aminopeptidase N (APN/CD13) using FU3 immunoaffinity chromatography and N-terminal amino acid sequencing. Frequent (80%) and high-grade (>50% of cells) expression of APN/CD13 was observed in MFH, although low-grade expression was seen in some other sarcomas. Moreover, small interfering RNA (siRNA) that specifically targets APN/CD13 significantly suppressed MFH cell invasion in vitro. The newly developed monoclonal antibody FU3 specifically recognizes CD13 on MFH cells. Decreased expression of CD13, mediated by siRNA-mediated knockdown, attenuated the invasive capacity of MFH cells. Thus, results indicate that APN/CD13 could be an important diagnostic biomarker and therapeutic target for MFH. PMID- 23677131 TI - Blood pressure-lowering effect of simvastatin: a placebo-controlled randomized clinical trial with 24-h ambulatory blood pressure monitoring. AB - Part of the efficacy of statins in the prevention of cardiovascular events can be attributed to their blood pressure-lowering effect, but clinical trials primarily designed to investigate this effect are scarce. In a double-blind parallel placebo-controlled clinical trial with ambulatory blood pressure (ABP) monitoring, 79 hypertensive patients were randomly assigned to 40 mg of simvastatin (n=40) or placebo (n=39) taken in the morning for 2 months. Between group deltas of ABP change, adjusted for the corresponding baseline BP, were 2.8 mm Hg (95% CI: 0.4-5.1; P=0.02) for 24-h diastolic blood pressure (DBP), 4.2 mm Hg (95% CI: 0.1-8.4; P=0.04) for daytime systolic BP and 3.1 mm Hg (95% CI: 0.4 5.9; P=0.02) for daytime DBP. There was no effect on nighttime BP. There was an interaction between baseline cholesterol levels and treatment effect, which was restricted to patients with cholesterol above the median of the whole sample. There was no significant change in office BP. In conclusion, simvastatin lowers ABP in patients with hypertension, particularly in the presence of higher levels of cholesterol. This effect may contribute to the beneficial effects of statins in the prevention of cardiovascular disease. PMID- 23677133 TI - Cooperative spin-crossover-like transitions in the inhomogeneous chain of exchange clusters. AB - A statistical theory of temperature-induced spin-crossover-like transitions has been developed for spin chains with a few exchange clusters in a unit cell. Using static magnetic susceptibility measurements, a general expression for the effective magnetic moment MU(eff) of exchange clusters is obtained for an arbitrary structure of cluster terms. For heterospin Cu(hfac)2L(R) complexes ("breathing crystals") with a "head-to-head" chain motif, a two-point approximation for a partition function of the Jahn-Teller Cu(+2) paramagnetic center (spin 1/2) is suggested. Theoretical results are compared with available experimental data on thermal spin-crossover-like transitions in the "breathing crystal" compounds. It is shown that the model developed is able to successfully describe both of the cases of smooth and abrupt (cooperative) spin transitions for chains of three-spin exchange clusters. Spin-crossover-like transitions of a new type with step-wise changes in a positive exchange integral are predicted. PMID- 23677134 TI - Influence of reflected UV irradiance on occupational exposure from combinations of reflective wall surfaces. AB - Outdoor workers who occupationally spend large periods of time exposed to ultraviolet irradiance are at increased risk of developing certain types of non melanoma skin cancer in addition to being prone to erythema and eye damage. UV exposure to workers is affected by a number of factors including geographic location, season, individual biological factors and the local surroundings. Urban environments can provide surrounds that contain surfaces that reflect UV radiation which can enhance UV exposure to construction workers, in both the vertical as well as horizontal plane. However it was unknown how different constructed configurations of the surfaces may additionally influence UV exposure for a worker, such as corners opposed to walls. This study shows that for highly UV reflective surfaces the influence on erythemal UV exposure is approximately the same regardless of constructive type, but there is statistically significant difference observed for lower UV reflecting surfaces in conjunction with constructive type. This is comparable to influence of body site on relative UV exposure, and together may provide a method that may assist in reduction in UV exposures. Regression analysis provides a more effective means to determine a UV reflective factor for a surface type, than previously used averaging methods. Additionally, this knowledge may be used by workers, workplaces and advisory bodies to assist with developing further protective strategies that aim to provide more moderate UV exposures to outdoor workers. PMID- 23677135 TI - Endoresection versus iodine-125 plaque brachytherapy for the treatment of choroidal melanoma. AB - PURPOSE: To compare the effectiveness of pars plana vitrectomy endoresection with iodine-125 brachytherapy in the treatment of choroidal melanoma. DESIGN: A nested case-control study (1:2) from a surgical cohort. METHODS: The study comprised 81 choroidal melanoma patients treated with either endoresection or iodine-125 brachytherapy. Twenty-seven patients who had undergone endoresection were matched according to tumor height and postequatorial tumor location with 54 cases treated with iodine-125 brachytherapy. Metastatic disease, overall survival, local tumor recurrence, visual acuity, and secondary enucleation rates were analyzed and compared between groups. RESULTS: Metastatic spread was observed in 11 patients in the iodine-125 brachytherapy group vs only 1 patient in the endoresection group (20.4% and 3.7%, respectively, P = .053). Fourteen patients died during follow-up: 11 in the brachytherapy arm vs 3 in the endoresection arm (20.4% and 11.1%, respectively, P = .238). For the iodine-125 brachytherapy and endoresection groups, respectively, the 5-year Kaplan-Meier estimates were as follows: overall survival, 81.5% vs 89.2% (log-rank test, P = .429;); relapse free survival, 96.6% vs 92.4% (P = .2); visual acuity retention equal or superior to 20/200, 66.4% vs 59.9% (P = .083), and eye retention, 85.7% vs 87.8% (P = .942). CONCLUSIONS: Endoresection for choroidal melanoma is an effective treatment modality in selected cases of posterior choroidal melanomas, with outcomes similar to those obtained with iodine-125 brachytherapy. PMID- 23677136 TI - Multimodal imaging of optic disc drusen. AB - PURPOSE: To evaluate optic disc drusen, extracellular protein deposits known to contain numerous aggregates of mitochondria, using multimodal modalities featuring optical coherence tomography (OCT) and autofluorescence imaging. DESIGN: Retrospective observational case series. METHODS: Eyes with optic nerve drusen were examined with enhanced depth imaging (EDI)-OCT, swept source OCT, and fundus autofluorescence using a fundus camera. RESULTS: Twenty-six eyes of 15 patients with optic disc drusen were evaluated. EDI-OCT and swept source OCT showed multiple optic disc drusen at different levels; most were located immediately anterior to the lamina cribrosa. The drusen were ovoid regions of lower reflectivity that were bordered by hyperreflective material, and in 12 eyes (46.2%) there were internal hyperreflective foci. The mean diameter of the optic disc drusen as measured in OCT images was 686.8 (standard deviation +/- 395.2) MUm. There was a significant negative correlation between the diameter of the optic disc drusen and the global retinal nerve fiber layer thickness (r = -0.61, P = .001). There was a significant negative correlation between proportion of the optic disc drusen area occupied by optic nerve drusen as detected by autofluorescence imaging and the global retinal nerve fiber layer thickness (r = 0.63, P = .001). CONCLUSIONS: Deeper-penetration OCT imaging demonstrated the internal characteristics of optic disc drusen and their relationship with the lamina cribrosa in vivo. This study also showed that both the larger the drusen and the more area of the optic canal occupied by drusen, the greater the associated retinal nerve fiber layer abnormalities. PMID- 23677137 TI - Posterior capsule opacification with the iMics1 NY-60 and AcrySof SN60WF 1-piece hydrophobic acrylic intraocular lenses: 3-year results of a randomized trial. AB - PURPOSE: To compare the intensity of posterior capsule opacification (PCO) 3 years after implantation of 2 different 1-piece foldable hydrophobic acrylic intraocular lenses (IOLs). DESIGN: Randomized, prospective, patient- and examiner masked clinical trial with intraindividual comparison. METHODS: One hundred patients with bilateral age-related cataract (200 eyes) had standard cataract surgery with implantation of an iMics1 NY-60 IOL (Hoya Corp) in one eye and an AcrySof SN60WF IOL (Alcon Laboratories) in the other eye. Follow-up examinations were performed at 1 week and 3 years. Digital retroillumination images were obtained of each eye. The main outcome measure was PCO score (scale, 0 to 10) assessed subjectively at the slit lamp and objectively using automated image analysis software (Automated Quantification of After-Cataract) 3 years after surgery. RESULTS: The objective PCO score (mean +/- standard deviation) was 3.0 +/- 2.0 for the iMics1 NY-60 IOL and 1.9 +/- 1.4 for the AcrySof SN60WF IOL (P < .001). Three years after surgery, 35.6% of patients underwent a neodymium:yttrium aluminum-garnet capsulotomy in the iMics1 NY-60 eye and 13.7% underwent a capsulotomy in the AcrySof SN60WF eye (P = .001). There was no statistically significant difference in best-corrected visual acuity, rhexis-IOL overlap, capsular folds, or anterior capsule opacification. Glistening formations were found in no iMics1 NY-60 IOLs, but in 97% of the AcrySof SN60WF IOLs. CONCLUSIONS: Comparison of 2 sharp-edged single-piece IOLs of similar design and hydrophobic acrylic material indicated a statistically significant difference in PCO and neodymium:yttrium-aluminum-garnet capsulotomy rate 3 years after surgery. PMID- 23677138 TI - Influence of cataract surgery on optical coherence tomography and neurophysiology measurements in patients with retinitis pigmentosa. AB - PURPOSE: To evaluate the effect of uncomplicated cataract phacoemulsification on the measurements of visual evoked potentials (VEP), pattern electroretinogram (PERG), and macular and retinal nerve fiber layer (RNFL) using 2 spectral-domain optical coherence tomography (OCT) instruments, the Cirrus OCT (Carl Zeiss Meditech) and Spectralis OCT (Heidelberg Engineering), in patients with retinitis pigmentosa (RP), and to assess the reliability of the OCT measurements before and after cataract surgery. DESIGN: Observational cross-sectional study. METHODS: Thirty-five eyes of 35 patients with RP (20 men and 15 women, 45-66 years) who underwent cataract phacoemulsification were studied. At 1 month before and 1 month after surgery, visual acuity, VEP, PERG, and 3 repetitions of scans using the RNFL and macular analysis protocols of the Cirrus and Spectralis OCT instruments were performed. The differences in measurements between the 2 visits were analyzed. Repeatability of OCT measurements was evaluated by calculating the coefficients of variation. RESULTS: VEP amplitude, RNFL thicknesses provided by Cirrus and Spectralis, and macular measurements provided by Cirrus OCT differed between the 2 visits. VEP latency, PERG measurements, and macular thicknesses provided by the Spectralis OCT before surgery did not differ significantly from those after surgery. The OCT repeatability was better after surgery, with lower coefficients of variation for scans performed after surgical removal of the cataract. The nuclear, cortical, and posterior subcapsular types of cataracts did not show different repeatability. CONCLUSIONS: The presence of cataracts affects VEP amplitude, RNFL, and macular measurements performed with OCT in eyes with RP. Image repeatability significantly improves after cataract phacoemulsification. PMID- 23677139 TI - Long-term echographic surveillance of elevated choroidal nevi. AB - PURPOSE: To report the outcomes of choroidal nevi monitoring and to compare the detection of ultrasonographic hollowness, a risk factor of malignant transformation, from a B-scan with results from an A-scan examination. DESIGN: Retrospective cohort study. METHODS: Standardized A- and B-scan echography and ophthalmoscopy in 358 consecutive patients with median age 69 years and baseline choroidal nevus higher or lower than 1.5 mm in 51 (14%) and 307 (86%) eyes, respectively. RESULTS: No growth or change in echographic or ophthalmoscopic features were found in 307 nevi with a median elevation of 0.9 mm (range, 0.7 to 1.5 mm) and a median follow-up of 6 years (range, 4 to 9 years). After 2 to 6 years, decreased internal reflectivity on standardized A-scan and ultrasonographic hollowness on B-scan were detected in 7 (18%) of 38 initially highly reflective choroidal nevi (thickness, 1.98 +/- 0.37 mm); 2 (5%) nevi grew into melanoma 15 years after the first observation. Of 13 choroidal nevi (thickness, 2.75 +/- 0.66 mm), with initial atypical medium to high reflectivity on standardized A-scan (100%) and hollowness on B-scan (85%), 6 (46%) were plaqued 6 to 15 months later because of the presence of multiple risk factors. CONCLUSIONS: No changes in thickness or echographic features of choroidal nevi elevated up to 1.5 mm were recorded during the follow-up period. In initially typical choroidal nevi higher than 1.5 mm, strong agreement was detected between decreased reflectivity on standardized A-scan and ultrasonographic hollowness on B-scan found after up to 15 years of stability. The vast majority of choroidal nevi with initial atypical standardized A-scan features showed ultrasonographic hollowness. PMID- 23677140 TI - Do tibiofemoral contact point and posterior condylar offset influence outcome and range of motion in a mobile-bearing total knee arthroplasty? AB - PURPOSE: The posterior condylar offset (PCO) and the tibiofemoral contact point (CP) have been reported as important factors that can influence range of motion and clinical outcome after total knee arthroplasty. A mobile-bearing knee implant with an anterior posterior gliding insert would in theory be more sensitive for changes in PCO and CP. For this reason, we analysed the PCO and CP and the relation with outcome and range of motion in 132 patients from a prospectively documented cohort in this type of implant. METHODS: The prosthesis used was a posterior cruciate retaining AP gliding mobile-bearing total knee replacement (SAL II Sulzer Medica, Switzerland). In 132 knees, the pre- and postoperative PCO and postoperative CP were evaluated. Measurements were made on X-rays of the knee taken in approximately 90 degrees of flexion and with less than 3-mm rotation of the femur condyles. The outcome parameters, range of motion (ROM) and the knee society score (KSS), for each knee were determined preoperatively and at 5-year follow-up. RESULTS: The mean KSS improved from 91 to 161 at 5-year follow-up (p < 0.001) and the mean ROM from 102 to 108 (p < 0.05). The mean PCO difference (postoperative PCO-preoperative PCO) was--0.05 mm (SD 2.15). The CP was on average 53.9% (SD 5.5%). ROM was different between the 3 PCO groups (p = 0.05): patients with 3 or more mm decrease in PCO had the best postoperative ROM (p = 0.047). There was no statistical difference between the postoperative ROM between patients with a stable PCO and those with an increased PCO. There was no correlation between the difference in PCO and the difference in ROM; R Pearson = 0.056. There was no difference in postoperative ROM or postoperative total KSS between CP <60% and CP >60%: p = 0.22, p = 0.99, for ROM and KSS, respectively. Scatter plots showed uniform clouds of values: increase or decrease in PCO and CP had no significant influence on ROM or KSS. CONCLUSION: The hypotheses that a stable PCO and a more natural CP increase postoperative ROM and improve clinical outcome could not be confirmed. On the contrary, a decreased PCO seemed to improve knee flexion. Furthermore, a relationship between PCO and CP could not be found. LEVEL OF EVIDENCE: Prospective cohort study, Level II. PMID- 23677141 TI - Quality of harvest and role of cell dose in unrelated bone marrow transplantation: an Italian Bone Marrow Donor Registry-Gruppo Italiano Trapianto di Midollo Osseo Study. AB - In this study, we investigated the factors affecting cell dose harvest and the role of cell dose on outcome. We analysed data from a cohort of 703 patients who underwent unrelated bone marrow transplantation facilitated by IBMDR in GITMO centers between 2002 and 2008. The median-infused cell doses is 3.7 * 10(8)/kg, the correlation between the nucleated cells requested from transplant centers and those harvested by collection centers was adequate. A harvested/requested cells ratio lower than 0.5 was observed only in 3% of harvests. A volume of harvested marrow higher than the median value of 1270 ml was related to a significant lower infused cell dose (chi(2): 44.4; P < 0.001). No patient- or donor-related variables significantly influenced the cell dose except for the recipient younger age (chi(2): 95.7; P < 0.001) and non-malignant diseases (chi(2): 33.8; P < 0.001). The cell dose resulted an independent predictor factor for a better outcome in patients affected by non-malignant disease (P = 0.05) while early disease malignant patients receiving a lower cell dose showed a higher risk of relapse (P = 0.05). PMID- 23677142 TI - Controlling avalanche criticality in 2D nano arrays. AB - Many physical systems respond to slowly changing external force through avalanches spanning broad range of sizes. Some systems crackle even without apparent external force, such as bursts of neuronal activity or charge transfer avalanches in 2D molecular layers. Advanced development of theoretical models describing disorder-induced critical phenomena calls for experiments probing the dynamics upon tuneable disorder. Here we show that isomeric structural transitions in 2D organic self-assembled monolayer (SAM) exhibit critical dynamics with experimentally tuneable disorder. The system consists of field effect transistor coupled through SAM to illuminated semiconducting nanocrystals (NCs). Charges photoinduced in NCs are transferred through SAM to the transistor surface and modulate its conductivity. Avalanches of isomeric structural transitions are revealed by measuring the current noise I(t) of the transistor. Accumulated surface traps charges reduce dipole moments of the molecules, decrease their coupling, and thus decrease the critical disorder of the SAM enabling its tuning during experiments. PMID- 23677144 TI - Production of calcite nanocrystal by a urease-positive strain of enterobacter ludwigii and study of its structure by SEM. AB - The present research aimed at evaluating the effects of urease enzyme and increasing pH on calcite nanocrystal formation. Unlike some researches, the results showed that CaCO3 precipitation is not a general phenomenon among the bacteria and if a bacterium has not this ability, it will not be able to produce calcite even with an increase in pH. All urease-positive bacteria had this ability, while only some urease-negative bacteria were able to produce calcite. Production and characterization of nanocrystals on precipitating medium were shown primarily by light microscopy and then confirmed by X-ray diffraction (XRD) analysis. Crystallite particle size was determined using Scherrer formula that was sub-100-nm in all samples. Based on qualitative and quantitative studies, strain C8 was selected as the best calcite-producing strain. Phylogenetic analysis indicated that this isolate has 99 % similarity with Enterobacter ludwigii. 16S rRNA sequence of isolate was deposited in GenBank with accession number JX666242. The morphology and exact composition of nanocrystalline particles were determined using scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX). According to data obtained by SEM, we suggest that nanocrystals of CaCO3 adhere to bacteria and each other to form small aggregates and then complex crystalline networks to trap bacteria. Many holes are present in these crystalline networks that seem to be due to the aggregation of nanocrystals. PMID- 23677145 TI - Microbiota regulates the TLR7 signaling pathway against respiratory tract influenza A virus infection. AB - Although intestinal flora are crucial in maintaining immune homeostasis of the intestine, the role of intestinal flora in immune responses at other mucosal surfaces remains less clear. Here, we show that intestinal flora composition critically regulates the toll-like receptor 7 (TLR7) signaling pathway following respiratory influenza virus infection. TLR7 ligands rescued the immune impairment in antibiotic-treated mice. Intact microbiota provided signals leading to the expression of mRNA for TLR7, MyD88, IRAK4, TRAF6, and NF-kappaB at steady state. Significant changes in the composition of culturable commensal bacteria reduced the expression levels of components of the TLR7 signaling pathway. Our results reveal the importance of intestinal flora in regulating immunity in the respiratory mucosa through the upregulation of the TLR7 signaling pathway for the proper activation of inflammasomes. PMID- 23677146 TI - Investigating the diversity of pseudomonas spp. in soil using culture dependent and independent techniques. AB - Less than 1 % of bacterial populations present in environmental samples are culturable, meaning that cultivation will lead to an underestimation of total cell counts and total diversity. However, it is less clear whether this is also true for specific well-defined groups of bacteria for which selective culture media is available. In this study, we use culture dependent and independent techniques to describe whether isolation of Pseudomonas spp. on selective nutrient-poor NAA 1:100 agar-medium can reflect the full diversity, found by pyrosequencing, of the total soil Pseudomonas community in an urban waste field trial experiment. Approximately 3,600 bacterial colonies were isolated using nutrient-poor NAA 1:100 medium from soils treated with different fertilizers; (i) high N-level sewage sludge (SA), (ii) high N-level cattle manure (CMA), and (iii) unfertilized control soil (U). Based on Pseudomonas specific quantitative-PCR and Pseudomonas CFU counts, less than 4 % of Pseudomonas spp. were culturable using NAA 1:100 medium. The Pseudomonas selectivity and specificity of the culture medium were evaluated by 454 pyrosequencing of 16S rRNA gene amplicons generated using Bacteria- and Pseudomonas-specific primers. Pyrosequencing results showed that most isolates were Pseudomonas and that the culturable fraction of Pseudomonas spp. reflects most clusters of the total Pseudomonas diversity in soil. This indicates that NAA 1:100 medium is highly selective for Pseudomonas species, and reveals the ability of NAA 1:100 medium to culture mostly the dominant Pseudomonas species in soil. PMID- 23677147 TI - Straightforward synthesis of [Au(NHC)X] (NHC = N-heterocyclic carbene, X = Cl, Br, I) complexes. AB - An improved protocol for the synthesis of [Au(NHC)X] (X = Cl, Br, I) complexes is reported. This versatile one-step synthetic methodology proceeds under mild conditions, in air, using technical grade solvents, is scalable and is applicable to a wide range of imidazolium and imidazolidinium salts. PMID- 23677148 TI - Mechanochemistry of fullerenes and related materials. AB - The low or lack of solubility of fullerenes, carbon nanotubes and graphene/graphite in organic solvents and water severely hampers the study of their chemical functionalizations and practical applications. Covalent and noncovalent functionalizations of fullerenes and related materials via mechanochemistry seem appealing to tackle these problems. In this review article, we provide a comprehensive coverage on the mechanochemical reactions of fullerenes, carbon nanotubes and graphite, including dimerizations and trimerizations, nucleophilic additions, 1,3-dipolar cycloadditions, Diels-Alder reactions, [2 + 1] cycloadditions of carbenes and nitrenes, radical additions, oxidations, etc. It is intriguing to find that some reactions of fullerenes can only proceed under solvent-free conditions or undergo different reaction pathways from those of the liquid-phase counterparts to generate completely different products. We also present the application of the mechanical milling technique to complex formation, nanocomposite formation and enhanced hydrogen storage of carbon-related materials. PMID- 23677149 TI - [Accuracy and diagnostic utility of IgM in Bartonella henselae infections]. AB - INTRODUCTION: Laboratory diagnosis of cat scratch disease (CSD) is based on the determination of specific antibodies anti-Bartonella henselae by different techniques. The CDC recommends IgG by immunofluorescent assay (IFA) as the gold standard. OBJECTIVE: To determine the accuracy and diagnostic utility of anti B.henselae IgM by IFA for CSD. MATERIAL AND METHODS: Anti-B. henselae IgG was determined in serum of 108 patients with CSD suspicion; in addition, specific IgM was determined separately and blindly by two thoroughly trained laboratory professionals. We calculated sensitivity (S), specificity (Sp), predictive values both positive (PPV) and negative (NPV), and likelihood ratio (LR) for IgM positive (LR +) and negative (LR-). RESULTS: In 37 patients with positive anti B.henselae IgG, IgM was positive in 16 and negative in 21; in 71 patients with negative IgG, IgM was negative in 69 and positive in 2. Therefore, IgM showed S 43%, E 97%, PPV 88%, NPV 77%, LR (+) 15 and LR (-) 0.58. CONCLUSIONS: The results show that a positive IgM supports, but a negative one does not rule out a B. henselae infection. Therefore, IgG should be still considered as the gold standard for the diagnosis of CSD. PMID- 23677150 TI - [Reducing the incidence of ventilator-associated pneumonia following heart surgery: 13-year experience of epidemiologic surveillance in a teaching hospital]. AB - OBJECTIVES: To report the results of 13 years worth of epidemiologic surveillance of ventilator-associated pneumonia (VAP) following heart surgery and the main interventions applied in order to reduce VAP incidence. METHODS: This is a retrospective and descriptive study of active epidemiologic surveillance of VAP. National diagnostic criteria were used. Interventions associated with a decrease in VAlP incidence in adults who underwent heart surgery are described. RESULTS: A significant and sustained reduction was observed in the rate of VAP; being 56.7 per 1,000 ventilator-days in 1998 vs 4.7 per 1,000 ventilator-days in 2010 (p < 0.001). The strongest reduction was observed following 2003 (34.4 to 14.8 per 1,000 ventilator-days in 2004, p < 0.001). The interventions with greatest impact were the implementation of an early-weaning protocol, the introduction of trained nurses to perform the mechanical ventilator equipment management and the routine use of alcohol-based hand rubs. CONCLUSION: Epidemiologic surveillance associated with the establishment of a multifactorial intervention program applied in collaboration with the attending team, have demonstrated a significant reduction of VAP incidence after heart surgery. PMID- 23677151 TI - [Molecular analysis of fluoroquinolones and macrolides resistance in Campylobacter jejuni isolates from humans, bovine and chicken meat]. AB - BACKGROUND: Campylobacter sp.- one of the leading causes of bacterial food-borne gastrointestinal illness worldwide- is increasingly resistant to fluoroquinolone and macrolide antimicrobials, which has become a major concern for public health. OBJECTIVE: To describe the susceptibility patterns of Campylobacter jejuni strains to erythromycin and ciprofloxacin and to explore the origin of its resistance in human isolates. MATERIAL AND METHOD: In this study, fifty-five ciprofloxacin and erythromycin susceptibility patterns of C. jejuni strains isolated from humans with diarrheal disease, performed by broth microdilution MIC, were compared with 55 and 44 isolates from chicken meat and bovines respectively, obtained from the Metropolitan Region, Chile. RESULTS: Of the 55 human isolates of C. jejuni, 33 (60%) were resistant to ciprofloxacin and all were sensitive to erythromycin. Of the 55 isolates from chicken meat, 32 (58.2%) were resistant to ciprofloxacin and 1.8% were resistant to erythromycin. Of the 44 isolates of C. jejuni from cattle, 8 (18.2%) were resistant to ciprofloxacin and all were sensitive to erythromycin. Four PFGE patterns matched with certain resistance profiles and grouped isolates from human and animal. CONCLUSION: The findings showed continued effectiveness of erythromycin for campylobacteriosis and a high percentage of C. jejuni strains ciprofloxacin-resistant. This is interesting because it is considered that the presence of ciprofloxacin resistant strains in broiler meat can be in part the source of resistance to this antimicrobial in humans. PMID- 23677152 TI - [Impact of mass spectrometry by MALDI-TOF MS for the rapid identification of aerobic and anaerobic bacteria of clinical importance]. AB - BACKGROUND: MALDI-TOF MS (Matrix Assisted Laser Desorption Ionization -Time of Flight Mass Spectrometry) technology, recently introduced in the microbiology laboratory has proven to be a precise and rapid method for bacterial identification. OBJECTIVE: To evaluate the performance, costs associated and turnaround time of MALDI-TOF in a routine laboratory. MATERIAL AND METHOD: Five hundred and sixty one clinical isolates (281 aerobes and 280 anaerobes) previously identified by conventional methods were evaluated. Discordances were resolved by means of 16S rRNA sequencing. RESULTS: MALDI-TOF identified 95, 7% of the aerobes isolates and 86, 4% of the anaerobes. The groups with better performance were the enterobacteriacea and Bacteroides spp with 95% and 100% identification at the species level. The error rate of MALDI-TOF and conventional methods compared to sequencing was 0, 39% and 9, 4% respectively. The costs associated were 8 times lower with a turnaround time of 6 hours. CONCLUSION: MALDI-TOF proved to be simple, precise and less expensive technology compared to the traditional methods. PMID- 23677153 TI - [Acanthamoeba spp. as opportunistic pathogens parasites]. AB - Among free-living amoeba in nature, species of the genus Acanthamoeba have been associated with human disease. These amoeba are among the most abundant protozoa in nature due to its cosmopolitan distribution and are able to survive in a wide variety of habitats because its low demand for food and in harsh environments by forming structures known as cysts. However, ecological changes and incursion of its different habitats have made this organism can invade a host and live as parasites within him. That's why this type of protozoa are known as amphizoic organism, because human can be constituted as its host, causing infections in the central nervous system, disseminated infections in skin and lungs, and keratitis. Thus, since an increase in the number of cases of Acanthamoeba infections has occurred worldwide, these protozoa have become increasingly important as agents of human disease. This review summarizes what is known of this kind of free living amoeba, focusing on the biology, ecology, pathogenesis, diagnosis, treatment and human defense mechanism against infection by the amoeba. PMID- 23677154 TI - [Malignancies in HIV-infected patients: descriptive study of 129 cases between 1993 and 2010]. AB - INTRODUCTION: The development of malignancies is a problem associated with HIV infection. The incidence and spectrum of malignancies has been modified with the addition of highly active antiretroviral therapy (HAART). AIM: To describe the clinical and epidemiological characteristics and prognosis of HIV patients who have developed a malignancy. METHODS: Retrospective observational study was conducted in HIV + patients who developed a malignancy between 1993-2010 in a referral hospital. AIDS-defining malignancies (ADN) and non-AIDS-defining malignancies (NADN) were compared. RESULTS: 125 patients were identified with at least one malignancy. The most frequent malignancies were: non-Hodgkin lymphoma (n; 39; 30.2%), Kaposi's sarcoma (n: 20; 15.5%), Hodgkin's disease (n: 11; 8.8%), lung cancer (n: 20; 15.5%) and hepatocellular carcinoma (n: 9; 6.9 %). The mean age was 42 +/- 11 years, 84% male, 55.8% were coinfected with HBV and or HCV. The risk behaviors were: 45.6% intravenous drug users, 16.8% men who have sex with men and 20% heterosexuals). There were 67 (52%) NADN and 62 (48%) ADN; NADN patients had a longer story of HIV infection and longer exposure to HAART, better level of immunodeficiency and better virological control than ADN patients. Four patients developed a second malignancy. Overall survival was 34.7%. CONCLUSIONS: We found an increased incidence of NADN, appearing in patients with better virological and immunological control than ADN group. Mortality of patients with HIV infection and malignancy is still very high. PMID- 23677155 TI - [Eikenella corrodens]. PMID- 23677156 TI - [Multidisciplinary approach of Clostridium difficile infection]. AB - Clostridium difficile is the most common cause of infectious diarrhea in adults healthcare institutions. Recent studies have shown an increase in the incidence, severity and recurrence of C. difficile infection (CDI). Factors associated with the patient and medical care provided contribute to establishing colonization and, in some cases, subsequent progression to symptomatic disease. The availability of new microbiological techniques has contributed greatly to improving care for these patients. A diagnostic algorithm is provided for cases in which CDI is suspected based on current evidence regarding the effectiveness of microbiological and radiological methods. In cases in which CDI is confirmed, the first and most effective measure is the withdrawal of any antibiotic treatment the patient is receiving, if possible. The antimicrobial treatment of CDI is based on three classic agents: metronidazole, vancomycin and teicoplanin, along with the recent addition of fidaxomicin. Patients presenting serious symptoms, in addition to appropriate support and monitoring measures, may require surgical treatment. Infection prevention and control strategies can interrupt the transmission mechanism. This manuscript reviews current evidence on the approach of this entity from a multidisciplinary point of view. PMID- 23677157 TI - [Detection of human papilloma virus infection in men]. AB - Globally, human papillomavirus (HPV) is the most frequent sexually transmitted infection (STI) and it affects men and women equally. In men, HPV has been mainly associated with skin lesions like ano-genital warts and intraepithelial neoplasia of penis and anus in recent years. HPV prevalence in men varies extremely due to kind of sample and detection techniques. The most widely used samples to study HPV in men are: penile shaft, glans, prepuce, coronal sulcus, urine and semen, and its detection is usually performed with techniques like reverse line blot (RLB) and hybrid capture (HC). Given that the highest infection rates are in Africa and Latin America, the aim of this review is to describe the pathogenesis of HPV and its main detection techniques in men. PMID- 23677158 TI - [Epidemiology of febrile neutropenia in adult patients with hematologic neoplasms in a period of 26 months in Hospital Pablo Tobon Uribe, Colombia]. AB - BACKGROUND: Febrile neutropenia (FN) is a significant adverse effect post chemotherapy due to its high morbidity and mortality. There are few studies in our country with these kind of patients. OBJECTIVE: To describe the characteristics and mortality in patients with hematologic neoplasms who developed FN post-chemotherapy. METHODOLOGY: A descriptive case series in patients with hematologic neoplasms who developed FN post-chemotherapy in Hospital Pablo Tobon Uribe. RESULTS: 101 episodes of FN in 43 patients. The median age was 44 years. 63.5% of patients had no apparent clinical focus of infection at admission, 11.8% had soft tissue compromise and 8.9% urinary tract infection. Bacteremia was documented in 41.5% and catheter-associated bacteremia in 3.9%. The most common organisms were Escherichia coli 43.4%, Klebsiella pneumoniae 17.3% and Staphylococcus aureus 8.6%. Of those isolated in blood 84.7% were Gram negative rods and 15.2% were Gram positive bacteria. Piperacillin/tazobactam was the most common empirically prescribed antibiotic (81.1%). Mortality of FN episodes occurred in 8 (7.92%) patients, 5 (62.5%) attributable to infection and 3 (37.5%) due to progression of hematologic malignancy with a resolution of FN. CONCLUSIONS: In our case series of FN the microbiological characteristics differed significantly from developed countries, but a similar mortality rate per episode was observed. PMID- 23677159 TI - [Mycobacterium tuberculosis infection in a pediatric patient who underwent a hematopoietic stem cell transplant]. AB - We report the case of a 10 year old girl with a relapsed acute lymphoblastic leukemia, who underwent a haploidentical hematopoietic stem cell transplant (HSCT), with grade II skin and digestive graft versus host disease, treated with corticosteroids and cyclosporine. On day + 54, she presented fever, with no other remarkable clinical findings. Imaging study showed the presence of lung and liver nodules, liver biopsy was performed. The study included histology, staining and culture for bacteria and fungi, and the preservation of a piece of tissue at -20 degrees C for future prospective studies. Ziehl Nielsen stain was positive, and study for Mycobacterium infection was performed. Microbiological smears of tracheal and gastric aspirate, and bronchial fluid obtained by bronchoalveolar lavage (BAL) were positive. The final report confirmed Mycobacterium tuberculosis in gastric content, sputum, BAL and liver tissue, susceptible to rifampin, isoniazid, streptomycin and ethambutol, with determination of mutations for genes rpobeta and kat G (-). Tuberculosis (TB) diagnosis was confirmed. The girl received daily therapy for two months and then she continued on three times per week therapy for 9 months. Controlled by the transplant, infectious diseases and respiratory teams, the patient remained in good general condition, with radiologic resolution of pulmonary and liver involvement and negative smears. We conclude that Mycobacterium tuberculosis infection should be part of differential diagnosis of febrile illness in patients undergoing HSCT, and biopsy should be a standard practice of early diagnosis in these patients. PMID- 23677160 TI - [Chile between pandemic: the influenza of 1918, globalization and the new medicine]. AB - In 1918 Chile met the deadly presence of the Spanish influenza pandemic twentieth century's most important. For many historians, this event is an important milestone in the historical process of the unification of the world through sickness and in which our country has been involved. In this context, this paper aims to examine how the flu broke into Chilean society and how that situation helped give new impetus to the modernization of the Chilean public health and the establishment in the 1920s to model new medicine or preventive medicine. PMID- 23677161 TI - [Visceral leishmaniasis in patient with HIV infection]. AB - Leishmaniasis is a parasitic disease caused by the protozoa of the genus Leishmania transmitted by sandfly bites. It causes subclinical infection and diverse clinical manifestations with cutaneous, mucosal or visceral involvement. The last one, called visceral leishmaniasis, is usually fatal without treatment and in VIH patients with deep immunosuppression, has been recognized as an opportunistic infection with a high degree of difficulty in diagnosis and treatment. We present the case of a patient with HIV infection and visceral leishmaniasis. The clinical presentation was a prolonged febril syndrome with hepatosplenomegaly, lymphadenopathy and pancytopenia. The differential diagnosis was made with lymphoma and other opportunistic infections, as mycobacteriosis. The bone marrow aspirate reveled parasite amastigotes. The patient received treatment with amphotericin B deoxycholate for 14 days and 2 months after he relapsed. Then he was treated with the same drug for 21 days and after that he has been in prophylaxis for 29 months with good outcome, without any other relapse. PMID- 23677162 TI - [Premastication: a new way of transmitting HIV. First pediatric case reported in Chile]. AB - The incorporation of the protocol to prevent vertical transmission (PMTCT) of HV in pregnant women has reduced the rate of HV transmission in children to less than 2%. In Chile, currently the diagnosis of HIV infection in children is rare. Thus, one positive finding should lead us to audit compliance of the PMTCT and if this has been fully implemented should be reviewed other possible routes of HIV transmission. We present a case report that suggest that HV can be transmitted through the consumption of foods that have been premasticated by a person infected with HV. Premastication is a transmission path that had not been reported, being a possible explanation for some cases of late transmission of HIV in infants, so far attributed to breastfeeding. Understanding that premastication is a common behavior, you should educate people about the potential risk of transmission of diseases, including HIV, through this practice and advise HIV infected caregivers against this practice. PMID- 23677163 TI - [Pharmacokinetics of oseltamivir in children younger than 2 years with influenza]. PMID- 23677164 TI - [Pertussis epidemics and changes in vaccination schedules: Chile 2012. ?Questions remain?]. PMID- 23677165 TI - MicroRNA Expression Profiling in the Histological Subtypes of Barrett's Metaplasia. AB - OBJECTIVES: The histological definition of Barrett's esophagus (BE) is debated, particularly regarding the phenotype of its metaplastic columnar epithelium. Histologically proven intestinal metaplasia (IM) was the sine qua non condition for a diagnosis of BE but, more recently, non-intestinalized (i.e., cardiac gastric-type; GM) columnar metaplasia has been re-included in the spectrum of Barrett's histology. MicroRNAs modulate cell commitment, and are also reportedly dysregulated in Barrett's carcinogenesis. This study investigates miRNA expression in the histological spectrum of esophageal columnar metaplastic changes, specifically addressing the biological profile of GM vs. IM. METHODS: A study was performed to discover microRNA microarray in 30 matching mucosa samples obtained from 10 consecutive BE patients; for each patient, biopsy tissue samples were obtained from squamous, GM and intestinalized epithelium. Microarray findings were further validated by qRT-PCR analysis in another bioptic series of 75 mucosa samples. RESULTS: MicroRNA profiling consistently disclosed metaplasia specific microRNA signatures. Six microRNAs were significantly dysregulated across the histological phenotypes considered; five of them (two overexpressed (hsa-miR-192; -miR-215) and three under-expressed (hsa-miR-18a*; -miR-203, and miR-205)) were progressively dysregulated in the phenotypic sequence from squamous to gastric-type, to intestinal-type mucosa samples. CONCLUSIONS: A consistent microRNA expression signature underlies both gastric- and intestinal type esophageal metaplasia. The pattern of microRNA dysregulation suggests that GM may further progress to IM. The clinico-pathological implications of these molecular profiles prompt further study on the "personalized" cancer risk associated with each of these metaplastic transformations. PMID- 23677166 TI - Creation of differentiation-specific genomic maps of human epidermis through laser capture microdissection. PMID- 23677167 TI - Molecular signatures in skin associated with clinical improvement during mycophenolate treatment in systemic sclerosis. AB - Heterogeneity in systemic sclerosis (SSc) confounds clinical trials. We previously identified "intrinsic" gene expression subsets by analysis of SSc skin. Here we test the hypotheses that skin gene expression signatures including intrinsic subset are associated with modified Rodnan skin score (MRSS) improvement during mycophenolate mofetil (MMF) treatment. Gene expression and intrinsic subset assignment were measured in 12 SSc patients' biopsies and 10 controls at baseline, and from serial biopsies of 1 cyclophosphamide-treated patient and 9 MMF-treated patients. Gene expression changes during treatment were determined using paired t-tests corrected for multiple hypothesis testing. MRSS improved in four of seven MMF-treated patients classified as the inflammatory intrinsic subset. Three patients without MRSS improvement were classified as normal-like or fibroproliferative intrinsic subsets. A total of 321 genes (false discovery rate (FDR)<5%) were differentially expressed at baseline between patients with and without MRSS improvement during treatment. The expression of 571 genes (FDR<10%) changed between pre- and post-MMF treatment biopsies for patients showing MRSS improvement. Gene expression changes in skin are only seen in patients with MRSS improvement. Baseline gene expression in skin, including intrinsic subset assignment, may identify SSc patients whose MRSS will improve during MMF treatment, suggesting that gene expression in skin may allow targeted treatment in SSc. PMID- 23677168 TI - Enpp2/Autotaxin in dermal papilla precursors is dispensable for hair follicle morphogenesis. AB - Systematic ablation of previously identified dermal papilla (DP) signature genes in embryonic DP precursors will reveal their functional roles during hair follicle morphogenesis. In this study, we validate Enpp2/Autotaxin as one of the highest expressed signature genes in postnatal DP, and demonstrate specific expression of this lysophosphatidic acid (LPA)-generating enzyme in embryonic dermal condensates. We further identify dermal and epidermal expression of several LPA receptors, suggesting that LPA signaling could contribute to follicle morphogenesis in both mesenchymal and epithelial compartments. We then use the recently characterized Cre-expressing Tbx18 knock-in line to conditionally ablate Enpp2 in embryonic DP precursors. Despite efficient gene knockout in embryonic day 14.5 (E14.5) dermal condensates, morphogenesis proceeds regularly with normal numbers, lengths, and sizes of all hair follicle types, suggesting that Enpp2 is not required for hair follicle formation. To interrogate DP signature gene expression, we finally isolate control and Enpp2-null DP precursors and identify the expression and upregulation of LIPH, an alternative LPA-producing enzyme, suggesting that this gene could functionally compensate for the absence of Enpp2. We conclude that future coablation of both LPA-producing enzymes or of several LPA receptors may reveal the functional role of LPA signaling during hair follicle morphogenesis. PMID- 23677169 TI - Pituitary tumor transforming gene 1 induces tumor necrosis factor-alpha production from keratinocytes: implication for involvement in the pathophysiology of psoriasis. AB - Proliferation and differentiation in the epidermis must be tightly regulated. This regulation is known to involve a range of transcription factors, including pituitary tumor transforming gene 1 (PTTG1), a ubiquitously distributed transcription factor that regulates keratinocyte proliferation and differentiation. Psoriasis is a common but refractory skin disorder, the pathophysiology of which is characterized by hyperproliferation and impaired differentiation in the epidermis. The present study was conducted to clarify the less well-known roles of PTTG1 in the pathophysiology of psoriasis, focusing on its relationship with tumor necrosis factor-alpha (TNF-alpha), which is a critical mediator of the disease. The levels of PTTG1 expression were increased in the psoriatic epidermis. Overexpression of PTTG1 resulted in the overproduction of TNF-alpha, and TNF-alpha itself had an inductive effect on PTTG1 expression, suggesting that their expression may involve autoinduction. Moreover, overexpression of PTTG1 involved augmented the expression of cyclin A and B1 proteins in both cultured keratinocytes and the psoriatic epidermis. Therefore, enhanced expression of PTTG1 in the psoriatic epidermis may result in aberrant regulation of the cell cycle and impaired differentiation via the interplay between PTTG1 and TNF-alpha. PMID- 23677170 TI - A multifunctional helical Cu(I) coordination polymer with mechanochromic, sensing and photocatalytic properties. AB - A multifunctional Cu(I) coordination polymer constructed from helical chains showed unusual mechanochromic, sensing of nitrobenzene and photocatalytic properties on degradation of organic dyes. PMID- 23677172 TI - On the role of non-covalent interactions in the assembly of 3D zirconium methyl- and ethyl-N,N-bis phosphonates. AB - Novel Zr methyl- and ethyl-N,N-bis(methylphosphonates), with formula ZrF2[(O3PCH2)2NHCH3] and Zr[(HO3PCH2)(O3PCH2)NHC2H5]2, respectively, were prepared in mild solvothermal conditions and their structures were solved ab initio by laboratory X-ray powder diffraction data. Despite the chemical homology between the molecular building blocks, and the similar synthetic conditions, the two compounds showed different stoichiometry and crystal structure. A comparative analysis of these structures and that of homologous longer chain Zr phosphonates, previously reported, revealed the important contribution of the hydrophobic groups in the building of the crystal structure, in a way that can be compared to that observed in the assembly of amphiphilic systems. PMID- 23677171 TI - Reciprocal influences between leptin and glucocorticoids during acute Trypanosoma cruzi infection. AB - Leptin and glucocorticoids (GCs) are involved in metabolic functions, thymic homeostasis and immune activity through complex interactions. We recently showed that C57BL/6 mice infected with Trypanosoma cruzi revealed a fatal disease associated with a dysregulated immune-endocrine response characterized by weight loss, deleterious synthesis of pro-inflammatory cytokines and GCs-driven thymus atrophy. Extending this study, we now explored the relationship between leptin and GCs, in terms of infection outcome, thymic and metabolic changes. T. cruzi infected mice showed a food intake reduction, together with hypoglycemia and lipolysis-related changes. Infected animals also displayed a reduction in systemic and adipose tissue levels of leptin, paralleled by a down-regulation of their receptor (ObR) in the hypothalamus. Studies in infected mice subjected to adrenalectomy (Adx) showed a worsened course of infection accompanied by even more diminished systemic and intrathymic leptin levels, for which GCs are necessary not only to decrease inflammation but also to sustain leptin secretion. Adx also protected from thymic atrophy, independently of the reduced leptin contents. Leptin administration to infected mice aggravated inflammation, lowered parasite burden and attenuated GCs release, but did not normalize thymic atrophy or metabolic parameters. Acute T. cruzi infection in C57BL/6 mice coexists with a dysregulation of leptin/hypothalamic ObR circuitry dissociated from body weight and food intake control. Endogenous GCs production attempted to reestablish systemic leptin concentrations, but failed to improve leptin-protective activities at the thymic level, suggesting that the leptin/GCs intrathymic relationship is also altered during this infection. PMID- 23677173 TI - In situ spectroscopic investigation of oxidative dehydrogenation and disproportionation of benzyl alcohol. AB - In the solvent free oxidation of benzyl alcohol, using supported gold-palladium nanoalloys, toluene is often one of major by-products and it is formed by the disproportionation of benzyl alcohol. Gold-palladium catalysts on acidic supports promote both the disproportionation of benzyl alcohol and oxidative dehydrogenation to form benzaldehyde. Basic supports completely switch off disproportionation and the gold-palladium nanoparticles catalyse the oxidative dehydrogenation reaction exclusively. In an attempt to provide further details on the course of these reactions, we have utilized in situ ATR-IR, in situ DRIFT and inelastic neutron scattering spectroscopic methods, and in this article we present the results of these in situ spectroscopic studies. PMID- 23677174 TI - Assessment of peripapillary retinal nerve fiber layer thickness in children with vitamin B12 deficiency. AB - PURPOSE: Vitamin B(12) deficiency is a worldwide problem. It affects all ages, including children. It is one of the most common nutritional disorders and can cause harmful effects on the nervous system. In this study, we compared the peripapillary retinal nerve fiber layer thickness (RNFLT) in a healthy control group with children with vitamin B(12) deficiency. In our study, we aimed to evaluate the effect of vitamin B(12) deficiency on the RNFLT in children with the optical coherence tomography (OCT) method. METHODS: Sixty-six children with a diagnosis of vitamin B(12) deficiency (patient group) and 66 age- and sex-matched healthy children (control group) were enrolled in this prospectively designed study. Blood counts, vitamin B(12) levels, folate levels, and full biochemical parameters were obtained for all the subjects in each group. Peripapillary RNFLT measurements were performed with Cirrus HD spectral domain OCT. RESULTS: The thickness of the superior retinal nerve fiber layer (RNFL) in the vitamin B(12) deficiency group was significantly lower than that of the control group (p = 0.037). Although the average thickness of the RNFL was lower in the patient group, there was no statistically significant differences (p = 0.216). In the vitamin B(12) deficiency group, the average RNFL thickness and the superior RNFL thickness were significantly correlated with vitamin B(12) levels ((r1) = 0.353, (p1) < 0.004 and (r2) = 0.416, (p2) = 0.001, respectively). CONCLUSION: Our study showed that a deficiency in vitamin B(12), elsewhere it is important for the development of the central nervous system, is associated with a reduction in the thickness of the superior RNFL. PMID- 23677175 TI - Somatostatin receptor subtype 2 (sst2) is a potential prognostic marker and a therapeutic target in medulloblastoma. AB - INTRODUCTION: Neuroectodermal tumors in general demonstrate high and dense expression of the somatostatin receptor subtype 2 (sst2). It controls proliferation of both normal and neoplastic cells. sst2 has thus been suggested as a therapeutic target and prognostic marker for certain malignancies. METHODS: To assess global expression patterns of sst 2 mRNA, we evaluated normal (n = 353) and tumor tissues (n = 340) derived from previously published gene expression profiling studies. These analyses demonstrated specific upregulation of sst 2 mRNA in medulloblastoma (p < 0.001). sst2 protein was investigated by immunohistochemistry in two independent cohorts. RESULTS: Correlation of sst2 protein expression with clinicopathological variables revealed significantly higher levels in medulloblastoma (p < 0.05) compared with CNS-PNET, ependymoma, or pilocytic astrocytoma. The non-SHH medulloblastoma subgroup tumors showed particularly high expression of sst2, when compared to other tumors and normal tissues. Furthermore, we detected a significant survival benefit in children with tumors exhibiting high sst2 expression (p = 0.02) in this screening set. A similar trend was observed in a validation cohort including 240 independent medulloblastoma samples. CONCLUSION: sst2 is highly expressed in medulloblastoma and deserves further evaluation in the setting of prospective trials, given its potential utility as a prognostic marker and a therapeutic target. PMID- 23677176 TI - Changes in third ventricular size in pediatric patients undergoing endoscopic third ventriculostomy. AB - PURPOSE: Optimal methods of evaluating radiographic data following endoscopic third ventriculostomy (ETV) are not yet known. This study analyzes imaging parameters, including third ventricular width and cross-sectional area (CSA), in pediatric ETV patients. METHODS: Hydrocephalic pediatric patients treated by ETV at the senior authors' institution from 2004 to 2011 were stratified clinically (successful versus unsuccessful outcome) and retrospectively reviewed. Measured from pre- and post-operative imaging studies, third ventricular parameters included maximal width and mid-sagittal CSA, while lateral ventricular parameters included the ratio of greatest frontal horn width to co-linear skull internal diameter and the frontal-occipital horn ratio. RESULTS: Ten successful ETV patients (mean age 10.6 years; range 11 months to 19.8 years) obtained imaging at least 2.75 months following surgery, while four unsuccessful ETV patients (mean age 9.8 years; range 4 months to 17.3 years) underwent imaging before repeat intervention. Third ventricular width showed an average decline of 0.32 cm and 17.4 % in the successful ETV cohort, but average increases of 0.35 cm and 21.0 % in the ETV failure group. Successful ETV patients exhibited mean decreases of 1.85 cm(2) and 19.7 % in third ventricular mid-sagittal CSA, while unsuccessful ETV patients showed mean increases of 1.17 cm(2) and 17.3 % per patient. These differences were statistically significant. Measures of lateral ventricular size showed similar trends, but with lower magnitude. CONCLUSIONS: Third ventricular imaging parameters (width and mid-sagittal CSA) exhibited more pronounced responses to ETV than lateral ventricular measurements in pediatric hydrocephalic patients. PMID- 23677178 TI - Responsive hydrogels--structurally and dimensionally optimized smart frameworks for applications in catalysis, micro-system technology and material science. AB - Although the technological and scientific importance of functional polymers has been well established over the last few decades, the most recent focus that has attracted much attention has been on stimuli-responsive polymers. This group of materials is of particular interest due to its ability to respond to internal and/or external chemico-physical stimuli, which is often manifested as large macroscopic responses. Aside from scientific challenges of designing stimuli responsive polymers, the main technological interest lies in their numerous applications ranging from catalysis through microsystem technology and chemomechanical actuators to sensors that have been extensively explored. Since the phase transition phenomenon of hydrogels is theoretically well understood advanced materials based on the predictions can be prepared. Since the volume phase transition of hydrogels is a diffusion-limited process the size of the synthesized hydrogels is an important factor. Consistent downscaling of the gel size will result in fast smart gels with sufficient response times. In order to apply smart gels in microsystems and sensors, new preparation techniques for hydrogels have to be developed. For the up-coming nanotechnology, nano-sized gels as actuating materials would be of great interest. PMID- 23677177 TI - Histologic grade and extent of resection are associated with survival in pediatric spinal cord ependymomas. AB - PURPOSE: Prognostic factors affecting outcomes in pediatric spinal cord ependymomas are limited. We sought to investigate potential associations between extent of resection and histologic grade on progression-free survival (PFS) and overall survival (OS). METHODS: A comprehensive literature search was performed to identify pediatric patients who underwent surgical resection for spinal cord ependymomas. Only manuscripts with clearly defined age, tumor grade, extent of resection, and clinical follow-up were included. RESULTS: A total of 80 patients were identified with a histologic distribution as follows: 36 % myxopapillary (grade I), 54 % classical (grade II), and 10 % anaplastic (grade III). There was no association between tumor grade and PFS. The only factor associated with improved PFS was gross total resection (GTR), which remained significant in a multivariate model (hazard ratio (HR) = 0.248, p = 0.022). Moreover, older age (HR = 0.818, p = 0.026), GTR (HR = 0.042, p = 0.013), and anaplastic grade (HR = 19.847, p = 0.008) demonstrated a significant association with OS in a multivariate model. CONCLUSIONS: Among pediatric patients with spinal cord ependymomas, PFS did not differ across histologic grades but was prolonged among patients who underwent GTR. Age, extent of resection, and tumor grade were all significantly associated with survival. PMID- 23677179 TI - The 'thousand-dollar genome': an ethical exploration. AB - Sequencing an individual's complete genome is expected to be possible for a relatively low sum 'one thousand dollars' within a few years. Sequencing refers to determining the order of base pairs that make up the genome. The result is a library of three billion letter combinations. Cheap whole-genome sequencing is of greatest importance to medical scientific research. Comparing individual complete genomes will lead to a better understanding of the contribution genetic variation makes to health and disease. As knowledge increases, the 'thousand-dollar genome' will also become increasingly important to healthcare. The applications that come within reach raise a number of ethical questions. This monitoring report addresses the issue. PMID- 23677180 TI - Dual inhibition of EGFR and c-Met kinase activation by MJ-56 reduces metastasis of HT29 human colorectal cancer cells. AB - Quinazolinone derivatives are known to possess anticancer activities on cell metastasis and cell death in different human cancer cell lines. Here, we studied the anti-metastasis activity and the underlying mechanisms of the novel quinazoline derivative MJ-56 (6-pyrrolidinyl-2-(3-bromostyryl)quinazolin-4-one). MJ-56 inhibited cell migration and invasion of HT29 human colorectal cancer cells by wound-healing and Matrigel-coated transwell assays in a concentration dependent manner. MJ-56-treated cells resulted in the reduced expression of matrix metalloproteinase (MMP)-2, -7, -9 and -10 and the reduced enzymatic activities of MMP-2 and MMP-9. In contrast, MJ-56-treated cells enhanced the expression of the tissue inhibitors of metalloproteinases (TIMPs) TIMP-1 and TIMP 2. Further analyses showed that MJ-56 attenuated the activities of epidermal growth factor receptor (EGFR), c-Met and the downstream ERK-mediated MAPK and PI3K/AKT/mTOR signaling pathways, which led to decreased protein synthesis by dephosphorylating the translation initiation factors eIF-4B, eIF-4E, eIF-4G and S6 ribosomal protein. In addition, MJ-56 interfered with the NF-kappaB signaling via impairing PI3K/AKT activation and subsequently reduced the NF-kappaB-mediated transcription of MMPs. Taken together, the reduced expression of phosphor-EGFR and c-MET is chiefly responsible for all events of blocking metastasis. Our results suggest a potential role of MJ-56 on therapy of colorectal cancer metastasis. PMID- 23677181 TI - Solvent-dependent excited state intramolecular proton transfer (ESIPT) pathways from phenol to carbon in 2,5-dihydroxyphenyl arenes. AB - The ESIPT of three 2,5-dihydroxyphenyl-substituted arenes 9-11 was studied in various solvent systems, to investigate the direction of the proton transfer from the phenol to the respective carbons of naphthyl, phenanthrenyl and anthryl aromatic rings. In neat CH3CN, 9-11 undergo direct ESIPT from the phenolic OH to the ipso-position of the corresponding aromatic carbon acceptors, via an intramolecular charge transfer state (S(1,ct)), giving rise to observable zwitterions, ZIs 35, 25, 27, respectively. Surprisingly, the generated ZI in 9 proceeds via a 1,2-phenyl migration followed by re-aromatization to afford 16 (a structural isomer of 9) in quantitative yield. In 10 and 11, the corresponding ZIs proceed via electrocyclic ring closure to furnish 20 and 28, respectively. In the case of 10, another intrinsic ESIPT pathway takes place to the 10-position of a phenanthrenyl ring, giving QM 26 in high quantum efficiency (Phiex = 0.72). In aqueous solution, 9 undergoes formal ESIPT to the more distal 2'- and 7' positions of the naphthalene ring, delivering QMs 18 and 38, which either revert back to the starting material or proceed via electrocyclic ring closure, respectively. In 11 in aqueous solution, formal ESIPT to the 10-position of the anthracene ring takes place delivering QM 29, which readily aromatizes to regenerate starting material. PMID- 23677182 TI - [Effect of metformin on the expression of tumor necrosis factor-alpha, Toll like receptors 2/4 and C reactive protein in obese type-2 diabetic patients]. AB - BACKGROUND: The pharmacological action of metformin goes beyond mere glycemic control, decreasing markers of inflammation and contributing to the reduction of oxidative stress. AIM: To evaluate biochemical, anthropometric and pro inflammatory markers in obese type 2 diabetic patients treated or not with metformin. PATIENTS AND METHODS: Obese patients with type 2 diabetes were invited to participate in the study if they were aged more than 40 years, were not receiving insulin, did not have cardiovascular diseases and were not taking anti inflammatory drugs. A pharmacological history was taken and patients were stratified in two groups whether they were using metformin or not. A fasting blood sample was obtained to measure blood glucose, insulin, lipid levels, C reactive protein (hsCRP) and to isolate peripheral blood mononuclear cells. RNA was isolated from these cells to measure expression of tumor necrosis factor alpha (TNF-alpha), Interleukin-6 (IL-6), nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB), Toll-Like Receptor 2/4 (TLR 2/4) and beta 2-microglobulin (B2M). RESULTS: Thirty participants were studied. Of these, 16 subjects aged 54.4 +/- 5.5years were treated with metformin and 14 subjects aged 54.9 +/- 6.4 years did not receive the drug. Participants receiving metformin had lower levels of hsCRP and lower mRNA relative abundance of TNF-alpha and TLR 2/4. There were no differences in glucose levels or lipid profile between both groups. CONCLUSIONS: Obese diabetic patients treated with metformin had lower levels of hsCRP expression of TNF-alpha and TLR 2/4, than their counterparts not receiving the drug. PMID- 23677183 TI - [Spontaneous activity of cutaneous nociceptors in patients with painful polyneuropathy. Report of three patients]. AB - Painful polyneuropathy may result from selective impairment of small diameter nerve fibers, while tactile and motor functions are preserved. In these patients clinical and electrophysiological assessment is usually unrevealing. We report three patients with a pure painful polyneuropathy. One of them had neurogenic pruritus additionally. Quantitative sensory analysis disclosed a slight warm hypoesthesia (3/3) and paradoxical hot sensation (2/3) in the feet. Intraneural recordings from the peroneal nerve demonstrated abnormal spontaneous activity in 8 of 17 nociceptive afferents. One of them displayed double firing reflecting impulse multiplication. These results support the notion that patients with pain or pruritus with a distal distribution similar to a polyneuropathy, could have small diameter afferent fiber damage, despite normal function of large diameter fibers. PMID- 23677184 TI - [Clinical practice guidelines in the Chilean health sector reform: a critical assessment of their quality]. AB - BACKGROUND: Clinical practice guidelines are widely used as tools for improving quality of health care. However, there is increasing concern about limitations in their development process conducting to inconsistent recommendations. During the last decade the use of guidelines has been promoted in the Chilean health system, but their quality has not yet been evaluated systematically. AIM: To assess the quality of clinical practice guidelines developed by the Chilean guidelines program. MATERIAL AND METHODS: All the guidelines developed by the Chilean program between 2005 and 2009 were retrieved from the Ministry of Health website. Each guideline was assessed independently by three appraisers using the Appraisal of Guidelines, Research and Evaluation (AGREE) instrument. Standardized scores were obtained for each dimension in each guideline and across the whole set of guidelines. RESULTS: Sixty guidelines were assessed. The 'scope and purpose' dimension scored significantly higher (mean 82.2%, range: 25.9%-100%) and the 'applicability' dimension scored significantly lower (mean 23.3%, range: 0% 72.4%) than any other dimension. 'Publication date' was the only variable consistently associated with dimension scores. CONCLUSIONS: The quality of Chilean clinical practice guidelines is far from ideal. Although they seem to have a strong sense of purpose and vision, methodological procedures should be strengthened, especially those related to applicability. PMID- 23677185 TI - [Frequency of subclinical thyroid problems among women during the first trimester of pregnancy]. AB - BACKGROUND: Thyroid hormones play an important role in fetal neural and cognitive development. Therefore thyroid abnormalities should be detected and treated early during pregnancy. AIM: To assess the frequency and risk factors for functional thyroid disorders during the first trimester of pregnancy. MATERIAL AND METHODS: A blood sample was obtained from women during their first trimester of pregnancy, consulting in a prenatal care facility. Women with known thyroid diseases were excluded from the study. Thyroid stimulating hormone (TSH), total thyroxine (T4) and free thyroxine (fT4) were measured by electrochemoluminiscence. Antithyroid peroxidase antibodies (anti TPO) were measured by enzyme immunoassay. RESULTS: Five hundred and ten women aged 25.7 +/- 6.6 years were assessed. The frequency of clinical hypothyroidism was 0.6%, subclinical hypothyroidism 35.3% and clinical hyperthyroidism 1%. Five percent of women with hypothyroidism and 3.5% of euthyroid women had positive anti TPO antibodies. There was no association between the frequency of thyroid diseases and risk factors for thyroid diseases. CONCLUSIONS: There is a high frequency of subclinical thyroid diseases among women consulting in this prenatal care clinic. PMID- 23677186 TI - [Attention deficit hyperactivity disorder in Aymara children]. AB - BACKGROUND: The assessment of Attentional Deficit Hyperactivity Disorder (ADHD) among ethnic groups may reveal environmental or cultural variables that influence the appearance of this disorder. AIM: To assess the presence and characteristics of ADHD in two communities of the inland Arica valleys (Azapa and Lluta), where the Aymara population predominates. MATERIAL AND METHODS: Starting from a screening based on the Conner's test, we evaluated 79 children aged 8 to 13 years. Sixty children were of Aymara origin and 19 children were of non-Aymara origin. Twenty Aymara and 9 non-Aymara children had ADHD. They were compared with a group of patients from Santiago, Chile (110 children) that were previously assessed. RESULTS: Patients from Azapa/Lluta displayed similar characteristics to those from Santiago. However the former had significantly less psychiatric comorbidities than the latter. On the other hand, the non-Aymara subgroup of Azapa/Lluta displayed an increased rate of comorbidities and was exclusively of the combined subtype, although their sample size is too small to draw strong conclusions. CONCLUSIONS: Although we cannot dismiss biological variables, the importance of family values and the respect to authorities may be protective factors for ADHD, associated to Aymara culture. Our findings suggest that the clinical characteristics of ADHD are not uniform among ethnic groups and cultures. The relative contribution of environmental and genetic factors in this variability remain to be determined. PMID- 23677187 TI - [Risk factors and behaviors among children and adolescents hospitalized for a suicidal attempt]. AB - BACKGROUND: Suicidal behavior is the result of the interaction of several factors and represents an increasing health problem. AIM: To characterize epidemiologically children and adolescents with suicidal attempts and compare them to a control group. MATERIAL AND METHODS: A case-control and prospective study, based on clinical interviews and tests performed to 30 children and adolescents hospitalized due to a suicidal attempt and their parents or tutors, (GIS) and 40 ambulatory controls without such history (CG). Psychopathological disorders, risk behaviors (substance use, maltreatment, peer violence, sexual abuse and early sexual relations), family factors and their association with suicidal attempts, were analyzed. RESULTS: Seventy seven percent of participants with a history of suicidal attempt had psychopathological disorders (depression in 38%) and a higher prevalence of suicidal behavior, maltreatment, substance and sexual abuse. Male sex was a risk factor for suicide among children under 12 years and female sex was a risk factor for adolescents aged over 12 years. Other risk factors detected were a risky communication between parents and siblings. CONCLUSIONS: Children and adolescents who attempted suicide and their families have a higher prevalence of risk behaviors than the control group. PMID- 23677188 TI - [Airway humidification practices in Chilean intensive care units]. AB - BACKGROUND: In patients with an artificial airway, inspired gases can be humidified and heated using a passive (heat and moisture exchange filter - HMEF), or an active system (heated humidifier). AIM: To assess how humidification is carried out and what is the usual clinical practice in this field in Chilean intensive care units (ICUs). MATERIAL AND METHODS: A specific survey to evaluate humidification system features as well as caregivers' preferences regarding humidification systems, was carried out on the same day in all Chilean ICUs. RESULTS: Fifty-five ICUs were contacted and 44 of them completed the survey. From a total of 367 patients, 254 (69%) required humidification because they were breathing through an artificial airway. A heated humidifier was employed only in 12 patients (5%). Forty-three ICUs (98%) used HMEF as their routine humidification system. In 52% of surveyed ICUs, heated humidifiers were not available. CONCLUSIONS: In Chile the main method to humidify and heat inspired gases in patients with an artificial airway is the HMEF. Although there are clear indications for the use of heated humidifiers, they are seldom employed. PMID- 23677189 TI - [A clinical teaching course for residents improves self-perception about preparation to teach]. AB - BACKGROUND: Medical doctors need to be competent to teach patients, their families, students, and the health care team. In a previous study we determined that although the residents attach great importance to have teaching skills, they do not feel prepared to meet this role. AIM: To assess self-perception of learning in a formal course of training how to teach for residents. MATERIAL AND METHODS: In 2004 we implemented the course "Residents as Clinical Teachers", based on the Stanford Faculty Development Center for Medical Teachers Model (SFDC), for residents of a Medical School. Residents of all the post graduate programs were invited to take the course as an elective during the period 2004 2011. At the end of the course each resident completed the pre/post Seminar Series Housestaff/student Questionnaire; assessing perceptions of learning, expressed in a Likert scale from 1-5. RESULTS: The implementation of the course in 111 residents significantly improved self-perception of general preparation for teaching and improved self-perception of preparedness in each educational category. The personal goals most commonly established by participants were on feedback (52,2%), control of session (44%) and communication of goals (40%). Barriers for teaching most frequently identified were lack of time to do clinical teaching (51,3%) and environmental limitations (16,2%). The main impact of the course reported by residents were acquisition of teaching skills or tools for teaching (39,6%), enhancing of motivation (14%), and a richer understanding of teaching principles (14%). CONCLUSIONS: A clinical teaching course for residents improves their self-perception of preparation to teach and enhances motivation for clinical teaching. PMID- 23677190 TI - [Neuropsychological assessment of patients with relapsing remitting multiple sclerosis prior to the use of immunomodulatory drugs]. AB - BACKGROUND: The detection of cognitive changes (CC) and psychiatric disorders in relapsing remitting multiple sclerosis (MS-RR) contributes to patient clinical monitoring. AIM: To assess the frequency and characteristics of CC and psychiatric disorders in Chilean patients with MS-RR, before starting immunomodulatory treatment. PATIENTS AND METHODS: Retrospective review of data that was obtained following a standard assessment protocol. It consisted in the application of the Expanded Disability Status Scale of Kurtzke (EDSS), Multiple Sclerosis Functional Composite (MSFC), fatigue intensity scale of Krupp, brief repeatable battery of neuropsychological Rao (BRN-R) and Hamilton's depression and anxiety questionnaires. RESULTS: We evaluated 129 patients aged between 12 and 60 years of age (69% women). Ninety four percent of patients had eight or more years of schooling. The average EDSS score was 2.83. CC were detected in 62% of participants, in at least one subtest of the BRN-R. The main changes were verbal memory and speed in the processing information. The frequency of cognitive impairment (CI), defined as at least two BRN-R subtests altered, was 36%. The figures decreased to 17% when significant major depression or associated fatigue were excluded. Depressive symptoms were observed in 58% and anxiety in 76.7%. CONCLUSIONS: The results are consistent with those described in the literature. The type of instruments used in the investigation of CC and the definition of CI in MS should be standardized. PMID- 23677191 TI - [Priapism associated with risperidone use: Report of one case]. AB - The use of drugs with alpha-adrenergic antagonistic effect is one of the most prominent etiologies of priapism. We report a 32-year-old schizophrenic male in treatment with risperidone who consulted in the emergency room for a painful priapism. A low flow priapism was diagnosed. Medical treatment was unsuccessful and the patient was subjected to a proximal corporo-spongiosal shunt (Quackels technique), with good results. The patient was discharged in good conditions. PMID- 23677192 TI - [Cardiac hydatidosis: Report of one case]. AB - Hydatidosis is an endemic zoonosis in Chile. We report a 48-year-old former slaughterman, with a previous history of pulmonary hydatidosis, who presented a stroke without associated cardiovascular symptoms. An echocardiogram revealed a tumor mass with cystic features in the left ventricle. The patient was operated and the cyst was successfully excised. During the follow up, the patient remains asymptomatic. PMID- 23677193 TI - [Parvovirus B19 arthritis: Report of three cases]. AB - Parvovirus B19 infection is highly prevalent in children and the most common manifestation is a facial rash. In adults, acute polyarthritis and skin rash are often the presenting features. We report three patients with the disease. A 40 year-old female presenting with fever, myalgias and painful swelling of elbows, knees, wrists and feet, with functional limitation, after having a respiratory infection. Additionally, an erythematous skin rash appeared in both extremities. IgM antibodies against Parvovirus B19 were positive. The skin biopsy disclosed a leukocytoclastic vasculitis. The patient was treated with anti-inflammatory drugs and antihistaminics. A 40-year-old female, presenting with skin rash and pain in wrists and hands. IgM antibodies against parvovirus were positive. The patient was treated successfully with acetaminophen. A 38-year-old male with psoriasis, presenting with generalized and progressive polyarthralgia. A Parvovirus viral load determination found 239000 copies of the virus and IgM antibodies were positive. He was successfully treated with non-steroidal anti-inflammatory drugs. PMID- 23677194 TI - [Homozygous germline mutation in MUTYH gene in familial adenomatous polyposis]. AB - Recently, MUTYH mutations have been reported to predispose to the development of polyposis. However, polyposis caused by mutations in MUTYH has been characterized as an autosomal recessive hereditary disease, different from the autosomal dominant pattern observed in polyposis caused by APC mutations. We report a 41 year-old female consulting for anemia. Colonoscopy detected multiple sessile polyps and a cecal carcinoma. The patient was operated and in the surgical piece, the tumor invaded serosa and there was lymph node involvement. Approximately 100 polyps were found. The patient received 5-fluorouracil, as adjuvant therapy. The patient had a sister (of a total of 12 brothers) with a colorectal carcinoma. The genetic study identified a homozygous mutation of the MUTYH gene, called c.340T > C, that produces an amino acid change of tyrosine for histidine called p.Y114H. The sister with colorectal cancer was a heterozygous carrier of this mutation. PMID- 23677195 TI - [Folate, vitamin B12 and human health]. AB - During the past decade the role of folate and vitamin B12 in human nutrition have been under constant re-examination. Basic knowledge on the metabolism and interactions between these essential nutrients has expanded and multiple complexities have been unraveled. These micronutrients have shared functions and intertwined metabolic pathways that define the size of the "methyl donor" pool utilized in multiple metabolic pathways; these include DNA methylation and synthesis of nucleic acids. In Chile, folate deficiency is virtually nonexistent, while vitamin B12 deficiency affects approximately 8.5-51% depending on the cut off value used to define deficiency. Folate is found naturally mainly in vegetables or added as folic acid to staple foods. Vitamin B12 in its natural form is present only in foods of animal origin, which is why deficit is more common among strict vegetarians and populations with a low intake of animal foods. Poor folate status in vulnerable women of childbearing age increases the risk of neural tube birth defects, so the critical time for the contribution of folic acid is several months before conception since neural tube closure occurs during the first weeks of life. The absorption of vitamin B12 from food is lower in older adults, who are considered to have higher risk of gastric mucosa atrophy, altered production of intrinsic factor and acid secretion. Deficiency of these vitamins is associated with hematological disorders. Vitamin B12 deficiency can also induce clinical and sub-clinical neurological and of other disorders. The purpose of this review is to provide an update on recent advances in the basic and applied knowledge of these vitamins relative to human health. PMID- 23677197 TI - [Risk stratification of pulmonary thromboembolism]. AB - The prognosis of pulmonary thromboembolism (PE) is related to the cardiopulmonary reserve of the patient and the magnitude of the embolus that impacts pulmonary circulation. The presence of hemodynamic instability (shock) stratifies a group of patients with high mortality, which should be treated with thrombolysis. Patients without shock but with right ventricular dysfunction can have a dismal evolution and should be managed aggressively. CAT scan, echocardiography and serum markers can be of value to define patients with a higher mortality. The available evidence to define the best diagnostic and therapeutic strategy is scanty, controversial and inconclusive. A good combination of clinical, imaging and biological markers should be defined to identify those patients without shock but with a high rate of complications and mortality, that could benefit from aggressive treatments. PMID- 23677196 TI - [Latent autoimmune diabetes in adults]. AB - Latent Autoimmune Diabetes in Adults (LADA) is the term used to describe adults who have a slowly progressive form of diabetes mellitus (DM) of autoimmune etiology, but that may be treated initially without insulin. Although it shares some immunological and genetic aspects with type 1 DM, it affects an age group that is typically affected by type 2 DM. Therefore, it could be considered an intermediate type. Diagnosis is based on clinical and laboratory criteria: age of onset, initial response to oral hypoglycemic agents and the presence of specific antibodies for diabetes. Although the definitive treatment is insulin, glitazones may be useful in early stages of the disease. Currently, its management represents a challenge for the physician, including specialists, and it is a form of DM to keep in mind. PMID- 23677198 TI - [The law of rights and duties of persons in health care from the viewpoint of bioethics]. AB - The enactment of Law 20.584 in April of 2012 promotes a change in the physician patient relationship, with recognition of people's rights and duties in healthcare by all the health professional and entities. The legal obligation, and not only the ethical one, as it currently happens, for humane treatment and regard for the dignity of the sick, informed consent, medical data confidentiality, the possibility to reject treatments, etc., is established. This review analyzes the contents of this law, especially those parts affecting physicians. It exposes its limitations, especially those related to minors' consent, living wills and research in people with mental disabilities. It also highlights positive aspects such as the promotion of a humane healthcare. This Law begins to consider patients' autonomy shyly. However, from a bioethical viewpoint, there are still many issues to be perfected such as healthcare humanization, excellence of patient care, healthcare quality and medical professionalism, considering competence, social service, charity and solidarity. It is a first step that must be supplemented with a greater development of medical deontology, and the development of clinical and institutional bioethics. PMID- 23677199 TI - [The contribution of Jose Juan Bruner to Chilean psychiatry]. AB - The contribution of Dr. Bruner to psychology and psychiatry is largely unknown. This is a summary of the ideas proposed in his "Medical-Psychological Monograph" from 1857, that was written after a case of a possibly possessed woman from Santiago. In this work Dr. Bruner discards the spirit-brain duality, proposes a functional morphology of the brain, recognizes the importance of remote history taking when interviewing patients, proposes a theory for self-formation and the risks of self-fragmentation. He proposes that the case of the woman corresponds to a brain disease, opposing the thought of an ovarian and uterine origin. He proposes a hypothesis of the psychogenic origin of the disease, the importance of what happened during dreams and beyond the conscience of the patient. Many of his ideas preceded by decades those of Charcot and Freud, but they have not had a proper recognition. PMID- 23677200 TI - [Analysis of the use of testosterone for the treatment of androgen deficiency syndrome in adult patients treated for prostate cancer]. PMID- 23677201 TI - [Self-directed learning and self-regulated learning: two different concepts]. PMID- 23677202 TI - [Follow up of subjects without known thyroid pathology, participants in a study that assessed the frequency of positive anti-thyroperoxidase autoantibodies (ATPO)]. PMID- 23677205 TI - Efficient panchromatic inorganic-organic heterojunction solar cells with consecutive charge transport tunnels in hole transport material. AB - A simple solution-processing method was employed to fabricate panchromatic mp TiO2/CH3NH3PbI3/P3HT-MWNT/Au solar cells. MWNTs in a P3HT-MWNT composite acted as efficient nanostructured charge transport tunnels and induce crystallization of P3HT, hence significantly enhancing the conductivity of the composite. The fill factor of the hybrid solar cells was greatly enhanced by 26.7%. PMID- 23677204 TI - Extended Stokes shift in fluorescent proteins: chromophore-protein interactions in a near-infrared TagRFP675 variant. AB - Most GFP-like fluorescent proteins exhibit small Stokes shifts (10-45 nm) due to rigidity of the chromophore environment that excludes non-fluorescent relaxation to a ground state. An unusual near-infrared derivative of the red fluorescent protein mKate, named TagRFP675, exhibits the Stokes shift, which is 30 nm extended comparing to that of the parental protein. In physiological conditions, TagRFP675 absorbs at 598 nm and emits at 675 nm that makes it the most red shifted protein of the GFP-like protein family. In addition, its emission maximum strongly depends on the excitation wavelength. Structures of TagRFP675 revealed the common DsRed-like chromophore, which, however, interacts with the protein matrix via an extensive network of hydrogen bonds capable of large flexibility. Based on the spectroscopic, biochemical, and structural analysis we suggest that the rearrangement of the hydrogen bond interactions between the chromophore and the protein matrix is responsible for the TagRFP675 spectral properties. PMID- 23677206 TI - A victory for global public health in the Indian Supreme Court. AB - On 1 April of this year, the Indian Supreme Court upheld the decision of the Indian Patent Office to refuse the patent grant for Novartis imatinib mesylate (Gleevec). The patent application failed to meet the requirements for patentability under Indian law. The global public health community followed the case closely. Its outcome could affect the Indian generics industry - an important supplier of low cost medicines to the developing world. PMID- 23677207 TI - Severe autoimmune hemolytic anemia with renal neoplasm. AB - Autoimmune hemolytic anemia is a type of hemolytic anemia characterized by autoantibodies directed against red blood cells shortening their survival. When autoimmune hemolytic anemia is secondary to a paraneoplastic process, severe anemia can occur leading to significant morbidity and even mortality. Here we discuss the literature and present the case of a child with autoimmune hemolytic anemia from a paraneoplastic syndrome secondary to a renal tumor. PMID- 23677208 TI - Genetic diversity in Mycobacterium tuberculosis. AB - Recent years have witnessed an increased appreciation of the extent and relevance of strain-to-strain variation in Mycobacterium tuberculosis. This paradigm shift can largely be attributed to an improved understanding of the global population structure of this organism, and to the realisation that the various members of the M. tuberculosis complex (MTBC) harbour more genetic diversity than previously realised. Moreover, many studies using experimental models of infection have demonstrated that MTBC diversity translates into significant differences in immunogenecity and virulence . However, linking these experimental phenotypes to relevant clinical phenotypes has been difficult, and to date, largely unsuccessful. Nevertheless, emerging high-throughput technologies, in particular next-generation sequencing , offer new opportunities, and have already lead to important new insights. Given the complexity of the host-pathogen interaction in tuberculosis, systems approaches will be key to define the role of MTBC diversity in the fight against one of humankind's most important pathogens. PMID- 23677209 TI - Redefining medicine, transforming healthcare: the Lee Kong Chian School of Medicine. PMID- 23677210 TI - Does periprostatic block increase the transrectal ultrasound (TRUS) biopsy sepsis rate in men with elevated PSA? AB - INTRODUCTION: Periprostatic nerve block (PPNB) is a common local anaesthetic technique in transrectal ultrasound-guided (TRUS) prostate biopsy, but concerns remain over the increased theoretical risks of urinary tract infection (UTI) and sepsis from the additional transrectal needle punctures. This study reviewed our biopsy data to assess this risk. MATERIALS AND METHODS: Retrospective data collected from 177 men who underwent TRUS biopsy between July 2007 and December 2009 in a single institution were analysed. PPNB was administered using 1% xylocaine at the prostatic base and apex and repeated on the contralateral side under ultrasound guidance. Complications, including UTI sepsis, bleeding per rectum and acute retention of urine (ARU) were noted. Every patient was tracked for the first 2 weeks for complications until his clinic review. Demographic profi le, biopsy parameters and histological fi ndings were reviewed. Univariate and multivariate analysis of possible risk factors for development of sepsis after TRUS biopsy were performed. Statistical analysis was performed using SPSS 17.0. RESULTS: Ninety (51%) men received PPNB and 87 (49%) did not. The groups were matched in age (PPNB: mean 62.7 +/- 5.8 years; without PPNB: mean 64.4 +/- 5.7 years) and prebiopsy prostate specific antigen (PSA) levels (PPNB: mean 8.2 +/- 3.9 ng/mL; without PPNB: mean 8.3 +/- 3.7 ng/mL). The PPNB group had a larger prostate volume, with more cores taken (P <0.05). On univariate and multivariate analysis controlling for age, PSA, prostate volume, number of cores taken and histological prostatitis, PPNB was not a significant risk factor for sepsis. Sepsis rates were 5.6% in the PPNB group and 5.7% in the other group (P = 0.956). Overall prostate cancer detection rate was 33.3%. CONCLUSION: The risk of sepsis was not increased in patients who received PPNB, even though this group had larger gland volumes and more biopsy cores taken. PMID- 23677211 TI - Rates and predictors for influenza vaccine prescriptions among HIV-infected clinic patients in Singapore. AB - INTRODUCTION: Although Singapore national guidelines recommend influenza vaccination for individuals with comorbidities, the vaccine uptake remains relatively low. This study examines the rates of influenza vaccine prescriptions in a clinic population, and patient, doctor and clinic factors that could affect the vaccine prescribing rates. MATERIALS AND METHODS: This retrospective review utilised electronic medical records from HIV-infected patients seen in an infectious disease (ID) specialist clinic. Data from 40 randomly selected patients per physician were analysed for the outcome of influenza vaccine prescriptions from 1 January to 31 December 2007. All 7 consultants and the 6 ID registrars who had spent at least 4 months in the Department during 2007 were included. Data analysed included patient, physician, and clinic characteristics, and clinically relevant outcomes of admission within a year, and the length of hospital stay. RESULTS: Of the 461 HIV-infected patients analysed for this study, only 107 (23%) were prescribed influenza vaccine in 2007. Vaccine prescribing rates by individual physicians ranged from 0% to 77%. The outcome of vaccine prescribing was analysed by patient demographics (age >40 years, gender, race), physician characteristics (doctor grade, gender and training), and clinic volumes (number of patients per clinic session). Multivariate analysis demonstrated that patients with female doctors (OR 1.8, 95% CI, 1.1 to 3.0, P = 0.017), and doctors with overseas medical training (OR 11.6, 95% CI, 6.0 to 22.2, P <0.001) were significantly more likely to have influenza vaccine prescribed. On univariate analysis, patients were more likely to be admitted if they were male (OR 2.1, 95% CI, 1.0 to 5.1, P = 0.041), and over 40 years old (OR 2.1, 95% CI, 1.1 to 4.5, P = 0.024). Patients prescribed influenza vaccine showed a non-significant trend for protection against admission (OR 0.7, P = 0.288), and shorter length of stay (median 5 vs 9 days, P = 0.344). CONCLUSION: Influenza vaccine prescribing for HIV-infected outpatients in 2007 was only 23%, even in an ID specialist clinic. There was substantial variability in prescribing rates by individual physicians. Neither patient demographics nor patient volumes per clinic session had an impact on the prescribing rates, but significant predictors included physician gender and medical school training. Patients prescribed influenza vaccine had fewer admissions and shorter hospital lengths of stay, although these trends were non significant. PMID- 23677212 TI - Revision total knee arthroplasty: causes and outcomes. AB - INTRODUCTION: Local data on revision total knee arthroplasty (TKA) are limited. This study aims to assess the causes and outcomes of revision TKA in a single institution, with a 2-year follow-up. MATERIALS AND METHODS: A retrospective review of case records of patients who underwent revision TKA in 2008 and 2009 in the authors' institution was performed. Outcome was assessed using SF-36, Oxford knee score and Knee Society Clinical Rating System preoperatively, at 6 months and at 2 years' follow-up. RESULTS: Forty-one patients (41 knees) were included in the study. Indications for revision were aseptic loosening in 13 (31.7%), mechanical wear/component failure in 10 (24.4%), infection in 9 (22.0%), malalignment in 4 (9.8%), instability in 3 (7.3%), periprosthetic fracture in 1 (2.4%) and persistent stiffness in 1 (2.4%). Significant improvements were seen postoperatively in all 3 instruments used to evaluate clinical outcome. These improvements were seen at 6 months after surgery, and were maintained through the 2-year follow-up period. There were no significant changes in all scores between 6 months and 2 years follow-up. There was 100% survivorship of the implants with no postoperative complications requiring surgical intervention. CONCLUSION: Indications for revision TKA locally are similar to those in other large centres. Revision total knee arthroplasty results in significantly improved function and quality of life for patients, which is maintained over a 2-year follow-up period. In our series, we obtained 100% implant survivorship. PMID- 23677213 TI - Clinical characteristics and outcomes of patients undergoing drug provocation tests (DPTs). AB - INTRODUCTION: Patients who have an adverse drug reaction are frequently labelled drug allergic without undergoing proper evaluation and confirmatory testing. These drug allergy labels may be inaccurate, leading to unnecessary lifelong avoidance. The aim of this study was to review the patients that underwent drug provocation tests (DPTs) in our centre and examine the usefulness of DPTs in confirming or rejecting a diagnosis of drug hypersensitivity. MATERIALS AND METHODS: The study design was a retrospective chart review of all adult patients who underwent drug provocation in the allergy unit at the National University Hospital, Singapore, for single or multiple suspected drug allergies from the period January 2009 to June 2011. RESULTS: Eighty-seven patients underwent 123 DPTs (median age 41; interquartile range 28 to 50). Twenty-one patients underwent multiple DPTs. The most common culprit drugs reported were antibiotics (43.9%) of which beta-lactams were implicated in 75.9% of the cases. This was followed by non-steroidal anti-inflammatory drugs (NSAIDS) in 15.4%, paracetamol in 7.3% and both NSAIDs and paracetamol in 3.3%. Rash was the most commonly reported symptom (41.5%), followed by angioedema (32.5%), anaphylaxis (9.8%), and other symptoms including respiratory (2.4%), gastrointestinal (0.8%) and others (13.0%). The majority of DPTs were performed to antibiotics (43.9%), NSAIDs (19.5%) and paracetamol (6.5%). DPTs were negative in 93.5% of subjects and positive in 6.5%. Of the 8 positive DPTs, none had a serious reaction, with 5 patients requiring rescue therapy, which comprised solely of oral antihistamines. CONCLUSION: Suspected drug hypersensitivity is common but true drug allergy is rare. DPTs remain the gold standard and should be included as part of an investigative protocol. DPTs are a safe and valuable diagnostic tool in the hands of the experienced clinician. PMID- 23677214 TI - Guidelines on management of prostate cancer. PMID- 23677215 TI - The mental capacity act: implications for patients and doctors faced with difficult choices. AB - The Mental Capacity Act (MCA) came into effect in March 2010 but the impact of this groundbreaking legislation on the doctor-patient relationship has not yet been studied in Singapore. It is evident that communication between healthcare professionals, patients and their loved ones has never been so critical. Translating this into practice, healthcare professionals must identify the decision-maker to obtain consent from the correct person. Consent for healthcare and treatment must be obtained from the patient with capacity or the patient's legally appointed proxy decision-maker under a Lasting Power of Attorney (LPA) where the patient lacks capacity. However, the doctor is the decision-maker for patients lacking capacity in matters of life-sustaining treatment or treatment to prevent a serious deterioration of the patient's health. All decisions made on behalf of persons lacking capacity must be made in their best interests. Capacity assessments must be properly conducted and if a patient has the capacity to make the decision then healthcare professionals must take practicable steps to help them make a decision. PMID- 23677216 TI - Will the local ACGME-trained surgeon be adequately prepared? An estimate of the impact of duty hour restrictions on operative experience. PMID- 23677218 TI - Re: dengue knowledge, attitudes, and practices among primary care physicians in Singapore. PMID- 23677217 TI - The use of n-butyl-2 cyanoacrylate as an embolic agent in the minimally invasive treatment of renal arteriovenous malformations. PMID- 23677219 TI - Re: Assoc Prof BG (ret) Dr Lim Meng Kin (1950 - 2013). PMID- 23677220 TI - On the gas-phase dimerization of negatively charged closo-dodecaborates: a theoretical study. AB - We have studied the intriguing gas-phase dimerization of the B12In(-) (n = 9, 8) anions to B24I2n(2-) dianions by means of density functional theory calculations. The dimerization of B12I9(-) to B24I18(2-) has been detected experimentally in a previous study (Phys. Chem. Chem. Phys., 2011, 13, 5712) utilizing electrospray ionization ion trap mass spectrometry (ESI-IT-MS), whereas the formation of B24I16(2-) from B12I8(-) is modeled here prior to experiment. Calculations are carried out to determine the molecular and electronic structures, the bonding situation and the stability of the dimers relative to the respective monomers. The dimerization process is found to be thermodynamically favorable, and the stability of the lowest-energy structures is substantiated by molecular dynamics simulations. The calculations imply that the experimentally observed B24I18(2-) and the hypothetical B24I16(2-) species are formed through dimerization of the respective B12In(-) (n = 9, 8) monomers, rather than through loss of two I radicals from B24I2n+2(2-) dimers. Electronic properties such as natural charges, vertical detachment energies (VDEs), frontier molecular orbitals (FMOs), and HOMO LUMO gaps are computed and analyzed in detail for all monomers and dimers. The analysis shows that the most stable B24I2n(2-) dimers are formed through two 2c 2e B-B and two 3c-2e B-I-B bridges between the parent B12In(-) (n = 9, 8) monomers. These new bridging bonds engage the deiodinated (bare) faces of the two B12 icosahedra, as well as one (per monomer) of the nearest boron neighbors and its iodine substituent. PMID- 23677222 TI - Citizen science provides valuable data for monitoring global night sky luminance. AB - The skyglow produced by artificial lights at night is one of the most dramatic anthropogenic modifications of Earth's biosphere. The GLOBE at Night citizen science project allows individual observers to quantify skyglow using star maps showing different levels of light pollution. We show that aggregated GLOBE at Night data depend strongly on artificial skyglow, and could be used to track lighting changes worldwide. Naked eye time series can be expected to be very stable, due to the slow pace of human eye evolution. The standard deviation of an individual GLOBE at Night observation is found to be 1.2 stellar magnitudes. Zenith skyglow estimates from the "First World Atlas of Artificial Night Sky Brightness" are tested using a subset of the GLOBE at Night data. Although we find the World Atlas overestimates sky brightness in the very center of large cities, its predictions for Milky Way visibility are accurate. PMID- 23677223 TI - [Clinical characteristics, complications and mortality in 506 patients with infective endocarditis and determinants of survival rate at 10 years]. AB - BACKGROUND: Rates of morbidity and mortality in Infective Endocarditis (IE) remain high and prognosis in this disease is still difficult and uncertain. AIM: To study IE in Chile in its active phase during inpatient hospital stay and long term survival rates. MATERIAL AND METHODS: Observational prospective national cohort study of 506 consecutive patients included between June 1,1998 and July 31, 2008, from 37 Chilean hospitals (secondary and tertiary centers) nationwide. RESULTS: The main findings were the presence of Rheumatic valve disease in 22.1 % of patients, a history of intravenous drug abuse (IVDA) only in 0.7%, the presence of Staphylococcus aureus in 29.2% of blood cultures, negative blood cultures in 33.2%, heart failure in 51.7% and native valve involvement in 86% of patients. Echocardiographic diagnosis was achieved in 94% of patients. Hospital mortality was 26.1% and its prognostics factors were persisting infection (Odds ratio (OR) 6.43, Confidence Interval (CI) 1.45-28.33%), failure of medical treatment and no surgical intervention (OR 48.8; CI 6.67-349.9). Five and 10 years survival rates were 75.6 and 48.6%, respectively. The significant prognostic factors for long term mortality, determined by multivariate analysis were the presence of diabetes, Staphylococcus aureus infection, sepsis, heart failure, renal failure and lack of surgical treatment during the IE episode. CONCLUSIONS: The microbiologic diagnosis of IE must be urgently improved in Chile. Mortality rates are still high (26.1%) partly because of a high incidence of negative blood cultures and the need for more surgical valve interventions during in-hospital period. Long term prognostic factors for mortality should be identified early to improve outcome. PMID- 23677224 TI - [Results of chronic hepatitis C treatment in a public hospital]. AB - BACKGROUND: Chronic hepatitis C is an important health problem in Chile. In 2005, the Ministry of Health started a pilot treatment program with peg interferon and ribavirin, to be developed in public hospitals all over the country. AIM: To report the results of hepatitis C treatment obtained at our institution. PATIENTS AND METHODS: Between 2005 and 2009, 63 patients were referred for treatment. In all, the viral load and genotype were determined. Peg interferon alpha-2a or alpha-2b plus ribavirin were used for therapy for up to 48 weeks in genotypes (G) 1 or 4 or 24 weeks in genotypes 2 or 3. If at the end of treatment, viral load measured by polymerase chain reaction (PCR) was negative, it was repeated 6 months later. A negative viral load at that time was considered a sustained viral response (SVR). RESULTS: Among the 51 patients who started treatment, 42 (80.4%) were G1,1 was G2,1 was G4 and 7 were G3. A SVR was reached in 51.1% of G 1 and 4 and in 87.5% in G 3 and 2. In a univariate analysis, the variables significantly associated with a positive viral response were the degree of fibrosis and body mass index. CONCLUSIONS: These results are similar to those obtained in other international series, demonstrating that Hispanic ethnicity does not influence the response to treatment. Our good results could be explained by the excellent compliance of the patients to the treatment. A higher degree of fibrosis and a higher BMI were associated with a poor response. PMID- 23677225 TI - [Quantification of visceral adipose tissue using magnetic resonance imaging compared with anthropometry, in type 2 diabetic patients]. AB - BACKGROUND: Visceral fat accumulation is associated with the development of metabolic diseases. Anthropometry is one of the methods used to quantify it. AIM: to evaluate the relationship between visceral adipose tissue volume (VAT), measured with magnetic resonance imaging (MRI), and anthropometric indexes, such as body mass index (BMI) and waist circumference (WC), in type 2 diabetic patients (DM2). PATIENTS AND METHODS: Twenty four type 2 diabetic patients aged 55 to 78 years (15 females) and weighting 61.5 to 97 kg, were included. The patients underwent MRI examination on a Philips Intera(r) 1.5T MR scanner. The MRI protocol included a spectral excitation sequence centered at the fat peak. The field of view included from L4-L5 to the diaphragmatic border. VAT was measured using the software Image J(r). Weight, height, BMI, WC and body fat percentage (BF%), derived from the measurement of four skinfolds with the equation of Durnin and Womersley, were also measured. The association between MRIVAT measurement and anthropometry was evaluated using the Pearson's correlation coefficient. RESULTS: Mean VAT was 2478 +/- 758 ml, mean BMI29.5 +/- 4.7 kg/m2, and mean WC was 100 +/- 9.7 cm. There was a poor correlation between VAT, BMI (r = 0.18) and WC (r = 0.56). CONCLUSIONS: BMI and WC are inaccurate predictors of VAT volume in type 2 diabetic patients. PMID- 23677226 TI - [Pleural empyema due to Gemella spp: report of 12 cases]. AB - BACKGROUND: Gemella genus bacteria can produce localized or generalized severe infections, but very rarely they have been described as causing pulmonary infections or pleural empyemas. AIM: To characterize patients with empyema caused by Gemella genus bacteria. MATERIAL AND METHODS: The database of a Microbiology laboratory of a Spanish hospital was reviewed, searching for Gemella positive cultures of pleural effusions in a period of five years. RESULTS: We identified 12 patients (11 males) with Gemella spp pleural empyema. Eight were infected with G. haemolysans and four with G. morbillorum. All patients had predisposing factors such as poor oral hygiene, smoking, chronic cardiovascular or respiratory disease, alcoholism or malignancies. In ten cases, a thoracic drainage tube was placed with fibrinolysis in seven. One patient needed surgery because of a relapse of the empyema. Two patients died because of an advanced neoplasm, and the empyema was resolved in the rest. CONCLUSIONS: Gemella pleural empyema can occur and its isolation must not be seen as a contamination. PMID- 23677227 TI - [Validation of quality of life questionnaire ConQol for Chilean children with congenital heart diseases]. AB - BACKGROUND: ConQoL questionnaire assesses health related quality of life among children with congenital heart diseases. It has a version for children aged 8 to 11 years and another for children aged 12 to 16 years. AIM: To validate ConQol questionnaire for Chilean children with a congenital heart disease. MATERIAL AND METHODS: Using a multicentric cross sectional design, 334 children from four hospitals (54% males), were surveyed. Among them 45% were aged 8 to 11 years and 55%, 12 to 16 years. The study involved three stages: cross cultural adjustment of the original questionnaire, pre-test study, and estimation of its psychometric properties. Content, construct and criterion validity and internal consistency with Cronbach's alpha, were assessed. RESULTS: The version for children aged 8 to 11 years and comprised by three domains (symptoms, activity and relationships), obtained and alpha >= 0.60. In the questionnaire for children aged 12 to 16 years, there is one more domain called coping, which obtained an alpha of 0.53, that was different to the other three domains that obtained an alpha > 0.70. The correlation between Health Quality of Life and Perception of Health Quality of Life was statistically significant for both groups. The association between Health Quality of Life and health capability was only significant among children aged 12 to 16 years (p < 0.01). CONCLUSIONS: The adapted ConQol questionnaire matched properly with the original one. The adapted questionnaire is valid and reliable to assess Health Quality of Life among Chilean children with congenital heart diseases. PMID- 23677228 TI - [Evaluation of the educational environment in medical specialty programs]. AB - BACKGROUND: The Postgraduate Hospital Education Environment Measure (PHEEM) questionnaire, is a valid and reliable instrument to measure the educational environment (EE) in postgraduate medical education. AIM: To evaluate the EE perceived by the residents of a postgraduate training program using the PHEEM. MATERIAL AND METHODS: The PHEEM was applied in 2010-2011 in 35 specialty programs. We calculated their individual results and compared means of both global and individual domain scores of the PHEEM, by gender, university of origin and nationality. Cronbach's alpha coefficients and D study (Generalizability theory) were performed for reliability. RESULTS: Three hundred eighteen residents were surveyed (75.7% of the total universe). The mean score of the PHEEM was 105.09 +/- 22.46 (65.7% of the maximal score) which is considered a positive EE. The instrument is highly reliable (Cronbach's alpha = 0.934). The D study found that 15 subjects are required to obtain reliable results (G coefficient = 0.813). There were no significant differences between gender and university of origin. Foreigners evaluated better the EE than Chileans and racism was not perceived. The programs showed a safe physical environment and teachers with good clinical skills. The negative aspects perceived were a lack of information about working hours, insufficient academic counseling, and scanty time left for extracurricular activities. CONCLUSIONS: This questionnaire allowed us to identify positive aspects of the EE, and areas to be improved in the specialty programs. The PHEEM is a useful instrument to evaluate the EE in Spanish-speaking participants of medical specialty programs. PMID- 23677229 TI - [Validation of the Spanish version of the Eating Disorders Diagnostic Scale]. AB - BACKGROUND: The Eating Disorders Diagnostic Scale (EDDS) is a self-administered low cost psychometric instrument with excellent levels of temporal reliability and validity. AIM: To adapt and validate the EDDS in Chile. MATERIAL AND METHODS: The factorial structure, internal consistency and test-retest reliability of the Spanish-language version of the EDDS was analyzed in a sample of 1964 university and high school students. The concurrent validity was tested in a sample of 50 primary care patients with ED and 59 controls, comparing its results with those of a structured psychiatric interview (CIDI). RESULTS: The EDDS showed a high internal consistency, moderate test-retest reliability, an appropriate factorial structure (in women) and an excellent convergent validity. Also, the diagnosis of ED obtained with the EDDS is moderately consistent with the structured psychiatric interview. CONCLUSIONS: The Spanish-language version of the EDDS showed a satisfactory psychometric behavior and a good capacity for detecting ED, according to the DSM criterion. PMID- 23677230 TI - [Food quality and nutritional status in university students of eleven Chilean regions]. AB - BACKGROUND: The Chilean population has inadequate lifestyles and high prevalence of chronic diseases. AIM: To analyze eating behaviors, nutritional status and history of previous diseases, in students of higher education. MATERIAL AND METHODS: Cross-sectional study in students of 54 higher education centers across the country. They answered a survey about dietary habits, physical activity, smoking, previous diseases and opinion of their nutritional condition. Weight and height were measured under standardized conditions and nutritional status classified according to body mass index. RESULTS: We studied 6,823 students aged 17 to 29 years. Forty seven percent did not have breakfast and 35% did not have lunch every day. A low proportion had a daily consumption of vegetables (51.2%), fruits (39.4%) and dairy products (57.5%). There was a high frequency of soft drinks, chips, cakes and sweets consumption. Seventy six percent were sedentary, 40.3% smokers and 27.4% overweight or obese. The latter had a significantly higher frequency of diabetes, hypertension and hypercholesterolemia. There was a poor agreement between actual nutritional status and self-perception, especially in males (Kappa index 0.38). Recipients of a food scholarship provided by the Ministry of Education ate lunch usually with a higher frequency (p < 0.05). CONCLUSIONS: A high prevalence of inadequate eating and physical activity patterns in these young subjects with good educational level was observed. The food scholarship has some positive effects, although differences in socioeconomic levels limited comparisons. PMID- 23677231 TI - [Complete remission of nephrotic syndrome associated with carcinoma of the cervix after treatment of the tumor: report of two cases]. AB - Nephrotic syndrome secondary to paraneoplastic glomerulopathies is exceptional. We are aware of only three cases reported of cervical carcinomas associated with nephrotic syndrome. Two women, aged 40 and 79 years, presented with nephrotic syndrome. The first had a membranous nephropathy and the second was not biopsied. The first women had a metrorrhagia after 8 months of unsuccessful therapy with corticosteroids and immunosuppressive drugs. An advanced cervical carcinoma with lymph node metastases was found. In the second patient, a cervical carcinoma and hematometra was discovered two months after diagnosis ofa nephrotic syndrome. The syndrome subsided completely, nine months after radiotherapy and chemotherapy in the first patient and 10 months after hysterectomy in the second patient. PMID- 23677232 TI - [Leser-Trelat sign associated with gastric cancer: report of one case]. AB - We report a 66-year-old male presenting with malaise, heartburn and pruritic seborrheic keratoses in both feet of sudden onset, suggesting a Leser-Trelat sign. An upper gastrointestinal endoscopy disclosed a gastric cancer. The patient was subjected to a total gastrectomy and during follow up, the skin lesions had disappeared. PMID- 23677233 TI - [Necrotizing herpes folliculitis. Report of one case]. AB - Herpes folliculitis is a rare manifestation of herpes virus infection. It usually represents a diagnostic challenge, due to the absence of characteristic skin manifestations such as vesicles or pustules. The reported cases are mainly associated with varicella zoster virus (VZV) and less commonly with herpes simplex viruses (HSV-1 y HSV-2). We report a 51-year-old male with a relapsing non-Hodgkin Lymphoma under chemotherapy, with history of extensive follicular lesions lasting one month. The pathologic study of the lesions was consistent with necrotizing herpes folliculitis. The patient was treated with Valacyclovir, achieving remission of the lesions. The appearance of folliculitis, especially in an immunocompromised patient, should raise the suspicion of herpes virus infection. Polymerase chain reaction may help to elucidate the diagnosis when pathologic findings are non-specific. PMID- 23677234 TI - [A new physiopathological classification of diabetic neuropathy]. AB - Nowadays, Diabetic Neuropathy (DN) is considered the most common cause of peripheral neuropathy in clinical practice. It can affect sensitive, motor or autonomic nerve fibers, with symmetric, asymmetric, acute or chronic presentations. Due to this variability, with multiple physiopathologic mechanisms involved, a complex clinical classification has been used until recently. The aim of this review is to present a new classification of diabetic neuropathy, based on its physiopathology. It is divided in metabolic microvascular and hypoxic, autoimmune and inflammatory, compressive, secondary to complications of diabetes and related to treatment. It must be understood that DN is not just a functional disease, but a complication of diabetes with molecular and pathological substrates caused by hyperglycemia. Therefore, normalization of blood glucose is a fundamental step towards the successful prevention and treatment of DN. PMID- 23677235 TI - [Essential competences for the management of health care networks]. AB - We suggest that in order to fulfill the health needs of the majority of the Chilean population, which is beneficiary of the public health system, essential organizational skills should be developed for network administration among Self administered Hospitals, Network Manager and Primary Health Care facilities. Self administered Hospitals should be competent in managing service options according to their strategy for development, reference and counter-reference mechanisms and waiting lists, to optimize queuing. The Network Manager should be competent in demand management that is regulated, investments management that determines future development in terms of population needs and stakeholders' management, which is a political viability type of management. Finally, the Primary Health Care manager should be competent in demand management as a strategic partner of the Network Manager, community participation and management of interlinked areas, articulating social networks and sanitary impact management. At each level and within levels, there are crossroads that promote synergies. Based on the development of essential skills, a practice with strategic intentions, organization managers will develop team work skills. PMID- 23677236 TI - Bioimpedance: do we actually have to use gel? PMID- 23677237 TI - [Toward trustworthy clinical practice guidelines: the Ministry of Health guideline for management of influenza]. PMID- 23677238 TI - [Reflections on current biomedical research, in Chile]. PMID- 23677239 TI - [Reflections on current biomedical research, in Chile: reply]. PMID- 23677241 TI - Efficient epoxidation of olefins by H2O2 catalyzed by iron "helmet" phthalocyanines. AB - High yields of epoxides were obtained in the oxidation of a large range of olefins using 1.2-2 equiv. of H2O2 in the presence of iron helmet phthalocyanines. The involvement of high-valent iron oxo species was evidenced using cryospray mass spectrometry. PMID- 23677242 TI - RAGE-mediated interstitial fibrosis in neonatal obstructive nephropathy is independent of NF-kappaB activation. AB - Urinary tract obstruction during nephron development causes tubular apoptosis, tubular atrophy, and interstitial fibrosis. Leukocyte recruitment is critical in the development of obstructive nephropathy leading to interstitial inflammation and renal fibrosis. RAGE, the receptor of advanced glycation end products, is implicated in chronic inflammation and has been recently identified as a novel receptor for the beta2-integrin Mac-1, cooperating with ICAM-1 and thereby directly mediating leukocyte recruitment in vivo. Here, we studied the role of RAGE and ICAM-1 in a model of unilateral ureteral obstruction in neonatal mice. Interestingly, the number of infiltrating leukocytes was independent of RAGE and ICAM-1 in the ureteral obstructed neonatal kidney. By contrast, galectin-3, a marker for profibrogenic M2 macrophages, was strongly reduced in ureteral obstructed RAGE and RAGE-Icam1 knockout mice. Snail expression and loss of E cadherin but not NF-kappaB activation were attenuated in both knockout models. Epithelial cell cycle arrest at G2/M, which mediates kidney fibrosis, and transforming growth factor-beta expression were reduced in ureteral obstructed RAGE knockout mice. Thus, RAGE and ICAM-1 promote renal fibrosis in the developing kidney upon ureteral obstruction. Combined RAGE- and ICAM-1-blocking strategies may prove beneficial in neonatal obstructive nephropathy. PMID- 23677243 TI - No difference in bleeding risk between subcutaneous enoxaparin and heparin for thromboprophylaxis in end-stage renal disease. AB - Enoxaparin, a low-molecular-weight form of heparin, is not approved for use in dialysis patients in the United States, because it is eliminated through the kidneys and could therefore accumulate and cause inadvertent bleeding. Accordingly, it is unknown if enoxaparin is as safe to prescribe as subcutaneous heparin for thromboprophylaxis in patients with chronic renal failure. Here we conducted a retrospective comparative effectiveness study in a large population of chronic maintenance dialysis patients initiated with subcutaneous injections of enoxaparin or heparin for thromboprophylaxis. The primary study end point was hospitalization or death related to bleeding, with a secondary end point of venous thromboembolism. Among 7721 dialysis patients started on subcutaneous enoxaparin or heparin at doses for thromboprophylaxis, the crude rate for bleeding requiring hospitalization or resulting in death was 15.2 (95% confidence interval (CI) 12.7-18.2) events per 100 patient-years in the enoxaparin group, which did not differ from the heparin group in which the crude rate was 16.2 (95% CI 14.0-18.7) events per 100 patient-years. In risk factor-adjusted Poisson models, enoxaparin was not associated with more bleeding in comparison to heparin (risk ratio, 0.98; 95% CI 0.78-1.23). The risk of venous thromboembolism was not associatively worse with enoxaparin (risk ratio, 0.77; 95% CI 0.49-1.22). Thus, in dialysis patients, daily enoxaparin for thromboprophylaxis was not associated with increased serious bleeding or less effective compared to subcutaneous heparin. PMID- 23677244 TI - JC polyoma virus interacts with APOL1 in African Americans with nondiabetic nephropathy. AB - Individuals with HIV infection and two apolipoprotein L1 gene (APOL1) risk variants frequently develop nephropathy. Here we tested whether non-HIV viral infections influence nephropathy risk via interactions with APOL1 by assessing APOL1 genotypes and presence of urine JC and BK polyoma virus and plasma HHV6 and CMV by quantitative polymerase chain reaction. We analyzed 300 samples from unrelated and related first-degree relatives of African Americans with nondiabetic nephropathy using linear and nonlinear mixed models to account for familial relationships. The four groups evaluated were APOL1 zero/one versus two risk alleles, with or without nephropathy. Urine JCV and BKV were detected in 90 and 29 patients, respectively, whereas HHV6 and CMV were rare. Adjusting for family age at nephropathy, gender, and ancestry, presence of JCV genomic DNA in urine and APOL1 risk alleles were significantly negatively associated with elevated serum cystatin C, albuminuria (albumin-to-creatinine ratio over 30 mg/g), and kidney disease defined as an eGFR under 60 ml/min per 1.73 m(2) and/or albuminuria in an additive (APOL1 plus JCV) model. BK viruria was not associated with kidney disease. Thus, African Americans at increased risk for APOL1 associated nephropathy (two APOL1 risk variants) with JC viruria had a lower prevalence of kidney disease, suggesting that JCV interaction with APOL1 genotype may influence kidney disease risk. PMID- 23677245 TI - Major bleeding events and risk stratification of antithrombotic agents in hemodialysis: results from the DOPPS. AB - Benefits and risks of antithrombotic agents remain unclear in the hemodialysis population. To help clarify this we determined variation in antithrombotic agent use, rates of major bleeding events, and factors predictive of stroke and bleeding in 48,144 patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases I-IV. Antithrombotic agents including oral anticoagulants (OACs), aspirin (ASA), and anti-platelet agents (APAs) were recorded along with comorbidities at study entry, and clinical events including hospitalization due to bleeding were then collected every 4 months. There was wide variation in OAC (0.3-18%), APA (3-25%), and ASA use (8-36%), and major bleeding rates (0.05-0.22 events/year) among countries. All-cause mortality, cardiovascular mortality, and bleeding events requiring hospitalization were elevated in patients prescribed OACs across adjusted models. The CHADS2 score predicted the risk of stroke in atrial fibrillation patients. Gastrointestinal bleeding in the past 12 months was highly predictive of major bleeding events; for patients with previous gastrointestinal bleeding, the rate of bleeding exceeded the rate of stroke by at least twofold across all categories of CHADS2 score, including patients at high stroke risk. Appropriate risk stratification and a cautious approach should be considered before OAC use in the dialysis population. PMID- 23677248 TI - [Joint contractures in nursing textbooks]. AB - BACKGROUND: The transparency criteria of the German statutory health insurance on joint contracture prevention have led to controversies about the appropriate assessment, prevention and treatment as well as to various actions in nursing practice. However, appropriate nursing assessments and proven treatment options are lacking so far. It is unclear whether textbooks on nursing reflect these uncertainties. METHODS: Search for textbooks on nursing through internet-based search engines and publisher registers, data extraction by one investigator and control by a second. RESULTS: A total of 35 textbooks with contributions on joint contractures were identified of which 25 included a definition, causes/risk factors are presented in 32 textbooks and assessments are presented in 5 books. Most often positioning into a physiological or functional neutral position and passive moving of limbs are recommended as passive prophylaxis. Recommended therapeutic and preventive options do not differ. None of the textbooks reflect that there is a lack of scientific knowledge on the subject. CONCLUSION: Textbooks on nursing do not deal with complete and scientific sound information on joint contractures. PMID- 23677247 TI - Sensitivity of the Pig-a assay for detecting gene mutation in rats exposed acutely to strong clastogens. AB - Clastogens are potential human carcinogens whose detection by genotoxicity assays is important for safety assessment. Although some endogenous genes are sensitive to the mutagenicity of clastogens, many genes that are used as reporters for in vivo mutation (e.g. transgenes) are not. In this study, we have compared responses in the erythrocyte Pig-a gene mutation assay with responses in a gene mutation assay that is relatively sensitive to clastogens, the lymphocyte Hprt assay, and in the reticulocyte micronucleus (MN) assay, which provides a direct measurement of clastogenicity. Male F344 rats were treated acutely with X-rays, cyclophosphamide (CP) and Cis-platin (Cis-Pt), and the frequency of micronucleated reticulocytes (MN RETs) in peripheral blood was measured 1 or 2 days later. The frequencies of CD59-deficient Pig-a mutant erythrocytes and 6 thioguanine-resistant Hprt mutant T-lymphocytes were measured at several times up to 16 weeks after the exposure. All three clastogens induced strong increases in the frequency of MN RETs, with X-rays and Cis-Pt producing near linear dose responses. The three agents also were positive in the two gene mutation assays although the assays detected them with different efficiencies. The Pig-a assay was more efficient in detecting the effect of Cis-Pt treatment, whereas the Hprt assay was more efficient for X-rays and CP. The results indicate that the erythrocyte Pig-a assay can detect the in vivo mutagenicity of clastogens although its sensitivity is variable in comparison with the lymphocyte Hprt assay. PMID- 23677246 TI - Divergent functions of the Rho GTPases Rac1 and Cdc42 in podocyte injury. AB - Podocytes are highly specialized epithelial cells with complex actin cytoskeletal architecture crucial for maintenance of the glomerular filtration barrier. The mammalian Rho GTPases Rac1 and Cdc42 are molecular switches that control many cellular processes, but are best known for their roles in the regulation of actin cytoskeleton dynamics. Here, we employed podocyte-specific Cre-lox technology and found that mice with deletion of Rac1 display normal podocyte morphology without glomerular dysfunction well into adulthood. Using the protamine sulfate model of acute podocyte injury, podocyte-specific deletion of Rac1 prevented foot process effacement. In a long-term model of chronic hypertensive glomerular damage, however, loss of Rac1 led to an exacerbation of albuminuria and glomerulosclerosis. In contrast, mice with podocyte-specific deletion of Cdc42 had severe proteinuria, podocyte foot process effacement, and glomerulosclerosis beginning as early as 10 days of age. In addition, slit diaphragm proteins nephrin and podocin were redistributed, and cofilin was dephosphorylated. Cdc42 is necessary for the maintenance of podocyte structure and function, but Rac1 is entirely dispensable in physiological steady state. However, Rac1 has either beneficial or deleterious effects depending on the context of podocyte impairment. Thus, our study highlights the divergent roles of Rac1 and Cdc42 function in podocyte maintenance and injury. PMID- 23677249 TI - Desmopressin melt improves response and compliance compared with tablet in treatment of primary monosymptomatic nocturnal enuresis. AB - Primary nocturnal enuresis is a prevalent childhood condition that can persist into adulthood. Desmopressin is an antidiuretic available as orally disintegrating lyophilisate (melt) or solid tablet. Recent findings suggesting different food interactions and clinical characteristics, including compliance, between desmopressin melt and tablet motivated a post hoc analysis of a previously reported randomised, crossover study. The efficacy of desmopressin melt compared with tablet was evaluated using the International Children's Continence Society (ICCS) responder definitions. Compliance was further analysed using detailed criteria, and the association between efficacy and compliance was examined. In total, 221 patients aged 5-15 years, already receiving desmopressin tablets were randomised to the treatment sequence melt (120/240 MUg)/tablet (0.2/0.4 mg) or tablet/melt in two consecutive 3-week periods. The probability of being a responder (partial or full) during either period was significantly more likely with desmopressin melt compared with tablet (odds ratio, 2.0; confidence intervals, 1.07-3.73; p = 0.03). There was no period effect on compliance in the tablet/melt sequence and no difference in the number of completely compliant patients in each formulation group; however, more patients were >75 % compliant in period 1 compared with period 2 in the melt/tablet sequence. Increased compliance was associated with greater reductions in the number of wet nights for both formulations. CONCLUSIONS: Desmopressin melt, compared with tablet, improves the probability of being a responder. Switching from tablet to melt formulation increased patient compliance. Increased compliance was associated with increased efficacy. Switching to desmopressin melt may benefit patients with suboptimal responses to desmopressin tablet. PMID- 23677250 TI - Late renal sequelae in intravenously treated complicated urinary tract infection. AB - BACKGROUND: The treatment of complicated urinary tract infection in children is still a matter of debate. In our hospital, antimicrobial treatment is initiated intravenously, and the duration of this treatment is adapted according to the results of a Tc-99m dimercaptosuccinic acid (DMSA) scintigraphy. AIM: This study was conducted to evaluate retrospectively the frequency and the importance of late renal sequelae when treating intravenously for 7 days those patients with an abnormal acute DMSA. METHODS: A review was conducted of the medical charts of all patients consecutively admitted between 2005 and 2008 with positive urine culture and clinical and biological evidence of complicated urinary tract infection (UTI). RESULTS: There were 144 patients (59 %) with abnormal early DMSA scintigraphy and 98 (41 %) with normal scintigraphy. The median duration of intravenous treatment was 7.0 days in the children with DMSA lesions and 5.0 days in those without lesions. Obvious renal sequelae were observed on late DMSA scintigraphy in 4 (6 %) out of the 65 patients with an abnormal early DMSA who came back for control scintigraphy. CONCLUSION: Sequelae of acute DMSA lesions observed during complicated UTI treated 7 days intravenously were infrequent. Whether the mode and duration of antimicrobial treatment might explain the low rate of sequelae remains to be demonstrated. PMID- 23677251 TI - Leukemia kidney infiltration can cause secondary polycythemia by activating hypoxia-inducible factor (HIF) pathway. AB - Secondary polycythemia with increased production of erythropoietin (EPO) is known to occur in kidney diseases such as hydronephrosis and cystic disease, but the mechanism remains unclear. We report an 18-year-old female with isolated renal relapse of acute lymphoblastic leukemia accompanied by polycythemia. At the relapse, she presented with bilateral nephromegaly, mild renal dysfunction, and erythrocytosis with increased serum EPO levels up to 52.1 mIU/mL (9.1-32.8). Renal biopsy demonstrated diffuse lymphoblastic infiltration. The expression of hypoxia-inducible factor (HIF)-1alpha, which is undetectable in normal kidney, was observed in the renal tubule epithelium compressed by lymphoblastic cells. These findings suggest that erythrocytosis was caused by renal ischemia due to leukemic infiltration. Polycythemia probably became apparent because of the lack of leukemic involvement of the bone marrow. With chemotherapy, the serum EPO level rapidly decreased to normal range accompanied by the normalization of kidney size and function. Renal leukemic infiltration may enhance EPO production, although not recognized in the majority of cases because of bone marrow involvement. CONCLUSION: Our case has clarified the mechanism of previously reported polycythemia associated with renal diseases as renal ischemia. Furthermore, we have added renal ischemia resulting from tumor infiltration to the list of causes of secondary polycythemia. PMID- 23677252 TI - Primary Budd-Chiari syndrome in a 3-year-old boy with homozygous factor V Leiden G1691A mutation. AB - Budd-Chiari syndrome (BCS) is an uncommon disorder characterized by obstruction of hepatic venous outflow. The primary BCS is a rare disease with an incidence about 0.2 per million inhabitants per year. We present a 3-year-old boy with intrahepatic inferior vena cava clot. Because of decreased levels of protein C (38.7 %), F II (69.1 %), and activated protein C resistance (1.43), a mutational gene analysis was performed. The patient was found to be homozygous for the FV G1691A mutation. CONCLUSION: The primary BCS is a rare disease especially in childhood. Activated protein C resistance caused by the factor V Leiden mutation may be responsible for primary BCS. Prompt recognition of underlying prothrombotic disease and early initiation of their specific therapy might translate into rapid improvement of liver disease. PMID- 23677253 TI - Bufalin induces G2/M phase arrest and triggers autophagy via the TNF, JNK, BECN-1 and ATG8 pathway in human hepatoma cells. AB - Liver cancer is the fifth most common cause of cancer death worldwide. The study of more effective anti-hepatoma drugs is urgently required. Bufalin has been isolated from a traditional Chinese medicine and possesses less toxicity to normal cells. However, it has been found to inhibit growth of cancer cells. In this study, we aimed to investigate the efficacy and mechanism of bufalin in Huh7, Hep3B and HA22T human hepatoma cells. The three cell lines were treated with bufalin, the proliferation was detected by WST-1 assay and cell cycle was detected by flow cytometry analysis. The results showed that bufalin inhibited the proliferation of hepatoma cells and regulated the hepatoma cell death program in a dose- and time-dependent manner without typical features of apoptosis. RT PCR arrays were used to investigate the autophagy transcriptional response triggered by bufalin and 13 genes were altered and further confirmed by real-time PCR. The translation levels of selected genes were examined by western blot analysis to reveal the bufalin-induced autophagy cascade. Bufalin synergized with the JNK pathway to induce autophagy of hepatoma cells and is closely associated with the upregulation of TNF, BECN-1, MAPK and ATG8, together with the downregulation of Bcl-2 and Bid. Our study provided a multi-angle evaluation system for anti-hepatoma pharmacology for pre-clinical drug investigation. In this case, bufalin was capable of inducing hepatoma cell autophagy, suggesting a potential regimen for single or combined chemotherapy to overcome hepatoma in clinical practice. PMID- 23677254 TI - Inkjet printed (bio)chemical sensing devices. AB - Inkjet printing has evolved from an office printing application to become an important tool in industrial mass fabrication. In parallel, this technology is increasingly used in research laboratories around the world for the fabrication of entire (bio)chemical sensing devices or single functional elements of such devices. Regularly stated characteristics of inkjet printing making it attractive to replace an alternative material deposition method are low cost, simplicity, high resolution, speed, reproducibility, flexibility, non-contact, and low amount of waste generated. With this review, we give an overview over areas of (bio)chemical sensing device development profiting from inkjet printing applications. A variety of printable functional sensor elements are introduced by examples, and the advantages and challenges of the inkjet method are pointed out. It is demonstrated that inkjet printing is already a routine tool for the fabrication of some (bio)chemical sensing devices, but also that novel applications are being continuously developed. Finally, some inherent limitations of the method and challenges for the further exploitation of this technology are pointed out. PMID- 23677255 TI - PQ1, a quinoline derivative, induces apoptosis in T47D breast cancer cells through activation of caspase-8 and caspase-9. AB - Apoptosis, a programmed cell death, is an important control mechanism of cell homeostasis. Deficiency in apoptosis is one of the key features of cancer cells, allowing cells to escape from death. Activation of apoptotic signaling pathway has been a target of anti-cancer drugs in an induction of cytotoxicity. PQ1, 6 methoxy-8-[(3-aminopropyl)amino]-4-methyl-5-(3 trifluoromethylphenyloxy)quinoline, has been reported to decrease the viability of cancer cells and attenuate xenograft tumor growth. However, the mechanism of the anti-cancer effect is still unclear. To evaluate whether the cytotoxicity of PQ1 is related to induction of apoptosis, the effect of PQ1 on apoptotic pathways was investigated in T47D breast cancer cells. PQ1-treated cells had an elevation of cleaved caspase-3 compared to controls. Studies of intrinsic apoptotic pathway showed that PQ1 can activate the intrinsic checkpoint protein caspase-9, enhance the level of pro-apoptotic protein Bax, and release cytochrome c from mitochondria to cytosol; however, PQ1 has no effect on the level of anti apoptotic protein Bcl-2. Further studies also demonstrated that PQ1 can activate the key extrinsic player, caspase-8. Pre-treatment of T47D cells with caspase-8 or caspase-9 inhibitor suppressed the cell death induced by PQ1, while pre treatment with caspase-3 inhibitor completely counteracted the effect of PQ1 on cell viability. This report provides evidence that PQ1 induces cytotoxicity via activation of both caspase-8 and caspase-9 in T47D breast cancer cells. PMID- 23677256 TI - Phosphorylation and nuclear translocation of integrin beta4 induced by a chemical small molecule contribute to apoptosis in vascular endothelial cells. AB - Integrin beta4 and its Y-1494 phosphorylation play an important role in cell signaling. We found a small molecule, ethyl1-(3-(4-chlorophenoxy)-2 hydroxypropyl)-3-(4-chlorophenyl)-1H-pyrazole-5-carboxylate (ECPC), that could elevate the levels of KIT ligand (KITLG), interleukin 8 (IL-8), prostaglandin endoperoxide synthase 2 (PTGS2) and activating transcription factor 3 (ATF3) and promote apoptosis in vascular endothelial cells (VECs) through integrin beta4. We investigated the underlying mechanism of integrin beta4 participating in this process. ECPC treatment increased the phosphorylation of Y-1494 in the integrin beta4 cytoplasmic domain via a well-known receptor tyrosine kinase, fibroblast growth factor receptor 1 (FGFR1), and integrin beta4 translocated from the cytoplasm to nucleus. With suppression of Y-1494 phosphorylation by FGF-2 or siRNA of FGFR1, ECPC failed to promote integrin beta4 nuclear translocation and could not increase the expression of KITLG, IL-8, PTGS2 or ATF3. Y-1494 phosphorylation and nuclear translocation of integrin beta4 may be important during ECPC-induced apoptosis in VECs. PMID- 23677257 TI - Vibrational self-consistent field calculations for spectroscopy of biological molecules: new algorithmic developments and applications. AB - This review describes the vibrational self-consistent field (VSCF) method and its other variants for computing anharmonic vibrational spectroscopy of biological molecules. The superiority and limitations of this algorithm are discussed with examples. The spectroscopic accuracy of the VSCF method is compared with experimental results and other available state-of-the-art algorithms for various biologically important systems. For large biological molecules with many vibrational modes, the scaling of computational effort is investigated. The accuracy of the vibrational spectra of biological molecules using the VSCF approach for different electronic structure methods is also assessed. Finally, a few open problems and challenges in this field are discussed. PMID- 23677258 TI - Functionalized cyclopentadienyl rhodium(III) bipyridine complexes: synthesis, characterization, and catalytic application in hydrogenation of ketones. AB - A series of highly functionalized cyclopentadienyl rhodium(III) complexes, [Cp'Rh(bpy)Br](ClO4) (Cp' = substituted cyclopentadienyl), was synthesized from various multi-substituted cyclopentadienes (Cp'H). [Rh(cod)Cl]2 and Cp'H were firstly converted to [Cp'Rh(cod)] complexes, which were then treated with Br2 to give the rhodium(III) dibromides [Cp'RhBr2]2. The novel complexes [Cp'Rh(bpy)Br](ClO4) were obtained readily by the reaction of 2,2'-bipyridine with [Cp'RhBr2]2. These rhodium complexes [Cp'Rh(bpy)Br](ClO4) were fully characterized and utilized in the hydrogenation of cyclohexanone and acetophenone with generally high yields, but they did not exhibit the same reactivity trends for the two substrate ketones. The different activity of these complexes for the different substrates may be due to the influence of the substituents on the Cp' rings. PMID- 23677259 TI - A protein kinase assay based on FRET between quantum dots and fluorescently labeled peptides. AB - A novel protein kinase assay was developed, based on FRET between QDs and fluorescently-labeled substrate peptides. The negatively charged QDs recognize the change in net charge of the peptide upon phosphorylation. Despite its simple mechanism, this assay is sensitive and robust enough to be applied to the evaluation of protein kinase inhibitors. PMID- 23677260 TI - Disability in Saudi Arabia. AB - Disability is a complex, influential, dynamic, multidimensional challenge, and it can substantially limit major life activities of human beings and their ability to integrate/reintegrate into society. According to the World Health Organization reports almost 15% of the world's population lives with certain types of disability, of whom 2-4% experience substantial difficulties in functioning. In Saudi Arabia, very limited research has been conducted on the prevalence and incidence of disability, and most of this is on disabled children. There are several difficulties associated with conducting research on disability related issues in Saudi Arabia. Here, we review the current situation of disability, disability research, and rehabilitation in Saudi Arabia from the published literature. PMID- 23677261 TI - Oral health considerations in cancer survivors. AB - Over the past decade, advances in cancer treatment have helped in prolonging the survival rate for cancer patients. However, the patients who undergo treatment for cancer are potentially at high-risk for developing a number of oral complications, including oral mucositis, infections, hyposalivation, dental caries, and jaw osteonecrosis. Cancer survivors may remain at life-long risk of developing oral complications, and therefore require long-term dental follow-up, well after completion of cancer therapy. Patients should typically undergo thorough oral examination prior to initiation of therapy, during and after therapy to identify any active infection. In addition, and in order to maintain adequate oral health throughout treatment, patients should continue normal oral hygiene with tooth brushing and interproximal cleaning. The aim of this review is to discuss potential oral complications as a result of cancer therapy, and the certain precautions we should be aware of these patients. PMID- 23677262 TI - Modulation of proinflammatory cytokines and leukocyte mobilization by melatonin in response to sterile tissue injury in Wistar albino rats. AB - OBJECTIVE: To test the hypothesis that the neurohormone, melatonin, differentially activates the release of the proinflammatory cytokines, such as, interleukin-1 beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), as well as inducing leukocyte mobilization into the peripheral blood in response to a sterile tissue injury. METHODS: This study was conducted between November 2011 and September 2012 at the Department of Physiology, College of Medicine, King Khalid University, Abha, Kingdom of Saudi Arabia. Sterile tissue injury of either skin injury or gastric ulceration was induced in equal numbers in Wistar albino rats aged 7-8 weeks (150-200 g) (20 each), with each group being equally divided into melatonin treated or vehicle-treated. RESULTS: Melatonin treatment and sterile tissue injuries significantly (p<0.05) increased the plasma levels of IL 1beta and TNF-alpha compared to baseline levels. However, higher levels of IL 1beta compared with TNF-alpha were obtained only with melatonin treatment. Furthermore, melatonin treatment significantly increased (p<0.05) total leukocyte counts before the induction of skin injury and gastric ulceration, and remained elevated for a longer period than injured, but vehicle-treated rats. In addition, our methods of inducing skin injury or gastric ulceration caused an increase in leukocyte levels in the blood circulation (p<0.05). CONCLUSION: Melatonin differentially stimulated plasma IL-1beta and TNF-alpha, and increased blood leukocyte counts before and after sterile tissue injuries. It is worth pursuing further investigation into the therapeutic effect of melatonin in inflammatory disease that involves leukocyte recruitment to sites of injury. PMID- 23677263 TI - Simvastatin inhibits neutrophil degranulation induced by anti-neutrophil cytoplasm auto-antibodies and N-formyl-methionine-leucine-phenylalanine (fMLP) peptide. AB - OBJECTIVE: To test the hypothesis that simvastatin is capable of blocking human neutrophil degranulation induced by proteinase 3 (PR3)-anti-neutrophil cytoplasm auto-antibodies (ANCA) and myeloperoxidase (MPO)-ANCA, and by the chemotactic and inflammatory peptide N-formyl-methionine-leucine-phenylalanine (fMLP). METHODS: This study was conducted between March 2010 and September 2011 at the Renal Institute of Birmingham, University of Birmingham, Birmingham, United Kingdom. Immunoglobulin G (IgG) was purified from the plasma of 20 randomly selected patients with ANCA-associated vasculitis (10 PR3- and 10 MPO-ANCA), and their ability to induce neutrophil degranulation in the presence or absence of simvastatin (10 uM) was tested. The ability of the same dose of simvastatin to block fMLP-induced neutrophil degranulation was also tested. In addition, the ability of serum obtained from rats that received simvastatin at a dose of 25 mg/kg/day to block neutrophil degranulation in vitro was tested. RESULTS: The addition of simvastatin significantly inhibited ANCA IgG-induced neutrophil degranulation by 48% (p=0.02). There was no significant difference in response to simvastatin inhibition (p=0.73) between PR3- and MPO-ANCA. Simvastatin also inhibited neutrophil degranulation induced by 1 uM fMLP (30%, p=0.04). We further demonstrated that serum from rats that received simvastatin significantly inhibited neutrophil degranulation induced by ANCA (31.7%, p=0.01) and fMLP (23.5%, p=0.03) compared to serum from control animals. CONCLUSION: Simvastatin blocked both ANCA and fMLP-induced neutrophil degranulation. It is worth pursuing further therapeutic investigation of statins in vascular inflammatory diseases that involve neutrophil degranulation in their pathogenesis. PMID- 23677264 TI - The relationship between cytokine gene polymorphism and unexplained recurrent spontaneous abortion in Saudi females. AB - OBJECTIVE: To investigate the relationships between unexplained recurrent spontaneous abortion (RSA) and single nucleotide polymorphisms tumor necrosis factor-alpha (TNF-alpha) (-238 G/A, -308 G/A), interleukin (IL)-6 (-634 G/C) and IL-10 (-592 C/A) in the promoter region of 3 different interleukin (TNF-alpha, IL 6, and IL-10) genes. METHODS: The study group comprised 65 women (mean age: 34.1+/-6.2; range: 15-45 years) with unexplained RSA, consecutively referred to the Recurrent Abortion Clinic, King Khaled University Hospital, Riyadh, Kingdom of Saudi Arabia from January 2010 to January 2011. The control group consisted of 65 females with at least 2 successful pregnancies and no history of abortion. Blood samples were drawn and deoxyribonucleic acid (DNA) was extracted using Puregene DNA purification kit. Utilizing polymerase chain reaction, the promoter region was amplified and sequenced on an Applied Biosystems Integrated sequencer to study the polymorphic sites of interest. All polymorphisms were identified in the case and control samples. RESULTS: A significant association was identified only between the -308 G/A polymorphism in the TNF-alpha gene promoter and the occurrence of unexplained RSA, and there was no significant association with other positions. CONCLUSION: The TNF-alpha gene polymorphism at position -308 could be a genetic predisposing factor for unexplained RSA. PMID- 23677265 TI - The potential role of anti tumor necrosis factor-alpha antibodies on some renal functions and vasoregulatory factors in preeclamptic pregnant Wistar rats. AB - OBJECTIVE: To investigate the potential role of anti-tumor necrosis factor-alpha (TNF-alpha) antibodies on some renal functions and release of vasoregulatory peptides using nitric oxide synthase deprived pregnant rats. METHODS: This study was carried out at King Khalid University Hospital, King Saud University, Riyadh, Kingdom of Saudi Arabia from December 2011 to November 2012. Forty female Wistar rats were divided into 4 groups (10 rats each); Group I - included virgin non pregnant rats. Group II - included pregnant rats that received saline, Group III received NG-nitro-L-arginine methyl ester (L-NAME), and Group IV - received both L-NAME and anti TNF-alpha antibodies. Mean arterial blood pressure, urine volume, creatinine clearance and 24 hours urinary albumin excretion were measured on day 20 of gestation. Blood samples were taken on day 20 of gestation for measurement of plasma endothelin-1 (ET-1), angiotensin II (Ag II) and serum levels of total nitric oxide (NO) products, interleukin-6 (IL-6) and soluble vascular cell adhesion molecule (sVCAM-1). Viable pups were also weighed. RESULTS: Anti TNF alpha antibodies reversed hypertension, improved renal function, decreased release of vasoactive substances and increased pup weight. CONCLUSION: Preeclampsia is associated with disturbed renal function, overproduction of cytokines and vasoregulatory factors, and fetal growth restriction. Treatment of pregnant rats with anti TNF-alpha antibodies, restored urine volume, creatinine clearance, plasma ET-1, serum IL-6 and sVCAM-1 to normal levels. Hence, anti TNF alpha antibodies may have beneficial effects in preeclampsia. Additional studies are warranted to confirm these results. PMID- 23677266 TI - The effects of cholecalciferol treatment on mineral metabolism and inflammation markers in Turkish hemodialysis patients. AB - OBJECTIVE: To evaluate the effects of 25-hydroxycholecalciferol 25-[OH] D on bone mineral metabolism and inflammation parameters in hemodialysis patients. METHODS: The study was carried out at Hitit University Corum Education and Research Hospital, Corum, Turkey between July and September 2012. All of the 36 patients that underwent treatment in our hemodialysis unit were included in this study. Four patients were excluded from the study due to other complications. Of the remaining 32 patients, 28 patients mean age; 52+/- 18 years; 15 males and 13 females with a 25-OH vitamin D level of <30 ng/mL were included in the study. Four of the 32 remaining patients were excluded as their 25-OH vitamin D levels was >30 ng/ml. Patients with a 25-OH D level of <30 ng/mL were treated with 20,000 IU oral cholecalciferol once a week for 12 weeks. The level of vitamin D, mineral metabolism markers, and C-reactive protein CRP were evaluated. RESULTS: After the treatment, the 25-OH D levels increased to >30 ng/mL in all patients 12.5+/-7.1 ng/mL versus 59.9+/-15.5 ng/mL; p<0.001. While there was a significant, but not life-threatening, increase in calcium levels 7.9 [7.26 to 8.32] mg/dL versus 8.48 [7.55 to 9.25] mg/dL, p<0.001, a statistically significant decrease was observed in CRP levels 9.34+/-4.4mg/L versus 4.4+/ 1.6mg/L; p<0.001. Alkaline phosphatase, phosphorus, and parathyroid hormone levels did not change. CONCLUSION: Vitamin D deficiency is a common problem in HD patients. Short-term weekly cholecalciferol treatment is safe and effective in this patient group, and cholecalciferol treatment had a positive effect on inflammatory markers. PMID- 23677267 TI - An experience of laparoscopic sleeve gastrectomy in obese, morbidly obese, and super morbid obese patients. AB - OBJECTIVE: To report experience with laparoscopic sleeve gastrectomy (LSG) in obese, morbidly obese, and super morbid obese patients, and to evaluate comparative efficacy of LSG among these patient groups. METHODS: A total of 147 patients underwent LSG between March 2008 and December 2011 at the Department of Surgery, King Saud Medical City, Riyadh, Kingdom of Saudi Arabia. Patients were grouped according to the preoperative body mass index (BMI) into obese (35-39.9 kg/m2), morbidly obese (40-49.9 kg/m2), and super morbid obese (>50 kg/m2). Patients who did not have a regular follow-up (n=38) were excluded, and 108 patients were included in this prospective study. RESULTS: The mean total weight loss (TWL) among the super morbid obese group (41.31 +/- 21.23 kg) was statistically significantly greater compared to the obese group (24.31 +/- 13.00 kg, p=0.009) and morbidly obese group (26.81 +/- 15.56 kg, p=0.001). The mean percentage excess weight loss (EWL) was clinically significant among obese (57.8%), morbidly obese (42.5%), and super morbid obese patients (45.7%), however, it was not statistically significant between the groups (F[2,105]=2.132, p=0.124). There was no mortality; however, 6 major complications occurred including intra-abdominal collection with suspected leak, staple line bleeding, bowel ischemia, and inferior vena cava injury. CONCLUSION: Laparoscopic sleeve gastrectomy resulted in satisfactory and effective EWL in all 3 groups of obesity patients at 30-months follow-up. PMID- 23677268 TI - Frequency of retinal detachment after cataract surgery in highly myopic patients. AB - OBJECTIVE: To determine the potential risk factors for retinal detachment after cataract surgery. METHODS: In this retrospective cohort study, medical records of patients operated on between 2000 and 2010 at the Department of Ophthalmology, King Abdulaziz University Hospital, Riyadh, Kingdom of Saudi Arabia were retrospectively reviewed for both demographic and clinical data. Cases were identified as having an ocular axial length >/=25 mm, while a control group of 500 eyes (axial length range; 22-24 mm) was sampled. Data were analyzed to compare both groups, and to assess potential risk factors for post-cataract retinal detachment. RESULTS: We reviewed 852 eyes of 721 patients; 352 eyes with documented high myopia were compared with 500 control eyes. After a mean follow up of 45.1 +/- 27.9 months, the postoperative mean LogMAR visual acuity significantly differed; 0.51 +/- 0.48 for cases and 0.38 +/- 0.41 for controls (p<0.0001). Controls showed significantly better postoperative vision as measured by LogMAR (0.92 +/- 0.7) than cases (0.71 +/- 0.61) (p<0.0001). Twelve eyes (1.4%) had retinal detachments postoperatively. The RD prevalence was significantly higher among cases (10 [2.8%]) than controls (2 [0.4%]) (p=0.007). High axial length was the only significant risk factor for retinal detachment (p=0.005) even after multivariate adjustment (p=0.019). CONCLUSION: High axial length among myopic cataract patients may increase the risk of postoperative retinal detachment. PMID- 23677269 TI - Cultural adaptation of the Arabic version of the Infants' Dermatitis Quality of Life Index. AB - OBJECTIVE: To create and validate an Arabic version of the Infants' Dermatitis Quality of Life Index (IDQoL), and to evaluate its reliability and validity in Saudi infants with atopic dermatitis (AD) of various grades of severity. METHODS: This is a study involving a validation of a newly developed Arabic version of the IDQol. The research was conducted at the dermatology clinics and hospitals affiliated to Qassim University, Buraidah, Kingdom of Saudi Arabia between June 2011 and June 2012. This Arabic generic version of the IDQoL was developed using a translation/back-translation system by 2 bilingual Arabic and English scholars followed by validation and reliability assessment analysis. The developed IDQoL contains a 10-item questionnaire that assesses the impact of AD on different aspects of life. The IDQoL was applied to 370 families with infants with AD, and to 120 control families with infants without AD. The severity of AD was evaluated by the SCORAD Index. RESULTS: This newly developed IDQoL scale showed higher scores among AD infants compared with their respective controls (p=0.00), and the scores were also higher in the severe AD compared to moderate or mild AD groups (p=0.00). The Cronbach's alpha was found to be 0.87. The item-item, item-total score, or item-severity correlations ranged from moderate to high (>/=0.6), and were statistically significant (p=0.00). CONCLUSION: This novel Arabic version of the IDQoL proved to be an excellent tool to measure the disease impact in Arabic families with infants with AD. PMID- 23677271 TI - Medical and dental health status of orphan children in central Saudi Arabia. AB - OBJECTIVE: To evaluate the medical and dental health status of orphan children from 4 to 12-years-old, and compare them with children living with their parents. METHODS: This analytical, cross-sectional study took place in 3 government orphanages and 3 ordinary schools in Riyadh, Saudi Arabia from July 2011 to January 2012. All orphans aged 4-12 year were selected (N=90). Ninety children living with their parents were selected randomly to serve as the controls. Demographic data, medical, and dental history were obtained through a questionnaire answered by the orphans' foster mothers and children's parents. The study groups were examined to evaluate their caries status using the Decayed Missing and-Filled Teeth/Surface indices (DMFT/DMFS) for permanent teeth and (dmft/dmfs) for primary teeth. Oral hygiene status (OHI), plaque deposition (PI), and gingival health (GI) were also assessed. Pearson Chi-square, Mann-Whitney, and Kruskal-Wallis tests were used for statistical analysis. RESULTS: Approximately 36% of the orphans had medical conditions compared to 14.4% of the control children. The control children visited the dentist more than the orphans (p<0.001). Approximately 96% of the orphans had dental caries compared to 90% of the control children (p<0.001). Decayed-missing and-filled teeth/surface index scores were higher among orphans (p=0.004) compared to the control children (p<0.001). Orphans scored higher in PI (p=0.009), GI (p=0.002), and OHI (p<0.001). CONCLUSION: Medical health conditions were more prevalent among orphans living in government orphanages, but they were provided with good and continuous medical care. However, they had more dental caries and worse oral hygiene, as dental care was provided to them only in case of emergency. PMID- 23677270 TI - The effect of obesity and periodontitis on the expression of antimicrobial peptides in gingival tissues. AB - OBJECTIVE: To compare the expression of human beta-defensins (HBD) in the gingival tissues of obese and normal weight systemically healthy subjects. METHODS: This cross-sectional study was conducted at the Faculty of Dentistry, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia from March 2010 to November 2011. Twenty obese (10 affected with periodontitis and 10 periodontally healthy), and 20 normal weight subjects (10 affected with periodontitis and 10 periodontally healthy) were selected. Gingival tissue samples were collected and subjected to immunohistochemistry assay to evaluate the expression of HBD-1 and 2. RESULTS: In the epithelium, the staining was almost limited to the basal and supra-basal cells, while the superficial layers and keratin were negative. In the connective tissue, some of the chronic inflammatory cells and fibroblasts were also stained. Endothelial cells lining blood or lymphatic vessels were mostly positive with HBD-2 and were almost negative with HBD-1. The percentage of positively stained areas did not show any differences in the expression of HBD-1 and -2 in obese compared to normal weight subjects whether they were affected or not affected with periodontitis. CONCLUSION: The results of this study did not demonstrate an association between the expression of HBD-1 and -2 and obesity and periodontitis. PMID- 23677272 TI - Skin pseudolymphoma caused by cutaneous leismaniasia. AB - Cutaneous leishmaniasis is a common disease in the Kingdom of Saudi Arabia. A patient with a usual presentation is easy to diagnose by histological examination. However, atypical cases may serve as a problem for both the clinician and the pathologist on the diagnostic level. Here we present a case, in which the clinical presentation and microscopic features mimic cutaneous B-cell lymphoma and pseudolymphoma. PMID- 23677273 TI - Cytologically diagnosed metastatic small cell lung carcinoma in the mandibular soft tissue. AB - Metastatic tumors to the oral and maxillofacial region are relatively rare, they constitute 1% of all malignant tumors of the oral cavity. The purpose of this case report is to evaluate the efficiency of fine needle aspiration cytology (FNAC) in the diagnosis of metastatic small cell lung carcinoma. A 50-year-old female patient presenting with a 4x5 cm firm, hemorrhagic, tender swelling on the left mandibular bicuspid gingiva was evaluated. Her past medical history revealed a mass measuring 8x5 cm in the left pulmonary hilar area with pleural effusion, which was diagnosed as small cell lung carcinoma. A FNAC was performed to the oral mucosal swelling, and cytological examination revealed metastatic small cell lung carcinoma. The duration between diagnosis of the primary lung and development of metastasis was 6 months. The FNAC is a rapid, non-invasive, and safe diagnostic method when carried out with a proper technique, and proved to be a valuable adjunct to a careful physical and radiological examination of the oro maxillofacial lesions. PMID- 23677274 TI - Epsilometer test for determining in-vitro activity of tigecycline against rapidly growing mycobacteria from central Saudi Arabia. PMID- 23677275 TI - Selective laser trabeculoplasty after canaloplasty improves the efficacy of intraocular pressure reduction in eyes with open angle glaucoma. PMID- 23677276 TI - A retrospective study on traumatic spinal cord injury in an inpatient rehabilitation unit in central Saudi Arabia. PMID- 23677277 TI - David Cole-Hamilton - the perfect academic. PMID- 23677278 TI - Snake velvet black: hierarchical micro- and nanostructure enhances dark colouration in Bitis rhinoceros. AB - The West African Gaboon viper (Bitis rhinoceros) is a master of camouflage due to its colouration pattern. Its skin is geometrically patterned and features black spots that purport an exceptional spatial depth due to their velvety surface texture. Our study shades light on micromorphology, optical characteristics and principles behind such a velvet black appearance. We revealed a unique hierarchical pattern of leaf-like microstructures striated with nanoridges on the snake scales that coincides with the distribution of black colouration. Velvet black sites demonstrate four times lower reflectance and higher absorbance than other scales in the UV-near IR spectral range. The combination of surface structures impeding reflectance and absorbing dark pigments, deposited in the skin material, provides reflecting less than 11% of the light reflected by a polytetrafluoroethylene diffuse reflectance standard in any direction. A view angle independent black structural colour in snakes is reported here for the first time. PMID- 23677279 TI - Observation of the long-lived triplet excited state of perylenebisimide (PBI) in C^N cyclometalated Ir(III) complexes and application in photocatalytic oxidation. AB - Perylenebisimide (PBI) was used to prepare C^N cyclometalated Ir(III) complexes that show strong absorption of visible light and it is the first time the long lived triplet excited state of PBI chromophore was observed in a transition metal complex (tauT = 22.3 MUs). Previously, the lifetime of the triplet state of PBI in transition metal complexes was usually shorter than 1.0 MUs. Long-lived triplet excited states are useful for applications in photocatalysis or other photophysical processes concerning triplet-triplet-energy-transfer. PBI and amino PBI were used for preparation of cyclometalated Ir(III) complexes (Ir-2 and Ir 3), in which the PBI chromophore was connected to the coordination center via C=C pi-conjugation bond. The new complexes show strong absorption in visible region (epsilon = 34,200 M(-1) cm(-1) at 541 nm for Ir-2, and epsilon = 19,000 at 669 nm for Ir-3), compared to the model complex Ir(ppy)(bpy)[PF6] Ir-1 (epsilon < 5000 M(-1) cm(-1) in the region beyond 400 nm). The nanosecond time-resolved transient absorption and DFT calculations indicated that PBI-localized long-lived (3)IL states were populated for Ir-2 and Ir-3 upon photoexcitation. The complexes were used as triplet photosensitizers for (1)O2-mediated photooxidation of 1,5 dihydronaphthalene to produce juglone, an important intermediate for preparation of anti-cancer compounds. (1)O2 quantum yields (Phi(Delta)) up to 91% were observed for the new Ir(III) complexes and the overall photosensitizing ability is much higher than the conventional Ir(III) complex Ir-1, which shows the typical weak visible light absorption in visible region. Our results are useful for preparation of transition metal complexes that show strong absorption of visible light and long-lived triplet excited state and for the application of these complexes in photocatalysis. PMID- 23677281 TI - Insertional activation of myb by F-MuLV in SCID mice induces myeloid leukemia. AB - Identification of retrovirus integration sites is a powerful method to identify cancer-related genes. This approach led to the discovery of the Friend murine leukemia virus (F-MuLV) integration site-1 (fli-1). Viral insertion at the fli-1 locus induces erythroleukemia in susceptible strains of mice. Our recent data demonstrated that, F-MuLV-infected SCID mice, in contrast to wt CB17 controls, developed a non-erythroleukemic leukemia without viral integration at the fli-1 locus. Using ligation-mediated polymerase chain reaction (LM-PCR) approach we identified a total of 15 viral integration sites in F-MuLV-infected SCID mice. One of the identified insertion sites was located about 62 kb upstream of the myeloblastosis (myb) gene. While integration within or surrounding the myb gene has been reported before for murine leukemia viruses, the location of the viral integration site identified in F-MuLV-infected SCID mice is novel and has never been reported. Using PCR analysis we showed that viral integration at the myb locus occurs with a frequency of 35% and therefore is considered as a common integration site. Integration of F-MuLV in this locus resulted in upregulation of the MYB protein. Flow cytometry analysis and methylcellulose culture of leukemic cells isolated from tumors with viral integration close to the myb indicated tumors of myeloid origin. Our findings indicate that, in contrast to wt CB17 mice, F-MuLV-infected SCID mice display viral integration within myeloid specific gene loci that result in the development of myelogenous leukemia. PMID- 23677282 TI - A dissenting opinion on DSM-5 pedophilic disorder. PMID- 23677283 TI - Carotid and vertebral artery sacrifice with a combination of Onyx and coils: technical note and case series. AB - INTRODUCTION: Permanent vessel sacrifice has become a routine for the management of aneurysms, pseudoaneurysms, tumors, and carotid blowouts. The purpose of this study is to describe a new technique for carotid and vertebral artery sacrifice using a combination of Onyx and coils and to assess its feasibility, safety, and efficacy. METHODS: The technique consists of deploying a few coils in the parent vessel under proximal flow arrest followed by Onyx embolization directly into the coil mass. A total of 41 patients underwent carotid/vertebral artery sacrifice using this technique in our institution. RESULTS: A total of 26 internal carotid arteries and 15 vertebral arteries were treated. In all but one patient, a balloon test occlusion was performed prior to permanent arterial sacrifice. The mean number of coils used was 6.8 (range, 2-19). The total volume of Onyx used was 1.3 ml on average (range, 0.2-5.2 ml). All 41 (100%) parent arteries were successfully occluded. No distal migration of Onyx or coils was noted. Periprocedural complications occurred in 14.6% (6/41) of cases causing permanent morbidity in 7.3% (3/41). No patient developed a recurrence during the follow-up period (mean, 14 months). CONCLUSION: Parent vessel sacrifice with a combination of Onyx and coils appears to be feasible, safe, and effective and may be an alternative to the traditional deconstruction technique with coils alone. The risk of thromboembolism exists with this technique, but there were no instances of Onyx migration. PMID- 23677285 TI - On the directionality of halogen bonding. AB - The origin of the high directionality of halogen bonding was investigated quantum chemically by a detailed comparison of typical adducts in two different orientations: linear (most stable) and perpendicular. Energy decomposition analyses revealed that the synergy between charge-transfer interactions and Pauli repulsion are the driving forces for the directionality, while electrostatic contributions are more favourable in the less-stable, perpendicular orientation. PMID- 23677284 TI - Transarterial chemoembolization for pain relief in patients with hypervascular painful metastatic spinal tumors refractory to percutaneous vertebroplasty. AB - PURPOSE: This study is aimed at evaluating the safety and efficacy of transarterial chemoembolization (TACE) for patients with hypervascular painful metastatic spinal tumors refractory to percutaneous vertebroplasty (PVP). METHODS: A total of 11 patients with hypervascular painful metastatic spinal tumors refractory to PVP were recruited for testing the safety and efficacy of TACE. Individual patients were subjected to infusion with 40 mg/m(2) epirubicin and 20-60 mg polyvinyl alcohol foam (PVA) particles (300-500 MUm) or gel-foam strips for embolization through the dominant arteries to the tumor. The degrees of pain the patients suffered were evaluated using the visual analogue scale (VAS) score one day before, 5 days, and 2 weeks after TACE. The neurologic symptoms and skin/muscle complications were observed. RESULTS: A total of 12 lumbar vertebrae from 11 patients were treated with TACE through 21 vertebral arteries. Twelve out of 21 arteries were embolized with PVA particles, and other nine arteries were embolized with gel-foam strips. The analgesic rate of TACE in those patients was 90.9% at 5 and 14 days postprocedure. The VAS scores in those patients were reduced from preoperative 8.6 +/- 1.1 to 3.9 +/- 1.38 on day 5 and to 3.6 +/- 1.7 at 2 weeks post-TACE, respectively. There was no obvious neurologic symptom or skin/muscle necrosis in those patients. CONCLUSIONS: Transarterial chemoembolization (TACE) is a safe and effective therapy for pain relief in patients with hypervascular painful metastatic spinal tumors refractory to PVP. PMID- 23677288 TI - The Cover. Two or three things. PMID- 23677290 TI - New analyses of hot spring waters. PMID- 23677291 TI - ACP, state medical boards offer advice on online professionalism for physicians. PMID- 23677292 TI - Volunteer corps aims to improve training for clinicians in developing countries. PMID- 23677303 TI - Cephalosporin resistance in Neisseria gonorrhoeae infections. PMID- 23677304 TI - Cephalosporin resistance in Neisseria gonorrhoeae infections--reply. PMID- 23677305 TI - Cephalosporin resistance in Neisseria gonorrhoeae infections--reply. PMID- 23677306 TI - Use of administrative data for public reporting of outcomes. PMID- 23677307 TI - Use of administrative data for public reporting of outcomes--reply. PMID- 23677308 TI - Temporal trends in smokeless tobacco use among US middle and high school students, 2000-2011. PMID- 23677310 TI - Contraception is a fundamental primary care service. PMID- 23677311 TI - Contraceptives and the law: a view from a Catholic medical institution. PMID- 23677312 TI - A piece of my mind. Patient's sister, seeking job. PMID- 23677313 TI - Long-term outcomes following abdominal sacrocolpopexy for pelvic organ prolapse. AB - IMPORTANCE: More than 225 000 surgeries are performed annually in the United States for pelvic organ prolapse (POP). Abdominal sacrocolpopexy is considered the most durable POP surgery, but little is known about safety and long-term effectiveness. OBJECTIVES: To describe anatomic and symptomatic outcomes up to 7 years after abdominal sacrocolpopexy, and to determine whether these are affected by concomitant anti-incontinence surgery (Burch urethropexy). DESIGN, SETTING, AND PARTICIPANTS: Long-term follow-up of the randomized, masked 2-year Colpopexy and Urinary Reduction Efforts (CARE) trial of women with stress continence who underwent abdominal sacrocolpopexy between 2002 and 2005 for symptomatic POP and also received either concomitant Burch urethropexy or no urethropexy. Ninety-two percent (215/233) of eligible 2-year CARE trial completers were enrolled in the extended CARE study; and 181 (84%) and 126 (59%) completed 5 and 7 years of follow-up, respectively. The median follow-up was 7 years. MAIN OUTCOMES AND MEASURES: Symptomatic POP failure requiring retreatment or self-reported bulge; or anatomic POP failure requiring retreatment or Pelvic Organ Prolapse Quantification evaluation demonstrating descent of the vaginal apex below the upper third of the vagina, or anterior or posterior vaginal wall prolapse beyond the hymen. Stress urinary incontinence (SUI) with more than 1 symptom or interval treatment; or overall UI score of 3 or greater on the Incontinence Severity Index. RESULTS: By year 7, the estimated probabilities of treatment failure (POP, SUI, UI) from parametric survival modeling for the urethropexy group and the no urethropexy group, respectively, were 0.27 and 0.22 for anatomic POP (treatment difference of 0.050; 95% CI, -0.161 to 0.271), 0.29 and 0.24 for symptomatic POP (treatment difference of 0.049; 95% CI, -0.060 to 0.162), 0.48 and 0.34 for composite POP (treatment difference of 0.134; 95% CI, -0.096 to 0.322), 0.62 and 0.77 for SUI (treatment difference of -0.153; 95% CI, -0.268 to 0.030), and 0.75 and 0.81 for overall UI (treatment difference of -0.064; 95% CI, -0.161 to 0.032). Mesh erosion probability at 7 years (estimated by the Kaplan-Meier method) was 10.5% (95% CI, 6.8% to 16.1%). CONCLUSIONS AND RELEVANCE: During 7 years of follow-up, abdominal sacrocolpopexy failure rates increased in both groups. Urethropexy prevented SUI longer than no urethropexy. Abdominal sacrocolpopexy effectiveness should be balanced with long-term risks of mesh or suture erosion. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00099372. PMID- 23677314 TI - Association of single- vs dual-chamber ICDs with mortality, readmissions, and complications among patients receiving an ICD for primary prevention. AB - IMPORTANCE: Randomized trials of implantable cardioverter-defibrillators (ICDs) for primary prevention predominantly used single-chamber devices. In clinical practice, patients often receive dual-chamber ICDs, even without clear indications for pacing. The outcomes of dual- vs single-chamber devices are uncertain. OBJECTIVE: To compare outcomes of single- and dual-chamber ICDs for primary prevention of sudden cardiac death. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of admissions in the National Cardiovascular Data Registry's (NCDR) ICD registry from 2006-2009 that could be linked to Centers for Medicare & Medicaid Services fee-for-service Medicare claims data. Patients were included if they received an ICD for primary prevention and did not have a documented indication for pacing. MAIN OUTCOMES AND MEASURES: Adjusted risks of 1 year mortality, all-cause readmission, heart failure readmission, and device related complications within 90 days were estimated with propensity-score matching based on patient, clinician, and hospital factors. RESULTS: Among 32,034 patients, 12,246 (38%) received a single-chamber device and 19,788 (62%) received a dual-chamber device. In a propensity-matched cohort, rates of complications were lower for single-chamber devices (3.51% vs 4.72%; P < .001; risk difference, -1.20 [95% CI, -1.72 to -0.69]), but device type was not significantly associated with 1-year mortality (unadjusted rate, 9.85% vs 9.77%; hazard ratio [HR], 0.99 [95% CI, 0.91 to 1.07]; P = .79), 1-year all-cause hospitalization (unadjusted rate, 43.86% vs 44.83%; HR, 1.00 [95% CI, 0.97-1.04]; P = .82), or hospitalization for heart failure (unadjusted rate, 14.73% vs 15.38%; HR, 1.05 [95% CI, 0.99-1.12]; P = .19). CONCLUSIONS AND RELEVANCE: Among patients receiving an ICD for primary prevention without indications for pacing, the use of a dual-chamber device compared with a single-chamber device was associated with a higher risk of device-related complications and similar 1-year mortality and hospitalization outcomes. Reasons for preferentially using dual-chamber ICDs in this setting remains unclear. PMID- 23677315 TI - Do findings on routine examination identify patients at risk for primary open angle glaucoma? The rational clinical examination systematic review. AB - IMPORTANCE: Glaucoma is the second leading cause of blindness worldwide, and its insidious onset is often associated with diagnostic delay. Since glaucoma progression can often be effectively diminished when treated, identifying individuals at risk for glaucoma could potentially lead to earlier detection and prevent associated vision loss. OBJECTIVE: To quantify the diagnostic accuracy of examination findings and relevant risk factors in identifying individuals with primary open-angle glaucoma (POAG), the most common form of glaucoma in North America. DATA SOURCES: Structured Medline (January 1950-January 2013) search and a hand search of references and citations of retrieved articles yielding 57 articles from 41 studies. STUDY SELECTION: Population-based studies of high-level methods relating relevant examination findings of cup-to-disc ratio (CDR), CDR asymmetry, intraocular pressure (IOP), and demographic risk factors to the presence of POAG. RESULTS: The summary prevalence of glaucoma in the highest quality studies was 2.6% (95% CI, 2.1%-3.1%). Among risk factors evaluated, high myopia (>=6 diopters; odds ratio [OR], 5.7; 95% CI, 3.1-11) and family history (OR, 3.3; 95% CI, 2.0-5.6) had the strongest association with glaucoma. Black race (OR, 2.9; 95% CI, 1.4-5.9) and increasing age (especially age >80 years; OR, 2.9; 95% CI, 1.9-4.3) were also associated with an increased risk. As CDR increased, the likelihood for POAG increased with a likelihood ratio (LR) of 14 (95% CI, 5.3-39) for CDR of 0.7 or greater. Increasing CDR asymmetry was also associated with an increased likelihood for POAG (CDR asymmetry >=0.3; LR, 7.3; 95% CI, 3.3-16). No single threshold for CDR or asymmetry ruled out glaucoma. The presence of a disc hemorrhage (LR, 12; 95% CI, 2.9-48) was highly suggestive of glaucoma, but the absence of a hemorrhage was nondiagnostic (LR, 0.94; 95% CI, 0.83-0.98). At the commonly used cutoff for high IOP (>=22), the LR was 13 (95% CI, 8.2-17), while lower IOP made glaucoma less likely (LR, 0.65; 95% CI, 0.55 0.76). We found no studies of screening examinations performed by generalist physicians in a routine setting. CONCLUSIONS AND RELEVANCE: Individual findings of increased CDR, CDR asymmetry, disc hemorrhage, and elevated IOP, as well as demographic risk factors of family history, black race, and advanced age are associated with increased risk for POAG, but their absence does not effectively rule out POAG. The best available data support examination by an ophthalmologist as the most accurate way to detect glaucoma. PMID- 23677316 TI - Do TNF inhibitors reduce the risk of myocardial infarction in psoriasis patients? AB - OBJECTIVE: To assess whether patients with psoriasis treated with tumor necrosis factor (TNF) inhibitors have a decreased risk of myocardial infarction (MI) compared with those not treated with TNF inhibitors. DESIGN: Retrospective cohort study. SETTING: Kaiser Permanente Southern California health plan. PATIENTS: Patients with at least 3 International Classification of Diseases, Ninth Revision, Clinical Modification, codes for psoriasis (696.1) or psoriatic arthritis (696.0) (without antecedent MI) between January 1, 2004, and November 30, 2010. MAIN OUTCOME MEASURE: Incident MI. RESULTS: Of 8845 patients included, 1673 received a TNF inhibitor for at least 2 months (TNF inhibitor cohort), 2097 were TNF inhibitor naive and received other systemic agents or phototherapy (oral/phototherapy cohort), and 5075 were not treated with TNF inhibitors, other systemic therapies, or phototherapy (topical cohort). The median duration of follow-up was 4.3 years (interquartile range, 2.9, 5.5 years), and the median duration of TNF inhibitor therapy was 685 days (interquartile range, 215, 1312 days). After adjusting for MI risk factors, the TNF inhibitor cohort had a significantly lower hazard of MI compared with the topical cohort (adjusted hazard ratio, 0.50; 95% CI, 0.32-0.79). The incidence of MI in the TNF inhibitor, oral/phototherapy, and topical cohorts were 3.05, 3.85, and 6.73 per 1000 patient years, respectively. CONCLUSIONS: Use of TNF inhibitors for psoriasis was associated with a significant reduction in MI risk and incident rate compared with treatment with topical agents. Use of TNF inhibitors for psoriasis was associated with a non-statistically significant lower MI incident rate compared with treatment with oral agents/phototherapy. PMID- 23677317 TI - Pelvic organ prolapse surgery: long-term outcomes and implications for shared decision making. PMID- 23677318 TI - JAMA patient page. Misuse of opioid medication. PMID- 23677319 TI - Tetranuclear organometallic complexes based on 1,2-ethanedithiolate ligands as potential precursors for CuMS2 (M = Ga, In). AB - The synthesis and characterization of a series of homologous tetranuclear complexes [((i)Pr3PCu)2(MR2)2(SCH2CH2S)2] (MR2 = GaMe2 (2), GaEt2 (3), Ga(i)Pr2 (4), Ga(n)Bu2 (5) and InMe2 (6), InEt2 (7), In(i)Pr2 (8), In(n)Bu2 (9)) and of related compounds [((i)Pr3PCu)3(MR2)(SCH2CH2S)2] (MR2 = GaMe2 (10), GaEt2 (11), Ga(i)Pr2 (12), Ga(n)Bu2 (13) and InMe2 (14), InEt2 (15), In(i)Pr2 (16), In(n)Bu2 (17)) are presented. The molecular structures of these were determined by single crystal X-ray diffraction. Thermolysis processes of all the representatives of 2 9 were investigated by simultaneous thermal analysis and thermal decomposition in a nitrogen atmosphere in a quartz glass tube. According to powder X-ray diffraction studies these thermolysis residues predominantly consist of CuMS2 (M = Ga, In), which mainly occurred in the well known tetragonal chalcopyrite-type structure and partially in the hexagonal wurtzite-type structure. As expected from their composition, representatives of 10-17 form mixtures of CuMS2 and large amounts of Cu(2-x)S upon thermolysis. PMID- 23677320 TI - HLA-B*44 is associated with a lower viral set point and slow CD4 decline in a cohort of Chinese homosexual men acutely infected with HIV-1. AB - HLA class I alleles have been shown to have differential impacts on the viral load and the outcome of HIV-1 disease progression. In this study, HLA class I types from residents of China with acute HIV-1 infection, diagnosed between 2006 and 2011, were identified and the association between expression of individual HLA alleles and the level of the set point viral load was analyzed. A lower level of set point viral load was found to be associated with the Bw4 homozygote on HLA B alleles. B*44 and B*57 alleles have also been found to be associated with lower set point viral load. The set point viral load of B*44-positive individuals homozygous for Bw4 was significantly lower than that of B*44-negative individuals homozygous for Bw4 (P = 0.030). The CD4 count declined to <350 in fewer B*44 positive individuals than B*44-negative individuals (X(2) = 7.295, P = 0.026). B*44-positive individuals had a lower magnitude of p24 pool-specific T cell responses than B*44-negative individuals homozygous for Bw4, though this was not statistically significant. The p24 pool-specific T cell responses were also inversely correlated with lower viral load (rs = -0.88, P = 0.033). Six peptides within p24 were recognized to induce the specific-T cell response in B*44 positive individuals, and the peptide breadth of response was same as that in B*44-negative individuals homozygous for Bw4, but the median magnitude of specific-T cell responses to the recognized peptides in B*44-positive individuals was lower than that in B*44-negative individuals homozygous for Bw4 (P = 0.049). These findings imply that weak p24-specific CD8(+) T cell responses might play an important role in the control of HIV viremia in B*44 allele-positive individuals. Such studies might contribute to the development of future therapeutic strategies that take into account the genetic background of the patients. PMID- 23677321 TI - Vaccination with lentiviral vector expressing the nfa1 gene confers a protective immune response to mice infected with Naegleria fowleri. AB - Naegleria fowleri, a pathogenic free-living amoeba, causes fatal primary amoebic meningoencephalitis (PAM) in humans and animals. The nfa1 gene (360 bp), cloned from a cDNA library of N. fowleri, produces a 13.1-kDa recombinant protein which is located on pseudopodia, particularly the food cup structure. The nfa1 gene plays an important role in the pathogenesis of N. fowleri infection. To examine the effect of nfa1 DNA vaccination against N. fowleri infection, we constructed a lentiviral vector (pCDH) expressing the nfa1 gene. For the in vivo mouse study, BALB/c mice were intranasally vaccinated with viral particles of a viral vector expressing the nfa1 gene. To evaluate the effect of vaccination and immune responses of mice, we analyzed the IgG levels (IgG, IgG1, and IgG2a), cytokine induction (interleukin-4 [IL-4] and gamma interferon [IFN-gamma]), and survival rates of mice that developed PAM. The levels of both IgG and IgG subclasses (IgG1 and IgG2a) in vaccinated mice were significantly increased. The cytokine analysis showed that vaccinated mice exhibited greater IL-4 and IFN-gamma production than the other control groups, suggesting a Th1/Th2 mixed-type immune response. In vaccinated mice, high levels of Nfa1-specific IgG antibodies continued until 12 weeks postvaccination. The mice vaccinated with viral vector expressing the nfa1 gene also exhibited significantly higher survival rates (90%) after challenge with N. fowleri trophozoites. Finally, the nfa1 vaccination effectively induced protective immunity by humoral and cellular immune responses in N. fowleri infected mice. These results suggest that DNA vaccination using a viral vector may be a potential tool against N. fowleri infection. PMID- 23677322 TI - Protection against experimental melioidosis following immunization with live Burkholderia thailandensis expressing a manno-heptose capsule. AB - Melioidosis is a severe infectious disease caused by Burkholderia pseudomallei. It is highly resistant to antibiotic treatment, and there is currently no licensed vaccine. Burkholderia thailandensis is a close relative of Burkholderia pseudomallei but is essentially avirulent in mammals. In this report, we detail the protective efficacy of immunization with live B. thailandensis E555, a strain which has been shown to express an antigenic capsule similar to that of B. pseudomallei. Immunization with E555 induced significant protection against a lethal intraperitoneal B. pseudomallei challenge in a mouse model of infection, with no mice succumbing to infection over the course of the study, even with challenges of up to 6,000 median lethal doses. By comparison, mice immunized with B. thailandensis not expressing a B. pseudomallei-like capsule had significantly decreased levels of protection. E555-immunized mice had significantly higher levels of IgG than mice immunized with noncapsulated B. thailandensis, and these antibody responses were primarily directed against the capsule. PMID- 23677323 TI - Influence of oxidation and multimerization on the immunogenicity of a thioredoxin l2 prophylactic papillomavirus vaccine. AB - Current commercial prophylactic human papillomavirus (HPV) vaccines are based on virus-like particles assembled from the major capsid protein L1 and show excellent safety and efficacy profiles. Still, a major limitation is their rather narrow range of protection against different HPV types. In contrast, the minor capsid protein L2 contains a so-called major cross-neutralizing epitope that can induce broad-range protective responses against multiple HPV types. This epitope is conserved among different papillomaviruses (PV) and contains two cysteine residues that are present in the L2 proteins of all known PV types. The main challenge in developing L2-directed vaccines is to overcome the intrinsically low immunogenicity of the L2 protein. Previously, we developed a recombinant L2-based prototype vaccine by inserting peptide epitopes spanning the cross-neutralizing L2 sequence into a bacterial thioredoxin (Trx) scaffold. These antigens induced high-titer neutralizing antibodies in mice. Here, we address the question of whether Trx scaffold multimerization may further enhance the immunogenicity of the TrxL2 vaccine. We also demonstrate that the oxidation state of the conserved cysteine residues is not essential for vaccine functionality, but it contributes to immunogenicity. PMID- 23677324 TI - Impact of analytical variability on clinical interpretation of multiplex pneumococcal serology assays. AB - The response to pneumococcal vaccination can be used to assess a patient's humoral immune response to polysaccharide antigens. Multiplex assays measuring serotype-specific levels of pneumococcal antibodies are often used for this purpose, and clinical algorithms have been published to assist in the definition of an adequate immune response. We evaluated whether interlaboratory variability in multiplex pneumococcal serology assays would affect the clinical classification of the immune response. Specimens from 57 patients were analyzed at three reference laboratories with different multiplex assays to measure pneumococcal serology. Analytical correlation and clinical agreement in the classification of a patient's vaccination status by the three methods were compared. Although substantial variation in the quantitative antibody levels measured by different laboratories was seen, the qualitative classification of individual serologic results showed a high degree of agreement between labs and the ultimate classification of a patient as "protected" or "nonprotected" was the same for most patients. The majority of discordant classifications were driven by a systematic bias in results from one of the assays rather than by random error. These data suggest that the use of integrated assessments based on multiple serotypes can compensate for much of the analytical variability seen between laboratories. Knowledge of the analytical performance characteristics of a particular assay is most important when evaluating patients with results near clinical cut points. PMID- 23677326 TI - Assessment of 126,913 inguinal hernia repairs in the Emilia-Romagna region of Italy: analysis of 10 years. AB - PURPOSE: Inguinal hernioplasty could be used as an indicator of the surgical quality offered in different health institutions and countries, thereby establishing a scientific basis from which the procedure can be critically assessed and ultimately improved. Quality assessment of hernioplasties could be conducted using two different methods: either analyzing dedicated regional/national databases (DD) or reviewing administrative databases (AD). METHODS: A retrospective study of inguinal hernioplasties was carried out in the Emilia-Romagna hospitals between 2000 and 2009. Data were obtained by analyzing Hospital Discharge records regional Databases (HDD). Descriptive and multivariate statistical analysis was performed. RESULTS: 126,913 inguinal hernioplasty procedures were performed. The annual rate was on average 34 per 10,000 inhabitants. An increase of the case mix complexity and relevant changes in procedure technique were recorded. From multivariate analysis, the following independent factors related to a hospitalization longer than 1 day emerged: procedures in urgent setting (OR 3.6, CI 3.4-3.7), Charlson's score >=2 (OR 3.4, CI 3.1-3.7), laparoscopy (OR 2.1, CI 1.9-2.3), no mesh use (OR 2.1, CI 2-2.3), age >65 years (OR 1.9, CI 1.8-1.9), associated interventions (OR 1.9, CI 1.8 1.9), bilateral hernia (OR 1.7, CI 1.6-1.8), recurrent hernia (OR 1.2, CI 1.1 1.2) and female gender (OR 1.2, CI 1.2-1.3). Factors related to non-prosthetic hernioplasty were: bilateral hernia (OR 2.7, CI 2.5-2.9), female gender (OR 1.8, CI 1.8-2.0), emergency setting (OR 1.6, CI 1.5-1.8), recurrences (OR 1.5, CI 1.4 1.6) and associated interventions (OR 1.5, CI 1.4-1.6). CONCLUSION: Inguinal hernia should be treated as an outpatient procedure in the majority of patients. Precise guidelines are necessary. HDD demonstrated to be a good and trustworthy system to collect clinical data. When precise guidelines are lacking, legal/institutional indications play a pivotal role in shifting the hernia surgery toward a one-day surgery regimen. PMID- 23677325 TI - Seroprevalence of antipolio antibodies among children <15 years of age in border provinces in China. AB - Despite remarkable progression toward polio eradication worldwide, wild poliovirus (WPV) importation has been a great challenge for China, as it shares borders with countries where WPV is endemic. The objective of this study was to estimate poliovirus antibody seroprevalence among children <15 years of age in 3 border provinces (Yunnan Province, Tibet Autonomous Region, and Xinjiang Uygur Autonomous Region) in China. A cross-sectional, hospital-based study was undertaken in 3 border provinces in 2010. Individuals <15 years old who visited hospitals at the prefecture level or above to have their blood drawn for any reason were invited to participate in our study. Neutralizing antibody titers to polio serotypes 1 (P1), P2, and P3 were assayed according to the World Health Organization manual for the virological investigation of polio. Antibody titers of >=8 were considered positive. Among the 1,360 subjects enrolled, 1,220 (89.7%), 1,259 (92.6%), and 1,112 (81.8%) were seropositive to P1, P2, and P3, respectively, and 1,051 (77.3%) subjects were seropositive to all three serotypes. The highest seropositive rates were observed in Xinjiang Uygur Autonomous Region. By age, 3- to 5-year-old subjects had the highest rate of seropositivity, and seropositivity decreased significantly with increasing age. The risk of WPV importation will continue until WPV transmission has been interrupted worldwide. Consistent with the Global Polio Eradication Initiative's polio endgame strategy, China must maintain its polio-free status by ensuring adequate population immunity against polio. Because immunity wanes with increasing age, a booster dose with bivalent type 1 and 2 oral poliovirus vaccine could be considered for teenagers in China. PMID- 23677328 TI - Bone marrow mesenchymal stem cell transplantation in acute brain trauma. Improvement of brain glucose metabolism in a rat model. AB - AIM: This study was performed to evaluate the effects of intravenously transplanted rat bone-marrow derived mesenchymal stem cells (rBMSCs) in an acute brain trauma model using serial 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) in rat models. ANIMALS, METHODS: Trauma models were made using a controlled cortical impact injury device. The stem cell treatment group was treated with intravenous injections of BMSCs, and models without stem cell therapy comprised the control group. Serial 18F-FDG PET images were obtained 1, 7, 14, 21, and 28 days after trauma. The difference in 18F-FDG uptake between day 1 and each time point after trauma was analyzed with SPM2 (uncorrected p < 0.005). RESULTS: The stem cell treatment group demonstrated significantly higher 18F-FDG uptake in the right parietal region at 14 days after trauma than at 1 day after trauma. An increase in glucose metabolism in the right parietal cortex appeared on days 21 and 28 after trauma in the group without stem cell treatment. The 18F-FDG uptake in the brain was improved over a broader area, including the right parietal and right primary somatosensory cortex, on days 21 and 28 after trauma in the stem cell treatment group compared with the group without stem cell treatment. CONCLUSION: BMSC therapy in trauma models led to improved glucose metabolism. This result might support the therapeutic effect of stem cells in brain trauma. PMID- 23677329 TI - Pd-mediated construction of a cyclopentane ring fused with indoles. AB - Unprecedented synthesis of functionalized indoles of potential pharmacological interest has been developed via a Pd-mediated cascade reaction involving an intramolecular Heck coupling followed by the construction of a fused cyclopentane ring in a single pot. PMID- 23677330 TI - Factors that influence parathyroid hormone half-life: determining if new intraoperative criteria are needed. AB - IMPORTANCE: Minimally invasive parathyroidectomy using intraoperative parathyroid hormone monitoring remains the standard approach to the majority of patients with primary hyperparathyroidism. This study demonstrates that individual patient characteristics do not affect existing criteria for intraoperative parathyroid hormone monitoring. OBJECTIVE: To identify patient characteristics, such as age, sex, race, body mass index (BMI), and renal function, that may affect existing criteria for intraoperative parathyroid hormone (IOPTH) levels during minimally invasive parathyroidectomy. DESIGN: Retrospective review of a prospectively collected parathyroid database populated from August 2005 to April 2011. SETTING: Academic medical center. PARTICIPANTS: Three hundred six patients with sporadic primary hyperparathyroidism who underwent initial parathyroidectomy between August 2005 and April 2011. INTERVENTIONS: All patients underwent minimally invasive parathyroidectomy with complete IOPTH information. MAIN OUTCOME AND MEASURES: Individual IOPTH kinetic profiles were fitted with an exponential decay curve and individual IOPTH half-lives were determined. Univariate and multivariate analyses were performed to determine the association between patient demographics or laboratory data and IOPTH half-life. RESULTS: Mean age of the cohort was 60 years, 78.4% were female, 90.2% were white, and median BMI was 28.3. Overall, median IOPTH half-life was 3 minutes, 9 seconds. On univariate analysis, there was no association between IOPTH half-life and patient age, renal function, or preoperative serum calcium or parathyroid hormone levels. Age, BMI, and an age * BMI interaction were included in the final multivariate median regression analysis; race, sex, and glomerular filtration rate were not predictors of IOPTH half-life. The IOPTH half-life increased with increasing BMI, an effect that diminished with increasing age and was negligible after age 55 years (P = .001). CONCLUSIONS AND RELEVANCE: Body mass index, especially in younger patients, may have a role in the IOPTH half-life of patients undergoing parathyroidectomy. However, the differences in half-life are relatively small and the clinical implications are likely not significant. Current IOPTH criteria can continue to be applied to all patients undergoing parathyroidectomy for sporadic primary hyperparathyroidism. PMID- 23677331 TI - Pharmacological inhibition of macrophage migration inhibitory factor interferes with the proliferation and invasiveness of squamous carcinoma cells. AB - Recent clinical observations and experimental studies of our group indicate that macrophage migration inhibitory factor (MIF) may contribute to tumor progression in head and neck squamous cell carcinomas (HNSCC). The present study was undertaken to examine the effects of the irreversible MIF inhibitor 4-iodo-6 phenylpyrimidine (4-IPP) on proliferation and invasiveness of the squamous carcinoma cell line SCCVII. Cell counting, crystal violet assay and flow cytometry were used to analyze the effects of 4-IPP on SCCVII cell growth. The impact of 4-IPP on cell invasiveness was assessed by Boyden chamber assay. Knockdown of the MIF receptor CD74 was achieved by transduction with lentiviral vectors encoding anti-CD74 shRNAs. As shown by immunofluorescence staining, SCCVII cells express both MIF and CD74. Decreased MIF immunoreactivity as a result of exposure to 4-IPP suggested a covalent modification of the cytokine. 4 IPP inhibited SCCVII cell proliferation and invasiveness. Moreover, the cytostatic effect of 4-IPP was enhanced by CD74 knockdown. The inhibitory effects of 4-IPP on cell proliferation and invasiveness strongly suggest that MIF is involved in proliferative activity and invasive properties of squamous carcinoma cells. In conclusion, MIF inhibition may open possibilities for target-directed treatment of head and neck squamous cell carcinoma. PMID- 23677332 TI - Body mass index, body mass change, and risk of oral cavity cancer: results of a large population-based case-control study, the ICARE study. AB - OBJECTIVE: The association between body mass index (BMI) and the risk of oral cavity cancer, suggested by the few available studies, is controversial because of weight loss preceding cancer diagnosis and possible confounding by tobacco and alcohol consumption. The aim of this study was to evaluate in France, a high incidence country, the association between the risk of oral cavity cancer and body mass index at interview, 2 years before the interview and at age 30, as well as BMI change. METHODS: We used data from a population-based case-control study, the Investigation of occupational and environmental CAuses of REspiratory cancers study, with personal interviews and standardized questionnaires including 689 cases of oral cavity squamous cell carcinoma and 3,481 controls. Odds ratios (ORs) and 95% confidence intervals (95% CI) were estimated by unconditional logistic regression and were adjusted for gender, age, area of residence, education, tobacco smoking, and alcohol drinking. RESULTS: ORs were increased in underweight subjects at interview (OR 6.25, 95% CI 3.74-10.45). No association with underweight 2 years before the interview and at age 30 was found. Overweight and obesity at interview, 2 years before the interview and at age 30 were associated with decreased ORs (ranging from 0.13 to 0.60). BMI gain greater than 5% between age 30 and 2 years before the interview was inversely associated with oral cavity cancer (OR 0.42, 95% CI 0.33-0.54). These associations were stronger in men, and in smokers and drinkers. CONCLUSION: These results add further support to the existence of a reduced risk of oral cavity cancer among overweight and obese people or among people who increased their BMI in adulthood. The underlying mechanisms remain to be clarified. PMID- 23677334 TI - Association between non-steroidal anti-inflammatory drug use and melanoma risk: a meta-analysis of 13 studies. AB - PURPOSE: Results of the association between non-steroidal anti-inflammatory drugs (NSAIDs) and melanoma risk have been inconsistent. We performed a meta-analysis of relevant studies to investigate the hypothesis of an association between NSAID use and melanoma risk. METHODS: Systematic searches of the PubMed and several other databases up to 23 March 2013 were retrieved. All epidemiologic studies regarding NSAIDs and melanoma risk were included. Fixed- or random-effects meta analytical models were used to calculate relative risk (RR) and corresponding 95 % confidence intervals (CIs). Sensitivity analyses, Galbraith plots, and subgroup analyses were also performed. RESULTS: Six case-control studies including 93,432 melanoma cases and 401,251 controls, six cohort studies consisting of 563,380 subjects, and one randomized controlled trial encompassing 39,876 participants were included in this analysis. Compared to non-use, ever use of any NSAIDs was not statistically significantly associated with melanoma risk based on the random effects models (RR = 0.97, 95 % CI = 0.90-10.4, p = 0.401). No differences were found in the effects on melanoma risk of aspirin, non-aspirin NSAIDs, and cyclooxygenase-2 inhibitor use overall and stratified by gender. However, a slight reduction in the risk of melanoma by taking aspirin was observed in case control studies (RR = 0.88, 95 % CI = 0.80-0.96, p = 0.004). CONCLUSIONS: Findings from this pooled analysis do not support the hypothesis that NSAID use provides potential benefits in preventing melanoma. More and larger randomized trials, including adequate numbers of patients, are required to further evaluate the relationship between NSAID use and melanoma. PMID- 23677333 TI - Rural-urban differences in health behaviors and implications for health status among US cancer survivors. AB - PURPOSE: Rural US adults have increased risk of poor outcomes after cancer, including increased cancer mortality. Rural-urban differences in health behaviors have been identified in the general population and may contribute to cancer health disparities, but have not yet been examined among US survivors. We examined rural-urban differences in health behaviors among cancer survivors and associations with self-reported health and health-related unemployment. METHODS: We identified rural (n = 1,642) and urban (n = 6,162) survivors from the cross sectional National Health Interview Survey (2006-2010) and calculated the prevalence of smoking, physical activity, overweight/obesity, and alcohol consumption. Multivariable models were used to examine the associations of fair/poor health and health-related unemployment with health behaviors and rural urban residence. RESULTS: The prevalence of fair/poor health (rural 36.7 %, urban 26.6 %), health-related unemployment (rural 18.5 %, urban 10.6 %), smoking (rural 25.3 %, urban 15.8 %), and physical inactivity (rural 50.7 %, urban 38.7 %) was significantly higher in rural survivors (all p < .05); alcohol consumption was lower (rural 46.3 %, urban 58.6 %), and there were no significant differences in overweight/obesity (rural 65.4 %, urban 62.6 %). All health behaviors were significantly associated with fair/poor health and health-related unemployment in both univariate and multivariable models. After adjustment for behaviors, rural survivors remained more likely than urban survivors to report fair/poor health (OR = 1.21, 95 % CI 1.03-1.43) and health-related unemployment (OR = 1.49, 95 % CI 1.18-1.88). CONCLUSIONS: Rural survivors may need tailored, accessible health promotion interventions to address health-compromising behaviors and improve outcomes after cancer. PMID- 23677335 TI - Excess treatment reduction including anthracyclines results in higher incidence of relapse in core binding factor acute myeloid leukemia in children. PMID- 23677337 TI - Vibration driven vehicle inspired from grass spike. AB - Searching and detecting in some harsh environments such as collapsed buildings, pipes, small cracks are crucial for human rescue and industrial detection, military surveillance etc. However, the drawbacks of traditional moving modes of current vehicles make them difficult to perform such tasks. So developing some new vehicles is urgent. Here, we report a Setaria viridis spike's interesting behavior on a vibrating track, and inspired by that phenomena we develop a concept for cargo delivery, and give a detailed discussion about its working mechanism. This vehicle can move on a wide range of smooth and rough surfaces. Moreover, its climbing capability in tilted and even vertical smooth pipe is also outstanding. These features make it suitable for search-rescue, military reconnaissance, etc. Finally, this vehicle can be reduced into micro/nano-scale, which makes it would play an important role in target-drug delivery, micro electromechanical systems (MEMS). PMID- 23677338 TI - Crystallization kinetics of lithium niobate glass: determination of the Johnson Mehl-Avrami-Kolmogorov parameters. AB - The formation of crystalline LiNbO3 (LN) from LN glass has been studied by means of differential scanning calorimetry and in situ synchrotron X-ray diffraction. The LN glass with no glass former was prepared by the polymerized complex method. The isothermal kinetics of the crystallization process is described using the Johnson-Mehl-Avrami-Kolmogorov (JMAK) equation and the Avrami exponent n is found to be ~2.0, indicating that the crystallization mechanism is diffusion-controlled growth with a decreasing nucleation rate. The effective activation energy of crystallization calculated from isothermal measurements is 6.51 eV. It is found that the LN glass directly transforms into a rhombohedral LN crystal without any intermediate crystalline phase and most crystal grains are confined within the size of ~40 nm irrespective of different isothermal temperatures. Application of JMAK theory to the non-isothermal thermoanalytical study of crystallization of LN glass is discussed. PMID- 23677339 TI - The effect of population structure on the rate of evolution. AB - Ecological factors exert a range of effects on the dynamics of the evolutionary process. A particularly marked effect comes from population structure, which can affect the probability that new mutations reach fixation. Our interest is in population structures, such as those depicted by 'star graphs', that amplify the effects of selection by further increasing the fixation probability of advantageous mutants and decreasing the fixation probability of disadvantageous mutants. The fact that star graphs increase the fixation probability of beneficial mutations has lead to the conclusion that evolution proceeds more rapidly in star-structured populations, compared with mixed (unstructured) populations. Here, we show that the effects of population structure on the rate of evolution are more complex and subtle than previously recognized and draw attention to the importance of fixation time. By comparing population structures that amplify selection with other population structures, both analytically and numerically, we show that evolution can slow down substantially even in populations where selection is amplified. PMID- 23677340 TI - First report on chitinous holdfast in sponges (Porifera). AB - A holdfast is a root- or basal plate-like structure of principal importance that anchors aquatic sessile organisms, including sponges, to hard substrates. There is to date little information about the nature and origin of sponges' holdfasts in both marine and freshwater environments. This work, to our knowledge, demonstrates for the first time that chitin is an important structural component within holdfasts of the endemic freshwater demosponge Lubomirskia baicalensis. Using a variety of techniques (near-edge X-ray absorption fine structure, Raman, electrospray ionization mas spectrometry, Morgan-Elson assay and Calcofluor White staining), we show that chitin from the sponge holdfast is much closer to alpha chitin than to beta-chitin. Most of the three-dimensional fibrous skeleton of this sponge consists of spicule-containing proteinaceous spongin. Intriguingly, the chitinous holdfast is not spongin-based, and is ontogenetically the oldest part of the sponge body. Sequencing revealed the presence of four previously undescribed genes encoding chitin synthases in the L. baicalensis sponge. This discovery of chitin within freshwater sponge holdfasts highlights the novel and specific functions of this biopolymer within these ancient sessile invertebrates. PMID- 23677341 TI - Demographic loss, genetic structure and the conservation implications for Indian tigers. AB - India is home to approximately 60 per cent of the world's remaining wild tigers, a species that has declined in the last few centuries to occupy less than 7 per cent of its former geographical range. While Indian tiger numbers have somewhat stabilized in recent years, they remain low and populations are highly fragmented. Therefore, the application of evidence-based demographic and genetic management to enhance the remaining populations is a priority. In this context, and using genetic data from historical and modern tigers, we investigated anthropogenic impacts on genetic variation in Indian tigers using mitochondrial and nuclear genetic markers. We found a very high number of historical mitochondrial DNA variants, 93 per cent of which are not detected in modern populations. Population differentiation was higher in modern tigers. Simulations incorporating historical data support population decline, and suggest high population structure in extant populations. Decreased connectivity and habitat loss as a result of ongoing fragmentation in the Indian subcontinent has therefore resulted in a loss of genetic variants and increased genetic differentiation among tiger populations. These results highlight that anthropogenic fragmentation and species-specific demographic processes can interact to alter the partitioning of genetic variation over very short time scales. We conclude that ongoing strategies to maximize the size of some tiger populations, at the expense of losing others, is an inadequate conservation strategy, as it could result in a loss of genetic diversity that may be of adaptive significance for this emblematic species. PMID- 23677342 TI - Genetic consequences of a century of protection: serial founder events and survival of the little spotted kiwi (Apteryx owenii). AB - We present the outcome of a century of post-bottleneck isolation of a long-lived species, the little spotted kiwi (Apteryx owenii, LSK) and demonstrate that profound genetic consequences can result from protecting few individuals in isolation. LSK were saved from extinction by translocation of five birds from South Island, New Zealand to Kapiti Island 100 years ago. The Kapiti population now numbers some 1200 birds and provides founders for new populations. We used 15 microsatellite loci to compare genetic variation among Kapiti LSK and the populations of Red Mercury, Tiritiri Matangi and Long Islands that were founded with birds from Kapiti. Two LSK native to D'Urville Island were also placed on Long Island. We found extremely low genetic variation and signatures of acute and recent genetic bottleneck effects in all four populations, indicating that LSK have survived multiple genetic bottlenecks. The Long Island population appears to have arisen from a single mating pair from Kapiti, suggesting there is no genetic contribution from D'Urville birds among extant LSK. The Ne/NC ratio of Kapiti Island LSK (0.03) is exceptionally low for terrestrial vertebrates and suggests that genetic diversity might still be eroding in this population, despite its large census size. PMID- 23677343 TI - Stability of within-host-parasite communities in a wild mammal system. AB - Simultaneous infection by multiple parasite species is ubiquitous in nature. Interactions among co-infecting parasites may have important consequences for disease severity, transmission and community-level responses to perturbations. However, our current view of parasite interactions in nature comes primarily from observational studies, which may be unreliable at detecting interactions. We performed a perturbation experiment in wild mice, by using an anthelminthic to suppress nematodes, and monitored the consequences for other parasite species. Overall, these parasite communities were remarkably stable to perturbation. Only one non-target parasite species responded to deworming, and this response was temporary: we found strong, but short-lived, increases in the abundance of Eimeria protozoa, which share an infection site with the dominant nematode species, suggesting local, dynamic competition. These results, providing a rare and clear experimental demonstration of interactions between helminths and co infecting parasites in wild vertebrates, constitute an important step towards understanding the wider consequences of similar drug treatments in humans and animals. PMID- 23677344 TI - Integrating genealogical and dynamical modelling to infer escape and reversion rates in HIV epitopes. AB - The rates of escape and reversion in response to selection pressure arising from the host immune system, notably the cytotoxic T-lymphocyte (CTL) response, are key factors determining the evolution of HIV. Existing methods for estimating these parameters from cross-sectional population data using ordinary differential equations (ODEs) ignore information about the genealogy of sampled HIV sequences, which has the potential to cause systematic bias and overestimate certainty. Here, we describe an integrated approach, validated through extensive simulations, which combines genealogical inference and epidemiological modelling, to estimate rates of CTL escape and reversion in HIV epitopes. We show that there is substantial uncertainty about rates of viral escape and reversion from cross sectional data, which arises from the inherent stochasticity in the evolutionary process. By application to empirical data, we find that point estimates of rates from a previously published ODE model and the integrated approach presented here are often similar, but can also differ several-fold depending on the structure of the genealogy. The model-based approach we apply provides a framework for the statistical analysis and hypothesis testing of escape and reversion in population data and highlights the need for longitudinal and denser cross-sectional sampling to enable accurate estimate of these key parameters. PMID- 23677345 TI - Cooperation creates selection for tactical deception. AB - Conditional social behaviours such as partner choice and reciprocity are held to be key mechanisms facilitating the evolution of cooperation, particularly in humans. Although how these mechanisms select for cooperation has been explored extensively, their potential to select simultaneously for complex cheating strategies has been largely overlooked. Tactical deception, the misrepresentation of the state of the world to another individual, may allow cheaters to exploit conditional cooperation by tactically misrepresenting their past actions and/or current intentions. Here we first use a simple game-theoretic model to show that the evolution of cooperation can create selection pressures favouring the evolution of tactical deception. This effect is driven by deception weakening cheater detection in conditional cooperators, allowing tactical deceivers to elicit cooperation at lower costs, while simple cheats are recognized and discriminated against. We then provide support for our theoretical predictions using a comparative analysis of deception across primate species. Our results suggest that the evolution of conditional strategies may, in addition to promoting cooperation, select for astute cheating and associated psychological abilities. Ultimately, our ability to convincingly lie to each other may have evolved as a direct result of our cooperative nature. PMID- 23677346 TI - Divergent allele advantage at MHC-DRB through direct and maternal genotypic effects and its consequences for allele pool composition and mating. AB - It is still debated whether main individual fitness differences in natural populations can be attributed to genome-wide effects or to particular loci of outstanding functional importance such as the major histocompatibility complex (MHC). In a long-term monitoring project on Galapagos sea lions (Zalophus wollebaeki), we collected comprehensive fitness and mating data for a total of 506 individuals. Controlling for genome-wide inbreeding, we find strong associations between the MHC locus and nearly all fitness traits. The effect was mainly attributable to MHC sequence divergence and could be decomposed into contributions of own and maternal genotypes. In consequence, the population seems to have evolved a pool of highly divergent alleles conveying near-optimal MHC divergence even by random mating. Our results demonstrate that a single locus can significantly contribute to fitness in the wild and provide conclusive evidence for the 'divergent allele advantage' hypothesis, a special form of balancing selection with interesting evolutionary implications. PMID- 23677347 TI - Hydrolysis of aromatic beta-glucosides by non-pathogenic bacteria confers a chemical weapon against predators. AB - Bacteria present in natural environments such as soil have evolved multiple strategies to escape predation. We report that natural isolates of Enterobacteriaceae that actively hydrolyze plant-derived aromatic beta-glucosides such as salicin, arbutin and esculin, are able to avoid predation by the bacteriovorous amoeba Dictyostelium discoideum and nematodes of multiple genera belonging to the family Rhabditidae. This advantage can be observed under laboratory culture conditions as well as in the soil environment. The aglycone moiety released by the hydrolysis of beta-glucosides is toxic to predators and acts via the dopaminergic receptor Dop-1 in the case of Caenorhabditis elegans. While soil isolates of nematodes belonging to the family Rhabditidae are repelled by the aglycone, laboratory strains and natural isolates of Caenorhabditis sp. are attracted to the compound, mediated by receptors that are independent of Dop 1, leading to their death. The beta-glucosides-positive (Bgl(+)) bacteria that are otherwise non-pathogenic can obtain additional nutrients from the dead predators, thereby switching their role from prey to predator. This study also offers an evolutionary explanation for the retention by bacteria of 'cryptic' or 'silent' genetic systems such as the bgl operon. PMID- 23677348 TI - Costly reproductive competition between females in a monogamous cooperatively breeding bird. AB - In many cooperatively breeding societies, only a few socially dominant individuals in a group breed, reproductive skew is high, and reproductive conflict is common. Surprisingly, the effects of this conflict on dominant reproductive success in vertebrate societies have rarely been investigated, especially in high-skew societies. We examine how subordinate female competition for breeding opportunities affects the reproductive success of dominant females in a monogamous cooperatively breeding bird, the Southern pied babbler (Turdoides bicolor). In this species, successful subordinate reproduction is very rare, despite the fact that groups commonly contain sexually mature female subordinates that could mate with unrelated group males. However, we show that subordinate females compete with dominant females to breed, and do so far more often than expected, based on the infrequency of their success. Attempts by subordinates to obtain a share of breeding impose significant costs on dominant females: chicks fledge from fewer nests, more nests are abandoned before incubation begins, and more eggs are lost. Dominant females appear to attempt to reduce these costs by aggressively suppressing potentially competitive subordinate females. This empirical evidence provides rare insight into the nature of the conflicts between females and the resultant costs to reproductive success in cooperatively breeding societies. PMID- 23677349 TI - Infection deflection: hosts control parasite location with behaviour to improve tolerance. AB - Anti-parasite behaviour can reduce parasitic infections, but little is known about how such behaviours affect infection location within the host's body and whether parasite distribution ultimately affects tolerance of infection. To assess these questions, we exposed both anaesthetized (no behaviour) and non anaesthetized Hyla femoralis tadpoles to plagiorchiid cercariae (larval trematodes), and quantified resistance, tolerance (relationship between mass change and infection intensity) and encystment location. Non-anaesthetized tadpoles had significantly more infections in their tail region than anaesthetized tadpoles, which had the majority of their infections in the head. This pattern indicates that parasites preferred to infect the head, but that hosts shunted infections to the tail when possible. Furthermore, there was a significant effect of encystment location on tolerance, with head-infected tadpoles having poorer tolerance to infection than tail-infected tadpoles. Variance partitioning suggests that, among infected tadpoles, behaviour contributed more to tolerance than resistance. These results suggest that, in addition to using behaviour to resist parasites, H. femoralis tadpoles also use behaviour to enhance infection tolerance by deflecting infections posteriorly, away from their vital sensory organs. These findings highlight the need to assess how widespread and important behaviour is to the tolerance of infections. PMID- 23677350 TI - Grizzly bear predation links the loss of native trout to the demography of migratory elk in Yellowstone. AB - The loss of aquatic subsidies such as spawning salmonids is known to threaten a number of terrestrial predators, but the effects on alternative prey species are poorly understood. At the heart of the Greater Yellowstone ecosystem, an invasion of lake trout has driven a dramatic decline of native cutthroat trout that migrate up the shallow tributaries of Yellowstone Lake to spawn each spring. We explore whether this decline has amplified the effect of a generalist consumer, the grizzly bear, on populations of migratory elk that summer inside Yellowstone National Park (YNP). Recent studies of bear diets and elk populations indicate that the decline in cutthroat trout has contributed to increased predation by grizzly bears on the calves of migratory elk. Additionally, a demographic model that incorporates the increase in predation suggests that the magnitude of this diet shift has been sufficient to reduce elk calf recruitment (4-16%) and population growth (2-11%). The disruption of this aquatic-terrestrial linkage could permanently alter native species interactions in YNP. Although many recent ecological changes in YNP have been attributed to the recovery of large carnivores--particularly wolves--our work highlights a growing role of human impacts on the foraging behaviour of grizzly bears. PMID- 23677351 TI - Does seed mass drive the differences in relative growth rate between growth forms? AB - The idea that herbaceous plants have higher relative growth rates (RGRs) compared with woody plants is fundamental to many of the most influential theories in plant ecology. This difference in growth rate is thought to reflect systematic variation in physiology, allocation and leaf construction. Previous studies documenting this effect have, however, ignored differences in seed mass. As woody species often have larger seeds and RGR is negatively correlated with seed mass, it is entirely possible the lower RGRs observed in woody species is a consequence of having larger seeds rather than different growth strategies. Using a synthesis of the published literature, we explored the relationship between RGR and growth form, accounting for the effects of seed mass and study-specific effects (e.g. duration of study and pot volume), using a mixed-effects model. The model showed that herbaceous species do indeed have higher RGRs than woody species, and that the difference was independent of seed mass, thus at all seed masses, herbaceous species on average grow faster than woody ones. PMID- 23677352 TI - Adverse local tissue reaction arising from corrosion at the femoral neck-body junction in a dual-taper stem with a cobalt-chromium modular neck. AB - BACKGROUND: Femoral stems with dual-taper modularity were introduced to allow additional options for hip-center restoration independent of femoral fixation in total hip arthroplasty. Despite the increasing availability and use of these femoral stems, concerns exist about potential complications arising from the modular neck-body junction. METHODS: This was a multicenter retrospective case series of twelve hips (eleven patients) with adverse local tissue reactions secondary to corrosion at the modular neck-body junction. The cohort included eight women and three men who together had an average age of 60.1 years (range, forty-three to seventy-seven years); all hips were implanted with a titanium alloy stem and cobalt-chromium-alloy neck. Patients presented with new-onset and increasing pain at a mean of 7.9 months (range, five to thirteen months) following total hip arthroplasty. After serum metal-ion studies and metal artifact reduction sequence (MARS) magnetic resonance imaging (MRI) revealed abnormal results, the patients underwent hip revision at a mean of 15.2 months (range, ten to twenty-three months). Tissue specimens were examined by a single histopathologist, and the retrieved implants were studied with use of light and scanning electron microscopy. RESULTS: Serum metal levels demonstrated greater elevation of cobalt (mean, 6.0 ng/mL) than chromium (mean, 0.6 ng/mL) or titanium (mean, 3.4 ng/mL). MRI with use of MARS demonstrated adverse tissue reactions in eight of nine patients in which it was performed. All hips showed large soft tissue masses and surrounding tissue damage with visible corrosion at the modular femoral neck-body junction. Available histology demonstrated large areas of tissue necrosis in seven of ten cases, while remaining viable capsular tissue showed a dense lymphocytic infiltrate. Microscopic analysis was consistent with fretting and crevice corrosion at the modular neck-body interface. CONCLUSIONS: Corrosion at the modular neck-body junction in dual-tapered stems with a modular cobalt-chromium-alloy femoral neck can lead to release of metal ions and debris resulting in local soft-tissue destruction. Adverse local tissue reaction should be considered as a potential cause for new-onset pain in patients with these components, and early revision should be considered given the potentially destructive nature of these reactions. A workup including serologic studies (erythrocyte sedimentation rate and C-reactive protein), serum metal levels, and MARS MRI can be helpful in establishing this diagnosis. PMID- 23677353 TI - The effect of recombinant human bone morphogenetic protein-2 in single-level posterior lumbar interbody arthrodesis. AB - BACKGROUND: In this prospective, randomized controlled trial, our objective was to assess both the clinical and radiographic effect of recombinant human bone morphogenetic protein-2 (rhBMP-2) in patients treated with an instrumented single level posterior lumbar interbody arthrodesis with polyetheretherketone cages. METHODS: Forty patients were randomized with a 1:1 ratio. Two patients who had a two-level arthrodesis (L4-L5 and L5-S1) were excluded. Patients completed the Oswestry Disability Index, the Short Form-36, and the visual analog scale preoperatively and postoperatively at three, six, twelve, and twenty-four months. Computed tomography scans with coronal and sagittal reconstructions were made at three, six, and twelve months postoperatively. Interbody arthrodesis was performed using polyetheretherketone cages, which were filled with 8 mg of rhBMP 2 in the study group and 2.5 mL of autologous bone in the control group. RESULTS: Baseline demographic data showed no significant difference between groups, except for the body mass index, which was higher in the study group (p = 0.032). There were no significant differences in the clinical results (visual analog scale, Oswestry Disability Index, and Short Form-36) between the groups at each postoperative visit. At three months, end-plate resorption was noted around the cages filled with rhBMP-2 in all patients in the study group. No cage migration or subsidence was observed. Bridging trabecular bone scale scores and bone density measures were significantly lower in the study group. Osteolysis and ectopic bone formation occurred in seven of nineteen patients in the study group and did not occur in the control group. This did not result in radicular symptoms within the time span of this study. At one year, computed tomography scans showed osseous healing in all patients. There were no revision procedures. CONCLUSIONS: This trial showed no clinical difference when rhBMP-2 was used in posterior lumbar interbody arthrodesis compared with autologous bone. On computed tomography scans, fusion was equally achieved, but trabecular bone formation occurred at a slower rate and interbody bone density was lower within the first year after surgery when rhBMP-2 was used. End-plate resorption, osteolysis, and ectopic bone formation were frequently noted in the rhBMP-2 group. PMID- 23677354 TI - Ulnar collateral ligament injuries of the thumb: phalangeal translation during valgus stress in human cadavera. AB - BACKGROUND: The clinical diagnosis of thumb ulnar collateral ligament disruption has been based on joint angulation during valgus stress testing. This report describes a definitive method of distinguishing between complete and partial ulnar collateral ligament injuries by quantifying translation of the proximal phalanx on the metacarpal head during valgus stress testing. METHODS: Sixty-two cadaveric thumbs underwent standardized valgus stress testing under fluoroscopy with the ulnar collateral ligament intact, following an isolated release of the proper ulnar collateral ligament, and following a combined release of both the proper and the accessory ulnar collateral ligament (complete ulnar collateral ligament release). Following complete ulnar collateral ligament release, the final thirty-seven thumbs were also analyzed after the application of a valgus force sufficient to cause 45 degrees of valgus angulation at the metacarpophalangeal joint to model more severe soft-tissue injury. Two independent reviewers measured coronal plane joint angulation (in degrees), ulnar joint line gap formation (in millimeters), and radial translation of the proximal phalanx on the metacarpal head (in millimeters) on digital fluoroscopic images that had been randomized. RESULTS: Coronal angulation across the stressed metacarpophalangeal joint progressively increased through the stages of the testing protocol: ulnar collateral ligament intact (average [and standard deviation], 20 degrees +/- 8.1 degrees ), release of the proper ulnar collateral ligament (average, 23 degrees +/- 8.3 degrees ), and complete ulnar collateral ligament release (average, 30 degrees +/- 8.9 degrees ) (p < 0.01 for each comparison). Similarly, gap formation increased from the measurement in the intact state (5.1 +/- 1.3 mm), to that following proper ulnar collateral ligament release (5.7 +/- 1.5 mm), to that following complete ulnar collateral ligament release (7.2 +/- 1.5 mm) (p < 0.01 for each comparison). Radial translation of the proximal phalanx on the metacarpal head did not increase after isolated release of the proper ulnar collateral ligament (1.6 +/- 0.8 mm vs. 1.5 +/- 0.9 mm in the intact state). There was a significant increase in translation following release of the complete ulnar collateral ligament complex (3.0 +/- 0.9 mm; p < 0.01) and an additional increase after forcible angulation of the joint to 45 degrees (4.1 +/- 0.9 mm; p < 0.01). Translation 2 mm greater than that in the stressed control was 100% specific for complete disruption of the ulnar collateral ligament complex. CONCLUSIONS: While transection of the proper ulnar collateral ligament leads to an increase in metacarpophalangeal joint angulation and gapping on stress fluoroscopic evaluation, only release of both the accessory and the proper ulnar collateral ligament significantly increases translation of the proximal phalanx on the metacarpal head. PMID- 23677355 TI - Comparison of functional outcomes following bridge synostosis with non-bone bridging transtibial combat-related amputations. AB - BACKGROUND: The prevalence of penetrating wartime trauma to the extremities has increased in recent military conflicts. Substantial controversy remains in the orthopaedic and prosthetic literature regarding which surgical technique should be performed to obtain the most functional transtibial amputation. We compared self-reported functional outcomes associated with two surgical techniques for transtibial amputation: bridge synostosis (modified Ertl) and non-bone-bridging (modified Burgess). METHODS: A review of the prospective military amputee database was performed to identify patients who had undergone transtibial amputation between June 2003 and December 2010 at three military institutions receiving the majority of casualties from the most recent military conflicts; two of those institutions, Walter Reed Army Medical Center and National Naval Medical Center, have since been consolidated. Short Form-36, Prosthesis Evaluation Questionnaire, and functional data questions were completed by twenty-seven modified Ertl and thirty-eight modified Burgess isolated transtibial amputees. RESULTS: The average duration of follow-up after amputation (and standard deviation) was 32 +/- 22.7 months, which was similar between groups. Residual limb length was significantly longer in the modified Ertl cohort by 2.5 cm (p < 0.005), and significantly more modified Ertl patients had delayed amputations (p < 0.005). There were no significant differences between groups with regard to any of the Short Form-36 domains or Prosthesis Evaluation Questionnaire subsections. CONCLUSIONS: The modified Ertl and Burgess techniques offer similar functional outcomes in the young, active-duty military population managed with transtibial amputation. PMID- 23677356 TI - Magnetic resonance imaging findings in symptomatic versus asymptomatic subjects following metal-on-metal hip resurfacing arthroplasty. AB - BACKGROUND: Although pseudotumors have been reported at the sites of well functioning and painful metal-on-metal hip prostheses, there are no objective data on the magnitude of the adverse reaction. This observational study was performed to investigate the ability of modified magnetic resonance imaging (MRI) to detect and quantify adverse synovial responses in symptomatic and asymptomatic subjects following metal-on-metal hip resurfacing. We hypothesized that the magnitude of the synovial reactions would be greater in symptomatic patients. METHODS: Sixty-nine patients (seventy-four hips) with hip resurfacing were divided into three groups: asymptomatic (twenty-two hips), symptomatic with a mechanical cause (twenty), and unexplained pain (thirty-two). The volume of synovitis was calculated on MRI for all patients. RESULTS: Synovitis was detected in fifteen asymptomatic hips (68%), fifteen (75%) with symptoms with a mechanical causes, and twenty-five (78%) with unexplained pain. The mean volume (and standard deviation) of the synovitis in these groups was 5 +/- 7 cm3, 10 +/- 16 cm3, and 31 +/- 47 cm3, respectively. The coefficient of repeatability between the examiners was 1.8 cm3 for measurement of synovitis. Of the thirteen subjects with revision arthroplasty, six had an adverse local tissue reaction. This subgroup had the highest volumes of synovitis on MRI. CONCLUSIONS: An adverse synovial reaction was detected on MRI in both symptomatic and asymptomatic subjects. We found a larger volume of synovitis in symptomatic patients; this increase reached significance only in the group with an adverse local tissue reaction. Synovial volume on MRI may be a valuable marker in the longitudinal assessment of asymptomatic patients with a metal-on-metal hip resurfacing and in identifying patients with adverse local tissue reaction. PMID- 23677357 TI - Modern unicompartmental knee arthroplasty with cement: a concise follow-up, at a mean of twenty years, of a previous report. AB - We previously evaluated the three to ten-year results of 160 consecutive unicompartmental knee arthroplasties that had been performed by two surgeons in 147 patients with use of the cemented metal-backed Miller-Galante prosthesis. The average age of the patients at the time of the index procedure was sixty-six years. The purpose of the present study was to report the updated results of this series after a mean duration of follow-up of twenty years. Sixty-two patients (seventy knees) were living, and seven had been lost to follow-up. Eleven knees had undergone conversion to total knee arthroplasty, three had had an addition of a patellofemoral prosthesis, and five had had polyethylene exchange. Ten knees had had revision since the three to ten-year evaluation. The reasons for revision included progression of osteoarthritis in twelve knees, aseptic loosening (which had been absent at the three to ten-year evaluation) in two knees, and polyethylene wear (which was treated with liner exchange at an average of twelve years) in five knees. The average clinical and functional Knee Society scores were 91 and 88 points, respectively, at the time of the latest follow-up. The average flexion was 127 degrees (range, 80 degrees to 145 degrees ). We concluded that modern cemented metal-backed unicompartmental implants, evaluated at a mean of twenty years of follow-up in patients with osteoarthritis that was limited to one tibiofemoral compartment of the knee, provided durable pain relief and long-term restoration of knee function without compromising future conversion to conventional total knee arthroplasty. PMID- 23677358 TI - Comparison of functional outcomes of reverse shoulder arthroplasty with those of hemiarthroplasty in the treatment of cuff-tear arthropathy: a matched-pair analysis. AB - BACKGROUND: Rotator cuff-tear arthropathy has traditionally represented a challenge to the shoulder arthroplasty surgeon. The poor results of conventional total shoulder arthroplasty in rotator-cuff-deficient shoulders due to glenoid component loosening have led to hemiarthroplasty being the traditional preferred surgical option. Recently, reverse total shoulder arthroplasty has gained increasing popularity because of a clinical perception of an improved functional outcome, despite the lack of comparative data. The aim of this study was to compare the early functional results of hemiarthroplasty with those of reverse shoulder arthroplasty in the management of cuff-tear arthropathy. METHODS: The results of 102 primary hemiarthroplasties for rotator cuff-tear arthropathy were compared with those of 102 reverse shoulder arthroplasties performed for the same diagnosis. Patients were identified from the New Zealand Joint Registry and matched for age, sex, and American Society of Anesthesiologists (ASA) scores. Oxford Shoulder Scores (OSS) collected at six months postoperatively as well as mortality and revision rates were compared between the two groups. RESULTS: There were fifty-one men and fifty-one women in each group, with a mean age of 71.6 years in the hemiarthroplasty group and 72.6 years in the reverse shoulder arthroplasty group. The mean OSS at six months was 31.1 in the hemiarthroplasty group and 37.5 in the reverse shoulder arthroplasty group. At the time of follow up, there were nine revisions in the hemiarthroplasty group and five in the reverse shoulder arthroplasty group. No difference in mortality rate was seen between the two groups. CONCLUSIONS: In this unselected population with rotator cuff-tear arthropathy, controlled for age, sex, and ASA score, reverse shoulder arthroplasty resulted in a functional outcome that was superior to that of hemiarthroplasty. Longer-term follow-up is needed to confirm these findings. PMID- 23677359 TI - Prospective comparison of 1.5 and 3.0-T MRI for evaluating the knee menisci and ACL. AB - BACKGROUND: MRI (magnetic resonance imaging) is widely used to diagnose meniscal pathology and ACL (anterior cruciate ligament) tears. Because of the enhanced signal-to-noise ratio and improved image quality at higher field strength, knee MRI equipment is shifting from 1.5 to 3.0 T. To date, objective evidence of improved diagnostic ability at 3.0 T is lacking. The purpose of this prospective study was to assess the accuracy of 1.5 and 3.0-T MRI of the knee, in the same individuals, for diagnosing meniscal pathology and ACL tears, utilizing arthroscopy as the reference standard. METHODS: Two hundred patients underwent MRI of the knee at 1.5 and 3.0 T. All MRI examinations consisted of multiplanar turbo spin-echo sequences. One hundred patients underwent subsequent knee arthroscopy. Two blinded independent radiologists assessed all MRI studies to identify meniscal pathology and ACL tears. In patients with MRI results indicating the need for surgical treatment, the sensitivity and specificity of the 1.5 and 3.0-T protocols for detecting these lesions were determined, utilizing arthroscopy as the reference standard, and compared with use of the McNemar test. The kappa statistic for inter-reader agreement in the 200 patients was calculated. RESULTS: For medial meniscal tears, the mean sensitivity and specificity for the two readers were 93% and 90%, respectively, at 1.5 T and 96% and 88%, respectively, at 3.0 T. For lateral meniscal tears, the mean sensitivity and specificity were 77% and 99%, respectively, at 1.5 T and 82% and 98%, respectively, at 3.0 T. For ACL tears, the mean sensitivity and specificity were 78% and 100%, respectively, at 1.5 T and 80% and 100%, respectively, at 3.0 T. None of the values for either reader differed significantly between the 1.5 and 3.0-T MRI protocols. Inter-reader agreement was almost perfect to perfect (kappa = 0.82 to 1.00). CONCLUSIONS: Routine use of a 3.0-T MRI protocol did not significantly improve accuracy for evaluating the knee menisci and ACL compared with a similar 1.5-T protocol. PMID- 23677360 TI - The effect of immobilization on the native and repaired tendon-to-bone interface. AB - BACKGROUND: Little is known of the cellular events that occur in native or repaired tendons as a result of immobilization after injury. To examine this issue, we compared (1) native tendons without immobilization, (2) native tendons with immobilization, and (3) surgically repaired tendons with immobilization. METHODS: Eighty-one rats underwent either patellar tendon repair followed by immobilization or immobilization of the native tendon without repair. A custom external fixation device was used for immobilization. The tendon-bone insertion site was evaluated after two and four weeks of immobilization with use of histologic, radiographic, and biomechanical analyses. RESULTS: Immobilization of the native tendon led to a significant decrease in the load to failure (p < 0.01) and stiffness (p < 0.05) compared with the native tendon at both two and four weeks. The repaired/immobilized group had a significantly lower load to failure at two weeks compared with the native/immobilized group (p < 0.05); however, by four weeks, the repaired group was significantly stronger (p < 0.01). Micro computerized tomography demonstrated no significant differences in bone microstructure at two weeks but demonstrated increased bone mineral density and bone volume fraction in the repaired/immobilized group at four weeks. There was significantly more MMP-13 (matrix metalloproteinase-13) staining in the native/immobilized specimens compared with the native specimens at both time points (p < 0.01). CONCLUSIONS: Immobilization had a significant detrimental effect on the bone-tendon complex. At two weeks there was a significant decrease in the mechanical properties of the native tendon, but the immobilized, native tendon remained significantly stronger than the repaired and immobilized tendon. However, four weeks of immobilization led to a significant loss of strength of the bone-tendon complex in the native tendon, such that it was significantly weaker than the repaired and immobilized tendon. Surgeons who manage patients with immobilization should be aware of the changes at the bone-tendon complex. PMID- 23677361 TI - Multilevel surgery for equinus gait in children with spastic diplegic cerebral palsy: medium-term follow-up with gait analysis. AB - BACKGROUND: In children with spastic diplegia, surgery for ankle equinus contracture is associated with a high prevalence of both overcorrection, which may result in a calcaneal deformity and crouch gait, and recurrent equinus contracture, which may require revision surgery. We sought to determine if conservative surgery for equinus gait, in the context of multilevel surgery, could result in the avoidance of overcorrection and crouch gait as well as an acceptable rate of recurrent equinus contracture at the time of medium-term follow-up. METHODS: This was a retrospective, consecutive cohort study of children with spastic diplegia who had had surgery for equinus gait between 1996 and 2006. All children had distal gastrocnemius recession or differential gastrocnemius-soleus complex lengthening, on one or both sides, as part of single event multilevel surgery. The primary outcome measures were the Gait Variable Scores (GVS) and Gait Profile Score (GPS) at two time points after surgery. RESULTS: Forty children with spastic diplegia, Gross Motor Function Classification System (GMFCS) level II or III, were included in this study. There were twenty-five boys and fifteen girls. The mean age was ten years at the time of surgery and seventeen years at the time of final follow-up. The mean postoperative follow-up period was 7.5 years. The mean ankle GVS improved from 18.5 degrees before surgery to 8.7 degrees at the time of short-term follow-up (p < 0.005) and 7.8 degrees at the time of medium-term follow-up. The equinus gait was successfully corrected in the majority of children, with a low rate of overcorrection (2.5%) and a high rate of recurrent equinus (35%), as determined by sagittal ankle kinematics. Mild recurrent equinus was usually well tolerated and conferred some advantages, including contributing to strong coupling at the knee and independence from using an ankle-foot orthosis. CONCLUSIONS: Surgical treatment for equinus gait in children with spastic diplegia was successful, at a mean of seven years, in the majority of cases when combined with multilevel surgery, orthoses, and rehabilitation. No patient developed crouch gait, and the rate of revision surgery for recurrent equinus was 12.5%. PMID- 23677362 TI - Intra-articular infusion with bupivacaine decreased pain and opioid consumption after total knee arthroplasty. PMID- 23677363 TI - Hemiarthroplasty did not confer any benefit in older patients with four-part humeral fractures. PMID- 23677364 TI - Platelet-rich plasma added to the patellar tendon harvest site during anterior cruciate ligament reconstruction enhanced healing. PMID- 23677365 TI - What's new in foot and ankle surgery. AB - This update summarizes recent research pertaining to orthopaedic foot and ankle surgery that was published or presented between August 2011 and July 2012. The sources of these studies include The Journal of Bone and Joint Surgery (American and British Volumes); Foot and Ankle International; and the proceedings of Specialty Day at the annual meeting of the American Academy of Orthopaedic Surgeons (AAOS), on February 11, 2012, in San Francisco, California, and the summer meeting of the American Orthopaedic Foot & Ankle Society (AOFAS), on June 20 through 23, 2012, in San Diego, California. PMID- 23677366 TI - Do oblique views add value in the diagnosis of spondylolysis in adolescents? AB - BACKGROUND: Anteroposterior, lateral, and right and left oblique lumbar spine radiographs are often a standard part of the evaluation of children who are clinically suspected of having spondylolysis. Recent concerns regarding radiation exposure and costs have brought the value of oblique radiographs into question. The purpose of the present study was to determine the diagnostic value of oblique views in the diagnosis of spondylolysis. METHODS: Radiographs of fifty adolescents with L5 spondylolysis without spondylolisthesis and fifty controls were retrospectively reviewed. All controls were confirmed not to have spondylolysis on the basis of computed tomographic scanning, magnetic resonance imaging, or bone scanning. Anteroposterior, lateral, and right and left oblique radiographs of the lumbar spine were arranged into two sets of slides: one showing four views (anteroposterior, lateral, right oblique, and left oblique) and one showing two views (anteroposterior and lateral only). The slides were randomly presented to four pediatric spine surgeons for diagnosis, with four-view slides being presented first, followed by two-view slides. The slides for twenty random patients were later reanalyzed in order to calculate of intra-rater agreement. A power analysis demonstrated that this study was adequately powered. Inter-rater and intra-rater agreement were assessed on the basis of the percentage of overall agreement and intraclass correlation coefficients (ICCs). PCXMC software was used to generate effective radiation doses. Study charges were determined from radiology billing data. RESULTS: There was no significant difference in sensitivity and specificity between four-view and two-view radiographs in the diagnosis of spondylolysis. The sensitivity was 0.59 for two view studies and 0.53 for four-view studies (p = 0.33). The specificity was 0.96 for two-view studies and 0.94 for four-view studies (p = 0.60). Inter-rater agreement, intra-rater agreement, and agreement with gold-standard ICC values were in the moderate range and also demonstrated no significant differences. Percent overall agreement was 78% for four-view studies and 82% for two-view studies. The radiation effective dose was 1.26 mSv for four-view studies and 0.72 mSv for two-view studies (difference, 0.54 mSv). The charge for four-view studies was $145 more than that for two-view studies. CONCLUSIONS: There is no difference in sensitivity and specificity between four-view and two-view studies. Although oblique views have long been considered standard practice by some, our data could not identify a diagnostic benefit that might outweigh the additional cost and radiation exposure. PMID- 23677367 TI - Heterotopic ossification after surgery for fractures and fracture-dislocations involving the proximal aspect of the radius or ulna. AB - BACKGROUND: The objectives of this study were to (1) determine the prevalence of heterotopic ossification after surgery for fractures and fracture-dislocations involving the proximal aspect of the radius or ulna, (2) identify risk factors associated with the development of heterotopic ossification in these injuries, and (3) characterize the severity and location of the heterotopic ossification and the associated range of elbow motion. METHODS: From 2004 to 2008, 142 elbow fractures and fracture-dislocations involving the proximal aspect of the radius or ulna were treated surgically at our institution. Records and radiographs of 130 elbows with adequate follow-up were retrospectively reviewed to identify cases of heterotopic ossification, characterize the ectopic bone, and analyze associated risk factors. The most frequent injuries included olecranon fractures, Monteggia fracture-dislocations, and various combinations of fractures of the radial head and coronoid with or without dislocation or subluxation. RESULTS: Heterotopic bone was identified on the radiographs of forty-eight elbows (37%). Heterotopic ossification interfered with motion in twenty-six elbows (20%), and thirteen elbows (10%) underwent additional surgery to remove heterotopic bone with the goal of improving motion. Risk factors associated with the development of heterotopic ossification included elbow subluxation or dislocation at the time of presentation, an open fracture, a severe chest injury, and a delay in definitive surgical treatment. Ectopic bone was preferentially located at the origin of torn soft-tissue structures or around fracture sites, and it was particularly common around the posterior aspect of the ulna and the neck of the radius. Heterotopic ossification was classified on radiographs as hazy immature in twenty-two elbows, limited mature in eighteen, extensive mature in five, and a complete bone bridge in three. Heterotopic ossification was more common in patients with an associated distal humeral fracture, radial head and coronoid fractures with an associated elbow dislocation (terrible triad injury), and a transolecranon fracture-dislocation. CONCLUSIONS: Thirty-seven percent of elbows treated surgically for fractures involving the proximal aspect of the radius and/or ulna developed heterotopic ossification. In twenty percent of elbows, heterotopic ossification was associated with clinically relevant motion deficits. More severe heterotopic ossification was encountered in patients presenting with an associated distal humeral fracture, terrible triad injury, transolecranon fracture-dislocation, or Monteggia fracture-dislocation. Patients with an open injury, instability, severe chest trauma, or delay in definitive surgical treatment had a higher prevalence of heterotopic ossification. PMID- 23677368 TI - Evaluating the extent of clinical uncertainty among treatment options for patients with early-onset scoliosis. AB - BACKGROUND: Literature guiding the management of early-onset scoliosis consists primarily of studies with a low level of evidence. Evaluation of clinical equipoise (i.e., when there is no known superiority among treatment modalities) allows for prioritization of research efforts. The objective of this study was to evaluate areas of clinical uncertainty among pediatric spine surgeons regarding the treatment of early-onset scoliosis. METHODS: Fourteen experienced pediatric spine surgeons participated in semistructured interviews to identify clinical variables that influence decision making in the treatment of early-onset scoliosis. A series of case scenarios of 315 patients with idiopathic and neuromuscular early-onset scoliosis was then developed to be representative of those encountered in clinical practice. Using an online survey, eleven surgeons selected their choice of eight treatment options for each case scenario. Associations between case characteristics and treatment choices were assessed with chi-square and logistic regression analysis. Participants then reviewed the areas of treatment uncertainty identified in the survey, nominated additional research questions of interest, and ranked their interest to further explore the identified research questions. RESULTS: Collective equipoise was identified in numerous scenarios in the survey spanning a range of ages and magnitudes of scoliosis, and additional questions were identified during the nominal group technique. Areas that had the greatest clinical uncertainty included the management of patients who have finished treatment with a growing-rod, timing of rod-lengthening intervals, and indications for spine-based and rib-based proximal instrumentation anchors. The use of rib anchors compared with spine-based anchors was ranked highly for consideration in future clinical trials. CONCLUSIONS: Variability in decision making with regard to the optimum treatment of certain subsets of patients with early-onset scoliosis reflects gaps in the available evidence. Structured consensus methods identified priorities for higher levels of research in this area of scoliosis. Higher-level studies, including randomized trials, should focus on answering the questions highlighted in this report. PMID- 23677369 TI - Magnetic resonance imaging of the hand and wrist: techniques and spectrum of disease: AAOS exhibit selection. PMID- 23677370 TI - Patient satisfaction: Implications and predictors of success. AB - Patient satisfaction is an individual's cognitive evaluation of, and emotional reaction to, his or her health-care experience. This concept is increasing in importance as survey data are being used by health-care facilities for self assessment, accreditation requirements, and compensation formulas. High patient satisfaction is associated with increased market share, financial gains, decreased malpractice claims, and improved reimbursement rates. Modifiable factors that contribute to satisfaction include physician-patient communication, the setting of appropriate expectations, minimization of waiting times, and provision of continuity of care. There are also factors that are less amenable to change, including chronic illness, opioid dependence, and sociodemographic status. Satisfaction with a surgical outcome differs from satisfaction with an office visit. Accurate expectations and patient-reported outcome measures are important determinants of satisfaction after a surgical procedure. Physicians can improve patient satisfaction in their practice by understanding the implications of satisfaction and the predictors of success. PMID- 23677371 TI - High-fidelity simulations for orthopaedic residents: medical complications and systems challenges. PMID- 23677372 TI - That's why we call it BIOmechanics!: commentary on an article by H. John Cooper, MD, et al.: "Adverse local tissue reaction arising from corrosion at the femoral neck-body junction in a dual-taper stem with a cobalt-chromium modular neck". PMID- 23677373 TI - Recombinant human bone morphogenetic protein-2: what's a spine surgeon to do?: commentary on an article by J. Michielsen, MD, et al.: "The effect of recombinant human bone morphogenetic protein-2 in single-level posterior lumbar interbody arthrodesis". PMID- 23677374 TI - New and improved medical test costs just one cent: commentary on an article by Kathleen E. McKeon, MD, et al.: "Ulnar collateral ligament injuries of the thumb. Phalangeal translation during valgus stress in human cadavera". PMID- 23677375 TI - C1q-targeted monoclonal antibody prevents complement-dependent cytotoxicity and neuropathology in in vitro and mouse models of neuromyelitis optica. AB - Neuromyelitis optica (NMO) is an autoimmune disorder with inflammatory demyelinating lesions in the central nervous system, particularly in the spinal cord and optic nerve. NMO pathogenesis is thought to involve binding of anti aquaporin-4 (AQP4) autoantibodies to astrocytes, which causes complement dependent cytotoxicity (CDC) and downstream inflammation leading to oligodendrocyte and neuronal injury. Vasculocentric deposition of activated complement is a prominent feature of NMO pathology. Here, we show that a neutralizing monoclonal antibody against the C1q protein in the classical complement pathway prevents AQP4 autoantibody-dependent CDC in cell cultures and NMO lesions in ex vivo spinal cord slice cultures and in mice. A monoclonal antibody against human C1q with 11 nM binding affinity prevented CDC caused by NMO patient serum in AQP4-transfected cells and primary astrocyte cultures, and prevented complement-dependent cell-mediated cytotoxicity (CDCC) produced by natural killer cells. The anti-C1q antibody prevented astrocyte damage and demyelination in mouse spinal cord slice cultures exposed to AQP4 autoantibody and human complement. In a mouse model of NMO produced by intracerebral injection of AQP4 autoantibody and human complement, the inflammatory demyelinating lesions were greatly reduced by intracerebral administration of the anti-C1q antibody. These results provide proof-of-concept for C1q-targeted monoclonal antibody therapy in NMO. Targeting of C1q inhibits the classical complement pathway directly and causes secondary inhibition of CDCC and the alternative complement pathway. As C1q-targeted therapy leaves the lectin complement activation pathway largely intact, its side-effect profile is predicted to differ from that of therapies targeting downstream complement proteins. PMID- 23677376 TI - Phenotypic characterization and in vivo localization of human adipose-derived mesenchymal stem cells. AB - Human adipose-derived mesenchymal stem cells (hADMSCs) are a potential cell source for autologous cell therapy due to their regenerative ability. However, detailed cytological or phenotypic characteristics of these cells are still unclear. Therefore, we determined and compared cell size, morphology, ultrastructure, and immunohistochemical (IHC) expression profiles of isolated hADMSCs and cells located in human adipose tissues. We also characterized the localization of these cells in vivo. Light microscopy examination at low power revealed that hADMSCs acquired a spindle-shaped morphology after four passages. Additionally, high power views showed that these cells had various sizes, nuclear contours, and cytoplasmic textures. To further evaluate cell morphology, transmission electron microscopy was performed. hADMSCs typically had ultrastructural characteristics similar to those of primitive mesenchymal cells including a relatively high nuclear/cytosol ratio, prominent nucleoli, immature cytoplasmic organelles, and numerous filipodia. Some cells contained various numbers of lamellar bodies and lipid droplets. IHC staining demonstrated that PDGFR and CD10 were constitutively expressed in most hADMSCs regardless of passage number but expression levels of alpha-SMA, CD68, Oct4 and c-kit varied. IHC staining of adipose tissue showed that cells with immunophenotypic characteristics identical to those of hADMSCs were located mainly in the perivascular adventitia not in smooth muscle area. In summary, hADMSCs were found to represent a heterogeneous cell population with primitive mesenchymal cells that were mainly found in the perivascular adventitia. Furthermore, the cell surface markers would be CD10/PDGFR. To obtain defined cell populations for therapeutic purposes, further studies will be required to establish more specific isolation methods. PMID- 23677377 TI - Decreased mitochondrial OGG1 expression is linked to mitochondrial defects and delayed hepatoma cell growth. AB - Many solid tumor cells exhibit mitochondrial respiratory impairment; however, the mechanisms of such impairment in cancer development remain unclear. Here, we demonstrate that SNU human hepatoma cells with declined mitochondrial respiratory activity showed decreased expression of mitochondrial 8-oxoguanine DNA glycosylase/lyase (mtOGG1), a mitochondrial DNA repair enzyme; similar results were obtained with human hepatocellular carcinoma tissues. Among several OGG1-2 variants with a mitochondrial-targeting sequence (OGG1-2a, -2b, -2c, -2d, and 2e), OGG1-2a was the major mitochondrial isoform in all examined hepatoma cells. Interestingly, hepatoma cells with low mtOGG1 levels showed delayed cell growth and increased intracellular reactive oxygen species (ROS) levels. Knockdown of OGG1-2 isoforms in Chang-L cells, which have active mitochondrial respiration with high mtOGG1 levels, significantly decreased cellular respiration and cell growth, and increased intracellular ROS. Overexpression of OGG1-2a in SNU423 cells, which have low mtOGG1 levels, effectively recovered cellular respiration and cell growth activities, and decreased intracellular ROS. Taken together, our results suggest that mtOGG1 plays an important role in maintaining mitochondrial respiration, thereby contributing to cell growth of hepatoma cells. PMID- 23677378 TI - Comparative proteomic analysis of cysteine oxidation in colorectal cancer patients. AB - Oxidative stress promotes damage to cellular proteins, lipids, membranes and DNA, and plays a key role in the development of cancer. Reactive oxygen species disrupt redox homeostasis and promote tumor formation by initiating aberrant activation of signaling pathways that lead to tumorigenesis. We used shotgun proteomics to identify proteins containing oxidation-sensitive cysteines in tissue specimens from colorectal cancer patients. We then compared the patterns of cysteine oxidation in the membrane fractions between the tumor and non-tumor tissues. Using nano-UPLC-MS(E) proteomics, we identified 31 proteins containing 37 oxidation-sensitive cysteines. These proteins were observed with IAM-binding cysteines in non-tumoral region more than tumoral region of CRC patients. Then using the Ingenuity pathway program, we evaluated the cellular canonical networks connecting those proteins. Within the networks, proteins with multiple connections were related with organ morphology, cellular metabolism, and various disorders. We have thus identified networks of proteins whose redox status is altered by oxidative stress, perhaps leading to changes in cellular functionality that promotes tumorigenesis. PMID- 23677379 TI - The role of lysyl oxidase-like 2 in the odontogenic differentiation of human dental pulp stem cells. AB - Adult human dental pulp stem cells (hDPSCs) are a unique population of precursor cells those are isolated from postnatal dental pulp and have the ability to differentiate into a variety of cell types utilized for the formation of a reparative dentin-like complex. Using LC-MS/MS proteomics approaches, we identified the proteins secreted from the differentiating hDPSCs in mineralization media. Lysyl oxidase-like 2 (LOXL2) was identified as a protein that was down-regulated in the hDPSCs that differentiate into odontoblast-like cells. The role of LOXL2 has not been studied in dental pulp stem cells. LOXL2 mRNA levels were reduced in differentiating hDPSCs, whereas the levels of other LOX family members including LOX, LOXL1, LOXL3, and LOXL4, are increased. The protein expression and secretion levels of LOXL2 were also decreased during odontogenic differentiation. Recombinant LOXL2 protein treatment to hDPSCs resulted in a dose-dependent decrease in the early differentiation and the mineralization accompanying with the lower levels of odontogenic markers such as DSPP, DMP-1 and ALP. These results suggest that LOXL2 has a negative effect on the differentiation of hDPSCs and blocking LOXL2 can promote the hDPSC differentiation to odontoblasts. PMID- 23677380 TI - Combined and independent impact of diabetes mellitus and chronic kidney disease on residual platelet reactivity. AB - Patients with both chronic kidney disease (CKD) and diabetes mellitus (DM) are at increased risk for thrombotic events compared to those with one abnormality alone. Whether this can be attributed to changes in platelet reactivity among those with both CKD and DM is unknown. We prospectively studied 438 clopidogrel naive patients undergoing percutaneous coronary intervention (PCI). Platelet function tests were performed 4-6 hours after loading with 600 mg of clopidogrel. Platelet reactivity was assessed using the VerifyNow system and expressed as P2Y12 reaction units (PRU). High residual platelet reactivity (HRPR) was defined as PRU > 230. Patients were categorised into four groups by the presence or absence of CKD and DM. Among those without CKD or DM (n=166), DM alone (n=150), CKD alone (n=60) and both CKD and DM (n=62) the mean PRU levels were 201.6 +/- 96.3, 220.5 +/- 101.1, 254.9 +/- 106.7 and 275.0 +/- 94.5, respectively (p<0.001). Analogously, the prevalence of HRPR was 42.3%, 50.7%, 63.3% and 75.8%, respectively (p< 0.001). Associations between either CKD or DM alone and HRPR were attenuated after multivariable adjustment while the odds for HRPR associated with both CKD and DM remained significant (OR [95% CI]: 2.61 [1.16 - 5.86]). In conclusion, the presence of both CKD and DM confers a synergistic impact on residual platelet reactivity when compared to either condition alone. Whether more potent platelet inhibitors may improve outcomes among patients with both abnormalities warrants investigation. PMID- 23677382 TI - Preliminary findings of a telehealth approach to parent training in autism. AB - Telehealth or online communication technologies may lessen the gap between intervention requirements for children with autism spectrum disorders (ASDs) and the available resources to provide these services. This study used a video conferencing and self-guided website to provide parent training in the homes of children with ASD. The first eight families to complete the 12-week online intervention and three-month follow up period served as pilot data. Parents' intervention skills and engagement with the website, as well as children's verbal language and joint attention skills were assessed. Preliminary research suggests telehealth may support parental learning and improve child behaviors for some families. This initial assessment of new technologies for making parent training resources available to families with ASD merits further, in-depth study. PMID- 23677384 TI - Decreased expression of miR-430 promotes the development of bladder cancer via the upregulation of CXCR7. AB - MicroRNAs (miRNAs) have been demonstrated to be involved in the development of numerous types of malignant tumor. However, the role of miRNA-430 (miR-430) in bladder cancer remains unclear. In the present study, we observed that the expression of miR-430 was significantly downregulated in bladder cancer. Furthermore, the overexpression of miR-430 in human bladder cancer 5637 cells significantly inhibited cell proliferation, migration and colony formation efficiency. These findings were contrary to those obtained following the overexpression of CXCR7, which was found to be a direct target of miR-430 in this study. Further analysis showed that cell proliferation- and migration-related genes, including ERK, matrix metalloproteinase-2 (MMP-2) and MMP-9, were significantly downregulated in miR-430 overexpressed 5637 cells, while they were markedly upregulated in CXCR7 overexpressed 5637 cells. In conclusion, our study reveals important roles of miR-430 and CXCR7 in bladder cancer, and suggests that the downregulation of miR-430 enhances the development of bladder cancer, partly via the upregulation of CXCR7. PMID- 23677385 TI - Intraoperative parathyroid hormone criteria: the quest for perfection: Comment on "Factors that influence parathyroid hormone half-life". PMID- 23677386 TI - Clinically significant improved fitness and weight loss among overweight persons with serious mental illness. AB - OBJECTIVE: The objective of this study was to evaluate the effectiveness of a fitness health mentor program (In SHAPE) in improving physical fitness and weight loss among overweight and obese adults with serious mental illness. METHODS: A randomized controlled trial was conducted with 133 persons with serious mental illness and a body mass index (BMI) >25 who were assigned either to the In SHAPE program (one year of weekly sessions with a fitness trainer plus a fitness club membership) or to one year of fitness club membership and education. Assessments were conducted at baseline and three, six, nine, and 12 months later. RESULTS: Participants had a mean baseline weight of 231.8+/-54.8 pounds and a mean BMI of 37.6+/-8.2. At 12-month follow-up, In SHAPE (N=67) compared with fitness club membership and education (N=66) was associated with three times greater fitness club attendance, twice as much participation in physical exercise, greater engagement in vigorous physical activity, and improvement in diet. Twice the proportion of participants (40% versus 20%) achieved clinically significant improvement in cardiorespiratory fitness (>50 m on the six-minute walk test). Weight loss and BMI did not differ between groups. Among In SHAPE participants, 49% achieved either clinically significant increased fitness or weight loss (5% or greater), and 24% achieved both clinically significant improved fitness and weight loss. CONCLUSIONS: The In SHAPE program achieved clinically significant reduction in cardiovascular risk for almost one-half of participants at 12 months. Although the intervention showed promise in improving fitness, optimizing weight loss may require additional intensive, multicomponent dietary interventions. PMID- 23677387 TI - Differences in high on-treatment platelet reactivity between intra-coronary and peripheral blood after dual anti-platelet agents in patients with coronary artery disease. AB - The differences of high on-treatment platelet reactivity (HPR) between the coronary arteries and peripheral veins might be associated with poor prediction of adverse cardiovascular events in patients with coronary artery diseases. HPR from the peripheral blood might not adequately reflect the platelet responses in the coronary artery. A total of 21 patients were recruited, and regional differences in HPR were compared between blood samples from the intra-coronary artery (IC), femoral artery (FA), and femoral vein (FV) by light aggregometry (agonists: arachidonic acid, LTA-AA; ADP, LTA-ADP), VerifyNow P2Y12 assays, and a platelet function analyser (PFA-100, collagen and epinephrine cartridge, PFA CEPI). There were regional differences in the platelet reactivities observed by LTA-AA, VerifyNow P2Y12 assays, and PFA-CEPI. Platelets from the IC had higher platelet reactivities than those from the FV and FA by the VerifyNow P2Y12 assays but lower reactivities by LTA-AA and PFA-CEPI. HPR values from the blood in the FA were more similar to those from the IC than those from the FV by any test. The monocyte percentages were the only factors associated with differences in HPR between the FV and IC by the VerifyNow P2Y12 assays. Triglyceride levels were associated with the differences in HPR between the FV and IC by LTA-ADP. During the six-month follow-up period, two patients developed cardiovascular events and exhibited differences in HPR between different sites by VerifyNow P2Y12 assays. In conclusions, there were regional differences in HPR in patients with coronary artery diseases, which might prevent the adequate prediction of cardiovascular events. PMID- 23677388 TI - In vivo studies of aquaporins 3 and 10 in human stratum corneum. AB - Aquaporins (AQPs) constitute one family of transmembrane proteins facilitating transport of water across cell membranes. Due to their specificity, AQPs have a broad spectrum of physiological functions, and for keratinocytes there are indications that these channel proteins are involved in cell migration and proliferation with consequences for the antimicrobial defense of the skin. AQP3 and AQP10 are aqua-glyceroporins, known to transport glycerol as well as water. AQP3 is the predominant AQP in human skin and has previously been demonstrated in the basal layer of epidermis in normal human skin, but not in stratum corneum (SC). AQP10 has not previously been identified in human skin. Previous studies have demonstrated the presence of AQP3 and AQP10 mRNA in keratinocytes. In this study, our aim was to investigate if these aquaporin proteins were actually present in human SC cells. This can be seen as a first step toward elucidating the possible functional role of AQP3 and AQP10 in SC hydration. Specifically we investigate the presence of AQP3 and AQP10 in vivo in human SC using "minimal invasive" technique for obtaining SC samples. SC samples were obtained from six healthy volunteers. Western blotting and immunohistochemistry were used to demonstrate the presence of AQP3 as well as AQP10. The presence of AQP3 and AQP10 was verified by Western blotting, allowing for detection of proteins by specific antibodies. Applying immunohistochemistry, cell-like structures in the shape of corneocytes were identified in all samples by AQP3 and AQP10 antibodies. In conclusion, identification of AQP3 and AQP10 protein in SC in an in vivo model is new. Together with the new "minimal-invasive" method for SC collection presented, this opens for new possibilities to study the role of AQPs in relation to function of the skin barrier. PMID- 23677389 TI - Age-related differences in tongue-palate pressures for strength and swallowing tasks. AB - The tongue plays a key role in the generation of pressures for transporting liquids and foods through the mouth in swallowing. Recent studies suggest that there is an age-related decline in tongue strength in healthy adults. However, whether age-related changes occur in tongue pressures generated for the purpose of swallowing remains unclear. Prior literature in this regard does not clearly explore the influence of task on apparent age-related differences in tongue pressure amplitudes. Furthermore, differences attributable to variations across individuals in strength, independent of age, have not clearly been elucidated. In this study, our goal was to clarify whether older adults have reduced tongue palate pressures during maximum isometric, saliva swallowing, and water swallowing tasks, while controlling for individual variations in strength. Data were collected from 40 healthy younger adults (under age 40) and 38 healthy mature adults (over age 60). As a group, the mature participants had significantly lower maximum isometric pressures (MIPs). Swallowing pressures differed significantly by task, with higher pressures seen in saliva swallows than in water swallows. Age-group differences were not seen in swallowing pressures. Consideration of MIP as a covariate in the analysis of swallowing pressures revealed significant correlations between strength and swallowing pressures in the older participant group. Age-group differences were evident only when strength was considered in the model, suggesting that apparent age-related differences are, in fact, explained by differences in strength, which tends to be lower in healthy older adults. Our results show no evidence of independent differences in swallowing pressures attributable to age. PMID- 23677390 TI - Feasibility of pulse oximetry screening for critical congenital heart disease at 2643-foot elevation. AB - To evaluate the feasibility of implementing a pulse oximetry screening protocol at a city of mild elevation with a specific focus on the false-positive screening rate. Pulse oximetry screening was performed according to the proposed guidelines endorsed by the American Academy of Pediatrics at a center in Tucson, AZ, at an elevation of 2,643 ft (806 m). During a 10-month period in 2012, 1069 full-term asymptomatic newborns were screened >= 24 h after birth. The mean preductal oxygen saturation was 98.5 +/- 1.3 % (range 92-100 %), and the mean postductal oxygen saturation was 98.6 +/- 1.3 % (range 94-100 %). Of 1,069 patients screened, 7 were excluded secondary to protocol violations, and 1 screened positive. An echocardiogram was performed on the newborn with the positive screen, and it was normal with the exception of right-to-left shunting across a patent foramen ovale. The false-positive rate was 1/1,062 or 0.094 %. The pulse oximetry screening guidelines recommended by the American Academy of Pediatrics are feasible at an elevation of 2,643 ft (806 m) with a low false-positive rate. Adjustments to the protocol are not required for centers at elevations <= 2,643 ft. Future studies at greater elevations are warranted. PMID- 23677391 TI - Feasibility and effectiveness of three-dimensional echocardiography in diagnosing congenital heart diseases. AB - Three-dimensional echocardiography (3DE), a novel approach employed in detecting congenital heart disease (CHD), has gained popularity since it was made commercially available in 2002. This modality is now accepted as an important diagnostic tool for diagnosing CHD. Advancement in transducer technologies and digital data processing allows the use of 3DE in daily clinical practice. In this review, modes of 3DE data acquisition and storage methods in the echocardiogram's machine's hard disk (data processing) are examined. Analysis of the acquired data (cropping or slicing the data set) and methods of illustrating the cropped data set for cardiologists and pediatric cardiovascular surgeons are also discussed. Published literature was searched in PubMed using the keywords "three-dimensional echocardiography", "congenital heart disease", "cropping", and "echoangiogram". This search produced 100 articles, which were further short-listed to 30 articles. Based on this algorithm, the final selected 30 articles were extensively examined in the current review. The clinical applications of real time transthoracic 3DE, as well as novel transesophageal 3DE and color flow 3DE data set analyses (echoangiogram) in the routine practice of CHD assessment, are also reviewed. Finally, the limitations 3DE, together with the potential future developments required to improve various techniques of 3DE to make it more readily applicable, are examined. PMID- 23677392 TI - Highly rapid amplification-free and quantitative DNA imaging assay. AB - There is an urgent need for rapid and highly sensitive detection of pathogen derived DNA in a point-of-care (POC) device for diagnostics in hospitals and clinics. This device needs to work in a 'sample-in-result-out' mode with minimum number of steps so that it can be completely integrated into a cheap and simple instrument. We have developed a method that directly detects unamplified DNA, and demonstrate its sensitivity on realistically sized 5 kbp target DNA fragments of Micrococcus luteus in small sample volumes of 20 MUL. The assay consists of capturing and accumulating of target DNA on magnetic beads with specific capture oligonucleotides, hybridization of complementary fluorescently labeled detection oligonucleotides, and fluorescence imaging on a miniaturized wide-field fluorescence microscope. Our simple method delivers results in less than 20 minutes with a limit of detection (LOD) of ~5 pM and a linear detection range spanning three orders of magnitude. PMID- 23677396 TI - Spontaneous sulfur dioxide activation by Group V metal (V, Nb, Ta) atoms in excess argon at cryogenic temperatures. AB - Reactions of laser-ablated V, Nb and Ta atoms with SO2 in excess argon during condensation gave new absorptions in the M=O stretching region, which were assigned to metal sulfide oxides SMO2 and anions SMO2(-) (M = V, Nb, Ta). The metal oxide complex OV(eta(2)-SO) was also identified through the V=O and the characteristic side-on coordinated S-O stretching modes. The assignments of major vibrational modes were confirmed by appropriate S(18)O2 and (34)SO2 isotopic shifts, and density functional frequency calculations. DFT calculations were employed to study the behavior of reactions of Group V bare metal atoms with SO2, and a representative profile was derived which not only showed the preferred coordinating fashion of metal atoms but also tracked the path of S-O bond activation. The eta(2)-O,O' bridge coordinated complexes are preferred with energy decreases of ca. 50 kcal mol(-1) for all three metals, which facilitate the activation of two S-O bonds in succession and finally direct the reaction to the most stable molecules SMO2 (M = V, Nb, Ta) along the potential energy surface (PES). Finally the SMO2 molecules capture electrons to give anions SMO2(-) with about 3.6 eV electron affinities based on DFT calculations. PMID- 23677393 TI - Tomato FRUITFULL homologues act in fruit ripening via forming MADS-box transcription factor complexes with RIN. AB - The tomato MADS-box transcription factor RIN acts as a master regulator of fruit ripening. Here, we identified MADS-box proteins that interact with RIN; we also provide evidence that these proteins act in the regulation of fruit ripening. We conducted a yeast two-hybrid screen of a cDNA library from ripening fruit, for genes encoding proteins that bind to RIN. The screen identified two MADS-box genes, FUL1 and FUL2 (previously called TDR4 and SlMBP7), both of which have high sequence similarity to Arabidopsis FRUITFULL. Expression analyses revealed that the FUL1 mRNA and FUL1 protein accumulate in a ripening-specific manner in tomato fruits and FUL2 mRNA and protein accumulate at the pre-ripening stage and throughout ripening. Biochemical analyses confirmed that FUL1 and FUL2 form heterodimers with RIN; this interaction required the FUL1 and FUL2 C-terminal domains. Also, the heterodimers bind to a typical target DNA motif for MADS-box proteins. Chromatin immunoprecipitation assays revealed that FUL1 and FUL2 bind to genomic sites that were previously identified as RIN-target sites, such as the promoter regions of ACS2, ACS4 and RIN. These findings suggest that RIN forms complexes with FUL1 and FUL2 and these complexes regulate expression of ripening related genes. In addition to the functional redundancy between FUL1 and FUL2, we also found they have potentially divergent roles in transcriptional regulation, including a difference in genomic target sites. PMID- 23677398 TI - Folate forever--all methyl group donations welcome! PMID- 23677397 TI - Identification of integrin beta1 as a prognostic biomarker for human lung adenocarcinoma using 2D-LC-MS/MS combined with iTRAQ technology. AB - To discover novel lung adenocarcinoma (AdC) biomarkers, isobaric tags for relative and absolute quantitation (iTRAQ)-tagging combined with 2D-LC-MS/MS analysis was used to identify differentially expressed plasma membrane proteins in lung AdC and paired paraneoplastic normal lung tissues (PNLTs) adjacent to tumors. In this study, significant caveolin-1 downregulation and integrin beta1 upregulation was observed in primary lung AdC vs. PNLT. As there has been no report on the association of integrin beta1 with lung AdC, immunohistochemical staining was performed to detect the expression of integrin beta1 in an independent set of archival tissue specimens including 42 cases of PLNT, 46 cases of without lymph node metastasis primary AdC (non-LNM AdC) and 62 cases of LNM AdC; the correlation of their expression levels with clinicopathological characteristics and clinical outcomes were evaluated. Based on the data, upregulation of integrin beta1 was significantly correlated with advanced clinical stage and lymph node metastasis. Integrin beta1 overexpression was significantly associated with advanced clinical stage (P<0.05), lymph node metastasis (P<0.05), increased relapse rate (P<0.05) and decreased overall survival (P<0.05) in AdCs. Cox regression analysis indicated that integrin beta1 overexpression is an independent prognostic factor. The data suggest that integrin beta1 is a potential biomarker for LNM and prognosis of AdC and integrin beta1 upregulation may play an important role in the pathogenesis of AdC. PMID- 23677400 TI - FDA delays decision to remove powdered gloves. PMID- 23677401 TI - Fate of the rectal stump after subtotal colectomy for ulcerative colitis in the era of ileal pouch-anal anastomosis. AB - IMPORTANCE: Total proctocolectomy with ileal pouch-anal anastomosis is considered the procedure of choice for patients requiring elective surgery for ulcerative colitis, but some patients undergoing subtotal colectomy with end ileostomy are satisfied with an ileostomy and do not choose to undergo later pelvic pouch surgery. The need and timing for completion proctectomy in this setting are uncertain. OBJECTIVE: To assess the long-term fate of the retained rectum compared with the morbidity associated with completion proctectomy in patients who underwent subtotal colectomy for ulcerative colitis. DESIGN AND SETTING: Retrospective review of a prospective database in an academic medical center. PARTICIPANTS: Patients who underwent subtotal colectomy with ileostomy for ulcerative colitis from July 1, 1990, to December 31, 2010. MAIN OUTCOMES AND MEASURES: Proctectomy, surgical complications, and symptoms from the retained rectum. RESULTS: One hundred eight patients underwent subtotal colectomy for ulcerative colitis during the study period: 73 for acute disease, 18 for advanced age and/or comorbidities, and 17 to avoid the risk of sexual dysfunction or infertility. Of these patients, 71 (65.7%) underwent subsequent ileal pouch-anal anastomosis, 2 died of other causes, and 3 were lost to follow-up. Of the remaining 32 patients, 20 chose rectal stump surveillance and 12 underwent elective proctectomy. Median follow-up was 13.8 years. No difference was noted in age, sex, surgical complications, pad use, or urinary dysfunction between the 2 groups. Only 8 of 20 patients in the surveillance group were compliant with follow-up endoscopy, and 13 were able to maintain their rectum; 2 required proctectomy at 11 and 16 years, respectively, for rectal cancer; neither has developed recurrent disease. One patient in each group reported erectile dysfunction. CONCLUSIONS AND RELEVANCE: Management of the retained rectum after subtotal colectomy remains an important issue even in the era of ileal pouch-anal anastomosis. Considering the risk of rectal cancer, the low success rate of long term rectal preservation, and the safety of surgery, a more aggressive approach to early completion proctectomy seems justified in this situation. PMID- 23677402 TI - The out-of-circuit rectum in ulcerative colitis: the bumpy road less traveled: Comment on " Fate of rectal stump after subtotal colectomy for ulcerative colitis in the era of ileal pouch-anal anastomosis". PMID- 23677403 TI - Characteristics of highly ranked applicants to general surgery residency programs. AB - IMPORTANCE: With duty hour debates, specialization, and sex distribution changes in the applicant pool, the relative competitiveness for general surgery residency (GSR) is undefined. OBJECTIVE: To determine the modern attributes of top-ranked applicants to GSR. DESIGN Validation cohort, survey. SETTING: National sample of university and community-based GSR programs. PARTICIPANTS: Data were abstracted from Electronic Residency Application Service files of the top 20-ranked applicants to 22 GSR programs. We ranked program competitiveness and blinded review of personal statements. MAIN OUTCOMES AND MEASURES: Characteristics associated with applicant ranking by the GSR program (top 5 vs 6-20) and ranking by highly competitive programs were identified using t and chi2 tests and modified Poisson regression. RESULTS: There were 333 unique applicants among the 440 Electronic Residency Application Service files. Most applicants had research experience (93.0%) and publications (76.8%), and 28.4% had Alpha Omega Alpha membership. Nearly half were women (45.2%), with wide variation by program (20.0% 75.0%) and a trend toward fewer women at programs in the South and West (38.0% and 37.5%, respectively). Men had higher United States Medical Licensing Examination Step 1 scores (238.0 vs 230.1; P < .001) but similar Step 2 scores (245.3 vs 244.5; P = .54). Using bivariate analysis, highly competitive programs were more likely to rank applicants with publications, research experience, Alpha Omega Alpha membership, higher Step 1 scores, and excellent personal statements and those who were male or Asian. However, the only significant predictors were Step 1 scores (relative risk [RR], 1.36 for every 10-U increase), publications (RR, 2.20), personal statements (RR, 1.62), and Asian race (RR, 1.70 vs white). Alpha Omega Alpha membership (RR, 1.62) and Step 1 scores (RR, 1.01) were the only variables predictive of ranking in the top 5. CONCLUSIONS AND RELEVANCE: This national sample shows GSR is a highly competitive, sex-neutral discipline in which academic performance is the most important factor for ranking, especially in the most competitive programs. This study will inform applicants and program directors about applicants to the GSR program. PMID- 23677404 TI - Characteristics of highly ranked applicants to general surgery residency programs: are we assessing the right criteria?: Comment on "Characteristics of highly ranked applicants to general surgery residency programs". PMID- 23677405 TI - Immunocompromised status in patients with necrotizing soft-tissue infection. AB - IMPORTANCE: There is a scarcity of research on immunocompromised patients with necrotizing soft-tissue infection (NSTI). OBJECTIVE: To evaluate the effect of immunocompromised status in patients with NSTI. DESIGN AND SETTING: Single institution retrospective cohort study at a tertiary academic teaching hospital affiliated with a major cancer center. PARTICIPANTS: Patients with NSTI. EXPOSURE: Treatment at Brigham and Women's Hospital and Dana-Farber Cancer Institute between November 25, 1995, and April 25, 2011. MAIN OUTCOME AND MEASURE: Necrotizing soft-tissue infection-associated in-hospital mortality. RESULTS: Two hundred one patients were diagnosed as having NSTI. Forty-six were immunocompromised (as defined by corticosteroid use, active malignancy, receipt of chemotherapy or radiation therapy, diagnosis of human immunodeficiency virus or AIDS, or prior solid organ or bone marrow transplantation with receipt of chronic immunosuppression). At presentation, immunocompromised patients had lower systolic blood pressure (105 vs 112 mm Hg, P = .02), glucose level (124 vs 134 mg/dL, P = .03), and white blood cell count (6600/MUL vs 17 200/MUL, P < .001) compared with immunocompetent patients. Immunocompromised patients were less likely to have been transferred from another institution (26.1% vs 52.9%, P = .001), admitted to a surgical service (45.7% vs 83.2%, P < .001), or undergone surgical debridement on admission (4.3% vs 61.3%, P = .001). Time to diagnosis and time to first surgical procedure were delayed in immunocompromised patients (P < .001 and P = .001, respectively). Immunocompromised patients had higher NSTI associated in-hospital mortality (39.1% vs 19.4%, P = .01). CONCLUSIONS: AND RELEVANCE Immunocompromised status in patients with NSTI in this study is associated with delays in diagnosis and surgical treatment and with higher NSTI associated in-hospital mortality. At presentation, immunocompromised patients may fail to exhibit typical clinical and laboratory signs of NSTI. Physicians caring for similar patient populations should maintain a heightened level of suspicion for NSTI and consider early surgical evaluation and treatment. PMID- 23677406 TI - Surgical residents' perceptions of 2011 Accreditation Council for Graduate Medical Education duty hour regulations. AB - IMPORTANCE: In 2010, the Accreditation Council for Graduate Medical Education (ACGME) proposed increased regulation of work hours and supervision for residents. New Common Program requirements that took effect in July 2011 dramatically changed the customary 24-hour in-house call schedule. Surgical residents are more likely to be affected by these duty hour restrictions. OBJECTIVE: To examine surgical residents' views of the 2011 ACGME Common Program requirements after implementation in July 2011. DESIGN: A 20-question electronic survey was administered 6 months after implementation of 2011 ACGME regulations to 123 participating institutions. SETTING: ACGME-accredited teaching hospitals in the United States and US territories. PARTICIPANTS: The total sample was 1013 voluntarily participating residents in general surgery and surgical specialties at ACGME-accredited institutions. MAIN OUTCOMES AND MEASURES: Residents' perceptions of changes in education, patient care, and quality of life after institution of 2011 ACGME duty hour regulations and their compliance with these rules. RESULTS: A subset of 1013 residents training in general surgery or a surgical subspecialty was identified from a demographically representative sample of 6202 survey respondents. Most surgical residents indicated that education (55.1%), preparation for senior roles (68.4%), and work schedules (50.7%) are worse after implementation of the 2011 regulations. They reported no change in supervision (80.8%), safety of patient care (53.4%), or amount of rest (57.8%). Although quality of life is perceived as better for interns (61.9%), most residents believe that it is worse for senior residents (54.4%). A majority report increased handoffs (78.2%) and a shift of junior-level responsibilities to senior residents (68.7%). Finally, many residents report noncompliance (67.6%) and duty hour falsification (62.1%). CONCLUSIONS AND RELEVANCE: A majority of surgical residents disapprove of 2011 ACGME Common Program requirements (65.9%). The proposed benefits of the increased duty hour restrictions-improved education, patient care, and quality of life-have ostensibly not borne out in surgical training. It may be difficult for residents, particularly in surgical fields, to learn and care for patients under the 2011 ACGME regulations. PMID- 23677407 TI - The Accreditation Council for Graduate Medical Education duty hour regulations: how do we make the best of an unpopular situation in training the surgeons of tomorrow? PMID- 23677408 TI - Transvaginal cholecystectomy: effect on quality of life and female sexual function. AB - IMPORTANCE: Transvaginal cholecystectomy (TVC) is the leading natural orifice transluminal endoscopic surgery to date and has the potential to offer improved cosmesis, less pain, and shorter recovery times for female patients. OBJECTIVE: To investigate quality of life and female sexual function in our patients undergoing TVC. DESIGN: A prospective cohort study from August 14, 2009, to June 12, 2012, of TVCs performed at our institution to date. SETTING: Tertiary academic referral center. PARTICIPANTS: The first 47 consecutive female patients (aged 18-65 years) who received a TVC by a single surgeon. INTERVENTIONS: A hybrid TVC was performed by a 5-mm umbilical trocar and a 12-mm transvaginal trocar with standard laparoscopic instruments. MAIN OUTCOMES AND MEASURES: Quality-of-life index (36-Item Short Form Health Survey) and female sexual function (Female Sexual Function Index) scores. RESULTS: A total of 47 TVCs were performed, with a mean age of 39 years, mean body mass index (calculated as weight in kilograms divided by height in meters squared) of 31, and mean operative time of 65 minutes. No difference was noted in overall female sexual function from preoperatively to 1 and 3 months postoperatively. When comparing quality of life preoperatively vs 1 and 3 months postoperatively, there were significant improvements in physical function (P = .02), energy and fatigue (P = .001), emotional well-being (P = .01), pain (P < .001), and general health (P = .03). No significant changes were noted in physical limitations (P = .18), emotional problems (P = .72), and social function (P = .12). CONCLUSIONS AND RELEVANCE: In our experience to date, female sexual function is unchanged and quality of life either is unchanged or improves at 1 and 3 months following TVC. Undergoing TVC does not appear to negatively affect female sexual function or quality of life in the short term. PMID- 23677409 TI - Transvaginal cholecystectomy: does a go from below halt the thunder down under?: Comment on "Transvaginal cholecystectomy". PMID- 23677410 TI - Image of the month. Malignant peripheral nerve sheath tumor. PMID- 23677412 TI - Image of the month. Appendiceal endometriosis. PMID- 23677414 TI - A novel V(IV)O-pyrimidinone complex: synthesis, solution speciation and human serum protein binding. AB - The pyrimidinones mhcpe, 2-methyl-3H-5-hydroxy-6-carboxy-4-pyrimidinone ethyl ester (mhcpe, 1), 2,3-dimethyl-5-benzyloxy-6-carboxy-4-pyrimidinone ethyl ester (dbcpe, 2) and N-methyl-2,3-dimethyl-5-hydroxy-6-carboxyamido-4-pyrimidinone (N MeHOPY, 3), are synthesized and their structures determined by single crystal X ray diffraction. The acid-base properties of 1 are studied by potentiometric and spectrophotometric methods, the pK(a) values being 1.14 and 6.35. DFT calculations were carried out to determine the most stable structure for each of the H2L(+), HL and L(-) forms (HL = mhcpe) and assign the groups involved in the protonation-deprotonation processes. The mhcpe(-) ligand forms stable complexes with V(IV)O(2+) in the pH range 2 to 10, and potentiometry, EPR and UV-Vis techniques are used to identify and characterize the V(IV)O-mhcpe species formed. The results are consistent with the formation of V(IV)O, (V(IV)O)L, (V(IV)O)L2, (V(IV)O)2L2H(-2), (V(IV)O)L2H(-1), (V(IV)O)2L2H(-3), (V(IV)O)LH(-2) species and V(IV)O-hydrolysis products. Calculations indicate that the global binding ability of mhcpe towards V(IV)O(2+) is similar to that of maltol (Hmaltol = 3-hydroxy-2 methyl-4H-pyran-4-one) and lower than that of 1,2-dimethyl-3-hydroxy-4-pyridinone (Hdhp). The interaction of V(IV)O-complexes with human plasma proteins (transferrin and albumin) is studied by circular dichroism (CD), EPR and (51)V NMR spectroscopy. V(IV)O-mhcpe-protein ternary complexes are formed in both cases. The binding of V(IV)O(2+) to transferrin (hTF) in the presence of mhcpe involves mainly (V(IV)O)1(hTF)(mhcpe)1, (V(IV)O)2(hTF)(mhcpe)1 and (V(IV)O)2(hTF)(mhcpe)2 species, bound at the Fe(III) binding sites, and the corresponding conditional formation constants are determined. Under the conditions expected to prevail in human blood serum, CD data indicate that the V(IV)O-mhcpe complexes mainly bind to hTF; the formation of V(IV)O-hTF-mhcpe complexes occurs in the presence of Fe(III) as well, distinct EPR signals being clearly obtained for Fe(III)-hTF and to V(IV)O-hTF-mhcpe species. Thus this study indicates that transferrin plays the major role in the transport of V(IV)O-mhcpe complexes under blood plasma conditions in the form of ternary V(IV)-ligand protein complexes. PMID- 23677415 TI - Perceived mental health treatment need and substance use correlates among young adults. AB - OBJECTIVES: The relationship between perceived need for mental health treatment, reasons for not receiving care, substance use, and race and gender among young adults was examined to identify barriers to mental health care. METHODS: Data from the 2010 National Survey on Drug Use and Health for 14,718 adults ages 18 to 23 were used. Logistic regression analysis compared substance use among young adults with perceived mental health treatment need grouped by race and gender. RESULTS: A total of 7.6% of young adults wanted mental health treatment but did not receive care. Persons with perceived treatment need were more likely than recipients of treatment to smoke cigarettes, use marijuana, meet criteria for marijuana abuse or dependence, and engage in binge drinking, after analyses controlled for income and health insurance. White males with perceived need were 3.2 times more likely to smoke and to meet criteria for marijuana abuse or dependence and were 2.6 times more likely to engage in binge drinking. Hispanic males were 2.9 times more likely to smoke and meet criteria for marijuana abuse or dependence. White females were 1.7 times more likely than other subgroups to perceive need for mental health care. CONCLUSIONS: Young adults with perceived mental health treatment need are at high risk of substance abuse and dependence. Results support targeting knowledge and attitudes surrounding mental health services by race-ethnicity and gender to improve willingness to receive care. PMID- 23677416 TI - Analysis of SYCP3 encoding synaptonemal complex protein 3 in human aneuploidies. AB - OBJECTIVES: To test the hypothesis that mutations of SYCP3 encoding synaptonemal complex protein 3, result in increased frequency of aneuploidies in humans. METHODS: Mutation analysis of the PCR-amplified 8 coding exons and exon-intron boundaries of the SYCP3 gene was done by direct sequencing of DNA isolated from 35 aneuploid fetuses of women having a potentially increased likelihood for an underlying genetic predisposition for chromosomal non-disjunction. RESULTS: Based on the results of conventional karyotyping, the 35 aneuploid fetuses of 33 women were divided into separate groups: 9 aneuploid conceptuses of couples with recurrent aneuploid conceptions (4 of the women 35 years or younger), 12 conceptuses with double/multiple aneuploidies (5 of the women 35 years or younger), and 14 conceptuses with single aneuploidies of women younger than 35 years (8 trisomies and 6 monosomies). No pathogenic mutations in the SYCP3 coding exons and the immediately flanking intronic sequences were found. CONCLUSIONS: Under the assumption that genetic predisposition for chromosomal non-disjunction leading to aneuploidy is most likely polygenic in nature, our data suggest that SYCP3 mutations are not one of the common causes in humans. PMID- 23677417 TI - Preventing ovarian hyperstimulation syndrome: cabergoline versus coasting. AB - PURPOSE: The use of cabergoline and coasting are both effective in reducing the risk of ovarian hyperstimulation syndrome (OHSS). Our aim was to compare the effectiveness of cabergoline with coasting to prevent moderate-severe OHSS. METHODS: Fifty-seven consecutive infertile patients (81 cycles) at risk of developing OHSS were enrolled through our computerized IVF database system. Inclusion criteria were: (i) E2 level on the day of human chorionic gonadotrophin (hCG) greater than 3,500 pg/ml; (ii) patients who underwent luteal long GnRH agonist cycle; (iii) patients who used cabergoline for OHSS prevention; (iv) patients who underwent coasting for OHSS prevention. The cabergoline group constituted 17 patients (26 cycles) who started using 0.5 mg oral cabergoline daily for 8 days on the day of hCG, whereas the coasting group constituted 40 patients (55 cycles) who underwent coasting. RESULTS: Both groups were comparable regarding the women's mean age, body mass index and duration of infertility. Implantation rate, clinical pregnancy per embryo transfer and miscarriage rates were not different between the two groups. There was no OHSS in the cabergoline group (0 %), whereas there were two OHSS (3.6 %) in the coasting group; however, this difference was not significant. CONCLUSIONS: In conclusion, 0.5 mg daily use of cabergoline for 8 days beginning from hCG administration is a very effective way to reduce moderate-severe OHSS without sacrificing pregnancy rates in patients at risk of developing OHSS. PMID- 23677418 TI - Impact of vaginal ascorbic acid on abnormal vaginal microflora. AB - PURPOSE: To evaluate the impact of vaginal ascorbic acid (vitamin C) as a treatment/maintenance regimen on increased vaginal pH and abnormal microflora on wet mounts in premenopausal women. METHODS: A randomized study of 140 asymptomatic, low-risk pregnant and non-pregnant premenopausal women with vaginal pH >= 4.5 and a variety of partly/completely disrupted Lactobacillus microflora patterns on wet mounts in five outpatient clinics was carried out. Participants were randomized to the intervention group [250 mg vitamin C tablets vaginally at bedtime once a day for 6 days (treatment phase), followed by a one tablet per week, for 12 weeks (maintenance phase)] or the control group (no treatment). Outcomes were evaluated 4 months after randomizing, i.e., 2-3 weeks after the last vitamin C tablet insertion. RESULTS: Normalization to normal flora was observed in 51.4 % of all ascorbic acid and in 24.3 % of control group patients (difference 27.1 %, 95 % CI 11.7-42.6, p < 0.05, ITT population). In the per protocol population, normalization was confirmed in 53.5 % of the intervention and 22.4 % of the control group (difference 31 %, 95 % CI 14.3-47.8, p < 0.05). Results of pregnant subgroup analysis showed better outcomes for the subgroup: difference of normalization rate between ascorbic acid and control group was 41.2 % (95 % CI 21.8-60.1, p < 0.05). Itching occurred in 19 %; 23 % of women reported irritation and 10 % stopped the treatment because of side effects. CONCLUSIONS: Vaginal ascorbic acid improves abnormal vaginal pH and microflora, especially in pregnant women, but is not well tolerated by all women. PMID- 23677419 TI - Oral contraceptives usage patterns: study of knowledge, attitudes and experience in Belgrade female medical students. AB - PURPOSE: The purpose of this survey was to quantify oral contraceptive pill (OCP) use and to analyze attitudes and knowledge about the pill in a sample of female medical students. METHODS: A cross-sectional study, conducted between November 28 and December 20, 2011, included 464 female participants from the Faculty of Medicine, University of Belgrade. Data were collected before the start of compulsory practical sessions in the classrooms through a 37-item questionnaire and assessed statistically. RESULTS: Prevalence of OCP use was 11.3 %. Highest proportion of the pill use was in the third year (15.4 %). Approximately, 61 % used the pill as a therapy for dysmenorrhea. Difference in knowledge scores was observed between users and non-users (t = 3.596, p < 0.001). Advancing year at the faculty was highly statistically significantly associated with greater knowledge about health effects of the pill (rho = 0.506, p < 0.001). There was no difference regarding attitude score among users and non-users (t = -0.9, p = 0.369). In the multivariate regression model the knowledge score was the only predictor of pill use. CONCLUSION: The results of our survey indicate that oral contraceptive pill requires further promotion and reproductive health education in a broader context. PMID- 23677420 TI - Copeptin concentrations are not elevated in gestational diabetes mellitus. AB - PURPOSE: To investigate copeptin levels in women with GDM and women with uncomplicated pregnancies. METHODS: This case-control study was conducted on 45 women with GDM and 40 women with uncomplicated pregnancies. The maternal serum levels of copeptin were measured with enzyme-linked immunosorbent assay. RESULTS: Copeptin levels were not different among groups (0.93 +/- 0.75 vs. 1.15 +/- 0.93 ng/ml, p: 0.24). HOMA-IR and insulin levels were significantly higher in woman with GDM when compared with control group (2.90 +/- 1.88 vs. 1.91 +/- 0.50, p: 0.002; 11.74 +/- 6.43 vs. 8.52 +/- 2.28, p: 0.004, respectively). The copeptin concentrations were significantly correlated with insulin levels and HOMA-IR values (r = 0.329 p = 0.002, r = 0.289 p = 0.007, respectively). CONCLUSIONS: The present study shows that serum copeptin concentrations did not differ in woman with GDM and non-GDM patients. However, we found a significant correlation between copeptin and HOMA-IR. Future studies are needed with larger populations in gestational diabetic patients on copeptin secretion, metabolism and action. PMID- 23677421 TI - Evidence-based hydro- and balneotherapy in Hungary--a systematic review and meta analysis. AB - Balneotherapy is appreciated as a traditional treatment modality in medicine. Hungary is rich in thermal mineral waters. Balneotherapy has been in extensive use for centuries and its effects have been studied in detail. Here, we present a systematic review and meta-analysis of clinical trials conducted with Hungarian thermal mineral waters, the findings of which have been published by Hungarian authors in English. The 122 studies identified in different databases include 18 clinical trials. Five of these evaluated the effect of hydro- and balneotherapy on chronic low back pain, four on osteoarthritis of the knee, and two on osteoarthritis of the hand. One of the remaining seven trials evaluated balneotherapy in chronic inflammatory pelvic diseases, while six studies explored its effect on various laboratory parameters. Out of the 18 studies, 9 met the predefined criteria for meta-analysis. The results confirmed the beneficial effect of balneotherapy on pain with weight bearing and at rest in patients with degenerative joint and spinal diseases. A similar effect has been found in chronic pelvic inflammatory disease. The review also revealed that balneotherapy has some beneficial effects on antioxidant status, and on metabolic and inflammatory parameters. Based on the results, we conclude that balneotherapy with Hungarian thermal-mineral waters is an effective remedy for lower back pain, as well as for knee and hand osteoarthritis. PMID- 23677422 TI - Transient ischemic attack-like episodes without stroke-like lesions in MELAS. AB - A stroke-like episode is a core symptom in mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Proton magnetic resonance spectroscopy (1H-MRS) is useful in the diagnosis of mitochondrial diseases. We report an 8-year-old girl with MELAS, presenting with a seizure and blindness. 1H-MRS showed a strikingly elevated lactate peak in the right occipital region, where no abnormal signals appeared on either T2-W or diffusion weighted MRI. She recovered completely within a day. We describe this mild clinical condition with abnormal lactate peak in normal-appearing gray matter as a transient ischemic attack-like episode in MELAS. PMID- 23677423 TI - Prenatal MRI characterization of brainstem glioma. AB - We describe a unique case of prenatally diagnosed diffuse brainstem glioma, detected during routine obstetric ultrasound and characterized with fetal magnetic resonance imaging. The diagnosis was supported by early postpartum imaging and confirmed at autopsy. Few examples of these rare lesions have been described in neonates by imaging and fewer cases have been confirmed by histopathological examination. Our case contributes to the limited literature concerning the clinical, MRI, and pathological correlates of brainstem gliomas in the perinatal period. PMID- 23677424 TI - Aortopulmonary collateral flow in cystic fibrosis assessed with phase-contrast MRI. AB - BACKGROUND: Cystic fibrosis (CF) is a common genetic disease in Caucasians. Chronic pulmonary disease with progressive destruction of the pulmonary parenchyma is two of the major morbidities, but the relationship between clinical severity of CF and aortopulmonary collateral blood flow has not been assessed. OBJECTIVE: The purpose of this study is to measure changes in aortopulmonary collateral blood flow by phase-contrast magnetic resonance imaging (MRI) in children with CF across the spectrum of disease severity as measured by the forced expiratory volume in one second as percent predicted value (FEV1% predicted). MATERIALS AND METHODS: Sixteen patients with CF were prospectively evaluated. Eight were classified as having mild CF lung disease (FEV1 >=80% predicted) and eight were classified as having moderate to severe CF lung disease (FEV1 <80% predicted). Seventeen age- and gender-matched non-CF subjects without cardiac or lung disease served as controls. Phase-contrast flow was measured at the ascending aorta, main pulmonary artery and both pulmonary arteries. Aortopulmonary collateral blood flow was calculated for each subject. The relationship between collateral flow and FEV1% predicted was modeled using nonparametric regression. Group differences were assessed by analysis of variance. RESULTS: Aortopulmonary collateral blood flow began to increase as FEV1% predicted in subjects with CF fell below 101.5% with significant further increase in the aortopulmonary collateral blood flow in the subjects with CF with moderate to severe lung disease compared to controls (0.89 vs. 0.20 L/min, P < 0.0001). Aortopulmonary collateral blood flow correlated negatively with FEV1% predicted (r=0.70, P = 0.0050) confirming its relationship to this established marker of disease severity. There was no statistically significant difference in results obtained from two independent observers. CONCLUSION: These preliminary findings suggest that phase-contrast MRI can be performed reliably with consistent results and without interobserver variability. While the aortopulmonary collateral blood flow is within the normal range in subjects with mild CF disease, it begins to increase even when lung function is still in the normal range. A significant increase in the aortopulmonary collateral blood flow compared to controls is measured in patients with moderate to severe CF lung disease. The studies support the notion that aortopulmonary collateral blood flow may serve as a novel and sensitive biomarker of early pulmonary disease in cystic fibrosis. PMID- 23677425 TI - Shiga toxin-producing Escherichia coli in Central Greece: prevalence and virulence genes of O157:H7 and non-O157 in animal feces, vegetables, and humans. AB - In Greece, Shiga toxin-producing Escherichia coli (STEC) have only been sporadically reported. The objective of this study was to estimate the prevalence of STEC and Escherichia coli O157:H7 in farm animals, vegetables, and humans in Greece. A total number of 1,010 fecal samples were collected from farm animals (sheep, goats, cattle, chickens, pigs), 667 diarrheal samples from humans, and 60 from vegetables, which were cultured in specific media for STEC isolates. Enzyme linked immunosorbent assay (ELISA) was used to detect toxin-producing colonies, which, subsequently, were subjected to a multiplex polymerase chain reaction (PCR) for stx1, stx2, eae, rfbE O157, and fliC h7 genes. Eighty isolates (7.9 %) from animal samples were found to produce Shiga toxin by ELISA, while by PCR, O157 STEC isolates were detected from 8 (0.8 %) samples and non-O157 STEC isolates from 43 (4.2 %) samples. STEC isolates were recovered mainly from sheep and goats, rarely from cattle, and not from pigs and chickens, suggesting that small ruminants constitute a potential risk for human infections. However, only three human specimens (0.4 %) were positive for the detection of Shiga toxins and all were PCR-negative. Similarly, all 60 vegetable samples were negative for toxin production and for toxin genes, but three samples (two roman rockets and one spinach) were positive by PCR for rfbE O157 and fliC h7 genes. These findings indicate that sheep, goats, cattle, and leafy vegetables can be a reservoir of STEC and Escherichia coli O157:H7 isolates in Greece, which are still rarely detected among humans. PMID- 23677427 TI - A case of continuous-type splenogonadal fusion. AB - Splenogonadal fusion is a rare developmental anomaly in which an abnormal connection between the splenic tissue and gonads or mesonephric derivatives is present. Less than 200 cases have been reported since it was first described in 1883. Preoperative misdiagnosis is common and may lead to unnecessary orchidectomy if testicular neoplasm is suspected. To avoid such outcomes, it is important to be aware of the features of splenogonadal fusion. We report the case of a five-month-old male infant with continuous-type, left-sided splenogonadal fusion, which was discovered during groin exploration for a scrotal mass. Although the lesion was first noted during an episode of nonspecific viral fever, such an association is uncommon. Preoperative ultrasonographic evaluation favoured a diagnosis of a large haemangioma. This is the first reported case of splenogonadal fusion from Sri Lanka. PMID- 23677426 TI - Architectural switches in plant thylakoid membranes. AB - Recent progress in elucidating the structure of higher plants photosynthetic membranes provides a wealth of information. It allows generation of architectural models that reveal well-organized and complex arrangements not only on whole membrane level, but also on the supramolecular level. These arrangements are not static but highly responsive to the environment. Knowledge about the interdependency between dynamic structural features of the photosynthetic machinery and the functionality of energy conversion is central to understanding the plasticity of photosynthesis in an ever-changing environment. This review summarizes the architectural switches that are realized in thylakoid membranes of green plants. PMID- 23677428 TI - Paradoxical increase in uric acid level with allopurinol use in pyrazinamide induced hyperuricaemia. AB - We report the case of a 36-year-old man with psoriatic arthritis and miliary tuberculosis, whose serum uric acid (SUA) level increased after the initiation of antituberculosis treatment, which included pyrazinamide. Most strikingly and paradoxically, the patient's SUA level increased after treatment with allopurinol. On cessation of allopurinol, his SUA level decreased substantially, and complete normalisation was observed following the discontinuation of pyrazinamide treatment. PMID- 23677430 TI - Regioselective control of aromatic halogenation reactions in carbon nanotube nanoreactors. AB - The use of single-walled carbon nanotubes as effective nanoreactors for preparative chemical reactions has been demonstrated for the first time. Extreme spatial confinement of reactant molecules inside nanotubes has been shown to drastically affect both the regioselectivity and kinetics of aromatic halogenation reactions. PMID- 23677432 TI - Ectopic bone in the abdominal cavity: a surgical nightmare. AB - INTRODUCTION: Heterotopic mesenteric ossification (HMO) is a rare clinical entity with less than 40 reported cases in the literature. Frequently associated with prior abdominal surgery or trauma, the precise etiology and optimal approach to its management remain undefined. CASE REPORT: The index patient is a 58-year-old male who originally presented with perforated diverticulitis. Following resection, the patient developed an enterocutaneous fistula. After a trial of conservative management, the patient underwent exploration and was found to have widespread intra-abdominal calcification. Sheets of calcific tissue were resected, and a diagnosis of HMO was confirmed via pathology. The patient had a postoperative course complicated by bleeding and redevelopment of enteric fistula. Following a prolonged hospital course requiring multiple operations, the fistula persists, and the patient remains on parenteral nutrition. DISCUSSION: The etiology of HMO is unknown. Diagnosis requires a high degree of clinical suspicion, as radiologic findings are often misleading. A review of 18 cases demonstrates significant morbidity associated with operative intervention. Nonsteroidals, in particular indomethacin, have been shown to decrease heterotopic ossification, but their role in mesenteric disease is not clearly defined. CONCLUSION: HMO is a rare but complicated pathologic process. A trial of conservative management with NSAIDs, bowel rest, and total parenteral nutrition is prudent, given the high rate of morbidity and mortality associated with operative intervention. PMID- 23677433 TI - A silk fibroin/chitosan scaffold in combination with bone marrow-derived mesenchymal stem cells to repair cartilage defects in the rabbit knee. AB - Bone marrow-derived mesenchymal stem cells (BMSCs) were seeded in a three dimensional scaffold of silk fibroin (SF) and chitosan (CS) to repair cartilage defects in the rabbit knee. Totally 54 rabbits were randomly assigned to BMSCs + SF/CS scaffold, SF/CS scaffold and control groups. A cylindrical defect was created at the patellofemoral facet of the right knee of each rabbit and repaired by scaffold respectively. Samples were prepared at 4, 8 and 12 weeks post-surgery for gross observation, hematoxylin-eosin and toluidine blue staining, type II collagen immunohistochemistry, Wakitani histology. The results showed that differentiated BMSCs proliferated well in the scaffold. In the BMSCs + SF/CS scaffold group, the bone defect was nearly repaired, the scaffold was absorbed and immunohistochemistry was positive. In the SF/CS scaffold alone group, fiber like tissues were observed, the scaffold was nearly degraded and immunohistochemistry was weakly positive. In the control group, the defect was not well repaired and positive immunoreactions were not detected. Modified Wakitani scores were superior in the BMSCs + SF/CS scaffold group compared with those in other groups at 4, 8 and 12 weeks (P < 0.05). A SF/CS scaffold can serve as carrier for stem cells to repair cartilage defects and may be used for cartilage tissue engineering. PMID- 23677434 TI - Influence of ibuprofen addition on the properties of a bioactive bone cement. AB - Bioactive bone cements can promote bone growth and the formation of a strong chemical bond between the implant and bone tissue increasing the lifetime of the prosthesis. This study aims at synthesizing a new bioactive bone cement with different amounts of ibuprofen (5, 10 and 20 wt%) using a low toxicity activator, and investigating its in vitro release profile. The effect of ibuprofen (IB) on the setting parameters, residual monomer and bioactivity in synthetic plasma was also evaluated. It was verified that the different IB contents do not prevent the growth of calcium phosphate aggregates on composite surfaces, confirming that the cements are potentially bioactive. A relevant advantage of these formulations was a significant improvement in their curing parameters with increasing IB amount, associated to a reduction of the peak temperature and an extension of the setting time. The investigated cements released an average of about 20 % of the total incorporated ibuprofen during 30 days test, with IB20 liberating the highest percentage of drug 20.6 %, and IB10 and IB5, respectively 19.1 and 17.6 %. This behavior was attributed to the low solubility of this drug in aqueous media and was also related with the hydrophobic character of the polymer. Regarding the therapeutic concentration sufficient to suppress inflammation, the cement with 10 % of ibuprofen achieved the required release rate for 1 week and the cement with 20 % for 2 weeks. PMID- 23677435 TI - Influence of solvent composition on the performance of carbodiimide cross-linked gelatin carriers for retinal sheet delivery. AB - Gelatin is a protein molecule that displays bioaffinity and provides a template to guide retinal pigment epithelial (RPE) cell organization and growth. We have recently demonstrated that the carbodiimide cross-linked gelatin membranes can be used as retinal sheet carriers. The purpose of this work was to further determine the role of solvent composition in the tissue delivery performance of chemically modified biopolymer matrices. The gelatin molecules were treated with 1-ethyl-3 (3-dimethyl aminopropyl) carbodiimide (EDC) in the presence of binary ethanol/water mixtures with varying ethanol concentrations (70-95 vol%) to obtain the carriers with different cross-linking efficiencies and mechanical properties. Results of melting point measurements and in vitro degradation tests showed that when the cross-linking index reached a high level of around 45 %, the EDC cross linked gelatin materials have sufficient thermal stability and resistance to enzymatic degradation, indicating their suitability for the development of carriers for retinal sheet delivery. Irrespective of the solvent composition, the chemically modified gelatin samples are compatible toward human RPE cells without causing toxicity and inflammation. In particular, the membrane carriers prepared by the cross-linking in the presence of solvent mixtures containing 80-90 vol% of ethanol have no impact on the proliferative capacity of ARPE-19 cultures and possess good efficiency in transferring and encapsulating the retinal tissues. It is concluded that, except for cell viability and pro-inflammatory cytokine expression, the retinal sheet delivery performance strongly depends on the solvent composition for EDC cross-linking of gelatin molecules. PMID- 23677436 TI - Effect of low-level laser therapy on types I and III collagen and inflammatory cells in rats with induced third-degree burns. AB - Low-level laser therapy (LLLT) has been increasingly used to accelerate wound healing in third-degree burns. This study investigated the effects of lasers on the tissue repair process of third-degree burns. Burns were produced on the backs of male Wistar rats. The animals were divided into four groups (n = 12): control, injury, LLLT 3 J/cm(2), and LLLT 4 J/cm(2). Each group was further divided into two subgroups; the rats in one subgroup were killed on day 8 and those in the other, on day 16 after injury. The animals in LLLT 3 J/cm(2) and LLLT 4 J/cm(2) were irradiated 1 h after injury, and irradiation was repeated every 48 h. Laser (660 nm, 35 mW) treatment at fluences of 3 and 4 J/cm(2) were used. After killing the rats, tissue fragments from the burnt area were removed for histological analysis. The LLLT-treated groups showed a significant decrease (p <0.05) in the number of inflammatory cells and increased collagen deposition compared to the injury group. Laser irradiation (both 3 and 4 J/cm(2)) resulted in reduction in the inflammatory process and improved collagen deposition, thereby ameliorating the healing of third-degree burns. PMID- 23677438 TI - Enhancement of electroluminescence in zirconium poly carboxylic acid-based light emitting diodes by bathophenanthroline ligand. AB - The reactions of a zirconium salt with 1,2,4,5-benzenetetracarboxylate (btec), bathophenanthroline (Bphen) and thiocyanate ions were synthesized and studied by changing the mole ratio, the order of reactant and their pH. It is found that the coordination mode of btec acid depends on the control of reaction conditions. Monodentate, bidentate and bridging modes were investigated by FT-IR spectroscopy. The structures of Zr(btec) and Zr(btec)(Bphen) complexes were also characterized by UV-Vis, CHN, ICP-AES, (1)H NMR and cyclic voltammetry. The role of Bphen ligand in the photopysical properties of Zr(btec)(Bphen) complexes was investigated by DFT calculation. The photoluminescence (PL) emission of nine Zr(btec) complexes that have two peaks, a sharp and intense band for the first peak from 320 to 430 nm in comparison to the second peak with a less intensity and broadened in the regions of 650-780 nm. PL spectra of twelve Zr(btec)(Bphen) complexes also showed bands at 450, 550, 625 nm. LED devices with Zr complex as emitter layer and the structure ITO/PEDOT:PSS/PVK:PBD/zirconium complex/Al emitted a broad band centered at 550 and 650 originating from the Zr complexes. The EL spectra of Zr(btec) and Zr(btec)(Bphen) complexes indicated a long red shift rather than PVK:PBD blend. We believe that the electroplex occurring at PVK Zr complexes interface is responsible for the green-red emission in the EL of the device. These observations suggest an important role for the Bphen ligand to improve EL performance. PMID- 23677437 TI - Influence of Er:YAG and Ti:sapphire laser irradiation on the microtensile bond strength of several adhesives to dentin. AB - The aim of the present study was to evaluate the influence of erbium:yttrium aluminum-garnet (Er:YAG) and Ti:sapphire laser irradiation on the microtensile bond strength (MTBS) of three different adhesive systems to dentin. Flat dentin surfaces from 27 molars were divided into three groups according to laser irradiation: control, Er:YAG (2,940 nm, 100 MUs, 2.7 W, 9 Hz) and Ti:sapphire laser (795 nm, 120 fs, 1 W, 1 kHz). Each group was divided into three subgroups according to the adhesive system used: two-step total-etching adhesive (Adper Scotchbond 1 XT, from now on XT), two-step self-etching adhesive (Clearfil SE Bond, from now on CSE), and all-in-one self-etching adhesive (Optibond All-in One, from now on OAO). After 24 h of water storage, beams of section at 1 mm(2) were longitudinally cut from the samples. Each beam underwent traction test in an Instron machine. Fifteen polished dentin specimens were used for the surface morphology analysis by scanning electron microscopy (SEM). Failure modes of representative debonded microbars were SEM-assessed. Data were analyzed by ANOVA, chi-square test, and multiple linear regression (p < 0.05). In the control group, XT obtained higher MTBS than that of laser groups that performed equally. CSE showed higher MTBS without laser than that with laser groups, where Er:YAG attained higher MTBS than ultrashort laser. When OAO was used, MTBS values were equal in the three treatments. CSE obtained the highest MTBS regardless of the surface treatment applied. The Er:YAG and ultrashort laser irradiation reduce the bonding effectiveness when a two-step total-etching adhesive or a two-step self etching adhesive are used and do not affect their effectiveness when an all-in one self-etching adhesive is applied. PMID- 23677439 TI - Albumin-coated structural lyophilized bone allografts: a clinical report of 10 cases. AB - Bone replacement and the use of bone supplementary biological substances have become widespread in clinical practice. Although autografts have excellent properties, their limited availability, difficulties with shaping and donor site morbidity have made allografts a viable and increasingly preferred alternative. The main drawback of allografts is that the preparation destroys osteogenic cells and results in denaturation of osteoinductive proteins. Serum albumin is a well known constituent of stem cell culture media and we found that lyophilizing albumin onto bone allografts markedly improves stem-cell attachment and bone healing in animal models thus replacing some of the osteoinductive potential. As a first step in the clinical introduction of albumin coated grafts, we aimed to test surgical handling and early incorporation in aseptic revision arthroplasty in humans. We selected patients who needed large structural allografts and the current operation was the last attempt at preserving a moving joint. In a series of 10 cases of hip and knee revision surgery we did not experience any drawbacks of the albumin-coated grafts during handling and implantation. Twelve months radiographic and SPECT-CT follow-up showed that the graft was well received by the host and active remodelling was observed. The lack of graft-related complications and the good 1-year results indicate that controlled trials may be initiated in more common bone grafting indications where long-term effectiveness can be evaluated. PMID- 23677440 TI - Haemarthrosis stimulates the synovial fibrinolytic system in haemophilic mice. AB - Recurrent joint bleeding is the most common manifestation of haemophilia resulting in haemophilic arthropathy (HA). The exact pathophysiology is unknown, but it is suggested that arthropathy is stimulated by liberation of fibrinolytic activators from the synovium during haemarthrosis. The aim of this study was to test the hypothesis that haemarthrosis activates the local synovial fibrinolytic system in a murine haemophilia model. The right knees of haemophilic and control mice were punctured to induce haemarthrosis. The left knees served as internal control joints. Synovial levels of urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor 1 (PAI-1), plasmin, and alpha-2-antiplasmin (A2AP) were compared between the punctured and control knees. In haemophilic mice, an increase in synovial cells expressing urokinase-type plasminogen activator (uPA) in the right punctured knee versus the left unaffected knee was observed: (47% vs 43%) (p=0.03). Additionally, in haemophilic mice, haemarthrosis induced an increase in uPA (0.016 ng/ml vs 0.01 ng/ml) (p=0.03) and plasmin (0.53 MUg/ml vs 0.46 MUg/ml) (p=0.01) as promoters of fibrinolysis. Synovial levels of PAI-1 (0.32 ng/ml vs 0.17 ng/ml) (p<0.01) was also increased, whereas synovial levels of A2AP were unchanged: (0.021 MUg/ml vs 0.021 MUg/ml) (p=0.15). Enhanced uPA production was confirmed in human stimulated synovial fibroblast cultures and elevated levels of plasmin were confirmed harmful to human cartilage tissue explants. In this study we demonstrate that haemarthrosis in haemophilic mice induces synovial uPA expression and results in an increase in synovial plasmin levels, making the joint more vulnerable to prolonged and subsequent bleedings, and adding directly to cartilage damage. PMID- 23677441 TI - Influence of valine and other amino acids on total diacetyl and 2,3-pentanedione levels during fermentation of brewer's wort. AB - Undesirable butter-tasting vicinal diketones are produced as by-products of valine and isoleucine biosynthesis during wort fermentation. One promising method of decreasing diacetyl production is through control of wort valine content since valine is involved in feedback inhibition of enzymes controlling the formation of diacetyl precursors. Here, the influence of valine supplementation, wort amino acid profile and free amino nitrogen content on diacetyl formation during wort fermentation with the lager yeast Saccharomyces pastorianus was investigated. Valine supplementation (100 to 300 mg L(-1)) resulted in decreased maximum diacetyl concentrations (up to 37 % lower) and diacetyl concentrations at the end of fermentation (up to 33 % lower) in all trials. Composition of the amino acid spectrum of the wort also had an impact on diacetyl and 2,3-pentanedione production during fermentation. No direct correlation between the wort amino acid concentrations and diacetyl production was found, but rather a negative correlation between the uptake rate of valine (and also other branched-chain amino acids) and diacetyl production. Fermentation performance and yeast growth were unaffected by supplementations. Amino acid addition had a minor effect on higher alcohol and ester composition, suggesting that high levels of supplementation could affect the flavour profile of the beer. Modifying amino acid profile of wort, especially with respect to valine and the other branched chain amino acids, may be an effective way of decreasing the amount of diacetyl formed during fermentation. PMID- 23677444 TI - Comparing neighborhoods of adults with serious mental illness and of the general population: research implications. AB - OBJECTIVE: The International Classification of Functioning, Disability and Health emphasizes the importance of assessing the impact of environmental factors on functioning and disability. Drawing on this emphasis, this study used a set of objective measures to compare the characteristics of neighborhoods of adults with serious mental illness and of the general population. It also examined the relationship between neighborhood characteristics and neighborhood concentration of persons with serious mental illness. METHODS: The sample comprised 15,246 adults who were treated for serious mental illness in Philadelphia between 1997 and 2000. Principal-components analysis of 22 neighborhood characteristics resulted in an ideal-factor solution of six components. The mean values of each component in neighborhoods of persons with serious mental illness were compared with values in an equally sized group of neighborhoods created by randomly generated addresses representative of the city's general population. Ordinary least-squares regression was used to assess the association between neighborhood characteristics and neighborhood concentration of persons with serious mental illness. RESULTS: Neighborhoods in which adults with serious mental illness resided had higher levels of physical and structural inadequacy, drug-related activity, and crime than comparison neighborhoods. Higher levels of physical and structural inadequacy, crime, drug-related activity, social instability, and social isolation were associated with higher concentration of persons with serious mental illness in the neighborhood's adult population. CONCLUSIONS: The differences in neighborhood characteristics identified in this study point to factors that merit closer attention as potential barriers or facilitators in the functioning, participation, and community integration of persons with serious mental illness. PMID- 23677445 TI - Silencing of pancreatic adenocarcinoma upregulated factor by RNA interference inhibits the malignant phenotypes of human colorectal cancer cells. AB - Aberrant expression of pancreatic adenocarcinoma upregulated factor (PAUF), a novel secretory protein, has been reported in several types of cancer. However, in colorectal cancer (CRC), whether PAUF also plays its oncogenic role through the Wnt/beta-catenin pathway and its effect in regulating malignant phenotypes of CRC is unknown. In this study, we detected PAUF and beta-catenin expression levels by immunohistochemical analysis and real-time PCR in CRC tissues, adjacent non-tumor tissues (NATs) and 5 CRC cell lines. The results demonstrated that the expression of PAUF and beta-catenin in tumor tissues was higher than in NATs. Moreover, the expression of PAUF was correlated with the expression of beta catenin in both tumor tissues and NATs. The HCT116 cell line, which has the highest PAUF expression of the 5 cell lines, was transfected with small interfering RNA (siRNA) targeting on PAUF, which significantly downregulated the expression of PAUF in cancer cells. Successful transfection was confirmed by using RT-PCR and western blot analysis. Further studies demonstrated that PAUF siRNA inhibited the proliferation of CRC cells, promoted their apoptosis and induced G0/G1 cell cycle arrest. At the same time, PAUF-siRNA inhibited the invasion, adhesion and migration of the tumor cells. In conclusion, this study suggested that PAUF was expressed in CRC at a high frequency. Interference of PAUF may be an effective strategy for regulating malignant phenotypes of CRC through the Wnt/beta-catenin pathway. PMID- 23677446 TI - Histogenesis and prognostic value of myenteric spread in colorectal cancer: a Japanese multi-institutional study. AB - BACKGROUND: The histogenesis of the pattern of cancer spread along Auerbach's plexus (myenteric spread: MS) remains unclear and its prognostic value in colorectal cancer (CRC) has not been thoroughly investigated. METHODS: Pathology slides of 2845 pT2/pT3/pT4 CRCs stained with hematoxylin-eosin (H&E) were reviewed at 10 institutions. MS was classified into 2 groups depending on whether it was accompanied by the finding of perineural invasion (PN) within the lesion. In addition, immunohistochemical staining (D2-40, S100, CD56, synaptophysin) was performed for serially sectioned specimens from 50 CRCs diagnosed as having PN negative MS. RESULTS: MS was observed in 504 patients (17.7 %); 360 patients were classified as having PN-positive MS and 144 as having PN-negative MS. The 5-year disease-free survival rate of patients with MS was lower than that of patients without MS (63.3 vs 82.7 %, P < 0.0001); however, there was no significant difference in survival outcome according to the presence or absence of intralesion PN in MS. Multivariate analysis showed that the prognostic impact of MS was independent of conventional prognosticators including T and N stages, vascular invasion and extramural PN. In all the tumors having PN-negative MS, remnants of neural tissue were identified within or around cancer nests located at the leading edge of MS. CONCLUSIONS: MS is an important prognostic factor for CRC. This feature is the result of cancer development with replacement of Auerbach's plexus and can be classified as intramural PN. The clinical significance of "Pn1" in the UICC/AJCC TNM classification could be enhanced by individual assessment both intramurally and extramurally. PMID- 23677442 TI - Lactobacillus surface layer proteins: structure, function and applications. AB - Bacterial surface (S) layers are the outermost proteinaceous cell envelope structures found on members of nearly all taxonomic groups of bacteria and Archaea. They are composed of numerous identical subunits forming a symmetric, porous, lattice-like layer that completely covers the cell surface. The subunits are held together and attached to cell wall carbohydrates by non-covalent interactions, and they spontaneously reassemble in vitro by an entropy-driven process. Due to the low amino acid sequence similarity among S-layer proteins in general, verification of the presence of an S-layer on the bacterial cell surface usually requires electron microscopy. In lactobacilli, S-layer proteins have been detected on many but not all species. Lactobacillus S-layer proteins differ from those of other bacteria in their smaller size and high predicted pI. The positive charge in Lactobacillus S-layer proteins is concentrated in the more conserved cell wall binding domain, which can be either N- or C-terminal depending on the species. The more variable domain is responsible for the self-assembly of the monomers to a periodic structure. The biological functions of Lactobacillus S layer proteins are poorly understood, but in some species S-layer proteins mediate bacterial adherence to host cells or extracellular matrix proteins or have protective or enzymatic functions. Lactobacillus S-layer proteins show potential for use as antigen carriers in live oral vaccine design because of their adhesive and immunomodulatory properties and the general non-pathogenicity of the species. PMID- 23677447 TI - Structural modulation of the biological activity of gold nanoparticles functionalized with a carbonic anhydrase inhibitor. AB - Gold nanoparticles (AuNPs) have gained attention for their potential and application in different fields, e.g. nanomedicine. This study explores the surface functionalization of AuNP with inhibitors of carbonic anhydrases (CAs, EC 4.2.1.1). Some CA transmembrane isoforms have been recognized as therapeutic targets for the treatment of hypoxic tumors. Embedding a CA inhibitory function onto a nanosized unit has been proved to enable selective targeting of transmembrane isoforms. We report the preparation in aqueous media, the characterization and CA inhibition tests of AuNPs coated with a sulfonamide (SA) derivative, already known for its inhibitory activity toward CAs. The physico chemical characterization of SA-coated AuNPs was performed with a combination of scattering and spectroscopic techniques. We detect a threshold effect of the SA concentration on the final hydrodynamic and core sizes of the capped nanoparticles and on their stability over aggregation. These modified nanoparticles were assayed for inhibition of some CA transmembrane isoforms (CA IX and XII) as well as of two cytosolic isoforms (CA I and II), and show interesting inhibitory efficiency in the submicromolar range and some selectivity for transmembrane isoforms. PMID- 23677448 TI - Movement in a gravitational field: The question of limb interarticular coordination in terrestrial vertebrates. AB - In this paper, we demonstrated that interarticular coordination of terrestrial tetrapods emerges from an environment highly constrained by friction and the gravitational field. We briefly review recent works on the jumping behavior in squamates, lemurs and amphibians. We then explore previously published work as well as some unpublished experimental data on human jumping. Finally, we end by inferring locomotion in some of the first limbed vertebrates using a simulation procedure. All these data show that despite changes in shape, structure, and motor controls of taxa, the same spatio-temporal sequence of joint displacements always occurs when the movement is executed in a terrestrial environment. Comparison with aquatic locomotion argues for the hypothesis that this pattern emerged in early terrestrial tetrapods as a response to the gravitational constraint and the terrestrial frictional environment. PMID- 23677449 TI - Flu-like symptoms and associated immunological response following therapy with botulinum toxins. AB - We aimed to define the frequency and risk factors associated with flu-like symptoms (FLS) and other systemic symptoms following treatment with botulinum toxins (BoNT) and correlate them with the immunological response as determined by blood cytokines. The study involved prospective clinical and serological evaluation for cytokine analysis in patients receiving BoNT for movement disorders. We interviewed 218 patients about FLS following BoNT injections and prospectively studied 117 patients (females 67.5 %; mean age 59.74 +/- 12.39 years) treated with BoNT in a total of 143 treatment cycles. While no patient reported any FLS at baseline, the symptom complex was subsequently reported in 19 patients (16.3 %) and in 20 (14 %) treatment cycles, with at least one systemic symptom reported in 49 (42 %) patients in 59 (41.3 %) treatment cycles. FLS and at least one symptom were reported more frequently by women (P = 0.006 and P = 0.049, respectively) and by younger patients: 55.6 versus 61.7 years (P = 0.022). Although the symptoms were usually considered mild, they were rated as moderate to serious after 18 (12 %) cycles. The following interleukins showed increased levels at 7-10 days after the BoNT injections: IL-1beta, IL-8, GROalpha, eotaxin, MCP-1 and 2, RANTES, TARC, and inducible protein 10 (IP10), but only the latter showed significantly increased levels in patients with FLS: 69 versus 3 pg/ml (P = 0.007). FLS and other systemic symptoms occur after about 14 % of treatment visits in patients receiving BoNT. IP10 levels correlate with the presence and severity of FLS. PMID- 23677450 TI - The effects of cocaine on different redox forms of cysteine and homocysteine, and on labile, reduced sulfur in the rat plasma following active versus passive drug injections. AB - The aim of the present studies was to evaluate cocaine-induced changes in the concentrations of different redox forms of cysteine (Cys) and homocysteine (Hcy), and products of anaerobic Cys metabolism, i.e., labile, reduced sulfur (LS) in the rat plasma. The above-mentioned parameters were determined after i.p. acute and subchronic cocaine treatment as well as following i.v. cocaine self administration using the yoked procedure. Additionally, Cys, Hcy, and LS levels were measured during the 10-day extinction training in rats that underwent i.v. cocaine administration. Acute i.p. cocaine treatment increased the total and protein-bound Hcy contents, decreased LS, and did not change the concentrations of Cys fractions in the rat plasma. In turn, subchronic i.p. cocaine administration significantly increased free Hcy and lowered the total and protein bound Cys concentrations while LS level was unchanged. Cocaine self administration enhanced the total and protein-bound Hcy levels, decreased LS content, and did not affect the Cys fractions. On the other hand, yoked cocaine infusions did not alter the concentration of Hcy fractions while decreased the total and protein-bound Cys and LS content. This extinction training resulted in the lack of changes in the examined parameters in rats with a history of cocaine self-administration while in the yoked cocaine group an increase in the plasma free Cys fraction and LS was seen. Our results demonstrate for the first time that cocaine does evoke significant changes in homeostasis of thiol amino acids Cys and Hcy, and in some products of anaerobic Cys metabolism, which are dependent on the way of cocaine administration. PMID- 23677452 TI - Receptors to interleukin-6 and adhesion molecules on circulating monocyte subsets in acute myocardial infarction. AB - The role of individual monocyte subsets in inflammation and recovery post myocardial infarction (MI) is insufficiently understood. It was the objective of this study to evaluate the dynamics of monocyte expression of receptors to vascular cell adhesion molecule (VCAM-1r), intercellular adhesion molecule (ICAM 1r), and interleukin-6 (IL-6r) following MI and their relation to inflammatory cytokines, fibrinolytic factors and annexin V-binding microparticles. Expression of VCAM-1r, ICAM-1r, IL-6r on CD14++CD16-(Mon1), CD14++CD16+(Mon2), CD14+CD16++(Mon3) monocyte subsets were quantified by flow cytometry in patients with ST-elevation MI (STEMI, n=50), non-STEMI (n=48) and stable coronary artery disease (n=40). In STEMI, parameters were measured on days 1, 3, 7, 30. On admission with STEMI, VCAM-1r expression was reduced on Mon1 (p=0.007), Mon2 (p=0.036), Mon3 (p=0.005), whilst in NSTEMI there was significant up-regulation of expression by Mon2 (p=0.024) and Mon3 (p=0.049). VCAM-1r on Mon1 correlated positively with plasma IL-1beta levels (p=0.001). IL-6r was reduced on Mon2 in acute STEMI, with upregulation of the receptor on Mon1 and Mon2 during follow-up. IL-6r density correlated negatively with plasma levels of tissue-type plasminogen activator (p=0.0005 for Mon1, p=0.001 for Mon2 and Mon3), and positively with annexin V-binding microparticles (p=0.03 for Mon1, p=0.005 for Mon2 and p=0.005 for Mon3). There was no change in monocyte ICAM-1r expression. In conclusion, expression of IL-6r and VCAM-1r is reduced on circulating monocyte subsets involved in inflammatory responses in STEMI. This may represent a regulatory feed back mechanism aiming to re-balance the marked inflammation which is typically present following acute MI or selective homing of monocytes with high receptor expression to damaged myocardium. PMID- 23677453 TI - Surgery and proton pump inhibitors for treatment of vocal process granulomas. AB - The aim of this study was to analyze the outcomes of vocal process granulomas treated with surgery and proton pump inhibitors and to specify related factors of recurrence. The medical records of patients with diagnosis of vocal process granuloma between 2000 and 2012 were reviewed. All patients were treated with surgery and proton pump inhibitors for at least 1 month. Forty-one patients were reviewed; mean follow-up time was 45 months. There was no recurrence among the patients who had a recent history of intubation. The recurrence rates of contact granuloma was 38.7 %, and significantly related to the frequency of surgery (P = 0.042), but was not significantly associated with the history of acid reflux (P = 0.676) and vocal abuse (P = 0.447), lesion size (P = 0.203) or surgical techniques (P = 0.331). Surgery combined with proton pump inhibitors was partially effective for the vocal process granulomas, especially with intubated patients. However, repeat surgery for recurrent contact granuloma should be preceded with caution due to high recurrence rates. PMID- 23677454 TI - Bypassing the challenges of lower-limb electromyography by using ultrasonography: AnatoMUS-II. PMID- 23677455 TI - Evaporation kinetics of aqueous acetic acid droplets: effects of soluble organic aerosol components on the mechanism of water evaporation. AB - The presence of organic surfactants in atmospheric aerosol may lead to a depression of cloud droplet growth and evaporation rates affecting the radiative properties and lifetime of clouds. Both the magnitude and mechanism of this effect, however, remain poorly constrained. We have used Raman thermometry measurements of freely evaporating micro-droplets to determine evaporation coefficients for several concentrations of acetic acid, which is ubiquitous in atmospheric aerosol and has been shown to adsorb strongly to the air-water interface. We find no suppression of the evaporation kinetics over the concentration range studied (1-5 M). The evaporation coefficient determined for 2 M acetic acid is 0.53 +/- 0.12, indistinguishable from that of pure water (0.62 +/- 0.09). PMID- 23677456 TI - Synthesis and characterization of inorganic-organic hybrid materials based on the intercalation of stable organic radicals into a fluoromica clay. AB - Hybrid materials, in which stable organic radical cations are intercalated into layered inorganic host materials, can be successfully synthesized via an ion exchange reaction in a layered fluoromica clay, to yield recyclable heterogeneous catalysts for oxidation of various alcohols. We have conducted systematic synthetic and structural studies on the intercalation of the radical cations 4 (diethylmethylammonium)-2,2,6,6-tetramethylpiperidin-1-oxyl (DEMTEP), 1-[2-(4 amino-2,2,6,6-tetramethyl-1-piperidinyloxyl)-2-oxoethyl]-1'-methyl-4,4' bipyridinium (VIOTEP), and 2-(3-N-methylpyridinium)-4,4,5,5-tetramethyl-4,5 dihydro-1H-imidazol-1-oxyl-3-N-oxide (m-MPYNN) into a synthetic fluoromica clay named Somasif(r) ME 100, Na(2x)Mg(3.0-x)Si4O10(F(y)OH(1-y))2 (x = 0.33, y = 0.98). The guest-host interactions in these intercalation compounds have been characterized by X-ray powder diffraction and solid-state NMR of the constituent nuclei ((23)Na, (19)F, and (29)Si) of the Somasif structure. The intercalation process can be conveniently monitored using (23)Na MAS-NMR. Guest-guest interactions have been probed by magnetic susceptibility measurements as well as EPR and (1)H MAS NMR experiments. The (1)H MAS-NMR line widths and chemical shifts probe modifications in the electron spin density distributions and/or intermolecular interactions between the electron spins of the guest species. Despite these indications of weakly interacting spins, magnetic susceptibility measurements are consistent with the near-absence of cooperative magnetism. The VIOTEP and DEMTEP inclusion compounds demonstrate catalytic activity for the oxidation of benzyl alcohol, using NaOCl as a co-oxidant. Although the radical ion species is partially leached out under these conditions (ionic exchange with Na(+) in solution) the catalytic activity remains for up to 40 subsequent cycles. Fully leached materials can be regenerated by catalyst re-loading and this process can be conveniently monitored by X-band EPR spectroscopy. PMID- 23677457 TI - The predictive influence of family and neighborhood assets on fighting and weapon carrying from mid- to late adolescence. AB - Using a developmental, social-ecological approach to understand the etiology of health-risk behavior and inform primary prevention efforts, we assess the predictive effects of family and neighborhood social processes on youth physical fighting and weapon carrying. Specifically, we focus on relationships among youth and their parents, family communication, parental monitoring, as well as sense of community and neighborhood informal social control, support, concerns, and disorder. This study advances knowledge through its investigation of family and neighborhood structural factors and social processes together, employment of longitudinal models that estimate effects over adolescent development, and use of self-report and observational measures. Data from 1,093 youth/parent pairs were analyzed from the Youth Assets Study using a Generalized Estimating Equation approach; family and neighborhood assets and risks were analyzed as time varying and lagged. Similar family assets affected physical fighting and weapon carrying, whereas different neighborhood social processes influenced the two forms of youth violence. Study findings have implications for the primary prevention of youth violence, including the use of family-based approaches that build relationships and parental monitoring skills and community-level change approaches that promote informal social control and reduce neighborhood concerns about safety. PMID- 23677458 TI - Examining the process of change in an evidence-based parent training intervention: a qualitative study grounded in the experiences of participants. AB - While strong research evidence demonstrates that parent training interventions are capable of preventing child behavioral problems, much less is known about how the participants in these programs experience the change process. The purpose of this study was to provide a better understanding of how parents' experiences in an evidence-based parent training intervention led to change in their parenting practices, based on the first-person accounts of program participants. Qualitative data were collected through in-depth, individual interviews with parents who had completed the intervention known as Parent Management Training the Oregon Model (PMTOTM). Data were analyzed according to principles of the grounded theory approach, using the constant comparative method and a sequential process of open, axial, and selective coding. Study findings suggest that parents make active and intentional efforts to attempt, appraise, and apply the intervention material within their various life contexts, contributing to change in their parenting practices. Aspects of intervention content, method of delivery, and the role of the interventionist were also found to be important. This study can guide further prevention research into the mechanisms of change operating in parent training interventions and has the potential to inform continued efforts to adapt and implement evidence-based parent training interventions. PMID- 23677459 TI - Strain-induced macroscopic magnetic anisotropy from smectic liquid-crystalline elastomer-maghemite nanoparticle hybrid nanocomposites. AB - We combine tensile strength analysis and X-ray scattering experiments to establish a detailed understanding of the microstructural coupling between liquid crystalline elastomer (LCE) networks and embedded magnetic core-shell ellipsoidal nanoparticles (NPs). We study the structural and magnetic re-organization at different deformations and NP loadings, and the associated shape and magnetic memory features. In the quantitative analysis of a stretching process, the effect of the incorporated NPs on the smectic LCE is found to be prominent during the reorientation of the smectic domains and the softening of the nanocomposite. Under deformation, the soft response of the nanocomposite material allows the organization of the nanoparticles to yield a permanent macroscopically anisotropic magnetic material. Independent of the particle loading, the shape memory properties and the smectic phase of the LCEs are preserved. Detailed studies on the magnetic properties demonstrate that the collective ensemble of individual particles is responsible for the macroscopic magnetic features of the nanocomposite. PMID- 23677460 TI - What do outpatients with schizophrenia and mood disorders want to learn about their illness? AB - OBJECTIVE: Psychiatric patients currently have access to a plethora of information about their illness. However, little systematic research has explored what psychiatric patients would like to learn about their illness. This study addressed the knowledge gap by asking outpatients with schizophrenia and mood disorders what they wished to learn about their illness and how they preferred to learn this information. METHODS: An exploratory survey of psychiatric outpatients was conducted between April 2011 and June 2012. A total of 202 outpatients with a diagnosis of either schizophrenia or related disorder (ICD-10 codes F20-F29) (N=106) or mood disorder (ICD-10 codes F30-F39) (N=96) were interviewed after routine meetings with their psychiatrist. Interviews were conducted with open- and closed-ended questions in outpatient clinics across East London, United Kingdom. Open-ended questions were analyzed qualitatively, and closed-ended questions were analyzed quantitatively. RESULTS: Over two-thirds of psychiatric outpatients (68%) reported that they would like to learn more about their illness. Overall, patients' wishes for learning were heterogeneous. However, both diagnostic groups ranked "the cause of the illness" as their top information need. Most patients preferred to learn through one-to-one conversations with their psychiatrist (schizophrenia, 92%; mood disorder, 84%). CONCLUSIONS: In regard to educating patients about their illness, there is no one-size-fits-all approach. Health care professionals need to be sensitive to individual learning preferences, which vary and can include group-based approaches. The results have implications for the training of psychiatrists. In particular, psychiatrists need to be equipped to address patients' questions about the cause of the illness. PMID- 23677461 TI - Capsule commentary on Efird et al., identifying the risks of anticoagulation in patients with substance abuse. PMID- 23677462 TI - Depression research in under-resourced populations: an academic-community partnership. PMID- 23677464 TI - CD11c(high)CD8+ regulatory T cell feedback inhibits CD4 T cell immune response via Fas ligand-Fas pathway. AB - Regulatory T cells can restrict the uncontrolled immune response and inflammation, avoiding pathologic immune injury to the host and thus playing important roles in the maintenance of immune homeostasis. Until recently, many subsets of CD4 and CD8 regulatory T cells have been reported. In this study, we identified CD11c(high)CD8(+) T cells as a new subset of CD8(+) regulatory T cells. During Listeria monocytogenes and Staphylococcus aureus infection, two subsets of CD8 T cells were classified according to the expression level of CD11c, including CD11c(low)CD8(+) and CD11c(high)CD8(+) T cells. CD11c(low)CD8(+) T cells, existing during the whole period of infection, act as conventional activated T cells to kill target cells in a perforin-dependent manner. Interestingly, CD11c(high)CD8(+) T cells appeared only at a late stage of infection, expressed relatively high CD122 and low CD69, did not secrete IFN gamma, IL-10, TGF-beta, and exhibited much more potent cytotoxicity against target cells via Fas ligand-Fas pathway in an Ag-independent manner. Ligation of CD11c was important in the cytotoxicity of CD11c(high)CD8(+) T cells. Furthermore, CD11c(high)CD8(+) T cells could directly kill the activated CD4 T cells both in vitro and in vivo, whereas CD11c(low)CD8(+) T cells could not. Thus, we identified an infection-induced new subset of CD11c(high)CD8(+) regulatory T cells, which might contribute to protect host from pathological immune injure. Our results indicate that CD11c(+)CD8(+) T cells are constitute a heterogeneous population that can be divided further into regulatory CD11c(high)CD8(+) T cell subset and effector CD11c(low)CD8(+) T cell subset, thus adding insight to the role of CD8 T cells in immune response and regulation. PMID- 23677463 TI - Intraoperative ICG plasma disappearance rate helps to predict absence of early postoperative complications after orthotopic liver transplantation. AB - Early postoperative complications after orthotopic liver transplantation (OLT) are a common problem in intensive care medicine. Adequate assessment of initial graft function remains difficult, however, plasma disaperance rate of indocyanine green (PDRICG) may have an additional diagnostic and prognostic value in this setting. We retrospectively evaluated the ability of intraoperative PDRICG values to predict absence of early postoperative complications in 62 subjects. PDRICG was measured non-invasively by pulse dye densitometry during surgery and was correlated with initial graft function. At the end of surgery, PDRICG was higher in patients without complications: 24.9 % min(-1) (n = 40) versus 21.0 % min(-1), (n = 22; p = 0.034). An area under the ROC curve (AUROC) for PDRICG was 0.70, while the AUROC for pH, lactate and PT at ICU admission were 0.53, 0.50 and 0.46, respectively. The AUROC of serum bilirubin and PT at postoperative day 5 were 0.68 and 0.49, respectively. The optimal cut-off PDRICG value for predicting absence of development early postoperative complications was determined to be 23.5 % min(-1) with 72.4 % sensitivity and 71.0 % specificity. Intraoperative point-of-care PDRICG measurement during OLT already predicts absence of early postoperative complications, better and earlier than clinically used laboratory parameters. PMID- 23677465 TI - Glia maturation factor-gamma negatively modulates TLR4 signaling by facilitating TLR4 endocytic trafficking in macrophages. AB - TLR4 signaling must be tightly regulated to provide both effective immune protection and avoid inflammation-induced pathology. Thus, the mechanisms that negatively regulate the TLR4-triggered inflammatory response are of particular importance. Glia maturation factor-gamma (GMFG), a novel actin depolymerization factor/cofilin superfamily protein that is expressed in inflammatory cells, has been implicated in mediating neutrophil and T cell migration, but its function in macrophage immune response remains unclear. In the current study, the role of GMFG in the LPS-induced TLR4-signaling pathway was investigated in THP-1 macrophages and human primary macrophages. LPS stimulation of macrophages decreased GMFG mRNA and protein expression. We show that GMFG negatively regulates LPS-induced activation of NF-kappaB-, MAPK-, and IRF3-signaling pathways and subsequent production of proinflammatory cytokines and type I IFN in human macrophages. We found that endogenous GMFG localized within early and late endosomes. GMFG knockdown delayed LPS-induced TLR4 internalization and caused prolonged TLR4 retention at the early endosome, suggesting that TLR4 transport from early to late endosomes is interrupted, which may contribute to enhanced LPS induced TLR4 signaling. Taken together, our findings suggest that GMFG functions as a negative regulator of TLR4 signaling by facilitating TLR4 endocytic trafficking in macrophages. PMID- 23677467 TI - Human IL-2 mutein with higher antitumor efficacy than wild type IL-2. AB - IL-2 has been used for the treatment of melanoma and renal cell carcinoma, but this therapy has limited efficacy and severe toxicity. Currently, it is assumed that part of the limited efficacy is due to the IL-2-driven preferential expansion of regulatory T cells, which dampen the antitumor immunity. In this study, we characterize a human IL-2 mutant with higher antitumor efficacy and lower toxicity than wild type human IL-2 (wtIL-2). The mutant differs from wtIL-2 by four mutations at the interface with the alpha subunit of IL-2R. The IL-2 mutant induces in vitro proliferation of CD8(+)CD44(hi) and NK1.1 cells as efficiently as does wtIL-2, but it shows a reduced capacity to induce proliferation of CD4(+)Foxp3(+) regulatory T cells. The IL-2 mutant shows a higher antimetastatic effect than does wtIL-2 in several transplantable tumor models: the experimental metastasis model of MB16F0 melanoma and the experimental and spontaneous metastasis models for the mouse pulmonary carcinoma 3LL-D1222. Relevantly, the IL-2 mutant also exhibits lower lung and liver toxicity than does wtIL-2 when used at high doses in mice. In silico simulations, using a calibrated mathematical model, predict that the properties of IL-2 mutein are a consequence of the reduction, of at least two orders of magnitude, in its affinity for the alpha subunit of IL-2R (CD25). The human IL-2 mutant described in the present work could be a good candidate for improving cancer therapy based on IL-2. PMID- 23677466 TI - B lymphocyte "original sin" in the bone marrow enhances islet autoreactivity in type 1 diabetes-prone nonobese diabetic mice. AB - Effective central tolerance is required to control the large extent of autoreactivity normally present in the developing B cell repertoire. Insulin reactive B cells are required for type 1 diabetes in the NOD mouse, because engineered mice lacking this population are protected from disease. The Cg-Tg(Igh 6/Igh-V125)2Jwt/JwtJ (VH125Tg) model is used to define this population, which is found with increased frequency in the periphery of NOD mice versus nonautoimmune C57BL/6 VH125Tg mice; however, the ontogeny of this disparity is unknown. To better understand the origins of these pernicious B cells, anti-insulin B cells were tracked during development in the polyclonal repertoire of VH125Tg mice. An increased proportion of insulin-binding B cells is apparent in NOD mice at the earliest point of Ag commitment in the bone marrow. Two predominant L chains were identified in B cells that bind heterologous insulin. Interestingly, Vkappa4-57-1 polymorphisms that confer a CDR3 Pro-Pro motif enhance self-reactivity in VH125Tg/NOD mice. Despite binding circulating autoantigen in vivo, anti-insulin B cells transition from the parenchyma to the sinusoids in the bone marrow of NOD mice and enter the periphery unimpeded. Anti-insulin B cells expand at the site of autoimmune attack in the pancreas and correlate with increased numbers of IFN gamma-producing cells in the repertoire. These data identify the failure to cull autoreactive B cells in the bone marrow as the primary source of anti-insulin B cells in NOD mice and suggest that dysregulation of central tolerance permits their escape into the periphery to promote disease. PMID- 23677469 TI - Spontaneous miscarriages are explained by the stress/glucocorticoid/lipoxin A4 axis. AB - Despite various suspected causes, ranging from endocrine and genetic to infectious and immunological aspects, the molecular mechanisms of miscarriage still remain enigmatic. This work provides evidence that downregulation of 11beta hydroxysteroid dehydrogenase (HSD) type 2, the key enzyme inactivating glucocorticoid activities, insults the pregnant inflammatory milieu by inhibiting the biosynthesis of lipoxin A4 (LXA4), a metabolite of arachidonic acid, leading to an early loss of the pregnancy. Both LXA4 and its biosynthetic enzymes were found to be decreased in women with spontaneous miscarriages and in the murine miscarriage model. Replenishing LXA4 reversed LPS-induced miscarriages in mouse models, whereas blocking LXA4 signaling resulted in miscarriages in the pregnant mice. The protective effect of LXA4 might be explained by LXA4's role in regulating uterine and placental inflammatory factors and mast cells. The underlying molecular mechanism involved miscarriage-inducing infections or stresses that downregulate the expression of 11beta-HSD2, but not 11beta-HSD1, resulting in increases in glucocorticoid activity and decreases in LXA4. Together, these findings suggest that the stress/glucocorticoid/LXA4 axis might be a common pathway through which miscarriages occur. PMID- 23677468 TI - Identification of a novel mode of complement activation on stimulated platelets mediated by properdin and C3(H2O). AB - Elevated numbers of activated platelets circulate in patients with chronic inflammatory diseases, including atherosclerosis and coronary disease. Activated platelets can activate the complement system. Although complement activation is essential for immune responses and removal of spent cells from circulation, it also contributes to inflammation and thrombosis, especially in patients with defective complement regulation. Proinflammatory activated leukocytes, which interact directly with platelets in response to vascular injury, are among the main sources of properdin, a positive regulator of the alternative pathway. The role of properdin in complement activation on stimulated platelets is unknown. Our data show that physiological forms of human properdin bind directly to human platelets after activation by strong agonists in the absence of C3, and bind nonproportionally to surface CD62P expression. Activation of the alternative pathway on activated platelets occurs when properdin is on the surface and recruits C3b or C3(H2O) to form C3b,Bb or a novel cell-bound C3 convertase [C3(H2O),Bb], which normally is present only in the fluid phase. Alternatively, properdin can be recruited by C3(H2O) on the platelet surface, promoting complement activation. Inhibition of factor H-mediated cell surface complement regulation significantly increases complement deposition on activated platelets with surface properdin. Finally, properdin released by activated neutrophils binds to activated platelets. Altogether, these data suggest novel molecular mechanisms for alternative pathway activation on stimulated platelets that may contribute to localization of inflammation at sites of vascular injury and thrombosis. PMID- 23677470 TI - Accelerated turnover of MHC class II molecules in nonobese diabetic mice is developmentally and environmentally regulated in vivo and dispensable for autoimmunity. AB - The H2-A(g7) (A(g7)) MHC class II (MHCII) allele is required for type 1 diabetes (T1D) in NOD mice. A(g7) not only has a unique peptide-binding profile, it was reported to exhibit biochemical defects, including accelerated protein turnover. Such defects were proposed to impair Ag presentation and, thus, self-tolerance. Here, we report measurements of MHCII protein synthesis and turnover in vivo. NOD mice and BALB/c controls were labeled continuously with heavy water, and splenic B cells and dendritic cells were isolated. MHCII molecules were immunoprecipitated and digested with trypsin. Digests were analyzed by liquid chromatography/mass spectrometry to quantify the fraction of newly synthesized MHCII molecules and, thus, turnover. MHCII turnover was faster in dendritic cells than in B cells, varying slightly between mouse strains. Some A(g7) molecules exhibited accelerated turnover in B cells from young, but not older, prediabetic female NOD mice. This acceleration was not detected in a second NOD colony with a high incidence of T1D. Turnover rates of A(g7) and H2-A(d) were indistinguishable in (NOD * BALB/c) F1 mice. In conclusion, accelerated MHCII turnover may occur in NOD mice, but it reflects environmental and developmental regulation, rather than a structural deficit of the A(g7) allele. Moreover, this phenotype wanes before the onset of overt T1D and is dispensable for the development of autoimmune diabetes. Our observations highlight the importance of in vivo studies in understanding the role of protein turnover in genotype/phenotype relationships and offer a novel approach for addressing this fundamental research challenge. PMID- 23677471 TI - Control of chronic mycobacterium tuberculosis infection by CD4 KLRG1- IL-2 secreting central memory cells. AB - The bacille Calmette-Guerin vaccine provides very efficient protection in standard animal models of Mycobacterium tuberculosis challenge. We show in this article that although bacille Calmette-Guerin controlled M. tuberculosis growth for 7 wk of infection, the protection was gradually lost as the infection entered the chronic phase. The regrowth of M. tuberculosis coincided with an almost complete disappearance of IL-2-producing CD4 T cells. Booster vaccination with a subunit vaccine (Ag85B-ESAT-6+CAF01) expanded IL-2(+) CD4(+) T cell coexpressing either TNF-alpha or TNF-alpha/IFN-gamma, and the maintenance of this population in the late stage of infection was associated with enhanced control of bacterial growth. The IL-2(+) CD4(+) T cell subsets were KLRG1(-) (nonterminally differentiated), were found to be CD62L(high), and further maintained a pronounced proliferative and cytokine-producing potential in the draining lymph nodes, when the animals were challenged 2 y postvaccination. These results suggest that the CD4(+) KLRG1(-) IL-2-secreting subsets are central memory T cells with the potential to continuously replenish the T cells at the site of infection and prevent attrition and functional exhaustion. PMID- 23677472 TI - Canonical and noncanonical Wnt proteins program dendritic cell responses for tolerance. AB - Ag-presenting dendritic cells (DCs) interpret environmental signals to orchestrate local and systemic immune responses. They govern the balance between tolerance and inflammation at epithelial surfaces, where the immune system must provide robust pathogen responses while maintaining tolerance to commensal flora and food Ags. The Wnt family of secreted proteins, which control epithelial and hematopoietic development and homeostasis, is emerging as an important regulator of inflammation. In this study, we show that canonical and noncanonical Wnts directly stimulate murine DC production of anti-inflammatory cytokines. Wnt3A triggers canonical beta-catenin signaling and preferentially induces DC TGF-beta and VEGF production, whereas Wnt5A induces IL-10 through alternative pathways. The Wnts also alter DC responses to microbe- or pathogen-associated molecular patterns, inhibiting proinflammatory cytokine induction in response to TLR ligands and promoting DC generation of Foxp3(+) regulatory T cells. Moreover, although both Wnts suppress proinflammatory responses to bacterial endotoxin and to TLR1/2, TLR7, and TLR9 ligands, Wnt5A, but not Wnt3A, inhibits IL-6 production in response to the viral mimic, polyinosinic:polycytidylic acid. Thus, Wnt family members directly and differentially regulate DC functions, an ability that may contribute to the balance between tolerance and inflammation at epithelial sites of exposure to microbes and environmental Ags. PMID- 23677474 TI - Pseudogout-associated inflammatory calcium pyrophosphate dihydrate microcrystals induce formation of neutrophil extracellular traps. AB - Pseudogout is an autoinflammatory condition triggered by calcium pyrophosphate dehydrate (CPPD) crystal deposition in the joints. The innate immune system is irritated by and responds to the presence of the crystals with an inflammatory response. The synovial fluid contains activated inflammatory macrophages and neutrophil granulocytes. Several details of crystal-induced macrophage activation were recently uncovered, but very little is known about interactions of CPPD crystals with neutrophils. In this study, we show that human neutrophils engulf CPPD crystals and form large amounts of neutrophil extracellular traps (NETs) in vitro. Released extracellular DNA binds myeloperoxidase and citrullinated histone H4. CPPD crystal-stimulated neutrophils and their nuclear DNA undergo morphological changes characteristic for NET formation. The ERK/MEK signaling pathway, heat shock protein 90, PI3K, and an intact cytoskeleton are required for CPPD-induced NET formation. Blocking crystal-activated respiratory burst has, however, no effect on NETs. Human neutrophils release IL-1beta and IL-8 in response to CPPD crystals, and blocking CXCR2, the main IL-8R, diminishes NET formation. Proinflammatory cytokines, TNF-alpha, GM-CSF, and IL-1beta, increase NET release by the crystals. Enhanced bacterial killing by CPPD-induced NETs demonstrates their ability to cause cellular damage. Our work documents and provides details about extracellular trap release in human neutrophils activated by CPPD microcrystals. We suggest that crystal-triggered NET formation can be a novel contributor to inflammatory conditions observed in CPPD crystal-driven synovitis. PMID- 23677473 TI - Dipeptidyl peptidase IV is a human and murine neutrophil chemorepellent. AB - In Dictyostelium discoideum, AprA is a secreted protein that inhibits proliferation and causes chemorepulsion of Dictyostelium cells, yet AprA has little sequence similarity to any human proteins. We found that a predicted structure of AprA has similarity to human dipeptidyl peptidase IV (DPPIV). DPPIV is a serine protease present in extracellular fluids that cleaves peptides with a proline or alanine in the second position. In Insall chambers, DPPIV gradients below, similar to, and above the human serum DPPIV concentration cause movement of human neutrophils away from the higher concentration of DPPIV. A 1% DPPIV concentration difference between the front and back of the cell is sufficient to cause chemorepulsion. Neutrophil speed and viability are unaffected by DPPIV. DPPIV inhibitors block DPPIV-mediated chemorepulsion. In a murine model of acute respiratory distress syndrome, aspirated bleomycin induces a significant increase in the number of neutrophils in the lungs after 3 d. Oropharyngeal aspiration of DPPIV inhibits the bleomycin-induced accumulation of mouse neutrophils. These results indicate that DPPIV functions as a chemorepellent of human and mouse neutrophils, and they suggest new mechanisms to inhibit neutrophil accumulation in acute respiratory distress syndrome. PMID- 23677475 TI - Sialyltransferase ST3Gal-III regulates Siglec-F ligand formation and eosinophilic lung inflammation in mice. AB - Sialic acid-binding, Ig-like lectin (Siglec)-F is highly expressed on mouse eosinophils and plays an important role in regulating levels of eosinophilic lung inflammation. In this study we investigated the mechanism of constitutive and inducible Siglec-F ligand expression by lung airway epithelial cells and inflammatory cells in wild-type (WT) and genetically altered mice (ST3Gal-III heterozygotes, Fuc-TIV/VII double null, STAT6 null). Flow cytometry demonstrated that Siglec-F ligands are constitutively expressed in vitro and in vivo in selected lung cell types (epithelial cells, eosinophils, macrophages, and mast cells, but not CD4, CD8, or B cells) and are induced in response to divergent stimuli, including innate stimuli (TLR ligands, Alternaria), Th2 cytokines (IL-4, IL-13), and adaptive immune stimuli (OVA allergen). Furthermore, studies of deficient mice demonstrated the greater importance of the sialyltransferase ST3Gal-III compared with fucosyltransferases Fuc-TIV/VII in the synthesis of the constitutive and inducible Siglec-F ligands by lung epithelial and nonepithelial cells. In keeping with this, ST3Gal-III heterozygote mice (deficient in expression of Siglec-F ligands) also had significantly enhanced OVA-induced eosinophilic airway inflammation associated with reduced eosinophil apoptosis. Reduced eosinophil apoptosis in the lung of ST3Gal-III-deficient mice is likely mediated by reduced epithelial expression of Siglec-F ligands as WT eosinophils (which highly express Siglec-F) cultured with ST3Gal-III-deficient epithelial cells (which do not express Siglec-F ligand) showed reduced eosinophil apoptosis compared with WT eosinophils cultured with WT epithelial cells. Overall, these studies demonstrate that ST3Gal-III plays an important role in Siglec-F ligand formation and eosinophil apoptosis with resultant effects on eosinophilic inflammation in the lung. PMID- 23677476 TI - Assembly of the TLR2/6 transmembrane domains is essential for activation and is a target for prevention of sepsis. AB - TLR2, together with TLR1 and TLR6, is essential for detecting lipopeptides and bacterial cell wall components such as lipoteichoic acid from Gram-positive bacteria. In this study, we report that transmembrane domain (TMD)-derived peptides from TLR2 and TLR6 specifically inhibit TLR2 activation. Secretion of the cytokines TNF-alpha and IL-6 by cultured macrophages (RAW264.7 cell line) was inhibited by these peptides in response to TLR2 activation by lipoteichoic acid (TLR2/6 activator) or palmitoyl (3)-Cys-Ser-Lys(4)-OH (TLR2/1 activator) but not by LPS (TLR4 activator). Extensive biophysical and biochemical assays, combined with GALLEX experiments, show that these peptides heterodimerize with their complementary TMDs on their reciprocal protein. These results suggest that TLR2/6/1 TMD assembly is essential for activating this complex. Importantly, when administered to mice inflicted by TLR2, but not TLR4-driven lethal inflammation, a selected peptide rescued 60% of these septic mice, showing potent in vivo inhibition of TNF-alpha and IL-6 secretion. Furthermore, this peptide also showed high protection in a whole bacteria model. Owing to the importance of TLR2 regulation under a variety of pathological conditions, compounds that can fine tune this activity are of great importance. PMID- 23677477 TI - Soluble CD27-pool in humans may contribute to T cell activation and tumor immunity. AB - The interaction between CD27 and its ligand, CD70, has been implicated in regulating cellular immune responses to cancer. In this article, we report on the role of soluble CD27 (sCD27) in T cell activation and its elevation in the serum of cancer patients after immunotherapy. In vitro, sCD27 is preferentially derived from activated CD4(+) T cells. Adding sCD27 to stimulated PBMCs increases T cell activation and proliferation, and is associated with the immunologic synapse related proteins myosin IIA, high mobility group box 1, and the TCR Vbeta-chain. The pool of serum sCD27 is shown to be greater in healthy donors than in cancer patients. However, metastatic cancer patients treated with immunotherapy showed a significant increase in the serum sCD27-pool posttherapy (p < 0.0005); there was also an increased trend toward an association between enhanced sCD27-pool posttherapy and overall survival (p = 0.022). The identification of sCD27 as an immune modulator associated with enhanced human T cell activation in vitro and in vivo provides a rationale for developing new immunotherapeutic strategies aimed at enhancing sCD27 for treating cancer and potentially other diseases. PMID- 23677478 TI - A potential suppressive effect of natural antisense IL-1beta RNA on lipopolysaccharide-induced IL-1beta expression. AB - Although more than half of genomic loci are believed to have antisense transcription, whether antisense transcription is involved in cytokine expression has not been studied. In this study, we show that some loci of innate immunity related genes do have antisense transcripts. We investigated the effect of several antisense RNAs, including anti-4-1BBL, anti-p100, and anti-IL-1beta, on their cognate sense gene's expression in macrophages. We found that overexpression of antisense IL-1beta transcript suppressed IL-1beta expression. Anti-IL-1beta is complementary to the sequence in the 5' upstream region of the IL-1beta promoter. Its mediated inhibition of IL-1beta production occurred at the transcriptional level. Anti-IL-1beta did not alter the methylation status of the IL-1beta promoter. However, chromatin immunoprecipitation assays revealed that the anti-IL-1beta transcript can change the chromatin structure of the IL-1beta promoter by decreasing H3K4 trimethylation on the promoter, which is at least part of the mechanism underlying the reduced binding of RNA polymerase II to the IL-1beta promoter upon anti-IL-1beta expression. Our data suggest that some antisense transcripts of innate immunity-related genes play a role by regulating cytokine expression. PMID- 23677479 TI - Basic fibroblast growth factor upregulates survivin expression in hepatocellular carcinoma cells via a protein kinase B-dependent pathway. AB - Basic fibroblast growth factor (bFGF) plays an important role in tumor angiogenesis. Several studies have reported that bFGF may influence cell apoptosis through different signaling pathways. The aim of the present investigation was to study the effect of bFGF on the activities of protein kinase B (PKB)/survivin and cell apoptosis in hepatocellular carcinoma cells (Bel-7402). We treated Bel-7402 cells with bFGF and wortmannin [phosphatidylinositol 3-kinase (PI3K)-specific inhibitor] separately to observe the expression of PKB and survivin detected with RT-PCR and western blotting. The cell cycle and apoptosis were assayed with flow cytometry. We found a significant increase in PKB expression in the group treated with 25 ng/ml bFGF for 10 min (P<0.05), and this effect was significantly inhibited by pretreatment with wortmannin (200 nM) for 1 h. After treatment with 10 ng/ml bFGF, the expression of survivin mRNA in Bel 7402 cells increased significantly, and reached the peak at 16 h (P<0.05); however, this effect could be significantly inhibited by pretreatment with wortmannin (200 mM) in a time-dependent manner. Following incubation with 25 ng/ml bFGF for 10 min, the apoptosis rate and M phase were significantly decreased and S phase cells increased compared with the wortmannin (200 nM) treated group. When this group was pretreated with wortmannin (200 nM) for 1 h, the apoptosis rate and S phase were significantly increased, M phase cells decreased. The results revealed that wortmannin could induce high apoptosis rates in hepatocellular carcinoma cells, and bFGF could inhibit the cell apoptosis induced by wortmannin. These findings indicate that bFGF could rapidly activate the PKB activities, enhance the expression of survivin and the proliferation of hepatocellular carcinoma cells via the PI3K pathway, thus it may serve as a novel molecule for early targeting therapy of hepatocellular carcinoma. PMID- 23677480 TI - Effects of outpatient treatment on risk of arrest of adults with serious mental illness and associated costs. AB - OBJECTIVE: This study examined whether possession of psychotropic medication and receipt of outpatient services reduce the likelihood of posthospitalization arrest among adults with serious mental illness. A secondary aim was to compare service system costs for individuals who were involved with the justice system and those who were not. METHODS: Claims data for prescriptions and treatments were used to describe patterns and costs of outpatient services between 2005 and 2012 for 4,056 adult Florida Medicaid enrollees with schizophrenia or bipolar disorder after discharge from an index hospitalization. Multivariable time-series analysis tested the effects of medication and outpatient services on arrest (any, felony, or misdemeanor) in subsequent 30-day periods. RESULTS: A total of 1,263 participants (31%) were arrested at least once during follow-up. Monthly medication possession and receipt of outpatient services reduced the likelihood of any arrests (misdemeanor or felony) and of misdemeanor arrests. Possession of medications for 90 days after hospital discharge also reduced the likelihood of arrest. Prior justice involvement, minority racial-ethnic status, and male sex increased the risk of arrest, whereas older age decreased it. Criminal justice and behavioral health system costs were significantly higher for the justice involved group than for the group with no justice involvement. CONCLUSIONS: Routine outpatient treatment, including medication and outpatient services, may reduce the likelihood of arrest among adults with serious mental illness. Medication possession over a 90-day period after hospitalization appears to confer additional protection. Overall, costs were lower for those who were not arrested, even when they used more outpatient services. PMID- 23677481 TI - Evidence on the global measurement model of the Minnesota Living with Heart Failure Questionnaire. AB - PURPOSE: The Minnesota Living with Heart Failure Questionnaire (MLHFQ) is the most widely used health-related quality of life measure in both clinical and research settings. Nevertheless, its measurement model has never been confirmed. This study aims to fill that gap with a large international sample. METHODS: Data from eight studies (3,847 patients with heart failure) from 21 countries were merged and analysed. Common variables included MLHFQ scores, functional capacity, cardiovascular risk factors and the socio-demographic characteristics of the patient. The measurement model of the MLHFQ was assessed by means of exploratory and confirmatory factor analyses (EFA-CFA). The reliability of MLHFQ scores was evaluated using Cronbach's alpha coefficient and the MLHFQ's ability to differentiate among known groups was assessed through severity levels. RESULTS: Findings from the EFA and CFA suggest that the MLHFQ total and domain-specific scores fall within a bifactor model. The physical and emotional scores were supported within the sample, as was the original total score. Furthermore, a third factor was revealed regarding social environment. The reliability coefficient reached 0.9 for almost all physical and total scores. All the MLHFQ mean scores showed the ability to differentiate among functional capacity groups, with most of the effect size coefficients reaching 0.8. CONCLUSIONS: Beyond the suitable degree of reliability and validity displayed by the MLHFQ scores in the different country-specific versions, our results confirmed for the first time the unidimensionality of the most commonly used score in HF patients: the total MLHFQ score. Moreover, the social environment domain identified in this study can now be considered when assessing these patients' HRQL, especially as a relevant outcome with regard to disease management. PMID- 23677482 TI - The effects of primary care on breast cancer mortality and incidence among Medicare beneficiaries. AB - BACKGROUND: Primary care physician (PCP) services may have an impact on breast cancer mortality and incidence, possibly through greater use of screening mammography. METHODS: The authors conducted a retrospective, 1:1 matching case control study using the Surveillance, Epidemiology, and End Results (SEER) Medicare-linked database to examine use of PCP services and their association with breast cancer mortality and incidence. SEER cases representing the 3 outcomes of interest (breast cancer mortality, all-cause mortality among women diagnosed with breast cancer, and breast cancer incidence) were matched to unaffected controls from the 5% Medicare random sample. Conditional logistic regression was used to examine associations between physician visits and breast cancer outcomes while controlling for other covariates. RESULTS: Women who had 2 or more PCP visits during the 24-month assessment interval had lower odds of breast cancer mortality, all-cause mortality, and late-stage breast cancer diagnosis compared with women who had no PCP visits or 1 PCP visit while adjusting for other covariates, including mammography and non-PCP visits. Women who had 5 to 10 PCP visits had 0.69 times the odds of breast cancer mortality (95% confidence interval, 0.63-0.75), 0.83 times the odds of death from any cause having been diagnosed with breast cancer (95% confidence interval, 0.79-0.87), and 0.67 times the odds of a late-stage breast cancer diagnosis (95% confidence interval, 0.61-0.73) compared with those who had no PCP visits or 1 PCP visit. CONCLUSIONS: The current findings suggest that PCPs play an important role in reducing breast cancer mortality among the Medicare population. Further research is needed to better understand the impact of primary care on breast cancer and other cancers that are amendable to prevention or early detection. PMID- 23677483 TI - Lipoma arborescens of the biceps tendon sheath. AB - Lipoma arborescens, described as lipomatous infiltration and distention of synovial villi resulting in a frond-like appearance, most frequently affects the suprapatellar recess of the knee. While there have been reports of this entity involving the upper extremity joints, bursa, and tendon sheaths, we present the first reported case of lipoma arborescens isolated to the biceps tendon sheath. We describe imaging and histologic findings with clinical correlation. PMID- 23677484 TI - A highly selective ratiometric fluorescent chemosensor for Cd2+ ions. AB - A phenanthroxazole-based fluorescent sensor for Cd(2+) has been developed. Of particular significance is the specific ratiometric response of the sensor toward Cd(2+) without interference from other biologically important metal ions including Zn(2+). The test paper made of this sensor exhibits both absorption and fluorescent color changes when exposed to Cd(2+) aqueous solution. PMID- 23677485 TI - Multimodality imaging evaluation of esophageal cancer: staging, therapy assessment, and complications. AB - Esophageal cancer is among the leading causes of cancer-related deaths worldwide. The management of patients with esophageal cancer is determined to a large extent by patient performance status, location of the primary cancer, and stage of disease at presentation. Multimodality regimens combining neoadjuvant chemotherapy and/or radiotherapy followed by surgery have been increasingly used in suitable candidates with locally advanced cancer. There is substantial morbidity and mortality associated with this treatment strategy, which makes appropriate patient selection important. Endoscopic esophageal ultrasound is the optimal modality to evaluate the local extent of the primary tumor and diagnose locoregional nodal metastasis. Computed tomography is more useful in detecting distant nodal and systemic metastasis. Positron emission tomography/CT is increasingly being used in patient management and improves the accuracy of staging, particularly in the detection of distant nodal and systemic metastatic disease. In this article, we review the role of imaging in the staging, assessment of therapeutic response, and detection of recurrent disease, as well as the evaluation of therapeutic complications in patients with esophageal cancer. PMID- 23677486 TI - Characteristics of fundus autofluorescence and drusen in the fellow eyes of Japanese patients with exudative age-related macular degeneration. AB - BACKGROUND: The main purpose of this study is to investigate the characteristics of fundus autofluorescence (FAF) and area of soft drusen among the fellow eyes of unilateral typical age-related macular degeneration (typical AMD) and polypoidal choroidal vasculopathy (PCV) in Japanese patients. METHODS: FAF images were obtained from the fellow eyes of unilateral typical AMD (n = 64), unilateral PCV (n = 95), unilateral retinal angiomatous proliferation (RAP) (n = 4) and 56 control subjects, then classified into normal, minimal-change, and abnormal patterns by two graders. Interobserver variability between two graders and intraobserver variability were assessed for FAF classifications, and cases with inconsistent decisions were finally classified by the third grader. Soft drusen were segmented and their total areas were compared between the fellow eyes of typical AMD and PCV. Area(s) with increased autofluorescence were segmented to assess the relationship with soft drusen area(s). RESULTS: Assessment for interobserver variability between two graders and intraobserver variability in one grader showed substantial agreement (kappa = 0.70) and almost perfect agreement (kappa = 0.85), respectively. In the final decision mediated by third grader, the proportions of eyes with either minimal-change FAF pattern or abnormal FAF pattern in the fellow eyes of both typical AMD (37 cases, 58 %) and PCV (47 cases, 49 %) were significantly higher than that of the control cases (15 cases, 27 %; p < 0.01). The proportion of abnormal FAF pattern in the fellow eyes of typical AMD (20 cases, 31 %) was higher than that of PCV (15 cases, 16 %; p < 0.05). Total soft drusen areas in the fellow eyes of typical AMD (0.369 +/- 0.718 mm(2)) were larger than those of PCV (0.173 +/- 0.408 mm(2); p < 0.05), and those in the eyes with abnormal FAF pattern were larger than those with minimal-change FAF pattern or normal FAF pattern (p < 0.01). Image analysis revealed a relationship between increased autofluorescence and soft drusen, especially in the cases with large total soft drusen areas. CONCLUSIONS: FAF characteristics were different between the fellow eyes of unilateral typical AMD and PCV in Japan, which might be due to the difference of total soft drusen areas between them. PMID- 23677487 TI - Osmoprotective effects of supplemental epidermal growth factor in an ex vivo multilayered human conjunctival model under hyperosmotic stress. AB - BACKGROUND: To analyze the effects of supplemental epidermal growth factor (EGF) and the roles of inflammatory cytokines (interleukin [IL]-6) in an ex vivo dry eye model under hyperosmotic stress using a multilayered culture of human conjunctival epithelial cells (HCECs). METHODS: Multilayered cultures of HCECs were exposed to hyperosmotic stress (400 mOsm/L) for 24 h in addition to 0.5 ng/mL EGF (low-EGF group) or 25 ng/mL EGF (high-EGF group). Apoptosis was analyzed using the TUNEL assay. Cell proliferation was measured using the [3H] thymidine incorporation assay. The expression of IL-6, EGF, EGF receptor (EGFR), and phosphorylated extracellular signal-regulated kinase (p-ERK) was measured by western blot analysis. The secretion of IL-6 was measured using ELISA. Western blot analysis was also performed using antibodies against cleaved caspase-3. RESULTS: The percentage of apoptotic cells was lower in the high-EGF group (6.7%) than in the low-EGF group (10.3%). The high-EGF group demonstrated increased proliferation (323.7 counts/min in the low-EGF group vs 649.1 counts/min in the high-EGF group). EGF induced higher phosphor-EGFR expression and upregulated p ERK in HCECs. In addition, EGF significantly decreased the secretion of IL-6 and cleaved caspase-3 in HCECs. CONCLUSIONS: The level of IL-6 was increased in the ex vivo HCEC dry-eye model that was under hyperosmotic stress. Supplemental EGF reduces the level of IL-6, decreases apoptosis, and increases proliferation. These findings indicate that EGF has potential as a therapeutic agent for the treatment of dry eyes. PMID- 23677488 TI - Putting a face in its place: in- and out-group membership alters the N170 response. AB - Two mechanisms have been proposed to account for the difficulty in recognizing faces of other racial groups (the other-race effect; ORE): perceptual expertise and social cognitive factors. Focusing on the social cognitive factors alone, we manipulated in-group and out-group memberships based on two social categories (nationality and university affiliation), and controlled for perceptual expertise by testing Caucasian participants with Caucasian faces only. Using event-related potentials (ERPs) and focusing on the N170, a brain electrical component sensitive to faces, we provide for the first time strong support for the social cognitive influence on face processing within 200 ms. After participants learned the social categories, the N170 latency differentiated between double in-group and double out-group faces, taking longer to process the latter. In comparison, without group memberships, there was no difference in N170 latency among the faces. These results are consistent with recent findings of behavioral and imaging research, providing further support for the social cognitive model and its potential for understanding ORE. PMID- 23677489 TI - Age-related differences in event-related potentials for early visual processing of emotional faces. AB - With advancing age, processing resources are shifted away from negative emotional stimuli and toward positive ones. Here, we explored this 'positivity effect' using event-related potentials (ERPs). Participants identified the presence or absence of a visual probe that appeared over photographs of emotional faces. The ERPs elicited by the onsets of angry, sad, happy and neutral faces were recorded. We examined the frontocentral emotional positivity (FcEP), which is defined as a positive deflection in the waveforms elicited by emotional expressions relative to neutral faces early on in the time course of the ERP. The FcEP is thought to reflect enhanced early processing of emotional expressions. The results show that within the first 130 ms young adults show an FcEP to negative emotional expressions, whereas older adults show an FcEP to positive emotional expressions. These findings provide additional evidence that the age-related positivity effect in emotion processing can be traced to automatic processes that are evident very early in the processing of emotional facial expressions. PMID- 23677491 TI - Setbacks, pleasant surprises and the simply unexpected: brainwave responses in a language comprehension task. AB - This event-related potential (ERP) study explored the behaviour of N400 and post N400 frontal positivities (pN400FP) during the processing of emotionally biased and unbiased sentences that randomly led to highly expected or unexpected word outcomes. Unexpected outcomes (as determined by sentence completion written tests) elicited significantly larger N400 and pN400FP responses than did highly expected outcomes. Emotionally neutral outcomes triggered a significant N400 expectancy effect across all scalp locations, including frontal sites, whereas emotionally biased outcomes elicited a significant N400 effect localized to posterior scalp regions. The subsequent pN400FP effect was significant only when emotional expectations were violated and not when emotionally neutral sentences led to unexpected outcomes. This frontal effect, linked to the processing of lexically unexpected but plausible words, showed larger amplitudes for unexpected pleasant surprises than for unexpected setbacks. Our results support the view that the pN400FP response to unexpected verbal outcomes entails more than a generic reaction to a lexical 'misprediction'. Rather, they favour the hypothesis that the affective content of the sentence being processed influences the effort needed to override a lexical prediction, such that more effort is needed to override a pessimistic prediction than an optimistic one. PMID- 23677490 TI - Impaired inhibitory control in anorexia nervosa elicited by physical activity stimuli. AB - Besides food restriction, hyperactivity is considered a key behavioral trait of anorexia nervosa (AN), playing a major role in the pathogenesis and progression of the disorder. However, the underlying neurophysiology remains poorly understood. We used functional magnetic resonance imaging during two affective go/no-go tasks to probe inhibitory control in response to stimuli depicting physical activity vs inactivity and food vs non-food in AN patients compared with 26 healthy athlete and non-athlete controls. We hypothesized that neural correlates of behavioral inhibition are biased by the emotional information of the stimuli in AN patients, leading to a differential neural inhibitory pattern during the two tasks. Indeed, we found reduced response inhibition for food and non-food images in the putamen, while stimuli depicting physical activity resulted in an exaggerated response of the prefrontal cortex (PFC) and cerebellum in AN patients. However, both AN patients and athletes revealed an increased response in the somatosensory cortex to physical activity stimuli. These results suggest that physical activity stimuli might place an increased demand on the inhibitory control system in AN patients. The resulting hyperactivity of the PFC and cerebellum may lead to altered executive function and motor control, sustaining increased physical activity in AN patients. PMID- 23677492 TI - Protecting a transgene expression from the HAC-based vector by different chromatin insulators. AB - Human artificial chromosomes (HACs) are vectors that offer advantages of capacity and stability for gene delivery and expression. Several studies have even demonstrated their use for gene complementation in gene-deficient recipient cell lines and animal transgenesis. Recently, we constructed an advance HAC-based vector, alphoid(tetO)-HAC, with a conditional centromere. In this HAC, a gene loading site was inserted into a centrochromatin domain critical for kinetochore assembly and maintenance. While by definition this domain is permissive for transcription, there have been no long-term studies on transgene expression within centrochromatin. In this study, we compared the effects of three chromatin insulators, cHS4, gamma-satellite DNA, and tDNA, on the expression of an EGFP transgene inserted into the alphoid(tetO)-HAC vector. Insulator function was essential for stable expression of the transgene in centrochromatin. In two analyzed host cell lines, a tDNA insulator composed of two functional copies of tRNA genes showed the highest barrier activity. We infer that proximity to centrochromatin does not protect genes lacking chromatin insulators from epigenetic silencing. Barrier elements that prevent gene silencing in centrochromatin would thus help to optimize transgenesis using HAC vectors. PMID- 23677493 TI - Factors associated with diagnosis and operability of chronic thromboembolic pulmonary hypertension. A case-control study. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary hypertension (IPAH) share a similar clinical presentation, and a differential diagnosis requires a thorough workup. Once CTEPH is confirmed, patients who can be safely operated have to be identified. We investigated risk factors associated with CTEPH and IPAH, and the criteria for the selection of operable CTEPH patients. This case-control study included 436 consecutive patients with CTEPH and 158 with IPAH in eight European centres, between 2006 and 2010. Conditions identified as risk factors for CTEPH included history of acute venous thromboembolism (p < 0.0001), large size of previous pulmonary embolism (p = 0.0040 in univariate analysis), blood groups non-O (p < 0.0001 in univariate analysis), and older age (p = 0.0198), whereas diabetes mellitus (p = 0.0006), female gender (p = 0.0197) and higher mean pulmonary artery pressure (p = 0.0103) were associated with increased likelihood for an IPAH diagnosis. Operability of CTEPH patients was associated with younger age (p = 0.0108), proximal lesions (p <= 0.0001), and pulmonary vascular resistance below 1200 dyn.s.cm-5 (p = 0.0080). Non-operable CTEPH patients tended to be less differentiable from IPAH patients by risk factor analysis than operable patients. This study confirmed the association of CTEPH with history of acute venous thromboembolism and blood groups non-O, and identified diabetes mellitus and higher mean pulmonary artery pressure as factors suggesting an IPAH diagnosis. Non-operable CTEPH is more similar to IPAH than operable CTEPH regarding risk factors. PMID- 23677494 TI - No need to compete, better to cooperate. PMID- 23677495 TI - Elucidation of monomerization effect of PVP on chlorin e6 aggregates by spectroscopic, chemometric, thermodynamic and molecular simulation studies. AB - Molecular aggregation in aqueous media is one of the factors which largely affects the efficacy of photosensitizers in photodynamic therapy. Chlorin e6 (Ce6) in aggregated form is known to exhibit markedly reduced therapeutic effects. In the present study, aggregate to monomer conversion of Ce6 was investigated as a function of pH and polyvinylpyrrolidone (PVP) concentration by simple absorption and fluorescence spectroscopic techniques. Aggregation of Ce6 was observed in the pH range of 2 to 6 as indicated by changes in UV-vis absorption spectra, fluorescence emission spectra and relative quantum yield. Novel chemometric approach was considered for determining the relative monomerization efficiency of different grades of PVP. The chemometric analysis and binding constant study both strongly revealed that the Ce6-PVP complex was more efficiently formed with PVP of the lowest molecular weight (K17). Thermodynamic parameters, such as the heat of entropy and enthalpy, showed that complex formation was largely attributed to hydrophobic interaction between Ce6 and PVP. This was found to be consistent with the results obtained from molecular simulation study. PMID- 23677496 TI - Baroreflex sensitivity analysis: spontaneous methodology vs. Valsalva's maneuver. AB - INTRODUCTION: Spontaneous analysis techniques and Valsalva's maneuver (VM) are often used as a non-pharamcological approach to assess both sympathetic (sBRS) and cardiovagal (cBRS) baroreflex sensitivity. Despite their wide utilization, no studies have assessed the intra-individual reliability between these analysis techniques. Accordingly, we hypothesized that spontaneous BRS would be positively correlated to VM BRS. METHODS: Heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) were measured in 26 healthy subjects (age, 22 +/- 1 year; 14 men and 12 women) during 10 min supine rest and 3 VM at 40 mmHg expiratory pressure (15 s, 1 min recoveries). For spontaneous BRS, relations between diastolic BP and MSNA were used to determine sBRS, while relations between systolic BP and R-R interval were used to determine cBRS. During VM, sBRS was the ratio of MSNA and the maximum diastolic BP reduction during early phase II, and cBRS was derived from linear relations between systolic BP and R-R interval during early phase II (i.e., hypotensive stimulus) and phase IV (i.e., hypertensive stimulus). RESULTS: Spontaneous sBRS was significantly correlated to VM sBRS (r = 0.516, p = 0.036). In contrast, spontaneous cBRS from up-up sequence was not correlated to VM phase IV cBRS (r = 0.274, p = 0.109). Similarly, spontaneous cBRS from down-down sequence was not correlated to VM phase II cBRS (r = 0.199, p = 0.207). CONCLUSION: In conclusion, our findings demonstrate positive association between spontaneous sBRS and VM sBRS, but there is no correlation between spontaneous and VM cBRS. PMID- 23677498 TI - Non-recovery of ACT in a patient with heparin-induced thrombocytopenia type II during mitral valve replacement using argatroban anticoagulation. AB - Argatroban was used as the anticoagulant during cardiopulmonary bypass (CPB) in a patient with heparin-induced thrombocytopenia (HIT) type II undergoing mitral valve replacement. Dosage was reduced because of preoperative congestive liver disorder. Perioperative coagulability was poor, and, ultimately, failure of hemostasis led to a fatal outcome. Although argatroban use as an anticoagulant for HIT is reported, the optimal dose has not been established. During long-term CPB, increasing the total dosage may extend anticoagulant ability, leading to dose dependence. Because no antagonist for argatroban exists, failure of hemostasis might occur. PMID- 23677497 TI - Bcl10 is an essential regulator for A20 gene expression. AB - A20, a tumor suppressor in several types of lymphomas, has been suggested to be an nuclear factor kappa B (NF-kappaB) target gene; conversely, the deubiquitylation activity of A20 is required for inhibition of Bcl10-mediated activation of NF-kappaB. BCL10, which is activated in a recurrent chromosomal translocation that causes human mucosa-associated lymphoid tissue lymphomas, is known to be essential for NF-kappaB activation in B cells. We report here that Bcl10 upregulates endogenous A20 gene expression in B lymphocytes upon B-cell receptor engagement of anti-IgM. Transient transfection assays in HEK 293 cells indicate that Bcl10 can activate the A20 promoter, which contains NF-kappaB binding sites. We also construct a theoretical structure of mouse Bcl10 and analyze the structure by molecular modeling and molecular dynamics simulation. Lastly, we found that marginal zone B cells from BCL10-transgenic mice proliferate more readily than wild-type B cells, whereas, surprisingly, the transgenic follicular B cells from these mice proliferate comparably to wild-type cells. Collectively, our results indicate that Bcl10 is an essential regulator of A20 gene expression and B-cell proliferation mediated by B-cell receptor signaling. PMID- 23677499 TI - The unrelenting fall of the pharmacological treatment of obesity. AB - Nowadays pharmacological therapy to limit obesity has reached a critical stage: not only have Authorities limited the use of antiobesity drugs due to their proven inefficacy and dangerous side effects, but bariatric surgery has delivered better results. At present, when the number of obese subjects is growing exponentially worldwide and more and more pathological mechanisms inducing fat accumulation have been discovered, no drugs are available to help patients and physicians to limit one the most dreadful causes of death. Following the failures of promising drugs as sibutramine and rimonabant, many companies stopped to invest in the field of obesity pharmacotherapy. At the same time, leading Authorities have started to require more solid evidence before providing authorization for these drugs to enter the market. This review aims at revising the failed promises of antiobesity drugs and describing the few potential future candidates in order to shed some light in the still uncertain field of antiobesity drugs. It also provides a critical contribution to the ongoing debate among scientists, clinicians, patients and Authorities on the possibility to treat obesity with pharmacological drugs. PMID- 23677500 TI - Cytotoxic T-lymphocyte associated antigen 4 polymorphism and Hashimoto's thyroiditis susceptibility: a meta-analysis. AB - The association between cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) exon 1 +49 A/G polymorphism and Hashimoto's thyroiditis (HT) has been widely studied. The results, however, are mixed. This study provides a comprehensive evaluation of the relationship between the genetic risks of CTLA-4 +49 A/G polymorphism and HT. A meta-analysis was conducted in over 4,600 subjects included in 18 case control studies that were published up to November 15th, 2012. Our meta-analysis indicated that the CTLA-4 genotype was associated with the risk of HT in the allele comparison, homozygote comparison, heterozygote comparison, the dominant genetic model and the recessive genetic model. In the dominant genetic model, variant G allele carriers (GG + GA) of CTLA-4 +49 A/G polymorphism increased the risk of HT comparing to the homozygote AA [odds ratio (OR) = 1.70, 95% confidence interval (CI) 1.37-2.12 for GG + AG vs. AA]. The analysis by ethnicity groups suggested that Asian population (OR = 2.13, 95% CI 1.48-3.07 for GG + AG vs. AA) and Caucasian population (OR = 1.47, 95% CI 1.13-1.91 for GG + AG vs. AA) had significant increased HT risks. The association remained significant after adjusting for publication bias using the trim and fill method. Sensitivity analysis showed that the results were less stable, suggesting that these results should be explained with caution. In summary, this meta-analysis suggested that CTLA-4 +49 A/G polymorphism may be a risk factor for HT. PMID- 23677501 TI - [Stem-cell transplantation in systemic sclerosis?--Cardiac health is decisive for the patient's benefit]. PMID- 23677502 TI - [Acute upper gastrointestinal bleeding outside regular working hours: do prognostic scores make sense?]. PMID- 23677503 TI - [Pre-endoscopic assessment to predict outcome of acute upper gastrointestinal bleeding--a retrospective study in patients subject to emergency endoscopy outside regular working hours]. AB - BACKGROUND AND OBJECTIVES: To evaluate the predictive value of pre-endoscopic risk scores in patients with upper gastrointestinal bleeding (UGI-B). PATIENTS AND METHODS: The medical records of patients evaluated by emergency esophago gastro-duodenoscopy (E-EGD) for suspected UGI-B outside regular working hours were retrospectively analysed. RESULTS: During the 75 months of the study period 112 E-EGDs met the inclusion criteria. Mean age was 65.5 +/- 14.7 years. 38.4 % of patients were female. Endoscopy revealed 41 gastro-duodenal ulcers, 16 Mallory Weiss, 13 varices, 4 neoplasia. 72 patients received transfusions, 39 had endoscopic interventions. 2 patients were surgically treated, 16 had recurrent bleeding. 16 of the 110 patients died during hospitalisation. The following sensitivities were found for the Blatchford score (cut-off > 1), the clinical Rockall score (cut-off > 0) and the Adamopoulos score (cut-off > 2) in predicting need for clinical intervention (endoscopic or surgical intervention or transfusion): 100/97.7/93%, recurrent bleeding: 100/100/93.8%, in-hospital mortality: 100/93.8/93.8%, respectively. CONCLUSIONS: The Blatchford score is a suitable tool in determining the need for clinical intervention and the risk of recurrent bleeding and death in patients with UGI-B. The clinical Rockall score and the Adamopoulos score (the latter had originally been developed to predict active UGI-B at endoscopy and was used with a lower cut-off in our study) are inferior alternatives. PMID- 23677504 TI - [Medial calcific sclerosis under long-term anticoagulation with vitamin K antagonists]. AB - BACKGROUND: Vitamin K antagonists not only influence the synthesis of coagulation factors but also the activation of other vitamin K dependent proteins. Among other possible side effects, arterial calcification has been focused on in recent years. HISTORY AND FINDINGS: Four patients under long-term anticoagulation for more than 10 years developed medial calcific sclerosis. In case 1 we identified an unexplained medial calcific sclerosis on x-ray after a trauma by chance. After that we examined the ankle-brachial index of blood pressure in all patients who had received long-term anticoagulation for more than 10 years. Where the index exceeded 1,3 we performed a x-ray-examination of the forefoot. Of the four described patients no one suffered from diabetes mellitus, renal failure or hyperparathyreoidism. Serum calcium was normal in all patients. The severity of the medial calcific sclerosis could not be explained by the initial vascular risk factors. CONCLUSION: In certain patients, even at low vascular risk, a medial calcific sclerosis can appear under long-term anticoagulation with vitamin K antagonists. We conclude that vitamin K antagonists inhibit several proteins which protect the vessels from calcification leading to medial calcific sclerosis. PMID- 23677505 TI - [40-year-old patient with dyspnoe one year after lung transplantation]. PMID- 23677506 TI - [Diabetes treatment in patients with chronic kidney disease]. PMID- 23677507 TI - [Thromboembolic complications in nephrotic syndrome]. AB - Thromboembolic complications are among the most important extrarenal consequences of nephrotic syndrome (NS). In addition to deep vein thrombosis in the legs and pulmonary embolism, NS is very frequently accompanied by renal vein thrombosis. Due to enhanced procoagulatory and antifibrinolytic potential and reduced anticoagulatory potential, multifactor disruption of hemostatic equilibrium leads to hypercoagulability in NS patients, which is aggravated by an increase in blood viscosity and endothelial dysfunction. Circulating antibodies against alpha enolase, a plasmin(ogen)-binding protein, and the possibility of certain molecules being renally eliminated in specific manner are discussed as reasons for the particular frequency of thromboembolic complications in patients with idiopathic membranous nephropathy. Serum albumin concentration is an indicator for the risk of thrombosis in NS patients. When applying the current KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline for glomerulonephritis to NS patients with a serum albumin concentration of less than 25 g/l and at least one additional thrombogenic risk factor, primary prophylactic anticoagulation ("conditioned prophylaxis") with an orally administered vitamin K antagonist (target INR 2-3) is recommended as long as the serum albumin concentration is less than 30 g/l. PMID- 23677508 TI - Cardiac myxosarcoma with thoracic spinal metastasis. AB - Echocardiography revealed a left atrial tumor in a 59-year-old man with back pain that concurrently worsened with left foot drop and loss of the left ankle reflex soon after admission to our hospital. Magnetic resonance imaging of the spine revealed an epidural tumor extending from Th5 with spinal cord compression. The patient was immediately treated by emergency Th4-5 laminectomy and epidural decompression. One month later, a cardiac tumor excised via the left atrial approach was histopathologically diagnosed as myxosarcoma, and the Th5 tumor was consistent with this finding. This is the first report to describe spinal metastasis of cardiac myxosarcoma. PMID- 23677509 TI - Suicide risk among US Service members after psychiatric hospitalization, 2001 2011. AB - OBJECTIVE: The rising rate of suicide and the increase in psychiatric hospitalizations in the U.S. military underscore the need to determine risk among service members in psychiatric care so that targeted interventions and prevention programs are implemented. The purpose of this study was to determine the suicide rates of active-duty U.S. service members after discharge from a psychiatric hospitalization. METHODS: Data from 68,947 patients who had psychiatric hospitalizations at military treatment facilities between 2001 and 2011 were obtained from the Defense Medical Surveillance System. Rates of suicide were compared between the cohort group and the general active-duty U.S. military population. Survival analysis was used to determine time-dependent patterns of suicide after hospital discharge. RESULTS: A total of 153 suicides occurred among the 68,947 service members. The overall suicide rate in the cohort was 71.6 per 100,000 person-years, compared with the rate of 14.2 per 100,000 person-years in the general active-duty U.S. military population. Personnel released from a psychiatric hospitalization were therefore five times more likely to die from suicide. The risk of dying from suicide within the first 30 days after a psychiatric hospitalization was 8.2 times higher than the risk at more than one year after hospitalization. CONCLUSIONS: Active-duty U.S. service members who are released from a psychiatric hospitalization are a group at high risk of suicide. Aggressive safety planning and targeted interventions during and after hospitalization are recommended. PMID- 23677510 TI - The effect of CYP2C9, VKORC1 and CYP4F2 polymorphism and of clinical factors on warfarin dosage during initiation and long-term treatment after heart valve surgery. AB - The dosage of warfarin is restricted due to its narrow therapeutic index, so, the required dose must be adapted individually to each patient. Variations in warfarin dosage are influenced by genetic factors, the changes in patient diet, anthropometric and clinical parameters. To determine whether VKORC1 G3730A and CYP4F2 G1347A genotypes contribute to warfarin dosage in patients during initiation and long-term anticoagulation treatment after heart valve surgery. From totally 307 patients, who underwent heart valve surgery, 189 patients (62 %) who had been treated with warfarin more than 3 months, were included into the study. A hierarchical stepwise multivariate linear regression model showed, that during initiation clinical factors can explain 17 % of the warfarin dose variation. The addition of CYP2C9 and VKORC1 G-1639A genotype raises the accuracy about twice-to 32 %. The CYP4F2 G1347A genotype can add again about 2-34 %. During long-term treatment clinical factors explain about 26 % of warfarin dose variation. If the CYP2C9 *2, *3, VKORC1*2 alleles are detected, model can explain about 49 % in dose variation. The *3 allele of VKORC1 raises the accuracy by 1-50 %. The carriers of CYP4F2 A1347A genotype required higher daily warfarin doses during initiation of warfarin therapy after heart valve surgery than comparing to G/G and G/A carriers, but during the longer periods of warfarin use, the dosage of warfarin depended significantly on VKORC1 *3 allele (G3730A polymorphism) and on the thyroid stimulating hormone level in the blood plasma. PMID- 23677511 TI - Late dislocation is associated with recurrence after total hip arthroplasty. AB - PURPOSE: This study was conducted to examine the risk factors for recurrent dislocation after total hip arthroplasty (THA) and test the hypothesis that late dislocations are associated with recurrence. METHODS: A total of 1,250 hips in 1,017 patients were retrospectively reviewed. All operations were performed through the posterolateral approach with posterior soft tissue repair. An early or late dislocation was defined as a dislocation occurring before or after one year postoperatively, respectively. RESULTS: Dislocation occurred in 36 hips (2.9 %) and 20 of them experienced recurrence. Recurrent dislocations were observed in ten out of 25 hips (40.0 %) with early dislocation; however, ten out of 11 hips (90.9 %) with late dislocation experienced recurrence (p = 0.0046). Multivariate analysis revealed that late dislocation was significantly associated with recurrence with odds ratio of 5.94 per year. Seven in 20 hips with recurrent dislocation required surgical treatment. CONCLUSION: Late dislocation significantly contributed to the development of recurrent dislocations. PMID- 23677513 TI - A role for Myh1 in DNA repair after treatment with strand-breaking and crosslinking chemotherapeutic agents. AB - The highly conserved DNA glycosylase MutY is implicated in repair of oxidative DNA damage, in particular in removing adenines misincorporated opposite 7,8 dihydro-8-oxoguanine (8-oxo-G). The MutY homologues (MutYH) physically associate with proteins implicated in replication, DNA repair, and checkpoint signaling, specifically with the DNA damage sensor complex 9-1-1 proteins. Here, we ask whether MutYH could have a broader function in sensing and repairing different types of DNA damage induced by conventional chemotherapeutics. Thus, we examined if deletion of the Schizosaccharomyces pombe MutY homologue, Myh1, alone or in combination with deletion of either component of the 9-1-1 sensor complex, influences survival after exposure to different classes of DNA damaging chemotherapeutics that do not act primarily by causing 8-oxoG lesions. We show that Myh1 contributes to survival on genotoxic stresses induced by the oxidizing, DNA double strand break-inducing, bleomycins, or the DNA crosslinking platinum compounds, particularly in a rad1 mutant background. Exposure of cells to cisplatin leads to a moderate overall accumulation of Myh1 protein. Interestingly, we found that DNA damage induced by phleomycin results in increased chromatin association of Myh1. Further, we demonstrate that Myh1 relocalizes to the nucleus after exposure to hydrogen peroxide or chemotherapeutics, most prominently seen after phleomycin treatment. These observations indicate a wider role of Myh1 in DNA repair and DNA damage-induced checkpoint activation than previously thought. PMID- 23677512 TI - Cerebrospinal fluid and plasma oxidative stress biomarkers in different clinical phenotypes of neuroinflammatory acute attacks. Conceptual accession: from fundamental to clinic. AB - Oxidative stress is revealed as the main contributor in the pathophysiology of neuroinflammation. Analyzing plasma and cerebrospinal fluid (CSF) of patients with different clinical phenotypes of neuroinflammation, defined as clinically isolated syndrome (CIS), and those defined as relapsing remitting multiples sclerosis (RRMS), we tested peripheral and CNS oxidative stress intensity in these neuroinflammatory acute attacks. All obtained values changes were assessed regarding clinical and radiological features of CNS inflammation. The obtained results revealed an increase in malondialdehyde levels in plasma and CSF in CIS and RRMS patients compared to control values (p < 0.05). The obtained values were most prevailed in both study group, CIS and RRMS, in patients with severe clinical presentation (p < 0.05). Measured activities of catalase and total superoxide dismutase were higher in CIS and RRMS patients in plasma compared to control values (p < 0.05), parallel with an increased catalase activity and decrease in superoxide dismutase activity in CSF regarding values obtained in control group (p < 0.05). The positive correlations regarding clinical score were obtained for all tested biomarkers (p < 0.01). Although the positive correlations were observed in MDA levels in plasma and CSF, for both study patients, and their radiological findings (p < 0.01), and a negative correlation in plasma SOD activity and CIS patients' radiological findings (p < 0.01), no other similar correlations were obtained. These findings might be useful in providing the earliest antioxidative treatment in neuroinflammation aimed to preserve total and CNS antioxidative capacity parallel with delaying irreversible, later neurological disabilities. PMID- 23677514 TI - In vivo Gram staining of tinea versicolor. PMID- 23677515 TI - High incidence of venous thromboembolism despite electronic alerts for thromboprophylaxis in hospitalised cancer patients. AB - Many cancer patients are at high risk of venous thromboembolism (VTE) during hospitalisation; nevertheless, thromboprophylaxis is frequently underused. Electronic alerts (e-alerts) have been associated with improvement in thromboprophylaxis use and a reduction of the incidence of VTE, both during hospitalisation and after discharge, particularly in the medical setting. However, there are no data regarding the benefit of this tool in cancer patients. Our aim was to evaluate the impact of a computer-alert system for VTE prevention in patients with cancer, particularly in those admitted to the Oncology/Haematology ward, comparing the results with the rest of inpatients at a university teaching hospital. The study included 32,167 adult patients hospitalised during the first semesters of years 2006 to 2010, 9,265 (28.8%) with an active malignancy. Appropriate prophylaxis in medical patients, significantly increased over time (from 40% in 2006 to 57% in 2010) and was maintained over 80% in surgical patients. However, while e-alerts were associated with a reduction of the incidence of VTE during hospitalisation in patients without cancer (odds ratio [OR] 0.31; 95% confidence interval [CI], 0.15-0.64), the impact was modest in cancer patients (OR 0.89; 95% CI, 0.42-1.86) and no benefit was observed in patients admitted to the Oncology/Haematology Departments (OR 1.11; 95% CI, 0.45 2.73). Interestingly, 60% of VTE episodes in cancer patients during recent years developed despite appropriate prophylaxis. Contrary to the impact on hospitalised patients without cancer, implementation of e-alerts for VTE risk did not prevent VTE effectively among those with malignancies. PMID- 23677516 TI - Reducing cancer risk in rural communities through supermarket interventions. AB - Cancer risk is high, and prevention efforts are often minimal in rural communities. Feasible means of encouraging lifestyles that will reduce cancer risk for residents of rural communities are needed. This project developed and tested a model that could be feasibly adopted by rural communities to reduce cancer risk. This model focuses on incorporating multi-faceted cancer risk education in the local supermarket. As the supermarket functions both as the primary food source and an information source in small rural communities, the supermarket focus encourages the development of a community environment supportive of lifestyles that should reduce residents' risk for cancer. The actions taken to implement the model and the challenges that communities would have in implementing the model are identified. PMID- 23677518 TI - High testosterone levels and sensitivity to acute stress in perpetrators of domestic violence with low cognitive flexibility and impairments in their emotional decoding process: a preliminary study. AB - Hormonal and neuropsychological impairment in intimate partner violence (IPV) perpetrators could play a role in domestic violence. For characterizing whether there is a specific psychobiological response to stress, participants who had previously been jailed for IPV and controls were compared for testosterone and cortisol levels, tested for 2D:4D ratio (as an indicator of masculinization), and given several trait questionnaires and neuropsychological tests related to executive functions and theory of mind. After performing the Trier Social Stress Test (TSST), IPV perpetrators experienced decreases in salivary testosterone (T) levels, a moderate worsening of mood, slight anxiety, and a salivary cortisol (C) level increase. Moreover, high basal T was related with high levels of anger and anxiety and worse mood. However, that basal mood does not significantly alter T levels in response to stress. Nonetheless, controls experienced smaller changes in T and larger changes in C and psychological mood. With respect to neuropsychological and cognitive empathic features, IPV perpetrators showed poorer executive performance and emotional recognition than controls. In addition, deficits in both neuropsychological domains were positively associated. Regarding emotional empathy, IPV perpetrators showed higher levels of personal distress than controls. The 2D:4D ratio was lower in IPV perpetrators than in controls. Moreover, only in the former a smaller 2D:4D ratio was related to large increases in T in response to stress and poor emotional recognition. Together with social aspects involved in IPV, differences in psychobiological variables and their relationships could play a relevant role in the onset and perpetuation of violent behavior. PMID- 23677517 TI - CD161 expression characterizes a subpopulation of human regulatory T cells that produces IL-17 in a STAT3-dependent manner. AB - Treg cells are critical for the prevention of autoimmune diseases and are thus prime candidates for cell-based clinical therapy. However, human Treg cells are "plastic", and are able to produce IL-17 under inflammatory conditions. Here, we identify and characterize the human Treg subpopulation that can be induced to produce IL-17 and identify its mechanisms. We confirm that a subpopulation of human Treg cells produces IL-17 in vitro when activated in the presence of IL 1beta, but not IL-6. "IL-17 potential" is restricted to population III (CD4(+) CD25(hi) CD127(lo) CD45RA(-) ) Treg cells expressing the natural killer cell marker CD161. We show that these cells are functionally as suppressive and have similar phenotypic/molecular characteristics to other subpopulations of Treg cells and retain their suppressive function following IL-17 induction. Importantly, we find that IL-17 production is STAT3 dependent, with Treg cells from patients with STAT3 mutations unable to make IL-17. Finally, we show that CD161(+) population III Treg cells accumulate in inflamed joints of patients with inflammatory arthritis and are the predominant IL-17-producing Treg-cell population at these sites. As IL-17 production from this Treg-cell subpopulation is not accompanied by a loss of regulatory function, in the context of cell therapy, exclusion of these cells from the cell product may not be necessary. PMID- 23677519 TI - Chronic health conditions and work ability in the ageing workforce: the impact of work conditions, psychosocial factors and perceived health. AB - PURPOSE: The aim of this study was to determine the influence of work conditions, psychosocial factors and perceived health on the association between the presence of a chronic health condition and (single-item) work ability among workers aged 45 years and older. In addition, we aimed to examine variables associated with work ability for workers with and without a chronic health condition separately. METHODS: The data of this cross-sectional study were obtained from 5,247 workers aged 45 years and older in five different work sectors. Work ability was assessed with the first item of the Work Ability Index. The presence of a chronic health condition was assessed by self-report. Independent variables in the multivariable linear regression analysis were work conditions, psychosocial factors and perceived health status. RESULTS: The presence of a chronic health condition was negatively associated with work ability (B = -0.848). The strength of this association slightly attenuated after subsequently adding individual characteristics (B = -0.824), work conditions (B = -0.805) and more so after adding psychosocial factors (B = -0.704) and especially perceived health variables (B = -0.049) to the model. Variables associated with work ability for workers with and without a chronic health condition were similar. CONCLUSION: Perceived health and psychosocial factors, rather than work conditions, explained the association between the presence of a chronic health condition and work ability. Substantial differences in variables associated with work ability for workers with and without a chronic health condition were not found. Based on the lower mean scores for workers with a chronic health condition and work ability as well for predictors, these workers might have the most benefit by a policy focussing on enhancing these associated variables. PMID- 23677520 TI - Functional and occupational characteristics predictive of a return to work within 18 months after stroke in Japan: implications for rehabilitation. AB - OBJECTIVE: This study examined clinical, functional, and occupational factors associated with return to work within 18 months after stroke, specifically focusing on the impact of higher cortical dysfunction on return to work in the chronic phase. METHODS: This prospective cohort study in 21 hospitals specializing in clinical and occupational health recruited consecutive working age inpatients receiving acute care for their first stroke (n = 351). A unified database was used to extract patient information from hospital records at the time of admission, discharge, and follow-up at 18 months post-stroke. Cox proportional hazard regression analysis was conducted to determine clinical, functional, and occupational factors influencing return to work within 18 months. RESULTS: Of 351 registered stroke patients (280 males, 71 females, mean age +/- SD, 55.3 +/- 7.2 years) who met inclusion criteria, 250 responded to the follow up survey and 101 were lost to follow-up. Half (51%) succeeded in returning to work during the 18-month follow-up after stroke onset. After adjusting for age, gender, and Barthel index at initial rehabilitation, the following factors were identified as significant predictors of a return to work: white-collar versus blue-collar occupation (hazard ratio (HR) 1.5; 95% confidence interval (CI) 1.1 2.2), no aphasia (HR 3.0; 95% CI 1.5-5.9), no attention dysfunction (HR 2.0; 95% CI 1.0-4.0), and walking ability (HR 3.1; 95% CI 1.3-7.1). CONCLUSIONS: This study indicated the importance of tailored rehabilitation to alleviate the impact of higher cortical dysfunction and to support return to work by stroke survivors. PMID- 23677521 TI - Right ventricular metastasis of lung cancer. Persistent ST-segment elevation and constrictive physiology. PMID- 23677522 TI - Does the cement stiffness affect fatigue fracture strength of vertebrae after cement augmentation in osteoporotic patients? AB - PURPOSE: Normal progression of osteoporosis or the rigid reinforcement of the fractured vertebral body with polymethyl methacrylate (PMMA) cement is being discussed as a cause for adjacent-level fractures after vertebroplasty. The purpose of this study was to investigate whether augmentation with low stiffness cement can decrease the risk of adjacent-level fractures in low-quality bone. METHODS: Eighteen female osteoporotic lumbar specimens (L1-L5) were harvested and divided into three groups according to bone mineral density: (I) native; (II) PMMA; (III) modified PMMA (lower stiffness). For the PMMA and modified PMMA groups, a compression fracture was first mechanically induced in L3, and then the fracture received vertebroplasty treatment. The cement stiffness reduction of the modified PMMA group was achieved via an addition of 8 mL of serum to the typical PMMA base. All specimens were exposed to cyclic loading (4 Hz) and a stepwise increasing applied peak force. Cement stiffness was tested according to ISO 5833. RESULTS: A 51% decrease in cement stiffness was achieved in the modified PMMA group (954 +/- 141 vs. 1,937 +/- 478 MPa, p < 0.001). Fatigue fracture force (the force level during cyclic loading at which the deformation experienced a sudden increase; FFF) was significantly affected by bone quality (r (2) = 0.39, p = 0.006) and by the initial fracture force (the force necessary to create the initial fracture in L3 prior to augmentation; r (2) = 0.82, p < 0.001). Using initial fracture force as a covariate, the FFF of the modified PMMA group (1,764 +/- 49 N) was significantly higher than in the PMMA group (1,544 +/- 55 N; p = 0.03). CONCLUSIONS: A possible method to reduce adjacent-level fractures after vertebroplasty in patients with reduced bone quality could be the use of a lower modulus cement. Therefore, mixing cement with biocompatible fluids could prove useful to tailor cement properties in the operating theater. PMID- 23677523 TI - Depressive symptoms are a risk factor for all-cause mortality: results from a prospective population-based study among 3,080 cancer survivors from the PROFILES registry. AB - BACKGROUND: The goal of this large prospective population-based study was to examine the association between depressive symptoms and all-cause mortality among cancer survivors up to 10 years post-diagnosis. METHODS: All currently alive individuals diagnosed with endometrial or colorectal cancer (CRC) between 1998 and 2007 or with lymphoma or multiple myeloma between 1999 and 2008, as registered in the Eindhoven Cancer Registry, received a questionnaire on depressive symptoms (Hospital Anxiety and Depression Scale (HADS)) in 2008 or 2009, respectively; 69 % (n = 3,080) responded. Survival status was obtained from the Central Bureau for Genealogy. RESULTS: Clinically elevated levels of depressive symptoms (HADS cutoff value >=8) were more prevalent in those who died compared to those who survived (38 vs. 19 %, respectively; p < 0.0001). This was also evident across different types of cancer. After adjustment for independent predictors of all-cause mortality, 1-10-year survivors with depressive symptoms had an increased risk of death (hazard ratio (HR) 2.07; 95 % confidence interval (CI) 1.56-2.74; p < 0.0001), and this was also found among 1-2-year survivors (HR, 2.20; 95 % CI, 1.41-3.43; p < 0.001). Sub-analyses among CRC survivors gave the opportunity to adjust for metastasis and showed that depressive symptoms among 1-10-year CRC survivors and 1-2-year CRC survivors increased the risk of death (HR, 1.88; 95 % CI, 1.24-2.83; p < 0.01 and HR, 2.55; 95 % CI, 1.44-4.51; p < 0.001, respectively). CONCLUSIONS: This study showed that patients with depressive symptoms had twofold risk for all-cause mortality, even after adjustment for major clinical predictors. IMPLICATIONS FOR CANCER SURVIVORS: Paying more attention to the recognition and treatment of depressive symptoms seems warranted since depressive symptoms are often underdiagnosed and undertreated in cancer patients. PMID- 23677525 TI - Anxiolytic action of pterostilbene: involvement of hippocampal ERK phosphorylation. AB - Pterostilbene, a natural analog of resveratrol, has diverse health-beneficial properties. However, the neurological activities of this compound are largely unexplored. Here, we report that pterostilbene shows anxiolytic-like actions by down-regulating phosphorylated levels of extracellular regulated kinases in the hippocampus of mice. Adult male mice administered pterostilbene (1-10 mg/kg, p. o.) were subjected to the elevated plus maze test. Pterostilbene manifested anxiolytic activity at 1 and 2 mg/kg doses, demonstrated by increases in % permanence time and number of open arm entries. The locomotor activity of the animals was unaffected at all doses. Western blot analysis revealed a decrease in both extracellular regulated kinase 1 and extracellular regulated kinase 2 phosphorylation in hippocampal homogenates from mice treated with 1 and 2 mg/kg pterostilbene. Moreover, pterostilbene was detected in the plasma and brains of mice following single oral administration. Anxiolytic activity was not observed at the higher doses (5 and 10 mg/kg). However, no impairment of motor function was observed either, suggesting a favorable safety index for the compound. These results suggest that pterostilbene has the potential for therapeutic drug development for anxiety disorders. PMID- 23677524 TI - Receipt of recommended surveillance among colorectal cancer survivors: a systematic review. AB - PURPOSE: Regular surveillance decreases the risk of recurrent cancer in colorectal cancer (CRC) survivors. However, studies suggest that receipt of follow-up tests is not consistent with guidelines. This systematic review aimed to: (1) examine receipt of recommended post-treatment surveillance tests and procedures among CRC survivors, including adherence to established guidelines, and (2) identify correlates of CRC surveillance. METHODS: Systematic searches of Medline, PubMed, PsycINFO, CINAHL Plus, and Scopus databases were conducted using terms adapted for each database's keywords and subject headings. Studies were screened for inclusion using a three-step process: (1) lead author reviewed abstracts of all eligible studies; (2) coauthors reviewed random 5 % samples of abstracts; and (3) two sets of coauthors reviewed all "maybe" abstracts. Discrepancies were adjudicated through discussion. RESULTS: Thirty-four studies are included in the review. Overall adherence ranged from 12 to 87 %. Within the initial 12 to 18 months post-treatment, adherence to recommended office visits was 93 %. Adherence ranged from 78 to 98 % for physical exams, 18-61 % for colonoscopy, and 17-71 % for carcinoembryonic antigen (CEA) testing. By 2 to 3 years post-treatment, cumulative adherence ranged from 70 to 88 % for office visits, 89-93 % for physical exams, 49-94 % for colonoscopy, and 7-79 % for CEA testing. Between 18 and 28 % of CRC survivors received greater than recommended overall surveillance; overuse of physical exams (42 %), colonoscopy (24-76 %), and metastatic disease testing (1-29 %) was also prevalent. Studies of correlates of CRC surveillance focused on sociodemographic and disease/treatment characteristics, and patterns of association were inconsistent across studies. CONCLUSIONS: Deviation from surveillance recommendations includes both under- and overuse. Examination of modifiable determinants is needed to inform interventions targeting appropriate and timely receipt of recommended surveillance. IMPLICATIONS FOR CANCER SURVIVORS: Among CRC survivors, it remains unclear what modifiable psychosocial factors are associated with the observed under- and overuse of surveillance. Understanding and intervening with these psychosocial factors is critical to improving adherence to guideline-recommended surveillance and thereby reducing mortality among this group of survivors. PMID- 23677526 TI - Wound-healing potential of the root extract of Albizzia lebbeck. AB - The present investigation is an attempt to scientifically validate the traditional use of the roots of the plant Albizzia lebbeck in Ayurvedic system of medicine for curing wounds. The study included phytochemical standardization of the ethanol root extract of A. lebbeck, which was further subjected to oral acute toxicity study. Wound-healing activity of the ethanol root extract was evaluated using incision and excision wound models. Biochemical parameters such as hydroxyproline, hexuronic acid, hexosamine, and antioxidant enzymes like superoxide dismutase, reduced glutathione and free radical parameters including lipid peroxidation and nitric oxide were evaluated on the 10th post-wounding day following dead space method. For confirmation of activity, histopathology of the wounds and granulation tissues from excision and dead space wound model were performed. The study also included assessment of antibacterial activity of ethanol root extract against strains implicated in wound infection. The ethanol root extract was found to be highly rich in flavonoids, saponins, phenols, and tannins, while the amount of rutin was found to be 4.66 % w/w. It significantly increased the wound breaking strength showing a ceiling effect at 500 mg/kg p. o. The ethanol root extract at 500 mg/kg p. o. depicted an optimum wound contraction on the 18th day, while complete wound contraction was observed at the 22nd post wound day. It also demonstrated a significant increase in dry tissue weight, total protein, hydroxyproline, hexosamine, hexuronic acid, superoxide dismutase, and reduced glutathione levels, whereas a decrease in the levels of lipid peroxidation and nitric oxide was also observed with a potential antibacterial activity. Histopathological studies revealed a normal epithelization and fibrosis which was evidenced through an increase in collagen density. Thus, the study scientifically validated the wound-healing activity of the ethanol root extract along with a potential antibacterial property which may be attributed to the enhanced collagen synthesis and a potential antioxidant activity. PMID- 23677527 TI - Differences in body temperature, cell viability, and HSP-70 concentrations between Pelibuey and Suffolk sheep under heat stress. AB - Pelibuey and Suffolk sheep were compared as to their capacity to regulate body temperature under environmental hyperthermia by measuring their differences in cellular response to heat stress (HS). In a first experiment, seven Pelibuey and seven Suffolk ewes were kept in a climatic chamber for 6 h daily during 10 days (temperatures within the 18 to 39.5 degrees C range). As chamber temperature rose, sheep rectal temperature increased in both groups, but to a lesser extent in Pelibuey (0.3 degrees C) than in Suffolk sheep (0.7 degrees C) (P < 0.05). In a second experiment, cellular viability was assessed using cultured blood mononuclear cells from 15 Pelibuey and 15 Suffolk sheep. They were incubated at 37 degrees C for 24 h (control) or 43 degrees C for 6 h followed by 18 h at 37 degrees C (HS). In a third experiment, another blood mononuclear cells culture from eight Pelibuey and eight Suffolk sheep was kept at 37 degrees C for 15 h; these were subsequently cultured for 6 h at 37 degrees C (controls) or 43 degrees C (HS). Next, HSP-70 concentration was determined. HS reduced the percentage of viable cells to a greater extent in Suffolk [37 degrees C (73.7 %) vs. 43 degrees C (61.9 %); P < 0.05] than in Pelibuey sheep [37 degrees C (74.9 %) vs. 43 degrees C (66.7 %); P > 0.05]. HS significantly increased HSP-70 average concentrations for both breeds at 43 degrees C. A significant effect was observed for the breed by temperature interaction (P < 0.05) caused by a greater difference between Pelibuey and Suffolk at 43 degrees C (2.85 vs. 0.53 ng/mL, respectively; P < 0.05) than at 37 degrees C (0.05 vs. 0.03 ng/mL, respectively; P > 0.05). In conclusion, Pelibuey sheep show more effective body temperature regulation under conditions of environmental hyperthermia. Also, cell viability after HS was higher in Pelibuey than in Suffolk, an effect that could be mediated by an HSP-70-related mechanism. PMID- 23677528 TI - Anxiety-promoting parenting behaviors: a comparison of anxious mothers and fathers. AB - The majority of research identifying anxiety-promoting parenting behaviors has been conducted with mothers, leaving a gap in current knowledge about the role of fathers' parenting behaviors. In an attempt to fill this gap, this study compared anxiety-promoting parenting behaviors of anxious mothers and fathers. Parents completed self-report measures of parenting behavior and independent coders rated parenting behaviors (i.e., overcontrol, granting of autonomy, warmth, hostility, anxious behavior) of mothers (n = 34) and fathers (n = 21) during a challenging parent-child interaction task (children were ages 6-12). Results indicated that anxious fathers were observed to be more controlling than anxious mothers; while anxious mothers reported using more punishment and reinforcement of children's dependence in anxiety provoking situations compared to fathers. Findings extend our knowledge about anxious fathers, and highlight the need for additional research on the impact of fathers' parenting with respect to the development of child anxiety. PMID- 23677529 TI - Enhanced succinic acid production by Actinobacillus succinogenes after genome shuffling. AB - Succinic acid is an important platform chemical for synthesis of C4 compounds. We applied genome shuffling to improve fermentative production of succinic acid by A. succinogenes. Using a screening strategy composed of selection in fermentation broth, cultured in 96-deep-well plates, and condensed HPLC screening, a starting population of 11 mutants producing a higher succinic acid concentration was selected and subjected to recursive protoplasts fusion. After three rounds of genome shuffling, strain F3-II-3-F was obtained, producing succinic acid at 1.99 g/l/h with a yield of 95.6 g/l. The genome shuffled strain had about a 73 % improvement in succinic acid production compared to the parent strain after 48 h in fed-batch fermentation. The genomic variability of F3-II-3-F was confirmed by amplified fragment-length polymorphism. The activity levels of key enzymes involved in end-product formation from glucose and metabolic flux distribution during succinic acid production were compared between A. succinogenes CGMCC 1593 and F3-II-3-F. Increased activity of glucokinase, fructose-1,6-bisphosphate aldolase, PEP carboxykinase and fumarase, as well as decreased activity of pyruvate kinase, pyruvate formate-lyase, and acetate kinase explained the enhanced succinic acid production and decreased acetic acid formation. Metabolic flux analysis suggested that increased flux to NADH was the main reason for increased activity of the C4 pathway resulting in increased yields of succinic acid. The present work will be propitious to the development of a bio-succinic acid fermentation industry. PMID- 23677530 TI - Policy interactions in human-landscape systems. AB - Given the heightened pace and extent of human interactions with landscapes, there is increasing recognition of the interdependence of hydrogeomorphological, ecological, and human systems in understanding human-landscape interactions. There is also widespread agreement for greater integration across disciplinary boundaries to generate new knowledge urgently needed for theory building to understand, predict, and respond to rapidly changing human-landscape systems. The development of new conceptual frameworks, methods, tools, and collaborations linking across the natural and social sciences are key elements to such integration. In an effort to contribute to a broader conceptual framework for human-landscape systems, this paper describes how environmental policy research has contributed to four integrative themes--thresholds and tipping points; spatial scales and boundaries; feedback loops; and time scales and lags- developed by participants in an NSF-sponsored interdisciplinary workshop. As a broad and heterogeneous body of literature, environmental policy research reflects a diversity of methodological and theoretical approaches around institutions, actors, processes, and ideas. We integrate across multiple subfields and research programs to help identify complementarities in research that may support future interdisciplinary collaborative work. We conclude with a discussion of future research questions to help advance greater interdisciplinary research around human-landscape systems. PMID- 23677532 TI - Nurse induced respiratory depression by succinylcholine--the 'hero syndrome'. AB - A nurse administered the neuromuscular blocking agent succinylcholine (SUX) to at least one patient and gave first aid in the therapy of unexpected respiratory depression. SUX is regarded as an undetectable and thus perfect poison due to its short half-life and degradation to the endogenous compounds choline and succinic acid. However, SUX and especially its metabolite succinylmonocholine (SMC) were found in plasma and urine a few hours after administration by means of high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Compared to clinical studies, the window of detection was sufficient to gain definite proof; in other cases no samples were collected. The nurse enjoyed high reputation with the doctors. According to the court she wanted to present herself spectacularly as the first and decisive rescuer to demonstrate her special abilities and capacities, perhaps to receive a better job in the hospital. Considering the actual case, the hero syndrome is not limited to fire-fighters. PMID- 23677531 TI - Probing the coordination environment of the human copper chaperone HAH1: characterization of Hg(II)-bridged homodimeric species in solution. AB - Although metal ion homeostasis in cells is often mediated through metallochaperones, there are opportunities for toxic metals to be sequestered through the existing transport apparatus. Proper trafficking of Cu(I) in human cells is partially achieved through complexation by HAH1, the human metallochaperone responsible for copper delivery to the Wilson and Menkes ATPase located in the trans-Golgi apparatus. In addition to binding copper, HAH1 strongly complexes Hg(II), with the X-ray structure of this complex previously described. It is important to clarify the solution behavior of these systems and, therefore, the binding of Hg(II) to HAH1 was probed over the pH range 7.5 to 9.4 using (199)Hg NMR, (199m)Hg PAC and UV-visible spectroscopies. The metal dependent protein association over this pH range was examined using analytical gel-filtration. It can be concluded that at pH 7.5, Hg(II) is bound to a monomeric HAH1 as a two coordinate, linear complex (HgS2), like the Hg(II)-Atx1 X ray structure (PDB ID: 1CC8). At pH 9.4, Hg(II) promotes HAH1 association, leading to formation of HgS3 and HgS4 complexes, which are in exchange on the MUs ns time scale. Thus, structures that may represent central intermediates in the process of metal ion transfer, as well as their exchange kinetics have been characterized. PMID- 23677533 TI - Evolution of the vertebrate bone matrix: an expression analysis of the network forming collagen paralogues in amphibian osteoblasts. AB - The emergence of vertebrates is closely associated to the evolution of mineralized bone tissue. However, the molecular basis underlying the origin and subsequent diversification of the skeletal mineralized matrix is still poorly understood. One efficient way to tackle this issue is to compare the expression, between vertebrate species, of osteoblastic genes coding for bone matrix proteins. In this work, we have focused on the evolution of the network forming collagen family which contains the Col8a1, Col8a2, and Col10a1 genes. Both phylogeny and synteny reveal that these three paralogues are vertebrate-specific and derive from two independent duplications in the vertebrate lineage. To shed light on the evolution of this family, we have analyzed the osteoblastic expression of the network forming collagens in endochondral and intramembraneous skeletal elements of the amphibian Xenopus tropicalis. Remarkably, we find that amphibian osteoblasts express Col10a1, a gene strongly expressed in osteoblasts in actinopterygians but not in amniotes. In addition, while Col8a1 is known to be robustly expressed in mammalian osteoblasts, the expression levels of its amphibian orthologue are dramatically reduced. Our work reveals that while a skeletal expression of network forming collagen members is widespread throughout vertebrates, osteoblasts from divergent vertebrate lineages express different combinations of network forming collagen paralogues. PMID- 23677534 TI - Gastric adenocarcinoma in familial adenomatous polyposis can occur without previous lesions. PMID- 23677535 TI - Genetic risk assessment for women with epithelial ovarian cancer: referral patterns and outcomes in a university gynecologic oncology clinic. AB - Little is known about genetic service utilization and ovarian cancer. We identified the frequency and outcome of genetic counseling referral, predictors of referral, and referral uptake for ovarian cancer patients. Using pathology reports, we identified all epithelial ovarian cancer patients seen in a university gynecologic oncology clinic (1/04-8/06). Electronic medical records (EMR) were used to document genetic service referral, time from diagnosis-to referral, point-in-treatment at referral, personal/family cancer history, demographics, and genetic test results. Groups were compared using chi-squared and Fisher's exact test for categorical variables and t-tests for continuous variables. The study population consisted of 376 women with ovarian cancer, 72 (19 %) of who were referred for genetic counseling/testing, primarily during surveillance. Of those referred, 42 (58 %) had personal or family genetic counseling and 34 (47 %) were ultimately tested or identified due to known family mutation. Family history and prior cancer were associated with referral. Family history, living in a larger community, higher-stage disease, and serous histology were associated with undergoing genetic counseling. Risk assessment identified 20 BRCA1/2 (5.3 %) and 1 HNPCC (0.3 %) mutation carriers. Based on recent estimates that 11.7-16.6 % of women with ovarian cancer are BRCA carriers and 2 % are HNPCC carriers, results suggest under-identification of carriers and under-utilization of genetic services by providers and patients. Interventions to increase medical providers' referrals, even in a specialized oncology clinic, are necessary and may include innovations in educating these providers using web-based methods. Ease of referral by the introduction of an electronic cancer genetic referral form represents another new direction that may increase genetic risk assessment for high-risk women with ovarian cancer. PMID- 23677536 TI - Genetic counseling: a transnational perspective. AB - Although the basic goal and components of genetic counseling appears to be the same across the globe, judged by my experiences there are significant differences in the provision of genetic counseling services in Australasia (Australia and New Zealand) and India. There is poor recognition of the professional status of a genetic counselor in India at present. This may be partly because genetic counseling itself is a relatively new discipline within the medical field in India, although some types of genetic services and research have been conducted since 1960s. In this paper, I aim to provide insight from my personal transnational experiences. PMID- 23677538 TI - [Psycho-oncology in dermatology]. AB - Psycho-oncology is a young discipline-in dermatology as well as in the medicine. The topic is heterogeneous and not clearly defined. The proportion of indications for emotional care in oncology is up to 50%, depending on the method of diagnosis. In daily dermatological practice, careful distribution of information and helping with coping are essential in order to not overwhelm the patient. The doctor should ask questions about the patient's expectations, fears, and any unclear items. PMID- 23677537 TI - A network perspective on unraveling the role of TRP channels in biology and disease. AB - Transient receptor potential (TRP) channels are a large family of non-selective cation channels that mediate numerous physiological and pathophysiological processes; however, still largely unknown are the underlying molecular mechanisms. With data generated on an unprecedented scale, network-based approaches have been revolutionizing the way in which we understand biology and disease, discover disease genes, and develop therapeutic strategies. These circumstances have created opportunities to encounter TRP channel research to data-intensive science. In this review, we provide an introduction of network based approaches in biomedical science, describe the current state of TRP channel network biology, and discuss the future direction of TRP channel research. Network perspective will facilitate the discovery of latent roles and underlying mechanisms of TRP channels in biology and disease. PMID- 23677539 TI - [Somatoform pruritus: a psychosomatic disease model]. AB - Pruritus is an interdisciplinary symptom that is difficult to diagnose and treat. When there is no evidence of an organic cause, it is challenge for both the patient and the doctor. Itching affecting non-inflamed and otherwise normal skin is often classified as somatoform pruritus. When treated in an interdisciplinary manner with psychosomatic specialists, the patient increasingly becomes aware of still-unrecognized inner-emotional conflicts. At the same time, however, it must be taken into account that the pruritus may precede an underlying disease by a long time and that the diagnosis must be checked regularly. Basic psychosomatic competence and experience in the administration of psychopharmaceuticals is recommended for dermatologists. Taking a psychosomatic concept of disease into account may improve patient satisfaction and compliance, and help to avoid doctor hopping. PMID- 23677540 TI - [The association of unwanted drug effects and increased psychovegetative lability]. AB - OBJECTIVE: Based on a history of unwanted drug effects, patients had to undergo a series of exposure tests to identify alternative non-invasive drugs. In our study we examined if psychosomatic factors (in the sense of psychovegetative lability) occurred more frequently in patients with unwanted drug effects. METHODS: For this purpose, 91 patients filled out a series of questionnaires for the assessment of mental factors. The questionnaires used were the BEB (a questionnaire for the assessment of psychosomatic complaints), the TICS questionnaire (Trierer questionnaire of chronic stress), the scale "critical life events" of LRF-LE and the anxiety questionnaire "STAI". RESULTS: All scales which were used for the assessment of the psychosomatic complaint status (BEB) showed increased values. Chronic stress factors (TICS) and anxiety (STAI) did not play a role. Critical life events occurred more often. CONCLUSION: The occurrence of unwanted drug effects is associated with psychosomatic complaints and acute critical life events. This enables the patient to get a complex understanding for the explanation of the complaints. PMID- 23677541 TI - [Bullous autoimmune disorders in children]. AB - We review the pathogenesis, clinical features, diagnosis, differential diagnosis, and therapy of autoimmune bullous skin diseases of childhood, especially of the most common linear IgA dermatosis. In autoimmune bullous diseases, autoantibodies are formed against different adhesion molecules of the skin. These are not only pathophysiologically relevant, but also serve as basis for diagnosis and follow up of these diseases. In case an autoimmune bullous disease is suspected, histopathology and immunohistopathology (direct immunofluorescence microscopy) as well as serological tests (indirect immunofluorescence microscopy, ELISA, immunoblot) should be performed. Therapy depends on the diagnosis. In IgA mediated pathogenesis, dapsone can be successfully used. In IgG-mediated diseases, immunosuppression with corticosteroids and steroid-sparing agents should be initiated, although only local therapy is sufficient to control a self limiting pemphigus neonatorum. In dermatitis herpetiformis, a life-long gluten free diet is recommended. PMID- 23677542 TI - [Serious complications following gluteal injection of silicone]. AB - Silicone has a broad range of medical applications and plays an important role, for example, in plastic reconstruction. The use of silicone, however, may result in unpredictable consequences for the patient. These range from swelling and erythema at the site of injection and regional lymphadenopathy to the development of disseminated granulomas distant from the administration site. We report a woman who developed extensive distally-spreading ulcerations in both buttocks several years after gluteal silicone injection. Potential systemic reactions of silicone include intrapulmonary granulomas, embolism and related pneumonitis. Moreover, an association with the development of autoimmune diseases and neoplasias has been discussed. Therapeutic options include surgically removing the silicone and topical or systemic anti-inflammatory drug therapy. However, due to the diffuse dissemination of silicone, the former is often not completely possible and for the latter empirical data are limited and follow-up studies are missing. Liquid silicone is no longer authorized in Europe or in the U.S.A. When silicone implants are used, the decision should be weighed carefully and the patient adequately counseled. In addition, follow-up care on a regular basis is mandatory for both those with implants and those who obtained injections of liquid silicone in the past. PMID- 23677543 TI - Reply to the comments of Sokouti et al.: Genitourinary hydatid disease. PMID- 23677544 TI - Activated ion ETD performed in a modified collision cell on a hybrid QLT-Oribtrap mass spectrometer. AB - We describe the implementation and characterization of activated ion electron transfer dissociation (AI-ETD) on a hybrid QLT-Orbitrap mass spectrometer. AI-ETD was performed using a collision cell that was modified to enable ETD reactions, in addition to normal collisional activation. The instrument manifold was modified to enable irradiation of ions along the axis of this modified cell with IR photons from a CO2 laser. Laser power settings were optimized for both charge (z) and mass to charge (m/z) and the instrument control firmware was updated to allow for automated adjustments to the level of irradiation. This implementation of AI-ETD yielded 1.6-fold more unique identifications than ETD in an nLC-MS/MS analysis of tryptic yeast peptides. Furthermore, we investigated the application of AI-ETD on large scale analysis of phosphopeptides, where laser power aids ETD, but can produce b- and y-type ions because of the phosphoryl moiety's high IR adsorption. nLC-MS/MS analysis of phosphopeptides derived from human embryonic stem cells using AI-ETD yielded 2.4-fold more unique identifications than ETD alone, demonstrating a promising advance in ETD sequencing of PTM containing peptides. PMID- 23677545 TI - Sexual dysfunction in pre-menopausal diabetic women: clinical, metabolic, psychological, cardiovascular, and neurophysiologic correlates. AB - An increased prevalence of female sexual dysfunction (FSD) has been reported in women with diabetes mellitus (DM). Our aim was to evaluate correlates (psychological, cardiovascular, and neurophysiologic) of FSD in DM women without chronic diabetic complications. Female Sexual Function Index (FSFI), Beck Depression Inventory (BDI), Michigan Diabetic Neuropathy Index (DNI), and the symptoms of diabetic neuropathy (SDN) questionnaires, metabolic variables, endothelial vascular function (flow-mediated dilation, FMD), echocardiography, and electromyography were studied. 109 pre-menopausal women (18-50 years) [48 with DM (14 type 1 DM, 34 type 2 DM, duration 12.6 +/- 1.91 years), and 61 healthy women] received the above questionnaires; physical activity, smoking habits, parity, BMI, waist circumference, HOMA-IR index, fibrinogen, cholesterol (total, HDL, LDL), triglycerides, HbA1c, high-sensitivity C-reactive protein, total testosterone, and estradiol were measured; echocardiography, assessment of intima-media thickness (IMT), FMD, ECG (heart rate and Qtc, indexes of sympathetic activity), and electromyography were performed. FSFI total score and score for arousal, lubrication, and orgasm domains were lower in DM women than in controls (P < 0.05); DM women had higher BDI, Doppler A wave peak velocity, DNI, and SDN score (P < 0.001 to P < 0.04). Doppler E wave peak velocity, peroneal, posterior tibial and sural nerves conduction velocity and amplitude were lower in diabetic women than in controls (P < 0.05 to P < 0.001). FSFI score was positively correlated with physical activity, Doppler E wave peak velocity, and peroneal nerve amplitude and negatively with BDI, parity, IMT, SDN, and HbA1c (P < 0.05 to P < 0.001). At stepwise regression, SDN score (negatively) and Doppler E wave peak velocity (positively) predicted FSFI score (r = 507, P < 0.001). In conclusion, cardiovascular and neurological impairments are associated with FSD in diabetic women. Follow-up studies are required to evaluate sexual dysfunction as a risk factor for future cardiovascular or neurological events. PMID- 23677547 TI - Botulinum toxin induces chemodenervation of intrafusal and extrafusal fibers. PMID- 23677546 TI - B-1-cell subpopulations contribute differently to gut immunity. AB - In mice, B-1 (B1a/B1b) cells are mainly located in the peritoneal cavity. B-1 cells are well known for their role in the early stages of Ab-mediated immune responses against pathogenic invasion as well as for the production of natural IgM antibodies. Although such B cells have been claimed to give rise to intestinal plasma cells producing IgA, a clear role of B-1 cells in IgA production in the gut-associated tissues is still not defined. Here, we employed the transgenic L2 mouse model characterized by the lack of B-2 cells and presence of B-1 cells as major B-cell subpopulation. The oligoclonality of the Ab repertoire in this mouse allowed us to take typical B1a cell VH sequences as indicators of the presence of IgM-producing B-1a cells in Peyer's patches as well as in lamina propria. However, amongst the IgAVH sequences recovered from the same tissues, none of the sequences showed B1a-cell specificity. Interestingly, all IgAVH sequences derived from the lamina propria of L2 mice displayed extensive numbers of nucleotide exchanges, indicating somatic hypermutation, and affinity maturation. This suggests that the contribution of natural unmutated IgA by B-1a cells to intestinal immunity is negligible. PMID- 23677548 TI - Response: Botulinum toxin induces chemodenervation of intrafusal and extrafusal fibers. PMID- 23677552 TI - [Gender-specific difference in lung cancer]. AB - More and more differences in lung cancer are being detected between men and women. Lung cancer, at the beginning of the last century a rare disease in women, has a growing incidence in women, in particular in young females. Lung cancer is a leading cause of cancer death in women in developed countries with different histological types and adenocarcinomas are more frequent in women than in men. Cigarette smoking is the most prevalent cause of lung cancer in women, in addition susceptibility to carcinogens may differ between the sexes. As more non smoking women than men develop lung cancer, it is likely that they are exposed to excessive environmental carcinogens such as second-hand-smoking, in-house-radon or cooking fumes. Furthermore, genetic and hormonal influences play a role in lung cancer etiology for women. Taken together, women have a better overall survival than men with lung cancer. Differences in molecular susceptibility patterns are observed between men and women, and show that molecular targets such as EGFR or ALK more frequent in women. PMID- 23677553 TI - [Dynamic hyperinflation in pulmonary arterial hypertension: "hyperinflator" and "non-hyperinflator"]. AB - BACKGROUND: The dynamic decrease in inspiratory capacity (IC) during exercise with restriction of tidal volume (VT) is known as dynamic hyperinflation (DH) and is described mostly in patients with COPD differentiating between a "hyperinflator" and a "non-hyperinflator". Recent studies have revealed DH in patients with idiopathic pulmonary arterial hypertension (iPAH), but the influence of the DH on the reduced exercise capacity with exertional dyspnoae is still being debated. METHODS: We analysed flow-volume curves during cardiopulmonary exercise testing (CPET) in idiopathic PAH (n = 19), in COPD (n = 17), in idiopathic pulmonary fibrosis (IPF) (n = 19) and a control group (n = 30). We measured IC at rest and during maximal exercise and furthermore ventilation, VT and oxygen uptake (VO2 peak). In iPAH a right heart catheter test and a 6-minute walk test (6MWT) were performed, also the B-type naturetic peptide (BNP) and the NYHA/WHO functional class were determined. RESULTS: The IC decreased significantly in 11 PAH "hyperinflators" (PAH-H) (Delta IC: - 0.34 +/- 0.14 L, p < 0.001) compared to 8 PAH "non-hyperinflators" (PAH-NH) (Delta IC: 0.08 +/- 0.2 L). COPD patients exhibited a characteristic hyperinflation pattern with a decrease in IC throughout exercise (Delta IC: - 0.61 +/- 0.3 L, p < 0.001), while patients with IPF (Delta IC: 0.03 +/- 0.15 L) and the control group responsed to exercise with a non-hyperinflator pattern (Delta IC: 0.1 +/- 0.2 L). Both PAH collectives showed a reduced IC/TLC, while VT/IC was elevated with a decreased peak VO2 and max. performance compared to the control group. Correlations of the IC rest/max (L) were shown in PAH-H and PAH-NH with the VO2 peak, max. performance and VT. CONCLUSION: The analysis of flow-volume curves during CPET can indentify DH in a subgroup of patients with iPAH. The DH contributes significantly but slightly to the development of exertional limitations and dyspnoe in a subgroup of iPAH. Further studies with a larger sample size will be required to definitively measure the impact of the DH seen in these patients. PMID- 23677554 TI - [COPD screening in primary care practice with a lung function quick-meter]. PMID- 23677555 TI - [Reply]. PMID- 23677556 TI - [Size of the pulmonary artery is correlated with exacerbations]. PMID- 23677550 TI - The cooperative international neuromuscular research group Duchenne natural history study--a longitudinal investigation in the era of glucocorticoid therapy: design of protocol and the methods used. AB - Contemporary natural history data in Duchenne muscular dystrophy (DMD) is needed to assess care recommendations and aid in planning future trials. METHODS: The Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD-NHS) enrolled 340 individuals, aged 2-28 years, with DMD in a longitudinal, observational study at 20 centers. Assessments obtained every 3 months for 1 year, at 18 months, and annually thereafter included: clinical history; anthropometrics; goniometry; manual muscle testing; quantitative muscle strength; timed function tests; pulmonary function; and patient-reported outcomes/health-related quality-of-life instruments. RESULTS: Glucocorticoid (GC) use at baseline was 62% present, 14% past, and 24% GC-naive. In those >=6 years of age, 16% lost ambulation over the first 12 months (mean age 10.8 years). CONCLUSIONS: Detailed information on the study methodology of the CINRG DMD-NHS lays the groundwork for future analyses of prospective longitudinal natural history data. These data will assist investigators in designing clinical trials of novel therapeutics. PMID- 23677557 TI - Primary urachal malignancy: case report and literature review. PMID- 23677558 TI - The challenges of female adolescents' health needs. AB - Due to adolescents' future crucial roles, their health needs should be included in the national health system policy. In this cross-sectional study 2010 female adolescents were recruited from randomly selected schools in Iran. To obtain their health needs, the participants completed a self-administrated questionnaire. It was revealed that emotional needs were the most important health needs of adolescents. Furthermore, there was a meaningful relationship between health needs' score with the adolescents' age and their mothers' education level. Finally, the mean score of health needs was significantly higher in urban adolescents. Therefore, it is suggested that adolescents' emotional health needs to be paid attention; otherwise irrecoverable serious problems may occur in the next generation's health. PMID- 23677559 TI - H(OEt2)2[P(1,2-O2C6Cl4)3]: synthesis, characterization, and application as a single-component initiator for the carbocationic polymerization of olefins. AB - The development of novel Bronsted acids featuring the hexacoordinate phosphorus(V) anion [TRISPHAT](-) {[1](-)=[P(1,2-O2C6Cl4)3](-)} are reported. The title compound, H(OEt2)2[1], was synthesized from 1,2-(HO)2C6Cl4 (3 equiv) and PCl5 in the presence of diethyl ether. This compound was fully characterized by (1)H, (31)P and (13)C NMR spectroscopy, X-ray crystallography and elemental microanalysis. Dissolution of H(OEt2)2[1] in acetonitrile results in the slow precipitation of crystalline H(OEt2)(NCMe)[1], which was characterized by X-ray diffraction; however, in CD2Cl2 solution the [TRISPHAT](-) anion protonated and ring-opened. The weighable, solid H(OEt2)2[1] was found to be a competent initiator for the polymerization of n-butyl vinyl ether, alpha-methylstyrene, styrene and isoprene at a variety of temperatures and monomer-to-initiator ratios. At low temperatures, polymers with M(n) >10(5) were obtained for n-butyl vinyl ether and alpha-methylstyrene whereas slightly lower molecular weights were obtained with styrene and isoprene (10(4) < M(n) <10(5)). The poly(alpha methylstyrene) synthesized at -78 degrees C is syndiotactic-rich (ca. 87% rr) whereas the polystyrene obtained at -50 degrees C is atactic. The polyisoprene obtained possessed all possible modes of enchainment as well as branched and/or cyclic structures that are often observed in polyisoprene. PMID- 23677560 TI - Batrachochytrium dendrobatidis infection and lethal chytridiomycosis in caecilian amphibians (Gymnophiona). AB - Batrachochytrium dendrobatidis (Bd) is commonly termed the 'amphibian chytrid fungus' but thus far has been documented to be a pathogen of only batrachian amphibians (anurans and caudatans). It is not proven to infect the limbless, generally poorly known, and mostly soil-dwelling caecilians (Gymnophiona). We conducted the largest qPCR survey of Bd in caecilians to date, for more than 200 field-swabbed specimens from five countries in Africa and South America, representing nearly 20 species, 12 genera, and 8 families. Positive results were recovered for 58 specimens from Tanzania and Cameroon (4 families, 6 genera, 6+ species). Quantities of Bd were not exceptionally high, with genomic equivalent (GE) values of 0.052-17.339. In addition, we report the first evidence of lethal chytridiomycosis in caecilians. Mortality in captive (wild-caught, commercial pet trade) Geotrypetes seraphini was associated with GE scores similar to those we detected for field-swabbed, wild animals. PMID- 23677561 TI - Effect of diabetes on outcomes in patients undergoing emergent cholecystectomy for acute cholecystitis. AB - BACKGROUND: The purpose of the present study was to determine the prevalence of diabetes and its effect on surgical outcomes in patients undergoing emergent, in patient cholecystectomy for acute cholecystitis. Some 8.3 % of the U.S. population has diabetes and this number is projected to rise to 21-33 % by 2050. Diabetes is considered to be associated with a higher incidence of acute cholecystitis; however, its impact on outcomes is unknown. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried to identify all patients with acute cholecystitis who underwent emergent in-patient cholecystectomy from 2004 to 2010. The study population was divided into two groups: diabetics and non-diabetics. Diabetics were further subdivided into those taking oral medication and those on insulin. Demographics, co morbidities, and wound classification were compared with univariate analysis, and 30-day outcomes were compared with univariate and multivariate analyses. RESULTS: A total of 5,460 patients met the inclusion criteria. Of these 770 (14.10 %) had a diagnosis of diabetes. Mortality was higher for diabetics than for non diabetics [4.4 vs 1.4 %, adjusted odds ratio (AOR) (95 % CI): 1.79 (1.09, 2.94), adj-p = 0.022]. Preoperative perforation rates were 25.1 and 13.0 %, respectively [AOR (95 % CI): 1.34 (1.09, 1.65), adj-p = 0.005]. The adjusted risk of cardiovascular events and renal failure was significantly higher for diabetics. Insulin treatment, but not oral medication, was associated with a significant increase in mortality, preoperative perforation, superficial surgical site infection, septic shock, cardiovascular incidents, and renal insufficiency. CONCLUSIONS: In patients undergoing cholecystectomy for acute cholecystitis, diabetes increases the risk of mortality, cardiovascular events, and renal failure. Insulin-treated diabetics have more co-morbidities and poorer outcomes. PMID- 23677563 TI - 3 Tesla (1) H MR spectroscopy of hip bone marrow in a healthy population, assessment of normal fat content values and influence of age and sex. AB - PURPOSE: To evaluate in a healthy population normal spectroscopic fat content (FC) values of the hip bone marrow and to assess the influence of age and sex on bone marrow conversion. MATERIALS AND METHODS: Eighty volunteers (40 men; 40 women; ages: 20-60 years; divided into four consecutive groups) underwent acetabulum, femoral head, femoral neck, greater trochanter, and diaphysis localized (1) H MR spectroscopy. FC values of each anatomical site were obtained according to the following formula: Fat content = CH2 /(CH2 + Water)*100. To assess bone marrow conversion, a spectroscopic conversion index (SCI) was calculated as FC neck/FC greater trochanter. RESULTS: FC values showed a gradient as follows: greater trochanter > femoral head > femoral neck > diaphysis > acetabulum in every age group both in men and in women. SCI increased with age both in men and women, showing lower values in women for every age group. CONCLUSION: We obtained normal spectroscopic FC values from different areas of the hip, according to age and sex. These values may be used as reference values to evaluate, by the means of (1) H MR spectroscopy, pathological conditions affecting hip bone marrow. PMID- 23677562 TI - Influence of prophylactic neck dissection on rate of retreatment for papillary thyroid carcinoma. AB - BACKGROUND: Prophylactic neck dissection (PND) for papillary thyroid cancer is controversial. The objective of this study was to analyze the influence of PND on the rate of retreatment. METHODS: In this retrospective case-control study, papillary thyroid carcinomas >10 mm without ultrasonographic evidence of nodal disease (cN0) were treated with total thyroidectomy (TT) or TT with bilateral central compartment PND. All received postoperative radioactive iodine ((131)I) and were followed for at least 1 year. We compared the rate of retreatment (surgery or (131)I). RESULTS: Altogether, 246 patients (mean age 46 years, 78 % women) underwent TT (n = 91) or TT + PND (n = 155). The groups were similar in age, sex, tumor size, and follow-up (median 6.3 years) (p > 0.05). Overall, 11 (12 %) of the patients in the TT group underwent reoperation in the central compartment for recurrence versus 3 (2 %) in the TT + PND group (p < 0.001). There were 1.18 administrations of (131)I for the TT group versus 1.08 for the TT + PND group (p = 0.08). The average cumulative dose of (131)I was 3.9 +/- 1.8 GBq for the TT group and 3.8 +/- 1.3 GBq for the TT + PND group (p = 0.52). Actuarial (Kaplan-Meier) 5-year retreatment rates were 14.7 % in the TT group and 6.5 % in the TT + PND group (p = 0.01, log-rank). The rate of permanent recurrent nerve paralysis was 2 % for the TT group and 1 % for the TT + PND group (p = 0.98). The rates of permanent hypoparathyroidism were 7 versus 3 %, respectively (p = 0.12). CONCLUSIONS: Five-year retreatment rates were lower in patients treated with PND, with no added permanent morbidity. PMID- 23677564 TI - [Precancerous colorectal tumors]. AB - Preneoplastic lesions of colorectal carcinoma can be divided in non-serrated and serrated lesions. Non-serrated lesions include conventional adenomas (tubular, tubulovillous and villous) and dysplasias associated with inflammatory bowel disease like flat intraepithelial neoplasia, dysplasia-associated lesions or masses (DALM) and adenoma-like masses (ALM). Conventional adenomas are mostly sporadic, but also found in hereditary adenomatous-polyposis syndromes. Hamartous polyposis syndromes are also associated with colorectal cancer. Serrated lesions include hyperplastic polyps, sessile serrated adenomas and traditional serrated adenomas. Based on these precancerous colorectal lesions different molecular subtypes were identified. Histological subtype, size and grade of dysplasia of polyps are essential for risk assessment of colorectal cancer. PMID- 23677565 TI - [Update carotid artery stenosis]. AB - Stenosis of the extracranial carotid artery is a treatable cause of ischemic stroke and can reliably be detected and graded by vascular ultrasound. The differentiation between symptomatic and asymptomatic stenosis, the perioperative risk and the estimated life expectancy of the patient guide the therapy. Therapy is based on an optimal treatment of cardiovascular risk factors and antiplatelet drugs. Revascularization using surgical carotid endarterectomy is efficient for the prevention of stroke in patients with a high grade symptomatic stenosis. Endovascular therapy using stent-protected angioplasty of the carotid artery is an alternative in patients with a higher surgical risk with low complication rates when performed in experienced centres. Patients with asymptomatic carotid artery stenosis are primarily treated conservatively and revascularization is indicated in patients with a low surgical and global cardiovascular risk. PMID- 23677566 TI - [Mild bleeding diathesis in a 62-year-old woman with hereditary thrombocytopenia]. AB - A 62-year-old woman presented with severe, isolated thrombocytopenia. Due to the positive family history and normal thrombocyte morphology ANKRD26-associated thrombocytopenia 2 (THC2) was suspected. The diagnosis was confirmed by DNA sequencing. Although this is the first case report on THC2 in Germany, we anticipate that THC2 might be a frequent cause of hereditary thrombocytopenia. A specific therapy was not necessary, but would consist of platelet supplementation. PMID- 23677567 TI - A phytase gene is overexpressed in root nodules cortex of Phaseolus vulgaris rhizobia symbiosis under phosphorus deficiency. AB - Phosphorus is an essential nutrient for rhizobial symbioses to convert N2 into NH4 usable for N nutrition in legumes and N cycle in ecosystems. This N2 fixation process occurs in nodules with a high energy cost. Phytate is the major storage form of P and accounts for more than 50 % of the total P in seeds of cereals and legumes. The phytases, a group of enzymes widely distributed in plant and microorganisms, are able to hydrolyze a variety of inositol phosphates. Recently, phytase activity was discovered in nodules. However, the gene expression localization and its role in N2-fixing nodules are still unknown. In this work, two recombinant inbred lines (RILs) of common bean (Phaseolus vulgaris L.), selected as contrasting for N2 fixation under P deficiency, namely RILs 115 (P efficient) and 147 (P-inefficient) were inoculated with Rhizobium tropici CIAT 899, and grown under hydroaeroponic conditions with sufficient versus deficient P supply. With in situ RT-PCR methodology, we found that phytase transcripts were particularly abundant in the nodule cortex and infected zone of both RILs. Under P deficiency, phytase transcripts were significantly more abundant for RIL115 than for RIL147, and more in the outer cortex than in the infected zone. Additionally, the high expression of phytase among nodule tissues for the P deficient RIL115 was associated with an increase in phytase (33 %) and phosphatase (49 %) activities and efficiency in use of the rhizobial symbiosis (34 %). It is argued that phytase activity in nodules would contribute to the adaptation of the rhizobia-legume symbiosis to low-P environments. PMID- 23677568 TI - The co-expression of ERbeta2 and IL-12Rbeta2 is better prognostic factor in non small-cell lung cancer progression. AB - Estrogens and IL-12 play a pivotal role in the development and progression of non small-cell lung cancer (NSCLC); at the same time, estrogen receptor beta2 and (interleukin-12 receptor beta2)IL-12Rbeta2 are their important receptors, respectively. With the functions of ERbeta2 and IL-12Rbeta2 explored further in NSCLC, some questions on the relation between ERbeta2 and IL-12Rbeta2 expression need to be solved. In this study, our aim is to elucidate relationship and roles of ERbeta2 and IL-12Rbeta2 in NSCLC. The expression of estrogen receptors beta2 and IL-12Rbeta2 was confirmed by Western blot and RT-PCR analysis in frozen tissues. The correlation between their expression levels and clinical characteristics was evaluated by Mann-Whitney and Kruskal-Wallis test. Using Kaplan-Meier plots and Cox proportional hazard models analyses, overall survival (OS) was evaluated. In contrast to benign pulmonary, ERbeta2 and IL-12Rbeta2 were over-expressed in NSCLC (p = 0.000). IHC results showed significant correlation between ERbeta2 and IL-12Rbeta2 (R = 0.382, p = 0.005). By analyzing the relation between ERbeta2, IL-12Rbeta2 mRNA expression levels and clinical characteristics, it was revealed that ERbeta2 and IL-12Rbeta2 were significant correlated with regional lymph node metastasis, T stage and clinical stage (p = 0.000/0.000; 0.001/0.000; 0.031/0.003 respectively), and both protein expression levels were lower with TNM stage being higher. In a Kaplan-Meier analysis, compared to both ERbeta2 and IL-12Rbeta2 or one low expression, high expression levels of ERbeta2 and IL-12Rbeta2 were identified in a group of patients with the longest overall survival (OS). Cox proportional hazard models revealed that ERbeta2 and IL 12Rbeta5 had longer OS. This is the first study to uncover that both ERbeta2 and IL-12Rbeta2 were over-expressed and further show that they were co-expressed in NSCLC. Moreover, we found that high expression levels of ERbeta2 and IL-12Rbeta2 may be positively correlated with OS and have prognostic values for the progression of NSCLC. PMID- 23677569 TI - Oligonucleotide suppression of bcl-2 in LNCaP cells is compensated by increased androgen sensitivity, p53 and oncogene activity, and suppressed caspase-3. AB - Antisense oligonucleotides (oligos) have been employed against prostate cancer models in both in vivo and in vitro systems. While most target growth factors or their receptors, other oligos are directed against inhibitors of apoptosis or mediators of androgen action. Those which suppress bcl-2 activity (in prostate cancer patients) have even reached clinical trials. We evaluated a set of oligos which targeted and comparably suppressed the expression of bcl-2, an apoptosis inhibitory protein. Our first study reported that LNCaP cells were adapted by suppression of caspase-3 (a promoter of apoptosis). In this study we evaluated additional proteins associated with tumor progression and found the expression of the androgen receptor, its p300 and IL-6 co-activators, as well as v-myc (oncogenic) and (unexpectedly) tumor suppressor p53 genes to be enhanced. We conclude that oligo treatment directed against bcl-2, intended to stimulate apoptosis, can be evaded through compensatory changes in gene activity associated with additional regulators of apoptosis, androgen sensitivity and oncogenesis. This suggests that therapeutic suppression of bcl-2 can promote tumor resistance and transformation to a more aggressive (androgen and oncogene driven) phenotype. PMID- 23677570 TI - Ischemic heart disease and its related factors in Mongolia: a nationwide survey. AB - Ischemic heart disease (IHD) remains one of the most important disorders associated with disability and mortality worldwide, and is one of the major causes of cardiovascular diseases in Mongolia. The objective of the current study was to determine the prevalence of IHD and its related factors in a general population in Mongolia. We conducted a nationwide cross-sectional survey between March and September, 2009. General participants were recruited from urban to rural regions in a multistage random cluster sampling method. The diagnosis of IHD was based on the Rose questionnaire (World Health Organization) and electrocardiographic findings. A total of 369 (16.2 %) subjects with IHD were diagnosed among 2,280 participants. The prevalence of subjects with IHD was significantly increased by age: from 9.9 % in individuals age 40-44 years compared to 17.7 % in those over 60 years. Smoking habits (former and current) and non-frequent intake of fruits and vegetables were significantly positively associated with IHD in men, while heavy alcohol drinking habits and lower education period of time were significantly positively associated with IHD in women. IHD was found to be prevalent, especially among people aged over 40 years, in Mongolia. Statistical factors related to IHD were found to be significantly different based on sex. The current data may provide relevant information to prevent IHD in the Mongolian population. PMID- 23677571 TI - Hox Gene Deformed is likely involved in mandibular regression during presoldier differentiation in the nasute termite Nasutitermes takasagoensis. AB - Division of labor is a distinguishing characteristic of eusocial insects. To understand the proximate factors underlying caste determination, it is essential to clarify the developmental mechanisms during the differentiation of each caste. Termite soldiers have species-specific and diverse morphologies that are specialized for colony defense. Soldiers of the subfamily Nasutitermitinae (Termitidae), one of the most derived termite groups, possess a long, horn-like frontal projection (nasus), an invaginated glandular structure in the head (frontal gland), and regressed mandibles. These morphological changes occur prior to the molt into presoldiers (the preceding stage of soldiers). In Drosophila and other insects, Hox genes determine segment identities; thus they might be involved in such body-part-specific modifications during soldier differentiation. Deformed (Dfd) functions not only in the formation of the mandible and maxilla but also in other head parts (e.g., eye-antennal disc) in other insects. In this study, we examined Dfd functions in nasus/frontal gland formation and mandibular regression in Nasutitermes takasagoensis. Relative expression analyses showed that Dfd expression levels in the mouthparts were significantly higher than those in any other body parts of workers before presoldier molt. Dfd RNA interference resulted in the inhibition of mandibular regression during presoldier differentiation, but nasus and frontal gland formation were not affected. These results suggest that Dfd is involved in the determination of mandibular positional information and specific modification during presoldier differentiation in N. takasagoensis. This is the first work to show the effects of Hox genes on caste-specific morphogenesis in social insects. PMID- 23677572 TI - Hormonal and reproductive risk factors for sporadic microsatellite stable and unstable endometrial tumors. AB - Hormonal and reproductive factors modulate bioavailable estrogen to influence endometrial cancer risk. Estrogen affects the microsatellite status of tumors, but the relation between these estrogen-related factors and microsatellite instability (MSI) status of endometrial tumors is not known. We evaluated associations between hormonal and reproductive factors and risks of microsatellite stable (MSS) and MSI endometrial cancer among postmenopausal women (MSS cases = 258, MSI cases = 103, and controls = 742) in a population-based case control study in Alberta, Canada (2002-2006). Polytomous logistic regression was used to estimate ORs and 95% confidence intervals (95% CI). We observed a significant trend in risk reduction for MSI (Ptrend = 0.005) but not MSS (Ptrend = 0.23) cancer with oral contraceptive use; with 5-year use or more, the risk reduction was stronger for MSI (OR = 0.42; 95% CI, 0.23-0.77) than for MSS cancer (OR = 0.80; 95% CI, 0.54-1.17; Pheterogeneity = 0.05). For more recent use (<30 years), the risk reduction was stronger for MSI (OR = 0.36; 95% CI, 0.19-0.69) than for MSS cancer (OR = 0.77; 95% CI, 0.51-1.15; Pheterogeneity = 0.032). No differential risk associations were observed for menopausal hormone use, parity and age at menarche, menopause or first pregnancy. We found limited evidence for statistical heterogeneity of associations of endometrial cancer risk with hormonal and reproductive factors by MSI status, except with oral contraceptive use. This finding suggests a potential role for the MMR system in the reduction of endometrial cancer risk associated with oral contraceptive use, although the exact mechanism is unclear. This study shows for the first time that oral contraceptive use is associated with a reduced risk for MSI but not for MSS endometrial cancer. PMID- 23677574 TI - Physical activity and risk of lymphoma: a meta-analysis. AB - BACKGROUND: Physical activity has a protective effect on some types of cancer. The aim of the present meta-analysis was to explore the literature on the association between physical activity and risk of lymphoma. METHODS: A meta analysis was conducted for cohort and case-control studies examining the association between self-reported physical activity and risk of lymphoma. Depending on statistical heterogeneity, a random or fixed effects model was used to estimate the summary OR and corresponding 95% confidence interval (CI). RESULTS: Seven case-control studies and 5 cohort studies were included. When data from both study designs were combined, no significant influence of physical activity on risk of lymphoma was found (pooled OR = 0.90; 95% CI: 0.79-1.02; P = 0.10). Subgroup analysis revealed a significant protective influence of physical activity on risk of lymphoma in case-control studies (pooled OR = 0.81; 95% CI: 0.68-0.96; P = 0.02). In contrast, cohort studies, which have a higher level of evidence than case-control studies, confirm the results of the primary meta analysis (pooled OR = 1.02; 95% CI: 0.88-1.19; P = 0.76). A subsequent subgroup analysis found no significant differences between results for Hodgkin lymphoma and non-Hodgkin lymphoma (chi(2) = 0.16; P = 0.69), nor between results for recreational and occupational activities (chi(2) = 1.01; P = 0.31). CONCLUSIONS: Epidemiologic research indicates no significant influence of physical activity on risk of lymphoma. IMPACT: Future research should examine the association between sedentary behavior and risk of lymphoma and investigate the dose-response and timing effect of physical activity on risk of lymphoma. PMID- 23677573 TI - Genome-wide association study identifies possible genetic risk factors for colorectal adenomas. AB - BACKGROUND: Colorectal cancer is the second leading cause of cancer-related death, and most colorectal cancer usually arises from colorectal adenomas. Removal of polyps reduces mortality from colorectal cancer. Colorectal adenomas are known to aggregate in families; however, the genetic determinants for risk of polyps are largely unknown. METHODS: In this study, we used data from the Tennessee Colorectal Polyp Study and the Tennessee-Indiana Adenoma Recurrence Study to conduct a GWAS of adenoma cases and controls. Our design consisted of discovery and replication phases for a total of 2,551 Caucasian adenoma cases and 3,285 Caucasian controls. We carried out logistic regression to test for association in both the discovery and replication phase and further examined the results with meta-analysis. RESULTS: No single nucleotide polymorphism (SNP) achieved a genome-wide significant P value; however, the most significantly associated SNPs were either previously associated with colorectal cancer in GWAS, such as rs10505477 in the gene POU5F1 [odds ratio (OR) = 0.87; 95% confidence interval (CI) 0.81-0.94; P = 4.4 * 10(-4)), or have been biologically linked to benign growths in other tissues, such as rs1919314 in the gene histone deacetylase 9 (OR = 1.32; 95% CI, 1.18-1.47; P = 1.1 * 10(-6)). CONCLUSIONS: This study suggests that several SNPs may be related to adenoma risk and provides clues for future studies. IMPACT: These results suggest that some known genetic risk factors of colorectal cancer are necessary but not sufficient for carcinogenesis. PMID- 23677575 TI - The clinical and economic burden of a sustained increase in thyroid cancer incidence. AB - BACKGROUND: Thyroid cancer incidence is increasing worldwide at an alarming rate, yet little is known of the impact this increase will have on society. We sought to determine the clinical and economic burden of a sustained increase in thyroid cancer incidence in the United States and to understand how these burdens correlate with the National Cancer Institute's (NCI) prioritization of thyroid cancer research funding. METHODS: We used the NCI's SEER 13 database (1992-2009) and Joinpoint regression software to identify the current clinical burden of thyroid cancer and to project future incidence through 2019. We combined Medicare reimbursement rates with American Thyroid Association guidelines, and our clinical practice to create an economic model of thyroid cancer. We obtained research-funding data from the NCI's Office of Budget and Finance. RESULTS; By 2019, papillary thyroid cancer will double in incidence and become the third most common cancer in women of all ages at a cost of $18 to $21 billion dollars in the United States. Despite these substantial clinical and economic burdens, thyroid cancer research remains significantly underfunded by comparison, and in 2009 received only $14.7 million (ranked 30th) from the NCI. CONCLUSION: The impact of thyroid cancer on society has been significantly underappreciated, as is evidenced by its low priority in national research funding levels. IMPACT: Increased awareness in the medical community and the general public of the societal burden of thyroid cancer, and substantial increases in research on thyroid cancer etiology, prevention, and treatment are needed to offset these growing concerns. PMID- 23677576 TI - Cancer risk in patients with manifest vascular disease: effects of smoking, obesity, and metabolic syndrome. AB - BACKGROUND: Patients with vascular disease may be at increased risk of cancer because of shared risk factors and common pathogenesis. METHODS: Patients with vascular disease (n = 6,172) were prospectively followed for cancer incidence. Standardized incidence ratios (SIRs) were calculated to compare the cancer incidence of the study population with that of the general population. Multivariable-adjusted hazard ratio's (HRs) of cancer were estimated for smoking status, pack-years, body mass index, waist circumference and visceral adipose tissue (VAT), and metabolic syndrome (MetS). RESULTS: During a median follow-up of 5.5 years, 563 patients were diagnosed with cancer. Patients with vascular disease were at increased risk of cancer [SIR = 1.19; 95% confidence interval (CI), 1.10-1.29]. Specifically, risk of lung cancer (SIR = 1.56; 95% CI, 1.31 1.83), as well as bladder cancer (SIR = 1.60; 95% CI, 1.11-2.24) and cancer of the lip, oral cavity, or pharynx in men (SIR = 1.51; 95% CI, 0.89-2.39), and colorectal (SIR = 1.71; 95% CI, 1.11-2.53) and kidney cancer (SIR = 2.92; 95% CI, 1.05-6.38) in women was increased. A relation between smoking and cancer risk was observed (HR for current smokers = 1.37; 95% CI, 1.05-1.73), whereas an increase in VAT was associated with higher breast cancer risk in women (HR = 1.42; 95% CI, 1.03-1.96). No relation between MetS and cancer risk was found. CONCLUSIONS: Patients with vascular disease have a 19% higher cancer risk compared to the general population. Smoking increased cancer risk and abdominal obesity is a risk factor for breast cancer in female patients with vascular disease. IMPACT: These results call for awareness of the increased cancer risk in patients with vascular disease among physicians and underline the necessity of lifestyle improvement not only for reducing cardiovascular risk. PMID- 23677577 TI - C-reactive protein, lipid-soluble micronutrients, and survival in colorectal cancer patients. AB - BACKGROUND: Identification of biomarkers associated with survival in patients with cancer is important for elucidating the underlying mechanisms of cancer progression and identifying possible interventions to reduce cancer morbidity and mortality. METHODS: Using stored patient plasma samples from a multiethnic population-based case-control study of invasive colorectal cancer, we measured posttreatment blood levels of C-reactive protein (CRP) and lipid-soluble micronutrients. Patients (n = 368) were followed after phlebotomy (mean of 8 years), during which time 47% died (25% colorectal cancer specific). HRs were estimated by Cox proportional hazards regression with adjustment for stage, age at diagnosis, ethnicity, sex, smoking status, and month of blood draw. RESULTS: A positive association with overall risk of death was observed for CRP [HR for highest vs. lowest quintile: 1.80; 95% confidence interval (CI), 1.07-3.04; Ptrend = 0.01], whereas inverse associations were generally observed for retinol and carotenoids (HRs for overall risk of death for the highest quintile ranging from 0.5-0.8); these associations were significant for retinol (Ptrend = 0.0002), alpha-carotene (Ptrend = 0.02), and total carotenoids (Ptrend = 0.02) and were generally consistent across subgroups (sex, ethnicity, cancer anatomical subtype, and stage). HRs for retinol and carotenoids were attenuated somewhat after adjustment for CRP. Similar trends for CRP were observed for colorectal cancer specific deaths (HR for highest vs. lowest tertile: 2.06; 95% CI, 1.18-3.61; Ptrend = 0.01) as for deaths from all other causes (Pheterogeneity = 0.78). CONCLUSIONS: These observations are consistent with a direct relationship between circulating CRP and overall survival among patients with colorectal cancer. IMPACT: These results, if reproduced, suggest that reduction of inflammation should be explored as a potential complementary treatment strategy. PMID- 23677578 TI - Plasma levels of nitrate and risk of prostate cancer: a prospective study. AB - BACKGROUND: Nitrate and nitrite supplements have recently been shown to improve cardiovascular health, but there is concern that these supplements could contribute to the development of cancer. Previous small, cross-sectional studies reported positive associations between circulating nitrate/nitrite levels and cancer. Prospective studies examining the association between plasma nitrate and cancer, especially prostate cancer, are lacking. METHODS: We conducted a nested case-control study within the Health Professionals Follow-up Study. Baseline blood samples were collected in 1994, and incident cases of prostate cancer were identified from 1997 to 2005. Baseline plasma levels of nitrate were measured in the 630 cases and 630 matched controls. RESULTS: We have found that baseline levels of plasma nitrate were not associated with risk of prostate cancer. Compared to quintile 1, the relative risk from quintiles 2 to 5 were 1.13 [95% confidence interval (CI), 0.78-1.63], 0.93 (95% CI, 0.63-1.38), 0.95 (95% CI, 0.65-1.39), and 0.99 (95% CI, 0.68-1.48); Ptrend was 0.9 after adjustment of multivariate risk factors. When analyses were restricted to men fasting more than 6 hours, the trend was similar. Furthermore, plasma nitrate seemed to be inversely associated with advanced-stage prostate cancer. The relative risk across extreme quartiles was 0.44 (95% CI, 0.17-1.12; Ptrend = 0.07) for the whole dataset and 0.30 (95% CI, 0.09-0.99; Ptrend = 0.05) for the fasting dataset. CONCLUSIONS: In summary, we did not find an increased risk of prostate cancer associated with higher plasma nitrate levels. A potential protective association between nitrate and aggressive forms of prostate cancer requires confirmation. IMPACT: Nitrate-nitrite-nitric oxide pathway has emerged as a new therapeutic pathway for chronic diseases. The results of this study certainly merit replications in other prospective studies. PMID- 23677579 TI - New breast cancer risk variant discovered at 10q25 in East Asian women. AB - BACKGROUND: Recently, 41 new genetic susceptibility loci for breast cancer risk were identified in a genome-wide association study (GWAS) conducted in European descendants. Most of these risk variants have not been directly replicated in Asian populations. METHODS: We evaluated nine of those nonreplication loci in East Asians to identify new risk variants for breast cancer in these regions. First, we analyzed single-nucleotide polymorphisms (SNP) in these regions using data from two GWAS conducted among Chinese and Korean women, including 5,083 cases and 4,376 controls (stage 1). In each region, we selected an SNP showing the strongest association with breast cancer risk for replication in an independent set of 7,294 cases and 9,404 controls of East Asian descents (stage 2). Logistic regression models were used to calculate adjusted ORs and 95% confidence intervals (CI) as a measure of the association of breast cancer risk and genetic variants. RESULTS: Two SNPs were replicated in stage 2 at P < 0.05: rs1419026 at 6q14 [per allele OR, 1.07; 95% confidence interval (CI), 1.03-1.12; P = 3.0 * 10(-4)] and rs941827 at 10q25 (OR, 0.92, 95% CI, 0.89-0.96; P = 5.3 * 10(-5)). The association with rs941827 remained highly statistically significant after adjusting for the risk variant identified initially in women of European ancestry (OR, 0.88; 95% CI, 0.82-0.97; P = 5.3 * 10(-5)). CONCLUSION: We identified a new breast cancer risk variant at 10q25 in East Asian women. IMPACT: Results from this study improve the understanding of the genetic basis for breast cancer. PMID- 23677580 TI - Heterologous expression of an aspartic protease gene from biocontrol fungus Trichoderma asperellum in Pichia pastoris. AB - Trichoderma asperellum parasitizes a large variety of phytopathogenic fungi. The mycoparasitic activity of T. asperellum depends on the secretion of complex mixtures of hydrolytic enzymes able to degrade the host cell wall and proteases which are a group of enzymes capable of degrading proteins from host. In this study, a full-length cDNA clone of aspartic protease gene, TaAsp, from T. asperellum was obtained and sequenced. The 1,185 bp long cDNA sequence was predicted to encode a 395 amino acid polypeptide with molecular mass of 42.3 kDa. The cDNA of TaAsp was inserted into the pPIC9K vector and transformed into yeast Pichia pastoris GS115 for heterologous expression. A clearly visible band with molecular mass about 42 kDa in the SDS-PAGE gel indicated that the transformant harboring the gene TaAsp had been successfully translated in P. pastoris and produced a recombinant protein. Enzyme characterization test showed that the optimum fermentation time for P. pastoris GS115 transformant was 72 h. Enzyme activity of the recombinant aspartic proteinase remained relatively stable at 25 60 degrees C and pH 3.0-9.0, which indicated its good prospect of application in biocontrol. The optimal pH value and temperature of the enzyme activity were pH 4.0 and 40 degrees C, and under this condition, with casein as the substrate, the recombinant protease activity was 18.5 U mL(-1). In order to evaluate antagonistic activity of the recombinant protease against pathogenic fungi, five pathogenic fungi, Fusarium oxysporum, Alternaria alternata, Cytospora chrysosperma, Sclerotinia sclerotiorum and Rhizoctonia solani, were applied to the test of in vitro inhibition of their mycelial growth by culture supernatant of P. pastoris GS115 transformant. PMID- 23677581 TI - Mouse TIGIT inhibits NK-cell cytotoxicity upon interaction with PVR. AB - The activity of natural killer (NK) cells is controlled by a balance of signals derived from inhibitory and activating receptors. TIGIT is a novel inhibitory receptor, recently shown in humans to interact with two ligands: PVR and Nectin2 and to inhibit human NK-cell cytotoxicity. Whether mouse TIGIT (mTIGIT) inhibits mouse NK-cell cytotoxicity is unknown. Here we show that mTIGIT is expressed by mouse NK cells and interacts with mouse PVR. Using mouse and human Ig fusion proteins we show that while the human TIGIT (hTIGIT) cross-reacts with mouse PVR (mPVR), the binding of mTIGIT is restricted to mPVR. We further demonstrate using surface plasmon resonance (SPR) and staining with Ig fusion proteins that mTIGIT binds to mPVR with higher affinity than the co-stimulatory PVR-binding receptor mouse DNAM1 (mDNAM1). Functionally, we show that triggering of mTIGIT leads to the inhibition of NK-cell cytotoxicity, that IFN-gamma secretion is enhanced when mTIGIT is blocked and that the TIGIT-mediated inhibition is dominant over the signals delivered by the PVR-binding co-stimulatory receptors. Additionally, we identify the inhibitory motif responsible for mTIGIT inhibition. In conclusion, we show that TIGIT is a powerful inhibitory receptor for mouse NK cells. PMID- 23677583 TI - Characterization of hepatitis E virus from sporadic hepatitis cases and sewage samples from Vellore, south India. AB - BACKGROUND: Hepatitis E virus (HEV) is endemic in India and causes epidemics and sporadic cases. However, the exact transmission route for sporadic hepatitis E remains unclear. This study investigated HEV in sporadic hepatitis cases and sewage samples, as sewage is the major source of contamination of water in developing countries. METHODS: Monthly sampling and testing for HEV in sewage samples from Vellore, India was carried out for 1 year (November 2009-October 2010) and plasma and/or fecal samples from sporadic hepatitis cases presenting to a hospital in Vellore during 2006-2010 were tested for HEV RNA. A total of 144 raw sewage samples and 94 samples from sporadic hepatitis cases were tested for HEV RNA using RT-PCR. RESULTS: The prevalence of HEV RNA in sewage and sporadic cases was 55.6% and 9.6%, respectively. HEV strains isolated from sewage showed 94-100% nucleotide sequence similarity with the HEV strains isolated from the sporadic hepatitis cases. HEV RNA in sewage was identified more often during the summer (81.2%) than the monsoon season (14.5%) (p < 0.001). CONCLUSION: This study indicates that sewage may be a source of contamination for sporadic hepatitis and also underscores the need for preventive measures to protect drinking water from sewage contamination, particularly in the summer. GENBANK ACCESSION NUMBERS: HEV strains isolated from this study were deposited in GenBank under accession numbers JF972766-JF972773, JN705651-JN705659 and JN705660 JN705662. PMID- 23677582 TI - Painful and painless diabetic neuropathy: one disease or two? AB - Painful diabetic polyneuropathy (PDPN) is generally considered a variant of diabetic polyneuropathy (DPN) but the identification of distinctive aspects that characterize painful compared with painless DPN has however been addressed in many studies, mainly with the purpose of better understanding the mechanisms of neuropathic pain in the scenario of peripheral nerve damage of DPN, of determining risk markers for pain development, and also of recognizing who might respond to treatments. This review is aimed at examining available literature dealing with the issue of similarities and differences between painful and painless DPN in an attempt to respond to the question of whether painful and painless DPN are the same disease or not and to address the conundrum of why some people develop the insensate variety of DPN whilst others experience distressing pain. Thus, from the perspective of comparing painful with painless forms of DPN, this review considers the clinical correlates of PDPN, its distinctive framework of symptoms, signs, and nerve functional and structural abnormalities, the question of large and small fiber involvement, the peripheral pain mechanisms, the central processing of pain and some new insights into the pathogenesis of pain in peripheral polyneuropathies and PDPN. PMID- 23677589 TI - Assessment of anti-mutagenic, anti-histopathologic and antioxidant capacities of Egyptian bee pollen and propolis extracts. AB - Bee pollen and propolis are popular, traditional health foods. The objective of the current study was to investigate the anti-mutagenic, anti-histopathologic and antioxidant effects among water extracts of Egyptian bee pollen (WEBP) and brown powder of water-soluble derivative propolis (WSDP) on cisplatin (CDDP) induced hepatic, renal, testicular and genotoxicity in male albino mice (Mus muscullus), in addition to their effects on the oxidant/antioxidant status in the tested organs. Hepatic, renal and testicular dysfunctions were evaluated histologically; while genotoxicity and cytotoxicity were evaluated by the bone marrow chromosomal aberration assay and mitotic index, respectively. Moreover, oxidative stress was explored via determination of lipid peroxidation, catalase activity and the concentration of the reduced form of glutathione. The treatment of mice with WEBP and WSDP at doses 140 and 8.4 mg/kg b. wt./day, respectively for 14 days simultaneously with CDDP (2.8 mg/kg b. wt.) resulted in significant protection. The positive control animals taken CDDP alone showed toxic histological and genetical manifestations (at P < 0.05) accompanied with an elevated content of peroxidized lipid and lowered catalase activity and glutathione concentration in the homogenate of liver, kidney and testis tissues (at P < 0.001). These toxic side effects in all tested organs were greatly ablated with a significant reduction in lipid peroxidation level and elevation in catalase activity and glutathione concentration (P < 0.001) when using both WEBP and WSDP. On the basis of the present assays, Bee pollen appears more potent in exerting an ameliorative effect and this effect was more pronounced in testis. PMID- 23677590 TI - The gracefully aging immune system. AB - Prolonged life expectancy in the 20th century has been one of humankind's greatest triumphs. However, the substantial increase in the human life span has ushered in a new concern: healthy aging. Because infectious diseases prominently contribute to morbidity in the particularly vulnerable elderly population, strategies for preventing these diseases would have a clear impact on improving healthy aging. Thus, vaccines and immunization strategies tailored for the elderly population are needed, and vaccines should be developed to take into consideration the peculiar age-induced variations of immune responsiveness. The conference "Ageing and Immunity" recently held in Siena, Italy, has reviewed and discussed several possible causes of immune senescence, as well as strategies for counteracting this waning of immune responsiveness and for restoring immunocompetence. In addition, examples of diseases that should be targeted by vaccination in the senior population were considered. PMID- 23677591 TI - Cyclophosphamide triggers follicle activation and "burnout"; AS101 prevents follicle loss and preserves fertility. AB - Premature ovarian failure and infertility are major side effects of chemotherapy treatments in young cancer patients. A more thorough understanding of the mechanism behind chemotherapy-induced follicle loss is necessary to develop new methods to preserve fertility in these patients. We show that the alkylating agent cyclophosphamide (Cy) activates the growth of the quiescent primordial follicle population in mice, resulting in loss of ovarian reserve. Despite the initial massive apoptosis observed in growing, though not in resting, follicles of Cy-treated mice, differential follicle counts demonstrated both a decrease in primordial follicles and an increase in early growing follicles. Immunohistochemistry showed that granulosa cells were undergoing proliferation. Analysis of the phosphatidylinositol 3-kinase signaling pathway demonstrated that Cy increased phosphorylation of proteins that stimulate follicle activation in the oocytes and granulosa cells. Coadministration of an immunomodulator, AS101, reduced follicle activation, thereby increasing follicle reserve and rescuing fertility after Cy, and also increased the efficacy of Cy against breast cancer cell lines. These findings suggest that the mechanism in Cy-induced loss of ovarian reserve is accelerated primordial follicle activation, which results in a "burnout" effect and follicle depletion. By preventing this activation, AS101 shows potential as an ovarian-protective agent, which may be able to preserve fertility in female cancer patients. PMID- 23677592 TI - Oncolytic and immunotherapeutic vaccinia induces antibody-mediated complement dependent cancer cell lysis in humans. AB - Oncolytic viruses cause direct cytolysis and cancer-specific immunity in preclinical models. The goal of this study was to demonstrate induction of functional anticancer immunity that can lyse target cancer cells in humans. Pexa Vec (pexastimogene devacirepvec; JX-594) is a targeted oncolytic and immunotherapeutic vaccinia virus engineered to express human granulocyte macrophage colony-stimulating factor (GM-CSF). Pexa-Vec demonstrated replication, GM-CSF expression, and tumor responses in previous phase 1 trials. We now evaluated whether Pexa-Vec induced functional anticancer immunity both in the rabbit VX2 tumor model and in patients with diverse solid tumor types in phase 1. Antibody-mediated complement-dependent cancer cell cytotoxicity (CDC) was induced by intravenous Pexa-Vec in rabbits; transfer of serum from Pexa-Vec-treated animals to tumor-bearing animals resulted in tumor necrosis and improved survival. In patients with diverse tumor types treated on a phase 1 trial, CDC developed within 4 to 8 weeks in most patients; normal cells were resistant to the cytotoxic effects. T lymphocyte activation in patients was evidenced by antibody class switching. We determined that patients with the longest survival duration had the highest CDC activity, and identified candidate target tumor cell antigens. Thus, we demonstrated that Pexa-Vec induced polyclonal antibody mediated CDC against multiple tumor antigens both in rabbits and in patients with diverse solid tumor types. PMID- 23677593 TI - Targeting the TLR co-receptor CD14 with TLR2-derived peptides modulates immune responses to pathogens. AB - Dysregulation of Toll-like receptor (TLR) responses to pathogens can lead to pathological inflammation or to immune hyporesponsiveness and susceptibility to infections, and may affect adaptive immune responses. TLRs are therefore attractive therapeutic targets. We assessed the potential of the TLR co-receptor CD14 as a target for therapeutics by investigating the magnitude of its influence on TLR responses. We studied the interaction of CD14 with TLR2 by conducting peptide screening and site-directed mutagenesis analysis and found TLR2 leucine rich repeats 5, 9, 15, and 20 involved in interaction with CD14. Peptides representing these regions interacted with CD14 and enhanced TLR2- and TLR4 mediated proinflammatory responses to bacterial pathogens in vitro. Notably, the peptides' immune boosting capacity helped to rescue proinflammatory responses of immunosuppressed sepsis patients ex vivo. In vivo, peptide treatment increased phagocyte recruitment and accelerated bacterial clearance in murine models of Gram-negative and Gram-positive bacterial peritonitis. Up-modulating CD14's co receptor activity with TLR2-derived peptides also enhanced antigen-induced dendritic cell (DC) maturation and interleukin-2 production and, most notably, differentially affected DC cytokine profile upon antigen stimulation, promoting a T helper 1-skewed adaptive immune response. Biochemical, cell imaging, and molecular docking studies showed that peptide binding to CD14 accelerates microbial ligand transfer from CD14 to TLR2, resulting in increased and sustained ligand occupancy of TLR2 and receptor clustering for signaling. These findings reveal the influence that CD14 exerts on TLR activities and describe a potential therapeutic strategy to amplify responses to different pathogens mediated by different TLRs by targeting the common TLR co-receptor, CD14. PMID- 23677595 TI - Using "threading followed by shrinking" to synthesize highly stable dialkylammonium-ion-based rotaxanes. AB - Herein, we report a "threading followed by shrinking" approach for the synthesis of rotaxanes by using an "oxygen-deficient" macrocycle that contained two arylmethyl sulfone units and the dumbbell-shaped salt bis(3,5 dimethylbenzyl)ammonium tetrakis(3,5-trifluoromethylphenyl)borate as the host and guest components, respectively. The extrusion of SO2 from both of the arylmethyl sulfone units of the macrocyclic component in the corresponding [2]pseudorotaxane resulted in a [2]rotaxane that was sufficiently stable to maintain its molecular integrity in CD3 SOCD3 at 393 K for at least 5 h. PMID- 23677594 TI - Synthetic generation of influenza vaccine viruses for rapid response to pandemics. AB - During the 2009 H1N1 influenza pandemic, vaccines for the virus became available in large quantities only after human infections peaked. To accelerate vaccine availability for future pandemics, we developed a synthetic approach that very rapidly generated vaccine viruses from sequence data. Beginning with hemagglutinin (HA) and neuraminidase (NA) gene sequences, we combined an enzymatic, cell-free gene assembly technique with enzymatic error correction to allow rapid, accurate gene synthesis. We then used these synthetic HA and NA genes to transfect Madin-Darby canine kidney (MDCK) cells that were qualified for vaccine manufacture with viral RNA expression constructs encoding HA and NA and plasmid DNAs encoding viral backbone genes. Viruses for use in vaccines were rescued from these MDCK cells. We performed this rescue with improved vaccine virus backbones, increasing the yield of the essential vaccine antigen, HA. Generation of synthetic vaccine seeds, together with more efficient vaccine release assays, would accelerate responses to influenza pandemics through a system of instantaneous electronic data exchange followed by real-time, geographically dispersed vaccine production. PMID- 23677596 TI - [The symptom checklist SCL-27-plus for patients with eating disorders]. AB - The symptom checklist-27-plus has demonstrated good psychometric properties in various samples, but clinical data have not yet been published. Data from 690 mostly young female patients with eating disorders show reliabilities ranging from acceptable to very good (Cronbachs alpha between 0.76 und 0.89). Data from intake and discharge show a good ability to measure change (Cohen's d between 0.27 und 1.31). At intake, patients display a very high symptom load, which has decreased significantly at discharge. PMID- 23677597 TI - Endovascular treatment of cerebral hemorrhage in a patient with a left ventricular assist device: report of a case. AB - Cerebral hemorrhage is a common lethal complication associated with left ventricular assist device (LVAD) management. We performed cerebral angiography on patients with LVAD who developed cerebral hemorrhage and determined that ruptured aneurysms were the cause in some cases. Endovascular management of patients with LVAD can be a therapeutically useful approach for cerebral hemorrhage caused by aneurysm rupture. PMID- 23677598 TI - Treatment strategies for gastric cancer patients with peritoneal metastasis. AB - Although the treatment of gastric cancer improves the clinical outcomes, the survival of gastric cancer patients with peritoneal metastasis is still very poor. Effective drugs against peritoneal metastasis, coupled with new therapeutic modalities, are needed to improve the prognoses of these patients. Paclitaxel and TS-1 are candidate drugs for peritoneal metastasis, and intraperitoneal chemotherapy and targeted therapy are potential new therapeutic modalities. Two phase II studies using TS-1 and intraperitoneal and systemic paclitaxel for gastric cancer patients with peritoneal metastasis showed respectable survival results. In addition, peritoneal metastatic lesions showed high levels of epithelial cellular adhesion molecule (ECAM) and very low levels of human epidermal growth factor receptor 2 (HER2), thus indicating that an anti-ECAM monoclonal antibody, catumaxomab, would be effective against gastric cancer derived peritoneal metastasis. Although catumaxomab and intraperitoneally administered paclitaxel are not generally used in Japan at present, these treatment strategies might therefore be effectively used in Japan in the near future. PMID- 23677604 TI - Response to 'Red blood cell distribution width is a predictor of readmission in cardiac patients'. PMID- 23677605 TI - Changes in postoperative recurrence and prognostic risk factors for patients with gastric cancer who underwent curative gastric resection during different time periods. AB - BACKGROUND: Current rates of survival for gastric cancer patients are much improved compared with those of the past. The purpose of our study was to analyze the survival of gastric cancer patients according to time period and to examine how different prognostic factors are related to changing survival rates. METHODS: We analyzed data from 7,757 patients who underwent curative gastrectomy after diagnoses of gastric cancer at Samsung Medical Center from 1994 to 2006. Clinicopathologic characteristics and prognostic factors were analyzed retrospectively, with patients divided into period I, from 1994 to 2001, and period II, from 2002 to 2006. RESULTS: The 5-year, disease-free survival rate of patients with gastric cancer increased significantly from 76.7 % during period I to 85.9 % during period II (p < 0.001). The prognosis of the patient who underwent surgery during period I was worse than that of the patient in period II. When multivariate analyses were performed for each time period, independent prognostic factors for period I included patient age >60 years, tumor located in the whole stomach, tumor size, stage, vascular invasion, perineural invasion, and adjuvant chemotherapy. For period II, tumor size, vascular, and adjuvant chemotherapy were no longer independent prognostic risk factors. CONCLUSIONS: The disease-free survival of gastric cancer improved and prognostic factors changed over time. Active, concurrent chemoradiotherapy together with radical gastric resection performed by an expert surgeon seemed to contribute to the improvement in the survival rates of gastric cancer. PMID- 23677607 TI - An optogenetic tool for the activation of endogenous diaphanous-related formins induces thickening of stress fibers without an increase in contractility. AB - We have developed an optogenetic technique for the activation of diaphanous related formins. Our approach is based on fusion of the light-oxygen-voltage 2 domain of Avena sativa Phototrophin1 to an isolated Diaphanous Autoregulatory Domain from mDia1. This "caged" diaphanous auto-regulatory domain was inactive in the dark but in the presence of blue light rapidly activated endogenous diaphanous-related formins. Using an F-actin reporter, we observed filopodia and lamellipodia formation as well as a steady increase in F-actin along existing stress fibers, starting within minutes of photo-activation. Interestingly, we did not observe the formation of new stress fibers. Remarkably, a 1.9-fold increase in F-actin was not paralleled by an increase in myosin II along stress fibers and the amount of tension generated by the fibers, as judged by focal adhesion size, appeared unchanged. Our results suggest a decoupling between F-actin accumulation and contractility in stress fibers and demonstrate the utility of photoactivatable diaphanous autoregulatory domain for the study of diaphanous related formin function in cells. PMID- 23677608 TI - BAGEL3: Automated identification of genes encoding bacteriocins and (non )bactericidal posttranslationally modified peptides. AB - Identifying genes encoding bacteriocins and ribosomally synthesized and posttranslationally modified peptides (RiPPs) can be a challenging task. Especially those peptides that do not have strong homology to previously identified peptides can easily be overlooked. Extensive use of BAGEL2 and user feedback has led us to develop BAGEL3. BAGEL3 features genome mining of prokaryotes, which is largely independent of open reading frame (ORF) predictions and has been extended to cover more (novel) classes of posttranslationally modified peptides. BAGEL3 uses an identification approach that combines direct mining for the gene and indirect mining via context genes. Especially for heavily modified peptides like lanthipeptides, sactipeptides, glycocins and others, this genetic context harbors valuable information that is used for mining purposes. The bacteriocin and context protein databases have been updated and it is now easy for users to submit novel bacteriocins or RiPPs. The output has been simplified to allow user-friendly analysis of the results, in particular for large (meta-genomic) datasets. The genetic context of identified candidate genes is fully annotated. As input, BAGEL3 uses FASTA DNA sequences or folders containing multiple FASTA formatted files. BAGEL3 is freely accessible at http://bagel.molgenrug.nl. PMID- 23677609 TI - A concept of eliminating nonhomologous recombination for scalable and safe AAV vector generation for human gene therapy. AB - Scalable and efficient production of high-quality recombinant adeno-associated virus (rAAV) for gene therapy remains a challenge despite recent clinical successes. We developed a new strategy for scalable and efficient rAAV production by sequestering the AAV helper genes and the rAAV vector DNA in two different subcellular compartments, made possible by using cytoplasmic vaccinia virus as a carrier for the AAV helper genes. For the first time, the contamination of replication-competent AAV particles (rcAAV) can be completely eliminated in theory by avoiding ubiquitous nonhomologous recombination. Vector DNA can be integrated into the host genomes or delivered by a nuclear targeting vector such as adenovirus. In suspension HeLa cells, the achieved vector yield per cell is similar to that from traditional triple-plasmid transfection method. The rcAAV contamination was undetectable at the limit of our assay. Furthermore, this new concept can be used not only for production of rAAV, but also for other DNA vectors. PMID- 23677610 TI - IslandViewer update: Improved genomic island discovery and visualization. AB - IslandViewer (http://pathogenomics.sfu.ca/islandviewer) is a web-accessible application for the computational prediction and analysis of genomic islands (GIs) in bacterial and archaeal genomes. GIs are clusters of genes of probable horizontal origin and are of high interest because they disproportionately encode virulence factors and other adaptations of medical, environmental and industrial interest. Many computational tools exist for the prediction of GIs, but three of the most accurate methods are available in integrated form via IslandViewer: IslandPath-DIMOB, SIGI-HMM and IslandPick. IslandViewer GI predictions are precomputed for all complete microbial genomes from National Center for Biotechnology Information, with an option to upload other genomes and/or perform customized analyses using different settings. Here, we report recent changes to the IslandViewer framework that have vastly improved its efficiency in handling an increasing number of users, plus better facilitate custom genome analyses. Users may also now overlay additional annotations such as virulence factors, antibiotic resistance genes and pathogen-associated genes on top of current GI predictions. Comparisons of GIs between user-selected genomes are now facilitated through a highly requested side-by-side viewer. IslandViewer improvements aim to provide a more flexible interface, coupled with additional highly relevant annotation information, to aid analysis of GIs in diverse microbial species. PMID- 23677611 TI - WebScipio: Reconstructing alternative splice variants of eukaryotic proteins. AB - Accurate exon-intron structures are essential prerequisites in genomics, proteomics and for many protein family and single gene studies. We originally developed Scipio and the corresponding web service WebScipio for the reconstruction of gene structures based on protein sequences and available genome assemblies. WebScipio also allows predicting mutually exclusive spliced exons and tandemly arrayed gene duplicates. The obtained gene structures are illustrated in graphical schemes and can be analysed down to the nucleotide level. The set of eukaryotic genomes available at the WebScipio server is updated on a daily basis. The current version of the web server provides access to ~3400 genome assembly files of >1100 sequenced eukaryotic species. Here, we have also extended the functionality by adding a module with which expressed sequence tag (EST) and cDNA data can be mapped to the reconstructed gene structure for the identification of all types of alternative splice variants. WebScipio has a user-friendly web interface, and we believe that the improved web server will provide better service to biologists interested in the gene structure corresponding to their protein of interest, including all types of alternative splice forms and tandem gene duplicates. WebScipio is freely available at http://www.webscipio.org. PMID- 23677612 TI - Human mitochondrial disease-like symptoms caused by a reduced tRNA aminoacylation activity in flies. AB - The translation of genes encoded in the mitochondrial genome requires specific machinery that functions in the organelle. Among the many mutations linked to human disease that affect mitochondrial translation, several are localized to nuclear genes coding for mitochondrial aminoacyl-transfer RNA synthetases. The molecular significance of these mutations is poorly understood, but it is expected to be similar to that of the mutations affecting mitochondrial transfer RNAs. To better understand the molecular features of diseases caused by these mutations, and to improve their diagnosis and therapeutics, we have constructed a Drosophila melanogaster model disrupting the mitochondrial seryl-tRNA synthetase by RNA interference. At the molecular level, the knockdown generates a reduction in transfer RNA serylation, which correlates with the severity of the phenotype observed. The silencing compromises viability, longevity, motility and tissue development. At the cellular level, the knockdown alters mitochondrial morphology, biogenesis and function, and induces lactic acidosis and reactive oxygen species accumulation. We report that administration of antioxidant compounds has a palliative effect of some of these phenotypes. In conclusion, the fly model generated in this work reproduces typical characteristics of pathologies caused by mutations in the mitochondrial aminoacylation system, and can be useful to assess therapeutic approaches. PMID- 23677613 TI - The helicase FBH1 is tightly regulated by PCNA via CRL4(Cdt2)-mediated proteolysis in human cells. AB - During replication, DNA damage can challenge replication fork progression and cell viability. Homologous Recombination (HR) and Translesion Synthesis (TLS) pathways appear as major players involved in the resumption and completion of DNA replication. How both pathways are coordinated in human cells to maintain genome stability is unclear. Numerous helicases are involved in HR regulation. Among them, the helicase FBH1 accumulates at sites of DNA damage and potentially constrains HR via its anti-recombinase activity. However, little is known about its regulation in vivo. Here, we report a mechanism that controls the degradation of FBH1 after DNA damage. Firstly, we found that the sliding clamp Proliferating Cell Nuclear Antigen (PCNA) is critical for FBH1 recruitment to replication factories or DNA damage sites. We then showed the anti-recombinase activity of FBH1 is partially dependent on its interaction with PCNA. Intriguingly, after its re-localization, FBH1 is targeted for degradation by the Cullin-ring ligase 4 Cdt2 (CRL4(Cdt2))-PCNA pathway via a PCNA-interacting peptide (PIP) degron. Importantly, expression of non-degradable FBH1 mutant impairs the recruitment of the TLS polymerase eta to chromatin in UV-irradiated cells. Thus, we propose that after DNA damage, FBH1 might be required to restrict HR and then degraded by the Cdt2-proteasome pathway to facilitate TLS pathway. PMID- 23677614 TI - aLeaves facilitates on-demand exploration of metazoan gene family trees on MAFFT sequence alignment server with enhanced interactivity. AB - We report a new web server, aLeaves (http://aleaves.cdb.riken.jp/), for homologue collection from diverse animal genomes. In molecular comparative studies involving multiple species, orthology identification is the basis on which most subsequent biological analyses rely. It can be achieved most accurately by explicit phylogenetic inference. More and more species are subjected to large scale sequencing, but the resultant resources are scattered in independent project-based, and multi-species, but separate, web sites. This complicates data access and is becoming a serious barrier to the comprehensiveness of molecular phylogenetic analysis. aLeaves, launched to overcome this difficulty, collects sequences similar to an input query sequence from various data sources. The collected sequences can be passed on to the MAFFT sequence alignment server (http://mafft.cbrc.jp/alignment/server/), which has been significantly improved in interactivity. This update enables to switch between (i) sequence selection using the Archaeopteryx tree viewer, (ii) multiple sequence alignment and (iii) tree inference. This can be performed as a loop until one reaches a sensible data set, which minimizes redundancy for better visibility and handling in phylogenetic inference while covering relevant taxa. The work flow achieved by the seamless link between aLeaves and MAFFT provides a convenient online platform to address various questions in zoology and evolutionary biology. PMID- 23677615 TI - IGF2BP1 promotes mesenchymal cell properties and migration of tumor-derived cells by enhancing the expression of LEF1 and SNAI2 (SLUG). AB - The oncofetal IGF2 mRNA-binding protein 1 (IGF2BP1) controls the migration and invasiveness of primary as well as tumor-derived cells in vitro. Whether the protein also modulates epithelial-mesenchymal-transition (EMT), a hallmark of tumor progression involved in tumor cell dissemination, remained elusive. In this study, we reveal that IGF2BP1 enhances mesenchymal-like cell properties in tumor derived cells by promoting the expression of the transcriptional regulators LEF1 and SLUG (SNAI2). IGF2BP1 associates with LEF1 transcripts and prevents their degradation in a 3'-UTR-dependent manner resulting in an upregulation of LEF1 expression. LEF1 promotes transcription of the mesenchymal marker fibronectin by associating with the fibronectin 1 promoter. Moreover, LEF1 enforces the synthesis of the 'EMT-driving' transcriptional regulator SNAI2. Accordingly, IGF2BP1 knockdown causes MET-like (mesenchymal-epithelial-transition) morphological changes, enhances the formation of cell-cell contacts and reduces cell migration in various mesenchymal-like tumor-derived cells. However, in epithelial-like tumor-derived cells characterized by a lack or low abundance of IGF2BP1, the protein fails to induce EMT. These findings identify IGF2BP1 as a pro-mesenchymal post-transcriptional determinant, which sustains the synthesis of 'EMT-driving' transcriptional regulators, mesenchymal markers and enhances tumor cell motility. This supports previous reports, suggesting a role of IGF2BP1 in tumor cell dissemination. PMID- 23677616 TI - CovalentDock Cloud: a web server for automated covalent docking. AB - Covalent binding is an important mechanism for many drugs to gain its function. We developed a computational algorithm to model this chemical event and extended it to a web server, the CovalentDock Cloud, to make it accessible directly online without any local installation and configuration. It provides a simple yet user friendly web interface to perform covalent docking experiments and analysis online. The web server accepts the structures of both the ligand and the receptor uploaded by the user or retrieved from online databases with valid access id. It identifies the potential covalent binding patterns, carries out the covalent docking experiments and provides visualization of the result for user analysis. This web server is free and open to all users at http://docking.sce.ntu.edu.sg/. PMID- 23677617 TI - SGAtools: one-stop analysis and visualization of array-based genetic interaction screens. AB - Screening genome-wide sets of mutants for fitness defects provides a simple but powerful approach for exploring gene function, mapping genetic networks and probing mechanisms of drug action. For yeast and other microorganisms with global mutant collections, genetic or chemical-genetic interactions can be effectively quantified by growing an ordered array of strains on agar plates as individual colonies, and then scoring the colony size changes in response to a genetic or environmental perturbation. To do so, requires efficient tools for the extraction and analysis of quantitative data. Here, we describe SGAtools (http://sgatools.ccbr.utoronto.ca), a web-based analysis system for designer genetic screens. SGAtools outlines a series of guided steps that allow the user to quantify colony sizes from images of agar plates, correct for systematic biases in the observations and calculate a fitness score relative to a control experiment. The data can also be visualized online to explore the colony sizes on individual plates, view the distribution of resulting scores, highlight genes with the strongest signal and perform Gene Ontology enrichment analysis. PMID- 23677618 TI - Strong bending of the DNA double helix. AB - During the past decade, the issue of strong bending of the double helix has attracted a lot of attention. Here, we overview the major experimental and theoretical developments in the field sorting out reliably established facts from speculations and unsubstantiated claims. Theoretical analysis shows that sharp bends or kinks have to facilitate strong bending of the double helix. It remains to be determined what is the critical curvature of DNA that prompts the appearance of the kinks. Different experimental and computational approaches to the problem are analyzed. We conclude that there is no reliable evidence that any anomalous behavior of the double helix happens when DNA fragments in the range of 100 bp are circularized without torsional stress. The anomaly starts at the fragment length of about 70 bp when sharp bends or kinks emerge in essentially every molecule. Experimental data and theoretical analysis suggest that kinks may represent openings of isolated base pairs, which had been experimentally detected in linear DNA molecules. The calculation suggests that although the probability of these openings in unstressed DNA is close to 10(-5), it increases sharply in small DNA circles reaching 1 open bp per circle of 70 bp. PMID- 23677619 TI - Tel1 and Rad51 are involved in the maintenance of telomeres with capping deficiency. AB - Vertebrate-like T2AG3 telomeres in tlc1-h yeast consist of short double-stranded regions and long single-stranded overhang (G-tails) and, although based on Tbf1 capping activity, they are capping deficient. Consistent with this idea, we observe Y' amplification because of homologous recombination, even in the presence of an active telomerase. In these cells, Y' amplification occurs by different pathways: in Tel1(+) tlc1h cells, it is Rad51-dependent, whereas in the absence of Tel1, it depends on Rad50. Generation of telomeric G-tail, which is cell cycle regulated, depends on the MRX (Mre11-Rad50-Xrs2) complex in tlc1h cells or is MRX-independent in tlc1h tel1Delta mutants. Unexpectedly, we observe telomere elongation in tlc1h lacking Rad51 that seems to act as a telomerase competitor for binding to telomeric G-tails. Overall, our results show that Tel1 and Rad51 have multiple roles in the maintenance of vertebrate-like telomeres in yeast, supporting the idea that they may participate to evolutionary conserved telomere protection mechanism/s acting at uncapped telomeres. PMID- 23677620 TI - Comparison of three-dimensional pseudo-continuous arterial spin labeling perfusion imaging with gradient-echo and spin-echo dynamic susceptibility contrast MRI. AB - PURPOSE: To compare the relative cerebral blood flow (CBF) obtained by pseudo continuous arterial spin labeling sequence incorporated with volumetric fast spin echo readout (3D-PCASL) with those by gradient-echo (GE) and spin-echo (SE) dynamic susceptibility contrast (DSC) MRI. MATERIALS AND METHODS: Thirty patients with various neurological diseases participated in this study. In addition to 3D PCASL, 15 patients received GE-DSC and the others received SE-DSC imaging on a 3 Tesla scanner. A cortical gray matter (GM) to white matter (WM) and a thalamus (TM) to WM CBF ratio were determined from each perfusion scan. In addition, histograms of relative CBF distributions were obtained from each method for comparison. RESULTS: Significant correlations of CBF ratios were found between 3D PCASL and the two DSC methods (P < 0.05). The 3D-PCASL resulted in GM/WM CBF ratios similar to SE-DSC but significantly smaller than GE-DSC (P = 2.3 * 10(-7) ). TM/WM CBF ratio obtained by 3D-PCASL was significantly smaller than those by GE- and SE-DSC (P = 4.1 * 10(-7) and 1.2 * 10(-6) , respectively). The histogram of relative CBF maps obtained from SE-DSC, after applied spatial smoothing, agreed well with that from 3D-PCASL. CONCLUSION: This study suggested that perfusion images obtained from 3D-PCASL exhibited significant correlations with DSC-MRI, with greater microvascular weighting like SE-DSC. PMID- 23677621 TI - Where is the acid coming from? Esophago-gastric fistula following laparoscopic nissen fundoplication. PMID- 23677622 TI - Improvement of cloning efficiency in minipigs using post-thawed donor cells treated with roscovitine. AB - Massachusetts General Hospital miniature pigs (MGH minipigs) have been established for organ transplantation studies across the homozygous major histocompatibility complex, but cloning efficiency of MGH minipigs is extremely low. This study was designed to increase the productivity of MGH minipigs by nuclear transfer of post-thaw donor cells after 1 h co-incubation with roscovitine. The MGH minipig cells were genetically modified with GT KO (alpha1,3 galactosyltransferase knock-out) and hCD46 KI (human CD46 knock-in) and used as donor cells. The GT KO/hCD46 KI donor cells were cultured for either 3 days (control group) or 1 h after thawing with 15 MUM roscovitine (experimental group) prior to the nuclear transfer. The relative percentage of the transgenic donor cells that entered into G0/G1 was 93.7 % (+/-2.54). This was different from the donor cells cultured for 1 h with the roscovitine-treated group (84.6 % +/-4.6) (P < 0.05) and without roscovitine (78.6 % +/-5.5) (P < 0.01), respectively. The pregnancy rate and delivery rate in the roscovitine group (8/12 and 6/8, respectively) were significantly higher (P < 0.01) than those in the control group (6/19 and 3/6, respectively). In the experimental group, 12 GT KO/hCD46 KI transgenic minipigs were successfully generated, and five minipigs among them survived for more than 6 months so far. The recipient-based individual cloning efficiency ranged from 0.74 to 2.54 %. In conclusion, gene-modified donor cells can be used for cloning of MGH minipigs if the cells are post-thawed and treated with roscovitine for 1 h prior to nuclear transfer. PMID- 23677623 TI - The sympathetic nervous system in obesity hypertension. AB - Abundant evidence supports a role of the sympathetic nervous system in the pathogenesis of obesity-related hypertension. However, the nature and temporal progression of mechanisms underlying this sympathetically mediated hypertension are incompletely understood. Recent technological advances allowing direct recordings of renal sympathetic nerve activity (RSNA) in conscious animals, together with direct suppression of RSNA by renal denervation and reflex-mediated global sympathetic inhibition in experimental animals and human subjects have been especially valuable in elucidating these mechanisms. These studies strongly support the concept that increased RSNA is the critical mechanism by which increased central sympathetic outflow initiates and maintains reductions in renal excretory function, causing obesity hypertension. Potential determinants of renal sympathoexcitation and the differential mechanisms mediating the effects of renal specific versus reflex-mediated, global sympathetic inhibition on renal hemodynamics and cardiac autonomic function are discussed. These differential mechanisms may impact the efficacy of current device-based approaches for hypertension therapy. PMID- 23677625 TI - [Are urban dwellers more depressed and anxious than the rural population? Results of a representative survey]. AB - This study investigates the association between urbanicity and mental health in the general population. We conducted a representative survey (N = 5,036) measuring depression (PHQ-2), anxiety (GAD-2) as well as life satisfaction (FLZM). Results support the assumption that the prevalence rate for pathological scores of depression and anxiety are higher in urban than in rural areas. But, there is no clear linear association between urbanicity and mental health. Urbanicity seems to be a distal factor for higher rates in anxiety and depression. Urban-rural differences in other studies can not be transferred to the German population that easily. Future studies have to take variables on an individual and community level into account to analyse the relationship between urbanicity and mental health. PMID- 23677624 TI - Hedgehog and Gli signaling in embryonic mammary gland development. AB - The first mouse mutation associated with a heritable defect in embryonic mammary gland development was Extratoes. It represents a functional null-mutation of the gene encoding Gli3, which is best known as a transcription factor mediating canonical Hedgehog (Hh) signaling. Here we review the roles of Hh and Gli proteins in murine embryonic mammary development. We propose that an off-state for Hh signaling, mediated by Gli3-repressor, is determinant for induction of a mammary instead of hair follicle fate in the trunk surface ectoderm. PMID- 23677626 TI - [Stigmatization in HIV/AIDS: first German adaptation of the HIV-stigma scale (HSS D)]. AB - Despite improvements in medical treatment and numerous public health campaigns stigmatization remains a potent stressor for people living with HIV/ AIDS. This study provides an initial German adaptation of the HIV Stigma Scale (HSS-D). Participants were 167 HIV-positive homosexual men aged 22-74 years. Exploratory factor analysis replicated the original four-factor structure (subscales: enacted stigma, disclosure concerns, negative self-image, concern with public attitudes). Further psychometric analysis led to a revised version comprising 21 items (HSS D21). The scale showed high reliability (alpha=0.90). Significant associations with anxiety, depres-sion, life satisfaction and perceived social support confirmed for construct validity. The majority of the respondents expressed high acceptance of the stigma measure. In order to eslish a thorough German adaptation further research with diverse samples is needed. PMID- 23677627 TI - [KoMPASS--design, implementation and experiences concerning a structured communication skills training for physicians dealing with oncology]. AB - Goal of the KoMPASS project is to develop and test a training program that effectively improves oncologists' communication skills. The training draws with regard to concept, content and didactic methods to the specific challenges arising in interactions with cancer patients. Concept and didactical methods for an intensive training (KoMPASS Training) are being presented and complemented with experiences gathered during 39 trainings with 335 physicians, as well as findings from the training evaluation by participants. The participants' feedback after 4 months indicates successful transfer into clinical practice along with personal relief, improved self-efficacy, and communicative competencies. Even experienced practitioners ascribe high practical usefulness, and personal learning achievements to the KoMPASS training. The results of the concomitant study concerning self-efficacy, empathy, work-related stress and communicative competence will be published later. PMID- 23677629 TI - Key aspects of antimicrobial stewardship. PMID- 23677630 TI - Antimicrobial de-escalation strategies in hospitalized patients with pneumonia, intra-abdominal infections, and bacteremia. AB - Increasing numbers of serious hospital/healthcare- or community-acquired infections are caused by resistant (often multi-drug resistant) bacterial pathogens. Because delayed or ineffective initial therapy can have severe negative consequences, patients at risk for these types of infections typically receive initial empiric antibiotic therapy with a broad-spectrum regimen covering the most likely pathogens, based on local surveillance data and risk factors for infection with a resistant microorganism. While improving the likelihood of a successful outcome, use of broad-spectrum, often high-dose, empiric antimicrobial therapy also creates pressure for the selection or development of resistant microorganisms, as well as increasing costs and possibly exposing patients to adverse events or collateral damage such as Clostridium difficile-associated disease. De-escalation is a strategy that attempts to balance the competing aims of providing initial empiric therapy that is appropriate and covers the likely pathogens, and limiting antimicrobial exposure and increased risk for emergence of resistant pathogens. More specifically, the de-escalation strategy involves collection of cultures for later microbiological assessment before initiating broad-spectrum empiric therapy covering the most likely pathogens, with the intention of streamlining or de-escalating to a more narrow-spectrum antimicrobial regimen 2-3 days later if warranted by clinical status and culture results. In some cases, negative culture results and subsequent clinical review may allow for termination of initial empiric therapy. In this manner, de escalation enables more effective targeting of the causative pathogen(s), elimination of redundant therapy, a decrease in antimicrobial pressure for emergence of resistance, and cost savings. This article examines application of the de-escalation strategy to 3 case patients, one with healthcare-associated pneumonia, another with complicated intra-abdominal infection, and a third with central line-associated bacteremia. PMID- 23677631 TI - Empiric antibiotic selection strategies for healthcare-associated pneumonia, intra-abdominal infections, and catheter-associated bacteremia. AB - Initial selection and early deployment of appropriate/adequate empiric antimicrobial therapy is critical to minimize the significant morbidity and mortality associated with hospital- or healthcare-associated infections (HAIs). Initial empiric therapy that inadequately covers the pathogen(s) causing a serious HAI has been associated with increased mortality, longer hospital stay, and elevated healthcare costs. Moreover, subsequent modification of initial inadequate therapy, later in the disease process when culture results become available, may not remedy the impact of the initial choice. Because of this, it is important that initial empiric therapy covers the most likely pathogens associated with infection in a particular patient, even if this initial regimen turns out to be unnecessarily broad, based on subsequent culture results. The current paradigm for management of serious HAIs is to initiate empiric therapy with a broad-spectrum regimen covering likely pathogens, based on local surveillance and susceptibility data, and presence of risk factors for involvement of a resistant microorganism. Subsequent modification (de-escalation) of the initial regimen becomes possible later, when culture results are available and clinical status can be better assessed, 2 to 4 days after initiation of empiric therapy. When possible, de-escalation and other steps to modify antimicrobial exposure are important for minimizing risk of antimicrobial resistance development. This article examines the general process for selection of initial empiric antibiotic therapy for patients with HAIs, illustrated through 3 case studies dealing with healthcare-associated pneumonia, complicated intra abdominal infection, and catheter-associated bacteremia, respectively. PMID- 23677632 TI - Duration and cessation of antimicrobial treatment. AB - Shortening the duration of antimicrobial therapy is an important strategy for optimizing patient care and reducing the spread of antimicrobial resistance. It is best used in the context of an overall approach to infection management that includes a focus on selecting the right initial drug and dosing regimen for empiric therapy, and de-escalation to a more narrowly focused drug regimen (or termination) based on subsequent culture results and clinical data. In addition to reducing resistance, other potential benefits of shorter antimicrobial courses include lowered antimicrobial costs, reduced risk of superinfections (including Clostridium difficile-associated diarrhea), reduced risk of antimicrobial-related organ toxicity, and improved drug compliance. There have been relatively few randomized clinical trials that study the optimal treatment durations for such serious infections as pneumonia (community- and healthcare/hospital-acquired), complicated intra-abdominal infection, and catheter-related bloodstream infection (CRBSI). Nonetheless, a growing number of studies have explored the possibilities of reducing the duration of antimicrobial therapy for at least certain patients with these infections, under certain circumstances. Professional organizations have compiled these data and used them to develop clinical practice guidelines to aid clinicians in choosing optimal treatment durations for individual patients. Many patients with hospital-acquired pneumonia, ventilator-associated pneumonia, or healthcare-associated pneumonia can be treated for 7-8 days, while 4-7 days and 14-day treatment durations may suffice for many patients with complicated intra-abdominal infections and uncomplicated CRBSI, respectively. This article first provides a general background on the rationale and data supporting shortened courses of antimicrobial therapy, before using 3 case studies to explore the practical implications of current knowledge and treatment guidelines when making decisions about treatment duration for individual patients with healthcare-associated pneumonia, complicated intra-abdominal infection, and CRBSI. PMID- 23677633 TI - Infections, bacterial resistance, and antimicrobial stewardship: the emerging role of hospitalists. AB - The care of patients with serious infections both within and outside healthcare settings is increasingly complicated by the high prevalence of resistant or multidrug-resistant (MDR) pathogens. Moreover, infections caused by MDR versus susceptible bacteria or other pathogens are associated with significantly higher mortality, length of hospital stay, and healthcare costs. Antimicrobial misuse or overuse is the primary driver for development of antimicrobial resistance, suggesting that better use of antimicrobials will translate into improved patient outcomes, more efficient use of hospital resources, and lowered healthcare costs. Antimicrobial stewardship refers to the various practices and procedures utilized to optimize antimicrobial use. The primary goal of antimicrobial stewardship is to improve patient outcomes and lower antimicrobial resistance and other unintended consequences of antimicrobial therapy. Secondary goals are to reduce length of hospital stays and healthcare-related costs. Hospitalists are increasingly involved in the care of hospitalized patients throughout the United States. Expertise in managing conditions requiring hospitalization, and experience in quality improvement across a wide range of clinical conditions, make hospitalists well positioned to participate in the development and implementation of hospital-based antimicrobial stewardship programs designed to improve patient outcomes, reduce antimicrobial resistance, and provide more efficient and lower-cost hospital care. PMID- 23677634 TI - Prognostic value of the D-dimer test in oesophageal cancer during the perioperative period. AB - BACKGROUND: There has been little research on the perioperative D-dimer levels in oesophageal cancer patients. Plasma D-dimer levels can be used to predict the outcome in cancer patients. METHODS: A cancer group of 66 oesophageal cancer patients and a control group of 12 patients with benign disease were enrolled in this cohort study. The plasma D-dimer levels during the pre-operation and 3rd and 9th day post-operation periods were prospectively examined and analysed between the two groups. Plasma D-dimer levels were also compared with the clinicopathological characteristics and 3-year survival of the oesophageal cancer patients. RESULTS: Plasma D-dimer levels increased in both groups after surgery, but they were significantly higher in the cancer group. In oesophageal cancer patients, pre-operation plasma D-dimer levels were significantly higher in TNM stage IV patients. Perioperative plasma D-dimer levels significantly increased after surgery, and the survival was shortened in those patients whose D-dimer levels on the 3rd and 9th post-operative day above the median. In addition, increased plasma D-dimer levels at the 3rd and 9th days after surgery were influenced by the patient's age. CONCLUSION: In oesophageal cancer patients, D dimer levels increased after surgery, and the increases were associated with poor outcomes. PMID- 23677635 TI - Stepwise encapsulation of sulfate ions by ferrocenyl-functionalized tripodal hexaurea receptors. AB - Three ferrocenyl-functionalized tripodal hexaurea anion receptors with ortho- (L(2)), meta- (L(3)), and para-phenylene (L(4)) bridges, which showed strong binding affinities toward sulfate ions, have been designed and synthesized. In particular, meta-phenylene-bridged ligand L(3), owing to its trigonal bipyramidal structure, can encapsulate two SO4(2-) ions in its "inner" and "outer" tripodal clefts, respectively, as supported by their clearly distinct NMR resonances and by molecular modeling. The sulfate complex of ortho-ligand L(2), (TBA)2[SO4?L(2)].2H2O (1), displays a caged tetrahedral structure with an encapsulated sulfate ion that is hydrogen bonded by the six urea groups of ligand L(2). CV studies showed two types of electrochemical response of the ferrocene/ferrocenium redox couple upon anion binding, that is, a shift of the wave and the appearance of a new peak. Quantitative binding data were obtained from the NMR and CV titrations. PMID- 23677636 TI - Frequency of different human mollicutes species in the mucosa of the oropharynx, conjunctiva, and genitalia of free-ranging and captive capuchin monkeys (Cebus spp.). AB - This study is the first to evaluate the occurrence of several Mollicutes species in Brazilian capuchin monkeys (Cebus spp.). Mollicutes were detected by culture and polymerase chain reaction (PCR) in samples of the oropharyngeal, conjuctiva, and genital mucosae of 58 monkeys. In the oropharynx, Mollicutes in general (generic PCR to the Class), and those of the genus Ureaplasma (genus PCR), were detected in 72.4% and 43.0% of the samples, respectively. The identified species in this site included: Mycoplasma arginini (43.1%), M. salivarium (41.4%), and M. pneumoniae (19.0%). Both Ureaplasma and Mycoplasma are genera of the order Mycoplasmatales. In the preputial/vaginal mucosa, PCR detected Mollicutes in general in 27.58% of the samples, the genus Ureaplasma in 32.7%, the species M. arginini in 8.6%, and Acholeplasma laidlawii of the order Acholeplasmatales in 1.7% In the conjunctiva, Mollicutes in general were detected in 29.3% of the samples, with 1.7% being identified as A. laidlawii. Culturing was difficult due to contamination, but two isolates were successfully obtained. The Mollicutes species of this study provided new insights into these bacteria in Brazilian Cebus. Studies are lacking of the actual risk of Mollicutes infection or the frequency at which primates serve as permanent or temporary reservoirs for Mollicutes. In the present study, the samples were collected from monkeys without clinical signs of infection. The mere presence of Mollicutes, particularly those also found in humans, nevertheless signals a need for studies to evaluate the impact of these microorganisms on the health of non-human primates (NHPs) and the possibility of cross-species transmission between NHPs and humans. PMID- 23677637 TI - Clinical outcomes of unstable thoracolumbar junction burst fractures: combined posterior short-segment correction followed by thoracoscopic corpectomy and fusion. AB - BACKGROUND: There is significant controversy surrounding the ideal management of thoracolumbar burst fractures. While several treatment and management algorithms have been proposed, the ideal treatment strategy for these fractures remains unsettled. The authors review their experience with short-segment posterior fusion followed by anterior thoracoscopic corpectomy for the treatment of unstable thoracolumbar burst fractures. METHODS: We identified all patients treated by a single surgeon at our institution from 2002 to 2009 with short segment posterior fusion followed by anterior thoracoscopic corpectomy for unstable thoracolumbar junction burst fractures. Demographic data, mechanism of injury, classification of fracture, Cobb angle, American Spinal Injury Association score, associated injuries, tobacco use, follow-up duration, and radiographic studies were all collected. Outcomes were assessed for fracture alignment (preoperative, postoperative, and long-term follow-up kyphosis), rate of fusion, neurological outcome, and treatment complications. RESULTS: Thirty-two patients with burst fracture of the thoracolumbar junction defined as T10 to L1 were included. At a mean follow-up of 20.4 months, 90 % of patients had demonstrated radiographic evidence of fusion and 91 % retained the correction of their kyphotic deformity. There were three complications in the series. CONCLUSIONS: Short-segment posterior fusion with thoracoscopic anterior corpectomy represents an alternative to traditional open treatment of thoracolumbar burst fractures. A thoracoscopic approach allows for a short segment posterior fusion, reducing the loss of adjacent motion segments, minimizes morbidity associated with traditional open anterior approaches, allows for anterior and posterior column stabilization, and is associated with a high rate of bony fusion. PMID- 23677638 TI - Performance of density functional theory in computing nonresonant vibrational (hyper)polarizabilities. AB - A set of exchange-correlation functionals, including BLYP, PBE0, B3LYP, BHandHLYP, CAM-B3LYP, LC-BLYP, and HSE, has been used to determine static and dynamic nonresonant (nuclear relaxation) vibrational (hyper)polarizabilities for a series of all-trans polymethineimine (PMI) oligomers containing up to eight monomer units. These functionals are assessed against reference values obtained using the Moller-Plesset second-order perturbation theory (MP2) and CCSD methods. For the smallest oligomer, CCSD(T) calculations confirm the choice of MP2 and CCSD as appropriate for assessing the density functionals. By and large, CAM B3LYP is the most successful, because it is best for the nuclear relaxation contribution to the static linear polarizability, intensity-dependent refractive index second hyperpolarizability, static second hyperpolarizability, and is close to the best for the electro-optical Pockels effect first hyperpolarizability. However, none of the functionals perform satisfactorily for all the vibrational (hyper)polarizabilities studied. In fact, in the case of electric field-induced second harmonic generation all of them, as well as the Hartree-Fock approximation, yield the wrong sign. We have also found that the Pople 6-31+G(d) basis set is unreliable for computing nuclear relaxation (hyper)polarizabilities of PMI oligomers due to the spurious prediction of a nonplanar equilibrium geometry. PMID- 23677640 TI - Mechanical & cell culture properties of elastin-like polypeptide, collagen, bioglass, and carbon nanosphere composites. AB - Collagen, the most commonly used extra-cellular matrix protein for tissue engineering applications, displays poor mechanical properties. Here, we report on the preparation and characterization of novel multi-component composite systems that incorporate a genetically engineered, biocompatible polymer (elastin-like polypeptide, ELP), biodegradable ceramic (45S5 bioglass), carbon nanosphere chains (CNSC), and minimal amount (~25% w/w) of collagen. We hypothesized that incorporation of bioglass and CNSC would improve mechanical properties of the composites. Our results showed that the tensile strength and elastic modulus nearly doubled after addition of the bioglass and CNSC compared to the control ELP-collagen hydrogels. Further, MC3T3-E1 pre-osteoblasts were cultured within the composite hydrogels and a thorough biochemical and morphological characterization was performed. Live/dead assay confirmed high cell viability (>95%) for all hydrogels by day 21 of culture. Alkaline phosphatase (ALP) activity and osteocalcin (OCN) production assessed the pre-osteoblast differentiation. Normalized ALP activity was highest for the cells cultured within ELP-bioglass-collagen hydrogels, while normalized OCN production was equivalent for all hydrogels. Alizarin red staining confirmed the mineral deposition by the cells within all hydrogels. Thus, the multi-component composite hydrogels displayed improved mechanical and cell culture properties and may be suitable scaffold materials for bone tissue engineering. PMID- 23677639 TI - In vitro treatment of carcinoma cell lines with pancreatic (pro)enzymes suppresses the EMT programme and promotes cell differentiation. AB - BACKGROUND: Previous research has suggested a putative utility of pancreatic (pro)enzymes in cancer treatment. The aim of the present study was to investigate the in vitro effects of a mixture of two pancreatic pro-enzymes, i.e., Chymotrypsinogen and Trypsinogen, and the enzyme Amylase on three human cancer cell lines, i.e., OE33 (derived from an oesophageal carcinoma), Panc1 (derived from a pancreatic carcinoma) and Caco-2 (derived from a colon carcinoma). RESULTS: After treatment of the three cancer cell lines with different doses of the (pro)enzymes for up to 7 days, we observed (i) growth inhibition in a dose dependent manner, (ii) enhanced expression of beta-catenin and E-cadherin and decreased expression of several epithelial-mesenchymal transition (EMT) associated genes, such as Vimentin, Snail and Slug, (iii) differentiation of Caco 2 cells, including the appearance of cell-specific differentiated structures such as microvilli and tight junctions, the acquisition of a more regular polygonal morphology, and an increased expression of the intestinal differentiation markers alkaline phosphatase and cytokeratin 8, and (iv) differentiation of Panc1 cells, including the formation of cell aggregates, an increment on lamellar bodies and an increased expression of the pancreatic differentiation markers glucagon and insulin. CONCLUSIONS: Our results show that the treatment of three different human cancer cell lines with pancreatic (pro)enzymes results in an enhancement of cell adhesion, an attenuation of several EMT-associated markers, and an increase in the expression of several differentiation-associated markers, suggesting the acquisition of a less malignant phenotype and a decrease in proliferative capacity due to lineage-specific cellular differentiation. PMID- 23677641 TI - P-glycoprotein is a marker of tissue eosinophilia and radiographic inflammation in chronic rhinosinusitis without nasal polyps. AB - BACKGROUND: P-glycoprotein (P-gp) is a membrane-bound efflux pump that is upregulated in chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) and participates in epithelial cytokine secretion. Eosinophilic CRS (ECRS) shares a similar cytokine profile with CRSwNP and is associated with significant inflammation and poor surgical outcomes. The goal of this study is to determine if P-gp expression is associated with degree of eosinophilia and severity of radiographic inflammation in patients with CRS without polyps (CRSsNP). METHODS: An institutional review board (IRB)-approved study using sinus tissue in 39 steroid-naive patients with CRS. P-gp expression was calculated using quantitative fluorescent immunohistochemistry (Q-FIHC) to generate an epithelial to background staining ratio. Patients were stratified into low and high epithelial expression groups (<3 and >=3, respectively). Average eosinophils per high powered field (hpf) and Lund-Mackay scores were calculated and compared with P-gp staining ratios using a 2-tailed Student t test. RESULTS: Among the 39 patients, 7 (17.95%) had high P-gp expression ratios (mean +/- SD, 4.86 +/- 1.33) while 32 (82.05%) had low expression ratios (1.91 +/- 0.45). The number of eosinophils/hpf were significantly greater in the high P-gp expression group as compared to the low expression group (62.38 +/- 83.69 vs 5.11 +/- 10.12, p = 0.0003). The Lund-Mackay scores were significantly greater in the high P-gp expression group as compared to the low expression group (11.86 +/- 2.79 vs 6.84 +/- 4.19, p = 0.005). CONCLUSION: P-gp is known to be overexpressed in CRSwNP. This study suggests that among patients with CRSsNP, P-gp is similarly overexpressed in those with high tissue eosinophilia and correlates with severity of radiographic inflammation. PMID- 23677642 TI - Perspectives on stem cell-based elastic matrix regenerative therapies for abdominal aortic aneurysms. AB - Abdominal aortic aneurysms (AAAs) are potentially fatal conditions that are characterized by decreased flexibility of the aortic wall due to proteolytic loss of the structural matrix. This leads to their gradual weakening and ultimate rupture. Drug-based inhibition of proteolytic enzymes may provide a nonsurgical treatment alternative for growing AAAs, although it might at best be sufficient to slow their growth. Regenerative repair of disrupted elastic matrix is required if regression of AAAs to a healthy state is to be achieved. Terminally differentiated adult and diseased vascular cells are poorly capable of affecting such regenerative repair. In this context, stem cells and their smooth muscle cell-like derivatives may represent alternate cell sources for regenerative AAA cell therapies. This article examines the pros and cons of using different autologous stem cell sources for AAA therapy, the requirements they must fulfill to provide therapeutic benefit, and the current progress toward characterizing the cells' ability to synthesize elastin, assemble elastic matrix structures, and influence the regenerative potential of diseased vascular cell types. The article also provides a detailed perspective on the limitations, uncertainties, and challenges that will need to be overcome or circumvented to translate current strategies for stem cell use into clinically viable AAA therapies. These therapies will provide a much needed nonsurgical treatment option for the rapidly growing, high-risk, and vulnerable elderly demographic. PMID- 23677644 TI - An observational clinical study in cats and rabbits of an anatomically designed supraglottic airway device for use in companion animal veterinary anaesthesia. PMID- 23677643 TI - Neural precursor cells cultured at physiologically relevant oxygen tensions have a survival advantage following transplantation. AB - Traditionally, in vitro stem cell systems have used oxygen tensions that are far removed from the in vivo situation. This is particularly true for the central nervous system, where oxygen (O2) levels range from 8% at the pia to 0.5% in the midbrain, whereas cells are usually cultured in a 20% O2 environment. Cell transplantation strategies therefore typically introduce a stress challenge at the time of transplantation as the cells are switched from 20% to 3% O2 (the average in adult organs). We have modeled the oxygen stress that occurs during transplantation, demonstrating that in vitro transfer of neonatal rat cortical neural precursor cells (NPCs) from a 20% to a 3% O2 environment results in significant cell death, whereas maintenance at 3% O2 is protective. This survival benefit translates to the in vivo environment, where culture of NPCs at 3% rather than 20% O2 approximately doubles survival in the immediate post-transplantation phase. Furthermore, NPC fate is affected by culture at low, physiological O2 tensions (3%), with particularly marked effects on the oligodendrocyte lineage, both in vitro and in vivo. We propose that careful consideration of physiological oxygen environments, and particularly changes in oxygen tension, has relevance for the practical approaches to cellular therapies. PMID- 23677645 TI - Balling gun-induced trauma in cattle: clinical presentation, diagnosis and prevention. AB - Pharyngeal trauma in cattle can occur during the administration of oral medication using a balling gun. The number of cases of severe complications due to bolus application that have been referred to our hospital has increased from nil between 1996 and 2008 to three or four per year. In our experience, reports by bovine veterinarians of patients with severe and often fatal pharyngeal trauma, which were not referred to the clinic, have become more common in recent years as well. The incidence of this complication is likely to be higher than this number of referrals suggests. Diagnosis without the help of imaging techniques, such as radiography and endoscopy, may be difficult, especially in cases where exploration of the pharynx cannot be carried out, or is unable to confirm the absence or presence of a lesion. Prognosis is often poor in cases where perforation has been confirmed. Boluses are increasingly administered by the owners or farm personnel without the supervision of a veterinarian. In order to prevent losses due to balling gun-induced injuries, the veterinarian plays a crucial role in giving advice to his clients. Five cases of cattle suffering from varying degrees of balling gun-induced trauma are presented, and consideration is given to incorrect application techniques. PMID- 23677646 TI - beta-Arrestins as potential therapeutic targets for Alzheimer's disease. AB - beta-arrestins represent a small family of G protein-coupled receptors (GPCRs) regulators, which provide modulating effects by facilitating desensitization and internalization of GPCRs as well as initiating their own signalings. Recent reports have demonstrated that beta-arrestins levels were correlated with amyloid beta peptide (Abeta) pathology in brains of Alzheimer's disease (AD) patients and animal models. beta-arrestins could enhance the activity of gamma-secretase via interacting with anterior pharynx defective 1 subunit, which increased Abeta production and contributed to the pathogenesis of AD. In addition, Abeta-induced internalization of beta2-adrenergic receptor internalization and loss of dendritic spine in neurons were proven to be mediated by beta-arrestins, further establishing their pathogenic role in AD. More importantly, deletion of beta arrestins markedly attenuated AD pathology, without causing any gross abnormality. Here, we review the evidence about the roles of beta-arrestins in the progression of AD. In addition, the established and postulated mechanisms by which beta-arrestins mediated in AD pathogenesis are also discussed. Based on the role of beta-arrestins in AD pathogenesis, genetically or pharmacologically targeting beta-arrestins might provide new opportunities for AD treatment. PMID- 23677648 TI - A new recombinant MnSOD prevents the cyclosporine A-induced renal impairment. AB - BACKGROUND: Cyclosporine A (CsA) is one of the most frequently used anticalcineurinic drugs for preventing graft rejection and autoimmune disease. Its use is hampered by nephrotoxic effects, namely an impairment of the glomerular filtration rate (GFR) and hypertension. Evidence suggests that reactive oxygen species (ROS) play a causal role in the nephrotoxicity. The present study aims to investigate in vivo the effects of a new recombinant mitochondrial manganese-containing superoxide dismutase (rMnSOD), a strong antioxidant, on the CsA-induced nephotoxicity. METHODS: Rats were treated with CsA (25 mg/kg/day) alone or in combination with rMnSOD (10 ug/kg/day) for 7 days. At the end of the treatment, GFR was estimated by inulin clearance (mL/min/100 g b.w.) and the mean arterial pressure (MAP) was recorded through a catheter inserted in the carotid artery. Superoxide concentration within the cells of the abdominal aorta was quantified from the oxidation of dihydroethidium (DHE). In kidney tissues, ROS levels were measured by the 2'7' dichloroflurescin diacetate assay. Renal morphology was examined at the histochemistry level. RESULTS: CsA treated rats showed a severe decrease in GFR (0.34 +/- 0.17 versus 0.94 +/- 0.10 in control, P < 0.001) which was prevented by rMnSOD co-administration (0.77 +/- 0.10). CsA-injected animals presented with higher blood pressure which was unaffected by rMnSOD. ROS levels both in the aorta and in renal tissue were significantly increased by CsA treatment, and normalized by the co-administration with rMnSOD. This effect was, partly, paralleled by the recovery from CsA-induced morphological lesions. CONCLUSIONS: Administration of rMnSOD prevents CsA mediated impairment of the GFR along with morphological alteration. This effect could be related to the inhibition of ROS. PMID- 23677647 TI - PLK2 modulates alpha-synuclein aggregation in yeast and mammalian cells. AB - Phosphorylation of alpha-synuclein (aSyn) on serine 129 is one of the major post translation modifications found in Lewy bodies, the typical pathological hallmark of Parkinson's disease. Here, we found that both PLK2 and PLK3 phosphorylate aSyn on serine 129 in yeast. However, only PLK2 increased aSyn cytotoxicity and the percentage of cells presenting cytoplasmic foci. Consistently, in mammalian cells, PLK2 induced aSyn phosphorylation on serine 129 and induced an increase in the size of the inclusions. Our study supports a role for PLK2 in the generation of aSyn inclusions by a mechanism that does not depend directly on serine 129 phosphorylation. PMID- 23677649 TI - Gap-junction-mediated communication in human periodontal ligament cells. AB - Periodontal tissue homeostasis depends on a complex cellular network that conveys cell-cell communication. Gap junctions (GJs), one of the intercellular communication systems, are found between adjacent human periodontal ligament (hPDL) cells; however, the functional GJ coupling between hPDL cells has not yet been elucidated. In this study, we investigated functional gap-junction-mediated intercellular communication in isolated primary hPDL cells. SEM images indicated that the cells were in contact with each other via dendritic processes, and also showed high anti-connexin43 (Cx43) immunoreactivity on these processes. Gap junctional intercellular communication (GJIC) among hPDL cells was assessed by fluorescence recovery after a photobleaching (FRAP) analysis, which exhibited dye coupling between hPDL cells, and was remarkably down-regulated when the cells were treated with a GJ blocker. Additionally, we examined GJs under hypoxic stress. The fluorescence recovery and expression levels of Cx43 decreased time dependently under the hypoxic condition. Exposure to GJ inhibitor or hypoxia increased RANKL expression, and decreased OPG expression. This study shows that GJIC is responsible for hPDL cells and that its activity is reduced under hypoxia. This is consistent with the possible role of hPDL cells in regulating the biochemical reactions in response to changes in the hypoxic environment. PMID- 23677650 TI - Carbon nanotubes: directions and perspectives in oral regenerative medicine. AB - One of the main goals of bone tissue engineering is to identify and develop new biomaterials and scaffolds for structural support and controlled cell growth, which allow for formation or replacement of bone tissue. Recently, carbon nanotubes (CNT) have emerged as a potential candidate for bone tissue engineering. CNT present remarkable mechanical, thermal, and electrical properties with easy functionalization capability and biocompatibility. In oral regenerative medicine, bone reconstruction is an essential requirement for functional rehabilitation of the stomatognathic system. Autologous bone still represents the gold standard graft material for bone reconstruction. However, the small amounts of bone available in donor regions, together with the high costs of surgeries, are critical aspects that hinder the selection of this procedure. Thus, CNT alone or combined with biopolymers have promise to be used as novel potential biomaterials for the restoration of bone defects. Indeed, recent evidence demonstrates CNT to be a feasible material that can increase the formation of bone in tooth sockets of rats. The purpose of this review is to summarize the recent developments in bone repair/regeneration with CNT or CNT based composites. We further provide an overview of bone tissue engineering and current applications of biomaterials, especially of CNT, to enhance bone regeneration. PMID- 23677651 TI - Exhaustion of racing sperm in nature-mimicking microfluidic channels during sorting. AB - Fertilization is central to the survival and propagation of a species, however, the precise mechanisms that regulate the sperm's journey to the egg are not well understood. In nature, the sperm has to swim through the cervical mucus, akin to a microfluidic channel. Inspired by this, a simple, cost-effective microfluidic channel is designed on the same scale. The experimental results are supported by a computational model incorporating the exhaustion time of sperm. PMID- 23677652 TI - Dual reporter gene imaging for tracking macrophage migration using the human sodium iodide symporter and an enhanced firefly luciferase in a murine inflammation model. AB - PURPOSE: The purpose of this study is to visualize the migration of reporter macrophages expressing both the human sodium iodide symporter (hNIS) and enhanced firefly luciferase (effluc) gene in mice with chemically induced inflammation. PROCEDURES: A macrophage cell line expressing both hNIS and effluc genes (Raw264.7/hNIS-effluc, herein referred to as a Raw264.7/NF) was established by cotransduction of two genes into a murine macrophage cell line (Raw264.7), and cell proliferation and phagocytic activity were compared between parental Raw264.7 and Raw264.7/NF cells. Both serial bioluminescence imaging (BLI) and small animal positron emission tomography (PET) imaging with I-124 were performed in inflammation-induced mice at various time points after intravenous injection of either Raw264.7 or Raw264.7/NF cells. RESULTS: There was no significant difference in cellular proliferation and phagocytic activity between parental Raw264.7 and Raw264.7/NF cells. Early distribution of Raw264.7/NF cells was successfully visualized in the lung and spleen by BLI, but not by I-124 PET imaging. BLI signals, but not PET signals, were observed from the inflammation site at day 4 after the injection of Raw264.7/NF cells, and the signal intensity gradually increased until day 8. In contrast, focal uptake of I-124 was first detected at the site of inflammation at postinjection day 8, and signal intensity from the inflamed lesion was highest at that time point. While visualization of the inflamed lesion was possible by both BLI and PET imaging until day 14, it was only possible by BLI until day 21 after injection. CONCLUSIONS: Tracking of macrophage migration toward inflammation foci was successfully achieved in vivo from early time points by dual reporter gene imaging with a combination of nuclear and optical reporters. Multimodal reporter imaging of macrophages might successfully overcome the limitations of single reporter gene imaging in preclinical models of inflammation. PMID- 23677655 TI - Rare treatable neurologic diseases. PMID- 23677653 TI - A randomized, multi-center, open-label, phase II study of once-per-cycle DA-3031, a biosimilar pegylated G-CSF, compared with daily filgrastim in patients receiving TAC chemotherapy for early-stage breast cancer. AB - BACKGROUNDS: A pegylated form of recombinant granulocyte-colony stimulating factor (G-CSF) was developed for prophylactic use in breast cancer. The aim of this study was to evaluate the efficacy and safety of once-per-cycle DA-3031 in patients receiving chemotherapy for breast cancer. METHODS: A total of 61 patients receiving docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy were randomized in cycle 1 to receive daily injections of filgrastim (100 MUg/m(2)) or a single subcutaneous injection of pegylated filgrastim DA-3031 at a dose of either 3.6 mg or 6 mg. RESULTS: The mean duration of grade 4 neutropenia in cycle 1 was comparable among the treatment groups (2.48, 2.20, and 2.05 days for filgrastim, DA-3031 3.6 mg and 6 mg, respectively; P=0.275). No statistically significant differences were observed in the incidence of febrile neutropenia between the treatment groups (9.5 %, 15.0 %, and 5.0 % for filgrastim, DA-3031 3.6 mg and 6 mg, respectively; P=0.681) in cycle 1. The incidences of adverse events attributable to G-CSF were similar among the treatment groups. CONCLUSIONS: Fixed doses of 3.6 mg or 6 mg DA-3031 have an efficacy comparable to that of daily injections of filgrastim in ameliorating grade 4 neutropenia in patients receiving TAC chemotherapy. PMID- 23677656 TI - Inflammatory and toxic myopathy. AB - Although muscle diseases are relatively rare, several treatable myopathies must be recognized by the clinician to maximize the possibility of restoring strength in affected patients. The inflammatory myopathies, including polymyositis, dermatomyositis, inflammatory necrotizing myopathy, and myositis in association with mixed connective tissue disease, typically respond well to immunosuppressive treatment. Inclusion body myositis, a myopathy that has features of both inflammation and primary degeneration, may not be treatable at this time, but treatments are actively being sought. Muscle dysfunction caused by toxins must also be recognized because removal of the offending toxin usually results in restoration of normal muscle function. Important muscle toxins include cholesterol-lowering medications, colchicine, zidovudine, corticosteroids, emetine, and ethanol. PMID- 23677657 TI - Multifocal motor neuropathy. AB - Multifocal motor neuropathy is an acquired disorder in which demyelination of motor axons, presumably due to autoimmune attack, results in progressive painless weakness without sensory loss. Motor axonal damage also occurs. It is a frequent mimic of motor neuron disease. Recognition of multifocal motor neuropathy is critical because it tends to be very responsive to treatment. Infusion of intravenous immunoglobulin is the initial treatment of choice, but other immunosuppressive treatments may also be effective. It appears that corticosteroids produce minimal benefit. PMID- 23677658 TI - Late-onset Pompe's disease. AB - Glycogen storage disease type II, also known as Pompe's disease or acid maltase deficiency, is caused by a deficiency in acid alpha-glucosidase. Severe enzyme deficiency results in infantile Pompe's disease with multiorgan involvement; a partial deficiency produces a less severe phenotype mainly consisting of a myopathy, with a later age of onset. Treatment is now available with intravenous infusion of recombinant acid alpha-glucosidase. Such treatment results in marked improvement in patients with infantile Pompe's disease, and modest improvement or stabilization in patients with late-onset Pompe's disease. PMID- 23677659 TI - Miller Fisher's syndrome. AB - Miller Fisher's syndrome is a rare variant of Guillain-Barre's syndrome characterized by the acute development of ataxia, ophthalmoparesis, and areflexia. Most patients have a measureable antibody in serum directed against the GQ1b ganglioside. This antibody is also present in the serum of patients with other forms of Guillain-Barre's syndrome who have prominent ataxia or ophthalmoplegia as part of their clinical presentation. Miller Fisher's syndrome generally is self-limited and has an excellent prognosis. PMID- 23677660 TI - Calcineurin inhibitor encephalopathy. AB - Calcineurin inhibitor encephalopathy (CIE) is a rare condition occurring in patients who are undergoing treatment with drugs from the calcineurin inhibitor (CI) family of immunosuppressants, either cyclosporine (CsA) or tacrolimus (TAC, FK506). Generally acute in onset, the symptoms are commonly reversible if properly managed in a timely fashion. The differential diagnosis is broad and an evaluation should include toxic, metabolic, infectious and ischemic causes, with abnormal cerebrospinal fluid (CSF) results (aside from elevated protein concentration in isolation), suggesting an etiology other than CIE. Neurologic deficits are generally reversible; however, the risk of permanent deficits or poor outcomes increases the longer the condition goes unrecognized. PMID- 23677661 TI - Pine mouth (pine nut) syndrome: description of the toxidrome, preliminary case definition, and best evidence regarding an apparent etiology. AB - Pine mouth syndrome (PMS), otherwise known as pine nut syndrome, is a relatively new condition. At least several thousand cases have now been described in the literature. The author describes the PMS toxidrome, offers a preliminary case definition, and discusses current best evidence regarding the etiology and risk factors related to the development of PMS.A clinically compatible case of PMS must include taste disturbance, usually characterized as bitter or metallic, following the ingestion of affected pine nuts by 1 to 3 days. Affected nuts would appear to include all, or some portion, of nuts harvested from species Pinus armandii (Chinese white pine), but could include nuts from other species. The specific toxin that is apparently present in affected nuts has not yet been isolated, and the mechanism of toxicity and factors determining PMS susceptibility need to be further detailed. There are no proven therapies for PMS. The only treatment is to cease ingesting implicated nuts and to wait for symptoms to abate. PMID- 23677662 TI - Psychosis related to malaria prophylaxis. AB - Malaria is a worldwide health problem. Fortunately, there are treatments for the disease, and measures including antimalarials that significantly reduce the risk of acquiring malaria. Unfortunately, nearly all of the available preventatives have potential serious medical and psychiatric consequences, and should be considered as a cause of disturbed behavior in patients who have traveled to countries where malaria is prevalent. PMID- 23677663 TI - Tick paralysis. AB - Tick paralysis is a rare, but readily treatable condition that if missed can lead to significant morbidity and death. The classic clinical presentation of tick paralysis is the development of an unsteady, ataxic type gait followed by an acute symmetric ascending flaccid paralysis. Symptoms generally begin within 2 to 6 days of tick attachment. If the tick continues to feed, the weakness ascends to the upper extremities over a matter of hours, followed by cranial nerve involvement. Due to the similarity in its presentation, tick paralysis is often misdiagnosed as Guillain-Barre's syndrome, particularly the Miller Fisher's subtype, given its cranial nerve involvement. However, the weakness seen in tick paralysis progresses more quickly than what is generally seen in Guillain-Barre's syndrome and the protein concentration is not elevated in the cerebrospinal fluid. The mainstay of treatment for tick paralysis is tick removal. The time to full neurologic recovery after tick removal is estimated to be around 1.5 days with initial improvement generally within hours. PMID- 23677664 TI - Acetazolamide-responsive ataxia. AB - Acetazolamide-responsive ataxia represents a unique collection of genetically distinct episodic ataxia (EA) disorders associated with paroxysmal cerebellar symptoms many of which are responsive to medical treatment with acetazolamide, a carbonic anhydrase inhibitor. Among all of the subtypes of episodic ataxia, types 2 (EA2), 3 (EA3), and 5 (EA5) are thought be the most medication responsive. Some patients with episodic ataxia type 1 (EA1) will also describe improvement with acetazolamide. Each of these individual genetic syndromes is characterized by its own unique mechanism and clinical presentation. In this review, the author provides an overview of the pathophysiology of acetazolamide-responsive ataxia, its natural history, and its clinical management. PMID- 23677665 TI - Recognition and treatment of neurologic Wilson's disease. AB - As Wilson's disease is both preventable and treatable, the diagnosis must not be missed. Despite this, it is usually misdiagnosed. Misdiagnosis and delay in treatment are clinically relevant because if left untreated, Wilson's disease progresses to hepatic failure or severe neurologic disability, and death. Those adequately treated have a normal life span. Wilson's disease is an autosomal recessive disease caused by mutations in the ATP7B gene. Mutations in ATP7B result in abnormal copper metabolism and subsequent toxic accumulation of copper. The clinical manifestations of neurologic Wilson's disease include variable combinations of dysarthria, dystonia, tremor, parkinsonism, ataxia, and choreoathetosis. Once the possibility of Wilson's disease is considered, diagnosis is straight forward. Currently available treatments, including zinc acetate and trientine, are generally well tolerated and effective. PMID- 23677666 TI - Stiff Person syndrome and other anti-GAD-associated neurologic disorders. AB - Antibodies directed against glutamic acid decarboxylase (GAD) are present in many patients with stiff person syndrome and increasingly found in patients with other symptoms indicative of central nervous system (CNS) dysfunction, such as ataxia. The classic clinical features of stiff person syndrome include muscular stiffness with superimposed painful muscular spasms. Gait is often impaired. Other CNS disorders associated with GAD antibodies include progressive encephalomyelitis with rigidity and myoclonus (PERM), limbic encephalitis, and even epilepsy. Glutamic acid decarboxylase is the rate-limiting enzyme in the production of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter. Presumably, antibodies directed against GAD impair GABA production, but the precise pathogenic mechanism of GAD-antibody-related neurologic disorders is uncertain. Many patients respond to treatment with immunomodulating therapy. Symptomatic treatment with agents that enhance GABA activity, such as benzodiazepines and baclofen, is also helpful for many patients. PMID- 23677667 TI - Racemose neurocysticercosis. AB - Neurocysticercosis is one of the most common infections of the central nervous system in the developing world. Most often, neurocysticerci are found in the brain parenchyma, at the gray-white matter junction. A rare form of neurocysticercosis is the development of cysts at the basal subarachnoid region, termed racemose neurocysticercosis. PMID- 23677669 TI - Cancer survivors with self-reported late effects: their health status, care needs and service utilisation. AB - OBJECTIVE: Cancer survivors (CSs) are at risk of developing late effects (LEs) associated with the disease and its treatment. This paper compares the health status, care needs and use of health services by CSs with LEs and CSs without LEs. METHODS: Cancer survivors (n = 613) were identified via the Northern Ireland Cancer Registry and invited to participate in a postal survey that was administered by their general practitioner. The survey assessed self-reported LEs, health status, health service use and unmet care needs. A total of 289 (47%) CSs responded to the survey, and 93% of respondents completed a LEs scale. RESULTS: Forty-one per cent (111/269) of CSs reported LEs. Survivors without LEs and survivors with LEs were comparable in terms of age and gender. The LEs group reported a significantly greater number of co-morbidities, lower physical health and mental health scores, greater overall health service use and more unmet needs. Unadjusted logistic regression analysis found that cancer site, time since diagnosis and treatment were significantly associated with reporting of LEs. CSs who received combination therapies compared with CSs who received single treatments were over two and a half times more likely to report LEs (OR = 2.63, 95% CI = 1.32-5.25) after controlling for all other variables. CONCLUSIONS: The CS population with LEs comprises a particularly vulnerable group of survivors who have multiple health care problems and needs and who require tailored care plans that take account of LEs and their impact on health-related quality of life. PMID- 23677670 TI - Changes in the structural dimensionality of selenidostannates in ionic liquids: formation, structures, stability, and photoconductivity. AB - In situ transformations of selenidostannate frameworks in ionic liquids (ILs) were initiated by treatment of the starting phase K2[Sn2Se5] and the consecutive reaction products by means of temperature increase and/or amine addition. Along the reaction pathway, the framework dimensionalities of the five involved selenidostannate anions develop from 3D to 1D and back, both in top-down and bottom-up style. Addition of ethane-1,2-diamine (en) led to the reversion of the 2D->1D step from 2D-{[Sn24Se56](16-)} to 1D-{[Sn6Se14](4-)}. As rationalized by DFT investigations, the 2D anion is thermodynamically favored. Photoconductivity measurements reveal that all samples show Schottky contact behavior with absolute thresholds below 10 V. One of the samples exhibits conductive states within the energy range of visible photons. PMID- 23677671 TI - Cysts of the maxillary sinus: a literature review. AB - BACKGROUND: Patients with isolated mucosal cysts of the maxillary sinus (MMC) often undergo surgical treatment despite the absence of relevant symptoms. Some physicians believe that MMC might increase in size and cause complications in the future. The anticipated value of this study is to consolidate and improve the understanding of MMC based on published data and to contribute to avoiding unnecessary interventions. METHODS: We performed a comprehensive review of the literature regarding definition, etiology, epidemiology, natural course, and best treatment of MMC. RESULTS: Among the 988 papers found in the literature search, 33 studies were selected to be relevant. Among those studies, there are only a few prospective controlled studies. Their prevalence rates range broadly from 3.6% to 35.6% according to different diagnostic methods as well as different indications for imaging. Recent prospective studies showed no correlation of MMC with sinonasal complaints or Lund-Mackay computed tomography (CT) score. The natural course is characterized by a decrease in size of MMC in 30% of the cases, an unchanged status in 50% to 60%, and an increase in 8% to 20% of the cases. CONCLUSION: MMC are harmless, mostly asymptomatic lesions that usually do not need surgical treatment. If surgery is indicated, endonasal endoscopic techniques should be the gold-standard approach. PMID- 23677674 TI - Comment on "QSAR model reproducibility and applicability: A case study of rate constants of hydroxyl radical reaction models applied to polybrominated diphenyl ethers and (Benzo-)triazoles". PMID- 23677673 TI - Endothelial FoxO1 is an intrinsic regulator of thrombospondin 1 expression that restrains angiogenesis in ischemic muscle. AB - Peripheral artery disease (PAD) is characterized by chronic muscle ischemia. Compensatory angiogenesis is minimal within ischemic muscle despite an increase in angiogenic factors. This may occur due to the prevalence of angiostatic factors. Regulatory mechanisms that could evoke an angiostatic environment during ischemia are largely unknown. Forkhead box O (FoxO) transcription factors, known to repress endothelial cell proliferation in vitro, are potential candidates. Our goal was to determine whether FoxO proteins promote an angiostatic phenotype within ischemic muscle. FoxO1 and the angiostatic matrix protein thrombospondin 1 (THBS1) were elevated in ischemic muscle from PAD patients, or from mice post femoral artery ligation. Mice with conditional endothelial cell-directed deletion of FoxO proteins (Mx1Cre (+), FoxO1,3,4 (L/L) , referred to as FoxODelta) were used to assess the role of endothelial FoxO proteins within ischemic tissue. FoxO deletion abrogated the elevation of FoxO1 and THBS1 proteins, enhanced hindlimb blood flow recovery and improved neovascularization in murine ischemic muscle. Endothelial cell outgrowth from 3D explant cultures was more robust in muscles derived from FoxODelta mice. FoxO1 overexpression induced THBS1 production, and a direct interaction of endogenous FoxO1 with the THBS1 promoter was detectable in primary endothelial cells. We provide evidence that FoxO1 directly regulates THBS1 within ischemic muscle. Altogether, these findings bring novel insight into the regulatory mechanisms underlying the repression of angiogenesis within peripheral ischemic tissues. PMID- 23677676 TI - Complete genome sequence of a polyvalent bacteriophage, phiKP26, active on Salmonella and Escherichia coli. AB - Bacteriophages are viruses that specifically infect and lyse prokaryotic cells and therefore might be used as biocontrol agents. However, it is necessary to acquire genomic information to predict and understand the phage's characteristics for the efficient and safe use of bacteriophages as biocontrol agents against bacterial pathogens. In this study, the complete genome sequence of a novel enterobacteriophage, phiKP26, was determined by pyrosequencing. Genomic analysis of phiKP26 revealed a genome size of 47,285 bp with an overall G + C content of 44.3 %. Seventy-eight open reading frames (ORFs) in the phiKP26 genome were grouped into the modules of replication, DNA packaging, morphogenesis, cell lysis and absence of genes related to virulence and lysogeny. PMID- 23677677 TI - Survival after resection of cutaneous adnexal carcinomas with eccrine differentiation: risk factors and trends in outcomes. AB - BACKGROUND: Current staging systems do not specifically address cutaneous adnexal carcinomas with eccrine differentiation. Due to their rarity, prognosis and management strategies are not well established. A population-based study was performed to determine prognostic factors and survival. METHODS: Patients diagnosed with cutaneous adnexal carcinomas with eccrine differentiation were identified using the surveillance, epidemiology, and end results population-based cancer registry. Associations between risk factors, treatment modalities, and survival were calculated using logistical regression, Kaplan-Meier estimates and log-rank analysis. RESULTS: The incidence of distinct eccrine subtypes was determined within 1,045 patients with cutaneous adnexal tumors containing eccrine differentiation. All-cause 5-year survival (OS) was 82%, while age-adjusted survival was 94%. Patients with microcystic adnexal carcinoma had improved OS (90%) compared to patients with hidradenocarcinoma (74%), spiradenocarcinoma (77%), porocarcinoma (79%), and eccrine adenocarcinoma (81%). The majority of patients were treated with surgical excision and a small subset with surgery plus radiation, with similar OS. Patients with well-to-moderately differentiated tumors demonstrated improved OS compared to those with poorly differentiated/anaplastic disease. CONCLUSIONS: Histological subtype and grade were associated with survival, and should be specified in biopsies and excised specimens. Surgical excision is appropriate, and the addition of adjuvant radiation may not be associated with survival. These results highlight survival data and high-risk prognostic factors that warrant prospective validation, and may augment current staging systems. PMID- 23677678 TI - Testing for post-copulatory selection for major histocompatibility complex genotype in a semi-free-ranging primate population. AB - A large body of evidence suggests that major histocompatibility complex (MHC) genotype influences mate choice. However, few studies have investigated MHC mediated post-copulatory mate choice under natural, or even semi-natural, conditions. We set out to explore this question in a large semi-free-ranging population of mandrills (Mandrillus sphinx) using MHC-DRB genotypes for 127 parent-offspring triads. First, we showed that offspring MHC heterozygosity correlates positively with parental MHC dissimilarity suggesting that mating among MHC dissimilar mates is efficient in increasing offspring MHC diversity. Second, we compared the haplotypes of the parental dyad with those of the offspring to test whether post-copulatory sexual selection favored offspring with two different MHC haplotypes, more diverse gamete combinations, or greater within haplotype diversity. Limited statistical power meant that we could only detect medium or large effect sizes. Nevertheless, we found no evidence for selection for heterozygous offspring when parents share a haplotype (large effect size), genetic dissimilarity between parental haplotypes (we could detect an odds ratio of >=1.86), or within-haplotype diversity (medium-large effect). These findings suggest that comparing parental and offspring haplotypes may be a useful approach to test for post-copulatory selection when matings cannot be observed, as is the case in many study systems. However, it will be extremely difficult to determine conclusively whether post-copulatory selection mechanisms for MHC genotype exist, particularly if the effect sizes are small, due to the difficulty in obtaining a sufficiently large sample. PMID- 23677679 TI - Perforated bicontinuous cubic phases with pH-responsive topological channel interconnectivity. AB - Lipidic lyotropic liquid crystals are at the frontline of current research for release of target therapeutic molecules due to their unique structural complexity and the possibility of engineering stimuli-triggered release of both hydrophilic and hydrophobic molecules. One of the most suitable lipidic mesophases for the encapsulation and delivery of drugs is the reversed double diamond bicontinuous cubic phase, in which two distinct and parallel networks of ~4 nm water channels percolate independently through the lipid bilayers, following a Pn3m space group symmetry. In the unperturbed Pn3m structure, the two sets of channels act as autonomous and non-communicating 3D transport pathways. Here, a novel type of bicontinuous cubic phase is introduced, where the presence of OmpF membrane proteins at the bilayers provides unique topological interconnectivities among the two distinct sets of water channels, enabling molecular active gating among them. By a combination of small-angle X-ray scattering, release and ion conductivity experiments, it is shown that, without altering the Pn3m space group symmetry or the water channel diameter, the newly designed perforated bicontinuous cubic phase attains transport properties well beyond those of the standard mesophase, allowing faster, sustained release of bioactive target molecules. By further exploiting the pH-mediated pore-closing response mechanism of the double amino acid half-ring architecture in the membrane protein, the pores of the perforated mesophase can be opened and closed with a pH trigger, enabling a fine modulation of the transport properties by only moderate changes in pH, which could open unexplored opportunities in the targeted delivery of bioactive compounds. PMID- 23677680 TI - Competitive sorption of Cd, Cu, Mn, Ni, Pb and Zn in polluted and unpolluted calcareous soils. AB - The objectives of this study were to investigate competitive sorption behaviour of heavy metals (Cd, Cu, Mn, Ni, Pb and Zn) under different management practices and identify soil characteristics that can be correlated with the retention and mobility of heavy metals using 65 calcareous soil samples. The lowest sorption was found for Mn and Ni in competition with the other metals, indicating the high mobility of these two cations. The Freundlich equation adequately described heavy metals adsorption. On the basis of Freundlich distribution coefficient, the selectivity sequence of the metal adsorption was Cu > Pb > Cd > Zn > Ni > Mn. The mean value of the joint distribution coefficient (K dSigmasp) was 182.1, 364.1, 414.7, 250.1, 277.7, 459.9 and 344.8 l kg(-1) for garden, garlic, pasture, potato, vegetables, wheat and polluted soils, respectively. The lowest observed K dSigmasp in garden soil samples was due to the lower cation exchange capacity and lower carbonate content. The results of the geochemical modelling under low and high metal addition indicated that Cd, Ni, Mn and Zn were mainly retained via adsorption, while Pb and Cu were retained via adsorption and precipitation. Stepwise forward regression analysis showed that clay, organic matter and CaCO3 were the most important soil properties influencing competitive adsorption of Cd, Mn, Ni and Zn. The results in this study point to a relatively easy way to estimate distribution coefficient values. PMID- 23677681 TI - Effect of a reservoir in the water quality of the Reconquista River, Buenos Aires, Argentina. AB - The lower portion of the Reconquista River is highly polluted. However, little is known about the state of the high and middle basins. The aims of this work were to assess the water quality on the high and middle Reconquista River basins and to determinate if the presence of a reservoir in the river has a positive effect on the water quality. We conducted a seasonal study between August 2009 and November 2010 at the mouth of La Choza, Durazno, and La Horqueta streams at the Roggero reservoir--which receives the water from the former streams--at the origin of the Reconquista River and 17 km downstream from the reservoir. We measured 25 physical and chemical parameters, including six heavy metal concentrations, and performed a multivariate statistical analysis to summarize the information and allow the interpretation of the whole data set. We found that the Durazno and La Horqueta streams had better water quality than La Choza, and the presence of the reservoir contributed to the improvement of the water quality, allowing oxygenation of the water body and processing of organic matter and ammonia. The water quality of the Reconquista River at its origin is good and similar to the reservoir, but a few kilometers downstream, the water quality declines as a consequence of the presence of industries and human settlements. Therefore, the Roggero reservoir produces a significant improvement of water quality of the river, but the discharge of contaminants downstream quickly reverses this effect. PMID- 23677684 TI - A novel microendoscopically assisted approach for the treatment of recurrent lumbar disc herniation: transosseous discectomy surgery. AB - BACKGROUND AND OBJECT: Microendoscopic discectomy (MED) is still regarded as contraindicated for the treatment of recurrent lumbar disc herniation by many surgeons. Moreover, the presence of epidural scar tissue makes surgical manipulation difficult. To successfully remove the herniated disc in such cases, an open technique with a wide exposure may be required. We devised a new minimally invasive endoscopic approach, which is using a transosseous route. This is a retrospective review of a consecutive case series to examine the operative and clinical results of this new approach. MATERIAL AND METHODS: Fifty-seven patients who underwent surgery for recurrent lumbar disc herniation were divided into two groups based on the operative procedure. Thirty patients underwent microendoscopic transosseous discectomy (TD) and 27 underwent MED. We graded operative results and clinical outcomes using the Japanese Orthopaedic Association (JOA) score for low-back pain before surgery and 1 year after surgery and compared the scores of the two groups. RESULTS: No conversion to open procedure was necessary in either group. The mean TD operative time was 89.2 minutes with a mean intraoperative blood loss of 16.5 mL. Mean MED operative time was 92.0 minutes with a mean blood loss of 19.3 mL. There were two dural tears in the MED group, and one tear was combined with a fracture of the inferior articular process. No dural tears occurred in the TD group. No patients in either group had experienced re-recurrence of lumbar disc herniation at the time of the last follow-up. The JOA score improved significantly after surgery in both groups (p < 0.001). CONCLUSION: TD is a safe and effective surgical approach for the treatment of recurrent lumbar disc herniation. Operative time, intraoperative blood loss, and clinical results compare favorably with MED. PMID- 23677682 TI - Headache and sleep in children. AB - Several scientific studies report a close relationship between sleep and headache: sleep changes may reflect the onset and increase of both duration and frequency of headache attacks. Variations in sleep architecture, together with a poor sleep hygiene in children, may indeed be responsible for the onset of headache and its development into a chronic disease. For a correct clinical management of children with headache, it is therefore fundamental to investigate their sleep habits, architecture and potential disturbances, in order to develop adequate therapeutic plans for both sleep and headache. PMID- 23677685 TI - Translating Life Course Theory to clinical practice to address health disparities. AB - Life Course Theory (LCT) is a framework that explains health and disease across populations and over time and in a powerful way, conceptualizes health and health disparities to guide improvements. It suggests a need to change priorities and paradigms in our healthcare delivery system. In "Rethinking Maternal and Child Health: The Life Course Model as an Organizing Framework," Fine and Kotelchuck identify three areas of rethinking that have relevance to clinical care: (1) recognition of context and the "whole-person, whole-family, whole-community systems approach;" (2) longitudinal approach with "greater emphasis on early ("upstream") determinants of health"; and (3) need for integration and "developing integrated, multi-sector service systems that become lifelong "pipelines" for healthy development". This paper discusses promising clinical practice innovations in these three areas: addressing social influences on health in clinical practice, longitudinal and vertical integration of clinical services and horizontal integration with community services and resources. In addition, barriers and facilitators to implementation are reviewed. PMID- 23677686 TI - Ni-catalyzed cascade cyclization-Kumada alkyl-alkyl cross-coupling. AB - Suggesting novel disconnections: A powerful Ni-catalyzed cascade reaction involving cyclization followed by cross-coupling allows the formation of up to three alkyl-alkyl bonds in a single operation by using alkene-containing alkyl iodides and Grignard reagents (see scheme; acac = acetylacetonate; TMEDA = N,N',N'-tetramethyl ethylenediamine). Mechanistic experimental and computational studies suggest a Ni(I)-Ni(II)-Ni(III) catalytic cycle and the intermediacy of radicals. PMID- 23677688 TI - Influence of pH and temperature on the expression of sboA and ituD genes in Bacillus sp. P11. AB - Temperature and pH are key factors influencing the production of antimicrobial peptides. In this work, qRT-PCR methodology was used to demonstrate the effect of these two variables on sboA (subtilosin A) and ituD (iturin A) expression in Bacillus sp. P11, an isolate from aquatic environment of the Amazon. Bacillus sp. P11 was incubated in BHI broth for 36 h at 30, 37 and 42 degrees C, and the pH values were 6.0, 7.4 and 8.0. The production of subtilosin A and iturin A was confirmed by mass spectrometry. The sboA expression increased 200-fold when the initial pH was 8.0. In contrast, ituD expression was maximum at pH 6.0. Increased temperature (42 degrees C) was adverse for both genes, but ituD expression increased at 37 degrees C. Expression of sboA and ituD was strongly affected by pH and temperature and qRT-PCR proved to be a powerful tool to investigate the potential of Bacillus strains to produce subtilosin A and iturin A. PMID- 23677689 TI - Unexpectedly low variation in liver ischemia preconditioning study. PMID- 23677687 TI - Anatomical and biochemical studies of bicolored flower development in Muscari latifolium. AB - The inflorescence of the broad-leafed grape hyacinth, Muscari latifolium, shows an interesting, two-tone appearance with the upper flowers being pale blue and the lower ones purple. To elucidate the mechanism of the differential color development, anatomical research was carried out and a cytological study of the colored protoplasts in which the shapes of the cells accumulating anthocyanin were observed by scanning electron microscopy. Next, vacuolar pH was recorded using a pH meter with a micro combination pH electrode, and the sap's metal-ion content was measured by inductively coupled plasma mass spectrometry. The anthocyanin and co-pigment composition was determined by high-performance liquid chromatography (HPLC). Chemical analyses reveal that the difference in metal-ion content of the two parts was not great. The vacuolar pHs of the upper and lower flowers were 5.91 and 5.84, respectively, with the difference being nonsignificant. HPLC results indicate that the dihydroflavonol and flavonol contents are also very similar in the two sorts of flower. However, the upper flowers contained only delphinidin, whereas the lower flowers also contained cyanidin. The total anthocyanin content in the lower flowers was 4.36 mg g(-1), which is approximately seven times higher than in the upper flowers, while the delphinidin content is four times higher. Quantitative real-time PCR analysis established that the two-tone flower was a result of different expressions of the F3'5'H, F3'H and DFR genes, and these lead to different amounts of anthocyanin. PMID- 23677690 TI - Prevalence of obesity and extreme obesity in children aged 3-5 years. AB - BACKGROUND: Early childhood adiposity may have significant later health effects. This study examines the prevalence and recognition of obesity and severe obesity among preschool-aged children. METHODS: The electronic medical record was used to examine body mass index (BMI), height, sex and race/ethnicity in 42,559 children aged 3-5 years between 2007 and 2010. Normal or underweight (BMI < 85th percentile); overweight (BMI 85th-94th percentile); obesity (BMI >= 95th percentile); and severe obesity (BMI >= 1.2 * 95th percentile) were classified using the 2000 Centers for Disease Control and Prevention growth charts. Provider recognition of elevated BMI was examined for obese children aged 5 years. RESULTS: Among 42,559 children, 12.4% of boys and 10.0% of girls had BMI >= 95th percentile. The prevalence was highest among Hispanics (18.2% boys, 15.2% girls), followed by blacks (12.4% boys, 12.7% girls). A positive trend existed between increasing BMI category and median height percentile, with obesity rates highest in the highest height quintile. The prevalence of severe obesity was 1.6% overall and somewhat higher for boys compared with girls (1.9 vs. 1.4%, P < 0.01). By race/ethnicity, the highest prevalence of severe obesity was seen in Hispanic boys (3.3%). Among those aged 5 years, 77.9% of obese children had provider diagnosis of obesity or elevated BMI, increasing to 89.0% for the subset with severe obesity. CONCLUSIONS: Obesity and severe obesity are evident as early as age 3-5 years, with race/ethnic trends similar to older children. This study underscores the need for continued recognition and contextualization of early childhood obesity in order to develop effective strategies for early weight management. PMID- 23677691 TI - Regulation of CCN1 via the 3'-untranslated region. AB - The 3'-untranslated region (UTR) is known to be a critical regulator of post transcriptional events that determine the gene expression at the RNA level. The gene CCN1 is one of the classical members of the matricellular CCN family and is involved in a number of biological processes during mammalian development. In the present study, the 600-bp 3'-UTR of CCN1 was functionally characterized. Reporter gene analysis revealed that the entire 3'-UTR profoundly repressed gene expression in cis in different types of the cells, to which both the proximal and distal-halves of the 3'-UTR segments contributed almost equally. Deletion analysis of the 3'-UTR indicated a distinct functional element in the proximal half, whereas a putative target for microRNA-181s was predicted in silico in the distal half. Of note, the repressive RNA element in the proximal half was shown to be capable of forming a stable secondary structure. However, unexpectedly, a reporter construct with a tandem repeat of the predicted miR-181 targets failed to respond to miR-181a. In addition, the other major structured element predicted in the distal half was similarly characterized. To our surprise, the second element rather enhanced the reporter gene expression in cis. These results indicate the involvement of multiple regulatory elements in the CCN1 3'-UTR and suggest the complexity of the miRNA action as well as the 3'-UTR-mediated gene regulation. PMID- 23677692 TI - beta3-receptor agonists for overactive bladder--new frontier or more of the same? AB - The new information generated over the last decade on the physiology/pharmacology of the normal bladder and on the pathophysiology of the overactive bladder has resulted in the introduction of a new therapeutic principle, beta3-adrenoceptor (AR) agonism, and the approval of mirabegron, a selective agonist at beta3-ARs. It may be asked in what respects the beta3-AR agonists as a group, and mirabegron in particular, differ from the antimuscarinics, and what can clinically be gained by the beta3-AR agonists. In this short review, the mechanisms of action, clinical efficacy, and adverse effect profiles of the two groups of drugs are compared and discussed. PMID- 23677694 TI - Diagnosis and treatment of pediatric psoriasis: current and future. AB - Psoriasis is a common yet complex inflammatory dermatosis that may be seen in infants, children, and adolescents. The clinical presentation and course may be quite variable, and while patients with mild disease are often easily managed, those with recalcitrant or more severe disease often present a therapeutic dilemma given the number of therapies available and the relative lack of data on the efficacy and safety of use of these therapies in children. This review presents the reader with an overview of the current understanding of the pathophysiology, diagnosis, and treatment of pediatric psoriasis, with an emphasis on the available data in the literature that pertains to the use in children of currently available topical and systemic therapies, including topical corticosteroids, vitamin D analogs, phototherapy, systemic immunosuppressive medications, and biologic agents. PMID- 23677695 TI - Rectal cancers in patients with familial adenomatous polyposis. AB - Patients with familial adenomatous polyposis may develop rectal cancer at their initial presentation (primary) or after colectomy and ileorectal anastomosis (secondary). Little is known about whether differences in presentation impact survival. We hypothesize that patients with secondary rectal cancer have better oncologic outcomes. Patients with rectal cancer in the context of familial adenomatous polyposis were classified into 3 groups: known rectal cancer at presentation, incidental rectal cancer unrecognized before proctocolectomy, and rectal cancer diagnosed after ileorectal anastomosis. Primary endpoint was 5-year survival. There were 58 patients, 39 with primary rectal cancer, 5 of which were incidental, and 19 with secondary rectal cancer. Median ages at diagnosis were 32 years (range 14-56) for primary cancer, 35 years (range 22-56) for incidental cancer and 49 years (range 24-66) for secondary cancer (p = 0.001). 76% of those with primary rectal cancer had symptoms, similar to those with incidental cancer (60%) but more than secondary cancer (21%) (p < 0.001). 47% of primary cancers were advanced (stages III and IV) compared to 20% of incidental cancers and 32% of secondary cancers. There was no local recurrence in any patient, but 9 patients had distant recurrences (16% overall). Overall 5-year survival of patients with primary cancer was 72.4%, incidental cancer was 100%, and secondary cancer was 69.7% (p = 0.031). More patients with primary rectal cancer have advanced disease but survival is similar to those with cancer diagnosed on surveillance. More patients with primary rectal cancer have a restorative resection when compared to other groups. PMID- 23677693 TI - Optimal management of metastatic melanoma: current strategies and future directions. AB - Melanoma is increasing in incidence and remains a major public health threat. Although the disease may be curable when identified early, advanced melanoma is characterized by widespread metastatic disease and a median survival of less than 10 months. In recent years, however, major advances in our understanding of the molecular nature of melanoma and the interaction of melanoma cells with the immune system have resulted in several new therapeutic strategies that are showing significant clinical benefit. Current therapeutic approaches include surgical resection of metastatic disease, chemotherapy, immunotherapy, and targeted therapy. Dacarbazine, interleukin-2, ipilimumab, and vemurafenib are now approved for the treatment of advanced melanoma. In addition, new combination chemotherapy regimens, monoclonal antibodies blocking the programmed death-1 (PD 1)/PD-ligand 1 pathway, and targeted therapy against CKIT, mitogen-activated protein/extracellular signal-regulated kinase (MEK), and other putative signaling pathways in melanoma are beginning to show promise in early-phase clinical trials. Further research on these modalities alone and in combination will likely be the focus of future clinical investigation and may impact the outcomes for patients with advanced melanoma. PMID- 23677698 TI - XPS of oxygen atoms on Ag(111) and Ag(110) surfaces: accurate study with SAC/SAC CI combined with dipped adcluster model. AB - O1s core-electron binding energies (CEBE) of the atomic oxygens on different Ag surfaces were investigated by the symmetry adapted cluster-configuration interaction (SAC-CI) method combined with the dipped adcluster model, in which the electron exchange between bulk metal and adsorbate is taken into account properly. Electrophilic and nucleophilic oxygens (O(elec) and O(nuc)) that might be important for olefin epoxidation in a low-oxygen coverage condition were focused here. We consider the O1s CEBE as a key property to distinguish the surface oxygen states, and series of calculation was carried out by the Hartree Fock, Density functional theory, and SAC/SAC-CI methods. The experimental information and our SAC/SAC-CI results indicate that O(elec) is the atomic oxygen adsorbed on the fcc site of Ag(111) and that O(nuc) is the one on the reconstructed added-row site of Ag(110) and that one- and two-electron transfers occur, respectively, to the O(elec) and O(nuc) adclusters from the silver surface. PMID- 23677697 TI - Promotion of autophagy at the maturation step by IL-6 is associated with the sustained mitogen-activated protein kinase/extracellular signal-regulated kinase activity. AB - Increased autophagic vacuoles (AVs) occur in injured or degenerating neurons, under both developmental and pathological situations. Although an induced autophagy has been shown in inflammation response to cell factors, the underlying mechanism(s) remain(s) unknown. Here, we show that both cell factor IL-6 and environmental toxin MPP(+) promote the formation of vacuolation in SHSY5Y cells. By electron and immunofluorescent microscopy analyses, we showed that these structures are acid autolysosomes, containing cellular debris, and labeled by LC3 or LAMP1, markers of autophagosomes or lysosomes, respectively. Combining MPP(+) and IL-6 do not further increase vacuolation of SHSY5Y cells, and the vacuolation is less than that in the MPP(+)-treated group. MPP(+)-induced vacuolation results from significant increase in autophagy formation and delay in autophagy degradation, in relation to a decline of the lysosomal activity of arylsulfatase A. At molecular level, we show that this defect in autolysosomal maturation is independent of mammalian target of rapamycin and p38 inhibitions. Most importantly, we provide the first evidence that activation of ERK pathway is sufficient to commit cell to autophagic vacuolation. The sustained activation is required for MPP(+) to disrupt the autophagic pathway. IL-6 also induces a temporary and significant activation of ERK, but not sustained activation, and change sustained activation in MPP(+)-treated group into temporary activation. Taken together, these findings strongly support that IL-6 promotes the maturation of autophagosomes into functional autolysosomes by regulating ERK. PMID- 23677696 TI - VAMP4 is required to maintain the ribbon structure of the Golgi apparatus. AB - The Golgi apparatus forms a twisted ribbon-like network in the juxtanuclear region of vertebrate cells. Vesicle-associated membrane protein 4 (VAMP4), a v SNARE protein expressed exclusively in the vertebrate trans-Golgi network (TGN), plays a role in retrograde trafficking from the early endosome to the TGN, although its precise function within the Golgi apparatus remains unclear. To determine whether VAMP4 plays a functional role in maintaining the structure of the Golgi apparatus, we depleted VAMP4 gene expression using RNA interference technology. Depletion of VAMP4 from HeLa cells led to fragmentation of the Golgi ribbon. These fragments were not uniformly distributed throughout the cytoplasm, but remained in the juxtanuclear area. Electron microscopy and immunohistochemistry showed that in the absence of VAMP4, the length of the Golgi stack was shortened, but Golgi stacking was normal. Anterograde trafficking was not impaired in VAMP4-depleted cells, which contained intact microtubule arrays. Depletion of the cognate SNARE partners of VAMP4, syntaxin 6, syntaxin 16, and Vti1a also disrupted the Golgi ribbon structure. Our findings suggested that the maintenance of Golgi ribbon structure requires normal retrograde trafficking from the early endosome to the TGN, which is likely to be mediated by the formation of VAMP4-containing SNARE complexes. PMID- 23677699 TI - Platinum(IV) complexes with some derivatives of 5-methyl-5-(4-pyridyl) hydantoin. Synthesis, study and comparative pharmacological investigation. AB - 3 Pt(IV) complexes with 3-ethyl-5-methyl-5-(4-pyridyl)hydantoin (4), 3-propyl-5 methyl-5-(4-pyridyl)hydantoin (5) and 3-benzyl-5-methyl-5-(4-pyridyl)hydantoin (6) with general formulae cis-[Pt(L)2Cl4] were synthesized. The novel compounds were characterized by elemental analysis, IR, 1H, 13C, NMR spectra in solid state and in solution. The studies showed that the ligands coordinate to the platinum ions in a monodentate manner through the nitrogen atom from the pyridine ring. The cytotoxic activity in vitro of newly synthesized complexes as well as their previously prepared analogous of Pt(IV) with other derivatives like 3-amino-5 methyl-5-(4-pyridyl)hydantoin (1), 5-methyl-5-(4-pyridyl)hydantoin (2), 3,5 dimethyl-5-(4-pyridyl)hydantoin (3) was screened against a panel of human tumor cell lines. The tested compounds displayed cytotoxic activity which was invariably superior with the Pt(IV) complex with 3-benzyl-5-methyl-5-(4 pyridyl)hydantoin (6) causing 50% inhibition of cellular viability at micromolar concentration, though the activity of the other studied Pt(IV) complexes proved to greatly decrease in the order 5-4-3-2-1. PMID- 23677700 TI - The inhibition of monoamine oxidase by esomeprazole. AB - Virtual screening of a library of drugs has suggested that esomeprazole, the S enantiomer of omeprazole, may possess binding affinities for the active sites of the monoamine oxidase (MAO) A and B enzymes. Based on this finding, the current study examines the MAO inhibitory properties of esomeprazole. Using recombinant human MAO-A and MAO-B, IC50 values for the inhibition of these enzymes by esomeprazole were experimentally determined. To examine the reversibility of MAO inhibition by esomeprazole, the recoveries of the enzymatic activities after dilution of the enzyme-inhibitor complexes were evaluated. In addition, reversibility of inhibition was also examined by measuring the recoveries of enzyme activities after dialysis of enzyme-inhibitor mixtures. Lineweaver-Burk plots were constructed to evaluate the mode of MAO inhibition and to measure Ki values. The results document that esomeprazole inhibits both MAO-A and MAO-B with IC50 values of 23 uM and 48 uM, respectively. The interactions of esomeprazole with MAO-A and MAO-B are reversible and most likely competitive with Ki values for the inhibition of the respective enzymes of 8.99 uM and 31.7 uM. Considering the available pharmacokinetic data and typical therapeutic doses of esomeprazole, these inhibitory potencies are unlikely to be of pharmacological relevance in humans. The MAO inhibitory effects of esomeprazole should however be taken into consideration when using this drug in animal experiments where higher doses are often administered. PMID- 23677701 TI - A simply HPLC method for determination of cefpodoxime in Chinese volunteer and pharmacokinetic study. AB - A sensitive HPLC method was developed for the determination of cefpodoxime in human plasma. After protein precipitation with acetonitrile, sample was injected into the HPLC system for analysis. The chromatographic separation was carried out on a Diamonsil C18 column with a mobile phase consisting of acetonitrile-water. The mobile phase composed of water (containing 20 mmol/L monoammonium phosphate) and acetonitrile (90: 10, v/v). The detection wavelength was set at 254 nm. The standard curve for cefpodoxime was linear over the concentration range of 0.05-8 MUg/mL with a lower limit of quantification of 0.05 MUg/mL. The intra- and inter day RSD values were lower than 10%, and the RE values were within+/-5%. For the pharmacokinetic analysis of plasma, the mean (SD) values obtained for the formulation were: Cmax, 4.21 (0.62) ug/mL; Tmax, 2.47 (0.61) h; t1/2, 2.38 (0.46) h; AUC0-24 h, 21.13 (3.39) ug/mL/h; and AUC0-infinity, 23.34 (3.87) ug/mL/h; MRT, 2.21 (0.41) h, respectively. PMID- 23677702 TI - Reactivity of Lewis basic platinum complexes towards fluoroboranes. AB - We herein report detailed investigations into the interaction of Lewis acidic fluoroboranes, for example BF2Pf (Pf=perfluorophenyl) and BF2Ar(F) (Ar(F)=3,5 bis(trifluoromethyl)phenyl), with Lewis basic platinum complexes such as [Pt(PEt3)3] and [Pt(PCy3)2] (Cy=cyclohexyl). Two presumed Lewis adducts could be identified in solution and corresponding secondary products of these Lewis adducts were characterized in the solid state. Furthermore, the concept of frustrated Lewis pairs (FLP) was applied to the activation of ethene in the system [Pt(BPf3)(CH2CH2)(dcpp)] (dcpp=1,3-bis(dicyclohexylphosphino)propane; Pf=perfluorophenyl). Finally, DFT calculations were performed to determine the interaction between the platinum-centered Lewis bases and the boron-centered Lewis acids. Additionally, several possible mechanisms for the oxidative addition of the boranes BF3, BCl3, and BF2Ar(F) to the model complex [Pt(PMe3)2] are presented. PMID- 23677703 TI - Castleman disease in the parapharyngeal space: a case report and review of the literature. AB - Castleman disease is most commonly found in the mediastinum, while the head and neck is the second most common location. The disease exists in a unicentric and multicentric variety and is usually successfully treated with surgical resection alone. Early identification is important for treatment planning. Castleman disease has been reported to mimic other disease processes, however there has been only one report of the disease mimicking a nerve sheath tumor in the parapharyngeal space. Here we report the second case of Castleman disease mimicking a schwannoma in the parapharyngeal space. PMID- 23677705 TI - Simultaneous determination of nucleosides and their bases in Cordyceps sinensis and its substitutes by matrix solid-phase dispersion extraction and HPLC. AB - Nine nucleosides and nucleobases, including uracil, adenine, thymine, uridine, adenosine, thymidine, cytidine, guanosine, and cordycepin in natural Cordyceps sinensis, cultured Cordyceps mycelia, and Cordyceps fruiting bodies were extracted by matrix solid-phase dispersion (MSPD) and determined by HPLC. The experimental conditions for the MSPD extraction were optimized. Florisil was used as dispersant, petroleum ether as washing solvent, and methanol as elution solvent. The Florisil-to-sample ratio was selected to be 4:1 and no additional clean-up sorbent was needed. The calibration curves had good linear relationships (r > 0.9997). The LOD and LOQ were in the range of 12~79 and 41~265 ng/mL, respectively. The intra- and interday precision were lower than 8.3%. The recoveries were between 61.5 and 93.2%. The present method consumed less sample compared with ultrasonic extraction and heating reflux extraction (HRE). The extraction yields obtained by using the present method are much higher than those obtained by UE and comparable to those obtained by HRE. PMID- 23677704 TI - Managing cardiotoxicity of chemotherapy. AB - OPINION STATEMENT: The increase in survivorship of cancer patients makes the understanding of the available options for prevention and treatment of cardiotoxicity induced by antineoplastic agents a crucial topic both for cardiologists and oncologists. The most frequent and typical clinical manifestation of cardiotoxicity is asymptomatic or symptomatic left ventricular dysfunction, which may progress to overt heart failure. It may be induced not only by conventional cancer therapy, like anthracyclines, but also by new antitumoral targeted therapy such as trastuzumab. The current standard for monitoring cardiac damage during antineoplastic treatment, mainly based on the quantification of left ventricular ejection fraction, detects cardiac toxicity only when a functional impairment has already occurred. Evaluation of cardiac biomarkers such as troponin, however, has shown excellent sensitivity in the early detection of cardiotoxicity by the identification of patients with subclinical cardiac injury that precedes the development of cardiac dysfunction. The use of angiotensin-converting enzyme inhibitors in patients with troponin elevation during chemotherapy may be an effective tool to prevent left ventricular ejection fraction reduction and late cardiac events. There are no well established recommendations for treatment of cancer patients who develop cardiac dysfunction. Angiotensin-converting enzyme inhibitors and beta-blockers have proven to be effective in this setting. However, there are concerns in using these medications in cancer patients, and therefore the tendency is to treat patients only if symptomatic. However, the clinical benefit of these medications may be more evident in asymptomatic patients, and the recovery of cardiac function strongly depends on the amount of time elapsed from the end of chemotherapy to the start of heart failure therapy. This observation suggests that the early detection of cardiac damage is crucial and early use of angiotensin-converting enzyme inhibitors and beta-blockers should be considered in patients with left ventricular dysfunction induced by antineoplastic agents. PMID- 23677706 TI - Medicare fee-for-service enrollees with primary acute myeloid leukemia: an analysis of treatment patterns, survival, and healthcare resource utilization and costs. AB - BACKGROUND: Acute myeloid leukemia (AML) is the most common form of acute leukemia affecting adults, with incidence increasing with patient age. Previous studies have found that older AML patients, constituting the majority of the AML population, generally have poor outcomes, high healthcare expenditures, and median survival of <3 months. Because up-to-date information on treatment patterns, survival trends, and costs of care for elderly AML patients are lacking in the literature, we examined Medicare fee-for-service enrollees with primary AML to update these estimates and report on changes in treatment for this population. OBJECTIVE: The primary objective of this study was to examine real world data on treatment patterns, survival, and costs in elderly patients with primary AML. Factors associated with receipt of chemotherapy and with mortality also were assessed. METHODS: This is a retrospective database analysis using the Surveillance, Epidemiology, and End Results cancer registry and linked Medicare claims. Patients aged 65 years and older, who were newly diagnosed with AML between 1 January 1997 and 31 December 2007 were selected if they had no previous neoplasm or hematological disease. Patients were followed until death or to the end of the observation period (31 December 2007). Study measures included chemotherapy and supportive care (SC) received, survival time, and all-cause healthcare utilization and costs accrued from AML diagnosis until death or observation period end. Regression analyses assessed factors associated with receipt of chemotherapy (logistic) and mortality among chemotherapy and SC users (Cox). RESULTS: Of the 4,058 patients meeting the inclusion criteria, 43 % received chemotherapy; 57 % received SC only. Among patients receiving chemotherapy, 69.1 % died within 1 year; median survival was 7.0 months. Among patients receiving only SC, 95.0 % died within 1 year; median survival was 1.5 months. The most significant factors associated with receipt of chemotherapy were patient age [odds ratio (OR) = 0.420 among patients 75-84 years and 0.099 among patients 85+ years, compared with patients aged 65-74 years) and Charlson Comorbidity Index (CCI) score (OR = 0.614 for patients with a CCI = 2 or 3 and 0.707 for patients with a CCI >3, compared with patients with a CCI = 0) (all P < 0.001). The most significant factors associated with mortality among patients receiving chemotherapy were patient age [hazard ratio (HR) = 1.321 among patients 75-84 years and 1.832 among patients 85+ years, compared with patients aged 65-74 years] and CCI score (OR = 1.287 for patients with a CCI = 2 or 3 and 1.220 for patients with a CCI >3, compared with patients with a CCI = 0) (all P < 0.01). Mean (standard deviation) all-cause healthcare costs were $96,078 ($109,072); the largest component was inpatient utilization (76.3 %). CONCLUSIONS: Younger patients with fewer comorbidities were more likely to receive chemotherapy and had longer survival. AML is associated with a substantial economic burden, and treatment outcomes appear to be suboptimal, with limited therapy options currently available. PMID- 23677707 TI - Correction of hypocalcemia allows optimal recruitment of FGF-23-dependent phosphaturic mechanisms in acute hyperphosphatemia post-phosphate enema. AB - Both parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) are phosphaturic hormones. These hormones should increase in response to phosphate excess. However, they also regulate serum calcium; PTH increases serum calcium concentration and FGF23 suppresses renal production of calcitriol, favoring hypocalcemia. We report the case of an 83-year-old woman with hyperphosphatemia and hypocalcemia resulting from phosphate-containing enemas. PTH and calcitriol increased in response to hypocalcemia, and FGF23 increased in response to hyperphosphatemia. Unexpectedly, peak FGF23 did not coincide with peak serum phosphate. Rather, peak FG23 was observed only after severe hypocalcemia was partially corrected with exogenous calcium administration, even though serum phosphate had been already decreasing for 32 h. Correction of severe hypocalcemia was thus associated with peak FGF23 values and with a precipitous decrease in PTH. Peak FGF23 was followed by an accelerated decrease in serum phosphate and significant phosphaturia. This clinical report is consistent with experimental data in rats showing a blunted FGF23 response to high phosphate in the presence of severe hypocalcemia. Thus, complementary experimental and clinical data suggest that partial correction of severe hypocalcemia is required for optimal FGF23-mediated phosphaturia, which takes place despite correction of PTH levels. We believe this the first human report suggesting blunting of the FGF23 response to high phosphate by severe hypocalcemia. PMID- 23677708 TI - Children of mothers who have recurrent depression in addition to anxiety, antisocial behaviour or problem alcohol use, are at increased risk of developing a new psychiatric condition. PMID- 23677710 TI - Label-free quantitative proteomics analysis of dormant terminal buds of poplar. AB - Induction and break of bud dormancy are important features for perennial plants surviving extreme seasonal variations in climate. However, the molecular mechanism of the dormancy regulation, still remain poorly understood. To better understand the molecular basis of poplar bud dormancy, we used a label-free quantitative proteomics method based on nanoscale ultra performance liquid chromatography-ESI-MS(E) for investigation of differential protein expression during dormancy induction, dormancy, and dormancy break in apical buds of poplar (Populus simonii * P. nigra). Among these identified over 300 proteins during poplar bud dormancy, there are 74 significantly altered proteins, most of which involved in carbohydrate metabolism (22 %), redox regulation (19 %), amino acid transport and metabolism (10 %), and stress response (8 %). Thirty-one of these proteins were up-regulated, five were down-regulated during three phase, and thirty-eight were expressed specifically under different conditions. Pathway analysis suggests that there are still the presence of various physiological activities and a particular influence on photosynthesis and energy metabolism during poplar bud dormancy. Differential expression patterns were identified for key enzymes involved in major metabolic pathways such as glycolysis and the pentose phosphate pathway, thus manifesting the interplay of intricate molecular events in energy generation for new protein synthesis in the dormant buds. Furthermore, there are significant changes present in redox regulation and defense response proteins, for instance in peroxidase and ascorbate peroxidase. Overall, this study provides a better understanding of the possible regulation mechanisms during poplar bud dormancy. PMID- 23677711 TI - Haplotype analysis of QTLs attributed to salinity tolerance in wheat (Triticum aestivum). AB - A diverse collection of wheat germplasm, consisting of 100 bread wheat lines with varying levels of salinity tolerance were evaluated based on incomplete block design (lattice) with two replications in field conditions. Plant material was screened for salinity tolerance under normal and saline field conditions. Subsequently in order to assess the haplotype diversity of QTLs attributed to salinity tolerance in wheat (Triticum aestivum), a collection of 30 extremes tolerant and sensitive genotypes among them were selected for genotyping on the basis of morphological, physiological and phenological traits. Genotyping was done using microsatellite markers which had been detected as the flanking regions of large effect QTLs attributed to salinity tolerance on chromosomes 2A, 4D and 3B. Combined analysis of saline and normal conditions revealed that genotypes showed highly significant responses. Association analysis of SSR markers with traits, showed markers Xcfa2121b, Xgwm10 and Xgwm296 on chromosome 2A and markers Xgwm194 and xgwm624 for chromosome 4D, had significant association with most of measured traits. Haplotype diversity analysis showed markers Xgwm10, Xgwm445, Xbarc353.2, Xgwm312, Xgwm515 and Xwmc296 on chromosome 2A as well as markers Xwmc326 and Xgwm345, Xbarc48.4 on chromosomes 3B and 4D were identified as the best markers attributed to salinity tolerance and they can be informative markers for improvement of salinity tolerance through marker-assisted selection programs. PMID- 23677709 TI - The 46359CT polymorphism of DNMT3B is associated with the risk of cervical cancer. AB - Abnormal methylation is related to cancer development. Since DNMT3B is an enzyme that modulates genomic methylation, we hypothesized that genetic variants of the promoter DNMT3B may be associated with an increased risk of developing cervical cancer. Our aim was to investigate the association between -579GT and 46359CT polymorphisms of DNMT3B and cervical cancer, high-grade squamous intraepithelial lesions (HSIL), and low-grade squamous intraepithelial lesions (LSIL). Samples from 200 healthy women and 130 women with squamous intraepithelial lesions (70 with cervical cancer, 30 with HSIL, and 30 with LSIL) were analyzed. Polymorphism genotyping was performed using PCR and restriction fragment length polymorphism. The -579GT polymorphism was not associated with cervical cancer, HSIL, or LSIL. The CT genotype of 46359CT polymorphism was significantly associated with cervical cancer risk (OR 8.75, CI 1.27-374.1), whereas the TT genotype was associated with a significantly decreased risk of HSIL (OR 0.66, CI 0.01-0.32) and LSIL (OR 0.11, CI 0.026-0.45). Our results suggest that genotyping the 46359CT polymorphism in DNMT3B may help identify women who are genetically susceptible to cervical cancer development. Additional studies with larger sample sizes are necessary to confirm our findings. PMID- 23677712 TI - Molecular characterization of calcineurin B from the non-virulent Trypanosoma rangeli kinetoplastid indicates high gene conservation. AB - Calcineurin B, the regulatory subunit of calcineurin, a serine/threonine protein phosphatase, is highly conserved throughout the evolutionary scale including trypanosomatids such as Trypanosoma cruzi, and Leishmania major. Thus, in these flagellates the protein is required for mammalian host cell invasion and virulence and stress responses. With the aim of determining the presence of calcineurin B in Trypanosoma rangeli, a non-virulent trypanosome for mammals, the respective gene was amplified by PCR, cloned and sequenced. Two sequences of 531 bp in length showing a nucleotide polymorphism (314A>C) were obtained in spite of a single-copy gene was revealed by Southern blot. These sequences, probably the alleles from the gene, showed a 79% of identity with those from T. cruzi and clustered as the sister group of this trypanosome species in a Maximum Parsimony analysis. Deduced amino acid sequence comparison with trypanosomatids and other organisms through the phylogenetic scale as well as the obtained protein structural homology model suggested the presence of the four potential EF-hand regions and the corresponding calcium binding sites of the last three of these domains. Having assessed the expression of this protein in T. rangeli epimastigotes, and taking into account the following facts: (i) calcineurin inhibitors have inhibitory effect on the in vitro replication of T. cruzi, (ii) L. major promastigote growth is inhibited by chelating agents, and (iii) T. rangeli does not seem to productively infect mammalian cells, it is hypothesized herein that the function of this protein in T. rangeli is required for epimastigote growth. PMID- 23677713 TI - Telomerase downregulation induces proapoptotic genes expression and initializes breast cancer cells apoptosis followed by DNA fragmentation in a cell type dependent manner. AB - The aim of the study was to analyze the consequence of silencing genes coding for the key subunits of the telomerase complex, i.e. TERT, TERC and TP1 in human breast cancer MCF7 and MDA-MB-231cells. The transfection was performed using Lipofectamine2000 and pooled siRNAs. The cytotoxic and/or antiproliferative effect of siRNA was measured by the SRB assay, the cell cycle was analysed by flow cytometry and DNA fragmentation by TUNEL analysis. Telomerase activity was assessed by TRAP, followed by PAGE and ELISA assays. Telomerase downregulation was also assessed using qPCR in order to estimate the changes in the expression profile of genes engaged in apoptosis. It was revealed that treatment of breast cancer cells with different siRNAs (100 nM) resulted in a cell type and time dependent effects. The downregulation of telomerase subunits was followed by reduction of telomerase activity down to almost 60% compared to control cells. However, a significant effect was only observed when the TERT subunit was downregulated. Its silencing resulted in a significant (p<0.05) increase of apoptosis (over 10% in MCF7 and about 5% in MDA-MB-231 cells, corresponding to the Annexin V assay) and DNA fragmentation (almost 30% in MCF7 and over 25% in MDA-MB-231 cells). Interestingly, also several proapoptotic genes were induced after the downregulation of the key telomerase subunit, including Bax, Bik or caspase-1 and caspase-14, as well as NGFR and TNFSF10 which were upregulated twice and more. PMID- 23677714 TI - Luteolin inhibits migration of human glioblastoma U-87 MG and T98G cells through downregulation of Cdc42 expression and PI3K/AKT activity. AB - Luteolin (3',4',5,7-tetrahydroxyflavone) is a common flavonoid in many types of plants and has several beneficial biological effects, including anti inflammation, anti-oxidant, and anti-cancer properties. However, the detail mechanisms of luteolin in suppressing tumor invasion and metastasis are poorly understood. Here, we investigated the effects of luteolin on suppressing glioblastoma tumor cell invasion and migration activity. Under the non-cytotoxic doses (15 and 30 MUM), luteolin exhibited an inhibitory effect on migration and invasion in U-87 MG and T98G glioblastoma cells. Additionally, filopodia assembly in U-87 MG cells was markedly suppressed after luteolin treatment. The treatment of luteolin also showed a decrease of Cdc42 (cell division cycle 42) protein levels and reduced PI3K/AKT activation, whereas there was no association between this decrease and phosphorylated ERK or altered transcription levels of Cdc42. Over expression of constitutive Cdc42 (Q61L) using transient transfection in U-87 MG cells induced a partial cell migration, but did not affected the degradation of the protein levels of Cdc42 after luteolin treatment. Moreover, inhibition of the proteaosome pathway by MG132 caused a significant recovery in the migration ability of U-87 MG cells and augmented the Cdc42 protein levels after luteolin treatment, suggesting that pharmacological inhibition of migration via luteolin treatment is likely to preferentially facilitate the protein degradation of Cdc42. Taken together, the study demonstrated that flavonoids of luteolin prevent the migration of glioblastoma cells by affecting PI3K/AKT activation, modulating the protein expression of Cdc42 and facilitating their degradation via the proteaosome pathway. PMID- 23677715 TI - Determination of caprolactam and residual vinyl caprolactam monomer in soluplus by mixed mode gel permeation chromatography. AB - Soluplus, a graft copolymer of polyethylene glycol, vinyl caprolactam and vinyl acetate, is designed to solubilize poorly soluble active pharmaceutical ingredients. A straightforward aqueous gel permeation chromatography method that exploits both size exclusion and adsorption modes of separation was used to separate and quantify the related residual vinyl caprolactam monomer and caprolactam impurity present in Soluplus. This methodology offers a single step analysis of caprolactam and the residual vinyl caprolacatam monomer, yielding similar results to reversed-phase chromatography measurements, which are time consuming and may involve multi-step sample preparation. The results of this study demonstrate that gel permeation chromatography provides a viable option to traditional reversed-phase chromatography in the quantitative analysis of residual caprolactam and vinyl caprolactam monomers and can be extended to other monomer-polymeric systems. PMID- 23677716 TI - Prepared polymethacrylate-based monoliths for the separation of cations by non suppressed capillary ion chromatography. AB - This paper describes a novel analytical system for non-suppressed capillary ion chromatography. Methacrylate monolithic columns were prepared from silanized fused-silica capillaries of 320 um i.d. by in situ polymerization of glycidyl methacrylate and ethylene dimethacrylate in the presence of 1,4-butanediol, 1 propanol and water as the porogen solvents. The introduction of cation-exchange sites was achieved by sulfonating the matrix with sodium sulfite to produce total cation-exchange capacities in the range of 45-105 MUequiv/mL for a 25 cm column. The conditions (concentrations of sodium sulfite solution, reacting time and modified flow rate) of sulfonation were optimized. The hydrodynamic and chromatographic performances were estimated. Coupled with a conductivity detector, a capillary ion chromatography system was set up with the prepared column. Finally, the resultant column was used for the separations of five common univalent cations (Li(+), Na(+), NH4(+), K(+) and Cs(+)) using methanesulfonic acid as the eluent and four divalent cations (Mg(2+), Ca(2+), Sr(2+) and Ba(2+)) by non-suppressed capillary ion chromatography; the chromatographic parameters were further researched. PMID- 23677717 TI - Determination of 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1 phenylethanone by liquid chromatography-tandem mass spectrometry. AB - 2-(3-Benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone (KR 66344), a 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor, is newly developed for the control of type 2 diabetes mellitus (T2DM) and metabolic syndrome. A method for the determination of KR-66344 in rat plasma was developed by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI MS-MS) to evaluate the pharmacokinetics of KR-66344. Plasma samples were processed by a liquid-liquid extraction method with ethyl acetate and introduced onto the LC-MS-MS system. The analyte and imipramine (internal standard) were analyzed by multiple reaction monitoring based on transitions at m/z 420.1 -> 105.0 and 282.2 -> 86.0, respectively. The calibration curve was linear (r = 0.9993) over the concentration range of 1.0-1,000 ng/mL. The mean recovery values for KR-66344 and imipramine were 83.8 and 86.2%, respectively. The mean inter-day and intra-day assay precision values were 3.9 and 2.4%, respectively. KR-66344 was stable under various handling and storage conditions. This developed method was applied to a pharmacokinetic study after the oral administration of KR-66344 in rats. The concentration of KR-66344 was readily measurable in rat plasma up to 24 h post-dose after an oral administration, suggesting that current assay is applicable to pharmacokinetic studies for KR-66344. PMID- 23677718 TI - Construction and characterization of a BAC library from the Coffea arabica genotype Timor Hybrid CIFC 832/2. AB - Most of the world's coffee production originates from Coffea arabica, an allotetraploid species with low genetic diversity and for which few genomic resources are available. Genomic libraries with large DNA fragment inserts are useful tools for the study of plant genomes, including the production of physical maps, integration studies of physical and genetic maps, genome structure analysis and gene isolation by positional cloning. Here, we report the construction and characterization of a Bacterial Artificial Chromosome (BAC) library from C. arabica Timor Hybrid CIFC 832/2, a parental genotype for several modern coffee cultivars. The BAC library consists of 56,832 clones with an average insert size of 118 kb, which represents a dihaploid genome coverage of five to sixfold. The content of organellar DNA was estimated at 1.04 and 0.5 % for chloroplast and mitochondrial DNA, respectively. The BAC library was screened for the NADPH dependent mannose-6-phosphate reductase gene (CaM6PR) with markers positioned on four linkage groups of a partial C. arabica genetic map. A mixed approach using PCR and membrane hybridization of BAC pools allowed for the discovery of nine BAC clones with the CaM6PR gene and 53 BAC clones that were anchored to the genetic map with simple sequence repeat markers. This library will be a useful tool for future studies on comparative genomics and the identification of genes and regulatory elements controlling major traits in this economically important crop species. PMID- 23677719 TI - Congenital short QT syndrome: landmarks of the newest arrhythmogenic cardiac channelopathy. AB - Congenital or familial short QT syndrome is a genetically heterogeneous cardiac channelopathy without structural heart disease that has a dominant autosomal or sporadic pattern of transmission affecting the electric system of the heart. Patients present clinically with a spectrum of signs and symptoms including irregular palpitations due to episodes of paroxysmal atrialfibrillation, dizziness and fainting (syncope) and/or sudden cardiac death due to polymorphic ventricular tachycardia and ventricular fibrillation. Electrocardiographic (ECG) findings include extremely short QTc intervals (QTc interval <=330 ms) not significantly modified with heart rate changes and T waves of great voltage witha narrow base. Electrophysiologic studies are characterized by significant shortening of atrial and ventricular refractory periods and arrhythmias induced by programmed stimulation. A few families have been identified with specific genotypes: 3 with mutations in potassium channels called SQT1 (Iks), SQT2 (Ikr) and SQT3 (Ik1). These 3 potassium channel variants are the "genetic mirror image" of long QT syndrome type 2, type 1 and Andersen-Tawil syndrome respectively because they exert opposite gain-of-function effects on the potassium channels in contrast to the loss-of-function of the potassium channels in the long QT syndromes. Three new variants with overlapping phenotypes affecting the slow inward calcium channels havealso been described. Finally, another variant with mixed phenotype affecting the sodium channel was reported. This review focuses the landmarks of this newest arrhythmogenic cardiac channelopathy on the main clinical, genetic, and proposed ECG mechanisms. In addition therapeutic options and the molecular autopsy of this fascinating primary electrical heart disease are discussed. PMID- 23677720 TI - The metabolic syndrome entanglement: Cutting the Gordian knot. AB - Questions have been raised on the clinical value of the metabolic syndrome (MS). The negative opinion regarding MS is anchored basically on a separate analysis of 4 conditions: obesity, dyslipidemia, hypertension and glucose intolerance. The common denominator of these 4 sets of arguments is that they represent an utterly simplistic view of MS as a solely predictive tool of morbidity or mortality. We believe that it is inequitable to compare it with statistically constructed predictive tools, including stronger prognostic variables even unrelated to one another from the biological point of view. Several recent large meta-analyses - one of them including nearly one million patients - systematically showed that people with MS are at increased risk of cardiovascular (CV) events. MS was associated with a 2-fold increase in CV outcomes and a 1.5-fold increase in all cause mortality rates. A very important finding was that CV risk still remained high in patients with MS but without diabetes. The presence of MS possesses a definitely predictive value, but above all it is a widely accepted concept regarding a biological condition based on complex and interrelated pathophysiological mechanisms emanating from excess central adiposity and insulin resistance. The risk factors are multiplicative, meaning that the risk of a CV disease from risk factors rises geometrically, not linearly, as the number of risk factors increases. Therefore, currently available evidences strongly support the concept of the MS as a critical clustering of CV risk factors and diabetes, representing a true and solid evolving clinical entity. PMID- 23677721 TI - Cardiac pathology and modern therapeutic approach in Behcet disease. AB - Behcet disease (BD) is an enigmatic inflammatory disorder with multisystemic complications which is endemic in some countries but can be seen in the entire world. Valid diagnostic criteria are available. The pathology is related to a specific perivasculitis with involvement of both arteries and veins of all sizes. Minor arterial and cardiac involvement is frequent in BD but is usually asymptomatic. In exceptional cases cardiac symptoms may be the 1st manifestation of BD. The prevalence of severe cardiac complications (cardio-Behcet) should be < 10%. An impressive therapeutic improvement has been achieved by using appropriate catheterization techniques, coronary and intra-arterial stents, colchicine, drug response modifying drugs and immunotherapy but, still cardio-Behcet has a poor prognosis. Efforts are undertaken to improve morbidity and prognosis with the use of newer drugs. An important part of the complications in BD are related to the frequent thromboembolic complications and there is high possibility that newer oral anticoagulants will be superior to the classical anticoagulants presently used. Available biologic agents have already been frequently used and seem to have improved the prognosis, but efforts are undertaken to find newer biologic agents with better therapeutic performance and less side-effects. Summarizing as much as possible the effects of the presently used biotherapy in BD, interferon alpha is effective against many ocular, genital and perhaps vascular manifestations, but its effectiveness is limited by frequent adverse-effects (even if not dangerous for the cardiovascular system). Infliximab is a valid option in the therapy of ocular and cutaneous manifestations but it is less convincing in the therapy of vascular manifestations in vascular- and neuro Behcet; furthermore, side-effects, including severe cardiovascular complications, are seen in a minority of patients; perhaps worse, infliximab seems to loose efficacy in the long-term therapy, while pharmacogenetics and receptor polymorphism may explain the existence of non-responders and the occurrence of resistance. Adalimumab might be a promising alternative for infliximab and seems to exert a good effect in an eurysmatic and other vascular complications. However, we lack long-term studies. Other biologic agents have been used only in few cases and it is too early to say if they offer new therapeutic perspectives. PMID- 23677722 TI - Association of interleukin-4 gene polymorphisms with ischemic heart failure. AB - BACKGROUND: As of the potential immunomodulatory effects of interleukin-4 (IL-4) and its importance in inhibiting the production of proinflammatory cytokines by monocytes and activated T cells, the IL-4 gene polymorphisms were investigated in a group of patients with chronic heart failure due to ischemic heart disease. METHODS: Forty three patients with ischemic heart failure (IHF) were enrolled in this study and compared with 139 healthy individuals. The allele and genotype frequency of 3 single nucleotide polymorphisms within the IL-4 gene were determined. RESULTS: The frequency of the IL-4 -590/T allele in the patient group was significantly higher than in the control group (p < 0.0001). The most frequent genotypes in patients with IHF were IL-4 (-590) CC (p < 0.0001), IL-4 ( 33) CC (p = 0.021), and IL-4 (-33) TT (p < 0.0001). The frequency of the following genotypes was significantly lower in patients compared to controls: IL 4 (-1098) TG (p = 0.035), IL-4 (-590) TC (p < 0.0001), and IL-4 (-33) TC (p < 0.0001). The most frequent IL-4 haplotypes in the patient group, which were significantly higher than in the control group, were TCC (p < 0.0001), TCT (p = 0.0242), and GCT (p = 0.0108) haplotypes. In contrast, the frequencies of the following haplotypes in the patient group were significantly lower than in the controls: GCC (p = 0.032), TTT (p = 0.0268), and TTC (p = 0.0399). CONCLUSIONS: Certain alleles, genotypes, and haplotypes in IL-4 gene were over represented inpatients with IHF, which may, in turn, predispose individuals to this disease. PMID- 23677724 TI - Chronic resveratrol administration improves diabetic cardiomyopathy in part by reducing oxidative stress. AB - BACKGROUND: Based on the key role of hyperglycemia-mediated oxidative stress in the pathogenesis of diabetic cardiomyopathy, increasing antioxidant defense would represent a novel therapeutic approach for management of diabetic cardiomyopathy. This study was designed to seek the effectiveness of chronic treatment with resveratrol, a potent natural antioxidant, on streptozotocin-nicotinamide experimental model of type 2 diabetic hearts. METHODS: Male rats randomized into four groups (n = 12): control, diabetic, control + resveratrol, and diabetic + resveratrol. RESULTS: Four-month oral resveratrol administration to diabetic rats (5 mg/kg/day) alleviated the reduction of cardiac antioxidant enzymes activities (3.88 +/- 0.48 vs. 1.49 +/- 0.43 U, p < 0.05 for superoxide dismutase, and 2.72 +/- 0.26 vs. 1.18 +/- 0.19 nmol/min/mL, p < 0.05 for catalase) and the enhancement of cardiac oxidative markers (5.01 +/- 0.37 vs. 7.23 +/- 0.51 ng, p < 0.05 for 8-isoprostane, 6.03 +/- 0.87 vs. 8.49 +/- 0.52 MUmol, p < 0.05 for nitrite/nitrate, and 0.44 +/- 0.03 vs. 0.59 +/- 0.04, p < 0.05 for oxidized/reduced glutathione ratio), nuclear factor kappa B activity (0.37 +/- 0.09 vs. 0.60 +/- 0.11, p < 0.05) and apoptosis rate (0.98 +/- 0.28 vs.1.63 +/- 0.16, p < 0.05). Moreover, it improved left ventricular developed pressure (72.46 +/- 8.16 vs. 52.01 +/- 11.32 mm Hg, p < 0.05) and coronary flow (14.08 +/- 1.09 vs. 11.75 +/- 1.43 mL/min * g, p < 0.05). CONCLUSIONS: These beneficial cardioprotective observations suggest that treatment with resveratrol can potentially delay or attenuate the progression of diabetes-related cardiac complications. PMID- 23677723 TI - Vitamin D level and extent of coronary stenotic lesions in patients with first acute myocardial infarction. AB - BACKGROUND: The study aimed to examine the relationship between vitamin D levels and the extent of coronary stenotic lesions in patients with ST-segment elevation myocardial infarction (STEMI). Experimental evidence points to the involvement of multiple factors in coronary plaque formation, including vitamin D. Little is known, however, about the association of vitamin D level with the intensity of atherosclerosis. METHODS: Serum concentrations of 25-hydroxyvitamin D [25(OH)D] were measured in 130 consecutive patients with the first acute STEMI treated with primary percutaneous coronary intervention. STEMI was the first symptom of coronary artery disease (CAD). The study population was divided into patients with single and multi-vessel CAD. The angiographic severityof CAD was also determined based on the Gensini score. RESULTS: The median 25(OH)D concentration was 11.12 ng/mL (25th and 75th percentile: 6.05; 17.12). Insufficient (20-30 ng/mL), deficient (10-20 ng/mL) and severely deficient(< 10 ng/mL) 25(OH)D levels were present in 18%, 35% and 45% of the individuals, respectively. Only 2 (2%) of patients had proper 25(OH)D levels (> 30 ng/mL). The 25(OH)D concentrations between patients with single- and multi-vessel CAD did not differ significantly (10.2 vs. 11.4 ng/mL, p = 0.62). There was no significant correlation between 25(OH)D levels and Gensini score (r = -0.0221, p = 0.81). CONCLUSIONS: The study demonstrated that vitamin D level is not associated with the severity of coronary lesions in patients with the first STEMI. A high prevalence of vitamin D deficiency in these patients was confirmed. PMID- 23677725 TI - The incidence and risk factors of stroke in patients with acute myocardial infarction treated invasively and concomitant impaired renal function. AB - BACKGROUND: Impaired renal function is a marker of poor prognosis in patients with acute myocardial infarction (AMI). The aim of the study was to assess the incidence and independent predictors of stroke in population of patients with AMI treated invasively and concomitant impaired renal function (IRF). METHODS: We analyzed 2,520 consecutive AMI patients admitted to our Center between 2003 and 2007 and treated with percutaneous coronary intervention. The whole population was divided into patients with IRF, defined as glomerular filtration rate < 60 mL/min/1.73 m(2) or contrast induced nephropathy (IRF group, n = 933; 37.02%) and patients without IRF (control group, n = 1587; 62.98%). The IRF group was subjected to further analysis. Data on long-term follow-up were screened to identify the patients who experienced stroke. RESULTS: During median of 25.5 months of follow-up 52 (2.07%) the patients experienced stroke - 33 (3.54%) in the IRF group and 19 (1.2%) patients in the control group. The risk of major adverse cardiovascular events in the IRF group, including repeated AMI (68.8 vs.14.9%, p < 0.001) and death (45.5 vs. 25.1%, p < 0.05) was significantly higher in patients with stroke. Previous stroke (HR 6.85), female gender (HR 3.13), as well as STEMI anterior (HR 2.55) were independent risk factors of stroke in this population. CONCLUSIONS: Patients with AMI treated invasively and concomitant IRF were at higher risk of stroke occurrence in the future. Stroke was associated with poor outcome in the studied population. Independent predictors of stroke in patients with IRF and AMI treated invasively were different from commonly recognized stroke predictors. PMID- 23677726 TI - Impact of methanol intoxication on the human electrocardiogram. AB - BACKGROUND: Methanol is a common commercial compound that can lead to significant morbidity and mortality with high levels of exposure. The purpose of this study was to describe electrocardiographic (ECG) changes associated with methanol intoxication. METHODS: A retrospective chart review was conducted with data from Kingston General Hospital collected between 2006 and 2011. Patient data, including demographics, medications, and laboratory data were recorded. Twelve lead ECGs were obtained and changes were noted in relation to timing and extent of methanol intoxication. RESULTS: Nine patients with a mean age of 45 years were analyzed. All patients ingested methanol orally and presented to hospital between < 1 to 25 h after ingestion. The mean plasma methanol concentration on admission was 49.8 mmol/L. A lower pH and higher plasma methanol concentration were associated with multiple ECG changes. On admission, ECG changes included sinus tachycardia (44%), PR prolongation (11%), QTc prolongation (22%) and non-specific T-wave changes (66%). One patient developed a type-1 Brugada ECG pattern. During their course in hospital, 7 patients required dialysis, 3 required mechanical ventilation, 3 developed visual impairment, and 1 died. All ECG changes normalized while in hospital. CONCLUSIONS: Methanol intoxication can lead to several ECG changes with sinus tachycardia and non-specific T-wave changes being the most common. These changes were more prominent in cases of severe acidosis. PMID- 23677727 TI - Evaluated plasma interleukin-18/interleukin-10 ratio is a risk factor for acute coronary syndromes in patients with stable angina pectoris. AB - BACKGROUND: Studies suggested that interleukin-18 (IL-18)/interleukin-10 (IL-10) ratio is an independent predictor of adverse cardiovascular events in patients with acute coronary syndromes (ACS). In this study we aimed to evaluate the predictive significance of IL-18/IL-10 for the occurrence of ACS in patients with stable angina pectoris (SAP) over a 40-month follow-up. METHODS: The IL-18, IL-10 levels of 257 patients with SAP were determined by Enzyme-Linked Immunosorbent Assay (ELISA). Two hundred and fifty-two patients, 42 of whom had ACS and 210 were event-free, were divided into two groups according to the presence or absence of the occurrence of ACS during the 40-month follow-up. RESULTS: Plasma IL-18 and IL-18/IL-10 ratios were both significantly higher (p = 0.001 and p = 0.044, respectively) among patients with ACS, however, IL-10 level was lower (p = 0.046) compared to the patients without ACS. The elevation of plasma IL-18/IL-10 ratio and the number of coronary artery lesions made the advantage ratio of ACS in patients with SAP increase 4.242 times and 1.942 times (p = 0.000 and p = 0.011, respectively). CONCLUSIONS: Plasma IL-18 and IL-10 levels in patients with SAP are closely related to the occurrence of ACS, elevated IL-18/IL-10 ratio has a positive predictive value for the occurrence of ACS in patients with SAP. PMID- 23677728 TI - Factor XIII Val34Leu polymorphism in patients with cardiac syndrome X. AB - BACKGROUND: The aim of the study was to examine the frequency of factor XIII polymorphism among patients with cardiac syndrome X (CSX). METHODS: This study was designed as a cross-sectional and observational study. Forty-eight female patients with CSX and 36 controls matched by age, gender, diabetes, and hypertension were studied. CSX was defined as typical chest pain during rest or effort, abnormal test result for exercise ECG, and presence of angiographically normal epicardial coronary arteries after ruling out inducible spasm. Factor XIII gene polymorphism was investigated by using CVD Strip Assay (ViennaLab Diagnostic GmbH) commercial kit. RESULTS: The frequency of factor XIII (Val/Leu + Leu/Leu) mutation was significantly higher in patients with CSX (43%) than in controls (19%) (p = 0.02). Frequency of the Leu allele was significantly higher in the patient group (23.5% vs. 11.1%, p = 0.04). Factor XIII (Val/Leu + Leu/Leu) mutation (p = 0.01, OR = 3.42; 95% CI 1.22-9.58) and smoking (p = 0.04, OR = 3.33, 95% CI 1.05-10.58) were identified as independent predictors of the disease in multivariate regression analysis. CONCLUSIONS: This study indicates that there is an evidence for association between factor XIII Val34Leu polymorphism and CSX. PMID- 23677729 TI - Major contribution of vasospasm-induced coronary blood flow reduction to anaphylactic ventricular dysfunction assessed in isolated blood-perfused rat heart. AB - BACKGROUND: Cardiac anaphylaxis is accompanied by coronary spasm and decreased left ventricular (LV) contractility. However, it has not been determined experimentally whether LV dysfunction during anaphylaxis is induced mainly by reduced coronary blood flow (CBF) or direct negative inotropic actions of chemical mediators. To demonstrate the major role of CBF reduction in anaphylactic LV dysfunction, we determined LV contractility during anaphylaxis and forcible CBF reduction maneuver to reproduce the anaphylaxis-induced CBF reduction in isolated blood-perfused rat hearts. METHODS: Isolated hearts from Wistar rats in the ovalbumin-sensitized anaphylaxis, non-sensitized flow reduction, and non-sensitized time control group were subjected to coronary perfusion with blood at a constant pressure and measurements of CBF and LV pressure. Cardiac anaphylaxis was induced by intracoronary injections of ovalbumin antigen. RESULTS: In response to antigen administrations, sensitized anaphylaxis group rat hearts showed decreases in CBF and the maximum increasing rate of systolic LV pressure (dP/dtmax) with an increased coronary vascular resistance as evidence of coronary spasm. The non-sensitized flow reduction group rat hearts whose CBF was forcibly reduced as in anaphylaxis showed the same degree of dP/dtmax reduction. CONCLUSIONS: The contractile failure during cardiac anaphylaxis is caused mainly by decreased CBF due to coronary spasm. PMID- 23677731 TI - Catalytic enantioselective synthesis of tetrahydroisoquinolines and their analogues bearing a C4 stereocenter: formal synthesis of (+)-(8S,13R) cyclocelabenzine. AB - A one-pot wonder: 1,2,3,4-Tetrahydroisoquinolines with a C4 stereocenter can be formed by using a one-pot multicomponent chiral phosphoric acid catalyzed transformation of a mixture of oxetane-tethered benzaldehydes, amines, and the dimethyl ester derivative of the Hantzsch ester (see scheme). This transformation can be used to prepare the spermidine alkaloid (+)-(8S,13R)-cyclocelabenzine. PMID- 23677730 TI - The atrial fibrillation in Turkey: Epidemiologic Registry (AFTER). AB - BACKGROUND: AFTER (Atrial Fibrillation in Turkey: Epidemiologic Registry) is a prospective, multicenter study designed with the aim of describing the prevalence and epidemiology of AF practice in Turkey. This study aims to evaluate stroke risk in non-valvular atrial fibrillation (AF) and anticoagulant drug utilization within conformity to AF guidelines. METHODS: Patients were recruited in 17 referral hospitals reflecting all the population of 7 geographical regions of Turkey. 2242 consecutive patients who had been admitted with AF on ECG were included in the study. 1745 of these patients, who had non-valvular AF, were included in the statistical evaluation. Stroke risk was evaluated with the CHA2DS2-VASc score. RESULTS: The average age of participants was determined to be 69.2 +/- 11.5 years (56% female). Persistent-permanent AF was found to be the most common type of non-valvular AF (78%). The most common comorbid disorder was hypertension (73%). It was found that oral anticoagulant therapy was used by 40% of all patients, 37% of whom had effective INR (2.0-3.0). Upon multivariate analysis, age was found to be the only independent predictor of stroke among the variables' effects on thromboembolic events that created CHA2DS2-VASc abbreviations (OR 1.026, p < 0.001). CONCLUSIONS: These results suggest that stroke risk scores should be thoroughly heeded based on guidelines, and that anticoagulation must be applied according to their guidance. PMID- 23677732 TI - Frontal network syndrome testing: clinical tests and positron emission tomography brain imaging help distinguish the 3 most common dementia subtypes. AB - BACKGROUND: Dementia diagnosis and the various subtypes are challenging in the absence of biomarkers. AIM: To examine available tests and neuroimaging procedures that may help distinguish these disorders. METHODS: Alzheimer's disease (AD), cognitive vascular disorder (CVD), and Frontotemporal lobe disorders (FTLD) were tested with a hierarchical neuropsychological battery that included the Frontal Systems Behavior Scale, Mini-Mental State Examination, Montreal Cognitive Assessment Test, and subtests. All patients had multimodality magnetic resonance imaging and (18)F fluorodeoxyglucose-positron emission tomography (FDG-PET) brain scans. RESULTS: Of the 161 patients evaluated for dysmemory and cognitive impairment, 31 satisfied the full protocol. The mean T scores for the 3 principal frontal system syndromes for the AD group were all abnormal save disinhibition. For the CVD and FTLD groups, all the 4 subcategory scores were abnormal. Disinhibition differed significantly between the AD and FTD group (analysis of variance [ANOVA], P = .02) and there was a strong association between the memory for 5 words test and a significant difference in the word list generation test score among the 3 groups (ANOVA, P = .0233). There was a strong association between the FDG-PET and the disease subtype (P < .0001). CONCLUSION: Evaluation for disinhibition, word list generation, 5-word memory testing and PET brain imaging may help distinguish the 3 most common dementia subtypes. PMID- 23677733 TI - Safe home program: a suite of technologies to support extended home care of persons with dementia. AB - OBJECTIVE: To report the implementation/adoption of the Safe Home Program to support caregivers of persons with dementia in (1) ongoing surveillance, (2) provision of care, (3) prevention of injuries, and (4) improving home safety. METHODS: For this demonstration project 4 assessment questionnaires (Safety Assessment Scale, Vigilance Scale, Peace of Mind Scale, and Sleep Disorders Inventory) were administered to each dyad to understand their technological needs. After identification and installation of appropriate technologies and education of the caregiver, a final visit (at 3 months) determined whether technologies were useful and being used. RESULTS: The majority of caregivers utilized technologies for ongoing surveillance; other technologies included an identification program and medication organizer. CONCLUSION: Technologies focused on ongoing surveillance for persons with dementia at the home are needed. These technologies could be quickly adopted by caregivers to ameliorate some of the stress and burden associated with providing care for persons with dementia. PMID- 23677734 TI - The neglected role of histamine in Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by beta amyloid plaques accumulation and cognitive impairment. Both environmental factors and heritable predisposition have a role in AD. Histamine is a biogenic monoamine that plays a role in several physiological functions, including induction of inflammatory reactions, wound healing, and regeneration. The Histamine mediates its functions via its 4 G-protein-coupled Histamine H1 receptor (H1R) to histamine H1 receptor (H4R). The histaminergic system has a role in the treatment of brain disorders by the development of histamine receptor agonists, antagonists. The H1R and H4R are responsible for allergic inflammation. But recent studies show that histamine antagonists against H3R and regulation of H2R can be more efficient in AD therapy. In this review, we focus on the role of histamine and its receptors in the treatment of AD, and we hope that histamine could be an effective therapeutic factor in the treatment of AD. PMID- 23677735 TI - Alzheimer's disease: learning from the past, looking to the future. AB - Our understanding on the pathophysiology and clinical aspects related to Alzheimer's Disease (AD) have been largely improved since the first case recorded in the medical literature in the beginning of the 20(th) century. Regarding the age of onset of AD, an important change seems to have happened in the last century: from several AD cases reported in middle aged and young adults in the first half of the 20(th) century, the age of onset of AD seems to have increased at the end of that century and the beginning of the 21(st) century. Since the 1 century-long time interval is very narrow to make a hypothesis on a genetic modification, it is possible that modifiable risk factors of AD played a role in increasing the age of onset of AD. Although the exact etiology of AD remains unknown, experts currently agree that it is multifactorial, being the result of complex interactions among genetic, environmental and lifestyle factors, such as physical activity, nutrition, and smoking. In the present article, we briefly discuss how lifestyle trends in the last century may have contributed to the increase in the age of onset of AD, and propose future directions for research on AD and lifestyle factors. PMID- 23677736 TI - Dyslipidemia: another brick in the wall. A feasible link in the OSA cardiovascular disease axis. PMID- 23677737 TI - Snoring in a sitting position and neck circumference are predictors of sleep apnea in Chinese patients. AB - BACKGROUND: Snoring is a common symptom among the adult population, and it is the most common complaint in patients with obstructive sleep apnea (OSA) syndrome. Patients who snore in a sitting position while taking a nap or sleeping may have a narrower upper airway. The aim of this study was to evaluate if snoring in a sitting position is a predictor of OSA in patients. METHOD: We prospectively enrolled 166 SS+ (with a history of snoring in a sitting position) subjects and 139 SS- (who denied having a history of snoring in a sitting position) patients. All of the participants received questionnaires as well as a standard polysomnography thereafter. RESULT: Patients with self-reported snoring in a sitting position (with a tilt position greater than 70 degrees , SS+ group) had a higher body mass index as well as greater neck, waist, and buttock circumference and scored higher on the Epworth Sleepiness Scale. During the polysomnographic study, the SS+ group had a higher percentage of N1 sleep and lower percentage of N2 sleep. In addition, the SS+ group had a higher apnea-hypopnea index (AHI) as well as higher arousal index and oxygen desaturation index. The sensitivity and specificity of the SS+ group for OSA (defined as AHI >= 5) were 0.59 and 0.73, respectively, with a positive predictive value of 0.93. The likelihood ratio was 2.2. On the other hand, the sensitivity and specificity of the SS+ group for moderate to severe OSA (defined as AHI >= 15) were 0.82 and 0.48, respectively. Both SS+ and greater neck circumference have a high likelihood ratio for diagnosing OSA. CONCLUSION: In the present study, the symptoms of self-reported snoring in a sitting position and greater neck circumference can be useful clinical predictors of OSA in Chinese patients. PMID- 23677738 TI - Comparison of a new high-resolution monolithic column with core-shell and fully porous columns for the analysis of retinol and alpha-tocopherol in human serum and breast milk by ultra-high-performance liquid chromatography. AB - The reduction of analysis time, cost, and improvement of separation efficiency are the main requirements in the development of high-throughput assay methods in bioanalysis. It can be achieved either by ultra-high-performance liquid chromatography (UHPLC) using stationary phases with small particles (<2 MUm) at high back pressures or by using opposite direction--monolithic stationary phases with low back pressures. The application of new types of monolithic stationary phases for UHPLC is a novel idea combining these two different paths. The aim of this work was to test the recently introduced second-generation of monolithic column Chromolith(r) HighResolution for UHPLC analysis of liposoluble vitamins in comparison with core-shell and fully porous sub-2 MUm columns with different particle sizes, column lengths, and shapes. The separation efficiency, peak shape, resolution, time of analysis, consumption of mobile phase, and lifetime of columns were calculated and compared. The main purpose of the study was to find a new, not only economical option of separation of liposoluble vitamins for routine practice. PMID- 23677739 TI - Care of the professional athlete: what standard of care? PMID- 23677740 TI - The use of guided self-help incorporating a mobile component in people with eating disorders: a pilot study. AB - OBJECTIVE: The aim of this pilot study was to test the acceptability and benefit of a guided self-help intervention incorporating a mobile component in eating disorders (EDs). METHOD: Eighteen people with Anorexia Nervosa and eleven people with Bulimia Nervosa were included in the study for 3 weeks and self-report and behavioural assessments were made before and after the intervention which included 10 video clips, a manual, and limited guidance. RESULTS: The most reported positive comment associated with the use of the vodcasts was the increased awareness about the illness. Adherence was good (29/31 subjects completed). A medium sized increase in Body Mass Index was found in participants with Anorexia Nervosa, and significantly lowered EDs and mood symptoms (effect size range = 0.72/1.35), and improvement in cognitive flexibility were reported post-intervention. DISCUSSION: A guided self-help intervention incorporating a mobile component was both acceptable and associated with symptom change in people with EDs. PMID- 23677743 TI - Pharmacokinetics, tolerability, and safety of intranasal administration of reformulated OxyContin((r)) tablets compared with original OxyContin ((r)) tablets in healthy adults. AB - BACKGROUND AND OBJECTIVE: Reformulated OxyContin((r)) (oxycodone-HCl controlled release) tablets (ORF) became available in the United States in August 2010. The original formulation of OxyContin((r)) (oxycodone-HCl controlled release) tablets (OC) used a delivery system that did not provide inherent resistance to crushing and dissolving. The objective of this study was to compare the pharmacokinetics, tolerability, and safety of finely crushed ORF tablets, coarsely crushed ORF tablets, and finely crushed OC tablets. METHODS: This randomized, single-blind, single-dose, single-center, six-sequence, triple-treatment, triple-period crossover study enrolled eligible healthy adults (aged 18-55 years inclusive). The study evaluated the pharmacokinetics, tolerability, and safety of intranasally administered ORF, both finely crushed and coarsely crushed, as well as finely crushed OC tablets. Plasma oxycodone concentrations were quantified and analyzed to determine the maximum observed plasma concentration (C max), time to maximum plasma concentration (t max), area under the plasma concentration-time curve from hour 0 to the last measurable plasma concentration (AUC(last)), and area under the plasma concentration-time curve extrapolated to infinity (AUC(infinity)). The abuse quotient (AQ), calculated as C(max)/t(max), served as an index of the average rate of increase in drug concentration from dosing to t max. Intranasal tolerability rating scales (discomfort, itching, burning, pain, runny nose, and stuffiness) and intranasal endoscopy were conducted. Safety assessments included adverse events, vital signs, pulse oximetry (SpO2), and electrocardiograms. RESULTS: Of 83 subjects screened and enrolled, 30 were randomized to period 1, with 1 subject subsequently discontinuing due to the subject's choice. Mean C max values for finely crushed ORF (17.1 ng/mL) and coarsely crushed ORF (15.5 ng/mL) were lower than that for finely crushed OC (22.2 ng/mL). Median t max for finely crushed OC (1.0 h) was shorter than that for either finely crushed ORF (2.0 h) or coarsely crushed ORF (3.0 h). Mean AQ values were approximately 66 and 80 % lower, respectively, for finely crushed ORF and coarsely crushed ORF than that for finely crushed OC. Finely crushed ORF, coarsely crushed ORF, and finely crushed OC demonstrated similar total oxycodone exposures (AUC(infinity)). Insufflation of ORF produced greater nasal discomfort and stuffiness than finely crushed OC, although the latter produced higher runny nose scores. No significant difference was found in other nasal tolerability measures. The overall safety profile was as expected following opioid administration in healthy subjects. CONCLUSIONS: In contrast to OC, both finely and coarsely crushed ORF retained some control of oxycodone release. Reduced C(max) and increased t max for ORF resulted in lower AQ scores for ORF compared with OC. ORF was associated with greater intranasal irritation than OC. These data suggest that ORF has a lower intranasal abuse potential than OC. PMID- 23677744 TI - Aquaporin-4 antibody-positive cases beyond current diagnostic criteria for NMO spectrum disorders. AB - OBJECTIVES: To analyze aquaporin-4 (AQP4) antibody-positive patients who do not fulfill the current diagnostic criteria of neuromyelitis optica (NMO) and NMO spectrum disorders (NMOSD). METHODS: We used a cell-based assay (CBA) with AQP4 transfected cells to detect AQP4 antibody in 298 consecutive patients with inflammatory CNS disorders seen at Tohoku University Hospital from 2007 to 2012. The patients were diagnosed as NMO, NMOSD, multiple sclerosis, or others using the respective current diagnostic criteria. The seropositive samples by CBA were also tested using a commercial ELISA. RESULTS: Seventy-two patients were AQP4 antibody positive. Among them, 18.1% (13/72) did not meet the NMO or NMOSD criteria (7 with monophasic optic neuritis, 2 with attacks restricted to the brainstem, and 4 with myelitis with less than 3 vertebral segments) and 84.6% (11/13) of these had only a single attack. The ELISA results were negative in 38.4% (5/13) of those patients, and they had lower antibody titers by CBA than patients with NMO/NMOSD. Although these patients had a shorter follow-up and few attacks, they shared some clinical features with NMO/NMOSD patients such as onset age, female predominance, presence of other autoantibodies, severe optic neuritis attacks, centrally located spinal cord lesions, persisting hiccups, and nausea or vomiting episodes. CONCLUSIONS: AQP4 antibody-positive patients with single or recurrent attacks of optic neuritis, myelitis, or brain/brainstem disease not fulfilling the current criteria of NMO or NMOSD may not be uncommon, and they should also be included in the NMO spectrum. PMID- 23677745 TI - Crack cocaine use due to dopamine agonist therapy in Parkinson disease. PMID- 23677746 TI - Nonmelanoma skin cancer is associated with reduced Alzheimer disease risk. AB - OBJECTIVE: To explore the association of nonmelanoma skin cancer (NMSC) and Alzheimer disease (AD) in the Einstein Aging Study, an epidemiologic study of aging in New York City. METHODS: Community-residing volunteers aged 70 years or older were assessed annually, followed by multidisciplinary diagnostic consensus. Cancer status and type was obtained by self-report. Cox proportional hazards models were used to test associations between NMSC and subsequent risk of developing a neurocognitive disorder. To deduce a biologically specific association between AD and NMSC, we considered 3 nested outcomes groups: only AD (probable or possible AD as the sole diagnosis), any AD (probable AD or possible AD, as well as mixed AD/vascular dementia), and all-cause dementia. RESULTS: We followed 1,102 adults with a mean age of 79 years at enrollment. Prevalent NMSC was associated with reduced risk of only AD (hazard ratio = 0.21; 95% confidence interval = 0.051-0.87; p = 0.031) among subjects after adjustment for demographics, hypertension, diabetes, and coronary heart disease. APOE epsilon4 genotypes were available in 769 individuals. The association was similar in magnitude, but nonsignificant, when the number of APOE epsilon4 alleles was included in the model. No significant association was found between NMSC and subsequent development of any AD or all-cause dementia. CONCLUSIONS: This population-based longitudinal study shows that individuals older than 70 years with NMSC have a significantly reduced risk of developing AD compared with individuals without NMSC. We deduce Alzheimer-specific neuroprotection, because the effect is attenuated or eliminated when considering less-specific diagnoses such as AD with another diagnosis (any AD) or all-cause dementia. PMID- 23677747 TI - Stereotactic laser induced thermotherapy (LITT): a novel treatment for brain lesions regrowing after radiosurgery. AB - Since the inception of radiosurgery, the management of brain metastases has become a common problem for neurosurgeons. Although the use of stereotactic radiosurgery and/or whole brain radiation therapy serves to control the majority of disease burden, patients who survive longer than 6-8 months sometimes face the problem of symptomatic radiographically regrowing lesions with few treatment options. Here we investigate the feasibility of use of MRI-guided stereotactic laser induced thermotherapy (LITT) as a novel treatment option for these lesions. Six patients who had previously undergone gamma knife stereotactic radiosurgery for brain metastases were selected. All patients had an initial favorable response to radiosurgery but subsequently developed regrowth of at least one lesion associated with recurrent edema and progressive neurological symptoms requiring ongoing steroids for symptom control. All lesions were evaluated for craniotomy, but were deemed unresectable due to deep location or patient's comorbidities. Stereotactic biopsies were performed prior to the thermotherapy procedure in all cases. LITT was performed using the Visualase system and follow up MRI imaging was used to determine treatment response. In all six patients biopsy results were negative for tumor and consistent with adverse radiation effects also known as radiation necrosis. Patients tolerated the procedure well and were discharged from the hospital within 48 h of the procedure. In 4/6 cases there was durable improvement of neurological symptoms until death. In all cases steroids were weaned off within 2 months. One patient died from systemic causes related to his cancer a month after the procedure. One patient had regrowth of the lesion 3 months after the procedure and required re-initiation of steroids and standard craniotomy for surgical resection. There were no complications directly related to the thermocoagulation procedure. Stereotactic laser induced thermotherapy is a feasible alternative for the treatment of symptomatic regrowing metastatic lesions after radiosurgery. The procedure carries minimal morbidity and, in this small series, shows some effectiveness in the symptomatic relief of edema and neurological symptoms paralleled by radiographic lesional control. Further studies are necessary to elucidate the safety of this technology. PMID- 23677748 TI - Mood disturbance in glioma patients. AB - Patients diagnosed with primary brain tumors such as glioma experience psychological distress throughout the illness trajectory. Determining which patient characteristics are associated with more severe mood disturbance throughout the illness trajectory can help identify patients at risk and assist in developing targeted interventions based on these factors. Adult glioma patients were eligible for participation. Data collection tools included an investigator completed clinician assessment tool, patient completed demographic form and the Profile of mood states-short form. A multiple regression model was used to describe the relationship between the patient groups and clinical factors. The study enrolled 186 glioma patients of various tumor grades, who were categorized in three groups (newly diagnosed, on-treatment, follow-up) based on disease status at time of visit. Newly diagnosed patients experienced more total mood disturbance than all the other groups. Characteristics associated with more severe mood disturbance varied by patient group: newly diagnosed patients who were not on corticosteroids and were not married were more likely to have higher mood disturbance [R(2) = 0.27, F (2, 29) = 5.31, p < 0.02]. For those on treatment, the use of concomitant medications, having more than 1 recurrence and low income predicted higher mood disturbance [R(2) = 0.417, F (4, 67) = 11.98, p < 0.001]. For those not on active treatment, female sex, anti-depressant use and having a lower income was associated with higher mood disturbance [R(2) = 0.183, F (3, 55) = 4.11, p < 0.02]. Additionally, when compared to other cancer groups, glioma patients reported similar mood disturbance to those with breast cancer. Factors other than disease characteristics are associated with higher mood disturbance and vary according to current disease status. The use of concomitant medications, demographic factors, recurrence and income are associated with mood disturbance and interventions may need to be tailored to these underlying factors. PMID- 23677749 TI - Cognitive rehabilitation for early post-surgery inpatients affected by primary brain tumor: a randomized, controlled trial. AB - Cognitive impairment is one of the most common neurological disorders in neuro oncological patients and exerts a deep negative impact on quality of life interfering with familiar, social and career-related activities. To test the effectiveness of early cognitive rehabilitation treatment for inpatients affected by primary brain tumors. Out of 109 consecutive patients enrolled in the study, 58 patients were randomly assigned to a rehabilitation group or to a control group. The rehabilitation consisted of 16 one-hour individual sessions of therapist-guided cognitive training, spread over 4 weeks, combining computer exercises and metacognitive training. Patients in the control group received usual care without cognitive training. All patients were evaluated by means of a comprehensive neuropsychological battery at the admission (T0) and after 4 weeks (T1). Patients in the rehabilitation group showed a significant improvement of cognitive functions. In particular, the domains that benefited most from the training were visual attention and verbal memory. The control group exhibited only a slightly, not statistically relevant, enhancement of cognitive performances. Cognitive rehabilitation for neuro-oncological inpatients resulted in a significant enhancement of cognitive performances after the training, also providing a foundation for early administration. Future research should be aimed to clarify the patients' characteristics that predict neuropsychological improvement, to identify the most effective elements in rehabilitative programs and to study the effects of treatment extension to everyday life. PMID- 23677750 TI - Trace metals in flounder, Platichthys flesus (Linnaeus, 1758), and sediments from the Baltic Sea and the Portuguese Atlantic coast. AB - Trace metals were examined in the muscle tissue of flatfish species of flounder, Platichthys flesus (Linnaeus, 1758), sediments from two southern Baltic Sea sites (Gdansk Bay and Ustecko-Lebskie as a reference) and in two areas of the Portuguese Atlantic coast (Douro River estuary and Atlantic fishing ground as a reference) to evaluate spatial differences in trace metals. Additionally, the accumulation of trace metals in flounder of different length classes was assessed. Flounder from the Gdansk Bay area contained twofold more cupper (Cu), lead (Pb) and mercury (Hg) than did flounder from the Douro River estuary, but zinc (Zn) and cadmium (Cd) were at similar concentrations. The sediments from Gdansk Bay contained significantly more Zn and threefold more Cd, while concentrations of Cu and Pb were twofold lower. The concentrations of metals in the sediments did not correlate with those in the flounder. Spatial differences were noted in metal concentrations in flounder from the southern Baltic Sea and the Portuguese Atlantic coast as well as within these regions, with higher concentrations in the flounder from the Baltic Sea Gdansk Bay. The flounder in length class 25-30 cm from Gdansk Bay contained metal concentrations comparable to those of class 40-45 cm specimens from the Atlantic coast. The accumulation of metals in flounder length classes differed in the two regions. PMID- 23677751 TI - Assessing the impact of organic and inorganic amendments on the toxicity and bioavailability of a metal-contaminated soil to the earthworm Eisenia andrei. AB - Metal-contaminated soil, from the El Arteal mining district (SE Spain), was remediated with organic (6% compost) and inorganic amendments (8% marble sludge) to reduce the mobility of metals and to modify its potential environmental impact. Different measures of metal bioavailability (chemical analysis; survival, growth, reproduction and bioaccumulation in the earthworm Eisenia andrei), were tested in order to evaluate the efficacy of organic and inorganic amendments as immobilizing agents in reducing metal (bio)availability in the contaminated soil. The inorganic amendment reduced water and CaCl2-extractable concentrations of Cd, Pb, and Zn, while the organic amendment increased these concentrations compared to the untreated soil. The inorganic treatment did not significantly reduce toxicity for the earthworm E. andrei after 28 days exposure. The organic amendment however, made the metal-contaminated soil more toxic to the earthworms, with all earthworms dying in undiluted soil and completely inhibiting reproduction at concentrations higher than 25%. This may be due to increased available metal concentrations and higher electrical conductivity in the compost amended soil. No effects of organic and inorganic treatments on metal bioaccumulation in the earthworms were found and metal concentrations in the earthworms increased with increasing total soil concentrations. PMID- 23677752 TI - Anthropometric, socioeconomic, and maternal health determinants of placental transfer of organochlorine compounds. AB - The aim of this study was to relate placental transfer, quantified by the cord to maternal serum concentration ratio (C/M), of five organochlorine pesticides (OCP) hexachlorobenzene (HCB), beta-hexachlorocyclohexane (beta-HCH), gamma hexachlorocyclohexane (gamma-HCH) , p,p'-DDT, p,p'-DDE and 15 polychlorinated biphenyl (PCB) congeners (28, 52, 101, 105, 114, 118, 123(+149), 138(+163), 153, 156(+171), 157, 167, 170, 180, and 189) to anthropometric, socioeconomic, and maternal health characteristics. We included into the study 1,134 births during the period 2002-2004 from two districts in eastern Slovakia with high organochlorine concentrations relative to other areas of the world. Only concentrations >LOD were taken into account. Variables as age, weight and height of mothers, parity, ethnicity, alcohol consumption, illness during pregnancy, smoking during pregnancy, hypertension, respiratory diseases, rheumatoid arthritis and diabetes mellitus, and birth weight were related to C/M. Results of regression analyses showed that C/M was predicted by several factors studied. Positive associations were observed for gestational alcohol consumption, fewer illnesses during pregnancy, maternal age, and maternal weight. Caucasians had a greater C/M compared to Romani for wet weight data of congeners 170 and 180 and in contrast C/M for HCB was greater in Romani. Our results show that drinking mothers compared to abstaining expose their fetuses not only to alcohol but to an increased level of several PCB congeners. A straightforward explanation of associations between C/M shifts and factors studied is very difficult, however, with regard to the high lipophilicity of OCPs and PCBs, changes in their kinetics probably reflect lipid kinetics. PMID- 23677753 TI - Fast determination of sulfonamides and their acetylated metabolites from environmental water based on magnetic molecularly imprinted polymers. AB - Group-selective magnetic molecularly imprinted polymers (MMIPs) that can extract four widely used sulfonamide antibiotics and their acetylated metabolites from environmental water were synthesized in this study. The MMIPs with saturation magnetization value of 16.7 emu g(-1) could be separated from the environmental water samples easily by the application of an adscititious magnetic field, reducing the time consumption of pretreatment. The extraction conditions were evaluated, and optimal extraction conditions were as follows: extraction time, 25 min; amount of polymers, 90 mg; washing solvent, 30 % methanol aqueous solution; and elution solvent, methanol-acetic acid (95:5, v/v). The target analytes were detected by liquid chromatography-tandem mass spectrometry, and the detection limits of the method are in the range of 0.38-1.32 ng L(-1). The relative standard deviations of intra- and inter-day are in the range of 1.3-6.8 % and 1.7 9.1 %, respectively. The proposed method is suitable for the analysis of environmental water samples. PMID- 23677754 TI - Remediation and management of POPs-contaminated soils in a warming climate: challenges and perspectives. PMID- 23677756 TI - The first issue of Nuclear Medicine Review for 2013. Editorial. PMID- 23677755 TI - Dynamics of cyanobacterial bloom formation during short-term hydrodynamic fluctuation in a large shallow, eutrophic, and wind-exposed Lake Taihu, China. AB - Short-term hydrodynamic fluctuations caused by extreme weather events are expected to increase worldwide because of global climate change, and such fluctuations can strongly influence cyanobacterial blooms. In this study, the cyanobacterial bloom disappearance and reappearance in Lake Taihu, China, in response to short-term hydrodynamic fluctuations, was investigated by field sampling, long-term ecological records, high-frequency sensors and MODIS satellite images. The horizontal drift caused by the dominant easterly wind during the phytoplankton growth season was mainly responsible for cyanobacterial biomass accumulation in the western and northern regions of the lake and subsequent bloom formation over relatively long time scales. The cyanobacterial bloom changed slowly under calm or gentle wind conditions. In contrast, the short term bloom events within a day were mainly caused by entrainment and disentrainment of cyanobacterial colonies by wind-induced hydrodynamics. Observation of a westerly event in Lake Taihu revealed that when the 30 min mean wind speed (flow speed) exceeded the threshold value of 6 m/s (5.7 cm/s), cyanobacteria in colonies were entrained by the wind-induced hydrodynamics. Subsequently, the vertical migration of cyanobacterial colonies was controlled by hydrodynamics, resulting in thorough mixing of algal biomass throughout the water depth and the eventual disappearance of surface blooms. Moreover, the intense mixing can also increase the chance for forming larger and more cyanobacterial colonies, namely, aggregation. Subsequently, when the hydrodynamics became weak, the cyanobacterial colonies continuously float upward without effective buoyancy regulation, and cause cyanobacterial bloom explosive expansion after the westerly. Furthermore, the results of this study indicate that the strong wind happening frequently during April and October can be an important cause of the formation and expansion of cyanobacterial blooms in Lake Taihu. PMID- 23677757 TI - Role of F18-FDG-PET/CT in restaging patients affected by renal carcinoma. AB - BACKGROUND: Renalcancers account for around 3% of all cancers and the most common type of (90%) is renal cell carcinoma Five-year survival rate in renal cancer patients is 68.4%. AIM: The aim of our study was to establish the role of F18-FDG PET/CT in restaging patients with renal carcinoma who underwent partial or radical nephrectomy. Secondary aim of the study was to identify histological characteristics of the primary tumour that may be responsible for the metabolic behaviour of neoplastic lesions. MATERIALS AND METHODS: We retrospectively evaluated 68 patients with renal carcinoma in whom F18-FDG-PET/CT was performed. RESULTS: Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of F18-FDG PET/CT were 82%, 100%, 100%, 66.7% and 86.8%, respectively. CONCLUSIONS: The results of our study suggest that F18-FDG PET/CT is characterised by high specificity and positive predictive value and can be useful in restaging patients affected by renal carcinoma. However, due to low negative predictive value, this method cannot be recommended for definitely ruling out suspected disease relapse. PMID- 23677758 TI - Optimization of image reconstruction method for SPECT studies performed using [99mTc-EDDA/HYNIC] octreotate in patients with neuroendocrine tumors. AB - BACKGROUND: Somatostatin receptor scintigraphy (SRS) is a useful tool in the assessment of GEP-NET (gastroenteropancreatic neuroendocrine tumor) patients. The choice of appropriate settings of image reconstruction parameters is crucial in interpretation of these images. The aim of the study was to investigate how the GEP NET lesion signal to noise ratio (TCS/TCB) depends on different reconstruction settings for Flash 3D software (Siemens). METHODS: SRS results of 76 randomly selected patients with confirmed GEP-NET were analyzed. For SPECT studies the data were acquired using standard clinical settings 3-4 h after the injection of 740 MBq 99mTc-[EDDA/HYNIC] octreotate. To obtain final images the OSEM 3D Flash reconstruction with different settings and FBP reconstruction were used. First, the TCS/TCB ratio in voxels was analyzed for different combinations of the number of subsets and the number of iterations of the OSEM 3D Flash reconstruction. Secondly, the same ratio was analyzed for different parameters of the Gaussian filter (with FWHM = 2-4 times greater from the pixel size). Also the influence of scatter correction on the TCS/TCB ratio was investigated. RESULTS: With increasing number of subsets and iterations, the increase of TCS/TCB ratio was observed. With increasing settings of Gauss [FWHM coefficient] filter, the decrease of TCS/TCB ratio was reported. The use of scatter correction slightly decreases the values of this ratio. CONCLUSIONS: OSEM algorithm provides a meaningfully better reconstruction of the SRS SPECT study as compared to the FBP technique. A high number of subsets improves image quality (images are smoother). Increasing number of iterations gives a better contrast and the shapes of lesions and organs are sharper. The choice of reconstruction parameters is a compromise between image qualitative appearance and its quantitative accuracy and should not be modified when comparing multiple studies of the same patient. PMID- 23677759 TI - Sentinel lymph nodes and planar scintigraphy and SPECT/CT in various types of tumours. Estimation of some factors influencing detection success. AB - BACKGROUND: Aim ot the study was to assess the role of planar lymphoscintigraphy and fusion imaging of SPECT/CT in sentinel lymph node (SLN) detection in patients with various types of tumours and to estimate some factors influencing detection success - age and body mass index. MATERIAL AND METHODS: Planar scintigraphy and hybrid modality SPECT/CT were performed in 550 consecutive patients (mean age 58.1 +/- 13.1 years): 69 pts with gynaecological tumours (37 pts with cervical cancer, 25 pts with endometrial cancer, 7 pts with vulvar carcinoma; mean age 54.4 +/- 13.2 years), 161 consecutive patients with melanomas (mean age 57.1 +/- 14.8 years), and 320 consecutive women with breast cancer (mean age 59.4 +/- 12.0 years). The radiopharmaceutical was injected around the tumour (gynaecologic and breast cancers, melanomas), subareolarly (in some breast cancers), or around the scar (in melanomas after their removal). Planar and SPECT/CT images were interpreted separately by two nuclear medicine physicians. RESULTS: Planar scintigraphy did not show SLN in 77 patients (14.0%): in 8 pts with gynaecologic tumours, in 23 pts with melanomas and in 46 pts with breast cancer. SPECT/CT was negative in 49 patients (8.9%): in 4 pts with gynaecologic tumours, in 12 pts with melanomas and in 33 pts with breast cancer. In 199 (36.2%) patients the number of SLNs captured on SPECT/CT was higher than on planar imaging. 35 foci of uptake (3.1% from totally visible 1134 foci on planar images) interpreted on planar images as hot LNs were found to be false positive non-nodal sites of uptake when further assessed on SPECT/CT. SPECT/CT showed the exact anatomical location of all visualized sentinel nodes. Influence of the age and BMI: The group of patients with higher number of detected SLN on SPECT/CT than on planar scintigraphy had lower average age than the group of patients with the same number of detected SLN on SPECT/CT and on planar scintigraphy, the difference was statistically significant (P=0.008). BMI did not differ between the two groups. CONCLUSION: In some patients with gynaecologic and breast cancers and melanomas, SPECT/CT improves detection of sentinel lymph nodes. It can image nodes not visible on planar scintigrams, exclude false positive uptake and exactly localize axillary, inguinal, pelvic and paraaortic SLNs. It improves anatomical localization of SLNs. We have found the influence of the age on the difference in the number of SLNs detected by the fusion of SPECT/CT and planar lymphoscintigraphy. On the other hand, this difference was not influenced by BMI. PMID- 23677760 TI - Estimation of sacroiliac joint index in normal subjects of various age groups: comparative evaluation of four different methods of quantification in skeletal scintigraphy. AB - BACKGROUND: To estimate and compare the sacroiliac joint (SIJ) index in skeletal scintigraphy by four different methods of quantification employed in normal subjects of different age groups. MATERIAL AND METHODS: The whole-body skeletal survey of 100 subjects, who underwent skeletal scintigraphy three hours after injection of 99mTc-Methylene Diphosphonate (MDP), were selected for this analysis. The patients having previous history of low back pain, joint pain or any benign bone joint disorders (e.g. ankylosing spondylitis, metabolic bone disease, and osteoarthritis), documented bone lesions or tumors within the pelvis region were excluded from the study. All subjects had normal posterior pelvis view on visual assessment in the respective study. Sacroiliac joint index was calculated by quantitative sacroiliac scintigraphy. In each subject, four different methods of quantification were carried out: 1. irregular region of interest (ROI) method, 2. rectangular ROI method, 3. profile peak counts (PPC) method and 4. profile integrated counts (PIC) method and applied to calculate SIJ index. SIJ indices for left and right sacroiliac joints were calculated by dividing the count for each joint by the count for the sacrum. Results obtained by the four methods were compared statistically. RESULTS: The overall SIJ index was found to range from 1.06 to 1.36 in the study population of 100 subjects encompassing all age groups. There was no significant difference in the estimated SIJ index within each age group obtained by the four different methods employed in this study. The values of SIJ index were as follows: in patients aged 2-20 years - they ranged from 1.22 to 1.36; in patients aged 21-40 years - from 1.07 to 1.19; for patients aged 41-60 years - from 1.08 to 1.19 and in patients aged 61 years and older, SIJ values were slightly lower than in other groups and ranged from 1.06 to 1.13. CONCLUSION: Methods of selecting a region of interest have no significant effect on the calculation of SIJ index and in healthy subjects its values range between 1.06 and 1.36, depending on the age of the subject. The maximum value was observed in patients aged 2-20 years and minimum values were noted in patients aged 61 and older. PMID- 23677761 TI - Quantitative evaluation of crossed cerebellar diaschisis, using voxel-based analysis of Tc-99m ECD brain SPECT. AB - BACKGROUND: In the recent literature there is no consensus regarding the relationships between crossed cerebellar diaschisis (CCD) with the primary lesion size, severity or location. Thus, the aim of the present study was to investigate relationship between the size and severity of cerebral lesions and CCD in patients with chronic stroke, using voxel-based analysis of Tc-99m ECD single photon emission computed tomography (SPECT). MATERIAL AND METHODS: We retrospectively reviewed data of 57 patients with chronic ischemic lesions localized unilaterally in the cerebral hemisphere. SPECT evaluation was performed with the voxel-based analysis. The percentage inter-hemispheric asymmetry index (AI) and the volume of abnormal clusters of voxels (CV) were ascertained for hypoperfusion in the supratentorial lesion and contralateral cerebellum. RESULTS: CCD was present in 35.1% cases. In Group CCD (+), the CV and AI of supratentorial hypoperfusion (median 128.1 ml and 21.9%, respectively) were significantly higher compared with Group CCD(-) (median 41.4 ml and 18.0%, respectively). Statistically significant correlation was found between CV of supratentorial and cerebellar perfusion defects (r = 0.4; p < 0.05), between AI of supratentorial and cerebellar perfusion defects (r = 0.6; p < 0.05) and between CV of supratentorial defect and AI of cerebellar perfusion defects (r = 0.6; p < 0.05). CONCLUSIONS: Our data suggest, that in the chronic stage of stroke, the size and severity of the supratentorial lesion are determinants of CCD, correlating with the degree of cerebellar hypoperfusion. PMID- 23677762 TI - Neurological applications for myocardial MIBG scintigraphy. AB - Signs or symptoms of impaired autonomic regulation of circulation are typically present in patients affected by Parkinson's disease (PD), in agreement with the cardiac sympathetic denervation discovered by Goldstein more than 15 yrs. ago. In particular, the majority of PD patients have a diffuse left ventricular myocardial sympathetic denervation, being a normal neurological condition present only in a small number of affected subjects. Actually MIBG cardiac imaging is a universally accepted method to estimate cardiac sympathetic innervations. This review covers the role of MIBG cardiac imaging in PD as well as in other parkinsonisms, focusing the attention on technical problems and pathophysiological premises for cardiac denervation. In particular new emerging data support the role of MIBG as biomarker of PD, also before motor symptoms became clinically evident. Therefore the timing of cardiac noradrenergic denervation in PD is a key issue and we want to update the analysis of autonomic cardiovascular abnormalities studied with MIBG in PD and related disorders. PMID- 23677763 TI - 18F-FDG PET finding of an inflammatory abdominal aortic aneurysm leading to fatal rupture: case report. PMID- 23677764 TI - False-positive defects on exercise 99mTc-sestamibi SPECT imaging, but not on dipyridamole 99mTc-sestamibi SPECT imaging, in a patient with right bundle branch block (RBBB). AB - False-positive findings with myocardial perfusion imaging (MPI) have frequently been identified in the presence of left bundle branch block (LBBB) and tend to lower the accuracy of MPI in individuals with normal coronary angiographs. Pharmacologic stress is recognized as the preferred method for MPI in patients with LBBB. In contrast, very few studies have evaluated the effect of right bundle branch block (RBBB) on MPI, and there is no consensus regarding the selection of pharmacologic versus exercise stress during MPI for the RBBB patient. In this study, we present a 45-year-old man with RBBB, who has a normal coronary artery angiography, but who showed abnormal myocardial perfusion with exercise MPI, and normal perfusion on dipyridamole MPI. The aim of the study is to stimulate awareness that the stress method selected for patients with RBBB can potentially interfere with the accuracy of the data. PMID- 23677765 TI - 13th Convention of the Polish Society of Nuclear Medicine. PMID- 23677766 TI - Rate dependent left bundle branch block: does it have any effect on the myocardial perfusion SPECT. PMID- 23677767 TI - The value of measuring impact alongside symptoms in children and adolescents: a longitudinal assessment in a community sample. AB - The impact that psychiatric symptoms have on the lives of young people is central to clinical practice and classification. However, there is relatively little research on impact and its association with symptoms. This paper examines how well impact can be measured and how it relates to psychiatric outcomes. On four separate occasions over 3 years, symptoms and impact were assessed in a UK epidemiological sample (n = 4,479; 51.5 % boys) using the Strengths and Difficulties Questionnaire (SDQ) as reported by parents, youths and teachers. Disorders were ascertained using the Development and Well-Being Assessment. An impact scale made of items about distress and impairment demonstrated considerable internal consistency, cross-informant correlations, and longitudinal stability by all reporting sources. Impact at baseline was a strong predictor of psychiatric disorder 3 years later after accounting for psychiatric disorders and symptoms measured at baseline: odds ratio OR = 2.10, 95 % Confidence Interval (CI) [1.50, 2.94] according to parent-rated impact and OR = 1.71, CI [1.08, 2.72] according to teacher-rated impact. Changes in impact over time were predicted, but not fully accounted for, by symptoms measured at baseline. Impact can be reliably and easily measured across time, and it may be clinically useful as an independent predictor of future symptoms and psychiatric disorders. More studies are needed to understand inter-individual variation in the impact caused by equivalent symptoms. PMID- 23677768 TI - Universality of bereavement life review for spirituality and depression in bereaved families. AB - The present study aimed to investigate the effects of the Bereavement Life Review on depression and spiritual well-being of bereaved families in a setting that does not specialize in palliative care. The participants were 20 bereaved family members who underwent the Bereavement Life Review over 2 sessions in 2 weeks. Beck Depression Inventory Second Edition scores significantly decreased from 14.4 +/- 9.2 to 11.6 +/- 7.4 (t = 2.15, P = .045) and Functional Assessment Chronic Illness Therapy-Spiritual scores increased from 24.3 +/- 10.1 to 25.9 +/- 11 (t = -1.0, P = .341) from pre- to postintervention. These results show that the Bereavement Life Review can decrease depression and improve spiritual well-being of bereaved families after the death of a family member in a setting without specialized palliative care. The results also suggest the universality of this therapy. PMID- 23677769 TI - In men and women with COPD the presence of urinary incontinence is associated with poorer quality of life. PMID- 23677770 TI - Synthesis of 1-substituted tetrahydroisoquinolines by lithiation and electrophilic quenching guided by in situ IR and NMR spectroscopy and application to the synthesis of salsolidine, carnegine and laudanosine. AB - The lithiation of N-tert-butoxycarbonyl (N-Boc)-1,2,3,4-tetrahydroisoquinoline was optimized by in situ IR (ReactIR) spectroscopy. Optimum conditions were found by using n-butyllithium in THF at -50 degrees C for less than 5 min. The intermediate organolithium was quenched with electrophiles to give 1-substituted 1,2,3,4-tetrahydroisoquinolines. Monitoring the lithiation by IR or NMR spectroscopy showed that one rotamer reacts quickly and the barrier to rotation of the Boc group was determined by variable-temperature NMR spectroscopy and found to be about 60.8 kJ mol(-1), equating to a half-life for rotation of approximately 30 s at -50 degrees C. The use of (-)-sparteine as a ligand led to low levels of enantioselectivity after electrophilic quenching and the "poor man's Hoffmann test" indicated that the organolithium was configurationally unstable. The chemistry was applied to N-Boc-6,7-dimethoxy-1,2,3,4 tetrahydroisoquinoline and led to the efficient synthesis of the racemic alkaloids salsolidine, carnegine, norlaudanosine and laudanosine. PMID- 23677772 TI - Total synthesis of the antibiotic BE-43472B. PMID- 23677771 TI - Clinical pharmacology of axitinib. AB - Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3 that is approved in the US and several other countries for treatment of patients with advanced renal cell carcinoma after failure of one prior systemic therapy. The recommended clinical starting dose of axitinib is 5 mg twice daily, taken with or without food. Dose increase (up to a maximum of 10 mg twice daily) or reduction is permitted based on individual tolerability. Axitinib pharmacokinetics are dose-proportional within 1-20 mg twice daily, which includes the clinical dose range. Axitinib has a short effective plasma half-life (range 2.5-6.1 h), and the plasma accumulation of axitinib is in agreement with what is expected based on the plasma half-life of the drug. Axitinib is absorbed relatively rapidly, reaching maximum observed plasma concentrations (C max) within 4 h of oral administration. The mean absolute bioavailability of axitinib is 58 %. Axitinib is highly (>99 %) bound to human plasma proteins with preferential binding to albumin and moderate binding to alpha1-acid glycoprotein. In patients with advanced renal cell carcinoma, at the 5-mg twice-daily dose in the fed state, the geometric mean (% coefficient of variation) C max and area under the plasma concentration-time curve (AUC) from time 0-24 h (AUC24) were 27.8 ng/mL (79 %) and 265 ng.h/mL (77 %), respectively. Axitinib is metabolized primarily in the liver by cytochrome P450 (CYP) 3A4/5 and, to a lesser extent (<10 % each), by CYP1A2, CYP2C19, and uridine diphosphate glucuronosyltransferase (UGT) 1A1. The two major human plasma metabolites, M12 (sulfoxide product) and M7 (glucuronide product), are considered pharmacologically inactive. Axitinib is eliminated via hepatobiliary excretion with negligible urinary excretion. Although mild hepatic impairment does not affect axitinib plasma exposures compared with subjects with normal hepatic function, there was a 2-fold increase in AUC from time zero to infinity (AUCinfinity) following a single 5-mg dose in subjects with moderate hepatic impairment. In the presence of ketoconazole, a strong CYP3A4/5 inhibitor, axitinib C max and AUCinfinity increased by 1.5- and 2-fold, respectively, whereas co-administration of rifampin, a strong CYP3A4/5 inducer, resulted in a 71 and 79 % decrease in the C max and AUCinfinity, respectively. Axitinib does not inhibit CYP3A4/5, CYP1A2, CYP2C8, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or UGT1A1 at concentrations obtained with the clinical doses and is not expected to have major interactions with drugs that are metabolized by these enzymes. Axitinib is an inhibitor of the efflux transporter P-glycoprotein (P-gp) in vitro, but is not expected to inhibit P-gp at therapeutic plasma concentrations. A two-compartment population pharmacokinetic model with first-order absorption and lag time was used to describe axitinib pharmacokinetics. No clinically relevant effects of age, sex, body weight, race, renal function, UGT1A1 genotype, or CYP2C19 inferred phenotype on the clearance of axitinib were identified. PMID- 23677773 TI - Derivatization following hollow-fiber microextraction with tetramethylammonium acetate as a dual-function reagent for the determination of benzoic acid and sorbic acid by GC. AB - Derivatization at the injection port following hollow-fiber-based liquid-liquid liquid microextraction with tetramethylammonium acetate as a dual-function reagent, i.e. an acceptor and derivatization reagent, for the determination of benzoic acid (BA) and sorbic acid (SA) in real samples by GC was developed. BA and SA were extracted from aqueous samples to an organic phase impregnated into the pores of the hollow fiber wall, and then back-extracted to the acceptor solution located inside the lumen of the hollow fiber. Upon injection, the extracted analytes were quantitatively derivatized to their methyl esters with tetramethylammonium acetate in the GC injection port. Several parameters related to the derivatization and extraction efficiency were optimized. The linearity was satisfactory over a concentration range of 0.1-50 mg/L with r > 0.993 for both analytes. The LODs were 2.0 MUg/L for SA and 20 MUg/L for BA. The recoveries (83 116%) and precisions (RSDs of 1.2-11.4% (n = 3)) were examined by analyzing real spiked samples. The enrichment factors of BA and SA were 300 and 425. The results demonstrated that this is a simple, rapid, accurate, and sensitive method for the determination of BA and SA in various samples. PMID- 23677774 TI - Botanical origin of dietary supplements labeled as "Kwao Keur", a folk medicine from Thailand. AB - In the course of our study on the quality of dietary supplements in Japan, both the internal transcribed spacer (ITS) sequence of nrDNA and the rps16 intron sequence of cpDNA of products labeled as "Kwao Keur" were investigated. As a result, the DNA sequence of Pueraria candollei var. mirifica, which is the source plant of Kwao Keur, was observed in only about half of the products. Inferred from the determined sequences, source plants in the other products included Medicago sativa, Glycyrrhiza uralensis, Pachyrhizus erosus, and Ipomoea batatas, etc. These inferior products are estimated to lack the efficacy implied by their labeling. In order to guarantee the quality of dietary supplements, it is important to identify the source materials exactly; in addition, an infrastructure that can exclude these inferior products from the market is needed for the protection of consumers from potential damage to their health and finances. The DNA analysis performed in this study is useful for this purpose. PMID- 23677776 TI - miR-9*- and miR-124a-Mediated switching of chromatin remodelling complexes is altered in rat spina bifida aperta. AB - Neural tube defects (NTDs) are complex congenital malformations resulting from incomplete neurulation. Our previous work has demonstrated that motor and sensory neurons develop defectively in rat embryos with spina bifida aperta. To identify whether neural development-associated miRNAs play a role in the neurological deficits of NTDs, we screened a panel of neural development-related miRNAs, including miR-9, miR-9*, miR-124a, miR-10a, miR10b, miR-34a, miR-221 and miR-222, in the spinal cords of rats with retinoic acid-induced spina bifida aperta. We discovered that the expression of miR-9, miR-9* and miR-124a was specifically down-regulated compared to spinal cords without spina bifida. To further clarify whether down-regulation of miR-9* and miR-124a contributes to the neurological deficits of NTDs, we investigated the levels of genes involved in switching in the subunit composition of Swi/Snf-like BAF (Brg/Brm associated factor) complexes modulated by miR-9* and miR-124a and neuronal differentiation. In addition to the down-regulation of miR-9* and miR-124a expression, we also observed increased expression of repressor element silencing transcription factor (REST) and BAF53a and decreased expression of BAF53b, Brg1 and NeuroD1. Our results suggest that REST-regulated miR-9*- and the miR-124a-mediated chromatin remodelling regulatory mechanism may participate in the neuronal deficits of spina bifida. PMID- 23677775 TI - Acetyl-CoA the key factor for survival or death of cholinergic neurons in course of neurodegenerative diseases. AB - Glucose-derived pyruvate is a principal source of acetyl-CoA in all brain cells, through pyruvate dehydogenase complex (PDHC) reaction. Cholinergic neurons like neurons of other transmitter systems and glial cells, utilize acetyl-CoA for energy production in mitochondria and diverse synthetic pathways in their extramitochondrial compartments. However, cholinergic neurons require additional amounts of acetyl-CoA for acetylcholine synthesis in their cytoplasmic compartment to maintain their transmitter functions. Characteristic feature of several neurodegenerating diseases including Alzheimer's disease and thiamine diphosphate deficiency encephalopathy is the decrease of PDHC activity correlating with cholinergic deficits and losses of cognitive functions. Such conditions generate acetyl-CoA deficits that are deeper in cholinergic neurons than in noncholinergic neuronal and glial cells, due to its additional consumption in the transmitter synthesis. Therefore, any neuropathologic conditions are likely to be more harmful for the cholinergic neurons than for noncholinergic ones. For this reason attempts preserving proper supply of acetyl CoA in the diseased brain, should attenuate high susceptibility of cholinergic neurons to diverse neurodegenerative conditions. This review describes how common neurodegenerative signals could induce deficts in cholinergic neurotransmission through suppression of acetyl-CoA metabolism in the cholinergic neurons. PMID- 23677778 TI - Predictors of locoregional recurrence in T1-2N0 tongue cancer patients. AB - Locoregional recurrence of oral tongue squamous cell carcinoma (OTSCC) has been considered a poor prognostic entity in terms of survival rate. The purpose of this study was to evaluate the incidence of locoregional recurrence and to identify significant risk factors for locoregional recurrence in early-stage OTSCC. We retrospectively reviewed the records of 58 patients who underwent radical surgery for T1-2N0 OTSCC. The local recurrence and regional recurrence rates were 10.3 % (6/58 patients) and 15.5 % (9/58 patients) in this study, respectively. The survival rate of patients with local recurrence was 66.7 %, which was significantly lower than that (96.2 %) of patients without local recurrence, whereas the survival rates of patients with or without regional recurrence were not significantly difference. Pattern of invasion (POI), neoadjuvant chemotherapy (NAC) and the status of the surgical margin were identified as factors influencing local recurrence. In particular, the status of the deep surgical margin was a high potential independent risk factor. The deep surgical margin was resected closely in many NAC-treated cases, suggesting that NAC may lead to local recurrence and a poor outcome. No efficacy of NAC was observed, suggesting that the standard treatment for early OTSCC is surgery alone. PMID- 23677780 TI - Radiologic interpretation of central venous catheter placement. AB - When used in veterinary medicine, central venous catheters are typically inserted through the external jugular vein, with their caudal extension within the cranial vena cava. Radiographic or fluoroscopic guidance is recommended to assist in correctly placing these catheters. This article provides radiologic examples of common central venous catheter malpositions and complications. PMID- 23677779 TI - Residual pulmonary hypertension after retrograde pulmonary embolectomy: long-term follow-up of 30 patients with massive and submassive pulmonary embolism. AB - OBJECTIVES: Pulmonary hypertension is a major cause of morbidity and mortality in patients following acute pulmonary embolism. Although thrombolytic therapy decreases pulmonary arterial pressure, compared with anticoagulation alone, it has the propensity for haemorrhagic complications, distal embolization and incomplete recanalization, with the potential risk of late pulmonary hypertension. Surgical embolectomy-once performed solely on critically-ill patients-has now gained favour in a wider range of patients. In this paper we present the outcomes of patients who underwent surgical embolectomy complemented with retrograde technique and follow-up systolic pulmonary arterial pressure (SPAP). METHODS: From January 2004 to December 2010, 30 consecutive patients with a mean age of 58+/-15 years underwent pulmonary embolectomy at our centre. The patients were followed for a mean period of 30.5+/-12 months. Their New York Heart Association (NYHA) classifications were assessed and their SPAPs were measured by echocardiography. RESULTS: The overall mortality rate was 13.2% (4/30). Of the remaining patients, 19 patients (73.1%) were in NYHA classes I and II, 7 patients (26.9%) in class III and no patient in class IV. The patients' preoperative and postoperative mean SPAPs were 44.9+/-5.7 and 34.9+/-7.1 mmHg, respectively, which showed a significant reduction (P<0.001). The mean SPAP in the follow-up was 29.4+/-11.5 mmHg, which again showed significant reduction compared with early postoperation values (P<0.001). No significant correlations were found between the level of SPAP reduction in patients' follow-up with age (P=0.727) and total days of ICU admission (P=0.700), but weak correlations with sex (P=0.016) and total intubation time were noticed (P=0.035). CONCLUSIONS: This is the first series reporting the long-term outcome of patients undergoing surgical embolectomy complemented by retrograde embolectomy technique, demonstrating the safety and favourable long-term outcome of this technique. It is also a new element in the growing body of evidence regarding the relevance of surgical embolectomy in patients with acute pulmonary embolism. We concluded that, following surgery, not only does the pulmonary arterial pressure drop immediately, but also the trend toward normalization continues long after operation. PMID- 23677777 TI - Piracetam prevents scopolamine-induced memory impairment and decrease of NTPDase, 5'-nucleotidase and adenosine deaminase activities. AB - Piracetam improves cognitive function in animals and in human beings, but its mechanism of action is still not completely known. In the present study, we investigated whether enzymes involved in extracellular adenine nucleotide metabolism, adenosine triphosphate diphosphohydrolase (NTPDase), 5'-nucleotidase and adenosine deaminase (ADA) are affected by piracetam in the hippocampus and cerebral cortex of animals subjected to scopolamine-induced memory impairment. Piracetam (0.02 MUmol/5 MUL, intracerebroventricular, 60 min pre-training) prevented memory impairment induced by scopolamine (1 mg/kg, intraperitoneal, immediately post-training) in the inhibitory avoidance learning and in the object recognition task. Scopolamine reduced the activity of NTPDase in hippocampus (53 % for ATP and 53 % for ADP hydrolysis) and cerebral cortex (28 % for ATP hydrolysis). Scopolamine also decreased the activity of 5'-nucleotidase (43 %) and ADA (91 %) in hippocampus. The same effect was observed in the cerebral cortex for 5'-nucleotidase (38 %) and ADA (68 %) activities. Piracetam fully prevented scopolamine-induced memory impairment and decrease of NTPDase, 5' nucleotidase and adenosine deaminase activities in synaptosomes from cerebral cortex and hippocampus. In vitro experiments show that piracetam and scopolamine did not alter enzymatic activity in cerebral cortex synaptosomes. Moreover, piracetam prevented scopolamine-induced increase of TBARS levels in hippocampus and cerebral cortex. These results suggest that piracetam-induced improvement of memory is associated with protection against oxidative stress and maintenance of NTPDase, 5'-nucleotidase and ADA activities, and suggest the purinergic system as a putative target of piracetam. PMID- 23677781 TI - Treatment of systemic hypertension associated with kidney disease. AB - Systemic hypertension is an increasingly diagnosed disorder in dogs and cats and frequently occurs secondary to chronic kidney disease. Prevention of damage to organs such as the kidneys, brain, heart, and eyes is one of the primary concerns in the management of veterinary patients with hypertension. This article reviews the guidelines for antihypertensive therapy in patients with, or at risk for, kidney disease, including the initiation of treatment and currently recommended medications. PMID- 23677782 TI - Iliopsoas muscle injury in dogs. AB - The iliopsoas muscle is formed by the psoas major and iliacus muscles. Due to its length and diameter, the iliopsoas muscle is an important flexor and stabilizer of the hip joint and the vertebral column. Traumatic acute and chronic myopathies of the iliopsoas muscle are commonly diagnosed by digital palpation during the orthopedic examination. Clinical presentations range from gait abnormalities, lameness, and decreased hip joint extension to irreversible fibrotic contracture of the muscle. Rehabilitation of canine patients has to take into account the inciting cause, the severity of pathology and the presence of muscular imbalances. PMID- 23677783 TI - Old or new? A comparison of mitotane and trilostane for the management of hyperadrenocorticism. AB - Hyperadrenocorticism (HAC) is a common endocrinopathy in dogs. With better recognition of the disease, more cases are being presented to clinicians for management. Mitotane, a 3- to 4-decade-old therapy, remains a viable and useful option for management of this disease. Thorough education and understanding of the drug are important, however, as the learning curve of how to manage its effects can be significant. Trilostane, a newer option for management of HAC, offers a simplified protocol and, often, smoother and faster control of the disease. It also requires a comfortable knowledge of expected outcome and possible adverse effects. With either drug, careful monitoring and client communication are crucial. PMID- 23677784 TI - Water plasticizes only a small part of the amorphous phase in nylon-6. AB - It is known that Polyamide 6 absorbs water in its amorphous phase. The exact composition of the amorphous phase will determine the uptake process. The heterogeneity in the amorphous phase with respect to plasticization by water uptake is quantified in this paper using NMR relaxometry. It is shown that water occupies and plasticizes only a small part (~6%) of the nylon matrix. This part is located in between the crystalline domains where polymer chain mobility is higher. At low moisture content (<4%) water molecules are tightly bound to the polymer and have the same dynamics. A highly mobile pool of guest-hydrogen nuclei is detected starting at a moisture content of 4%. Here, water is absorbed in clusters and the interaction between the polymer chains and water molecules decreases, leading to decoupling of the dynamics of water and polymer. PMID- 23677785 TI - Human papillomavirus type 16 does not require cathepsin L or B for infection. AB - Cathepsin L (CatL) and cathepsin B (CatB) are lysosomal proteases that many viruses utilize for capsid disassembly. We tested whether CatL and CatB are required for infection by human papillomavirus type 16 (HPV16). CatL- and CatB deficient mouse embryonic fibroblasts had higher levels of infection when compared with wild-type cells. Similar results were obtained in HaCaT keratinocytes treated with CatL- or CatB-specific small interfering RNA. Thus, CatL and CatB are not required for HPV16 infection but instead appear to restrict infection. PMID- 23677787 TI - Transmissible gastroenteritis virus infection induces cell apoptosis via activation of p53 signalling. AB - Transmissible gastroenteritis virus (TGEV) infection induced apoptosis in several cell lines in vitro. Our previous studies demonstrated that TGEV could activate FasL- and mitochondria-mediated pathways to induce apoptosis in PK-15 cells. In this study, we investigated the regulation of p53 and p38 mitogen-activated protein kinases (MAPK) signalling pathways in the interaction of TGEV with host cells. We observed that TGEV infection decreased p300/CBP, downregulated MDM2 and promoted p53 phosphorylation at serines 15, 20 and 46, resulting in accumulation and activation of p53 in PK-15 cells. TGEV infection induced the transient activation of p38 MAPK in the early phase of inoculation and constant activation in the later phase of infection. However, UV-irradiated TGEV did not promote the activation of p53 and p38 MAPK in the later phase, whereas it only triggered the transient activation of p38 MAPK in the early phase. Blocking of p53 activation significantly inhibited the occurrence of apoptosis through suppressing the TGEV induced FasL expression, Bcl-2 reduction, Bax and cytochrome c redistribution, while inhibition of p38 activity moderately blocked apoptosis induction and partly attenuated the accumulation and activation of p53. However, inhibition of p38 and p53 activity had no significant effects on viral gene transcription at 12 and 24 h post-infection. Taken together, these results demonstrated that TGEV infection promoted the activation of p38 MAPK and p53 signalling, and p53 signalling might play a dominant role in the regulation of cell apoptosis. These findings provide new insights into the function of p53 and p38 MAPK in the interaction of TGEV with host cells. PMID- 23677786 TI - Proposals for the classification of human rhinovirus species A, B and C into genotypically assigned types. AB - Human rhinoviruses (HRVs) frequently cause mild upper respiratory tract infections and more severe disease manifestations such as bronchiolitis and asthma exacerbations. HRV is classified into three species within the genus Enterovirus of the family Picornaviridae. HRV species A and B contain 75 and 25 serotypes identified by cross-neutralization assays, although the use of such assays for routine HRV typing is hampered by the large number of serotypes, replacement of virus isolation by molecular methods in HRV diagnosis and the poor or absent replication of HRV species C in cell culture. To address these problems, we propose an alternative, genotypic classification of HRV-based genetic relatedness analogous to that used for enteroviruses. Nucleotide distances between 384 complete VP1 sequences of currently assigned HRV (sero)types identified divergence thresholds of 13, 12 and 13 % for species A, B and C, respectively, that divided inter- and intra-type comparisons. These were paralleled by 10, 9.5 and 10 % thresholds in the larger dataset of >3800 VP4 region sequences. Assignments based on VP1 sequences led to minor revisions of existing type designations (such as the reclassification of serotype pairs, e.g. A8/A95 and A29/A44, as single serotypes) and the designation of new HRV types A101-106, B101-103 and C34-C51. A protocol for assignment and numbering of new HRV types using VP1 sequences and the restriction of VP4 sequence comparisons to type identification and provisional type assignments is proposed. Genotypic assignment and identification of HRV types will be of considerable value in the future investigation of type-associated differences in disease outcomes, transmission and epidemiology. PMID- 23677788 TI - Lytic infection of Kaposi's sarcoma-associated herpesvirus induces DNA double strand breaks and impairs non-homologous end joining. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) has been associated with the development of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease. Cytogenetic studies have revealed chromosome abnormalities in KS tissues, including recurring copy number changes in chromosomes and the loss of chromosomes. Unfaithful DNA repair may contribute to the genomic instability that is one of the most common hallmarks of tumours. We found that lytic infection of KSHV can cause severe DNA double-strand breaks (DSBs) and impair non-homologous end joining (NHEJ) in host cells. Processivity factor 8 (PF-8) of KSHV was identified as interacting with Ku70 and Ku86, and the interaction was dependent on DSBs and DNA. Overexpression of PF-8 in HeLa cells impaired NHEJ by blocking the interaction between the Ku complex and the DNA dependent protein kinase catalytic subunit. These results suggest that KSHV lytic replication may contribute to tumorigenesis by causing DNA DSBs and interfering with the repair of DSBs. PMID- 23677789 TI - The respiratory syncytial virus nucleoprotein-RNA complex forms a left-handed helical nucleocapsid. AB - Respiratory syncytial virus (RSV) is an important human pathogen. Its nucleocapsid (NC), which comprises the negative sense RNA viral genome coated by the viral nucleoprotein N, is a critical assembly that serves as template for both mRNA synthesis and genome replication. We have previously described the X ray structure of an NC-like structure: a decameric ring formed of N-RNA that mimics one turn of the helical NC. In the absence of experimental data we had hypothesized that the NC helix would be right-handed, as the N-N contacts in the ring appeared to more easily adapt to that conformation. We now unambiguously show that the RSV NC is a left-handed helix. We further show that the contacts in the ring can be distorted to maintain key N-N-protein interactions in a left handed helix, and discuss the implications of the resulting atomic model of the helical NC for viral replication and transcription. PMID- 23677790 TI - Polymorphism in the promoter region of the Toll-like receptor 9 gene and cervical human papillomavirus infection. AB - Polymorphism in the Toll-like receptor (TLR) 9 gene has been shown to have a significant role in some diseases; however, little is known about its possible role in the natural history of human papillomavirus (HPV) infections. We investigated the association between a single-nucleotide polymorphism (SNP) (rs5743836) in the promoter region of TLR9 (T1237C) and type-specific HPV infections. Specimens were derived from a cohort of 2462 women enrolled in the Ludwig-McGill Cohort Study. We randomly selected 500 women who had a cervical HPV infection detected at least once during the study as cases. We defined two control groups: (i) a random sample of 300 women who always tested HPV negative, and (ii) a sample of 234 women who were always HPV negative but had a minimum of ten visits during the study. TLR9 genotyping was performed using bidirectional PCR amplification of specific alleles. Irrespective of group, the WT homozygous TLR9 genotype (TT) was the most common form, followed by the heterozygous (TC) and the mutant homozygous (CC) forms. There were no consistent associations between polymorphism and infection risk, either overall or by type or species. Likewise, there were no consistently significant associations between polymorphism and HPV clearance or persistence. We concluded that this polymorphism in the promoter region of TLR9 gene does not seem to have a mediating role in the natural history of the HPV infection. PMID- 23677791 TI - Human papillomavirus type 16 viral load measurement as a predictor of infection clearance. AB - Viral load measurements may predict whether human papillomavirus (HPV) type 16 infections may become persistent and eventually lead to cervical lesions. Today, multiple PCR methods exist to estimate viral load. We tested three protocols to investigate viral load as a predictor of HPV clearance. We measured viral load in 418 HPV16-positive cervical smears from 224 women participating in the Ludwig McGill Cohort Study by low-stringency PCR (LS-PCR) using consensus L1 primers targeting over 40 known HPV types, and quantitative real-time PCR (qRT-PCR) targeting the HPV16 E6 and L1 genes. HPV16 clearance was determined by MY09/11 and PGMY PCR testing on repeated smears collected over 5 years. Correlation between viral load measurements by qRT-PCR (E6 versus L1) was excellent (Spearman's rank correlation, rho = 0.88), but decreased for L1 qRT-PCR versus LS PCR (rho = 0.61). Viral load by LS-PCR was higher for HPV16 and related types independently of other concurrent HPV infections. Median duration of infection was longer for smears with high copy number by all three PCR protocols (log rank P<0.05). Viral load is inversely related to HPV16 clearance independently of concurrent HPV infections and PCR protocol. PMID- 23677792 TI - Characterization of full-length hepatitis C virus sequences for subtypes 1e, 1h and 1l, and a novel variant revealed Cameroon as an area in origin for genotype 1. AB - In this study, we characterized the full-length genome sequences of seven hepatitis C virus (HCV) isolates belonging to genotype 1. These represent the first complete genomes for HCV subtypes 1e, 1h, 1l, plus one novel variant that qualifies for a new but unassigned subtype. The genomes were characterized using 19-22 overlapping fragments. Each was 9400-9439 nt long and contained a single ORF encoding 3019-3020 amino acids. All viruses were isolated in the sera of seven patients residing in, or originating from, Cameroon. Predicted amino acid sequences were inspected and unique patterns of variation were noted. Phylogenetic analysis using full-length sequences provided evidence for nine genotype 1 subtypes, four of which are described for the first time here. Subsequent phylogenetic analysis of 141 partial NS5B sequences further differentiated 13 subtypes (1a-1m) and six additional unclassified lineages within genotype 1. As a result of this study, there are now seven HCV genotype 1 subtypes (1a-1c, 1e, 1g, 1h, 1l) and two unclassified genotype 1 lineages with full-length genomes characterized. Further analysis of 228 genotype 1 sequences from the HCV database with known countries is consistent with an African origin for genotype 1, and with the hypothesis of subsequent dissemination of some subtypes to Asia, Europe and the Americas. PMID- 23677793 TI - Association of serum fibroblast growth factor 23 (FGF23) and incident fractures in older men: the Osteoporotic Fractures in Men (MrOS) study. AB - Normal mineral metabolism is critical for skeletal integrity, and recently serum fibroblast growth factor 23 (FGF23) levels were found to be directly related to overall fracture risk in elderly Swedish men. To confirm this association, we performed a prospective case-cohort study to understand the relation of FGF23 and fracture risk in older white men enrolled in the Osteoporotic Fractures in Men (MrOS) study. In the cohort of 5994 men attending the baseline MrOS examination, we evaluated a subgroup of 387 men with incident nonvertebral fracture including 73 hip fractures and a sample of 1385 men randomly selected from the cohort with baseline mineral and calcium hormone measurements. FGF23 was measured in baseline serum samples by ELISA (Millipore, Billerica, MA, USA). Modified Cox proportional hazards models that account for case-cohort study design were used to estimate the relative hazards (RH) of fracture in men across quartiles of FGF23. Subjects were also stratified by renal function, and RH per strata was estimated in men with the highest quartile of FGF23 compared with quartiles 3, 2, and 1. Overall, there was no difference in risk of nonspine or hip fracture by baseline FGF23. However, associations differed by strata of eGFRCrCy . Among men with eGFRCrCys <60 mL/min/1.73 m2 (n = 73/313 nonspine fractures), the RH in the highest quartile of FGF23 compared with the rest was 2.02 (95% confidence interval [CI] 1.07-3.79), but in men with eGFRCrCy , >60 mL/min/1.73 m2 (304/1370 fractures) the RH was 0.91 (95% CI 0.66-1.25) after adjustment for age, clinic site, body mass index, race, total hip bone mineral density, vitamin D, parathyroid hormone, alcohol use, physical activity, fracture history, and serum phosphorus. Serum FGF23 levels are not associated with incident fractures in elderly men overall. However, higher levels of serum FGF23 are associated with fracture risk in those with poor renal function. PMID- 23677794 TI - Effectiveness of a pharmacist-led drug counseling on enhancing antihypertensive adherence and blood pressure control: a randomized controlled trial. AB - Adherence to antihypertensive medications represents a crucial success factor for optimal blood pressure (BP) control in clinical practice. This study evaluated whether an additional pharmacist-led medication counseling could achieve better optimal BP control and enhance compliance. In a designated family clinic in a region with similar resident characteristics to Hong Kong, patients taking >= one antihypertensive agent with suboptimal compliance were randomly allocated to a brief 3-minute drug advice (control; n = 161) or pharmacist counseling (intervention; n = 113). The two groups were compared by repeated measure ANOVA at 3-months and 6-months with BP control and medication compliance as outcome variables, respectively. The proportions of patients having optimal compliance increased from 0% to 41.1% at 3 months and 61.9% at 6 months (P < 0.001). The proportion of patients having optimal BP control improved from 64.1% at baseline to 74.0% at 3 months and 74.5% at 6 months (P = 0.023). There were no significant differences between the two groups in the changes of BP control and compliance levels. This study implied that even a brief 3-minute drug advice might lead to improved BP levels among patients on antihypertensive medications in general practice, but did not demonstrate additional effects by pharmacist counseling. PMID- 23677795 TI - COMMD1 and ion transport proteins: what is the COMMection? Focus on "COMMD1 interacts with the COOH terminus of NKCC1 in Calu-3 airway epithelial cells to modulate NKCC1 ubiquitination". PMID- 23677796 TI - Feedback regulation of cone cyclic nucleotide channels by phosphoinositides. Focus on "CNGA3 achromatopsia-associated mutation potentiates the phosphoinositide sensitivity of cone photoreceptor CNG channels by altering intersubunit interactions". PMID- 23677797 TI - An inversin convergence. Focus on "Inversin modulates the cortical actin network during mitosis". PMID- 23677798 TI - Civil, sensible, and constructive peer review in APS journals. PMID- 23677799 TI - Claudin-2 pore function requires an intramolecular disulfide bond between two conserved extracellular cysteines. AB - Claudins constitute a family of tight junction transmembrane proteins whose first extracellular loop (ECL1) determines the paracellular permeability and ion selectivity in epithelia. There are two cysteines in the ECL1 that are conserved among all claudins. We hypothesized that these extracellular cysteines are linked by an intramolecular disulfide bond that is necessary for correct pore folding and function. To test this, we mutated C54 and C64 in claudin-2, either individually or together to alanine or serine, and generated stable Madin-Darby canine kidney (MDCK) I Tet-off cell lines. Immunoblotting showed a higher molecular mass band in the mutants with a single cysteine mutation, consistent with a claudin-2 dimer, suggesting that the two conserved cysteines normally form an intramolecular disulfide bond in wild-type claudin-2. By immunofluorescent staining, the alanine mutants were mislocalized intracellularly, while the serine mutants were expressed at the tight junction. Thus dimerization of both C54A and C64A did not require tight junction expression, suggesting that C54 and C64 are located near an intermolecular interface involved in cis-interaction. The conductance and Na(+) permeability of the serine mutants were markedly lower than the wild type, but there was no difference between the single mutants and the double mutant. We conclude that the disulfide bond between the conserved extracellular cysteines in claudin-2 is necessary for pore formation, probably by stabilizing the ECL1 fold, but is not required for correct protein trafficking. We further speculate that this role is generalizable to other claudin family members. PMID- 23677801 TI - Rivaroxaban: a review of its use in the prevention of stroke and systemic embolism in patients with atrial fibrillation. AB - Rivaroxaban (Xarelto((r))), a direct factor Xa inhibitor, is approved for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF) in Canada or those with nonvalvular AF (NVAF) in the EU, US and Japan. It is administered at a fixed oral dose and generally does not require routine monitoring of coagulation parameters. In the ROCKET AF trial in patients with NVAF and a moderate to high risk of stroke, oral rivaroxaban 20 mg once daily (15 mg once daily in patients with moderate renal impairment) was noninferior to oral dose-adjusted warfarin once daily in preventing primary endpoint events (i.e. stroke and systemic embolism) in the per-protocol population (primary noninferiority analysis) and superior in the on-treatment safety population (primary superiority analysis). Several ROCKET AF subgroup analyses indicated that the treatment effect of rivaroxaban was consistent across patient subgroups stratified according to baseline factors, including the presence or absence of previous stroke or transient ischaemic attack. Patients with moderate renal impairment receiving the reduced rivaroxaban dosage (15 mg once daily) showed a treatment effect consistent with that seen with rivaroxaban 20 mg once daily in patients with normal renal function. The tolerability profile of rivaroxaban was generally acceptable in ROCKET AF, with no significant difference between rivaroxaban and warfarin in the incidence of major or nonmajor clinically relevant bleeding events (primary safety endpoint). In the Japanese ROCKET AF trial, rivaroxaban 15 mg once daily (10 mg once daily in patients with moderate renal impairment) was noninferior to oral dose-adjusted warfarin once daily in the incidence of major or nonmajor clinically-relevant bleeding (primary study outcome). Thus, rivaroxaban is a reasonable alternative to warfarin for the prevention of stroke and systemic embolism in patients with NVAF. PMID- 23677800 TI - DIDS inhibits Na-K-ATPase activity in porcine nonpigmented ciliary epithelial cells by a Src family kinase-dependent mechanism. AB - The anion transport inhibitor DIDS is known to reduce aqueous humor secretion but questions remain about anion dependence of the effect. In some tissues, DIDS is reported to cause Na-K-ATPase inhibition. Here, we report on the ability of DIDS to inhibit Na-K-ATPase activity in nonpigmented ciliary epithelium (NPE) and investigate the underlying mechanism. Porcine NPE cells were cultured to confluence on permeable supports, treated with drugs added to both sides of the membrane, and then used for (86)Rb uptake measurements or homogenized to measure Na-K-ATPase activity or to detect protein phosphorylation. DIDS inhibited ouabain sensitive (86)Rb uptake, activated Src family kinase (SFK), and caused a reduction of Na-K-ATPase activity. PP2, an SFK inhibitor, prevented the DIDS responses. In BCECF-loaded NPE, DIDS was found to reduce cytoplasmic pH (pHi). PP2-sensitive Na-K-ATPase activity inhibition, (86)Rb uptake suppression, and SFK activation were observed when a similar reduction of pHi was imposed by low-pH medium or an ammonium chloride withdrawal maneuver. PP2 and the ERK inhibitor U0126 prevented robust ERK1/2 activation in cells exposed to DIDS or subjected to pHi reduction, but U0126 did not prevent SFK activation or the Na-K-ATPase activity response. The evidence points to an inhibitory influence of DIDS on NPE Na-K-ATPase activity by a mechanism that hinges on SFK activation associated with a reduction of cytoplasmic pH. PMID- 23677802 TI - Inhaled glycopyrronium bromide: a review of its use in patients with moderate to severe chronic obstructive pulmonary disease. AB - Inhaled glycopyrronium bromide (Seebri((r)) Breezhaler((r)) capsules; NVA237) is a once-daily, long-acting muscarinic receptor antagonist (LAMA) that is approved in several countries, including the EU, as a maintenance bronchodilator for the symptomatic treatment of adult patients with chronic obstructive pulmonary disease (COPD). In the randomized, controlled, phase III GLOW (GLycopyrronium bromide in chronic Obstructive pulmonary disease airWays clinical study)-1 and -2 trials, treatment with inhaled glycopyrronium bromide 50 MUg once daily was associated with significantly better lung function than placebo in patients with moderate to severe COPD in terms of the trough forced expiratory volume in one second (FEV1) at 12 weeks (primary endpoint). Significant between-group differences in trough FEV1 in favour of inhaled glycopyrronium bromide were maintained for up to 52 weeks. Dyspnoea scores, health status and exacerbation rates were also improved to a greater extent in the inhaled glycopyrronium bromide than placebo groups in these trials. In the randomized, controlled, phase III GLOW3 trial, inhaled glycopyrronium bromide was associated with a significantly longer exercise endurance time than placebo after 3 weeks' treatment in patients with moderate to severe COPD. The drug was generally well tolerated over the 26-week (GLOW1) or 52-week (GLOW2) study duration, and had a tolerability profile that was generally similar to that of tiotropium bromide. Serious adverse events were consistent with those expected in patients with moderate to severe COPD. In conclusion, inhaled glycopyrronium bromide is a once daily LAMA that is an effective bronchodilator for use in the treatment of patients with moderate to severe COPD. PMID- 23677803 TI - Optimizing the use of aspirin for cardiovascular prevention. AB - This article describes the mechanism of action, pharmacokinetics, and pharmacodynamics of aspirin at doses used for cardiovascular prevention and provides specific management recommendations for optimal use in clinical practice. The paper highlights practical aspects related to antiplatelet therapy, including the optimal dose of aspirin, concomitant treatment with other NSAIDs, and strategies for the prevention of gastrointestinal toxicity. Specifically, we revise the benefits and hazards in different clinical settings to help the clinician in the decision-making process for individuals who have different risks for cardiovascular and gastrointestinal bleeding events. PMID- 23677805 TI - Profilin 1: do we have a novel proteome-found biomarker predicting response to anticancer therapy? AB - About three decades ago, profilin 1 was described as a 15 kDa small protein. It was later shown that profilin 1 is a tumor suppressor in human carcinomas. Recent proteome-based data additionally demonstrated that the levels of profilin 1 expression could help to predict malignant tumor aggressiveness, response to anticancer therapy and risk of recurrence development. PMID- 23677804 TI - Apixaban: a review of its use for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. AB - The direct factor Xa inhibitor apixaban (Eliquis((r))) has predictable pharmacodynamics and pharmacokinetics and does not require routine anticoagulation monitoring. This article reviews the efficacy and tolerability of oral apixaban to reduce the risk of stroke or systemic embolism in patients with nonvalvular atrial fibrillation (AF). In the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial in patients with AF and at least one additional risk factor for stroke, apixaban recipients were significantly less likely than warfarin recipients to experience stroke or systemic embolism, major bleeding or death; the beneficial effects of treatment with apixaban versus warfarin were generally maintained across various patient subgroups. Apixaban recipients also had a significantly lower risk of intracranial haemorrhage than warfarin recipients. In the AVERROES (Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients who have Failed or are Unsuitable for Vitamin K Antagonist Therapy) trial in patients with AF and at least one additional risk factor for stroke for whom vitamin K antagonist therapy was unsuitable, apixaban was associated with a significantly lower risk of stroke or systemic embolism than aspirin, without an increase in the risk of major bleeding. In conclusion, although longer-term efficacy and safety data are needed, apixaban is an important new option for use in patients with nonvalvular AF to reduce the risk of stroke or systemic embolism. PMID- 23677807 TI - Norman B. Hecht: (December 14, 1940-February 28, 2013). PMID- 23677810 TI - Design and synthesis of chiral oxathiozinone scaffolds: efficient synthesis of hindered enantiopure sulfinamides and sulfinyl ketimines. PMID- 23677809 TI - Store-operated calcium entry in neuroglia. AB - Neuroglial cells are homeostatic neural cells. Generally, they are electrically non-excitable and their activation is associated with the generation of complex intracellular Ca(2+) signals that define the "Ca(2+) excitability" of glia. In mammalian glial cells the major source of Ca(2+) for this excitability is the lumen of the endoplasmic reticulum (ER), which is ultimately (re)filled from the extracellular space. This occurs via store-operated Ca(2+) entry (SOCE) which is supported by a specific signaling system connecting the ER with plasmalemmal Ca(2+) entry. Here, emptying of the ER Ca(2+) store is necessary and sufficient for the activation of SOCE, and without Ca(2+) influx via SOCE the ER store cannot be refilled. The molecular arrangements underlying SOCE are relatively complex and include plasmalemmal channels, ER Ca(2+) sensors, such as stromal interaction molecule, and possibly ER Ca(2+) pumps (of the SERCA type). There are at least two sets of plasmalemmal channels mediating SOCE, the Ca(2+)-release activated channels, Orai, and transient receptor potential (TRP) channels. The molecular identity of neuroglial SOCE has not been yet identified unequivocally. However, it seems that Orai is predominantly expressed in microglia, whereas astrocytes and oligodendrocytes rely more on TRP channels to produce SOCE. In physiological conditions the SOCE pathway is instrumental for the sustained phase of the Ca(2+) signal observed following stimulation of metabotropic receptors on glial cells. PMID- 23677811 TI - Bioequivalence of eslicarbazepine acetate from two different sources of its active product ingredient in healthy subjects. AB - PURPOSE: To compare the bioavailability (BA) and pharmacokinetic (PK) properties and to demonstrate the bioequivalence (BE) between two active product ingredient (API) sources of eslicarbazepine acetate (ESL) in healthy volunteers. DESIGN, SUBJECTS AND METHODS: Forty healthy male and female subjects aged 18-40 years were randomized to treatment with 400 or 800 mg ESL marketed (MF) formulation [current active pharmaceutical ingredient (API) source] and 400 or 800 mg ESL to be-marketed (TBM) formulation (new API source) under a gender-balanced, two period, two-sequence crossover open-label study design. Subjects were assigned to receive either 400 or 800 mg ESL dose strengths, and each was randomly administered on two occasions--either a single oral tablet of MF or a single oral tablet of TBM--separated by a washout period of at least 7 days. Formulations were to be considered bioequivalent if, for both 400 or 800 mg ESL dosage strengths, the test (TBM)/reference (MF) geometric mean ratios (GMR) and 90% confidence intervals (90% CI) of the area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) were within the predetermined range of 80-125%. RESULTS: Test/reference GMR (90% CI) for the Cmax and AUC was respectively 100% (94-109%) and 96% (94-98%) following 400 mg ESL and 100% (95 105%) and 100% (97-103%) following 800 mg ESL. CONCLUSION: Oral tablet formulations of either 400 or 800 mg ESL from the new API source were found to be bioequivalent to the corresponding marketed Zebinix(r) formulation according to the regulatory definition of bioequivalence. PMID- 23677812 TI - Insights into molecular assembly of ACCase heteromeric complex in Chlorella variabilis--a homology modelling, docking and molecular dynamic simulation study. AB - Acetyl-CoA carboxylase (ACCase), a biotin-dependent enzyme that catalyses the first committed step of fatty acid biosynthesis, is considered as a potential target for improving lipid accumulation in oleaginous feedstocks, including microalgae. ACCase is composed of three distinct conserved domains, and understanding the structural details of each catalytic domain assumes great significance to gain insights into the molecular basis of the complex formation and mechanism of biotin transport. In the absence of a crystal structure for any single heteromeric ACCase till date, here we report the first heteromeric association model of ACCase from an oleaginous green microalga, Chlorella variabilis, using a combination of homology modelling, docking and molecular dynamic simulations. The binding site of the docked biotin carboxylase (BC) and carboxyltransferase (CT) were predicted to be contiguous but distinct in biotin carboxyl carrier protein (BCCP) molecule. Simulation studies revealed considerable flexibility for the BC and CT domains in the BCCP-bound forms, thus indicating the adaptive behaviour of BCCP. Further, principal component analysis revealed that in the presence of BCCP, the BC and CT domains exhibited an open state conformation via the outward clockwise rotation of the binding helices. These conformational changes might be responsible for binding of BCCP domain and its translocation to the respective active sites. Various rearrangements of inter domain hydrogen bonds (H-bonds) contributed to conformational changes in the structures. H-bond interactions between the interacting residue pairs involving Glu201BCCP/Arg255BC and Asp224BCCP/Gln228CT were found to be essential for the intermolecular assembly. The present findings are consistent with previous biochemical studies. PMID- 23677814 TI - Trabecular homogeneity index derived from plain radiograph to evaluate bone quality. AB - Radiographic texture analysis has been developed lately to improve the assessment of bone architecture as a determinant of bone quality. We validate here an algorithm for the evaluation of trabecular homogeneity index (HI) in the proximal femur from hip radiographs, with a focus on the impact of the principal compressive system of the trabecular bone, and evaluate its correlation with femoral strength, bone mineral density (BMD), and volumetric trabecular structure parameters. A semiautomatic custom-made algorithm was applied to calculate the HI in the femoral neck and trochanteric areas from radiographs of 178 femoral bone specimens (mean age 79.3 +/- 10.4 years). Corresponding neck region was selected in CT scans to calculate volumetric parameters of trabecular structure. The site specific BMDs were assessed from dual-energy X-ray absorptiometry (DXA), and the femoral strength was experimentally tested in side-impact configuration. Regression analysis was performed between the HI and biomechanical femoral strength, BMD, and volumetric parameters. The correlation between HI and failure load was R(2) = 0.50; this result was improved to R(2) = 0.58 for cervical fractures alone. The discrimination of bones with high risk of fractures (load <3000 N) was similar for HI and BMD (AUC = 0.87). Regression analysis between the HIs versus site-specific BMDs yielded R(2) = 0.66 in neck area, R(2) = 0.60 in trochanteric area, and an overall of R(2) = 0.66 for the total hip. Neck HI and BMD correlated significantly with volumetric structure parameters. We present here a method to assess HI that can explain 50% of an experimental failure load and determines bones with high fracture risk with similar accuracy as BMD. The HI also had good correlation with DXA and computed tomography-derived data. PMID- 23677815 TI - Antihypertensive use before and after initiation of fixed-dose combination products in Australia: a retrospective study. AB - BACKGROUND National guidelines in Australia advise that patients should be stabilised on both individual antihypertensive medicines before initiating a fixed-dose combination (FDC) product. OBJECTIVE: The aim of this study was to examine the antihypertensive medicines use before and after initiation of four antihypertensive FDC products recently listed under the Australian Pharmaceutical Benefits Scheme--olmesartan or valsartan with hydrochlorothiazide, valsartan with amlodipine and ramipril with felodipine. SETTING Australian veteran population METHODS: This was a retrospective cohort study using Australian Government Department of Veterans' Affairs pharmacy claims data. Subjects initiating a FDC between 2008 and 2010 were included. Their antihypertensive medicine use was investigated in the 12-months prior to and post FDC product initiation. MAIN OUTCOME MEASURE: Proportions of FDC initiators dispensed one or both of the individual medicines, or who had antihypertensive medicines other than the individual ones were assessed for the 12 months prior to initiation. For the post history, proportions of patients who continued the FDC as a sole therapy, had other antihypertensives co-administered with FDC, or ceased the FDC were established. RESULTS: 2,513 participants initiated one of the four FDC products in the study period. Immediately prior to FDC initiation, below 1 % had both individual medicines, 29 % had one of the individual medicines, 58 % had antihypertensive medicines other than the individual ones, and 12 % had no antihypertensive therapy. At 12 months post initiation, 25 % of the FDC initiators continued it as a sole treatment, 35 % required an additional antihypertensive medicine in addition to FDC product, and 40 % ceased the FDC. CONCLUSION: A minority of patients initiated combination products after being stabilised on both individual medicines. Significant number had no prior history of antihypertensive use. One-third of FDC initiators still required additional antihypertensive medication concurrently with the FDC product at 12 months post initiation. PMID- 23677817 TI - Population pharmacokinetic analysis of orally-administered ruxolitinib (INCB018424 Phosphate) in patients with primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET MF). AB - Ruxolitinib is a selective inhibitor of Janus kinase 1 and 2, which is approved to treat intermediate or high-risk myelofibrosis. The population pharmacokinetics for ruxolitinib were characterized by a modeling dataset of 272 subjects from a Phase 2 and a Phase 3 study and validated by an external validation dataset of 142 subjects from a second Phase 3 study. The PK of ruxolitinib was adequately described by a two-compartment disposition model with first-order absorption and linear elimination. All model parameters were estimated with good precision. Gender and body weight were identified as covariates for oral clearance (CL/F) and volume of distribution for central compartment (Vc/F), respectively. Apparent oral clearance was 22.1 and 17.7 L/h for a typical male and female subject, respectively, with 39.1% unexplained inter-individual variability (IIV). The typical Vc /F for a subject with a median weight of 72.9 kg was estimated to be 58.6 L, with 28% unexplained IIV. The model predictive performance was validated by visual predictive check (VPC) and the external validation dataset. This analysis suggests that effects of gender and body weight on ruxolitinib PK are not clinically significant and hence no dose adjustment is needed based on gender and weight. PMID- 23677816 TI - Impact of pharmaceutical care on knowledge, quality of life and satisfaction of postmenopausal women with osteoporosis. AB - BACKGROUND: This study describes the analysis of secondary outcomes from a previously published randomised controlled trial, which assessed the effects of pharmaceutical care on medication adherence, persistence and bone turnover markers. The main focus of this manuscript is the effect of the provision of pharmaceutical care on these secondary outcomes, and details on the design of the intervention provided, the osteoporosis care plan and materials used to deliver the intervention. OBJECTIVES: To evaluate the effects of pharmaceutical care on knowledge, quality of life (QOL) and satisfaction of postmenopausal osteoporotic women prescribed bisphosphonates, and their associating factors. SETTING: Randomised controlled trial, performed at an osteoporosis clinic of a tertiary hospital in Malaysia. METHODS: Postmenopausal women diagnosed with osteoporosis (T-score <=-2.5/lowtrauma fracture), just been prescribed weekly alendronate/risedronate were randomly allocated to receive intervention or standard care (controls). Intervention participants received a medication review, education on osteoporosis, risk factors, lifestyle modifications, goals of therapy, side effects and the importance of medication adherence at months 0, 3, 6 and 12. MAIN OUTCOMES MEASURE: Knowledge, QOL and satisfaction. RESULTS: A total of 198 postmenopausal osteoporotic women were recruited: intervention = 100 and control = 98. Intervention participants reported significantly higher knowledge scores at months 3 (72.50 vs. 62.50 %), 6 (75.00 vs. 65.00 %) and 12 (78.75 vs. 68.75 %) compared to control participants. QOL scores were also lower (which indicates better QOL) at months 3 (29.33 vs. 38.41), 6 (27.50 vs. 36.56) and 12 (27.53 vs. 37.56) compared to control participants. Similarly, satisfaction score was higher in intervention participants (93.67 vs. 84.83 %). More educated women, with back pain, who were provided pharmaceutical care had better knowledge levels. Similarly, older, more educated women, with previous falls and back pain tend to have poorer QOL, whilst women who exercised more frequently and were provided pharmaceutical care had better QOL. Satisfaction also increased as QOL increases and when provided pharmaceutical care. CONCLUSION: The provision of pharmaceutical care improved knowledge, QOL and satisfaction in Malaysian postmenopausal osteoporotic women, showing that pharmacists have the potential to improve patients' overall bone health. Policymakers should consider placing a clinical pharmacist in the osteoporosis clinic to provide counselling to improve these outcomes. PMID- 23677818 TI - Short-term splenic impact of single-strand DNA functionalized multi-walled carbon nanotubes intraperitoneally injected in rats. AB - In recent years, a great deal of studies have focused on the possible toxicity of carbon nanotubes (CNT), as a result of their potential applications in the field of nanotechnologies. The investigation of spleen toxicity is part of the carbon nanotubes-induced toxicity assessment. In this study, we investigated the possible toxic effects of CNT on the rat spleen, after intraperitoneally (i.p.) administration of a single dose [1.5 ml; 2 mg multi-walled (MW) CNT per body weight (bw)] of multi-walled carbon nanotubes (exterior diameter 15-25 nm, interior diameter 10-15 nm, surface 88 m(2) g(-1) ) functionalized 1:1 with single-strand DNA (ss-DNA-MWCNT, 270 mg l(-1) ). CNT functionalization with DNA determines a stable dispersion in the body fluids. For the detection of carbon nanotubes in the spleen, Raman spectroscopy, histopathologic examination, confocal microscopy and transmission electron microscopy (TEM) were performed at different time points (1, 6, 24, 48 and 144 h) after MWCNT administration. The dynamics of oxidative stress parameters (malondialdehyde, protein carbonyls and reduced glutathione), along with nitrosative stress parameters (nitric oxide, inducible NO synthase), the pro-inflammatory cytokines [interleukin-(IL)-1beta] and the number of cells expressing caspase 3 and proliferating cell nuclear antigen (PCNA) were assessed. Our results indicate that, after i.p. administration, MWCNT translocate progressively in the spleen, with a peak of concentration after 48 h, and determine lymphoid hyperplasia and an increase in the number of cells which undergo apoptosis, in parallel with the enhancement of the mitosis in the white pulp and with transient alterations of oxidative stress and inflammation that need further investigations for a longer period of monitoring. PMID- 23677820 TI - Focus on nutrition: dietary management of gastrointestinal disease. AB - Nutrition plays a key role in the management of gastrointestinal disease, and some patients may be managed by dietary therapy alone. Dietary ingredients can have a negative or positive effect on the bowel. Negative factors in a diet may include toxins, allergens, toxic dietary excesses, or nutritional deficiencies. Diet also has a direct effect on intestinal physiology, affecting motility, cell renewal rate, intestinal microbiome, enzyme production, ammonia production, and volatile fatty acid content. This article discusses dietary therapy of acute gastroenteritis, chronic gastroenteropathies, and feline constipation. PMID- 23677821 TI - Feline small cell lymphosarcoma versus inflammatory bowel disease: diagnostic challenges. AB - Inflammatory bowel disease (IBD) and small cell lymphosarcoma (SCLSA) are common causes of chronic gastrointestinal (GI) tract disease in cats. The history, clinical signs, and results of blood work and imaging for these conditions are nonspecific and often overlap. After a thorough diagnostic workup and treatment trials to rule out other conditions, a definitive diagnosis requires histopathologic evaluation of GI tract biopsy specimens. Full-thickness tissue samples appear to be superior to endoscopic biopsy samples in providing an accurate diagnosis. Adding advanced diagnostics such as polymerase chain reaction and immunohistochemistry to traditional histopathology may improve the diagnostic utility of small samples such as the ones obtained via endoscopy. Treatment of and prognosis for IBD and SCLSA are discussed in a companion article. PMID- 23677822 TI - Hepatic encephalopathy: etiology, pathogenesis, and clinical signs. AB - Hepatic encephalopathy (HE) is a manifestation of clinical signs that may result from a variety of liver diseases. In small animals, HE is most commonly a result of portosystemic shunting. The pathogenesis is not completely understood, although it is likely multifactorial. Theories of pathogenesis include altered ammonia metabolism and glutamine and glutamate transmission, an increase in gamma aminobutyric acid agonists and benzodiazepine-like substances, alterations of the serotonergic system and amino acid metabolism, elevated taurine levels, contributions from inflammatory mediators, and toxic effects of manganese. An understanding of the underlying mechanisms that result in HE may lead to new treatments in the future. PMID- 23677823 TI - Hepatic encephalopathy: diagnosis and treatment. AB - Hepatic encephalopathy (HE) is a neurologic syndrome resulting from the synergistic action of multiple pathologic factors, which are discussed in a companion article. Early recognition of the clinical signs can improve treatment outcome, as well as reduce the incidence of risk factors. Multimodal treatment of HE is usually indicated. Studies on the pathogenesis and treatment of HE in people may shed new light on further treatment modalities in small animal patients. PMID- 23677827 TI - Childhood obesity and type 2 diabetes: the frightening epidemic. PMID- 23677826 TI - Translation regulation gets its 'omics' moment. AB - The fate of cellular RNA is largely determined by complex networks of protein-RNA interactions through ribonucleoprotein (RNP) complexes. Despite their relatively short half-life, transcripts associate with many different proteins that process, modify, translate, and degrade the RNA. Following biogenesis some mRNPs are immediately directed to translation and produce proteins, but many are diverted and regulated by processes including miRNA-mediated mechanisms, transport and localization, as well as turnover. Because of this complex interplay estimates of steady-state expression by methods such as RNAseq alone cannot capture critical aspects of cellular fate, environmental response, tumorigenesis, or gene expression regulation. More selective and integrative tools are needed to measure protein-RNA complexes and the regulatory processes involved. One focus area is measurements of the transcriptome associated with ribosomes and translation. These so-called polysome or ribosome profiling techniques can evaluate translation efficiency as well as the interplay between translation initiation, elongation, and termination-subject areas not well understood at a systems biology level. Ribosome profiling is a highly promising technique that provides mRNA positional information of ribosome occupancy, potentially bridging the gap between gene expression (i.e., RNAseq and microarray analysis) and protein quantification (i.e., mass spectrometry). In combination with methods such as RNA immunoprecipitation, miRNA profiling, or proteomics, we obtain a fresh view of global post-transcriptional and translational gene regulation. In addition, these techniques also provide new insight into new regulatory elements, such as alternative open reading frames, and translation regulation under different conditions. PMID- 23677828 TI - Sexual precocity and its treatment. AB - BACKGROUND: Puberty is a complex and dynamic period in development during which individuals transition from the juvenile to adult state. Regulated by multiple genetic and endocrine controls, it is characterized by somatic growth and sexual maturation. Sexual precocity is defined as the appearance of secondary sexual characteristics before the lower limit of the normal age for pubertal onset. DATA SOURCES: Based on recent publications and the experience with the disease of our group, we reviewed the normal timing and order of puberty, the definition of sexual precocity, the classification of sexual precocity, the differential diagnosis of sexual precocity, variations in pubertal development, the diagnosis of sexual precocity, and the treatment of sexual precocity. RESULTS: Sexual precocity can be classified as either gonadotropin-releasing hormone (GnRH) dependent or GnRH-independent. Regardless of the etiology, sexual precocity causes increased height velocity, somatic development, and skeletal maturation, which may have profound physical and psychological implications. CONCLUSIONS: The treatment of sexual precocity is focused on its cause and must address both its psychosocial and clinical implications. For GnRH-dependent precocious puberty, GnRH agonists are the main pharmacological agents used. Alternatively, the treatment of disorders causing GnRH-independent sexual precocity is directed toward the underlying abnormality. PMID- 23677830 TI - Environmental risk factor assessment: a multilevel analysis of childhood asthma in China. AB - BACKGROUND: Rapid changes in socioeconomic environment and their diverse patterns in China raise a question: how socio-environmental factors affect childhood asthma in China. We performed a multilevel analysis based on a 2005 national survey to understand the association between environmental factors and asthma, and to provide insights on developing prevention strategies. METHODS: A multi center, cross-sectional survey was conducted in 2018 school-aged children chosen from eight Chinese cities. Children of 6-13 years old were chosen randomly from schools of 39 centers in 8 cities. The multilevel analysis was made to assess both individual-level and city-level risk factors. The effect of gross domestic product (GDP) was further investigated by analysis of the factors. RESULTS: Analysis of city-level environmental factors showed that GDP [adjusted odds ratio (OR)=1.88], particulate matter with aerodynamic diameter <=10 MUm (PM10) (adjusted OR=1.37), and average humidity (adjusted OR=1.33) were strong risk factors. Further analysis of the factors decomposed GDP into two major factors, the first represented by urban construction, energy consumption, nitrogen dioxide concentration, and the second represented by health-system coverage. This suggested that the negative effects of GDP outweighed its positive effects on asthma. CONCLUSIONS: The prevalence of childhood asthma varies significantly in the eight Chinese cities. Socioenvironmental factors such as GDP, PM10 and average humidity are strong risk factors controlling individual attributes, suggesting that balance is needed between public health and economic development in China. PMID- 23677829 TI - Controversial role of pets in the development of atopy in children. AB - BACKGROUND: Exposure to environmental allergens originating from different sources has been implicated in the sensitization to the respective allergens and development of atopic diseases. Keeping domestic animals is associated with exposure to relevant allergens but there are controversial data whether this exposure promotes or protects from the development of atopy. DATA SOURCES: We herein reviewed the literature regarding the available data for the exposure to pets (cats and/or dogs) and the development of atopy. For this purpose, we searched the PubMed database. RESULTS: This review attempts to answer the following questions that arise from the daily practice and the relevant studies, which are: a) is pet keeping associated with sensitization? b) is there an association between keeping pets and the development of asthma, allergic rhinitis and eczema, and, c) what is the underlying mechanism of any possible protective association? Despite the fact that several studies and meta-analyses have been conducted to explore the role of pets in the development of atopy, there are still conflicting pieces of evidence. It seems that there are different effects depending on the type of pets, the time and duration of exposure, and the genetic background of the individual. CONCLUSION: Further appropriately designed birth cohort studies are needed to explore whether exposure to relevant allergens from pets promotes or protects from the development of atopy. PMID- 23677831 TI - Status and trends of diabetes in Chinese children: analysis of data from 14 medical centers. AB - BACKGROUND: Childhood diabetes has become a growing concern. We conducted a study to evaluate the status and trend of diabetes from 14 medical centers in China. Pre-diabetic status among obese children was also noted. METHODS: Hospital medical records were reviewed, and data of diabetes were collected from 1995 through 2010. We took every five years as a calculation unit to analyze the trend of new-onset diabetes. Data on obesity were collected in the recent five years. RESULTS: A total of 4 337 836 patients aged 0-18 years were discharged from the 14 centers. The prevalence (per 100 000 persons) of new-onset type 1 diabetes, type 2 diabetes and other types of diabetes were 96.8, 8.0, and 3.3, respectively. The prevalence of type 1 diabetes increased from 90.9 to 92.9 and 101.4, while type 2 diabetes increased from 4.1 to 7.1 and 10.0 in every five years (P<0.0001). The increasing trend was significant from Southwest to East and North China (type 1 diabetes from 59.76 to 80.02 and 120.45, type 2 diabetes from 2.52 to 3.77 and 15.64 (per 100 000 persons) (all P<0.0001). Well developed areas in China had a higher prevalence compared to less developed areas [type 1 diabetes: 151.51 vs. 32.2 (per 100 000 persons); type 2 diabetes: 15.16 vs. 1.64 and others: 7.54 vs. 0.42 (per 100 000 persons)]. Of the 3153 obese children, 18.24% had impaired fasting glucose (IFG), 5.99% had impaired gulose tolerance (IGT), and 4% had combined IFG and IGT. CONCLUSIONS: The prevalence of childhood diabetes in China has increased dramatically, with type 2 diabetes exceeding type 1 diabetes. The incidence rate of abnormal glucose metabolism in obese children has reached 28.26%. PMID- 23677832 TI - Persistent asymptomatic isolated hematuria in children: clinical and histopathological features and prognosis. AB - BACKGROUND: This study involving 351 children who had undergone kidney biopsy secondary to persistent asymptomatic isolated hematuria was undertaken to assess histological diagnosis of the disease and its natural history and prognosis. METHODS: The patients were divided into two groups: 215 patients with asymptomatic isolated microhematuria (AIMH; proteinuria <0.1 g/day) and 136 patients with persistent asymptomatic microhematuria, recurrent macrohematuria and/or proteinuria (AMHP; proteinuria 0.1-0.25 g/day). After kidney biopsy, the patients were monitored for 2-10 years. RESULTS: Normal biopsies or minor abnormalities were more frequent in AIMH patients than those in AMHP patients, who exhibited IgA nephropathy more frequently. During the 2- to 10-year follow-up period, adverse renal events (i.e., development of proteinuria, hypertension, or impaired renal function) were observed in 13/215 (6.0%) patients with AIMH and 31/136 (22.8%) patients with AMHP (chi(2)=15.521, P<0.001). CONCLUSIONS: Normal biopsies or minor abnormalities were more frequently observed in AIMH patients, whereas IgA nephropathy and adverse renal events were more frequent in AMHP. Microscopic hematuria, especially when accompanied by macroscopic hematuria and proteinuria, may represent an important risk factor for the development of chronic kidney disease. PMID- 23677833 TI - Trampoline related injuries in children: risk factors and radiographic findings. AB - BACKGROUND: Backyard trampolines are immensely popular among children, but are associated with an increase of trampoline-related injuries. The aim of this study was to evaluate radiographs of children with trampoline related injuries and to determine the risk factors. METHODS: Between 2003 and 2009, 286 children under the age of 16 with backyard trampoline injuries were included in the study. The number of injuries increased from 13 patients in 2003 to 86 in 2009. The median age of the 286 patients was 7 years (range: 1-15 years). Totally 140 (49%) patients were males, and 146 (51%) females. Medical records and all available diagnostic imaging were reviewed. A questionnaire was sent to the parents to evaluate the circumstances of each injury, the type of trampoline, the protection equipment and the experience of the children using the trampoline. The study was approved by the Institutional Ethics Committee of the University Hospital of Bern. RESULTS: The questionnaires and radiographs of the 104 patients were available for evaluation. A fracture was sustained in 51 of the 104 patients. More than 75% of all patients sustaining injuries and in 90% of patients with fractures were jumping on the trampoline with other children at the time of the accident. The most common fractures were supracondylar humeral fractures (29%) and forearm fractures (25%). Fractures of the proximal tibia occurred especially in younger children between 2-5 years of age. CONCLUSIONS: Children younger than 5 years old are at risk for specific proximal tibia fractures ("Trampoline Fracture"). A child jumping simultaneously with other children has a higher risk of suffering from a fracture. PMID- 23677834 TI - Radiation exposure in extremely low birth weight infants during their neonatal intensive care unit stay. AB - BACKGROUND: Extremely low birth weight (ELBW <1000 g) infants may have increased sensitivity to radiation exposure. Our objective was to estimate the radiation exposure in survivors of ELBW infants during their neonatal intensive care unit (NICU) stay. METHODS: In this retrospective cohort study, medical records of all ELBW infants who had been admitted to our NICU between May 1999 and October 2009 were reviewed. The infants' total entrance skin exposure [ESE in micro-Gray (MUGy)] was estimated. RESULTS: Among 450 survivors, the mean gestational age (GA) was 26.3+/-2.1 weeks, and the mean birth weight (BW) was 774.2+/-144.4 g. Infants received a median of 32 (range: 1-159) X-rays, with an estimated ESE of 1471 MUGy (range: 28-9264). Total ESE was inversely proportional to GA (r=-0.34; P<0.01), and BW (r=-0.39; P=0.01) and proportional to the severity of illness [score for neonatal acute physiology-perinatal extension (SNAPPE), r=0.39; P=0.01]. In a linear regression analysis, GA, SNAPPE and necrotizing enterocolitis were associated with radiation exposure (ESE) in ELBW infants (r2=0.133; P<0.001). CONCLUSIONS: During their NICU stay, ELBW infants were subjected to a significant number of diagnostic X-ray procedures. Our data highlight the need to closely monitor the number of X-ray procedures ordered to ELBW infants to avoid unnecessary radiation exposure. PMID- 23677835 TI - Frontal plane running biomechanics in female runners with previous iliotibial band syndrome. AB - Proximal factors such as excessive frontal plane pelvis and trunk motion have been postulated to be biomechanical risk factors associated with iliotibial band syndrome. In addition, lateral core endurance deficiencies may be related to increased pelvis and trunk motion during running. The purpose of this cross sectional investigation was to determine if differences in biomechanics during running, as well as lateral core endurance exist between female runners with previous iliotibial band syndrome and controls. Gait and lateral core endurance were assessed in 34 female runners (17 with previous iliotibial band syndrome). Multivariate analysis of variance was performed to assess between group difference in pelvis, trunk, hip, and knee variables of interest. Runners with previous iliotibial band syndrome exhibited similar peak trunk lateral flexion, peak contralateral pelvic drop, peak hip adduction, and peak external knee adduction moment compared with controls. In addition, trunk-pelvis coordination was similar between groups. Contrary to our hypotheses, both groups exhibited trunk ipsilateral flexion. Lateral core endurance was not different between groups. These findings provide the first frontal plane pelvis and trunk kinematic data set in female runners with previous iliotibial band syndrome. Frontal plane pelvis and trunk motion may not be associated with iliotibial band syndrome. PMID- 23677837 TI - Single and double N-H bond activation of ammonia by [Al2O3 ]+: room temperature formation of the aminyl radical and nitrene. PMID- 23677836 TI - Challenges in the pharmacologic management of obesity and secondary dyslipidemia in children and adolescents. AB - The rise in childhood obesity has lead to an increased number of children with lipid abnormalities and the predominance of a combined dyslipidemic pattern characterized by a moderate-to-severe elevation in triglycerides, normal-to-mild mild elevation in LDL cholesterol and reduced HDL cholesterol. Although recently published National Heart, Lung and Blood Institute (NHLBI) guidelines represent a significant step forward in managing primary dyslipidemias in pediatric patients, there is still no general consensus regarding the pharmacologic treatment of obesity-related lipid abnormalities in children. The use of early pharmacologic intervention to control dyslipidemias and reduce cardiovascular risk in young children is only expected to increase given the steady increase in obesity and emergence of atherosclerotic disease in pre-adolescents. Despite the increasing use of lipid-lowering therapy in children over the last few years, diet and lifestyle modification remain the first line therapy. Given the challenges of instituting and maintaining lifestyle modification in pediatric patients, however, it is likely that institution of drug therapy may be required in many children. Of all the medications currently available, the fibric acid derivatives have a cholesterol lowering profile that is most likely to be effective in obese children with the high TG/low HDL phenotype and data from a recently published study of gemfibrozil in children with metabolic syndrome are promising. However, additional information regarding the short and long-term safety and efficacy of fibrate therapy in children with obesity-related lipid disorders is needed before use of these agents can be recommended. PMID- 23677839 TI - The 3rd Salivary Gland Tumor Workshop meeting report. PMID- 23677838 TI - Hepatitis C co-infection and severity of liver disease as risk factors for osteoporotic fractures among HIV-infected patients. AB - Osteoporosis is increasingly reported in the aging HIV-positive population, and co-infection with hepatitis C virus (HCV) may further increase the risk of osteoporosis. However, it remains unclear whether HCV-related increased fracture risk is a function of the severity of liver disease. We calculated the time updated alanine aminotransferase to platelet ratio index (APRI) score (an indirect marker of hepatic fibrosis) in all HIV-infected patients enrolled in the Veterans Affairs' Clinical Case Registry between 1984 and 2009. The association between HCV co-infection and incident osteoporotic fracture (defined as closed wrist, vertebral, or hip fracture) was assessed in univariate and multivariate Cox survival models adjusting for traditional risk factors for osteoporosis and APRI score or the presence of cirrhosis. A total of 772 osteoporotic fractures were identified among 56,660 HIV-infected patients (98.1% male; 31.3% HCV co infected; median age 44.0 years) contributing 305,237 patient-years of follow-up. Fracture rates were significantly higher among HIV/HCV patients than HIV-only patients (2.57 versus 2.07/1000 patient-years, relative risk = 1.24, p < 0.0001). In a Cox multivariable model including age, race, smoking, drug use, body mass index, and antiretroviral therapy, HCV co-infection remained an independent predictor of osteoporotic fractures after controlling for presence of cirrhosis (hazard ratio [HR] = 1.32; p <0.001) or APRI score (HR = 1.30; p = 0.003). Among HIV/HCV co-infected patients, cirrhosis strongly predicted osteoporotic fractures (HR = 1.65; 95% confidence interval [CI] 1.11-2.44; p = 0.012), but APRI score was a weaker predictor (HR = 1.008; 95% CI 1.002-1.014; p = 0.015). In conclusion, among HIV-infected patients, severity of liver disease partly explains the HCV-associated increased risk of osteoporotic fractures. Other determinants of this increased risk remain to be defined. PMID- 23677840 TI - Hidden dangers in the kitchen: common foods toxic to dogs and cats. AB - Many foods and food additives that are safe for human consumption can be extremely toxic to pets. Recognizing the clinical signs and clinicopathologic changes associated with these toxins allows prompt initiation of appropriate therapy. As with many other toxins, decontamination and supportive care are the mainstays of therapy for food toxicosis. Educating owners about foods and food additives that are unsafe for dogs and cats can help prevent toxicosis. PMID- 23677841 TI - Heatstroke: thermoregulation, pathophysiology, and predisposing factors. AB - Heatstroke is a common veterinary emergency that, depending on the severity of injury, can progress to a life-threatening condition. Heatstroke can be classic (nonexertional) or exertional. Classic heatstroke develops when the body is exposed to high external temperatures, whereas exertional heatstroke is caused by strenuous exercise. Thermoregulation is the intrinsic ability of the body to maintain core body temperature within normal limits through an intricate balance of heat conservation and heat dissipation. Severe disease ensues when persistent hyperthermia causes injury to the body for which these mechanisms can no longer adequately compensate. The first stages of heatstroke are characterized by initial thermoregulation, acute phase response, and activation of heat shock proteins. The organ systems most commonly affected during heatstroke are the gastrointestinal tract and the coagulation, renal, cardiac, pulmonary, and central nervous systems. PMID- 23677842 TI - Cardiovascular effects of thyroid disease. AB - Thyroid hormones have many effects on cardiovascular function, and deficiency or excess of thyroid hormones can result in cardiac dysfunction. Abnormalities of the cardiovascular system are often identified during examination of hyperthyroid and hypothyroid patients. This article addresses the effects of thyroid hormones on the cardiovascular system and the clinical relevance of the cardiovascular response to thyroid dysfunction. In addition, treatment recommendations are presented. PMID- 23677843 TI - Cutaneous viral dermatoses in dogs and cats. AB - Cutaneous viral dermatoses are often underdiagnosed in dogs and cats because they are rare, and because it is difficult to identify an exact causative agent. Even so, practitioners in primary care may encounter some characteristic clinical features. This article reviews commonly encountered dermatoses, particularly papillomavirus-associated dermatoses in dogs and cats. It also provides a brief overview of several other dermatoses associated with feline herpesvirus, feline calicivirus, FeLV, and feline poxvirus. PMID- 23677844 TI - A quantitative analysis of the spontaneous reporting of congestive heart failure related adverse events with systemic anti-fungal drugs. AB - To investigate spontaneous reporting relationships between representative antifungal agents and congestive heart failure (CHF)-related adverse events (AE) we performed multiple disproportionality analyses of the US FDA AERS database. Specifically we performed analysis of drug-AE associations (2D) plus drug-drug-AE and drug-AE-AE-associations (3D), the latter two to explore the potential contribution of reported pharmacodynamic interactions, overexposure from pharmacokinetic interactions, and drug overdose. Itraconazole displayed a pattern of statistical reporting dependencies across multiple analyses (2D and 3D). Amphotericin B was the only other antifungal that demonstrated a 2D SDR with CHF related events. Itraconazole demonstrated multiple SDRs with calcium channel blockers in suspect drug-only 3D analysis. There was one other SDR with fluconazole and propanolol and three SDRs involving valproate and fluconazole that may have been do at least in part to duplicate reporting. Less specific 3D analysis including both suspect plus concomitant medications showed a greater number and variety of SDRs with multiple antifungals. Statistical reporting dependencies with CHF-related events did not appear to be a consistent pharmacological (e.g., azole/triazole)/therapeutic (i.e., antifungal) class effect. Itraconzole was unique in the pattern of statistical reporting dependencies with CHF-related events which is consistent with findings from independent data sets. PMID- 23677845 TI - Clinical outcomes after myocardial revascularization according to operator training status: cohort study of 22,697 patients undergoing percutaneous coronary intervention or coronary artery bypass graft surgery. AB - AIMS: Myocardial revascularization by either coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PCI) carries the risk of serious complications. Observational data suggest that outcomes may be improved by experienced operators, but there are few studies that have analysed the relationship between mortality and primary operator grade. The aim of this study was to investigate the effect of operator grade (trainee vs. consultant) upon outcomes of revascularization procedures. METHODS AND RESULTS: This was an observational study at a tertiary cardiology centre with accredited training programmes, between 2003 and 2011. A total of 22 697 consecutive patients undergoing either CABG or PCI were included. Associations between operator grade and mortality were assessed by hazard ratios, estimated by Cox regression analyses; 6689 patients underwent CABG, whereas 16 008 underwent PCI. Trainees performed 1968 (29.4%) CABG procedures and 8502 (53.1%) PCI procedures. The proportion of procedures performed by trainees declined over time for both CABG (30.2% in 2003 vs. 26.0% in 2010) and for PCI (58.1% in 2003 vs. 44.5% in 2010). In the unadjusted Cox analysis, consultant operator grade was associated with an increased 5-year mortality after both CABG [HR: 1.26 (95% CI: 1.07-1.47)] and PCI procedures [HR: 1.34 (95% CI: 1.22-1.47)] compared with a trainee operator. However, following multiple adjustment, consultant grade was no longer associated with mortality after either procedure [CABG: HR: 1.02 (95% CI: 0.87-1.20), PCI: HR: 1.08 (95% CI: 0.98-1.20)]. CONCLUSION: There was no observed detrimental effect on patient outcomes arising from procedures undertaken by trainees working in a structured training environment compared with consultants. PMID- 23677846 TI - Prognostic significance of prolonged PR interval in the general population. AB - AIMS: Prolonged PR interval, or first degree AV block, has been traditionally regarded as a benign electrocardiographic finding in healthy individuals, until recent studies have suggested that it may be associated with increased mortality and morbidity. The aim of this study was to further elucidate clinical and prognostic importance of prolonged PR interval in a large middle-aged population with a long follow-up. METHODS AND RESULTS: We evaluated 12-lead electrocardiograms of 10 785 individuals aged 30-59 years (mean age 44 years, 52% males) recorded between 1966 and 1972, and followed the subjects for 30 +/- 11 years. Prolonged PR interval was defined as PR >200 ms, with further analysis performed using PR >=220 ms. Main endpoints were all-cause mortality, cardiovascular mortality, and sudden cardiac death, and other endpoints included hospitalizations due to cardiovascular causes. During the baseline examination, prolonged PR interval >200 ms was present in 2.1% of the subjects, but PR interval normalized to <=200 ms in 30% of these individuals during the follow-up. No increase in mortality or in hospitalizations due to coronary artery disease, heart failure, atrial fibrillation, or stroke was associated with prolonged PR interval (P = non-significant for all endpoints). These results were not changed after multivariate adjustment or in several subanalyses. CONCLUSION: In the middle-aged general population, prolonged PR interval normalizes in a substantial proportion of subjects during the time course, and it is not associated with an increased risk of all-cause or cardiovascular mortality. PMID- 23677847 TI - The relationship between excessive daytime sleepiness and depressive and anxiety disorders in women. AB - OBJECTIVE: Excessive daytime sleepiness (EDS) is a common clinical symptom that affects women more than men. However, the association of excessive sleepiness with depressive and anxiety disorders in the broader population is unclear. The aim of this study was, therefore, to examine the association between excessive daytime sleepiness as measured by the Epworth Sleepiness Scale, and depressive and anxiety disorders in a population-based sample of women. METHODS: Using the Structured Clinical Interview for DSM-IV Disorders (Non-Patient) (SCID-I/NP), 944 women aged 20-97 years (median 49 years, IQR 33-65 years) were assessed for depressive and anxiety disorders as part of the Geelong Osteoporosis Study. EDS was assessed using the Epworth Sleepiness Scale (ESS, cut-off > 10). Lifestyle factors were documented by self-report, height and weight were measured, and socioeconomic status categorised according to the Index of Relative Socio Economic Advantage and Disadvantage. RESULTS: Overall, 125 (13.2%) of the women were identified with EDS. EDS was associated with an increased likelihood for both current (OR = 2.11, 95% CI 1.10-4.06) and lifetime history (OR = 1.95, 95% CI 1.28-2.97) of depressive disorders, but not anxiety disorders, independent of age and alcohol consumption. These findings were not explained by antidepressant or sedative use, body mass index, physical activity, smoking, or socioeconomic status. CONCLUSIONS: These results suggest that excessive daytime sleepiness is associated with current and lifetime depressive, but not anxiety disorders. Clinically, this highlights the need to take into account the possible bidirectional relationship between depressive disorders and excessive sleepiness when assessing mental health issues in patients with EDS. PMID- 23677848 TI - Beliefs of Australian health professionals about the helpfulness of interventions for mental disorders: differences between professions and change over time. AB - OBJECTIVE: To assess the beliefs of general practitioners (GPs), psychiatrists and clinical psychologists about the helpfulness of different interventions for mental disorders, and to examine change in beliefs over time. METHODS: A questionnaire was mailed to 6848 GPs, psychiatrists and clinical psychologists registered with Medicare Australia. The questionnaire was based around one of six vignettes describing a person with a mental disorder: depression, depression with suicidal thoughts, early schizophrenia, chronic schizophrenia, social phobia and post-traumatic stress disorder. The depression and early schizophrenia vignettes were identical to those used in a similar survey of health professionals conducted in 1996. A range of interventions were rated for their likely helpfulness for each disorder, and consensus was defined as at least 66% of each profession rating an intervention as helpful. RESULTS: Responses were received from 1536 health professionals. A broader array of interventions were endorsed for depression than in 1996, including GPs, psychiatrists, psychologists, becoming more physically active, reading about people with similar problems and how they have dealt with them, psychotherapy, and cognitive behaviour therapy. For the schizophrenia vignettes, GPs, psychiatrists and antipsychotics were thought to be helpful by a majority of professionals. A variety of professionals, psychological treatments and lifestyle activities were endorsed for the anxiety disorders. Differences between professions were noted in beliefs about the helpfulness of antidepressants and counsellors for anxiety disorders and depression, as well as cognitive behaviour therapy for schizophrenia. CONCLUSION: Consensus across professions was reached on the helpfulness of a variety of interventions for each mental disorder, although there were some notable differences in beliefs. The study gives an updated overview of treatment beliefs for mental disorders by Australian health professionals, which can be used as a benchmark with which to compare the beliefs of the Australian public. PMID- 23677849 TI - The antioxidant activity of copper(II) (3,5-diisopropyl salicylate)4 and its protective effect against streptozotocin-induced diabetes mellitus in rats. AB - Oxidative stress has been suggested as a potential contributor to the development of diabetic complications. In this study, we investigated the protective effect of a strong antioxidant copper complex against streptozotocin (STZ)-induced diabetes in animals. Out of four copper complexes used, copper(II) (3,5 diisopropyl salicylate)4 (Cu(II)DIPS) was found to be the most potent antioxidant copper complex. Pretreatment with Cu(II)DIPS (5 mg/kg) twice a week prior to the injection of streptozotocin (50 mg/kg) has reduced the level of hyperglycemia by 34 % and the mortality rate by 29 %. Injection of the same dosage of the ligand 3,5-diisopropyl salicylate has no effect on streptozotocin-induced hyperglycemia. The same copper complex has neither hypoglycemic activity when injected in normal rats nor antidiabetic activity when injected in STZ-induced diabetic rats. The protective effect of Cu(II)DIPS could be related to its strong antioxidant activity compared to other copper complexes median effective concentration (MEC) = 23.84 MUg/ml and to Trolox MEC = 29.30 MUg/ml. In addition, it reduced serum 8 hydroxy-2'-deoxyguanosine, a biomarker of oxidative DNA damage, by 29 %. This effect may explain why it was not effective against diabetic rats, when beta Langerhans cells were already destroyed. Similar protective activities were reported by other antioxidants like Trolox. PMID- 23677850 TI - Influence of different amounts and sources of selenium supplementation on performance, some blood parameters, and nutrient digestibility in lambs. AB - Two trials were conducted in a 2 * 2 + 1 factorial arrangement based on a completely randomized design to evaluate the effects of different sources of selenium (Se) on performance, blood metabolites, and nutrient digestibility in male lambs on a barley-based diet. The first trial lasted for 70 days and consisted of 30 lambs (35.6 +/- 2.6 kg mean body weight, about 4-5 months of age) which were randomly allotted to five treatments including: (1) basal diet (containing 0.06 mg Se/kg DM; control) without supplementary Se, (2) basal diet + 0.20 mg/kg Se as sodium selenite (SeS 0.20), (3) basal diet + 0.40 mg/kg Se as sodium selenite (SeS 0.40), (4) basal diet + 0.20 mg/kg Se as selenium yeast (SeY 0.20), and (5) basal diet + 0.40 mg/kg Se as selenium yeast (SeY 0.40). For the second trial, four lambs from each group of experiment 1 were randomly allocated to individual metabolic cages for 14 days to measure the effects of dietary Se on nutrient digestibility. The results revealed that there were no significant differences for average daily gain, average daily feed intake, feed/gain ratio, hematological parameters (packed cell volume, red blood cell, white blood cell, and hemoglobin values), serum total protein, albumin, globulin, aspartate amino transferase, alkaline phosphatase, and creatine phosphokinase due to supplementation of different amounts and sources of Se in lambs. Dietary Se supplementation significantly improved (P < 0.001) glutathione peroxidase activity in blood. Furthermore, at the end of the trial, serum tri-iodothyronine (T3) amount also increased (P < 0.05), while serum thyroxine (T4) amount decreased (P < 0.05). Digestibility of dry matter, organic matter, crude protein, neutral detergent fiber, and acid detergent fiber increased (P < 0.05) by Se yeast supplementation. It may be concluded that supplementation of Se in lambs had no significant effect on performance and blood hematology, but increased blood glutathione peroxidase activity and serum T3 amount and decreased serum T4 amount as compared to non-supplemented control lambs. Furthermore, Se yeast improved nutrient digestibility in lambs. PMID- 23677851 TI - Nonylphenol-induced apoptotic cell death in mouse TM4 Sertoli cells via the generation of reactive oxygen species and activation of the ERK signaling pathway. AB - Nonylphenol (NP), a representative endocrine disruptor, interferes with reproductive function in aquatic organisms and animals. Although many previous studies have focused on apoptotic cell death by NP, the fundamental mechanism of NP on apoptosis remains poorly understood. Here, we investigated the molecular mechanism on NP-induced apoptotic cell death in mouse TM4 Sertoli cells. To evaluate NP treatment on cell viability, formazan and lactate dehydrogenase (LDH) assays were performed. Results indicate that NP reduced cell viability and increased the release of LDH in dose- and time-dependent manners. The reduction of cell viability by NP treatment appeared to involve necrosis as well as apoptosis based on nuclear fragmentation, an increase in the sub G1 population, and the detection of poly(ADP ribose) polymerase and caspase-3 cleavage. Additionally, the anti-apoptotic protein Bcl-2 diminished, whereas the pro apoptotic protein Bax increased in a time-dependent manner. Note that NP-induced apoptotic cell death was enhanced by the generation of reactive oxygen species (ROS) and activation of extracellular signal-regulated kinase (ERK) signaling. Pretreatment with N-acetylcysteine, an antioxidant, attenuated NP-induced apoptotic cell death. Moreover, NP caused a transient activation of the MAPK pathway. In particular, NP-induced cell death was significantly suppressed by U0126, a specific inhibitor of ERK. Taken together, our results suggest that NP induces apoptosis in mouse TM4 Sertoli cells via ROS generation and ERK activation. PMID- 23677852 TI - One-pot, template-free synthesis of Pd-Pt single-crystalline hollow cubes with enhanced catalytic activity. AB - Hollow structures have attracted ever-growing interest owing to their various excellent properties. However, a facile strategy for their fabrication is still desired. Herein, Pd-Pt alloy with three different morphologies, that is, cubes, hollow cubes, and truncated octahedrons, is synthesized by using a one-pot, template-free method. The mechanism and dynamics of this system is also studied in detail. In particular, the hollow cubic structure represents enhanced catalytic activity in both coupling reactions and in the electrochemical oxidation of formic acid. PMID- 23677853 TI - Cloning and heterologous expression of the aurachin RE biosynthesis gene cluster afford a new cytochrome P450 for quinoline N-hydroxylation. AB - Aurachin RE is a prenylated quinoline antibiotic that was first isolated from the genus Rhodococcus. It shows potent antibacterial activity against a variety of Gram-positive bacteria. Here we have identified a minimal biosynthesis gene cluster for aurachin RE in Rhodococcus erythropolis JCM 6824 by using random transposon mutagenesis and heterologous production. The Rhodococcus aurachin (rau) gene cluster consists of genes encoding cytochrome P450 (rauA), prenyltransferase, polyketide synthase, and farnesyl pyrophosphate synthase, as well as others including genes involved in regulation and transport. Markerless gene disruption of rauA resulted in the complete loss of aurachin RE production and in the accumulation of a new aurachin derivative lacking the N-hydroxy group. When the recombinant RauA was expressed in Escherichia coli, it catalyzed N hydroxylation of the derivative to form aurachin RE. This study establishes the biosynthetic pathway of aurachin RE and provides experimental evidence for the role of P450 RauA in catalyzing N-hydroxylation of the quinoline ring, which is indispensable for the antibacterial activity of aurachin RE. PMID- 23677854 TI - Three-dimensional kinematics of the talocrural and subtalar joints during drop landing. AB - The bones and soft tissues of the foot act as a shock attenuator and the relative bony motions of the talocrural and subtalar joints are the subject of research interest for their roles in lower extremity pathology. Despite this interest, little information exists on the precise in vivo talocrural and subtalar joint kinematics during dynamic activities. Therefore, the purpose of this study was to quantify the three-dimensional kinematics of the talocrural and subtalar joints during landing by using single-plane fluoroscopic imaging and shape matching techniques. Three-dimensional bone positions for 6 subjects during landing from a 10 cm height were determined by using 3D-2D model-image registration techniques. The primary talocrural joint motion after toe contact was dorsiflexion with rotation ranges averaging 12 degrees +/- 7 degrees dorsiflexion, 2 degrees +/- 2 degrees eversion, and 3 degrees +/- 2 degrees internal rotation. The subtalar joint exhibited similar patterns of increased dorsiflexion, eversion, and external rotation up to 150 ms after landing. The angular changes were 5 degrees +/- 3 degrees dorsiflexion, 7 degrees +/- 3 degrees eversion, and 6 degrees +/- 2 degrees external rotation. This study contributes to the quantitative understanding of the function of the normal talocrural and subtalar joints and can be used for comparison with data obtained from injured feet. PMID- 23677855 TI - Social adversity experience and blood pressure control following antihypertensive medication use in a community sample of older adults. AB - BACKGROUND: Psychosocial stress is a risk factor for hypertension and has been shown to affect response to treatment for psychiatric illnesses. PURPOSE: We investigate the relationship between a history of social adversity experience and blood pressure control following antihypertensive medication use. METHODS: A total of 1,186 participants selected from the European Prospective Investigation into Cancer-Norfolk study (531 men and 655 women, aged 42 to 80 years) had attended two health checks at which blood pressure measurements were taken; were taking antihypertensive medication at the second, but not the first health check; and had completed a questionnaire assessment of their social and psychological circumstances which included details of traumatic experiences in childhood and of adverse life events, long-term difficulties, and perceived stress in adulthood. RESULTS: Experience of recent loss events in adulthood was associated with a smaller reduction in systolic blood pressure after starting hypertension treatment (beta = 1.78, 95 % confidence interval 0.15-3.40, per life event), independently of age, sex, preexisting health conditions, cigarette smoking history, alcohol consumption, physical activity, and obesity. CONCLUSION: Results from this study suggest that stress caused by recent losses may be associated with reduced effectiveness of treatment for hypertension. Subject to replication, these findings may help determine the specific physiological mechanisms by which medication treatment effectiveness is affected by stress. PMID- 23677856 TI - Engineering insights for multiplexed real-time nucleic acid sequence-based amplification (NASBA): implications for design of point-of-care diagnostics. AB - BACKGROUND: Nucleic acid sequence-based amplification (NASBA) offers huge potential for low-cost, point-of-care (POC) diagnostic devices, but has been limited by high false-positive rates and the challenges of primer design. OBJECTIVE: We offer a systematic analysis of NASBA design with a view toward expanding its applicability. METHODS: We examine the parameters that effect dimer formations, and we provide a framework for designing NASBA primers that will reduce false-positive results and make NASBA suitable for more POC diagnostic applications. Then we compare three different oligonucleotide sets to examine (1) the inhibitory effect of dimer formations, (2) false positives with poorly designed primers, and (3) the effect of beacon target location during real-time NASBA. The required T7 promoter sequence adversely affects the reaction kinetics, although the common abridged sequence can improve kinetics without sacrificing accuracy. RESULTS: We demonstrate that poorly designed primers undergo real-time exponential amplification in the absence of target RNA, resulting in false positives with a time to half of the peak value (t(1/2)) of 50 min compared to 45 min for true positives. Redesigning the oligonucleotides to avoid inhibitory dimers eliminated false positives and reduced the true positive t(1/2) by 10 min. Finally, we confirm the efficacy of two molecular beacon design schemes and discuss their multiplexing utility in two clinical scenarios. CONCLUSION: This study provides a pathway for using NASBA in developing POC diagnostic assays. PMID- 23677857 TI - Do MDR1 and SLCO1B1 polymorphisms influence the therapeutic response to atorvastatin? A study on a cohort of Egyptian patients with hypercholesterolemia. AB - BACKGROUND: Statins are among the most prescribed drugs worldwide to reduce the risk of cardiovascular events. Interindividual variability in drug response is a major clinical problem and is of concern during drug development. Statins, such as atorvastatin, are taken orally and access to their site of action in the liver is greatly facilitated by both intestinal and hepatic transporters. OBJECTIVE: To examine the impact of polymorphisms of the multidrug resistance 1(MDR1) and solute carrier organic anion transporter 1B1 (SLCO1B1) genes on the therapeutic response to atorvastatin as well as the presence of gender-gene interaction. METHODS: Serum lipid levels were determined at baseline and 4 weeks following 40 mg/day atorvastatin treatment in 50 Egyptian hypercholesterolemic patients (27 males and 23 females). Identification of MDR1 C3435T and SLCO1B1 A388G gene polymorphisms was performed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Treatment with atorvastatin resulted in a mean reduction of total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and triglyceride (TG) of 8.7 %, 9.2 %, and 4.1 %, respectively, and a mean increase of high density lipoprotein cholesterol (HDL C) of 1 %. Baseline and post-treatment HDL-C levels were statistically significantly higher in the MDR 1 TT homozygotes when compared with the CC wild type. The percentage change in TC, LDL-C, TG, and HDL-C did not show any statistically significant difference when compared among the different MDR 1 C3435T or SLCO1B1 A388G genotypes. The SLCO1B1 GG homozygotes showed a decrease in TG, whereas there was an increase in TG following atorvastatin treatment in AA and AG carriers in females; however, males did not show any statistically significant difference. There was no statistically significant association between either the coronary artery disease (CAD) risk factors (family history of CAD, hypertension, diabetes mellitus, smoking) or concomitant medications with the percentage change in different lipid parameters. CONCLUSION: MDR1 C3435T was associated with baseline and post-treatment HDL-C variation. SLCO1B1 A388G showed gender-related effects on TG change following atorvastatin treatment. None of the comorbidities or the concomitant medications influenced the percentage change of lipid parameters following atorvastatin treatment. The results of this study may lead to an improved understanding of the genetic determinants of lipid response to atorvastatin treatment. PMID- 23677858 TI - Pharmacokinetic and pharmacodynamic interaction of nadolol with itraconazole, rifampicin and grapefruit juice in healthy volunteers. AB - To evaluate effects of itraconazole, rifampicin and grapefruit juice on pharmacokinetics and pharmacodynamics of a hydrophilic non-selective beta adrenoceptor blocker nadolol, we conducted an open-label, four-way crossover study in 10 healthy male volunteers. A single oral dose of 30 mg nadolol was administered with water (control), itraconazole (100 mg), or grapefruit juice (300 mL), or after a 6-day pretreatment with rifampicin (450 mg/day). Plasma concentrations and urinary excretions of nadolol were measured over 48 hours after its dosing. Systolic and diastolic blood pressures and pulse rate were periodically recorded after nadolol administration as pharmacodynamic parameters. Itraconazole increased the peak plasma concentration and the area under the plasma concentration-time curve (AUC0-infinity ) of nadolol by 468% and 224% of control, respectively (P < .001). A slight, but not statistically significant, decrease in AUC0-infinity of nadolol was observed in rifampicin and grapefruit juice phases as compared to control. Elimination half-life for nadolol did not differ among the four phases. During itraconazole phase, nadolol reduced pharmacodynamic parameters to a greater extent than the other phases. These results suggest that itraconazole substantially increases the oral availability of nadolol possibly by the inhibition of intestinal P-glycoprotein, whereas grapefruit juice has little effect on nadolol pharmacokinetics. PMID- 23677859 TI - Osteoblasts display different responsiveness to TRAIL-induced apoptosis during their differentiation process. AB - Apoptosis can occur throughout the life span of osteoblasts (OBs), beginning from the early stages of differentiation and continuing throughout all stages of their working life. Here, we investigated the effects of tumor necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL) on normal human OBs showing for the first time that the expression of TRAIL receptors is modulated during OB differentiation. In particular, the TRAIL receptor ratio was in favor of the deaths because of the low expression of DcR2 in undifferentiated OBs, differently it was shifted toward the decoys in differentiated ones. Undifferentiated OBs treated with TRAIL showed reduced cell viability, whereas differentiated OBs displayed TRAIL resistance. The OB sensitiveness to TRAIL was due to the up regulation of DR5 and the down-regulation of DcR2. The main death receptor involved in TRAIL-reduced OB viability was DR5 as demonstrated by the rescue of cell viability observed in the presence of anti-DR5 neutralizing antibody. Besides the ratio of TRAIL receptors, the sensitivity of undifferentiated OBs to TRAIL-cytotoxic effect was also associated with low mRNA levels of intracellular anti-apoptotic proteins, such as cFLIP, the activation of caspase-8 and -3, as well as the DNA fragmentation. This study suggests that apoptotic effect exerted by TRAIL/TRAIL-receptor system on normal human OB is strictly dependent upon cell differentiation status. PMID- 23677860 TI - Influence of amino acids Shiff bases on irradiated DNA stability in vivo. AB - To reveal protective role of the new Mn(II) complexes with Nicotinyl-L-Tyrosinate and Nicotinyl-L-Tryptophanate Schiff Bases against ionizing radiation. The DNA of the rats liver was isolated on 7, 14, and 30 days after X-ray irradiation. The differences between the DNA of irradiated rats and rats pre-treated with Mn(II) complexes were studied using the melting, microcalorimetry, and electrophoresis methods. The melting parameters and the melting enthalpy of rats livers DNA were changed after the X-ray irradiation: melting temperature and melting enthalpy were decreased and melting interval was increased. These results can be explained by destruction of DNA molecules. It was shown that pre-treatment of rats with Mn(II) complexes approximates the melting parameters to norm. Agarose gel electrophoresis data confirmed the results of melting studies. The separate DNA fragments were revealed in DNA samples isolated from irradiated animals. The DNA isolated from animals pre-treated with the Mn(II) chelates had better electrophoretic characteristics, which correspond to healthy DNA. Pre-treatment of the irradiated rats with Mn(II)(Nicotinil-L-Tyrosinate) and Mn(II)(Nicotinil-L Tryptophanate)2 improves the DNA characteristics. PMID- 23677862 TI - Early neonatal feeding is common and associated with subsequent breastfeeding behavior in rural Bangladesh. AB - Exclusive breastfeeding of newborns, a practice recommended by WHO, is hindered in many countries by practices such as prelacteal feeding (feeding other foods before breast milk is fed to infants). This paper describes maternal and infant characteristics and trends over time associated with early neonatal feeding (ENF) in Bangladesh. The analysis used data from 24,992 participants in a randomized controlled trial supplementing vitamin A and beta-carotene to women in northwestern rural Bangladesh. A majority of newborns (89.2%) were fed substances other than breast milk in the first 3 d of life. Early neonatal feeding practices were found to be significantly associated with lower maternal education, higher gravidity, lower socioeconomic status, and younger maternal age. A perceived inability to suckle normally after birth was closely related to the risk of an infant being fed a food other than breast milk in the first 3 d of life [OR = 0.09 (95% CI: 0.08, 0.11)]. Only 18.8% of newborns fed an early neonatal food were exclusively breastfed between 3 d and 3 mo postpartum compared with 70.6% of those not fed an early neonatal food during this period (P < 0.05). Early neonatal feeding practices should be addressed when scaling-up exclusive breastfeeding in South Asia. Maternal education, antenatal care, and support during labor and delivery may help reduce ENF and promote exclusive breastfeeding. PMID- 23677864 TI - Dietary resistant starch prevents urinary excretion of 25-hydroxycholecalciferol and vitamin D-binding protein in type 1 diabetic rats. AB - Diabetes is a rapidly growing epidemic affecting millions of Americans and has been implicated in a number of devastating secondary complications. We previously demonstrated that type 2 diabetic rats exhibit vitamin D deficiency due to aberrant megalin-mediated endocytosis and excessive urinary excretion of 25 hydroxycholecalciferol (25D3) and vitamin D-binding protein (DBP). Here, we examined whether a model of type 1 diabetes [T1D; streptozotocin (STZ)-treated Sprague-Dawley rats] would similarly excrete abnormally high concentrations of 25D3 and DBP due to renal damage and compromised expression of megalin and its endocytic partner, disabled-2 (Dab2). Moreover, we tested whether feeding diabetic rats starch that is resistant to digestion could alleviate these abnormalities. Control (n = 12) rats were fed a standard, semipurified diet (AIN 93G) containing 55% total dietary starch and STZ-treated rats were fed the AIN 93G diet (n = 12) or a diet containing 55% high-amylose maize that is partially resistant to digestion [20% total dietary resistant starch (RS); n = 12] for 2 and 5 wk. The RS diet attenuated weight loss and polyuria in STZ-treated rats. Histology and immunohistochemistry revealed that dietary RS also attenuated the loss of Dab2 expression in renal proximal tubules. Moreover, urinary concentrations of both 25D3 and DBP were elevated ~10-fold in STZ-treated rats (5 wk post STZ injection), which was virtually prevented by the RS. We also observed a ~1.5-fold increase in megalin mRNA expression in STZ-treated rats, which was attenuated by feeding rats the RS diet for 2 wk. Taken together, these studies indicate that consumption of low-glycemic carbohydrates can attenuate disruption of vitamin D homeostasis in T1D through the rescue of megalin-mediated endocytosis in the kidney. PMID- 23677863 TI - Nutrient supplementation with n3 polyunsaturated fatty acids, lutein, and zeaxanthin decrease A2E accumulation and VEGF expression in the retinas of Ccl2/Cx3cr1-deficient mice on Crb1rd8 background. AB - The Age-Related Eye Diseases Study 2 (AREDS2) clinical trial is assessing the effects of higher dietary xanthophyll (lutein and zeaxanthin) and long-chain n3 polyunsaturated fatty acid (LCPUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) intake on progression to advanced age-related macular degeneration (AMD). This study's purpose was to examine the retinal effects of the AREDS2 formulation on Chemokine (C-C motif) ligand 2 (Ccl2(-/-))/CX3C chemokine receptor 1 (Cx3cr1(-/-)) mice on Crumbs homolog 1 retinal degeneration phenotype 8 (Crb1(rd8)) background (DKO), which develop focal retinal lesions with certain features similar to AMD. DKO and C57BL/6N rd8 background mice (WT) were bred and randomized into 4 groups. Two groups, WT mice on AREDS2 diet (A-WT) and DKO mice on AREDS2 diet (A-DKO), were supplemented daily with 1.76 MUmol of lutein, 35.1 MUmol of zeaxanthin, 215 MUmol EPA, and 107 MUmol of DHA, and 2 control groups, WT mice on control diet (C-WT) and DKO mice on control diet (C DKO), were fed an isocaloric diet. All mice had monthly fundus photos and were killed after 3 mo for biochemical and histologic analyses. After 3 mo, 81% of A DKO mice had lesion regression compared with 25% of C-DKO mice (P < 0.05). Toxic retinal 2-[2,6-dimethyl-8-(2,6,6-trimethyl-1-cyclohexen-1-yl)-1E,3E,5E,7E octatetra-enyl]-1-(2-hydroxyethyl)-4-[4-methyl-6(2,6,6-trimethyl-1-cyclohexen-1 yl) 1E,3E,5E,7E-hexatrienyl]-pyridinium (A2E) concentrations were significantly lower in A-DKO compared with C-DKO mice. The outer nuclear layer thickness in A DKO mice was significantly greater than that in C-DKO mice. Retinal expression of inducible nitric oxide synthase (iNos) tumor necrosis factor-alpha (Tnf-alpha), Cyclooxygenase-2 (Cox-2), interleukin1beta (IL-1beta), and vascular endothelial growth factor (Vegf) was significantly lower in A-DKO compared with C-DKO mice. Xanthophylls and LCPUFAs have antiinflammatory, neuroprotective, and antiangiogenic properties. Our data provide potential mechanisms by which the AREDS2 formula has a protective effect on retinal lesions in DKO mice. PMID- 23677866 TI - Shock pathophysiology. AB - Shock, defined as the state where oxygen delivery to tissues is inadequate for the demand, is a common condition in veterinary patients and has a high mortality rate if left untreated. The key to a successful outcome for any patient in shock involves having a clear understanding of the pathophysiology and compensatory mechanisms associated with shock. This understanding allows more efficient identification of patients in shock based on clinical signs and timely initiation of appropriate therapies based on the type and stage of shock identified. PMID- 23677865 TI - Porcine serum can be biofortified with selenium to inhibit proliferation of three types of human cancer cells. AB - Our objectives were to determine if porcine serum could be enriched with selenium (Se) by feeding pigs with high concentrations of dietary Se and if the Se biofortified serum inhibited proliferation of 3 types of human cancer cells. In Expt. 1, growing pigs (8 wk old, n = 3) were fed 0.02 or 3.0 mg Se/kg (as sodium selenite) for 16 wk and produced serum with 0.5 and 5.4 MUmol/L Se, respectively. In Expt. 2, growing pigs (5 wk old, n = 6) were fed 0.3 or 1.0 mg Se/kg (as Se enriched yeast) for 6 wk and produced serum with 2.6 and 6.2 MUmol/L Se, respectively. After the Se-biofortified porcine sera were added at 16% in RPMI 1640 to treat NCI-H446, DU145, and HTC116 cells for 144 h, they decreased (P < 0.05) the viability of the 3 types of human cancer cells by promoting apoptosis, compared with their controls. This effect was replicated only by adding the appropriate amount of methylseleninic acid to the control serum and was mediated by a downregulation of 8 cell cycle arrest genes and an upregulation of 7 apoptotic genes. Along with 6 previously reported selenoprotein genes, selenoprotein T (Selt), selenoprotein M (Selm), selenoprotein H (Selh), selenoprotein K (Selk), and selenoprotein N (Sepn1) were revealed to be strongly associated with the cell death-related signaling induced by the Se-enriched porcine serum. In conclusion, porcine serum could be biofortified with Se to effectively inhibit the proliferation of 3 types of human cancer cells and the action synchronized with a matrix of coordinated functional expression of multiple selenoprotein genes. PMID- 23677867 TI - Canine struvite urolithiasis. AB - Struvite calculi, composed of magnesium ammonium phosphate, have existed for thousands of years in human medicine and are a leading cause of calculi in companion animals. Struvite stones have also been called urease, infection induced, phosphatic, and triple phosphate stones. They are the most common uroliths in dogs, in which most cases of struvite urolithiasis are associated with infection. Management of struvite urolithiasis requires a multimodal approach that addresses the presence of the urolith(s) and associated infection while identifying risk factors that predispose to the development of infection. PMID- 23677868 TI - Siglec-15 regulates osteoclast differentiation by modulating RANKL-induced phosphatidylinositol 3-kinase/Akt and Erk pathways in association with signaling Adaptor DAP12. AB - Siglecs are a family of sialic acid-binding immunoglobulin-like lectins that regulate the functions of cells in the innate and adaptive immune systems through glycan recognition. Here we show that Siglec-15 regulates osteoclast development and bone resorption by modulating receptor activator of nuclear factor kappaB ligand (RANKL) signaling in association with DNAX-activating protein 12 kDa (DAP12), an adaptor protein bearing an immunoreceptor tyrosine-based activation motif (ITAM). Among the known Siglecs expressed in myeloid lineage cells, only Siglec-15 was upregulated by RANKL in mouse primary bone marrow macrophages. Siglec-15-deficient mice exhibit mild osteopetrosis resulting from impaired osteoclast development. Consistently, cells lacking Siglec-15 exhibit defective osteoclast development and resorptive activity in vitro. RANKL-induced activation of phosphatidylinositol 3-kinase (PI3K)/Akt and Erk pathways were impaired in Siglec-15-deficient cells. Retroviral transduction of Siglec-15-null osteoclast precursors with wild-type Siglec-15 or mutant Siglec-15 revealed that the association of Siglec-15 with DAP12 is involved in the downstream signal transduction of RANK. Furthermore, we found that the ability of osteoclast formation is preserved in the region adjacent to the growth plate in Siglec-15 deficient mice, indicating that there is a compensatory mechanism for Siglec-15 mediated osteoclastogenesis in the primary spongiosa. To clarify the mechanism of this compensation, we examined whether osteoclast-associated receptor (OSCAR)/Fc receptor common gamma (FcRgamma) signaling, an alternative ITAM-mediated signaling pathway to DAP12, rescues impaired osteoclastogenesis in Siglec-15 deficient cells. The ligands in type II collagen activate OSCAR and rescue impaired osteoclastogenesis in Siglec-15-deficient cells when cultured on bone slices, indicating that Siglec-15-mediated signaling can be compensated for by signaling activated by type II collagen and other bone matrix components in the primary spongiosa. Our findings indicate that Siglec-15 plays an important role in physiologic bone remodeling by modulating RANKL signaling, especially in the secondary spongiosa. PMID- 23677869 TI - Poly-epsilon-caprolactone scaffold and reduced in vitro cell culture: beneficial effect on compaction and improved valvular tissue formation. AB - Tissue-engineered heart valves (TEHVs), based on polyglycolic acid (PGA) scaffolds coated with poly-4-hydroxybutyrate (P4HB), have shown promising in vivo results in terms of tissue formation. However, a major drawback of these TEHVs is compaction and retraction of the leaflets, causing regurgitation. To overcome this problem, the aim of this study was to investigate: (a) the use of the slowly degrading poly-epsilon-caprolactone (PCL) scaffold for prolonged mechanical integrity; and (b) the use of lower passage cells for enhanced tissue formation. Passage 3, 5 and 7 (P3, P5 and P7) human and ovine vascular-derived cells were seeded onto both PGA-P4HB and PCL scaffold strips. After 4 weeks of culture, compaction, tissue formation, mechanical properties and cell phenotypes were compared. TEHVs were cultured to observe retraction of the leaflets in the native like geometry. After culture, tissues based on PGA-P4HB scaffold showed 50-60% compaction, while PCL-based tissues showed compaction of 0-10%. Tissue formation, stiffness and strength were increased with decreasing passage number; however, this did not influence compaction. Ovine PCL-based tissues did render less strong tissues compared to PGA-P4HB-based tissues. No differences in cell phenotype between the scaffold materials, species or cell passage numbers were observed. This study shows that PCL scaffolds may serve as alternative scaffold materials for human TEHVs with minimal compaction and without compromising tissue composition and properties, while further optimization of ovine TEHVs is needed. Reducing cell expansion time will result in faster generation of TEHVs, providing more rapid treatment for patients. PMID- 23677870 TI - Functional MRI in conscious rats using a chronically implanted surface coil. AB - PURPOSE: To establish procedures for functional MRI (fMRI) in rats without the need for anesthetic agents. MATERIALS AND METHODS: Rats were trained to habituate to restraint in a harness and scanner noise. Under anesthesia, rats were then prepared with a cranial implant that permitted stabilization of the head during subsequent imaging experiments. The cranial implant included an radiofrequency (RF) coil that was used to transmit and receive radiofrequency signals during imaging. Further training was then conducted to habituate the animals to head fixation whilst in the MR scanner. RESULTS: Using this method, we were able to successfully and repeatedly record BOLD fMRI responses to hypercapnia and whisker stimulation in awake rats. Electrical stimulation of the whisker pad produced a ~7% increase in BOLD signal in the corresponding barrel cortex as well as adjacent negative BOLD responses, whilst hypercapnia produced larger increases in BOLD signal amplitude. CONCLUSION: This methodology leaves the face and limbs free from obstruction, making possible a range of behavioral or sensory stimulation protocols. Further development of this animal model could enable traditional behavioral neuroscience techniques to be combined with modern functional neuroimaging. PMID- 23677871 TI - Low serum 25-hydroxyvitamin D level and risk of upper respiratory tract infection in children and adolescents. AB - BACKGROUND: Vitamin D may be important for immune function. Studies to date have shown an inconsistent association between vitamin D and infection with respiratory viruses. The purpose of this study was to determine if serum 25 hydroxyvitamin D (25(OH)D) was associated with laboratory-confirmed viral respiratory tract infections (RTIs) in children. METHODS: Serum 25(OH)D levels were measured at baseline and children from Canadian Hutterite communities were followed prospectively during the respiratory virus season. Nasopharyngeal specimens were obtained if symptoms developed and infections were confirmed using polymerase chain reaction. The association between serum 25(OH)D and time to laboratory-confirmed viral RTI was evaluated using a Cox proportional hazards model. RESULTS: Seven hundred forty-three children aged 3-15 years were followed between 22 December 2008 and 23 June 2009. The median serum 25(OH)D level was 62.0 nmol/L (interquartile range, 51.0-74.0). A total of 229 participants (31%) developed at least 1 laboratory-confirmed viral RTI. Younger age and lower serum 25(OH)D levels were associated with increased risk of viral RTI. Serum 25(OH)D levels <75 nmol/L increased the risk of viral RTI by 50% (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.10-2.07, P = .011) and levels <50 nmol/L increased the risk by 70% (HR, 1.67; 95% CI, 1.16-2.40, P = .006). CONCLUSIONS: Lower serum 25(OH)D levels were associated with increased risk of laboratory confirmed viral RTI in children from Canadian Hutterite communities. Interventional studies evaluating the role of vitamin D supplementation to reduce the burden of viral RTIs are warranted. PMID- 23677872 TI - Readmission following hospitalization for pneumonia: the impact of pneumonia type and its implication for hospitals. AB - BACKGROUND: Readmission rates following discharge after pneumonia are thought to represent the quality of care. Factors associated with readmission, however, remain poorly described. It is unclear if readmission rates vary based on pneumonia type. METHODS: We retrospectively identified adults admitted to an index hospital with non-nosocomial pneumonia (January through December 2010) and who survived to discharge. We only included patients with bacterial evidence of infection. Readmission in the 30 days following discharge to any of 9 hospitals comprising the index hospital's healthcare system served as the primary end point. We recorded demographics, severity of illness, comorbidities, and infection-related factors. We noted whether the patient had healthcare-associated pneumonia (HCAP) versus community-acquired pneumonia. We utilized logistic regression analysis to determine factors independently associated with readmission. RESULTS: The cohort included 977 subjects; 78.9% survived to discharge. The readmission rate equaled 20%. Neither disease severity nor the rate of initially inappropriate antibiotic therapy correlated with readmission. Subjects with HCAP were 7.5 (95% confidence interval [CI], 3.6-15.7) times more likely to be readmitted. Four HCAP criteria were independently associated with readmission: admission from long-term care (adjusted odds ratio [AOR], 2.2 [95% CI, 1.4-3.4]); immunosuppression (AOR, 1.9 [95% CI, 1.3-2.9]); prior antibiotics (AOR, 1.7 [95% CI, 1.2-2.6]); and prior hospitalization (AOR, 1.7 [95% CI, 1.1 2.5]). CONCLUSIONS: Readmission for pneumonia is common but varies based on pneumonia type. The variables associated with readmission do not reflect factors that hospitals directly control. Use of one rule to guide payment that fails to account for HCAP and the HCAP criteria on readmission seems inappropriate. PMID- 23677873 TI - Editorial commentary: "excess readmissions" for pneumonia: a dilemma with a penalty. PMID- 23677876 TI - Abstracts of the RANZCP (Royal Australian and New Zealand College of Psychiatrists) 2013 Congress. May 26-30, 2013. Sydney, Australia. PMID- 23677874 TI - Relapse after treatment of pediatric Hodgkin lymphoma: outcome and role of surveillance after end of therapy. AB - BACKGROUND: The outcome of treatment for pediatric Hodgkin lymphoma (HL) is excellent using chemotherapy and radiation. However, a minority of patients will relapse after treatment, but additional therapy achieves durable second remission in many cases. The optimal surveillance strategy after modern therapy for HL has not been well defined. PROCEDURES: We reviewed the outcomes of pediatric patients with HL treated between 1990 and 2006 to determine the primary event that led to the detection of relapse. We determined the probability of relapse detection by routine follow-up procedures, including history, physical examination, laboratory tests, and imaging, and determined the impact of each of these screening methods on the likelihood of survival after relapse. RESULTS: Relapse occurred in 64 of 402 evaluable patients (15.9%) at a median of 1.7 years from the time of diagnosis. The majority of relapses (60%) were diagnosed at a routine visit, and patient complaint was the most common initial finding that led to a diagnosis of relapse (47% of relapses). An abnormal finding on physical examination was the primary event in another 17% of relapses, and imaging abnormalities led to the diagnosis in the remaining 36%. Laboratory abnormalities were never the primary finding. The method of detection of relapse and timing (whether detected at a routine visit or an extra visit) did not impact survival. CONCLUSIONS: In pediatric HL, most relapses are identified through history and physical examination. Frequent imaging of asymptomatic patients does not appear to impact survival and is probably not warranted. PMID- 23677877 TI - Case of retroesophageal right subclavian artery, with special reference to the second intercostal artery, retroesophageal right vertebral artery, and thoracic duct. AB - We report a case of retroesophageal right subclavian artery identified in a 59 year-old Japanese female during routine dissection in Nagasaki University School of Medicine. This kind of variation is relatively rare; however, reports of such cases have accumulated. We paid attention to the intersegmental arteries and above all, the second intercostal artery. On the other hand, there have been reports of a retroesophageal right vertebral artery, although such cases are extremely rare. It is considered that both retroesophageal arteries are formed by similar mechanisms. In other words, the distal part of the right dorsal aorta remained in such cases. However, in the case of a retroesophageal right vertebral artery, there might be the possibility of intercostal arteries developing into the vertebral artery, and we discuss such points here. PMID- 23677879 TI - Add another killer for interfered vascular function: natural killer cells produced interferon-gamma is a cue. PMID- 23677878 TI - Interpreting inflammation: smooth muscle positional identity and nuclear factor kappaB signaling. PMID- 23677880 TI - Macrophage polarization at the crossroad between HIV-1 infection and cancer development. AB - Mononuclear phagocytes play a fundamental role in the tissue homeostasis and innate defenses against viruses and other microbial pathogens. In addition, they are likely involved in several steps of cancer development. Circulating monocytes and tissue macrophages are target cells of viral infections, including human cytomegalovirus, human herpes virus 8, and the HIV, and alterations of their functional and phenotypic properties are likely involved in many tissue degenerative diseases, including atherosclerosis and cancer. Different tissue microenvironments as well as their pathological alterations can profoundly affect the polarization state of macrophages toward the extreme phenotypes conventionally termed M1 and M2. Thus, targeting disease-associated macrophages is considered a potential approach particularly in the context of cancer associated tumor-associated macrophages, supporting malignant cell growth and progression toward a metastatic phenotype. Of note is the fact that tumor associated macrophages isolated from established tumors display phenotypic and functional features similar to those of in vitro-derived M2-polarized cells. Concerning HIV-1 infection, viral eradication strategies in the context of combination antiretroviral therapy should also consider the possibility to deplete, at least transiently, certain mononuclear phagocytes subsets, although the possibility of distinguishing those that are either infected or pathogenically altered remains a goal of future research. In the present review, we will focus on the recent literature concerning the role of human macrophage polarization in viral infections and cancer. PMID- 23677886 TI - Radix Puerariae: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. AB - Radix Puerariae has been traditionally used for the treatment of diarrhea, acute dysentery, deafness and cardiovascular diseases. Yege (Gegen or Radix Puerariae lobatae), the dried root of Pueraria lobata (Wild.) Ohwi, has been widely used in China and, to a lesser extent, in Japan, Korea, and the United States. Although they have been classified into different categories in Chinese Pharmacopoeia, Yege is often used interchangeably in practice with Fenge (Radix Puerariae thomsonii), which is the dried root of Pueraria thomsonii Benth. Among various commercially available products of Radix Puerariae, injection of puerarin, the major isoflavone from Radix Puerariae, has been most widely used as a vasodilator for the treatment of angina and myocardial infarction. Considering the extensive clinical usage and recent alert of fatal herb-drug interaction of Radix Puerariae, the current review is proposed to cover its traditional applications, pharmacological activities, pharmacokinetics, clinical efficacy, and potential herb-drug interactions aiming to fill in the information gaps of this herb for frontline practitioners. Although various small, poorly designed clinical trials have demonstrated the safety, efficacy, and significant clinical benefits of Radix Puerariae, prospective randomized controlled clinical trials are needed to further establish its effective and safe use. PMID- 23677887 TI - Reply: To PMID 22736240. PMID- 23677888 TI - Mismatch DNA repair mRNA expression profiles in oral melanin pigmentation lesion and hamartomatous polyp of a child with Peutz-Jeghers syndrome. AB - Mismatch DNA repair (MMR) mRNA expression analysis was performed on a biopsy of oral mucosa melanin pigmentation lesion, a hamartomatous polyp and peripheral blood derived from a 12-year-old child with Peutz-Jeghers Syndrome (PJS). We present a deficient MMR system, in a PJS patient, which demonstrated low mRNA levels of hMSH6 and hPMS2 and an increasing MMR deficiency from the non dysplastic lesion to hamartomatous polyp of PJS with a high risk of cancer. PMID- 23677889 TI - The relationship between spatiotemporal gait asymmetry and balance in individuals with chronic stroke. AB - Falls are common after stroke and often attributed to poor balance. Falls often occur during walking, suggesting that walking patterns may induce a loss of balance. Gait after stroke is frequently spatiotemporally asymmetric, which may decrease balance. The purpose of this study is to determine the relationship between spatiotemporal gait asymmetry and balance control. Thirty-nine individuals with chronic stroke walked at comfortable and fast speeds to calculate asymmetry ratios for step length, stance time, and swing time. Balance measures included the Berg Balance Scale, step width during gait, and the weight distribution between legs during standing. Correlational analyses determined the relationships between balance and gait asymmetry. At comfortable and fast gait speeds, step width was correlated with stance time and swing time asymmetries (r = 0.39-0.54). Berg scores were correlated with step length and swing time asymmetries (r = -0.36 to -0.63). During fast walking, the weight distribution between limbs was correlated with stance time asymmetry (r = -0.41). Spatiotemporal gait asymmetry was more closely related to balance measures involving dynamic tasks than static tasks, suggesting that gait asymmetry may be related to the high number of falls poststroke. Further study to determine if rehabilitation that improves gait asymmetry has a similar influence on balance is warranted. PMID- 23677890 TI - Enhancement of liver and pancreas on late hepatic arterial phase imaging: quantitative comparison among multiple gadolinium-based contrast agents at 1.5 Tesla MRI. AB - PURPOSE: To compare enhancement of the liver and pancreas quantitatively on late hepatic arterial phase images among various gadolinium-based contrast agents (GBCAs) at 1.5 Tesla (T) MRI. MATERIALS AND METHODS: Patients underwent consecutive MR studies with the following GBCAs: gadopentetate dimeglumine (0.1 mmol/kg) gadobenate dimeglumine (0.05 mmol/kg), gadoxetic acid, and gadobutrol group. The enhancement of liver and pancreas was evaluated quantitatively on late hepatic arterial phase. Relative pancreas-to-liver enhancement ratio was also calculated. RESULTS: Mean % enhancement of the liver and the pancreas was 21.57 and 55.40, and mean relative pancreas to liver enhancement was 2.23. Mean % enhancement of the liver for gadopentetate, gadobenate, gadoxetic, and gadobutrol were 20.4 +/- 12.3, 21.7 +/- 7.1, 16.2 +/- 6.1, 29.1 +/- 21.9. Significant difference was observed for % enhancement of liver comparing gadobutrol and gadoxetic (P = 0.048). Mean % enhancement of pancreas for gadopentetate, gadobenate, gadoxetic, and gadobutrol were 53.6 +/- 12.6, 60.1 +/- 13.7, 52.7 +/- 10.6, 54.7 +/- 19.5. No significant differences were observed for % enhancement of pancreas (P > 0.05). No significant differences were observed for relative pancreas-to-liver enhancement ratio (P > 0.05). CONCLUSION: Our study describes % enhancement of liver and pancreas using various GBCAs. The data may provide reference material on relaxation properties of GBCAs in vivo. PMID- 23677891 TI - Fine-needle aspiration of histoplasmosis in the era of endoscopic ultrasound and endobronchial ultrasound: cytomorphologic features and correlation with clinical laboratory testing. AB - BACKGROUND: Histoplasmosis has a textbook cytologic description with numerous intracellular organisms that are readily apparent on routine stains. This is based on series and reports describing histoplasmosis in immunosuppressed patients with disseminated disease. With the advent of ultrasound-guided (US) fine-needle aspiration (FNA) techniques, a marked increase in the cytologic diagnosis of histoplasmosis in immunocompetent patients is noted. METHODS: A search identified all cytology cases diagnosed with Histoplasma within the past 10 years. Cases were reviewed, along with patient demographic, clinical, and laboratory data. RESULTS: A total of 40 FNA cases of histoplasmosis were identified. Patients ranged in age from 15 years to 86 years. There were 23 female patients and 17 male patients; 37 were immunocompetent and 3 were immunosuppressed. Sixteen patients were being staged for primary tumors of other sites; others presented with primary pulmonary symptoms or histoplasmosis was noted incidentally. Specimens were composed of bland acellular necrosis, most commonly with granulomas (77.5%); only rare intracellular organisms were present on routine stains, and variable extracellular organisms were noted on Grocott methenamine silver stain (GMS) stain. GMS stain on direct smears was found to be more sensitive than cell block. Laboratory studies for urine antigen, yeast, and mycelial antibody (by compliment fixation), serum antibody (by immunodiffusion), and culture were positive in 11.8%, 59.1%, 4.5%, 47.6%, and 3.4% of cases, respectively. CONCLUSIONS: In an endemic region, histoplasmosis presents more commonly in immunocompetent patients as localized fibrocaseous disease on FNA and is often identified by high-resolution imaging. FNA is increasingly used in the diagnosis because of endoscopic ultrasound and endobronchial ultrasound. GMS stain on direct smears is more sensitive than cell block. In general, laboratory tests have low sensitivity in this patient population. PMID- 23677892 TI - Management of work-related stress by Finnish occupational physicians. AB - BACKGROUND: Occupational stress is a serious threat to the well-being of employees and organizations and may cause ill-health and loss of productivity. Determining the methods that occupational health (OH) services and employers use to manage work-related stress can help to detect both barriers and facilitating factors for effective stress management. AIMS: To examine stress management methods used by OH physicians in Finland. METHODS: Anonymous, self-administered e mail questionnaire to Finnish OH physicians. RESULTS: A total of 222 OH physicians responded. Neither OH services nor their client organizations used standardized tools to assess or manage work-related stress. Work-related stress was assessed using patient interviews. Physicians reported that the main method used to manage occupational stress was supporting the individual employee. Half of the physicians attempted to involve workplaces in stress management by asking their patients to contact their supervisors regarding stress issues. CONCLUSIONS: In order to tackle work-related stress consistently and effectively employers and OH services should have agreed standardized protocols for managing stress in the workplace. PMID- 23677893 TI - Do perceived social stress and resilience influence the effects of psychopathy linked narcissism and CU traits on adolescent aggression? AB - The current study explored the influences of social stress and resilience on the relation between psychopathy-linked personality characteristics (i.e., narcissism, dimensions of CU traits) and aggression with the expectation that social stress would exacerbate the relation, whereas resilience would mitigate it. In a sample of 154 at-risk adolescents (ages 16-18; 84% male), contrary to expectations, high social stress attenuated the relations of narcissism and callousness with aggression. Self-reported resilience attenuated the relation between callousness and aggression. The implications for understanding the role that these moderators might play in the association between adolescent psychopathic tendencies, particularly callousness, and aggression are discussed. PMID- 23677894 TI - Coactivation of direct and indirect pathways: insights into the basal ganglia and normal movement control. PMID- 23677895 TI - DNA as the next digital information storage support. PMID- 23677896 TI - Metabolic disorders causing movement disorders in childhood; an addition to the list. PMID- 23677897 TI - Delayed onset of progressive chorea after acute basal ganglia injury. PMID- 23677898 TI - Corticomuscular coherence in asymptomatic first-degree relatives of patients with essential tremor. AB - BACKGROUND: Essential tremor (ET) follows an autosomal dominant type of inheritance in the majority of patients, yet its genetic basis has not been identified. Its exact origin is still elusive, but coherence measurements between electromyography tremor bursts and electroencephalography unequivocally demonstrate a correlation. METHODS: We tested these measurements in 37 healthy first-degree relatives (children) of patients with essential tremor (ET) and a group of 37 age-matched and sex-matched controls. Pooled coherence spectra of the maximally coherent electroencephalogram electrodes were computed for ET relatives and controls. RESULTS: The maximal coherence and its frequency were significantly higher in ET relatives than in controls during the pinch grip task and during slow hand movements. Electromyography amplitude (root-mean-square) was slightly but significantly greater in ET relatives, whereas 2-Hz to 40-Hz power and spectral peak frequency were not different. CONCLUSIONS: The presymptomatic alteration in corticomuscular interaction may reflect a role of genetic factors. PMID- 23677899 TI - Environmental bio-monitoring with high-throughput sequencing. AB - There is much interest in using high-throughput DNA sequencing methodology to monitor microorganisms, complex plant and animal communities. However, there are experimental and analytical issues to consider before applying a sequencing technology, which was originally developed for genome projects, to ecological projects. Many of these issues have been highlighted by recent microbial studies. Understanding how high-throughput sequencing is best implemented is important for the interpretation of recent results and the success of future applications. Addressing complex biological questions with metagenomics requires the interaction of researchers who bring different skill sets to problem solving. Educators can help by nurturing a collaborative interdisciplinary approach to genome science, which is essential for effective problem solving. Educators are in a position to help students, teachers, the public and policy makers interpret the new knowledge that metagenomics brings. To do this, they need to understand, not only the excitement of the science but also the pitfalls and shortcomings of methodology and research designs. We review these issues and some of the research directions that are helping to move the field forward. PMID- 23677900 TI - Editorial comment: Frozen elephant trunk surgery: where do we go from here? PMID- 23677901 TI - Experience with the conventional and frozen elephant trunk techniques: a single centre study. AB - OBJECTIVES: The treatment of patients with extensive thoracic aortic disease involving the arch and descending/thoracoabdominal aorta is often performed using an elephant trunk procedure. We retrospectively analysed our results comparing two different techniques: the conventional elephant trunk (cET) and the frozen elephant trunk (FET) operation. METHODS: Between January 2003 and December 2011, 171 consecutive patients underwent total aortic arch replacement with either a cET (n = 125) or FET (n = 46) technique. The mean age was 64 +/- 13 years and was significantly higher in the FET group (P < 0.01). Acute Type A aortic dissection was the indication for surgery in 53.6% of cET and 17.4% of FET patients, and degenerative or atherosclerotic aneurysm accounted for 33.6% of cET and 58.7% of FET patients. The remaining patients were operated on for chronic Type A or acute or chronic Type B dissections with arch involvement. RESULTS: In-hospital mortality was 21.6 vs 8.7% for cET and FET patients, respectively (P = 0.1). Logistic regression analysis revealed Type A aortic dissection (odds ratio (OR) 3.1, P = 0.01) as the only independent predictor of hospital mortality. Stroke occurred in 16 vs 13% of cET vs FET patients (P = 0.4). Type A aortic dissection was an independent predictor of stroke by multivariable analysis (OR 2.6, P = 0.03), and axillary arterial cannulation was protective against stroke (OR 0.4, P = 0.04). The occurrence of new-onset paraplegia was significantly higher in the FET group (21.7 vs 4.0%, P < 0.001), and aortic repair with the FET technique was an independent predictor for paraplegia (OR 6.6, P = 0.001). Among patients receiving FET, a body core temperature during circulatory arrest of >= 28 degrees C in combination with a prolonged circulatory arrest time of >40 min was an independent predictor for permanent spinal cord injury (OR 5.0, 95% CI 1.1-20, P = 0.038). The estimated 1-, 3- and 5-year survival were 70 +/- 4, 70 +/- 4 and 68 +/- 4% (cET) and 4 +/- 7 and 60 +/- 9, 40 +/- 1% (FET), with mean survival time 5.2 +/- 0.3 vs 3.8 +/- 0.5 years (cET vs FET, log-rank P = 0.9). CONCLUSIONS: The FET procedure for extensive thoracic aortic disease is associated with an acceptable mortality rate, but with a higher incidence of perioperative spinal cord injury than cET. Arch replacement with a cET technique should be strongly considered in patients with expected prolonged circulatory arrest times, particularly if operated on under mild or moderate hypothermia. Axillary cannulation is associated with superior neurological outcomes and Type A acute aortic dissection is a risk factor for mortality and poor neurological outcomes in this patient population. PMID- 23677902 TI - Performance of EuroSCORE II in patients who have undergone heart valve surgery: a multicentre study in a Chinese population. AB - OBJECTIVES: The EuroSCORE II is an updated version of the EuroSCORE. This multicentre study validated the EuroSCORE II and logistic EuroSCORE in Chinese patients who underwent heart valve surgery. METHODS: A total of 11 170 adult patients underwent heart valve surgery from January 2008 to December 2011. Model discrimination and calibration were assessed for both EuroSCORE II and logistic EuroSCORE. The patients were divided into three subgroups according to the weight of the procedures, and the performance of EuroSCORE II for each group was assessed. A correlation analysis was performed for operative complications and EuroSCORE II. RESULTS: The in-hospital mortality of this series was 2.02% (226 of 11 170), and the predicted mortality rate was 2.62+/-5.75% by EuroSCORE II and 2.55+/-6.51% by logistic EuroSCORE (LES). The C-statistics of EuroSCORE II and LES were 0.72 [95% confidence interval (CI) 0.69-0.75] and 0.67 (95% CI 0.63 0.70), respectively. Both models failed the Hosmer-Lemeshow goodness-of-fit test, with a P<0.05. According to the weight of the procedure, the isolated non-CABG subgroup had the best discrimination (C-statistics: 0.76 in the non-CABG group, 0.67 in the 2 procedures group and 0.73 in the 3+ procedures group). The complication ratio was strongly related to the EuroSCORE II-predicted mortality (Pearson correlation coefficient: 0.90 for ARDS, 0.97 for acute renal failure, 0.97 for prolonged ventilation and 0.94 for a prolonged ICU stay). CONCLUSIONS: EuroSCORE II was an improvement upon its original logistic model for Chinese patients who underwent heart valve surgery, particularly for a single-valve procedure. The EuroSCORE II-predicted mortality correlated with the operative complications. PMID- 23677903 TI - Association between baseline fetal hemoglobin levels and incidence of severe vaso occlusive pain episodes in children with sickle cell anemia. AB - The ameliorating effect of high fetal hemoglobin (HbF) levels on the incidence of pain episodes in sickle cell anemia (SCA) is well-known; however, in children this relationship is less clearly established. We hypothesized that higher HbF levels in children with SCA are associated with fewer severe pain episodes. A meta-analysis of data from the Silent Infarct Transfusion Trial (n = 456) and the Cooperative Study of Sickle Cell Disease (n = 764), demonstrated that baseline HbF levels were associated with the incidence of severe pain, commonly defined across studies as an event requiring hospitalization (P-value = 0.02). PMID- 23677904 TI - Common genetic variants of MGP are associated with calcification on the arterial wall but not with calcification present in the atherosclerotic plaques. AB - BACKGROUND: Two endophenotypes of arterial calcification, calcification on arterial wall and calcification in atherosclerotic plaques, are associated with different types of cardiovascular events. Mgp-deficient mice showed matrix Gla protein (MGP) is strongly associated with calcification on arterial wall without atherosclerotic plaques, and MGP variants were not significantly associated with myocardial infarction. MGP may play different roles in the 2 endophenotypes. METHODS AND RESULTS: We analyzed the associations of MGP variants rs4236, rs1800801, and rs1800802 with the 2 endophenotypes determined by multidetector computed tomography angiography. A total of 585 with calcification on coronary artery wall, 675 with calcification in coronary atherosclerotic plaques, 454 with calcification on aortic wall, and 725 controls were enrolled. After Bonferroni correction, rs4236 and rs1800801 were still associated with calcification on arterial wall, the odds ratios were 0.708 (95% confidence interval, 0.540-0.928) for rs4236 and 0.652 (95% confidence interval, 0.479-0.888) for rs1800801 in coronary artery wall calcification, and 0.699 (95% confidence interval, 0.525 0.931) for rs4236 and 0.650 (95% confidence interval, 0.467-0.905) for rs1800801 in aortic wall calcification, respectively. The variants were correlated with calcification severity by ln(CAC Agatston score+1) in coronary artery wall calcification but not in atherosclerotic plaque calcification. In accordance with their associations with calcification on arterial wall, rs4236C and rs1800801A were associated with higher MGP plasma levels, whereas rs1800802C was associated with lower MGP levels in normal controls. Because of the role of calcification in plaque vulnerability, their associations with acute myocardial infarction were also determined in 771 controls and 752 patients, no association was found. CONCLUSIONS: MGP genetic variants showed association with calcification on arterial wall but not with calcification in atherosclerotic plaques. PMID- 23677905 TI - The cardiac phenotype in patients with a CHD7 mutation. AB - BACKGROUND: Loss-of-function mutations in CHD7 cause Coloboma, Heart Disease, Atresia of Choanae, Retardation of Growth and/or Development, Genital Hypoplasia, and Ear Abnormalities With or Without Deafness (CHARGE) syndrome, a variable combination of multiple congenital malformations including heart defects. Heart defects are reported in 70% to 92% of patients with a CHD7 mutation, but most studies are small and do not provide a detailed classification of the defects. We present the first, detailed, descriptive study on the cardiac phenotype of 299 patients with a CHD7 mutation and discuss the role of CHD7 in cardiac development. METHODS AND RESULTS: We collected information on congenital heart defects in 299 patients with a pathogenic CHD7 mutation, of whom 220 (74%) had a congenital heart defect. Detailed information on the heart defects was available for 202 of these patients. We classified the heart defects based on embryonic cardiac development and compared the distribution to 1007 equally classified nonsyndromic heart defects of patients registered by EUROCAT, a European Registry of Congenital Anomalies. Heart defects are highly variable in patients with CHD7 mutations, but atrioventricular septal defects and conotruncal heart defects are over-represented. Sex did not have an effect on the presence of heart defects, but truncating CHD7 mutations resulted in a heart defect significantly more often than missense or splice-site mutations (chi2, P<0.001). CONCLUSIONS: CHD7 plays an important role in cardiac development, given that we found a wide range of heart defects in 74% of a large cohort of patients with a CHD7 mutation. Conotruncal defects and atrioventricular septal defects are over-represented in patients with CHD7 mutations compared with patients with nonsyndromic heart defects. PMID- 23677906 TI - Crushed rephased orthogonal slice selection (CROSS) for simultaneous acquisition of two orthogonal proton resonance frequency temperature maps. AB - PURPOSE: To evaluate a novel imaging sequence termed crushed rephased orthogonal slice selection (CROSS) that uses the available time in long echo time (TE) gradient echo (GRE) imaging-as employed for proton resonance frequency (PRF) shift thermometry-to simultaneously acquire two orthogonal magnetic resonance imaging (MRI) temperature maps around the target region. MATERIALS AND METHODS: The CROSS sequence encodes a second orthogonal slice between excitation and data readout in long-TE imaging and applies dedicated crusher (CR) gradients to separate the signals from the two slices. Numerical simulations of the Bloch equations and phantom experiments were performed to analyze the MR signal. In phantom and in vivo experiments with two domestic pigs, the applicability of the CROSS sequence for temperature mapping of thermal therapies with focused ultrasound and laser was studied. RESULTS: A successful separation of the signals from the two slices was achieved for CR dephasing lengths approaching the in plane resolution. In the two animal experiments, CROSS temperature mapping could be successfully demonstrated at a temporal resolution of 2-3 seconds and a temperature uncertainty of 3-4K. CONCLUSION: At the expense of a reduced signal in the overlap of the two slices, the CROSS sequence achieves an improvement of temporal resolution by 50%, without requiring further acceleration techniques such as parallel imaging, over conventional sequential GRE sequences employing the same repetition time as the CROSS sequence acquires two slices within one repetition interval. PMID- 23677907 TI - Influence of ankle injury on muscle activation and postural control during ballet grand plie. AB - Ballet deep squat with legs rotated externally (grand plie) is a fundamental movement for dancers. However, performing this task is a challenge to ankle control, particularly for those with ankle injury. Thus, the purpose of this study was to investigate how ankle sprains affect the ability of postural and muscular control during grand plie in ballet dancers. Thirteen injured dancers and 20 uninjured dancers performed a 15 second grand plie consisting of lowering, squatting, and rising phases. The lower extremity motion patterns and muscle activities, pelvic orientation, and center of pressure (COP) excursion were measured. In addition, a principal component analysis was applied to analyze waveforms of muscle activity in bilateral medial gastrocnemius, peroneus longus, and tibialis anterior. Our findings showed that the injured dancers had smaller pelvic motions and COP excursions, greater maximum angles of knee flexion and ankle dorsiflexion as well as different temporal activation patterns of the medial gastrocnemius and tibialis anterior. These findings suggested that the injured dancers coped with postural challenges by changing lower extremity motions and temporal muscle activation patterns. PMID- 23677908 TI - False-negative rate of endoscopic ultrasound-guided fine-needle aspiration for pancreatic solid and cystic lesions with matched surgical resections as the gold standard: one institution's experience. AB - BACKGROUND: The diagnosis of pancreatic tumors is often complicated because of sampling and interpretive challenges. The current study was performed to determine the rates, types, and causes of diagnostic discrepancies. METHODS: The authors retrospectively reviewed cytology cases from 2004 to 2010 using matched surgical resection cases as the gold standard. RESULTS: A total of 733 cases were divided into 3 categories: 1) positive or suspicious (290 cases); 2) negative or atypical (403 cases); and 3) unsatisfactory (40 cases). Of these cases, 101 fine needle aspiration (FNA) cases had matched surgical resections including 58 positive diagnoses, 39 negative diagnoses, and 4 unsatisfactory diagnoses. All 19 discrepant cases represented false-negative diagnoses without any false-positive cases noted, which included 2 cases with interpretive errors (10%) and 17 cases with sampling errors (90%). All matched cytology cases were divided into 5 subgroups based on the type of lesion or type of error and were analyzed for sensitivity and specificity. The sampling error rate in cystic lesions (8 of 24; 33%) was significantly higher than that in solid lesions (9 of 73; 12%). The false-negative rate in the interpretive error group (3%) was significantly lower than that in the sampling error group (23%). CONCLUSIONS: The results of the current study confirm that pancreatic endoscopic ultrasound-guided FNA diagnosis has a very low false-positive rate but a relatively high false-negative rate using matched surgical resections as the gold standard. The major cause of a false-negative cytology diagnosis is sampling error and the rate of sampling error in cystic lesions is significantly higher than that in solid lesions. PMID- 23677909 TI - Defining the epsilon-sarcoglycan (SGCE) gene phenotypic signature in myoclonus dystonia: a reappraisal of genetic testing criteria. AB - Mutations or exon deletions of the epsilon-sarcoglycan (SGCE) gene cause myoclonus-dystonia (M-D), but a subset of M-D patients are mutation-negative and the sensitivity and specificity of current genetic testing criteria are unknown. We screened 46 newly enrolled M-D patients for SGCE mutations and deletions; moreover, 24 subjects previously testing negative for SGCE mutations underwent gene dosage analysis. In our combined cohorts, we calculated sensitivity, specificity, positive and negative predictive values, and area under the curve of 2 published sets of M-D diagnostic criteria. A stepwise logistic regression was used to assess which patients' characteristics best discriminated mutation carriers and to calculate a new mutation predictive score ("new score"), which we validated in previously published cohorts. Nine of 46 (19.5%) patients of the new cohort carried SCGE mutations, including 5 novel point mutations and 1 whole-gene deletion; in the old cohort, 1 patient with a complex phenotype carried a 5.9-Mb deletion encompassing SGCE. Current diagnostic criteria had a poor ability to discriminate SGCE-positive from SGCE-negative patients in our cohort; conversely, age of onset, especially if associated with psychiatric features (as included in the new score), showed the best discriminatory power to individuate SGCE mutation carriers, both in our cohort and in the validation cohort. Our results suggest that young age at onset of motor symptoms, especially in association with psychiatric disturbance, are strongly predictive for SGCE positivity. We suggest performing gene dosage analysis by multiple ligation-dependent probe amplification (MLPA) to individuate large SGCE deletions that can be responsible for complex phenotypes. PMID- 23677910 TI - Novel frameshift mutations in ADAMTS13 in two families with hereditary thrombotic thrombocytopenic purpura. PMID- 23677911 TI - Aspirin Half Maximal Inhibitory Concentration Value on Platelet Cyclooxygenase1 in Severe Type-2 Diabetes Mellitus is not Significantly Different from that of Healthy Individuals. AB - It is implicated that diabetic patients are more resistant to aspirin therapy than patients with other diseases or healthy individuals. We evaluated the inhibitory effects of aspirin on aggregation and the cyclooxygenase activity of platelets of 10 patients with severe type-2 diabetes mellitis (DM) and compared the results with those of healthy individuals. Although platelet aggregation had a tendency to be more resistant to aspirin with the DM group, there was no significant difference in half maximal inhibitory concentration 50 values of aspirin on the cyclooxygenase activity between the patients with DM and healthy individuals. Thus, the residual platelet aggregability uninhibited by aspirin appears to be independent of the cyclooxygenase activity. Since adenosine diphosphate (ADP) receptor blocking almost completely inhibited the residual platelet aggregability, it is suggested that hyperreactivity to ADP is more prevalent in patients with DM. PMID- 23677912 TI - Acquired hemophilia a: retrospective analysis of 49 cases from a single Chinese hemophilia center. AB - Acquired hemophilia A (AHA) is a rare bleeding disorder caused by the autoantibody directed against factor VIII in patients without previous history of a bleeding disorder. We retrospectively analyzed the characteristics and outcomes of 49 patients with AHA diagnosed in our center from February 1994 to October 2012. Twenty-four patients with acute bleeding episodes were treated with prothrombin complex concentrate (PCC) at a relative low dose of 30 to -50 U/kg/d and achieved good outcomes without any adverse reaction. Corticosteroids alone or in combination with cyclophosphamide were used as the first-line therapy to eradicate the inhibitors. In 39 evaluable patients, 35 (89.7%) achieved complete remission (CR). This study demonstrates that when bypassing agents such as recombinant activated factor VII and activated PCCs are not affordable or available, low dose PCC is effective and safe to control acute bleeding in patients with AHA. First-line therapy achieved good outcomes with a CR rate of 89.7%. PMID- 23677913 TI - Factor VIII in the setting of acute ischemic stroke among patients with suspected hypercoagulable state. AB - BACKGROUND: Elevation of factor VIII is associated with higher risk of large vessel arterial occlusions including stroke. METHODS: Factor VIII levels were examined in consecutive patients with acute ischemic stroke (AIS) presenting to a single center between July 2008 and May 2012. Factor VIII levels exceeding the laboratory reference range were considered elevated (>150%). RESULTS: Factor VIII level was elevated in 72.4% (84 of 116) of the patients. Elevated factor VIII level was more frequent in blacks, diabetics, and patients who were anemic. Patients with elevated factor VIII had higher median baseline National Institute of Health Stroke Scale (NIHSS; 5 vs 2, P = .0295) and twice the frequency of neuroworsening (21.4% vs 9.4%), but discharge NIHSS and modified Rankin Scale were similar in the groups. CONCLUSIONS: High factor VIII level was found in the majority of tested patients with AIS. Several baseline differences were found between patients with normal and high factor VIII levels, but no differences were identified in outcome. PMID- 23677914 TI - Phenolphthalein induces centrosome amplification and tubulin depolymerization in vitro. AB - Aneuploidy is a major cause of human reproductive failure and plays a large role in cancer. Phenolphthalein (PHT) induces tumors in rodents but its primary mechanism does not seem to be DNA damage. In heterozygous TSG-p53((r)) mice, PHT induces lymphomas and also micronuclei (MN), many containing kinetochores (K), implying chromosome loss (aneuploidy). The induction of aneuploidy would be compatible with the loss of the normal p53 gene seen in the lymphomas. In this study, we confirm PHT's aneugenicity and determine the aneugenic mechanism of PHT by combining traditional genetic toxicology assays with image and flow cytometry methods. The data revealed that PHT induces tubulin polymerization abnormalities and deregulates the centrosome duplication cycle causing centrosome amplification. We also show that one of the consequences of these events is apoptosis. PMID- 23677916 TI - Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome. AB - BACKGROUND: Long QT syndrome (LQTS) is the most common cardiac channelopathy with 15 elucidated LQTS-susceptibility genes. Approximately 20% of LQTS cases remain genetically elusive. METHODS AND RESULTS: We combined whole-exome sequencing and bioinformatic/systems biology to identify the pathogenic substrate responsible for nonsyndromic, genotype-negative, autosomal dominant LQTS in a multigenerational pedigree, and we established the spectrum and prevalence of variants in the elucidated gene among a cohort of 102 unrelated patients with "genotype-negative/phenotype-positive" LQTS. Whole-exome sequencing was used on 3 members within a genotype-negative/phenotype-positive family. Genomic triangulation combined with bioinformatic tools and ranking algorithms led to the identification of a CACNA1C mutation. This mutation, Pro857Arg-CACNA1C, cosegregated with the disease within the pedigree, was ranked by 3 disease network algorithms as the most probable LQTS-susceptibility gene and involves a conserved residue localizing to the proline, gltamic acid, serine, and threonine (PEST) domain in the II-III linker. Functional studies reveal that Pro857Arg CACNA1C leads to a gain of function with increased ICa,L and increased surface membrane expression of the channel compared to wild type. Subsequent mutational analysis identified 3 additional variants within CACNA1C in our cohort of 102 unrelated cases of genotype-negative/phenotype-positive LQTS. Two of these variants also involve conserved residues within Cav1.2's PEST domain. CONCLUSIONS: This study provides evidence that coupling whole-exome sequencing and bioinformatic/systems biology is an effective strategy for the identification of potential disease-causing genes/mutations. The identification of a functional CACNA1C mutation cosegregating with disease in a single pedigree suggests that CACNA1C perturbations may underlie autosomal dominant LQTS in the absence of Timothy syndrome. PMID- 23677917 TI - Non-invasive indices of right ventricular function are markers of ventricular arterial coupling rather than ventricular contractility: insights from a porcine model of chronic pressure overload. AB - AIMS: To investigate the physiological correlates of indices of RV function in a model of chronic pressure overload. METHODS AND RESULTS: Chronic pulmonary hypertension (PH) was induced in piglets by ligation of the left pulmonary artery (PA) followed by weekly embolization of right lower lobe arteries for 5 weeks (the PH group, n = 11). These animals were compared with sham-operated animals (controls, n = 6). At 6 weeks, a subgroup of five PH pigs underwent surgical reperfusion of the left lung and four others were followed until 12 weeks without treatment. Right ventricular function was assessed using echocardiography and conductance catheter measurements. At 6 weeks, mean PA pressure was higher in PH group compared with controls (35 +/- 9 vs. 14 +/- 2 mmHg, P < 0.01). Although RV elastance (Ees) increased at 6 weeks in the PH group (0.55 +/- 0.09 vs. 0.38 +/- 0.05 mmHg/mL, P < 0.001), ventricular-arterial coupling measured by the ratio of Ees on PA elastance (Ea) was decreased (0.68 +/- 0.17 vs. 1.18 +/- 0.18, P < 0.001). There was a strong direct relationship between Ees/Ea and indices of RV function, while relationship between Ees and indices of RV function was moderate. Changes in indices of RV function with time and after left lung reperfusion were associated with changes in Ees/Ea. CONCLUSION: Usual indices of RV function are associated with ventricular-arterial coupling rather than with ventricular contractility in a model of chronic pressure overload. PMID- 23677918 TI - Accuracy of Doppler-echocardiographic parameters for the detection of aortic bileaflet mechanical prosthetic valve dysfunction. AB - AIMS: In vitro and in vivo studies were performed to evaluate the diagnostic accuracy of the different Doppler-echocardiographic parameters proposed in the American Society of Echocardiography guidelines to identify dysfunction of bileaflet mechanical valves (BMV) in the aortic position. METHODS AND RESULTS: Two models of BMV (St Jude HP, MCRI On-X) of different sizes (21;23;25;27 mm) were tested in vitro under a wide range of cardiac outputs (3-7 L/min). The motion of one or both leaflets was restricted to induce a mild (25% restriction in total valve orifice area) and moderate-to-severe (50% restriction in total valve area). Doppler-echocardiographic parameters of valve function were also measured in 17 patients with BMV of whom 4 had valve dysfunction confirmed by cinefluoroscopy. The specificity of all the parameters was high (in vitro: 83 100%; in vivo: 69-100%), but the sensitivity was low (range: 0-83% and 25-100%, respectively). A higher cut-off value for the ratio of peak left ventricular outflow tract velocity to peak aortic velocity or Doppler velocity index (DVI) (<0.35 instead of 0.3 or 0.25) improved the sensitivity (>90%) for the detection of moderate-to-severe dysfunction but remained low for mild dysfunction (50%). Furthermore, a difference of normal reference effective orifice area (EOA) minus measured EOA (EOA-D) >1 standard deviation identified mild and moderate-to-severe dysfunction with sensitivity of 61 and 100%, respectively. CONCLUSION: The Doppler-echocardiographic parameters and criteria proposed in the guidelines lack sensitivity for the detection of BMV dysfunction. The utilization of a DVI < 0.35 or an EOA-D > 1 SD improved the sensitivity (>90%) for the detection of moderate to-severe dysfunction, but the sensitivity remained suboptimal (<65%) for detection of mild dysfunction. PMID- 23677919 TI - Early but limited effects of raltegravir intensification on CD4 T cell reconstitution in HIV-infected patients with an immunodiscordant response to antiretroviral therapy. AB - BACKGROUND: Immune hyperactivation in immunodiscordant patients can induce residual HIV replication and limit CD4 T cell recovery. We assessed the impact of raltegravir intensification on CD4 T cell recovery and viral persistence. METHODS: We performed a randomized, controlled, pilot trial. Patients with CD4 T cell counts <350 cells/mm(3) despite suppressive antiretroviral therapy were randomized (2 : 1) to intensify with raltegravir (intensified arm, n = 30) or to continue with the same regimen (control arm, n = 14) for 48 weeks. Then, the control individuals intensified their treatment for 24 weeks (delayed intensification arm). We analysed changes in CD4 T cell counts, total and episomal HIV DNA in peripheral blood mononuclear cells and predictive factors for response. RESULTS: Raltegravir intensification induced a rapid increase in CD4 T cell counts (week 12) (P = 0.007), although this was not sustained over time. Control patients maintained constant but slow increases in CD4 T cell counts (present in the pre-study period), reaching CD4 T cell counts similar to those of patients in the intensification arm at week 48. This effect was confirmed by the analysis of the delayed-intensification arm. Proviral DNA levels remained stable in both arms over time; episomal DNA forms and ultrasensitive plasma viral load were barely detected during the study. Increases in CD4 T cell counts were associated with low baseline CD95 expression in CD4 and CD8 T cells (P = 0.020). CONCLUSIONS: Raltegravir intensification modestly impacts viral dynamics and induces a rapid but limited gain in CD4 T cell counts in immunodiscordant patients. Residual viral replication does not seem to be the main cause of unsatisfactory CD4 T cell recovery in these patients. PMID- 23677920 TI - Maraviroc treatment in non-R5-HIV-1-infected patients results in the selection of extreme CXCR4-using variants with limited effect on the total viral setpoint. AB - OBJECTIVES: Using deep sequencing methods, we intensively investigated the selective pressure of maraviroc on the viral population in four patients with dual/mixed HIV-1 experiencing treatment failure. METHODS: Patients received maraviroc add-on therapy (n = 4). Tropism was determined by Monogram's Trofile assay and/or 'deep' sequencing. Longitudinal 'deep' sequence analysis used triplicate HIV V3 RT-PCR on plasma samples. Sequences were interpreted using the geno2phenocoreceptor algorithm with a 3.5% false-positive rate (FPR) cut-off. RESULTS: Patients had a median viral load of 4.7 log10 HIV RNA copies/mL with a median of 24% chemokine (C-X-C motif) receptor 4 (CXCR4)-using virus at baseline. Following maraviroc exposure, the chemokine (C-C motif) receptor 5 (CCR5)-using virus (R5) plasma viral load decreased by at least 1 log10, and only non-R5 variants with extremely low FPR values predominated after 21 days. Virus with an FPR <=1.8% accounted for more than 90% of the circulating virus, having expanded to occupy the 'space' left by the suppression of R5 variants. Population genetic estimates of viral fitness in the presence of maraviroc showed a steep rise around an FPR value of 2%. CONCLUSIONS: Longitudinal analysis of independent R5 and non-R5 HIV populations shows that maraviroc selects viruses with an extremely low FPR, implying that the antiviral activity of maraviroc may extend to a broader range of HIV variants than previously suspected. PMID- 23677921 TI - MKK5 regulates high light-induced gene expression of Cu/Zn superoxide dismutase 1 and 2 in Arabidopsis. AB - Superoxide dismutases (SODs) convert the superoxide radical to hydrogen peroxide and molecular oxygen, and play crucial roles in plant tolerance to oxidative stress. Expression of many genes encoding SODs is promoted in response to environmental stresses, but the exact mechanism of such promotion is largely unknown. Here, we report that MKK5, a mitogen-activated protein kinase kinase, mediated the high light-induced expression of genes of two copper/zinc SODs, CSD1 and CSD2, and was involved in the oxidative adaptation to high light stress. In response to high light, wild-type Arabidopsis plants showed much enhanced expression of CSD1 and CSD2 and higher enzyme activity of MKK5. In the MKK5-RNAi (RNA interference) lines, however, the induction of CSD1 and CSD2 as well as the activation of MKK5 activity were completely arrested. In contrast, overexpression of MKK5 promoted the expression of CSD1 and CSD2. MKK5-RNAi gene silencing and CSD1/2-RNAi suppression plants became much more sensitive to high light stress than wild-type plants, and the double mutant mkk5 csd1 exhibited hypersensitivity to the stress. Plants overexpressing MKK5 showed enhanced tolerance to high light stress. Our results demonstrate that MKK5 mediated a signal of the high light induced expression of the genes CSD1 and CSD2. Manipulating MKK5 and thereby up regulating the levels of CSD1 and CSD2 transcripts can improve plant tolerance to high light stress. PMID- 23677922 TI - 4-coumarate: CoA ligase partitions metabolites for eugenol biosynthesis. AB - Biosynthesis of eugenol shares its initial steps with that of lignin, involving conversion of hydroxycinnamic acids to their corresponding coenzyme A (CoA) esters by 4-coumarate:CoA ligases (4CLs). In this investigation, a 4CL (OS4CL) was identified from glandular trichome-rich tissue of Ocimum sanctum with high sequence similarity to an isoform (OB4CL_ctg4) from Ocimum basilicum. The levels of OS4CL and OB4CL_ctg4-like transcripts were highest in O. sanctum trichome, followed by leaf, stem and root. The eugenol content in leaf essential oil was positively correlated with the expression of OS4CL in the leaf at different developmental stages. Recombinant OS4CL showed the highest activity with p coumaric acid, followed by ferulic, caffeic and trans-cinnamic acids. Transient RNA interference (RNAi) suppression of OS4CL in O. sanctum leaves caused a reduction in leaf eugenol content and trichome transcript level, with a considerable increase in endogenous p-coumaric, ferulic, trans-cinnamic and caffeic acids. A significant reduction in the expression levels was observed for OB4CL_ctg4-related transcripts in suppressed trichome compared with transcripts similar to the other four isoforms (OB4CL_ctg1, 2, 3 and 5). Sinapic acid and lignin content were also unaffected in RNAi suppressed leaf samples. Transient expression of OS4CL-green fluorescent protein fusion protein in Arabidopsis protoplasts was associated with the cytosol. These results indicate metabolite channeling of intermediates towards eugenol by a specific 4CL and is the first report demonstrating the involvement of 4CL in creation of virtual compartments through substrate utilization and committing metabolites for eugenol biosynthesis at an early stage of the pathway. PMID- 23677923 TI - Cross-reactivity of designer drugs, including cathinone derivatives, in commercial enzyme-linked immunosorbent assays. AB - Since the introduction of synthetic heroin, designer drugs have been increasing in prevalence in the United States drug market over the past few decades. Recently, 'legal highs' sold as 'bath salts' have become a household term for one such class of designer drugs. While a number of federal and state bans have been enacted, the abuse of these designer drugs still continues. Few assays have been developed for the comprehensive detection of such compounds, so it is important to investigate how they may or may not react in presumptive screens, i.e. pre existing commercial immunoassays. In this experiment, 16 different ELISA reagents were evaluated to determine the cross-reactivity of 30 designer drugs, including 24 phenylethylamines (including 8 cathinone derivatives), 3 piperazines, and 3 tryptamines. Cross-reactivity towards most drugs was <4% in assays targeting amphetamine or methamphetamine. Compounds such as MDA, MDMA, ethylamphetamine, and alpha-methyltryptamine demonstrated cross-reactivities in the range of 30 250%, but data were consistent with both manufacturer's inserts and published literature. When tested against the Randox Mephedrone/Methcathinone kit, cathinone derivatives demonstrated cross-reactivity at concentrations as low as 150 ng/ml. Since this same reagent did not cross-react with other amphetamine like compounds, it opens the possibility to screen post-mortem specimens without the interference of putrefactive amines. All other assays demonstrated essentially no cross-reactivity towards any of the analytes evaluated. Given these results, a great need exists for more broad-range screening techniques to be applied when analyzing biological specimens by immunoassays for drugs of abuse, specifically the more recent designer drugs. PMID- 23677924 TI - Physical fitness and risk for heart failure and coronary artery disease. AB - BACKGROUND: Multiple studies have demonstrated strong associations between cardiorespiratory fitness and lower cardiovascular disease mortality. In contrast, little is known about associations of fitness with nonfatal cardiovascular events. METHODS AND RESULTS: Linking individual participant data from the Cooper Center Longitudinal Study with Medicare claims files, we studied 20642 participants (21% women) with fitness measured at the mean age of 49 years and who survived to receive Medicare coverage from 1999 to 2009. Fitness was categorized into age- and sex-specific quintiles (Q) according to Balke protocol treadmill time with Q1 as low fitness. Fitness was also estimated in metabolic equivalents according to treadmill time. Associations between midlife fitness and hospitalizations for heart failure and acute myocardial infarction after the age of 65 years were assessed by applying a proportional hazards model to the multivariate failure time data. After 133514 person-years of Medicare follow-up, we observed 1051 hospitalizations for heart failure and 832 hospitalizations for acute myocardial infarction. Compared with high fitness (Q4-5), low fitness (Q1) was associated with a higher rate of heart failure hospitalization (14.3% versus 4.2%) and hospitalization for myocardial infarction (9.7% versus 4.5%). After multivariable adjustment for baseline age, blood pressure, diabetes mellitus, body mass index, smoking status, and total cholesterol, a 1 unit greater fitness level in metabolic equivalents achieved in midlife was associated with ~20% lower risk for heart failure hospitalization after the age of 65 years (men: hazard ratio [95% confidence intervals], 0.79 [0.75-0.83]; P<0.001 and women: 0.81 [0.68 0.96]; P=0.01) but just a 10% lower risk for acute myocardial infarction in men (0.91 [0.87-0.95]; P<0.001) and no association in women (0.97 [0.83-1.13]; P=0.68). CONCLUSIONS: Fitness in healthy, middle-aged adults is more strongly associated with heart failure hospitalization than acute myocardial infarction outcomes decades later in older age. PMID- 23677925 TI - Understanding recovery in children following traffic-related injuries: exploring acute traumatic stress reactions, child coping, and coping assistance. AB - Millions of children incur potentially traumatic physical injuries every year. Most children recover well from their injury but many go on to develop persistent traumatic stress reactions. This study aimed to describe children's coping and coping assistance (i.e., the ways in which parents and peers help children cope) strategies and to explore the association between coping and acute stress reactions following an injury. Children (N = 243) rated their acute traumatic stress reactions within one month of injury and reported on coping and coping assistance six months later. Parents completed a measure of coping assistance at the six-month assessment. Children used an average of five to six coping strategies (out of 10), with wishful thinking, social support, and distraction endorsed most frequently. Child coping was associated with parent and peer coping assistance strategies. Significant acute stress reactions were related to subsequent child use of coping strategies (distraction, social withdrawal, problem-solving, blaming others) and to child report of parent use of distraction (as a coping assistance strategy). Findings suggest that children's acute stress reactions may influence their selection of coping and coping assistance strategies. To best inform interventions, research is needed to examine change in coping behaviors and coping assistance over time, including potential bidirectional relationships between trauma reactions and coping. PMID- 23677927 TI - Building on our strengths. PMID- 23677926 TI - Children of treated substance-abusing mothers: a 10-year prospective study. AB - This study examined children of substance-abusing mothers approximately 10 years after mothers' admission to drug abuse treatment, and identified maternal characteristics that may be risk factors for child behavior problems on the Child Behavior Checklist. Data were obtained from 396 mothers who were included in a sample consecutively admitted to 44 treatment programs in 13 California counties during 2000-2002. The Addiction Severity Index was administered at both intake and follow-up. Each mother reported on one child 6-17 years of age. All of the children had been exposed to drugs, either in utero or postnatally. At follow-up about 22% of the children demonstrated borderline or clinical range problem behaviors. Child behavior problems were related significantly to the mothers' ethnicity (lower among Hispanics relative to white), and problem severity in family/social relationship and mental health, marginally related to her prior medical/health problem, and not related to severity of alcohol, drug, legal and employment problems. Assisting mothers to address their family/social relationship and psychological problems may have an added value to prevent or reduce behavioral problems of their children. PMID- 23677928 TI - Ensuring that research and discovery remain core values of dentistry. PMID- 23677929 TI - Implication of insulin receptor A isoform and IRA/IGF-IR hybrid receptors in the aortic vascular smooth muscle cell proliferation: role of TNF-alpha and IGF-II. AB - To assess the role of insulin receptor (IR) isoforms (IRA and IRB) in the proliferation of vascular smooth muscle cells (VSMCs) involved in the atherosclerotic process, we generated new VSMC lines bearing IR (wild-type VSMCs; IRLoxP(+/+) VSMCs), lacking IR (IR(-/-) VSMCs) or expressing IRA (IRA VSMCs) or IRB (IRB VSMCs). Insulin and different proatherogenic stimuli induced a significant increase of IRA expression in IRLoxP(+/+) VSMCs. Moreover, insulin, through ERK signaling, and the proatherogenic stimuli, through ERK and p38 signaling, induced a higher proliferation in IRA than IRB VSMCs. The latter effect might be due to IRA cells showing a higher expression of angiotensin II, endothelin 1, and thromboxane 2 receptors and basal association between IRA and these receptors. Furthermore, TNF-alpha induced in a ligand-dependent manner a higher association between IRA and TNF-alpha receptor 1 (TNF-R1). On the other hand, IRA overexpression might favor the atherogenic actions of IGF-II. Thereby, IGF-II or TNF-alpha induced IRA and IGF-I receptor (IGF-IR) overexpression as well as an increase of IRA/IGF-IR hybrid receptors in VSMCs. More importantly, we observed a significant increase of IRA, TNF-R1, and IGF-IR expression as well as higher association of IRA with TNF-R1 or IGF-IR in the aorta from ApoE(-/-) and BATIRKO mice, 2 models showing vascular damage. In addition, anti-TNF-alpha treatment prevented those effects in BATIRKO mice. Finally, our data suggest that the IRA isoform and its association with TNF-R1 or IGF-IR confers proliferative advantage to VSMCs, mainly in response to TNF-alpha or IGF-II, which might be of significance in the early atherosclerotic process. PMID- 23677930 TI - ERalpha-targeted therapy in ovarian cancer cells by a novel estradiol platinum(II) hybrid. AB - As we previously showed, we have synthesized a new family of 17beta-estradiol platinum(II) hybrids. Earlier studies revealed the VP-128 hybrid to show high efficiency compared with cisplatin toward hormone-dependent breast cancer cells. In the present research, we have studied the antitumor activity of VP-128 in vitro and in vivo against ovarian cancer. In nude mice with ovarian xenografts, VP-128 displayed selective activity toward hormone-dependent tumors and showed higher efficiency than cisplatin to inhibit tumor growth. Similarly, in vitro, transient transfection of estrogen receptor (ER)-alpha in ERalpha-negative A2780 cells increased their sensitivity to VP-128-induced apoptosis, confirming the selectivity of VP-128 toward hormone-dependent tumor cells. In agreement, Western blot analysis revealed that VP-128 induced higher caspase-9, caspase-3, and poly (ADP-ribose) polymerase cleavage compared with cisplatin. The activation of caspase-independent apoptosis was also observed in ERalpha-negative A2780 cells, in which VP-128 rapidly induced the translocation of apoptosis-inducing factor to the nucleus. Conversely, subcellular localization of apoptosis-inducing factor was not modified in ERalpha-positive Ovcar-3 cells. We also discovered that VP 128 induces autophagy in ovarian cancer cells because of the formation of acidic vesicular organelles (AVOs) and increase of Light Chain 3B-II protein responsible for the formation of autophagosomes; pathways related to autophagy (AKT and mammalian target of rapamycin) were also down-regulated, supporting this mechanism. Finally, the inhibition of autophagy using chloroquine increased VP 128 efficiency, indicating a possible combination therapy. Altogether these results highlight the beneficial value of VP-128 for the treatment of hormone dependent ovarian cancers and provide preliminary proof of concept for the efficient targeting of ERalpha- by 17beta-estradiol-Pt(II)-linked chemotherapeutic hybrids in these tumors. PMID- 23677931 TI - Dietary vitamin D restriction in pregnant female mice is associated with maternal hypertension and altered placental and fetal development. AB - Epidemiology has linked vitamin D deficiency with preeclampsia in humans. We hypothesized that low vitamin D status in pregnant mice may lead to symptoms of preeclampsia. Female BL6 mice were raised on vitamin D-sufficient or -deficient diets from weeks 4 of age and then mated with vitamin D-sufficient BL6 males at week 8. The resulting pregnant mice were either allowed to deliver pups and monitored for blood pressure (BP) and weight of offspring or euthanized at day 14 or 18 of gestation (E14 or E18) for analysis of serum, placental/kidney tissues, and fetuses. At E14 serum concentrations of 25-hydroxyvitamin D (30.1 +/- 5.0 vs 1.8 +/- 0.6 ng/mL, P < .001) and 1,25-dihydroxyvitamin D (119.5 +/- 18.7 vs 37.4 +/- 5.1 pg/mL, P < .01) were higher in sufficient vs deficient pregnant mice. At E14 BP was significantly elevated in vitamin D-deficient pregnant mice relative to vitamin D-sufficient mice for both systolic BP (124.89 +/- 2.28 vs 105.34 +/- 3.61 mm Hg, P < .001) and mean arterial pressure (115.33 +/- 1.93 vs 89.33 +/- 5.02 mm Hg, P < .001). This elevation continued through pregnancy until 7 days postpartum (PP7) but returned to baseline by PP14. Analysis of maternal kidneys showed increased expression of mRNA for renin and the angiotensin II receptor (3- and 4-fold, respectively) in vitamin D-deficient vs -sufficient mice at E14. Histological analysis of E14 placentas from vitamin D-deficient mice showed decreased vascular diameter within the labyrinth region. E14 and E18 fetuses from vitamin D-deficient mice were larger than those from vitamin D-sufficient mothers. However, by PP14 pups from vitamin D-deficient mothers weighed significantly less than those from vitamin D-sufficient mothers. Resupplementation of vitamin D periconceptually partially reversed the effects of vitamin D deficiency. These data provide further evidence that low vitamin D status may predispose pregnant women to dysregulated placental development and elevated blood pressure. PMID- 23677932 TI - CRTC2 is required for beta-cell function and proliferation. AB - Previous work in insulinoma cell lines has established that calcineurin plays a critical role in the activation of cAMP-responsive element binding protein (Creb), a key transcription factor required for beta-cell function and survival, by dephosphorylating the Creb coactivator Creb-regulated transcription coactivator (Crtc)2 at 2 regulatory sites, Ser171 and Ser275. Here, we report that Crtc2 is essential both for glucose-stimulated insulin secretion and cell survival in the beta-cell. Endogenous Crtc2 activation is achieved via increasing glucose levels to the physiological feeding range, indicating that Crtc2 is a sensor that couples ambient glucose concentrations to Creb activity in the beta cell. Immunosuppressant drugs such as cyclosporin A and tacrolimus that target the protein phosphatase calcineurin are commonly administered after organ transplantation. Chronic use is associated with reduced insulin secretion and new onset diabetes, suggestive of pancreatic beta-cell dysfunction. Importantly, we show that overexpression of a Crtc2 mutant rendered constitutively active by introduction of nonphosphorylatable alanine residues at Ser171 and Ser275 permits Creb target gene activation under conditions when calcineurin is inhibited. Taken together, these data suggest that promoting Crtc2-Creb activity is required for beta-cell function and proliferation and promoting this pathway could ameliorate symptoms of new onset diabetes after transplantation. PMID- 23677933 TI - Cavernous sinus syndrome due to osteochondromatosis in a cat. AB - A 1-year-old sexually intact male Korat cat was referred for ophthalmological consultation due to anisocoria. Mydriasis with external ophthalmoplegia and absence of pupillary light responses in the right eye and nasofacial hypalgesia were seen. Cavernous sinus syndrome (CSS) was suspected. Bilateral deformities of the jaw and phalangeal bones, severe spinal pain and abnormal conformation of the lumbar spine were also present. Radiographic examination revealed several mineralised masses in the appendicular and axial skeleton, indicative of multiple cartilaginous exostoses. For further investigation of the CSS-related neurological deficits, the cat underwent computed tomography (CT) examination of the skull. CT images revealed a non-vascularised, calcified, amorphous mass originating from the right lateral skull base and superimposing on the sella turcica. Based on the severity of diffuse lesions and owing to the clinical signs of extreme pain, the cat was euthanased. A diffuse skeletal and intracranial osteochondromatosis was diagnosed histologically. PMID- 23677934 TI - Transsplenic portal scintigraphy using 99mTc-pertechnetate for the diagnosis of portosystemic shunts in cats: a retrospective review of 12 patients. AB - Portosystemic shunts (PSS), congenital or acquired, occur uncommonly in the feline population. The diagnostic approach is similar to one in dogs suspected of a PSS based on the clinical signs and haematological and biochemical changes. Diagnostic imaging, however, is key for the confirmation of a PSS. Although abdominal ultrasound is the first-choice diagnostic imaging modality, the results are not always unequivocal. Transsplenic portal scintigraphy (TSPS) using (99m)Tc pertechnetate is a well-established technique in canine medicine, providing relatively fast and easy confirmation of the presence or absence of a PSS. As the prevalence of PSS is much lower in the feline population, this technique has not been widely used in cats. This retrospective study of 12 cases gives an overview of the potential of TSPS in the diagnostic work-up of PSS in cats (2005-2012). PMID- 23677935 TI - Unusual rib metastasis in two cats with pulmonary carcinoma. AB - Two cats had chronic respiratory signs associated with pulmonary carcinoma. In each case, computed tomography demonstrated similar pulmonary masses, pleural fluid and osteolytic expansile rib lesions as a result of local costal spread. This is the first report of feline primary pulmonary adenocarcinoma with local spread to the ribs, causing osteolysis. Although pleural involvement is common with this neoplasm, local spread to ribs is rarely reported. PMID- 23677936 TI - Nonredundant function of zeins and their correct stoichiometric ratio drive protein body formation in maize endosperm. AB - Zeins, the maize (Zea mays) prolamin storage proteins, accumulate at very high levels in developing endosperm in endoplasmic reticulum membrane-bound protein bodies. Products of the multigene alpha-zein families and the single-gene gamma zein family are arranged in the central hydrophobic core and the cross-linked protein body periphery, respectively, but little is known of the specific roles of family members in protein body formation. Here, we used RNA interference suppression of different zein subclasses to abolish vitreous endosperm formation through a variety of effects on protein body density, size, and morphology. We showed that the 27-kilodalton (kD) gamma-zein controls protein body initiation but is not involved in protein body filling. Conversely, other gamma-zein family members function more in protein body expansion and not in protein body initiation. Reduction in both 19- and 22-kD alpha-zein subfamilies severely restricted protein body expansion but did not induce morphological abnormalities, which result from reduction of only the 22-kD alpha-zein class. Concomitant reduction of all zein classes resulted in severe reduction in protein body number but normal protein body size and morphology. PMID- 23677937 TI - Localized induction of the ATP-binding cassette B19 auxin transporter enhances adventitious root formation in Arabidopsis. AB - Adventitious roots emerge from aerial plant tissues, and the induction of these roots is essential for clonal propagation of agriculturally important plant species. This process has received extensive study in horticultural species but much less focus in genetically tractable model species. We have explored the role of auxin transport in this process in Arabidopsis (Arabidopsis thaliana) seedlings in which adventitious root initiation was induced by excising roots from low-light-grown hypocotyls. Inhibition of auxin transport from the shoot apex abolishes adventitious root formation under these conditions. Root excision was accompanied by a rapid increase in radioactive indole-3-acetic acid (IAA) transport and its accumulation in the hypocotyl above the point of excision where adventitious roots emerge. Local increases in auxin-responsive gene expression were also observed above the site of excision using three auxin-responsive reporters. These changes in auxin accumulation preceded cell division events, monitored by a cyclin B1 reporter (pCYCB1;1:GUS), and adventitious root initiation. We examined excision-induced adventitious root formation in auxin influx and efflux mutants, including auxin insensitive1, pin-formed1 (pin1), pin2, pin3, and pin7, with the most profound reductions observed in ATP-binding cassette B19 (ABCB19). An ABCB19 overexpression line forms more adventitious roots than the wild type in intact seedlings. Examination of transcriptional and translational fusions between ABCB19 and green fluorescent protein indicates that excision locally induced the accumulation of ABCB19 transcript and protein that is temporally and spatially linked to local IAA accumulation leading to adventitious root formation. These experiments are consistent with localized synthesis of ABCB19 protein after hypocotyl excision leads to enhanced IAA transport and local IAA accumulation driving adventitious root formation. PMID- 23677938 TI - RNA-seq analysis of allele-specific expression, hybrid effects, and regulatory divergence in hybrids compared with their parents from natural populations. AB - Hybridization is a prominent process among natural plant populations that can result in phenotypic novelty, heterosis, and changes in gene expression. The effects of intraspecific hybridization on F1 hybrid gene expression were investigated using parents from divergent, natural populations of Cirsium arvense, an invasive Compositae weed. Using an RNA-seq approach, the expression of 68,746 unigenes was quantified in parents and hybrids. The expression levels of 51% of transcripts differed between parents, a majority of which had less than 1.25* fold-changes. More unigenes had higher expression in the invasive parent (P1) than the noninvasive parent (P2). Of those that were divergently expressed between parents, 10% showed additive and 81% showed nonadditive (transgressive or dominant) modes of gene action in the hybrids. A majority of the dominant cases had P2-like expression patterns in the hybrids. Comparisons of allele-specific expression also enabled a survey of cis- and trans-regulatory effects. Cis- and trans-regulatory divergence was found at 70% and 68% of 62,281 informative single nucleotide polymorphism sites, respectively. Of the 17% of sites exhibiting both cis- and trans-effects, a majority (70%) had antagonistic regulatory interactions (cis x trans); trans-divergence tended to drive higher expression of the P1 allele, whereas cis-divergence tended to increase P2 transcript abundance. Trans effects correlated more highly than cis with parental expression divergence and accounted for a greater proportion of the regulatory divergence at sites with additive compared with nonadditive inheritance patterns. This study explores the nature of, and types of mechanisms underlying, expression changes that occur in upon intraspecific hybridization in natural populations. PMID- 23677939 TI - A hierarchical model of transcriptional dynamics allows robust estimation of transcription rates in populations of single cells with variable gene copy number. AB - MOTIVATION: cis-regulatory DNA sequence elements, such as enhancers and silencers, function to control the spatial and temporal expression of their target genes. Although the overall levels of gene expression in large cell populations seem to be precisely controlled, transcription of individual genes in single cells is extremely variable in real time. It is, therefore, important to understand how these cis-regulatory elements function to dynamically control transcription at single-cell resolution. Recently, statistical methods have been proposed to back calculate the rates involved in mRNA transcription using parameter estimation of a mathematical model of transcription and translation. However, a major complication in these approaches is that some of the parameters, particularly those corresponding to the gene copy number and transcription rate, cannot be distinguished; therefore, these methods cannot be used when the copy number is unknown. RESULTS: Here, we develop a hierarchical Bayesian model to estimate biokinetic parameters from live cell enhancer-promoter reporter measurements performed on a population of single cells. This allows us to investigate transcriptional dynamics when the copy number is variable across the population. We validate our method using synthetic data and then apply it to quantify the function of two known developmental enhancers in real time and in single cells. AVAILABILITY: Supporting information is submitted with the article. PMID- 23677940 TI - Identification of hidden relationships from the coupling of hydrophobic cluster analysis and domain architecture information. AB - MOTIVATION: Describing domain architecture is a critical step in the functional characterization of proteins. However, some orphan domains do not match any profile stored in dedicated domain databases and are thereby difficult to analyze. RESULTS: We present here an original novel approach, called TREMOLO-HCA, for the analysis of orphan domain sequences and inspired from our experience in the use of Hydrophobic Cluster Analysis (HCA). Hidden relationships between protein sequences can be more easily identified from the PSI-BLAST results, using information on domain architecture, HCA plots and the conservation degree of amino acids that may participate in the protein core. This can lead to reveal remote relationships with known families of domains, as illustrated here with the identification of a hidden Tudor tandem in the human BAHCC1 protein and a hidden ET domain in the Saccharomyces cerevisiae Taf14p and human AF9 proteins. The results obtained in such a way are consistent with those provided by HHPRED, based on pairwise comparisons of HHMs. Our approach can, however, be applied even in absence of domain profiles or known 3D structures for the identification of novel families of domains. It can also be used in a reverse way for refining domain profiles, by starting from known protein domain families and identifying highly divergent members, hitherto considered as orphan. AVAILABILITY: We provide a possible integration of this approach in an open TREMOLO-HCA package, which is fully implemented in python v2.7 and is available on request. Instructions are available at http://www.impmc.upmc.fr/~callebau/tremolohca.html. CONTACT: isabelle.callebaut@impmc.upmc.fr SUPPLEMENTARY INFORMATION: Supplementary Data are available at Bioinformatics online. PMID- 23677941 TI - Relation between sequence and structure in membrane proteins. AB - MOTIVATION: Integral polytopic membrane proteins contain only two types of folds in their transmembrane domains: alpha-helix bundles and beta-barrels. The increasing number of available crystal structures of these proteins permits an initial estimation of how sequence variability affects the structure conservation in their transmembrane domains. We, thus, aim to determine the pairwise sequence identity necessary to maintain the transmembrane molecular architectures compatible with the hydrophobic nature of the lipid bilayer. RESULTS: Root-mean square deviation (rmsd) and sequence identity were calculated from the structural alignments of pairs of homologous polytopic membrane proteins sharing the same fold. Analysis of these data reveals that transmembrane segment pairs with sequence identity in the so-called 'twilight zone' (20-35%) display high structural similarity (rmsd < 1.5 A). Moreover, a large group of beta-barrel pairs with low-sequence identity (<20%) still maintain a close structural similarity (rmsd < 2.5 A). Thus, we conclude that fold preservation in transmembrane regions requires less sequence conservation than for globular proteins. These findings have direct implications in homology modeling of evolutionary-related membrane proteins. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23677942 TI - PconsD: ultra rapid, accurate model quality assessment for protein structure prediction. AB - SUMMARY: Clustering methods are often needed for accurately assessing the quality of modeled protein structures. Recent blind evaluation of quality assessment methods in CASP10 showed that there is little difference between many different methods as far as ranking models and selecting best model are concerned. When comparing many models, the computational cost of the model comparison can become significant. Here, we present PconsD, a fast, stream-computing method for distance-driven model quality assessment that runs on consumer hardware. PconsD is at least one order of magnitude faster than other methods of comparable accuracy. AVAILABILITY: The source code for PconsD is freely available at http://d.pcons.net/. Supplementary benchmarking data are also available there. CONTACT: arne@bioinfo.se SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23677943 TI - Updating RNA-Seq analyses after re-annotation. AB - The estimation of isoform abundances from RNA-Seq data requires a time-intensive step of mapping reads to either an assembled or previously annotated transcriptome, followed by an optimization procedure for deconvolution of multi mapping reads. These procedures are essential for downstream analysis such as differential expression. In cases where it is desirable to adjust the underlying annotation, for example, on the discovery of novel isoforms or errors in existing annotations, current pipelines must be rerun from scratch. This makes it difficult to update abundance estimates after re-annotation, or to explore the effect of changes in the transcriptome on analyses. We present a novel efficient algorithm for updating abundance estimates from RNA-Seq experiments on re annotation that does not require re-analysis of the entire dataset. Our approach is based on a fast partitioning algorithm for identifying transcripts whose abundances may depend on the added or deleted isoforms, and on a fast follow-up approach to re-estimating abundances for all transcripts. We demonstrate the effectiveness of our methods by showing how to synchronize RNA-Seq abundance estimates with the daily RefSeq incremental updates. Thus, we provide a practical approach to maintaining relevant databases of RNA-Seq derived abundance estimates even as annotations are being constantly revised. AVAILABILITY AND IMPLEMENTATION: Our methods are implemented in software called ReXpress and are freely available, together with source code, at http://bio.math.berkeley.edu/ReXpress/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23677944 TI - ReviSTER: an automated pipeline to revise misaligned reads to simple tandem repeats. AB - MOTIVATION: Simple tandem repeats are highly variable genetic elements and widespread in genomes of many organisms. Next-generation sequencing technologies have enabled a robust comparison of large numbers of simple tandem repeat loci; however, analysis of their variation using traditional sequence analysis approaches still remains limiting and problematic due to variants occurring in repeat sequences confusing alignment programs into mapping sequence reads to incorrect loci when the sequence reads are significantly different from the reference sequence. RESULTS: We have developed a program, ReviSTER, which is an automated pipeline using a 'local mapping reference reconstruction method' to revise mismapped or partially misaligned reads at simple tandem repeat loci. RevisSTER estimates alleles of repeat loci using a local alignment method and creates temporary local mapping reference sequences, and finally remaps reads to the local mapping references. Using this approach, ReviSTER was able to successfully revise reads misaligned to repeat loci from both simulated data and real data. AVAILABILITY: ReviSTER is open-source software available at http://revister.sourceforge.net. CONTACT: garner@vbi.vt.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23677958 TI - Clinical and radiological outcomes of the Ivory arthroplasty for trapeziometacarpal joint osteoarthritis with a minimum of 5 years of follow-up: a prospective single-centre cohort study. AB - We present the results of a 5 year prospective follow-up study on the functional outcome after total replacement of the trapeziometacarpal joint with the Ivory prosthesis (Memometal, Stryker Corporate, Kalamazoo, Michigan, USA) in 22 patients. The female to male ratio was 21:1 and the mean age was 66 (range 54-78) years. The mean follow-up period was 67 (range 60-77) months after operation. Patient satisfaction was high. The mobility of the operated thumb was restored to a range of motion comparable to the contralateral thumb. Key pinch and grip strength improved by 13% and 31%, respectively. Overall function, according to Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) score, improved by 59%. Pain decreased by 85% according to the numerical rating scale. Radiological evaluation revealed no loosening of the implant after 5 years except in one patient who required revision due to polythene wear with secondary joint instability. Another patient had asymptomatic polythene wear that required no revision but remains in follow-up. The 5 year overall survival of the prosthesis was 95%. These medium-term results suggest that the Ivory arthroplasty is a reliable option for treating advanced trapeziometacarpal arthritis, because it appears to give a very good functional outcome and has the potential for long term survival rates. PMID- 23677959 TI - Aneurysmal bone cyst of lunate treated by excision without intercarpal fusion: a case report. PMID- 23677957 TI - Application of the fecal microRNA test to the residuum from the fecal occult blood test. AB - OBJECTIVE: Though the fecal occult blood test is used for colorectal cancer screening worldwide, it does not have a particularly high sensitivity for detecting colorectal cancer. Here we investigated the applicability of the fecal microRNA test to fecal samples that had been used for a previous fecal occult blood test and stored under various conditions. METHODS: Five colorectal cancer patients and five healthy volunteers were enrolled. Fecal samples were stored for 0-5 days at 4 degrees C, room temperature or 37 degrees C. Total RNA was extracted from the fecal occult blood test residuum and microRNA expression was analyzed by real-time reverse transcription polymerase chain reaction. RESULTS: There were no remarkable differences either in colorectal cancer patients or in controls with regard to the concentration of RNA extracted from the fecal occult blood test residuum in any of the storage groups compared with the samples prepared on day 0 (Group 0). Ribosomal RNA stored at room temperature or 37 degrees C degraded rapidly. In contrast, the ribosomal RNA stored at 4 degrees C remained intact for at least 5 days. The microRNAs in samples stored at 4 degrees C and room temperature were conserved; however, the microRNAs stored at 37 degrees C were significantly degraded compared with Group 0 (P < 0.05). In the residuum stored at 4 degrees C up to 5 days, the relative quantification of miR 106a normalized with miR-24 in colorectal cancer patients was significantly higher than those in healthy volunteers (P < 0.05). In contrast, the quantification of normalized miR-106a was remarkably low in samples stored at room temperature and 37 degrees C. CONCLUSIONS: Fecal microRNA of sufficient quality for reverse transcription polymerase chain reaction analysis was extracted from the fecal occult blood test residuum stored at 4 degrees C for up to 5 days. PMID- 23677960 TI - Comparison of palmar fixed-angle plate fixation with K-wire fixation of distal radius fractures (AO A2, A3, C1) in elderly patients. AB - The objective of this prospective, randomized, controlled trial was to compare the results of two operative techniques used for the treatment of unstable distal radius fractures in elderly patients classified as AO types A2, A3, and C1. Patients were treated with either fixed-angle volar plates or K-wires using a combined Kapandji and Willenegger technique. The functional results were determined after 3, 6, and 12 months. We included 40 patients aged over 65 years. Twenty-one patients were treated with plate fixation and 19 with K-wire fixation. The functional results, after 1 year, were nearly the same in both treatment groups, suggesting that either method is suitable for the treatment of unstable distal radius fractures of AO types A2, A3, and C1 in elderly patients. Sixteen of 21 patients with plate fixation and 17 of 19 patients with K-wire fixation present good results as assessed by the Castaing score. The median DASH score was three in both groups after 1 year. The patients with plate fixation were able to resume activities of daily living 4 weeks earlier. The most common complication was an intermediate post-traumatic median nerve irritation. Both methods are suitable for the treatment of elderly patients with unstable distal radius fractures of AO types A2, A3, and C1. If early functional post-operative care is important, palmar fixed-angle plate fixation is an ideal treatment approach. Otherwise, K-wire fixation is an effective, minimally invasive method with comparable clinical results. PMID- 23677961 TI - Free iliac flap for treating multiple skin defects of the hand and digits. AB - A total of eight cases with multiple skin defects of the hand and digits were resurfaced using a free iliac flap. The lesions involved both the hand and multiple digits in five patients and multiple digits in three patients. The average skin flap size was 89.3 cm(2). In three, a piece of of vascularized iliac bone was included. There was no flap loss. Flap debulking was performed in five patients at 10-12 weeks post-surgery during the operation for flap separation and inset. Secondary flap debulking was performed in one patient at 6 months post surgery. The average static 2-point discrimination was 15.4 mm in five patients, whereas the remaining patients only exhibited sensation to pressure. This procedure may require additional refinement; however, the free iliac flap with technical refinements is a viable option for the treatment of multiple skin defects of the hand and digits. PMID- 23677962 TI - No correlation between sonographic and electrophysiological parameters in carpal tunnel syndrome. AB - A prospective study was carried out to investigate any correlation between electrophysiological and sonographic findings in patients with a clinical diagnosis of carpal tunnel syndrome. A total of 113 patients (113 wrists) in 90 women and 23 men, with a mean age of 60 years, underwent sonographic and electrophysiological examination. Fifty-five patients (48%) had mild, 43 (38%) moderate and 12 (11%) had severe conduction disturbances and three patients had normal conduction. Sonographic measurements showed a cross-sectional area of the median nerve of 9.9 mm(2) at the forearm and 17.8 mm(2) at the tunnel inlet. The mean anteroposterior diameter (height) of the nerve at the tunnel inlet was 2.7 mm, and the lowest height inside the tunnel was 1.8 mm. No correlation was found between sonographic and electrophysiological parameters. PMID- 23677963 TI - Patients with metal-on-metal articulation in trapeziometacarpal total joint arthroplasty may have elevated serum chrome and cobalt. AB - Serum chrome and cobalt was measured in 50 patients with trapeziometacarpal total joint replacement with metal-on-metal articulation and compared with serum chrome and cobalt values in 23 patients with trapeziometacarpal total joint replacement with metal-on-polyethylene articulation. In 10 of 50 (20%) patients with metal-on metal articulation, slightly elevated serum chrome or cobalt values were found compared with only one in 23 (4%) patients with metal-on-polyethylene articulation. All metal values were lower than accepted 'normal values' for metal on-metal hip arthroplasty and so considered not to be a general health risk. However, the mean disabilities of the arm, shoulder and hand (DASH) score was 24 in patients with elevated serum chrome or cobalt compared with 10 in patients with normal metal values (p < 0.05) suggesting a local clinical effect of the elevated serum chrome or cobalt values. We recommend that patients with trapeziometacarpal total joint replacement with metal-on-metal articulation are followed with DASH score and radiological examination every 3-5 years and serum chrome and cobalt should be analysed in symptomatic cases to learn more about possible local complications leading to, or arising from, metal debris. PMID- 23677964 TI - The influence of age, smoking, antiretroviral therapy, and esophagitis on the local immunity of the esophagus in patients with AIDS. AB - Studies have shown immunological and morphological alterations in the esophagus during the course of AIDS. Esophageal postmortem samples of 22 men with AIDS autopsied in a teaching hospital between 1982 and 2009 were collected. We carried out revision of the autopsy reports and medical records, morphometric analysis (Image J and KS-300 Kontron-Zeiss), and immunohistochemical (anti-S100, anti-IgA, anti-IgG, and anti-IgM) analysis of the esophagus. In accordance with most of the parameters evaluated, age and the smoking habit harmed the esophageal local immunity, whereas the use of antiretroviral therapy improved the immune characteristics of this organ. Patients with esophagitis also presented immunological fragility of the esophagus. This leads to the conclusion that alterations in the esophageal epithelium of patients with AIDS are not only caused by direct action of HIV but also the clinical and behavioral characteristics of the patient. PMID- 23677965 TI - Male victims of adult sexual assault: a descriptive study of survivors' use of sexual assault treatment services. AB - This descriptive study aims to provide new information about the services used by sexually assaulted men and adolescent boys presenting to specialized hospital based sexual assault programs and further insight into the factors that may be associated with their victimization. Information was collected from 38 male clients aged 12+ presenting to 29 sexual assault treatment centers in Ontario, Canada over 12 months. Variables were examined across 6 domains: time to presentation, client sociodemographics, assailant characteristics, assault characteristics, physical health consequences, and service delivery and utilization. A substantial minority of participants reported vulnerabilities such as young age; being Aboriginal; being transgendered, unemployed and/or on disability; working in the sex trade; and living on the streets, in a rehabilitative center, or in a correctional facility. Almost one-third identified or were documented as having a disability and, for most of these victims, it was either psychiatric in nature or developmental delay. All participants accepted at least one service offered; 86% used five or more services, most commonly those related to health care on-site such as crisis counseling, treatment of injuries, and referral for follow-up care for supportive counseling, injury redocumentation, and testing for sexually transmitted infections. These findings reveal that male clients' uptake of specialized sexual assault services is significant and it is, therefore, important to provide access to a comprehensive range of psychological, medical, and forensic treatment options and referrals to other community services for ongoing support. Implications for future research and practice are discussed. PMID- 23677966 TI - Impact of poly-victimization on mental health: the mediator and/or moderator role of self-esteem. AB - The current study examines the relationship between the total kinds of victimization (TKV) experienced, self-esteem, and internalizing symptoms (IS) and externalizing symptoms (ES). It also explores the mediator and/or moderator role of two self-esteem facets: self-liking (SL) and self-competence (SC). The sample comprised 736 adolescents recruited from eight secondary schools in Catalonia, Spain. The Rosenberg Self-Esteem Scale, the Youth Self Report, and the Juvenile Victimization Questionnaire were used to assess self-esteem facets (SL and SC), psychological distress (IS and ES), and the TKV suffered. This article has several innovative features. On one hand, it considers that self-esteem is comprised of two different but related factors: SL and SC. On the other hand, it is the first study to provide evidence for the mediator/moderator role of SL and SC between victimization and psychological symptoms, taking account of the TKV experienced. Results suggest that SL is more relevant to mental health than SC. A low sense of being a worthy social being (SL) is more closely related to both victimization and poor mental health than a low sense of personal efficacy (SC). Moreover, SL seems to partially mediate the relationship between TKV and both IS and ES, whereas SC only acts as a partial mediator for the TKV-IS relationship in girls. At the same time, SL acts as a partial moderator of the TKV-IS relationship in boys. These findings support the importance of self-esteem in buffering the impact of victimization on mental health and may indicate that proper prevention and treatment policies should focus on adolescents' sense of being a good person, according to their own criteria of worth. PMID- 23677967 TI - Threats and physical violence in the workplace: a comparative study of four areas of human service work. AB - The aim of this study was to investigate threats and physical violence in the workplace by comparing four areas of human service work, namely psychiatry, eldercare, the Prison and Probation Service (PPS), and special schools (SS). The results revealed that there were statistically significant differences in the frequency of threats and violence among these areas of human service work. In particular, employees in SS were frequently exposed. More exposure was related to a higher degree of reporting incidents in writing to the workplace. However, exposure was not consistently related to self-rated seriousness of the incidents or attitudes that reflect accept of workplace threats and violence. Both threats and physical violence were rated within a moderate range of seriousness in all these areas of work. PPS and SS expressed more accept (attitude) of workplace threats and violence in comparison to psychiatry and eldercare. CONCLUSION: workplace threats and violence toward staff in areas of human service work is a widespread phenomenon. There is a particular need for better prevention in SS, more research on the seriousness of threats in general, and more knowledge about the relationship between work environment and attitudes about workplace threats and violence. PMID- 23677968 TI - Lorentzian-like image blur of gold nanoparticles on thick amorphous silicon films in ultra-high-voltage transmission electron microscopy. AB - We quantitatively analyzed the contrast degradation and blur of 20-nm gold nanoparticles adsorbed on the top of amorphous silicon films of thicknesses of 0.54, 1.09, 1.63 and 2.2 MUm in bright-field transmission electron microscope (TEM) images taken at accelerating voltages of 0.5, 1, 2 and 3 MeV. The thickness dependence of the transmission was well explained and consistent with our calculations. The blur function, derived by assuming that the TEM image of a thick specimen can be reproduced by convolving the TEM image of a very thin specimen with it, was found to be expressed by a two-dimensional Lorentzian function. Considering the two characteristics of the Lorentzian function, a sharp peak around the center and a long tail, we concluded that, for TEM observations of thick specimens, the image contrast is degraded predominantly by inelastic scattering and the image is blurred predominantly by multiple elastic scattering. PMID- 23677969 TI - Instrumentation and hardware. PMID- 23677971 TI - Locomotory fatigue and size in the Atlantic blue crab, Callinectes sapidus. PMID- 23677972 TI - Locomotory fatigue during moderate and severe hypoxia and hypercapnia in the Atlantic blue crab, Callinectes sapidus. AB - The Atlantic blue crab, Callinectes sapidus (Rathbun), is a highly mobile crustacean that must locomote to find food, evade predators, find mates, and avoid adverse conditions such as hypoxia. In this study we tested the effects of two levels of hypoxia (10.4 kPa, 50% air saturation = moderate hypoxia; 4 kPa, 20% air saturation = severe hypoxia) and hypercapnic hypoxia (50% air saturation O(2) with Pco(2) = 2 kPa) on fatigue during sustained continuous exercise. Fatigue was induced by an exercise trial that entailed continuous sideways hexapedal walking on an underwater treadmill. Fatigue was quantified using two methods: (1) a pull force test that measures the holding strength of the legs, and (2) the number of fatigue-resisting behaviors (180 degrees turns and stopping). Fatigue was defined as a pull force of 67% or less of the initial pre exercise pull force and was reached after 6.12 h of walking for crabs in well aerated normoxic seawater, 4 h in 50% air saturation, 2.07 h in 20% air saturation, and 4.58 h in 50% air saturation and hypercapnia. The number of fatigue-resisting behaviors increased with walking time in all treatments. Performance decreased in hypoxia, with fatigue being reached more quickly as the level of hypoxia intensified. Hypercapnia in moderate hypoxia did not have a deleterious influence on behavior and lengthened slightly the time it took crabs to fatigue. In addition, severe hypoxia exacerbated changes in gait kinematics as crabs became fatigued, by significantly increasing stride length and decreasing stride frequency. PMID- 23677973 TI - Energetics of byssus attachment and feeding in the green-lipped mussel Perna canaliculus. AB - In most animals, significant increases in metabolic rate are due to activity and to feeding (known as apparent specific dynamic action). We determined the energetic costs of activity and feeding in adult green-lipped mussels (Perna canaliculus). Maximal metabolic rate was determined, using closed-chamber respirometry, during byssus re-attachment, during specific dynamic action after 16 h of feeding with Isochrysis galbana, and for the two activities combined, in 23 mussels. Metabolic rate was significantly elevated above rest by about 1.9 fold during byssus attachment (17.1 +/- 1.53 MUg O(2) h(-1) g(-1) whole mussel wet weight at rest, increased to 27.9 +/- 0.91 MUg O(2) h(-1) g(-1)), and by 2.2 fold after feeding (31.4 +/- 1.20 MUg O(2) h(-1) g(-1)). Combined feeding and byssus attachment led to a still higher metabolic rate (34.0 +/- 1.23 MUg O(2) h( 1) g(-1)). Behavior was also significantly altered, with mussels being almost continuously open during attachment and after feeding (90%-99% of the time); however, the time spent open during the day decreased, reaching a minimum of 52% +/- 9% 3 days after feeding, and remained low (67%-82%) for the following 45-day starvation period. Significant diurnal differences were observed, with mussels continuously (92%-100%) open at night. The key findings from this study are that green-lipped mussels (1) have an aerobic scope of approximately 2-fold; (2) reach a higher metabolic rate during feeding than during activity, and the two combined can raise the metabolic rate higher still; (3) display a marked diurnal behavior. PMID- 23677974 TI - Latitudinal diversity of sea anemones (Cnidaria: Actiniaria). AB - We sought to determine if the global distribution of sea anemones (cnidarian order Actiniaria) conforms to the classic pattern of biogeography--taxon richness at the equator with attenuation toward the poles--a pattern that is derived almost entirely from data on terrestrial plants and animals. We plotted the empirical distribution of species occurrences in 10 degrees bands of latitude based on published information, then, using the Chao2 statistic, inferred the completeness of that inventory. We found the greatest species richness of sea anemones at 30-40 degrees N and S, with lower numbers at tropical latitudes and the fewest species in polar areas. The Chao2 statistic allowed us to infer that the richness pattern we found is not due to particularly poor knowledge of tropical sea anemones. No 10 degrees band of latitude has less than 60% of the theoretical number of species known, but for only about half of them could we reject the null hypothesis (P = 0.05) that information is complete; anemone diversity is best documented at high latitudes. We infer that the 1089 valid species currently known constitute about 70% of the theoretical total of about 1500 species of Actiniaria. The distribution pattern of sea anemone species resembles that of planktonic foraminiferans and benthic marine algae, although planktonic bacteria, marine bivalves, and shallow and deep scleractinian corals show the terrestrial pattern of equatorial richness attenuating with latitude. Sea anemone species richness is complementary to that of scleractinian corals at many scales; our findings affirm it at the global scale. PMID- 23677975 TI - Nematocysts of the invasive hydroid Cordylophora caspia (Cnidaria: Hydrozoa). AB - Although there is significant genetic diversity among populations of the hydroid Cordylophora caspia, the species has not been split into multiple species or subspecies, in part because its members also show great physiological and morphological plasticity. This plasticity makes new taxonomic units hard to define or identify and obscures the connection between historically used names and the genetically defined clades. We explore variation in nematocysts, a character system not previously assessed in Cordylophora but which has demonstrated phylogenetic signal in other cnidarian taxa. We measured more than 5000 capsules from 112 individuals belonging to 14 populations, including representatives of the major genetic lineages. We found no correlation between the size range of capsules and either clade or salinity. Thus, for C. caspia, nematocysts are neither phenotypically plastic with respect to salinity nor taxonomically informative. Nematocyst size and density in particular tissues may be correlated to other environmental factors (such as prey type, size, and abundance in the location of each population) and may aid in distinguishing more distantly related species. PMID- 23677976 TI - Vertical visual features have a strong influence on cuttlefish camouflage. AB - Cuttlefish and other cephalopods use visual cues from their surroundings to adaptively change their body pattern for camouflage. Numerous previous experiments have demonstrated the influence of two-dimensional (2D) substrates (e.g., sand and gravel habitats) on camouflage, yet many marine habitats have varied three-dimensional (3D) structures among which cuttlefish camouflage from predators, including benthic predators that view cuttlefish horizontally against such 3D backgrounds. We conducted laboratory experiments, using Sepia officinalis, to test the relative influence of horizontal versus vertical visual cues on cuttlefish camouflage: 2D patterns on benthic substrates were tested versus 2D wall patterns and 3D objects with patterns. Specifically, we investigated the influence of (i) quantity and (ii) placement of high-contrast elements on a 3D object or a 2D wall, as well as (iii) the diameter and (iv) number of 3D objects with high-contrast elements on cuttlefish body pattern expression. Additionally, we tested the influence of high-contrast visual stimuli covering the entire 2D benthic substrate versus the entire 2D wall. In all experiments, visual cues presented in the vertical plane evoked the strongest body pattern response in cuttlefish. These experiments support field observations that, in some marine habitats, cuttlefish will respond to vertically oriented background features even when the preponderance of visual information in their field of view seems to be from the 2D surrounding substrate. Such choices highlight the selective decision-making that occurs in cephalopods with their adaptive camouflage capability. PMID- 23677978 TI - Mice stage-specific claudin 3 expression regulates progression of meiosis in early stage spermatocytes. AB - Claudin 3 is a protein component of the tight junction strands. Tight junctions between adjacent Sertoli cells form the blood-testis barrier (BTB). During spermatogenesis, seminiferous stage-specific expression of claudin 3 is believed to regulate the migration of preleptotene/leptotene spermatocytes across the BTB. Here, we determined the cell types expressing claudin 3 in adult mouse testis and investigated spermatogenesis after testis-specific in vivo knockdown of claudin 3. The results of in situ hybridization revealed that claudin 3 mRNA was predominantly expressed in germ cells near the basal lamina of seminiferous tubules at stages VI-IX. Furthermore, claudin 3 protein was localized not only to the BTB but also to the cell membrane of STRA8-expressing preleptotene/leptotene spermatocytes in the testis of adult ICR.Cg-Tg(Stra8-EGFP)1Ysa/YsaRbrc mice. Although claudin 3 knockdown did not affect BTB integrity, it did cause a partial delay in spermatocyte migration across the BTB. Moreover, claudin 3 knockdown resulted in a prolonged preleptotene phase during spermatogenesis. These data indicate that the seminiferous stage-specific expression and localization of claudin 3 during spermatogenesis regulate the progression of meiosis by promoting germ cell migration across the BTB. PMID- 23677977 TI - A 1.1-Mb segmental deletion on the X chromosome causes meiotic failure in male mice. AB - The mammalian X chromosome contains a large number of multicopy genes that are expressed during spermatogenesis. The roles of these genes during germ cell development and the functional significance of gene multiplication remain mostly unexplored, as the presence of multicopy gene families poses a challenge for genetic studies. Here we report the deletion of a 1.1-Mb segment of the mouse X chromosome that is syntenic with the human Xq22.1 region and contains 20 genes that are expressed predominantly in testis and brain, including three members of the nuclear export factor gene family (Nxf2, Nxf3, and Nxf7) and five copies of preferentially expressed antigen in melanoma-like 3 (Pramel3). We have shown that germline-specific Cre/loxP-mediated deletion of this 1.1-Mb segment is efficient and causes defective chromosomal synapsis, meiotic arrest, and sterility in male mice. Our results demonstrate that this 1.1-Mb region contains one or more novel X-linked factors that are essential for male meiosis. PMID- 23677979 TI - FOXC1 is enriched in the mammary luminal progenitor population, but is not necessary for mouse mammary ductal morphogenesis. AB - Expression of FOXC1, a forkhead box transcription factor, correlates with the human basal-like breast cancer (BLBC) subtype, and functional analyses have revealed its importance for in vitro invasiveness of BLBC cells. Women diagnosed with this breast tumor subtype have a poorer outcome because of the lack of targeted therapies; thus, continued investigation of factors driving these tumors is critical to uncover novel therapeutic targets. Several processes that dictate normal mammary morphogenesis parallel cancer progression, and enforced expression of FOXC1 can induce a progenitor state in more-differentiated mammary epithelial cells. Consequently, evaluating how FOXC1 functions in the normal gland is critical to further understand BLBC biology. Although FOXC1 is well known to control normal development of a number of tissues, its role in the mammary gland has not yet been investigated. Herein, we describe FOXC1 expression patterning in the normal breast, where it is localized to the basal/myoepithelium, suggesting that FOXC1 would be required for normal development. However, mammary glands lacking Foxc1 have no overt defect in ductal outgrowth, alveologenesis, or lineage specification. Of significant interest, we found that expression of FOXC1 is enriched in the normal luminal progenitor population, which is the postulated cell of origin of BLBC. These results indicate that FOXC1 is unnecessary for mammary morphogenesis and that its role in BLBC likely involves processes that are unrelated to cell lineage specification. PMID- 23677981 TI - Control of spontaneous activation of rat oocytes by regulating plasma membrane Na+/Ca2+ exchanger activities. AB - Inhibiting oocyte spontaneous activation (SA) is essential for successful rat cloning by nuclear transfer (NT). This study tested the hypothesis that activities of the Na(+)/Ca(2+) exchanger (NCX) would decrease with oocyte aging and that SA of rat oocytes could be inhibited if the intraoocyte Ca(2+) rises were prevented by activating the NCX through increasing Na(+) concentrations in the culture medium. Elevating Na(+) levels in culture medium by supplementing NaCl inhibited SA of rat oocytes, while maintaining a constant level of maturation-promoting factor and mitogen-activated protein kinase activities. Experiments using the NCX inhibitor bepridil, the Na(+)/K(+)-ATPase inhibitor ouabain, and an assay for intraoocyte Ca(2+) concentrations showed that extracellular Na(+) inhibited rat oocyte SA by enhancing NCX activity and preventing intracellular Ca(2+) rises. Immunohistochemical quantification indicated that the density of NCX1 decreased significantly in aged oocytes that were prone to SA compared with that in freshly ovulated oocytes whose SA rates were low during in vitro culture. Cumulus cell NT showed that sham enucleation caused marked SA in freshly ovulated rat oocytes and that Na(+) supplementation prevented the manipulation-induced SA and improved the in vitro and in vivo development of rat somatic cell NT embryos. Taken together, the results have confirmed our hypothesis that the NCX is active in rat oocytes and its activity decreases with oocyte aging and that activating the NCX by increasing extracellular Na(+) inhibits SA of rat oocytes and improves the development of rat somatic cell NT embryos. These data are also important for understanding the mechanisms of oocyte aging. PMID- 23677982 TI - NHE1 is the sodium-hydrogen exchanger active in acute intracellular pH regulation in preimplantation mouse embryos. AB - Sodium-hydrogen exchangers (NHE) of the Slc9 gene family are the major regulators of intracellular pH against acidosis in mammalian cells. Of five plasma membrane NHE isoforms, mouse oocytes and preimplantation embryos express mRNAs encoding NHE1 (SLC9A1), NHE3 (SLC9A3), and NHE4 (SLC9A4), with higher mRNA levels for each in oocytes through one-cell stage embryos and lower levels after the two-cell stage. NHE2 (SLC9A2) and NHE5 (SLC9A5) are not expressed. Measurements of intracellular pH during recovery from induced acidosis indicated that recovery occurred via NHE activity at all preimplantation stages assessed (one-cell, two cell, eight-cell and morula). Recovery from acidosis at each stage was entirely inhibited by cariporide, which is very highly selective for NHE1. In contrast, the moderately NHE3-selective inhibitor S3226 did not preferentially block recovery, nor did adding S3226 increase inhibition over cariporide alone, indicating that NHE3 did not play a role. There was no indication of NHE4 activity. Another regulator of intracellular pH against acidosis, the sodium dependent bicarbonate/chloride exchanger (NDBCE; SLC4A8), had low or absent activity in two-cell embryos. Thus, NHE1 appears to be the only significant regulator of intracellular pH in preimplantation mouse embryos. Culturing embryos from the one-cell or two-cell stages in acidotic medium inhibited their development. Unexpectedly, inhibition of NHE1 with cariporide, NDBCE with DIDS, or both together did not affect embryo development to the blastocyst stage more substantially under conditions of chronic acidosis than at normal pH. Preimplantation mouse embryos thus appear to have limited capacity to resist chronic acidosis using intracellular pH regulatory mechanisms. PMID- 23677983 TI - Lipopolysaccharide drives alternation of heat shock proteins and induces failure of blastocyst implantation in mouse. AB - The objective of the present study is to investigate the role of heat shock proteins (Hsps) in preimplantation embryonic development and uterine receptivity during lipopolysaccharide (LPS)-induced pregnancy loss. Mice were treated with PBS or LPS on Day 0.5 of pregnancy, and preimplantation embryos and uterus were collected on Days 1.5-4.42 of pregnancy. The individual preimplantation embryos were assessed for their morphologic appearance and DNA damage during the preimplantation period of pregnancy. The expression of Hsp90, Hsp70, Hsp60, and Hsp25 was determined in preimplantation embryos and uterus by RT-PCR. Comet studies showed that LPS treatment significantly increased the percentage of abnormal embryos and DNA damage in the embryos. The expression of Hsp90, Hsp70, and Hsp60 was significantly lower in preimplantation embryos recovered from LPS treated mice when compared to their respective controls. The expression of Hsp90, Hsp70, Hsp60, and Hsp25 was altered in uterus of LPS-treated mice when compared to their respective controls. Immunohistochemistry studies showed that at the time of implantation (i.e., Day 4.42), levels of Hsp90 and Hsp60 were decreased in stromal cells of LPS-treated uterus when compared to their respective controls. Hsp25 was highly expressed in the endometrium and stromal cells of LPS treated uterus. Our results clearly showed that lowering of embryonic expression of Hsps induces DNA damage, which leads to degeneration and degradation of preimplantation embryos, and altered uterine expression of Hsps may not prepare the uterus for implantation. This may ultimately lead to implantation failure in mouse. PMID- 23677984 TI - Transcriptional wiring for establishing cell lineage specification at the blastocyst stage in cattle. AB - Mice and cattle use distinct pathways for the first cell segregation into inner cell mass (ICM) and trophectoderm (TE) lineages at the blastocyst stage. However, limited knowledge is available regarding the reliable transcriptional networks that orchestrate the complex developmental processes at this stage in nonrodent species. In order to elucidate the site-dominant transcriptomic properties of bovine blastocysts, we separated cell samples into the ICM and TE using both mechanical and chemical methods and performed in silico prescreening for candidate genes that were site-dominantly expressed in bovine blastocysts. We further performed quantitative real-time PCR and in situ hybridization using the site-specific cell samples. As a result, we identified seven ICM-dominant genes and five TE-dominant genes not found in earlier studies. Our findings provide novel insights into the mechanism of cell-fate specification in the pre implantation bovine embryo. PMID- 23677985 TI - Low 17beta-estradiol levels in CNR1 knock-out mice affect spermatid chromatin remodeling by interfering with chromatin reorganization. AB - The type 1-cannabinoid receptor, CNR1, regulates differentiation of spermatids. Indeed, we have recently reported that the genetic inactivation of Cnr1 in mice influenced chromatin remodeling of spermatids, by reducing histone displacement and then sperm chromatin quality indices (chromatin condensation and DNA integrity). Herein, we have studied, at both central and testicular levels, the molecular signals potentially involved in histone displacement. In particular, investigation of the neuroendocrine axis involved in estrogen production demonstrated down-regulation of the axis supporting FSH/estrogen secretion in Cnr1-knockout male mice. Conversely, Cnr1-knockout male mice treated with 17beta estradiol showed a weak increase of pituitary Fsh-beta subunit mRNA levels and a rescue of sperm chromatin quality indices demonstrating that estrogens, possibly in combination with FSH secretion, play an important role in regulating chromatin remodeling of spermatids. PMID- 23677986 TI - Biosynthesis and degradation of canine placental prostaglandins: prepartum changes in expression and function of prostaglandin F2alpha-synthase (PGFS, AKR1C3) and 15-hydroxyprostaglandin dehydrogenase (HPGD). AB - There is no distinct explanation of the mechanism for the prepartal prostaglandin F2alpha (PGF2alpha) increase in pregnant dogs. Although the PGF2alpha-synthase (PGFS [AKR1C3]) mRNA expression and localization profiles have been previously investigated in canine utero/placental compartments, the availability and biochemical activity of the PGFS (AKR1C3) protein remain unknown. In order to better understand the regulation of canine uterine PGF2alpha availability and eventual prepartum release in luteolytic amounts in dogs, canine-specific PGFS (AKR1C3) and 15-hydroxyprostaglandin dehydrogenase (HPGD) antibodies were generated and used to characterize the expression, cellular localization, and biochemical properties of PGFS (AKR1C3) and HPGD in the utero/placental compartments and corpus luteum throughout pregnancy and at prepartum luteolysis. PGFS (AKR1C3) expression was weak or absent in luteal samples. Uterine PGFS (AKR1C3) was up-regulated postimplantation and declined prepartum. The utero/placental expression of PGFS (AKR1C3) was identified in the superficial uterine glands throughout gestation and in the trophoblast cells within the feto maternal contact zone during placentation, suggesting a possible role for PGFS (AKR1C3) in the trophoblast invasion. Utero-placental HPGD was up-regulated until postimplantation, lower at midgestation, and greatly suppressed at prepartum. Expression was routinely identified in the endometrial surface and glandular epithelia, and positive signals were also observed in the trophoblast cells at the feto-maternal contact zone. The biochemical activity of recombinant PGFS (AKR1C3) and HPGD was confirmed after its expression in a heterologous system. The colocalization of HPGD with PGFS (AKR1C3) expression suggests a modulatory role for HPGD as a gatekeeper of the supply of prostaglandin in the pregnant canine uterus. PMID- 23677987 TI - In vivo optical coherence tomography (OCT) in periocular basal cell carcinoma: correlations between in vivo OCT images and postoperative histology. AB - AIM: To investigate in vivo optical coherence tomography (OCT) for imaging of periocular basal cell carcinoma (BCC). METHODS: Consecutive patients with periocular BCC were prospectively investigated with VivoSight OCT imaging prior to surgical excision. Histology sections were compared with OCT images with regard to lesion measurements (x, y and z dimensions) and histological features. RESULTS: A total of 15 patients with biopsy proven BCC were recruited. The OCT horizontal margins correlated positively with histology (r=0.8 and 0.66, x and y axes) and could be identified in 3/15 (x axis) and 6/15 (y axis) cases. The vertical margin correlation was r=0.43 and BCC depth could be measured in 9/15 cases. The following histological features of BCC could be identified on OCT images: (1) lobular pattern (100%); (2) dilated blood vessels (80%); (3) reflective margins of tumour lobules (100%); and (4) epidermal thinning overlying BCC lobules (100%). CONCLUSIONS: This study indicated a strong positive correlation between the margins of periocular BCCs measured using in vivo OCT and histology, and a weak positive correlation with depth of invasion. VivoSight OCT produced high resolution images of BCC morphology. The limitations in horizontal margin measurements could potentially be overcome by design modification of the scanning probe. PMID- 23677988 TI - Efficacy of split hours part-time patching versus continuous hours part-time patching for treatment of anisometropic amblyopia in children: a pilot study. AB - AIM: To compare efficacy of 'split hours part-time patching' and 'continuous hours part-time patching' for the treatment of anisometropic amblyopia. METHODS: We designed a prospective, interventional, non-randomised, comparative pilot study involving children between 4 and 11 years of age with anisometropic amblyopia who were treated with either continuous wear (Group A) or split hours part-time patching (Group B) as per parents wish, after appropriate discussion with the parents. Children were followed-up for the improvement in visual acuity and the compliance at each follow-up visit. RESULTS: 44 and 24 children were recruited in Group A and Group B, respectively (mean +/- SD baseline BCVA of the amblyopic eye: 0.99 +/- 0.32 and 0.95 +/- 0.23 logMAR, respectively). BCVA (adjusted for baseline BCVA and age) at 3 months in Group A (0.59 +/- 0.24) was comparable (p=0.08) with that in Group B (0.71 +/- 0.24). This was same even at 6 months (0.51 +/- 0.25 in Group A and 0.59 +/- 0.25 in Group B, p=0.25). The improvement in BCVA at 3 months was also comparable (p=0.06) in Group A (0.39 +/- 0.23) and Group B (0.26 +/- 0.23). The improvement in BCVA at 6 months was also comparable (p=0.14) in Group A (0.47 +/- 0.26) and Group B (0.37 +/- 0.26). CONCLUSIONS: Both patching regimens lead to significant and comparable improvement in BCVA in anisometropic amblyopia up to 6 months of follow-up. PMID- 23677989 TI - Nilotinib induces autophagy in hepatocellular carcinoma through AMPK activation. AB - Hepatocellular carcinoma (HCC) is the most common liver cancer and the third leading cause of cancer death worldwide. Nilotinib is an orally available receptor tyrosine kinase inhibitor approved for chronic myelogenous leukemia. This study investigated the effect of nilotinib on HCC. Nilotinib did not induce cellular apoptosis. Instead, staining with acridine orange and microtubule associated protein 1 light chain 3 revealed that nilotinib induced autophagy in a dose- and time-dependent manner in HCC cell lines, including PLC5, Huh-7, and Hep3B. Moreover, nilotinib up-regulated the phosphryaltion of AMP-activated kinase (AMPK) and protein phosphatase PP2A inactivation were detected after nilotinib treatment. Up-regulating PP2A activity suppressed nilotinib-induced AMPK phosphorylation and autophagy, suggesting that PP2A mediates the effect of nilotinib on AMPK phosphorylation and autophagy. Our data indicate that nilotinib induced AMPK activation is mediated by PP2A, and AMPK activation and subsequent autophagy might be a major mechanism of action of nilotinib. Growth of PLC5 tumor xenografts in BALB/c nude mice was inhibited by daily oral treatment with nilotinib. Western blot analysis showed both increased phospho-AMPK expression and decreased PP2A activity in vivo. Together, our results reveal that nilotinib induces autophagy, but not apoptosis in HCC, and that the autophagy-inducing activity is associated with PP2A-regulated AMPK phosphorylation. PMID- 23677990 TI - Conserved gating elements in TRPC4 and TRPC5 channels. AB - TRPC4 and TRPC5 proteins share 65% amino acid sequence identity and form Ca(2+) permeable nonselective cation channels. They are activated by stimulation of receptors coupled to the phosphoinositide signaling cascade. Replacing a conserved glycine residue within the cytosolic S4-S5 linker of both proteins by a serine residue forces the channels into an open conformation. Expression of the TRPC4G503S and TRPC5G504S mutants causes cell death, which could be prevented by buffering the Ca(2+) of the culture medium. Current-voltage relationships of the TRPC4G503S and TRPC5G504S mutant ion channels resemble that of fully activated TRPC4 and TRPC5 wild-type channels, respectively. Modeling the structure of the transmembrane domains and the pore region (S4-S6) of TRPC4 predicts a conserved serine residue within the C-terminal sequence of the predicted S6 helix as a potential interaction site. Introduction of a second mutation (S623A) into TRPC4G503S suppressed the constitutive activation and partially rescued its function. These results indicate that the S4-S5 linker is a critical constituent of TRPC4/C5 channel gating and that disturbance of its sequence allows channel opening independent of any sensor domain. PMID- 23677991 TI - Specificity of intersubunit general anesthetic-binding sites in the transmembrane domain of the human alpha1beta3gamma2 gamma-aminobutyric acid type A (GABAA) receptor. AB - GABA type A receptors (GABAAR), the brain's major inhibitory neurotransmitter receptors, are the targets for many general anesthetics, including volatile anesthetics, etomidate, propofol, and barbiturates. How such structurally diverse agents can act similarly as positive allosteric modulators of GABAARs remains unclear. Previously, photoreactive etomidate analogs identified two equivalent anesthetic-binding sites in the transmembrane domain at the beta(+)-alpha(-) subunit interfaces, which also contain the GABA-binding sites in the extracellular domain. Here, we used R-[(3)H]5-allyl-1-methyl-5-(m-trifluoromethyl diazirynylphenyl) barbituric acid (R-mTFD-MPAB), a potent stereospecific barbiturate anesthetic, to photolabel expressed human alpha1beta3gamma2 GABAARs. Protein microsequencing revealed that R-[(3)H]mTFD-MPAB did not photolabel the etomidate sites at the beta(+)-alpha(-) subunit interfaces. Instead, it photolabeled sites at the alpha(+)-beta(-) and gamma(+)-beta(-) subunit interfaces in the transmembrane domain. On the (+)-side, alpha1M3 was labeled at Ala-291 and Tyr-294 and gamma2M3 at Ser-301, and on the (-)-side, beta3M1 was labeled at Met-227. These residues, like those in the etomidate site, are located at subunit interfaces near the synaptic side of the transmembrane domain. The selectivity of R-etomidate for the beta(+)-alpha(-) interface relative to the alpha(+)-beta(-)/gamma(+)-beta(-) interfaces was >100-fold, whereas that of R mTFD-MPAB for its sites was >50-fold. Each ligand could enhance photoincorporation of the other, demonstrating allosteric interactions between the sites. The structural heterogeneity of barbiturate, etomidate, and propofol derivatives is accommodated by varying selectivities for these two classes of sites. We hypothesize that binding at any of these homologous intersubunit sites is sufficient for anesthetic action and that this explains to some degree the puzzling structural heterogeneity of anesthetics. PMID- 23677992 TI - High specificity in CheR methyltransferase function: CheR2 of Pseudomonas putida is essential for chemotaxis, whereas CheR1 is involved in biofilm formation. AB - Chemosensory pathways are a major signal transduction mechanism in bacteria. CheR methyltransferases catalyze the methylation of the cytosolic signaling domain of chemoreceptors and are among the core proteins of chemosensory cascades. These enzymes have primarily been studied Escherichia coli and Salmonella typhimurium, which possess a single CheR involved in chemotaxis. Many other bacteria possess multiple cheR genes. Because the sequences of chemoreceptor signaling domains are highly conserved, it remains to be established with what degree of specificity CheR paralogues exert their activity. We report here a comparative analysis of the three CheR paralogues of Pseudomonas putida. Isothermal titration calorimetry studies show that these paralogues bind the product of the methylation reaction, S-adenosylhomocysteine, with much higher affinity (KD of 0.14-2.2 MUM) than the substrate S-adenosylmethionine (KD of 22-43 MUM), which indicates product feedback inhibition. Product binding was particularly tight for CheR2. Analytical ultracentrifugation experiments demonstrate that CheR2 is monomeric in the absence and presence of S-adenosylmethionine or S-adenosylhomocysteine. Methylation assays show that CheR2, but not the other paralogues, methylates the McpS and McpT chemotaxis receptors. The mutant in CheR2 was deficient in chemotaxis, whereas mutation of CheR1 and CheR3 had either no or little effect on chemotaxis. In contrast, biofilm formation of the CheR1 mutant was largely impaired but not affected in the other mutants. We conclude that CheR2 forms part of a chemotaxis pathway, and CheR1 forms part of a chemosensory route that controls biofilm formation. Data suggest that CheR methyltransferases act with high specificity on their cognate chemoreceptors. PMID- 23677993 TI - Deregulation of apoptotic factors Bcl-xL and Bax confers apoptotic resistance to myeloid-derived suppressor cells and contributes to their persistence in cancer. AB - Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells that accumulate in response to tumor progression. Compelling data from mouse models and human cancer patients showed that tumor-induced inflammatory mediators induce MDSC differentiation. However, the mechanisms underlying MDSC persistence is largely unknown. Here, we demonstrated that tumor-induced MDSCs exhibit significantly decreased spontaneous apoptosis as compared with myeloid cells with the same phenotypes from tumor-free mice. Consistent with the decreased apoptosis, cell surface Fas receptor decreased significantly in tumor-induced MDSCs. Screening for changes of key apoptosis mediators downstream the Fas receptor revealed that expression levels of IRF8 and Bax are diminished, whereas expression of Bcl-xL is increased in tumor-induced MDSCs. We further determined that IRF8 binds directly to Bax and Bcl-x promoter in primary myeloid cells in vivo, and IRF8-deficient MDSC-like cells also exhibit increased Bcl-xL and decreased Bax expression. Analysis of CD69 and CD25 levels revealed that cytotoxic T lymphocytes (CTLs) are partially activated in tumor-bearing hosts. Strikingly, FasL but not perforin and granzymes were selectively activated in CTLs in the tumor-bearing host. ABT-737 significantly increased the sensitivity of MDSCs to Fas-mediated apoptosis in vitro. More importantly, ABT-737 therapy increased MDSC spontaneous apoptosis and decreased MDSC accumulation in tumor bearing mice. Our data thus determined that MDSCs use down-regulation of IRF8 to alter Bax and Bcl-xL expression to deregulate the Fas-mediated apoptosis pathway to evade elimination by host CTLs. Therefore, targeting Bcl-xL is potentially effective in suppression of MDSC persistence in cancer therapy. PMID- 23677994 TI - Negative regulation of the acetyltransferase TIP60-p53 interplay by UHRF1 (ubiquitin-like with PHD and RING finger domains 1). AB - Numerous studies indicate the importance of acetylation in p53-mediated stress responses upon DNA damage. We and others previously showed that TIP60 (Tat interacting protein of 60 kDa)-mediated acetylation of p53 at K120 is crucial for p53-dependent apoptotic responses. Nevertheless, it remains unclear how TIP60 mediated effects on p53 are dynamically regulated in vivo. Here, we report that UHRF1 (ubiquitin-like with PHD and RING finger domains 1) interacts with TIP60 both in vitro and in vivo and induces degradation-independent ubiquitination of TIP60. Moreover, UHRF1 expression markedly suppresses the ability of TIP60 to acetylate p53. In contrast, RNAi-mediated knockdown of UHRF1 increases the endogenous levels of p53 acetylation at K120 and p53-mediated apoptosis is significantly enhanced in UHRF1-depleted cells. To elucidate the mechanisms of this regulation, we found that the interaction between TIP60 and p53 is severely inhibited in the presence of UHRF1, suggesting that UHRF1 modulates TIP60 mediated functions in both K120 acetylation-dependent and -independent manners. Consistent with this notion, UHRF1 knockdown promotes activation of p21 and PUMA but not MDM2. These findings demonstrate that UHRF1 is a critical negative regulator of TIP60 and suggest that UHRF1-mediated effects on p53 may contribute, at least in part, to its role in tumorigenesis. PMID- 23677995 TI - HIV-2 and SIVmac accessory virulence factor Vpx down-regulates SAMHD1 enzyme catalysis prior to proteasome-dependent degradation. AB - SAMHD1, a dGTP-regulated deoxyribonucleoside triphosphate (dNTP) triphosphohydrolase, down-regulates dNTP pools in terminally differentiated and quiescent cells, thereby inhibiting HIV-1 infection at the reverse transcription step. HIV-2 and simian immunodeficiency virus (SIV) counteract this restriction via a virion-associated virulence accessory factor, Vpx (Vpr in some SIVs), which loads SAMHD1 onto CRL4-DCAF1 E3 ubiquitin ligase for polyubiquitination, programming it for proteasome-dependent degradation. However, the detailed molecular mechanisms of SAMHD1 recruitment to the E3 ligase have not been defined. Further, whether divergent, orthologous Vpx proteins, encoded by distinct HIV/SIV strains, bind SAMHD1 in a similar manner, at a molecular level, is not known. We applied surface plasmon resonance analysis to assess the requirements for and kinetics of binding between various primate SAMHD1 proteins and Vpx proteins from SIV or HIV-2 strains. Our data indicate that Vpx proteins, bound to DCAF1, interface with the C terminus of primate SAMHD1 proteins with nanomolar affinity, manifested by rapid association and slow dissociation. Further, we provide evidence that Vpx binding to SAMHD1 inhibits its catalytic activity and induces disassembly of a dGTP-dependent oligomer. Our studies reveal a previously unrecognized biochemical mechanism of Vpx-mediated SAMHD1 inhibition: direct down-modulation of its catalytic activity, mediated by the same binding event that leads to SAMHD1 recruitment to the E3 ubiquitin ligase for proteasome-dependent degradation. PMID- 23677996 TI - Biochemical features of a catalytic antibody light chain, 22F6, prepared from human lymphocytes. AB - Human antibody light chains belonging to subgroup II of germ line genes were amplified by a seminested PCR technique using B-lymphocytes taken from a human adult infected with influenza virus. Each gene of the human light chains was transferred into the Escherichia coli system. The recovered light chain was highly purified using a two-step purification system. Light chain 22F6 showed interesting catalytic features. The light chain cleaved a peptide bond of synthetic peptidyl-4-methyl-coumaryl-7-amide (MCA) substrates, such as QAR-MCA and EAR-MCA, indicating amidase activity. It also hydrolyzed a phosphodiester bond of both DNA and RNA. From the analysis of amino acid sequences and molecular modeling, the 22F6 light chain possesses two kinds of active sites as amidase and nuclease in close distances. The 22F6 catalytic light chain could suppress the infection of influenza virus type A (H1N1) of Madin-Darby canine kidney cells in an in vitro assay. In addition, the catalytic light chain clearly inhibited the infection of the influenza virus of BALB/c mice via nasal administration in an in vivo assay. In the experiment, the titer in the serum of the mice coinfected with the 22F6 light chain and H1N1 virus became considerably lowered compared with that of 22F6-non-coinfected mice. Note that the catalytic light chain was prepared from human peripheral lymphocyte and plays an important role in preventing infection by influenza virus. Considering the fact that the human light chain did not show any acute toxicity for mice, our procedure developed in this study must be unique and noteworthy for developing new drugs. PMID- 23677997 TI - Hydrolysis of extracellular ATP by ectonucleoside triphosphate diphosphohydrolase (ENTPD) establishes the set point for fibrotic activity of cardiac fibroblasts. AB - The establishment of set points for cellular activities is essential in regulating homeostasis. Here, we demonstrate key determinants of the fibrogenic set point of cardiac fibroblasts (CFs) by focusing on the pro-fibrotic activity of ATP, which is released by CFs. We tested the hypothesis that the hydrolysis of extracellular ATP by ectonucleoside triphosphate diphosphohydrolases (ENTPDs) regulates pro-fibrotic nucleotide signaling. We detected two ENTPD isoforms, ENTPD-1 and -2, in adult rat ventricular CFs. Partial knockdown of ENTPD-1 and -2 with siRNA increased basal extracellular ATP concentration and enhanced the pro fibrotic effect of ATP stimulation. Sodium polyoxotungstate-1, an ENTPD inhibitor, not only enhanced the pro-fibrotic effects of exogenously added ATP but also increased basal expression of alpha-smooth muscle actin, plasminogen activator inhibitor-1 and transforming growth factor (TGF)-beta, collagen synthesis, and gel contraction. Furthermore, we found that adenosine, a product of ATP hydrolysis by ENTPD, acts via A2B receptors to counterbalance the pro fibrotic response to ATP. Removal of extracellular adenosine or inhibition of A2B receptors enhanced pro-fibrotic ATP signaling. Together, these results demonstrate the contribution of basally released ATP in establishing the set point for fibrotic activity in adult rat CFs and identify a key role for the modulation of this activity by hydrolysis of released ATP by ENTPDs. These findings also imply that cellular homeostasis and fibrotic response involve the integration of signaling that is pro-fibrotic by ATP and anti-fibrotic by adenosine and that is regulated by ENTPDs. PMID- 23677998 TI - Dynamics of the antigen-binding grooves in CD1 proteins: reversible hydrophobic collapse in the lipid-free state. AB - CD1 proteins mediate the presentation of endogenous and foreign lipids on the cell surface for recognition by T cell receptors. To sample a diverse antigen pool, CD1 proteins are repeatedly internalized and recycled, assisted, in some cases, by lipid transfer proteins such as saposins. The specificity of each CD1 isoform is, therefore, conferred in part by its intracellular pathway but also by distinct structural features of the antigen-binding domain. Crystal structures of CD1-lipid complexes reveal hydrophobic grooves and pockets within these binding domains that appear to be specialized for different lipids. However, the mechanism of lipid loading and release remains to be characterized. Here we gain insights into this mechanism through a meta-analysis of the five human CD1 isoforms, in the lipid-bound and lipid-free states, using all-atom molecular dynamics simulations. Strikingly, for isoforms CD1b through CD1e, our simulations show the near-complete collapse of the hydrophobic cavities in the absence of the antigen. This event results from the spontaneous closure of the binding domain entrance, flanked by two alpha-helices. Accordingly, we show that the anatomy of the binding cavities is restored if these alpha-helices are repositioned extrinsically, suggesting that helper proteins encountered during recycling facilitate lipid exchange allosterically. By contrast, we show that the binding cavity of CD1a is largely preserved in the unliganded state because of persistent electrostatic interactions that keep the portal alpha-helices at a constant separation. The robustness of this binding groove is consistent with the observation that lipid exchange in CD1a is not dependent on cellular internalization. PMID- 23677999 TI - Evolutionary changes in chlorophyllide a oxygenase (CAO) structure contribute to the acquisition of a new light-harvesting complex in micromonas. AB - Chlorophyll b is found in photosynthetic prokaryotes and primary and secondary endosymbionts, although their light-harvesting systems are quite different. Chlorophyll b is synthesized from chlorophyll a by chlorophyllide a oxygenase (CAO), which is a Rieske-mononuclear iron oxygenase. Comparison of the amino acid sequences of CAO among photosynthetic organisms elucidated changes in the domain structures of CAO during evolution. However, the evolutionary relationship between the light-harvesting system and the domain structure of CAO remains unclear. To elucidate this relationship, we investigated the CAO structure and the pigment composition of chlorophyll-protein complexes in the prasinophyte Micromonas. The Micromonas CAO is composed of two genes, MpCAO1 and MpCAO2, that possess Rieske and mononuclear iron-binding motifs, respectively. Only when both genes were introduced into the chlorophyll b-less Arabidopsis mutant (ch1-1) was chlorophyll b accumulated, indicating that cooperation between the two subunits is required to synthesize chlorophyll b. Although Micromonas has a characteristic light-harvesting system in which chlorophyll b is incorporated into the core antennas of reaction centers, chlorophyll b was also incorporated into the core antennas of reaction centers of the Arabidopsis transformants that contained the two Micromonas CAO proteins. Based on these results, we discuss the evolutionary relationship between the structures of CAO and light-harvesting systems. PMID- 23678001 TI - Identification of a highly conserved surface on Tat variants. AB - Extracellular Tat is suspected to protect HIV-1-infected cells from cellular immunity. Seropositive patients are unable to produce neutralizing antibodies against Tat, and Tat is still secreted under antiviral treatment. In mice, the Tat OYI vaccine candidate generates neutralizing antibodies such as the mAb 7G12. A peptide called MIMOOX was designed from fragments of Tat OYI identified as the possible binding site for mAb 7G12. MIMOOX was chemically synthesized, and its structure was stabilized with a disulfide bridge. Circular dichroism spectra showed that MIMOOX had mainly beta turns but no alpha helix as Tat OYI. MIMOOX was recognized by mAb 7G12 in ELISA only in reduced conditions. Moreover, a competitive recognition assay with mAb 7G12 between MIMOOX and Tat variants showed that MIMOOX mimics a highly conserved surface in Tat variants. Rat immunizations with MIMOOX induce antibodies recognizing Tat variants from the main HIV-1 subtypes and confirm the Tat OYI vaccine approach. PMID- 23678000 TI - Cardiomyocyte ATP production, metabolic flexibility, and survival require calcium flux through cardiac ryanodine receptors in vivo. AB - Ca(2+) fluxes between adjacent organelles are thought to control many cellular processes, including metabolism and cell survival. In vitro evidence has been presented that constitutive Ca(2+) flux from intracellular stores into mitochondria is required for basal cellular metabolism, but these observations have not been made in vivo. We report that controlled in vivo depletion of cardiac RYR2, using a conditional gene knock-out strategy (cRyr2KO mice), is sufficient to reduce mitochondrial Ca(2+) and oxidative metabolism, and to establish a pseudohypoxic state with increased autophagy. Dramatic metabolic reprogramming was evident at the transcriptional level via Sirt1/Foxo1/Pgc1alpha, Atf3, and Klf15 gene networks. Ryr2 loss also induced a non-apoptotic form of programmed cell death associated with increased calpain-10 but not caspase-3 activation or endoplasmic reticulum stress. Remarkably, cRyr2KO mice rapidly exhibited many of the structural, metabolic, and molecular characteristics of heart failure at a time when RYR2 protein was reduced 50%, a similar degree to that which has been reported in heart failure. RYR2-mediated Ca(2+) fluxes are therefore proximal controllers of mitochondrial Ca(2+), ATP levels, and a cascade of transcription factors controlling metabolism and survival. PMID- 23678002 TI - Differential regulation of c-Jun protein plays an instrumental role in chemoresistance of cancer cells. AB - The chemotherapeutic drug cisplatin (cis-diamminedichloroplatinum(II) (CDDP)) is widely used in the treatment of human cancers. However, the mechanism underlying intrinsic tumor resistance to CDDP remains elusive. Here, we demonstrate that treatment with CDDP resulted in down-regulation of c-Jun expression via caspase-9 dependent cleavage of c-Jun at Asp-65 and MEKK1-mediated ubiquitylation and degradation of c-Jun in CDDP-sensitive cancer cells. In contrast, activation of JNK2 (but not JNK1) phosphorylated and up-regulated the expression of c-Jun in CDDP-resistant cells. Activated c-Jun bound to the promoter regions of the MDR1 gene and promoted the expression of MDR1. Expression of a cleavage-resistant c Jun mutant (D65A) suppressed CDDP-induced apoptosis of CDDP-sensitive cells, whereas depletion of JNK2, c-Jun, or MDR1 in CDDP-resistant cancer cells promoted apoptosis upon CDDP treatment. In addition, mammary gland tumors induced by polyomavirus middle T antigen in JNK2(-/-) mice were more sensitive to CDDP compared with those in JNK2(+/+) mice. These findings highlight the instrumental role of c-Jun in the resistance of tumors to treatment with CDDP and indicate that c-Jun is a molecular target for improving cancer therapy. PMID- 23678003 TI - Adenosine production by human B cells and B cell-mediated suppression of activated T cells. AB - Antibody-independent role of B cells in modulating T-cell responses is incompletely understood. Freshly isolated or cultured B cells isolated from the peripheral blood of 30 normal donors were evaluated for CD39 and CD73 coexpression, the ability to produce adenosine 5'-monophosphate (AMP) and adenosine (ADO) in the presence of exogenous adenosine triphosphate (ATP) as well as A1, A2A, A2B, and A3 adenosine receptor (ADOR) expression. Human circulating B cells coexpress ectonucleotidases CD39 and CD73, hydrolyze exogenous ATP to 5' AMP and ADO, and express messenger RNA for A1R, A2AR, and A3R. 2-chloroadenosine inhibited B-cell proliferation and cytokine expression, and only A3R selective antagonist restored B-cell functions. This suggested that B cells use the A3R for autocrine signaling and self-regulation. Mediated effects on B-cell growth +/- ADOR antagonists or agonists were tested in carboxyfluorescein diacetate succinimidyl ester assays. In cocultures, resting B cells upregulated functions of CD4+ and CD8+ T cells. However, in vitro-activated B cells downregulated CD73 expression, mainly produced 5'-AMP, and inhibited T-cell proliferation and cytokine production. These B cells acquire the ability to restrict potentially harmful effects of activated T cells. Thus, B cells emerge as a key regulatory component of T cell-B cell interactions, and their dual regulatory activity is mediated by the products of ATP hydrolysis, 5'-AMP, and ADO. PMID- 23678005 TI - Effects and outcome of a policy of intermittent imatinib treatment in elderly patients with chronic myeloid leukemia. AB - We report a study of an alternative treatment schedule of imatinib (IM) in chronic myeloid leukemia (CML). Seventy-six Philadelphia-positive (Ph+), BCR-ABL positive patients aged 65 years or older who had been treated with IM for more than 2 years and who were in stable complete cytogenetic response (CCgR) and major molecular response (MMR) were enrolled in a single-arm study to test the effects of a policy of intermittent IM (INTERIM) therapy for 1 month on and 1 month off. With a minimum follow-up of 4 years, 13 patients (17%) lost CCgR and MMR and 14 (18%) lost MMR only. All these patients resumed continuous IM and all but one (lost to follow-up) regained CCgR and MMR. No patients progressed to accelerated or blastic phase or developed clonal chromosomal abnormalities in Ph+ cells or BCR-ABL mutations. In elderly Ph+ CML patients carefully selected for a stable CCgR (lasting >2 years), the policy of INTERIM treatment affected the markers of residual disease, but not the clinical outcomes (overall and progression-free survival). This trial was registered at www.clinicaltrials.gov as NCT 00858806. PMID- 23678004 TI - Parp-2 is required to maintain hematopoiesis following sublethal gamma irradiation in mice. AB - Hematopoietic stem cells self-renew for life to guarantee the continuous supply of all blood cell lineages. Here we show that Poly(ADP-ribose) polymerase-2 (Parp 2) plays an essential role in hematopoietic stem/progenitor cells (HSPC) survival under steady-state conditions and in response to stress. Increased levels of cell death were observed in HSPC from untreated Parp-2-/- mice, but this deficit was compensated by increased rates of self-renewal, associated with impaired reconstitution of hematopoiesis upon serial bone marrow transplantation. Cell death after gamma-irradiation correlated with an impaired capacity to repair DNA damage in the absence of Parp-2. Upon exposure to sublethal doses of gamma irradiation, Parp-2-/- mice exhibited bone marrow failure that correlated with reduced long-term repopulation potential of irradiated Parp-2-/- HSPC under competitive conditions. In line with a protective role of Parp-2 against irradiation-induced apoptosis, loss of p53 or the pro-apoptotic BH3-only protein Puma restored survival of irradiated Parp-2-/- mice, whereas loss of Noxa had no such effect. Our results show that Parp-2 plays essential roles in the surveillance of genome integrity of HSPC by orchestrating DNA repair and restraining p53-induced and Puma-mediated apoptosis. The data may affect the design of drugs targeting Parp proteins and the improvement of radiotherapy-based therapeutic strategies. PMID- 23678006 TI - Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. AB - Blinatumomab is a CD19/CD3-bispecific T-cell receptor-engaging (BiTE) antibody with efficacy in refractory B-precursor acute lymphoblastic leukemia. Some patients treated with blinatumomab and other T cell-activating therapies develop cytokine release syndrome (CRS). We hypothesized that patients with more severe toxicity may experience abnormal macrophage activation triggered by the release of cytokines by T-cell receptor-activated cytotoxic T cells engaged by BiTE antibodies and leading to hemophagocytic lymphohistiocytosis (HLH). We prospectively monitored a patient during blinatumomab treatment and observed that he developed HLH. He became ill 36 hours into the infusion with fever, respiratory failure, and circulatory collapse. He developed hyperferritinemia, cytopenias, hypofibrinogenemia, and a cytokine profile diagnostic for HLH. The HLH continued to progress after discontinuation of blinatumomab; however, he had rapid improvement after IL-6 receptor-directed therapy with tocilizumab. Patients treated with T cell-activating therapies, including blinatumomab, should be monitored for HLH, and cytokine-directed therapy may be considered in cases of life-threatening CRS. This trial was registered at www.clinicaltrials.gov as #NCT00103285. PMID- 23678007 TI - The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions. AB - Although earlier, seminal studies demonstrated that the gut per se has the intrinsic ability to regulate the rates of iron absorption, the spotlight in the past decade has been placed on the systemic regulation of iron homeostasis by the hepatic hormone hepcidin and the molecular mechanisms that regulate its expression. Recently, however, attention has returned to the gut based on the finding that hypoxia inducible factor-2 (HIF-2alpha) regulates the expression of key genes that contribute to iron absorption. Here we review the current understanding of the molecular mechanisms that regulate iron homeostasis in the gut by focusing on the role of HIF-2 under physiological steady-state conditions and in the pathogenesis of iron-related diseases. We also discuss implications for adapting HIF-2-based therapeutic strategies in iron-related pathological conditions. PMID- 23678008 TI - p53 suppresses BRCA2-stimulated ATPase and strand exchange functions of human RAD51. AB - Although homologous recombination (HR) is an important pathway for DNA repair, it can also be a cause for deleterious genomic rearrangements leading to carcinogenesis. Therefore, cells have evolved elaborate mechanisms to regulate HR, positively as well as negatively. Among many molecular components that regulate HR are tumour suppressors p53, a negative regulator and breast cancer early-onset (BRCA)2, a positive regulator. Both the players not only interact with each other but also directly interact with human RAD51 (hRAD51), the key recombinase in HR. Here, for the first time we studied HR regulation by the combined action of p53 and BRCA2, in vitro. While BRC4 peptide inhibits ATP hydrolysis by hRAD51, BRCA2(BRC1-8) stimulates DNA-independent and double stranded DNA-dependent ATPase several fold and only marginally single-stranded DNA-dependent ATPase. Pull down assays demonstrated the occurrence of complex comprising of all three proteins and DNA, where p53 tends to compete out hRAD51 and BRCA2(BRC1-8), leading to not only the decline in ATP hydrolysis but also the strand exchange function of hRAD51 that was stimulated by BRCA2(BRC1-8). Our findings suggest a rigorous p53-mediated regulation on hRAD51 functions in HR even in the presence of BRCA2. PMID- 23678010 TI - Implicit representations of luminance and the temporal structure of moving stimuli in multiple regions of human visual cortex revealed by multivariate pattern classification analysis. AB - The generation of a behaviorally relevant cue to the speed of objects around us is critical to our ability to navigate safely within our environment. However, our perception of speed is often distorted by prevailing conditions. For instance, as luminance is reduced, our perception of the speed of fast-moving patterns can be increased by as much as 30%. To investigate how the cortical representation of speed may vary under such conditions, we have measured the functional MRI blood oxygen level-dependent (BOLD) response of visual cortex to drifting sine gratings at two very different luminances. The average BOLD response in all areas was band-pass with respect to speed (or equivalently, temporal frequency) and thus contained no unambiguous speed information. However, a multivariate classifier was able to predict grating speed successfully in all cortical areas measured. Similarly, we find that a multivariate classifier can predict stimulus luminance. No differences in either the mean BOLD response or the multivariate classifier response with respect to speed were found as luminance changed. However, examination of the spatial distribution of speed preferences in the primary visual cortex revealed that perifoveal locations preferred slower speeds than peripheral locations at low but not high luminance. We conclude that although an explicit representation of perceived speed has yet to be demonstrated in the human brain, multiple visual regions encode both the temporal structure of moving stimuli and luminance implicitly. PMID- 23678011 TI - Modulation of chest wall intermuscular coherence: effects of lung volume excursion and transcranial direct current stimulation. AB - Chest wall muscle recruitment varies as a function of the breathing task performed. However, the cortical control of the chest wall muscles during different breathing tasks is not known. We studied chest wall intermuscular coherence during various task-related lung volume excursions in 10 healthy adults (34 +/- 15 yr; 2 men, 8 women) and determined if transcranial direct current stimulation (tDCS) could modulate chest wall intermuscular coherence during these tasks. Simultaneous assessment of regional intercostal and oblique electromyographic activity was measured while participants performed standardized tidal breathing, speech, maximum phonation, and vital capacity tasks. Lung volume and chest wall kinematics were determined using variable inductance plethysmography. We found that chest wall area of intermuscular coherence was greater during tidal and speech breathing compared with phonation and vital capacity (all P < 0.05) and between tidal breathing compared with speech breathing (P < 0.05). Anodal tDCS increased chest wall area of intermuscular coherence from 0.04 +/- 0.09 prestimulation to 0.18 +/- 0.19 poststimulation for vital capacity (P < 0.05). Sham tDCS and cathodal tDCS had no effect on coherence during lung volume excursions. Chest wall kinematics were not affected by tDCS. Our findings indicate that lung volume excursions about the midrange of vital capacity elicit a greater area of chest wall intermuscular coherence compared with lung volume excursions spanning the entire range of vital capacity in healthy adults. Our findings also demonstrate that brief tDCS may modulate the cortical control of the chest wall muscles in a stimulation- and lung volume excursion task-dependent manner but does not affect chest wall kinematics in healthy adults. PMID- 23678009 TI - Phase shift in the 24-hour rhythm of hippocampal EEG spiking activity in a rat model of temporal lobe epilepsy. AB - For over a century epileptic seizures have been known to cluster at specific times of the day. Recent studies have suggested that the circadian regulatory system may become permanently altered in epilepsy, but little is known about how this affects neural activity and the daily pattern of seizures. To investigate, we tracked long-term changes in the rate of spontaneous hippocampal EEG spikes (SPKs) in a rat model of temporal lobe epilepsy. In healthy animals, SPKs oscillated with near 24-h period; however, after injury by status epilepticus, a persistent phase shift of ~12 h emerged in animals that later went on to develop chronic spontaneous seizures. Additional measurements showed that global 24-h rhythms, including core body temperature and theta state transitions, did not phase shift. Instead, we hypothesized that locally impaired circadian input to the hippocampus might be responsible for the SPK phase shift. This was investigated with a biophysical computer model in which we showed that subtle changes in the relative strengths of circadian input could produce a phase shift in hippocampal neural activity. MRI provided evidence that the medial septum, a putative circadian relay center for the hippocampus, exhibits signs of damage and therefore could contribute to local circadian impairment. Our results suggest that balanced circadian input is critical to maintaining natural circadian phase in the hippocampus and that damage to circadian relay centers, such as the medial septum, may disrupt this balance. We conclude by discussing how abnormal circadian regulation may contribute to the daily rhythms of epileptic seizures and related cognitive dysfunction. PMID- 23678012 TI - Robotic loading during treadmill training enhances locomotor recovery in rats spinally transected as neonates. AB - Loading on the limbs has a powerful influence on locomotion. In the present study, we examined whether robotic-enhanced loading during treadmill training improved locomotor recovery in rats that were spinally transected as neonates. A robotic device applied a force on the ankle of the hindlimb while the rats performed bipedal stepping on a treadmill. The robotic force enhanced loading during the stance phase of the step cycle. One group of spinally transected rats received 4 wk of bipedal treadmill training with robotic loading while another group received 4 wk of bipedal treadmill training but without robotic loading. The two groups exhibited similar stepping performance during baseline tests of bipedal treadmill stepping. However, after 4 wk, the spinally transected rats that received bipedal treadmill training with robotic loading performed significantly more weight-bearing steps than the bipedal treadmill training only group. Bipedal treadmill training with robotic loading enhanced the ankle trajectory and ankle velocity during the step cycle. Based on immunohistochemical analyses, the expression of the presynaptic marker, synaptophysin, was significantly greater in the ventral horn of the lumbar spinal cord of the rats that received bipedal treadmill training with robotic loading. These findings suggested that robotic loading during bipedal treadmill training improved the ability of the lumbar spinal cord to generate stepping. The results have implications for the use of robotic-enhanced gait training therapies that encourage motor learning after spinal cord injury. PMID- 23678013 TI - Individual differences in attention strategies during detection, fine discrimination, and coarse discrimination. AB - Interacting with the environment requires the ability to flexibly direct attention to relevant features. We examined the degree to which individuals attend to visual features within and across Detection, Fine Discrimination, and Coarse Discrimination tasks. Electroencephalographic (EEG) responses were measured to an unattended peripheral flickering (4 or 6 Hz) grating while individuals (n = 33) attended to orientations that were offset by 0 degrees , 10 degrees , 20 degrees , 30 degrees , 40 degrees , and 90 degrees from the orientation of the unattended flicker. These unattended responses may be sensitive to attentional gain at the attended spatial location, since attention to features enhances early visual responses throughout the visual field. We found no significant differences in tuning curves across the three tasks in part due to individual differences in strategies. We sought to characterize individual attention strategies using hierarchical Bayesian modeling, which grouped individuals into families of curves that reflect attention to the physical target orientation ("on-channel") or away from the target orientation ("off-channel") or a uniform distribution of attention. The different curves were related to behavioral performance; individuals with "on-channel" curves had lower thresholds than individuals with uniform curves. Individuals with "off-channel" curves during Fine Discrimination additionally had lower thresholds than those assigned to uniform curves, highlighting the perceptual benefits of attending away from the physical target orientation during fine discriminations. Finally, we showed that a subset of individuals with optimal curves ("on-channel") during Detection also demonstrated optimal curves ("off-channel") during Fine Discrimination, indicating that a subset of individuals can modulate tuning optimally for detection and discrimination. PMID- 23678014 TI - Evidence for a retinal velocity memory underlying the direction of anticipatory smooth pursuit eye movements. AB - To compute spatially correct smooth pursuit eye movements, the brain uses both retinal motion and extraretinal signals about the eyes and head in space (Blohm and Lefevre 2010). However, when smooth eye movements rely solely on memorized target velocity, such as during anticipatory pursuit, it is unknown if this velocity memory also accounts for extraretinal information, such as head roll and ocular torsion. To answer this question, we used a novel behavioral updating paradigm in which participants pursued a repetitive, spatially constant fixation gap-ramp stimulus in series of five trials. During the first four trials, participants' heads were rolled toward one shoulder, inducing ocular counterroll (OCR). With each repetition, participants increased their anticipatory pursuit gain, indicating a robust encoding of velocity memory. On the fifth trial, they rolled their heads to the opposite shoulder before pursuit, also inducing changes in ocular torsion. Consequently, for spatially accurate anticipatory pursuit, the velocity memory had to be updated across changes in head roll and ocular torsion. We tested how the velocity memory accounted for head roll and OCR by observing the effects of changes to these signals on anticipatory trajectories of the memory decoding (fifth) trials. We found that anticipatory pursuit was updated for changes in head roll; however, we observed no evidence of compensation for OCR, representing the absence of ocular torsion signals within the velocity memory. This indicated that the directional component of the memory must be coded retinally and updated to account for changes in head roll, but not OCR. PMID- 23678015 TI - Parkinsonism-related features of neuronal discharge in primates. AB - Parkinson's disease is known to be associated with abnormal electrical spiking activities of basal ganglia neurons, including changes in firing rate, bursting activities and oscillatory firing patterns and changes in entropy. We explored the relative importance of these measures through optimal feature selection and discrimination analysis methods. We identified key characteristics of basal ganglia activity that predicted whether the neurons were recorded in the normal or parkinsonian state. Starting with 29 features extracted from the spike timing of neurons recorded in normal and parkinsonian monkeys in the internal or external segment of the globus pallidus or the subthalamic nucleus (STN), we used a method that incorporates a support vector machine algorithm to find feature combinations that optimally discriminate between the normal and parkinsonian states. Our results demonstrate that the discrimination power of combinations of specific features is higher than that of single features, or of all features combined, and that the most discriminative feature sets differ substantially between basal ganglia structures. Each nucleus or class of neurons in the basal ganglia may react differently to the parkinsonian condition, and the features used to describe this state should be adapted to the neuron type under study. The feature that was overall most predictive of the parkinsonian state in our data set was a high STN intraburst frequency. Interestingly, this feature was not correlated with parameters describing oscillatory firing properties in recordings made in the normal condition but was significantly correlated with spectral power in specific frequency bands in recordings from the parkinsonian state (specifically with power in the 8-13 Hz band). PMID- 23678017 TI - Global attractor alphabet of neural firing modes. AB - The elementary set, or alphabet, of neural firing modes is derived from the widely accepted conductance-based rectified firing-rate model. The firing dynamics of interacting neurons are shown to be governed by a multidimensional bilinear threshold discrete iteration map. The parameter-dependent global attractors of the map morph into 12 attractor types. Consistent with the dynamic modes observed in biological neuronal firing, the global attractor alphabet is highly visual and intuitive in the scalar, single-neuron case. As synapse permeability varies from high depression to high potentiation, the global attractor type varies from chaotic to multiplexed, oscillatory, fixed, and saturated. As membrane permeability decreases, the global attractor transforms from active to passive state. Under the same activation, learning and retrieval end at the same global attractor. The bilinear threshold structure of the multidimensional map associated with interacting neurons generalizes the global attractor alphabet of neuronal firing modes to multineuron systems. Selective positive or negative activation and neural interaction yield combinatorial revelation and concealment of stored neuronal global attractors. PMID- 23678016 TI - Daily rhythms in locomotor circuits in Drosophila involve PDF. AB - The neuropeptide pigment-dispersing factor (PDF) has been studied extensively in Drosophila, and its role in circadian time-keeping has been firmly established. The role of PDF outside of the clock circuit, however, is poorly understood. A recent study suggested that PDF may act on the ellipsoid body (EB) to link the clock and sleep/activity circuits. We performed whole brain optical imaging with the fluorescence resonance energy transfer (FRET)-based cAMP sensor Epac1-camps expressed under control of the pdfR promoter to address how the clock and sleep deprivation affect the physiology of these cells. Basal cAMP levels in EB were regulated both by PDF and synaptic inputs that are controlled by the circadian clock. Acute application of PDF to the brain caused a significant, and PDF receptor-dependent, increase in cAMP in EB cells. Application of TTX to block circuit-mediated effects of PDF increased the morning response but not the response at night, implying the existence of a temporally regulated, PDF stimulated input that blocks cAMP generation. ACh produced both direct (TTX insensitive) and indirect (TTX-sensitive) increases in cAMP during the day but was totally TTX-insensitive at night, indicating that ACh-stimulated inputs to the EB are suppressed at night. Sleep deprivation did not affect the cAMP responses of these cells to either PDF or ACh. These results suggest a novel role for PDF as a modulator of activity outside of the clock circuit. By elucidating the mechanisms by which the neuropeptide PDF act on its target cells, our work contributes to our understating of how the central clock coordinates activity and sleep. PMID- 23678018 TI - Civil, sensible, and constructive peer review in APS journals. PMID- 23678019 TI - Pinprick-evoked brain potentials: a novel tool to assess central sensitization of nociceptive pathways in humans. AB - Although hyperalgesia to mechanical stimuli is a frequent sign in patients with inflammation or neuropathic pain, there is to date no objective electrophysiological measure for its evaluation in the clinical routine. Here we describe a technique for recording the electroencephalographic (EEG) responses elicited by mechanical stimulation with a flat-tip probe (diameter 0.25 mm, force 128 mN). Such probes activate Adelta nociceptors and are widely used to assess the presence of secondary hyperalgesia, a psychophysical correlate of sensitization in the nociceptive system. The corresponding pinprick-evoked potentials (PEPs) were recorded in 10 subjects during stimulation of the right and left hand dorsum before and after intradermal injection of capsaicin into the right hand and in 1 patient with a selective lesion of the right spinothalamic tract. PEPs in response to stimulation of normal skin were characterized by a vertex negative-positive (NP) complex, with N/P latencies and amplitudes of 111/245 ms and 3.5/11 MUV, respectively. All subjects developed a robust capsaicin-induced increase in the pain elicited by pinprick stimulation of the secondary hyperalgesic area (+91.5%, P < 0.005). Such stimulation also resulted in a significant increase of the N-wave amplitude (+92.9%, P < 0.005), but not of the P wave (+6.6%, P = 0.61). In the patient, PEPs during stimulation of the hypoalgesic side were reduced. These results indicate that PEPs 1) reflect cortical activities triggered by somatosensory input transmitted in Adelta primary sensory afferents and spinothalamic projection neurons, 2) allow quantification of experimentally induced secondary mechanical hyperalgesia, and 3) have the potential to become a diagnostic tool to substantiate mechanical hyperalgesia in patients with presumed central sensitization. PMID- 23678020 TI - Discharge properties of abductor hallucis before, during, and after an isometric fatigue task. AB - Abductor hallucis is the largest muscle in the arch of the human foot and comprises few motor units relative to its physiological cross-sectional area. It has been described as a postural muscle, aiding in the stabilization of the longitudinal arch during stance and gait. The purpose of this study was to describe the discharge properties of abductor hallucis motor units during ramp and hold isometric contractions, as well as its discharge characteristics during fatigue. Intramuscular electromyographic recordings from abductor hallucis were made in 5 subjects; from those recordings, 42 single motor units were decomposed. Data were recorded during isometric ramp contractions at 60% maximum voluntary contraction (MVC), performed before and after a submaximal isometric contraction to failure (mean force 41.3 +/- 15.3% MVC, mean duration 233 +/- 116 s). Motor unit recruitment thresholds ranged from 10.3 to 54.2% MVC. No significant difference was observed between recruitment and derecruitment thresholds or their respective discharge rates for both the initial and postfatigue ramp contractions (all P > 0.25). Recruitment threshold was positively correlated with recruitment discharge rate (r = 0.47, P < 0.03). All motor units attained similar peak discharge rates (14.0 +/- 0.25 pulses/s) and were not correlated with recruitment threshold. Thirteen motor units could be followed during the isometric fatigue task, with a decline in discharge rate and increase in discharge rate variability occurring in the final 25% of the task (both P < 0.05). We have shown that abductor hallucis motor units discharge relatively slowly and are considerably resistant to fatigue. These characteristics may be effective for generating and sustaining the substantial level of force that is required to stabilize the longitudinal arch during weight bearing. PMID- 23678021 TI - Continuous theta-burst stimulation to primary motor cortex reveals asymmetric compensation for sensory attenuation in bimanual repetitive force production. AB - Studies of fingertip force production have shown that self-produced forces are perceived as weaker than externally generated forces. This is due to mechanisms of sensory reafference where the comparison between predicted and actual sensory feedback results in attenuated perceptions of self-generated forces. Without an external reference to calibrate attenuated performance judgments, a compensatory overproduction of force is exhibited. It remains unclear whether the force overproduction seen in the absence of visual reference stimuli differs when forces are produced bimanually. We studied performance of two versions of a bimanual sequential force production task compared with each hand performing the task unimanually. When the task goal was shared, force series produced by each hand in bimanual conditions were found to be uncorrelated. When the bimanual task required each hand to reach a target force level, we found asymmetries in the degree of force overproduction between the hands following visual feedback removal. Unilateral continuous theta-burst stimulation of the left primary motor cortex yielded a selective reduction of force overproduction in the hand contralateral to stimulation by disrupting sensory reafference processes. While variability was lower in bimanual trials when the task goal was shared, this influence of hand condition disappeared when the target force level was to be reached by each hand simultaneously. Our findings strengthen the notion that force control in bimanual action is less tightly coupled than other mechanisms of bimanual motor control and show that this effector specificity may be extended to the processing and compensation for mechanisms of sensory reafference. PMID- 23678022 TI - Common excitatory synaptic inputs to electrically connected cortical fast-spiking cell networks. AB - Cortical fast-spiking (FS) interneurons are electrically interconnected through gap junctions and form dendritic net structures extending over different functional columns. Here we investigated how pyramidal cells regulate FS cell network activity. Using paired recordings and glutamate puff stimulations, we found that FS cell pairs connected by electrical synapses shared common inputs from surrounding pyramidal cells more frequently than those unconnected or connected only by chemical synapses. Experimental and simulation results suggest that activity spread evoked by common inputs to electrically connected FS cells depends on network state. When cells were in the depolarized state, common inputs to electrically connected cells enhanced spike induction and induced inhibitory effects in surrounding FS cells. By contrast, in the hyperpolarized state, either sub- or suprathreshold inputs produced depolarizing potentials in nearby cells. Our results suggest that globally connected FS cell networks are locally regulated by pyramidal cells in an electrical connection- and network state dependent manner. PMID- 23678023 TI - Civil, sensible, and constructive peer review in APS journals. PMID- 23678024 TI - The (pro)renin receptor and body fluid homeostasis. AB - The renin-angiotensin system (RAS) has long been established as one of the major mechanisms of hypertension through the increased levels of angiotensin (ANG) II and its resulting effect on the sympathetic nerve activity, arterial vasoconstriction, water reabsorption, and retention, etc. In the central nervous system, RAS activation affects body fluid homeostasis through increases in sympathetic nerve activity, water intake, food intake, and arginine vasopressin secretion. Previous studies, however, have shown that ANG II can be made in the brain, and it could possibly be through a new component called the (pro)renin receptor. This review intends to summarize the central and peripheral effects of the PRR on body fluid homeostasis. PMID- 23678025 TI - Data diuresis: research "to go" from the Water and Electrolyte Homeostasis Section. PMID- 23678026 TI - Anti-inflammatory salicylate treatment alters the metabolic adaptations to lactation in dairy cattle. AB - Adapting to the lactating state requires metabolic adjustments in multiple tissues, especially in the dairy cow, which must meet glucose demands that can exceed 5 kg/day in the face of negligible gastrointestinal glucose absorption. These challenges are met through the process of homeorhesis, the alteration of metabolic setpoints to adapt to a shift in physiological state. To investigate the role of inflammation-associated pathways in these homeorhetic adaptations, we treated cows with the nonsteroidal anti-inflammatory drug sodium salicylate (SS) for the first 7 days of lactation. Administration of SS decreased liver TNF-alpha mRNA and marginally decreased plasma TNF-alpha concentration, but plasma eicosanoids and liver NF-kappaB activity were unaltered during treatment. Despite the mild impact on these inflammatory markers, SS clearly altered metabolic function. Plasma glucose concentration was decreased by SS, but this was not explained by a shift in hepatic gluconeogenic gene expression or by altered milk lactose secretion. Insulin concentrations decreased in SS-treated cows on day 7 compared with controls, which was consistent with the decline in plasma glucose concentration. The revised quantitative insulin sensitivity check index (RQUICKI) was then used to assess whether altered insulin sensitivity may have influenced glucose utilization rate with SS. The RQUICKI estimate of insulin sensitivity was significantly elevated by SS on day 7, coincident with the decline in plasma glucose concentration. Salicylate prevented postpartum insulin resistance, likely causing excessive glucose utilization in peripheral tissues and hypoglycemia. These results represent the first evidence that inflammation-associated pathways are involved in homeorhetic adaptations to lactation. PMID- 23678027 TI - Ca2+-pumping impairment during repetitive fatiguing contractions in single myofibers: role of cross-bridge cycling. AB - The energy cost of contractions in skeletal muscle involves activation of both actomyosin and sarcoplasmic reticulum (SR) Ca2+-pump (SERCA) ATPases, which together determine the overall ATP demand. During repetitive contractions leading to fatigue, the relaxation rate and Ca2+ pumping become slowed, possibly because of intracellular metabolite accumulation. The role of the energy cost of cross bridge cycling during contractile activity on Ca2+-pumping properties has not been investigated. Therefore, we inhibited cross-bridge cycling by incubating isolated Xenopus single fibers with N-benzyl-p-toluene sulfonamide (BTS) to study the mechanisms by which SR Ca2+ pumping is impaired during fatiguing contractions. Fibers were stimulated in the absence (control) and presence of BTS and cytosolic calcium ([Ca2+]c) transients or intracellular pH (pHi) changes were measured. BTS treatment allowed normal [Ca2+]c transients during stimulation without cross-bridge activation. At the time point that tension was reduced to 50% in the control condition, the fall in the peak [Ca2+]c and the increase in basal [Ca2+]c did not occur with BTS incubation. The progressively slower Ca2+ pumping rate and the fall in pHi during repetitive contractions were reduced during BTS conditions. However, when mitochondrial ATP supply was blocked during contractions with BTS present (BTS + cyanide), there was no further slowing in SR Ca2+ pumping during contractions compared with the BTS-alone condition. Furthermore, the fall in pHi was significantly less during the BTS + cyanide condition than in the control conditions. These results demonstrate that factors related to the energetic cost of cross-bridge cycling, possibly the accumulation of metabolites, inhibit the Ca2+ pumping rate during fatiguing contractions. PMID- 23678028 TI - Does endoplasmic reticulum stress mediate endothelin-1-induced renal inflammation? AB - Endothelin-1 (ET-1) is the most potent vasoconstrictor peptide known. It exerts its actions through two pharmacologically different receptors: ETA and ETB receptors. In the renal vasculature, there is a majority of ETB receptors in the efferent arteriole, whereas a greater amount of ETA receptors are located in the afferent arteriole. The nephron is rich in ETB receptors, especially in the thick ascending limb and collecting ducts, while containing a smaller amount of ETA receptors. High levels of circulating or renal ET-1 have been described in cardiovascular diseases such as hypertension or diabetes, diseases also associated to renal inflammation. Despite extensive evidence associating high levels of ET-1 to increased renal inflammation, the molecular mechanism(s) by which ET-1 leads to renal immune infiltration and/or immune activation remains unknown. In this minireview, we propose that the ET-1/ETA pathway mediates an increase in renal endoplasmic reticulum (ER) stress, initially a survival mechanism that if prolonged, leads to the eventual death of the cell via apoptosis. PMID- 23678029 TI - Speed and accuracy of taste identification and palatability: impact of learning, reward expectancy, and consummatory licking. AB - Despite decades of study, it remains a matter of controversy as to whether in rats taste identification is a rapid process that occurs in about 250-600 ms (one to three licks) or a slow process that evolves over seconds. To address this issue, we trained rats to perform a taste-cued two-response discrimination task (2-RDT). It was found that, after learning, regardless of intensity, the delivery of 10 MUl of a tastant (e.g., NaCl or monopotassium glutamate, MPG) was sufficient to identify its taste with maximal accuracy within 400 ms. However, despite overtraining, rats rarely stopped licking in one lick. Thus, a one-drop lick reaction task was developed in which subjects had to rapidly stop licking after release of a stop signal (tastants including water) to obtain rewards. The faster they stopped licking, the greater the reward. Rats did not stop licking after receiving either hedonically positive or negative stop signals, and thus failed to maximize rewards even when reinforced with even larger rewards. In fact, the higher the sucrose concentration given as a stop signal, the greater the number of consummatory licks elicited. However, with a stop signal of 2 mM quinine HCl, they stopped licking in ~370 ms, a time faster than that for sucrose or water, thus showing that in this rapid period, quinine HCl evoked an unpalatable response. Indeed, only when rats licked an empty sipper tube would they usually elicit a single lick to obtain a reward (operant licking). In summary, these data indicate that within 400 ms, taste identification and palatability, must either occur simultaneously or with marked overlap. PMID- 23678030 TI - Role of vasopressin in maintenance of potassium homeostasis in severe hemorrhage. AB - Uncontrolled elevation in plasma potassium within minutes of rapid blood volume loss is associated with mortality and distinguishes nonsurvivors of severe hemorrhage from survivors. In a pig model of severe hemorrhage, we discovered that along with a sharp increase in plasma potassium coincident with a shut down of urine flow, nonsurvivors also had an insufficient vasopressin response to hemorrhage. In contrast, survivors did have elevated vasopressin levels in response to hemorrhage and maintained plasma potassium within normal limits. While it has been demonstrated for some time that vasopressin can influence secretion of potassium in the distal nephron, the magnitude of this effect and conditions under which this contributes to physiological modulation of potassium excretion has yet to be defined. In this review, we assess the evidence that would suggest that vasopressin plays a key role in modulating potassium excretion and is important in the regulation of potassium homeostasis during hemorrhage. PMID- 23678031 TI - Proton-facilitated ammonia excretion by ionocytes of medaka (Oryzias latipes) acclimated to seawater. AB - The proton-facilitated ammonia excretion is critical for a fish's ability to excrete ammonia in freshwater. However, it remains unclear whether that mechanism is also critical for ammonia excretion in seawater (SW). Using a scanning ion selective electrode technique (SIET) to measure H(+) gradients, an acidic boundary layer was detected at the yolk-sac surface of SW-acclimated medaka (Oryzias latipes) larvae. The H(+) gradient detected at the surface of ionocytes was higher than that of keratinocytes in the yolk sac. Treatment with Tricine buffer or EIPA (a NHE inhibitor) reduced the H(+) gradient and ammonia excretion of larvae. In situ hybridization and immunochemistry showed that slc9a2 (NHE2) and slc9a3 (NHE3) were expressed in the same SW-type ionocytes. A real-time PCR analysis showed that transfer to SW downregulated branchial mRNA expressions of slc9a3 and Rhesus glycoproteins (rhcg1, rhcg2, and rhbg) but upregulated that of slc9a2. However, slc9a3, rhcg1, rhcg2, and rhbg expressions were induced by high ammonia in SW. This study suggests that SW-type ionocytes play a role in acid and ammonia excretion and that the Na(+)/H(+) exchanger and Rh glycoproteins are involved in the proton-facilitated ammonia excretion mechanism. PMID- 23678033 TI - Low serum levels of 25-hydroxyvitamin D predict hip fracture in the elderly: a NOREPOS study. AB - BACKGROUND: Despite considerable interest, the relationship between circulating 25-hydroxyvitamin D and the risk of hip fracture is not fully established. OBJECTIVE: The objective of the study was to study the association between serum 25-hydroxyvitamin D concentrations [s-25(OH)D] and the risk of hip fracture in Norway, a high-latitude country that has some of the highest hip fracture rates worldwide. METHODS: A total of 21 774 men and women aged 65-79 years attended 4 community-based health studies during 1994-2001. Information on subsequent hip fractures was retrieved from electronic hospital discharge registers, with a maximum follow-up of 10.7 years. Using a stratified case-cohort design, s-25(OH)D was determined by HPLC-atmospheric pressure chemical ionization-mass spectrometry in stored serum samples in hip fracture cases (n = 1175; 307 men, 868 women) and in gender-stratified random samples (n = 1438). Cox proportional hazards regression adapted for the case-cohort design was performed. RESULTS: We observed an inverse association between s-25(OH)D and hip fracture; those with s-25(OH)D in the lowest quartile (<42.2 nmol/L) had a 38% [95% confidence interval (CI) 9 74%] increased risk of hip fracture compared with the highest quartile (>=67.9 nmol/L) in a model accounting for age, gender, study center, and body mass index. The association was stronger in men than in women: hazard ratio 1.65 (95% CI 1.04 2.61) vs hazard ratio 1.25 (95% CI 0.95-1.65). CONCLUSION: In this prospective case-cohort study of hip fractures, the largest ever reported, we found an increased risk of hip fracture in subjects in the lowest compared with the highest quartile of serum 25-hydroxyvitamin D. In accordance with the findings of previous community-based studies, low vitamin D status was a modest risk factor for hip fracture. PMID- 23678032 TI - Estradiol modulates recovery of REM sleep in a time-of-day-dependent manner. AB - Ovarian hormones are thought to modulate sleep and fluctuations in the hormonal milieu are coincident with sleep complaints in women. In female rats, estradiol increases waking and suppresses sleep. In this study, we asked whether this effect is mediated via circadian or homeostatic regulatory mechanisms. Ovariectomized female rats received daily injections of estradiol benzoate (EB) or sesame oil that mimicked the rapid increase and subsequent decline of circulating estradiol at proestrus. In one experiment, animals were sleep deprived for 6 h starting at lights-on, so that recovery began in the mid-light phase; in the second experiment, animals were sleep deprived starting in the mid light phase, so that recovery began at lights-off. EB suppressed baseline rapid eye movement (REM) and non-REM (NREM) sleep and increased waking in the dark phase. In both experiments, EB enhanced REM recovery in the light phase while suppressing it in the dark compared with oil; this effect was most pronounced in the first 6 h of recovery. By contrast, NREM recovery was largely unaffected by EB. In summary, EB enhanced waking and suppressed sleep, particularly REM sleep, in the dark under baseline and recovery conditions. These strong temporally dependent effects suggest that EB consolidates circadian sleep-wake rhythms in female rats. PMID- 23678034 TI - Comparative analysis of oncological outcomes and quality of life after robotic versus conventional open thyroidectomy with modified radical neck dissection in patients with papillary thyroid carcinoma and lateral neck node metastases. AB - OBJECTIVES: Robotic total thyroidectomy (TT) with modified radical neck dissection (MRND) using a gasless transaxillary approach has been reported safe and effective in patients with N1b papillary thyroid carcinoma (PTC), with notable cosmetic benefits when compared with conventional open TT. We have compared oncological outcomes and quality of life (QoL) in PTC patients undergoing robotic TT and MRND and those undergoing conventional open procedures. MATERIALS AND METHODS: Between March 2010 and July 2011, 128 patients with PTC and lateral neck node metastases underwent TT with MRND, including 62 who underwent robotic and 66 who underwent open TT. We compared oncologic outcomes and safety as well as functional outcomes such as postoperative subjective voice and swallowing difficulties. We also evaluated neck pain, sensory changes, and cosmetic satisfaction after surgery using various QoL symptom scales. Neck and shoulder disability was assessed using arm abduction tests (AAT) and questions from the neck dissection impairment index (NDII). RESULTS: Although the mean operating time was significantly longer in the robotic (mean, 271.8 +/- 50.2 min) than in the open group (mean, 208.9 +/- 56.3 min) (P < .0001), postoperative complication rates and oncologic outcomes, including the results of radioactive iodine scans and postoperative serum Tg concentrations, did not differ significantly. Subjective voice outcomes and postoperative AAT and neck dissection impairment index were also similar, but postoperative swallowing difficulties (P = .0041) and sensory changes (P < .0001) were significantly more frequent in the open than in the robotic group. In particular, mean cosmetic satisfaction score was significantly higher in the robotic than in the open group (P < .0001). CONCLUSIONS: Robotic TT with MRND yielded similar oncologic outcomes and safety as conventional open procedures, with similar recovery of neck and shoulder disability. However, the robot technique resulted in better QoL outcomes, including better cosmetic results and reductions in neck sensory changes and swallowing discomfort. PMID- 23678035 TI - Ovarian 11beta-hydroxysteroid dehydrogenase (11betaHSD) activity is suppressed in women with anovulatory polycystic ovary syndrome (PCOS): apparent role for ovarian androgens. AB - CONTEXT: Altered hepatic cortisol-cortisone metabolism by type 1 11beta hydroxysteroid dehydrogenase (11betaHSD1) has previously been linked with polycystic ovary (PCO) syndrome (PCOS). OBJECTIVES: Our objectives were to establish whether ovarian 11betaHSD activities are also altered in PCOS and to determine whether any changes in ovarian cortisol metabolism might reflect exposure to elevated concentrations of insulin or androgens. DESIGN: Cortisol and cortisone concentrations were measured in follicular fluid aspirated from size matched follicles dissected from normal, ovulatory, and anovulatory PCOs. Human granulosa-lutein cells, recovered during oocyte retrieval for assisted conception, were maintained in primary culture for 4 days, after which 11betaHSD1 activities were measured as the net oxidation of [(3)H]cortisol (100 nmol/L) in the absence and presence of insulin (100 nmol/L) with or without metformin (1 MUmol/L) or a range of androgens/oxy-androgen metabolites (0.01-10 MUmol/L). RESULTS: Intrafollicular cortisol to cortisone ratios were elevated in anovulatory PCOs (2.1 +/- 0.4, P < .05, n = 13) but did not differ between follicles from ovulatory PCOs (1.6 +/- 0.1, n = 24) and normal ovaries (1.2 +/- 0.1, n = 14). 11betaHSD1 activities were lower in granulosa-lutein cells recovered from patients with PCOS compared with all other causes of infertility (median = 5.8 vs 14.9 pmol cortisone/4 h, respectively; P < .05). Cortisol oxidation was unaffected by insulin with or without metformin, dehydroepiandrosterone, and androstenedione, but was inhibited in a concentration dependent manner by testosterone, 11beta-hydroxyandrostenedione, and 7alpha- and 7beta-hydroxy-dehydroepiandrosterone (P < .01). CONCLUSIONS: There is decreased inactivation of cortisol in follicles from anovulatory PCOS. This may reflect inhibition of 11betaHSD1 by androgens and their 7/11-oxy-metabolites, local concentrations of which are increased in PCOS, and may contribute to the block to folliculogenesis seen in PCOS. PMID- 23678036 TI - Effects of PGF2alpha on the expression of uterine activation proteins in pregnant human myometrial cells from upper and lower segment. AB - CONTEXT: The lower and upper segments of the uterus may play different roles in the process of parturition. The switch from pregnancy to delivery involves changes in expression of uterine activation proteins (UAPs). Prostaglandin (PG) F2alpha has multiple and complex roles in the birth process in addition to its vital contractile role. OBJECTIVE: The purpose of this study was to investigate whether PGF2alpha regulates the expression of UAPs in human myometrium and to compare PGF2alpha actions in lower and upper segments. DESIGN: Cultured human myometrial cells from upper and lower segments were treated with PGF2alpha. Western blotting was used to determine the levels of connexin 43 (CX-43), prostaglandin endoperoxide synthase-2 (PTGS-2; cyclooxygenase-2), oxytocin receptor (OTR), and PGF2alpha receptor (PTGFR) in the cells. The small interfering RNA approach was used to knock down PTGFR. RESULTS: PGF2alpha dose dependently increased CX-43 and PTGS-2 while decreasing PTGFR in upper and lower segments. PGF2alpha increased OTR in the lower segment while decreasing it in the upper segment. PGF2alpha lost its effects on PTGS-2 and OTR in PTGFR knockdown cells, but its effect on CX-43 remained. AL8810, a specific antagonist of PTGFR, reversed the actions of PGF2alpha on UAPs except for CX-43 in the lower segment. Indomethacin reversed the PGF2alpha-induced effects on CX-43 and PTGS-2, but it did not alter PGF2alpha-induced PTGFR and OTR expression. The stimulatory effects of PGF2alpha were enhanced in the presence of IL-1beta, which reversed the inhibitory effect of PGF2alpha on PTGFR. CONCLUSION: PGF2alpha regulates UAPs in both upper and lower segment cells through either direct or indirect pathways, indicating that PGF2alpha uniquely participates in uterine preparation for the onset of labor. PMID- 23678037 TI - Manipulation of PBF/PTTG1IP phosphorylation status; a potential new therapeutic strategy for improving radioiodine uptake in thyroid and other tumors. AB - CONTEXT: The clinical effectiveness of ablative radioiodine treatment of thyroid tumors is limited by the availability of the sodium iodide symporter (NIS) at the plasma membrane (PM) for uptake of 131I. A significant proportion of well differentiated thyroid tumors are unable to concentrate sufficient radioiodine for effective therapy, and in other tumor models such as breast tumors, where radioiodine uptake would be an attractive therapeutic option, uptake is insufficient. OBJECTIVE: Pituitary tumor-transforming gene-binding factor (PBF; PTTG1IP) is overexpressed in multiple cancers and significantly decreases NIS expression at the PM. The goal of this study was to identify a method by which PBF repression of NIS may be overcome in human tumors. RESULTS: Here, we identify PBF as a tyrosine phosphoprotein that specifically binds the proto-oncogene tyrosine protein kinase Src in mass spectrometry, glutathione S-transferase pulldown and coimmunoprecipitation assays. Src induction leads to phosphorylation at PBF residue Y174. Abrogation of this residue results in PM retention and a markedly reduced ability to bind NIS. The Src inhibitor PP1 inhibits PBF phosphorylation in multiple cell lines in vitro, including human primary thyroid cells. Of direct clinical importance to the treatment of thyroid cancer, PP1 stimulates iodide uptake by transfected NIS in TPC1 thyroid carcinoma cells and entirely overcomes PBF repression of iodide uptake in human primary thyroid cells. CONCLUSIONS: We propose that targeting PBF phosphorylation at residue Y174 via tyrosine kinase inhibitors may be a novel therapeutic strategy to enhance the efficacy of ablative radioiodine treatment in thyroid and other endocrine and endocrine-related tumors. PMID- 23678038 TI - Metabolic effects of oral versus transdermal 17beta-estradiol (E2): a randomized clinical trial in girls with Turner syndrome. AB - CONTEXT: The long-term effects of pure 17beta-estradiol (E2) depending on route of administration have not been well characterized. OBJECTIVE: Our objective was to assess metabolic effects of oral vs transdermal (TD) 17beta-E2 replacement using estrogen concentration-based dosing in girls with Turner syndrome (TS). PATIENTS: Forty girls with TS, mean age 16.7 +/- 1.7 years, were recruited. DESIGN: Subjects were randomized to 17beta-E2 orally or TD. Doses were titrated using mean E2 concentrations of normally menstruating girls as therapeutic target. E2, estrone (E1), and E1 sulfate (E1S) were measured by liquid chromatography tandem mass spectrometry and a recombinant cell bioassay; metabolites were measured, and dual-energy x-ray absorptiometry scan and indirect calorimetry were performed. MAIN OUTCOME: Changes in body composition and lipid oxidation were evaluated. RESULTS: E2 concentrations were titrated to normal range in both groups; mean oral dose was 2 mg, and TD dose was 0.1 mg. After 6 and 12 months, fat-free mass and percent fat mass, bone mineral density accrual, lipid oxidation, and resting energy expenditure rates were similar between groups. IGF-1 concentrations were lower on oral 17beta-E2, but suppression of gonadotropins was comparable with no significant changes in lipids, glucose, osteocalcin, or highly sensitive C-reactive protein between groups. However, E1, E1S, SHBG, and bioestrogen concentrations were significantly higher in the oral group. CONCLUSIONS: When E2 concentrations are titrated to the normal range, the route of delivery of 17beta-E2 does not affect differentially body composition, lipid oxidation, and lipid concentrations in hypogonadal girls with TS. However, total estrogen exposure (E1, E1S, and total bioestrogen) is significantly higher after oral 17beta-E2. TD 17beta-E2 results in a more physiological estrogen milieu than oral 17beta-E2 administration in girls with TS. PMID- 23678039 TI - Inhibition of ROMK channels by low extracellular K+ and oxidative stress. AB - We tested the hypothesis that low luminal K+ inhibits the activity of ROMK channels in the rat cortical collecting duct. Whole-cell voltage-clamp measurements of the component of outward K+ current inhibited by the bee toxin Tertiapin-Q (ISK) showed that reducing the bath concentration ([K+]o) to 1 mM resulted in a decline of current over 2 min compared with that observed at 10 mM [K+]o. However, maintaining tubules in 1 mM [K+]o without establishing whole-cell clamp conditions did not affect ISK. The [K+]o-dependent decline was not prevented by increasing cytoplasmic-side pH or by inhibition of phosphatase activity. It was, however, abolished by the inclusion of 0.5 mM DTT in the pipette solution to prevent oxidation of the intracellular environment. Conversely, treatment of intact tubules with the oxidant H2O2 (100 MUM) decreased ISK in a [K+]o-dependent manner. Treatment of the tubules with the phospholipase C inhibitor U73122 prevented the effect of low [K+]o, suggesting the involvement of this enzyme in the process. We examined these effects further using Xenopus oocytes expressing ROMK2 channels. A 50-min exposure to the permeant oxidizing agent tert-butyl hydroperoxide (t-BHP; 500 MUM) did not affect outward K+ currents with [K+]o = 10 mM but reduced currents by 50% with [K+]o = 1 mM and by 75% with [K+]o = 0.1 mM. Pretreatment of the oocytes with U73122 prevented the effects of t-BHP. Under conditions of low dietary K intake, K+ secretion by distal nephron segments may be suppressed by a combination of low luminal [K+]o and oxidative stress. PMID- 23678040 TI - mTOR plays a critical role in p53-induced oxidative kidney cell injury in HIVAN. AB - Oxidative stress has been implicated to contribute to HIV-induced kidney cell injury; however, the role of p53, a modulator of oxidative stress, has not been evaluated in the development of HIV-associated nephropathy (HIVAN). We hypothesized that mammalian target of rapamycin (mTOR) may be critical for the induction of p53-mediated oxidative kidney cell injury in HIVAN. To test our hypothesis, we evaluated the effect of an mTOR inhibitor, rapamycin, on kidney cell p53 expression, downstream signaling, and kidney cell injury in both in vivo and in vitro studies. Inhibition of the mTOR pathway resulted in downregulation of renal tissue p53 expression, associated downstream signaling, and decreased number of sclerosed glomeruli, tubular microcysts, and apoptosed and 8-hydroxy deoxyguanosine (8-OHdG)-positive (+ve) cells in Tg26 mice. mTOR inhibition not only attenuated kidney cell expression of p66ShcA and phospho-p66ShcA but also reactivated the redox-sensitive stress response program in the form of enhanced expression of manganese superoxide dismutase (MnSOD) and catalase. In in vitro studies, the mTOR inhibitor also provided protection against HIV-induced podocyte apoptosis. Moreover, mTOR inhibition downregulated HIV-induced podocyte (HP/HIV) p53 expression. Since HP/HIV silenced for mTOR displayed a lack of expression of p53 as well as attenuated podocyte apoptosis, this suggests that mTOR is critical for kidney cell p53 activation and associated oxidative kidney cell injury in the HIV milieu. PMID- 23678041 TI - Early life stress sensitizes the renal and systemic sympathetic system in rats. AB - We hypothesized that maternal separation (MS), an early life stress model, induces a sensitization of the sympathetic system. To test this hypothesis, we evaluated the renal and systemic sympathetic system in 12- to 14-wk-old male control or MS rats with the following parameters: 1) effect of renal denervation on conscious renal filtration capacity, 2) norepinephrine (NE) content in key organs involved in blood pressure control, and 3) acute systemic pressor responses to adrenergic stimulation or ganglion blockade. MS was performed by separating pups from their mothers for 3 h/day from day 2 to 14; controls were nonhandled littermates. Glomerular filtration rate (GFR) was examined in renal denervated (DnX; within 2 wk) or sham rats using I125-iothalamate plasma clearance. MS-DnX rats showed significantly increased GFR compared with MS-SHAM rats (3.8 +/- 0.4 vs. 2.4 +/- 0.2 ml/min, respectively, P < 0.05), whereas DnX had no effect in controls, indicating that renal nerves regulate GFR in MS rats. NE content was significantly increased in organ tissues from MS rats (P < 0.05, n = 6-8), suggesting a sensitization of the renal and systemic sympathetic system. Conscious MS rats displayed a significantly greater increase in mean arterial pressure (MAP) in response to NE (2 MUg/kg ip) and a greater reduction in MAP in response to mecamylamine (2 mg/kg ip, P < 0.05, n = 4) monitored by telemetry, indicating that MS rats exhibit exaggerated responses to sympathetic stimulation. In conclusion, these data indicate that MS sensitizes the renal and systemic sympathetic system ultimately impairing blood pressure regulation. PMID- 23678043 TI - Meet your new AJP-Renal Physiology editors. PMID- 23678042 TI - Functioning of an arteriovenous fistula requires heme oxygenase-2. AB - Heme oxygenase-2 (HO-2), the constitutive isoform of the heme-degrading enzyme heme oxygenase, may serve as an anti-inflammatory vasorelaxant, in part, by generating carbon monoxide. Arteriovenous fistulas (AVFs) are employed as hemodialysis vascular accesses because they provide an accessible, high-blood flow vascular segment. We examined the role of vascular expression of HO-2 in AVF function. An AVF was created in mice by anastomosing the carotid artery to the jugular vein. HO-2 expression was detected by immunohistochemistry in the intact carotid artery, mainly in endothelial cells and smooth muscle cells; expression of HO-2 protein and mRNA was modestly increased in the artery of the AVF. Creating an AVF in HO-2(-/-) mice compared with an AVF in HO-2(+/+) mice led to markedly reduced AVF blood flow and increased numbers of nonfunctioning AVFs. The impairment of AVF function in the setting of HO-2 deficiency could not be ascribed to either preexisting intrinsic abnormalities in endothelium-dependent and endothelium-independent relaxation of the carotid artery in HO-2-deficient mice or to impaired vasorelaxant responses in the intact carotid artery in vivo. HO-1 mRNA was comparably induced in the AVF in HO-2(+/+) and HO-2(-/-) mice, whereas the AVF in HO-2(-/-) mice compared with that in HO-2(+/+) mice exhibited exaggerated induction of matrix metalloproteinase (MMP)-9 but similar induction of MMP-2. HO-2 deficiency also led to lower AVF blood flow when AVFs were created in uremia, the latter induced by subtotal nephrectomy. We conclude that HO-2 critically contributes to the adequacy of AVF blood flow and function. PMID- 23678044 TI - Civil, sensible, and constructive peer review in APS journals. PMID- 23678046 TI - Bone morphogenetic protein-5 and early endothelial outgrowth cells (eEOCs) in acute ischemic kidney injury (AKI) and 5/6-chronic kidney disease. AB - Early endothelial outgrowth cells (eEOCs) reproducibly have been shown to act protectively in acute ischemic kidney injury (AKI) and chronic kidney injury. Bone morphogenetic protein-5 (BMP-5) acted antifibrotically in human hypertensive nephropathy. The aim of the current study was to analyze effects of BMP-5 treatment in an eEOC-based therapy of murine AKI and 5/6-nephrectomy. Male C57/Bl6N mice were either subjected to unilateral renal artery clamping postuninephrectomy or to 5/6-nephrectomy. Untreated or BMP-5-pretreated murine eEOCs were injected into recipient animals at the time of reperfusion (AKI) or at 2 and 5 days after 5/6-nephrectomy. Analysis of renal function and morphology was performed at 48 h and at 6 wk (AKI) or at 8 wk (5/6 model). Cellular consequences of eEOC treatment were evaluated using different in vitro assays. AKI was mitigated significantly by injecting BMP-5-pretreated eEOCs. Renal function was improved at 48 h [corrected] after cell therapy. In 5/6-nephrectomy, the cells failed to act renoprotectively, [corrected] but proteinuria was reduced after administering untreated eEOCs." Next, the original version read as "BMP-5 acts as a potent eEOC agonist in murine AKI in the short [corrected] term. Cell effects in 5/6-nephrectomy are heterogenous, but untreated cells act antifibrotically [corrected] without any impact on EnMT. PMID- 23678045 TI - ADAM17 mediates Nox4 expression and NADPH oxidase activity in the kidney cortex of OVE26 mice. AB - Matrix protein accumulation is a prominent feature of diabetic nephropathy that contributes to renal fibrosis and decline in renal function. The pathogenic mechanisms of matrix accumulation are incompletely characterized. We investigated if the matrix metalloprotease a disintegrin and metalloprotease1 7 (ADAM17), known to cleave growth factors and cytokines, is activated in the kidney cortex of OVE26 type 1 diabetic mice and the potential mechanisms by which ADAM17 mediates extracellular matrix accumulation. Protein expression and activity of ADAM17 were increased in OVE26 kidney cortex. Using a pharmacological inhibitor to ADAM17, TMI-005, we determined that ADAM17 activation results in increased type IV collagen, Nox4, and NADPH oxidase activity in the kidney cortex of diabetic mice. In cultured mouse proximal tubular epithelial cells (MCTs), high glucose increases ADAM17 activity, Nox4 and fibronectin expression, cellular collagen content, and NADPH oxidase activity. These effects of glucose were inhibited when cells were pretreated with TMI-005 and/or transfected with small interfering ADAM17. Collectively, these data indicate a novel mechanism whereby hyperglycemia in diabetes increases extracellular matrix protein expression in the kidney cortex through activation of ADAM17 and enhanced oxidative stress through Nox enzyme activation. Additionally, our study is the first to provide evidence that Nox4 is downstream of ADAM17. PMID- 23678047 TI - Acidosis-mediated regulation of the NHE1 isoform of the Na+/H+ exchanger in renal cells. AB - The mammalian Na+/H+ exchanger isoform 1 (NHE1) is a ubiquitous plasma membrane protein that regulates intracellular pH by removing a proton in exchange for extracellular sodium. Renal tissues are subject to metabolic and respiratory acidosis, and acidosis has been shown to acutely activate NHE1 activity in other cell types. We examined if NHE1 is activated by acute acidosis in HEK293 and Madin-Darby canine kidney (MDCK) cells. Acute sustained intracellular acidosis (SIA) activated NHE1 in both cell types. We expressed wild-type and mutant NHE1 cDNAs in MDCK cells. All the cDNAs had a L163F/G174S mutation, which conferred a 100-fold resistance to EMD87580, an NHE1-specific inhibitor. We assayed exogenous NHE1 activity while inhibiting endogenous activity with EMD87580 and while inhibiting the NHE3 isoform of the Na+/H+ exchanger using the isoform-specific inhibitor S3226. We examined the activation and phosphorylation of the wild-type and mutant NHE1 proteins in response to SIA. In MDCK cells we demonstrated that the amino acids Ser771, Ser776, Thr779, and Ser785 are important for NHE1 phosphorylation and activation after acute SIA. SIA activated ERK-dependent pathways in MDCK cells, and this was blocked by treatment with the MEK inhibitor U0126. Treatment with U0126 also blocked activation of NHE1 by SIA. These results suggest that acute acidosis activates NHE1 in mammalian kidney cells and that in MDCK cells this activation occurs through an ERK-dependent pathway affecting phosphorylation of a distinct set of amino acids in the cytosolic regulatory tail of NHE1. PMID- 23678057 TI - Intraventricular hemorrhage and multiple intracranial cysts associated with congenital cytomegalovirus infection. AB - Intraventricular hemorrhage with congenital cytomegalovirus (CMV) infection is rare and has been reported only in extremely premature infants or in association with thrombocytopenia. We report the first case of a full-term male infant with congenital CMV infection and intraventricular hemorrhage with a normal platelet count and coagulation profile. The infant also had a left subependymal cyst and bilateral occipital cysts without any other manifestations of CMV infection. PMID- 23678058 TI - Correlation of leukorrhea and Trichomonas vaginalis infection. AB - Trichomonas vaginalis is a common sexually transmitted infection (STI) causing vaginitis. Microscopy has poor sensitivity but is used for diagnosis of trichomoniasis in resource-poor settings. We aimed to provide a more reliable diagnosis of trichomoniasis by investigating an association with leukorrhea. Women presenting for evaluation of vaginal discharge, STI exposure, or preventative gynecologic examination were evaluated for Trichomonas infection. Vaginal pH was determined and microscopy was performed by the provider, who recorded the number of polymorphonuclear leukocytes (PMNLs) per epithelial cell and the presence of clue cells, yeast, and/or motile trichomonads. Leukorrhea was defined as greater than one PMNL per epithelial cell. Culture and a nucleic acid amplification test (NAAT) were used to detect T. vaginalis. Patients were evaluated for Chlamydia trachomatis and Neisseria gonorrhoeae using NAATs and bacterial vaginosis using Gram stains. Two hundred ninety-four women were enrolled, and 16% were found to have Trichomonas (46/294). Trichomonas infection was more common in parous non-Hispanic, black women, who reported low rates of contraceptive use (33% versus 17%; P = 0.02) and a STI history (85% versus 55%; P = 0.002). These women were more likely to report vaginal discharge (76% versus 59%; P = 0.02) and have an elevated vaginal pH (87% versus 48%; P < 0.001) and gonorrhea infection (15% versus 4%; P = 0.002). Leukorrhea was associated with a 4-fold-increased risk of Trichomonas infection. Leukorrhea on microscopy was associated with Trichomonas vaginitis. Patients with leukorrhea should be evaluated with more-sensitive tests for T. vaginalis, preferably NAATs, if microscopy is negative. PMID- 23678059 TI - Development and evaluation of a real-time PCR assay for detection of Pneumocystis jirovecii on the fully automated BD MAX platform. AB - Pneumocystis jirovecii is an opportunistic pathogen in immunocompromised and AIDS patients. Detection by quantitative PCR is faster and more sensitive than microscopic diagnosis yet requires specific infrastructure. We adapted a real time PCR amplifying the major surface glycoprotein (MSG) target from Pneumocystis jirovecii for use on the new BD MAX platform. The assay allowed fully automated DNA extraction and multiplex real-time PCR. The BD MAX assay was evaluated against manual DNA extraction and conventional real-time PCR. The BD MAX was used in the research mode running a multiplex PCR (MSG, internal control, and sample process control). The assay had a detection limit of 10 copies of an MSG-encoding plasmid per PCR that equated to 500 copies/ml in respiratory specimens. We observed accurate quantification of MSG targets over a 7- to 8-log range. Prealiquoting and sealing of the complete PCR reagents in conical tubes allowed easy and convenient handling of the BD MAX PCR. In a retrospective analysis of 54 positive samples, the BD MAX assay showed good quantitative correlation with the reference PCR method (R(2) = 0.82). Cross-contamination was not observed. Prospectively, 278 respiratory samples were analyzed by both molecular assays. The positivity rate overall was 18.3%. The BD MAX assay identified 46 positive samples, compared to 40 by the reference PCR. The BD MAX assay required liquefaction of highly viscous samples with dithiothreitol as the only manual step, thus offering advantages for timely availability of molecular-based detection assays. PMID- 23678060 TI - Systematic review and meta-analysis of a urine-based pneumococcal antigen test for diagnosis of community-acquired pneumonia caused by Streptococcus pneumoniae. AB - Standard culture methods for diagnosis of Streptococcus pneumoniae pneumonia take at least 24 h. The BinaxNOW urine-based test for S. pneumoniae (BinaxNOW-SP) takes only 15 min to conduct, potentially enabling earlier diagnosis and targeted treatment. This study was conducted to assess whether the use of BinaxNOW-SP at the time of hospital admission would provide adequate sensitivity and specificity for diagnosis of community-acquired pneumonia (CAP) in adult patients. We searched PubMed, EMBASE/OVID, Cochrane Collaboration, Centre for Reviews and Dissemination, INAHTA, and CADTH for diagnostic or etiologic studies of hospitalized predominately adult patients with clinically defined CAP that reported the diagnostic performance of BinaxNOW-SP versus cultures. Two authors independently extracted study details and diagnostic two-by-two tables. We found that 27 studies met our inclusion criteria, and three different reference standards were used between them. A bivariate meta-analysis of 12 studies using a composite of culture tests as the reference standard estimated the sensitivity of BinaxNOW-SP as 68.5% (95% credibility interval [CrI], 62.6% to 74.2%) and specificity as 84.2% (95% CrI, 77.5% to 89.3%). A meta-analysis of all 27 studies, adjusting for the imperfect and variable nature of the reference standard, gave a higher sensitivity of 74.0% (CrI, 66.6% to 82.3%) and specificity of 97.2% (CrI, 92.7% to 99.8%). The analysis showed substantial heterogeneity across studies, which did not decrease with adjustment for covariates. We concluded that the higher pooled sensitivity (compared to culture) and high specificity of BinaxNOW-SP suggest it would be a useful addition to the diagnostic workup for community-acquired pneumonia. More research is needed regarding the impact of BinaxNOW-SP on clinical practice. PMID- 23678061 TI - Evaluation of Xpert MTB/RIF for detection of tuberculosis from blood samples of HIV-infected adults confirms Mycobacterium tuberculosis bacteremia as an indicator of poor prognosis. AB - Tuberculosis (TB) remains a leading cause of death among HIV-infected adults, in part because of delayed diagnosis and therefore delayed initiation of treatment. Recently, the Gene-Xpert platform, a rapid, PCR-based diagnostic platform, has been validated for the diagnosis of TB with sputum. We have evaluated the Xpert MTB/RIF assay for the diagnosis of Mycobacterium tuberculosis bacteremia and investigated its impact on clinical outcomes. Consecutive HIV-infected adults with fever and cough presenting to Queen Elizabeth Central Hospital, Blantyre, Malawi, were recruited and followed up for 2 months. At presentation, three sputum samples were examined by smear, culture, and Xpert MTB/RIF assay for the presence of M. tuberculosis and blood was drawn for PCR with Xpert, for mycobacterial culture (Myco/F Lytic), and for aerobic culture. One hundred four patients were recruited, and 44 (43%) were sputum culture positive for M. tuberculosis. Ten were Xpert blood positive, for a sensitivity of 21% and a specificity of 100%. The 2-week mortality rate was significantly higher among patients who were Xpert blood positive than among those who were negative (40% versus 3%; multivariate odds ratio [OR] for death if positive, 44; 95% confidence interval [CI], 3 to 662). This effect persisted on assessment of the mortality rate at 2 months (40% versus 11%; OR, 5.6; 95% CI, 1.3 to 24.6). When screening uncomplicated patients presenting with a productive cough for pulmonary TB, Xpert blood offers no diagnostic advantage over sputum testing. Despite this, Xpert blood positivity is highly predictive of early death and this test rapidly identifies a group of patients in urgent need of initiation of treatment. PMID- 23678062 TI - Subtyping of Salmonella enterica serovar Newport outbreak isolates by CRISPR MVLST and determination of the relationship between CRISPR-MVLST and PFGE results. AB - Salmonella enterica subsp. enterica serovar Newport (S. Newport) is the third most prevalent cause of food-borne salmonellosis. Rapid, efficient, and accurate methods for identification are required to track specific strains of S. Newport during outbreaks. By exploiting the hypervariable nature of virulence genes and clustered regularly interspaced short palindromic repeats (CRISPRs), we previously developed a sequence-based subtyping approach, designated CRISPR-multi virulence-locus sequence typing (CRISPR-MVLST). To demonstrate the applicability of this approach, we analyzed a broad set of S. Newport isolates collected over a 5-year period by using CRISPR-MVLST and pulsed-field gel electrophoresis (PFGE). Among 84 isolates, we defined 38 S. Newport sequence types (NSTs), all of which were novel compared to our previous analyses, and 62 different PFGE patterns. Our data suggest that both subtyping approaches have high discriminatory abilities (>0.95) with a potential for clustering cases with common exposures. Importantly, we found that isolates from closely related NSTs were often similar by PFGE profile as well, further corroborating the applicability of CRISPR-MVLST. In the first full application of CRISPR-MVLST, we analyzed isolates from a recent S. Newport outbreak. In this blinded study, we confirmed the utility of CRISPR-MVLST and were able to distinguish the 10 outbreak isolates, as defined by PFGE and epidemiological data, from a collection of 20 S. Newport isolates. Together, our data show that CRISPR-MVLST could be a complementary approach to PFGE subtyping for S. Newport. PMID- 23678063 TI - Detection of Mycobacterium tuberculosis in blood by use of the Xpert MTB/RIF assay. AB - We have developed a novel blood lysis-centrifugation approach for highly sensitive Mycobacterium tuberculosis detection in large volumes of blood with the Xpert MTB/RIF assay. One through 20 ml of blood was spiked with 0.25 to 10 CFU/ml of the M. tuberculosis surrogate M. bovis BCG. Multiple replicates of each sample were processed by a new lysis-centrifugation method and tested with the Xpert MTB/RIF assay. The assay was very sensitive with increased blood volumes. In the 20-ml samples, BCG was detected in blood spiked with 10, 5, 1, and 0.25 CFU/ml 100, 100, 83, and 57% of the time, respectively, compared to 100, 66, 18, and 18%, of the time, respectively, in 1-ml blood samples. Assay sensitivity was influenced by the type of anticoagulant used, with acid-citrate-dextrose solution B (ACD-B) providing the best results. A limit of detection of 10 CFU/ml was established with BCG spiked into ACD-B-treated blood, and 92, 36, and 33% of the samples with 5, 1, and 0.5 CFU/ml, respectively, were assay positive. The lysis buffer was stable both at room temperature and at 4 degrees C for 2 months. The assay was tested with blood stored for 8 days without a change in sensitivity as measured by cycle threshold. This new assay format extends the capability of the Xpert MTB/RIF test, enabling up to 20 ml of blood to be tested rapidly for the presence of M. tuberculosis. This approach may be a useful method to detect extrapulmonary tuberculosis and the risk of death in immunocompromised patients. PMID- 23678064 TI - Comparison of restriction enzymes for pulsed-field gel electrophoresis typing of Moraxella catarrhalis. AB - NotI, the most prevalent restriction enzyme used for typing Moraxella catarrhalis, failed to digest genomic DNA from respiratory samples. An improved pulsed-field gel electrophoresis (PFGE) methodology determined SpeI as the best choice for typing this bacterial species, with a good restriction of clinical samples and a good clustering correlation with NotI. PMID- 23678066 TI - Quantitation of cytomegalovirus DNA load in dried blood spots correlates well with plasma viral load. AB - An assay to accurately quantitate cytomegalovirus (CMV) load in finger-stick collected dried blood spots (DBS) could potentially be useful for field studies or for analyzing patient self-collected specimens. We therefore assessed CMV DNA load in paired venipuncture-collected plasma samples and finger-stick DBS, using a previously validated quantitative PCR assay. Assay variability, sensitivity, and changes in viral load during antiviral therapy in finger-stick DBS were compared to the reference plasma quantitative PCR assay, using 106 prospectively collected pairs of finger-stick DBS and plasma samples from 35 solid-organ transplant (SOT) patients. The DBS assay showed good agreement with the reference plasma viral load assay on the log10 scale (Pearson correlation coefficient, 0.92; P < 0.001). The 95% limit of detection of the DBS assay was estimated at 2,700 plasma copies/ml (675 plasma IU/ml). In 94% (76/81) of paired DBS and plasma samples above the limit of detection, the difference in CMV load was <1 log10. CMV viral load changes during antiviral treatment were comparable in plasma and DBS. We conclude that finger-stick DBS provides a convenient sample type for quantitation of CMV load that correlates well with plasma levels. Future studies to optimize and evaluate this methodology for patient self-collected samples are warranted. PMID- 23678067 TI - Longitudinal analysis of methicillin-resistant and methicillin-susceptible Staphylococcus aureus carriage in healthy adolescents. AB - To determine the long-term carriage patterns, strain relatedness, and incidence of subsequent infections among methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) carriers, we screened 154 high school students for nasal carriage of S. aureus on 8 occasions over 11 months. Persistent carriage was defined as a positive culture on >=7 occasions. Two consecutive isolates from the same subject comprised a pair, and strain relatedness was determined for each pair by molecular typing. Of 1,232 nasal swab cultures obtained on 8 occasions, 323 (26.2%) were positive for S. aureus. Forty five isolates (3.7%) were MRSA and 278 isolates (22.6%) were MSSA from 12 and 63 subjects, respectively. Thirty-five (77.8%) MRSA isolates harbored a type IV or VT staphylococcal chromosomal cassette mec element. Among the 154 subjects, 52 (33.8%) were intermittent (1 to 6 positive swabs) carriers. Persistent carriage was identified in 23 (14.9%) subjects, and the incidence was not significantly different for MRSA and MSSA carriers (3/12 [25%] versus 20/63 [31.7%]; P=0.7449). The MRSA and MSSA isolates were composed of 33 and 215 strain pairs, respectively. Of them, an indistinguishable genotype was identified in 33 (100%) MRSA pairs and 173 (80.5%) MSSA pairs (P=0.0053). Five subjects developed cellulitis, and the incidence of this was higher for MRSA carriers (2/12 [16.7%]) than for MSSA carriers (1/63 [1.58%]; P=0.0632) and noncarriers (2/79 [2.56%]; P=0.0828). In conclusion, the long-term carriage patterns for MRSA and MSSA in healthy individuals were similar. MRSA carriers were more likely to carry a single strain, with a trend toward a higher chance of developing cellulitis than for MSSA carriers. PMID- 23678065 TI - Prevalence of porcine noroviruses, molecular characterization of emerging porcine sapoviruses from finisher swine in the United States, and unified classification scheme for sapoviruses. AB - Noroviruses (NoVs) and sapoviruses (SaVs) are important human pathogens. Although the involvement of porcine NoVs in disease in pigs is unclear, they are genetically and antigenically closely related to human NoVs. Human NoV-like strains have been detected in pigs, raising public health concerns of potential interspecies transmission. Porcine SaVs are highly diverse and emerging in swine populations. Recently, at least three new genogroups of porcine SaVs have been proposed. In this study, we tested 413 pooled fecal samples collected from apparently healthy finisher pigs in North Carolina swine farms during 2009. Reverse transcription (RT)-PCR coupled hybridization assays were performed to detect known porcine NoVs. The overall prevalence of porcine NoVs determined was 18.9% based on this method. Samples were then tested by RT-PCR targeting the 5' end of the capsid region for genogroup II (GII) NoVs, a group which includes human NoVs, followed by sequence analysis. All NoVs identified belonged to typical porcine NoV genotypes, and no human NoV-like strains were detected in specimens from these pigs. Porcine NoV-negative samples (n = 335) were subsequently screened using universal calicivirus primers, and 17 SaV strains were confirmed by sequencing. Based on the partial RNA-dependent RNA polymerase (RdRp) region, they clustered with GIII, GVII, and GVIII and with currently unclassified SaVs. According to analysis of the complete capsid sequences, 7 representative strains clustered with GVII, GVIII, and GIX? SaVs. We tentatively classified SaVs into 14 genogroups based on the complete capsid protein VP1. In summary, porcine NoVs and highly divergent SaVs were present in North Carolina finisher pigs. PMID- 23678068 TI - Rapid detection of human cytomegalovirus UL97 and UL54 mutations directly from patient samples. AB - Human cytomegalovirus (CMV) is a significant contributor to morbidity and mortality in immunocompromised patients, particularly in the transplant setting. The availability of anti-CMV drugs has improved treatment, but drug resistance is an emerging problem. Here, we describe an improved, rapid, sequencing-based assay for the two genes in CMV where drug resistance occurs, the UL97 and UL54 genes. This assay is performed in 96-well format with a single master mix and provides clinical results within 2 days. It sequences codons 440 to 645 in the UL97 gene and codons 255 to 1028 in the UL54 gene with a limit of detection of 240 IU/ml. With this assay, we tested 43 specimens that had previously been tested for UL97 drug resistance and identified 3 with UL54 mutations. One of these patients had no concurrent UL97 mutation, pointing toward the need for an assay that facilitates dual UL97/UL54 gene testing for complete resistance profiling. PMID- 23678069 TI - Long-term stability of human genomic and human papillomavirus DNA stored in BD SurePath and Hologic PreservCyt liquid-based cytology media. AB - We evaluated the effect of storage at 2 to 8 degrees C on the stability of human genomic and human papillomavirus (HPV) DNA stored in BD SurePath and Hologic PreservCyt liquid-based cytology media. DNA retained the ability to be extracted and PCR amplified for more than 2.5 years in both medium types. Prior inability to detect DNA in archived specimens may have been due to failure of the extraction method to isolate DNA from fixed cells. PMID- 23678070 TI - Antimicrobial susceptibility among Gram-positive organisms collected from pediatric patients globally between 2004 and 2011: results from the Tigecycline Evaluation and Surveillance Trial. AB - The Tigecycline Evaluation and Surveillance Trial (TEST) was designed to monitor global longitudinal changes in bacterial susceptibility to a panel of antimicrobial agents, including tigecycline. In this study, we examine susceptibility among Gram-positive isolates collected from pediatric patients globally between 2004 and 2011. A total of 9,422 Gram-positive isolates were contributed by 1,255 centers, predominantly from Europe and North America. One third of Staphylococcus aureus isolates were methicillin resistant, peaking in prevalence in 2007. All S. aureus isolates (n = 3,614) were susceptible to linezolid, tigecycline, and vancomycin; minocycline, imipenem, and meropenem were also highly active (>92% susceptibility). Ampicillin and penicillin susceptibility increased significantly during the study period (P < 0.0001 for both). Streptococcus pneumoniae isolates (n = 3,373) were highly susceptible to vancomycin (100%), linezolid (>99%), and levofloxacin and tigecycline (both >96%); imipenem susceptibility was low (32%) in Africa while minocycline susceptibility was low in Asia-Pacific Rim (38%). Penicillin resistance occurred in one-fifth of all S. pneumoniae isolates, with penicillin susceptibility ranging from 14% in Africa to 65% in Europe. Streptococcus agalactiae isolates (n = 1,056) were highly susceptible to most antimicrobials, although only 16% were susceptible to minocycline. Enterococcus faecalis isolates (n = 1,112) were highly susceptible (>97%) to ampicillin, linezolid, penicillin, tigecycline, and vancomycin globally, but only 34% were minocycline susceptible; minocycline susceptibility decreased significantly from 2004 to 2011 (P < 0.001). Tigecycline and linezolid were highly active against Enterococcus faecium (n = 267) globally (100% and 98% susceptible, respectively). Tigecycline and linezolid were highly active against Gram-positive pathogens from pediatric patients in TEST 2004 to 2011, with vancomycin and the carbapenems performing well against most pathogens. PMID- 23678072 TI - Easily modified factors contribute to delays in diagnosis of Clostridium difficile infection: a cohort study and intervention. AB - Although rapid laboratory tests are available for diagnosis of Clostridium difficile infection (CDI), delays in completion of CDI testing are common in clinical practice. We conducted a cohort study of 242 inpatients tested for CDI to determine the timing of different steps involved in diagnostic testing and to identify modifiable factors contributing to delays in diagnosis. The average time from test order to test result was 1.8 days (range, 0.2 to 10.6), with time from order to stool collection accounting for most of the delay (mean, 1.0 day; range, 0 to 10). Several modifiable factors contributed to delays, including not providing stool collection supplies to patients in a timely fashion, rejection of specimens due to incorrect labeling or leaking from the container, and holding samples in the laboratory for batch processing. Delays in testing contributed to delays in initiation of treatment for patients diagnosed with CDI and to frequent prescription of empirical CDI therapy for patients with mild to moderate symptoms whose testing was ultimately negative. An intervention that addressed several easily modified factors contributing to delays resulted in a significant decrease in the time required to complete CDI testing. These findings suggest that health care facilities may benefit from a review of their processes for CDI testing to identify and address modifiable factors that contribute to delays in diagnosis and treatment of CDI. PMID- 23678071 TI - Comparative evaluation of the Bruker Biotyper and Vitek MS matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry systems for identification of yeasts of medical importance. AB - We report the first comparative evaluation between the Bruker Biotyper MS (BMS) and the Vitek MS (VMS) for the identification of yeasts. The rate of correct identifications at the species level was comparable using the commercial databases (89.8% versus 84.3%; P = 0.712), but higher for BMS using an in-house extended database (100% versus 84.3%; P = 0.245). Importantly, the rate of misidentification was significantly higher for VMS (1% versus 12.1%; P < 0.0001), including the rate of major errors (0% versus 4.5%; P = 0.0036). PMID- 23678073 TI - Comparison of cytomegalovirus (CMV) enzyme-linked immunosorbent spot and CMV quantiferon gamma interferon-releasing assays in assessing risk of CMV infection in kidney transplant recipients. AB - Assessing cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) represents an appealing strategy for identifying transplant recipients at risk of infection. In this study, we compared two gamma interferon-releasing assays (IGRAs), Quantiferon-CMV and CMV enzyme-linked immunosorbent spot (ELISPOT), to determine the ability of each test to predict protective CMV-specific T-cell responses. Two hundred twenty-one Quantiferon-CMV and ELISPOT tests were conducted on 120 adult kidney transplant recipients (KTRs), including 100 CMV-seropositive transplant recipients (R+) and 20 CMV-seronegative transplant recipients of a CMV-positive donor (D+/R-). As a control cohort, 39 healthy adult subjects (including 33 CMV seropositive and 6 CMV-seronegative subjects) were enrolled. CMV IgG serology was used as a reference for both tests. In the CMV-seropositive individuals, the ELISPOT and Quantiferon-CMV assays provided 46% concordance with the serology, 12% discordance, 18% disagreement between ELISPOT or Quantiferon-CMV and the serology, and 24% gray areas when one or both tests resulted in weak positives. None of the CMV-seronegative subjects showed detectable responses in the ELISPOT or the Quantiferon-CMV test. In transplant recipients, both the ELISPOT and Quantiferon-CMV assays positively correlated with each other and negatively correlated with CMV DNAemia in a significant way (P<0.05). During the antiviral prophylaxis, all 20 D+/R- KTRs we examined displayed undetectable Quantiferon-CMV and ELISPOT results, and there was no evidence of CMV seroconversion. The receiving operator curve (ROC) statistical analysis revealed similar specificities and sensitivities in predicting detectable viremia (areas under the curve [AUC], 0.66 and 0.62 for Quantiferon-CMV and ELISPOT, respectively). ELISPOT and Quantiferon-CMV values of >150 spots/200,000 peripheral blood mononuclear cells (PBMCs) and >1 to 6 IU gamma interferon (IFN-gamma) were associated with protection from CMV infection (odds ratios [OR], 5 and 8.75, respectively). In transplant recipients, the two tests displayed similar abilities for predicting CMV infection. Both the ELISPOT and Quantiferon-CMV assays require several ameliorations to avoid false-negative results. PMID- 23678076 TI - UK antimicrobial resistance strategy must be set in a wider context. PMID- 23678074 TI - Identification of medically relevant species of arthroconidial yeasts by use of matrix-assisted laser desorption ionization-time of flight mass spectrometry. AB - Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) was used for an extensive identification study of arthroconidial yeasts, using 85 reference strains from the CBS-KNAW yeast collection and 134 clinical isolates collected from medical centers in Qatar, Greece, and Romania. The test set included 72 strains of ascomycetous yeasts (Galactomyces, Geotrichum, Saprochaete, and Magnusiomyces spp.) and 147 strains of basidiomycetous yeasts (Trichosporon and Guehomyces spp.). With minimal preparation time, MALDI-TOF MS proved to be an excellent diagnostic tool that provided reliable identification of most (98%) of the tested strains to the species level, with good discriminatory power. The majority of strains were correctly identified at the species level with good scores (>2.0) and seven of the tested strains with log score values between 1.7 and 2.0. The MALDI-TOF MS results obtained were consistent with validated internal transcribed spacer (ITS) and/or large subunit (LSU) ribosomal DNA sequencing results. Expanding the mass spectrum database by increasing the number of reference strains for closely related species, including those of nonclinical origin, should enhance the usefulness of MALDI-TOF MS-based diagnostic analysis of these arthroconidial fungi in medical and other laboratories. PMID- 23678077 TI - Roche continues to drag its feet on access to Tamiflu data. PMID- 23678078 TI - Time for an evidence based approach to staffing. PMID- 23678079 TI - Don't assume urinary tract infection is the cause of delirium in older adults. PMID- 23678080 TI - Parents worried about their newborn's sleep need professionals to support, not patronise, them. PMID- 23678082 TI - Access to patient records on the Co-ordinate My Care service ought to be simpler. PMID- 23678081 TI - Funding ignores clinical aspects of diabetes targets. PMID- 23678083 TI - How to hope for the best while planning for the worst in terminal illness. PMID- 23678084 TI - Authors' reply to Ninan. PMID- 23678085 TI - UK supply of chlortalidone for hypertension must be restored. PMID- 23678086 TI - The usefulness of metformin for diabetes control in older people. PMID- 23678087 TI - Food industry can cooperate in improving population health if government is committed. PMID- 23678088 TI - Why not encourage healthy eating through incentives? PMID- 23678089 TI - NHS research authority links approval of trials to registration and publication of results. PMID- 23678090 TI - India tops world table for number of babies who die on day of birth. PMID- 23678091 TI - NICE will create standards on obesity and use of tobacco and alcohol. PMID- 23678092 TI - "Frailty units" would help take pressure off emergency departments, say specialists. PMID- 23678093 TI - Philadelphia abortion doctor is convicted of murder. PMID- 23678094 TI - Uninterrupted anticoagulation during pacemaker or defibrillator surgery. PMID- 23678095 TI - Antibody against RSV helps prevent wheeze in infants. PMID- 23678096 TI - Response to increasing submissions. PMID- 23678097 TI - Avoidance and tolerance of freezing in ectothermic vertebrates. AB - Ectothermic vertebrates have colonized regions that are seasonally or perpetually cold, and some species, particularly terrestrial hibernators, must cope with temperatures that fall substantially below 0 degrees C. Survival of such excursions depends on either freeze avoidance through supercooling or freeze tolerance. Supercooling, a metastable state in which body fluids remain liquid below the equilibrium freezing/melting point, is promoted by physiological responses that protect against chilling injury and by anatomical and behavioral traits that limit risk of inoculative freezing by environmental ice and ice nucleating agents. Freeze tolerance evolved from responses to fundamental stresses to permit survival of the freezing of a substantial amount of body water under thermal and temporal conditions of ecological relevance. Survival of freezing is promoted by a complex suite of molecular, biochemical and physiological responses that limit cell death from excessive shrinkage, damage to macromolecules and membranes, metabolic perturbation and oxidative stress. Although freeze avoidance and freeze tolerance generally are mutually exclusive strategies, a few species can switch between them, the mode used in a particular instance of chilling depending on prevailing physiological and environmental conditions. PMID- 23678098 TI - Environment, behavior and physiology: do birds use barometric pressure to predict storms? AB - Severe storms can pose a grave challenge to the temperature and energy homeostasis of small endothermic vertebrates. Storms are accompanied by lower temperatures and wind, increasing metabolic expenditure, and can inhibit foraging, thereby limiting energy intake. To avoid these potential problems, most endotherms have mechanisms for offsetting the energetic risks posed by storms. One possibility is to use cues to predict oncoming storms and to alter physiology and behavior in ways that make survival more likely. Barometric pressure declines predictably before inclement weather, and several lines of evidence indicate that animals alter behavior based on changes in ambient pressure. Here we examined the effects of declining barometric pressure on physiology and behavior in the white crowned sparrow, Zonotrichia leucophrys. Using field data from a long-term study, we first evaluated the relationship between barometric pressure, storms and stress physiology in free-living white-crowned sparrows. We then manipulated barometric pressure experimentally in the laboratory and determined how it affects activity, food intake, metabolic rates and stress physiology. The field data showed declining barometric pressure in the 12-24 h preceding snowstorms, but we found no relationship between barometric pressure and stress physiology. The laboratory study showed that declining barometric pressure stimulated food intake, but had no effect on metabolic rate or stress physiology. These data suggest that white-crowned sparrows can sense and respond to declining barometric pressure, and we propose that such an ability may be common in wild vertebrates, especially small ones for whom individual storms can be life-threatening events. PMID- 23678099 TI - Activity-dependent gene expression in honey bee mushroom bodies in response to orientation flight. AB - The natural history of adult worker honey bees (Apis mellifera) provides an opportunity to study the molecular basis of learning in an ecological context. Foragers must learn to navigate between the hive and floral locations that may be up to miles away. Young pre-foragers prepare for this task by performing orientation flights near the hive, during which they begin to learn navigational cues such as the appearance of the hive, the position of landmarks, and the movement of the sun. Despite well-described spatial learning and navigation behavior, there is currently limited information on the neural basis of insect spatial learning. We found that Egr, an insect homolog of Egr-1, is rapidly and transiently upregulated in the mushroom bodies in response to orientation. This result is the first example of an Egr-1 homolog acting as a learning-related immediate-early gene in an insect and also demonstrates that honey bee orientation uses a molecular mechanism that is known to be involved in many other forms of learning. This transcriptional response occurred both in naive bees and in foragers induced to re-orient. Further experiments suggest that visual environmental novelty, rather than exercise or memorization of specific visual cues, acts as the stimulus for Egr upregulation. Our results implicate the mushroom bodies in spatial learning and emphasize the deep conservation of Egr related pathways in experience-dependent plasticity. PMID- 23678100 TI - An in vitro study of urea, water, ion and CO2/HCO3- transport in the gastrointestinal tract of the dogfish shark (Squalus acanthias): the influence of feeding. AB - In vitro gut sac preparations made from the cardiac stomach (stomach 1), pyloric stomach (stomach 2), intestine (spiral valve) and colon were used to examine the impact of feeding on transport processes in the gastrointestinal tract of the dogfish shark. Preparations were made from animals that were euthanized after 1-2 weeks of fasting, or at 24-48 h after voluntary feeding on a 3% ration of teleost fish (hake). Sacs were incubated under initially symmetrical conditions with dogfish saline on both surfaces. In comparison to an earlier in vivo study, the results confirmed that feeding caused increases in H(+) secretion in both stomach sections, but an increase in Cl(-) secretion only in stomach 2. Na(+) absorption, rather than Na(+) secretion, occurred in both stomach sections after feeding. All sections of the tract absorbed water and the intestine strongly absorbed Na(+) and Cl(-), regardless of feeding condition. The results also confirmed that feeding increased water absorption in the intestine (but not in the colon), and had little influence on the handling of Ca(2+) and Mg(2+), which exhibited negligible absorption across the tract. However, K(+) was secreted in the intestine in both fasted and fed preparations. Increased intestinal water absorption occurred despite net osmolyte secretion into the mucosal saline. The largest changes occurred in urea and CO2/HCO3(-) fluxes. In fasted preparations, urea was absorbed at a low rate in all sections except the intestine, where it was secreted. Instead of an increase in intestinal urea secretion predicted from in vivo data, feeding caused a marked switch to net urea absorption. This intestinal urea transport occurred at a rate comparable to urea reabsorption rates reported at gills and kidney, and was apparently active, establishing a large serosal-to-mucosal concentration gradient. Feeding also greatly increased intestinal CO2/HCO3(-) secretion; if interpreted as HCO3(-) transport, the rates were in the upper range of those reported in marine teleosts. Phloretin (0.25 mmol l(-1), applied mucosally) completely blocked the increases in intestinal urea absorption and CO2/HCO3(-) secretion caused by feeding, but had no effect on Na(+), Cl(-) or water absorption. PMID- 23678101 TI - Physiological plasticity of cardiorespiratory function in a eurythermal marine teleost, the longjaw mudsucker, Gillichthys mirabilis. AB - An insufficient supply of oxygen under thermal stress is thought to define thermal optima and tolerance limits in teleost fish. When under thermal stress, cardiac function plays a crucial role in sustaining adequate oxygen supply for respiring tissues. Thus, adaptive phenotypic plasticity of cardiac performance may be critical for modifying thermal limits during temperature acclimation. Here we investigated effects of temperature acclimation on oxygen consumption, cardiac function and blood oxygen carrying capacity of a eurythermal goby fish, Gillichthys mirabilis, acclimated to 9, 19 and 26 degrees C for 4 weeks. Acclimation did not alter resting metabolic rates or heart rates; no compensation of rates was observed at acclimation temperatures. However, under an acute heat ramp, warm-acclimated fish exhibited greater heat tolerance (CTmax=33.3, 37.1 and 38.9 degrees C for 9 degrees C-, 19 degrees C- and 26 degrees C-acclimated fish, respectively) and higher cardiac arrhythmia temperatures compared with 9 degrees C-acclimated fish. Heart rates measured under an acute heat stress every week during 28 days of acclimation suggested that both maximum heart rates and temperature at onset of maximum heart rates changed over time with acclimation. Hemoglobin levels increased with acclimation temperature, from 35 g l(-1) in 9 degrees C-acclimated fish to 60-80 g l(-1) in 19 degrees C- and 26 degrees C acclimated fish. Oxygen consumption rates during recovery from acute heat stress showed post-stress elevation in 26 degrees C-acclimated fish. These data, coupled with elevated resting metabolic rates and heart rates at warm temperatures, suggest a high energetic cost associated with warm acclimation in G. mirabilis. Furthermore, acclimatory capacity appears to be optimized at 19 degrees C, a temperature shown by behavioral studies to be close to the species' preferred temperature. PMID- 23678103 TI - Induced pluripotent stem cells and motor neuron disease: toward an era of individualized medicine. PMID- 23678104 TI - Neural context reinstatement predicts memory misattribution. AB - What causes new information to be mistakenly attributed to an old experience? Some theories predict that reinstating the context of a prior experience allows new information to be bound to that context, leading to source memory confusion. To examine this prediction, we had human participants study two lists of items (visual objects) on separate days while undergoing functional magnetic resonance imaging. List 1 items were accompanied by a stream of scene images during the intertrial interval, but list 2 items were not. As in prior work by Hupbach et al. (2009), we observed an asymmetric pattern of misattributions on a subsequent source memory test: participants showed a strong tendency to misattribute list 2 items to list 1 but not vice versa. We hypothesized that these memory errors were due to participants reinstating the list 1 context during list 2. To test this hypothesis, we used a pattern classifier to measure scene-related neural activity during list 2 study. Because scenes were visually present during list 1 but not list 2, scene-related activity during list 2 study can be used as a time-varying neural indicator of how much participants were reinstating the list 1 context during list 2 study. In keeping with our hypothesis, we found that prestimulus scene activation during the study of list 2 items was significantly higher for items subsequently misattributed to list 1 than for items subsequently correctly attributed to list 2. We conclude by discussing how these findings relate to theories of memory reconsolidation. PMID- 23678105 TI - Shh/Boc signaling is required for sustained generation of ipsilateral projecting ganglion cells in the mouse retina. AB - Sonic Hedgehog (Shh) signaling is an important determinant of vertebrate retinal ganglion cell (RGC) development. In mice, there are two major RGC populations: (1) the Islet2-expressing contralateral projecting (c)RGCs, which both produce and respond to Shh; and (2) the Zic2-expressing ipsilateral projecting RGCs (iRGCs), which lack Shh expression. In contrast to cRGCs, iRGCs, which are generated in the ventrotemporal crescent (VTC) of the retina, specifically express Boc, a cell adhesion molecule that acts as a high-affinity receptor for Shh. In Boc(-/-) mutant mice, the ipsilateral projection is significantly decreased. Here, we demonstrate that this phenotype results, at least in part, from the misspecification of a proportion of iRGCs. In Boc(-/-) VTC, the number of Zic2-positive RGCs is reduced, whereas more Islet2/Shh-positive RGCs are observed, a phenotype also detected in Zic2 and Foxd1 null embryos. Consistent with this observation, organization of retinal projections at the dorsal lateral geniculate nucleus is altered in Boc(-/-) mice. Analyses of the molecular and cellular consequences of introducing Shh into the developing VTC and Zic2 and Boc into the central retina indicate that Boc expression alone is insufficient to fully activate the ipsilateral program and that Zic2 regulates Shh expression. Taking these data together, we propose that expression of Boc in cells from the VTC is required to sustain Zic2 expression, likely by regulating the levels of Shh signaling from the nearby cRGCs. Zic2, in turn, directly or indirectly, counteracts Shh and Islet2 expression in the VTC and activates the ipsilateral program. PMID- 23678106 TI - Huntingtin mediates anxiety/depression-related behaviors and hippocampal neurogenesis. AB - Huntington disease (HD) is associated with early psychiatric symptoms including anxiety and depression. Here, we demonstrate that wild-type huntingtin, the protein mutated in HD, modulates anxiety/depression-related behaviors according to its phosphorylation at serines 1181 and 1201. Genetic phospho-ablation at serines 1181 and 1201 in mouse reduces basal levels of anxiety/depression-like behaviors. We observe that the reduction in anxiety/depression-like phenotypes is associated with increased adult hippocampal neurogenesis. By improving the attachment of molecular motors to microtubules, huntingtin dephosphorylation increases axonal transport of BDNF, a crucial factor for hippocampal adult neurogenesis. Consequently, the huntingtin-mediated increased BDNF dynamics lead to an increased delivery and signaling of hippocampal BDNF. These results support the notion that huntingtin participates in anxiety and depression-like behavior and is thus relevant to the etiology of mood disorders and anxiety/depression in HD. PMID- 23678107 TI - Specific acetylation of p53 by HDAC inhibition prevents DNA damage-induced apoptosis in neurons. AB - Histone deacetylase (HDAC) inhibitors have been used to promote neuronal survival and ameliorate neurological dysfunction in a host of neurodegenerative disease models. The precise molecular mechanisms whereby HDAC inhibitors prevent neuronal death are currently the focus of intensive research. Here we demonstrate that HDAC inhibition prevents DNA damage-induced neurodegeneration by modifying the acetylation pattern of the tumor suppressor p53, which decreases its DNA-binding and transcriptional activation of target genes. Specifically, we identify that acetylation at K382 and K381 prevents p53 from associating with the pro-apoptotic PUMA gene promoter, activating transcription, and inducing apoptosis in mouse primary cortical neurons. Paradoxically, acetylation of p53 at the same lysines in various cancer cell lines leads to the induction of PUMA expression and death. Together, our data provide a molecular understanding of the specific outcomes of HDAC inhibition and suggest that strategies aimed at enhancing p53 acetylation at K381 and K382 might be therapeutically viable for capturing the beneficial effects in the CNS, without compromising tumor suppression. PMID- 23678108 TI - Hearing silences: human auditory processing relies on preactivation of sound specific brain activity patterns. AB - The remarkable capabilities displayed by humans in making sense of an overwhelming amount of sensory information cannot be explained easily if perception is viewed as a passive process. Current theoretical and computational models assume that to achieve meaningful and coherent perception, the human brain must anticipate upcoming stimulation. But how are upcoming stimuli predicted in the brain? We unmasked the neural representation of a prediction by omitting the predicted sensory input. Electrophysiological brain signals showed that when a clear prediction can be formulated, the brain activates a template of its response to the predicted stimulus before it arrives to our senses. PMID- 23678109 TI - Genetic reconstruction of dopamine D1 receptor signaling in the nucleus accumbens facilitates natural and drug reward responses. AB - The dopamine D1 receptor (D1R) facilitates reward acquisition and its alteration leads to profound learning deficits. However, its minimal functional circuit requirement is unknown. Using conditional reconstruction of functional D1R signaling in D1R knock-out mice, we define distinct requirements of D1R in subregions of the nucleus accumbens (NAc) for specific dimensions of reward. We demonstrate that D1R expression in the core region of the NAc (NAc(Core)), but not the shell (NAc(Shell)), enhances selectively a unique form of pavlovian conditioned approach and mediates D1R-dependent cocaine sensitization. However, D1R expression in either the NAc(Core) or the NAc(Shell) improves instrumental responding for reward. In contrast, neither NAc(Core) nor NAc(Shell) D1R is sufficient to promote motivation to work for reward in a progressive ratio task or for motor learning. These results highlight dissociated circuit requirements of D1R for dopamine-dependent behaviors. PMID- 23678111 TI - Brain characteristics of individuals resisting age-related cognitive decline over two decades. AB - Some elderly appear to resist age-related decline in cognitive functions, but the neural correlates of successful cognitive aging are not well known. Here, older human participants from a longitudinal study were classified as successful or average relative to the mean attrition-corrected cognitive development across 15 20 years in a population-based sample (n = 1561). Fifty-one successful elderly and 51 age-matched average elderly (mean age: 68.8 years) underwent functional magnetic resonance imaging while performing an episodic memory face-name paired associates task. Successful older participants had higher BOLD signal during encoding than average participants, notably in the bilateral PFC and the left hippocampus (HC). The HC activation of the average, but not the successful, older group was lower than that of a young reference group (n = 45, mean age: 35.3 years). HC activation was correlated with task performance, thus likely contributing to the superior memory performance of successful older participants. The frontal BOLD response pattern might reflect individual differences present from young age. Additional analyses confirmed that both the initial cognitive level and the slope of cognitive change across the longitudinal measurement period contributed to the observed group differences in BOLD signal. Further, the differences between the older groups could not be accounted for by differences in brain structure. The current results suggest that one mechanism behind successful cognitive aging might be preservation of HC function combined with a high frontal responsivity. These findings highlight sources for heterogeneity in cognitive aging and may hold useful information for cognitive intervention studies. PMID- 23678110 TI - Novelty and anxiolytic drugs dissociate two components of hippocampal theta in behaving rats. AB - Hippocampal processing is strongly implicated in both spatial cognition and anxiety and is temporally organized by the theta rhythm. However, there has been little attempt to understand how each type of processing relates to the other in behaving animals, despite their common substrate. In freely moving rats, there is a broadly linear relationship between hippocampal theta frequency and running speed over the normal range of speeds used during foraging. A recent model predicts that spatial-translation-related and arousal/anxiety-related mechanisms of hippocampal theta generation underlie dissociable aspects of the theta frequency-running speed relationship (the slope and intercept, respectively). Here we provide the first confirmatory evidence: environmental novelty decreases slope, whereas anxiolytic drugs reduce intercept. Variation in slope predicted changes in spatial representation by CA1 place cells and novelty-responsive behavior. Variation in intercept predicted anxiety-like behavior. Our findings isolate and doubly dissociate two components of theta generation that operate in parallel in behaving animals and link them to anxiolytic drug action, novelty, and the metric for self-motion. PMID- 23678112 TI - Suppression of serotonin neuron firing increases aggression in mice. AB - Numerous studies link decreased serotonin metabolites with increased impulsive and aggressive traits. However, although pharmacological depletion of serotonin is associated with increased aggression, interventions aimed at directly decreasing serotonin neuron activity have supported the opposite association. Furthermore, it is not clear if altered serotonin activity during development may contribute to some of the observed associations. Here, we used two pharmacogenetic approaches in transgenic mice to selectively and reversibly reduce the firing of serotonin neurons in behaving animals. Conditional overexpression of the serotonin 1A receptor (Htr1a) in serotonin neurons showed that a chronic reduction in serotonin neuron firing was associated with heightened aggression. Overexpression of Htr1a in adulthood, but not during development, was sufficient to increase aggression. Rapid suppression of serotonin neuron firing by agonist treatment of mice expressing Htr1a exclusively in serotonin neurons also led to increased aggression. These data confirm a role of serotonin activity in setting thresholds for aggressive behavior and support a direct association between low levels of serotonin homeostasis and increased aggression. PMID- 23678113 TI - Evidence for encoding versus retrieval scheduling in the hippocampus by theta phase and acetylcholine. AB - The formation of new memories requires new information to be encoded in the face of proactive interference from the past. Two solutions have been proposed for hippocampal region CA1: (1) acetylcholine, released in novelty, selectively suppresses excitatory projections to CA1 from CA3 (mediating the products of retrieval), while sparing entorhinal inputs (mediating novel sensory information) and (2) encoding preferentially occurs at the pyramidal-layer theta peak, coincident with input from entorhinal cortex, and retrieval occurs at the trough, coincident with input from CA3, consistent with theta phase-dependent synaptic plasticity. We examined three predictions of these models: (1) in novel environments, the preferred theta phase of CA1 place cell firing should shift closer to the CA1 pyramidal-layer theta peak, shifting the encoding-retrieval balance toward encoding; (2) the encoding-related shift in novel environments should be disrupted by cholinergic antagonism; and (3) in familiar environments, cholinergic antagonism should shift the preferred theta firing phase closer to the theta trough, shifting the encoding-retrieval balance even further toward retrieval. We tested these predictions by recording from CA1 pyramidal cells in freely moving rats as they foraged in open field environments under the influence of scopolamine (an amnestic cholinergic antagonist) or vehicle (saline). Results confirmed all three predictions, supporting both the theta phase and cholinergic models of encoding versus retrieval dynamics. Also consistent with cholinergic enhancement of encoding, scopolamine attenuated the formation of distinct spatial representations in a new environment, reducing the extent of place cell "remapping." PMID- 23678114 TI - Strengthened effective connectivity underlies transfer of working memory training to tests of short-term memory and attention. AB - Although long considered a natively endowed and fixed trait, working memory (WM) ability has recently been shown to improve with intensive training. What remains controversial and poorly understood, however, are the neural bases of these training effects and the extent to which WM training gains transfer to other cognitive tasks. Here we present evidence from human electrophysiology (EEG) and simultaneous transcranial magnetic stimulation and EEG that the transfer of WM training to other cognitive tasks is supported by changes in task-related effective connectivity in frontoparietal and parieto-occipital networks that are engaged by both the trained and transfer tasks. One consequence of this effect is greater efficiency of stimulus processing, as evidenced by changes in EEG indices of individual differences in short-term memory capacity and in visual search performance. Transfer to search-related activity provides evidence that something more fundamental than task-specific strategy or stimulus-specific representations has been learned. Furthermore, these patterns of training and transfer highlight the role of common neural systems in determining individual differences in aspects of visuospatial cognition. PMID- 23678115 TI - State-dependent contribution of the hyperpolarization-activated Na+/K+ and persistent Na+ currents to respiratory rhythmogenesis in vivo. AB - How rhythms are generated by neuronal networks is fundamental to understand rhythmic behaviors such as respiration, locomotion, and mastication. Respiratory rhythm is generated by the preBotzinger complex (preBotC), an anatomically and functionally discrete population of brainstem neurons, central and necessary for respiratory rhythm. In specific in vitro conditions, preBotC neurons depend on voltage-dependent inward currents to generate respiratory rhythm. In the mature and intact organism, where preBotC neurons are deeply embedded in the respiratory network, the contribution of ionic currents to respiratory rhythm is unclear. We propose that a set of ionic currents plays a key role in generating respiratory rhythm in the mature organism in vivo. By microperfusing ionic current blockers into the preBotC of adult rats, we identify the hyperpolarization-activated cation current as a critical component of the mechanism promoting respiratory rhythm, and that this current, in combination with the persistent sodium current, is essential to respiratory rhythm in vivo. Importantly, both currents contribute to rhythmic activity in states of anesthesia, quiet wakefulness, and sleep, but not when the organism is engaged in active behaviors. These data show that a set of ionic currents at the preBotC imparts the network with rhythmicity in reduced states of arousal, although the network can override their contribution to adjust its activity for nonrhythmic behaviors in active wakefulness. PMID- 23678116 TI - Stimulus value signals in ventromedial PFC reflect the integration of attribute value signals computed in fusiform gyrus and posterior superior temporal gyrus. AB - We often have to make choices among multiattribute stimuli (e.g., a food that differs on its taste and health). Behavioral data suggest that choices are made by computing the value of the different attributes and then integrating them into an overall stimulus value signal. However, it is not known whether this theory describes the way the brain computes the stimulus value signals, or how the underlying computations might be implemented. We investigated these questions using a human fMRI task in which individuals had to evaluate T-shirts that varied in their visual esthetic (e.g., color) and semantic (e.g., meaning of logo printed in T-shirt) components. We found that activity in the fusiform gyrus, an area associated with the processing of visual features, correlated with the value of the visual esthetic attributes, but not with the value of the semantic attributes. In contrast, activity in posterior superior temporal gyrus, an area associated with the processing of semantic meaning, exhibited the opposite pattern. Furthermore, both areas exhibited functional connectivity with an area of ventromedial prefrontal cortex that reflects the computation of overall stimulus values at the time of decision. The results provide supporting evidence for the hypothesis that some attribute values are computed in cortical areas specialized in the processing of such features, and that those attribute-specific values are then passed to the vmPFC to be integrated into an overall stimulus value signal to guide the decision. PMID- 23678117 TI - Prefrontal cholinergic mechanisms instigating shifts from monitoring for cues to cue-guided performance: converging electrochemical and fMRI evidence from rats and humans. AB - We previously reported involvement of right prefrontal cholinergic activity in veridical signal detection. Here, we first recorded real-time acetylcholine release in prefrontal cortex (PFC) during specific trial sequences in rats performing a task requiring signal detection as well as rejection of nonsignal events. Cholinergic release events recorded with subsecond resolution ("transients") were observed only during signal-hit trials, not during signal miss trials or nonsignal events. Moreover, cholinergic transients were not observed for consecutive hits; instead they were limited to signal-hit trials that were preceded by factual or perceived nonsignal events ("incongruent hits"). This finding suggests that these transients mediate shifts from a state of perceptual attention, or monitoring for cues, to cue-evoked activation of response rules and the generation of a cue-directed response. Next, to determine the translational significance of the cognitive operations supporting incongruent hits we used a version of the task previously validated for use in research in humans and blood oxygenation level-dependent (BOLD)-functional magnetic resonance imaging. Incongruent hits activated a region in the right rostral PFC (Brodmann area 10). Furthermore, greater prefrontal activation was correlated with faster response times for incongruent hits. Finally, we measured tissue oxygen in rats, as a proxy for BOLD, and found prefrontal increases in oxygen levels solely during incongruent hits. These cross-species studies link a cholinergic response to a prefrontal BOLD activation and indicate that these interrelated mechanisms mediate the integration of external cues with internal representations to initiate and guide behavior. PMID- 23678119 TI - Nucleus accumbens activity dissociates different forms of salience: evidence from human intracranial recordings. AB - Theoretical models and empirical work indicate a critical role of the NAcc in salience processing. For instance, the NAcc not only responds to appetitive and aversive information, but it also signals novelty, contextual deviance, and action monitoring. However, because most studies have investigated only one specific type of salience independently, it remains unclear how the NAcc concurrently differentiates between different forms of salience. To investigate this issue, we used intracranial electroencephalography in human epilepsy patients together with a previously established visual oddball paradigm. Here, three different oddball categories (novel, neutral, and target images) were infrequently presented among a standard scene image, and subjects responded to the target via button press. This task allowed us to differentiate "item novelty" (new vs neutral oddballs) from "contextual deviance" (neutral oddballs vs standard images) and "targetness" (target vs neutral oddballs). Time-frequency analysis revealed a dissociation between item novelty and contextual deviance on the basis of decreases in either theta (4-8 Hz) or beta power (20-30 Hz). Targetness, on the other hand, was signaled by positive deflections in the stimulus-locked local field potentials, which, importantly, correlated with subjects' reaction times. These findings indicate that, in an ongoing stream of information, the NAcc differentiates between types of salience by distinct neural mechanisms to guide goal-directed behavior. PMID- 23678118 TI - Incentive memory: evidence the basolateral amygdala encodes and the insular cortex retrieves outcome values to guide choice between goal-directed actions. AB - Choice between goal-directed actions is determined by the relative value of their consequences. Such values are encoded during incentive learning and later retrieved to guide performance. Although the basolateral amygdala (BLA) and the gustatory region of insular cortex (IC) have been implicated in these processes, their relative contribution is still a matter of debate. Here we assessed whether these structures interact during incentive learning and retrieval to guide choice. In these experiments, rats were trained on two actions for distinct outcomes after which one of the two outcomes was devalued by specific satiety immediately before a choice extinction test. We first confirmed that, relative to appropriate controls, outcome devaluation recruited both the BLA and IC based on activation of the immediate early gene Arc; however, we found that infusion of the NMDAr antagonist ifenprodil into the BLA only abolished outcome devaluation when given before devaluation. In contrast, ifenprodil infusion into the IC was effective whether made before devaluation or test. We hypothesized that the BLA encodes and the IC retrieves incentive value for choice and, to test this, developed a novel sequential disconnection procedure. Blocking NMDAr activation unilaterally in the BLA before devaluation and then contralaterally in the IC before test abolished selective devaluation. In contrast, reversing the order of these infusions left devaluation intact. These results confirm that the BLA and IC form a circuit mediating the encoding and retrieval of outcome values, with the BLA encoding and the IC retrieving such values to guide choice. PMID- 23678120 TI - The ventral midline thalamus contributes to strategy shifting in a memory task requiring both prefrontal cortical and hippocampal functions. AB - Electrophysiological and neuroanatomical evidence for reciprocal connections with the medial prefrontal cortex (mPFC) and the hippocampus make the reuniens and rhomboid (ReRh) thalamic nuclei a putatively major functional link for regulations of cortico-hippocampal interactions. In a first experiment using a new water escape device for rodents, the double-H maze, we demonstrated in rats that a bilateral muscimol (MSCI) inactivation (0.70 vs 0.26 and 0 nmol) of the mPFC or dorsal hippocampus (dHip) induces major deficits in a strategy shifting/spatial memory retrieval task. By way of comparison, only dHip inactivation impaired recall in a classical spatial memory task in the Morris water maze. In the second experiment, we showed that ReRh inactivation using 0.70 nmol of MSCI, which reduced performance without obliterating memory retrieval in the water maze, produces an as large strategy shifting/memory retrieval deficit as mPFC or dHip inactivation in the double-H maze. Thus, behavioral adaptations to task contingency modifications requiring a shift toward the use of a memory for place might operate in a distributed circuit encompassing the mPFC (as the potential set-shifting structure), the hippocampus (as the spatial memory substrate), and the ventral midline thalamus, and therein the ReRh (as the coordinator of this processing). The results of the current experiments provide a significant extension of our understanding of the involvement of ventral midline thalamic nuclei in cognitive processes: they point to a role of the ReRh in strategy shifting in a memory task requiring cortical and hippocampal functions and further elucidate the functional system underlying behavioral flexibility. PMID- 23678121 TI - Parallel pathways for cross-modal memory retrieval in Drosophila. AB - Memory-retrieval processing of cross-modal sensory preconditioning is vital for understanding the plasticity underlying the interactions between modalities. As part of the sensory preconditioning paradigm, it has been hypothesized that the conditioned response to an unreinforced cue depends on the memory of the reinforced cue via a sensory link between the two cues. To test this hypothesis, we studied cross-modal memory-retrieval processing in a genetically tractable model organism, Drosophila melanogaster. By expressing the dominant temperature sensitive shibire(ts1) (shi(ts1)) transgene, which blocks synaptic vesicle recycling of specific neural subsets with the Gal4/UAS system at the restrictive temperature, we specifically blocked visual and olfactory memory retrieval, either alone or in combination; memory acquisition remained intact for these modalities. Blocking the memory retrieval of the reinforced olfactory cues did not impair the conditioned response to the unreinforced visual cues or vice versa, in contrast to the canonical memory-retrieval processing of sensory preconditioning. In addition, these conditioned responses can be abolished by blocking the memory retrieval of the two modalities simultaneously. In sum, our results indicated that a conditioned response to an unreinforced cue in cross modal sensory preconditioning can be recalled through parallel pathways. PMID- 23678122 TI - FACS array profiling identifies Ecto-5' nucleotidase as a striatopallidal neuron specific gene involved in striatal-dependent learning. AB - The striatopallidal (STP) and striatonigral (STN) neurons constitute the main neuronal populations of the striatum. Despite the increasing knowledge concerning their involvement in multiple tasks associated with the striatum, it is still challenging to understand the precise differential functions of these two neuronal populations and to identify and study new genes involved in these functions. Here, we describe a reliable approach, applied on adult mouse brain, to generate specific STP and STN neuron gene profiles. STP and STN neurons were identified in the same animal using the transgenic Adora2A-Cre * Z/EG mouse model combined with retrograde labeling, respectively. Gene profiling was generated from FACS-purified neurons leading to the identification of new STP and STN neuron-specific genes. Knock-down models based on Cre-dependent lentiviral vector were developed to investigate their function either in striatal or in STP neurons. Thereby, we demonstrate that ecto-5'-nucleotidase (NT5e) is specifically expressed in STP neurons and is at the origin of most of the extracellular adenosine produced in the striatum. Behavioral analysis of striatal and STP neuron knock-down mouse models as well as NT5e knock-out mice demonstrates the implication of this STP neuron enzyme in motor learning. PMID- 23678123 TI - Synaptic and intrinsic homeostatic mechanisms cooperate to increase L2/3 pyramidal neuron excitability during a late phase of critical period plasticity. AB - Visual deprivation profoundly affects visual cortical response properties, but the activity-dependent plasticity mechanisms that underlie these changes are poorly understood. Monocular deprivation (MD) induces ocular dominance (OD) shifts through biphasic changes in cortical excitability, first decreasing responsiveness to the deprived eye, and then slowly increasing responsiveness to both the deprived and spared eyes. It has been suggested that this slow gain of responsiveness is due to homeostatic synaptic scaling, but this prediction has not been tested directly. Here we show that, in rat monocular and binocular primary visual cortex (V1m and V1b), postsynaptic strength onto layer 2/3 (L2/3) pyramidal neurons is modulated in a biphasic manner by MD, first undergoing a net decrease after 1 and 2 d MD, increasing back to baseline after 3 d, and finally undergoing a net potentiation between 3 and 6 d. The time course and direction of these synaptic changes match well the known changes in visual responsiveness during OD plasticity. Viral-mediated delivery of the GluA2 C-tail in vivo blocked these synaptic changes, indicating that, like synaptic scaling in vitro, AMPA receptor trafficking via the GluA2 C-tail is required for the delayed increase in postsynaptic strength. Finally, we also observed a delayed increase in the intrinsic excitability of L2/3 pyramidal neurons following prolonged MD. These data indicate that synaptic and intrinsic homeostatic mechanisms cooperate to increase excitability of L2/3 pyramidal neurons following prolonged MD, and suggest that these homeostatic mechanisms contribute to the delayed gain of visual responsiveness during OD plasticity. PMID- 23678124 TI - Most vesicles in a central nerve terminal participate in recycling. AB - Studies over the last decade using FM dyes to label vesicles at many terminals, including the calyx-type nerve terminal, led to a well accepted "principle" that only a small fraction of vesicles (~5-20%) participate in recycling under physiological conditions. This principle imposes a large challenge in maintaining synaptic transmission during repetitive firing, because the small recycling pool may limit the number of available vesicles for release and nerve terminals would have to distinguish the recycling pool from the reserve pool and keep reserve pool vesicles from being used. By recording the presynaptic capacitance changes and the postsynaptic EPSC at rat calyx of Held synapses in the absence or presence of transmitter glutamate in nerve terminals, we developed a new method to count functional recycling vesicles. We found that essentially all vesicles in calyces participated in recycling, challenging the small-recycling-pool principle established by FM dye labeling. Nerve terminals may use all available vesicles to maximize their ability in maintaining synaptic transmission during repetitive firing. PMID- 23678125 TI - Paraventricular hypothalamic regulation of trigeminovascular mechanisms involved in headaches. AB - While functional imaging and deep brain stimulation studies point to a pivotal role of the hypothalamus in the pathophysiology of migraine and trigeminal autonomic cephalalgias, the circuitry and the mechanisms underlying the modulation of medullary trigeminovascular (Sp5C) neurons have not been fully identified. We investigated the existence of a direct anatomo-functional relationship between hypothalamic excitability disturbances and modifications of the activities of Sp5C neurons in the rat. Anterograde and retrograde neuronal anatomical tracing, intrahypothalamic microinjections, extracellular single-unit recordings of Sp5C neurons, and behavioral trials were used in this study. We found that neurons of the paraventricular nucleus of the hypothalamus (PVN) send descending projections to the superior salivatory nucleus, a region that gives rise to parasympathetic outflow to cephalic and ocular/nasal structures. PVN cells project also to laminae I and outer II of the Sp5C. Microinjections of the GABAA agonist muscimol into PVN inhibit both basal and meningeal-evoked activities of Sp5C neurons. Such inhibitions were reduced in acutely restrained stressed rats. GABAA antagonist gabazine infusions into the PVN facilitate meningeal-evoked responses of Sp5C neurons. PVN injections of the neuropeptide pituitary adenylate cyclase activating peptide (PACAP38) enhance Sp5C basal activities, whereas the antagonist PACAP6-38 depresses all types of Sp5C activities. 5-HT1B/D receptor agonist naratriptan infusion confined to the PVN depresses both basal and meningeal-evoked Sp5C activities. Our findings suggest that paraventricular hypothalamic neurons directly control both spontaneous and evoked activities of Sp5C neurons and could act either as modulators or triggers of migraine and/or trigeminal autonomic cephalalgias by integrating nociceptive, autonomic, and stress processing mechanisms. PMID- 23678126 TI - Sensory and striatal areas integrate auditory and visual signals into behavioral benefits during motion discrimination. AB - For effective interactions with our dynamic environment, it is critical for the brain to integrate motion information from the visual and auditory senses. Combining fMRI and psychophysics, this study investigated how the human brain integrates auditory and visual motion into benefits in motion discrimination. Subjects discriminated the motion direction of audiovisual stimuli that contained directional motion signal in the auditory, visual, audiovisual, or no modality at two levels of signal reliability. Therefore, this 2 * 2 * 2 factorial design manipulated: (1) auditory motion information (signal vs noise), (2) visual motion information (signal vs noise), and (3) reliability of motion signal (intact vs degraded). Behaviorally, subjects benefited significantly from audiovisual integration primarily for degraded auditory and visual motion signals while obtaining near ceiling performance for "unisensory" signals when these were reliable and intact. At the neural level, we show audiovisual motion integration bilaterally in the visual motion areas hMT+/V5+ and implicate the posterior superior temporal gyrus/planum temporale in auditory motion processing. Moreover, we show that the putamen integrates audiovisual signals into more accurate motion discrimination responses. Our results suggest audiovisual integration processes at both the sensory and response selection levels. In all of these regions, the operational profile of audiovisual integration followed the principle of inverse effectiveness, in which audiovisual response suppression for intact stimuli turns into response enhancements for degraded stimuli. This response profile parallels behavioral indices of audiovisual integration, in which subjects benefit significantly from audiovisual integration only for the degraded conditions. PMID- 23678127 TI - Spinal premotor interneurons mediate dynamic and static motor commands for precision grip in monkeys. AB - The extent of spinal interneuron (IN) contribution to dexterous hand movements is unclear. Here, we studied the response patterns and force relationships of spinal premotor INs (PreM-INs) in three awake, behaving monkeys performing a precision grip task. We recorded activity from the cervical spinal cord (C5-T1) simultaneously with electromyographic (EMG) activity from hand and arm muscles during the task. Spike-triggered averaging of EMGs showed that 25 PreM-INs had postspike effects on EMG activity. Most PreM-INs (23/25) displayed movement related firing rate modulations: 11 had phasic followed by tonic facilitation (p+t+); 4 were pure phasic; 4 were pure tonic; and 4 were deactivated, while their target muscles consistently had p+t+ activity (65/66 muscles). PreM-IN phasic activity started earlier than target muscle activity (49 +/- 81.4 ms, mean +/- SD), and the peak amplitude was correlated with the peak amplitude of the rate of change of grip force (4/17, p < 0.05), suggesting that they contributed to force initiation. In contrast, PreM-IN tonic activity started at almost the same time as the target muscle activity and the mean firing rate was correlated with the mean grip force during the hold period (4/15, p < 0.05), suggesting that they contributed to force maintenance. These results indicated that the neural pathway mediated by the spinal PreM-INs makes a significant contribution to the control of precision grip in primates. PMID- 23678128 TI - EPAC inhibition of SUR1 receptor increases glutamate release and seizure vulnerability. AB - EPAC (Exchange Proteins Activated by cAMP) regulates glutamate transmitter release in the central neurons, but a role underlying this regulation has yet to be identified. Here we show that EPAC binds directly to the intracellular loop of an ATP-sensitive potassium (KATP) channel type-1 sulfonylurea receptor (SUR1) receptor consisting of amino acids 859-881 (SUR1(859-881)). Ablation of EPAC or expression of SUR1(859-881), which intercepts EPAC-SUR1 binding, increases the open probability of KATP channels consisting of the Kir6.1 subunit and SUR1. Opening of KATP channels inhibits glutamate release and reduces seizure vulnerability in adult mice. Therefore, EPAC interaction with SUR1 controls seizure susceptibility and possibly acts via regulation of glutamate release. PMID- 23678129 TI - Dopaminergic control of motivation and reinforcement learning: a closed-circuit account for reward-oriented behavior. AB - Humans and animals take actions quickly when they expect that the actions lead to reward, reflecting their motivation. Injection of dopamine receptor antagonists into the striatum has been shown to slow such reward-seeking behavior, suggesting that dopamine is involved in the control of motivational processes. Meanwhile, neurophysiological studies have revealed that phasic response of dopamine neurons appears to represent reward prediction error, indicating that dopamine plays central roles in reinforcement learning. However, previous attempts to elucidate the mechanisms of these dopaminergic controls have not fully explained how the motivational and learning aspects are related and whether they can be understood by the way the activity of dopamine neurons itself is controlled by their upstream circuitries. To address this issue, we constructed a closed-circuit model of the corticobasal ganglia system based on recent findings regarding intracortical and corticostriatal circuit architectures. Simulations show that the model could reproduce the observed distinct motivational effects of D1- and D2-type dopamine receptor antagonists. Simultaneously, our model successfully explains the dopaminergic representation of reward prediction error as observed in behaving animals during learning tasks and could also explain distinct choice biases induced by optogenetic stimulation of the D1 and D2 receptor-expressing striatal neurons. These results indicate that the suggested roles of dopamine in motivational control and reinforcement learning can be understood in a unified manner through a notion that the indirect pathway of the basal ganglia represents the value of states/actions at a previous time point, an empirically driven key assumption of our model. PMID- 23678133 TI - Retraction: Savine and Braver, motivated cognitive control: reward incentives modulate preparatory neural activity during task-switching. PMID- 23678132 TI - The synchronous activity of lateral habenular neurons is essential for regulating hippocampal theta oscillation. AB - Lateral habenula (LHb) has attracted growing interest as a regulator of serotonergic and dopaminergic neurons in the CNS. However, it remains unclear how the LHb modulates brain states in animals. To identify the neural substrates that are under the influence of LHb regulation, we examined the effects of rat LHb lesions on the hippocampal oscillatory activity associated with the transition of brain states. Our results showed that the LHb lesion shortened the theta activity duration both in anesthetized and sleeping rats. Furthermore, this inhibitory effect of LHb lesion on theta maintenance depended upon an intact serotonergic median raphe, suggesting that LHb activity plays an essential role in maintaining hippocampal theta oscillation via the serotonergic raphe. Multiunit recording of sleeping rats further revealed that firing of LHb neurons showed significant phase-locking activity at each theta oscillation cycle in the hippocampus. LHb neurons showing activity that was coordinated with that of the hippocampal theta were localized in the medial LHb division, which receives afferents from the diagonal band of Broca (DBB), a pacemaker region for the hippocampal theta oscillation. Thus, our findings indicate that the DBB may pace not only the hippocampus, but also the LHb, during rapid eye movement sleep. Since serotonin is known to negatively regulate theta oscillation in the hippocampus, phase locking activity of the LHb neurons may act, under the influence of the DBB, to maintain the hippocampal theta oscillation by modulating the activity of serotonergic neurons. PMID- 23678130 TI - Ligand for translocator protein reverses pathology in a mouse model of Alzheimer's disease. AB - Ligands of the translocator protein (TSPO) elicit pleiotropic neuroprotective effects that represent emerging treatment strategies for several neurodegenerative conditions. To investigate the potential of TSPO as a therapeutic target for Alzheimer's disease (AD), the current study assessed the effects of the TSPO ligand Ro5-4864 on the development of neuropathology in 3xTgAD mice. The effects of the TSPO ligand on neurosteroidogenesis and AD related neuropathology, including beta-amyloid accumulation, gliosis, and behavioral impairment, were examined under both early intervention (7-month-old young-adult male mice with low pathology) and treatment (24-month-old, aged male mice with advanced neuropathology) conditions. Ro5-4864 treatment not only effectively attenuated development of neuropathology and behavioral impairment in young-adult mice but also reversed these indices in aged 3xTgAD mice. Reduced levels of soluble beta-amyloid were also observed by the combination of TSPO ligands Ro5-4864 and PK11195 in nontransgenic mice. These findings suggest that TSPO is a promising target for the development of pleiotropic treatment strategies for the management of AD. PMID- 23678131 TI - Dendritic GluN2A synthesis mediates activity-induced NMDA receptor insertion. AB - Long-term synaptic plasticity involves changes in the expression and membrane insertion of cell-surface proteins. Interestingly, the mRNAs encoding many cell surface proteins are localized to dendrites, but whether dendritic protein synthesis is required for activity-induced surface expression of specific proteins is unknown. Herein, we used microfluidic devices to demonstrate that dendritic protein synthesis is necessary for activity-induced insertion of GluN2A containing NMDA receptors in rat hippocampal neurons. Furthermore, visualization of activity-induced local translation of GluN2A mRNA and membrane insertion of GluN2A protein in dendrites was directly observed and shown to depend on a 3' untranslated region cytoplasmic polyadenylation element and its associated translation complex. These findings uncover a novel mechanism for cytoplasmic polyadenylation element-mediated posttranscriptional regulation of GluN2A mRNA to control NMDA receptor surface expression during synaptic plasticity. PMID- 23678134 TI - Evidence for increased tissue androgen sensitivity in neurturin knockout mice. AB - Neurturin (NTN) is a member of the glial cell line-derived neurotrophic factor (GDNF) family and signals through GDNF family receptor alpha 2 (GFRalpha2). We hypothesised that epithelial atrophy reported in the reproductive organs of Ntn (Nrtn)- and Gfralpha2 (Gfra2)-deficient mice could be due to NTN affecting the hormonal environment. To investigate this, we compared the reproductive organs of Ntn- and Gfralpha2-deficient male mice in parallel with an analysis of their circulating reproductive hormone levels. There were no significant structural changes within the organs of the knockout mice; however, serum and intratesticular testosterone and serum LH levels were very low. To reconcile these observations, we tested androgen sensitivity by creating a dihydrotestosterone (DHT) clamp (castration plus DHT implant) to create fixed circulating levels of androgens, allowing the evaluation of androgen-sensitive endpoints. At the same serum DHT levels, serum LH levels were lower and prostate and seminal vesicle weights were higher in the Ntn knockout (NTNKO) mice than in the wild-type mice, suggesting an increased response to androgens in the accessory glands and hypothalamus and pituitary of the NTNKO mice. Testicular and pituitary responsiveness was unaffected in the NTNKO males, as determined by the response to the human chorionic gonadotrophin or GNRH analogue, leuprolide, respectively. In conclusion, our results suggest that NTN inactivation enhances androgen sensitivity in reproductive and neuroendocrine tissues, revealing a novel mechanism to influence reproductive function and the activity of other androgen-dependent tissues. PMID- 23678148 TI - Dipeptidyl-peptidase-like proteins cast in a new role: enabling scorpion toxin block of A-type K+ channels. PMID- 23678135 TI - Adapting interpersonal psychotherapy for the prevention of excessive weight gain in rural African American girls. AB - OBJECTIVE: To obtain focus group data regarding the perspectives of rural African American (AA) girls, parents/guardians, and community leaders on obesity, loss of control (LOC) eating, relationships, and interpersonal psychotherapy for the prevention of excessive weight gain (IPT-WG). METHODS: 7 focus groups (N = 50 participants) were moderated and the transcripts analyzed by Westat researchers using widely accepted methods of qualitative and thematic analysis. A session was held with experts in health disparities to elucidate themes. RESULTS: Participants understood LOC eating; however, they had culturally specific perceptions including usage of alternative terms. Relationships were highly valued, specifically those between mothers and daughters. IPT-WG program components generally resonated with participants, although modifications were recommended to respect parental roles. Experts interpreted focus group themes and discussed potential barriers and solutions to recruitment and participation. CONCLUSION: Findings suggest that adapting IPT-WG may be acceptable to rural AA families. This research is the first step in developing a sustainable excessive weight gain and binge eating disorder prevention program for rural AA adolescents. PMID- 23678149 TI - Mechanisms and mechanics of auditory masking. PMID- 23678150 TI - Why does acetylcholine exacerbate myasthenia caused by anti-MuSK antibodies? PMID- 23678151 TI - Be still my beating brain--reduction of brain micromotion during in vivo two photon imaging. PMID- 23678153 TI - Golimumab in patients with active rheumatoid arthritis despite methotrexate therapy: results through 2 years of the GO-FORWARD study extension. AB - OBJECTIVE: To assess the longterm efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) therapy. METHODS: We randomized 444 RA patients with inadequate response to MTX (3:3:2:2) to placebo + MTX (Group 1), golimumab 100 mg + placebo (Group 2), golimumab 50 mg + MTX (Group 3), or golimumab 100 mg + MTX (Group 4). Subcutaneous golimumab/placebo was injected every 4 weeks. Patients could escape early (Group 1 added golimumab 50 mg, Group 2 added MTX, Group 3 increased golimumab to 100 mg, Group 4 continued 100 mg) based on Week 16 swollen and tender joint counts. From Week 24, Group 1 patients received golimumab 50 mg + MTX. After the Week 52 database lock, patients in the longterm extension received golimumab 50-100 mg +/ MTX. Coprimary endpoints [Week 14 American College of Rheumatology (ACR)20, Week 24 Health Assessment Questionnaire Disability Index (HAQ-DI)] and Week 52 findings have been published; 2-year findings (observed data by randomized group, no imputation) are presented. RESULTS: Of 444 randomized patients, 392 continued from Week 52 (Group 1: n = 116, Group 2: n = 116, Group 3: n = 84, Group 4: n = 76). Clinical improvement was maintained through Week 104; ~75% and 72% of patients randomized to golimumab 50 mg + MTX and 100 mg + MTX achieved ACR20 response, respectively. The majority [88% (105/120)] of golimumab + MTX-treated patients with Week 24 HAQ-DI improvement >= 0.25 maintained improved physical function through Week 104. Group 1 patients with delayed golimumab treatment exhibited more Week 104 radiographic progression (mean change score = 1.15) than golimumab + MTX-randomized patients (0.52). Incidences of serious infections were 2.24, 4.77, 5.78/100 patient-years of followup for golimumab 50 mg + MTX, 100 mg + placebo, and 100 mg + MTX, respectively. CONCLUSION: Clinical improvement was maintained and no new safety signals were identified with 2 years of golimumab + MTX. Golimumab efficacy and safety, including serious infections, will continue to be monitored through 5 years (Clinical Trial No. NCT00264550). PMID- 23678152 TI - Longitudinal peripheral blood lymphocyte subsets correlate with decreased disease activity in juvenile dermatomyositis. AB - OBJECTIVE: To determine the clinical characteristics and subsets of peripheral blood lymphocytes (PBL), which correlate with decreased disease activity in patients with juvenile dermatomyositis (JDM). METHODS: Peripheral blood mononuclear cells from 24 patients with JDM were collected at Mayo Clinic Rochester between 2007 and 2011. These were analyzed using fluorescence-activated cell sorting and flow cytometry. Clinical disease activity was determined by visual analog scales (VAS) collected in 2 consecutive visits and correlated with PBL subsets. RESULTS: The change in CD3+CD69+ T cells correlated with the change in global VAS scores. The change in HLA-DR- CD11c+ myeloid dendritic cells also correlated with the change in extramuscular VAS scores. There were trends toward decreased levels of HLA-DR- CD11c+ cells with decreased muscle and global VAS scores, but these did not reach significance. The change in HLA-DR- CD123+ plasmacytoid dendritic cells negatively correlated with the change in muscle VAS scores. Although not statistically significant, decreased levels of CD3-CD16- CD56+ natural killer (NK) cells and HLA-DR- CD86+ myeloid dendritic cells, and increased levels of CD16+CD56- NK cells, correlated with decreased VAS scores. CONCLUSION: Changes in CD3+CD69+ T cells, HLA-DR- CD11c+ myeloid dendritic cells, and HLA-DR- CD123+ plasmacytoid dendritic cells are associated with improved clinical course in JDM and could be used as markers for disease activity, but findings need to be verified in a larger, independent cohort. Lack of significant differences among most of our PBL subsets suggests that lymphocyte phenotyping may be difficult to definitively correlate with disease activity in JDM. PMID- 23678154 TI - Serum urate and incidence of kidney disease among veterans with gout. AB - OBJECTIVE: To study the association between serum urate level (sUA) and the risk of incident kidney disease among US veterans with gouty arthritis. METHODS: From 2002 through 2011 adult male patients with gout who were free of kidney disease were identified in the data from the Veterans Administration VISN 16 database and were followed until incidence of kidney disease, death, or the last available observation. Accumulated hazard curves for time to kidney disease were estimated for patients with average sUA levels > 7 mg/dl (high) versus <= 7 mg/dl (low) based on Kaplan-Meier analyses; and statistical comparison was conducted using a log-rank test. A Cox proportional hazard model with time-varying covariates was used to estimate the unadjusted and adjusted hazard ratios for kidney disease. RESULTS: Eligible patients (n = 2116) were mostly white (53%), with average age 62.6 years, mean body mass index 31.2 kg/m(2), and high baseline prevalence of hypertension (93%), hyperlipidemia (67%), and diabetes (20%). Mean followup time was 6.5 years. The estimated rates of all incident kidney disease in the overall low versus high sUA groups were 2% versus 4% at Year 1, 3% versus 6% at Year 2, and 5% versus 9% at Year 3, respectively (p < 0.0001). After adjustment, high sUA continued to predict a significantly higher risk of kidney disease development (HR 1.43, 95% CI 1.20-1.70). CONCLUSION: Male veterans with gout and sUA levels > 7 mg/dl had an increased incidence of kidney disease. PMID- 23678155 TI - HLA-G 3' untranslated region polymorphisms are associated with systemic lupus erythematosus in 2 Brazilian populations. AB - OBJECTIVE: HLA-G has well recognized tolerogenic properties in physiological and nonphysiological conditions. The 3' untranslated region (3'UTR) of the HLA-G gene has at least 3 polymorphic sites (14-bpINS/DEL, +3142C/G, and +3196C/G) described as associated with posttranscriptional influence on messenger RNA production; however, only the 14-bpINS/DEL and +3142C/G sites have been studied in systemic lupus erythematosus (SLE). METHODS: We investigated the HLA-G 3'UTR polymorphic sites (14-bpINS/DEL, +3003C/T, +3010C/G, +3027A/C, +3035C/T, +3142C/G, +3187A/G, and +3196C/G) in 190 Brazilian patients with SLE and 282 healthy individuals in allele, genotype, and haplotype analyses. A multiple logistic regression model was used to assess the association of the disease features with the HLA-G 3'UTR haplotypes. RESULTS: Increased frequencies were observed of the 14-bpINS (p = 0.053), +3010C (p = 0.008), +3142G (p = 0.006), and +3187A (p = 0.013) alleles, and increased frequencies of the 14-bpINS-INS (p = 0.094), +3010 C-C (p = 0.033), +3142 G-G (p = 0.021), and +3187 A-A (p = 0.035) genotypes. After Bonferroni correction, only the +3142G (p = 0.05) and +3010C (p = 0.06) alleles were overrepresented in SLE patients. The UTR-1 haplotype (14 bpDEL/+3003T/+3010G/+3027C/+3035C/+3142C/+3187G/+3196C) was underrepresented in SLE (pcorr = 0.035). CONCLUSION: These results indicate that HLA-G 3'UTR polymorphic sites, particularly +3142G and +3010C alleles, were associated with SLE susceptibility, whereas UTR-1 was associated with protection against development of SLE. PMID- 23678156 TI - Anterior chest wall pain in recent inflammatory back pain suggestive of spondyloarthritis. data from the DESIR cohort. AB - OBJECTIVE: To determine the prevalence of anterior chest wall (ACW) pain in patients with recent inflammatory back pain (IBP) suggestive of spondyloarthritis (SpA), and to investigate the influence of ACW pain on the overall features of these patients. METHODS: The DESIR cohort is a prospective, multicenter French cohort of patients with early IBP suggestive of SpA, including 708 patients (mean age 33.8 yrs, 53.8% females, 57.3% HLA-B27-positive). ACW pain was defined by at least 1 episode of chest wall pain attributed to SpA by the rheumatologist, after ruling out other causes of chest pain. Data on the baseline demographic characteristics, functional status and quality of life, imaging features, bone mineral density, and blood tests were compared in patients with and those without ACW pain. Factors associated with ACW pain were identified by univariate and multivariate analysis (logistic regression). RESULTS: The prevalence of ACW pain in the DESIR cohort (n = 316/708 patients) was 44.6% (95% CI 40.9-48.3). ACW pain occurred after the first symptoms of IBP in 62%. Localization was diffuse in 41% of the positive cases. A stepwise multivariate analysis found an association between ACW pain and the enthesitis score, involvement of thoracic spine, diagnosis of ankylosing spondylitis (AS), and radiographic abnormalities of sacroiliac joints. CONCLUSION: In recent IBP suggestive of SpA, presence of ACW pain is associated with enthesitis, thoracic spine involvement, radiographic sacroiliitis, diagnosis of AS, and with a more severe disease. ACW pain could be interpreted as a diagnostic feature for AS. PMID- 23678157 TI - Integrative analyses for functional mechanisms underlying associations for rheumatoid arthritis. AB - OBJECTIVE: Extensive association analyses including genome-wide association studies (GWAS) and powerful metaanalysis studies have identified a long list of loci associated with rheumatoid arthritis (RA) in very large populations, but most of them established statistical associations of genetic markers and RA only at the DNA level, without supporting evidence of functional relevance. Our study serves as a trial to detect the functional mechanisms underlying associations for RA by searching publicly available datasets and results. METHODS: Based on publicly available datasets and results, we performed integrative analyses (gene relationships across implicated loci analysis, differential gene expression analysis, and functional annotation clustering analysis) and combined them with the expression quantitative trait locus (eQTL) results to dissect functional mechanisms underlying the associations for RA. RESULTS: By searching 2 GWAS, Integrator and PheGenI, we selected 98 RA association results (p < 10(-5)). Among these associations, we found that 8 single-nucleotide polymorphisms (SNP; rs1600249, rs2736340, rs3093023, rs3093024, rs4810485, rs615672, rs660895, and rs9272219) serve as cis-effect regulators of the corresponding eQTL genes (BLK and CD4 in non-HLA region; CCR6, HLA-DQA1, and HLA-DQB1 in HLA region) that also were differentially expressed in RA-related cell groups. These 5 genes are closely related with immune response in function. CONCLUSION: Our results showed the functional mechanisms underlying the associations of 8 SNP and the corresponding genes. This study is an example of mining publicly available datasets and results in validation of significant disease-association results. Using public data resources for integrative analyses may provide insights into the molecular genetic mechanisms underlying human diseases. PMID- 23678158 TI - Systemic sclerosis in Canada's North American Native population: assessment of clinical and serological manifestations. AB - OBJECTIVE: Certain North American Native (NAN) populations are known to have higher rates of systemic sclerosis (SSc) compared to non-NAN; however, little is known of the specific disease characteristics in this population in Canada. This study compares the clinical and serological manifestations of SSc in NAN and white patients. METHODS: This cross-sectional, multicenter study included subjects enrolled in the Canadian Scleroderma Research Group registry between September 2004 and June 2012. Subjects were evaluated with complete medical histories, physical examinations, and self-questionnaires. Ethnicity was defined by self-report. Disease characteristics were compared between NAN and white patients and multivariate analyses were performed to determine the independent association between ethnicity and various clinical manifestations. RESULTS: Of 1278 patients, 1038 (81%) were white, 71 (6%) were NAN, and 169 (13%) were classified as non-white/non-NAN. There were important differences between NAN and white subjects with SSc. In multivariate analysis adjusting for socioeconomic differences and smoking status, NAN ethnicity was an independent risk factor for the severity of Raynaud phenomenon and more gastrointestinal symptoms, and was associated with a nonsignificant increase in the presence of digital ulcers. CONCLUSION: NAN patients with SSc have a distinct clinical phenotype. Our study provides a strong rationale to pursue further research into genetic and environmental determinants of SSc. PMID- 23678159 TI - Cholesteryl ester transfer protein in patients with rheumatoid arthritis. AB - OBJECTIVE: To investigate how cholesteryl ester transfer protein (CETP), one of the enzymes involved in the reverse cholesterol transfer, is expressed in patients with rheumatoid arthritis (RA) and its potential relationship with both dyslipidemia and the risk of cardiovascular mortality observed in these patients. METHODS: Plasma CETP concentrations and CETP activity were measured in 101 patients with RA and 115 sex- and age-matched controls. A multivariable analysis adjusted for standard cardiovascular risk factors, including high-density lipoprotein cholesterol, was performed to evaluate the influence of CETP on dyslipidemia and cardiovascular mortality risk, as assessed by the Systematic Coronary Risk Evaluation (SCORE) risk function. RESULTS: Patients with RA showed lower CETP activity [beta coefficient = -10.82 (95% CI -19.56 to 2.07) pmol/3 h; p = 0.02] and an inferior CETP mass [beta = -0.85 (95% CI -1.64 to 0.05) MUg/ml; p = 0.03] versus controls. Divided into those taking and those not taking glucocorticoids, patients taking glucocorticoids revealed lower CETP activity and mass [beta = -8.98 (95% CI -14.55 to 3.41) pmol/3 h; p = 0.00, for CETP activity; and beta = -0.77 (95% CI -1.46 to 0.08) MUg/ml; p = 0.03, for CETP mass]. Patients with RA not taking glucocorticoids showed no differences versus controls in either CETP activity or mass. Both current prednisone intake [beta = -16.14 (95% CI -24.87 to 7.41) pmol/3 h; p = 0.00] and average daily prednisone intake during the last 3 months [beta = -0.36 (95% CI -0.54 to 0.18) MUg/ml; p = 0.01] were strongly and inversely correlated with CETP activity and mass, respectively. CETP activity showed an inverse trend compared to SCORE risk, demonstrating that lower levels were effective predictors of total mortality when a higher SCORE risk was found [beta = -4.7 (95% CI -9.3 to 0.02) pmol/3 h; p = 0.04] in patients with RA. CONCLUSION: CETP is downregulated in patients with RA who are taking glucocorticoids. Low CETP activity is associated with an increased level of cardiovascular risk in patients with RA. PMID- 23678160 TI - Incidence of Spondyloarthropathy in patients with ulcerative colitis: a population-based study. AB - OBJECTIVE: Spondyloarthritis (SpA) is an important extraintestinal manifestation of inflammatory bowel disease (IBD). We assessed the cumulative incidence and clinical spectrum of SpA in a population-based cohort of patients with ulcerative colitis (UC). METHODS: The medical records of a population-based cohort of residents of Olmsted County, Minnesota, USA, diagnosed with UC from 1970 through 2004 were reviewed. Patients were followed longitudinally until moving from Olmsted County, death, or June 30, 2011. We used the European Spondylarthropathy Study Group, Assessment of Spondyloarthritis International Society (ASAS) criteria, and modified New York criteria to identify patients with SpA. RESULTS: The cohort included 365 patients with UC, of whom 41.9% were women. The median age at diagnosis of UC was 38.6 years (range 1.2-91.4). Forty patients developed SpA based on the ASAS criteria. The cumulative incidence of a diagnosis of SpA after an established diagnosis of UC was 4.8% at 10 years (95% CI 95% CI 2.2% 7.3%), 13.7% at 20 years (95% CI 9.0%-18.1%), and 22.1% at 30 years (95% CI 4.3% 29.1%). CONCLUSION: The cumulative incidence of all forms of SpA increased to about 22% by 30 years from UC diagnosis. This value is slightly greater than what we previously described in a population-based cohort of Crohn disease diagnosed in Olmsted County over the same time period. SpA and its features are associated with UC, and heightened awareness on the part of clinicians is needed for diagnosing and managing them. PMID- 23678161 TI - Intraarticular and systemic inflammatory profiles may identify patients with osteoarthritis. AB - OBJECTIVE: To determine whether cytokine/chemokine profiles from synovial fluid and sera discriminate mild/moderate osteoarthritis (OA) from normal and severe OA cohorts. METHODS: Multiplex technology was used to quantify expression levels for 42 cytokines in the synovial fluid of patients diagnosed with severe OA (n = 20) and mild/moderate OA (n = 12), as well as normal controls (n = 34). The same 42 cytokines were examined in serum samples of patients with severe OA (n = 26) and mild/moderate OA (n = 74) and normal individuals (n = 100). Treatment group comparisons followed by principal component analysis (PCA) and K-means clustering of the significantly different cytokines/chemokines revealed groupings of patients by physician diagnosis. RESULTS: Differences in cytokine/chemokine levels were found between control, mild/moderate OA, and severe OA synovial fluid samples, as well as between normal and mild/moderate OA serum samples, and between control and severe OA serum samples. No differences were observed between mild/moderate and severe OA serum samples. Visual groupings based on PCA were validated by K-means analysis, with the best results obtained from the comparison of normal and mild/moderate OA serum samples with 96% of normal and 93% of mild/moderate OA samples accurately identified. CONCLUSION: Our study suggests that comparing the expression levels of cytokines/chemokines in synovial fluid and/or serum of patients with OA may have promise as a diagnostic platform to identify patients early in their disease course. This high-throughput low-cost assay may be able to provide clinicians with a diagnostic test to complement existing clinical and imaging modalities currently used to diagnose OA. PMID- 23678162 TI - Follistatin-like protein 1 and the ferritin/erythrocyte sedimentation rate ratio are potential biomarkers for dysregulated gene expression and macrophage activation syndrome in systemic juvenile idiopathic arthritis. AB - OBJECTIVE: Follistatin-like protein 1 (FSTL-1) is a secreted glycoprotein overexpressed in certain inflammatory diseases. Our objective was to correlate FSTL-1 levels with gene expression, known biomarkers, and measures of disease activity in systemic juvenile idiopathic arthritis (sJIA), including macrophage activation syndrome (MAS). METHODS: FSTL-1 serum levels were measured by ELISA in 28 patients with sJIA, including 7 patients who developed MAS, and 30 healthy controls. Levels were correlated with erythrocyte sedimentation rate (ESR), ferritin, and soluble interleukin-2 receptor-alpha (sIL-2Ralpha). Gene expression based on FSTL-1 levels was analyzed in peripheral blood mononuclear cells (PBMC). RESULTS: Serum levels of FSTL-1 were elevated at time of presentation of sJIA (mean 200.7 ng/ml) and decreased to normal (mean 133.7 ng/ml) over 24 months (p < 0.01). FSTL-1 levels were markedly elevated during acute MAS (mean 279.8 ng/ml) and decreased to normal following treatment (p < 0.001). FSTL-1 levels correlated with serum markers of inflammation, including sIL-2Ralpha and ferritin. Ferritin/ESR ratio was superior to ferritin, sIL-2Ralpha, and FSTL-1 in discriminating MAS from new-onset sJIA. PBMC from patients with FSTL-1 levels > 200 ng/ml showed altered expression of genes related to innate immunity, erythropoiesis, and natural killer cell dysfunction. Two patients with the highest FSTL-1 levels at disease onset (> 300 ng/ml) ultimately developed MAS. CONCLUSION: Elevated pretreatment serum FSTL-1 levels in sJIA are associated with dysregulated gene expression suggestive of occult MAS, and may have utility in predicting progression to overt MAS. Ferritin/ESR ratio may be superior to ferritin alone in discriminating overt MAS from new-onset sJIA. PMID- 23678165 TI - The role of virulence in in vivo superinfection fitness of the vertebrate RNA virus infectious hematopoietic necrosis virus. AB - We have developed a novel in vivo superinfection fitness assay to examine superinfection dynamics and the role of virulence in superinfection fitness. This assay involves controlled, sequential infections of a natural vertebrate host, Oncorhynchus mykiss (rainbow trout), with variants of a coevolved viral pathogen, infectious hematopoietic necrosis virus (IHNV). Intervals between infections ranged from 12 h to 7 days, and both frequency of superinfection and viral replication levels were examined. Using virus genotype pairs of equal and unequal virulence, we observed that superinfection generally occurred with decreasing frequency as the interval between exposures to each genotype increased. For both the equal-virulence and unequal-virulence genotype pairs, the frequency of superinfection in most cases was the same regardless of which genotype was used in the primary exposure. The ability to replicate in the context of superinfection also did not differ between the genotypes of equal or unequal virulence tested here. For both genotype pairs, the mean viral load of the secondary virus was significantly reduced in superinfection while primary virus replication was unaffected. Our results demonstrate, for the two genotype pairs examined, that superinfection restriction does occur for IHNV and that higher virulence did not correlate with a significant difference in superinfection fitness. To our knowledge, this is the first assay to examine the role of virulence of an RNA virus in determining superinfection fitness dynamics within a natural vertebrate host. PMID- 23678166 TI - Induction of dendritic cell production of type I and type III interferons by wild type and vaccine strains of measles virus: role of defective interfering RNAs. AB - The innate immune response to viral infection frequently includes induction of type I interferons (IFN), but many viruses have evolved ways to block this response and increase virulence. In vitro studies of IFN production after infection of susceptible cells with measles virus (MeV) have often reported greater IFN synthesis after infection with vaccine than with wild-type strains of MeV. However, the possible presence in laboratory virus stocks of 5' copy-back defective interfering (DI) RNAs that induce IFN independent of the standard virus has frequently confounded interpretation of data from these studies. To further investigate MeV strain-dependent differences in IFN induction and the role of DI RNAs, monocyte-derived dendritic cells (moDCs) were infected with the wild-type Bilthoven strain and the vaccine Edmonston-Zagreb strain with and without DI RNAs. Production of type I IFN, type III IFN, and the interferon-stimulated genes (ISGs) Mx and ISG56 by infected cells was assessed with a flow cytometry-based IFN bioassay, quantitative reverse transcriptase PCR (RT-PCR), and immunoassays. Bilthoven infected moDCs less efficiently than Edmonston-Zagreb. Presence of DI RNAs in vaccine stocks resulted in greater maturation of moDCs, inhibition of virus replication, and induction of higher levels of IFN and ISGs. Production of type I IFN, type III IFN, and ISG mRNA and protein was determined by both the level of infection and the presence of DI RNAs. At the same levels of infection and in the absence of DI RNA, IFN induction was similar between wild-type and vaccine strains of MeV. PMID- 23678167 TI - Middle East respiratory syndrome coronavirus (MERS-CoV): announcement of the Coronavirus Study Group. PMID- 23678168 TI - Hepatitis C virus infection induces inflammatory cytokines and chemokines mediated by the cross talk between hepatocytes and stellate cells. AB - Inflammatory cytokines and chemokines play important roles in inflammation during viral infection. Hepatitis C virus (HCV) is a hepatotropic RNA virus that is closely associated with chronic liver inflammation, fibrosis, and hepatocellular carcinoma. During the progression of HCV-related diseases, hepatic stellate cells (HSCs) contribute to the inflammatory response triggered by HCV infection. However, the underlying molecular mechanisms that mediate HSC-induced chronic inflammation during HCV infection are not fully understood. By coculturing HSCs with HCV-infected hepatocytes in vitro, we found that HSCs stimulated HCV infected hepatocytes, leading to the expression of proinflammatory cytokines and chemokines such as interleukin-6 (IL-6), IL-8, macrophage inflammatory protein 1alpha (MIP-1alpha), and MIP-1beta. Moreover, we found that this effect was mediated by IL-1alpha, which was secreted by HSCs. HCV infection enhanced production of CCAAT/enhancer binding protein (C/EBP) beta mRNA, and HSC-dependent IL-1alpha production contributed to the stimulation of C/EBPbeta target cytokines and chemokines in HCV-infected hepatocytes. Consistent with this result, knockdown of mRNA for C/EBPbeta in HCV-infected hepatocytes resulted in decreased production of cytokines and chemokines after the addition of HSC conditioned medium. Induction of cytokines and chemokines in hepatocytes by the HSC conditioned medium required a yet to be identified postentry event during productive HCV infection. The cross talk between HSCs and HCV-infected hepatocytes is a key feature of inflammation-mediated, HCV-related diseases. PMID- 23678169 TI - Infection of mice, ferrets, and rhesus macaques with a clinical mumps virus isolate. AB - In recent years, many mumps outbreaks have occurred in vaccinated populations worldwide. The reasons for these outbreaks are not clear. Animal models are needed to investigate the causes of outbreaks and to understand the pathogenesis of mumps virus (MuV). In this study, we have examined the infection of three animal models with an isolate of mumps virus from a recent outbreak (MuV-IA). We have found that while both ferrets and mice generated humoral and cellular immune responses to MuV-IA infection, no obvious signs of illness were observed in these animals; rhesus macaques were the most susceptible to MuV-IA infection. Infection of rhesus macaques via both intranasal and intratracheal routes with MuV-IA led to the typical clinical signs of mumps 2 weeks to 4 weeks postinfection. However, none of the infected macaques showed any fever or neurologic signs during the experimental period. Mumps viral antigen was detected in parotid glands by immunohistochemistry (IHC). Rhesus macaques represent the best animal model for the study of mumps virus pathogenesis. PMID- 23678164 TI - HIV populations are large and accumulate high genetic diversity in a nonlinear fashion. AB - HIV infection is characterized by rapid and error-prone viral replication resulting in genetically diverse virus populations. The rate of accumulation of diversity and the mechanisms involved are under intense study to provide useful information to understand immune evasion and the development of drug resistance. To characterize the development of viral diversity after infection, we carried out an in-depth analysis of single genome sequences of HIV pro-pol to assess diversity and divergence and to estimate replicating population sizes in a group of treatment-naive HIV-infected individuals sampled at single (n = 22) or multiple, longitudinal (n = 11) time points. Analysis of single genome sequences revealed nonlinear accumulation of sequence diversity during the course of infection. Diversity accumulated in recently infected individuals at rates 30 fold higher than in patients with chronic infection. Accumulation of synonymous changes accounted for most of the diversity during chronic infection. Accumulation of diversity resulted in population shifts, but the rates of change were low relative to estimated replication cycle times, consistent with relatively large population sizes. Analysis of changes in allele frequencies revealed effective population sizes that are substantially higher than previous estimates of approximately 1,000 infectious particles/infected individual. Taken together, these observations indicate that HIV populations are large, diverse, and slow to change in chronic infection and that the emergence of new mutations, including drug resistance mutations, is governed by both selection forces and drift. PMID- 23678170 TI - Epstein-Barr virus-encoded microRNA BART15-3p promotes cell apoptosis partially by targeting BRUCE. AB - Epstein-Barr Virus (EBV) generates a variety of viral microRNAs (miRNAs) by processing the BHRF1 and BamHI A rightward (BART) transcripts. BART miRNAs are expressed in all cells latently infected with EBV, but the functions of most BART miRNAs remain unknown. The results of a cell proliferation assay revealed that miR-BART15-3p inhibited cell proliferation. Fluorescence-activated cell sorting following staining with annexin V or propidium iodide showed that miR-BART15-3p promoted apoptosis. Furthermore, the inhibitor for miR-BART15-3p increased cell growth and reduced apoptosis in EBV-infected cells. Using bioinformatic analyses, we predicted that miR-BART15-3p may target the antiapoptotic B-cell lymphoma 2 (BCL2), BCL2L2, DEAD (Asp-Glu-Ala-Asp) box polypeptide 42 (DDX42), and baculovirus inhibitor of apoptosis repeat-containing ubiquitin-conjugating enzyme (BRUCE) mRNAs. The luciferase reporter assay showed that only the 3' untranslated region (UTR) of BRUCE was affected by miR-BART15-3p. Two putative seed-matched sites for miR-BART15-3p were evident on the BRUCE 3' UTR. The results of a mutation study indicated that miR-BART15-3p hybridized only with the first seed matched site on the BRUCE 3' UTR. miR-BART15-3p downregulated the BRUCE protein in EBV-negative cells, while the inhibitor for miR-BART15-3p upregulated the BRUCE protein in EBV-infected cells without affecting the BRUCE mRNA level. miR BART15-3p was secreted from EBV-infected gastric carcinoma cells, and the level of miR-BART15-3p was 2- to 16-fold higher in exosomes than in the corresponding cells. Our data suggest that miR-BART15-3p can induce apoptosis partially by inhibiting the translation of the apoptosis inhibitor BRUCE. Further study is warranted to understand the role of miR-BART15-3p in the EBV life cycle. PMID- 23678171 TI - Novel inhibitors of severe acute respiratory syndrome coronavirus entry that act by three distinct mechanisms. AB - Severe acute respiratory syndrome (SARS) is an infectious and highly contagious disease that is caused by SARS coronavirus (SARS-CoV) and for which there are currently no approved treatments. We report the discovery and characterization of small-molecule inhibitors of SARS-CoV replication that block viral entry by three different mechanisms. The compounds were discovered by screening a chemical library of compounds for blocking of entry of HIV-1 pseudotyped with SARS-CoV surface glycoprotein S (SARS-S) but not that of HIV-1 pseudotyped with vesicular stomatitis virus surface glycoprotein G (VSV-G). Studies on their mechanisms of action revealed that the compounds act by three distinct mechanisms: (i) SSAA09E2 {N-[[4-(4-methylpiperazin-1-yl)phenyl]methyl]-1,2-oxazole-5-carboxamide} acts through a novel mechanism of action, by blocking early interactions of SARS-S with the receptor for SARS-CoV, angiotensin converting enzyme 2 (ACE2); (ii) SSAA09E1 {[(Z)-1-thiophen-2-ylethylideneamino]thiourea} acts later, by blocking cathepsin L, a host protease required for processing of SARS-S during viral entry; and (iii) SSAA09E3 [N-(9,10-dioxo-9,10-dihydroanthracen-2-yl)benzamide] also acts later and does not affect interactions of SARS-S with ACE2 or the enzymatic functions of cathepsin L but prevents fusion of the viral membrane with the host cellular membrane. Our work demonstrates that there are at least three independent strategies for blocking SARS-CoV entry, validates these mechanisms of inhibition, and introduces promising leads for the development of SARS therapeutics. PMID- 23678172 TI - The B-cell-specific transcription factor and master regulator Pax5 promotes Epstein-Barr virus latency by negatively regulating the viral immediate early protein BZLF1. AB - The latent-to-lytic switch of Epstein-Barr virus (EBV) is mediated by the immediate early protein BZLF1 (Z). However, the cellular factors regulating this process remain incompletely characterized. In this report, we show that the B cell-specific transcription factor Pax5 helps to promote viral latency in B cells by blocking Z function. Although Z was previously shown to directly interact with Pax5 and inhibit its activity, the effect of Pax5 on Z function has not been investigated. Here, we demonstrate that Pax5 inhibits Z-mediated lytic viral gene expression and the release of infectious viral particles in latently infected epithelial cell lines. Conversely, we found that shRNA-mediated knockdown of endogenous Pax5 in a Burkitt lymphoma B-cell line leads to viral reactivation. Furthermore, we show that Pax5 reduces Z activation of early lytic viral promoters in reporter gene assays and inhibits Z binding to lytic viral promoters in vivo. We confirm that Pax5 and Z directly interact and show that this interaction requires the carboxy-terminal DNA-binding/dimerization domain of Z and the amino-terminal DNA-binding domain of Pax5. A Pax5 DNA-binding mutant (V26G/P80R) that interacts with Z retains the ability to inhibit Z function, whereas a Pax5 mutant (Delta106-110) that is deficient for interaction with Z does not inhibit Z-mediated lytic viral reactivation. Since the B-cell-specific transcription factor Oct-2 also directly interacts with Z and inhibits its function, these results suggest that EBV uses multiple redundant mechanisms to establish and maintain viral latency in B cells. PMID- 23678173 TI - Activation of the B cell antigen receptor triggers reactivation of latent Kaposi's sarcoma-associated herpesvirus in B cells. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic herpesvirus and the cause of Kaposi's sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman's disease. Latently infected B cells are the main reservoir of this virus in vivo, but the nature of the stimuli that lead to its reactivation in B cells is only partially understood. We established stable BJAB cell lines harboring latent KSHV by cell-free infection with recombinant virus carrying a puromycin resistance marker. Our latently infected B cell lines, termed BrK.219, can be reactivated by triggering the B cell receptor (BCR) with antibodies to surface IgM, a stimulus imitating antigen recognition. Using this B cell model system we studied the mechanisms that mediate the reactivation of KSHV in B cells following the stimulation of the BCR and could identify phosphatidylinositol 3 kinase (PI3K) and X-box binding protein 1 (XBP-1) as proteins that play an important role in the BCR-mediated reactivation of latent KSHV. PMID- 23678174 TI - Phosphorylation of Kaposi's sarcoma-associated herpesvirus processivity factor ORF59 by a viral kinase modulates its ability to associate with RTA and oriLyt. AB - ORF59 of Kaposi's sarcoma-associated herpesvirus (KSHV) plays an essential role in viral lytic replication by providing DNA processivity activity to the viral DNA polymerase (ORF9). ORF59 forms a homodimer in the cytoplasm and binds and translocates ORF9 into the nucleus, where it secures ORF9 to the origin of lytic DNA replication (oriLyt) in order to synthesize long DNA fragments during replication. ORF59 binds to oriLyt through an immediate early protein, replication and transcription activator (RTA). Here, we show that viral kinase (ORF36) phosphorylates serines between amino acids 376 and 379 of ORF59 and replacement of the Ser378 residue with alanine significantly impairs phosphorylation. Although mutating these serine residues had no effect on binding between ORF59 and ORF9, viral polymerase, or ORF36, the viral kinase, it significantly reduced the ability of ORF59 to bind to RTA. The results for the mutant in which Ser376 to Ser379 were replaced by alanine showed that both Ser378 and Ser379 contribute to binding to RTA. Additionally, the Ser376, Ser378, and Ser379 residues were found to be critical for binding of ORF59 to oriLyt and its processivity function. Ablation of these phosphorylation sites reduced the production of virion particles, suggesting that phosphorylation is critical for ORF59 activity and viral DNA synthesis. PMID- 23678175 TI - Herpes simplex virus 1 glycoprotein M and the membrane-associated protein UL11 are required for virus-induced cell fusion and efficient virus entry. AB - Herpes simplex virus 1 (HSV-1) facilitates virus entry into cells and cell-to cell spread by mediating fusion of the viral envelope with cellular membranes and fusion of adjacent cellular membranes. Although virus strains isolated from herpetic lesions cause limited cell fusion in cell culture, clinical herpetic lesions typically contain large syncytia, underscoring the importance of cell-to cell fusion in virus spread in infected tissues. Certain mutations in glycoprotein B (gB), gK, UL20, and other viral genes drastically enhance virus induced cell fusion in vitro and in vivo. Recent work has suggested that gB is the sole fusogenic glycoprotein, regulated by interactions with the viral glycoproteins gD, gH/gL, and gK, membrane protein UL20, and cellular receptors. Recombinant viruses were constructed to abolish either gM or UL11 expression in the presence of strong syncytial mutations in either gB or gK. Virus-induced cell fusion caused by deletion of the carboxyl-terminal 28 amino acids of gB or the dominant syncytial mutation in gK (Ala to Val at amino acid 40) was drastically reduced in the absence of gM. Similarly, syncytial mutations in either gB or gK did not cause cell fusion in the absence of UL11. Neither the gM nor UL11 gene deletion substantially affected gB, gC, gD, gE, and gH glycoprotein synthesis and expression on infected cell surfaces. Two-way immunoprecipitation experiments revealed that the membrane protein UL20, which is found as a protein complex with gK, interacted with gM while gM did not interact with other viral glycoproteins. Viruses produced in the absence of gM or UL11 entered into cells more slowly than their parental wild-type virus strain. Collectively, these results indicate that gM and UL11 are required for efficient membrane fusion events during virus entry and virus spread. PMID- 23678176 TI - Molecular determinants of hepatitis B and D virus entry restriction in mouse sodium taurocholate cotransporting polypeptide. AB - Human hepatitis B virus (HBV) and its satellite virus, hepatitis D virus (HDV), primarily infect humans, chimpanzees, or tree shrews (Tupaia belangeri). Viral infections in other species are known to be mainly restricted at the entry level since viral replication can be achieved in the cells by transfection of the viral genome. Sodium taurocholate cotransporting polypeptide (NTCP) is a functional receptor for HBV and HDV, and amino acids 157 to 165 of NTCP are critical for viral entry and likely limit viral infection of macaques. However, the molecular determinants for viral entry restriction in mouse NTCP (mNTCP) remain unclear. In this study, mNTCP was found to be unable to support either HBV or HDV infection, although it can bind to pre-S1 of HBV L protein and is functional in transporting substrate taurocholate; comprehensive swapping and point mutations of human NTCP (hNTCP) and mNTCP revealed molecular determinants restricting mNTCP for viral entry of HBV and HDV. Remarkably, when mNTCP residues 84 to 87 were substituted by human counterparts, mNTCP can effectively support viral infections. In addition, a number of cell lines, regardless of their species or tissue origin, supported HDV infection when transfected with hNTCP or mNTCP with residues 84 to 87 replaced by human counterparts, highlighting the central role of NTCP for viral infections mediated by HBV envelope proteins. These studies advance our understanding of NTCP-mediated viral entry of HBV and HDV and have important implications for developing the mouse model for their infections. PMID- 23678177 TI - Analysis of the role of vaccinia virus H7 in virion membrane biogenesis with an H7-deletion mutant. AB - Essential vaccinia virus genes are often studied with conditional-lethal inducible mutants. Here, we constructed a deletion mutant lacking the essential H7R gene (the DeltaH7 mutant) with an H7-expressing cell line. Compared to an inducible H7 mutant, the DeltaH7 mutant showed a defect at an earlier step of virion membrane biogenesis, before the development of short crescent-shaped precursors of the viral envelope. Our studies refine the role of H7 in virion membrane biogenesis and highlight the values of analyzing deletion mutants. PMID- 23678178 TI - New insights into the evolution of Entomopoxvirinae from the complete genome sequences of four entomopoxviruses infecting Adoxophyes honmai, Choristoneura biennis, Choristoneura rosaceana, and Mythimna separata. AB - Poxviruses are nucleocytoplasmic large DNA viruses encompassing two subfamilies, the Chordopoxvirinae and the Entomopoxvirinae, infecting vertebrates and insects, respectively. While chordopoxvirus genomics have been widely studied, only two entomopoxvirus (EPV) genomes have been entirely sequenced. We report the genome sequences of four EPVs of the Betaentomopoxvirus genus infecting the Lepidoptera: Adoxophyes honmai EPV (AHEV), Choristoneura biennis EPV (CBEV), Choristoneura rosaceana EPV (CREV), and Mythimna separata EPV (MySEV). The genomes are 80% AT rich, are 228 to 307 kbp long, and contain 247 to 334 open reading frames (ORFs). Most genes are homologous to those of Amsacta moorei entomopoxvirus and encode several protein families repeated in tandem in terminal regions. Some genomes also encode proteins of unknown functions with similarity to those of other insect viruses. Comparative genomic analyses highlight a high colinearity among the lepidopteran EPV genomes and little gene order conservation with other poxvirus genomes. As with previously sequenced EPVs, the genomes include a relatively conserved central region flanked by inverted terminal repeats. Protein clustering identified 104 core EPV genes. Among betaentomopoxviruses, 148 core genes were found in relatively high synteny, pointing to low genomic diversity. Whole-genome and spheroidin gene phylogenetic analyses showed that the lepidopteran EPVs group closely in a monophyletic lineage, corroborating their affiliation with the Betaentomopoxvirus genus as well as a clear division of the EPVs according to the orders of insect hosts (Lepidoptera, Coleoptera, and Orthoptera). This suggests an ancient coevolution of EPVs with their insect hosts and the need to revise the current EPV taxonomy to separate orthopteran EPVs from the lepidopteran-specific betaentomopoxviruses so as to form a new genus. PMID- 23678179 TI - Increased early RNA replication by chimeric West Nile virus W956IC leads to IPS-1 mediated activation of NF-kappaB and insufficient virus-mediated counteraction of the resulting canonical type I interferon signaling. AB - Although infections with "natural" West Nile virus (WNV) and the chimeric W956IC WNV infectious clone virus produce comparable peak virus yields in type I interferon (IFN) response-deficient BHK cells, W956IC infection produces higher levels of "unprotected" viral RNA at early times after infection. Analysis of infections with these two viruses in IFN-competent cells showed that W956IC activated NF-kappaB, induced higher levels of IFN-beta, and produced lower virus yields than WNV strain Eg101. IPS-1 was required for both increased induction of IFN-beta and decreased yields of W956IC. In Eg101-infected cells, phospho STAT1/STAT2 nuclear translocation was blocked at all times analyzed, while some phospho-STAT1/STAT2 nuclear translocation was still detected at 8 h after infection in W956IC-infected mouse embryonic fibroblasts (MEFs), and early viral protein levels were lower in these cells. A set of additional chimeras was made by replacing various W956IC gene regions with the Eg101 equivalents. As reported previously, for three of these chimeras, the low early RNA phenotype of Eg101 was restored in BHK cells. Analysis of infections with two of these chimeric viruses in MEFs detected lower early viral RNA levels, higher early viral protein levels, lower early IFN-beta levels, and higher virus yields similar to those seen after Eg101 infection. The data suggest that replicase protein interactions directly or indirectly regulate genome switching between replication and translation at early times in favor of translation to minimize NF-kappaB activation and IFN induction by decreasing the amount of unprotected viral RNA, to produce sufficient viral protein to block canonical type I IFN signaling, and to efficiently remodel cell membranes for exponential genome amplification. PMID- 23678181 TI - Human parainfluenza virus type 2 V protein inhibits TRAF6-mediated ubiquitination of IRF7 to prevent TLR7- and TLR9-dependent interferon induction. AB - Paramyxovirus V proteins block Toll-like receptor 7 (TLR7)- and TLR9-dependent signaling leading to alpha interferon production. Our recent study has provided evidence that interaction of the V proteins with IRF7 is important for the blockade. However, the detailed mechanisms still remain unclear. Here we reexamined the interaction of the human parainfluenza virus type 2 (HPIV2) V protein with signaling molecules involved in TLR7/9-dependent signaling. Immunoprecipitation experiments in HEK293T cells transfected with V protein and one of the signaling molecules revealed that the V protein interacted with not only IRF7 but also TRAF6, IKKalpha, and MyD88. Whereas overexpression of TRAF6 markedly enhanced the level of V protein associating with IRF7, IKKalpha, and MyD88 in HEK293T cells, the level of V protein associating with TRAF6 was little affected by overexpression of IRF7, IKKalpha, and MyD88. Moreover, knockdown or knockout of endogenous TRAF6 in HEK293T or mouse embryonic fibroblast cells resulted in dissociation of the V protein from IRF7, IKKalpha, and MyD88. These results demonstrate that binding of the V protein to IRF7, IKKalpha, and MyD88 is largely indirect and mediated by endogenous TRAF6. It was found that the V protein inhibited TRAF6-mediated lysine 63 (K63)-linked polyubiquitination of IRF7, which is prerequisite for IRF7 activation. Disruption of the tryptophan rich motif of the V protein significantly affected its TRAF6-binding efficiency, which correlated well with the magnitude of inhibition of K63-linked polyubiquitination and the resultant activation of IRF7. Taken together, these results suggest that the HPIV2 V protein prevents TLR7/9-dependent interferon induction by inhibiting TRAF6-mediated K63-linked polyubiquitination of IRF7. PMID- 23678182 TI - Adaptor protein 1 promotes cross-presentation through the same tyrosine signal in major histocompatibility complex class I as that targeted by HIV-1. AB - Certain antigen-presenting cells (APCs) process and present extracellular antigen with major histocompatibility complex class I (MHC-I) molecules to activate naive CD8(+) T cells in a process termed cross-presentation. We used insights gained from HIV immune evasion strategies to demonstrate that the clathrin adaptor protein adaptor protein 1 (AP-1) is necessary for cross-presentation by MHC-I molecules containing a cytoplasmic tail tyrosine signal (murine MHC-I molecules, human MHC-I HLA-A and HLA-B allotypes). In contrast, AP-1 activity was not needed for cross-presentation by MHC-I molecules containing a human MHC-I HLA-C cytoplasmic tail, which does not contain a tyrosine signal. AP-1 activity was also dispensable for presentation of endogenous antigens by MHC-I via the classical pathway. In APCs, we show that HIV Nef disrupts cross-presentation by MHC-I containing the tyrosine signal but does not affect cross-presentation by MHC-I containing the HLA-C cytoplasmic tail. Thus, we provide evidence for two separable cross-presentation pathways, only one of which is targeted by HIV. PMID- 23678183 TI - The first structure of a mycobacteriophage, the Mycobacterium abscessus subsp. bolletii phage Araucaria. AB - The unique characteristics of the waxy mycobacterial cell wall raise questions about specific structural features of their bacteriophages. No structure of any mycobacteriophage is available, although ~3,500 have been described to date. To fill this gap, we embarked in a genomic and structural study of a bacteriophage from Mycobacterium abscessus subsp. bolletii, a member of the Mycobacterium abscessus group. This opportunistic pathogen is responsible for respiratory tract infections in patients with lung disorders, particularly cystic fibrosis. M. abscessus subsp. bolletii was isolated from respiratory tract specimens, and bacteriophages were observed in the cultures. We report here the genome annotation and characterization of the M. abscessus subsp. bolletii prophage Araucaria, as well as the first single-particle electron microscopy reconstruction of the whole virion. Araucaria belongs to Siphoviridae and possesses a 64-kb genome containing 89 open reading frames (ORFs), among which 27 could be annotated with certainty. Although its capsid and connector share close similarity with those of several phages from Gram-negative (Gram(-)) or Gram(+) bacteria, its most distinctive characteristic is the helical tail decorated by radial spikes, possibly host adhesion devices, according to which the phage name was chosen. Its host adsorption device, at the tail tip, assembles features observed in phages binding to protein receptors, such as phage SPP1. All together, these results suggest that Araucaria may infect its mycobacterial host using a mechanism involving adhesion to cell wall saccharides and protein, a feature that remains to be further explored. PMID- 23678180 TI - Sequence analysis of in vivo defective interfering-like RNA of influenza A H1N1 pandemic virus. AB - Influenza virus defective interfering (DI) particles are naturally occurring noninfectious virions typically generated during in vitro serial passages in cell culture of the virus at a high multiplicity of infection. DI particles are recognized for the role they play in inhibiting viral replication and for the impact they have on the production of infectious virions. To date, influenza virus DI particles have been reported primarily as a phenomenon of cell culture and in experimentally infected embryonated chicken eggs. They have also been isolated from a respiratory infection of chickens. Using a sequencing approach, we characterize several subgenomic viral RNAs from human nasopharyngeal specimens infected with the influenza A(H1N1)pdm09 virus. The distribution of these in vivo derived DI-like RNAs was similar to that of in vitro DIs, with the majority of the defective RNAs generated from the PB2 (segment 1) of the polymerase complex, followed by PB1 and PA. The lengths of the in vivo-derived DI-like segments also are similar to those of known in vitro DIs, and the in vivo-derived DI-like segments share internal deletions of the same segments. The presence of identical DI-like RNAs in patients linked by direct contact is compatible with transmission between them. The functional role of DI-like RNAs in natural infections remains to be established. PMID- 23678184 TI - Upregulation of CHOP/GADD153 during coronavirus infectious bronchitis virus infection modulates apoptosis by restricting activation of the extracellular signal-regulated kinase pathway. AB - Induction of the unfolded protein response (UPR) is an adaptive cellular response to endoplasmic reticulum (ER) stress that allows a cell to reestablish ER homeostasis. However, under severe and persistent ER stress, prolonged UPR may activate unique pathways that lead to cell death. In this study, we investigated the activation of the protein kinase R-like ER kinase (PERK) pathway of UPR in cells infected with the coronavirus infectious bronchitis virus (IBV) and its relationship with IBV-induced apoptosis. The results showed moderate induction of PERK phosphorylation in IBV-infected cells. Meanwhile, activating transcription factor 4 (ATF4) was upregulated at the protein level in the infected cells, resulting in the induction in trans of the transcription factor ATF3 and the proapoptotic growth arrest and DNA damage-inducible protein GADD153. Knockdown of PERK by small interfering RNA (siRNA) suppressed the activation of GADD153 and the IBV-induced apoptosis. Interestingly, knockdown of protein kinase R (PKR) by siRNA and inhibition of the PKR kinase activity by 2-aminopurine (2-AP) also reduced the IBV-induced upregulation of GADD153 and apoptosis induction. In GADD153-knockdown cells, IBV-induced apoptosis was suppressed and virus replication inhibited, revealing a key role of GADD153 in IBV-induced cell death and virus replication. Analysis of the pathways downstream of GADD153 revealed much more activation of the extracellular signal-related kinase (ERK) pathway in GADD153-knockdown cells during IBV infection, indicating that GADD153 may modulate apoptosis through suppression of the pathway. This study provides solid evidence that induction of GADD153 by PERK and PKR plays an important regulatory role in the apoptotic process triggered by IBV infection. PMID- 23678185 TI - Productive entry of HIV-1 during cell-to-cell transmission via dynamin-dependent endocytosis. AB - HIV-1 can be transmitted as cell-free virus or via cell-to-cell contacts. Cell-to cell transmission between CD4(+) T cells is the more efficient mode of transmission and is predominant in lymphoid tissue, where the majority of virus resides. Yet the cellular mechanisms underlying productive cell-to-cell transmission in uninfected target cells are unclear. Although it has been demonstrated that target cells can take up virus via endocytosis, definitive links between this process and productive infection remain undefined, and this route of transmission has been proposed to be nonproductive. Here, we report that productive cell-to-cell transmission can occur via endocytosis in a dynamin dependent manner and is sensitive to clathrin-associated antagonists. These data were obtained in a number of CD4(+) T-cell lines and in primary CD4(+) T cells, using both CXCR4- and CCR5-tropic virus. However, we also found that HIV-1 demonstrated flexibility in its use of such endocytic pathways as certain allogeneic transmissions were seen to occur in a dynamin-dependent manner but were insensitive to clathrin-associated antagonists. Also, depleting cells of the clathrin accessory protein AP180 led to a viral uptake defect associated with enhanced infection. Collectively, these data demonstrate that endosomal uptake of HIV-1 during cell-to-cell transmission leads to productive infection, but they are also indicative of a flexible model of viral entry during cell-to-cell transmission, in which the virus can alter its entry route according to the pressures that it encounters. PMID- 23678186 TI - The L60V variation in hepatitis B virus core protein elicits new epitope-specific cytotoxic T lymphocytes and enhances viral replication. AB - Mutations in the core protein (HBc) of hepatitis B virus (HBV) are associated with aggressive hepatitis and advanced liver diseases in chronic hepatitis B (CHB). In this study, we identified the L60V variation in HBc that generates a new HLA-A2-restricted CD8(+) T cell epitope by screening an overlapping 9-mer peptide pool covering HBc and its variants. The nonameric epitope V60 was determined by structural and immunogenic analysis. The HBc L60V variation is correlated with hepatic necroinflammation and higher viral levels, and it may be associated with a poor prognosis in CHB patients. Immunization with the defined HBV epitope V60 peptide elicited specific cytotoxic T lymphocyte (CTL)-induced liver injury in HLA-A2(+) HBV transgenic mice. In addition, in vitro and in vivo experiments both demonstrated that the HBc L60V variation facilitates viral capsid assembly and increases HBV replication. These data suggest that the HBc L60V variation can impact both HBV replication and HBV-specific T cell responses. Therefore, our work provides further dissection of the impact of the HBc L60V variation, which orchestrates HBV replication, viral persistence, and immunopathogenesis during chronic viral infection. PMID- 23678188 TI - Synthesis of symmetrical 1,5-disubstituted granatanines. AB - A general entry into symmetrical 1,5-disubstituted granatanines that involves an alkylative ring-closure on a 2,6-bis enolate piperidine intermediate is described. PMID- 23678190 TI - Globally consistent coding systems for medical products of human origin. PMID- 23678191 TI - Policy coherence for improved medical innovation and access. PMID- 23678192 TI - Public health round-up. PMID- 23678193 TI - Gabon gets everyone under one social health insurance roof. AB - Gabon's comprehensive health insurance system is attracting virtually all of its citizens, but to be sustainable it will need to get costs under control. Gary Humphreys reports. PMID- 23678194 TI - Rocky road from the Semashko to a new health model. Interview by Fiona Fleck. AB - Health care is receiving much higher priority and more funds than ever before in the Russian Federation. Russian health economist Igor Sheiman talks to Fiona Fleck. PMID- 23678195 TI - Breastfeeding rates in central and western China in 2010: implications for child and population health. AB - OBJECTIVE: To describe breastfeeding practices in rural China using globally recommended indicators and to compare them with practices in neighbouring countries and large emerging economies. METHODS: A community-based, cross sectional survey of 2354 children younger than 2 years in 26 poor, rural counties in 12 central and western provinces was conducted. Associations between indicators of infant and young child feeding and socioeconomic, demographic and health service variables were explored and rates were compared with the most recent data from China and other nations. FINDINGS: Overall, 98.3% of infants had been breastfed. However, only 59.4% had initiated breastfeeding early (i.e. within 1 hour of birth); only 55.5% and 9.4% had continued breastfeeding for 1 and 2 years, respectively, and only 28.7% of infants younger than 6 months had been exclusively breastfed. Early initiation of breastfeeding was positively associated with at least five antenatal clinic visits (adjusted odds ratio, aOR: 3.48; P < 0.001) and negatively associated with delivery by Caesarean (aOR: 0.53; P < 0.001) or in a referral-level facility (aOR: 0.6; P = 0.014). Exclusive breastfeeding among children younger than 6 months was positively associated with delivery in a referral-level facility (aOR: 2.22; P < 0.05). Breastfeeding was not associated with maternal age or education, ethnicity or household wealth. Surveyed rates of exclusive and continued breastfeeding were mostly lower than in other nations. CONCLUSION: Despite efforts to promote breastfeeding in China, rates are very low. A commitment to improve infant and young child feeding is needed to reduce mortality and morbidity. PMID- 23678196 TI - Trends in smoking and lung cancer mortality in Japan, by birth cohort, 1949-2010. AB - OBJECTIVE: To determine smoking trends in Japan in comparison with lung cancer mortality. METHODS: Age-specific smoking prevalence among cohorts born between 1897 and 1985 were determined for the period 1949-2010. The percentages of the cohorts born between 1893 and 1979 who initiated smoking early (e.g. before the age of 20 years) were determined. The results were compared against lung cancer mortality rates in people aged 40-84 years belonging to cohorts born between 1868 and 1968. FINDINGS: In males, smoking prevalence was generally high, particularly among those born before the late 1950s, and early initiation was fairly uncommon. Early initiation was most common among recent birth cohorts of males, who showed relatively low prevalences of smoking. In females, the prevalence of smoking was generally low and early initiation was very uncommon, particularly among those born in the late 1930s and before the late 1940s, respectively. Recent cohorts of females showed relatively high prevalences of smoking and relatively high percentages of early initiation. In both sexes, lung cancer mortality was generally low but increased over the study period. CONCLUSION: Lung cancer mortality in Japanese males was relatively low given the high prevalence of smoking, perhaps because early initiation was fairly uncommon. Over the last four decades, however, early initiation of smoking has become more common in both sexes. The adverse effect this is likely to have on lung cancer mortality rates has probably not been observed because of the long time lag between smoking initiation and death from lung cancer. PMID- 23678197 TI - Determinants of reduced child stunting in Cambodia: analysis of pooled data from three demographic and health surveys. AB - OBJECTIVE: To assess how changes in socioeconomic and public health determinants may have contributed to the reduction in stunting prevalence seen among Cambodian children from 2000 to 2010. METHODS: A nationally representative sample of 10 366 children younger than 5 years was obtained from pooled data of cross-sectional surveys conducted in Cambodia in 2000, 2005, and 2010. The authors used a multivariate hierarchical logistic model to examine the association between the prevalence of childhood stunting over time and certain determinants. They estimated those changes in the prevalence of stunting in 2010 that could have been achieved through further improvements in public health indicators. FINDINGS: Child stunting was associated with the child's sex and age, type of birth, maternal height, maternal body mass index, previous birth intervals, number of household members, household wealth index score, access to improved sanitation facilities, presence of diarrhoea, parents' education, maternal tobacco use and mother's birth during the Khmer Rouge famine. The reduction in stunting prevalence during the past decade was attributable to improvements in household wealth, sanitation, parental education, birth spacing and maternal tobacco use. The prevalence of stunting would have been further reduced by scaling up the coverage of improved sanitation facilities, extending birth intervals, and eradicating maternal tobacco use. CONCLUSION: Child stunting in Cambodia has decreased owing to socioeconomic development and public health improvements. Effective policy interventions for sanitation, birth spacing and maternal tobacco use, as well as equitable economic growth and education, are the keys to further improvement in child nutrition. PMID- 23678198 TI - Episiotomy rate in Vietnamese-born women in Australia: support for a change in obstetric practice in Viet Nam. AB - OBJECTIVE: To describe the use of episiotomy among Vietnamese-born women in Australia, including risk factors for, and pregnancy outcomes associated with, episiotomy. METHODS: This population-based, retrospective cohort study included data on 598 305 singleton, term (i.e. >= 37 weeks' gestation) and vertex presenting vaginal births between 2001 and 2010. Data were obtained from linked, validated, population-level birth and hospitalization data sets. Contingency tables and multivariate analysis were used to compare risk factors and pregnancy outcomes in women who did or did not have an episiotomy. FINDINGS: The episiotomy rate in 12 208 Vietnamese-born women was 29.9%, compared with 15.1% in Australian born women. Among Vietnamese-born women, those who had an episiotomy were significantly more likely than those who did not to be primiparous, give birth in a private hospital, have induced labour or undergo instrumental delivery. In these women, having an episiotomy was associated with postpartum haemorrhage (adjusted odds ratio, aOR: 1.26; 95% confidence interval, CI: 1.08-1.46) and postnatal hospitalization for more than 4 days (aOR: 1.14; 95% CI: 1.00-1.29). Among multiparous women only, episiotomy was positively associated with a third- or fourth-degree perineal tear (aOR: 2.00; 95% CI: 1.31-3.06); in contrast, among primiparous women the association was negative (aOR: 0.47; 95% CI: 0.37-0.60). CONCLUSION: Episiotomy was performed in far fewer Vietnamese-born women giving birth in Australia than in Viet Nam, where more than 85% undergo the procedure, and was not associated with adverse outcomes. A lower episiotomy rate should be achievable in Viet Nam. PMID- 23678199 TI - Recurrence of adverse perinatal outcomes in developing countries. AB - OBJECTIVE: To evaluate the risk of recurrence of adverse perinatal outcomes in second pregnancies in developing countries. METHODS: Data from the 2004-2008 Global Survey on Maternal and Perinatal Health were used to determine the outcomes of singleton second pregnancies for 61 780 women in 23 developing countries. The mother-infant pairs had been followed up until discharge or for 7 days postpartum. FINDINGS: At the end of their second pregnancies, women whose first pregnancy had ended in stillbirth (n = 1261) or been followed by neonatal death (n = 1052) were more likely than women who had not experienced either outcome to have given birth to a child with a birth weight of < 1500 g (odds ratio, OR: 2.52 and 2.78, respectively) or 1500-2499 g (OR: 1.22 and 1.60, respectively), or to an infant requiring admission to an intensive care unit (OR: 1.64 and 1.68, respectively). At the end of their second pregnancies, those whose first pregnancy had ended in a stillbirth were at increased risk of another stillbirth (OR: 2.35) and those whose first infant had died as a neonate were at increased risk of having the second infant die within the first 7 days of life (OR: 2.82). These trends were found to be largely unaffected by the continent in which the women lived. CONCLUSION: In the developing world, a woman whose first pregnancy ends in stillbirth or is followed by the death of the neonate is at increased risk of experiencing the same outcomes in her second pregnancy. PMID- 23678200 TI - Entry and exit screening of airline travellers during the A(H1N1) 2009 pandemic: a retrospective evaluation. AB - OBJECTIVE: To evaluate the screening measures that would have been required to assess all travellers at risk of transporting A(H1N1)pdm09 out of Mexico by air at the start of the 2009 pandemic. METHODS: Data from flight itineraries for travellers who flew from Mexico were used to estimate the number of international airports where health screening measures would have been needed, and the number of travellers who would have had to be screened, to assess all air travellers who could have transported the H1N1 influenza virus out of Mexico during the initial stages of the 2009 A(H1N1) pandemic. FINDINGS: Exit screening at 36 airports in Mexico, or entry screening of travellers arriving on direct flights from Mexico at 82 airports in 26 other countries, would have resulted in the assessment of all air travellers at risk of transporting A(H1N1)pdm09 out of Mexico at the start of the pandemic. Entry screening of 116 travellers arriving from Mexico by direct or connecting flights would have been necessary for every one traveller at risk of transporting A(H1N1)pdm09. Screening at just eight airports would have resulted in the assessment of 90% of all air travellers at risk of transporting A(H1N1)pdm09 out of Mexico in the early stages of the pandemic. CONCLUSION: During the earliest stages of the A(H1N1) pandemic, most public health benefits potentially attainable through the screening of air travellers could have been achieved by screening travellers at only eight airports. PMID- 23678202 TI - Health systems and services: the role of acute care. PMID- 23678201 TI - Viral suppression after 12 months of antiretroviral therapy in low- and middle income countries: a systematic review. AB - OBJECTIVE: To establish estimates of viral suppression in low- and middle-income countries (LMICs) in patients who received antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection. METHODS: Data on viral suppression after 12 months of ART in LMICs were collected from articles published in 2003 to 2011 and from abstracts of conferences held between 2009 and 2011. Pooled proportions for on-treatment and intention-to-treat populations were used as summary estimates. Random-effects models were used for heterogeneous groups of studies (I (2) > 75%). FINDINGS: Overall, 49 studies covering 48 cohorts and 30 016 individuals met the inclusion criteria. With thresholds for suppression between 300 and 500 copies of viral ribonucleic acid (RNA) per ml of plasma, 84.3% (95% confidence interval, CI: 80.4-87.9) of the pooled on-treatment population and 70.5% (95% CI: 65.2-75.6) of the intention-to-treat population showed suppression. Use of different viral RNA thresholds changed the proportions showing suppression: to 84% and 76% of the on-treatment population with thresholds set above 300 and at or below 200 RNA copies per ml, respectively, and to 78%, 71% and 63% of the intention-to-treat population at thresholds set at 1000, 300 to 500, and 200 or fewer copies per ml, respectively. CONCLUSION: The pooled estimates of viral suppression recorded after 12 months of ART in LMICs provide benchmarks that other ART programmes can use to set realistic goals and perform predictive modelling. Evidence from this review suggests that the current international target - i.e. viral suppression in > 70% of the intention-to-treat population, with a threshold of 1000 copies per ml - should be revised upwards. PMID- 23678204 TI - SYNCHROTRON X-RAY MICROTOMOGRAPHY AND INTERFACIAL PARTITIONING TRACER TEST MEASUREMENTS OF NAPL-WATER INTERFACIAL AREAS. AB - Interfacial areas between an immiscible organic liquid (NAPL) and water were measured for two natural porous media using two methods, aqueous-phase interfacial partitioning tracer tests and synchrotron X-ray microtomography. The interfacial areas measured with the tracer tests were similar to previously reported values obtained with the method. The values were, however, significantly larger than those obtained from microtomography. Analysis of microtomography data collected before and after introduction of the interfacial tracer solution indicated that the surfactant tracer had minimal impact on fluid-phase configuration and interfacial areas under conditions associated with typical laboratory application. The disparity between the tracer-test and microtomography values is attributed primarily to the inability of the microtomography method to resolve interfacial area associated with microscopic surface heterogeneity. This hypothesis is consistent with results recently reported for a comparison of microtomographic analysis and interfacial tracer tests conducted for an air-water system. The tracer-test method provides a measure of effective, total (capillary and film) interfacial area, whereas microtomography can be used to determine separately both capillary-associated and film-associated interfacial areas. Both methods appear to provide useful information for given applications. A key to their effective use is recognizing the specific nature of the information provided by each, as well as associated limitations. PMID- 23678206 TI - Little black bags, ophthalmoscopy, and the Roth spot. PMID- 23678205 TI - Similar Neural Correlates for Language and Sequential Learning: Evidence from Event-Related Brain Potentials. AB - We used event-related potentials (ERPs) to investigate the time course and distribution of brain activity while adults performed (a) a sequential learning task involving complex structured sequences, and (b) a language processing task. The same positive ERP deflection, the P600 effect, typically linked to difficult or ungrammatical syntactic processing, was found for structural incongruencies in both sequential learning as well as natural language, and with similar topographical distributions. Additionally, a left anterior negativity (LAN) was observed for language but not for sequential learning. These results are interpreted as an indication that the P600 provides an index of violations and the cost of integration of expectations for upcoming material when processing complex sequential structure. We conclude that the same neural mechanisms may be recruited for both syntactic processing of linguistic stimuli and sequential learning of structured sequence patterns more generally. PMID- 23678207 TI - Some thoughts about the historic events that led to the first clinical implantation of a total artificial heart. PMID- 23678208 TI - Proper use of the stethoscope: three heads and one tale. PMID- 23678209 TI - Hearing voices. PMID- 23678211 TI - Simvastatin activates the PPARgamma-dependent pathway to prevent left ventricular hypertrophy associated with inhibition of RhoA signaling. AB - Left ventricular hypertrophy is an independent risk factor for major adverse cardiovascular events. Statins have positive effects on this condition; however, the mechanisms are incompletely understood. In this study, we examined whether the effect of simvastatin on left ventricular hypertrophy can be mediated with the peroxisome proliferator-activated receptor (PPAR)gamma-dependent pathway in rabbits with nonischemic heart failure (HF). We induced aortic insufficiency and constriction in 48 rabbits and divided them equally into control, HF, and HF with simvastatin therapy (HF-SIM) groups. The HF-SIM group was given 10 mg/kg/d of simvastatin. We echocardiographically measured baseline and 8-week cardiac structure and function, and we used Western blot, polymerase chain reaction, and electrophoretic analytic techniques to evaluate messenger RNA expression and protein expression and activity. In comparison with the HF group, the HF-SIM rabbits had an increased ejection fraction and decreased left ventricular mass index, interventricular septal thickness, ventricular posterior-wall thickness, and collagen volume fraction. Moreover, the messenger RNA and protein expression of PPARgamma in the HF-SIM rabbits were significantly higher than those in the HF rabbits; and the activity and expression of nuclear factor-kappaB subunit p65, RhoA, and Rho GTPase were significantly lower. Our results indicate that simvastatin therapy attenuates the PPARgamma-dependent pathway in association with the inhibition of RhoA and Rho GTPase signaling to inhibit nuclear factor kappaB activation, thus preventing the development of left ventricular hypertrophy and fibrosis in rabbits with nonischemic heart failure. PMID- 23678212 TI - Preventing sudden cardiac death in athletes: in search of evidence-based, cost effective screening. AB - Sudden cardiac death in athletes is a recurrent phenomenon at sporting events and during training. Recent studies have associated sudden cardiac death with such cardiovascular conditions as coronary artery anomalies, cardiomyopathies, and electrocardiographic abnormalities, most of which are screenable with modern imaging techniques. We recently inaugurated the Center for Coronary Artery Anomalies at the Texas Heart Institute, which is dedicated to preventing sudden cardiac death in the young and investigating coronary artery anomalies. There, we are conducting 2 cross-sectional studies intended to firmly establish and quantify, in a large group of individuals from a general population, risk factors for sudden cardiac death that arise from specific cardiovascular conditions. In a pilot screening study, we are using a brief, focused clinical questionnaire, electrocardiography, and a simplified novel cardiovascular magnetic resonance screening protocol in approximately 10,000 unselected 11- to 15-year-old children. Concurrently, we are prospectively studying the prevalence of these same conditions, their severity, and their relation to exercise and mode of death in approximately 6,500 consecutive necropsy cases referred to a large forensic center. Eventually, we hope to use our findings to develop a more efficient method of preventing sudden cardiac death in athletes. We believe that these studies will help quantify sudden cardiac death risk factors and the relevance of associated physical activities--crucial information in evaluating the feasibility and affordability of cardiovascular magnetic resonance-based screening. We discuss the rationale for and methods of this long-term endeavor, in advance of reporting the results. PMID- 23678213 TI - Predicting early death after cardiovascular surgery by using the Texas Heart Institute Risk Scoring Technique (THIRST). AB - Preoperative risk-prediction models are an important tool in contemporary surgical practice. We developed a risk-scoring technique for predicting in hospital death for cardiovascular surgery patients. From our institutional database, we obtained data on 21,120 patients admitted from 1995 through 2007. The outcome of interest was early death (in-hospital or within 30 days of surgery). To identify mortality predictors, multivariate logistic regression was performed on data from 14,030 patients from 1995 through 2002 and risk scores were computed to stratify patients (low-, medium-, and high-risk). A recalibrated model was then created from the original risk scores and validated on data from 7,090 patients from 2003 through 2007. Significant predictors of death included urgent surgery within 48 hours of admission, advanced age, renal insufficiency, repeat coronary artery bypass grafting, repeat aortic aneurysm repair, concomitant aortic aneurysm or left ventricular aneurysm repair with coronary bypass or valvular surgery, and preoperative intra-aortic balloon pump support. Because the original model overpredicted death for operations performed from 2003 through 2007, this was adjusted for by applying the recalibrated model. Applying the recalibrated model to the validation set revealed predicted mortality rates of 1.7%, 4.2%, and 13.4% and observed rates of 1.1%, 5.1%, and 13%, respectively. Because our model discriminates risk groups by using preoperative clinical criteria alone, it can be a useful bedside tool for identifying patients at greater risk of early death after cardiovascular surgery, thereby facilitating clinical decision-making. The model can be recalibrated for use in other types of patient populations. PMID- 23678214 TI - Is rheumatic mitral valve repair still a feasible alternative?: indications, technique, and results. AB - Rheumatic heart disease is still a major cause of mitral valve dysfunction in developing countries. We present our early results of rheumatic mitral valve repair. From August 2009 through July 2011, 60 patients (24 male and 36 female) with rheumatic disease underwent mitral repair. The mean age was 51.1 +/- 13.8 years (range, 16-77 yr). Forty-nine patients were in New York Heart Association functional class III or IV. Repair procedures included chordal and papillary muscle splitting, secondary chordal division, mitral ring annuloplasty (n=58), commissurotomy (n=36), chordal replacement (n=9), posterior leaflet extension (n=4), annular decalcification (n=2), and quadrangular resection (n=2). Secondary procedures included tricuspid ring annuloplasty, left atrial ablation, obliteration of left atrial appendage, aortic valve replacement, and left atrial reduction. The early (30-d) mortality rate was 1.7%. The mean follow-up time was 14.9 +/- 5 months (range, 4-26 mo). Follow-up echocardiography revealed trivial or no mitral regurgitation (MR) in 35.5% and mild (1+) MR in 49.1% of patients. Only 1 patient presented with severe (3+) MR. The mean MR grade decreased from 3.2 +/- 0.9 to 0.3 +/- 0.4 postoperatively (P=0.001). Left ventricular end diastolic diameter and left atrial diameter significantly decreased postoperatively (P=0.006 and P=0.001, respectively). The mean gradient over the mitral valve decreased significantly from 11 +/- 5.9 mmHg to 3.5 +/- 1.8 mmHg (P=0.001). Because current techniques of mitral repair can effectively correct valve dysfunction in most patients with rheumatic disease, the number of repair procedures should be increased in developing countries to prevent complications of mechanical valve placement. PMID- 23678215 TI - Surgical approach to aortic valve replacement after previous bilateral internal thoracic artery grafting. AB - The authors present a manubrium-sparing sternotomy technique for aortic valve replacement in patients who have undergone previous myocardial revascularization with both internal thoracic arteries. They have found that preoperative 64 multislice computed tomographic imaging facilitates surgical planning by delineating the course of patent grafts and, in particular, the relationship between the sternum and the right internal thoracic artery graft. A manubrium sparing sternotomy can in such instances avoid injury to the right internal thoracic artery graft during both resternotomy and adhesion dissection, thus reducing surgical risk and operative time. PMID- 23678210 TI - Preventing deep wound infection after coronary artery bypass grafting: a review. AB - The consequences of deep wound infections before, during, and after coronary artery bypass grafting have prompted research to clarify risk factors and explore preventive measures to keep infection rates at an irreducible minimum. An analysis of 42 studies in which investigators used multivariate logistic regression analysis revealed that diabetes mellitus and obesity are by far the chief preoperative risk factors. A 4-point preoperative scoring system based on a patient's body mass index and the presence or absence of diabetes is one practical way to determine the risk of mediastinitis, and other risk-estimate methods are being refined. Intraoperative risk factors include prolonged perfusion time, the use of one or more internal mammary arteries as grafts, blood transfusion, and mechanical circulatory assistance. The chief postoperative risk factor is reoperation, usually for bleeding. Unresolved issues include the optimal approach to Staphylococcus aureus nasal colonization and the choice of a prophylactic antibiotic regimen. We recommend that cardiac surgery programs supplement their audit processes and ongoing vigilance for infections with periodic, multidisciplinary reviews of best-practice standards for preoperative, intraoperative, and postoperative patient care. PMID- 23678216 TI - Excising a giant: report of a 7-cm coronary artery aneurysm. AB - Giant coronary artery aneurysms are variously defined as more than 20 to 50 mm in size. They are rare, with a prevalence of 0.02% in a large surgical population. We present the case of a 68-year-old woman who reported an increased awareness of her chest. Multiple imaging techniques revealed a 7-cm coronary aneurysm. The aneurysm arose from a septal branch of the left anterior descending coronary artery and drained into the main pulmonary artery. Surgical excision with revascularization was successful. We recommend definitive surgical intervention as a good long-term treatment for giant coronary artery aneurysms, after preoperative imaging has yielded the safest course of resection. PMID- 23678217 TI - Endovascular treatment of acute type B dissection complicating aortic coarctation. AB - Surgical treatment poses a high risk to patients with concomitant aortic coarctation and dissection, and an interventional approach could be an alternative. We describe the case of a 52-year-old man with a long history of untreated hypertension and aortic coarctation who emergently presented at our institution with an acute Stanford type B dissection. The patient's elevated serum creatinine level, perfusion deficit in the right lower limb, and hypertension did not respond to medical therapy, and he did not consent to surgery. By endovascular means, we used a self-expandable stent-graft to cover the entry point of the dissection; then, we deployed a balloon-expandable bare metal stent to correct residual stenosis. To our knowledge, this is the first report of the endovascular treatment of aortic coarctation complicated by type B dissection. PMID- 23678218 TI - Complex endovascular repair of a large dissection of the ascending aorta in a 70 year-old man. AB - We report the case of a 70-year-old man who presented with a large dissection of the ascending aorta related to coronary artery bypass grafting 3 years earlier. One graft was patent; however, a reverse venous graft to the right coronary artery was occluded, and that artery was substantially stenotic. The patient was a high-risk surgical candidate, so we treated a large dissection successfully by endovascular means with a thoracic endograft. This case suggests that this approach can be applied safely and effectively to other high-surgical-risk patients who have complex ascending aortic disease. PMID- 23678219 TI - Primary cardiac angiosarcoma in a 25-year-old man: excision, adjuvant chemotherapy, and multikinase inhibitor therapy. AB - Primary cardiac tumors do not occur frequently, and only one quarter of them, chiefly sarcomas, are malignant. Patients with angiosarcoma typically have a shorter survival time than do patients with other sarcomas, and the prognosis for survival depends strictly on the stage of the disease at the time of diagnosis and the possibility of complete surgical excision. Chemotherapy and radiotherapy have well-established postoperative roles because of the high probability of metastasis. We report the case of a 25-year-old man who presented with pericardial effusion and echocardiographic evidence of an intracavitary right atrial mass but without the bulky, infiltrative growth typical of this location of the disease. Malignancy was suggested by the clinical presentation, the location of the mass in the right side of the heart, and the absence of conditions favoring thrombus formation. After complete surgical excision, the mass was confirmed to be an angiosarcoma. Conventional adjuvant chemotherapy and maintenance therapy with inhibitors of CD117 (c-kit) and vascular endothelial growth factor relieved the patient's clinical symptoms and enabled his long-term, disease-free survival. In addition to reporting this case, we discuss aspects of the diagnosis and treatment of angiosarcoma. PMID- 23678220 TI - Mediastinal paraganglioma between the great vessels in an 81-year-old woman. AB - Nonfunctional paragangliomas are slow-growing, typically benign tumors that arise from the extra-adrenal paraganglion of the autonomic nervous system. They are identified and characterized with the use of computed tomography and other imaging methods; for definitive diagnosis, histopathologic evaluation is crucial. Surgical resection is the treatment of choice, and results of postoperative biochemical testing can reveal recurrence. Because of this lesion's familial association, genetic testing is suggested. We report the case of an 81-year-old woman who presented with neck pain, intermittent palpitations, hypertension, and dyspnea. Contrast-enhanced computed tomography of the chest revealed a multilobular, high-density lesion between the aorta and the pulmonary artery in the superior mediastinum. The patient's 24-hour urinary vanillylmandelic acid levels were not elevated, which suggested a nonfunctional tumor. Mediastinal exploration revealed a large, vascular, irregular, consistently firm mass that adhered to the aortic arch. Upon histopathologic analysis after complete resection, the mass was determined to be a paraganglioma with a low index of mitosis. The patient had postoperative respiratory insufficiency that necessitated tracheostomy, but she recovered well after rehabilitation. In addition to reporting our patient's case, we discuss the nature, diagnosis, and treatment of paragangliomas. PMID- 23678221 TI - Cardiac amyloidosis presenting with prolonged QT interval and recurrent polymorphic ventricular tachycardia. AB - Cardiac amyloidosis results in severely symptomatic heart failure that has a poor prognosis because of the development of a restrictive cardiomyopathy. The diagnosis of cardiac amyloidosis is often delayed because of nonspecific signs and symptoms. We report the case of a 66-year-old woman who had been diagnosed with sick sinus syndrome and presented 5 months later with a long QT interval and recurrent polymorphic ventricular tachycardia. The diagnosis of cardiac amyloidosis was confirmed upon analysis of endomyocardial biopsy results. The patient was subsequently diagnosed with and treated for underlying plasma cell myeloma and later died of cardiac arrest. This atypical presentation of cardiac amyloidosis underscores the need to consider it in the differential diagnosis of patients who have ventricular arrhythmias. To our knowledge, the combination of long QT interval and polymorphic ventricular tachycardia has not been previously reported in association with amyloid heart disease. PMID- 23678222 TI - Transcatheter aortic valve replacement in a nonagenarian. AB - Approximately 30% to 40% of elderly patients with severe, symptomatic aortic valve stenosis are deemed ineligible for surgery because of high perioperative risk. We describe the use of an alternative transfemoral approach known as transcatheter aortic valve implantation in a nonagenarian patient with severe aortic stenosis. Our patient recovered successfully, and by the time of her most recent follow-up visit, 7 months after the procedure, she had regained a substantial degree of function. This result suggests that transcatheter aortic valve implantation can enable some high-risk patients who are ineligible for surgery to undergo valve replacement, thereby regaining both quality and length of life. PMID- 23678223 TI - Single-stage repair of aortic coarctation and multiple concomitant cardiac lesions through a median sternotomy. AB - Through a median sternotomy, we performed a single-stage repair of severe aortic coarctation, ventricular septal defect, patent foramen ovale, and mitral valve insufficiency. The severe aortic coarctation was repaired by interposing a synthetic graft between the distal ascending aorta and the descending aorta. We first repaired the coarctation with the 38-year-old man on cardiopulmonary bypass, before aortic cross-clamping, in order to shorten the cross-clamp time. PMID- 23678224 TI - Perioperative management of a levoatrial cardinal vein in the absence of the brachiocephalic vein. AB - Levoatrial cardinal vein is a rare congenital anomaly of the systemic veins. It is commonly associated with left-sided obstructive conditions such as aortic atresia, mitral atresia, and cor triatriatum. We report the case of a 14-year-old boy who was undergoing surgery for correction of a secundum atrial septal defect. Intraoperatively, we discovered that he had a levoatrial cardinal vein and no brachiocephalic vein. However, collateral vessels provided adequate flow to the right atrium, and the patient's left-sided venous pressure was not excessive, so we ligated the levoatrial cardinal vein and directly repaired the septal defect. Postoperatively, the left venous drainage was satisfactory and the patient was asymptomatic. In addition to our patient's case, we discuss the embryology, diagnosis, and treatment of levoatrial cardinal vein. PMID- 23678225 TI - Fertile eunuch syndrome in association with biventricular noncompaction, bicuspid aortic valve, severe aortic stenosis, and talipes equinovarus. AB - Noncompaction of the ventricular myocardium is a congenital cardiomyopathy characterized by prominent ventricular trabeculations and deep intertrabecular recesses. In most cases, noncompaction is an isolated disease confined to the left ventricular myocardium. Fertile eunuch syndrome is a hypogonadotropic hormonal disorder in which the levels of testosterone and follicle-stimulating hormone are low. We report a case of biventricular noncompaction in association with bicuspid aortic valve and severe aortic stenosis in a 42-year-old man who was diagnosed with talipes equinovarus and fertile eunuch syndrome during childhood. PMID- 23678226 TI - Quadricuspid aortic: valve revealed by real-time, 3-dimensional transesophageal echocardiography. PMID- 23678227 TI - Quadruple-valve infective endocarditis and ventricular septal defect. PMID- 23678228 TI - Computed tomography AIDS minimally invasive mitral valve surgery. PMID- 23678229 TI - Abdominal aortic aneurysm with double rupture into the retroperitoneum and the inferior vena cava. PMID- 23678230 TI - Family Correlates of Adjustment Profiles in Mexican-Origin Female Adolescents. AB - This study used a person-centered approach to examine patterns of adjustment along psychological (i.e., depression, self-esteem, anxiety) and academic (i.e., academic motivation) domains in a sample (N = 338) of Mexican-origin female adolescents. Four adjustment profiles were identified. A High Functioning (n = 173) group, which exhibited high positive adjustment and academic functioning, an Average Functioning (n = 83) group, who exhibited average psychological and academic functioning, an Academically Oriented and Stressed (n = 19) group, who exhibited high academic motivation, but poor psychological functioning in anxiety and negative affect, and a Low Functioning" (n = 25) group, who exhibited poor adjustment overall. Further, paternal and maternal parenting characteristics (i.e., autonomy granting, parent-adolescent conflict, and supportive parenting) were differentially related to Mexican-origin female adolescents' profiles, providing further evidence for the existence of the profiles. Results contribute to the current literature on Latino adolescents and highlight the importance of examining psychological and academic domains concurrently to determine how these two domains of adjustment are linked among this population. PMID- 23678231 TI - The consumption of seaweed as a protective factor in the etiology of breast cancer: proof of principle. AB - Daily consumption of seaweed has been proposed as a factor in explaining lower postmenopausal breast cancer (BC) incidence and mortality rates in Japan. This clinical trial assessed the impact of introducing seaweed- to non-seaweed consuming American postmenopausal women. Fifteen healthy postmenopausal women were recruited for a 3-month single-blinded placebo controlled clinical trial; five had no history of BC (controls) and ten were BC survivors. Participants ingested ten capsules daily (5 g day-1) of placebo for 4 weeks, seaweed (Undaria) for 4 weeks, then placebo for another 4 weeks. Blood and urine samples were collected after each treatment period. Urinary human urokinase-type plasminogen activator receptor concentrations (uPAR) were analyzed by ELISA, and urine and serum were analyzed for protein expression using surface-enhanced laser desorption/ionization-time-of-flight mass spectrometry (SELDI-TOF-MS). Urinary creatinine standardized uPAR (in pg mL MUg-1 creatinine) changed significantly between groups, decreasing by about half following seaweed supplementation (placebo 1, 1.5 (95 % CI, 0.9-2.1) and seaweed, 0.9 (95 % CI, 0.6-1.1) while placebo 2 returned to pre-seaweed concentration (1.7 (95 % CI, 1.2-2.2); p = 0.01, ANOVA). One SELDI-TOF-MS-identified urinary protein (m/z 9,776) showed a similar reversible decrease with seaweed and is reported to be associated with cell attachment. One serum protein (m/z 8,928) reversibly increased with seaweed and may be the immunostimulatory complement activation C3a des-arginine. uPAR is higher among postmenopausal women generally, and for BC patients, it is associated with unfavorable BC prognosis. By lowering uPAR, dietary seaweed may help explain lower BC incidence and mortality among postmenopausal women in Japan. PMID- 23678233 TI - Preface, MSM 2013. PMID- 23678232 TI - Improving the Design of a MscL-Based Triggered Nanovalve. AB - The mechanosensitive channel of large conductance, MscL, has been proposed as a triggered nanovalve to be used in drug release and other nanodevices. It is a small homopentameric bacterial protein that has the largest gated pore known: greater than 30 A. Large molecules, even small proteins can be released through MscL. Although MscL normally gates in response to membrane tension, early studies found that hydrophilic or charged residue substitutions near the constriction of the channel leads to pore opening. Researchers have successfully changed the modality of MscL to open to stimuli such as light by chemically modifying a single residue, G22, within the MscL pore. Here, by utilizing in vivo, liposome efflux, and patch clamp assays we compared modification of G22 with that of another neighboring residue, G26, and demonstrate that modifying G26 may be a better choice for triggered nanovalves used for triggered vesicular release of compounds. PMID- 23678234 TI - Neuropsychiatry: where are we and where do we go from here? AB - INTRODUCTION: Neuropsychiatry has generally been regarded as a hybrid discipline that lies in the borderland between the disciplines of psychiatry and neurology. There is much debate on its current and future identity and status as a discipline. MATERIALS AND METHODS: Taking a historical perspective, the future of neuropsychiatry is placed within the context of recent developments in clinical neuroscience. RESULTS: The authors argue that with the maturation of the discipline, it must define its own identity that is not dependent entirely upon the parent disciplines. The requirements for this are the claiming of neuropsychiatric territory, a strong training agenda, an emphasis on treatments that are uniquely neuropsychiatric, and a bold embrace of new developments in clinical neuroscience. CONCLUSION: The exponential growth in neuroscientific knowledge places neuropsychiatry in an excellent position to carve out a strong identity. It is imperative that the leaders of the discipline seize the moment. PMID- 23678235 TI - What makes people healthy, happy, and fulfilled in the face of current world challenges? AB - Recent research on the relations of personality to well-being shows that the people who are most healthy, happy and fulfilled are those who are high in all three of the character traits of self-directedness, cooperativeness, and self transcendence as measured by the Temperament and Character Inventory. In the past, the healthy personality has often been considered to require only high self directedness and high cooperativeness. However, now the self-centred behaviour of people who are low in self-transcendence is degrading the conditions needed for sustainable life by all human beings. Consequently, human beings need to and can develop their capacity for self-transcendence in order to maintain their individual and collective well-being. PMID- 23678236 TI - Psychopharmacological Practice: The DSM Versus The Brain. AB - In 1952, the Diagnostic and Statistical Manual of Mental Disorders (DSM) system of creating, validating, studying and employing a diagnostic system in clinical psychiatric practice was introduced. There have been several updates and revisions to this manual and, regardless of its a theoretical framework, it actually does have a framework and presupposition. Essentially the DSM dictates that all psychiatric disorders are syndromes, or a collection of symptoms that commonly occur together and impair psychosocial functioning. These syndromes allow for homogenous groups of patients to be studied and psychotherapies and pharmacotherapies to be developed. This editorial will examine the DSM system with regards to its applicability to central nervous system dysfunction where psychiatric disorders are concerned. Specifically, the brain does not follow categorical, or syndromal, constructs. In fact, the psychiatric patient likely inherits several risk genes that promote abnormal proteins along several neuropathways in the brain. These abnormalities create dysfunctional neurocircuits which create individual psychiatric symptoms, but not a categorical syndrome or diagnosis. The concept that the DSM may be excellent for clinical diagnostic purposes, but less correct in its assumptions for a psychopharmacologist's treatment approaches will be discussed. PMID- 23678237 TI - Psychiatry's Catch 22, Need For Precision, And Placing Schools In Perspective. AB - The catch 22 situation in psychiatry is that for precise diagnostic categories/criteria, we need precise investigative tests, and for precise investigative tests, we need precise diagnostic criteria/categories; and precision in both diagnostics and investigative tests is nonexistent at present. The effort to establish clarity often results in a fresh maze of evidence. In finding the way forward, it is tempting to abandon the scientific method, but that is not possible, since we deal with real human psychopathology, not just concepts to speculate over. Search for clear-cut definitions/diagnostic criteria in psychiatry must be relentless. There is a greater need to be ruthless and blunt in this, rather than being accommodative of diverse opinions. Investigative tests - psychological, serum, CSF, or neuroimaging - are only corroborative at present; they need to become definitive. Medicalisation appears most prominent in psychiatry; so, diagnostic proliferation and fuzziness appear inevitable. And yet, the established diagnostic entities need to forward greater and conclusive precision. Also, the need for clarity and precision must outweigh pandering to and mollifying diverse interests, moreso in the upcoming revision of diagnostic manuals. This is specially because the DSM-5, being an Association manual, may need to accommodate powerful member lobbies; and ICD-11 may similarly need to cater to diverse country lobbies. Finding precise biological correlates of psychiatric phenomena, whether through neuroimaging, molecular neurobiology and/or neurogenomics, is the right way forward. It is in the 1.5-kg structure in the cranium that all secrets of psychiatric conditions lie. Social forces, behavioural modification, psychosocial restructuring, study of intrapsychic processes, and philosophical insights are not to be discounted, but they are supplementary to the primary goal - studying and deciphering those brain processes that result in psychiatric malfunction. Experimental breakthroughs, both in psychiatric aetiology and therapeutics, will come mainly from biology and its adjunct, psychopharmacology; while supplementary and complementary breakthroughs will come from the psychosocial, cognitive and behavioural approaches; the support base will come from phenomenology, epidemiology, nosology and diagnostics; while insights and leads can hopefully come from many fields, especially the psychosocial, the behavioural, the cognitive and the philosophical. Major energies must now be marshalled towards finding biomarkers and deciphering the precise phenotype-genotype-endophenotype axis of psychiatric disorders. Energies also need to be focussed on unravelling those critical processes in the brain that tip the scale towards psychiatric disorders. At how those critical processes are set into motion by forces de novo, in utero, in the genes and their expression, by the environment's psychopathological social forces - stress, peer pressure, poverty, deprivation, alienation, malnutrition, discrimination of various types (caste, gender, race, etc.), mass conflicts (war, terror attacks, etc.), disasters (natural and man-made), religious/ideological fascism - or social institutions like marriage, family, work place, political governance, etc. Ultimately, we must decipher how the brain goes into malfunction when such varied forces impinge on it, which precise cortical areas and neuronal cellular and molecular processes are involved in such malfunction and its manifestation, as also which of these are involved when malfunction ceases and health is restored, and the psychosocial processes and institutions which aid such health restoration, as also those which promote well-being and help in primary prevention. Emphasis on the brain and its intimate neurological and molecular mechanisms will not impinge on, or nullify, importance of the 'mind,' wherein subtle and gross brain functions in the form of behaviour, thought and emotions in all their ramifications will continue to be the focus of psychological, cognitive, sociological, psychopharmacological, behavioural and philosophical research. Progress in brain research must move in tandem with progress in 'mind' research. PMID- 23678238 TI - Reflections on psychiatry and international mental health. AB - This paper reflects on the needs for close interaction between psychiatry and all partners in international mental health for the improvement of mental health and advancement of the profession, with a particular view to the relationships between mental health, development and human rights. The World Health Organisation identifies strong links between mental health status and development for individuals, communities and countries. In order to improve population mental health, countries need effective and accessible treatment, prevention, and promotion programmes. Achieving adequate support for mental health in any country requires a unified approach. Strong links between psychiatrists, community leaders and patients and families that are based on negotiation and respect, are vital for progress. When strong partnerships exist, they can contribute to community understanding and advancement of psychiatry. This is the first step towards scaling up good quality care for those living with mental illnesses, preventing illnesses in those at risk, and promoting mental health through work with other community sectors. Partnerships are needed to support education and research in psychiatry, and improvements in quality of care wherever psychiatry is practiced, including primary health and community mental health services, hospitals and private practice. There are important roles for psychiatry in building the strength of organisations that champion the advocacy and support roles of service users and family carers, and encouraging partnerships for mental health promotion in the community. PMID- 23678239 TI - Psychoanalysis and politics: historicising subjectivity. AB - In this paper, I compare three different views of the relation between subjectivity and modernity: one proposed by Elisabeth Young-Bruehl, a second by theorists of institutionalised individualisation, and a third by writers in the Foucaultian tradition of studies of the history of governmentalities. The theorists were chosen because they represent very different understandings of the relation between contemporary history and subjectivity. My purpose is to ground psychoanalytic theory about what humans need in history and so to question what it means to talk ahistorically about what humans need in order to thrive psychologically. Only in so doing can one assess the relation between psychoanalysis and progressive politics. I conclude that while psychoanalysis is a discourse of its time, it can also function as a counter-discourse and can help us understand the effects on subjectivity of a more than thirty year history in the West of repudiating dependency needs and denying interdependence. PMID- 23678240 TI - Polypharmacy in psychiatry: a review. AB - Psychiatric polypharmacy refers to the prescription of two or more psychiatric medications concurrently to a patient. It can be categorised as same-class, multi class, adjunctive, augmentation and total polypharmacy. Despite advances in psychopharmacology and a better understanding of the principles of therapeutics, its practice is increasing rapidly. The prevalence of polypharmacy in psychiatry varies between 13%-90%. There are various clinical and pharmaco-economic factors associated with it. Dealing with polypharmacy requires an understanding of its associated factors. Education, guidelines and algorithms for the appropriate management of various conditions are effective ways to avoid irrational polypharmacy. PMID- 23678243 TI - A Commentary On De Sousa's "Towards An Integrative Theory Of Consciousness". AB - De Sousa's comprehensive two-part review of a diversity of contemporary approaches to the study of consciousness is highly welcome. He makes us aware of a proliferation of theoretical and empirical approaches targeting a common theme, but diverging in many ways. He skilfully accomplishes a classification of kinds of approach, identification of the main representatives, their contributions, and respective limitations. However, he does not show how the desired integration could be accomplished. Besides summarising De Sousa's efficient analytical work, I make critical comments and briefly report my contribution for the integration project. PMID- 23678242 TI - Towards an integrative theory of consciousness: part 2 (an anthology of various other models). AB - The study of consciousness has today moved beyond neurobiology and cognitive models. In the past few years, there has been a surge of research into various newer areas. The present article looks at the non-neurobiological and non cognitive theories regarding this complex phenomenon, especially ones that self psychology, self-theory, artificial intelligence, quantum physics, visual cognitive science and philosophy have to offer. Self-psychology has proposed the need to understand the self and its development, and the ramifications of the self for morality and empathy, which will help us understand consciousness better. There have been inroads made from the fields of computer science, machine technology and artificial intelligence, including robotics, into understanding the consciousness of these machines and their implications for human consciousness. These areas are explored. Visual cortex and emotional theories along with their implications are discussed. The phylogeny and evolution of the phenomenon of consciousness is also highlighted, with theories on the emergence of consciousness in fetal and neonatal life. Quantum physics and its insights into the mind, along with the implications of consciousness and physics and their interface are debated. The role of neurophilosophy to understand human consciousness, the functions of such a concept, embodiment, the dark side of consciousness, future research needs and limitations of a scientific theory of consciousness complete the review. The importance and salient features of each theory are discussed along with certain pitfalls, if present. A need for the integration of various theories to understand consciousness from a holistic perspective is stressed. PMID- 23678244 TI - Conscious States: where are they in the brain and what are their necessary ingredients? AB - One of the final obstacles to understanding consciousness in physical terms concerns the question of whether conscious states can exist in posterior regions of the brain without active connections to the brain's prefrontal lobes. If they can, difficult issues concerning our knowledge of our conscious states can be resolved. This paper contains a list of types of conscious states that may meet this criterion, including states of coma, states in which subjects are absorbed in a perceptual task, states in brains with damaged prefrontal lobes, states of meditation and conscious states of some infants and animals. Recent evidence also suggests that conscious states of some autistic people may meet this criterion. PMID- 23678241 TI - Towards an integrative theory of consciousness: part 1 (neurobiological and cognitive models). AB - The study of consciousness is poised today at interesting crossroads. There has been a surge of research into various neurobiological underpinnings of consciousness in the past decade. The present article looks at the theories regarding this complex phenomenon, especially the ones that neurobiology, cognitive neuroscience and cognitive psychology have to offer. We will first discuss the origin and etymology of word consciousness and its usage. Neurobiological correlates of consciousness are discussed with structures like the ascending reticular activating system, the amygdala, the cerebellum, the thalamus, the frontoparietal circuits, the prefrontal cortex and the precuneus. The cellular and microlevel theories of consciousness and cerebral activity at the neuronal level contributing to consciousness are highlighted, along with the various theories posited in this area. The role of neuronal assemblies and circuits along with firing patterns and their ramifications for the understanding of consciousness are discussed. A section on the role of anaesthesia and its links to consciousness is presented, along with details of split-brain studies in consciousness and altered states of awareness, including the vegetative states. The article finally discusses the progress cognitive psychology has made in identifying and theorising various perspectives of consciousness, perceptual awareness and conscious processing. Both recent and past researches are highlighted. The importance and salient features of each theory are discussed along with the pitfalls, if present. A need for integration of various theories to understand consciousness from a holistic perspective is stressed, to enable one to reach a theory that explains the ultimate neurobiology of consciousness. PMID- 23678245 TI - The embodied embedded character of system 1 processing. AB - In the last thirty years, a relatively large group of cognitive scientists have begun characterising the mind in terms of two distinct, relatively autonomous systems. To account for paradoxes in empirical results of studies mainly on reasoning, Dual Process Theories were developed. Such Dual Process Theories generally agree that System 1 is rapid, automatic, parallel, and heuristic-based and System 2 is slow, capacity-demanding, sequential, and related to consciousness. While System 2 can still be decently understood from a traditional cognitivist approach, I will argue that it is essential for System 1 processing to be comprehended in an Embodied Embedded approach to Cognition. PMID- 23678246 TI - What affective neuroscience means for science of consciousness. AB - The field of affective neuroscience has emerged from the efforts of Jaak Panksepp in the 1990s and reinforced by the work of, among others, Joseph LeDoux in the 2000s. It is based on the ideas that affective processes are supported by brain structures that appeared earlier in the phylogenetic scale (as the periaqueductal gray area), they run in parallel with cognitive processes, and can influence behaviour independently of cognitive judgements. This kind of approach contrasts with the hegemonic concept of conscious processing in cognitive neurosciences, which is based on the identification of brain circuits responsible for the processing of (cognitive) representations. Within cognitive neurosciences, the frontal lobes are assigned the role of coordinators in maintaining affective states and their emotional expressions under cognitive control. An intermediary view is the Damasio-Bechara Somatic Marker model, which puts cognition under partial somatic-affective control. We present here our efforts to make a synthesis of these views, by proposing the existence of two interacting brain circuits; the first one in charge of cognitive processes and the second mediating feelings about cognitive contents. The coupling of the two circuits promotes an endogenous feedback that supports conscious processes. Within this framework, we present the defence that detailed study of both affective and cognitive processes, their interactions, as well of their respective brain networks, is necessary for a science of consciousness. PMID- 23678247 TI - Reviewer index: a new proposal of rewarding the reviewer. AB - Science is strengthened not by research alone, but by publication of original research articles in international scientific journals that gets read by a global scientific community. Research publication is the 'heart' of a journal and the 'soul' of science - the outcome of collective efforts of authors, editors and reviewers. The publication process involves author-editor interaction for which both of them get credit once the article gets published - the author directly, the editor indirectly. However, the remote reviewer who also plays a key role in the process remains anonymous and largely unrecognised. Many potential reviewers therefore, stay away from this 'highly honorary' task. Appropriate peer review controls quality of an article and thereby ensures quality and integrity of the journal. Recognising and rewarding the role of the reviewer is therefore vital. In this article, we propose a novel idea of Reviewer Index (RI), Reviewer Index Directory (RID) and Global Reviewer Index Directory (GRID), which will strengthen science by focussing on the reviewer, as well as the author. By adopting this innovative Reviewer Centric Approach, a new breed of well-trained reviewers of high quality and sufficient quantity will be available for eternity. Moreover, RI, RID and GRID would also enable grading and ethical rewarding of reviewers. PMID- 23678248 TI - Radiology request. PMID- 23678249 TI - Communication is key. PMID- 23678250 TI - Revised Template for MSM Submissions 2013. PMID- 23678251 TI - The relationship of alcohol and crime in Korea. PMID- 23678252 TI - Beyond substance addiction: broadening the concept of addiction to include behavioral addiction. PMID- 23678253 TI - Korean association of medical journal editors at the forefront of improving the quality and indexing chances of its member journals. AB - The article overviews some achievements and problems of Korean medical journals published in the highly competitive journal environment. Activities of Korean Association of Medical Journal Editors (KAMJE) are viewed as instrumental for improving the quality of Korean articles, indexing large number of local journals in prestigious bibliographic databases and launching new abstract and citation tracking databases or platforms (eg KoreaMed, KoreaMed Synapse, the Western Pacific Regional Index Medicus [WPRIM]). KAMJE encourages its member journals to upgrade science editing standards and to legitimately increase citation rates, primarily by publishing more great articles with global influence. Experience gained by KAMJE and problems faced by Korean editors may have global implications. PMID- 23678254 TI - Management of cancer survivors in clinical and public health perspectives: current status and future challenges in Korea. AB - The number of cancer survivors is increasing dramatically. Many cancer survivors face lifetime risks associated with their cancer therapy, with a significant proportion at risk for serious morbidity and premature mortality. Concerns regarding the long-term physical, psychosocial, and economic effects of cancer treatment on cancer survivors and their families are increasingly being recognized and addressed by public and private sector. This article summarizes economic burden of cancer survivors, main post-treatment health problems including secondary primary cancer and comorbidities, health behaviors such as smoking, exercise and physical activity, nutrition, and psychosocial problems. Faced with various health and psychosocial problems specific to this population, several healthcare and policy models are being suggested to address these issues, including 'shared care model' and 'integrative supportive care service delivery system for cancer survivors'. More effort is needed to make the cancer survivorship agenda a reality, attended by a wide variety of stakeholders including researchers, patients, providers, and policy makers. PMID- 23678255 TI - Incidence and mortality rates of disasters and mass casualty incidents in Korea: a population-based cross-sectional study, 2000-2009. AB - The objective of study was to evaluate the incidence and mortality rates of disasters and mass casualty incidents (MCIs) over the past 10 yr in the administrative system of Korea administrative system and to examine their relationship with population characteristics. This was a population-based cross sectional study. We calculated the nationwide incidence, as well as the crude mortality and injury incidence rates, of disasters and MCIs. The data were collected from the administrative database of the National Emergency Management Agency (NEMA) and from provincial fire departments from January 2000 to December 2009. A total of 47,169 events were collected from the NEMA administrative database. Of these events, 115 and 3,079 cases were defined as disasters and MCIs that occurred in Korea, respectively. The incidence of technical disasters/MCIs was approximately 12.7 times greater than that of natural disasters/MCIs. Over the past 10 yr, the crude mortality rates for disasters and MCIs were 2.36 deaths per 100,000 persons and 6.78 deaths per 100,000 persons, respectively. The crude injury incidence rates for disasters and MCIs were 25.47 injuries per 100,000 persons and 152 injuries per 100,000 persons, respectively. The incidence and mortality of disasters/MCIs in Korea seem to be low compared to that of trend around the world. PMID- 23678256 TI - Inappropriateness of quinolone in scrub typhus treatment due to gyrA mutation in Orientia tsutsugamushi Boryong strain. AB - The use of quinolone for treatment of rickettsial diseases remains controversial. Recent clinical studies suggest that quinolone is not as effective as others in patients with rickettsial diseases including scrub typhus, although the mechanism is not well understood. In this study, we evaluated the mutation in gyrA associated with quinolone resistance. We prospectively enrolled scrub typhus patients, collected blood samples and clinical data from October, 2010 to November, 2011. Among the 21 patients enrolled, one initially received ciprofloxacin for 3 days but was switched to doxycycline due to clinical deterioration. We obtained the gyrA gene of Orientia tsutsugamushi from 21 samples (20 Boryong strain, 1 Kato strain) and sequenced the quinolone resistance determining region. All of 21 samples had the Ser83Leu mutation in the gyrA gene, which is known to be associated with quinolone resistance. This suggests that quinolones may be avoided for the treatment of serious scrub typhus. PMID- 23678257 TI - Improvement of the diagnostic sensitivity of scrub typhus using a mixture of recombinant antigens derived from Orientia tsutsugamushi serotypes. AB - Diagnosis of scrub typhus is difficult because its symptoms are very similar to other acute febrile illnesses, such as leptospirosis, murine typhus, and other viral hemorrhagic fevers. To differentiate scrub typhus from other acute febrile diseases, a rapid and reliable serological diagnosis is important. We have developed a chimeric recombinant antigen cr56 and two other recombinant antigens, r21 and kr56, from various serotypes of Orientia tsutsugamushi. They were tested for the detection of antibodies against O. tsutsugamushi in the patient's serum samples using enzyme-linked immunosorbent assay (ELISA) and dot-blot analyses. As of conventional immunofluorescence assay (IFA), when the mixture of these three recombinant antigens was used, both sensitivity and specificity of the recombinant antigens were increased up to 98% in IgM and IgG at ELISA and dot blotting. Additionally, both sensitivity and specificity by detection of IgM and IgG antibodies at rapid diagnostic test (RDT), using the mixture of three antigens and gold conjugated antibodies, were 99%. Our results suggest the use of mixture of these recombinant antigen proteins in ELISA or RDT is suitable as a diagnostic test for scrub typhus. PMID- 23678258 TI - Prevalence and risk factor of neck pain in elderly Korean community residents. AB - Neck pain is a common musculoskeletal condition, which causes substantial medical cost. In Korea, prevalence of neck pain in community based population, especially in elderly subjects, has scarcely been reported. We evaluated the prevalence, the severity and the risk factors of neck pain in elderly Korean community residents. Data for neck pain were collected for 1,655 subjects from a rural farming community. The point, 6-months and cumulative lifetime prevalence of neck pain was obtained in addition to the measurement of the severity of neck pain. The mean age of the study subjects was 61 yr and 57% were females. The lifetime prevalence of neck pain was 20.8% with women having a higher prevalence. The prevalence did not increase with age, and the majority of individuals had low intensity/low-disability pain. Subjects with neck pain had a significantly worse SF-12 score in all domains except for mental health. The prevalence of neck pain was significantly associated with female gender, obesity and smoking. This is the first large-scale Korean study estimating the prevalence of neck pain in elderly population. Although the majority of individuals had low-intensity/low-disability pain, subjects with neck pain had a significantly worse SF-12 score indicating that neck pain has significant health impact. PMID- 23678259 TI - Safety of megestrol acetate in palliating anorexia-cachexia syndrome in patients with castration-resistant prostate cancer. AB - There are concerns whether megestrol acetate (MA) stimulates the growth of prostate cancer in castration-resistant prostate cancer (CRPC). We evaluated the effect of cumulative doses of MA on the disease-specific survival (DSS) in patients with CRPC who were receiving Docetaxel-based chemotherapy. From July 2003 through June 2009, we identified 109 consecutive patients with CRPC and who had received docetaxel-based chemotherapy. Of these patients, 68 (62.4%) have not received MA, whereas 21 patients (19.3%) and 20 patients (18.3%) had received low dose MA (total <= 18,400 mg) and high dose MA (total > 18,400 mg), respectively. We assessed the effect of several variables on DSS. None of the clinicopathological variables differed among the three groups. When comparing DSS using Kaplan-Meier analysis, there was no statistically significant survival differences among the three groups (P = 0.546). Using multivariate Cox proportional analyses with backward elimination, the number of docetaxel cycles was only significant factor predicting DSS (HR: 0.578, 95% CI: 0.318-0.923, P = 0.016). Cumulative doses of MA as adjuvant treatment for patients with CRPC and who are receiving docetaxel-based chemotherapy, did not affect their DSS. Therefore, MA can be safely administered in cachexic patients with CRPC. PMID- 23678260 TI - Differentiated thyroid carcinoma of children and adolescents: 27-year experience in the yonsei university health system. AB - Thyroid carcinomas are uncommon in childhood and adolescence. The aim of this study was to analyze clinical features and clinical outcomes of thyroid cancer in the pediatric population treated in the Yonsei University Health System. From September 1982 to June 2009, 90 patients (75 females, 15 males; female:male ratio of 5:1) with differentiated thyroid carcinoma were identified in our institute. The mean age at diagnosis was 15.8 yr old (range 4.8-19.9 yr). Cervical masses were most common clinical manifestations at diagnosis in 65 patients (72.2%). Forty-two patients underwent less than total thyroidectomy and 18 patients underwent total thyroidectomy. Thirty patients (33.3%) had lateral neck lymph node metastasis and seven patients (7.8%) had lung metastasis at the time of surgery. Among the 90 patients, recurrence occurred in 14 patients (15.5%). Mean follow-up period for patients with differentiated thyroid carcinoma was 81.6 months (13-324 months). No patients died of differentiated thyroid carcinoma. Patients with differentiated thyroid carcinoma who were < 20-yr-of-age were present with aggressive local disease and a high frequency of lymph node and distant metastasis. It is recommended that pediatric thyroid cancer should be managed mostly using proper surgical approach with thyroidectomy and lymph node dissection when indicated. PMID- 23678261 TI - An Angiotensin receptor blocker prevents arrhythmogenic left atrial remodeling in a rat post myocardial infarction induced heart failure model. AB - This study investigated the role of angiotensin II receptor blocker in atrial remodeling in rats with atrial fibrillation (AF) induced by a myocardial infarction (MI). MIs were induced by a ligation of the left anterior descending coronary artery. Two days after, the rats in the losartan group were given losartan (10 mg/kg/day for 10 weeks). Ten weeks later, echocardiography and AF induction studies were conducted. Ejection fraction was significantly lower in the MI rats. Fibrosis analysis revealed much increased left atrial fibrosis in the MI group than sham (2.22 +/- 0.66% vs 0.25 +/- 0.08%, P = 0.001) and suppression in the losartan group (0.90 +/- 0.27%, P 0.001) compared with the MI group. AF inducibility was higher in the MI group than sham (39.4 +/- 43.0% vs 2.0 +/- 6.3%, P = 0.005) and significantly lower in losartan group (12.0 +/- 31.6%, P = 0.029) compared with the MI. The left atrial endothelial nitric oxide synthase (NOS) and sarco/endoplasmic reticulum Ca(2+)-ATPase levels were lower in the MI group and higher in the losartan group significantly. The atrial inducible NOS and sodium-calcium exchanger levels were higher in the MI and lower in the losartan group significantly. Losartan disrupts collagen fiber formation and prevents the alteration of the tissue eNOS and iNOS levels, which prevent subsequent AF induction. PMID- 23678262 TI - Association of apolipoprotein b/apolipoprotein A1 ratio and coronary artery stenosis and plaques detected by multi-detector computed tomography in healthy population. AB - Despite the noninvasiveness and accuracy of multidetector computed tomography (MDCT), its use as a routine screening tool for occult coronary atherosclerosis is unclear. We investigated whether the ratio of apolipoprotein B (apoB) to apolipoprotein A1 (apoA1), an indicator of the balance between atherogenic and atheroprotective cholesterol transport could predict occult coronary atherosclerosis detected by MDCT. We collected the data of 1,401 subjects (877 men and 524 women) who participated in a routine health screening examination of Asan Medical Center. Significant coronary artery stenosis defined as > 50% stenosis was detected in 114 subjects (8.1%). An increase in apoB/A1 quartiles was associated with increased percentages of subjects with significant coronary stenosis and noncalcified plaques (NCAP). After adjustment for confounding variables, each 0.1 increase in serum apoB/A1 was significantly associated with increased odds ratios (ORs) for coronary stenosis and NCAP of 1.23 and 1.18, respectively. The optimal apoB/A1 ratio cut off value for MDCT detection of significant coronary stenosis was 0.58, which had a sensitivity of 70.2% and a specificity of 48.2% (area under the curve, 0.61; 95% CI, 0.58-0.63, P < 0.001). Our results indicate that apoB/A1 ratio is a good indicator of occult coronary atherosclerosis detected by coronary MDCT. PMID- 23678263 TI - Clinical implication of surgical resection for the rare cardiac tumors involving heart and great vessels. AB - This study aimed to investigate the clinical implication of surgical resection for the malignancies of heart and great vessels. Between January 2001 and May 2011, a retrospective review of the results in 12 patients was conducted. There were 6 patients with primary cardiac tumor including leiomyosarcoma, angiosarcoma, undifferentiated type sarcoma and malignant fibrous histiocytoma. The remaining 6 patients had the metastatic tumors or adjacent invasion to the heart and great vessels. Six of seven patients who underwent complete resection had no evidence of recurrence. However, four of five patients who underwent incomplete resection or biopsy showed local recurrence or distant metastasis of residual tumor, and one of them required reoperation for recurred tumor. In hospital mortality was 8.3% and the mean survival of all patients was 22.2 +/- 6.1 months. Survival of the incomplete resection group, except for the two biopsy cases, was 25.9 +/- 7.9 months, and there was no mortality in the complete resection group. Therefore, clinical outcomes in patients who had malignancies of the heart and great vessels may be improved when the aggressive and complete resection, or possible debulking for palliation, was performed. Moreover, adjuvant multimodality therapy may be imperative to prevent recurrence or metastasis, and to provide improved survival. PMID- 23678264 TI - COMP-angiopoietin-1 promotes cavernous angiogenesis in a type 2 diabetic rat model. AB - Cartilage oligomeric matrix protein-angiopoietin-1 (COMP-Ang1) is an angiogenic factor for vascular angiogenesis. The aim was to investigate the effect of an intracavernosal injection of COMP-Ang1 on cavernosal angiogenesis in a diabetic rat model. Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats made up the experimental group (1 yr old) and Long-Evans Tokushima Otsuka (LETO) rats made up the control group. The experimental group was divided into vehicle only, 10 ug COMP-Ang1, and 20 ug COMP-Ang1. COMP-Ang1 was injected into the corpus cavernosum of the penis. After 4 weeks, the penile tissues of the rats were obtained for immunohistochemistry and Western blot analysis. The immunoreactivity of PECAM-1 and VEGF was increased in the COMP-Ang1 group compared with the vehicle only group. Moreover, the expression of PECAM-1 and VEGF was notably augmented in the 20 ug Comp Ang-1 group. In the immunoblotting study, the expression of PECAM-1 and VEGF protein was significantly less in the OLEFT rats than in the control LETO rats. However, this expression was restored to control level after intracavernosal injection of COMP-Ang1. These results show that an intracavernosal injection of COMP-Ang1 enhances cavernous angiogenesis by structurally reinforcing the cavernosal endothelium. PMID- 23678265 TI - Clinical significance of serum autoantibodies in idiopathic interstitial pneumonia. AB - Although autoantibodies are routinely screened in patients with idiopathic interstitial pneumonia, there are no reliable data on their clinical usefulness. The aim of this study was to investigate the prognostic value of autoantibodies for predicting the development of new connective tissue disease in these patients and also mortality. We conducted retrospective analysis of the baseline, and follow-up data for 688 patients with idiopathic interstitial pneumonia (526 with idiopathic pulmonary fibrosis, 85 with nonspecific interstitial pneumonia, and 77 with cryptogenic organizing pneumonia) at one single tertiary referral center. The median follow-up period was 33.6 months. Antinuclear antibody was positive in 34.5% of all subjects, rheumatoid factor in 13.2%, and other specific autoantibodies were positive between 0.7%-6.8% of the cases. No significant difference in patient survival was found between the autoantibody-positive and negative groups. However, the presence of autoantibodies, especially antinuclear antibody with a titer higher than 1:320, was a significant predictor for the future development of new connective tissue diseases (relative risk, 6.4), although the incidence was low (3.8% of all subjects during follow-up). In conclusion, autoantibodies are significant predictors for new connective tissue disease development, although they have no prognostic value. PMID- 23678266 TI - Effects of home-based pulmonary rehabilitation with a metronome-guided walking pace in chronic obstructive pulmonary disease. AB - Despite documented efficacy and recommendations, pulmonary rehabilitation (PR) in chronic obstructive pulmonary disease (COPD) has been underutilized. Home-based PR was proposed as an alternative, but there were limited data. The adequate exercise intensity was also a crucial issue. The aim of this study was to investigate the effects of home-based PR with a metronome-guided walking pace on functional exercise capacity and health-related quality of life (HRQOL) in COPD. The subjects participated in a 12-week home-based PR program. Exercise intensity was initially determined by cardiopulmonary exercise test, and was readjusted (the interval of metronome beeps was reset) according to submaximal endurance test. Six-minute walk test, pulmonary function test, cardiopulmonary exercise test, and St. George's Respiratory Questionnaire (SGRQ) were done before and after the 12-week program, and at 6 months after completion of rehabilitation. Thirty-three patients participated in the program. Six-minute walking distance was significantly increased (48.8 m; P = 0.017) and the SGRQ score was also improved (-15; P < 0.001) over the six-month follow-up period after rehabilitation. There were no significant differences in pulmonary function and peak exercise parameters. We developed an effective home-based PR program with a metronome-guided walking pace for COPD patients. This rehabilitation program may improve functional exercise capacity and HRQOL. PMID- 23678267 TI - Interobserver variability and accuracy of high-definition endoscopic diagnosis for gastric intestinal metaplasia among experienced and inexperienced endoscopists. AB - Accurate diagnosis of gastric intestinal metaplasia is important; however, conventional endoscopy is known to be an unreliable modality for diagnosing gastric intestinal metaplasia (IM). The aims of the study were to evaluate the interobserver variation in diagnosing IM by high-definition (HD) endoscopy and the diagnostic accuracy of this modality for IM among experienced and inexperienced endoscopists. Selected 50 cases, taken with HD endoscopy, were sent for a diagnostic inquiry of gastric IM through visual inspection to five experienced and five inexperienced endoscopists. The interobserver agreement between endoscopists was evaluated to verify the diagnostic reliability of HD endoscopy in diagnosing IM, and the diagnostic accuracy, sensitivity, and specificity were evaluated for validity of HD endoscopy in diagnosing IM. Interobserver agreement among the experienced endoscopists was "poor" (kappa = 0.38) and it was also "poor" (kappa = 0.33) among the inexperienced endoscopists. The diagnostic accuracy of the experienced endoscopists was superior to that of the inexperienced endoscopists (P = 0.003). Since diagnosis through visual inspection is unreliable in the diagnosis of IM, all suspicious areas for gastric IM should be considered to be biopsied. Furthermore, endoscopic experience and education are needed to raise the diagnostic accuracy of gastric IM. PMID- 23678268 TI - Clinical usefulness of plasma chromogranin a in pancreatic neuroendocrine neoplasm. AB - Chromogranin A (CgA) is widely used as an immunohistochemical marker of neuroendocrine neoplasms and has been measurable in plasma of patients. We assessed the clinical role of plasma CgA in diagnosing pancreatic neuroendocrine neoplasm (PNEN). CgA was checked in 44 patients with pancreatic mass who underwent surgical resection from 2009 through 2011. The cutoff value for diagnosing PNEN and the relationships between CgA and clinicopathologic variables were analyzed. Twenty-six patients were PNENs and 18 patients were other pancreatic disorders. ROC analysis showed a cutoff of 60.7 ng/mL with 77% sensitivity and 56% specificity, and the area under the curve (AUC) was 0.679. Among PNEN group, the sensitivity and specificity of diagnosing metastasis were 100% and 90% respectively when CgA cutoff was 156.5 ng/mL. The AUC was 0.958. High Ki-67 index (160.8 vs 62.1 ng/mL, P = 0.001) and mitotic count (173.5 vs 74.6 ng/mL, P = 0.044) were significantly correlated with plasma CgA, but the tumor size was not. In conclusion, CgA has a little value in diagnosing PNEN. However, the high level of CgA (more than 156.5 ng/mL) can predict the metastasis. Also, plasma CgA level correlates with Ki-67 index and mitotic count which represents prognosis of PNENs. PMID- 23678269 TI - Increasing and worsening late effects in childhood cancer survivors during follow up. AB - Recent advances in childhood cancer treatment have increased survival rates to 80%. Two out of three survivors experience late effects (LEs). From a group of 241 survivors previously described, 193 were followed at the long-term follow-up clinic (LTFC) of Severance Hospital in Korea; the presence of LEs was confirmed by oncologists. We reported the change in LEs during 3 yr of follow-up. The median follow-up from diagnosis was 10.4 yr (5.1-26.2 yr). Among 193 survivors, the percentage of patients with at least one LE increased from 63.2% at the initial visit to 75.1% at the most recent visit (P = 0.011). The proportion of patients having multiple LEs and grade 2 or higher LEs increased from the initial visit (P = 0.001 respectively). Forty-eight non-responders to the LTFC were older and had less frequent and severe LEs than responders at initial visit (all P < 0.05). In multivariate analysis, younger age at diagnosis, older age at initial visit, a diagnosis of a brain tumor or lymphoma, and use of radiotherapy were significant risk factors for LEs (all P < 0.05). Adverse changes in LEs were seen among the survivors, regardless of most clinical risk factors. They need to receive comprehensive, long-term follow up. PMID- 23678270 TI - Reliability and validity of the Korean version of the internet addiction test among college students. AB - We developed a Korean translation of the Internet Addiction Test (KIAT), widely used self-report for internet addiction and tested its reliability and validity in a sample of college students. Two hundred seventy-nine college students at a national university completed the KIAT. Internal consistency and two week test retest reliability were calculated from the data, and principal component factor analysis was conducted. Participants also completed the Internet Addiction Diagnostic Questionnaire (IADQ), the Korea Internet addiction scale (K-scale), and the Patient Health Questionnaire-9 for the criterion validity. Cronbach's alpha of the whole scale was 0.91, and test-retest reliability was also good (r = 0.73). The IADQ, the K-scale, and depressive symptoms were significantly correlated with the KIAT scores, demonstrating concurrent and convergent validity. The factor analysis extracted four factors (Excessive use, Dependence, Withdrawal, and Avoidance of reality) that accounted for 59% of total variance. The KIAT has outstanding internal consistency and high test-retest reliability. Also, the factor structure and validity data show that the KIAT is comparable to the original version. Thus, the KIAT is a psychometrically sound tool for assessing internet addiction in the Korean-speaking population. PMID- 23678271 TI - Current smoking is associated with a poor visual acuity improvement after intravitreal ranibizumab therapy in patients with exudative age-related macular degeneration. AB - In this study, the risk factors that may influence visual improvement after intravitreal ranibizumab (IVR) treatment for exudative age-related macular degeneration (AMD) were examined. From 2008 to 2012, 420 patients (448 eyes) with exudative AMD were prospectively registered at Seoul National University Hospital. From this group of patients, 125 eyes were included in this study. All patients were treated with 3 consecutive IVR injections. The visual acuity (VA) was evaluated at baseline and 1 month after the third ranibizumab injection. To evaluate the risk factors associated with VA improvement after IVR, patient demographic data and systemic risk factors were analyzed. Patients were divided into a poor VA improvement group and a good VA improvement group, with reference to the median visual improvement in all eyes. Among 125 eyes, 66 eyes (52.8%) were included in the responder group and 59 eyes (47.2%) in the non-responder group. The median VA improvement after 3 monthly ranibizumab injections was -0.05 logMAR. Multivariate analyses revealed that current smoking (adjusted OR, 7.540; 95% CI, 1.732-32.823) was independently associated with poor VA improvement after IVR treatment for exudative AMD. In conclusion, cigarette smoking is an independent risk factor for lower VA gains with IVR treatment for exudative AMD. PMID- 23678272 TI - Three new single nucleotide polymorphisms identified by a genome-wide association study in Korean patients with vitiligo. AB - Genetic susceptibility is involved in the pathogenesis of vitiligo. Association studies with a whole genome-based approach instead of a single or a few candidate genes may be useful for discovering new susceptible genes. Although the etiology of non-segmental and segmental types is different, the association between gene polymorphisms and vitiligo has been reported, without defining types or in non segmental type. Whole genome-based single nucleotide polymorphisms (SNPs) were examined in patients with non-segmental and segmental types of vitiligo using the Affymetrix GeneChip 500K mapping array, and 10 functional classes of significant SNPs were selected. Genotyping and data analysis of selected 10 SNPs was performed using real-time PCR. Genotype and allele frequencies were significantly different between both types of vitiligo and three of the target SNPs, DNAH5 (rs2277046), STRN3 (rs2273171), and KIAA1005 (rs3213758). A stronger association was suggested between the mutation in KIAA1005 (rs3213758) and the segmental type compared to the non-segmental type of vitiligo. DNAH5 (rs2277046), STRN3 (rs2273171), and KIAA1005 (rs3213758) may be new vitiligo-related SNPs in Korean patients, either non-segmental or segmental type. PMID- 23678273 TI - First Korean family with a mutation in TPM2 associated with Sheldon-Hall syndrome. AB - Sheldon-Hall syndrome (SHS) is a rare autosomal dominant, inherited arthrogryposis syndrome characterized by multiple congenital contractures of the distal limbs. To date, four genes that encode the skeletal muscle fiber complex have been confirmed as the causative genes. Mutations in MYH3 have been identified most frequently and few cases of SHS caused by TPM2 mutations have been reported worldwide. This report describes, for the first time, a Korean family with two generations of SHS resulting from a rare TPM2 mutation, p.R133W. The affected mother and daughter manifested typical facial features of SHS including a triangular face with downslanting palpebral fissures, small mouth, high arched palate, and prominent nasolabial folds, and showed camptodactyly of fingers and deformities of feet with congenital vertical tali. Generalized myopathy with relative sparing of the slow-twitch muscle fibers was also revealed by electromyography in the affected mother. PMID- 23678274 TI - A novel mutation of the TAZ gene in Barth syndrome: acute exacerbation after contrast-dye injection. AB - A 14-month-old boy was transferred because of dilated and hypertrophied left ventricle, neutropenia, and developmental delay. After checking computed tomographic angiography with contrast-dye, the patient showed acute exacerbation and finally died from multi-organ failure despite intensive cares. From genetic analysis, we revealed that the patient had Barth syndrome and found a novel hemizygous frame shift mutation in his TAZ gene, c.227delC (p.Pro76LeufsX7), which was inherited from his mother. Herein, we report a patient with Barth syndrome who had a novel mutation in TAZ gene and experienced unexpected acute exacerbation after contrast dye injection for computed tomographic angiography. PMID- 23678275 TI - Sudden cardiac arrest during anesthesia in a 30-month-old boy with syndactyly: a case of genetically proven Timothy syndrome. AB - Timothy syndrome, long QT syndrome type 8, is highly malignant with ventricular tachyarrhythmia. A 30-month-old boy had sudden cardiac arrest during anesthesia induction before plastic surgery for bilateral cutaneous syndactyly. After successful resuscitation, prolonged QT interval (QTc, 0.58-0.60 sec) and T-wave alternans were found in his electrocardiogram. Starting beta-blocker to prevent further tachycardia and collapse event, then there were no more arrhythmic events. The genes KCNQ1, KCNH2, KCNE1 and 2, and SCN5A were negative for long QT syndrome. The mutation p.Gly406Arg was confirmed in CACNA1C, which maintains L type calcium channel depolarization in the heart and other systems. PMID- 23678276 TI - Narcolepsy with obstructive sleep apnea in a 4-year-old Korean girl: a case report. AB - A 4-yr-old girl has exhibited severe snoring, restless sleep and increasing daytime sleepiness over the last 3 months. The physical examination showed that she was not obese but had kissing tonsils. Polysomnography demonstrated increased apnea-hypopnea index (AHI) of 5.2, and multiple sleep latency tests (MSLT) showed shortened mean sleep latency and one sleep-onset REM period (SOREMP). She was diagnosed with obstructive sleep apnea (OSA) and underwent tonsillectomy and adenoidectomy. After the surgery, her sleep became much calmer, but she was still sleepy. Another sleep test showed normal AHI of 0.2, the mean sleep latency of 8 min, and two SOREMPs. Diagnosis of OSA to be effectively treated by surgery and narcolepsy without cataplexy was confirmed. Since young children exhibiting both OSA and narcolepsy can fail to be diagnosed with the latter, it's desirable to conduct MSLT when they have severe daytime sleepiness or fail to get better even with good treatment. PMID- 23678277 TI - Formation of the peripheral-central transitional zone in the postnatal mouse cochlear nerve. AB - OBJECTIVES: Determine the formation of peripheral and central nervous system (CNS and PNS) transitional zone (PCTZ) along the postnatal mouse cochlear nerve. STUDY DESIGN: Prospective, basic science. SETTING: Research laboratory. SUBJECTS AND METHODS: A novel cryosection model of cochlea-cochlear nerve-brainstem was used in this study. The sections were harvested from a total of 45 mice in 9 groups of postnatal-day-0 to postnatal-day-60 mice (n = 5). Differential interference contrast microscopy and immunofluorescence were used to study the formation of PCTZ along the cochlear nerve of the postnatal mouse. RESULTS: The CNS tissue extended peripherally along the cochlear nerve from postnatal-day-0 to postnatal day-7 and then stably located at the level of the spiral lamina of the basal cochlear turn. The PCTZ reached a mature pattern along the cochlear nerve after postnatal-day-7. A long segment of the CNS tissue extended along the cochlear nerve in the postnatal mouse. CONCLUSION: In the early postnatal days, the PCTZ extended peripherally toward the cochlea and obtains a mature pattern along the neonatal mouse cochlear nerve. PMID- 23678278 TI - Image-guided surgery influences perioperative morbidity from endoscopic sinus surgery: a systematic review and meta-analysis. AB - OBJECTIVE: Although image-guided surgery (IGS) is considered a valuable tool, its impact on perioperative morbidity for endoscopic sinus surgery (ESS) remains unclear. The evidence from reported literature is systematically reviewed with meta-analysis. DATA SOURCES: MEDLINE (1946 to September 14, 2012, week 2) and EMBASE (1974 to September 14, 2012, week 37). REVIEW METHODS: MEDLINE and EMBASE were searched using a search strategy for publications on IGS during ESS that reported original data on perioperative morbidity. PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines were followed. Both comparative cohort studies with non-IGS cases and case series were included. Primary outcome was major and total complications. Secondary outcomes were specific orbital and intracranial injury, major hemorrhage, ability to complete the operation, and revision surgery. The incidence of these events was defined as dichotomous variables and expressed as a risk ratio (RR) in a fixed-effects model. RESULTS: In total, 2586 articles fulfilled the search, producing 55 included studies. Fourteen were comparative cohorts of IGS and non-IGS sinus surgical patient populations used for meta-analysis. Among the cohorts, major complications were more common in the non-IGS group (RR = 0.48; 95% confidence interval [CI], 0.28-0.82; P = .007). Total complications were greater in the non IGS group (RR = 0.66; 95% CI, 0.47-0.94; P = .02). All other outcomes did not reach significance on meta-analysis. CONCLUSION: Contrary to current review articles on the topic of IGS use during ESS, there is evidence from published studies that the use of IGS for sinus surgery, within selected populations, is associated with a lower risk of major and total complications compared with non IGS sinus surgery. PMID- 23678279 TI - Unilateral cochlear nerve deficiency in children. AB - OBJECTIVE: Cochlear nerve deficiency (CND) is increasingly diagnosed in children with sensorineural hearing loss (SNHL). We sought to determine the prevalence of CND, its imaging characteristics, and correlations with audiologic phenotype in children with unilateral SNHL. DESIGN: Case series with chart review. SETTING: Tertiary pediatric hospital. SUBJECTS/METHODS: In 128 consecutive children with unilateral SNHL who underwent high-resolution magnetic resonance imaging, the diameters, area, and signal intensity of the cochlear nerve (CN) were measured and normalized to the ipsilateral facial nerve. Presence of CND was determined by comparison to normative data. Relationships among hearing loss severity, progression, and nerve size were investigated. RESULTS: Cochlear nerve deficiency was present in 26% of children with unilateral SNHL. Its prevalence was higher (48%) in severe to profound SNHL, especially when in infants (100%). Width of the bony cochlear nerve canal (BCNC) correlated strongly with relative CN diameter, density, and area (R = 0.5); furthermore, a narrow BCNC (<1.7 mm) strongly predicted CND. Severity of hearing loss modestly correlated with nerve size, although significant variability was observed. Progression never occurred unless there were other inner ear malformations, whereas in the non-CND group, it occurred in 22%. Ophthalmologic abnormalities were very common (67%) in CND children, particularly oculomotor disturbances. CONCLUSION: Cochlear nerve deficiency is a common cause of unilateral SNHL, particularly in congenital unilateral deafness. Width of the BCNC effectively predicts CND, a finding useful when only computed tomography imaging is available. In an ear with CND, hearing can be expected to remain stable over time. Diagnosis should prompt evaluation by an ophthalmologist. PMID- 23678280 TI - Causes of spinal cord injury. AB - BACKGROUND: Knowledge of the causes of spinal cord injury (SCI) and associated factors is critical in the development of successful prevention programs. OBJECTIVE: This study analyzed data from the National SCI Database (NSCID) and National Shriners SCI Database (NSSCID) in the United States to examine specific etiologies of SCI by age, sex, race, ethnicity, day and month of injury, and neurologic outcomes. METHODS: NSCID and NSSCID participants who had a traumatic SCI from 2005 to 2011 with known etiology were included in the analyses (N=7,834). Thirty-seven causes of injury documented in the databases were stratified by personal characteristics using descriptive analysis. RESULTS: The most common causes of SCI were automobile crashes (31.5%) and falls (25.3%), followed by gunshot wounds (10.4%), motorcycle crashes (6.8%), diving incidents (4.7%), and medical/surgical complications (4.3%), which collectively accounted for 83.1% of total SCIs since 2005. Automobile crashes were the leading cause of SCI until age 45 years, whereas falls were the leading cause after age 45 years. Gunshot wounds, motorcycle crashes, and diving caused more SCIs in males than females. The major difference among race/ethnicity was in the proportion of gunshot wounds. More SCIs occurred during the weekends and warmer months, which seemed to parallel the increase of motorcycle- and diving-related SCIs. Level and completeness of injury are also associated with etiology of injury. CONCLUSIONS: The present findings suggest that prevention strategies should be tailored to the targeted population and major causes to have a meaningful impact on reducing the incidence of SCI. PMID- 23678281 TI - Assessment and evaluation of primary prevention in spinal cord injury. AB - Although the incidence of spinal cord injury (SCI) is low, the consequences of this disabling condition are extremely significant for the individual, family, and the community. Sequelae occur in the physical, psychosocial, sexual, and financial arenas, making global prevention of SCI crucial. Understanding how to assess and evaluate primary prevention programs is an important competency for SCI professionals. Assessing a program's success requires measuring processes, outcomes, and impact. Effective evaluation can lead future efforts for program design while ensuring accountability for the program itself. The intended impact of primary prevention programs for SCI is to decrease the number of individuals who sustain traumatic injury; many programs have process and outcome goals as well. An understanding of the basic types of evaluation, evaluation design, and the overall process of program evaluation is essential for ensuring that these programs are efficacious. All health care professionals have the opportunity to put prevention at the forefront of their practice. With the current paucity of available data, it is important that clinicians share their program design, their successes, and their failures so that all can benefit and future injury can be prevented. PMID- 23678282 TI - Evidence-based practice in primary prevention of spinal cord injury. AB - A spinal cord injury (SCI) not only causes paralysis, but also has long-term impact on physical and mental health. There are between 236,000 to 327,000 individuals living with the consequences of SCI in the United States, and the economic burden on the individuals sustaining the injury, their support network, and society as a whole is significant. The consequences of SCI require that health care professionals begin thinking about primary prevention. Efforts are often focused on care and cure, but evidence-based prevention should have a greater role. Primary prevention efforts can offer significant cost benefits, and efforts to change behavior and improve safety can and should be emphasized. Primary prevention can be applied to various etiologies of injury, including motor vehicle crashes, sports injuries, and firearm misuse, with a clear goal of eliminating unnecessary injury and its life-changing impact. PMID- 23678283 TI - Relationship between neurological injury and patterns of upright mobility in children with spinal cord injury. AB - BACKGROUND: The predictors and patterns of upright mobility in children with a spinal cord injury (SCI) are poorly understood. OBJECTIVE: The objective of this study was to develop a classification system that measures children's ability to integrate ambulation into activities of daily living (ADLs) and to examine upright mobility patterns as a function of their score and classification on the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) exam. METHODS: This is a cross-sectional, multicenter study that used a convenience sample of subjects who were participating in a larger study on the reliability of the ISNCSCI. A total of 183 patients between 5 and 21 years old were included in this study. Patients were asked if they had participated in upright mobility in the last month and, if so, in what environment and with what type of bracing. Patients were then categorized into 4 groups: primary ambulators (PrimA), unplanned ambulators (UnPA), planned ambulators (PlanA), and nonambulators. RESULTS: Multivariate analyses found that only lower extremity strength predicted being a PrimA, whereas being an UnPA was predicted by both lower extremity strength and lack of preservation of S45 pinprick sensation. PlanA was only associated with upper extremity strength. CONCLUSIONS: This study introduced a classification system based on the ability of children with SCI to integrate upright mobility into their ADLs. Similar to adults, lower extremity strength was a strong predictor of independent mobility (PrimA and UnPA). Lack of pinprick predicted unplanned ambulation, but not being a PrimA. Finally, upper extremity strength was a predictor for planned ambulation. PMID- 23678284 TI - Comparative study on the wrist positions during raise maneuver and their effect on hand function in individuals with paraplegia. AB - OBJECTIVE: To determine the appropriate wrist position in individuals with high level paraplegia during the RAISE (relief of anatomical ischial skin embarrassment) maneuver. METHOD: Thirty individuals with high-level paraplegia were randomly selected; 15 individuals performed RAISE maneuver with extended wrist and 15 with neutral wrist. All the subjects who were at least 1 year post spinal cord injury were screened for positive carpal tunnel syndrome symptoms. All the subjects were allowed to participate in a trial of the Jebsen-Taylor Test of Hand Function to familiarize them with the test. Hand function was measured using the Jebsen-Taylor test. RESULTS: During the RAISE maneuver, individuals with paraplegia weight bearing on their hands with wrists in the neutral position showed better hand function (P < .001) when compared to those weight bearing with their wrists in extension. CONCLUSION: Weight bearing with the wrist in neutral position is advisable for paraplegics to prevent the deterioration in hand function due to carpal tunnel syndrome. PMID- 23678285 TI - Leg strength, preferred walking speed, and daily step activity in adults with incomplete spinal cord injuries. AB - BACKGROUND: The reduction in physical activity that accompanies spinal cord injury (SCI) contributes to the development of secondary health concerns. Research has explored potential strategies to enhance the recovery of walking and lessen the impact of physical disability following SCI, but further work is needed to identify determinants of community walking activity in this population. OBJECTIVES: To quantify relationships among lower extremity strength (LES), preferred walking speed (PWS), and daily step activity (DSA) in adults with incomplete SCI (iSCI) and determine the extent to which LES and PWS predict DSA in persons with iSCI. METHODS: Participants were 21 adults (age range, 21 to 62 years; AIS levels C and D) with iSCI. Maximal values of hip abduction, flexion, and extension, knee flexion and extension, and ankle dorsiflexion and plantar flexion were measured using handheld dynamometry and were summed to determine LES. PWS was calculated using a photoelectric cell-based timing system, and participants were fitted with activity monitors to measure DSA in a natural setting. RESULTS: Statistically significant (P <; .05) correlations of moderate to high magnitude (.74 to .87) were observed among LES, PWS, and DSA. Multiple regression analysis revealed that LES and PWS accounted for 83% (adjusted R2) of the variation in DSA (P <; .001). CONCLUSION: A significant proportion of the explained variance in DSA can be predicted from knowledge of LES and PWS in adults with iSCI. These findings suggest that future efforts to improve community walking behavior following SCI should be directed toward increasing LES and PWS. PMID- 23678286 TI - Renal tract ultrasonography for routine surveillance in spinal cord injury patients. AB - OBJECTIVES: To report the efficacy of a urinary tract surveillance regime based on annual renal tract ultrasound without routine use of urodynamic testing (UDS) in our population of spinal cord injury (SCI) patients managed with clean intermittent catheterization (CIC). METHODS: Data was gathered retrospectively from the records of 48 SCI patients (40 males and 8 females). After establishing a safe system with initial urodynamics, renal ultrasonography was done annually for surveillance. UDS was repeated only when patients presented with new symptoms. The primary endpoint was the report of ultrasound findings at last follow-up. Findings of dilatation, calculi, scarring, and reflux were noted. RESULTS: Mean follow-up was 6.8 years. By final follow-up, pelvicaliectasis was present in 4 (8%) subjects. Mild-moderate hydronephrosis was present in 3 (6%) subjects: 1 stable and 2 (4%) new compared to initial assessment. No severe cases of hydronephrosis were noted. Six (13%) subjects had renal/ureteral calculi. No new cases of renal cortical scarring or thinning were noted. One (2%) subject had high-grade reflux on UDS secondary to a double J stent. CONCLUSIONS: Data relating to the efficacy of sequential surveillance studies in SCI patients are scarce, thus there is great variability in urologic surveillance methods worldwide. Upper tract abnormalities detected in our patients were early consequences of acute obstruction rather than late manifestations of detrusor changes and could not have been prevented with more regular urodyamic testing. These results suggest that annual ultrasound monitoring without routine urodynamic testing is an effective surveillance strategy in SCI patients managed with CIC. PMID- 23678287 TI - Neuropathic pain post spinal cord injury part 1: systematic review of physical and behavioral treatment. AB - BACKGROUND: Neuropathic pain has various physiologic and psychosocial aspects. Hence, there is a growing use of adjunct nonpharmacological therapy with traditional pharmacotherapy to reduce neuropathic pain post spinal cord injury (SCI). OBJECTIVE: The purpose of this study was to conduct a systematic review of published research on nonpharmacological treatment of neuropathic pain after SCI. METHODS: MEDLINE, CINAHL, EMBASE, and PsycINFO databases were searched for articles addressing nonpharmacological treatment of pain post SCI. Articles were restricted to the English language. Article selection was conducted by 2 independent reviewers with the following inclusion criteria: the subjects participated in a treatment or intervention for neuropathic pain; at least 50% of the subjects had an SCI; at least 3 subjects had an SCI; and a definable intervention was being studied. Data extracted included study design, study type, subject demographics, inclusion and exclusion criteria, sample size, outcome measures, and study results. Randomized controlled trials (RCTs) were assessed for quality using the Physiotherapy Evidence Database (PEDro) assessment scale. Levels of evidence were assigned to each intervention using a modified Sackett scale. RESULTS: The 16 articles selected for this review fell into 1 of 2 categories of nonpharmacological management of pain after SCI: physical and behavioral treatments. The pooled sample size of all studies included 433 participants. Of the 16 studies included, 7 were level 1, 3 were level 2, and 6 were level 4 studies. CONCLUSIONS: Physical interventions demonstrated the strongest evidence based on quality of studies and numbers of RCTs in the nonpharmacological treatment of post-SCI pain. Of these interventions, transcranial electrical stimulation had the strongest evidence of reducing pain. Despite a growing body of literature, there is still a significant lack of research on the use of nonpharmacological therapies for SCI pain. PMID- 23678288 TI - Neuropathic pain post spinal cord injury part 2: systematic review of dorsal root entry zone procedure. AB - BACKGROUND: Pharmacotherapy may not sufficiently reduce neuropathic pain in many individuals post spinal cord injury (SCI). The use of alternative therapies such as surgery may be effective in reducing neuropathic pain in these individuals. However, because of the invasive nature of surgery, it is important to examine the evidence for use of this treatment. OBJECTIVE: The purpose of this study was to conduct a systematic review of published literature on the surgical treatment of neuropathic pain after SCI. METHODS: MEDLINE, CINAHL, EMBASE, and PsycINFO databases were searched for articles in which surgical treatment of pain after SCI was examined. Articles were restricted to the English language. Article selection was conducted by 2 independent reviewers with the following inclusion criteria: the subjects participated in a surgical intervention for neuropathic pain; at least 50% of the subjects had an SCI; at least 3 subjects had an SCI; and a definable intervention involving the dorsal root entry zone (DREZ) procedure was used to reduce pain. Data extracted included study design, study type, subject demographics, inclusion and exclusion criteria, sample size, outcome measures, and study results. Randomized controlled trials (RCTs) were assessed for quality using the Physiotherapy Evidence Database (PEDro) assessment scale. Levels of evidence were assigned to each intervention using a modified Sackett scale. RESULTS: Eleven studies met the inclusion criteria. One study provided level 2 evidence, and the rest provided level 4 evidence. The DREZ procedure was shown to be more effective for segmental pain than for diffuse pain after SCI. Further, individuals with conus medullaris level injury were found to have a higher level of neuropathic pain relief than those with cervical, thoracic, or cauda equina injury. CONCLUSIONS: The studies demonstrated that the DREZ procedure may be effective in reducing segmental pain. Hence, DREZ may be important in treatment of neuropathic pain in individuals resistant to less invasive treatments. Because the studies lacked control conditions and examination of long-term effects, there is a need for larger trials with more stringent conditions. PMID- 23678289 TI - Modulation of cell cycle progression by 5-azacytidine is associated with early myogenesis induction in murine myoblasts. AB - Myogenesis is a multistep process, in which myoblasts withdraw from the cell cycle, cease to divide, elongate and fuse to form multinucleated myotubes. Cell cycle transition is controlled by a family of cyclin-dependent protein kinases (CDKs) regulated by association with cyclins, negative regulatory subunits and phosphorylation. Muscle differentiation is orchestrated by myogenic regulatory factors (MRFs), such as MyoD and Myf-5. DNA methylation is crucial in transcriptional control of genes involved in myogenesis. Previous work has indicated that treatment of fibroblasts with the DNA-demethylating agent 5 azacytidine (AZA) promotes MyoD expression. We studied the effects of AZA on cell cycle regulation and MRFs synthesis during myoblast proliferation and early myogenesis phases in C2C12 cells. During the proliferation phase, cells were incubated in growth medium with 5uM AZA (GMAZA) or without AZA (GM) for 24 hours. At 70% confluence, cells were kept in growth medium in order to spontaneously achieve differentiation or transferred to differentiation medium with 5MUM AZA (DMAZA) or without AZA (DM) for 12 and 24 hours. Cells used as control were unstimulated. In the proliferation phase, AZA-treated cells seemed to lose their characteristic circular shape and become elongated. The presence of AZA resulted in significant increases in the protein contents of Cyclin-D (FC:1.23 GMAZA vs GM p<=0.05), p21 (FC: 1.23 GMAZA vs GM p<=0.05), Myf-5 (FC: 1.21 GMAZA vs GM p<=0.05) and MyoD (FC: 1.20 GMAZA vs GM p<=0.05). These results propose that AZA could inhibit cell proliferation. During 12 hours of differentiation, AZA decreased the downregulation of genes involved in cell cycle arrest and in restriction point (G1 and G1/S phase) and the expression of several cyclins, E2F Transcription Factors, cyclin-dependent kinase inhibitors, specific genes responsible of cell cycle negative regulation. During 24 hours of differentiation, AZA induced an increment in the protein expression of Myf-5 (FC: 1.57 GMAZA vs GM p<=0.05), MyoD (FC: 1.14 DM vs GM p<=0.05; FC: 1.47 DMAZA vs GM p<=0.05), p21 (FC: 1.36 GMAZA vs GM p<=0.01; FC: 1.49 DM vs GM p<=0.05; FC: 1.82 DMAZA vs GM p<=0.01) and MyHC (FC: 1.40 GMAZA vs GM p<=0.01; FC: 2.39 DM vs GM p<=0.05; FC: 3.51 DMAZA vs GM p<=0.01). Our results suggest that AZA-induced DNA demethylation can modulate cell cycle progression and enhance myogenesis. The effects of AZA may open novel clinical uses in the field of muscle injury research and treatment. PMID- 23678290 TI - A novel aurora-A inhibitor, BPR1K0609S1, sensitizes colorectal tumor cells to 5 fluorofracil (5-FU) treatment. AB - Small synthetic compounds have been implicated in treatment of human cancers. We have synthesized a small compound, BPR1K0609S1 (hereafter, BP), which inhibits Aurora-A kinase. In the present study, we studied the mechanism of BP suppression of tumorigenesis induced by Aurora-A. Given our previous results that inactivation of p53 accelerates MMTV-Aurora-A-mediated tumorigenesis in vivo, we studied the roles of p53 pathway using the isogenic human colon carcinoma cell lines of HCT116, in which p53, Puma, Bax, p21 or Chk2 is deleted. When these isogenic cell lines are treated with BP for 48 h, accumulation of G2M phase and aneuploidy are commonly observed, and HCT116 p21(-) cells show increase in apoptosis. In xenograft assay, s.c. injection of BP efficiently inhibits tumorigenesis of HCT116 deficient for Chk2 or p21. Re-transplantation of BP resistant tumors indicates that these resistant cells do not acquire advanced tumor growth. Significantly, 5-FU (5-fluorouracil) treatment further induces apoptosis of BP-resistant HCT116 deficient for Chk2 or Puma. These results demonstrate that p21 deficiency enhances BP-mediated suppression of tumor growth, and that BP and 5-FU can collaborate for tumor regression. PMID- 23678291 TI - PairMotif+: a fast and effective algorithm for de novo motif discovery in DNA sequences. AB - The planted (l, d) motif search is one of the most widely studied problems in bioinformatics, which plays an important role in the identification of transcription factor binding sites in DNA sequences. However, it is still a challenging task to identify highly degenerate motifs, since current algorithms either output the exact results with a high computational cost or accomplish the computation in a short time but very often fall into a local optimum. In order to make a better trade-off between accuracy and efficiency, we propose a new pattern driven algorithm, named PairMotif+. At first, some pairs of l-mers are extracted from input sequences according to probabilistic analysis and statistical method so that one or more pairs of motif instances are included in them. Then an approximate strategy for refining pairs of l-mers with high accuracy is adopted in order to avoid the verification of most candidate motifs. Experimental results on the simulated data show that PairMotif+ can solve various (l, d) problems within an hour on a PC with 2.67 GHz processor, and has a better identification accuracy than the compared algorithms MEME, AlignACE and VINE. Also, the validity of the proposed algorithm is tested on multiple real data sets. PMID- 23678292 TI - PIG3 functions in DNA damage response through regulating DNA-PKcs homeostasis. AB - The p53-inducible gene 3 (PIG3) recently has been reported to be a new player in DNA damage signaling and response, but the crucial mechanism remains unclear. In the present study, the potential mechanism of PIG3 participation in the DNA damage response induced by ionizing radiation (IR) was investigated in multiple cell lines with depleted expression of PIG3 transiently or stably by the small interference RNA and lentivirus-mediated shRNA expression strategies. PIG3 knockdown led to an abnormal DNA damage response, including decreased IR-induced phosphorylation of H2AX, Chk1, Chk2 and Kap-1 as well as a prolonged G2-M arrest and aberrant mitotic progression. Notably, PIG3 knockdown resulted in a striking depression of cellular DNA-PKcs protein level, and was accompanied by a downregulation of ATM. Re-expression of PIG3 effectively rescued the depression of DNA-PKcs in PIG3-depleted cells. This negative regulation of DNA-PKcs by depleting PIG3 seemed to take place at the translational level but not at the levels of transcription or protein degradation. However, a compensatory feedback of increased mRNA expression of DNA-PKcs was formed in PIG3-depleted cells after a few passages or cell cycles of subculture, which led the recovery of the DNA PKcs protein level and the consequent recovered efficiency of the DNA damage response. These results provide a new insight into the mechanism of PIG3's functioning in DNA damage signaling and the regulation network of cellular DNA PKcs expression homeostasis. PMID- 23678293 TI - The C-kit receptor-mediated signal transduction and tumor-related diseases. AB - As an important member of tyrosine kinase family, c-kit receptor causes specific expression of certain genes, regulates cell differentiation and proliferation, resists cell apoptosis, and plays a key role in tumor occurrence, development, migration and recurrence through activating the downstream signaling molecules following interaction with stem cell factor (SCF). The abnormality of SCF/c-kit signaling pathway is closely related to some certain tumors. The discovery of c kit receptor-targeted drugs has promoted clinical-related cancer's diagnosis and treatment. In this paper, we review recent research progress on c-kit receptor mediated signal transduction and its potential therapeutic application as a target in tumor-related diseases. PMID- 23678294 TI - Nanos3 gene targeting in medaka ES cells. AB - Gene targeting (GT) by homologous recombination offers the best precision for genome editing in mice. nanos3 is a highly conserved gene and encodes a zinc finger RNA binding protein essential for germ stem cell maintenance in Drosophila, zebrafish and mouse. Here we report nanos3 GT in embryonic stem (ES) cells of the fish medaka as a lower vertebrate model organism. A vector was designed for GT via homologous recombination on the basis of positive-negative selection (PNS). The ES cell line MES1 after gene transfer and PNS produced 56 colonies that were expanded into ES cell sublines. Nine sublines were GT-positive by PCR genotyping, 4 of which were homologous recombinants as revealed by Southern blot. We show that one of the 4, A15, contains a precisely targeted nanos3 allele without any random events, demonstrating the GT feasibility in medaka ES cells. Importantly, A15 retained all features of undifferentiated ES cells, including stable self-renewal, an undifferentiated phenotype, pluripotency gene expression and differentiation during chimeric embryogenesis. These results provide first evidence that the GT procedure and genuine GT on a chromosomal locus such as nanos3 do not compromise pluripotency in ES cells of a lower vertebrate. PMID- 23678295 TI - Overexpression of microRNA-1 causes atrioventricular block in rodents. AB - The present study was designed to investigate whether microRNAs (miRNAs) are involved in atrioventricular block (AVB) in the setting of myocardial ischemia (MI). A cardiac-specific miR-1 transgenic (Tg) mouse model was successfully established for the first time in this study using microinjection. miR-1 level was measured by real-time qRT-PCR. Whole-cell patch clamp was employed to record L-type calcium current (I Ca,L) and inward rectifier K(+) current (I K1). Expression of connexin 43 (Cx43) protein was determined by western blot analysis. Alternations of [Ca(2+)]i was detected by laser scanning confocal microscopy in ventricular myocytes. The incidence of AVB was higher in miR-1 Tg mice than that in wild-type (WT) mice. The normalized peak current amplitude of I Ca,L was lower in ventricular myocytes from miR-1 Tg mice as compared with WT mice. Similarly, the current density of I K1 was decreased in miR-1 Tg mice than that in WT mice. Compared with WT mice, miR-1 Tg mice exhibited a significant decrease of the systolic [Ca(2+)]i in ventricular myocytes but a prominent increase of the resting [Ca(2+)]i. Moreover, Cx43 protein was downregulated in miR-1 Tg mice compared to that in WT mice. Administration of LNA-modified antimiR-1 reversed all the above changes. miR-1 overexpression may contribute to the increased susceptibility of the heart to AVB, which provides us novel insights into the molecular mechanisms underlying ischemic cardiac arrhythmias. PMID- 23678296 TI - Karyotypic and molecular genetic changes associated with fetal cardiovascular abnormalities: results of a retrospective 4-year ultrasonic diagnosis study. AB - OBJECTIVE: To investigate the incidence of aneuploidy in fetuses with congenital heart defects (CHDs) and to further identify submicroscopic changes and global DNA methylation levels as potential biomarkers in complex CHD cases. METHODS: Fetuses at high risk for birth defects or with obvious sonographic anomalies were recruited at the Prenatal Diagnosis Center and Ultrasonic Diagnosis Center. Elective fetal karyotyping and DNA copy number and promoter methylation analyses were carried out following parental consent. G-banded karyotyping was performed to detect fetal aneuploidy. Copy number variations (CNVs) were detected using the Affymetrix SNP Array 6.0 and validated by real time PCR. Global DNA methylation analyses were conducted using a Roche NimbleGen Human DNA Methylation 3x720K Array, and DNA methylation differences were assayed by a Sequenom MassARRAY EpiTYPER. RESULTS: Conventional karyotyping identified 30 cases with aneuploidy in 179 CHD fetuses. Various CNVs were found in two aneuploid fetuses and in five euploid CHD fetuses. Verified segmental deletion or duplications were not directly associated with cardiovascular malformations except in DAAM1 and GATA6. Verifiable aberrant DNA methylation could not be identified in three complex CHD fetuses. CONCLUSIONS: In this study, Trisomy 18, Trisomy 21 and 45,XO were the most common aneuploidies identified in CHD fetuses. In the affected samples, only DAAM1 deletion and GATA6 amplification could be associated with cardiovascular biological processes. PMID- 23678297 TI - National society cardiovascular journals of europe: almanac 2011. PMID- 23678299 TI - Quality of life with removable dentures. AB - GOAL: To measure change in a quality of life after treatment with removable dentures and to describe differences in quality of life in patients with new and worn out dentures. MATERIALS AND METHODS: Measuring instrument was OHIP-49, translated from English into one of the languages in Bosnia-Herzegovina. Sample consisted of patients who wanted to make/replace mobile dentures or came to repair a broken dentures. Comprehensibility of the OHIP-BH49 was tested on a sub sample of patients. Three measurements were made: before and after the insertion of dentu res and when patients came to repair their mobile dentures. RESULTS: Sample consisted of 67 patients: 32 patients who sought prosthetic treatment, and 35 who came to repair their broken dentures. We received 89.7% correctly filled questionnaires. Minor changes were made in four (4) questions. Statistical analysis performed with the T-test revealed the significant differences, before and after the treatment with mobile dentures (t=39.5, p<0.001). There was a significant difference in OHIP scores in patients with a new dentures, compared to the patients who had worn out dentures (t=44.30, p<0.001). Substantial differences, between OHIP scores, regarding the time of wearing dentures or patients' age were not observed. DISCUSSION: Patients who wore dentures longer than 5 years, showed better quality of life, because they became accustomed to the dentures. CONCLUSIONS: Self-reported life quality improved considerably after insertion of a new dentures. Patients with a new dentures showed significantly better quality of life than patients with worn out dentures. One part of OHIP validation in Bosnia-Herzegovina has been done. PMID- 23678298 TI - Almanac 2011: stable coronary artery disease. The national society journals present selected research that has driven recent advances in clinical cardiology. PMID- 23678300 TI - Development prospects of health and reform of the fiscal system in bosnia and herzegovina. AB - The functions of the health system, according to the key objectives and relationships within the sub-systems that are available to the policy makers and managers in the Health Care system in Bosnia and Herzegovina - B&H, have been elaborated in detail, with the analytical overview of relevant indicators, thus confirming the limitations of the health promotion in B&H. The ability to overcome the expressed problems is in the startup of process for structural adjustment of the health sector, reform of the health care system and its financing. The reform in health system implies fundamental changes that need to take place, in B&H, as a state in health policy and institutions in the health care system, in order to improve the functioning of health systems with the aim of ensuring better health of the population. Reform implies the existence of documents with clearly formulated health policy objectives, for which the state stands, and for which a consensus was reached on the national level with all key actors in the political structure: public promotion of the basic principles for carrying out the reform, its implementation within a reasonable time frame, the corresponding effects for providers and customer satisfaction, as well as improving health services' efficacy (i.e. micro and macro) and the quality of healthcare. In this article, we elaborated the criteria for the classification of health systems, whereby the scientifically-based and empirical analysis is conducted on the health system in B&H and elaborated the key levers of the system. Leveraged organizational arrangements relating to the economic and political environment, organization and management functions, in connection with the services of finance, funds, customers and service providers, from which it follows the framework of state legislation related to health policy and health institutions at the state level are responsible for finance, planning, the organization, payment, regulation and conduct. If we start from the administrative criteria for the classification of "health sub-systems" in B&H, it is difficult to fit them in a pluralistic, decentralized or monistic, because in the system for each organization, there should be health policy at the state level, which is in the most countries represents the Ministry of Health. PMID- 23678301 TI - Hairy cell leukemia treatment: where we are now? AB - Hairy cell leukemia (HCL) is a very rare type of leukemia, in which abnormal B lymphocytes, present in the bone marrow, spleen, and peripheral blood stream, get worse slowly or do not get worse at all. HCL is the disease where patients have pancytopenia with splenomegalia over 90% percent, palpable lymphadenopathy occur in 35% of patients, some form of serious infection eventually developed in over 50% of patients and was the most common cause of death in patients. HCL is dominantly a male disease, with the male-female ratio, ranging from 4:1 to 7:1. Treatment and prognosis of HCL depends on: the number of HC in the peripheral blood or bone marrow, if the spleen is enlarged and on the existence of the visible leukemia infection symptoms. Prognostic factors are similar to the above mentioned and also if the basic disease HCL is aggressive or the number of HC grow slowly and there is no need for treatment. Starting from September 1985 till September 2010, we observed a group with total number of 28 patients (22 males and 6 females) at the age of 30-76 (median range 46 years), all with HCL disease. From the total number of participants, 20 patients (71,43%) received hemotherapy, Cladribine and 8 patients (28,57%) received different type of therapy, such as immunomodulator therapy, surgery or combination of both, without Cladribine. Most effective therapy for HCL, from all of the above mentioned was definitely Cladribine which is dominant with a resulting response rates of 80-100%, where 70 90% of patients were achieving a complete remission, as defined by a complete disappearance of hairy cells in the bone marrow. PMID- 23678302 TI - Erectile dysfunction as a complication after treatment of prostate cancer. AB - INTRODUCTION: Treatment of localized prostate cancer refers to two basic modes which are the radical retro pubic prostatectomy and external radiotherapy. However, according to most authors, radical prostatectomy is the gold standard for long-term survival. OBJECTIVE: To determine the occurrence of erectile dysfunction after radical operative treatment and irradiation therapy. MATERIAL AND METHODS: In this paper we have examined the occurrence of erectile dysfunction after conducted treatment for localized prostate cancer. In this paper we have examined 84 of 138 patients who underwent radical retro pubic prostatectomy at the Urology Clinic in the period from January 2009 to December 2010 and 26 patients who underwent radical external radiotherapy in the same period, because of localized prostate cancer. RESULTS: The average age of surgical patients was 65 years, the youngest patient was 49 years and the oldest 81 years. From the 84 patients which underwent surgery, neurovascular preservation of nerve bundles was done in 36 (42.8%) patients from which bilateral in 28 patients (77.7%) and unilateral in 8 patients (22.2%). Average age of patients who underwent irradiation therapy was 68 years. CONCLUSION: Erectile dysfunction occurs in greater proportion after radical retro pubic prostatectomy compared to radiation treatment, and the preservation of both neurovascular bundles reduces this difference. PMID- 23678303 TI - Program of the university clinic of toxicology, skopje, republic of macedonia in treatment of drug addiction (buprenorfin treatment protocol). AB - The program of our Clinic includes, not only treatment of acute intoxication with opioids and other drugs, but also comprehends clinical investigations and treatment of the somatic complications of this population. For the first time in our country our Clinic offers to this population the alternative way of treatment with Buprenorfin. The Clinic started with this protocol on August 1, 2009. During a period of two years, the treatment with Buprenorfine has been initiated in 353 patients, of which 211 regularly attend the medical check ups. This model is used according to the national clinical guidelines and procedures for the use of buprenorfine in the treatment of opioid dependence The dose of this medicament depends on the evolution of the withdrawal symptoms. We have used the objective and subjective opioid withdrawal scale for the observation of these symptoms (OOWS ; SOWS - Handelsman et al 1987). This protocol starts with a complete clinical investigations, (i.e. where all patients undergo the inclusion and exclusion criteria with a written consent). Afterwards, the patients are hospitalized and start with a Buprenorfin teratment. After period of 7-10 days hospitalization they come to our Clinic, like outpatients for a regular controls. We have precise evidence for every patient who comes for control (e.g. medical record with all biochemical and toxicological screenings). All patients are recommended a tight cooperation with psychiatrists who are specialized to treat the problematic drug addictions. PMID- 23678304 TI - Sleep disorders in patients with bronchial asthma. AB - Respiratory disturbances during sleep are recognized as extremely common disorders with important clinical consequences. Breathing disorders during sleep can result in broad range of clinical manifestations, the most prevalent of which are unrefreshing sleep, daytime sleepiness and fatigue, and cognitive impairmant. There is also evidence that respiratory-related sleep disturbances can contribute to several common cardiovascular and metabolic disorders, including systemic hypertension, cardiac dysfunction, and insulin-resistance. Correlations are found between asthma-related symptoms and sleep disturbances. Difficulties inducing sleep, sleep fragmentation on polysomnography, early morning awakenings and daytime sleepiness are more common in asthmatics compared with subjects without asthma. The "morning deep" in asthma is relevant for the characterization of asthma severity, and impact drugs' choices. Sleep and night control of asthma could be relevant to evaluate disease's control. Appropriate asthma control recovering is guarantor for better sleep quality in these patients and less clinical consequences of respiratory disturbances during sleep. PMID- 23678305 TI - The scientific conferences organized during war time (1992-1995) in sarajevo. AB - Author of this paper spent 1479 days in the siege of Sarajevo, during the period of war time in Bosnia and Herzegovina (B&H). This siege, lasting from 1992 to 1995 (e.g. Dayton Piece agreement was signed in November, 1995) represents the longest siege in the history of the world. Besides usual daily work, as the associate professor of Health education, Medical deontology and Medical informatics for the students of the Faculty of medicine, Faculty of dental medicine, Faculty of Pharmacy and Nursing college of University of Sarajevo, the author organized by himself and contributors, 10 scientific conferences in a sieged Sarajevo. All presented papers at those conferences are published in Proceedings abstract books, as the proof of continuing scientific work, in Sarajevo and other cities in B&H. Additionally, the author continued to publish, in that time, unique PubMed/MedLine indexed journal, - Medical Archives, (i.e. established in 1947) and, in 1993 formed a new journal named - "Acta Informatica Medica" (AIM) , as the Journal of the Bosnian Society of Medical informatics. Bosnian Society of Medical Informatics, thus became the first scientific association from Bosnia and Herzegovina, included in 1994, in the European Federation of Medical Informatics (EFMI) and the International Medical Informatics Assiciation (IMIA) , which was "miracle" from the besieged Sarajevo and war time result of aggression on Bosnia and Herzegovina. It should be noted that the importance of maintaining these academic gatherings, in the circumstances of war, was multifaceted. First of all, thanks to these meetings, the continuity of scientific meetings and activities in the besieged city of Sarajevo was not broken, as well as the continuity of scientific publication, which was crucial for the maintenance of the teaching staff at the university and, finally, in the expansion of the "scientific truth" about what happened in Sarajevo and B&H in these difficult times. All of this was critical to the "survival" of B&H and its people. Some of the published articles, especially in the Medical Archives journal, which even in difficult war conditions did not break the continuity of its publication, and then it was the only scientific journal indexed in B&H, having been consequently cited in the major biomedical data bases in the world. Many scientists abroad have had the opportunity to learn about some of the wonders of Sarajevo "war medicine", thanks to this journal. Finally, despite the fact that it is another way of expressing its resistance to the aggression on B&H, the organized symposia in the war represented the continuity of the scientific research activities. Bosnia and Herzegovina and Sarajevo under siege, in this way, kept in touch with the civilized world and modern achievements, despite the fact that they were victims of medieval barbarism. In addition, these meetings sent a powerful message to the world about the willingness to register and systematize all the war experiences, especially those related to medicine and medical practice, in terms of what Europe has not known, since the Second World War. Partially, we succeeded in that. The total number of 286 presentations were presented in seven war Conferences, as quantitative and qualitative contribution to the scientific activities, despite the inhuman conditions, in which these articles emerged. These presentations and Conferences testify to the enthusiasm of B&H community and academic institutions that have collaborated with it. Authors and co-authors presented the "war" articles that deserve to be mentioned in the monograph "1479 days of the siege of Sarajevo". Unfortunately, many of these brave authors are not alive and cannot read this. The task for us remains to remember them by their own good. Old Persian proverb says; "The event which is not recorded is as like it had never happened". Sapienti sat. PMID- 23678306 TI - Effects of conservative treatment for osteoporotic thoracolumbal spine fractures. AB - INTRODUCTION: Osteoporosis has a significant role in the etiology of thoracolumbal spinal fractures in older patients. It is the segment where the relatively immobile thoracic segment transfers into a mobile lumbar spine. The clinical picture is always with the back pain after minimal trauma or sometimes even without injury. Diagnosis always includes X-ray and then CAT scan. Treatment depends on the stability of the fracture, neurological findings, and the size of the deformity. Consequences include pain in the legs, back, spinal deformity, reduced lung function, walking disturbances, etc. GOAL: In this paper we will present the patients who were treated by conservative approach for osteoporotic fractures in thoracolumbal spine. MATERIAL AND METHODS: They were treated at the Clinic for Orthopedics and Traumatology of Clinical Center university of Sarajevo from December 1st until December 31st 2010. Patients were divided into two groups: group I consisted of patients who were treated with orthoses, and group II patients treated with plaster corset. Both treatments have their use. RESULTS AND DISCUSSION: Plaster corset gives stability; patients with orthoses are more mobile without skin changes. Orthosis is recommended for most disciplined patients and the best is that all the patients have plaster corset for six weeks, followed until the recovery by three points orthoses. PMID- 23678307 TI - Pregnancy outcome in women with threatened miscarriage: a year study. AB - INTRODUCTION: Patients with threatened miscarriage associated with adverse pregnancy outcomes because of associated pregnancy and labor complications. OBJECTIVES: To evaluate the effect of threatened miscarriage on early and late pregnancy outcome. METHODS: A retrospective case-controlled study was performed on 89 women with threatened miscarriage (study group) at Maternity and Children Hospital Buraidah, KSA from January 2010 to December 2010. They were matched for age and parity to 45 cases (control group) attending route antenatal clinic at the same time. Data recorded included, demographic characteristics and detailed pregnancy outcome and ultrasound finding including gestational age, cardiac activity and subchorionic hematoma. RESULTS: The overall adverse pregnancy outcome was significantly higher in the studied cases compared to the control group (p=015).The miscarriage rate was significantly higher in study group compared to the controls group, (16.9%vs 2.2%, p=0000). Preterm delivery, babies with low birth weight and premature rupture of membranes were significantly higher in the miscarriage group compared to the controls group, (15.7% vs 2.2%, p=0.001), (15.7% vs 2.2%), p=0.001) and (6.7%) vs 4.45), p=0.016). There were no significant differences in other pregnancy outcomes. CONCLUSION: threatened miscarriage is associated with increased incidence of adverse pregnancy outcome. The risk is specially increased in premature rupture of the membranes, preterm delivery and neonatal birth weight. PMID- 23678308 TI - Interferon treatment of multiple sclerosis. AB - INTRODUCTION: IN THE TREATMENT OF MULTIPLE SCLEROSIS (MS) DIFFER: treatment of relapse, treatment slow the progression of the disease (immunomodulators and immunosuppression), and symptomatic treatment. THE AIM: The aim of this study is to analyze the application of interferon therapy in the treatment of MS-E: Process the disease, patients with multiple sclerosis who have passed the commission for multiple sclerosis at the Neurology Clinic of Clinical Center of Sarajevo University as a reference center for referral to the Commission for multiple sclerosis from the Federal Ministry of Health in 2009 year in terms of total number examined, gender differences, diagnostic tests (MRI, CSF, EP), neurological findings and EDSS scores. Provide a section through the continuous support and education of patients during the introduction Betaferon in therapy with the goal of education for self-use and reduce the incidence of side effects of interferon therapy. MATERIALS AND METHODS: The material for the work they were histories of patients who are registered as patients who have undergone a commission for MS at Department of Neurology, University Clinical Center in Sarajevo. The evaluation was retrospective. It was used a specially designed form, which is usually applied to patients referred to this committee. After the collected material was carried out data processing. The study comprised 34 patients who have undergone a commission of which 16 patients received interferon therapy. RESULTS: In 2009 at the Neurology Clinic CCUS have treated 34 patients who passed the committee for recommendation to interferon therapy (25 women and 9 men). The diagnosis of multiple sclerosis is safe based on the criteria of international panel in 2000. EDSS Average score for men was 1.8, 1.9 for women, the total EDSS score was 1.8. The gender ratio is 3:1 in women than in men. Sixteen patients received interferon by the Commission for multiple sclerosis, the Federal Ministry of Health and their therapy was initiated at the clinic. CONCLUSION: For the period of 2009, a total of 34 patients were examined with multiple sclerosis who received interferon treatment recommendations at the expense of the Federal Solidarity Fund at the Neurology Clinic CCUS Sarajevo. The average EDSS score was 1.8. There were no significant differences in neurological findings between patients who were previously treated with interferon and patients who were waiting for treatment. PMID- 23678309 TI - Public and private sector in the health care system of the Federation bosnia and herzegovina: policy and strategy. AB - In Bosnia and Herzegovina citizens receive health care from both public and private providers. The current situation calls for a clear government policy and strategy to ensure better position and services from both parts. This article examines how health care services are delivered, particularly with respect to relationship between public and private providers. The paper notes that the public sector is plagued by a number of weaknesses in terms of inefficiency of services provision, poorly motivated staff, prevalent dual practice of public employees, poor working conditions and geographical imbalances. Private sector is not developing in ways that address the weaknesses of the public sector. Poorly regulated, it operates as an isolated entity, strongly profit-driven. The increasing burdens on public health care system calls for government to abandon its passive role and take action to direct growth and use potential of private sector. The paper proposes a number of mechanisms that can be used to influence private as well as public sector, since actions directed toward one part of the system will inevitable influence the other. PMID- 23678310 TI - Prevalence of polypharmacy and drug interaction among hospitalized patients: opportunities and responsabilities in pharmaceutical care. AB - GOAL: Polypharmacy and drug-related problems (DRPs) have been shown to prevail in hospitalized patients. We evaluated the prevalence of polypharmacy; and investigated relationship between polypharmacy and: symptoms of DRPs, number of drugs and OTC, index of cumulative morbidity, length of exposure to polypharmacy and the number of days of hospital stay among hospitalized patients. METHODOLOGY: A study was performed in Pharmacies "Eufarm Edal" Tuzla from 2010 to 2011. Polypharmacy was defined as using >= 3 drugs. The total study sample of 226 examiners were interviewed with special constructed questionnaires about DRPs. Experimental study group consisted of hospital patients with polypharmacy (n=166) and control group hospital patients without polypharmacy (n=60). Mann-Whitney test was used to test for significant self-reported symptom differences between groups and cross sectional subgroups, t- test and chi(2)- test for age, gender and treatment data in hospital. RESULTS: The prevalence of polypharmacy was 74% among 226 hospitalized patients. The vulnerable age subgroup of hospitalized patients was men and hospitalized patients aged from 46 to 50 years (not geriatric patients). The prevalence of index of cumulative morbidity was 65%. The most common exposures varied by patient age and by hospital type, with various antibiotics, antidepressants, analgesics, sedatives, antihypertensives, flixotide, ranitidine and others. The prevalence of exposure to OTC and self- treatment was 80%. The prevalence of symptoms of drug-related problems were significantly differed among patients of experimental in relationship of control study group patients (P<0.001). CONCLUSION: In addition to helping to resolve the above mentioned issues, the results from this study could provide baseline information quantifying the problem of drug- related problems among hospitalized patients receiving polypharmacy and contribute to the formulation and implementation of risk management strategies for pharmacists and physicians in primary care health. PMID- 23678311 TI - The analysis of reasons for malignant skin tumors late diagnosis. AB - INTRODUCTION: Timely diagnosis is a prerequisite for the successful treatment of malignant skin tumors. Late diagnosis leads a patient into a situation of losing valuable time and chance for cure. MATERIAL AND METHODS: A prospective study was conducted from February 2006 until August 2011 which analyzed the reasons that led to establishing the diagnosis of malignant skin tumors in 220 patients. Patients were divided into two groups: Group A (102 patients), patients with diagnosed melanoma, and group B (118 patients) of patients suffering from basocellular (BCC) and planocellular cell (PCC) skin cancer. Parameters for comparison of analysis results were the reasons for coming to examination and reasons for not coming to the examination, because of which skin cancers were not diagnosed in time. GOAL: To determine the factors that influences the establishment of late diagnosis and treatment of skin tumors. RESULTS: It was confirmed that the prejudices of patients that tumors of the skin "should not be operated because it is dangerous" is the main reason for late diagnosis. At the same time it is confirmed that the belief that it is unnecessary to operate congenital changes of the skin is the second most important reason for delayed diagnosis of malignant skin tumors. PMID- 23678312 TI - Frequency, etiology and several sociodemographic characteristics of acute poisoning in children treated in the intensive care unit. AB - AIM: The aim of this work has been to present the frequency, etiology and several other socio-demographic characteristics of acute poisoning in children. THE TREATED PATIENTS AND METHODS OF WORK: The treated patients were children of all age groups hospitalized in the Pediatric Clinic of Prishtina during year 2009. The study was done retrospectively. The diagnosis was done on the basis of heteroanamnesis and in several cases on the basis of the anamnesis data of a child, routine laboratory tests and toxicologic analysis. RESULTS: 66 (9.4%) poisoned children were treated in the Intensive Care Unit. The biggest number of patients, 37 (56.06%) of them, were male, and out of that number 36 (54.55%) cases were coming from rural areas. The biggest number of them 49 (74.98%) were over 2-6 years old. The poisoning was mostly caused through the digestive tract (ingestion), it happened with 55 cases (83.33%), 56 cases (84,80%) suffered from severe poisoning, whereas 59 cases (89,50%) suffered from accidental poisoning. Regarding the type of the substances that caused poisoning, the most frequent were drugs in 34 (51.50%) cases and pesticides in 20 (30.30%) cases. Among drugs, the most dominant were those belonging to a group of benzodiazepines (10 cases) and metoclopramide (4 cases). Among pesticides the most dominant one that caused poisoning was malation (5 cases), then paration and cipermetrina appeared in 3 cases each. The biggest number of cases, 64 (96.96%) of them, were treated, whereas 2 cases (3.40%) passed away. CONCLUSION: The practice proved that that our people are not well informed about the poisoning in general, therefore it is necessary that they be educated by the use of all media, written and electronic, as well as other methods of medical education. PMID- 23678313 TI - Pleiotropic and Lipid-lowering Effects of Statins in Hypertension. AB - BACKGROUND: Data on the lowering effects of statins in hypertensive patients have been mixed and highly controversial. Some studies shows reductions effects of statins in blood pressure, whereas others do not. The evidence in the literature on the effects of statins on blood pressure raises the possibility that statins may directly lower blood pressure in addition to reduce cholesterol levels pleiotropic effects of statins. AIM OF THE STUDY: The role of statins as additional treatment in patients with severe hypertension and advanced aortic atherosclerotic plaques. Methods. We enrolled 62 patients. Study has been approved by Committee of Ethics and patients signed a Term of Free Informed Consent. All patients were studied with transoesophageal echocardiography at baseline and 12 months after enrolment. Inclusion criteria were severe hypertension and presence of aortic atherosclerotic plaques. Patients have been divided into two groups; group A (treated with antihypertenives and statins) and group B (treated, just with antihypertensives). RESULTS: Twenty patients, of totally 38, from group A (20/38 or 52.6%) had significantly plaque reduction. One patient of totally 24 (1/24 or 4.1% ) from group B had significantly atherosclerotic plaque reduction. Difference of plaques reduction between two groups was highly significant. Regarding blood pressure levels, statins users had significantly reduction on systolic and diastolic blood pressure compared to statins nonusers. CONCLUSION: Hypertensive patients with presence of AA plaques treated with antihypertensives and statins have more BP reduction compared will hypertensive patients treated with antihypertensives alone. PMID- 23678314 TI - Obesity as a risk factor for artherial hypertension. AB - INTRODUCTION: Today's lifestyle is characterized by increased intake of calories with reduced physical activity, which benefits a real epidemic of obesity in the population. The increase in the prevalence of hypertension in the population follows a significant increase in the prevalence of obesity. Parallel to the trend of increasing the number of older population with increased cardiovascular disease. THE AIM: The aim of our study was to determine the value of body mass index and determine the correlation of obesity and arterial hypertension. MATERIAL AND METHODS: The study was conducted in family medicine Clinic of the Primary Health Care Center Zenica. Out of 600 patients of both sexes aged over 18 years, randomly are formed groups of 188 patients with hypertension and 189 patients without hypertension of the same gender and same age. The study included patients with primary or essential hypertension, and excluded patients with secondary hypertension, hypertension due to renal disease, pheochromocytoma, coarctation of the aorta, as a result of taking oral contraceptives, corticosteroids, and cocaine. We used the method of anthropometric measurements (body weight, body height from which is calculated the body mass index) measurement of blood pressure with the statistical data processing at the significance level of p <0.05. RESULTS AND DISCUSSION: The increased value of BMI in the sample with hypertension are present in much higher percentage (87.23%), compared to the tested sample without hypertension (60.10%). In patients with hypertension, the highest percentage (51.06%) of the respondents has the BMI in range between 25 and 30, then BMI in the range between 30 and 35 (25%). BMI of 35 40 have 6.38% of patients, and 3.72 patients BMI over 40. In patients without hypertension was significantly smaller percentage of respondents in the previous group (39.15%) with a BMI in the range 25-30, then BMI in the range between 30 and 35 (18.51%). BMI of 35-40 had 3.17% of respondents, and 1.05% of patients had BMI over 40. Correlation between groups of patients with and without hypertension compared to the value of BMI indicate the presence of strong positive correlation (Rho = 0.737). Correlation between groups of subjects with hypertension and without hypertension compared to triglycerides was statistically significant (Rho = 0.123). PMID- 23678315 TI - Total fats, saturated Fatty acids, processed foods and acute coronary syndrome in transitional Albania. AB - BACKGROUND: We aimed was to assess the association of acute coronary syndrome (ACS) with selected food groups pertinent to non-Mediterranean prototype in Albania, a transitional post-communist country in Southeast Europe. METHODS: We conducted a case-control study in Tirana in 2003-2006 including 467 non-fatal consecutive ACS patients (370 men aged 59.1+/-8.7 years, 97 women aged 63.3+/-7.1 years; 88% response) and a population-based control group (469 men aged 53.1+/ 10.4 years, 268 women aged 54.0+/-10.9 years; 69% response). A semi-quantitative food frequency questionnaire including 105 food items was administered to all participants based on which the daily calorie intake for selected food groups (meat products, overall oils and fats, sweets, and junk food) was calculated. General linear model was used to assess the association of food groups with ACS. RESULTS: Mean age-adjusted values of meat products, overall oils and fats, sweets and junk food were all considerably higher in cases than controls in both sexes. Cases had significantly higher mean "non-Mediterranean" diet scores (consisting of junk food, sweets, oils and fats except olive oil) than controls (10.3% vs. 5.9% in men and 15.2% vs. 8.3% in women, P<0.01 for both). CONCLUSIONS: In this Albanian population, intake of total fats, in particular saturated fatty acids was associated with a higher risk of ACS in both sexes. Furthermore, the consumption of processed foods was associated with considerable excess coronary risk which points to serious health implications for the Albanian adult population. PMID- 23678317 TI - Comparisons of health care systems in the United States, Germany and Canada. AB - THE PURPOSE OF THIS RESEARCH PAPER IS TO COMPARE HEALTH CARE SYSTEMS IN THREE HIGHLY ADVANCED INDUSTRIALIZED COUNTRIES: The United States of America, Canada and Germany. The first part of the research paper will focus on the description of health care systems in the above-mentioned countries while the second part will analyze, evaluate and compare the three systems regarding equity and efficiency. Finally, an overview of recent changes and proposed future reforms in these countries will be provided as well. We start by providing a general description and comparison of the structure of health care systems in Canada, Germany and the United States. PMID- 23678316 TI - Asthma and Chronic Obstructive Pulmonary Disease (COPD) - Differences and Similarities. AB - Bronchial asthma and COPD (chronic obstructive pulmonary disease) are obstructive pulmonary diseases that affected millions of people all over the world. Asthma is a serious global health problem with an estimated 300 million affected individuals. COPD is one of the major causes of chronic morbidity and mortality and one of the major public health problems worldwide. COPD is the fourth leading cause of death in the world and further increases in its prevalence and mortality can be predicted. Although asthma and COPD have many similarities, they also have many differences. They are two different diseases with differences in etiology, symptoms, type of airway inflammation, inflammatory cells, mediators, consequences of inflammation, response to therapy, course. Some similarities in airway inflammation in severe asthma and COPD and good response to combined therapy in both of these diseases suggest that they have some similar patophysiologic characteristics. The aim of this article is to show similarities and differences between these two diseases. Today asthma and COPD are not fully curable, not identified enough and not treated enough and the therapy is still developing. But in future better understanding of pathology, adequate identifying and treatment, may be and new drugs, will provide a much better quality of life, reduced morbidity and mortality of these patients. PMID- 23678318 TI - Wrist instability after injury. AB - Fractures of the bones that make the wrist joint together with injury to the ligaments and joint capsules are frequent traumas. It can cause besides limited movement also the pathological mobility. These mild injuries often do not provide the degree of recognizable symptoms and signs. They are diagnosed by X-ray imaging, stress images. Before arthrography was an important method, but nowadays arthroscopy has the advantage. Fresh bone and ligament injuries can be and should be repaired in the early posttraumatic period. Unrecognized and undiagnosed injuries are leading to instability of the wrist, to motion abnormalities or impingement overload syndrome. In the treatment of instability important place have reconstruction of the ligaments and arthrodesis of the wrist. PMID- 23678320 TI - Why Has COPE Developed Guidelines for Cooperation Between Journals and Research Institutions? PMID- 23678319 TI - Corrosive poisonings in adults. AB - Ingestion of corrosive substances may cause severe to serious injuries of the upper gastrointestinal tract and the poisoning can even result in death. Acute corrosive intoxications pose a major problem in clinical toxicology since the most commonly affected population are the young with psychic disorders, suicidal intent and alcohol addiction. The golden standard for determination of the grade and extent of the lesion is esophagogastroduodenoscopy performed in the first 12 24 hours following corrosive ingestion. The most common late complications are esophageal stenosis, gastric stenosis of the antrum and pyloris, and rarely carcinoma of the upper gastrointestinal tract. Treatment of the acute corrosive intoxications include: neutralization of corrosive agents, antibiotics, anti secretory therapy, nutritional support, collagen synthesis inhibitors, esophageal dilation and stent placement, and surgery. PMID- 23678321 TI - Study of formulation of mild pharmaceutical forms of paracetamol in medical practice. AB - INTRODUCTION: Paracetamol is one of the most used antipyretic- analgesic preparation, which can be found in different pharmaceutical forms and in different doses. Due to its wide utilization in the clinical practice, determination of paracetamol in pharmaceutical formulation is of a great importance since that over dosage with paracetamol may cause the hepatic fulminant necroses and other toxic effects. MATERIAL AND METHODS: Study has included two formulations of paracetamol suppositories with doses of 125 mg widely used in the paediatric practice. Suppositories prepared according to these two formulations by the melting method and spilling into forms was subject to the quality control by implementing a series of trials and analyses for that aim, such are: reactions of identification, average mass, disintegration time, and homogeneity whilst quantitative determination was performed by applying two methods of instrumental analyze: spectrophotometry in UV zone and cromatography in liquid phase with high pressure. RESULTS AND DISCUSSION: Results of these analyses, performed immediately following the preparation and 3 months after the preparation, showed that content of paracetamol in both of two formulations is within the norms of Pharmacopoeia. Suppositories of paracetamol in doses of 125 mg prepared as per formulation 1 are to be considered as more appropriate because it contains semi synthetic glycerides as excipient which has better features than other suppository excipients. PMID- 23678322 TI - Way of life as emphasizing factors in the progression of idiophatic scoliosis in adolescence era. AB - INTRODUCTION: Idiopathic scoliosis is a significant health problem which occurs in 2%-4% school kids in adolescent age. Reasons of occurrence are not quite clear, there are many theories, but probably it is multifactor disease. Among the theories that are mentioned some of them included environmental and behavioral factors. AIM: Research the impact of some environmental and behavioral factor on development and progression of idiopathic scoliosis in school kids. METHODOLOGY: Research was conducted on 421 pupil in adolescent age, where 120 pupils was from urban schools and 301 pupil from rural schools. Environmental factors and habits like the bigger osteomuscular structure mobility at kids from rural schools, longer outdoor time spending, different nutrition, alcoholism and smoking, different obligations, etc. factors which can be cause of scoliosis development. RESULTS: In this research we assumed that different environmental and behavioral factors of school kids, which exist in rural and urban areas, can develop to different expression of scoliosis in these areas. In our research we proved that the scoliosis occurrence is more often in urban areas than in rural (Fisher's exact test P<0.001). CONCLUSION: It is necessary to research all factors of lifestyle individually, which are different between the urban and rural kids. PMID- 23678323 TI - The frequency of depression and the comorbidity of psychotic disorders at day hospital of psychiatric clinic, clinical center of sarajevo university. AB - INTRODUCTION: Numerous epidemiological international studies as well as knowledge based on clinical experience show high prevalence and the importance of the psychiatric comorbidity with depressive and anxiety disorders. GOAL: The aim of this study is to analyze prevalence of comorbid anxiety disorders and depression in subjects at the Day Hospital of the Psychiatric Clinic, Clinical Center of Sarajevo University (CCUS) and examine the demographic profile of the patients. MATERIAL AND METHODS: Study involved 230 randomly selected patients (aged between 18 and 65 years, N=230, who were hospitalized at the Day Hospital of the Psychiatric Clinic of Clinical center of University of Sarajevo from January 1(st) to December 31(st) 2011) and who were interviewed by the Structural Clinical Interview (SCID) which generated ICD-X diagnoses and assessment of the comorbidity. Depressive symptoms were assessed by Beck's Depression Inventory with 28 items. Anxiety symptoms were assessed with Beck's Anxiety Inventory scale with 21 items. Study is retrospective, clinical and epidemiological. RESULTS: Of the total number of patients (230) it was determined that 107 (46.5%) have depressive episode; 71 (30.9%) anxiety disorder. Comorbidity of these two disorders was found in 14 (6.1%) cases. Anxiety disorders were more represented in women (61.2%), as well as depressive disorders and comorbidity (70.1% and 85.7%). Subjects with depression on average was 52.9+/-7.4 years old (range 29-64 years), patients with anxious disorders 50+/-9.5 years (range 22-65 years) while patients with comorbidity of these two entities was at mean age of 54.5+/-4.5 years. The least common category of education was retired persons and respondents with university education for all three entities. Hospitalization duration for depression, anxiety, and comorbidity of these two disorders is highest for depression (47.1+/-9.7 days) and shortest in case of comorbidity (45.9+/-6.9 days). CONCLUSION: Depression and anxiety often coexist. When they occur in comorbidity, both anxiety and depression appear to be more severe. Severely depressed and anxious patients have reduced capacity to work and as such represents a considerable burden to the family and the community. Overview of depression, anxiety and the comorbidity of these two diagnoses (listed as primary diagnosis) in the baseline sample showed that there was most patients with depression (107 or 46.5%), followed by anxiety (71 or 30.9%) and comorbidity with 14 patients or 6.1%. Effective assessment, evaluation, diagnosis and treatment can lead to better treatment outcomes in primary care and improved quality of life. PMID- 23678324 TI - Incidence and Resistotyping Profiles of Bacillus subtilis Isolated from Azadi Teaching Hospital in Duhok City, Iraq. AB - BACKGROUND: Bacillus subtilis are opportunistic, spore forming bacteria, common soil inhabitants. A resistant spore allows bacteria to endure extreme conditions of heat and desiccation in the environments promotes their survival in many instances, even in environments like hospitals. OBJECTIVES: This paper purposes to find out the incidence of Bacillus subtilis from various sources at Azadi Teaching Hospital in Duhok city, Iraq. The susceptibility test and resistotyping (antibiotypes) profile of isolates were also studied. METHODS: During a period of eight months between Januarys to April, 2011, a total of 128 samples were collected from various sources and locations at Azadi Teaching Hospital in Duhok city. A sterile cotton swabs were used to collect the samples and analyzed by plating on Blood agar, Chocolate agar and MacConkey agar followed by the identification of the isolates based on their cultural characteristics and their reactions in standard biochemical tests. All the isolates were tested for antimicrobial susceptibility by the disk diffusion technique according to the Clinical and Laboratory Standards Institute guidelines on Muller Hinton Agar. RESULTS: Out of the 128 collected samples, 84 samples yielded bacterial growth, of them 31(24.2%) were Bacillus subtilis . Moreover, other bacterial groups were also isolated and identified. The results showed that the occurrence of Bacillus subtilis was higher than the other groups of bacteria. The susceptibility test of Bacillus subtilis isolates; the organism exhibited high susceptibility rate to gentamicin (96.7%) and ciprofloxacin (93.5%) While, cefotaxime (19.3%) and ampicillin (16.2%) demonstrated the lowest percentage of susceptibility rate. Resistotyping (antibiotypes) profiles of Bacillus subtilis isolates were determined. Out of 31 isolates, 22 of them were multiple resistant and belonged to 3 resistotype patterns; resistotype 1 was predominant among isolates. CONCLUSION: This study shows that there is an increased rate of incidence of Bacillus subtilis in hospital environments in study area and some of these isolates were multi-drug resistant and showed different resistotyping profiles. PMID- 23678325 TI - The effect of physical activity on cognition - physiological mechanisms. AB - The presumption that physical activity, i.e. exercise, as an independent and separated factor influences different aspects of cognitive mechanisms is substantially supported by the literature. The investigations of the influence of physical activity on cognitive functioning have offered several mechanisms which could explain this relationship. Physiological mechanisms including increased cerebral blood flow, changes in neurotransmitter release, structural changes in central nervous system and altered arousal levels are based on physical changes that occur in the body as a consequence of the physical activity. There is evidence that physical training selectively increases angiogenesis, synaptogenesis and neurogenesis. The role of central (BDNF) and peripheral (estrogens, corticosteroids, growth hormone, IGF-1) factors in mediation of the effects of physical exercise on brain functions, has been promoted. Also, there is convergent data on molecular and cellular level, as well as on behavioral and systemic level which support the presumption that physical activity is beneficial to cognition. These data emphasizes the importance of promotion of physical activity during the life span for the prevention of contemporary (obesity, diabetes and cardiovascular) diseases and cognitive decline in humans. PMID- 23678326 TI - The Importance of HbA1c Control in Patients with Subclinical Hypothyroidism. AB - GOAL: To investigate the correlation between TSH and HbA1c in the treatment of L thyroxine in the process of glycemic control in patients with subclinical hypothyroidism. PATIENTS AND METHODS: The sample consisted of 100 patients, mean age 51.75+/-3.23 years, BMI=27.97+/-4.52 kg/m(2), with SH (TSH>4.2 mU/L and normal serum T3 and T4). Laboratory diagnosis included the determination of free T3, free T4, thyroid antibodies, Tg, insulin, C-peptide and glucose during the OGTT, HbA1c, CRP and lipid levels. 20 patients with SH had prediabetes and 38 patients had DM. All patients were treated with low doses of L-thyroxine (25 50ug) and all were physically active. RESULTS: After 6 months of treatment with L thyroxine, the patients had normal or decreased TSH (5.85+/-0.92 vs. 3.54+/-0.55 mU/L), insulin levels (114.64+/-24.11 vs. 96.44+/-17.26 pmol/L) significantly reduced HbA1c (6.74+/-1.01 vs. 6.26+/-1.12) is reduced. CONCLUSION: The correlation between TSH and HbA1c was positive and significant (r=0.46). This indicates a significant effect of treatment with L-thyroxine on glycemic control in patients with subclinical hypothyroidism. PMID- 23678327 TI - Rate and time trend of perinatal, infant, maternal mortality, natality and natural population growth in kosovo. AB - AIM: THE AIM OF WORK HAS BEEN THE PRESENTATION OF THE RATE AND TIME TRENDS OF SOME INDICATORS OF THE HEATH CONDITION OF MOTHERS AND CHILDREN IN KOSOVO: fetal mortality, early neonatal mortality, perinatal mortality, infant mortality, natality, natural growth of population etc. The treated patients were the newborn and infants in the post neonatal period, women during their pregnancy and those 42 days before and after the delivery. METHODS: THE DATA WERE TAKEN FROM: register of the patients treated in the Pediatric Clinic of Prishtina, World Health Organization, Mother and Child Health Care, Reproductive Health Care, Ministry of Health of the Republic of Kosovo, Statistical Department of Kosovo, the National Institute of Public Health and several academic texts in the field of pediatrics. Some indicators were analyzed in a period between year 1945-2010 and 1950-2010, whereas some others were analyzed in a time period between year 2000 and 2011. RESULTS: The perinatal mortality rate in 2000 was 29.10/00, whereas in 2011 it was 18.70/00. The fetal mortality rate was 14.50/00 during the year 2000, whereas in 2011 it was 11.00/00, in 2000 the early neonatal mortality was 14.80/00, in 2011 it was 7.50/00. The infant mortality in Kosovo was 1640/00 in 1950, whereas in 2010 it was 20.50/00. The most frequent causes of infant mortality have been: lower respiratory tract infections, acute infective diarrhea, perinatal causes, congenital malformations and unclassified conditions. Maternal death rate varied during this time period. Maternal death in 2000 was 23 whereas in 2010 only two cases were reported. Regarding the natality, in 1950 it reached 46.1 0/00, whereas in 2010 it reached 140/00, natural growth of population rate in Kosovo was 29.10/00 in 1950, whereas in 2011 it was 11.00/00. CONCLUSION: Perinatal mortality rate in Kosovo is still high in comparison with other European countries (Turkey and Kyrgyzstan have the highest perinatal mortality rate), even though it is in a continuous decrease. Infant mortality considerably decreased (from 1640/00 in 1950 to 20.50/00 in 2010). The causes of infant mortality have still been tightly related with the causes of the developing countries. Next to this, natality and the natural population growth have experienced a considerably decrease in Kosovo. Even though there have been some improvements within the health care in Kosovo, there is still a lot to be done with the aim of constant improvement of health care in order to promote the health care for mothers and children. PMID- 23678328 TI - Early and correct diagnosis of celiac disease in the prevention of growth disorders and child development. AB - Coeliac, in ordinary people known as "flour allergy" and in medicine world known as gluten enteropathy which means enteric damage caused by gluten. Data about incidence of gluten enteropathy is different in different countries around the World and depend on is it or is it not the right diagnosis for enteric disorder. Sometimes, this disease is unrecognized because of unspecific clinical signs. This disease is happening in every moment of a lifetime, most common during the childhood when the children try to eat any food which contains gluten. Anyway, if children had no symptoms it doesn'tct mean that disease not exists, and thatcis because we have to do diagnostic tests to confirm gluten enteropathy. Gluten intolerance is chronic disease and demand use of the specific non gluten food during the lifetime. Early diagnosis is right way to prevent unregularly growth. Aim of this study was to show the influence of early diagnostic about growth. For each patient we had a permission of parents and we showed our original results for three month we investigated. PMID- 23678329 TI - Fat embolism among patients with hip and long bone fractures in Albania. AB - OBJECTIVE: The aim of this study was to assess the incidence and the effectiveness of treatment of fat embolism in patients with hip and long bone fractures (femur and tibia) in Albania. METHODS: 229 patients (68% men) with combined hip and long bone fractures (femur and tibia) hospitalized at the Orthopedics-Traumatology Services of the University Center "Mother Teresa" during 2004-2006 were included in the study. Patients were classified into three groups based on astrupogram data: PaO2<60mmHg, 65mmHg75mmHg. Chi square test was used to compare fracture differences between men and women and the effectiveness of combined use of metilprednisolon and anticoagulants vs. anticoagulants alone. RESULTS: Poly traumas combined with femur fracture were more frequent in 2005. These combined poly traumas combined were more frequent among men than women (P<0.001). Remarkably, femur fractures were more frequent among men than women (9:1). Coli femur fractures peaked in the age-group 76-85 years. In general, poly traumas were less frequent in the older age groups, with a peak between 36-55 years, being more frequent among men, but the difference was not statistically significant. Fractures of coli femur and those of tibia were more frequent in 2006, while in 2004 femur fractures were more frequent. In almost all age groups fractures of coli femur were more frequent, followed by fractures of femur and tibia. In general, poly traumas were more frequent among men than women, ranging from 6:1 for fractures of femur to 2:1 for tibia fractures. The incidence of fat embolism ranged from 4.9% to 8.9% for the period 2004-2006. Among fat embolism patients, 100% of them had tachycardia, 88.2% had petechia, 84% tachipnea, 23.5% cyanosis and blood sputum, and 41.2% obnubilation. In general, during 2004-2006 the frequency of combined use of metilprednisolon and anticoagulants has increased. CONCLUSIONS: Clinical diagnosis remains the most important element for the detection of fat embolism syndrome. The incidence of fat embolism was 8-9 times higher than the rates reported in literature. This finding is linked with trauma gravity in Albania. Combined use of metilprednisolon with anticoagulants seems to be more effective than use of anticoagulants alone in preventing fat embolism (P<0.05) and patients using the combined therapy have experienced milder forms of disease. Therefore, the combined treatment should be preferred over the single treatment for the prevention of fat embolism. PMID- 23678330 TI - Inadequacy the health system in serbia and corrupt institutions. AB - Rapid changes in the health system require a new trained professionals who fully understand the processes of health and organizational problems and have the knowledge and skills that enable them to manage health care services. Health services to their largely rests on a system of solidarity and "socialism", and only partly on market principle, and more than in other sectors of the economy requires individuals who are able to bridge that gap. Realize savings in the system that one side is not profitable, on the other hand is able to swallow a huge media arts is that simply needs to learn-just relying on common sense and intuition that no longer helps. The increase in costs. Advances in medicine and technology, and discovery of new drugs, namely, the almost daily increase the costs of diagnosis and treatment. Advances in medicine prolongs life expectancy by increasing the number of patients, especially those with chronic diseases, the biggest consumer of drugs and frequent guests hospital. PMID- 23678331 TI - Smoking and periodontal disease. AB - Periodontitis is a group of inflammatory diseases affecting the supporting tissues of the tooth (periodontium). The periodontium consists of four tissues : gingiva, alveolar bone and periodontal ligaments. Tobbaco use is one of the modifiable risk factors and has enormous influance on the development, progres and tretmen results of periodontal disease. The relationship between smoking and periodontal health was investigated as early as the miiddle of last century. Smoking is an independent risk factor for the initiation, extent and severity of periodontal disease. Additionally, smoking can lower the chances for successful tretment. Tretmans in patients with periodontal disease must be focused on understanding the relationship between genetic and environmental factors. Only with individual approach we can identify our pacients risks and achieve better results. PMID- 23678332 TI - Materia Socio Medica is Indexed in Pubmed and Archived in PubMed Central. AB - Materia Socio Medica Journal has been accepted for archiving in PubMed Central from 2011. The journal started in 1993 as offi cial journal of Social Medicine Association of B&H. During last 3 years Mat Soc Med has included in almost all femous on-line databases (except WoS). All issues of Mat Soc Med published in 2012 are now visible on PubMed/PubMed Central. PMID- 23678333 TI - Association between maternal nutritional status of pre pregnancy, gestational weight gain and preterm birth. AB - INTRODUCTION: Maternal nutritional status of pre pregnancy and gestational weight gain affects the preterm birth. The association between maternal nutritional status of pre pregnancy and preterm birth appears to be complex and varied by studies from different countries, thus this association between the gestational weight gain and preterm birth is more consolidated. OBJECTIVE: The study aims to determine any association between the pre pregnancy maternal nutritional status, gestational weight gain and the preterm birth rate in the Albanian context. METHOD AND MATERIALS: In case control study, we analyzed women who have delivered in obstetric institutions in Tirana during the year 2012. Body mass index and gestational weight gain of 150 women who had a preterm delivery were compared with those of 150 matched control women who had a normal delivery regarding the gestation age. The self-reported pre pregnancy weight, height, gestational weight gain, age, education and parity are collected through a structured questioner. The body mass index and gestational weight gain are categorized based on the Institute of Medicine recommendation. The multiple logistic regression is used to measure the association between the nutritional status of pre pregnancy and gestational weight gain and the preterm birth rate. RESULTS: The women which have a underweight status or obese of pre pregnancy are more likely to have a preterm birth compared to the women of a normal pre-pregnancy nutritional status (respectively OR =2.7 and 4.3 p<0.05). Women who do not reach the recommended gestational weight gain are more likely to have a preterm birth compared to the women which reach this weight (OR=1.8 p< 0.05). DISCUSSION: Maternal nutritional status and gestational weight gain affects the risk for preterm birth. Pre pregnancy and gestation nutritional assessments should be part of routine prenatal visits. PMID- 23678334 TI - Socio-demographic, Clinical and Laboratory Features of Rotavirus Gastroenteritis in Children Treated in Pediatric Clinic. AB - AIM: The aim of work was presentation of several socio-demographic, clinical and laboratory characteristics of gastroenteritis caused by rotavirus. THE EXAMINEES AND METHODS: The examinees were children under the age of five years treated at the Pediatric Clinic due to acute gastroenteritis caused by rotavirus. Rotavirus is isolated by method chromatographic immunoassay by Cer Test Biotec. RESULTS: From the total number of patients (850) suffering from acute gastroenteritis, feces test on bacteria, viruses. protozoa and fungi was positive in 425 (49.76%) cases. From this number the test on bacteria was positive in 248 (58.62%) cases, on viruses it was positive in 165 (39.0%), on protozoa in 9 (2.12%) cases and on fungi only one case. Rotavirus was the most frequent one in viral test, it was isolated in 142 (86.06%) cases, adenoviruses were found in 9 (5.45%) cases and noroviruses in only one case. The same feces sample that contained rotavirus and adenoviruses were isolated in five cases, whereas rotavirus with bacteria was isolated in the same feces sample in five cases. The biggest number of cases 62 (43.66%) were of the age 6-12 months, whereas the smallest number 10 (7.04%) cases were of the age 37-60 months. There were 76 (53.52%) of cases of male gender, from rural areas there were 81 (57.04%) cases and there were 58 (40.80%) cases during the summer period. Among the clinical symptoms the most prominent were diarrhea, vomiting, high temperature, whereas the different degree of dehydration were present in all cases (the most common one was moderate dehydration). The most frequent one was isonatremic dehydration in 91 (64.08%) cases, less frequent one was hypernatremic dehydration in 14 (9.85%) cases. The majority of cases (97.89%) had lower blood pH values, whereas 67 (47.17%) cases had pH values that varied from 7.16 -7.20 (curve peak), normal values were registered in only 3 (2.11%) cases. Urea values were increased in 45 (31.07%) cases (the maximum value was 26.5 mmol/L), whereas creatinine value was increased in 41 (28.87%) cases (maximum value was 302 mmol/L). CONCLUSION: The results show the high frequency of rotavirus infections in children hospitalized with acute gastroenteritis. Rotavirus may cause different dehydration degree with electrolyte, acid-base and other biochemical disorders. Preventing the infection caused by rotavirus is of a great importance. PMID- 23678335 TI - Incidence, prevalence and clinical manifestations of systemic sclerosis in dukagjini plain. AB - INTRODUCTION: Progressive systemic sclerosis (PSS) is an inflammatory disease of connective tissue, with onset as edema that continues with fibrosis, induration, and skin atrophy, followed by attacks on the joints, internal organs, and secondary proliferation of connective tissue. PURPOSE: To research in which residence locations and among which group age is the most frequent incidence, prevalence and clinical manifestations of systemic sclerosis in Dukagjini Plain which is inhabited by 698450 resident citizens. MATERIAL AND METHODS: 51 patients with progressive systemic sclerosis were studied, out them 44 were females (86.3%) and 7 males (13.7%) respectively, during the period from 2005 to 2010. Their illness was active from 18 to 60 months in accordance with EUSTAR criteria. They are of different age, median age is 44.2 +/-10.1. Their diagnose is determined based on revised ACR criteria. Prevalence of patients with PSS was 14.61/100.000, while the incidence was 2.8/100.000, whereas CI (Confidence interval) or limit of accuracy was 95%. RESULTS: Largest number of patients per 100.000 citizens has Istog municipality which has the largest number of patients with PSS. It is followed by Mamusha and Rahovec municipalities. The largest examined group age is 35-44 year old, 41.2% respectively. CONCLUSION: Additional studies are necessary to carry out in order to find the reasons of asymmetrical distribution of patients with systemic sclerosis in the municipalities of Dukagjini Plain. PMID- 23678336 TI - Puerperal sepsis in a rural hospital in Sudan. AB - BACKGROUND: Increasingly, women in rural areas in Sudan reported to hospital with puerperal infections. AIMS: This study was design to identify the common pathogens causing puerperal infections and their susceptibility to current antibiotics. SUBJECTS AND METHODS: We prospectively studied 170 women from January, 2011 through January 2012 attended Hussein Mustafa Hospital for Obstetrics and Gynecology at Gadarif State, Sudan. We included patients if they met the criteria proposed by the WHO for definition of maternal sepsis. Blood was collected on existing infection guidelines for clean practice and equipments. RESULTS: Out of the 170 samples, 124 (72.9%) were pathogen-positive samples. Out the 124 positive cases, aerobes were the predominant isolates 77 (62.1 %%) which included Staph.aureus 49 (39.5%), Staph. epidemics 7 (5.6%) and Listeria monocytogenes 21 (16.9%). The anaerobes isolates were Clostridium perfringens 34 (27.4 %) and Entrobactor cloacae 13 (10.5%). Standard biochemical test were for bacterial isolation. Higher rate of infections followed vaginal delivery compared to Cesarean section 121 (97.6%), 3 (2.5%) respectively. All strains of Staph were sensitive to Vancomycin, Gentamicin and Ceftriaxone. C. perfringens were sensitive to Ceftriaxone, Penicillins, Vancomycin and Metronidazole, while E. cloacae were sensitive to Gentamicin and Ceftriaxone. CONCLUSION: Despite the limited resources in the developing countries, treatment based on cultures remains the only solution to reduce maternal morbidity and mortality rates following puerperal infections. PMID- 23678337 TI - The marketing mix and development of medical tourism in shiraz. AB - INTRODUCTION: In recent years, medical tourism market has been raised as one of the income-earning and competitive industries in the world and is considered as a modern field of advanced tourism. Therefore, a great number of countries are seeking to develop this type of tourism and one of the strategies for developing this industry is using the marketing mix elements. METHODS: This study was a descriptive-analytic and cross sectional one. The research community included all the public and private hospitals of Shiraz among which, 7 public and 9 private hospitals were studied. The study data were collected through a researcher-made check list whose face and content validity was confirmed by the experts. Then, the data were entered into the SPSS statistical software. According to the objectives of the study, the descriptive results were presented in frequency tables and Chi-square test was used for data analysis. In addition, P<0.05 was considered as statistically significant. RESULTS: According to the results, both public and private hospitals of Shiraz were in the best condition regarding staff and physician mix and in the worst condition concerning promoting and facilities mixes. No significant difference was found between public and private hospitals regarding the mixes. CONCLUSION: From marketing mix elements view, paying more attention to media advertisements and providing more facilities can improve the status of the hospitals which, consequently, results in attracting more medical tourists and developing this industry in Shiraz. PMID- 23678338 TI - Evaluation of outsourcing in nursing services: a case study of kashani hospital, isfahan in 2011. AB - BACKGROUND: Hospitals need to focus on their core activities, thus outsourcing of services may be effective in some instances. However, monitoring and supervision is a vital mechanism to preserving and enhancing the quality of outsourced services, and to identify the benefits and losses occurred. The purpose of this study is evaluation of nursing services outsourced in a general hospital from different point of views. METHODS: This is a descriptive and applied study done by case study (before and after) method. Outsourcing nursing services of clinical wards (ENT and Neurosurgery) of Kashani Hospital in 2011 has been studied. We extracted data from a handmade questionnaire about internal customer's satisfaction and semi-structured interviews with officials, and also survey of financial and administrative documents and records related to the topic. RESULTS: The findings indicate an increased number of graduated nurses per bed to fulfill the main objective of outsourcing in this case. But achieving this objective is accompanied with remarkable increased costs per bed after outsourcing. Besides, we noticed minor changes in internal customer satisfaction rate. CONCLUSION: While outsourcing should bring about staff and patients' satisfaction and increase the efficiency and effectiveness, outsourcing nursing workforce singly, leaded to a loss of efficiency. Therefore, the applied outsourcing has not met the productivity for the hospital. PMID- 23678339 TI - Cultural Intelligence and Social Adaptability: A Comparison between Iranian and Non-Iranian Dormitory Students of Isfahan University of Medical Sciences. AB - INTRODUCTION: At the modern age, to acquire knowledge and experience, the individuals with their own specific culture have to enter contexts with cultural diversity, adapt to different cultures and have social interactions to be able to have effective inter-cultural relationships.To have such intercultural associations and satisfy individual needs in the society, cultural intelligence and social adaptability are deemed as inevitable requirements, in particular for those who enter a quite different culture. Hence, the present study tries to compare the cultural intelligence and its aspects and social adaptability in Iranian and non-Iranian dormitory students of Isfahan University of Medical Sciences in 2012. METHODOLOGY: The study was of descriptiveanalytical nature. The research population consisted of Iranian and non-Iranian students resided in the dormitories of Isfahan University of Medical Sciences which are 2500, totally. For Iranian students, two-stage sampling method was adopted. At the first stage, classified sampling and at the second stage, systematic random sampling was conducted. In this way, 441 students were selected. To form non-Iranian students' sample, consensus sampling method was applied and a sample of 37 students were obtained. The research data was collected by using Earley & Ang's Cultural Intelligence Questionnaire with the Cronbach's coefficient alpha of 76% and California Social Adaptability Standard Questionnaire with the Cronbach's coefficient alpha of over 70%. Then, the data were put into SPSS software to be analyzed. Finally, the results were presented by descriptive and inferential statistics methods. RESULTS: The study findings revealed that there was no statistically significant difference between cultural intelligence and cognitive aspect of cultural intelligence in Iranian and non-Iranian students (P>=0/05). However, Iranian and non-Iranian students statistically differed in terms of the following aspects of cultural intelligence: meta-cognitive aspect (61.8% for Iranian students vs. 47.6% for non-Iranians), motivational aspect (59.0% vs. 42.6%), behavioral aspect (31.8% vs. 41.2%) as well as social adaptability as the other variable in question ( 68.9% vs. 56.2%) (p<0.001). CONCLUSION: The comparison of the mean scores gained for meta-cognitive and motivational aspects of cultural intelligence as well as social adaptability in Iranian and non Iranian students resided in the dormitories of Isfahan University of Medical Sciences revealed that the Iranian students had the higher rank. On the other hand, the mean score acquired for the behavioral aspect in Iranian and non Iranian students were comparable, with non-Iranian students having the higher mean scores. Therefore, it can be said that the meta-cognitive and motivational aspects of cultural intelligence and social adaptability of non-Iranian students and the behavioral aspect of Iranian students' cultural intelligence may be promoted by educational planning, thereby, taking effective steps towards their achievement in contexts with inter-cultural interaction . In this way, their mental health will be enhanced, as well. PMID- 23678340 TI - Incineration or autoclave? A comparative study in isfahan hospitals waste management system (2010). AB - INTRODUCTION: Medical wastes are among hazardous wastes and their disposal requires special methods prior to landfilling. Medical wastes are divided into infected and non-infected wastes and the infected wastes require treatment. Incineration is one of the oldest methods for treatment of medical wastes, but their usage have faced wide objections due to emission of hazardous gases such as CO2 and CO as well as Carcinogenic gases such as Dioxins and Furans which are generated as a result of incomplete combustion of compositions like PVCs. Autoclave is one the newest methods of medical wastes treatment which works based on wet disinfection. METHODS: The statistical population in this descriptive, comparative study includes hospitals located in Isfahan city and the sample hospitals were selected randomly. To environmentally evaluate the Autoclave method, TST (time, steam, temperature) and Spore tests were used. Also, samples were made from incinerator's stack gases and their analyses results were compared with WHO standards. FINDINGS: TST and spore tests results were negative in all cases indicating the success of treatment process. The comparison of incinerator's stack gases with WHO standards showed the high concentration of CO in some samples indicating the incomplete combustion. Also, the incineration efficiency in some cases was less than 99.5 percent, which is the efficiency criterion according to the administrative regulations of wastes management law of Iran. No needle stick was observed in Autoclave method during the compaction of bags containing wastes, and the handlers were facing no danger in this respect. The comparison of costs indicated that despite higher capital investment for purchasing autoclave, its current costs (e.g. maintenance, etc) are much less than the incineration method. DISCUSSION: Totally, due to inappropriate operation of incinerators and lack of air pollution control devices, the use of incinerators doesn't seem rational anymore. Yet, despite the inefficiency of autoclaves in treatment of bulky wastes such as Anatomical wastes, their usage seems logic considering the very low amounts of such wastes. Also, considering the amount of generated wastes in Isfahan hospitals, a combination of centralized and non-centralized autoclaves is recommended for treatment of infected wastes. Mobile autoclaves may also be considered according to technical and economical conditions. It must not be forgotten that the priority must be given to the establishment of waste management systems particularly to personnel training to produce less wastes and to well separate them. PMID- 23678341 TI - NMRbot: Python scripts enable high-throughput data collection on current Bruker BioSpin NMR spectrometers. AB - To facilitate the high-throughput acquisition of nuclear magnetic resonance (NMR) experimental data on large sets of samples, we have developed a simple and straightforward automated methodology that capitalizes on recent advances in Bruker BioSpin NMR spectrometer hardware and software. Given the daunting challenge for non-NMR experts to collect quality spectra, our goal was to increase user accessibility, provide customized functionality, and improve the consistency and reliability of resultant data. This methodology, NMRbot, is encoded in a set of scripts written in the Python programming language accessible within the Bruker BioSpin TopSpinTM software. NMRbot improves automated data acquisition and offers novel tools for use in optimizing experimental parameters on the fly. This automated procedure has been successfully implemented for investigations in metabolomics, small-molecule library profiling, and protein ligand titrations on four Bruker BioSpin NMR spectrometers at the National Magnetic Resonance Facility at Madison. The investigators reported benefits from ease of setup, improved spectral quality, convenient customizations, and overall time savings. PMID- 23678343 TI - Changes of phenolic secondary metabolite profiles in the reaction of narrow leaf lupin (Lupinus angustifolius) plants to infections with Colletotrichum lupini fungus or treatment with its toxin. AB - Plant interactions with environmental factors cause changes in the metabolism and regulation of biochemical and physiological processes. Plant defense against pathogenic microorganisms depends on an innate immunity system that is activated as a result of infection. There are two mechanisms of triggering this system: basal immunity activated as a result of a perception of microbe-associated molecular patterns through pattern recognition receptors situated on the cell surface and effector-triggered immunity (ETI). An induced biosynthesis of bioactive secondary metabolites, in particular phytoalexins, is one of the mechanisms of plant defense to fungal infection. Results of the study on narrow leaf lupin (Lupinus angustifolius L.) plants infected with the anthracnose fungus Colletotrichum lupini and treated with fungal phytotoxic metabolites are described in the paper. The C. lupini phytotoxins were isolated from liquid cultures, purified and partially characterized with physicochemical methods. Accumulation of secondary metabolites on leaf surface and within the tissues of plants either infected, treated with the fungal phytotoxin or submitted to both treatments was studied using GC-MS and LC-MS, respectively. Substantial differences in isoflavone aglycones and glycoconjugate profiles occurred in response to different ways of plant treatment. PMID- 23678342 TI - Granger causality in integrated GC-MS and LC-MS metabolomics data reveals the interface of primary and secondary metabolism. AB - Metabolomics has emerged as a key technique of modern life sciences in recent years. Two major techniques for metabolomics in the last 10 years are gas chromatography coupled to mass spectrometry (GC-MS) and liquid chromatography coupled to mass spectrometry (LC-MS). Each platform has a specific performance detecting subsets of metabolites. GC-MS in combination with derivatisation has a preference for small polar metabolites covering primary metabolism. In contrast, reversed phase LC-MS covers large hydrophobic metabolites predominant in secondary metabolism. Here, we present an integrative metabolomics platform providing a mean to reveal the interaction of primary and secondary metabolism in plants and other organisms. The strategy combines GC-MS and LC-MS analysis of the same sample, a novel alignment tool MetMAX and a statistical toolbox COVAIN for data integration and linkage of Granger Causality with metabolic modelling. For metabolic modelling we have implemented the combined GC-LC-MS metabolomics data covariance matrix and a stoichiometric matrix of the underlying biochemical reaction network. The changes in biochemical regulation are expressed as differential Jacobian matrices. Applying the Granger causality, a subset of secondary metabolites was detected with significant correlations to primary metabolites such as sugars and amino acids. These metabolic subsets were compiled into a stoichiometric matrix N. Using N the inverse calculation of a differential Jacobian J from metabolomics data was possible. Key points of regulation at the interface of primary and secondary metabolism were identified. PMID- 23678344 TI - Phytochemical composition of Potentilla anserina L. analyzed by an integrative GC MS and LC-MS metabolomics platform. AB - Potentilla anserina L. (Rosaceae) is known for its beneficial effects of prevention of pre-menstrual syndrome (PMS). For this reason P. anserina is processed into many food supplements and pharmaceutical preparations. Here we analyzed hydroalcoholic reference extracts and compared them with various extracts of different pharmacies using an integrative metabolomics platform comprising GC-MS and LC-MS analysis and software toolboxes for data alignment (MetMAX Beta 1.0) and multivariate statistical analysis (COVAIN 1.0). Multivariate statistics of the integrated GC-MS and LC-MS data showed strong differences between the different plant extract formulations. Different groups of compounds such as chlorogenic acid, kaempferol 3-O-rutinoside, acacetin 7-O rutinoside, and genistein were reported for the first time in this species. The typical fragmentation pathway of the isoflavone genistein confirmed the identification of this active compound that was present with different abundances in all the extracts analyzed. As a result we have revealed that different extraction procedures from different vendors produce different chemical compositions, e.g. different genistein concentrations. Consequently, the treatment may have different effects. The integrative metabolomics platform provides the highest resolution of the phytochemical composition and a mean to define subtle differences in plant extract formulations. PMID- 23678345 TI - Pancreatic carcinoma, pancreatitis, and healthy controls: metabolite models in a three-class diagnostic dilemma. AB - Metabolomics as one of the most rapidly growing technologies in the "-omics" field denotes the comprehensive analysis of low molecular-weight compounds and their pathways. Cancer-specific alterations of the metabolome can be detected by high-throughput mass-spectrometric metabolite profiling and serve as a considerable source of new markers for the early differentiation of malignant diseases as well as their distinction from benign states. However, a comprehensive framework for the statistical evaluation of marker panels in a multi-class setting has not yet been established. We collected serum samples of 40 pancreatic carcinoma patients, 40 controls, and 23 pancreatitis patients according to standard protocols and generated amino acid profiles by routine mass spectrometry. In an intrinsic three-class bioinformatic approach we compared these profiles, evaluated their selectivity and computed multi-marker panels combined with the conventional tumor marker CA 19-9. Additionally, we tested for non-inferiority and superiority to determine the diagnostic surplus value of our multi-metabolite marker panels. Compared to CA 19-9 alone, the combined amino acid-based metabolite panel had a superior selectivity for the discrimination of healthy controls, pancreatitis, and pancreatic carcinoma patients [Formula: see text] We combined highly standardized samples, a three-class study design, a high throughput mass-spectrometric technique, and a comprehensive bioinformatic framework to identify metabolite panels selective for all three groups in a single approach. Our results suggest that metabolomic profiling necessitates appropriate evaluation strategies and-despite all its current limitations-can deliver marker panels with high selectivity even in multi-class settings. PMID- 23678346 TI - Increased unsaturation of lipids in cytoplasmic lipid droplets in DAOY cancer cells in response to cisplatin treatment. AB - Increases in 1H nuclear magnetic resonance spectroscopy (NMR) visible lipids are a well-documented sign of treatment response in cancers. Lipids in cytoplasmic lipid droplets (LDs) are the main contributors to the NMR lipid signals. Two human primitive neuroectodermal tumour cell lines with different sensitivities to cisplatin treatment were studied. Increases in NMR visible saturated and unsaturated lipids in cisplatin treated DAOY cells were associated with the accumulation of LDs prior to DNA fragmentation due to apoptosis. An increase in unsaturated fatty acids (UFAs) was detected in isolated LDs from DAOY cells, in contrast to a slight decrease in UFAs in lipid extracts from whole cells. Oleic acid and linoleic acid were identified as the accumulating UFAs in LDs by heteronuclear single quantum coherence spectroscopy (HSQC). 1H NMR lipids in non responding PFSK-1 cells were unchanged by exposure to 10 MUM cisplatin. These findings support the potential of NMR detectable UFAs to serve as a non-invasive marker of tumour cell response to treatment. PMID- 23678347 TI - Long-acting Injectable Antipsychotics in First-episode Schizophrenia. AB - Antipsychotic medications are important for the successful management of schizophrenia. Continuous treatment with medication is superior in relapse prevention and non-adherence to antipsychotic medication is associated with a poor clinical outcome. Long-acting injectable antipsychotics (LAIs) that can guarantee adherence to a treatment regimen could be a useful treatment option. With the introduction of second-generation atypical antipsychotics-long acting injection (SGA-LAI), the risks for extrapyramidal adverse events are decreased. The indications for SGA-LAI have been extended from chronic, stabilized patients to acute psychotic patients. Some studies investigated the use of LAI in first episode schizophrenia patients and raised the possibility of prescribing LAI as a treatment option. However, there is still limited research using LAI in first episode schizophrenia. More well-designed, randomized, controlled clinical trials using SGA-LAIs in first episode schizophrenia are needed. Additionally, studies on side effects of SGA-LAI in long-term use are required prior to recommending LAI for patients with first episode schizophrenia. PMID- 23678348 TI - Phentermine, sibutramine and affective disorders. AB - A safe and effective way to control weight in patients with affective disorders is needed, and phentermine is a possible candidate. We performed a PubMed search of articles pertaining to phentermine, sibutramine, and affective disorders. We compared the studies of phentermine with those of sibutramine. The search yielded a small number of reports. Reports concerning phentermine and affective disorders reported that i) its potency in the central nervous system may be comparatively low, and ii) it may induce depression in some patients. We were unable to find more studies on the subject; thus, it is unclear presently whether phentermine use is safe in affective disorder patients. Reports regarding the association of sibutramine and affective disorders were slightly more abundant. A recent study that suggested that sibutramine may have deleterious effects in patients with a psychiatric history may provide a clue for future phentermine research. Three explanations are possible concerning the association between phentermine and affective disorders: i) phentermine, like sibutramine, may have a depression inducing effect that affects a specific subgroup of patients, ii) phentermine may have a dose-dependent depression-inducing effect, or iii) phentermine may simply not be associated with depression. Large-scale studies with affective disorder patients focusing on these questions are needed to clarify this matter before investigation of its efficacy may be carried out and it can be used in patients with affective disorders. PMID- 23678349 TI - No Association between the Response to Methylphenidate and DRD4 Gene Polymorphism in Korean Attention Deficit Hyperactivity Disorder: A Case Control Study. AB - OBJECTIVE: Recently the relationship between alleles frequency distribution, drug response and the attention deficit hyperactivity disorder (ADHD), has been actively researched. We investigated the association between the genetic type, alleles and drug response for the dopamine receptor D4 (DRD4) gene in ADHD patients in Korea. METHODS: One hundred fourteen patients diagnosed with ADHD according to the the Diagnostic and Statistical Manual of Mental Disorders version IV (DSM-IV) diagnostic criteria were selected for the study. The clinical features of patients were confirmed by Korean version of Conners' parent rating scale, Attention deficit Diagnostic System, Korean version of Spielberger state trait anxiety scale. Blood samples were taken from the 198 subjects. DNA was extracted from blood lymphocytes, PCR was performed for DRD4 Polymorphism. Alleles, genotype frequencies, the Clinical Global Impression (CGI) improvement score were compared using the chi-square test. Korean ADHD Rating Scale (K-ARS) and CGI severity scores were compared using the t-test. RESULTS: In comparing the ADHD with 4/4 repeats group and without the ADHD with 4/4 repeats group, no significant difference was seen between the DRD4 genetic type, alleles distribution, and CGI drug response. CONCLUSION: As a result, it is viewed that there is no relationship between ADHD and DRD4, but final decision is indefinite. Follow up studies with larger patient or pure subgroups are expected. PMID- 23678350 TI - Factor structure of the targeted inventory on problems in schizophrenia. AB - OBJECTIVE: The aim of this study was to explore the factor structure of a novel, 10-item rating scale, the Targeted Inventory on Problems in Schizophrenia (TIP Sz). Determining the factor structure will be useful in the brief evaluation of medication and non-medication treatment of the disease. METHODS: An exploratory factor analysis was performed on TIP-Sz scores obtained from 100 patients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for schizophrenia. RESULTS: THE FACTOR ANALYSIS EXTRACTED FOUR FACTORS THAT WERE DEEMED CLINICALLY PERTINENT, WHICH WE LABELED: disorganization, social cooperativeness, functional capacity, and emotional state. The items exhibited cross-loadings on the first three factors (i.e., some items loaded on more than one factor). In particular, the 'behavioral dyscontrol and disorganization,' 'insight and reality testing,' and 'overall prognostic impression' items had comparable cross-loadings on all of the first three factors. The emotional state factor was distinct from the other factors in that the items loading on it did not cross-load on other factors. CONCLUSION: The TIP-Sz scale comprises factors that are associated with the psychosocial functioning and emotional state of patients, which are important outcome parameters for successful treatment of the disease. PMID- 23678351 TI - A Longitudinal Study of Relation between Side-effects and Clinical Improvement in Schizophrenia: Is There a Neuro-metabolic Threshold for Second Generation Antipsychotics? AB - OBJECTIVE: Classical studies demonstrated Neuroleptic Induced Extrapyramidal Side effects (NIES; Neuroleptic threshold) to correlate with the efficacy of first generation antipsychotics. Second generation antipsychotics (SGAs), in addition to the extrapyramidal side effects, are also associated with metabolic side effects. This prospective study on antipsychotic-naive schizophrenia patients, for the first-time, examined concurrently the relationship between clinical improvement and these side-effects NIES and Neuroleptic Induced Metabolic Side effects. METHODS: Thirty six-antipsychotic-naive schizophrenia (DSM-IV) patients were examined at baseline and after 5 weeks of treatment with antipsychotics. At baseline and follow-up, we recorded the body mass index (BMI) and assessed psychopathology using Scale for Assessment of Positive-symptoms (SAPS) and Scale for Assessment of Negative-symptoms (SANS), extrapyramidal symptoms using Simpson Angus Extra Pyramidal Scale (SAEPS) and improvement using Clinical Global Impression Improvement (CGI). RESULTS: After treatment, patients showed significant reduction in SAPS (baseline, 27.97+/-14.47; follow-up, 14.63+/-13.25; p<0.001) and SANS total scores (baseline, 63.77+/-28.96; follow-up, 49.30+/ 28.77; p=0.001) and a significant increase in BMI (baseline, 18.5+/-3.37; follow up, 19.13+/-3.17; p<0.001). At follow-up CGI-Improvement score was (2.55+/-0.65) and SAEPS score was (0.8+/-1.32). CGI-Improvement score had a significant negative correlation with magnitude of increase in BMI (rs=-0.39; p=0.01) and SAEPS symptom score at follow-up (rs=-0.58; p<0.001). In addition, magnitude of increase in BMI showed positive correlation with the magnitude of reduction in SAPS total score (rs=0.33; p=0.04). CONCLUSION: The study findings suggest a possible relation between clinical improvement and antipsychotic-induced neuroleptic as well as metabolic side-effects in schizophrenia. Though the mechanism of this relation is yet to be elucidated, insulin signaling pathways and lipid homeostasis are potential mechanisms in addition to the established neurotransmitter hypothesis. Theoretically findings support the novel hypothetical construct of 'Neuro-Metabolic threshold' in the treatment of schizophrenia. PMID- 23678352 TI - Pharmacokinetics and Safety of Duloxetine Enteric-coated Tablets in Chinese Healthy Volunteers: A Randomized, Open-label, Single- and Multiple-dose Study. AB - OBJECTIVE: Duloxetine hydrochloride is a selective serotonin (5 hydroxytryptamine) and norepinephrine reuptake inhibitor. It is approved for effective treatment for major depressive disorder. The pharmacokinetics (PK) of duloxetine has been studied, but few pharmacokinetics properties in Chinese subjects are available. This study explored the dose proportionality and determined duloxetine levels in human plasma by comparing the PK properties after administration of single or multiple doses in healthy volunteers. METHODS: Thirty six subjects were divided randomly into three groups and received a single dose of 15, 30, or 60 mg duloxetine. Those who received 30 mg continued on to the multiple-dose phase and received 30 mg daily for 7 days. Liquid chromatography/mass spectroscopy was applied to determine concentrations. The PK properties were calculated and included maximum plasma concentration (Cmax), time when maximum plasma concentration was reached (Tmax), time when half-maximum plasma concentration was reached (t1/2), area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC0-t), mean concentration levels (AUC0-infinity), and apparent total clearance of the drug from plasma after oral administration (CL/F). RESULTS: The standard calibration curve was linear in the concentration range 0.11-112 ng/ml (r>0.992). Linear PK properties were found at doses of 15-60 mg. The Cmax and AUC were proportional to dose, but the Tmax and t1/2 did not increase with increasing dose. CONCLUSION: No significant differences in the PK parameters were found among the three groups during the single-dose phase. The AUC and Cmax were greater in the multiple-dose phase, indicating duloxetine accumulation following multiple-dose administration. PMID- 23678353 TI - Follow-up Study on Electroconvulsive Therapy in Treatment-resistant Depressed Patients after Remission: A Chart Review. AB - OBJECTIVE: Electroconvulsive therapy (ECT) has proven to be effective in treatment-resistant depression (TRD). In recent reports, 70% to 90% of patients with TRD responded to ECT. However, post-ECT relapse is a significant problem. There are no studies investigating risk factors associated with reintroducing ECT in depressive patients after remission previously achieved with former ECT. The aim of the present study is to examine such risk factors using a sample of TRD patients. METHODS: We conducted a chart review to examine patient outcomes and adverse events over short- and long-term periods. Forty-two patients met the criteria for major depressive disorder. RESULTS: The response rate was 85.7% (36/42). There were no significant differences in the baseline characteristics of patients exhibiting remission, response or non-response. The rate of adverse events was 21.4% (9/42). Among 34 patients who were available for follow-up, 18 patients relapsed (relapse rate, 52.9%), and 6 patients were reintroduced to ECT. The patients' age and age of onset were significantly higher in the re-ECT group than non re-ECT group. CONCLUSION: Our results suggest that older age and older age of onset might be considered for requirement of re-ECT after remission previously achieved with former ECT. PMID- 23678354 TI - Prolonged Delirium Secondary to Hypoxic-ischemic Encephalopathy Following Cardiac Arrest. AB - Hypoxic-ischemic brain injury encompasses a complex constellation of pathophysiological and cellular brain injury induced by hypoxia, ischemia, cytotoxicity, or combinations of these mechanisms and can result in poor outcomes including significant changes in personality and cognitive impairments in memory, cognition, and attention. We report a case of a male patient with normal premorbid functioning who developed prolonged delirium following hypoxic-ischemic brain insults subsequent to cardiac arrest. The case highlights the importance of adopting a multidisciplinary treatment approach involving the coordinated care of medical and nursing teams to optimise management of patients suffering from such a debilitating organic brain syndrome. PMID- 23678355 TI - Potential role of the sigma-1 receptor chaperone in the beneficial effects of donepezil in dementia with lewy bodies. PMID- 23678356 TI - Diffuse alveolar hemorrhage. AB - Diffuse alveolar hemorrhage (DAH) is a life-threatening and medical emergency that can be caused by numerous disorders and presents with hemoptysis, anemia, and diffuse alveolar infiltrates. Early bronchoscopy with bronchoalveolar lavage is usually required to confirm the diagnosis and rule out infection. Most cases of DAH are caused by capillaritis associated with systemic autoimmune diseases such as anti-neutrophil cytoplasmic antibody-associated vasculitis, anti glomerular basement membrane disease, and systemic lupus erythematosus, but DAH may also result from coagulation disorders, drugs, inhaled toxins, or transplantation. The diagnosis of DAH relies on clinical suspicion combined with laboratory, radiologic, and pathologic findings. Early recognition is crucial, because prompt diagnosis and treatment is necessary for survival. Corticosteroids and immunosuppressive agents remain the gold standard. In patients with DAH, biopsy of involved sites can help to identify the cause and to direct therapy. This article aims to provide a general review of the causes and clinical presentation of DAH and to recommend a diagnostic approach and a management plan for the most common causes. PMID- 23678357 TI - Incidence and risk factors of contrast-induced nephropathy after bronchial arteriography or bronchial artery embolization. AB - BACKGROUND: In uncontrolled hemoptysis patient, bronchial arteriography and bronchial artery embolization (BAE) is a important procedure in diagnosis and treatment. The aim of this study is to assess the incidence of contrast-induced nephropathy and the risk factors of contrast-induced nephropathy (CIN) after bronchial arteriography and BAE. METHODS: We retrospectively reviewed the medical records of the patients who underwent bronchial arteriography and BAE in two university hospitals from January 2003 to December 2011. CIN was defined as rise of serum creatinine more than 25% of baseline value or 0.5 mg/dL at between 48 hours and 96 hours after bronchial arteriography and BAE. We excluded patients who already had severe renal insufficiency (serum creatinine>=4.0) or had been receiving dialysis. RESULTS: Of the total 100 screened patients, 88 patients met the enrollment criteria. CIN developed in 7 patients (8.0%). The mean duration between the exposure and development of CIN was 2.35+/-0.81 days. By using multivariate analysis, serum albumin level was found to be significantly associated with the development of CIN (p=0.0219). CONCLUSION: These findings suggest that the incidence of CIN was higher than expected and patients with hypoalbuminemia should be monitored more carefully to prevent the development of CIN after bronchial arteriography and BAE. PMID- 23678358 TI - Endobronchial metastases from extrathoracic malignancies: recent 10 years' experience in a single university hospital. AB - BACKGROUND: Although the lung is a common site of metastasis, endobronchial metastases (EBM) from extrathoracic malignancies are rare. Previous studies were retrospective reviews of the cases from each single institute, and the last one was performed between 1992 and 2002. We evaluated the characteristics of patients with EBM who had been diagnosed in recent 10 years in our hospital. METHODS: We retrospectively reviewed 1,275 patients who had undergone diagnostic bronchoscopic procedures between 2001 and 2011. An EBM was defined as bronchoscopically notable lesion, which was histopathologically identical to the primary tumor. RESULTS: A total of 18 cases of EBM were identified. The mean age was 53 years, and 12 cases of the 18 patients were female. The most common primary malignancies were colorectal cancer and breast cancer (4 cases each), followed by cervix cancer (3 cases) and renal cell carcinoma (2 cases). Cough was the most common symptom. The most common radiologic finding was atelectasis, which was identified in 27.7% of the cases. The median interval from the diagnosis of primary malignancy to the diagnosis of EBM was 14 months (range, 0 112 months). The median survival time from the diagnosis of EBM was 10 months (range, 1-39 months). CONCLUSION: EBM from extrathoracic malignancies were rare. Colorectal cancer and breast cancer were common as primary malignancies. Fiberoptic bronchoscopy should be performed in all patients, who are suspected of having EBM. If atypical clinical and pathological features are present, appropriate diagnostic studies should be undertaken. PMID- 23678359 TI - Bronchogenic cyst rupture and pneumonia after endobronchial ultrasound-guided transbronchial needle aspiration: a case report. AB - We report a 54-year-old woman who presented with a well-defined, homogeneous, and non-enhancing mass in the retrobronchial region of the bronchus intermedius. The patient underwent endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for histological confirmation. Serous fluid was aspirated by EBUS-TBNA. Cytological examination identified an acellular smear with negative microbiological cultures. The patient was finally diagnosed with bronchogenic cysts by chest computed tomography (CT) and EBUS-TBNA findings. However, 1 week after EBUS-TBNA, the patient developed bronchogenic cyst rupture and pneumonia. Empirical antibiotics were administered, and pneumonia from the bronchogenic cyst rupture had resolved on follow-up chest CT. To our knowledge, this is the first reported case of pneumonia from bronchogenic cyst rupture after EBUS-TBNA. PMID- 23678360 TI - A case of synchronous presentation of primary non-small cell lung carcinoma and pheochromocytoma. AB - We report a rare synchronous presentation of primary lung cancer and adrenal pheochromocytoma. A 59-year-old woman was diagnosed with right upper lobe non small cell lung carcinoma measuring 2.8 cm and a right adrenal gland mass measuring 3.5 cm, which displayed increased metabolic activity on (18)F fluorodeoxyglucose positron emission tomography-computed tomography. The adrenal lesion was revealed to be asymptomatic. The patient underwent right adrenalectomy and histological examination revealed a pheochromocytoma. Ten days later, right upper lobectomy was performed for lung cancer. This case indicates that incidental adrenal lesions found in cases of resectable primary lung cancer should be investigated. PMID- 23678361 TI - Nontuberculous Mycobacterial Lung Disease Caused by Mycobacterium lentiflavum in a Patient with Bronchiectasis. AB - We report a rare case of lung disease caused by Mycobacterium lentiflavum in a previously healthy woman. A 54-year-old woman was referred to our hospital due to chronic cough and sputum. A computed tomography scan of the chest revealed bilateral bronchiectasis with bronchiolitis in the right middle lobe and the lingular division of the left upper lobe. Nontuberculous mycobacteria were isolated twice from three expectorated sputum specimens. All isolates were identified as M. lentiflavum by multilocus sequence analysis based on rpoB, hsp65, and 16S rRNA fragments. To the best of our knowledge, this is the first documented case of M. lentiflavum lung disease in an immunocompetent adult in Korea. PMID- 23678362 TI - Nontuberculous Mycobacterial Lung Disease Caused by Mycobacterium chelonae: A Case Report. AB - Mycobacterium chelonae lung disease is very rare. We report a case of lung disease caused by M. chelonae in a previously healthy woman. A 69-year-old woman was referred to our hospital because of hemoptysis. A computed tomography (CT) scan of the chest revealed bronchiolitis associated with bronchiectasis in the lingular division of the left upper lobe. Nontuberculous mycobacteria were isolated three times from sputum specimens. All isolates were identified as M. chelonae by various molecular methods that characterized rpoB and hsp65 gene sequences. Although some new lesions including bronchiolitis in the superior segment of the left lower lobe developed on the chest CT scan 35 months after diagnosis, she has been followed up without antibiotic therapy because of her mild symptoms. To the best of our knowledge, this is the first case of M. chelonae lung disease in Korea in which the etiologic organisms were confirmed using molecular techniques. PMID- 23678364 TI - Promise of endothelial progenitor cell for treatment of diabetic retinopathy. AB - Progressive obliteration of the retinal microvessels is a characteristic of diabetic retinopathy. The resultant retinal ischemia leads to sight-threatening neovascularization and macular edema. Bone marrow-derived endothelial progenitor cells play a critical role in vascular maintenance and repair and forms the basis of cellular therapy for revascularization of ischemic myocardium and ischemic limbs. Emerging studies show potential of these cells in revascularization of ischemic retina and this review summarizes this possibility. We also report current pharmacological options to correct diabetes-associated defects in endothelial progenitor cells for their therapeutic transfer. PMID- 23678365 TI - Venus and Mars or Down to Earth: Stereotypes and Realities of Gender Differences. AB - Psychological scientists, like lay people, often think in categorical dichotomies that contrast men and women and exaggerate the differences between groups. These value-laden divides tend to privilege one side over the other, often to the advantage of the scientists' own identity group. Besides balancing perspectives in the academic marketplace of ideas, scientists can recognize the complexity of stigma. Gender, like many categories, entails two fundamental dimensions that characterize intergroup stigma (and all interpersonal perception): perceived warmth and competence. These dimensions identify groups viewed with ambivalence (e.g., traditional women are stereotypically warm but incompetent, whereas professional women are allegedly competent but cold). In gender and in other areas, psychological scientists can go beyond value-laden dichotomies and consider the fundamental, continuous dimensions along which we think about stigma. PMID- 23678367 TI - Effects of age and symptomatology on cortical thickness in autism spectrum disorders. AB - Several brain regions show structural and functional abnormalities in individuals with autism spectrum disorders (ASD), but the developmental trajectory of abnormalities in these structures and how they may relate to social and communicative impairments are still unclear. We assessed the effects of age on cortical thickness in individuals with ASD, between the ages of 7 and 39 years in comparison to typically developing controls. Additionally, we examined differences in cortical thickness in relation to symptomatology in the ASD group, and their association with age. Analyses were conducted using a general linear model, controlling for sex. Social and communication scores from the Autism Diagnostic Interview-Revised (ADI-R) were correlated with the thickness of regions implicated in those functions. Controls showed widespread cortical thinning relative to the ASD group. Within regions-of-interest, increased thickness in the rostral anterior cingulate cortex was associated with poorer social scores. Additionally, a significant interaction between age and social impairment was found in the orbitofrontal cortex, with more impaired younger children having decreased thickness in this region. These results suggest that differential neurodevelopmental trajectories are present in individuals with ASD and some differences are associated with diagnostic behaviours. PMID- 23678366 TI - Role of cellular iron and oxygen in the regulation of HIV-1 infection. AB - Despite efficient antiretroviral therapy, eradication of HIV-1 infection is challenging and requires novel biological insights and therapeutic strategies. Among other physiological and environmental factors, intracellular iron greatly affects HIV-1 replication. Higher iron stores were shown to be associated with faster progression of HIV-1 infection and to inversely correlate with the survival of HIV-1 infected patients. Iron is required for several steps in the HIV-1 life cycle, including reverse transcription, HIV-1 gene expression and capsid assembly. Here, the authors present a comprehensive review of the molecular mechanisms involved in iron- and oxygen-mediated regulation of HIV-1 replication. We also propose key intracellular pathways that may be involved in regulating HIV-1 replication, via protein kinase complexes, CDK9/cyclin T1 and CDK 2/cyclin E, protein phosphatase-1 and other host factors. PMID- 23678368 TI - Plasma cell-free DNA in paediatric lymphomas. AB - BACKGROUND: Extracellular circulating DNA (cfDNA) can be found in small amounts in plasma of healthy individuals. Increased levels of cfDNA have been reported in patients with cancer of breast, cervix, colon, liver and it was shown that cfDNA can originate from both tumour and non-tumour cells. OBJECTIVES: Levels of cfDNA of a large series of children with lymphoma were evaluated and analyzed in relation with clinical characteristics. METHODS: plasma cfDNA levels obtained at diagnosis in 201 paediatric lymphoma patients [43 Hodgkin lymphomas (HL), 45 anaplastic large cell lymphomas (ALCL), 88 Burkitt lymphomas (BL), 17 lymphoblastic (LBL), 8 diffuse large B cell lymphoma (DLBCL)] and 15 healthy individuals were determined using a quantitative PCR assay for POLR2 gene and, in addition, for NPM-ALK fusion gene in ALCL patients. Wilcoxon rank sum test was used to compare plasma levels among different patient subgroups and controls and to analyze relationship between levels of cfDNA and clinical characteristics. RESULTS: Levels of cfDNA in lymphoma patients were significantly higher compared with controls (p<0.0001). CfDNA was associated with median age (p=0.01) in HL, and with stage in ALCL (p=0.01). In HL patients high cfDNA levels were correlated with poor prognosis (p=0.03). In ALCL we found that most of the cfDNA (77%) was non-tumor DNA. CONCLUSION: level of plasma cfDNA might constitute an important non-invasive tool at diagnosis in lymphoma patients' management; in particular in patients with HL, cfDNA seems to be a promising prognostic biomarker. PMID- 23678369 TI - Modeling efficacy of bevacizumab treatment for metastatic colon cancer. AB - PURPOSE: Bevacizumab, an FDA-approved adjuvant treatment for metastatic colon cancer, has extended survival for many patients. However, factors predicting response to treatment remain undefined. PATIENTS AND METHODS: Relevant clinical and environmental data were abstracted from medical records of 149 evaluable patients treated with bevacizumab for metastatic colon cancer at a multi specialty clinic. Tumor response was calculated from radiologic reports using Response Evaluation Criteria in Solid Tumors (RECIST) criteria and verified by oncologist review. Patients with at least one occurrence of complete or partial response or stable disease were classified as responders; those exhibiting progressive disease were classified as non-responders. RESULTS: Univariate analysis demonstrated that blood in stool (P<0.05), unexplained weight loss (P<0.05), primary colon cancer site (P<0.05), chemotherapy treatment of primary tumor site (P<0.05), and adenocarcinoma versus adenoma subtype (P<0.05) was associated with tumor responsiveness. Factors remaining statistically significant following multivariate modeling included adenocarcinoma as tumor cell type versus other adenocarcinoma subtypes (OR=6.35, 95% CI: 1.08-37.18), chemotherapy treatment applied to primary tumor (OR= 0.07, 95% CI: 0.0-0.76,), tumor localization to cecal/ascending colon (OR=0.061, 95% CI: 0.006-0.588,), and unexplained weight loss (OR=0.1, 95% CI: 0.02-0.56,). Chemotherapy treatment of primary tumor, unexplained weight loss, and cecal/ascending localization of the tumor were associated with poorer outcomes. Adenocarcinoma as cell type compared to other adenocarcinoma subtypes was associated with better response to bevacizumab treatment. CONCLUSION: RESULTS suggest that response to bevacizumab therapy may be predicted by modeling clinical factors including symptomology on presentation, tumor location and type, and initial response to chemotherapy. PMID- 23678370 TI - Low Grade Micropapillary Urothelial Carcinoma, Does It Exist? - Analysis of Management and Outcomes from the Surveillance, Epidemiology and End Results (SEER) Database. AB - OBJECTIVE: To elucidate the oncologic behavior of Micropapillary Urothelial Bladder Carcinoma (MPBC), a rare aggressive variant histology. METHODS: All MPBC patients in SEER 17 database were compared with those with traditional urothelial carcinoma (UC). Kaplan-Meier curves were used to determine OS and CSS. A Cox proportional hazards model (CPH) was constructed to test the effect of covariates on outcomes. RESULTS: From 2001-2008, 120 MPBC patients were identified, 0.1% of all bladder cancer. MPBC presented with more high grade (86.1% vs. 38.7%, p<0.0001) and more high stage disease (40.8% NMI vs. 90.4% NMI, p < 0.0001) than UC. Low grade (LG) NMI MPBC had worse OS and CSS compared to LG UC (p=0.0037, p<0.0001 respectively), and did no better than high grade (HG) NMI MPBC. No difference was detected between HG NMI MPBC and HG NMI UC pts. A CPH model controlling for stage, grade, treatment, age, race, and sex detected no significant survival difference in MPBC vs. UC (HR 1.04, p=0.7966). For NMI MPBC (n=49), only 4 patients underwent definitive therapy, of whom none died of disease. However, in those not receiving definitive therapy (n=45), 7 cancer specific deaths occurred (15.6%). CONCLUSION: Controlling for stage and grade, no survival difference could be detected between MPBC and UC. Low grade NMI MPBC behaved similarly to both high grade MPBC and high grade UC. We propose that all MPBC (regardless of grade) be managed as high grade disease, and that strong consideration for definitive therapy should be given in all cases. PMID- 23678371 TI - Isolation and characterization of muscle fatigue substance with anti-tumor activities. AB - Research during the 1950's indicated that exercise played a role in the reduction of tumor growth. In the 1960's our studies confirmed that tumor-bearing rats, exercised to fatigue, demonstrated tumor inhibition. Our further studies isolated an extract (Fatigue Substance, or F-Substance) from rectus femoris muscles of rats which had been electrically stimulated to fatigue. This extract significantly inhibited growth of transplanted rat tumors. Research continued until 1978 when it became apparent the methodology at that time was not able to further identify the substance's active components. Using current technology, we now report on the further isolation and characterization of F-Substance. In cell proliferation assays, extracts from electrically stimulated rat rectus femoris muscles had more significant inhibitory effect on the breast cancer cell line MCF 7 than those isolated from unstimulated muscles. To identify the molecule(s) responsible for the antitumor activity, a rat cytokine antibody array was used to profile the cytokines in the substances. Among the 29 different cytokines contained on the array, 3 showed greater than 3-fold difference between the substances isolated from the stimulated and unstimulated muscles. LIX (also known as CXCL5) is 6-fold higher in the substances isolated from stimulated muscles than those from the unstimulated muscles. TIMP-1 is 4.6 fold higher and sICAM is 3.6 fold higher in the substances from the stimulated muscles. Our results indicated that cytokines released from contracting muscles might be responsible for the antitumor effect of F-Substance. PMID- 23678372 TI - Single operator choledochoscopy and its role in daily endoscopy routine. AB - Different diagnostic procedures exist for the detection of bile duct lesions in clinical practice. However, neither retrograde contrast imaging of the bile duct endoscopic retrograde cholangiopancreatogram nor other imaging procedures allow a safe diagnosis of the lesions. Therefore choledochoscopy may be a useful diagnostic procedure in macroscopic assessing lesions of the bile duct. Even if the diagnostic sensitivity and specificity is not sufficient, first studies suggest an enhanced diagnostic accuracy for choledochoscopy. Since the progress of choledochoscopy has started in the 1970 different improvements were achieved. Meanwhile, the examination can be performed by an examiner and samples can be taken. Image and Resolution quality has improved over the past years, also. The SpyGlass system is a technically advanced cholangioscopic device to provide endoscopic diagnosis in case of inconclusive bile duct findings. Further more, two more lumina allow specific biopsy forceps and optical fibers for electrohydraulic or laser lithotripsy. The most frequent useful insert of SpyGlass in clinical practice are in complex gallstones and bile duct lesions of unclear dignity. PMID- 23678373 TI - Endoscopic papillary balloon dilation after sphincterotomy for difficult choledocholithiasis: A case-controlled study. AB - AIM: To evaluate the efficacy and safety of endoscopic sphincterotomy (EST) + endoscopic papillary large balloon dilation (EPLBD) vs isolated EST. METHODS: We conducted a retrospective single center study over two years, from February 2010 to January 2012. Patients with large (>= 10 mm), single or multiple bile duct stones (BDS), submitted to endoscopic retrograde cholangio-pancreatography (ERCP) were included. Patients in Group A underwent papillary large balloon dilation after limited sphincterotomy (EST+EPLBD), using a through-the-scope balloon catheter gradually inflated to 12-18 mm according to the size of the largest stone and the maximal diameter of the distal bile duct on the cholangiogram. Patients in Group B (control group) underwent isolated sphincterotomy. Stones were removed using a retrieval balloon catheter and/or a dormia basket. When necessary, mechanical lithotripsy was performed. Complete clearance of the bile duct was documented with a balloon catheter cholangiogram at the end of the procedure. In case of residual lithiasis, a double pigtail plastic stent was placed and a second ERCP was planned within 4-6 wk. Some patients were sent for extracorporeal lithotripsy prior to subsequent ERCP. Outcomes of EST+EPLBD (Group A) vs isolated EST (Group B) were compared regarding efficacy (complete stone clearance, number of therapeutic sessions, mechanical and/or extracorporeal lithotripsy, biliary stent placement) and safety (frequency, type and grade of complications). Statistical analysis was performed using chi(2) or Fisher's exact tests for the analysis of categorical parameters and Student's t test for continuous variables. A P-value of less than 0.05 was considered statistically significant. RESULTS: One hundred and eleven patients were included, 68 (61.3%) in Group A and 43 (38.7%) in Group B. The mean diameter of the stones was similar in the two groups (16.8 +/- 4.4 and 16.0 +/- 6.7 in Groups A and B, respectively). Forty-eight (70.6%) patients in Group A and 21 (48.8%) in Group B had multiple BDS (P = 0.005). Overall, balloon dilation was performed up to 12 mm in 10 (14.7%) patients, 13.5 mm in 17 (25.0%), 15 mm in 33 (48.6%), 16.5 mm in 2 (2.9%) and 18 mm in 6 (8.8%) patients, taking into account the diameter of the largest stone and that of the bile duct. Complete stone clearance was achieved in sixty-five (95.6%) patients in Group A vs 30 (69.8%) patients in Group B, and was attained within the first therapeutic session in 82.4% of patients in Group A vs 44.2% in Group B (P < 0.001). Patients submitted to EST+EPLBD underwent fewer therapeutic sessions (1.1 +/- 0.3 vs 1.8 +/- 1.1, P < 0.001), and fewer required mechanical (14.7% vs 37.2%, P = 0.007) or extracorporeal (0 vs 18.6%, P < 0.001) lithotripsy, as well as biliary stenting (17.6% vs 60.5%, P < 0.001). The rate of complications was not significantly different between the two groups. CONCLUSION: EST+EPLBD is a safe and effective technique for treatment of difficult BDS, leading to high rates of complete stone clearance and reducing the need for lithotripsy and biliary stenting. PMID- 23678374 TI - Small bowel polypectomy by double balloon enteroscopy: Correlation with prior capsule endoscopy. AB - AIM: To investigate the feasibility of small bowel polypectomy using double balloon enteroscopy and to evaluate the correlation with capsule endoscopy (CE). METHODS: This is a retrospective review of a single tertiary hospital. Twenty five patients treated by enteroscopy for small bowel polyps diagnosed by CE or other imaging techniques were included. The correlation between CE and enteroscopy (correlation coefficient of Kendall for the number of polyps, intra class coefficient for the size and coefficient of correlation kappa for the location) was evaluated. RESULTS: There were 31 polypectomies and 12 endoscopic mucosal resections with limited morbidity and no mortality. Histological analysis revealed 27 hamartomas, 6 adenomas and 3 lipomas. Strong agreement between CE and optical enteroscopy was observed for both location (Kappa value: 0.90) and polyp size (Kappa value: 0.76), but only moderate agreement was found for the number of polyps (Kendall value: 0.47). CONCLUSION: Double balloon enteroscopy is safe for performing polypectomy. Previous CE is useful in selecting the endoscopic approach and to predicting the difficulty of the procedure. PMID- 23678375 TI - Colonoscopy in rats: An endoscopic, histological and tomographic study. AB - AIM: To describe colon anatomy with colonoscopy and computed tomography (CT) to develop a rat model for future studies of therapeutic colonoscopy. METHODS: Eighteen male Sprague-Dawley rats, on average 400-420 g, underwent total colonoscopy, CT and histological examination. Colonoscopy was performed after bowel preparation with a baby upper gastrointestinal endoscopy with an outer diameter of 6.7 mm. CT obtained a 3D image of total colon after a rectal enema with radiological contrast. Macroscopic and microscopic examinations were examined with a conventional technique (hematoxylin and eosin). Colonic wall thickness, length and diameter measurements were taken from the anus, 3, 7, 14 and 20 cm from the anal margin. RESULTS: The median colonoscope depth was 24 cm (range 20-28 cm). Endoscopic and tomographic study of colon morphology showed an easy access with tubular morphology in the entire left colon (proximal left colon and rectum). Transverse colon was unapparent on colonoscopy. Right colon, proximal to the splenic flexure, was the largest part of the colon and assumed saccular morphology with tangential trabecula. Radiological measurements of the colonic length and diameter substantiate a subdivision of the right colon into two parts, the cecum and distal right colon. In addition, histological measurement of the colonic wall thickness confirmed a progressive decrease from rectum to cecum. The muscular layer was thinner in the proximal left colon. CONCLUSION: The combination of colonoscopy, tomography and histology leads to a better characterization of the entire colon. These data are important for deciding when to perform endoscopic resections or when to induce perforations to apply endoscopic treatments. PMID- 23678376 TI - Usefulness of applying lidocaine in esophagogastroduodenoscopy performed under sedation with propofol. AB - AIM: To determine whether topical lidocaine benefits esophagogastroduoduenoscopy (EGD) by decreasing propofol dose necessary for sedation or procedure-related complications. METHODS: The study was designed as a prospective, single centre, double blind, randomised clinical trial and was conducted in 2012 between January and May (NCT01489891). Consecutive patients undergoing EGD were randomly assigned to receive supplemental topical lidocaine (L; 50 mg in an excipient solution which was applied as a spray to the oropharynx) or placebo (P; taste excipients solution without active substance, similarly delivered) prior to the standard propofol sedation procedure. The propofol was administered as a bolus intravenous (iv) dose, with patients in the L and P groups receiving initial doses based on the patient's American Society of Anaesthesiologists (ASA) classification (ASA I II: 0.50-0.60 mg/kg; ASA III-IV: 0.25-0.35 mg/kg), followed by 10-20 mg iv dose every 30-60 s at the anaesthetist's discretion. Vital signs, anthropometric measurements, amount of propofol administered, sedation level reached, examination time, and the subjective assessments of the endoscopist's and anaesthetist's satisfaction (based upon a four point Likert scale) were recorded. All statistical tests were performed by the Stata statistical software suite (Release 11, 2009; StataCorp, LP, College Station, TX, United States). RESULTS: No significant differences were found between the groups treated with lidocaine or placebo in terms of total propofol dose (310.7 +/- 139.2 mg/kg per minute vs 280.1 +/- 87.7 mg/kg per minute, P = 0.15) or intraprocedural propofol dose (135.3 +/- 151.7 mg/kg per minute vs 122.7 +/- 96.5 mg/kg per minute, P = 0.58). Only when the L and P groups were analysed with the particular subgroups of female, < 65-year-old, and lower anaesthetic risk level (ASA I-II) was a statistically significant difference found (L: 336.5 +/- 141.2 mg/kg per minute vs P: 284.6 +/- 91.2 mg/kg per minute, P = 0.03) for greater total propofol requirements). The total incidence of complications was also similar between the two groups, with the L group showing a complication rate of 32.2% (95%CI: 21.6 45.0) and the P group showing a complication rate of 26.7% (95%CI: 17.0-39.0). In addition, the use of lidocaine had no effect on the anaesthetist's or endoscopist's satisfaction with the procedure. Thus, the endoscopist's satisfaction Likert assessments were equally distributed among the L and P groups: unsatisfactory, [L: 6.8% (95%CI: 2.2-15.5) vs P: 0% (95%CI: 0-4.8); neutral, L: 10.1% (95%CI: 4.2-19.9) vs P: 15% (95%CI: 7.6-25.7)]; satisfactory, [L: 25.4% (95%CI: 10-29.6) vs P: 18.3% (95%CI: 15.5-37.6); and very satisfactory, L: 57.6% (95%CI: 54-77.7) vs P: 66.6% (95%CI: 44.8-69.7)]. Likewise, the anaesthetist's satisfaction Likert assessments regarding the ease of maintaining a patient at an optimum sedation level without agitation or modification of the projected sedation protocol were not affected by the application of lidocaine, as evidenced by the lack of significant differences between the scores for the placebo group: unsatisfactory, L: 5.8% (95%CI: 1.3-13.2) vs P: 0% (95%CI: 0-4.8); neutral, L: 16.9% (95%CI: 8.9-28.4) vs P: 16.7% (95%CI: 8.8-27.7); satisfactory, L: 15.2% (95%CI: 7.7-26.1) vs P: 20.3% (95%CI: 11.3-31.6); and very satisfactory, L: 62.7% (95%CI: 49.9-74.3) vs P: 63.3% (95%CI: 50.6-74.7). CONCLUSION: Topical pharyngeal anaesthesia is safe in EGD but does not reduce the necessary dose of propofol or improve the anaesthetist's or endoscopist's satisfaction with the procedure. PMID- 23678377 TI - Risk of colorectal polyps in patients with sporadic gastric polyps: A case control study. AB - AIM: To assess the risk of colonic polyps, adenomas and advanced neoplastic lesions (ANL) in patients with sporadic gastric polyps, especially those with fundic gland polyps (FGP). METHODS: Clinical records of patients who had performed an upper and a lower digestive endoscopy between September 2007 and August 2008 were retrospectively analyzed. A case-control study was carried out, calling patients with gastric polyps as "cases" and patients without gastric polyps as "controls". The risk of colonic polyps, adenomas and ANL (villous component >= 25%, size >= 10 mm, or high grade dysplasia) was assessed [odds ratio (OR) and its corresponding 95%CI]. RESULTS: Two hundred and forty seven patients were analyzed: 78 with gastric polyps (cases) and 169 without gastric polyps (controls). Among the cases, the majority of gastric polyps were FGP (80%, CI: 69-88) and hyperplastic (20%, CI: 12-31); 25% had colonic polyps (25% hyperplastic and 68% adenomas, from which 45% were ANL). Among the controls, 20% had colonic polyps (31% hyperplastic and 63% adenomas, from which 41% were ANL). The patients with sporadic FGP had an OR of 1.56 (CI: 0.80-3.04) for colonic polyps, an OR of 1.78 (CI: 0.82-3.84) for colonic adenomas, and an OR of 0.80 (CI: 0.21-2.98) for ANL. Similar results were found in patients with gastric polyps in general. CONCLUSION: The results of this study did not show more risk of colorectal adenomas or ANL neither in patients with sporadic gastric polyps nor in those with FGP. PMID- 23678378 TI - Endocoil placement after endoscopic ultrasound-guided biliary drainage may prevent a bile leak. AB - AIM: To further reduce the risk of bleeding or bile leakage. METHODS: We performed endoscopic ultrasound guided biliary drainage in 6 patients in whom endoscopic retrograde cholangiopancreatography (ERCP) had failed. Biliary access of a dilated segment 2 or 3 duct was achieved from the stomach using a 19G needle. After radiologically confirming access a guide wire was placed, a transhepatic tract created using a 6 Fr cystotome followed by balloon dilation of the stricture and antegrade metallic stent placement across the malignant obstruction. This was followed by placement of an endocoil in the transhepatic tract. RESULTS: Dilated segmental ducts were observed in all patients with the linear endoscopic ultrasound scope from the proximal stomach. Transgastric biliary access was obtained using a 19G needle in all patients. Biliary drainage was achieved in all patients. Placement of an endocoil was possible in 5/6 patients. All patients responded to biliary drainage and no complications occurred. CONCLUSION: We show that placing endocoils at the time of endoscopic ultrasound guided biliary stenting is feasible and may reduce the risk of bleeding or bile leakage. PMID- 23678379 TI - Endoscopic ultrasonography in patients with elevated carbohydrate antigen 19-9 of obscure origin. AB - AIM: To evaluate the efficacy of endoscopic ultrasonography (EUS) in patients with elevated carbohydrate antigen (CA) 19-9 levels of obscure origin. METHODS: Patients who had visited Pusan National University Hospital because of elevated serum CA 19-9 levels, between January 2007 and December 2009, were retrospectively enrolled. EUS had been performed on all subjects, in addition to routine blood tests, endoscopy, abdominal computed tomography (CT) and other clinical exams, which had not revealed any abnormal findings suggestive of the origin of the elevated CA 19-9 levels. RESULTS: Of the 17 patients, gallbladder sludge was detected in 16 patients (94.1%) and common bile duct sludge was observed in 3 patients (17.6%). After the administration of ursodeoxycholic acid to 12 of the patients with gallbladder sludge, CA 19-9 levels normalized in 6 of the patients after a median of 4.5 mo. CONCLUSION: EUS is a useful diagnostic method for patients with elevated CA 19-9 levels of obscure origin, even if the reason for abnormal levels of this serum marker cannot be determined through prior examinations, including abdominal CT. PMID- 23678381 TI - Serrated adenoma of the stomach: Case report and literature review. AB - Gastric serrated adenomas are histologically characterized by protruding glands with lateral saw tooth-like indentations lined with stratified dysplastic cells containing abundant eosinophilic cytoplasm. Since the first case of gastric serrated adenoma found in 2001, 18 additional cases have been reported. Gastric serrated adenomas have a particular proclivity to progress to invasive carcinoma; 75% or 15 of the 20 cases now in record - including the present one - exhibited invasive carcinoma. The 20(th) case of gastric serrated adenoma reported here differs from the preceding ones in as much as it evolved in a patient with Lynch syndrome, implying that this adenoma phenotype may develop not only sporadically but also in patients with hereditary traits. PMID- 23678380 TI - Miniprobe EUS in management of pancreatic pseudocyst. AB - Pancreatic pseudocysts (PP) arise from trauma and pancreatitis; endoscopic gastro cyst drainage (EGCD) under endoscopic ultrasonography (EUS) in symptomatic PP is the treatment of choice. Miniprobe EUS (MEUS) allows EGCD in children. We report our experience on MEUS-EGCD in PP, reviewing 13 patients (12 children; male:female = 9:3; mean age: 10 years, 4 mo; one 27 years, malnourished male Belardinelli-syndrome; PP: 10 post-pancreatitis, 3 post-traumatic). All patients underwent ultrasonography, computed tomography and magnetic resonance imaging. Conservative treatment was the first option. MEUS EGCD was indicated for retrogastric cysts larger than 5 cm, diameter increase, symptoms or infection. EGCD (stent and/or nasogastrocystic tube) was performed after MEUS (20-MHz miniprobe) identification of place for diathermy puncture and wire insertion. In 8 cases (61.5%), there was PP disappearance; one, surgical duodenotomy and marsupialization of retro-duodenal PP. In 4 cases (31%), there was successful MEUS-EGCD; stent removal after 3 mo. No complications and no PP relapse in 4 years of mean follow-up. MEUS EGCD represents an option for PP, allowing a safe and effective procedure. PMID- 23678382 TI - Biodegradable stent for the treatment of a colonic stricture in Crohn's disease. AB - Biodegradable polydioxanone stents were developed for the treatment of refractory benign esophageal strictures but have been suggested as a new therapeutic option for intestinal strictures. The primary advantage of biodegradable stents over self-expandable metallic stents is that removal is not required. There are, however, few data available on their use in the small or large bowel. We herein describe the case of a 33-year-old patient with long-standing Crohn's disease (CD) who developed a fibrotic stricture of the sigmoid too long to be amenable to balloon dilation. The use of a biodegradable polydioxanone stent was chosen to avoid surgery. Combined endoscopic and fluoroscopic placement of the stent was technically simple, safe and clinically successful, and no recurrence of obstructive symptoms occurred during a 16-mo follow-up. Further studies are needed to evaluate the long-term efficacy and safety of biodegradable stents in the treatment of intestinal strictures, particularly in the context of CD. PMID- 23678383 TI - Boerhaave's syndrome during bowel preparation with polyethylene glycol in a patient with postpolypectomy bleeding. AB - Boerhaave's syndrome is spontaneous rupture of the esophagus, a rare condition with high mortality that occurs most often after forceful vomiting. Polyethylene glycol (PEG) solution is the most common preparation used for colonoscopy. Since large volumes have to be ingested, PEG may induce severe vomiting or retching. However, Boerhaave's syndrome has rarely been reported as a potential problem related to PEG solution. We report a case of spontaneous esophageal rupture due to violent vomiting during bowel preparation with PEG solution in a patient with postpolypectomy bleeding. PMID- 23678384 TI - Is idiopathic recurrent pancreatitis attributed to small stones? AB - Idiopathic recurrent pancreatitis remains a clinical challenge. Intraductal ultrasonography in the management of idiopathic recurrent pancreatitis may be a new strategy for undetermined causes after initial diagnostic approaches, including endoscopic retrograde cholangio-pancreatography (ERCP). However, no definite cause after ERCP should be defined under optimal settings and with experienced technique. PMID- 23678385 TI - lambda-Meta Dynamics Approach To Compute Absolute Solvation Free Energy. AB - We present a new approach to combine lambda dynamics with meta-dynamics (named lambda-meta dynamics) to compute free energy surface with respect to lambda. Particularly, the lambda-meta dynamics method extends meta-dynamics to a single virtual variable lambda, i.e., the coupling parameter between solute and solvent, to compute absolute solvation free energy as an exemplary application. We demonstrate that lambda-meta dynamics simulations can recover the accurate potential of mean force surface with respect to lambda compared to the benchmark results from traditional lambda-dynamics with umbrella sampling. The solvation free energy results for five small organic molecules from lambda-meta dynamics simulations using the same filling scheme show that the statistical errors are within +/-0.5 kcal/mol. The new lambda-meta dynamics method is general and other variables such as order parameters to describe conformational changes can be easily combined with lambda-meta dynamics. This should allow for efficient samplings on high-dimension free energy landscapes. PMID- 23678386 TI - Compassionate ethics for clinics. PMID- 23678388 TI - Peri-implant bone length changes and survival rates of implants penetrating the sinus membrane at the posterior maxilla in patients with limited vertical bone height. AB - PURPOSE: The aim of this study was to measure the peri-implant bone length surrounding implants that penetrate the sinus membrane at the posterior maxilla and to evaluate the survival rate of these implants. METHODS: Treatment records and orthopantomographs of 39 patients were reviewed and analyzed. The patients had partial edentulism at the posterior maxilla and limited vertical bone height below the maxillary sinus. Implants were inserted into the posterior maxilla, penetrating the sinus membrane. Four months after implant insertion, provisional resin restorations were temporarily cemented to the abutments and used for one month. Then, a final impression was taken at the abutment level, and final cement retained restorations were delivered with mutually protected occlusion. The complications from the implant surgery were examined, the number of failed implants was counted, and the survival rate was calculated. The peri-implant bone lengths were measured using radiographs. The changes in initial and final peri implant bone lengths were statistically analyzed. RESULTS: Nasal bleeding occurred after implant surgery in three patients. No other complications were found. There were no failures of the investigated implants, resulting in a survival rate of 100%. Significantly more bone gain around the implants (estimated difference=-0.6 mm, P=0.025) occurred when the initial residual bone height was less than 5 mm compared to the >5 mm groups. No significant change in peri-implant bone length was detected when the initial residual bone height was 5 mm or larger. CONCLUSIONS: This study suggests that implants penetrating the sinus membrane at the posterior maxilla in patients with limited vertical bone height may be safe and functional. PMID- 23678387 TI - Occlusion for implant-supported fixed dental prostheses in partially edentulous patients: a literature review and current concepts. AB - Implant treatment has become the treatment of choice to replace missing teeth in partially edentulous areas. Dental implants present different biological and biomechanical characteristics than natural teeth. Occlusion is considered to be one of the most important factors contributing to implant success. Most literature on implant occlusal concepts is based on expert opinion, anecdotal experiences, in vitro and animal studies, and only limited clinical research. Furthermore, scientific literature regarding implant occlusion, particularly in implant-supported fixed dental prostheses remains controversial. In this study, the current status of implant occlusion was reviewed and discussed. Further randomized clinical research to investigate the correlation between implant occlusion, the implant success rate, and its risk factors is warranted to determine best clinical practices. PMID- 23678389 TI - Role of collagen membrane in lateral onlay grafting with bovine hydroxyapatite incorporated with collagen matrix in dogs. AB - PURPOSE: The objective of this study was to elucidate the role of collagen membranes (CMs) when used in conjunction with bovine hydroxyapatite particles incorporated with collagen matrix (BHC) for lateral onlay grafts in dogs. METHODS: The first, second, and third premolars in the right maxilla of mongrel dogs (n=5) were extracted. After 2 months of healing, two BHC blocks (4 mm*4 mm*5 mm) were placed on the buccal ridge, one with and one without the coverage by a CM. The animals were sacrificed after 8 weeks for histometric analysis. RESULTS: The collagen network of the membranes remained and served as a barrier. The quantity and quality of bone regeneration were all significantly greater in the membrane group than in the no-membrane group (P<0.05). CONCLUSIONS: The use of barrier membranes in lateral onlay grafts leads to superior new bone formation and bone quality compared with bone graft alone. PMID- 23678390 TI - Phototoxic effect of blue light on the planktonic and biofilm state of anaerobic periodontal pathogens. AB - PURPOSE: The purpose of this study was to compare the phototoxic effects of blue light exposure on periodontal pathogens in both planktonic and biofilm cultures. METHODS: Strains of Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum, and Porphyromonas gingivalis, in planktonic or biofilm states, were exposed to visible light at wavelengths of 400.520 nm. A quartz-tungsten-halogen lamp at a power density of 500 mW/cm(2) was used for the light source. Each sample was exposed to 15, 30, 60, 90, or 120 seconds of each bacterial strain in the planktonic or biofilm state. Confocal scanning laser microscopy (CSLM) was used to observe the distribution of live/dead bacterial cells in biofilms. After light exposure, the bacterial killing rates were calculated from colony forming unit (CFU) counts. RESULTS: CLSM images that were obtained from biofilms showed a mixture of dead and live bacterial cells extending to a depth of 30-45 um. Obvious differences in the live-to-dead bacterial cell ratio were found in P. gingivalis biofilm according to light exposure time. In the planktonic state, almost all bacteria were killed with 60 seconds of light exposure to F. nucleatum (99.1%) and with 15 seconds to P. gingivalis (100%). In the biofilm state, however, only the CFU of P. gingivalis demonstrated a decreasing tendency with increasing light exposure time, and there was a lower efficacy of phototoxicity to P. gingivalis as biofilm than in the planktonic state. CONCLUSIONS: Blue light exposure using a dental halogen curing unit is effective in reducing periodontal pathogens in the planktonic state. It is recommended that an adjunctive exogenous photosensitizer be used and that pathogens be exposed to visible light for clinical antimicrobial periodontal therapy. PMID- 23678391 TI - Effect of scaling and root planing combined with systemic doxycycline therapy on glycemic control in diabetes mellitus subjects with chronic generalized periodontitis: a clinical study. AB - PURPOSE: The purpose of study was to compare glycemic control using glycated hemoglobin levels (HbA1c) in diabetic patients with chronic generalized periodontitis (CGP) undergoing scaling and root planing (SRP) with and without systemic doxycycline. METHODS: Fifty subjects with type 2 diabetes mellitus (T2DM) and CGP receiving antidiabetic therapy were selected for study. The selected subjects were randomly assigned to two groups (test group [TG] and control group [CG]) comprising 25 patients each. The TG received SRP followed by systemic doxycycline. The CG received treatment with SRP only. The periodontal parameters were recorded at baseline (day zero), and every 1 month for 4 months and included probing depth, clinical attachment level, plaque index, gingival index, and HbA1c level were recorded at baseline (day zero) and at the end of 4 months. RESULTS: A statistically significant effect was demonstrated for the periodontal parameters for both the TG and CG. HbA1c values did not show a statistically significant difference in the treatment group as compared to the CG. CONCLUSIONS: The authors concluded that nonsurgical periodontal therapy improved glycemic control in patients with T2DM in both groups, but no statistical difference was observed with adjunctive systemic doxycycline therapy. A further study with a larger sample size is required. PMID- 23678392 TI - The expression of a nitric oxide derivative, tissue inhibitors of metalloproteinase-3, and tissue inhibitors of metalloproteinase-4 in chronic periodontitis with type 2 diabetes mellitus. AB - PURPOSE: The purpose of this study was to analyze the expression of inducible nitric oxide synthases (iNOS), tissue inhibitors of metalloproteinase (TIMP)-3, and TIMP-4 in the gingival tissues of periodontal patients with or without type 2 diabetes mellitus (DM). METHODS: Depending on the patient's systemic condition and clinical criteria of the gingiva, each gingival sample was classified into one of three groups. Sixteen clinically, systemically healthy patients (group 1), 16 periodontal patients (group 2), and 16 periodontal patients with DM (group 3) were included. Tissue samples in each group were collected, prepared, and analyzed by western blotting. Quantification of the relative amount of TIMP-3, TIMP-4, and iNOS was performed. RESULTS: The expression levels of iNOS and TIMP-3 both increased in group 1, group 2, and group 3 in increasing order, and were significantly higher in both group 2 and group 3 as compared to group 1 (P<0.05). The expression levels of TIMP-4 increased in the same order, but significantly increased in group 2 as compared to group 1, in group 3 as compared to group 1, and group 3 as compared to group 2 (P<0.05). CONCLUSIONS: This study demonstrated that iNOS, TIMP-3, and TIMP-4 might be involved in the progression of periodontal inflammation associated with type 2 DM. It is thought that further study of these factors can be applied practically for the diagnosis and control of periodontitis in diabetics. PMID- 23678393 TI - Association among stress, salivary cortisol levels, and chronic periodontitis. AB - PURPOSE: Chronic periodontitis (CP) seems to be associated with stress and depression, but little information on this possible association is available in the literature. Thus, the objective of this study was to evaluate the association among stress, the salivary cortisol level (SCL), and CP. METHODS: Seventy systemically healthy subjects were included in the study from January to September 2011. Full medical and dental histories were obtained, and the following measurements were recorded: 1) probing depth; 2) clinical attachment level; 3) bleeding on probing; and 4) tooth mobility. Saliva samples were collected for the evaluation of SCL (via a highly sensitive electrochemiluminescence immunoassay), and all subjects also answered a questionnaire (i.e., the Zung Self-rating Depression Scale). The odds ratio (OR) with a 95% confidence interval (CI) was calculated, and one way analysis of variance and the Tukey-Kramer method were performed. RESULTS: A total of 36 subjects with CP (51.4%) and 34 without CP were evaluated. Of them, all of the subjects with CP and one periodontally healthy subject were diagnosed with depression. Subjects with moderate CP had statistically significantly higher levels of SCL than subjects with a diagnosis of slight CP (P=0.006). Also, subjects with severe CP showed the same outcome when compared to those with slight CP (P=0.012). In addition, 46 subjects presented high SCL whereas 24 had a normal level. CP was found to be correlated with the SCL, with an OR of 4.14 (95% CI, 1.43 to 12.01). CONCLUSIONS: Subjects with a high SCL and depression may show an increased risk for CP. PMID- 23678394 TI - Comparison of the effect of hand instruments, an ultrasonic scaler, and an erbium doped yttrium aluminium garnet laser on root surface roughness of teeth with periodontitis: a profilometer study. AB - PURPOSE: The present study aimed to measure root surface roughness in teeth with periodontitis by a profilometer following root planning with ultrasonic and hand instruments with and without erbium-doped yttrium aluminium garnet (Er:YAG) laser irradiation. METHODS: Sixty single-rooted maxillary and mandibular teeth, extracted because of periodontal disease, were collected. The crowns and apices of the roots were cut off using a diamond bur and water coolant. The specimens were mounted in an acrylic resin block such that a plain root surface was accessible. After primary evaluation and setting a baseline, the samples were divided into 4 groups. In group 1, the samples were root planned using a manual curette. The group 2 samples were prepared with an ultrasonic scaler. In group 3, after scaling with hand instrumentation, the roots were treated with a Smart 1240D plus Er:YAG laser and in group 4, the roots were prepared with ultrasonic scaler and subsequently treated with an Er:YAG laser. Root surface roughness was then measured by a profilometer (MahrSurf M300+RD18C system) under controlled laboratory conditions at a temperature of 25C and 41% humidity. The data were analyzed statistically using analysis of variance and a t-test (P<0.05). RESULTS: Significant differences were detected in terms of surface roughness and surface distortion before and after treatment. The average reduction of the surface roughness after treatment in groups 1, 2, 3, and 4 was 1.89, 1.88, 1.40, and 1.52, respectively. These findings revealed no significant differences among the four groups. CONCLUSIONS: An Er:YAG laser as an adjunct to traditional scaling and root planning reduces root surface roughness. However, the surface ultrastructure is more irregular than when using conventional methods. PMID- 23678395 TI - Chemoprevention of Colon Cancer by iNOS-Selective Inhibitors. AB - Nitric oxide (NO) is a short-lived pleiotropic regulator and is required for numerous pathophysiological functions, including macrophage-mediated immunity and cancer. It is a highly reactive free radical produced from l-arginine by different isoforms of NO synthases (NOSs). Sustained induction of inducible NOS (iNOS) during chronic inflammatory conditions leads to the formation of reactive intermediates of NO, which are mutagenic and cause DNA damage or impairment of DNA repair, alter cell signaling, and promote proinflammatory and angiogenic properties of the cell, thus contributing to carcinogenesis. Besides its well established role in inflammation, increased expression of iNOS has been observed in colorectal tumors and other cancers. NO-related signaling pathways involved in colon tumorigenesis seem to progress through stimulation of proinflammatory cytokines and via posttranslational protein modifications of important antiapoptotic molecules in the tumors. NO can stimulate and enhance tumor cell proliferation by promoting invasive, angiogenic, and migratory activities. In contrast, studies also suggest that high levels of NO may be protective against tumor growth by inducing tumor cell death. However, a number of in vitro studies and particularly experimental animal data support the notion that NO and its reactive metabolite peroxynitrite stimulate cyclooxygenase-2 activity, leading to generation of prostaglandins that enhance tumor growth. These prostaglandins further augment tumor promotion and invasive properties of tumor cells. Hence, selective inhibitors of iNOS and combination strategies to inhibit both iNOS and cyclooxygenase-2 may have a preventive role in colon cancer. PMID- 23678396 TI - The Effects of Early Neglect on Cognitive, Language, and Behavioral Functioning in Childhood. AB - OBJECTIVES: Few studies have explored the impact of different types of neglect on children's development. Measures of cognition, language, behavior, and parenting stress were used to explore differences between children experiencing various forms of neglect, as well as to compare children with and without a history of early neglect. METHODS: Children, ages 3 to 10 years with a history of familial neglect (USN), were compared to children with a history of institutional rearing (IA) and children without a history of neglect using the Differential Abilities Scale, Test of Early Language Development, Child Behavior Checklist, and Parenting Stress Index. Factors predicting child functioning were also explored. RESULTS: Compared with youth that were not neglected, children with a history of USN and IA demonstrated lower cognitive and language scores and more behavioral problems. Both internalizing and externalizing behavior problems were most common in the USN group. Externalizing behavior problems predicted parenting stress. Higher IQ could be predicted by language scores and an absence of externalizing behavior problems. When comparing the two neglect groups, shorter time spent in a stable environment, lower scores on language skills, and the presence of externalizing behavior predicted lower IQ. CONCLUSION: These findings emphasize the importance of early stable, permanent placement of children who have been in neglectful and pre-adoptive international settings. While an enriching environment may promote resilience, children who have experienced early neglect are vulnerable to cognitive, language and behavioral deficits and neurodevelopmental and behavioral evaluations are required to identify those in need of intervention. PMID- 23678398 TI - A holistic evolutionary and structural study of flaviviridae provides insights into the function and inhibition of HCV helicase. AB - Viral RNA helicases are involved in duplex unwinding during the RNA replication of the virus. It is suggested that these helicases represent very promising antiviral targets. Viruses of the flaviviridae family are the causative agents of many common and devastating diseases, including hepatitis, yellow fever and dengue fever. As there is currently no available anti-Flaviviridae therapy, there is urgent need for the development of efficient anti-viral pharmaceutical strategies. Herein, we report the complete phylogenetic analysis across flaviviridae alongside a more in-depth evolutionary study that revealed a series of conserved and invariant amino acids that are predicted to be key to the function of the helicase. Structural molecular modelling analysis revealed the strategic significance of these residues based on their relative positioning on the 3D structures of the helicase enzymes, which may be used as pharmacological targets. We previously reported a novel series of highly potent HCV helicase inhibitors, and we now re-assess their antiviral potential using the 3D structural model of the invariant helicase residues. It was found that the most active compound of the series, compound C4, exhibited an IC50 in the submicromolar range, whereas its stereoisomer (compound C12) was completely inactive. Useful insights were obtained from molecular modelling and conformational search studies via molecular dynamics simulations. C12 tends to bend and lock in an almost "U" shape conformation, failing to establish vital interactions with the active site of HCV. On the contrary, C4 spends most of its conformational time in a straight, more rigid formation that allows it to successfully block the passage of the oligonucleotide in the ssRNA channel of the HCV helicase. This study paves the way and provides the necessary framework for the in-depth analysis required to enable the future design of new and potent anti viral agents. PMID- 23678397 TI - Ammonium hydroxide treatment of Abeta produces an aggregate free solution suitable for biophysical and cell culture characterization. AB - Alzheimer's disease is the leading cause of dementia in the elderly. Pathologically it is characterized by the presence of amyloid plaques and neuronal loss within the brain tissue of affected individuals. It is now widely hypothesised that fibrillar structures represent an inert structure. Biophysical and toxicity assays attempting to characterize the formation of both the fibrillar and the intermediate oligomeric structures of Abeta typically involves preparing samples which are largely monomeric; the most common method by which this is achieved is to use the fluorinated organic solvent 1,1,1,3,3,3-hexafluoro 2-propanol (HFIP). Recent evidence has suggested that this method is not 100% effective in producing an aggregate free solution. We show, using dynamic light scattering, size exclusion chromatography and small angle X-ray scattering that this is indeed the case, with HFIP pretreated Abeta peptide solutions displaying an increased proportion of oligomeric and aggregated material and an increased propensity to aggregate. Furthermore we show that an alternative technique, involving treatment with strong alkali results in a much more homogenous solution that is largely monomeric. These techniques for solubilising and controlling the oligomeric state of Abeta are valuable starting points for future biophysical and toxicity assays. PMID- 23678399 TI - The method to divide a sentence of requirement into individual requirements and the development of requirement specification editor which can describe individual requirements. AB - BACKGROUND: Agile software development gains requirements from the direct discussion with customers and the development staff each time, and the customers evaluate the appropriateness of the requirement. If the customers divide the complicated requirement into individual requirements, the engineer who is in charge of software development can understand it easily. This is called division of requirement. However, the customers do not understand how much and how to divide the requirements. RESULTS: This paper proposes the method to divide a complicated requirement into individual requirements. Also, it shows the development of requirement specification editor which can describe individual requirements. CONCLUSIONS: The engineer who is in charge of software development can understand requirements easily. PMID- 23678400 TI - DNA hypermethylation of zygote arrest 1 (ZAR1) in hepatitis C virus positive related hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common human malignancies in the world, and its prognosis is generally poor. Epigenetic alteration such as DNA methylation has been shown to be important in the development of human cancers including HCC. Here, we analyzed the methylation status of ZAR1, which has been reported to be aberrantly methylated in a few human cancers. METHODS: We investigated the methylation status of ZAR1 in 88 HCV positive HCC and matched nontumorous liver tissue samples and 4 normal liver tissue samples used as a control using MassARRAY EpiTYPER. Further statistical analysis was performed to determine the relationship between methylation level and patient clinicopathological features and prognosis. RESULTS: CpG islands in ZAR1 exon 1 showed a higher methylation level in all 88 HCC than in nontumorous tissues. The hypermethylation group, whose cancer tissues showed a twofold or higher methylation level compared with nontumorous tissues, showed a significantly higher serum AFP (p = 0.018) and lower serum albumin (p = 0.001) and single rather than multiple tumors (p = 0.031) compared with the hypomethylation group. Multivariate regression analyses were performed to identify which of the following factors were the predictors of the hypermethylation group: serum albumin, AFP, and tumor multiplicity. This study showed that patients who had Zar1 hypermethylation in the HCC tissues had a significantly lower serum albumin level than those in the hypomethylation group (p = 0.007). CONCLUSION: Although it is still unknown how ZAR1 hypermethylation affects HCC development, it could be a potential marker to detect HCV-related HCC. PMID- 23678401 TI - Why BioImpacts? AB - Integration of in vitro and in vivo investigations has brought the body of new emerging life sciences about. This inspirational domain needs a scientific platform to cover the relevant publications. BioImpacts (BI), as a peer-reviewed multidisciplinary international open access journal, intends to deal with all aspects of biological and biomedical researches at dimensions of molecular, cellular, functional and translational dimensions. PMID- 23678402 TI - Integration of Molecular, Cellular and Translational Researches in BioImpacts. AB - Integration of molecular cellular biology with advanced technologies (e.g., bioinformatics, omics,biophotonics and nanobiosensing) has significantly improved the translational medicine field. The integrative research in various biomedical sciences has also fastened the progression of drug discovery and development.Aiming to meet the highest standards of publication, the newly established multidisciplinary open access journal "BioImpacts"grants a free platform for all authors and readers to facilitate the integration of different scientific domains in biomedical sciences. PMID- 23678403 TI - Impacts of nanomedicines in ocular pharmacotherapy. AB - INTRODUCTION: The integrity of the cells/tissues in anterior and/or posterior segments of the eye plays a crucial role in biofunctions of the vision. To maintain ocular homeostasis, selective restrictiveness of the ophthalmic membranes and barriers control must act on shuttling of biomolecules. Thus, not all attempts to apply de novo nanotechnology approaches for ocular pharmacotherapy have met with the same successes as those cited here in this review, and sometimes these novel technologies tools provoke a great deal of challenges and hurdles mainly because of functional presence of these barriers. METHODS: Recent published articles related to applications of ocular nanomedicines were reviewed and highlighted in this review article. RESULTS: It seems the emergence of nanomedicines have arisen great hopes for ophthalmic pharmacotherapy, in which nanostructured medicines are expected to be able to cross the restrictive barriers of the eye. Although such fast inauguration of ocular nanomedicines will literally convey new challenges in the regulatory and translational processes, it will also grant a prolific platform from which many exciting, and yet unimagined, applications of biomedical nanotechnology will emerge for pharmacotherapy of the eye. CONCLUSION: This review provides recent advancements on ocular nanomedicines. PMID- 23678404 TI - Cytotoxic impacts of linear and branched polyethylenimine nanostructures in a431 cells. AB - INTRODUCTION: Polyethylenimine (PEI), as a nonviral cationic polymer, has been widely used as gene delivery nanosystem. Although a number of investigations have highlighted its toxic impacts on target cells through induction of apoptosis/necrosis, still it is essential to look at its structural impacts on target cells. METHODS: In this current study, cytogenomic impacts of 25 kD linear and branched PEI (LPEI and BPEI, respectively) in A431 cells are reported to address possible mechanism for induction of apoptosis. At 40-50% confluency, A431 cells were exposed to PEI at a recommended concentration for 4 hr. After 24 hr, to detect apoptosis and DNA damage, the treated cells were subjected to MTT assay, FITC-labeled annexin V flow cytometry and comet assay. RESULTS: Flow cytometry assessments revealed that the BPEI can result in greater internalization than the linear PEI, which also induced greater cytotoxicity. Annexin V assay confirmed early and late apoptosis by BPEI, imposing somewhat DNA damage detected by comet assay. Western blot analysis resulted in induction of Akt-kinase which is possibly one of biomolecules affected by PEI. CONCLUSION: These results highlight that, despite induction of Akt-kinase, the BPEI can elicit apoptosis in target cells. PMID- 23678405 TI - Aptamer-based Nanosensors: Juglone as an Attached-Redox Molecule for Detection of Small Molecules. AB - INTRODUCTION: Among several biosensing approaches, electrochemical-based procedures have been described as one of the most common and useful methods for sensing because of their simplicity, sensitivity, accuracy, and low cost. The electroactive species, which called redox, play a main role in the electrochemical-based approaches. Among several redox molecules used for electrochemical experiments, ferrocene is one of the commonly used redox molecules. However, instability of ferrocenium ion in the chloride containing solutions appeared to be weakness of this redox molecule limiting its utilization. METHODS: In the current study, Juglone was attached (using EDC/NHS coupling method) to the 3'-amino-modified terminus of the immobilized specific aptamer of codeine, which was successfully used in a cyclic electrochemical voltammetry procedure. RESULTS: The cyclic voltammogram peak of aptamer-attached Juglone was observed in the potential range of +0.4 to +0.9 V and the fabricated aptamer-based sensor was used for detection of different concentrations of codeine in the phosphate buffer 0.1 M solution containing 2 M NaCl. CONCLUSION: Based on these findings, it can be suggested that the new aptamer-attached Juglone could be considered as an effective alternative redox molecule in particular with oligonucleotide-based sensing systems. PMID- 23678406 TI - Effect of Antioxidants and Carbohydrates in Callus Cultures of Taxus brevifolia: Evaluation of Browning, Callus Growth, Total Phenolics and Paclitaxel Production. AB - INTRODUCTION: To control the tissue browning phenomenon, callus growth, total phenolics and paclitaxel production, in the current investigation, we evaluated the effects of citric acid and ascorbic acid (as antioxidants) and glucose, fructose and sucrose in callus cultures of Taxus brevifolia. METHODS: To obtain healthy callus/cell lines of Taxus brevifolia, the effects of two antioxidants ascorbic acid (100-1000 mg/L) and citric acid (50-500 mg/L), and three carbohydrates (glucose, fructose and sucrose (5-10 g/L)) were studied evaluating activities of polyphenol oxidase (PPO) and peroxidase (PO) enzymes, callus growth/browning, total phenolics and paclitaxel production. RESULTS: These antioxidants (ascorbic acid and citric acid) failed to show significant effects on callus growth, browning intensity or paclitaxel production. However, the carbohydrates imposed significant effects on the parameters studied. High concentrations of both glucose and sucrose increased the browning intensity, thus decreased callus growth. Glucose increased paclitaxel production, but sucrose decreased it. CONCLUSION: These results revealed that the browning phenomenon can be controlled through supplementation of the growth media with glucose, sucrose (5 g/L) and fructose (10 g/L), while increased paclitaxel production can be obtain by the optimized media supplemented with glucose (10 g/L), sucrose and fructose (5 g/L). PMID- 23678407 TI - Characterization of Streptomyces Isolates with UV, FTIR Spectroscopy and HPLC Analyses. AB - INTRODUCTION: Streptomyces, gram-positive and aerobic bacteria, are distinguished genus of Actinomycetes. This economically important genus is well studied owing to its capacity in producing more than 70% of antibiotics. In fact, need for novel, safe and more efficient antibiotics is a key challenge to the pharmaceutical industry today, moreover, increase in opportunistic infections in the immune compromised host has influenced this demand. Nowadays, evaluating morphological and biochemical differences as well as studying streptomyces genetic diversity via molecular indicators seem to be the most common method for screening this genus. METHODS: In this research we evaluate the potential of antibiotic production and characterize the UV and FTIR spectroscopy and HPLC (High performance liquid chromatography) analysis pattern of streptomyces from various locations in northwest of Iran. Regarding this, 30 soil samples were collected randomly from different zones of northwest region of Iran. Then, following the extraction of secondary metabolite, the UV and FTIR spectroscopy analysis was carried out for characterization of the various extracts. RESULTS: Considering the coordinate analysis of UV and FTIR spectroscopy pattern, the isolate G614C1 with substantial antimicrobial activity exhibited absorption at 3411 cm-1 which is indicator of hydroxyl groups, absorption at 2856 and 2915 cm-1 indicating hydrocarbon chassis, and absorption at 1649 cm-1 indicating a double bond of polygenic compound. CONCLUSION: These results highlight the importance of streptomyces isolates in antibiotic production. HPLC confirmed the production when compared with standards. PMID- 23678408 TI - Simultaneous Determination of 6-Mercaptopurine and its Oxidative Metabolites in Synthetic Solutions and Human Plasma using Spectrophotometric Multivariate Calibration Methods. AB - INTRODUCTION: 6-Mercaptopurine (6MP) is an important chemotherapeutic drug in the conventional treatment of childhood acute lymphoblastic leukemia (ALL). It is catabolized to 6-thiouric acid (6TUA) through 8-hydroxo-6-mercaptopurine (8OH6MP) or 6-thioxanthine (6TX) intermediates. METHODS: High-performance liquid chromatography (HPLC) is usually used to determine the contents of therapeutic drugs, metabolites and other important biomedical analytes in biological samples. In the present study, the multivariate calibration methods, partial least squares (PLS-1) and principle component regression (PCR) have been developed and validated for the simultaneous determination of 6MP and its oxidative metabolites (6TUA, 8OH6MP and 6TX) without analyte separation in spiked human plasma. Mixtures of 6MP, 8-8OH6MP, 6TX and 6TUA have been resolved by PLS-1 and PCR to their UV spectra. RESULTS: Recoveries (%) obtained for 6MP, 8-8OH6MP, 6TX and 6TUA were 94.5-97.5, 96.6-103.3, 95.1-96.9 and 93.4-95.8, respectively, using PLS 1 and 96.7-101.3, 96.2-98.8, 95.8-103.3 and 94.3-106.1, respectively, using PCR. The NAS (Net analyte signal) concept was used to calculate multivariate analytical figures of merit such as limit of detection (LOD), selectivity and sensitivity. The limit of detections for 6MP, 8-8OH6MP, 6TX and 6TUA were calculated to be 0.734, 0.439, 0.797 and 0.482 MUmol L-1, respectively, using PLS and 0.724, 0.418, 0783 and 0.535 MUmol L-1, respectively, using PCR. HPLC was also applied as a validation method for simultaneous determination of these thiopurines in the synthetic solutions and human plasma. CONCLUSION: Combination of spectroscopic techniques and chemometric methods (PLS and PCR) has provided a simple but powerful method for simultaneous analysis of multicomponent mixtures. PMID- 23678409 TI - Synthesis of New Functionalized Citric Acid-based Dendrimers as Nanocarrier Agents for Drug Delivery. AB - INTRODUCTION: Citric acid-polyethylene glycol-citric acid (CPEGC) triblock dendrimers can serve as potential delivery systems. METHODS: In this investigation, CPEGC triblock dendrimers were synthesized and then imidazole groups were conjugated onto the surface of the G1, G2 and G3 of the obtained dendrimers. In order to study the type of the interactions between the functionalized dendrimers and a drug molecule, Naproxen which contains acidic groups, was examined as a hydrophobic drug in which the interactions would be of the electrostatic kind between its acidic groups and the lone pair electrons of nitrogen atom in imidazole groups. The quantity of the trapped drug and also the amount of its release were measured with UV spectrometric method in pH 1, 7.4 and 10. The average diameter of the nanocarriers was measured by Dynamic Light Scattering (DLS) technique. RESULTS: The size range of particles was determined to be 16-50 nm for different generations. The rate of the release increased in pH=10 in all generations due to the increases in Naproxen solubility and the hydrolysis of the esteric bonds in the mentioned pH. The results showed that the amount of the trapped drug increased with the increase in the generation of the dendrimer and pH. CONCLUSION: Based on our findings, we suggest CPEGC triblock dendrimers possess great potential to be used as drug/gene delivery system. PMID- 23678410 TI - Translational researches require effective protocols for knowledge and technology transfer and integration. AB - Integration of several disciplines (nonclinical, preclinical and clinical researches) during drug discovery and development through learning and confirmation process needs a dynamic process; "translational medicine" (TM) to give a holistic understanding of the entire process. To achieve the highest impacts, however, effective standard protocols need to be performed. PMID- 23678411 TI - A glance at DNA microarray technology and applications. AB - INTRODUCTION: Because of huge impacts of "OMICS" technologies in life sciences, many researchers aim to implement such high throughput approach to address cellular and/or molecular functions in response to any influential intervention in genomics, proteomics, or metabolomics levels. However, in many cases, use of such technologies often encounters some cybernetic difficulties in terms of knowledge extraction from a bunch of data using related softwares. In fact, there is little guidance upon data mining for novices. The main goal of this article is to provide a brief review on different steps of microarray data handling and mining for novices and at last to introduce different PC and/or web-based softwares that can be used in preprocessing and/or data mining of microarray data. METHODS: To pursue such aim, recently published papers and microarray softwares were reviewed. RESULTS: It was found that defining the true place of the genes in cell networks is the main phase in our understanding of programming and functioning of living cells. This can be obtained with global/selected gene expression profiling. CONCLUSION: Studying the regulation patterns of genes in groups, using clustering and classification methods helps us understand different pathways in the cell, their functions, regulations and the way one component in the system affects the other one. These networks can act as starting points for data mining and hypothesis generation, helping us reverse engineer. PMID- 23678412 TI - Comet assay: a method to evaluate genotoxicity of nano-drug delivery system. AB - INTRODUCTION: Drug delivery systems could induce cellular toxicity as side effect of nanomaterials. The mechanism of toxicity usually involves DNA damage. The comet assay or single cell gel electrophoresis (SCGE) is a sensitive method for detecting strand damages in the DNA of a cell with applications in genotoxicity testing and molecular epidemiology as well as fundamental research in DNA damage and repair. METHODS: In the current study, we reviewed recent drug delivery researches related to SCGE. RESULTS: We found that one preference for choosing the assay is that comet images may result from apoptosis-mediated nuclear fragmentation. This method has been widely used over the last decade in several different areas. Overall cells, such as cultured cells are embedded in agarose on a microscope slide, lysed with detergent, and treated with high salt. Nucleoids are supercoiled DNA form. When the slide is faced to alkaline electrophoresis any breakages present in the DNA cause the supercoiling to relax locally and loops of DNA extend toward the anode as a ''comet tail''. CONCLUSION: This article provides a relatively comprehensive review upon potentiality of the comet assay for assessment of DNA damage and accordingly it can be used as an informative platform in genotoxicity studies of drug delivery systems. PMID- 23678413 TI - Simulation of blood flow coronary artery with consecutive stenosis and coronary coronary bypass. AB - INTRODUCTION: In this research the behavior of coronary arteries has been studied with symmetric and asymmetric consecutive stenosis, and grafted vessels. METHODS: The incompressible Navier-Stokes and energy equations were discretized with second-order upwind method. Assumptions such as Newtonian fluid, wall rigidity and steady-flow were used. RESULTS: All the calculations showed the same results with Newtonians and non- Newtonian fluids. It was found that the possibility of stenosis be reduced by increasing the graft angle. However, there exists further stenosis possibility. Among the three graft angles 20, 30 and 40, the 30 was found to be the reliable ones. CONCLUSION: Based on these findings, it can be deduced that there would be a high risk of further atherosclerosis when the first stenose has the maximum percentage. PMID- 23678414 TI - Investigation into alternative sugars as potential carriers for dry powder formulation of budesonide. AB - INTRODUCTION: Dry powder inhaler (DPI) formulations are so far being used for pulmonary drug delivery, mainly for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Currently most of DPI formulations rely on lactose as a carrier in the drug powder blend. However, due to reducing sugar function of lactose which makes it incompatible with some drugs such as budesonide, it is realistic to investigate for alternative sugars that would overcome the concerned drawback but still have the positive aspects of lactose. METHODS: The study was conducted by characterizing carriers for their physico chemical properties and preparing drug/carrier blends with concentration of 5% and 10% drug with the carrier. The mixing uniformity (homogeneity) of Budesonide in the blends was analyzed using spectrophotometer. The blend was then filled into NB7/2 Airmax inhaler device and the deposition profiles of the drug were determined using multi stage liquid impinger (MSLI) after aerosolization at 4 kPa via the inhaler. The morphology of the carriers conducted using the scanning electron microscope. RESULTS: The results determined that the mean fine particle fraction (FPF) of 5% and 10% blends of mannitol was 61%, possibly due to fine elongated particles. Dextrose exhibited excellent flowability. Scanning electron microscope illustrated mannitol with fine elongated particles and dextrose presenting larger and coarse particles. It was found out that type of carriers, particle size distribution, and morphology would influence the FPF of budesonide. CONCLUSION: It may be concluded that mannitol could be suitable as a carrier on the basis of its pharmaceutical performance and successful achievement of FPF whereas the more hygroscopic sugars such as sorbitol or xylitol showed poor dispersibility leading to lower FPF. PMID- 23678415 TI - Gap junctions: the claymore for cancerous cells. AB - INTRODUCTION: Gap junctions play an important role in the cell proliferation in mammalian cells as well as carcinogenesis. However, there are controversial issues about their role in cancer pathogenesis. This study was designed to evaluate genotoxicity and cytotoxicity of Carbenoxolone (CBX) as a prototype of inter-cellular gap junction blocker in MCF7 and BT20 human breast cancer cells. METHODS: The MCF7and BT20 human breast cancer cell lines were cultivated, and treated at designated confluency with different doses of CBX. Cellular cytotoxicity was examined using standard colorimetric assay associated with cell viability tests. Gene expression evaluation was carried out using real time polymerase chain reaction (PCR). RESULTS: MCF7 and BT20 cells were significantly affected by CBX in a dose dependent manner in cell viability assays. Despite varying expression of genes, down regulation of pro- and anti-apoptotic genes was observed in these cells. CONCLUSION: Based upon this investigation, it can be concluded that CBX could affect both low and high proliferative types of breast cancer cell lines and disproportionate down regulation of both pre- and anti apoptotic genes may be related to interacting biomolecules, perhaps via gap junctions. PMID- 23678417 TI - Apoptosis resistance in endometriosis. AB - INTRODUCTION: In a cytological analysis of endometriotic lesions neither granulocytes nor cytotoxic T-cells appear in an appreciable number. Based on this observation we aimed to know, whether programmed cell death plays an essential role in the destruction of dystopic endometrium. Disturbances of the physiological mechanisms of apoptosis, a persistence of endometrial tissue could explain the disease. Another aspect of this consideration is the proliferation competence of the dystopic mucous membrane. METHODS: Endometriotic lesions of 15 patients were examined through a combined measurement of apoptosis activity with the TUNEL technique (terminal deoxyribosyltransferase mediated dUTP Nick End Labeling) and the proliferation activity (with the help of the Ki-67-Antigens using the monoclonal antibody Ki-S5). RESULTS: Twelve out of 15 women studied showed a positive apoptotic activity of 3-47% with a proliferation activity of 2 25% of epithelial cells. Therefore we concluded that the persistence of dystopic endometrium requires proliferative epithelial cells from middle to lower endometrial layers. CONCLUSION: A dystopia misalignment of the epithelia of the upper layers of the functionalism can be rapidly eliminated by apoptotic procedures. PMID- 23678416 TI - Effect of vitamin e and selenium supplement on paraoxonase-1 activity, oxidized low density lipoprotein and antioxidant defense in diabetic rats. AB - INTRODUCTION: The aim of the present study was to assess the effects of vitamin E and selenium supplementation on serum paraoxonase (PON1) activity, lipid peroxidation and antioxidant defense in streptozotocin-induced diabetic rats. METHODS: Thirty two female Sprague Dawley rats were divided into 3 groups: the control group (n=8) received a standard diet; streptozotocin (STZ)-induced diabetic rats (n=12), received corn oil and physiological solution; and vitamin E and selenium supplemented diabetic rats (n=12) were treated with oral administration of vitamin E (300 mg/kg) and sodium selenite (0.5 mg/kg) once a day for 4 weeks. RESULTS: Significantly lower total antioxidant status (TAS), PON1and erythrocyte SOD activities and a higher fasting plasma glucose level were observed in the diabetic rats compared to the control. A significant increase in SOD and GPX activities in vitamin E and selenium supplemented diabetic group was observed after 5 weeks of the experiment. Compared to the normal rats, malondialdehyde (MDA) and oxidized LDL (Ox-LDL) levels were higher in the diabetic animals; however, these values reduced significantly following vitamin E and selenium supplementation. CONCLUSION: Vitamin E and selenium supplementation in diabetic rats has hypolipidemic, hypoglycemic and antioxidative effects and may slow down the progression of diabetic complications through its protective effect on PON1 activity and lipoproteins oxidation. PMID- 23678418 TI - Preparation and characterization of a novel smart polymeric hydrogel for drug delivery of insulin. AB - INTRODUCTION: Over the past years, temperature and pH-sensitive hydrogels was developed as suitable carriers for drug delivery. In this study temperature and pH-sensitive hydrogels was designed for an oral insulin delivery modeling. METHODS: NIPAAm-MAA -HEM copolymers were synthesized by radical chain reaction with 86:4:10 (5% w/v) ratios respectively. Reaction was carried out in 1,4 Dioxane under Nitrogen gas-flow. The copolymers were characterized with FT-IR, 1H NMR and DSC. Copolymers were loaded with regular insulin by modified double emulsion method with ratio of 1:10. Release study carried out in two different pH (pH=2 and 7.4 for stomach and intestine simulation respectively) at 37oC. For each pH, a 5 mL suspension of the insulin containing hydrogel was taken in to a cellulose acetate dialysis membrane, and the dialysis membrane was allowed to float in a beaker containing 15 mL of buffer solution. The beakers were placed in a shaker incubator maintained at 37oC. Phosphate buffer (0.1 M, pH 3)/ acetonitrile (60/40) was used as the mobile phase in HPLC assay. RESULTS: Yield of reaction was 86% with an optimum Lower Critical Solution Temperature point (30oC). In-vitro studies showed a control release behavior via pH changes which the amount of insulin releases was 80% and 20% at pH=2 and 7.4 respectively. CONCLUSION: Results showed that by optimizing polymerization and loading method we could achieve a suitable nano system for oral delivery of insulin. PMID- 23678419 TI - Smart multifunctional theranostics: simultaneous diagnosis and therapy of cancer. AB - Clinical applications of advanced nanomedicines such as PEGylated liposomal doxorubicin and paclitaxel-albumin bioconjugates have significantly improved the cancer treatment strategies. However, these pharmaceuticals lack early detection and single cell tracking capabilities. Thus, engineering of smart multifunctional theranostics appear to be our next step for simultaneous diagnosis and therapy of cancer. Clinical translation of multifunctional theranostics appears to be dependent upon specificity of cancer biomarkers, biocompatibility of components used for formulation, and advancement of bioconjugation techniques. While many cancer biomarker candidates often fail to be used for clinical diagnosis/therapy because of their nonspecific functional expression in normal tissues, biocompatibility of materials used for bioconjugation also needs to be approved. All these issues need to be fully addressed prior to the translation of smart multifunctional cancer theranostics. PMID- 23678420 TI - Potential of microalgae and lactobacilli in biosynthesis of silver nanoparticles. AB - INTRODUCTION: Application of nanoparticles has been extensively increased in last decades. Nanoparticles of noble metals such as gold, platinum and especially silver are widely applied in medical and pharmaceutical applications. Although, variety of physical and chemical methods has been developed for production of metal nanoparticles, because of destructive effects of them on environment, biosynthetic methods have been suggested as a novel alternative. Some bacteria and microalgae have different ranges of potentiality to uptake metal ions and produce nanoparticles during detoxification process. In the present work, we study the potential of three Lactobacilli and three algal species in production of AgNPs in different concentrations of silver nitrate. METHODS: Utilizing AAS, XRD and TEM methods, Nannochloropsis oculata, Dunaliella salina and Chlorella vulgaris as three algal species in addition to three Lactobacilli including L. acidophilus, L. casei, L. reuteri were monitored for production of silver nanoparticles. Three concentrations of AgNO3 (0.001, 0.002, 0.005 M) and two incubation times (24h and 48h) were included in this study. RESULTS: Our findings demonstrated that C. vulgaris, N. oculata and L. acidophilus have the potential of nanosilver production in a culture medium containing 0.001 M of AgNO3 within 24 hours. Also L. casei and L. reuteri species exhibited their potential for production of silver nanoparticles in 0.002 M concentration of AgNO3 in 24 hours. The size range of particles was approximately less than 15 nm. The uptake rate of silver in the five species was between 1.0 to 2.7 mg/g of dry weight. Nanoparticle production was not detected in other treatments and the algae Dunaliella. CONCLUSION: The biosynthesis of silver nanoparticles in all of three Lactobacilli and two algal species including N. oculata and C. vulgaris was confirmed. PMID- 23678421 TI - Barrier functionality of porcine and bovine brain capillary endothelial cells. AB - INTRODUCTION: To date, isolated cell based blood-brain barrier (BBB) models have been widely used for brain drug delivery and targeting, due to their relatively proper bioelectrical and permeability properties. However, primary cultures of brain capillary endothelial cells (BCECs) isolated from different species vary in terms of bioelectrical and permeability properties. METHODS: To pursue this, in the current investigation, primary porcine and bovine BCECs (PBCECs and BBCECs, respectively) were isolated and used as an in vitro BBB model. The bioelectrical and permeability properties were assessed in BCECs co-cultured with C6 cells with/without hydrocortisone (550 nM). The bioelectrical properties were further validated by means of the permeability coefficients of transcellular and paracellular markers. RESULTS: The primary PBCECs displayed significantly higher trans-endothelial electrical resistance (~900 Omega.cm(2)) than BBCECs (~700 Omega.cm(2)) - both cocultured with C6 cells in presence of hydrocortisone. Permeability coefficients of propranolol/diazepam and mannitol/sucrose in PBCECs were ~21 and ~2 (*10(-6) cm.sec(-1)), where these values for BBCECs were ~25 and ~5 (*10(-6) cm.sec(-1)). CONCLUSION: Upon our bioelectrical and permeability findings, both models display discriminative barrier functionality but porcine BCECs seem to provide a better platform than bovine BCECs for drug screening and brain targeting. PMID- 23678422 TI - Comparison of the effects of genistein and daidzein with dexamethasone and soy protein on rheumatoid arthritis in rats. AB - INTRODUCTION: We have already shown the protective effects of soy protein on rheumatoid arthritis in rats. In this study, the effects of genistein and daidzein, two isoflavones from soy on rheumatoid arthritis prognosis and prevention in rats have been investigated. METHODS: Rheumatoid arthritis was induced in female Sprague-Dawley rats using collagen type II plus adjuvant. Rats were then treated with soy protein (7 g/kg), dexamethasone (1 mg/kg), genistein (20 mg/kg genistein), daidzein (20 mg/kg genistein) and casein (in control groups) by daily gavage feedings for 50 days. Scores of arthritis were recorded every day for each paw of animal. Serum concentrations of TNF-alpha, IL-6, adiponectin and leptin were characterized. Tibiotarsal tissue was used for histopathologic analyses. RESULTS: Treatment with genistein and daidzein resulted in not only a reduction in disease symptoms but also a delay in the onset of symptoms. Results from delayed-type hypersensitivity test demonstrated that the ear thickness in treated rats was significantly lower than that in the control group (p<0.05). There was a reduction in TNF-alpha, IL-6, adiponectin and leptin serum concentrations after treatment with genistein and daidzein. Dexamethasone reduced the serum concentrations of TNF-alpha, IL-6 and adiponectin but increased leptin serum level. Prevention of the tissue damage and joint inflammation was also observed following treatment with two soy isoflavones. CONCLUSION: soy isoflavones, daidzein and especially genistein, could significantly improve rheumatoid arthritis symptoms in rats. The structural similarity of isoflavones to estrogen could be the possible underlying mechanism involved in the function. PMID- 23678423 TI - Radiofrequency ablation for treatment of atrial fibrillation. AB - INTRODUCTION: Atrial Fibrillation (AF) is the most common cardiac arrhythmia which represents a major public health problem. The main purpose of this research is to evaluate the Radiofrequency (RF) ablation effects in the patients with chronic AF scheduled for cardiac surgery because of different heart diseases. METHODS: The descriptive and prospective study was conducted on 60 patients with AF scheduled for surgery along with RF ablation. The data were collected by questionnaire and included: patients' age, sex, NYHA class, operation type, past medical history, type and cause of valvular heart disease, preoperative ECG (electrocardiogram), duration of surgery, clamping time, cardiopulmonary bypass, and RF ablation time. RF ablation was followed by the main operation. The follow up examination, ECG, and echocardiography were performed 3 and 6 months after operation. RESULTS: The mean age of patients was 48+/-10 years (18-71 years). Forty one patients had permanent AF and 19 had the persistent AF. The left ventricular ejection fraction was 48.27+/-9.75 percent before operation, and reached to 56.27+/-7.87 percent after the surgery (P<0.001). The mean NYHA class before the surgery was 2.83+/-0.68 which decreased to 1.34+/-0.46 6 months after the surgery with RF ablation (P<0.001). One patient (1.6%) died after surgery. Complete relief and freedom from AF recurrence was observed in 70% of patients in the mean follow up in 7 months after the surgery. The sinus rhythm with efficient atrial contraction was established in 100% of discharged patients. CONCLUSION: RF ablation is an effective procedure to cure atrial fibrillation in patients undergoing cardiac surgeries. PMID- 23678424 TI - Planning genomic study in an animal model of depression: a preliminary report. AB - INTRODUCTION: Interaction of several genes is responsible for psychiatric diseases such as depression. Despite the numerous microarray studies in this field, findings are controversial and hard to conclude. METHODS: Male Wistar rats were randomly selected to receive Chronic Mild Stress model for 4 weeks. Different aspects of depression were measured by forced swimming test, open field trial and sucrose preference tests in the experience group and controls. RESULTS: Sucrose was preferred by 40% of CMS group and 80% of controls (p=0.025). Twenty percent of CMS group and 80% of controls were "active" (p=0.001). Last escape was at minute 238 for CMS group and minute 245 for controls and controls had more escape efforts. CONCLUSION: This paper is a preliminary report of a genomic study on animal model of depression which tries to achieve reliable results by a joint of clinical view with recent techniques. Predicted challenges in this procedure and the solutions as well as the limitations may be helpful for future researches. PMID- 23678425 TI - Highly effective DNA extraction method from fresh, frozen, dried and clotted blood samples. AB - INTRODUCTION: Today, with the tremendous potential of genomics and other recent advances in science, the role of science to improve reliable DNA extraction methods is more relevant than ever before. The ideal process for genomic DNA extraction demands high quantities of pure, integral and intact genomic DNA (gDNA) from the sample with minimal co-extraction of inhibitors of downstream processes. Here, we report the development of a very rapid, less-hazardous, and high throughput protocol for extracting of high quality DNA from blood samples. METHODS: Dried, clotted and ethylene diamine tetra-acetic acid (EDTA) treated fresh and frozen blood samples were extracted using this method in which the quality and integrity of the extracted DNA were corroborated by agarose gel electrophoresis, PCR reaction and DNA digestion using restricted enzyme. The UV spectrophotometric and gel electrophoresis analysis resulted in high A260/A280 ratio (>1.8) with high intactness of DNA. RESULTS: PCR and DNA digestion experiments indicated that the final solutions of extracted DNA contained no inhibitory substances, which confirms that the isolated DNA is of good quality. CONCLUSION: The high quality and quantity of current method, no enzymatic processing and accordingly its low cost, make it appropriate for DNA extraction not only from human but also from animal blood samples in any molecular biology labs. PMID- 23678426 TI - Microsurgeon Hirudo medicinalis as a Natural Bioshuttle for Spontaneous Mass Vaccination against Influenza A Virus. AB - INTRODUCTION: Recent report on existence of a stem region of hemagglutinin has arisen new hopes for vaccination of influenza A as it consist of a conserve fusion peptide shared across several influenza subtypes and can be targeted by human immune system. METHODS: Given that traditional vaccination based on live attenuated viruses often fails to surpass such viral infection, a great deal of attention has been devoted to develop a safe yet efficient system for vaccination influenza A. We believe that a natural bioshuttle can be recruited for spontaneous mass vaccination. RESULTS: Thus, here, we hypothesize that a bioengineered transgenic Hirudo medicinalis can be considered as an alive bioshuttle for in-situ vaccination against influenza A virus. By introducing the designated gene(s) encoding the target fragment (i.e., stem region of hemagglutinin), this microsurgeon can act as a rapid microproducer of viral proteins for in-house mass vaccination through imparting the necessary proteins such as those, naturally presented in leech's saliva. CONCLUSION: This peculiar bioshuttle can be easily exploited as a medical modality choice at home resulting in greater patient compliance. PMID- 23678427 TI - Scientometric Analysis of Nanotechnology in MEDLINE. AB - INTRODUCTION: Nanotechnology is the study and application of extremely small materials and can be used across all the other science fields, such as chemistry, biology, physics, materials science, and engineering. An alternative method for considering the trend of research activities in countries is quantitative analysis of scientific output. The objective of current study is to analyze and visualize the trend of scientific output in the field of nanotechnology in MEDLINE during a period of 10 years 2001-2010. METHODS: The extraction of data was restricted to the data set that was indexed under the major heading of "nanotechnology" in MEDLINE through years 2001 - 2010. Data on patent applications was obtained from WIPO Statistics Database. Database of Science Citation Index Expanded (SCIE) was selected from Web of Science to obtain publications indexed under the topic of nanotechnology. RESULTS: Analysis of data showed that the research activities in the field of nanotechnology have been increased steadily through the period of study. The number of publications in 2010 was ~ 84 times greater than those in 2001. English language consisting of 98% of total publications was the most dominant language of publications. Based on Bradford's scattering's law the journal of "Nanoscience and Nanotechnology" distributing 12.8% of total publications was the most prolific journal. CONCLUSION: The USA contributing 39% of world's publications in the field was the most productive country followed by China (10%), Germany (6%), Japan (6%), Korea (5%) and UK (4%). The majority of world's publications (70%) were produced by these six countries. The tremendous growth of publications was simultaneously with the rapid growth of patent application in the field of Micro-structural and nano-technology in WIPO. PMID- 23678428 TI - CNT Nanobombs for Specific Eradication of Cancer Cells: A New Concept in Cancer Theranostics. AB - Whole extermination of cancerous cells/tissue seems no longer to be a dream. Exploiting advanced photoactive nanomaterials such as functionalized fullerenes and carbon nano-tubes (CNTs) can act as CNT nanobombs (CNT-NBs) when exposed to the near infrared (NIR) radiation. PEGylated CNTs tagged with an antibody/aptamer can target cancer cells. Once attached to cancer cells, the NIR emission (700 1100 nm), in which body tissues are mostly transparent, can be applied to CNT-NBs which can absorb the light and get heated up. The resultant enhanced temperature can abolish the cancer. Once stealth CNT-NBs are tagged with imaging moieties, it would be a matter of computer gaming for physician who can inject it for real time visualization and destruction of cancer by activation of the NIR laser. While, many nanosystems (NSs) are still in waiting list for clinical translation, our dreams may come true by applying stealth CNT-NBs against cancer. PMID- 23678429 TI - Antiviral activity of natural products extracted from marine organisms. AB - Many epidemics have broken out over the centuries. Hundreds and thousands of humans have died over a disease. Available treatments for infectious diseases have always been limited. Some infections are more deadly than the others, especially viral pathogens. These pathogens have continuously resisted all kinds of medical treatment, due to a need for new treatments to be developed. Drugs are present in nature and are also synthesized in vitro and they help in combating diseases and restoring health. Synthesizing drugs is a hard and time consuming task, which requires a lot of man power and financial aid. However, the natural compounds are just lying around on the earth, may it be land or water. Over a thousand novel compounds isolated from marine organisms are used as antiviral agents. Others are being pharmacologically tested. Today, over forty antiviral compounds are present in the pharmacological market. Some of these compounds are undergoing clinical and preclinical stages. Marine compounds are paving the way for a new trend in modern medicine. PMID- 23678431 TI - Rosa canina L. Fruit Hydro-Alcoholic Extract Effects on Some Immunological and Biochemical Parameters in Rats. AB - INTRODUCTION: This research investigates the possible potential of Rosa canina (RC) as an immunomodulator in rats and its effects on some biochemical parameters. METHODS: In this experiment, 45 male Wistar rats were obtained and divided into three groups (n = 15). These groups received normal saline (10 mg/kg), RC fruit extract (250 mg/kg) and RC fruit extract (500 mg/kg) as oral gavages every day for a period of four weeks, respective-ly. After obtaining blood samples (at the end of each week), differential white blood cell (WBC) counts, phagocyte activity (number), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphates (ALP) albumin and globulins levels of sam-ples were obtained. The malondialdehyde (MDA) and glutathione (GSH) levels in the se-rum were determined only in day 28 of study. The radical scavenger activity (RSA) of the RC extract was measured spectrophotometrically. RESULTS: the gamma globulin level, neu-trophil and monocyte counts and phagocyte activity increased significantly in comparison with the normal saline group. ALT, AST and ALP had not significantly differences in compared to control group. RC extract significantly increased thiobarbituric acid reactive substances (TBARS) and also decreased GSH levels in comparing to control group in day 28. CONCLUSION: the data suggest that the RC extract has been used in traditional medicine might have immunomodulatory effects. PMID- 23678430 TI - Gene and stem cell therapy: alone or in combination? AB - INTRODUCTION: Both gene and stem cell therapies hold great promise in the treatment of many genetic diseases and are currently focus of interest for many investigators. While both approaches are offering great and valuable treatment options for devastating and life-threatening diseases, they hold much greater promise in combination. METHODS: As there are multiple options in selecting gene transfer vehicles among the non-viral and viral vectors, there are also many options among the different transplantable cell types ranging from lineage restricted progenitor cells to multipotent and pluripotent stem cells. Here, combination of the gene therapy and stem cell therapy is discussed. RESULTS: Several suc-cessful gene and stem cell therapies have been reported both in animal and human trials. Combination of the gene therapy and stem cell therapy can be carried out sequentially where the cell transplantation and the in vivo gene therapy are accomplished one after the other; or, as it is more commonly practiced, they can be carried out as ex vivo gene therapy where the transplantable cells are genetically modified outside the body before being transplanted into the body. CONCLUSION: The combination of the stem-cell technology with gene therapy has the potential of providing both regenerative tissue and therapeutic material simultaneously; therefore, having the benefits of both technologies. PMID- 23678432 TI - Possibility of atherosclerosis in an arterial bifurcation model. AB - INTRODUCTION: Arterial bifurcations are susceptible locations for formation of atherosclerotic plaques. In the present study, steady blood flow is investigated in a bifurcation model with a non-planar branch. METHODS: The influence of different bifurcation angles and non-planar branch is demonstrated on wall shear stress (WSS) distribution using three-dimensional Navier-Stokes equations. RESULTS: The WSS values are low in two locations at the top and bottom walls of the mother vessels just before the bifurcation, especially for higher bifurcation angles. These regions approach the apex of bifurcation with decreasing the bifurcation angle. The WSS magnitudes approach near to zero at the outer side of bifurcation plane and these locations are separation-prone. By increasing the bifurcation angle, the minimum WSS decreases at the outer side of bifurcation plane but low WSS region squeezes. WSS peaks exist on the inner side of bifurcation plane near the entry section of daughter vessels and these initial peaks drop as bifurcation angle is increased. CONCLUSION: It is concluded that the non-planarity of the daughter vessel lowers the minimum WSS at the outer side of bifurcation and increases the maximum WSS at the inner side. So it seems that the formation of atherosclerotic plaques at bifurcation region in direction of non-planar daughter vessel is more risky. PMID- 23678433 TI - Transient Expression of cor Gene in Papaver somniferum. AB - INTRODUCTION: Papaver somniferum is the commercial source of morphine and codeine. The isolation of effective genes involved in the morphine biosynthesis of P. somniferum is very important in the production of specific metabolites achieved using metabolic engi-neering techniques. In this pathway, the key enzyme COR is involved in the conversion of codeinone to codeine and morphinone to morphine. METHODS: the gene encoding of this enzyme was isolated using primers designed on the base of gene sequence available on (NCBI) for P. somniferum. This gene correct size around (960 bp) was first subcloned into pTZ57RIT vector then cloned into expression vectors (pBI121) between BamHI and SacI sites to allow the expression of cor gene driven by the cauliflower mosaic virus 35S pro-moter. The result was confirmed through different molecular methods e.g. PCR and en-zyme digestion by BamHI and SacI. The recombinant plasmid was transformed into the E. coli strain DH5alpha using a freeze-thaw method. Having selected positive colones on selection medium, plasmid was extracted by miniprep method and recombinant plasmids were selected based on PCR and digestion. The construct was then mobilized in Agrobacterium tumefaciens C58/pGV3850 (KmR RifR). After gene transformation to P. somniferum plants, the agroinfiltration method was also used for transient expression of COR enzyme. RESULTS: evaluation results showed that morphine and codeine were detectable in the leaves of transgenic plants containing cor transgene and there was significant difference in the final production. After completing this experiment for three times, results showed that in 11 sets from 15 sets of leaves experiment tested, main alkaloids (codeine, morphine, papaverin, noscapine and thebaine) were detectable. CONCLUSION: Whereas no signal was detected in non-infiltrated control leaves or in leaves infiltrated with non-recombinant bacteria for morphine and codeine, others such as thebaine and papaverine were detectable. PMID- 23678434 TI - Reduction of anterior shoulder dislocation in emergency department; is entonox((r)) effective? AB - INTRODUCTION: An appropriate procedural sedation and analgesia (PSA) is crucial to reduce a dislocated shoulder successfully in emergency department. This study compares sedative effect of inhalational Entonox((r)) (En) to intra-venous (IV) Midazolam plus Fentanyl (F+M). METHODS: 120 patients with recurrent anterior shoulder dislocation were randomly assigned into two groups. 60 patients (group F+M) received 0.1 mg/kg IV Midazolam plus 3ug/kg IV Fentanyl and 60 patients (group En) received Entonox((r)) with self administration face mask on an on demand basis. Traction/counter-traction method was used to reduce the dislocated shoulder joint in both groups. RESULTS: 48 out of 60 (80%) patients in group F+M and 6 out of 60 (10%) patients in group En had successful reduction (p < 0.0001). The mean pain score reduction was 6.3 +/- 1.2 for group F+M and 3 +/- 0.9 for group En (p < 0.0001). There was a statistically significant difference in mean patient satisfaction (assessed with Likert score) between two groups (4.45 +/- 0.6 for group F+M and 2.3 +/- 1 for group En; p < 0.0001). Duration of entire procedure (since the beginning of PSA up to the end of successful or unsuccessful reduction) was shorter in Group F+M, but successful reductions occurred earlier in group En. No major side effect such as airway compromise, retracted respiratory depression, or circulatory failure was occurred in any group. CONCLUSION: Entonox((r)) may not be an appropriate agent to help reducing a dislocated shoulder. PMID- 23678435 TI - Free Radical Scavenging Potential and Essential Oil Composition of the Dorema glabrum Fisch. C.A. Mey Roots from Iran. AB - INTRODUCTION: Dorema glabrum is an endangered species that grow in Transcaucasia and North West of Iran. The plant has extensive uses e.g. as an herbal remedy or food additive in these regions. The chemical composition of hydrodistilled oil of D. glabrum growing in Iran was analyzed by GC-MS for the first time. METHODS: The essential oil of air-dried roots was obtained by hydrodistillation using a Clevenger type apparatus. The oil was sub-jected to GC-MS analysis and its free radical scavenging properties were determined by DPPH method. RESULTS: Thirty four constituents were identified that represented 81.6% of the total oil. The main compounds were delta-Cadinene (12.77%), beta-bisabolene (7.48%), alpha Fenchyl acetate (6.32%), Copaene (5.68%) and Cubenol (5.42%). The essential oil had weak free radical scavenging properties with the RC50 value of 2.24 mg/mL. CONCLUSION: Present work is the first report on chemical composition of the essential oil obtained from D. glabrum roots. GC-MS Analysis showed that the oil was rich in sesquiterpenes. It deems that weak free radical scavenging activity of the oil is due to absence of potent antioxidant compounds. PMID- 23678436 TI - Targeting tumor microenvironment: the key role of immune system. AB - In recent years, huge investigations on cancer progression and invasion have led to under-stand the pivotal role of tumor microenvironment. The current era of cancer therapy is based on the concept of simply targeting precise mechanisms to kill or to suppress the growth and expansion of malignant cells. Clinical data clearly correlate with in-vitro re-sults, emphasizing the direct impact of cancer environment on disease progression. This provides the opportunity to advance cancer therapy by virtue of targeting cancerous cells and non-cancerous component of tumor in a combinatorial manner. This tailor-made strategy demands the profound knowledge of cross talk between the bio-factors of tumor environment and corresponding pharmacology of drug candidates. The neighborhood of tumor is critical for how cancer cells grow and invade surrounding tissues. It appears that the tumor microenvironment as a "co-op" includes malignant cells, blood vessels, im-mune/inflammatory factors and extracellular matrix. As a longstanding dilemma, it is well-proved that immune system plays a direct role in the existence and progression of such coop. In some cases, immune cells e.g. tumor associated macrophages (TAMs) infiltrate into tumor and instead of fighting cancer cells, support them to grow. As an important fact, this tumor complexity should not be taken as granted where it can be advantageous in cancer therapy as well as early detection and prevention. The central aim of this editorial article is to highlight the importance of tumor microenvironment for successful cancer therapy. PMID- 23678437 TI - Impacts of blood-brain barrier in drug delivery and targeting of brain tumors. AB - INTRODUCTION: Entry of blood circulating agents into the brain is highly selectively con-trolled by specific transport machineries at the blood brain barrier (BBB), whose excellent barrier restrictiveness make brain drug delivery and targeting very challenging. METHODS: Essential information on BBB cellular microenvironment were reviewed and discussed towards impacts of BBB on brain drug delivery and targeting. RESULTS: Brain capillary endothelial cells (BCECs) form unique biological structure and architecture in association with astrocytes and pericytes, in which microenvironment the BCECs express restrictive tight junctional complexes that block the paracellular inward/outward traverse of biomolecules/compounds. These cells selectively/specifically control the transportation process through carrier and/or receptor mediated transport machineries that can also be exploited for the delivery of pharmaceuticals into the brain. Intelligent molecular therapies should be designed using such transport machineries for the efficient delivery of designated drugs into the brain. For better clinical outcomes, these smart pharmaceuticals should be engineered as seamless nanosystems to provide simultaneous imaging and therapy (multimodal theranostics). CONCLUSION: The exceptional functional presence of BBB selectively controls inward and outward transportation mechanisms, thus advanced smart multifunctional nanomedicines are needed for the effective brain drug delivery and targeting. Fully understanding the biofunctions of BBB appears to be a central step for engineering of intelligent seamless therapeutics consisting of homing device for targeting, imaging moiety for detecting, and stimuli responsive device for on-demand liberation of therapeutic agent. PMID- 23678439 TI - Prophylactic Antibiotic Therapy in Contaminated Traumatic Wounds: Two Days versus Five Days Treatment. AB - INTRODUCTION: Emergency department manages several kinds of wounds including simple, non-bite traumatic wounds and lacerations. Prophylactic antibiotic therapy is one of pre-scribed treatment in these conditions. We aimed to compare the clinical efficacy of the two day regimen of prophylactic antimicrobial agents with the five day regimen in simple traumatic but highly contaminated wounds. METHODS: Between January 2010 and May 2010, patients presenting with simple traumatic wounds or lacerations in different parts of the body, highly contaminated with soil, debris or feces in emergency department of a referral educational hospital in Tehran (Rasul-Akram hospital), Iran, went for primary closure. All of the patients were provided prophylactic antibiotic, however, prescribed for one group (A) of patients for 2 days and other group (B) received for 5 days, according to the physician concerned. As these treatments were routine, we selected 70 patients from each group using table of random numbers. The patients were warned about the signs of infection including long-lasting erythema, purulent discharge and inflammation and were supposed to inform the concerned physician in any of such alarming situations. Oral Cephalexin 500 mg qid was prescribed for all patients enrolled for prophylaxis treatment. RESULTS: On follow-up 11 (8.2%) patients were found to develop sutured site infection (6 out of 70 (8.57%) in group A, and five out of 70 (7.14%) in group B (P=0.31)). There was no statistical difference between infection rates between men (8.6%) in comparison to women (6.25%) (P>0.05; CI=95%). CONCLUSION: Our study showed that 2 day prophylactic antibiotic therapy using Cephalexin is at least as effective as a 5-day regimen in relation to development of surgical site infection in patients with simple traumatic contaminated wounds or lacerations. PMID- 23678438 TI - An update to space biomedical research: tissue engineering in microgravity bioreactors. AB - INTRODUCTION: The severe need for constructing replacement tissues in organ transplanta-tion has necessitated the development of tissue engineering approaches and bioreactors that can bring these approaches to reality. The inherent limitations of conventional bioreactors in generating realistic tissue constructs led to the devise of the microgravity tissue engineering that uses Rotating Wall Vessel (RWV) bioreactors initially developed by NASA. METHODS: In this review article, we intend to highlight some major advances and accomplishments in the rapidly-growing field of tissue engineering that could not be achieved without using microgravity. RESULTS: Research is now focused on assembly of 3 dimensional (3D) tissue fragments from various cell types in human body such as chon-drocytes, osteoblasts, embryonic and mesenchymal stem cells, hepatocytes and pancreas islet cells. Hepatocytes cultured under microgravity are now being used in extracorporeal bioartificial liver devices. Tissue constructs can be used not only in organ replacement therapy, but also in pharmaco toxicology and food safety assessment. 3D models of vari-ous cancers may be used in studying cancer development and biology or in high-throughput screening of anticancer drug candidates. Finally, 3D heterogeneous assemblies from cancer/immune cells provide models for immunotherapy of cancer. CONCLUSION: Tissue engineering in (simulated) microgravity has been one of the stunning impacts of space research on biomedical sciences and their applications on earth. PMID- 23678440 TI - Effects of orange juice and hesperetin on serum paraoxonase activity and lipid profile in hyperuricemic rats. AB - INTRODUCTION: Hypouricemic, antioxidant and xanthine oxidase inhibitory effects of orange juice and hesperetin have been already indicated. The objective of this study was to investigate the effects of orange juice and hesperetin on paraoxonase and arylesterase activity and lipid profile of hyperuricemic rats. METHODS: Forty eight male Wistar rats were divided into 8 equal groups of healthy control, healthy+orange juice, healthy+hesperetin, healthy+allopurinol, hyperuricemic control, hyperuricemic+orange juice, hyperurice-mic+hesperetin and hyperuricemic+allopurinol. Hyperuricemia was induced using potassi-um oxonate (250 mg/kg ip). The treatments were carried out by daily gavage of 5 ml/kg orange juice, 5 mg/kg hesperetin and 5 mg/kg allopurinol for 2 weeks. Paraoxonase activi ty in serum was measured spectrophotometrically using paraoxon and phenylacetate as substrates. Serum lipids levels were determined using enzymatic colorimetric methods. RESULTS: Hyperuricemia-induced reduction of paraoxonase and arylesterase activity was restored after treatment with orange juice and hesperetin (p<0.05). The effect of both treatments on lipid profile was marginal and only orange juice could significantly increase the levels of HDL-C. CONCLUSION: Supplementation of orange juice and hesperetin could restore paraoxonase and arylesterase activity in hyperuricemic rats. Orange juice could also partially improve the lipid profile. These effects could have major implications with respect to the prevention of cardiovascular disease in hyperuricemic patients. However, more studies are needed in future investigations. PMID- 23678441 TI - Antioxidant, total phenol and flavonoid contents of two pedicularis L. Species from eastern azerbaijan, iran. AB - INTRODUCTION: Pedicularis sibthorpii and P. wilhelmsiana are endemic species mainly found in North-West of Iran. Plants of genus Pedicularis produce some important poly-phenols and flavonoids. In the present work, total phenol and flavonoid contents of the mentioned species as well as their antioxidant capacity have been evaluated. METHODS: Methanol extract of samples was fractionated by SPE method using an ODS cartridge and their (1)H-NMR spectra were recorded. Total phenols and flavonoids of methanol extracts were determined using Folin- Ciocalteu and aluminum chloride methods. For determining antioxidant activity of the extracts and fractions, bleaching of purple color methanol solu-tion of 1, 1 diphenylpycryl hydrazyl (DPPH) was measured by spectrophotometric assay. RESULTS: Total phenols of Pedicularis sibthorpii and P. wilhelmsiana were in the range of 8-30 mg g(-1) and 9-20 mg g(-1), respectively. The 40% and 60% fractions of P. sibthorpii and the 20%, 40% and 60% fractions of P. wilhelmsiana showed higher amounts of phenolic compounds. The total flavonoid contents of P. sibthorpii and P. wilhelmsiana were in the range of 0-215 mg g(-1) and 0-177 mg g(-1), respectively, whereas the 40% and 60% fractions showed higher flavonoid amounts. Antioxidant activity of P. sibthorpii and P. wil-helmsiana were in the range of 0.01-0.7 mg mL(-1) and 0.01-1.02 mg mL(-1). In the same manner, the 20% and 40% fractions of P. sibthorpii and the 40% and 60% fractions of P. wilhelmsiana had lower RC50 than that of other fractions. CONCLUSION: Fractions with lower RC50 had higher contents of phenolic and flavonoid compounds. The results of NMR spectra were parallel with these findings and show that it is worth to do phytochemi-cal studies on P. sibthorpii and P. wilhelmsiana. PMID- 23678442 TI - Promoters of cancer genes for recombinant protein expression in human cancer cell lines. AB - INTRODUCTION: Production of complex human recombinant proteins is an important issue in medical biotechnology. These proteins are mostly expressed in non-human mammalian host cells. This has some problems including non-human post translational modifications, application of high-cost agents for inducing protein expression and low yields. Thus, it is necessary to use new expression systems to overcome the indicated challenges. METHODS: In this paper, we hypothesize the application of promoter regions of cancer genes, which have a high rate of transcription in human cancer cell lines, for designing new expression vectors. RESULTS: After designing, these vectors could be applied to produce complex hu man recombinant proteins in the human cancer cell lines as production hosts. CONCLUSION: Application of these expression vectors for the production of recombinant human proteins in the human cancer cell lines have some advantages including authentic post-translational modifications, proper-cost of commercialization, and high yields. PMID- 23678443 TI - How to select a journal to submit and publish your biomedical paper? AB - INTRODUCTION: journal selection for publication purposes is one of the concerns of biomedi-cal researchers. They apply various criteria for choosing appropriate journal. Here, we have tried to collect main criteria biomedical researchers use to select a journal to submit their works. METHODS: we collected these criteria through focus group conversations with researchers during our careers, feedbacks from participants of our scientific writing work-shops and non-systematic review of some related literature. RESULTS: we have presented a summative and informative guidance in the selection of journals for biomedical paper submission and publication. CONCLUSION: Categorized criteria as a mnemonic tool for au-thors may help the authors in journal selection process. PMID- 23678444 TI - Nanocapsules: the weapons for novel drug delivery systems. AB - INTRODUCTION: Nanocapsules, existing in miniscule size, range from 10 nm to 1000 nm. They consist of a liquid/solid core in which the drug is placed into a cavity, which is surrounded by a distinctive polymer membrane made up of natural or synthetic polymers. They have attracted great interest, because of the protective coating, which are usually pyrophoric and easily oxidized and delay the release of active ingredients. METHODS: Various technical approaches are utilized for obtaining the nanocapsules; however, the methods of interfacial polymerization for monomer and the nano-deposition for preformed polymer are chiefly preferred. Most important characteristics in their preparation is particle size and size distribution which can be evaluated by using various techniques like X-ray diffraction, scanning electron microscopy, transmission electron microscopy, high-resolu!tion transmission electron microscopy, X-ray photoelectron spectroscopy, superconducting quantum interference device, multi angle laser light scattering and other spectroscopic techniques. RESULTS: Nanocapsules possessing extremely high reproducibility have a broad range of life science applications. They may be applied in agrochemicals, genetic engineering, cosmetics, cleansing products, wastewater treatments, adhesive component applications, strategic delivery of the drug in tumors, nanocapsule bandages to fight infec!tion, in radiotherapy and as liposomal nanocapsules in food science and agriculture. In addition, they can act as self-healing materials. CONCLUSION: The enhanced delivery of bio!active molecules through the targeted delivery by means of a nanocapsule opens numerous challenges and opportunities for the research and future development of novel improved therapies. PMID- 23678445 TI - Applications of diatoms as potential microalgae in nanobiotechnology. AB - INTRODUCTION: Diatoms are single cell eukaryotic microalgae, which present in nearly every water habitat make them ideal tools for a wide range of applications such as oil explora-tion, forensic examination, environmental indication, biosilica pattern generation, toxicity testing and eutrophication of aqueous ecosystems. METHODS: Essential information on diatoms were reviewed and discussed towards impacts of diatoms on biosynthesis and bioremediation. RESULTS: In this review, we present the recent progress in this century on the application of diatoms in waste degradation, synthesis of biomaterial, biomineraliza-tion, toxicity and toxic effects of mineral elements evaluations. CONCLUSION: Diatoms can be considered as metal toxicity bioindicators and they can be applied for biomineralization, synthesis of biomaterials, and degradation of wastes. PMID- 23678446 TI - Electrochemical impedance spectroscopic sensing of methamphetamine by a specific aptamer. AB - INTRODUCTION: Electrochemical impedance spectroscopy (EIS) is a simple and highly sensitive technique that can be used for evaluation of the aptamer-target interaction even in a label-free approach. METHODS: To pursue the effectiveness of EIS, in the current study, the folding properties of specific aptamer for methamphetamine (METH) (i.e., aptaMETH) were evaluated in the presence of METH and amphetamine (Amph). Folded and unfolded aptaMETH was mounted on the gold electrode surface and the electron charge transfer was measured by EIS. RESULTS: The Ret of methamphetamine-aptaMETH was significantly increased in comparison with other folding conditions, indicating specific detection of METH by aptaMETH. CONCLUSION: Based on these findings, methamphetamine-aptaMETH on the gold electrode surface displayed the most interfacial electrode resistance and thus the most folding situation. This clearly indicates that the aptaMETH can profoundly and specifically pinpoint METH; as a result we suggest utilization of this methodology for fast and cost-effective identification of METH. PMID- 23678447 TI - Novel aldehyde-terminated dendrimers; synthesis and cytotoxicity assay. AB - INTRODUCTION: Polyamidoamine (PAMAM) dendrimers are a unique family of dendritic polymers with numerous pharmaceutical and biomedical applications. One major problem with these polymers is their cytotoxicity. The purpose of this study was to synthesize novel dendrimers with aldehyde terminal groups and compare their cytotoxicity with that of dendri!mers containing amine-terminated groups. METHODS: G1(first generation) and G2 (second generation) dendrimers with amine terminated groups were synthesized by divergent method and then the amine terminated groups were converted to the aldehyde groups using surface modification of the functional group inversion (FGI) method. The cytotoxicity of the novel G1 and G2 polyamidoaldehyde (PAMAL) dendrimers together with that of G1 and G2 PAMAM-NH2 dendrimers was investigated by MTT assay using MCF-7 cell line. RESULTS: The results showed that cytotoxicity of dendrimers with aldehyde terminated groups is much lower than that of G1 and G2 PAMAM-NH2 dendri!mers. CONCLUSION: Dendrimers with aldehyde-terminated groups could be used as novel and convenient carriers for drug delivery with low cytotoxic effect compared with the amine-terminated dendrimers. The results revealed that the same generations of the dendri!mers with aldehyde-terminated groups are far less toxic than the corresponding amine-terminated dendrimers. PMID- 23678448 TI - Ontogenetic Variation of Total Phenolics and Antioxidant Activity in Roots, Leaves and Flowers of Astragalus compactus Lam. (Fabaceae). AB - INTRODUCTION: The potential health risks and toxicity of synthetic antioxidants resulted in an upsurge of interest in phytochemicals as new sources of natural antioxidants. Phenolics of Astragalus L. (Fabaceae) possess antioxidant properties and have been shown to have a protective effect against several degenerative diseases. The objective of this study was to determine total phenolics and antioxidant activity of methanolic extracts from different parts of A. compactus Lam. at different phenological phases and to investigate the correlations between antioxidation and the contents of the total phenolics. METHODS: Total phenolic content (TPC) was determined using the Folin-Ciocalteau reagent and the antioxidant capacity was evaluated with the 1,1-diphenyl-2 picrylhydrazyl (DPPH) test. RESULTS: Generally, the TPC in leaves was higher than that of the roots and flowers. TPC in leaves, roots and flowers of the species varied from 5.01-8.25, 4.29-7.89 and 4.19 MUg GAE/mg DW, respectively. In addition, roots and leaves at fructification stage possessed higher TPC than vegetative and flowering stages. Therefore, the leaf extracts at fructification phase showed the highest TPC that accompanied with best antioxidant activity. In the root extracts, fructification stage was also characterized by the highest antioxidant activity. CONCLUSION: A positive relationship between antioxidant activity and TPC showed that phenolics were the dominant antioxidant components in the species. The results obtained suggest that A. compactus methanolic extracts may serve as potential sources of natural phenolic antioxidants and that the fructification phase could be considered as the best stage for the harvesting of this plant. PMID- 23678449 TI - Research Performances of Organization of Islamic Conference (OIC) Members. AB - INTRODUCTION: Scientometric analysis of academic institutions provides useful information for policy makers, international and national organizations to invest in the research fields of the institutions to gain more outputs with less cost. The objectives of this work were to report a scientometric analysis of Islamic states considering a number of indicators. METHODS: The number of articles and patents published by members of organization of Islamic conference were extracted from Scopus(TM) along with the top journals, authors, document type, universities, language of the publications and subjects. RESULTS: The analyses of data revealed that Turkey is the leading country followed by Iran, Egypt, Malaysia and Nigeria when total numbers of indexed articles in Scopus(TM) are considered. When the articles of 2006-2010 are considered the ranks are Turkey, Iran, Malaysia, Egypt and Pakistan. CONCLUSION: the increased pattern was observed for scientific performances of OIC members however, more investments are required to fill the gap between OIC members and the leading countries. PMID- 23678450 TI - Recombinant proteins: hopes for tissue engineering. AB - Proteins constitute a group of key molecules with many applications in tissue engineering. Use of proteins provided from natural sources has several limitations which are overcome by the use of recombinant proteins. So far, the recombinant forms of many proteins with tissue engineering applications have been developed including structural proteins, growth factors and cytokines. This technology has enabled the development of specifically designed proteins such as growth factors with matrix binding domains, and hybrid structural proteins with improved mechanical properties. Recombinant proteins are produced either ex vivo or in vivo, by local gene therapy protocols, and are of medical and economic benefits. Due to the high applicability of recombinant proteins in tissue engineering, it is recommended to include this platform as an infrastructural element in any tissue engineering program. PMID- 23678451 TI - Translational Approaches towards Cancer Gene Therapy: Hurdles and Hopes. AB - INTRODUCTION: Of the cancer gene therapy approaches, gene silencing, suicide/apoptosis inducing gene therapy, immunogene therapy and targeted gene therapy are deemed to sub-stantially control the biological consequences of genomic changes in cancerous cells. Thus, a large number of clinical trials have been conducted against various malignancies. In this review, we will discuss recent translational progresses of gene and cell therapy of cancer. METHODS: Essential information on gene therapy of cancer were reviewed and discussed towards their clinical translations. RESULTS: Gene transfer has been rigorously studied in vitro and in vivo, in which some of these gene therapy endeavours have been carried on towards translational investigations and clinical applications. About 65% of gene therapy trials are related to cancer therapy. Some of these trials have been combined with cell therapy to produce personalized medicines such as Sipuleucel-T (Provenge(r), marketed by Dendreon, USA) for the treatment of asymptomatic/minimally symptomatic metastatic hormone-refractory prostate cancer. CONCLUSION: Translational approach links two diverse boundaries of basic and clinical researches. For successful translation of geno-medicines into clinical applications, it is essential 1) to have the guidelines and standard operating procedures for development and application of the genomedicines specific to clinically relevant biomarker(s); 2) to conduct necessary animal experimental studies to show the "proof of concept" for the proposed genomedicines; 3) to perform an initial clinical investigation; and 4) to initiate extensive clinical trials to address all necessary requirements. In short, translational researches need to be refined to accelerate the geno medicine development and clinical applications. PMID- 23678453 TI - Effect of turmeric and carrot seed extracts on serum liver biomarkers and hepatic lipid peroxidation, antioxidant enzymes and total antioxidant status in rats. AB - INTRODUCTION: Pathogenic role of free radicals are well known in various metabolic diseases. They originate from internal and external sources of body. Essential roles of antioxidant defense system for cellular redox regulation and free radical scavenging activity were described in this study. Many in vitro investigations have shown that turmeric (TE) and carrot seed extract (CSE) exhibits to possess antioxidant activities. In this study, we evaluated the antioxidant potentials of ethanolic TE and CSE based on in vivo experiment in the rats. METHODS: ANIMALS WERE ASSIGNED TO SIX GROUPS: the 1st and 2nd groups were control groups and 2nd group received 0.2 ml dimethyl sulphoxide as vehicle treated group; other four experimental groups received different doses of TE (100, 200 mg/kg b.w.) and CSE (200, 400 mg/kg b.w.) by gavages, respectively for a period of one month. The indicators of oxidative stress, lipids peroxidation, markers of hepatocyte injury and biliary function markers were measured. RESULTS: The levels of superoxide dismutase, catalase, and glutathione peroxidase were significantly stimulated in the hepatic tissue of treatment groups. The malondialdehyde contents of liver tissue were significantly reduced in the groups fed with TE and CSE. Serum levels of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase, in treated groups were found to be significantly decreased, whereas albumin and total protein increased as compared to the control groups (P<0.05). CONCLUSION: this study showed that the regular intake of TE and CSE through the diet can improve antioxidant status and inhibit peroxidation activity in the liver tissue so that using these extracts may protect tissue oxidative stress. PMID- 23678452 TI - Inhibition of MEK/ERK1/2 Signaling Affects the Fatty Acid Composition of HepG2 Human Hepatic Cell Line. AB - INTRODUCTION: The extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase pathway, also known as the MEK/ERK1/2 kinase cascade, has recently been implicated in the regulation of lipid metabolism and fatty liver disease. However, its functional effect on cellular fatty acid composition is unknown. Herein, we examined the effect of a pharmacological inhibitor of MEK, the upstream kinase activator of ERK1/2, on fatty acid composition of hepatocellular carcinoma cell line HepG2. METHODS: HepG2 cells cultured in RPMI-1640 were exposed to the commonly used ERK1/2 pathway inhibitor PD98059 and were investigated with respect to fatty acid composition by gas-liquid chromatography. RESULTS: Exposure of cells to the ERK1/2 pathway inhibitor induced an increase in monounsaturated fatty acids and the fatty acid desaturation index and a decrease in polyunsaturated fatty acid content. Specifically, we showed a significant increase of oleic acid (18:1n-9; +29%, P=0.003) and arachidonic acid (20:4n 6)/linoleic acid (18:2n-6) ratio (3.5-fold; P<0.001) in HepG2 cells. CONCLUSION: Cellular fatty acid composition of HepG2 cells appeared to be differentially regulated by ERK1/2 pathway, thus suggesting related metabolic pathways as potential mediators of the effects of ERK1/2 signaling on hepatic fatty acid composition. PMID- 23678454 TI - Assessment of Long-Lasting Insecticidal Nets (LLINs) on Vectors and Malaria Transmission in the Commune of Aguegues, Benin. AB - INTRODUCTION: To overcome the problems of periodic re-impregnation of mosquito nets and low rates of treatment, the commune of Aguegues was chosen to evaluate the effects of Olyset((r)) nets on malaria transmission and against An. gambiae. METHODS: 87 old Olyset((r)) nets installed five years ago were identified in the village 'Akpadon'. 10 untreated nets were installed in 10 structures of type "a bedroom and parlour" in the village 'Akodji'. Four rooms without nets were identified in the village 'Donoukpa'. Entomological and epidemiological evaluations were conducted during the May to October 2011. 24 sessions of capture or 2088 men-nights resulted in the capture of 30,608 mosquitoes. RESULTS: The entrance of anopheles was significantly reduced in the village with Olyset((r)) nets. 45% of mosquitoes captured inside rooms with Olyset((r)) nets were found dead after 24 hrs of obser-vation. Overall, parasitemia was very low in the treated village (4.52%). 18 (4.64%) cases of malaria fever were from Akpadon with 7.5% positive blade smear, 29 (10.98%) were from Akodji with 8.37% positive blade smear, and 80 (95.23%) come from Donoukpa with 38.09% positive blade smear. The Olyset((r)) nets and untreated net were adjusted hemoglobin levels. CONCLUSION: Olyset((r)) net had a very high knock down effect and is an alternative in malaria control. PMID- 23678455 TI - Evaluation of ovarian reserve after laparoscopic surgery in patients with polycystic ovary syndrome. AB - INTRODUCTION: Ovarian reserve depends on the size and quality of oocytes stored in ovary. Aging and some diseases reduce ovarian reserve, leading to decreased reproductive performance. Laparoscopic surgery is used to treat infertility in women with PCOS. The purpose of this study was measurement of ovarian reserve in patients with PCOS before and after laparoscopic surgery. METHODS: In this study thirty infertile patients with PCOS that had not responded to initial treatment with drug were selected. We assessed the serum levels of anti-mullerian hormone, testosterone, luteinizing hormone (LH), and the number of antral follicles before laparoscopic surgery and 1 week, 3 and 6 months after the surgery. RESULTS: The average amount of anti-mullerian hormone serum levels was 8.4+/-4.7 before laparoscopic surgery and 7.5+/-4.5, 7+/-4.5, and 7.7+/-4.4 ng/ml one week, 3 and 6 months after surgery, respectively. Serum levels of LH was 13.6+/-6.7 and 12.7+/-11.1 IU /ml (P=0.87) before surgery and 6 months after laparoscopy, respectively. Mean serum testosterone levels were 0.9+/-0.8, 0.8+/-0.9 ng/ml (P=0.86) before and after surgery. Annual reproductive rate was 26.7 percent in this population. CONCLUSION: Laparoscopic ovarian puncture didn't change anti mullerian hormone serum, testosterone and LH in women with PCOS and hence has no adverse effects on the ovarian reserve. PMID- 23678456 TI - How to Manage Rejected Scientific Papers? UNAIS as Final Solution. AB - Before publication, biomedical papers might undergo a very complex process, from journal selection, authors' motivations for submissions, modifications, and final publication or refusal. UNAIS (Unpublished Articles In Science) is an online repository in which authors can publish previously rejected scientific articles or articles that have never been submitted for publication. At UNAIS, authors can also publish the reasons behind the refusals to publication. UNAIS is more than an e-journal: it is a scientific drop box in which scientists can find indicative and negative results, as well as ideas that can inspire others. UNAIS's goal is also to help students and scientists who want to learn how to write scientific articles. UNAIS' aim is to exchange and promote knowledge. Have a look on www.unais.net. PMID- 23678457 TI - Pharmaceutical nanoparticles and the mucin biopolymer barrier. AB - Mucus in the gastrointestinal tract remains a tenacious barrier that restricts the passage of many orally administered compounds into the GIT's epithelial layer and consequently into the systemic circulation. This results in significant decreases in the oral bioavailability of many therapeutic molecules. Nanoparticles offer an avenue to surpass this mucus barrier. They can be used as drug carriers to improve the bioavailability of many compounds that are restricted by mucus. Nanoparticles achieve penetration of the mucus barrier through a multitude of properties that they possess as their size, charge density, and surface functional groups which can all be tailored to achieve optimal penetration of the thick and fibrous mucus barrier. This article offers a quick review about the use of nanoparticles as drug carriers to increase mucus penetration in the gastro intestinal tract. PMID- 23678458 TI - The role of oral controlled release matrix tablets in drug delivery systems. AB - Formulations that are able to control the release of drug have become an integral part of the pharmaceutical industry. In particular oral drug delivery has been the focus of pharmaceutical research for many years. This type of drug delivery has been at the centre of research due to its many benefits over conventional dosage. The focus of this review is on matrix tablets due to their widely use and simplicity of the formulation. This includes the discussion of various types of matrix tablets and factors affecting the drug release from these formulations. The mechanism of drug release from HPMC matrices is also discussed. PMID- 23678459 TI - Effect of Aggregated beta-Amyloid (1-42) on Synaptic Plasticity of Hippocampal Dentate Gyrus Granule Cells in Vivo. AB - INTRODUCTION: Alzheimer's disease (AD) is a common neurodegenerative disorder in elderly people with an impairment of cognitive decline and memory loss. beta amyloid (Abeta) as a potent neurotoxic peptide has a pivotal role in the pathogenesis of AD. This disease begins with impairment in synaptic functions before developing into later neuro!degeneration and neuronal loss. The aim of this study was to evaluate the synaptic plasticity and electrophysiological function of granule cells in hippocampal dentate gyrus (DG) after intracerebroventricular (i.c.v.) administration of aggregated Abeta (1-42) peptide in vivo. METHODS: Animals were divided to control and Abeta (1-42) groups. Long-term potentia!tion (LTP) in perforant path-DG synapses was assessed in order to investigate the effect of aggregated Abeta (1-42) on synaptic plasticity. Field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude were measured. RESULTS: Administration of Abeta (1-42) significantly decreased fEPSP slope and PS amplitude in Abeta (1-42) group comparing with the control group and had no effect on baseline activity of neurons. CONCLUSION: The present study indicates that administration of aggregated form of Abeta (1-42) into the lateral ventricle effectively inhibits LTP in granular cells of the DG in hippocampus in vivo. PMID- 23678460 TI - Numerical investigation of pulsatile blood flow in a bifurcation model with a non planar branch: the effect of different bifurcation angles and non-planar branch. AB - INTRODUCTION: Atherosclerosis is a focal disease that susceptibly forms near bifurcations, anastomotic joints, side branches, and curved vessels along the arterial tree. In this study, pulsatile blood flow in a bifurcation model with a non-planar branch is investigated. METHODS: Wall shear stress (WSS) distributions along generating lines on vessels for different bifurcation angles are calculated during the pulse cycle. RESULTS: The WSS at the outer side of the bifurcation plane vanishes especially for higher bifurcation angles but by increasing the bifurcation angle low WSS region squeezes. At the systolic phase there is a high possibility of formation of a separation region at the outer side of bifurcation plane for all the cases. WSS peaks exist on the inner side of bifurcation plane near the entry section of daughter vessels and these peaks drop as bifurcation angle is increased. CONCLUSION: It was found that non-planarity of the daughter vessel lowers the minimum WSS at the outer side of the bifurcation and increases the maximum WSS at the inner side. So it seems that the formation of atherosclerotic plaques at bifurcation region in direction of non-planar daughter vessel is more risky. PMID- 23678461 TI - Allelic Prevalence of ABO Blood Group Genes in Iranian Azari Population. AB - INTRODUCTION: ABO blood group system is the most important blood group in transfusion and has been widely used in population studies. Several molecular techniques for ABO allele's detection are widely used for distinguishing various alleles of glycosyl transferase locus on chromosome 9. METHODS: 744 randomly selected samples from Azari donors of East Azerbaijan province (Iran) were examined using well-adjusted multiplex allele- specific PCR ABO genotyping technique. RESULTS: The results were consistent for all individuals. The ABO blood group genotype of 744 healthy Azari blood donors was: 25.8% AA/AO (2), 7.6% AO (1), 1.6% BB, 11.3% B0 (1), 10% AB, 9.3% 0(1)0(1) and 15.3%0(1)0(2). The highest genotype frequency belonged to O01/O02 genotype (15.3%) and the lowest frequency belonged to A101/A102 genotype (0.4%). CONCLUSIONS: The frequencies of ABO alleles didn't show significant differences between East Azerbaijan province population and that of other areas of the country. Meanwhile, statistical analysis of frequencies of A and B alleles between East Azerbaijan province population and neighbor countries showed significant differences whereas the frequency of allele O between them did not show significant difference (P>0.05). CONCLUSIONS: The frequencies of ABO alleles didn't show significant differences between East Azerbaijan province population and that of other areas of the country. Meanwhile, statistical analysis of frequencies of A and B alleles between East Azerbaijan province population and neighbor countries showed significant differences whereas the frequency of allele O between them did not show significant difference (P>0.05). PMID- 23678462 TI - Annual fasting; the early calories restriction for cancer prevention. AB - Essentially, people's diet and nutritional status has been changed substantially worldwide and several lines of evidence suggest that these changes are to the detriment of their health. Additionally, it has been well documented that unhealthy diet especially the fast foods, untraditional foods or bad-eating habits influence the human gut microbiome. The gut microbiota shapes immune responses during human life and affects his/her metabolomic profiles. Furthermore, many studies highlight the molecular pathways that mediate host and symbiont interactions that regulate proper immune function and prevention of cancer in the body. Intriguingly, if cancer forms in a human body due to the weakness of immune system in detriment of microbiome, the removal of cancer stem cells can be carried out through early Calories Restriction with Annual Fasting (AF) before tumor development or progress. Besides, fasting can balance the gut microbiome for enhancement of immune system against cancer formation. PMID- 23678463 TI - Heavy Chain Only Antibodies: A New Paradigm in Personalized HER2+ Breast Cancer Therapy. AB - Unlike conventional antibodies, heavy chain only antibodies derived from camel contain a single variable domain (VHH) and two constant domains (CH2 and CH3). Cloned and isolated VHHs possess unique properties that enable them to excel conventional therapeutic antibodies and their smaller antigen-binding fragments in cancer targeting and therapy. VHHs express low immunogenicity, are highly robust and easy to manufacture and have the ability to recognize hidden or uncommon epitopes. We highlight the utility of VHH in design of new molecular, multifunctional particulate and immune cell-based systems for combating HER2+ breast cancer. PMID- 23678464 TI - The role of epidermal growth factor receptor in diabetes-induced cardiac dysfunction. AB - The incidence of diabetes mellitus is increasing rapidly and set to reach near epidemic proportions with the latest estimates suggesting that by 2030 there will be over 550 million people with this debilitating disease. Cardiovascular complications and dysfunctions are three- to eight-folds more likely in diabetic patients and are major causes of increased mortality. The exact underlying mechanisms for the development of complications of the diabetic heart are poorly understood and may involve multiple signaling pathways that are affected by hyperglycemia. This focused article reviews the recent evidence for a possible dual role of epidermal growth factor receptor signaling in diabetes-induced cardiac dysfunction. PMID- 23678466 TI - QSAR models for the prediction of plasma protein binding. AB - INTRODUCTION: The prediction of plasma protein binding (ppb) is of paramount importance in the pharmacokinetics characterization of drugs, as it causes significant changes in volume of distribution, clearance and drug half life. This study utilized Quantitative Structure - Activity Relationships (QSAR) for the prediction of plasma protein binding. METHODS: Protein binding values for 794 compounds were collated from literature. The data was partitioned into a training set of 662 compounds and an external validation set of 132 compounds. Physicochemical and molecular descriptors were calculated for each compound using ACD labs/logD, MOE (Chemical Computing Group) and Symyx QSAR software packages. Several data mining tools were employed for the construction of models. These included stepwise regression analysis, Classification and Regression Trees (CART), Boosted trees and Random Forest. RESULTS: Several predictive models were identified; however, one model in particular produced significantly superior prediction accuracy for the external validation set as measured using mean absolute error and correlation coefficient. The selected model was a boosted regression tree model which had the mean absolute error for training set of 13.25 and for validation set of 14.96. CONCLUSION: Plasma protein binding can be modeled using simple regression trees or multiple linear regressions with reasonable model accuracies. These interpretable models were able to identify the governing molecular factors for a high ppb that included hydrophobicity, van der Waals surface area parameters, and aromaticity. On the other hand, the more complicated ensemble method of boosted regression trees produced the most accurate ppb estimations for the external validation set. PMID- 23678465 TI - Formulation study of topically applied lotion: in vitro and in vivo evaluation. AB - INTRODUCTION: This article presents the development and evaluation of a new topical formulation of diclofenac diethylamine (DDA) as a locally applied analgesic lotion. METHODS: To this end, the lotion formulations were formulated with equal volume of varying concentrations (1%, 2%, 3%, 4%; v/v) of permeation enhancers, namely propylene glycol (PG) and turpentine oil (TO). These lotions were subjected to physical studies (pH, viscosity, spreadability, homogeneity, and accelerated stability), in vitro permeation, in vivo animal studies and sensatory perception testing. In vitro permeation of DDA from lotion formulations was evaluated across polydimethylsiloxane membrane and rabbit skin using Franz cells. RESULTS: It was found that PG and TO content influenced the permeation of DDA across model membranes with the lotion containing 4% v/v PG and TO content showed maximum permeation enhancement of DDA. The flux values for L4 were 1.20+/ 0.02 MUg.cm(-2).min(-1) and 0.67 +/- 0.02 MUg.cm(-2).min(-1) for polydimethylsiloxane and rabbit skin, respectively. Flux values were significantly different (p < 0.05) from that of the control. The flux enhancement ratio of DDA from L4 was 31.6-fold and 4.8-fold for polydimethylsiloxane and rabbit skin, respectively. In the in vivo animal testing, lotion with 4% v/v enhancer content showed maximum anti-inflammatory and analgesic effect without inducing any irritation. Sensatory perception tests involving healthy volunteers rated the formulations between 3 and 4 (values ranging between -4 to +4, indicating a range of very bad to excellent, respectively). CONCLUSION: It was concluded that the DDA lotion containing 4% v/v PG and TO exhibit the best performance overall and that this specific formulation should be the basis for further clinical investigations. PMID- 23678467 TI - Effect of photon beam energy, gold nanoparticle size and concentration on the dose enhancement in radiation therapy. AB - INTRODUCTION: Gold nanoparticles have been used as radiation dose enhancing materials in recent investigations. In the current study, dose enhancement effect of gold nanoparticles on tumor cells was evaluated using Monte Carlo (MC) simulation. METHODS: We used MCNPX code for MC modeling in the current study. A water phantom and a tumor region with a size of 1*1*1 cm3 loaded with gold nanoparticles were simulated. The macroscopic dose enhancement factor was calculated for gold nanoparticles with sizes of 30, 50, and 100 nm. Also, we simulated different photon beams including mono-energetic beams (50-120 keV), a Cobalt-60 beam, 6 & 18 MV photon beams of a conventional linear accelerator. RESULTS: We found a dose enhancement factor (DEF) of from 1.4 to 3.7 for monoenergetic kilovoltage beams, while the DEFs for megavoltage beams were negligible and less than 3% for all GNP sizes and concentrations. The optimum energy for higher DEF was found to be the 90 keV monoenergetic beam. The effect of GNP size was not considerable, but the GNP concentration had a substantial impact on achieved DEF in GNP-based radiation therapy. CONCLUSION: The results were in close agreement with some previous studies considering the effect of photon energy and GNP concentration on observed DEF. Application of GNP-based radiation therapy using kilovoltage beams is recommended. PMID- 23678468 TI - Development of a Microemulsion High Performance Liquid Chromatography (MELC) Method for Determination of Salbutamol in Metered-Dose Inhalers (MDIS). AB - INTRODUCTION: A sensitive and rapid oil-in-water (O/W) microemulsion high performance liquid chromatography (MELC) method has been developed. The water-in oil (w/o) microemulsion was used as a mobile phase in the determination of salbutamol in aqueous solutions. In addition, the influence of operating parameters on the separation performance was examined. METHODS: The samples were injected into C18, (250mm*4.6mm) analytical columns maintained at 25(o)C with a flow rate 1 ml/min. The mobile phase was 95.5% v/v aqueous orthophosphate buffer 20 mM (adjusted to pH 3 with orthophosphoric acid), 0.5% ethyl acetate, 1.5% Brij35, and 2.5% 1-butanol, all w/w. The salbutamol and internal standard peaks were detected by fluorescence detection at the excitation and emission wavelengths of 267 and 313 nm respectively. RESULTS: The method had an accuracy of > 97.78% and the calibration curve was linear (r2 = 0.99) over salbutamol concentrations ranging from 25 to 500 ng/mL. The intra-day and inter-day precisions (CV %) were <1.6 and <1.8, respectively. The limit of detection (LOD) and limit of quantitation (LOQ) were 9.61ng/ml and 29.13ng/ml, respectively. CONCLUSION: The method reported is simple, precise and accurate, and has the capacity to be used for determination of salbutamol in the pharmaceutical preparation. PMID- 23678469 TI - Association of Expanded Disability Status Scale and Cytokines after Intervention with Co-supplemented Hemp Seed, Evening Primrose Oils and Hot-natured Diet in Multiple Sclerosis Patients(?). AB - INTRODUCTION: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Because of limited efficacy and adverse side effects, identifying novel therapeutic and protective agents is important. The aim of this study is to examine the correlations between expanded disability status scale (EDSS) and cytokines after intervention with co-supplemented hemp seed and evening primrose oils and hot-natured diet in patients with relapsing remitting multiple sclerosis (RRMS). METHODS: We studied a group of 23 patients with clinically definite RRMS, with EDSS<6 who received co-supplemented hemp seed and evening primrose oils with advising hot-natured diet. Clinically EDSS and immunological factors (plasma cytokines of IL-4, IFN-gamma and IL-17) were assessed at baseline and after 6 months. RESULTS: Mean follow-up was 180+/-2.9 days (N=23, 7 Male and 16 Females aged 25.0+/-7.5 years with disease duration 6.26+/-3.9 years). After 6 months, significant improvements in extended disability status score were found in the patients in agreement with decrease cytokines of IFN-gamma and IL-17 and increase cytokines of IL-4. Clinical and immunological parameters showed improvement in the patients after the intervention. CONCLUSION: Our study shows that co-supplemented hemp seed and evening primrose oils with hot-natured diet can have beneficial effects in improving clinical symptoms in relapsing remitting MS patients and significant correlation was found between EDSS and immunological findings. PMID- 23678470 TI - Role of statins in coronary artery disease. AB - Statins have been known to significantly reduce cardiovascular events in patients with cardiovascular disease. This review was undertaken to examine the current evidence for the effect of statins in patients with coronary artery disease. Further research is needed to clarify questions concerning the optimal timing, dosage, and type of statin therapy as well as the problems associated with adverse effects. PMID- 23678471 TI - Mechanical and Histopathological Comparison between Commercialized and Newly Designed Coronary Bare Metal Stents in a Porcine Coronary Restenosis Model. AB - The aim of this study was to compare the stent designed by Chonnam National University Hospital (designated as CNUH) with commercial cobalt-chromium coronary stent in a porcine coronary overstretch restenosis model. CNUH stent was subjected to mechanical performance tests. Pigs were randomized into two groups in which the coronary arteries (10 pigs, 10 coronaries in each group) had either CNUH stent or control commercial bare metal stent. Histopathologic analysis was assessed at 28 days after stenting. In mechanical performance tests, CNUH stent showed 2.65N, 35.1N, 0.52N, 1.94%, 4.29% in the flat plate radial compression, radial force, 3 point bending, Foreshortening and recoil test, respectively. There was no significant difference in the injury score, internal elastic lamina (IEL), lumen area, neointima area, percent area stenosis, inflammation score and fibrin score between the two groups (1.2+/-0.35, 4.1+/-0.41 mm(2), 2.7+/-0.56 mm(2), 1.6+/-0.47 mm(2), 36.7+/-11.2%, 1.2+/-0.62, 0.2+/-0.34 in CNUH stent group vs. 1.2+/-0.38, 3.7+/-0.64 mm(2), 2.5+/-0.49 mm(2), 1.5+/-0.61 mm(2), 36.3+/ 12.17%, 1.1+/-0.12, 0.4+/-0.46 in commercial stent group, respectively). In the mechanical performance test, CNUH stent showed the moderated performance under the guideline of FDA. CNUH stent demonstrated similar histological reactions compared with commercial cobalt-chromium stent in a porcine coronary overstretch restenosis model. PMID- 23678472 TI - Comparison of Endoscopic Variceal Ligation and Endoscopic Variceal Obliteration in Patients with GOV1 Bleeding. AB - The aim of this study was to compare the efficacy, rebleeding rates, survival, and complications of endoscopic variceal ligation (EVL) with those of endoscopic variceal obliteration (EVO) in patients with acute type 1 gastroesophageal variceal (GOV1) bleeding. Data were collected retrospectively at a single center. A total of 84 patients were selected (20 patients underwent EVL; 64 patients underwent EVO) from February 2004 to September 2011. Their clinical characteristics, laboratory results, vital signs, Child-Pugh score, Model for End stage Liver Disease (MELD) score, and overall mortality were evaluated. There were no significant differences in baseline characteristics between the two groups. The success rate in initial control of active bleeding was not significantly different between the EVL and EVO groups (18/20 EVL, or 90.0%, compared with 62/64 EVO, or 96.9%; p=0.239). The early rebleeding rate was also not significantly different between the groups (3/18 EVL, or 16.7% compared with 17/62 EVO, or 27.4%; p=0.422). The late rebleeding rate of the EVL group was lower than that of the EVO group (3/18 EVL, or 16.7%, compared with 26/59 EVO, or 44.1%; p=0.042). The time-to-rebleeding was 594 days for the EVL group and 326 days for the EVO group (p=0.054). In the multivariate analysis, portal vein thrombosis (PVT) was a significant risk factor for early rebleeding. Hepatocellular carcinoma (HCC) and previous history of bleeding were significant risk factors for very late rebleeding. In conclusion, EVL is better than EVO in reducing late rebleeding in acute GOV1 bleeding. HCC, PVT, and previous bleeding history were significant risk factors for rebleeding. PMID- 23678473 TI - Clinical Usefulness of (18)F-FDG PET/CT in the Detection of Early Recurrence in Treated Cervical Cancer Patients with Unexplained Elevation of Serum Tumor Markers. AB - We investigated the diagnostic value of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) for restaging of treated uterine cervix squamous cell cancer with tumor maker elevation that was not explained by other conventional evaluation. We enrolled 32 cases who underwent PET/CT for the restaging of treated cervical cancer with tumor marker elevation that was not explained by recent conventional evaluation. All enrolled cases had squamous cell carcinoma. Increased tumor markers included squamous cell carcinoma antigen (SCC Ag) and carcinoembryonic antigen (CEA). PET/CT findings were determined by pathologic confirmation or clinical follow-up. We compared PET/CT accuracy and clinical parameters including normalization of tumor markers in both the SCC Ag elevation group and the CEA elevation group. The sensitivity, specificity, positive predictive value, and negative predictive value of PET/CT in detecting recurrence were 100%, 83.3%, 82.4%, and 100%, respectively. Accuracy was significantly different between the SCC Ag elevation group and the CEA elevation group (p=0.0169). PET/CT with SCC Ag elevation was more accurate (100%) than PET/CT with CEA elevation (66.7%). Normalization of tumor markers was observed more often in the SCC Ag elevation group than in the CEA elevation group (p=0.0429). PET/CT showed high negative predictive value and sensitivity in the restaging of cervical cancer with unexplained tumor marker elevation. PET/CT was more accurate in patients with SCC Ag elevation than in those with CEA elevation. PMID- 23678474 TI - Impact of Physician's Education on Adherence to Tuberculosis Treatment for Patients of Low Socioeconomic Status in Bangladesh. AB - Successful tuberculosis control depends on good adherence to treatment. Yet, limited data are available on the efficacy of methods for improving the adherence of patients of low socioeconomic status. We evaluated the impact of physician provided patient education on adherence to anti-tuberculosis medication in a low socioeconomic status and resource-limited setting. A pre-/post-intervention study was conducted at a suburban primary health care clinic in Bangladesh where an intensive education strategy was established in May 2006. Treatment outcomes of tuberculosis patients from March 2005 to April 2006 (pre-intervention) and from May 2006 to December 2007 (post-intervention) were compared. Among 354 patients, 198 (56%) were treated before intervention and 156 (44%) were treated after intervention. Cumulative adherence to anti-tuberculosis medication was significantly greater in the intervention group than in the control group in univariate and multivariate analyses. Physician's education can contribute to increasing the adherence of patients in resource-limited settings. PMID- 23678475 TI - Rosuvastatin does not affect fasting glucose, insulin resistance, or adiponectin in patients with mild to moderate hypertension. AB - The effects of statins on insulin resistance and new-onset diabetes are unclear. The purpose of this study was to evaluate the effects of rosuvastatin on insulin resistance and adiponectin in patients with mild to moderate hypertension. In a randomized, prospective, single-blind study, 53 hypertensive patients were randomly assigned to the control group (n=26) or the rosuvastatin (20 mg once daily) group (n=27) during an 8-week treatment period. Both groups showed significant improvements in systolic blood pressure and flow-mediated dilation (FMD) after 8 weeks of treatment. Rosuvastatin treatment improved total cholesterol, low-density lipoprotein (LDL)-cholesterol, and triglyceride levels. The control and rosuvastatin treatment groups did not differ significantly in the change in HbA1c (3.0+/-10.1% vs. -1.3+/-12.7%; p=0.33), fasting glucose (-1.3+/ 18.0% vs. 2.5+/-24.1%; p=0.69), or fasting insulin levels (5.2+/-70.5% vs. 22.6+/ 133.2%; p=0.27) from baseline. Furthermore, the control and rosuvastatin treatment groups did not differ significantly in the change in the QUICKI insulin sensitivity index (mean change, 2.2+/-11.6% vs. 3.6+/-11.9%; p=0.64) or the HOMA index (11.6+/-94.9% vs. 32.4+/-176.7%; p=0.44). The plasma adiponectin level increased significantly in the rosuvastatin treatment group (p=0.046), but did not differ significantly from that in the control group (mean change, 23.2+/ 28.4% vs. 23.1+/-27.6%; p=0.36). Eight weeks of rosuvastatin (20 mg) therapy resulted in no significant improvement or deterioration in fasting glucose levels, insulin resistance, or adiponectin levels in patients with mild to moderate hypertension. PMID- 23678476 TI - Changes in (18)f-fluorodeoxyglucose uptake in the spinal cord in a healthy population on serial positron emission tomography/computed tomography. AB - We aimed to determine the changes in (18)F-fluorodeoxyglucose (FDG) uptake in the spinal cord on two serial positron emission tomography/computed tomography (PET/CT) scans in a healthy population. We retrospectively enrolled healthy people who underwent PET/CT twice for cancer screening. We excluded those who had degenerative vertebral disease, neurologic disease, or a history of a vertebral operation. The standardized uptake value (SUVmax) of the spinal cord of each mid vertebral body was obtained by drawing a region of interest on an axial image of PET/CT. For analysis, the cord-to-background ratio (CTB) was used (CTB=SUVmax of each level/SUVmax of L5 level). Differences in pattern, sex, age, and intervals of the two serial PET/CT scans were analyzed. A total of 60 PET/CT images of 30 people were analyzed. The mean interval between the two PET/CT imaging studies was 2.80+/-0.94 years. On the follow-up PET/CT, significant change was shown only at the level of the C6 and T10 vertebrae (p<0.005). Mean CTB showed a decreasing pattern from cervical to lumbar vertebrae. There were two peaks at the lower cervical level (C4-6) and at the lower thoracic level (T12). Neither sex nor age significantly affected CTB. The FDG uptake of the spinal cord changed significantly on follow-up PET/CT only at the level of the C6 and T10 vertebrae. This finding is valuable as a baseline reference in the follow-up of metabolic changes in the spinal cord. PMID- 23678477 TI - Laparoscopic management of complicated urachal remnants. AB - Managing persistent and symptomatic urachal anomalies requires wide surgical excision of all anomalous tissue with a cuff of bladder tissue via the open approach. We report 7 cases with complete laparoscopic removal of symptomatic urachal remnants with or without a cuff of bladder tissue. We expected that this technique would be less invasive and have lower morbidity. We report on the feasibility of this approach, including efficacy and outcomes. Eight patients with a mean age of 36.5 years who had symptomatic urachal diseases underwent laparoscopic excision between July 2004 and July 2012. With the use of four ports, the urachal remnant was dissected transperitoneally and then removed via the umbilicus port. The clinical results of laparoscopic urachal remnant excision as a minimally invasive surgery, the perioperative records, and pathologic results were evaluated. There were no intraoperative or postoperative complications. Mean surgery time was 2.7 hours. Mean hospital stay was 14.6 days. The patients with bladder cuff resection had a long admission and Foley catheterization period (mean, 14.4 and 11 days). Pathological evaluations were 6 cases of infected urachal cysts, 1 case of infected urachal sinus, and 1 case of urachal adenocarcinoma. We found no postoperative complications including any symptom recurrence or voiding difficulty during a mean follow-up of 46.3 months. The perioperative surgical outcomes achieved infection control and symptomatic relief and additionally good cosmesis. Complete laparoscopic removal of symptomatic urachal remnants with or without a cuff of bladder tissue seems to be a safe, effective, and better cosmetic alternative with the advantages of a minimally invasive approach. PMID- 23678478 TI - Gross hematuria associated with genitourinary tuberculosis. AB - A 27-year-old man presented to the emergency department with sudden onset of massive gross hematuria and urinary retention. Contrast-enhanced computed tomography imaging showed uneven, dilated calices and a narrowing of the renal pelvis in the left kidney; in addition, a large hematoma was noted in the urinary bladder. An emergency cystoscopy was performed following detection of the hematoma and blood clots were removed. A lesional biopsy, a tuberculosis (TB) culture, and urine cytology showed positive results for Mycobacterium tuberculosis. The clinical manifestations of genitourinary tuberculosis are nonspecific and are usually detected at a chronic stage. In conclusion, we report an unusual cause of acute kidney injury associated with a subacute stage of genitourinary tuberculosis that caused mucosal erosion and bleeding in the bladder. PMID- 23678479 TI - Successfully treated femoral artery thrombosis in a patient with minimal change nephrotic syndrome. AB - In contrast to widely recognized venous thrombotic complications, peripheral arterial thrombosis as a complication of nephrotic syndrome, especially without preceding iatrogenic venous puncture, corticosteroid treatment, or coagulation factor abnormalities, has rarely been reported in adult female patients. We report the case of a 39-year-old woman who presented with pain in the right lower leg accompanied by minimal change nephrotic syndrome. Lower-extremity angiography showed total occlusion of the right superficial femoral artery. Thrombectomy was performed with a balloon catheter, and the thrombi were successfully aspirated. Our experience indicates that even if few traditional risk factors for atherosclerosis are identified, a high index of suspicion and aggressive treatment of arterial thrombosis in adult nephrotic syndrome are crucial to minimize serious ischemic injuries. PMID- 23678480 TI - Influence of degree of conversion on the biocompatibility of different composites in vivo. AB - PURPOSE: To evaluate the relationship between biocompatibility and degree of monomer conversion of composites used to bond brackets to enamel, porcelain, resin, or metal surfaces at different time intervals. MATERIALS AND METHODS: Twenty-four male Wistar rats were used, divided into 4 groups (n = 6) as follows: group C (control, polyethylene), group TCC (Transbond Color Change), group QC (Quick-Cure), and group EB (Eagle Bond). These substances were inserted into subcutaneous tissue. The events of inflammatory infiltrate, edema, necrosis, granulation tissue, multinuclear giant cells, young fibroblasts, and collagen formation were analyzed. The degree of conversion was evaluated by the Fourier method using infrared spectroscopy. Biocompatibility and degree of conversion were statistically analyzed using the Kruskal-Wallis and Dunn tests, and ANOVA and Tukey's test, respectively (p < 0.05). RESULTS: The composites caused a small amount of inflammatory infiltrate, edema, and granulation tissue at all experimental time intervals, showing a gradual reduction over time (p > 0.05). Group TCC showed the highest amount of fibroblasts and EB the smallest at the time interval of 15 days (p = 0.035). Group TCC showed the highest amount of collagen fibers and EB the smallest throughout the experiment; there was a significant difference in terms of collagen fibers between groups QC and EB, which differed from the control at 7 days (p = 0.006), and between groups EB and TCC (p = 0.018) at 30 days. Monomer conversion ranged from 64.1% in group EB at 7 days to 85.3% in group TCC at 30 days. CONCLUSION: Transbond Color Change composite showed a higher degree of conversion and a better healing process compared to Eagle Bond composite at 15 and 30 days. Quick-cure composite demonstrated a better degree of conversion and healing process than that of Eagle Bond, but this was not statistically significantly different. PMID- 23678481 TI - The benefits of adhesion. PMID- 23678482 TI - Radiation-induced grafting of carbon nanotubes on HPLC silica microspheres: theoretical and practical aspects. AB - Multi-walled carbon nanotubes (MWCNTs) were grafted for the first time by gamma radiation onto silica microspheres in the presence of polybutadiene (PB) as the linking agent, obtaining a novel hybrid material with chromatographic properties, with an alternative approach to the existing procedures. The synthesis involves the one-pot gamma-radiation-induced grafting of MWCNTs onto silica microspheres in the presence of PB as a linking agent. PB also serves as a coating layer of the silica particles, to which MWCNTs are anchored through stable chemical bonds formed via radical chain reaction with the polymer. The product (MWCNT-PB modified silica) resulted in MWCNT bundles interlaying the silica particles which acted as a support and as a spacer. This new material highlights the unquestionable properties of CNTs also when grafted in a composite, thus allowing the disposition of a more robust material whose properties are still related to the nanotube structure. The grafting was confirmed by Raman spectroscopy. The surface area, determined by BET isotherms, resulted in 132 m(2) g(-1), about 34% lower than that of pure silica, pointing to the cross-linking effect of PB in the silica matrix. The evaluation of MWCNT-PB-modified silica as a LC stationary phase was performed by separation of aromatics, with satisfactory resolution and reproducibility, while structural selectivity was proved by isomer separation. A good resolution was obtained also for acid/basic compounds as barbiturates. A comparison with a commercial C18 sorbent highlighted the advantage in using the CNT column for separating aromatic hydrocarbons. Control experiments on the PB coated silica column proved the key role of MWCNTs in the chromatographic performance. PMID- 23678483 TI - A compact high resolution ion mobility spectrometer for fast trace gas analysis. AB - Drift tube ion mobility spectrometers (IMS) are widely used for fast trace gas detection in air, but portable compact systems are typically very limited in their resolving power. Decreasing the initial ion packet width improves the resolution, but is generally associated with a reduced signal-to-noise-ratio (SNR) due to the lower number of ions injected into the drift region. In this paper, we present a refined theory of IMS operation which employs a combined approach for the analysis of the ion drift and the subsequent amplification to predict both the resolution and the SNR of the measured ion current peak. This theoretical analysis shows that the SNR is not a function of the initial ion packet width, meaning that compact drift tube IMS with both very high resolution and extremely low limits of detection can be designed. Based on these implications, an optimized combination of a compact drift tube with a length of just 10 cm and a transimpedance amplifier has been constructed with a resolution of 183 measured for the positive reactant ion peak (RIP(+)), which is sufficient to e.g. separate the RIP(+) from the protonated acetone monomer, even though their drift times only differ by a factor of 1.007. Furthermore, the limits of detection (LODs) for acetone are 180 pptv within 1 s of averaging time and 580 pptv within only 100 ms. PMID- 23678484 TI - Reagent-free monitoring of multiple clinically relevant parameters in human blood plasma using a mid-infrared quantum cascade laser based sensor system. AB - We present a semi-automated point-of-care (POC) sensor approach for the simultaneous and reagent-free determination of clinically relevant parameters in blood plasma. The portable sensor system performed direct mid-infrared (MIR) transmission measurements of blood plasma samples using a broadly tunable external-cavity quantum cascade laser source with high spectral power density. This enabled the use of a flow cell with a long path length (165 MUm) which resulted in high signal-to-noise ratios and a rugged system, insensitive to clogging. Multivariate calibration models were built using well established Partial-Least-Squares (PLS) regression analysis. Selection of spectral pre processing procedures was optimized by an automated evaluation algorithm. Several analytes, including glucose, lactate, triglycerides, cholesterol, total protein as well as albumin, were successfully quantified in routinely taken blood plasma samples from 67 critically ill patients. Although relying on a spectral range from 1030 cm(-1) to 1230 cm(-1), which is optimal for glucose and lactate but rather unusual for protein analysis, it was possible to selectively determine the albumin and total protein concentrations with sufficient accuracy for POC application. PMID- 23678486 TI - Research and the National Institute for Prevention and Health Education. Editorial. PMID- 23678487 TI - Introduction. The necessary contribution of science to prevention. PMID- 23678488 TI - [The families support program: a description of the factors influencing program implementation in France]. PMID- 23678489 TI - [Evaluation of training program with ongoing support to promote health in French primary schools: practical implications]. PMID- 23678490 TI - [Sociological assessment of a proposed improvement in food offerings (excluding school meals) in middle schools and high schools of Aquitaine: perception and analysis of students on education activities for health]. PMID- 23678492 TI - [Lack of dietary and lifestyle advice given to hypertension patients, their characteristics and those of their general practitioner]. PMID- 23678491 TI - [Opinions and practices from a panel of French general practitioner doctors regarding vaccination]. PMID- 23678493 TI - [Analysis of perceived stress by hospital caregivers in the practice of therapeutic education: implications for supervision]. PMID- 23678494 TI - [Implementation of a program for transfer and measurement of skills towards the cardiovascular patient]. PMID- 23678495 TI - ["Training and provisions", the change in dietary habits and physical education for health, the case of obesity and cardiovascular disease]. PMID- 23678498 TI - Supporting families in challenging contexts: the CAPEDP project. AB - Although France has one of the most generous health and social care systems for infant and maternal well-being in the Western world, professionals have been increasingly concerned by the rising number of children being referred for mental health problems. The present article describes the first home-visiting program in France to specifically target mental health questions in families living in vulnerable contexts. The CAPEDP project, involving 440 women and their families, took place in Paris and its inner suburbs from 2006 to 2011. To be eligible for inclusion, women had to be (i) under 26 years old, (ii) less that 27 weeks pregnant, (iii) sufficiently fluent in French to give truly informed consent to participate in the study and benefit from the intervention and (iv) presenting with one or more of the following social vulnerability factors: low income, low educational level, and/or intending to bring up the child without the child's father. The intervention consisted of 44 home visits from the third trimester of pregnancy through to the child's second birthday. The aim of the intervention was to promote infant mental health and reduce the incidence of infant mental health problems at the age of two years. The intervention paid particular attention to postnatal maternal depression and promoting parenting skills and attachment security, particularly through the use of video during home-visits. A major issue was that of adapting international best practice recommendations with regard to home-visiting programs to the particularities of the existing French social and health care system. An original aspect of the intervention was to use trained clinical psychologists to conduct all home visits. PMID- 23678499 TI - Implementation and assessment of an early home-based intervention on infant attachment organisation: the CAPEDP attachment study in France. AB - Attachment is a long-term emotional link between infants and their mothers. Attachment quality influences subsequent psychosocial relationships, the ability to manage stress and, consequently, later mental health. Home intervention programmes targeting infant attachment have been implemented in several contexts with varying degrees of efficacy. Within the CAPEDP study (Parental Skills and Attachment in Early Childhood: reduction of risks linked to mental health problems and promotion of resilience), a subsample of 120 families were recruited with the objective of assessing the impact of this home-visiting programme on infant attachment organisation using the Strange Situation Procedure. The present paper describes the methodology used in this ancillary study. PMID- 23678500 TI - Process evaluation of a school-based overweight and obesity screening strategy in adolescents. AB - The PRALIMAP (PRomotion de l'ALIMentation et de l'Activite Physique) trial highlights the effectiveness of implementing a screening strategy in high schools to prevent overweight/obesity among adolescents. The strategy comprises three steps: i) body measurements to detect overweight/obese adolescents, ii) a medical interview with each adolescent identified to discuss the findings, and iii) an adapted care management consisting of seven group educational sessions. A process evaluation was conducted in the PRALIMAP trial to assess the effective implementation of the screening strategy activities, and the participation of adolescents and school professionals in them, from a qualitative and a quantitative point of view. The present paper describes the process and the implementation of the screening strategy as performed in the PRALIMAP trial, and discusses the feasibility of such an intervention in high school settings. The ability of nurses to explain the screening results improved with the addition of specialist support. The ability of adolescents to take part in the screening strategy improved when the adapted care management was conducted inside schools and could be increased even further if the waiting time between the three steps could be minimised. PMID- 23678501 TI - Self-efficacy and implementation intentions-based interventions on fruit and vegetable intake among adults: impact at 12-month follow-up. AB - This study tested the effect of theory-based interventions designed to increase fruit and vegetable intake (FVI). Adults (n = 291) were randomized into four groups: implementation intentions (II) group; self-efficacy (SE) group; combination of implementation intentions and self-efficacy (II+SE) group; and a control group receiving written information on nutrition. They were reassessed at 1, 3, 6 and 12 month follow-up. This study found that short interventions such as SE and II+SE can achieve significant differences in FVI at six-month follow-up compared to the control group. However, this effect was not maintained at 12 month follow-up. Practitioners should add materials or follow up meetings to ensure maintenance of behavioral change. PMID- 23678502 TI - The 'Ossebo' intervention for the prevention of injurious falls in elderly women: background and design. AB - This paper reviews the literature that contributed to the design of the 'Ossebo' intervention and describes the study that is underway. BACKGROUND: Falls and fall related injuries are a major cause of morbidity and mortality among older people. Extensive research into falls prevention has established physical exercise as an efficient method to reduce falls, but the effect of exercise on serious injuries caused by falls remains unclear. Moreover, populations that would benefit most from these interventions, as well as factors that determine adherence to exercise remain underreported. THE OSSEBO INTERVENTION: 'Ossebo' is an on-going multicenter randomized controlled trial, aiming to assess the effect of a two year community-based group physical exercise program on the prevention of falls among women aged 75-85 years old. The primary outcome examined is the rate of falls and injurious falls: secondary outcomes include functional capacities, fear of falling and quality of life. This study will help determine the effectiveness of a large scale falls prevention program and the factors that can potentially assist its success. PMID- 23678503 TI - Therapeutic education among adults with type 2 diabetes: effects of a three-day intervention on perceived competence, self-management behaviours and glycaemic control. AB - The purpose of this study was to evaluate the impact of a three-day therapeutic education programme on perceived competence, self-management behaviours (i.e. physical activity, diet and medication) and glycaemic control among adults with type 2 diabetes. A total of 120 participants were included in this randomized, wait list control group trial. The results confirm that therapeutic education may be a powerful healthcare intervention to improve lifestyle and health status of people with type 2 diabetes. We observed that the education programme used in this study generated positive changes in glycaemic control and adherence to physical activity and diet after three months follow-up. Furthermore, the intervention positively impacted participants' perceived competence towards physical activity and diet. The latter finding is of particular importance, given that perceived competence has been found to be involved in long-term adherence to self-management behaviours. PMID- 23678504 TI - Efficiency of brief interventions on alcohol-related risks in occupational medicine. AB - AIM: To evaluate the effectiveness of brief interventions (BIs) in reducing alcohol use among hazardous drinkers consulting their occupational doctors. MATERIALS AND METHODS: DESIGN: Randomized controlled trial with 12-month follow up, conducted between November 2004 and September 2006. SETTING: Fifteen French regional occupational medicine centers with 147 doctors and 157 assistants who were trained in BI and screening with the AUDIT questionnaire. PARTICIPANTS: We invited 33,488 individuals to fill out AUDIT. These patients were eligible if their scores were 6-12 for women and 7-12 for men, indicating hazardous drinking without dependence (found in 7.1% of respondents). INTERVENTION: After randomization, BIs (informative advice using motivational approach, with 10 minute average duration) were performed by the occupational doctors. The control group received information booklets from the doctors' assistants. MEASUREMENTS: Situations were evaluated 12 months after inclusion. OUTCOME MEASURES: AUDIT scores, self-reported alcohol consumption (SRAC) and biological assays. The main criteria were the differences observed between groups for SRAC, the AUDIT score at follow-up, and any reduction in score between inclusion and final assessment. Success of intervention, which was defined as an AUDIT score below the hazardous drinking threshold at follow-up, was considered to analyze the variables associated with the efficiency of intervention. RESULTS: The analyzed sample included 787 persons, among whom 435 were met again 12 months later. In the BI group, we found a lower AUDIT score (p = 0.01), a higher reduction in reported consumptions (-60 g/week versus -44 g/week, p = 0.04) and in AUDIT scores (p = 0.009). In the control group, 44.8% reduced their AUDIT scores below hazardous drinking thresholds, as compared to 51.6% in the BI group (p = 0.15). Success was associated with a significant reduction in biological and clinical indices. CONCLUSIONS: Though the high attrition rate led to careful conclusions, BIs seem to be efficient in occupational medicine, in comparison with written information, which also seems to influence drinking behavior. PMID- 23678508 TI - Retinal vessel caliber and lifelong neuropsychological functioning: retinal imaging as an investigative tool for cognitive epidemiology. AB - Why do more intelligent people live healthier and longer lives? One possibility is that intelligence tests assess health of the brain, but psychological science has lacked technology to evaluate this hypothesis. Digital retinal imaging, a new, noninvasive method to visualize microcirculation in the eye, may reflect vascular conditions in the brain. We studied the association between retinal vessel caliber and neuropsychological functioning in the representative Dunedin birth cohort. Wider venular caliber was associated with poorer neuropsychological functioning at midlife, independently of potentially confounding factors. This association was not limited to any specific test domain and extended to informants' reports of cohort members' cognitive difficulties in everyday life. Moreover, wider venular caliber was associated with lower childhood IQ tested 25 years earlier. The findings indicate that retinal venular caliber may be an indicator of neuropsychological health years before the onset of dementing diseases and suggest that digital retinal imaging may be a useful investigative tool for psychological science. PMID- 23678509 TI - Motor activation during the prediction of nonexecutable actions in infants. AB - Although it is undeniable that the motor system is recruited when people observe others' actions, the inferences that the brain generates from motor activation and the mechanisms involved in the motor system's recruitment are still unknown. Here, we challenged the popular hypothesis that motor involvement in action observation enables the observer to identify and predict an agent's goal by matching observed actions with existing and corresponding motor representations. Using a novel neural indication of action prediction--sensorimotor-cortex activation measured by electroencephalography--we demonstrated that 9-month-old infants recruit their motor system whenever a context suggests an impending action, but that this recruitment is not dependent on being able to match the observed action with a corresponding motor representation. Our data are thus inconsistent with the view that action prediction depends on motor correspondence; instead, they support an alternative view in which motor activation is the result of, rather than the cause of, goal identification. PMID- 23678521 TI - A strategic orthodontic marketing plan, Part 2. PMID- 23678522 TI - [Reaction on 'An increase of compulsory admissions in Belgium and the Netherlands: an epidemiological exploration'. Reply to Wierdsma]. PMID- 23678523 TI - [Reaction on 'The effect of energy drinks on the cognitive performance of adolescents'. Reply to Wierdsma]. PMID- 23678524 TI - [Reaction on 'Addition of fluvoxamine to clozapine: theory and practice'. Reply to Sommer]. PMID- 23678525 TI - [Reaction on 'Assessing aggressive behaviour at the psychiatric emergency service with a checklist: a replication study'. Reply to Wierdsma]. PMID- 23678526 TI - [Reaction on 'Chronic fatigue syndrome; the closing of the treatment centres for CFS in Belgium: quo vadis?'. reply to Twisk]. PMID- 23678527 TI - [Heart failure in women: challenges and opportunities]. PMID- 23678528 TI - [Heart failure phenotype in women]. AB - Although one half of patients affected by heart failure (HF) are women, the clinical phenotype differs between genders. In women HF develops later in life, is more often associated with preserved systolic function and is less frequently attributable to ischemic heart disease. Although survival tends to be better in women than in men, females are more symptomatic, have a worse quality of life and a longer length of stay during acute HF admissions. Italian data from institutional databases of the Lazio, Basilicata and Veneto regions are in agreement with international evidences on this topic. Gender differences in clinical phenotypes are based on different structural and functional patterns: the female heart undergoes more often concentric remodeling, with thicker walls, smaller volumes and greater chamber stiffness. There are no specific therapeutic evidences for the elderly, prevalently female, HF population. Treatment strategies are derived from studies carried out in relatively young male populations with left ventricular systolic dysfunction. Therapeutic strategies tailored to the peculiar female HF phenotype should be better explored in future treatment trials. PMID- 23678529 TI - [Risk factors for heart failure in women: diabetes]. AB - Diabetes mellitus has become increasingly prevalent in recent years, the most dramatic increase being observed in younger women. Diabetes is a multiplier of cardiovascular risk and decreases life expectancy more in women than in men. Diabetic women are less likely to achieve therapeutic targets for cardiovascular risk factors and to be optimally treated. They present more often with atypical symptoms that cause delays in timely recognition and management of cardiovascular disease. Diabetes is an independent risk factor for heart failure and is associated with a worse outcome in women than in men affected by heart failure. Despite the high prevalence of early asymptomatic ventricular dysfunction in diabetics observed in the DYDA and SHORTWAVE studies, female gender was neither a protective nor predisposing factor to ventricular dysfunction or heart failure. Among 1129 outpatients with heart failure, data from the Cardiovascular Epidemiologic Observatory of Trieste show a prevalence of diabetes of 39% in men and 28% in women. In this ongoing epidemiological study, a significantly better prognosis was observed in female than in male diabetics, whereas diabetic and non diabetic women showed comparable mortality and hospital admission rates. These findings underscore the impact and effectiveness of strict follow-up and management in the high-risk female diabetic population. PMID- 23678530 TI - [Risk factors for heart failure in women: atrial fibrillation]. AB - In patients with heart failure (HF) the prevalence of atrial fibrillation (AF) is higher than in the general population, and the risk of developing AF is greater in women than in men. The occurrence of AF in HF patients correlates with increased mortality and greater incidence of thromboembolic events, which seem to occur more frequently in women. The increased risk of bleeding during oral anticoagulant therapy associated with HF determines an underuse of anticoagulants in these patients, in particular in female subjects. Since mortality related to the use of antiarrhythmic drugs is increased in patients with AF and HF and the efficacy of both pharmacological and electrical cardioversion is lower than in patients without HF, rate control is the more frequently used therapeutic strategy. A higher incidence of cardiovascular events has been demonstrated particularly in women with HF and AF using a rhythm control approach. AF can induce HF and persistence over time of high rate AF may result in tachycardiomyopathy, a form of dilated cardiomyopathy characterized by severe left ventricular dysfunction. PMID- 23678532 TI - [Cardiac resynchronization therapy in women]. AB - Cardiac resynchronization therapy (CRT) is a well established option in patients with moderate to severe heart failure on optimal medical therapy, NYHA functional class Ill-IV, reduced systolic function (left ventricular ejection fraction < or =35%), broad QRS complex (>120 ms), but data addressing sex differences in response to CRT are lacking. Women are underrepresented in clinical and observational trials on CRT (<30%) but, when examining response across recent studies, there is evidence of a more positive effect of CRT in women. Also our data show that females seem to achieve a greater survival benefit with CRT than male recipients. While larger trials remain the ideal way to specifically address the question of a gender effect, with some uncertainties on the understanding of the greater benefit still present (specific factors intrinsic to women are responsible for this difference? pre-CRT clinical characteristics, prevalence of nonischemic cardiomyopathy and left bundle branch block, other than female gender itself?), current evidence supports the notion of increasing access to CRT for women with the appropriate indication, to allow them to exploit the distinctive benefits associated with this treatment strategy. PMID- 23678533 TI - [Treatment of advanced heart failure in women: heart transplantation and ventricular assist devices]. AB - Women candidates for heart transplantation are definitely less than men, just 20% of all patients transplanted; even in the INTERMACS registry they represent only 21% of all ventricular assist devices (VAD) implanted. The reasons for this big difference are discussed in this article. Why women are less frequently assessed for unconventional therapies? Are they sicker or just less regarded? Our experience and the literature show us clear epidemiological, clinical and treatment differences that could lead to a lower prevalence of end-stage disease in women of an age suitable for unconventional therapies. Once on the transplant list, women wait less than men for a heart transplant, because they present with more severe disease, have a lower body mass index and undergo less VAD implants. After transplantation women's survival is comparable to men's, although they usually complain of a lower quality of life. Females receive less often a VAD than men. The main reasons for this include presentation with advanced heart failure at an older age than men, worse outcomes related to small body surface area, and lower survival rates on VAD when implanted as bridge to heart transplantation. PMID- 23678534 TI - [Acquired and congenital heart diseases during pregancy]. AB - Heart diseases are the leading cause of maternal morbidity and mortality. The number of patients with congenital heart diseases reaching childbearing age, as well as the proportion of women with acquired conditions, such as ischemic heart disease, becoming pregnant is constantly increasing. All women with known heart disease should have pre-pregnancy counseling, to assess maternal and fetal risk. Women at moderate or high risk should be under the care of a specialist prenatal team with experience in managing women with heart disease during pregnancy. Conditions that are considered at particularly high risk (mortality >10%) include Marfan syndrome with dilated aortic root, severe left ventricular dysfunction, severe left heart obstructive lesions, and pulmonary hypertension. Peripartum cardiomyopathy is a rare and potentially fatal disease related to pregnancy and the postnatal period that presents with symptoms of congestion and/or hypoperfusion and may rapidly progress to acute and life-threatening heart failure. However, the majority of women with heart disease can tolerate pregnancy; therefore an adequate multidisciplinary approach with the gynecologist, anesthesiologist and cardiologist should be advocated in order to reduce maternal and fetal risks associated with pregnancy. PMID- 23678535 TI - [Heart failure in women treated with adjuvant trastuzumab for breast cancer]. AB - The amplification of the HER receptor system is present in approximately 20% of breast cancers and confers a marked malignancy and a poor prognosis. Trastuzumab, a monoclonal antibody directed against the HER2 receptor, has dramatically improved the prognosis of patients with HER2+ metastatic and early breast cancer. However, the use of trastuzumab is associated with the possible development of myocardial dysfunction and heart failure. Trastuzumab-induced cardiac injury may be reversible, and a substantial proportion of patients can complete therapy. For this reason, careful monitoring of cardiac function, an aggressive treatment of hypertension and possibly the use of non-anthracycline-containing chemotherapy protocols are required during trastuzumab treatment. Owing to the selection of patients enrolled in major randomized trials, the safety profile of trastuzumab is currently unclear in elderly women, in patients at high cardiovascular risk and in those with structural heart disease on optimal treatment. Further studies are therefore needed to determine whether this highly effective therapy in breast cancer survival can be extended to such categories of patients. PMID- 23678536 TI - A toddler stole the show. PMID- 23678531 TI - [Data from the IN-HF Outcome registry]. AB - The IN-HF Outcome registry enrolled 1855 patients admitted for acute heart failure and 3755 outpatients with chronic heart failure seen at 64 cardiology units of the Italian Network-Heart Failure. We assessed gender-related differences in clinical characteristics, management, and short- and long-term mortality and morbidity outcomes. Women were older, more often hypertensive and with a higher prevalence of heart failure with preserved systolic function. Aggressive management was less frequent in women who underwent less often diagnostic and therapeutic procedures. We found no gender-related differences in either acute or long-term mortality nor in hospital readmissions. PMID- 23678537 TI - The antibody race. PMID- 23678538 TI - Neutralizing HIV tat-specific antibodies might be involved in protection. PMID- 23678539 TI - Cell phone radiation exposure on brain and associated biological systems. AB - Wireless technologies are ubiquitous today and the mobile phones are one of the prodigious output of this technology. Although the familiarization and dependency of mobile phones is growing at an alarming pace, the biological effects due to the exposure of radiations have become a subject of intense debate. The present evidence on mobile phone radiation exposure is based on scientific research and public policy initiative to give an overview of what is known of biological effects that occur at radiofrequency (RF)/ electromagnetic fields (EMFs) exposure. The conflict in conclusions is mainly because of difficulty in controlling the affecting parameters. Biological effects are dependent not only on the distance and size of the object (with respect to the object) but also on the environmental parameters. Health endpoints reported to be associated with RF include childhood leukemia, brain tumors, genotoxic effects, neurological effects and neurodegenerative diseases, immune system deregulation, allergic and inflammatory responses, infertility and some cardiovascular effects. Most of the reports conclude a reasonable suspicion of mobile phone risk that exists based on clear evidence of bio-effects which with prolonged exposures may reasonably be presumed to result in health impacts. The present study summarizes the public issue based on mobile phone radiation exposure and their biological effects. This review concludes that the regular and long term use of microwave devices (mobile phone, microwave oven) at domestic level can have negative impact upon biological system especially on brain. It also suggests that increased reactive oxygen species (ROS) play an important role by enhancing the effect of microwave radiations which may cause neurodegenerative diseases. PMID- 23678540 TI - Sonic hedgehog inhibition induces mouse embryonic stem cells to differentiate toward definitive endoderm. AB - In the experimental group (shh inhibited group), there were significant decreases in the expression of Oct4, Nanog, Shh, GATA4, Brachyury and Goosecoid, while increases were observed for TAT and Pdx1. The expression of Sox17 did not differ between two control and experimental groups. In experimental group, the amount of GSC positive cells was somehow lower but it seems that there was no difference for Sox17. Shh inhibition induces ESCs to differentiate toward definitive endoderm by committing mesendodermal lineages. PMID- 23678541 TI - Expression of JMJD2A in infiltrating duct carcinoma was markedly higher than fibroadenoma, and associated with expression of ARHI, p53 and ER in infiltrating duct carcinoma. AB - Jumonji Domain Containing 2A (JMJD2A) may be a cancer-associated gene involved in human breast cancer. With a view to investigating expression of JMJD2A in human breast cancer and benign lesion tissues as well as relationship between JMJD2A and tumor related proteins, histological and immunohistochemical analysis, Western blot and quantitative real-time PCR in infiltrating duct carcinoma and fibroadenoma for JMJD2A and immunohistochemical analysis and quantitative real time PCR in infiltrating duct carcinoma for tumor related proteins (ARHI, p53, ER, PR and CerbB-2) were performed. Histological examination validated the clinical diagnosis. The JMJD2A positive rate of infiltrating duct carcinoma was significantly higher than fibroadenoma by immunohistochemical analysis. The mean optical density of JMJD2A in infiltrating duct carcinoma was higher than fibroadenoma by western blot. JMJD2A mRNA level in infiltrating duct carcinoma was higher than fibroadenoma by quantitative real-time PCR. Spearman correlation analysis revealed that the expression of JMJD2A was associated with ARHI, p53 and ER from immunohistochemical results respectively. Pearson correlation analysis revealed that the expression of JMJD2A was associated with ARHI, p53 and ER from quantitative real-time PCR results respectively. Expression of JMJD2A in infiltrating duct carcinoma was higher, and associated with ARHI, p53 and ER. The results may take JMJD2A as a potential diagnostic and therapeutic target in human breast cancer. PMID- 23678542 TI - Regulation of luteinizing hormone receptor in hippocampal neurons following different long-lasting treatments of castrated adult rats. AB - The aim of this study was to investigate the effects of different Luteinizing hormone (LH) and steroid hormones levels on LH receptor (LHR) expression in the hippocampal cells. Rats (24 males and 24 females) were assigned to four groups: one control and three experimental [gonadectomy (GDX), gonadectomy + gonadotropin releasing hormone analogue (GDX+GnRHa) and GDX+GnRHa+estradiol (E2) or testosterone (T)] independently for each gender. All experimental rats were gonadectomized; then GnRHa was administrated to GDX+GnRHa group, and GnRHa plus steroid hormone to GDX+GnRHa+E2 or T group in both genders for four-month. LHR mRNA expression and its protein level in hippocampal cells were measured using QRT-PCR and Western blotting. Quantification of mRNA revealed a decrease in LHR transcripts level in GDX+GnRHa group of females. A significant change was observed between GDX groups and GDX+GnRHa+E2 or T versus GDX+GnRHa group in females. High levels of LH decreased significantly the immature isoform of LHR in GDX group compared to control group in both genders, but low LH concentrations in GDX+GnRHa group induced immature LHR isoform production only in females. Therefore increased LH concentration induces production of incomplete LHR transcripts in hippocampal cells and decreases immature LHR at the protein level. This implies that LH decreases the efficiency of translation through either producing non-functional LHR molecules or preventing their translation. PMID- 23678543 TI - Intravenous human umbilical cord blood improves electrophysiological and metabolic properties in ISO induced myocardial necrosis in rats. AB - Rats treated with isoproterenol (ISO, 85 mg/kg, sc, twice at an interval of 24 h) showed a significant increase in heart rate, mean arterial blood pressure, pressure rate index, ST elevation on ECG, and a significant increase in the levels of cardiac marker enzymes- lactate dehydrogenase, and creatine kinase in serum and a significant reduction in superoxide dismutase, and catalase and increase in thiobarbituric acid reactive substance activity in heart tissue. Treatment with Human umbilical cord blood (hUCBC; 500 and 1000 microL, iv, via the tail vein; 2 h after the second dose of ISO) significantly restored back to normal levels and showed a lesser degree of cellular infiltration and infarct size in histopathological and planimetry studies respectively. Thus, hUCBC ameliorates cardiotoxic effects of isoproterenol and may be of value in the treatment of myocardial infarction. PMID- 23678544 TI - Effect of Naja naja Laurenti shed skin extract on estrous cycle, hormone - cytokine profiles, histopathology of ovary and uterus of Swiss albino mice. AB - The snake shed skin though considered as biological waste products have been mentioned in folk and traditional medicine for treatment of ailments like skin disorders, parturition problems etc. Shedded skin extract (5 mg.kg-1, sc) did not produce any change in the estrous cycle of normal cycling female mice. However in 10 mg.kg-1, sc dose, the extract caused a temporary cessation of the estrous cycle at diestrous phase in normal cycling female mice for 10 days. SSAE (10 mg.kg-1, sc) caused a significant change in the level of LH, FSH, progesterone, estradiol, IL-beta, IL-6 and TNF-alpha. Histopathology of uterus and ovary showed structural disorientation in both. The results substantiate the influence of snake shed skin in mice reproductive cycle. PMID- 23678545 TI - Protective effect of eicosapentaenoic acid-docosahexaenoic acid and alpha linolenic acid rich phytosterol ester on brain antioxidant status and brain lipid composition in hypercholesterolemic rats. AB - With a view to investigate the ameliorative effects of sitosterol esters against degenerative effects of hypercholesterolemia brain antioxidant enzyme assays, brain lipid profile, brain phospholipid compositional change and brain neurotransmitter concentrates (glutamic acid, asparctic acid, glycine) were measured in hypercholesterolemic rats. The results indicated that phytosterol esters have a role in countering hypercholesterolemia-related changes in the brain by decreasing the cholesterol levels, increasing the phospholipid levels and increasing the level of antioxidant enzymes. The results suggest that phytosterol esters may be of therapeutic significance and may offer new and effective options for the treatment of hypercholesterolemia-induced changes in the brain. PMID- 23678546 TI - Effects of fluoride and ethanol administration on lipid peroxidation systems in rat brain. AB - Exposure to fluoride and excessive ethanol consumption has been identified as a serious public health problem in many parts of the world, including India. Thus, the effect of co-exposure to fluoride and ethanol for 3-6 weeks was studied on lipid peroxidation (LPO) and oxidative stress related parameters in the rat brain. After 3 weeks, co-treated animals showed 95% increase in LPO levels compared to control. However, the levels of reduced glutathione, total and protein thiols were decreased. These changes were accompanied by a decrease in the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase. Rats exposed to fluoride together with ethanol for 6 weeks resulted in 130% increase in LPO and decrease in the reduced glutathione levels. The activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S transferase were reduced under these conditions. Brain histology revealed excessive lymphocytes, edema and spongeosis in the cortical region after six weeks of fluoride and ethanol treatment. These results suggest that exposure to fluoride together with ethanol enhances lipid peroxidation by affecting antioxidant defence systems in the rat brain. PMID- 23678547 TI - Protective effect of lawsone on L-Arginine induced acute pancreatitis in rats. AB - The efficacy of lawsone against L-arginine induced acute pancreatitis was determined at 24 h by determination of serum levels of amylase, lipase and proinflammatory cytokines [tumor necrosis factor (TNF)-alpha, C-reactive proteins and interleukin (IL)], pancreatic myeloperoxidase (MPO) activity, lipid peroxidation (thiobarbituric acid reactive substances (TBARS)], nitrate/nitrite levels, and the wet weight/body weight ratio. Lawsone and methylprednisolone treatments significantly attenuated the L-arginine- induced increases in pancreatic wet weight/body weight ratio, and decreased the serum levels of amylase and lipase, and TNF-alpha and IL-6 and significantly lowered pancreatic levels of MPO, TBARS, and nitrate/nitrite. The histoimmunological findings further proved the amelioration of pancreatic injury by lawsone and further proved anti-inflammatory and antioxidant agent property of lawsone. PMID- 23678548 TI - Biodiesel production from marine cyanobacteria cultured in plate and tubular photobioreactors. AB - Carbon (neutral) based renewable liquid biofuels are alternative to petroleum derived transport fuels that contribute to global warming and are of a limited availability. Microalgae based biofuels are considered as promising source of energy. Lyngbya sp. and Synechococcus sp. were studied for the possibility of biodiesel production in different media such as ASNIII, sea water enrichment medium and BG11. The sea water enrichment medium was found superior in enhancing the growth rate of these microalgae. Nitrogen depletion has less effect in total chlorophyll a content, at the same time the lipid content was increased in both Lyngbya sp. and Synechococcus sp. by 1.4 and 1.2 % respectively. Increase in salinity from 0.5-1.0 M also showed an increase in the lipid content to 2.0 and 0.8 % in these strains; but a salinity of 1.5 M has a total inhibitory effect in the growth. The total biomass yield was comparatively higher in tubular LED photobioreactor than the fluorescent flat plated photobioreactor. Lipid extraction was obtained maximum at 60 degrees C in 1:10 sample: solvent ratio. GC MS analysis of biodiesel showed high content of polyunsaturated fatty acids (PUFA; 4.86 %) than saturated fatty acid (SFA; 4.10 %). Biodiesel production was found maximum in Synechococcus sp. than Lyngbya sp. The viscosity of the biodiesel was closely related to conventional diesel. The results strongly suggest that marine microalgae could be used as a renewable energy source for biodiesel production. PMID- 23678549 TI - Meaningful use: what to do if you're behind in your preparations. PMID- 23678550 TI - For success, lean requires facilitywide commitment. PMID- 23678551 TI - Health system grades patient educators. PMID- 23678552 TI - Can nurses reduce readmissions? PMID- 23678553 TI - Cutaneous hypersensitivity to multiple NSAIDs: never take tolerance to selective COX-2 inhibitors (COXIBs) for granted! PMID- 23678554 TI - Overview of hereditary angioedema caused by C1-inhibitor deficiency: assessment and clinical management. AB - Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1-INH) is a rare, autosomal-dominant disease. HAE-C1-INH is characterized by recurrent attacks of marked, diffuse, nonpitting and nonpruritic skin swellings, painful abdominal attacks, and laryngeal edema. The extremities and the gastrointestinal tract are most commonly affected. Swelling of the upper respiratory mucosa poses the greatest risk because death from asphyxiation can result from laryngealedema. HAE C1-INH attacks are variable, unpredictable, and may be induced by a variety of stimuli, including stress or physical trauma. Because the clinical presentation of HAE-C1-INH is similar to other types of angioedema, the condition may be a challenge to diagnose. Accurate identification of HAE-C1-INH is critical in order to avoid asphyxiation by laryngeal edema and to improve the burden of disease. Based on an understanding of the underlying pathophysiology of IHAE-C1-INH, drugs targeted specifically to the disease, such as C1-inhibitor therapy, bradykinin B2 receptor antagonists, and kallikrein-inhibitors, have become available for both treatment and prevention of angioedema attacks. This article reviews the clinical features, differential diagnosis, and current approaches to management of HAE-C1 INH. PMID- 23678555 TI - Asthma phenotypes today. AB - PubMed databases were searched for articles regarding asthma phenotypes. Asthma has long been recognized as a heterogeneous disease, with hallmark features including age of onset, pattern of severity and other clinical characteristics, but recently it is no longer considered as single disease but rather as a series of complex, overlapping individual phenotypes, and a novel classification of the disease according to the nature of the underlying airway inflammation has been suggested. It has become increasingly clear that asthma is a complex syndrome. Recognition of specific subphenotypes may improve our understanding of underlying genetic basis and of pathophysiologic mechanisms as well as of response to treatment. PMID- 23678557 TI - Antihistamines in daily practice: Italian allergologists' opinion. PMID- 23678558 TI - Specialty pharmacy management adjusts to new financial realities. PMID- 23678556 TI - Assessment of biofilm by nasal cytology in different forms of rhinitis and its functional correlations. AB - BACKGROUND: Recently, it has been reported that nasal cytology in light microscopy can identify biofilms, which appear as cyan-stained "Infectious Spots". We assessed by the same method and in the same population, the presence of biofilms in different nasal disorders, and estimated if a correlation with the functional grade of obstruction existed. METHODS: Subjects suffering from different nasal disorders, after a detailed clinical history and ENT examination, underwent nasal fibroendoscopy, skin prick test, rhinomanometry and nasal cytology. The presence of biofilm was linked to the type ofdisease and to the grade of obstruction. RESULTS: Among 1,410 subjects previously studied, the infectious spot was found in 107 patients (7.6%), and this percentage reached 55.4% in subjects with cytologic signs of infectious rhinitis (presence of bacteria/fungi). Biofilms were largely more frequent in patients with adenoid hypertrophy (57.4%), followed by nasal polyposis (24%), chronic rhinosinusitis (9.5%) and non-allergic rhinitis (7.6%). Nasal cytology was normal in the remaining patients, where no infectious spot was detectable. Statistical analysis showed that nasal resistances were significantly higher in presence of biofilms in patients with adenoid hypertrophy (p = 0.003), nasal polyposis (p < 0.001), chronic rhinosinusitis (p = 0.018) and septal deviation (p = 0.001). CONCLUSION: The results demonstrate that biofilm is present not only in infectious rhinitis, but also in inflammatory and/or immune-mediated diseases. The presence of biofilms significantly correlates with the degree of nasal obstruction as assessed by rhinomanometry. PMID- 23678559 TI - A conversation with Suzanne F. delbanco, PhD. Employers enlist health plans in campaign for payment reform. Interview by John Marcille. PMID- 23678560 TI - Good news on preterm births creates financial challenges. PMID- 23678561 TI - Planning biotech development requires knowing payers' needs. PMID- 23678562 TI - Trials wrap on interferon-free hepatitis C regimen. PMID- 23678563 TI - Molecular diagnostics more important, still underutilized. PMID- 23678564 TI - Vagus nerve stimulation for treating chronic heart failure A summary of ECRI Institute's Health Technology Forecast report. PMID- 23678565 TI - Missed rebate opportunities dog medical benefit. PMID- 23678566 TI - Shortage of IT workers coming, but there is a glimmer of hope. PMID- 23678567 TI - Large employers agree on rewarding healthy behavior. PMID- 23678568 TI - [Advances in the production of humanized glycoprotein by different expression systems--a review]. AB - Theraputic glycoprotein is increasingly important for human health with new developments of the recombinant DNA technology and the protein glycosylation theory. Most glycoproteins are produced in mammalian cells with high cost and low yield as the bottleneck in production. Bacterial expression systerm is important but rather diffcult by the restriction of both theory and technology. Therefore, yeast glycoprotein expression systems have been established, and they are of the utmost importance. This review summarized N-linked glycosylation processes of the different expression systems and genetic engineering of the glycosylation pathways to "humanized" glycoproteins. PMID- 23678569 TI - [Archaeal community structure and diversity in Urumqi No. 10 cold sulfur spring analyzed by culture-independent approach]. AB - OBJECTIVE: We explored the composition and diversity of archaea in a cold sulfur spring water in Xinjiang earthquake fault zone. METHODS: Environmental total DNA was extracted directly with enzymatic lysis method from a cold sulfur spring water. We constructed clone library of 16S rRNA gene amplified with archaeal specific primers. A total of 115 positive clones were selected randomly from the library and identified by restriction length polymorphism (RFLP) with enzyme Alu I and Afa I. The unique RFLP patterns corresponded clones were selected for sequencing, BLAS alignment and constructing 16S rRNA gene phylogenetic tree. RESULTS: In total, 44 operational taxonomic units (OTUs) were determined from the library. BLAST and phylogenetic analysis indicated that these OTUs were affiliated with Euryarchaeota (94.78%) and Thaumarchaeota (4.35%). Only one Thaumarchaeotal clone was detected and most related to the genus Nitrosopumilus with 93% similarity. Euryarchaeotal clones were abundant and diverse. Of them, 42.61% of clones belonged to RC-V cluster; 13.91% of clones, 20.87% of clones were classified into LDS cluster and Methanomicrobiales respectively; 4.35% of clones had high similarity with ANME-1a-FW, which were involved in Anaerobic oxidation of methane (AOM). In addition, we also detected some (13.05%) unknown Euryarchaotal clones. CONCLUSION: Euryarchaeota in the environment were diverse, and possibly with a large fraction of potential novel species. PMID- 23678570 TI - [Transcriptional regulation of exosporium basal layer structural gene exsB in Bacillus thuringiensis by SigmaK and GerE]. AB - OBJECTIVE: To identify the transcriptional regulation of exosporium basal layer structural gene exsB in Bacillus thuringiensis. METHODS: We analyzed exsB and its promoter sequence in Bacillus cereus group by sequence alignment. We performed beta-galactosidase assay of exsB-lacZ gene fusion to analyze transcriptional activation of exsB promoter; we used Electrophoretic mobility shift assays to detect binding of GerE and exsB promoter. RESULTS: exsB was the high similarity in Bacillus cereus group strains. Beta-galactosidase assay showed that exsB promoter had the strong transcriptional activation on the late sporulation phase. Deletion of gerE or sigK gene decreased the activation of exsB promoter. Electrophoretic mobility shift assays showed that GerE could bind with exsB promoter. CONCLUSION: The exsB gene is regulated by SigmaK and GerE on the late sporulation phase. PMID- 23678571 TI - [Function of nitric oxide in initiating production of lignin degrading peroxidases by Phanerochaete chrysosporium]. AB - OBJECTIVE: By analyzing the function and mechanism of nitric oxide in initiating producing lignin peroxidases by phanerochaete chrysosporium, we studied the regulation mechanism triggering the secondary metabolism of white-rot fungi. METHODS: Mutant (pcR5305) and wild-type (pc530) strains of phanerochaete chrysosporium were respectively cultured under both the conditions of nitrogen limitation and nitrogen sufficiency. To compare their lignin peroxidases (LiP) production and nitric oxide(NO)-production kinetics and their different influences on producing LiP after the NO donor Sodium Nitroprusside (SNP) and scavenger cPTIO were respectively added to the nitrogen limitation or sufficiency culture medium to show the function and mechanism of nitric oxide in initiating production of lignin peroxidases by white-rot fungi. RESULTS: Both strains produced nitric oxide (NO) under the two opposite nutritional conditions, but the levels of NO produced were related with the type of strain and the nutritional conditions. Strain pc530 produced NO requiring nutrition depletion and producing of NO was strongly delayed and reduced when it was cultured under nitrogen sufficiency condition. On the contrary, pcR5305 did not require nitrogen depletion to trigger and the levels of NO were higher than that of pc530. The results indicate that LiP content had positive correlation with NO value except the occurrence time of LiP peak value was later than that of NO. The ability of producing LiP was promoted after the NO donor SNP added, but SNP affected more on pc530 than pcR5305 in promoting producing LiP. 15mM cPTIO would greatly repress producing LiP, but could not completely restrain the synthesis of LiP for both strains. CONCLUSION: By producing NO, Phanerochaete chrysosporium triggers LiP synthesis. However, the evidences do not indicate that NO participates or effect directly in LiP synthesis. It is more likely that NO is reacting as an upstream signal molecule. Besides NO, there are other signal molecules that have a positive effect on NO levels also involving in the regulation producing LiP. The mechanism of the resistance to nutritional repression of pcR5305 in synthesizing lignin degrading peroxidases may be the answer to the different NO production mechanism of pcR5305 from pc530. PMID- 23678572 TI - [Expression of hemolytic phospholipase C from Pseudomonas aeruginosa in Escherichia coli]. AB - OBJECTIVE: In this study, we constructed a recombinant Escherichia coli (E. coli) strain to produce hemolytic phospholipase C and optimized the fermentation conditions. METHODS: We screened a high phospholipase C activity strain, Pseudomonas aeruginosa (P. aeruginosa) 41, through yolk borax plate method, and cloned the hemolytic phospholipase C gene (plcH) from it. The plcH was inserted into pET-28a (+) and then obtained the recombinant expression plasmid (pET28a plcH). We selected the correct recombinant plasmid and transformed it into E. coli BL21 (DE3). Furthermore, we determined the PLC activity and hemolytic activity in positive transformants on yolk borax plate and columbia blood agar plate. Finally, we optimized the fermentation conditions. RESULTS: We successfully constructed a recombinant E. coli strain (E. coli BL21 (DE3)/pET28a plcH) that showed significant phospholipase C activity. Moreover, hemolytic phospholipase C of the recombinant strain showed strong hemolytic activity. The enzyme activity of phospholipase C was 722.9 +/- 0.47 U/mL with 5% of inoculation amount, 200 r/min for 4 hours at temperature of 37, induced by 0.9 mmol/L IPTG for 14 hours. CONCLUSION: We constructed a recombinant E. coli strain with high hemolytic phospholipase C activity under optimized fermentation conditions. It is the first time in domestic to successfully clone and express phospholipase C gene from P. aeruginosa in E. coli. These research results are helpful to advance the industrialization and application of phospholipase C. PMID- 23678573 TI - [Diversity of endophytic bacteria in rice seeds and their secretion of indole acetic acid]. AB - OBJECTIVE: This study aimed to investigate the diversity of endophytic bacteria isolated from rice seeds, and screen indole acetic acid secrecting srtains. METHOD: Conventional culture-dependent methods were used to isolate the endopytic bacteria from rice seeds. Phylogenetic analysis was done based on partial 16s rRNA gene sequences. The ability to indole acetic acid secretion of tested strains was analyzed qualitatively and quantitatively by colorimetry. RESULT: In total 66 isolates were identified as belonging to 26 species of 15 genera of 5 phyla. Of them 26 strains were chosen to test indole acetic acid secretion. Four isolates had more ability of indole acetic acid secretion; they belonged to the genera of Staphylococcus, Rhizobium, Microbacterium and Methylobacterium. CONCLUSION: The endophytic bacteria in rice seeds are diverse. Some of them could produce indole acetic acid. PMID- 23678574 TI - [Construction and virulence evaluation of the virB1-89K gene knockout mutant of type IV-like secretion system of Streptococcus suis serotype 2]. AB - OBJECTIVE: To construct the virB1-89K gene knockout mutant and its complementary strain of Streptococcus suis serotype 2 (SS2) highly virulent strain 05ZYH33 and evaluate the role of virB1-89K in the pathogenesis of SS2. METHODS: The virB1-89K gene was knocked out by homologous recombination, then multiple-PCR and sequence analysis were used to identify the knockout strain deltavirB1-89K. The virB1-89K gene and its upstream promoter were cloned into the E. coli-S. suis shuttle vector pSET1, and the recombinant plasmid was electrotransformed into the deltavirB1-89K mutant to generate the complementary strain CvirB1-89K. The effects of virB1-89K deletion on the basic biological characteristics and virulence of SS2 were then determined in this study. RESULTS: The isogenic mutant deltavirB1-89K and its complementary strain CvirB1-89K were successfully constructed. No significant differences in biological characteristics were found among the three strains. However, the virulence of the deltavirB1-89K mutant was reduced to 30% of the wild-type level and functional complementation of virB1-89K restored its pathogenicity. CONCLUSION: The virB1-89K gene plays an important role in the pathogenesis of S. suis 2 infection. PMID- 23678575 TI - [Preparation and identification of polyclonal antibody to serotype I Mareks disease virus sorf2 protein]. AB - OBJECTIVE: To obtain mice and rabbit polyclonal antibody of serotype I Marek's disease virus (MDV) sorf2 protein with higher titer and to identify the specificity. METHODS: Using serotype I MDV GX0101 as template, we amplified sorf2 gene and then cloned it into pET-28a (+) and pET-32a (+) respectively. The recombinant plasmid pET-28a-sorf2 and pET-32a-sorf2 was separately transformed into Escherichia coli BL21 (Rosetta) competent cell which was induced with isopropylthio-beta-D-galactoside (IPTG). After purification, immuned 6-8 Balb/c mice and adult New Zealand white rabbit with the purified fusion protein and the anti-sorf2 polyclonal antibody were prepared. The specificity of the serum was detected by Western blot and the indirect immunofluorescence assay (IFA) method. RESULTS: Serotype I MDV sorf2 protein was expressed successfully in the recombinant E coli. Mice and rabbit anti-sorf2 polyclonal antibody with higher titer could react with sorf2 protein specifically. CONCLUSION: The prepared anti sorf2 polyclonal antibody could identify MDV sorf2 gene deletion strain specifically. In addition, it could be used for differential of MDV vaccine poison HVT and serotype I MDV, which was useful for the separation and identification of clinical MDV. PMID- 23678576 TI - [Detection of Yersinia pestis sRNA by digoxigenin-labeled Northern blot]. AB - OBJECTIVE: With the application of high-throughput sequencing methods, more and more sRNAs are required to be verified. In this study, we developed the digoxigenin-labeled Northern blot method for detection of Yersinia pestis sRNA. METHODS: Total RNAs extracted from Yersinia pestis grown under low-iron conditions were loaded onto 10% denaturing urea polyacrylamide gel (dPAGE), electrophoresed and transferred to nylon membranes. Northern blots were fixed to the membrane by UV cross-linking and subjected to hybridization with 3' -end digoxigenin-labeled oligonucleotides RNA probe for RyhB1 and RyhB2 overnight and followed by washing, blocking, immunological detection and finally exposed to film. RESULTS: Exposure time of digoxigenin-labelled Northern blot was 20s-3 min. The detection sensitivity of RyhB1 and RyhB2 was 0.005 microg and 0.05 microg, respectively. RyhB1 and RyhB2 probe specificity was high and no cross reaction with each other was found. Positively charged or neutral nylon membranes are applicable to the hybridization reaction. Hybridization for RNA probe can proceed within 42 to 65 degrees C with reduced non-specific probe interactions by increasing the temperature while the hybridization temperature for DNA oligonucleotide probes seemed to be determined empirically. CONCLUSION: A digoxigenin-labeled Northern blot has been developed for detection of Yersinia pestis sRNA, which was characterized by good specificity, high sensitivity, longer shelf life and short exposure times and provided an power tool for validation of bacterial sRNAs and function studies. PMID- 23678577 TI - [Detection of fps tumor antigen with mono-specific anti-fps serum in tumors induced by acute transforming ALV]. AB - OBJECTIVE: To prepare anti-fps mono-specific serum, and detect the fps antigen in tumors induced by acute transforming avian leukosis/sarcoma virus containing v fps oncogene. METHODS: Two part of v-fps gene was amplified by RT-PCR using the Fu-J viral RNA as the template. Mono-specific serum was prepared by immuning Kunming white mouse with both two recombinant infusion proteins expressed by the prokaryotic expression system. Indirect immunofluorescent assay was used to detect fps antigen in tumor tissue suspension cells and CEF infected by sarcoma supernatant. Immunohistochemical method was used to detect fps antigen in tumor tissue. RESULTS: The mouse mono-specific serum was specific as it had no cross reaction with classical ALV-J strains. The result reveals that the tumor tissue suspension cells, the CEF infected by sarcoma supernatant, and the slice immunohistochemistry of the sarcoma showed positive results. CONCLUSION: The anti fps mono-specific serum was prepared, and the detection method was established, which laid the foundation for the study of viral biological characteristics and mechanism of tumourgenesis of acute transforming avian leukosis/sarcoma virus containing v-fps oncogene. PMID- 23678578 TI - [Selection of reference genes for virulence gene expression in Vibrio parahaemolyticus]. AB - OBJECTIVE: We selected reference genes for virulence gene expression of Vibrio parahaemolyticus under different environmental conditions. METHOD: Using qRT-PCR, we evaluated the expression stability of four housekeeping genes (GAPDH, pvuA, pvsA and rpoS) of V. parahaemolyticus cultivated separately in seawater, filtered seawater, shrimp and Tryptone Soya Broth. RESULT: The result shows that all the candidate reference genes could be amplified specifically in qRT-PCR reaction. The expression stability of the four reference genes ranked pvuA (2.906) > pvsA (3.197) > GAPDH (3.746) > rpoS (6.512). Further analysis with geNorm program reveals that the highest stability was observed in pvuA and pvsA. The geometric average score of the two genes was considered as the most appropriate reference gene for normalizing the expression of virulence genes of V. parahaemolyticus. CONCLUSION: The pvuA and pvsA genes could be used as reference genes to study the virulence gene expression of V. parahaemolyticus. PMID- 23678579 TI - [Effect of autoinducer 2 on Riemerell antatipestifer adherence and invasion to Vero cells]. AB - OBJECTIVE: Autoinducer 2 (AI-2), used to communicate among bacterial species, regulates numerous physiological functions of bacteria. In this study, we studied the effect of AI-2 on adherence and invasion of Riemerella antatipestifer (RA) strain CH3 to Vero cells and transcriptional levels of virulence-related and metabolism-related genes were investigated. METHODS: To verify whether the adherence and invasion of CH3 was affected by AI-2, we added different concentrations of AI-2 to the cocultures of Vero cells and CH3 and then calculated adherence percentages and invasion percentages of tested groups. We further added AI-2 (184.0 micromol/L) to the tryptone soya broth culture of CH3 and then detected the effect of transcriptional levels of related genes of CH3 using real-time PCR. RESULTS: The adherence of CH3 to Vero cells was decreased most to 62% with 18.4 micromol/L AI-2 and the invasion of CH3 to Vero cells was increased most to 194% with 184.0 micromol/L AI-2. The result of real-time PCR shows that AI-2 increased transcriptional levels of some virulence-related genes and decreased transcriptional levels of some metabolism-related genes. CONCLUSION: These results suggest that AI-2 affected adherence and invasion of CH3 to Vero cells. Moreover, AI-2 could regulate some genes of CH3 to modulate particular physiological behaviors. PMID- 23678580 TI - [Present leprosy situation in the world in 2012]. AB - The epidemiological situation of leprosy is reported by the health division of each country to WHO. The reported data is collected by WHO and is immediately run on the Weekly Epidemiological Record. On this latest edition, data from the beginning of 2012 was reported. The Enhanced global strategy for further reducing the disease burden due to leprosy (plan period: 2011-2015) emphasizes reducing grade-2 disabilities among new cases. The sustained and committed efforts by the national programmes along with the continued support from national and international partners have led to a decline in the global burden of leprosy. It is important that all endemic countries continue to provide innovative solutions to address barriers to timely case detection and treatment completion, to ensure that the current declining trend is sustained. PMID- 23678581 TI - [Molecular neuroimaging in schizophrenia]. PMID- 23678582 TI - [Recent development of understanding and psychiatric care on schizophrenia]. AB - Recent development of understanding and psychiatric care on schizophrenia during past 30 years was reviewed. Slight brain volume reduction during early several years of the disease and association of psychotic symptoms with excess dopamine release in striatum were confirmed. A discovery of duration of untreated psychosis (DUP) has encouraged early intervention, hope for recovery from schizophrenia and liberation from old Kraepelin concept. PMID- 23678584 TI - [Molecular pathology of schizophrenia]. AB - Dopamine hypothesis has dominated as a molecular pathology of schizophrenia over the past few decades and anti-dopaminergic drugs are currently the most widespread available treatment option. Converging lines of evidence suggest altered regulation of other neurotransmitters including glutamate, GABA and acetylcholine, results in the dysregulation of dopaminergic neurons in schizophrenia, and is involved in the comprehensive symptoms such as positive, negative, and cognitive dysfunction. In the prefrontal cortex of patients with schizophrenia; dysfunctional NMDA-type glutamate receptors on GABAergic interneurons cause disinhibition of pyramidal glutamatergic neurons, resulting in increase in the firing of dopaminergic neurons. Cognitive dysfunction of schizophrenia may be a representation of asynchronous glutamatergic and GABAergic neurons. In addition to the effects of NMDA receptor modulators including D serine, emerging evidences of the roles of nicotinic acetylcholine receptors on glutamatergic and dopaminergic regulations suggest new treatment options for schizophrenia. PMID- 23678583 TI - [Epidemiology of schizophrenia]. AB - Schizophrenia exhibits wide variation in epidemiological characteristics. Through the past few decades, we have learned much about schizophrenia epidemiology, providing important findings for etiological research, clinical care and public health. In this article, we provide overview of current research on incidence, prevalence, risk factors, mortality and outcome of schizophrenia. Contrary to traditional understanding, the incidence and prevalence of schizophrenia show prominent variation between locations. Risk factors for schizophrenia include urbanicity, migration, sex, season of birth and pregnancy and birth complications. Schizophrenia patients have an increased mortality risk compared with the general population. Recent studies about outcome show not so tragic, especially in regard to social functioning. Over the recent decades, circumstances have been changing around schizophrenia. As to treatment, for example, 'the second generation antipsychotics' have replaced conventional ones and 'early intervention' is developing. However, we have only limited evidences of current schizophrenia. Further epidemiological development is needed. PMID- 23678585 TI - [Genetics of schizophrenia]. AB - Many studies have reported that genetic variants play a major role in the pathogenesis of schizophrenia. In the past five years, the genetics knowledge base of schizophrenia has advanced considerably. These advances have mostly been through genome-wide association studies (GWAS) and copy number variations (CNVs) studies. Moreover, exome sequencing by using the next-generation DNA sequencers is launched in recent years. In the next few years, the high-throughput sequencing is likely to play an important role. These findings have produced new hypotheses about etiology of schizophrenia and they can indicate future research strategies. Therefore, it is expected that further studies will yield deeper insights. PMID- 23678586 TI - [Current status of epigenetics of schizophrenia]. AB - The patients with schizophrenia suffer from a lot of severe symptoms; positive symptoms, negative symptoms and cognitive impairment. However, the pathophysiology remains almost unknown, and no curative therapy is available for the patients. Thus, the elucidation of the pathophysiology and development of curative therapy are imperative. Epigenetics is a promising approach in that it can explain the environmental effects as well as gene-environmental interaction. Here, we review the recent progress of epigenetic studies in relation to schizophrenia and discuss the limitation of previous studies. Epigenetic studies applying the recent progress of genomics and neuroscience will contribute to better understanding of schizophrenia pathophysiology and the development of therapeutic strategy. PMID- 23678587 TI - [Intermediate phenotype of schizophrenia]. AB - Genes are major contributors to schizophrenia. The intermediate phenotype concept represents a strategy for identifying risk genes for schizophrenia and for characterizing the neural systems affected by risk gene variants to elucidate quantitative, mechanistic aspects of brain function implicated in schizophrenia. Intermediate phenotypes are defined by being heritable, being able to measure quantitatively; being related to the disorder and its symptoms in the general population; being stable over time; showing increased expression in unaffected relatives of probands; and cosegregation with the disorder in families. Intermediate phenotypes in schizophrenia are neurocognition, neuroimaging, neurophysiology, etc. In this review, we present concept, recent work, and future perspective of intermediate phenotype. PMID- 23678588 TI - [Neuroimaging studies of social cognition in schizophrenia]. AB - In various social situations, individuals with schizophrenia often have difficulties in keeping appropriate relationships with others. To elucidate the neural basis of such difficulties, we explored associations between brain morphological alterations and dysfunction of social cognition in schizophrenia, using MRI. Several important findings have been yielded: For instance, amygdala volume reduction was correlated with impaired facial emotion recognition ability, while reductions in the medial prefrontal cortex was correlated with impairment in emotion attribution to protagonists in social situations. These results suggest that individuals with schizophrenia have various domains of impaired social cognition. Moreover, in schizophrenia, the brain regions involved in such impairments might differ according to the domains of social cognition. PMID- 23678589 TI - [Structural brain changes in schizophrenia]. AB - Studies using structural brain imaging techniques such as magnetic resonance imaging (MRI) have provided important clues to help our understanding of the pathophysiology of schizophrenia. There have been a variety of brain morphological changes reported in schizophrenia including (1) premorbid structural deviation possibly due to early neurodevelopmental abnormalities, (2) active progressive changes occurring before and after the onset of first psychosis, and (3) further progressive changes in chronic phase in some patients. Although causes of these changes remains elusive, a number of genetic and environmental factors have been suggested to underlie the morphological abnormalities in schizophrenia. Treatment strategies to prevent the progression of brain morphological changes could contribute to improving long-term outcome. PMID- 23678590 TI - [Diagnosis, clinical course, and differential diagnosis of schizophrenia]. AB - Schizophrenia is a disease whose symptoms are shown to a little less than 1% at adolescence. Since the morbidity elucidation is not yet made many of psychiatry diseases including schizophrenia, a useful biological marker or image inspection, and a physiological inspection are not in diagnosis. About diagnosis of a psychiatric disorder, the symptoms study diagnostic method never must be used. Then, diagnosis needs to be made appropriately and carefully and differential diagnosis must also perform it exactly. It is because medical treatment may differ depending on diagnosis. If this is not made appropriately, it may lead to medication of an unnecessary and aimless antipsychotic. In this paper, diagnosis and differential diagnosis of schizophrenia, and clinical course were summarized. PMID- 23678591 TI - [The significance of the early detection and intervention for schizophrenia]. AB - Early detection of, and intervention for, schizophrenia improve the social and functional outcome of the schizophrenia patient. A shorter duration of untreated psychosis (DUP) is an indication of a good prognosis for schizophrenia, but the DUP in Japan is comparatively long. There are some reports which have suggested shortening the DUP, for example, the Buckingham project and TIPS. They show early intervention services reduce the rate of onset of schizophrenia, and improve functions of schizophrenia patients. Intervention for patients with At Risk Mental State (ARMS) may stop or delay the onset of schizophrenia. Furthermore, intensive cares for patients in the critical period can also induce better clinical and functional outcomes. A shorter DUP and an intensive and comprehensive approach within the critical period are eagerly awaited in Japan. PMID- 23678592 TI - [Therapeutic goal and pharmacotherapy according to clinical stages of schizophrenia]. AB - Schizophrenia is chronically progressed disease with a functional decline and adequate treatment is needed for respective clinical stages. Duration of psychosis before treatment is called DUP (duration of untreated psychosis) and may be an important predictor of outcome. Furthermore, the early phase of schizophrenia including DUP is considered a critical period, in which long-term outcome is predictable. Therefore, that shows the importance of early detection and intervention for schizophrenia and relapse prevention during a critical period. The atypical antipsychotics now play the leading role in pharmacotherapy of schizophrenia. They clearly decrease adverse effects, and may prevent the relapse and improve long-term outcome. However, better pharmacotherapy needs the viewpoint of adherence and we do not have to remember the importance of psychosocial therapy. PMID- 23678593 TI - [Predictors of adverse effects induced by antipsychotics]. AB - Atypical antipsychotic drugs are superior to typical antipsychotic drugs in having a lower incidence of extrapyramidal side-effects, so atypical antipsychotic drugs have become the mainstream in the clinic. However, there is growing interest in the effects of antipsychotic treatment on other serious side effects such as metabolic abnormalities, sexual function and QT prolongation. There is a need for biomarkers that can help in early identification of patients who are at risk for these serious side-effects. Hence, we have conducted psychopharmacological studies using OGTT, measurement of adipokines, holter ECG and genetic methods, aiming to identify key biomarkers to drive personalized medicine and new treatment development. PMID- 23678594 TI - [Pharmacology and clinical implication of typical antipsychotics]. AB - Typical antipsychotic drugs were introduced in 1950's. Atypical antipsychotics developed in 1990's and 2000's have been reported to show superiority over typical antipsychotics. However, when comparison was made with a low dose of a typical drug, the superiority disappeared in some studies. Both types of antipsychotics have in common a pharmacological property to decrease dopamine D2 receptor neurotransmission. Polypharmacy once prevailed in Japan and a high dose therapy once dominated in western countries should not be used anymore. The proper dose of typical antipsychotics is much lower than the dose used previously. Typical as well as atypical antipsychotics should be used as monotherapy with a proper dosage. It is of clinical significance for treatment staffs to become to pay more attention to quality of life and rehabilitation of patients. PMID- 23678595 TI - [Paliperidone, risperidone]. AB - Risperidone, a serotonin-dopamine antagonist, is effective in preventing delusions and hallucinations by D2 receptor antagonism and treating negative symptoms by 5-HT2A receptor antagonism. It is less likely to produce extrapyramidal symptoms than conventional antipsychotics, enabling safe drug therapy for schizophrenia. Paliperidone, based on 9OH-risperidone(major metabolite of risperidone), was developed to make the best use of the high therapeutic efficacy of Risperdal and enable continued treatment with lower prevalence of adverse events. Its mechanism of action as an extended-release tablet ensures slow release of the active ingredient, contributing to the lower prevalence of adverse events. With these pharmacological characteristics in mind, the two drugs can serve as safe and effective drug therapy. PMID- 23678596 TI - [Blonanserin in the treatment of schizophrenia]. AB - Blonanserin was developed in Japan in 2008 as an antipsychotic drug. It has high affinity for dopamine D2/3 and serotonin 5-HT2A receptors, but shows low affinity for adrenergic alpha1, histamine H1, and muscarinic M1 receptors. Several short term double-blind trials demonstrated that blonanserin was well tolerated and had equal efficacy to haloperidol and risperidone in terms of positive symptoms and depressive symptoms in patients with chronic schizophrenia. It was also superior to haloperidol in improving negative symptoms. We have recently reported that blonanserin may improve some types of cognitive function associated with the frontal lobe activity in patients with first-episode schizophrenia. Taken together, blonanserin may be a promising candidate for a first-line antipsychotic for patients with first-episode and chronic schizophrenia. PMID- 23678597 TI - [Olanzapine]. AB - Olanzapine is one of the SGAs (second-generation antipsychotics) which have been used for the treatment of patients with schizophrenia and bipolar disorder in Japan. Olanzapine has various affinities for multiple receptors, including dopamine D2 receptor, serotonin 5-HT2A, 5-HT2C, 5-HT6 receptors, and adrenaline alpha1, histamine H1, muscarine M1-M5 receptors as well. Therefore, olanzapine is known as MARTA(multi-acting receptor targeted antipsychotics). Numerous studies have been conducted to compare the effectiveness of olanzapine between SGAs and FGAs (first-generation antipsychotics). According to the head-to-head meta analysis and large-scale studies like CATIE and EUFEST, olanzapine seems to have not only higher efficacy but also less discontinuation comparing to other anti psychotics. PMID- 23678598 TI - [Quetiapine]. AB - Quetiapine is a unique antipsychotic drug characterized by the weakest affinity for dopamine D2 receptors of all the antipsychotics. This drug certainly binds D2 receptors, but rapidly dissociates from them. Therefore, it is necessary to establish how to use quetiapine in the different way from potent and sustained D2 receptor antagonists such as haloperidol. Plenty dose of quetiapine is effective for schizophrenia patients suffered from severe insomnia, catatonia, emotional instability, impulsiveness and aggressiveness. However, in order to avoid metabolic side effects including weight gain and diabetes mellitus, we have to continue a longitudinal blood glucose monitoring in schizophrenia patients treated with quetiapine. PMID- 23678599 TI - [Clozapine]. AB - Clozapine is a drug used in the management of treatment-resistant schizophrenia. Numerous clinical trials, including randomized double-blind clinical trials and large cohort studies, have revealed that clozapine is more effective than any other antipsychotic drugs. However, the same studies have also shown that this drug has several adverse effects such as an agranulocytosis. Therefore, in Japan, clozapine is approved for administration to only patients with treatment resistant schizophrenia in whom treatment with other antipsychotic drugs was ineffective. Clozapine is prescribed only at approved institutes that are under the registration called Clozaril Patient Monitoring Service (CPMS), and white blood cell counts and prescription dosage of clozapine are strictly monitored under this service. PMID- 23678600 TI - [Aripiprazole as "dopamine sensitivity stabilizer"]. AB - Aripiprazole (ARI) is one of atypical antipsychotics used for the treatment of schizophrenia all over the world, owing to its tolerability and ability to keep antipsychotic effect for an extended period of time. Its unique pharmacological feature, which is known as dopamine partial agonist, enables clinically relevant dopamine(2) receptor blockade and prevents extrapyramidal adverse effects. On the basis of our preclinical experiments and clinical case study, we discovered that ARI had an ability to stabilize the sensitivity to dopamine. Excessive sensitivity to dopamine is hypothesized to lead to exacerbation or relapse of psychotic symptoms. Therefore, we speculate that ARI can prevent schizophrenic patients from exacerbation or relapse of psychotic symptoms by reducing excessive sensitivity to dopamine. PMID- 23678601 TI - [Cognitive remediation]. AB - Cognitive deficits are a core symptom of schizophrenia and marked in the sub domains of cognition. They have been shown to predict whether a patient will be able to meet functional goals. Because of the small effect size of pharmacotherapy on cognitive function, cognitive remediation has gradually been introduced into the psychiatric rehabilitation. This non-pharmacological treatment for improving neurocognition aims to enhance the neurocognitive strategies relevant to their chosen recovery goals through engaging the participants in learning activities in a highly motivated way. Most meta-analytic studies on this new treatment report moderate effect sizes on cognition with the notable differences in their effects possibly due to their distinct practice methods. The impact of this treatment on daily functioning, however, has been found to be smaller than that on neurocognitive skills. It is thus suggested that cognitive remediation should be implemented in concert with other types of programs for psychiatric rehabilitation. PMID- 23678602 TI - [Electroconvulsive therapy in schizophrenia]. AB - Electroconvulsive therapy (ECT) was initially developed as a treatment for schizophrenia. Currently, the application of ECT for schizophrenia is controversial because of several international guidelines; however, catatonia is acceptable for the indications by all guidelines. Schizophrenic patients with affective, catatonic, and positive symptoms of recent onset may respond favorably to ECT. Additionally, ECT may improve responsivity to pharmacotherapy for some indications. Therefore, a combination of ECT with pharmacotherapy including clozapine may be effective for the pharmacotherapy -resistant schizophrenia. Another argument is that the relapse rate after ECT response is very high compared to that of mood disorders; development of maintenance therapy(pharmacotherapy or ECT) is anticipated for the prevention of relapse. Because maintenance ECT seems to be a burden on remitted patients, to study both maintenance pharmacotherapy and the novel application of non-invasive treatment, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), for maintenance therapy instead of ECT could be fruitful. PMID- 23678603 TI - [Childhood-onset schizophrenia]. AB - Childhood-onset schizophrenia has been clinically studied and is believed to be on a continuum with adult-onset schizophrenia. However, childhood-onset schizophrenia is more difficult to diagnose than it is in adults, since children are in a developmental state. This article reviewed the literature regarding childhood-onset schizophrenia. This article discusses the clinical features, development until manifestation, possibility of early diagnosis, and treatment. Early intervention may improve the prognosis of psychotic disorders such as schizophrenia. However, early intervention of childhood-onset schizophrenia requires case histories with accurate descriptions of the development of the disease until its onset. PMID- 23678604 TI - [Late-onset schizophrenia]. AB - We conducted clinical research at Jichi Medical University Hospital psychiatric ward on 38 patients over the age of 40 with late-onset schizophrenia and on 278 patients under the age of 40 with early-onset schizophrenia. Cases with onset after age 40 reported in 12% of the total population. Female cases were 20.4%, and the result was significantly higher than the male cases of 4.3%. Paranoid type was 55.3% of the total population of the late-onset cases, and it was significantly higher than the early-onset cases of younger than 40 years old. 55.3% of late-onset cases were combined with depressive symptoms, and they rated significantly higher than early-onset cases. PMID- 23678605 TI - [Implementation of appropriate administration of antipsychotics--measures to reduce high-dose multiple antipsychotics]. AB - In Japan, multiple antipsychotic drugs are administered at a high dose to schizophrenia patients. Many patients suffer from side effects, among which extrapyramidal and autonomic side effects frequently occur. We suggest a method in which antipsychotic drugs are slowly reduced as follows: for low potency drugs, the dose is decreased with 25 mg or lower of a chlorpromazine-equivalent dose per week, and, for high potency drugs, the dose is decreased with 50mg or lower of a chlorpromazine-equivalent dose per week. A randomized controlled trial involving 10 hospitals demonstrated that antipsychotic drugs can be reduced with relative safety according to our method. Our method is also expected to be useful to switch between antipsychotics to avoid polypharmacy. PMID- 23678606 TI - [About mental health outreach services in Japan]. AB - Outreach services are very important in community mental health care. There are two types for outreach services. One is mental health activities, such as early intervention and consultation, and the other is intended to prevent recurrence and readmission by supporting the daily living activities of a patient in a community. We have 2.73 psychiatric care beds in hospitals per 1,000 population. So, it is just the beginning in changing from hospital centered psychiatry to community mental health care. Outreach services are being tried in several places in our country. In this essay, we describe mental health outreach services in Japan and we have illustrated vocational rehabilitation and outreach job support in our day treatment program. PMID- 23678607 TI - [ACT and the trends of psychiatric community care]. AB - Bleuler has said that we have to provide community care for people with schizophrenia. In Japan, the process of modernization already ended by the miraculously swift growth of the economy in the postwar era. So it will be difficult to maintain facilities such as psychiatric hospital because the maintenance costs are too high. The core of mental health system should be community care in the future. The deinstitutionalization is essential to realize community care. Assertive community treatment (ACT) is the effective support system for people with severe mental illness (SMI). A characteristic of ACT is multidisciplinary team consisting of specialists in welfare and in medical service (ex. nurse, psychiatric social worker, occupational therapist, doctor, etc.) providing care for people with SMI. The following are detailed explanations of ACT. PMID- 23678608 TI - [Current state and vision of the development of new antipsychotic drugs]. AB - To date, antipsychotic drugs have been developed mainly by targeting dopamine D2 receptors. No significant changes have occurred in this trend despite mental disorders being treated more frequently with so-called "atypical" antipsychotic drugs. The action of antipsychotic drugs on dopamine D2 receptors can play an important role in the development of future antipsychotic drugs. However, there is a growing trend of developing new antipsychotic drugs by targeting new pathways. In this article, we discuss the vision for future antipsychotic drugs through an increase in the number of new antipsychotic drugs that are currently being developed or are already on international markets. PMID- 23678609 TI - [The present and the prospect of study on Blau syndrome/early-onset sarcoidosis]. AB - Blau syndrome (BS) and early-onset sarcoidosis (EOS) are both systemic granulomatous disease evoked by the mutated NOD2. It occurs in children younger than 4 years of age and is characterized by a distinct triad of skin, joint, and eye disorders without apparent pulmonary involvement. NOD2 encodes an intracellular receptor for muramyl dipeptide (MDP), the common component of bacterial cell wall peptidoglycan, and is expressed in cytoplasm of monocytic cells and epithelial cells. While its loss-of-function mutations are recognized in Crohn's disease, the mutations observed in BS/EOS are gain-of-function, and induced MDP-independent basal NF-kappaB activation. But we still do not know the precious molecular mechanism how the activation of NOD2 induces granuloma formation in the skin, joints and eyes. PMID- 23678610 TI - [Nicotinic acetylcholine receptor in Alzheimer's disease]. AB - Nicotinic acetylcholine receptor (nAChR) mediates pleiotropic actions in brain not only for nicotinic neurotransmission but also glutamatergic, dopaminergic, norepinephrinergic, GABAergic, and serotonergic transmissions, especially through allosteric potentiating ligand (APL) action. Because nAChR is rich in thalamus, the direct stimulation of nAChR through APL action is expected to show increasing function of cerebral cortex and limbic system through thalamic activation. In fact, a choline esterase inhibitor with this APL action such as galantamine exerts both cognitive and affective improvements which is called dual benefit for Alzheimer's disease patients. PMID- 23678611 TI - [Selective serotonin reuptake inhibitor and gastrointestinal hemorrhage]. AB - Selective serotonin reuptake inhibitors (SSRI) are widely used antidepressants characterized by less-frequent adverse effects compared with classical anti depressive agents. On the other hand, SSRI can cause hemorrhagic events more due to impaired platelet aggregation induced by a depletion of serotonin in the peripheral platelet. Epidemiological studies have indicated that patients taking SSRI are predisposed to gastrointestinal hemorrhage, especially in case that nonsteroidal anti-inflammatory drugs are prescribed concomitantly. Here we describe a risk of the gastrointestinal hemorrhage in patients taking SSRI. PMID- 23678612 TI - Visual search and visual discomfort. AB - Certain visual stimuli evoke perceptions of discomfort in non-clinical populations. We investigated the impact of stimuli previously judged as uncomfortable by non-clinical populations on a visual search task. One stimulus that has been shown to affect discomfort judgments is noise that has been filtered to have particular statistical properties (Juricevic et al, 2010 Perception 39 884-899). A second type of stimulus associated with visual discomfort is striped patterns (Wilkins et al, 1984 Brain 107 989-1017). These stimuli were used as backgrounds in a visual search task, to determine their influence on search performance. Results showed that, while striped backgrounds did have an impact on visual search performance, this depended on the similarity between the target and background in orientation and spatial frequency. We found no evidence for a more generalised effect of discomfort on performance. PMID- 23678613 TI - Onset time of binocular rivalry and duration of inter-dominance periods as psychophysical markers of ADHD. AB - Attention deficit hyperactivity disorder (ADHD) is one of the main neurobiological disorders in young children. Despite its prevalence, current diagnosis is debated. In this study we tested whether measures of binocular rivalry (BR) can contribute to the diagnosis of ADHD. BR is a phenomenon that is produced when two different images are presented to the two eyes simultaneously. Under these conditions the image presented to one eye competes with that presented to the other eye in seeking to achieve perceptual dominance. This competition is resolved through the activation of a given percept coupled with the suppression of the percept that had predominated until that point. We assume that the difficulty with inhibiting responses of ADHD children also affects their ability to inhibit the dominant image in a BR context. We analyzed the time to rivalry onset and the inter-dominance periods as measures of the temporal cost of resolving how long it takes for the brain to select (or suppress) one percept over the other. Our results show that the time to onset of rivalry (the first dominance) was longer in the clinical groups (ADHD-C and ADHD-I) than in the control group. As regards the inter-dominance periods, these were longer in the ADHD-C group than among controls, with the shortest period corresponding to the ADHD-I group. This study shows that BR can be used as a tool to develop a behavioral indicator of ADHD. PMID- 23678614 TI - Effects of subtle stimulus strength on the attentional blink. AB - The attentional blink refers to a type of impairment in detecting a second target (T2) after detecting a first target (T1) in rapid serial visual presentation (RSVP). Until recently, the role of T1 and how it is related to limitations in postperceptual processing such as selective attention and memory have been intensively studied. Here, we focus on the role of T2 and investigate whether an unnoticeable difference in the stimulus strength of T2, as indexed by the contrast of stimuli, can still influence this postperceptual process. We found that T2 performance was modulated by subtle T2 strength differences, although the T2 strength difference was not perceptually noticeable within the RSVP stream. These results suggest that T2 strength is important in the postperceptual stages of T2 processing-consolidation. PMID- 23678615 TI - Changes in angular size and speed affect the judged height of objects moving over a ground surface. AB - Kersten et al (1997, Perception 26 171-192) showed that the perceived path of an object moving over a ground surface can be manipulated by changing the path of a shadow. Using a scene similar to Kersten's "ball-in-a-box" scene, we investigated the effect of angular size and angular speed in determining the perceived height of a moving sphere when optical contact (the position at which the object contacted the ground in the image) indicated that the sphere was receding in depth. In four experiments we examined both the effects of changes in size and speed, and the effects of constant levels of size and speed. Increases in angular size or speed during a motion sequence resulted in judgments of increased height above the ground plane. The angular size at the end of the motion sequence was also important in determining judged height, with greater height judged with larger final sizes. PMID- 23678616 TI - Replicating and extending Bourdon's (1902) experiment on motion parallax. AB - Bourdon conducted the first laboratory experiment on observer-produced motion parallax as a cue to depth. In three experiments, we replicated and extended Bourdon's experiment. In experiment 1, we reproduced his finding: when the two cues, motion parallax and relative height, were combined, accuracy of depth perception was high, and when the two cues were in conflict, accuracy was lower. In experiment 2, the relative height cue was replaced with relative retinal image size. As in experiment 1, when the two cues (motion parallax and relative retinal image size) were combined, accuracy was high, but when they were in conflict, it was lower. In experiment 3, the stimuli from experiments 1 and 2 were viewed monocularly with head movement and binocularly without head movement. In the binocular conditions, accuracy, certainty, and the extent of perceived depth were higher than in the monocular condition. In the conflict conditions, accuracy, certainty, and the extent of perceived depth were lower than in the no-conflict condition, but the extent of perceived motion was larger. These results are discussed in terms of recent findings about the effectiveness of motion parallax as a cue for depth. PMID- 23678617 TI - Understanding transparency perception in architecture: presentation of the simplified perforated model. AB - Issues of transparency perception are addressed from an architectural perspective, pointing out previously neglected factors that greatly influence this phenomenon in the scale of a building. The simplified perforated model of a transparent surface presented in the paper has been based on previously developed theories and involves the balance of light reflected versus light transmitted. Its aim is to facilitate an understanding of non-intuitive phenomena related to transparency (eg dynamically changing reflectance) for readers without advanced knowledge of molecular physics. A verification of the presented model has been based on the comparison of optical performance of the model with the results of Fresnel's equations for light-transmitting materials. The presented methodology is intended to be used both in the design and explanatory stages of architectural practice and vision research. Incorporation of architectural issues could enrich the perspective of scientists representing other disciplines. PMID- 23678618 TI - Discrimination of brief gaps marked by two stimuli: effects of sound length, repetition, and rhythmic grouping. AB - We examined the effects of sound marker length, marker repetition, and rhythmic grouping on auditory gap discrimination. The discrimination ofthe duration of a gap between two markers was impaired by lengthening these markers (from 150 to 262.5 ms). Discrimination was impaired by lengthening the preceding marker relative to lengthening the following marker, while the impairment was not increased when both markers were lengthened compared with when only the preceding marker was lengthened. This indicates that the level of discrimination is not decided by a simple summation of the effects of the preceding and of the following marker's length. Moreover, discrimination of a gap between a short (S) and a long (L) marker and of a gap between a long and a short marker was improved by repeating the presentation of these gaps (ie by repeating the markers alternately as SLSLSL...): both types of discrimination led to near identical performance. Finally, under the repetition condition each type of discrimination was not related to the tendency for each individual to perceive the stimulus sequences as segmented into rhythmic chunks of a short tone followed by a long tone (as [SL][SL][SL]...), or those of a long tone followed by a short tone (as S][LS][LS][L...). PMID- 23678619 TI - Back view of beauty: a bias in attractiveness judgment. AB - Attractiveness judgment based on visual appearance seems easy and almost automatic. However, it becomes difficult when we need to rely on glances of a person's back view (eg while passing on the street). How is attractiveness judgment from the back view consistent with that from full-front view? In experiment 1 participants rated the attractiveness of human heads photographed from behind and from the front. Attractiveness ratings between the back and front views were weakly but significantly correlated. However, on average, the back view photographs were rated more attractive than the front-view photographs. The tendency was most conspicuous when the male participants viewed the photographs of women. In experiment 2 participants were explicitly asked to predict the facial attractiveness of each head's front view based on the back view. Again, the predicted attractiveness based on the back view was higher than the actual rating of the front-view photographs, and the difference reached significance when the male participants viewed the women photographs. These biases in attractiveness judgment would be related to attractiveness judgments in everyday situations where straight full-frontal encounters are rare. PMID- 23678620 TI - The effect of "anatomical plausibility" of hand angle on the rubber-hand illusion. AB - In the rubber-hand illusion (RHI), when an actual hand hidden from view and a rubber hand in view are simultaneously stimulated, participants mistakenly perceive tactile sensation as arising from the rubber hand, not from the actual hand. Some studies have revealed that the magnitude of RHI decreases when the actual and rubber hand are incongruent in terms of hand angle. However, the acceptable range of angular deviations between the actual and rubber hand and its determination factor has not been investigated so far. I attempt to examine the angle-congruency effect between the actual and rubber hands on RHI. The left rubber hand simulated by 3-D computer graphics was rotated at 8 angles. Participants perceived higher ownership of the stimulated rubber hand when the angles were at 0 degrees, 45 degrees, 90 degrees, and 315 degrees (these are easy to mimic with the actual hand) than at 180 degrees, 225 degrees, and 270 degrees (these are difficult to mimic with the actual hand). The perceived location of the actual hand became closer to that of the simulated rubber hand with increased perception of ownership of the rubber hand. Moreover, the onset duration of RHI became shorter, especially for the angles of 0 degrees, 45 degrees, and 315 degrees. These results suggest that RHI occurs mainly within the range where people usually rotate their hand and that body representation might include the knowledge of "anatomical plausibility". PMID- 23678621 TI - Evidence for a positive relationship between working-memory capacity and detection of low-prevalence targets in visual search. AB - Our ability to detect a target in visual search relates to the prevalence of the target, whereby rare targets are missed more than common targets. The current study sought to identify operator characteristics that could account for the higher miss rates associated with rare targets. The results found that working memory capacity, which is strongly related to attentional control and inhibition of irrelevant information, was significantly correlated with the ability to detect low-prevalence targets. High-capacity observers also exhibited lengthened target-absent responses with rare targets, suggesting that the high-capacity observers were more persistent in their searches than others. PMID- 23678622 TI - The effect of motion lines on apparent-motion correspondence under dichoptic presentation. AB - Motion lines enhance the impression of motion when viewing static/dynamic images. I investigated the binocularity of the motion-enhancing effect in an ambiguous apparent-motion display. Even in the dichoptic presentation condition, the effect of motion lines on apparent- motion correspondence was as strong as that in the monoptic condition. Additionally, there were no effects of stereo-depth separation. These results suggest that the effect of motion lines arises from a higher-level motion-processing mechanism that occurs after integrating information from both eyes. PMID- 23678623 TI - Object-based integration of motion information during attentive tracking. AB - How do observers track multiple moving objects simultaneously? Previous work has shown that adding conflicting texture motion to the tracked objects impairs tracking performance. Here, we test whether texture motion is integrated with object motion in an object-based manner, or whether adding conflicting texture motion to a display causes global interference effects. We added a moving texture onto the surface of tracked objects with the texture moving either in the same or opposite direction to the objects. In the critical trials, we presented both types of texture motion. In these trials, we found a selective impairment for the objects with opposite texture motion, suggesting that multiple motion information sources are integrated in an object-based manner during tracking. The integrated motion signals might be used to anticipate prospective object locations in order to enhance tracking. PMID- 23678624 TI - [Legal issues of physician-assisted euthanasia. Part III--Passive euthanasia, comparison of international legislation, conclusions for medical practice]. AB - The generic term "passive euthanasia" includes different issues dealing with the omission, discontinuation or termination of life-sustaining or life-prolonging medical treatments. The debate around passive euthanasia focuses on the constitutional right of self-determination of every human being on the one hand and the constitutional mandate of the State to protect human life on the other. Issues of passive euthanasia always require a differentiated approach. Essentially, it comes down to the following: In Germany, the human right of self determination includes the right to prohibit the performance of life-sustaining treatments, even if this leads to the death of the patient. A physician who does not take life-sustaining treatment measures because this is the free will expressed by the patient is not subject to prosecution. On the other hand, if the physician treats the patient against his will, this can be deemed a punishable act of bodily injury. The patient's will is decisive even if his concrete state of health does no longer allow him to freely express his will. In the Patient's Living Will Act of 2009, the German legislator clarified the juridical assessment of such constellations being of particular relevance in practice. A written living will of a person in which he requests to take or not to take certain medical treatment measures in case that he is no longer able to make the decision himself shall be binding for the people involved in the process of medical treatment. If there is no living will, the supposed will of the patient shall be relevant. In its judgment in the "Putz case", the German Federal Court of Justice ruled in 2010 that actions terminating a life-sustaining treatment that does not correspond to the patient's will must be limited to letting an already ongoing disease process run its course. In this context it is not important, however, whether treatment is discontinued by an active act or by omission. Under certain circumstances, the termination of life-sustaining measures can also be permitted if they are no longer medically indicated. Looking to other European countries and the USA it becomes evident that euthanasia is the subject of controversial discussion and interpretation not only in Germany. PMID- 23678625 TI - [Phentermine--a "weighty" or a dangerous substance?]. AB - According to international surveys, the appetite suppressant phentermine has frequently been seized although its approval has been withdrawn in Germany. Phentermine is an isomer of methamphetamine though is not optically active such as e. g. amphetamine. The drug acts as a potent substrate at the norepinephrine transporter simultaneously promoting its release; it has a weaker activity at the dopamine transporter whereas its activity towards the serotonin transporter is negligible. Overall, its pharmacological action is comparable to that of amphetamine albeit less strong. Due to its declining effect with time and its addiction potential it has been recommended that phentermine should be used for a few weeks only. Phentermine hydrochloride is a readily soluble salt; absorption of the resinate compound is considerably slower. The drug is not extensively biotransformed; p- and N-hydroxyphentermine are the primary metabolites also being excreted as glucuronide conjugates. Gas chromatographic techniques to identify and to quantify phentermine in biological specimens are applicable following derivatization; however, liquid chromatography coupled to mass spectrometry is currently preferred for analysis of urine, serum or hair. Short term clinical studies having been performed in the 80s and 90s revealed no serious harmful side effects. However, there are case reports proposing that phentermine usage might be associated with severe health risks due to hypertension, vasoconstriction and vasculopathy; in some individuals, mental illness had been observed. Apart from the legal consequences following purchase of drugs that have been withdrawn its user will simultaneously run serious and unpredictable health risks. PMID- 23678626 TI - [Putrefaction in a mortuary cold room? Unusual progression of postmortem decomposition processes]. AB - This article illustrates the rare case of rapid body decomposition in an uncommonly short postmortem interval. A clear discrepancy between early postmortem changes at the crime scene and advanced body decomposition at the time of autopsy were seen. Subsequent police investigation identified a failure in the cooling system of the morgue as probable cause. However, due to the postmortem status of the body, a moderate rise in temperature alone is not considered to have caused the full extent of postmortem changes. Therefore, other factors must have been present, which accelerated the postmortem decomposition processes. In our opinion, the most reasonable explanation for this phenomenon would be a rather long resting time of the corpse in a non-refrigerated hearse on a hot summer day. PMID- 23678627 TI - Sex selection and the procreative liberty framework. AB - The practice of sex selection for social reasons has raised serious criticism. Advocates of this practice, however, insist that objections to it are unfounded and that legal bans are ethically unjustified. Usually, proponents use a rights based liberal approach as the framework to evaluate this practice. Under this framework, reproductive choice is a basic freedom and interference with individuals' autonomous reproductive choices is illegitimate, unless their actions are shown to seriously harm others. As persuasive as this framework might be in relation to many aspects of reproduction, I argue that it is inappropriate when dealing with sex selection for social purposes. PMID- 23678628 TI - "Obligated aliens": recognizing sperm donors' ethical obligation to disclose genetic information. AB - Sperm donors' obligations are typically constrained to the immediate circumstances surrounding the donation and to its time frame. This paper makes the case for recognizing an ongoing ethical obligation that binds sperm donors to disclose, in a timely manner, meaningful genetic information to recipients and donor-conceived children. The paper delineates and conceptualizes the suggested (potentially reciprocal) duty and argues that it is not the genetic link between the donor and the donor-conceived child that binds donors by said duty, but rather social responsibility. Accordingly, an original perception of the donor as an obligated alien is suggested and developed. The main thesis of the paper is supported inter alia by a comparison between transmitting infectious diseases and passing faulty genes on to donor-conceived children. The paper also provides an in-depth analysis of the conflicting interests of the parties generated by such an obligation and proposes a model for embedding this ethical duty in a (legal) contractual framework. PMID- 23678629 TI - Brain death, paternalism, and the language of "death". AB - The controversy surrounding the dead donor rule and the adequacy of neurological criteria for death continues unabated. However, despite disagreement on fundamental theoretical questions, I argue that there is significant (but not complete) agreement on the permissibility of organ retrieval from heart-beating donors. Many disagreements are rooted in disputes surrounding language meaning and use, rather than the practices of transplant medicine. Thus I suggest that the debate can be fruitfully recast in terms of a dispute about language. Given this recasting, I argue that the language used to describe organ donation is misleading and paternalistic. Finally, I suggest that the near-agreement on the permissibility of heart-beating organ retrieval ought to be reconsidered. If the paternalism is not justified, then either the language used to describe organ transplantation must change radically, or it would seem to follow that much of the transplant enterprise lacks ethical justification. PMID- 23678630 TI - Second Biomedical Conference Supplement. PMID- 23678631 TI - Researching the vulnerables: issues of consent and ethical approval. AB - Imagine you are a biomedical scientist attempting to cross a busy, beggar-crowded road in Lagos. You suddenly notice that the loud horns of the speeding cars, trucks and trailers draw no visible physiologic response from any of the beggars including their children and babies, unlike the rest of the crowd. Consequently, certain questions such as the following begin to engage your mind: Is this phenomenon a kind of habituation? If so, is its onset the same for the blind ones amongst them? Have these beggars acquired a neural system absent from "normal" people? If so, just how long does it take for such a system to be established? At the very height of this creative outburst, you however realize that the informed consent and ethical approval you would need for this particular research differs from the type you have previously encountered in your career.... Although the above scenario suggests that new and difficult ethical questions may confront scientists while pursuing their curiosity, our research ethics guidelines do not currently address this issue. This paper explores some of the ethical challenges involved in carrying out basic research on vulnerable subjects such as beggars. It highlights how the notions of autonomy and informed consent in this context become vague, thus, liable to exploitation. Ultimately, the paper offers a useful framework in relation to developing a research ethics committee charged with the moral mandate of overseeing the integrity of research involving this vulnerable population in particular and basic biomedical research in general. PMID- 23678632 TI - Transposable elements in the genomes: parasites, junks or drivers of evolution? AB - In many organisms with large and complex genomes, transposable elements (TEs) constitute up to 50% of the genomic DNA. TEs have been widely studied and they showed high similarities across kingdoms. Several reasons have been adduced for the diverse TEs among plants and animal species. Activities of TEs could give rise to altered gene or genome at very high frequencies in both germinal and somatic tissues. TE-induced genetic variability can range widely; from changes in the arrangement of the whole genome to changes in single nucleotides. This may produce major effects on the phenotypic traits or small silent changes detectable only at the DNA sequence level. TE-induced mutation in the regulatory sequences may be of evolutionary significance and insertions in promoter sequences can alter tissue-specific patterns of gene expression. In addition, transposons can be involved in amplification and dispersal of genes by taking up portions of other sequences within the TEs themselves, moving them to new locations, thereby increasing their copy number. Therefore, mobilization of TEs might benefit the host through enhancement of genetic diversity. However, TE movement have been linked with undesirable traits in plants, hybrid dysgenesis in Drosophila and genome instability and diseases in mammals. This review summarises the diversity of TEs across plant and animal kingdoms and their impact and possible role in genomic evolution. It also describes some adverse effects of TEs as agents of genomic instability and diseases such as cancers, and the genetic regulations of their activities. PMID- 23678633 TI - Therapeutic effects of various solvent fractions of Alstonia boonei (apocynaceae) stem bark on Plasmodium berghei-induced malaria. AB - Malaria, the most important parasitic disease afflicting man is the leading cause of mortality and morbidity in the world. Chemotherapy remains the mainstay for the treatment and prevention of the disease in the absence of an effective vaccine. The incidence of resistance of malaria parasites to chemotherapy is increasing and complicated. This study was therefore undertaken in order to evaluate the therapeutic effects of fractions of the stem bark of A. boonei on P. berghei-induced malaria using chloroquine as control. Different doses (200 mg/kg and 400 mg/kg body weight) of methanolic extract (ME), n-hexane (HF), chloroform (CF), ethylacetate(EF) and aqueous (AF) fractions of the stem bark of A. boonei were administered orally to albino mice. Five milligrammes chloroquine base per kilogramme body weight (5 mg/kg bw) was used as positive control while the negative control mice received only the vehicle (5% v/v tween 80). The results obtained showed that the 400 mg/kg bw dose was more effective with respect to the parasite clearance than the 200 mg/kg bw dose. The 400 mg/kg bw dose of ME gave 68.1% percent parasite clearance. The CF gave the highest clearance of 98.4% at 400 mg/kg bw after 7 days treatment while chloroquine at 5 mg/kg bw gave 100% parasite clearance. The order of increasing potency of the fractions (parasite clearance) was (EF 50.0% < AF 60.3% < HF 63.1%, < CF 98.4%) indicating that the active principle in the stem bark was highest in the CF. Percentage parasitemia following exposure to these fractions also decreased in all groups in the same order and was only significant (p < 0.05) in CF (0.11%) compared to the untreated control group. The ME of A. boonei also caused increase in PCV by 15.5%. Purification enhanced PCV value as the HF and CF fractions gave 19.0% and 24.5% increases, respectively. However, 31.5% increase in PCV was obtained in the albino mice treated with chloroquine. The EF and AF gave increase of 10.0% and 11.0% increase relative to the negative control treated mice. The high bioactivity of CF and HF indicate that the putative compound(s) in A. boonei are lipophillic and further purification could enhance greater activity. Further work is required to isolate the bioactive compound for a promising antimalarial drug from the chloroform fraction. PMID- 23678634 TI - Ocimum grastissimum extract inhibits stimulated acid secretion by carbachol and induces gastric mucus secretion. AB - In this study, the effects of ethanol extract of Ocimum gratissimum (EEOG) on both basal and stimulated gastric acid secretion and gastric mucus secretion were investigated in Albino rats treated with the extract. Four groups of animals were used. Sub-group 1A serves as control. Animals in Group 2A, 3B and 4B were pretreated with 200 mg/kg of (E3EOG) for 1, 7 and 14 days respectively. Basal gastric effluents were collected from all the groups of animals at intervals of 10 mins for 60 mins. Thereafter, Subgroups 1A, 2A, 3A and 4A were administered with 50 micro/kg b.w. of carbachol (i.p.) intraperitonialy and effluents collected. Animals in Sub-group B were used for gastric mucus study. Carbachol stimulates gastric acid secretion in animals pretreated with the extract for 1, 7 and 14 days. 50-400 mg/kg b.w. doses of the extract significantly increase gastric mucus secretion. These results indicate the mechanism of anti-ulcer activity of the extract may be due to stimulation of gastric mucus secretion amongst pathways. PMID- 23678635 TI - Cocoa powder extracts exhibits hypolipidemic potential in cholesterol-fed rats. AB - INTRODUCTION: Hypercholesterolemia and oxidative stress are risk factors of cardiovascular diseases. OBJECTIVES: This study investigated the hypolipidemic effect of cocoa powder extract (CPE) in an experimental model of hypercholesterolemia, using Questran as a reference. METHODS: Hypercholesterolemia in rats was induced by oral administration of 30 mg/kg cholesterol for eight weeks. Three groups concurrently received Questran (0.26 g/kgb) and CPE (100 mg/kg and 200 mg/kg) respectively. Hypercholesterolemia and dyslipidemia were assessed by lipid profile. Reduced glutathione (GSH), Superoxide dismutase (SOD), Catalase (CAT), Glutathione-S-transferase (GST) and malondialdehyde (MDA) level were also assessed to evaluate the antioxidant status of rats. RESULTS: There was 56% and 97% increase in total and LDL-cholesterol and 59% decrease in HDL-cholesterol levels on cholesterol administration. Concurrent administration of CPE (100 mg/kg) significantly (p < 0.05) decreased total cholesterol (19%) and LDL-cholesterol (22%) and increased HDL-cholesterol (286%) levels while at 200 mg/kg, 55% and 64% reductions in total and LDL-cholesterol and 250% increase in HDL-cholesterol levels were observed. No significant changes were observed in phospholipid levels. Body weights of rats were not significantly different among groups and CPE (100 mg/kg) ameliorated the cholesterol-induced enlargement of the liver and heart by 14% and 15% respectively and at 200 mg/kg by 21% in the heart. GSH and CAT were significantly depleted, and MDA and SOD significantly elevated in liver and heart of Cholesterol-fed rats. No significant changes in GST, alanine and aspartate aminotransferases occurred among groups. CPE treatment modulated these changes. CONCLUSION: Cocoa powder possesses hypolipidemic potential and may be relevant in treating pathologies with dyslipidemia as an underlying cause. PMID- 23678636 TI - Relationship between serum levels of testosterone, zinc and selenium in infertile males attending fertility clinic in Nnewi, south east Nigeria. AB - In the recent years, male infertility and sub-fertility have increased, which is attributable to many factors. Some trace elements such as zinc and selenium have been shown to play a role in reproduction. The study was designed to determine the serum levels of zinc, selenium and testosterone in infertile males attending fertility clinic in Nnewi. We investigated fifty apparently infertile males (subjects) and twenty apparently healthy fertile males (controls) between the ages of twenty five and fifty five years. The serum levels of zinc and selenium were determined using Atomic Absorption Spectrophotometer while the serum level of testosterone was determined using Enzyme Immunoassay techniques. The results showed that there were significant differences in the mean serum zinc, selenium and testosterone when compared between the two groups. The results also showed a strong positive correlation between serum levels of zinc and selenium, a negative correlation between serum levels of testosterone and zinc, and a strong positive correlation between serum testosterone and selenium in the infertile males. We therefore conclude that there is a relationship between the serum levels of zinc, selenium and testosterone in infertile males and that these parameters be considered when investigating cases of infertility in males. PMID- 23678637 TI - Sizes and developmental viability of sequentially oviposited eggs of dog ticks: Rhipicephalus sanguineus and Haemaphysalis leachi leachi. AB - Sizes and developmental viability of sequentially oviposited eggs of up to 12th day oviposition by dog ticks Rhipicephalus sanguineus and Haemaphysalis leachi leachi were studied. The mean length and breadth of eggs oviposited on days 1 and 2 were greater (0.45 +/- 0.111 and 0.44 +/- 0.042) than those of subsequent ovipositions. The eclosion periods of eggs laid from 7th to 12th day of oviposition were progressively shorter (17, 16, 14 and 19, 17, 0 days) than those of eggs laid on days 1 and 2 (20 and 22 days) by R. sanguineus and H. leachi leachi, respectively. The percentage mortality of eggs of days 11 and 12 oviposition (70.3% and 100%) was significantly higher than that of earlier ovipositions (9.6% and 31.7%) for R. sanguineus and H. leachi leachi, respectively. The numbers of larvae which engorged on rabbits after hatching from eggs of 11th and 12th day oviposition (43 and 0) were significantly fewer than those which hatched from eggs of days 1 and 2 (79 and 63) for R. sanguineus and H. leachi leachi, respectively. A total of 383 larvae of R. sanguineus engorged on rabbits compared to 225 larvae of H. leachi leachi. It is concluded that eggs of early ovipositions of R. sanguineus and H. leachi leachi are longer and wider and more viable than those laid later in the oviposition cycle. The significance of these findings in terms of hatchability of eggs is discussed. PMID- 23678638 TI - HIV-1 drug resistant mutations in chronically infected treatment naive individuals in the pre-ARV era in Nigeria. AB - In Nigeria the Federal Government rolled out antiretroviral drugs for the management of HIV infection in year 2002. This study was carried out to determine the circulating antiviral drug mutations among ARV naive patients with chronic HIV infection during the pre-ARV roll out era in the country. DNA was extracted from stored whole blood samples collected from 75 HIV positive patients attending the Medical outpatient clinic between December 1996 and November 2001. The Reverse transcriptase (RT) and the protease (PR) regions of the viral genome were amplified by nested PCR and then sequenced by cycle sequencing and analyzed using the ABI 3100 DNA sequencer to determine the mutations associated with protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI) and non nucleoside reverse transcriptase inhibitor (NNRTI). Ten of the 64 (15.6%) samples with positive PCR had mutations for PR inhibitors (PI) including R8D, I 15V, G16E, M36I, M46L, L63P and H69K, while 5 of 63 harbored RT inhibitor (NRTI/NNRTI); V179I, A98T, V179E and A98S. Detection ofARV drug resistant mutations when ARV was not known to be in use in Nigeria calls for caution in the interpretation of drug resistance profile of HIV-1 from infected persons on treatment ARVs in the country. PMID- 23678639 TI - Nigerian bonny light crude oil induces irreversible reproductive toxicity in adult male rats. AB - BACKGROUND: The reversibility of reproductive toxicity induced by the Nigerian Bonny light crude oil (BLCO) was investigated in rats. METHOD: Adult male Wistar rats were orally treated with BLCO at 0, 50, 100 and 200mg kg(-1) for 21 days. One-half of the rats were sacrificed on day 22 while the remaining one-half stayed additional 21 days without treatment. RESULTS: While sperm quality was compromised in dose-dependent manner, testis histopathology was only evident at 200 mg kg(-1) after 21 days. BLCO significantly decreased activities of superoxide dismutase, catalase and glucose-6-phosphate dehydrogenase but markedly elevated gamma glutamyltransferase and glutathione S-transferase activities as well as malondialdehyde, hydrogen peroxide and glutathione levels in both testes and sperm. Most of the above-mentioned parameters were consistent in animals from withdrawal experiment. CONCLUSION: Taken together, BLCO exposure impaired fertility via increased oxidative stress and was not reversible upon withdrawal of treatment within the time course of investigation in male rats. BLCO exposure poses a risk for impaired fertility and its contribution to infertility in the Nigerian male population may not be excluded. PMID- 23678640 TI - Polymerase chain reaction (PCR) investigations of prepatent Schistosoma haematobium cercariae incidence in five water bodies, South West, Nigeria. AB - This study investigated the levels of prepatent S. haematobium infection in water samples collected from Schistosomiasis haematobium transmission namely: International Institute of Tropical Agriculture (IITA) river and Eleyele river in Oyo state, Oyan dam and Shokori river in Ogun state, Badagry Lagoon and Lagoon (University of Lagos, Lagos state). METHODOLOGY: Polymerase chain reaction (PCR) assay amplifying the Dra I repeated sequence of S. haematobium cercariae from the water samples was used. Samples of cercariae obtained from a laboratory population of Bulinus globosus and Bulinus rohlfsi snails were assayed following DNA extraction as control. Physico-chemical parameters of the water bodies were determined. RESULTS: Physico-chemical parameters showed that salinity, conductivity and total dissolved solids were relatively high in the Lagoon front samples (41.91 ppt, 62400.87 micros/cm, 31000.14 mg/L and 7.79), and low in the river samples (13.27 ppt, 1325.67 micros/cm, 11470 mg/L and 8.36 respectively) while pH were similar. PCR showed that 3 out of the 6 water bodies sampled namely IITA river, Eleyele river and Oyan Dam are S. haematobium endemic sites as they gave positive signals. CONCLUSION: Three surveyed sites with relatively low salinity namely IITA river, Eleyele river and Oyan dam are high S. haematobium endemic areas and schistosomes survive perhaps best in low salinity environment. PCR could be a more valuable tool in the study of incidence and prevalence of S. haematobium infection compared with conventional cercariae shedding method. On the known strength of focal effects of environmental conditions, implications of these results in the epidemiology and design of control activities are encouraging. PMID- 23678641 TI - Free radical scavenging activities of guava extract in vitro. AB - INTRODUCTION: Psidium guajava (guava) is used in folk medicine in treating diverse human ailments. The therapeutic benefit of medicinal plants is often attributed to their antioxidant properties. OBJECTIVES: This study evaluated the radical scavenging potentials of ethanolic extract of Psidium guajava (EEPG) in vitro. METHOD: Radical scavenging potential of EEPG was determined by assessing its reducing power, extent of LPO, NO, H2O2, DPPH inhibition and TEAC. RESULT: AAPH-induced LPO was significantly (P < 0.05) inhibited by 56.5%, 65.3%, 55.1%, 54.4%, 53.1%, at 25-400 micro/g of EEPG. The reference drug, catechin at 50 microg, produced 39.5% inhibition of LPO induced by AAPH respectively with respect to control. EEPG produced significant (p < 0.05) inhibition of deoxyribose degradation at 100-800 microg concentrations by 30.9% (p < 0.01), 42.5%, 55.7%, 72.8% (p < 0.001) respectively with respect to control. Catechin also show potency, producing 55.5% at 25 microg (p < 0.001). Furthermore, the antioxidant activity of EEPG ranged from 763.08 to 1206.2 micromol trolox equivalent in the TEAC assay at 50-200 microg (p < 0.001) and 24.62 to 14.77 micromol trolox equivalent at 800-2000 microg (p < 0.001). Catechin exhibited a TEAC value of 2338.5 micromol trolox equivalent (p < 0.001). EEPG exhibited maximum radical scavenging activities of 30.1% on NO radical (p < 0.01), 98.72% on H2O2 (p < 0.001), at 50 microg and 70.45% on DPPH radical (p < 0.001) at 100 microg. EEPG also demonstrated marked reducing power, increasing absorbance values from 0.24 +/- 0.01 to 1.86 +/- 0.20 at 25-160 microg. The reducing power of EEPG at 200 microg (0.41 +/- 0.07) almost compares with that of catechin at 50 microg (0.45 +/- 0.028). CONCLUSION: These results demonstrate that the ethanolic extract of Psidium guajava (EEPG) exhibited significant free radical scavenging and antioxidant activities in vitro. PMID- 23678642 TI - Human erythrocyte membrane Ca(2+)-ATPase during occupational exposure to lead. AB - OBJECTIVE: Erythrocyte membrane Ca(2+)-ATPase activity was determined in workers occupationally exposed to lead because of the prevalence of elevated blood lead in auto-mobile workers in some urban areas in Nigeria. MATERIALS AND METHODS: Blood lead levels, biochemical profiles, lipid peroxidation, basal and calmodulin stimulated Ca(2+)-ATPase activities were determined in erythrocytes of different categories of workers occupationally exposed to lead. These subjects were mainly battery chargers (BC), spray painters (SP) and auto mechanics (MC). RESULTS: Estimation of erythrocyte Ca(2+)-ATPase activity in the absence of calmodulin (basal activity) in test groups indicated that there were significant reductions in the pump function and this correlated very well with the levels of lead in their blood. Specifically, blood lead levels were of the order: BC (5.5 folds) > SP (4 folds) > MC, although there was no significant difference between the blood lead levels in MC (10.60 +/- 2.55 microgPb2+/dl) and CT (8.51 +/- 4.55 microgPb2+/dl). Similarly, the order of reduction in Ca(2+)-ATPase activity was BC (69.8%) > SP (52.8%) > MC (32.6%). There was significant difference in the values obtained for MC and CT, ATPase activity being lower in MC compared to CT or healthy individuals. In the presence of calmodulin, basal ATPase activity was increased by at least four fold in erythrocytes from healthy subjects (CT) while the basal activity of the enzymes in membranes of BC, SP and MC was enhanced by about one and half times the activity of the pump in membranes from CT. The levels of total serum protein and albumin increased significantly in BC, SP and MC when compared to healthy subjects (CT). C-reactive proteins (C-RP) levels were higher in BC, SP and MC in comparison to CT. The levels of MDA were high in all lead-exposed workers, BC > SP > MC relative to CT. Although, there were significant decreases in the PCV values of all the groups occupationally exposed to lead compared to values obtained for CT, cholesterol level increased significantly only in BC when compared to the other groups. CONCLUSION: These observations are probably due to the integrity of the plasma membrane of these workers and the ability of the heavy metal to compete with Ca2+ in the catalytic cycle and Ca2+ transport mechanism of the pump protein. PMID- 23678643 TI - Phytochemical and antifungal activities of Uvaria. chamae leaves and roots, Spondias mombin leaves and bark and Combretum racemosum leaves. AB - The effects of crude and dilutions of aqueous, methanolic and n-hexane extracts of Uvaria chamae (roots and leaves), Spondias mombin (leaves and bark) and Combretum racemosum (Leaves), on pathogenic candida albicans and aspergillus niger was studied. The aim was to contribute to the search for a cheaper, conventional cure for both fungi. Phytochemical analysis revealed varying degrees of alkaloids, glycosides, saponin, lipid and oil, tannins, flavonoids, terpenoids and acids. Agar diffusion method was used for anti fungal assay. Minimum inhibitory concentration (mic) used was 10 mg/ml of extract and dilutions of the non polar solvents of 10 (-1) and 10(-2) was used. Results showed that none of the plant parts was active against aspergillus niger. Combretum racemosum had no antifungal effect on tested organisms as well as the different dilutions. However crude methanolic extract of uvaria (roots and leaves), spondias ( bark and leaves ), and n-hexane extracts of uvaria (leaves and roots), produced anti candidal effects with diameters in this order 14.67 +/- 0.72mm, 10.67 +/- 0.52 mm, 11.00 +/- 0.47 mm, 15.00 +/- 0.47 mm, and 14.67 +/- 0.72 mm respectively. Some of the plant parts especially uvaria had zones of inhibition at a confidence limit comparable with control drug which is ketoconazole and it had inhibitory effects at a diameter of 20.06 +/- 0.40 mm. PMID- 23678644 TI - High default rate in thyroid cancer management in Ibadan, Nigeria: a need for health insurance. AB - BACKGROUND: Differentiated thyroid cancer is a potentially curable disease provided there is early diagnosis and full compliance with management modalities. This however becomes a problem in a resource poor environment where most patients pay out of pocket resulting in poor compliance and inability to access standard care due to poverty. This retrospective study was carried out to evaluate the percentage of patients that could afford the cost of care in a premier nuclear medicine facility of a tertiary centre. PATIENTS, MATERIAL AND METHOD: A total 56 patients with differentiated thyroid cancer managed since the inception of the Nuclear Medicine Department, University College Hospital from June 2006 to March 2010 were included in the study. Socioeconomic status of the patients and the affordability of the nuclear medicine procedure for differentiated thyroid cancer post thyroidectomy were evaluated. RESULT: A total of 20 out of 56 (35.7%) patients had total thyroidectomy at presentation, while, 36 had subtotal thyroidectomy. The commonest type of thyroid malignancy was papillary thyroid cancer (51.8%), while follicular cancer accounted for 41.1%. Medullary and Anaplastic thyroid cancers were the least common. Majority of the patients evaluated were within the income bracket of 10,000-30,000 naira ($67- $200) per month). The average cost of management of thyroid cancer post total thyroidectomy was $2500 (N375 000.00) at this centre. Twenty one out of 56 patients (37.5%) could afford the $300 cost of diagnostic whole body iodine scan while only 16 patients out 21 (28.6%) could afford the ($1200) cost of radioactive iodine treatment. CONCLUSION: With average cost of management of management of thyroid cancer beyond the yearly income of majority of the patients studied, there is need for a comprehensive health insurance policy to make accessibility of care of this potentially curable disease available to most Nigerians. PMID- 23678645 TI - Survival of Listeria monocytogenes, and other food spoilage microbes in vacuum packaged West African soft cheese 'wara'. AB - 'Wara' soft cheese is traditionally produced in Nigeria and has a poor microbial quality. This study assessed the survivability of Listeria monocytogenes and other food spoilage microbes (enterobacteriacea, molds and yeasts) in vacuum packaged soft cheese treated independently with Carica papaya (Vcpc), Terminalia cattapa (Vtcc) crude extracts, nisin (Vnc), and the combination of these three treatments (V+3) stored at 15 degrees C and 28 degrees C for a three week storage period. Vacuum packaging did not suppress Listeria monocytogenes, and there were no significant differences in the L. monocytogenes counts throughout the storage weeks (P > 0.05). The enterobacteriacea counts were suppressed to undetectable levels at 15 degrees C storage temperature by the third week of storage in all treatments except the Vnc and V+3. Molds and yeasts were undetectable in all treatments throughout the storage weeks. Significant differences occurred in the microbial count at the two storage temperatures and storage weeks (P < 0.05). It can therefore be concluded from this work that Vacuum packaging and addition of crude extracts (Carica papaya, Terminalia cattapa) in soft cheese storage can suppress enterobacteriacea, molds and yeasts. Food technologists developing industrialized 'wara should consider including these extracts and vacuum packaging in their production. Therefore, their use in extension of the shelf life of soft cheese is recommended. PMID- 23678646 TI - The protective effects of methyl jasmonate against adriamycin--induced hepatic and renal toxicities. AB - The aim of the study was to investigate the protective effect of methyl jasmonate (MJ) in adriamycin (ADR) induced hepatic and renal toxicities. 36 BALB/c mice were randomly divided into control, ADR (20 mg/kg), MJ (50 mg/kg) only, MJ (100 mg/kg) only, MJ (50 mg/ kg) + ADR, MJ (100 mg/kg) + ADR groups (n = 6). The 2 doses of MJ was administered for 7 days in MJ only groups, ADR was administered intraperitoneally on the 8th day after pretreatment with the 2 different doses of MJ while ADR was administered on the 8th day only for the ADR only group. The malondialdehyde (MDA), glutathione (GSH), H2O2 generation, superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea and creatinine in the liver, kidneys and serum samples as applicable were estimated. Tissue MDA, H2O2 generation, and GST activity were markedly elevated while GSH content, CAT and SOD activities were significantly reduced in the tissues when compared to the control (p < 0.05). Pretreatment with MJ ameliorated ADR toxicities, with a significant reduction in serum urea concentration, ALT activity, MDA level, H2O2 generation, GST activity and a significant elevation in GSH content, CAT and SOD activities in the organ tissues. MJ induced significant reduction in MDA level and increase of GSH content in liver and kidney tissues. This study suggests that MJ may play an overall protective effect on ADR-induced toxicities in liver and kidneys and the inhibition of tissue peroxidative damage might contribute to this beneficial effect. PMID- 23678647 TI - Effects of extracts of the leaves of Brysocarpus coccineus on rat liver mitochondrial membrane permeability transition (MMPT) pore. AB - OBJECTIVE: To examine the influence or the effect of the extracts of Brysocarpus coccineus leaves on the mitochondrial membrane permeability transition (MMPT) pore opening in rats with a view to establishing if any bioactive constituent of the plant could become useful in the chemotherapy of cancer. MATERIALS AND METHODS: The effects of extracts of the leaves of Brysocarpus coccineus, a medicinal plant with anti-tumour, anti-inflammatory and analgesic properties, were assessed on rat liver mitochondrial membrane permeability transition (MMPT) pore in the presence and absence of calcium in vitro and in vivo. RESULTS: The results obtained show that calcium ions induced the opening of MMPT pore significantly (P < 0.05) in rat liver mitochondria, while spermine inhibited calcium-induced opening of pore, indicating that the mitochondria were intact ab initio. The results further revealed the inhibitory effects of different concentrations (200, 600, 1000, 1400, and 1800 microg/ml) of the various extracts of the leaves compared with spermine. Specifically, the data revealed that chloroform and ethylacetate extracts reversed calcium-induced opening of MMPT pore in a concentration-dependent manner (74%, 79%, 85%, 86%, 87%) for the chloroform extract and (36%, 37%, 59%, 71% and 83%) for the ethylacetate extract, respectively. On the contrary, pre-incubation of normal healthy mitochondria with the extracts in the absence of calcium resulted in the induction of the MMPT pore opening to varying degrees by these concentrations of the extracts. The chloroform extract induced pore opening in a concentration-dependent manner in the order 2.4, 2.4, 2.5, 2.6 and 3.0 folds while the ethylacetate extracts induced the opening of the pore by 1.1, 1.2, 1.3, 1.3 and 1.4 folds between 200 1800 microg/ml, respectively. The results obtained using rats orally exposed to various doses of methanol extract of the leaves of B. coccineus for fourteen days showed that there was significant (p < 0.05) induction of mitochondrial membrane permeability transition pore opening in the absence of calcium in a dose dependent manner. Maximum induction of 26-fold was obtained at 200 mg/kgbwt while the least dose (50 mg/kgbwt) gave 17 fold induction. CONCLUSION: The ability of the extracts of B. coccineus to induce MMPT pore opening in the absence of calcium in vitro and in vivo suggest that the leaves of the plant contain certain bioactive substances capable of inducing MMPT opening either in the original form or as formed biotrans derivative with eventual release of apoptotic proteins which may lead to apoptosis. The property of the extracts could be exploited for cancer chemotherapy when increased rate of apoptosis is required. PMID- 23678648 TI - HBV infectivity among Nigerians. AB - The study involved 60 (non-immunized), 14 (immunized against HBV), healthy Nigerian adults and 28 Nigerian patients with hepatitis. Their sera were tested for HBsAg, HBeAg, anti-HBe, anti-HBc, anti-HBs and anti-HCV while only 15 subjects with chronic hepatitis had HBV DNA assay by PCR. The subjects aged 21 to 72 years and comprised 75 male and 27 female adults. The prevalence of HBV infection by HBsAg and/or anti-HBc sero-positivity was 55.9%. Only HBsAg and anti HBs were detectable in 21% each among immunized while HBsAg, HBeAg, anti-HBe, anti-HBc, anti-HBs were present in 58%, 20%, 6%, 32%, and 42% respectively in the non-immunized subjects. HBV DNA was positive in 86.7% of the 15 subjects. About fifty five percent of all subjects were infectious of HBV with 13.7%, 3.9%. 32.3% and 4.9% accounting for high, medium, low and very low infectivity respectively while 44.1% and 1% of the subjects were susceptible and naturally immuned to HBV respectively. Coinfection with HCV tends to favour HBV infectivity. In conclusion, the infectivity of HBV among Nigeria is varied but high and a great proportion of the population is susceptible. PMID- 23678649 TI - Effects of low protein diet and pregnancy on course of Plasmodium berghei infection in mice. AB - Pregnancy and malnutrition influence the severity or trend of malaria especially in sub-Saharan Africa where parasitic infections are highly predominant. This study was used to evaluate the combined effects of low protein diet and pregnancy on the course of Plasmodium berghei infection in mice. Thirty female BALB/c mice were divided into six groups viz: Non-infected mice fed on normal diet (NIND), Infected mice fed on normal diet (IND), Noninfected mice fed on low protein diet (NILP), Infected mice fed on low protein diet (ILP), Non-infected gravid mice fed on low protein diet (NIGLP) and Gravid infected mice fed on low protein diet (GILP). Malaria parasite count, packed cell volume, body weight and plasma nitric oxide (NO) production were determined. Data were compared statistically across the groups using Student t-test and ANOVA. Parasite detection in peripheral blood was delayed in ILP (day 7) and GILP (day 11) relative to IND (day 3). The peak parasitaemia and mean survival time were significantly lower (p < 0.05) in GILP relative to other infected groups. GILP could not carry the pregnancy to term. Nitric oxide production was observed to increase more rapidly in IND relative to ILP after parasite detection with a peak production by day 15. Mortality commenced in both groups afterwards. Low protein diet delayed the peak production of NO supporting its protective influence on malaria infection. However, the combined effects of low protein diet and pregnancy resulted in early mortality and inability of mice to carry pregnancy to term. PMID- 23678650 TI - Lipid peroxidation in Nigerians affected with haematological malignancies. AB - This study investigated Lipid peroxidation status in twenty Nigerians; five (5) healthy subjects and 15 (fifteen) Haematological cancer patients; 5 affected with Chronic Myeloid leukaemia (CML), 5 (five) with Non-Hodgkin's Lymphoma and 5 (five) with Multiple Myeloma. Consents were sought and received from all participants used in the study. 10 mls of blood samples were collected in lithium heparin bottles from all subjects used in the study. Free plasma Malondialdehyde (MDA) quantification was used to assess lipid peroxidation in all subjects. MDA levels were increased in CML and Non-Hodgkin Lymphoma patients compared with that of control subjects at P < 0.001. However, a decreased non-significant free plasma MDA level was observed in multiple myeloma patients compared with control subjects. Increase in lipid peroxidation status in Nigerians affected with Haematological malignancies may be associated with a dysregulation of antioxidant system. Lipid peroxidation status could be used as clinical clue for diagnosis, prognosis and treatment of patients affected with haematological malignancies. PMID- 23678651 TI - Neurotoxic effects of administration of artemisinin combination therapy (artemether and quinine) and ascorbic acid on the cytoarchitecture of the cerebellum and trapezoid nuclei in adult rats. AB - This study investigated the neurotoxic effects of the combined intramuscular administration of Artemether (0.5 mg/kg/b.w.), Quinine (5.14 mg/kg/b.w.) and Ascorbic acid (0.21 mg/kg/b.w) on the cerebellum, trapezoid nuclei and behavioural functions in male Wistar rats for a period of seven days. Statistical analyses showed no significant differences between the average weight of the brain and cerebellum of the experimental group compared with the control group. All experimental rats showed normal histology on completion of the experimental procedures in comparison with control rats. Histological assessment of the cerebellum and trapezoid nuclei in all groups showed normal cytoarchitecture. All rats displayed normal balance and co-ordination. This study observed that the combined therapy regime over a seven day period did not cause neurohistopathological effects on the cytoarchitecture of the cerebellum and trapezoid nuclei indicating that the current therapeutic doses of Artemether combined with Quinine used in the treatment of malaria are probably safe. PMID- 23678652 TI - Modulation of opening of rat liver mitochondrial membrane permeability transition pore by different fractions of the leaves of Cnestis ferruginea. D.C. AB - BACKGROUND: Increased attention is now directed towards the search for novel naturally occurring anticancer agents that can induce mitochondrial membrane permeability transition (MMPT) pore opening and cell death as a chemotherapeutic mechanism to combat cancer incidence. AIM: The inductive effects of partially purified fractions of leaves of Cnestis ferruginea- on rat liver MMPT pore opening was investigated. METHOD: De-fatted methanol extract of leaves of Cnestis ferruginea was partitioned between water, chloroform, ethylacetate, or butanol separately in succession. The extract solutions were concentrated at 40 degrees C to obtain water (WF), chloroform (CF), ethylacetate (EF) and butanol (BF) fractions. The effects of these fractions (0.2- 1.4 mg/ml) on MMPT pore opening or mitochondrial swelling in the presence and absence of calcium were evaluated The effects of these fractions on the rat liver mitochondrial F0F1-ATPase activity were also assessed. RESULTS: Ca(2+)-induced MMPT pore opening was inhibited by 1 mg/ml each of MECF, CF, BF, WF and EF by 75.0%, 83.0%, 88.0%, 68.0%, and 71.0%, respectively and compared with the effect of spermine, a standard inhibitor. However, in the absence of Ca2+, the fractions significantly induced MMPT pore opening in intact mitochondria by 7.0, 5.7, 0.7, 4.8, 10.9 folds, respectively. In normal rat liver mitochondria, F1F0-ATPase activity was stimulated maximally by MECF, CF, EF, BF and WF by 4.7, 12.7, 1.6, 3.6 and 1.5 folds, respectively, thus indicating that the chloroform fraction is the most potent and therefore contains the active principle in the plant. CONCLUSION: The present study revealed that the leaves of Cnestis ferruginea contain bioactive substances that induced mitochondrial membrane permeability transition and activated the specific activity of F0F1 ATPase. Thus, suggesting strongly that these bioactive agents may serve as a useful chemotherapeutic strategy in cancer therapy. PMID- 23678653 TI - Genetic diversity analysis of cyanogenic potential (CNp) of root among improved genotypes of cassava using simple sequence repeat markers. AB - Cyanogenic potential (CNp) of cassava constitutes a serious problem for over 500 million people who rely on the crop as their main source of calories. Genetic diversity is a key to successful crop improvement for breeding new improved variability for target traits. Forty-three improved genotypes of cassava developed by International Institute of Tropical Agriculture (ITA), Ibadan, were characterized for CNp trait using 35 Simple Sequence.Repeat (SSR) markers. Essential colorimetry picric test was used for evaluation of CNp on a color scale of 1 to 14. The CNp scores obtained ranged from 3 to 9, with a mean score of 5.48 (+/- 0.09) based on Statistical Analysis System (SAS) package. TMS M98/ 0068 (4.0 +/- 0.25) was identified as the best genotype with low CNp while TMS M98/0028 (7.75 +/- 0.25) was the worst. The 43 genotypes were assigned into 7 phenotypic groups based on rank-sum analysis in SAS. Dissimilarity analysis representatives for windows generated a phylogenetic tree with 5 clusters which represented hybridizing groups. Each of the clusters (except 4) contained low CNp genotypes that could be used for improving the high CNp genotypes in the same or near cluster. The scatter plot of the genotypes showed that there was little or no demarcation for phenotypic CNp groupings in the molecular groupings. The result of this study demonstrated that SSR markers are powerful tools for the assessment of genetic variability, and proper identification and selection of parents for genetic improvement of low CNp trait among the IITA cassava collection. PMID- 23678654 TI - Recovery rates of Mycobacterium tuberculosis using five decontamination methods. AB - Tuberculosis (TB) caused by Mycobacterium tuberculosis remains one of the leading infectious diseases in resource limited countries of the world, including Nigeria. For optimal care of patients with pulmonary TB, effective decontamination methods are required for isolation and identification of M. tuberculosis from other fast growing organisms found in sputum samples of infected patients. Five methods of sputum decontamination including the Petroff, oxalic, bleach, simplified concentration and Kudoh methods were assessed prior to mycobacterial culture. In all, thirty human sputum samples were processed and results analysed after eight weeks of incubation. Overall, there was a significant difference in the growth yield using the different methods (Friedman test statistic, Q(K) = 36.3; P < 0.05). Again, a significant difference (Friedman test statistic, Q(K) = 48.0; P < 0.05) was observed between the valuable and non valuable yield of mycobacteria. Furthermore, the simplified concentration method had the best performance in terms of pure culture growth/minimal media contamination coupled with a cost benefit ratio of 0.10; the bleach method being the least. Given these findings, coupled with laboratory challenges in developing countries as well as ease of use on the field/cost effectiveness; we propose the simplified concentration as an optimal decontamination method for use in resource limited settings where TB remains an endemic problem. PMID- 23678655 TI - Are patients with primary hepatocellular carcinoma infectious of hepatitis B, C and D viruses? AB - Primary HepatoCellular Carcinoma (PHCC) has been strongly associated with HBV and HCV infections among other aetiological factors. However; do the patients still spread the viruses? This study involved forty one Nigerian adult patients with PHCC and 45 controls who were tested for HBsAg, HBeAg, Anti-HBe, Anti-HBs, anti HCV IgM and IgG, anti-HDV and HDV antigen using ELISA. Statistical analysis was carried out with the student - t - test and Mc Nemar test at p < 0.05. The subjects consisted of male:female ratio of 3:1 for both the PHCC patients and controls. Evidence of exposure to hepatitis B, C and D viruses was detected in 95.1%, 44% and 0% of the patients respectively while the respective values of 24%, 11.1% and 0% were obtained for the controls. Indication for high (HBeAg) and low (anti HBe) HBV viral replication, and acute HBV infection were detected in 12.5%, 92.7% and 2.2% respectively among the patients while only 35.6% of the controls had low HBV viral replication. Acute and chronic infections of HCV were also found in 26.8% and 24.4% of the patients respectively compared to the respective values of 2.2% and 11.1% of the controls. Occult HBV infection occurred in equal proportions (11%) of both the patients (31.7%) and controls (35.6%). In conclusion, infectious HBV and HCV particles are present among Nigerian patients with PHCC while HDV infection is uncommon. Hence, safe medical care should be practised for all patients with PHCC while relatives should be screened for these viruses. PMID- 23678656 TI - Radioactive iodine ablation therapy: a viable option in the management of Graves' disease in Nigeria. AB - BACKGROUND: Graves' disease is an autoimmune disorder characterized by hyperthyroidism and associated features. Management of this disease condition for many decades has been largely by surgical and medical intervention. Usage of anti thyroid medication ameliorates the symptoms and effects of excessive production of thyroid hormones. Recently in Nigeria, Nuclear medicine facility became available with the option radioiodine ablative therapy for the management of Graves disease. This study highlights the benefits of radioiodine therapy against the background of equally viable medical and surgical practice. PATIENTS MATERIAL AND METHOD: All the 36 patients seen from the inception of Nuclear Medicine facility at the University College Hospital from June 2006 to May 2010 were included in this study. Sources of referral were compiled. All the patients were on anti thyroid medication at presentation. Thyroid scan was performed by Siemens E- cam gamma camera 20 minutes after intravenous injection of 3-5 mCi of Tc-99m Pertechnetate. The patients with "diffuse toxic goiter" on thyroid scan were given 10 mCi of Iodine-131 orally and discharged home with radiosafety precautions. Most of the patients were treated 5 days post discontinuation of antithyroid medication. The patients were followed-up monthly with thyroid function tests to determine commencement of replacement therapy. RESULT: Peak incidence of Graves' disease was at 6th decade (38.9%) of all patients studied. This disease was commoner in women with a ratio of 8 to 1. Ten (27.8%) patients became hypothyroid at the 3rd month post radioactive iodine-131 treatment, while the remaining 20 (55.6%) patients became hypothyroid at the 5th month. Six patients were lost to follow up. There was no recurrence of hyperthyroidism in all patients treated. Twenty eight (93.3%) patients were maintained on 100 mcg of levo-thyroxine daily, while 2 (6.7%) patients had more than 100 mcg of levo- thyroxine daily as maintenance dose. CONCLUSION: Radioactive iodine therapy presents a safe and effective alternative to the older conventional mode of management of Graves' disease PMID- 23678657 TI - Managing pipeline systems: key roles. AB - While the UK has an enviable safety record in the management of medical gas systems, it is only via strict adherence to the four tenets - 'continuity, adequacy, identity, and quality' - embodied within Health Technical Memorandum 02 01: 2006 - 'Medical Gas Pipeline Systems' (MGPS) that we can be certain that patients will not be harmed by these systems. So says Geoff Dillow, a former training head at the forerunner to today's Eastwood Park, the National Centre for Hospital Engineering, and co-author of the HTM, who has over 35 years' professional experience in assessing medical gas systems for compliance. In the first of four HEJ guidance articles on 'Managing Medical Gas Pipeline Systems' planned for coming months, he examines the critical role of the MGPS Permit to Work System (PTWS), and describes the parts played by those involved in its implementation and day-to-day management. PMID- 23678658 TI - Getting the best value from refurb projects. AB - Professor Branka Dimitrijevic, director of CIC Start Online, a project funded by the Scottish Government and European Regional Development Fund combining the resources of seven Scottish universities that aims to embed sustainable building design and refurbishment into practice, reports on a conference jointly staged in Glasgow recently by the organisation and Health Facilities Scotland that considered this topical issue in some depth. PMID- 23678659 TI - Supportive design for people with dementia. AB - A recent King's Fund report, 'Developing Supportive Design for People with Dementia',' describes the positive outcomes of 26 projects completed by 23 NHS Trusts across England under a Department of Health-funded programme, all of which set out to improve the care environment for people with dementia in hospital. Sarah Waller, CBE, RGN, FRSA, who, as programme director, leads the King's Fund's Enhancing the Healing Environment programme team that evaluated the schemes' impact and benefits, describes the main outcomes, and suggests some of the practical ways that estates and facilities staff can support clinical colleagues in improving the care of people with dementia. PMID- 23678660 TI - Cutting energy, reducing costs. AB - Over the past few years medical air and vacuum have seen a number of significant innovations. The major benefit to the estates and facilities manager has been to open up new avenues for reducing energy costs. Medical gas equipment specialist, BeaconMedaes, has been particularly active in this respect, and here Andy Tudor, the company's product and marketing manager, explains how some of the key technologies work, and outlines the long-term benefits. PMID- 23678661 TI - Harnessing natural ventilation benefits. AB - Making sure that a healthcare establishment has a good supply of clean fresh air is an important factor in keeping patients, staff, and visitors, free from the negative effects of CO2 and other contaminants. John O'Leary of Trend Controls, a major international supplier of building energy management solutions (BEMS), examines the growing use of natural ventilation, and the health, energy-saving, and financial benefits, that it offers. PMID- 23678662 TI - Does compliance make a facility safe? AB - 'Every defect is a treasure, if the company can uncover its cause and work to prevent it across the corporation' - Kiichiro Toyoda, founder, Toyota. This quote, as true in healthcare as it in the manufacturing sphere, set the tone for discussion at a recent Dublin conference, which examined the thorny issue of whether compliance is really enough to ensure safety. Focusing especially on water safety, the event aimed to promote collaboration and knowledge sharing between Irish and UK healthcare professionals, including technical services managers, infection control staff, quality and risk personnel, support service managers, hospital directors, and CEOs. Susan Pearson BSc, a freelance journalist and communications consultant specialising in medicine and the environment, reports. PMID- 23678663 TI - Pioneer surgeon drove ultra clean technology. AB - On the 50th anniversary of the development of his ground-breaking hip replacement surgical technique, Amanda Parkin, communications consultant with clean air technology specialist, Howorth Air Technology, examines Professor Sir John Charnley's influence on orthopaedic surgery, and explains how his realisation that any subsequent infection may not appear until long after the operation, and that keeping bacteria away from the wound during the procedure is the the key to minimising the risk, led to the emergence of 'ultra clean' operating theatre technology - within which Howorth was an early pioneer. PMID- 23678664 TI - Aiding recovery and changing perceptions. AB - Next month (14-15 May) will see staged at Birmingham's National Motorcycle Museum the first in a planned new series of Design in Mental Health Conference and Exhibition events. Here Joe Forster, a highly experienced mental health nurse practitioner, and chair of the Design in Mental Health Network, which has brought together designers and users of mental healthcare facilities since 2005, and James Lee, event director at Step Exhibitions, explain why the Network was established, and outline some of the key features visitors to this exciting new sector-specific event can look forward to. PMID- 23678665 TI - [Progress with management of hereditary angioedema]. AB - Hereditary angioedema (HAE) is a rare type of angioedema caused by a quantitative or functional deficit of C1 inhibitor (C1 INH) that leads to excess production of bradykinin, which can result in acute localized swelling attacks in the skin or mucous membranes of the mouth, head and neck, extremities, gastrointestinal (GI) tract, genitals, trunk, and larynx. Angioedema in the respiratorytract maycause airway obstruction; severe abdominal pain, vomiting, or diarrhea may occur in the GI tract. Patients with HAE may be diagnosed and managed by HAE specialists or by primary care physicians depending on individual circumstances. Proper treatment requires differentiation from other forms of angioedema. Patients with HAE who are managed appropriately with medications that treat and prevent atttacks may have a lower risk of death from laryngeal edema and a better quality of life. Less frequent attacks may allow them to attend work, school, and leisure activities more regularlyand be free of the pain and disfigurement of HAE attacks moreoften. PMID- 23678666 TI - [Bariatric surgery - significance, risks, long term consequences]. AB - In recent years the number of bariatric surgery has markedly increased in industrial nations. Surgery provides a more rapid decrease of body weight than conservative approach. However a long term conservative follow up therapy is mandatory to stabilize reduced weight. Due to increasing knowledge from long term follow up of surgically treated obese patients there is a growing body of evidence that frequently there is necessity of reoperations and of substitution both of trace elementsand of minerals or vitamins due to their hampered enteral resorption. Additionally therapy of surgery induced endocrine alterations not seldom is necessary.These insights are of outstanding importance because meanwhile an enlargement of the indications for bariatric surgery as a therapeutic option for metabolic disorders is being discussed. This review refers to the recent internationally published papers concerning consequences of bariatric surgery. PMID- 23678667 TI - [Importance of the different i.v. iron generations for everyday medical practice]. AB - BACKGROUND: Iron deficiency and anaemia occur in particular in women or as comorbid conditions to a varietyof chronic diseases. Besides oral preparations, parenteral iron therapies are also available for the treatment of iron deficiency or anaemia. In the light of the growing importance and increasing number of parenteral iron preparations, theirpharmacology and application as well as the chronology of their approvals and thecharacteristicsof the various preparations are presented herefor comparison. METHOD: Review. RESULTS: To date, there are three different generations of parenteral iron preparations, which differ in terms of stability, safety and dosage. In particular, the active substances of the third generation, ferric carboxymaltose, iron isomaltoside and ferumoxytol are characterised by high complex stability and comparable safety, also allowing rapid application of high doses of iron. CONCLUSIONS: High molecular weight iron dextran, as a representative of 1st generation iron preparations, should no longer be used if possible, as more recent i.v. iron preparations are available with considerably lower risk of serious anaphylactic reactions. Ferrous gluconate and iron sucrose, as representatives of the 2nd generation, are very efficient preparations, but they require frequent visits to the clinic or the doctor, as they may only be administered in low doses because of labile iron complexes. The three 3rd generation parenteral iron formulations have advantages in handling in everyday practice, since they offer comparably good safety profiles, high complex stability and thus the possibility of rapid application of high doses of iron up to the total cumulative dose. Furthermore, test doses are not required with these preparations, which also simplifies their use. PMID- 23678668 TI - [Pain therapy in the elderly:7-day transdermal buprenorphine patch in clinical practice. Results of a non-interventional study]. AB - BACKGROUND: Chronic pain in the elderly is common. Especially in the elderly inadequate treatment of pain can cause significant functional impairmentand deterioration of qualityof life. METHODS: Theaim of this post-marketing surveillance study was to collect data from clinical practice on the analgesic efficacy and safety of the 7-day transdermal buprenorphine patch in patients with chronic non-malignant pain pre-treated with opioids. A total of 2713 elderly multimorbid patients were switched to 7-day transdermal buprenorphine patch from previous opioid treatment mainly due to inadequate analgesia. 83% of patients received a 7-day transdermal buprenorphine patch dosage > or = 10 microg/h. During the 8-weekobservation period, data on pain intensity, quality of sleep/life (NRS-11 point scales) and safety wererecorded. RESULTS: Mean pain intensity decreased by 4 points with 7-day transdermal buprenorphine patch (p < or = 0.001). Quality of sleep and life as well as social activities and self reliance improved significantly. Compliance and tolerability were assessed as very good/good in > 90% of patients. Adverse drug reactions (ADRs) occurred in 3% of patients and corresponded to 90.1% to the already-known spectrum of ADRs of 7 daytransdermal buprenorphinepatch. CONCLUSIONS: The results confirm that elderly patients with opioid pre-treatment benefit from a switch to 7-day transdermal buprenorphine patch with regard to reduction of pain and improved quality of life. PMID- 23678669 TI - [Topical gel formulation of ibuprofen in the treatment of acute and chronic joint and soft tissue pain. Results of a non-interventional observational trial]. AB - BACKGROUND: Pain, inflammation or swelling of soft tissues orjoints is often treated with oral or topical formulation of lbuprofen. METHOD: Thetherapeutic effect of a topical gel formulation of Ibuprofen (doc Ibuprofen Schmerzgel) was investigated in an observational trial. A total of 170 patients suffering either from pain, inflammation or swelling of soft tissues or joints or having experienced a blunt trauma were enrolled into this study. Physicians and patients evaluated typical symptoms at study entry and after 1 week at the final visit. Further, the patients were asked and instructed to monitor their symptoms in a daily diary over this week. RESULTS: Patientssufferingfromacute trauma (group A (symptoms existent up to 48 hours) as well as patients with chronic symptoms (group B) experienced a fast and prominent improvement of symptoms. In group A total reduction of all symptoms after one week was recorded to amount to considerably more than 80%, in group B a reduction of more than 50% compared to the initial scores could be seen. Evaluation done by physicians and patients were extremely concordant with regard to timecourse and final outcome of the treatment. After first use on day one group A noted a reduction of pain symptoms after approximately 25 minutes, while in group B a considerable relief of pain was reported after approximately 37 minutes. During this one-week treatment period no adverse-effects were reported.Tolerability and applicability were classified as good to excellent. CONCLUSIONS: The results of this study confirm findings from existing clinical trials data. In acute traumata a faster symptom relief is found, in chronic conditions the product leads to symptom reduction in case seven where pretreatment has shown insufficient results. Thus this topical treatment provides a treatment option either alone or in combination with orally taken NSAIDS. PMID- 23678670 TI - The 2013 Retirement Confidence Survey: perceived savings needs outpace reality for many. PMID- 23678671 TI - [Head and neck soft tissue sarcoma]. AB - Soft tissue sarcoma arising as a head and neck lesion is very rare in adults. Therefore, no standardized treatment exists for this entity of disease. We retrospectively analyzed 11 cases of head and neck soft tissue sarcomas treated at Osaka University Hospital from 1991 to 2011. They were pathologically classified as follows: 5 cases with rhabdomyosarcoma, 2 cases with liposarcoma, 2 cases with undifferentiated sarcoma and one each of epithelioid hemangioendothelioma and malignant fibrous histocytoma. Rhabdomyosarcomas were treated with multimodality therapy. Other sarcomas were treated mainly with surgery. The prognosis of patients with sarcoma depended on the histology, histological grade, tumor size and tumor stage. Patients with larger tumors, high grade tumors and advanced stage tumors had a poor prognosis, while those with rhabdomyosaracoma had a better prognosis. Further investigation is required to establish the new treatment protocol for adult soft tissue sarcoma and to improve survival. PMID- 23678672 TI - [A case report: a repeated cerebrospinal fluid otorrhea]. AB - Cerebrospinal fluid (CSF) otorrhea, leakage of CSF through the ear structures, may occur from a traumatic or operative defect in the skull, tumor, cholesteatoma, or congenital anomalies. A case of repeated CSF otorrhea is uncommon. In this report, we presented a case of a repeated CSF otorrhea which occurred a decade after the first middle ear surgery for chronic otitis media. The first CSF leakage, which might have been due to bone defects in the tegmen at the first middle ear sutgery, was surgically repaired using a transmastoid approach. However, CSF leakage with a meningoencephalocele occurred again 8 years after our first surgery for the CSF and the fistula was repaired using a transmiddle cranial fossa approach. Although 2 years have passed since the surgery, the CSF leakage has not recurred. PMID- 23678673 TI - [A case of a large neonatal pharyngeal teratoma]. AB - The congenital teratoma is a rare malformation. We present herein on the case of a large teratoma that arose from the epipharynx in a neonate. The obstructive mass caused maternal polyhydramnios and was identified prenatally by ultrasonography at another hospital. The mother was transferred to our hospital for delivery. We explained about the ex utero intrapartum treatment (EXIT) because of the risk of airway obstruction at birth, but EXIT was refused by the parents. Delivery was accomplished by cesarean section at the 35 th week. Since the newborn had a severe respiratory disorder due to a large intraoral tumor and intratracheal intubation was very difficult, a tracheostomy was done under local anesthesia for 7 min. The tumor was removed successfully on the 9th day and 44th day of age. PMID- 23678674 TI - [A modified technique for transsubmucosal maxilloethmoid sinus surgery through the inferior turbinate--transsubmucosal sinus surgery through the inferior turbinate]. AB - In 1993, in the Journal of the Oto-Rhino-Laryngological Society of Japan, the authors published an endoscopic endonasal approach to surgery for chronic sinusitis, performing a transsubmucosal maxillectomy, ethmoidectomy and sphenoidectomy through the inferior turbinate, which the authors tentatively termed "swinging of the nasolacrimal duct and inferior turbinate." With the original technique, some bony structure was left partially exposed during resection of the mucosa in some patients, who suffered from postoperative crust formation. This technique thus required improvement. To solve this problem, the authors made an antero-posterior incision along the inferior turbinate during submucosal turbinectomy. This technique has solved most of the problems and greatly reduced postoperative crust formation, thereby considerably reducing the time for postoperative wound healing as compared with that seen with the original technique. The authors report herein on this surgical technique and indication, an improvement on the original method. PMID- 23678675 TI - Medical devices; general hospital and personal use monitoring devices; classification of the ingestible event marker. Final order. AB - : The Food and Drug Administration (FDA) is classifying the ingestible event marker into class II (special controls). The Agency is classifying the device into class II (special controls) in order to provide a reasonable assurance of safety and effectiveness of the device. PMID- 23678676 TI - Schedules of controlled substances: temporary placement of three synthetic cannabinoids into Schedule I. Final order. AB - The Deputy Administrator of the Drug Enforcement Administration (DEA) is issuing this final order to temporarily schedule three synthetic cannabinoids under the Controlled Substances Act (CSA) pursuant to the temporary scheduling provisions of 21 U.S.C. 811(h). The substances are (1-pentyl-1H-indol-3-yl)(2,2,3,3 tetramethylcyclopropyl)methanone (UR-144), [1-(5-fluoro-pentyl)-1H-indol-3 yl](2,2,3,3-tetramethylcyclopropyl)methanone (5-fluoro-UR-144, XLR11) and N-(1 adamantyl)-1-pentyl-1H-indazole-3-carboxamide (APINACA, AKB48). This action is based on a finding by the Deputy Administrator that the placement of these synthetic cannabinoids and their salts, isomers and salts of isomers into Schedule I of the CSA is necessary to avoid an imminent hazard to the public safety. As a result of this order, the full effect of the CSA and the Controlled Substances Import and Export Act (CSIEA) and their implementing regulations including criminal, civil and administrative penalties, sanctions and regulatory controls of Schedule I substances will be imposed on the manufacture, distribution, possession, importation, and exportation of these synthetic cannabinoids. PMID- 23678677 TI - Experimental studies on the hypocholesterolemic effect of Commiphora mukul Engl. (Guggul). 1969. PMID- 23678678 TI - [Review on studying the early warning of influenza based on the data from Internet]. PMID- 23678679 TI - [Response and evaluation of the disinfection effects on an anthrax outbreak in human being and cattle in Guizhou]. PMID- 23678680 TI - [Epidemiological study of HIV/AIDS in women of childbearing age in Liangshan Yi Areas, China]. PMID- 23678681 TI - Using an iPad in research with children and adolescents. AB - The features of the iPad and its widespread adoption support its use as a tool in research involving children and adolescents. Although use in our current research has been limited to a hospital-based setting,the iPad's design and features support its potential use in home- and community-based settings as well.In addition to collecting data through web-based platforms and applications, the iPad may facilitate telehealth-based interventions through the use of its built in camera and Face Time applications.In our experience with children and adolescents,the iPad has been a useful tool to support multiple types of data collection as well as support other aspects of the research process. The use of iPad application technology certainly opens up opportunities for new and novel ways to collect meaningful data and support research with individuals across the lifespan. PMID- 23678683 TI - Abstracts of the 10th Congress of the European Academy of Paediatric Dentistry. June 4-6, 2010. Harrogate, United Kingdom. PMID- 23678684 TI - Keep building inukshuks--show others the way. PMID- 23678682 TI - Vaccinate boys with the HPV vaccine? Really? PMID- 23678685 TI - India's decision on Gleevec: implications for the future. PMID- 23678686 TI - 5 ways to better manage risk under reform. PMID- 23678687 TI - Buyer's brief: coronary artery stents. PMID- 23678688 TI - What CFOs should know before venturing into the cloud. AB - There are three major trends in the use of cloud-based services for healthcare IT: Cloud computing involves the hosting of health IT applications in a service provider cloud. Cloud storage is a data storage service that can involve, for example, long-term storage and archival of information such as clinical data, medical images, and scanned documents. Data center colocation involves rental of secure space in the cloud from a vendor, an approach that allows a hospital to share power capacity and proven security protocols, reducing costs. PMID- 23678690 TI - Don Berwick, MD on transitioning to value-based health care. PMID- 23678689 TI - Conversations with your actuary: getting to the right number. AB - A healthcare finance leader can guarantee recognition of his or her organization's insurance program and better manage the program's liability by discussing changes in the following areas with an actuary: Claims management. Exposure. Coverage or retention Financial reporting of losses. Management goals. Other insurance and operational matters. PMID- 23678691 TI - Today's trends in capital financing. AB - A health system's approach to capital access in the coming year should include an in-depth analysis of different financing options, including: Tax-exempt fixed rate bonds. Tax-exempt variable rate bonds. Taxable bonds. Direct purchases. New financing products. PMID- 23678692 TI - 12 strategies for managing capital projects. AB - To reduce the amount of time and cost associated with capital projects, healthcare leaders should: Begin the project with a clear objective and a concise master facilities plan. Select qualified team members who share the vision of the owner. Base the size of the project on a conservative business plan. Minimize incremental program requirements. Evaluate the cost impact of the building footprint. Consider alternative delivery methods. PMID- 23678693 TI - A new tool for system building. AB - A hybrid deal is an innovative type of joint venture between for-profit and not for-profit entities designed for the purpose of improving healthcare delivery in a mutually accretive manner. Not-for-profit health systems, in particular, find hybrid deals attractive because these systems typically take a minority stake in the venture, requiring significantly less capital investment from not-for-profits than an outright acquisition. Hybrid deals allow not-for-profits to preserve capital for other needs while often maintaining some level of governance. PMID- 23678694 TI - How the choice of issuing authority affects hospital debt financing costs. AB - All other things being equal, bonds issued by statewide authorities have lower yields than bonds issued by local authorities. However, lower yields may be offset by higher issuance costs for statewide authorities, as reflected in the true interest cost. Higher issuance costs may provide benefits for investors and for issuing hospitals. PMID- 23678695 TI - Funding alternatives in EHR adoption: beyond HITECH incentives and traditional approaches. AB - The meaningful use incentives under HITECH may be inadequate to address the financial challenges many hospitals face in implementing electronic health records (EHRs). Hospitals can fill the capital gap between EHR costs and available funds by exploring other potential funding sources. These sources include additional grants, funding permissible under EHR regulations, vendor financing, and tax benefits under IRS Section 179. PMID- 23678696 TI - Financing strategic healthcare facilities: the growing attraction of alternative capital. AB - Community health system leaders often dismiss use of alternative capital to finance strategic facilities as being too expensive and less strategically useful, preferring to follow historical precedent and use tax-exempt bonding to finance such facilities. Proposed changes in accounting rules should cause third party-financed facility lease arrangements to be treated similarly to tax-exempt debt financings with respect to the income statement and balance sheet, increasing their appeal to community health systems. An in-depth comparison of the total costs associated with each financing approach can help inform the choice of financing approaches by illuminating their respective advantages and disadvantages. PMID- 23678697 TI - Determining the right level for your IT security investment. AB - Investing sufficiently in IT security not only is essential for a healthcare organization's protection, but also is a responsibility to patients, and its success depends on its being addressed at all levels of management. Hospital data security breaches have the potential to cost as much as $7 million, including fines, litigation, and damaged reputation. Response and cleanup alone can cost hundreds of thousands of dollars. Developing and following an annual action plan for IT security can lower hospitals' IT security costs in the long run. PMID- 23678698 TI - Developing a consumer pricing strategy. AB - Healthcare providers can learn a variety of pricing lessons from the retail market: For providers, wholesale pricing--"the price to play"--alone is not enough. Once a hospital or health system chooses a market position, the provider creates an expectation that must be met-consistently. Consumer loyalty is fluid, and the price of care or service is not always the motivator for choosing one organization over another; intangibles such as location and level of customer service also drive purchasing decisions. PMID- 23678699 TI - How providers can proceed with electronic remittance. PMID- 23678700 TI - 'Value combos' for health care. PMID- 23678701 TI - The urgent need to create healthcare value. PMID- 23678702 TI - Rethinking asset allocation: the case for portfolio diversification. PMID- 23678703 TI - Harnessing the financial power of primary care physicians. PMID- 23678704 TI - [Analysis of sperm morphology: yes or no?]. AB - The analysis of sperm morphology can be used to evaluate sperm fertilizing ability and spontaneous conception status, and especially the overall analysis of the sperm head, neck and tail, along with the patient's living habits, occupation and clinical manifestations, may contribute to the primary diagnosis of the patients potentia generandi. It can also be employed to assess the effects of the treatment of semen samples. Although oocyte fertilization can be achieved by the technologies of intracytoplasmic sperm injection (ICSI), motile sperm organelle morphology examination (MSOME) and intracytoplasmic morphologically selected sperm injection (IMSI) regardless of sperm morphology and / or motility, which may somewhat weaken the clinical application of sperm morphology analysis, the standardized procedure and the practice of quality control for the analysis of sperm morphology can significantly improve the accuracy of its results and largely promote its clinical application. Therefore, it is of positive necessity as well as clinical application value to perform sperm morphology analysis in andrology laboratories, reproductive centers, sperm banks and the department of laboratory medicine. PMID- 23678705 TI - [Erectile function of male rats in different age groups: an experimental study]. AB - OBJECTIVE: To explore the relationship between aging and erectile function changes in rats in order to establish a rat model of aging-related erectile dysfunction (ED). METHODS: Eighty male Wistar rats were equally divided into four age groups (3-, 6-, 12- and 18-month) and treated with intragastric administration of sildenafil citrate (Sn) for penile erection tests. Twenty 3 month-old female Wistar rats were randomized to four groups as oestrous rat models. We recorded the rate and frequency of penile erections of the male rats in different age groups. RESULTS: The rates of penile erection were 85%, 75%, 40% and 30% and erectile frequencies were 2.27 +/- 0.80, 2.00 +/- 0.61, 1.40 +/- 0.51 and 1.29 +/- 0.49 in the 3-, 6-, 12- and 18-month rats, respectively, with statistically significant differences among different age groups (P < 0.01). And their erectile function exhibited a tendency to decrease with the increase of age. Besides, comparison of the 3-month with the 6-, 12- and 18-month groups showed significantly reduced erectile function in the 18-month rats (P < 0.05) but no remarkable difference between the 3-month and the 6- and 12-month groups (P > 0.05). CONCLUSION: Aging is one of the main risk factors of rat erectile dysfunction, and 18-month-old male rats are qualified for the establishment of the rat model of aging-related erectile dysfunction. PMID- 23678706 TI - [Establishing a mouse model of Sertoli-cell-only syndrome by administration of busulfan]. AB - OBJECTIVE: To establish a stable and reliable model of Sertoli-cell-only syndrome in mice. METHODS: We randomly divided 60 NIH mice into two groups of equal number to receive intraperitoneal injection of busulfan (30 mg/kg) and 30 or 60 minutes of testis cooling. At 2, 4 and 8 weeks after treatment, we recorded the survival rate of the mice, weight of the testis and Johnsen scores, and conducted quantitative analysis on the degrees of spermatogenetic failure. RESULTS: There were no significant differences in the baseline body weight and survival rate between the intervention and control groups (P > 0.05). At 4 and 8 weeks, the testis weight and Johnsen score were significantly lower in the intervention group than in the control ([0.04 +/- 0.01] g and [0.05 +/- 0.01] g vs [0.09 +/- 0.03] g and [0.11 +/- 0.02] g, P < 0.05; 3.86 +/- 0.50 and 2.70 +/- 0.67 vs 9.60 +/- 0.25 and 9.76 +/- 0.43, P < 0.01). At 2, 4 and 8 weeks, the testis weights were (0.07 +/- 0.02) g, (0.06 +/- 0.01) g and (0.09 +/- 0.01) g, respectively, in the 30-min cooling group and (0.05 +/- 0.01) g, (0.04 +/- 0.02) g and (0.04 +/- 0.02) g in the 60-min cooling group, significantly lower than in the control side at the same time points ([0.11 +/- 0.01] g, [0.11 +/- 0.01] g and [0.12 +/- 0.00] g) (P < 0.05), and the Johnsen scores were 4.70 +/- 0.67, 2.70 +/- 0.84 and 6.10 +/- 1.14 in the 30-min and 1.67 +/- 0.58, 1.20 +/- 0.45 and 1.00 +/- 0.00 in the 60-min cooling group, remarkably lower than in the control side (9.60 +/- 3.23, 9.60 +/- 0.55 and 9.70 +/- 0.45) (P < 0.01). Histopathological examination of the cooled testes revealed considerable atrophy of seminal tubules, necrosis of seminiferous epithelia and peritubular fibrosis. CONCLUSION: Administration of busulfan has no obvious influence on the survival of mice, and is a reliable method for constructing a mouse model of Sertoli-cell-only syndrome. PMID- 23678707 TI - [Radiation-induced oxidative stress and claudin-11 mRNA expression in the testis]. AB - OBJECTIVE: To investigate the role of claudin-11, a tight junction component of Sertoli cells, in spermatogenic dysfunction induced by oxidative stress in mice exposed to local radiation. METHODS: We randomly allocated 48 male Kunming mice to a blank control group (A) and three radiation groups (B, C and D) of equal number, the latter three exposed to local radiation of the lower abdomen with 2 Gy, 6 Gy and 10 Gy of 60Co-gamma-ray, respectively, to induce oxidative stress. Four weeks later, we killed the animals, obtained their body and testis weights, observed the histological changes of the testis by HE staining, measured the levels of serum FSH, testosterone and LH by ELISA, and determined the mRNA levels of claudin-11 and inhibin beta B in Sertoli cells by real time quantitative PCR. RESULTS: After exposure to 60Co-gamma-ray radiation, the testis weights were (129.4 +/- 10.81), (87.5 +/- 16.83) and (56.1 +/- 12.36) mg in groups B, C and D, significantly decreased as compared with (182.9 +/- 8.43) mg in group A (P < 0.05); the testis indexes were (3.39 +/- 0.57), (2.46 +/- 0.46) and (1.63 +/- 0.44) mg/g in groups B, C and D, remarkably lower than (4.28 +/- 0.31) mg/g in group A (P < 0.01). Histological analysis revealed obviously decreased diameters of seminiferous tubules, reduced seminiferous epithelia and disarranged spermatogenic cells in the three radiation groups. The tubule differentiation indexes (TDI) were markedly lower in groups B, C and D than in A (P < 0.01). The levels of serum FSH were (6.74 +/- 1.95), (8.41 +/- 2.44) and (10.93 +/- 3.16) IU/L in groups B, C and D, 1.9 times higher in D than in A. With increased dose of radiation, the mRNA levels of inhibin beta in the testis tissue were descended, while the transcription levels of claudin-11 elevated, significantly higher in groups C and D than in A (P < 0.01). CONCLUSION: Local radiation induced testicular oxidative stress can decrease the mRNA level of inhibin beta , increase serum FSH, damage Sertoli cells and elevate the expression of claudin-11 in the testis tissue. Increased claudin-11 and serum FSH may delay the cyclical restitution of hemo-testicular barrier and reduce the number of meiotic spermatocytes in the seminiferous epithelium, which consequently leads to male infertility. PMID- 23678708 TI - [DAZL gene polymorphisms and astheno-teratozoospermia]. AB - OBJECTIVE: To investigate the association between single nucleotide polymorphism (SNP) of the DZAL gene in infertile Han Chinese males with astheno teratozoospermia. METHODS: We collected semen samples from 173 infertile Han Chinese men with astheno-teratozoospermia (case group) and 175 age-matched normal male volunteers (control group) for semen routine and morphological analyses. We obtained genomic DNA, genotyped the polymorphisms of the DAZL gene A260G and A386G via the Sequenom MassARRAY system, and compared the frequencies of the genotypes between the case and control groups. RESULTS: The AA nucleotide variant was found in the A260G and A386G polymorphisms of the DZAL gene in both the cases and controls, but the heterozygous AG variant in neither. CONCLUSION: The A260G and A386G polymorphisms of the DAZL gene are not correlated with astheno teratozoospermia-induced male infertility in the Han Chinese population, and therefore could not be considered as molecular markers of male infertility. PMID- 23678709 TI - [Expressions of SIgA and alpha 1-AR in benign prostatic hyperplasia combined with chronic prostatitis and their implications]. AB - OBJECTIVE: To explore the expressions of SIgA and alpha l-AR in benign prostatic hyperplasia (BPH) complicated by chronic prostatitis (CP) and their implications. METHODS: According to the preoperative findings of expressed prostatic secretion (EPS), transrectal prostate ultrasonography, prostate-specific antigen (PSA), international prostate symptom score (IPSS), clinical symptoms, chronic pelvic pain syndrome (CPPS) and postoperative histopathology, 62 cases of BPH pathologically confirmed after transurethral plasma kinetic resection of the prostate (PKRP) were divided into a BPH group (n = 32) and a BPH + CP group (n = 30). The expressions of SIgA and alpha 1-AR in the prostate tissue were determined by immunohistochemistry and PT-PCR. RESULTS: Of the 62 cases, 30 were found to be BPH + CP, and the other 32 to be BPH. The expressions of SIgA and alpha1-AR were significantly higher in the BPH + CP than in the BPH group (0.380 8 +/- 0.144 3 vs 0.295 4 +/- 0.008 4 and 0.440 5 +/- 0.104 1 vs 0.383 2 +/- 0.013 6, P < 0.05). CONCLUSION: The upregulated expressions of SIgA and alpha1-AR expression in BPH complicated by CP suggest a certain association between CP and BPH, and that inflammation may be a pathogenic factor of BPH and correlate with its pathological development. PMID- 23678710 TI - [Long-term effect and safety of non-occlusive intra-vas device for male contraception]. AB - OBJECTIVE: To assess the long-term effect and safety of non-occlusive intra-vas device (IVD) for male contraception in comparison with no-scalpel vasectomy (NSV). METHODS: We conducted a follow-up investigation on 100 males who had received IVD and another 50 who had undergone NSV 6 years before. We compared the rates of sperm absence and complications between the two groups. RESULTS: Follow up visits were successfully performed on 95 males (95%) of the IVD group and 44 (88%) of the NSV group. Pregnancy was not found in any of the cases. Spermatozoa (> or = 5 x 10(6)/ml) were not detected in 87 cases (91.58%) in the IVD group and in 44 cases (95.45%) in the NSV group, with no significant differences between the two groups (P > 0.05). The rate of postoperative complications in the IVD group (11.58%) showed no significant difference from that of the NSV group (4.55%) (P > 0.05). CONCLUSION: IVD is as effective and safe as NSV for male contraception. PMID- 23678711 TI - [Prevalence of benign prostatic hyperplasia in Pingliang, Gansu: investigation and clinical analysis]. AB - OBJECTIVE: To investigate the prevalence of benign prostatic hyperplasia (BPH) in Pingliang City of Gansu Province. METHODS: We performed a cross-sectional randomized study of 836 men aged > or = 40 years from 26 communities of Pingliang, obtained their IPSS, measured the prostate volume by transabdominal ultrasonography, recorded the maximum flow (Qmax) by uroflowmetry, and processed the data by one-way analysis of variance. RESULTS: Totally 820 subjects meeting the study criteria were included in the investigation. The men ranged in age from 40 to 83 years, averaging 61.5 years. The mean IPSS, prostate volume and Qmax were 9.3 +/- 7.8, (29.2 +/- 18.6) ml and (15.3 +/- 7.2) ml/s, respectively, all correlated with age. The prevalence of moderate-severe lower urinary tract symptoms (LUTS) was 46.8% (384/820). The prostate volume was > 20 ml in 63.5% (521/820), and Qmax <15 ml/s in 48.5% (398/805) of the subjects. The incidence rate of BPH, defined as IPSS >7, Qmax <15 ml/s and prostate volume > 20 ml, was 23.5% (193/820). CONCLUSION: Among the men aged > or = 40 years in Pingliang, LUTS and prostate volume were correlated positively, while Qmax negatively with age, and the prevalence of BPH was 23.5%. PMID- 23678712 TI - [Sexual function of middle-aged and older males in Beijing: urban versus suburban area]. AB - OBJECTIVE: To investigate and compare the prevalence of erectile dysfunction, hyposexuality and ejaculation disorder among middle-aged and older males in the urban and suburban areas of Beijing. METHODS: Using the random sampling method, we selected 1 656 men aged > or = 50 years from 15 communities in Beijing. We recorded their scores on the International Index of Erectile Function-5 (IIEF-5) and Brief Male Sexual Function Inventory for Urology (O'Leary 1995), and analyzed the obtained data using SPSS 17.0. RESULTS: Totally, 1 644 of the subjects were qualified for the study, 1 244 from the urban area and the other 400 from the suburbs. The median scores on IIEF-5, sexual desire and ejaculation were 5, 2 and 4 in the urban males as compared with 13, 2 and 5 in the suburban men, with statistically significant differences between the two groups (P < 0.01). The IIEF 5 score was significantly correlated with age, diabetes, cardio-cerebrovascular diseases, drinking and administration of 5alpha-reductase inhibitor in both the urban and suburban groups (P < 0.01). CONCLUSION: The sexual function of the middle-aged and older males is better in the suburbs than in the urban area of Beijing. The main reasons might be the lower incidences of diabetes and cardio cerebrovascular diseases, moderate drinking and less use of 5alpha-reductase inhibitor among the suburban men. PMID- 23678713 TI - [Shang Ring, sleeve and conventional circumcisions for redundant prepuce and phimosis: A comparative study of 918 cases]. AB - OBJECTIVE: To compare the clinical effects of conventional, sleeve and Shang Ring circumcisions in the treatment of redundant prepuce and phimosis. METHODS: We reviewed the clinical data of 918 patients with redundant prepuce or phimosis, 279 treated by conventional circumcision, 354 by sleeve circumcision and 285 by Shang Ring circumcision. We documented the preoperative characteristics, intra operative blood loss, operation time, 4-hour and 7-day postoperative visual analogue scores, surgeons' satisfaction, incision healing time, degrees of preputial edema, postoperative complications, patients' satisfaction with penile appearance and peri-operative cost, and compared them among the three groups. RESULTS: Shang Ring circumcision significantly reduced the operation time and intra-operative blood loss as compared with conventional and sleeve circumcisions (P < 0.05). The postoperative incision healing time was (18.6 +/- 5.2) d in the conventional circumcision group, (11.4 +/- 3.7) d in the sleeve circumcision group and (20.3 +/- 5.7) d in the Shang Ring circumcision group, significantly shorter in the sleeve group than in the other two (P < 0.05). As for the surgeons' satisfaction, postoperative complications, degree of preputial edema and patients' satisfaction with penile appearance, sleeve circumcision showed similar effects to Shang Ring circumcision but significantly better than conventional circumcision (P < 0.05). The 7-day postoperative visual analogue score and peri-operative cost were significantly lower in the conventional and sleeve circumcision groups than in the Shang Ring group (P < 0.05). CONCLUSION: Each of the three circumcision methods has its own advantages and disadvantages. The treatment decision should be individualized and based on a comprehensive consideration of the patients' age and economic status as well as surgeons' advice and surgical skills. PMID- 23678714 TI - [Oral tadalafil on alternate days for erectile dysfunction that fails to respond to on-demand sildenafil: a report of 15 cases]. AB - OBJECTIVE: To sum up the experience in administering oral tadalafil on alternate days for the treatment of erectile dysfunction (ED) that fails to respond to on demand medication. METHODS: We retrospectively analyzed the clinical data of 15 cases of ED treated with oral tadalafil on alternate days from September 2010 to March 2012. All the patients had failed to respond to on-demand medication of sildenafil previously. RESULTS: After 4 weeks of tadalafil treatment, 11 (73.3%) of the cases were remarkably improved, with significant difference in IIEF-5 scores before and after treatment (P < 0.05). Transient adverse reactions were observed in the other 4 cases, including mild headache in 2, slight backache in 1, and facial flush in 1. CONCLUSION: Oral tadalafil on alternate days is safe and effective in the treatment of ED that fails to respond to on-demand medication of sildenafil. PMID- 23678715 TI - [Morinda officialis how extract improves microwave-induced reproductive impairment in male rats]. AB - OBJECTIVE: To investigate the effects of different concentrations of Morinda Officialis How (MOH) extracts on microwave radiation-induced injury to the spermatogenic function of male rats. METHODS: Forty SD male rats were equally divided into four groups: control, microwave injury model, aqueous extract of MOH treatment, and alcohol extract of MOH treatment. Models of microwave-induced injury were made by exposing the rats to microwave radiation from a microwave signal generator (900 MHz 1.0 W) at 218 microm/cm2, 12 h/d, for 2 weeks. The model rats of the two treatment groups were intragastrically given aqueous extract and alcohol extract of MOH, respectively, both at 20 g per kg per day for 2 weeks. Then we observed the growth, capture incubation period (CIP), capture times (CT), changes in testicular and epididymal weight and morphology, sperm concentration and malformation, and levels of serum testosterone. RESULTS: Compared with the controls, the rats of the model group showed a slightly reduced body weight, markedly prolonged CIP and decreased CT (P < 0.05), significantly reduced sperm concentration (P < 0.05) and remarkably in- creased sperm malformation (P < 0.05), but no statistically significant differences in the testosterone level. The two treatment groups exhibited obviously decreased body weight, CIP and sperm malformation compared with the control group (P < 0.05) but markedly increased CT, sperm concentration and testosterone level as compared with the models (P < 0.05). The microwave radiation-induced testis injury was repaired perfectly in the two treatment groups, the epididymal ducts filled with sperm and cast-off cells. CONCLUSION: Both aqueous and alcohol extracts of MOH can promote spermatogenesis and repair of reproductive injury induced by microwave radiation. PMID- 23678716 TI - [Improving effect of Shengjingsan on spermatogenic function following testicular torsion/detorsion in rats and its mechanism]. AB - OBJECTIVE: To study the effect of Shengjingsan on spermatogenic function following testicular torsion/detorsion in rats and its action mechanism. METHODS: Forty SD male rats were equally randomized to groups A (sham operation), B (control), C (low-dose Shengjingsan), D (medium-dose Shengjingsan) and E (high dose Shengjingsan). The model of testicular torsion was established by 720 degrees clockwise torsion of the left testis for 4 hours. An hour before operation, the rats of group B received daily gavage of normal saline at 1 ml per kg per d, while those in groups C, D and E that of Shengjingsan at 0.01, 0.02 and 0.03 g per kg per d, all for 35 days. Then all the rats were sacrificed for measuring the semen parameters by CASA and detecting the expression of the CatSper1 gene in the sperm by RT-PCR. RESULTS: Compared with group A, Sperm concentration, the percentage of grade a + b sperm, sperm vitality and CatSper1 expression were significantly lower in group B ([15.30 +/- 6.30] %, [44.42 +/- 6.36] %, [21.00 +/- 6.14] x 10(6)/ml and 1.12 +/- 0.50) than in A ([51.30 +/- 6.60]%, [69.01 +/- 7.20]%, [40.53 +/- 7.01] x 10(6)/ml and 2.04 +/- 0.77) (P < 0.01). Compared with group B, the four parameters were increased remarkably in groups D ([51.63 +/- 3.20] %, [72.09 +/- 2.20]%, [55.30 +/- 5.90] x10(6)/ml and 2.11 +/- 0.20) andE ([55.93 +/- 3.17]%, [73.01 +/- 2.11]%, [58.33 + 4.90] x 10(6)/ml and 2.31 +/- 0.17) (P < 0.01), but not significantly in C ([18.02 +/- 0.23]%, [48.04 +/- 7.01]%, [22.87 +/- 2.10] x 10(6)/ml and 1.19 +/- 0.51) (P > 0.05). CONCLUSION: Shengjingsan can improve sperm parameters following testicular torsion/ detorsion in male rats by regulating their spermatogenic function and improving the expression of CatSper1 in the sperm. PMID- 23678717 TI - [Advances in superenzyme gene therapy in penile rehabilitation]. AB - Erectile dysfunction (ED) is an almost unavoidable complication of radical prostatectomy. At present, though the concept of penile rehabilitation (PR) is accepted by most clinicians, the outcomes of erectile function recovery vary widely. Prostacyclin (PGI2) is a prostanoid and a main vasoprotectant which induces smooth muscle relaxation, but not used for replacement therapy because of its high unstability. SuperEnzyme is capable of continuous, specific and targeted promotion of PGI2 synthesis, and helps PR in ED patients after radical prostatectomy. SuperEnzyme gene therapy has a promising prospect for PR and the management of ED. This review updates SuperEnzyme gene therapy in PR. PMID- 23678718 TI - [Peyronie's disease: an update]. AB - Peyronie's disease is currently considered a wound healing disorder that presents with a fibrous inelastic scar of the tunica albuginea, which is believed to occur in genetically susceptible individuals following trauma to the penis. It is characterized by the development of a palpable scar, which in the erectile state causes a variety of deformities, erectile dysfunction and painful erections, and its pathogenesis is unclear. There are many therapeutic options and each has its advantages and disadvantages. This article outlines the advances in the recent studies of Peyronie's disease. PMID- 23678719 TI - [Epithelial-mesenchymal transition in prostate cancer]. AB - Prostate cancer (PCa) is a common disease in elderly men, its incidence ranking the second among all malignancies in males in Western countries and increasing in China in the last decade. Tumor metastasis is the main cause of death of PCa patients. In the development and progression of tumor, the tumorous cells in the infiltration area interact with their microenvironment, undergo epithelial mesenchymal transition (EMT) and consequently cause distant metastases. So to study the role of EMT in the development and progression of tumor is of great significance for the treatment of PCa. This article reviews the relevant literature of the last 3 years and gives an overview of the factors affecting EMT in prostate cancer, aiming at a therapeutic target. PMID- 23678720 TI - [Application of adipose-derived stem cells in lower urinary tract reconstruction]. AB - Adipose-derived stem cells have self-renewal and multi-differentiation potentials, which can differentiate into smooth muscle cells, urinary epithelial like cells, endothelial cells, neuron-like cells, etc. and secrete a variety of growth factors. As a result, the research on adipose-derived stem cells in lower urinary tract reconstruction using tissue engineering has been a highlight in recent years. This review focuses on the application of adipose-derived stem cells as seed cells to lower urinary tract reconstruction by tissue engineering in such diseases as bladder defect, stress urinary incontinence, and erectile dysfunction. PMID- 23678721 TI - [Tadalafil for erectile dysfunction: an overview]. AB - Erectile dysfunction (ED) is a common male disease and frequently encountered in Andrology. PDE5 inhibiter can competitively inhibit the hydrolysis of cyclic guanosine monophosphate (cGMP), increase the cGMP concentration in the smooth muscle cells of the corpus cavernosum penis, and achieve the therapeutic effect on ED. Tadalafil can elevate the level of cGMP in the corpus cavernosum and effectively improve ED of various causes and degrees. Tadalafil therapy for ED, characterized by long efficacy, high safety, easy acceptance by patients and their partners, and obvious promotion of patients'self-confidence and natural experience in sexual activities, can achieve satisfactory physiological and psychological results and effectively improve the quality of patients' sexual life. Therefore tadalafil deserves an extensive clinical application in the treatment of ED. PMID- 23678722 TI - Characteristics of pigeon paramyxovirus serotype-1 isolates (PPMV-1) from the Russian Federation from 2001 to 2009. AB - Monitoring programs for highly dangerous avian diseases in the Russian Federation from 2001 to 2009 detected 77 samples that were PCR positive for avian paramyxovirus serotype-1 (APMV-1) from sick or dead feral and domestic pigeons. Nucleotide sequences of the fusion (F) gene, including a nucleotide sequence encoding the F protein cleavage site, were determined for these isolates. All of the studied isolates possessed virulent F0 protein cleavage sites (112KRKKRF117, 112RRQKRF117, or 112KRQKRF117). Intracerebral pathogenicity index (ICPI) values determined for seven of the isolates exceeded the value of 0.7 (the range from 0.8 to 1.41). Based on partial genome sequencing and phylogenetic analysis, the isolates were assigned to two individual sublineages within class II genotype VIb. It was determined that most of these Newcastle disease virus isolates (70/77) recovered from the pigeons belonged to a relatively poorly studied sublineage VIb/2. The complete nucleotide sequence of the genome for the Pigeon/Russia/Vladimir/687/05 isolate of sublineage VIb/2 was determined. PMID- 23678723 TI - Infectivity and pathogenicity of Newcastle disease virus strains of different avian origin and different virulence for mallard ducklings. AB - Experimental infections of Newcastle disease virus (NDV) strains of different avian origin and different virulence in mallard (Anas platyrhynchos) ducklings were undertaken to evaluate infectivity and pathogenicity of NDV for ducks and the potential role of ducks in the epidemiology of Newcastle disease (ND). Ducklings were experimentally infected with seven NDV strains, and their clinical sign, weight gain, antibody response, virus shedding, and virus distribution in tissues were investigated. The duck origin virulent strain duck/Jiangsu/JSD0812/2008 (JSD0812) and the Chinese standard virulent strain F48E8 were highly pathogenic for ducklings. They caused high morbidity and mortality, and they distributed extensively in various tissues of infected ducklings. Other strains, including pigeon origin virulent strain pigeon/Jiangsu/JSP0204/2002 (JSP0204), chicken origin virulent strain chicken/Jiangsu/JSC0804/2008 (JSC0804), goose origin virulent goose/Jiangsu/JSG0210/2002 (JSG0210), and vaccine strains Mukteswar and LaSota had no pathogenicity to ducklings. They produced neither clinical signs of the disease nor adverse effect on growth of infected ducklings, and they persisted in duck bodies for only a short period. Virus shedding was detectable in all infected ducklings, but its period and route varied with the virulence of NDV strains. The results suggest that NDV with high pathogenicity in ducks may arise from the evolution within its corresponding host, further confirming that the ducks play an important role in the epidemiology of ND. PMID- 23678724 TI - Molecular characterization of contaminating infectious anemia virus of chickens in live commercial vaccines produced in the 1990s. AB - The presence of infectious chicken anemia virus (CAV) was detected in a previous study by nested-PCR as a contaminant in seven commercial vaccines, produced in the 1990s by three different manufacturers, prepared against the most relevant virus etiologies. In order to phylogenetically characterize the genome and compare it to CAV isolates from Brazil and other parts of the world, sequences of approximately 675 bp of the gene encoding the hypervariable region of VP1 protein of three CAV vaccine contaminant strains were studied. The CAV genome in contaminated vaccines showed high similarity (> 98.9%) with the Brazilian BR91/99 and Argentinian ArgA001028 (> 99%) strains. However, the comparison with the Cuxhaven-1 vaccine strain showed a lower identity of between 96.8% and 97.7%, and comparing it with the CAV26P4 vaccine strain showed an identity between 97.2% and 98.2%; both are available in Brazil. Such differences might be relevant for the highly conserved CAV genome. CAV contaminants were positioned in the same genetic group (clusters) with the Brazilian strain BR91/99 and Argentinian strain ArgA001028. Results indicated that the contamination of live vaccines by CAV may have influenced CAV epidemiology in the Brazilian and Argentinian poultry industry. PMID- 23678725 TI - Detection of Salmonella enteritidis in pooled poultry environmental samples using a serotype-specific real-time-polymerase chain reaction assay. AB - While real-time-polymerase chain reaction (RT PCR) has been used as a rapid test for detection of Salmonella Enteritidis in recent years, little research has been done to assess the feasibility of pooling poultry environmental samples with a Salmonella Enteritidis-specific RT PCR assay. Therefore the objective of this study was to compare RT PCR Salmonella Enteritidis detection in individual and pooled (in groups of two, three, and four) poultry environmental drag swab samples to traditional cultural methods. The drag swabs were collected from poultry facilities previously confirmed positive for Salmonella Enteritidis and were cultured according to National Poultry Improvement Plan guidelines. Initial, Salmonella Enteritidis-specific RT PCR assay threshold cycle cutoff values of < or = 36, < or = 30, and < or = 28 were evaluated in comparison to culture. The average limit of detection of the RT PCR assay was 2.4 x 10(3) colony-forming units (CFUs)/ml, which corresponded to an average threshold cycle value of 36.6. Before enrichment, samples inoculated with concentrations from 10(2) to 10(5) CFUs/ml were detected by RT PCR, while after enrichment, samples inoculated from 10(0) to 10(5) CFUs/ml were detected by RT PCR. Threshold cycle cutoff values were used in the subsequent field trial from which Salmonella Enteritidis was cultured in 7 of 208 environmental samples (3.4%). Individual samples were 99.0%, 100%, and 100% in agreement with the RT PCR at threshold cycle (C(t)) cutoff values of < or = 36, < or = 30, and < or = 28 respectively. The agreement for pooled samples also followed the same trend with highest agreement at C(t) < or = 28 (pool of 2 = 100.0%, pool of 3 = 100.0%, pool of 4 = 100.0%), midrange agreement at C(t) < or = 30 (pool of 2 = 99.0%, pool of 3 = 100.0%, pool of 4 = 100.0%), and lowest agreement at C(t) < or = 36 (pool of 2 = 98.1%, pool of 3 = 97.1%, pool of 4 = 98.1%). In conclusion, regardless of the level of pooling after tetrathionate enrichment, sensitivity was very good, and results would be comparable to what would have been found with individual culture or individual RT PCR at C(t) < or = 36. PMID- 23678726 TI - Safety and efficacy of a metabolic drift live attenuated Salmonella Gallinarum vaccine against fowl typhoid. AB - Fowl typhoid (FT), a systemic disease that results in septicemia in poultry, is caused by Salmonella enterica serovar Gallinarum biovar Gallinarum (SG). Mortality and morbidity rates from FT can reach up to 80%. Attenuated live Salmonella vaccine candidates have received considerable attention because they confer solid immunity, and they can produce systemic and mucosal immunity in the gut when administered orally. In the present study, five metabolic drift (MD) mutants with a single-(designated SG-Rif1, SG-Sm6) or double-attenuating marker (designated SG-Rif1-Sm4, SG-Sm6-Rif10, and SG-Rif1-Sm10) were isolated. The relative colony sizes to wild-type strain after 24 hr at 37 C incubation were 50%, 40%, 30%, 30%, and 20%, respectively. The probability of a back mutation can almost be excluded because the reduced colony sizes were stable after at least 50 passages on culture media. The safety and immunogenicity were evaluated in susceptible 1-day-old commercial layer chickens. After oral administration of 10(8) colony-forming units (CFU), all developed MD mutants proved to be safe and did not cause death of any infected birds during 15 days postvaccination, whereas chickens receiving 10(6) CFU SG wild-type strain showed a high mortality rate (40%). Vaccination of commercial layer chicks with SG-Rif1, SG-Sm6, SG-Rif1-Sm4, and SG-Sm6-Rif10 MD mutants could protect chickens against challenge by homologous wild-type strain; however, SG-Rif1-Sm10 could not protect against challenge, indicating hyperattenuation. In conclusion, vaccination with SG MD mutant vaccine appears to be safe and offers protection against FT in chickens. PMID- 23678727 TI - Comparing presence of avian paramyxovirus-1 through immunohistochemistry in tracheas of experimentally and naturally infected chickens. AB - Tracheas from chickens infected both in the field and experimentally with lentogenic Newcastle disease virus (also known as avian paramyxovirus-1 [APMV-1] and referred to here as "lentogenic NDV") were examined histopathologically to score degree of pathologic changes and by immunohistochemistry to determine presence of viral protein. In the field cases there was often a striking lack of correlation between severity of tracheal lesions and amount of immunohistochemical signal for APMV-1 protein. Experimental cases had minimal pathologic changes and also minimal immunohistochemical signal. Positive cells were often associated with surface deciliation. It may be that lentogenic NDV has only a minor role as a respiratory pathogen, merely compromising the mucosa to allow other respiratory pathogens to infect and worsen the clinical and pathologic presentation. PMID- 23678728 TI - Multivalent virus-like-particle vaccine protects against classic and variant infectious bursal disease viruses. AB - Nucleotide sequences that encode the pVP2 proteins from a variant infectious bursal disease virus (IBDV) strain designated USA08MD34p and a classic IBDV strain designated Mo195 were produced with the use of reverse-transcriptase polymerase chain reaction (RT-PCR) and cloned into a pGEM-T Easy vector. A nucleotide sequence that encodes the VP3 protein was also produced from the USA08MD34p viral genome with the use of RT-PCR and cloned into a pGEM-T Easy vector. The VP3 and pVP2 clones were inserted into the pVL1393 baculovirus transfer vector and sequenced to confirm their orientation to the promoter and to ensure they contained uninterrupted open reading frames. Recombinant baculoviruses were constructed by transfection in Sf9 cells. Three recombinant baculoviruses were produced and contained the USA08MD34p-VP3, USA08MD34p-pVP2, or Mo195-pVP2 genomic sequences. Virus-like particles (VLPs) were observed with the use of transmission electron microscopy when the USA08MD34p-VP3 baculovirus was co-inoculated into Sf9 cells with either of the pVP2 constructs. VLPs were also observed when the USA08MD34p-pVP2 and Mo195-pVP2 were coexpressed with USA08MD34p VP3. These multivalent VLPs contained both classic and variant pVP2 molecules. Stability tests demonstrated the VLPs were stable at 4 and 24 C for 8 wk. The USA08MD34p, Mo195, and multivalent VLPs were used to vaccinate chickens. They induced an IBDV-specific antibody response that was detected by enzyme-linked immunosorbent assay (ELISA), and virus-neutralizing antibodies were detected in vitro. Chickens vaccinated with the multivalent VLPs were protected from a virulent variant IBDV strain (V1) and a virulent classic IBDV strain (STC). The results indicate the multivalent VLPs maintained the antigenic integrity of the variant and classic viruses and have the potential to serve as a multivalent vaccine for use in breeder-flock vaccination programs. PMID- 23678729 TI - Surveillance of Salmonella enteritidis in layer houses: a retrospective comparison of the Food and Drug Administration's egg safety rule (2010-2011) and the California Egg Quality Assurance Program (2007-2011). AB - Between July 2007 and December 2011, 2660 environmental drag swab samples were collected in total from California layer flocks on behalf of the California Egg Quality Assurance Program (CEQAP), the egg safety rule (21 CFR Parts 16 and 118) of the Food and Drug Administration (FDA), or both. The samples were processed by the California Animal Health and Food Safety Lab, and positive or negative results for Salmonella enterica serovar Enteritidis (SE) were recorded. This study retrospectively compares the differences between the FDA and CEQAP programs with respect to their SE environmental sampling surveillance results. To accomplish this comparison, two different CEQAP (new and old) data sets representing different SE environmental surveillance approaches in the life of the flock were compared against each other and against the FDA's SE environmental testing plan. Significant differences were noted between the CEQAP and FDA programs with respect to the prevalence of SE in the farm environment. Analyses of the prevalence of SE at different stages in the flock's life cycle (chick papers, preproduction, midproduction, postmolt, and premarket) found the highest prevalence of SE in premarket (11.9%), followed by postmolt (3.5%) and midproduction (3.4%), and there was a tie between chick papers and preproduction (2.1%). To assess the main effects of the presence of SE in the farm environment, backwards binary logistic regression was used. Of six independent variables examined (age of flock, year, season, owner, CEQAP membership, and analysis of pooled samples vs. individual swabs), only age of flock, owner, and year were determined to be significant factors in the final model. Although CEQAP membership and pooling vs. individuals swabs were not included in the final model, Pearson chi-square tests did show significantly higher odds of SE for non CEQAP member farms and higher odds of SE in pooled samples vs. individual swabs. PMID- 23678730 TI - Molecular evidence for a geographically restricted population of infectious bursal disease viruses. AB - A population of infectious bursal disease virus (IBDV) in northeast Ohio that appears to be geographically restricted was identified. Thirteen broiler farms containing a total of 36 houses were examined for the presence of IBDV. Twenty four of the 36 houses were positive for IBDV, and of those viruses, 15 viruses from six different broiler farms formed a unique phylogenetic group. Nucleotide sequence analysis identified glutamic acid (E) at position 253 in all 15 viruses. Only one other virus in the GenBank database contained this mutation, and it was also from northeast Ohio. All 15 viruses from this study and the one identified in GenBank also had a unique VP1 sequence. The amino acids located at position 253 in VP2 are typically histidine (attenuated viruses) and glutamine (pathogenic viruses). Because amino acid 253 has been linked to pathogenicity in IBDV, two viruses from the E253 population were selected for pathogenicity studies. They were observed to be pathogenic in 4-wk-old specific-pathogen-free layer chicks. When these two viruses were used to challenge broilers from the parent flock that supplies the birds to all 13 broiler farms examined in this study, the viruses were able to break through the maternal immunity at 14 and 21 days of age but not at 7 days of age. A similar scenario was observed on the six broiler farms that had these viruses. The phylogeographic data suggest this population of IBDV has been restricted for more than 14 yr to northeast Ohio. Because commercially available classic and variant vaccines do not effectively control this population of IBDV, other alternatives are needed. PMID- 23678731 TI - Characterization of nephropathogenic infectious bronchitis virus DMV/1639/11 recovered from Delmarva broiler chickens in 2011. AB - A limited outbreak of nephropathogenic infectious bronchitis (NIB) occurred in three Delmarva (DMV) commercial broiler chicken flocks in 2011. Isolates of NIB virus (NIBV)--DMV/1639/11, DMV/3432/11, and DMV/3902/11--were characterized by sequence analysis of the N-terminal subunit (S1) of the spike (S) gene. Findings indicated that the isolates were identical to each other and to PA/9579A/10, a 2010 isolate from poultry in Pennsylvania. The 2010 and 2011 isolates appear to have originated from a 1997-2000 NIB outbreak in Pennsylvania. DMV/1639/11 and PA/9579A/10 were determined to be nephropathogenic in susceptible chickens, yielding virus reisolations from kidney and inducing characteristic interstitial nephritis microscopic lesions. In a controlled laboratory study, 40% of chickens vaccinated with a combination live vaccine containing infectious bronchitis virus (IBV) strains Massachusetts (Mass) + Connecticut (Conn) were positive on virus isolation attempts after challenge with DMV/1639/11, compared with only 13% of Mass + Arkansas (Ark) vaccinates. Both combination vaccines gave partial protection against the development of DMV/1639/11-induced renal lesions. Although numerically fewer chickens vaccinated with Mass + Conn had interstitial nephritis compared with those vaccinated with Mass + Ark, neither vaccine combination offered greater protection (P < 0.05) than observed in unvaccinated chickens challenged with DMV/1639/11. Mass + Ark vaccinations, applied under commercial conditions in the hatchery (spray) and on-farm (spray), did not protect the trachea or kidney from DMV/1639/11 challenge. Serologic testing of broiler flocks found < 3% (2 of 69) tested to possess specific antibodies to DMV/1639/11, indicating the virus had not become established in the region. PMID- 23678732 TI - Detection of anti-reticuloendotheliosis virus antibody by blocking enzyme-linked immunosorbent assay with expression envelope protein. AB - The current reticuloendotheliosis virus (REV) antibody detection kit that uses enzyme-linked immunosorbent assay (ELISA) needs concentrated virus, which is difficult to obtain due to its poor propagation in cells. In addition, this kit detects only chicken antibody but not other species. To overcome these disadvantages, we cloned and expressed REV env gene to develop monoclonal antibodies (mAbs), which we used for antibody detection in ELISA. Three mAbs were prepared from mice. These three mAbs could recognize REVs from ducks and geese by immunodot assay. In addition, the epitopes that the three mAbs recognized were determined by using three different env protein fragments by western blotting. One mAb was used to develop a blocking ELISA (bELISA) coated with expressed env protein to detect anti-REV antibody in chicken serum. This assay had a 98.8% (79/80) agreement with a commercial ELISA kit. Another 146 chicken sera with known neutralization antibodies were used as positive controls to evaluate this bELISA. The sensitivity and specificity this bELISA were 88.9% (40/45) and 94.8% (91/96), respectively. Thus, this bELISA could be used for anti-REV antibody detection in birds. PMID- 23678733 TI - Historical, spatial, temporal, and time-space epidemiology of very virulent infectious bursal disease in California: a retrospective study 2008-2011. AB - In December of 2008 very virulent infectious bursal disease virus (vvIBDV) was identified in a commercial flock in northern California. Since then several other backyard and commercial facilities in California have had flocks affected by the same strain and other unique (previously unseen) strains of IBDV. Previous to this incident, very virulent infectious bursal disease (vvIBD) had never been identified in North America. Following the initial outbreak in 2008, California became the first state to undertake a voluntary surveillance effort to try to determine the geographical prevalence of vvIBD based on sequencing of a portion of the segment A region of the vvIBDV genome. To date we have complete geographical information on approximately 500 separate accessions representing approximately 1500 birds from over 200 commercial (-85% of the facilities) and backyard facilities (-15% of the facilities) throughout the state. Sequencing of targeted regions of both the segment A and segment B regions of the genome has revealed three distinct types of IBDV in California chickens. One type is genetically and in pathogenically consistent with vvIBDV. The second and third types only have a segment A region consistent with vvIBDV. Geographic information system mapping coupled with spatial-temporal cluster analysis identified significant spatial and time-space clustering; however, no temporal clustering was noted. The lack of temporal clustering coupled with negative vvIBDV results in tested avian wildlife implies that avian wildlife in California do not currently appear to play a significant role in vvIBDV transmission. In the voluntary surveillance that was done in the Central Valley of California, which has a high density of commercial poultry, no positive farms were found when 142 of 504 farms were sampled. Given this level of sampling, the confidence (probability) of detecting an affected commercial flock was calculated to be between 28% and 81% depending on whether one or five hypothetically affected farms were affected. PMID- 23678734 TI - H9N2 avian influenza virus-induced conjunctivitis model for vaccine efficacy testing. AB - Clinical signs such as respiratory signs, egg drop, and mortality have been reported in field cases of low pathogenic avian influenza by H9N2 avian influenza virus (AIV) but have rarely been reproduced by the virus alone. Thus, virus reisolation rates and titers in tissues were measured for vaccine efficacy testing. In the present study, we established a clinical sign-based vaccine efficacy test by reproduction of highly frequent conjunctivitis (77.8%-90%) via binocular instillation of an H9N2 virus (01310) strain, 1 x 10(6) EID50/10 microl for each eye). Specific-pathogen-free chickens were assigned to vaccine and control groups, and the vaccine group was inoculated intramuscularly with a commercial H9N2 inactivated oil emulsion vaccine. The chickens were challenged by 01310 via binocular instillation at 2 and 4 wk postvaccination (WPV). The positive rates of conjunctivitis and virus reisolation were significantly different between the vaccine and control groups (conjunctivitis at 2 WPV, 0% vs. 77.8%, and at 4 WPV, 0% vs. 80%). Vaccine antibody was detected in tears as well as in serum samples of the vaccine group before challenge. The conjunctivitis model may be useful for efficacy testing of AI vaccine due to a clinical symptom based read of results, but further efficacy testings with different types, doses of AI vaccines, and challenge viruses will be required to complete the evaluation of our model. PMID- 23678735 TI - Construction of an attenuated Salmonella delivery system harboring genes encoding various virulence factors of avian pathogenic Escherichia coli and its potential as a candidate vaccine for chicken colibacillosis. AB - An attenuated Salmonella (deltalon, deltacpxR, and deltaasdA16) delivery system containing the genes encoding P-fimbriae (papa and papG), aerobactin receptor (iutA), and CS31A surface antigen (clpG) of avian pathogenic Escherichia coli (APEC) was constructed, and its potential as a vaccine candidate against APEC infection in chickens was evaluated. The birds were divided into three groups designated group A (nonvaccinated control), group B (given a single immunization), and group C (administered prime and boost immunizations). Prime and booster vaccinations with the constructions were administered to 1-day-old and 14-day-old birds, respectively. Immune responses were measured postimmunization, and the birds were challenged via an intra-air sac route with a virulent APEC strain at the second, third, and fourth weeks of age. Group B birds were partially protected against the challenge and showed increased levels of plasma immunoglobulin (Ig)G, mucosal IgA antibodies, and lymphocyte proliferation. Group C birds showed greater protection against the challenge, with significantly stronger immune responses compared with the birds in the other groups. Overall, our data suggest that the Salmonella delivery system with recombinant constructs is capable of inducing robust immune responses and induces effective protection against colibacillosis caused by APEC. PMID- 23678736 TI - Isolation and characterization of a turkey arthritis reovirus. AB - During the spring and summer of 2011, the Minnesota Veterinary Diagnostic Laboratory at the University of Minnesota received 14 submissions of 15-to-18 week-old tom turkeys that were recumbent with wing tip bruises ("wing walkers") and uni- or bilateral swelling of the hock (tibiotarsal) joints. Gastrocnemius or digital flexor tendons were occasionally ruptured. A total of five turkey arthritis reoviruses (TARV-MN1 through TARV-MN5) were isolated in specific pathogen-free embryonated chicken eggs and QT-35 cells. The identity of the isolates was confirmed by electron microscopy, reverse transcription-polymerase chain reaction, and gene sequence analysis. BLAST analysis on the basis of a 880 bp nucleotide sequence of the S4 gene confirmed all isolates as a reovirus. Phylogenetic analysis divided the five isolates into two subgroups: subgroup I containing TARV-MN1, -2, -3, and -5, and the other subgroup containing TARV-MN4. Isolates in subgroup I had a similarity of 97%-100% with each other, while subgroup II (TARV-MN4) had a similarity of only 89.2% with subgroup I viruses. This isolate showed 90%-93% similarity with turkey enteric reoviruses in the United States, while the other four isolates in subgroup I had 89%-97.6% similarity. These results indicate divergence within TARVs as well as from enteric viruses, which needs to be confirmed by complete genome sequence analysis. Further experimental studies are planned to determine the role of these isolates in turkey arthritis and to compare them with classical chicken reovirus. PMID- 23678738 TI - The seroprevalence of avipoxvirus and its association with avian malaria (Plasmodium spp.) infection in introduced passerine birds in the southern regions of the North Island of New Zealand. AB - Blood samples were collected from 65 free-ranging birds from six species in the southern North Island of New Zealand. Sera from the birds were tested for the presence of avipoxvirus (APV) antibodies by enzyme-linked immunosorbent assay (ELISA), and blood cells from 55 birds were also tested for Plasmodium spp. by PCR. Forty-five birds (69.2%) tested seropositive to APV. Song thrushes (Turdus philomelos) presented the highest seroprevalence at 100% (4/4), followed by Eurasian blackbirds (Turdus merula) (96.86%, 31/32), chaffinches (Fringilla coelebs) (54.55%, 6/11), starlings (Sturnus vulgaris) (25%, 3/12), greenfinches (Carduelis chloris) (25%, 1/4), and European goldfinches (Carduelis carduelis) (0%, 0/2). Plasmodium spp. DNA was detected in 15/55 birds (27.3%), including 11 Eurasian blackbirds, one song thrush, and three starlings. Eight Eurasian blackbird isolates (73%) grouped within the subgenus Novyella. Two Eurasian blackbird isolates and the song thrush isolate clustered within a different group with previously reported lineages LINN1 and AFTRU5. In addition, all three starling isolates clustered within the well-characterized lineage Plasmodium (Huffia) elongatum GRW06. All Plasmodium-positive Eurasian blackbirds and the song thrush were seropositive to APV, whereas only 67% of Plasmodium-positive starlings showed evidence of previous exposure to APV. A significant relationship between birds seropositive to APV and birds infected by Plasmodium spp. was observed (chi2 = 5.69, df = 1, P = 0.0086). To the authors' knowledge this is the first report describing the seroprevalence of APV and its association with Plasmodium spp. infection in introduced bird species in New Zealand. PMID- 23678739 TI - Role of motAB in adherence and internalization in polarized Caco-2 cells and in cecal colonization of Campylobacter jejuni. AB - Campylobacter jejuni, a gram-negative motile bacterium commonly found in the chicken gastrointestinal tract, is one of the leading causes of bacterial gastroenteritis in humans worldwide. An intact and functional flagellum is important for C. jejuni virulence and colonization. To understand the role of C. jejuni motility in adherence and internalization in polarized Caco-2 cells and in cecal colonization of chickens we constructed a C. jejuni NCTC11168 V1 deltamotAB mutant. The motAB genes code for the flagellar motor, which enables the rotation of the flagellum. The nonmotile deltamotAB mutant expressed a full-length flagellum, which allowed us to differentiate between the roles of full-length flagella and motility in the ability of C. jejuni to colonize. To study the adherence and invasion abilities of the C. jejuni deltamotAB mutant we chose to use polarized Caco-2 cells, which are thought to be more representative of in vivo intestinal cell architecture and function. Although the C. jejuni deltamotAB mutant adhered significantly better than the wild type to the Caco-2 cells, we observed a significant reduction in the ability to invade the cells. In this study we obtained evidence that the flagellar rotation triggers C. jejuni invasion into polarized Caco-2 cells and we believe that C. jejuni is propelled into the cell with a drill-like rotation. The deltamotAB mutant was also tested for its colonization potential in a 1-day-old chicken model. The nonmotile C. jejuni deltamotAB mutant was not able to colonize any birds at days 3 and 7, suggesting that motility is essential for C. jejuni colonization. PMID- 23678741 TI - Isolation and genotyping of Toxoplasma gondii from free-range ducks in Malaysia. AB - Toxoplasma gondii is a parasitic protozoan that infects nearly one-third of humans. The present study was performed to isolate and genotype T. gondii from free-range ducks in Malaysia. Sera, heads, and hearts from 205 ducks were obtained from four states in Peninsular Malaysia, and 30 (14.63%) sera were found to be seropositive when assayed with the modified agglutination test (MAT > or = 1:6). All the positive samples were inoculated into mice, and T. gondii was successfully isolated from four individual duck samples (1.95%), which were initially found to be strongly seropositive (MAT > or = 1:24). The isolates were subjected to PCR-RFLP analysis, and two T. gondii strains were identified: type I and type II. This is the first reported study on the genetic characterization of T. gondii isolates from free-range farm animals in Southeast Asia. PMID- 23678740 TI - Chicken parvovirus-induced runting-stunting syndrome in young broilers. AB - Previously we identified a novel parvovirus from enteric contents of chickens that were affected by enteric diseases. Comparative sequence analysis showed that the chicken parvovirus (ChPV) represented a new member in the Parvoviridae family. Here, we describe some of the pathogenic characteristics of ChPV in young broilers. Following experimental infection, 2-day-old broiler chickens showed characteristic signs of enteric disease. Runting-stunting syndrome (RSS) was observed in four of five experimental groups with significant growth retardation between 7 and 28 days postinoculation (DPI). Viral growth in small intestine and shedding was detected at early times postinoculation, which was followed by viremia and generalization of infection. ChPV could be detected in most of the major tissues for 3 to 4 wk postinoculation. Immunohistochemistry staining revealed parvovirus-positive cells in the duodenum of inoculated birds at 7 and 14 DPI. Our data indicate that ChPV alone induces RSS in broilers and is important determinant in the complex etiology of enteric diseases of poultry. PMID- 23678742 TI - Naturally occurring neoplasms in pigeons in a research colony: a retrospective study. AB - This study reports the gross and microscopic pathology of naturally occurring neoplasms in adult pigeons that were presented for necropsy at the Indiana Animal Disease Diagnostic Laboratory from 2001 to 2011. The study population consisted of white carneau and mixed-breed pigeons used in behavioral studies in the Department of Psychological Sciences at Purdue University. Twelve types of neoplasms or proliferative disorders were identified in 28 of 83 pigeons (33.7%). Five pigeons had two or three types of neoplasms-proliferative disorders. Of the 83 pigeons, 11 (13.3%) had seminoma, five (6.0%) had thyroid adenoma, four (4.8%) had lymphoma, four (4.8%) had adenocarcinoma of female reproductive tract origin, two (2.4%) had pulmonary carcinoma, and two (2.4%) had cutaneous vascular hamartomas. Also identified were single incidences of dysgerminoma, mesothelioma, liposarcoma, cloacal papilloma, cloacal adenocarcinoma, and gizzard carcinoma. The most frequently occurring tumor was seminoma; 7/11 cases effaced both testicles and 3/11 cases had metastasis to the liver or kidney. The relatively high prevalence of neoplasms in pigeons in the present study is most likely related to the advanced ages of pigeons kept in the research colony. PMID- 23678743 TI - Total anomalous pulmonary venous connection in a chicken. AB - This report describes a case of total anomalous pulmonary venous connection (TAPVC) in a 5-wk-old male white leghorn chicken that presented with growth retardation. This chicken was a specific-pathogen-free chicken bred in an isolator. At 5 wk of age, the chicken was euthanatized and autopsied. Macroscopically, the right ventricle and right atrium were significantly enlarged whereas the left atrium was small and blind-ending with no connection to the pulmonary veins. The pulmonary veins were connected directly to the right atrium. The above abnormality was accompanied by an ostium secundum-type atrial septal defect. No other malformations were observed. TAPVC is a very rare congenital cardiac abnormality that has not been reported in avian species to date. PMID- 23678744 TI - A colibacillosis outbreak in farmed red-legged partridges (Alectoris rufa). AB - Colibacillosis in different forms is responsible for significant economic losses in the poultry industry worldwide. Escherichia coli strains frequently implicated in poultry disease are designated as avian pathogenic E. coli (APEC). Natural infections and disease due to APEC have been described in wild birds, but not as yet in red-legged partridges. During an outbreak in an experimental partridge farm, 23 of 43 1-day-old chicks belonging to the same batch died. Putative APEC strains were detected and isolated both in cloacal swabs and in tissues originating from the same individuals and from different birds showing similar clinical signs. This is the first study that identifies APEC strains linked to a colibacillosis outbreak in farmed red-legged partridges, and also confirms the importance of farmed partridges as fecal carriers and potential spreaders of APEC. PMID- 23678737 TI - Comparison of multilocus sequence analysis and virulence genotyping of Escherichia coli from live birds, retail poultry meat, and human extraintestinal infection. AB - To examine the correlations between virulence genotyping and multilocus sequence analysis of Escherichia coli from poultry and humans, 88 isolates were examined. The isolates were selected from a population of over 1000 based on their assignment to nine different virulence genotyping clusters. Clustering based on multilocus sequence analysis mostly correlated with virulence genotyping, although multilocus sequence analysis demonstrated higher discriminatory ability and greater reliability related to inferred phylogenetic relationships. No distinct patterns in host source were observed using inferred phylogeny through multilocus sequence analysis, indicating that human, avian, and retail meat isolates are diverse, and some belong to multiple shared clonal complexes. Clonal complexes with host source overlap included ST95 and ST23 and additional novel groups, underscoring the diversity of avian pathogenic E. coli and the potential importance of these novel groups as avian and zoonotic pathogens. PMID- 23678745 TI - Fatal verminous pharyngitis and esophagitis caused by Streptocara incognita in mute swans (Cygnus olor). AB - Streptocara spp. infections are reported to cause gastritis, proventriculitis, esophagitis, and pharyngitis in various waterfowls, especially diving ducks. In the present paper, we describe severe fatal diphtheritic pharyngitis and esophagitis caused by Streptocara incognita in three female mute swans (Cygnus olor) in Bosnia and Herzegovina. Prior to death, the swans were showing signs of lethargy, anorexia, and reluctance to move. At necropsy, in all swans severe diphtheritic pharyngitis and esophagitis with deep, dark red hemorrhagic ulcerations were observed. Numerous thin, white, up to 1-cm-long nematodes, identified as S. incognita, were observed embedded in the pharyngeal and esophageal mucosa under the diphtheritic membranes. Histopathology revealed severe fibrinonecrotic inflammation with numerous cross-sections of the parasites. To the authors' knowledge, this is the first report of severe, fatal streptocariasis in mute swans. PMID- 23678746 TI - Antimicrobial resistance of Escherichia coli isolated from chickens with colibacillosis in and around Harare, Zimbabwe. AB - Colibacillosis, a disease caused by avian pathogenic Escherichia coli (APEC), can lead to great economic losses in the poultry industry. The aim of this study was to determine the prevalence of antibiotic resistance and antibiotic resistance patterns in APEC in Zimbabwe. From 503 chickens diagnosed with colibacillosis, 103 E. coli isolates were obtained. Isolation and identification of E. coli were carried out using microscopy and biochemical tests. The disc diffusion method was used to determine antibiotic susceptibility of the isolates to 8 commercial antibiotics. Many isolates exhibited resistance to more than one antibiotic. Antibiogram profiles indicated maximum resistance to tetracycline (100%), bacitracin (100%), and cloxacillin (100%) and a high prevalence of resistance to ampicillin (94.1%). However; there were high prevalences of sensitivity to ciprofloxacin (100%) and gentamycin (97.1%). The isolates showed moderate rates of sensitivity to chloramphenicol and neomycin. All isolates in this study showed multidrug resistance because they were all resistant to 3 or more antibiotics. Seven multidrug resistance patterns were observed. The most common pattern (resistance to ampicillin, bacitracin, cloxacillin, and tetracycline) was exhibited by 30 isolates. Our findings show that there is emerging drug resistance in APEC associated with colibacillosis in Zimbabwe. The observed high level of multidrug resistance could hamper the treatment of colibacillosis in Zimbabwe. PMID- 23678748 TI - Adenoviral gizzard erosion in broiler chickens in Germany. AB - Avian adenovirus infections cause important disease complexes in chickens, but many of the viruses also infect chickens without resulting in overt disease. Previously several outbreaks of gizzard erosions caused by a fowl adenovirus A serotype-1 (FAdV-1) were reported from Japan. Here we report an outbreak of gizzard erosions in 12 broiler flocks in Germany in 2011. Chickens had a reduced daily weight gain and a higher total mortality rate of up to 8%. The birds showed a severe detachment of the koilin layer and ulcerative to necrotizing lesions of the underlying mucosa. Histopathologically, necrotizing ventriculitis with basophilic, intranuclear inclusion bodies in epithelial cells was diagnosed. Immunohistochemistry, egg culture, and electron microscopic examination revealed adenovirus-like particles in the samples. No concurrent infectious agent could be identified. The virus was genotyped as FAdV-1 by PCR and subsequent sequencing. Phylogenetic analysis of the hexon loop L1 gene yielded 100% sequence identity to the chicken embryo lethal orphan strain. These findings suggest that outbreaks of adenoviral gizzard erosion can lead to significant economic losses in Germany and may be caused by an unusual virulent FAdV-1 strain. PMID- 23678747 TI - Prevalence of low pathogenic avian influenza virus in one live bird market in Eastern China from 2002-2011. AB - The role of live bird markets (LBMs) in the perpetuation of avian influenza virus (AIV) has been well studied worldwide; however, there is a paucity of information on the prevalence of different AIV subtypes in LBMs in Eastern China. In this study, long-term surveillance was conducted to investigate the prevalence of AIV in chickens, ducks, and geese in an LBM in Yangzhou city, Jiangsu province, Eastern China, between July 2002 and May 2011. The study used primary virus isolation and subtype-specific reverse-transcription-PCR. In total, 23 different HA-NA subtype combinations were detected, mainly in domestic ducks. This result suggests that domestic ducks play a more important role in LBMs in Eastern China. PMID- 23678749 TI - [Treatment for displaced supracondylar fractures of the humerus in children]. PMID- 23678750 TI - [Kirschner wires and tension-band fixation through posterolaterla minimal incision combined with plaster fixation at supinated position for the treatment of Garland type III supracondylar humeral fractures in children]. AB - OBJECTIVE: To evaluate the efficacy of Kirschner wires and tension-band fixation through posterolateral minimal incision for the treatment of displaced supracondylar humeral fractures in children. METHODS: From January 2005 to December 2010, there were 62 children (38 males and 24 females, ranging in age from 2 to 14 years, averaged 6.8 years) with Gartland type III supracondylar humeral fractures. All the injuries were caused by falling, and all the fractures were fresh injuries. The duration from injury to surgery ranged from 5 to 20 hours. All the children were treated with open reduction through a posterolateral minimal approach, Kirschnere wires and tension-band fixation were fixed with plaster at 90 degrees of elbow flexion, forearm supination, and palms facing upwards. The kirschner pins and wires were removed after fractures healing. The Flynn's criterion was used to evaluate therapeutic effects. RESULTS: The operation time ranged from 30 to 50 min (averaged 45 min). All the patients achieved solid union. Sixty patients were followed up, and the mean follow-up time was 15 months (ranged from 6 to 24 months). At the 6th month after operation, 48 patients got an excellent result, 9 good, 3 bad (light cubitus varus with varus angle about 6 degree, without infection on function) according to Flynn's criteria. There were no complications such as procedure-related pin tract infection, iatrogenic nerve and vascular injuries and myositis ossificans. CONCLUSION: The Kirschner wires and tension-band fixation through posterolateral minimal incision approach can obtain clearer surgical field, simple in operation, and few wound complications. Therefore, this modified treatment is an effective and reliable method for pediatric displaced Gartland type III supracondylar humeral fractures. PMID- 23678751 TI - [Relationship between the degree of displacement and the Baumnann angle in pediatric supracondylar humeral fractures]. AB - OBJECTIVE: To analyze the relationship between the degree of displacement and Baumann angle in pediatric supracondylar humeral fractures by using Excel, and to guide treatment for humeral fractures of children. METHODS: From July 2010 to July 2011,56 children with humeral supracondylar fractures were collected (34 boys and 22 girls, 15 patients with radial deviation and 41 patients with ulnar deviation,ranging in age from 3 to 14 years). The data of the patients about fracture displacement and the Baumann angle measured by MB-Ruler were input in Excel and then were analyzed to obtain data fitting curve. RESULTS: There were close results between two methods, and the tangent of the radial deviation was more than tangent of ulnar deviation, which indicated that the influence of ulnar deviation was stronger than that of the radial deviation in pediatric supracondylar humeral fractures,so the correction should be paid attention to in clinic. When the radial deviation coefficient was less than -0.18 and ulnar deviation coefficient was more than 0.50,the Baumann angle would change to the reverse trend, so the angle range of Baumann in clinic should be between 65.70 and 96.77 degree. When the ulnar deviation factor was more than 0.15(including 0.15) and Baumann angle more than 82 degrees(including 82 degree), cubitus varus deformity occurred inevitably,so the practices and surgical reduction should be focused on in clinic. CONCLUSION: According to data curves analysis results,the influence of ulnar deviation is stronger than that of the radial deviation in pediatric supracondylar humeral fractures. When the ulnar deviation factor is more than 0.15 (including 0.15), correction should be focused on in order to prevent cubitus varus deformity. PMID- 23678752 TI - [Closed reduction and fixation for the treatment of Gartland type II and III supracondylar fracture of humerus in children]. AB - OBJECTIVE: To evaluate the feasibility and results of closed reduction and fixation for the treatment of Gartland type I and III supracondylar fracture of humerus in children. METHODS: From January 2004 to December 2011,110 children with supracondylar fracture of humerus were treated. Among them, 76 patients were boy and 34 patients were girl, ranging in age from 2 to 13 years old, averaged 7 years old. Ninety-eight patients were extension type and 12 patients were flexion type. There were 32 patients with fracture of Gartland type II and 78 patients with fractures of Gartland type III. Thirty-seven patients had distal rotational displacement. Under anesthesia, the upper arm and forearm of the affected limb were treated with contraction for several minutes. The patients were treated with closed manipulative reduction and plaster external fixation while the satisfactory reduction was confirmed by C-arm X-ray. After the reduction, 1 to 2 Kirschner pins were used through the radial side of the skin and plaster external fixation was carried out. Radiographic examination was conducted within 3 to 4 weeks after surgery,and the plaster and Kirschner pins were then removed, accompanied by rehabilitation training of the patients. RESULTS: All the patients were followed up,and the duration ranged from 3 to 18 months,with a mean of 12 months. All fractures healed within 6 to 8 weeks and the average healing time was 6.9 weeks. No complications such as cubitus varus deformity, neurovascular injury or Volkmann's contracture occurred. According to Flynn evaluation criteria,74 patients got an excellent result, 26 good and 10 fair. CONCLUSION: Through carefully reading X-ray films,Gartland type II and III supracondylar fracture of the humerus in children can be treated with closed reduction, plaster external fixation combined with percutaneous pinning for unstable fracture, which is a simple, less-invasive and satisfactory treatment method. PMID- 23678753 TI - [X-ray characteristics of sacroiliac joint disorders and its clinical significance]. AB - OBJECTIVE: To study the X-ray characteristics of sacroiliac joint disorders and its clinical significance,so as to provide clinical diagnosis basis for Tuina treatment of sacroiliac joint disorder. METHODS: From July 2009 to March 2011,104 patients with sacroiliac joint disorder were reviewed,including 64 males and 40 females,ranging in age from 18 to 81 years, with an average of (45.39 +/- 1.30) years. The duration of the disease ranged from 1 to 144 months,with an average of (12.64 +/- 2.19) months. One hundred and four pelvic plain films and 97 lumbar spine lateral films of the patients with sacroiliac joint disorder were taken. On the lateral X-ray of lumbar,the sacral horizontal angles (lumbosacral angle) were measured; and on the X-ray of pelvis,the vertical distance of two side iliac crest (iliac crest difference), the distance from lateral border to medial margin of two hips (hip width),the clip angle between sacral spin connection and vertical axis were measured,and then the data were analyzed. RESULTS: The mean difference of iliac crest was (10.34+/-0.73) mm; the mean width difference of hip'was (6.73+/-1.01) mm; and the mean difference of the iliac crest was larger than that of mean difference of hip (P<0.01). The occurrence rate of inequal width of hip was higher(P<0.01). The mean abnormal lumbosacral angle was (7.29 +/ 1.86) degrees,and the mean angle of sacral crest tilting to left or right was (3.18 +/- 0.47) degrees; the mean abnormal lumbosacral angle was larger than that of angle of sacral crest tilting to left or right (P<0.01), and the occurrence rate of sacral crest tilting to left or right was higher PMID- 23678754 TI - [Hhigh-frequency ultrasound research on the normal adult sciatic nerve]. AB - OBJECTIVE: To explore the application value of the high-frequency ultrasound examination of the normal adult sciatic nerve. METHODS: The high frequency ultrasound was used to examine 60 cases ,a total of 120 normal adult sciatic nerve (28 males and 32 females ranging in age from 19 to 38 years old, averaged 23.8 years old). The age between men and women, height and weight showed no significant difference. The cross-sectional scanning and longitudinal scanning, if necessary, Panoramic Imaging were conducted. The cross section area of sciatic nerve was measured at the hip line, the middle of the thigh, the edge of the popliteal fossa, and the relationship betwen the sciatic nerve and surrounding muscle group was observed in each cross-section. Probe was rotated 90 degree to display the long axis of sciatic nerve, to get the longitudinal section along the long axis from top to bottom. So the sciatic nerve in the vertical axis and the surrouunding muscles was displayed by above method combined with panoramic imaging. The data of coss-sectional area of sciatic nerve were obtained at the central of hip line, the middle of the thigh, the edge of the popliteal fossa, and then were divided into different groups by gender and sides to do statistical analysis. RESULTS: The applicatic nerve in thigh can be clearly displayed by high frequency ultrasound in this group of 60 people with 120 nerves, but low display rate of sciatic nerve in hip, approximatley 31.4% (21/66). The longitudinal section of the sciatic nerve displayed as the banded isoechoic or slightly hyperechoic, parallel partial hyperechoic line could be seen in it; in the cross section, it showed a clear edge of the sieve-like isoechoic or slightly hyperechnie, which could be oval ,trapezoidal, triangular and irregular in shape; the sciatic nerve bad visible passive movement and shape change when muscle contracted. There were statistically significant differences of cross-sectional area of sciatic nerves at the hip line ,the middle of thigh and edge of the popliteal fossa between 56 sciatic nerves in 28 males and 64 sciatic nerves in 32 females (P< 0.05); but there were no significant differences between left and right sides (P>0.05). CONCLUSION: High frequency ultrasound can be used as the first choice of the sciatic nerve when an imaging method preferred. PMID- 23678755 TI - [Treatment of anteromedial coronoid facet fractures with open reduction and internal fixation through anteromedial approach]. AB - OBJECTIVE: To investigate the approach of open reduction and internal fixation for the treatment of anteromedial coronoid facet fractures and associated injury. METHODS: From July 2009 to August 2011, 6 coronoid anteromedial facet fractures were treated (4 males and 2 females,the average age was 32.6 years old,ranged from 19 to 49 years old) in our hospital. Three patients had fractures in the left side and 3 in the right(4 dominant sides and 2 non dominant sides). All the patients had close fractures. All the fractures were subtype 2 or subtype 3 of coronoid anteromedial facet fracture according to O'Driscoll classification. The anteromedial incision of elbow and the approach of splitting flexor digitorum superficialis between flexor carpi radialis and palmaris longus were used to apply internal fixation with mini-plate. After fixation of coronoid fracture, widening of radiohumeral joint interspace under varus stress occurred in 3 cases,elbow varus posteromedial rotational instability was showed,and the exploration and repair of radial collateral ligament was not carried out. Plaster was applied for 2 weeks before rehabilitation and the time of plaster application extended to 4 weeks in the patients showed varus posteromedial rotational instability. The motion degree,pain and stability, strength of elbow and hand were recorded,the elbows were evaluated with modified An and Morrey functional rating index. RESULTS: All the patients were followed up,and the average duration was 9.3 months (ranged from 7.5 to 13 months). The strength of elbow and hand were equal to that in the contralateral side. The average flexion was (129.0+/ 6.5) degree (ranged from 120 to 135 degree); the average extention was (4.0+/ 4.2) degree (ranged from 0 to 10 degree); the average forearm pronation was (84.0+/-6.5) degree (ranged from 75 to 90 degree); average supination was (89.0+/ 7.1) degree (ranged from 80 to 100 degree). One patient had ulnar sensory neuropathy after operation and healed in half-year, no postoperative complications as pain and instability accured. All the patients obtained excellent results according to modified An and Morrey functional rating index. CONCLUSION: The approach of splitting flexor digitorum superficialis between flexor carpi radialis and palmaris longus could be used in open reduction and internal fixation of anteromedial coronoid facet farcture, rehabilitation should be postponed in the patient showed elbow varus posteromedial rotational instability. PMID- 23678756 TI - [Analysis on arthroscopic debridement and visco supplement for the treatment of degenerative osteoarthropathy of ankle]. AB - OBJECTIVE: To evaluate effects of arthroscopic debridement and visco supplement for the treatment of degenerative osteoarthropathy of ankle. METHODS: From October 2008 to May 2012, 30 patients with degenerative osteoarthropathy of ankle were treated with arthroscopy after ineffective treatment with conservative methods. Two patients lost follow-up. Among the patients, 19 patients were male and 9 patients were female, ranging in age from 28 to 56 years old, with a mean of (40.0+ 5.9)years old. Patients who had inflammatory or postinfectious arthritis,rheumatoid,gout,tuberculosis were excluded. Other exclusion criteria included previous arthroscopic treatment for ankle osteoarthropathy, intraarticular corticosteroid injection within the previous 6 months, a major neurologic deficit, serious medical illness and pregnancy. Articular cartilage iijuries were classified according to Outerbridge by the same doctor. Follow procedures were involved in the surgery: synovectomy,debridement or excision of fragments of articular cartilage or chondral flaps and osteophytes that prevented full extension. Microfracture of chondral defects was not performed. Ogilvie Harris criteria was used to evaluate therapeutic effects. RESULTS: According to Ogilvie-Harris criteria, 10 patients got an excellent results, 14 good, 3 poor and 1 bad. The mean VAS score of pain decreased from preoperative 7.5+/-1.3 to postoperative 2.4+/-2.3. The score of dorsiflexion range (ROM-D) had no obvious change after operation [preoperative(27.0+/-7.3)degree and postoperative(29.0+/ 5.6)degree]. The mean Tegner score increased from preoperative 2.7+/-1.3 to postoperative 5.6+/-2.2. CONCLUSION: Synovectomy, debridement or excision of chondral flaps and osteophytes under arthroscopy, as well as scheduled intraarticular sodium hyaluronate injection should be recommened to treat ankle degenerative osteoarthropathy. PMID- 23678757 TI - [Treatment of infected total knee arthroplasty with a self-made, antibiotic loaded cement articulating spacer]. AB - OBJECTIVE: To study the efficacy of self-made, antibiotic-loaded cement articulating spacer in the treatment of infected total knee arthroplasty. METHODS: The self-made molds were used to form the spacer during the operation. From March 2002 to March 2007, 22 patients with infected knee arthroplasty (10 males with 10 knees, 12 females with 12 knees) were treated with this kind of spacer in our center. The mean age of the patients was 59.6 years old (33 to 75 years old). The interval time between primary arthroplasty and first onset of infective syndrome was 6.7 months (1 to 14 months). The diagnosis was established by the clinical presentation,serum laboratory inflammatory markers (white blood cell count,erythrocyte sedimentation rate and C-reactive protein) and knee aspiration. The serum laboratory inflammatory markers were used to measure the systemic response to infection. Clinical and radiographic follow-up was regularly performed by HSS score system and X-ray. RESULTS: All the patients were followed, the average interval between debridement and reimplantation was 4.7 months (3 to 9 months) and the infection control rate was 100% after the implantation of spacer. The average follow-up duration after reimplantation was 29.8 months (10 to 64 months) and there was no recurrence of infection at the latest follow-up. The HSS score increased from 40.5+/-5.9 to 65.8+/-7.5 after the implantation of spacer, furthermore, the score reached 88.7+/-5.1 in average at the latest follow up. The patient satisfaction rate was 95.3%. CONCLUSION: This self-made molds and spacers is a reliable approach for the management of infected knee arthroplasty with some virtues, such as providing a mobile and functional joint through the treatment course, decreasing the difficulty of reimplantation, avoiding of a long term post-operative infusion and high effective for eradicating infection. PMID- 23678758 TI - [Arthroscopic single bundle anterior cruciate ligament anatomical reconstruction with remnant preservation]. AB - OBJECTIVE: To investigate the feasibility and clinical effects of single bundle anterior cruciate ligament anatomical reconstruction with remnant preservation. METHODS: From October 2007 to November 2009, 17 patients (10 male and 7 female, ranging in age from 28 to 62 years, with an average of 39.3 years) with posterior cruciate ligament injuries were treated with single bundle anatomical reconstruction with remnant preservation. Nine patients had the injuries caused by traffic accident; 6 patients caused by falling down; and 2 patients caused by sports injuries. The average time from injury to surgery was 8.5 days (ranging from 2 to 14 days). The international knee documentation committee knee evaluation form (IKDC) and Lysholm were used to analysis the effect of surgery. RESULTS: All the patients obtained the follow-up and the average time was 29.5 months (ranging from 24 to 39 months). There were no complications such as injuries of popliteal fossa artery, tibial nerves or peroneal nerve. Twelve patients had knee joint recovering to normal; 1 patient had stiff joints and was treated with arthroscopic surgery to release after 6 months,who had postoperative flexion lack of 20 degree and straight to normal. Three patients had flexion loss of 5 to 10 degree, and 1 patient had hyperextension limitation of 5 degree. Posterior drawer test in 17 patients and the Lachman test were negative. IKDC scores of the 17 patients achieved normal(16 patients) or near normal(1 patient). IKDC overall score normal in 16 patients (94.1%), close to normal in 1 case (5.9%). The IKDC subjective score was 94.3+/-5.1 and Lysholm score was 94.7+/-3.1 at the latest follow-up. CONCLUSION: The single bundle anterior cruciate ligament with remnant preservation anatomical reconstruction can provide good clinical results. PMID- 23678759 TI - [The lateral superior genicular artery perforator iliotibial band flap for the treatment of scar contraction of popliteal fossa]. AB - OBJECTIVE: To discuss clinical results of the lateral superior genicular artery perforator iliotibial band flap for the treatment of scar contracture of popliteal fossa. METHODS: Form January 1999 to December 2011, 11 patients with scar contraction of popliteal fossa were treated with the lateral superior genicular artery perforator iliotibial band flap. Among the patients, 7 patients were male and 4 patients were female,ranging in age from 24 to 58 years old,with an average of 33 years old. The operation time ranged from 3 months to 1 year after trauma. Eight patients had injuries in the right side and 3 patients had the injuries in the left. Five patients had the injuries caused by traffic,3 patients had the injuries caused by hot compression and other 3 patients suffered from burns. The flap area ranged from 7.0 cm x 4.0 cm to 20.0 cm x 8.0 cm. RESULTS: All the flaps survived. Three patients had epidermis necrosis. After 5 months to 2 years follow-up period,the knee function recovered,the flap shape was favorable and the skin firmness was moderated. CONCLUSION: The lateral superior genicular artery perforator iliotibial band flap is a practical, simple and an ideal donor in the reconstruction of popliteal fossa scar contracture. PMID- 23678760 TI - [Case-control study on volar and dorsal plate for the treatment of dorsal unstable distal radius fractures]. AB - OBJECTIVE: To investigate the internal fixation methods in the two different surgical approach to the unstable distal radius fractures. METHODS: From August 2006 to October 2010,47 patients with distal radius fractures were treated with open reduction and plate internal fixation. Among the patients, 21 patients were male and 26 patients were female,ranging in age from 39 to 73 years old. All the patients were divided into two groups: 32 patients were treated with plate fixation at the palm side with palm side incision (group A),including locking plate used in 27 patients and ordinary T shape plate used in 5 patients; 15 patients were treated with dorsal plate fixation (group B), including locking plate used in 7 patients and ordinpry T shape plate used in 8 patients. The postoperative wrist function, X-ray score,complications were compared between the two groups. RESULTS: Compare to preoperative, postoperative volar tilt,ulnar deviation and radial styloid height of both groups improved; and comparison between 1 week after operation and 6 months after operation,volar tilt,ulnar deviation and radial styloid height of both groups had no obvious loss. In group A, 1 patient had tension injury of median nerve, 1 patient had incision infection, 2 patients had adhesion of tendon; and in group B,1 patient had incision swelling and infection, 1 patient had adhesion of tendon,3 patients had stimulation of extensor pollicis longus muscle tendon. The complication occurrence rate of group A is lower than that of group B. The wrist functional assessment: 17 patients got an excellent results, 11 good, 3 poor and 1 bad in group A; and 8 excellent, 4 good, 2 poor and 1 bad in group B. There was no statistically significant difference of wrist function between the two groups. CONCLUSION: Plate fixation at the palm side for the treatment of unstable distal radius fractures can also achieve a good reduction,and has less complication such as tendon damage than that of dorsal plate fixation. PMID- 23678761 TI - [Case-control study on cancellous screw and compression bolt in the treatment of calcaneal fractures wih minimally invasive plate]. AB - OBJECTIVE: To evaluate percutaneous reduction by Kirschner pin and internal fixation with cancellous screw and plate through minimal incision at the lateral side of heel for the treatment of intra-articular displacement fracture of calcaneus. METHODS: From September 2009 to June 2012, 80 patients with close intra-articular displacement fractures of calcaneus were divided into treatment group and control group. There were 40 patients in the control group, including 21 males and 19 females, ranging in age from 23 to 64 years old, averaged (39.1 +/-11.7) years old; and the patients were treated with fixation by compress screws and plates of self-broken type. There were 40 patients in the treatment group, including 24 males and 16 females,ranging in age from 21 to 67 years old, averaged (39.6+/-14.3) years old;and the patients were treated with full thread cancellous screws and plates fixation. The fixation time,intra-operative blood loss and the number of injured medial plntar nerve were compared between the two groups. The Bohler angle, Gissane angle and the correction degree of calcaneal width were measured at 1 year after operation. The internal fixators were taken out after 1 year. The AOFAS ankle-hindfoot score was used to evaluate therapeutic effects. RESULTS: All the patients were followed up,and the duration ranged from 9 to 32 months, with a mean of 16 months. There were shorter operation time, less injury, satisfactory postoperative Bohler angle and calcaneal width in treatment group compared with control group,which reduced the medial neurovascular injuries, and the plate was easily removed after fracture healing. CONCLUSION: Full thread cancellous screws and plate fixation for the treatment of calcaneal fractures could get same therapeutic effects as compress screws and plate of self broken type fixation, and also has follow advantages: shortening the operation time, reducing blood loss, easily to be removed, avoiding the medial neurovascular damage, reducing the incidence of complications. PMID- 23678762 TI - [Effect of Jingang Jiangu pill (see text) on expression of integrin beta1 and alphavbeta3 in ovariectomized osteoporosis model rats]. AB - OBJECTIVE: To investigate the regulatory effect of Jingang Jiangu pill (see text, JGJG) on expression of integrin in ovariectomized rats. METHODS: Fifty ovariectomized 10 months old female rats were randomly divided into 5 groups: Fushanmei group (FSM), Jingang Jiangu pill (see text) group (JGJG), Gusongbao granule group (GSB), Model group (OVX), Sham group. After ovariectomized,the rats were raised in the same environment for 13 weeks. The rats in JGJG group took 0.13 g JGJG pill orally each day for each rat; the rats in GSB group took 0.86 g GSB granule orally each day for each rat; the rats in FSM group took 0.28 mg FSM orally each day for each rat; and the rats in OVX and sham groups took sodium. The treatment duration of rats in above 5 groups was 13 weeks. Bone mineral density (BMD) and the expression of integrin beta1 and alphavbeta3 were detected in each group after the treatment. RESYKTS: The BMD and the expression of integrin beta1 in FSM group, JGJG group and GSB group improved obviously than that of OVX group. There were statistical difference between these groups (P<0.05). The expression of integrin alphavbeta3 of the three treating groups significantly depressed. CONCLUSION: The JGJG pill improves BMD and express of integrin beta1, in ovariectomized rats and reduces express of integrin alphavbeta3 through the regulation of the coupling of osteoblasts and osteoclasts. PMID- 23678763 TI - [Influence of serum containing Liuwei Dihuang decoction (see text) on proliferation of osteoblasts under stretch-stress environment]. AB - OBJECTIVE: To study influence of serum containing Liuwei Dihuang decoction (see text) on proliferation and differentiation of osteoblast form neonatal SD rats cultured in vitro at different times and different stretch stress. METHODS: After osteoblast cultured for 24 hours in the serum containing Liuwei Dihuang decoction (see text) and serum in control group, the 0.5 Hz frequency, 6% and 12% stretch stress were added. The MTT1 and the activity of ALP were measured at the 12th and 24th hours, and the data were analyzed. RESULTS: 1. In the environment of stretch stress to the frequency of 0.5 Hz, and stretched for 24 hours, the osteoblast was stimulated under elongation rate of 6% and 12%; the proliferation and differentiation of osteoblast was more active under elongation rate of 12% than that of 6%. 2. There were no stimulating effects on osteoblast proliferation and differentiation of serum containing Liuwei Dihuiang decoction (see text) acted on osteoblast cells of SD rats cultured in vitro for a shot time. CONCLUSION: Stretch stress environment can enhance osteoblast proliferation and differentiation cultured in vitro. PMID- 23678764 TI - [Sudden paralysis caused by pyogenic vertebral osteomyelitis with epidural abscess infected by MRSA: one case report]. PMID- 23678765 TI - [Anatomical study on the treatment of complex acetabular fractures with self designed 3-dimensional anatoimical locking plate]. AB - OBJECTIVE: To design a new 3-dimensional anatomical locking plate internal fixation on the basis of anatomic character of acetabulum for treating complex acetabular fractures except the posterior wall and posterior column fracture, and to investigate its advantages and disadvantages. METHODS: Five fresh adult cadavers and 40 biopsy specimens of pelvic cavity were collected. The length and radian of iliopectineal crest and pecten pubis,the distance from acetabular index to iliopectineal crest were measured to guide the research and development of the 3-dimensional anatomical locking plate internal fixation for complex acetabular fractures through the ilioinguinal approach or combined with Stoppa approach. RESULTS: The average lengths of iliopectineal crest of male and female were (54.12+/-5.42) mm and (58.24+/-6.60) mm;and the radians were (64.26+/10.28)degrees and(60.32+/-12.26)degrees. The lengths of bow pubic were(122.21+/-8.02) mm and(126.52+/-7.84) mm;and the radians were (66.24+/ 13.10)degrees and(63.25+/-12.10) degrees. The distance from acetabular index to iliopectineal crest of male and female were (18.6 + 2.2) mm and (18.9+/-2.5) mm. The 3-dimensional anatomical locking plate was used to treat compound acetabular fractures through ilio-inguinal groove incision or combined with Stoppa incision,including dislocated acetabular fractures at quadratic district,but not including paries posterior and columma posterior fractures. CONCLUSION: The self designed 3-dimensional anatomical locking plate internal fixation has the characteristics of operational convenience, accurate fixation, mini operational trauma,short operational time and low operational risk,therefore it is especially suit for the complex acetabular fractures except the posterior wall and posterior column fracture which is difficult to be solved by contentional internal fixation. PMID- 23678766 TI - [Total hip arthroplasty for crowe type IV developmental dysplasia of the hip with S-ROM prosthesis]. AB - OBJECTIVE: To develop the techniques of total hip arthroplasty(THA) for Crowe type IV developmental dysplasia of the hip (DDH) with S-ROM prosthesis,and to assess its clinical results. METHODS: From October 2000 to October 2011,30 patients (36 hips) with Crowe type IV DDH underwent THA,including 6 patients with bilateral hip involved and 24 patients with unilateral. S-ROM prosthesis was adopted together with subtrochanteric transverse osteotomy. All the cementless acetabular cups were placed at the original anatomic location. The threaded cups were put in or near the level of the true acetabulum in all patients. Full coating stems were used in femoral side. All the patients were evaluated by using the Modified Harris Hip Score. Radiographic evaluations were made preoperatively and during follow-up. RESULTS: Two patients lost of follow-up. Twenty-seven patients with 32 hips were followed up,and the average duration was 48 months (ranging from 7 to 84 months). There was 1 patient with bilateral THA died from hemorrhagic shock. Two patients could walk freely with the visible fracture lines at 12th and 18th months postoperatively. There were no complications such as infection or nerve injuries. Modified Harris Hip Score improved from preoperative 41.7+/-3.7 to postoperative 89.1+/-2.9. There was no acetabular or femoral component revision because of mal-position or loosening of the prostheses in all patients. Postoperative X-ray showed that all the prostheses in place,good integration between acetabular cups,femoral prosthesis and host bone without loosening. All bone grafts were integrated. All the hips acquired union of osteotomy and bone in-growth. None of the patients had radiographic evidence of aseptic loosening of prosthesis. CONCLUSION: For the complex DDH, follow methods should be used to improve therapeutic effects:good exposure of the true acetabulum,deepen acetabulum, femoral shortening, oblique osteotomy, using the S ROM prosthesis. PMID- 23678767 TI - [Internal fixation for the treatment of anteromedial facet fracture of the coronoid process of ulna]. AB - OBJECTIVE: To investigate the effect of operative treatment for anteromedial facet fracture of the coronoid process of ulna,and to study its surgical exposures and fixation techniques. METHODS: From March 2005 to March 2010,18 patients with anteromedial facet fracture of the coronoid process of ulna were treated with open reduction and internal fixation. There were 12 males and 6 females with an average age of 37.8 years. A single midline posterior incision was used to expose the entire elbow joint. After elevating the full-thickness skin flaps, a lateral incision was made to expose and repair the lateral collateral ligament. Three intervals in the flexor-pronator musculature were used to gain access to the coronoid,depending on the size of the fracture fragment and the planned fixation technique. Fractures were fixed by using mini-plate or with screws. The therapeutic effects were evaluated by Mayo Elbow Performance Score (MEPS) and system of Broberg & Morrey. RESULTS: Seventeen patients were followed up, no patient complained pain and elbow unstable at a mean follow-up period of 38 months(1 to 6 years). The fractures were clinically healed at an average time of 11.6 weeks(ranged from 8 to 16 weeks). The average MEPS was 95.4+/-4.6 (ranged, 82 to 100). The average functional rating of system of Broberg & Morrey was 92.3+/-5.8 (ranged,75 to 100). CONCLUSION: Open reduction and internal fixation is effective to reach anatomical reduction and strong fixation for the treatment of anteromedial facet fracture of the coronoid process of ulna. PMID- 23678768 TI - [Analysis of the causes of X-ray misdiagnosis of avascular femur head necrosis]. AB - OBJECTIVE: To study the cause of X-ray misdiagnosis of the avascular femur head necrosis, so as to reduce the misdiagnosis rate and raise the early diagnosis level. METHODS: The clinical and X-ray data of 99 patients(123 hips) with avascular femur head necrosis diagnosed by MRI were analyzed retrospectively. Among the patients, 56 patients were male and 43 patients were female,ranging in age from 21 to 84 years old,with an average of 53 years old. The patients had symptoms such as hip pain,functional restriction in flexion, adduction, abduction and internal rotation,and some patients had limping. The duration of the disease ranged from 1 week to 2 years. RESULTS: Among 99 patients(123 hips),46 patients(52 hips) was misdiagnosed by the X-ray, the misdiagnosis rate was 42.27%, 100.00% in 0 stage, 100.00% in I stage, 83.67% in II stage, 18.18% in II stage, 0.00% in IV stage, 0.00% in V stage; the X-ray stage was negatively correlated with the rate of misdiagnosis. The careless film-reading and invigorating large enterprises while relaxing control over small ones was the main reason of misdiagnosis,then the lack of clinical histories and low-quality of X-ray projection. CONCLUSION: The relevant clinical history and comprehensive careful film-reading is the key to reduce the rate of misdiagnosis. PMID- 23678769 TI - [Clinical treatment of diabetes mellitus complicated with chronic osteomyelitis]. AB - OBJECTIVE: To investigate treatment methods for diabetes complicated with chronic osteomyelitis. METHODS: The clinical data of 39 diabetic patients with chronic osteomyelitis from 2000 to 2011 were studied. Among the patients, 23 patients were male and 16 patients were female,ranging in age from 21 to 81 years old,with a mean of 45 years old. All the patients had symptoms such as red,swelling,hot and pain to different degrees,and the duration of the disease lasted over more than 3 months,among which,25 patients had preoperative sinus formation. Routine preoperative drainage fluid culture, X-ray and CT examination were performed. Twenty-seven patients underwent debridement, one stage bone grafting and external fixation; 12 patients underwent debridement and antibiotic treatment. The examination results of ESR, CRP and blood routine before and after treatment were compared to evaluate clinical effects. RESULTS: After treatment, the values of ESR(preoperative 35 patients with higher value, and postoperative 32 patients with normal value), blood routine (preoperative 25 patients with abnormal value,and postoperative 23 patients with normal value), and CRP(preoperative 36 patients with higher value, and postoperative 33 patients with normal value) all improved. The liquor puris cultures were negative after treatment. Among 39 patients, 33 patients had clinical cure; 6 patients recurred within 4 months to 4 years. CONCLUSION: The treatment of diabetes should be paid attention when the chronic osteomyelitis was treated,and the combination treatment can significantly improve the cure rate of diabetes complicated with chronic osteomyelitis. PMID- 23678770 TI - [Mental and behavioral abnormalities after arthroplasty and incomplete cerebral fat embolism]. AB - OBJECTIVE: To investigate the relationship between mild consciousness and mental disorders after arthroplasty and incomplete cerebral fat embolism. METHODS: A retrospective analysis of 12 patients with incomplete cerebral fat embolism after arthroplasty was performed from June 2004 to December 2011. There were 5 males and 7 females,ranging in age from 36 to 82 years old,averaged 56.8 years old. Four patients had femoral neck fractures; 3 patients had avascular necrosis of the femoral head; 3 patients had rheumatoid arthritis; 1 patient had ankylosed hip and 1 patient had knee osteoarthritis. The patients had consciousness and mental disorders after arthroplasty (femoral head replacement in 3 cases, total hip replacement in 7 cases, and knee joint surface replacement in 2 cases), changes of vital sign and abnormal brain MRI examination. RESULTS: Twelve patients had mild consciousness and mental disorders,and the NIHSS score was 1.92+/-3.78,which was correlated with incomplete cerebral fat embolism after arthroplasty. The patients recovered conscious within 24 to 72 hours after treatment with expansion of blood volume,dehydrating agent and neuroprotective drugs,improving respiratory and circulatory function, hormone protection and antibiotic application. The patients were followed up with a mean period of 18 months (ranging from 10 to 36 months). The patients had neurological function recovering to normal without sequelae, and the NIHSS score decreased to 0. CONCLUSION: Incomplete cerebral fat embolism after arthroplasty is the main reason causing mild awareness and mental disorders, which is often to be misdiagnosed or ignored because of not typical clinical manifestations. PMID- 23678771 TI - [Recent advances in X-ray observation index of hallux valgus and their applications]. AB - X-ray measurement is one of the most important methods for diagnosing hallux valgus. To choose the right photographed way and the proper X-ray observation index has important significance on accurate diagnosis and correct treatment. As the in-depth research on the pathogenesis and pathological changes of hallux valgus,more new X-ray measuring methods and index have appeared. X-ray in the weight-bearing and non-weight-bearing position, dorsoplantar radiograph, lateral radio-graph, oblique radiograph and sesamoid radiograph can be taken. Many observation index can be chosen,including angles, distances,the position of sesamoid et al,can be used to evaluate deformity degree before surgery and curative effect after surgery. The following is a summary of the international and domestic recent researches about X-ray observation index of hallux valgus and their applications. PMID- 23678773 TI - Charting a course for the development of ACN. PMID- 23678772 TI - [Research on repair strategies for articular cartilage defects]. AB - Articular cartilage damage is very common in clinical practices. Due to the low self-healing abilities of articular cartilage, the repair strategies for articular cartilage such as arthroscopic lavage and debridement,osteaochondral or chondrocytes transplantation, tissue engineering and hydrogel based artificial cartilage materials are the primary technologies of repairing articular cartilage defect. In this paper,the main repair strategies for the articular cartilage damage and the advantages or disadvantages of each repair technology are summarized. The arthroscopic lavage and debridement is successful in treating the early stage of osteoarthritis. Osteochondral and chondrocytes transplantation are beneficial to treat small full thickness defects. The technology of tissue engineering becomes a new method to heal articular cartilage damage, but the major problem is the absence of bonding strength between the implants and natural defect surfaces. Hydrogel based artificial cartilage possesses similar bio mechanical and bio-tribological performances to that of natural articular cartilage. However, both bioactivity and interfacial bonding strength between the implant and natural cartilage could be further improved. How to simultaneously optimize the mechanical and bioactive as well as biotribological properties of hydrogel based materials is a focus problem concerned. PMID- 23678774 TI - Response to editorial: Meeting the needs of rural and regional families: educating midwives. PMID- 23678775 TI - Response to editorial: Meeting the needs of rural and regional families: educating midwives. PMID- 23678776 TI - Response to editorial: Meeting the needs of rural and regional families: educating midwives. PMID- 23678777 TI - Response to editorial: Meeting the needs of rural and regional families: educating midwives. PMID- 23678778 TI - Response to editorial: Meeting the needs of rural and regional families: educating midwives. PMID- 23678779 TI - Response to editorial: Meeting the needs of rural and regional families: educating midwives. PMID- 23678780 TI - Exploring resilience in paediatric oncology nursing staff. AB - Resilience has been suggested as an important coping strategy for nurses working in demanding settings, such as paediatric oncology. This qualitative study explored paediatric oncology nurses' perceptions of their development of resilience and how this resilience underpinned their ability to deal with work related stressors. Five paediatric oncology nurses were interviewed about their understanding of the concept of resilience, their preferred coping mechanisms, and their day-today work in paediatric oncology. Using thematic analysis, the interviews were subsequently grouped together into seventeen initial themes. These themes were then grouped into seven major aspects that described how the participants perceived resilience underpinned their work. These "seven aspects of forming resilience" contributed to an initial understanding of how paediatric oncology nurses develop resilience in the face of their personal and professional challenges. Several key strategies derived from the findings, such as improved rostering, support to a nurse's friend and family, and a clinical support nursing role, could be implemented at an organizational level to support resilience development within the paediatric oncology setting. PMID- 23678781 TI - The use of physical assessment skills by registered nurses in Australia: issues for nursing education. AB - The purpose of pre-service nursing education programs is to prepare competent graduates who are able to function as safe, professional registered nurses. An extensive element of these programs is the teaching of physical assessment skills, with most programs educating students to perform over 120 such skills. Previous research from North America suggests that the majority of skills taught to nurses in their pre-service programs are not used in practice. As part of a larger study, an online survey was used to explore use of 121 physical assessment skills by Australian nurses. Recruitment occurred via mailed invitation to members of the Australian Nursing Federation. Data were extracted from 1220 completed questionnaires returned by nurses who were mostly employed in New South Wales, were female and experienced nurses. Respondents indicated that they used only 34% of skills routinely. Results reinforce evidence found in the literature that many of the skills taught to nurses are either not used at all (35.5%) or are used rarely (31%). These findings have implications for the teaching of physical assessment skills in pre-service nursing programs, and raise questions about the value of extensive skills teaching in the context of contemporary health care. Further research into barriers to the use of physical assessment skills in nursing and the need for comprehensive skills preparation for the generalist nurse is likely to offer some solutions to these questions. PMID- 23678782 TI - How acceptable are primary health care nurse practitioners to Australian consumers? AB - International evidence indicates that nurses working in primary care can provide effective care and achieve positive health outcomes for patients similar to that provided by doctors. Nurse practitioners employed in primary health care perform some tasks previously exclusive to the GP role due to their advanced skills, knowledge and training. In November 2010 Medicare provider rights and Pharmaceutical Benefits Scheme rights were provided for nurse practitioners working in private practice, and in collaboration with a medical practitioner. However, there is limited evidence about how acceptable nurse practitioners are to Australian consumers and what knowledge consumers have of the nurse practitioner role in the delivery of primary health care. The aim of this study was to examine Australian health care consumers' perceptions of nurse practitioners working in primary health care. This paper reports on the results of seven focus groups (n = 77 participants) conducted around Australia. Focus groups participants were asked how acceptable nurse practitioners are as provides of primary health care. Although there was some confusion about the role of nurse practitioners and how this role differed from other primary health care nurses, participants in the focus groups were very positive about nurse practitioners and would find them acceptable in providing primary health care. PMID- 23678783 TI - Barriers to providing school-based health care: international case comparisons. AB - BACKGROUND: This article reports on an international collaborative study which compared school-based health care in the United States of America, Canada and Australia. METHOD: Tri-nation school-based health care was compared and contrasted through the utilisation of a series of interpretive case studies. Grounded theory approaches informed the data analysis and reporting processes. FINDINGS: Unlike the US, Canadian and Australian school students rarely have access to school-based health care on site. All three nations face structural, cultural and societal barriers, often related to limited resources which limit the effectiveness of school-based health care. DISCUSSION: The benefits of school based health care and providing comprehensive services through schools can include healthier children, better learning, healthier parents, and healthier communities. Unfortunately, based on our research, comprehensive school health services have not been adequately implemented in the US, Canada or Australia. IMPLICATIONS FOR PRACTICE: Given the findings of this study, increased comprehensive school-based health services are urgently needed in the US, Canada and Australia. PMID- 23678784 TI - Complementary health therapies: moving towards an integrated health model. AB - BACKGROUND: There is increasing use of complementary and alternative medicines (CAMs), particularly amongst patients with cancer. This paper aims to better understand the types of CAM people are using and explore the reasons for using these approaches. This paper will also identify what patients want from health professionals in relation to CAM and the actions and attitudes of health professionals towards CAM. Finally, this paper will discuss the potential implications for health services. METHOD: Two surveys were conducted, a self administered survey was completed by oncology patients; and a second online survey completed by staff. RESULTS: Patients used CAM as an adjunct to services they receive from conventional health services, not as an alternative. The positive and empowering role that complementary health practices play in people's lives was a common theme as was the need for CAM to be used with care. Survey responses by health care staff revealed mixed views of CAM. Most staff had positive views about CAM as a treatment adjunct and said they responded to patients accordingly. Only a minority expressed scepticism and were less inclined to support CAM use by their patients. Nevertheless, few staff instigated discussions around CAM. CONCLUSION: This paper presents key considerations for health services wanting to better respond to CAM and adopt an integrated approach to health care. PMID- 23678785 TI - Accidental insider: living the PhD study. AB - This paper explores the concept of 'insider' and 'outsider' and the challenges involved in conducting research when the researches finds themself living the phenomenon under study. Recent literature has been drawn on to explain the context of the 'insider' and 'outsider' in regard to the stance of the researcher. This is followed by an overview of the personal experiences of the author. The advantages and disadvantages of being an insider within the context of the phenomenon of study are discussed along with the challenges and implications for a researcher 'living their PhD research'. PMID- 23678786 TI - Cancer care coordinator: promoting multidisciplinary care--a pilot study in Australian general practice. AB - AIM: We hypothesised that patients treated for breast cancer would benefit from targeted therapeutic action delivered by general practitioners on the recommendations of a multidisciplinary team based in primary care. METHODS: Patients scheduled for follow-up visits at a hospital surgical clinic were invited to complete a self-administered care needs assessment and be interviewed by a breast care nurse. Members of the multidisciplinary team discussed the audio recorded interviews within 2 weeks. The team made recommendations for each patient, which were presented to the general practitioner as a suggested 'care plan'. Health status information was collected via the Short Form 36 and Anxiety and Depression data via the Hospital anxiety and Depression Scale at recruitment and 3 months later. RESULTS: Among the 74 women who were invited to participate, 21 were recruited over a 6-month period (28%), 19 of whom completed the study (90%). The mean age was 55 years (range 38-61 years) and the mean time in follow up was 23 months (range 16-38 months). The team identified a median of three problems per patient (range 2-7) and made an average of two recommendations per patient for referral to an allied health professional (range 0-5). At 3 months, 17 women had attended their general practitioner, 11 of whom felt their condition had improved as a result of the intervention. There was no significant change in Short Form 36 or Hospital Anxiety and Depression Scale score after the intervention. CONCLUSIONS: Primary care-based multidisciplinary review of treated breast cancer patients is feasible and, for most, results in benefit. However, only a minority of eligible patients participated in this pilot study and the logistics of organising the reviews warrants careful consideration. PMID- 23678787 TI - The politics of information: informed consent in abortion and end-of-life decision making. AB - The politics of reproduction dominate the political landscape now more than ever. One area of controversy has been informed consent statutes for abortion, which have been praised by the pro-life movement but derided by the pro-choice movement. More recently, legislatures have begun to enact informed consent statutes with respect to end-of-life decision making, an area almost as politically controversial as abortion. Like many abortion disclosure laws, some of these have been entitled "Right to Know" statutes. Yet, the supporters and opponents of each set of statutes tend not to be the same, aligning to a large extent based on their place in the culture wars over life and death. In this Article, I strive not only to show the remarkably similar critiques each side marshals but also to use these concerns to think in more nuanced ways about the goals of informed consent and whether the disclosure mandates achieve those goals. I first argue in favor of the aspirational goals of informed consent as a process that allows patients to participate in their medical decision making. While conceding the inherently political nature of abortion and end-of-life care, I also contend that the significance of decisions regarding those matters warrants, at least in theory, legislative efforts to ensure that patients have the opportunity to engage in deliberative and informed decision making. In describing and responding to the similar critiques of both sets of laws--the political bias of the statutes; the efforts to persuade, especially with non medical information; the potential vulnerability of the targeted audience; and the interference with physician discretion--I uncover and challenge some of the presumptions about informed consent inherent in those critiques. Although information that persuades or influences is not per se problematic, I argue that disclosure of information that is inaccurate, untrue, or emotionally inflammatory harms informed consent. Even well-crafted informed consent mandates, however, are insufficient to promote truly deliberative decision making because they oversimplify the complexity of these decisions and fail to respond to the fact that informed consent is a process that requires more than simply the delivery of information; it also requires dialogue and discussion. This Article ends with suggestions for ways to try to promote such a dialogue. PMID- 23678788 TI - Retiree out-of-pocket healthcare spending: a study of consumer expectations and policy implications. AB - Even though most American retirees benefit from Medicare coverage, a mounting body of research predicts that many will face large and increasing out-of-pocket expenditures for healthcare costs in retirement and that many already struggle to finance these costs. It is unclear, however, whether the general population understands the likely magnitude of these out-of-pocket expenditures well enough to plan for them effectively. This study is the first comprehensive examination of Americans' expectations regarding their out-of-pocket spending on healthcare in retirement. We surveyed over 1700 near retirees and retirees to assess their expectations regarding their own spending and then compared their responses to experts' estimates. Our main findings are twofold. First, overall expectations of out-of-pocket spending are mixed. While a significant proportion of respondents estimated out-of-pocket costs in retirement at or above expert estimates of what the typical retiree will spend, a disproportionate number estimated their future spending substantially below what experts view as likely. Estimates by members of some demographic subgroups, including women and younger respondents, deviated relatively further from the experts' estimates. Second, respondents consistently misjudged spending uncertainty. In particular, respondents significantly underestimated how much individual health experience and changes in government policy can affect individual out-of-pocket spending. We discuss possible policy responses, including efforts to improve financial planning and ways to reduce unanticipated financial risk through reform of health insurance regulation. PMID- 23678789 TI - A time to step in: legal mechanisms for protecting those with declining capacity. AB - Current estimates approximate that the population over sixty-five years of age will increase from 40 million in 2010 to 72.1 million by 2030. As society ages, the number of elderly with cognitive deficits that impair decision-making abilities will also increase. This will place additional burdens on families and probate courts seeking to balance individual autonomy with necessary protections. A legal determination of incompetency is a prerequisite to a judicial order appointing a guardianship or other protective mechanism. The current legal medical model for competency determinations fails to reflect the complexities of declining capacity in an aging population. A global structure for competency determinations leaves a critical gap between competent and incompetent. The gap between competence and incompetence not only raises concerns about how to classify those that fall between the two, but also highlights the lack of legal protections for those within the gap. A revised model is needed to provide protections to individuals who do not yet meet the threshold for incompetence but require additional protections for their personal or financial welfare. This Article provides an unprecedented examination of the legal model for determining competence through a comparison of the medical model for evaluating capacity. While a number of legal scholars have examined the appointment and oversight of guardians, fewer articles have critically examined the process by which individuals are declared incompetent. This Article presents a comprehensive overview of competency and clinical capacity determination procedures, legal mechanisms available to protect individuals with declining capacity, and policy recommendations for improving legal protections in light of inefficiencies related to legal competency determinations. PMID- 23678790 TI - Am I liable? The problem of defining falsity under the False Claims Act. PMID- 23678791 TI - Metabolites from the aerial parts of the Sicilian population of Artemisia alba. AB - Phytochemical investigation of the CH2Cl2 extract of the aerial parts of Artemisia alba Turra afforded one new irregular sesquiterpenoid, artemiric acid, and five known metabolites: hydroxydavanone, the coumarins isofraxidin and scopoletin, (6S*, 7S*,10R*)-6,10 -dimethyl-7,10-epoxyocta-11-enoic acid and artalbic acid. From the MeOH extract three flavonoids were identified: chrysoeriol, quercetin and isorhamnetin. The possible biogenetic pathways of artemiric and artalbic acids are discussed. PMID- 23678792 TI - New bioactive secondary metabolites from Bornean red alga, Laurencia similis (Ceramiales). AB - A Bomean red algal population of Laurencia similis Nam et Saito was analyzed for its secondary metabolite composition. Seven compounds were identified: ent-1(10) aristolen-9beta-ol (1), (+)-aristolone (2), axinysone B (3), 9-aristolen-1alpha ol (4), 2,3,5,6-tetrabromoindole (5), 1-methyl-2,3,5,6-tetrabromoindole (6), and 1-methyl-2,3,5-tribromoindole (7). Compound 1 was identified as a new optical isomer of 1(10)-aristolen-9beta-ol. Compounds 1, 4 and 5 exhibited good antibacterial activity against antibiotic resistant clinical bacteria and cytotoxic effects against selected cancer cell lines. PMID- 23678793 TI - A new bioactive sesquiterpenoid quinone from the Mediterranean Sea marine sponge Dysidea avara. AB - Investigation of the marine sponge Dysidea avara, family Dysideidae, afforded a new sesquiterpene (-)-N-methylmelemeleone-A (5), in addition to four known sesquiterpenes (+)-avarol (1), (+)-avarone (2), (-)-3'-methylaminoavarone (3) and (-)-4'-methylaminoavarone (4). The structure elucidation of compound 5 was based on 1D and 2D NMR spectroscopic, and HR-MS studies, as well as by comparison with the literature. Cytotoxicity, proteinkinase inhibition, inhibition of NFkB activity and insecticidal activity were evaluated for the isolated compounds. PMID- 23678794 TI - An efficient oxyfunctionalization of quinopimaric acid derivatives with ozone. AB - An access to oxyfunctionalized quinopimaric acid derivatives is reported. The ozonolysis of methyl dihydroquinopimarate occurs through 1,2-cycloaddition of ozone to the bridging double bond followed by intermolecular rearrangements and formation of nontrivial 4beta-hydroxy-4alpha,14alpha-epoxy-13(15)-ene derivative 2. The oxidation of methyl furfurilydene dihydroquinopimarate with ozone led to anhydride 5 and unexpected carboxymethyl substituted cyclopentane lactone 6. The structure of compound 6 was confirmed by X-Ray analysis of its methyl ester. PMID- 23678795 TI - Plants from northeast Mexico with anti-HSV activity. AB - Based on chemotaxonomic and ethno-pharmacological criteria, three Mexican plants (Jatropha dioica, Salvia texana and S. ballotaeflora) were studied for in vitro activity against HSV-1 and HSV-2. Hydro-methanolic extracts were initially evaluated for their toxicity to Vero cells. Both Salvia species displayed cytotoxicity at the lowest dose (125 microg/mL). The J. dioica extract showed only negligible cytotoxicity (CC50 644 microg/mL). Its anti-HSV activity was evaluated using the plaque reduction assay with HSV-1 and HSV-2 (from clinical isolates) infected Vero cells. The hydro-methanolic extract of J. dioica showed IC50s of 280 and 370 microg/mL against HSV-1 and HSV-2, respectively. The n hexane liquid-liquid partition of J. dioica extract contained the majority of the active principle(s) with IC50 values of 300 and 270 microg/mL for HSV-1 and HSV 2, respectively. Bioassay-guided isolation led to the known diterpene, riolozatrione. PMID- 23678796 TI - The true identity of the triterpene component of Wyethia mollis, a lanosta-diene containing a tetrahydropyran E-ring. AB - The crystal structure of a triterpene component of Wyethia mollis has been obtained and compared with the previously reported structure of the compound. The compound in the crystal structure, lanosta-8,24-dien-3-one, 16,23-epoxy-(161beta, 23R), (1), is different from the previously reported compound, but has identical NMR and mass spectrometric data. The revised structure contains a tetrahydropyran E ring, a structural moiety rare in steroid triterpenes. PMID- 23678797 TI - Structures and biological activities of typicosides A1, A2, B1, C1 and C2, triterpene glycosides from the sea cucumber Actinocucumis typica. AB - Five new minor triterpene glycosides, typicosides A1 (1), A2 (2), B1 (3), C1 (4) and C2 (5), along with two known glycosides, intercedenside A and holothurin B3, have been isolated from the sea cucumber Actinocucumis typica. Structures of the glycosides were elucidated by 2D NMR spectroscopy andMS. Glycosides 1-5 are linear mono- and disulfated tetraosides differing from each other in both aglycone structures and monosaccharide composition of the carbohydrate chains. Typicosides A1 (1) and A2 (2) have identical monosulfated carbohydrate moieties with a xylose residue as the third monosaccharide unit and differ from each other in aglycon structures. Typicoside B1 (3) has glucose as the third monosaccharide residue. Typicosides C1 (4) and C2 (5) contain the same disulfated carbohydrate chains and differ from each other in structures of aglycone side chains. Antifungal activity of glycosides 1-5 against three species of fungi along with cytotoxic activity against mouse spleen lymphocytes and mouse Ehrlich carcinoma cells (ascite form), as well as hemolytic activities against mouse erythrocytes have been studied. All new glycosides, except for typicoside C1 (4), containing a hydroxy-group in the aglycone side chain, demonstrate rather strong hemolytic and cytotoxic activities. PMID- 23678798 TI - Preparation and application of reversed phase Chromatorotor for the isolation of natural products by centrifugal preparative chromatography. AB - A method of preparation of rotors with a reversed phase (RP) solid silica gel sorbent layer has been developed for centrifugal preparative chromatography (CPC), also known as rotational planar chromatography (RPC). The rotors consist of binder free RP solid SiO2 layers of different thicknesses packed between two supported circular glass discs and can be used in any appropriate device for centrifugal chromatography, like Chromatotron and CycloGraph. Polar and /or semi polar compounds with close R(f) values, as well as extracts and column fractions were separated and/or purified in a preparative and/or semi-preparative scale using the RP rotors, eluted with mixtures of aqueous-based solvents. We herein report three examples of its application, using RP Chromatorotors, for the isolation of the diastereoisomeric alkaloids banistenosides I and II from Banisteriopsis caapi, saponins III and IV from Fagonia cretica, and the sesquiterpenes artemisinin (V) and artemisinic acid (VI) from Artemisia annua. PMID- 23678799 TI - Chemical constituents of the leaves of Dracaena thalioides. AB - Two new furostanol bisdesmosides (1 and 2) and seven known compounds (3-9) were isolated from the leaves of Dracaena thalioides (Agavaceae). The structures of the new compounds were determined on the basis of spectroscopic data and the results of hydrolytic cleavage. The isolated compounds were evaluated for cytotoxic activity against HL-60 human promyelocytic leukemia cells. Compound 5, a glyceroglycolipid-related compound assigned as (2S)-1-O-linoleoyl-3-O-beta-D galactopyranosylglycerol, was found to induce apoptotic cell death in HL-60 cells with an IC50 value of 25.8 microM. PMID- 23678800 TI - 7-Oxodioscin, a new spirostan steroid glycoside from the rhizomes of Dioscorea nipponica. AB - Nine glycosides of spirostan (1-7) and furostan (8 and 9) type steroids including a new compound, 7-oxodioscin (1), were isolated from the rhizomes of Dioscorea nipponica. The structure of 1 was established as (25R)-3beta-O-[(alpha-L rhamnopyranosyl-(1 --> 4)-O-[alpha-L-rhamnopyranosyl-(1 --> 2)]-beta-D glucopyranosyl)oxy]spirost-5-en-7-one by extensive spectroscopic techniques including HRESI-TOFMS, 1D and 2D NMR, and chemical methods. Known compounds were elucidated as dioseptemloside G (2), (25R)-dracaenoside G (3), orbiculatoside B (4), dioscin (5), progenin III (6), gracillin (7), (3beta3,22alpha,25R)-26-(beta D-glucopyranosyloxy)-22-methoxyfurost-5-en-3-yl O-[alpha-L-rhamnopyranosyl-(1 - 4)]-beta-D-glucopyranoside (8), and methylprotodioscin (9). PMID- 23678802 TI - GC-MS investigation of Amaryllidaceae alkaloids in Galanthus xvalentinei nothosubsp. subplicatus. AB - A GC-MS analysis of alkaloids in the aerial parts and bulbs of Galanthus xvalentinei nothosubsp. subplicatus was performed for the first time. Totally, twenty-six alkaloids were identified, of which tazettine and galanthindole were the major ones. Acetylcholinesterase inhibitory activity of the alkaloidal extracts was determined using modified in vitro Ellman's method. Significant anticholinesterase activity was observed in the tested samples (bulbs: IC50 = 21.3 microg/mL, aerial parts: IC50 = 16.3 microg/mL). PMID- 23678801 TI - Two spirostan steroid glycoside fatty esters from Dioscorea cayenensis. AB - Two new fatty acid-spirostan steroid glycoside esters, progenin III palmitate (1) and progenin III linoleate (2), were isolated from the MeOH extract of Dioscorea cayenensis rhizomes. The extract also yielded seven previously known spirostan and furostan steroid glycosides (3-9). The structures of the new compounds were established as (25R)-spirost-5-en-3beta-yl O-alpha-L-rhamnopyranosyl-(1 --> 2)-[6 O-palmitoyl]-O-beta-D-glucopyranoside (1) and (25R)-spirost-5-en-3beta-yl O-alpha L-rhamnopyranosyl-(1 --> 2)-[6-O-linoleoyl]-O-beta-D-glucopyranoside (2) by chemical and spectroscopic methods, including 1D and 2D NMR. The known compounds were identified as progenin III (3), dioscin (4), deltonin (5), asperin (6), gracillin (7), protodioscin (8)], and methyl protodioscin (9). PMID- 23678803 TI - Antifouling indole alkaloids from two marine derived fungi. AB - In order to find non-toxic antifouling natural products from marine microorganisms, the chemical constituents of two marine derived fungi Penicillium sp. and Aspergillus sydowii have been investigated under bio-guided fractionation. A new indolyl diketopiperazine compound, penilloid A (1), together with 15 known ones were isolated from these two strains. The structure of 1 was elucidated on the basis of NMR and mass spectra. Some alkaloids showed significant antifouling and antibacterial activities. The results indicate that indole alkaloids could be a potential antifouling agent resource. PMID- 23678804 TI - Andrographidine G, a new flavone glucoside from Andrographis paniculata. AB - A new flavone glucoside, andrographidine G (1), was isolated from Andrographis paniculata together with 13 known compounds, including flavonoids, diterpenoids, and iridoids. The structure of 1 was established by spectroscopic and spectrometric techniques, including HR-ESI-TOF-MS, 1D and 2D NMR, and chemical methods. The known compounds were identified as andrographidine A (2), (2R)-5 hydroxy-7,8-dimethoxyflavanone-5-O-beta-D-glucopyranoside (3), acanthoside B (4), neoandrographiside (5), andropanoside (6), andrographiside (7), andrographolide (8), 14-deoxy-11,12-didehydroandrographiside (9), 14-deoxy-11,12 didehydroandrographolide (10), procumbide (11), procumboside (12), 6-epi-8-O acetylharpagide (13), and curvifloruside F (14). PMID- 23678805 TI - Geranyl flavonoids from Robinia pseudoacacia. AB - A new geranyl flavonol, robipseudin A (1), and a known geranyl flavone, kuwanon S (2), were isolated from the leaves of Robinia pseudoacacia. The structure of the new compound was determined by spectroscopic methods. Compounds 1 and 2 showed moderate antioxidant activities in the DPPH radical scavenging assay. PMID- 23678806 TI - Antibacterial activity against Ralstonia solanacearum of phenolic constituents isolated from dragon's blood. AB - Ralstonia solanacearum is a worldwide and devastating plant pathogen infesting over 200 host species. Synthetic bactericides against the pathogen have only achieved limited success and always cause both crop contamination and environmental pollution. However, natural bactericides are effective for protecting cultivated crops from destruction by disease, without the adverse effects of chemical bactericides. In this paper, fifteen phenolic constituents from dragon's blood were screened for their antimicrobial activity against Ralstonia solanacearum, and all exhibited inhibitory activity. These compounds are potential leading compounds for the development of bactericides against wilt diseases caused by Ralstonia solanacearum. PMID- 23678807 TI - Interaction of dihydromyricetin and alpha-amylase. AB - The interaction of dihydromyricetin (DMY) and alpha-amylase was investigated. The complex formed between DMY and alpha-amylase resulted in decreased antioxidant activity of DMY and the catalytic activity of the enzyme, as well as efficient quenching of the intrinsic fluorescence of alpha-amylase. An alpha-amylase molecule provides one binding site for a DMY molecule. These results will be useful for exploiting this compound to combat diseases efficiently. PMID- 23678808 TI - Effect of the isoflavone genistein on tumor size, metastasis potential and melanization in a B16 mouse model of murine melanoma. AB - The isoflavonoid genistein, the aglycone of the heteroside genistin, possesses preventive effect on coronary heart disease and osteoporosis, antioxidant, anthelmintic, antineoplastic and anti-inflammatory properties. Much research has been undertaken regarding the action of genistein on cancer-preventing/treating effects, especially on breast and prostate cancer. The aim of this study was to analyze the effect of this compound in vivo by observing tumor size, metastasis potential and melanization in a mouse model of murine melanoma, employing the B164A5 melanoma cell line and C57BL/6J mice. Genistein decreased the tumor volume and weight by approximately 30%. Non-invasive measurements for both melanin and erythema showed that genistein reduced the quantity of melanin and the degree of erythema in direct proportion to the number of days of treatment. HE analysis diagnosed malignant melanoma in both groups, but no metastasis was recorded in the treated group compared with the liver metastasis in the untreated group after a period of 15 days of experiment at a dose of 15 mg/kg body weight of genistein. Genistein showed beneficial effects regarding tumor size, metastasis potential and melanization in a B16 mouse model of murine melanoma. PMID- 23678809 TI - Quantitative analysis of total flavonoids and total phenolic acids in thirty Hypericum taxa. AB - The content of total flavonoids and total phenolic acids in the aerial parts of thirty Hypericum taxa collected over two consecutive seasons was investigated by spectrophotometric methods. All taxa examined contained flavonoids and phenolic acids in different quantities, although the differences between species and year's harvest were not found to be significant. The quantity of total flavonoids ranged from 0.1 to 1.6%. The highest content of flavonoids was found in the samples of H. japonicum (1.6%) and H. perforatum (1.5%), while the samples of H. androsaemum and H. balearicum comprised the lowest flavonoid amount (0.13%). The content of total phenolic acids in the investigated samples was found to be between 1.1-10.4%. The samples of H. perforatum were found to contain the highest quantity of phenolic acids (10.4% and 10.2%), whereas the sample ofH. linarifolium showed the lowest amount of phenolic acids (1.1%). PMID- 23678810 TI - New diarylheptanoids and a hydroxylated ottelione from Ottelia alismoides. AB - Ten new diarylheptanoids (2, 3, 4, 5a-d, 6, 7, and 8) have been isolated from an extract of Ottelia alismoides. The structures of these previously unknown metabolites were determined by NMR spectroscopic analysis. A previously unknown, hydroxylated analog of the known otteliones A and B (1a and 1b)--namely, 3a hydroxyottelione (13)--was also isolated. The 1H NMR analysis of the Mosher esters of alcohols derived from otteliones A and B (S-17/R-17 and S-20/R-20) are also reported. PMID- 23678811 TI - Evaluation of the in vivo anti-inflammatory and analgesic and in vitro anti cancer activities of curcumin and its derivatives. AB - Curcumin, obtained from turmeric, has several biological properties to make it a desirable template for drug development. A lipophilic derivative of curcumin, diacetyl curcumin (DAC) and a hydrophilic derivative, diglutaryl curcumin (DGC) were synthesized and their in vivo analgesic and anti-inflammatory activities were compared with those of curcumin and aspirin. The in vitro anti-cancer activities of curcumin and the two derivatives against three cell cancer lines were compared with those against a non-cancerous cell line. The inhibitory effects were comparable to each other and nearing that of curcumin while they showed low inhibitory effect towards the non-cancerous cell line. The mouse tail flick assay showed that curcumin, DAC and DGC increased latency time. DGC was most effective as an analgesic, even more so than aspirin. The maximum percentage effect (MPE) was highest with DGC at 3 hours. The carrageenan induced paw edema model indicated anti-inflammatory activity of all three curcumin formulations. The percentage inhibition of paw edema was maximum for DAC, followed by aspirin and curcumin. PMID- 23678812 TI - Chemical constituents from Dendropanax dentiger. AB - Nineteen compounds and an HPLC inseparable mixture, composed of compounds 20 and 21, were isolated from the leaves and twigs of Dendropanax dentiger (Harms ex Diels) Merr. Of these, syringin (1) is the most abundant, 6'-O-apiofuranosyl dendranthemoside A (16) is a new megastigmane glycoside, and 3-methoxy-D-mannono 1,4-lactone (21) is a new hexono-1,4-lactone. Their structures were elucidated based on NMR spectroscopic and MS analyses. PMID- 23678813 TI - Six new phenolic glycosides and a new ceramide from the flowers of Wedelia biflora and their cytotoxicity against some cancer cell lines. AB - The plant Wedelia biflora has been used in traditional medicine in India and Vietnam to treat various symptoms. However, the chemical composition of its flowers remains mostly unknown. Therefore, we now report the isolation and structural elucidation of six new phenolic glycosides {wedebicoside A - F (1-6)} and one new ceramide [wedebiceramide (9)], together with six known compounds, 1-O (2',4'-diangeloyloxy-beta-D-fucopyranosyl)-6-hydroxythymol (7), 1-O-[2',4' diangeloyloxy-3'-(3"-angeloyloxy-beta-D-fucopyranosyl)-beta-D-fucopyransyl]-6 hydroxythymol (8), anhydrosecoisolariciresinol (10), friedeline (11), epifriedelanol (12) and stigmasterol (13) from the flowers of Wedelia biflora. Their structures were established by 1D and 2D NMR spectroscopy, as well as by high resolution ESI-MS analysis and comparison with literature data. The cytotoxic activities against HeLa, MCF-7 and NCI-H460 were evaluated on some purified compounds at the concentration of 100 microg/mL. Compounds 1, 2, 3 and 5 showed strong cytotoxic activities against three surveyed cancer cell lines. Consequently, this study elucidated the phytochemical composition of W. biflora, as well as the potential use of some of the new compounds against some cancers. PMID- 23678814 TI - Antimicrobials from the marine algal endophyte Penicillium sp. AB - An endophytic fungus identified as Penicillium sp. was isolated from the brown alga Fucus spiralis collected from the Shetland Islands, United Kingdom. Bioassay guided fractionation of an extract of the fungus led to the isolation of cladosporin, epiepoformin, phyllostine, and patulin, all of which showed antimicrobial activity against either Staphylococcus aureus or Pseudomonas aeruginosa. Cladosporin has not previously been identified from a fungus of the genus Penicillium, and, despite being biosynthetically related, epiepoformin, phyllostine and patulin have not been previously reported from one source. PMID- 23678815 TI - Antioxidant and cytoprotective effects of an ethanol extract of Acalypha wilkesiana var. macafeana from Malaysia. AB - In the annals of biomedical theory perhaps no single class of natural product has enjoyed more ingenious speculation than antioxidants formally aimed at counteracting oxidative insults which are involved in the pathophysiology of Alzheimer's and Parkinson's disease, cancer, amyotrophic lateral sclerosis, skin ageing and wound healing. In pursuing our study of Malaysian traditional medicines with antioxidant properties, we became interested in Acalypha wilkesiana var. macafeana hort., used traditionally to heal wounds. To examine whether Acalypha wilkesiana var. macafeana hort. could suppress oxidation an ethanol extract was tested by conventional chemical in vitro assays i.e., ferric reducing antioxidant potential assay (FRAP), DPPH scavenging assay and beta carotene bleaching (BCB) assay. To explore whether Acalypha wilkesiana var. macafeana hort. protected cells against oxidative injuries, we exposed human hepatocellular liver carcinoma (HepG2) cells to tert-butylhydroperoxide (t-BHP). In all the aforementioned experiments, the ethanol extracts elicited potent antioxidant and cytoprotective activities. To gain a better understanding of the phytochemical nature of the antioxidant principle involved, five fractions (F1 F5) obtained from the ethanol extract were tested using FRAP, DPPH and BCB assays. Our results provided evidence that F5 was the most active fraction with antioxidant potentials equal to 2.090 +/- 0.307 microg/mL, 0.532 +/- 0.041 microg/mL, 0.032 +/- 0.025 microg/mL in FRAP, DPPH and BCB assay, respectively. Interestingly, F5 protected HepG2 against t-BHP oxidative insults. To further define the chemical identity of the antioxidant principle, we first performed a series of phytochemical tests, followed by liquid-chromatography and mass spectrometry (LC/MS) profiling which showed that the major compound contained in F5 was geraniin. To the best of our knowledge, this is the first report showing that the wound healing property of Acalypha wilkesiana var. macafeana hort. is mediated by a geraniin containing extract. Furthermore, our data leads us to conclude that geraniin could be used as a potential pharmaceutical and/or cosmetic topical agent. PMID- 23678816 TI - A new antimicrobial and anticancer peptide producing by the marine deep sediment strain "Paenibacillus profundus" sp. nov. Sl 79. AB - A new linear glyceryl acid derived heptapeptide (1), together with known isocoumarin antibiotic, Y-05460M-A (2), were isolated from the culture of the deep sea sediment strain SI 79 classified as "Paenibacillus profundus" sp. nov. Their structures were determined by 1D- and 2D- NMR techniques and ESI-MS/MS experiments. HPLC analysis of the Marfey derivatives in comparison to their analogs of authentic amino acids revealed that all amino acids in peptide 1, with an exception of Val, have the D-configuration. The compound 1 showed inhibitory activity against Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, Enterococcus faecium as well as cytotoxic and moderate colony growth inhibitory activity against SK-MEL-28 cell line. PMID- 23678817 TI - Potential applications for Annona squamosa leaf extract in the treatment and prevention of foodborne bacterial disease. AB - Foodborne disease is a major public health problem. The present study examined Annona squamosa leaves, which are traditionally used to treat diarrhea and other infections, for their potential to be used in modern food safety or medicine. Active constituents were partially purified by ethanol extraction and column chromatography. MICs of the extract were 62.5 to 125 microg/mL against Bacillus cereus, Listeria monocytogenes and Staphylococcus aureus, and 250 microg/mL against Campylobacter jejuni. In time-kill assays, 500 microg/mL of the extract reduced colony forming unit numbers of C. jejuni almost 10 000-fold within 12 hours. Similar decreases were seen against B. cereus, but over a longer time frame. LC-MS analysis indicated the presence of reticuline and oxophoebine. Assessment of stability by MIC assay showed activity was heat-labile, with loss of activity greatest following high temperature treatments. Activity was relatively stable at refrigeration temperature. These results indicate A. squamosa has broad-spectrum but heat-labile activity against foodborne bacterial pathogens, and bactericidal activity against B. cereus and C. jejuni. This bactericidal activity is not sufficiently rapid for A. squamosa to be used as a food sanitizer, but the extract could potentially be developed as an additive for refrigerated foods, or a modern treatment for foodborne illness. PMID- 23678818 TI - Genoprotective effect of the Chinese herbal decoction xiao jian zhong tang. AB - The Chinese herbal decoction formula Xiao Jian Zhong Tang (XJZT) is one of the classic formulas from the classic traditional Chinese medicine (TCM). Previous studies on XJZT found that it is effective for treating peptic ulcer, irritable bowel syndrome, functional gastroenteritis and similar psychosomatic disorders of the digestive organs. It has also been shown that all the herbs used in XJZT contain antioxidants. In this study, we investigated the in vitro DNA protection effect of the individual herb extracts and the whole formula. Water extract of the herbs and XJZT were used to pre-treat human lymphocytes. The lymphocytes were then exposed to hydrogen peroxide. The in vitro DNA protection effect of the herbs was investigated by comet assay. No DNA protective effect (P < 0.05) was found for individual herb extracts, but XJZT showed protection of human lymphocytic DNA upon oxidative stress (P < 0.05). The in vitro DNA protection effect of XJZT was conferred by the synergistic effect of the herbs, while the individual herbs had no such effect. PMID- 23678819 TI - Effect of nine plant volatiles in the field on the sex pheromones of Leguminivora glycinivorella. AB - Attraction of the soybean pod borer, Leguminivora glycinivorella (Matsumura), an economically important pest of soybean, to nine plant volatiles, alone or combined with two kinds of synthetic sex pheromone, ((E,E)-8,10-dodecadienyl acetate (EE8,10-12:Ac), or a blend of EE8,10-12:Ac and (E)-10-dodecenyl acetate in a 10:1 ratio), was evaluated in field trapping experiments in a soybean field in Harbin, China. By themselves, the plant volatiles (dose) linalool (0.1 mg), (Z)-3-hexenyl acetate (0.1 mg), and geraniol (0.1 mg, 1.0 mg) were weakly attractive to L. glycinivorella males, but significantly reduced mean catches when higher doses were combined with pheromones. Conversely, (E)-2-hexenal, benzaldehyde, and phenylacetaldehyde were not attractive to L. glycinivorella males at any dose tested, but significantly increased mean catch when certain doses were combined with the binary pheromone blend. Other plant volatiles, such as (Z)-3-hexen-1-ol, (Z)-3-hexenyl acetate, and (E)-2-hexenyl acetate, were unattractive on their own, but significantly reduced mean catch of L. glycinivorella males when certain doses were combined with the pheromones. These results suggest that efficacy of pheromone-baited traps for survey and monitoring of L. glycinivorella male moths may be enhanced by the addition of specific plant volatiles and that the relative dose is critical. PMID- 23678820 TI - Induction of defensive response in Eucalyptus globulus plants and its persistence in vegetative propagation. AB - The expression of defensive compounds derived from secondary metabolism in plants of Eucalyptus globulus Labill, and the persistence of these in vegetative propagation was evaluated by gas chromatography with flame ionization (GC-FID) and mass spectrometry (MS). The plants were induced by attack from the insect Ctenarytaina eucalypti ("blue gum psyllid") and by mechanical damage. Defense responses were activated in plants for the different types of tested induction. We identified four defensive compounds present in the leaves of plants induced in entomological form (beta-terpineol, aromadendrene, caryophyllene-oxide and eremophilene); all remained in the vegetative propagation. After mechanical induction, we identified three compounds (beta-terpineol, aromadendrene and ledol), of which ledol and aromadendrene persisted in the vegetative propagation. Virtually all the compounds detected, in addition to persisting in the vegetative propagation, showed specificity for the induction type, whether entomological or mechanical, except for aromadendrene, which was expressed in both types of induction. PMID- 23678821 TI - Chemical composition of the essential oil of Baccharoides lilacina from India. AB - The essential oil composition from the aerial parts of Baccharoides lilacina (Dalzell & A. Gibson) M. R. Almeida was analyzed by gas chromatography (GC) and gas chromatography/mass spectrometry (GC/MS). A total of 41 compounds have been identified, representing 97.4% of the total oil. The main constituents were identified as beta-caryophyllene (27.7%), epi-alpha-cadinol (25.1%), caryophyllene oxide (9.9%), alpha-muurolol (7.6%), alpha-cadinene (6.1%) and alpha-cadinol 4.5%). The oil was found to be rich in oxygenated sesquiterpenes (47.1%) and sesquiterpene hydrocarbons (46.2%). PMID- 23678822 TI - Chemical composition and anti-Trypanosoma cruzi activity of essential oils obtained from leaves of Xylopia frutescens and X. laevigata (Annonaceae). AB - Essential oils from leaves of Xylopia frutescens (XFMJ) and two specimens of Xylopia laevigata (XLMC and XLSI) were obtained by hydrodistillation using a Clevenger-type apparatus, and analyzed by GC-MS and GC-FID. Sesquiterpenes dominated the essential oils. The main constituents of XFMJ were (E) caryophyllene (24.8%), bicyclogermacrene (20.8%), germacrene D (17.0%), beta elemene (7.9%), and (E)-beta-ocimene (6.8%). XLMC contained significant quantities of germacrene D (18.9%), bicyclogermacrene (18.4%), beta-elemene (9.5%), delta-selinene (9.2%), (E)-caryophyllene (8.5%), germacrene B (5.7%) and gamma-muurolene (5.7%), while germacrene D (27.0%), bicyclogermacrene (12.8%), (E)-caryophyllene (8.6%), gamma-muurolene (8.6%), delta-cadinene (6.8%), and germacrene B (6.0%) were the main components of XLSI. The essential oils had trypanocidal activity against the Y strain of Trypanosoma cruzi, with IC50 values lower than 30 microg x mL(-1) and 15 microg x mL(-1) against epimastigote and trypomastigote forms of T. cruzi, respectively, and were also able to reduce the percentage in vitro of T. cruzi-infected macrophages and the intracellular number of amastigotes at concentrations that were non-cytotoxic to macrophages. PMID- 23678823 TI - Chemical composition and biological activities of the essential oil from Artemisia herba-alba growing wild in Tunisia. AB - Aromatic plants can interfere in the Mediterranean ecosystem, mainly by the introduction in the environment of volatile compounds. For this reason, we studied the chemical composition and the possible phytotoxic and antimicrobial activities of the essential oil extracted from leaves of Tunisian Artemisia herba alba Asso. The chemical composition of the essential oil, obtained by hydrodistillation, was analyzed by GC and GC-MS. In all, 24 compounds were identified. The main components were camphor (39.1%), chrysanthenone (15.0%) and cis-thujone (7.8%). The essential oil was evaluated for its in vitro phytotoxic activity against germination and initial radical growth of Raphanus sativus L., Lepidium sativum L., Sinapis arvensis L., Triticum durum L. and Phalaris canariensis L. seeds. The radicle elongation of the five seeds was affected to different extents by the oil, while germination was not affected. The oil, when tested against eight selected bacterial strains, showed low antimicrobial activity. The chemical composition of the oil of A. herba-alba can help in the chemosystematics of this complex genus. However, the recorded biological activities seem to be neither ecologically nor medicinally significant. PMID- 23678824 TI - Aloe ferox seed: a potential source of oil for cosmetic and pharmaceutical use. AB - Aloe ferox is an important medicinal plant in Southern Africa whose seeds could be useful as a source of oil. The fatty acid composition of A. ferox seed oil was determined using gas chromatography. The physicochemical properties of the oil were analysed using standard methods. The seeds yielded 19.4% of a light textured oil using the Blight and Dyer's method and 12.3% using the Soxhlet extraction method. The saponification value of the seed oil was 241.9 mg KOH/g and the peroxide value was 8.9 meq/kg. The acid value of the seed oil was 51.5 mg KOH/g (25.9% free fatty acids). The major fatty acids found in the seed oil were linoleic acid (71.8%), oleic acid (12.0%), palmitic acid (11.2%) and stearic acid (2.9%). The results obtained suggest that as A. ferox seed oil is high in linoleic acid, it could be potentially exploited in the cosmetic and pharmaceutical industries. PMID- 23678825 TI - Therapeutic effects of glycyrrhizic acid. AB - Glycyrrhizic acid (GA), belonging to a class of triterpenes, is a conjugate of two molecules, namely glucuronic acid and glycyrrhetinic acid. It is naturally extracted from the roots of licorice plants. With its more common uses in the confectionery and cosmetics industry, GA extends its applications as a herbal medicine for a wide range of ailments. At low appropriate doses, anti inflammatory, anti-diabetic, antioxidant, anti-tumor, antimicrobial and anti viral properties have been reported by researchers worldwide. This review summarizes the effects of GA on metabolic syndrome, tumorigenesis, microbes and viruses, oxidative stress, and inflammation, as well as the reported side effects of the drug. PMID- 23678826 TI - Natural products of mineral origin. AB - Natural products of mineral origin (alum, bismuth, calcium, magnesium, silicates and zinc compounds) have maintained their popularity as drugs over the course of time. Some evidence still suggests potential benefit of these substances. Therefore, this paper reviews the characteristic features of the respective minerals and their salts along the course of studies on these products. PMID- 23678827 TI - Review of Journal "Medical Archives" in 2012. PMID- 23678828 TI - Alpha lipoic acid and glycaemic control in diabetic neuropathies at type 2 diabetes treatment. AB - INTRODUCTION: Diabetes mellitus is a metabolic, chronic and incurable disease which reduces span and quality of life. Over 50% of diabetic patients have clinical manifestations of diabetic neuropathy. AIM: To show a positive influence of alpha lipoic acid on clinically manifested diabetic neuropathy symptoms as well as the effect of alpha lipoic acid in patients glycaemic control. MATERIAL AND METHODS: Testing has been conducted in Cantonal Hospital"Irfan Ljubijankic MD" in Bihac and included 20 diabetes type 2 patients who were diagnosed with clinically manifested diabetic neuropathy. All the patients' conditions were evaluated by: medical history, clinical parameters, detailed internal examination, laboratory analyses for glycaemic control assessment and mono filament test. They were treated with oral anti-diabetics and insulin as well as with alpha lipoic acid preparation in duration of four months. They were divided into two groups, with good (HbA1c < 7%) and poor (HbAc > or = 7%) glycaemic control. Medical control has been conducted four months after the research started. RESULTS: Twenty patients took part in the research, 7 male and 13 female. The average age of the patients was 58.6 in the first and 55.6 years in the second group. The average patients' disease duration was 13.4 +/- 6.6 years in the first and 11.2 +/- 5.4 years in the second group. The difference in gender, average age and disease duration in both groups statistically is not significant (p < or = 0.05). The number of negative points after the therapy has been reduced for 56.4% in the first and 43.1% for the second group (p < or = 0.05). Prior to the treatment, all the patients in both groups had paresthesia. At medical checkup, there were 40% less patients in the first group and 10% in the second one (p < or = 0.01). The difference is statistically significant (p < or = 0.05) in night pain occurrence between two groups of patients after alpha lipoic acid treatment (40% more patients had night pain in the second group after the treatment). The same number of patients in both groups, 40% had muscle atrophy and difficulty in walking. At medical checkup, 30% in first group and 20% less patients had discomforts (p > or = 0.05). Regression of subjective sensations in both groups of patients after alpha lipoic acid treatment has been noted. CONCLUSION: Alfa lipoic acid is an effective drug in the treatment of diabetic distal sensory-motor neuropathy and its therapeutic effect is more effective in patients with good glycaemic control. PMID- 23678829 TI - Intestinal amebiasis in a group of patients with ulcerative colitis: influence on clinical course of the disease. AB - INTRODUCTION: Ulcerative colitis (UC) is a common disease with a chronic and relapsing presentation requiring regular clinical follow up. Epidemiological and microbiologic studies suggest that enteropathogenic microorganisms play a substantial role in the clinical presentation and extent of inflammatory bowel disease. GOAL: To evaluate the presence of intestinal infections by Entamoeba hystolitica in patients with ulcerative colitis, their impact on clinical outcome, and to identify associated risk factors. MATERIAL AND METHODS: A total of 31 patients hospitalized on Gastroenterohepatology Department with patohystologically proved ulcerative colitis were studied. Fresh feces samples taken from 20 patients were examined immediately using Eosin and Lugol-staining methods and analyzing the presence of vegetative and MIFC (Meriolat and Iod staining). RESULTS: A total of 16 female and 15 male hospitalized UC patients were analysed in a period of two years (2010-2011). The mean age at diagnosis was 43 years. We analyzed relation of amoeba infection with localization of ulcerative colitis. Our results indicate that amoeba infection is related to extent of disease (they were mostly present in pancolitis). Presence of amoeba is not related to age nor gender. Furthermore, presence of amoeba was not associated with more severe clinical course of disease. Similarly, higher value of serum marker of inflammation was not associated with amoeba infection. DISCUSSION AND CONCLUSION: Amoeba infections in UC patients treated at Gastroenterohepatology Department was not related to the grade of disease activity, and other clinical variables such as gender, age and parameters of inflammation. These microorganisms could be a contributing cause of extended localization of disease. PMID- 23678830 TI - Etiology of bacterial meningitis in children in Tuzla Canton. AB - INTRODUCTION: Bacterial meningitis is one of the most serious infectious diseases in childhood. AIM: To identify the most common causes of bacterial meningitis in children in Tuzla Canton. PATIENTS AND METHODS: This is a retrospective study which included 140 children, aged from 1 month to 14 years, treated at the Clinic for Infectious Diseases Tuzla, in the period 1999-2009, who had clinical and laboratory parameters of bacterial meningitis. RESULTS: In Tuzla Canton in ten year period were registered 140 cases of bacterial meningitis in children aged 1 month to 14 years. Prevalence was 1.53/1000. The average age of patients was 3.6 +/- 3.8 years. Male to female ratio was 1.3:1. April, May and November were the months with the most reported cases of bacterial meningitis (p = 0.02). Most affected were children 1-12 months of age (p < 0.001). The most common pathogens of bacterial meningitis were Haemophilus influenzae (13.6%), Neisseria meningitides (8.6%) and Streptococcus pneumoniae (5.7%) (p < 0.001). Mortality was 2.14%. CONCLUSION: Bacterial meningitis is present in Tuzla Canton, and three major pathogens are Haemophilus influenzae, Neisseria meningitis and Streptococcus pneumoniae. The most affected were children 1-12 months of age, and most cases of bacterial meningitis occurred in spring. PMID- 23678831 TI - Causes of infectious acute diarrhea in infants treated at pediatric clinic. AB - AIM: The aim of this work has been a presentation of causes of acute infectious diarrhea. MATERIAL AND METHODOLOGY: The examinees have been the infants treated at the Pediatric Clinic. The diagnosis has been established on the basis ofanamnesis, physical examination and feces examination on bacteria, viruses, protozoa and fungi. RESULTS: During the period of seven years a number of patients that suffered from acute infectious diarrhea was 1050 (31.82%) out of a total number (3300) with diarrhea. The bacteriological examination proved positive on majority of them or in 655 (62.38%) cases, the viral examination proved positive in 375 (35.72%) cases, whereas fungi examination proved positive in only 3 cases (0.28%). The most frequent bacteria have been Salmonellae species in 255 (38.93%) cases and E. coli in 142 (21.69%) cases, the less frequent have been Yersinia enterocolitica in 16 (2.44%) cases and Bacillus cereus in 4 (0.61%) cases. The most frequent serotypes of Salmonella have been S. Wien in 92 (36.07%) and S. Gloucester in 42 (16.47%) cases. Enteropathogenic E. Coli (most frequent serotypes O111 and O55) has been found in 112 (78.88%) cases. From the group of Shigella the most frequent has been Sh. Flexneri (most frequent serotypes 6 and 4) in 35 (58.33%) cases. The same feces sample of the majority of examinees 501 (76.48%) cases contained only one bacteria (single bacteria), two bacteria (associated bacteria) have been found in 102 (15.17%) cases, three types of bacteria have been found in 17 (2.59%) cases. Rotavirus has been isolated in 271 (72.26%) cases in comparison to adenoviruses that have been isolated in 65 (17.33%) cases. Rotavirus and adenoviruses have been isolated in 39 (10.40%) cases. CONCLUSION: Infectious acute diarrhea appears frequently, and as causes of it usually appear to be pathogenic bacteria in comparison to viruses, protozoa and fungi. PMID- 23678832 TI - Correlation between hyperprolactinemia, MRI of hypophysis and clinical presentation in infertile patients. AB - The aim of the study was to investigate symptoms of hyperprolactinemia such as oligomenorrhea, amenorrhea, galactorrhea, and correlation between hyperprolactinemia and MRI of hypophysis in infertile women. MATERIAL AND METHODS: During the 10 years period, we have studied 87 patients investigated for infertility causes and with hyperprolactinemia findings, in our patients we have controled the serum prolactin levels, performed MRI of hypophysis, evaluated menstrual cycle disturbances and galactorrhea. Patients were between 20-43 of age. RESULTS: MRI of hypophysis confirmed prolactinoma (microadenoma) in 75.86% of our patients, while 24.14% had a normal MRI. Galactorrhea was demonstrated in 56.32% of patients. Oligomenorrhoea occured in 25.29%, and secondary amenorrhea in 14.94% of patients with hyperprolactinemia and infertility. The results show statistically significant difference in the average findings of serum prolactin levels on the day 8 and 21 of menstrual cycle in patients with or without microadenoma. CONCLUSIONS: Menstrual cycle disturbancies (oligomenorrhea and secondary amenorrhea) in patients with hyperprolactinemia and infertility occured in 40.33% of patients. We have noted statisctically significant correlation between the serum prolactin levels on the day 8 of menstrual cycle and the microadenoma size, which was not found on the 21 day of menstrual cycle. PMID- 23678833 TI - Prevalence of Mycoplasma hominis and Ureaplazma urealyticum among women of reproductive age in Albania. AB - AIM: The aim of our study was to assess the prevalence of Mycoplasma Hominis (MH) and Ureaplasma Urealyticum (UU) among infertile women and women who had abortion in the first trimester in Albania. METHODS: Our study included 150 women of reproductive age hospitalized at the Obstetric-Gynecologic University Hospital "Mother Geraldine" in Tirana during the period 2011-2012. All women were tested for the presence of MH and UU. In addition, data on the age of women, age of the first intercourse, number and type of abortion, number of births, and number of sexual partners were collected. RESULTS: The overall prevalence of MH was 30.4%, whereas the prevalence of UU was 54.3%. The prevalence of MH and/or UU was the highest among women who had experienced spontaneous abortions (P = 0.02 and P = 0.04, respectively), women who reported more than one abortion (P = 0.02 for both), women with more than one sexual partner (P = 0.01 and P = 0.02, respectively), and women who reported early first (before the age of 18 years) sexual intercourse (P = 0.03 and P = 0.05, respectively). CONCLUSION: Our findings indicate a high prevalence of both MH and UU in Albanian women seeking specialized Obstetric-Gynecologic care in Tirana. We conclude that for each case of spontaneous abortion it should be carried out the analysis of MH and UU. Conversely, among infertile women, the testing for MH and UU is recommended in the absence of another confirmed etiologic factor. PMID- 23678834 TI - The frequence of renal cell carcinoma in population of patients with kidney tumors. AB - INTRODUCTION: A kidney tumor is an abnormal growth within the kidney that usually occurs over a period of a time. Each tumor has its own characteristics and it is important to know what tumor the patient has so that the proper treatment can be administered. Kidney tumors can be benign or malignant. Symptoms of all types of kidney tumors are very similar and unspecific. The aims of study: a) To determine how many patients, who were clinically and radiologically diagnosed with kidney tumor, after surgical intervention, have histopathologicaly confirmed renal cell carcinoma; b) To compare number of female and male patients have histopathologicaly confirmed renal cell carcinoma; c) To compare numbers of patients with renal cell carcinoma who are older than 50 years with the ones who are younger than 50 years; d) To determine the most common risk factors for renal cell carcinoma; e) To determine the most common symptoms of renal cell carcinoma; f) To determine what was the most common stage of kidney cancer in the time when it was histopathologicaly confirmed. MATERIAL AND METHODS: This study was observational, descriptive, retrospective study of renal cell carcinoma. The study consisted of 28 patients who were clinically and radiologically diagnosed with kidney tumor, which was surgically removed and histopathologicaly tested. All patients were surgically treated at the Urological Clinic of Clinical Centre University of Sarajevo from 1/1/2012 to 06/30/.2012. RESULTS: from 28 patients with a kidney tumor 26 had RCC, the most of patients with RCC were older than 50 years (22 patients), there was 7 female and 19 male patients, the most common symptom was pain (10 patients), the most common risk factor, excluding age, was hypertension (11 patients), patients with RCC was usually diagnosed stage 4 Fuhrman (11 patients). CONCLUSION: Doctors should give their intention to discover early symptoms of renal cell carcinoma and to do preventive exams and tests in the population of patients who have one or more risk factors for developing this disease. Early diagnose and appropriate therapy could reduce mortality and morbidity of the patients with renal cell carcinoma, and could also reduce costs of treatment. PMID- 23678835 TI - Ophthalmologists' awareness of informed consent and their compliance to its requirements. AB - INTRODUCTION: Healthcare providers' awareness of laws governing medical documents and patients' health-related information is essential in securing the patients' rights. Given the existing legal problems in documentation of medical record of Consent and Acquittal, we decided to perform an investigation examining the levels of ophthalmologists' awareness of legal requirements for medical record of consent and acquittal and how they complied with such requirements at Feiz Teaching Hospital, Isfahan in the year 2011. METHODOLOGY: This research is an applied, descriptive-analytic one. The research population for awareness measurement includes attending ophthalmologists at Feiz Hospital. Filled-in consent record forms recorded in medical document were used to examine the levels of compliance with legal requirements governing medical record of consent and acquittal. Sampling among the attending ophthalmologists was performed using consensus which included 14 ophthalmologists. The files were samples using the statistical formula, resulting in a sample of 303 files. Data collection tools included a questionnaire and a check list. The questionnaire's reliability was estimated through Cronbach's alpha calculation (0.8); and the check list was completed through a survey among professors of Health Information Technology Management department. In a first step, investigators handed a questionnaire containing 12 items to the ophthalmologists in order to assess their levels of awareness from legal Aspects of medical Informed consent and acquittal, and received the completed questionnaire after answering their possible queries on the issue. In the next step the researchers went to the hospital and evaluated the levels of compliance with legal aspects of medical informed consent and acquittal within the files using a check list and by direct observation. Analytic statistics and SPSS software were used to analyze the data; and Pearson test was applied to evaluate the assumed relationship. The findings were descriptively analyzed, results of which are presented in scored tables (scores 0-50: undesirable; 51-81: relatively desirable; 81 and above: desirable). RESULTS: The ophthalmologists' level of awareness from legal aspects of informed consent and acquittal was 78.72% and their level of compliance with these requirements was 53.17%. There was a weak and reverse correlation between awareness and compliance (r = -0/187, P-value = 0/001). CONCLUSION: There is a significant association between the ophthalmologists' levels of awareness from legal aspects for obtaining informed consent and acquittal and the levels of their compliance with such requirements as seen in completed record of consent and acquittal; but there is low correlation between them. PMID- 23678836 TI - Ventriculoperitoneal shunt complications in a developing country: a single institution experience. AB - INTRODUCTION: Shunting a hydrocephalus is among the most commonly performed neurosurgical procedures. Hydrocephalus constitute a significant medical problem in terms of urgency and treatment. Shunting of cerebrospinal fluid has dramatically reduced the morbidity and mortality of hydrocephalus, but they have potential complications that may need multiple surgical procedures during a patient's lifespan. MATERIALS AND METHODS: We evaluated the following individual characteristics in relation to shunt complication rates: sex, ethnicity, age at the time of the first shunt placement (1 month [neonate], 1 to 12 months [infant], 1 to 18 years [child], 18 years [adult]), hydrocephalus type (spina bifida, congenital excluding spina bifida, communicating, obstructive) and socioeconomic status. In this retrospective study 193 patients were analyzed, unfortunately 27 where lost in the procedure of follow up and 12 died this patients were excluded from studies. RESULTS: Obstructive hydrocephalus (47.9%) was the most common diagnosis followed by communicating hydrocephalus (13.3%). Patients with ventriculoperitoneal shunt that were followed over time in 37% of cases experienced at least one surgical shunt complication during the study period and 13% of patients had multiple shunt complications. DISCUSSION: The causes for shunt malfunction include shunt infection, obstruction, distal catheter migration, shunt disconnection etc. Neonates and children experienced the highest complication rates. By 5 years of follow-up almost half of the children required a repeat surgical procedure. Children with obstructive hydrocephalus experienced the greatest risk of needing an initial shunt revision. CONCLUSION: Ventriculoperitoneal shunts constitute a significant medical problem, in terms of both urgency of treatment and economic costs. In conclusion, young infants are at highest risk for CSF shunt revision. PMID- 23678837 TI - Outcomes of ulnar nerve grafting. AB - INTRODUCTION: The ulnar nerve is a mixed motor and sensory nerve, which making nerve repair more difficult and functional recovery less predictable than pure sensory nerves. Recovery of muscle activity and restoration of sensibility are essential for a functional extremity. A nerve graft, if performed in a tensionless manner, has been shown to generally have better results than an end to-end approximation performed under tension. PATIENTS AND METHODS: In study period from 1993 through 2008, evaluation was performed in 48 patients with adequate follow-up. The mean follow-up period was 3.4 years (range, 24 months to 8.3 years). The average patient age was 32.4 years (range, from 6 to 71 years). There were 37 male patients and 11 female patients. RESULTS: We analyzed the effect of the age of the patient, level of injury, graft lenght and denervation time on motor and sensory recovery. Values of p < 0.05 were considered significant. Results of motor (chi-square = 8.04, p = 0.154) and sensory recovery (chi-square = 7.53, p = 0.184) were not significantly better in patients younger than 25 years compared to the group of patients older than 25 years. The level of the ulnar nerve injury had an impact on the outcome, with better results both sensory (chi-square = 161., p = 0.000) and motor recovery (chi-square = 238., p = 0.000) in patients with distal lesions. The results were significantly better in the group with graft lenght less than 5 cm compared to those longer than 5 cm for both sensory (chi-square = 72.6, p = 0.000) and motor recovery (chi-square = 196., p = 0.000). The functional results were significantly better for both sensory (chi-square 13.4, p = 0.020) and motor recovery (chi-square = 133., p = 0.000) in the group of patients with denervation time shorther than 6 months. CONCLUSION: The graft length, level of injury and denervation time significantly influenced the functional outcome in both motor and sensory recovery. Better results were in the patients in which the autograft length was up to 5 cm, in patients who were operated within six months from the injury and in patients with distal lesions. PMID- 23678838 TI - Mortality among third age patients with hip fracture and high cardiac risk. AB - INTRODUCTION: Mortality after hip fracture remains high in spite of the progress of medicine. Due to the trend toward longer life, the problem of hip fracture is getting more significant. The aim of this study is to determine the effects of surgical treatment in patients with high risk of hip fracture on mortality reduction. METHODS: In the retrospective-prospective study, 66 patients aged 65 92 with a hip fracture and a high cardiac risk have been analyzed. The risk estimation was based on the Lee index. The patients with three or more risk factors were considered high-risk. The first group consisted of surgically treated patients with a hip fracture and at high cardiac risk, and in the second group were conservatively treated patients with a hip fracture and high cardiac risk. RESULTS: In the group of conservatively treated patients, 75% were women and in operatively treated group 67.6%. Patient in both group are similar in relation to the participation of risk factor. A difference has been noticed in terms of renal insufficiency (RI). There was 18.8% conservatively treated patient with RI and 2.9% in operatively treated group. CONCLUSION: Patients with hip fracture and at high cardiac risk have lower mortality when treated surgically. PMID- 23678839 TI - The incidence of postoperative delirium in elderly patients after urologic surgery. AB - BACKGROUND: Postoperative delirium (POD) is a frequent postoperative disorder to the sick and elderly, and always has been associated with extended of day stay in hospital, and certainly more cost for the hospital as well. Additionally, delirium is associated with increased postoperative complications, longer length of stay, longer intensive care unit stay (ICU), and much higher rates of discharge to a nursing home. As a result, delirium adds significant cost to hospitalization and subsequent medical care. The delirium causes an increased mortality and an increasing of mental status deterioration characterized by reduction of environmental recognition as well as the disorder of alertness. The purposes of this study are: a) the effectiveness of routine screening of postoperative Delirium in the elderly using Confusion Assessment Method (CAM)). In those cases psychiatrists are not necessary; b) understanding of risk factors and strategies for prevention and treatment; c) understanding of the impact of this psychotic disorders in postoperative morbidity and mortality; d) recognition of the economic impact of these disorders in the health service; e) describing of the etiology and incidence of Delirium post-operative. MATERIAL AND METHODS: In this study are included 640 patients aged over 65 years who underwent an operation at the urologic clinic. This study is prospective and casual. Are excluded from the study all patients with psychological problems in admission and that were treated for these pathologies before admission in Urology Clinic. RESULTS: Are evaluated all the data taken from patients and from their examinations as: age, use of medications, symptoms and problems, biochemical and clinical balance, hemodynamic examination, and preoperative, intra operative and postoperative evaluations. Is observed that post operative Delirium occurred at 166 patients from 640 in total on the average of 26% of patients. Incidence was increased with increasing of age from 19% to 31%. CONCLUSION: Postoperative Delirium occurs as a result of the combination of several factors, not just those related to internal physiological age, but combining of these factors with the diseases which carries this age, with medications used for this age, with surgical stress, with biochemical imbalances, hemodynamic problems, and electrolytic disorders as well. PMID- 23678840 TI - Sexual dysfunction as a side effect of hyperprolactinemia in methadone maintenance therapy. AB - Although endocrine abnormalities are recognized in opiate users, very little is known about the range of hormones affected, their pathophysiology and their clinical relevance. various endocrine abnormalities have been reported in these patients including, increased prolactin levels and abnormalities in sexual hormone. Path physiological mechanism postulated does explain these findings including direct action of heroin or methadone at the hypothalamic pituitary level. The aim of this study was to explore the effects of heroin and methadone maintenance treatment on the plasma prolactin levels and sexual function. MATERIAL AND METHODS: We evaluated 20 male narcotic addicts maintained of methadone more than 3 years on oral high dose methadone 60-120 mgr/day. Patients taking neuroleptic therapy were excluded from the study because neuroleptic included hyperprolactinemia. We also evaluated group of twenty male heroin addicts on the street heroin .The prolactin plasma levels were assayed using the chemiluminescent immunometric essay (CLIA)--high sensitive methods. The normal range of prolactin levels was 1,5-17 ng/ml (53-360 nmol/l) for men and 1,90-25,0 ng/ml for women. The sexual function was assessed using a Questionnaire: International Index of Erectile Function (IIEF) with 15 items in four levels of sexual function. The differences between two examination groups were determined by a students t test. The results show that street heroin addicts (55% of them have high level of prolactin) have significantly higher plasma prolactin levels (p = 0.006) then the group of methadone maintenance patients (only 15% of them have high prolactin level). In our study, when we compared sexual dysfunction in examination groups in some domains, we did not find statistical significant results (sexual desire p = 0.52 and overall satisfaction p = 0.087). But in domains of erectile function p = 0.011 and orgasm function p = 0.033 we got statistical significant results. PMID- 23678841 TI - Job characteristic perception and intrinsic motivation in medical record department staff. AB - INTRODUCTION: Human resources are key factors in service organizations like hospitals. Therefore, motivating human recourses to achieve the objectives of an organization is important. Job enrichment is a strategy used to increase job motivation in staffs. The goal of the current study is to determine the relationship between job characteristics and intrinsic motivation in medical record staff in hospitals related to Medical Science University in Isfahan in 2011-2012 academic year. METHOD: The type of the study is descriptive and corelational of multi variables. The population of the study includes all the medical record staffs of medical record department working in Medical Science hospitals of Isfahan. One hundred twentyseven subjects were selected by conducting a census. In the present study, data collected by using two questionnaires of job characteristics devised by Hackman and Oldeham, and of intrinsic motivation. Content validity was confirmed by experts and its reliability was calculated through coefficient of Cronbach's alpha (r1 = 0.84- r2 = 0.94). The questionnaires completed were entered into SPSS(18) software; furthermore, statistical analysis done descriptively (frequency percent, mean, standard deviation, Pierson correlation coefficient,...) and inferentially (multiple regression, MANOVA, LSD). FINDINGS: A significant relationship between job characteristics as well as its elements (skill variety, task identity, task significance, autonomy and feedback) and intrinsic motivation was noticed. (p < or = 0.05). Also the results of multivariable regression showed that the relationship between job characteristic and intrinsic motivation was significant and job feedback had the most impact upon the intrinsic motivation. No significant difference was noticed among the mean amounts of job characteristic perception according to age, gender, level of education, and the kind of educational degree in hospitals. However, there was a significant difference among the mean amounts of job characteristic perception according to the unit of service and the years of servicein hospitals. CONCLUSION: The findings show that all job characteristics had positive effect upon intrinsic motivations and job feedback had the most effect on intrinsic motivation. Hence, it is necessary to take into account that job characteristics have a great role in changing the level of intrinsic motivation in the staffs. PMID- 23678842 TI - Reproductive risk of the silent carrier of Robertsonian translocation. AB - AIM: The aim of this study was the evaluation of risk among the couples various types of Robertsonian translocations. METHODS: Cytogenetic diagnosis has been carried out according to the Moorhead and Seabright method. RESULTS: Cytogenetics diagnosis was performed in 17 couples having Robertsonian translocations. Among our examined cases, the most frequent (82.3%) cases were with Robertsonian translocations formed by aberrant fusion between heterologous chromosomes 13q and 14q. Three out of seventeen couples affected with Robertsonian translocation 13q;14q suffered from primary infertility. The total number of pregnancy among the couples with Robertsonian translocation has been 45. Of these 80% of pregnancies resulted in spontaneous miscarriages, while 20% of others have gave birth to alive or dead children. In one couple a Robertsonian translocation was caused as a result of fusion of two homologous chromosomes 15q;15q. A patient with this translocation has had 7 pregnancies and all of them ended with abortions. CONCLUSION: Robertsonian translocation caused the primary infertility in three couples and lowering reproductive abilities in 14 others. Robertsonian translocation between 15q;15q caused intrauterine death and spontaneous failures of all pregnancies of the carrier with this translocation. PMID- 23678843 TI - Social exclusion as a determining health factor of the Roma population. AB - INTRODUCTION: Poverty, social inequality and marginalization of certain population groups cause the exclusion of these groups from the society and the benefits provided by the social relations of the community. GOAL: The goal of this study was to evaluate the characteristics of social exclusion of the Roma population in the local community and to determine how this exclusion affects the health status of the population. MATERIAL AND METHODS: Included-survey, medical examination and laboratory testing of full blood, blood glucose and markers of hepatitis B on 612 Roma. The data obtained are compared to those of the general population of the local community. RESULTS AND CONCLUSION: The social exclusion of the Roma population in the local community causes its significantly worse health status. Infectious diseases caused by poor hygienic conditions in Roma settlements and chronic diseases caused by stress, inadequate nutrition and poor housing conditions occur 5-20 times more frequently than in the general population. PMID- 23678844 TI - Patient access to electronic health record: a comparative study on laws, policies and procedures in selected countries. AB - INTRODUCTION: The e-health system must have the capability of patient access to electronic health record. The advantage of access to their record lets them have better understanding of their condition and treatment. It can also raise the reliability of consistency and correctness of data in health care system. Finally it will improve the maintenance quality of medical records and guarantee better results of medication. This study aimed to carry out a comparative study concerning laws, policies and procedures upon patients' access right to EHR in selected countries and to suggest appropriate solutions for Iran. METHOD: This was a comparative descriptive study. The study population was the laws, policies and procedures of patients' access right to EHR belong to countries like Canada, Australia, New Zealand and Iran. Data were collected by taking notes on index cards. In this study in order to collect data, at first, the researcher studied the websites related to Health Ministry of the countries and existing laws and policies through related links in the websites. In next step, the health information management association websites were studied and the related data were collected. The gathered data were analyzed through content analysis. RESULTS: The findings of research showed that in every four countries there are generally some laws, policies and procedures. Although Canada and New Zealand concerning the number of laws and policies related to the subject subsequently are ranked after Australia, they are ranked prior to Australia regarding benefiting the laws and specified policies. CONCLUSION: Given the necessity of EHR implementing and codifying the planning of SEPAS in Iran, as there is no specified laws or procedures regarding patients' access right to EHR, the obligation of paying attention to assigning a law or at least obvious policies and procedures and providing the details is absolutely apparent. PMID- 23678845 TI - Why some previous drug abuse preventive programs had low effectiveness? AB - INTRODUCTION: Considering the significant increase of drug abuse in national and international scopes, and the priority of the preventive programs (due to savings in cost and energy), this study aims to investigate the efficiency of drug abuse preventive programs. METHODS: This is an analytical-descriptive study, conducted in Iran on a sample of 600 individuals composed of academicians, experts, specialists, and officials. Verbal, individual interviews were performed based on a semi-structured interview-guide, and the resulted data was coded, categorized, and reported. RESULTS: The causes of lower effectiveness of previous preventive programs were as following: a) the features of preventive programs (37.7%): unsustainability, not matching the target group's characteristics, Lack of targeted programs, etc., b) sociocultural issues (19.79%): families, and society's unawareness, adverse social factors, etc. CONCLUSION: The drug abuse preventive programs are of significant importance. However, their efficiency and effectiveness are subjected to special requirements and considerations that if not met, results will not be achieved. PMID- 23678846 TI - Incarcerated Morgagni hernia in an octogenarian with incidental right-sided colonic malignancy. AB - We present an incarcerated Morgagni hernia in an octogenarian with incidental right-sided colonic malignancy who was admitted to clinic due to abdominal pain and symptoms of intestinal obstruction. An 85-old male patient had a history of constipation, abdominal distension, pain, vomiting, nausea and radiographic features of bowel obstruction and mediastinal mass in right lower chest. Under suspicion of acute intestinal obstruction due to transverse colon herniation in thorax through Morgagni foramen, emergent laparotomy was performed. Morgagni foramen was located on the right-sided anterior diaphragm and Morgagni hernia which contained of incarcerated transverse colon, greater omentum and 70 cm small bowel after releasing the adhesions was gently reduced. In the same time right sided colon malignancy was found. Morgagni foramen measuring 7 cm in diameter was sutured first and decompressive bypass ileocolic anastomosis was created. The role of emergent surgery, even in advanced age, is emphasized. PMID- 23678847 TI - Inevitable cesarean myomectomy following delivery through posterior hysterotomy in a case of uterine torsion. AB - BACKGROUND: Torsion of the pregnant uterus at term is a very infrequent obstetric event. It is usually associated with the presence of myoma or congenital deformities. Maternal prognosis is good after surgical treatment; however, prenatal mortality is high. CASE REPORT: We report a case of posterior low transverse hysterectomy in a case of uterine torsion at 38 weeks' gestation, due to a large myoma. At presentation, her cervix was unfavorable and cardiotocography showed spontaneous deceleration demanding delivery by cesarean section. Following delivery, it was realized that the incision had been made on the posterior wall of the uterus and that the uterus was axially rotated by 180 degrees. The mother recovered uneventfully and both mother and the baby were discharged on the fifth postoperative day. CONCLUSION: Obstetricians must have uterine torsion in mind when performing a cesarean section in patients with myomas. PMID- 23678848 TI - Anaortic technique in off-pump coronary artery bypass surgery. AB - INTRODUCTION: Techniques of coronary artery revascularisation on the beating heart have evolved with an attempt to reduce the potential deleterious effects of extracorporeal circulation. It is of particular value in those with a calcified or atheromatous ascending aorta. Total arterial revascularisation is ideal. CASE REPORT: We describe a case of 66 year-old male patient, previously suffered mild cerebrovascular incident, schedueled for myocardial revascularisation of double coronary disease with Left main stenosis. METHOD: Sternotomy was done in standard fashion. Both mamary artery were harvested and distal anastomoses were made in standard fashion by Prolen 8/0. For local stabilisation Medtronic Octopus vaccum stabiliser was used. DISCUSSION: Feasibility to perform arterial revascularistion by using off-pump aorta no-thouch techniqe (anaortic technique) on the patient previously suffered stroke and with increasd risk of the same complication was presented. This technique is recommended whenever technically feasible. PMID- 23678849 TI - Nanofluidic platform for single mitochondria analysis using fluorescence microscopy. AB - Using nanofluidic channels in PDMS of cross section 500 nm * 2 MUm, we demonstrate the trapping and interrogation of individual, isolated mitochondria. Fluorescence labeling demonstrates the immobilization of mitochondria at discrete locations along the channel. Interrogation of mitochondrial membrane potential with different potential sensitive dyes (JC-1 and TMRM) indicates the trapped mitochondria are vital in the respiration buffer. Fluctuations of the membrane potential can be observed at the single mitochondrial level. A variety of chemical challenges can be delivered to each individual mitochondrion in the nanofluidic system. As sample demonstrations, increases in the membrane potential are seen upon introduction of OXPHOS substrates into the nanofluidic channel. Introduction of Ca(2+) into the nanochannels induces mitochondrial membrane permeabilization (MMP), leading to depolarization, observed at the single mitochondrial level. A variety of applications in cancer biology, stem cell biology, apoptosis studies, and high throughput functional metabolomics studies can be envisioned using this technology. PMID- 23678850 TI - Brain haemosiderin in older people: pathological evidence for an ischaemic origin of magnetic resonance imaging (MRI) microbleeds. AB - INTRODUCTION: Magnetic resonance imaging (MRI) cerebral microbleeds (CMB) arise from ferromagnetic haemosiderin iron assumed to derive from extravasation of erythrocytes. Light microscopy of ageing brain frequently reveals foci of haemosiderin from single crystalloids to larger, predominantly perivascular, aggregates. The pathological and radiological relationship between these findings is not resolved. METHODS: Haemosiderin deposition and vascular pathology in the putamen were quantified in 200 brains donated to the population-representative Medical Research Council Cognitive Function and Ageing Study. Molecular markers of gliosis and tissue integrity were assessed by immunohistochemistry in brains with highest (n = 20) and lowest (n = 20) levels of putamen haemosiderin. The association between haemosiderin counts and degenerative and vascular brain pathology, clinical data, and the haemochromatosis (HFE) gene H63D genotype were analysed. The frequency of MRI CMB in 10 cases with highest and lowest burden of putamen haemosiderin, was compared using post mortem 3T MRI. RESULTS: Greater putamen haemosiderin was significantly associated with putaminal indices of small vessel ischaemia (microinfarcts, P < 0.05; arteriolosclerosis, P < 0.05; perivascular attenuation, P < 0.001) and with lacunes in any brain region (P < 0.023) but not large vessel disease, or whole brain measures of neurodegenerative pathology. Higher levels of putamen haemosiderin correlated with more CMB (P < 0.003). CONCLUSIONS: The MRI-CMB concept should take account of brain iron homeostasis, and small vessel ischaemic change in later life, rather than only as a marker for minor episodes of cerebrovascular extravasation. These data are of clinical relevance, suggesting that basal ganglia MRI microbleeds may be a surrogate for ischaemic small vessel disease rather than exclusively a haemorrhagic diathesis. PMID- 23678851 TI - Urinary incontinence and risk of functional decline in older women: data from the Norwegian HUNT-study. AB - BACKGROUND: The main objective of the present study was to determine whether UI is an independent predictor of ADL decline and IADL decline in elderly women. We also aimed to find out whether incontinent subjects were at higher risk of needing help from formal home care or home nursing care during 11 year follow-up. METHODS: A prospective cohort study conducted as part of the North-Trondelag Health Study 2 and 3. Women aged 70-80 years when participating in the HUNT 2 study, who also participated in the HUNT 3 study, were included in this study. Analyses on self-reported urinary incontinence at baseline and functional decline during a11-year period were performed for incontinent and continent subjects. RESULTS: Baseline prevalence of urinary incontinence was 24%. At on average eleven year follow up, logistic regression analysis showed a significant association between incontinence and decline in activities of daily living (ADL) (OR =2.37, 95% CI =1.01-5.58) (P=0.04). No association between urinary incontinence and instrumental activities of daily living (IADL) in incontinent women compared with continent women was found (OR=1.18, CI=.75-1.86) (P=.46). Data were adjusted for ADL, IADL and co morbid conditions at baseline. No significant differences in need of more help from formal home care and home nursing care between continent and incontinent women were found after 11 years of follow-up. CONCLUSIONS: Urinary incontinence is an important factor associated with functional decline in women aged 70-80 years living in their own homes. At eleven years of follow up, no significant differences in need of more help from formal home care and home nursing care between continent and incontinent women were found. PMID- 23678852 TI - Myelin imaging in amyotrophic and primary lateral sclerosis. AB - Primary lateral sclerosis (PLS) has been regarded as a rare, extreme form of amyotrophic lateral sclerosis (ALS). Like ALS, it is a clinical diagnosis without established biomarkers. We sought to explore loss of cerebral myelin in relation to clinical features, including cognitive impairment, in cases of both ALS and PLS. A novel MRI sequence (mcDESPOT) sensitive to water pools within myelin and intra- and extra-cellular spaces was applied to 23 ALS patients, seven PLS patients and 12 healthy controls, with interval follow-up in 15 ALS and four PLS patients. Results demonstrated that PLS patients were distinguished by widespread cerebral myelin water fraction reductions, independent of disease duration and clinical upper motor neuron burden. ALS patients showed a significant increase in intra- and extra-cellular water, indirectly linked to neuroinflammatory activity. Limited measures of cognitive impairment in the ALS group were associated with myelin changes within the anterior corpus callosum and frontal lobe projections. Longitudinal changes were only significant in the PLS group. In conclusion, in this exploratory study, myelin imaging has potential to distinguish PLS from ALS, and may have value as a marker of extramotor involvement. PLS may be a more active cerebral pathological process than its rate of clinical deterioration suggests. PMID- 23678853 TI - Theacrine, a purine alkaloid obtained from Camellia assamica var. kucha, attenuates restraint stress-provoked liver damage in mice. AB - Theacrine (1,3,7,9-tetramethyluric acid), a purine alkaloid, has proven to be beneficial in maintaining several brain functions and is being studied for potential medicinal uses in recent years. In this study, we isolated theacrine from Camellia assamica var. kucha and investigated its protective effects on liver damage induced by restraint stress in mice. Results showed that 18 h of restraint stress could induce liver damage, with an obvious increase in levels of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST). This finding was further confirmed by hepatic pathological examination, which showed inflammatory cell infiltration and focal necrosis of hepatocytes. However, oral administration of theacrine (10, 20, 30 mg/kg for 7 consecutive days) was found to decrease plasma ALT and AST levels, reduce hepatic mRNA levels of inflammatory mediators (IL-1beta, TNF-alpha, IL-6, and IFN-gamma), and reverse the histologic damages in stressed mice. Simultaneously, theacrine also significantly decreased the content of malondialdehyde and increased oxygen radical absorbance capacity (ORAC) level in the plasma and liver of stressed mice. These results suggested that the protective effects of theacrine on stress-induced liver damage might be correlated with its antioxidative activity. The antioxidative capacity of theacrine was further evaluated by in vitro ORAC and cellular antioxidant activity assay. The results suggested that the antioxidative capacity of theacrine was not due to the direct action on free radical clearance. Moreover, the elevated activities and gene expressions of superoxide dismutase, catalase, and glutathione peroxidase, as well as the reduced activity of xanthine oxidase by theacrine treatment in stressed mice suggested that the antioxidative activity might be due to the strengthening of the antioxidant system in vivo. On the basis of the above results, theacrine is possibly a good candidate for protecting against or treating lifestyle diseases and might contribute to the study of natural products. PMID- 23678854 TI - Effectiveness of a specialized outpatient palliative care service as experienced by patients and caregivers. AB - OBJECTIVES: In Germany since 2007 patients with advanced life-limiting diseases are eligible for Specialized Outpatient Palliative Care (SOPC). To provide this service, SOPC teams have been established as a new facility in the health care system. The objective of this study was to evaluate the effectiveness of one of the first SOPC teams based at the Munich University Hospital. METHODS: All patients treated by the SOPC team and their primary caregivers were eligible for this prospective nonrandomized study. The main topics of the surveys before and after involvement of the SOPC team were: for patients, the assessment of symptom burden (Minimal Documentation System for Palliative Medicine, MIDOS), satisfaction with quality of palliative care (Palliative Outcome Scale, POS), and quality of life (McGill Quality of Life Questionnaire, MQOL); for caregivers, burden of care (Hausliche Pflegeskala, home care scale, HPS), anxiety and depression (Hospital Anxiety and Depression Scale, HADS), and quality of life (Quality of Life in Life-Threatening Illness-Family Carer Version, QOLLTI-F). RESULTS: Of 100 patients treated between April and November 2011, 60 were included in the study (median age 67.5 years, 55% male, 87% oncological diseases). In 23 of 60 patients, only caregivers could be interviewed. The median interval between the first and second interview was 2.5 weeks. Quality of life increased significantly in patients (p<0.05) and caregivers (p<0.001), as did the patients' perception of quality of palliative care (POS, p<0.001), while the caregivers' psychological distress and burden of care significantly decreased (HADS, p<0.001; HPS, p<0.001). CONCLUSIONS: The involvement of an SOPC team leads to a significant improvement in the quality of life of patients and caregivers and can lower the burden of home care for the caregivers of severely ill patients. PMID- 23678855 TI - Core medicines for quality care of the dying. PMID- 23678856 TI - Four essential drugs: differing opinions or heresy? PMID- 23678857 TI - Evaluation of linear lesions in the left and right atrium in ablation of long standing atrial fibrillation. AB - BACKGROUND: This randomized prospective study compared three ablation strategies in patients with long-standing persistent atrial fibrillation (LPeAF). It also explored the best procedural endpoint from among the following: circumferential pulmonary vein isolation (PVI) + left atrial (LA) linear lesions (roofline, mitral isthmus) + complex fractionated atrial electrogram (CFAE) ablation, PVI + LA linear lesions + cavotricuspid isthmus (CTI) ablation + CFAE ablation, and PVI + CFAE ablation. METHODS AND RESULTS: A total of 210 patients with LPeAF referred for catheter ablation were enrolled and randomized into three ablation groups. The patients in group A (n = 70) underwent PVI followed by LA linear and CFAE ablation; in 93% of patients the primary endpoint was achieved (five patients with incomplete linear lesions). Of the 70 patients in group B who were subjected to PVI followed by LA linear, CFAE, and CTI ablations, in 94% of patients the primary endpoint was achieved (four patients with incomplete linear lesions). All patients in group C (n = 70) successfully underwent PVI and CFAE ablation. Direct current cardioversion was performed upon PVI, CFAE elimination, and completion of linear lesions. Patients were followed-up for atrial tachyarrhythmia recurrence for at least 24 months. After a single ablation procedure, group C (36%) exhibited the lowest success compared with group A (54%) and group B (51%) (P = 0.06). At the mean follow-up of 32 +/- 9 months after the final ablation procedure, 53 patients (76%) in group A, 53 (76%) in group B, and 41 (59%) in group C were in sinus rhythm without antiarrhythmic drugs (P = 0.03). CONCLUSIONS: In LPeAF, linear lesions in the LA help improve outcome of ablation, additional CTI ablation does not. PMID- 23678858 TI - Design, characterization and in vitro evaluation of SMEDDS containing an anticancer peptide, linear LyP-1. AB - LyP-1 (CGNKRTRGC) is a nine amino acid peptide that shows high specificity for tumor lymphatics. The aim of this study was to develop lipid-based formulations containing the linear form of LyP-1 for lymphatic targeting. Self microemulsifying drug delivery systems (SMEDDS) were designed for the delivery of linear LyP-1 by itself and as a solid dispersion (SD). Formulations were characterized in terms of physical stability, pH, morphological properties, droplet size distribution and zeta potential. Thermodynamically stable microemulsions were obtained with an average droplet size around 20 nm and zeta potential near neutrality. Cytotoxicity studies of blank and peptide-containing SMEDDS were carried out on Caco-2 cell line. Bioactivity studies of peptide containing formulations were carried out on MDA-MB-231 breast cancer cell line. It was shown that blank and peptide-containing SMEDDS formulations were not cytotoxic to Caco-2 cell line. However, formulations containing the peptide and peptide SD led to a significant decrease in cell viability on breast cancer cells. It could be concluded that the SMEDDS formulations containing the linear LyP-1 were successfully developed for the lymphatic targeting of solid tumors in vitro. PMID- 23678859 TI - NMR relaxometry study of the interaction of water with a Nafion membrane under acid, sodium, and potassium forms. Evidence of two types of bound water. AB - Through (1)H NMR relaxometry techniques (determination of the spin-lattice relaxation time as a function of the NMR measurement frequency), we have investigated, on a molecular scale, the water behavior in Nafion NRE 212 under acid, sodium, and potassium forms, the latter arising from different chemical treatments (with and without EDTA). Quantitatively, it turns out that (i) EDTA removes unwanted cations that may affect water mobility and (ii) the natural countercations (sodium and potassium) also affect water mobility according to their size. In order to go further, we have developed a new methodology that rests on the comparison between samples prepared with H2O and D2O. For the latter, residual protons allow us to exclusively access intermolecular contribution to proton relaxation and, thus, enable us to deduce the intramolecular contribution of proton relaxation in H2O. The analysis of this contribution reveals, for the first time, two types of bound water in Nafion. PMID- 23678863 TI - Hybrid uranyl arsonate coordination nanocages. AB - Nanoscopic uranyl coordination cages have been prepared by a facile route involving self-assembly via temperature and solvent-driven, in situ ligand synthesis. The synthesis of hydrogen arsenate and pyroarsonate ligands in situ enhances flexibility, which is an important factor in producing these compounds. PMID- 23678861 TI - Inhibition of vacuolar ATPase attenuates the TRAIL-induced activation of caspase 8 and modulates the trafficking of TRAIL receptosomes. AB - Tumour necrosis factor (TNF) related apoptosis inducing ligand (TRAIL), a membrane-bound ligand from the TNF family, has attracted significant attention due to its rather specific and effective ability to induce apoptotic death in various types of cancer cells via binding to and activating its pro-apoptotic death receptors. However, a significant number of primary cancer cells often develop resistance to TRAIL treatment, and the signalling platform behind this phenomenon is not fully understood. Upon blocking endosomal acidification by the vacuolar ATPase (V-ATPase) inhibitors bafilomycin A1 (BafA1) or concanamycin A, we observed a significantly reduced initial sensitivity of several, mainly colorectal, tumour cell lines to TRAIL-induced apoptosis. In cells pretreated with these inhibitors, the TRAIL-induced processing of caspase-8 and the aggregation and trafficking of the TRAIL receptor complexes were temporarily attenuated. Nuclear factor kappaB or mitogen activated protein/stress kinase signalling from the activated TRAIL receptors remained unchanged, and neither possible lysosomal permeabilization nor acid sphingomyelinase was involved in this process. The cell surface expression of TRAIL receptors and their TRAIL induced internalization were not affected by V-ATPase inhibitors. The inhibitory effect of BafA1, however, was blunted by knockdown of the caspase-8 inhibitor cFLIP. Altogether, the data obtained provide the first evidence that endosomal acidification could represent an important regulatory node in the proximal part of TRAIL-induced pro-apoptotic signalling. PMID- 23678860 TI - Prevalence and predictors of alanine aminotransferase elevation among normal weight, overweight and obese youth in Mexico. AB - OBJECTIVE: This study aimed to determine the prevalence of and risk factors associated with elevated alanine aminotransferase (ALT) levels among a sample of normal weight, overweight and obese youth from two urban populations in Central Mexico. METHODS: Baseline data from 1262 youth aged 8-19 years who participated in the Mexican Health Worker Cohort Study from March 2004 to April 2006 were reviewed, including 680 girls and 582 boys, with a total of 83 participants with elevated ALT level (>40 U/L). Information was obtained from self-administered questionnaires, anthropometric results and clinical measurements. Associations of interest were examined using multivariate logistic regression models. RESULTS: A total of 3.8% of girls and 9.8% of boys had elevated ALT levels. Elevated ALT was observed in 28.9% of the obese and 14.2% of the overweight participants. Metabolic syndrome (MS) occurred in 6.1% of the study population and those with MS had a high percentage of elevated ALT (14.5% of girls and 40.0% of boys, respectively). Abdominal obesity and insulin resistance were also associated with a greater risk of elevated ALT. CONCLUSIONS: Obesity and certain metabolic risk factors are important predictors for elevated ALT. Screening for ALT levels in obese youth could help to identify those at risk and reduce the possibility of future liver diseases. PMID- 23678864 TI - Focal nodular hyperplasia of the liver in children after hematopoietic stem cell transplantation. AB - FNH is a non-malignant neoplasia of the liver rarely described in children. A significant percentage of the pediatric cases have been reported in patients with a history of malignant disease treated with chemo-radiation therapy and in children who were given HSCT. Little is known about the pathogenesis of FNH in transplanted children, but many risk factors linked to the HSCT procedure have been hypothesized. The detection of hepatic nodules, particularly in children who underwent HSCT for a previous malignancy, always raises a diagnostic dilemma. To help the physicians in the diagnostic management of this rare entity, we have retrospectively evaluated a series of transplanted children diagnosed with FNH in our Center over the last 15 yr. In this period, we found 10 new diagnoses of FNH. The diagnostic work-up included CEUS, abdominal CT, and MRI. A liver biopsy was performed in two patients. The median FUP time after diagnosing FNH was 3.8 yr, with an abdominal US and no malignant transformation were observed. Possible risk factors and indications for the management of FNH in transplanted children are reported and discussed in a comprehensive review of the literature. PMID- 23678865 TI - Systematic review of the effects of telecare provided for a person with social care needs on outcomes for their informal carers. AB - Telecare devices have been put forward as a potentially effective intervention to benefit the well-being and functioning of informal carers of people with social care needs, and to reduce the negative effects of providing care to a family member or friend. Much of the evidence used to support this view is qualitative, and therefore does not provide good-quality evidence to answer questions about its effect on carer outcomes. This review aimed to document and evaluate the quantitative evidence base for the effect of telecare interventions on outcomes for informal carers. A systematic search was conducted between October 2009 and January 2010 to identify peer-reviewed and 'grey' intervention evaluations, using electronic databases and expert/interested party recommendations. Clear inclusion and exclusion criteria and a reliable screening process were applied to select papers for inclusion in the review, and a checklist was used to assess risk of bias for each evaluation. Of 1071 identified evaluations, seven fulfilled the inclusion and exclusion criteria. Of these, two were peer-reviewed, and the remainder were unpublished or internal reports. Included evaluations were heterogeneous; they had investigated diverse technologies and outcomes, using varied evaluation designs and measures. All included evaluations were rated as being of weak methodological quality, indicating risk of bias within the evidence base. The evidence tentatively indicated that telecare exerts a positive effect on carer stress and strain, but there is no evidence to indicate benefits on burden or quality of life. The evidence is conflicting about the effect of telecare on the amount of time carers spend on their caring duties, and on relationships between the carer, cared-for person and other family members. Additional good-quality evaluations are required to establish the effects of telecare on informal carer outcomes. PMID- 23678866 TI - Blending through-space and through-bond pi-pi-coupling in [2,2']-paracyclophane oligophenylenevinylene molecular wires. AB - A series of ZnP-pCp-oPPV-C60 conjugates covalently connected through [2,2'] paracyclophane-oligophenylenevinylene (pCp-oPPV) bridges containing one, two, and three [2,2']-paracyclophanes (pCps) has been prepared in multistep synthetic procedures involving Horner-Wadsworth-Emmons olefination reactions and/or Heck type Pd-catalyzed reactions. Molecular modeling suggests that charge transfer is effectively mediated by the pCp-oPPVs through a predominant hole-transfer mechanism. Photophysical investigation supports molecular modeling and reveals two major trends. On one hand, C60 excitation of 1, 2, and 3 leads exclusively to charge transfer between pCp and C60 to afford a ZnP-(pCp-oPPV)(*+)-C60(*-) radical ion pair state without giving rise to a subsequent charge shift to yield the ZnP(*+)-pCp-oPPV-C60(*-) radical ion pair state. On the other hand, ZnP excitation of 1, 2, and 3 results in a rather slow charge transfer between ZnP and C60, after which the ZnP(*+)-pCp-oPPV-C60(*-) radical ion pair state evolves. In temperature-dependent ZnP fluorescence experiments, which were performed in the temperature range from 273 to 338 K, two domains are discernible: low and high temperature behaviors. In the low temperature range (i.e., below 30 degrees C) the rate constants do not change, suggesting that a superexchange mechanism is the modus operandi. In the high temperature range (i.e., >30 degrees C) the rate constants increase. Moreover, we find rather strong distance dependence for 1 and 2 and weak distance dependence for 2 and 3. A damping factor of 0.145 A(-1) is derived for the former pair and 0.012 A(-1) for the latter. PMID- 23678867 TI - The outcome of the movement disorder in methcathinone abusers: clinical, MRI and manganesemia changes, and neuropathology. AB - BACKGROUND AND PURPOSE: There is limited knowledge regarding the long-term outcome of the methcathinone/manganese-induced movement disorder. Our purpose was to define prognosis in intravenous methcathinone abusers affected by this distinctive disorder attributed to manganese (Mn) toxicity. Also, neuropathology from a globus pallidus region biopsy from a former user is reported. METHODS: Eighteen methcathinone abusers were categorized as active (five), discontinued (four) or former (nine) users. They were reassessed after a median of 32.5 months (range 3.4-59.6) clinically, on rating scales, and with MRI and blood Mn levels. The biopsy was examined ultrastructurally. RESULTS: Overall the group showed a slight tendency to deterioration at follow-up on clinical assessment of motor functioning, especially the active users. No significant change occurred on parkinsonian rating scale reassessment. Significant reduction in Mn levels occurred in former users, and decreased T1-weighted hyperintensity on basal ganglia MRI occurred in 3 of 4 former and 2 of 3 discontinued users, despite lack of clinical improvement. The biopsy consisted of white matter showing decompacted myelin sheaths and frequent abnormalities of mitochondria. CONCLUSIONS: No improvement in this Mn-induced movement disorder occurs after cessation of methcathinone abuse despite improvement of Mn blood levels and/or MRI abnormalities. Ultrastructural abnormalities in a former user confirm structural damage to white matter is associated with the disorder. Methcathinone/Mn toxicity is an important, disabling and permanent medical sequel of intravenous drug abuse in the former Soviet Union. PMID- 23678868 TI - Human parainfluenza type 3 virus impairs the efficacy of glucocorticoids to limit allergy-induced pulmonary inflammation in guinea-pigs. AB - Viral exacerbations of allergen-induced pulmonary inflammation in pre-clinical models reportedly reduce the efficacy of glucocorticoids to limit pulmonary inflammation and airways hyper-responsiveness to inhaled spasmogens. However, exacerbations of airway obstruction induced by allergen challenge have not yet been studied. hPIV-3 (human parainfluenza type 3 virus) inoculation of guinea pigs increased inflammatory cell counts in BAL (bronchoalveolar lavage) fluid and caused hyper-responsiveness to inhaled histamine. Both responses were abolished by treatment with either dexamethasone (20 mg/kg of body weight, subcutaneous, once a day) or fluticasone propionate (a 0.5 mg/ml solution aerosolized and inhaled over 15 min, twice a day). In ovalbumin-sensitized guinea-pigs, allergen (ovalbumin) challenge caused two phases of airway obstruction [measured as changes in sGaw (specific airways conductance) using whole body plethysmography]: an immediate phase lasting between 4 and 6 h and a late phase at about 7 h. The late phase, airway hyper-responsiveness to histamine and inflammatory cell counts in BAL were all significantly reduced by either glucocorticoid. Inoculation of guinea-pigs sensitized to ovalbumin with hPIV-3 transformed the allergen-induced airway obstruction from two transient phases into a single sustained response lasting up to 12 h. This exacerbated airway obstruction and airway hyper responsiveness to histamine were unaffected by treatment with either glucocorticoid whereas inflammatory cell counts in BAL were only partially inhibited. Virus- or allergen-induced pulmonary inflammation, individually, are glucocorticoid-sensitive, but in combination generate a phenotype where glucocorticoid efficacy is impaired. This suggests that during respiratory virus infection, glucocorticoids might be less effective in limiting pulmonary inflammation associated with asthma. PMID- 23678869 TI - Predicting developmental plasticity after perinatal stroke. PMID- 23678870 TI - Resisting chocolate temptation using a brief mindfulness strategy. AB - OBJECTIVES: We examined the effects of two mindfulness-based strategies on chocolate consumption amongst individuals who were trying to reduce the amount of chocolate they consumed. METHODS: Participants (n = 137) were allocated to one of three conditions and employed either cognitive defusion, acceptance, or relaxation (control) techniques to help them resist chocolate over 5 days. During this period, they carried a bag of chocolates with them and recorded any chocolate or chocolate-related products they consumed. They also completed a questionnaire measure of the extent to which chocolate consumption was automatic, both before and after the 5-day period. RESULTS: Results showed that compared to controls, those in the cognitive defusion group ate significantly less chocolate from the bag (p = .046) and less chocolate according to the diary measure (p = .053). There was evidence that these changes were brought about by reductions in the extent to which chocolate consumption was automatic. There were no differences in chocolate consumption between the acceptance and control groups. CONCLUSIONS: Our results point to a promising brief intervention strategy and highlight the importance of disentangling the effects of different mindfulness based techniques. STATEMENT OF CONTRIBUTION: What is already known on this subject? Multicomponent mindfulness interventions have been successfully applied to a range of health behaviours. Low levels of self-control are associated with weight gain and a higher BMI. What does this study add? The results show that a brief mindfulness strategy (defusion) helps individuals resist chocolate over 5 days. The results suggest this may be brought about by reductions in the extent to which eating chocolate is automatic. A second brief mindfulness strategy (acceptance) failed to help individuals resist chocolate. PMID- 23678871 TI - Discovery of a highly potent, nonabsorbable apical sodium-dependent bile acid transporter inhibitor (GSK2330672) for treatment of type 2 diabetes. AB - The apical sodium-dependent bile acid transporter (ASBT) transports bile salts from the lumen of the gastrointestinal (GI) tract to the liver via the portal vein. Multiple pharmaceutical companies have exploited the physiological link between ASBT and hepatic cholesterol metabolism, which led to the clinical investigation of ASBT inhibitors as lipid-lowering agents. While modest lipid effects were demonstrated, the potential utility of ASBT inhibitors for treatment of type 2 diabetes has been relatively unexplored. We initiated a lead optimization effort that focused on the identification of a potent, nonabsorbable ASBT inhibitor starting from the first-generation inhibitor 264W94 (1). Extensive SAR studies culminated in the discovery of GSK2330672 (56) as a highly potent, nonabsorbable ASBT inhibitor which lowers glucose in an animal model of type 2 diabetes and shows excellent developability properties for evaluating the potential therapeutic utility of a nonabsorbable ASBT inhibitor for treatment of patients with type 2 diabetes. PMID- 23678872 TI - Chytridiomycosis and seasonal mortality of tropical stream-associated frogs 15 years after introduction of Batrachochytrium dendrobatidis. AB - Assessing the effects of diseases on wildlife populations can be difficult in the absence of observed mortalities, but it is crucial for threat assessment and conservation. We performed an intensive capture-mark-recapture study across seasons and years to investigate the effect of chytridiomycosis on demographics in 2 populations of the threatened common mist frog (Litoria rheocola) in the lowland wet tropics of Queensland, Australia. Infection prevalence was the best predictor for apparent survival probability in adult males and varied widely with season (0-65%). Infection prevalence was highest in winter months when monthly survival probabilities were low (approximately 70%). Populations at both sites exhibited very low annual survival probabilities (12-15%) but high recruitment (71-91%), which resulted in population growth rates that fluctuated seasonally. Our results suggest that even in the absence of observed mortalities and continued declines, and despite host-pathogen co-existence for multiple host generations over almost 2 decades, chytridiomycosis continues to have substantial seasonally fluctuating population-level effects on amphibian survival, which necessitates increased recruitment for population persistence. Similarly infected populations may thus be under continued threat from chytridiomycosis which may render them vulnerable to other threatening processes, particularly those affecting recruitment success. PMID- 23678874 TI - A novel HLA-A allele detected by sequence-based typing: HLA-A*24:223. AB - Compared with A*24:02:01:01, HLA-A*24:223 shows one nucleotide difference at genomic nt 149 G>A (codon 26 GGC>GAC) in exon 2. PMID- 23678875 TI - Promoting clinical and patient-oriented research to identify the pathogenesis of amyotrophic lateral sclerosis. PMID- 23678873 TI - The objectives, design and implementation of the INTERGROWTH-21st Project. AB - INTERGROWTH-21(st) is a multicentre, multiethnic, population-based project, being conducted in eight geographical areas (Brazil, China, India, Italy, Kenya, Oman, UK and USA), with technical support from four global specialised units, to study growth, health and nutrition from early pregnancy to infancy. It aims to produce prescriptive growth standards, which conceptually extend the World Health Organization (WHO) Multicentre Growth Reference Study (MGRS) to cover fetal and newborn life. The new international standards will describe: (1) fetal growth assessed by clinical and ultrasound measures; (2) postnatal growth of term and preterm infants up to 2 years of age; and (3) the relationship between birthweight, length and head circumference, gestational age and perinatal outcomes. As the project has selected healthy cohorts with no obvious risk factors for intrauterine growth restriction, these standards will describe how all fetuses and newborns should grow, as opposed to traditional charts that describe how some have grown at a given place and time. These growth patterns will be related to morbidity and mortality to identify levels of perinatal risk. Additional aims include phenotypic characterisation of the preterm and impaired fetal growth syndromes and development of a prediction model, based on multiple ultrasound measurements, to estimate gestational age for use in pregnant women without access to early/frequent antenatal care. PMID- 23678876 TI - Deciphering amyotrophic lateral sclerosis: what phenotype, neuropathology and genetics are telling us about pathogenesis. AB - Amyotrophic lateral sclerosis (ALS) is characterized phenotypically by progressive weakness and neuropathologically by loss of motor neurons. Phenotypically, there is marked heterogeneity. Typical ALS has mixed upper motor neuron (UMN) and lower motor neuron (LMN) involvement. Primary lateral sclerosis has predominant UMN involvement. Progressive muscular atrophy has predominant LMN involvement. Bulbar and limb ALS have predominant regional involvement. Frontotemporal dementia has significant cognitive and behavioral involvement. These phenotypes can be so distinctive that they would seem to have differing biology. However, they cannot be distinguished, at least neuropathologically or genetically. In sporadic ALS (SALS), they are mostly characterized by ubiquitinated cytoplasmic inclusions of TDP-43. In familial ALS (FALS), where phenotypes are indistinguishable from SALS and similarly heterogeneous, each mutated gene has its own genetic and molecular signature. Overall, since the same phenotypes can have multiple causes including different gene mutations, there must be multiple molecular mechanisms causing ALS - and ALS is a syndrome. Since, however, multiple phenotypes can be caused by one single gene mutation, a single molecular mechanism can cause heterogeneity. What the mechanisms are remain unknown, but active propagation of the pathology neuroanatomically seems to be a principal component. Leading candidate mechanisms include RNA processing, cell cell interactions between neurons and non-neuronal neighbors, focal seeding from a misfolded protein that has prion-like propagation, and fatal errors introduced during neurodevelopment of the motor system. If fundamental mechanisms could be identified and understood, ALS therapy could rationally target progression and stop the disease - a goal that seems increasingly achievable. PMID- 23678878 TI - Current pathways for epidemiological research in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease. The current status of the epidemiology, challenges to its study, and novel study design options are discussed in this paper. We focus on recent results from large-scale population based prospective studies, case-control studies and population based registries, risk factors, and neuropathologic findings in chronic traumatic encephalomyelopathy. We identify areas of interest for future research, including time-trends in the incidence and prevalence of ALS; the meaning of lifetime risk; the phenotypic description of ALS; the definition of familial versus sporadic ALS, syndromic aspects of ALS; specific risk factors such as military service, life style factors such as smoking, the use of statins, and the presence of beta-N-methylamino-L-alanine (BMAA), an excitotoxic amino acid derivative possibly produced by cyanobacteria found in almost every terrestrial and aquatic habitat; the emergence and disappearance of an endemic ALS in areas of the Pacific; and gene-environment interactions in the etiology of ALS. To move the epidemiology forward, we suggest using well characterized cohorts of newly diagnosed ALS patients to identify risk and prognostic factors; storing biological material for future studies; building on the National ALS Registry as a resource of future studies; working in multidisciplinary consortia; and addressing the possible early life etiology of ALS. PMID- 23678879 TI - Genetic and epigenetic studies of amyotrophic lateral sclerosis. AB - The identification of genetic and epigenetic factors that are associated with an increased risk of developing amyotrophic lateral sclerosis (ALS), or that modify the age of onset or rate of progression, requires a multimodal research strategy, facilitated through international collaboration. The discovery of several ALS genes strongly linked to RNA biology, the proteasome pathway, and axonal transport suggest they have an important role in pathogenesis, but the immense complexity of these processes is also apparent. The increasing rate of genetic discoveries brings the hope of designing more targeted and efficacious therapies. PMID- 23678880 TI - Infrastructure resources for clinical research in amyotrophic lateral sclerosis. AB - Clinical trial networks, shared clinical databases, and human biospecimen repositories are examples of infrastructure resources aimed at enhancing and expediting clinical and/or patient oriented research to uncover the etiology and pathogenesis of amyotrophic lateral sclerosis (ALS), a rapidly progressive neurodegenerative disease that leads to the paralysis of voluntary muscles. The current status of such infrastructure resources, as well as opportunities and impediments, were discussed at the second Tarrytown ALS meeting held in September 2011. The discussion focused on resources developed and maintained by ALS clinics and centers in North America and Europe, various clinical trial networks, U.S. government federal agencies including the National Institutes of Health (NIH), the Agency for Toxic Substances and Disease Registry (ATSDR) and the Centers for Disease Control and Prevention (CDC), and several voluntary disease organizations that support ALS research activities. Key recommendations included 1) the establishment of shared databases among individual ALS clinics to enhance the coordination of resources and data analyses; 2) the expansion of quality controlled human biospecimen banks; and 3) the adoption of uniform data standards, such as the recently developed Common Data Elements (CDEs) for ALS clinical research. The value of clinical trial networks such as the Northeast ALS (NEALS) Consortium and the Western ALS (WALS) Consortium was recognized, and strategies to further enhance and complement these networks and their research resources were discussed. PMID- 23678881 TI - Funding agencies and disease organizations: resources and recommendations to facilitate ALS clinical research. AB - Ten groups presented their perspectives on facilitating clinical research in ALS including four federal agencies, four disease organizations, one foundation and one advocacy group. The federal agencies (National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, Office of Rare Diseases Research, Department of Defense) encourage fostering a team approach between pre-clinical and clinical research investigators, coordinating with patient groups in the early phases of clinical studies, enhancing private and public partnerships, and investigating the interplay between genetic susceptibility and environmental exposure. The disease organizations (Muscular Dystrophy Association, ALS Association, ALS Society of Canada, and the Motor Neurone Disease Association UK) support fellowship training programs to develop ALS clinician scientists, and encourage work on the epidemiology of ALS, on genetic and epigenetic mechanisms that are relevant to ALS pathogenesis, on developing ALS registries and biobanks, and building bridges of collaboration among study groups. The Foundation supports innovative projects, including stem cell research, and Patient Advocacy is committed to supporting excellence in ALS research and patient care, and believes strongly in enhancing communication between patients and members of the research community. PMID- 23678877 TI - Mechanisms, models and biomarkers in amyotrophic lateral sclerosis. AB - The last 30 years have seen a major advance in the understanding of the clinical and pathological heterogeneity of amyotrophic lateral sclerosis (ALS), and its overlap with frontotemporal dementia. Multiple, seemingly disparate biochemical pathways converge on a common clinical syndrome characterized by progressive loss of upper and lower motor neurons. Pathogenic themes in ALS include excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation, altered energy metabolism, and most recently RNA mis-processing. The transgenic rodent, overexpressing mutant superoxide dismutase-1, is now only one of several models of ALS pathogenesis. The nematode, fruit fly and zebrafish all offer fresh insight, and the development of induced pluripotent stem cell-derived motor neurons holds promise for the screening of candidate therapeutics. The lack of useful biomarkers in ALS contributes to diagnostic delay, and the inability to stratify patients by prognosis may be an important factor in the failure of therapeutic trials. Biomarkers sensitive to disease activity might lessen reliance on clinical measures and survival as trial endpoints and reduce study length. Emerging proteomic markers of neuronal loss and glial activity in cerebrospinal fluid, a cortical signature derived from advanced structural and functional MRI, and the development of more sensitive measurements of lower motor neuron physiology are leading a new phase of biomarker-driven therapeutic discovery. PMID- 23678883 TI - Evidence for multiple introductions and clonality in Spanish populations of Fusarium circinatum. AB - Fusarium circinatum is thought to have been moved around the world with pine planting stock consisting, most probably, of infected seed. In this effort, we investigate the genetic structure of F. circinatum in Spain and globally. In total, 223 isolates were studied from five regions in northern Spain and eight countries. Eight microsatellite markers revealed 66 multilocus genotypes (MLGs). Minimum spanning network analysis of MLGs by region within Spain as well as globally, discriminant analysis of principal components, and analysis of molecular variance revealed that Spanish populations are significantly differentiated and structured into two distinct groups, each one including one of the dominant genotypes observed. This result suggests that two independent introductions occurred into Spain that subsequently underwent clonal divergence and admixture. This result is further supported by the linkage disequilibrium and clonality observed for F. circinatum populations in northern Spain. The maintenance of differentiation between the clusters could result from the lack of or rare sexual reproduction in Spain. Possible introduction pathways from other countries and subsequent routes of dispersion of F. circinatum in Spain are discussed. PMID- 23678882 TI - Peer recommendations on how to improve clinical research, and Conference wrap-up. AB - To promote clinical and patient oriented research, as part of the Second International ALS Conference in Tarrytown, NY, USA, seven pairs of clinicians and scientists were asked to lead discussions with meeting attendees on six major topics (one of which was discussed by two groups); each one the focus of a 90-min Breakout Session. Approximately 25 meeting attendees participated in each session. The Breakout Sessions considered six major themes: 1) Approaches to encourage clinicians to engage in more clinical research to discover the pathogenesis and cause of ALS; 2) Exploring avenues to build more effective partnerships between basic scientists and ALS physicians; 3) Increasing patient interest and commitment to participating in non-trial clinical research; 4) Brainstorming about factors that are most critical to the discovery of the pathogenesis and cause of ALS; 5) Finding ways to incorporate clinical research projects into clinical trials; and 6) Developing state-of-the-art epidemiological studies to solve the mystery of ALS. In this paper, we present the reports from each of the Breakout Sessions; and we provide a wrap-up of the entire conference. PMID- 23678885 TI - Comparison between totally laparoscopic and laparoscopically assisted distal gastrectomy for gastric cancer with a short follow-up: a meta-analysis. AB - Laparoscopic surgery has become common in the treatment of gastric cancer because of improvements of both surgical techniques and devices. The aim of this study was to compare totally laparoscopic distal gastrectomy (TLDG) with laparoscopically assisted distal gastrectomy (LADG) implemented by experienced laparoscopic surgeons. Studies and relevant literature regarding LADG versus TLDG were searched for in the PubMed and Embase databases. Operative time, volume of bleeding, number of retrieved lymph nodes, time to first flatus, duration of postoperative hospitalization, and postoperative complications in LADG and TLDG were pooled and compared by meta-analysis. Odds ratios (ORs) and weighted mean differences (WMDs) were calculated with 95% confidence intervals (CIs) to evaluate the effect of TLDG. Six recent studies of 1644 patients were included in the meta-analysis. Compared with LADG, TLDG had advantages of less bleeding (WMD 17.79, 95% CI -32.57 to -3.02, P=.02), shorter time to first flatus (WMD -0.14, 95% CI -0.23 to -0.06, P=.001), and shorter postoperative hospitalization (WMD 0.32, 95% CI -0.53 to -0.12, P=.002). Operative time, mean number of lymph nodes retrieved, and postoperative complication rate were not statistically different (P>.05). Compared with LADG, TLDG significantly reduced bleeding, time to first flatus, and postoperative hospital stay and can be considered a useful technique for patients with gastric cancer. PMID- 23678884 TI - The preparation of PLL-GRGDS modified PTSG copolymer scaffolds and their effects on manufacturing artificial salivary gland. AB - We prepared two-dimentional (2D) and three-dimentional (3D) scaffolds with biodegradable poly(butylene terephthalate)-co-poly(butylene succinate)-b poly(ethylene glycol) (i.e. PTSG), mainly for the purpose of investigating its cytocompatibility and mechanical property as artificial salivary gland material. The surface of 2D scaffold (i.e. PTSG film) was modified by O(2) plasma treatment and the following coating of Gly-Arg-Gly-Asp-Ser (GRGDS) decorated poly(L-lysine) (i.e. PLL-GRGDS). The obtained film was named PLL-GRGDS/PTSG (O). Its surface properties were characterized using contact angles, surface energies, X-ray photoelectron spectroscopy and Fourier transform infrared; and cytocompatibility tests in vitro including morphology, attachment and proliferation of human salivary gland (HSG) epithelial cells were further performed on PTSG films. Meanwhile, 3D scaffold with the shape of porous tube was constructed using hydrogel-rapid prototyping and the performance of 3D scaffold including mechanical property, pore structure, degradation and water uptake was also evaluated. Results revealed that PLL-GRGDS/PTSG (O) possessed the high surface free energy (63.89 mJ/m(2)) and could immobilize a great amount of PLL-GRGDS, which attributed to the formation of some polar oxygen-containing groups such as carboxyl and carbonyl ones in the process of O(2) plasma treatment. Cell tests in vitro suggested the efficiency of surface modification in enhancing the cytocompatibility of PTSG. Furthermore, the manufacturing scaffold was proved to possess excellent pore structures (porosity 88.9%, connectivity 97.5% and average pore size 35.4 MUm) and good mechanical properties (E-modulus 88.4 +/- 4.1 kPa, yield stress 45.7 +/- 2.3 kPa, yield strain 56 +/- 2%, fracture stress 52.2 +/- 3.5 kPa and fracture strain 63 +/- 3%). After four weeks hydrolysis reaction, the degradation of the scaffold reached 8% and equilibrium water uptake declined from 51 to 45%. The decline of water uptake was probably caused by the decrease of the hydrophilic units in PTSG copolymer during degradation. These results satisfied the demands for constructing the artificial salivary gland scaffold. PMID- 23678887 TI - Class A G-protein-coupled receptor (GPCR) dimers and bivalent ligands. AB - G-protein-coupled receptors (GPCRs) represent the largest family of membrane proteins involved in cellular signal transduction and are activated by various different ligand types including photons, peptides, proteins, but also small molecules like biogenic amines. Therefore, GPCRs are involved in diverse physiological processes and provide valuable drug targets for numerous diseases. Emerging body of evidence suggests that GPCRs exist as monomers or cross-react forming dimers and higher-ordered oligomers. In this Perspective we will review current biochemical and biophysical techniques to visualize GPCR dimerization, functional consequences of homo- and heterodimers, and approaches of medicinal chemists to target these receptor complexes with homo- and heterobivalent ligands. PMID- 23678888 TI - Lipoic acid lessens Th1-mediated inflammation in lipopolysaccharide-induced uveitis reducing selectively Th1 lymphocytes-related cytokines release. AB - Inflammation results in the production of free radicals. We evaluated the anti inflammatory and antioxidant capacity of lipoic acid in an experimental uveitis model upon a subcutaneous injection of endotoxin into Lewis rats. The role of oxidative stress in the endotoxin-induced uveitis model is well-known. Besides, the Th1 response classically performs a central part in the immunopathological process of experimental autoimmune uveitis. Exogenous sources of lipoic acid have been shown to exhibit antioxidant and anti-inflammatory properties. Our results show that lipoic acid treatment plays a preventive role in endotoxin-induced oxidative stress at 24 h post-administration and reduced Th1 lymphocytes-related cytokines by approximately 50-60%. Simultaneously, lipoic acid treatment caused a significant reduction in uveal histopathological grading and in the protein concentration in aqueous humors, but not in cellular infiltration. PMID- 23678889 TI - Behavioural laterality as a factor in emotional regulation. AB - Individuals who perform a variety of tasks using one side of their bodies (i.e., high-dominance people) are thought to differ from individuals who perform a variety of tasks with both sides of their body (i.e., low-dominance people) in several neurological and cognitive characteristics. We examined whether behavioural laterality predicted the efficacy of different emotional regulation strategies. Specifically, we thought that behavioural laterality would influence verbal strategies (associated with left hemisphere activation) when regulating anxiety (associated with right hemisphere activation). In three studies participants presented in front of small audiences. Behavioural laterality (as measured by a modified handedness inventory) positively correlated with presentation anxiety, such that "low-dominance" participants reported less anxiety than "high-dominance" participants, but only when using cognitive reappraisal (a verbal strategy), not attention deployment or response modulation (behavioural strategies). These results provide preliminary evidence that individual differences in behavioural laterality mediate the efficacy of certain emotional regulation strategies. PMID- 23678890 TI - Clinical and histological features of leprosy and human immunodeficiency virus co infection in Brazil. AB - BACKGROUND: Both leprosy and human immunodeficiency virus (HIV) are infectious diseases, and are an important global health problem. Patients with leprosy who are co-infected with HIV seem to be at higher risk of developing leprosy reactions. AIM: To examine the histological features of leprosy in patients with HIV and leprosy co-infection, particularly to determine whether the typical leprosy histopathology is present in skin biopsies, and to assess the histological features of leprosy reactions in co-infected patients. METHODS: This was a matched cohort study with 11 co-infected patients and 31 HIV-negative patients with leprosy. A structured protocol for skin-biopsy evaluation was followed, focusing on inflammation of the skin and dermal nerves. RESULTS: Of the 11 HIV-positive patients, 7 (63%) had borderline tuberculoid (BT) leprosy and 5 (70%) of these 7 patients had developed a type 1 reaction. The lesions in these patients were immunologically active, with 100% of biopsies having evidence of compact granulomas, 90% evidence of oedema and 30% evidence of necrosis. CONCLUSIONS: In this study, patients co-infected with HIV and M. leprae had the typical histological lesions of leprosy. There was evidence of immune activation in patients who received combination antiretroviral therapy, and these patients had BT leprosy and leprosy-upgrading reactions. PMID- 23678892 TI - The role of leadership in the implementation of person-centred care using Dementia Care Mapping: a study in three nursing homes. AB - AIM: The aim of this study was to investigate the role of leadership in the implementation of person-centred care (PCC) in nursing homes using Dementia Care Mapping (DCM). BACKGROUND: Leadership is important for the implementation of nursing practice. However, the empirical knowledge of positive leadership in processes enhancing person-centred culture of care in nursing homes is limited. METHOD: The study has a qualitative descriptive design. The DCM method was used in three nursing homes. Eighteen staff members and seven leaders participated in focus-group interviews centring on the role of leadership in facilitating the development process. RESULTS: The different roles of leadership in the three nursing homes, characterized as 'highly professional', 'market orientated' or 'traditional', seemed to influence to what extent the DCM process led to successful implementation of PCC. CONCLUSION AND IMPLICATIONS FOR NURSING MANAGEMENT: This study provided useful information about the influence of leadership in the implementation of person-centred care in nursing homes. Leaders should be active role models, expound a clear vision and include and empower all staff in the professional development process. PMID- 23678891 TI - The exopolysaccharide of Xylella fastidiosa is essential for biofilm formation, plant virulence, and vector transmission. AB - Exopolysaccharides (EPS) synthesized by plant-pathogenic bacteria are generally essential for virulence. The role of EPS produced by the vector-transmitted bacterium Xylella fastidiosa was investigated by knocking out two genes implicated in the EPS biosynthesis, gumD and gumH. Mutant strains were affected in growth characteristics in vitro, including adhesion to surfaces and biofilm formation. In addition, different assays were used to demonstrate that the mutant strains produced significantly less EPS compared with the wild type. Furthermore, gas chromatography-mass spectrometry showed that both mutant strains did not produce oligosaccharides. Biologically, the mutants were deficient in movement within plants, resulting in an avirulent phenotype. Additionally, mutant strains were affected in transmission by insects: they were very poorly transmitted by and retained within vectors. The gene expression profile indicated upregulation of genes implicated in cell-to-cell signaling and adhesins while downregulation in genes was required for within-plant movement in EPS-deficient strains. These results suggest an essential role for EPS in X. fastidiosa interactions with both plants and insects. PMID- 23678893 TI - Crabgrass (Digitaria sanguinalis) allelochemicals that interfere with crop growth and the soil microbial community. AB - Three chemicals, veratric acid, maltol, and (-)-loliolide, were isolated from crabgrass and their structures were identified by spectroscopic analysis. The chemicals were detected in crabgrass root exudates and rhizosphere soils, and their concentrations ranged from 0.16 to 8.10 MUg/g. At an approximate concentration determined in crabgrass root exudates, all chemicals significantly inhibited the growth of wheat, maize, and soybean and reduced soil microbial biomass carbon. Phospholipid fatty acid profiling showed that veratric acid, maltol, and (-)-loliolide affected the signature lipid biomarkers of soil bacteria, actinobacteria, and fungi, resulting in changes in soil microbial community structures. There were significant relationships between crop growth and soil microbes under the chemicals' application. Chemical-specific changes in the soil microbial community generated negative feedback on crop growth. The results suggest that veratric acid, maltol, and (-)-loliolide released from crabgrass may act as allelochemicals interfering with crop growth and the soil microbial community. PMID- 23678895 TI - The decline and rise of coronary heart disease: understanding public health catastrophism. AB - The decline of coronary heart disease mortality in the United States and Western Europe is one of the great accomplishments of modern public health and medicine. Cardiologists and cardiovascular epidemiologists have devoted significant effort to disease surveillance and epidemiological modeling to understand its causes. One unanticipated outcome of these efforts has been the detection of early warnings that the decline had slowed, plateaued, or even reversed. These subtle signs have been interpreted as evidence of an impending public health catastrophe. This article traces the history of research on coronary heart disease decline and resurgence and situates it in broader narratives of public health catastrophism. Juxtaposing the coronary heart disease literature alongside the narratives of emerging and reemerging infectious disease helps to identify patterns in how public health researchers create data and craft them into powerful narratives of progress or pessimism. These narratives, in turn, shape public health policy. PMID- 23678894 TI - Examination of potential sources of bias in the US Coal Workers' Health Surveillance Program. AB - OBJECTIVES: We examined the potential influences of certain selection factors on the utility of the Coal Workers' Health Surveillance Program (CWHSP) data for tracking disease distribution and trends. METHODS: We combined data from the CWHSP and the Energy Information Administration to examine any influence of variable worker participation on observed disease prevalence. We evaluated effects of differential participation by coal mining region, temporal changes in employment, and active surveillance efforts. RESULTS: The published findings of pneumoconiosis distribution and trends from the CWHSP were robust compared with the various participation factors that might have affected their validity for population-based estimates of disease burden. Exploration of factors that could potentially bias the findings generally led to small increases in the primary estimates, mostly for the early years of the program. CONCLUSIONS: We confirmed previously reported findings that there was a high prevalence of coal worker pneumoconiosis (CWP) around 1970-1974, a substantial decline in 1995-1999, and indications of an increase since then. Overall our findings suggest that the previously reported distribution and trends in CWP prevalence were broadly accurate. PMID- 23678896 TI - Creating smoke-free places through the UN Convention on the Rights of Persons With Disabilities. AB - In some high-, middle-, and low-income countries, law has been employed to limit individuals' secondhand smoke exposure. Innovative legal tools are still needed, especially in low- and middle-income countries where smoking prevalence continues to rise. For some persons with severe respiratory conditions, the presence of secondhand smoke is intolerable and prevents their entrance into restaurants and other venues. With its adoption of the Convention on the Rights of Persons with Disabilities (CRPD) in 2006, the United Nations gave countries a new way to promote the rights of disabled individuals and simultaneously address secondhand smoke exposure. We analyze the CRPD's potential to advance tobacco control goals and offer recommendations for advocates, policymakers, and others seeking to apply this approach. PMID- 23678897 TI - Adapting Western research methods to indigenous ways of knowing. AB - Indigenous communities have long experienced exploitation by researchers and increasingly require participatory and decolonizing research processes. We present a case study of an intervention research project to exemplify a clash between Western research methodologies and Indigenous methodologies and how we attempted reconciliation. We then provide implications for future research based on lessons learned from Native American community partners who voiced concern over methods of Western deductive qualitative analysis. Decolonizing research requires constant reflective attention and action, and there is an absence of published guidance for this process. Continued exploration is needed for implementing Indigenous methods alone or in conjunction with appropriate Western methods when conducting research in Indigenous communities. Currently, examples of Indigenous methods and theories are not widely available in academic texts or published articles, and are often not perceived as valid. PMID- 23678898 TI - Smoking and tobacco use within the Department of Veterans Affairs. PMID- 23678899 TI - Factors explaining racial/ethnic disparities in rates of physician recommendation for colorectal cancer screening. AB - OBJECTIVES: Physician recommendation plays a crucial role in receiving endoscopic screening for colorectal cancer (CRC). This study explored factors associated with racial/ethnic differences in rates of screening recommendation. METHODS: Data on 5900 adults eligible for endoscopic screening were obtained from the National Health Interview Survey. Odds ratios of receiving an endoscopy recommendation were calculated for selected variables. Planned, sequenced logistic regressions were conducted to examine the extent to which socioeconomic and health care variables account for racial/ethnic disparities in recommendation rates. RESULTS: Differential rates were observed for CRC screening and screening recommendations among racial/ethnic groups. Compared with Whites, Hispanics were 34% less likely (P < .01) and Blacks were 26% less likely (P < .05) to receive this recommendation. The main predictors that emerged in sequenced analysis were education for Hispanics and Blacks and income for Blacks. After accounting for the effects of usual source of care, insurance coverage, and education, the disparity reduced and became statistically insignificant. CONCLUSIONS: Socioeconomic status and access to health care may explain major racial/ethnic disparities in CRC screening recommendation rates. PMID- 23678900 TI - Question context and priming meaning of health: effect on differences in self rated health between Hispanics and non-Hispanic Whites. AB - OBJECTIVES: We examined the implications of the current recommended data collection practice of placing self-rated health (SRH) before specific health related questions (hence, without a health context) to remove potential context effects, between Hispanics and non-Hispanics. METHODS: We used 2 methodologically comparable surveys conducted in English and Spanish that asked SRH in different contexts: before and after specific health questions. Focusing on the elderly, we compared the influence of question contexts on SRH between Hispanics and non Hispanics and between Spanish and English speakers. RESULTS: The question context influenced SRH reports of Spanish speakers (and Hispanics) significantly but not of English speakers (and non-Hispanics). Specifically, on SRH within a health context, Hispanics reported more positive health, decreasing the gap with non Hispanic Whites by two thirds, and the measurement utility of SRH was improved through more consistent mortality prediction across ethnic and linguistic groups. CONCLUSIONS: Contrary to the current recommendation, asking SRH within a health context enhanced measurement utility. Studies using SRH may result in erroneous conclusions when one does not consider its question context. PMID- 23678901 TI - Socioeconomic inequality in disability among adults: a multicountry study using the World Health Survey. AB - OBJECTIVES: We compared national prevalence and wealth-related inequality in disability across a large number of countries from all income groups. METHODS: Data on 218,737 respondents participating in the World Health Survey 2002-2004 were analyzed. A composite disability score (0-100) identified respondents who experienced significant disability in physical, mental, and social functioning irrespective of their underlying health condition. Disabled persons had disability composite scores above 40. Wealth was evaluated using an index of economic status in households based on ownership of selected assets. Socioeconomic inequalities were measured using the slope index of inequality and the relative index of inequality. RESULTS: Median age-standardized disability prevalence was higher in the low- and lower middle-income countries. In all the study countries, disability was more prevalent in the poorest than in the richest wealth quintiles. Pro-rich inequality was statistically significant in 43 of 49 countries, with disability prevalence higher among populations with lower wealth. Median relative inequality was higher in the high- and upper middle-income countries. CONCLUSIONS: Integrating equity components into the monitoring of disability trends would help ensure that interventions reach and benefit populations with greatest need. PMID- 23678902 TI - Increasing children's physical activity during school recess periods. AB - OBJECTIVES: We examined whether schools' participation in the Recess Enhancement Program (REP) in the spring of 2011 was associated with higher rates of children's vigorous physical activity. METHODS: In REP, a coach guides children through age-appropriate games aimed at increasing their physical activity. During recess at 25 New York City public elementary schools (15 REP, 10 non-REP), researchers visually scanned predetermined areas (n = 1339 scans), recording the number of sedentary, walking, and very active children. RESULTS: Multivariate statistical analysis found that participation in REP was a significant predictor (P = .027) of the rate of vigorous physical activity (percentage very active in scan area) whose least-squares means were 41% in REP schools and 27% in non-REP schools. A significantly higher rate in REP schools persisted when the coach was not in the scan area, suggesting a change in the recess culture of REP schools. CONCLUSIONS: The rate of vigorous physical activity in REP schools was 14 percentage points, or 52%, higher than the rate in non-REP schools. This low-cost intervention might be a valuable addition to the tools for combating childhood obesity and worth replicating elsewhere. PMID- 23678903 TI - Reducing traumatic brain injuries in youth sports: youth sports traumatic brain injury state laws, January 2009-December 2012. AB - OBJECTIVES: I sought to describe current state-wide youth sports traumatic brain injury (TBI) laws and their relationship to prevailing scientific understandings of youth sports TBIs, and to facilitate further research by creating an open source data set of current laws. METHODS: I used Westlaw and LexisNexis databases to create a 50-state data set of youth sports TBI laws enacted between January 2009 and December 2012. I collected and coded the text and citations of each law and developed a protocol and codebook to facilitate future research. RESULTS: Forty-four states and Washington, DC, passed youth sports TBI laws between 2009 and 2012. No state's youth sports TBI law focuses on primary prevention. Instead, such laws focus on (1) increasing coaches' and parents' ability to identify and respond to TBIs and (2) reducing the immediate risk of multiple TBIs. CONCLUSIONS: Existing youth sports TBI laws were not designed to reduce initial TBIs. Evaluation is required to assess their effectiveness in reducing the risk and consequences of multiple TBIs. Continued research and evaluation of existing laws will be needed to develop a more comprehensive youth TBI-reduction solution. PMID- 23678904 TI - Predictors and a framework for fostering community advocacy as a community health worker core function to eliminate health disparities. AB - OBJECTIVES: Using a mixed-method, participatory research approach, we investigated factors related to community health worker (CHW) community advocacy that affect social determinants of health. METHODS: We used cross-sectional survey data for 371 CHWs to assess demographics, training, work environment, and leadership qualities on civic, political, and organizational advocacy. We present advocacy stories to further articulate CHW activities. The data reported are from the recently completed National Community Health Workers Advocacy Study. RESULTS: CHWs are involved in advocacy that is community-focused, although advocacy differs by intrinsic leadership, experience, training, and work environment. We propose a framework to conceptualize, support, and evaluate CHW advocacy and the iterative processes they engage in. These processes create opportunities for community voice and action to affect social and structural conditions that are known to have wide-ranging health effects on communities. CONCLUSIONS: The framework presented may have utility for CHWs, their training programs, and their employers as well as funders and policymakers aiming to promote health equity. PMID- 23678905 TI - Installation of a bridge barrier as a suicide prevention strategy in Montreal, Quebec, Canada. AB - OBJECTIVES: We investigated whether the installation of a suicide prevention barrier on Jacques-Cartier Bridge led to displacement of suicides to other jumping sites on Montreal Island and Monteregie, Quebec, the 2 regions it connects. METHODS: Suicides on Montreal Island and Monteregie were extracted from chief coroners' records. We used Poisson regression to assess changes in annual suicide rates by jumping from Jacques-Cartier Bridge and from other bridges and other sites and by other methods before (1990-June 2004) and after (2005-2009) installation of the barrier. RESULTS: Suicide rates by jumping from Jacques Cartier Bridge decreased after installation of the barrier (incidence rate ratio [IRR] = 0.24; 95% confidence interval [CI] = 0.13, 0.43), which persisted when all bridges (IRR = 0.39; 95% CI = 0.27, 0.55) and all jumping sites (IRR = 0.66; 95% CI = 0.54, 0.80) in the regions were considered. CONCLUSIONS: Little or no displacement to other jumping sites may occur after installation of a barrier at an iconic site such as Jacques-Cartier Bridge. A barrier's design is important to its effectiveness and should be considered for new bridges with the potential to become symbolic suicide sites. PMID- 23678906 TI - Getting actionable about community resilience: the Los Angeles County Community Disaster Resilience project. AB - Community resilience (CR)--ability to withstand and recover from a disaster--is a national policy expectation that challenges health departments to merge disaster preparedness and community health promotion and to build stronger partnerships with organizations outside government, yet guidance is limited. A baseline survey documented community resilience-building barriers and facilitators for health department and community-based organization (CBO) staff. Questions focused on CBO engagement, government-CBO partnerships, and community education. Most health department staff and CBO members devoted minimal time to community disaster preparedness though many serve populations that would benefit. Respondents observed limited CR activities to activate in a disaster. The findings highlighted opportunities for engaging communities in disaster preparedness and informed the development of a community action plan and toolkit. PMID- 23678907 TI - Effects of household socialization on youth susceptibility to smoke: differences between youth age groups and trends over time. AB - A Canadian biennial youth survey facilitated repeating investigation of susceptibility to smoke and household socialization. We operationalized susceptibility to smoke by 3 levels on the basis of intention and behavior. Variables consistently predicting greater susceptibility across time and age groups were sibling smoking, household restrictions, and vehicle smoke exposure. Gender was predictive among older youths. Household restrictions and emerging legislation to ban smoking in vehicles with youth passengers provide protection against secondhand smoke exposure and sustained resolve to remain smoke-free. PMID- 23678908 TI - Rolison et al. respond. PMID- 23678909 TI - Motorcycle engine capacity may not underlie increased risks. PMID- 23678910 TI - Achieving population health in accountable care organizations. AB - Although "population health" is one of the Institute for Healthcare Improvement's Triple Aim goals, its relationship to accountable care organizations (ACOs) remains ill-defined and lacks clarity as to how the clinical delivery system intersects with the public health system. Although defining population health as "panel" management seems to be the default definition, we called for a broader "community health" definition that could improve relationships between clinical delivery and public health systems and health outcomes for communities. We discussed this broader definition and offered recommendations for linking ACOs with the public health system toward improving health for patients and their communities. PMID- 23678911 TI - Early life exposure to the 1918 influenza pandemic and old-age mortality by cause of death. AB - OBJECTIVES: We sought to analyze how early exposure to the 1918 influenza pandemic is associated with old-age mortality by cause of death. METHODS: We analyzed the National Health Interview Survey (n = 81,571; follow-up 1989-2006; 43,808 deaths) and used year and quarter of birth to assess timing of pandemic exposure. We used Cox proportional and Fine-Gray competing hazard models for all cause and cause-specific mortality, respectively. RESULTS: Cohorts born during pandemic peaks had excess all-cause mortality attributed to increased noncancer mortality. We found evidence for a trade-off between noncancer and cancer causes: cohorts with high noncancer mortality had low cancer mortality, and vice versa. CONCLUSIONS: Early disease exposure increases old-age mortality through noncancer causes, which include respiratory and cardiovascular diseases, and may trigger a trade-off in the risk of cancer and noncancer causes. Potential mechanisms include inflammation or apoptosis. The findings contribute to our understanding of the causes of death behind the early disease exposure-later mortality association. The cancer-noncancer trade-off is potentially important for understanding the mechanisms behind these associations. PMID- 23678912 TI - Associations between health literacy and established predictors of smoking cessation. AB - OBJECTIVES: We examined associations between health literacy and predictors of smoking cessation among 402 low-socioeconomic status (SES), racially/ethnically diverse smokers. METHODS: Data were collected as part of a larger study evaluating smoking health risk messages. We conducted multiple linear regression analyses to examine relations between health literacy and predictors of smoking cessation (i.e., nicotine dependence, smoking outcome expectancies, smoking risk perceptions and knowledge, self-efficacy, intentions to quit or reduce smoking). RESULTS: Lower health literacy was associated with higher nicotine dependence, more positive and less negative smoking outcome expectancies, less knowledge about smoking health risks, and lower risk perceptions. Associations remained significant (P < .05) after controlling for demographics and SES-related factors. CONCLUSIONS: These results provide the first evidence that low health literacy may serve as a critical and independent risk factor for poor cessation outcomes among low-socioeconomic status, racially/ethnically diverse smokers. Research is needed to investigate potential mechanisms underlying this relationship. PMID- 23678913 TI - Density and proximity of fast food restaurants and body mass index among African Americans. AB - OBJECTIVES: The purpose of this study was to address current gaps in the literature by examining the associations of fast food restaurant (FFR) density around the home and FFR proximity to the home, respectively, with body mass index (BMI) among a large sample of African American adults from Houston, Texas. METHODS: We used generalized linear models with generalized estimating equations to examine associations of FFR density at 0.5-, 1-, 2-, and 5-mile road network buffers around the home with BMI and associations of the closest FFR to the home with BMI. All models were adjusted for a range of individual-level covariates and neighborhood socioeconomic status. We additionally investigated the moderating effects of household income on these relations. Data were collected from December 2008 to July 2009. RESULTS: FFR density was not associated with BMI in the main analyses. However, FFR density at 0.5, 1, and 2 miles was positively associated with BMI among participants with lower incomes (P <= .025). Closer FFR proximity was associated with higher BMI among all participants (P < .001), with stronger associations emerging among those of lower income (P < .013) relative to higher income (P < .014). CONCLUSIONS: Additional research with more diverse African American samples is needed, but results supported the potential for the fast food environment to affect BMI among African Americans, particularly among those of lower economic means. PMID- 23678915 TI - Protecting public places. PMID- 23678914 TI - Influence of friends on children's physical activity: a review. AB - We examined evidence for friendship influences on children's physical activity (PA) through systematic searches of online databases in May 2012. We identified 106 studies (25 qualitative) published in English since 2000 that analyzed indicators of friendship influences (e.g., communication about PA, friends' PA, and PA with friends) among persons younger than 19 years. Children's PA was positively associated with encouragement from friends (43 of 55 studies indicating a positive relationship), friends' own PA (30/35), and engagement with friends in PA (9/10). These findings are consistent with friends influencing PA, but most studies did not isolate influence from other factors that could explain similarity. Understanding friendship influences in childhood can facilitate the promotion of lifelong healthy habits. PA with friends should be considered in health promotion programs. PMID- 23678916 TI - Applying community engagement to disaster planning: developing the vision and design for the Los Angeles County Community Disaster Resilience initiative. AB - Community resilience (CR) is a priority for preparedness, but few models exist. A steering council used community-partnered participatory research to support workgroups in developing CR action plans and hosted forums for input to design a pilot demonstration of implementing CR versus enhanced individual preparedness toolkits. Qualitative data describe how stakeholders viewed CR, how toolkits were developed, and demonstration design evolution. Stakeholders viewed community engagement as facilitating partnerships to implement CR programs when appropriately supported by policy and CR resources. Community engagement exercises clarified motivations and informed action plans (e.g., including vulnerable populations). Community input identified barriers (e.g., trust in government) and CR-building strategies. A CR toolkit and demonstration comparing its implementation with individual preparedness were codeveloped. Community partnered participatory research was a useful framework to plan a CR initiative through knowledge exchange. PMID- 23678917 TI - A new urban planning code's impact on walking: the residential environments project. AB - OBJECTIVES: We examined whether people moving into a housing development designed according to a state government livable neighborhoods subdivision code engage in more walking than do people who move to other types of developments. METHODS: In a natural experiment of 1813 people building homes in 73 new housing developments in Perth, Western Australia, we surveyed participants before and then 12 and 36 months after moving. We measured self-reported walking using the Neighborhood Physical Activity Questionnaire and collected perceptions of the environment and self-selection factors. We calculated objective measures of the built environment using a Geographic Information System. RESULTS: After relocation, participants in livable versus conventional developments had greater street connectivity, residential density, land use mix, and access to destinations and more positive perceptions of their neighborhood (all P < .05). However, there were no significant differences in walking over time by type of development (P > .05). CONCLUSIONS: Implementation of the Livable Neighborhoods Guidelines produced more supportive environments; however, the level of intervention was insufficient to encourage more walking. Evaluations of new urban planning policies need to incorporate longer term follow-up to allow time for new neighborhoods to develop. PMID- 23678918 TI - Offen et al. respond. PMID- 23678919 TI - Disparities in exposure to automobile and truck traffic and vehicle emissions near the Los Angeles-Long Beach port complex. AB - OBJECTIVES: We assessed how traffic and mobile-source air pollution impacts are distributed across racial/ethnic and socioeconomically diverse groups in port adjacent communities in southern Los Angeles County, which may experience divergent levels of exposure to port-related heavy-duty diesel truck traffic because of existing residential and land use patterns. METHODS: We used spatial regression techniques to assess the association of neighborhood racial/ethnic and socioeconomic composition with residential parcel-level traffic and vehicle related fine particulate matter exposure after accounting for built environment and land use factors. RESULTS: After controlling for factors associated with traffic generation, we found that a higher percentage of nearby Black and Asian/Pacific Islander residents was associated with higher exposure, a higher percentage of Hispanic residents was associated with higher traffic exposure but lower vehicle particulate matter exposure, and areas with lower socioeconomic status experienced lower exposure. CONCLUSIONS: Disparities in traffic and vehicle particulate matter exposure are nuanced depending on the exposure metric used, the distribution of the traffic and emissions, and pollutant dispersal patterns. Future comparative research is needed to assess potential disparities in other transportation and goods movement corridors. PMID- 23678920 TI - Bicycle guidelines and crash rates on cycle tracks in the United States. AB - OBJECTIVES: We studied state-adopted bicycle guidelines to determine whether cycle tracks (physically separated, bicycle-exclusive paths adjacent to sidewalks) were recommended, whether they were built, and their crash rate. METHODS: We analyzed and compared US bicycle facility guidelines published between 1972 and 1999. We identified 19 cycle tracks in the United States and collected extensive data on cycle track design, usage, and crash history from local communities. We used bicycle counts and crash data to estimate crash rates. RESULTS: A bicycle facility guideline written in 1972 endorsed cycle tracks but American Association of State Highway and Transportation Officials (AASHTO) guidelines (1974-1999) discouraged or did not include cycle tracks and did not cite research about crash rates on cycle tracks. For the 19 US cycle tracks we examined, the overall crash rate was 2.3 (95% confidence interval = 1.7, 3.0) per 1 million bicycle kilometers. CONCLUSIONS: AASHTO bicycle guidelines are not explicitly based on rigorous or up-to-date research. Our results show that the risk of bicycle-vehicle crashes is lower on US cycle tracks than published crashes rates on roadways. This study and previous investigations support building cycle tracks. PMID- 23678921 TI - Evaluating the impact of dental care on housing intervention program outcomes among homeless veterans. AB - OBJECTIVES: In this retrospective longitudinal cohort study, we examined the impact of dental care on outcomes among homeless veterans discharged from a Department of Veterans Affairs (VA) transitional housing intervention program. METHODS: Our sample consisted of 9870 veterans who were admitted into a VA homeless intervention program during 2008 and 2009, 4482 of whom received dental care during treatment and 5388 of whom did not. Primary outcomes of interest were program completion, employment or stable financial status on discharge, and transition to permanent housing. We calculated descriptive statistics and compared the 2 study groups with respect to demographic characteristics, medical and psychiatric history (including alcohol and substance use), work and financial support, and treatment outcomes. RESULTS: Veterans who received dental care were 30% more likely than those who did not to complete the program, 14% more likely to be employed or financially stable, and 15% more likely to have obtained residential housing. CONCLUSIONS: Provision of dental care has a substantial positive impact on outcomes among homeless veterans participating in housing intervention programs. This suggests that homeless programs need to weigh the benefits and cost of dental care in program planning and implementation. PMID- 23678922 TI - Patterns of older Americans' health care utilization over time. AB - OBJECTIVES: We analyzed correlates of older Americans' continuous and transitional health care utilization over 4 years. METHODS: We analyzed data for civilian, noninstitutionalized US individuals older than 50 years from the 2006 and 2008 waves of the Health and Retirement Study. We estimated multinomial logistic models of persistent and intermittent use of physician, inpatient hospital, home health, and outpatient surgery over the 2004-2008 survey periods. RESULTS: Individuals with worse or worsening health were more likely to persistently use medical care and transition into care and not transition out of care over time. Financial variables were less often significant and, when significant, were often in an unexpected direction. CONCLUSIONS: Older individuals' health and changes in health are more strongly correlated with persistence of and changes in care-seeking behavior over time than are financial status and changes in financial status. The more pronounced sensitivity to health status and changes in health are important considerations in insurance and retirement policy reforms. PMID- 23678923 TI - Pathways to early violent death: the voices of serious violent youth offenders. AB - Quantitative studies have uncovered factors associated with early violent death among youth offenders detained in the juvenile justice system, but little is known about the contextual factors associated with pathways to early violent death among youths detained in adult jails. We interviewed young Black male serious violent youth offenders detained in an adult jail to understand their experience of violence. Their narratives reveal how the code of the street, informal rules that govern interpersonal violence among poor inner-city Black male youths, increases the likelihood of violent victimization. Youth offenders detained in adult jails have the lowest rate of service provision among all jail populations. We have addressed how services for youth offenders can be improved to reduce the pathways to early violent death. PMID- 23678924 TI - Multidrug-resistant tuberculosis among patients in Baja California, Mexico, and Hispanic patients in California. AB - OBJECTIVES: We sought to compare prevalence and determinants of multidrug resistant tuberculosis (MDR-TB) between tuberculosis patients in Baja California, Mexico, and Hispanic patients in California. METHODS: Using data from Mexico's National TB Drug Resistance Survey (2008-2009) and California Department of Public Health TB case registry (2004-2009), we assessed differences in MDR-TB prevalence comparing (1) Mexicans in Baja California, (2) Mexico-born Hispanics in California, (3) US-born Hispanics in California, and (4) California Hispanics born elsewhere. RESULTS: MDR-TB prevalence was 2.1% in Baja California patients, 1.6% in Mexico-born California patients, 0.4% in US-born California patients, and 2.7% in Hispanic California patients born elsewhere. In multivariate analysis, previous antituberculosis treatment was associated with MDR-TB (odds ratio [OR] = 6.57; 95% confidence interval [CI] = 3.34, 12.96); Mexico-born TB patients in California (OR = 5.08; 95% CI = 1.19, 21.75) and those born elsewhere (OR = 7.69; 95% CI = 1.71, 34.67) had greater odds of MDR-TB compared with US-born patients (reference category). CONCLUSIONS: Hispanic patients born outside the US or Mexico were more likely to have MDR-TB than were those born within these countries. Possible explanations include different levels of exposure to resistant strains and inadequate treatment. PMID- 23678925 TI - Bullying and quality of life in youths perceived as gay, lesbian, or bisexual in Washington State, 2010. AB - OBJECTIVES: We examined the association between perceived sexual orientation (PSO), bullying, and quality of life (QOL) among US adolescents. METHODS: We analyzed data from the 2010 Washington State Healthy Youth Survey collected in public school grades 8, 10, and 12 (n = 27,752). Bullying status was characterized as never bullied, bullied because of PSO, or bullied for other reasons. Survey-weighted regression examined differences in QOL, depressed mood, and consideration of suicide by bullying status. RESULTS: Among male students, 14%, 11%, and 9% reported being bullied because of PSO in 8th, 10th, and 12th grades, respectively; and among female students, 11%, 10%, and 6%. In all gender and grade strata, being bullied because of PSO was associated with lower QOL scores and increased the odds of depressed mood or consideration of suicide. Moreover, the magnitudes of these associations were greater than for being bullied for other reasons. CONCLUSIONS: Bullying because of PSO is widely prevalent and significantly affects several facets of youth QOL. Bully-prevention or harm-reduction programs must address bullying because of PSO. PMID- 23678926 TI - Community health workers in low- and middle-income countries: what do we know about scaling up and sustainability? AB - OBJECTIVES: We sought to provide a systematic review of the determinants of success in scaling up and sustaining community health worker (CHW) programs in low- and middle-income countries (LMICs). METHODS: We searched 11 electronic databases for academic literature published through December 2010 (n = 603 articles). Two independent reviewers applied exclusion criteria to identify articles that provided empirical evidence about the scale-up or sustainability of CHW programs in LMICs, then extracted data from each article by using a standardized form. We analyzed the resulting data for determinants and themes through iterated categorization. RESULTS: The final sample of articles (n = 19) present data on CHW programs in 16 countries. We identified 23 enabling factors and 15 barriers to scale-up and sustainability, which were grouped into 3 thematic categories: program design and management, community fit, and integration with the broader environment. CONCLUSIONS: Scaling up and sustaining CHW programs in LMICs requires effective program design and management, including adequate training, supervision, motivation, and funding; acceptability of the program to the communities served; and securing support for the program from political leaders and other health care providers. PMID- 23678928 TI - The shale gas boom and the need for rational policy. AB - High-volume, slick water hydraulic fracturing of shale relies on pumping millions of gallons of surface water laced with toxic chemicals and sand under high pressure to create fractures to release the flow of gas. The process, however, has the potential to cause serious and irreparable damage to the environment and the potential for harm to human and animal health. At issue is how society should form appropriate policy in the absence of well-designed epidemiological studies and health impact assessments. The issue is fraught with environmental, economic, and health implications, and federal and state governments must establish detailed safeguards and ensure regulatory oversight, both of which are presently lacking in states where hydraulic fracturing is allowed. PMID- 23678927 TI - Public health and law collaboration: the Philadelphia Lead Court study. AB - OBJECTIVES: We determined whether Philadelphia Lead Court is effective in enforcing lead hazard remediation in the homes of children with elevated blood lead levels. METHODS: We created a deidentified data set for properties with an initial failed home inspection (IFHI) for lead hazards from January 1, 1998, through December 31, 2008, and compared compliance rates within the first year and time to compliance for lead hazard remediation between 1998 and 2002 (precourt period) and between 2003 and 2008 (court period). We evaluated predictors of time to compliance. RESULTS: Within 1 year of the IFHI, 6.6% of the precourt and 76.8% of the court cases achieved compliance (P < .001) for the 3764 homes with data. Four years after the IFHI, 18% had attained compliance in the precourt period compared with 83.1% for the court period (P < .001). A proportional hazard analysis found that compliance was 8 times more likely in the court than the precourt period (P < .001). CONCLUSIONS: Lead court was more effective than precourt enforcement strategies. Most properties were remediated within 1 year of the IFHI, and time to compliance was significantly reduced. This model court could be replicated in other cities with similar enforcement problems. PMID- 23678929 TI - Impact of welfare reform on mortality: an evaluation of the Connecticut jobs first program, a randomized controlled trial. AB - OBJECTIVES: We examined whether Jobs First, a multicenter randomized trial of a welfare reform program conducted in Connecticut, demonstrated increases in employment, income, and health insurance relative to traditional welfare (Aid to Families with Dependent Children). We also investigated if higher earnings and employment improved mortality of the participants. METHODS: We revisited the Jobs First randomized trial, successfully linking 4612 participant identifiers to 15 years of prospective mortality follow-up data through 2010, producing 240 deaths. The analysis was powered to detect a 20% change in mortality hazards. RESULTS: Significant employment and income benefits were realized among Jobs First recipients relative to traditional welfare recipients, particularly for the most disadvantaged groups. However, although none of these reached statistical significance, all participants in Jobs First (overall, across centers, and all subgroups) experienced higher mortality hazards than traditional welfare recipients. CONCLUSIONS: Increases in income and employment produced by Jobs First relative to traditional welfare improved socioeconomic status but did not improve survival. PMID- 23678930 TI - Impact of Connecticut legislation incentivizing elimination of unhealthy competitive foods on National School Lunch Program participation. AB - OBJECTIVES: We analyzed the impact of Connecticut legislation incentivizing voluntary school district-level elimination of unhealthy competitive foods on National School Lunch Program (NSLP) participation. METHODS: We analyzed data on free, reduced, and paid participation in the NSLP from 904 schools within 154 Connecticut school districts from the 2004-2005 to the 2009-2010 school year, resulting in 5064 observations of annual school-level meal participation. We used multilevel regression modeling techniques to estimate the impact of the state competitive food legislation on the count of NSLP lunches served per student in each school. RESULTS: Overall, the state statute was associated with an increase in school lunch participation. We observed increases between 7% and 23% for middle- and high-school meal programs, and a slight decrease of 2.5% for the elementary school free meal eligibility category, leading to an estimated revenue increase of roughly $30 000 for an average school district per school year. CONCLUSIONS: This study provides support for national implementation of proposed rigorous competitive food standards that can improve the health of students while supporting local school district finances. PMID- 23678933 TI - Reassuring or risky: the presentation of seafood safety in the aftermath of the British Petroleum Deepwater Horizon Oil Spill. AB - The BP Deepwater Horizon Oil Spill was enormously newsworthy; coverage interlaced discussions of health, economic, and environmental impacts and risks. We analyzed 315 news articles that considered Gulf seafood safety from the year following the spill. We explored reporting trends, risk presentation, message source, stakeholder perspectives on safety, and framing of safety messages. Approximately one third of articles presented risk associated with seafood consumption as a standalone issue, rather than in conjunction with environmental or economic risks. Government sources were most frequent and their messages were largely framed as reassuring as to seafood safety. Discussions of prevention were limited to short-term, secondary prevention approaches. These data demonstrate a need for risk communication in news coverage of food safety that addresses the larger risk context, primary prevention, and structural causes of risk. PMID- 23678932 TI - Continuing the dialogue on health: insights from the 2010 APHA Delegation to Cuba. PMID- 23678931 TI - Job strain and health-related lifestyle: findings from an individual-participant meta-analysis of 118,000 working adults. AB - OBJECTIVES: We examined the associations of job strain, an indicator of work related stress, with overall unhealthy and healthy lifestyles. METHODS: We conducted a meta-analysis of individual-level data from 11 European studies (cross-sectional data: n = 118,701; longitudinal data: n = 43,971). We analyzed job strain as a set of binary (job strain vs no job strain) and categorical (high job strain, active job, passive job, and low job strain) variables. Factors used to define healthy and unhealthy lifestyles were body mass index, smoking, alcohol intake, and leisure-time physical activity. RESULTS: Individuals with job strain were more likely than those with no job strain to have 4 unhealthy lifestyle factors (odds ratio [OR] = 1.25; 95% confidence interval [CI] = 1.12, 1.39) and less likely to have 4 healthy lifestyle factors (OR = 0.89; 95% CI = 0.80, 0.99). The odds of adopting a healthy lifestyle during study follow-up were lower among individuals with high job strain than among those with low job strain (OR = 0.88; 95% CI = 0.81, 0.96). CONCLUSIONS: Work-related stress is associated with unhealthy lifestyles and the absence of stress is associated with healthy lifestyles, but longitudinal analyses suggest no straightforward cause-effect relationship between work-related stress and lifestyle. PMID- 23678934 TI - Community resilience and public health practice. PMID- 23678935 TI - Timeliness of pediatric influenza vaccination compared with seasonal influenza activity in an urban community, 2004-2008. AB - OBJECTIVES: We assessed pediatric influenza vaccination in relation to community influenza activity. METHODS: We examined seasonal influenza vaccination in 34,012 children aged 6 months through 18 years from 5 academically affiliated clinics in northern Manhattan, New York (an urban low-income community) during the 2004-2008 seasons using hospital and city immunization registries. We calculated the cumulative number of administered influenza vaccine doses and proportion of children with any (>= 1 dose) or full (1-2 doses per age recommendations) vaccination at the onset and peak of community polymerase chain reaction confirmed influenza activity according to state surveillance reports and by March 31 each season. RESULTS: Influenza vaccine administration began before October 1, peaked before influenza activity onset, and declined gradually over each season. Coverage at influenza activity onset, peak, and by March 31 increased over the 5 seasons. However, most children lacked full vaccination at these time points, particularly adolescents, minorities, and those requiring 2 doses. CONCLUSIONS: Despite early initiation of influenza vaccination, few children were fully vaccinated when influenza began circulating. Interventions should address factors negatively affecting timely influenza vaccination, especially in high-risk populations. PMID- 23678937 TI - Building community disaster resilience: perspectives from a large urban county department of public health. AB - An emerging approach to public health emergency preparedness and response, community resilience encompasses individual preparedness as well as establishing a supportive social context in communities to withstand and recover from disasters. We examine why building community resilience has become a key component of national policy across multiple federal agencies and discuss the core principles embodied in community resilience theory-specifically, the focus on incorporating equity and social justice considerations in preparedness planning and response. We also examine the challenges of integrating community resilience with traditional public health practices and the importance of developing metrics for evaluation and strategic planning purposes. Using the example of the Los Angeles County Community Disaster Resilience Project, we discuss our experience and perspective from a large urban county to better understand how to implement a community resilience framework in public health practice. PMID- 23678936 TI - Racial/Ethnic disparities in health care receipt among male cancer survivors. AB - OBJECTIVES: We examined racial/ethnic disparities in health care receipt among a nationally representative sample of male cancer survivors. METHODS: We identified men aged 18 years and older from the 2006-2010 National Health Interview Survey who reported a history of cancer. We assessed health care receipt in 4 self reported measures: primary care visit, specialist visit, flu vaccination, and pneumococcal vaccination. We used hierarchical logistic regression modeling, stratified by age (< 65 years vs >= 65 years). RESULTS: In adjusted models, older African American and Hispanic survivors were approximately twice as likely as were non-Hispanic Whites to not see a specialist (odds ratio [OR] = 1.78; 95% confidence interval [CI] = 1.19, 2.68 and OR = 2.09; 95% CI = 1.18, 3.70, respectively), not receive the flu vaccine (OR = 2.21; 95% CI = 1.45, 3.37 and OR = 2.20; 95% CI = 1.21, 4.01, respectively), and not receive the pneumococcal vaccine (OR = 2.24; 95% CI = 1.54, 3.24 and OR = 3.10; 95% CI = 1.75, 5.51, respectively). CONCLUSIONS: Racial/ethnic disparities in health care receipt are evident among older, but not younger, cancer survivors, despite access to Medicare. These survivors may be less likely to see specialists, including oncologists, and receive basic preventive care. PMID- 23678939 TI - Epidemiology and public health in 1906 England: Arthur Newsholme's methodological innovation to study breastfeeding and fatal diarrhea. AB - In 1906 Arthur Newsholme linked artificial feeding and fatal diarrhea in infants aged one year and younger on the basis of two independent sources of information: mortality registration and a three-year (1903-1905) census of infants from Brighton, United Kingdom. Artificial feeding was more common in the infants who had died (89.3%) than in those in the survey (22.3%). However, boldly assuming the two data sources were nested, Newsholme computed the risks of fatal diarrhea: these were 48 times greater for infants fed fresh cow's milk and 94 times greater for those fed condensed milk than for infants who were exclusively breastfed. This mode of computing risks and risk ratios before the invention of the cohort study design was more innovative than was the usual investigation techniques of his contemporary epidemiologists. Newsholme's conclusions were consistent with the current knowledge that breastfeeding protects against fatal diarrhea. PMID- 23678938 TI - Acute use of alcohol and methods of suicide in a US national sample. AB - OBJECTIVES: We explored age, gender, and racial/ethnic differences with alcohol use and firearms, hanging or asphyxiation, and poisoning methods of suicide. METHODS: We analyzed data for 37,993 suicide decedents aged 18 years and older from the 2005-2010 National Violent Death Reporting System database. Multinomial logistic regressions examined associations of method with alcohol use defined by blood alcohol content. Two-way interactions tested the effects of age, gender, and race/ethnicity on the associations between alcohol use and method of suicide. RESULTS: Alcohol was present among decedents who used the 3 leading methods of suicide: firearm (35.0%), hanging (36.8%), and poisoning (32.7%). Two-way interaction tests suggested that in young and middle adulthood, individuals were more likely to drink alcohol when they used a firearm or hanging (compared with poisoning), but in older adulthood, the reverse was true, with alcohol use more likely with poisoning. Interaction tests also suggested that Asians and Pacific Islanders were most likely to use alcohol in poisonings and that Blacks were least likely to use alcohol in hangings. CONCLUSIONS: The results suggested that alcohol use before suicide was influenced by several factors, including age, race/ethnicity, and suicide method. PMID- 23678940 TI - Neuropsychological course of voltage-gated potassium channel and glutamic acid decarboxylase antibody related limbic encephalitis. AB - BACKGROUND AND PURPOSE: Autoantibodies (abs) to glutamic acid decarboxylase (GAD) and to voltage-gated potassium channels (VGKC) induce distinct courses of limbic encephalitis, related to MRI findings, seizure outcome and cognition. METHODS: A detailed analysis of the cognitive course of the two forms is presented, spanning a median time interval of 28 months, including parameters of attention, learning and memory in 15 VGKC-ab-positive and 16 GAD-ab-positive patients. RESULTS: In both groups, the initially significantly impaired attention performance recovered to a putatively premorbid level. In VGKC patients the partially severely impaired learning and memory performance improved under treatment but remained subnormal at last follow-up. By contrast, GAD-ab-positive patients had initially less impaired learning and memory scores but did not show an improvement under treatment. CONCLUSIONS: The results provide evidence of distinct relations between inductive processes and cognitive outcome in VGKC-ab-positive and GAD-ab positive subforms of limbic encephalitis, which possibly depend on differences in pathogenic molecular mechanisms and affected cerebral loci. PMID- 23678941 TI - Rab27 effectors, pleiotropic regulators in secretory pathways. AB - Rab27, a member of the small GTPase Rab family, is widely conserved in metazoan, and two Rab27 isoforms, Rab27A and Rab27B, are present in vertebrates. Rab27A was the first Rab protein whose dysfunction was found to cause a human hereditary disease, type 2 Griscelli syndrome, which is characterized by silvery hair and immunodeficiency. The discovery in the 21st century of three distinct types of mammalian Rab27A effectors [synaptotagmin-like protein (Slp), Slp homologue lacking C2 domains (Slac2), and Munc13-4] that specifically bind active Rab27A has greatly accelerated our understanding not only of the molecular mechanisms of Rab27A-mediated membrane traffic (e.g. melanosome transport and regulated secretion) but of the symptoms of Griscelli syndrome patients at the molecular level. Because Rab27B is widely expressed in various tissues together with Rab27A and has been found to have the ability to bind all of the Rab27A effectors that have been tested, Rab27A and Rab27B were initially thought to function redundantly by sharing common Rab27 effectors. However, recent evidence has indicated that by interacting with different Rab27 effectors Rab27A and Rab27B play different roles in special types of secretion (e.g. exosome secretion and mast cell secretion) even within the same cell type. In this review article, I describe the current state of our understanding of the functions of Rab27 effectors in secretory pathways. PMID- 23678942 TI - Molecular analysis of regulative events in the developing chick limb. AB - The developing chick limb has the remarkable ability to regulate for the loss of large amounts of mesenchyme and maintain a normal limb pattern in early (Hamburger and Hamilton Stage 19; E3) limbs. How the limb can regulate for tissue loss and why this ability is lost as development proceeds (after Hamburger and Hamilton Stage 21; E3.5) is unclear. We have investigated the origins of cells involved in regulative processes and, for the first time, the molecular changes occurring, and find striking differences between developmental time points just 0.5 days apart. We demonstrate that subtle changes in cell dispersal and cell proliferation occur in HH St21 limbs but not in HH St19 limbs and also demonstrate that there is no net replacement of removed tissue at either HH St21 or St19. We further show that changes in the Fgf8/Shh/Bmp4/Gremlin signaling pathway together with the appearance of distal Hox gene activation coincide with the limbs' ability to regulate for large tissue loss. We also demonstrate that following small tissue loss, limbs can regulate for missing tissue to produce normal pattern with no net replacement of missing tissue, as seen in limbs following large tissue loss. Our results indicate the regulative ability of the limb is not due to changes in cell proliferation, cell lineage nor replacement of the missing tissue - regulative ability is reliant upon the signaling environment remaining. PMID- 23678943 TI - Quantifying uncertainty of determination by standard additions and serial dilutions methods taking into account standard uncertainties in both axes. AB - The analytical expressions for the calculation of the standard uncertainty of the predictor variable either extrapolated or interpolated from a calibration line that takes into account uncertainties in both axes have been derived and successfully verified using the Monte Carlo modeling. These expressions are essential additions to the process of the analyte quantification realized with either the method of standard additions (SAM) or the method of serial dilutions (MSD). The latter one has been proposed as an alternative approach to the SAM procedure. In the MSD approach instead of the sequence of standard additions, the sequence of solvent additions to the spiked sample is performed. The comparison of the calculation results based on the expressions derived to their equivalents obtained from the Monte Carlo simulation, applied to real experimental data sets, confirmed that these expressions are valid in real analytical practice. The estimation of the standard uncertainty of the analyte concentration, quantified via either SAM or MSD or simply a calibration curve, is of great importance for the construction of the uncertainty budget of an analytical procedure. The correct estimation of the standard uncertainty of the analyte concentration is a key issue in the quality assurance in the instrumental analysis. PMID- 23678944 TI - Cp*Rh-based heterometallic metallarectangles: size-dependent Borromean link structures and catalytic acyl transfer. AB - A series of Cp*Rh-based functional metallarectangles have been synthesized from metallaligands. Enlargement of one linker leads to the isolation of two novel Borromean link architectures. All these complexes are intact in solution, as evident from ESI-MS spectroscopic analysis. Arising from the combination of open Cu centers and favorable cavity space, {(Cp*Rh)4(bpe)2[Cu(opba).2MeOH]2}4(OTf).6MeOH shows extraordinary catalytic abilities with high efficiency and wide substrate selectivity in the acyl transfer reaction. PMID- 23678945 TI - Advanced intravital subcellular imaging reveals vital three-dimensional signalling events driving cancer cell behaviour and drug responses in live tissue. AB - The integration of signal transduction pathways plays a fundamental role in governing disease initiation, progression and outcome. It is therefore necessary to understand disease at the signalling level to enable effective treatment and to intervene in its progression. The recent extension of in vitro subcellular image-based analysis to live in vivo modelling of disease is providing a more complete picture of real-time, dynamic signalling processes or drug responses in live tissue. Intravital imaging offers alternative strategies for studying disease and embraces the biological complexities that govern disease progression. In the present review, we highlight how three-dimensional or live intravital imaging has uncovered novel insights into biological mechanisms or modes of drug action. Furthermore, we offer a prospective view of how imaging applications may be integrated further with the aim of understanding disease in a more physiological and functional manner within the framework of the drug discovery process. PMID- 23678946 TI - Relation between occupancy and abundance for a territorial species, the California spotted owl. AB - Land and resource managers often use detection-nondetection surveys to monitor the populations of species that may be affected by factors such as habitat alteration, climate change, and biological invasions. Relative to mark-recapture studies, using detection-nondetection surveys is more cost-effective, and recent advances in statistical analyses allow the incorporation of detection probability, covariates, and multiple seasons. We examined the efficacy of using detection-nondetection data (relative to mark-recapture data) for monitoring population trends of a territorial species, the California Spotted Owl (Strix occidentalis occidentalis). We estimated and compared the finite annual rates of population change (lambdat ) and the resulting realized population change (Deltat ) from both occupancy and mark-recapture data collected over 18 years (1993 2010). We used multiseason, robust-design occupancy models to estimate that territory occupancy declined during our study (Deltat = 0.702, 95% CI 0.552 0.852) due to increasing territory extinction rates (epsilon(1993) = 0.019 [SE 0.012]; epsilon(2009) = 0.134 [SE 0.043]) and decreasing colonization rates (gamma(1993) = 0.323 [SE 0.124]; gamma(2009) = 0.242 [SE 0.058]). We used Pradel's temporal-symmetry model for mark-recapture data to estimate that the population trajectory closely matched the trends in territory occupancy (Deltat = 0.725, 95% CI 0.445-1.004). Individual survival was constant during our study (phi(1993) = 0.816 [SE 0.020]; phi(2009) = 0.815 [SE 0.019]), whereas recruitment declined slightly (f(1993) = 0.195 [SE 0.032]; f(2009) = 0.160 [SE 0.023]). Thus, we concluded that detection-nondetection data can provide reliable inferences on population trends, especially when funds preclude more intensive mark-recapture studies. PMID- 23678947 TI - Is that a rodent in your luggage? A mixed method approach to describe bushmeat importation into the United States. AB - Bushmeat, defined as meat derived from wild animals, is a potential source of zoonotic pathogens. Bushmeat from restricted animals is illegal to import into the United States under US federal regulations. We reviewed US Centers for Disease Control and Prevention (CDC) port of entry surveillance records from September 2005 through December 2010 and conducted focus group studies to describe trends in and reasons for bushmeat importation into the United States. In total, 543 confiscated bushmeat items were recorded. Half of the confiscated bushmeat items identified were rodents. Africa was the most frequent continent of origin. Seasonality was evident, with bushmeat confiscations peaking in late spring to early summer. Four times more bushmeat was confiscated during an enhanced surveillance period in June 2010 compared with the same period in previous years, suggesting that routine surveillance underestimated the amount of bushmeat detected at US Ports of Entry. Focus groups held in three major US cities revealed that bushmeat importation is a multifaceted issue. Longstanding cultural practices of hunting and eating bushmeat make it difficult for consumers to acknowledge potential health and ecologic risks. Also, US merchants selling African goods, including bushmeat, in their stores have caused confusion among importers as to whether importation is truly illegal. Enhancing routine surveillance for bushmeat and consistent enforcement of penalties at all ports of entry, along with health education aimed at bushmeat importers, might be useful to deter illegal importation. PMID- 23678948 TI - KIR diversity in three ethnic populations of Assam state, Northeast India. AB - Killer immunoglobulin-like receptors (KIR) exhibit extensive diversity and it has been observed that populations with different ethno-history, linguistic, geographic and genetic backgrounds can differ in KIR profile. In this context, we have investigated the KIR complex in three ethnic populations-Kachari (n = 108), Ahom (n = 104) and Adivasi (n = 101) of Assam, Northeast India. The three populations had 145 distinct KIR genotypes in 313 individuals typed. The two Mongoloid populations--Kachari and Ahom had close genetic affinities with their parental East Asian groups where the Kachari clustered with Chinese populations and the Ahom in another clade clustered with Thailand Bangkok and Polynesian populations. The Adivasi differed markedly from these Mongoloid populations in having higher KIR 2DL2, 2DS2, 2DS3 and 2DS5, but lower 2DL3 (P value <0.0001). Like the other native Indian populations, the Adivasi had higher share of Bx haplogroup and C4Tx genotype (37/101). However, unlike other Indian populations, KIR 3DS1 gene frequency was lower in Adivasi (21%) and was comparable to the African populations. The neighbor-joining dendogram generated on the basis of KIR gene frequencies of our study populations with 43 world populations also placed the Adivasi with African populations. Interestingly, the three populations in the dendogram are consistent with their migration histories. In summary, our data suggest that KIR profile of the three ethnic populations displayed ethnic diversity and was consistent with their migration history thereby supporting the concept that KIR diversity may be used to understand genetic affinity and migration history of populations. PMID- 23678949 TI - Gender differences in home care clients and admission to long-term care in Ontario, Canada: a population-based retrospective cohort study. AB - BACKGROUND: Home care is integral to enabling older adults to delay or avoid long term care (LTC) admission. To date, there is little population-based data about gender differences in home care users and their subsequent outcomes. Our objectives were to quantify differences between women and men who used home care in Ontario, Canada and to determine if there were subsequent differences in LTC admission. METHODS: This is a population-based retrospective cohort study. We identified all adults aged 76+ years living in Ontario and receiving home care on April 1, 2007 (baseline). Using the Resident Assessment Instrument - Home Care (RAI-HC) linked to other databases, we characterized the cohort by living condition, health and functioning, and identified all acute care and LTC use in the year following baseline. RESULTS: The cohort consisted of 51,201 women and 20,102 men. Women were older, more likely to live alone, and more likely to rely on a child or child-in-law for caregiver support. Men most frequently identified a spouse as caregiver and their caregivers reported distress twice as often as women's caregivers. Men had higher rates of most chronic conditions and were more likely to experience impairment. Men were more likely to be admitted to hospital, to have longer stays in hospital, and to be admitted to LTC. CONCLUSIONS: Understanding who uses home care and why is critical to ensuring that these programs effectively reduce LTC use. We found that women outnumbered men but that men presented with higher levels of need. This detailed gender analysis highlights how needs differ between older women, men, and their respective caregivers. PMID- 23678950 TI - A novel RNA polymerase-binding protein controlling genes involved in spore germination in Bacillus subtilis. AB - A growing class of proteins regulates transcription through interaction with DNA dependent RNA polymerase. Here we report that a recently identified, highly conserved sporulation gene ylyA encodes a novel RNA polymerase-binding protein that influences the expression of genes under the control of the late-acting, sporulation sigma factor sigma(G) in Bacillus subtilis. Spores from a ylyA mutant exhibited defects in germination corresponding to changes in the levels of membrane receptors for spore germinants and a protein channel governing the release of dipicolinic acid and hydration of the spore core during germination. Purified YlyA interacted with RNA polymerase and stimulated transcription from promoters dependent on sigma(G) but not promoters dependent on the housekeeping sigma factor sigma(A) . YlyA is a previously unrecognized RNA polymerase-binding protein that is dedicated to modulating the expression of genes involved in spore germination. PMID- 23678953 TI - Dying scenarios improve recall as much as survival scenarios. AB - Merely contemplating one's death improves retention for entirely unrelated material learned subsequently. This "dying to remember" effect seems conceptually related to the survival processing effect, whereby processing items for their relevance to being stranded in the grasslands leads to recall superior to that of other deep processing control conditions. The present experiments directly compared survival processing scenarios with "death processing" scenarios. Results showed that when the survival and dying scenarios are closely matched on key dimensions, and possible congruency effects are controlled, the dying and survival scenarios produced equivalently high recall levels. We conclude that the available evidence (cf. Bell, Roer, & Buchner, 2013; Klein, 2012), while not definitive, is consistent with the possibility of overlapping mechanisms. PMID- 23678954 TI - Comparative evaluation of equations predicting methane production of dairy cattle from feed characteristics. AB - Techniques that allow direct measurements on animals to quantify methane (CH4) emissions are costly and difficult to transfer to herd level. Mathematical approaches have been developed to predict methane emissions of cattle based on diet and intake characteristics, which were calibrated against largely varying calorimetry data. In this study, nine CH4 prediction equations were applied to five typical Central European dairy cow diets in order to compare their applicability. The five diets differed in respect of forage proportion and type. In a first attempt, regression equations were selected containing easily accessible data such as dry matter intake (DMI, kg/d) forage proportion, as well as neutral and acid detergent fibre that can also be extracted from on-farm datasets. Smallest differences to mean values were observed with the application of equations using neutral detergent fibre, while standard deviations were highest. Therefore, the best capability to differentiate between diets was shown, when using equations that operated with forage proportion and DMI. Nevertheless, the role of CH4 prediction equations should not be overestimated. The differences in CH4 estimates show that frequently used equations are still inaccurate and may only serve as implications to locate trends. It should be taken into consideration to expand datasets, involving future CH4 measurements, on animal and herd level, feeding typical, up-to-date regional diets in order to get more precise equations, suitable for a greater range of estimations. To ease and simplify the future applications, the prediction equations could be classified into groups, clearly stating by which data they were derived, for example, regional origin and diet composition. PMID- 23678956 TI - The new skinny in two-dimensional nanomaterials. AB - While the advent of graphene has focused attention on the extraordinary properties of two-dimensional (2D) materials, graphene's lack of an intrinsic band gap and limited amenability to chemical modification has sparked increasing interest in its close relatives and in other 2D layered nanomaterials. In this issue of ACS Nano, Bianco et al. report on the production and characterization of one of these related materials: germanane, a one-atom-thick sheet of hydrogenated puckered germanium atoms structurally similar to graphane. It is a 2D nanomaterial generated via mechanical exfoliation from GeH. Germanane has been predicted to have technologically relevant properties such as a direct band gap and high electron mobility. Monolayer 2D materials like germanane, in general, have attracted enormous interest for their potential technological applications. We offer a perspective on the field of 2D layered nanomaterials and the exciting growth areas and discuss where the new development of germanane fits in, now and in the foreseeable future. PMID- 23678955 TI - Progressive symmetrical erythrokeratoderma: report of two Chinese families and evaluation for mutations in the loricrin, connexin 30.3 and connexin 31 genes. PMID- 23678952 TI - In situ tissue regeneration: chemoattractants for endogenous stem cell recruitment. AB - Tissue engineering uses cells, signaling molecules, and/or biomaterials to regenerate injured or diseased tissues. Ex vivo expanded mesenchymal stem cells (MSC) have long been a cornerstone of regeneration therapies; however, drawbacks that include altered signaling responses and reduced homing capacity have prompted investigation of regeneration based on endogenous MSC recruitment. Recent successful proof-of-concept studies have further motivated endogenous MSC recruitment-based approaches. Stem cell migration is required for morphogenesis and organogenesis during development and for tissue maintenance and injury repair in adults. A biomimetic approach to in situ tissue regeneration by endogenous MSC requires the orchestration of three main stages: MSC recruitment, MSC differentiation, and neotissue maturation. The first stage must result in recruitment of a sufficient number of MSC, capable of effecting regeneration, to the injured or diseased tissue. One of the challenges for engineering endogenous MSC recruitment is the selection of effective chemoattractant(s). The objective of this review is to synthesize and evaluate evidence of recruitment efficacy by reported chemoattractants, including growth factors, chemokines, and other more recently appreciated MSC chemoattractants. The influence of MSC tissue sources, cell culture methods, and the in vitro and in vivo environments is discussed. This growing body of knowledge will serve as a basis for the rational design of regenerative therapies based on endogenous MSC recruitment. Successful endogenous MSC recruitment is the first step of successful tissue regeneration. PMID- 23678957 TI - The MRI-compatible neonatal incubator in practice. PMID- 23678951 TI - Standardisation of crown-rump length measurement. AB - Correct estimation of gestational age is essential for any study of ultrasound biometry and for everyday clinical practice. However, inconsistency in pregnancy dating may occur through differences in measurement methods or errors during measurement. In the INTERGROWTH-21(st) Project, pregnancies are dated by the last menstrual period, provided that it is certain and associated with a regular menstrual cycle, and the gestational age by dates concurs with a first-trimester ultrasound crown-rump length (CRL) estimation. Hence, there was a need to standardise CRL measurement methodology across the study sites in this international, multicentre project to avoid systematic differences in dating. To achieve uniformity we undertook the following steps: the ultrasound technique was standardised by disseminating an illustrated, operating manual describing CRL plane landmarks and calliper application, and posters describing the correct acquisition technique were disseminated for quick reference. To ensure that all ultrasonographers understood the methodology, they forwarded a log-book to the INTERGROWTH-21(st) Ultrasound Coordinating Unit, containing the answers to a written test on the manual material and five images of a correctly acquired CRL. Interpretation of CRL was also standardised by ensuring that the same CRL regression formula was used across all study sites. These methods should minimise potential systematic errors in dating associated with pooling data from different health institutions, and represent a model for standardising CRL measurement in future studies. PMID- 23678958 TI - Synthetic analogues of the natural compound cryphonectric acid interfere with photosynthetic machinery through two different mechanisms. AB - A series of isobenzofuran-1(3H)-ones (phthalides), analogues of the naturally occurring phytotoxin cryphonectric acid, were designed, synthesized, and fully characterized by NMR, IR, and MS analyses. Their synthesis was achieved via condensation, aromatization, and acetylation reactions. The measurement of the electron transport chain in spinach chloroplasts showed that several derivatives are capable of interfering with the photosynthetic apparatus. Few of them were found to inhibit the basal rate, but a significant inhibition was brought about only at concentrations exceeding 50 MUM. Some other analogues acted as uncouplers or energy transfer inhibitors, with a remarkably higher effectiveness. Isobenzofuranone addition to the culture medium inhibited the growth of the cyanobacterium Synechococcus elongatus , with patterns consistent with the effects measured in vitro upon isolated chloroplasts. The most active derivatives, being able to completely suppress algal growth at 20 MUM, may represent structures to be exploited for the design of new active ingredients for weed control. PMID- 23678959 TI - Sterically controlled, palladium-catalyzed intermolecular amination of arenes. AB - We report the Pd-catalyzed amination of arenes to form N-aryl phthalimides with regioselectivity controlled predominantly by steric effects. Mono-, di-, and trisubstituted arenes lacking a directing group undergo amination reactions with moderate to high yields and high regioselectivities from sequential addition of PhI(OAc)2 as an oxidant in the presence of Pd(OAc)2 as catalyst. This sterically derived selectivity contrasts that for analogous arene acetoxylation. PMID- 23678960 TI - A national approach to a healthcare epidemic. PMID- 23678961 TI - Determination of three-dimensional muscle architectures: validation of the DTI based fiber tractography method by manual digitization. AB - In the last decade, diffusion tensor imaging (DTI) has been used increasingly to investigate three-dimensional (3D) muscle architectures. So far there is no study that has proved the validity of this method to determine fascicle lengths and pennation angles within a whole muscle. To verify the DTI method, fascicle lengths of m. soleus as well as their pennation angles have been measured using two different methods. First, the 3D muscle architecture was analyzed in vivo applying the DTI method with subsequent deterministic fiber tractography. In a second step, the muscle architecture of the same muscle was analyzed using a standard manual digitization system (MicroScribe MLX). Comparing both methods, we found differences for the median pennation angles (P < 0.001) but not for the median fascicle lengths (P = 0.216). Despite the statistical results, we conclude that the DTI method is appropriate to determine the global fiber orientation. The difference in median pennation angles determined with both methods is only about 1.2 degrees (median pennation angle of MicroScribe: 9.7 degrees ; DTI: 8.5 degrees ) and probably has no practical relevance for muscle simulation studies. Determining fascicle lengths requires additional restriction and further development of the DTI method. PMID- 23678962 TI - Atrial fibrillation in young stroke patients: do we underestimate its prevalence? AB - BACKGROUND AND PURPOSE: The prevalence of atrial fibrillation (AF) in young stroke patients has rarely been reported and is considered an uncommon ischaemic stroke (IS) aetiology. Our objective was to analyse the prevalence of AF in IS patients up to 50 years of age and its relationship with stroke severity and outcomes. METHODS: This was an observational study of consecutive IS patients up to 50 years of age admitted to a stroke centre during a 5-year period (2007 2011). A complete cardiology study was performed with a daily electrocardiogram and cardiac monitoring for 72 h as well as echocardiography. In cases of stroke of unknown aetiology a 24-h Holter monitoring was performed. Baseline data, previously or newly diagnosed AF, structural heart disease (SHD) (valvulopathy/cardiomyopathy), stroke severity on admission as measured by the National Institutes of Health Stroke Scale (NIHSS) (moderate-severe stroke if NIHSS >= 8) and 3-month outcomes according to the modified Rankin Scale (mRS) (good outcome if mRS <= 2) were analysed. AF was classified as AF associated with SHD (AF-SHD) and AF not associated with SHD (AF-NSHD). RESULTS: One hundred and fifty-seven patients were included (mean age 43 years, 58.6% male). Fourteen subjects (8.9%) presented with AF, four with AF-NSHD and 10 with AF-SHD. AF was previously known in 10 patients (6.3%), two with AF-NSHD and eight with AF-SHD. A multivariate analysis showed an independent association between AF and moderate severe IS (odds ratio 3.771, 95% CI 1.182-12.028), but AF was not an independent prognostic factor. CONCLUSION: AF may be more common than expected in young patients with IS and is associated with increased NIHSS scores. PMID- 23678963 TI - Detection and structural elucidation of esterified oxylipids in human synovial fluid by electrospray ionization-fourier transform ion-cyclotron mass spectrometry and liquid chromatography-ion trap-MS(3): detection of esterified hydroxylated docosapentaenoic acid containing phospholipids. AB - Here, we present the application of a cross-platform approach, combining rapid direct infusion high-resolution/accurate mass electrospray ionization Fourier transform ion-cyclotron mass spectrometry (ESI-FTICRMS) with in-depth data dependent LC-MS(2) and LC-MS(3) analysis for lipid profiling. The analytical approach as well as the subsequent data handling is described. The method was applied to human synovial fluid samples from osteo- and rheumatoid arthritis patients. Multivariate statistical analysis revealed esterified oxylipids as molecular features in a subset of the patient samples. Employing LC-MS(2) and LC MS(3) analysis of these species, we were able to clarify the hypothesized lipid structures initially based on the accurate mass measurements performed on the ESI FTICRMS platform. LC-MS(3) analysis of intact esterified oxy-lipids and LC-MS(2) analysis of the hydrolysis products allowed for the detection of positional isomers. The approach led to the structural elucidation of hydroxylated docosapentaenoic acid-containing diacyl-phosphatidylcholine type phospholipids in human synovial fluid. PMID- 23678964 TI - A novel HLA-DQB1*04 allele, DQB1*04:10, identified in a Japanese individual. AB - In this paper, we characterize a novel human leukocyte antigen (HLA) DQB1*04:10 allele. PMID- 23678965 TI - Translocating kilobase RNA through the Staphylococcal alpha-hemolysin nanopore. AB - The electrophoretic translocation of polynucleotides through nanopores may permit direct single-molecule nucleic acid sequencing. Here we describe the translocation of ssRNA heteropolymers (91-6083 bases) through the alpha-hemolysin nanopore. Translocation of these long ssRNAs is characterized by surprisingly long, almost complete ionic current blockades with durations averaging milliseconds per base (at +180 mV). The event durations decrease exponentially with increased transmembrane potential but are largely unaffected by the presence of urea. When the ssRNA is coupled at the 3' end to streptavidin, which cannot translocate through the pore, permanent blockades are observed, supporting our conclusion that the transient blockades arise from ssRNA translocation. PMID- 23678968 TI - Indirect effects of pandemic deer overabundance inferred from caterpillar-host relations. AB - Externally feeding phytophagous insect larvae (i.e., caterpillars, here, larval Lepidoptera and sawflies, Hymenoptera: Symphyta) are important canopy herbivores and prey resources in temperate deciduous forests. However, composition of forest trees has changed dramatically in the eastern United States since 1900. In particular, browsing by high densities of white-tailed deer (Odocoileus virginianus) has resulted in forests dominated by browse-tolerant species, such as black cherry (Prunus serotina), and greatly reduced relative abundance of other tree species, notably pin cherry (Prunus pensylvanica) and birches (Betula spp.). To quantify effects of these changes on caterpillars, we sampled caterpillars from 960 branch tips of the 8 tree species that comprise 95% of trees in Allegheny hardwood forests: red maple (Acer rubrum), striped maple (Acer pensylvanicum), sugar maple (Acer saccharum), sweet birch (Betula lenta), yellow birch (Betula allegheniensis), American beech (Fagus grandifolia), black cherry, and pin cherry. We collected 547 caterpillar specimens that belonged to 66 Lepidoptera and 10 Hymenoptera species. Caterpillar density, species richness, and community composition differed significantly among tree species sampled. Pin cherry, nearly eliminated at high deer density, had the highest density and diversity of caterpillars. Pin cherry shared a common caterpillar community with black cherry, which was distinct from those of other tree hosts. As high deer density continues to replace diverse forests of cherries, maples, birches, and beech with monodominant stands of black cherry, up to 66% of caterpillar species may be eliminated. Hence, deer-induced changes in forest vegetation are likely to ricochet back up forest food webs and therefore negatively affect species that depend on caterpillars and moths for food and pollination. PMID- 23678967 TI - Membrane association and destabilization by Aggregatibacter actinomycetemcomitans leukotoxin requires changes in secondary structures. AB - Aggregatibacter actinomycetemcomitans is a common inhabitant of the upper aerodigestive tract of humans and non-human primates and is associated with disseminated infections, including lung and brain abscesses, pediatric infective endocarditis, and localized aggressive periodontitis. Aggregatibacter actinomycetemcomitans secretes a repeats-in-toxin protein, leukotoxin, which exclusively kills lymphocyte function-associated antigen-1-bearing cells. The toxin's pathological mechanism is not fully understood; however, experimental evidence indicates that it involves the association with and subsequent destabilization of the target cell's plasma membrane. We have long hypothesized that leukotoxin secondary structure is strongly correlated with membrane association and destabilization. In this study, we tested this hypothesis by analysing lipid-induced changes in leukotoxin conformation. Upon incubation of leukotoxin with lipids that favor leukotoxin-membrane association, we observed an increase in leukotoxin alpha-helical content that was not observed with lipids that favor membrane destabilization. The change in leukotoxin conformation after incubation with these lipids suggests that membrane binding and membrane destabilization have distinct secondary structural requirements, suggesting that they are independent events. These studies provide insight into the mechanism of cell damage that leads to disease progression by A. actinomycetemcomitans. PMID- 23678969 TI - Superoxide poisons mononuclear iron enzymes by causing mismetallation. AB - Superoxide (O(2)(-)) is a primary agent of intracellular oxidative stress. Genetic studies in many organisms have confirmed that excess O(2)(-) disrupts metabolism, but to date only a small family of [4Fe-4S] dehydratases have been identified as direct targets. This investigation reveals that in Escherichia coli O(2)(-) also poisons a broader cohort of non-redox enzymes that employ ferrous iron atoms as catalytic cofactors. These enzymes were inactivated by O(2)(-) both in vitro and in vivo. Although the enzymes are known targets of hydrogen peroxide, the outcome with O(2)(-) differs substantially. When purified enzymes were damaged by O(2)(-) in vitro, activity could be completely restored by iron addition, indicating that the O(2)(-) treatment generated an apoprotein without damaging the protein polypeptide. Superoxide stress inside cells caused the progressive mismetallation of these enzymes with zinc, which confers little activity. When O(2)(-) stress was terminated, cells gradually restored activity by extracting zinc from the proteins. The overloading of cells with zinc caused mismetallation even without O(2)(-) stress. These results support a model in which O(2)(-) repeatedly excises iron from these enzymes, allowing zinc to compete with iron for remetallation of their apoprotein forms. This action substantially expands the physiological imprint of O(2)(-) stress. PMID- 23678970 TI - Pilot comparative effectiveness study of surface perturbation treadmill training to prevent falls in older adults. AB - BACKGROUND: Falls are the leading cause of fatal and non-fatal injuries among older adults. Exercise programs appear to reduce fall risk, but the optimal type, frequency, and duration of exercise is unknown. External perturbations such as tripping and slipping are a major contributor to falls, and task-specific perturbation training to enhance dynamic stability has emerged as a promising approach to modifying fall risk. The purpose of this pilot study was 1) to determine the feasibility of conducting a large pragmatic randomized trial comparing a multidimensional exercise program inclusive of the surface perturbation treadmill training (SPTT) to multidimensional exercise alone (Standard PT); and 2) to assess fall outcomes between the two groups to determine whether an effect size large enough to warrant further study might be present. METHODS: A randomized pilot study at two outpatient physical therapy clinics. Participants were over age 64 and referred for gait and balance training. Feasibility for a larger randomized trial was assessed based on the ability of therapists to incorporate the SPTT into their clinical practice and acceptance of study participation by eligible patients. Falls were assessed by telephone interview 3 months after enrollment. RESULTS: Of 83 patients who were screened, 73 met inclusion criteria. SPTT was successfully adapted into clinical practice and 88% of eligible subjects were willing to be randomized, although 10% of the SPTT cohort dropped out prior to treatment. The SPTT group showed fewer subjects having any fall (19.23% vs. 33.33% Standard PT; p < 0.227) and fewer having an injurious fall (7.69% vs. 18.18%; p < 0.243). These results were not statistically significant but this pilot study was not powered for hypothesis testing. CONCLUSIONS: Physical therapy inclusive of surface perturbation treadmill training appears clinically feasible, and randomization between these two PT interventions is acceptable to the majority of patients. These results appear to merit longer-term study in an adequately powered trial. TRIAL REGISTRATION: clinicaltrials.gov: NCT01006967. PMID- 23678971 TI - Multipass millimeter/submillimeter spectrometer to probe dissociative reaction dynamics. AB - We present here the instrument design and first experimental results from a multipass millimeter/submillimeter spectrometer designed to probe dissociative reaction dynamics. This work focuses on benchmarking the instrument performance through detection of the CH3O and H2CO products from methanol dissociation induced by a high-voltage plasma discharge. Multiple rotational lines from CH3O and H2CO were observed when this plasma discharge was applied to a sample of methanol vapor seeded in an argon supersonic expansion. The rotational temperature of the dissociation products and their abundance with respect to methanol were determined using a Boltzmann analysis. The minimum detectable absorption coefficient for this instrument was determined to be alphamin <= 5 * 10(-9) cm(-1). We discuss these results in the context of future applications of this instrument to the study of photodissociation branching ratios for small organic molecules that are important in complex interstellar chemistry. PMID- 23678972 TI - Clinical embryology teaching: is it relevant anymore? AB - BACKGROUND: Embryology finds itself jostling for precious space in the crowded medical curriculum, yet remains important for helping students understand birth defects. It has been suggested that teaching embryology through clinical scenarios can increase its relevance and interest. The aim of this research was to determine the attitudes of final-year medical students to learning embryology and whether clinical scenarios aid understanding. METHODS: Final-year medical students undertaking their paediatric rotation in 2009 and 2010 were invited to attend an optional lecture on clinical embryology and participate in the research. In the lecture, three clinical scenarios were presented, in which the lecturer traced the normal development of a foetus and the abnormal development that resulted in a birth defect. Outcomes were assessed quantitatively using a paper-based survey. RESULTS: The vast majority of students who valued embryology teaching in their medical programme thought it would assist them with clinical management, and believed learning through case scenarios helped their understanding. Students were divided in their beliefs about when embryology should be taught in the medical programme and whether it would increase their workload. CONCLUSION: Embryology teaching appears to be a valuable part of the medical curriculum. Embryology teaching was valued when taught in the clinical environment in later years of the medical programme. Students, clinicians and medical educators should be proactive in finding clinical learning opportunities for embryology teaching. PMID- 23678966 TI - Conceptual basis for prescriptive growth standards from conception to early childhood: present and future. AB - BACKGROUND: Healthy growth in utero and after birth is fundamental for lifelong health and wellbeing. The World Health Organization (WHO) recently published standards for healthy growth from birth to 6 years of age; analogous standards for healthy fetal growth are not currently available. Current fetal growth charts in use are not true standards, since they are based on cross-sectional measurements of attained size under conditions that do not accurately reflect normal growth. In most cases, the pregnant populations and environments studied are far from ideal; thus the data are unlikely to reflect optimal fetal growth. A true standard should reflect how fetuses and newborns 'should' grow under ideal environmental conditions. OBJECTIVE: The development of prescriptive intrauterine and newborn growth standards derived from the INTERGROWTH-21(st) Project provides the data that will allow us for the first time to establish what is 'normal' fetal growth. METHODS: The INTERGROWTH-21(st) study centres provide the data set obtained under pre-established standardised criteria, and details of the methods used are also published. DESIGN: Multicentre study with sites in all major geographical regions of the world using a standard evaluation protocol. RESULTS: These standards will assess risk of abnormal size at birth and serve to evaluate potentially effective interventions to promote optimal growth beyond securing survival. DISCUSSION: The new normative standards have the potential to impact perinatal and neonatal survival and beyond, particularly in developing countries where fetal growth restriction is most prevalent. They will help us identify intrauterine growth restriction at earlier stages of development, when preventive or corrective strategies might be more effective than at present. CONCLUSION: These growth standards will take us one step closer to effective action in preventing and potentially reversing abnormal intrauterine growth. Achieving 'optimal' fetal growth requires that we act not only during pregnancy but that we optimize the maternal uterine environment from the time before conception, through embryonic development until fetal growth is complete. The remaining challenge is how 'early' will we be able to act, now that we can better monitor fetal growth. PMID- 23678973 TI - A trick in steri-strips application: the zig-zag pattern. PMID- 23678974 TI - Fast quantitative method for the analysis of carotenoids in transgenic maize. AB - A fast method was developed to determine carotenoid content in transgenic maize seeds. The analysis was carried out using an ultrahigh-pressure liquid chromatograph coupled to a photodiode array detector and a mass spectrometer (UHPLC-PDA-MS/MS). Sixteen carotenoid pigments were detected and quantified in <13 min. In addition, it was possible to obtain good resolution of both polar xanthophylls and nonpolar carotenes. The method exhibited (a) a high degree of repeatability (%RSD < 13%), (b) linear calibration curves (R2 > 0.9952), (c) satisfactory recoveries for most of the pigments (between 82 and 108%), and (d) low detection (from 0.02 to 0.07 MUg/mL) and quantification limits (from 0.05 to 0.20 MUg/mL) (LOD and LOQ, respectively). The methodology was applied to the analysis of transgenic maize lines TM1, TM2, and TM3, expressing several carotenogenic genes. PMID- 23678975 TI - Roger Cotton histopathology prize 2012. PMID- 23678976 TI - Total synthesis of entecavir. AB - Entecavir (BMS-200475) was synthesized from 4-trimethylsilyl-3-butyn-2-one and acrolein. The key features of its preparation are: (i) a stereoselective boron aldol reaction to afford the acyclic carbon skeleton of the methylenecylopentane moiety; (ii) its cyclization by a Cp2TiCl-catalyzed intramolecular radical addition of an epoxide to an alkyne; and (iii) the coupling with a purine derivative by a Mitsunobu reaction. PMID- 23678977 TI - The Royal Australasian College of Physicians immunisation position statement. PMID- 23678978 TI - Charge-controlled switchable CO2 capture on boron nitride nanomaterials. AB - Increasing concerns about the atmospheric CO2 concentration and its impact on the environment are motivating researchers to discover new materials and technologies for efficient CO2 capture and conversion. Here, we report a study of the adsorption of CO2, CH4, and H2 on boron nitride (BN) nanosheets and nanotubes (NTs) with different charge states. The results show that the process of CO2 capture/release can be simply controlled by switching on/off the charges carried by BN nanomaterials. CO2 molecules form weak interactions with uncharged BN nanomaterials and are weakly adsorbed. When extra electrons are introduced to these nanomaterials (i.e., when they are negatively charged), CO2 molecules become tightly bound and strongly adsorbed. Once the electrons are removed, CO2 molecules spontaneously desorb from BN absorbents. In addition, these negatively charged BN nanosorbents show high selectivity for separating CO2 from its mixtures with CH4 and/or H2. Our study demonstrates that BN nanomaterials are excellent absorbents for controllable, highly selective, and reversible capture and release of CO2. In addition, the charge density applied in this study is of the order of 10(13) cm(-2) of BN nanomaterials and can be easily realized experimentally. PMID- 23678979 TI - Prediction of a two-dimensional organic topological insulator. AB - Topological insulators (TI) are a class of materials exhibiting unique quantum transport properties with potential applications in spintronics and quantum computing. To date, all of the experimentally confirmed TIs are inorganic materials. Recent theories predicted the possible existence of organic TIs (OTI) in two-dimensional (2D) organometallic frameworks. However, those theoretically proposed structures do not naturally exist and remain to be made in experiments. Here, we identify a recently experimentally made 2D organometallic framework, consisting of pi-conjugated nickel-bis-dithiolene with a chemical formula Ni3C12S12, which exhibits nontrivial topological states in both a Dirac band and a flat band, therefore confirming the existence of OTI. PMID- 23678980 TI - Hydrophilic material for the selective enrichment of 5-hydroxymethylcytosine and its liquid chromatography-tandem mass spectrometry detection. AB - 5-Methylcytosine (5-mC), an important epigenetic modification involved in development, can be converted enzymatically to 5-hydroxymethylcytosine (5-hmC). 5 hmC is considered an intermediate of active DNA cytosine demethylation and makes itself serve as an epigenetic mark. 5-hmC content in most mammalian cells is low and the quantification of 5-hmC by liquid chromatography-mass spectrometry (LC MS) frequently suffers from ion suppression by the presence of unmodified nucleosides. To circumvent this problem, we developed a method to selectively transfer a glucosyl group to the hydroxymethyl moiety of 5-hmC and form a more hydrophilic residue (beta-glucosyl-5-hydroxymethyl-2'-deoxycytidine, 5-gmdC) by using T4 beta-glucosyltransferase. The more hydrophilic 5-gmdC can be selectively enriched by using NH2-silica via hydrophilic interaction prior to liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, which eliminates the ion suppression and significantly improves the detection sensitivity and accuracy. Using this method, we successfully quantified 5-hmC content in genomic DNA of three human cell lines and seven yeast strains. To the best of our knowledge, this is the first report about the existence of 5-hmC in the model organism of yeast. In addition, the contents of 5-hmC in two yeast strains of Schizosaccharomyces pombe are even higher than those of 5-mC, indicating that 5 hmC may play important roles on the physiological functions of yeast. PMID- 23678981 TI - Quantitative evaluation of mechanical properties in tissue-engineered auricular cartilage. AB - Tissue-engineering (TE) efforts for ear reconstruction often fail due to mechanical incompetency. It is therefore key for successful auricular cartilage (AUC) TE to ensure functional competency, that is, to mimic the mechanical properties of the native ear tissue. A review of past attempts to engineer AUC shows unsatisfactory functional outcomes with various cell-seeded biodegradable polymeric scaffolds in immunocompetent animal models. However, promising improvements to construct stability were reported with either mechanically reinforced scaffolds or novel two-stage implantation techniques. Nonetheless, quantitative mechanical evaluation of the constructs is usually overlooked, and such an evaluation of TE constructs alongside a benchmark of native AUC would allow real-time monitoring and improve functional outcomes of auricular TE strategies. Although quantitative mechanical evaluation techniques are readily available for cartilage, these techniques are designed to characterize the main functional components of hyaline and fibrous cartilage such as the collagen matrix or the glycosaminoglycan network, but they overlook the functional role of elastin, which is a major constituent of AUC. Hence, for monitoring AUC TE, novel evaluation techniques need to be designed. These should include a characterization of the specific composition and architecture of AUC, as well as mechanical evaluation of all functional components. Therefore, this article reviews the existing literature on AUC TE as well as cartilage mechanical evaluation and proposes recommendations for designing a mechanical evaluation protocol specific for AUC, and establishing a benchmark for native AUC to be used for quantitative evaluation of TE AUC. PMID- 23678982 TI - Novel contribution of cell surface and intracellular M1-muscarinic acetylcholine receptors to synaptic plasticity in hippocampus. AB - Muscarinic acetylcholine receptors (mAChRs) are well known to transmit extracellular cholinergic signals into the cytoplasm from their position on the cell surface. However, we show here that M1-mAChRs are also highly expressed on intracellular membranes in neurons of the telencephalon and activate signaling cascades distinct from those of cell surface receptors, contributing uniquely to synaptic plasticity. Radioligand-binding experiments with cell-permeable and impermeable ligands and immunohistochemical observations revealed intracellular and surface distributions of M1-mAChRs in the hippocampus and cortex of rats, mice, and humans, in contrast to the selective occurrence on the cell surface in other tissues. All intracellular muscarinic-binding sites were abolished in M1 mAChR-gene-knockout mice. Activation of cell surface M1-mAChRs in rat hippocampal neurons evoked phosphatidylinositol hydrolysis and network oscillations at theta rhythm, and transiently enhanced long-term potentiation. On the other hand, activation of intracellular M1-mAChRs phosphorylated extracellular-regulated kinase 1/2 and gradually enhanced long-term potentiation. Our data thus demonstrate that M1-mAChRs function at both surface and intracellular sites in telencephalon neurons including the hippocampus, suggesting a new mode of cholinergic transmission in the central nervous system. PMID- 23678983 TI - Rocuronium and sugammadex in patients with myasthenia gravis undergoing thymectomy. AB - BACKGROUND: The use of neuromuscular blocking agents is still controversial in myasthenic patients but rocuronium could be useful after the introduction of sugammadex as a selective antagonist. The aim of the study was to evaluate the use of rocuronium-sugammadex in myasthenic patients undergoing thoracoscopic thymectomy. METHODS: After ethical approval, 10 myasthenic patients undergoing videothoracoscopic-assisted thymectomy were enrolled in the study. Neuromuscular block was achieved with 0.3 mg/kg rocuronium and additional doses were given according to train-of-four (TOF) monitoring or movement of the diaphragm. Sugammadex 2 mg/kg was given after surgery. Recovery time (time to obtain a TOF value > 0.9) was recorded for all subjects. RESULT: All patients were extubated in the operating room after administration of sugammadex. Mean rocuronium dose was 48 mg and the average operation time was 62 min. Recovery time after sugammadex administration was 111 s (min 35; max 240). CONCLUSIONS: A rapid recovery of neuromuscular function was found in myasthenic patients receiving rocuronium when sugammadex was used for reversal. This combination could be a rational alternative for myasthenic patients for whom neuromuscular blockade is mandatory during surgery. PMID- 23678985 TI - 454 pyrosequencing analyses of bacterial and archaeal richness in 21 full-scale biogas digesters. AB - The microbial community of 21 full-scale biogas reactors was examined using 454 pyrosequencing of 16S rRNA gene sequences. These reactors included seven (six mesophilic and one thermophilic) digesting sewage sludge (SS) and 14 (ten mesophilic and four thermophilic) codigesting (CD) various combinations of wastes from slaughterhouses, restaurants, households, etc. The pyrosequencing generated more than 160,000 sequences representing 11 phyla, 23 classes, and 95 genera of Bacteria and Archaea. The bacterial community was always both more abundant and more diverse than the archaeal community. At the phylum level, the foremost populations in the SS reactors included Actinobacteria, Proteobacteria, Chloroflexi, Spirochetes, and Euryarchaeota, while Firmicutes was the most prevalent in the CD reactors. The main bacterial class in all reactors was Clostridia. Acetoclastic methanogens were detected in the SS, but not in the CD reactors. Their absence suggests that methane formation from acetate takes place mainly via syntrophic acetate oxidation in the CD reactors. A principal component analysis of the communities at genus level revealed three clusters: SS reactors, mesophilic CD reactors (including one thermophilic CD and one SS), and thermophilic CD reactors. Thus, the microbial composition was mainly governed by the substrate differences and the process temperature. PMID- 23678986 TI - Effects of conjugated linoleic acids and dietary concentrate proportion on performance, milk composition, milk yield and metabolic parameters of periparturient dairy cows. AB - The study aimed to examine effects of supplemented conjugated linoleic acids (CLA) to periparturient cows receiving different concentrate proportions ante partum (a.p.) to investigate CLA effects on lipid mobilisation and metabolism. Compared to adapted feeding, a high-concentrate diet a.p. should induce a ketogenic metabolic situation post partum (p.p.) to better understand how CLA works. Sixty-four pregnant German Holstein cows had ad libitum access to partial mixed rations 3 weeks prior to calving until day 60 p.p. Ante partum, cows received control fat (CON) or a CLA supplement at 100 g/d, either in a low concentrate (CON-20, CLA-20) or high-concentrate diet (CON-60, CLA-60). Post partum, concentrate proportion was adjusted, while fat supplementation continued. After day 32 p.p., half of the animals of CLA-groups changed to CON supplementation (CLA-20-CON, CLA-60-CON). A ketogenic metabolic situation p.p. was not achieved and therefore impacts of CLA could not be examined. Live weight, milk yield and composition, blood parameters remained unaffected by the treatments. Only a slightly reduced milk fat yield (not significant) was recorded for Group CLA-20. The proportion of trans-10,cis-12 (t10,c12) CLA in milk fat was significantly increased in CLA-groups compared to CON-groups. With the exception of a reversible CLA effect on milk fat in Group CLA-20, no post-treatment effects occurred. Dry matter intake (DMI) of Group CLA-60 was highest before calving, resulting in a significantly improved estimated energy balance after calving. Ante partum, net energy intakes were significantly increased in high-concentrate groups. Overall, supplemented CLA preparation did not relieve metabolism and lipid mobilisation of early lactating cows. But feeding CLA in a high-concentrate diet a.p. seems to increase DMI and thereby improve the energy balance of cows immediately after calving. PMID- 23678988 TI - Diagnosis of drug-induced parkinsonism: can transcranial sonography make the difference? PMID- 23678987 TI - Control of post-translational modifications in antithrombin during murine post natal development by miR-200a. AB - BACKGROUND: Developmental haemostatic studies may help identifying new elements involved in the control of key haemostatic proteins like antithrombin, the most relevant endogenous anticoagulant. RESULTS: In this study, we showed a significant reduction of sialic acid content in neonatal antithrombin compared with adult antithrombin in mice. mRNA levels of St3gal3 and St3gal4, two sialyltransferases potentially involved in antithrombin sialylation, were 85% lower in neonates in comparison with adults. In silico analysis of miRNAs overexpressed in neonates revealed that mir-200a might target these sialyltransferases. Moreover, in vitro studies in murine primary hepatocytes sustain this potential control. CONCLUSIONS: These data suggest that in addition to the direct protein regulation, microRNAs may also modulate qualitative traits of selected proteins by an indirect control of post-translational processes. PMID- 23678989 TI - The contribution of language to the right-hemisphere conceptual representations: a selective survey. AB - Although levels of verbal and pictorial performance are known to depend on the degree of left versus right atrophy in the early stages of semantic dementia, the nature of these differences remains controversial. It has been proposed that there is a unitary, bilaterally represented, abstract semantic system and that differential task performance reflects the impact of greater connectivity between the left anterior temporal lobe (ATL) and the left dominant language systems. This interpretation explains the greater involvement of the left ATL in verbally coded semantic knowledge, but not the prevalence of the right hemisphere in pictorial representations. An alternative account is provided by the sensory motor model of conceptual knowledge, which assumes that each conceptual representation results from the convergence of different perceptual, motor, and verbally coded sources of knowledge in a given brain area. According to this model, the weight of verbal information should prevail in left ATL conceptual representations, because of the dominance of the left hemisphere for language, whereas the weight of sensory-motor sources of knowledge should be greater in the right ATL representations, because the right hemisphere plays a greater role in processing sensory-motor information. If the difference between right and left conceptual representations is quantitative and due to the different weight of sensory-motor and verbal sources of knowledge in their composition, we should observe an elementary, but selective representation of semantic-lexical knowledge in the intact right hemisphere and a mild but selective semantic-lexical impairment in right-brain-damaged patients. Results of the present survey support this hypothesis. PMID- 23678990 TI - Prognostic importance of myocardial injury in critically ill dogs with systemic inflammation. AB - BACKGROUND: In noncardiac critical disease in humans, myocardial injury as detected by cardiac troponin I and T (cTnI and cTnT) has been linked to high intensive care unit (ICU) death independent of prognostic composite scoring. HYPOTHESIS: Presence of myocardial injury predicts short-term death in critically ill dogs with systemic inflammation and provides additional prognostic information when combined with established canine prognostic composite scores. ANIMALS: Forty-two dogs admitted to the ICU with evidence of systemic inflammation and no primary cardiac disease. METHODS: Prospective cohort study. Blood samples were obtained at ICU admission for the measurement of cTnI and cTnT, C-reactive protein, and several cytokines. The acute patient physiologic and laboratory evaluation (APPLE) score and the survival prediction index were calculated within the first 24 hours of admission. Receiver operating characteristic (ROC) curves were used to examine the prognostic capacity of each biomarker and severity score. Multiple logistic regression analysis was performed to evaluate whether cardiac markers significantly contributed to severity scores. RESULTS: Twenty-eight day case fatality rate was 26% (11/42 dogs). cTnI concentrations were (median [range]) 0.416 [0.004-141.5] ng/mL and cTnT concentrations were 13.5 [<13-3,744] ng/L. cTnI, cTnT, and the APPLE score were all significant prognosticators with areas under the ROC curves [95% CI] of 0.801 [0.649; 0.907], 0.790 [0.637; 0.900], and 0.776 [0.621; 0.889], respectively. cTnI significantly contributed to the APPLE score in providing additional prognostic specificity (P = .025). CONCLUSIONS AND CLINICAL IMPORTANCE: Markers of myocardial injury predict short-term death in dogs with systemic inflammation and cTnI significantly contributes to the APPLE score. PMID- 23678992 TI - Arm dominance does not affect healing in acute wounds. PMID- 23678991 TI - X4 viruses are frequently archived in patients with long-term HIV infection but do not seem to influence the "inflamm-aging" process. AB - BACKGROUND: Co-receptor tropism (CRT) in patients with a long history of HIV-1 infection and antiretroviral treatment has been rarely investigated to date. The aim of this study was to determine the prevalence of X4 and R5 strains in patients with a >15-year follow-up and to investigate the demographical, viral, immunological, clinical and therapeutic determinants of CRT in this population. The possible influence of CRT on the inflammation state related to chronic HIV infection was also examined. METHODS: A total of 118 HIV-1 infected patients with an initial HIV-1-positive test before 1997, and still on follow-up, were enrolled and consecutively submitted to blood sampling. Of these, 111 were on antiretroviral therapy and 89/111 (80.2%) had a plasma viral load (pVL) <25 copies/ml at testing. HIV-1 DNA was extracted and amplified from PBMCs for env gp120 sequencing. CRT was assigned by using geno2pheno and isolates were classified as X4 (FPR <=20%) or R5 (FPR >20%). Level of serological inflammation biomarkers including IL-6, hsPCR, and D-dimers were measured. RESULTS: An X4 virus was evidenced in HIV-1 proviral DNA of 50 patients (42%) while the remaining 68 patients were classified as R5. The median follow-up was 19 years (range 15-25). No association was observed between CRT and sex, age, nationality, subtype, HIV risk factor, HBV/HCV co-infection, baseline CD4+ cell count and pVL, overall duration of antiretroviral therapy, past exposure to mono-or dual therapies, and duration of NNRTI or PI-based therapy. The presence of an X4 strain was associated with CD4 nadir (p = 0.005), CD4 absolute count over time (p < 0.001), and cumulative positive (copy/years) viremia (p <0.001) during the whole patient history. No differences were found between R5 and X4 patients regarding inflammation marker levels including Il-6, hsPCR and D-dimers. CONCLUSIONS: An archived X4 virus was demonstrated in 42% of patients with a >15 year-history of HIV infection. This presence was clearly associated with a greater exposure to positive viremia and a poorer CD4 trend over time compared to R5, independent of type and duration of antiretroviral treatment. CRT does not seem to influence the inflammation rate of patients aging with HIV. PMID- 23678994 TI - Genome-wide sequencing of Phytophthora lateralis reveals genetic variation among isolates from Lawson cypress (Chamaecyparis lawsoniana) in Northern Ireland. AB - Phytophthora lateralis is a fungus-like (oomycete) pathogen of trees in the family Cupressaceae, including Chamaecyparis lawsoniana (Lawson cypress or Port Orford cedar). Known in North America since the 1920s, presumably having been accidentally introduced from its assumed East Asian centre of origin, until recently, this pathogen has not been identified causing disease in Europe except for a few isolated outbreaks. However, since 2010, there have been several reports of infection of C. lawsoniana by P. lateralis in the United Kingdom, including Northern Ireland. We sequenced the genomes of four isolates of P. lateralis from two sites in Northern Ireland in 2011. Comparison with the closely related tree and shrub pathogen P. ramorum (cause of ramorum disease of larch and other species in the UK) shows that P. lateralis shares 91.47% nucleotide sequence identity over the core conserved compartments of the genome. The genomes of the four Northern Ireland isolates are almost identical, but we identified several single-nucleotide polymorphisms (SNPs) that distinguish between isolates, thereby presenting potential molecular markers of use for tracking routes of spread and in epidemiological studies. Our data reveal very low rates of heterozygosity (compared with P. ramorum), consistent with inbreeding within this P. lateralis population. PMID- 23678996 TI - Biphasic versus monophasic cathodal ventricular pacing. PMID- 23678995 TI - Ligand-dependent activation and deactivation of the human adenosine A(2A) receptor. AB - G-protein-coupled receptors (GPCRs) are membrane proteins with critical functions in cellular signal transduction, representing a primary class of drug targets. Acting by direct binding, many drugs modulate GPCR activity and influence the signaling pathways associated with numerous diseases. However, complete details of ligand-dependent GPCR activation/deactivation are difficult to obtain from experiments. Therefore, it remains unclear how ligands modulate a GPCR's activity. To elucidate the ligand-dependent activation/deactivation mechanism of the human adenosine A2A receptor (AA2AR), a member of the class A GPCRs, we performed large-scale unbiased molecular dynamics and metadynamics simulations of the receptor embedded in a membrane. At the atomic level, we have observed distinct structural states that resemble the active and inactive states. In particular, we noted key structural elements changing in a highly concerted fashion during the conformational transitions, including six conformational states of a tryptophan (Trp246(6.48)). Our findings agree with a previously proposed view that, during activation, this tryptophan residue undergoes a rotameric transition that may be coupled to a series of coherent conformational changes, resulting in the opening of the G-protein binding site. Further, metadynamics simulations provide quantitative evidence for this mechanism, suggesting how ligand binding shifts the equilibrium between the active and inactive states. Our analysis also proposes that a few specific residues are associated with agonism/antagonism, affinity, and selectivity, and suggests that the ligand-binding pocket can be thought of as having three distinct regions, providing dynamic features for structure-based design. Additional simulations with AA2AR bound to a novel ligand are consistent with our proposed mechanism. Generally, our study provides insights into the ligand-dependent AA2AR activation/deactivation in addition to what has been found in crystal structures. These results should aid in the discovery of more effective and selective GPCR ligands. PMID- 23678997 TI - The dimethoxyphenylbenzyl protecting group: an alternative to the p-methoxybenzyl group for protection of carbohydrates. AB - A reliable reagent system for the cleavage of 4-(3,4-dimethoxyphenyl)benzyl (DMPBn) ethers under acidic conditions has been established. Treatment of DMPBn protected mono- and pseudodisaccharides with TFA in anhydrous CH2Cl2 and 3,4 (methylenedioxy)toluene as a cation scavenger resulted in the selective cleavage of the DMPBn ether giving the corresponding deprotected products in moderate to high yields. Examples are reported which show that allyl, benzyl, and p bromobenzyl ethers, esters, and glycosidic linkages are stable to these reaction conditions. The selective cleavage of allyl, p-bromobenzyl, and PMB ethers in protected carbohydrates containing DMPBn ethers are also demonstrated. This work establishes the 4-(3,4-dimethoxyphenyl)benzyl ether as an effective and robust alternative to p-methoxybenzyl as a protecting group for alcohols. PMID- 23678998 TI - Does proclination of maxillary incisors really affect the sagittal position of point A? AB - OBJECTIVE: To examine the effect of maxillary incisor proclination due to orthodontic treatment upon the sagittal position of point A and evaluate the effect of this possible movement of point A on sella-nasion-point A (SNA) angle. MATERIALS AND METHODS: A study group was formed from 25 subjects (12 male and 13 female) who had Class II division 2 malocclusion with retroclined upper incisors, and a control group was formed from 25 subjects (12 male and 13 female) who had minor crowding in the beginning of the treatment and required no or minimal maxillary anterior tooth movement. Treatment changes in maxillary incisor inclination, sagittal position of point A, SNA angle, and movement of incisor root apex and incisal edge were calculated on pretreatment and posttreatment lateral cephalographs. RESULTS: Maxillary incisors were significantly proclined (17.33 degrees ) in the study group and not significantly proclined (1.81 degrees ) in the control group. This proclination resulted in 2.12-mm backward movement of the root apex and 5.76-mm forward movement of the incisal edge of maxillary incisors. Point A moved 1.04 mm backward (P = .582) and 0.48 mm (P = .811) forward in the study and control groups, respectively. Incisor root apex and incisal edge almost remained stable in the control group. No significant change was observed in the value of the SNA angle in both the study and control groups. CONCLUSIONS: Proclination of maxillary incisors accompanied by backward movement of incisor root apex caused posterior movement of point A. However, this posterior movement does not significantly affect the SNA angle. PMID- 23678993 TI - Implementation of the INTERGROWTH-21st Project in India. AB - The South Asian site in the INTERGROWTH-21(st) Project was the city of Nagpur, in Maharashtra State, India, with approximately 4500 births per year among the target population with middle to high socio-economic status. These deliveries are mainly concentrated in 20 small private hospitals, most of which are in the city centre. The sample for the Newborn Cross-Sectional Study (NCSS) was drawn from ten of these hospitals, covering 76% of the target low-risk pregnant population. The Fetal Growth Longitudinal Study (FGLS) sample was recruited from the largest of these institutions, Ketkar Hospital, as well as several ancillary antenatal care clinics. Special activities to encourage participation and raise awareness of the study at this site included translating patient information leaflets into local languages and securing local media interest. Among the unique challenges of the Indian site was the coordination of the large number of hospitals involved in NCSS, a task that required careful planning and organisation by the field teams. PMID- 23678999 TI - Torque efficiency of different archwires in 0.018- and 0.022-inch conventional brackets. AB - OBJECTIVE: To compare the archwires inserted during the final stages of the orthodontic treatment with the generated moments at 0.018- and 0.022-inch brackets. MATERIALS AND METHODS: The same bracket type, in terms of prescription, was evaluated in both slot dimensions. The brackets were bonded on two identical maxillary acrylic resin models, and each model was mounted on the orthodontic measurement and simulation system. Ten 0.017 * 0.025-inch TMA and ten 0.017 * 0.025-inch stainless steel archwires were evaluated in the 0.018-inch brackets. In the 0.022-inch brackets, ten 0.019 * 0.025-inch TMA and ten 0.019 * 0.025-inch stainless steel archwires were measured. A 15 degrees buccal root torque (+15 degrees ) and then a 15 degrees palatal root torque (-15 degrees ) were gradually applied to the right central incisor bracket, and the moments were recorded at these positions. A t-test was conducted to compare the generated moments between wires within the 0.018- and 0.022-inch bracket groups separately. RESULTS: The 0.017 * 0.025-inch archwire in the 0.018-inch brackets generated mean moments of 9.25 Nmm and 14.2 Nmm for the TMA and stainless steel archwires, respectively. The measured moments in the 0.022-inch brackets with the 0.019 * 0.025-inch TMA and stainless steel archwires were 6.6 Nmm and 9.3 Nmm, respectively. CONCLUSION: The 0.017 * 0.025-inch stainless steel and beta-Ti archwires in the 0.018-inch slot generated higher moments than the 0.019 * 0.025 inch archwires because of lower torque play. This difference is exaggerated in steel archwires, in comparison with the beta-Ti, because of differences in stiffness. The differences of maximum moments between the archwires of the same cross-section but different alloys were statistically significant at both slot dimensions. PMID- 23679000 TI - Negligible surface reactivity of topological insulators Bi2Se3 and Bi2Te3 towards oxygen and water. AB - The long-term stability of functional properties of topological insulator materials is crucial for the operation of future topological insulator based devices. Water and oxygen have been reported to be the main sources of surface deterioration by chemical reactions. In the present work, we investigate the behavior of the topological surface states on Bi2X3 (X = Se, Te) by valence-band and core level photoemission in a wide range of water and oxygen pressures both in situ (from 10(-8) to 0.1 mbar) and ex situ (at 1 bar). We find that no chemical reactions occur in pure oxygen and in pure water. Water itself does not chemically react with both Bi2Se3 and Bi2Te3 surfaces and only leads to slight p doping. In dry air, the oxidation of the Bi2Te3 surface occurs on the time scale of months, in the case of Bi2Se3 surface of cleaved crystal, not even on the time scale of years. The presence of water, however, promotes the oxidation in air, and we suggest the underlying reactions supported by density functional calculations. All in all, the surface reactivity is found to be negligible, which allows expanding the acceptable ranges of conditions for preparation, handling and operation of future Bi2X3-based devices. PMID- 23679001 TI - Solvent exchange module for LC-NMR hyphenation using machine vision-controlled droplet evaporation. AB - We report the use of pendant droplet evaporation for exchange of eluents for (1)H nuclear magnetic resonance ((1)H NMR) purposes. Analytes are fed and retained in 500 nL droplets, which are concentrated by evaporation and subsequently redissolved in deuterated solvent. Droplet size is monitored by machine vision (MV), and heating rates are adjusted concordingly to maintain a stable droplet volume. Evaporation control is independent of solvent properties, and the setup handles feed rates up to 7 MUL min(-1). The interface is capable of exchanging up to 90% of solvent for deuterated solvent, with a good recovery and repeatability for tomato extracts (Solanum lycopersicum). The system was capable of handling both polar and nonpolar analytes in one run. Volatiles such as formate, acetate, and lactate and the thermosensitive compound epigallocatechin gallate were recovered without significant losses. Ethanol and propionate were recovered with significant losses due to the formation of a minimum boiling azeotrope. The current setup is ideally suited for on- and off-line hyphenation of liquid chromatography and NMR, as it is comprehensive, fully automated, and easy to operate. PMID- 23679002 TI - Pour some sugar on it: the expanding world of bacterial protein O-linked glycosylation. AB - Protein glycosylation was once considered as an eccentricity of a few bacteria. However in the recent years multiple O-glycosylation mechanisms have been identified in bacterial species from the most diverse genera, including various important human pathogens. This review focuses on summarizing the structural diversity, the various pathways and the physiological roles of this post translational protein modification. We propose a classification of O glycosylation based on the requirement of an oligosaccharyltransferase (OTase). OTase-dependent glycosylation utilizes an oligosaccharide synthesized on a lipid carrier that is transferred to proteins en bloc by an OTase. Multiple proteins, including the pilins, are glycosylated using this mechanism. OTase-independent glycosylation refers to the pathway in which glycosyltransferases sequentially add monosaccharides onto the target proteins. This pathway is employed for glycosylation of flagella and autotransporters. Both systems play key roles in pathogenesis. Exploiting glycosylation machineries it is now possible to generate glycoconjugates made of different proteins attached to polysaccharides derived from LPS or capsule biosynthesis. These recombinant glycoproteins can be exploited for vaccines and diagnostics of bacterial infections. Furthermore, O glycosylation systems are promising targets for antibiotic development. Technological advances in MS and NMR will facilitate the discovery of novel glycosylation systems. Likely, the O-glycosylation pathways we currently know constitute just the tip of the iceberg of a still largely uncharacterized bacterial glycosylation world. PMID- 23679003 TI - Self-similar nested flux closure structures in a tetragonal ferroelectric. AB - In specific solid-state materials, under the right conditions, collections of magnetic dipoles are known to spontaneously form into a variety of rather complex geometrical patterns, exemplified by vortex and skyrmion structures. While theoretically, similar patterns should be expected to form from electrical dipoles, they have not been clearly observed to date: the need for continued experimental exploration is therefore clear. In this Letter we report the discovery of a rather complex domain arrangement that has spontaneously formed along the edges of a thin single crystal ferroelectric sheet, due to surface related depolarizing fields. Polarization patterns are such that nanoscale "flux closure" loops are nested within a larger mesoscale flux closure object. Despite the orders of magnitude differences in size, the geometric forms of the dual scale flux closure entities are rather similar. PMID- 23679004 TI - Extended spectrum beta-lactamase and fluoroquinolone resistance genes and plasmids among Escherichia coli isolates from zoo animals, Czech Republic. AB - Commensal Escherichia coli isolates from healthy zoo animals kept in Ostrava Zoological Garden, Czech Republic, were investigated to evaluate the dissemination of extended-spectrum beta-lactamase (ESBL) and plasmid-mediated quinolone resistance (PMQR) genes. A total of 160 faecal samples of various animal species were inoculated onto MacConkey agar with cefotaxime (2 mg L(-1)) or ciprofloxacin (0.05 mg L(-1)) to obtain ESBL- or PMQR-positive E. coli isolates. Clonality of E. coli isolates was investigated by multilocus sequence typing and pulsed-field gel electrophoresis. Plasmids carrying ESBL or PMQR genes were typed by PCR-based replicon typing, plasmid multilocus sequence typing and restriction fragment length polymorphism. Forty-nine (71%, n = 69) cefotaxime resistant and 15 (16%, n = 94) ciprofloxacin-resistant E. coli isolates harboured ESBL or PMQR genes. Isolates were assigned to 18 sequence types (ST) and 20 clusters according to their macrorestriction patterns by pulsed-field gel electrophoresis. The genes blaCTX -M-1 and qnrS1 were detected on highly related IncI1 plasmids assigned to clonal complex 3 (ST3, ST38) and on non-related IncN plasmids of ST1 and ST3, respectively. The gene qnrS1 was located on related IncX1 plasmids. Dissemination of antibiotic resistance is associated with spreading of particular E. coli clones and plasmids of specific incompatibility groups among various animal species. PMID- 23679005 TI - Role of salivary epithelial toll-like receptors 2 and 4 in modulating innate immune responses in chronic periodontitis. AB - BACKGROUND AND OBJECTIVE: Chronic periodontitis is initiated by sequential colonization with a broad array of bacteria and is perpetuated by an immune inflammatory response to the changing biofilm. Host recognition of microbes is largely mediated by toll-like receptors (TLRs), which interact with conserved pathogen-associated molecular patterns. Based on ligand recognition, TLR-2 and TLR-4 interact with most periodontal pathogens. Extracrevicular bacterial reservoirs, such as the oral epithelial cells, contribute to the persistence of periodontitis. Human saliva is a rich source of oral epithelial cells that express functional TLRs. In this study we investigated the role of salivary epithelial cell (SEC) TLR-2 and TLR-4 in patients with generalized chronic periodontitis. MATERIAL AND METHODS: Unstimulated whole saliva (UWS) was collected from patients with generalized chronic periodontitis and from healthy individuals after obtaining informed consent. Epithelial cells isolated from each UWS sample were assessed for TLR-2, TLR-4, peptidoglycan recognition protein (PGRP)-3 and PGRP-4 by quantitative real-time PCR. In addition, the SECs were stimulated in vitro with microbial products for up to 24 h. The culture supernatant was assessed for cytokines by ELISA. RESULTS: Stimulation with TLR-2- or TLR-4-specific ligands induced cytokine secretion with differential kinetics and up-regulated TLR2 and TLR4 mRNAs, respectively, in cultures of SECs from patients with periodontitis. In addition, the SECs from patients with periodontitis exhibited reduced PGRP3 and PGRP4 mRNAs, the TLR-responsive genes with antibacterial properties. CONCLUSION: SECs derived from the UWS of patients with chronic periodontitis are phenotypically distinct and could represent potential resources for assessing the epithelial responses to periodontal pathogens in the course of disease progression and persistence. PMID- 23679006 TI - Effect of monensin on in vitro fermentation of silages and microbial protein synthesis. AB - The objective of the study was to investigate the effects of monensin on silage fermentation and microbial net protein synthesis. In Experiment 1, monensin (0.5, 1, 2, 4, 6, or 10 ug) was added to syringes that contained 120 mg of grass silage (GS), grass silage and concentrate (GS + C), or maize silage (MS), resulting in concentrations of 4.2, 8.3, 16.7, 33.3, 50.0 and 83.3 mg monensin/kg feed. Samples were incubated for 24 h to determine the monensin concentration that resulted in the maximum reduction in methane production without effects on the total gas production. In Experiment 2, GS and GS + C were incubated in a rumen simulation technique (Rusitec) to assess the monensin effects (133 and 266 mg/kg feed) on the production of total gas, methane and volatile fatty acids (VFA), degradation of nutrients and microbial net protein synthesis. In Experiment 1, methane production was reduced without significant effects on the total gas production; the reductions were 17% (GS), 10% (GS + C) and 13% (MS) with 16.7 (GS), 50.0 (GS + C) and 33.3 (MS) mg monensin/kg feed. Monensin reduced the total gas and methane production in GS and GS + C in Experiment 2. Propionate production was enhanced by monensin, accompanied by a decrease in acetate production. Along with a reduction in crude protein (CP) degradation, monensin reduced the ammonia nitrogen concentration in the effluent of both treatments. While the protein produced by liquid-associated microbes increased with monensin, protein production by solid-associated microbes was reduced. Total microbial net protein synthesis increased in the presence of monensin. Monensin influenced the production of total gas, methane and VFA from the silages without an effect on the degradation of organic matter (OM). Different microbial fractions were affected differently by monensin supplementation. If monensin is used as a tool to reduce methane emission, the supplementation level must be carefully chosen to avoid negative effects on overall fermentation in the rumen. PMID- 23679007 TI - Disk-based k-mer counting on a PC. AB - BACKGROUND: The k-mer counting problem, which is to build the histogram of occurrences of every k-symbol long substring in a given text, is important for many bioinformatics applications. They include developing de Bruijn graph genome assemblers, fast multiple sequence alignment and repeat detection. RESULTS: We propose a simple, yet efficient, parallel disk-based algorithm for counting k mers. Experiments show that it usually offers the fastest solution to the considered problem, while demanding a relatively small amount of memory. In particular, it is capable of counting the statistics for short-read human genome data, in input gzipped FASTQ file, in less than 40 minutes on a PC with 16 GB of RAM and 6 CPU cores, and for long-read human genome data in less than 70 minutes. On a more powerful machine, using 32 GB of RAM and 32 CPU cores, the tasks are accomplished in less than half the time. No other algorithm for most tested settings of this problem and mammalian-size data can accomplish this task in comparable time. Our solution also belongs to memory-frugal ones; most competitive algorithms cannot efficiently work on a PC with 16 GB of memory for such massive data. CONCLUSIONS: By making use of cheap disk space and exploiting CPU and I/O parallelism we propose a very competitive k-mer counting procedure, called KMC. Our results suggest that judicious resource management may allow to solve at least some bioinformatics problems with massive data on a commodity personal computer. PMID- 23679008 TI - Ecological effects of environmental change. AB - This Special Issue of Ecology Letters presents contributions from an international meeting organised by Centre National de la Recherche Scientifique (CNRS) and Ecology Letters on the broad theme of ecological effects of global environmental change. The objectives of these articles are to synthesise, hypothesise and illustrate the ecological effects of environmental change drivers and their interactions, including habitat loss and fragmentation, pollution, invasive species and climate change. A range of disciplines is represented, including stoichiometry, cell biology, genetics, evolution and biodiversity conservation. The authors emphasise the need to account for several key ecological factors and different spatial and temporal scales in global change research. They also stress the importance of ecosystem complexity through approaches such as functional group and network analyses, and of mechanisms and predictive models with respect to environmental responses to global change across an ecological continuum: population, communities and ecosystems. Lastly, these articles provide important insights and recommendations for environmental conservation and management, as well as highlighting future research priorities. PMID- 23679009 TI - Scale-dependent effect sizes of ecological drivers on biodiversity: why standardised sampling is not enough. AB - There is little consensus about how natural (e.g. productivity, disturbance) and anthropogenic (e.g. invasive species, habitat destruction) ecological drivers influence biodiversity. Here, we show that when sampling is standardised by area (species density) or individuals (rarefied species richness), the measured effect sizes depend critically on the spatial grain and extent of sampling, as well as the size of the species pool. This compromises comparisons of effects sizes within studies using standard statistics, as well as among studies using meta analysis. To derive an unambiguous effect size, we advocate that comparisons need to be made on a scale-independent metric, such as Hurlbert's Probability of Interspecific Encounter. Analyses of this metric can be used to disentangle the relative influence of changes in the absolute and relative abundances of individuals, as well as their intraspecific aggregations, in driving differences in biodiversity among communities. This and related approaches are necessary to achieve generality in understanding how biodiversity responds to ecological drivers and will necessitate a change in the way many ecologists collect and analyse their data. PMID- 23679010 TI - Beyond climate change attribution in conservation and ecological research. AB - There is increasing pressure from policymakers for ecologists to generate more detailed 'attribution' analyses aimed at quantitatively estimating relative contributions of different driving forces, including anthropogenic climate change (ACC), to observed biological changes. Here, we argue that this approach is not productive for ecological studies. Global meta-analyses of diverse species, regions and ecosystems have already given us 'very high confidence' [sensu Intergovernmental Panel on Climate Change (IPCC)] that ACC has impacted wild species in a general sense. Further, for well-studied species or systems, synthesis of experiments and models with long-term observations has given us similarly high confidence that they have been impacted by regional climate change (regardless of its cause). However, the role of greenhouse gases in driving these impacts has not been estimated quantitatively. Should this be an ecological research priority? We argue that development of quantitative ecological models for this purpose faces several impediments, particularly the existence of strong, non-additive interactions among different external factors. However, even with current understanding of impacts of global warming, there are myriad climate change adaptation options already developed in the literature that could be, and in fact are being, implemented now. PMID- 23679012 TI - Microbial community responses to anthropogenically induced environmental change: towards a systems approach. AB - The soil environment is essential to many ecosystem services which are primarily mediated by microbial communities. Soil physical and chemical conditions are altered on local and global scales by anthropogenic activity and which threatens the provision of many soil services. Despite the importance of soil biota for ecosystem function, we have limited ability to predict and manage soil microbial community responses to change. To better understand causal relationships between microbial community structure and ecological function, we argue for a systems approach to prediction and management of microbial response to environmental change. This necessitates moving beyond concepts of resilience, resistance and redundancy that assume single optimum stable states, to ones that better reflect the dynamic and interactive nature of microbial systems. We consider the response of three soil groups (ammonia oxidisers, denitrifiers, symbionts) to anthropogenic perturbation to motivate our discussion. We also present a network re-analysis of a saltmarsh microbial community which illustrates how such approaches can reveal ecologically important connections between functional groups. More generally, we suggest the need for integrative studies which consider how environmental variables moderate interactions between functional groups, how this moderation affects biogeochemical processes and how these feedbacks ultimately drive ecosystem services provided by soil biota. PMID- 23679011 TI - A road map for integrating eco-evolutionary processes into biodiversity models. AB - The demand for projections of the future distribution of biodiversity has triggered an upsurge in modelling at the crossroads between ecology and evolution. Despite the enthusiasm around these so-called biodiversity models, most approaches are still criticised for not integrating key processes known to shape species ranges and community structure. Developing an integrative modelling framework for biodiversity distribution promises to improve the reliability of predictions and to give a better understanding of the eco-evolutionary dynamics of species and communities under changing environments. In this article, we briefly review some eco-evolutionary processes and interplays among them, which are essential to provide reliable projections of species distributions and community structure. We identify gaps in theory, quantitative knowledge and data availability hampering the development of an integrated modelling framework. We argue that model development relying on a strong theoretical foundation is essential to inspire new models, manage complexity and maintain tractability. We support our argument with an example of a novel integrated model for species distribution modelling, derived from metapopulation theory, which accounts for abiotic constraints, dispersal, biotic interactions and evolution under changing environmental conditions. We hope such a perspective will motivate exciting and novel research, and challenge others to improve on our proposed approach. PMID- 23679013 TI - Predicting community and ecosystem outcomes of mycorrhizal responses to global change. AB - Mycorrhizal symbioses link the biosphere with the lithosphere by mediating nutrient cycles and energy flow though terrestrial ecosystems. A more mechanistic understanding of these plant-fungal associations may help ameliorate anthropogenic changes to C and N cycles and biotic communities. We explore three interacting principles: (1) optimal allocation, (2) biotic context and (3) fungal adaptability that may help predict mycorrhizal responses to carbon dioxide enrichment, nitrogen eutrophication, invasive species and land-use changes. Plant microbial feedbacks and thresholds are discussed in light of these principles with the goal of generating testable hypotheses. Ideas to develop large-scale collaborative research efforts are presented. It is our hope that mycorrhizal symbioses can be effectively integrated into global change models and eventually their ecology will be understood well enough so that they can be managed to help offset some of the detrimental effects of anthropogenic environmental change. PMID- 23679014 TI - Folding coupled with assembly in split green fluorescent proteins studied by structure-based molecular simulations. AB - Split green fluorescent protein (GFP) is a powerful tool for imaging of protein protein interactions in living cells, but molecular mechanisms of the folding and the assembly of split GFPs are poorly understood. Here, using a simple Go model that is based on the energy landscape theory, we performed comprehensive folding simulations of six split GFPs with different split points. Of the six, the fluorescence recovery was reported in four but not in the other two. In the simulations, we found that when the complete folding and assembly were observed, the N-terminal fragment always folded earlier than the C-terminal fragment. The in silico folding rates of the split GFPs were larger for the four split GFPs that the fluorescence recovery was reported in literature. The stability of standalone N-terminal fragments were well-correlated with the folding rates of split GFPs. These suggest that the efficient folding and assembly of split GFPs are realized when the N-terminal fragment folds spontaneously with the central alpha-helix as a nucleation core and that the C-terminal fragment folding is coupled to the assembly to the preformed N-terminal fragment. PMID- 23679015 TI - Epidemiology of chronic inflammatory neuropathies in southeast England. AB - BACKGROUND AND PURPOSE: There is little information about the prevalence and disease burden of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN) and paraproteinaemic demyelinating neuropathy (PDN). METHODS: Multiple sources were used to study the prevalence and clinical features of these diseases in a southeast England population of 3,557,352 people. RESULTS: The crude prevalences were as follows: CIDP, 2.84 (95% CI 2.31-3.45); MMN, 0.53 (95% CI 0.32-0.83); and PDN, 1.04 (95% CI 0.73-1.43) per 100,000 population. All three diseases were more common in men than in women. The peak decade of onset was older in those with CIDP (70-79 years) and PDN (70-79 years) than in those with MMN (50-59 years). Disability was greater in CIDP and PDN, with median (range) overall neuropathy limitations scores of 4 (0-8) and 4 (1-6), respectively, than in MMN, with a score of 2 (1-5). CONCLUSION: The common forms of chronic inflammatory neuropathy cause a considerable disease burden in the community. PMID- 23679016 TI - Catalytic asymmetric oxidation of N-sulfonyl imines with hydrogen peroxide trichloroacetonitrile system. AB - An efficient and highly enantioselective Payne-type oxidation of N-sulfonyl imines is developed. The reaction exhibits broad substrate generality and unique chemoselectivity based on the combined use of hydrogen peroxide and trichloroacetonitrile under the catalysis of P-spiro chiral triaminoiminophosphorane. PMID- 23679017 TI - Skeletal muscle tissue engineering: which cell to use? AB - Tissue-engineered skeletal muscle is urgently required to treat a wide array of devastating congenital and acquired conditions. Selection of the appropriate cell type requires consideration of several factors which amongst others include, accessibility of the cell source, in vitro myogenicity at high efficiency with the ability to maintain differentiation over extended periods of time, susceptibility to genetic manipulation, a suitable mode of delivery and finally in vivo differentiation giving rise to restoration of structural morphology and function. Potential stem-progenitor cell sources include and are not limited to satellite cells, myoblasts, mesoangioblasts, pericytes, muscle side-population cells, CD133(+) cells, in addition to embryonic stem cells, mesenchymal stem cells, amniotic fluid stem cells and induced pluripotent stem (iPS) cells. The relative merits and inherent limitations of these cell types within the field of tissue-engineering are discussed in the light of current research. Recent advances in the field of iPS cells should bear the fruits for some exciting developments within the field in the forthcoming years. PMID- 23679018 TI - Brunner's gland hyperplasia and adenoma associated with colic in an aged Arabian mare. PMID- 23679019 TI - Impact of a first treatment with phosphodiesterase inhibitors on men and partners' quality of sexual life: results of a prospective study in primary care. AB - INTRODUCTION: Phosphodiesterase type 5 inhibitors (PDE5is) as oral treatment for erectile dysfunction (ED) facilitate the management of ED in primary care. Still, compliance is low and general practitioners (GPs) do not always feel confident with this pathology. AIM.: The aim of this paper is to evaluate the impact of a first treatment with PDE5i on the patient and his partner and the management of ED by GPs. METHODS: The Evaluation apres traitement de la dyfonction erectile, du bien-etre emotionnel d'un patient en fonction de la rigidite de son erection survey was a longitudinal, observational French study with prospective collection of data from the GP, the patient, and his partner at baseline and after 3 months of treatment. GPs benefited from a short educational session before starting the survey. MAIN OUTCOME MEASURES: The main outcome measures are the Erection Hardness Score (EHS), Self-Esteem and Relationship (SEAR) questionnaire, Index of Sexual Life (ISL), and Erectile Dysfunction Inventory of Treatment Satisfaction. RESULTS: A total of 478 men aged 19-80 years (mean 57 years) were included in the survey by 229 GPs. Before treatment, EHS was mostly grade 1 (28%) or 2 (44%). At the end of the survey, an improvement was reported for 88% of the patients and 58% achieved maximum score EHS 4 (penis completely hard and fully rigid). Mean SEAR scores significantly increased after 3 months for self-esteem, overall and sexual relationship, and more notably with greater improvement in EHS (P < 0.001). Improvement in partners' ISL scores was significantly higher with greater improvement in EHS (P < 0.001) and in SEAR score for self-esteem. The safety profile of PDE5i was good with few adverse events, mostly headaches. More than 80% of the participating GPs considered that the survey had changed their management of ED. CONCLUSION: After 3 months of treatment with PDE5i, a significant improvement in self-esteem was observed in patients with ED, associated with improvement in erection. PMID- 23679020 TI - Charge transfer and blue shifting of vibrational frequencies in a hydrogen bond acceptor. AB - A comprehensive Raman spectroscopic/electronic structure study of hydrogen bonding by pyrimidine with eight different polar solvents is presented. Raman spectra of binary mixtures of pyrimidine with methanol and ethylene glycol are reported, and shifts in nu1, nu3, nu6a, nu6b, nu8a, nu8b, nu9a, nu15, nu16a, and nu16b are compared to earlier results obtained for water. Large shifts to higher vibrational energy, often referred to as blue shifts, are observed for nu1, nu6b, and nu8b (by as much as 14 cm(-1)). While gradual blue shifts with increasing hydrogen bond donor concentration are observed for nu6b and nu8b, nu1 exhibits three distinct spectral components whose relative intensities vary with concentration. The blue shift of nu1 is further examined in binary mixtures of pyrimidine with acetic acid, thioglycol, phenylmethanol, hexylamine, and acetonitrile. Electronic structure computations for more than 100 microsolvated structures reveal a significant dependence of the magnitude of the nu1 blue shift on the local microsolvation geometry. Results from natural bond orbital (NBO) calculations also reveal a strong correlation between charge transfer and blue shifting of pyrimidine's normal modes. Although charge transfer has previously been linked to blue shifting of the X-H stretching frequency in hydrogen bond donors, here, a similar trend in a hydrogen bond acceptor is demonstrated. PMID- 23679021 TI - Second conference on esophageal atresia. PMID- 23679022 TI - Epidemiology of esophageal atresia. AB - Esophageal atresia (EA) is a rare congenital malformation consisting of a lack of continuity between the upper and lower esophageal pouches, frequently associated with tracheoesophageal fistula. The prevalence of such rare abnormalities is established by global birth surveillance programs over the world. EUROCAT is a European program covering 1.7 million births since its creation. The prevalence of EA in Europe seems stable over decades. The National Birth Defects Prevention Network in the USA also shows a stable prevalence with a wide range between states or regions. In France, with the implementation of the national rare diseases plan, a reference center for congenital abnormalities of the esophagus was created in 2006 and a national registry for EA began patient inclusion in 2008. This has resulted in the establishment of the national live birth prevalence for EA, prenatal diagnosis rates, and clinical characteristics of EA patients, early survival, and early morbidity. Prevalence rates seem stable all over the world since many decades. Continuous surveillance of congenital abnormalities and specific registries are useful for epidemiologic data but also for public health authorities for helping families of rare diseases patients. PMID- 23679023 TI - Genetic and cellular mechanisms of the formation of esophageal atresia and tracheoesophageal fistula. AB - Foregut separation involves dynamic changes in the activities of signaling pathways and transcription factors. Recent mouse genetic studies demonstrate that some of these pathways interact with each other to form a complex network, leading to a unique dorsal-ventral patterning in the early foregut. In this review, it is discussed how this unique dorsal-ventral patterning is set prior to the foregut separation and how disruption of this patterning affects the separation process. Roles of downstream targets of these pathways in regulating separation at cellular and molecular levels would be discussed further. Understanding the mechanism of normal separation process will provide insights into the pathobiology of a relatively common birth defect, esophageal atresia with/without tracheoesophageal fistula. PMID- 23679024 TI - Thoracoscopic repair of esophageal atresia and tracheoesophageal fistula in neonates, first decade's experience. AB - The first thoracoscopic esophageal atresia with tracheoesophageal fistula (EATEF) repair was performed in March of 2000. This report evaluates the results and evolution of the technique in a single surgeons' experience after the first decade of thoracoscopic EATEF repair. From March 2000 to September 2012, 52 consecutive patients with type 3 EATEF, and an additional nine patients with pure esophageal atresia (EA) were repaired by or under the direct supervision of a single surgeon. Patient weight ranged from 1.2 to 3.8 kg (mean 2.6 kg). Twenty two patients had significant associated congenital anomalies. The repairs were performed using three ports. The fistula was ligated using a single endoscopic clip, and the anastomosis was performed using a single layer of interrupted sutures. A transanastomotic tube and chest drain were left in all cases. Fifty one of the 52 procedures were completed successfully thoracoscopically. Operative times ranged from 50 to 120 minutes (average 85 minutes). There were three clinical leaks, one in an EATEF and two in patients with long-gap pure EA, all resolved with conservative therapy. Oral feedings were started on day 5 in all other patients. Twelve of 61 patients required dilations (1-9), and 18 required a Nissen fundoplication for severe reflux. One patient required a thoracoscopic aortopexy for severe tracheomalacia. All patients are currently on full oral feedings. No patient has any evidence of chest wall asymmetry, winged scapula, or clinically significant scoliosis. There have been no recurrent fistulas. Thoracoscopic EA repair has proven to be an effective and safe technique. Initial experience resulted in a higher stricture rate, but this improved with experience and changes in technique. The results are superior to that of documented open series and avoid the morbidity of an open thoracotomy. PMID- 23679025 TI - Thoracotomy for repair of esophageal atresia: not as bad as they want you to think! AB - Is it outdated now to do a thoracotomy to repair esophageal atresia (EA)? Our practices and the literature on the subject of thoracoscopic and open thoracotomy repair of EA were reviewed, seeking answers to the following questions: Is it correct to compare the new thoracoscopic approach for the repair of EA against the thoracotomy techniques of 15-30 years ago? Should post-thoracotomy scoliosis/thoracic deformity reported in up to 56% of patients be a significant current concern? Are the clips used to close the fistula in thoracoscopic repairs as safe as open suture closures? Is the leak and stricture rate similar with thoracoscopic surgery? Are the anesthesia, period of ventilation, pain, time to first feeding, and the length of hospital stay significantly different with current thoracotomy techniques compared with thoracoscopic methods? Is the cosmetic result of a thoracoscopic repair significantly better? Is the learning curve for EA thoracoscopic repair harming patients for minimal long-term benefit? These questions were scientifically unanswerable at this time. The limited EA thoracotomies currently performed have a track record of proven safety and minimal morbidity. The results published by surgeons who are pioneers in thoracoscopy may not be generalizable, and the complication rate from teams with less experience is likely underreported. In selected patients and with experienced teams, thoracoscopic EA repair is appropriate. However, EA repair via thoracotomy should, for now, remain as the 'gold standard'. Further registry based, multicenter, comparative studies on EA repair methodologies and outcomes should provide important answers. PMID- 23679026 TI - Long-gap esophageal atresia: traction-growth and anastomosis - before and beyond. AB - Long-gap esophageal atresia (LGEA) is still a major surgical challenge. Options for esophageal reconstruction include the use of native esophagus or esophageal replacement with stomach, colon, or small intestine. Nonetheless, there is a consensus among most pediatric surgeons that the preservation of the native esophagus is associated with better postoperative outcomes. Thus, every effort should be made to conserve the native esophagus. The present study is aimed at critically reporting our experience focused on a standardized protocol based on the preoperative assessment of the gap in all cases and reviewing the present literature because no consensus is available regarding many aspects of LGEA (from definition to treatment). All newborn infants treated since 1995 for esophageal atresia (EA), regardless of type, were included in the present study. Identification of LGEA patients (gap >=3 vertebral bodies) was performed based on preoperative esophageal gap measurement. The selected patients were grouped based on EA type (A/B vs. C/D) and whether they were referred from an outside institution or not. Postoperative outcome was compared. Statistical analysis was performed with the Fisher's exact test and Mann-Whitney test as appropriate, with P < 0.05 considered statistically significant. Two hundred and nineteen patients have been consecutively treated between 1995 and 2012 with the following EA subtypes: type: A 25 (11.4%); B 6 (2.7%); C 182 (83.1%); D 3 (1.4%); E 3 (1.4%). Fifty-seven patients (26%) were classified as LGEA: type A-B, 31 (54.4%); type C D, 26 (45.6%). Twenty seven (47%) of these patients were referred after at least one failed attempt at esophageal correction: type A-B, 15 (55%); type C-D, 12 (45%). Only one patient ultimately required esophageal substitution, with an overall survival rate of 94%. A standardized perioperative protocol enhances the possibility of preserving the native esophagus in cases of LGEA. Gap measurement can be accurately defined before surgery in all patients with EA. Esophageal anastomosis (either immediate or delayed repair) is almost always feasible; esophageal substitution should only be considered after a rigorous attempt at achieving end-to-end esophageal anastomosis. PMID- 23679027 TI - Diagnosis and surgical management of recurrent tracheoesophageal fistulas. AB - Recurrent tracheoesophageal fistula (TEF) is difficult to diagnose and even more difficult to repair. The key to the diagnosis is an adequate contrast study and bronchoscopy. The key to the repair is complete separation of the esophagus from the trachea, with the placement of viable tissue between the two suture lines. I have presented a personal experience with 38 consecutive repairs of recurrent TEFs. The original series of 26 patients had three recurrences, all of which were re-repaired successfully. My more recent experience with the last 12 patients, who were far more complex, was also successful in ultimately repairing the recurrent TEFs. PMID- 23679028 TI - Refractory strictures post-esophageal atresia repair: what are the alternatives? AB - Esophageal strictures remain the most frequent complication after esophageal atresia (EA) repair despite refinements in operative techniques. With an incidence of anastomotic stricture between 8% and 49%, EA is the most frequent cause of benign esophageal stricture in children. The mainstay of treatment for esophageal stricture is dilatation with a 58-96% success rate. In order to relieve dysphagia, between 1 and 15 dilatations will be required in each EA patient with an esophageal stricture. However dilatations may lead to complications including perforation (0.1-0.4% of all esophageal benign strictures) and sociopsychological morbidity. Fifty percent of EA strictures will improve in 6 months. However, 30% will persist and require repeat dilatations. The present article explores the variety of non-surgical alternative treatments for anastomotic strictures after EA repair, focusing on triamcinolone acetonide, mitomycin C and esophageal stents. We propose an algorithm for a more standardized therapeutic approach, with the hope that an international panel of experts could meet and establish a consensus. PMID- 23679029 TI - Dynamic esophageal stents. AB - Esophageal stenting represents a new strategy in the treatment of resistant or recurrent stenosis that obviates the need for multiple dilations. Our custom dynamic stent (DS) improves esophageal motility unlike the widespread self expandable plastic or metallic esophageal stents. The DS allows food and secretions to pass in the space between the esophageal wall and the stent wall. This contrasts with the other types of stent, in which food passes into the stent that presses into the esophageal wall. Until the stent patent is complete, we use slices of silicon drains overlapped with each other to fashion the stent to the desired length and diameter (7-, 9-, or 12.7-mm external diameter). It is built coaxially on a nasogastric tube that guarantees the correct position. The two ends are tailored to allow an easy introduction and food passage between stent and esophageal wall. The stent is inserted after stricture dilations (Savary Gilliard dilators) under fluoroscopic guidance. All patients who underwent stenting were treated with dexamethasone (2 mg/kg/day) for 3 days and proton pump inhibitors (omeprazole or lansoprazole, 1-2 mg/kg/day). From 1992 to 2012, 387 patients (mean age 38.6 months; range 3-125 months) with post-surgical esophageal stricture because of esophageal atresia correction were enrolled in this study. Twenty-six of 387 patients (6.7%) underwent custom DS placement for recurrent stricture instead of a program of serial dilations. The stent was left in place for at least 40 days and was effective in 21 (80.7%) of 26 patients. There were two stent-related major complications (subclavian-esophageal fistula). Our custom stent represents an effective and safe option in the treatment of severe and recurrent post-surgical esophageal strictures. Surgery with stricture resection, and reanastomosis or jeunoplasty represents the rescue strategy. PMID- 23679030 TI - Psychological impact of esophageal atresia: review of the research and clinical evidence. AB - Esophageal atresia (EA) occurs in one out of 2500 to 4500 live births. As the vast majority of infants are now surviving neonatal corrective surgery, the focus has shifted from mortality to morbidity associated with EA. However, little is known about its psychological morbidity. This paper synthesizes research and clinical evidence to highlight the psychological sequelae of EA, including its impact on parents' psychological functioning and its effects on child development from infancy to adulthood. Whether it is discovered at birth or prenatally, EA is a psychologically traumatic event, and parents are at risk for developing traumatic stress reactions following diagnosis. Neonatal surgery and intensive care, risk of complications, associated anomalies, and genetic etiologies multiply risk for parents' acute and post-traumatic stress disorders (PTSD). Parental PTSD has a negative impact on infant and child development through its effects on parenting skills and parent-child interactions. EA children are also at risk for PTSD because of invasive and stressful procedures they undergo during the neonatal period. Consequences of EA can have an important long-term impact on children's psychological and social development. The scant studies pertaining to cognitive functioning suggest that EA does not affect mental development during infancy, but may be associated with deficits as children reach school age. Long term sequelae are unclear because psychological functioning in adults has not yet been adequately examined. Research and clinical evidence of psychological morbidity associated with EA has implications for clinical practice. Psychological support for parents must begin during the neonatal period and should continue as an integral component of long-term follow up for both children and parents. Support is best provided within the context of a multidisciplinary treatment team that follows patients from birth through childhood and adolescence. Psychological follow up should continue into adulthood, as patients grow up and transition from pediatric to adult health-care settings. PMID- 23679031 TI - Anti-reflux surgery for patients with esophageal atresia. AB - Gastroesophageal reflux (GER) is almost constant in esophageal atresia and tracheoesophageal fistula (EA/TEF). These patients resist medical treatment and require antireflux surgery quite often. The present review examines why this happens, the long-term consequences of GER and the main indications and results of fundoplication in this particular group of patients. The esophagus of EA/TEF patients is malformed and has abnormal extrinsic and intrinsic innervation and, consequently, deficient sphincter function and dysmotility. These anomalies are permanent. Fifty percent of patients overall have GER, and one-fifth have Barrett's metaplasia. Close to 100%, GER of pure and long-gap cases require fundoplication. In the long run, these patients have 50-fold higher risk of carcinoma than the control population. GER in EA/TEF does not respond well to dietary, antacid, or prokinetic medication. Surgery is necessary in protracted anastomotic stenoses, in pure and long-gap cases, and when there is an associated duodenal atresia. It should be indicated as well in other symptomatic cases when conservative treatment fails. However, confection of a suitable wrap is anatomically difficult in this condition as shown by a failure rate of 30% that is also explained by the persistence for life of the conditions facilitating GER. PMID- 23679032 TI - Esophageal dysmotility: characterization and pathophysiology. AB - Esophageal dysmotility is a considerable long-term issue in patients born with esophageal atresia (EA). To better characterize it, the normal esophageal motility is briefly reviewed with emphasis on the specific defects in EA. Multiple studies attempted to describe the dysmotility seen in patients with operated EA using esophageal manometry. Recently, high-resolution manometry has improved our understanding of normal esophageal motility. Using this new technology, it is now possible to better characterize the esophageal motility of patients operated on for EA. Three different patterns are described and presented: aperistalsis, pressurization, and distal peristalsis. Up to now, it has not been possible to find a correlation between the dysmotility severity and the patient's symptomatology. Different pathophysiological hypotheses of esophageal dysmotility in that population are discussed. Developmental neuronal defects are certainly present from the beginning. Surgical trauma can also contribute to the dysmotility. Finally, defective esophageal acid clearance capacity is a cause of gastroesophageal reflux disease, but the resultant esophagitis can also impair the normal esophageal function. The evolution of esophageal dysmotility in patients with repaired EA is not known and further studies will be necessary to clarify it. PMID- 23679033 TI - Feeding difficulties in children with esophageal atresia: treatment by a multidisciplinary team. AB - Esophageal atresia (EA) is one of the congenital neonatal anomalies whose immediate consequence for the newborn is the inability to feed. Most centers strive to minimize the effects of surgeries and subsequent postoperative complications such as esophageal strictures, respiratory problems, and gastrointestinal reflux on the child's ability or motivation to feed. Feeding difficulties in early infancy may not only interrupt maternal expectations of becoming providers of nutrition to their infants but may also influence the infant's development of sensory motor skills and parent-child relationships. Early involvement by a multidisciplinary team consisting of occupational therapist, nutritionist, and psychologist is an important addition to the surgical and medical team. The team assists in preparing mothers for feeding related difficulties, providing anticipatory guidance to improve feeding abilities and relationships, especially for children with multiple surgical involvements and prolonged periods of non-oral feeding. PMID- 23679034 TI - Long-term respiratory complications of congenital esophageal atresia with or without tracheoesophageal fistula: an update. AB - Despite early surgical repair, congenital esophageal atresia with or without tracheoesophageal fistula (EA +/- TEF) has long-term effects on respiratory and gastrointestinal function. This review updates summarizes research published since 2003 on long-term respiratory complications in patients with a history of EA +/- TEF. Pulmonary hypoplasia appears to not be rare in patients with EA +/- TEF. Tracheomalacia is common and is associated with respiratory symptoms in childhood. Aspiration, associated with esophageal dysmotility and/or gastroesophageal reflux, may lead to reduced pulmonary function and bronchiectasis. Pulmonary function is generally normal, although lower than in control patients, and restrictive defects tend to be commoner than obstructive defects. Abnormal airway reactivity is common and, along with respiratory symptoms, is associated with atopy. However, the inflammatory profile in EA +/- TEF patients based on bronchial biopsies and exhaled nitric oxide differs from typical allergic asthma. Recent studies suggest that in older patients, respiratory symptoms tend to be associated with atopy, but abnormal lung function tends to be associated with gastroesophageal reflux and with chest wall abnormalities. Early detection and management of aspiration may be important to help prevent decrements in pulmonary function and serious long-term complications in EA +/- TEF patients. PMID- 23679035 TI - Esophageal atresia: long-term morbidities in adolescence and adulthood. AB - Survival rates in esophageal atresia (EA) patients have reached 90%. In long-term follow-up studies the focus has shifted from purely surgical or gastrointestinal evaluation to a multidisciplinary approach. We evaluated the long-term morbidity in adolescent and adult EA patients and discussed mainly nonsurgical issues. Dysphagia is common and reported in up to 85% of patients. In young adults gastroesophageal reflux disease occurs frequently with development of Barrett esophagus in 6% reported in different series. It is difficult to estimate respiratory morbidity from the literature because many different definitions, questionnaires, and study designs have been used. However, many patients seem to suffer from respiratory problems even into adulthood. In conclusion, morbidity is not only restricted to surgical problems but many different domains are involved. These are all related and together determine to a large extent the quality of life of EA patients and also of their families. We assume that a multidisciplinary care approach seems best to address their special needs. PMID- 23679036 TI - Follow-up of adult patients with repaired esophageal atresia: how, when, and for how long? AB - Esophageal atresia (EA) is the most common congenital anomaly of the esophagus. With the progress of surgical and anesthetic techniques, the survival is now more than 90% and the majority of children survives and eventually reaches adulthood. However, even if the continuity of the esophagus is anatomically replaced by the surgery, there are some new pieces of evidence that suggest considerable long term morbidity. In this paper, we will illustrate how symptomatic gastroesophageal reflux, dysphagia, and esophageal motility disturbances, as well as columnar epithelial metaplasia, are common in adults with repaired EA. The ideal follow-up for adult patients born with EA has not been clearly defined, and routine endoscopic assessment has not been widely advocated. It is well known that the patient's symptoms have a poor correlation with histological findings. However, routine follow-up may be expensive and time consuming. With the growing number of children reaching adulthood, it is now essential to know and understand the natural history of this condition to improve the management of these patients. PMID- 23679037 TI - Esophageal atresia: metaplasia, Barrett. AB - Barrett's esophagus is characterized by the replacement of squamous epithelium by columnar epithelium that is intestinal metaplasia-positive or -negative in the distal esophagus. Gastroesophageal reflux disease, which is frequent and prolonged in esophageal atresia, probably plays a major role in the development of Barrett's esophagus through repeated mucosal damage. Long-term acid exposure contributes to carcinogenesis in Barrett's esophagus of intestinal type, but its effect on gastric metaplasia is less well defined. Recent studies have suggest that metaplasia arises in about 15% of patients with esophageal atresia, with a lag time to developing metaplasia from initial surgical correction of about 10 years. Preliminary data from an ongoing multicenter study including 88 patients with esophageal atresia aged 15-19 years showed gastric metaplasia in 42% of patients (29 fundic and 7 cardial metaplasia), while one patient presented intestinal metaplasia. Esophageal mucosal abnormalities can be observed in esophageal atresia patients at endoscopy despite the absence of symptoms. Whether prolonged, aggressive, acid suppression is beneficial in these situations remains to be determined. Barrett's metaplasia can be removed by endoscopic mucosal resection or destroyed with endoscopic ablative techniques, such as photodynamic therapy, radiofrequency ablation, and cryotherapy. The risk of developing esophageal carcinoma is still a controversial issue as only a few clinical cases have been reported in young adults with esophageal atresia. As late complications of esophageal atresia, particularly esophagitis and Barrett's esophagus, are increasingly being recognized, long-time systematic follow up of the esophageal mucosa including multistage biopsies is therefore required even in asymptomatic patients. PMID- 23679039 TI - Attention modulates saccadic inhibition magnitude. AB - Visual transient events during ongoing eye movement tasks inhibit saccades within a precise temporal window, spanning from around 60-120 ms after the event, having maximum effect at around 90 ms. It is not yet clear to what extent this saccadic inhibition phenomenon can be modulated by attention. We studied the saccadic inhibition induced by a bright flash above or below fixation, during the preparation of a saccade to a lateralized target, under two attentional manipulations. Experiment 1 demonstrated that exogenous precueing of a distractor's location reduced saccadic inhibition, consistent with inhibition of return. Experiment 2 manipulated the relative likelihood that a distractor would be presented above or below fixation. Saccadic inhibition magnitude was relatively reduced for distractors at the more likely location, implying that observers can endogenously suppress interference from specific locations within an oculomotor map. We discuss the implications of these results for models of saccade target selection in the superior colliculus. PMID- 23679038 TI - Longitudinal genetic analyses of Staphylococcus aureus nasal carriage dynamics in a diverse population. AB - BACKGROUND: Staphylococcus aureus (SA) nasal colonization plays a critical role in the pathogenesis of staphylococcal infections and SA eradication from the nares has proven to be effective in reducing endogenous infections. To understand SA nasal colonization and its relation with consequent disease, assessment of nasal carriage dynamics and genotypic diversity among a diverse population is a necessity. RESULTS: We have performed extensive longitudinal monitoring of SA nasal carriage isolates in 109 healthy individuals over a period of up to three years. Longitudinal sampling revealed that 24% of the individuals were persistent SA nasal carriers while 32% were intermittent. To assess the genetic relatedness between different SA isolates within our cohort, multi locus sequence typing (MLST) was performed. MLST revealed that not only were strains colonizing intermittent and persistent nasal carriers genetically similar, belonging to the same clonal complexes, but strain changes within the same host were also observed over time for both types of carriers. More highly discriminating genetic analyses using the hypervariable regions of staphylococcal protein A and clumping factor B virulence genes revealed no preferential colonization of specific SA strains in persistent or intermittent carriers. Moreover, we observed that a subset of persistent and intermittent carriers retained clinically relevant community acquired methicillin-resistant SA (CA-MRSA) strains in their nares over time. CONCLUSIONS: The findings of this study provides added perspective on the nasal carriage dynamics between strains colonizing persistent and intermittent carriers; an area currently in need of assessment given that persistent carriers are at greater risk of autoinfection than intermittent carriers. PMID- 23679041 TI - What can mathematical models bring to the control of equine influenza? AB - Mathematical modelling of infectious disease is increasingly regarded as an important tool in the development of disease prevention and control measures. This article brings together key findings from various modelling studies conducted over the past 10 years that are of relevance to those on the front line of the battle against equine influenza. PMID- 23679042 TI - 2D-ToGo workflow: increasing feasibility and reproducibility of 2-dimensional gel electrophoresis. AB - Two-dimensional gel electrophoresis (2-DE) is one of the most powerful methods for studying global protein profiles. However, due to the multiple manual steps involved in gel based processing it is challenging to achieve the necessary overall reproducibility for a reliable comparative analysis, especially between different laboratories. To improve the 2-DE technique for quantitative analyses we have set up a robust 2-DE workflow, called 2D-ToGo, which utilizes latest innovations concerning instrumentation, consumables and protocols. Quantitative data analyses indicate the high reproducibility between replicate gels processed at a single site (intra-laboratory variation: CV 20%). The data-sets of the inter laboratory comparison revealed similar results displaying a variation of CV 23%. The technical improvements given by our 2-DE workflow have a positive impact on process robustness and most importantly, reproducibility. Accordingly, many of the well-known challenges for resolving and quantitating up to thousands of different protein components in a given biological sample are minimized. PMID- 23679043 TI - Laryngeal spasm after general anaesthesia due to Ascaris lumbricoides. AB - Postoperative upper airway obstruction during recovery from general anaesthesia may have several causes. This is a report of a young girl who developed laryngeal spasm as a result of an ectopic roundworm Ascaris lumbricoides. PMID- 23679044 TI - Statistical study of deep submicron dual-gated field-effect transistors on monolayer chemical vapor deposition molybdenum disulfide films. AB - Monolayer molybdenum disulfide (MoS2) with a direct band gap of 1.8 eV is a promising two-dimensional material with a potential to surpass graphene in next generation nanoelectronic applications. In this Letter, we synthesize monolayer MoS2 on Si/SiO2 substrate via chemical vapor deposition (CVD) method and comprehensively study the device performance based on dual-gated MoS2 field effect transistors. Over 100 devices are studied to obtain a statistical description of device performance in CVD MoS2. We examine and scale down the channel length of the transistors to 100 nm and achieve record high drain current of 62.5 mA/mm in CVD monolayer MoS2 film ever reported. We further extract the intrinsic contact resistance of low work function metal Ti on monolayer CVD MoS2 with an expectation value of 175 Omega.mm, which can be significantly decreased to 10 Omega.mm by appropriate gating. Finally, field-effect mobilities (MUFE) of the carriers at various channel lengths are obtained. By taking the impact of contact resistance into account, an average and maximum intrinsic MUFE is estimated to be 13.0 and 21.6 cm(2)/(V s) in monolayer CVD MoS2 films, respectively. PMID- 23679046 TI - The effects of matrix inhomogeneities on the cellular mechanical environment in tissue-engineered cartilage: an in silico investigation. AB - Mechanical stimulation during cartilage tissue-engineering enhances extracellular matrix (ECM) synthesis and thereby improves the mechanical properties of tissue engineered (TE) cartilage. Generally, these mechanical stimuli are of a fixed magnitude. However, as a result of ECM synthesis and spatial variations thereof at both the macroscopic and microscopic scales, the internal mechanical conditions in the constructs change with time. Consequently, the physical signals in the environment of the cells will vary spatially and temporally, even though macroscopically the same loading is applied to the construct. The purpose of the present study was to numerically quantify such effects and thereby reveal the importance of adjusting loading regimes during cartilage tissue-engineering. A validated nonlinear fiber-reinforced poroviscoelastic swelling cartilage model that can accommodate for effects of collagen reinforcement and swelling by proteoglycans was used. At the microscopic scale, ECM was gradually varied from localized in the pericellular area, toward equally distributed throughout the surrounding interterritorial matrix. At the macroscopic tissue scale, ECM was gradually varied from predominantly localized in the periphery of the TE construct toward homogeneously distributed. Both concentration of ECM in the pericellular area and concentration of ECM in the periphery of a construct alter the physical signals up to an order of magnitude compared to those at the onset of the culture. Of particular interest, is the effect of elevated osmotic swelling pressure in the pericellular area, which shields not only the cells from receiving external mechanical compression, but also directly induces tension on the cells. Based on the present computational simulations, it is therefore, proposed that cartilage TE studies should consider ECM distribution as an important factor when developing loading protocols for cartilage culturing process. For instance, the level of mechanical compression should gradually increase to sufficiently deform chondrocytes over time, in case there is matrix accumulation in the pericellular area. PMID- 23679045 TI - Efficient algorithms for biological stems search. AB - BACKGROUND: Motifs are significant patterns in DNA, RNA, and protein sequences, which play an important role in biological processes and functions, like identification of open reading frames, RNA transcription, protein binding, etc. Several versions of the motif search problem have been studied in the literature. One such version is called the Planted Motif Search (PMS)or (l, d)-motif Search. PMS is known to be NP complete. The time complexities of most of the planted motif search algorithms depend exponentially on the alphabet size. Recently a new version of the motif search problem has been introduced by Kuksa and Pavlovic. We call this version as the Motif Stems Search (MSS) problem. A motif stem is an l mer (for some relevant value of l)with some wildcard characters and hence corresponds to a set of l-mers (without wildcards), some of which are (l, d) motifs. Kuksa and Pavlovic have presented an efficient algorithm to find motif stems for inputs from large alphabets. Ideally, the number of stems output should be as small as possible since the stems form a superset of the motifs. RESULTS: In this paper we propose an efficient algorithm for MSS and evaluate it on both synthetic and real data. This evaluation reveals that our algorithm is much faster than Kuksa and Pavlovic's algorithm. CONCLUSIONS: Our MSS algorithm outperforms the algorithm of Kuksa and Pavlovic in terms of the run time as well as the number of stems output. Specifically, the stems output by our algorithm form a proper (and much smaller)subset of the stems output by Kuksa and Pavlovic's algorithm. PMID- 23679047 TI - Cigarette smoke inhalation increases the alveolar bone loss caused by primary occlusal trauma in a rat model. AB - BACKGROUND AND OBJECTIVE: Occlusal trauma (OT) and smoking are both factors that alter alveolar bone metabolism and therefore could synergistically act on alveolar bone loss. The aim of this experimental study was to evaluate the influence of short-term cigarette smoke inhalation (CSI) on inter-radicular alveolar bone loss promoted by primary OT in a rat model. MATERIAL AND METHODS: Forty-eight animals were randomly assigned to one of three groups based on treatment type: OT + CSI (n = 16), animals were exposed to CSI three times per day, for 8 min per exposure, and they concomitantly received unilateral vertical augmentation creating an occlusal interference inducing experimental OT; OT (n = 16), animals received only unilateral vertical augmentation; negative control (NC; n = 16), animals maintained for equal periods to achieve periodontal baseline values of periodontal ligament dimension. Each group was divided into two subgroups (n = 8) based on treatment length: 7 or 14 d. RESULTS: After 7 d, the OT + CSI group exhibited significantly higher bone loss compared to the NC group (p = 0.0022). After 14 d, the OT (p < 0.0001) and OT + CSI (p < 0.0001) groups presented significantly higher bone loss compared to the NC group, and OT + CSI resulted in significantly higher bone loss than OT alone (p = 0.0241). The number of tartrate-resistant acid phosphatase-positive cells on the linear surface of the bone crest after 7 d was significantly higher in the OT + CSI group as compared to the NC and OT groups (p < 0.0001 and p = 0.0045, respectively) and remained significantly higher in the OT + CSI group after 14 d, compared to the OT group (p < 0.0001). CONCLUSION: Short-term CSI increases early bone loss in association with OT after 7 d, and this worsens in severity after 14 d of exposure. PMID- 23679049 TI - Fabrication of supported cuprous sites at low temperatures: an efficient, controllable strategy using vapor-induced reduction. AB - Selective reduction of supported CuO to Cu2O was realized using the strategy of vapor-induced reduction, in which HCHO/H2O vapor diffuses into the pores of the support and interacts with predispersed CuO. This new strategy allows the fabrication of supported cuprous sites at much lower temperatures within a short time, avoids the formation of Cu(0) with a Cu(I) yield of nearly 100%, and results in materials with good adsorption performance, which is impossible to achieve by conventional methods. PMID- 23679040 TI - Managing data for the international, multicentre INTERGROWTH-21st Project. AB - The INTERGROWTH-21(st) Project data management was structured incorporating both a centralised and decentralised system for the eight study centres, which all used the same database and standardised data collection instruments, manuals and processes. Each centre was responsible for the entry and validation of their country-specific data, which were entered onto a centralised system maintained by the Data Coordinating Unit in Oxford. A comprehensive data management system was designed to handle the very large volumes of data. It contained internal validations to prevent incorrect and inconsistent values being captured, and allowed online data entry by local Data Management Units, as well as real-time management of recruitment and data collection by the Data Coordinating Unit in Oxford. To maintain data integrity, only the Data Coordinating Unit in Oxford had access to all the eight centres' data, which were continually monitored. All queries identified were raised with the relevant local data manager for verification and correction, if necessary. The system automatically logged an audit trail of all updates to the database with the date and name of the person who made the changes. These rigorous processes ensured that the data collected in the INTERGROWTH-21(st) Project were of exceptionally high quality. PMID- 23679050 TI - Vulvar and vaginal atrophy in postmenopausal women: findings from the REVIVE (REal Women's VIews of Treatment Options for Menopausal Vaginal ChangEs) survey. AB - INTRODUCTION: Vulvar and vaginal atrophy (VVA) is a chronic medical condition experienced by many postmenopausal women. Symptoms include dyspareunia (pain with intercourse), vaginal dryness, and irritation and may affect sexual activities, relationships, and activities of daily life. AIM: The aim of this study is to characterize postmenopausal women's experience with and perception of VVA symptoms, interactions with healthcare professionals (HCPs), and available treatment options. METHODS: An online survey was conducted in the United States in women from KnowledgePanel((r)) , a 56,000-member probability-selected Internet panel projectable to the overall US population. Altogether, 3,046 postmenopausal women with VVA symptoms (the largest US cohort of recent surveys) responded to questions about their knowledge of VVA, impact of symptoms on their activities, communication with HCPs, and use of available treatments. MAIN OUTCOME MEASURES: Percent is calculated as the ratio of response over total responding for each question for all and stratified participants. RESULTS: The most common VVA symptoms were dryness (55% of participants), dyspareunia (44%), and irritation (37%). VVA symptoms affected enjoyment of sex in 59% of participants. Additionally, interference with sleep, general enjoyment of life, and temperament were reported by 24%, 23%, and 23% of participants, respectively. Few women attributed symptoms to menopause (24%) or hormonal changes (12%). Of all participants, 56% had ever discussed VVA symptoms with an HCP and 40% currently used VVA-specific topical treatments (vaginal over-the-counter [OTC] products [29%] and vaginal prescription therapies [11%]). Of those who had discussed symptoms with an HCP, 62% used OTC products. Insufficient symptom relief and inconvenience were cited as major limitations of OTC products and concerns about side effects and cancer risk limited use of topical vaginal prescription therapies. CONCLUSIONS: VVA symptoms are common in postmenopausal women. Significant barriers to treatment include lack of knowledge about VVA, reluctance to discuss symptoms with HCPs, safety concerns, inconvenience, and inadequate symptom relief from available treatments. PMID- 23679048 TI - Peptidoglycan at its peaks: how chromatographic analyses can reveal bacterial cell wall structure and assembly. AB - The peptidoglycan (PG) cell wall is a unique macromolecule responsible for both shape determination and cellular integrity under osmotic stress in virtually all bacteria. A quantitative understanding of the relationships between PG architecture, morphogenesis, immune system activation and pathogenesis can provide molecular-scale insights into the function of proteins involved in cell wall synthesis and cell growth. High-performance liquid chromatography (HPLC) has played an important role in our understanding of the structural and chemical complexity of the cell wall by providing an analytical method to quantify differences in chemical composition. Here, we present a primer on the basic chemical features of wall structure that can be revealed through HPLC, along with a description of the applications of HPLC PG analyses for interpreting the effects of genetic and chemical perturbations to a variety of bacterial species in different environments. We describe the physical consequences of different PG compositions on cell shape, and review complementary experimental and computational methodologies for PG analysis. Finally, we present a partial list of future targets of development for HPLC and related techniques. PMID- 23679052 TI - Tristability in cancer-associated microRNA-TF chimera toggle switch. AB - Cell fate decisions during embryonic development and tumorigenesis pose a major research challenge in modern developmental and cancer biology. Binary cell fate decisions are usually regulated by gene circuits incorporating either classical toggle switches with two mutually inhibiting transcription factor (TF) genes or chimera toggle switches with a mutually inhibiting pair of microRNA (miRNA) and TF gene. These circuits can explain binary cell fate decisions. Importantly, intermediate cell types can exist during the differentiation of both stem cells and cancer cells. It has been shown that TF-TF self-activating toggle switches (SATS) can have coexistence of three metastable states (tristability), yet the role of chimera toggle switches in opening these additional states remains elusive. Here we present a generalized framework for both the TF-TF SATS and miRNA-TF chimera SATS, starting from the TF-promoter and miRNA-mRNA binding/unbinding dynamics. We show that the chimera SATSs can also have tristability. We demonstrate that the dynamics of miRNA-TF SATS is qualitatively different from that of the TF-TF SATS because the nonlinear effects of translational silencing by miRNA are distinct from those of transcriptional repression. We discuss the possible relevance of these findings to fate decisions by cancer cells. PMID- 23679051 TI - Defining pseudoprogression in glioblastoma multiforme. AB - BACKGROUND AND PURPOSE: Pseudoprogression is a frequent phenomenon observed since the introduction of postoperative therapy with radiotherapy and temozolomide (RT/TMZ) in glioblastoma multiforme (GBM) patients. However, the criteria defining pseudoprogression, its incidence, the time of occurrence and its impact on therapy and outcome remain poorly defined. METHODS: The objective of this study is to compare two sets of criteria (liberal and stringent), defining pseudoprogression, in a cohort of patients treated before and after the introduction of RT/TMZ in the standard postoperative treatment. This retrospective review includes 136 unselected and consecutively treated patients with pathologically diagnosed GBM. RESULTS: Pseudoprogression was observed in 10 (12%) cases applying the stringent criteria, and in 18 (23%) patients when using the liberal criteria, in the cohort treated with RT/TMZ. Pseudoprogression was observed in only one patient treated with RT alone. The median time to pseudoprogression was 4 weeks after the end of RT. Patients with pseudoprogression had a median survival time of 28 months, compared with 12 months for patients without pseudoprogression. CONCLUSIONS: The incidence of pseudoprogression after RT/TMZ strongly depends on the applied criteria. However, regardless of the stringency of the criteria, the impact on survival remains the same. PMID- 23679053 TI - Static electric dipole polarizabilities of tri- and tetravalent U, Np, and Pu ions. AB - High-quality static electric dipole polarizabilities have been determined for the ground states of the hard-sphere cations of U, Np, and Pu in the III and IV oxidation states. The polarizabilities have been calculated using the numerical finite field technique in a four-component relativistic framework. Methods including Fock-space coupled cluster (FSCC) and Kramers-restricted configuration interaction (KRCI) have been performed in order to account for electron correlation effects. Comparisons between polarizabilities calculated using Dirac Hartree-Fock (DHF), FSCC, and KRCI methods have been made using both triple- and quadruple-zeta basis sets for U(4+). In addition to the ground state, this study also reports the polarizability data for the first two excited states of U(3+/4+), Np(3+/4+), and Pu(3+/4+) ions at different levels of theory. The values reported in this work are the most accurate to date calculations for the dipole polarizabilities of the hard-sphere tri- and tetravalent actinide ions and may serve as reference values, aiding in the calculation of various electronic and response properties (for example, intermolecular forces, optical properties, etc.) relevant to the nuclear fuel cycle and material science applications. PMID- 23679054 TI - Transition-metal salt-containing silica nanocapsules elaborated via salt-induced interfacial deposition in inverse miniemulsions as precursor to functional hollow silica particles. AB - Aqueous core-silica shell nanocapsules were successfully prepared using liquid droplets containing transition-metal salt as templates in inverse miniemulsions. The formation of the silica shell was attributed to the interfacial deposition of silica species induced by the presence of the transition-metal salt. In addition to the control of the particle morphology, the incorporated transition-metal salts could be used to derivatize the particles and confer additional functionalities to the hollow silica particles. To demonstrate the derivatization, the magnetic hollow silica particles were prepared by converting iron salts to magnetic iron oxides by heat treatment. The particle morphology, size, and size distribution were characterized by transmission electron microscopy and scanning electron microscopy. The results show that the particle properties strongly depend on the type and the amount of salts, the amount of tetraethoxysilane (TEOS), the pH of the droplets, and the ratios of 2 hydroxyethyl methacrylate to aqueous HCl solution. The specific surface area and pore properties were characterized by N2 sorption measurements. The pore properties and specific surface area could be tuned by varying the amount of salt. Levels of elements and of iron oxides in the magnetic hollow particles were measured by energy-dispersive X-ray spectroscopy. Iron was distributed homogenously with silicon and oxygen in the sample. The magnetization measured by a magnetic property measurement system confirmed the successful conversion of the iron salts to magnetic iron oxides. PMID- 23679056 TI - Short-term inactivation rates of selected Gram-positive and Gram-negative bacteria attached to metal oxide mineral surfaces: role of solution and surface chemistry. AB - Metal oxides such as ferric or aluminum oxides can play an important role in the retention of bacteria in granular aquatic environments; however, their role in bacterial inactivation is not well understood. Herein, we examined the role of water chemistry and surface chemistry on the short-term inactivation rates of three bacteria when adhered to surfaces. To evaluate the role of water chemistry on the inactivation of attached bacteria, the loss in membrane integrity of bacteria attached to an iron oxide (Fe2O3) surface was measured over a range of water ionic strengths of either monovalent or divalent salts in the absence of a growth substrate. The influence of surface chemistry on the inactivation of attached bacteria was examined by measuring the loss in membrane integrity of cells attached to three surfaces (SiO2, Fe2O3, and Al2O3) at a specific water chemistry (10 mM KCl). Bacteria were allowed to attach onto the SiO2 or metal oxide coated slides mounted in a parallel-plate flow cell, and their inactivation rate (loss in membrane integrity) was measured directly without removing the cells from the surface and without disturbing the system. X-ray photoelectron spectroscopy analysis revealed a high correlation between the amounts of C-metal or O-metal bonds and the corresponding bacterial inactivation rates for each surface. Finally, for all three surfaces, a consistent increase in inactivation rate was observed with the type of bacterium in the order: Enterococcus faecalis, Escherichia coli O157:H7, and Escherichia coli D21f2. PMID- 23679057 TI - The DnaA N-terminal domain interacts with Hda to facilitate replicase clamp mediated inactivation of DnaA. AB - DnaA activity for replication initiation of the Escherichia coli chromosome is negatively regulated by feedback from the DNA-loaded form of the replicase clamp. In this process, called RIDA (regulatory inactivation of DnaA), ATP-bound DnaA transiently assembles into a complex consisting of Hda and the DNA-clamp, which promotes inter-AAA+ domain association between Hda and DnaA and stimulates hydrolysis of DnaA-bound ATP, producing inactive ADP-DnaA. Using a truncated DnaA mutant, we previously demonstrated that the DnaA N-terminal domain is involved in RIDA. However, the precise role of the N-terminal domain in RIDA has remained largely unclear. Here, we used an in vitro reconstituted system to demonstrate that the Asn-44 residue in the N-terminal domain of DnaA is crucial for RIDA but not for replication initiation. Moreover, an assay termed PDAX (pull-down after cross-linking) revealed an unstable interaction between a DnaA-N44A mutant and Hda. In vivo, this mutant exhibited an increase in the cellular level of ATP bound DnaA. These results establish a model in which interaction between DnaA Asn 44 and Hda stabilizes the association between the AAA+ domains of DnaA and Hda to facilitate DnaA-ATP hydrolysis during RIDA. PMID- 23679058 TI - Modified Atkins diet vs classic ketogenic formula in intractable epilepsy. AB - OBJECTIVES: The study was designed to evaluate the efficacy, safety, and tolerability of the ketogenic diet (KD) whether classic 4:1 formula or the modified Atkins diet (MAD) in intractable childhood epilepsy. PATIENTS AND METHODS: Anthropometric measurements and serum lipid profile were measured upon enrollment and after 3 and 6 months in 40 patients with symptomatic intractable epilepsy. Fifteen were given MAD diet, ten were kept on classic 4:1 ketogenic liquid formula, and the rest were allowed to eat as desired. RESULTS: The liquid ketogenic formula group showed significantly higher body mass index compared with those who did not receive KD after 6 months. The lipid profile of KD patients was within normal limits for age and sex during the study period. The rate of change of frequency and severity of seizures showed best improvement in ketogenic liquid formula patients followed by the MAD group than the patients on anti-epileptic medications alone. CONCLUSION: The KD whether classic 4:1 or MAD is a tolerable, safe, and effective adjuvant therapy for intractable symptomatic childhood epilepsy with limited adverse effects on the growth parameters and accepted changes in the lipid profile. The liquid ketogenic formula patients showed better growth pattern and significantly more seizure control. PMID- 23679060 TI - The role of similarity in updating numerical information in working memory: decomposing the numerical distance effect. AB - The present study investigates the process of updating representations in working memory (WM) and how similarity between the information involved influences this process. In WM updating tasks, the similarity in terms of numerical distance between the number to be substituted and the new one facilitates the updating process. We aimed to disentangle the possible effect of two dimensions of similarity that may contribute to this numerical effect: numerical distance itself and common digits shared between the numbers involved. Three experiments were conducted in which different ranges of distances and the coincidence between the digits of the two numbers involved in updating were manipulated. Results showed that the two dimensions of similarity had an effect on updating times. The greater the similarity between the information maintained in memory and the new information that substituted it, the faster the updating. This is consistent both with the idea of distributed representations based on features, and with a selective updating process based on a feature overwriting mechanism. Thus, updating in WM can be understood as a selective substitution process influenced by similarity in which only certain parts of the representation stored in memory are changed. PMID- 23679059 TI - "Induced sputum versus gastric lavage for the diagnosis of pulmonary tuberculosis in children". AB - BACKGROUND: Diagnosis of pulmonary tuberculosis (PTB) is difficult in infants and young children. For microbiological confirmation of PTB children, sequential gastric lavage (GL) is recommended. Induced sputum (IS) may be an alternative or complementary tool, but the information is limited in children in developed countries. The aim of this study is to assess the safety and diagnostic yield from IS combined with GL for PTB diagnosis in non-HIV infected children. METHODS: The study involved 22 children with suspected PTB admitted to the Getafe Hospital from January 2007 to May 2011. IS and GL were performed on three consecutive days, according to a standardized protocol. In all samples, BK staining, culture and PCR were carried out, including Genotype MTBDR plus for resistance to INH-RIF (Isoniazid-Rifampin) since 2008. A preliminary analysis of an ongoing prospective study is presented. RESULTS: Median age was 72 months (range 1 month to 14 years of age). Seven (33%) were <= 5 years of age. Seventeen were clinically diagnosed of PTB based on positive PPD and radiological criteria. Microbiological confirmation was achieved in 10 (58.8%) by either GL or IS. M. tuberculosis was identified by GL in 8 children (47.1%) and by IS in 7 (41.2%). One infant (2 IS samples) had transient oxygen desaturation recovered spontaneously. CONCLUSIONS: IS appears to be safe and well tolerated by children for diagnosis of PTB and is more convenient. Increasing the diagnostic yield of PTB in children with PTB may be a complementary technique. Largest studies are necessary to define the role of IS in paediatric PTB. PMID- 23679061 TI - The development of pediatric critical care medicine at The Children's Hospital of Philadelphia: an interview with Dr. John J. 'Jack' Downes. AB - Dr. John J. 'Jack' Downes (1930-), the anesthesiologist-in-chief at The Children's Hospital of Philadelphia (1972-1996), has made numerous contributions to pediatric anesthesia and critical care medicine through a broad spectrum of research on chronic respiratory failure, status asthmaticus, postoperative risks of apnea in premature infants, and home-assisted mechanical ventilation. However, his defining moment was in January 1967, when The Children's Hospital of Philadelphia inaugurated its pediatric intensive care unit--the first of its kind in North America. During his tenure, he and his colleagues trained an entire generation of pediatric anesthesiologists and intensivists and set a standard of care and professionalism that continues to the present day. Based on an interview with Dr. Downes, this article reviews a career that advanced pediatric anesthesia and critical care medicine and describes the development of that first pediatric intensive care unit at The Children's Hospital of Philadelphia. PMID- 23679062 TI - Calcium (Ca2+) waves data calibration and analysis using image processing techniques. AB - BACKGROUND: Calcium (Ca2+) propagates within tissues serving as an important information carrier. In particular, cilia beat frequency in oviduct cells is partially regulated by Ca2+ changes. Thus, measuring the calcium density and characterizing the traveling wave plays a key role in understanding biological phenomena. However, current methods to measure propagation velocities and other wave characteristics involve several manual or time-consuming procedures. This limits the amount of information that can be extracted, and the statistical quality of the analysis. RESULTS: Our work provides a framework based on image processing procedures that enables a fast, automatic and robust characterization of data from two-filter fluorescence Ca2+ experiments. We calculate the mean velocity of the wave-front, and use theoretical models to extract meaningful parameters like wave amplitude, decay rate and time of excitation. CONCLUSIONS: Measurements done by different operators showed a high degree of reproducibility. This framework is also extended to a single filter fluorescence experiments, allowing higher sampling rates, and thus an increased accuracy in velocity measurements. PMID- 23679064 TI - Prognostic value of 24-hour ambulatory ECG (Holter) monitoring in Boxer dogs. AB - BACKGROUND: Boxer dogs are reported to be predisposed to arrhythmogenic right ventricular cardiomyopathy (ARVC), but the natural history has not been well characterized and inconsistent diagnostic criteria have been applied to identify affected dogs. Echocardiographic examination findings are unremarkable in many affected Boxer dogs, and in these dogs, 24-hour ambulatory ECG (Holter) monitoring often is used for diagnostic and prognostic purposes, despite limited information available relating Holter findings to outcome. HYPOTHESIS/OBJECTIVES: Boxers with complex ventricular arrhythmias at initial presentation will have shorter survival times. The objective was to investigate the prognostic value of Holter monitoring in Boxer dogs. ANIMALS: One hundred and twenty-two Boxer dogs seen at 3 university referral hospitals. METHODS: Retrospective study. Survival times were obtained for Boxer dogs evaluated by echocardiography and a 24-hour Holter ECG. Kaplan-Meier survival analysis was used to estimate the median survival time and Cox proportional hazards analysis was used to identify variables independently associated with cardiac mortality. RESULTS: Outcome data were obtained for 122/163 dogs meeting the inclusion criteria. Of the 70 dogs that had died, 45 were considered to have suffered cardiac-related deaths. Median survival was significantly longer in dogs with a left ventricular systolic diameter (LVIDs) <= 35 mm compared with those with LVIDs > 35 mm (P < .001). Multivariable analysis in dogs with LVIDs <= 35 mm showed that the presence of ventricular tachycardia, age >4.5 years, and male sex were independent predictors of cardiac mortality. CONCLUSIONS AND CLINICAL IMPORTANCE: Holter monitoring in Boxer dogs provides valuable prognostic information. PMID- 23679063 TI - Ultrasound-guided biopsy of the cricoarytenoideus lateralis muscle: technique and safety in horses. AB - REASONS FOR PERFORMING STUDY: Current diagnosis of recurrent laryngeal neuropathy (RLN) depends upon disease recognition in the clinically affected horse. Biopsy of the intrinsic laryngeal muscles may provide a method to identify the changes in fibre-type composition that occur in RLN before clinical signs become apparent. OBJECTIVE: To develop an ultrasound-guided biopsy technique of the left cricoarytenoideus lateralis muscle (CALM) and evaluate its efficacy and safety in vivo. STUDY DESIGN: A longitudinal descriptive study. METHODS: Six standing horses underwent ultrasound-guided biopsy of the left CALM. Frozen muscle cores were obtained with a breast biopsy tool. Serial endoscopic, ultrasonographic and physical examinations before and for 8 weeks after the biopsy were assessed for iatrogenic trauma. Histologies of representative muscle core cross-sections were analysed for the total number of muscle fibres obtained with each biopsy. RESULTS: There were no immediate complications of the procedure and the left CALM was harvested in all instances. Biopsy samples had an average weight of 0.043 g (range = 0.023-0.077 g) and contained 3418 fibres in cross-section (range = 711 7143). Laryngeal endoscopic grade did not change significantly between prebiopsy and the end of the 8 week follow-up. The left CALM had significantly greater echogenicity than the right throughout the study (P<0.001), but there was no difference between the prebiopsy CALM echogenicity and that at completion of the study. CONCLUSIONS: Ultrasound-guided biopsy of the left CALM is safe and well tolerated, providing a minimally invasive method to obtain muscle from healthy horses. This new technique may be applicable in research and clinical settings. PMID- 23679065 TI - Microbial biogeochemistry of Boiling Springs Lake: a physically dynamic, oligotrophic, low-pH geothermal ecosystem. AB - Boiling Springs Lake (BSL) in Lassen Volcanic National Park, California, is North America's largest hot spring, but little is known about the physical, chemical, and biological features of the system. Using a remotely operated vessel, we characterized the bathymetry and near-surface temperatures at sub-meter resolution. The majority of the 1.2 ha, pH 2.2 lake is 10 m deep and 50-52 degrees C, but temperatures reach 93 degrees C locally. We extracted DNA from water and sediments collected from warm (52 degrees C) and hot (73-83 degrees C) sites separated by 180 m. Gene clone libraries and functional gene microarray (GeoChip 3.0) were used to investigate the BSL community, and uptake of radiolabeled carbon sources was used to assess the relative importance of heterotrophic vs. autotrophic production. Microbial assemblages are similar in both sites despite the strong temperature differential, supporting observations of a dynamic, convectively mixed system. Bacteria in the Actinobacteria and Aquificales phyla are abundant in the water column, and Archaea distantly related to known taxa are abundant in sediments. The functional potential appears similar across a 5-year time span, indicating a stable community with little inter-annual variation, despite the documented seasonal temperature cycle. BSL water-derived DNA contains genes for complete C, N, and S cycles, and low hybridization to probes for N and S oxidation suggests that reductive processes dominate. Many of the detected genes for these processes were from uncultivated bacteria, suggesting novel organisms are responsible for key ecosystem services. Selection imposed by low nutrients, low pH, and high temperature appear to result in low diversity and evenness of genes for key functions involved in C, N, and S cycling. Conversely, organic degradation genes appear to be functionally redundant, and the rapid assimilation of radiolabeled organic carbon into BSL cells suggests the importance of allochthonous C fueling heterotrophic production in the BSL C cycle. PMID- 23679066 TI - Psychological characteristics of BDSM practitioners. AB - INTRODUCTION: It has been generally thought that the practice of bondage discipline, dominance-submission, sadism-masochism (BDSM) is in some form associated with psychopathology. However, several more recent studies suggest a relative good psychological health of BDSM practitioners. AIM: The aim of this study was to compare scores of BDSM practitioners and a control group on various fundamental psychological characteristics. METHODS: For this aim, 902 BDSM and 434 control participants completely filled out online questionnaires. Associations were examined using chi(2) tests of independence with phi and Cramer's V as effect size measures and eta or Pearson's correlation. Group differences were tested using analysis of covariance, with partial eta(2) as effect size measure. A priori contrasts were tested using alpha = 0.01 to correct for multiple testing; for all other tests we used alpha = 0.05, two tailed. MAIN OUTCOME MEASURES: The study used Big Five personality dimensions (NEO Five-Factor Inventory), attachment styles (Attachment Styles Questionnaire), rejection sensitivity (Rejection Sensitivity Questionnaire), and subjective well-being (World Health Organization-Five Well-being Index). RESULTS: The results mostly suggest favorable psychological characteristics of BDSM practitioners compared with the control group; BDSM practitioners were less neurotic, more extraverted, more open to new experiences, more conscientious, less rejection sensitive, had higher subjective well-being, yet were less agreeable. Comparing the four groups, if differences were observed, BDSM scores were generally more favorably for those with a dominant than a submissive role, with least favorable scores for controls. CONCLUSION: We conclude that BDSM may be thought of as a recreational leisure, rather than the expression of psychopathological processes. PMID- 23679067 TI - Role of solvent on nonenzymatic peptide bond formation mechanisms and kinetic isotope effects. AB - Based on the hypothesis that similar mechanisms are involved in the peptide bond formation in aqueous solution and in the ribosome, the aminolysis of esters in aqueous solution has been the subject of numerous studies as the reference reaction for the catalyzed process. The mechanisms proposed in the literature have been explored in the present paper by hybrid QM/MM molecular dynamics simulations. The free energy profiles have been computed with the QM region of the system described at semiempirical AM1 level and by DFT within the M06-2X functional. According to the results, the formation of adduct zwitterion species is a preliminary step required for all possible mechanisms. Then, from different conformers of this species, four different paths were found: three of them taking place through concerted mechanisms of four-, six- and eight-membered ring transition states, and a stepwise mechanism through a neutral intermediate. Comparison of the free energy profiles indicates that the concerted mechanisms would be kinetically favored, with free energy barriers in very good agreement with experimental data. Calculations of kinetic isotope effects, when including the solute interactions with the first solvation shell, show that the 8-membered ring TS renders values in better agreement with available experimental data. Quantitative discrepancies can be attributed to different employed models in experiments and calculations. PMID- 23679068 TI - LiNi(0.5)Mn(1.5)O4 porous nanorods as high-rate and long-life cathodes for Li-ion batteries. AB - Spinel-type LiNi0.5Mn1.5O4 porous nanorods assembled with nanoparticles have been prepared and investigated as high-rate and long-life cathode materials for rechargeable lithium-ion batteries. One-dimensional porous nanostructures of LiNi0.5Mn1.5O4 with ordered P4332 phase were obtained through solid-state Li and Ni implantation of porous Mn2O3 nanorods that resulted from thermal decomposition of the chain-like MnC2O4 precursor. The fabricated LiNi0.5Mn1.5O4 delivered specific capacities of 140 and 109 mAh g(-1) at 1 and 20 C rates, respectively. At a 5 C cycling rate, a capacity retention of 91% was sustained after 500 cycles, with extremely low capacity fade (<1%) during the initial 300 cycles. The remarkable performance was attributed to the porous 1D nanostructures that can accommodate strain relaxation by slippage at the subunits wall boundaries and provide short Li-ion diffusion distance along the confined dimension. PMID- 23679069 TI - The Fukushima disaster and Japan's nuclear plant vulnerability in comparative perspective. AB - We consider the vulnerability of nuclear power plants to a disaster like the one that occurred at Fukushima Daiichi. Examination of Japanese nuclear plants affected by the earthquake and tsunami on March 11, 2011 shows that three variables were crucial at the early stages of the crisis: plant elevation, sea wall elevation, and location and status of backup generators. Higher elevations for these variables, or waterproof protection of backup generators, could have mitigated or prevented the disaster. We collected information on these variables, along with historical data on run-up heights, for 89 coastal nuclear power plants in the world. The data shows that 1. Japanese plants were relatively unprotected against potential inundation in international comparison, but there was considerable variation for power plants within and outside of Japan; 2. Older power plants and plants owned by the largest utility companies appear to have been particularly unprotected. PMID- 23679070 TI - In vitro method for real-time, direct observation of cell-vascular graft interactions under simulated blood flow. AB - In the development of engineered vascular grafts, assessing the material's interactive properties with peripheral blood cells and its capacity to endothelialize are important for predicting in vivo graft behavior. Current in vitro techniques used for characterizing cell adhesion at the surface of engineered scaffolds under flow only facilitate a terminal quantification of cell/surface interactions. Here, we present the design of an innovative flow chamber for real-time analysis of blood-biomaterial interactions under controllable hemodynamic conditions. Decellularized human umbilical veins (dHUV) were used as model vascular allografts to characterize platelet, leukocyte, and endothelial cell (EC) adhesion dynamics. Confluent EC monolayers adhered to the lumenal surface of the grafting material were flow conditioned to resist arterial shear stress levels (up to 24 dynes/cm(2)) over a 48 h period, and shown to maintain viability over the 1 week assessment period. The basement membrane was imaged while whole blood/neutrophil suspensions were perfused across the HUV surface to quantify cell accumulation. This novel method facilitates live visualization of dynamic events, including cell adhesion, migration, and morphological adaptation at the blood-graft interface on opaque materials, and it can be used for preliminary assessment of clinically relevant biomaterials before implantation. PMID- 23679071 TI - Effect of fasting in Ramadan on body composition and nutritional intake: a prospective study. AB - BACKGROUND: The present study aimed to assess the effects of Ramadan intermittent fasting on body weight and composition and the effects of age and sex. METHODS: Body weight, height, waist and hip circumferences were measured, body mass index (BMI) was calculated and fat mass, fat-free mass and percentage body fat were assessed by bioelectrical impedance on 240 adult subjects (male: 158) who fasted between sunrise and sunset for at least 20 days. Measurements were taken 1 week before and 1 week after Ramadan. Energy and macronutrient intakes were assessed using a 3-day food frequency questionnaire on a sub-sample of subjects before and during Ramadan. RESULTS: Subjects were grouped according to age and sex: <=35 years (n = 82, males: 31) and 36-70 years (n = 158, males: 127). There were significant reductions in weight and BMI (P < 0.001) in almost all subjects, with the biggest being in males <=35 years [-2.2% (SE 2.2%), P < 0.001]. Waist and hip circumferences fell in most subjects, except females aged 36-70 years. Fat mass fell in most subjects, ranging from 2.3% to 4.3% from baseline, except in females aged 36-70 years who did not experience a significant change. Fat-free mass was significantly reduced in all subjects (P < 0.001), whereas percentage body fat was lower only in males by 2.5% (SE 3.2%) (P = 0.029) in those aged <=35 years and by 1.1% (SE 1.5%) (P < 0.001) in those aged 36-70 years. Dietary intake was similar before and during Ramadan, except in males whose protein intake fell during Ramadan (P = 0.032). CONCLUSIONS: Ramadan fasting leads to weight loss and fat-free mass reductions. Body composition changes vary depending on age and sex. PMID- 23679072 TI - The uncertain bond energy of the NaAu molecule: experimental redetermination and coupled cluster calculations. AB - The dissociation energy of the intermetallic molecule NaAu, for which two largely at variance experimental values are available in the literature, has been redetermined by the Knudsen effusion mass spectrometry method. The molecule has been produced in the vapor phase by a specially designed experimental setting inspired by the double oven technique. The equilibrium of dissociation to atoms as well as the exchange equilibrium with the gold dimer were monitored mass spectrometrically over about a 600 K temperature range. The third-law analysis of the equilibrium data provides the dissociation energy D0 degrees (NaAu, g) = 245.3 +/- 6.8 kJ/mol, corresponding to a formation enthalpy at 298 K of 228.3 +/- 7.5 kJ/mol. The NaAu species was also studied computationally at the CCSD(T) level with basis sets of increasing zeta quality thus allowing to evaluate the molecular parameters and the dissociation energy at the complete basis set limit. PMID- 23679073 TI - Genomic and physiological variability within Group II (non-proteolytic) Clostridium botulinum. AB - BACKGROUND: Clostridium botulinum is a group of four physiologically and phylogenetically distinct bacteria that produce botulinum neurotoxin. While studies have characterised variability between strains of Group I (proteolytic) C. botulinum, the genetic and physiological variability and relationships between strains within Group II (non-proteolytic) C. botulinum are not well understood. In this study the genome of Group II strain C. botulinum Eklund 17B (NRP) was sequenced and used to construct a whole genome DNA microarray. This was used in a comparative genomic indexing study to compare the relatedness of 43 strains of Group II C. botulinum (14 type B, 24 type E and 5 type F). These results were compared with characteristics determined from physiological tests. RESULTS: Whole genome indexing showed that strains of Group II C. botulinum isolated from a wide variety of environments over more than 75 years clustered together indicating the genetic background of Group II C. botulinum is stable. Further analysis showed that strains forming type B or type F toxin are closely related with only toxin cluster genes targets being unique to either type. Strains producing type E toxin formed a separate subset. Carbohydrate fermentation tests supported the observation that type B and F strains form a separate subset to type E strains. All the type F strains and most of type B strains produced acid from amylopectin, amylose and glycogen whereas type E strains did not. However, these two subsets did not differ strongly in minimum growth temperature or maximum NaCl concentration for growth. No relationship was found between tellurite resistance and toxin type despite all the tested type B and type F strains carrying tehB, while the sequence was absent or diverged in all type E strains. CONCLUSIONS: Although Group II C. botulinum form a tight genetic group, genomic and physiological analysis indicates there are two distinct subsets within this group. All type B strains and type F strains are in one subset and all type E strains in the other. PMID- 23679074 TI - Late HBsAg seroreversion of mutated hepatitis B virus after bone marrow transplantation. AB - BACKGROUND: About ninety percent of immunocompetent adults recover from hepatitis B virus (HBV) infection within 6 months after transmission. The infection is considered to be terminated if the antibodies (HBsAb) to the hepatitis B surface antigen (HBsAg) become detectable and the HBsAg and Hepatitis B virus DNA (HBV DNA,) are no longer perceptible. After recovery from an acute infection, the detection of HBsAb is assumed to indicate lifelong immunity. However, after initiation of severe immunosuppression, HBV reactivation, as detected by HBsAg seroreversion may be observed in patients with previously resolved HBV infections. CASE PRESENTATION: We present an unusual case of a 64-year-old Caucasian woman showing clinically apparent HBV seroreversion more than 45 months after hematopoietic stem cell transplantation (HSCT). Despite living without immunosuppressive agents for more than 40 months, she developed a fulminant HBV infection with detection of a mutated hepatitis B virus carrying two immune escape mutations (D144E/G145R) in the HBsAg (HBsIE mutation). CONCLUSION: After HSCT, the absence of risk factors such as strong immunosuppression and graft versus-host disease decreases the risk of HBV seroreversion but may rearward seroreversion to a later time. Therefore, when monitoring HSCT, patients with serological markers of a resolved HBV infection [HBcAb + (hepatitis B core antibody), HBsAb+, and HBsAg-], the follow up has to be extended over several years to exclude HBV reactivation with HBsAg seroreversion. Furthermore, this case demonstrates the complexity of virus evolution after HBsAg seroreversion as a result of immunosuppression after HSCT. PMID- 23679075 TI - Decreased striatal dopamine transporter uptake in the non-fluent/agrammatic variant of primary progressive aphasia. AB - BACKGROUND AND PURPOSE: Patients with the non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) may develop atypical parkinsonian syndromes. However, there is no current biomarker to assess which patients are at high risk of developing parkinsonism. 123I-2beta-carbomethoxy-3beta-(4-iodophenyl)-N-(3 fluoropropyl)-nortropane (123I-FP-CIT)-SPECT detects striatal dopamine dysfunction in vivo. The objective of the present study was to study whether non fluent/agrammatic patients without parkinsonism at baseline present decreased striatal 123I-FP-CIT uptake. METHODS: Visual and semi-quantitative assessments of the striatal 123I-FP-CIT uptake ratio were carried out in 15 patients with nfvPPA, eight patients with the logopenic variant of PPA (lvPPA) and 18 controls. To rule out progranulin mutations or underlying Alzheimer's disease (AD), serum progranulin levels and cerebrospinal fluid (CSF) biomarkers of AD (Abeta42 , total-tau, phosphorylated-tau181 ) were determined. A second 123I-FP-CIT-SPECT analysis in the biomarker-enriched groups was also carried out. RESULTS: Patients with nfvPPA presented reduced striatal 123I-FP-CIT binding, especially in the left hemisphere (P = 0.002), compared with controls. All lvPPA patients had normal striatal 123I-FP-CIT uptake. 123I-FP-CIT striatal binding in nfvPPA patients with normal progranulin and CSF biomarker levels (nfvPPA/bio-) was also significantly reduced (P < 0.05) compared with lvPPA patients with positive AD biomarkers. Sixty-four per cent (9/14) of nfvPPA patients and 80% of nfvPPA/bio- patients (8/10) showed a diminished individual left striatal 123I-FP-CIT uptake ratio. On follow-up, seven nfvPPA/bio- patients developed parkinsonism (median 1.9 years; range 1.2-2.9), six of them with baseline reduced 123I-FP-CIT uptake. CONCLUSIONS: Reduced striatal tracer uptake in nfvPPA patients prior to clinical parkinsonism can be detected by 123I-FP-CIT-SPECT, especially in those with nfvPPA/bio-, suggesting subclinical nigrostriatal degeneration. Decreased striatal 123I-FP-CIT binding might identify PPA patients at increased risk of developing atypical parkinsonian syndromes, probably related to tau-pathology. PMID- 23679076 TI - Ultrasound-guided injection of the maxillary nerve in the horse. AB - REASONS FOR PERFORMING STUDY: Infiltration of the equine maxillary nerve with local anaesthetic can be useful for both diagnostic and surgical procedures. The deep location and proximity of the nerve to surrounding vascular and orbital structures make an accurate, complication-free injection a challenge using traditional techniques reliant upon surface anatomical landmarks. OBJECTIVES: To develop an ultrasound-guided injection technique of the maxillary nerve in equine cadavers and to evaluate its efficacy and potential for complications in vivo. STUDY DESIGN: Descriptive cadaver anatomical and clinical study. METHODS: The relevant anatomy of the pterygopalatine fossa was reviewed in 6 cadaver heads from mature horses of a range of ages, breeds and genders. In an additional 13 cadaver heads, ultrasound-guided injection of 0.2 ml New Methylene Blue dye was performed on both left and right maxillary nerves (n = 26 attempts) in the pterygopalatine fossa. An independent observer dissected the area and recorded the number of times that dye successfully contacted the nerve, along with inadvertent penetration of other structures. The procedure was then performed on 8 clinical cases undergoing a variety of standing surgical procedures on the head. RESULTS: Dye was successfully deposited in contact with the nerve during all attempts on cadaver heads, with no penetration of the orbital cone, deep facial vein and maxillary artery or associated branches. In a single cadaver, a unilateral gas artefact in the masseter muscle prohibited an injection attempt. Analgesia of the maxillary nerve was achieved in <15 min in all clinical cases, with complete loss of ipsilateral cutaneous sensation over the rostral face. No gross or ultrasonographic abnormalities were detected following the procedure. CONCLUSIONS: Using ultrasonographic landmarks of the pterygopalatine fossa, local anaesthetic can be deposited around the maxillary nerve without the inadvertent penetration of adjacent vital structures. POTENTIAL RELEVANCE: The technique allows for vascular structures to be visualised and avoided, which is currently not possible using traditional blind approaches. PMID- 23679077 TI - Oxymetazoline and hypertensive crisis in a child: can we prevent it? AB - BACKGROUND: Oxymetazoline nasal spray is not FDA approved for use in children less than 6 years; however, its safety and efficacy are widely accepted, and it is in widespread use in children prior to procedures that may lead to epistaxis. We report a case of intraoperative oxymetazoline toxicity in a 4-year-old boy that led to a hypertensive crisis. While examining the possible causes for this problem, we became aware that the method of drug delivery led to an unanticipated overdose. The position in which the bottle is held causes pronounced variation in the quantity of oxymetazoline dispensed. METHODS: To examine the impact that bottle position has on the volume delivered, we measured the volume of oxymetazoline dispensed with the bottle in the upright and inverted position. We also measured the volume of a drop of oxymetazoline dispensed from the bottle. Because an additional source of oxymetazoline exposure is from packing the nares with surgical pledgets, we analyzed the volume of oxymetazoline absorbed by each pledget. RESULTS: Squeezing the bottle in the upright position results in a fine spray of fluid that averaged 28.9 +/- 6.8 MUl and was largely independent of effort. This volume is nearly identical to the measured volume of a drop of oxymetazoline, which was 30 MUl. However, squeezing the bottle in the inverted position resulted in a steady stream of fluid, and the volume administered was completely effort dependent. Multiple tests in the inverted position demonstrated an average volume of 1037 +/- 527 MUl, with a range of 473-2196 MUl. Lastly, the volume of oxymetazoline absorbed by each surgical pledget was 1511 +/- 184 MUl. DISCUSSION: Our testing indicates that bottle position during oxymetazoline administration can cause up to a 75-fold increase in intended drug administration. PMID- 23679078 TI - Interaction of phospholipid Langmuir monolayers with an antibiotic peptide conjugate. AB - The interactions between phospholipid monolayers and a peptide conjugate of the antituberculotic agent isoniazide (INH) were investigated by sum-frequency vibrational spectroscopy. The primary objective of the present work was to provide a detailed picture of the molecular interactions of the INH-peptide conjugate with phospholipid monolayers by detecting the changes in the monolayer structure resulting from these interactions. In order to gain a thorough understanding, three types of experiment were performed: (i) changes induced in the structure of the precompressed phospholipid monolayer upon injection of the INH-peptide conjugate were followed; (ii) the structures of the phospholipid monolayers spread onto the solution of the INH-peptide conjugate were characterized; (iii) the structures of mixed monolayers of phospholipid and the INH-peptide conjugate were studied. Using a chain perdeuterated phospholipid, it was possible to examine the changes in alkyl chain ordering without interference from INH-peptide conjugate vibrations and investigate the effect of the INH peptide conjugate on the ordering of the phosphocholine headgroups. We confirmed that peptide conjugation strongly influences the interactions of INH with the lipid monolayer, resulting in enhanced cell penetration ability. The interactions formed between the INH-peptide conjugate in its ordered adsorption layer and the phospholipid molecules deposited onto this solution were found to be significantly stronger than those formed by the INH-peptide conjugate with a compressed lipid monolayer. Nonetheless, both types of interaction contribute with a condensing effect to an increased ordering of the phospholipid alkyl chains in the monolayer. PMID- 23679079 TI - Bimetallic Ag-Au nanowires: synthesis, growth mechanism, and catalytic properties. AB - Silver-gold (Ag-Au) bimetallic nanowires were controllably synthesized by a newly developed wet-chemical method at room temperature. The Ag nanowires and Au nanoparticles were sequentially formed by reduction with vanadium oxide (V2O3) nanoparticles so as to form Ag-Au bimetal, in which the Ag nanowires show a diameter of ~20 nm and length up to 10 MUm. A few unique features were noted in our new approach: it was rapid (within a few minutes), controllable in shape and size, reproducible, and there was no need for any surface modifiers. The formation and growth mechanisms of these Ag-Au bimetallic nanostructures driven by lattice match and a unique reducing agent (V2O3) have been proposed in this study. Moreover, the application of such bimetallic nanoparticles for catalytic reduction of 4-nitrophenol to 4-aminophenol was performed, and they exhibit catalytic properties superior to those of the Ag nanowires, Au nanoparticles, and Ag-Pd bimetallic nanostructures prepared under the reported conditions. These Ag Au bimetallic nanoparticles have potential to be highly efficient catalysts for the reduction of 4-nitrophenol. This study may lead to new path for the generation of other bimetallic nanostructures with excellent catalytic efficiency. PMID- 23679080 TI - Thia-prins bicyclization approach for the stereoselective synthesis of dithia- and azathia-bicycles. AB - A novel thia-Prins bicyclization approach has been developed for the first time for the synthesis of hexahydro-2H-thieno[3,2-c]thiopyran derivatives from the coupling of homoallylic mercaptans such as hex-3-ene-1,6-dithiol with various aldehydes using 10 mol % InBr3 in dichloromethane with high selectivity. In addition, the coupling of (E)-N-(6-mercaptohex-3-enyl)-4-methylbenzenesulfonamide with aldedydes affords the corresponding N-tosyloctahydrothiopyrano[4,3-b]pyrrole derivatives in good yields. This reaction is a stereoselective affording trans fused product from E-homoallyllic mercaptan and cis-fused product from Z homoallyllic mercaptan. PMID- 23679081 TI - Involvement of the dual-specificity phosphatase M3/6 in c-Jun N-terminal kinase inactivation following cerebral ischemia in the rat hippocampus. AB - The c-Jun N-terminal kinase (JNK) undergoes complete inactivation following the intense activation induced by cerebral ischemia and reperfusion in rat hippocampi. This study examines the molecular mechanism underlying JNK dephosphorylation and inactivation evoked by dual-specificity phosphates following cerebral ischemia. The results revealed upregulation of dual specificity phosphatase M3/6 (DUSP8) activity at 4 h of reperfusion in rat hippocampi. This was accompanied by the dephosphorylation of JNK. The M3/6 inhibitor, anisomycin, was found to enhance JNK activity following postischemic reperfusion, suggesting that M3/6 is closely associated with JNK inactivation following cerebral ischemia. Cerebral ischemia also induced an increase in heat shock protein (HSP70) levels, which is involved in the upregulation of soluble cytoplasmic M3/6 levels. The inhibition of HSP70 using quercetin resulted in an elevation of JNK activity by decreasing the cytoplasmic solubility of M3/6. The findings of the current study suggest that M3/6 is implicated in the inactivation of JNK in response to cerebral ischemia, which requires the molecular chaperone HSP70 to facilitate the correction of folding defects. PMID- 23679082 TI - Endometriosis of conus medullaris: a case report. AB - Endometriosis involving the neural axis is extremely rare. A twenty-five-year-old woman presented with acute onset paraparesis with bladder involvement of five-day duration. We missed her history of cyclical back-ache related to menses at the emergency room. Magnetic resonance imaging (MRI) of spinal cord showed an intramedullary tumour with bleeding at conus-epiconus level. She was operated in the emergency department with laminectomy-durotomy and tumour decompression. Histopathology of the tumour was suggested endometriosis. PMID- 23679083 TI - Stenting venous outflow gives symptomatic improvement in a patient with an inoperable brainstem arteriovenous malformation. AB - The extent to which arterial steal or venous hypertension contributes to symptoms in patients with high flow brain arteriovenous malformations (AVMs) is not always clear. We describe a patient with an inoperable AVM of the pons, presenting with headache and neurological deficit where improving venous outflow by stenting produced substantial clinical benefit. PMID- 23679084 TI - No evidence of cardiomyopathy in spinal and bulbar muscular atrophy. AB - OBJECTIVES: Spinal and bulbar muscular atrophy (SBMA) is a lower motor neuron disease caused by a CAG repeat expansion within the androgen receptor (AR) gene. Toxic nuclear accumulation of mutant AR has been observed in tissues other than nervous system including cardiac muscle. Moreover, CAG polymorphism length within AR has been associated with an increased risk of heart disease. MATERIALS AND METHODS: To test the hypothesis of the presence of cardiomyopathy in SBMA, a full cardiac protocol was applied to 25 SBMA patients. RESULTS: Patients' age ranged between 32 and 75 years. Cardiologic examination, 12-lead ECG, and echocardiography showed no abnormalities other than those consistent with hypertensive heart disease. One patient showed frequent supraventricular premature beats in absence of other significant arrhythmias at the 24-h ECG Holter. CONCLUSIONS: Our findings do not support the hypothesis of a primary cardiomyopathy in SBMA. PMID- 23679085 TI - Individual differences in the delayed execution of prospective memories. AB - Working memory processes play a critical role in actively maintaining, rehearsing, and retrieving goal-relevant information during cognitively engaging tasks. In the current study, we examined individual differences in prospective memory between young adults with high versus low working memory capacity (WMC) when they had to momentarily delay their intentions for either 6 or 42 s. In Experiments 1 and 2, high-WMC individuals performed significantly better at both delay intervals than did low-WMC individuals under standard ongoing task conditions. In Experiment 2, we included an interrupting task during the longer delay that decreased performance in the low-WMC relative to the high-WMC individuals. These results suggest that prospective memory performance is generally impaired across all retention intervals in low-WMC individuals, and that high-WMC individuals may be better able to retrieve the intention from long term memory even when attention is interrupted by intervening activities. PMID- 23679086 TI - Hepatoselectivity and the evolution of insulin. AB - In spite of major developments in insulin production, purification, pharmaceutical formulation and methods of delivery, problems remain both in the day to day management of insulin-treated diabetes and with regard to its long term complications. The risks of hypoglycaemia and weight gain are major concerns particularly for the patient, and the persistence of microvascular and premature macrovascular complications as the main causes of morbidity and mortality in both type 1 and type 2 diabetes is a constant reminder that our therapeutic and management strategies are inadequate. One clear and striking difference between currently available insulin treatments and normal physiology is the relative difference in exposure to insulin of the liver versus peripheral tissues. Hepatoselective insulin analogues have the potential to restore the normal hepatic to peripheral gradient in insulin action. Here, we discuss the possible therapeutic potential that such analogues may have over currently available insulin preparations. These benefits could include a lower risk of hypoglycaemia, less weight gain and a potential reduction in microvascular and macrovascular complications. We explore the evolution of insulin with hepatoselectivity in mind and possible strategies to create hepatoselective insulins. PMID- 23679087 TI - Sexual function in childhood cancer survivors: a report from Project REACH. AB - INTRODUCTION: Of the approximately 12,000 children and adolescents that will be diagnosed with cancer in 2013, it is expected that over 80% of them will become long-term adult survivors of childhood cancer. Although it has been well established that cancer treatment often has profound negative impact on sexual functioning, sexual functioning in adult survivors of childhood cancer is not well understood. AIM: The aim of the current study was to examine the report of sexual function in adult survivors of childhood cancer in relationship to both physical and emotional functioning. METHODS: Two hundred ninety-one participants enrolled in Project REACH, a longitudinal study of childhood cancer survivors, completed questionnaires as part of an annual health survey. MAIN OUTCOME MEASURE: Primary outcome measures included the sexual functioning subscale of the Swedish Health-Related Quality of Life Survey, the SF-12, and the BSI-18. RESULTS: Results indicate that 29% of young adult survivors reported two or more discrete symptoms of sexual dysfunction. Females were twice as likely to report sexual problems. Sexual problems were not related to specific types of childhood cancer treatments such as type of chemotherapy or radiation. Young adults with sexual dysfunction did report poorer functioning across the range of SF-12 subscales including physical functioning, general health, fatigue, and mental health. CONCLUSIONS: Significant sexual dysfunction is common in adult survivors of childhood cancer. A greater understanding of the particular relationship between sexual dysfunction and both physical and emotional well-being in this relatively young population is needed. Even when long-term cancer survivors are young adults and report generally good health, results underscore the need for clinicians to specifically assess sexual functioning. PMID- 23679088 TI - Circulating cell-free DNA levels in hemodialysis patients and its association with inflammation, iron metabolism, and rhEPO doses. PMID- 23679089 TI - A retrospective study of acute kidney injury in cats and development of a novel clinical scoring system for predicting outcome for cats managed by hemodialysis. AB - BACKGROUND: Information regarding acute kidney injury (AKI) in cats is limited, and there are no reliable tools to objectively assess disease severity and predict outcome. OBJECTIVES: To assess clinical signs, clinicopathologic abnormalities, etiology, and outcome of cats with AKI, and to develop models using clinical metrics and empirically derived scores to predict outcome. ANIMALS: One hundred and thirty-two client-owned cats. METHODS: Retrospective study. Bivariate logistic regression analyses were performed to identify variables predictive of 30-day survival. Continuous variables outside the reference range were divided into quartiles to yield quartile-specific odds ratios (OR) for survival. Models were developed incorporating weighting factors assigned to each quartile based on the OR. A predictive score for each model was calculated for each cat by summing all weighting factors. A second, multivariable logistic regression model was created from actual values of the same variables. Receiver operating characteristic curve analyses were performed to determine the models' performance. Models were further tested using a subset of cases not used in initial assessment. RESULTS: Fifty five of 132 cats (42%) remained dialysis independent for at least 30 days after discharge, and the remaining 77 cats either died (n = 37, 28%) or were euthanized (n = 40, 30%). The most common etiology was ureteral obstruction (n = 46, 35%). Higher scores were associated with decreased probability of survival (P < .001). Models correctly classified outcomes in 75-77% of the cases and 84-89% of the cases in the subsequent evaluation. CONCLUSIONS AND CLINICAL IMPORTANCE: Models can provide objective guidance in assessing AKI prognosis and severity, but should be validated in other cohorts of cats. PMID- 23679090 TI - Parathyroid hormone, vitamin D levels and urine albumin excretion in older persons: the 2011 Korea National Health and Nutrition Examination Survey (KNHANES). AB - OBJECTIVE: Persistent elevation of urinary albumin excretion (UAE), even within normal range, is an independent predictor for cardiovascular disease. Accumulating research suggests that low levels of vitamin D and high levels of parathyroid hormone (PTH) also increase cardiovascular disease risk. This study is intended to investigate the relationship between PTH, vitamin D levels and UAE. METHODS: We examined 2897 adults aged 50 and above, participating in the second year of the fifth Korea National Health and Nutrition Examination Survey (KNHANES V-2). Anthropometric and laboratory measurements were performed. Elevated UAE was defined as spot urinary albumin creatinine ratio equal or above 10. RESULTS: The proportion of elevated UAE (21.8%, 23.2%, 23.2%, 31.8%; P for trend = 0.002) rose with increasing quartiles of PTH. The odds ratio for elevated UAE in the highest quartile of PTH was 72% higher than the lowest quartile group. There was no relationship between vitamin D and elevated UAE. CONCLUSIONS: Elevated PTH levels are associated with elevated UAE in Korean adults aged 50 and above. Additional studies are needed to clarify this relationship. PMID- 23679091 TI - Repeated supra-maximal sprint cycling with and without sodium bicarbonate supplementation induces endothelial microparticle release. AB - Under normal homeostatic conditions, the endothelium releases microparticles (MPs), which are known to increase under stressful conditions and in disease states. CD105 (endoglin) and CD106 (vascular cell adhesion molecule-1) are expressed on the surface of endothelial cells and increased expression in response to stress may be observed. A randomised-controlled double-blinded study aimed to examine the use of endothelial MPs as a marker for the state of one's endothelium, as well as whether maintaining acid-base homeostasis affects the release of these MPs. This study tested seven healthy male volunteers, who completed a strenuous cycling protocol, with venous blood analysed for CD105+ and CD106+ MPs by flow cytometry at regular intervals. Prior to each trial participants consumed either 0.3 g.kg(-1) body mass of sodium bicarbonate (NaHCO3), or 0.045 g.kg(-1) body mass of sodium chloride (NaCl). A significant rise in endothelial CD105+ MPs and CD106+ MPs (p<0.05) was observed at 90 min post-exercise. A significant trend was shown for these MPs to return to resting levels 180 min post-exercise in both groups. No significance was found between experimental groups, suggesting that maintaining acid-base variables closer to basal levels has little effect upon the endothelial stress response for this particular exercise mode. In conclusion, strenuous exercise is accompanied by MP release and the endothelium is able to rapidly recover in healthy individuals, whilst maintaining acid-base homeostasis does not attenuate the MP release from the endothelium after exercise. PMID- 23679092 TI - Toxicity and deficiency of copper in Elsholtzia splendens affect photosynthesis biophysics, pigments and metal accumulation. AB - Elsholtzia splendens is a copper-tolerant plant species growing on copper deposits in China. Spatially and spectrally resolved kinetics of in vivo absorbance and chlorophyll fluorescence in mesophyll of E. splendens were used to investigate the copper-induced stress from deficiency and toxicity as well as the acclimation to excess copper stress. The plants were cultivated in nutrient solutions containing either Fe(III)-EDTA or Fe(III)-EDDHA. Copper toxicity affected light-acclimated electron flow much stronger than nonphotochemical quenching (NPQ) or dark-acclimated photochemical efficiency of PSIIRC (Fv/Fm). It also changed spectrally resolved Chl fluorescence kinetics, in particular by strengthening the short-wavelength (<700 nm) part of NPQ altering light harvesting complex II (LHCII) aggregation. Copper toxicity reduced iron accumulation, decreased Chls and carotenoids in leaves. During acclimation to copper toxicity, leaf copper decreased but leaf iron increased, with photosynthetic activity and pigments recovering to normal levels. Copper tolerance in E. splendens was inducible; acclimation seems be related to homeostasis of copper and iron in E. splendens. Copper deficiency appeared at 10 mg copper per kg leaf DW, leading to reduced growth and decreased photosynthetic parameters (F0, Fv/Fm, PhiPSII). The importance of these results for evaluating responses of phytoremediation plants to stress in their environment is discussed. PMID- 23679093 TI - Biotransformation of osthole by Alternaria longipes. AB - The biotransformation of osthole (1) by Alternaria longipes was carried out, and five transformed products were obtained in the present research work. Based on their extensive spectral data, the structures of these metabolites were characterized as 4'-hydroxyl-osthole (2), 4'-hydroxyl-2',3'-dihydroosthole (3), 2',3'-dihydroxylosthole (4), osthole-4'-oic acid methyl ester (5), and osthole-4' oic acid glucuron-1-yl ester (6), respectively. Among them, products 5 and 6 were new compounds. PMID- 23679094 TI - Polymorphisms in FGF12, VCL, CX43 and VAX1 in Brazilian patients with nonsyndromic cleft lip with or without cleft palate. AB - BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common orofacial birth defect with a wide range prevalence among different populations. Previous association studies with populations from Europe and Asia have identified putative susceptibility markers for NSCL/P in fibroblast growth factor 12 (FGF12), vinculin (VCL), connexin 43 (CX43) and in a region close to the ventral anterior homeobox 1 (VAX1) gene. However, there have thus far been no studies of these markers in NSCL/P Brazilian patients, and as the genetic ancestry of the Brazilian population is highly varied, the predisposition to those disease markers can be different. METHODS: Herein we conducted a structured association study conditioned on the individual ancestry proportions to determine the role of 16 polymorphic markers within those genes in 300 patients with NSCL/P and 385 unaffected controls. RESULTS: None of the alleles and genotypes showed association with NSCL/P, though there was a significant association of the haplotype formed by VAX1 rs10787760, rs6585429 and rs1871345 polymorphisms with NSCL/P that did not persist Bonferroni correction for multiple tests. CONCLUSIONS: Our results are consistent with a lack of involvement of FGF12, VCL and CX43 variants with NSCL/P pathogenesis in Brazilian patients. Furthermore, the higher frequency of a haplotype of VAX1 with NSCL/P patients suggests a low penetrant gene for oral cleft, and warrants further studies. PMID- 23679095 TI - Acute haemolytic reaction due to anti-Wb: a case report. AB - A 73-year-old Greek woman presented with symptomatic anaemia requiring red cell transfusion in the setting of progressive chronic lymphocytic leukaemia (CLL). Based on a negative antibody screen, two units of red blood cells (RBCs) were provided for transfusion. During the transfusion, the patient developed an acute haemolytic transfusion reaction (HTR), but recovered with supportive measures. Subsequent antibody investigation confirmed that the patient had an anti-Wb antibody and that the implicated RBC unit was Wb-positive. This is the first report of an anti-Wb causing a clinically significant acute HTR in the literature. PMID- 23679097 TI - Influence of temperature on lithium-oxygen battery behavior. AB - In this Letter we report an electrochemical and morphological study of the response of lithium-oxygen cells cycled at various temperatures, that is, ranging from -10 to 70 degrees C. The results show that the electrochemical process of the cells is thermally influenced in an opposite way, that is, by a rate decrease, due to a reduced diffusion of the lithium ions from the electrolyte to the electrode interface, at low temperature and a rate enhancement, due to the decreased electrolyte viscosity and consequent increased oxygen mobility, at high temperature. In addition, we show that the temperature also influences the crystallinity of lithium peroxide, namely of the product formed during cell discharge. PMID- 23679096 TI - GenK-catalyzed C-6' methylation in the biosynthesis of gentamicin: isolation and characterization of a cobalamin-dependent radical SAM enzyme. AB - The existence of cobalamin (Cbl)-dependent enzymes that are members of the radical S-adenosyl-l-methionine (SAM) superfamily was previously predicted on the basis of bioinformatic analysis. A number of these are Cbl-dependent methyltransferases, but the details surrounding their reaction mechanisms have remained unclear. In this report we demonstrate the in vitro activity of GenK, a Cbl-dependent radical SAM enzyme that methylates an unactivated sp(3) carbon during the biosynthesis of gentamicin, an aminoglycoside antibiotic. Experiments to investigate the stoichiometry of the GenK reaction revealed that 1 equiv each of 5'-deoxyadenosine and S-adenosyl-homocysteine are produced for each methylation reaction catalyzed by GenK. Furthermore, isotope-labeling experiments demonstrate that the S-methyl group from SAM is transferred to Cbl and the aminoglycoside product during the course of the reaction. On the basis of these results, one mechanistic possibility for the GenK reaction can be ruled out, and further questions regarding the mechanisms of Cbl-dependent radical SAM methyltransferases, in general, are discussed. PMID- 23679098 TI - Episodic memory in former professional football players with a history of concussion: an event-related functional neuroimaging study. AB - Previous research has demonstrated that sport-related concussions can have short term effects on cognitive processes, but the long-term consequences are less understood and warrant more research. This study was the first to use event related functional magnetic resonance imaging (fMRI) to examine long-term differences in neural activity during memory tasks in former athletes who have sustained multiple sport-related concussions. In an event-related fMRI study, former football players reporting multiple sport-related concussions (i.e., three or more) were compared with players who reported fewer than three concussions during a memory paradigm examining item memory (i.e., memory for the particular elements of an event) and relational memory (i.e., memory for the relationships between elements). Behaviorally, we observed that concussion history did not significantly affect behavioral performance, because persons in the low and high concussion groups had equivalent performance on both memory tasks, and in addition, that concussion history was not associated with any behavioral memory measures. Despite demonstrating equivalent behavioral performance, the two groups of former players demonstrated different neural recruitment patterns during relational memory retrieval, suggesting that multiple concussions may be associated with functional inefficiencies in the relational memory network. In addition, the number of previous concussions significantly correlated with functional activity in a number of brain regions, including the medial temporal lobe and inferior parietal lobe. Our results provide important insights in understanding the long-term functional consequences of sustaining multiple sports related concussions. PMID- 23679101 TI - Microwave spectrum, conformational properties, and dipole moment of cyclopropylmethyl isocyanide (C3H5CH2NC). AB - The microwave spectrum of cyclopropylmethyl isocyanide, C3H5CH2NC, has been investigated in the 25-75 GHz spectral range. The spectra of two conformers were assigned. The H-C-C-N chain of atoms is antiperiplanar in the conformer denoted ap and synclinal in the sc rotamer. The sc conformer tends to be slightly more stable than the ap form. The internal energy difference was determined to be Eap Esc = 0.2(7) kJ/mol from relative intensity measurements. The spectra of the ground vibrational state and six vibrationally excited states belonging to two different normal vibrations were assigned for sc. The frequencies of these two modes were determined by relative intensity measurements. The dipole moment of this conformer was determined to be MUa = 12.16(6), MUb = 5.91(4), MUc = 0 (preset), and MUtot = 13.52(6) * 10(-30) C m [4.05 (2) debye]. The spectra of the ground and of two vibrationally excited states belonging to the torsion and lowest bending vibration were assigned for ap. The microwave work was supported by quantum chemical calculations at the CCSD/cc-pVTZ and B3LYP/cc-pVTZ levels of theory. Most, but not all, of the theoretical predictions are in good agreement with experiment. PMID- 23679100 TI - Plasma and pulmonary pharmacokinetics of desfuroylceftiofur acetamide after weekly administration of ceftiofur crystalline free acid to adult horses. AB - REASONS FOR PERFORMING STUDY: Current labelling for the use of ceftiofur crystalline free acid (CCFA) in horses states that 2 i.m. doses must be administered 4 days apart to provide 10 days of therapeutic coverage. A 10 day treatment regimen is not sufficient for the long-term treatment of horses with severe lung consolidation or pleuropneumonia. There are currently no data to guide an appropriate dosing interval when a longer treatment regimen is warranted. OBJECTIVES: To determine steady-state plasma and pulmonary epithelial lining fluid (PELF) concentrations of desfuroylceftiofur acetamide (DCA) after weekly i.m. administration of CCFA to adult horses. STUDY DESIGN: Experimental study. METHODS: Seven adult horses received i.m. CCFA at a dose of 6.6 mg/kg bwt on Day 0, Day 4 and every 7 days thereafter for 3 additional doses. Concentrations of DCA in plasma and PELF were measured at various time intervals. RESULTS: After weekly i.m. administration, the mean (+/- s.d.) steady-state peak DCA concentration in plasma (2.87 +/- 1.50 MUg/ml) was significantly higher than that in PELF (0.84 +/- 0.53 MUg/ml). Mean terminal half-lives in plasma (77.5 +/- 17.5 h) and PELF (92.8 +/- 59.0 h) were not significantly different. Concentrations of DCA in plasma and PELF remained in the therapeutic range for the entire dosing interval. CONCLUSIONS: After the initial 2-dose regimen 4 days apart, weekly i.m. administration of CCFA was well tolerated and resulted in plasma and PELF DCA concentrations above the minimal inhibitory concentration that inhibits growth of at least 90% of common lower respiratory tract pathogens of horses. POTENTIAL RELEVANCE: Weekly administration of CCFA would appear appropriate when a treatment regimen longer than 10 days is warranted based on clinical signs and disease severity. PMID- 23679099 TI - Genetic parameters and genome-wide association study of hyperpigmentation of the visceral peritoneum in chickens. AB - BACKGROUND: Hyperpigmentation of the visceral peritoneum (HVP) has recently garnered much attention in the poultry industry because of the possible risk to the health of affected animals and the damage it causes to the appearance of commercial chicken carcasses. However, the heritable characters of HVP remain unclear. The objective of this study was to investigate the genetic parameters of HVP by genome-wide association study (GWAS) in chickens. RESULTS: HVP was found to be influenced by genetic factors, with a heritability score of 0.33. HVP had positive genetic correlations with growth and carcass traits, such as leg muscle weight (rg = 0.34), but had negative genetic correlations with immune traits, such as the antibody response to Newcastle disease virus (rg = -0.42). The GWAS for HVP using 39,833 single nucleotide polymorphisms indicated the genetic factors associated with HVP displayed an additive effect rather than a dominance effect. In addition, we determined that three genomic regions, involving the 50.5 54.0 Mb region of chicken (Gallus gallus) chromosome 1 (GGA1), the 58.5-60.5 Mb region of GGA1, and the 10.5-12.0 Mb region of GGA20, were strongly associated (P < 6.28 * 10-7) with HVP in chickens. Variants in these regions explained >50% of additive genetic variance for HVP. This study also confirmed that expression of BMP7, which codes for a bone morphogenetic protein and is located in one of the candidate regions, was significantly higher in the visceral peritoneum of Huiyang Beard chickens with HVP than in that of chickens without pigmentation (P < 0.05). CONCLUSIONS: HVP is a quantitative trait with moderate heritability. Genomic variants resulting in HVP were identified on GGA1 and GGA20, and expression of the BMP7 gene appears to be upregulated in HVP-affected chickens. Findings from this study should be used as a basis for further functional validation of candidate genes involved in HVP. PMID- 23679102 TI - Selenium status in a group of schoolchildren from the region of Madrid, Spain. AB - BACKGROUND: To assess the selenium status of a group of schoolchildren from the Region of Madrid, Spain. METHODS: Study subjects comprised 483 children (216 boys and 267 girls) aged between 8 and 13 years. Selenium intake was determined using a 3-day food record. The foods consumed were transformed into energy and nutrients, and the selenium intake was compared with that recommended. Serum selenium levels were also recorded. RESULTS: Mean (SD) selenium intake [91.0 (25.2) MUg day(-1) ] was above the recommended level in 99.4% of subjects; the main dietary sources were cereals, meats, fish and milk products. The serum selenium concentration [mean (SD) 71.1 (14.4) MUg L(-1) ], however, was <60 MUg L(-1) in 13.9% of subjects, and <45 MUg L(-1) in 5.6%. The serum selenium concentration correlated with the selenium intake (r = 0.169; P < 0.05). Children with a serum selenium concentration of <75 MUg L(-1) had significantly smaller selenium intakes than those with a serum concentration of >=75 MUg L(-1) . CONCLUSIONS: Although selenium intake was generally above that recommended, the serum selenium concentration of the children could be improved. This could be achieved by increasing the relative consumption of cereals and other selenium rich foods such as fish. PMID- 23679103 TI - Oxidative rearrangement of internal alkynes to give one-carbon-shorter ketones via manganese porphyrins catalysis. AB - Oxidative rearrangement of internal alkynes catalyzed by manganese(III) porphyrin is described, which opens a new access to one-carbon-shorter ketones using molecular oxygen. Under the standard conditions, a variety of alkynes including diarylalkynes and arylalkylalkynes rearranged smoothly to the corresponding ketones in high yields. Based upon experimental observations, a plausible reaction mechanism is proposed. PMID- 23679104 TI - Preoperative erectile function is an independent predictor for decision to spare cavernous nerves during radical prostatectomy. AB - INTRODUCTION: Cavernous nerve sparing (NS) is critical for recovery of erectile function (EF) as well as erectile tissue preservation following radical prostatectomy (RP). Clinical experience suggests that surgeons may opt for non-NS RP in patients with impaired baseline EF. AIM: This study was performed to define if baseline EF is an independent predictor of NS status during RP. METHODS: A total of 2,323 mean (mean age 59 +/- 7 years) who underwent RP at a tertiary referral academic medical center were retrospectively evaluated. Patients who underwent preoperative radiation therapy or androgen deprivation treatment were excluded. MAIN OUTCOME MEASURES: Preoperative parameters evaluated included biopsy pathological characteristics, prostate-specific antigen (PSA) level, patient age, and EF. Baseline EF was graded on a validated five-point patient reported scale. NSS was graded intraoperatively by the surgeon, using a four point NS score assigned to each nerve where 1 = fully preserved, 2 = partially preserved, 3 = minimally preserved, and 4 = resected. NS surgery was defined as NSS of 1 or 2 on both sides, and nerve resection surgery was defined as NSS of 3 or greater on both sides. RESULTS: On univariate analysis, factors related to nerve resection surgery included (all P < 0.01): increasing age (r = 0.16), Gleason score (r = 0.19), EF score (r = 0.21), percentage biopsy cores positive (r = 0.11), higher preoperative PSA (relative risk [RR] 1.72, 95% confidence interval [CI] 1.23-2.40), and clinical stage >=T2 (RR 2.17, 95% CI 1.68-2.78). On multivariable analysis, factors independently predicting for non-NS surgery included (all P < 0.01): baseline EF (odds ratio [OR] 1.50, 95% CI 1.33-1.68), biopsy Gleason sum (OR 1.95, 95% CI 1.65-2.36), clinical T stage >=T2 (OR 1.59, 95% CI 1.15-2.20), patient age (OR 1.07, 95% CI 1.04-1.09), and percentage of biopsy cores positive (OR 1.01, 95% CI 1.00-1.02). CONCLUSIONS: While unfavorable clinical and prostate biopsy characteristics predict less NS, we have shown that poorer baseline EF also independently predicts for nerve resection RP. For every point increase in EF score (that is, worsening EF) the odds of not receiving NS during surgery increase by a factor of 1.5. Although NS is not associated with worse cancer outcomes in appropriately selected patients, failure to spare nerves is associated with poor post-operative EF, urinary continence, and increased severity of cavernous venous leak. Patient anxiety related to cancer diagnosis and impending treatment may lead to falsely-worsened apparent EF when recent erections are assessed during a pre-operative planning visit. For these reasons prostatectomists should consider NS based solely on factors other than patient's baseline EF, even when it is impaired. PMID- 23679105 TI - Preceding pain symptoms and Parkinson's disease: a nationwide population-based cohort study. AB - BACKGROUND AND PURPOSE: Painful sensations are recently reported to be a non motor feature of Parkinson's disease (PD). The non-steroidal anti-inflammatory drug ibuprofen is a common painkiller and was reported to be associated with a decreased risk of PD. The aim of the present study was to examine the relationship amongst preceding pain symptoms, use of ibuprofen and risk of PD in a nationwide population-based cohort. METHODS: The data of participants who were free of PD at baseline were obtained from two large National Health Interview Surveys (NHIS) in Taiwan, conducted in 2001 and 2005. The information regarding pain status included severity and location of pain. Information regarding pain status, use of ibuprofen, comorbidity of depression and PD-associated risk/protective behaviors was adjusted using proportional hazards models. RESULTS: Amongst 33 388 participants, 32 cases of incident PD were identified after a mean follow-up of 3 years. After adjusting for the use of ibuprofen and other PD risk factors, subjects with preceding pain symptoms had a higher incidence of PD than those without pain at baseline, and the hazard ratio was 1.79 (95% CI: 0.71-4.51, P = 0.21) for mild pain and 2.88 (95% CI: 1.05-7.86, P = 0.04) for moderate or severe pain. The PD risk increased by 34% with each additional increment in pain score [hazard ratio = 1.34 (1.03-1.75), P = 0.03], showing a dose-response relationship. CONCLUSIONS: These findings support the hypothesis that pain is associated with PD in the pre-motor stage of the disease. Further research is needed to clarify the role of sensory system involvement in the pre-motor phase of PD. PMID- 23679106 TI - Kinetics of re-equilibrium of oppositely charged hydrogel-surfactant system and its application in controlled release. AB - We report a study of re-equilibrium kinetics of an oppositely charged hydrogel surfactant system (cationically modified hydroxyethyl cellulose (cat-HEC) and sodium dodecyl sulfate (SDS)) and an application of the formulation for delivery of a water-insoluble molecule. Hydrogels have been applied for long-term delivery of water-soluble drugs due to their controlled-release property. However, the release mechanism of drugs solubilized by surfactants has not been clear. In the present study, SDS was used to solubilize a hydrophobic model drug, and thereafter, by electrostatic interaction between cat-HEC and SDS, the solubilized model drug was loaded into two types of cat-HEC hydrogels with different charge density. We found that the charge density of the polymers had a crucial effect on the loading capacity, without affecting the re-equilibrium kinetics. By an elaborate design of the experiments, the release profiles were fitted with one dimensional Fickian law where we found the diffusivity of the drug to be constant and comparable to free micelles over a wide region of surfactant concentrations. The observed long-term controlled diffusion is discussed from a thermodynamic point of view. PMID- 23679107 TI - Three new guaiane sesquiterpene lactones from rhizomes of Curcuma wenyujin. AB - Three new guaiane sesquiterpene lactones (4S)-4-hydroxy-gweicurculactone (1), zedoalactone G (2), and (1R, 4R, 5S, 10S)-zedoalactone B (3), and three known guaiane sesquiterpene lactones, including zedoarolide B (4), zedoalactone B (5), and a new natural product (+)-zedoalactone A (6), were isolated from the rhizomes of Curcuma wenyujin Y.H. Chen et C. Ling. The structures were elucidated by spectroscopic methods including 1D and 2D NMR and HR-ESI-MS. The absolute configuration of 2 was determined via the calculated electronic circular dichroism (ECD), whereas the absolute configurations of 1 and 3 were determined via the ECD data of the [Rh2(OCOCF3)4] complex and [Mo2(OAc)4] complex, respectively. The inhibitory effects of compounds 1-6 on nitric oxide production in lipopolysaccharide-activated macrophages were evaluated. All of them exhibited weak anti-inflammatory activity. PMID- 23679108 TI - Small, highly active DNAs that hydrolyze DNA. AB - DNA phosphoester bonds are exceedingly resistant to hydrolysis in the absence of chemical or enzymatic catalysts. This property is particularly important for organisms with large genomes, as resistance to hydrolytic degradation permits the long-term storage of genetic information. Here we report the creation and analysis of two classes of engineered deoxyribozymes that selectively and rapidly hydrolyze DNA. Members of class I deoxyribozymes carry a catalytic core composed of only 15 conserved nucleotides and attain an observed rate constant (k(obs)) of ~1 min(-1) when incubated near neutral pH in the presence of Zn(2+). Natural DNA sequences conforming to the class I consensus sequence and structure were found that undergo hydrolysis under selection conditions (2 mM Zn(2+), pH 7), which demonstrates that the inherent structure of certain DNA regions might promote catalytic reactions, leading to genomic instability. PMID- 23679109 TI - Goitre and urinary iodine excretion survey in schoolchildren of Kashmir Valley. AB - BACKGROUND: An extensive survey on schoolchildren in Kashmir Valley in 1995 showed a high prevalence of goitre, making it imperative to have a relook at our iodine status, 15 years postiodization. OBJECTIVE: To study the total prevalence of goitre and urinary iodine excretion (UIE) in Kashmiri schoolchildren, 15 years postiodization. DESIGN: A cross-sectional survey, covering 9576 schoolchildren, aged 5-15 years (5988 in 6-12 year age group) was conducted. Goitres were graded as per WHO/UNICEF/ICCIDD. UIE was measured by the arsenic acid reduction in ceric ions method and was estimated in 208 subsampled children. Results were compared with that of 1995 survey. RESULTS: The overall prevalence of goitre in the present study was 3.8% (95% CI: 3.4-4.2) and 3.7% (95% CI: 3.2-4.2) in those aged 6-12 years. No significant difference in prevalence of goitre was observed between boys and girls overall (3.6% vs 4.1%. P > 0.2), nor in the 6-12 year age group (3.3% vs 4.0%, P > 0.1). There was a significant trend of increasing prevalence of goitre with age (P < 0.005). UIE ranged from 12 to 397 MUg/g.creatinine (median, 104); 11% subjects had UIE of <50 MUg/g.creatinine. Overall, prevalence of goitre was significantly lower (3.8% vs 45.2%, P < 0.001), and mean UIE was significantly higher (123.6 +/- 5.3 vs 49.60 +/- 3.55 MUg/g.creatinine, P < 0.001), compared to that in the 1995 survey. CONCLUSION: The marked improvement in overall iodine nutrition in Kashmir Valley- one and a half decades after implementation of salt iodization should encourage healthcare providers to make tangible efforts for implementation of iodization programmes in areas with iodine deficiency. PMID- 23679110 TI - Are highly hypnotizable people naturally aware of their hypnotic talents? Implications for human potentialities. AB - This article investigated the degree to which high hypnotizables are aware of their capability and assessed their ability to produce it without guidance from a hypnotist. Qualitative data suggest that most participants reported being surprised by their hypnotic responsiveness and the realness of the suggestions. Quantitative data tended to support this trend, in which participants had higher overall responsiveness scores, both objectively and subjectively, when the suggestions were given by a hypnotist compared to self-hypnosis. Though some were able to self-produce some hypnotic phenomena, all participants reported that it was easier to experience the suggested effects when given by the hypnotist. An explanation accounting for this finding, implications for future research, and limitations of the study are also provided. PMID- 23679111 TI - A comparison of the clinical effectiveness of various acupuncture points in reducing anxiety to facilitate hypnotic induction. AB - This study determined if any acupuncture point (acupoint) known for its calming effects also aided hypnotic induction. Hypnosis was offered to 108 patients requiring minor surgical or dental procedures. All had a history of panic attacks and surgical or dental phobias that complicated or prevented treatment. Unpleasant intruding thoughts of imminent invasive treatments handicapped their ability to accept hypnotic induction; however, acupuncture therapy was proposed to the consenting patient to facilitate hypnotic induction and augment its effects. Each patient received one selected acupoint for acupuncture therapy. Of the 6 acupoints used (LI 4, H 7, SP 6, P 6, GV 24, and Ext-hn-21), GV 24 was best at enhancing hypnotic induction whereas LI 4 produced the best muscular relaxation and P 6 for reducing tension. PMID- 23679112 TI - Self-regulation therapy to reproduce drug effects: a suggestion technique to change personality and the DRD3 gene expression. AB - This study proposes a strategy, based on self-regulation therapy, to change personality and its biological substrate, the DRD3 gene expression. It has been demonstrated that acute doses of stimulating drugs, like methylphenidate, are able to change personality and the expression of certain genes in the short term. On the other hand, self-regulation therapy has been proven to reproduce the effects of drugs. Thus, it is feasible to hope that self-regulation therapy is equally effective as methylphenidate in changing personality and the gene expression. This is a preliminary study with a single-case experimental design with replication in which 2 subjects participated. The results and potential implications for research and psychotherapy are discussed. PMID- 23679114 TI - The relationships between suggestibility, influenceability, and relaxability. AB - This research explores the relationships between relaxability and various aspects of suggestibility and influenceability. The Jacobson Progressive Muscle Relaxation procedure was used to induce relaxation. Tests of direct suggestibility, relating to the susceptibility of overt suggestions, and indirect suggestibility, referring to indirect hidden influence, as well as self description questionnaires on suggestibility and the tendency to comply were used. Thayer's Activation-Deactivation Adjective Check List, measuring various kinds of activation and used as a pre- and posttest, determined the efficacy of the relaxation procedure. Indirect, direct, and self-measured suggestibility proved to be positively related to the ability to relax, measured by Thayer's subscales relating to emotions. Compliance was not related to relaxability. The results are discussed in terms of the aspects of relaxation training connected with suggestibility. PMID- 23679113 TI - Anxiety reduction using hypnotic induction and self-guided imagery for relaxation during dermatologic procedures. AB - Many patients experience some degree of anxiety during dermatologic procedures. A prospective, randomized-control trial of hypnotic induction followed by self guided imagery was conducted with patients in 3 groups: live induction, recorded induction, or control. By 20 minutes into the procedure, there was significantly reduced anxiety reported in the live-induction group compared with the control, whereas reported anxiety in the recorded-induction group was similar to that of the control group. All 13 in the live induction, 11 of the 13 in the recorded induction, and none of the 13 in the control group imagined scenes. The findings of this study suggest that live hypnotic induction followed by self-guided imagery can help to reduce anxiety experienced by many patients during dermatologic procedures. PMID- 23679115 TI - An unanticipated allergic reaction to a hypnotic suggestion for anesthesia: a brief communication and commentary. AB - During a demonstration of hypnotically induced anesthesia and following a suggestion for a Novocain-like numbness, a totally unanticipated and dramatic swelling of 1 cheek appeared. The participant had forgotten to inform the psychologist that she had experienced the identical reaction to Novocain when she received an injection a few weeks earlier. The swelling was quickly removed by a countersuggestion based upon a simulated injection of the antidote previously administered by the dentist. This case report is relevant to current research and theorizing on the interaction of hypnosis with the immune system. The fact that it was retrospectively recognized as a single-case time-series B-A-B design significantly enhances its scientific value beyond that afforded by the traditional case report. PMID- 23679116 TI - A pilot investigation of guided self-hypnosis in the treatment of hot flashes among postmenopausal women. AB - Previous research has demonstrated that a hypnotic intervention can reduce hot flashes, a significant problem for some women. Based on the authors' previous research, the present study was developed to evaluate the feasibility of a guided self-hypnosis intervention for hot flashes. Thirteen postmenopausal women received 5 sessions of guided self-hypnosis in which all hypnotic inductions were recordings. Guidance regarding symptom monitoring, individualization of mental imagery, and practice of self-hypnosis were provided. Hot flashes were determined through diaries. Results indicated average frequency of hot flashes decreased by 72% (p < .001) and hot-flash scores decreased by 76% (p < .001) on average. Guided self-hypnosis reduced perceived hot flashes in the pilot study with postmenopausal women supporting the possible feasibility and potential benefit of the intervention. PMID- 23679117 TI - An eye for an I: a 35-year-old woman with fluctuating oculomotor deficits and dissociative identity disorder. AB - Physiologic changes, including neurological or pseudo-neurological symptoms, occur across identity states in dissociative identity disorder DID) and can be objectively measured. The idea that dissociative phenomena might be associated with changes in brain function is consistent with research on the brain effects of hypnosis. The authors report a case of psycho-physiologic differences among 4 alter personalities manifested by a 35-year-old woman with DID. Differences in visual acuity, frequency of pendular nystagmus, and handedness were observed in this patient both when the alter personalities appeared spontaneously and when elicited under hypnosis. The authors consider several diagnostic possibilities for these findings and discuss whether prevailing treatment recommendations for DID patients could possibly be modified to ameliorate such visual and neurologic symptoms. PMID- 23679118 TI - Impact of hepatitis C virus co-infection on HIV patients before and after highly active antiretroviral therapy: an immunological and clinical chemistry observation, Addis Ababa, Ethiopia. AB - BACKGROUND: Hepatitis C virus (HCV) is an RNA virus which has been known to cause acute and chronic necro-inflammatory disease of the liver. It is the leading cause of end-stage liver disease and hepatocellular carcinoma. HIV is known to have a negative impact on the natural disease outcome and immune response of HCV infection, whereas the reverse remains unclear. We evaluated the impact of HCV co infection on recovery of CD4+ and CD8+ T-cells and liver enzyme levels before and after initiation of highly active antiretroviral therapy (HAART) in HIV/HCV co infected patients. METHODS: A hospital-based, observational, prospective cohort study design was used for this study. Pre-antiretroviral treatment (Pre-ART) and under HAART HIV mono-infected and HCV/HIV co-infected individuals who are under regular follow-up were recruited for this study. 387 blood samples were collected from volunteer, known HIV positive Ethiopian patients and screened for HCV. Twenty five HCV/HIV co-infected patients were prospectively followed for four years. CD4+ and CD8+ T-cells and liver enzyme levels were determined annually for each of the participant. RESULTS: The prevalence of HCV/HIV co-infection in this study was 6.5%. Both HCV/HIV co-infected and HIV mono-infected under HAART groups showed CD4+ recovery (343 Vs 426; P < 0.004, OR = 4.97, 95% CI = 2.41 to 10.27) respectively; but, the recovery rate was higher in mono-infected (80 Vs 426) than co-infected group (148 Vs 343). The recovery and/or decline pattern of CD8+ T cells was the same with that of CD4+. In 75% of co-infected groups, the mean alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were above the upper limit of normal reference range. Analyses restricted to individuals who initiated HAART and pre-ART showed similar results. CONCLUSION: We found that CD4+ T-cell recovery was negatively affected by the presence of ongoing HCV replication in under HAART co-infected individuals and fast decline of CD4+ T-cells in pre-ART patients. It was also associated with increased ALT and AST enzyme levels in both HAART initiated and treatment naive co-infected patients. PMID- 23679119 TI - Characterization of cyanobacteria isolated from biofilms on stone monuments at Santiniketan, India. AB - Cyanobacterial biofilms occurring on the exterior of three stone monuments at Santiniketan, India were analyzed. Species of Scytonema and Tolypothrix were the major components of these biofilms. Identification was obtained by morphometric procedures and 16S rRNA gene sequencing. Biofilms cultured for prolonged periods revealed the presence of several other cyanobacteria belonging to 14 different genera. Cyanobacteria on stone in the tropical environment of India formed a distinct cluster that was quite different from that of cyanobacteria reported for a similar substratum in temperate regions. Absorption spectra of the organisms from Santiniketan showed a high quantity of scytonemin, mycosporine-like amino acids, and carotenoids. All of the organisms survived in a desiccated state and rapidly revived after wetting. The organisms were heterocystous and nitrogenase activity was reactivated within 24 h of wetting by which time heterocysts in their filaments had also appeared. PMID- 23679120 TI - Ballet dancers cardiorespiratory, oxidative and muscle damage responses to classes and rehearsals. AB - This study aimed to describe and compare ballet dancers' cardiorespiratory responses, muscle damage and oxidative stress levels during a ballet class (practice of isolated ballet exercises performed with barre/hand-rail support and across-the-floor movements to improve technical skills) and rehearsal (practice of ballet choreography involving technical-artistic skills to improve dancers' performance for shows). The 12 advanced female ballet dancers undertook three exercise sessions: maximum effort test, class and rehearsal. Heart rate (HR) and oxygen consumption (VO2) were continuously measured. Lactate was determined before 15 min and after class and rehearsal. Blood was sampled pre, post and 48 h after class and rehearsal for creatine kinase (CK), lipid peroxides (LPO) and glutathione analysis (GSSG/GSH). Class was of lower intensity than rehearsal as shown by VO2, HR and lactate values: VO2 (mL.kg(-1).min(-1)): 14.5+/-2.1 vs. 19.1+/-1.7 (p < 0.001); HR (bpm.min(-1)): 145.7+/-17.9 vs. 174.5+/-13.8 (p < 0.001); lactate (mmol.L(-1)): 4.2+/-1.1 vs. 5.5+/-2.7 (p = 0.049). CK (IU) increased following class and rehearsal, remaining high 48 h after: class (pre = 109.3+/-48.5; post = 144+/-60; 48 h = 117.2+/-64.6); rehearsal (pre = 78.6+/ 52.1; post = 122+/-70.7; 48 h = 104.9+/-89.5). LPO (uM) increased from pre-class (1.27+/-0.19) to post-class (1.41+/-0.19) and went down after 48 h (1.20+/-0.22). No LPO time-course changes followed the rehearsal. GSSG/GSH decreased 48 h after class and rehearsal. Greater increases in LPO post-class suggest it promotes CK release by an oxidative membrane-damage mechanism. Physiological increases of LPO and CK in class indicate it prepares the dancers for exercise-induced oxidative stress and muscle damage during rehearsals. Ballet dancers' muscle damage and oxidative stress responses seem not to be dependent on exercise intensity based on VO2 responses. PMID- 23679121 TI - Vascular access surveillance: time to end the controversy. PMID- 23679124 TI - Evaluation of three different validation procedures regarding the accuracy of template-guided implant placement: an in vitro study. AB - PURPOSE: The study aims to evaluate the accuracy of the NobelGuideTM (Medicim/Nobel Biocare, Goteborg, Sweden) concept maximally reducing the influence of clinical and surgical parameters. Moreover, the study was to compare and validate two validation procedures versus a reference method. MATERIAL AND METHODS: Overall, 60 implants were placed in 10 artificial edentulous mandibles according to the NobelGuideTM protocol. For merging the pre- and postoperative DICOM data sets, three different fusion methods (Triple Scan Technique, NobelGuideTM Validation software, and AMIRA(r) software [VSG - Visualization Sciences Group, Burlington, MA, USA] as reference) were applied. Discrepancies between the virtual and the actual implant positions were measured. RESULTS: The mean deviations measured with AMIRA(r) were 0.49 mm (implant shoulder), 0.69 mm (implant apex), and 1.98 degrees mm (implant axis). The Triple Scan Technique as well as the NobelGuideTM Validation software revealed similar deviations compared with the reference method. A significant correlation between angular and apical deviations was seen (r = 0.53; p < .001). A greater implant diameter was associated with greater deviations (p = .03). CONCLUSION: The Triple Scan Technique as a system-independent validation procedure as well as the NobelGuideTM Validation software are in accordance with the AMIRA(r) software. The NobelGuideTM system showed similar or less spatial and angular deviations compared with others. PMID- 23679125 TI - A case report on autosomal recessive total congenital anonychia. AB - A 21-year-old woman presented with a history of the absence of the nails of all her fingers and toes since birth. Her grandfathers were first degree relatives. Her two brothers (26 and 28 years old) had the same anomalies. Autosomal recessive inheritance of this disease was supported in our cases because the parents were consanguineous and the disease occurred in two brothers and a sister. PMID- 23679126 TI - Indoleamine 2,3-dioxygenase is differentially expressed by different white blood cell populations of rhesus macaques (Macaca mulatta). AB - BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is involved in immune processes such as transplant and fetal rejection, autoimmunity, cancer, and infection; however, its expression in rhesus macaques has not been fully addressed. METHODS: Indoleamine 2,3-dioxygenase mRNA and protein in the white blood cells (WBCs) of Chinese rhesus macaques were examined by RT-PCR, western blotting, real-time RT PCR, and flow cytometry. RESULTS: Both IDO protein and mRNA could be readily detected in WBCs or peripheral blood mononuclear cells (PBMCs) of normal rhesus macaques. IDO+ cell frequency was the highest among CD14(+) mononuclear cells, followed by CD56(+) cells and DCs. No difference in the frequency of IDO+ cells between CD4(+) and CD8(+) T cells; however, Th17 cells have higher frequency of IDO+ cells than Th1 cells, with Th2 cells the lowest. Toll-like receptor (TLR) stimulation significantly increased IDO protein level in CD14(+) , CD56(+) , CD1c(+) , CD11c(+) , and CD123(+) myeloid cells. CONCLUSION: Rhesus macaques express IDO differentially in their leukocyte subsets and are suitable for IDO related pathophysiological studies. PMID- 23679127 TI - Insensitivity and oversensitivity to answer diagnosticity in hypothesis testing. AB - Two experiments examined how people perceive the diagnosticity of different answers ("yes" and "no") to the same question. We manipulated whether the "yes" and the "no" answers conveyed the same amount of information or not, as well as the presentation format of the probabilities of the features inquired about. In Experiment 1, participants were presented with only the percentages of occurrence of the features, which most straightforwardly apply to the diagnosticity of "yes" answers. In Experiment 2, participants received in addition the percentages of the absence of features, which serve to assess the diagnosticity of "no" answers. Consistent with previous studies, we found that participants underestimated the difference in the diagnosticity conveyed by different answers to the same question. However, participants' insensitivity was greater when the normative (Bayesian) diagnosticity of the "no" answer was higher than that of the "yes" answer. We also found oversensitivity to answer diagnosticity, whereby participants valued as differentially diagnostic two answers that were normatively equal in terms of their diagnosticity. Presenting to participants the percentages of occurrence of the features inquired about together with their complements increased their sensitivity to the diagnosticity of answers. We discuss the implications of these findings for confirmation bias in hypothesis testing. PMID- 23679128 TI - Biomimetic asymmetric 1,3-dioplar cycloaddition: amino acid precursors in biosynthesis serve as latent azomethine ylides. AB - The first asymmetric catalytic biomimetic three-component 1,3-dipolar cycloaddition of alpha-keto esters and benzylamine with electron-deficient olefins, inspired by the transamination of alpha-keto acids involving pyridoxal phosphate (PLP)-dependent enzymes in biological systems, giving several families of structurally diverse pyrrolidine derivatives in high yields and excellent enantioselectivities (up to 99% ee) under mild conditions is described. PMID- 23679129 TI - How to improve the quality of research reporting? PMID- 23679130 TI - Risk assessment on irrigation of Vitis vinifera L. cv Malbec with Hg contaminated waters. AB - Concerns regard watering crops with Hg contaminated waters have arisen worldwide recently. In these sense Hg uptake by Vitis vinifera L. cv. Malbec was evaluated under greenhouse conditions by the administration of Hg(2+) for 4 days through irrigation water (short-term administration). Vines uptake Hg translocating it from roots through stems to leaves. Roots accumulated the higher Hg concentration. Hg in stems and leaves was accumulated mostly as organic Hg, bind to different moieties. Size exclusion chromatography (SEC) and ion pair chromatography (IPC) were employed to reach insights into these ligands. Hg is distributed mainly in high molecular weight fractions of 669 kDa in vine plants. In stems and leaves, Hg-S associations were found in 669 and 66 kDa fractions. Hg S association at 66 kDa suggests a possible protein or peptide binding affecting vines normal physiology. Since Hg contamination through organomercurials is more harmful than Hg(2+) itself, methyl mercury, dimethyl mercury, and phenyl mercury, more toxic Hg species were evaluated with negative results. PMID- 23679131 TI - Molecular relativistic corrections determined in the framework where the Born Oppenheimer approximation is not assumed. AB - In this work, we describe how the energies obtained in molecular calculations performed without assuming the Born-Oppenheimer (BO) approximation can be augmented with corrections accounting for the leading relativistic effects. Unlike the conventional BO approach, where these effects only concern the relativistic interactions between the electrons, the non-BO approach also accounts for the relativistic effects due to the nuclei and due to the coupling of the coupled electron-nucleus motion. In the numerical sections, the results obtained with the two approaches are compared. The first comparison concerns the dissociation energies of the two-electron isotopologues of the H2 molecule, H2, HD, D2, T2, and the HeH(+) ion. The comparison shows that, as expected, the differences in the relativistic contributions obtained with the two approaches increase as the nuclei become lighter. The second comparison concerns the relativistic corrections to all 23 pure vibrational states of the HD(+) ion. An interesting charge asymmetry caused by the nonadiabatic electron-nucleus interaction appears in this system, and this effect significantly increases with the vibration excitation. The comparison of the non-BO results with the results obtained with the conventional BO approach, which in the lowest order does not describe the charge-asymmetry effect, reveals how this effect affects the values of the relativistic corrections. PMID- 23679133 TI - Discourse analysis and the impact of the philosophy of Enlightenment in nursing research. AB - Discourse analysis has been introduced into nursing research as an approach which has the potential to offer new perspectives and to pose new questions to taken for-granted assumptions. However, critique has arisen that when applied to nursing studies, the epistemological foundation of the discourse analysis is often overlooked. It is furthermore claimed that the methodological inspiration does not lead to any new insights and that these studies can hardly be differentiated from more traditional studies. This study supports this critique, arguing that the challenges of implementing discourse analysis in nursing research reflect a dominant pattern of thought in the discourse of the nursing profession that have held sway throughout the last century. We argue that this pattern of thought stems from the Western philosophy of consciousness and the conception of the sovereign subject. By applying a discourse analytical perspective to the discourse of the nursing profession itself, this study elucidates the challenges of applying discourse analysis in nursing research. PMID- 23679132 TI - Habitual snoring and depressive symptoms during pregnancy. AB - BACKGROUND: Depression is frequently observed in patients with untreated sleep disordered breathing (SDB) in the general population. Pregnant women are particularly vulnerable since pregnancy increases the risk of both SDB and depressive symptoms. However, no study has investigated whether SDB symptoms prior to or in early pregnancy are associated with such mood problems. METHODS: A retrospective chart review of pregnant women. Women were included if they attended prenatal clinics between June 2007 and July 2010, were >=18 years old, pregnant with a single fetus, and had been screened for habitual snoring as well as depressive symptoms using the Edinburgh Postnatal Depression Scales (EPDS). RESULTS: In total, 362 women were included and 32.3% reported habitual snoring. Twenty-nine percent of women had an EPDS score >=10. Significantly more snoring women, compared to non-snorers, had an EPDS score >=10 (42.7% vs. 22.9%, p < 0.001) despite the mean EPDS values not reaching statistical significance (6.1 +/ 4.9 vs. 5.4 +/- 5.0, p = 0.2). In a logistic regression model controlling for parity, the presence of pre-pregnancy obesity, presence of a partner, sleep quality, African American race, maternal educational level, pre-eclampsia, and diabetes, snoring was independently associated with a prenatal EPDS score >=10 (O.R. 2.0, 95%CI 1.13-3.46; p = 0.023). CONCLUSION: Maternal snoring may be a risk factor for prenatal depressive symptoms. Further investigation of the temporal relationship between maternal snoring and depressive symptoms is warranted. PMID- 23679134 TI - Food choice and nutrient intake amongst homeless people. AB - BACKGROUND: Homeless people in the UK and elsewhere have typically been found to consume a nutritionally inadequate diet. There is need for contemporary research to update our understanding within this field. The present study aimed to provide an insight into the nutrient intake and food choice of a sample of homeless adults. METHODS: In this mixed-methods study, 24 homeless individuals accessing two charitable meal services in Sheffield, UK, participated in up to four 24-h dietary recalls between April and August 2012. Twelve individuals took part in a semi-structured interview focusing on food choice. RESULTS: Energy intake was significantly lower than the estimated average requirement. Median intakes of vitamin A, zinc, magnesium, potassium and selenium were significantly lower than reference nutrient intakes. Contributions of saturated fat and nonmilk extrinsic sugars to total energy intake were significantly higher, whereas dietary fibre was significantly lower, than population average intakes. Charitable meals made an important contribution to intakes of energy and most micronutrients. Thematic analysis of interview transcripts revealed three major themes: food aspirations; constraints over food choice; and food representing survival. CONCLUSIONS: The present study reveals risk of dietary inadequacies amongst homeless people alongside a lack of control over food choices. Charitable meal services are suggested as a vehicle for improving the dietary intake and nutritional health of homeless people. PMID- 23679135 TI - Two new acetylated flavonoid glycosides from Phyllanthus urinaria. AB - Two new acetylated flavonoid glycosides, quercetin 3-O-alpha-l-(2,4-di-O-acetyl) rhamnopyranoside-7-O-alpha-l-rhamnopyranoside (1) and quercetin 3-O-alpha-l-(3,4 di-O-acetyl) rhamnopyranoside-7-O-alpha-l-rhamnopyranoside (2), together with two known compounds, quercetin (3) and quercetin 3-O-alpha-l-rhamnopyranoside (4), were isolated from the ethanol extract of Phyllanthus urinaria. The structures of the new compounds were determined on the basis of extensive spectroscopic data including IR, HR-ESI-MS, 1D NMR, and 2D NMR. PMID- 23679136 TI - Identification of Candida species in the clinical laboratory: a review of conventional, commercial, and molecular techniques. AB - In healthy individuals, Candida species are considered commensal yeasts of the oral cavity. However, these microorganisms can also act as opportunist pathogens, particularly the so-called non-albicans Candida species that are increasingly recognized as important agents of human infection. Several surveys have documented increased rates of C. glabrata, C. tropicalis, C. guilliermondii, C. dubliniensis, C. parapsilosis, and C. krusei in local and systemic fungal infections. Some of these species are resistant to antifungal agents. Consequently, rapid and correct identification of species can play an important role in the management of candidiasis. Conventional methods for identification of Candida species are based on morphological and physiological attributes. However, accurate identification of all isolates from clinical samples is often complex and time-consuming. Hence, several manual and automated rapid commercial systems for identifying these organisms have been developed, some of which may have significant sensitivity issues. To overcome these limitations, newer molecular typing techniques have been developed that allow accurate and rapid identification of Candida species. This study reviewed the current state of identification methods for yeasts, particularly Candida species. PMID- 23679137 TI - Health-related quality of life, ethnicity and perceived discrimination among immigrants and natives in Spain. AB - OBJECTIVES: The current study compares subjective mental and physical health among native Spaniards and immigrant groups, and examines the effects of ethnicity and perceived discrimination (PD) on subjective health in immigrants. DESIGN: Two random samples of 1250 immigrants to Spain from Colombia, Bolivia, Romania, Morocco, and Sub-Saharan Africa and 500 native Spaniards, aged between 18 and 65, were recruited for this cross-sectional study. Several hierarchical regression analyses of ethnicity and PD on subjective mental and physical health (assessed using the health-related quality of life items, HRQLSF-12) were carried out separately for men and women. RESULTS: Male immigrants from Colombia and Sub Saharan Africa showed better physical health than natives, controlling for age and socioeconomic and marital status. The immigrants - except for the Colombians had poorer mental health than natives, especially African men and Bolivian women. Socioeconomic status had no impact on these differences. Among immigrants, PD was the best predictor of physical and mental health (controlling for socio demographic variables). African men, Bolivian women and women without legal status exhibited the poorest self-rated mental health. CONCLUSION: Clear differences in health status among natives and immigrants were recorded. The self selection hypothesis was plausible for physical health of Colombians and Sub Saharan African men. Acculturation stress could explain poorer mental health in immigrants compared with natives. The association between ethnicity and poor self reported mental health appears to be partially mediated by discrimination. PMID- 23679138 TI - Controlling electrostatic charging of nanocrystalline diamond at nanoscale. AB - Constant electrical current in the range of -1 to -200 pA is applied by an atomic force microscope (AFM) in contact mode regime to induce and study local electrostatic charging of oxygen-terminated nanocrystalline diamond (NCD) thin films. The NCD films are deposited on silicon in 70 nm thickness and with 60% relative sp(2) phase content. Charging current is monitored by conductive AFM. Electric potential contrast induced by the current is evaluated by Kelvin force microscopy (KFM). KFM shows well-defined, homogeneous, and reproducible microscopic patterns that are not influenced by inherent tip-surface junction fluctuations during the charging process. The charged patterns are persistent for at least 72 h due to charge trapping inside the NCD film. The current-induced charging also clearly reveals field-induced detrapping at current amplitudes >-50 pA and tip instability at >-150 pA, both of which limit the achievable potential contrast. In addition, we show that the field also determines the range of electronic states that can trap the charge. We present a model and discuss implications for control of the nanoscale charging process. PMID- 23679139 TI - Reaction pathways for the thermal decomposition of methyl butanoate. AB - In recent years, biodiesel fuels, consisting of long-chain alkyl (methyl, ethyl, propyl) esters, have emerged as viable alternatives to petroleum-based fuels. From a combustion chemistry standpoint, there is great interest in developing accurate reaction models for these new molecules that can be used to predict their behaviors in various regimes. In this paper, we report a detailed study of the unimolecular decomposition pathways of methyl butanoate (MB), a short-chain ester that contains the basic chemical structure of biodiesel fuels. Using ab initio/DFT methods, we identified five homolytic fissions of C-C and C-O bonds and five hydrogen transfer reactions. Rate constants were determined using the G3B3 theory coupled with both variational transition state theory and Rice Ramsperger-Kassel-Marcus/master equation simulations with hindered rotation corrections. Branching ratios in the temperature range 1500-2200 K indicate that the main pathway for thermal decomposition of MB is the reaction CH3CH2CH2C(?O)OCH3 -> C2H5 + CH2C(?O)OCH3. The results, in terms of reaction pathways and rate constants, can be used for future development of mechanisms for long alkyl-chain esters. PMID- 23679140 TI - Analysis of entries into the penalty area as a performance indicator in soccer. AB - This study examines entries into the penalty area as a performance indicator that distinguishes between winning, drawing and losing soccer teams. It assesses whether entries into the penalty area are influenced by match status, a player's dismissal and the respective quality of the competing teams. Two observers analysed the relation between defensive and offensive strategies and their scoring consequences for all 64 matches played in the 2006 World Cup. Kappa values ranged between 0.93 and 0.98 for intra-reliability and between 0.88 and 0.98 for inter-reliability. It was found that winning teams received significantly fewer entries into their own penalty area (mean=41.42, s=11.86) than drawing (mean=50.07, s=14.75) and losing teams (mean=47.23, s=12.14). Teams that received more entries into their own penalty area than the opposing team were significantly more likely to concede a goal (P <0.001). Teams losing by one (mean=0.41, s=0.21), two (mean=0.42, s=0.26) or more than two goals (mean=0.34, s=0.13) received significantly fewer entries into the penalty area per minute than teams winning by one (mean=0.55, s=0.27) or two goals (mean=0.59, s=0.39). Teams with fewer players on the pitch received significantly more entries into the penalty area per minute than teams with more (mean=0.22, s=0.07) or the same number (mean=0.14, s=0.05) of players. Based on these results, it is suggested that teams should enter the opposing team's penalty area but should not allow their opponents to do the same. These results also highlight the significance of the dismissal of a player. PMID- 23679141 TI - The influence of relative age on the composition of professional soccer squads. AB - Children born shortly after the cut-off date applying for age grouping in minor sports profit from being able to remain for almost an additional year in their respective age group compared to those born later in the same year. A shift of the cut-off date in German youth soccer in 1997 allowed us to investigate the effect of a favourable relative age as well as the effect of a change of the cut off date on the birth-date distribution of soccer players in the Bundesliga (Division 1), the highest professional soccer league in Germany. Both the cut-off date and the change of the cut-off date exerted a significant influence on the composition of professional senior squads. In the 1997/98 season, there was an overrepresentation of players profiting from the old cut-off date of 1 August. In the 2007/08 season, 10 years after the change of the cut-off date, there was an overrepresentation of players born shortly after the new cut-off date of 1 January. This pattern of results shows that owing to the cut-off dates applying in youth soccer, the date of birth of young players systematically influences their later professional success and career. PMID- 23679142 TI - The sports performance application of vibration exercise for warm-up, flexibility and sprint speed. AB - Since the turn of the 21st century, there has been a resurgence of vibration technology to enhance sport science especially for power and force development. However, vibration exercise has been trialled in other areas that are central to athlete performance such as warm-up, flexibility and sprint speed. Therefore, the aim of this review was to attempt to gain a better understanding of how acute and short-term vibration exercise may impact on warm-up, flexibility and sprint speed. The importance of warming up for sporting performance has been well documented and vibration exercise has the capability to be included or used as a standalone warm-up modality to increase intramuscular temperature at a faster rate compared to other conventional warm-up modalities. However, vibration exercise does not provide any additional neurogenic benefits compared to conventional dynamic and passive warm-up interventions. Vibration exercise appears to be a safe modality that does not produce any adverse affects causing injury or harm and could be used during interval and substitution breaks, as it would incur a low metabolic cost and be time-efficient compared to conventional warm-up modalities. Acute or short-term vibration exercise can enhance flexibility and range of motion without having a detrimental effect on muscle power, however it is less clear which mechanisms may be responsible for this enhancement. It appears that vibration exercise is not capable of improving sprint speed performance; this could be due to the complex and dynamic nature of sprinting where the purported increase in muscle power from vibration exercise is probably lost on repeated actions of high force generation. Vibration exercise is a safe modality that produces no adverse side effects for injury or harm. It has the time-efficient capability of providing coaches, trainers, and exercise specialists with an alternative modality that can be implemented for warm-up and flexibility either in isolation or in conjunction with other conventional training methods. PMID- 23679143 TI - Kinematic characteristics of elite men's 50 km race walking. AB - Race walking is an endurance event which also requires great technical ability, particularly with respect to its two distinguishing rules. The 50 km race walk is the longest event in the athletics programme at the Olympic Games. The aims of this observational study were to identify the important kinematic variables in elite men's 50 km race walking, and to measure variation in those variables at different distances. Thirty men were analysed from video data recorded during a World Race Walking Cup competition. Video data were also recorded at four distances during the European Cup Race Walking and 12 men analysed from these data. Two camcorders (50 Hz) recorded at each race for 3D analysis. The results of this study showed that walking speed was associated with both step length (r=0.54,P=0.002) and cadence (r=0.58,P=0.001). While placing the foot further ahead of the body at heel strike was associated with greater step lengths (r=0.45,P=0.013), it was also negatively associated with cadence (r= 0.62,P<0.001). In the World Cup, knee angles ranged between 175 and 186 degrees at initial contact and between 180 and 195 degrees at midstance. During the European Cup, walking speed decreased significantly (F=9.35,P=0.002), mostly due to a decrease in step length between 38.5 and 48.5 km (t=8.59,P=0.014). From this study, it would appear that the key areas a 50 km race walker must develop and coordinate are step length and cadence, although it is also important to ensure legal walking technique is maintained with the onset of fatigue. PMID- 23679144 TI - Motor performance and bodyweight of children and adolescents in Saarland -- status quo. AB - The motor performance of children and adolescents has been a subject of controversial discussion. As part of a pilot project, 839 schoolchildren from 14 different schools in Saarland were studied and their height, weight and sport motor performance were measured using the German motor performance test DMT 6-18. The results show a slight increase in the number of overweight children compared to reference samples. However, these discrepancies are minor and cannot be judged to be practically relevant because of the weakness of the effects. The average motor test performances of the Saarland schoolchildren were above the average performance of the reference samples in almost all individual performances. There are also hardly any weaker performances in comparison to older studies. The current results for motor performance of Saarland children and adolescents do not, therefore, give any great reason for concern. Further evaluation steps will be needed to clarify the influences that might be associated with adverse characteristics for motor performance (socio-economic status, living situation, leisure behaviour, school performance, etc.). PMID- 23679145 TI - Influence of electrically assisted cycling on physiological parameters in untrained subjects. AB - Electrically assisted bicycles (EAB) as a form of transport not only offer the potential to reduce energy use and environmental impact but could also be an effective way of encouraging active living. The purpose of this study is to assess the influence of physical active commuting to work using an EAB, on physiological parameters in 20 untrained men and women. Tests were performed at three different time points over a 10-week period, including four weeks of passive (control period) and six weeks of active commuting (intervention period). ANOVA for repeated measures was used to test differences between the testing series for the most important physiological parameters: Pmax.kg(-1), VO2peak.kg( 1), fixed blood lactate concentration (2, 4 mmol.l(-1)). The subjects performed over a 6-week period a mean total cycling distance of 405.1+/-156.0 km with a weekly frequency of 4.1+/-1.7 days.week(-1) for men and 246.0+/-116.3 km with a frequency of 2.9+/-1.0 days.week(-1) for women. Pmax.kg(-1) significantly increased in men and women after 6 weeks of active commuting. Power output at 2 mmol.l(-1) significantly increased in women (P=0.001) but not in men (P=0.0604). Power output at 4 mmol.l(-1) significantly increased for men and women. VO2peak.kg(-1) did not differ. With respect to the study limitations, it is concluded that cycling to work on an EAB was effective in increasing the maximal power output and power output at 4 mmol.l(-1) in these untrained subjects. Cycling on an EAB seems to be a promising tool as a health enhancing physical activity, for those who will benefit the most in terms of health related fitness, namely the physically inactive, unfit and older people. PMID- 23679146 TI - Effect of nutritional intervention on body composition and performance in elite athletes. AB - Strength training and positive energy intake are the most important factors related to lean body mass (LBM) gain. Most studies investigating weight-gain interventions are based recreationally active subjects and less is known about optimal weight-gain protocols in elite athletes. The purpose of this study was to evaluate the effect of nutritional guidance in an 8- to 12-week weight-gain period in elite athletes. Thirty-nine elite athletes were randomised to either a 'nutritional counseling group' (NCG, n=21, 19.1+/-2.9 years, 70.9+/-8.9 kg) or 'ad libitum group' (ALG, n=18, 19.6+/-2.7 years, 75.0+/-5.9 kg). All athletes continued their sport-specific training which included an additional four strength-training sessions per week. NCG followed a meal plan providing a positive energy balance, while the ALG athletes had an ad libitum energy intake. Body weight (BW), body composition, one repetition maximum (1RM), 40 m sprint and counter movement jump (CMJ) were measured pre- and post-intervention. Energy intake was higher in the NCG than in the ALG (3585+/-601 vs. 2964+/-884 kcal) and consequently BW increased more in NCG than in ALG (3.9+/-0.6% vs. 1.5+/-0.4%). Fat mass (FM) increased more in NCG than in ALG (15+/-4 vs. 3+/-3%), but gain in LBM was not different between groups. All 1RM results improved in both groups (6 12%), whereas 40 m sprint and CMJ remained unchanged, except for a significant decrease in 40 m sprint for the athletes in NCG. Athletes with nutritional guidance increased BW more, however, excess energy intake in a weight-gain protocol should be considered carefully due to undesirable increases in body fat. PMID- 23679147 TI - Endurance and sprint benefits of high-intensity and supramaximal interval training. AB - This study examined the effect of two different interval training programs-high intensity interval training (HIT) and supramaximal interval training (SMIT)-on measures of sprint and endurance performance. Physically active individuals (Females: n=32; age 19.3, s=2.2 years; mass 67.6, s=9.1 kg; stature 172.7, s=6.6 cm. Males: n=23; age 20.0, s=2.7 years; mass 71.3, s=8.3 kg; stature 176.6, s=5.8 cm) completed pre-testing that comprised (1) 3000 m time-trial, (2) 40 m sprint, and (3) repeated sprint ability (RSA-6*40 m sprints, 24 s active recovery) performance. Participants were then matched for average 3000 m running velocity (AV) and randomly assigned to one of three groups: (i) HIT, n=19, 4 min at 100% AV, 4 min passive recovery, 4-6 bouts per session; (ii) SMIT, n=20, 30 s at 130% AV, 150 s passive recovery, 7-12 bouts per session; and (iii) control group, n=16, 30 min continuous running at 75% AV. Groups trained three times per week for six weeks. When time to complete each test were compared among groups: (i) improvements in 3000 m time trial performance were greater following SMIT than continuous running, and (ii) improvements in 40 m sprint and RSA performance were greater following SMIT than HIT and continuous running. In addition, a gender effect was observed for the 3000 m time trial only, where females changed more following the training intervention than males. In summary, for concurrent improvements in endurance, sprint and repeated sprint performance, SMIT provides the greatest benefits for physically active individuals. PMID- 23679149 TI - Daily physical activity and sports participation among children from ethnic minorities in Denmark. AB - The purpose of this study was to investigate whether Danish children from immigrant backgrounds are less physically active than children from the ethnic majority, and to investigate the possible reasons for any differences found. Accelerometer measures of physical activity as well as questionnaire data about organised sports, family demography, resources and values were collected from 594 children of whom 67 had other ethnic background than Danish. Data were collected when the children were 6-7 years old and again later when the children were 9-10 years old. It was found that children from immigrant backgrounds were not less physically active than other children when their amounts of daily physical activity were measured by direct objective measures, despite their participation rate in organised sports being much lower. Using multiple logistic regression modelling, this study showed that lack of parental experience with organised sports and lack of economic/material resources explained much of the difference in sports participation. Children of immigrant background had significant lower participation in club sports but this did not affect their overall physical activity level. PMID- 23679148 TI - Internal social processes of discipline formation: the case of kinanthropometry. AB - In 1972, the term 'kinanthropometry', derived from the Greek words 'kinein' (to move), 'anthropos' (human) and 'metrein' (to measure), was launched in the international, Francophone journal Kinanthropologie by the Canadian William Ross and the Belgians, Marcel Hebbelinck, Bart Van Gheluwe and Marie-Louise Lemmens. The authors defined this neologism as 'the scientific discipline for the study of the size, shape, proportion, scope and composition of the human being and its gross motor functions'. Presenting a theoretical framework for the analysis of the internal social processes of discipline formation - derived from the social history-of-science tradition - this article critically examines whether kinanthropometry was indeed promoted and developed by its community members as a scientific discipline. Therefore, the focus will be on its conceptualisation and positioning within the field of kinanthropology/kinesiology and on its development by a scholarly association, i.e. the International Working Group on Kinanthropometry (IWGK). The strong emphasis of the kinanthropometry community on the standardisation of measurement techniques and its practical and professional application hampered its disciplinary development. Findings of this study could serve as a basis for future 'fundamental' investigations addressing questions of disciplinary development within the field(s) of physical education, kinesiology and sport science(s). PMID- 23679150 TI - Comparison of three models of actigraph accelerometers during free living and controlled laboratory conditions. AB - The aim of this study was to compare the outputs of three commonly used uniaxial Actigraph models (Actitrainer, 7164 and GT1M) under both free-living and controlled laboratory conditions. Ten adults (mean age = 24.7+/-1.1 years) wore the three Actigraph models simultaneously during one of day free-living and during a progressive exercise protocol on a treadmill at speeds between 1.5 and 5.5 miles per hour (mph). During free-living the three Actigraph models produced comparable outputs in moderate, vigorous and moderate-to-vigorous physical activity (MVPA) with effect sizes typically <0.2, but lower comparability was seen in sedentary and light categories, as well as in total step counts (effect sizes often >0.30). In controlled conditions, acceptable comparability between the three models was seen at all treadmill speeds, the exception being walking at 1.5 mph (mean effect size = 0.48). It is concluded that care should be taken if different Actigraph models are to be used to measure and compare light physical activity, step counts and walking at very low speeds. However, using any of these three different Actigraph models to measure and compare levels of MVPA in free living adults seems appropriate. PMID- 23679151 TI - Pelvic floor muscle problems mediate sexual problems in young adult rape victims. AB - INTRODUCTION: Prior studies have addressed sexual abuse and sexual function in adult women. No studies have focused on the effect of adolescence rape on sexual functioning. AIM: To investigate the effect of rape on sexual problems and on pelvic floor problems, as well as the mediating role of pelvic floor problems on sexual problems, in a homogenous group of victims of adolescence rape without a history of childhood sexual, physical, and/or emotional abuse. MAIN OUTCOME MEASURES: Sexual functioning and pelvic floor functioning were assessed using self-report questionnaires. METHODS: In this cross-sectional study, a group of 89 young women aged 18-25 years who were victimized by rape in adolescence was compared with a group of 114 nonvictimized controls. The rape victims were treated for posttraumatic stress disorder (PTSD) 3 years prior to participation in the study. RESULTS: Three years posttreatment, rape victims were 2.4 times more likely to have a sexual dysfunction (lubrication problems and pain) and 2.7 times more likely to have pelvic floor dysfunction (symptoms of provoked vulvodynia, general stress, lower urinary tract, and irritable bowel syndrome) than nonvictimized controls. The relationship between rape and sexual problems was partially mediated by the presence of pelvic floor problems. Rape victims and controls did not differ with regard to sexual activities. CONCLUSIONS: Rape victims suffer significantly more from sexual dysfunction and pelvic floor dysfunction when compared with nontraumatized controls, despite the provision of treatment for PTSD. Possibly, physical manifestations of PTSD have been left unaddressed in treatment. Future treatment protocols should consider incorporating (physical or psychological) treatment strategies for sexual dysfunction and/or pelvic floor dysfunction into trauma exposure treatments. PMID- 23679153 TI - Decision making and action implementation: evidence for an early visually triggered motor activation specific to potential actions. AB - To make a decision may rely on accumulating evidence in favor of one alternative until a threshold is reached. Sequential-sampling models differ by the way of accumulating evidence and the link with action implementation. Here, we tested a model's prediction of an early action implementation specific to potential actions. We assessed the dynamics of action implementation in go/no-go and between-hand choice tasks by transcranial magnetic stimulation of the motor cortex (single- or paired-pulse TMS; 3-ms interstimulus interval). Prior to implementation of the selected action, the amplitude of the motor evoked potential first increased whatever the visual stimulus but only for the hand potentially involved in the to-be-produced action. These findings suggest that visual stimuli can trigger an early motor activation specific to potential actions, consistent with race-like models with continuous transmission between decision making and action implementation. PMID- 23679154 TI - Holistic systems biology approaches to molecular mechanisms of human helper T cell differentiation to functionally distinct subsets. AB - Current knowledge of helper T cell differentiation largely relies on data generated from mouse studies. To develop therapeutical strategies combating human diseases, understanding the molecular mechanisms how human naive T cells differentiate to functionally distinct T helper (Th) subsets as well as studies on human differentiated Th cell subsets is particularly valuable. Systems biology approaches provide a holistic view of the processes of T helper differentiation, enable discovery of new factors and pathways involved and generation of new hypotheses to be tested to improve our understanding of human Th cell differentiation and immune-mediated diseases. Here, we summarize studies where high-throughput systems biology approaches have been exploited to human primary T cells. These studies reveal new factors and signalling pathways influencing T cell differentiation towards distinct subsets, important for immune regulation. Such information provides new insights into T cell biology and into targeting immune system for therapeutic interventions. PMID- 23679155 TI - Emotion recognition: the role of featural and configural face information. AB - Several studies investigated the role of featural and configural information when processing facial identity. A lot less is known about their contribution to emotion recognition. In this study, we addressed this issue by inducing either a featural or a configural processing strategy (Experiment 1) and by investigating the attentional strategies in response to emotional expressions (Experiment 2). In Experiment 1, participants identified emotional expressions in faces that were presented in three different versions (intact, blurred, and scrambled) and in two orientations (upright and inverted). Blurred faces contain mainly configural information, and scrambled faces contain mainly featural information. Inversion is known to selectively hinder configural processing. Analyses of the discriminability measure (A') and response times (RTs) revealed that configural processing plays a more prominent role in expression recognition than featural processing, but their relative contribution varies depending on the emotion. In Experiment 2, we qualified these differences between emotions by investigating the relative importance of specific features by means of eye movements. Participants had to match intact expressions with the emotional cues that preceded the stimulus. The analysis of eye movements confirmed that the recognition of different emotions rely on different types of information. While the mouth is important for the detection of happiness and fear, the eyes are more relevant for anger, fear, and sadness. PMID- 23679152 TI - Comparative analysis of the repertoire of G protein-coupled receptors of three species of the fungal genus Trichoderma. AB - BACKGROUND: Eukaryotic organisms employ cell surface receptors such as the seven transmembrane G protein-coupled receptors (GPCRs) as sensors to connect to the environment. GPCRs react to a variety of extracellular cues and are considered to play central roles in the signal transduction in fungi. Several species of the filamentous ascomycete Trichoderma are potent mycoparasites, i.e. can attack and parasitize other fungi, which turns them into successful bio-fungicides for the protection of plants against fungal phytopathogens. The identification and characterization of GPCRs will provide insights into how Trichoderma communicates with its environment and senses the presence of host fungi. RESULTS: We mined the recently published genomes of the two mycoparasitic biocontrol agents Trichoderma atroviride and Trichoderma virens and compared the identified GPCR-like proteins to those of the saprophyte Trichoderma reesei. Phylogenetic analyses resulted in 14 classes and revealed differences not only among the three Trichoderma species but also between Trichoderma and other fungi. The class comprising proteins of the PAQR family was significantly expanded both in Trichoderma compared to other fungi as well as in the two mycoparasites compared to T. reesei. Expression analysis of the PAQR-encoding genes of the three Trichoderma species revealed that all except one were actually transcribed. Furthermore, the class of receptors with a DUF300 domain was expanded in T. atroviride, and T. virens showed an expansion of PTH11-like receptors compared to T. atroviride and T. reesei. CONCLUSIONS: Comparative genome analyses of three Trichoderma species revealed a great diversity of putative GPCRs with genus- and species- specific differences. The expansion of certain classes in the mycoparasites T. atroviride and T. virens is likely to reflect the capability of these fungi to establish various ecological niches and interactions with other organisms such as fungi and plants. These GPCRs consequently represent interesting candidates for future research on the mechanisms underlying mycoparasitism and biocontrol. PMID- 23679156 TI - Occupational health literacy and work-related injury among U.S. adolescents. AB - Building on the concept of 'health literacy' used in the U.S., we developed an analogous measure specific to safety in the workplace labeled 'occupational health literacy' (OHL) and investigated whether OHL is a protective factor against work-related injury (WRI) among adolescents. Using cross-sectional survey data from 2262 14 to 18-year olds in five high schools across the US, we found that OHL (level of occupational safety and health (OSH) information and training received combined with knowledge and awareness of OSH information and concepts) is positively associated with WRI prevalence. This association appears to be largely driven by the OHL subscale on respondents' receipt of safety training, which likely represents job hazardousness and may be overwhelming any protective effect of OHL on work injury. This exploratory study has shown that more precise measurement of OHL and confounding variables (job hazardousness) will be crucial in further studies exploring a OHL-WRI relationship. PMID- 23679157 TI - Epidemiology of ophthalmologic disease associated with erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis in hospitalized children in the United States. AB - The objective of the current study was to characterize the epidemiology and resource use of U.S. children hospitalized with ophthalmologic disease secondary to erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). We studied children ages 5 to 19 years hospitalized in 2005 in 11 states, encompassing 38% of the U.S. pediatric population. Using International Classification of Diseases, Ninth Revision, Clinical Modification codes, we identified admissions of children with EM, SJS, or TEN and the presence of concurrent ophthalmologic disease, analyzed patient and hospitalization characteristics, and generated age- and sex-adjusted national estimates. We identified 460 children admitted with EM, SJS, or TEN, corresponding to 1,229 U.S. hospitalizations in 2005. Of the children with EM, SJS, or TEN, 60 (13.0%) had ophthalmologic disease, primarily (90.0%) disorders of the conjunctiva. Children with the highest proportions of ophthalmologic disease included those with mycoplasma pneumonia (26.7%), herpes simplex virus (15.6%), upper respiratory infection (13.9%), and lower respiratory infection (13.7%). Individuals with EM, SJS, or TEN and ophthalmologic disease were more likely than those without ophthalmologic disease to receive intensive care unit care (28.3% vs 17.0%, p = 0.03) and to be admitted to a children's hospital (63.3% vs 48.8%, p = 0.03). Ophthalmologic disease was also associated with a significantly longer median length of stay (6.0 days, interquartile range [IQR] 3-9 days vs 3.0 days, IQR 2-6 days, p < 0.001) and median hospital cost ($7,868, IQR $3,539-$17,440 vs $2,969, IQR $1,603-$8,656, p < 0.001). In children with EM, SJS, or TEN, ophthalmologic disease was most common in those with concurrent Mycoplasma pneumoniae and herpes simplex virus infections. Ophthalmologic disease was associated with considerably higher inpatient resource use in this population. Children with EM, SJS, or TEN should be screened and treated early for ophthalmologic disease to prevent morbidity and minimize long-term sequellae. PMID- 23679158 TI - Significant others, situations and infant feeding behaviour change processes: a serial qualitative interview study. AB - BACKGROUND: Exclusive breastfeeding until six months followed by the introduction of solids and continued breastfeeding is recommended by the World Health Organisation. The dominant approach to achieving this has been to educate and support women to start and continue breastfeeding rather than understanding behaviour change processes from a broader perspective. METHOD: Serial qualitative interviews examined the influences of significant others on women's feeding behaviour. Thirty-six women and 37 nominated significant others participated in 220 interviews, conducted approximately four weekly from late pregnancy to six months after birth. Responses to summative structured questions at the end of each interview asking about significant influences on feeding decisions were compared and contrasted with formative semi-structured data within and between cases. Analysis focused on pivotal points where behaviour changed from exclusive breastfeeding to introducing formula, stopping breastfeeding or introducing solids. This enabled us to identify processes that decelerate or accelerate behaviour change and understand resolution processes afterwards. RESULTS: The dominant goal motivating behaviour change was family wellbeing, rather than exclusive breastfeeding. Rather than one type of significant other emerging as the key influence, there was a complex interplay between the self-baby dyad, significant others, situations and personal or vicarious feeding history. Following behaviour change women turned to those most likely to confirm or resolve their decisions and maintain their confidence as mothers. CONCLUSIONS: Applying ecological models of behaviour would enable health service organisation, practice, policy and research to focus on enhancing family efficacy and wellbeing, improving family-centred communication and increasing opportunities for health professionals to be a constructive influence around pivotal points when feeding behaviour changes. A paradigm shift is recommended away from the dominant approach of support and education of individual women towards a more holistic, family-centred narrative approach, whilst acknowledging that breastfeeding is a practical skill that women and babies have to learn. PMID- 23679159 TI - Double crown-retained maxillary overdentures: 5-year follow-up. AB - BACKGROUND: There is a lack of data concerning implant-supported overdentures (IODs) retained by double crowns in the edentulous maxilla. PURPOSE: To perform a retrospective evaluation of clinical outcomes (survival/success rates) of maxillary overdentures retained on four implants via double crowns. MATERIAL AND METHODS: Between 1993 and 2011, 28 patients with edentulous maxillae were restored with overdentures supported by four implants with a Morse taper connection (Ankylos, Dentsply Friadent, Mannheim, Germany) and double crowns according to the Marburg Double Crown (MDC) technique in a private practice. For retrospective evaluation of implant and prosthetic survival (in situ criterion) and success (event-free observational period), only patients attending a professional maintenance program were included (n = 20). RESULTS: Twenty patients (13 female/ seven male, mean age: 63.45 +/- 7.18 years) with 80 implants met the inclusion criteria. The mean follow-up period was 5.64 +/- 3.50 years. One implant was lost (cumulative survival rate: 98.75%). Eight implants (10.1%) in two patients (10%) showed peri-implantitis; both patients were active smokers (cumulative success rate: 88.75%). All dentures were still functional (prosthetic survival rate 100%) at the time of investigation. Technical maintenance procedures (e.g., abutment loosening, screw loosening, acrylic fracture or relining) were required at a rate of 0.222/patient-year. CONCLUSIONS: Within the limitations of this study, we conclude that MDC-IODs are a promising treatment alternative for edentulous maxillae offering high implant and prosthesis survival rates > 98% and a limited incidence of biological and technical complications after a mean observational period of >5 years. PMID- 23679160 TI - Synthesis, characterization, protonation reactions, and electrochemistry of substituted open-chain pentapyrroles and sapphyrins in nonaqueous media. AB - Open-chain pentapyrroles were isolated as side-products from the synthesis of triaryl-corroles and then converted to the corresponding sapphyrins by catalytic oxidation in acidic media. The investigated compounds were characterized by UV vis and (1)H NMR spectroscopy, mass spectrometry, electrochemistry, and spectroelectrochemistry and are represented as (Ar)4PPyH3 and (Ar)4SH3, where Ar is a F(-) or Cl(-) substituted phenyl group, PPy is a trianion of the open-chain pentapyrrole, and S is a trianion of the sapphyrin. Cyclic voltammetry and thin layer UV-vis spectroelectrochemistry measurements were carried out in PhCN and CH2Cl2 containing 0.1 M tetra-n-butylammonium perchlorate. The open-chain pentapyrroles undergo two reversible one-electron reductions and two reversible one-electron oxidations to generate [(Ar)PPyH3](-), [(Ar)PPyH3](2-), [(Ar)PPyH3](+), and [(Ar)PPyH3](2+) which were spectroscopically characterized. The corresponding sapphyrins exhibit two or three reversible one-electron oxidations in PhCN, but the reductions of these compounds are irreversible because of coupled chemical reactions following electron transfer. Comparisons are made between redox potentials and spectral properties of the open-chain pentapyrroles, sapphyrins, and structurally related corroles. Protonation of the open-chain pentapyrroles and sapphyrins was also carried out in CH2Cl2, and equilibrium constants were calculated by monitoring the spectral changes during titrations with trifluoroacetic acid. The pentapyrroles undergo a simultaneous two-proton addition to generate [(Ar)4PPyH5](2+) while the sapphyrins undergo two stepwise single proton additions to give [(Ar)4SH4](+) and [(Ar)4SH5](2+), respectively. PMID- 23679161 TI - First Japanese case of Pierson syndrome with mutations in LAMB2. AB - Pierson syndrome (OMIM 609049) is typically characterized by congenital nephritic syndrome and peculiar ocular anomalies with microcoria. It is caused by mutations in LAMB2, which encodes laminin beta2. Approximately 50 mutations of LAMB2 from approximately 40 unrelated families have been identified; however, most of them were from Western countries. Although three patients in Asia with mutations of LAMB2 have been reported, they were not typical cases. We report the first Japanese case of Pierson syndrome with proven causative LAMB2 mutations. She presented with congenital nephrotic syndrome and bilateral microcoria at birth, and developed end-stage renal disease at 2 months of age. This is the first report of a typical case from Asia. LAMB2 analysis by direct sequencing revealed the compound heterozygous mutations c.3974_3975insA (p.N1325KfsX1331, maternal, novel) in exon 25 and c.4519C>T (p.Q1507X, paternal) in exon 27. The phenotype due to LAMB2 mutations appears to be similar between different ethnic groups. PMID- 23679162 TI - Elizabethkingia meningoseptica: Emergent bacteria causing pneumonia in a critically ill child. AB - Elizabethkingia meningoseptica is an unusual, highly resistant, gram- negative bacillus. While E. meningoseptica-associated meningitis outbreaks have been well documented in hospital neonatal wards and among immunocompromised adults, reports describing this microorganism in critically ill children are scarce. The purpose of this report was to describe a case of a 3 year-old girl who developed pneumonia caused by E. meningoseptica in the setting of previous use of broad spectrum antibiotics and to review the pediatric literature regarding this pathogen. PMID- 23679163 TI - Hallopeau-Siemens dystrophic epidermolysis bullosa due to homozygous 5818delC mutation in the COL7A gene. AB - Epidermolysis bullosa (EB) is a group of inherited mechanobullous skin disease. The dystrophic EB (DEB), one subtype of EB, is inherited in an autosomal dominant DEB or in an autosomal recessive (RDEB). DEB is caused by mutations in the COL7A1 gene encoding type VII collagen, the major component of anchoring fibrils. Over 300 pathogenic mutations have been detected within COL7A in DEB. Patients with the Hallopeau-Siemens type (HS-RDEB), most severe form of DEB, frequently have premature termination codon (PTC) mutations on both alleles. PTC mutations on both alleles result in depleted mRNA and alpha1 helix, and failure to form the triple helix structure characteristic of type VII collagen. As patients with HS RDEB usually have a pair of heterozygous PTC mutations, there have been rarely reported homozygous ones in HS-RDEB. We report the first case of HS-RDEB homozygous PTC mutations of 5818delC in both COL7A1 alleles. This case report suggests the positional effect of PTC mutations and vigilance against early infantile death in EB including HS-RDEB. PMID- 23679164 TI - Coronary artery dilatation and vasculitis in a case of rabies: similarity with Kawasaki disease? AB - A 9-year-old boy died of rabies complications. We report the unusual combination between rabies, coronary dilatation on echocardiography and coronary vasculitis documented upon autopsy. In the search for the etiological agent of Kawasaki disease, we suggest that a viral infection with potential antigenic similarities to rabies virus should be entertained. PMID- 23679165 TI - Rapidly progressive and fatal neurocutaneous melanosis presenting as recurrent headache. AB - Neurocutaneous melanosis is an extremely rare disease characterized by large or multiple congenital melanocytic nevi and benign or malignant proliferation of melanocytes in the central nervous system. Neurological manifestations usually develop during the first three years of life and the prognosis of patients with NCM who manifest neurological symptoms is very poor. Here we describe a 9-year old girl who manifested neurological symptoms caused by communicating hydrocephalus and died of proliferation of melanocytes in the central nervous system 11 months after the initial symptoms. Serum and cerebrospinal fluid 5-S-CD levels could be a useful marker of disease progression, even in patients with NCM without apparent malignant findings at initial biopsy. PMID- 23679166 TI - Successful use of BiPAP in infants with congenital myotonic dystrophy. AB - Reported herein are two cases of severe phenotype of congenital myotonic dystrophy (CDM) with presentation of respiratory insufficiency at birth. The infants were successfully managed with bi-level positive airway pressure (BiPAP) via nasal mask. The use of BiPAP in infants with CDM has not been reported before. The rationale for using BiPAP is discussed. BiPAP may be more effective than continuous positive airway pressure in managing respiratory insufficiency, especially in infants with the more severe phenotype of CDM. PMID- 23679167 TI - Long-term survivor of relapsed stage IV malignant rhabdoid tumor of the kidney. AB - The prognosis for metastatic malignant rhabdoid tumor (MRT) is poor, and metastatic (stage IV) MRT was resistant to conventional treatment, with less than 20% of cure rate. Moreover, there have been no reports of patients who have survived relapsed stage IV MRT. Here we report a long-term survivor of relapsed MRT with lung metastasis at diagnosis. He was diagnosed as MRT of the kidney at 5 month-old. After resection of the renal tumor, he was treated with ICE (ifosfamide, carboplatin, and etoposide), total abdominal irradiation 10.8 Gy and high-dose chemotherapy using thiotepa and melphalan. Six months after initial treatment, a relapse in the lung was detected, and he received chemotherapy including doxorubicin/pirarubicin for 78 weeks. He is alive at five years of follow up, without any evidence of disease. Our report suggests the important role of anthracycline in treatment of MRT. PMID- 23679168 TI - Successful coil embolization for life-threatening hemorrhage in childhood leukemia induction therapy. AB - An 11-year-old boy was experienced severe life-threatening hemorrhage from a branch of the superior mesenteric artery (SMA) after acute lymphoblastic leukemia induction therapy. The patient had a history of attention deficit hyperactivity disorder (ADHD), diagnosed at 3 years of age. Subsequent to discontinuing his psychotropic medication, the patient's mental status deteriorated and treatment with midazolam for 3 weeks was necessary to allow the completion of the leukemia induction regimen. On day 51, although there was no indication of thrombocytopenia or a coagulation disorder, the patient began to hemorrhage suddenly from anal with resulting hypovolemic shock, and large-volume blood transfusion was initiated. Although upper and lower endoscopy failed to determine the location of the hemorrhage, angiography enabled us to determine that it was a branch of the SMA (the middle colic artery #6), and selective arterial embolization was used to arrest the bleeding. There could have been underlying causes, such as, a probable malformation or aneurysm in that area, although there was no indication before or after the event. This is a rare case of arterial hemorrhage from a branch of the SMA that occurred in a pediatric patient idiopathically during the induction therapy of leukemia. PMID- 23679169 TI - Diagnosis of epilepsy using an implantable loop recorder in a child with long-QT syndrome type 3. AB - We describe a case of a 10-year-old girl with genetically confirmed LQTS type 3 developed recurrent episodes of loss of consciousness due to epilepsy that was diagnosed by using an implantable loop recorder (ILR). PMID- 23679170 TI - Osteoma cutis. PMID- 23679171 TI - Severe post-streptococcal acute glomerulonephritis and periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. PMID- 23679172 TI - Association between neonatal hyperbilirubinemia and UDP-glucuronosyltransferase 1A1 gene polymorphisms. PMID- 23679173 TI - Endoscopic papillary balloon dilation for a 7-year-old girl with choledocholithiasis. AB - A 7-year-old girl was referred to our hospital for severe abdominal pain and elevated serum levels of amylase and aminotransferase. Radiological examinations revealed choledocholithiasis. EPBD was performed under intravenous anesthesia using midazolam and ketamine chloride. After fluoroscopic confirmation of a bile duct stone, a dilation balloon (30 mm-long, 8 mm-diameter) was passed over the guidewire and placed across the papilla. The balloon was gradually inflated until the notch created by the papillary sphincter disappeared. At 4 atm, the notch disappeared and the pressure was maintained for 15 s. Stone extraction was performed by using a retrieval balloon catheter. Abdominal pain disappeared immediately after EPBD, and she resumed oral intake 2 days after EPBD. In conclusion, EPBD may be a safe and effective technique for the treatment of choledocholithiasis in pediatric patients. EPDB should be selected as a treatment for pediatric choledocholithiasis in view of its advantages of preserving papillary function. PMID- 23679174 TI - Continuous regional arterial infusion effective for children with acute necrotizing pancreatitis even under neutropenia. AB - Severe acute pancreatitis is one of the critical conditions that may develop in children with cancer. The leading cause of death due to acute pancreatitis is infectious pancreatitis or circulation collapse. Therefore, patients who develop acute pancreatitis while undergoing chemotherapy or after hematopoietic transplantation are at risk for a life-threatening and fatal course. We treated 140 patients with malignancy from April 2002 to March 2009 at our hospital and encountered 3 patients under neutropenia who developed severe acute pancreatitis. Two of them were successfully treated with continuous regional arterial infusion of a protease inhibitor and antibiotic even under agranulocytosis. Another patient was treated with conventional therapy with intravenous antibiotics plus a protease inhibitor and total or partial parenteral nutrition. Even though the two patients treated with continuous regional arterial infusion presented much more severe conditions, their symptoms resolved earlier. In conclusion, acute pancreatitis is one of the severe complications of childhood malignancy. Even under agranulocytosis, continuous regional arterial infusion of a protease inhibitor and antibiotic was well tolerated and effective among our cases and might reduce early death due to pancreatitis. PMID- 23679175 TI - Rare case of an abdominal mass presenting as acute abdomen: torsion of the vermiform appendix. AB - Torsion of the vermiform appendix is a rarely observed acute abdominal emergency. The clinical manifestations are similar to acute appendicitis. It should be included in the differential diagnosis if a patient presents with intermittent abdominal pain and an acute abdominal emergency. Here, we describe a 4-year-old male patient with a mass located in the right lower abdominal quadrant, whose clinical findings were consistent with an acute abdomen. The gangrenous appendix was found in the pelvic cavity and its stump was twisted clockwise. A 1.5-cm fecalith was detected in the appendix lumen and appendectomy was performed. PMID- 23679176 TI - Girl with xanthogranulomatous pyelonephritis and bronchiectasis: case report. AB - Xanthogranulomatous pyelonephritis (XGP) is a rare chronic inflammatory disorder of the kidney. Infiltration to lung and liver can occur. We present a rare complication of locally invasive XGP extending beyond the diaphragm to the lung to cause bronchiectasis in an adolescent girl with chronic productive cough, weight loss and no urinary symptoms. The patient underwent open left radical nephrectomy, where it was noted that the left kidney lay very high with significant perinephric inflammation and was densely adherent to the diaphragm and partially adherent to the spleen. XGP was confirmed on histology. PMID- 23679177 TI - Peritoneal tuberculosis due to multidrug-resistant Mycobacterium tuberculosis. AB - The emergence of drug-resistant Mycobacterium tuberculosis has been widely reported throughout the world, but there are very few data regarding children. We describe the case of a 14-year-old Peruvian adolescent who had been living in Italy since the age of 8 years and was diagnosed as having peritoneal tuberculosis (TB). While she was receiving first-line anti-TB therapy, she developed pyrazinamide-associated thrombocytopenia and cultures revealed a multidrug-resistant strain of Mycobacterium tuberculosis. Pyrazinamide, rifampicin and isoniazid were replaced by moxifloxacin, which was continued for 9 months together with ethambutol. The patient recovered without experiencing any drug-related adverse event or the recurrence of TB in the following year. In conclusion, this case illustrates some of the problems that can arise when multidrug-resistant TB has to be treated in children and adolescents, and also highlights the fact that further studies are needed to clarify which drugs should be used and for how long. PMID- 23679178 TI - Subcutaneous fat necrosis after selective head cooling in an infant. AB - Hypoxic-ischemic encephalopathy in neonates causes irreversible damage to tissue and organs and results in multiple organ failure and poor outcome. Therapeutic hypothermia is the most effective therapy in neonates with hypoxic-ischemic encephalopathy. We report here a case of subcutaneous fat necrosis (SCFN) after therapeutic hypothermia by selective head cooling. Selective head cooling was provided for 72 h after birth. SCFN developed on the patient's cheeks and back at the age of 21 days. Thus, SCFN may be caused by selective head cooling, similarly to whole-body cooling. PMID- 23679179 TI - Glycemic variability in preterm infants receiving intermittent gastric tube feeding: report of three cases. AB - Late-onset hypoglycemia (day 12-16, blood glucose <50 mg/dL) was detected in three preterm infants (birthweight 998-1780 g; gestational age 27-30 weeks) by routine screening. All infants showed high serum insulin levels and extremely low ketone levels at the time of hypoglycemia. Continuous glucose monitoring was conducted at 31-34 weeks' postconceptual age when the infants were receiving intermittent gastric tube feeding with no intravenous glucose infusion. The continuous glucose monitoring results showed characteristic postprandial glucose increases and subsequent sharp deceases along with many hyper- and hypoglycemic events. This fluctuating pattern disappeared at 38-40 weeks' postconceptual age. These observations suggest that prolonged insulin oversecretion may be associated with early aggressive intravenous nutrition, and that large glycemic variability is a common feature of tube-fed preterm infants that can be explained by immature glucose homeostasis. PMID- 23679180 TI - Osteoid osteoma mimicking Brodie's abscess in a 13-year-old girl. AB - Osteoid osteoma is a solitary, benign lesion of bone causing significant nocturnal pain. Magnetic resonance imaging (MRI), computed tomography (CT), and bone scan are commonly used in this diagnosis. A case of osteoid osteoma of the distal femur mimicking chronic osteomyelitis with Brodie's abscess is reported and discussed. Initial radiographs and MRI showed a lesion of the distal femur consistent with subacute osteomyelitis with a Brodie's abscess. Because primary malignant tumor could not be eliminated, surgical biopsy was carried out. Histological examination showed a typical nidus consistent with the diagnosis of osteoid osteoma. Subacute osteomyelitis (Brodie's abscess) may be difficult to distinguish from other malignant or benign bone lesions as osteoid osteoma. CT usually is recommended as the best imaging procedure to identify the nidus and confirm the diagnosis. MRI also can be used for this purpose. Surgical biopsy remains mandatory for unclear lesions before deciding on appropriate treatment. PMID- 23679182 TI - Mask face: bilateral simultaneous facial palsy in an 11-year-old boy. AB - Bilateral facial paralysis is an uncommon clinical entity especially in the pediatric age group and occurs frequently as a manifestation of systemic disease. The most important causes are trauma, infectious diseases, neurological diseases, metabolic, neoplastic, autoimmune diseases and idiopathic disease (Bell's palsy). We report a case of an 11-year-old boy presenting with bilateral simultaneous peripheral facial paralysis. All possible infectious causes were excluded and the patient was diagnosed as having Bell's palsy (idiopathic). The most important approach in these cases is to rule out a life-threatening disease. PMID- 23679181 TI - Japanese boy with maturity-onset diabetes of the young type 3 who developed diabetes at 19 months old. AB - Maturity-onset diabetes of the young type 3 (MODY3) is caused by hepatocyte nuclear factor 1alpha gene mutation and is clinically characterized by young onset and insufficient insulin secretion. We report a 19-month-old Japanese boy with a family history of young-onset diabetes who was initially diagnosed with type 1 diabetes. Mutational analysis of the hepatocyte nuclear factor 1alpha gene revealed a novel heterozygous frameshift mutation (c.593delA p.Lys198fs) resulting in a truncated protein in the patient and his father. The patient was diagnosed as having MODY3 and was successfully treated with insulin glargine. We could not determine the genetic or environmental factors to explain the difference in the age of disease onset within the same family. This is the youngest case of a MODY3 child presenting with overt diabetes. Our experience suggests that clinicians should always consider the possible diagnosis of MODY3 in a diabetic child with a family history of young-onset diabetes and should perform molecular investigations. PMID- 23679183 TI - Chylopericardium and chylothorax: unusual mechanical complications of central venous catheters. AB - Obstruction and thrombosis of major systemic veins can occur due to indwelling central venous catheters. If obstruction of the innominate vein or superior vena cava occurs, lymphatic drainage can be impaired due to an increase in pressure in the thoracic duct and lymphatics. We describe a case where superior vena cava syndrome, chylopericardium and chylothorax occurred in a 16-year-old girl due to an indwelling central venous catheter. This was successfully treated with removal of the line, anticoagulation and angioplasty of the innominate vein and superior vena cava. PMID- 23679184 TI - Congenital chylothorax and pulmonary hypertension complicated with heart failure and hepatopathy. AB - Respiratory difficulty resulting from congenital chylothorax is usually relieved by postnatal thoracentesis, closed chest drainage, and oxygen therapy. However, early occurrence of congenital chylothorax or accumulation of a large amount of chylous fluid sometimes leads to pulmonary hypoplasia or persistent pulmonary hypertension of the newborn, which requires further customized mechanical ventilatory support. In these cases, conventional mechanical ventilation is primarily used during initial treatment and is later replaced by high-frequency ventilation, but the advantages of inhaled nitric oxide treatment have rarely been described. This case suggests the benefits of inhaled nitric oxide in patients with congenital chylothorax, even when mechanical ventilation cannot improve respiratory distress because of severe pulmonary hypertension of the newborn leading to right cardiac dysfunction and possibly cholestasis. PMID- 23679185 TI - Recombination of allyl radicals in the high temperature fall-off regime. AB - The recombination of allyl radicals (C3H5), generated from the dissociation of 1,5-hexadiene or allyl iodide dilute in krypton, has been investigated in a diaphragmless shock tube using laser schlieren densitometry, LS, (900-1700 K, 10 +/- 1, 29 +/- 3, 57 +/- 3, and 120 +/- 4 Torr). The LS density gradient profiles were simulated and excellent agreement was found between simulations and experimental profiles. Rate coefficients for C3H5I -> C3H5 + I and C3H5 + C3H5 -> C6H10 were obtained and showed strong fall-off. Second order rate coefficients for allyl radical recombination were determined as k(1a,124Torr) = (2.6 +/- 0.8) * 10(55)T( -12.995) exp(-8426/T), k(1a,57Torr) = (1.7 +/- 0.5) * 10(60)T( -14.49) exp(-9344/T), and k(1a,30Torr) = (7.5 +/- 2.3) * 10(66)T( -15.935) exp(-10192/T) cm(3) mol(-1)s(-1). The contribution of a disproportionation channel in allyl radical reactions was assessed, and the best agreement was obtained with no more than 5% disproportionation. Notably, because both the forward and back reactions of C6H10 ? C3H5 + C3H5 were measured, utilizing two different precursors, the equilibrium constant of this reaction could be found, suggesting an entropy of formation of 1,5-hexadiene, 87.3 cal mol(-1 )K(-1), which is significantly smaller than that group additivity predicts, but larger than other reference literature values. PMID- 23679186 TI - Reproductive and maternity health care services in Finland: perceptions and experiences of Somali-born immigrant women. AB - OBJECTIVE: To explore immigrant Somali women's experiences of reproductive and maternity health care services (RMHCS) and their perceptions about the service providers. DESIGN: Five focus group discussions were conducted from April 1999 to June 2000 using a purposeful sampling strategy in order to reach multiparous female Somali-born Immigrants with experiences from the maternity health care in Finland. PARTICIPANTS: A total of 70 married Somali women aged 18-50 and mother of 2-10 children were studied. Among them, 18 came from Kenya, 32 from Mogadishu and 20 from Hargeysa. SETTINGS: Of the participants, 45 were living in the city of Vantaa, 22 in the city of Helsinki and 13 in the city of Turku. RESULTS: Participants were satisfied with the RMHCS they received in Finland. Despite their satisfaction, the health care providers' social attitudes towards them were perceived as unfriendly, and communication as poor. CONCLUSIONS: The women's experiences revealed that they have access to good quality RMHCS in Finland. While their experiences are significant, their perceptions are important for physicians, nurses and midwives in order to achieve culturally competent care. PMID- 23679187 TI - Does prenatal nicotine exposure alter the brain's response to nicotine in adolescence? A neuroanatomical analysis. AB - This study examined changes in dendritic morphology and spine density in multiple brain regions [Zilles' areas: (i) the Cg3 region of the anterior cingulate cortex or the medial prefrontal cortex, layer III (Cg3); (ii) the dorsal agranular insular cortex, layer III (AID); (iii) the PAR I region of the parietal cortex, layer III (Par1) and (iv) the nucleus accumbens (NAc)]of Long-Evans rats following exposure to nicotine prenatally, in late adolescence, or both prenatally and in adolescence. Prenatal nicotine exposure induced enduring changes in neuroanatomical organisation that varied between male and female offspring, with males exhibiting increased dendritic complexity of neurons in AID and NAc whereas females experienced increased dendritic complexity in Par1 but decreased dendritic complexity of neurons in NAc. Similarly, nicotine given in late adolescence dramatically reorganised neural circuitry of both male and female offspring, with males exhibiting decreased dendritic complexity of neurons in Par1 and Cg3 but increased dendritic complexity in AID, and females exhibiting decreased dendritic complexity in Cg3 and NAc but increased complexity in AID. Exposure to nicotine both prenatally and in adolescence produced few neuroanatomical parameters that demonstrated a prenatal experience * adolescent drug administration interaction. Females showed additive effects in Par1, Cg3 and NAc whereas males demonstrated additive effects only in AID. Thus, the timing of nicotine exposure produced differential effects on cerebral organisation in a regionally specific manner. PMID- 23679189 TI - Efficient cobalt-catalyzed oxidative conversion of lignin models to benzoquinones. AB - Phenolic lignin model monomers and dimers representing the primary substructural units of lignin were successfully oxidized to benzoquinones in high yield with molecular oxygen using new Co-Schiff base catalysts bearing a bulky heterocyclic nitrogen base as a substituent. This is the first example of a catalytic system able to convert both S and G lignin model phenols in high yield, a process necessary for effective use of lignin as a chemical feedstock. PMID- 23679188 TI - Ghrelin suppression is associated with weight loss and insulin action following gastric bypass surgery at 12 months in obese adults with type 2 diabetes. AB - Roux-en-Y gastric bypass (RYGB) surgery reverses type 2 diabetes mellitus (T2DM) in approximately 80% of patients. Ghrelin regulates glucose homeostasis, but its role in T2DM remission after RYGB surgery is unclear. Nine obese T2DM subjects underwent a mixed meal tolerance test before and at 1 and 12 months after RYGB surgery. Changes in ghrelin, body weight, glucagon-like polypeptide-1 (GLP-1, glucose tolerance and insulin sensitivity (IS) were measured. At 1 month, body weight, glycaemia and IS were improved, while ghrelin concentrations were reduced (p < 0.05). After 12 months, body weight and fasting glucose were reduced (30 and 16%, respectively; p < 0.05) and IS was enhanced (threefold; p < 0.05). Ghrelin suppression improved by 32% at 12 months (p < 0.05), and this was associated with weight loss (r = 0.72, p = 0.03), enhanced IS (r = -0.78, p = 0.01) and peak postprandial GLP-1 (r = -0.73, p = 0.03). These data suggest that postprandial ghrelin suppression may be part of the mechanism that contributes to diabetes remission after RYGB surgery. PMID- 23679190 TI - The development and validation of a brief Quality of Sexual Experience (QSE) scale: results from a nationally representative sample of men and women in the United States. AB - INTRODUCTION: Much scientific research focuses on assessing and understanding individuals' perceptions of sexual pleasure, enjoyment and satisfaction. Many existing measures of pleasure and satisfaction provide valuable information but are limited in their ability to assess event-level quality. AIMS: To develop a scale for measuring the event-level quality of a sexual experience that could be used regardless of the age, gender, sexual orientation, and relationship status of the individual and across sexual activity types. METHODS: Interviews about the measurement of sexual quality and pleasure were conducted with 15 experts in the field of sexual health and informed the development of an event-level scale to measure the quality of sexual experiences. Scale items were administered to a cross-sectional nationally representative probability survey of Americans ages 18 to 60. MAIN OUTCOME MEASURES: Socio-demographic items; Quality of Sexual Experience (QSE) scale items; event-level items related to overall sexual quality ("Quality item"), comparison to other sexual events ("Comparison item"), and orgasm ("Orgasm item"). RESULTS: QSE scores were significantly correlated with responses to the Quality Item (r=0.901, P<0.001 for both women and men). Better experiences were associated with significantly higher QSE scores than were worse experiences; significant linear relationships were found for both women (GLM F[4,1461]=129.46, P<0.001) and men (GLM F[4,864]=71.84, P<0.001). QSE scores were significantly related to responses on the Orgasm Item for women [F[3,1430]=246.53, P<0.001] and men [F[3,858]=117.24, P<0.001]. CONCLUSIONS: The QSE scale is a valid and reliable event-level measure of the quality of a sexual experience in both women and men with outstanding psychometric properties. Clinical and research implications are discussed. PMID- 23679191 TI - Basal forebrain activation controls contrast sensitivity in primary visual cortex. AB - BACKGROUND: The basal forebrain (BF) regulates cortical activity by the action of cholinergic projections to the cortex. At the same time, it also sends substantial GABAergic projections to both cortex and thalamus, whose functional role has received far less attention. We used deep brain stimulation (DBS) in the BF, which is thought to activate both types of projections, to investigate the impact of BF activation on V1 neural activity. RESULTS: BF stimulation robustly increased V1 single and multi-unit activity, led to moderate decreases in orientation selectivity and a remarkable increase in contrast sensitivity as demonstrated by a reduced semi-saturation contrast. The spontaneous V1 local field potential often exhibited spectral peaks centered at 40 and 70 Hz as well as reliably showed a broad gamma-band (30-90 Hz) increase following BF stimulation, whereas effects in a low frequency band (1-10 Hz) were less consistent. The broad gamma-band, rather than low frequency activity or spectral peaks was the best predictor of both the firing rate increase and contrast sensitivity increase of V1 unit activity. CONCLUSIONS: We conclude that BF activation has a strong influence on contrast sensitivity in V1. We suggest that, in addition to cholinergic modulation, the BF GABAergic projections play a crucial role in the impact of BF DBS on cortical activity. PMID- 23679192 TI - Randomized controlled trial of toremifene 120 mg compared with exemestane 25 mg after prior treatment with a non-steroidal aromatase inhibitor in postmenopausal women with hormone receptor-positive metastatic breast cancer. AB - BACKGROUND: After the failure of a non-steroidal aromatase inhibitor (nsAI) for postmenopausal patients with metastatic breast cancer (mBC), it is unclear which of various kinds of endocrine therapy is the most appropriate. A randomized controlled trial was performed to compare the efficacy and safety of daily toremifene 120 mg (TOR120), a selective estrogen receptor modulator, and exemestane 25 mg (EXE), a steroidal aromatase inhibitor. The primary end point was the clinical benefit rate (CBR). The secondary end points were objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicity. METHODS: Initially, a total of 91 women was registered in the study and randomly assigned to either TOR120 (n = 46) or EXE (n = 45) from October 2008 to November 2011. Three of the 46 patients in the TOR120 arm were not received treatment, 2 patients having withdrawn from the trial by their preference and one having been dropped due to administration of another SERM. RESULTS: When analyzed after a median observation period of 16.9 months, the intention-to-treat analysis showed that there were no statistical difference between TOR120 (N = 46) and EXE (n = 45) in terms of CBR (41.3% vs. 26.7%; P = 0.14), ORR (10.8% vs. 2.2%; P = 0.083), and OS (Hazard ratio, 0.60; P = 0.22). The PFS of TOR120 was longer than that of EXE, the difference being statistically significant (Hazard ratio, 0.61, P = 0.045). The results in treatment-received cohort (N = 88) were similar to those in ITT cohort. Both treatments were well-tolerated with no severe adverse events, although the treatment of 3 of 43 women administered TOR120 was stopped after a few days because of nausea, general fatigue, hot flush and night sweating. CONCLUSIONS: TOR120, as a subsequent endocrine therapy for mBC patients who failed non-steroidal AI treatment, could potentially be more beneficial than EXE. TRIAL REGISTRATION NUMBER: UMIN000001841. PMID- 23679193 TI - Excited-state characteristics of tetracyanidonitridorhenium(V) and -technetium(V) complexes with N-heteroaromatic ligands. AB - Six-coordinate tetracyanidonitridorhenium(V) and -technetium(V) with axial N heteroaromatic ligands, (PPh4)2[MN(CN)4L] [M = Re, L = 4-(dimethylamino)pyridine (dmap), 3,5-lutidine (lut), 4-picoline (pic), 4-phenylpyridine (ppy), pyridine (py), 3-benzoylpyridine (3bzpy), 4,4'-bipyridine (bpy), pyrazine (pz), 4 cyanopyridine (cpy), or 4-benzoylpyridine (4bzpy); M = Tc, L = dmap, lut, pic, py, pz, or cpy] were synthesized and characterized. The crystal structures of 11 complexes were determined by single-crystal X-ray analysis. All of the complexes showed photoluminescence in the crystalline phase at room temperature. The emission maximum wavelengths (lambda(em)) of the rhenium complexes with dmap, lut, pic, ppy, or py were similar to one another with a quite high emission quantum yield (Phi(em)): lambda(em) = 539-545 nm, Phi(em) = 0.39-0.93, and emission lifetime (tau(em)) = 10-45 MUs at 296 K. The emission spectra at 77 K exhibited vibronic progressions, and the emissive excited state is characterized as (3)[(d(xy))(1)(dpi*)(1)] (dpi* = d(xz), d(yz)). On the other hand, the emission maximum wavelength of the rhenium complex with 3bzpy, bpy, pz, cpy, or 4bzpy was significantly dependent on the nature of the axial ligand in the crystalline phase: lambda(em) = 564-669 nm, Phi(em) <= 0.01-0.36, and tau(em) = 0.03-13.3 MUs at 296 K. The emission spectra at 77 K in the crystalline phase did not show vibronic progressions. The emissive excited state of the rhenium complex with bpy, pz, cpy, or 4bzpy is assignable to originate from the metal-to-N heteroaromatic ligand charge-transfer (MLCT)-type emission with a spin-triplet type. The change in the excited-state characteristics of rhenium complexes by the N-heteroaromatic ligand is a result of stabilization of the pi* orbital of the N- heteroaromatic ligand to a lower energy level than the dpi* orbitals. The emission spectral shapes of technetium complexes were almost independent of the nature of the N-heteroaromatic ligand with lambda(em) = 574-581 nm at room temperature. The different emission characteristics between the pz and cpy coordinate rhenium complexes and the technetium analogues would be due to stabilization of technetium-centered orbitals compared with the rhenium ones in energy. PMID- 23679194 TI - Generation of soluble NKG2D ligands: proteolytic cleavage, exosome secretion and functional implications. AB - The activating natural killer group 2 member D (NKG2D) receptor is expressed on NK cells, cytotoxic T cells and additional T cell subsets. Ligands for human NKG2D comprise two groups of MHC class I-related molecules, the MHC class I chain related proteins A and B (MICA/B) and 6 UL16-binding proteins (ULBP1-6). While NKG2D ligands are absent from most normal cells, expression is induced upon stress and malignant transformation. In fact, most solid tumours and leukaemia/lymphomas constitutively express at least one NKG2D ligand and thereby are susceptible to NKG2D-dependent immunosurveillance. However, soluble NKG2D ligands are released from tumour cells and can down-modulate NKG2D activation as a means of tumour immune escape. In some tumour entities, levels of soluble NKG2D ligands in the serum correlate with tumour progression. NKG2D ligands can be proteolytically shed from the cell surface or liberated from the membrane by phospholipase C in the case of glycosylphosphatidylinositol (GPI)-anchored molecules. Moreover, NKG2D ligands can be secreted in exosomal microvesicles together with other tumour-derived molecules. Depending on the specific tumour/immune cell setting, these various forms of soluble and/or exosome-bound NKG2D ligands can exert multiple effects on NKG2D/NKG2D ligand interactions. In this review, we focus on the role of various proteases in the shedding of human NKG2D ligands from tumour cells and discuss the not completely unanimous reported functional implications of soluble and exosome-secreted NKG2D ligands for immunosurveillance. PMID- 23679195 TI - Contributions of Hebb and Vygotsky to an integrated science of mind. AB - Hebb and Vygotsky are two of the most influential figures of psychology in the first half of the twentieth century. They represent cultural and biological approaches to explaining human development, and thus a number of their ideas remain relevant to current psychology and cognitive neuroscience. In this article, we examine similarities and differences between these two important figures, exploring possibilities for a theoretical synthesis between their two literatures, which have had little contact with each other. To pursue these goals, the following topics are discussed: (a) Hebb and Vygotsky's lives and training; (b) their innovations in theory building relating to an "objective psychology" and objective science of mind; (c) their developmental approach; (d) their treatment of mediation and neuropsychology; and (e) their current relevance and possible integration of their views. We argue that considering the two together improves prospects for a more complete and integrated approach to mind and brain in society. PMID- 23679196 TI - Making beautiful music: less dogma, more harmonious progress. PMID- 23679198 TI - Empowering Hispanic families to embrace healthy lifestyles. PMID- 23679199 TI - A pilot study to explore how low-income mothers of different ethnic/racial backgrounds perceive and implement recommended childhood obesity prevention messages. AB - BACKGROUND: Mothers often serve as the "gatekeepers" of food and the eating experience for young children in the home. Children of different ethnic/racial groups have different obesity prevalence rates, but little is known about how mothers of these groups interpret or implement common childhood obesity prevention messages. The purpose of this mixed methods pilot study was to explore comprehension and implementation of common childhood obesity prevention messages and to identify feeding styles among low-income mothers of young children. METHODS: White, black, and Hispanic low-income mothers (n=30) of children ages 3 10 were recruited from Indiana. Mothers were interviewed individually regarding the perception and implementation of eight commonly used nutrition and/or physical activity messages. Other outcomes included the results of the Caregiver Feeding Styles Questionnaire and self-reported weight of mothers and child(ren). Interviews were analyzed using thematic analysis to find common themes among the different ethnic/racial groups. RESULTS: Childhood obesity prevention messages were often interpreted or implemented differently among the different ethnic/racial groups. For example, white mothers cited control as a means to manage a child's weight more often compared to the other racial/ethnic groups, whereas black and Hispanic mothers reported catering to a child's preference more frequently compared to white mothers. CONCLUSION: The pilot study provides evidence that it may be prudent to tailor nutrition messages to mothers of different ethnic/racial backgrounds during nutrition education. PMID- 23679200 TI - Coping strategies, depressive symptoms and quality of life in hypertensive patients: mediational and prospective relations. AB - This study examined whether depressive symptoms mediated the association between coping strategies and quality of life (QoL) in a sample of hypertensive patients, and the prospective contribution of depressive symptoms and coping strategies in the prediction of their QoL. One hundred and fifty patients (50% males and 50% females) with a diagnosis of essential hypertension were recruited from a general hospital. Symptoms of depression, coping and QoL measures (global score and dimensions) were collected at baseline. Sixty-three participants completed the QoL questionnaire again one year later (T2). The results indicated that the relations between emotion coping and QoL (global score, satisfaction and social support) were totally mediated by depressive symptoms. The association between emotion coping and well-being was, however, partially mediated by depressive symptoms. Furthermore, only baseline instrumental coping strategies predicted higher levels of QoL (global score, well-being and social support) at T2. Neither emotion coping nor depressive symptoms were significantly associated with prospective QoL. These findings suggest that depressive symptoms may be a mechanism linking the manner in which patients cope with their hypertension and their QoL. They also emphasise the adaptive role played by instrumental coping responses in the management of hypertension in the long term. PMID- 23679201 TI - Chromophores arranged as "magnetic meta atoms": building blocks for molecular metamaterials. AB - Benzoperylenetriscarboximides were parallel arranged by stiff spacers where exciton interactions could be controlled by their distance. The most bathochromic electronic transition of the chromophores essentially exhibits only an electric component where an orthogonal magnetic component was established by the distance controlled interaction of chromophores. Such arrangements were discussed as building blocks for molecular metamaterials. PMID- 23679202 TI - Fundamental studies of methyl iodide adsorption in DABCO impregnated activated carbons. AB - Methyl iodide capture from a water vapor stream using 1,4 diazabicyclo[2.2.2]octane (DABCO)-impregnated activated carbons is, for the first time, fundamentally described here on the atomic level by means of both molecular dynamics and grand canonical Monte Carlo simulations. A molecular dynamics annealing strategy was adopted to mimic the DABCO experimental impregnation procedure in a selected slitlike carbon pore. Predictions, restricted to the micropore region, are made about the adsorption isotherms of methyl iodide, water, and nitrogen on both impregnated and bare activated carbon models. Experimental and simulated nitrogen adsorption isotherms are compared for the validation of the impregnation strategy. Selectivity analyses of the preferential adsorption toward methyl iodide over water are also reported. These simulated adsorption isotherms sum up to previous experimental studies to provide an enhanced picture for this adsorption system of widespread use at nuclear plant HVAC facilities for the capture of radioactive iodine compounds. PMID- 23679203 TI - Aggravation of inflammatory bowel diseases by oral streptococci. AB - OBJECTIVES: Streptococcus mutans can aggravate colitis in mice. We evaluated the virulence of colitis using type strains as well as blood isolates of several oral streptococcal species. MATERIALS AND METHODS: We investigated the susceptibility of blood isolates of several oral streptococci to phagocytosis, adhesion to and invasion of hepatic cells and interferon-gamma secretion. A mouse model of dextran sodium sulphate-induced colitis was used to evaluate bacterial aggravation of colitis. In addition, interferon-gamma antibody was administered to mice with prominent aggravation of colitis. RESULTS: In vitro analyses showed that Streptococcus sanguinis ATCC 10556 was a possible virulent strain among type strains of several oral streptococci, and that analysis of blood isolates of S. sanguinis TW289 revealed a potential virulent strain. Intravenous administration of ATCC 10556 and TW289 caused prominent aggravation of dextran sodium sulphate induced colitis, and histopathological examinations showed that interferon-gamma secretion due to infection of hepatic cells caused colitis aggravation. Administration of interferon-gamma antibody suppressed TW289-induced colitis. CONCLUSION: These results suggest that some virulent oral streptococcal strains are associated with the aggravation of colitis induced by enhanced secretion of interferon-gamma when they invade the bloodstream. PMID- 23679204 TI - Specific-gene studies of evolutionary mechanisms in an age of genome-wide surveying. AB - The molecular tools of genomics have great power to reveal patterns of genetic difference within or among species, but must be complemented by the mechanistic study of the genetic variants found if these variants' evolutionary meaning is to be well understood. Central to this purpose is knowledge of the organisms' genotype-phenotype-environment interactions, which embody biological adaptation and constraint and thus drive natural selection. The history of this approach is briefly reviewed. Strategies embracing the complementarity of genomics and specific-gene studies in evolution are considered. Implementation of these strategies, and examples showing their feasibility and power, are discussed. Initial generalizations emphasize: (1) reproducibility of adaptive mechanisms; (2) evolutionary co-importance of variation in protein sequences and expression; (3) refinement of rudimentary molecular functions as an origin of evolutionary innovations; (4) identification of specific-gene mechanisms as underpinnings of genomic or quantitative genetic variation; and (5) multiple forms of adaptive or constraining epistasis among genes. Progress along these lines will advance understanding of evolution and support its use in addressing urgent medical and environmental applications. PMID- 23679206 TI - Single pulse shock tube study of allyl radical recombination. AB - The recombination and disproportionation of allyl radicals has been studied in a single pulse shock tube with gas chromatographic measurements at 1-10 bar, 650 1300 K, and 1.4-2 ms reaction times. 1,5-Hexadiene and allyl iodide were used as precursors. Simulation of the results using derived rate expressions from a complementary diaphragmless shock tube/laser schlieren densitometry study provided excellent agreement with precursor consumption and formation of all major stable intermediates. No significant pressure dependence was observed at the present conditions. It was found that under the conditions of these experiments, reactions of allyl radicals in the cooling wave had to be accounted for to accurately simulate the experimental results, and this unusual situation is discussed. In the allyl iodide experiments, higher amounts of allene, propene, and benzene were found at lower temperatures than expected. Possible mechanisms are discussed and suggest that iodine containing species are responsible for the low temperature formation of allene, propene, and benzene. PMID- 23679205 TI - Transcriptome resources and functional characterization of monoterpene synthases for two host species of the mountain pine beetle, lodgepole pine (Pinus contorta) and jack pine (Pinus banksiana). AB - BACKGROUND: The mountain pine beetle (MPB, Dendroctonus ponderosae) epidemic has affected lodgepole pine (Pinus contorta) across an area of more than 18 million hectares of pine forests in western Canada, and is a threat to the boreal jack pine (Pinus banksiana) forest. Defence of pines against MPB and associated fungal pathogens, as well as other pests, involves oleoresin monoterpenes, which are biosynthesized by families of terpene synthases (TPSs). Volatile monoterpenes also serve as host recognition cues for MPB and as precursors for MPB pheromones. The genes responsible for terpene biosynthesis in jack pine and lodgepole pine were previously unknown. RESULTS: We report the generation and quality assessment of assembled transcriptome resources for lodgepole pine and jack pine using Sanger, Roche 454, and Illumina sequencing technologies. Assemblies revealed transcripts for approximately 20,000 - 30,000 genes from each species and assembly analyses led to the identification of candidate full-length prenyl transferase, TPS, and P450 genes of oleoresin biosynthesis. We cloned and functionally characterized, via expression of recombinant proteins in E. coli, nine different jack pine and eight different lodgepole pine mono-TPSs. The newly identified lodgepole pine and jack pine mono-TPSs include (+)-alpha-pinene synthases, (-)-alpha-pinene synthases, (-)-beta-pinene synthases, (+)-3-carene synthases, and (-)-beta-phellandrene synthases from each of the two species. CONCLUSION: In the absence of genome sequences, transcriptome assemblies are important for defence gene discovery in lodgepole pine and jack pine, as demonstrated here for the terpenoid pathway genes. The product profiles of the functionally annotated mono-TPSs described here can account for the major monoterpene metabolites identified in lodgepole pine and jack pine. PMID- 23679207 TI - Association between delayed initiation of adjuvant CMF or anthracycline-based chemotherapy and survival in breast cancer: a systematic review and meta analysis. AB - BACKGROUND: Adjuvant chemotherapy (AC) improves survival among patients with operable breast cancer. However, the effect of delay in AC initiation on survival is unclear. We performed a systematic review and meta-analysis to determine the relationship between time to AC and survival outcomes. METHODS: PubMed, EMBASE, Cochrane Database of Systematic Reviews, and Web-of-Science databases (between January-1 1978 and January-29, 2013) were searched for eligible studies. Hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) from each study were converted to a regression coefficient (beta) corresponding to a continuous representation per 4-week delay of AC. Most used regimens of chemotherapy in included studies were CMF (cyclophosphamide, methotrexate, and fluorouracil) or anthracycline-based. Individual adjusted beta were combined using a fixed-effects or random-effects model depending on heterogeneity. RESULTS: We included 7 eligible studies with 9 independent analytical groups involving 34,097 patients, 1 prospective observational study, 2 secondary analyses in randomized trials (4 analytical groups), and 4 hospital-/population based retrospective study. The overall meta-analysis demonstrated that a 4-week increase in time to AC was associated with a significant decrease in both OS (HR = 1.15; 95% confidence interval [CI], 1.03-1.28; random-effects model) and DFS (HR = 1.16; 95% CI, 1.01-1.33; fixed-effects model). One study caused a significant between-study heterogeneity for OS (P < 0.001; I2 = 75.4%); after excluding that single study, there was no heterogeneity (P = 0.257; I2 = 23.6%) and the HR was more significant (HR = 1.17; 95% CI, 1.12-1.22; fixed-effects model). Each single study did not fundamentally influence the positive outcome and no evidence of publication bias was observed in OS. CONCLUSIONS: Longer time to AC is probably associated with worse survival in breast cancer patients. PMID- 23679208 TI - Salivary gland choristoma (heterotopic salivary gland tissue) on the anterior chest wall of a newborn. AB - Salivary gland choristoma (heterotopic salivary gland tissue) is a rare condition typically seen in the newborn period. This developmental heterotopia is generally nonprogressive, with little risk of malignant transformation. We present the second known reported case of a salivary gland choristoma located on the anterior chest wall. Knowledge of this rare entity will allow for accurate diagnosis and management of this benign anatomic variant. PMID- 23679209 TI - Rhodium-catalyzed decarbonylative C-H arylation of 2-aryloxybenzoic acids leading to dibenzofuran derivatives. AB - Rhodium-catalyzed intramolecular C-H arylation of 2-aryloxybenzoic acids proceeded accompanied by decarbonylation to give dibenzofuran derivatives in high yields. The present reaction is widely applicable to substrates bearing various functionalities. PMID- 23679210 TI - Neuroscience and colorectal surgery--divided by a common language? PMID- 23679215 TI - Chronic myelogenous leukemia in a 4-year-old boy. PMID- 23679216 TI - Increased vesicular gamma-GABA transporter and decreased phosphorylation of synapsin I in the rostral preoptic area is associated with decreased gonadotrophin-releasing hormone and c-Fos coexpression in middle-aged female mice. AB - Hypothalamic glutamate (Glu) and gamma-GABA neurotransmission are involved in the ovarian hormone-induced gonadotrophin-releasing hormone (GnRH)/luteinising hormone (LH) surge in rodents. Studies have shown that reduced Glu and increased gamma-GABA in the rostral preoptic area (rPOA) of the hypothalamus, where most activated GnRH neurones are located, play a key role in decreasing the reproductive function of female rats. However, the mechanism underlying the altered balance of these neurotransmitters is poorly understood. In the present study, we observed a decline in the function of GnRH neurones in the rPOA at the time of the GnRH/LH surge in middle-aged intact female mice with regular oestrous cycles. In young mice, there is an increase of vesicular Glu transporter 2 on the pro-oestrus afternoon, which is not observed in middle-aged mice. By contrast, vesicular gamma-GABA transporter levels in young mice decrease at the time of the LH surge, whereas they increase in middle-aged mice. Of note, we found that, in middle-aged mice at the time of the GnRH/LH surge, the phosphorylation of synapsin I at Ser603 and Ca(2+) /calmodulin-dependent kinase IIalpha was significantly lower than in young mice. These data suggest that, in middle-aged mice, higher levels of presynaptic stores of GABA, a lack of increase of Glu and a decreased ability of synaptic vesicle mobilisation could account for the imbalance of Glu and GABA in the rPOA, which decreases the activation of GnRH neurones. PMID- 23679217 TI - Psoriasis and Sexual Behavior in Men: examination of the National Health and Nutrition Examination Survey (NHANES) in the United States. AB - INTRODUCTION: Epidemiologic data on sexual behavior in psoriasis patients are lacking. AIM: We aim to examine and compare the sexual behaviors between men with and without psoriasis in the United States. METHODS: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2006 and 2009 to 2010. Responses from male participants to the dermatology and sexual behavior questionnaires of the NHANES were collated and analyzed. MAIN OUTCOME MEASURES: Outcome measures included sexual orientation, age of first sexual encounter, number of oral and non-oral sexual partners, and frequency of unprotected sex. RESULTS: Among 6,444 U.S. men that responded to the psoriasis question, 170 (2.6%) reported a physician-given diagnosis of psoriasis. Heterosexual men accounted for 95.5% and nonheterosexual men 4.5% of the overall study population. On multivariate analysis, psoriasis was not associated with differences in sexual orientation (odds ratio 1.78, 95% confidence interval [CI] 0.75-4.15). Heterosexual men with psoriasis experienced first sexual encounter at an earlier age than those without psoriasis (weighted difference -0.9 years, P = 0.002). Heterosexual men with psoriasis had significantly fewer female oral sexual partners compared with heterosexual men without psoriasis on multivariate analysis (lifetime partner number: rate ratio [RR] 0.65, 95% CI 0.45-0.95; past year partner number: RR 0.64, 95% CI 0.42-0.97). No significant differences existed between heterosexual men with and without psoriasis regarding frequency of unprotected sex (RR 0.96, 95% CI 0.85-1.09). Among nonheterosexual men with and without psoriasis, no significant differences existed in age first had sex, number of sexual partners, or frequency of unprotected sex. CONCLUSION: Heterosexual men with psoriasis have significantly fewer lifetime female oral sexual partners compared with those without psoriasis. Dermatologists and other healthcare providers need to examine the genital region routinely and initiate appropriate therapy to improve patients' sexual health. PMID- 23679218 TI - Self-assembled Ln(III)4 (Ln = Eu, Gd, Dy, Ho, Yb) [2 * 2] square grids: a new class of lanthanide cluster. AB - Self-assembly of the Ln(III) ions (Ln = Eu, Gd, Dy, Ho, Yb) into square [2 * 2] grid-like arrays has been readily effected using simple, symmetric ditopic ligands based on a carbohydrazone core. The metal ions are connected via single atom bridges (e.g., MU2-O(hydrazone), MU2-OH, MU2-OMe, MU2-1,1-N3(-), MU4-O), depending on reaction conditions. The Gd(III)4 examples exhibit intramolecular antiferromagnetic exchange (-J < 0.11 cm(-1)), and in one Dy(III)4 example, with a combination of MU2-1,1-N3(-), and MU4-O bridges linking adjacent metal ions, SMM behavior is observed. One thermally driven relaxation process is observed in the temperature range 10-25 K (tau0 = 6.5(1) * 10(-7) s, U(eff) = 110(1) K) in the presence of an 1800 Oe external field, employed to suppress a second quantum based relaxation process. The extended group of Ln(III) ions which submit to this controlled self-assembly, typical of the transition metal ions, indicates the general applicability of this approach to the lanthanides. This occurs despite the anticipated limitations based on larger ionic radii and coordination numbers, and is an encouraging sign for extension to larger grids with appropriately chosen polytopic ligands. PMID- 23679219 TI - Public views about health causation, attributions of responsibility, and inequality. AB - Success in addressing health disparities and their social determinants will require understanding public perceptions of health causation, attributions of responsibility, and potential solutions. To explore these perceptions, the authors conducted 12 focus groups (6 with liberals, 6 conservatives; N = 93 participants) in a large U.S. Northeastern state. Participants communicated highly nuanced views about health causation and disparities, identifying layers of responsibility for health. However, individual behaviors and personal responsibility dominated the discussion and served as a counterargument to the significance of social determinants. Participants also showed limited awareness of the range of policies that could be adopted to address health disparities. As policy initiatives benefit from public support in gaining political traction, the authors suggest research paths and possible communication strategies for scholars and advocates. PMID- 23679220 TI - Family caregiving for dependent older adults in Thai families. AB - PURPOSE: The aim of this study was to understand how Thai families care for dependent older adults. DESIGN AND METHODS: The methodology used for the study was grounded dimensional analysis. Participants were 30 adult family members from 15 families who were involved in caregiving. A total of 46 interviews were conducted. Data were collected and analyzed in three phases: (a) calling up dimensions, (b) assigning relative value to each of the dimension considers, and (c) inferring. FINDINGS: In Thai families, "natural caregiving" precedes care of dependent older persons (dependent caregiving). Dependent caregiving begins when dependency is first noticed and care needs are identified. Dependent caregiving is a dynamic process integrating three major processes: (a) mobilizing family members, (b) performing dependent care, and (c) maintaining continuity of care. The consequences of performing dependent care and unpredictable changes lead to care remobilizing. CONCLUSIONS: Dependent care for older adults varies across and is influenced by many conditions. Health personnel need to assess and monitor these varying conditions in order to support Thai families caring for dependent older adults. CLINICAL RELEVANCE: The conceptual model developed from the findings of this study provide a starting place for increasing our understanding of how to help Thai families care effectively and continuously for their older family members. PMID- 23679221 TI - Pregnancy outcomes in a cohort of women with a preconception body mass index >50 kg/m2. AB - We describe characteristics and risk factors regarding pregnancy outcome in women with a preconception body mass index (BMI) >50 kg/m2 compared with women with BMI <=50 kg/m2 in a retrospective population cohort study in singleton pregnancies from the Danish Medical Birth Registry. Results were analyzed as relative risks by a two-proportion z-test. Women with preconception BMI >50 kg/m2 smoked, developed gestational diabetes and pre-eclampsia, and needed induction of labor more frequently than mothers with BMI <=50 kg/m2. Examination of the case records showed that many attempted vaginal delivery without epidural analgesia, 21% needed an emergency cesarean section (compared with 12% among women with BMI <=50 kg/m2), and 25% underwent general anesthesia in this context. Many neonates were macrosomic and 34% needed neonatal intensive care and early feeding compared with 6% of neonates from women with BMI <=50 kg/m2. Women with an extremely high preconception BMI develop more pregnancy complications and their neonates appear affected by this as well. PMID- 23679222 TI - Memory B cells in mouse models. AB - One of the principles behind vaccination, as shown by Edward Jenner in 1796, and host protection is immunological memory, and one of the cells central to this is the antigen-experienced memory B cell that responds rapidly upon re-exposure to the initiating antigen. Classically, memory B cells have been defined as progenies of germinal centre (GC) B cells expressing isotype-switched and substantially mutated B cell receptors (BCRs), that is, membrane-bound antibodies. However, it has become apparent over the last decade that this is not the only pathway to B cell memory. Here, we will discuss memory B cells in mice, as defined by (1) cell surface markers; (2) multiple layers; (3) formation in a T cell-dependent and either GC-dependent or GC-independent manner; (4) formation in a T cell-independent fashion. Lastly, we will touch upon memory B cells in; (5) mouse models of autoimmune diseases. PMID- 23679223 TI - Covalent inhibition of serine beta-lactamases by novel hydroxamic acid derivatives. AB - The effectiveness of beta-lactam antibiotics is greatly limited by the ability of bacteria to produce beta-lactamases. These enzymes catalyze the hydrolysis of beta-lactams and thus loss of their antibiotic activity. The search for inhibitors of beta-lactamases began soon after beta-lactams were introduced into medical practice and continues today. Some time ago, we introduced a new class of covalent serine beta-lactamase inhibitors, the O-aryloxycarbonyl hydroxamates, that inactivated these enzymes by a unique mechanism in which the active site became cross-linked. We describe in this paper some new variants of this class of inhibitor. First, we investigated compounds in which more polar hydroxamates were incorporated. These were generally not more active than the original compounds against representative class A and class C beta-lactamases, but one of them, 1 (benzoyl)-O-(phenoxycarbonyl)-3-hydroxyurea, was significantly more stable in solution, thus revealing a useful platform for further design. Second, we describe a series of O-(arylphosphoryl) hydroxamates that are also irreversible inactivators of class A and class C beta-lactamases, by phosphorylation of the enzyme, as revealed by mass spectra. These compounds did not, however, cross-link the enzyme active site. A striking feature of their structure-activity profile was that hydroxamate remained the leaving group on enzyme phosphorylation rather than aryloxide, even though the aryloxide was intrinsically the better leaving group, as indicated by pKa values and demonstrated by the products of hydrolysis in free solution. Model building suggested that this phenomenon arises from the relative affinity of the enzyme active site components for the two leaving groups. The results obtained for both groups of inhibitors are important for further optimization of these inhibitors. PMID- 23679224 TI - Neurologic heuristics and artistic whimsy: the cerebral cartography of Wilder Penfield. AB - Neurosurgeon Wilder Penfield played a singularly important role in expanding our knowledge of functional neuroanatomy and neurophysiology in the twentieth century. Trained under Charles Sherrington, William Osler, and Otfrid Foerster, Penfield was an early leader in efforts to map the cerebral cortex via direct electrical stimulation of the brain. In 1937, Penfield introduced an entirely new concept for illustrating the relative sizes and locations of discrete functional regions within the sensorimotor cortex--the homunculus-to exemplify the "order and comparative extent" of specific functional regions. Over the subsequent two decades, Penfield and colleagues introduced several more "little men" to portray the functional maps of other important brain structures (i.e., supplementary motor area, insular cortex, thalamus). These later homunculi were more crudely drawn, and Penfield referred to them as essentially heuristic devices. The actual intent in producing these homunculi remains uncertain, and despite the extraordinary impact of these artistic renderings on the field, the question is raised as to whether the allure of the artwork seemed to wrest control from-and then to guide-the dissemination of science, rather than the other way around. PMID- 23679225 TI - Synthesis, guest-binding, and reduction-responsive degradation properties of water-soluble cyclophanes having disulfide moieties. AB - Water-soluble cationic cyclophane having diphenyl disulfide moieties (1a) was synthesized as a reduction-responsive degradable host. The stoichiometry for the complex of 1a with anionic fluorescence guests, such as 4,4'-bis(1 anilinonaphthalene-8-sulfonate) (Bis-ANS) and 4-(1-pyrene)-butanoic acid (PBA), was confirmed to be 1:1 host:guest by a Job plot. The binding constants (K) of 1a toward Bis-ANS and PBA were evaluated to be 6.7 * 10(3) and 4.5 * 10(4) M(-1), respectively, as confirmed by fluorescence spectroscopy. Reduction of disulfide bonds of 1a by dithiothreitol gave its reduced form having poor guest-binding affinity that led to release of the entrapped guest molecules to the bulk aqueous phase. Meanwhile, anionic cyclophane 1b, which was derived from 1a by a reaction with succinic anhydride, binds cationic anticancer drugs, such as daunorubicin hydrochloride (DNR) and doxorubicin hydrochloride (DOX), with a K of 2.1 * 10(3) and 7.5 * 10(2) M(-1), respectively. A similar reduction-responsive guest release feature was observed when DNR and DOX were employed as a guest for complexation with 1b. PMID- 23679226 TI - Genistein and exercise do not improve cardiovascular risk factors in the ovariectomized rat. AB - OBJECTIVE: To investigate the effect of either genistein, or exercise, or both, on parameters that are indicators of cardiovascular health. METHODS: We investigated the effect of genistein treatment (300 mg genisten/kg body weight/day), or exercise training, or combined genistein and exercise training, for a period of 6 weeks on physical characteristics, cardiovascular plasma markers, blood pressure, aortic morphology, cardiac structure and oxidative stress in the ovariectomized (OVX) Sprague-Dawley rat. Comparisons were made with intact rats. RESULTS: Ovariectomy (compared to intact) resulted in significant decreases in uterine weight (6-fold, p < 0.0001), insulin levels (4-fold, p = 0.0214), insulin/glucose ratio (3-fold, p = 0.0029), and tumor necrosis factor alpha plasma levels (2-fold, p < 0.0001). Similarly, aortic blood pressure was significantly increased (by 8%, p < 0.0033) in OVX rats, without changes in aortic luminal or wall dimensions. Heart surface area was significantly increased (by 16%, p = 0.0160) in OVX rats and this was without changes in non-protein thiol levels (a marker of oxidative stress). Physical characteristics were not altered by treatment with genistein, or genistein with exercise, with the exception of increased uterine weight in OVX rats treated under these same conditions. There were no effects of genistein or exercise on indices of blood pressure and aortic morphology in the OVX rat. However, right ventricular nuclei count was reduced in sedentary genistein-treated rats compared to non-treated control OVX rats. CONCLUSION: Our results indicate that administration of genistein at this dose, treadmill running, or the combination of both, are not associated with any improvement in cardiovascular function and structure, and risk factors in an ovariectomy model of postmenopause. PMID- 23679227 TI - Dynamics of charge separation from second excited state and following charge recombination in zinc-porphyrin-acceptor dyads. AB - Intramolecular charge separation from the second singlet excited state of directly linked Zn-porphyrin-imide dyads and following charge recombination into the first singlet excited and the ground states has been investigated in the framework of a model incorporating four electronic states (the first and the second singlet excited, the charge separated, and the ground states) as well as their vibrational sublevels. Kinetics of the transitions between these states are described in terms of the stochastic point-transition approach involving reorganization of a number of high frequency vibrational modes. The influence of the model parameters (the number of high frequency vibrational modes, the magnitude of the reorganization energies of the medium and the high frequency intramolecular vibrations, the solvent polarity) on the kinetics of population of the second and first singlet excited states as well as the charge separated state has been investigated. Simulation of the kinetics of the charge separated state population allows quantitative reproducing of the distinctive features of the two humped kinetic curve observed in the experiment. PMID- 23679228 TI - Nonaqueous microemulsions based on n,n'-alkylimidazolium alkylsulfate ionic liquids. AB - The ternary system composed of the ionic liquid surfactant (IL-S) 1-butyl-3 methylimidazolium dodecylsulfate ([Bmim][DodSO4]), the room temperature ionic liquid (RTIL) 1-ethyl-3-methylimidazolium ethylsulfate ([Emim][EtSO4]), and toluene has been investigated. Three major mechanisms guiding the structure of the isotropic phase were identified by means of conductometric experiments, which have been correlated to the presence of oil-in-IL, bicontinuous, and IL-in-oil microemulsions. IL-S forms micelles in toluene, which swell by adding RTIL as to be shown by dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS) experiments. Therefore, it is possible to form water-free IL-in-oil reverse microemulsions <=10 nm in size as a new type of nanoreactor. PMID- 23679229 TI - Treatment for bovine Escherichia coli mastitis - an evidence-based approach. AB - Bovine mastitis caused by Escherichia coli can range from being a subclinical infection of the mammary gland to a severe systemic disease. Cow-dependent factors such as lactation stage and age affect the severity of coliform mastitis. Evidence for the efficacy of antimicrobial treatment for E. coli mastitis is very limited. Antimicrobial resistance is generally not a limiting factor for treatment, but it should be monitored to detect changes in resistance profiles. The only antimicrobials for which there is some scientific evidence of beneficial effects in the treatment for E. coli mastitis are fluoroquinolones and cephalosporins. Both are critically important drugs, the use of which in animals destined for food should be limited to specific indications and should be based on bacteriological diagnosis. The suggested routine protocol in dairy herds could target the primary antimicrobial treatment for mastitis, specifically infections caused by gram-positive bacteria. In E. coli mastitis with mild to moderate clinical signs, a non-antimicrobial approach (anti-inflammatory treatment, frequent milking and fluid therapy) should be the first option. In cases of severe E. coli mastitis, parenteral administration of fluoroquinolones, or third- or fourth-generation cephalosporins, is recommended due to the risk of unlimited growth of bacteria in the mammary gland and ensuing bacteremia. Evidence for the efficacy of intramammary-administered antimicrobial treatment for E. coli mastitis is so limited that it cannot be recommended. Nonsteroidal anti inflammatory drugs have documented the efficacy in the treatment for E. coli mastitis and are recommended for supportive treatment for clinical mastitis. PMID- 23679230 TI - Morphology and chronology of diphyodont dentition in miniature pigs, Sus Scrofa. AB - OBJECTIVE: There is little knowledge about the tooth replacement in large mammals. The aim of this study is to investigate the tooth replacement patterns in Chinese miniature pig (Sus Scrofa). MATERIALS AND METHODS: The developmental patterns of mandibular successional and additional teeth from Chinese miniature pig before and after birth were investigated by microanatomy, immunohistochemistry, and cone beam computed tomography. RESULTS: Secondary dental lamina for successional teeth was not visible until its predecessor progressed to late bell stage. Successional teeth reached early cap stage when their predecessor began to erupt. The development patterns and speed varied between anterior and posterior successional teeth. Additional molars, derived from the free end of additional dental lamina, initiated sequentially in mandible ramus, while previous additional molar progressed into late bell stage. Proliferating cells in the permanent primordium were distributed asymmetrically. CONCLUSIONS: Our findings identify the characteristic patterns about spatiotemporal morphogenesis of successional teeth in context of their predecessor and cascade initiation of additional molars in miniature pigs. Our study provides a basis toward better understanding the mechanisms underlying diphyodont replacement in human and also assists in tooth regeneration and tooth engineering in large animal. PMID- 23679231 TI - Heart failure in patients treated with bisphosphonates. AB - OBJECTIVES: The aim of this study was to investigate the occurrence of heart failure in patients treated with bisphosphonates. DESIGN: In this nationwide retrospective cohort study from Denmark, all users of bisphosphonates and raloxifene between 1996 and 2006 (n = 102 342) were included in the 'exposed' group and three age- and gender-matched subjects (n = 307.026) from the general population comprised the control group. The risk of heart failure was estimated by Cox proportional hazard analyses. RESULTS: The mean follow-up times were 2.8, 5.5 and 4.9 years for alendronate-, etidronate- and raloxifene-treated patients, respectively. The absolute risk of heart failure was 4.4% in the exposed group and 3.7% in the control group (P < 0.01). The relative risk (RR) of heart failure was significantly increased in users of bisphophonates: crude RR 1.71 [95% confidence interval (CI) 1.63-1.79]; adjusted hazard ratio (HR) 1.41 (95% CI 1.34 1.48). By comparison, raloxifene, which is used for the same indication but has a different mechanism of action, was not associated with an increased risk of heart failure: adjusted HR 1.07 (95% CI 0.76-1.50). When the two most commonly used bisphosphonates, alendronate and etidronate, were analysed separately, significant trends in the risk of heart failure were observed across refill compliance strata. The risk of heart failure increased significantly with increasing refill compliance for etidronate (P for trend < 0.01), whereas it decreased for alendronate (P for trend < 0.01). CONCLUSIONS: Bisphosphonate users were at increased risk of heart failure compared to age- and gender-matched control subjects. However, users of alendronate showed a dose-dependent reduction in this risk, suggesting that alendronate may reduce the risk of heart failure. PMID- 23679232 TI - DNA integrity of human leukocytes after magnetic resonance imaging. AB - PURPOSE: This study focuses on the effects of high-field (3T) magnetic resonance imaging (MRI) scans on the DNA integrity of human leukocytes in vitro in order to validate the study where genotoxic effects were obtained and published by Lee et al. MATERIALS AND METHODS: The scanning protocol and exposure situation were the same as those used under routine clinical brain MRI scan. Peripheral blood samples from healthy non-smoking male donors were exposed to electromagnetic fields (EMF) produced by 3T magnetic resonance imaging equipment for 0, 22, 45, 67, and 89 min during the scanning procedure. Samples of positive control were exposed to ionizing radiation (4 Gy of (60)Co-gamma). Single breaks of DNA in leukocytes were detected by single-cell gel electrophoresis (Comet assay). Chromosome breakage, chromosome loss and micronuclei formations were detected by a micronucleus test (MN). Three independent experiments were performed. RESULTS: The data of comet tail DNA%, olive tail moment and micronucleus frequency showed no DNA damages due to MRI exposure. CONCLUSIONS: The results of the Comet assay and the micronucleus test indicate that the applied exposure of MRI does not appear to produce breaks in the DNA and has no significant effect on DNA integrity. PMID- 23679234 TI - Association of circulating regulatory T cell number with the incidence and prognosis of diffuse large B-cell lymphoma. AB - Regulatory T (Treg) cells are essential for maintaining immune tolerance. High Treg frequencies have been reported in peripheral blood and tissue samples of patients with solid tumors while their role in lymphomas, including diffuse large B-cell lymphoma (DLBCL) has not been clearly established. In this study, we analyzed the circulating Treg numbers in 27 patients with newly diagnosed DLBCL and 17 healthy individuals. Tregs were detected by flow cytometry based on CD4(+) CD25(high) FoxP3(+) phenotype. In addition, the expression of CD45RA, HLA-DR, CD62L, CD39, and CTLA4 was analyzed. The number of circulating Treg cells was lower in patients with DLBCL than in healthy controls: median 23 (range, 4 107)/MUL vs. 41 (19-104)/MUL (P = 0.04). In particular, the number of Tregs expressing CD45RA (naive Tregs), HLA-DR (marker of activation), and CD62L (L selectin) was decreased in the DLBCL group. Lower (below median) number of circulating Tregs was associated with reduced chance of achieving complete remission (29% vs. 69%, P = 0.05) and reduced probability of even-free survival (24% vs. 84% at 1 yr, P = 0.0004), independently on the International Prognostic Index. We conclude that low number of circulating Tregs may be associated with poor prognosis in patients with DLBCL. However, our observations require confirmation in larger patient population. PMID- 23679233 TI - Alterations of the genes involved in the PI3K and estrogen-receptor pathways influence outcome in human epidermal growth factor receptor 2-positive and hormone receptor-positive breast cancer patients treated with trastuzumab containing neoadjuvant chemotherapy. AB - BACKGROUND: Chemotherapy with trastuzumab is widely used for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer, but a significant number of patients with the tumor fail to respond, or relapse. The mechanisms of recurrence and biomarkers that indicate the response to the chemotherapy and outcome are not fully investigated. METHODS: Genomic alterations were analyzed using single-nucleotide polymorphism arrays in 46 HER2 immunohistochemistry (IHC) 3+ or 2+/fluorescent in situ hybridization (FISH)+ breast cancers that were treated with neoadjuvant chemotherapy with paclitaxel, cyclophosphamid, epirubicin, fluorouracil, and trastuzumab. Patients were classified into two groups based on presence or absence of alterations of 65 cancer-associated genes, and the two groups were further classified into four groups based on genomic HER2 copy numbers or hormone receptor status (HR+/-). Pathological complete response (pCR) and relapse-free survival (RFS) rates were compared between any two of the groups. RESULTS AND DISCUSSION: The pCR rate was 54% in 37 patients, and the RFS rate at 3 years was 72% (95% CI, 0.55-0.89) in 42 patients. The analysis disclosed 8 tumors with nonamplified HER2 and 38 tumors with HER2 amplification, indicating the presence of discordance in tumors diagnosed using current HER2 testing. The 8 patients showed more difficulty in achieving pCR (P=0.019), more frequent relapse (P=0.018), and more frequent alterations of genes in the PI3K pathway (P=0.009) than the patients with HER2 amplification. The alterations of the PI3K and estrogen receptor (ER) pathway genes generally indicated worse RFS rates. The prognostic significance of the alterations was shown in patients with a HR+ tumor, but not in patients with a HR tumor when divided. Alterations of the PI3K and ER pathway genes found in patients with a HR+ tumor with poor outcome suggested that crosstalk between the two pathways may be involved in resistance to the current chemotherapy with trastuzumab. CONCLUSIONS: We recommend FISH analysis as a primary HER2 testing because patients with IHC 2+/3+ and nonamplified HER2 had poor outcome. We also support concurrent use of trastuzumab, lapatinib, and cytotoxic and anti-hormonal agents for patients having HR+ tumors with alterations of the PI3K and ER pathway genes. PMID- 23679235 TI - A structure-based model of energy transfer reveals the principles of light harvesting in photosystem II supercomplexes. AB - Photosystem II (PSII) initiates photosynthesis in plants through the absorption of light and subsequent conversion of excitation energy to chemical energy via charge separation. The pigment binding proteins associated with PSII assemble in the grana membrane into PSII supercomplexes and surrounding light harvesting complex II trimers. To understand the high efficiency of light harvesting in PSII requires quantitative insight into energy transfer and charge separation in PSII supercomplexes. We have constructed the first structure-based model of energy transfer in PSII supercomplexes. This model shows that the kinetics of light harvesting cannot be simplified to a single rate limiting step. Instead, substantial contributions arise from both excitation diffusion through the antenna pigments and transfer from the antenna to the reaction center (RC), where charge separation occurs. Because of the lack of a rate-limiting step, fitting kinetic models to fluorescence lifetime data cannot be used to derive mechanistic insight on light harvesting in PSII. This model will clarify the interpretation of chlorophyll fluorescence data from PSII supercomplexes, grana membranes, and leaves. PMID- 23679236 TI - Refractory Trichophyton rubrum infection in lamellar ichthyosis. AB - A 10-month-old boy with congenital lamellar ichthyosis presented with a chronic Trichophyton rubrum infection. There was no history of atopy or immunosuppression, and examination revealed high total immunoglobulin E (IgE) with a positive specific IgE for T. rubrum. Multiple treatments with fluconazole were necessary to control the infection. T. rubrum is present worldwide and is responsible for the vast majority of chronic dermatophytosis. Lamellar ichthyosis is a risk factor for chronic dermatophytosis because of excessive keratin and the barrier defect. A delayed-type hypersensitivity reaction to T. rubrum is associated with cure, whereas immediate hypersensitivity and IgE are not protective and may lead to chronic infection. Atopy and the Th2 profile therefore seem to be associated with chronic dermatophytosis. The association between ichthyosis and atopy is well documented. T. rubrum also has an interesting ability to evade immunity, which helps explain the chronic infection. Finally, in ichthyosis, it is likely that fluconazole has difficulty penetrating the acanthotic stratum corneum, which explains treatment failure. We report this case to alert clinicians to the possible association between lamellar ichthyosis and chronic dermatophytosis and to report the difficulties of management. PMID- 23679237 TI - Cruciferous vegetables: dietary phytochemicals for cancer prevention. AB - Relationships between diet and health have attracted attention for centuries; but links between diet and cancer have been a focus only in recent decades. The consumption of diet-containing carcinogens, including polycyclic aromatic hydrocarbons and heterocyclic amines is most closely correlated with increasing cancer risk. Epidemiological evidence strongly suggests that consumption of dietary phytochemicals found in vegetables and fruit can decrease cancer incidence. Among the various vegetables, broccoli and other cruciferous species appear most closely associated with reduced cancer risk in organs such as the colorectum, lung, prostate and breast. The protecting effects against cancer risk have been attributed, at least partly, due to their comparatively high amounts of glucosinolates, which differentiate them from other vegetables. Glucosinolates, a class of sulphur- containing glycosides, present at substantial amounts in cruciferous vegetables, and their breakdown products such as the isothiocyanates, are believed to be responsible for their health benefits. However, the underlying mechanisms responsible for the chemopreventive effect of these compounds are likely to be manifold, possibly concerning very complex interactions, and thus difficult to fully understand. Therefore, this article provides a brief overview about the mechanism of such compounds involved in modulation of carcinogen metabolising enzyme systems. PMID- 23679238 TI - Progress on understanding the anticancer mechanisms of medicinal mushroom: inonotus obliquus. AB - Cancer is a leading cause of death worldwide. Recently, the demand for more effective and safer therapeutic agents for the chemoprevention of human cancer has increased. As a white rot fungus, Inonotus obliquus is valued as an edible and medicinal resource. Chemical investigations have shown that I. obliquus produces a diverse range of secondary metabolites, including phenolic compounds, melanins, and lanostane-type triterpenoids. Among these are active components for antioxidant, antitumoral, and antiviral activities and for improving human immunity against infection of pathogenic microbes. Importantly, their anticancer activities have become a hot recently, but with relatively little knowledge of their modes of action. Some compounds extracted from I. obliquus arrest cancer cells in the G0/G1 phase and then induce cell apoptosis or differentiation, whereas some examples directly participate in the cell apoptosis pathway. In other cases, polysaccharides from I. obliquus can indirectly be involved in anticancer processes mainly via stimulating the immune system. Furthermore, the antioxidative ability of I. obliquus extracts can prevent generation of cancer cells. In this review, we highlight recent findings regarding mechanisms underlying the anticancer influence of I. obliquus, to provide a comprehensive landscape view of the actions of this mushroom in preventing cancer. PMID- 23679240 TI - Strategies of functional food for cancer prevention in human beings. AB - Functional food for prevention of chronic diseases is one of this century's key global challenges. Cancer is not only the first or second leading cause of death in China and other countries across the world, but also has diet as one of the most important modifiable risk factors. Major dietary factors now known to promote cancer development are polished grain foods and low intake of fresh vegetables, with general importance for an unhealthy lifestyle and obesity. The strategies of cancer prevention in human being are increased consumption of functional foods like whole grains (brown rice, barley, and buckwheat) and by products, as well some vegetables (bitter melon, garlic, onions, broccoli, and cabbage) and mushrooms (boletes and Tricholoma matsutake). In addition some beverages (green tea and coffee) may be protective. Southwest China (especially Yunnan Province) is a geographical area where functional crop production is closely related to the origins of human evolution with implications for anticancer influence. PMID- 23679239 TI - Expression and role of icam-1 in the occurrence and development of hepatocellular carcinoma. AB - Intercellular adhesion molecule-1 (ICAM-1) is a member of the immunoglobulin superfamily, its main function being to participate in recognition and adhesion between cells. ICAM-1 is considered closely related to occurrence, development, metastasis and invasion process of hepatocellular carcinoma (HCC). A variety of inflammatory cytokines and stimulus affect its expression through the nuclear factor-kappa B (NF-kappaB) signal transduction pathway. In the initial stage of inflammation, hepatocirrhosis and tumor development, ICAM-1 is expressed differently, and has varied effects on different cells to promote occurrence of malignancy and metastasis. ICAM-1 has diagnostic significance for AFP-negative or suspected HCC, and may be a prognositic significance. It is thus widely used in studies as a biomarker which reflects cancer cells metastasis as well as curative effect of drugs. Many new treatments of HCC may be based on the effects of ICAM-1 on different levels of function. PMID- 23679241 TI - Palliative treatment of advanced cervical cancer with radiotherapy and thai herbal medicine as supportive remedy - analysis of survival. AB - BACKGROUND: To evaluate outcomes using a Thai herbal medicine, Vilac Plus (G716/45) with standard radiotherapy in comparison with historic controls from literature reports of the results of treatment in stage IIIB cervical cancer. MATERIALS AND METHODS: Between March 2003 and June 2005, thirty patients with advanced cervical cancer stage IIIB-IV who had a poor performance status were treated by palliative radiotherapy along with an adjuvant daily dose of 15-30 ml of Thai herbal tonic solution (Vilac Plus G716/45) administered orally three times after meals as an additional supportive therapy. The results were analyzed from the aspect of the overall survival rates with curves estimated by the Kaplan Meier method. RESULTS: The median follow -up time for stage IIIB was 4.2 years with a range of 7.9 months - 6.1 years. The overall 1, 3, and 5 year survival rates for stage IIIB were 88%, 60% and 52%. CONCLUSIONS: The overall 5 year survival rate for stage IIIB with a poor performance status was 52% when compared with 34-54.8% for historic controls. The combined complementary palliative radiotherapy (CCPR) had low rates of radiation morbidity. It was a simple technique and feasible for developing countries. The pilot study was limited by the small number of patients and further research will be necessary to assess interrelated and confounding factors in treatment of cervical cancer patients. PMID- 23679242 TI - Serum levels of CA15-3, AFP, CA19-9 and CEA tumor markers in cancer care and treatment of patients with impaired renal function on hemodialysis. AB - Since renal failure causes decrease in tumor marker excretion, use of these markers in cancer care and treatment in patients with renal insufficiency or hemodialysis is controversial. The aim of this study was to investigate differences of serum levels of tumor markers CA15-3, AFP, CA19-9 and CEA in patients with impaired renal function. A total of 100 patients referred to the Tabriz Immam Reza and Amiralmomenin hospital from June 2010 to November 2011 were selected for study. Subjects were divided to 3 groups of healthy, dialysis and renal failure but non hemodialysis cases, the last category being re-grouped based on creatinine clearance. No significant relationship between different groups in serum levels of CEA (P=0.99) and CA19-9 (P=0.29) tumor markers was found. A significant correlation was observed between serum levels of AFP (P<0.001) and CA15-3 (P<0.001) and also a tendency between creatinine clearance and CEA (r=0.05, P=0.625). Creatinine clearance significantly correlated with AFP (P<0.001, r=0.53) and CA15-3 (p=0.00, r=-0.412), but not CA19-9 (P=0.089, r= 0.171). According to results of this study it appears that use of tumor markers in patients with impaired renal function should be performed with special precautions. PMID- 23679243 TI - Detection of circulating tumor cells in breast cancer patients: prognostic predictive role. AB - A determination of circulating tumor cell (CTC) effectiveness for prediction of progression-free survival (PFS) and overall survival (OS) was conducted as an adjunct to standard treatment of care in breast cancer management. Between November 2008 and March 2009, 22 metastatic and 12 early stage breast carcinoma patients, admitted to Ankara Oncology Training and Research Hospital, were included in this prospective trial. Patients' characteristics, treatment schedules and survival data were evaluated. CTC was detected twice by CellSearch method before and 9-12 weeks after the initiation of chemotherapy. A cut-off value equal or greater than 5 cells per 7.5 ml blood sample was considered positive. All patients were female. Median ages were 48.0 (range: 29-65) and 52.5 (range: 35-66) in early stage and metastatic subgroups, respectively. CTC was positive in 3 (13.6%) patients before chemotherapy and 6 (27.3%) patients during chemotherapy in the metastatic subgroup whereas positive in only one patient in the early stage subgroup before and during chemotherapy. The median follow-up was 22.0 (range: 21-23) and 19.0 (range: 5-23) months in the early stage and metastatic groups, respectively. In the metastatic group, both median PFS and OS were significantly shorter in any time CTC positive patients compared to CTC negative patients (PFS: 4.0 vs 14.0 months, Log-Rank p=0.013; and OS: 8.0 months vs. 20.5 months, Log-Rank p<0.001). OS was affected from multiple visceral metastatic sites (p=0.055) and higher grade (p=0.044) besides CTC positivity (log rank p<0.001). Radiological response of chemotherapy was also correlated with better survival (p<0.001). As a result, CTC positivity was confirmed as a prospective marker even in a small patient population, in this single center study. Measurement of CTC by CellSearch method in metastatic breast carcinoma cases may allow indications of early risk of relapse or death with even as few as two measurements during a chemotherapy program, but this finding should be confirmed with prospective trials in larger study populations. PMID- 23679244 TI - Influence of intravenous contrast medium on dose calculation using CT in treatment planning for oesophageal cancer. AB - OBJECTIVE: To evaluate the effect of intravenous contrast on dose calculation in radiation treatment planning for oesophageal cancer. METHODS: A total of 22 intravein-contrasted patients with oesophageal cancer were included. The Hounsfield unit (HU) value of the enhanced blood stream in thoracic great vessels and heart was overridden with 45 HU to simulate the non-contrast CT image, and 145 HU, 245 HU, 345 HU, and 445 HU to model the different contrast-enhanced scenarios. 1000 HU and -1000 HU were used to evaluate two non-physiologic extreme scenarios. Variation in dose distribution of the different scenarios was calculated to quantify the effect of contrast enhancement. RESULTS: In the contrast-enhanced scenarios, the mean variation in dose for planning target volume (PTV) was less than 1.0%, and those for the total lung and spinal cord were less than 0.5%. When the HU value of the blood stream exceeded 245 the average variation exceeded 1.0% for the heart V40. In the non-physiologic extreme scenarios, the dose variationof PTV was less than 1.0%, while the dose calculations of the organs at risk were greater than 2.0%. CONCLUSIONS: The use of contrast agent does not significantly influence dose calculation of PTV, lung and spinal cord. However, it does have influence on dose accuracy for heart. PMID- 23679245 TI - Prognostic value of matrix metalloproteinase 9 expression in breast cancer patients: a meta-analysis. AB - BACKGROUND: Matrix metalloproteinase 9 (MMP-9) is related to tumor invasion and metastasis. However, the role of MMP-9 expression in breast cancer survival remains controversial. The purpose of this study was to accomplish a more accurate estimation of the association between MMP-9 expression and survival results in breast cancer patients through meta-analysis. METHODS: A meta-analysis of published studies investigating the effects of positive MMP-9 expression on both relapse free survival (RFS) and overall survival (OS) was performed. Relevant literature was confirmed by searching electronic databases including PubMed, Ovid, EMBASE and China National Knowledge Infrastructure (CNKI) before November 1, 2012. Individual hazard ratios (HRs) and 95% confidence intervals (CIs) were extracted and pooled HRs with 95% CIs were used to evaluate the strength of the association between positive MMP-9 expression and survival results of breast cancer patients. Funnel plot and Egger's regression tests were used to evaluate publication bias. Heterogeneity and sensitivity analysis was also conducted. All the work was completed using STATA. RESULTS: A total of 2,344 patients from 15 evaluative studies were finally included. Pooled HRs and 95% CIs suggested that MMP-9 overexpression had an unfavorable impact on both OS (HR: 1.70, 95% CI: 1.41-2.04) and RFS (HR: 1.54, 95% CI: 1.17-2.01) in breast cancer patients. There was no significant heterogeneity observed in the studies reported for OS (P=0.360, I2=8.8%), but not RFS (P=0.002, I2=67%). Publication bias was absent among the studies both in OS and RFS cases (t=-0.54, P=0.605 and t=1.71, P=0.131, respectively). Omission of any single study had little effect on the combined risk estimates on sensitivity analysis. CONCLUSION: The results of this meta-analysis suggest that positive MMP-9 expression confers a higher risk of relapse and a worse survival in patients with breast cancer. Larger prospective studies are now needed to evaluate the clinical utility of MMP-9 expression. PMID- 23679246 TI - Factors affecting survival time of cholangiocarcinoma patients: a prospective study in Northeast Thailand. AB - Cholangiocarcinoma (CCA) is a major health problem and cause of death among people in Northeastern Thailand. In this prospective study 171 patients newly diagnosed with CCA by physicians in 5 tertiary hospitals in four provinces of northeastern of Thailand between February and July 2011 were followed up to January 2012. The outcome was survival time from diagnosis to death. A total of 758.4 person-months of follow-up were available. The mortality rate was 16.9 per 100 person-months (95%CI: 14.1-20.1). The median survival time among CCA patients was 4.3 months (95%CI: 3.3-5.1). Cox's proportional hazard model was used to study the independent effects of factors affecting survival time among patients. Statistically significant factors included advanced stage at diagnosis (HR: 2.5, 95%CI: 1.7-3.8), presentation with jaundice (HR: 1.7, 95%CI: 1.1-2.4) or ascites (HR: 2.8, 95%CI: 1.8-4.4), and positive serum carcinoembryonic antigen (HR: 2.3, 95%CI: 1.2-4.3). Patients who had received standard treatment had a better prognosis that those who did not (HR: 0.5, 95%CI: 0.3-0.7). PMID- 23679247 TI - Comparison of univariate and multivariate gene set analysis in acute lymphoblastic leukemia. AB - BACKGROUND: Gene set analysis (GSA) incorporates biological with statistical knowledge to identify gene sets which are differentially expressed that between two or more phenotypes. MATERIALS AND METHODS: In this paper gene sets differentially expressed between acute lymphoblastic leukaemia (ALL) with BCR-ABL and those with no observed cytogenetic abnormalities were determined by GSA methods. The BCR-ABL is an abnormal gene found in some people with ALL. RESULTS: The results of two GSAs showed that the Category test identified 30 gene sets differentially expressed between two phenotypes, while the Hotelling's T2 could discover just 19 gene sets. On the other hand, assessment of common genes among significant gene sets showed that there were high agreement between the results of GSA and the findings of biologists. In addition, the performance of these methods was compared by simulated and ALL data. CONCLUSIONS: The results on simulated data indicated decrease in the type I error rate and increase the power in multivariate (Hotelling's T2) test as increasing the correlation between gene pairs in contrast to the univariate (Category) test. PMID- 23679248 TI - Antigenic proteins of Helicobacter pylori of potential diagnostic value. AB - Helicobacter pylori antigen was prepared from an isolate from a patient with a duodenal ulcer. Serum samples were obtained from culture-positive H. pylori infected patients with duodenal ulcers, gastric ulcers and gastritis (n=30). As controls, three kinds of sera without detectable H. pylori IgG antibodies were used: 30 from healthy individuals without history of gastric disorders, 30 from patients who were seen in the endoscopy clinic but were H. pylori culture negative and 30 from people with other diseases. OFF-GEL electrophoresis, SDS PAGE and Western blots of individual serum samples were used to identify protein bands with good sensitivity and specificity when probed with the above sera and HRP-conjugated anti-human IgG. Four H. pylori protein bands showed good (>= 70%) sensitivity and high specificity (98-100%) towards anti-Helicobacter IgG antibody in culture- positive patients sera and control sera, respectively. The identities of the antigenic proteins were elucidated by mass spectrometry. The relative molecular weights and the identities of the proteins, based on MALDI TOF/ TOF, were as follows: CagI (25 kDa), urease G accessory protein (25 kDa), UreB (63 kDa) and proline/pyrroline- 5-carboxylate dehydrogenase (118 KDa). These identified proteins, singly and/or in combinations, may be useful for diagnosis of H. pylori infection in patients. PMID- 23679249 TI - Scoring system and management algorithm assessing the role of survivin expression in predicting progressivity of HPV infections in precancerous cervical lesions. AB - BACKGROUND: To identify the risk factors and assess the role of survivin in predicting progessivity precancerous cervical lesions. MATERIALS AND METHODS: This case-control study was conducted from October 2009 until May 2010. We obtained 74 samples, classified according to the degree of cervical intraepithelial neoplasia (CIN): 19 samples for CIN 1, 18 samples for CIN 2, 18 samples for CIN 3, and 19 samples as controls. Demographic profiles and risk factors assesment, histopathologic examination, HPV DNA tests, immunocytochemistry (ICC) and immunohistochemistry (IHC) staining for survivin expression were performed on all samples. Data was analyzed with bivariate and multivariate analysis. RESULTS: Multivariate analysis revealed significant risk factors for developing precancerous cervical lesions are age <41 years, women with >=2 sexual partners, course of education >=13 years, use of oral contraceptives, positive high-risk HPV DNA, and high survivin expression by ICC or IHC staining. These factors were fit to a prediction model and we obtained a scoring system to predict the progressivity of CIN lesions. CONCLUSIONS: Determination of survivin expression by immunocytochemistry staining, along with other significant risk factors, can be used in a scoring system to predict the progressivity of CIN lesions. Application of this scoring system may be beneficial in determining the action of therapy towards the patient. PMID- 23679250 TI - Clinical application of transcatheter arterial chemoembolization combined with synchronous C-arm cone-beam CT guided radiofrequency ablation in treatment of large hepatocellular carcinoma. AB - OBJECTIVE: This work aimed to evaluate the safety and clinical efficacy of transcatheter arterial chemoembolization (TACE) combined with c-arm cone-beam CT guided synchronous radiofrequency ablation (RFA) in treatment of large hepatocellular carcinoma (HCC). METHODS: 21 patients with large HCC were studied from January 2010 to March 2012. TACE combined with synchronous C-arm cone-beam CT guided RFA were performed on a total of 25 lesions. Conventional imaging examination (CEUS, enhanced CT or MRI) and AFP detection were regularly conducted to evaluate the technical success rate of combined treatment, complications, treatment response, time without disease recurrence and survival rate. RESULTS: The technical success rate of combined treatment was 100%, without any significant complication. After 1 month, there were 19 cases with complete response and 2 cases with partial response, with an complete response rate of 90.4% (19/21) and a clinical effective rate of 100% (21/21). The complete response rates of single nodular lesions (100%, 17/17) was significantly higher than that of multiple nodular lesions (50%, 2/4) (P < 0. 05). During 2 to 28 months of follow- up, in 19 cases with complete response, the average time without disease recurrence was 10.8 +/- 6 months. The total survival rates of 6, 12 and 18 months in 21 patients were 100%, respectively. CONCLUSION: TACE combined with synchronous C-arm CT guided RFA is safe and effective for treatment of large HCC. The treatment efficacy for single nodular lesion is better than that for multiple nodular lesions. PMID- 23679251 TI - Quantification of Her-2/Neu gene in breast cancer patients using real time polymerase chain reaction (Q-PCR) and correlation with immunohistochemistry findings. AB - BACKGROUND: HER-2/neu is a proto-oncogene that encodes a transmembrane tyrosine kinase growth factor which is crucial for stimulating growth and cellular motility. Overexpression of HER-2/neu is observed in 10-35% of human breast cancers and is associated with pathogenesis, prognosis as well as response to therapy. Given the imperative role of HER-2/neu overexpression in breast cancer, it is important to determine the magnitude of amplification which may facilitate a better prognosis as well as personalized therapy in affected patients. In this study, we determined HER-2/neu protein expression by immunohistochemistry (IHC) concurrently with HER-2/neu DNA amplification by quantitative real time polymerase chain reaction (Q-PCR). MATERIALS AND METHODS: A total of 53 paired tissue samples from breast cancer patients were frozen-sectioned to characterize the tumour and normal tissues. Only tissues with 80% tumour cells were used in this study. For confirmation, Q-PCR was used to determine the HER-2/neu DNA amplification. RESULTS: We found 20/53 (37.7%) of the tumour tissues to be positive for HER-2/neu protein overexpression using IHC. Out of these twenty, only 9/53 (17%) cases were in agreement with the Q-PCR results. The concordance rate between IHC and Q-PCR was 79.3%. Approximately 20.7% of positive IHC cases showed no HER-2/neu gene amplification using Q-PCR. CONCLUSION: In conclusion, IHC can be used as an initial screening method for detection of the HER-2/neu protein overexpression. Techniques such as Q-PCR should be employed to verify the IHC results for uncertain cases as well as determination of HER-2/neu gene amplification. PMID- 23679252 TI - Personalized cancer treatment for ovarian cancer. AB - Recently there have been numerous advances in understanding the genetic basis of cancer which have resulted in more appropriate treatments. In this paper we describe the experience of the Burzynski Clinic, involved in treatment of numerous patients based on personalized approach using novel combinations for difficult-to-treat malignancies, with gynecological cancers. This retrospective study was conducted by extracting data from Burzynski Clinic's medical records and comprehensive review. Among the advanced refractory ovarian cancers cases (N=33), an objective response (OR) was found in 42.4%. We anticipate that with improved technology and novel therapeutics this rate will increase and adverse events will be reduced. PMID- 23679253 TI - Lymph node ratio assessment of brain metastasis in early breast cancer cases. AB - BACKGROUND: Ten to 30% of early breast cancer (EBC) patients develop brain metastasis (BM) during their follow-up. In this study, we aimed to evaluate importance of the lymph node ratio (LNR) in development of BM in EBC cases. MATERIALS AND METHODS: Ninety patients whom had axillary metastases in lymph nodes at their initial diagnosis and developed BM during 5-year follow-up were detected in 950 EBC patients. LNR values were calculated for all patients and after categorization into 4 molecular sub-types as luminal A, luminal B HER-2 (+), HER-2 overexpressing and basal- like. Comparison was with control group patients who had similar characteristics. RESULTS: In the comparison of all molecular sub-types of LNR, 54.9% and 28.4% values were found in patients with and without BM respectively (p<0.001). In the comparison of the LNR with control groups, a statistically significant differences were found with luminal A with BM (p=0.001), luminal B HER-2 (p=0.001), HER-2 overexpressing (p=0.027) and basal like groups (p<0.001). In the evaluation of patients with BM, the highest ratio was found in the basal-like group (67.9%) and there was a statistically significant difference between this group and the others (p=0.048). CONCLUSIONS: EBC patients developing BM within 5 years follow- up had significantly higher LNRs for all molecular sub-types, especially in the basal-like group. Larger scale studies are now needed for evaluating LNR prognostic importance for EBC regarding BM development. PMID- 23679254 TI - Correlation of cancer incidence with diet, smoking and socio- economic position across 22 districts of Tehran in 2008. AB - BACKGROUND: Variation in cancer incidence in geographical locations is due to different lifestyles and risk factors. Diet and socio-economic position (SEP) have been identified as important for the etiology of cancer but patterns are changing and inconsistent. The aim of this study was to investigate correlations of the incidence of common cancers with food groups, total energy, smoking, and SEP. MATERIALS AND METHODS: In an ecological study, disaggregated cancer data through the National Cancer Registry in Iran (2008) and dietary intake, smoking habits and SEP obtained through a population based survey within the Urban Health Equity Assessment (Urban-HEART) project were correlated across 22 districts of Tehran. RESULTS: Consumption of fruit, meat and dairy products adjusted for energy were positively correlated with bladder, colorectal, prostate and breast and total cancers in men and women, while these cancers were adversely correlated with bread and fat intake. Also prostate, breast, colorectal, bladder and ovarian cancers had a positive correlation with SEP; there was no correlation between SEP and skin cancer in both genders and stomach cancer in men. CONCLUSIONS: The incidence of cancer was higher in some regions of Tehran which appeared to be mainly determined by SEP rather than dietary intake. Further individual data are required to investigate reasons of cancer clustering. PMID- 23679255 TI - Survival in patients treated with definitive chemo- radiotherapy for non metastatic esophageal cancer in north- west iran. AB - BACKGROUND: Areas of Iran have among the highest incidences of esophageal cancer in the world. Definitive chemo-radiotherapy (DCRT) is used for locally advanced esophageal cancer and for inoperable tumors asan alternative to surgical treatment. MATERIALS AND METHODS: This retrospective study was conducted in North West Iran 2006-2011, including 267 consecutive patients with non-metastatic esophageal cancer. Eligible inoperable patients were treated with DCRT or definitive radiotherapy (DRT) alone. Radiotherapy (RT) was delivered at 1.8-2 Gy/day for five consecutive days in a given week. Chemotherapy (CT) consisted of cisplatin and 5-fluorouracil. RESULTS: The median survival was 12.7 months with 1, 3 and 5 year survival rates of 55%, 18% and 11%, respectively. On univariate analysis, relations with age at diagnosis (p=0.015), N-stage (p=0.04), total dose of RT (p=0.001), fraction (p<0.001), Gap status (p=0.025), chemotherapeutic regimens (P=0.027), and 5-Fu Mg/m2 (P=0.004) were apparent. Comparing DCRT to DRT, there was a significant difference in survival. Multivariate analysis was performed for comparison between DCRT and DRT showed significant association with age group >=65 to <65 (P=0.02; OR: 1.46), the total RT dose (Gy) >=50 to <50 (P=0.01; OR: 0.65) and the fraction group >=25 to <25 (P=<0.001; OR: 0.54). CONCLUSIONS: The survival rates of esophageal cancer treated with DCRT in North West of Iran is poor; therefore, early detection and improved treatment methods, with clinical trials are a high priority. PMID- 23679256 TI - Tissue expression, serum and salivary levels of IL-10 in patients with head and neck squamous cell carcinoma. AB - BACKGROUND: Head and neck SCC is a common cancer related to various factors. IL 10, a pleiotropic cytokine produced by macrophages, T-helper-2 cells, and B lymphocytes, is thought to play a potential pathogenetic or therapeutic role in a number of human conditions, such as inflammation, autoimmunity and cancer. The present study was designed to evaluate the relation between tissue expression, serum and salivary levels of IL-10 in head and neck squamous cell carcinomas (HNSCCs) and their correlation with clinicopathologic features. MATERIALS AND METHODS: Samples were collected from 30 patients with HNSCCs and 24 healthy volunteers. IHC analysis was used to examine the tissue expression and ELISA was employed to measure serum and salivary levels. RESULTS: Our study showed tissue expression of IL-10 to be significantily higher in patients (P: 0.001), but there was no relation between tissue expression , serum and salivary levels of the marker (P>0.05). Also except for a positive correlation between tissue expression of IL-10 and stage (P: 0.044), there was no relation between this marker and clinicopathologic features. There was no correlation between serum and salivary levels in either patients or controls. CONCLUSIONS: It seems there is no correlation between level of IL-10 in serum and saliva and this marker in saliva and serum does not reflect tissue expression. PMID- 23679257 TI - Genetic screening for mutations in the chip gene in intracranial aneurysm patients of Chinese Han nationality. AB - We performed a case-control study to investigate whether SNPs of CHIP might affect the development of IA in Chinese Han nationality. We believe we are the first to have screened IA patients for mutations in the CHIP gene to determine the association with these variants. The study group comprised 224 Chinese Han nationality patients with at least one intracranial aneurysm and 238 unrelated healthy Han nationality controls. Genomic DNA was isolated from blood leukocytes. The entire coding regions of CHIP were genotyped by PCR amplification and DNA sequencing. Differences in genotype and allele frequencies between patients and controls were tested by the chi-square method. Genotype and allele frequencies of the SNP rs116166850 was demonstrated to be in Hardy-Weinberg equilibrium. No significant difference in genotype or allele frequencies between case and control groups was detected at the SNP. Our data do not support the hypothesis of a major role for the CHIP gene in IA development in the Chinese Han population. PMID- 23679258 TI - No association between tea consumption and risk of renal cell carcinoma: a meta analysis of epidemiological studies. AB - OBJECTIVE: To evaluate the association between tea consumption and the risk of renal cell carcinoma. METHODS: We searched PubMed,Web of Science and Scopus between 1970 and November 2012. Two evaluators independently reviewed and selected articles based on predetermined selection criteria. RESULTS: Twelve epidemiological studies (ten case-control studies and two cohort studies) were included in the final analysis. In a meta-analysis of all included studies, when compared with the lowest level of tea consumption, the overall relative risk (RR) of renal cell carcinoma for the highest level of tea consumption was 1.03 (95% confidence interval [CI] 0.89-1.21). In subgroup meta-analyses by study design, there was no significant association between tea consumption and renal cell carcinoma risk in ten case-control studies using adjusted data (RR=1.08, 95% CI 0.84-1.40). Furthermore, there was no significant association in two cohort studies using adjusted data (RR=0.95, 95% CI 0.81-1.12). CONCLUSION: Our findings do not support the conclusion that tea consumption is related to decreased risk of renal cell carcinoma. Further prospective cohort studies are required. PMID- 23679259 TI - Meta-analysis of GSTM1 and GSTT1 polymorphisms and risk of nasopharyngeal cancer. AB - BACKGROUND: Studies of associations between genetic polymorphism of glutathione S transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) with risk of nasopharyngeal cancer (NPC) have generated conflicting results. Thus, a meta analysis was performed to clarify the effects of GSTM1 and GSTT1 polymorphisms on the risk of developing NPC. MATERIALS AND METHODS: A literature search in two electronic databases namely PubMed and EMBASE up to December 2012 was conducted and eligible papers were finally selected based on the inclusion and exclusion criteria. The pooled odds ratio (OR) and presence of heterogeneity and publication bias in those studies were evaluated. RESULTS: A total of 9 studies concerning nasopharyngeal cancer were evaluated. Analyses of all relevant studies showed increased NPC risk to be significantly associated with the null genotypes of GSTMI (OR=1.43, 95%CI 1.24-1.66) and GSTT1 (OR=1.28, 95%CI=1.09-1.51). In addition, evidence of publication bias was detected among the studies on GSTM1 polymorphism. CONCLUSIONS: This meta-analysis demonstrated the GSTM1 and GSTT1 null genotypes are associated with an increased risk of NPC. PMID- 23679260 TI - In vitro and in vivo evaluation of the antitumor efficiency of resveratrol against lung cancer. AB - Lung cancer remains a deadly disease with unsatisfactory overall survival. Resveratrol (Res) has the potential to inhibit growth of several types of cancer such as prostate and colorectal examples. In the current study, we evaluated in vitro and in vivo anticancer efficiency of Res in a xenograft model with A549 cells. Cell inhibition effects of Res were measured by MTT assay. Apoptotis of A549 cells was assessed with reference to caspase-3 activity and growth curves of tumor volume and bodyweight of the mice were measured every two days. In vitro cytotoxicity evaluation indicated Res to exert dose-dependent cell inhibition effects against A549 cells with activation of caspase-3. In vivo evaluation showed Res to effectively inhibit the growth of lung cancer in a dose- dependent manner in nude mice. Therefore, we believe that Res might be a promising phytomedicine for cancer therapy and further efforts are needed to explore this potential therapeutic strategy. PMID- 23679261 TI - Education and counseling of pregnant patients with chronic hepatitis B: perspectives from obstetricians and perinatal nurses in Santa Clara County, California. AB - BACKGROUND: This study aimed to better understand the barriers to perinatal hepatitis B prevention and to identify the reasons for poor hepatitis B knowledge and delivery of education to hepatitis B surface-antigen- positive pregnant women among healthcare providers in Santa Clara County, California. MATERIALS AND METHODS: Qualitative interviews were conducted with 16 obstetricians and 17 perinatal nurses in Santa Clara County, California, which has one of the largest populations in the United States at high risk for perinatal hepatitis B transmission. RESULTS: Most providers displayed a lack of self-efficacy attributed to insufficient hepatitis B training and education. They felt discouraged from counseling and educating their patients because of a lack of resources and discouraging patient attitudes such as stigma and apathy. Providers called for institutional changes from the government, hospitals, and nonprofit organizations to improve care for patients with chronic hepatitis B. CONCLUSIONS: Early and continuing provider training, increased public awareness, and development of comprehensive resources and new programs may contribute to reducing the barriers for health care professionals to provide counseling and education to pregnant patients with chronic hepatitis B infection. PMID- 23679262 TI - Effects of differential distribution of microvessel density, possibly regulated by miR-374a, on breast cancer prognosis. AB - BACKGROUND: The discovery that microRNAs (miRNAs) regulate proliferation, invasion and metastasis provides a principal molecular basis of tumor heterogeneity. Microvessel distribution is an important characteristic of solid tumors, with significant hypoxia occurring in the center of tumors with low blood flow. The distribution of miR-374a in breast tumors was examined as a factor likely to be important in breast cancer progression. METHODS: Breast tissue samples from 40 patients with breast cancer were classified into two groups: a highly invasive and metastatic group (HIMG) and a low-invasive and metastatic Group (LIMG). Samples were collected from the center and edge of each tumor. In each group, six specimens were examined by microRNA array, and the remaining 14 specimens were used for real-time RT-qPCR, Western blot and immunohistochemical analyses. Correlation analysis was performed for the miRNAs and target proteins. Follow-up was carried out during 28 months to 68 months after surgery, and survival data were analyzed. RESULTS: In the LIMG, the relative content of miR 374a was lower in the center of the tumor than at its edge; in the HIMG, it was lower at the edge of the tumor, and miR-374a levels were lower in breast cancer tissues than in normal tissues. There was no difference between VEGF-A and VCAM-1 mRNA levels at the edge and center of the tumor; however, we observed a significant difference between VEGF-A and VCAM-1 protein expression levels in these two regions. There was a negative correlation between miR-374a and target protein levels. The microvessel density (MVD) was lower in the center of the tumor than at its edge in HIMG, but the LIMG vessels were uniformly distributed. There was a significant positive correlation between MVD and the number of lymph node metastases (Pearson correlation, r=0.912, P<0.01). The median follow-up time was 48.5 months. LIMG had higher rate of disease-free survival (100%, P=0.013) and longer median survival time (66 months) than HIMG, which had a lower rate of 75% and shorter median survival time (54 months). CONCLUSIONS: Our data demonstrated miR-374a to be differentially distributed in breast cancer; VEGF-A and VCAM-1 mRNA had coincident distribution, and the distribution of teh respective proteins was uneven and opposite to that for the miR-374a. These data might explain the differences in the distribution of MVD in breast cancer and variation in breast cancer prognosis. PMID- 23679263 TI - Epirubicin inhibits soluble CD25 secretion by Treg cells isolated from diffuse large B-cell lymphoma patients. AB - OBJECTIVE: To investigate the effect of epirubicin on soluble CD25 (sCD25) secretion by CD4+CD25+ regulatory T (Treg) cells isolated from diffuse large B cell lymphoma (DLBCL) patients. METHODS: Treg cells were isolated from the peripheral blood mononuclear cells isolated from the newly diagnosed DBLCL patients. The concentration of sCD25 in the supernatant was determined with a commercial sCD25 (IL-2R) enzyme-linked immunosorbent assay (ELISA) kit. The fluorescence intensity of CD25 was detected by flow cytometry. RESULTS: Cell survival rate was significantly decreased along with the increase of epirubicin concentration after treatment for 24 h. There was also a significant difference in the concentration of sCD25 between the epirubicin group and the control group (P<0.01). A positive correlation between the Treg cells survival rate and the concentration of sCD25 was detected (r=0.993, P<0.01). When equal numbers of CD4+CD25+ Treg cells of the epirubicin group and the control group were cultured for another 24 h without epirubicin the CD25 fluorescence intensity on the surface of Treg cells was obviously higher in the epirubicin group than that in the control group (P<0.01), while the sCD25 concentration in the supernatant in the epirubicin group was significantly lower than that in the control group (P<0.05). CONCLUSION: Epirubicin may improve the body's immune functions by inhibiting the sCD25 secretion by Treg cells in DLBCL patients. PMID- 23679264 TI - Prognostic significance of circulating tumor cells and serum CA15-3 levels in metastatic breast cancer, single center experience, preliminary results. AB - BACKGROUND: Breast cancer is the second leading cancer causing death in women. Circulating tumor cells are among the prognostic factors while tumor markers are of diagnostic value and can be used for follow-up. The aim of this study was to investigate the correlation between the prognostic significance of the serum CA15 3 levels, number of circulating tumor cells and histopathological tumor factors. MATERIALS AND METHODS: Thirty patients recently diagnosed with breast cancer were included in the study. Number of circulating tumor cells and serum CA15-3 level were assessed when metastasis was detected and diagnostic value was assessed. Presence of associations with estrogen and progesterone receptors, c-erbB2, Ki-67 proliferation index and histological grade were also evaluated. RESULTS: Median overall survival of the patients with serum CA15-3 levels of >108 ng/dl was 19 months whereas for those with a low serum level it was 62 months. Median overall survival for CTC >=5vs CTC<5 patients was 19 months and 40 months respectively. The difference between the two groups was statistically significant. CONCLUSIONS: Prognostic significance of the CTC count and CA15-3 levels in metastatic breast cancer patients was demonstrated. PMID- 23679265 TI - Exploration of molecular mechanisms of diffuse large B-cell lymphoma development using a microarray. AB - OBJECTIVE: We aimed to identify key genes, pathways and function modules in the development of diffuse large B-cell lymphoma (DLBCL) with microarray data and interaction network analysis. METHODS: Microarray data sets for 7 DLBCL samples and 7 normal controls was downloaded from the Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) were identified with Student's t-test. KEGG functional enrichment analysis was performed to uncover their biological functions. Three global networks were established for immune system, signaling molecules and interactions and cancer genes. The DEGs were compared with the networks to observe their distributions and determine important key genes, pathways and modules. RESULTS: A total of 945 DEGs were obtained, 272 up regulated and 673 down-regulated. KEGG analysis revealed that two groups of pathways were significantly enriched: immune function and signaling molecules and interactions. Following interaction network analysis further confirmed the association of DEGs in immune system, signaling molecules and interactions and cancer genes. CONCLUSIONS: Our study could systemically characterize gene expression changes in DLBCL with microarray technology. A range of key genes, pathways and function modules were revealed. Utility in diagnosis and treatment may be expected with further focused research. PMID- 23679266 TI - Compliance with screening recommendations according to breast cancer risk levels in Izmir, Turkey. AB - Early diagnosis has a major role in improving prognosis of breast cancer. The purpose of this study was to assess the risk status of women 35-69 years of age using risk assessment models and the prevalence of mammography in a community setting. The sample of this cross sectional study consisted of 227 women, 35-69 years of age residing in Izmir, a city located in western region of Turkey. A questionnaire was used to collect data and the Gail and Cuzick-Tyrer models were applied to assess the risk of breast cancer. In this study, 52.7% of women had mammography at least once, and 41.3% of the women over the age of 40 had mammography screening in the last two years. The five years risk for breast cancer was high in 15.8% of women according to the Gail model and ten years risk was high in 21.7% with the Cuzick-Tyrer model. In the present study, the breast cancer risk levels were assessed in a population setting for the first time in Turkey using breast cancer risk level assessment models. Being in 60-69 age group, having low education and not being in menopause were significant risk factors for not having mammography according to logistic regression analysis. Mammography utilization rate was low. Women must be educated about breast cancer screening methods and early diagnosis. The women in the high risk group should be informed on their risk status which may increase their attendance at breast cancer screening. PMID- 23679267 TI - Clinical and histopathological analysis of 66 cases with cardiac myxoma. AB - BACKGROUND AND PURPOSE: Cardiac myxoma is a major primary heart tumor which often causes unexpected symptoms or sudden death. This present study was designed to investigate its clinical pathological features and biological behavior. METHODS: A retrospective analysis of the clinical pathologic and immunohistochemical features of 66 cases with cardiac myxoma was conducted. RESULTS: In 66 patients with cardiac myxoma, 61 cases had involvement of the left atrium, one case in both the right ventricular and left atria. The female: male ratio was 2.7:1. Patients had symptoms of blood flow obstruction and systemic alterations with performance of arterial embolization. Tumors were spherical, lobulated or irregular in shape, and soft and brittle. Immunohistochemical markers of vimentin and CD34 in tumor cells were positive. CONCLUSION: Cardiac myxoma always exists in the left atrium and is more common in women, with diverse clinical manifestations and pathomorphism. Although proliferative activity and the recurrence rate are low, in addition to thorough surgical resection, strengthened review is important for young patients. PMID- 23679268 TI - Determinants of smoking initiation and susceptibility to future smoking among school-going adolescents in Lagos State, Nigeria. AB - BACKGROUND: It is projected that low and middle-income countries will bear a major burden of tobacco related morbidity and mortality, yet, only limited information is available on the determinants of smoking initiation among youth in Africa. This study aimed to assess the determinants of smoking initiation and susceptibility to future smoking among a population of high school school students in Lagos, Nigeria. MATERIALS AND METHODS: Baseline data from an intervention study designed to assess the effect of an anti-smoking awareness program on the knowledge, attitudes and practices of adolescents was analyzed. The survey was carried out in six randomly selected public and private secondary schools in local government areas in Lagos state, Nigeria. A total of 973 students completed self-administered questionnaires on smoking initiation, health related knowledge and attitudes towards smoking, susceptibility to future smoking and other factors associated with smoking. RESULTS: Of the respondents, 9.7% had initiated smoking tobacco products with the predominant form being cigarettes (7.3%). Males (OR: 2.77, 95%CI: 1.65-4.66) and those with more pro-smoking attitudes (OR: 1.44, 95%CI: 1.34-1.54) were more likely to have initiated smoking. Those with parents and friends who are smokers were 3.47 (95%CI: 1.50 8.05) and 2.26 (95%CI: 1.27-4.01) times more likely to have initiated smoking. Non-smoking students, in privately owned schools (OR: 5.08), with friends who smoke (5.09), with lower knowledge (OR: 0.87) and more pro-smoking attitudes (OR 1.13) were more susceptible to future smoking. In addition, respondents who had been sent to purchase cigarettes by an older adult (OR: 3.68) were also more susceptible to future smoking. CONCLUSIONS: Being male and having parents who smoke are predictors of smoking initiation among these students. Consistent with findings in other countries, peers not only influence smoking initiation but also influence smoking susceptibility among youth in this African setting. Prevention programs designed to reduce tobacco use among in-school youth should take these factors into consideration. In line with the recommendations of article 16 of the WHO FCTC, efforts to enforce the ban on the sales of cigarettes to minors should be also emphasised. PMID- 23679269 TI - Low prevalence of HPV in male sexual partners of HR-HPV infected females and low concordance of viral types in couples in Eastern Guangdong. AB - OBJECTIVE: To investigate the prevalence of genital high-risk human papillomavirus (HR-HPV) in male sexual partners of HR-HPV infected women and the concordance of viral types in couples in China, and comprehend the role of men play in HPV transmission to women. METHODS/MATERIALS: 94 asymptomatic women and their husbands from rural Chaozhou participated in epidemiologic screening for HPV infection. Cervical cells from females were collected for high risk HPV screening by real time-PCR, and they were positive for at least 1 of 13 HR-HPV subtypes, then these samples were genotyped. Approximately one mouth later, penile epithelial cells from 94 asymptomatic husbands were collected for HPV genotyping. At the same time, a cross-sectional study was conducted in 366 male patients from sexually transmitted disease (STD) outpatient clinic in China for the prevalence of genital HR-HPV infection in men having frequent sex behavior. Penial epithelial cells were collected for HPV 6/11 and HPV 16/18 detection by fluorescent real-time quantified PCR. RESULTS: Among 94 couples, the prevalence of genital HR-HPV infection in men whose wife was positive for cervical HR-HPV was 5.32% (5/94). Only 2.63% (2/76) had the same high risk viral type presented by their wife. HPV 16 proved to be the most prevalent viral type in men and in couples. Of 366 male patients from STD outpatient clinic, the prevalence of HPV 16/18 infection in men with or without HPV 6/11 was 6.85% and 8.16%, respectively. The incidence of HPV 16/18 was higher in men aged more than 35 years than the young men (18-35 years). CONCLUSION: The prevalence of genital HR HPV infection in male sexual partners of HPV-positive women in China was lower than that expected, and the concordance of high risk viral type between couples was extremely low. These data suggested that infected men consitute an important viral reservoir, contributing to transmission of HR-HPV to women and maintenance of infection, but HR-HPV infection may be less likely to persist in men than in women. PMID- 23679270 TI - Quality of life and chemotherapy-related symptoms of Turkish cancer children undergoing chemotherapy. AB - This cross-sectional and descriptive study was designed to determine symptoms emerging due to chemotherapy treatment and their effects on children's quality of life. The research was carried out between February 2008 and February 2009 at the pediatric oncology clinics in four hospitals, focusing on 93 patients receiving chemotherapy. A survey form, the Pediatric Quality of Life Inventory (PedsQL 4.0) and the Memorial Symptom Assessment Scale (MSAS) were used as data collection tools. Chi-square and Student t tests were performed for data analysis. Some 51.6% of the children were aged 13-15 years old, and 51.8% were boys and 50.5% were diagnosed as having solid tumors. There were significant relations between: antimetabolite chemotherapeutics and feeling irritable and worrying (p=0.001, p=0.030); vinkoalkaloid and numbness/tingling in hands/feet (p=0.043); antracyclines and lack of energy and skin changes (p=0.021, p=0.004); and corticosteroids and lack of appetite, nausea and sadness (p=0.008, p=0.009, p=0.009). Several symptoms such as feeling sad, worrying and feeling irritable caused a significant decrease in the total domain of quality of life scores (p=0.034, p=0.012, p=0.010, respectively). Chemotherapeutic drugs can cause symptoms that can seriously affect quality of life in children. PMID- 23679271 TI - Positive association between miR-499A>G and hepatocellular carcinoma risk in a Chinese population. AB - A case-control study of the association of miR-499A>G rs3746444 with risk of hepatocellular carcinoma (HCC)was conducted. Patients with HCC and healthy control subjects were recruited for genotyping of miR- 499A>G using duplex polymerase-chain-reaction with confronting-two-pair primer(PCR-RFLP) analysis. The MiR-499 GG genotype was associated with a decreased risk of HCC as compared with the miR-499 AA genotype (adjusted OR=0.74, 95%CI=0.24-0.96). Similarly, the GG genotype showed a 0.45-fold decreased HCC risk in a recessive model. The MiR 499 G allele was significantly associated with decreased risk of HCC among patients infected with HBV in a dominant model (OR=0.09, 95%CI= 0.02-0.29). In conclusion, the MiR-499A>G rs3746444 polymorphism is associated with HCC risk in the Chinese population, and may be useful predictive marker for CAD susceptibility. PMID- 23679272 TI - Prevalence of the metabolic syndrome and associated factors in korean cancer survivors. AB - BACKGROUND: This study was designed to evaluate prevalence of the metabolic syndrome among cancer survivors compared to non-cancer controls from a population based sample and to identify associated risk factors. MATERIALS AND METHODS: Data from the fourth Korean National Health and Nutrition Examination Survey were analyzed to compare the prevalence of metabolic syndrome, as defined by 2009 consensus criteria. Associated factors with were identified using multiple logistic regression analysis among cancer survivors. RESULTS: The prevalence of the metabolic syndrome in cancer survivors (n = 335) was similar to that in the non-cancer population (n = 10,671). However, gastric cancer survivors showed lower risk of metabolic syndrome than non-cancer controls (adjusted odds ratio [aOR] 0.42, 95% confidence interval [CI] 0.20-0.86). Age of more than 60 years (aOR 4.83, 95% CI 1.94?12.03), BMI between 23 and 25 (aOR 6.71, 95% CI 2.90?15.6), BMI more than 25 (aOR 12.23, 95% CI 5.20?28.77) were significantly associated with the metabolic syndrome in cancer survivors. CONCLUSIONS: Cancer survivors are unlikely to have a higher risk of the metabolic syndrome than non cancer controls in Korea. This finding may be due to a relatively high proportion of gastric cancer survivors in Korea than in Western countries. The risk for metabolic syndrome among cancer survivors would appear to vary according to oncological and non-oncological factors. PMID- 23679273 TI - Comparative assessment of skin and subcutaneous toxicity in patients of advanced colorectal carcinoma treated with different schedules of FOLFOX. AB - OBJECTIVE: The study was designed to assess the skin and subcutaneous toxicity in patients with advanced colorectal carcinoma treated with four different schedules of FOLFOX. METHODS: The patients with histologically confirmed advanced colorectal carcinoma (CRC) were included in the study as per specified inclusion criteria. Toxicity was graded according to CTC v2.0. The frequency of grade 3 and 4 adverse effects were comparatively assessed in each treatment arm. RESULTS: Very severe toxicity was attributed to the FOLFOX7 schedule. The difference between the incidence rate of grade 4 toxicity with all other grades for all parameters of skin and subcutaneous toxicity was highly significant (p=0.00<0.001). Grade 4 hand and foot syndrome was reported only in the FOLFOX7 treatment arm. The most frequent adverse symptom of skin and subcutaneous toxicity reported in the patients treated with modified schedule of FOLFOX was pruritus (grade 1). Frequency and onset of skin and subcutaneous toxic symptoms like alopecia (p=0.000), nail discoloration (p=0.021) and pruritis (p=0.000) was significantly different in each FOLFOX treatment arm. A few cases of oncholysis were also reported in the FOLFOX7 treatment arm. Hand and foot syndrome was fast progressing in patients with grade 1 toxicity. CONCLUSION: Higher frequency and severity of hand and foot syndrome and pruritus wasa found in the FOLFOX7 treatment arm. Skin and subcutaneous toxicity was comparatively low in the FOLFOX6 treatment arm. PMID- 23679274 TI - ZD1839 and cisplatin alone or in combination for treatment of a nasopharyngeal carcinoma cell line and Xenografts. AB - This study evaluated the effects of ZD1839, an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, on nasopharyngeal carcinoma (NPC) both in vitro and in vivo. Influence of ZD1839 alone or combined with cisplatin on the NPC cell line CNE2 was detected by MTT assay with flow cytometry assessment of cell cycle distribution and apoptosis rates. Nude mice NPC xenografts were also used to evaluate the effects of ZD1839 alone or combined with cisplatin. The Student's t test evaluated statistical significance. ZD1839 alone or combined with cisplatin inhibited CNE2 cell line proliferation. ZD1839 induced CNE2 cell cycle arrest in the G1 phase, and higher concentrations induced apoptosis. Xenograft tumors were significantly smaller when treated with 200 mg/kg ZD1839, cisplatin, or cisplatin combined with 100 mg/kg ZD1839 than untreated controls. ZD1839 (200 mg/kg) alone showed good tumor inhibition effects, reduction of tumor weights, and smaller tumor volume without loss of body weight. ZD1839 (200 mg/kg) might provide a good and effective therapeutic reagent for NPC. PMID- 23679275 TI - Growth inhibition and apoptosis induction of human umbilical vein endothelial cells by apogossypolone. AB - AIMS AND BACKGROUND: Prostate cancer is one of the most common malignant tumors in the male reproductive system, which causes the second most cancer deaths of males, and control of angiogenesis in prostate lesions is of obvious importance. This study assessed the effect of apogossypolone (ApoG2) on proliferation and apoptosis of human umbilical vein endothelial cells (HUVECs). SUBJECTS AND METHODS: HUVECs were treated with different concentrations of ApoG2. The survival rate of HUVECs were determined by MTT assay. Utrastructural changes of HUVECs were assessed with transmission electron microscopy. Apoptosis in HUVECs was analyzed by flow cytometry and cell migration by Boyden chamber assay. Matrigel assays were used to quantify the development of tube-like networks. RESULTS: ApoG2 significantly inhibited HUVEC growth even at 24 h (P<0.05). The inhibitory effect of ApoG2 is more obvious as the concentration and the culture time increased (P<0.05). These results indicate that ApoG2 inhibits the proliferation of HUVECs in a time- and concentration-dependent manner with increase of the apoptosis rate. Besides, ApoG2 reduced the formation of total pseudotubule length and network branches of HUVECs. CONCLUSIONS: The results suggest that ApoG2 inhibits angiogenesis of HUVECs by growth inhibition and apoptosis induction. PMID- 23679276 TI - Clinical factors related with helicobacter pylori infection--is there an association with gastric cancer history in first-degree family members? AB - BACKGROUND: The aim of this study was to assess clinical factors associated with Helicobacter pylori positivity and to evaluate the incidence of gastric carcinoma in first-degree family members of infected patients. A total of 580 patients (mean age:38+/-17) with gastrointestinal complaints underwent C-14 urea breath test (UBT). Patients were grouped as: Group-1, untreated patients (n:384); and Group-2, patients who previously treated with eradication triple therapy (n:196). C-14 UBT was performed 1-2 months after the completion of eradication therapy. Associations of H pylori positivity with age, gender, ABO and Rhesus groups, smoking, dietary habits, and history of gastric cancer in first-degree family members were evaluated. The frequency of H pylori positivity was significantly higher in group-1 (58%) compared to group-2 (20%), p=0.001. There were no correlations between H pylori positivity and age, gender, ABO groups, Rhesus subgroups, smoking and dietary habits in both patient groups. The frequency of gastric cancer in family members was significantly higher in patients with H pylori infection among group-1, compared to infected patients among group-2 (56% vs. 28.6% respectively, p=0.03). We observed a significant association between H pylori positivity and the presence of gastric cancer in first-degree relatives of group-1 patients. Our results provide some confirmation of the presence of a link between gastric cancer development and H pylori. C-14 UBT is a sensitive, reliable and a widely recommended test for the detection of H pylori infection and recurrence. We suggest that detection and eradication of H pylori may contribute to a reduced risk of gastric cancer in the family members of infected patients. PMID- 23679277 TI - Prognostic value of preoperative serum CA 242 in Esophageal squamous cell carcinoma cases. AB - PURPOSE: Carbohydrate antigen (CA) 242 is inversely related to prognosis in many cancers. However, few data regarding CA 242 in esophageal cancer (EC) are available. The aim of this study was to determine the prognostic value of CA 242 and propose an optimum cut-off point in predicting survival difference in patients with esophageal squamous cell carcinoma (ESCC). METHODS: A retrospective analysis was conducted of 192 cases. A receiver operating characteristic (ROC) curve for survival prediction was plotted to verify the optimum cuf- off point. Univariate and multivariate analyses were performed to evaluate prognostic parameters for survival. RESULTS: The positive rate for CA 242 was 7.3% (14/192). The ROC curve for survival prediction gave an optimum cut-off of 2.15 (U/ml). Patients with CA 242 <= 2.15 U/ml had significantly better 5-year survival than patients with CA 242 >2.15 U/ml (45.4% versus 22.6%; P=0.003). Multivariate analysis showed that differentiation (P=0.033), CA 242 (P=0.017), T grade (P=0.004) and N staging (P<0.001) were independent prognostic factors. CONCLUSIONS: Preoperative CA 242 is a predictive factor for long-term survival in ESCC, especially in nodal-negative patients. We conclude that 2.15 U/ml may be the optimum cuf-off point for CA 242 in predicting survival in ESCC. PMID- 23679278 TI - Incidence trends of colorectal cancer in the West of Iran during 2000-2005. AB - BACKGROUND: Colorectal cancer is a main leading cause of cancer death in western countries. Although many studies have been conducted on incidence trends all over the world in recent years, information regarding changes in incidence of colorectal cancer in Iran is insufficient. The present study of colorectal cancer in the west of Iran during recent years was therefore performed. MATERIALS AND METHODS: The registered data for colorectal cancer cases in National Cancer Registry System were extracted from the Ministry of Health and Medical Education, Center for Disease Control and Management. The codes from 18-21 among cancers were selected for colon and rectum cancers. Incidence rates were standardized directly using WHO population. The significance of incidence rate trends during 2000-2005 was tested through Poisson regression. RESULTS: 762 cases of colorectal cancer were observed during 6 years in this region, with a gender ratio of men to women of 1.2. It increased from 65 cases in 2000 to 213 cases in 2005 or from 1.5 per100,000 per persons per year to 4.8. Significant increasing trends were evident in Kermanshah and Hamadan provinces; however, change did not reach significance in Ilam and Kurdistan provinces. CONCLUSIONS: Colorectal cancer has an increasing trend in the west of Iran. Although it seems that the increasing rate of colorectal cancer is due to increasing of cancer risk factors, some proportion may be related to the improvement of surveillance systems in Iran. PMID- 23679279 TI - Seroreactivity to Helicobacter pylori antigens as a risk indicator of gastric cancer. AB - BACKGROUND: Multiple etiologic factors are suspected to cause gastric cancer, the most important of which is infection with virulent types of Helicobacter pylori. MATERIALS AND METHODS: We have compared 102 gastric cancer patients with 122 non ulcer, non-cancer dyspeptic patients. Gastric specimens were evaluated for H. pylori infection by tissue-based detection methods. Patient sera underwent antigen-specific ELISA and western blotting using a Helicoblot 2.1 kit and antibody responses to various H. pylori antigens were assessed. RESULTS: The absolute majority (97-100%) of both groups were H. pylori seropositive. Multivariate regression analysis demonstrated serum antibodies to the low molecular weight 35kDa protein to be protective and reduce the risk of gastric cancer by 60% (OR:0.4; 95%CI:0.1-0.9). Conversely, seroreactivity to the 89kDa (VacA) protein was significantly higher in gastric cancer patients (OR:2.7; 95%CI:1.0-7.1). There was a highly significant association (p<0.001) between seroreactivity to the 116kDa (CagA) and 89kDa (VacA) proteins, and double positive subjects were found at nearly five fold (OR:4.9; 95%CI:1.0-24.4) enhanced risk of gastric cancer as compared to double negative subjects. CONCLUSIONS: Seroreactivity to H. pylori low (35kDa) and high (116kDa/89kDa) molecular weight antigens were respectively revealed as protective and risk indicators for gastric cancer. PMID- 23679280 TI - Analysis of key genes and pathways associated with colorectal cancer with microarray technology. AB - OBJECTIVE: Microarray data were analyzed to explore key genes and their functions in progression of colorectal cancer (CRC). METHODS: Two microarray data sets were downloaded from Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) were identified using corresponding packages of R. Functional enrichment analysis was performed with DAVID tools to uncover their biological functions. RESULTS: 631 and 590 DEGs were obtained from the two data sets, respectively. A total of 32 common DEGs were then screened out with the rank product method. The significantly enriched GO terms included inflammatory response, response to wounding and response to drugs. Two interleukin-related domains were revealed in the domain analysis. KEGG pathway enrichment analysis showed that the PPAR signaling pathway and the renin-angiotensin system were enriched in the DEGs. CONCLUSIONS: Our study to systemically characterize gene expression changes in CRC with microarray technology revealed changes in a range of key genes, pathways and function modules. Their utility in diagnosis and treatment now require exploration. PMID- 23679281 TI - Increased migration and local invasion potential of SiHa cervical cancer cells expressing Aquaporin 8. AB - Overexpression of several aquaporins (AQPS) has been reported in different types of human cancer but roles in human carcinogenesis have yet to be clearly defined. Here, we up-regulated expression of the AQP8 gene in SiHa human cervical cancer cells with a lentivirus transfection system and investigated its effects as a potential therapeutic target for cervical cancer. Results showed AQP8 overexpression did not affect their substrate adherence and proliferation, but accelerated migration as assessed by transwell migration and wound healing assays. Moreover, AQP8 overexpression significantly enhanced local invasion of SiHa cells in nude mice. These findings altogether indicate that AQP8 overexpression increases migration of SiHa cells and probably participates in the process of tumor local invasion. PMID- 23679282 TI - In vitro cytotoxic activity of seed oil of fenugreek against various cancer cell lines. AB - In the present study, investigations were carried out to screen the anticancer activities of fenugreek seed oil against cancer cell lines (HEp-2, MCF-7, WISH cells), and a normal cell line (Vero cells). Cytotoxicity was assessed with MTT and NRU assays, and cellular morphological alterations were studied using phase contrast light microscopy. All cells were exposed toi 10-1000 MUg/ml of fenugreek seed oil for 24 h. The results show that fenugreek seed oil significantly reduced the cell viability, and altered the cellular morphology in a dose dependent manner. Among the cell lines, HEp-2 cells showed the highest decrease in cell viability, followed by MCF-7, WISH, and Vero cells by MTT and NRU assays. Cell viability at 1000 MUg/ml was recorded as 55% in HEp-2 cells, 67% in MCF-7 cells, 75% in WISH cells, and 86% in Vero cells. The present study provides preliminary screening data for fenugreek seed oil pointing to potent cytotoxicity against cancer cells. PMID- 23679283 TI - Inhibition of metastatic lung cancer in C57BL/6 mice by marine mangrove Rhizophora apiculata. AB - Metastasis is one of the hallmarks of malignant neoplasms and is the leading cause of death in many cancer patients. A major challenge in cancer treatment is to find better ways to specifically target tumor metastasis. In this study, the anti-metastatic potential of the methanolic extract of Rhizophora apiculata (R.apiculata) was evaluated using the B16F-10 melanoma induced lung metastasis model in C57BL/6 mice. Metastasis was induced in C57BL/6 mice by injecting highly metastatic B16F-10 melanoma cells through the lateral tail vein. Simultaneous treatment with R.apiculata extract (10 mg/kg b.wt (intraperitoneal) significantly (p<0.01) inhibited pulmonary tumor nodule formation (41.1 %) and also increased the life span (survival rate) 107.3 % of metastatic tumor bearing animals. The administration of R.apiculata extract significantly (p<0.01) reduced biochemical parameters such as lung collagen hydroxyproline, hexosamine, uronic acid content, serum nitric oxide (NO), gamma-glutamyl transpeptidase (GGT) and sialic acid levels when compared to metastasis controls. These results correlated with lung histopathology analysis of R.apiculata extract treated mice showing reduction in lung metastasis and tumor masses. Taken together, our findings support that R.apiculata extract could be used as a potential anti-metastasis agent against lung cancer. PMID- 23679284 TI - Salvage therapy of gemcitabine plus endostar significantly improves progression free survival (PFS) with platinum-resistant recurrent epithelial ovarian cancer. AB - Anti-angiogenic agents have played crucial roles in the treatment of ovarian cancer in recent years, but potential benefits of endostatin have been largely unexplored. The present retrospective study evaluated its efficacy and toxicity with two cohorts of patients with platinum-resistant recurrent ovarian cancer. One cohort received gemcitabine plus endostar (rh-endostatin), and the second cohort received gemcitabine regimen alone, with totals of 31 and 27 patients, respectively. The main endpoints were disease control rate (DCR), PFS, overall survival (OS) and safety. There were statistically significant differences in DCR (70.9% vs. 40.7%; P = 0.02) and PFS (6.3 months vs. 3.2 months, P = 0.001) between the two cohorts. Though the endostar cohort also improved median OS by 2.1 months, there was no statistically significant difference compared with gemcitabine alone cohort in this case (12.5 months vs. 10.4 months, P = 0.201). Treatment was well tolerated for most patients, and toxicity of endostar was negligible. Gemcitabine plus endostar significantly improved the prognosis in patients with platinum-resistant recurrent ovarian cancer, especially in those with malignant effusion. The endostar- containing regimen is recommended in this setting. PMID- 23679285 TI - Effect of Xeroderma pigmentosum complementation group F polymorphisms on gastric cancer risk and associations with H.pylori infection. AB - We conducted a hospital case-control study by genotyping four potential functional single nucleotide polymorphisms (SNPs) to assess the association of Xeroderma pigmentosum complementation group F (XPF) with gastric cancer susceptibility, and role of XPF polymorphisms in combination with H.pylori infection in risk definition. A total of 331 patients with gastric cancer and 355 controls were collected. Four SNPs of XPF, rs180067, rs1799801, rs2276466 and rs744154, were genotyped by Taqman real-time PCR method with a 7900 HT sequence detector system. The gastric cancer patients were more likely to have smoking habit, a family history of cancer and H.pylori infection. We did not find any significant difference in the genotype distributions of XPF rs180067, rs1799801, rs2276466 and rs744154 between cases and controls. However, multivariate logistic analysis showed a non-significant decreased risk in patients carrying rs180067 G allele, rs1799801 T allele or rs2276466 T allele genotypes. A non-significant increased risk of gastric cancer was found in individuals carrying the rs744154 GG genotype. Stratification by H.pylori infection and smoking was not significantly different in polymorphisms of XPF rs180067, rs1799801, rs2276466 and rs744154. The four XPF SNPs did not show significant interaction with H.pylori infection and smoking status (P for interaction was 0.35 and 0.18, respectively). Our study indicated that polymorphisms in rs180067, rs1799801, rs2276466 and rs744154 may affect the risk of gastric cancer but further large sample size studies are needed to validate any association. PMID- 23679286 TI - Diurnal variation, vertical distribution and source apportionment of carcinogenic polycyclic aromatic hydrocarbons (PAHs) in Chiang-Mai, Thailand. AB - Diurnal variation of particulate polycyclic aromatic hydrocarbons (PAHs) was investigated by collecting PM10 at three different sampling altitudes using high buildings in the city center of Chiang-Mai, Thailand, during the relatively cold period in late February 2008. At site-1 (12 m above ground level), B[a]P concentrations ranged from 30.3 -1,673 pg m-3 with an average of 506+/-477 pg m 3, contributing on average, 8.09+/-8.69% to ?PAHs. Ind and B[b]F concentrations varied from 54.6 to 4,579 pg m-3 and from 80.7 to 2,292 pg m-3 with the highest average of 1,187+/-1,058 pg m-3 and 963+/-656 pg m-3, contributing on average, 19.0+/-19.3% and 15.4+/-12.0% to ?PAHs, respectively. Morning maxima were predominantly detected in all observatory sites, which can be described by typical diurnal variations of traffic flow in Chiang-Mai City, showing a morning peak between 6 AM. and 9 AM. Despite the fact that most monitoring sites might be subjected to specific-site impacts, it could be seen that PAH profiles in Site-1 and Site-2 were astonishingly homogeneous. The lack of differences suggests that the source signatures of several PAHs become less distinct possibly due to the impacts of traffic and cooking emissions from ground level. PMID- 23679287 TI - Vertical distribution and potential risk of particulate polycyclic aromatic hydrocarbons in high buildings of Bangkok, Thailand. AB - Vertical variations of polycyclic aromatic hydrocarbon (PAH) concentrations in PM10 were investigated in order to assess the factors controlling their behavior in the urban atmosphere of Bangkok City, Thailand. Air samples were collected every three hours for three days at three different levels at Bai-Yok Suit Hotel (site-1 and site-2) and Bai-Yok Sky Hotel (site-3) in February 18th-21st, 2008. The B[a]P concentration showed a value 0.54 fold, lower than the United Kingdom Expert Panel on Air Quality Standard (UK-EPAQS; i.e. 250 pg m-3) at the top level. In contrast, the B[a]P concentrations exhibited, at the ground and middle level, values 1.50 and 1.43 times higher than the UK-EPAQS standard respectively. PAHs displayed a diurnal variation with maximums at night time because of the traffic rush hour coupled with lower nocturnal mixing layer, and the decreased wind speed, which consequently stabilized nocturnal boundary layer and thus enhanced the PAH contents around midnight. By applying Nielsen's technique, the estimated traffic contributions at Site-3 were higher than those of Site-1: about 10% and 22% for Method 1 and Method 2 respectively. These results reflect the more complicated emission sources of PAHs at ground level in comparison with those of higher altitudes. The average values of incremental individual lifetime cancer risk (ILCR) for all sampling sites fell within the range of 10?7-10?6, being close to the acceptable risk level (10?6) but much lower than the priority risk level (10?4). PMID- 23679288 TI - Temporal and spatial distribution of particulate carcinogens and mutagens in Bangkok, Thailand. AB - To investigate the level of genotoxicity over Bangkok atmosphere, PM10 samples were collected at the Klongchan Housing Authority (KHA), Nonsree High School (NHS), Watsing High School (WHS), Electricity Generating Authority of Thailand (EGAT), Chokchai 4 Police Station (CPS), Dindaeng Housing Authority (DHA) and Badindecha High School (BHS). For all monitoring stations, each sample covered a period of 24 hours taken at a normal weekday every month from January-December 2006 forming a database of 84 individual air samples (i.e. 12?7=84). Atmospheric concentrations of low molecular weight PAHs (i.e. phenanthrene, anthracene, pyrene and fluoranthene) were measured in PM10 at seven observatory sites operated by the pollution control department of Thailand (PCD). The mutagenicity of extracts of the samples was compared in Salmonella according to standard Ames test method. The dependence of the effects on sampling time and on sampling location was investigated with the aid of a calculation of mutagenic index (MI). This MI was used to estimate the increase in mutagenicity above background levels (i.e. negative control) at the seven monitoring sites in urban area of Bangkok due to anthropogenic emissions within that area. Applications of the AMES method showed that the average MI of PM10 collected at all sampling sites were 1.37+/ 0.10 (TA98; +S9), 1.24+/-0.08 (TA98; -S9), 1.45+/-0.10 (TA100; +S9) and 1.30+/ 0.09 (TA100; -S9) with relatively less variations. Analytical results reconfirm that the particulate PAH concentrations measured at PCD air quality monitoring stations are moderately low in comparison with previous results observed in other countries. In addition, the concept of incremental lifetime particulate matter exposure (ILPE) was employed to investigate the potential risks of exposure to particulate PAHs in Bangkok atmosphere. PMID- 23679289 TI - Clinical outcomes of basaloid squamous cell carcinoma of the esophagus: a retrospective analysis of 142 cases. AB - BACKGROUND: Basaloid squamous cell carcinoma of the esophagus (BSCCE) is a rare and distinctive tumor with no standard treatment. This study aimed to explore treatment in relation to prognosis of the disease. METHODS: A total of 142 patients with BSCCE that underwent treatment in our hospital from March 1999 to July 2010 were retrospectively analyzed. All patients received surgery, 42 postoperative radiotherapy and 28 patients chemotherapy. RESULTS: There were 26 patients included in stage I, 60 in stage II, 53 in stage III and 3 in stage IV. The clinical symptoms and macroscopic performances of BSCCE did not differ from those of typical esophageal squamous cell carcinoma. Among 118 patients receiving endoscopic biopsy, only 12 were diagnosed with BSCCE. The median survival time (MST) of the entire group was 32 months, with 1-, 3- and 5-year overall survival (OS) of 81.4%, 46.8% and 31.0%, respectively. The 5-year OS of stage I and II patients was significantly longer than that of stages III/IV, at 60.3%, 36.1% and 10.9%, respectively (p<0.001, p=0.001). The MST and 5-year OS were 59.0 months and 47.4% in patients with tumors located in the lower thoracic esophagus, and 27.0 months and 18.1% in those with lesions in the upper/middle esophagus (p=0.002). However, the survival was not significantly improved in patients undegoing adjunctive therapy. Multivariate analysis showed TNM stage and tumor location to be independent prognostic factors. Furthermore, distant metastasis was the most frequent failure pattern, with a median recurrence time of 10 months. CONCLUSION: BSCCE is an aggressive disease with rapid progression and a propensity for distant metastasis. It is difficult to make a definitive diagnosis via preoperative biopsy. Multidisciplinary therapy including radical esophagectomy with extended lymphadenectomy should be recommended, while the effectiveness of radiochemotherapy requires further validation for BSCCE. PMID- 23679290 TI - Lifestyle practice among Malaysian university students. AB - BACKGROUND: It is well established that a healthy lifestyle is of benefit in the prevention of diseases such as cancer and promotion of well-being. Therefore, the objective of this study was to determine lifestyle practice and associated factors among university students in Malaysia. MATERIALS AND METHODS: A cross sectional study was conducted over six months from November 2011 until May 2012 among the students from the Management and Science University. This study was approved by its ethical committee , the students being explained the objective and invited to participate. A consent form was signed by all study participants. Questionnaire was distributed randomly to the students of the five faculties through their lecturers in different faculty. For univariate analysis t-test and ANOVA test were performed. Multiple linear regression used for multivariate analysis using SPSS 13.0. RESULTS: A total number of 1100 students participated with a mean age of 22.1+/-2.21 (SD) years. The majority were 22 years or younger (56.3%), female (54%), Malay (61.5%), single (92.3%), with family monthly income >=5000 Ringgit Malaysia (41.2%). Regarding lifestyle, about were 31.6% smokers, 75.6% never drank alcohol and 53.7% never exercised. Multivariate analysis showed that age, sex, race, parent marital status, participant marital status, type of faculty, living status, smoking status, exercise, residency, brushing teeth, fiber intake and avoid fatty food significantly influenced the practice of drinking alcohol among university students (p=0.006, p=0.042, p<0.001, p=0.003, p=0.002, p<0.001, p<0.001, p<0.001, p<0.001, p<0.001, p<0.001, p=0.003, p<0.001; respectively). It similarly showed that sex, race, parent marital status, participant marital status, monthly family income, exercise, residency, brushing teeth and fiber intake significantly influenced the practice of sun protection (p<0.001, p<0.001, p<0.001, p<0.001, p<0.001, p=0.017, p<0.001, p<0.001, p<0.001; respectively) and that age, sex, parent marital status, participant marital status, type of faculty, living status, exercise, taking non- prescribed medication, brushing the teeth, coffee consumption and fiber intake were significantly influenced the practice of fruits consumption (p=0.008, p<0.001, p<0.001, p<0.001, p<0.001, p<0.001, p<0.001, p<0.001, p=0.002, p<0.001, P<0.001; respectively). CONCLUSIONS: This study showed a poor practice of healthy lifestyle among university students. Therefore universities should emphasize a healthy lifestyle in all faculties as a required subject. Socio-demographic characteristics significantly influenced practice and thus should be considered when planning preventive measures among university students. Frequent campaigns and educational seminars are to be encouraged. PMID- 23679291 TI - Patient and clinical variables account for changes in health- related quality of life and symptom burden as treatment outcomes in colorectal cancer: a longitudinal study. AB - OBJECTIVE: The aim of the current study was to evaluate changes in treatment outcomes in terms of health- related quality of life (HRQoL) and symptom burden at zero, one, three, and six months after an initial diagnosis of colorectal cancer. The demographic and clinical characteristics that account for outcome changes in patients were investigated using a repeated measures framework. METHODS AND MATERIALS: A cohort study was performed of 134 colorectal cancer patients followed from diagnosis to 6 months post-treatment in Central Taiwan. HRQoL and symptoms were assessed at diagnosis and one, three, and six months thereafter. The Functional Assessment of Cancer Therapy-Colon (FACT-C) questionnaire, VAS pain, and the Memorial Symptom Assessment Scale (MSAS) were used for data collection. A generalized estimating equation (GEE) was applied for statistical analysis. RESULTS: The majority of the patients were male (55%) and married (91.5%). The mean age was 60.4 years (SD = 11.71). Most were diagnosed stage III and IV colorectal cancer (54.5%). All underwent surgery; some also received chemotherapy (CT) or concurrent chemoradiation therapy (CCRT). The results of the GEE showed that overall, the HRQoL, pain, and symptoms of the patients significantly improved over the treatment period. Patients with stage IV disease who had received surgery and CCRT showed the worst HRQoL. Females, patients with comorbidity, and stage IV patients had higher pain scores over time. Female and stage IV patients had more severe physical symptoms, whereas stage II and IV patients had worse psychological symptoms over time. CONCLUSION: The patients' HRQoL, pain, and symptoms significantly improved over the 6-month treatment period. Certain patient and clinical variables accounted for changes in treatment outcomes regarding HRQoL and symptom burden in colorectal cancer patients. PMID- 23679292 TI - Carotenoid intake and esophageal cancer risk: a meta-analysis. AB - This meta-analysis was conducted to evaluate the association between intake of carotenoids and risk of esophageal cancer. A systematic search using PubMed, Cochrane Library, Web of Science, Scopus, CNKI, and CBM (updated to 6 May 2012) identified ten articles meeting the inclusion criteria with 1,958 cases of esophageal cancer and 4,529 controls. Higher intake of beta-carotene, alpha carotene, lycopene, beta-cryptoxanthin, lutein, and zeaxanthin reduced esophageal cancer risk with pooled ORs of 0.58 (95% CI 0.44, 0.77), 0.81 (95% CI 0.70, 0.94), 0.75 (95% CI 0.64, 0.86), 0.80 (95% CI 0.66, 0.97), and 0.71 (95% CI 0.59, 0.87), respectively. In subgroup analyses, beta-carotene showed protective effects against esophageal adenocarcinoma in studies located in Europe and North America. Alpha-carotene, lycopene, and beta-cryptoxanthin showed protection against esophageal squamous cell cancer. This meta-analysis suggested that higher intake of carotenoids (beta-carotene, alpha- carotene, lycopene, beta cryptoxanthin, lutein, and zeaxanthin) is associated with lower risk of esophageal cancer. Further research with large-sample studies need to be conducted to better clarify the potentially protective mechanisms of carotenoid associations risk of different types of esophageal cancer. PMID- 23679293 TI - Smoking and associated factors among the population aged 40-64 in Shahroud, Iran. AB - BACKGROUND: Smoking is known as a major risk factor for different types of cancer, as well as cardiovascular disease. Its prevalence is increasing in developing countries. The aims of this study were to determine the prevalence of smoking and its associated factors among the population aged 40-64 years in the city of Shahroud which is a representative urban population in Iran. MATERIALS AND METHODS: A cross-sectional population-based study with stratified random cluster sampling was conducted in 2009 as the first phase of Shahroud Eye Cohort Study. Of 6,311 people, 5,190 participated (82.2%). Information about smoking habit was obtained by face-to- face interview. RESULTS: The overall prevalence of current tobacco smoking was 11.3% (95%CI: 10.5-12.3). It was significantly higher among males than females (25.7% and 0.71%, P<0.001). The prevalence of current cigarette smoking was 10.8% and 1.75% were past smokers. The smoking rate of water-pipe was 0.67%. Unemployed people smoked more than employed (OR=2.66, 95%CI: 1.38-5.14). CONCLUSIONS: The prevalence of smoking is low in Shahroud compared with other parts of Iran and other countries. Age, sex, job and marital status were associated with smoking. The low smoking rate among women may be attributed to cultural and social reasons. PMID- 23679294 TI - Association between MDM2 SNP309 T>G and risk of gastric cancer: a meta-analysis. AB - BACKGROUND: As a negative regulator of P53, MDM2 plays an important role in carcinogenesis; a polymorphism in its promoter region. SNP309 T>G, is known to increase the expression of MDM2, thus being considered related to higher susceptibility to neoplasia. However, no agreement has been achieved regarding its effects on gastric cancer. METHODS: The present systematic meta-analysis was performed based on comprehensive literature search from Pubmed, Web of science and CBM databases. RESULTS: It was suggested from 6 independent studies that the GG genotype is associated with a significantly increased risk of gastric cancer (Recessive: OR = 1.43, 95% CI = 1.08-1.91, P = 0.013), and subgroup analysis also confirmed the relationship (English publications-recessive model: OR = 1.45, 95% CI = 1.10-1.91, P = 0.009; Studies in China-recessive model: OR = 1.58, 95% CI = 1.08-2.30, P = 0.017). No publication bias was detected. CONCLUSION: The meta analysis indicated a significant inverse association between GG genotype carriage and elevated risk of gastric cancer. However, more studies and detailed information are needed to fully address the topic. PMID- 23679295 TI - Determinants of tobacco cessation behaviour among smokers and smokeless tobacco users in the states of Gujarat and Andhra Pradesh, India. AB - BACKGROUND: This study was undertaken to identify the socio-demographic determinants of quit attempts among smokers and smokeless tobacco users to identify correlates of tobacco cessation behaviour in India. MATERIALS AND METHODS: This was a cross-sectional study for the outcome of quit attempts made by current tobacco users in last 12 months in twelve districts in two states. Simple and multivariable logistic regression analysis was used to obtain the odds ratios (ORs) of socio-demographic variables (age, gender, education, occupation, socio- economic status, community, area, type of family) and tobacco user status (smoker/smokeless). RESULTS: In the combined analysis, a smoker had higher predicted probability of attempting quitting (OR- 1.41,CI 1.14 -1.90), in comparison to a smokeless tobacco user and a tobacco user in the state of Gujarat was less likely to attempt quitting than a user in Andhra Pradesh (OR-0.60, CI 0.47-0.78). The probability of making a quit attempt was higher among tobacco users who were more educated (OR-1.40, CI 1.04-1.94), having a higher socio economic status (SES) (OR-2.39, CI 1.54-3.69), and belonging to non-agricultural labourer occupational group (OR-1.90, CI 1.29-2.78). The effects were maintained even after adjusting for all other variables. In disaggregated analysis, findings were similar except in smokeless as a separate group, education level was not significantly associated with quit attempts and with lower odds (OR-0.91, CI 0.58 1.42). CONCLUSIONS: This is one of the first studies to provide useful insight into potential determinants for quit attempts of tobacco users in India including smokeless tobacco users, exploring the socio-demographic patterning of correlates of quit attempts. PMID- 23679296 TI - Different association of manganese superoxide dismutase gene polymorphisms with risk of prostate, esophageal, and lung cancers: evidence from a meta-analysis of 20,025 subjects. AB - Altered expression or function of manganese superoxide dismutase (MnSOD) has been shown to be associated with cancer risk but assessment of gene polymorphisms has resulted in inconclusive data. Here a search of published data was made and 22 studies were recruited, covering 20,025 case and control subjects, for meta- analyses of the association of MnSOD polymorphisms with the risk of prostate, esophageal, and lung cancers. The data on 12 studies of prostate cancer (including 4,182 cases and 6,885 controls) showed a statistically significant association with the risk of development in co-dominant models and dominant models, but not in the recessive model. Subgroup analysis showed there was no statistically significant association of MnSOD polymorphisms with aggressive or nonaggressive prostate cancer in different genetic models. In addition, the data on four studies of esophageal cancer containing 620 cases and 909 controls showed a statistically significant association between MnSOD polymorphisms and risk in all comparison models. In contrast, the data on six studies of lung cancer with 3,375 cases and 4,050 controls showed that MnSOD polymorphisms were significantly associated with the decreased risk of lung cancer in the homozygote and dominant models, but not the heterozygote model. A subgroup analysis of the combination of MnSOD polymorphisms with tobacco smokers did not show any significant association with lung cancer risk, histological type, or clinical stage of lung cancer. The data from the current study indicated that the Ala allele MnSOD polymorphism is associated with increased risk of prostate and esophageal cancers, but with decreased risk of lung cancer. The underlying molecular mechanisms warrant further investigation. PMID- 23679297 TI - Component analysis of esophageal cancer incidence in Kazakhstan. AB - Esophageal cancer (EC) incidence rates in Kazakhstan were assessed by component analysis based on primary registered cases in 2001-2010. It was found that despite an apparent general decrease in the number of EC patients in Kazakhstan, a potential increase should be evaluated, due to changes in aging as well as the increase in population. Some problems of EC patients' registration were broached with an emphasis on the importance of the expected absolute number and reasons for undercounting in the country. Based on these, ways of improving the recording and registration of such patients in the country were suggested. PMID- 23679298 TI - Genetic polymorphism of MTHFR A1298C and esophageal cancer susceptibility: a meta analysis. AB - BACKGROUND: Associations between the methylenetetrahydrofolate reductase (MTHFR) A1298C polymorphism and esophageal cancer risk have been reported in many articles recently, but results were controversial. Therefore the present meta analysis was conducted to to provide a more precise estimation. METHODS: Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of associations. RESULTS: Finally, six case- control studies involving a total of 1,302 cases and 2,391controls for the A1298C polymorphism were included. The meta-analysis showed that significantly increased risk for Asians (CC versus AA, OR=3.799, 95%CI=1.541-9.365, P=0.004; CCversusCA+AA, OR=3.997, 95%CI=1.614 9.900, P=0.003) and Caucasians (CC versus AA, OR=1.797, 95%CI=1.335-2.418, P=0.000; CC+CA versus AA,OR=1.240, 95%CI=1.031-1.492, P=0.022; CCversusCA+AA, OR=1.693, 95%CI=1.280-2.240, P=0.000). In addition, there was an association with risk for both ESCC (CC versus AA, OR=2.529, 95%CI=1.688-3.788, P=0.000; CCversusCA+AA, OR=2.572, 95%CI=1.761-3.758, P=0.000) and esophageal adenocarcinoma (EAC) (CC versus AA, OR=1.592, 95%CI=1.139-2.227, P=0.007; CC+CA versus AA,OR=1.247, 95%CI=1.016-1.530, P=0.035; CCversusCA+AA, OR=1.466, 95%CI=1.069-2.011, P=0.018). CONCLUSION: This meta-analysis suggested associations of the A1298C polymorphism with increased risk of esophageal cancer in both Asians and Caucasians. In addition, we found that the MTHFR A1298C polymorphism might influence risk ofESCC and EAC in the overall studies. PMID- 23679299 TI - Oral cancer awareness and its determinants among a selected Malaysian population. AB - OBJECTIVE: To assess oral cancer awareness, its associated factors and related sources of information among a selected group of Malaysians. METHODS: A cross sectional survey was conducted on all Malaysian ethnic groups aged >=15 years old at eight strategically chosen shopping malls within a two week time period. Data were analysed using chi-square tests and multiple logistic regression. Significance level was set at alpha<0.05. RESULTS: Most (84.2%) respondents had heard of oral cancer. Smoking was the most (92.4%) recognized high risk habit. Similar levels of awareness were seen for unhealed ulcers (57.3%) and red/white patches (58.0%) as signs of oral cancer. Age, gender, ethnicity, marital status, education, occupation and income were significantly associated with oral cancer awareness (p<0.05). CONCLUSIONS: There was a general lack of awareness regarding the risk habits, early signs and symptoms, and the benefits of detecting this disease at an early stage. Mass media and health campaigns were the main sources of information about oral cancer. In our Malaysian population, gender and age were significantly associated with the awareness of early signs and symptoms and prevention of oral cancer, respectively. PMID- 23679300 TI - Impact of various tumor markers in prognosis of gastric cancer. A hospital based study from tertiary care hospital of Kathmandu valley. AB - BACKGROUND: To obtain the maximum additional information about the prognosis of gastric cancer, we compared CA-50 with other previously defined markers. MATERIALS AND METHODS: This hospital based study was carried out in the Department of Biochemistry of Nepalese Army Institute of Health Sciences between 1st July 2012 and 31st December 2012. The variables collected were age, gender, AFP, CEA, CA19-9, and CA50, assayed with ELISA reader for all cases. The cut off values for serum AFP, CEA, CA19-9, and CA-50 were 10 MUg/l, 10 MUg/l, 37 U/ml, and 20 U/ml, respectively according to the manufacturer's instructions. Approval for the study was obtained from the institutional research ethical committee. RESULTS: Of the 40 examined patients, 13 patients had tumors located in the upper third of the stomach, 6 patients had tumors in the middle third, 16 patients had tumors in the lower third, and 5 patients had tumors occupying two-thirds of the stomach or more. The distribution of lymph node staging of the patients was as follows: 7 patients belonged to N0, 9 patients to N1 stage, 10 patients to N2 stage, and 14 patients to N3 stage. The statistical method of Cox proportional hazards using multivariate analysis also illustrated that tumor markers including CEA (2.802), CA19-9 (2.690), CA50 (2.101), were independent prognostic factors, as tumor size (1.603), and lymph node stage (1.614). CONCLUSIONS: The tumour markers now available, like CEA, CA 19-9 and CA 50, chiefly perceive advanced gastric cancer. The preoperative rise in those tumour marker level have a prognostic significance and may be clinically helpful in choosing patients for adjuvant management. PMID- 23679301 TI - Knowledge of colorectal cancer screening among young Malaysians. AB - The objective of this study was to determine the knowledge and associated factors regarding colorectal cancer screening among university students in Malaysia. The questionnaire consisted of three parts: socio-demographic characteristics, lifestyle practice and knowledge of colorectal screening. A cross-sectional study was conducted among 300 students (21.3+/-1.4 years old). The majority of the participants were Malay with a monthly family income of less than 5,000 Ringgit Malaysia (equal to 1,700 USD) (67.0% and 76.0%, respectively). Regarding their lifestyle practices, the majority were non-smokers and had never consumed alcohol (83.7%, and 88.0%, respectively). The majority of the participants had no knowledge of digital rectal examination, colonoscopy, barium enema and fecal occult blood screening (63.3%, 60.7%, 74.0% and 62.3%, respectively). Univariate and multivariate analysis revealed that their age and the discipline which the students were studying significantly influenced their level of knowledge about colorectal screening. The present study results indicate that education campaigns about colorectal cancer should be promoted. PMID- 23679302 TI - Expression and significance of the Wip1 proto-oncogene in colorectal cancer. AB - AIM: To investigate the level of expression of proto-oncogene Wip1 and its physiological significance in colorectal cancer. METHODS: Immunohistochemistry, semi-quantitative RT-PCR, and Western blotting were used to analyze Wip1 mRNA and protein expression in 120 cases of colorectal cancer and normal tissues to study relationships with clinical symptoms and disease prognosis. RESULTS: The level of Wip1 protein expression was found to be significantly higher in colorectal cancer tissues (85% (102/120)) than in normal tissues (30% (36/120)) (P < 0.05). The relative amount of Wip1 protein in colorectal cancer tissue was also found to be significantly higher (P < 0.05) than in normal tissues (1.060+/-0.02 and 0.640+/ 0.023, respectively). Semi-quantitative RT-PCR showed average Wip1 mRNA expression levels to be 1.113 +/-0.018 and 0.658+/-0.036 for colorectal cancer tissue and adjacent normal tissue (P < 0.05). The level of Wip1 protein expression was not correlated with age, gender, or tumor site, but appeared linked with lymph node metastasis, Dukes stage, histological grade, and liver metastasis. Individuals with high and low levels of Wip1 expression showed statistically significant differences in the five-year overall survival and recurrence-free survival rates (P < 0.05). CONCLUSION: Wip1 mRNA and protein are highly expressed in colorectal cancers and may be associated with colorectal cancer development and progression. PMID- 23679303 TI - Adjuvant trastuzumab for 6 months is effective in patients with HER2-positive stage II or III breast cancer. AB - OBJECTIVE: The optimal duration of adjuvant trastuzumab treatment in patients with HER2-positive breast cancer is not known. The aim of this study was to evaluate the efficacy of 6 months of adjuvant trastuzumab treatment in patients with stage II or III HER2-positive breast cancer. METHODS: The records of patients with HER2-positive stage II or III breast cancer who were admitted to the Breast Center of Taipei Medical University Hospital and Yuan's General Hospital between 2000 and 2008 were reviewed. All patients received adjuvant trastuzumab at an initial dose of 4 mg/kg followed by a maintenance dose of 2 mg/kg/week for 22 weeks in combination with chemotherapy. RESULTS: A total of 51 patients were included with a mean age of 46.9 years. Approximately 55% of the patients had stage III disease. The mean follow-up time from initiation of treatment was 45.2 months (range, 0.9 to 85 months). During follow-up, 46 patients (90.2%) did not experience tumor recurrence. The mean estimated disease free survival was 80.2 months. The estimated 1- , 2-, 5-, and 7-year survival rates were 97.9%, 93.1%, 93.1%, and 93.1%, respectively. The most common adverse effects were gastrointestinal symptoms (21.6%), chills (17.6%), dizziness (9.8%), and bone pain (7.8%). No cardiac or hematologic adverse events occurred. CONCLUSION: Adjuvant therapy with trastuzumab for 6 months resulted in a clinical benefit in patients with HER2-positive breast cancer. PMID- 23679304 TI - Decreased expression of LKB1 correlates with poor prognosis in hepatocellular carcinoma patients undergoing hepatectomy. AB - AIM: To study any correlation of LKB1 expression with prognosis in hepatocellular carcinoma (HCC) cases. METHODS: A total of 70 HCC patients and 20 primary intrahepatic stone patients in the first affiliated hospital of Wenzhou Medical College were enrolled in this study. LKB1 expression was detected by immunohistochemistry. Patients were followed-up and prognostic factors were evaluated. RESULT: LKB1 expression was decreased in the HCC samples. Loss of LKB1 expression in HCC was significantly related to histologic grade (P=0.010), vascular invasion (P=0.025) and TMN stage (P=0.011). Patients showing negative LKB1 expression had a significantly shorter disease-free and overall survival than those with positive expression (P = 0.001, P=0.000, respectively). Multivariate Cox regression analysis indicated that LKB1 expression level was an independent factor of survival (P = 0.033). CONCLUSION: HCC patients with decreased expression LKB1 have a poor prognosis. The loss of LKB1 expression is correlated with a lower survival rate. PMID- 23679305 TI - Incidence and clinicopathologic features of primary lung cancer: a North-Eastern Anatolia region study in Turkey (2006-2012). AB - BACKGROUND: Lung cancer is the most frequent cancer among men and second highest among women overall, including in Turkey. Cigarette smoking is the most important etiologic factor for the development of cancer in both men and women. OBJECTIVE: To determine the lung cancer incidence in Northeastern Anatolia Region of Turkey with a focus on clinical properties, cancer subtypes, the relationships of tumors with cigarette smoking and radiological properties of the lesions. MATERIALS AND METHODS: In a retrospective study design, 566 lung cancer cases diagnosed at the Pathology Department of Ataturk University in Erzurum over the last seven years extending from January 2006 to June 2012 were investigated. The results were compared with statistical analyses. RESULTS: The most common histopathological subtype of primary bronchogenic carcinoma in our study was found to be the squamous cell carcinoma, 46.1% (261 out of 566), and the second was small cell lung carcinoma 15.7% (89 out of 566). Based on our data, an overall male predominance was noted with a male/female ratio of 6.1/1. While 296 (52.2%) of the patients were found to be smokers at the time of diagnosis, 125 (22.0%) were nonsmokers and 145 (25.6%) were ex-smokers. Smoking status was found to have a strong correlation with primary lung cancer (p <0.05), and there were significant differences between males and females (p<0.001). CONCLUSION: Although relative prominence of subtypes of lung cancers differ between Turkish and other populations, lung cancer overall remains as an important health problem in Turkey. Our findings stress the critical need for effective cancer prevention programs such as anti-smoking campaigns. PMID- 23679306 TI - hMSH2 and nm23 expression in sporadic colorectal cancer and its clinical significance. AB - OBJECTIVE: To study the expression of the mismatch repair proteins hMSH2 and nm23 in sporadic colorectal cancer, determine any inter-relationship, and further investigate any clinical significance. METHODS: Expression of hMSH2 and nm23 proteins was assessed in 87 colorectal cancer tissues by SP immunohistochemistry, with analysis of survival using follow-up data. RESULTS: In the sporadic colorectal cancer tissues, nm23 protein expression appeared independent of the histological type (P > 0.05), but correlated with the invasion depth and lymphatic metastasis (P < 0.05). In contrast, hMSH2 protein expression was not significantly correlated with these clinicopathologic features (P > 0.05), although it positively correlated with that of nm23 protein in the sporadic colorectal cancers (rs=0.635, P < 0.05). Combined expression of the two was found to be related with invasion depth, lymphatic metastasis and prognosis of sporadic colorectal cancer (P < 0.05). CONCLUSION: nm23 protein level was related with the degree of malignancy, and could be used as an index to predict the invasion and metastasis potential. The expression of hMSH2 protein is positively correlated that of nm23 protein, and the combined expression of the two has certain guiding significance for the prognosis of sporadic colorectal cancer. PMID- 23679307 TI - Primary care physicians' cancer screening recommendation practices and perceptions of cancer risk of Asian Americans. AB - Asian Americans experience disproportionate incidence and mortality rates of certain cancers, compared to other racial/ethnic groups. Primary care physicians are a critical source for cancer screening recommendations and play a significant role in increasing cancer screening of their patients. This study assessed primary care physicians' perceptions of cancer risk in Asians and screening recommendation practices. Primary care physicians practicing in New Jersey and New York City (n=100) completed a 30-question survey on medical practice characteristics, Asian patient communication, cancer screening guidelines, and Asian cancer risk. Liver cancer and stomach cancer were perceived as higher cancer risks among Asian Americans than among the general population, and breast and prostate cancer were perceived as lower risks. Physicians are integral public health liaisons who can be both influential and resourceful toward educating Asian Americans about specific cancer awareness and screening information. PMID- 23679308 TI - Potential predictors of sensitivity to pemetrexed as first-line chemotherapy for patients with advanced non-squamous NSCLCs. AB - BACKGROUND: Pemetrexed (PEM) is effective in first-line treatment for patients with non-squamous non-small cell lung cancer (NSCLC). However there are currently no definitive determinants to certify which patients could benefit from PEM. To improve the efficacy of PEM combined with platinum as first-line therapy for advanced non-squamous NSCLC, we conducted this retrospective study to detect potential determinants of this regimen. METHODS: We recruited 109 patients with advanced non-squamous NSCLC who received PEM with a platinum as first-line therapy from June 2006 to February 2013 in Jiangsu Cancer Hospital. Multiple variables (age, sex, smoking, degree of cell differentiation, hemoglobin, platinum drugs combined, positions of metastasis) were selected. Logistic regression analysis was used to analyse relationships between these variables and tumor response. RESULT: In univariate analysis, we found that age and platinum significantly influenced the results of PEM therapy (P<0.05). In multivariable analysis, no factors were independently significant. CONCLUSION: Our analysis did not suggest that the age, sex, metastasis of liver or other organs, hemoglobin, smoking history and pathological differentiation are associated with the response of PEM. We should conduct further analyses with larger sample size to reconfirm this issue. PMID- 23679309 TI - Phase II study on safety and efficacy of Yadanzi(r) (Javanica oil emulsion injection) combined with chemotherapy for patients with gastric cancer. AB - OBJECTIVE: To investigate the efficacy and safety of Yadanzi(r) (Javanica oil emulsion injection) combined with chemotherapy for treatment of patients with advanced gastric cancer. METHODS: From January 2011 to December 2012, we recruited 75 patients with advanced gastric cancer, who received javanica oil emulsion injection together with chemotherapy. After two cycles of treatment, efficacy and safety of the combined therapies were evaluated. RESULTS: Overall response rate of 75 patients after treatment was 85.3% (CR+PR+SD). Treatment related side effects were recorded. No treatment related death occurred. CONCLUSIONS: Javanica oil emulsion injection combined with chemotherapy could be considered as a safe and effective regimen in treating patients with advanced gastric cancer. Further randomized clinical trials should be conducted to confirm whether the addition of Yadanzi(r) to chemotheraphy could be associated with reduced toxicity, enhanced tolerability and improved quality of life for patients with advanced gastric cancer. PMID- 23679310 TI - Effects of two chemotherapy regimens, anthracycline-based and CMF, on breast cancer disease free survival in the Eastern Mediterranean Region and Asia: a meta analysis approach for survival curves. AB - BACKGROUND: To compare the effects of two adjuvant chemotherapy regimens, anthracycline-based and cyclophosphamide, methotrexate, fluorourical (CMF) on disease free survival for breast cancer patients in the Eastern Mediterranean region and Asia. METHODS: In a systematic review with a multivariate mixed model meta-analysis, the reported survival proportion at multiple time points in different studies were combined. Our data sources were studies linking the two chemotherapy regimens on an adjuvant basis with disease free survival published in English and Persian in the Eastern Mediterranean region and Asia. All survival curves were generated with Graphdigitizer software. RESULTS: 14 retrospective cohort studies were located from electronic databases. We analyzed data for 1,086 patients who received anthracycline-based treatment and 1,109 given CMF treatment. For determination of survival proportions and time we usesb the transformation Ln (-Ln(S)) and Ln (time) to make precise estimations and then fit the model. All analyses were carried out with STATA software. CONCLUSIONS: Our findings showed a significant efficacy of anthracycline-based adjuvant therapy regarding disease free survival of breast cancer. As a limitation in this meta analysis we used studies with different types of anthracycline-based regimens. PMID- 23679311 TI - Phase II study of pemetrexed as second or third line combined chemotherapy in patients with colorectal cancer. AB - PURPOSE: To investigate the safety and efficacy of pemetrexed combined with chemotherapy as second or third line in patients with stage IV colorectal cancer (CRC). PATIENTS AND METHODS: This trial was conducted to evaluate the effectiveness and safety of pemetrexed given to patients with recurrent or metastatic colorectal carcinoma who previously received 5-FU-based chemotherapy. All patients were required to have a histological diagnosis of colorectal adenocarcinoma with measurable metastatic disease and prior chemotherapy. Patients received pemetrexed at a dose of 500 mg/m2 by 10 minute infusion on day 1, repeated every 21 days. Doses were modified depending on nadir counts. Combined chemotherapy included Oxaliplatin, Irinotecan and cis-platinum. RESULTS: Thirty patients were enrolled and twenty-nine were evaluable for response. One patient did not have repeat radiological testing to determine response because he went off study after only one cycle of treatment for economic reasons. For 29 evaluable patients, 1 partial response, 6 stable disease and 22 progressive disease were recorded. Response rate was 3.45% (1/29). All responses occurred in patients receiving a starting dose of pemetrexed 500 mg/m2. Median time to progression for all eligible patients was 2.5 months. The most common toxicities experienced were mild to moderate fever, hepatic damage, myelosuppression, nausea, vomiting, constipation, abdominal pain, diarrhea, and skin rash. CONCLUSION: Pemetrexed at 500 mg/m2 given every three weeks combined with chemotherapy is associated with moderate response and good tolerability in patients with stage IV CRC. PMID- 23679312 TI - Orphan nuclear receptor nurr1 as a potential novel marker for progression in human prostate cancer. AB - A number of studies have indicated that Nurr1, which belongs to a novel class of orphan nuclear receptors (the NR4A family), is important for carcinogenesis. Here we investigated expression of Nurr1 protein in benign and malignant human prostate tissues and association with clinicopathologic features using immunohistochemical techniques. Moreover, we also investigated the ability of Nurr1 to influence proliferation, migration, invasion and apoptosis of human prostate cancer cells using small interfering RNA silencing. Immunohistochemical analysis revealed that the expression of Nurr1 protein was higher in prostate cancer tissues than in benign prostate tissue (P < 0.001), levels being positively correlated with tumor T classification (P = 0.003), N classification (P = 0.017), M classification (P = 0.011) and the Gleason score (P = 0.020) of prostate cancer patients. In vitro, silencing of endogenous Nurr1 attenuated cell proliferation, migration and invasion, and induced apoptosis of prostate cancer cells. These results suggest that Nurr1 may be used as an indicator for prostate cancer progression and be useful for novel potential therapeutic strategies. PMID- 23679313 TI - Survey of willingness to accept chemotherapy among elderly Malaysian patients. AB - BACKGROUND: The geriatric population in Malaysia is predicted to increase from 4% of the total population in 1998 to 9.8% by 2020, in parallel with developments in the socioeconomy. Cancer is expected to be a major medical issue among this population. However, the decision for treatment in Malaysia is always decided by the caregivers instead of the elderly patients themselves. OBJECTIVE: The aim of the study was to assess the willingness to accept chemotherapy among elderly Malaysians. MATERIALS AND METHODS: In this cross-sectional study, patients aged 60 and above from various clinics/wards were recruited. Those giving consent were interviewed using a questionnaire. RESULTS: A total of 75 patients were recruited, 35 patients (47%) with a history of cancer. The median age was 73 years old. There were 29 Chinese (38.7%), 22 Indian (29.3%), 20 Malay (26.7%) and four other ethnicity patients. Some 83% and 73% of patients willing to accept strong and mild chemotherapy, respectively. Patients with cancer were more willing to accept strong and mild chemotherapy compared to the non-cancer group (88.6% vs 62.5%, P=0.005, 94% vs 80%, P=0.068). On sub-analysis, 71.4% and 42.9% of Chinese patients without a history of cancer were not willing to receive strong and mild chemotherapy, respectively. CONCLUSIONS: The majority of elderly patients in UMMC were willing to receive chemotherapy if they had cancer. Experience with previous treatment had positive influence on the willingness to undergo chemotherapy. PMID- 23679314 TI - The XRCC1 Arg280His gene polymorphism and hepatocellular carcinoma risk: a meta analysis. AB - Many studies have suggested that the XRCC1 Arg280His gene polymorphism might be involved in the development of hepatocellular carcinoma (HCC). However, the results have been inconsistent. In this study, the authors performed a meta analysis to assess the association between XRCC1 Arg280His and HCC susceptibility. Published literature from PubMed, EMBASE and CNKI Data was searched. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed- or random- effects models when appropriate. Begg's test was used to measure publication bias. A total of 7 case-control studies covering 1,448 HCC cases and 1,544 controls were included. No significant variation in HCC risk was detected in any of the genetic models overall. In the stratified analysis, four studies with sample sizes over 300 produced similar results. The corresponding pooled ORs were not substantially altered after the exclusion of three studies deviating from Hardy-Weinberg equilibrium in the control group, which indicated reliability for our meta-analysis results. PMID- 23679315 TI - Importance of serum SELDI-TOF-MS analysis in the diagnosis of early lung cancer. AB - BACKGROUND: Different methods of diagnosis have been found to be inefficient in terms of screening and early diagnosis of lung cancer. Cancer cells produce proteins whose serum levels may be elevated during the early stages of cancer development. Therefore, those proteins may be recognized as potential cancer markers. The aim of this study was to differentiate healthy individuals and lung cancer cases by analyzing their serum protein profiles and evaluate the efficacy of this method in the early diagnosis of lung cancer. MATERIALS AND METHODS: 170 patients with lung cancer, 53 under high risk of lung cancer, and 47 healthy people were included in our study. Proteomic analysis of the samples was performed with the SELDI-TOF-MS approach. RESULTS: The most discriminatory peak of the high risk group was 8141. When tree classification analysis was performed between lung cancer and the healthy control group, 11547 was determined as the most discriminatory peak, with a sensitivity of 85.5%, a specificity of 89.4%, a positive predictive value (PPV) of 96.7% and a negative predictive value (NPV) of 62.7%. CONCLUSIONS: We determined three different protein peaks 11480, 11547 and 11679 were only present in the lung cancer group. The 8141 peak was found in the high-risk group, but not in the lung cancer and control groups. These peaks may prove to be markers of lung cancer which suggests that they may be used in the early diagnosis of lung cancer. PMID- 23679316 TI - Older women breast cancer survivors: decision making, sources of information and wellness activities in Malaysia. AB - The purpose of this study ??s to profile older breast cancer survivors in Malaysia. In a survey study, ? custom made questionnaire was administered to 69 breast cancer patients and survivors between 60 and 84 years of age in Peninsular Malaysia. The main ethnic group recorded was Chinese, followed by Malay and Indian. The majority of women were married (87%) and had children (84.1%). Just over half (53.6%) had primary and secondary education, whereas 24.7% had higher education. Fifty five percent of the study participants made their own decision on treatment, 60.8% exercised at least 3 times in a week, and 56.6% sought information from specialists. Our study suggests that older breast cancer survivors are aware of the importance of exercise in their daily lives and make attempts to be cancer free (e.g. doing exercise, recreational activity and have good relationships with friends and family). PMID- 23679317 TI - Single nucleotide polymorphisms in the NER pathway and clinical outcome of patients with bone malignant tumors. AB - The effects of polymorphisms in ERCC5, ERCC6, XPC, CCNH and MMS19L on osteosarcoma response to chemotherapy and the survival of the affected patients were assessed. Genotyping of ERCC5, ERCC6, XPC, CCNH and MMS19L was performed by PCR-RFLP assay. The median PFS was 12.8 months, and the median OS was 18.6 months. Individuals carrying homozygous genotypes of ERCC5 rs17655 and ERCC5 rs1047768 were more like to have good response to treatment, while those carrying homozygous genotypes of MMS19L rs29001322 showed poor response. Osteosarcoma patients carrying TT genotype of ERCC5 rs1047768 showed a significantly longer PFS (16.8 months) and OS (21.4 months) than CC genotype, with HRs(95% CI) of 0.31 (0.10-0.93) and 0.32 (0.06-0.97), respectively. Conversely, those with the TT genotype of MMS19L rs29001322 demonstrated shorter PFS and OS, the HRs (95% CI) being 2.23 (1.08-4.15) and 4.62 (1.45-16.08), respectively. Our findings showed polymorphisms in ERCC5 rs1047768 and MMS19L rs29001322 to be associated with clinical outcome of osteosarcoma patients undergoing chemotherapy. PMID- 23679318 TI - Plasma vascular endothelial growth factors A and C in patients undergoing prostatic biopsy and TURP for suspected prostatic neoplasia. AB - BACKGROUND: Formation of new blood vessels is necessary for the development and spread of neoplasms more than 1 mm3 in volume, angiogenesis being responsible for formation of new from pre-existing blood vessels. Vascular endothelial growth factor (VEGF) is pivotal and the best studied angiogenic factor in all human cancers. Therefore we designed this study to investigate the role of VEGF-A and VEGF-C in prostate cancer in comparison with BPH controls in a north Indian population. METHODS: In this case-control study a total of 100 subjects were included on the basis of confirmed histopathological reports, out of which 50 were prostate cancer patients and the other 50 were BPH patients with PSA levels >2 ng/ml and abnormal digital rectal examination (DRE) findings during September 2009 to August 2011 from the Department of Urology, KGMU, Lucknow, India. Plasma levels of VEGF were determined using quantitative immunoassay (ELISA- enzyme linked immunosorbent assay). Statistical analysis was carried out using SPSS 15.0 version. RESULTS: The mean age of prostate cancer (67.6+/-5.72) patients was significantly higher (p=0.005) than BPH (63.6+/-7.92) patients. Expression of VEGF-A was not significantly higher in disease stage C1 than D1 or D2 and A or B (p=0.13) while the level of VEGF-A was significantly higher (p=0.04) in prostate cancer as compared to BPH subjects (PCa=13.0 pg/ml, BPH=6.8 pg/ml). Levels of VEGF-C were similar in both groups (PCa=832.6 pg/ml, BPH=823.7 pg/ml). In ROC curve, the area under curve (AUC) was 0.70 (95%CI: 0.60-0.80) and the cut-off value for which a higher proportion of patients was correctly classified (20%) was 26.0 pg/mL. CONCLUSION: Although VEGF-A is increased in cancer prostate patients a statistically significant correlation could not be established in this study. VEGF-C was not found to be a useful biomarker. PMID- 23679319 TI - The National Cancer Screening Program for breast cancer in the Republic of Korea: is it cost-effective? AB - This goal of this research was to evaluate the cost-effectiveness of the National Cancer Screening Program (NCSP) for breast cancer in the Republic of Korea from a government expenditure perspective. In 2002-2003 (baseline), a total of 8,724,860 women aged 40 years or over were invited to attend breast cancer screening by the NCSP. Those who attended were identified using the NCSP database, and women were divided into two groups, women who attended screening at baseline (screened group) and those who did not (non-screened group). Breast cancer diagnosis in both groups at baseline, and during 5-year follow-up was identified using the Korean Central Cancer Registry. The effectiveness of the NCSP for breast cancer was estimated by comparing 5-year survival and life years saved (LYS) between the screened and the unscreened groups, measured using mortality data from the Korean National Health Insurance Corporation and the National Health Statistical Office. Direct screening costs, indirect screening costs, and productivity costs were considered in different combinations in the model. When all three of these costs were considered together, the incremental cost to save one life year of a breast cancer patient was 42,305,000 Korean Won (KW) (1 USD=1,088 KW) for the screened group compared to the non-screened group. In sensitivity analyses, reducing the false-positive rate of the screening program by half was the most cost-effective (incremental cost-effectiveness ratio, ICER=30,110,852 KW/LYS) strategy. When the upper age limit for screening was set at 70 years, it became more cost-effective (ICER=39,641,823 KW/LYS) than when no upper age limit was set. The NCSP for breast cancer in Korea seems to be accepted as cost-effective as ICER estimates were around the Gross Domestic Product. However, cost-effectiveness could be further improved by increasing the sensitivity of breast cancer screening and by setting appropriate age limits. PMID- 23679320 TI - Mortality from stomach cancer in Serbia, excluding the province of Kosovo, in the 1991-2009 period. AB - BACKGROUND/AIM: Stomach cancer is the second most common cause of death from all malignant tumors in the world (third in men, fifth in women), with a strong decreasing trend in most developed countries. The aim of this descriptive epidemiological study was to analyze mortality of stomach cancer in Serbia, excluding the Province of Kosovo, in the 1991-2009 period. MATERIALS AND METHODS: In data analysis, we used mortality rates which were standardized directly using those of the world population as a standard. In order to analyze the mortality trend from stomach cancer, linear trend and regression analysis were used. Confidence intervals (CIs) for the average age-adjusted and age-specific mortality rates were assessed with 95% level of probability. Mortality data were derived from the data file of the Statistical Office of the Republic of Serbia. RESULTS: During the 1991-2009 period, a significant downward trend in mortality of stomach cancer was recorded in Serbia (y=9.78 - 0.13x, p=0.000; average annual percent change was - 6.3 (95%CI, -7.8 to - 4.8). During the same period, a significant decrease in mortality trend was found both in male (y=14.13 - 0.20x; p=0.000; % change was -7.7 (95%CI, -10.9 to -4.5) and female populations (y=6.27 0.08x; p=0.000; % change was - 4.4 (95%CI, -5.3 to -3.6). CONCLUSION: Decreasing trends in mortality from stomach cancer in Serbia are similar to those in most developed countries. PMID- 23679321 TI - Analysis of the relationships between esophageal cancer cases and climatic factors using a Geographic Information System (GIS): a case study of Ardabil province in Iran. AB - Esophageal cancer is a mjaor health problems in many parts of the world. A geographical information system (GIS) allows investigation of the geographical distribution of diseases. The purpose of the present study was to explore the relationship between esophageal cancer and effective climatic factors using GIS. The dispersion distribution and the relationship between environmental factors effective on cancer were measured using Arc GIS. The highest degree of spread was in Germi town and the least was in Ardabil city. There was a significant relationship between effective environmental factors and esophageal cancer in Ardabil province. The results indicated that environmental factors probably are influential in determining the incidence of esophageal cancer. Also, these results can be considered as a window to future comprehensive research on esophageal cancer and related risk factors. PMID- 23679322 TI - Process of coping with mastectomy: a qualitative study in Iran. AB - BACKGROUND: Breast cancer is the most prevalent cancer among Iranian women and mastectomy comprises 81% of surgeries for treatment of breast cancer. Mastectomy may create feelings such as deformation or impairment in patients, cause body image disorder, and reduce sexuality and sexual activity which in turn may entail mental disorders. The study aimed to elaborate coping processes. MATERIALS AND METHODS: A grounded theory method was used in conducting this study. Twenty Iranian participants undergoing mastectomy were recruited with purposive sampling. An open, semi-structured questionnaire were developed. Obtaining consent, conversations were recorded and immediately transcribed after each session. Data analysis was carried out with the constant comparative method using the Strauss Corbin approach. RESULTS: Analyzing the collected data, the study came up with seven main categories which affected the coping process in patients with breast cancer, namely: reactions to mastectomy; loss and death contest; reconstruction of evaluation system; consent for undergoing mastectomy; reactions and troubles after loss; confrontation of loss and health; and reorganization and compatibility with changes. CONCLUSIONS: The results of the study indicated: when patients become informed of their breast cancer and the necessity of undergoing mastectomy as the treatment, they probably pass through seven categories to adapt after mastectomy. Having insight about them is likely to contribute medical personnel in leading patients to the highest degree of feeling healthy. PMID- 23679323 TI - Does hopelessness of Turkish women affect their behavior regarding cervical cancer prevention and early diagnosis? AB - BACKGROUND: The purpose of this descriptive study was to investigate attitudes women of towards cervical cancer prevention applications and early diagnosis, and whether or not their hopelessness levels had any influence. MATERIALS AND METHODS: The present study was carried out in Isparta with a descriptive design. A sample of 251 individuals was recruited from January 2011 through May 2011 in the largest tea garden (restaurant- cafe). The data collection tool consisted of two parts: a "Questionnaire Form" identifying women; and the "Beck Hopelessness Scale". Data were analyzed using the Statistical Package for the Social Sciences (SPSS version 16.0 for Windows for the numerical and percentage distribution, average, standard deviation with the ANOVA and Mann-Whitney tests. RESULTS: Some 70.2 % of the woman indicated that they had not taken the Pap test. There was a significant relationship between the hopelessness level and women believing that they could protect themselves from getting cervical cancer (F=10.11 p=0.00). There was a significant relationship between hopelessness levels and believing whether or not early diagnosis tests are deterministic (F=8.781 p=0.00). CONCLUSION: Our study concluded that the hopelessness level of women had an effect on their thoughts about cervical cancer prevention and early diagnosis. PMID- 23679324 TI - Validity and necessity of sub-classification of N3 in the 7th UICC TNM stage of gastric cancer. AB - BACKGROUND: The 7th TNM staging is the first authoritative standard for evaluation of effectiveness of treatment of gastric cancer worldwide. However, revision of pN classification within TNM needs to be discussed. In particular, the N3 sub-stage is becoming more conspicuous. METHODS: Clinical data of 302 pN3M0 stage gastric cancer patients who received radical gastrectomy in Tianjin Medical University Cancer Institute and Hospital from January 2001 to May 2006 were retrospectively analyzed. RESULTS: Location of tumor, depth of invasion, extranodal metastasis, gastric resection, combined organs resection, lymph node metastasis, rate of lymph node metastasis, negative lymph nodes count were important prognostic factors of pN3M0 stage gastric cancers. TNM stage was also associated with prognosis. Patients at T2N3M0 stage had a better prognosis than other sub-classification. T3N3M0 and T4aN3aM0 patients had equal prognosis which followed the T2N3M0. T4aN3bM0 and T4bN3aM0 had lower survival rate than the formers. T4bN3bM0 had worst prognosis. In multivariate analysis, TNM stage group and rate of lymph node metastasis were independent prognostic factors. CONCLUSIONS: The sub-stage of N3 may be useful for more accurate prediction of prognosis; it should therefore be applied in the TNM stage system. PMID- 23679325 TI - Statistical modelling and forecasting of cervix cancer cases in radiation oncology treatment: a hospital based study from Western Nepal. AB - BACKGROUND: To estimate the numbers and trends in cervix cancer cases visiting the Radiotherapy Department at Manipal Teaching Hospital, Pokhara, Nepal, statistical modelling from retrospective data was applied. MATERIALS AND METHODS: A retrospective study was carried out on data for a total of 159 patients treated for cervix cancer at Manipal Teaching Hospital, Pokhara, Nepal, between 28th September 2000 and 31st December 2008. Theoretical statistics were used for statistical modelling and forecasting. RESULTS: Using curve fitting method, Linear, Logarithmic, Inverse, Quadratic, Cubic, Compound, Power and Exponential growth models were validated. Including the constant term, none of the models fit the data well. Excluding the constant term, the cubic model demonstrated the best fit, with R2=0.871 (p=0.004). In 2008, the observed and estimated numbers of cases were same (12). According to our model, 273 patients with cervical cancer are expected to visit the hospital in 2015. CONCLUSIONS: Our data predict a significant increase in cervical cancer cases in this region in the near future. This observation suggests the need for more focus and resource allocation on cervical cancer screening and treatment. PMID- 23679326 TI - Prognostic and predictive value of hematologic parameters in patients with metastatic renal cell carcinoma: second line sunitinib treatment following IFN alpha. AB - BACKGROUND: Long-term survival is a problem with locally advanced and metastatic renal cell carcinomas. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor, but data on sunitinib use as a second line treatment in metastatic renal cell carcinoma (mRCC) are limited. Prognostic and predictive value of peripheral blood markers has been shown for many cancers. MATERIALS AND METHODS: Efficacy and safety profiles of sunitinib after interferon alpha were evaluated based on retrospective data for 23 patients with mRCC. Hematological parameters (neutrophils, lymphocytes, platelets, mean platelet volume, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio) were recorded at the time of metastasis. It was evaluated whether hematological parameters were prognostic and predictive factors. RESULTS: Median progression-free survival (PFS) time was 16.5 months (95%CI: 0-34.5). Median overall survival (OS) time was 25.7 months (95%CI: 10.8 40.0). Most common side effects were neutropenia (52.2%), stomatitis (26.1%) and hand-food syndrome (26.1%). PFS was found 3.13 vs 17.1 months in patients with neutrophil / lymphocyte ratio (NLR)>3 vs NLR<=3 (p:0.012). Median OS was 6.96 vs 27.1 months in patients with NLR>3 vs NLR<=3 (p:0.001).While 75% of patients who responded to sunitinib had NLR<=3, in 72% of patients with no response to sunitinib NLR>3 was detected (p:0.036). The association between the Memorial Sloan-Kettering Cancer Center (MSKCC) criteria and NLR was statistically significant (p:0.022). CONCLUSIONS: Data on second line sunitinib treatment following cytokine in mRCC are limited. In our study, we observed second line sunitinib treatment following IFN-alpha to be effective and tolerable. NLR appeared to have prognostic and predictive value. PMID- 23679327 TI - Agreement of Iranian breast cancer data and relationships with measuring quality of care in a 5-year period (2006-2011). AB - OBJECTIVES: To investigate data agreement of cancer registries and medical records as well as the quality of care and assess their relationship in a 5-year period from 2006 to 2011. METHODS: The present cross-sectional, descriptive analytical study was conducted on 443 cases summarized through census and using a checklist. Data agreement of Nemazi hospital-based cancer registry and the breast cancer prevention center was analyzed according to their corresponding medical records through adjusted and unadjusted Kappa. The process of care quality was also computed and the relationship with data agreement was investigated through chi-square test. RESULTS: Agreement of surgery, radiotherapy, and chemotherapy data between Nemazi hospital-based cancer registry and medical records was 62.9%, 78.5%, and 81%, respectively, while the figures were 93.2%, 87.9%, and 90.8%, respectively, between breast cancer prevention center and medical records. Moreover, quality of mastectomy, lumpectomy, radiotherapy, and chemotherapy services assessed in Nemazi hospital-based cancer registry was 12.6%, 21.2%, 35.2%, and 15.1% different from the corresponding medical records. On the other hand, 7.4%, 1.4%, 22.5%, and 9.6% differences were observed between the quality of the above-mentioned services assessed in the breast cancer prevention center and the corresponding medical records. A significant relationship was found between data agreement and quality assessment. CONCLUSION: Although the results showed good data agreement, more agreement regarding the cancer stage data elements and the type of the received treatment is required to better assess cancer care quality. Therefore, more structured medical records and stronger cancer registry systems are recommended. PMID- 23679328 TI - Expression of MiR200a, miR93, metastasis-related gene RECK and MMP2/MMP9 in human cervical carcinoma--relationship with prognosis. AB - AIM AND BACKGROUND: Cervical cancer remains the third most common cancer in women globally after breast and colorectal cancer. Well-characterized biomarkers are necessary for early diagnosis and to predict metastatic progression and effective therapy. MiRNAs can regulate gene expression, cell growth, differentiation and apoptosis by targeting mRNAs for translational repression or degradation in tumor cells. The present study was conducted to assess expression of miR93, miR200a, RECK, MMP2, MMP9 in invasive cervical carcinoma, and analyze their clinical significance. METHOD: A total of 116 patients with invasive cervical carcinoma and 100 patients undergoing hysterectomy for benign lesions were retrospectively examined. Quantitative real-time PCR was performed to determine expression of miR93 and miR200a while RECK, MMP2, MMP9 and MVD were assessed by immunohistochemical staining. RESULTS: Cervical carcinoma patients demonstrated up-regulation of miR-93, miR-200a, MMP2 and MMP9, with down-regulation of RECK as compared to benign lesion tissues. RECK was significantly inversely related to invasion and lymphatic metastasis. The 5-year survival rate for patients with strong RECK expression was significantly higher than that with weakly expressing tumors. CONCLUSION: MiR-93 and miR-200a are associated with metastasis and invasion of cervical carcinoma. Thus together with RECK they are potential prognostic markers for cervical carcinoma. RECK cooperating with MMP2, MMP9 expression is a significant prognostic factor correlated with long-term survival for patients with invasive cervical carcinoma. PMID- 23679329 TI - Assessment of cervical cancer risk in women between 15 and 49 years of age: case of Izmir. AB - BACKGROUND: The aim of the study was to determine risk factors for cervical cancer for women in Izmir. METHODS: This cross-sectional, descriptive field covered a population of 4319 women of reproductive age (15-49) (household registration in the Mukhtar's office-2007). A total of 1,637 women were included in the sample given a four-part questionnaire through face-to-face interview by visiting the women in their homes in order to determine socio-demographic factors, obstetric history, genital hygiene and the use of family planning methods. In addition, during the data collection process, the women were given group training in order to raise awareness of cervical cancer. The number and percentage distributions of the data were calculated. RESULTS: While the average age of the women was 31.9+/-9.77 (Min: 15.00-Max: 49.00), education level of 43.4% of them was elementary school only. It was determined that 70.3% of the women experienced at least one pregnancy, 71.0% had vaginal delivery and 75.9% used a contraceptive method. In the study it was determined that among the cervical cancer related risks vaginal delivery, vaginal lavage and having three or more pregnancies had the highest rates, while having sexual intercourse before 16 years of age and having more than one sexual partner constituted lower rates. The rate of the women who stated not having a smear in the last three years was 82.4%. CONCLUSIONS: Considering the case in terms of having Pap smear test, women's awareness on the risk factors and early diagnosis of cervical cancer was found to be low. Due to this reason, awareness of women has to be raised through education. PMID- 23679330 TI - Inhibition of proliferation of cervical and leukemic cancer cells by penicillin G. AB - Cancer, despite all the efforts, still causes one in five deaths worldwide. Surgery, chemotherapy and radiotherapy provide inadequate protection and instead affect normal cells along with cancer cells. The search for cancer cures from natural products (plants and animals) has been practice for over a decade and the use of purified chemical to treat cancer still continues. Several studies have been undertaken during last three decades to find the anti-cancerous property of various plant extract and toxins secreted by animals and micro-organism. These lead to the discovery of several promising molecule having anticancer activity, some of which are in clinical trial and may emerged to be a potential future drug in cancer therapy. In this study we have used penicillin to evaluate its anti cancer activity. It shown significant effects at cellular and molecular levels against growth of HeLa and K562 cell lines. PMID- 23679332 TI - Evidence for U.S. Preventive Services Task Force (USPSTF) recommendations against routine mammography for females between 40-49 years of age. AB - Breast cancer is the most common cancer among females, worldwide, accounting for 22.9% of all cancers (excluding non-melanoma skin cancer) in women. Mammography is a sensitive (77-95%) and specific (94-97%) screening method for breast cancer. Previously, females between the 40-50 years old were recommended to have mammograms every one to two years. However, based on current evidence, in 2009, USPSTF recommended that the decision to start regular, biennial screening mammography for females younger than 50 years should be an individual decision and take patient context into account, including patient values regarding specific benefits and harms. This decision was based on findings regarding radiation exposure, false-positive and false-negative rates, over-diagnosis, and pain and psychological responses. The goal of this paper is to focus on evidence for updating the U.S. Preventive Services Task Force (USPSTF) recommendation against routine mammography for females between 40-49 years of age. PMID- 23679331 TI - Salvage chemotherapy in recurrent platinum-resistant or refractory epithelial ovarian cancer with Carboplatin and distearoylphosphatidylcholine pegylated liposomal Doxorubicin (lipo-dox(r)). AB - BACKGROUND: To evaluate the efficacy and safety of distearoylphosphatidylcholine pegylated liposomal doxorubicin (DPLD) combined with carboplatin for the treatment of platinum resistant or refractory epithelial ovarian cancer (EOC) or fallopian tube cancer. MATERIALS AND METHODS: A retrospective analysis of women who received DPLD with carboplatin for recurrent EOC or fallopian tube cancer in King Chulalongkorn Memorial Hospital Thailand from January 2006 to August 2011 was conducted. Patients were identified from the medical records and data on demographic factors, stage, histology, surgical findings, cytoreduction status, and prior chemotherapies were abstracted. The efficacy and toxicity of DPLD/carboplatin were evaluated. Progression-free (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. RESULTS: A total of 65 patients, 64 with platinum resistant or refractory epithelial ovarian cancer and 1 with fallopian tube cancer, were enrolled. DPLD and carboplatin were given for an average of 4.46 cycles per patient with a total of 273 cycles. Among the 65 evaluable patients, 0% achieved CR, 7.69% PR, 15.4% SD and 76.% PD. The overall response rate was 23.1%. With a median follow-up of 27.4 months, the median progression-free and median overall survival in the 36 patients was 4.46 months and 8.76 months respectively. In the aspect of side effects, palmar-plantar erythrodysesthesia (PPE) occurred in 33.3% (Grade I 22.2%, Grade II 11.1%) and mucositis in 41.7% (Grade I 27.8%, Grade II 13.9%) of all treatment cycles, all Grade 1 or 2. Anemia, leukopenia and thrombocytopenia occurred in 58.3% (Grade I 41.7%, Grade II 16.7%), 66.7% (Grade I 47.2%, Grade II 19.4%), and 22.2% (Grade I 16.6%, Grade II 5.56%) of cycle respectively, and were mostly Grade 1 or 2. CONCLUSIONS: DPLD, the second-generation PLD drug combined with carboplatin every 4 weeks, is effective and has low toxicity for treatment of patients with recurrent platinum-resistant or refractory epithelial ovarian cancer. PMID- 23679333 TI - Gynecological cancer services in Arab countries: present scenario, problems and suggested solutions. AB - Gynecological malignancies account for 9% of all female cancers worldwide. In the Arab countries Breast cancer is the leading cancer in women followed by cervical cancer. Ovarian cancer ranks as fourth leading cancer in women. There are huge differences in the available resources among Arab countries. However the challenges facing the provision of gynecological cancers services shared similarities like the cultural and religious background. Most of the gynecological cancers are diagnosed at a later stage in Arab countries due to the lack of reproductive health awareness especially among older women combined with the cultural stigma of seeking medical advice for gynecological symptoms. This article discusses the current situation of gynecological cancer services in Arab countries and suggests some practical solutions. PMID- 23679334 TI - Adapting the Australian system: is an organized screening program feasible in Malaysia?--an overview of cervical cancer screening in both countries. AB - Cervical cancer is the third most common form of cancer that strikes Malaysian women. The National Cancer Registry in 2006 and 2007 reported that the age standardized incidence (ASR) of cervical cancer was 12.2 and 7.8 per 100,000 women, respectively. The cumulative risk of developing cervical cancer for a Malaysian woman is 0.9 for 74 years. Among all ethnic groups, the Chinese experienced the highest incidence rate in 2006, followed by Indians and Malays. The percentage cervical cancer detected at stage I and II was 55% (stage I: 21.0%, stage II: 34.0%, stage III: 26.0% and stage IV: 19.0%). Data from Ministry of Health Malaysia (2006) showed a 58.9% estimated coverage of pap smear screening conducted among those aged 30-49 years. Only a small percentage of women aged 50-59 and 50-65 years old were screened, 14% and 13.8% coverage, respectively. Incidence of cervical cancer was highest (71.6%) among those in the 60-65 age group (MOH, 2003). Currently, there is no organized population-based screening program available for the whole of Malaysia. A pilot project was initiated in 2006, to move from opportunistic cervical screening of women who attend antenatal and postnatal visits to a population based approach to be able to monitor the women through the screening pathway and encourage women at highest risk to be screened. The project was modelled on the screening program in Australia with some modifications to suit the Malaysian setting. Substantial challenges have been identified, particularly in relation to information systems for call and recall of women, as well as laboratory reporting and quality assurance. A cost-effective locally-specific approach to organized screening, that will provide the infrastructure for increasing participation in the cervical cancer screening program, is urgently required. PMID- 23679335 TI - A systematic review of the utility of anticonvulsant pharmacotherapy in the treatment of vulvodynia pain. AB - INTRODUCTION: Anticonvulsants have increasingly been invoked in the treatment of vulvodynia. However, the evidence supporting this treatment approach has not been systematically assessed. AIM: The study aims to evaluate the efficacy of anticonvulsant pharmacotherapy in the treatment of vulvodynia. METHODS: A comprehensive search of the available literature was conducted. MAIN OUTCOME MEASURE: An assessment of the methodological quality of published reports addressing the utility of anticonvulsants in the treatment of vulvodynia was undertaken. RESULTS: The search yielded nine published reports, i.e., one open label trial, six nonexperimental studies, and two case reports. A number of methodological shortcomings were identified in several of the reports with respect to study design, including small sample sizes, lack of placebo or other comparison groups, inadequate outcome measures, among others. The vast majority of studies employed gabapentin. Evidence supporting the benefit of anticonvulsants studied to date was limited, i.e., based predominantly upon descriptive/observational reports. There were no systematic investigations into the comparative efficacy of different anticonvulsant agents in the treatment of vulvodynia. CONCLUSION: Although some vulvodynia-afflicted patients derive symptom relief from anticonvulsants, there is, as yet, insufficient evidence to support the recommendation of anticonvulsant pharmacotherapy in the treatment of vulvodynia. Additional investigations, employing randomized controlled trials, are warranted. PMID- 23679336 TI - Frontotemporal lobar degeneration with writing disturbance mainly consisting of omission of kana letters. AB - A right-handed woman developed pseudobulbar palsy and a particular writing disturbance mainly composed of omission of kana letters (OKL) at the age of 79, followed by gradual progression of generalized motor disturbance and mutism. She died at the age of 88. Postmortem examination revealed frontotemporal lobar degeneration. The precentral cortex and premotor area were the most severely degenerated among the affected frontal, parietal, and temporal lobes. The omission of kana letters has been recently reported as a characteristic feature of writing disturbance in Japanese amyotrophic lateral sclerosis (ALS). Our case indicates that OKL is not specific to ALS, and that the prefrontal and precentral cortices, common lesions between our case and ALS, are responsible for OKL. This case also shows that OKL can be caused by a pathomechanism independent from other types of writing error. The neurolinguistic analysis of our case suggests the disturbance of the moraic frame of words in the transcription process of morae into kana letters or kana-letter cards. PMID- 23679337 TI - ESAT-6-gpi DNA vaccine augmented the specific antitumour efficacy induced by the tumour vaccine B16F10-ESAT-6-gpi/IL-21 in a mouse model. AB - In this study, we hypothesized that the mice immunized with the glycosylphosphatidylinositol (GPI) anchored 6-kDa early-secreted antigenic target (ESAT-6) DNA vaccine (ESAT-6-gpi) and the tumour vaccine B16F10-ESAT-6-gpi/IL-21 might significantly enhance immune responses and antimelanoma efficacy. Our experimental results indicated that the anti-ESAT-6 antibody induced by the DNA vaccine ESAT-6-gpi bound ESAT-6 to the surface of tumour vaccine to activate a complement classical pathway and resulted in the B16F10 tumour cell lysis and apoptosis, which served as a potential trigger for breaking melanomatous immune tolerance to elicit an initiation of natural antimelanoma immunity. Our innovative approach of using the DNA vaccine ESAT-6-gpi priming and the tumour vaccine B16F10-ESAT-6-gpi/IL-21 boosting induced strong antimelanoma immunity that inhibited melanomatous growth. These findings highlighted the DNA vaccine ESAT-6-gpi as an immune enhancer to augment the immune efficacy of the tumour vaccine B16F10-ESAT -6-gpi/IL-21 against melanoma in a mouse model. PMID- 23679338 TI - Complicated postoperative recovery increases omission, delay and discontinuation of adjuvant chemotherapy in patients with Stage III colon cancer. AB - AIM: The study included investigation of factors determining suboptimal adjuvant chemotherapy of patients diagnosed with Stage III colon cancer. METHOD: All 606 patients diagnosed with Stage III colon cancer between 2006 and 2008 in the western part of the Netherlands were included. Patient [gender, age, comorbidity and socio-economic status (SES)], tumour (location, stage and grade) and treatment (emergency surgery, laparoscopic surgery, reoperation, hospital stay and multidisciplinary meeting) factors were examined in logistic regression analyses predicting a complicated postoperative period and omission, delay and discontinuation of adjuvant chemotherapy. RESULTS: Overall, 27% of all patients experienced a complicated postoperative period, which was independently associated with emergency surgery, older age, multiple comorbidity, male gender and poor tumour grade. Of patients who survived this period, 60% received chemotherapy. Chemotherapy was omitted more often in women, the elderly and in patients with Stage IIIB, reoperation, prolonged hospital stay and (borderline) after open surgery. Of patients who received chemotherapy, 86% started within 8 weeks after surgery. Patients with a higher SES, reoperation and prolonged hospital stay had a higher probability of a delayed start. Sixty-seven per cent of patients completed their chemotherapy. For women, elderly patients and patients with prolonged hospital stay a higher probability of discontinuation was noted. CONCLUSION: Age was the most important predictive factor for receiving adjuvant chemotherapy. However, at all ages, complicated postoperative recovery negatively influenced the administration of chemotherapy to Stage III colon cancer patients, as well as a timely start and completion of chemotherapy. PMID- 23679339 TI - Exploration of the origin and evolution of globular proteins by mRNA display. AB - The questions of how proteins first appeared on the primitive earth and how they evolved into functional proteins are fundamental. If we can understand the origins and evolution of proteins, we should be able to create novel functional proteins. Evolutionary protein engineering or directed protein evolution has been used to create artificial proteins with novel functions by repeated mutation, selection, and amplification, mimicking Darwinian evolution in the laboratory. For this purpose, display technology, such as mRNA display, to link genotype with phenotype is extremely important. Here I focus on three hypotheses regarding the origin and evolution of proteins. First, Eigen's GNC hypothesis proposes that the early genetic code began from the directionless codons GNC and GNN, where N denotes U, C, A, or G. Second, Ohno's gene duplication theory proposes that gene duplication produces two functionally redundant, paralogous genes, of which one retains the original function, leaving the second free to evolve adaptively. Third, Gilbert's exon shuffling theory proposes that new genes are formed through shuffling of small segments corresponding to exons. I then review various experimental approaches to evolutionary protein engineering using mRNA display, such as the creation of functional proteins from random sequences with limited sets of amino acids, randomly mutated folded proteins, and block-shuffled sequence proteins, and I discuss the results in relation to these three hypotheses. PMID- 23679340 TI - An experimental study on the uptake factor of tungsten oxide particles resulting from an accidentally dropped storage container. AB - A test procedure was developed and verified to measure the airborne concentrations of particles of different sizes (0.5-20 MUm) within the vicinity of a dropped container when a significant portion of the tungsten oxide powder (simulating uranium oxide) is ejected from the container. Tests were carried out in a full-scale stainless steel environmental chamber with an interior volume of 24.1 m(3). Thirty-two drop tests were performed, covering variations in dropping height, room air movement, landing scenario, and lid condition. Assuming a breathing rate of 1.2 m(3)/hr, the uptake factor during the first 10 min was calculated to be between 1.13 * 10(-9) and 1.03 * 10(-7) in reference to the amount loaded; or between 6.44 * 10(-8) and 3.55 * 10(-4) in reference to the amount spilled. Results provide previously unavailable data for estimating the exposure and associated risk to building occupants in the case of an accidental dropping of heavy powder containers. The test data show that for spills larger than 0.004 g, the power-law correlation between the spill uptake factor and the spilled mass (i.e., SUF = 2.5 * 10(-5) * Spill_Mass(-0.667)) established from the test data is smaller and a more accurate estimate than the constant value of 10( 3) assumed in the Department of Energy Nuclear Material Packaging Manual. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplementary resource: an online supplementary table of all cumulative uptake amounts at 10 min for all test data.]. PMID- 23679342 TI - LIPS database with LIPService: a microscopic image database of intracellular structures in Arabidopsis guard cells. AB - BACKGROUND: Intracellular configuration is an important feature of cell status. Recent advances in microscopic imaging techniques allow us to easily obtain a large number of microscopic images of intracellular structures. In this circumstance, automated microscopic image recognition techniques are of extreme importance to future phenomics/visible screening approaches. However, there was no benchmark microscopic image dataset for intracellular organelles in a specified plant cell type. We previously established the Live Images of Plant Stomata (LIPS) database, a publicly available collection of optical-section images of various intracellular structures of plant guard cells, as a model system of environmental signal perception and transduction. Here we report recent updates to the LIPS database and the establishment of a database table, LIPService. DESCRIPTION: We updated the LIPS dataset and established a new interface named LIPService to promote efficient inspection of intracellular structure configurations. Cell nuclei, microtubules, actin microfilaments, mitochondria, chloroplasts, endoplasmic reticulum, peroxisomes, endosomes, Golgi bodies, and vacuoles can be filtered using probe names or morphometric parameters such as stomatal aperture. In addition to the serial optical sectional images of the original LIPS database, new volume-rendering data for easy web browsing of three-dimensional intracellular structures have been released to allow easy inspection of their configurations or relationships with cell status/morphology. We also demonstrated the utility of the new LIPS image database for automated organelle recognition of images from another plant cell image database with image clustering analyses. CONCLUSIONS: The updated LIPS database provides a benchmark image dataset for representative intracellular structures in Arabidopsis guard cells. The newly released LIPService allows users to inspect the relationship between organellar three-dimensional configurations and morphometrical parameters. PMID- 23679341 TI - Characterization of an M28 metalloprotease family member residing in the yeast vacuole. AB - The systematic and complete characterization of the Saccharomyces cerevisiae genome and proteome has been stalled in some cases by misannotated genes. One such gene is YBR074W, which was initially annotated as two independent open reading frames (ORFs). We now report on Ybr074, a metalloprotease family member that was initially predicted to reside in the endoplasmic reticulum (ER). Therefore, we tested the hypothesis that Ybr074 may be an ER quality control protease. Instead, indirect immunofluorescence images indicate that Ybr074 is a vacuolar protein, and by employing protease protection assays, we demonstrate that a conserved M28 metalloprotease domain is oriented within the lumen. Involvement of Ybr074 in ER protein quality control was ruled out by examining the stabilities of several well-characterized substrates in strains lacking Ybr074. Finally, using a proteomic approach, we show that disrupting Ybr074 function affects the levels of select factors implicated in vacuolar trafficking and osmoregulation. Together, our data indicate that Ybr074 is the only multispanning vacuolar membrane protease found in the yeast Saccharomyces cerevisiae. PMID- 23679343 TI - Anxiety and depression following preeclampsia or hemolysis, elevated liver enzymes, and low platelets syndrome. A systematic review. AB - Women who suffered from pregnancy complications are at increased risk for anxiety and depression. The aim of this study was to evaluate whether having suffered from preeclampsia (PE) or HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome is associated with anxiety and depression, and whether PE/HELLP is an independent risk factor for developing anxiety and depression. Systematic search on PubMed and PsycInfo with no time limit. Studies presenting original data, including women with a history of PE/HELLP and at least one comparison group of women without PE/HELLP, reporting the results for each group separately or in a multivariate regression analysis with PE/HELLP as an independent variable. Study characteristics and outcomes were extracted using a prespecified form. If necessary, additional calculations were performed. The search yielded 267 articles, with only six being suitable for inclusion in this review. Studies on depression (six studies) showed generally positive associations between PE/HELLP and the prevalence of depression or severity of depressive symptoms. However, the results of three studies were not statistically significant. Studies addressing anxiety (two studies) did not show significant associations between PE/HELLP and anxiety scores. Associations between post traumatic stress and PE/HELLP, investigated in four studies, were often nonsignificant. Due to heterogeneity of study methods, a meta-analysis of the results was not possible. In most studies, confounder control was poor. Evidence is mixed but generally points to positive associations between various forms of psychopathology and previous PE/HELLP. Causality of the associations can, however, not be judged adequately. PMID- 23679344 TI - Novel soft-chemistry route of Ag2Mo3O10.2H2O nanowires and in situ photogeneration of a Ag@Ag2Mo3O10.2H2O plasmonic heterostructure. AB - Ultrathin Ag2Mo3O10.2H2O nanowires (NWs) were synthesized by soft chemistry under atmospheric pressure from a hybrid organic-inorganic polyoxometalate (CH3NH3)2[Mo7O22] and characterized by powder X-ray diffraction, DSC/TGA analyses, FT-IR and FT-Raman spectroscopies, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Their diameters are a few tens of nanometers and hence much thinner than that found for silver molybdates commonly obtained under hydrothermal conditions. The optical properties of Ag2Mo3O10.2H2O NWs before and after UV irradiation were investigated by UV-vis-NIR diffuse reflectance spectroscopy revealing, in addition to photoreduction of Mo(6+) to Mo(5+) cations, in situ photogeneration of well-dispersed silver Ag(0) nanoparticles on the surface of the NWs. The resulting Ag@Ag2Mo3O10.2H2O heterostructure was confirmed by electron energy-loss spectroscopy (EELS), X-ray photoelectron spectroscopy (XPS), and Auger spectroscopy. Concomitant reduction of Mo(6+) and Ag(+) cations under UV excitation was discussed on the basis of electronic band structure calculations. The Ag@Ag2Mo3O10.2H2O nanocomposite is an efficient visible-light-driven plasmonic photocatalyst for degradation of Rhodamine B dye in aqueous solution. PMID- 23679346 TI - Straightforward access to spisulosine and 4,5-dehydrospisulosine stereoisomers: probes for profiling ceramide synthase activities in intact cells. AB - A stereoselective synthesis of spisulosine (ES285) and 4,5-dehydrospisulosine stereoisomers is described. Hydrozirconation of 1-pentadecyne with Schwartz reagent, followed by diastereocontrolled addition to L- or D-alaninal afforded the required 2-amino-1,3-diol framework. The resulting sphingoid bases revealed as excellent probes for the profiling of ceramide synthase activity in intact cells. Among the sphingoid bases described in this work, spisulosine (ES285), RBM1-77, and RBM1-73 were the most suitable ones because of their highest acylation rates. These molecules should prove useful to study the role of the different ceramide synthases and the resulting N-acyl (dihydro)ceramides in cell fate. PMID- 23679345 TI - Sequencing-grade de novo analysis of MS/MS triplets (CID/HCD/ETD) from overlapping peptides. AB - Full-length de novo sequencing of unknown proteins remains a challenging open problem. Traditional methods that sequence spectra individually are limited by short peptide length, incomplete peptide fragmentation, and ambiguous de novo interpretations. We address these issues by determining consensus sequences for assembled tandem mass (MS/MS) spectra from overlapping peptides (e.g., by using multiple enzymatic digests). We have combined electron-transfer dissociation (ETD) with collision-induced dissociation (CID) and higher-energy collision induced dissociation (HCD) fragmentation methods to boost interpretation of long, highly charged peptides and take advantage of corroborating b/y/c/z ions in CID/HCD/ETD. Using these strategies, we show that triplet CID/HCD/ETD MS/MS spectra from overlapping peptides yield de novo sequences of average length 70 AA and as long as 200 AA at up to 99% sequencing accuracy. PMID- 23679348 TI - Cruciferous vegetable consumption and gastric cancer risk: a meta-analysis of epidemiological studies. AB - The relationship between consumption of cruciferous vegetables (CV) and risk of gastric cancer has been investigated by many studies, but remains controversial. We carried out a meta-analysis to summarize available evidence from epidemiological studies on this point. Relevant published reports of CV intake and gastric cancer were identified using MEDLINE (PubMed), EMBASE, and Web of Science databases through to the end of September 2012. We pooled the relative risk from individual studies using a fixed- or random-effects model and carried out heterogeneity and publication bias analyses. Sixteen case-control and six prospective studies were included in our analysis. When all studies were pooled, we yielded a significantly inverse association between CV (relative risk = 0.81; 95% confidence interval, 0.75-0.88) intake and gastric cancer risk, with little heterogeneity (Q = 27.27, P = 0.292, I(2) = 12.0%). Specific analysis for cabbage intake yielded similar result. When separately analyzed, case-control studies of CV intake yielded significant results and the results of prospective studies showed borderline statistical significance. Moreover, significant results were consistent for high-quality studies, for North American, European, and Asian studies, for studies on males, and for studies on non-cardia gastric cancer. Findings from this meta-analysis provide evidence that high intake of CV was inversely associated with the risk of gastric cancer and non-cardia gastric cancer in humans. Further studies on other specific CV, food preparation methods, and stratified results by anatomic cancer site and histological type should be extended in the future. PMID- 23679349 TI - Intra and intersubject variability in auditory steady-state response amplitude with high modulation rates to 1000 Hz amplitude modulated and tone pip stimuli. AB - OBJECTIVE: This study set out to provide further information on how high modulation/stimulus rates affect the auditory steady-state response (ASSR) amplitude for a 1000-Hz tone, and how this effect varies between individuals. Both sinusoidal amplitude modulated tones and tone pip stimuli were investigated. DESIGN: Modulation/stimulus rates were 70, 80, and 90 Hz and the peak to peak stimulus levels were matched for the two different types of stimuli, at 90.5 dBSPLppe. STUDY SAMPLE: The study was carried out on fourteen normally-hearing adults (9 males and 5 females) RESULTS: Overall the ASSR amplitude to the two types of stimuli was similar. In general there was an increasing response amplitude between rates of 70 and 90 Hz; The relationship between the amplitude of the response and the modulation /stimulus rate varied considerably between subjects. CONCLUSIONS: Optimum stimulus rates based on group data may not give the best rate in a significant proportion of subjects. Currently tone pip ABR is the primary method used in assessing hearing in babies. Finding a way of avoiding suboptimal stimulus rates for '80-Hz' ASSR in babies will improve the likelihood of ASSR being seen as an alternative. PMID- 23679347 TI - One-year extension study of ACCORD COPD I: safety and efficacy of two doses of twice-daily aclidinium bromide in patients with COPD. AB - This was a 52-week, double-blind, extension study in which COPD patients previously treated with twice-daily (BID) aclidinium bromide 200 MUg or 400 MUg during a 12-week lead-in study (ACCORD COPD I) continued the same treatment, while patients previously receiving placebo were rerandomized (1:1) to aclidinium 200 MUg or 400 MUg BID. The primary objective of this study was to evaluate the long-term safety and tolerability of aclidinium treatment. Efficacy outcomes included bronchodilation, health status, and rescue medication use. A total of 467 patients completed the lead-in study and 291 patients consented to participate in the extension. At study end, the percentages of patients who reported a treatment-emergent adverse event (TEAE) were similar for both treatments (200 MUg, 77.4%; 400 MUg, 73.7%). Incidence of anticholinergic TEAEs was low and similar for both treatments, with dry mouth reported in only 1 patient (400 MUg). Cardiac TEAEs were reported by a similarly low percentage of patients (<5% for any event in any group) with no apparent dose dependence. Improvements from baseline in lung function were greatest for patients who received continuous aclidinium treatment and those who were rerandomized from placebo to aclidinium 400 MUg; these improvements were generally sustained throughout the study. Health status and overall rescue medication use was improved from baseline for both treatments. The safety profile of twice-daily aclidinium and sustained improvements in lung function and health status throughout the 52-week extension study support its use as a long-term maintenance treatment for patients with COPD. (Clinical trial registration number NCT00970268). PMID- 23679350 TI - Oxidative stress and antibody levels to periodontal bacteria in adults: the Nagasaki Islands study. AB - OBJECTIVE: Periodontitis is a chronic inflammatory disease of the tissues supporting the teeth and is caused by subgingival plaque. Systemic increases in reactive oxygen species are involved in pathogenesis of periodontitis. This study addressed the relationship between levels of serum oxidative stress and antibodies against putative periodontopathic bacteria and their association with periodontal conditions, in a community-based study. SUBJECTS AND METHODS: Serum samples were measured for reactive oxygen metabolite (ROM) levels and anti oxidant capacity. The serum levels of immunoglobulin G (IgG) antibodies to Porphyromonas gingivalis (Pg), Prevotella intermedia (Pi), Aggregatibacter actinomycetemcomitans (Aa), and Eikenella corrodens (Ec) were determined by ELISA. RESULTS: The participants with greater clinical attachment loss had higher serum ROM levels and IgG antibody titers to Pg. Serum ROM levels were positively correlated with antibody titers to Pg, Pi, and Ec. When the participants with greater probing pocket depth and clinical attachment loss were used as the dependent variables, high ROM levels showed a statistically significant associations in multivariate logistic analyses; the adjusted odds ratios were 2.9 (95% confidence interval = 1.0-8.5) and 6.0 (95% confidence interval = 2.0-17.6), respectively. CONCLUSIONS: It was concluded that an increased oxidative stress may be detrimental to periodontitis in Japanese community-dwelling adults. PMID- 23679352 TI - Spatially selective formation of hydrocarbon, fluorocarbon, and hydroxyl terminated monolayers on a microelectrode array. AB - A protection-deprotection strategy, using gold oxide as a passivating layer, was used to direct the self-assembly of monolayers (SAMs) selectively at individual gold microelectrodes in an array. This approach allowed the formation of hydroxyl terminated monolayers, without side reactions, in addition to hydrocarbon and fluorocarbon SAMs. Fluorescence microscopy was used to visualize selective dewetting of hydrophobic monolayers by an aqueous dye solution, and spatially resolved X-ray photoelectron spectroscopy was used to demonstrate a lack of cross contamination on neighboring microelectrodes in the array. PMID- 23679351 TI - The effect of different dosing regimens of motesanib on the gallbladder: a randomized phase 1b study in patients with advanced solid tumors. AB - BACKGROUND: Gallbladder toxicity, including cholecystitis, has been reported with motesanib, an orally administered small-molecule antagonist of VEGFRs 1, 2 and 3; PDGFR; and Kit. We assessed effects of motesanib on gallbladder size and function. METHODS: Patients with advanced metastatic solid tumors ineligible for or progressing on standard-of-care therapies with no history of cholecystitis or biliary disease were randomized 2:1:1 to receive motesanib 125 mg once daily (Arm A); 75 mg twice daily (BID), 14-days-on/7-days-off (Arm B); or 75 mg BID, 5-days on/2-days-off (Arm C). Primary endpoints were mean change from baseline in gallbladder size (volume by ultrasound; independent review) and function (ejection fraction by CCK-HIDA; investigator assessment). RESULTS: Forty-nine patients received >=1 dose of motesanib (Arms A/B/C, n = 25/12/12). Across all patients, gallbladder volume increased by a mean 22.2 cc (from 38.6 cc at baseline) and ejection fraction decreased by a mean 19.2% (from 61.3% at baseline) during treatment. Changes were similar across arms and appeared reversible after treatment discontinuation. Three patients had cholecystitis (grades 1, 2, 3, n = 1 each) that resolved after treatment discontinuation, one patient developed grade 3 acute cholecystitis requiring cholecystectomy, and two patients had other notable grade 1 gallbladder disorders (gallbladder wall thickening, gallbladder dysfunction) (all in Arm A). Two patients developed de novo gallstones during treatment. Twelve patients had right upper quadrant pain (Arms A/B/C, n = 8/1/3). The incidence of biliary "sludge" in Arms A/B/C was 39%/36%/27%. CONCLUSIONS: Motesanib treatment was associated with increased gallbladder volume, decreased ejection fraction, biliary sludge, gallstone formation, and infrequent cholecystitis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00448786. PMID- 23679353 TI - Synthesis and characterization of patronite form of vanadium sulfide on graphitic layer. AB - With the exploding interest in transition metal chalcogenides, sulfide minerals containing the dianion S2(2-), such as pyrite (FeS2), cattierite (CoS2), and vaesite (NiS2), have recently attracted much attention for potential applications in energy conversion and storage devices. However, the synthesis of the patronite structure (VS4, V(4+)(S2(2-))2) and its applications have not yet been clearly demonstrated because of experimental difficulties and the existence of nonstoichiometric phases. Herein, we report the synthesis of VS4 using a simple, facile hydrothermal method with a graphene oxide (GO) template and the characterization of the resulting material. Tests of various templates such as CNT, pyrene, perylene-3,4,9,10-tetracarboxylic dianhydride (PTCDA), and graphite led us to the conclusion that the graphitic layer plays a role in the nucleation during growth of VS4. Furthermore, the VS4/rGO hybrid was proved to be a promising functional material in energy storage devices. PMID- 23679354 TI - Molluscum contagiosum-like lesions in histoid leprosy in a 10-year-old Indian boy. AB - Histoid leprosy is extremely rare in children. Molluscum contagiosum-like lesions in the setting of histoid leprosy is a highly atypical presentation and may signify the process of "transepidermal elimination" in lesions with high bacillary load. A case of histoid leprosy with umbilicated papules and nodules mimicking molluscum contagiosum is reported in a 10-year-old Indian boy. PMID- 23679355 TI - Ratchet effect driven by Coulomb friction: the asymmetric Rayleigh piston. AB - The effect of Coulomb friction is studied in the framework of collisional ratchets. It turns out that the average drift of these devices can be expressed as the combination of a term related to the lack of equipartition between the probe and the surrounding bath, and a term featuring the average frictional force. We illustrate this general result in the asymmetric Rayleigh piston, showing how Coulomb friction can induce a ratchet effect in a Brownian particle in contact with an equilibrium bath. An explicit analytical expression for the average velocity of the piston is obtained in the rare collision limit. Numerical simulations support the analytical findings. PMID- 23679356 TI - Kardar-Parisi-Zhang universality class in (2+1) dimensions: universal geometry dependent distributions and finite-time corrections. AB - The dynamical regimes of models belonging to the Kardar-Parisi-Zhang (KPZ) universality class are investigated in d=2+1 by extensive simulations considering flat and curved geometries. Geometry-dependent universal distributions, different from their Tracy-Widom counterpart in one dimension, were found. Distributions exhibit finite-time corrections hallmarked by a shift in the mean decaying as t( beta), where beta is the growth exponent. Our results support a generalization of the ansatz h=v(infinity)t+(Gammat)(beta)chi+eta+zetat(-beta) to higher dimensions, where v(infinity), Gamma, zeta, and eta are nonuniversal quantities whereas beta and chi are universal and the last one depends on the surface geometry. Generalized Gumbel distributions provide very good fits of the distributions in at least four orders of magnitude around the peak, which can be used for comparisons with experiments. Our numerical results call for analytical approaches and experimental realizations of the KPZ class in two-dimensional systems. PMID- 23679357 TI - Granular Brownian motors: role of gas anisotropy and inelasticity. AB - We investigate the motion of a two-dimensional wedge-shaped object (a granular Brownian motor), which is restricted to move along the x axis and cannot rotate as gas particles collide with it. We show that its steady-state drift, resulting from inelastic gas-motor collisions, is dramatically affected by anisotropy in the velocity distribution of the gas. We identify the dimensionless parameter providing the dependence of this drift on shape, masses, inelasticity, and anisotropy: The anisotropy leads to dramatically enhanced drift of the motor, which should easily be visible in experimental realizations. PMID- 23679358 TI - Capillarylike fluctuations of a solid-liquid interface in a noncohesive granular system. AB - One of the most noticeable collective motion of noncohesive granular matter is clustering under certain conditions. In particular, when a quasi-two-dimensional monolayer of monodispersed noncohesive particles is vertically vibrated, a solid liquid-like transition occurs when the driving amplitude exceeds a critical value. Here the physical mechanism underlying particle clustering relies on the strong interactions mediated by grain collisions, rather than on grain-grain cohesive forces. In average, the solid cluster resembles a drop, with a striking circular shape. We experimentally investigate the coarse-grained solid-liquid interface fluctuations, which are characterized through the static and dynamic correlation functions in the Fourier space. These fluctuations turn out to be well described by the capillary wave theory, which allows us to measure the solid liquid interface surface tension and mobility once the granular "thermal" kinetic energy is determined. Despite that the system is strongly out of equilibrium and that the granular temperature is not uniform, there is energy equipartition at the solid-liquid interface, for a relatively large range of angular wave numbers. Furthermore, both surface tension and mobility are consistent with a simple order of magnitude estimation considering the characteristic energy, length, and time scales, which is very similar to what can be done for atomic systems. PMID- 23679359 TI - Chiral solutes can seed the formation of enantiomorphic domains in a twist-bend nematic liquid crystal. AB - The twist-bend nematic, an enantiomorphic liquid-crystalline phase, exhibited by the structurally symmetric liquid-crystal dimer CB7CB is induced to form a single domain of uniform handedness, in the bulk, by the addition of the dopant chiral solute (S)-1-phenylethanol. Addition of a nonracemic (or scalemic) mixture of both R and S enantiomers of this solute produced equal volumes of P and M chiral domains for the twist-bend nematic phase. This seeding of the domains in an enantiomorphic nematic conglomerate is revealed using deuterium NMR spectroscopy. PMID- 23679360 TI - Memory effect and fluctuating anomalous dynamics of a tagged monomer. AB - We analyze the anomalous dynamics of a tagged monomer under external navigation. The memory effect causing the anomaly is elucidated, which depends on the magnitude of the force. In particular, the nonlinear and nonequilibrium memory effect under strong force is characterized by the force-dependent self-affine process for the tension transmission along the connectivity. Utilizing such knowledge, a generalized Langevin equation approach is proposed to quantify the fluctuating dynamics of driven anomalous walkers. PMID- 23679361 TI - Unifying autocatalytic and zeroth-order branching models for growing actin networks. AB - The directed polymerization of actin networks is an essential element of many biological processes, including cell migration. Different theoretical models considering the interplay between the underlying processes of polymerization, capping, and branching have resulted in conflicting predictions. One of the main reasons for this discrepancy is the assumption of a branching reaction that is either first order (autocatalytic) or zeroth order in the number of existing filaments. Here we introduce a unifying framework from which the two established scenarios emerge as limiting cases for low and high filament numbers. A smooth transition between the two cases is found at intermediate conditions. We also derive a threshold for the capping rate above which autocatalytic growth is predicted at sufficiently low filament number. Below the threshold, zeroth-order characteristics are predicted to dominate the dynamics of the network for all accessible filament numbers. Together, these mechanisms allow cells to grow stable actin networks over a large range of different conditions. PMID- 23679362 TI - Hyperbolic chaos of standing wave patterns generated parametrically by a modulated pump source. AB - We outline a possibility of hyperbolic chaotic dynamics associated with the expanding circle map for spatial phases of parametrically excited standing wave patterns. The model system is governed by a one-dimensional wave equation with nonlinear dissipation. The phenomenon arises due to the pump modulation providing the alternating excitation of modes with the ratio of characteristic scales 1:3. PMID- 23679363 TI - Ultrafast physical generation of random numbers using hybrid Boolean networks. AB - We describe a high-speed physical random number generator based on a hybrid Boolean network with autonomous and clocked logic gates, realized on a reconfigurable chip. The autonomous logic gates are arranged in a bidirectional ring topology and generate broadband chaos. The clocked logic gates receive input from the autonomous logic gates so that random numbers are generated physically that pass standard randomness tests without further postprocessing. The large number of logic gates on reconfigurable chips allows for parallel generation of random numbers, as demonstrated by our implementation of 128 physical random number generators that achieve a real-time bit rate of 12.8Gbits/s. PMID- 23679364 TI - Turbulence and columnar vortex formation through inertial-wave focusing. AB - In this experimental and numerical study, we consider the role of inertial waves in the inverse energy cascade and the transfer of momentum in a rotating fluid. An oscillating torus generates two inertial-wave cones with their energy focusing at their apex. For high wave amplitudes, turbulence is generated locally around the focal point, resulting in angular momentum mixing and the generation of a columnar cyclonic vortex. The results suggest that nonlinear dynamics is essential for the wave induced momentum transport towards columnar vortices in rotating turbulence. PMID- 23679365 TI - Nonlinear electrokinetic flow about a polarized conducting drop. AB - In the thin-double-layer limit kappaa>>1, electrokinetic flows about free surfaces are driven by a combination of an electro-osmotic slip and effective shear-stress jump. An intriguing case is that of a highly conducting liquid drop of radius a, where the inability to balance the viscous shear by Maxwell stresses results in an O(kappaa) velocity amplification relative to the familiar electro osmotic scale. To illuminate the inherent nonlinearity we consider uncharged drops, where the induced surface-charge distribution results in a fore-aft symmetric electrokinetic flow profile with no attendant drop translation. This problem is analyzed using a macroscale model, where the double layer is represented by effective boundary conditions. Because of the intense flow, ionic convection within the O(1/kappa)-wide diffuse-charge layer is manifested by a moderate-zeta-potential surface-conduction effect. The drop deforms to a prolate shape in response to the combination of hydrodynamic forces and the effective electrocapillary reduction of the surface-tension coefficient, both mechanisms being asymptotically comparable. The flow field and the concomitant drop deformation are calculated using both a weak-field approximation and numerical simulations of the nonlinear macroscale model. PMID- 23679366 TI - Lagrangian single-particle turbulent statistics through the Hilbert-Huang transform. AB - The Hilbert-Huang transform is applied to analyze single-particle Lagrangian velocity data from numerical simulations of hydrodynamic turbulence. The velocity trajectory is described in terms of a set of intrinsic mode functions C(i)(t) and of their instantaneous frequency omega(i)(t). On the basis of this decomposition we define the omega-conditioned statistical moments of the C(i) modes, named q order Hilbert spectra (HS). We show that such quantities have enhanced scaling properties as compared to traditional Fourier transform- or correlation-based (structure functions) statistical indicators, thus providing better insights into the turbulent energy transfer process. We present clear empirical evidence that the energylike quantity, i.e., the second-order HS, displays a linear scaling in time in the inertial range, as expected from a dimensional analysis. We also measure high-order moment scaling exponents in a direct way, without resorting to the extended self-similarity procedure. This leads to an estimate of the Lagrangian structure function exponents which are consistent with the multifractal prediction in the Lagrangian frame as proposed by Biferale et al. [Phys. Rev. Lett. 93, 064502 (2004)]. PMID- 23679367 TI - Robustness of first-order phase transitions in one-dimensional long-range contact processes. AB - It has been proposed [Ginelli et al., Phys. Rev. E 71, 026121 (2005)] that, unlike the short-range contact process, the long-range counterpart may lead to the existence of a discontinuous phase transition in one dimension. Aiming to explore such a link, here we investigate thoroughly a family of long-range contact processes. They are introduced through the transition rate 1+al(-sigma), where l is the length of inactive islands surrounding particles. In the former approach we reconsider the original model (called the sigma-contact process) by considering distinct mechanisms of weakening the long-range interaction toward the short-range limit. In addition, we study the effect of different rules, including creation and annihilation by clusters of particles and distinct versions with infinitely many absorbing states. Our results show that for all examples presenting a single absorbing state, a discontinuous transition is possible for small sigma. On the other hand, the presence of infinite absorbing states leads to a distinct scenario depending on the interactions at the perimeter of inactive sites. PMID- 23679368 TI - Multicomponent fluid of nonadditive hard spheres near a wall. AB - A recently proposed rational-function approximation [Phys. Rev. E 84, 041201 (2011)] for the structural properties of nonadditive hard spheres is applied to evaluate analytically (in Laplace space) the local density profiles of multicomponent nonadditive hard-sphere mixtures near a planar nonadditive hard wall. The theory is assessed by comparison with NVT Monte Carlo simulations of binary mixtures with a size ratio 1:3 in three possible scenarios: a mixture with either positive or negative nonadditivity near an additive wall, an additive mixture with a nonadditive wall, and a nonadditive mixture with a nonadditive wall. It is observed that, while the theory tends to underestimate the local densities at contact (especially in the case of the big spheres) it captures very well the initial decay of the densities with increasing separation from the wall and the subsequent oscillations. PMID- 23679369 TI - Changing the state of a memristive system with white noise. AB - Can we change the average state of a resistor by simply applying white noise? We show that the answer to this question is positive if the resistor has memory of its past dynamics (a memristive system). We also prove that, if the memory arises only from the charge flowing through the resistor-an ideal memristor-then the current flowing through such memristor cannot charge a capacitor connected in series and, therefore, cannot produce useful work. However, the memristive system may skew the charge probability density on the capacitor, an effect that can be measured experimentally. PMID- 23679370 TI - Information-theoretic versus thermodynamic entropy production in autonomous sensory networks. AB - For sensory networks, we determine the rate with which they acquire information about the changing external conditions. Comparing this rate with the thermodynamic entropy production that quantifies the cost of maintaining the network, we find that there is no universal bound restricting the rate of obtaining information to be less than this thermodynamic cost. These results are obtained within a general bipartite model consisting of a stochastically changing environment that affects the instantaneous transition rates within the system. Moreover, they are illustrated with a simple four-states model motivated by cellular sensing. On the technical level, we obtain an upper bound on the rate of mutual information analytically and calculate this rate with a numerical method that estimates the entropy of a time series generated with a simulation. PMID- 23679371 TI - Link-disorder fluctuation effects on synchronization in random networks. AB - We consider one typical system of oscillators coupled through disordered link configurations in networks, i.e., a finite population of coupled phase oscillators with distributed intrinsic frequencies on a random network. We investigate the collective synchronization behavior, paying particular attention to link-disorder fluctuation effects on the synchronization transition and its finite-size scaling (FSS). Extensive numerical simulations as well as the mean field analysis have been performed. We find that link-disorder fluctuations effectively induce uncorrelated random fluctuations in frequency, resulting in the FSS exponent nu[over -]=5/2, which is identical to that in the globally coupled case (no link disorder) with frequency-disorder fluctuations. PMID- 23679372 TI - Percolation thresholds on planar Euclidean relative-neighborhood graphs. AB - In the present article, statistical properties regarding the topology and standard percolation on relative neighborhood graphs (RNGs) for planar sets of points, considering the Euclidean metric, are put under scrutiny. RNGs belong to the family of "proximity graphs"; i.e., their edgeset encodes proximity information regarding the close neighbors for the terminal nodes of a given edge. Therefore they are, e.g., discussed in the context of the construction of backbones for wireless ad hoc networks that guarantee connectedness of all underlying nodes. Here, by means of numerical simulations, we determine the asymptotic degree and diameter of RNGs and we estimate their bond and site percolation thresholds, which were previously conjectured to be nontrivial. We compare the results to regular 2D graphs for which the degree is close to that of the RNG. Finally, we deduce the common percolation critical exponents from the RNG data to verify that the associated universality class is that of standard 2D percolation. PMID- 23679373 TI - Microscopic reversibility and heat for thermostatted systems. AB - In order to test the universality of a symmetry for the trajectory obtained for Hamiltonian dynamics, we investigate the case of Nose-Hoover thermostatted dynamics with the use of a clear separation between the system and reservoir. Remarkably, the same symmetry as the Hamiltonian dynamics holds despite the presence of the dissipation, which causes the phase volume contraction. As a nontrivial application of the symmetry, we further show that the microscopic reversibility for open systems holds just as in the Hamiltonian dynamics. This bridges the first and second laws of thermodynamics under the proper definition of the work and heat. PMID- 23679374 TI - Strong fluctuation theorem for nonstationary nonequilibrium systems. AB - We present a finite-time detailed fluctuation theorem of the form P(DeltaS(env))=e(DeltaS(env))P(-DeltaS(env)) for an appropriately weighted probability density P(DeltaS(env)) of the external entropy production in the environment DeltaS(env). The fluctuation theorem is valid for nonequilibrium systems with constant rates starting with an arbitrary initial probability distribution. We discuss the implication of this relation for the case of a temperature quench in classical equilibrium systems. The fluctuation theorem is tested numerically for a Markov jump process with six states and for a surface growth model. PMID- 23679375 TI - Transport coefficients from the boson Uehling-Uhlenbeck equation. AB - Expressions for the bulk viscosity, shear viscosity, and thermal conductivity of a quantum degenerate Bose gas above the critical temperature for Bose-Einstein condensation are derived using the Uehling-Uhlenbeck kinetic equation. For contact potentials and hard sphere interactions, the eigenvalues (relaxation rates) of the Uehling-Uhlenbeck collision operator have an upper cutoff. This cutoff requires summation over all discrete eigenvalues and eigenvectors of the collision operator when computing transport coefficients. We numerically compute the shear viscosity and thermal conductivity for any boson gas that interacts via a contact potential. We find that the bulk viscosity of the degenerate boson gas remains identically zero, as it is for the classical gas. PMID- 23679376 TI - Absence of thermalization for systems with long-range interactions coupled to a thermal bath. AB - We investigate the dynamics of a small long-range interacting system, in contact with a large long-range thermal bath. Our analysis reveals the existence of striking anomalies in the energy flux between the bath and the system. In particular, we find that the evolution of the system is not influenced by the kinetic temperature of the bath, as opposed to what happens for short-range collisional systems. As a consequence, the system may get hotter also when its initial temperature is larger than the bath temperature. This observation is explained quantitatively in the framework of the collisionless Vlasov description of toy models with long-range interactions and shown to be valid whenever the Vlasov picture applies, from cosmology to plasma physics.. PMID- 23679377 TI - Adequacy of the virial equation of state and cluster expansion. AB - The limits for the accuracy of the virial expansion and the problem of its divergence have been investigated using the exact cluster expansion of the configuration integral. In the subcritical temperature regimes the virial equation of state is applicable up to the singularity point of the isothermal compressibility, i.e., to the possible beginning of the condensation process. At supercritical temperatures this equation should be applicable within the region where the cluster expansion is adequate. The problem of the virial series divergence has been found to be irrelevant to the actual behavior of the cluster expansion. Considering the Lennard-Jones fluid as well as the system of hard spheres, the inadequate behavior of the cluster expansion has been discovered in the high density regime. The major reason for this inadequacy should be the basic simplification of the cluster expansion: the integration of irreducible diagrams over the infinite limits. PMID- 23679378 TI - Fluctuation corrections to thermodynamic functions: finite-size effects. AB - The explicit thermodynamic functions, in particular, the specific heat of a spin system interacting with a spin bath which exerts finite dissipation on the system are determined. We show that the specific heat is a sum of the products of a thermal equilibration factor that carries the temperature dependence and a dynamical correction factor, characteristic of the dissipative energy flow under steady state from the system. The variation of specific heat with temperature is accompanied by an abrupt transition that depends on these dynamical factors characteristic of the finite system size. PMID- 23679379 TI - Exact evaluation of the cutting path length in a percolation model on a hierarchical network. AB - This work presents an approach to evaluate the exact value of the fractal dimension of the cutting path d(f)(CP) on hierarchical structures with finite order of ramification. Our approach is based on a renormalization group treatment of the universality class of watersheds. By making use of the self-similar property, we show that d(f)(CP) depends only on the average cutting path (CP) of the first generation of the structure. For the simplest Wheastone hierarchical lattice (WHL), we present a mathematical proof. For a larger WHL structure, the exact value of d(f)(CP) is derived based on a computer algorithm that identifies the length of all possible CP's of the first generation. PMID- 23679380 TI - Distance-weighted city growth. AB - Urban agglomerations exhibit complex emergent features of which Zipf's law, i.e., a power-law size distribution, and fractality may be regarded as the most prominent ones. We propose a simplistic model for the generation of citylike structures which is solely based on the assumption that growth is more likely to take place close to inhabited space. The model involves one parameter which is an exponent determining how strongly the attraction decays with the distance. In addition, the model is run iteratively so that existing clusters can grow (together) and new ones can emerge. The model is capable of reproducing the size distribution and the fractality of the boundary of the largest cluster. Although the power-law distribution depends on both, the imposed exponent and the iteration, the fractality seems to be independent of the former and only depends on the latter. Analyzing land-cover data, we estimate the parameter-value gamma~2.5 for Paris and its surroundings. PMID- 23679382 TI - Finite-temperature crossover from a crystalline to a cluster phase for a confined finite chain of ions. AB - Employing Monte Carlo simulation techniques we investigate the statistical properties of equally charged particles confined in a one-dimensional box trap and detect a crossover from a crystalline to a cluster phase with increasing temperature. The corresponding transition temperature depends separately on the number of particles N and the box size L, implying nonextensivity due to the long range character of the interactions. The probability density of the spacing between the particles exhibits at low temperatures an accumulation of discrete peaks with an overall asymmetric shape. In the vicinity of the transition temperature it is of a Gaussian form, whereas in the high-temperature regime an exponential decay is observed. The high-temperature behavior shows a cluster phase with a mean cluster size that first increases with the temperature and then saturates. The crossover is clearly identifiable also in the nonlinear behavior of the heat capacity with varying temperature. The influence of the trapping potential on the observed results as well as possible experimental realizations are briefly addressed. PMID- 23679381 TI - Universal spatial correlations in random spinor fields. AB - We identify universal spatial fluctuations in systems with nontrivial spin dynamics. To this end we calculate by exact numerical diagonalization a variety of experimentally relevant correlations between spinor amplitudes, spin polarizations, and spin currents, both in the bulk and near the boundary of a confined two-dimensional clean electron gas in the presence of spin-orbit interaction. We support our claim of universality with the excellent agreement between the numerical results and system-independent spatial correlations of a random field defined on both the spatial and spin degrees of freedom. A rigorous identity relating our universal predictions with response functions provides a direct physical interpretation of our results in the framework of linear response theory. PMID- 23679383 TI - Scaling behavior of an airplane-boarding model. AB - An airplane-boarding model, introduced earlier by Frette and Hemmer [Phys. Rev. E 85, 011130 (2012)], is studied with the aim of determining precisely its asymptotic power-law scaling behavior for a large number of passengers N. Based on Monte Carlo simulation data for very large system sizes up to N=2(16)=65536, we have analyzed numerically the scaling behavior of the mean boarding time and other related quantities. In analogy with critical phenomena, we have used appropriate scaling Ansatze, which include the leading term as some power of N (e.g., [proportionality]N(alpha) for ), as well as power-law corrections to scaling. Our results clearly show that alpha=1/2 holds with a very high numerical accuracy (alpha=0.5001+/-0.0001). This value deviates essentially from alpha=/~0.69, obtained earlier by Frette and Hemmer from data within the range 2<=N<=16. Our results confirm the convergence of the effective exponent alpha(eff)(N) to 1/2 at large N as observed by Bernstein. Our analysis explains this effect. Namely, the effective exponent alpha(eff)(N) varies from values about 0.7 for small system sizes to the true asymptotic value 1/2 at N->infinity almost linearly in N(-1/3) for large N. This means that the variation is caused by corrections to scaling, the leading correction-to-scaling exponent being theta~1/3. We have estimated also other exponents: nu=1/2 for the mean number of passengers taking seats simultaneously in one time step, beta=1 for the second moment of t(b), and gamma~1/3 for its variance. PMID- 23679384 TI - Narrow-escape problem for the unit sphere: homogenization limit, optimal arrangements of large numbers of traps, and the N(2) conjecture. AB - A narrow-escape problem is considered to calculate the mean first passage time (MFPT) needed for a Brownian particle to leave a unit sphere through one of its N small boundary windows (traps). A procedure is established to calculate optimal arrangements of N>>1 equal small boundary traps that minimize the asymptotic MFPT. Based on observed characteristics of such arrangements, a remarkable property is discovered, that is, the sum of squared pairwise distances between optimally arranged N traps on a unit sphere is integer, equal to N(2). It is observed for 2<=N<=1004 with high precision. It is conjectured that this is the case for such optimal arrangements for all N. A dilute trap limit of homogenization theory when N->infinity can be used to replace the strongly heterogeneous Dirichlet-Neumann MFPT problem with a spherically symmetric Robin problem for which an exact solution is readily found. Parameters of the Robin homogenization problem are computed that capture the first four terms of the asymptotic MFPT. Close agreement of asymptotic and homogenization MFPT values is demonstrated. The homogenization approach provides a radically faster way to estimate the MFPT since it is given by a simple formula and does not involve expensive global optimization to determine locations of N>>1 boundary traps. PMID- 23679385 TI - Efficiency at maximum power of a heat engine working with a two-level atomic system. AB - We consider the finite-time operation of a quantum heat engine whose working substance is composed of a two-level atomic system. The engine cycle, consisting of two quantum adiabatic and two quantum isochoric (constant-frequency) processes and working between two heat reservoirs at temperatures T(h) and T(c)(/~20, we find three regimes in e depending on the behavior of n(coll) in the hard-sphere limit: (i) an uncollapsing regime for 1>=e>e(c1), where n(coll) converges to a finite value, (ii) a logarithmically collapsing regime for e(c1)>e>e(c2), where n(coll) diverges as n(coll)~logk, and (iii) a power-law collapsing regime for e(c2)>e>0, where n(coll) diverges as n(coll)~k(alpha) with an exponent alpha that depends on N. The power-law collapsing regime shrinks as N decreases and seems not to exist for the system with N=3, while, for large N, the size of the uncollapsing and the logarithmically collapsing regime decreases as e(c1)=/~1-2.6/N and e(c2)=/~1 3.0/N. We demonstrate that this difference between large and small systems exists already in the inelastic collapse without external drive and gravity. PMID- 23679400 TI - Area coverage of radial Levy flights with periodic boundary conditions. AB - We consider the area coverage of radial Levy flights in a finite square area with periodic boundary conditions. From simulations we show how the fractal path dimension d(f) and thus the degree of area coverage depends on the number of steps of the trajectory, the size of the area, and the resolution of the applied box counting algorithm. For sufficiently long trajectories and not too high resolution, the fractal dimension returned by the box counting method equals two, and in that sense the Levy flight fully covers the area. Otherwise, the determined fractal dimension equals the stable index of the distribution of jump lengths of the Levy flight. We provide mathematical expressions for the turnover between these two scaling regimes. As complementary methods to analyze confined Levy flights we investigate fractional order moments of the position for which we also provide scaling arguments. Finally, we study the time evolution of the probability density function and the first passage time density of Levy flights in a square area. Our findings are of interest for a general understanding of Levy flights as well as for the analysis of recorded trajectories of animals searching for food or for human motion patterns. PMID- 23679402 TI - Dark breathers in granular crystals. AB - We present a study of the existence, stability, and bifurcation structure of families of dark breathers in a one-dimensional uniform chain of spherical beads under static load. A defocusing nonlinear Schrodinger equation (NLS) is derived for frequencies that are close to the edge of the phonon band and is used to construct targeted initial conditions for numerical computations. Salient features of the system include the existence of large amplitude solutions that emerge from the small amplitude solutions described by the NLS equation, and the presence of a nonlinear instability that, to the best of the authors' knowledge, has not been observed in classical Fermi-Pasta-Ulam lattices. Finally, it is also demonstrated that these dark breathers can be detected in a physically realistic experimental settings by merely actuating the ends of an initially at rest chain of beads and inducing destructive interference between their signals. PMID- 23679403 TI - Segregation in mixtures of granular chains and spherical grains under vertical vibration. AB - We experimentally investigate segregation behaviors of binary granular mixtures consisting of granular chains and spherical grains with different interstitial media under vertical vibrations. A quantitative criterion is proposed to locate the boundaries between different vibrating phases. The water-immersed granular mixture exhibits two interesting types of segregation behaviors: chain-on-top and sandwich patterns. However, the phenomenon of sandwich segregation is absent for the air-immersed mixture. The topological differences of phase diagrams between two different environments indicate that the interstitial fluid plays an important role on the granular demixing. Additionally, the phase behaviors of mixtures for the different chain lengths show a not significant discrepancy. Finally, the vibrating thickness ratio determining the phase boundary characterizes the mixing extent of the granular bed. The estimated ratios for various chain lengths exhibit a monotonically decreasing dependence, when the vibration frequency increases. PMID- 23679404 TI - Orifice jamming of fluid-driven granular flow. AB - The three-dimensional jamming of neutrally buoyant monodisperse, bidisperse, and tridisperse mixtures of particles flowing through a restriction under fluid flow has been studied. During the transient initial accumulation of particles at the restriction, a low probability of a jamming event is observed, followed by a transition to a steady-state flowing backlog of particles, where the jamming probability per particle reaches a constant. Analogous to the steady-state flow in gravity-driven jams, this results in a geometric distribution describing the number of particles that discharge prior to a jamming event. We develop new models to describe the transition from an accumulation to a steady-state flow, and the jamming probability after the transition has occurred. Predictions of the behavior of the geometric distribution see the log-probability of a jam occurring proportionally to (R(2)(2)-1), where R(2) is the ratio of opening diameter to the second moment number average particle diameter. This behavior is demonstrated to apply to more general restriction shapes, and collapses for all mixture compositions for the restriction sizes tested. PMID- 23679405 TI - Fragility and hysteretic creep in frictional granular jamming. AB - The granular jamming transition is experimentally investigated in a two dimensional system of frictional, bidispersed disks subject to quasistatic, uniaxial compression without vibrational disturbances (zero granular temperature). Three primary results are presented in this experimental study. First, using disks with different static friction coefficients (MU), we experimentally verify numerical results that predict jamming onset at progressively lower packing fractions with increasing friction. Second, we show that the first compression cycle measurably differs from subsequent cycles. The first cycle is fragile-a metastable configuration with simultaneous jammed and unjammed clusters-over a small packing fraction interval (phi(1)/~1 MHz), perhaps indicating its more complex underlying physics. The measurements are made possible by dualizing the Michelson interferometry measurements and employing the averaged correlation of signals, in which the shot noise is statistically reduced. The method works in the presence of the quantum noise of a coherent state of light. The optical part of the experimental setup is essentially the same as that of Michelson interferometry so that the method can be applied when Michelson interferometry can be used. Furthermore, the measurement method requires a relatively low light power and a short time so that it has a wide range of applicability. PMID- 23679426 TI - Nonlinear evolution of surface morphology under shadowing. AB - Fluorocarbon thin-film deposition is studied, which shows an anomalous high dynamic growth exponent and therefore does not fit in any universal class of fractal surface growth models. A detailed analysis of the nonlinear behavior of the surface morphology evolution is carried out, quantifying several features of the shadowing instability. A synergy effect with the Kardar-Parisi-Zhang nonlinearity, which couple the large scales induced by shadowing with intermediate scales, may explain the anomalous high growth exponent. PMID- 23679427 TI - Selection theory of free dendritic growth in a potential flow. AB - The Kruskal-Segur approach to selection theory in diffusion-limited or Laplacian growth is extended via combination with the Zauderer decomposition scheme. This way nonlinear bulk equations become tractable. To demonstrate the method, we apply it to two-dimensional crystal growth in a potential flow. We omit the simplifying approximations used in a preliminary calculation for the same system [Fischaleck, Kassner, Europhys. Lett. 81, 54004 (2008)], thus exhibiting the capability of the method to extend mathematical rigor to more complex problems than hitherto accessible. PMID- 23679428 TI - Static fluctuations of a thick one-dimensional interface in the 1+1 directed polymer formulation. AB - Experimental realizations of a one-dimensional (1D) interface always exhibit a finite microscopic width xi>0; its influence is erased by thermal fluctuations at sufficiently high temperatures, but turns out to be a crucial ingredient for the description of the interface fluctuations below a characteristic temperature T(c)(xi). Exploiting the exact mapping between the static 1D interface and a 1+1 directed polymer (DP) growing in a continuous space, we study analytically both the free-energy and geometrical fluctuations of a DP, at finite temperature T, with a short-range elasticity and submitted to a quenched random-bond Gaussian disorder of finite correlation length xi. We derive the exact time-evolution equations of the disorder free energy F[over -](t,y), which encodes the microscopic disorder integrated by the DP up to a growing time t and an endpoint position y, its derivative eta(t,y), and their respective two-point correlators C[over -](t,y) and R[over -](t,y). We compute the exact solution of its linearized evolution R[over -](lin)(t,y) and we combine its qualitative behavior and the asymptotic properties known for an uncorrelated disorder (xi=0) to justify the construction of a "toy model" leading to a simple description of the DP properties. This model is characterized by Gaussian Brownian-type free-energy fluctuations, correlated at small |y|=4% by weight and the Sm-C* phase disappears completely for a 6% polymer sample. PMID- 23679437 TI - Effective-medium theory of a filamentous triangular lattice. AB - We present an effective-medium theory that includes bending as well as stretching forces, and we use it to calculate the mechanical response of a diluted filamentous triangular lattice. In this lattice, bonds are central-force springs, and there are bending forces between neighboring bonds on the same filament. We investigate the diluted lattice in which each bond is present with a probability p. We find a rigidity threshold p(b) which has the same value for all positive bending rigidity and a crossover characterizing bending, stretching, and bend stretch coupled elastic regimes controlled by the central-force rigidity percolation point at p(CF)=/~2/3 of the lattice when fiber bending rigidity vanishes. PMID- 23679438 TI - Elasticity of a filamentous kagome lattice. AB - The diluted kagome lattice, in which bonds are randomly removed with probability 1-p, consists of straight lines that intersect at points with a maximum coordination number of 4. If lines are treated as semiflexible polymers and crossing points are treated as cross-links, this lattice provides a simple model for two-dimensional filamentous networks. Lattice-based effective-medium theories and numerical simulations for filaments modeled as elastic rods, with stretching modulus MU and bending modulus kappa, are used to study the elasticity of this lattice as functions of p and kappa. At p=1, elastic response is purely affine, and the macroscopic elastic modulus G is independent of kappa. When kappa=0, the lattice undergoes a first-order rigidity-percolation transition at p=1. When kappa>0, G decreases continuously as p decreases below one, reaching zero at a continuous rigidity-percolation transition at p=p(b)~0.605 that is the same for all nonzero values of kappa. The effective-medium theories predict scaling forms for G, which exhibit crossover from bending-dominated response at small kappa/MU to stretching-dominated response at large kappa/MU near both p=1 and p(b), that match simulations with no adjustable parameters near p=1. The affine response as p->1 is identified with the approach to a state with sample-crossing straight filaments treated as elastic rods. PMID- 23679439 TI - Dielectric relaxations of poly(acrylic acid)-graft-poly(ethylene oxide) aqueous solution: analysis coupled with scaling approach and hydrogen-bonding complex. AB - Dielectric properties of poly(acrylic acid)-graft-poly(ethylene oxide) (PAA-g PEO) aqueous solution were measured as a function of concentration and temperature over a frequency range of 40 Hz to 110 MHz. After subtracting the contribution of electrode polarization, three relaxation processes were observed at about 20 kHz, 220 kHz, and 4 MHz, and they are named low-, mid- and high frequency relaxation, respectively. The relaxation parameters of these three relaxations (dielectric increment Deltaepsilon and relaxation time tau) showed scaling relations with the polyelectrolyte concentration. The mechanisms of the three relaxations were concluded in light of the scaling theory: The relaxations of low- and mid frequency were attributed to the fluctuation of condensed counterions, while the high-frequency relaxation was ascribed to the fluctuation of free counterions. Based on the dielectric measurements of varying temperatures, the thermodynamic parameters (enthalpy change DeltaH and entropy change DeltaS) of the three relaxations were calculated and these relaxation processes were also discussed from the microscopic thermodynamical view. In addition, the impacts of PEO side chains on the conformation of PAA-g-PEO chains were discussed. PEO side chains greatly strengthen the hydrogen-bonding interactions between PAA-g-PEO chains, resulting in the chains overlapping at a very low concentration and the formation of a hydrogen-bonding complex. Some physicochemical parameters of PAA-g-PEO molecules were calculated, including the overlap concentration, the effective charge of the chain, the friction coefficient, and the diffusion coefficient of hydrogen counterions. PMID- 23679440 TI - Translocation of a polymer through a nanopore across a viscosity gradient. AB - The translocation of a polymer through a pore in a membrane separating fluids of different viscosities is studied via several computational approaches. Starting with the polymer halfway, we find that as a viscosity difference across the pore is introduced, translocation will predominately occur towards one side of the membrane. These results suggest an intrinsic pumping mechanism for translocation across cell walls which could arise whenever the fluid across the membrane is inhomogeneous. Somewhat surprisingly, the sign of the preferred direction of translocation is found to be strongly dependent on the simulation algorithm: for Langevin dynamics (LD) simulations, a bias towards the low viscosity side is found while for Brownian dynamics (BD), a bias towards the high viscosity is found. Examining the translocation dynamics in detail across a wide range of viscosity gradients and developing a simple force model to estimate the magnitude of the bias, the LD results are demonstrated to be more physically realistic. The LD results are also compared to those generated from a simple, one-dimensional random walk model of translocation to investigate the role of the internal degrees of freedom of the polymer and the entropic barrier. To conclude, the scaling of the results across different polymer lengths demonstrates the saturation of the directional preference with polymer length and the nontrivial location of the maximum in the exponent corresponding to the scaling of the translocation time with polymer length. PMID- 23679441 TI - Electrostatic repulsion-driven crystallization model arising from filament networks. AB - The crystallization of bundles in filament networks interacting via long-range repulsions in confinement is described by a phenomenological model. The model demonstrates the formation of the hexagonal crystalline order via the interplay of the confinement potential and the filament-filament repulsion. Two distinct crystallization mechanisms in the short- and large- screening length regimes are discussed, and the phase diagram is obtained. Simulation of large bundles predicts the existence of topological defects within the bundled filaments. This electrostatic repulsion-driven crystallization model arising from studying filament networks can even find a more general context extending to charged colloidal systems. PMID- 23679442 TI - Exploring the ability of a multiscale coarse-grained potential to describe the stress-strain response of glassy polystyrene. AB - A new particle-based bottom-up method to develop coarse-grained models of polymers is presented and applied to polystyrene. The multiscale coarse-graining (MS-CG) technique of Izvekov et al. [J. Chem. Phys. 120, 10896 (2004)] is applied to a polymer system to calculate nonbonded interactions. The inverse Boltzmann inversion method was used to parametrize the bonded and bond-angle bending interactions. Molecular dynamics simulations were performed, and the CG model exhibited a significantly lower modulus compared to the atomistic model at low temperature and high strain rate. In an attempt to improve the CG model performance, several other parametrization schemes were used to build other models from this base model. The first of these models included standard frictional forces through use of the constant-temperature dissipative particle dynamics method that improved the modulus, yet was not transferrable to higher temperatures and lower strain rates. Other models were built by increasing the attraction between CG beads through direct manipulation of the nonbonded potential, where an improvement of the stress response was found. For these models, two parametrization protocols that shifted the force to more attractive values were explored. The first protocol involved a uniform shift, while the other protocol shifted the force in a more localized region. The uniformly shifted potential greatly affected the structure of the equilibrium model as compared to the locally shifted potential, yet was more transferrable to different temperatures and strain rates. Further improvements in the coarse graining protocol to generate models that more satisfactorily capture mechanical properties are suggested. PMID- 23679443 TI - Ionic state and chain conformation for aqueous solutions of supergiant cyanobacterial polysaccharide. AB - We have investigated the electric conductivity, dielectric relaxation behavior, and viscosity for the aqueous solution of cyanobacterial megamolecules, molecular weight =1.6*10(7) g/mol, named sacran. Sacran is an anionic polyelectrolyte which has carboxylate and sulfate groups on the saccharide chain. The electric conductivity and the zero shear viscosity demonstrated three crossover concentrations at 0.004, 0.02, and 0.1 wt%. The viscosity was found to be scaled as ~c(1.5), ~c(0.5), ~c(1.5), and ~c(3.0) with increasing the sacran concentration. At 0.1 wt%, the sacran chain formed a weak gel which exhibits macroscopic liquid crystal domains including Schlieren texture. Therefore, these crossover concentrations are considered to be the overlap concentration, entanglement concentration, and gelation concentration (or critical polyelectrolyte concentration), respectively. Dielectric relaxation analysis exhibited the fact that sacran has two types of counterions with different counterion-polyion interaction, i.e., strongly bound and loosely bound counterions. The dielectric parameters such as relaxation time or relaxation strength are sensitive to both the entanglement concentration and the gelation concentration, but not the overlap concentration. The number density of bound counterions calculated from the relaxation strength revealed that the counterion is condensed on the sacran chain with raising the sacran concentrations. The decrease in the charge density of the sacran chain reduces the repulsive force between the chains and this would cause the helix transformation or gelation behavior. The chain conformation of sacran in pure water and the gelation mechanism are discussed in relation with the behavior of polyelectrolytes and liquid crystals. PMID- 23679444 TI - Finite-length effects on the coil-globule transition of a strongly charged polyelectrolyte chain in a salt-free solvent. AB - The nature of coil-globule transition and scaling behavior of a strongly charged polyelectrolyte chain in a solution system with explicit neutralizing counterions and solvent molecules are studied using replica-exchange Monte Carlo simulations, focusing on the effects of finite chain length. The results reveal that at the thermodynamic limit of infinitely long chain length, the coil-globule transition may remain first order. Phase transition temperatures at various ion concentrations are obtained by extrapolating the values obtained at finite chain lengths. Furthermore, it is found that the exponent nu of the radius of gyration, ~ N(2nu), can be slightly larger than 1 under some conditions. PMID- 23679445 TI - Parallel processing in immune networks. AB - In this work, we adopt a statistical-mechanics approach to investigate basic, systemic features exhibited by adaptive immune systems. The lymphocyte network made by B cells and T cells is modeled by a bipartite spin glass, where, following biological prescriptions, links connecting B cells and T cells are sparse. Interestingly, the dilution performed on links is shown to make the system able to orchestrate parallel strategies to fight several pathogens at the same time; this multitasking capability constitutes a remarkable, key property of immune systems as multiple antigens are always present within the host. We also define the stochastic process ruling the temporal evolution of lymphocyte activity and show its relaxation toward an equilibrium measure allowing statistical-mechanics investigations. Analytical results are compared with Monte Carlo simulations and signal-to-noise outcomes showing overall excellent agreement. Finally, within our model, a rationale for the experimentally well evidenced correlation between lymphocytosis and autoimmunity is achieved; this sheds further light on the systemic features exhibited by immune networks. PMID- 23679446 TI - Labyrinthine clustering in a spatial rock-paper-scissors ecosystem. AB - The spatial rock-paper-scissors ecosystem, where three species interact cyclically, is a model example of how spatial structure can maintain biodiversity. We here consider such a system for a broad range of interaction rates. When one species grows very slowly, this species and its prey dominate the system by self-organizing into a labyrinthine configuration in which the third species propagates. The cluster size distributions of the two dominating species have heavy tails and the configuration is stabilized through a complex spatial feedback loop. We introduce a statistical measure that quantifies the amount of clustering in the spatial system by comparison with its mean-field approximation. Hereby, we are able to quantitatively explain how the labyrinthine configuration slows down the dynamics and stabilizes the system. PMID- 23679447 TI - Dynamics of elastic interactions in soft and biological matter. AB - Cells probe their mechanical environment and can change the organization of their cytoskeletons when the elastic and viscous properties of their environment are modified. We use a model in which the forces exerted by small, contractile acto myosin filaments (e.g., nascent stress fibers in stem cells) on the extracellular matrix are modeled as local force dipoles. In some cases, the strain field caused by these force dipoles propagates quickly enough so that only static elastic interactions need be considered. On the other hand, in the case of significant energy dissipation, strain propagation is slower and may be eliminated completely by the relaxation of the cellular cytoskeleton (e.g., by cross-link dissociation). Here, we consider several dissipative mechanisms that affect the propagation of the strain field in adhered cells and consider these effects on the interaction between force dipoles and their resulting mutual orientations. This is a first step in understanding the development of orientational (nematic) or layering (smectic) order in the cytoskeleton. We use the theory to estimate the propagation time of the strain fields over a cellular distance for different mechanisms and find that in some cases it can be of the order of seconds, thus competing with the cytoskeletal relaxation time. Furthermore, for a simple system of two force dipoles, we predict that in some cases the orientation of force dipoles might change significantly with time, e.g., for short times the dipoles exhibit parallel alignment while for later times they align perpendicularly. PMID- 23679448 TI - Self-regulatory gene: an exact solution for the gene gate model. AB - The stochastic dynamics of gene expression is often described by highly abstract models involving only the key molecular actors DNA, RNA, and protein, neglecting all further details of the transcription and translation processes. One example of such models is the "gene gate model," which contains a minimal set of actors and kinetic parameters, which allows us to describe the regulation of a gene by both repression and activation. Based on this approach, we formulate a master equation for the case of a single gene regulated by its own product-a transcription factor-and solve it exactly. The obtained gene product distributions display features of mono- and bimodality, depending on the choice of parameters. We discuss our model in the perspective of other models in the literature. PMID- 23679449 TI - Stage-dependent model for Hantavirus infection: the effect of the initial infection-free period. AB - We propose a stage-dependent model with constant delay to study the effect of the initial infection-free period on the spread of Hantavirus infection in rodents. We analyze the model under various extreme weather conditions, in the context of the El Nino-La Nina Southern Oscillation phenomenon, and show how these variations determine the evolution of the system significantly. When the scenario corresponds to El Nino, the system presents a demographic explosion and a delayed outbreak of Hantavirus infection, whereas if the scenario is the opposite there is a rapid decline of the population, but with a possible persistence period that may imply a considerable risk for public health, a fact that is in agreement with available field data. We use the model to simulate a historical evolution that resembles the processes that occurred in the 1990s. PMID- 23679450 TI - Defining statistical perceptions with an empirical Bayesian approach. AB - Extracting statistical structures (including textures or contrasts) from a natural stimulus is a central challenge in both biological and engineering contexts. This study interprets the process of statistical recognition in terms of hyperparameter estimations and free-energy minimization procedures with an empirical Bayesian approach. This mathematical interpretation resulted in a framework for relating physiological insights in animal sensory systems to the functional properties of recognizing stimulus statistics. We applied the present theoretical framework to two typical models of natural images that are encoded by a population of simulated retinal neurons, and demonstrated that the resulting cognitive performances could be quantified with the Fisher information measure. The current enterprise yielded predictions about the properties of human texture perception, suggesting that the perceptual resolution of image statistics depends on visual field angles, internal noise, and neuronal information processing pathways, such as the magnocellular, parvocellular, and koniocellular systems. Furthermore, the two conceptually similar natural-image models were found to yield qualitatively different predictions, striking a note of warning against confusing the two models when describing a natural image. PMID- 23679451 TI - Statistical method for detecting phase shifts in alpha rhythm from human electroencephalogram data. AB - We developed a statistical method for detecting discontinuous phase changes (phase shifts) in fluctuating alpha rhythms in the human brain from electroencephalogram (EEG) data obtained in a single trial. This method uses the state space models and the line process technique, which is a Bayesian method for detecting discontinuity in an image. By applying this method to simulated data, we were able to detect the phase and amplitude shifts in a single simulated trial. Further, we demonstrated that this method can detect phase shifts caused by a visual stimulus in the alpha rhythm from experimental EEG data even in a single trial. The results for the experimental data showed that the timings of the phase shifts in the early latency period were similar between many of the trials, and that those in the late latency period were different between the trials. The conventional averaging method can only detect phase shifts that occur at similar timings between many of the trials, and therefore, the phase shifts that occur at differing timings cannot be detected using the conventional method. Consequently, our obtained results indicate the practicality of our method. Thus, we believe that our method will contribute to studies examining the phase dynamics of nonlinear alpha rhythm oscillators. PMID- 23679452 TI - Force dipoles and stable local defects on fluid vesicles. AB - An exact description is provided of an almost spherical fluid vesicle with a fixed area and a fixed enclosed volume locally deformed by external normal forces bringing two nearby points on the surface together symmetrically. The conformal invariance of the two-dimensional bending energy is used to identify the distribution of energy as well as the stress established in the vesicle. While these states are local minima of the energy, this energy is degenerate; there is a zero mode in the energy fluctuation spectrum, associated with area- and volume preserving conformal transformations, which breaks the symmetry between the two points. The volume constraint fixes the distance S, measured along the surface, between the two points; if it is relaxed, a second zero mode appears, reflecting the independence of the energy on S; in the absence of this constraint a pathway opens for the membrane to slip out of the defect. Logarithmic curvature singularities in the surface geometry at the points of contact signal the presence of external forces. The magnitude of these forces varies inversely with S and so diverges as the points merge; the corresponding torques vanish in these defects. The geometry behaves near each of the singularities as a biharmonic monopole, in the region between them as a surface of constant mean curvature, and in distant regions as a biharmonic quadrupole. Comparison of the distribution of stress with the quadratic approximation in the height functions points to shortcomings of the latter representation. Radial tension is accompanied by lateral compression, both near the singularities and far away, with a crossover from tension to compression occurring in the region between them. PMID- 23679453 TI - Mobility, fitness collection, and the breakdown of cooperation. AB - The spatial arrangement of individuals is thought to overcome the dilemma of cooperation: When cooperators engage in clusters, they might share the benefit of cooperation while being more protected against noncooperating individuals, who benefit from cooperation but save the cost of cooperation. This is paradigmatically shown by the spatial prisoner's dilemma model. Here, we study this model in one and two spatial dimensions, but explicitly take into account that in biological setups, fitness collection and selection are separated processes occurring mostly on vastly different time scales. This separation is particularly important to understand the impact of mobility on the evolution of cooperation. We find that even small diffusive mobility strongly restricts cooperation since it enables noncooperative individuals to invade cooperative clusters. Thus, in most biological scenarios, where the mobility of competing individuals is an irrefutable fact, the spatial prisoner's dilemma alone cannot explain stable cooperation, but additional mechanisms are necessary for spatial structure to promote the evolution of cooperation. The breakdown of cooperation is analyzed in detail. We confirm the existence of a phase transition, here controlled by mobility and costs, which distinguishes between purely cooperative and noncooperative absorbing states. While in one dimension the model is in the class of the voter model, it belongs to the directed percolation universality class in two dimensions. PMID- 23679454 TI - Suppression of cardiac alternans by alternating-period-feedback stimulations. AB - Alternans response, comprising a sequence of alternating long and short action potential durations in heart tissue, seen during rapid periodic pacing can lead to conduction block resulting in potentially fatal cardiac failure. A method of pacing with feedback control is proposed to reduce the alternans and therefore the probability of subsequent cardiac failure. The reduction is achieved by feedback control using small perturbations of constant magnitude to the original, alternans-generating pacing period T, viz., using sequences of two alternating periods of T+DeltaT and T-DeltaT, with DeltaT< and the correlation length of chi diverge. Our work should be useful as a template for understanding nonaffine displacements in realistic systems with or without disorder and as a means for developing computational tools for studying the effects of nonaffine displacements in melting, plastic flow, and the glass transition. PMID- 23679468 TI - Penetration of self-affine fractal rough rigid bodies into a model elastomer having a linear viscous rheology. AB - The penetration of a rigid body with a randomly rough, self-affine surface in a half space filled with a linearly viscous elastomer is studied numerically using the method of boundary elements. Using Radok's principle of functional equations, it is shown analytically that this problem is closely related to the recently investigated problem of contact of self-affine surfaces with an elastic half space. We show that the penetration velocity occurs to be a power function of the applied force and time, the corresponding exponents depending only on the Hurst exponent. For comparison, the same problem is solved using the method of reduction of dimensionality. Both three-dimensional numerical results and the method of reduction of dimensionality support the analytical predictions provided by general scaling arguments. PMID- 23679469 TI - Reexamination of explosive synchronization in scale-free networks: the effect of disassortativity. AB - Previous work [J. Gomez-Gardenes, S. Gomez, A. Arenas, and Y. Moreno, Phys. Rev. Lett. 106, 128701 (2011)] has reported that explosive synchronization can be achieved in heterogeneous networks with a microscopic correlation between the structural and dynamical properties of the networks. This phenomenon, however, cannot be observed in all heterogeneous networks even if this structure-dynamics correlation is preserved. It is therefore of particular interest to identify the general topological factors that can induce the first order synchronization transition and to understand the underlying mechanisms. Here we investigate this issue using the scenario of the smooth transformation from homogeneous Erdos Renyi networks to heterogeneous Barabasi-Albert networks. Specifically, we scrutinize how local and global properties of the network change during this process, and how these properties are associated with the emergence of explosive synchronization. We find that the local degree-degree correlation in the network contributes primarily to explosive synchronization, other than the global topological property or starlike subgraphs. We furthermore demonstrate that the degree of disassortative mixing also has a great effect in the presence of explosive synchronization. PMID- 23679470 TI - Dynamical and statistical behavior of discrete combustion waves: a theoretical and numerical study. AB - We present a detailed theoretical and numerical study of combustion waves in a discrete one-dimensional disordered system. The distances between neighboring reaction cells were modeled with a gamma distribution. The results show that the random structure of the microheterogeneous system plays a crucial role in the dynamical and statistical behavior of the system. This is a consequence of the nonlinear interaction of the random structure of the system with the thermal wave. An analysis of the experimental data on the combustion of a gasless system (Ti + xSi) and a wide range of thermite systems was performed in view of the developed model. We have shown that the burning rate of the powder system sensitively depends on its internal structure. The present model allows for reproducing theoretically the experimental data for a wide range of pyrotechnic mixtures. We show that Arrhenius' macrokinetics at combustion of disperse systems can take place even in the absence of Arrhenius' microkinetics; it can have a purely thermal nature and be related to their heterogeneity and to the existence of threshold temperature. It is also observed that the combustion of disperse systems always occurs in the microheterogeneous mode according to the relay-race mechanism. PMID- 23679471 TI - Evolution of emotions on networks leads to the evolution of cooperation in social dilemmas. AB - We show that the resolution of social dilemmas in random graphs and scale-free networks is facilitated by imitating not the strategy of better-performing players but, rather, their emotions. We assume sympathy and envy to be the two emotions that determine the strategy of each player in any given interaction, and we define them as the probabilities of cooperating with players having a lower and a higher payoff, respectively. Starting with a population where all possible combinations of the two emotions are available, the evolutionary process leads to a spontaneous fixation to a single emotional profile that is eventually adopted by all players. However, this emotional profile depends not only on the payoffs but also on the heterogeneity of the interaction network. Homogeneous networks, such as lattices and regular random graphs, lead to fixations that are characterized by high sympathy and high envy, while heterogeneous networks lead to low or modest sympathy but also low envy. Our results thus suggest that public emotions and the propensity to cooperate at large depend, and are in fact determined by, the properties of the interaction network. PMID- 23679472 TI - Stochastic model of agent interaction with opinion leaders. AB - We analyze the problem of agents' interactions in a given population. The purpose of this paper is twofold. Starting from a scheme proposed by Galam [Physica A 320, 571 (2003)], which is based on a majority rule to treat the individuals' interactions, we first study some of its relevant properties. Then, we introduce special individuals, called opinion leaders, who play a key role in information spreading in several practical applications. Opinion leaders have the special feature of strongly interfering with the process based on the majority rule, speeding up the diffusion. We consider a model describing agents' interactions, which encompasses Galam's proposal, where opinion leaders are included as special agents. Then we study its specific properties which significantly recast and extend some conclusions drawn for the models given by Galam and Ellero, Fasano, and Sorato [Physica A 388, 3901 (2009)]. Finally, we provide theoretical and numerical results concerning the dynamics of our model, showing that a small percentage of opinion leaders may both accelerate and/or even reverse the overall consensus among all the agents. PMID- 23679473 TI - Building up of individual inflexibility in opinion dynamics. AB - Two models of opinion dynamics are entangled in order to build a more realistic model of inflexibility. The first one is the Galam unifying frame (GUF), which incorporates rational and inflexible agents, and the other one is the Continuous Opinions and Discrete Actions model. While initially in GUF, inflexibility is a fixed given feature of an agent, it is now the result of an accumulation for a given agent who makes the same choice through repeated updates. Inflexibility thus emerges as an internal property of agents becoming a continuous function of the strength of its opinion. Therefore, an agent can be more or less inflexible and can shift from inflexibility along one choice to inflexibility along the opposite choice. These individual dynamics of the building up and falling off of agent inflexibility are driven by the successive local updates of the associated individual opinions. New results are obtained and discussed in terms of predicting outcomes of public debates. PMID- 23679474 TI - Computational capabilities of random automata networks for reservoir computing. AB - This paper underscores the conjecture that intrinsic computation is maximal in systems at the "edge of chaos". We study the relationship between dynamics and computational capability in random Boolean networks (RBN) for reservoir computing (RC). RC is a computational paradigm in which a trained readout layer interprets the dynamics of an excitable component (called the reservoir) that is perturbed by external input. The reservoir is often implemented as a homogeneous recurrent neural network, but there has been little investigation into the properties of reservoirs that are discrete and heterogeneous. Random Boolean networks are generic and heterogeneous dynamical systems and here we use them as the reservoir. A RBN is typically a closed system; to use it as a reservoir we extend it with an input layer. As a consequence of perturbation, the RBN does not necessarily fall into an attractor. Computational capability in RC arises from a tradeoff between separability and fading memory of inputs. We find the balance of these properties predictive of classification power and optimal at critical connectivity. These results are relevant to the construction of devices which exploit the intrinsic dynamics of complex heterogeneous systems, such as biomolecular substrates. PMID- 23679475 TI - Mean-field theory of echo state networks. AB - Dynamical systems driven by strong external signals are ubiquitous in nature and engineering. Here we study "echo state networks," networks of a large number of randomly connected nodes, which represent a simple model of a neural network, and have important applications in machine learning. We develop a mean-field theory of echo state networks. The dynamics of the network is captured by the evolution law, similar to a logistic map, for a single collective variable. When the network is driven by many independent external signals, this collective variable reaches a steady state. But when the network is driven by a single external signal, the collective variable is non stationary but can be characterized by its time averaged distribution. The predictions of the mean-field theory, including the value of the largest Lyapunov exponent, are compared with the numerical integration of the equations of motion. PMID- 23679476 TI - Optimal transport exponent in spatially embedded networks. AB - The imposition of a cost constraint for constructing the optimal navigation structure surely represents a crucial ingredient in the design and development of any realistic navigation network. Previous works have focused on optimal transport in small-world networks built from two-dimensional lattices by adding long-range connections with Manhattan length r(ij) taken from the distribution P(ij)~r(ij)(-alpha), where alpha is a variable exponent. It has been shown that, by introducing a cost constraint on the total length of the additional links, regardless of the strategy used by the traveler (independent of whether it is based on local or global knowledge of the network structure), the best transportation condition is obtained with an exponent alpha=d+1, where d is the dimension of the underlying lattice. Here we present further support, through a high-performance real-time algorithm, on the validity of this conjecture in three dimensional regular as well as in two-dimensional critical percolation clusters. Our results clearly indicate that cost constraint in the navigation problem provides a proper theoretical framework to justify the evolving topologies of real complex network structures, as recently demonstrated for the networks of the US airports and the human brain activity. PMID- 23679477 TI - Emergent patterns of localized damage as a precursor to catastrophic failure in a random fuse network. AB - We study the failure of disordered materials by numerical simulations of the random fuse model. We identify emergent patterns of localized damage prior to catastrophic failure by statistically averaging the density of damage around the eventual failure nucleation point. The resulting pattern depends on fracture density and obeys the same scaling relations as would be expected for the stress field generated by a critical crack nucleating in a finite, disorder-free effective medium of varying size. The growth of this critical crack absorbs preexisting clusters according to a well-defined scaling relation. Unfortunately, in single model runs such precursory signals are not obvious. Our results imply that reliable and accurate prediction of failure in time-independent, microscopically brittle random materials in a real case is inherently problematic, and degrades with system size. PMID- 23679478 TI - Coupled adaptive complex networks. AB - Adaptive networks, which combine topological evolution of the network with dynamics on the network, are ubiquitous across disciplines. Examples include technical distribution networks such as road networks and the internet, natural and biological networks, and social science networks. These networks often interact with or depend upon other networks, resulting in coupled adaptive networks. In this paper we study susceptible-infected-susceptible (SIS) epidemic dynamics on coupled adaptive networks, where susceptible nodes are able to avoid contact with infected nodes by rewiring their intranetwork connections. However, infected nodes can pass the disease through internetwork connections, which do not change with time: The dependencies between the coupled networks remain constant. We develop an analytical formalism for these systems and validate it using extensive numerical simulation. We find that stability is increased by increasing the number of internetwork links, in the sense that the range of parameters over which both endemic and healthy states coexist (both states are reachable depending on the initial conditions) becomes smaller. Finally, we find a new stable state that does not appear in the case of a single adaptive network but only in the case of weakly coupled networks, in which the infection is endemic in one network but neither becomes endemic nor dies out in the other. Instead, it persists only at the nodes that are coupled to nodes in the other network through internetwork links. We speculate on the implications of these findings. PMID- 23679479 TI - Random cascade model in the limit of infinite integral scale as the exponential of a nonstationary 1/f noise: application to volatility fluctuations in stock markets. AB - In this paper we propose a new model for volatility fluctuations in financial time series. This model relies on a nonstationary Gaussian process that exhibits aging behavior. It turns out that its properties, over any finite time interval, are very close to continuous cascade models. These latter models are indeed well known to reproduce faithfully the main stylized facts of financial time series. However, it involves a large-scale parameter (the so-called "integral scale" where the cascade is initiated) that is hard to interpret in finance. Moreover, the empirical value of the integral scale is in general deeply correlated to the overall length of the sample. This feature is precisely predicted by our model, which, as illustrated by various examples from daily stock index data, quantitatively reproduces the empirical observations. PMID- 23679480 TI - Flow motifs reveal limitations of the static framework to represent human interactions. AB - Networks are commonly used to define underlying interaction structures where infections, information, or other quantities may spread. Although the standard approach has been to aggregate all links into a static structure, some studies have shown that the time order in which the links are established may alter the dynamics of spreading. In this paper, we study the impact of the time ordering in the limits of flow on various empirical temporal networks. By using a random walk dynamics, we estimate the flow on links and convert the original undirected network (temporal and static) into a directed flow network. We then introduce the concept of flow motifs and quantify the divergence in the representativity of motifs when using the temporal and static frameworks. We find that the regularity of contacts and persistence of vertices (common in email communication and face to-face interactions) result on little differences in the limits of flow for both frameworks. On the other hand, in the case of communication within a dating site and of a sexual network, the flow between vertices changes significantly in the temporal framework such that the static approximation poorly represents the structure of contacts. We have also observed that cliques with 3 and 4 vertices containing only low-flow links are more represented than the same cliques with all high-flow links. The representativity of these low-flow cliques is higher in the temporal framework. Our results suggest that the flow between vertices connected in cliques depend on the topological context in which they are placed and in the time sequence in which the links are established. The structure of the clique alone does not completely characterize the potential of flow between the vertices. PMID- 23679481 TI - Exact epidemic analysis for the star topology. AB - A methodology is formulated for studying the effects of network structure on the dynamics and spread of an epidemic. We study the well known SIS (susceptible infected-susceptible) epidemic model and introduce exact moment equations relevant for any network connections. The equations take into account all possible 2^{N} states of the network and the specific topology of the network at hand. For the star topology we are able to calculate the threshold value analytically, and also the proportion of infected individuals at steady state for any parameters. Our analytical results are verified with computer simulations. This study of epidemic dynamics on the star network evaluates both the threshold as well as the stability properties of the model's steady state. PMID- 23679482 TI - Brittle-to-ductile transition in a fiber bundle with strong heterogeneity. AB - We analyze the failure process of a two-component system with widely different fracture strength in the framework of a fiber bundle model with localized load sharing. A fraction 0<=alpha<=1 of the bundle is strong and it is represented by unbreakable fibers, while fibers of the weak component have randomly distributed failure strength. Computer simulations revealed that there exists a critical composition alpha(c) which separates two qualitatively different behaviors: Below the critical point, the failure of the bundle is brittle, characterized by an abrupt damage growth within the breakable part of the system. Above alpha(c), however, the macroscopic response becomes ductile, providing stability during the entire breaking process. The transition occurs at an astonishingly low fraction of strong fibers which can have importance for applications. We show that in the ductile phase, the size distribution of breaking bursts has a power law functional form with an exponent MU=2 followed by an exponential cutoff. In the brittle phase, the power law also prevails but with a higher exponent MU=9/2. The transition between the two phases shows analogies to continuous phase transitions. Analyzing the microstructure of the damage, it was found that at the beginning of the fracture process cracks nucleate randomly, while later on growth and coalescence of cracks dominate, which give rise to power law distributed crack sizes. PMID- 23679483 TI - Scattering by a boundary with complex structure. AB - The distribution of escape times is usually studied in open billiards theory. In this work, we will concentrate on another important question: The distribution of outgoing rays by exit directions, which we refer to as billiard's indicatrix. It can be obtained analytically and consists of two parts: the symmetric diffuse part and the asymmetric directed part. The criterion for the separation of the indicatrix into these two parts is established. The asymmetry of the directed part of the indicatrix and the influence of the billiard's borders on it is investigated. We also propose a method of the creation of a matte surface model using open billiards with a fully diffuse indicatrix. PMID- 23679484 TI - Stochastic perturbations in open chaotic systems: random versus noisy maps. AB - We investigate the effects of random perturbations on fully chaotic open systems. Perturbations can be applied to each trajectory independently (white noise) or simultaneously to all trajectories (random map). We compare these two scenarios by generalizing the theory of open chaotic systems and introducing a time dependent conditionally-map-invariant measure. For the same perturbation strength we show that the escape rate of the random map is always larger than that of the noisy map. In random maps we show that the escape rate kappa and dimensions D of the relevant fractal sets often depend nonmonotonically on the intensity of the random perturbation. We discuss the accuracy (bias) and precision (variance) of finite-size estimators of kappa and D, and show that the improvement of the precision of the estimations with the number of trajectories N is extremely slow ([proportionality]1/lnN). We also argue that the finite-size D estimators are typically biased. General theoretical results are combined with analytical calculations and numerical simulations in area-preserving baker maps. PMID- 23679485 TI - Symmetry breaking and restoring wave transmission in diode-antidiode double chains. AB - We introduce a system of two parallel-coupled discrete nonlinear Schrodinger inhomogeneous chains. Each one favors the unidirectional transmission of incident packets, in the opposite directions with respect to each other. Two different configurations of the diode-antidiode pair are considered, i.e., a ladder and a plaquette. They feature, respectively, the uniform transverse linear coupling or the coupling limited to the central nonlinear segment of the system. In the case of weak linear coupling, the symmetry breaking is observed (i.e., the pair still features the diode behavior), while the moderately strong coupling restores the symmetry, making the transmission effectively bidirectional. In the case of the ladder, an oscillatory dependence of the transmission on the strength of the coupling is observed and qualitatively explained. PMID- 23679486 TI - Irregular excitation patterns in reaction-diffusion systems due to perturbation by secondary pacemakers. AB - Spatiotemporal excitation patterns in the FitzHugh-Nagumo model are studied, which result from the disturbance of a primary pacemaker by a secondary pacemaker. The primary and secondary pacemakers generate regular waves with frequencies f(pace) and f(pert), respectively. The pacemakers are spatially separated, but waves emanating from them encounter each other via a small bridge. This leads to three different types I-III of irregular excitation patterns in disjunct domains of the f(pace)-f(pert) plane. Types I and II are caused by detachments of waves coming from the two pacemakers at corners of the bridge. Type III irregularities are confined to a boundary region of the system and originate from a partial penetration of the primary waves into a space, where circular wave fronts from the secondary pacemaker prevail. For this type, local frequencies can significantly exceed f(pace) and f(pert). The degree of irregularity found for the three different types is quantified by the entropy of the local frequency distribution and an order parameter for phase coherence. PMID- 23679488 TI - Crisis, unstable dimension variability, and bifurcations in a system with high dimensional phase space: coupled sine circle maps. AB - The phenomenon of crisis in systems evolving in high-dimensional phase space can show unexpected and interesting features. We study this phenomenon in the context of a system of coupled sine circle maps. We establish that the origins of this crisis lie in a tangent bifurcation in high dimensions, and identify the routes that lead to the crisis. Interestingly, multiple routes to crisis are seen depending on the initial conditions of the system, due to the high dimensionality of the space in which the system evolves. The statistical behavior seen in the phase diagram of the system is also seen to change due to the dynamical phenomenon of crisis, which leads to transitions from nonspreading to spreading behavior across an infection line in the phase diagram. Unstable dimension variability is seen in the neighborhood of the infection line. We characterize this crisis and unstable dimension variability using dynamical characterizers, such as finite-time Lyapunov exponents and their distributions. The phase diagram also contains regimes of spatiotemporal intermittency and spatial intermittency, where the statistical quantities scale as power laws. We discuss the signatures of these regimes in the dynamic characterizers, and correlate them with the statistical characterizers and bifurcation behavior. We find that it is necessary to look at both types of correlators together to build up an accurate picture of the behavior of the system. PMID- 23679487 TI - Chiral symmetry breaking in a reaction-diffusion system. AB - The emergence of order in far-from-equilibrium systems is often accompanied by the formation of spatially asymmetric patterns. About 30 years ago, a general mechanism to select a chiral solution by coupling a reaction-diffusion system to an external chiral electric field was proposed by Nicolis and Prigogine [Proc. Natl. Acad. Sci. USA 78, 659 (1981)]. However, no experimental or even numerical evidence in reaction-diffusion systems has been reported yet. Here we report a chiral symmetry-breaking phenomenon in a reaction-diffusion system coupled to a circularly polarized electric field (CPEF). Specifically, we show that the CPEF breaks the zero-rotation chiral symmetry between clockwise and counterclockwise spiral defects and that ordered spiral waves with preferred chirality arise from defect-mediated turbulence. The occurrence of such chiral symmetry breaking can be understood by the competition between spiral defects with opposite chirality. PMID- 23679489 TI - Zig-zag networks of self-excited periodic oscillations in a tunnel diode and a fiber-ring laser. AB - We report numerical evidence showing that periodic oscillations can produce unexpected and wide-ranging zig-zag parameter networks embedded in chaos in the control space of nonlinear systems. Such networks interconnect shrimplike windows of stable oscillations and are illustrated here for a tunnel diode, for an erbium doped fiber-ring laser, and for the Henon map, a proxy of certain CO(2) lasers. Networks in maps can be studied without the need for solving differential equations. Tuning parameters along zig-zag networks allows one to continuously modify wave patterns without changing their chaotic or periodic nature. In addition, we report convenient parameter ranges where such networks can be detected experimentally. PMID- 23679490 TI - Topology-free design for amplitude death in time-delayed oscillators coupled by a delayed connection. AB - This paper deals with amplitude death in time-delayed oscillators coupled by a delayed connection with topology uncertainty. A systematic procedure without trial-and-error testing for designing connection parameters is proposed from a robust control theory viewpoint. This procedure has the following two advantages: the designed connection parameters are valid for any network topology and the procedure is valid even for long-delay oscillators. These analytical results are verified by some numerical simulations. PMID- 23679491 TI - Driving-induced bistability in coupled chaotic attractors. AB - We examine the effects of symmetry-preserving and -breaking interactions in a drive-response system where the response has an invariant symmetry in the absence of the drive. Subsequent to the onset of generalized synchronization, we find that there can be more than one stable attractor. Numerical as well as analytical results establish the presence of phase synchrony in such coexisting attractors. These results are robust to external noise. PMID- 23679492 TI - Discontinuous attractor dimension at the synchronization transition of time delayed chaotic systems. AB - The attractor dimension at the transition to complete synchronization in a network of chaotic units with time-delayed couplings is investigated. In particular, we determine the Kaplan-Yorke dimension from the spectrum of Lyapunov exponents for iterated maps and for two coupled semiconductor lasers. We argue that the Kaplan-Yorke dimension must be discontinuous at the transition and compare it to the correlation dimension. For a system of Bernoulli maps, we indeed find a jump in the correlation dimension. The magnitude of the discontinuity in the Kaplan-Yorke dimension is calculated for networks of Bernoulli units as a function of the network size. Furthermore, the scaling of the Kaplan-Yorke dimension as well as of the Kolmogorov entropy with system size and time delay is investigated. PMID- 23679493 TI - Interaction of traveling waves with mass-with-mass defects within a Hertzian chain. AB - We study the dynamic response of a granular chain of particles with a resonant inclusion (i.e., a particle attached to a harmonic oscillator, or a mass-with mass defect). We focus on the response of granular chains excited by an impulse, with no static precompression. We find that the presence of the harmonic oscillator can be used to tune the transmitted and reflected energy of a mechanical pulse by adjusting the ratio between the harmonic resonator mass and the bead mass. Furthermore, we find that this system has the capability of asymptotically trapping energy, a feature that is not present in granular chains containing other types of defects. Finally, we study the limits of low and high resonator mass, and the structure of the reflected and transmitted pulses. PMID- 23679494 TI - Bound states in sharply bent waveguides: analytical and experimental approach. AB - Quantum wires and electromagnetic waveguides possess common features since their physics is described by the same wave equation. We exploit this analogy to investigate experimentally with microwave waveguides and theoretically with the help of an effective potential approach the occurrence of bound states in sharply bent quantum wires. In particular, we compute the bound states, study the features of the transition from a bound to an unbound state caused by the variation of the bending angle, and determine the critical bending angles at which such a transition takes place. The predictions are confirmed by calculations based on a conventional numerical method as well as experimental measurements of the spectra and electric field intensity distributions of electromagnetic waveguides. PMID- 23679495 TI - Nature of weak generalized synchronization in chaotically driven maps. AB - Weak generalized synchrony in a drive-response system occurs when the response dynamics is a unique but nondifferentiable function of the drive, in a manner that is similar to the formation of strange nonchaotic attractors in quasiperiodically driven dynamical systems. We consider a chaotically driven monotone map and examine the geometry of the limit set formed in the regime of weak generalized synchronization. The fractal dimension of the set of zeros is studied both analytically and numerically. We further examine the stable and unstable sets formed and measure the regularity of the coupling function. The stability index as well as the dimension spectrum of the equilibrium measure can be computed analytically. PMID- 23679496 TI - Pattern formation based on the triple-layer coupling mechanism. AB - We report on the first investigation of the triple-layer coupling pattern formation in a dielectric barrier discharge system. The pattern basically consists of one discharge subpattern ignited in the gas gap and two surface charge subpatterns deposited on the dielectric surfaces. The coupling of the three subpatterns (layers) is presented by analyzing the time-resolved discharge sequence of a white-eye hexagonal super lattice pattern (WEHSP). A triple-layer coupling reaction-diffusion regime is also established to conduct simulations and the simulated WEHSP agrees well with the experiment. This paper will provide a deeper understanding for the layer coupling mechanism in pattern formation. PMID- 23679497 TI - Localized states in the conserved Swift-Hohenberg equation with cubic nonlinearity. AB - The conserved Swift-Hohenberg equation with cubic nonlinearity provides the simplest microscopic description of the thermodynamic transition from a fluid state to a crystalline state. The resulting phase field crystal model describes a variety of spatially localized structures, in addition to different spatially extended periodic structures. The location of these structures in the temperature versus mean order parameter plane is determined using a combination of numerical continuation in one dimension and direct numerical simulation in two and three dimensions. Localized states are found in the region of thermodynamic coexistence between the homogeneous and structured phases, and may lie outside of the binodal for these states. The results are related to the phenomenon of slanted snaking but take the form of standard homoclinic snaking when the mean order parameter is plotted as a function of the chemical potential, and are expected to carry over to related models with a conserved order parameter. PMID- 23679498 TI - Human brain detects short-time nonlinear predictability in the temporal fine structure of deterministic chaotic sounds. AB - Deterministic nonlinear dynamical processes are ubiquitous in nature. Chaotic sounds generated by such processes may appear irregular and random in waveform, but these sounds are mathematically distinguished from random stochastic sounds in that they contain deterministic short-time predictability in their temporal fine structures. We show that the human brain distinguishes deterministic chaotic sounds from spectrally matched stochastic sounds in neural processing and perception. Deterministic chaotic sounds, even without being attended to, elicited greater cerebral cortical responses than the surrogate control sounds after about 150 ms in latency after sound onset. Listeners also clearly discriminated these sounds in perception. The results support the hypothesis that the human auditory system is sensitive to the subtle short-time predictability embedded in the temporal fine structure of sounds. PMID- 23679499 TI - Spurious causalities with transfer entropy. AB - Transfer entropy (TE) seems currently to be the most widely used tool to characterize causal influences in ensembles of complex systems from observed time series. In particular, in an elemental case of two systems, nonzero TEs in both directions are usually interpreted as a sign of a bidirectional coupling. However, one often overlooks that both positive TEs may well be encountered for unidirectionally coupled systems so that a false detection of a causal influence on the basis of a nonzero TE is rather possible. This work highlights typical factors leading to such "spurious couplings": (i) unobserved state variables of the driving system, (ii) low temporal resolution, and (iii) observation errors. All are shown to be particular cases of a general problem: imperfect observations of states of the driving system. Importantly, exact values of TEs, rather than their statistical estimates, are computed here for selected benchmark systems. Conditions for a "spurious" TE to be large and even strongly exceed a "correct" TE are presented and discussed. PMID- 23679500 TI - Delayed feedback induces motion of localized spots in reaction-diffusion systems. AB - We study the formation of localized structures, often called localized spots, in reaction-diffusion systems subject to time delayed feedback control. We focus on the regime close to a second-order critical point marking the onset of a hysteresis loop. We show that the space-time dynamics of the FitzHugh-Nagumo model in the vicinity of that critical point could be described by the delayed Swift-Hohenberg equation. We show that the delayed feedback induces a spontaneous motion of localized spots. We characterize this motion by computing analytically the velocity and the threshold above which localized structures start to move in an arbitrary direction. Numerical solutions of the governing equation are in close agreement with those obtained from the delayed Swift-Hohenberg equation. PMID- 23679501 TI - Bifurcations of emerging patterns in the presence of additive noise. AB - A universal description of the effects of additive noise on super- and subcritical spatial bifurcations in one-dimensional systems is theoretically, numerically, and experimentally studied. The probability density of the critical spatial mode amplitude is derived. From this generalized Rayleigh distribution we predict the shape of noisy bifurcations by means of the most probable value of the critical mode amplitude. Comparisons with numerical simulations are in quite good agreement for cubic or quintic amplitude equations accounting for stochastic supercritical bifurcation and for cubic-quintic amplitude equation accounting for stochastic subcritical bifurcation. Experimental results obtained in a one dimensional Kerr-like slice subjected to optical feedback confirm the analytical expression prediction for the supercritical bifurcation shape. PMID- 23679502 TI - Chaos on the conveyor belt. AB - The dynamics of a spring-block train placed on a moving conveyor belt is investigated both by simple experiments and computer simulations. The first block is connected by a spring to an external static point and, due to the dragging effect of the belt, the blocks undergo complex stick-slip dynamics. A qualitative agreement with the experimental results can be achieved only by taking into account the spatial inhomogeneity of the friction force on the belt's surface, modeled as noise. As a function of the velocity of the conveyor belt and the noise strength, the system exhibits complex, self-organized critical, sometimes chaotic, dynamics and phase transition-like behavior. Noise-induced chaos and intermittency is also observed. Simulations suggest that the maximum complexity of the dynamical states is achieved for a relatively small number of blocks (around five). PMID- 23679503 TI - Using basis sets of scar functions. AB - We present a method to efficiently compute the eigenfunctions of classically chaotic systems. The key point is the definition of a modified Gram-Schmidt procedure which selects the most suitable elements from a basis set of scar functions localized along the shortest periodic orbits of the system. In this way, one benefits from the semiclassical dynamical properties of such functions. The performance of the method is assessed by presenting an application to a quartic two-dimensional oscillator whose classical dynamics are highly chaotic. We have been able to compute the eigenfunctions of the system using a small basis set. An estimate of the basis size is obtained from the mean participation ratio. A thorough analysis of the results using different indicators, such as eigenstate reconstruction in the local representation, scar intensities, participation ratios, and error bounds, is also presented. PMID- 23679504 TI - Modeling the transport of interacting matter waves in a disordered system by a nonlinear diffusion equation. AB - We model the expansion of an interacting atomic Bose-Einstein condensate in a disordered lattice with a nonlinear diffusion equation normally used for a variety of classical systems. We find approximate solutions of the diffusion equation that well reproduce the experimental observations for both short and asymptotic expansion times. Our study establishes a connection between the peculiar shape of the expanding density profiles and the microscopic nonlinear diffusion coefficients. PMID- 23679505 TI - Chaos pass filter: linear response of synchronized chaotic systems. AB - The linear response of synchronized time-delayed chaotic systems to small external perturbations, i.e., the phenomenon of chaos pass filter, is investigated for iterated maps. The distribution of distances, i.e., the deviations between two synchronized chaotic units due to external perturbations on the transferred signal, is used as a measure of the linear response. It is calculated numerically and, for some special cases, analytically. Depending on the model parameters this distribution has power law tails in the region of synchronization leading to diverging moments of distances. This is a consequence of multiplicative and additive noise in the corresponding linear equations due to chaos and external perturbations. The linear response can also be quantified by the bit error rate of a transmitted binary message which perturbs the synchronized system. The bit error rate is given by an integral over the distribution of distances and is calculated analytically and numerically. It displays a complex nonmonotonic behavior in the region of synchronization. For special cases the distribution of distances has a fractal structure leading to a devil's staircase for the bit error rate as a function of coupling strength. The response to small harmonic perturbations shows resonances related to coupling and feedback delay times. A bidirectionally coupled chain of three units can completely filter out the perturbation. Thus the second moment and the bit error rate become zero. PMID- 23679506 TI - Front speed in reactive compressible stirred media. AB - We investigated a nonlinear advection-diffusion-reaction equation for a passive scalar field. The purpose is to understand how the compressibility can affect the front dynamics and the bulk burning rate. We study two classes of flows: periodic shear flow and cellular flow, analyzing the system by varying the extent of compressibility and the reaction rate. We find that the bulk burning rate v(f) in a shear flow increases with compressibility intensity epsilon, following the relation Deltav(f)~epsilon(2). Furthermore, the faster the reaction is, the more important the difference is with respect to the laminar case. The effect has been quantitatively measured, and it turns out to be generally small. For the cellular flow, two extreme cases have been investigated, with the whole perturbation situated either in the center of the vortex or in the periphery. The dependence in this case does not show a monotonic scaling with different behavior in the two cases. The enhancing remains modest and is always less than 20%. PMID- 23679507 TI - Mode competition in cylindrical flows driven by sidewall oscillations. AB - The transition from a two-dimensional to three-dimensional flow in systems with spatial O(2) symmetry and spatiotemporal Z(2) symmetry happens in many fluid systems, like wakes or periodically forced flows. In most of these systems, the dynamics after the first bifurcation is very complex and involves cascades of bifurcations in a very narrow parameter range. A numerical study of a flow in an enclosed cylindrical cavity driven by axial oscillations of the sidewall, which allows a detailed study of the secondary bifurcations and the corresponding mode interactions, is presented. The study focuses on a codimension-2 point that acts as the organizing center of the dynamics for moderate values of the forcing frequency. The unraveled dynamics is very rich, including slow-fast dynamics and hysteresis, and may help understand the bifurcation cascades in more complex systems. PMID- 23679508 TI - Interaction of equal-size bubbles in shear flow. AB - The inertia-induced forces on two identical spherical bubbles in a simple shear flow at small but finite Reynolds number, for the case when the bubbles are within each other's inner viscous region, are calculated making use of the reciprocal theorem. This interaction force is further employed to model the dynamics of air bubbles injected to a viscous fluid sheared in a Couette device at the first shear flow instability where the bubbles are trapped inside the stable Taylor vortex. It was shown that, during a long time scale, the inertial interaction between the bubbles in the primary shear flow drives them away from each other and, as a result, equal-size bubbles eventually assume an ordered string with equal separation distances between all neighbors. We report on experiments showing the dynamic evolution of various numbers of bubbles. The results of the theory are in good agreement with the experimental observations. PMID- 23679509 TI - Dielectrophoretic Rayleigh-Benard convection under microgravity conditions. AB - Thermal convection in a dielectric fluid layer between two parallel plates subjected to an alternating electric field and a temperature gradient is investigated under microgravity conditions. A thermoelectric coupling resulting from the thermal variation of the electric permittivity of the fluid produces the dielectrophoretic (DEP) body force, which can be regarded as thermal buoyancy due to an effective gravity. This electric gravity can destabilize a stationary conductive state of the fluid to develop convection. The similarity of the DEP thermal convection with the Rayleigh-Benard (RB) convection is examined by considering its behavior in detail by a linear stability theory and a two dimensional direct numerical simulation. The results are analyzed from an energetic viewpoint and in the framework of the Ginzburg-Landau (GL) equation. The stabilizing effects of a thermoelectric feedback make the critical parameters different from those in the RB instability. The nonuniformity of the electric gravity arising from the finite variation of permittivity also affects the critical parameters. The characteristic constants of the GL equation are comparable with those for the RB convection. The heat transfer in the DEP convection is weaker than in the RB convection as a consequence of the feedback that impedes the convection. PMID- 23679510 TI - Dielectric fluid in inhomogeneous pulsed electric field. AB - We consider the dynamics of a compressible fluid under the influence of electrostrictive ponderomotive forces in strong inhomogeneous nonstationary electric fields. It is shown that if the fronts of the voltage rise at a sharp, needlelike electrode are rather steep (less than or about nanoseconds), the region of negative pressure arises, which can reach values at which the fluid loses its continuity with the formation of cavitation ruptures. If the voltage on the electrode is not large enough or the front is flatter, the cavitation in the liquid does not occur. However, a sudden shutdown of the field results in a reverse flow of liquid from the electrode, which leads to appearance of negative pressure, and, possibly, cavitation. PMID- 23679511 TI - Slow invasion of a fluid from multiple inlet sources in a thin porous layer: influence of trapping and wettability. AB - We study numerically the process of quasistatic invasion of a fluid in thin porous layers from multiple inlet injection sources focusing on the effect of trapping or mixed wettability, that is, when hydrophobic and hydrophilic pores coexist in the system. Two flow scenarios are considered. In the first one, referred to as the sequential scenario, the injection bonds at the inlet are activated one after the other. In the second one, referred to as the kinetic scenario, the injection bonds at the inlet are activated simultaneously. In contrast with the case of purely hydrophobic systems with no trapping, studied in a previous work, it is shown that the invasion pattern and the breakthrough point statistics at the end of the displacement depend on the flow scenario when trapping or mixed wettability effects are taken into account. The transport properties of the defending phase are also studied and it is shown that a one-to one relationship between the overall diffusive conductance and the mean saturation cannot be expected in a thin system. In contrast with thick systems, the diffusive conductance also depends on the thickness when the system is thin. After consideration of various generic aspects characterizing thin porous systems, the main results are briefly discussed in relation with the water management problem in proton exchange membrane fuel cells. PMID- 23679512 TI - Three-sphere swimmer in a nonlinear viscoelastic medium. AB - A simple model for a swimmer consisting of three colinearly linked spheres attached by rods and oscillating out of phase to break reciprocal motion is analyzed. With a prescribed forcing of the rods acting on the three spheres, the swimming dynamics are determined analytically in both a Newtonian Stokes fluid and a zero Reynolds number, nonlinear, Oldroyd-B viscoelastic fluid with Deborah numbers of order one (or less), highlighting the effects of viscoelasticity on the net displacement of swimmer. For instance, the model predicts that the three sphere swimmer with a sinusoidal, but nonreciprocal, forcing cycle within an Oldroyd-B representation of a polymeric Boger fluid moves a greater distance with enhanced efficiency in comparison with its motility in a Newtonian fluid of the same viscosity. Furthermore, the nonlinear contributions to the viscoelastic constitutive relation, while dynamically nontrivial, are predicted a posteriori to have no effect on swimmer motility at leading order, given a prescribed forcing between spheres. PMID- 23679513 TI - Superdispersion in homogeneous unsaturated porous media using NMR propagators. AB - The NMR propagator technique allows the measurements of the variance sigma(2)=<(xi-)(2)> of the displacements as a function of time t when flowing in a porous media. The time dependence of sigma is a very sensitive test of Gaussian behavior compared to the analysis of the shape of the propagators. Superdispersion occurs when sigma(2)[proportionality]t(alpha) with the exponent alpha larger than 1. In a homogeneous 30-MUm grain pack and 10 < Pe < 35, we observed weak superdispersion in saturated conditions (alpha = 1.17) and gradually strong superdispersion as the water saturation decreases (up to alpha = 1.5) during steady-state oil-water two-phase flow. In saturated conditions, the corresponding longitudinal propagators and breakthrough curves are Gaussian or nearly Gaussian, whereas in two-phase conditions, the longitudinal propagators are nonsymmetric and the breakthrough curves show a tail at long times. PMID- 23679514 TI - Transient solution for droplet deformation under electric fields. AB - A transient analysis to quantify droplet deformation under DC electric fields is presented. The full Taylor-Melcher leaky dielectric model is employed where the charge relaxation time is considered to be finite. The droplet is assumed to be spheroidal in shape for all times. The main result is an ODE governing the evolution of the droplet aspect ratio. The model is validated by extensively comparing predicted deformation with both previous theoretical and numerical studies, and with experimental data. Furthermore, the effects of parameters and stresses on deformation characteristics are systematically analyzed taking advantage of the explicit formulas on their contributions. The theoretical framework can be extended to study similar problems, e.g., vesicle electrodeformation and relaxation. PMID- 23679515 TI - Stokesian dynamics of pill-shaped Janus particles with stick and slip boundary conditions. AB - We study the forces and torques experienced by pill-shaped Janus particles of different aspect ratios where half of the surface obeys the no-slip boundary condition and the other half obeys the Navier slip condition of varying slip lengths. Using a recently developed boundary integral formulation whereby the traditional singular behavior of this approach is removed analytically, we quantify the strength of the forces and torques experienced by such particles in a uniform flow field in the Stokes regime. Depending on the aspect ratio and the slip length, the force transverse to the flow direction can change sign. This is a novel property unique to the Janus nature of the particles. PMID- 23679516 TI - Turbulent magnetic Prandtl number in helical kinematic magnetohydrodynamic turbulence: two-loop renormalization group result. AB - Using the field theoretic renormalization group technique, the influence of helicity (spatial parity violation) on the turbulent magnetic Prandtl number in the kinematic magnetohydrodynamic turbulence is investigated in the two-loop approximation. It is shown that the presence of helicity decreases the value of the turbulent magnetic Prandtl number and, at the same time, the two-loop helical contribution to the turbulent magnetic Prandtl number is at most 4.2% (in the case with the maximal helicity) of its nonhelical value. These results demonstrate, on one hand, the potential importance of the presence of asymmetries in processes in turbulent environments and, on the other hand, the rather strong stability of the properties of diffusion processes of the magnetic field in the conductive turbulent environment with the spatial parity violation in comparison to the corresponding systems without the spatial parity violation. In addition, obtained results are compared to the corresponding results found for the two-loop turbulent Prandtl number in the model of passively advected scalar field. It is shown that the turbulent Prandtl number and the turbulent magnetic Prandtl number, which are the same in fully symmetric isotropic turbulent systems, are essentially different when one considers the spatial parity violation. It means that the properties of the diffusion processes in the turbulent systems with a given symmetry breaking can considerably depend on the internal tensor structure of advected quantities. PMID- 23679517 TI - Numerical study of laminar-turbulent transition in particle-laden channel flow. AB - We present direct numerical simulations of subcritical transition to turbulence in a particle-laden channel flow, with particles assumed rigid, spherical, and heavier than the fluid. The equations describing the fluid flow are solved with an Eulerian mesh, whereas those describing the particle dynamics are solved by Lagrangian tracking. Two-way coupling between fluid and particles is modeled with Stokes drag. The numerical code is first validated against previous results from linear stability: the nonmodal growth of streamwise vortices resulting in streamwise streaks is still the most efficient mechanism for linear disturbance amplification at subcritical conditions as for the case of a single phase fluid. To analyze the full nonlinear transition, we examine two scenarios well studied in the literature: (1) transition initiated by streamwise independent counter rotating streamwise vortices and one three-dimensional mode and (2) oblique transition, initiated by the nonlinear interaction of two symmetric oblique waves. The threshold energy for transition is computed, and it is demonstrated that for both scenarios the transition may be facilitated by the presence of particles at low number density. This is due to the fact that particles may introduce in the system detrimental disturbances of length scales not initially present. At higher concentrations, conversely, we note an increase of the disturbance energy needed for transition. The threshold energy for the oblique scenario shows a more significant increase in the presence of particles, by a factor about four. Interestingly, for the streamwise-vortex scenario the time at which transition occurs increases with the particle volume fraction when considering disturbances of equal initial energy. These results are explained by considering the reduced amplification of oblique modes in the two-phase flow. The results from these two classical scenarios indicate that, although linear stability analysis shows hardly any effect on optimal growth, particles do influence secondary instabilities and streak breakdown. These effects can be responsible of the reduced drag observed in turbulent channel flow laden with heavy particles. PMID- 23679518 TI - Impact dynamics of oxidized liquid metal drops. AB - With exposure to air, many liquid metals spontaneously generate an oxide layer on their surface. In oscillatory rheological tests, this skin is found to introduce a yield stress that typically dominates the elastic response but can be tuned by exposing the metal to hydrochloric acid solutions of different concentration. We systematically studied the normal impact of eutectic gallium-indium (eGaIn) drops under different oxidation conditions and show how this leads to two different dynamical regimes. At low impact velocity (or low Weber number), eGaIn droplets display strong recoil and rebound from the impacted surface when the oxide layer is removed. In addition, the degree of drop deformation or spreading during impact is controlled by the oxide skin. We show that the scaling law known from ordinary liquids for the maximum spreading radius as a function of impact velocity can still be applied to the case of oxidized eGaIn if an effective Weber number We* is employed that uses an effective surface tension factoring in the yield stress. In contrast, no influence on spreading from different oxidations conditions is observed for high impact velocity. This suggests that the initial kinetic energy is mostly damped by bulk viscous dissipation. Results from both regimes can be collapsed in an impact phase diagram controlled by two variables, the maximum spreading factor P(m)=R(0)/R(m), given by the ratio of initial to maximum drop radius, and the impact number K=We*/Re(4/5), which scales with the effective Weber number We* as well as the Reynolds number Re. The data exhibit a transition from capillary to viscous behavior at a critical impact number K(c)~0.1. PMID- 23679519 TI - Hydrodynamics of Leidenfrost droplets in one-component fluids. AB - Using the dynamic van der Waals theory [Phys. Rev. E 75, 036304 (2007)], we numerically investigate the hydrodynamics of Leidenfrost droplets under gravity in two dimensions. Some recent theoretical predictions and experimental observations are confirmed in our simulations. A Leidenfrost droplet larger than a critical size is shown to be unstable and break up into smaller droplets due to the Rayleigh-Taylor instability of the bottom surface of the droplet. Our simulations demonstrate that an evaporating Leidenfrost droplet changes continuously from a puddle to a circular droplet, with the droplet shape controlled by its size in comparison with a few characteristic length scales. The geometry of the vapor layer under the droplet is found to mainly depend on the droplet size and is nearly independent of the substrate temperature, as reported in a recent experimental study [Phys. Rev. Lett. 109, 074301 (2012)]. Finally, our simulations demonstrate that a Leidenfrost droplet smaller than a characteristic size takes off from the hot substrate because the levitating force due to evaporation can no longer be balanced by the weight of the droplet, as observed in a recent experimental study [Phys. Rev. Lett. 109, 034501 (2012)]. PMID- 23679520 TI - Electrohydrodynamic interaction of spherical particles under Quincke rotation. AB - Weakly conducting dielectric particles suspended in a dielectric liquid of higher conductivity can undergo a transition to spontaneous sustained rotation when placed in a sufficiently strong dc electric field. This phenomenon of Quincke rotation has interesting implications for the rheology of these suspensions, whose effective viscosity can be controlled and reduced by application of an external field. While previous models based on the rotation of isolated particles have provided accurate estimates for this viscosity reduction in dilute suspensions, discrepancies have been reported in more concentrated systems where particle-particle interactions are likely significant. Motivated by this observation, we extend the classic description of Quincke rotation based on the Taylor-Melcher leaky dielectric model to account for pair electrohydrodynamic interactions between two identical spheres using the method of reflections. A coupled system of evolution equations for the dipole moments and angular velocities of the spheres is derived that accounts for electric dipole-dipole interactions and hydrodynamic rotlet interactions up to order O(R(-5)), where R is the separation distance between the spheres. A linear stability analysis of this system shows that interactions modify the value of the critical electric field for the onset of Quincke rotation: both electric and hydrodynamic interactions can either stabilize or destabilize the system depending on the orientation of the spheres, but the leading effect of interactions on the onset of rotation is hydrodynamic. We also analyze the dynamics in the nonlinear regime by performing numerical simulations of the governing equations. In the case of a pair of spheres that are fixed in space, we find that particle rotations always synchronize in magnitude at long times, though the directions of rotation of the spheres need not be the same. The steady-state angular velocity magnitude depends on the configuration of the spheres and electric field strength and agrees very well with an asymptotic estimate derived for corotating spheres. In the case of freely-suspended spheres, dipolar interactions are observed to lead to a number of distinct behaviors depending on the initial relative configuration of the spheres and on any infinitesimal initial perturbation introduced in the system: in some cases the spheres slowly separate in space while steadily rotating, while in other cases they pair up and either corotate or counterrotate depending on their orientation relative to the field. PMID- 23679521 TI - Rotating solitary wave at the wall of a cylindrical container. AB - This paper deals with the theoretical modeling of a rotating solitary surface wave that was observed during water drainage from a cylindrical reservoir, when shallow water conditions were reached. It represents an improvement of our previous study, where the radial flow perturbation was neglected. This assumption led to the classical planar Korteweg-de Vries equation for the wall wave profile, which did not account for the rotational character of the base flow. The present formulation is based on a less restricting condition and consequently corrects the last shortcoming. Now the influence of the background flow appears in the wave characteristics. The theory provides a better physical depiction of the unique experiment by predicting fairly well the wave profile at least in the first half of its lifetime and estimating the speed of the observed wave with good accuracy. PMID- 23679522 TI - Thermal relaxation and critical instability of near-critical fluid microchannel flow. AB - We present two-dimensional numerical investigations of the temperature and velocity evolution of a pure near-critical fluid confined in microchannels. The fluid is subjected to two sides heating after it reached isothermal steady state. We focus on the abnormal behaviors of the near-critical fluid in response to the sudden imposed heat flux. New thermal-mechanical effects dominated by fluid instability originating from the boundary and local equilibrium process are reported. Near the microchannel boundaries, the instability grows very quickly and an unexpected vortex formation mode is identified when near-critical thermal mechanical effect is interacting with the microchannel shear flow. The mechanism of the new kind of Kelvin-Helmholtz instability induced by boundary expansion and density stratification processes is also discussed in detail. This mechanism may bring about innovations in the field of microengineering. PMID- 23679523 TI - Fully nonlinear mode competitions of nearly bicritical spiral or Taylor vortices in Taylor-Couette flow. AB - Interactions between nearly bicritical modes in Taylor-Couette flow, which have been concerned with the framework of weakly nonlinear theory, are extended to fully nonlinear Navier-Stokes computation. For this purpose, a standard Newton solver for axially periodic flows is generalized to compute any mixed solutions having up to two phases, which typically arise from interactions of two spiral or Taylor vortex modes. Also, a simple theory is developed in order to classify the mixed solutions. With these methods, we elucidate pattern formation phenomena, which have been observed in a Taylor-Couette flow experiment. Focusing on the counter-rotating parameter range, all possible classes of interaction of various solutions with different azimuthal and axial wave numbers are considered within our computational restriction, and we observe numerous connection branches, e.g., footbridge solutions. Some of the mixed solutions result in a three-dimensional wavy spiral solution with axial relative periodicity or an axially doubly periodic toroidally closed vortex solution. The possible connection of the former solution family to spiral turbulence, which has been observed in highly counter rotating Taylor-Couette flow, is discussed. PMID- 23679524 TI - Role of the Kelvin-Helmholtz instability in the evolution of magnetized relativistic sheared plasma flows. AB - We explore, via analytical and numerical methods, the Kelvin-Helmholtz (KH) instability in relativistic magnetized plasmas, with applications to astrophysical jets. We solve the single-fluid relativistic magnetohydrodynamic (RMHD) equations in conservative form using a scheme which is fourth order in space and time. To recover the primitive RMHD variables, we use a highly accurate, rapidly convergent algorithm which improves upon such schemes as the Newton-Raphson method. Although the exact RMHD equations are marginally stable, numerical discretization renders them unstable. We include numerical viscosity to restore numerical stability. In relativistic flows, diffusion can lead to a mathematical anomaly associated with frame transformations. However, in our KH studies, we remain in the rest frame of the system, and therefore do not encounter this anomaly. We use a two-dimensional slab geometry with periodic boundary conditions in both directions. The initial unperturbed velocity peaks along the central axis and vanishes asymptotically at the transverse boundaries. Remaining unperturbed quantities are uniform, with a flow-aligned unperturbed magnetic field. The early evolution in the nonlinear regime corresponds to the formation of counter-rotating vortices, connected by filaments, which persist in the absence of a magnetic field. A magnetic field inhibits the vortices through a series of stages, namely, field amplification, vortex disruption, turbulent breakdown, and an approach to a flow-aligned equilibrium configuration. Similar stages have been discussed in MHD literature. We examine how and to what extent these stages manifest in RMHD for a set of representative field strengths. To characterize field strength, we define a relativistic extension of the Alfvenic Mach number M(A). We observe close complementarity between flow and magnetic field behavior. Weaker fields exhibit more vortex rotation, magnetic reconnection, jet broadening, and intermediate turbulence. Sufficiently strong fields (M(A)<6) completely suppress vortex formation. Maximum jet deceleration, and viscous dissipation, occur for intermediate vortex-disruptive fields, while electromagnetic energy is maximized for the strongest fields which allow vortex formation. Highly relativistic flows destabilize the system, supporting modes with near-maximum growth at smaller wavelengths than the shear width of the velocity. This helps to explain early numerical breakdown of highly relativistic simulations using numerical viscosity, a long-standing problem. While magnetic fields generally stabilize the system, we have identified many features of the complex and turbulent reorganization that occur for sufficiently weak fields in RMHD flows, and have described the transition from disruptive to stabilizing fields at M(A)~6. Our results are qualitatively similar to observations of numerous jets, including M87, whose knots may exhibit vortex-like behavior. Furthermore, in both the linear and nonlinear analyses, we have successfully unified the HD, MHD, RHD, and RMHD regimes. PMID- 23679525 TI - Wave spectra of a strongly coupled magnetized one-component plasma: quasilocalized charge approximation versus harmonic lattice theory and molecular dynamics. AB - Two different approaches to the calculation of the wave spectra of magnetized strongly coupled liquid one-component plasmas are analzyed: the semianalytical quasilocalized charge approximation (QLCA) and the angle-averaged harmonic lattice (AAHL) theory. Both theories are benchmarked against the numerical evidence obtained from molecular dynamics simulations. It is found that not too far from the melting transition (Gamma?100), the AAHL theory is superior to the QLCA, while further away from the transition, the QLCA performs comparably to or better than the AAHL theory. PMID- 23679526 TI - Collective modes in two-dimensional binary Yukawa systems. AB - We analyze via theoretical approaches and molecular dynamics simulations the collective mode structure of strongly coupled two-dimensional binary Yukawa systems, for selected density, mass, and charge ratios, both in the liquid and crystalline solid phases. Theoretically, the liquid phase is described through the quasilocalized charge approximation (QLCA) approach, while in the crystalline phase we study the centered honeycomb and the staggered rectangular crystal structures through the standard harmonic phonon approximation. We identify "longitudinal" and "transverse" acoustic and optic modes and find that the longitudinal acoustic mode evolves from its weakly coupled counterpart in a discontinuous nonperturbative fashion. The low-frequency acoustic excitations are governed by the oscillation frequency of the average atom, while the high frequency optic excitation frequencies are related to the Einstein frequencies of the systems. PMID- 23679527 TI - Kinetic helicity needed to drive large-scale dynamos. AB - Magnetic field generation on scales that are large compared with the scale of the turbulent eddies is known to be possible via the so-called alpha effect when the turbulence is helical and if the domain is large enough for the alpha effect to dominate over turbulent diffusion. Using three-dimensional turbulence simulations, we show that the energy of the resulting mean magnetic field of the saturated state increases linearly with the product of normalized helicity and the ratio of domain scale to eddy scale, provided this product exceeds a critical value of around unity. This implies that large-scale dynamo action commences when the normalized helicity is larger than the inverse scale ratio. Our results show that the emergence of small-scale dynamo action does not have any noticeable effect on the large-scale dynamo. Recent findings by Pietarila Graham et al. [Phys. Rev. E 85, 066406 (2012)] of a smaller minimal helicity may be an artifact due to the onset of small-scale dynamo action at large magnetic Reynolds numbers. However, the onset of large-scale dynamo action is difficult to establish when the kinetic helicity is small. Instead of random forcing, they used an ABC flow with time-dependent phases. We show that such dynamos saturate prematurely in a way that is reminiscent of inhomogeneous dynamos with internal magnetic helicity fluxes. Furthermore, even for very low fractional helicities, such dynamos display large-scale fields that change direction, which is uncharacteristic of turbulent dynamos. PMID- 23679528 TI - Equations of state and transport properties of warm dense beryllium: a quantum molecular dynamics study. AB - We have calculated the equations of state, the viscosity and self-diffusion coefficients, and electronic transport coefficients of beryllium in the warm dense regime for densities from 4.0 to 6.0 g/cm(3) and temperatures from 1.0 to 10.0 eV by using quantum molecular dynamics simulations. The principal Hugoniot curve is in agreement with underground nuclear explosive and high-power laser experimental results up to ~20 Mbar. The calculated viscosity and self-diffusion coefficients are compared with the one-component plasma model, using effective charges given by the average-atom model. The Stokes-Einstein relationship, which connects viscosity and self-diffusion coefficients, is found to hold fairly well in the strong coupling regime. The Lorenz number, which is the ratio between thermal and electrical conductivities, is computed via Kubo-Greenwood formula and compared to the well-known Wiedemann-Franz law in the warm dense region. PMID- 23679529 TI - Hydrodynamic theory for ion structure and stopping power in quantum plasmas. AB - We present a theory for the dynamical ion structure factor (DISF) and ion stopping power in an unmagnetized collisional quantum plasma with degenerate electron fluids and nondegenerate strongly correlated ion fluids. Our theory is based on the fluctuation dissipation theorem and the quantum plasma dielectric constant that is deduced from a linearized viscoelastic quantum hydrodynamical (LVQHD) model. The latter incorporates the essential physics of quantum forces, which are associated with the quantum statistical pressure, electron-exchange, and electron-correlation effects, the quantum electron recoil effect caused by the dispersion of overlapping electron wave functions that control the dynamics of degenerate electron fluids, and the viscoelastic properties of strongly correlated ion fluids. Both degenerate electrons and nondegenerate strongly correlated ions are coupled with each other via the space charge electric force. Thus, our LVQHD theory is valid for a collisional quantum plasma at atomic scales with a wide range of the ion coupling parameter, the plasma composition, and plasma number densities that are relevant for compressed plasmas in laboratories (inertial confinement fusion schemes) and in astrophysical environments (e.g., warm dense matter and the cores of white dwarf stars). It is found that quantum electron effects and viscoelastic properties of strongly correlated ions significantly affect the features of the DISF and the ion stopping power (ISP). Unlike previous theories, which have studied ion correlations in terms of the ion coupling parameter, by neglecting the essential physics of collective effects that are competing among each other, we have here developed a method to evaluate the dependence of the plasma static and dynamical features in terms of individual parameters, like the Wigner-Seitz radius, the ion atomic number, and the ion temperature. It is found that due to the complex nature of charge screening in quantum plasmas, the ion coupling parameter alone cannot be a good measure for determining ion correlation effects in a collisional quantum plasma, and such a characteristic of a dense quantum plasma should be evaluated against each of the plasma parameters involved. The present investigation thus provides testable predictions for the DISF and ISP and is henceforth applicable to a wide range of compressed plasma categories ranging from laboratory to astrophysical warm dense matter. PMID- 23679530 TI - Dust-ion-acoustic supersolitons in dusty plasmas with nonthermal electrons. AB - Supersolitons are a recent addition to the literature on large-amplitude solitary waves in multispecies plasmas. They are distinguished from the usual solitons by their associated electric field profiles which are inherently distinct from traditional bipolar structures. In this paper, dust-ion-acoustic modes in a dusty plasma with stationary negative dust, cold fluid protons, and nonthermal electrons are investigated through a Sagdeev pseudopotential approach to see where supersolitons fit between ranges of ordinary solitons and double layers, as supersolitons always have finite amplitudes. They therefore cannot be described by reductive perturbation treatments, which rely on a weak amplitude assumption. A systematic methodology and discussion is given to distinguish the existence domains in solitary wave speed and amplitude for the different solitons, supersolitons and double layers, in terms of compositional parameters for the plasma model under consideration. PMID- 23679531 TI - Radiative transfer with partial coherence in optically thick plasmas. AB - A quantum transport model for atomic line radiation in plasmas is developed and analyzed. It is found that the Wigner phase space formulation of QED provides a consistent way to address the wave-particle duality in radiative transfer problems. If the photons' thermal de Broglie length is much smaller than all of the spatial scales of the problem under consideration (large-spectral-band limit), the radiation is not coherent and radiative transfer can be addressed with the usual treatments. In the general case, the Heisenberg uncertainty relation yields ambiguities in the description of the radiation-matter interaction mechanisms. We examine this issue and show that an accurate description of radiative transfer should involve a model with nonlocal interactions and requires an appropriate coarse-graining procedure. Calculations of transmission factors and absorption spectra in ideal cases are performed and indicate that significant misinterpretations can be made in spectroscopic diagnostics if the radiation coherence is not well accounted for. Applications to laser physics are also discussed. PMID- 23679532 TI - Prepulse suppression and optimization of backward Raman amplification with a chirped pump laser beam. AB - Two-dimensional particle-in-cell (PIC) simulations have been performed to demonstrate how chirping the pump laser beam can make the seed backward Raman amplification more efficient. The PIC code ocean is detailed and validated with theoretical analysis of the three-wave coupling. Particular attention is devoted to the impact of numerical noise on Raman scattering. Once the numerical parameters are set, one- and two-dimensional simulations exhibit the ability to suppress the pedestal pulse preceding the amplified seed laser beam and lower the spontaneous Raman scattering by appropriately choosing the pump chirp value. PMID- 23679533 TI - Plasma expansion into vacuum assuming a steplike electron energy distribution. AB - The expansion of a semi-infinite plasma slab into vacuum is analyzed with a hydrodynamic model implying a steplike electron energy distribution function. Analytic expressions for the maximum ion energy and the related ion distribution function are derived and compared with one-dimensional numerical simulations. The choice of the specific non-Maxwellian initial electron energy distribution automatically ensures the conservation of the total energy of the system. The estimated ion energies may differ by an order of magnitude from the values obtained with an adiabatic expansion model supposing a Maxwellian electron distribution. Furthermore, good agreement with data from experiments using laser pulses of ultrashort durations tau(L) 2)-[beta-d-xylopyranosyl (1 -> 3)]-beta-d-glucopyranosyl-(1 -> 4)-beta-d-galactopyranoside (1, typaspidoside A), (25S)-26-O-beta-d-glucopyranosyl-furost-5-ene-12-one 3beta,22alpha,26-triol-3-O-beta-d-glucopyranosyl-(1 -> 2)-[beta-d-xylopyranosyl (1 -> 3)]-beta-d-glucopyranosyl-(1 -> 4)-beta-d-galactopyranoside (2, 25S typaspidoside A), and timosaponin H1 (3), based on the integrative spectroscopic analysis of 1D- and 2D-NMR experiments, ESI-MS data and chemical evidence. The investigation on the chemical components of this plant is reported for the first time. PMID- 23679567 TI - The impact of information on attitudes toward e-mental health services. AB - E-mental health services are Internet-based treatment options for mental illness. There has been a proliferation of these services in recent years, with online programs now available for the treatment of mood, anxiety, eating, adjustment, and substance use disorders. (1) E-mental health services allow for greater dissemination of psychological treatments, are cost effective, and may overcome a number of client barriers to care. (1) However, the limited research available indicates that attitudes about e-mental health services are less than optimal. Past research has found that providing information about services can improve attitudes. This study investigated the relationship between knowledge of e-mental health services and attitudes toward e-mental health services. The attitudes examined were the perceived helpfulness of e-mental health services and the likelihood of using the services. Participants (N=217) were randomly assigned to one of three conditions: provision of e-mental health information by means of film; provision of e-mental health information by text; or provision of no e mental health information. Results indicated that participants perceived online programs without therapist assistance as being significantly less helpful, and reported reduced likelihood of engaging in these programs when compared to other e-mental health services. Participants in the text intervention group reported higher likelihood of e-mental health use in the future, whereas there were no effects for the film group. Results indicate that participants perceive important differences between types of e-mental health services, and that a brief text intervention can improve attitudes toward these services. Limitations of the present study and directions for future research are discussed. PMID- 23679568 TI - Methodological issues in using data from social networking sites. AB - Social networking sites (SNS) have become increasingly popular in recent years. With the amount of data available on SNS, the potential exists for researchers to use these data for their research. However, like any research method, there are limitations in using data from SNS. First, as members of SNS are not representative of the population, there is the limitation in generalizing the findings to the population. Second, in SNS with a low level of activity, there is also the issue of whether the data are sufficient for analysis. Third, the validity of the postings by members of SNS should be considered, as members of SNS may not be truthful in their responses. In addition, as the environment for SNS favors a quick emotive response as opposed to a cognitive response, the review suggests that the researcher will need to be aware of possibly different behavior when members of a SNS are faced with a high involvement decision. This article concludes that while there is potential in analyzing data from SNS, researchers should be aware of the limitations in using these data. PMID- 23679566 TI - Target proteomic profiling of frozen pancreatic CD24+ adenocarcinoma tissues by immuno-laser capture microdissection and nano-LC-MS/MS. AB - Cellular heterogeneity of solid tumors represents a common problem in mass spectrometry (MS)-based analysis of tissue specimens. Combining immuno-laser capture microdissection (iLCM) and mass spectrometry (MS) provides a means to study proteins that are specific for pure cell subpopulations in complex tissues. CD24, as a cell surface marker for detecting pancreatic cancer stem cells (CSCs), is directly correlated with the development and metastasis of pancreatic cancer. Herein, we describe an in-depth proteomic profiling of frozen pancreatic CD24(+) adenocarcinoma cells from early stage tumors using iLCM and LC-MS/MS and a comparison with CD24(-) cells dissected from patient-matched adjacent normal tissues. Approximately 40 nL of tissue was procured from each specimen and subjected to tandem MS analysis in triplicate. A total of 2665 proteins were identified, with 375 proteins in common that were significantly differentially expressed in CD24(+) versus CD24(-) cells by at least a 2-fold change. The major groups of the differentially overexpressed proteins are involved in promoting tumor cell migration and invasion, immune escape, and tumor progression. Three selected candidates relevant to mediating immune escape, CD59, CD70, and CD74, and a tumor promoter, TGFBI, were further validated by immunohistochemistry analysis on tissue microarrays. These proteins showed significantly increased expression in a large group of clinical pancreatic adenocarcinomas but were negative in all normal pancreas samples. The significant coexpression of these proteins with CD24 suggests that they may play important roles in the progression of pancreatic cancer and could serve as promising prognosis markers and novel therapeutic targets for this deadly disease. PMID- 23679569 TI - Seniors, health information, and the Internet: motivation, ability, and Internet knowledge. AB - Providing health information to older adults is crucial to empowering them to better control their health, and the information is readily available on the Internet. Yet, little is known about the factors that are important in affecting seniors' Internet search for health information behavior. This work addresses this research deficit by examining the role of health information orientation (HIO), eHealth literacy, and Internet knowledge (IK) in affecting the likelihood of using the Internet as a source for health information. The analysis reveals that each variable in the study is significant in affecting Internet search likelihood. Results from the analysis also demonstrate the partial mediating role of eHealth literacy and the interaction between eHealth literacy and HIO. The findings suggest that improving seniors' IK and eHealth literacy would increase their likelihood of searching for and finding health information on the Internet that might encourage better health behaviors. PMID- 23679570 TI - Impulse purchases and trust: the mediating effect of stickiness and the mental budgeting account. AB - Impulse purchasing is a pervasive yet relatively little-discussed phenomenon. This study investigates the effect of impulse purchases on trust, as well as the mediating effect of stickiness and the mental budgeting account in the group buying context. Questionnaires were sent to group buying participants. The results show that impulse purchases have a positive effect on trust and that both stickiness and the mental budgeting account present a mediating effect. PMID- 23679571 TI - Ethics of social media research: common concerns and practical considerations. AB - Social media Websites (SMWs) are increasingly popular research tools. These sites provide new opportunities for researchers, but raise new challenges for Institutional Review Boards (IRBs) that review these research protocols. As of yet, there is little-to-no guidance regarding how an IRB should review the studies involving SMWs. The purpose of this article was to review the common risks inherent in social media research and consider how researchers can consider these risks when writing research protocols. We focused this article on three common research approaches: observational research, interactive research, and survey/interview research. Concomitant with these research approaches, we gave particular attention to the issues pertinent to SMW research, including privacy, consent, and confidentiality. After considering these challenges, we outlined key considerations for both researchers and reviewers when creating or reviewing SMW IRB protocols. Our goal in this article was to provide a detailed examination of relevant ethics and regulatory issues for both researchers and those who review their protocols. PMID- 23679572 TI - College students' use of communication technology with parents: comparisons between two cohorts in 2009 and 2011. AB - Although communication technology is beneficial to maintain important close relationships, not all findings suggest that communication technology use between college students and their parents is indicative of positive adjustment or relational qualities. A study in 2009 found that only 24.2% of college students used a social networking site (SNS) to communicate with a parent, yet those students reported more loneliness, anxious attachment, and conflict with their parent (Gentzler et al., 2011 ). Because technology and trends in use change rapidly, we investigated a new cohort of college students 2 years later to determine if rates of using communication technology with parents and their links to student adjustment have changed. Comparisons between 2009 and 2011 samples indicated that in-person contact and telephone use did not vary across cohorts. However, texting and SNS use with parents became more common, and using e-mail with parents declined. Consistent with the 2009 data, students' phone use with parents was related to positive relationship qualities (satisfaction, intimacy, support, instrumental aid). In the new 2011 sample, e-mail was linked to aid. However, the present findings indicate students' SNS use with parents is no longer linked to maladaptive outcomes. The study highlights how quickly the use and implications of communication technology changes, and suggests that communication patterns may reflect broader psychosocial adjustment and parent child dynamics. PMID- 23679573 TI - An industry perspective: dietary supplements and mortality rates in older women. AB - This special article seeks to provide balance and clarity to the confusion brought about by the conclusions resulting from a recent study published in Archives of Internal Medicine by Mursu et al. (2011). An examination of three key limitations of the study provides context to why additional research is needed: (a) Nonusers were poorly defined; (b) supplement users were healthier than nonusers; and (c) the number of supplement users increased throughout the study. Although the literature is limited, other similar observational studies have also shown positive effects on the risk mortality for both multivitamins and single nutrient supplements. Observational trials are an essential component of evidence based nutrition but do not offer certainty because other data, such as the one generated from randomized controlled trials, are equally important in regard to the totality of evidence. The Senior Scientific Advisory Committee for the Council for Responsible Nutrition, an industry trade group, feels that the conclusions of the study by Mursu et al. (2011) are overstated and suggests that researchers analyze cohort(s) designed to specifically examine vitamin and mineral supplements free of confounding from factors, such as hormone replacement therapy, to better assess their benefits to the general population. PMID- 23679575 TI - Role of T cell recruitment and chemokine-regulated intra-graft T cell motility patterns in corneal allograft rejection. AB - Keratoplasty is the primary treatment to cure blindness due to corneal opacification. However, immune-mediated rejection remains the leading cause of keratoplasty failure. Here, we utilize an in vivo imaging approach to monitor, track, and characterize in real-time the recruitment of GFP-labeled allo-specific activated (Bonzo) T cells during corneal allograft rejection. We show that the recruitment of effector T cells to the site of transplantation determined the fate of corneal allografts, and that local intra-graft production of CCL5 and CXCL9/10 regulated motility patterns of effector T cells in situ, and correlated with allograft rejection. We also show that different motility patterns associate with distinct in vivo phenotypes (round, elongated, and ruffled) of graft infiltrating effector T cells with varying proportions during progression of rejection. The ruffled phenotype was characteristic of activated effectors T cells and predominated during ongoing rejection, which associated with significantly increased T cell dynamics within the allografts. Importantly, CCR5/CXCR3 blockade decreased the motility, size, and number of infiltrating T cells and significantly prolonged allograft survival. Our findings indicate that chemokines produced locally within corneal allografts play an important role in the in situ activation and dynamic behavior of infiltrating effector T cells, and may guide targeted interventions to promote graft survival. PMID- 23679574 TI - Conditionally replicative adenoviral vectors for imaging the effect of chemotherapy on pancreatic cancer cells. AB - Pancreatic cancer has a poor prognosis after complete macroscopic resection combined with chemotherapy. Even after neoadjuvant chemotherapy, R0 resection is often not possible. Moreover, current imaging techniques cannot reliably distinguish viable cancer cells from scar tissue at the resectional margin. We investigated the use of a conditionally replicative adenovirus (CRAd), Ad5/3Cox2CRAd-DeltaE3ADP-Luc, for imaging the effects of chemotherapy. The CRAd infectivity of pancreatic cancer cells was enhanced by a chimeric Ad5/3 fiber, E1A expression was under the control of the Cox2 promoter, and the luciferase gene was inserted adjacent to the adenovirus death protein (ADP) gene. Subcutaneous xenografts of the pancreatic cancer cell line MiaPaCa-2 were established in 24 BALB/c nu/nu mice. When xenografts reached a diameter of 4-6 mm (day 1), the mice were injected i.p. with either PBS (group A; n = 12) or 1000 mg/kg gemcitabine (group B; n = 12), weekly. On days 19, 26, 33, and 40, CRAd were injected intratumorally into three mice in groups A and B. Bioluminescence was imaged 72 h after CRAd injection, and gross tumor volumes were measured then tumors were removed for ex vivo histopathology using H&E and Ki-67 staining. Correlations between gross tumor volume, pathological evaluation of the percentage of viable tumor area, and CRAd bioluminescence were analyzed. Bioluminescence correlated closely with the percentage of viable tumor area (R = 0.96), but not with gross tumor volume (R = 0.31). Therefore, CRAds might be reliable imaging tools for monitoring chemotherapy in pancreatic cancer, and could improve our ability to distinguish viable tumor cells from scar tissue. PMID- 23679577 TI - Abstracts of the Australasian College of Dermatologists 46th Annual Scientific Meeting. May 19-22, 2013. Sydney, New South Wales, Australia. PMID- 23679576 TI - Wnt5a inhibits human monocyte-derived myeloid dendritic cell generation. AB - Wnt5a is a non-canonical Wnt protein that is expressed at elevated levels in inflammatory conditions. Its role in inflammation remains unclear, although it is known that Wnt5a is expressed at a higher level in monocyte-derived myeloid dendritic cells (Mo-mDCs) than in monocytes and macrophages. The function of Wnt5a in dendritic cells (DCs) remains relatively unexplored. Here, we found that under Mo-mDC culture conditions, Wnt5a inhibited the generation of CD14(+/low) Mo mDCs while promoting the generation of CD14+/++ CD16+ monocytes. We could further show that stimulation of monocytes with rWnt5a induced a rapid IL-6 production and that the rWnt5a treated Mo-mDC differentiation was restored upon blocking of IL-6. Also, conditioned media from Wnt5a stimulated human breast cancer cells producing IL-6, specifically inhibited Mo-mDC differentiation. These observations are strengthened by our finding that patients with sepsis, a disease involving elevated Wnt5a and IL-6 levels, also showed a significant increase in the CD14+ CD16++/CD14+/++ CD16+ monocyte populations, which was accompanied by a significant decrease in circulating mDCs. We finally show that under typical Mo mDC culture conditions, monocytes isolated from patients with sepsis as compared to healthy controls, preferentially differentiated into CD14CD14+/++ HLA-DR++ cells. We suggest that Wnt5a is a possible candidate mediator for the CD14+/++ CD16+ monocyte accumulation seen in patients with infectious disease and cancer. PMID- 23679578 TI - Predictors of exclusive breastfeeding: observations from the Alberta pregnancy outcomes and nutrition (APrON) study. AB - BACKGROUND: Despite growing evidence that supports the importance of 6-month exclusive breastfeeding, few Canadian mothers adhere to this, and early weaning onto solids is a common practice. This study assessed infant feeding transitions during the first 6 months postpartum and factors that predicted exclusive breastfeeding to 3 and 6 months. METHODS: This prospective cohort study was part of the Alberta Pregnancy Outcomes and Nutrition study (APrON). From an initial sample of 600 pregnant women recruited from Edmonton and Calgary, 402 mothers provided complete details at 3 months postpartum; 300 stayed on to provide information at 6 months postpartum. During pregnancy and at 3 and 6 months postpartum, data on maternal and infant socio-demographic, behavior, and feeding were collected. RESULTS: Even though there was a high rate of "ever having breastfed" (98.6%), exclusive breastfeeding rates for 3 and 6 months were 54.0% and 15.3%, respectively. After controlling for potential confounders, the study showed that mothers who held post-graduate university degrees were 3.76 times more likely to breastfeed exclusively for 6 months than those without a university degree (95% CI: 1.30-10.92; p = 0.015). In addition, mother of previous children were more likely to breastfeed exclusively for 6 months (OR: 2.21, 95% CI: 1.08-4.52; p = 0.031). Mothers who were in the highest quartile of the Iowa Infant Feeding Attitude Score were 4.29 and 5.40 times more likely to breastfeed exclusively for 3 months (95% CI: 1.31-14.08; p-trend < 0.001) and 6 months (95% CI: 2.75-10.60; P-trend < 0.001), respectively. CONCLUSIONS: The 6 month exclusive breastfeeding rate in Alberta is considerably below national and international breastfeeding recommendations. Professional advice that focuses on prenatal maternal knowledge, attitudes, and misperceptions may promote adherence to World Health Organization breastfeeding guidelines. Knowing that exclusive breastfeeding is less likely to take place among lower-educated, primiparous women may help health practitioners focus their support and education for this group. PMID- 23679579 TI - Cytoskeletal disease: a role in the etiology of adult periodontitis. AB - All cells and organisms across the evolutionary spectrum, from the most primitive to the most complex, are mechanosensitive. As the cytoskeleton is a key in controlling the normal basal prestress of cells and therefore is involved in virtually all physiological cellular processes, abnormalities in this essential cellular characteristic may result in diseases. Indeed, many diseases have now been associated with abnormalities in cytoskeletal and nucleoskeletal proteins. We propose that adult periodontitis is, at least in part, such a cytoskeletal disease. It is well established that adult periodontitis starts by bacterial invasion at the interface between the tooth surface and marginal gingiva that induces a local inflammatory response. The inflammatory cells release metalloproteinases which degrade gingival collagenous fibrous tissue and loss of local tissue integrity that reduces the normal prestressed cell-extracellular matrix network. This is a major signaling trigger that induces a local and rapid release of ATP, which then activates P2X receptors and stimulates a calcium influx, further activating osteoclastic resorption of the alveolar bone. As periodontitis is a chronic disease, it seems reasonable to suggest that agents that maintain cytoskeletal tensegrity, for example, inhibitors of ATP receptors, may diminish the bone loss and may have a role in future periodontal therapy. PMID- 23679581 TI - Electrophoresis of a pH-regulated zwitterionic nanoparticle in a pH-regulated zwitterionic capillary. AB - We consider the electrophoresis of a rigid sphere along the axis of a narrow cylindrical capillary; both are pH-regulated and zwitterionic. This extends available analyses in the literature to a more general and realistic case. Adopting a titanium oxide (TiO2) particle in a silicon dioxide (SiO2) capillary as an example, we examine the capillary radius, the solution pH, and the electrolyte concentration (or double-layer thickness) for their influences on the electrophoretic behavior of a particle. Because the pH solution is adjusted by HCl and NaOH, the presence of four kinds of ionic species, namely, H(+), OH(-), Na(+), and Cl(-), should be considered if NaCl is the background electrolyte. This also extends conventional electrophoresis analyses to the case of multiple ionic species. The interactions of the electroosmotic flow, the properties of the particle and the solution, and the capillary wall yield complicated electrophoretic behavior that can be regulated by the solution pH and the background electrolyte concentration. The results gathered are necessary for the future design of nanopore-based electrophoresis devices. PMID- 23679580 TI - An endogenous artificial microRNA system for unraveling the function of root endosymbioses related genes in Medicago truncatula. AB - BACKGROUND: Legumes have the unique capacity to undergo two important root endosymbioses: the root nodule symbiosis and the arbuscular mycorrhizal symbiosis. Medicago truncatula is widely used to unravel the functions of genes during these root symbioses. Here we describe the development of an artificial microRNA (amiR)-mediated gene silencing system for M. truncatula roots. RESULTS: The endogenous microRNA (miR) mtr-miR159b was selected as a backbone molecule for driving amiR expression. Heterologous expression of mtr-miR159b-amiR constructs in tobacco showed that the backbone is functional and mediates an efficient gene silencing. amiR-mediated silencing of a visible marker was also effective after root transformation of M. truncatula constitutively expressing the visible marker. Most importantly, we applied the novel amiR system to shed light on the function of a putative transcription factor, MtErf1, which was strongly induced in arbuscule-containing cells during mycorrhizal symbiosis. MtPt4 promoter driven amiR-silencing led to strongly decreased transcript levels and deformed, non fully truncated arbuscules indicating that MtErf1 is required for arbuscule development. CONCLUSIONS: The endogenous amiR system demonstrated here presents a novel and highly efficient tool to unravel gene functions during root endosymbioses. PMID- 23679582 TI - One-step hydrothermal synthesis of manganese-containing MFI-type zeolite, Mn-ZSM 5, characterization, and catalytic oxidation of hydrocarbons. AB - Manganese-containing MFI-type Mn-ZSM-5 zeolite was synthesized by a facile one step hydrothermal method using tetrapropylammonium hydroxide (TPAOH) and manganese(III)-acetylacetonate as organic template and manganese salts, respectively. A highly crystalline MFI zeolite structure was formed under pH = 11 in 2 days, without the need for additional alkali metal cations. Direct evidence of the incorporation of Mn in the zeolite framework sites was observed by performing structure parameter refinements, supported by data collected from other characterization techniques such as IR, Raman, UV-vis, TGA, N2-adsorption, SEM, TEM, EDAX, and XPS. UV-vis spectra from the unique optical properties of Mn ZSM-5 show two absorption peaks at 250 and 500 nm. The absorption varies in different atmospheres accompanied by a color change of the materials due to oxygen evolution. Raman spectra show a significant and gradual red shift from 383 cm(-1) to 372 cm(-1) when the doping amount of Mn is increased from 0 to 2 wt %. This suggests a weakened zeolite structural unit induced by the Mn substitution. The catalytic activity was studied in both gas-phase benzyl alcohol oxidation and toluene oxidation reactions with remarkable oxidative activity presented for the first time. These reactions result in a 55% yield of benzaldehyde, and 65% total conversion of toluene to carbon dioxide for the 2% Mn-ZSM-5. Temperature programmed reduction (TPR) using CO in He demonstrates two reduction peaks: one between 300 and 500 degrees C and the other between 500 and 800 degrees C. The first reduction peak, due to manganese-activated oxidation sites shifted from higher temperature to lower temperature, and the peak intensity of CO2 rises when the dopant amount increases. For the first time, calculated photophysical properties of a model Mn(O-SiH3)4(-) compound, an Mn-embedded zeolite cluster, and model Mn oxides help to explain and interpret the diffuse reflectance spectroscopy of Mn-ZSM-5 zeolites. PMID- 23679583 TI - Early versus later presentations of venous malformations: where and why? AB - Venous malformations (VMs) are congenital anomalies of the venous vasculature, but not all are evident at birth. The factors that lead to presentation later in life are not well understood. The objective of this retrospective cohort study of patients with VMs evaluated at the University of California at San Francisco Birthmarks and Vascular Anomalies Center from 2005 to 2009 was to investigate the clinical presentation of VMs and correlate these features with different types of tissues (e.g., skin, subcutis, intramuscular). Main outcomes included the age at which lesions were first noticed, tissue type involved, presenting signs and symptoms, aggravating factors, and morbidities. A total of 115 subjects was included. The mean age when VM was first noted was 6.7 +/- 0.9 years. Tissue types involved included skin/subcutaneous (46%); intramuscular (40%); and bone, tendon, or joint (14%). Presenting signs/symptoms included soft tissue swelling (44%), discrete mass (34%), pain (33%), and skin discoloration (26%). When compared with VMs limited to the skin or subcutis, those restricted to the intramuscular compartment were less likely to present at birth (27% vs 53%, p < 0.05) but were more frequently painful (79% vs 60%, p < 0.05) and contained more phleboliths (28% vs 11%, p < 0.05), and were associated with more exercise limitation (35% vs 16%, p < 0.05). VMs differ in age of onset, clinical features, and complications based on differing tissues and sites of involvement, with isolated intramuscular involvement associated with later presentation and greater morbidity. PMID- 23679584 TI - Quantum process nonclassicality. AB - We propose a definition of nonclassicality for a single-mode quantum-optical process based on its action on coherent states. If a quantum process transforms a coherent state to a nonclassical state, it is verified to be nonclassical. To identify nonclassical processes, we introduce a representation for quantum processes, called the process-nonclassicality quasiprobability distribution, whose negativities indicate nonclassicality of the process. Using this distribution, we derive a relation for predicting nonclassicality of the output states for a given input state. We experimentally demonstrate our method by considering the single-photon addition as a nonclassical process and predicting nonclassicality of the output state for an input thermal state. PMID- 23679585 TI - Decoherence of a single-ion qubit immersed in a spin-polarized atomic bath. AB - We report on the immersion of a spin qubit encoded in a single trapped ion into a spin-polarized neutral atom environment, which possesses both continuous (motional) and discrete (spin) degrees of freedom. The environment offers the possibility of a precise microscopic description, which allows us to understand dynamics and decoherence from first principles. We observe the spin dynamics of the qubit and measure the decoherence times (T(1) and T(2)), which are determined by the spin-exchange interaction as well as by an unexpectedly strong spin nonconserving coupling mechanism. PMID- 23679586 TI - Macroscopicity of mechanical quantum superposition states. AB - We propose an experimentally accessible, objective measure for the macroscopicity of superposition states in mechanical quantum systems. Based on the observable consequences of a minimal, macrorealist extension of quantum mechanics, it allows one to quantify the degree of macroscopicity achieved in different experiments. PMID- 23679587 TI - Processing quantum information with relativistic motion of atoms. AB - We show that particle detectors, such as two-level atoms, in noninertial motion (or in gravitational fields) could be used to build quantum gates for the processing of quantum information. Concretely, we show that through suitably chosen noninertial trajectories of the detectors the interaction Hamiltonian's time dependence can be modulated to yield arbitrary rotations in the Bloch sphere due to relativistic quantum effects. PMID- 23679588 TI - Direct Bell states generation on a III-V semiconductor chip at room temperature. AB - We demonstrate the direct generation of polarization-entangled photon pairs at room temperature and telecom wavelength in an AlGaAs semiconductor waveguide. The source is based on spontaneous parametric down-conversion with a counterpropagating phase-matching scheme. The quality of the two-photon state is assessed by the reconstruction of the density matrix giving a raw fidelity to a Bell state of 0.83; a theoretical model, taking into account the experimental parameters, provides ways to understand and control the amount of entanglement. Its compatibility with electrical injection, together with the high versatility of the generated two-photon state, make this source an attractive candidate for completely integrated quantum photonics devices. PMID- 23679589 TI - s-Wave collisional frequency shift of a fermion clock. AB - We report an s-wave collisional frequency shift of an atomic clock based on fermions. In contrast to bosons, the fermion clock shift is insensitive to the population difference of the clock states, set by the first pulse area in Ramsey spectroscopy, theta(1). The fermion shift instead depends strongly on the second pulse area theta(2). It allows the shift to be canceled, nominally at theta(2)=pi/2, but correlations perturb the null to slightly larger theta(2). The frequency shift is relevant for optical lattice clocks and increases with the spatial inhomogeneity of the clock excitation field, naturally larger at optical frequencies. PMID- 23679590 TI - Subfemtotesla scalar atomic magnetometry using multipass cells. AB - Scalar atomic magnetometers have many attractive features but their sensitivity has been relatively poor. We describe a Rb scalar gradiometer using two multipass optical cells. We use a pump-probe measurement scheme to suppress spin-exchange relaxation and two probe pulses to find the spin precession zero crossing times with a resolution of 1 psec. We realize a magnetic field sensitivity of 0.54 fT/Hz(1/2), which improves by an order of magnitude the best scalar magnetometer sensitivity and exceeds, for example, the quantum limit set by the spin-exchange collisions for a scalar magnetometer with the same measurement volume operating in a continuous regime. PMID- 23679591 TI - Releasing scalar fields: cosmological simulations of scalar-tensor theories for gravity beyond the static approximation. AB - Several extensions of general relativity and high energy physics include scalar fields as extra degrees of freedom. In the search for predictions in the nonlinear regime of cosmological evolution, the community makes use of numerical simulations in which the quasistatic limit is assumed when solving the equation of motion of the scalar field. In this Letter, we propose a method to solve the full equations of motion for scalar degrees of freedom coupled to matter. We run cosmological simulations which track the full time and space evolution of the scalar field, and find striking differences with respect to the commonly used quasistatic approximation. This novel procedure reveals new physical properties of the scalar field and uncovers concealed astrophysical phenomena which were hidden in the old approach. PMID- 23679592 TI - Gravity from rational curves in twistor space. AB - This Letter presents a new formula which is conjectured to yield all tree amplitudes in N=8 supergravity. The amplitudes are described in terms of higher degree rational maps to twistor space. The resulting expression has manifest N=8 supersymmetry and is manifestly permutation symmetric in all external states. It depends monomially on the infinity twistor that explicitly breaks conformal symmetry to Poincare symmetry. We have carried out various nontrivial analytic and numerical checks of the formula for up to eight external states with arbitrary helicities. PMID- 23679594 TI - Pileup subtraction for jet shapes. AB - Jets in high energy hadronic collisions often contain the fingerprints of the particles that produced them. Those fingerprints, and thus the nature of the particles that produced the jets, can be read off with the help of quantities known as jet shapes. Jet shapes are, however, severely affected by pileup, the accumulation in the detector of the residues of the many simultaneous collisions taking place in the Large Hadron Collider (LHC). We introduce a method to correct for pileup effects in jet shapes. Relative to earlier, limited approaches, the key advance resides in its full generality, achieved through a numerical determination, for each jet, of a given shape's susceptibility to pileup. The method rescues the possibility of using jet shapes in the high pileup environment of current and future LHC running, as we show with examples of quark-gluon discrimination and top tagging. PMID- 23679593 TI - Improved search for nu-(MU)->nu-(e) oscillations in the MiniBooNE experiment. AB - The MiniBooNE experiment at Fermilab reports results from an analysis of nu[over ](e) appearance data from 11.27*10(20) protons on target in the antineutrino mode, an increase of approximately a factor of 2 over the previously reported results. An event excess of 78.4+/-28.5 events (2.8sigma) is observed in the energy range 200nu[over -](e), the best oscillation fit to the excess has a probability of 66% while the background-only fit has a chi(2) probability of 0.5% relative to the best fit. The data are consistent with antineutrino oscillations in the 0.01~O(1/ln|eB|)) at large magnetic field. PMID- 23679596 TI - Second-order QCD corrections to jet production at hadron colliders: the all-gluon contribution. AB - We report the calculation of next-to-next-to-leading order QCD corrections in the purely gluonic channel to dijet production and related observables at hadron colliders. Our result represents the first next-to-next-to-leading order calculation of a massless jet observable at hadron colliders, and opens the path towards precision QCD phenomenology with the LHC. PMID- 23679597 TI - Single photon K(-2) and K(-1)K(-1) double core ionization in C(2)H(2n) (n=1-3), CO, and N(2) as a potential new tool for chemical analysis. AB - We have observed single photon double K-shell photoionization in the C(2)H(2n) (n=1-3) hydrocarbon sequence and in N(2) and CO, using synchrotron radiation and electron coincidence spectroscopy. Our previous observations of the K(-2) process in these molecules are extended by the observations of a single photon double photoionization with one core hole created at each of the two neighboring atoms in the molecule (K(-1)K(-1) process). In the C(2)H(2n) sequence, the spectroscopy of K(-1)K(-1) states is much more sensitive to the bond length than conventional electron spectroscopy for chemical analysis spectroscopy based on single K-shell ionization. The cross section variation for single photon K(-1)K(-1) double core ionization in the C(2)H(2n) sequence and in the isoelectronic C(2)H(2n), N(2) and CO molecules validates a knock-out mechanism in which a primary ionized 1s photoelectron ejects another 1s electron of the neighbor atom. The specific Auger decay from such states is clearly observed in the CO case. PMID- 23679598 TI - Differential scattering cross-sections for the different product vibrational States in the ion-molecule reaction Ar(+)+N2. AB - The charge transfer reaction Ar(+)+N(2)->Ar+N(2)(+) has been investigated in a crossed-beam experiment in combination with three-dimensional velocity map imaging. Angular-differential state-to-state cross sections were determined as a function of the collision energy. We found that scattering into the first excited vibrational level dominates as expected, but only for scattering in the forward direction. Higher vibrational excitations up to v'=6 have been observed for larger scattering angles. For decreasing collision energy, scattering into higher scattering angles becomes increasingly important for all kinematically allowed quantum states. Our detailed measurements indicate that a quantitative agreement between experiment and theory for this basic ion-molecule reaction now comes within reach. PMID- 23679599 TI - Lifetime of the Bose gas with resonant interactions. AB - We study the lifetime of a Bose gas at and around unitarity using a Feshbach resonance in lithium 7. At unitarity, we measure the temperature dependence of the three-body decay coefficient L(3). Our data follow a L(3)=lambda(3)/T(2) law with lambda(3)=2.5(3)(stat)(6)(syst)*10(-20) (MUK)(2) cm(6) s(-1) and are in good agreement with our analytical result based on zero-range theory. Varying the scattering length a at fixed temperature, we investigate the crossover between the finite-temperature unitary region and the previously studied regime where |a| is smaller than the thermal wavelength. We find that L(3) is continuous across the resonance, and over the whole a<0 range our data quantitatively agree with our calculation. PMID- 23679600 TI - Nonclassical radiation from thermal cavities in the ultrastrong coupling regime. AB - Thermal or chaotic light sources emit radiation characterized by a slightly enhanced probability of emitting photons in bunches, described by a zero-delay second-order correlation function g((2))(0)=2. Here we explore photon-coincidence counting statistics of thermal cavities in the ultrastrong coupling regime, where the atom-cavity coupling rate becomes comparable to the cavity resonance frequency. We find that, depending on the system temperature and coupling rate, thermal photons escaping the cavity can display very different statistical behaviors, characterized by second-order correlation functions approaching zero or greatly exceeding two. PMID- 23679601 TI - Unconditional quantum-noise suppression via measurement-based quantum feedback. AB - We demonstrate unconditional quantum-noise suppression in a collective spin system via feedback control based on quantum nondemolition measurement. We perform shot-noise limited collective spin measurements on an ensemble of 3.7*10(5) laser-cooled (171)Yb atoms in their spin-1/2 ground states. Correlation between two sequential quantum nondemolition measurements indicates -0.80( 0.12)(+0.11) dB quantum-noise suppression in a conditional manner. Our feedback control successfully converts the conditional quantum-noise suppression into the unconditional one without significant loss of the noise reduction level. PMID- 23679602 TI - Unequivocal differentiation of coherent and chaotic light through interferometric photon correlation measurements. AB - We present a novel experimental technique that can differentiate unequivocally between chaotic light and coherent light with amplitude fluctuations, and thus permits us to characterize unambiguously the output of a laser. This technique consists of measuring the second-order intensity cross correlation at the outputs of an unbalanced Michelson interferometer. It is applied to a chaotic light source and to the output of a semiconductor nanolaser whose "standard" intensity correlation function above threshold displays values compatible with a mixture of coherent and chaotic light. Our experimental results demonstrate that the output of such lasers is not partially chaotic but is indeed a coherent state with amplitude fluctuations. PMID- 23679603 TI - Ultrasensitive two-mode interferometry with single-mode number squeezing. AB - A major challenge of the phase estimation problem is the engineering of high intensity entangled probe states. The goal is to significantly enhance above the shot-noise limit the sensitivity of two-mode interferometers. Here we show that this can be achieved by squeezing in input, and then measuring in output, the population fluctuations of a single mode. The second input mode can be left as an arbitrary nonvacuum (e.g., a bright coherent) state. This two-mode state belongs to a novel class of particle-entangled states which are not spin squeezed. Already a 2.4 db gain above shot noise can be obtained when just a single particle Fock state is injected into the empty input port of a classical interferometer configuration. Higher gains, up to the Heisenberg limit, can be reached with squeezed states of a larger number of particles. We finally study the robustness of this protocol with respect to detection noise. PMID- 23679604 TI - Photon solid phases in driven arrays of nonlinearly coupled cavities. AB - We introduce and study the properties of an array of QED cavities coupled by nonlinear elements, in the presence of photon leakage and driven by a coherent source. The nonlinear couplings lead to photon hopping and to nearest-neighbor Kerr terms. By tuning the system parameters, the steady state of the array can exhibit a photon crystal associated with a periodic modulation of the photon blockade. In some cases, the crystalline ordering may coexist with phase synchronization. The class of cavity arrays we consider can be built with superconducting circuits of existing technology. PMID- 23679605 TI - Oscillatory vertical coupling between a whispering-gallery resonator and a bus waveguide. AB - We report on a theoretical and experimental study of the optical coupling between a whispering-gallery type resonator and a waveguide lying on different planes. In contrast to the usual in-plane geometry, the present vertical one is characterized by an oscillatory behavior of the effective coupling as a function of the vertical gap. This behavior manifests itself as oscillations in both the resonance peak waveguide transmission and the mode quality factor. An analytical description based on coupled-mode theory and a two-port beam-splitter model of the waveguide-resonator vertical coupling is developed for arbitrary phase matching conditions and is successfully used to interpret the experimental observations. PMID- 23679606 TI - Nearly total omnidirectional reflection by a single layer of nanorods. AB - It is shown that a single-layer array of high electric permittivity (high epsilon) rods with a radius smaller than lambda/10 is capable of reflecting more than 97% of the energy of optical waves with an arbitrary incident angle. Here, lambda is the incident wavelength. The occurrence of the phenomenon depends on the construction of two particular grating modes (GMs) in the array which result in two corresponding transmitted wave components that cancel each other. The construction of the dominant GMs in the array benefits from the highly independent manipulability of the angular momenta components with opposite signs in high-epsilon particles. The effect offers the possibility to improve the optical elements integration level in on-chip optical circuits. PMID- 23679608 TI - Anomalously hot electrons due to rescatter of stimulated Raman scattering in the kinetic regime. AB - Using particle-in-cell simulations, we examine hot electron generation from electron plasma waves excited by stimulated Raman scattering and rescattering in the kinetic regime where the wave number times the Debye length (klambda(D)) is >/~0.3 for backscatter. We find that for laser and plasma conditions of possible relevance to experiments at the National Ignition Facility, anomalously energetic electrons can be produced through the interaction of a discrete spectrum of plasma waves generated from stimulated Raman scattering (back and forward scatter), rescatter, and the Langmuir decay of the rescatter-generated plasma waves. Electrons are bootstrapped in energy as they propagate into plasma waves with progressively higher phase velocities. PMID- 23679607 TI - Experimental observation of the spectral gap in microwave n-disk systems. AB - Symmetry reduced three-disk and five-disk systems are studied in a microwave setup. Using harmonic inversion the distribution of the imaginary parts of the resonances is determined. With increasing opening of the systems, a spectral gap is observed for thick as well as for thin repellers and for the latter case it is compared with the known topological pressure bounds. The maxima of the distributions are found to coincide for a large range of the distance to radius parameter with half of the classical escape rate. This confirms theoretical predictions based on rigorous mathematical analysis for the spectral gap and on numerical experiments for the maxima of the distributions. PMID- 23679609 TI - Beaming of high-order harmonics generated from laser-plasma interactions. AB - Beam divergences of high-order extreme ultraviolet harmonics from intense laser interactions with steep plasma density gradients are studied through experiment and Fourier analysis of the harmonic spatial phase. We show that while emission due to the relativistically oscillating mirror mechanism can be explained by ponderomotive surface denting, in agreement with previous results, the divergence of the emission due to the coherent wake emission mechanism requires a combination of the dent phase and an intrinsic emission phase. The temporal dependence of the divergences for both mechanisms is highlighted while it is also shown that the coherent wake emission divergence can be small in circumstances where the phase terms compensate each other. PMID- 23679610 TI - High power wideband gyrotron backward wave oscillator operating towards the terahertz region. AB - Experimental results are presented of the first successful gyrotron backward wave oscillator (gyro-BWO) with continuous frequency tuning near the low-terahertz region. A helically corrugated interaction region was used to allow efficient interaction over a wide frequency band at the second harmonic of the electron cyclotron frequency without parasitic output. The gyro-BWO generated a maximum output power of 12 kW when driven by a 40 kV, 1.5 A, annular-shaped large-orbit electron beam and achieved a frequency tuning band of 88-102.5 GHz by adjusting the cavity magnetic field. The performance of the gyro-BWO is consistent with 3D particle-in-cell numerical simulations. PMID- 23679611 TI - Antiferromagnetic spatial ordering in a quenched one-dimensional spinor gas. AB - We have experimentally observed the emergence of spontaneous antiferromagnetic spatial order in a sodium spinor Bose-Einstein condensate that was quenched through a magnetic phase transition. For negative values of the quadratic Zeeman shift, a gas initially prepared in the F=1, m(F)=0 state collapsed into a dynamically evolving superposition of all three spin projections, m(F)=0, +/-1. The quench gave rise to rich, nonequilibrium behavior where both nematic and magnetic spin waves were generated. We characterized the spatiotemporal evolution through two particle correlations between atoms in each pair of spin states. These revealed dramatic differences between the dynamics of the spin correlations and those of the spin populations. PMID- 23679612 TI - Phase separation in mixtures of repulsive Fermi gases driven by mass difference. AB - We show that phase separation must occur in a mixture of fermions with repulsive interaction if their mass difference is sufficiently large. This phenomenon is highly dimension dependent. Consequently, the density profiles of phase separated 3D mixtures are very different from those in 1D. Noting that the ferromagnetic transition of a spin-1/2 repulsive Fermi gas is the equal mass limit of the phase separation in mixtures, we show from the Bethe ansatz solution that a ferromagnetic transition will take place in the scattering states when the interaction passes through the strongly repulsive regime and becomes attractive. PMID- 23679613 TI - Exact solution for vortex dynamics in temperature quenches of two-dimensional superfluids. AB - An exact analytic solution for the dynamics of vortex pairs is obtained for rapid temperature quenches of a superfluid film starting from the line of critical points below the critical temperature T(KT). An approximate solution for quenches at and above above T(KT) provides insights into the origin of logarithmic transients in the vortex decay, and is in general agreement with recent simulations of the quenched XY model. These results confirm that there is no "creation" of vortices whose density increases with the quench rate as predicted by the Kibble-Zurek theory but only monotonic decay of the thermal vortices already present at the initial temperature. PMID- 23679614 TI - Interferometric approach to measuring band topology in 2D optical lattices. AB - Recently, optical lattices with nonzero Berry's phases of Bloch bands have been realized. New approaches for measuring Berry's phases and topological properties of bands with experimental tools appropriate for ultracold atoms need to be developed. In this Letter, we propose an interferometric method for measuring Berry's phases of two-dimensional Bloch bands. The key idea is to use a combination of Ramsey interference and Bloch oscillations to measure Zak phases, i.e., Berry's phases for closed trajectories corresponding to reciprocal lattice vectors. We demonstrate that this technique can be used to measure the Berry curvature of Bloch bands, the pi Berry's phase of Dirac points, and the first Chern number of topological bands. We discuss several experimentally feasible realizations of this technique, which make it robust against low-frequency magnetic noise. PMID- 23679615 TI - Compositional thresholds and anomalies in connection with stiffness transitions in network glasses. AB - The structural and dynamical properties of amorphous and liquid As(x)Se(1-x) (0.2 oriented chains in the pyrochlore lattice. Comparison of CsW(2)O(6), which has 1 electron per 2 W sites, to the fully d(0) analog CsTaWO(6) shows that the transitions are electronically driven. Corefinement of high resolution synchrotron x-ray and neutron diffraction data shows that the structural distortion that creates the W chains cannot be attributed to simple charge or orbital ordering. Density functional theory calculations suggest that the phase transition is driven by a sharply peaked electronic density of states near the Fermi energy in the cubic beta-pyrochlore phase. A further electronic instability is required to create the insulating ground state. PMID- 23679627 TI - Plasmon mode modifies the elastic response of a nanoscale charge density wave system. AB - The elastic response of suspended NbSe(3) nanowires is studied across the charge density wave phase transition. The nanoscale dimensions of the resonator lead to a large resonant frequency (~10-100 MHz), bringing the excited phonon frequency in close proximity of the plasmon mode of the electronic condensate-a parameter window not accessible in bulk systems. The interaction between the phonon and plasmon modes strongly modifies the elastic properties at high frequencies. This is manifested in the nanomechanics of the system as a sharp peak in the temperature dependence of the elastic modulus (relative change of 12.8%) in the charge density wave phase. PMID- 23679628 TI - Shallow impurity level calculations in semiconductors using ab initio methods. AB - An ab initio method is presented to calculate shallow impurity levels in bulk semiconductors. This method combines the GW calculation for the treatment of the central-cell potential with a potential patching method for large systems (with 64,000 atoms) to describe the impurity state wave functions. The calculated acceptor levels in Si, GaAs, and an isovalent bound state of GaP are in excellent agreement with experiments with a root-mean-square error of 8.4 meV. PMID- 23679629 TI - Extremely slow spin relaxation in a spin-unpolarized quantum Hall system. AB - Cyclotron spin-flip excitation in a nu=2 quantum Hall system, being separated from the ground state by a slightly smaller gap than the cyclotron energy and from upper magnetoplasma excitation by the Coulomb gap [S. Dickmann and I. V. Kukushkin, Phys. Rev. B 71, 241310(R) (2005); L. V. Kulik, I. V. Kukushkin, S. Dickmann, V. E. Kirpichev, A. B. Van'kov, A. L. Parakhonsky, J. H. Smet, K. von Klitzing, and W. Wegscheider, Phys. Rev. B 72, 073304 (2005)] cannot relax in a purely electronic way except only with the emission of a shortwave acoustic phonon (k~3*10(7)/cm). As a result, relaxation in a modern wide-thickness quantum well occurs very slowly. We calculate the characteristic relaxation time to be ~1 s. Extremely slow relaxation should allow the production of a considerable density of zero-momenta cyclotron spin-flip excitations in a very small phase volume, thus forming a highly coherent ensemble-the Bose-Einstein condensate. The condensate state can be controlled by short optical pulses (~1 MUs), switching it on and off. PMID- 23679630 TI - Proposal for direct measurement of topological invariants in optical lattices. AB - We propose an experimental technique for classifying the topology of band structures realized in optical lattices, based on a generalization of topological charge pumping in quantum Hall systems to cold atoms in optical lattices. Time-of flight measurement along one spatial direction combined with in situ detection along the transverse direction provides a direct measure of the system's Chern number, as we illustrate by calculations for the Hofstadter lattice. Based on an analogy with Wannier function techniques of topological band theory, the method is very general and also allows the measurement of other topological invariants, such as the Z(2) topological invariant of time-reversal symmetric insulators. PMID- 23679631 TI - Commensurability of the spin-density-wave state of (TMTSF)2PF6 observed by 13C NMR. AB - A spin-density-wave (SDW) for (TMTSF)(2)PF(6) has been reported to appear below T(SDW) (=/~12 K), with a subphase transition at T* (=/~4 K). To determine the structure of the subphase, we synthesized (TMTSF)(2)PF(6), in which one side of the central carbon bond in each TMTSF molecule was replaced by (13)C, and utilized this compound in (13)C nuclear magnetic resonance measurements. Below T(SDW), the spectrum became broad and T(1)(-1) decreased, in agreement with previous results. Below T*, fine structures emerged in the center of the spectrum and T(1)(-1) decreased exponentially. These phenomena were attributed to the emergence of commensurability at T*. PMID- 23679632 TI - Large temperature dependence of the number of carriers in co-doped BaFe(2)As(2). AB - Using angle-resolved photoemission spectroscopy, we study the evolution of the number of carriers in Ba(Fe(1-x)Co(x))(2)As(2) as a function of Co content and temperature. We show that there is a k-dependent energy shift compared to density functional calculations, which is large below 100 K at low Co contents and reduces the volume of hole and electron pockets by a factor 2. This k shift becomes negligible at high Co content and could be due to interband charge or spin fluctuations. We further reveal that the bands shift with temperature, changing significantly the number of carriers they contain (up to 50%). We explain this evolution by thermal excitations of carriers among the narrow bands, possibly combined with a temperature evolution of the k-dependent fluctuations. PMID- 23679633 TI - Spin density wave fluctuations and p-wave pairing in Sr2RuO4. AB - Recently, a debate has arisen over which of the two distinct parts of the Fermi surface of Sr(2)RuO(4) is the active part for the chiral p-wave superconductivity exhibited. Early theories proposed p-wave pairing on the two-dimensional gamma band, whereas a recent proposal focuses on the one-dimensional (alpha, beta) bands whose nesting pockets are the source of the strong incommensurate spin density wave (SDW) fluctuations. We apply a renormalization group theory to study quasi-one-dimensional repulsive Hubbard chains and explain the form of SDW fluctuations, reconciling the absence of long-range order with their nesting Fermi surface. The mutual exclusion of p-wave pairing and SDW fluctuations in repulsive Hubbard chains favors the assignment of the two-dimensional gamma band as the source of p-wave pairing. PMID- 23679634 TI - Microwave response of superconducting YBa2Cu3O(7-delta) nanowire bridges sustaining the critical depairing current: evidence of Josephson-like behavior. AB - We have investigated the zero-field critical supercurrent of YBa(2)Cu(3)O(7 delta) bridges patterned from 50 nm thick films as a function of bridge width, ranging from 2 MUm to 50 nm. The critical current density monotonically increases for decreasing bridge width even for widths smaller than the Pearl length. This behavior is accounted for by considering current crowding effects at the junction between the bridge and the wider electrodes. Comparison to numerical calculations of the current distributions in our bridge geometries of various widths yields a (local) critical current density at 4.2 K of 1.3*10(8) A/cm(2), the Ginzburg Landau depairing current density. The observation of up to 160 Shapiro-like steps in the current voltage characteristics under microwave irradiation substantiates the pristine character of our nanobridges with cross sections as small as 50*50 nm(2). PMID- 23679635 TI - Creating an artificial two-dimensional Skyrmion crystal by nanopatterning. AB - A Skyrmion crystal typically arises from helical spin structures induced by the Dzyaloshinskii-Moriya interaction. Experimentally its physical exploration has been impeded because it is a rarity and is found only within a narrow temperature and magnetic field range. We present a method for the assembly of a two dimensional Skyrmion crystal based upon a combination of a perpendicularly magnetized film and nanopatterned arrays of magnetic vortices that are geometrically confined within nanodisks. The practical feasibility of the method is validated by micromagnetic simulations and computed Skyrmion number per unit cell. We also quantify a wide range in temperature and field strength over which the Skyrmion crystal can be stabilized without the need for any intrinsic Dzyaloshinskii-Moriya interactions, which otherwise is needed to underpin the arrangement as is the case in the very few known Skyrmion crystal cases. Thus, our suggested scheme involves a qualitative breakthrough that comes with a substantial quantitative advance. PMID- 23679636 TI - Demonstration of quantum entanglement between a single electron spin confined to an InAs quantum dot and a photon. AB - The electron spin state of a singly charged semiconductor quantum dot has been shown to form a suitable single qubit for quantum computing architectures with fast gate times. A key challenge in realizing a useful quantum dot quantum computing architecture lies in demonstrating the ability to scale the system to many qubits. In this Letter, we report an all optical experimental demonstration of quantum entanglement between a single electron spin confined to a single charged semiconductor quantum dot and the polarization state of a photon spontaneously emitted from the quantum dot's excited state. We obtain a lower bound on the fidelity of entanglement of 0.59+/-0.04, which is 84% of the maximum achievable given the timing resolution of available single photon detectors. In future applications, such as measurement-based spin-spin entanglement which does not require sub-nanosecond timing resolution, we estimate that this system would enable near ideal performance. The inferred (usable) entanglement generation rate is 3*10(3) s(-1). This spin-photon entanglement is the first step to a scalable quantum dot quantum computing architecture relying on photon (flying) qubits to mediate entanglement between distant nodes of a quantum dot network. PMID- 23679637 TI - Optically controlled switching of the charge state of a single nitrogen-vacancy center in diamond at cryogenic temperatures. AB - In this Letter, the photoinduced switching of the single nitrogen-vacancy (NV) center between two different charge states, negative (NV(-)) and neutral (NV(0)), is studied under resonant excitation at liquid helium temperature. We show that resonant conversion of NV(0) to NV(-) significantly improves spectral stability of the NV(-) defect and allows high fidelity initialization of the spin qubit. Based on density functional theory calculations a novel mechanism involving an Auger ionization of NV(-) and charge transfer of an electron from the valence band to NV(0) is discussed. This study provides further insight into the charge dynamics of the NV center, which is relevant for quantum information processing based on an NV(-) defect in diamond. PMID- 23679638 TI - Evolution of the domain topology in a ferroelectric. AB - Topological materials, including topological insulators, magnets with Skyrmions and ferroelectrics with topological vortices, have recently attracted phenomenal attention in the materials science community. Complex patterns of ferroelectric domains in hexagonal REMnO(3) (RE: rare earths) turn out to be associated with the macroscopic emergence of Z(2)*Z(3) symmetry. The results of our depth profiling of crystals with a self-poling tendency near surfaces reveal that the partial dislocation (i.e., wall-wall) interaction, not the interaction between vortices and antivortices, is primarily responsible for topological condensation through the macroscopic breaking of the Z(2) symmetry. PMID- 23679641 TI - Nucleation process of a fibril precursor in the C-terminal segment of amyloid beta. AB - By extended atomistic simulations in explicit solvent and bias-exchange metadynamics, we study the aggregation process of 18 chains of the C-terminal segment of amyloid-beta, an intrinsically disordered protein involved in Alzheimer's disease and prone to form fibrils. Starting from a disordered aggregate, we are able to observe the formation of an ordered nucleus rich in beta sheets. The rate limiting step in the nucleation pathway involves crossing a barrier of approximately 40 kcal/mol and is associated with the formation of a very specific interdigitation of the side chains belonging to different sheets. This structural pattern is different from the one observed experimentally in a microcrystal of the same system, indicating that the structure of a "nascent" fibril may differ from the one of an "extended" fibril. PMID- 23679639 TI - Glucose suppresses biological ferroelectricity in aortic elastin. AB - Elastin is an intriguing extracellular matrix protein present in all connective tissues of vertebrates, rendering essential elasticity to connective tissues subjected to repeated physiological stresses. Using piezoresponse force microscopy, we show that the polarity of aortic elastin is switchable by an electrical field, which may be associated with the recently discovered biological ferroelectricity in the aorta. More interestingly, it is discovered that the switching in aortic elastin is largely suppressed by glucose treatment, which appears to freeze the internal asymmetric polar structures of elastin, making it much harder to switch, or suppressing the switching completely. Such loss of ferroelectricity could have important physiological and pathological implications from aging to arteriosclerosis that are closely related to glycation of elastin. PMID- 23679640 TI - Scaling of perceptual errors can predict the shape of neural tuning curves. AB - Weber's law, first characterized in the 19th century, states that errors estimating the magnitude of perceptual stimuli scale linearly with stimulus intensity. This linear relationship is found in most sensory modalities, generalizes to temporal interval estimation, and even applies to some abstract variables. Despite its generality and long experimental history, the neural basis of Weber's law remains unknown. This work presents a simple theory explaining the conditions under which Weber's law can result from neural variability and predicts that the tuning curves of neural populations which adhere to Weber's law will have a log-power form with parameters that depend on spike-count statistics. The prevalence of Weber's law suggests that it might be optimal in some sense. We examine this possibility, using variational calculus, and show that Weber's law is optimal only when observed real-world variables exhibit power-law statistics with a specific exponent. Our theory explains how physiology gives rise to the behaviorally characterized Weber's law and may represent a general governing principle relating perception to neural activity. PMID- 23679642 TI - Patterning of polar active filaments on a tense cylindrical membrane. AB - We study the dynamics and patterning of polar contractile filaments on the surface of a cylindrical cell using active hydrodynamic equations that incorporate couplings between curvature and filament orientation. Cables and rings spontaneously emerge as steady state configurations on the cylinder, and can be stationary or moving, helical or tilted segments moving along helical trajectories. We observe phase transitions in the steady state patterns upon changing cell diameter or motor-driven activity and make several testable predictions. Our results are relevant to the dynamics and patterning of a variety of active biopolymers in cylindrical cells. PMID- 23679644 TI - Coexistence and survival in conservative Lotka-Volterra networks. AB - Analyzing coexistence and survival scenarios of Lotka-Volterra (LV) networks in which the total biomass is conserved is of vital importance for the characterization of long-term dynamics of ecological communities. Here, we introduce a classification scheme for coexistence scenarios in these conservative LV models and quantify the extinction process by employing the Pfaffian of the network's interaction matrix. We illustrate our findings on global stability properties for general systems of four and five species and find a generalized scaling law for the extinction time. PMID- 23679643 TI - Revisiting blob theory for DNA diffusivity in slitlike confinement. AB - Blob theory has been widely applied to describe polymer conformations and dynamics in nanoconfinement. In slit confinement, blob theory predicts a scaling exponent of 2/3 for polymer diffusivity as a function of slit height, yet a large body of experimental studies using DNA produce a scaling exponent significantly less than 2/3. In this work, we develop a theory that predicts that this discrepancy occurs because the segment correlation function for a semiflexible chain such as DNA does not follow the Flory exponent for length scales smaller than the persistence length. We show that these short length scale effects contribute significantly to the scaling for the DNA diffusivity, but do not appreciably affect the scalings for static properties. Our theory is fully supported by Monte Carlo simulations, quantitative agreement with DNA experiments, and the results reconcile this outstanding problem for confined polymers. PMID- 23679645 TI - Boundary information inflow enhances correlation in flocking. AB - The most conspicuous trait of collective animal behavior is the emergence of highly ordered structures. Less obvious to the eye, but perhaps more profound a signature of self-organization, is the presence of long-range spatial correlations. Experimental data on starling flocks in 3D show that the exponent ruling the decay of the velocity correlation function, C(r)~1/r(gamma), is extremely small, gamma<<1. This result can neither be explained by equilibrium field theory nor by off-equilibrium theories and simulations of active systems. Here, by means of numerical simulations and theoretical calculations, we show that a dynamical field applied to the boundary of a set of Heisenberg spins on a 3D lattice gives rise to a vanishing exponent gamma, as in starling flocks. The effect of the dynamical field is to create an information inflow from border to bulk that triggers long-range spin-wave modes, thus giving rise to an anomalously long-ranged correlation. The biological origin of this phenomenon can be either exogenous-information produced by environmental perturbations is transferred from boundary to bulk of the flock-or endogenous-the flock keeps itself in a constant state of dynamical excitation that is beneficial to correlation and collective response. PMID- 23679646 TI - Creep measurements confirm steady flow after stress maximum in extension of branched polymer melts. AB - We provide conclusive evidence of nonmonotonic mechanical behavior in the extension of long-chain branched polymer melts. While nonmonotonic behavior is known to occur for solids, for the case of polymeric melts, this phenomenon is in direct contrast with current theoretical models. We rule out the possibility of the overshoot being an experimental artifact by confirming the existence of steady flow after a maximum in the ratio of stress to strain rate versus strain under both constant stress and constant strain-rate kinematics. This observation indicates the omission of important physics from current models for these industrially important materials, whose processing properties depend on extreme molecular extension. PMID- 23679647 TI - Propulsion efficiency of a dynamic self-assembled helical ribbon. AB - We study the dynamic self-assembly and propulsion of a ribbon formed from paramagnetic colloids in a dynamic magnetic field. The sedimented ribbon assembles due to time averaged dipolar interactions between the beads. The time dependence of the dipolar interactions together with hydrodynamic interactions cause a twisted ribbon conformation. Domain walls of high twist connect domains of nearly constant orientation and negligible twist and travel through the ribbon. The particular form of the domain walls can be controlled via the frequency and the eccentricity of the modulation. The flux of twist walls-a true ribbon property absent in slender bodies-provides the thrust onto the surrounding liquid that propels this biomimetic flagellum into the opposite direction. The propulsion efficiency increases with frequency and ceases abruptly at a critical frequency where the conformation changes discontinuously to a flat standing ribbon conformation. PMID- 23679648 TI - Modeling human dynamics of face-to-face interaction networks. AB - Face-to-face interaction networks describe social interactions in human gatherings, and are the substrate for processes such as epidemic spreading and gossip propagation. The bursty nature of human behavior characterizes many aspects of empirical data, such as the distribution of conversation lengths, of conversations per person, or of interconversation times. Despite several recent attempts, a general theoretical understanding of the global picture emerging from data is still lacking. Here we present a simple model that reproduces quantitatively most of the relevant features of empirical face-to-face interaction networks. The model describes agents that perform a random walk in a two-dimensional space and are characterized by an attractiveness whose effect is to slow down the motion of people around them. The proposed framework sheds light on the dynamics of human interactions and can improve the modeling of dynamical processes taking place on the ensuing dynamical social networks. PMID- 23679649 TI - Causal entropic forces. AB - Recent advances in fields ranging from cosmology to computer science have hinted at a possible deep connection between intelligence and entropy maximization, but no formal physical relationship between them has yet been established. Here, we explicitly propose a first step toward such a relationship in the form of a causal generalization of entropic forces that we find can cause two defining behaviors of the human "cognitive niche"-tool use and social cooperation-to spontaneously emerge in simple physical systems. Our results suggest a potentially general thermodynamic model of adaptive behavior as a nonequilibrium process in open systems. PMID- 23679650 TI - Correlation dimension of complex networks. AB - We propose a new measure to characterize the dimension of complex networks based on the ergodic theory of dynamical systems. This measure is derived from the correlation sum of a trajectory generated by a random walker navigating the network, and extends the classical Grassberger-Procaccia algorithm to the context of complex networks. The method is validated with reliable results for both synthetic networks and real-world networks such as the world air-transportation network or urban networks, and provides a computationally fast way for estimating the dimensionality of networks which only relies on the local information provided by the walkers. PMID- 23679651 TI - Comment on "Well-established nucleon resonances revisited by double-polarization measurements". PMID- 23679654 TI - Retraction: Age-related impairment of visual recognition memory correlates with impaired synaptic distribution of GluA2 and PKMzeta in the dentate gyrus. PMID- 23679652 TI - Thiel et al. reply:. PMID- 23679653 TI - Safety and efficacy of splenectomy in over 65-yrs-old patients with immune thrombocytopenia. AB - AIM: Few studies specifically focus on elderly splenectomized immune thrombocytopenia (ITP) patients. Older patients with ITP and excellent health are often excluded from surgery splenectomy. We aimed to compare the safety and efficacy of splenectomy in elderly and non-elderly ITP patients and to examine the effect of age on therapeutic response. MATERIAL AND METHODS: We carried out a retrospective analysis of a series of 218 patients who had undergone splenectomy for ITP. We compared the data from the elderly group (>=65 yrs, 57 patients) with the young group (<65 yrs, 162 patients). RESULTS: Surgical technique (laparoscopy or open laparotomy splenectomy) was comparable between the two age groups. The adjusted risk of major bleeding following splenectomy for elderly patients was three times that for young patients (OR 3.05, 95% CI: 1.44-6.52). The median duration of postoperative hospital stay was longer for elderly than for young patients (8 d vs. 4 d, P < 0.001). However, we identified a subgroup of elderly ITP patients, those aged between 65 and 70 yrs who had undergone laparoscopic splenectomy, with a low risk of postoperative complications. Of the 218 patients, 89% achieved a favorable response to splenectomy. A favorable response was significantly less common in elderly than in young people (79% vs. 92%, P = 0.005). However, we observed an acceptable long-term control of ITP in the elderly group, in which the probability of maintaining response for 14 yrs after splenectomy was 56%. CONCLUSIONS: Patients aged >=65 yrs experienced negative effects on safety and efficacy outcomes of splenectomy for ITP, but further studies are needed to identify predictors of postsplenectomy outcomes in this group. PMID- 23679655 TI - British pharmacists' work-life balance - is it a problem? AB - OBJECTIVES: Using a validated tool, the study aimed to explore pharmacists' experiences of maintaining work/life balance in a large, nationally representative sample of pharmacists in Great Britain (GB). METHODS: A two-page postal questionnaire was sent in 2008 to all GB-domiciled pharmacists who were registered with the regulatory body for pharmacy in GB (just over 44 000 pharmacists). Demographic information, work patterns and other employment data were collected and analysed using regression techniques to explore the link between these characteristics and a validated measure of work/life balance. KEY FINDINGS: The response rate to the census was 69.6% (n = 30 517). Eighty-three per cent (n = 25 243) of respondents were working as a pharmacist and were therefore eligible to complete the work/life balance statements. The results reported here relate to 12 364 individuals who had full data for the work/life balance scale and the demographic and work variables. Findings indicate that age, ethnicity, having caring responsibilities, sector of practice, hours of work and type of job are significant predictors of work/life balance problems. CONCLUSIONS: Pharmacy employers and government should recognise the changing demographic characteristics of the profession and consider what support might be available to the workforce to help alleviate work/life balance problems being experienced by certain groups of pharmacists. PMID- 23679656 TI - Peyronie's disease among men who have sex with men: characteristics, treatment, and psychosocial factors. AB - INTRODUCTION: We describe the characteristics of Peyronie's disease (PD) and its associated psychosocial implications in men who have sex with men (MSM). AIM: The aims of this article are to identify presenting characteristics and treatment for MSM with PD, compare these findings to non-MSM PD patients, and determine the psychosocial impact of PD among MSM. MAIN OUTCOME MEASURES: Subjective and objective presenting characteristics, MSM psychosocial factors. METHODS: We identified 27 MSM with PD presenting from 2000 to 2012 through a retrospective chart review. A random selection of 200 non-MSM PD patients was identified, who presented during the same time period. A prospective nonvalidated questionnaire was given to MSM PD patients for evaluation of psychosocial constructs. RESULTS: A traumatic event leading to activation of PD was identified equally among MSM and non-MSM (P = 0.815). Most common recognized activators of PD among MSM were: penetrative sexual intercourse (22.2%), self-stimulation (11.1%). More MSM presented with the primary complaint of penile deformity, including narrowing, indentation, hourglass, and hinge (11.1% MSM vs. 1.0% non-MSM, P = 0.01). No differences in total curvature, erection grade were found (P > 0.05). PD had a negative effect on emotional status (89.0% MSM, 80.5% non-MSM, P > 0.05) and intimate relationships (45.0% MSM, 64.0% non-MSM, P > 0.05). Nonsurgical treatment was given to 88.9% MSM and 76.5% non-MSM (P > 0.05), and corrective surgery in 29.6% MSM and 25.0% non-MSM (P > 0.05). Of the 75.0% of MSM engaging in anal sex, 41.7% reported penetrative anal intercourse as the activator of PD. Among MSM, 31.3% experienced decreased libido, 50.0% decreased frequency of sexual activity, 92.9% were self-conscious about the appearance of their penis, and 92.9% were dissatisfied with the size of their penis. CONCLUSIONS: Few differences exist in the clinical presentation and treatments used between MSM and non-MSM PD patients. There was evidence of emotional distress in both groups. As a result, psychosexual assessment and treatment, when indicated, should be considered essential to the patient presenting with PD. PMID- 23679657 TI - Investigating deaf students' knowledge of Persian syntax: further evidence for a critical period hypothesis. AB - The present study aims to investigate syntactic deficits in 13 Iranian deaf students aged between 17 and 21 years. Four tests in the form of sentence recognition and sentence-completion were administered to examine their knowledge of verb inflection, derivational morphology, word order, and prepositions. A between-category analysis of errors indicated a significant dissociation between categories, most notably between verb inflection and derivational morphology and between word order as the category with fewest errors and the three others. On theoretical grounds, the fact that subjects have not acquired much syntax even after years of learning seemed to strengthen the significance of acquiring syntax and morphology in the early years. PMID- 23679658 TI - A comparative study on dinuclear and multinuclear Ni(II), Pd(II), and Pt(II) complexes of a thiolato-functionalized, benzannulated N-heterocyclic carbene ligand. AB - Dimeric thiolato-bridged Ni(II) and Pt(II) NHC complexes 2 and 4 have been synthesized from ligand precursor A through a combined and in situ deprotonation/hydrolysis protocol of a thioester-functionalized benzimidazolium salt in the presence of the respective metal salts. Reactivity studies of 2 and 4, and their previously reported Pd(II) analogue 1a toward either Me3OBF4, NaOH, or Na2S.9H2O revealed clear differences. Complex 2 decomposed when treated with Me3OBF4. On the other hand, its reaction with aqueous NaOH solution in the presence of NaBF4 yielded trinuclear [Ni3S3O] complex 6, which possesses an interesting [Ni3S3] triangle with a capping MU3-oxido ligand. Pt(II) analogue 4 was converted to the tetranuclear [Pt4S4] macrocycle 5 when treated with Me3OBF4, in analogy to the result from 1a, while no defined products could be isolated when 4 was treated with either NaOH or Na2S.9H2O. Pd(II) analogue 1a reacted with Na2S.9H2O to give the tripalladium [Pd3S3S] complex 7 bearing a capping MU3 sulfido ligand. PMID- 23679659 TI - Who transitions to the community from nursing homes? Comparing patterns and predictors for short-stay and long-stay residents. AB - Little is known about characteristics of those who transition to the community after long stays in nursing facilities. Yet this information is highly relevant to efforts to reduce preventable nursing facility use. This study identifies and compares community transition among short-stay (1-90 days) and long-stay residents (91-365 days) aged 65 + using Kaplan-Meier survival estimates and logistic regression to analyze 3,762 episodes of care in Southern California. Over 90% of community discharges occurred in the first 90 days, and few characteristics predicted discharge after 90 days. The findings inform transition programs' efforts to identify and effectively target residents after 90-day stays. PMID- 23679660 TI - Comparing patient and provider perceptions of home- and community-based services: social network analysis as a service integration metric. AB - Integrated home- and community-based services (HCBS) for frail seniors require a unique style of teamwork and collaboration. In four case studies, patient perceptions of teamwork and collaboration among their HCBS care providers are compared with those of the providers themselves using network analysis. The degree of coherence between these perceived networks are examined using network analytics, and network visualizations are discussed. The value of network analysis in research on HCBS is considered. PMID- 23679661 TI - Factors associated with the utilization of maternal health care services among adolescent women in Malawi. AB - The poor maternal health care service utilization among adolescent women remains an intimidating challenge in Malawi. This study examines the factors associated with the utilization of selected maternal health care services among married adolescent women (aged 15-19 years) using data from the Malawi Demographic and Health Survey, 2010. Maternal age, household economic status, and status of the child were found to be significant factors associated with at least four antenatal care visits; whereas personal barriers, birth order and interval, religion, and ethnic group explain the variation in the utilization of postnatal care within 42 days of delivery. PMID- 23679662 TI - Home care safety markers: a scoping review. AB - Safety in home care is a new research frontier, and one in which demand for services continues to rise. A scoping review of the home care literature on chronic obstructive pulmonary disease and congestive heart failure was thus completed to identify safety markers that could serve to develop our understanding of safety in this sector. Results generated seven safety markers: (a) Home alone; (b) A fixed agenda in a foreign language; (c) Strangers in the home; (d) The butcher, the baker, the candlestick maker; (e) Medication mania; (f) Out of pocket: The cost of caring at home; and (g) My health for yours: Declining caregiver health. PMID- 23679663 TI - Behavioral and neurochemical changes in the zebrafish leopard strain. AB - The zebrafish leopard phenotype (leo) displays abnormal pigmentation and shows increased anxiety-like behavior. The neurochemical changes associated with this anxious phenotype are not known. Here, we demonstrate that leo show increased anxiety-like behavior in the light/dark box and in the novel tank test. This anxious phenotype is rescued by acute treatment with a dose of a serotonin reuptake inhibitor, fluoxetine, that is inactive in wild-type animals. Moreover, leo show decreased tissue levels of serotonin, increased serotonin turnover and slightly increased monoamine oxidase activity. These results suggest that the anxious phenotype observed in leo zebrafish is caused by a decrease in serotonin uptake. This work could open an important avenue in defining the neurochemical underpinning of natural variation in anxiety disorders. PMID- 23679664 TI - Phase I study of highly selective inhibitor of VEGFR tyrosine kinase, tivozanib, in Japanese patients with solid tumors. AB - Tivozanib is a potent and selective inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases. A previous clinical trial in the EU and USA indicated that tivozanib at the maximum tolerated dose of 1.5 mg/day showed an antitumor activity in patients with renal cell carcinoma. This Japanese phase I study was designed to determine the recommended phase II dose of tivozanib for Japanese patients; secondary objectives included pharmacokinetic/pharmacodynamic profiles and preliminary efficacy. Daily treatment with tivozanib in a 3-weeks on/1-week-off cycle was examined in nine Japanese patients with advanced solid tumors in the 3 + 3 design (Level 1, 1.0 mg; Level 2, 1.5 mg). No dose-limiting toxicity was observed throughout the study, and the maximum tolerated dose was not reached. The most commonly observed drug-related adverse events were diarrhea, dysphonia, rash, thyroid stimulating hormone increase, and with severity grade >=3, hand-foot skin reaction, hypertension, and proteinuria. Those adverse events were generally well-manageable and mostly resolved within the tolerability evaluation period. Serum exposure to tivozanib resulted in t1/2 of more than >60 h. Increase of plasma VEGF and decrease of plasma VEGFR-1 and VEGFR 2 were observed 1-3 weeks after tivozanib treatment. Although no complete or partial response was observed, long-term stable disease continuing more than 170 days was observed in three renal cell carcinoma patients who had failed prior VEGFR inhibitors. In conclusion, 1.5 mg/day of tivozanib in a 3-weeks-on/1-week off setting was tolerable in Japanese patients, and was recommended for further clinical trials in the Japanese population. Clinical trial Registration No: JapicCTI-090854. PMID- 23679665 TI - Effect of lipopolysaccharide administration on the number, phenotype and content of nuclear molecules in blood microparticles of normal human subjects. AB - Microparticles (MPs) are small membrane-bound vesicles that arise from activated and dying cells and promote inflammation and thrombosis. To characterize the in vivo release of MPs, we used flow cytometry to measure MPs in the blood of 15 healthy volunteers administered bacterial endotoxin (lipopolysaccharide or LPS) in the presence of a low dose of hydrocortisone with or without inhaled nitric oxide. MPs, defined as particles less than 1.0 MUm in size, were assessed following labelling for CD42a, CD14 and CD62E or CD144 antibodies to identify MPs from platelets (PMPs), monocytes (MMPs) and endothelial cells (EMPs). In addition, PMPs and MMPs were labelled with anti-HMGB1 and stained with SYTO13 to assess nuclear acid content. Administration of LPS led to an increase in the numbers of PMPs, MMPs and EMPs as defined by CD62E, as well as the number of MMPs and PMPs staining with anti-HMGB1 and SYTO13. Inhalation of NO did not influence these findings. Together, these studies show that LPS can increase levels of blood MPs and influence phenotype, including nuclear content. As such, particles may be a source of HMGB1 and other nuclear molecules in the blood during inflammation. PMID- 23679666 TI - Low phosphorus status might contribute to the onset of obesity. AB - Overweight and obesity are becoming global health problems. Although genetics certainly plays a role, weight gain is ultimately the result of a failure in the balance between energy expenditure and energy intake. Obesity during the past few decades was paralleled with several changes in dietary habits favouring low phosphorus consumption. This is believed to compromise adenosine triphosphate (ATP) production that is involved in the regulation of energy metabolism. Ingestion of high-carbohydrate-low phosphorus food is known to increase insulin release, to simultaneously stimulate peripheral uptake of phosphorus and the phosphorylation of many compounds. This creates a competition for phosphorus that compromises its availability for ATP production, possibly translated into low diet-induced thermogenesis. Moreover, reduced hepatic ATP production is believed to be transmitted through neural afferents to the central nervous system, resulting in an increase in food intake. On the other hand, the positive relation between phosphorus and red blood cell 2,3-diphosphoglycerate, which reduces oxygen affinity to haemoglobin, would be expected to reduce the capacity for physical activity. In line with that, plasma phosphorus status was reported to be inversely related to body weight. Adequate intakes of phosphorus are thus potentially protective against rising obesity epidemic across the globe. PMID- 23679667 TI - The integration of occupational therapy into primary care: a multiple case study design. AB - BACKGROUND: For over two decades occupational therapists have been encouraged to enhance their roles within primary care and focus on health promotion and prevention activities. While there is a clear fit between occupational therapy and primary care, there have been few practice examples, despite a growing body of evidence to support the role. In 2010, the province of Ontario, Canada provided funding to include occupational therapists as members of Family Health Teams, an interprofessional model of primary care. The integration of occupational therapists into this model of primary care is one of the first large scale initiatives of its kind in North America. The objective of the study was to examine how occupational therapy services are being integrated into primary care teams and understand the structures supporting the integration. METHODS: A multiple case study design was used to provide an in-depth description of the integration of occupational therapy. Four Family Health Teams with occupational therapists as part of the team were identified. Data collection included in-depth interviews, document analyses, and questionnaires. RESULTS: Each Family Health Team had a unique organizational structure that contributed to the integration of occupational therapy. Communication, trust and understanding of occupational therapy were key elements in the integration of occupational therapy into Family Health Teams, and were supported by a number of strategies including co-location, electronic medical records and team meetings. An understanding of occupational therapy was critical for integration into the team and physicians were less likely to understand the occupational therapy role than other health providers. CONCLUSION: With an increased emphasis on interprofessional primary care, new professions will be integrated into primary healthcare teams. The study found that explicit strategies and structures are required to facilitate the integration of a new professional group. An understanding of professional roles, trust and communication are foundations for interprofessional collaborative practice. PMID- 23679668 TI - N-octyl-N-arginine-chitosan (OACS) micelles for gambogic acid oral delivery: preparation, characterization and its study on in situ intestinal perfusion. AB - CONTEXT: Gambogic acid (GA) can inhibit the growth of various cancer cells. However, the low bioavailability caused by insolubility, limits its clinical application. L-arginine is always used with GA to form a complex to obtain the higher solubility. Moreover, guanidyl group from arginine, which can facilitate the cellular uptake, was identified. OBJECTIVE: In this study, L-arginine and chitosan (CS) were used for the first time to prepare N-octyl-N-arginine CS (OACS), a novel amphiphilic carrier for GA with solubility- and absorption enhancing functions; the characterization of the GA loaded OACS micelles (GA OACS) and its absorption-enhancing effect were also investigated. MATERIALS AND METHODS: GA-OACS were prepared by the dialysis method. The formed micelles were characterized and evaluated by atomic force microscope (AFM), dynamic light scattering, differential scanning calorimeter (DSC), solubility test, in vitro release and in situ intestinal perfusion. RESULTS: The GA-OACS micelles were successfully prepared attaining a 35.3% drug loading and 82.2% entrapment efficiency. GA-OACS had a homogeneous particle size of 160.3 nm; +21.8 mv zeta potential with smooth continuous surface was observed by using AFM. DSC diagram suggested that GA was encapsulated in the micelles. Meanwhile, GA encapsulated in micelles exhibited a desirable slow release in vitro experiment. The solubility of GA in OACS micelles was increased up to 3.16 +/- 0.13 mg/mL, 2320 times than that of free GA. The single pass perfusion showed that the absorption of GA-OACS micelles was enhanced 3.6-fold, 2.1-fold and 2.2-fold for jejunum, ileum and colon, respectively. DISCUSSION AND CONCLUSION: OACS provided excellent ability of drug loading, increasing solubility and enhanced absorption for GA, which indicated that OACS micelles as an oral drug delivery carrier may have potential research and application values. PMID- 23679669 TI - Hyperglycemia as a risk factor for the development of retinopathy of prematurity. AB - BACKGROUND: Hyperglycemia has recently been described as a risk factor for the development of retinopathy of prematurity (ROP), a proliferative vascular disease of the retina that primarily affects premature infants. This study was to evaluate the relationship of hyperglycemia and the development of ROP in premature infants less than 32 weeks gestation. METHODS: This was a retrospective cohort study of all infants less than 32 weeks gestation from 2003-2007 who survived to discharge in our NICU. Demographic data including birthweight, gestational age, Apgar scores, method of delivery, antenatal steroid use, neonatal steroid use, and size for gestational age was collected for each infant. Episodes of sepsis, grade of intraventricular hemorrhage, presence of a patent ductus arteriosus, number of days on the ventilator, and stage of necrotizing enterocolitis were assessed as well as days of hyperglycemia, defined as number of days with whole blood glucose > 150 mg/dl. In addition, the highest stage of ROP was recorded for each infant. A Student's two tailed t-test or Fisher's exact test was performed to identify significant clinical risk factors associated with the development of ROP. From this univariate analysis, a multiple logistic regression was performed to determine the effect of hyperglycemia on the development of ROP, adjusting for significant clinical risk factors. Statistical analysis was performed using SAS v.9.2. RESULTS: Univariate analysis demonstrated that infants with ROP were of lower birthweight and gestational age, and were affected by a patent ductus arteriosus, neonatal sepsis, intraventricular hemorrhage, have significant lung disease and received postnatal glucocorticoid therapy. Infants with ROP experienced more days with hyperglycemia (7 vs. 2, p = < 0.0001). Using multiple logistic regression analysis to compare no ROP vs. all stages of ROP, gestational age (OR 0.745, 95% CI [0.634, 0.877], p = 0.0004), mean days of hyperglycemia (OR 1.073, 95% CI [1.004, 1.146], p = 0.04), and mean days receiving mechanical ventilation (OR 1.012, 95% CI [1.000, 1.025], p = 0.05) remained significantly associated with ROP after adjusting for other risk factors. CONCLUSION: Our data suggests that hyperglycemia is associated with the development of ROP in premature infants. PMID- 23679670 TI - An inter-institutional collaboration: transforming education through interprofessional simulations. AB - An inter-institutional partnership of four post-secondary institutions and a health provider formed a learning community with the goal of developing, implementing and evaluating interprofessional learning experiences in simulation based environments. The organization, education and educational research activities of the learning community align with the institutional and instructional reforms recommended by the Lancet Commission on Health Professional Education for the 21st century. This article provides an overview of the inter institutional collaboration, including the interprofessional simulation learning experiences, instructor development activities and preliminary results from the evaluation. PMID- 23679671 TI - The development of student-led interprofessional education and collaboration. AB - Prominent healthcare organizations have called upon the academic and health communities to utilize interprofessional education (IPE) and collaboration to meet the changing needs of patients worldwide. Two student-led initiatives have overcome the various barriers that have historically impeded IPE and have embraced the call to improve the health of local and international underserved patients. This short report describes these two organizations, the International Health Service Collaborative at the University of South Florida and the Inter Health Professionals Alliance at Virginia Commonwealth University, and aims to encourage emerging health professional students and educators to embrace student led IPE. PMID- 23679672 TI - Shared decision-making and interprofessional collaboration in mental healthcare: a qualitative study exploring perceptions of barriers and facilitators. AB - Shared decision-making and interprofessional collaboration are important approaches to achieving consumer-centered care. The concept of shared decision making has been expanded recently to include the interprofessional healthcare team. This study explored healthcare providers' perceptions of barriers and facilitators to both shared decision-making and interprofessional collaboration in mental healthcare. Semi-structured interviews were conducted with 31 healthcare providers, including medical practitioners (psychiatrists, general practitioners), pharmacists, nurses, occupational therapists, psychologists and social workers. Healthcare providers identified several factors as barriers to, and facilitators of shared decision-making that could be categorized into three major themes: factors associated with mental health consumers, factors associated with healthcare providers and factors associated with healthcare service delivery. Consumers' lack of competence to participate was frequently perceived by mental health specialty providers to be a primary barrier to shared decision making, while information provision on illness and treatment to consumers was cited by healthcare providers from all professions to be an important facilitator of shared decision-making. Whilst healthcare providers perceived interprofessional collaboration to be influenced by healthcare provider, environmental and systemic factors, emphasis of the factors differed among healthcare providers. To facilitate interprofessional collaboration, mental health specialty providers emphasized the importance of improving mental health expertise among general practitioners and community pharmacists, whereas general health providers were of the opinion that information sharing between providers and healthcare settings was the key. The findings of this study suggest that changes may be necessary at several levels (i.e. consumer, provider and environment) to implement effective shared decision-making and interprofessional collaboration in mental healthcare. PMID- 23679673 TI - Effects of a graduate-level interprofessional education program on adult nurse practitioner student and internal medicine resident physician attitudes towards interprofessional care. AB - This article describes the development, implementation and evaluation of a longitudinal interprofessional education (IPE) experience for adult nurse practitioner students and internal medicine residents. This experience focused on providing care for complex community based patients during clinic and home visits, preceded by didactic learning that emphasized understanding one another's professional roles and education, teamwork and conflict management. Evaluation demonstrated significant improvements in attitudes and beliefs associated with professional role, respect among health professions' disciplines and conflict management. Results with regards to attitudes towards IPE and interprofessional practice, and valuing teamwork training were mixed. In particular, the curricular intervention did not change participants'self-reported skill in communication and did not affect attitudes and beliefs towards effects of interprofessional education on patient outcomes. PMID- 23679674 TI - Perceived impact of an interprofessional education program on community resilience: an exploratory study. AB - The purpose of this study was to explore the perceived impact of an interprofessional education (IPE) program for health sciences students on two culturally diverse, underserved communities. A community resilience/capacity framework, consisting of catalysts (primarily the creation of awareness) and capital components: human (workforce development), social (networking and empowerment) and economic (volunteer labor and money spent by the program), provided the conceptual underpinnings for the study. Focus groups with stakeholders in two communities, one rural and one metropolitan, were audio recorded, transcribed and analyzed by categorizing data according to each capital component. In addition to the concepts contained in the capacity framework a new category, informational capital (data specific to the community) emerged during the analysis. We suggest that by acting as a catalyst a community based interprofessional program can affect components of community resilience/capacity, primarily human, social, and informational capital. Using the community resilience/capacity framework facilitated exploration of the perceived impact of an educational program on one rural and one urban underserved community beyond assessing student outcomes or number of clients served. PMID- 23679675 TI - Evaluation of perceived collaborative behaviour amongst stakeholders and clinicians of a continuing education programme in arthritis care. AB - Successful implementation of new extended practice roles which transcend conventional boundaries of practice entails strong collaboration with other healthcare providers. This study describes interprofessional collaborative behaviour perceived by advanced clinician practitioner in arthritis care (ACPAC) graduates at 1 year beyond training, and relevant stakeholders, across urban, community and remote clinical settings in Canada. A mixed-method approach involved a quantitative (survey) and qualitative (focus group/interview) evaluation issued across a 4-month period. ACPAC graduates work across heterogeneous settings and are on teams of diverse size and composition. Seventy per cent perceived their team as actively working in an interprofessional care model. Mean scores on the Bruyere Clinical Team Self-Assessment on Interprofessional Practice subjective subscales were high (range: 3.66-4.26, scale: 1-5 = better perception of team's interprofessional practice), whereas the objective scale was lower (mean: 4.6, scale: 0-9 = more interprofessional team practices). Data from focus groups (ACPAC graduates) and interviews (stakeholders) provided further illumination of these results at individual, group and system levels. Issues relating to ACPAC graduate role recognition, as well as their deployment, integration and institutional support, including access to medical directives, limitation of scope of practice, remuneration conflicts and tenuous funding arrangements were barriers perceived to affect role implementation and interprofessional working. This study offers the opportunity to reflect on newly introduced roles for health professionals with expectations of collaboration that will challenge traditional healthcare delivery. PMID- 23679676 TI - Praxis and reflexivity for interprofessional education: towards an inclusive theoretical framework for learning. AB - While there is growing evidence of theoretical perspectives adopted in interprofessional education, learning theories tend to foreground the individual, focusing on psycho-social aspects of individual differences and professional identity to the detriment of considering social-structural factors at work in social practices. Conversely socially situated practice is criticised for being context-specific, making it difficult to draw generalisable conclusions for improving interprofessional education. This article builds on a theoretical framework derived from earlier research, drawing on the dynamics of Dewey's experiential learning theory and Archer's critical realist social theory, to make a case for a meta-theoretical framework enabling social-constructivist and situated learning theories to be interlinked and integrated through praxis and reflexivity. Our current analysis is grounded in an interprofessional curriculum initiative mediated by a virtual community peopled by health and social care users. Student perceptions, captured through quantitative and qualitative data, suggest three major disruptive themes, creating opportunities for congruence and disjuncture and generating a model of zones of interlinked praxis associated with professional differences and identity, pedagogic strategies and technology mediated approaches. This model contributes to a framework for understanding the complexity of interprofessional learning and offers bridges between individual and structural factors for engaging with the enablements and constraints at work in communities of practice and networks for interprofessional education. PMID- 23679677 TI - Designing for competence: spaces that enhance collaboration readiness in healthcare. AB - Many universities in the United States are investing in classrooms and campuses designed to increase collaboration and teamwork among the health professions. To date, we know little about whether these learning spaces are having the intended impact on student performance. Recent advances in the identification of interprofessional teamwork competencies provide a much-needed step toward a defined outcome metric. Rigorous study of the relationship between design and student competence in collaboration also requires clear specification of design concepts and development of testable frameworks. Such theory-based evaluation is crucial for design to become an integral part of interprofessional education strategies and initiatives. Current classroom and campus designs were analyzed for common themes and features in collaborative spaces as a starting place for specification of design concepts and model development. Four major themes were identified: flexibility, visual transparency/proximity, technology and environmental infrastructure. Potential models linking this preliminary set of design concepts to student competencies are proposed and used to generate hypotheses for future study of the impact of collaborative design spaces on student outcomes. PMID- 23679678 TI - Rapid dye adsorption via surface modification of TiO2 photoanodes for dye sensitized solar cells. AB - A facile method for increasing the reaction rate of dye adsorption, which is the most time-consuming step in the production of dye-sensitized solar cells (DSSCs), was developed. Treatment of a TiO2 photoanode with aqueous nitric acid solution (pH 1) remarkably reduced the reaction time required to anchor a carboxylate anion of the dye onto the TiO2 nanoparticle surface. After optimization of the reaction conditions, the dye adsorption process became 18 times faster than that of the conventional adsorption method. We studied the influence of the nitric acid treatment on the properties of TiO2 nanostructures, binding modes of the dye, and adsorption kinetics, and found that the reaction rate improved via the synergistic effects of the following: (1) electrostatic attraction between the positively charged TiO2 surface and ruthenium anion increases the collision frequency between the adsorbent and the anchoring group of the dye; (2) the weak anchoring affinity of NO3(-) in nitric acid with metal oxides enables the rapid coordination of an anionic dye with the metal oxide; and (3) sufficient acidity of the nitric acid solution effectively increases the positive charge density on the TiO2 surface without degrading or transforming the TiO2 nanostructure. These results demonstrate the developed method is effective for reducing the overall fabrication time without sacrificing the performance and long-term stability of DSSCs. PMID- 23679679 TI - Acute and chronic nicotine effects on behaviour and brain activation during intertemporal decision making. AB - Previous studies demonstrated higher discount rates for delayed rewards in smokers than non-smokers. We performed this study to determine whether those differences in intertemporal choice are due to pharmacological effects of nicotine and to track related brain regions. Thirty-three non-smokers and 27 nicotine-dependent smokers underwent functional magnetic resonance imaging while performing an intertemporal choice task consisting of 40 sets of monetary reward options that varied by delay to delivery. Smokers were investigated in a state of nicotine satiation. Non-smokers were investigated twice, receiving nicotine (2 mg) and placebo gums in a double-blinded, randomized cross-over design. Smokers displayed steeper temporal discounting than non-smokers. Those behavioural differences were reflected in the brain response during the decision between two alternative money/time pairs: smokers showed less activation in parietal and occipital areas (e.g. precuneus) than non-smokers under placebo. A single dose of nicotine in non-smokers led to a similar effect on brain activation but did not impact behaviour. Processing of the reward magnitude of money/time pairs differed between smokers and non-smokers: smokers showed decreased reactivity of the ventral striatum. Moreover, there was an acute nicotine effect in non-smokers on processing of the reward magnitude: nicotine increased the correlation of blood oxygen level-dependent response and mean amount in the left hippocampus, amygdala and anterior insula. We conclude that cross-sectional differences between smokers and non-smokers are only, in part, due to the acute pharmacological effects of nicotine. Longitudinal studies are needed to investigate pre-drug group characteristics as well as consequences of smoking on discounting behaviour and its neural correlates. PMID- 23679680 TI - Investigation into the prevalence, persistence and antibiotic resistance profiles of staphylococci isolated from euro currency. AB - AIMS: The study set out to sample ? 10 banknotes for the presence of coagulase positive staphylococci (CPS) such as Staphylococcus aureus (S. aureus) and coagulase-negative staphylococci (CoNS) in Southern Ireland, to assess the levels of antibiotic resistance among those isolated, and determine the persistence of S. aureus on ? 10 banknotes and ? 2 coins. METHODS AND RESULTS: We report that 97% of ? 10 banknotes screened (n = 155) harboured multiple species of staphylococci. From the generated bank of strains, a total of 150 representative staphylococci isolates were used for further study, 71 were CPS and 79 were CoNS. Of these, we found that 62% of the staphylococci demonstrated resistance to at least one of the first-line antibiotics (52.11% of CPS isolates and 76.71% of the CoNS isolates). Resistance to multiple antibiotics was seen in 31.18% of the resistant isolates. In relation to persistence studies, S. aureus was shown to remain viable on euro banknotes and coins for significant periods (on average, 19.33 days on ? 10 banknotes and 16.67 days on ? 2 coins) as determined using bioluminescence. CONCLUSIONS: We advocate the expansion of antibiotic surveillance programs, with a view to tracking/monitoring antibiotic resistance dissemination among environmental contaminants. Additionally, we propose that 'cashless transactions' should be encouraged in high-risk environments such as hospitals and healthcare settings, as well as stricter infection controls. SIGNIFICANCE AND IMPACT OF THE STUDY: Although it is accepted that circulating currency has the potential to harbour disease-causing pathogens, studies investigating prevalence and persistence of such pathogens on euro currency are virtually nonexistent. In an attempt to rectify this, we examined the prevalence of staphylococci on ? 10 banknotes in Ireland and reported relatively high levels of antibiotic resistance among the isolates. Furthermore, we have established the persistence of S. aureus on euro currency for the first time. PMID- 23679681 TI - Melatonin overcomes apoptosis resistance in human hepatocellular carcinoma by targeting survivin and XIAP. AB - Apoptosis resistance in hepatocellular carcinoma (HCC) is one of the most significant factors for hepatocarcinogenesis and tumor progression, and leads to resistance to conventional chemotherapy. It is well known that inhibitor of apoptosis proteins (IAPs) play key roles in apoptosis resistance, it has become an important target for antitumor therapy. In this study, we examined if melatonin, the main secretory product of the pineal gland, targeted IAPs, leading to the inhibition of apoptosis resistance. To accomplish this, we first observed that four members of IAPs (cIAP-1, cIAP-2, survivin, and XIAP) were overexpressed in human HCC tissue. Interestingly, melatonin significantly inhibited the growth of HepG2 and SMMC-7721 cells and promoted apoptosis along with the downregulation of survivin and XIAP, but had no effect on the expression of cIAP-1 and cIAP-2. These data suggest that the inhibition of survivin and XIAP by melatonin may play an important part in reversing apoptosis resistance. Notably, cIAP-1, survivin and XIAP were significantly associated with the coexpression of COX-2 in human HCC specimens. Melatonin also reduced the expression of COX-2 and inhibited AKT activation in HepG2 and SMMC-7721 cells. Inhibition of COX-2 activity with the selective inhibitor, NS398, and inhibition of AKT activation using the PI3K inhibitor, LY294002, in tumor cells confirmed that melatonin-induced apoptosis was COX-2/PI3K/AKT-dependent, suggesting that the COX-2/PI3K/AKT pathway plays a role in melatonin inhibition of IAPs. Taken together, these results suggest that melatonin overcomes apoptosis resistance by the suppressing survivin and XIAP via the COX-2/PI3K/AKT pathway in HCC cells. PMID- 23679682 TI - Clinical experience and psychometric properties of the Children's Dermatology Life Quality Index (CDLQI), 1995-2012. AB - The Children's Dermatology Life Quality Index (CDLQI) is a widely used questionnaire to measure the quality of life of children aged from 4 to 16 years. The purpose of this review is to summarize all published data regarding the clinical experience of the CDLQI and its psychometric properties as a single reference source for potential users. A literature search was carried out to identify all articles describing the use of the CDLQI from 1995 to November 2012. One hundred and six articles were identified, with four excluded. The CDLQI has been used in 28 countries in 102 clinical studies and is available in 44 languages, including six cultural adaptations; a cartoon version is available in 10 languages. It has been used in 14 skin conditions and used in the assessment of 11 topical drugs, nine systemic drugs, 13 therapeutic interventions and two epidemiological and other studies. There is evidence of high internal consistency, test-retest reliability, responsiveness to change, and significant correlation with other subjective and objective measures. Rasch analysis has not been carried out and more information is needed concerning minimal clinically important difference; these are areas requiring further study. PMID- 23679683 TI - Nonadiabatic dynamics of positive charge during photocatalytic water splitting on GaN(10-10) surface: charge localization governs splitting efficiency. AB - Photochemical water splitting is a promising avenue to sustainable, clean energy and fuel production. Gallium nitride (GaN) and its solid solutions are excellent photocatalytic materials; however, the efficiency of the process is low on pure GaN, and cocatalysts are required to increase the yields. We present the first time-domain theoretical study of the initial steps of photocatalytic water splitting on a GaN surface. Our state-of-the-art simulation technique, combining nonadiabatic molecular dynamics and time-dependent density functional theory, allows us to characterize the mechanisms and time scales of the evolution of the photogenerated positive charge (hole) and the subsequent proton transfer at the GaN/water interface. The calculations show that the hole loses its excess energy within 100 fs and localizes primarily on the nitrogen atoms of the GaN surface, initiating a sequence of proton-transfer events from the surface N-H group to the nearby OH groups and bulk water molecules. Water splitting requires hole localization on oxygen rather than nitrogen, necessitating nonadiabatic transitions uphill in energy on pure GaN. Such transitions happen rarely, resulting in low yields of the photocatalytic water splitting observed experimentally. We conclude that efficient cocatalysts should favor localization of the photogenerated hole on oxygen-containing species at the semiconductor/water interface. PMID- 23679684 TI - Effects of celecoxib treatment over the AKT pathway in head and neck squamous cell carcinoma. AB - BACKGROUND: Celecoxib, a non-steroidal anti-inflammatory drug that selectively inhibits cyclooxygenase-2 (COX-2), has shown an important anticarcinogenic effect for the treatment of squamous cell carcinoma. The use of COX-2 inhibitors has effectively inhibited the growth of Head and Neck Squamous Cell Carcinoma (HNSCC) cell lines, while a recent phase 1 trial demonstrated good response rate of cancer cells to this drug with minimal toxicity. Possible targets of celecoxib include proteins involved in cell proliferation and apoptosis control. Additionally, celecoxib antitumoral activity has been linked with a COX-2 independent event. METHODS: To better understand which cellular mechanisms are targeted by celecoxib, its effects upon the Akt signaling pathway using two different HNSCC cell lines were analyzed through cell viability assay, immunofluorescence, and Western blotting. RESULTS: The results showed decreased levels of Cyclin D1 and pAkt protein expression in vitro. The number of viable cells was also diminished after celecoxib treatment. CONCLUSION: As Akt pathway seems to be a valuable target for the HNSCC therapy, the results presented herein confirm that celecoxib can be considered as an alternative adjuvant drug for HNSCC treatment. PMID- 23679685 TI - Protein kinase Mzeta-dependent maintenance of GluA2 at the synapse: a possible target for preventing or treating age-related memory decline? AB - Age-related functional alterations in the perforant path projection from the entorhinal cortex to the dentate gyrus (DG) of the hippocampus play a major role in age-related memory impairments, but little is known about the molecular mechanisms responsible for these changes. In a recent interesting study, Hara and colleagues (J Neurosci 2012;32:7336-7344) tested young and aged monkeys on the visual recognition memory test "delayed nonmatching-to-sample" (DNMS). Then they performed electron microscopy immunocytochemistry in the hippocampal DG to determine the subcellular localization of the GluA2 subunit of the glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) and protein kinase Mzeta (PKMzeta), which promotes memory storage by regulating GluA2 containing AMPAR trafficking. The results obtained suggest that age-related deficits in visual recognition memory are coupled with impairment in PKMzeta dependent maintenance of GluA2 at the synapse. Together with previous evidence of the critical role of PKMzeta in memory consolidation, these data render this enzyme an attractive potential therapeutic target for preventing or treating age related memory decline, and support the view that the pharmacological manipulation of AMPAR trafficking in the synapses may provide new insights in the search of memory enhancers for aged individuals, including those affected by Alzheimer disease. PMID- 23679686 TI - Macroscopic quantum mechanics in a classical spacetime. AB - We apply the many-particle Schrodinger-Newton equation, which describes the coevolution of a many-particle quantum wave function and a classical space-time geometry, to macroscopic mechanical objects. By averaging over motions of the objects' internal degrees of freedom, we obtain an effective Schrodinger-Newton equation for their centers of mass, which can be monitored and manipulated at quantum levels by state-of-the-art optomechanics experiments. For a single macroscopic object moving quantum mechanically within a harmonic potential well, its quantum uncertainty is found to evolve at a frequency different from its classical eigenfrequency-with a difference that depends on the internal structure of the object-and can be observable using current technology. For several objects, the Schrodinger-Newton equation predicts semiclassical motions just like Newtonian physics, yet quantum uncertainty cannot be transferred from one object to another. PMID- 23679687 TI - Magnetic monopoles and synthetic spin-orbit coupling in Rydberg macrodimers. AB - We show that sizable Abelian and non-Abelian gauge fields arise in the relative motion of two dipole-dipole interacting Rydberg atoms. Our system exhibits two magnetic monopoles for adiabatic motion in one internal two-atom state. These monopoles occur at a characteristic distance between the atoms that is of the order of one micron. The deflection of the relative motion due to the Lorentz force gives rise to a clear signature of the effective magnetic field. In addition, we consider nonadiabatic transitions between two near-degenerate internal states and show that the associated gauge fields are non-Abelian. We present quantum mechanical calculations of this synthetic spin-orbit coupling and show that it realizes a velocity-dependent beam splitter. PMID- 23679688 TI - Universal properties of the Higgs resonance in (2+1)-dimensional U(1) critical systems. AB - We present spectral functions for the magnitude squared of the order parameter in the scaling limit of the two-dimensional superfluid to Mott insulator quantum phase transition at constant density, which has emergent particle-hole symmetry and Lorentz invariance. The universal functions for the superfluid, Mott insulator, and normal liquid phases reveal a low-frequency resonance which is relatively sharp and is followed by a damped oscillation (in the first two phases only) before saturating to the quantum critical plateau. The counterintuitive resonance feature in the insulating and normal phases calls for deeper understanding of collective modes in the strongly coupled (2+1)-dimensional relativistic field theory. Our results are derived from analytically continued correlation functions obtained from path-integral Monte Carlo simulations of the Bose-Hubbard model. PMID- 23679689 TI - Ontological models predictively inequivalent to quantum theory. AB - Recently, it has been argued that no extension of quantum theory can have improved predictive power under a strong assumption of free choice of the experimental settings and validity of quantum mechanics. Here, under a different free choice assumption, we describe a model which violates this statement for almost all states of a bipartite two-level system, in a possibly experimentally testable way. From consistency with quantum mechanics and the nonsignaling principle, we derive a bound on the local averages for the family of deterministic ontological theories that our model belongs to. PMID- 23679691 TI - Creating and detecting micro-macro photon-number entanglement by amplifying and deamplifying a single-photon entangled state. AB - We propose a scheme for the observation of micro-macro entanglement in photon number based on amplifying and deamplifying a single-photon entangled state in combination with homodyne quantum state tomography. The created micro-macro entangled state, which exists between the amplification and deamplification steps, is a superposition of two components with mean photon numbers that differ by approximately a factor of three. We show that for reasonable values of photon loss it should be possible to detect micro-macro photon-number entanglement where the macrosystem has a mean number of one hundred photons or more. PMID- 23679690 TI - Null values and quantum state discrimination. AB - We present a measurement protocol for discriminating between two different quantum states of a qubit with high fidelity. The protocol, called null value, is comprised of a projective measurement performed on the system with a small probability (also known as partial collapse), followed by a tuned postselection. We report on an optical experimental implementation of the scheme. We show that our protocol leads to an amplified signal-to-noise ratio (as compared with a straightforward strong measurement) when discerning between the two quantum states. PMID- 23679692 TI - Self-localization of polariton condensates in periodic potentials. AB - We predict the existence of novel spatially localized states of exciton-polariton Bose-Einstein condensates in semiconductor microcavities with fabricated periodic in-plane potentials. Our theory shows that, under the conditions of continuous nonresonant pumping, localization is observed for a wide range of optical pump parameters due to effective potentials self-induced by the polariton flows in the spatially periodic system. We reveal that the self-localization of exciton polaritons in the lattice may occur both in the gaps and bands of the single particle linear spectrum, and is dominated by the effects of gain and dissipation rather than the structured potential, in sharp contrast to the conservative condensates of ultracold alkali atoms. PMID- 23679693 TI - Quantum error correction via less noisy qubits. AB - Known quantum error correction schemes are typically able to take advantage of only a limited class of classical error-correcting codes. Entanglement-assisted quantum error correction is a partial solution which made it possible to exploit any classical linear codes over the binary or quaternary finite field. However, the known entanglement-assisted scheme requires noiseless qubits that help correct quantum errors on noisy qubits, which can be too severe an assumption. We prove that a more relaxed and realistic assumption is sufficient by presenting encoding and decoding operations assisted by qubits on which quantum errors of one particular kind may occur. As in entanglement assistance, our scheme can import any binary or quaternary linear codes. If the auxiliary qubits are noiseless, our codes become entanglement-assisted codes, and saturate the quantum Singleton bound when the underlying classical codes are maximum distance separable. PMID- 23679694 TI - Protocol for direct counterfactual quantum communication. AB - It has long been assumed in physics that for information to travel between two parties in empty space, "Alice" and "Bob," physical particles have to travel between them. Here, using the "chained" quantum Zeno effect, we show how, in the ideal asymptotic limit, information can be transferred between Alice and Bob without any physical particles traveling between them. PMID- 23679695 TI - Classification of topologically protected gates for local stabilizer codes. AB - Given a quantum error correcting code, an important task is to find encoded operations that can be implemented efficiently and fault tolerantly. In this Letter we focus on topological stabilizer codes and encoded unitary gates that can be implemented by a constant-depth quantum circuit. Such gates have a certain degree of protection since propagation of errors in a constant-depth circuit is limited by a constant size light cone. For the 2D geometry we show that constant depth circuits can only implement a finite group of encoded gates known as the Clifford group. This implies that topological protection must be "turned off" for at least some steps in the computation in order to achieve universality. For the 3D geometry we show that an encoded gate U is implementable by a constant-depth circuit only if UPU(?) is in the Clifford group for any Pauli operator P. This class of gates includes some non-Clifford gates such as the pi/8 rotation. Our classification applies to any stabilizer code with geometrically local stabilizers and sufficiently large code distance. PMID- 23679696 TI - Non-markovian models of blocking in concurrent and countercurrent flows. AB - We investigate models in which blocking can interrupt a particulate flow process at any time. Filtration, and flow in micro or nanochannels and traffic flow are examples of such processes. We first consider concurrent flow models where particles enter a channel randomly. If at any time two particles are simultaneously present in the channel, failure occurs. The key quantities are the survival probability and the distribution of the number of particles that pass before failure. We then consider a counterflow model with two opposing Poisson streams. There is no restriction on the number of particles passing in the same direction, but blockage occurs if, at any time, two opposing particles are simultaneously present in the passage. PMID- 23679697 TI - Generalized Floquet theory: application to dynamical systems with memory and Bloch's theorem for nonlocal potentials. AB - Floquet theory is a powerful tool in the analysis of many physical phenomena, and extended to spatial coordinates provides the basis for Bloch's theorem. However, in its original formulation it is limited to linear systems with periodic coefficients. Here, we extend the theory by proving a theorem for the general class of systems including linear operators commuting with the period-shift operator. The present theorem greatly expands the range of applicability of Floquet theory to a multitude of phenomena that were previously inaccessible with this type of analysis, such as dynamical systems with memory. As an important extension, we also prove Bloch's theorem for nonlocal potentials. PMID- 23679698 TI - Universal threshold for the dynamical behavior of lattice systems with long-range interactions. AB - Dynamical properties of lattice systems with long-range pair interactions, decaying like 1/r(alpha) with the distance r, are investigated, in particular the time scales governing the relaxation to equilibrium. Upon varying the interaction range alpha, we find evidence for the existence of a threshold at alpha=d/2, dependent on the spatial dimension d, at which the relaxation behavior changes qualitatively and the corresponding scaling exponents switch to a different regime. Based on analytical as well as numerical observations in systems of vastly differing nature, ranging from quantum to classical, from ferromagnetic to antiferromagnetic, and including a variety of lattice structures, we conjecture this threshold and some of its characteristic properties to be universal. PMID- 23679699 TI - Space-time velocity correlation function for random walks. AB - Space-time correlation functions constitute a useful instrument from the research toolkit of continuous-media and many-body physics. Here we adopt this concept for single-particle random walks and demonstrate that the corresponding space-time velocity autocorrelation functions reveal correlations which extend in time much longer than estimated with the commonly employed temporal correlation functions. A generic feature of considered random-walk processes is an effect of velocity echo identified by the existence of time-dependent regions where most of the walkers are moving in the direction opposite to their initial motion. We discuss the relevance of the space-time velocity correlation functions for the experimental studies of cold atom dynamics in an optical potential and charge transport on micro- and nanoscales. PMID- 23679700 TI - Topological Renyi entropy after a quantum quench. AB - We present an analytical study on the resilience of topological order after a quantum quench. The system is initially prepared in the ground state of the toric code model, and then quenched by switching on an external magnetic field. During the subsequent time evolution, the variation in topological order is detected via the topological Renyi entropy of order 2. We consider two different quenches: the first one has an exact solution, while the second one requires perturbation theory. In both cases, we find that the long-term time average of the topological Renyi entropy in the thermodynamic limit is the same as its initial value. Based on our results, we argue that topological order is resilient against a wide range of quenches. PMID- 23679701 TI - Catastrophic consequences of kicking the chameleon. AB - The physics of the "dark energy" that drives the current cosmological acceleration remains mysterious, and the dark sector may involve new light dynamical fields. If these light scalars couple to matter, a screening mechanism must prevent them from mediating an unacceptably strong fifth force locally. Here we consider a concrete example: the chameleon mechanism. We show that the same coupling between the chameleon field and matter employed by the screening mechanism also has catastrophic consequences for the chameleon during the Universe's first minutes. The chameleon couples to the trace of the stress-energy tensor, which is temporarily nonzero in a radiation-dominated universe whenever a particle species becomes nonrelativistic. These "kicks" impart a significant velocity to the chameleon field, causing its effective mass to vary nonadiabatically and resulting in the copious production of quantum fluctuations. Dissipative effects strongly modify the background evolution of the chameleon field, invalidating all previous classical treatments of chameleon cosmology. Moreover, the resulting fluctuations have extremely high characteristic energies, which casts serious doubt on the validity of the effective theory. Our results demonstrate that quantum particle production can profoundly affect scalar-tensor gravity, a possibility not previously considered. Working in this new context, we also develop the theory and numerics of particle production in the regime of strong dissipation. PMID- 23679702 TI - New method for gravitational wave detection with atomic sensors. AB - Laser frequency noise is a dominant noise background for the detection of gravitational waves using long-baseline optical interferometry. Amelioration of this noise requires near simultaneous strain measurements on more than one interferometer baseline, necessitating, for example, more than two satellites for a space-based detector or two interferometer arms for a ground-based detector. We describe a new detection strategy based on recent advances in optical atomic clocks and atom interferometry which can operate at long baselines and which is immune to laser frequency noise. Laser frequency noise is suppressed because the signal arises strictly from the light propagation time between two ensembles of atoms. This new class of sensor allows sensitive gravitational wave detection with only a single baseline. This approach also has practical applications in, for example, the development of ultrasensitive gravimeters and gravity gradiometers. PMID- 23679703 TI - 21-cm lensing and the cold spot in the cosmic microwave background. AB - An extremely large void and a cosmic texture are two possible explanations for the cold spot seen in the cosmic microwave background. We investigate how well these two hypotheses can be tested with weak lensing of 21-cm fluctuations from the epoch of reionization measured with the Square Kilometer Array. While the void explanation for the cold spot can be tested with Square Kilometer Array, given enough observation time, the texture scenario requires significantly prolonged observations, at the highest frequencies that correspond to the epoch of reionization, over the field of view containing the cold spot. PMID- 23679704 TI - Equivalent D = 3 supergravity amplitudes from double copies of three-algebra and two-algebra gauge theories. AB - We show that three-dimensional supergravity amplitudes can be obtained as double copies of either three-algebra super-Chern-Simons matter theory or two-algebra super-Yang-Mills theory when either theory is organized to display the color kinematics duality. We prove that only helicity-conserving four-dimensional gravity amplitudes have nonvanishing descendants when reduced to three dimensions, implying the vanishing of odd-multiplicity S-matrix elements, in agreement with Chern-Simons matter theory. We explicitly verify the double-copy correspondence at four and six points for N = 12,10,8 supergravity theories and discuss its validity for all multiplicity. PMID- 23679705 TI - Stationary holographic plasma quenches and numerical methods for non-killing horizons. AB - We explore use of the harmonic Einstein equations to numerically find stationary black holes where the problem is posed on an ingoing slice that extends into the interior of the black hole. Requiring no boundary conditions at the horizon beyond smoothness of the metric, this method may be applied for horizons that are not Killing. As a nontrivial illustration we find black holes which, via AdS-CFT, describe a time-independent CFT plasma flowing through a static spacetime which asymptotes to Minkowski in the flow's past and future, with a varying spatial geometry in between. These are the first nonperturbative examples of stationary black holes which do not have Killing horizons. When the CFT spacetime slowly varies, the CFT stress tensor derived from gravity is well described by viscous hydrodynamics. For fast variation it is not, and the solutions are stationary analogs of dynamical quenches, with the plasma being suddenly driven out of equilibrium. We find evidence these flows become unstable for sufficiently strong quenches, and speculate the instability may be turbulent. PMID- 23679707 TI - Explanation for the low flux of high-energy astrophysical muon neutrinos. AB - There has been some concern about the unexpected paucity of cosmic high-energy muon neutrinos in detectors probing the energy region beyond 1 PeV. As a possible solution we consider the possibility that some exotic neutrino property is responsible for reducing the muon neutrino flux at high energies from distant sources; specifically, we consider (i) neutrino decay and (ii) neutrinos being pseudo-Dirac-particles. This would provide a mechanism for the reduction of high energy muon events in the IceCube detector, for example. PMID- 23679708 TI - End point of a first-order phase transition in many-flavor lattice QCD at finite temperature and density. AB - Towards the feasibility study of the electroweak baryogenesis in realistic technicolor scenario, we investigate the phase structure of (2+N(f))-flavor QCD, where the mass of two flavors is fixed to a small value and the others are heavy. For the baryogenesis, an appearance of a first-order phase transition at finite temperature is a necessary condition. Using a set of configurations of two-flavor lattice QCD and applying the reweighting method, the effective potential defined by the probability distribution function of the plaquette is calculated in the presence of additional many heavy flavors. Through the shape of the effective potential, we determine the critical mass of heavy flavors separating the first order and crossover regions and find it to become larger with N(f). We moreover study the critical line at finite density and the first-order region is found to become wider as increasing the chemical potential. Possible applications to real (2+1)-flavor QCD are discussed. PMID- 23679706 TI - Electron neutrino and antineutrino appearance in the full MINOS data sample. AB - We report on nu(e) and nu(e) appearance in nu(MU) and nu(MU) beams using the full MINOS data sample. The comparison of these nu(e) and nu(e) appearance data at a 735 km baseline with theta13 measurements by reactor experiments probes delta, the theta23 octant degeneracy, and the mass hierarchy. This analysis is the first use of this technique and includes the first accelerator long-baseline search for nu(MU) -> nu(e). Our data disfavor 31% (5%) of the three-parameter space defined by delta, the octant of the theta23, and the mass hierarchy at the 68% (90%) C.L. We measure a value of 2sin(2)(2theta13)sin(2)(theta23) that is consistent with reactor experiments. PMID- 23679712 TI - Determination of the weak axial vector coupling lambda = gA/gV from a measurement of the beta-asymmetry parameter A in neutron beta decay. AB - We report on a new measurement of the neutron beta-asymmetry parameter A with the instrument Perkeo II. The main enhancements are the high neutron polarization of P = 99.7(1)% from a novel arrangement of supermirror polarizers and reduced background from improvements in beam line and shielding. The leading corrections were thus reduced by a factor of 4, pushing them below the level of statistical error and resulting in a significant reduction of systematic uncertainty compared to our previous experiments. We derive the beta-asymmetry parameter A0 = 0.11972(45)(stat)((-44)(+32))(sys) = -0.11972((-65)(+53)) and the ratio of the axial vector to the vector coupling constant lambda = gA/gV = -1.2761(12)(stat)(( 12)(+9))(sys) = -1.2761((-17)(+14)). PMID- 23679713 TI - Spins and magnetic moments of 49K and 51K: establishing the 1/2+ and 3/2+ level ordering beyond N = 28. AB - The ground-state spins and magnetic moments of (49,51)K have been measured using bunched-beam high-resolution collinear laser spectroscopy at ISOLDE CERN. For 49K a ground-state spin I = 1/2 was firmly established. The observed hyperfine structure of 51K requires a spin I > 1/2 and strongly suggests I = 3/2. From its magnetic moment MU(51K) = +0.5129(22)MU(N) a spin-parity I(pi) = 3/2+ with a dominant pi1d(3/2)(-1) hole configuration was deduced. This establishes for the first time the reinversion of the single-particle levels and illustrates the prominent role of the residual monopole interaction for single-particle levels and shell evolution. PMID- 23679710 TI - Leptonic-decay-constant ratio f(K+)/f(pi+) from lattice QCD with physical light quarks. AB - A calculation of the ratio of leptonic decay constants f(K+)/f(pi+) makes possible a precise determination of the ratio of Cabibbo-Kobayashi-Maskawa (CKM) matrix elements |V(us)|/|V(ud)| in the standard model, and places a stringent constraint on the scale of new physics that would lead to deviations from unitarity in the first row of the CKM matrix. We compute f(K+)/f(pi+) numerically in unquenched lattice QCD using gauge-field ensembles recently generated that include four flavors of dynamical quarks: up, down, strange, and charm. We analyze data at four lattice spacings a ~ 0.06, 0.09, 0.12, and 0.15 fm with simulated pion masses down to the physical value 135 MeV. We obtain f(K+)/f(pi+) = 1.1947(26)(37), where the errors are statistical and total systematic, respectively. This is our first physics result from our N(f) = 2+1+1 ensembles, and the first calculation of f(K+)/f(pi+) from lattice-QCD simulations at the physical point. Our result is the most precise lattice-QCD determination of f(K+)/f(pi+), with an error comparable to the current world average. When combined with experimental measurements of the leptonic branching fractions, it leads to a precise determination of |V(us)|/|V(ud)| = 0.2309(9)(4) where the errors are theoretical and experimental, respectively. PMID- 23679714 TI - Evidence for multiple chiral doublet bands in 133Ce. AB - Two distinct sets of chiral-partner bands have been identified in the nucleus 133Ce. They constitute a multiple chiral doublet, a phenomenon predicted by relativistic mean field (RMF) calculations and observed experimentally here for the first time. The properties of these chiral bands are in good agreement with results of calculations based on a combination of the constrained triaxial RMF theory and the particle-rotor model. PMID- 23679715 TI - Variation in displacement energies due to isospin-nonconserving forces. AB - For mirror nuclei with masses A=42-95, the effects of isospin-nonconserving nuclear forces are studied with the nuclear shell model using the Coulomb displacement energy and triplet displacement energy as probes. It is shown that the characteristic behavior of the displacement energies can be well reproduced if the isovector and isotensor nuclear interactions with J=0 and T=1 are introduced into the f(7/2) shell. These forces, with their strengths being found consistent with the nucleon-nucleon scattering data, tend to modify nuclear binding energies near the N=Z line. At present, no evidence is found that these forces are needed for the upper fp shell. Theoretical one- and two-proton separation energies are predicted accordingly, and locations of the proton drip line are thereby suggested. PMID- 23679711 TI - Coulomb excitation of 104Sn and the strength of the 100Sn shell closure. AB - A measurement of the reduced transition probability for the excitation of the ground state to the first 2+ state in 104Sn has been performed using relativistic Coulomb excitation at GSI. 104Sn is the lightest isotope in the Sn chain for which this quantity has been measured. The result is a key point in the discussion of the evolution of nuclear structure in the proximity of the doubly magic nucleus 100Sn. The value B(E2; 0+ -> 2+) = 0.10(4) e2b2 is significantly lower than earlier results for 106Sn and heavier isotopes. The result is well reproduced by shell model predictions and therefore indicates a robust N = Z = 50 shell closure. PMID- 23679716 TI - Nuclear multifragmentation time scale and fluctuations of the largest fragment size. AB - Distributions of the largest fragment charge, Zmax, in multifragmentation reactions around the Fermi energy can be decomposed into a sum of a Gaussian and a Gumbel distribution, whereas at much higher or lower energies one or the other distribution is asymptotically dominant. We demonstrate the same generic behavior for the largest cluster size in critical aggregation models for small systems, in or out of equilibrium, around the critical point. By analogy with the time dependent irreversible aggregation model, we infer that Zmax distributions are characteristic of the multifragmentation time scale, which is largely determined by the onset of radial expansion in this energy range. PMID- 23679717 TI - Fully differential single-photon double ionization of neon and argon. AB - Triply differential cross sections are calculated for one-photon double ionization of neon and argon at various photon energies and electron energy sharings by using a frozen-core treatment to represent the remaining electrons of the residual ion. Angular distributions agree well with all existing experimental data, showing that in spite of its simplicity the method can treat the double ionization of complex targets reliably. A comparison of the cross sections for helium, neon, and argon into the same final state symmetry at the same relative excess energies reveals a distinctive signature of the role of electron correlation in each target. PMID- 23679718 TI - Individual-ion addressing with microwave field gradients. AB - Individual-qubit addressing is a prerequisite for many instances of quantum information processing. We demonstrate this capability on trapped-ion qubits with microwave near fields delivered by electrode structures integrated into a microfabricated surface-electrode trap. We describe four approaches that may be used in quantum information experiments with hyperfine levels as qubits. We implement individual control on two 25Mg+ ions separated by 4.3 MUm and find spin-flip crosstalk errors on the order of 10(-3). PMID- 23679719 TI - Measurement of the Coulomb logarithm in a radio-frequency Paul trap. AB - Samples of ultracold 174Yb+ ions, confined in a linear radio-frequency Paul trap, are heated via micromotion interruption, while their temperature, density, and therefore structural phase are monitored and simulated. The observed time evolution of the ion temperature is compared to a theoretical model for ion-ion heating allowing a direct measurement of the Coulomb logarithm in a linear Paul trap. This result permits a simple, yet accurate, analytical description of ion cloud thermodynamic properties, e.g., density, temperature, and structural phase, as well as suggests limits to and improvements for ongoing trapped-ion quantum information efforts. PMID- 23679720 TI - Effect of compression on the relationship between viscosity and dielectric relaxation time in hydrogen-bonded primary alcohols. AB - High pressure viscosity and dielectric measurements were carried out on two monohydroxy alcohols, 2-ethyl-1-hexanol and 5-methyl-2-hexanol, at room temperature. Analysis of the dielectric relaxation times versus viscosity revealed the breakdown of the Einstein-Debye relation above some characteristic pressure. The failure of the Einstein-Debye relation is a manifestation of pressure induced changes of supramolecular hydrogen bonded structures which occur in these liquids. PMID- 23679721 TI - Deep inner-shell multiphoton ionization by intense x-ray free-electron laser pulses. AB - We have investigated multiphoton multiple ionization dynamics of xenon atoms using a new x-ray free-electron laser facility, SPring-8 Angstrom Compact free electron LAser (SACLA) in Japan, and identified that Xe(n+) with n up to 26 is produced at a photon energy of 5.5 keV. The observed high charge states (n>=24) are produced via five-photon absorption, evidencing the occurrence of multiphoton absorption involving deep inner shells. A newly developed theoretical model, which shows good agreement with the experiment, elucidates the complex pathways of sequential electronic decay cascades accessible in heavy atoms. The present study of heavy-atom ionization dynamics in high-intensity hard-x-ray pulses makes a step forward towards molecular structure determination with x-ray free-electron lasers. PMID- 23679722 TI - Control of resonant interaction between electronic ground and excited states. AB - We observe magnetic Feshbach resonances in a collision between the ground and metastable states of two-electron atoms of ytterbium (Yb). We measure the on-site interaction of doubly occupied sites of an atomic Mott-insulator state in a three dimensional optical lattice as a collisional frequency shift in a high-resolution laser spectroscopy. The observed spectra are well fitted by a simple theoretical formula, in which two particles with an s-wave contact interaction are confined in a harmonic trap. This analysis reveals a wide variation of the interaction with a resonance behavior around a magnetic field of about 1.1 G for the energetically lowest magnetic sublevel of 170Yb, as well as around 360 mG for the energetically highest magnetic sublevel of 174Yb. The observed Feshbach resonance can only be induced by an anisotropic interatomic interaction. This scheme will open the door to a variety of studies using two-electron atoms with tunable interaction. PMID- 23679723 TI - Spin-orbit suppression of cold inelastic collisions of aluminum and helium. AB - We present a quantitative study of suppression of cold inelastic collisions by the spin-orbit interaction. We prepare cold ensembles of >10(11) Al(2P(1/2)) atoms via cryogenic buffer-gas cooling and use a single-beam optical pumping method to measure their magnetic (m(J)-changing) and fine-structure (J-changing) collisions with 3He atoms at millikelvin temperatures over a range of magnetic fields from 0.5 to 6 T. The experimentally determined rates are in good agreement with the functional form predicted by quantum scattering calculations using ab initio potentials. This comparison provides direct experimental evidence for a proposed model of suppressed inelasticity in collisions of atoms in 2P(1/2) states [T. V. Tscherbul et al., Phys. Rev. A 80, 040701(R) (2009)], which may allow for sympathetic cooling of other 2P(1/2) atoms (e.g., In, Tl and metastable halogens). PMID- 23679724 TI - Deviation from universality in collisions of ultracold 6Li2 molecules. AB - Collisions of 6Li2 molecules with free 6Li atoms reveal a striking deviation from universal predictions based on long-range van der Waals interactions. Li2 closed channel molecules are formed in the highest vibrational state near a narrow Feshbach resonance and decay via two-body collisions with Li2, Li, and Na. For Li2 + Li2 and Li2 + Na, the decay rates agree with the universal predictions of the quantum Langevin model. In contrast, the rate for Li2 + Li is exceptionally small, with an upper bound 10 times smaller than the universal prediction. This can be explained by the low density of available decay states in systems of light atoms [G. Quemener, J.-M. Launay, and P. Honvault, Phys. Rev. A 75, 050701 (2007)], for which such collisions have not been studied before. PMID- 23679725 TI - Experimental eavesdropping based on optimal quantum cloning. AB - The security of quantum cryptography is guaranteed by the no-cloning theorem, which implies that an eavesdropper copying transmitted qubits in unknown states causes their disturbance. Nevertheless, in real cryptographic systems some level of disturbance has to be allowed to cover, e.g., transmission losses. An eavesdropper can attack such systems by replacing a noisy channel by a better one and by performing approximate cloning of transmitted qubits which disturb them but below the noise level assumed by legitimate users. We experimentally demonstrate such symmetric individual eavesdropping on the quantum key distribution protocols of Bennett and Brassard (BB84) and the trine-state spherical code of Renes (R04) with two-level probes prepared using a recently developed photonic multifunctional quantum cloner [Lemr et al., Phys. Rev. A 85, 050307(R) (2012)]. We demonstrated that our optimal cloning device with high success rate makes the eavesdropping possible by hiding it in usual transmission losses. We believe that this experiment can stimulate the quest for other operational applications of quantum cloning. PMID- 23679726 TI - Direct observation of sub-binomial light. AB - Nonclassical states of light are necessary resources for quantum technologies such as cryptography, computation and the definition of metrological standards. Observing signatures of nonclassicality generally requires inferring either the photon number distribution or a quasiprobability distribution indirectly from a set of measurements. Here, we report an experiment in which the nonclassical character of families of quantum states is assessed by direct inspection of the outcomes from a multiplexed photon counter. This scheme does not register the actual photon number distribution; the statistics of the detector clicks alone serve as a witness of nonclassicality, as proposed by Sperling et al. [Phys. Rev. Lett. 109, 093601 (2012)]. Our work paves a way for the practical characterization of increasingly sophisticated states and detectors. PMID- 23679727 TI - Cavity-mediated entanglement generation via Landau-Zener interferometry. AB - We demonstrate quantum control and entanglement generation using a Landau-Zener beam splitter formed by coupling two transmon qubits to a superconducting cavity. Single passage through the cavity-mediated qubit-qubit avoided crossing provides a direct test of the Landau-Zener transition formula. Consecutive sweeps result in Landau-Zener-Stuckelberg interference patterns, with a visibility that can be sensitively tuned by adjusting the level velocity through both the nonadiabatic and adiabatic regimes. Two-qubit state tomography indicates that a Bell state can be generated via a single passage, with a fidelity of 78% limited by qubit relaxation. PMID- 23679728 TI - PT metamaterials via complex-coordinate transformation optics. AB - We extend the transformation-optics paradigm to a complex spatial coordinate domain, in order to deal with electromagnetic metamaterials characterized by balanced loss and gain, giving special emphasis to parity-time (PT) symmetric metamaterials. We apply this general theory to complex-source-point radiation and anisotropic transmission resonances, illustrating the capability and potentials of our approach in terms of systematic design, analytical modeling, and physical insights into complex-coordinate wave objects and resonant states. PMID- 23679729 TI - Full coherent frequency conversion between two propagating microwave modes. AB - We demonstrate full frequency conversion in the microwave domain using a Josephson three-wave mixing device pumped at the difference between the frequencies of its fundamental eigenmodes. By measuring the signal output as a function of the intensity and phase of the three input signal, idler, and pump tones, we show that the device functions as a controllable three-wave beam splitter or combiner for propagating microwave modes at the single-photon level, in accordance with theory. Losses at the full conversion point are found to be less than 10(-2). Potential applications of the device include quantum information transduction and realization of an ultrasensitive interferometer with controllable feedback. PMID- 23679730 TI - Strong nonlocal coupling stabilizes localized structures: an analysis based on front dynamics. AB - We investigate the effect of strong nonlocal coupling in bistable spatially extended systems by using a Lorentzian-like kernel. This effect through front interaction drastically alters the space-time dynamics of bistable systems by stabilizing localized structures in one and two dimensions, and by affecting the kinetics law governing their behavior with respect to weak nonlocal and local coupling. We derive an analytical formula for the front interaction law and show that the kinetics governing the formation of localized structures obeys a law inversely proportional to their size to some power. To illustrate this mechanism, we consider two systems, the Nagumo model describing population dynamics and nonlinear optics model describing a ring cavity filled with a left-handed material. Numerical solutions of the governing equations are in close agreement with analytical predictions. PMID- 23679731 TI - Remote synchronization reveals network symmetries and functional modules. AB - We study a Kuramoto model in which the oscillators are associated with the nodes of a complex network and the interactions include a phase frustration, thus preventing full synchronization. The system organizes into a regime of remote synchronization where pairs of nodes with the same network symmetry are fully synchronized, despite their distance on the graph. We provide analytical arguments to explain this result, and we show how the frustration parameter affects the distribution of phases. An application to brain networks suggests that anatomical symmetry plays a role in neural synchronization by determining correlated functional modules across distant locations. PMID- 23679732 TI - Stochastic hydrodynamic synchronization in rotating energy landscapes. AB - Hydrodynamic synchronization provides a general mechanism for the spontaneous emergence of coherent beating states in independently driven mesoscopic oscillators. A complete physical picture of those phenomena is of definite importance to the understanding of biological cooperative motions of cilia and flagella. Moreover, it can potentially suggest novel routes to exploit synchronization in technological applications of soft matter. We demonstrate that driving colloidal particles in rotating energy landscapes results in a strong tendency towards synchronization, favoring states where all beads rotate in phase. The resulting dynamics can be described in terms of activated jumps with transition rates that are strongly affected by hydrodynamics leading to an increased probability and lifetime of the synchronous states. Using holographic optical tweezers we quantitatively verify our predictions in a variety of spatial configurations of rotors. PMID- 23679733 TI - Classical mechanics of nonconservative systems. AB - Hamilton's principle of stationary action lies at the foundation of theoretical physics and is applied in many other disciplines from pure mathematics to economics. Despite its utility, Hamilton's principle has a subtle pitfall that often goes unnoticed in physics: it is formulated as a boundary value problem in time but is used to derive equations of motion that are solved with initial data. This subtlety can have undesirable effects. I present a formulation of Hamilton's principle that is compatible with initial value problems. Remarkably, this leads to a natural formulation for the Lagrangian and Hamiltonian dynamics of generic nonconservative systems, thereby filling a long-standing gap in classical mechanics. Thus, dissipative effects, for example, can be studied with new tools that may have applications in a variety of disciplines. The new formalism is demonstrated by two examples of nonconservative systems: an object moving in a fluid with viscous drag forces and a harmonic oscillator coupled to a dissipative environment. PMID- 23679734 TI - Star-shaped crack pattern of broken windows. AB - Broken thin brittle plates like windows and windshields are ubiquitous in our environment. When impacted locally, they typically present a pattern of cracks extending radially outward from the impact point. We study the variation of the pattern of cracks by performing controlled transverse impacts on brittle plates over a broad range of impact speed, plate thickness, and material properties, and we establish from experiments a global scaling law for the number of radial cracks incorporating all these parameters. A model based on Griffith's theory of fracture combining bending elastic energy and fracture energy accounts for our observations. These findings indicate how the postmortem shape of broken samples are related to material properties and impact parameters, a procedure relevant to forensic science, archaeology, or astrophysics. PMID- 23679735 TI - Transition to turbulence and mixing in a viscoelastic fluid flowing inside a channel with a periodic array of cylindrical obstacles. AB - Using Lagrangian simulations of a viscoelastic fluid modeled with an Oldroyd-B constitutive equation, we demonstrate that the flow through a closely spaced linear array of cylinders confined in a channel undergoes a transition to a purely elastic turbulent regime above a critical Weissenberg number (We). The high-We regime is characterized by an unsteady motion and a sudden increase in the flow resistance in qualitative agreement with experimental observations. Furthermore, a power-law scaling behavior of the integral quantities as well as enhanced mixing of mass is observed. A stability analysis based on the dynamic mode decomposition method allows us to identify the most energetic modes responsible for the unsteady behavior, which correspond to filamental structures of polymer over- or underextension advected by the main flow preserving their shape. These time-dependent flow features strictly resemble the elastic waves reported in recent numerical simulations. PMID- 23679736 TI - Nonlinear elastic instability in channel flows at low Reynolds numbers. AB - It is presently believed that flows of viscoelastic polymer solutions in geometries such as a straight pipe or channel are linearly stable. Here we present experimental evidence that such flows can be nonlinearly unstable and can exhibit a subcritical bifurcation. Velocimetry measurements are performed in a long, straight microchannel; flow disturbances are introduced at the entrance of the channel system by placing a variable number of obstacles. Above a critical flow rate and a critical size of the perturbation, a sudden onset of large velocity fluctuations indicates the presence of a nonlinear subcritical instability. Together with the previous observations of hydrodynamic instabilities in curved geometries, our results suggest that any flow of polymer solutions becomes unstable at sufficiently high flow rates. PMID- 23679737 TI - Parametric phase locking in an electron rf oscillator. AB - We propose a way to achieve phase locking of output rf radiation produced by an oscillator driven by a cw electron beam. The locking mechanism is provided by fast periodic modulation of electromagnetic properties of the operating cavity. Ohmic loss and/or the eigenmode frequency are modulated using induced photoconductivity of a semiconductor insert, as affected by a laser with a pulse repetition rate equal to twice the rf frequency. PMID- 23679738 TI - Direct observation of density-gradient effects in harmonic generation from plasma mirrors. AB - High-order harmonics and attosecond pulses of light can be generated when ultraintense, ultrashort laser pulses reflect off a solid-density plasma with a sharp vacuum interface, i.e., a plasma mirror. We demonstrate experimentally the key influence of the steepness of the plasma-vacuum interface on the interaction, by measuring the spectral and spatial properties of harmonics generated on a plasma mirror whose initial density gradient scale length L is continuously varied. Time-resolved interferometry is used to separately measure this scale length. PMID- 23679739 TI - Scaling high-order harmonic generation from laser-solid interactions to ultrahigh intensity. AB - Coherent x-ray beams with a subfemtosecond (<10(-15) s) pulse duration will enable measurements of fundamental atomic processes in a completely new regime. High-order harmonic generation (HOHG) using short pulse (<100 fs) infrared lasers focused to intensities surpassing 10(18) W cm(-2) onto a solid density plasma is a promising means of generating such short pulses. Critical to the relativistic oscillating mirror mechanism is the steepness of the plasma density gradient at the reflection point, characterized by a scale length, which can strongly influence the harmonic generation mechanism. It is shown that for intensities in excess of 10(21) W cm(-2) an optimum density ramp scale length exists that balances an increase in efficiency with a growth of parametric plasma wave instabilities. We show that for these higher intensities the optimal scale length is c/omega0, for which a variety of HOHG properties are optimized, including total conversion efficiency, HOHG divergence, and their power law scaling. Particle-in-cell simulations show striking evidence of the HOHG loss mechanism through parametric instabilities and relativistic self-phase modulation, which affect the produced spectra and conversion efficiency. PMID- 23679740 TI - Magnetic response of odd-frequency s-wave Cooper pairs in a superfluid proximity system. AB - We investigate the magnetic response of a dirty-normal-Fermi-liquid-spin-triplet superfluid proximity system consisting of liquid 3He and aerogel. In contrast to bulk superfluids, Pauli spin susceptibility in the proximity system exceeds its normal-state value locally around the interface. This enhanced Pauli paramagnetism originates from odd-frequency s-wave pairing arising due to spatial inhomogeneity. A characteristic observable signature of the paramagnetic effect can be found in the spin susceptibility temperature dependence. PMID- 23679741 TI - Observation of thermally activated vortex pairs in a quasi-2D Bose gas. AB - We measure the in-plane distribution of thermally activated vortices in a trapped quasi-2D Bose gas, where we enhance the visibility of density-depleted vortex cores by radially compressing the sample before releasing the trap. The pairing of vortices is revealed by the two-vortex spatial correlation function obtained from the vortex distribution. The vortex density decreases gradually as temperature is lowered, and below a certain temperature, a vortex-free region emerges in the center of the sample. This shows the crossover from a Berezinskii Kosterlitz-Thouless phase containing vortex-pair excitations to a vortex-free Bose-Einstein condensate in a finite-size 2D system. PMID- 23679742 TI - Excimers He2* as tracers of quantum turbulence in 4He in the t = 0 limit. AB - We have studied the interaction of metastable 4He2* excimer molecules with quantized vortices in superfluid 4He in the zero temperature limit. The vortices were generated by either rotation or ion injection. The trapping diameter of the molecules on quantized vortices was found to be 96+/-6 nm at a pressure of 0.1 bar and 27+/-5 nm at 5.0 bar. We have also demonstrated that a moving tangle of vortices can carry the molecules through the superfluid helium. PMID- 23679743 TI - Measurement of a broadband negative index with space-coiling acoustic metamaterials. AB - We report the experimental demonstration of a broadband negative refractive index obtained in a labyrinthine acoustic metamaterial structure. Two different approaches were employed to prove the metamaterial negative index nature: one dimensional extractions of effective parameters from reflection and transmission measurements and two-dimensional prism-based measurements that convincingly show the transmission angle corresponding to negative refraction. The transmission angles observed in the latter case also agree very well with the refractive index obtained in the one-dimensional measurements and numerical simulations. We expect this labyrinthine metamaterial to become the unit cell of choice for practical acoustic metamaterial devices that require broadband and significantly negative indices of refraction. PMID- 23679744 TI - Coherent effects of high-energy particles in a graded Si(1-x)Ge(x) crystal. AB - A graded Si(1-x)Ge(x) crystal has been manufactured for operation with high energy protons to excite coherent interactions of the particles with the crystal such as channeling and volume reflection. The crystal had the shape of a parallelepiped though its (111) atomic planes were curved at a radius of 25.6 m because of the graded Ge content. The crystal was exposed to a 400 GeV/c proton beam at the external lines of CERN Super Proton Synchrotron to probe its capability to steer high-energy particles. Measured deflection efficiency was 62.0% under planar channeling and 96.0% under volume reflection. Such values are critically compared to their counterparts for a standard bent Si crystal under peer conditions. A Monte Carlo simulation of the dynamics of channeled and volume reflected particles in a graded crystal including the effect of Ge impurities and of lattice dislocations has been carried out. We found that the effect of crystal imperfections spoiled the efficiency of channeling while it negligibly affected the performance of volume reflection. We finally propose the usage of the graded crystal as a primary scatterer to aid halo collimation for the new generation of hadronic machines. As a unique feature, a properly cut graded crystal circumvents the problem of the miscut angle, which is currently a severe limitation for implementation of crystal-assisted collimation. PMID- 23679745 TI - Impurity sublattice localization in ZnO revealed by Li marker diffusion. AB - Sublattice localization of impurities in compound semiconductors, e.g., ZnO, determines their electronic and optical action. Despite that the impurity position may be envisaged based on charge considerations, the actual localization is often unknown, limiting our understanding of the incorporation and possible doping mechanisms. In this study, we demonstrate that the preferential sublattice occupation for a number of impurities in ZnO can be revealed by monitoring Li diffusion. In particular, using ion implantation, the impurity incorporation into the Zn sublattice (holds for, B, Mg, P, Ag, Cd, and Sb) manifests in the formation of Li-depleted regions behind the implanted one, while Li pileups in the region of the implantation peaks for impurities residing on O sites, e.g., N. The behavior appears to be of general validity and the phenomena are explained in terms of the apparent surplus of Zn and O interstitials, related to the lattice localization of the impurities. Furthermore, Cd+O and Mg+O co-doping experiments revealed that implanted O atoms act as an efficient blocking "filter" for fast diffusing Zn interstitials. PMID- 23679746 TI - Molecular scale simulation of homopolymer wall slip. AB - The first molecular scale simulation of highly entangled polydisperse homopolymers that is capable of capturing all three regions--no slip, weak slip, and strong slip--of the hydrodynamic boundary condition is presented. An on lattice dynamic Monte Carlo technique capable of correctly capturing both unentangled and entangled polymer dynamics is used to study the molecular details of wall slip phenomena for homopolymers and energetically neutral walls. For unentangled chains (those exhibiting Rouse dynamics) weak slip is not present but evidence of strong slip is manifest at very high shear rates. For entangled chains (of sufficient length to exhibit reptation dynamics), both weak and strong slip are observed. Consistent with numerous experimental studies, disentanglement and cohesive failure occur at high shear rates. Disentanglement is clearly evidenced in a nonlinear velocity profile that exhibits shear banding, in an excess of chain ends at the slip plane, and perhaps most importantly in a nonmonotonic stress versus shear rate response. The chain end density exhibits a pretransitional periodicity prior to disentanglement. Unentangled Rouse chains do not show this pretransitional response or a bifurcation in their stress versus shear rate response. Finally, it is shown that when polydispersity is introduced, slip phenomena are severely reduced and the inherent constitutive bifurcation is limited to a small region. Predictions are in post facto agreement with many experiments, are distinct from existing results obtained using molecular dynamics simulation techniques, and shed light on fundamental mechanisms of polymer wall slip. PMID- 23679747 TI - Formation of three-dimensional islands in subcritical layer deposition in Stranski-Krastanow growth. AB - A new method for the formation of three-dimensional (3D) strained islands in lattice-mismatched (B on A) heteroepitaxy is proposed. Once B forms a wetting layer of a subcritical thickness, material C is deposited, which is lattice matched to A and does not wet B. Then B and C phase separate forming local B-rich and C-rich domains on the surface. The thickness of B-rich domains thus exceeds locally that of the initial film of B, and 3D islands may form as it is demonstrated by modeled phase diagrams of the C/B/A system. We show that the growth of the subcritical InAs/GaAs(100) film followed by the deposition of AlAs results (i) in the formation of Al-rich and In-rich domains in the wetting layer, confirmed by chemically sensitive scanning transmission electron microscopy, and (ii) in the stimulated onset of 3D islands, as evidenced both by high resolution transmission electron microscopy and by a significant redshift of the photoluminescence spectrum, which is in agreement with the proposed model. PMID- 23679748 TI - Novel family of chiral-based topological insulators: elemental tellurium under strain. AB - Employing ab initio electronic structure calculations, we predict that trigonal tellurium consisting of weakly interacting helical chains undergoes a trivial insulator to strong topological insulator (metal) transition under shear (hydrostatic or uniaxial) strain. The transition is demonstrated by examining the strain evolution of the band structure, the topological Z2 invariant and the concomitant band inversion. The underlying mechanism is the depopulation of the lone-pair orbitals associated with the valence band via proper strain engineering. Thus, Te becomes the prototype of a novel family of chiral-based three-dimensional topological insulators with important implications in spintronics, magneto-optics, and thermoelectrics. PMID- 23679749 TI - Anomalous reduction of the Lorenz ratio at the quantum critical point in YbAgGe. AB - We report measurements of the electrical and thermal transport on the hexagonal heavy-fermion metal YbAgGe for temperatures T >= 40 mK and in magnetic fields H?ab up to 14 T. This distorted kagome-lattice system displays a series of magnetic states and a quantum critical point at H(c) = 4.5 T. The Lorenz ratio L(T)/L0 displays a marked reduction only close to H(c). A T-linear contribution below 120 mK, present at all different fields, allows us to extrapolate the Lorenz ratio towards T = 0. At the critical field this yields L/L0 = 0.92+/-0.03, suggesting a violation of the Wiedemann-Franz law due to strong inelastic scattering. PMID- 23679750 TI - Topological superconductor to Anderson localization transition in one-dimensional incommensurate lattices. AB - We study the competition of disorder and superconductivity for a one-dimensional p-wave superconductor in incommensurate potentials. With the increase in the strength of the incommensurate potential, the system undergoes a transition from a topological superconducting phase to a topologically trivial localized phase. The phase boundary is determined both numerically and analytically from various aspects and the topological superconducting phase is characterized by the presence of Majorana edge fermions in the system with open boundary conditions. We also calculate the topological Z2 invariant of the bulk system and find it can be used to distinguish the different topological phases even for a disordered system. PMID- 23679751 TI - Optical spectroscopy of spin noise. AB - Spontaneous fluctuations of the magnetization of a spin system in thermodynamic equilibrium (spin noise) manifest themselves as noise in the Faraday rotation of probe light. We show that the correlation properties of this noise over the optical spectrum can provide clear information about the composition of the spin system that is largely inaccessible for conventional linear optics. Such optical spectroscopy of spin noise, e.g., allows us to clearly distinguish between optical transitions associated with different spin subsystems, to resolve optical transitions that are unresolvable in the usual optical spectra, to unambiguously distinguish between homogeneously and inhomogeneously broadened optical bands, and to evaluate the degree of inhomogeneous broadening. These new possibilities are illustrated by theoretical calculations and by experiments on paramagnets with different degrees of inhomogeneous broadening of optical transitions [atomic vapors of 41K and singly charged (In,Ga)As quantum dots]. PMID- 23679752 TI - Distinguishing spin relaxation mechanisms in organic semiconductors. AB - A theory is introduced for spin relaxation and spin diffusion of hopping carriers in a disordered system. For disorder described by a distribution of waiting times between hops (e.g., from multiple traps, site-energy disorder, and/or positional disorder) the dominant spin relaxation mechanisms in organic semiconductors (hyperfine, hopping-induced spin-orbit, and intrasite spin relaxation) each produce different characteristic spin relaxation and spin diffusion dependences on temperature. The resulting unique experimental signatures predicted by the theory for each mechanism in organic semiconductors provide a prescription for determining the dominant spin relaxation mechanism. PMID- 23679753 TI - Materials design from nonequilibrium steady states: driven graphene as a tunable semiconductor with topological properties. AB - Controlling the properties of materials by driving them out of equilibrium is an exciting prospect that has only recently begun to be explored. In this Letter we give a striking theoretical example of such materials design: a tunable gap in monolayer graphene is generated by exciting a particular optical phonon. We show that the system reaches a steady state whose transport properties are the same as if the system had a static electronic gap, controllable by the driving amplitude. Moreover, the steady state displays topological phenomena: there are chiral edge currents, which circulate a fractional charge e/2 per rotation cycle, with the frequency set by the optical phonon frequency. PMID- 23679754 TI - Quantum Hall effect in hydrogenated graphene. AB - The quantum Hall effect is observed in a two-dimensional electron gas formed in millimeter-scale hydrogenated graphene, with a mobility less than 10 cm2/V.s and corresponding Ioffe-Regel disorder parameter (k(F)lambda)(-1) ? 1. In a zero magnetic field and low temperatures, the hydrogenated graphene is insulating with a two-point resistance of the order of 250h/e2. The application of a strong magnetic field generates a negative colossal magnetoresistance, with the two point resistance saturating within 0.5% of h/2e2 at 45 T. Our observations are consistent with the opening of an impurity-induced gap in the density of states of graphene. The interplay between electron localization by defect scattering and magnetic confinement in two-dimensional atomic crystals is discussed. PMID- 23679755 TI - Topologically protected quantum transport in locally exfoliated bismuth at room temperature. AB - We report electrical conductance measurements of Bi nanocontacts created by repeated tip-surface indentation using a scanning tunneling microscope at temperatures of 4 and 300 K. As a function of the elongation of the nanocontact, we measure robust, tens of nanometers long plateaus of conductance G0 = 2e2/h at room temperature. This observation can be accounted for by the mechanical exfoliation of a Bi(111) bilayer, a predicted quantum spin Hall (QSH) insulator, in the retracing process following a tip-surface contact. The formation of the bilayer is further supported by the additional observation of conductance steps below G0 before breakup at both temperatures. Our finding provides the first experimental evidence of the possibility of mechanical exfoliation of Bi bilayers, the existence of the QSH phase in a two-dimensional crystal, and, most importantly, the observation of the QSH phase at room temperature. PMID- 23679756 TI - Quantum interference mapping of Rashba-split Bloch states in Bi/Ag(111). AB - We report on low-temperature scanning tunneling spectroscopy investigations of the (sqrt[3]*sqrt[3]) Bi/Ag(111)R30 degrees surface alloy which provides a giant Rashba-type spin splitting. We observed spectroscopic features that are assigned to two Rashba-split bands. Quantum interference mapping shows that backscattering is not only allowed below but also above the Rashba energy. We argue that the observed behavior can be understood within the Bloch picture where k refers to the crystal momentum and the velocity of an electronic state is defined as v(n)(E) = 1/h ?(k)E(n)(k). The analysis of the energy dispersion of scattering channels reveals a conventional Rashba splitting for the unoccupied Rashba bands, while hybridization is observed in the occupied states. PMID- 23679757 TI - Fractional topological insulators of Cooper pairs induced by the proximity effect. AB - Certain insulating materials with strong spin-orbit interaction can conduct currents along their edges or surfaces owing to the nontrivial topological properties of their electronic band structure. This phenomenon is somewhat similar to the integer quantum Hall effect of electrons in strong magnetic fields. Topological insulators analogous to the fractional quantum Hall effect are also possible, but have not yet been observed in any material. Here we show that a quantum well made from a topological band insulator such as Bi2Se3 or Bi2Te3, placed in contact with a superconductor, can be used to realize a two dimensional topological state with macroscopic many-body quantum entanglement whose excitations carry fractional amounts of an electron's charge and spin. This fractional topological insulator is a "pseudogap" state of induced spinful p-wave Cooper pairs, a new strongly correlated quantum phase with possible applications to spintronic devices and quantum computing. PMID- 23679758 TI - Optimizing electronic structure and quantum transport at the graphene-Si(111) interface: an ab initio density-functional study. AB - We use ab initio density-functional calculations to determine the interaction of a graphene monolayer with the Si(111) surface. We find that graphene forms strong bonds to the bare substrate and accommodates the 12% lattice mismatch by forming a wavy structure consisting of free-standing conductive ridges that are connected by ribbon-shaped regions of graphene, which bond covalently to the substrate. We perform quantum transport calculations for different geometries to study changes in the transport properties of graphene introduced by the wavy structure and bonding to the Si substrate. Our results suggest that wavy graphene combines high mobility along the ridges with efficient carrier injection into Si in the contact regions. PMID- 23679759 TI - Unanticipated proximity behavior in ferromagnet-superconductor heterostructures with controlled magnetic noncollinearity. AB - Magnetization noncollinearity in ferromagnet-superconductor (F/S) heterostructures is expected to enhance the superconducting transition temperature (T(c)) according to the domain-wall superconductivity theory, or to suppress T(c) when spin-triplet Cooper pairs are explicitly considered. We study the proximity effect in F/S structures where the F layer is a Sm-Co/Py exchange spring bilayer and the S layer is Nb. The exchange-spring contains a single, controllable and quantifiable domain wall in the Py layer. We observe an enhancement of superconductivity that is nonmonotonic as the Py domain wall is increasingly twisted via rotating a magnetic field, different from theoretical predictions. We have excluded magnetic fields and vortex motion as the source of the nonmonotonic behavior. This unanticipated proximity behavior suggests that new physics is yet to be captured in the theoretical treatments of F/S systems containing noncollinear magnetization. PMID- 23679760 TI - Magnonlike dispersion of spin resonance in Ni-doped BaFe2As2. AB - Inelastic neutron scattering measurements on Ba(Fe0.963Ni0.037)2As2 manifest a neutron spin resonance in the superconducting state with anisotropic dispersion within the Fe layer. Whereas the resonance is sharply peaked at the antiferromagnetic (AFM) wave vector Q(AFM) along the orthorhombic a axis, the resonance disperses upwards away from Q(AFM) along the b axis. In contrast to the downward dispersing resonance and hourglass shape of the spin excitations in superconducting cuprates, the resonance in electron-doped BaFe2As2 compounds possesses a magnonlike upwards dispersion. PMID- 23679761 TI - Enhancement of the London penetration depth in pnictides at the onset of spin density-wave order under superconducting dome. AB - Recent measurements of the doping dependence of the London penetration depth lambda(x) at low T in clean samples of isovalent BaFe2(As(1-x)P(x))2 at T?T(c) [Hashimoto et al., Science 336, 1554 (2012)] revealed a peak in lambda(x) near optimal doping x=0.3. The observation of the peak at T?T(c), points to the existence of a quantum critical point beneath the superconducting dome. We associate such a quantum critical point with the onset of a spin-density-wave order and show that the renormalization of lambda(x) by critical magnetic fluctuations gives rise to the observed feature. We argue that the case of pnictides is conceptually different from a one-component Galilean invariant Fermi liquid, for which correlation effects do not cause the renormalization of the London penetration depth at T=0. PMID- 23679762 TI - Inhomogeneous superconducting States of mesoscopic thin-walled cylinders in external magnetic fields. AB - We theoretically investigate the appearance of spatially modulated superconducting states in mesoscopic superconducting thin-wall cylinders in a magnetic field at low temperatures. Quantization of the electron motion around the circumference of the cylinder leads to a discontinuous evolution of the spatial modulation of the superconducting order parameter along the transition line T(c)(H). We show that this discontinuity leads to the nonmonotonic behavior of the specific heat jump at the onset of superconductivity as a function of temperature and field. We argue that this geometry provides an excellent opportunity to directly and unambiguously detect distinctive signatures of the Fulde-Ferrell-Larkin-Ovchinnikov modulation of the superconducting order. PMID- 23679763 TI - Topology and origin of effective spin meron pairs in ferromagnetic multilayer elements. AB - We report on pairs of converging-diverging spin vortices in Co/Rh/NiFe trilayer disks. The lateral magnetization distribution of these effective spin merons is directly imaged by means of element-selective x-ray microscopy. By this method, both the divergence and circulation states of the individual layers are identified to be antisymmetric. Reversal measurements on corresponding continuous films reveal that biquadratic interlayer exchange coupling is the cause for the effective meron pair formation. Moreover, their three-dimensional magnetization structure is determined by micromagnetic simulations. Interestingly, the magnetic induction aligns along a flux-closing torus. This toroidal topology enforces a symmetry break, which links the core polarities to the divergence configuration. PMID- 23679764 TI - Direct imaging of thermally driven domain wall motion in magnetic insulators. AB - Thermally induced domain wall motion in a magnetic insulator was observed using spatiotemporally resolved polar magneto-optical Kerr effect microscopy. The following results were found: (i) the domain wall moves towards hot regime; (ii) a threshold temperature gradient (5 K/mm), i.e., a minimal temperature gradient required to induce domain wall motion; (iii) a finite domain wall velocity outside of the region with a temperature gradient, slowly decreasing as a function of distance, which is interpreted to result from the penetration of a magnonic current into the constant temperature region; and (iv) a linear dependence of the average domain wall velocity on temperature gradient, beyond a threshold thermal bias. Our observations can be qualitatively explained using a magnonic spin transfer torque mechanism, which suggests the utility of magnonic spin transfer torque for controlling magnetization dynamics. PMID- 23679765 TI - Terahertz radiation from magnetic excitations in diluted magnetic semiconductors. AB - We probed, in the time domain, the THz electromagnetic radiation originating from spins in CdMnTe diluted magnetic semiconductor quantum wells containing high mobility electron gas. Taking advantage of the efficient Raman generation process, the spin precession was induced by low power near-infrared pulses. We provide a full theoretical first-principles description of spin-wave generation, spin precession, and of emission of THz radiation. Our results open new perspectives for improved control of the direct coupling between spin and an electromagnetic field, e.g., by using semiconductor technology to insert the THz sources in cavities or pillars. PMID- 23679766 TI - Novel chiral magnetic domain wall structure in Fe/Ni/Cu(001) films. AB - Using spin-polarized low energy electron microscopy, we discovered a new type of domain wall structure in perpendicularly magnetized Fe/Ni bilayers grown epitaxially on Cu(100). Specifically, we observed unexpected Neel-type walls with fixed chirality in the magnetic stripe phase. Furthermore, we find that the chirality of the domain walls is determined by the film growth order with the chirality being right handed in Fe/Ni bilayers and left handed in Ni/Fe bilayers, suggesting that the underlying mechanism is the Dzyaloshinskii-Moriya interaction at the film interfaces. Our observations may open a new route to control chiral spin structures using interfacial engineering in transition metal heterostructures. PMID- 23679767 TI - Laser-induced magnetic nanostructures with tunable topological properties. AB - We report the creation and real-space observation of magnetic structures with well-defined topological properties and a lateral size as low as about 150 nm. They are generated in a thin ferrimagnetic film by ultrashort single optical laser pulses. Thanks to their topological properties, such structures can be classified as Skyrmions of a particular type that does not require an externally applied magnetic field for stabilization. Besides Skyrmions, we are able to generate magnetic features with topological characteristics that can be tuned by changing the laser fluence. The stability of such features is accounted for by an analytical model based on the interplay between the exchange and the magnetic dipole-dipole interactions. PMID- 23679768 TI - Evidence for the role of normal-state electrons in nanoelectromechanical damping mechanisms at very low temperatures. AB - We report on experiments performed at low temperatures on aluminum covered silicon nanoelectromechanical resonators. The substantial difference observed between the mechanical dissipation in the normal and superconducting states measured within the same device unambiguously demonstrates the importance of normal-state electrons in the damping mechanism. The dissipative component becomes vanishingly small at very low temperatures in the superconducting state, leading to exceptional values for the quality factor of such small silicon structures. A critical discussion is given within the framework of the standard tunneling model. PMID- 23679769 TI - Specific heat of the Skyrmion lattice phase and field-induced tricritical point in MnSi. AB - We report high-precision measurements of the temperature and magnetic field dependence of the specific heat, C(T,H), across the magnetic phase diagram of MnSi. Clear anomalies establish the Skyrmion lattice unambiguously as a thermodynamic phase. The evolution of the specific heat anomalies, the field dependence of the entropy released at the phase transitions, and the temperature versus field dependence of crossover lines provide striking evidence of a tricritical point at MU0H(TCP)(int) = 340 mT and T(TCP) = 28.5 K. The existence of this tricritical point represents strong support of a helimagnetic Brazovskii transition, i.e., a fluctuation-induced first-order transition at H = 0. PMID- 23679770 TI - Surpassing fundamental limits of oscillators using nonlinear resonators. AB - In its most basic form an oscillator consists of a resonator driven on resonance, through feedback, to create a periodic signal sustained by a static energy source. The generation of a stable frequency, the basic function of oscillators, is typically achieved by increasing the amplitude of motion of the resonator while remaining within its linear, harmonic regime. Contrary to this conventional paradigm, in this Letter we show that by operating the oscillator at special points in the resonator's anharmonic regime we can overcome fundamental limitations of oscillator performance due to thermodynamic noise as well as practical limitations due to noise from the sustaining circuit. We develop a comprehensive model that accounts for the major contributions to the phase noise of the nonlinear oscillator. Using a nanoelectromechanical system based oscillator, we experimentally verify the existence of a special region in the operational parameter space that enables suppressing the most significant contributions to the oscillator's phase noise, as predicted by our model. PMID- 23679771 TI - Magnetic dipole and higher pole interaction on a square lattice. AB - We have studied the magnetic interaction of circular magnetic islands with a dipole character on a square lattice. The square pattern consists of lithographically prepared polycrystalline PdFe islands, 150 nm in diameter and a periodicity of 300 nm. Below the Curie temperature at 260 K, the islands are in a single domain state with isotropic in-plane magnetization. Below 160 K, there is an onset of interisland interaction that leads to a change of the shape of the hysteresis, an increase of coercivity, and a development of in-plane anisotropy. Photoemission electron microscopy with circularly polarized incident x rays tuned to the L3 edge of Fe confirms the increasing correlation of the magnetic islands and the formation of elongated chains, as predicted by Vedmedenko et al. [Phys. Rev. Lett. 95, 207202 (2005)] for contributions from pole interactions of higher order than the dipolar one. Neighboring chains are found to be irregularly oriented either parallel or antiparallel. PMID- 23679772 TI - Accurate and facile determination of the index of refraction of organic thin films near the carbon 1s absorption edge. AB - A practical and accurate method to obtain the index of refraction, especially the decrement delta, across the carbon 1s absorption edge is demonstrated. The combination of absorption spectra scaled to the Henke atomic scattering factor database, the use of the doubly subtractive Kramers-Kronig relations, and high precision specular reflectivity measurements from thin films allow the notoriously difficult-to-measure delta to be determined with high accuracy. No independent knowledge of the film thickness or density is required. High confidence interpolation between relatively sparse measurements of delta across an absorption edge is achieved. Accurate optical constants determined by this method are expected to greatly improve the simulation and interpretation of resonant soft x-ray scattering and reflectivity data. The method is demonstrated using poly(methyl methacrylate) and should be extendable to all organic materials. PMID- 23679773 TI - Dielectric GaAs antenna ensuring an efficient broadband coupling between an InAs quantum dot and a Gaussian optical beam. AB - We introduce the photonic trumpet, a dielectric structure which ensures a nearly perfect coupling between an embedded quantum light source and a Gaussian free space beam. A photonic trumpet exploits both the broadband spontaneous emission control provided by a single-mode photonic wire and the expansion of this mode within a conical taper. Numerical simulations highlight the performance and robustness of this concept. As a first application in the field of quantum optics, we report the realization of an ultrabright single-photon source. The device, a high aspect ratio GaAs photonic trumpet containing a few InAs quantum dots, demonstrates a first-lens external efficiency of 0.75+/-0.1 and an external coupling efficiency to a Gaussian beam as high as 0.58+/-0.08. PMID- 23679774 TI - Liquid crystal tunable metamaterial absorber. AB - We present an experimental demonstration of electronically tunable metamaterial absorbers in the terahertz regime. By incorporation of active liquid crystal into strategic locations within the metamaterial unit cell, we are able to modify the absorption by 30% at 2.62 THz, as well as tune the resonant absorption over 4% in bandwidth. Numerical full-wave simulations match well to experiments and clarify the underlying mechanism, i.e., a simultaneous tuning of both the electric and magnetic response that allows for the preservation of the resonant absorption. These results show that fundamental light interactions of surfaces can be dynamically controlled by all-electronic means and provide a path forward for realization of novel applications. PMID- 23679775 TI - Optical emission of a strained direct-band-gap Ge quantum well embedded inside InGaAs alloy layers. AB - We studied the optical properties of a strain-induced direct-band-gap Ge quantum well embedded in InGaAs. We showed that the band offsets depend on the electronegativity of the layer in contact with Ge, leading to different types of optical transitions in the heterostructure. When group-V atoms compose the interfaces, only electrons are confined in Ge, whereas both carriers are confined when the interface consists of group-III atoms. The different carrier confinement results in different emission dynamics behavior. This study provides a solution to obtain efficient light emission from Ge. PMID- 23679776 TI - Coherent control of light scattering from nanostructured materials by second harmonic generation. AB - We introduce an active, all-optical method for controlling the intensity and directionality of light scattering from single nanostructures. The method is based on the coherent interplay between linear light scattering and second harmonic generation. The intensity and directionality of scattered light can be controlled by the phase delay and the relative angle between excitation beams. We discuss the principle of this coherent control technique and perform numerical model calculations. PMID- 23679777 TI - Direct measurement of Auger electrons emitted from a semiconductor light-emitting diode under electrical injection: identification of the dominant mechanism for efficiency droop. AB - We report on the unambiguous detection of Auger electrons by electron emission spectroscopy from a cesiated InGaN/GaN light-emitting diode under electrical injection. Electron emission spectra were measured as a function of the current injected in the device. The appearance of high energy electron peaks simultaneously with an observed drop in electroluminescence efficiency shows that hot carriers are being generated in the active region (InGaN quantum wells) by an Auger process. A linear correlation was measured between the high energy emitted electron current and the "droop current"--the missing component of the injected current for light emission. We conclude that the droop phenomenon in GaN light emitting diodes originates from the excitation of Auger processes. PMID- 23679778 TI - Imaging local polarization in ferroelectric thin films by coherent x-ray Bragg projection ptychography. AB - We used x-ray Bragg projection ptychography (BPP) to map spatial variations of ferroelectric polarization in thin film PbTiO3, which exhibited a striped nanoscale domain pattern on a high-miscut (001) SrTiO3 substrate. By converting the reconstructed BPP phase image to picometer-scale ionic displacements in the polar unit cell, a quantitative polarization map was made that was consistent with other characterization. The spatial resolution of 5.7 nm demonstrated here establishes BPP as an important tool for nanoscale ferroelectric domain imaging, especially in complex environments accessible with hard x rays. PMID- 23679779 TI - Large nuclear spin polarization in gate-defined quantum dots using a single domain nanomagnet. AB - The electron-nuclei (hyperfine) interaction is central to spin qubits in solid state systems. It can be a severe decoherence source but also allows dynamic access to the nuclear spin states. We study a double quantum dot exposed to an on chip single-domain nanomagnet and show that its inhomogeneous magnetic field crucially modifies the complex nuclear spin dynamics such that the Overhauser field tends to compensate external magnetic fields. This turns out to be beneficial for polarizing the nuclear spin ensemble. We reach a nuclear spin polarization of ?50%, unrivaled in lateral dots, and explain our manipulation technique using a comprehensive rate equation model. PMID- 23679780 TI - Chirality screening and metastable states in chiral nematic colloids. AB - We show that forces between two colloidal particles in a thin layer of a chiral nematic liquid crystal strongly depend on the chirality of the liquid crystal. The observed pair potentials are attractive, but are oscillatory functions of colloidal separation. The number and the position of local energy minima increase with increasing chirality. The pair interaction is the strongest for the pitch equal to the colloidal diameter and decreases with increasing chirality. We show that the chirality of the medium is responsible for this oscillatory nature and screening of the colloidal interaction in the far and near field. The measurements are in agreement with numerical calculations using Landau-de Gennes theory. PMID- 23679781 TI - Microscopic dynamics of polyethylene glycol chains interacting with silica nanoparticles. AB - We present high resolution neutron spectroscopic investigations of polyethylene glycol matrices interacting attractively with neat SiO2 nanoparticles. We observe a very rich dynamical picture that significantly contradicts earlier conclusions on such systems. Investigating a short chain matrix we realized that a fraction of chains is attached at the nanoparticle surface suppressing completely its translational diffusion. Nevertheless these attached chains undergo an unchanged segmental dynamics seemingly forming a micellelike corona of chains attached with their OH end groups. Changing to methyl-terminated chains the picture changes drastically, now showing a tightly adsorbed layer that however is not glassy as often assumed but undergoes fast picosecond local dynamics. With the singular importance of end groups, mean field approaches are not applicable and future simulations should be redirected to model such unexpected phenomena. PMID- 23679782 TI - Disorder-assisted melting and the glass transition in amorphous solids. AB - The mechanical response of solids depends on temperature, because the way atoms and molecules respond collectively to deformation is affected at various levels by thermal motion. This is a fundamental problem of solid state science and plays a crucial role in materials science. In glasses, the vanishing of shear rigidity upon increasing temperature is the reverse process of the glass transition. It remains poorly understood due to the disorder leading to nontrivial (nonaffine) components in the atomic displacements. Our theory explains the basic mechanism of the melting transition of amorphous (disordered) solids in terms of the lattice energy lost to this nonaffine motion, compared to which thermal vibrations turn out to play only a negligible role. The theory is in good agreement with classic data on melting of amorphous polymers (for which no alternative theory can be found in the literature) and offers new opportunities in materials science. PMID- 23679783 TI - Brain organization into resting state networks emerges at criticality on a model of the human connectome. AB - The relation between large-scale brain structure and function is an outstanding open problem in neuroscience. We approach this problem by studying the dynamical regime under which realistic spatiotemporal patterns of brain activity emerge from the empirically derived network of human brain neuroanatomical connections. The results show that critical dynamics unfolding on the structural connectivity of the human brain allow the recovery of many key experimental findings obtained from functional magnetic resonance imaging, such as divergence of the correlation length, the anomalous scaling of correlation fluctuations, and the emergence of large-scale resting state networks. PMID- 23679784 TI - Elements of coevolution in biological sequences. AB - Studies of coevolution of amino acids within and between proteins have revealed two types of coevolving units: coevolving contacts, which are pairs of amino acids distant along the sequence but in contact in the three-dimensional structure, and sectors, which are larger groups of structurally connected amino acids that underlie the biochemical properties of proteins. By reconciling two approaches for analyzing correlations in multiple sequence alignments, we link these two findings together and with coevolving units of intermediate size, called "sectons," which are shown to provide additional information. By extending the analysis to the co-occurrence of orthologous genes in bacterial genomes, we also show that the methods and results are general and relevant beyond protein structures. PMID- 23679786 TI - Complex oscillatory yielding of model hard-sphere glasses. AB - The yielding behavior of hard sphere glasses under large-amplitude oscillatory shear has been studied by probing the interplay of Brownian motion and shear induced diffusion at varying oscillation frequencies. Stress, structure and dynamics are followed by experimental rheology and Browian dynamics simulations. Brownian-motion-assisted cage escape dominates at low frequencies while escape through shear-induced collisions at high ones, both related with a yielding peak in G''. At intermediate frequencies a novel, for hard sphere glasses, double peak in G'' is revealed reflecting both mechanisms. At high frequencies and strain amplitudes a persistent structural anisotropy causes a stress drop within the cycle after strain reversal, while higher stress harmonics are minimized at certain strain amplitudes indicating an apparent harmonic response. PMID- 23679785 TI - Torque spectroscopy of DNA: base-pair stability, boundary effects, backbending, and breathing dynamics. AB - Changes in global DNA linking number can be accommodated by localized changes in helical structure. We have used single-molecule torque measurements to investigate sequence-specific strand separation and Z-DNA formation. By controlling the boundary conditions at the edges of sequences of interest, we have confirmed theoretical predictions of distinctive boundary-dependent backbending patterns in torque-twist relationships. Abrupt torque jumps are associated with the formation and collapse of DNA bubbles, permitting direct observations of DNA breathing dynamics. PMID- 23679787 TI - Speeding up of sedimentation under confinement. AB - We show an increase of the sedimentation velocity as small particles are confined in circular capillaries. In general, confinement slows down sedimentation. But, we show that at low Reynolds numbers and in 1D confinement this is not the case. Particle sedimentation velocity is not homogeneous, which can lead to the formation of structures. These structures are enhanced and stabilized in the presence of walls and in the absence of other dissipative mechanisms. As a consequence, it is possible to achieve sedimentation velocities that even exceed the Stokes velocity. The segregation at critical capillary diameters has been directly observed using a large scale model. These simple experiments offer a new insight into the old problem of sedimentation under confinement. PMID- 23679788 TI - Percolation description of the global topography of Earth and the moon. AB - Remarkable global correlations exist between geometrical features of terrestrial surfaces on Earth, current mean sea level, and its geological internal processes whose origins have remained an essential goal in the earth sciences. Theoretical modeling of the ubiquitous self-similar fractal patterns observed on Earth and their underlying rules is indeed of great importance. Here I present a percolation description of the global topography of Earth in which the present mean sea level is automatically singled out as a critical level in the model. This finding elucidates the origins of the appearance of scale invariant patterns on Earth. The criticality is shown to be accompanied by a continental aggregation, unraveling an important correlation between the water and long-range topographic evolutions. To have a comparison point in hand, I apply such an analysis to the lunar topography which reveals various characteristic features of the Moon. PMID- 23679789 TI - Comment on "Quantum coherence and sensitivity of avian magnetoreception". PMID- 23679790 TI - Bandyopadhyay, Paterek, and Kaszlikowski reply. AB - In this Reply to the preceding Comment by Gauger and Benjamin, we recognize that the numerical error was present in our software, and we explain which of our conclusions are affected by it. PMID- 23679791 TI - Comment on "Taming the pion cloud of the nucleon". PMID- 23679792 TI - Alberg and Miller reply. PMID- 23679793 TI - Comment on "Strangeness -2 hypertriton". PMID- 23679794 TI - Garcilazo and Valcarce reply. PMID- 23679795 TI - Factors that influence obesity, functional capacity, anxiety and depression outcomes following a Phase III cardiac rehabilitation programme. AB - AIMS AND OBJECTIVES: To examine changes in functional capacity, anxiety, depression and BMI in patients who completed a cardiac rehabilitation programme and to determine the influencing factors. BACKGROUND: While the effectiveness of cardiac rehabilitation is long established, more studies are needed to examine the combined effectiveness of this multicomponent intervention and the factors that influence this in the changed profile of patients currently attending cardiac rehabilitation. DESIGN: The study was a longitudinal retrospective study of patients following a six- or eight-week Phase III cardiac rehabilitation programme. METHODS: The study recruited 154 patients. Functional capacity, anxiety, depression, weight, waist circumference and BMI were assessed at the beginning and end of cardiac rehabilitation. t-tests were used to assess changes over time, and multivariate regression analysis was used to determine the influence of factors on these changes. RESULTS: Significant improvements were seen in functional capacity, waist circumference, weight and BMI, but not in depression and anxiety. Multivariate analysis revealed that being younger and less fit was associated with greater improvements in functional capacity while reason for referral, gender, depression or BMI did not influence improvements in functional capacity. Models testing the influence of the factors on BMI, anxiety and depression were not significant. CONCLUSION: Cardiac rehabilitation is still an effective method to instigate changes in cardiac risk factors despite the changes in patients profile attending programmes. RELEVANCE TO CLINICAL PRACTICE: Continued encouragement of the historically less typical patients to participate in cardiac rehabilitation is needed as reason for referral, gender, depression or BMI did not influence improvements in functional capacity. Despite psychosocial components within the programme, no significant improvements were observed over cardiac rehabilitation in depression or anxiety. While effectiveness was observed, there is room for further optimisation of practice and research by employing and documenting clearly the use of behavioural techniques. PMID- 23679796 TI - Reconfigurable biodegradable shape-memory elastomers via Diels-Alder coupling. AB - Synthetic biodegradable elastomers are a class of polymers that have demonstrated far-reaching utility as biomaterials for use in many medical applications. Biodegradable elastomers can be broadly classified into networks prepared by either step-growth or chain-growth polymerization. Each processing strategy affords distinct advantages in terms of capabilities and resulting properties of the network. This work describes the synthesis, processing, and characterization of cross-linked polyester networks based on Diels-Alder coupling reactions. Hyperbranched furan-modified polyester precursors based on poly(glycerol-co sebacate) are coupled with bifunctional maleimide cross-linking agents. The chemical and thermomechanical properties of the elastomers are characterized at various stages of network formation. Experimental observations of gel formation are compared to theoretical predictions derived from Flory-Stockmayer relationships. This cross-linking strategy confers unique advantages in processing and properties including the ability to fabricate biodegradable reconfigurable covalent networks without additional catalysts or reaction byproducts. Reconfigurable biodegradable networks using Diels-Alder cycloaddition reactions permit the fabrication of shape-memory polymers with complex permanent geometries. Biodegradable elastomers based on polyester networks with molecular reconfigurability achieve vastly expanded properties and processing capabilities for potential applications in medicine and beyond. PMID- 23679797 TI - Organoimido-derivatized hexamolybdates with a remote carboxyl group: syntheses and structural characterizations. AB - Four novel organoimido derivatives of hexamolybdate containing a remote carboxyl group have been synthesized: [Bu4N]2[Mo6O18(N-C6H4-3-COOH)] (1), [Bu4N]2[Mo6O18(N C6H4-2-CH3-4-COOH)] (2), [Bu4N]2[Mo6O18(N-C6H4-2-CH3-5-COOH)] (3), and [Bu4N]2[Mo6O18(N-C6H4-2-CH3-3-COOH)] (4) with 3-aminobenzoic acid, 4-amino-3 methylbenzoic acid, 3-amino-4-methylbenzoic acid, and 3-amino-2-methylbenzoic acid as the imido-releasing agents, respectively. Their structures have been characterized by IR, UV-vis, (1)H NMR, ESI-MS, and single-crystal X-ray diffraction techniques. Hydrogen bonding interactions play an important role in the supramolecular assemblies of these compounds in the solid state. Although the incorporated organic ligands are similar to each other, their supramolecular assembly behaviors are quite different. For compound 1, the dimer structure is formed via hydrogen bonding between the carboxyl group and the POM cluster of two neighboring cluster anions. For compound 2, the 1D chain structure is formed via hydrogen bonding between the carboxyl groups and the POM clusters of the cluster anions. For compound 3, the 2D plane structure is formed via two types of hydrogen bonding between the aromatic rings and the POM clusters of the cluster anions. For compound 4, the 1D plus 2D structures are formed via three types of hydrogen bonding between the aromatic rings and the POM clusters of the two types of cluster anions with different orientations. PMID- 23679798 TI - Current opinions on alternative reservoir placement for inflatable penile prosthesis among members of the Sexual Medicine Society of North America. AB - INTRODUCTION: The Sexual Medicine Society of North America (SMSNA) includes as its members the most experienced prosthetic surgeons in North America who implant inflatable penile prostheses (IPPs). Obliteration of the space of Retzius (SOR) resulting from robotic-assisted laparoscopic prostatectomy (RALP) is a growing concern that has prompted many surgeons to look for alternative locations for reservoir placement during IPP implantation. AIM: The aim of this article is to educate the community of prosthetic urologists about potential complications and alternative locations for IPP reservoir placement. METHODS: A panel of high volume experienced prosthetic surgeons discussed their views on alternative IPP reservoir implantation during a symposium focused on this topic. After reviewing reservoir complications, physician members of the SMSNA in attendance were surveyed using an audience response system (ARS) to facilitate sharing of knowledge, opinions, and recommendations related to reservoir implantation. MAIN OUTCOME MEASURES: Six ARS questions were used to identify the percentages of SMSNA member physicians with concerns about traditional IPP reservoir placement and utilizing alternative reservoir placement (ARP), and the impact of changing practice patterns on patient safety. RESULTS: A majority (81%) of experienced implant surgeons surveyed think that RALP sometimes or frequently makes traditional IPP reservoir placement more difficult. Placement of the reservoir in an alternative location is sometimes or frequently advantageous for patient safety. A vast majority (97%) of the 95 respondents indicated that ARP techniques should be included in physician training courses. CONCLUSIONS: Physicians have concerns about reservoir placement in the SOR in RALP patients, which may explain why ARP is popular among SMSNA members. Device manufacturers should support physician training that provides for ARP. Clinical outcomes in RALP patients are needed to better understand the risks and benefits, and define the ideal location of reservoir placement in this population. PMID- 23679800 TI - Social work, strengths perspective, and disaster management: roles of social workers and models for intervention. PMID- 23679799 TI - Cobalt nanoparticles growth on a block copolymer thin film: a time-resolved GISAXS study. AB - Cobalt sputter deposition on a nanostructured polystyrene-block-poly(ethylene oxide), P(S-b-EO), template is followed in real time with grazing incidence small angle X-ray scattering (GISAXS). The polymer template consists of highly oriented parallel crystalline poly(ethylene oxide) (PEO) domains that are sandwiched between two polystyrene (PS) domains. In-situ GISAXS shows that cobalt atoms selectively decorate the PS domains of the microphase-separated polymer film and then aggregate to form surface metal nanopatterns. The polymer template is acting as a directing agent where cobalt metal nanowires are formed. At high metal load, the characteristic selectivity of the template is lost, and a uniform metal layer forms on the polymer surface. During the early stage of cobalt metal deposition, a highly asymmetric nanoparticles agglomeration is dominating structure formation. The cobalt nanoparticles mobility in combination with the high tendency of the nanoparticles to coalescence and to form immobile large-sized particles at the PS domains are discussed as mechanisms of structure formation. PMID- 23679801 TI - Emergency management and social recovery from disasters in different countries. AB - Disaster management refers to the policies, administrative decisions, and operational activities carried out by different sectors of society in responding to disasters. The focus of this article is on disaster recovery and rebuilding. The preventive approach manages risks and engages in the process of risk avoidance and disaster preparedness. Such an approach frequently involves multiple layers of society working together. Social workers should be involved in social intervention and preparation as well as the prevention of disasters. Greater professionalization, integration, and coordination of emergency services are observed both within and between nations. PMID- 23679802 TI - Disaster recovery management in Australia and the contribution of social work. AB - This article describes Australia's broad disaster recovery planning and management approach, adopting a social and community recovery perspective. The role of social work in Australian disaster recovery management is discussed, and its increasing assertion and maturation of practice. Theoretical underpinnings include trauma, grief, and crisis intervention. Strengths-based, solution-focused approaches to intervention, and a sound understanding of community development principles, are essential to facilitating community recovery. Two examples (flood and bushfire) illustrate the full spectrum of planning, immediate psychosocial response, and longer term community and individual recovery. Issues such as effective multiagency practice, individual case management, and consideration of vulnerable groups are highlighted. PMID- 23679803 TI - Earthquake and disaster response in the Japanese community: a strengths and community perspective. AB - This article indicates that capability building in the local community and accumulation of collaborative practice experiences gained at the local community level prove effective in actual disaster response and recovery. A case study of the Japanese community is introduced to illustrate this point. The article concludes with a discussion of the role and function of social workers in the context of such a community. In terms of disaster response and recovery, one of the essential roles of social workers is to encourage local people to empower other local people, organizations, and community. PMID- 23679804 TI - Empowering disaster-affected communities for long-term reconstruction: intervening in Sri Lanka after the tsunami. AB - The 2004 Indian Ocean tsunami highlighted the importance of interdependencies between nations, delivery of humanitarian aid in an empowering manner, and long term reconstruction. I examine relationships between overseas actors and local residents in tsunami-affected villages in Sri Lanka in a project initiated by the International Association of Schools of Social Work through its Rebuilding People's Lives After Disasters Network and another based on an institutional endeavour supported by Durham University because these sought to empower local communities through local, egalitarian partnerships. Lacking sufficient educational resources, capacity building in social work education has become a long-term objective. PMID- 23679805 TI - Disaster management: vulnerability and resilience in disaster recovery in Thailand. AB - This project explores disaster management in Thailand with a focus on the vulnerability and resilience of women, children, the elderly, and the disabled population and on the impact of disaster on these subpopulations. The 2 main findings deal with the major models of disaster management in Thailand and building resilience for social recovery. The selected 5 major models currently employed in disaster management in Thailand are the (a) model of royal project and international cooperation on disaster preparedness and response, (b) ASEAN Socio-Cultural Blueprint, (c) rights-based approach, (d) welfare mix model, and (e) knowledge management model. PMID- 23679806 TI - Community resilience after disaster in Taiwan: a case study of Jialan Village with the strengths perspective. AB - This article examines community resilience in disaster recovery in Jialan Village, where many families lost their homes when Typhoon Morakot struck Taiwan in 2008. In-depth interviews were conducted with policymakers, social workers, resource coordinators, and leaders of the local aboriginal community. The main findings were (a) the village's recovery was due to the effective use and coordination of community resources; (b) partnership building between the public and private sectors was crucial in the community's recovery; and (c) the recovery was enhanced by values such as a strong sense of mutual help, good physical health, positive attitudes, and autonomy. PMID- 23679807 TI - Psychosocial recovery for children disabled in an earthquake: school social work in Dujiangyan, China. AB - In the Sichuan earthquake on May 12, 2008, schools were hardest hit. The School Social Work service at the You Ai School of Dujiangyan became a major factor in assisting 140 children, disabled in the disaster, in their psychosocial recovery. This article aims to identify indicators of recovery for children from early primary to junior high. Content analysis is used instead of a lengthy psychological scale, as the latter might not be applicable for young children. Results show that disabled children are capable of recovery 3 years after the disaster. Effects of social work intervention and inclusive education have yet to be studied. PMID- 23679709 TI - Measurement of associated production of vector bosons and top quark-antiquark pairs in pp collisions at sqrt[s]=7 TeV. AB - The first measurement of vector-boson production associated with a top quark antiquark pair in proton-proton collisions at sqrt[s] = 7 TeV is presented. The results are based on a data set corresponding to an integrated luminosity of 5.0 fb(-1), recorded by the CMS detector at the LHC in 2011. The measurement is performed in two independent channels through a trilepton analysis of ttZ events and a same-sign dilepton analysis of ttV (V = W or Z) events. In the trilepton channel a direct measurement of the ttZ cross section sigma(ttZ) = 0.28( 0.11)(+0.14) (stat)(-0.03)(+0.06) (syst) pb is obtained. In the dilepton channel a measurement of the ttV cross section yields sigma(ttV) = 0.43(-0.15)(+0.17) (stat)(-0.07)(+0.09) (syst) pb. These measurements have a significance, respectively, of 3.3 and 3.0 standard deviations from the background hypotheses and are compatible, within uncertainties, with the corresponding next-to-leading order predictions of 0.137(-0.016)(+0.012) and 0.306(-0.053)(+0.031) pb. PMID- 23679809 TI - Social work training curriculum in disaster management. AB - This article describes training approaches in disaster recovery for social workers, allied workers, and volunteers. Recovery workers from diverse disciplines require specific training in the theoretical constructs, interventions, tasks, and policy to undertake their roles. The article links the knowledge and skills base of disaster recovery to core social work professional education. Current debates in disaster recovery practice are discussed. An undergraduate and postgraduate program developed for Singaporean social work students is outlined in detail. Other models of training are described, including interagency programs, ongoing professional development, workshops after impact, specific training for volunteers, and training for the community itself. PMID- 23679808 TI - Role of the professional helper in disaster intervention: examples from the Wenchuan Earthquake in China. AB - This article highlights the different roles that social workers played in disaster intervention after the Wenchuan earthquake. Using 3 stages (i.e., rescue, temporary relocation, and reconstruction) as a time framework, we describe social workers' roles, their performance, and the achievements and challenges they faced while providing service to the people and communities affected by the earthquake. Moreover, we draw conclusions on best practices and lessons learned, and make recommendations for future practices and research. PMID- 23679810 TI - Policy and collaboration for social recovery after disaster. AB - The development of the structure and program for sustained intervention of disaster is the focus of this article. Structure consists of the framework for government, nonprofit groups, as well as local communities working together in response to disaster. It is concerned with the allocation of resources for effective service delivery. Collaboration at all levels and among public, private, and nonprofit organizations provides the basis for effective intervention. Policy also involves opening the boundaries and accepting international rescue and resources for long-term recovery. The article suggests a multisector, integrative, and evaluative approach to intervention for disaster recovery. PMID- 23679811 TI - Effect of tonsillectomy on health-related quality of life and costs. AB - CONCLUSION: Tonsillectomy (TE) seems to be a cost-saving procedure with a positive effect on a patient's health-related quality of life (HRQoL). OBJECTIVES: The aim of this study was to explore how TE affects health-related quality of life (HRQoL) and the costs due to health service use and absence from work. METHODS: All 557 patients over the age of 15 years undergoing scheduled TE in the Helsinki University Central Hospital's Otorhinolaryngological Department between February 2008 and June 2009 were asked to participate and to complete the 15D HRQoL questionnaire as well as a questionnaire exploring the use of health care services during the preceding 3 months. Follow-up questionnaires were sent 6 and 12 months after the operation. RESULTS: Of the 557 patients, 124 (22%) answered all three questionnaires. Preoperatively the patients were significantly worse off than the age- and gender-standardized general population. TE improved their HRQoL on 6 of the 15 dimensions, and overall (15D score improved from baseline 0.939 to 0.959 at 12 months, p < 0.001). The most marked improvement (p < 0.001) occurred on the dimensions of breathing, sleeping, and discomfort and symptoms. Self-reported costs due to health service use and absence from work distinctly diminished. PMID- 23679812 TI - Impact of positron emission tomography with the use of fluorodeoxyglucose on response to induction chemotherapy in patients with oropharyngeal and hypopharyngeal squamous cell carcinoma. AB - CONCLUSION: Maximum standardized uptake values (SUVmax) have prognostic value for induction chemotherapy (ICT) response and survival in oropharyngeal and hypopharyngeal squamous cell carcinoma (OHSCC) patients. Pretreatment positron emission tomography with the use of fluorodeoxyglucose ((18)F-FDG PET) may be an aid in deciding the treatment strategy in OHSCC patients. OBJECTIVES: We investigated the association between pretreatment (18)F-FDG PET and response to ICT and survival in OHSCC patients. METHODS: We conducted a retrospective cohort study of 58 OHSCC patients treated at Aichi Cancer Center Hospital. The predictive impact of SUVmax of the primary tumor site was evaluated using statistical multivariate proportional hazard models. RESULTS: Thirty-one cases (53%) were located in the oropharynx and 27 (47%) in the hypopharynx. Median SUVmax was 11.6 (range 3.2-23.5), and was significantly higher in the 8 patients with less than stable disease than in the 50 with more than partial response (median SUVmax, 17.3 vs 11.1; p = 0.002). In multivariate analysis, hazard ratios for the medium and high SUVmax groups relative to the low group were 3.07 (95% confidence interval, 0.62-15.29; p = 0.170) and 4.71 (0.97-22.89; p = 0.055), respectively, and the dose-response relationship was statistically significant (p trend = 0.047). A similar tendency was observed on subclassification by oropharynx and hypopharynx. PMID- 23679813 TI - Histological and prognostic importance of CD44(+) /CD24(+) /EpCAM(+) expression in clinical pancreatic cancer. AB - CD44(+) /CD24(+) /EpCAM(+) cells have been reported to be cancer stem cells in pancreatic cancer; however, the histological and clinical importance of these cells has not yet been investigated. Here we clarified the characteristics of CD44(+) /CD24(+) /EpCAM(+) cells in clinical specimens of pancreatic cancer using immunohistochemical assay. We used surgical specimens of pancreatic ductal adenocarcinoma from 101 patients. In view of tumor heterogeneity, we randomly selected 10 high-power fields per case, and triple-positive CD44(+) /CD24(+) /EpCAM(+) expression was identified using our scoring system. The distribution, histological characteristics, and prognostic importance of CD44(+) /CD24(+) /EpCAM(+) cells were then analyzed. As a result, the distribution of CD44(+) /CD24(+) /EpCAM(+) cells varied widely among the 101 cases examined, and CD44(+) /CD24(+) /EpCAM(+) expression was correlated with poor glandular differentiation and high proliferation. Survival analysis showed that CD44(+) /CD24(+) /EpCAM(+) expression was not correlated with patient outcome; however, CD44(+) /CD24(+) expression appeared to be correlated with poor prognosis. In conclusion, CD44(+) /CD24(+) /EpCAM(+) expression overlapped with poorly differentiated cells and possessed high proliferative potential in clinical pancreatic cancer. In particular, the presence of double-positive CD44(+) /CD24(+) expression seemed to have clinical relevance, associating with poor prognosis. PMID- 23679814 TI - The antioxidative effect of heat-shock protein 70 in dendritic cells. AB - Reactive oxygen species (ROS) are produced by dendritic cells (DCs) during antigen presentation in contact hypersensitivity (CHS). ROS cause a number of non enzymatic protein modifications, such as carbonylation. Carbonylated proteins in DCs in response to hapten have not been fully identified yet. To identify the proteins carbonylated by ROS, murine epidermis-derived DC line XS106 was challenged with a hapten, 2,4,6-trinitrobenzene sulphonic acid (TNBS). MALDI-TOF analysis revealed that heat-shock protein 70 (HSP70) was one of the carbonylated proteins induced by TNBS. To verify the role of HSP70 in TNBS-treated XS106 cell, we fused protein transduction domain (PTD) with HSP70 to facilitate protein delivery into the cell. The transfected fusion protein HSP70 within the cell caused transient increase of the cellular level of HSP70. Transient increase of HSP70 level in XS-106 DCs resulted in inhibition of ROS production, carbonylation of HSP70, p38 MAPK activation and subsequently IL-12 secretion. To investigate the effects of PTD-HSP70 in vivo, ear-swelling experiments with 2,4,6-trinitro-1 chlorobenzene (TNCB) were performed in BALB/c mice. Pretreatment of PTD-HSP70 reduced the CHS response to TNCB in vivo. We report here that carbonylation of HSP70 by ROS is associated with the pathogenesis of CHS, suggesting possibility of HSP70-targeting therapy in CHS. PMID- 23679815 TI - Bullous pemphigoid appearing both on thermal burn scars and split-thickness skin graft donor sites. PMID- 23679816 TI - Superior performance of copper based MOF and aminated graphite oxide composites as CO2 adsorbents at room temperature. AB - New composites Cu-BTC MOF and graphite oxide modified with urea (GO-U) are developed and tested as CO2 adsorbents at room temperature. The composite containing GO-U with the highest nitrogen content exhibits an excellent CO2 uptake (4.23 mmol/g) at dynamic conditions. The incorporation of GO-U into MOF changes the chemistry and microstructure of the parent MOF and results in synergistic features beneficial for CO2 retention on the surface. To identify these features the initial and exhausted materials were extensively characterized from the points of view of their porosity and chemistry. Although the adsorption forces are relatively strong, the results indicate that CO2 is mainly physisorbed on the composites at dry dynamic conditions at ambient temperature and pressure. The primary adsorption sites include small micropores specific for the composites, open Cu sites, and cage window sites. PMID- 23679817 TI - Inhibition by new glucocorticoid antedrugs [16alpha, 17alpha-d] isoxazoline and [16alpha, 17alpha-d]-3'-hydroxy-iminoformyl isoxazoline derivatives of chemotaxis and CCL26, CCL11, IL-8, and RANTES secretion. AB - The underlying inflammation present in chronic airway diseases is orchestrated by increased secretion of CC and CXC chemokines that selectively recruit the leukocyte populations into the pulmonary system. Human chemokines, eotaxins (CCL11 and CCL26), RANTES, and interleukin (IL)-8, are dramatically upregulated through G-protein receptors in cell inflammation, including human asthma. In previous studies, a series of new glucocorticoid antedrugs (GCAs) were synthesized as derivatives of isoxazoline and oxime, and their pharmacological properties based on the antedrug concepts were evaluated. Utilizing both human airway epithelium (HAE) and eosinophil (EOS) cell culture models, we carried out studies to test the hypothesis that new GCA cell treatment would ameliorate Th 1/Th-2-driven secretion of these asthmatic biomarkers, eotaxins (CCL11 and CCL26), RANTES, and IL-8 chemokines, that would in turn decrease recruitment, proliferation, and activation of EOS cells. Results demonstrate that isoxazoline and oxime derivatives exhibit concentration-dependent inhibition, and specifically the compound No. 7 decreases significantly the secretion of eotaxins, RANTES, and IL-8 in cytokine-stimulated HAE cells. It was shown that EOS proliferation and activation were reduced considerably, and cell apoptosis occurred when exposed to nonfluorinated isoxazoline derivatives. These results provide evidence that concentration and structural manipulation of GCAs could increase the anti-inflammatory potency in treatment of chronic diseases, including asthma. PMID- 23679819 TI - Effect of the kangaroo position on the electromyographic activity of preterm children: a follow-up study. AB - BACKGROUND: One of the components of the Kangaroo Method (KM) is the adoption of the Kangaroo Position. The skin-to-skin contact and the vertical position the child adopts when in this position may provide sensorial, vestibular and postural stimuli for the newborn. The Kangaroo Position may encourage vestibular stimuli and a flexed posture of the limbs, suggesting the hypothesis that the Kangaroo Position may have an impact on flexor muscle tone. The effect of these stimuli on the motor features of the newborn has not been the subject of much investigation. No study has yet been conducted to determine whether the Kangaroo Position may progressively increase electromyographic activity or whether this increase persists until term-equivalent age. The aim of this study was to evaluate the effect of the Kangaroo Position on the electromyographic activity of preterm children. METHOD: A follow-up study was carried out between July and November 2011 at the Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Recife Brazil, using a sample of 30 preterm children. Surface Eletromyography (SEMG) was used to investigate the muscle activity of biceps brachii. The electromyographic readings were taken immediately before (0 h) and after 24 h, 48 h, 72 h, 96 h of application of the Kangaroo Position as well as at the term equivalent age in each baby. Electromyographic activity was analyzed using the Root Mean Square (RMS) and the mean values of the times were analyzed by way of analysis of variance for repeated measures and the Tukey test. RESULTS: Electromyographic activity of the biceps brachii varied and increased over the whole 96h period (RMS:0 h = 36.5 and 96 h = 52.9) (F(5.174) = 27.56; p < 0.001) and remained constant thereafter (RMS: term-equivalent age = 54.2). The correlations between the corrected age and the values for electromyographic activity did not show any statistical significance. CONCLUSION: The Kangaroo Position leads to a growing increase in the electromyographic activity of preterm children's biceps brachii after up to 96 h of stimulation and this response persists until at least the 21st day after this period. PMID- 23679818 TI - Engagement of CD14 sensitizes primary monocytes to IFN-gamma to produce IL 12/23p40 and IL-23 through p38 mitogen-activated protein kinase and independent of the janus kinase/signal transducers and activators of transcription signaling. AB - Interferon (IFN)-gamma is a potent stimulator of the IL-12 family Th1 cytokines, including IL-12/23p40 and IL-23, responsible for coordinating the innate and adaptive immune responses. Our results show that IFN-gamma induced the production of IL-12/23p40 and IL-23p19 mRNA as well as IL-12p40 and IL-23 proteins in primary human monocytes isolated by positive selection through anti-CD14 microbeads. These results were confirmed by IFN-gamma stimulation of CD14 activated monocytes resulting in IL-12/23p40 and IL-23 production. We investigated the signaling pathways governing the regulation of IL-23 and its subunits IL-23p40 and IL-23p19 following IFN-gamma stimulation. We observed a differential regulation of IL-23p19, IL-12/23p40, and IL-23 following IFN-gamma stimulation. IFN-gamma-induced IL-23 and IL-12/23p40 expression was positively regulated by the p38 mitogen-activated protein kinases (MAPKs), independent of the Janus kinase (Jak)/signal transducers and activators of transcription (STAT) signaling. In contrast, IL-12 and IL-23 were negatively regulated by the Jak/STAT, phosphatidylinositol 3-kinase (PI3K), and the c-Jun-N-terminal kinase (JNK) MAPKs in IFN-gamma-stimulated monocytes. Overall, our results suggest for the first time a differential positive regulation of IL-12p40 and IL-23 by p38 MAPKs independent of the Jak/STAT pathways and negative regulation by the Jak/STAT, JNK, and PI3K pathways in CD14-activated primary human monocytes stimulated with IFN-gamma. PMID- 23679820 TI - Conceptualizing how group singing may enhance quality of life with Parkinson's disease. AB - Abstract Purpose: Group singing could be a promising component of neurorehabilitative care. This article aims to conceptualize how group singing may enable people with Parkinson's disease (PD) to synchronize their movement patterns to musical rhythm and enhance quality of life. METHOD: Spanning the medical and social sciences, the article draws conceptually on literature on PD, group singing and rhythm in music; personal experience; and reasoning. RESULTS: Conceptualizing PD in terms of disruptions to social and biological rhythms, we hypothesize how group singing may produce two socio-psychological states - connectedness and flow - that may entrain rhythm in people with PD. The states connect during group singing to elicit and enhance motor processes but may also reawaken after the group singing, through the recall and reactivation of the musical rhythms encoded during group singing. CONCLUSIONS: In people with PD, this continuity of flow is hypothesized to be conducive to rhythmic entrainment during and after group singing and in turn to reduced deficits in motor timing and emotional processing, and improvements in quality of life. Empirical studies are needed to test this hypothesis in people with movement disorders such as PD. Implications for Rehabilitation Musical rhythm in group singing may enhance quality of life, and rehabilitation, in people with PD. Use group singing to produce two socio-psychological states - connectedness and flow - that may yield these health benefits. Include people with PD in singing groups to facilitate perceptual exposure to familiar music with melodic distinctiveness and a regular beat. PMID- 23679821 TI - A program of nurse algorithm-guided care for adult patients with acute minor illnesses in primary care. AB - BACKGROUND: Attention to patients with acute minor-illnesses requesting same-day consultation represents a major burden in primary care. The workload is assumed by general practitioners in many countries. A number of reports suggest that care to these patients may be provided, at in least in part, by nurses. However, there is scarce information with respect to the applicability of a program of nurse management for adult patients with acute minor-illnesses in large areas. The aim of this study is to assess the effectiveness of a program of nurse algorithm guided care for adult patients with acute minor illnesses requesting same-day consultation in primary care in a largely populated area. METHODS: A cross sectional study of all adult patients seeking same day consultation for 16 common acute minor illnesses in a large geographical area with 284 primary care practices. Patients were included in a program of nurse case management using management algorithms. The main outcome measure was case resolution, defined as completion of the algorithm by the nurse without need of referral of the patient to the general practitioner. The secondary outcome measure was return to consultation, defined as requirement of new consultation for the same reason as the first one, in primary care within a 7-day period. RESULTS: During a two year period (April 2009-April 2011), a total of 1,209,669 consultations were performed in the program. Case resolution was achieved by nurses in 62.5% of consultations. The remaining cases were referred to a general practitioner. Resolution rates ranged from 94.2% in patients with burns to 42% in patients with upper respiratory symptoms. None of the 16 minor illnesses had a resolution rate below 40%. Return to consultation during a 7-day period was low, only 4.6%. CONCLUSIONS: A program of algorithms-guided care is effective for nurse case management of patients requesting same day consultation for minor illnesses in primary care. PMID- 23679823 TI - In vitro antistaphylococcal effects of a novel 45S5 bioglass/agar-gelatin biocomposite films. AB - AIMS: To assess the antibacterial efficacy of new composite materials developed from microparticles of 45S5 bioactive glass (BG) and agar-gelatin films. METHODS AND RESULTS: In vitro antibacterial activity was evaluated against Staphylococcus spp. because of the importance of this pathogen in damaged tissues and in failures associated with biomaterial implants. To our knowledge, this is the first paper reporting on the suitable combination of BG and agar-gelatin for bioactive and antibacterial films. Bacterial suspensions up or below 10(5) CFU ml(-1) reflecting situations of wound infection and of noninfection, respectively, were prepared and then put in contact with the biomaterials at 37 degrees C. After 24 and 48 h of incubation, the pH value was measured and the staphylococci strains viability was determined by counting in Mueller-Hinton agar plates. Moreover, the biomaterials were prepared for observation under scanning electron microscopy (SEM). Biocomposites (BCs) showed a strong antibacterial effect against all staphylococci strains tested. Some differences were found depending on the strain, the inoculum size and the contact time. This effect was correlated with an alkalinization of the media. By SEM analyses, no bacterial presence was observed on the surface of BCs in any of the cell concentrations tested at any time. CONCLUSIONS: Overall, the coating of 45S5 BG on agar-gelatin films promoted BCs with strong antistaphylococcal activity. The effect was efficient under bacterial concentration up or below 10(5) CFU ml(-1). Additionally, none of the strains were found on BCs surfaces. SIGNIFICANCE AND IMPACT OF STUDY: 45S5 bioglass/agar-gelatin biocomposite films are reported for the first time. The results suggest a potential application as wound dressing. PMID- 23679824 TI - Irreversibility and hysteresis in redox molecular conduction junctions. AB - In this work we present and discuss theoretical models of redox molecular junctions that account for recent observations of nonlinear charge transport phenomena, such as hysteresis and hysteretic negative differential resistance (NDR). A defining feature in such models is the involvement of at least two conduction channels--a slow channel that determines transitions between charge states of the bridge and a fast channel that dominates its conduction. Using Marcus' theory of heterogeneous electron transfer (ET) at metal-molecule interfaces we identify and describe different regimes of nonlinear conduction through redox molecular bridges, where the transferring charge can be highly localized around the redox moiety. This localization and its stabilization by polarization of the surrounding medium and/or conformational changes can lead to decoupling of the current response dynamics from the time scale of the voltage sweep (that is, the current does not adiabatically follow the voltage), hence to the appearance of memory (thermodynamic irreversibility) in this response that is manifested by hysteresis in current-voltage cycles. In standard voltammetry such irreversibility leads to a relative shift of the current peaks along the forward and backward voltage sweeps. The common origin of these behaviors is pointed out, and expressions of the threshold voltage sweep rates are provided. In addition, the theory is extended (a) to analyze the different ways by which such phenomena are manifested in single sweep cycles and in ensemble averages of such cycles and (b) to examine quantum effects in the fast transport channel. PMID- 23679825 TI - MicroRNAs in myeloid malignancies. AB - MicroRNAs (miRNAs) are key to the pathogenesis of human malignancies and increasingly recognized as potential biomarkers and therapeutic targets. Haematological malignancies, being the earliest human malignancies linked to aberrant miRNA expression, have consistently underpinned our understanding of the role that miRNAs play in cancer development. Here, we review the expanding roles attributed to miRNAs in the pathogenesis of different types of myeloid malignancies and highlight key findings. PMID- 23679826 TI - Melatonin treatment reduces endoplasmic reticulum stress and modulates the unfolded protein response in rabbits with lethal fulminant hepatitis of viral origin. AB - Hepatocyte apoptosis plays an important role in the development of fulminant hepatic failure (FHF). The objective of this study was to investigate whether endoplasmic reticulum (ER) stress and unfolded protein response (UPR) inhibition is an underlying mechanism of melatonin anti-apoptotic effects in an animal model of FHF of viral origin induced by the rabbit hemorrhagic disease virus (RHDV). Rabbits were experimentally infected with 2 * 10(4) hemagglutination units of a RHDV isolate and received melatonin at two concentrations of 10 mg/kg and 20 mg/kg at 0 hr, 12 hr and 24 hr postinfection. RHDV infection induced increased expression of CCAAT/enhancer-binding protein homologous protein (CHOP), immunoglobulin heavy chain binding protein (BiP/GRP78), glucose-regulated protein 94 (GRP94), phospho-c-Jun N-terminal kinase (JNK) and caspase-12. These effects were attenuated by melatonin. Double immunofluorescence staining showed colocalization of CHOP and cleaved caspase-3 in liver sections of RHDV-infected rabbits, while immunostaining decreased markedly with melatonin treatment. RHDV infection resulted in significant increases in the mRNA levels of activating transcription factor 6 (ATF6), ATF4, inositol-requiring enzyme 1 (IRE1), spliced X-box binding protein-1 (XBP1s) and tumor necrosis factor receptor-associated factor 2 (TRAF2). Melatonin attenuated the extent of the changes. Data obtained provide evidence that in rabbits with experimental infection by RHDV, reduction in apoptotic liver damage by melatonin is associated with attenuation of ER stress through a modulation of the three arms of UPR signaling and further support a potential hepatoprotective role of melatonin in FHF. PMID- 23679827 TI - Reversal of multidrug resistance by mitochondrial targeted self-assembled nanocarrier based on stearylamine. AB - Multidrug resistance (MDR) remains one of the major challenges for successful chemotherapy. Herein, we tried to develope a mitochondria targeted teniposide loaded self-assembled nanocarrier based on stearylamine (SA-TSN) to reverse MDR of breast cancer. SA-TSN was nanometer-sized spherical particles (31.59 +/- 3.43 nm) with a high encapsulation efficiency (99.25 +/- 0.21%). The MDR in MCF-7/ADR cells was obviously reduced by SA-TSN, which mainly attributed to the markedly reduced expression of P-gp, increased percentages in G2 phase, selectively accumulation in mitochondria, decrease of mitochondrial membrane potential, and greatly improved apoptosis. The plasma concentration of teniposide was greatly improved by SA-TSN, and the intravenously administered SA-TSN could accumulate in the tumor site and penetrate into the inner site of tumor in MCF-7/ADR induced xenografts. In particular, the in vivo tumor inhibitory efficacy of SA-TSN in MCF 7/ADR induced models was more effective than that of teniposide loaded self assembled nanocarrier without stearylamine (TSN) and teniposide solution (TS), which verified the effectiveness of SA-TSN in reversal of MDR. Thereby, SA-TSN has potential to circumvent the MDR for the chemotherapy of breast cancer. PMID- 23679828 TI - Determinants of anaemia among pregnant women in rural Uganda. AB - INTRODUCTION: In spite of intervention efforts, in Uganda, as in other developing countries, high levels of anaemia among pregnant women continue. Anaemia among women of reproductive age (15-49 years) is a matter of national concern. This study was carried out to assess determinants of anaemia in Kiboga district. METHODS: This was a single cross-sectional, descriptive survey. The anaemia status of the pregnant women was determined by measuring their haemoglobin levels. Possible determinant factors including socio-economic characteristics, knowledge, attitudes, practices and food intake were assessed using a structured questionnaire. RESULTS: Results showed that the prevalence of anaemia among pregnant women in Kiboga district was high enough (63.1%) to be described as a severe public health problem. The uptake and utilisation of the public-health intervention package to combat anaemia in pregnancy was low, with iron/folic acid supplementation at 13.2%, use of intermittent preventive treatment of malaria 45.4%, and use of de-worming medicines 14.5%. Women from households without a functional radio were 2.07 times more likely be anaemic (95%CI, 1.08-3.00) compared with women from households where there was a functional radio. There was little awareness and functional knowledge about anaemia among pregnant women. CONCLUSION: The high prevalence of anaemia observed in Kiboga district can be attributed to poverty and limited access to nutrition and health education information which lead to low uptake and utilization of the public-health intervention package to combat anaemia in pregnancy. PMID- 23679829 TI - In situ thermal imaging and absolute temperature monitoring by luminescent diphenylalanine nanotubes. AB - The temperature sensing capability of diphenylalanine nanotubes is investigated. The materials can detect local rapid temperature changes and measure the absolute temperature in situ with a precision of 1 degrees C by monitoring the temperature-dependent photoluminescence (PL) intensity and lifetime, respectively. The PL lifetime is independent of ion concentrations in the medium as well as pH in the physiological range. This biocompatible thermal sensing platform has immense potential in the in situ mapping of microenvironmental temperature fluctuations in biological systems for disease diagnosis and therapeutics. PMID- 23679822 TI - Ethical issues arising from the INTERGROWTH-21st Fetal Growth Longitudinal Study. AB - The INTERGROWTH-21st Project presented a complex set of ethical challenges given the involvement of health institutions in geographically and culturally diverse areas of the world, with differing attitudes to pregnancy. This paper addresses how the research team dealt with some of those issues. PMID- 23679830 TI - Serendipitous discovery of a prodrug of a PARP-1 inhibitor. AB - During SAR development of previously reported pyrrolocarbazole 1, a potent PARP-1 inhibitor, compound 14, was discovered serendipitously to be a prodrug of compound 1. PMID- 23679831 TI - Female sex workers who use amphetamine-type stimulants (ATS) in three cities of Vietnam: use and sexual risks related to HIV/AIDS. AB - Early evidence shows that amphetamine-type stimulant (ATS) use has been rapidly increasing in Vietnam. Female sex workers (FSWs) who use ATSs have increased sexual risks for HIV infection. This paper presents qualitative data from a mixed method study conducted from 2010 to 2011 that aimed to explore the use of ATS among FSWs in three major cities and to identify HIV-related sexual risks among this group. A total of 37 in-depth interviews were conducted, and thematic analysis was performed using NVIVO 8.0 software. Study participants reported that they perceive ATS to be more 'stylish', 'higher class' and much less 'addictive' than heroin. The study highlights multiple sexual risks among this group, including having prolonged sex; sex with multiple simultaneous partners or clients; lack of negotiation for safe sex; increased likelihood of group sex in the context of drug pooling and extended drug and sexual network; as well as unprotected sex. There is an urgent need to promote contextually appropriate interventions to reduce the HIV-related sexual risks among this group. PMID- 23679832 TI - Training of nurses in point-of-care testing: a systematic review of the literature. AB - AIMS AND OBJECTIVES: To review and describe the training of nurses in point-of care testing. BACKGROUND: Point-of-care tests are usually carried out by nurses. They are used in many healthcare units. Through training, nurses are able to improve their competence in performing point-of-care testing. DESIGN: Systematic review. METHOD: A literature search of electronic data was undertaken in autumn 2011 using CINAHL, The Cochrane Library, Medline (Ovid) and Scopus databases. RESULTS: From the available literature, six specific initiatives were analysed. The studies were performed on three continents and in five healthcare settings. The three interventions were related to glucose point-of-care testing. The training approaches involved seven aspects. The interventions were diverse, broad and multifaceted, but they appeared to be successful. The strength of the interventions lay in the involvement of laboratory staff. Quantitative synthesis of the data was not undertaken because of different designs for the studies. CONCLUSION: Training can improve nurses' competence, and many methods are available. There are very few studies of training nurses in point-of-care testing, although in-depth descriptions of interventions in different settings would be valuable. RELEVANCE TO CLINICAL PRACTICE: Nurses can be trained using a variety of methods in different healthcare settings. To save resources, especially in large hospitals and sparsely populated areas, distance learning is worth considering. However if training is delivered with the support of laboratory professionals, nurses subsequently perform good-quality point-of-care testing. PMID- 23679833 TI - Electronic properties of [core+exo]-type gold clusters: factors affecting the unique optical transitions. AB - Unusual visible absorption properties of [core+exo]-type Au6 (1), Au8 (2), and Au11 (3) clusters were studied from experimental and theoretical aspects, based on previously determined crystal structures. Unlike conventional core-only clusters having no exo gold atoms, these nonspherical clusters all showed an isolated visible absorption band in solution. Density functional theory (DFT) studies on corresponding nonphenyl models (1'-3') revealed that they had similar electronic structures with discrete highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) bands. The theoretical spectra generated by time-dependent DFT (TD-DFT) calculations agreed well with the experimentally measured properties of 1-3, allowing assignment of the characteristic visible bands to HOMO-LUMO transitions. The calculated HOMO-LUMO transition energies increased in the order Au11 < Au6 < Au8, as was found experimentally. Frontier orbital analyses indicated that the HOMO and LUMO were both found in proximity to the terminal Au3 triangles containing the exo gold atom, with the HOMO -> LUMO transition occurring in the core -> exo direction. The HOMO/LUMO distribution patterns of 1' and 3' were similar to each other but were markedly different from that of 2', which has longer core-to-exo distances. These findings showed that not only nuclearity (size) but also geometric structures have profound effects on electronic properties and optical transitions of the [core+exo]-type clusters. PMID- 23679834 TI - Monkey liver cytochrome P450 2C9 is involved in caffeine 7-N-demethylation to form theophylline. AB - Caffeine (1,3,7-trimethylxanthine) is a phenotyping substrate for human cytochrome P450 1A2. 3-N-Demethylation of caffeine is the main human metabolic pathway, whereas monkeys extensively mediate the 7-N-demethylation of caffeine to form pharmacological active theophylline. Roles of monkey P450 enzymes in theophylline formation from caffeine were investigated using individual monkey liver microsomes and 14 recombinantly expressed monkey P450 enzymes, and the results were compared with those for human P450 enzymes. Caffeine 7-N demethylation activity in microsomes from 20 monkey livers was not strongly inhibited by alpha-naphthoflavone, quinidine or ketoconazole, and was roughly correlated with diclofenac 4'-hydroxylation activities. Monkey P450 2C9 had the highest activity for caffeine 7-N-demethylation. Kinetic analysis revealed that monkey P450 2C9 had a high Vmax/Km value for caffeine 7-N-demethylation, comparable to low Km value for monkey liver microsomes. Caffeine could dock favorably with monkey P450 2C9 modeled for 7-N-demethylation and with human P450 1A2 for 3-N-demethylation. The primary metabolite theophylline was oxidized to 8 hydroxytheophylline in similar ways by liver microsomes and by recombinant P450s in both humans and monkeys. These results collectively suggest a high activity for monkey liver P450 2C9 toward caffeine 7-N-demethylation, whereas, in humans, P450 1A2-mediated caffeine 3-N-demethylation is dominant. PMID- 23679835 TI - Two new species of Hymenolepis (Cestoda: Hymenolepididae) from murid rodents (Rodentia: Muridae) in the Philippines. AB - Two previously unrecognized species of the genus Hymenolepis are described based on specimens obtained from murid rodent species Bullimus luzonicus , Apomys microdon , and Rattus everetti collected on Luzon Island, Philippines. Hymenolepis bicauda n. sp. differs from all known Hymenolepis spp. in relative position of the poral dorsal and ventral osmoregulatory canals, gravid uterus occupying less than half the length of proglottid, relatively few eggs, and the highly characteristic longitudinal split of proglottids at the end of the gravid strobila. Hymenolepis haukisalmii n. sp. differs from all known Hymenolepis spp. in the relative position of both poral and aporal dorsal and ventral osmoregulatory canals and uterus lacking dorsal and ventral diverticula. The shift in the relative position of the dorsal and ventral osmoregulatory canals was not known in Hymenolepis from rodents in other regions of the world and is reminiscent of the situation observed in Hymenolepis erinacei, parasitic in hedgehogs, and members of the genus Talpolepis, parasitic in moles. The cosmopolitan species Hymenolepis diminuta was the only member of the genus previously reported from the Philippines. PMID- 23679837 TI - On developing an intersubjective frame for intellectual disability work. AB - PURPOSE: This paper aims to show how an intersubjective view on disablist discourse and practice might craft an egalitarian space from which expert voices on living and working with intellectual impairment could emerge, and attempts to further bridge psychoanalytic and disability studies. METHOD: The paper shares the view on dispelling the notion that intellectually impaired individuals cannot benefit from psychoanalytic psychotherapy, and speaks to the slow progression of research on intellectual disability psychotherapies. It supports disability researchers' emphasis on moving studies from a third-person reporting style toward counter-hegemonic texts, and explores a way of forefronting impaired individuals' expertise. RESULTS: The discussion shows how subjectivities of both psychotherapist and intellectually impaired patient can intersect - thereby raising previously subdued voices to enable social action for the expression of dissatisfaction, equal (moral) rights, individuality and freedom from disablist practices. CONCLUSION: Intersubjective work could offer a new way of understanding psychotherapy and research with intellectually disabled individuals differing in degree and manner of impairment; address effects of subaltern voice, marginalisation, disempowerment and defense by equalising therapist-patient power (im)balances; and by virtue of its scientific literature base, provide a contextual clinical account of disability psychotherapy and research as anti discriminatory political and social processes. Implications for Rehabilitation Psychoanalytic intersubjectivity implies that there can be no analytic neutrality unaffected by the therapist's subjectivity, and that ongoing experiences of one's subjectivity are deeply influenced by the subjectivities of those with whom one is interacting. Cautious and thoroughly considered self-disclosure on the part of the therapist in experiencing the patient becomes a permissible therapeutic intervention. In intersubjective research texts, the experience of disability can ultimately be voiced by the real experts living with intellectual impairment in an often disabling world. PMID- 23679836 TI - What makes up good consultations? A qualitative study of GPs' discourses. AB - BACKGROUND: In medical literature, several principles that define 'good consultations' have been outlined. These principles tend to be prescriptive in nature, overlooking the complexity of general practitioners (GPs)' perspectives of everyday practice. Focusing on perspectives might be particularly relevant, since they may affect decisions and actions. Therefore, the present study adopts a bottom-up approach, analyzing GPs' narratives about 'good' and 'bad' consultations. We aimed at describing the range of discourses GPs use in relating on their practice. METHODS: Semi-structured interviews were conducted with 19 Belgian GPs. By means of a qualitative analysis, the authors mapped patterns in the interview narratives and described the range of different discourses. RESULTS: Four discourses were identified: a biomedically-centered discourse, a communication-focused discourse, a problem-solving discourse and a satisfaction oriented discourse. Each discourse was further specified in terms of predominant themes, problems the GPs prefer to deal with and inherent difficulties. Although most participants used elements from all four discourses, the majority of the GPs relied on an individual set of predominant discourses and focused on a limited number of themes. CONCLUSION: This study clearly indicates that there is no uniform way in which GPs perceive clinical practice. Each of the participants used a subtle mix of different criteria to define good and bad medical consultations. Some discourse elements appear to be rooted in medical literature, whereas others are of a more personal nature. By focusing on the limitations of each discourse, this study can shed new light on some of the difficulties GPs encounter in their daily practice: being confronted with specific problems might be an effect of adhering to a specific discourse. The typification of different discourses on consultations may function as a framework to help GPs reflect on how they perceive their practice, and help them manage some of the challenges met in daily practice. PMID- 23679838 TI - Role of dimerization efficiency of transmembrane domains in activation of fibroblast growth factor receptor 3. AB - Mutations in transmembrane (TM) domains of receptor tyrosine kinases are shown to cause a number of inherited diseases and cancer development. Here, we use a combined molecular modeling approach to understand molecular mechanism of effect of G380R and A391E mutations on dimerization of TM domains of human fibroblast growth factor receptor 3 (FGFR3). According to results of Monte Carlo conformational search in the implicit membrane and further molecular dynamics simulations, TM dimer of this receptor is able to form a number of various conformations, which differ significantly by the free energy of association in a full-atom model bilayer. The aforementioned mutations affect dimerization efficiency of TM segments and lead to repopulation of conformational ensemble for the dimer. Particularly, both mutations do not change the dimerization free energy of the predominant (putative "non-active") symmetric conformation of TM dimer, while affect dimerization efficiency of its asymmetric ("intermediate") and alternative symmetric (putative "active") models. Results of our simulations provide novel atomistic prospective of the role of G380 and A391E mutations in dimerization of TM domains of FGFR3 and their consecutive contributions to the activation pathway of the receptor. PMID- 23679839 TI - Roles of AML1/RUNX1 in T-cell malignancy induced by loss of p53. AB - AML1/RUNX1 is a frequent target of chromosome translocations and mutations in myeloid and B-cell leukemias, and upregulation of AML1 is also observed in some cases of T-cell leukemias and lymphomas. This study shows that the incidence of thymic lymphoma in p53-null mice is less frequent in the Aml1(+/-) than in the Aml1(+/+) background. AML1 is upregulated in p53-null mouse bone-marrow cells and embryonic fibroblasts. In the steady state, p53 binds to and inhibits the distal AML1 promoter. When the cells are exposed to stresses, p53 is released from the distal AML1 promoter, resulting in upregulation of AML1. Overexpression of AML1 stimulates T-lymphocyte proliferation. These results suggest that upregulation of AML1 induced by loss of p53 promotes lymphoid-cell proliferation, thereby inducing lymphoma development. PMID- 23679840 TI - Pulsed dye laser (FPDL) treatment of a plantar verruca vulgaris and in vivo monitoring of therapy with confocal laser scan microscopy (CLSM). PMID- 23679841 TI - Antidepressants in the treatment of depression/depressive symptoms in cancer patients: a systematic review and meta-analysis. AB - BACKGROUND: Over the past thirty years a number of studies have suggested that antidepressants can be effective in the treatment of depressive symptoms in patients with cancer. The aim of this paper was to review randomized controlled trials (RCTs) and to perform a meta-analysis in order to quantify their overall effect. METHODS: Pubmed and the Cochrane libraries were searched for the time period between 1980 and 2010. RESULTS: Nine RCTs were identified and reviewed. Six of them (with a total of 563 patients) fulfilled the criteria for meta analysis, but exhibited an unclear risk for bias. The estimated effect size was 1.56 with 95% CI: 1.07- 2.28 (p= 0.021). There were no differences in discontinuation rates between antidepressants and placebo groups (RR= 0.86 with 95% CI 0.47- 1.56, p=0.62). CONCLUSIONS: This meta-analysis suggests that antidepressants can be effective in treating depressive symptoms beside clinical depression. When considering the risk of side effects and interactions and the heterogeneity among the mostly small studies, a general recommendation cannot be made until well-controlled studies are conducted. PMID- 23679842 TI - Human adipose-derived mesenchymal stem cells can survive and integrate into the adult rat eye following xenotransplantation. AB - BACKGROUND: Novel threads of discovery provide the basis for optimism for the development of a stem-cell-based strategy for the treatment of retinal blindness. Accordingly, achievement to suitable cell source with potential-to-long-term survival and appropriate differentiation can be an effective step in this direction. METHODS: After derivation of human adipose-derived mesenchymal stem cells (HAD-MSCs), they were stably transfected with a vector containing Turbo green fluorescent protein (GFP) and JRed to be able to trace them after transplantation. Labeled HAD-MSCs were transplanted into the intact adult rat eye and their survival, integration, and migration during 6 months post transplantation were assessed. RESULTS: The transplanted cells were traceable in the rat vitreous humor (VH) up until 90 days after transplantation, with gradual reduction in numbers, their adhesion and expansion capacity after recovery. These cells were also integrated into the ocular tissues. Nonetheless, some of the implanted cells succeeded to cross the blood-retina barrier (BRB) and accumulate in the spleen with time. CONCLUSIONS: The survival of the HAD-MSCs for a period of 90 days in VH and even longer period of up to 6 months in other eye tissues makes them a promising source to be considered in regenerative medicine of eye diseases. However, the potency of crossing the BRB by the implanted cells suggests that use of HAD-MSCs must be handled with extreme caution. PMID- 23679845 TI - Insulin sensitivity and beta-cell function estimated by HOMA2 model in sprint trained athletes aged 20-90 years vs endurance runners and untrained participants. AB - There are no studies available that portray insulin sensitivity and beta-cell function in ageing sprint-trained athletes. We compared male young and master sprint-trained athletes to endurance-trained and untrained individuals. We hypothesised that ageing sprint-trained athletes would preserve insulin sensitivity and beta-cell function at a level similar to that of endurance trained peers and better than in untrained individuals. We showed the associations between age and parameters derived from the updated Homeostasis Model Assessment (HOMA2 model) in 52 sprint-trained track and field athletes (aged 20-90 years), 85 endurance runners (20-80 years) and 55 untrained individuals (20-70 years). Fasting glucose, fasting insulin, insulin sensitivity and beta-cell function were not associated with age in sprint-trained athletes. These variables remained relatively stable across a wide range of age and comparable to those observed in endurance-trained athletes. In contrast, the untrained group showed considerable age-related increase in fasting insulin and beta-cell activity and a strong decrease in insulin sensitivity compared to both athletic groups. HOMA2 parameters were significantly related to maximal oxygen in the combined group of participants. In summary, chronic training based on a "sprint model" of physical activity, that contains mixed exercise, seems to be effective in maintaining normal insulin sensitivity with ageing. PMID- 23679846 TI - Kinase inhibitors of marine origin. PMID- 23679848 TI - Dual luciferase assay for secreted luciferases based on Gaussia and NanoLuc. AB - Just recently, NanoLuc, a new engineered luciferase based on the small subunit of the luciferase from Oplophorus gracilirostris was introduced. Like the luciferase from Gaussia princeps, this luciferase is secreted into the medium. Both luciferases are the smallest and brightest luciferases known and well-suited for reporter assays. In our experiments, we demonstrate that both luciferases can be used together in a dual-reporter assay by solving the problem that NanoLuc produces a significant signal with coelenterazine, which is the substrate for Gaussia luciferase. We found that the background signal from NanoLuc with coelenterazine can be calculated from the determination of NanoLuc activity in the presence of its substrate furimazine. This in turn allows the precise determination of the activity of Gaussia which does not produce light in the presence of furimazine. Based on this observation, we developed a high sensitive dual secreted luciferase assay which allows the determination of both activities in a single cotransfection experiment. We demonstrate the versatility and robustness of the assay for the normalization of reporter gene activities. Since Gaussia luciferase and NanoLuc are nonhomologous reporters, the method to determine both luciferase activities may also be useful for coincidence reporter gene systems for high-throughput screening. PMID- 23679844 TI - The important role of T cells and receptor expression in Sjogren's syndrome. AB - Sjogren's syndrome (SjS), an autoimmune disease characterized by exocrine gland dysfunction leading to dry mouth and dry eye diseases, is typified by progressive leucocyte infiltrations of the salivary and lacrimal glands. Histologically, these leucocyte infiltrations generally establish periductal aggregates, referred to as lymphocytic foci (LF), which occasionally appear as germinal centre (GC) like structures. The formation and organization of these LF suggest an important and dynamic role for helper T cells (TH), specifically TH1, TH2 and the recently discovered TH17, in development and onset of clinical SjS, considered a B cell mediated hypersensitivity type 2 disease. Despite an ever-increasing focus on identifying the underlying aetiology of SjS, defining factors that initiate this autoimmune disease remain a mystery. Thus, determining interactions between infiltrating TH cells and exocrine gland tissue (auto-)antigens represents a fertile research endeavour. This review discusses pathological functions of TH cells in SjS, the current status of TH cell receptor gene rearrangements associated with human and mouse models of SjS and potential future prospects for identifying receptor-autoantigen interactions. PMID- 23679843 TI - Statistical considerations for the development of prescriptive fetal and newborn growth standards in the INTERGROWTH-21st Project. AB - The INTERGROWTH-21(st) Project has in its mandate to develop prescriptive standards for fetal, neonatal and preterm post-neonatal growth. The project comprises three components: the Fetal Growth Longitudinal Study (FGLS), the Preterm Postnatal Follow-up Study (PPFS), and the Newborn Cross-Sectional Study (NCSS). We consider here the statistical aspects of the three components as they relate to the construction of these standards, in particular the sample size, and outline the principles that will guide the planned main analyses. PMID- 23679850 TI - Real-time monitoring of relative peptide-protein interaction strengths in the yeast two-hybrid system. AB - The yeast two-hybrid (Y2H) system is one of the most technically straightforward, effective, and widely used tools for the discovery of the binary peptide or protein interactions. However, its exceptional detection sensitivity poses a serious challenge for affinity ranking and hence prioritizing the resultant large number of putative interactors for follow-up analyses. To overcome this apparent bottleneck, we describe here a novel yeast growth curve-based interaction monitoring approach that permits semiautomatic quantification, comparison, and statistically ascertained scoring of a large collection of Y2H interactions under real-time conditions. Initially, we conducted a proof-of-concept test of five literature-validated peptide-protein interactions with known affinities in the low MUM range, and subsequently used the method to classify 88 novel vitamin D receptor-binding peptides derived from high-throughput screening of a highly diverse artificial peptide aptamer library. Based on our in-depth data evaluation, we conclude that real-time monitoring of clone growth as a measure of relative binding strength offers a facile, cost-effective, accurate, reproducible, and further adaptable complement to standard Y2H-derived clone management. PMID- 23679849 TI - Development of a high-throughput screening-compatible assay for the discovery of inhibitors of the AF4-AF9 interaction using AlphaScreen technology. AB - Rearrangements of the mixed-lineage leukemia (MLL) gene occur predominately in pediatric leukemia cases and are generally predictors of a poor prognosis. These chromosomal rearrangements result in fusion of the protein MLL to one of more than 60 protein partners. MLL fusions are potent inducers of leukemia through activation of oncogene expression; therefore, targeting this transcriptional activation function may arrest MLL-rearranged (MLL-R) leukemia. Leukemic cell lines harboring the most common fusion protein, MLL-AF4, require the direct interaction of AF4 with the transcription factor AF9 to survive and self-renew; disrupting this interaction with a cell-penetrating AF4-derived peptide results in cell death, suggesting that the AF4-AF9 interaction could be a viable target for a novel MLL-R leukemia therapy. Here we describe the use of AlphaScreen technology to develop a high-throughput screening (HTS) assay to detect nonpeptidic inhibitors of AF4-AF9 binding. The assay is economical, requiring only low nanomolar concentrations of biotinylated AF4-derived peptide and FLAG tagged AF9 in low-volume 384-well plates. A Z'-factor of 0.71 and a signal-to background ratio of 21.3 showed the assay to be robust, and sensitivity to inhibition was demonstrated with competing AF4-derived peptides. Two pilot screens comprising 5,680 compounds served as validation for HTS at Nemours and the Broad Institute. Assay artifacts were excluded using a counterscreen comprising a biotinylated FLAG peptide. This is the first reported HTS-compatible assay to identify compounds that inhibit a key binding interaction of an MLL fusion partner, and the results presented here demonstrate suitability for screening large chemical libraries in high-density, low-volume plate formats. PMID- 23679851 TI - The tenth annual Ion Channel Retreat, Vancouver, Canada, June 25-27, 2012. AB - Ten years after Aurora Biomed (Vancouver, British Columbia, Canada) hosted the inaugural Ion Channel Retreat, this event is recognized as a leading conference for ion channel researchers. Held annually in Vancouver, this meeting consistently provides an outlet for researchers to share their findings while learning about new concepts, methods, and technologies. Researchers use this forum to discuss and debate a spectrum of topics from ion channel research and technology to drug discovery and safety. The Retreat covered key subjects in the ion channel industry, including ion channels as disease targets, transient receptor protein channels as pain and disease targets, ion channels as pain targets, ion channel structure and function, ion channel screening technologies, cardiac safety and toxicology, and cardiac function and pharmacology. PMID- 23679853 TI - Pain and pain-related situations surrounding community-dwelling older persons. AB - AIMS AND OBJECTIVES: To examine the pain prevalence in community-dwelling older adults and to explore the relationships between pain and physical and psychological parameters. BACKGROUND: Uncontrolled chronic pain is one of the barriers preventing older people from achieving active ageing. Effective pain management can enhance their mobility, increasing the happiness level and thus the quality of life. DESIGN: Exploratory cross-sectional study. METHOD: Cognitively intact community-dwelling older persons aged over 60 in Hong Kong were invited for a 20-25-minute interview. RESULTS: A total of 173 participants were recruited, with a mean age of 73.2. The average pain intensity was 3.97 +/- 1.80. Oral analgesic drugs were used by 47.1% of participants, and 86.0% used nonpharmacological methods to relieve pain. Compared with participants free of chronic pain, participants with pain had lower happiness levels (p < 0.05). In addition, levels of mobility (p < 0.05) and physical quality of life (p < 0.05) were lower for older people with pain. Pain intensity was negatively correlated with physical quality of life (p < 0.05) and self-efficacy (p < 0.05), and positively correlated with mystery (p < 0.05), permanence (p < 0.05) and self blame (p < 0.05) in pain belief. CONCLUSION: It was noted that nonpharmacological methods were commonly used by older persons as pain relief and that older persons with pain were less happy, less mobile and had a poorer quality of life as compared to their counterparts without pain. RELEVANCE TO CLINICAL PRACTICE: It is important to educate community-dwelling older persons on methods of pain management and to maintain their physical and psychological well-being in order to engage them in the community and lead a healthy and happy ageing. PMID- 23679852 TI - Synthesis, characterization, and biological evaluation of (99m) Tc(CO)3 -labeled peptides for potential use as tumor targeted radiopharmaceuticals. AB - During the past decade, several peptides containing Arg-Gly-Asp sequence have been conjugated with different chelating agents for labeling with various radionuclides for the diagnosis of tumor development. In this study, we report the synthesis of two tetrapeptides (Asp-Gly-Arg-His and Asp-Gly-Arg-Cys) and one hexapeptide [Asp-Gly-Arg-D-Tyr-Lys-His] by changing the amino acid sequence of the Arg-Gly-Asp motif. Peptide synthesis was initiated from aspartic acid. Aspartic acid placed at C-terminal end of the peptide chain can be conjugated with different drug molecules facilitating their transport to the site of action. The peptides were synthesized in excellent yield and labeled using freshly prepared [(99m) Tc(CO)3 (H2 O)3 ](+) intermediate. A complexation yield of over 97% was achieved under mild conditions even at low ligand concentrations of 10( 2) m. Radiolabeled peptides were characterized by HPLC and were found to be substantially stable in saline, in His solution as well as in rat serum and tissue (kidney, liver) homogenates. Internalization studies using Ehrlich ascites carcinoma cell line showed rapid and significant internalization (30-35% at 30 min of incubation attaining maximum value of about 40-60% after 2-4 h incubation). A good percentage of quick internalization was also observed in alphav beta3 -receptor-positive B16F10 mouse melanoma cell line (14-16% after 30 min of incubation and 25-30% after 2-4 h incubation). Imaging and biodistribution studies were performed in Swiss albino mice bearing Ehrlich ascites tumor in right thigh. Radiolabeled peptides exhibited fast blood clearance and rapid elimination through the urinary systems. (99m) Tc(CO)3 -tetra-Pep2 exhibited remarkable localization at tumor site (1.15%, 1.17%, and 1.37% ID/g at 2, 4, and 6 h p.i., respectively) which could be due to slow clearance of the radiolabeled peptide from blood in comparison with the other two radiolabeled peptides. However, (99m) Tc(CO)3 -hexa-Pep exhibited the highest tumor to muscle and tumor to blood ratios among the three. The preliminary results with these amino acid based peptides are encouraging enough to carry out further experiments for targeting tumor. PMID- 23679854 TI - Formation of MgO-supported manganese carbonyl complexes by chemisorption of Mn(CO)5CH3. AB - MgO-supported manganese carbonyl complexes were prepared by chemical vapor deposition of Mn(CO)5CH3 on partially dehydroxylated, high-area MgO powder. X-ray absorption spectra identify the resultant surface species, on average, as Mn(CO)4(Os)2 (where the two oxygen ligands are part of the MgO surface), and infrared spectra show that the chemisorption results from the reaction of Mn(CO)5CH3 with OH groups of the MgO surface. Electron paramagnetic resonance and X-ray absorption near edge data indicate that the manganese was in a positive oxidation state other than +2, but the value is not determined, and the IR spectra indicate the presence of a mixture of manganese carbonyls. Extended X-ray absorption fine structure spectra determine the average Mn-CO bond distance to be 1.87 A and the average Mn-O bond distance to be 2.12 A. The surface complex was found to be stable in O2 at room temperature. PMID- 23679855 TI - Crystal structures of human cholinesterases in complex with huprine W and tacrine: elements of specificity for anti-Alzheimer's drugs targeting acetyl- and butyryl-cholinesterase. AB - The multifunctional nature of Alzheimer's disease calls for MTDLs (multitarget directed ligands) to act on different components of the pathology, like the cholinergic dysfunction and amyloid aggregation. Such MTDLs are usually on the basis of cholinesterase inhibitors (e.g. tacrine or huprine) coupled with another active molecule aimed at a different target. To aid in the design of these MTDLs, we report the crystal structures of hAChE (human acetylcholinesterase) in complex with FAS-2 (fasciculin 2) and a hydroxylated derivative of huprine (huprine W), and of hBChE (human butyrylcholinesterase) in complex with tacrine. Huprine W in hAChE and tacrine in hBChE reside in strikingly similar positions highlighting the conservation of key interactions, namely, pi-pi/cation-pi interactions with Trp86 (Trp82), and hydrogen bonding with the main chain carbonyl of the catalytic histidine residue. Huprine W forms additional interactions with hAChE, which explains its superior affinity: the isoquinoline moiety is associated with a group of aromatic residues (Tyr337, Phe338 and Phe295 not present in hBChE) in addition to Trp86; the hydroxyl group is hydrogen bonded to both the catalytic serine residue and residues in the oxyanion hole; and the chlorine substituent is nested in a hydrophobic pocket interacting strongly with Trp439. There is no pocket in hBChE that is able to accommodate the chlorine substituent. PMID- 23679856 TI - Rhombus-shaped tetranuclear [Ln4] complexes [Ln = Dy(III) and Ho(III)]: synthesis, structure, and SMM behavior. AB - The reaction of a new hexadentate Schiff base hydrazide ligand (LH3) with rare earth(III) chloride salts in the presence of triethylamine as the base afforded two planar tetranuclear neutral complexes: [{(LH)2Dy4}(MU2-O)4](H2O)8.2CH3OH.8H2O (1) and [{(LH)2Ho4}(MU2-O)4](H2O)8.6CH3OH.4H2O (2). These neutral complexes possess a structure in which all of the lanthanide ions and the donor atoms of the ligand remain in a perfect plane. Each doubly deprotonated ligand holds two Ln(III) ions in its two distinct chelating coordination pockets to form [LH(Ln)2](4+) units. Two such units are connected by four [MU2-O](2-) ligands to form a planar tetranuclear assembly with an Ln(III)4 core that possesses a rhombus-shaped structure. Detailed static and dynamic magnetic analysis of 1 and 2 revealed single-molecule magnet (SMM) behavior for complex 1. A peculiar feature of the chiM" versus temperature curve is that two peaks that are frequency-dependent are revealed, indicating the occurrence of two relaxation processes that lead to two energy barriers (16.8 and 54.2 K) and time constants (tau0 = 1.4 * 10(-6) s, tau0 = 7.2 * 10(-7) s). This was related to the presence of two distinct geometrical sites for Dy(III) in complex 1. PMID- 23679857 TI - Predictive-property-ranked variable reduction with final complexity adapted models in partial least squares modeling for multiple responses. AB - For partial least-squares regression with one response (PLS1), many variable reduction methods have been developed. However, only a few address the case of multiple-response partial-least-squares (PLS2) modeling. The calibration performance of PLS1 can be improved by elimination of uninformative variables. Many variable-reduction methods are based on various PLS-model-related parameters, called predictor-variable properties. Recently, an important adaptation, in which the model complexity is optimized, was introduced in these methods. This method was called Predictive-Property-Ranked Variable Reduction with Final Complexity Adapted Models, denoted as PPRVR-FCAM or simply FCAM. In this study, variable reduction for PLS2 models, using an adapted FCAM method, FCAM-PLS2, is investigated. The utility and effectiveness of four new predictor variable properties, derived from the multiple response PLS2 regression coefficients, are studied for six data sets consisting of ultraviolet-visible (UV vis) spectra, near-infrared (NIR) spectra, NMR spectra, and two simulated sets, one with correlated and one with uncorrelated responses. The four properties include the mean of the absolute values as well as the norm of the PLS2 regression coefficients and their significances. The four properties were found to be applicable by the FCAM-PLS2 method for variable reduction. The predictive abilities of models resulting from the four properties are similar. The norm of the PLS2 regression coefficients has the best selective abilities, low numbers of variables with an informative meaning to the responses are retained. The significance of the mean of the PLS2 regression coefficients is found to be the least-selective property. PMID- 23679858 TI - Effect of proteins with different isoelectric points on the gene transfection efficiency mediated by stearic acid grafted chitosan oligosaccharide micelles. AB - A stearic acid-grafted chitosan oligosaccharide (CS-SA) micelle has been demonstrated as an effective gene carrier in vitro and in vivo. Although being advantageous for DNA package, protection, and excellent cellular internalization, a CS-SA based delivery system may lead to difficulties in the dissociation of polymer/DNA complexes in intracells. In this research, bovine serum albumin (BSA) with a different isoelectric point value (4.7, 6.0 and 9.3) was synthesized and incorporated into a CS-SA based gene delivery system. CS-SA/DNA binary complexes and CS-SA/BSA/DNA ternary complexes were then prepared and characterized. The binding ability of the CS-SA vector with DNA was not affected by the incorporation of BSA. However, referring to the transfection activity, the BSA of different isoelectric point value (pI) had a distinct influence on the CS SA/BSA/DNA complexes. CS-SA/BSA(4.7)/DNA and CS-SA/BSA(6.0)/DNA complexes had better transfection efficiency than binary complexes, especially CS SA/BSA(4.7)/DNA complexes which showed the highest transfection efficiency. On the contrary, CS-SA/BSA(9.3)/DNA complexes had undesirable performances. Interestingly, the incorporation of BSA(4.7) in CS-SA/DNA complexes significantly enhanced the dissociation of polymer/DNA complexes and improved the release of DNA intracellular without influencing their cellular uptake. The aforementioned results indicated that the acid group in protein played an important role in enhancing the transfection efficiency of CS/BSA/DNA complexes, and the study provided guidelines in the design of an efficient vector for DNA transfection. PMID- 23679859 TI - High tracking of apolipoprotein B levels from the prepubertal age to adolescence in Spanish children. AB - AIM: To assess tracking of lipid and apolipoproteins from the prepubertal age (baseline, 6-8 years old) to adolescence (follow-up, 13-16 years old) in Spanish children. METHODS: The sample population included 385 healthy children (179 boys and 206 girls). Tracking was estimated by correlations between baseline and follow-up levels, multiple regression models in which the follow-up lipid was the dependent variable and analysing the percentage of individuals who remained in the same lipid levels status from prepubertal age to adolescence. RESULTS: Correlations between baseline and follow-up levels for low density lipoprotein (LDL)-cholesterol and apolipoprotein B (apo B) were stronger in boys and for high density lipoprotein-cholesterol and apo A-I stronger in girls. Regression analyses showed that, after adjusting by body mass index (BMI), baseline LDL cholesterol and apo B levels explain 23% and 39% of the variation of follow-up LDL-cholesterol and apo B levels, respectively, in boys and 13% and 22%, respectively, in girls. The strength of tracking for LDL-cholesterol and apo B was 79% and 89%, respectively, in boys and 72% and 82%, respectively, in girls. CONCLUSION: Apolipoprotein B showed the strongest tracking in both sexes, stronger than for LDL-cholesterol, which supports the importance of determining apo B levels as a marker of dyslipidaemia in children. PMID- 23679860 TI - Disparity in embrasure fill and papilla height between tooth- and implant-borne fixed restorations in the anterior maxilla: a cross-sectional study. AB - PURPOSE: The objective of the present study was to compare inter-proximal fill and papilla height between different embrasures. MATERIAL & METHODS: One hundred and fifty non-smoking consecutive patients (mean age 54, range 32-73; 63 males and 87 females) without periodontal disease were selected in a multidisciplinary practice during regular supportive care. All had been treated for multiple tooth loss in the anterior maxilla at least 1 year earlier by means of a fixed restoration on teeth (n = 50) or implants (n = 100) using straightforward procedures (without hard and/or soft tissue augmentation). Embrasure fill was assessed by means of Jemt's papilla index and papilla height was registered following local anaesthesia by means of bone sounding by one clinician. RESULTS: Tooth-pontic and tooth-implant embrasures demonstrated comparable inter-proximal fill and papilla height (>=58% Jemt's score 3; mean papilla height >=4.1 mm). Between missing teeth, embrasure fill and papilla height were lower regardless of the embrasure type. The implant-implant and implant-pontic embrasure demonstrated comparable outcome (<=42% Jemt's score 3; mean papilla height <= 3.3 mm; p >= 0.416), which was significantly poorer when compared to the pontic-pontic embrasure (82% Jemt's score 3; mean papilla height 3.7 mm; p <= 0.019). Overall, papilla index and papilla height demonstrated a weak correlation (Spearman's correlation coefficient: 0.198; p = 0.002). CONCLUSIONS: The re-establishment of a papilla is difficult when there is no tooth involved. In that scenario a short papilla should be expected and implant-borne restorations demonstrate the poorest outcome. Moreover, an implant with a pontic may not perform better than adjacent implants. PMID- 23679861 TI - Is computed tomography volumetric assessment of the liver reliable in patients with cirrhosis? AB - OBJECTIVES: The estimation of liver volume (LV) has been widely studied in normal liver, the density of which is considered to be equivalent to 1 kg/l. In cirrhosis, volumetric evaluation and its correlation to liver mass remain unclear. The aim of this study was to evaluate the accuracy of computed tomography (CT) scanning to assess LV in patients with cirrhosis. METHODS: Liver volume was evaluated by CT (CTLV) and correlated to the explanted liver weight (LW) in 49 patients. Liver density (LD) and its association with clinical features were analysed. Commonly used formulae for estimating LV were also evaluated. The real density of cirrhotic liver was prospectively measured in explant specimens. RESULTS: Wide variations between CTLV (in ml) and LW (in g) were found (range: 3-748). Cirrhotic livers in patients with hepatitis B virus infection presented significantly increased LD (P = 0.001) with lower CTLV (P = 0.005). Liver volume as measured by CT was also decreased in patients with Model for End-stage Liver Disease scores of >15 (P = 0.023). Formulae estimating LV correlated poorly with CTLV and LW. The density of cirrhotic liver measured prospectively in 15 patients was 1.1 kg/l. CONCLUSIONS: In cirrhotic liver, LV assessed by CT did not correspond to real LW. Liver density changed according to the aetiology and severity of liver disease. Commonly used formulae did not accurately assess LV. PMID- 23679862 TI - X-ray crystal structures of the Escherichia coli RNA polymerase in complex with benzoxazinorifamycins. AB - Rifampin, a semisynthetic rifamycin, is the cornerstone of current tuberculosis treatment. Among many semisynthetic rifamycins, benzoxazinorifamycins have great potential for TB treatment due to their superior affinity for wild-type and rifampin-resistant Mycobacterium tuberculosis RNA polymerases and their reduced hepatic Cyp450 induction activity. In this study, we have determined the crystal structures of the Escherichia coli RNA polymerase complexes with two benzoxazinorifamycins. The ansa-naphthalene moieties of the benzoxazinorifamycins bind in a deep pocket of the beta subunit, blocking the path of the RNA transcript. The C3'-tail of benzoxazinorifamycin fits a cavity between the beta subunit and sigma factor. We propose that in addition to blocking RNA exit, the benzoxazinorifamycin C3'-tail changes the sigma region 3.2 loop position, which influences the template DNA at the active site, thereby reducing the efficiency of transcription initiation. This study supports expansion of structure-activity relationships of benzoxazinorifamycins inhibition of RNA polymerase toward uncovering superior analogues with development potential. PMID- 23679863 TI - Ligation-assisted endoscopic enucleation for the diagnosis and resection of small gastrointestinal tumors originating from the muscularis propria: a preliminary study. AB - BACKGROUND: Ligation-assisted endoscopic enucleation (EE-L) was developed for the pathological diagnosis and resection of small gastrointestinal tumors originating from the muscularis propria. The technique combines endoscopic band ligation and endoscopic enucleation. The aim of this study was to evaluate the efficacy and safety of EE-L in the diagnosis and resection of gastrointestinal tumors originating from the muscularis propria. METHODS: A total of 43 patients were eligible for inclusion in this study from June 2009 to June 2011. Endoscopic ligation was first performed to force the tumor to assume a polypoid form with a pseudostalk. EE-L was then performed until the tumor was completely enucleated from the muscularis propria. Wound closure was performed using clips and adhesive tissue. RESULTS: All 43 tumors were completely enucleated. The mean enucleation time was 7.2 minutes (range, 5-11 minutes). No perforation, massive hemorrhage, or peritonitis requiring further endoscopic or surgical intervention occurred. Histopathology, 19 lesions were identified as gastrointestinal stromal tumors and 24 lesions were identified as leiomyomas. The mean follow-up time was 20.4 months (range, 14-38 months). No recurrence has occurred during the follow-up period. CONCLUSIONS: EE-L appears to be a safe, effective, and relatively simple method for the histologic diagnosis and removal of small gastrointestinal tumors originating from the muscularis propria. PMID- 23679864 TI - Discovery of picomolar ABL kinase inhibitors equipotent for wild type and T315I mutant via structure-based de novo design. AB - Although the constitutively activated break-point cluster region-Abelson (ABL) tyrosine kinase is known to cause chronic myelogenous leukemia (CML), the prevalence of drug-resistant ABL mutants has made it difficult to develop effective anti-CML drugs. With the aim to identify new lead compounds for anti CML drugs, we carried out a structure-based de novo design using the scoring function improved by implementing an accurate solvation free energy term. This approach led to the identification of ABL inhibitors equipotent for the wild type and the most drug-resistant T315I mutant of ABL at the picomolar level. Decomposition analysis of the binding free energy showed that a decrease in the desolvation cost for binding in the ATP-binding site could be as important as the strengthening of enzyme-inhibitor interaction to enhance the potency of an ABL inhibitor with structural modifications. A similar energetic feature was also observed in free energy perturbation (FEP) calculations. Consistent with the previous experimental and computational studies, the hydrogen bond interactions with the backbone groups of Met318 proved to be the most significant binding forces to stabilize the inhibitors in the ATP-binding sites of the wild type and T315I mutant. The results of molecular dynamics simulations indicated that the dynamic stabilities of the hydrogen bonds between the inhibitors and Met318 should also be considered in designing the potent common inhibitors of the wild type and T315I mutant of ABL. PMID- 23679865 TI - Curcumin-derivative nanomicelles for the treatment of triple negative breast cancer. AB - BACKGROUND: Triple negative breast cancer (TNBC) is a subtype of breast cancer characterized by its poor outcome and a lack of targeted therapies. Recently, our laboratory has developed a second generation curcumin derivative, 3,5-bis(3,4,5 trimethoxybenzylidene)-1-methylpiperidine-4-one (RL71) that shows potent in vitro cytotoxicity. RL71 is hydrophobic with poor bioavailability which limits its clinical development. PURPOSE: We have designed styrene-co-maleic acid (SMA) micelles encapsulating 5, 10 or 15% RL71 by weight/weight ratio to improve its solubility and pharmacokinetic profile. METHODS: The micelles charge, size and release rate were characterized. We evaluated their cytotoxicity against TNBC cell lines. The internalization of the drug inside the cells was measured by HPLC and the efficiency of the micelles was tested using a tumor spheroid model. RESULTS: The micelles exhibited mean diameters of 125-185 nm and had a neutral charge. SMA-RL71 micelles have a cytotoxicity profile comparable to the free drug against several TNBC cell lines. Moreover, the 15% loaded micelles increased the stability of RL71 and demonstrated higher activity in a tumor spheroid model. CONCLUSION: The current study demonstrates the efficiency of SMA for drug delivery, the influence of physicochemical characteristics on cytotoxicity, and provides the basis for preclinical testing in vivo. PMID- 23679867 TI - Ball possession effectiveness in men's and women's elite basketball according to situational variables in different game periods. AB - The aim of the present study was to identify the importance of basketball performance indicators in predicting the effectiveness of ball possessions in men's and women's basketball, when controlling for situational variables and game periods. The sample consisted of 7234 ball possessions, corresponding to 40 games from the Spanish professional leagues. The effects of the predictor variables on successful ball possessions according to game period were analysed using binary logistic regressions. Results from men's teams show interactions with number of passes and ending player during the first five minutes, with starting and ending zone, defensive systems, screens used and possession duration during the middle thirty minutes, and there were interactions with passes used, possession duration and players involved during the last five minutes. Results from women's teams show interactions with starting and ending zone, passes used, defensive systems and ending player during the first five minutes, and with starting and ending zone, and screens used during the middle thirty minutes. The results show no interaction with situational variables in men's basketball, while league stage was important during the middle thirty minutes and last five minutes in women's basketball, whereas match status was only important during the last five minutes. PMID- 23679866 TI - Reasons for and factors associated with issuing sickness certificates for longer periods than necessary: results from a nationwide survey of physicians. AB - BACKGROUND: Physicians' work with sickness certifications is an understudied field. Physicians' experience of sickness certifying for longer periods than necessary has been previous reported. However, the extent and frequency of such sickness certification is largely unknown. The aims of this study were: a) to explore the frequency of sickness certifying for longer periods than necessary among physicians working in different clinical settings; b) to examine main reasons for issuing sickness certificates for longer periods than necessary; and c) to examine factors associated with unnecessary issued sickness certificates. METHODS: In 2008, all physicians living and working in Sweden (a total of 36,898) were sent an invitation to participate in a questionnaire study concerning their sick-listing practices. A total of 22,349 (60.6%) returned the questionnaire. In the current study, physicians reporting handling sickness certification consultations at least weekly were included in the analyses, a total of 12,348. RESULTS: The proportion of physicians reporting issuing sickness certificates for longer periods than actually necessary varied greatly between different types of clinics, with the highest frequency among those working at: occupational medicine, orthopedic, primary health care, and psychiatry clinics; and lowest among those working in: eye, dermatology, ear/nose/throat, oncology, surgery, and infection clinics. Logistic analyses showed that sickness certifying for longer periods than necessary due to limitations in the health care system was particularly common among physicians working at occupational medicine, orthopedic, and primary health care clinics. Sickness certifying for longer periods than necessary due to patient-related factors was much more common among physicians working at psychiatric clinics. In addition to differences between clinics, frequency of sickness certificates issued for longer periods than necessary varied by age, physicians' experiences of different situations, and perceived problems. CONCLUSIONS: This study showed that physicians issued sickness certificates for longer periods than actually necessary quite frequently at some types of clinics. Differences between clinics were to a large extent associated with frequency of problems, lack of time, delicate interactions with patients, and need for more competence. PMID- 23679868 TI - Infrared probes for studying the structure and dynamics of biomolecules. PMID- 23679869 TI - Do socioeconomic inequalities in mortality vary between different Spanish cities? a pooled cross-sectional analysis. AB - BACKGROUND: The relationship between deprivation and mortality in urban settings is well established. This relationship has been found for several causes of death in Spanish cities in independent analyses (the MEDEA project). However, no joint analysis which pools the strength of this relationship across several cities has ever been undertaken. Such an analysis would determine, if appropriate, a joint relationship by linking the associations found. METHODS: A pooled cross-sectional analysis of the data from the MEDEA project has been carried out for each of the causes of death studied. Specifically, a meta-analysis has been carried out to pool the relative risks in eleven Spanish cities. Different deprivation-mortality relationships across the cities are considered in the analysis (fixed and random effects models). The size of the cities is also considered as a possible factor explaining differences between cities. RESULTS: Twenty studies have been carried out for different combinations of sex and causes of death. For nine of them (men: prostate cancer, diabetes, mental illnesses, Alzheimer's disease, cerebrovascular disease; women: diabetes, mental illnesses, respiratory diseases, cirrhosis) no differences were found between cities in the effect of deprivation on mortality; in four cases (men: respiratory diseases, all causes of mortality; women: breast cancer, Alzheimer's disease) differences not associated with the size of the city have been determined; in two cases (men: cirrhosis; women: lung cancer) differences strictly linked to the size of the city have been determined, and in five cases (men: lung cancer, ischaemic heart disease; women: ischaemic heart disease, cerebrovascular diseases, all causes of mortality) both kinds of differences have been found. Except for lung cancer in women, every significant relationship between deprivation and mortality goes in the same direction: deprivation increases mortality. Variability in the relative risks across cities was found for general mortality for both sexes. CONCLUSIONS: This study provides a general overview of the relationship between deprivation and mortality for a sample of large Spanish cities combined. This joint study allows the exploration of and, if appropriate, the quantification of the variability in that relationship for the set of cities considered. PMID- 23679871 TI - Reducing emotional reasoning: an experimental manipulation in individuals with fear of spiders. AB - Emotional reasoning involves the tendency to use subjective responses to make erroneous inferences about situations (e.g., "If I feel anxious, there must be danger") and has been implicated in various anxiety disorders. The aim of this study of individuals with fear of spiders was to test whether computerised experimental training, compared to control training, would decrease emotional reasoning, reduce fear-related danger beliefs, and increase approach behaviour towards a fear-relevant stimulus. Effects were assessed shortly after the experimental manipulation and one day later. Results showed that the manipulation significantly decreased emotional reasoning in the experimental condition, not in the control condition, and resulted in lower danger estimates of a spider, which was maintained up to one day later. No differences in approach behaviour towards the spider were found. Reducing emotional reasoning may ultimately help patients with anxiety disorders attend more to objective situational information to correct erroneous danger beliefs. PMID- 23679870 TI - Stable RAGE-heparan sulfate complexes are essential for signal transduction. AB - RAGE (Receptor for Advanced Glycation End-Products) has emerged as a major receptor that mediates vascular inflammation. Signaling through RAGE by damage associated molecular pattern molecules often leads to uncontrolled inflammation that exacerbates the impact of the underlying disease. Oligomerization of RAGE is believed to play an essential role in signal transduction, but the molecular mechanism of oligomerization remains elusive. Here we report that RAGE activation of Erk1/2 phosphorylation on endothelial cells in response to a number of ligands depends on a mechanism that involves heparan sulfate-induced hexamerization of the RAGE extracellular domain. Structural studies of the extracellular V-C1 domain-dodecasaccharide complex by X-ray diffraction and small-angle X-ray scattering revealed that the hexamer consists of a trimer of dimers, with a stoichiometry of 2:1 RAGE:dodecasaccharide. Mutagenesis studies mapped the heparan sulfate binding site and the interfacial surface between the monomers and demonstrated that electrostatic interactions with heparan sulfate and intermonomer hydrophobic interactions work in concert to stabilize the dimer. The importance of oligomerization was demonstrated by inhibition of signaling with a new epitope-defined monoclonal antibody that specifically targets oligomerization. These findings indicate that RAGE-heparan sulfate oligomeric complexes are essential for signaling and that interfering with RAGE oligomerization might be of therapeutic value. PMID- 23679872 TI - Chronic annular lesions of the cheeks. Elastosis perforans serpiginosa (EPS). PMID- 23679873 TI - A solitary verrucous nodule on the arm. Granular cell tumor (GCT). PMID- 23679874 TI - Molecularly targeted therapies for nonmelanoma skin cancers. AB - Over the past two decades, advances in the fields of cancer genetics and molecular biology have elucidated molecular pathways that cause numerous cutaneous malignancies. This in turn has spurred the rational design of molecularly targeted therapies. In this review, we discuss the molecular pathways critical to the development of nonmelanoma skin cancers and the novel pharmacologic agents that target them. Included is a review of vismodegib for basal cell carcinoma, cetuximab for squamous cell carcinomas, imatinib for dermatofibrosarcoma protuberans, and sirolimus for Kaposi's sarcoma. PMID- 23679875 TI - Oral Kaposi's sarcoma: a review and update. AB - Kaposi's sarcoma (KS) is an important mucocutaneous neoplasm with four well-known clinicopathologic types. Involvement of the oral cavity may be seen in all variants but is most common with AIDS-KS. The latter may signal undiagnosed HIV infection. Its common association with disseminated disease has potentially important diagnostic and therapeutic implications. Oral KS (OKS) most often affects the hard and soft palate, gingiva, and dorsal tongue with plaques or tumors of coloration ranging from non-pigmented to brownish-red or violaceous. Its involvement ranges from an incidental finding to proliferative tumor formation that interferes with mastication. OKS needs to be distinguished clinically from other entities, including pyogenic granuloma, hemangioma, bacillary angiomatosis, and gingival enlargement caused by cyclosporine, a drug frequently used in recipients of organ transplantation. KS may flare as part of the immune reconstitution inflammatory syndrome in HIV patients or develop in the context of iatrogenic immunosuppression. Management, which may depend upon a variety of factors including the clinicopathologic type of KS and results of staging, ranges from no treatment to local measures such as intralesional vinblastine or systemic administration of cytotoxic chemotherapy for disseminated disease. Modification of immunosuppressive regimens often helps control post transplant OKS but enhances the risk of graft rejection. Screening donors and recipients of organ transplants for HHV-8, with prophylactic treatment if infected as well as institution of sirolimus early after transplantation, are proposed strategies aimed at preventing post-transplant OKS. PMID- 23679876 TI - First reported case of subcutaneous hyalohyphomycosis caused by Paecilomyces variotii. AB - BACKGROUND: Hyalohyphomycosis is a rare opportunistic fungal infection caused by saprophytes of genera such as Fusarium, Paecilomyces, Scedosporium, Penicillium, Scopulariopsis Acremonium, and similar fungi. The literature includes only one previous report of Paecilomyces variotii human infection and very few reports of subcutaneous mycosis caused by any of the hyalohyphomycosis group of fungi. METHODS: We report an instance of fungal infection in a 50-year-old woman, known to have diabetes, who presented with multiple raised lesions on the upper back of two years' duration. Dermatological examination revealed a 20 * 22-cm, swollen, indurated area on the upper back with multiple violaceous, exophytic nodules on the surface. RESULTS: Microscopy from pus and tissue smear revealed septate branching fungi. Periodic acid Schiff (PAS) stain was positive for fungal elements. Culture on three occasions yielded P. variotii. Slide culture mounts showed septate hyaline hyphae of P. variotii with elongated phialides demonstrating bulbous bases and tapering apices attached to the conidiophores. The patient was treated with itraconazole, to which she responded well. CONCLUSIONS: This is the first reported case of subcutaneous hyalohyphomycosis caused by P. variotii. It appears that this relatively rare fungal pathogen may be starting to assert itself as an important cause of infection in humans. PMID- 23679877 TI - Cutaneous tuberculosis of the pinna: a report of two cases. AB - BACKGROUND: Cutaneous tuberculosis (TB) is less common than other forms of TB but accounts for 1.5% of all cases of extrapulmonary TB. The source of mycobacterial infection and the immune status of the host determine the presentation of any of a wide spectrum of clinical manifestations. Lupus vulgaris (LV) is a post primary, paucibacillary form of TB caused by hematogeneous, lymphatic, or contiguous spread from elsewhere in the body. METHODS: We report two recent cases of LV in women presenting with the exclusive involvement of the ear lobe. In Patient 1, clinical presentation appeared as an apparently benign chronic eczematous process. In Patient 2, it appeared as a fulminant ulceronecrotic process. Both women were immunocompetent, and neither had a personal or family history of TB. RESULTS: Both patients were diagnosed with LV and treated with standard antitubercular therapy (ATT). In both patients, mycobacterial culture showed growth of Mycobacterium tuberculosis sensitive to streptomycin, rifampicin, and ethambutol. CONCLUSIONS: Lupus vulgaris is the most common form of cutaneous TB. It is important to diagnose LV because it can result in chronic disfigurement and because 10-20% of LV patients have active pulmonary TB or TB of the bones and joints. In addition, longstanding LV is known to lead to the development of squamous cell carcinoma, which can be avoided by early diagnosis and treatment with ATT. PMID- 23679878 TI - Correlation of dermoscopic findings with histopathologic variants of basal cell carcinoma. PMID- 23679879 TI - Acquired telangiectatic plaque-like glomangioma on the forehead. PMID- 23679880 TI - Hemophagocytic syndrome as a complication in a patient with Sezary syndrome. PMID- 23679881 TI - Anetodermic pilomatricoma: report of three cases. PMID- 23679882 TI - Successful management of airway hemangioma with propranolol. AB - Airway hemangiomas can be difficult to manage and cause anxiety in both the parents and the treating physician. Propranolol, a nonselective beta-blocker, has recently been used for treating proliferating infantile hemangiomas. We report successful management of a proliferating, large, mixed infantile hemangioma with subglottic extension in an Indian infant using oral propranolol in a dose of 2mg/kg/day without any side effects. Induction of early involution and freedom from the side effects of steroid therapy seem encouraging for using propranolol as a first line treatment modality in the management of troublesome hemangiomas. PMID- 23679883 TI - Isotretinoin and one patient's teary eyes: "please listen or I'll cry". PMID- 23679884 TI - The clinical presentations of penile tuberculosis. PMID- 23679885 TI - Nodular lesions on the tongue in the clinical presentation of dialysis-related amyloidosis. PMID- 23679886 TI - Extranodal natural killer (NK)/T-cell lymphoma presenting with recurrent lip swelling. PMID- 23679887 TI - Coalescence of multiple piloleiomyomas in an indurated hemifacial plaque. PMID- 23679889 TI - Impact of cardiac computed tomography of the interatrial septum before pulmonary vein isolation. AB - BACKGROUND: Multidetector computed tomography (MDCT) may be useful to identify patients with patent foramen ovale (PFO). The aim of this study was to analyze whether a MDCT performed before pulmonary vein isolation reliably detects a PFO that may be used for access to the left atrium. METHODS AND RESULTS: In 79 consecutive patients, who were referred for catheter ablation of symptomatic paroxysmal or persistent atrial fibrillation (AF), the presence of a PFO was explored by MDCT and transesophageal echocardiography (TEE). TEE was considered as the gold standard, and quality of TEE was good in all patients. In 16 patients (20.3%), MDCT could not be used for analysis because of artifacts, mainly because of AF. On TEE, a PFO was found in 15 (23.8%) of the 63 patients with usable MDCT. MDCT detected six PFO of which four were present on TEE. This corresponded to a sensitivity of 26.7%, a specificity of 95.8%, a negative predictive value of 80.7%, and a positive predictive value of 66.7%. The receiver operating characteristics curve of MDCT for the detection of PFO was 0.613 (95% confidence interval 0.493-0.732). CONCLUSIONS: MDCT may detect a PFO before pulmonary isolation. However, presence of AF may lead to artifacts on MDCT impeding a meaningful analysis. Furthermore, in this study sensitivity and positive predictive value of MDCT were low and therefore MDCT was not a reliable screening tool for detection of PFO. PMID- 23679891 TI - Spectroscopic characterization of B/KNO3 diode-laser induced combustion. AB - The combustion of a B/KNO3 pyrotechnic mixture was characterized by its chemiluminescence for the first time. The reaction was initiated by a continuous wave (cw) diode laser inside a novel multipurpose reaction cell, whose design and construction are described. As in the case of the extensively studied oxidation of boron by O2, the most intense luminescence, recorded in the 400-600 nm range, is assigned to BO2. Its appearance delay time (10(-2) to 10(-1) s) equals that measured for the pressure increase and is shortened as the laser power is increased. A band observed at 355 nm appears at longer delay times than the BO2 bands. The band, and some weaker ones, may be assigned to BO, although some bands expected for BO (based on reaction between B atoms and O2) are absent from the spectra. This observation is discussed in the text, and possible emission from BN is discussed. If the band is assigned to BO, the absence of known bands may be due to specific E-V resonance energy transfer. Possible oxidation mechanisms consistent with the different delay ignition times are discussed. PMID- 23679892 TI - A UK pilot study: the specificity of the Word Memory Test effort sub-tests in acute minimal to mild head injury. AB - The specificity of the Word Memory Test (WMT) effort indices was examined in 48 individuals with minimal to mild head injury (MHI) in the acute stages post injury. None of the individuals was involved in litigation or disability claims. At the established cut-offs, the WMT had an unacceptable false-positive rate (18%). T test analysis was also carried out for WMT passers and failures on a battery of neuropsychometric measures and across a range of demographic variables. The WMT was performed at a significantly lower level on the Wechsler Memory Scale-III word list sub-tests and verbal fluency tests (p < .05). This suggests that WMT failure may be indicative of a specific deficit in verbal processing in the acute phase of MHI. PMID- 23679893 TI - An odorant receptor from the common cutworm (Spodoptera litura) exclusively tuned to the important plant volatile cis-3-hexenyl acetate. AB - Olfaction plays an important role in insect behaviours. The odorant receptor (OR) repertoire, housed within the dendritic membrane of sensory neurons, is one of the primary determinants of odour recognition. ORs in moths could be classified into pheromone receptors (PRs) and non-pheromone receptors (non-PR ORs). Much research in the field of insect olfaction recently has been focused on PRs of the male moth, but few Lepidoptera studies have been done on the functional study of non-PR ORs. In the present study, we identified and characterized four non-PR ORs from Spodoptera litura (Lepidoptera: Noctuidae) antennae. The tissue expression pattern showed that the four ORs were mainly expressed in adult antennae and further in situ hybridization revealed SlituOR12 was expressed in both long and short sensilla trichodea and sensilla basiconica. A functional analysis of the four SlituORs was conducted in the heterologous expression system Xenopus oocytes. SlituOR12 was exclusively and sensitively tuned to cis-3-Hexenyl acetate and SlituOR19 slightly responded to 4'-Ethylacetophenone; however, SlituOR44 and SlituOR51 did not respond to any chemicals tested in this study. It is proposed that SlituOR12 might partially account for some key behaviours of the female, such as detection of host location and oviposition site. PMID- 23679894 TI - Urinary profile of catecholamines and metabolites in Parkinson patients with deep brain stimulation. AB - BACKGROUND AND PURPOSE: Deep brain stimulation of the subthalamic nucleus (DBS STN) is thought to continuously alter the activity of STN neurons in Parkinson's disease (PD). A chronic decrease in the levodopa dose with continuous STN stimulation may induce plastic neuronal changes. OBJECTIVE: The objective of this work was to study urinary excretion of catecholamines in patients with PD before and after DBS-STN. METHODS: Twenty-three patients were submitted to DBS-STN, and evaluated before and after surgery with respect to catecholamines and metabolites in 24-h urine measured by high-performance liquid chromatography with electrochemical detection. RESULTS: Of the 23 patients evaluated, a significant decrease of about 60% in the urinary excretion of L-3,4-dihydroxyphenylalanine (L DOPA; in nmol/mg creatinine/24 h) was observed 1 week after DBS-STN. Moreover, in 17 patients with a follow-up of 8 weeks after surgery, there was a further 50% decrease in urinary L-DOPA levels, dropping to about 75% of the values before surgery. There was also a significant decrease in dopamine (DA) and 3,4 dihydroxyphenylacetic acid (DOPAC) levels 1 week after DBS-STN that was no longer present 8 weeks after. A significant increase in the DA/l-DOPA ratio was observed 1 week after surgery, with a further increase 8 weeks after surgery. CONCLUSION: After DBS-STN, the DA/l-DOPA ratio, an indirect measure of DA synthesis, increased. These results show that DBS-STN may improve the efficacy of oral levodopa. PMID- 23679890 TI - In the absence of such comparative benchmark(s), there have even been calls for local growth standards and, indeed, a redefinition of the cut-offs for low birthweight. Introduction. PMID- 23679895 TI - Convergent evolution of chromatin modification by structurally distinct enzymes: comparative enzymology of histone H3 Lys27 methylation by human polycomb repressive complex 2 and vSET. AB - H3K27 (histone H3 Lys27) methylation is an important epigenetic modification that regulates gene transcription. In humans, EZH (enhancer of zeste homologue) 1 and EZH2 are the only enzymes capable of catalysing methylation of H3K27. There is great interest in understanding structure-function relationships for EZH2, as genetic alterations in this enzyme are thought to play a causal role in a number of human cancers. EZH2 is challenging to study because it is only active in the context of the multi-subunit PRC2 (polycomb repressive complex 2). vSET is a viral lysine methyltransferase that represents the smallest protein unit capable of catalysing H3K27 methylation. The crystal structure of this minimal catalytic protein has been solved and researchers have suggested that vSET might prove useful as an EZH2 surrogate for the development of active site-directed inhibitors. To test this proposition, we conducted comparative enzymatic analysis of human EZH2 and vSET and report that, although both enzymes share similar preferences for methylation of H3K27, they diverge in terms of their permissiveness for catalysing methylation of alternative histone lysine sites, their relative preferences for utilization of multimeric macromolecular substrates, their active site primary sequences and, most importantly, their sensitivity to inhibition by drug-like small molecules. The cumulative data led us to suggest that EZH2 and vSET have very distinct active site structures, despite the commonality of the reaction catalysed by the two enzymes. Hence, the EZH2 and vSET pair of enzymes represent an example of convergent evolution in which distinct structural solutions have developed to solve a common catalytic need. PMID- 23679896 TI - Effects of briakinumab treatment for moderate to severe psoriasis on health related quality of life and work productivity and activity impairment: results from a randomized phase III study. AB - BACKGROUND: Psoriasis is known to have a significant negative impact on a patient's health-related quality of life, including social, recreational and work activities. OBJECTIVE: To evaluate the effects of briakinumab on quality of life and work productivity measures in patients with moderate to severe psoriasis. METHODS: Patients received either briakinumab (n = 981) or placebo (n = 484) during the 12-week induction phase of trial M06-890. At week 12, patients with a Physician's Global Assessment score of 'Clear' or 'Minimal' entered the 40-week maintenance phase and were to receive briakinumab every 4 weeks, briakinumab every 12 weeks, or placebo. At weeks 12 and 52, treatment groups were compared using mean change from baseline in health-related quality of life and Work Productivity and Activity Impairment Questionnaire scores and the percentage of patients with minimum clinically important differences. RESULTS: At week 12, more than half of the briakinumab-treated patients achieved improvements meeting or exceeding minimum clinically important differences for Dermatology Life Quality Index (75.9%), and psoriasis- (64.8%), and psoriatic arthritis-related (54.1%) pain scores; 48.4% achieved improvements for activity impairment. Although improvements in quality of life and work productivity measures were maintained at week 52 for both briakinumab regimens, responder rates were consistently greater in the every-4-week group than in the every-12-week group. CONCLUSION: Briakinumab treatment resulted in clinically significant improvements in quality of life and work productivity in adults with moderate to severe psoriasis. Maintenance therapy was associated with a more pronounced benefit for the every-4 week briakinumab regimen. PMID- 23679897 TI - The relationship between term pre-eclampsia and the risk of early childhood caries. AB - OBJECTIVE: To test the hypothesis that pre-eclampsia is associated with higher incidence of early childhood caries in children aged between 3 and 5 years old. DESIGN: An observational non concurrent cohort study. SETTING: Al-Hayat National Hospital, Khamees Mushyat, Saudi Arabic Kingdom. POPULATION: Two hundred children aged 3-5 years who fulfilled the inclusion criteria. METHOD: A detailed dental examination was carried out for all children enrolled. We obtained all relevant obstetric data from mothers' and pediatric's medical records. Thirty cases were excluded due to missing data and therefore, only 170 children were considered for the statistical analysis. Results were tabulated and statistically analyzed. MAIN OUTCOME MEASURE: Early childhood caries. RESULTS: Sixty-three children (37%) of the 170 were affected with early childhood caries; 6 were delivered to pre eclamptic and 57 to non pre-eclamptic mothers. Using logistic regression curve, early childhood caries was significantly associated with low birthweight, low Apgar score at 1st min and with the pattern of infant feeding but not with pre eclampsia. The relative risk for early childhood caries was 2.84 among low birthweight infants (95%CI: 1.47-5.49), 1.95 among non breast fed children (95% CI: 1.11-4.20) and 2.64 among those delivered with an Apgar score less than 5 at 1 minute (95%CI:1.46-4.77). CONCLUSION: Pre-ecalampsia may not be associated with early childhood caries. A larger study and/or a study addressing the relation between pre-eclampsia and caries inducing lesions may provide more significant results. PMID- 23679898 TI - Development of a high-throughput laser-induced acoustic desorption probe and raster sampling for laser-induced acoustic desorption/atmospheric pressure chemical ionization. AB - Laser-induced acoustic desorption (LIAD) was recently coupled to atmospheric pressure chemical ionization (APCI) and shown to be of great utility for the analysis of a variety of thermally labile nonpolar analytes that are not amenable to ionization via electrospray ionization, such as nonvolatile hydrocarbons. Despite these advancements, LIAD still suffered from several limitations, including only being able to sample a small fraction of the analyte molecules deposited on a Ti foil for desorption, poor reproducibility, as well as limited laser power throughput to the backside of the foil. These limitations severely hinder the analysis of especially challenging analytes, such as asphaltenes. To address these issues, a novel high-throughput LIAD probe and an assembly for raster sampling of a LIAD foil were designed, constructed, and tested. The new probe design allows 98% of the initial laser power to be realized at the backside of the foil over the 25% achieved previously, thus improving reproducibility and allowing for the analysis of large nonvolatile analytes, including asphaltenes. The raster assembly provided a 5.7 fold increase in the surface area of a LIAD foil that could be sampled and improved reproducibility and sensitivity for LIAD experiments. The raster assembly can also improve throughput as foils containing multiple analytes can be prepared and analyzed. PMID- 23679899 TI - An evaluation of inertial sensor technology in the discrimination of human gait. AB - Inertial sensors may provide the opportunity for broader and more cost effective gait analysis; however some questions remain over their potential use in this capacity. The aim of the study was to determine whether an inertial sensor could discriminate between normal walking, fast walking, and running. A single group crossover design was used to compare acceleration profiles between three gait conditions: normal walking, fast walking, and running. An inertial sensor was placed on the sacrum of 12 participants (6 male, 6 female) who performed 3 trials of each gait condition on both overground and treadmill settings. A significant difference (P < 0.001) in the occurrence of heel strike in the gait cycle was found between running and both walking conditions. No differences were seen between overground and treadmill in any condition or variable. The results indicate that a single sacral mounted inertial sensor can differentiate running from normal walking and fast walking using temporal gait event measures. This study indicates that inertial sensors can differentiate walking from running gait in healthy individuals which may have potential for application in the quantification of physical activity in the health and exercise industry. PMID- 23679900 TI - Men's health: Is your willy working? PMID- 23679901 TI - Is tigecycline drug of choice for cIAI and cSSTI? PMID- 23679902 TI - Troponin, D-dimer and ... Copeptin? PMID- 23679903 TI - Impact of behaviour and lifestyle on bladder health. AB - Bladder conditions, including UTI, UI, and bladder cancer, are highly prevalent and affect a wide range of populations. There are a variety of modifiable behavioral and lifestyle factors that influence bladder health. Some factors, such as smoking and obesity, increase the risk or severity of bladder conditions, whereas other factors, such as pelvic floor muscle exercise, are protective. Although clinical practice may be assumed to be the most appropriate ground for education on behavioral and lifestyle factors that influence bladder health, it is also crucial to extend these messages into the general population through public health interventions to reach those who have not yet developed bladder conditions and to maximize the prevention impact of these behaviors. Appropriate changes in these factors have the potential for an enormous impact on bladder health if implemented on a population-based level. PMID- 23679904 TI - Clinical and microbiological efficacy of tigecycline for complicated skin-soft tissue and intra-abdominal infections in a Turkish university hospital. AB - OBJECTIVE: Tigecycline, a new glycylcycline antimicrobial agent, is indicated for the treatment of complicated skin structure infection (cSSTI), intra-abdominal infection (cIAI) and community acquired pneumonia. We aimed to evaluate the clinical and microbiological data together about tigecycline therapy. METHODS: Patients with cIAIs and cSSTIs were included in a prospective, observational follow-up. Patient follow-up forms were developed and clinical and microbiological data were recorded. RESULTS: Of the 107 patients, 67 had cSSTIs, 40 had cIAIs. Tigecycline was used empirically in 37.5% of cIAIs and in 50.7% of cSSTIs. In 85.0% of the patients with cIAI and in 73.1% of the patients with cSSTI, clinical and/or microbiological response could be achieved. A drug change was made in 26.9% and 7.5% of the patients with cSSTI and cIAI respectively. Superinfection was detected in 14.9% of the cSSTI and 7.5% of the cIAI patients. CONCLUSION: As a result, tigecycline can be safely used in the treatment of different infections. Compared with cSSTIs, the treatment response is better and the duration of treatment is shorter in cIAIs. However, MIC value must be determined at any rate if tigecycline is to be used in the treatment of Acinetobacter (MDR Acinetobacter, in particular) infections. Clinical cure and microbiological eradication rate of tigecycline therapy changes according to different clinical diagnosis and microorganism. PMID- 23679905 TI - Copeptin: a blood test marker of syncope. AB - AIMS: Copeptin (CPT) is regarded as a stress hormone, and as a novel marker of acute disease, and it has never been tested for a role in diagnosing syncope. The main objectives of the study were to measure CPT in patients suffering from syncope, to determine its diagnostic sensitivity and specificity, and compare it with that in patients with falls and mild trauma. The secondary objective was to determine whether different types of syncope correlate with different levels of CPT. METHODS: Fifty-one patients suffering from syncope and 51 suffering from falls without syncope were included in this study. Patients with a diagnosis of acute comorbidity were excluded. The diagnostic work was in accordance with the Guidelines of the European Cardiology Society. The level of CPT was measured in each patient evaluating the mean values in syncope vs. falls and in the different syncope type and the values over or under the normal threshold. RESULTS: Of the 51 patients with syncope, 44 had abnormal and 7 normal CPT levels. Of the 51 patients with falls, 47 had normal and 4 abnormal levels of CPT. There was no difference in mean CPT levels in patients with different types of syncope. There was no correlation between levels of CPT and age or sex. There was a relationship between normal CPT levels and falls. CONCLUSION: Copeptin is an efficient marker of syncope. It is useful for confirming or ruling out a diagnosis of syncope in patients who are unable to provide a definite history or when the event is unwitnessed. PMID- 23679906 TI - Differences in prostate cancer detection rates according to the level of glomerular filtration rate in patients with prostate specific antigen levels of 4.0-10.0 ng/ml. AB - AIMS: To investigate differences in prostate cancer detection rates according to the level of glomerular filtration rates (GFR). MATERIALS AND METHODS: Patients with prostate-specific antigen (PSA) levels of 4.0-10.0 ng/ml were analysed. Age, serum creatinine, estimated GFR, body mass index, total PSA (tPSA), free PSA (fPSA), per cent free PSA (%fPSA), comorbidities, biopsy Gleason sum and per cent positive core were retrospectively reviewed. All parameters were compared to show whether patients with GFR <60 ml/min/1.73 m(2) (group A) have higher risk of prostate cancer than patients with GFR >= 60 (group B). The primary endpoint was cancer detection rate and the secondary endpoints were differences in mean tPSA, fPSA, %fPSA and pathologic outcomes. RESULTS: A total of 1092 men (243 cancer patients) were included. Mean age was 65.8 +/- 7.7 years. No differences in mean age and tPSA were found between groups A and B. Mean fPSA, %fPSA and cancer detection rate were significantly higher in group A than group B. The incidence of %fPSA <25% was significantly lower in group A than in group B. GFR <60 ml/min/1.73 m(2) , fPSA and %fPSA <25% were significant predictors for the presence of prostate cancer in patients with tPSA between 4 and 10 ng/ml. However, %fPSA <25% was not a significant predictor for group A. CONCLUSIONS: Because of the increased cancer detection rates in patients with CKD of stage >= 3 whose tPSA levels are 4.0-10.0 ng/ml, performing prostate biopsy should be actively considered in patients with CKD. PMID- 23679907 TI - Anaemia in chronic obstructive pulmonary disease. Does it really matter? AB - Chronic obstructive pulmonary disease (COPD) is one of the most prevalent chronic diseases, with an increasing rate in morbidity and mortality. In recent years, there has been a greater awareness about the clinical importance of systemic effects and other chronic conditions associated with COPD, as these significantly impact on the course of disease. The most studied extrapulmonary manifestations in COPD include the presence of concomitant cardiovascular disease, skeletal muscle wasting, osteoporosis and lung cancer. Anaemia is a recognised independent marker of mortality in several chronic diseases. Recent studies have shown that anaemia in patients with COPD may be more frequent than expected, with a prevalence ranging from 5% to 33%. Some evidence suggests that systemic inflammation may play an important pathogenic role, but anaemia in COPD is probably multifactorial and may be caused by others factors, such as concealed chronic renal failure, decreased androgenic levels, iron depletion, angiotensin converting enzyme inhibitor treatment and exacerbations. Low levels of haemoglobin and haematocrit in COPD patients have been associated with poor clinical and functional outcomes as well as with mortality and increased healthcare costs. Despite the potential clinical benefit of successfully treating anaemia in these patients, evidence supporting the importance of its correction on the prognosis of COPD is uncertain. PMID- 23679908 TI - Prevalence, associated factors, and relationship to quality of life of lower urinary tract symptoms: a cross-sectional, questionnaire survey of cancer patients. AB - BACKGROUND: Few studies conducted outside of Asia have shown that lower urinary tract symptoms (LUTS) could be a concern for cancer patients. This gap necessitates more research on LUTS among cancer patients in Asia, particularly regarding associated factors and the relationship between quality of life and LUTS. OBJECTIVES: This study investigates the prevalence, associated factors, and relationship to quality of life of LUTS based on a sample of cancer patients. DESIGN: A cross-sectional, questionnaire survey. SETTINGS/PARTICIPANTS: This study was conducted at two oncology outpatient departments in two hospitals in Taiwan, and included 134 Asian cancer patients. METHODS: We collected information about each participant's individual characteristics, personal habits, LUTS, and quality of life by using a questionnaire. We calculated descriptive statistics to demonstrate the distribution of collected information, and used multivariate logistic regression to identify the factors associated with LUTS. We used Student's t-test to compare the mean quality of life scores for participants with and without LUTS. RESULTS: Ninety-nine (73.9%) participants experienced at least one type of LUTS, and the prevalence rates for various types of LUTS ranged from 3.7% to 52.2%. Radiotherapy and the time since the diagnosis of cancer were associated with LUTS. Participants with LUTS reported lower quality of life scores than participants without LUTS. CONCLUSIONS: The high prevalence of LUTS suggests that cancer treatment might be linked to LUTS, which in turn has a negative effect on a patient's quality of life. These results suggest that future research should involve studies in larger, more homogeneous samples. Health care providers should monitor the presence of LUTS and deliver the management and treatments of LUTS to optimise cancer patients' quality of life. PMID- 23679909 TI - The cutaneous adverse drug reactions: risk factors, prognosis and economic impacts. AB - AIMS: The aim of this study was to explore the factors associated with the occurrence, subsequent prognoses and need for additional medications following cutaneous adverse drug reactions (ADRs) among inpatients. METHODS AND MEASURES: This is a case-control study, nested in a large cohort study of 473,446 inpatients hospitalised from 2005 to 2008, examined cutaneous ADRs. A 1 : 5 strategy of individually matching age and principal diagnosis was applied to the data of cases (n = 700) and corresponding controls (n = 3365).The severity of ADRs was evaluated using Naranjo algorithms by senior pharmacists in the medical centre. Medical chart reviews and claim data analyses were analysed to explore risk factors associated with the occurrence and impact of cutaneous ADRs. Economic impacts in terms of length of stay and medical expenses were also analysed. RESULTS: The number of drug prescriptions and secondary diagnoses, and the department to which the patient was admitted, significantly contributed to the risk of cutaneous ADRs and subsequent prognosis. In addition to physician's seniority, the Naranjo score was also positively associated with patients' prognosis. Medical expenses associated with cutaneous ADRs patients ($US 916) were more than 2.5-fold higher than those patients who were not afflicted ($US 318). CONCLUSION: The study identified risk factors for cutaneous ADRs in terms of both patient characteristics and drug complexity. The present analyses indicate characteristics and mechanisms of cutaneous ADRs among inpatients, which provide clues for future intervention strategies and management issues in healthcare settings. PMID- 23679910 TI - Efficacies of different preparations of glucosamine for the treatment of osteoarthritis: a meta-analysis of randomised, double-blind, placebo-controlled trials. AB - OBJECTIVE: To determine the efficacies of different preparations of glucosamine for the treatment of osteoarthritis (OA). METHODS: Systematic searches of the bibliographic databases Medline, Embase, the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews for randomised, double-blind, placebo-controlled trials (RCTs) concerning glucosamine treatment of OA. Effect size (ES) was estimated using Cohen's standardised mean difference. Consistency was evaluated via the I(2) index. RESULTS: Nineteen trials (3159 patients) contributed to the meta-analysis, revealing a large degree of inconsistency among the trials in terms of pain-reduction outcome: the combined ES in glucosamine sulphate (GS) trials was -0.22 [95% confidence intervals (CI) 0.48, 0.04], I(2) was 82.3%. The combined ES in glucosamine hydrochloride (GH) trials was -0.03 (95% CI -0.14, 0.08), with an absence of heterogeneity. No treatment ES was observed [-0.38 (95% CI -0.99, 0.23)] favouring GS in trials of less than 24 weeks duration and the I(2) remained high (I(2) = 88.5%). No significant treatment ES -0.09 (95% CI -0.21, 0.03) was observed in trials of more than 24 weeks duration compared with placebo, with a heterogeneity of zero. In terms of function-modifying outcomes, GS showed no significant effect on Lequesne Index reduction vs. placebo in trials of less than 24 weeks duration (ES -0.55 (95% CI -1.22, 0.11)) with a high degree of heterogeneity (I(2) = 92.9%). Pooling data from studies with durations of more than 24 weeks presented a significant combined ES of -0.36 (95% CI: -0.56, -0.17) with an absence of heterogeneity. No risk of publication bias could be detected using Egger test. CONCLUSIONS: GH is ineffective for pain reduction in patients with knee OA. GS may have function-modifying effects in patients with knee OA when administered for more than 6 months. However, it showed no pain-reduction benefits after 6 months of therapy. PMID- 23679911 TI - Belief bias and the extinction of induced fear. AB - Some people show slower extinction of UCS expectancies than other people. Little is known about what predicts such delayed extinction. Extinction requires that people deduce the logical implication of corrective experiences challenging the previously learned CS-UCS contingency. "A strong habitual tendency to confirm beliefs" may therefore be a powerful mechanism immunising against refutation of UCS expectancies. This study investigated whether individual differences in such a belief confirming tendency (a process called "belief bias") may help in explaining individual differences in extinction. We tested whether relatively strong belief bias predicts delayed extinction of experimentally induced UCS expectancies. In a differential aversive conditioning paradigm, we used UCS irrelevant (Experiment 1) and UCS-relevant (Experiment 2) pictorial stimuli as CS+ and CS-, and electrical stimulation as UCS. Belief bias indeed predicted delayed extinction of UCS expectancies when the CS+ was UCS-relevant (as is typically the case for phobic stimuli, Experiment 2). The study provides preliminary evidence that enhanced belief bias may indeed play a role in the persistence of UCS expectancies, and can thereby contribute to the development and persistence of anxiety disorders. The results also point to the relevance of reasoning tendencies in the search for predictors of delayed extinction of UCS expectancies. PMID- 23679913 TI - Senescence-associated superoxide dismutase influences mitochondrial gene expression in budding tunicates. AB - A recent study has shown that in the budding tunicate Polyandrocarpa misakiensis, the mitochondrial respiratory chain (MRC) dramatically attenuates the gene activity during senescence. In this study, we examined the possible involvement of superoxide dismutase (SOD) in the attenuation of gene expression of cytochrome c oxidase subunit 1 (COX1) in aged zooids. By RT-PCR and in situ hybridization, Cu/Zn-SOD (SOD1) was found to be expressed in most cells and tissues of buds and juvenile zooids but showed a conspicuous decline in senescent adult zooids, except in the gonad tissue in which the cytoplasm of juvenile oocytes was stained heavily. This expression pattern of SOD1 was similar to that of COX1. In contrast to SOD1, Mn-SOD (SOD2) was expressed constitutively in both somatic and germline tissues of buds, juvenile zooids, and senescent adult zooids. Knockdown of SOD1 by RNAi diminished the gene activity of not only SOD1 but also of COX1. The resultant zooids had transient deficiencies in growth and budding, and they recovered from these deficiencies approximately 1 month later. Our results indicate that in P. misakiensis, SOD1 is a senescence-associated nuclear gene and that the experimental decline in SOD1 gene expression accompanies the attenuation of MRC gene activity. Although it is uncertain how SOD1 is downregulated during tunicate senescence, the decreased SOD1 activity could be one of the main causes of MRC gene attenuation during normal senescence. PMID- 23679914 TI - First-principles theoretical study of hydrolysis of stepped and kinked Ga terminated GaN surfaces. AB - : We have investigated the initial stage of hydrolysis process of Ga-terminated GaN surfaces by using first-principles theoretical calculations. We found that the activation barrier of H2O dissociation at the kinked site of the Ga terminated GaN surface is about 0.8 eV, which is significantly lower than that at the stepped site of about 1.2 eV. This is consistent with the experimental observation where a step-terrace structure is observed after the etching process of Ga-terminated GaN surfaces with catalyst-referred etching method. Detailed analysis on the nature of the chemical interaction uring the hydrolysis processes will be discussed. PMID- 23679912 TI - Oriented covalent immobilization of antibodies for measurement of intermolecular binding forces between zipper-like contact surfaces of split inteins. AB - In order to measure the intermolecular binding forces between two halves (or partners) of naturally split protein splicing elements called inteins, a novel thiol-hydrazide linker was designed and used to orient immobilized antibodies specific for each partner. Activation of the surfaces was achieved in one step, allowing direct intermolecular force measurement of the binding of the two partners of the split intein (called protein trans-splicing). Through this binding process, a whole functional intein is formed resulting in subsequent splicing. Atomic force microscopy (AFM) was used to directly measure the split intein partner binding at 1 MUm/s between native (wild-type) and mixed pairs of C and N-terminal partners of naturally occurring split inteins from three cyanobacteria. Native and mixed pairs exhibit similar binding forces within the error of the measurement technique (~52 pN). Bioinformatic sequence analysis and computational structural analysis discovered a zipper-like contact between the two partners with electrostatic and nonpolar attraction between multiple aligned ion pairs and hydrophobic residues. Also, we tested the Jarzynski's equality and demonstrated, as expected, that nonequilibrium dissipative measurements obtained here gave larger energies of interaction as compared with those for equilibrium. Hence, AFM coupled with our immobilization strategy and computational studies provides a useful analytical tool for the direct measurement of intermolecular association of split inteins and could be extended to any interacting protein pair. PMID- 23679915 TI - Medicinal chemistry of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. AB - Nicotinamide phoshophoribosyltransferase (NAMPT) plays a key role in the replenishment of the NAD pool in cells. This in turn makes this enzyme an important player in bioenergetics and in the regulation of NAD-using enzymes, such as PARPs and sirtuins. Furthermore, there is now ample evidence that NAMPT is secreted and has a role as a cytokine. An important role of either the intracellular or extracellular form of NAMPT has been shown in cancer, inflammation, and metabolic diseases. The first NAMPT inhibitors (FK866 and CHS828) have already entered clinical trials, and a surge in interest in the synthesis of novel molecules has occurred. The present review summarizes the recent progress in this field. PMID- 23679916 TI - Nucleolin targeting AS1411 modified protein nanoparticle for antitumor drugs delivery. AB - Over recent years, cell surface nucleolin as an anticancer target has attracted many researchers' attentions. To improve the antitumor efficacy, we developed a nucleolin targeted protein nanoparticle (NTPN) delivery system in which human serum albumin (HSA) was used as drug carrier and a DNA aptamer named AS1411, which had high affinity to nucleolin, was used as a bullet. The HSA nanoparticles (NPs-PTX) were fabricated by a novel self-assembly method and then modified with AS1411 (Apt-NPs-PTX). The resulted Apt-NPs-PTX were spherical. Compared with NPs PTX, the uptake of Apt-NPs-PTX displayed a significant increase in MCF-7 cells while there was a decrease in nontumor cell lines such as MCF-10A and 3T3 cells. In a cytotoxic study, Apt-NPs-PTX displayed an enhanced cytotoxicity in MCF-7 tumor cells while there was almost no cytotoxicity in MCF-10A cells. Endostatin, a nucleolin inhibitor, could significantly decrease the internalization of Apt NPs-PTX, suggesting nucleolin mediates the transmembrane process of Apt-NPs-PTX. Therefore, the AS1411 modified NTPN delivery system might be a promising targeted drug delivery system. PMID- 23679918 TI - Disorder-order structural transformation in electron-poor Sr3Au8Sn3 driven by chemical bonding optimization. AB - Sr3Au8Sn3 was synthesized through fusion of a stoichiometric amount of pure metals at 800 degrees C and annealing treatments at lower temperatures. Single crystal X-ray diffraction analyses revealed that Sr3Au8Sn3 has a La3Al11-type Immm structure (a = 4.6767(8) A, b = 9.646(2) A, c = 14.170(2) A, Z = 2) if annealed at 550 degrees C and above but a Ca3Au8Ge3-type structure (Pnnm, a = 9.6082(8) A, b = 14.171(1) A, c = 4.6719(4) A, Z = 2) if annealed at 400 degrees C. The transition occurs at about 454 degrees C according to DTA data. Both structures feature columns of Sr-centered pentagonal and hexagonal prisms of Au and Sn stacked along the respective longest axial directions, but different "colorings" of the polyhedra are evident. In the high-temperature phase (Immm) all sites shared between the two prisms adopt 50:50 mixtures of Au/Sn atoms, whereas in the low-temperature phase (Pnnm) Au or Sn are completely ordered. A Klassengleiche group-subgroup relationship was established between these two structures. LMTO-ASA calculations reveal that DeltaE for the disorder-to-order transformation on cooling is driven mainly by optimization of the Au-Au and Au-Sn bond populations around the former mixed Au/Sn sites, particularly those with extremely short bonds at the higher temperature. These gains also overcome the smaller effect of ordering on the entropy decrease. PMID- 23679917 TI - The saving and empowering young lives in Europe (SEYLE) randomized controlled trial (RCT): methodological issues and participant characteristics. AB - BACKGROUND: Mental health problems and risk behaviours among young people are of great public health concern. Consequently, within the VII Framework Programme, the European Commission funded the Saving and Empowering Young Lives in Europe (SEYLE) project. This Randomized Controlled Trial (RCT) was conducted in eleven European countries, with Sweden as the coordinating centre, and was designed to identify an effective way to promote mental health and reduce suicidality and risk taking behaviours among adolescents. OBJECTIVE: To describe the methodological and field procedures in the SEYLE RCT among adolescents, as well as to present the main characteristics of the recruited sample. METHODS: Analyses were conducted to determine: 1) representativeness of study sites compared to respective national data; 2) response rate of schools and pupils, drop-out rates from baseline to 3 and 12 month follow-up, 3) comparability of samples among the four Intervention Arms; 4) properties of the standard scales employed: Beck Depression Inventory, Second Edition (BDI-II), Zung Self-Rating Anxiety Scale (Z SAS), Strengths and Difficulties Questionnaire (SDQ), World Health Organization Well-Being Scale (WHO-5). RESULTS: Participants at baseline comprised 12,395 adolescents (M/F: 5,529/6,799; mean age=14.9+/-0.9) from Austria, Estonia, France, Germany, Hungary, Ireland, Israel, Italy, Romania, Slovenia and Spain. At the 3 and 12 months follow up, participation rates were 87.3% and 79.4%, respectively. Demographic characteristics of participating sites were found to be reasonably representative of their respective national population. Overall response rate of schools was 67.8%. All scales utilised in the study had good to very good internal reliability, as measured by Cronbach's alpha (BDI-II: 0.864; Z SAS: 0.805; SDQ: 0.740; WHO-5: 0.799). CONCLUSIONS: SEYLE achieved its objective of recruiting a large representative sample of adolescents within participating European countries. Analysis of SEYLE data will shed light on the effectiveness of important interventions aimed at improving adolescent mental health and well being, reducing risk-taking and self-destructive behaviour and preventing suicidality. TRIAL REGISTRATION: US National Institute of Health (NIH) clinical trial registry (NCT00906620) and the German Clinical Trials Register (DRKS00000214). PMID- 23679920 TI - Recent advances in organocatalytic asymmetric Morita-Baylis-Hillman/aza-Morita Baylis-Hillman reactions. PMID- 23679919 TI - N-Aroyl indole thiobarbituric acids as inhibitors of DNA repair and replication stress response polymerases. AB - Using a robust and quantitative assay, we have identified a novel class of DNA polymerase inhibitors that exhibits some specificity against an enzyme involved in resistance to anti-cancer drugs, namely, human DNA polymerase eta (hpol eta). In our initial screen, we identified the indole thiobarbituric acid (ITBA) derivative 5-((1-(2-bromobenzoyl)-5-chloro-1H-indol-3-yl)methylene)-2 thioxodihydropyrimidine-4,6(1H,5H)-dione (ITBA-12) as an inhibitor of the Y family DNA member hpol eta, an enzyme that has been associated with increased resistance to cisplatin and doxorubicin treatments. An additional seven DNA polymerases from different subfamilies were tested for inhibition by ITBA-12. Hpol eta was the most potently inhibited enzyme (30 +/- 3 MUM), with hpol beta, hpol gamma, and hpol kappa exhibiting comparable but higher IC50 values of 41 +/- 24, 49 +/- 6, and 59 +/- 11 MUM, respectively. The other polymerases tested had IC50 values closer to 80 MUM. Steady-state kinetic analysis was used to investigate the mechanism of polymerase inhibition by ITBA-12. Based on changes in the Michaelis constant, it was determined that ITBA-12 acts as an allosteric (or partial) competitive inhibitor of dNTP binding. The parent ITBA scaffold was modified to produce 20 derivatives and establish structure-activity relationships by testing for inhibition of hpol eta. Two compounds with N-naphthoyl Ar substituents, ITBA-16 and ITBA-19, were both found to have improved potency against hpol eta with IC50 values of 16 +/- 3 MUM and 17 +/- 3 MUM, respectively. Moreover, the specificity of ITBA-16 was improved relative to that of ITBA-12. The presence of a chloro substituent at position 5 on the indole ring appears to be crucial for effective inhibition of hpol eta, with the indole N-1-naphthoyl and N-2-naphthoyl analogues being the most potent inhibitors of hpol eta. These results provide a framework from which second-generation ITBA derivatives may be developed against specialized polymerases that are involved in mechanisms of radio- and chemo-resistance. PMID- 23679922 TI - Effects of a Brown-midrib corn hybrid on nutrient digestibility in wethers and on dry matter intake, performance, rumen and blood variables in dairy cows. AB - The aim of the present trials was to determine the effect of an experimental Brown-midrib (Bm) corn hybrid in relation to a commercial corn hybrid (Con) on digestibility in wethers and on dry matter intake (DMI), milk yield and milk composition in dairy cows. Digestibility of crude fibre (CF), neutral detergent fibre (NDFom) and acid detergent fibre (ADFom) were higher for Bm (CF Con: 57.8%; Bm: 67.2%; NDFom Con: 56.8%; Bm: 64.8%; ADFom Con: 52.0%; Bm: 63.9%), but concentration of net energy for lactation did not differ (Con: 6.4 MJ/kg DM; Bm: 6.3 MJ/kg DM). A total of 64 lactating German Holstein cows were assigned to one of the two dietary treatments Con or Bm according to milk yield, lactation number, days in milk and live weight. In Trial 1, cows were fed a total mixed ration consisting of 50% corn silage (Con or Bm) and 50% concentrate on dry matter (DM) basis. In Trial 2, the same animals were fed the respective silage for ad libitum intake and 5.3 kg of concentrate DM per animal per day. In Trial 1, DMI and milk-fat content were decreased significantly for the Bm-treatment (DMI Con: 22.5 kg/day; Bm: 21.5 kg/day; milk fat Con: 3.8%; Bm: 3.3%). In Trial 2, milk yield and fat-corrected milk (FCM) were increased significantly, whereas milk-fat% was decreased significantly (milk yield Con: 25.8 kg/day; Bm: 29.4 kg/day; FCM Con: 27.2 kg/day; Bm: 29.6 kg/day; fat Con: 4.4%; Bm: 4.0%). Diets did not influence ruminal pH or temperature. Diets, furthermore, did not influence rumination in either trial. Additional research on digestibility and rumen fermentation should, however, be carried out using dairy cows at respective intake levels as trials with wethers cannot be transferred to high-yielding ad libitum fed cows. PMID- 23679923 TI - Genetic diversity of HA1 domain of heammaglutinin gene of influenza A(H1N1)pdm09 in Tunisia. AB - We present major results concerning isolation and determination of the nucleotide sequence of hemagglutinin (HA1) of the pandemic (H1N1)pdm09 influenza viruses found in Tunisia. Amino acid analysis revealed minor amino acid changes in the antigenic or receptor-binding domains. We found mutations that were also present in 1918 pandemic virus, which includes S183P in 4 and S185T mutation in 19 of 27 viruses analyzed from 2011, while none of the 2009 viruses carried these mutations. Also two specific amino acid differences into N-glycosylation sites (N288T and N276H) were detected. The phylogenetic analysis revealed that the majority of the Tunisian isolates clustered with clade A/St. Petersburg/27/2011 viruses characterized by D97N and S185T mutations. However it also reveals a trend of 2010 strains to accumulate amino acid variation and form new phylogenetic clade with three specific amino acid substitutions: V47I, E172K and K308E. PMID- 23679921 TI - Implementation of the INTERGROWTH-21st Project in the UK. AB - There are approximately 10,000 births per year in the county of Oxfordshire in the UK, which is one of the two European sites for the International Fetal and Newborn Growth Consortium for the 21(st) Century (INTERGROWTH-21(st) ) Project. The samples for both components of the project--the Fetal Growth Longitudinal Study (FGLS) and Newborn Cross-Sectional Study (NCSS)--were drawn from the John Radcliffe Hospital, a major university hospital with a large regional role that covers more than 75% of deliveries in the county. Special activities to encourage participation in this population included the formation of a research coalition to streamline recruitment in the Maternity Unit and the distribution of study information leaflets to women using the hospital's antenatal care service. This was a demanding project and several challenges were overcome to reach recruitment targets and to maintain high standards of data quality. Amongst the major challenges for FGLS at this study site was the level of ineligibility because of maternal age, smoking and body mass index (BMI) >= 30. The major challenge for the NCSS field teams was to ensure that all anthropometric data were collected before the early discharge of uncomplicated deliveries, often within 6 hours of birth. It is evident from our experience in implementing this project that, when large-scale clinical studies are meticulously planned and avoid major disruption to routine clinical care, they are well received by hospital staff and can contribute to the improvement of the overall standard of clinical care. PMID- 23679925 TI - A2A adenosine receptors are up-regulated in lymphocytes from amyotrophic lateral sclerosis patients. AB - Adenosine, a purine nucleoside interacting with A1, A2A, A2B and A3 adenosine receptors (ARs), is a potent endogenous modulator of inflammatory and neuronal processes involved in the pathophysiology of several neurodegenerative diseases. In the present study, ARs were investigated in lymphocytes from patients with amyotrophic lateral sclerosis (ALS) and compared with age-matched healthy subjects. In ALS patients A2AARs were analysed by using RT-PCR, Western blotting and saturation binding experiments. The effect of A2AAR stimulation on cyclic AMP levels was evaluated in lymphocytes from ALS patients and healthy subjects. An up regulation of A2AARs was observed in ALS patients with respect to healthy subjects while A1, A2B and A3AR affinity and density did not change. In ALS patients, the A2AAR density values correlated with the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores. Furthermore, the stimulation of A2AARs mediated a significant increase in cyclic AMP levels in lymphocytes from ALS patients, with a higher potency than in lymphocytes from healthy subjects. In conclusion, the positive correlation between A2AAR density and ALSFRS-R scores could indicate a possible protective effect of this receptor subtype, representing an interesting starting point for the study of alternative therapeutic approaches for ALS based on A2AAR modulation. PMID- 23679926 TI - The effects of suppressing intrusive thoughts on dream content, dream distress and psychological parameters. AB - Suppressing unwanted thoughts can lead to an increased occurrence of the suppressed thought in dreams. This is explainable by the ironic control theory, which theorizes why the suppression of thoughts might make them more persistent. The present study examined the influence of thought suppression on dream rebound, dream distress, general psychiatric symptomatology, depression, sleep quality and perceived stress. Thirty healthy participants (good sleepers) were investigated over a period of 1 week. Half were instructed to suppress an unwanted thought 5 min prior to sleep, whereas the other half were allowed to think of anything at all. Dream content was assessed through a dream diary. Independent raters assessed whether or not the dreams were related to the suppressed target thought. The results demonstrated increased target-related dreams and a tendency to have more distressing dreams in the suppression condition. Moreover, the data imply that thought suppression may lead to significantly increased general psychiatric symptomatology. No significant effects were found for the other secondary outcomes. PMID- 23679924 TI - The potential role of phytochemicals in wholegrain cereals for the prevention of type-2 diabetes. AB - Diets high in wholegrains are associated with a 20-30% reduction in risk of developing type-2 diabetes (T2D), which is attributed to a variety of wholegrain components, notably dietary fibre, vitamins, minerals and phytochemicals. Most phytochemicals function as antioxidants in vitro and have the potential to mitigate oxidative stress and inflammation which are implicated in the pathogenesis of T2D. In this review we compare the content and bioavailability of phytochemicals in wheat, barley, rice, rye and oat varieties and critically evaluate the evidence for wholegrain cereals and cereal fractions increasing plasma phytochemical concentrations and reducing oxidative stress and inflammation in humans. Phytochemical content varies considerably within and among the major cereal varieties. Differences in genetics and agro-climatic conditions explain much of the variation. For a number of the major phytochemicals, such as phenolics and flavanoids, their content in grains may be high but because these compounds are tightly bound to the cell wall matrix, their bioavailability is often limited. Clinical trials show that postprandial plasma phenolic concentrations are increased after consumption of wholegrain wheat or wheat bran however the magnitude of the response is usually modest and transient. Whether this is sufficient to bolster antioxidant defences and translates into improved health outcomes is still uncertain. Increased phytochemical bioavailability may be achieved through bio-processing of grains but the improvements so far are small and have not yet led to changes in clinical or physiological markers associated with reduced risk of T2D. Furthermore, the effect of wholegrain cereals and cereal fractions on biomarkers of oxidative stress or strengthening antioxidant defence in healthy individuals is generally small or nonexistent, whereas biomarkers of systemic inflammation tend to be reduced in people consuming high intakes of wholegrains. Future dietary intervention studies seeking to establish a direct role of phytochemicals in mediating the metabolic health benefits of wholegrains, and their potential for mitigating disease progression, should consider using varieties that deliver the highest possible levels of bioavailable phytochemicals in the context of whole foods and diets. Both postprandial and prolonged responses in systemic phytochemical concentrations and markers of inflammation and oxidative stress should be assessed along with changes related to health outcomes in healthy individuals as well as those with metabolic disease. PMID- 23679927 TI - Enantioselective, desymmetrizing bromolactonization of alkynes. AB - Asymmetric bromolactonizations of alkynes are possible using a desymmetrization approach. The commercially available catalyst (DHQD)2PHAL promotes these cyclizations in combination with cheap NBS as a bromine source to give bromoenol lactones in high yield and with high enantioselectivity. The bromoenol lactone products, containing a tetrasubstituted alkene and a quaternary stereocenter, are valuable building blocks for synthetic chemistry. PMID- 23679928 TI - A large nationwide population-based case-control study of the association between intussusception and later celiac disease. AB - BACKGROUND: Case reports and case series studies suggest a positive association between intussusception and celiac disease (CD). METHODS: We contacted Sweden's 28 pathology departments and obtained data on 29,096 patients with biopsy verified CD (equal to Marsh stage 3) through biopsy reports. Patients with CD were matched for age, sex, calendar period and county of residence with up to five reference individuals from the general population (n=144,522). Cases of intussusception were identified from nationwide inpatient, hospital-based outpatient and day-surgery data from the Swedish Patient Register.Odds ratios (ORs) for future CD in patients with intussusception were estimated using conditional logistic regression. RESULTS: 34 (0.12%) individuals with CD had a diagnosis of intussusception vs. 143 (0.10%) reference individuals, suggesting that intussusception was not a risk factor for later CD (OR=1.17; 95% confidence interval (CI)=0.82-1.67). The OR for CD in patients with at least two records of intussusception was 0.40 (95% CI=0.06-2.99).In contrast, a post-hoc analysis showed that CD was associated with a statistically significantly increased risk of intussusception after CD diagnosis (hazard ratio=1.95; 95% CI=1.01-3.77); however, this analysis was based on only 12 cases with both CD and intussusception. CONCLUSION: We found no association between intussusception and future CD; and a mostly modest increased risk of intussusception after a diagnosis of CD. PMID- 23679929 TI - Cumulative survival rate and complication rates of single-tooth implant; focused on the coronal fracture of fixture in the internal connection implant. AB - This retrospective study evaluated the 5-year cumulative survival rate and complication rates of a 4.0-mm internal connection implant (MicroThreadTM OsseospeedTM, Astra Tech) installed for single-tooth restoration. The patients who were treated at Asan Medical Center between 2006 and 2007 were included in this study. A life table analysis was used to calculate the 5-year cumulative survival rate. Comparisons of cumulative survival rates among implant position (anterior, premolar and molar), jawbone (maxilla, mandible), gender and prosthesis type (screw-retained, cement-retained) were performed using the log rank test. Post-loading complications were analysed using Fisher's exact test. Twelve of 136 implants (anterior; 22, premolar; 25, molar; 89) were lost during the loading period, and 11 were removed due to coronal fracture of fixture. The 5 year cumulative survival rate of the whole arch was 91.9%, and that of the molar region was 87.6%. Statistically significant differences were observed in cumulative survival rates among implant position (P = 0.037), whereas no statistically significant differences were observed among gender, jawbone, prosthesis type. Forty-seven of 114 (41.2%) implants in the posterior region showed post-loading complications, including coronal fracture of fixture and abutment screw loosening. PMID- 23679930 TI - Thymus histology and concomitant autoimmune diseases in Japanese patients with muscle-specific receptor tyrosine kinase-antibody-positive myasthenia gravis. AB - BACKGROUND AND PURPOSE: The differences in the characteristics of thymus histology, coexisting autoimmune diseases and related autoantibodies between anti muscle-specific receptor tyrosine kinase (MuSK)-antibody (Ab)-positive myasthenia gravis (MG) patients, and anti-acetylcholine receptor (AChR)-Ab-positive MG patients are not clearly defined. METHODS: The types of thymus histology, coexisting autoimmune diseases and associated Abs in 83 MuSK-Ab-positive patients nationwide were investigated and were compared with those in AChR-Ab-positive patients followed at our institute (n = 83). As for the autoantibodies associated with thymoma, titin Abs were measured. RESULTS: Thymoma was not present in any of the MuSK-Ab-positive patients but presented in 21 patients (25.3%) amongst the AChR-Ab-positive patients. Titin Abs were absent in MuSK-Ab-positive patients but positive in 25 (30.1%) of the AChR-Ab-positive patients. Concomitant autoimmune diseases were present in eight MuSK-Ab-positive patients (9.6%) amongst whom Hashimoto's thyroiditis and rheumatoid arthritis predominated, whereas 22 AChR-Ab positive patients (26.5%) had one or more concomitant autoimmune diseases of which Graves' disease predominated. CONCLUSIONS: Differences in frequency of thymoma and thymic hyperplasia, coexisting autoimmune diseases and autoantibody positivity between MuSK-Ab-positive and AChR-Ab-positive MG were indicated, suggesting that, in contrast with AChR-Ab-positive MG, thymus does not seem to be involved in the pathogenic mechanisms of MuSK-Ab-positive MG. PMID- 23679931 TI - Experience of Lyme disease and preferences for precautions: a cross-sectional survey of UK patients. AB - BACKGROUND: Lyme disease (LD) is a tick-borne zoonosis currently affecting approximately 1000 people annually in the UK (confirmed through serological diagnosis) although it is estimated that the real figures may be as high as 3000 cases. It is important to know what factors may predict correct appraisal of LD symptoms and how the experience of LD might predict preferences for future precautionary actions. METHODS: A cross-sectional survey was conducted with early LD patients via the Lyme Borreliosis Unit at the Health Protection Agency. One hundred and thirty participants completed measures of awareness of having been bitten by ticks, knowledge of ticks and LD, interpretation of LD symptoms, suspicions of having LD prior to seeing the General Practitioner (GP), and preferences for precautionary actions during future countryside visits. Chi square tests and logistic regression were used to identify key predictors of awareness of having been bitten by ticks and of having LD. t-tests assessed differences between groups of participants on suspicions of having LD and preferences for future precautions. Pearson correlations examined relationships between measures of preferences for precautions and frequency of countryside use, knowledge of ticks and LD, and intentions to avoid the countryside in the future. RESULTS: 73.8% of participants (n = 96) reported a skin rash as the reason for seeking medical help, and 44.1% (n = 64) suspected they had LD before seeing the GP. Participants reporting a direct event in realizing they had been bitten by ticks (seeing a tick on skin or seeing a skin rash and linking it to tick bites) were more likely to suspect they had LD before seeing the doctor. Participants distinguished between taking precautions against tick bites during vs. after countryside visits, largely preferring the latter. Also, the more frequently participants visited the countryside, the less likely they were to endorse during visit precautions. CONCLUSIONS: The results suggest that the risk of LD is set in the context of the restorative benefits of countryside practices, and that it may be counterproductive to overemphasize pre- or during-visit precautions. Simultaneously, having experienced LD is not associated with any withdrawal from countryside. PMID- 23679932 TI - Transarterial chemoembolization of hepatocellular carcinoma--agents and drugs: an overview. Part 2. AB - INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the most common lethal malignancies. The prognosis is poor despite progress in early diagnosis. Transarterial chemoembolization (TACE) represents an important local therapy. More recently the embolic agent itself is used as a drug loaded carrier. An overview of the present situation in the field of TACE has been made, taking into account the materials constituting the embolizing agents and the way of controlled drug release. AREAS COVERED: Clinical overview of TACE with attention to the present limits and problems of this technique; focus on the present situation of the materials (polymers) used for the preparation of the microparticulate systems to administer with attention to the new possible materials. EXPERT OPINION: The use of TACE techniques is important in the treatment of HCCs. However, these techniques need to be improved, in particular taking into account the use of new materials for the preparation of embolizing agents able to control drug release. PMID- 23679934 TI - Corneal oedema and its medical treatment. AB - Corneal oedema is a common sign of acute or protracted corneal disease of various aetiologies. In this paper, we review the causes and pathophysiological bases of corneal oedema, as well as discussing the goals and modalities of its medical treatment. Corneal oedema, if adequately understood and appropriately treated, generally shows a good prognosis. PMID- 23679935 TI - Implant analyses by clinical teams: a response. PMID- 23679936 TI - Multiple anomalous left pulmonary venous connections detected with transthoracic echocardiography. AB - Partial anomalous pulmonary venous connection is a rare congenital anomaly in which one or more pulmonary veins are connected to the venous circulation. The condition is frequently misdiagnosed, and usually identified by transesophageal echocardiography or invasive cardiac catheterization. We present the case of a 26 year-old female with new onset dyspnea on exertion who was diagnosed with the left superior and inferior pulmonary veins draining into the innominate vein via a vertical vein by two and three-dimensional transthoracic echocardiography and multidetector computed tomographic angiography. PMID- 23679937 TI - Transjugular intrahepatic portosystemic shunt for symptomatic portal hypertension in hepatocellular carcinoma with portal vein tumor thrombosis. AB - AIM: Transjugular intrahepatic portosystemic shunt (TIPS) represents a major advance in the treatment of complications of portal hypertension. However, this procedure is contraindicated in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT). This study aims to evaluate the safety and efficacy of TIPS in these patients with portal hypertension and determine the predictors of survival after TIPS creation. METHODS: Between 2005 and 2011, 58 consecutive HCC patients with symptomatic portal hypertension and concomitant PVTT underwent TIPS placement. Procedure-related complications, treatment efficacy of portal hypertension complications and survival were evaluated. RESULTS: After TIPS, no patient experienced major procedure-related complications such as hemorrhage or contrast extravasation. Portosystemic pressure gradient was decreased by 14 mmHg on average. Refractory ascites was partially or completely resolved in 19 of 20 patients. Hydrothorax was decreased in all of eight patients. Acute variceal bleeding was successfully controlled in all of five patients. Severe diarrhea was controlled successfully in all of nine patients. During the follow-up period (mean, 78.5 days; range, 11-1713), 56 patients died and two patients remained alive. The median survival period after TIPS was 77 days. Multivariate Cox regression analysis showed that ascites (P = 0.026), white blood cell (P = 0.007) and degree of PVTT (P < 0.001) were independent predictors for survival. CONCLUSION: TIPS may be effective for the palliative treatment of portal hypertension in HCC patients with PVTT. Major procedure-related complications were rarely observed. Ascites, white blood cell and degree of PVTT were independently associated with survival. PMID- 23679938 TI - 'Laser chemistry' synthesis, physicochemical properties, and chemical processing of nanostructured carbon foams. AB - Laser ablation of selected coordination complexes can lead to the production of metal-carbon hybrid materials, whose composition and structure can be tailored by suitably choosing the chemical composition of the irradiated targets. This 'laser chemistry' approach, initially applied by our group to the synthesis of P containing nanostructured carbon foams (NCFs) from triphenylphosphine-based Au and Cu compounds, is broadened in this study to the production of other metal NCFs and P-free NCFs. Thus, our results show that P-free coordination compounds and commercial organic precursors can act as efficient carbon source for the growth of NCFs. Physicochemical characterization reveals that NCFs are low density mesoporous materials with relatively low specific surface areas and thermally stable in air up to around 600 degrees C. Moreover, NCFs disperse well in a variety of solvents and can be successfully chemically processed to enable their handling and provide NCF-containing biocomposite fibers by a wet-chemical spinning process. These promising results may open new and interesting avenues toward the use of NCFs for technological applications. PMID- 23679939 TI - Who should control postmortem explantation? PMID- 23679940 TI - Dynamin contributes to cytokinesis by stabilizing actin filaments in the contractile ring. AB - Dynamin has been proposed to play an important role in cytokinesis, although the nature of its contribution has remained unclear. Dictyostelium discoideum has five dynamin-like proteins: DymA, DymB, DlpA, DlpB and DlpC. Cells mutant for dymA, dlpA or dlpB presented defects in cytokinesis that resulted in multinucleation when the cells were cultured in suspension. However, the cells could divide normally when attached to the substratum; this latter process depends on traction-mediated cytokinesis B. A dynamin GTPase inhibitor also blocked cytokinesis in suspension, suggesting an important role for dynamin in cytokinesis A, which requires a contractile ring powered by myosin II. Myosin II did not properly localize to the cleavage furrow in dynamin mutant cells, and the furrow shape was distorted. DymA and DlpA were associated with actin filaments at the furrow. Fluorescence recovery after photobleaching and a DNase I binding assay showed that actin filaments in the contractile ring were significantly fragmented in mutant cells. Dynamin is therefore involved in the stabilization of actin filaments in the furrow, which, in turn, maintain proper myosin II organization. We conclude that the lack of these dynamins disrupts proper actomyosin organization and thereby disables cytokinesis A. PMID- 23679941 TI - Bright future for research in horse breeding! PMID- 23679942 TI - Optimal contribution selection applied to the Norwegian and the North-Swedish cold-blooded trotter - a feasibility study. AB - The aim of this study was to examine how to apply optimal contribution selection (OCS) in the Norwegian and the North-Swedish cold-blooded trotter and give practical recommendations for the future. OCS was implemented using the software Gencont with overlapping generations and selected a few, but young sires, as these turn over the generations faster and thus is less related to the mare candidates. In addition, a number of Swedish sires were selected as they were less related to the selection candidates. We concluded that implementing OCS is feasible to select sires (there is no selection on mares), and we recommend the number of available sire candidates to be continuously updated because of amongst others deaths and geldings. In addition, only considering sire candidates with phenotype above average within a year class would allow selection candidates from many year classes to be included and circumvent current limitation on number of selection candidates in Gencont (approx. 3000). The results showed that mare candidates can well be those being mated the previous year. OCS will, dynamically, recruit young stallions and manage the culling or renewal of annual breeding permits for stallions that had been previously approved. For the annual mating proportion per sire, a constraint in accordance with the maximum that a sire can mate naturally is recommended. PMID- 23679943 TI - Genetic correlations for foal and studbook traits with racing traits and implications for selection strategies in the Finnhorse and Standardbred trotter. AB - Genetic correlations for body measurements and conformation and functional traits in foals and studbook horses with racing traits were estimated in the Finnhorse and Standardbred. Genetic response and accuracy were estimated using records of animal, half-sibs and parents in selection scenarios for racing traits, for foal and racing traits, for studbook and racing traits, and using records of animal, half-sibs and parents for foal traits and racing traits of parents. Racing time and earnings were the breeding objective. Low-to-moderate genetic correlations for body measurements and racing traits indicated that selection favours bigger horses at all ages. Being mainly favourable for the breeding objective, genetic correlations for conformation and functional traits with racing traits were highest for the foal traits of type, trot and overall grade and for the studbook traits of character and movements. Genetic correlations for foal and studbook conformation with racing traits were low in the Finnhorse and moderate to high in the Standardbred. In foals, the highest genetic correlations were for trot with racing time (-0.54) and with earnings (0.52) in the Finnhorse, and for overall grade with racing time (-0.54) and with earnings (0.54) in the Standardbred. In studbook horses, genetic correlations were high for character with racing time and earnings in the Finnhorse (-0.68, 0.61) and in the Standardbred (-0.63, 0.70), and for movements with racing time and earnings in the Finnhorse (-0.70, 0.69) and in the Standardbred (-0.90, 0.88). To increase accuracy of conformation and functional traits, foal traits would be more useful in the index with racing traits, as being less preselected than studbook traits. The foal traits (type, trot, overall grade) having moderate heritability and genetic correlations with racing traits would be useful in multi-trait index before a racing career, where the greatest gain is because of a shorter generation interval. It would be feasible to implement for AI stallions. PMID- 23679944 TI - Genetic (co)variance components across age for Show Jumping performance as an estimation of phenotypic plasticity ability in Spanish horses. AB - The purpose of this study was to study phenotypic plasticity ability for Show Jumping performance in horses according to age differences. For this study, 11 352 participations, belonging to 1085 horses grouped by age (4-, 5- or 6-year olds), were analysed. repeatability animal models (RAM) and multiple trait animal models (MTAM) were compared. RAM assumed the same covariance components for all age groups, whereas MTAM considered the results of every animal at every age group as different (but correlated) traits. The age, sex, starting order and training level were included as fixed effects. The random effects were the animal, the individual permanent environment, the competition and the rider. Six models were compared, and the rider-horse interaction was added as a random effect; furthermore, heterogeneous residual variance was taken into consideration only for MTAM. The study of the genetic correlations between age groups highlighted the presence of an age-genotype interaction and, therefore, an underlying environmental effect. This study may allow us to select horses with a plastic response, which show either a gradual response or a precocious response and thus gain or lose genetic potential with age, respectively. PMID- 23679945 TI - The potential of embryo transfer in a German horse-breeding programme. AB - A reference horse-breeding programme with 13500 foals each year was modelled with ZPLAN+. This new software for the optimization of the structures in breeding programmes is based on ZPLAN. In two scenarios, the implementation of a rigorous selection of mares was implemented. In scenario I, the mare performance test was the point of selection, while in scenario II, further information on 20 competitions in two more years is available. These selected mares were used for embryo transfer (ET), partly in combination with multiple ovulation (MOET). The selection intensity and the number of foals out of (MO)ET were varied in both scenarios. It was expected that 250, 500 and 1000 mares are available for selecting 20, 50, 100 or 200 donor mares each year. The number of foals out of (MO)ET was varied between one and six foals per donor mare and year. Donor mares were used for ET for 4 years. It became clear that with high selection intensities of donor mares and high reproduction rates of them, the yearly genetic gain in a horse-breeding programme could increase over a large range. In scenario II, the additional information on 20 competitions increased the accuracy of the selection index to 0.85. With 200 selected donor mares of 1000 available mares and six foals per year, the genetic gain could almost be doubled compared to the reference scenario. The implementation of ET and a related higher usage of few selected mares entails rising costs and a reduction in the genetic variance. In the most extreme MOET scenario, the effective population size was reduced by 19% relative to the reference scenario. Only if the increase in genetic gain can be converted into higher return for the breeders, the implementation of (MO)ET schemes is a realistic and sensible option for horse-breeding programmes. PMID- 23679946 TI - An integration of external information for foreign stallions into the Belgian genetic evaluation for jumping horses. AB - The aim of this study was to test the integration of external information, i.e. foreign estimated breeding values (EBV) and the associated reliabilities (REL), for stallions into the Belgian genetic evaluation for jumping horses. The Belgian model is a bivariate repeatability Best Linear Unbiased Prediction animal model only based on Belgian performances, while Belgian breeders import horses from neighbouring countries. Hence, use of external information is needed as prior to achieve more accurate EBV. Pedigree and performance data contained 101382 horses and 712212 performances, respectively. After conversion to the Belgian trait, external information of 98 French and 67 Dutch stallions was integrated into the Belgian evaluation. Resulting Belgian rankings of the foreign stallions were more similar to foreign rankings according to the increase of the rank correlations of at least 12%. REL of their EBV were improved of at least 2% on average. External information was partially to totally equivalent to 4 years of contemporary horses' performances or to all the stallions' own performances. All these results showed the interest to integrate external information into the Belgian evaluation. PMID- 23679947 TI - Implementation of Optimum Contributions selection in endangered local breeds: the case of the Menorca Horse population. AB - Limiting the inbreeding rate (?F) while maximizing genetic gain for any trait of economic interest is especially important in small populations of local breeds, like the Menorca Horse. In this breed, dressage performance is important for the profitability of the breed and should be accounted in the selection criterion. The aim of this study was to assess if a breeding programme aiming at improved dressage performance is feasible in such a small breed. To perform the analysis, animals that were currently available for breeding (between 3 and 20 years) were used. Selection was based on the estimated breeding values for dressage obtained by BLUP. The pedigree and molecular coancestry between potential breeding horses was used (separately or in combination) to account for the restriction on ?F. Results show that it is possible to avoid large increases in inbreeding while obtaining acceptable levels of genetic gain (i.e. a ?F of 1% would imply a maximum loss in genetic gain of 2%). Thus, the Menorca Horse population is suitable for a management procedure which jointly optimizes the response to selection and the levels of variability and inbreeding (Optimal Contribution selection). Regarding the source of information used to calculate the relationships, molecular information would provide a greater range of solutions to increase genetic gain than using pedigree coancestry (gain was 1-4% higher for the same levels of restriction on the increase in inbreeding). PMID- 23679948 TI - Thoroughbred racehorse mitochondrial DNA demonstrates closer than expected links between maternal genetic history and pedigree records. AB - The potential future earnings and therefore value of Thoroughbred foals untested in the racing arena are calculated based on the performance of their forebears. Thus, lineage is of key importance. However, previous research indicates that maternally inherited mitochondrial DNA (mtDNA) does not correspond to maternal lineage according to recorded pedigree, casting doubt on the voracity of historic pedigrees. We analysed mtDNA of 296 Thoroughbred horses from 33 maternal lineages and identified an interesting trend. Subsequent to the founding of the Thoroughbred breed in the 16th century, well-populated maternal lineages were divided into sub-lineages. Only six in 10 of the Thoroughbreds sampled shared mitochondrial haplotype with other members of their maternal lineage, despite having a common maternal ancestor according to pedigree records. However, nine in 10 Thoroughbreds from the 103 sub-lineages sampled shared mtDNA with horses of their maternal pedigree sub-lineage. Thus, Thoroughbred maternal sub-lineage pedigree represents a more accurate breeding record than previously thought. Errors in pedigrees must have occurred largely, though, not exclusively, at sub lineage foundation events, probably due to incomplete understanding of modes of inheritance in the past, where maternal sub-lineages were founded from individuals, related, but not by female descent. PMID- 23679949 TI - The effects of dog breed development on genetic diversity and the relative influences of performance and conformation breeding. AB - Genetic diversity was compared among eight dog breeds selected primarily for conformation (Standard Poodle, Italian Greyhound and show English Setter), conformation and performance (Brittany), predominantly performance (German Shorthaired and Wirehaired Pointers) or solely performance (field English Setter and Red Setter). Modern village dogs, which better reflect ancestral genetic diversity, were used as the standard. Four to seven maternal and one to two Y haplotypes were found per breed, with one usually dominant. Diversity of maternal haplotypes was greatest in village dogs, intermediate in performance breeds and lowest in conformation breeds. Maternal haplotype sharing occurred across all breeds, while Y haplotypes were more breed specific. Almost all paternal haplotypes were identified among village dogs, with the exception of the dominant Y haplotype in Brittanys, which has not been identified heretofore. The highest heterozygosity based on 24 autosomal microsatellites was found in village dogs and the lowest in conformation (show) breeds. Principal coordinate analysis indicated that conformation-type breeds were distinct from breeds heavily used for performance, the latter clustering more closely with village dogs. The Brittany, a well-established dual show and field breed, was also genetically intermediate between the conformation and performance breeds. The number of DLA DRB1 alleles varied from 3 to 10 per breed with extensive sharing. SNPs across the wider DLA region were more frequently homozygous in all pure breeds than in village dogs. Compared with their village dog relatives, all modern breed dogs exhibit reduced genetic diversity. Genetic diversity was even more reduced among breeds under selection for show/conformation. PMID- 23679950 TI - A combination of mutations in AKR1D1 and SKIV2L in a family with severe infantile liver disease. AB - Infantile cholestatic diseases can be caused by mutations in a number of genes involved in different hepatocyte molecular pathways. Whilst some of the essential pathways have a well understood function, such as bile biosynthesis and transport, the role of the others is not known. Here we report the findings of a clinical, biochemical and molecular study of a family with three patients affected with a severe infantile cholestatic disease. A novel homozygous frameshift germline mutation (c.587delG) in the AKR1D1 gene; which encodes the enzyme Delta 4-3-oxosteroid 5beta-reductase that is required for synthesis of primary bile acids and is crucial for establishment of normal bile flow, was found in all 3 patients. Although the initial bile acid analysis was inconclusive, subsequent testing confirmed the diagnosis of a bile acid biogenesis disorder. An additional novel homozygous frameshift mutation (c.3391delC) was detected in SKIV2L in one of the patients. SKIV2L encodes a homologue of a yeast ski2 protein proposed to be involved in RNA processing and mutations in SKIV2L were recently described in patients with Tricohepatoenteric syndrome (THES). A combination of autozygosity mapping and whole-exome-sequencing allowed the identification of causal mutations in this family with a complex liver phenotype. Although the initial 2 affected cousins died in the first year of life, accurate diagnosis and management of the youngest patient led to successful treatment of the liver disease and disease-free survival. PMID- 23679951 TI - Renoprotective effects of metformin. AB - Metformin as a biguanid drug entered to the market 50 years ago and now is generally recommended as the first-line treatment in type 2 diabetes, especially in overweight patients, however in recent years new indications for its use have emerged . It improves peripheral and liver sensitivity to insulin, reduces basal hepatic glucose production, increases insulin-stimulated uptake and utilization of glucose by peripheral tissues, decreases hunger and causes weight reduction.Recently, much attention has been made toward the possible kidney protective efficacy of metformin. Recent studies have proven that metformin, possesses antioxidant properties, too. PMID- 23679952 TI - MutS stimulates the endonuclease activity of MutL in an ATP-hydrolysis-dependent manner. AB - In the initial steps of DNA mismatch repair, MutS recognizes a mismatched base and recruits the latent endonuclease MutL onto the mismatch-containing DNA in concert with other proteins. MutL then cleaves the error-containing strand to introduce an entry point for the downstream excision reaction. Because MutL has no intrinsic ability to recognize a mismatch and discriminate between newly synthesized and template strands, the endonuclease activity of MutL is strictly regulated by ATP-binding in order to avoid nonspecific degradation of the genomic DNA. However, the activation mechanism for its endonuclease activity remains unclear. In this study, we found that the coexistence of a mismatch, ATP and MutS unlocks the ATP-binding-dependent suppression of MutL endonuclease activity. Interestingly, ATPase-deficient mutants of MutS were unable to activate MutL. Furthermore, wild-type MutS activated ATPase-deficient mutants of MutL less efficiently than wild-type MutL. We concluded that ATP hydrolysis by MutS and MutL is involved in the mismatch-dependent activation of MutL endonuclease activity. PMID- 23679953 TI - Modified social ecological model: a tool to guide the assessment of the risks and risk contexts of HIV epidemics. AB - BACKGROUND: Social and structural factors are now well accepted as determinants of HIV vulnerabilities. These factors are representative of social, economic, organizational and political inequities. Associated with an improved understanding of multiple levels of HIV risk has been the recognition of the need to implement multi-level HIV prevention strategies. Prevention sciences research and programming aiming to decrease HIV incidence requires epidemiologic studies to collect data on multiple levels of risk to inform combination HIV prevention packages. DISCUSSION: Proximal individual-level risks, such as sharing injection devices and unprotected penile-vaginal or penile-anal sex, are necessary in mediating HIV acquisition and transmission. However, higher order social and structural-level risks can facilitate or reduce HIV transmission on population levels. Data characterizing these risks is often far more actionable than characterizing individual-level risks. We propose a modified social ecological model (MSEM) to help visualize multi-level domains of HIV infection risks and guide the development of epidemiologic HIV studies. Such a model may inform research in epidemiology and prevention sciences, particularly for key populations including men who have sex with men (MSM), people who inject drugs (PID), and sex workers. The MSEM builds on existing frameworks by examining multi level risk contexts for HIV infection and situating individual HIV infection risks within wider network, community, and public policy contexts as well as epidemic stage. The utility of the MSEM is demonstrated with case studies of HIV risk among PID and MSM. SUMMARY: The MSEM is a flexible model for guiding epidemiologic studies among key populations at risk for HIV in diverse sociocultural contexts. Successful HIV prevention strategies for key populations require effective integration of evidence-based biomedical, behavioral, and structural interventions. While the focus of epidemiologic studies has traditionally been on describing individual-level risk factors, the future necessitates comprehensive epidemiologic data characterizing multiple levels of HIV risk. PMID- 23679954 TI - Heterogenous nuclear ribonucleoprotein Q increases protein expression from HIV-1 Rev-dependent transcripts. AB - BACKGROUND: Heterogenous nuclear ribonucleoproteins (hnRNPs) control many processes of the gene expression machinery including mRNA transcription, splicing, export, stability and translation. Recent data show interaction of the HIV-1 Rev regulatory protein with a subset of hnRNP proteins, that includes hnRNP Q, suggesting that hnRNPs can contribute to regulation of HIV-1 gene expression by Rev. FINDINGS: In this work we address the effect of hnRNP Q on Rev-dependent gene expression. We show that hnRNP Q overexpression increased levels of proteins produced from a Rev-dependent reporter gene in the presence of Rev. Increased protein levels did not correlate with changes in either the levels or the nucleocytoplasmic distribution of Rev-dependent reporter mRNAs. Similar observations were made in persistently HIV-1 infected HeLa cells. In these cells, hnRNP Q overexpression increased levels of the HIV-1 Gag-p24 protein, while levels of viral Rev-dependent mRNAs were not affected. CONCLUSION: Our data indicate that hnRNP Q can stimulate the protein production of Rev-dependent mRNAs without changing mRNA levels and mRNA export, respectively. This suggests that hnRNP Q can boost HIV gene expression at the level of protein production. PMID- 23679955 TI - Antagonists for the orphan G-protein-coupled receptor GPR55 based on a coumarin scaffold. AB - The orphan G-protein-coupled receptor GPR55, which is activated by 1 lysophosphatidylinositol and interacts with cannabinoid (CB) receptor ligands, has been proposed as a new potential drug target for the treatment of diabetes, Parkinson's disease, neuropathic pain, and cancer. We applied beta-arrestin assays to identify 3-substituted coumarins as a novel class of antagonists and performed an extensive structure-activity relationship study for GPR55. Selectivity versus the related receptors CB1, CB2, and GPR18 was assessed. Among the 7-unsubstituted coumarins selective, competitive GPR55 antagonists were identified, such as 3-(2-hydroxybenzyl)-5-isopropyl-8-methyl-2H-chromen-2-one (12, PSB-SB-489, IC50 = 1.77 MUM, pA2 = 0.547 MUM). Derivatives with long alkyl chains in position 7 were potent, possibly allosteric GPR55 antagonists which showed ancillary CB receptor affinity. 7-(1,1-Dimethyloctyl)-5-hydroxy-3-(2 hydroxybenzyl)-2H-chromen-2-one (69, PSB-SB-487, IC50 = 0.113 MUM, KB = 0.561 MUM) and 7-(1,1-dimethylheptyl)-5-hydroxy-3-(2-hydroxybenzyl)-2H-chromen-2-one (67, PSB-SB-1203, IC50 = 0.261 MUM) were the most potent GPR55 antagonists of the present series. PMID- 23679956 TI - Early venous return in hepatic angiomyolipoma due to an intratumoral structure resembling an arteriovenous fistula. AB - Early venous return (EVR) is an important radiological feature of hepatic angiomyolipoma (HAML) that can aid in differential diagnosis, but the pathogenic mechanisms of EVR have yet to be elucidated. We present the first HAML case for which a probable mechanism for EVR is described. The patient was a 46-year-old woman, who had a growing 6-cm tumor with EVR in segment 3 of the liver as revealed by dynamic contrast-enhanced computed tomography. Left hepatic lobectomy was performed to prevent tumor rupture. Histopathological and immunohistochemical analyses of the excised tumor indicated HAML. Successive microsections of the tumor were stained with hematoxylin-eosin and Victoria blue to visualize the vascular structure within and around the tumor. These analyses led to three major findings. First, many well-defined thick-walled vessels, such as arteries, were found entering the tumor. Second, many thick-walled vessels within the tumor were connected directly to thin-walled vessels, resembling arteriovenous fistulae. Finally, thin-walled intratumoral vessels were connected directly to the hepatic vein. These histological findings suggested that the rich arterial flow into the tumor was being rapidly drained into the hepatic vein through intratumoral arteriovenous connections. We also detected these same anomalous circulatory pathways in tissue sections from three of four additional HAML cases with EVR. Aberrant arteriovenous fistulae within the tumor may account for many cases of EVR in HAML patients. PMID- 23679958 TI - Impacts of the minimum legal drinking age legislation on in-patient morbidity in Canada, 1997-2007: a regression-discontinuity approach. AB - AIMS: To provide novel, population-based estimates of the influence of minimum legal drinking age (MLDA) legislation on target in-patient hospital events in Canada. DESIGN: Regression-discontinuity analyses on rates of Canadian in-patient admissions. SETTING: All in-patient hospitalizations in Canada (except Quebec) between 1 April 1997 and 31 March 2007. PARTICIPANTS: Individuals aged 15-22 years admitted to hospital. MEASUREMENTS: International Classification of Diseases-9/10 codes for alcohol-use disorders/poisoning, injury, suicide, assault and motor vehicle accidents were considered as target morbidity conditions. FINDINGS: Compared with the baseline hospitalization rate just prior to the MLDA, admissions at the MLDA rose significantly (P <= 0.001) for alcohol-use disorders/poisoning for males (17.3%) and females (21.1%), as well as for suicide events for the combined sample (9.6%, P = 0.029). Among males, there was a significant 4.4% increase (P = 0.001) in a broad class of injuries, including a 9.2% jump (P = 0.020) in admissions for motor vehicle accidents compared with the baseline hospitalization rate just prior to the MLDA. CONCLUSION: Removal of minimum legal drinking age restrictions is associated with significant population level increases in hospital admissions among young adults in Canada for alcohol use disorders/poisoning, as well as for other serious injuries, especially among males. Current international minimum legal drinking age policy discussions should account for the impact of the minimum legal drinking age on severe morbidity outcomes. PMID- 23679959 TI - Normalisation of left ventricular systolic function after change from VVI pacing to biventricular pacing in a child with congenital complete atrioventricular block, long-QT syndrome, and congenital muscular dystrophy: a 10-year follow-up. AB - Development of dilated cardiomyopathy in patients with congenital complete atrioventricular block with or without pacemaker is well described. We report a case of dilated cardiomyopathy in a child with congenital complete atrioventricular block, long-QT syndrome, and VVI pacemaker. Temporary pacing in the right ventricular outflow tract demonstrated a 63% increase in cardiac output. After change to biventricular DDD pacing, left ventricular systolic function and diastolic dimensions normalised. PMID- 23679961 TI - Control and near-field detection of surface plasmon interference patterns. AB - The tailoring of electromagnetic near-field properties is the central task in the field of nanophotonics. In addition to 2D optics for optical nanocircuits, confined and enhanced electric fields are utilized in detection and sensing, photovoltaics, spatially localized spectroscopy (nanoimaging), as well as in nanolithography and nanomanipulation. For practical purposes, it is necessary to develop easy-to-use methods for controlling the electromagnetic near-field distribution. By imaging optical near-fields using a scanning near-field optical microscope, we demonstrate that surface plasmon polaritons propagating from slits along the metal-dielectric interface form tunable interference patterns. We present a simple way how to control the resulting interference patterns both by variation of the angle between two slits and, for a fixed slit geometry, by a proper combination of laser beam polarization and inhomogeneous far-field illumination of the structure. Thus the modulation period of interference patterns has become adjustable and new variable patterns consisting of stripelike and dotlike motifs have been achieved, respectively. PMID- 23679960 TI - Factors relating to eating style, social desirability, body image and eating meals at home increase the precision of calibration equations correcting self report measures of diet using recovery biomarkers: findings from the Women's Health Initiative. AB - BACKGROUND: The extent to which psychosocial and diet behavior factors affect dietary self-report remains unclear. We examine the contribution of these factors to measurement error of self-report. METHODS: In 450 postmenopausal women in the Women's Health Initiative Observational Study doubly labeled water and urinary nitrogen were used as biomarkers of objective measures of total energy expenditure and protein. Self-report was captured from food frequency questionnaire (FFQ), four day food record (4DFR) and 24 hr. dietary recall (24HR). Using regression calibration we estimated bias of self-reported dietary instruments including psychosocial factors from the Stunkard-Sorenson Body Silhouettes for body image perception, the Crowne-Marlowe Social Desirability Scale, and the Three Factor Eating Questionnaire (R-18) for cognitive restraint for eating, uncontrolled eating, and emotional eating. We included a diet behavior factor on number of meals eaten at home using the 4DFR. RESULTS: Three categories were defined for each of the six psychosocial and diet behavior variables (low, medium, high). Participants with high social desirability scores were more likely to under-report on the FFQ for energy (beta = -0.174, SE = 0.054, p < 0.05) and protein intake (beta = -0.142, SE = 0.062, p < 0.05) compared to participants with low social desirability scores. Participants consuming a high percentage of meals at home were less likely to under-report on the FFQ for energy (beta = 0.181, SE = 0.053, p < 0.05) and protein (beta = 0.127, SE = 0.06, p < 0.05) compared to participants consuming a low percentage of meals at home. In the calibration equations combining FFQ, 4DFR, 24HR with age, body mass index, race, and the psychosocial and diet behavior variables, the six psychosocial and diet variables explained 1.98%, 2.24%, and 2.15% of biomarker variation for energy, protein, and protein density respectively. The variations explained are significantly different between the calibration equations with or without the six psychosocial and diet variables for protein density (p = 0.02), but not for energy (p = 0.119) or protein intake (p = 0.077). CONCLUSIONS: The addition of psychosocial and diet behavior factors to calibration equations significantly increases the amount of total variance explained for protein density and their inclusion would be expected to strengthen the precision of calibration equations correcting self-report for measurement error. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00000611. PMID- 23679962 TI - Health for all? Patterns and predictors of allied health service use in Australia. AB - OBJECTIVE: To examine patterns and predictors of allied health service use among the Australian population. METHODS: Data from the 2007-08 longitudinal National Health Survey conducted by the Australian Bureau of Statistics in Australia were used to examine differences in use of allied health services among the population. The survey is based on 15779 adult respondents. Multivariate logistic regression models were used to model the probability of visiting an allied health service contingent on multiple factors of interest. RESULTS: Men, less educated people and people from non-English speaking backgrounds were low users compared with other groups. Interestingly, people with type 2 diabetes were substantially higher users compared with people with other chronic diseases, or no reported chronic disease, and ancillary health insurance had a strong positive effect on use. DISCUSSION: Further investigation of the social and economic circumstances surrounding allied health service use is required to determine areas of under use or unmet need. High use among people with diabetes might indicate the impact of policy incentives to enhance use. Yet, whether all those in need are able to access services is unknown. Further investigation of use among groups with different health needs and by type of financing will enhance policy. What is known about the topic? Inequities and variations in access to allied health services are commonplace. Effective policy initiatives to improve access, particularly among patients with chronic disease, will depend on improving the knowledge base about patterns of use of allied health services, and what determines use. What does this paper add? This paper reveals the high and low users of allied health services among the Australian population, those population groups who might be missing out and what might explain these patterns. This information will enable policy makers to target areas of potential unmet need. What are the implications for practitioners? Multidisciplinary team care is advocated in the management of chronic disease. Practitioners have a vital role in framing the benefits of allied health services to patients and in developing the evidence base about best practice in the management of chronic disease for diverse patient groups. PMID- 23679963 TI - Point: Access to transcatheter aortic valve replacement should be limited to high volume surgical centers. PMID- 23679964 TI - Counterpoint: Access to transcatheter aortic valve replacement should not be limited to high-volume surgical centers. PMID- 23679957 TI - Implementation of the INTERGROWTH-21st Project in Oman. AB - The Middle Eastern site in the INTERGROWTH-21(st) Project was Muscat, the capital city of Oman, with approximately 10,500 births per year. The sample for the Newborn Cross-Sectional Study (NCSS) was drawn from two hospitals covering 96% of the region's births. The Fetal Growth Longitudinal Study (FGLS) sample was recruited from four primary health facilities serving Khoula Hospital, using the eligibility criteria in the INTERGROWTH-21(st) protocol. Special activities to encourage participation in this population included local advocacy campaigns to encourage early antenatal booking and ultrasound dating in the population. The major challenges at the site were the recruitment of sufficient numbers of women at an early gestational age, and the timely measurement of all newborns within 12 hours of birth. Many individuals and institutions collaborated effectively over a period of several years on these studies, which required careful planning and close monitoring for their successful implementation. PMID- 23679965 TI - THE GooseMan: a simulator for transhiatal esophagectomy. PMID- 23679966 TI - Use of annulus washer after debridement: a new mitral valve replacement technique for patients with severe mitral annular calcification. PMID- 23679967 TI - The Senior Cardiovascular Surgical Society. PMID- 23679968 TI - Transfusions and morbidity after surgery of congenital heart disease: pure statistics or time for a paradigm shift? PMID- 23679969 TI - Reply to the editor. PMID- 23679970 TI - Cardiac magnetic resonance imaging for assessment of aortic valve morphology. PMID- 23679971 TI - Reply to the editor. PMID- 23679972 TI - Value of the tricuspid annular plane systolic excursion as a follow-up parameter in patients with hypoplastic left heart syndrome. PMID- 23679973 TI - Reply to the editor. PMID- 23679974 TI - Staged percutaneous coronary intervention and minimally invasive valve surgery: results of a hybrid approach to concomitant coronary and valvular disease. PMID- 23679975 TI - Adenosine-procaine cardioplegia and adenosine-lidocaine cardioplegia: Two sides of the same coin? PMID- 23679976 TI - Reply to the editor. PMID- 23679977 TI - Folding or plication technique in mitral valve repair: New or renamed? PMID- 23679978 TI - Reply to the editor. PMID- 23679979 TI - Is gender-specific survival in patients undergoing radial artery grafting influenced by hormone levels? PMID- 23679980 TI - Reply to the editor. PMID- 23679981 TI - Reply to the editor. PMID- 23679982 TI - A comparison of the Plusoptix S08 photorefractor to retinoscopy and cycloretinoscopy. AB - BACKGROUND: The aim was to compare outcome measures of refractive error by the Plusoptix S08 photorefractor with measures obtained by retinoscopy and cycloretinoscopy in children. METHOD: The refractive error of the right eye of 144 non-strabismic children, aged 2.5 to 5.5 years, was determined by Plusoptix S08 photorefraction, retinoscopy and cycloretinoscopy. Agreement between outcome measures of refractive error (spherical error, cylindrical error and spherical equivalent) by the three techniques were tested by Bland-Altman limits of agreement. RESULTS: The mean difference for spherical equivalent results of photorefraction (P(se)) minus those of retinoscopy (R(se)) and photorefraction minus those of cycloretinoscopy (CR(se)) were +0.53 +/- 0.62 D and -0.22 +/- 0.75 D, respectively. The 95 per cent limits of agreement for spherical photorefraction with retinoscopy and cycloretinoscopy were +/-1.22 D (range -0.69 to +1.75) and +/-1.47 D (range -1.69 to +1.25), respectively. The mean difference for cylindrical results of photorefraction (P(c)) minus those of retinoscopy (R(c)) and Pc minus those of cycloretinoscopy (CR(c)) were +0.11 +/- 0.39 D and +0.13 +/- 0.44 D, respectively. The 95 per cent limits of agreement for P(c) with R(c) and CR(c) were +/-0.76 D (range -0.65 to +0.87) and +/-0.86 D (range -0.73 to +0.99), respectively. The mean and standard deviation of weighted axes difference, comparing Plusoptix S08 and retinoscopy was 0.25 +/- 0.36 and comparing Plusoptix S08 and cycloretinoscopy was 0.29 +/- 0.51. Eighty-two per cent of the spherical equivalent findings in photorefraction and cycloretinoscopy show a difference of within 1.00 D. Regarding cylindrical power, this percentage is 96.6 per cent. CONCLUSION: As the findings demonstrate a fairly good consistency between the results of the Plusoptix S08 Photorefractor without using cycloplegic agents and those of cycloretinoscopy, the Plusoptix S08 is a fairly accurate tool to estimate refractive errors of children in the limited working range of the instrument. PMID- 23679983 TI - Functional remission and employment among patients with schizophrenia in Malaysia. AB - OBJECTIVE: The study aimed to determine the rates of functional remission and employment as well as the factors associated with functional remission among patients with Schizophrenia, receiving community psychiatric service in an urban setting in Malaysia. METHODS: From a total of 250 patients randomly selected, 155 fulfilled the study requirement and were assessed on their functional remission status using the Personal and Social Performance Scale. The relationships between functional remission and socio-demographic factors, clinical factors, social support, symptom remission and rates of hospitalization were examined. RESULTS: The results revealed that 74% (n=115) of the respondents had functional remission with only 20% (n=31) currently employed. Functional remission was found to be significantly associated with good social support (84.4% versus 36.4% p<0.001, OR=9.487 [95% CI=4.008-22.457]); shorter illness duration of less than 10 years (81.2% versus 66.7% p=0.038, OR=2.167 [95% CI=1.035-4.535]); good medication compliance (79.1% versus 50.0% p=0.002, OR=3.778 [95% CI=1.570-9.090]); hospital admissions of lower than 3 per year (80.5% versus 44.4% p<0.001 OR=5.150 [95% CI=2.145-12.365]) and; symptomatic remission (87.3% versus 37.4% p<0.001 [95% CI=0.070 (0.029-0.168]). A multiple regression analysis revealed only social support, lower hospitalization rate and symptom remission, as significant predictors of functional remission. CONCLUSION: A majority of patients with Schizophrenia in this study achieved functional remission, however, only a small percentage of them were employed. Functional remission was influenced by severity of illness and levels of social support in these patients. PMID- 23679984 TI - Replication modes of Maize streak virus mutants lacking RepA or the RepA-pRBR interaction motif. AB - The plant-infecting mastreviruses (family Geminiviridae) express two distinct replication-initiator proteins, Rep and RepA. Although RepA is essential for systemic infectivity, little is known about its precise function. We therefore investigated its role in replication using 2D-gel electrophoresis to discriminate the replicative forms of Maize streak virus (MSV) mutants that either fail to express RepA (RepA(-)), or express RepA that is unable to bind the plant retinoblastoma related protein, pRBR. Whereas amounts of viral DNA were reduced in two pRBR-binding deficient RepA mutants, their repertoires of replicative forms changed only slightly. While a complete lack of RepA expression was also associated with reduced viral DNA titres, the only traces of replicative intermediates of RepA(-) viruses were those indicative of recombination-dependent replication. We conclude that in MSV, RepA, but not RepA-pRBR binding, is necessary for single-stranded DNA production and efficient rolling circle replication. PMID- 23679985 TI - The 2b protein of Asparagus virus 2 functions as an RNA silencing suppressor against systemic silencing to prove functional synteny with related cucumoviruses. AB - Asparagus virus 2 (AV-2) is a member of the genus Ilarvirus in the family Bromoviridae. We cloned the coat protein (CP) and the 2b protein (2b) genes of AV 2 isolates from asparagus plants from various regions and found that the sequence for CP and for 2b was highly conserved among the isolates, suggesting that AV-2 from around the world is almost identical. We then made an AV-2 infectious clone by simultaneous inoculation with in vitro transcripts of RNAs 1-3 of AV-2 and in vitro-synthesized CP, which is necessary for initial infection. Because 2b of cucumoviruses in Bromoviridae can suppress systemic silencing as well as local silencing, we analyzed whether there is functional synteny of 2b between AV-2 and cucumovirus. Using the AV-2 infectious clone, we here provided first evidence that Ilarvirus 2b functions as an RNA silencing suppressor; AV-2 2b has suppressor activity against systemic silencing but not local silencing. PMID- 23679986 TI - Quantum interference effects at room temperature in OPV-based single-molecule junctions. AB - Interference effects on charge transport through an individual molecule can lead to a notable modulation and suppression on its conductance. In this letter, we report the observation of quantum interference effects occurring at room temperature in single-molecule junctions based on oligo(3)-phenylenevinylene (OPV3) derivatives, in which the central benzene ring is coupled to either para- or meta-positions. Using the break-junction technique, we find that the conductance for a single meta-OPV3 molecule wired between gold electrodes is one order of magnitude smaller than that of a para-OPV3 molecule. Theoretical calculations confirm the occurrence of constructive and destructive interference in the para- and meta-OPV3 molecules respectively, which arises from the phase difference of the transmission coefficients through the molecular orbitals. PMID- 23679987 TI - Clinical tools to assess balance in children and adults with cerebral palsy: a systematic review. AB - We aimed to review tools used to assess balance in clinical practice in children and adults with cerebral palsy (CP), to describe their content and measurement properties and to evaluate the quality of the studies that have examined these properties. CINAHL, Embase, and PubMed/MEDLINE were searched. The COnsensus-based Standards for selection of health Measurement INstruments (COSMIN) was used to assess the 'quality of studies' and the Terwee criteria were used to assess the 'result of studies'. Twenty-two clinical balance tools were identified from 35 papers. The content and focus of the tools varied significantly. There was moderate or limited levels of evidence for most of the measurement properties of the tools; the strongest level of evidence was found for the Trunk Control Measurement Scale and the Level of Sitting Scale, in the category 'maintain balance', the Timed Up and Go and the Segmental Assessment of Trunk Control in the categories 'achieve balance' and 'restore balance' respectively. Information on responsiveness was scarce. Further studies providing better evidence for reliability and responsiveness for clinical balance tools are needed. In the meantime, results of studies evaluating effects of treatment of balance in individuals with CP should be interpreted with caution. PMID- 23679988 TI - Molecular and cellular characterization of buffalo bone marrow-derived mesenchymal stem cells. AB - Immune privileged mesenchymal stem cells (MSCs) can differentiate into multiple cell types and possess great potential for human and veterinary regenerative therapies. This study was designed with an objective to isolate, expand and characterize buffalo bone marrow-derived MSCs (BM-MSCs) at molecular and cellular level. Buffalo BM-MSCs were isolated by Ficoll density gradient method and cultured in Dulbecco's modified Eagle's medium supplemented with fetal bovine serum (FBS). These cells were characterized through alkaline phosphatase (AP) staining, colony-forming unit (CFU) assay, mRNA expression analysis (CD 73, CD 90, CD 105, Oct4 and Nanog), immunolocalization along with flow cytometry (Stro 1, CD 73, CD 105, Oct4, Sox2 and Nanog) and in situ hybridization (Oct4 and Sox2). Multilineage differentiation (osteogenic, adipogenic and chondrogenic) was induced in vitro, which was further assessed by specific staining. Buffalo BM MSCs have the capacity to form plastic adherent clusters of fibroblast-like cells and were successfully maintained up to 16(th) passage. These cells were AP positive, and further CFU assay confirmed their clonogenic property. RT-PCR analysis and protein localization study showed that buffalo BM-MSCs are positive for various cell surface markers and pluripotency markers. Cytoplasmic distribution of mRNA for pluripotency markers in buffalo BM-MSCs and multilineage differentiation were induced in vitro, which was further assessed by specific staining. To the best of our knowledge, this is the first report of buffalo BM MSCs, which suggests that MSCs can be derived and expanded from buffalo bone marrow and can be used after characterization as a novel agent for regenerative therapy. PMID- 23679989 TI - Dmrta1 regulates proneural gene expression downstream of Pax6 in the mammalian telencephalon. AB - The transcription factor Pax6 balances cell proliferation and neuronal differentiation in the mammalian developing neocortex by regulating the expression of target genes. Using microarray analysis, we observed the down regulation of Dmrta1 (doublesex and mab-3-related transcription factor-like family A1) in the telencephalon of Pax6 homozygous mutant rats (rSey(2) /rSey(2) ). Dmrta1 expression was restricted to the neural stem/progenitor cells of the dorsal telencephalon. Overexpression of Dmrta1 induced the expression of the proneural gene Neurogenin2 (Neurog2) and conversely repressed Ascl1 (Mash1), a proneural gene expressed in the ventral telencephalon. We found that another Dmrt family molecule, Dmrt3, induced Neurog2 expression in the dorsal telencephalon. Our novel findings suggest that dual regulation of proneural genes mediated by Pax6 and Dmrt family members is crucial for cortical neurogenesis. PMID- 23679991 TI - Improved emollient use reduces atopic eczema symptoms and is cost neutral in infants: before-and-after evaluation of a multifaceted educational support programme. AB - BACKGROUND: Parents and carers of children with eczema often underuse emollient therapy, essential to repairing and protecting the defective skin barrier in atopic eczema. Educational interventions delivered by specialist dermatology nurses in hospital settings have been shown to improve emollient use and reduce symptoms of atopic eczema, but benefits of community-based interventions are uncertain. Support and information about appropriate care may often be inadequate for patients and carers in the community. METHODS: A multifaceted educational support programme was evaluated as a method of increasing emollient use and reducing atopic eczema in children. Support provided for parents and carers included an educational DVD, online daily diary and telephone helpline. The before and after study included 136 British children and their parents, providing baseline and 12 week follow-up data while receiving the programme. Measures included emollient use, POEM and PEST scores, and cost of care. RESULTS: Average emollient use increased by 87.6 g (95% CI: 81.9 to 119.5 g, p = 0.001) from baseline with the change being immediate and persistent. The POEM score reduced on average by 5.38 (95% CI: 4.36 to 6.41, p = 0.001), a 47% reduction from baseline. Similarly the PEST score reduced on average by 0.61 (95% CI: 0.47 to 0.75, p = 0.001), a 48% reduction from baseline. Sleep disturbance was reduced by 1.27 nights per week (95% CI: 0.85 to 1.68, p = 0.001) and parental feeling of control improved by 1.32 points (95% CI: 1.16 to 1.48, p = 0.001). From the NHS perspective, the programme was cost neutral overall within the study period. CONCLUSION: A community-based multifaceted educational support programme greatly increased emollient use, reducing symptoms of atopic eczema and general practitioner contacts, without increasing cost. Significant benefits may accrue to the families and carers of children with atopic eczema due to improved sleep patterns and greater feeling of control. PEST, a new simple measure of acute and remitting atopic eczema severity designed to help parents and children to monitor and manage eczema, merits further evaluation. PMID- 23679990 TI - Dandy-Walker malformation and Wisconsin syndrome: novel cases add further insight into the genotype-phenotype correlations of 3q23q25 deletions. AB - BACKGROUND: The Dandy-Walker malformation (DWM) is one of the commonest congenital cerebellar defects, and can be associated with multiple congenital anomalies and chromosomal syndromes. The occurrence of overlapping 3q deletions including the ZIC1 and ZIC4 genes in few patients, along with data from mouse models, have implicated both genes in the pathogenesis of DWM. METHODS AND RESULTS: Using a SNP-array approach, we recently identified three novel patients carrying heterozygous 3q deletions encompassing ZIC1 and ZIC4. Magnetic resonance imaging showed that only two had a typical DWM, while the third did not present any defect of the DWM spectrum. SNP-array analysis in further eleven children diagnosed with DWM failed to identify deletions of ZIC1-ZIC4. The clinical phenotype of the three 3q deleted patients included multiple congenital anomalies and peculiar facial appearance, related to the localization and extension of each deletion. In particular, phenotypes resulted from the variable combination of three recognizable patterns: DWM (with incomplete penetrance); blepharophimosis, ptosis, and epicanthus inversus syndrome; and Wisconsin syndrome (WS), recently mapped to 3q. CONCLUSIONS: Our data indicate that the 3q deletion is a rare defect associated with DWM, and suggest that the hemizygosity of ZIC1-ZIC4 genes is neither necessary nor sufficient per se to cause this condition. Furthermore, based on a detailed comparison of clinical features and molecular data from 3q deleted patients, we propose clinical diagnostic criteria and refine the critical region for WS. PMID- 23679992 TI - Cytotoxic evaluation of Melia azedarach in comparison with, Azadirachta indica and its phytochemical investigation. AB - BACKGROUND: Melia azedarach L. is an important medicinal plant that is used for variety of ailments in Iranian traditional medicine. Azadirachta indica A. Juss is its allied species and possesses similar properties and effects. The present study was undertaken to investigate anticancer activity of these M. azedarach in comparison with A. indica on cancer cell lines and also to evaluate their safety in humans by testing them on normal cell line. The study also aimed to determine the active components that are responsible for medicinal effects of M. azedarach in traditional usages. METHODS: In this study, the cytotoxic activity of crude extracts from M. azedarach and A. indica leaves, pulps and seeds as well as three main fractions of their leaf extracts were assayed against HT-29, A-549, MCF-7 and HepG-2 and MDBK cell lines. MTT assay was used to evaluate their cytotoxic activities. Methanol leaf fraction of M. azedarach as the safest leaf fraction in terms of cytotoxicity was subjected for phytochemical study. RESULTS: Results of the present study indicated that seed kernel extract of M. azedarach had the highest cytotoxic activity and selectivity to cancer cell lines (IC50 range of 8.18- 60.10 I1/4g mL-1). In contrast to crude seed extract of A. indica, crude pulp and crude leaf extracts of this plant showed remarkably stronger anti prolifrative activity (IC50 ranges of 83.45 - 212.16 I1/4g mL-1 and 34.11- 95.51 I1/4g mL-1 respectively) than those of M. azedarach (all IC50 values of both plants > 650 I1/4g mL-1). The phytochemical analysis led to the isolation of four flavonol 3-O-glycosides including rutin, kaempferol-3-O-robinobioside, kaempferol 3-O-rutinoside and isoquercetin along with a purin nucleoside, I2-adenosine. CONCLUSIONS: The anti-prolifrative potentials of extracts from different parts of M. azedarach and A. indica were determined. By comparison, methanol leaf fraction of M. azedarach seems to be safer in terms of cytotoxicity. Our study shows that flavonols are abundant in the leaves of M. azedarach and these compounds seem to be responsible for many of medicinal effects exploited in the traditional uses. PMID- 23679994 TI - Pulse oximetry in the pulmonary tissue for the non-invasive measurement of mixed venous oxygen saturation. AB - The oxygen saturation of the systemic arterial blood is associated with the adequacy of respiration, and can be measured non-invasively by pulse oximetry in the systemic tissue. The oxygen saturation of the blood in the pulmonary artery, the mixed venous blood, reflects the balance between oxygen supply to the systemic tissues and their oxygen demand. The mixed venous oxygen saturation has also clinical significance because it is used in Fick equation for the quantitative measurement of cardiac output. At present the measurement of the mixed venous oxygen saturation is invasive and requires insertion of a Swan-Ganz catheter into the pulmonary artery. We suggest a noninvasive method for the measurement of the mixed venous oxygen saturation in infants, pulmonary pulse oximetry. The method is similar to the systemic pulse oximetry, which is based on the different light absorption curves of oxygenated and deoxygenated hemoglobin and on the analysis of photoplethysmographic curves in two wavelengths. The proposed pulmonary pulse oximeter includes light-sources of two wavelengths in the infrared, which illuminate the pulmonary tissue through the thoracic wall. Part of the light which is scattered back from the pulmonary tissue and passes through the thoracic wall is detected, and for each wavelength a pulmonary photoplethysmographic curve is obtained. The pulmonary photoplethysmographic curves reflect blood volume increase during systole in the pulmonary arteries in the lung tissue, which contain mixed venous blood. The ratio R of the amplitude to-baseline ratio for the two wavelengths is related to the mixed venous oxygen saturation through equations derived for the systemic pulse oximetry. The method requires the use of extinction coefficients values for oxygenated and deoxygenated hemoglobin, which can be found in the literature. PMID- 23679995 TI - Telomerase inhibition may contribute to accelerated mitochondrial aging induced by anti-retroviral HIV treatment. AB - HIV-infected individuals undergoing long-term anti-retroviral treatment tend to show premature senescence. Accelerated mitochondrial aging induced by nucleoside reverse transcriptase inhibitors (NRTIs) has been implicated as a part of this phenomenon. Traditionally, this has been attributed to inhibition of mtDNA polymerase gamma by these drugs, but alternative explanations have been proposed. It is known that NRTIs can not only inhibit viral reverse transcriptase, but also human telomerase. A number of extratelomeric roles of telomerase, including protection of mitochondrial DNA and function, have emerged recently. In this paper, I propose that inhibition of mitochondrial telomerase activity by NRTI drugs contributes to the mitochondrial toxicity and premature aging seen in treated HIV patients, and discuss objections and experimental testing of the hypothesis. PMID- 23679996 TI - Changes in vagal reactivity to the sympathicotonia during the progression of heart failure: from self-suppression to counteraction. AB - Activities of both autonomic nervous system divisions, sympathetic and parasympathetic, are dual--continuous, tonic and changing, modulating. Tonic activity domination accompanies stationary (patho)physiological conditions, while modulating activity occurs with the change of stimuli. The intensity of the two activities is inversely proportional. In patients with heart failure, spectral analysis of heart rate variability displays reduced sympathetic modulation activity during illness, as a logical consequence of an increased sympathetic tone. On the other hand, vagal modulation activity slightly decreases or does not change at the very early stage of disease, soon afterwards it increases, and after a certain period of time, with the progression of the disease, vagal modulation decreases, and finally disappears. These changes reveal sequential response of vagal tone to the progression of heart failure and consequent sympathicotonia; slight initial oscillation or unresponsiveness, soon followed by self-suppression, and then, in an advanced heart failure, by counteraction to the sympathicotonia. This model of polyphasic reaction of vagal system, dependent on the stage of heart failure, challenges traditional concept of sympathovagal interaction. By this hypothesis, the self-suppression of vagal tone occurs in order to enable full sympathetic activation of compensatory mechanisms which aim to correct hemodynamic deterioration. Once the sympathicotonia becomes inefficient and even harmful, counter-regulatory increase in vagal tone develops, in order to decrease oxygen consumption and preserve or possibly enhance residual systolic and diastolic cardiac function. Decreased vagal tonic activity is probably mediated centrally. Later increase of vagal tone is probably triggered by an increased concentration of natriuretic peptides. The existence of predominantly adrenergic IL, Ca and predominantly cholinergic IK, Ach currents and of a common If current in sinoatrial nodal cells enables such dual- synergistic and antagonistic--sympatho-vagal relationship. In conclusion, a complex, polyphasic vagal reaction to the sympathicotonia and heart failure progression is suggested by the hypothesis. Clinical and experimental studies based on this hypothesis will probably allow better insight into autonomic functions. PMID- 23679998 TI - Calcium homeostasis, and clinical or subclinical vitamin D deficiency--can a hypothesis of "intestinal calcistat" explain it all? AB - The main physiological function of vitamin D is maintenance of calcium homeostasis by its effect on calcium absorption, and bone health in association with parathyroid gland. Vitamin D deficiency (VDD) is defined as serum 25-hydroxy vitamin D (25OHD) levels <20 ng/ml. Vitamin D insufficiency is called when serum 25OHD levels are between 20-29 ng/ml, though existence of this entity has been questioned. Do all subjects with VDD have clinical disease according to this definition? Analysis of published studies suggests that calcium absorption in inversely correlated with serum 25OHD levels and calcium intake. We hypothesize that there exist an intestinal calcistat, which controls the calcium absorption independent of PTH levels. It consists of calcium sensing receptor (CaSR) on intestinal brush border, which senses calcium in intestinal cells and vitamin D system in intestinal cells. CaSR dampens the generation of active vitamin D metabolite in intestinal cells and decrease active transcellular calcium transport. It also facilitates passive paracellular diffusion of calcium in intestine. This local adaptation adjusts the fractional calcium absorption according the body requirement. Failure of local adaptation due to decreased calcium intake, decreased supply of 25OHD, mutation in CaSR or vitamin D system decreases systemic calcium levels and systemic adaptations comes into the play. Systemic adaptations consist of rise in PTH and increase in active vitamin D metabolites. These adaptations lead to bone resorption and maintenance of calcium homeostasis. Not all subjects with varying levels of VDD manifest with secondary hyperparathyroidism and decreased in bone mineral density. We suggest that rise in PTH is first indicator of VDD is rise in PTH along with decrease in BMD depending on duration of VDD. Hence, subjects with any degree of VDD with normal PTH and BMD should not be labeled as vitamin D deficient. These subjects can be called subclinical VDD, and further studies are required to assess beneficial effect of vitamin D supplementation in this subset of population. This hypothesis further highlights pitfalls in treatment of hypoparathyroidism. PMID- 23679997 TI - A hydrophobic segment of some cytotoxic ribonucleases. AB - The exact mechanism by which cytotoxic ribonucleases reach the cytosol of tumor cells remains unclear. The interaction of ribonucleases with a lipid bilayer is involved in the translocation of ribonucleases across the endosomal membrane. Here, we aimed to study the hydropathy character of toxic antitumor ribonucleases (bovine seminal ribonuclease and binase) and two non-toxic ribonucleases (bovine pancreatic ribonuclease and human pancreatic ribonuclease) by sliding-window hydrophobicity analysis. Comparative hydropathy plot analysis of the non-toxic pancreatic ribonucleases and their toxic variants was also performed. The data obtained indicate that some cytotoxic ribonucleases have a hydrophobic segment, which is sterically available for the hydrophobic interaction with a tumor cell membrane and endosomal membrane. After dissociation, subunits of dimeric ribonucleases are probably capable of thermodynamically favorable interaction with the interfacial region of a lipid bilayer. Remarkably the hydrophobic segment is not identified in the amino acid sequences of non-toxic ribonucleases. The paper describes the hydrophobic properties of toxic RNases that are essential for both the model of a lipid-protein interaction and the cytotoxicity mechanism unraveling. PMID- 23679993 TI - Implementation of the INTERGROWTH-21st Project in China. AB - The East Asian site in the INTERGROWTH-21(st) Project was Shunyi County, Beijing, China, which is an affluent suburb of north Beijing delivering approximately 7000 women annually. The Newborn Cross-Sectional Study (NCSS) sample was drawn from two hospitals, covering >85% of births in the county. The Fetal Growth Longitudinal Study sample (FGLS) was recruited from the antenatal clinic of Shunyi Maternal & Child Health Hospital, the larger of the two institutions. Special activities to promote the study in this population included: (1) the distribution of health education materials about the importance of antenatal care and (2) the organisation of seminars by the study team to brief key stakeholders at the two hospitals about the goals of the research. One of the major challenges at this site in the early stages of the study was a reluctance to have an early ultrasound dating scan (<14(+0) weeks of gestation). This challenge was overcome after a thorough evaluation of the literature regarding the benefits of an early ultrasound scan for dating purposes, as a result of which there was a formal change in hospital policy. PMID- 23679999 TI - Does heterogeneity of depression diagnosis harm those with severe mood disorders? AB - The range of symptoms and clinical syndromes subsumed under the rubric "depression" is remarkably large. It covers the lay use of the word to describe transient sad feelings on the one hand and a devastating biological illness on the other. In consequence, society has failed to grasp that severe mood disorders do, in fact, represent life-threatening medical illness. In the present article, we outline the major historical and contemporary contributors to the present misapprehension of this severe illness and discuss the serious consequences for diagnosis, treatment, and clinical research. We suggest potential categorical and terminological revisions to current formulations of the disease and emphasize that being severely ill involves much more than is subsumed by the term "depression". PMID- 23680000 TI - NSAIDs can have adverse effects on bone healing. AB - The science of osteoimmunology, a relatively new field of research, reveals the important interactions between the immune system and skeletal system. Interactions occur between prostaglandin metabolism, inflammatory proteins and bone metabolism. Systemic as well as local sources of inflammation appear to be actively involved in both bone formation and resorption. Non Steroidal Anti Inflammatory Drugs (NSAIDs) can play a detrimental role in bone fractures, opposing the aim of the intervention, and can have such a negative impact on the synthesis of prostaglandins that they could even promote bone resorption. When used for a prolonged time, NSAIDs can also cause the development of an inflammatory cascade starting from the gastro-intestinal system, possibly resulting in bone resorption. Several studies show that the use of either selective or non-selective NSAIDs are intimately related to disturbances in immunological allostasis, bone metabolism and the inhibition or impediment of bone healing. PMID- 23680001 TI - Is there a role for intraperitoneal administration of heparin in hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis of colorectal cancer origin? Current data and future orientations. AB - In experimental studies, the intraperitoneal administration of heparin has been shown to attenuate cancer growth, reduce the formation of postoperative adhesions and possess immunomodulatory properties of oncological benefit for peritoneal carcinomatosis of colorectal cancer origin. Combined with data suggesting that the intraperitoneal administration of heparin can reduce the permeability and increase the ultrafiltration of the peritoneal membrane, we hypothesize that intraperitoneally administrated heparin could be a useful adjunction to the currently used hyperthermic intraperitoneal chemotherapy (HIPEC) regimens. PMID- 23680002 TI - Co-treatment with arsenic trioxide and ganciclovir reduces tumor volume in a murine xenograft model of nasopharyngeal carcinoma. AB - We have previously shown that disruption of promyelocytic leukemia nuclear bodies (PML NBs) is sufficient to activate the EBV lytic cycle thus making infected cells susceptible to ganciclovir (GCV) mediated killing in vitro. Here we show that co-administration of GCV and arsenic trioxide (ATO), a PML NB disruptor, reduces tumor volume in a xenograft model of nasopharyngeal carcinoma utilizing CNE1 cells. When administered at pharmacologic levels, both GCV and ATO reduced tumor growth while co-treatment with GCV + ATO resulted in a diminution of tumor volume. Treatment with GCV or ATO individually resulted in an increased number of apoptotic cells while co-treatment with GCV + ATO synergistically induced apoptosis. Treatment with ATO or co-treatment with GCV + ATO resulted in expression of EBV lytic proteins. These data suggest that co-treatment with GCV + ATO may provide an effective treatment for nasopharyngeal carcinoma patients. PMID- 23680003 TI - Long-term outcomes following off-label use of sirolimus-eluting stent. AB - OBJECTIVE: To clarify the impact of off-label use of drug-eluting stent (DES) on 5-year outcomes. BACKGROUND: Studies on the outcomes of on- vs. off-label use of DES have been limited by the duration of observation. METHODS: We analyzed 1937 patients from a multicenter registry that includes 95% of patients with 5-year follow-up data. We defined 10 variables as off-label indications according to the manufacturer's instructions for use, and 1665 of 1937 patients (86.0%) met the criteria for at least 1 off-label indication. RESULTS: At 5 years, there were no differences in the rates of death, myocardial infarction (MI), and stent thrombosis between off-label and on-label use. The frequency of major adverse cardiac events (MACE), target lesion revascularization (TLR), non-TL but target vessel revascularization (TVR), and target vessel failure were higher in the off label only during the first year. Among the off-label, having 2 indications was associated with TVR hazard ratio (HR) 1.62; 95% confidence interval (95%CI), 1.09 2.36 and TLR (HR, 1.90; 95%CI, 1.30-2.85). Moreover, having >=3 off-label indications increased the risk of MACE (HR, 1.70; 95% CI, 1.23-2.40) compared with on-label use. Thrombosis rates increased with the number of off-label indications; it was 0.32% with 1, 0.69% with 2, and 3.54% with >=3 off-label indications (p<0.001). This trend was also seen with other outcomes, except for non-TL TVR. Patients with >=3 off-label indications had a remarkably different clinical course. CONCLUSION: Off-label use did not increase rates of death and MI as compared with on-label use, but the number of off-label indications influenced outcomes at 5 years. PMID- 23680005 TI - Bleeding events and activated partial thromboplastin time with dabigatran in clinical practice. AB - BACKGROUND: Dabigatran has demonstrated promising results for the prevention of strokes in patients with non-valvular atrial fibrillation (NVAF). However, there have been episodes of major bleeding, especially in elderly patients or those with renal dysfunction. The purpose of this study was to retrospectively examine the relationship between the bleeding events and activated partial thromboplastin time (APTT) values under dabigatran usage in the everyday clinical practice. Moreover, we investigated which factors would contribute to the APTT values. METHODS AND RESULTS: A total of 139 NVAF patients (112 men, 65 +/- 11 years) were included. We evaluated the influence of the putative etiological variables and the bleeding score, HAS-BLED score, on APTT values: age greater than 70 years, renal function, gender, dose of dabigatran, and the concomitant prescription of a P-glycoprotein inhibitor. There were 50 patients with an age of >= 70 years (36.0%). A P-glycoprotein inhibitor was administered in 18 patients. During the observation period (median 120 days) there was 1 episode of asymptomatic cerebral infarction. There were no intrinsic major bleeding events, however, 11 patients had minor hemorrhagic events. The results of the APTT measurements exhibited a variety of values both among inter- and intra-individuals. On multivariable analysis, significant associations were found between the following risk factors and the APTT values: creatinine clearance, dose of dabigatran, and concomitant use of a P-glycoprotein inhibitor. The minor bleeding events did not correlate with the APTT values, nor HAS-BLED score. CONCLUSIONS: The APTT values became prolonged under dabigatran usage and exhibited a remarkable diversity. Although major bleeding did not occur unless APTT was prolonged excessively, minor bleeding arose irrespective of the APTT values even within the range of the APTT values not exceeding 80s. PMID- 23680004 TI - Longitudinal extent of lipid pool assessed by optical coherence tomography predicts microvascular no-reflow after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. AB - BACKGROUND: Distal embolization during percutaneous coronary intervention (PCI) may deteriorate microvascular reperfusion in patients with ST-elevation myocardial infarction (STEMI). Reperfusion at the coronary microvascular level is important for STEMI and culprit plaque is associated with distal embolization and microvascular reperfusion. ST-segment resolution (ST-R) in the electrocardiogram reflects microvascular reperfusion after primary PCI. Longitudinal extent of lipid pool assessed by optical coherence tomography (OCT) may predict the risk of failure of microvascular reperfusion after primary PCI. METHODS AND RESULTS: This study consisted of 39 patients with STEMI who underwent primary PCI within 24h after the onset of chest pain. Immediately after thrombectomy, OCT was performed and length of lipid pool was measured. Microvascular reperfusion after primary PCI was assessed by ST-R, which was defined as >50% decrease in ST elevation at 1h after primary PCI. There were 23 patients with ST-R and 16 patients without ST R, with no significant difference in baseline clinical and angiographical variables between the 2 groups. Final thrombolysis in myocardial infarction 3 flow was obtained in all of the patients. Peak creatine kinase was significantly higher in the ST-R (-) group than in the ST-R (+) group (p=0.01). Length of lipid pool was 10.1 +/- 2.8mm in the ST-R (-) group and 7.8 +/- 3.2mm in the ST-R (+) group (p=0.02). In receiver operating characteristics curve assessing the ability of length of lipid pool to predict ST-R, area under the curve was 0.74 (p=0.02). Length of lipid pool >9.0mm best predicted the absence of ST-R with sensitivity 88% and specificity 78%. CONCLUSIONS: These findings suggest that length of lipid pool estimated by OCT may predict microvascular no-reflow after primary PCI. PMID- 23680006 TI - Post-translational modifications of CFTR: insight into protein trafficking and cystic fibrosis disease. PMID- 23680008 TI - Central auditory development after long-term cochlear implant use. AB - OBJECTIVE: We aimed to determine whether long-term cortical auditory development is altered or delayed in children using cochlear implants relative to their normal hearing peers. We hypothesized that cortical development in children using unilateral cochlear implants follows a normal trajectory with long-term auditory input when the duration of bilateral auditory deprivation in childhood is limited. METHODS: Electrically-evoked cortical responses were recorded in 79 children who received one cochlear implant within 2.03 +/- 1.36 years of bilateral deafness and had up to ~16 years of time-in-sound experience, and in 58 peers with normal hearing. Amplitude differences between the responses from children using cochlear implants and with normal hearing were calculated between 0 and 300 ms. RESULTS: Responses from cochlear implant users remain different from those of their normal hearing peers. These differences decreased over time, but were not eliminated even after 10 years of time-in-sound. Specifically, the P(1)-N(1)-P(2)-N(2) complex, typical of a normally mature response, began to emerge by 10 years of time-in-sound experience, but the amplitudes of peaks P(2) and N(2) became abnormally large. CONCLUSION: Mature-like cortical responses emerge in children after long-term unilateral cochlear implant use, however, differences from normal persist. SIGNIFICANCE: Maturation of cortical responses with long-term cochlear implant use potentially underlies functional improvements in hearing. Persistent differences from normal could reflect an increase in attention or multi-sensory processing during listening. PMID- 23680007 TI - Effect of consumption of micronutrient enriched wheat steamed bread on postprandial plasma glucose in healthy and type 2 diabetic subjects. AB - BACKGROUND: Steamed wheat bread have previously been shown to induce comparatively high postprandial plasma glucose responses, on the contrary, buckwheat products induced lower postprandial plasma glucose. The present study was to assess the effects of micronutrient enriched bread wheat variety Jizi439 and buckwheat on postprandial plasma glucose in healthy and diabetic subjects comparing with buckwheat and other bread wheat varieties. METHODS: Two experiments were conducted to study the effects of bread wheat variety Jizi439 on the postprandial plasma glucose levels of the randomly selected subjects. The first experiment involved three types of steamed bread with equivalent of 50 g available carbohydrate fed to 10 normal weight young healthy subjects. Two types of steamed bread were made from two purple-grain bread wheat varieties, Jizi439 and Chu20, respectively, and the third type was made from the mixture of different white grain wheat varieties. Plasma glucose levels of each subject were measured at 15, 30, 45, 60, 120 min after eating. Glucose was used as a reference, the total area under curve (AUC) and glycemic index (GI) was calculated for test meal. The second experiment was performed among ten type 2 diabetics who were served equivalent of 50 g available carbohydrate of steamed bread made from Jizi 439, the mixture of white grain bread wheat and buckwheat, respectively. The plasma glucose increment was determined two hours thereafter. RESULTS: In the first experiment, consumption of the steamed bread made from Jizi439 resulted in the least increase in plasma glucose and the GI was significantly lower than that of Chu20 and the mixture. In the second experiment, the average of postprandial 2 h plasma glucose increment of Jizi439 was 2.46 mmol/L which was significantly lower than that of the mixture of white wheat but was not significantly different from buckwheat. CONCLUSIONS: The results indicated that consumption of Jizi439 steamed bread resulted in significantly lower plasma glucose in both healthy and diabetic subjects, compared with other types of test foods, except buckwheat bread. The steam bread made from Jizi439 would be an ideal food for preventing and treatment of diabetes. PMID- 23680009 TI - Developing a compassionate mind to enhance trauma-focused CBT with an adolescent female: a case study. AB - BACKGROUND: Shame and disgust are often associated with posttraumatic stress disorder (PTSD) following interpersonal traumas such as sexual assault. It has been suggested that individuals with high levels of shame might do less well in standard cognitive behavioural (CBT) interventions. AIMS: To see whether applying compassion-focused therapy and developing a compassionate mind can enhance trauma focused CBT in an adolescent with high levels of shame and disgust the way it has been shown to within the adult population. METHOD: This single case study describes how trauma-focused CBT was enhanced by compassionate mind training. It details work using this approach with an adolescent female experiencing shame and disgust-based flashbacks. Treatment was provided for 20 sessions over 8 months. Symptoms of PTSD, depression and self-criticism, as well as the ability to self soothe/reassure, were measured at assessment/start of treatment, mid- and end of treatment. RESULTS: Clinically significant reductions in PTSD, depressive, shame and self-attacking symptoms were found between assessment and completion of treatment. Clinically significant increases in self-reassurance were also reported. Following treatment, symptoms of PTSD and depression were sub-clinical. CONCLUSION: This case study suggests that developing a compassionate mind alongside trauma-focused CBT may be beneficial to adolescents experiencing shame and disgust with consideration for the young person's level of development and personal circumstances. PMID- 23680011 TI - Multi-morbidity: a system design challenge in delivering patient-centred care. PMID- 23680010 TI - Perceived pubertal timing and recent substance use among adolescents: a longitudinal perspective. AB - AIMS: To determine the longitudinal associations between perceived pubertal timing and recent substance use between the ages of 11 and 17 years. DESIGN, SETTING AND PARTICIPANTS: A school-based cohort sequential study of adolescents in rural North Carolina, USA (n = 6892, 50% female) in the 6-8th grades at baseline and interviewed across five consecutive semesters. MEASUREMENTS: Self administered questionnaires in a group setting measured perceived pubertal development using the Pubertal Development Scale and adolescents reported past 3 month use of cigarettes, alcohol and marijuana. Latent class growth analysis determined the longitudinal relationships between perceived pubertal timing (early, on-time and late) and use of the three substances. FINDINGS: A negative quadratic model was the best-fitting model for all three substances. Higher proportions of early developers had used cigarettes and marijuana within the past 3 months at age 11 compared with on-time (P < 0.001 and P = 0.013) and late developers (P = 0.010 and P = 0.014) and a higher proportion of early developers had recently used alcohol at age 11 compared with on-time adolescents (P < 0.001). However, the proportion of recent cigarette and marijuana users increased more across adolescence for on-time adolescents compared with early developers (P = 0.020 and P = 0.037). Desistance in the proportion of substance users was similar for all adolescents (all P > 0.050). CONCLUSIONS: Adolescents who believe they are more advanced in puberty than their peers are more likely to have used cigarettes, alcohol and marijuana recently compared with adolescents who believe they are on-time or late developing; these findings are mainly due to differences in use at age 11. PMID- 23680012 TI - Effectiveness and safety of psoralen-UVA (PUVA) topical therapy in palmoplantar psoriasis: a report on 48 patients. AB - INTRODUCTION: Palmoplantar psoriasis is an uncommon clinical form of psoriasis. Although localized to the palms and soles, it has a considerable impact on the patient's function and quality of life. OBJECTIVES: To study the effectiveness and safety of psoralen-UV-A (PUVA) therapy in palmoplantar psoriasis and investigate predictors of clinical response. MATERIAL AND METHODS: We performed a retrospective chart review of all patients with palmoplantar psoriasis treated with topical PUVA therapy at our hospital between 2008 and 2011. Data were collected on effectiveness (using physician global assessment [PGA] scores), safety, and a range of clinical, epidemiological, and treatment-related variables. RESULTS: We studied 48 patients (33 women and 15 men) with a mean age of 51 years. Treatment was considered to be effective (PGA score of 0 or 1) in 63% of cases. In addition to PUVA, systemic therapy was required in 47.9% of patients; the drug most often used was acitretin. Adverse effects were reported for 25% of patients during treatment. The most common effect was mild erythema, present in 18% of cases. CONCLUSIONS: In our experience, topical PUVA is an appropriate treatment alternative for palmoplantar psoriasis; it offers similar response rates to systemic treatments, but has a better tolerance and safety profile. Associated systemic treatment, with acitretin in most cases, improved the probability of a satisfactory response to PUVA and should be considered in patients who do not respond adequately after 8 to 10 sessions. PMID- 23680013 TI - The internet user profile of Italian families of patients with rare diseases: a web survey. AB - BACKGROUND: The use of the Internet for searching and sharing health information and for health care interactions may have a great potential for families of children affected with rare diseases. We conducted an online survey among Italian families of patients with rare diseases with the objective to describe their Internet user profile, and to explore how Internet use affects their health decisions. METHODS: All members of UNIAMIO FIMR, a federation of associations of patients with rare diseases, were invited via mail to participate in an online questionnaire including questions on socio-demographic and clinical information, Internet use with a specific focus on health, and impact of web information on health behaviors. Logistic regression models were used to explore the effect of socio-demographic variables and Internet user profile on dependent variables representing the impact of web information on health behaviors. Multiple imputation by chained equations was applied. RESULTS: A total of 516 parents of patients with rare diseases completed the online questionnaire. Mean age was 43 years. 87% of respondents accessed the Internet daily, 40% through their smartphones. 99% had an email account, 71% had a Facebook account. 66% participate in an online forum on health. 99% searched for information on disease characteristics, 93% on therapy, 89% on diagnosis, 63% on alternative therapies, 62% on nutrition and 54% on future pregnancies. 82% stated that web information increased comprehension of the disease, 65% that it improved management of the disease. For 52% web information increased his or her anxiety. 62% recognized diagnosis, 69% discussed online information with their physician. People participating in forums more frequently stated that Internet information was useful for recognizing their child's disease (OR 1.68; 95%CI 1.08-2.63) and for improving its management (OR 1.77; 95%CI 1.11-2.81). CONCLUSION: Italian parents of patients with rare diseases are active Internet users, engaged in information search and in online communities. PMID- 23680014 TI - Failure of silver nanowire transparent electrodes under current flow. AB - Silver nanowire transparent electrodes have received much attention as a replacement for indium tin oxide, particularly in organic solar cells. In this paper, we show that when silver nanowire electrodes conduct current at levels encountered in organic solar cells, the electrodes can fail in as little as 2 days. Electrode failure is caused by Joule heating which causes the nanowires to breakup and thus create an electrical discontinuity in the nanowire film. More heat is created, and thus failure occurs sooner, in more resistive electrodes and at higher current densities. Suggestions to improve the stability of silver nanowire electrodes are given. PMID- 23680015 TI - The potential for stem cell therapies to have an impact on cerebral palsy: opportunities and limitations. AB - Cerebral palsy (CP) is a chronic childhood disorder described by a group of motor and cognitive impairments and results in a substantial socio-economic burden to the individual, family, and healthcare system. With no effective biological interventions, therapies for CP are currently restricted to supportive and management strategies. Cellular transplantation has been suggested as a putative intervention for neural pathology, as mesenchymal and neural stem cells, as well as olfactory ensheathing glia and Schwann cells, have shown some regenerative and functional efficacy in experimental central nervous system disorders. This review describes the most common cell types investigated and delineates their purported mechanisms in vivo. Furthermore, it provides a cogent summary of both current early-phase clinical trials using neural precursor cells (NPCs) and the state of stem cell therapies for neurodegenerative conditions. Although NPCs are perhaps the most promising candidates for cell replacement therapy in the context of CP, much still remains to be understood regarding safety, efficacy, timing, dose, and route of transplantation, as well as the capacity for combinatorial strategies. PMID- 23680017 TI - Ecological comparison of cellular stress responses among populations - normalizing RT-qPCR values to investigate differential environmental adaptations. AB - BACKGROUND: Rising temperatures and other environmental factors influenced by global climate change can cause increased physiological stress for many species and lead to range shifts or regional population extinctions. To advance the understanding of species' response to change and establish links between individual and ecosystem adaptations, physiological reactions have to be compared between populations living in different environments. Although changes in expression of stress genes are relatively easy to quantify, methods for reliable comparison of the data remain a contentious issue. Using normalization algorithms and further methodological considerations, we compare cellular stress response gene expression levels measured by RT-qPCR after air exposure experiments among different subpopulations of three species of the intertidal limpet Nacella. RESULTS: Reference gene assessment algorithms reveal that stable reference genes can differ among investigated populations and / or treatment groups. Normalized expression values point to differential defense strategies to air exposure in the investigated populations, which either employ a pronounced cellular stress response in the inducible Hsp70 forms, or exhibit a comparatively high constitutive expression of Hsps (heat shock proteins) while showing only little response in terms of Hsp induction. CONCLUSIONS: This study serves as a case study to explore the methodological prerequisites of physiological stress response comparisons among ecologically and phylogenetically different organisms. To improve the reliability of gene expression data and compare the stress responses of subpopulations under potential genetic divergence, reference gene stability algorithms are valuable and necessary tools. As the Hsp70 isoforms have been shown to play different roles in the acute stress responses and increased constitutive defenses of populations in their different habitats, these comparative studies can yield insight into physiological strategies of adaptation to environmental stress and provide hints for the prudent use of the cellular stress response as a biomarker to study environmental stress and stress adaptation of populations under changing environmental conditions. PMID- 23680018 TI - Bone marrow derived cells in adult skeletal muscle tissue in humans. AB - BACKGROUND: During the past decade, several animal studies have demonstrated that in addition to local cells, cells from the bone marrow (BM) possess the ability to contribute to regeneration of injured skeletal muscle tissue. In addition, in mice, regular physical activity has been displayed to be a sufficient stimulus for BM-derived cell contribution to the muscle, indicating that this is part of the ongoing physiological remodeling of skeletal muscle. However, whether BM derived cells participate in human skeletal muscle remodeling is not known. To this end, we analyzed the incorporation of BM-derived cells in healthy human skeletal muscle in women transplanted with male BM. METHODS: Skeletal muscle biopsies were obtained from the m. vastus lateralis of women transplanted with male donor hematopoietic stem cells 6 to 12 years earlier. Healthy women served as controls. Immunohistochemical staining for skeletal muscle fibers, satellite cells (SCs) or endothelial cells (ECs) combined with fluorescent in situ hybridization (FISH) of X and Y chromosomes was used to identify cells of BM origin within the biopsies. Three dimensional confocal imaging was performed to demonstrate colocalization of Y chromosome and DAPI within muscle fibers. To further investigate whether BM-derived cells incorporate into the SC niche, myoblasts were extracted from the biopsies from the transplanted women, cultured, and analyzed using XY FISH and immunocytochemistry. RESULTS: Three dimensional confocal imaging indisputably demonstrated colocalization of Y chromosome and DAPI within muscle fibers. Some Y chromosomes were found within centrally located nuclei. No Y chromosomes were detected in CD56+ SCs in the tissue sections nor in the myoblasts cultured from the extracted SCs. Y chromosome+ ECs were found in all sections from the transplanted subjects. No Y chromosomes were found in the skeletal muscle biopsies obtained from healthy control women. CONCLUSIONS: We demonstrate that BM-derived cells contribute to skeletal muscle fibers and ECs. Our results support that BM contribution to skeletal muscle occurs via direct fusion to muscle fibers, and that the contributing cells derive from the hematopoietic lineage. Thus, the present findings encourage further studies of the importance of this process for the physiological adaptation occurring throughout life. PMID- 23680019 TI - Initiation of human astrovirus type 1 infection was blocked by inhibitors of phosphoinositide 3-kinase. AB - BACKGROUND: Upon initial contact with a virus, host cells activate a series of cellular signaling cascades that facilitate viral entry and viral propagation within the cell. Little is known about how the human astrovirus (HAstV) exploits signaling cascades to establish an infection in host cells. Recent studies showed that activation of extracellular signal-regulated kinase 1/2 (ERK1/2) is important for HAstV infection, though the involvement of other signaling cascades remains unclear. METHODS: A panel of kinase blockers was used to search for cellular signaling pathways important for HAstV1 infection. To determine their impact on the infectious process, we examined viral gene expression, RNA replication, and viral RNA and capsid protein release from host cells. RESULTS: Inhibitors of phosphoinositide 3-kinase (PI3K) activation interfered with the infection, independent of their effect on ERK 1/2 activation. Activation of the PI3K signaling cascade occurred at an early phase of the infection, judging from the timeframe of Akt phosphorylation. PI3K inhibition at early times, but not at later times, blocked viral gene expression. However, inhibiting the downstream targets of PI3K activation, Akt and Rac1, did not block infection. Inhibition of protein kinase A (PKA) activation was found to block a later phase of HAstV1 production. CONCLUSIONS: Our results reveal a previously unknown, essential role of PI3K in the life cycle of HAstV1. PI3K participates in the early stage of infection, possibly during the viral entry process. Our results also reveal the role of PKA in viral production. PMID- 23680021 TI - Time-course of attentional bias for positive social words in individuals with high and low social anxiety. AB - BACKGROUND: Although accumulating research demonstrates the association between attentional bias and social anxiety, the bias for positive stimuli has so far not been adequately studied. AIMS: The aim is to investigate the time-course of attentional bias for positive social words in participants with high and low social anxiety. METHOD: In a modified dot-probe task, word-pairs of neutral and positive social words were randomly presented for 100, 500, and 1250 milliseconds in a nonclinical sample of students to test their attentional bias. RESULTS: Non significant interaction of Group * Exposure Duration was found. However, there was a significant main effect of group, with significantly different response latencies between the high social anxiety (HSA) and low social anxiety (LSA) groups in the 100 ms condition, without for 500 or 1250 ms. With respect to attentional bias, the LSA group showed enhanced preferential attention for positive social words to which the HSA group showed avoidance in the 100 ms condition. In the 500 ms condition, preferential attention to positive social words was at trend in the LSA group, relative to the HSA group. Neither group showed attentional bias in the 1250 ms condition. CONCLUSIONS: These findings extend recent research about the attention training program and add to the empirical literature suggesting that the initial avoidance of positive stimuli may contribute to maintaining social anxiety. PMID- 23680020 TI - Performance assessment in brain-computer interface-based augmentative and alternative communication. AB - A large number of incommensurable metrics are currently used to report the performance of brain-computer interfaces (BCI) used for augmentative and alterative communication (AAC). The lack of standard metrics precludes the comparison of different BCI-based AAC systems, hindering rapid growth and development of this technology. This paper presents a review of the metrics that have been used to report performance of BCIs used for AAC from January 2005 to January 2012. We distinguish between Level 1 metrics used to report performance at the output of the BCI Control Module, which translates brain signals into logical control output, and Level 2 metrics at the Selection Enhancement Module, which translates logical control to semantic control. We recommend that: (1) the commensurate metrics Mutual Information or Information Transfer Rate (ITR) be used to report Level 1 BCI performance, as these metrics represent information throughput, which is of interest in BCIs for AAC; 2) the BCI-Utility metric be used to report Level 2 BCI performance, as it is capable of handling all current methods of improving BCI performance; (3) these metrics should be supplemented by information specific to each unique BCI configuration; and (4) studies involving Selection Enhancement Modules should report performance at both Level 1 and Level 2 in the BCI system. Following these recommendations will enable efficient comparison between both BCI Control and Selection Enhancement Modules, accelerating research and development of BCI-based AAC systems. PMID- 23680016 TI - Implementation of the INTERGROWTH-21st Project in Kenya. AB - The African site in the INTERGROWTH-21(st) Project was Parklands, a wealthy suburb of Nairobi, Kenya, with a largely middle-to-high socio-economic status population. There are three hospitals with obstetric units in Parklands, with approximately 4300 births per year. The Newborn Cross-Sectional Study (NCSS) sample was drawn from all three hospitals, covering 100% of births in this target population. The Fetal Growth Longitudinal Study (FGLS) sample was recruited from antenatal clinics serving these hospitals, using the eligibility criteria in the INTERGROWTH-21(st) protocol. Special activities to raise awareness of the study included securing media coverage and distributing leaflets in antenatal clinic waiting rooms. FGLS required women to be recruited in the first trimester; therefore, a major challenge at this study site was the high background frequency of first antenatal consultations in the second trimester. The problem was overcome by the study awareness campaign, as a result of which more women started attending antenatal care earlier in pregnancy. PMID- 23680022 TI - Intracellular distribution of human SIRT7 and mapping of the nuclear/nucleolar localization signal. AB - Sirtuins belong to a class of NAD-dependent deacetylases, and include seven distinct isoforms, of which SIRT7 is the least studied member. In the present study, the subcellular expression of SIRT7 in primary fibroblasts undergoing senescence was evaluated by immunocytochemistry and immunoblot assay. Expression of nucleolar SIRT7 in young fibroblast was very prominent, decreased in pre senescent cells, and became undetectable in the senescent cells. Interestingly, we observed previously unreported staining for cytoplasmic SIRT7 in fibroblasts, and report the existence of a steady-state level of SIRT7 in cytoplasm. Selective localization of the high-molecular-mass (47.5 kDa) SIRT7 in the cytoplasmic fraction and the low-molecular-mass (45 kDa) SIRT7 in the nuclear fraction was observed in the immunoblot analysis of various cell types. The specificity of the N-terminal antibodies for detection of cytoplasmic SIRT7 was confirmed by RNAi and peptide competition assays. The two forms of SIRT7 showed reciprocal expression following serum starvation, nocodazole and okadaic acid treatments, and also during senescence. Using a combination of deletion constructs and site directed mutagenesis, we defined the role of two distinct SIRT7 sequences in the N-terminal region (amino acids 61-76, LQGRSRRREGLKRRQE) and the C-terminal region (amino acids 392-400, KRTKRKKVT) for nuclear and nucleolar import, respectively. In conclusion, we report for the first time the existence of a cytoplasmic pool of SIRT7 in addition to its well-known nucleolar form, identify distinct localization signals for its nuclear/nucleolar targeting, and describe an association between loss of nucleolar SIRT7 and replicative senescence. PMID- 23680023 TI - Speckle tracking echocardiography in mature Irish Wolfhound dogs: technical feasibility, measurement error and reference intervals. AB - BACKGROUND: Two-dimensional strain measurements obtained by speckle tracking echocardiography (STE) have been reported in both humans and dogs. Incorporation of this technique into canine clinical practice requires the availability of measurements from clinically normal dogs, ideally of the same breed, taken under normal clinical conditions.The aims of this prospective study were to assess if it is possible to obtain STE data during a routine echocardiographic examination in Irish Wolfhound dogs and that these data will provide reference values and an estimation of measurement error. METHODS: Fifty- four healthy mature Irish Wolfhounds were used. These were scanned under normal clinical conditions to obtain in one session both standard echocardiographic parameters and STE data. Measurement error was determined separately in 5 healthy mature Irish Wolfhounds. RESULTS: Eight dogs were rejected by the software algorithm for reasons of image quality, resulting in a total of 46 dogs (85.2%) being included in the statistical analysis. In 46 dogs it was possible to obtain STE data from three scanning planes, as well as to measure the rotation of the left ventricle at two levels and thus calculate the torsion of the heart. The mean peak radial strain at the cardiac apex (RS-apex) was 45.1 +/- 10.4% (n = 44), and the mean peak radial strain at the base (RS-base) was 36.9 +/- 14.7% (n = 46). The mean peak circumferential strain at the apex (CS-apex) was -24.8 +/- 6.2% (n = 44), and the mean peak circumferential strain at the heart base (CS-base) was -15.9 +/- 3.2% (n = 44). The mean peak longitudinal strain (LS) was -16.2 +/- 3.0% (n = 46). The calculated mean peak torsion of the heart was 11.6 +/- 5.1 degrees (n = 45).The measurement error was 24.8%, 26.4%, 11.5%, 6.7%, 9.0% and 10 degrees, for RS apex, RS-base, CS-apex, CS-base, LS and torsion, respectively. CONCLUSIONS: It is concluded that this technique can be included in a normal echocardiographic examination in large breed dogs under clinical conditions. The usefulness of the reference values reported here, given their wide normal range, will ultimately be determined by the values that are obtained from a large numbers of diseased dogs. PMID- 23680024 TI - Length of stay variations between rural and urban patients with acute myeloid leukemia: a case-matched study. AB - BACKGROUND: Keeping patients in hospital longer than medically necessary is costly and occupies resources that could be better utilised. If patients from regional areas remain in hospital longer because of logistical issues such as transport and accommodation, then there is an argument for establishing or expanding appropriate medical services for rural areas. However, if the length of stay (LOS) for rural and urban patients is similar, it could be surmised that current logistic services appropriately meet demand. METHODS: This study reviews the cases of 40 patients with acute myeloid leukemia. This disease was selected as patients are generally required to travel to a metropolitan hospital for treatment, regardless of location. Twenty patients resided within the Sydney metropolitan area and 20 lived in rural New South Wales. Each of the 20 metropolitan patients were case-matched (1:1) with 20 rural patients with reference to sex, specific acute myeloid leukemia subtype (by World Health Organisation ICD-10 classification), and age. RESULTS: Following statistical non parametric (t-test) analysis, rural and urban medians were found to be very similar with a high t-value and small mean (urban median=29, rural median=29.5, t value=0.722, m=-0.95, s.d.=15.236, two-tailed P=0.789, 95% CI=-7.89, 5.99). This demonstrates that there was no statistically significant difference between mean LOS for rural or urban patients after case-matching, a conclusion supported by qualitative analysis of the data. CONCLUSION: Logistical issues are therefore unlikely to keep rural patients with AML in hospital beyond their immediate medical treatment. What is known about this topic? A United States-based study found that LOS in hospital for rural patients with human immunodeficiency virus was one-third longer than for urban patients across each of the 6 years analysed (from 1998 to 2003). However it was noted that after adjusting for covariates such as age and sex, differences between LOS for rural and urban residents were not of statistical significance. What does this paper add? This paper provides evidence that current services are utilised appropriately by demonstrating that rural and urban patients spend on average the same amount of time in hospital. Factors such as lack of transport or accommodation are therefore unlikely to keep rural patients in hospital beyond their immediate medical requirements. This paper adds to the limited research base within the Australian context. What are the implications for practitioners? It appears that support organisations adequately fulfil the needs of rural patients in the discharge process. LOS does not appear to correlate with the distance of residence from hospital. Practitioners should continue to support and encourage such support networks. PMID- 23680025 TI - Studies of single-walled carbon nanotubes-induced hepatotoxicity by NMR-based metabonomics of rat blood plasma and liver extracts. AB - The toxicological effects of single-walled carbon nanotubes (SWCNTs) were investigated after intratracheal instillation in male Wistar rats over a 15-day period using metabonomic analysis of 1H (nuclear magnetic resonance) NMR spectra of blood plasma and liver tissue extracts. Concurrent liver histopathology examinations and plasma clinical chemistry analyses were also performed. Significant changes were observed in clinical chemistry features, including alkaline phosphatase, total protein, and total cholesterol, and in liver pathology, suggesting that SWCNTs clearly have hepatotoxicity in the rat. 1H NMR spectra and pattern recognition analyses from nanomaterial-treated rats showed remarkable differences in the excretion of lactate, trimethylamine oxide, bilineurin, phosphocholine, amylaceum, and glycogen. Indications of amino acid metabolism impairment were supported by increased lactate concentrations and decreased alanine concentrations in plasma. The rise in plasma and liver tissue extract concentrations of choline and phosphocholine, together with decreased lipids and lipoproteins, after SWCNTs treatment indicated a disruption of membrane fluidity caused by lipid peroxidation. Energy, amino acid, and fat metabolism appeared to be affected by SWCNTs exposure. Clinical chemistry and metabonomic approaches clearly indicated liver injury, which might have been associated with an indirect mechanism involving nanomaterial-induced oxidative stress. PMID- 23680027 TI - The role of indoleamine 2,3-dioxygenase in LP-BPM5 murine retroviral disease progression. AB - BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an immunomodulatory intracellular enzyme involved in tryptophan degradation. IDO is induced during cancer and microbial infections by cytokines, ligation of co-stimulatory molecules and/or activation of pattern recognition receptors, ultimately leading to modulation of the immune response. LP-BM5 murine retroviral infection induces murine AIDS (MAIDS), which is characterized by profound and broad immunosuppression of T- and B-cell responses. Our lab has previously described multiple mechanisms regulating the development of immunodeficiency of LP-BM5 induced disease, including Programmed Death 1 (PD-1), IL-10, and T-regulatory (Treg) cells. Immunosuppressive roles of IDO have been demonstrated in other retroviral models, suggesting a possible role for IDO during LP-BM5-induced retroviral disease progression and/or development of viral load. METHODS: Mice deficient in IDO (B6.IDO-/-) and wildtype C57BL/6 (B6) mice were infected with LP BM5 murine retrovirus. MAIDS and LP-BM5 viral load were assessed at termination. RESULTS: As expected, IDO was un-inducible in B6.IDO-/- during LP-BM5 infection. B6.IDO-/- mice infected with LP-BM5 retrovirus succumbed to MAIDS as indicated by splenomegaly, serum hyper IgG2a and IgM, decreased responsiveness to B- and T cell mitogens, conversion of a proportion of CD4+ T cells from Thy1.2+ to Thy1.2 , and increased percentages of CD11b+Gr-1+ cells. LP-BM5 infected B6.IDO-/- mice also demonstrated the development of roughly equivalent disease kinetics as compared to infected B6 mice. Splenic viral loads of B6 and B6.IDO-/- mice were also equivalent after infection as measured by LP-BM5-specific Def Gag and Eco Gag viral mRNA, determined by qRT-PCR. CONCLUSIONS: Collectively, these results demonstrate IDO neither plays an essential role, nor is required, in LP-BM5 induced disease progression or LP-BM5 viral load. PMID- 23680028 TI - Psychometric properties of a French version of a Dutch scale for assessing breast and body image (BBIS) in healthy women. AB - BACKGROUND: Genetic testing among women for BRCA1/2 mutation can have various psychological effects, such as those focusing on body image. The aim of this study was to examine the psychometric properties of a generic scale assessing breast and body image (BBIS) in healthy women tested for BRCA1/2 mutations. METHODS: A Dutch body image scale focusing on both general and breast-related body image was translated into French. It was presented to a French cohort of female cancer-free BRCA1/2 mutation carriers and non-carriers (N = 568). The psychometric properties of the scale were studied by assessing its dimensional and factorial structure, internal consistency, construct-related validity, and external validity. RESULTS: The scale was found to be a satisfactory psychometric tool for assessing both body image and breast image. The three main dimensions which emerged were classified under the headings "values attached to body image", "satisfaction with body image and perceived attractiveness", and "satisfaction with breasts". The BBIS scores were not significantly associated with the participants' socio-demographic characteristics or their BRCA1/2 mutation carrier status, but significant associations were observed between these scores and the women's medical and behavioural characteristics. CONCLUSIONS: The BBIS is a generic tool which can be used to assess body image in either affected or unaffected women. The scale will have to be administered to other populations in order to confirm its validity. PMID- 23680029 TI - Nutritional contribution of street foods to the diet of people in developing countries: a systematic review. AB - OBJECTIVE: To review studies examining the nutritional value of street foods and their contribution to the diet of consumers in developing countries. DESIGN: The electronic databases PubMed/MEDLINE, Web of Science, Cochrane Library, Proquest Health and Science Direct were searched for articles on street foods in developing countries that included findings on nutritional value. RESULTS: From a total of 639 articles, twenty-three studies were retained since they met the inclusion criteria. In summary, daily energy intake from street foods in adults ranged from 13 % to 50 % of energy and in children from 13 % to 40 % of energy. Although the amounts differed from place to place, even at the lowest values of the percentage of energy intake range, energy from street foods made a significant contribution to the diet. Furthermore, the majority of studies suggest that street foods contributed significantly to the daily intake of protein, often at 50 % of the RDA. The data on fat and carbohydrate intakes are of some concern because of the assumed high contribution of street foods to the total intakes of fat, trans-fat, salt and sugar in numerous studies and their possible role in the development of obesity and non-communicable diseases. Few studies have provided data on the intake of micronutrients, but these tended to be high for Fe and vitamin A while low for Ca and thiamin. CONCLUSIONS: Street foods make a significant contribution to energy and protein intakes of people in developing countries and their use should be encouraged if they are healthy traditional foods. PMID- 23680031 TI - Autophagic cell death induced by resveratrol depends on the Ca(2+)/AMPK/mTOR pathway in A549 cells. AB - Resveratrol has many biological effects, including anti-tumor, antiviral activities, and vascular protection. Recent studies have suggested that resveratrol exert its antitumor effects through induction of autophagy by an unknown mechanism. In this study, we investigated the involvement of autophagy in resveratrol-induced cell death and its potential molecular mechanisms in A549 human lung adnocarcinoma cells. Resveratrol-induced growth inhibition and cell death was assessed by MTT and clonogenic assays. Activation of autophagy was characterized by monodansylcadaverine, transmission electron microscopy, and expression of autophagy marker protein LC3. Western blot analysis was used to study the cell signals involved in the mechanisms of autophagic death. Intracellular free calcium was detected with Fura2-AM staining. Our results indicated that resveratrol induced A549 cell death was mediated by autophagy. 3 methyladenine, an inhibitor of autophagy, suppressed resveratrol-induced autophagic cell death, and knockdown of autophagy-related genes Atg5 and Beclin-1 with siRNAs reversed RSV-induced cell death. Intracellular free calcium accumulated immediately following resveratrol addition, which led to the activation of phospho-AMPK and phospho-Raptor, and a reduction in the amount of phospho-p70S6K. These effects could be reversed by the AMPK inhibitor compound C, and the calcium ion-chelating agent EGTA. In conclusion, we demonstrate that resveratrol-induced A549 cell death was mediated by the process of autophagic cell death via Ca(2+)/AMPK-mTOR signaling pathway. PMID- 23680026 TI - Implementation of the INTERGROWTH-21st Project in Brazil. AB - The Latin American site in the INTERGROWTH-21(st) Project was Pelotas, Brazil, with approximately 4000 births per year. The sample for the Newborn Cross Sectional Study (NCSS) was drawn from four hospitals, covering 99% of births in the city. The Fetal Growth Longitudinal Study (FGLS) sample was recruited from one of the largest private ultrasound clinics in the city and 30 smaller, private, antenatal clinics serving middle to high socio-economic status women. Among this site's major challenges was the recruitment of women for FGLS from numerous different clinics. Several public relations activities were conducted to improve collaborative efforts between the research team and obstetricians, paediatricians and community leaders in Pelotas. PMID- 23680030 TI - Inhibition of mycobacterial alanine racemase activity and growth by thiadiazolidinones. AB - The genus Mycobacterium includes non-pathogenic species such as M. smegmatis, and pathogenic species such as M. tuberculosis, the causative agent of tuberculosis (TB). Treatment of TB requires a lengthy regimen of several antibiotics, whose effectiveness has been compromised by the emergence of resistant strains. New antibiotics that can shorten the treatment course and those that have not been compromised by bacterial resistance are needed. In this study, we report that thiadiazolidinones, a relatively little-studied heterocyclic class, inhibit the activity of mycobacterial alanine racemase, an essential enzyme that converts l alanine to d-alanine for peptidoglycan synthesis. Twelve members of the thiadiazolidinone family were evaluated for inhibition of M. tuberculosis and M. smegmatis alanine racemase activity and bacterial growth. Thiadiazolidinones inhibited M. tuberculosis and M. smegmatis alanine racemases to different extents with 50% inhibitory concentrations (IC50) ranging from <0.03 to 28MUM and 23 to >150MUM, respectively. The compounds also inhibited the growth of these bacteria, including multidrug resistant strains of M. tuberculosis. The minimal inhibitory concentrations (MIC) for drug-susceptible M. tuberculosis and M. smegmatis ranged from 6.25MUg/ml to 100MUg/ml, and from 1.56 to 6.25MUg/ml for drug-resistant M. tuberculosis. The in vitro activities of thiadiazolidinones suggest that this family of compounds might represent starting points for medicinal chemistry efforts aimed at developing novel antimycobacterial agents. PMID- 23680032 TI - The evolution of molecular hydrogen: a noteworthy potential therapy with clinical significance. AB - Studies on molecular hydrogen have evolved tremendously from its humble beginnings and have continued to change throughout the years. Hydrogen is extremely unique since it has the capability to act at the cellular level. Hydrogen is qualified to cross the blood brain barrier, to enter the mitochondria, and even has the ability to translocate to the nucleus under certain conditions. Once in these ideal locations of the cell, previous studies have shown that hydrogen exerts antioxidant, anti-apoptotic, anti-inflammatory, and cytoprotective properties that are beneficial to the cell. Hydrogen is most commonly applied as a gas, water, saline, and can be applied in a variety of other mediums. There are also few side effects involving hydrogen, thus making hydrogen a perfect medical gas candidate for the convention of novel therapeutic strategies against cardiovascular, cerebrovascular, cancer, metabolic, and respiratory diseases and disorders. Although hydrogen appears to be faultless at times, there still are several deficiencies or snares that need to be investigated by future studies. This review article seeks to delve and comprehensively analyze the research and experiments that alludes to molecular hydrogen being a novel therapeutic treatment that medicine desperately needs. PMID- 23680033 TI - Radiation, atherosclerotic risk factors, and stroke risk in survivors of pediatric cancer: a report from the Childhood Cancer Survivor Study. AB - PURPOSE: To test the hypotheses that (1) the increased risk of stroke conferred by childhood cranial radiation therapy (CRT) persists into adulthood; and (2) atherosclerotic risk factors further increase the stroke risk in cancer survivors. METHODS AND MATERIALS: The Childhood Cancer Survivor Study is a multi institutional retrospective cohort study of 14,358 5-year survivors of childhood cancer and 4023 randomly selected sibling controls with longitudinal follow-up. Age-adjusted incidence rates of self-reported late-occurring (>=5 years after diagnosis) first stroke were calculated. Multivariable Cox proportional hazards models were used to identify independent stroke predictors. RESULTS: During a mean follow-up of 23.3 years, 292 survivors reported a late-occurring stroke. The age-adjusted stroke rate per 100,000 person-years was 77 (95% confidence interval [CI] 62-96), compared with 9.3 (95% CI 4-23) for siblings. Treatment with CRT increased stroke risk in a dose-dependent manner: hazard ratio 5.9 (95% CI 3.5 9.9) for 30-49 Gy CRT and 11.0 (7.4-17.0) for 50+ Gy CRT. The cumulative stroke incidence in survivors treated with 50+ Gy CRT was 1.1% (95% CI 0.4-1.8%) at 10 years after diagnosis and 12% (95% CI 8.9-15.0%) at 30 years. Hypertension increased stroke hazard by 4-fold (95% CI 2.8-5.5) and in black survivors by 16 fold (95% CI 6.9-36.6). CONCLUSION: Young adult pediatric cancer survivors have an increased stroke risk that is associated with CRT in a dose-dependent manner. Atherosclerotic risk factors enhanced this risk and should be treated aggressively. PMID- 23680034 TI - Helical tomotherapy for whole-brain irradiation with integrated boost to multiple brain metastases: evaluation of dose distribution characteristics and comparison with alternative techniques. AB - PURPOSE: To quantitatively evaluate dose distribution characteristics achieved with helical tomotherapy (HT) for whole-brain irradiation (WBRT) with integrated boost (IB) to multiple brain metastases in comparison with alternative techniques. METHODS AND MATERIALS: Dose distributions for 23 patients with 81 metastases treated with WBRT (30 Gy/10 fractions) and IB (50 Gy) were analyzed. The median number of metastases per patient (N(mets)) was 3 (range, 2-8). Mean values of the composite planning target volume of all metastases per patient (PTV(mets)) and of the individual metastasis planning target volume (PTV(ind met)) were 8.7 +/- 8.9 cm(3) (range, 1.3-35.5 cm(3)) and 2.5 +/- 4.5 cm(3) (range, 0.19-24.7 cm(3)), respectively. Dose distributions in PTV(mets) and PTV(ind met) were evaluated with respect to dose conformity (conformation number [CN], RTOG conformity index [PITV]), target coverage (TC), and homogeneity (homogeneity index [HI], ratio of maximum dose to prescription dose [MDPD]). The dependence of dose conformity on target size and N(mets) was investigated. The dose distribution characteristics were benchmarked against alternative irradiation techniques identified in a systematic literature review. RESULTS: Mean +/- standard deviation of dose distribution characteristics derived for PTV(mets) amounted to CN = 0.790 +/- 0.101, PITV = 1.161 +/- 0.154, TC = 0.95 +/- 0.01, HI = 0.142 +/- 0.022, and MDPD = 1.147 +/- 0.029, respectively, demonstrating high dose conformity with acceptable homogeneity. Corresponding numbers for PTV(ind met) were CN = 0.708 +/- 0.128, PITV = 1.174 +/- 0.237, TC = 0.90 +/- 0.10, HI = 0.140 +/- 0.027, and MDPD = 1.129 +/- 0.030, respectively. The target size had a statistically significant influence on dose conformity to PTV(mets) (CN = 0.737 for PTV(mets) <=4.32 cm(3) vs CN = 0.848 for PTV(mets) >4.32 cm(3), P=.006), in contrast to N(mets). The achieved dose conformity to PTV(mets), assessed by both CN and PITV, was in all investigated volume strata well within the best quartile of the values reported for alternative irradiation techniques. CONCLUSIONS: HT is a well-suited technique to deliver WBRT with IB to multiple brain metastases, yielding high-quality dose distributions. A multi institutional prospective randomized phase 2 clinical trial to exploit efficacy and safety of the treatment concept is currently under way. PMID- 23680035 TI - Bowel ultrasonography as an aid for diagnosis of intestinal acute graft-versus host-disease after allogeneic haematopoietic stem cell transplantation. AB - OBJECTIVE: Aim of our prospective study was to investigate accuracy of bowel ultrasonography in detecting gastrointestinal acute graft versus host disease (GVHD), when using clinical assessment as gold standard. In a subgroup of patients, bowel ultrasonography was compared with colonoscopy and histology in diagnosing of gastrointestinal acute GVHD. METHODS: Fifty-two patients underwent allogeneic hematopoietic stem cell transplantation and developed gastrointestinal symptoms. RESULTS: Clinical assessment lead to a diagnosis of gastrointestinal acute GVHD in 17/52 patients, no gastrointestinal acute GVHD was detected in 20/52 patients, while 15 patients were not able to complete the study. Bowel ultrasonography detected either bowel wall thickness of the ileum and the colon or dilation in 16/17 patients and showed 94% sensitivity (95% CI 0.69-0.99), 95% specificity (95% CI 0.73-0.99), and 94.5% accuracy. Colonoscopy was performed in 13/52 patients, showing gastrointestinal acute GVHD in 11/13. In these 11 patients, histology confirmed the diagnosis of gastrointestinal acute GVHD, and bowel ultrasonography detected findings compatible with gastrointestinal acute GVHD in all 11 patients, and was negative in the 2 patients with no gastrointestinal acute GVHD. CONCLUSION: Bowel ultrasonography can be considered a valuable tool to add to clinical assessment for patients with suspected gastrointestinal acute GVHD for addressing a prompt and appropriate treatment. PMID- 23680036 TI - The effects of pre- and post-exercise consumption of multi-ingredient performance supplements on cardiovascular health and body fat in trained men after six weeks of resistance training: a stratified, randomized, double-blind study. AB - BACKGROUND: The cardiovascular (CV) and metabolic health benefits or risks associated with consumption of multi-ingredient performance supplements (MIPS) in conjunction with periodized resistance training (RT) in resistance-trained men are unknown. This population is a major target audience for performance supplements, and therefore, the purpose of this study was to investigate the combined effect of RT and commercially available pre- and post-exercise performance supplements on CV health and body fat in resistance-trained men. METHODS: Twenty-four resistance-trained men completed six weeks (three times/week) of periodized RT while either ingesting SHOT 15-min pre-exercise and SYN immediately post-exercise (multi-ingredient performance supplement group: MIPS) or an isocaloric maltodextrin placebo 15-min pre-exercise and immediately post-exercise (Placebo group). Before and after six weeks of RT and supplementation, resting heart rate (HR), blood pressure (BP), total body fat, android fat, gynoid fat, fat-free mass (FFM) and fasting blood measures of glucose, lipids, nitrate/nitrite (NOx), cortisol and high sensitivity C-reactive protein (hs-CRP) were measured. Statistical analysis was conducted using a one way ANOVA for baseline differences and a 2 * 2 (group * time) repeated measures ANOVA and Tukey post-hoc tests where appropriate. Significance was set at p < 0.05. RESULTS: There was no group * time interaction for HR, BP, blood glucose, lipids, NOx, hs-CRP, cortisol concentrations or body fat. However, there was a time effect where significant decreases in body fat (mean +/- SD; MIPS: -1.2 +/- 1.2%; Placebo: -0.9 +/- 1.1%), android fat (MIPS: -1.8 +/- 2.1%; Placebo: -1.6 +/ 2.0%), and gynoid fat (MIPS: -1.3 +/- 1.6%; Placebo: -1.0 +/- 1.4%) for both groups were observed. FFM increased in both groups, and a group * time interaction was observed with MIPS increasing significantly more than the Placebo group (4.2% vs. 1.9%). CONCLUSIONS: Six weeks of MIPS ingestion and periodized RT does not alter CV health parameters or blood indices of health or body fat more than a Placebo treatment in healthy, resistance-trained men. However, MIPS significantly increased FFM more than Placebo. PMID- 23680037 TI - Open-label salsalate for the treatment of pre-diabetes in people with schizophrenia. PMID- 23680038 TI - A saint in the history of Cardiology. AB - Niels Stensen (1638-1686) was born in Copenhagen. He took courses in medicine at the local university under the guidance of Professor Thomas Bartholin and later at Leiden under the tutelage of Franz de la Boe (Sylvius). While in Holland, he discovered the existence of the parotid duct, which was named Stensen's duct or stenonian duct (after his Latinized name Nicolaus Stenon). He also described the structural and functional characteristics of peripheral muscles and myocardium. He demonstrated that muscular contraction could be elicited by appropriate nerve stimulation and by direct stimulation of the muscle itself and that during contraction the latter does not increase in volume. Toward the end of 1664, the Academic Senate of the University of Leiden awarded him the doctor in medicine title. Later, in Florence, he was admitted as a corresponding member in the Academia del Cimento (Experimental Academy) and collaborated with the Tuscan physician Francesco Redi in studies relating to viviparous development. In the Tuscan capital, he converted from Lutheranism to Catholicism and was shortly afterwards ordained in the clergy. After a few years, he was appointed apostolic vicar in northern Germany and died in the small town of Schwerin, capital of the Duchy of Mecklenburg-Schwerin on November 25, 1686. He was beatified on October 23rd, 1988. PMID- 23680039 TI - [Gradual knowledge of the structure and function of the cardiovascular system]. AB - The first anatomical lexicon was established in old Egypt, Alexandria by the priests who ritually offered all the parts of the human corpses to their gods. About 500 years b. C. studies of comparative anatomy began due to the physician Alcmeon of Croton, author of the text seriously starting the history of scientific pathology according to Lain Entralgo. It was only during the III century b. C. that dissections of human corpses began at the famous Alexandrian School of Medicine in Ptolemaic Egypt. During the Roman era and in high Middle Ages, physicians carried out anatomical studies in humans in order to dismiss or confirm poisoning suspicions or to extrapolate their flindings in animals (monkeys, pigs, etc) to humans. However, in low Middle Ages (XIV century), direct studies in human corpses were performed once again. These studies reached their pinnacle in the XVI century allowing the discovery of the lesser blood circulation and later of the greater blood circulation. The XVII century saw the coming of microscopic anatomy and the XVIII century witnessed the zenith of pathological anatomy. These studies developed during the following century into clinical-anatomical comparison. Today the help of technological studies is mandatory. PMID- 23680040 TI - About the specialized myocardial conducting tissue. AB - The chronological succession of discoveries on the location and structure of the atrio-ventricular conducting system are described. The starting point of this system is located in the sinus atrial node, identified by the English scientists A. Keith and M. W. Flack in 1907. The atrioventricular conducting system was pointed out by the Swiss physician Wilhelm His Jr. in 1893. The atrioventricular node (AV) was first identified by the Japanese pathologist Sumao Tawara and his German professor Ludwig Aschoff in 1906. Likewise the structure and routes of the three internodal bundles are described. These bundles include: Bachmann's bundle (1916) connecting the right with the left atrium and the AV node; the middle Wenckebach's bundle (1910) and the posterior or Thorel's bundle (1910), extending from the region of the sinus atrial node towards the posterior margin of the AV node. Lastly, the ventricular left and right conduction systems are detailed. These include the main trunk and their peripheral subdivisions with respective networks. Regarding the controversial existence of the left middle subdivision, it can exist in animal and human hearts. Nevertheless, an intermediate left septal network of specialized fibers seems to act as a functional equivalent of this subdivision. PMID- 23680041 TI - Classification of emotional states from electrocardiogram signals: a non-linear approach based on Hurst. AB - BACKGROUND: Identifying the emotional state is helpful in applications involving patients with autism and other intellectual disabilities; computer-based training, human computer interaction etc. Electrocardiogram (ECG) signals, being an activity of the autonomous nervous system (ANS), reflect the underlying true emotional state of a person. However, the performance of various methods developed so far lacks accuracy, and more robust methods need to be developed to identify the emotional pattern associated with ECG signals. METHODS: Emotional ECG data was obtained from sixty participants by inducing the six basic emotional states (happiness, sadness, fear, disgust, surprise and neutral) using audio visual stimuli. The non-linear feature 'Hurst' was computed using Rescaled Range Statistics (RRS) and Finite Variance Scaling (FVS) methods. New Hurst features were proposed by combining the existing RRS and FVS methods with Higher Order Statistics (HOS). The features were then classified using four classifiers - Bayesian Classifier, Regression Tree, K- nearest neighbor and Fuzzy K-nearest neighbor. Seventy percent of the features were used for training and thirty percent for testing the algorithm. RESULTS: Analysis of Variance (ANOVA) conveyed that Hurst and the proposed features were statistically significant (p < 0.001). Hurst computed using RRS and FVS methods showed similar classification accuracy. The features obtained by combining FVS and HOS performed better with a maximum accuracy of 92.87% and 76.45% for classifying the six emotional states using random and subject independent validation respectively. CONCLUSIONS: The results indicate that the combination of non-linear analysis and HOS tend to capture the finer emotional changes that can be seen in healthy ECG data. This work can be further fine tuned to develop a real time system. PMID- 23680043 TI - Effect of focusing flow on stationary spot machining properties in elastic emission machining. AB - Ultraprecise optical elements are applied in advanced optical apparatus. Elastic emission machining (EEM) is one of the ultraprecision machining methods used to fabricate shapes with 0.1-nm accuracy. In this study, we proposed and experimentally tested the control of the shape of a stationary spot profile by introducing a focusing-flow state between the nozzle outlet and the workpiece surface in EEM. The simulation results indicate that the focusing-flow nozzle sharpens the distribution of the velocity on the workpiece surface. The results of machining experiments verified those of the simulation. The obtained stationary spot conditions will be useful for surface processing with a high spatial resolution. PMID- 23680042 TI - Characteristics of dioxins content in fly ash from municipal solid waste incinerators in China. AB - MSWI fly ashes sampled from 15 large-scale commercial municipal solid waste incineration plants in China were analyzed for seventeen polychlorinated dibenzo p-dioxins and polychlorinated dibenzofurans (PCDD/PCDFs) as well as twelve dioxin like polychlorinated biphenyls (dl-PCBs). The concentration of PCDD/PCDFs and dl PCBs in fly ash samples ranged from 2.8 to 190ngg(-1), and 59.6ngg(-1) on average. The toxic equivalent (TEQ) ranged from 34 to 2500ng WHO(2005)-PCDD/PCDF PCB-TEQkg(-1), and 790ng WHO(2005)-PCDD/PCDF-PCB-TEQkg(-1) on average. For PCDDs, hexa-chlorinated homolog was the dominant compound except two fly ash samples. Tetra-chlorinated homolog was dominant for PCDFs except one sample. The ratio of PCDDs/PCDFs ranged from 0.32 to 2.44 (average 0.97). The contribution of dl-PCBs to total concentration and TEQ was relatively minimal. Correlation between the concentration of three congeners and total TEQ values of fly ashes was also established. The findings obtained in this work provided overview information on the PCDD/PCDF-PCB content characterization of MSWI fly ash in China, which can be available for MSWI fly ash management in the environment. PMID- 23680044 TI - Validation of a model of the GAL regulatory system via robustness analysis of its bistability characteristics. AB - BACKGROUND: In Saccharomyces cerevisiae, structural bistability generates a bimodal expression of the galactose uptake genes (GAL) when exposed to low and high glucose concentrations. This indicates that yeast cells can decide between using either the limited amount of glucose or growing on galactose under changing environmental conditions. A crucial requirement for any plausible mechanistic model of this system is that it reproduces the robustness of the bistable response observed in vivo against inter-individual parametric variability and fluctuating environmental conditions. RESULTS: We show how a control-theoretic analysis of the robustness of a model of the GAL regulatory network may be used to establish the model's plausibility in characterizing the persistent memory of different carbon sources, without the need for extensive simulations. Chemical Reaction Network Theory is used to establish that the proposed network model is compatible with structural bistability. The robustness of each of the two operative conditions against fluctuations of the species concentrations is demonstrated by studying the Domains of Attraction of the corresponding equilibrium points. Finally, we use a global robustness analysis method based on Semi-Definite Programming to evaluate the modification of the bistable steady states induced by multiple parametric variations throughout bounded regions of the parameter space. CONCLUSIONS: Our analysis provides convincing evidence for the robustness, and hence plausibility, of the GAL regulatory network model. The proposed workflow also demonstrates the power of analytical methods from control theory to provide a direct quantitative characterization of the dynamics of multistable biomolecular regulatory systems without recourse to extensive computer simulations. PMID- 23680045 TI - Nutritional status and childhood wheezing in rural Bangladesh. AB - OBJECTIVE: To investigate the association between current childhood nutritional status and current wheezing among pre-school children in rural Bangladesh. DESIGN: Cross-sectional study. SETTING: Matlab region, rural Bangladesh. SUBJECTS: Children (n 912) aged 4.5 years. Anthropometric measurements of the mothers and their children were taken during a 1-year period from December 2007 to November 2008. Current wheezing was identified using the International Study of Asthma and Allergies in Childhood questionnaire. Serum total IgE was measured by human IgE quantitative ELISA. IgE specific antibody to dust mites (Dermatophagoides pteronyssinus) was measured by the CAP-FEIA system (Phadia AB, Uppsala, Sweden). RESULTS: Wheezing at 4.5 years old was significantly associated with stunting (OR = 1.58; 95 % CI 1.13, 2.22) and underweight (OR = 1.39; 95 % CI 1.00, 1.94). The association with stunting remained significant after adjustment for sex, birth weight, birth length, gestational age at birth, mother's parity, maternal BMI, family history of asthma, socio-economic status, season of birth and intervention trial arm (OR = 1.74; 95 % CI 1.19, 2.56). CONCLUSIONS: Stunting was a significant risk factor for wheezing among rural Bangladeshi children. Further studies will be required to confirm the relationship between nutritional status and allergic illnesses in developing countries. PMID- 23680046 TI - Clinician and patient perspectives of a new model of triage in a community rehabilitation program that reduced waiting time: a qualitative analysis. AB - BACKGROUND: A trial of a new model of triage (Specific and Timely Appointments for Triage: STAT) at a community rehabilitation program (CRP) reduced the mean time to first appointment from 17.5 to 10.0 days. However, quantitative findings reveal little about the impact of the system on those who used it. We aimed to explore the experiences of patients and clinicians following the introduction of STAT. METHOD: Qualitative study within a convergent mixed-methods design applied to a controlled before and after trial at a CRP. Semi-structured interviews (n=32) were conducted with clinicians who experienced the change to STAT, patients admitted to the CRP using STAT and patients who attended rehabilitation via a triaged wait list at another site. RESULTS: Clinicians reported shorter waiting times, more flexibility and increased efficiency with STAT, and noted the importance of effective change management. Patients reported a more efficient and consistent pathway to rehabilitation with STAT. Waiting had negative consequences for some patients at the triaged wait list site. CONCLUSIONS: The qualitative data provide context to the quantitative results by showing that the changes that reduced waiting times were also well accepted and perceived to be beneficial by both patients and clinicians. What is known about the topic? Triage systems are widely used but can contribute to inefficiencies in health care. An alternative method of triage (STAT) using early allocation to face-to-face appointments has been shown to reduce waiting times in a community rehabilitation service. What does this paper add? This paper explains and adds important context to the quantitative findings by exploring the perceptions of the staff and patients who experienced both the existing and alternative models of triage. What are the implications for practitioners? The STAT model was well received by staff and patients, suggesting that this simple intervention was a feasible and effective method of reducing waiting times for community rehabilitation, and may be applicable to other services that share similar features. PMID- 23680047 TI - Lactobacillus fermentation enhances the inhibitory effect of Hwangryun-haedok tang in an ovariectomy-induced bone loss. AB - BACKGROUND: Hwangryun-haedok-tang (HRT) is traditional herbal medicine used to treat inflammatory-related diseases in Asia. However, its effect on osteoclastogenesis and bone loss is still unknown. In this study, we evaluated the effect of HRT and its fermented product (fHRT) on the receptor activator for the nuclear factor-kappaB ligand-induced osteoclastogenesis using murine bone marrow-derived macrophages and postmenopausal bone loss using an ovariectomy (OVX) rat model. METHODS: Tartrate resistant acid phosphatase (TRAP) staining was employed to evaluate osteoclast formation. mRNA level of transcription factor and protein levels of signaling molecules were determined by real-time quantitative polymerase chain reaction and Western blot analysis, respectively. Effect of HRT or fHRT on OVX-induced bone loss was evaluated using OVX rats orally administered HRT, or fHRT with 300 mg/kg for 12 weeks. Micro-CT analysis of femora was performed to analyze bone parameter. RESULTS: HRT or fHRT treatment significantly decreased TRAP activity and the number of TRAP positive multinuclear cells on osteoclastogenesis. Interestingly, these inhibitory effects of HRT were enhanced by fermentation. Furthermore, fHRT significantly inhibited mRNA and protein expression of nuclear factor of activated T cells cytoplasmic 1, which leads to down-regulation of NFATc1-regulated mRNA expressions such as TRAP, the d2 isoform of vacuolar ATPase V(0) domain, and cathepsin K. Administration of fHRT significantly inhibited the decrease of bone mineral density, and improved bone parameter of femora more than that of HRT and vehicle in OVX rats. CONCLUSIONS: This study demonstrated that lactic bacterial fermentation fortifies the inhibitory effect of HRT on osteoclastogenesis and bone loss. These results suggest that fermented HRT might have the beneficial potential on osteoporosis by inhibiting osteoclastogenesis. PMID- 23680048 TI - Effect of perfluoroalkyl chain length on monolayer behavior of partially fluorinated oleic acid molecules at the air-water interface. AB - A series of oleic acid (OA) analogs containing terminal perfluoroalkyl groups (CF3, C2F5, n-C3F7, n-C4F9 or n-C8F17) was synthesized to clarify how the fluorinated chain length affects the stability and molecular packing of liquid expanded OA monolayers at the air-water interface. Although the substitution of terminal CF3 group for CH3 in OA had no effect on monolayer stability, further fluorination led to a gradual increase in monolayer stability at 25 degrees C. Surface pressure-area isotherm revealed that partially fluorinated OA analogs form more expanded monolayers than OA at low surface pressures, and that the monolayer behavior of OA analogs with the even-carbon numbered fluorinated chain is almost the same as that of OA upon monolayer compression, whereas the behavior of OA analogs with the odd-carbon numbered fluorinated chain significantly differs from that of OA. These results indicate: (i) the terminal short part (at least C2 residue) in OA predominantly determines the liquid-expanded monolayer stability; (ii) the molecular packing state of OA may be perturbed by the substitution of a short odd-carbon numbered fluorinated chain; (iii) hence, OA analogs with even-carbon numbered chain are considered to be preferable as hydrophobic building blocks for the synthesis of fluorinated phospholipids. PMID- 23680049 TI - Deferoxamine blocks death induced by glutathione depletion in PC 12 cells. AB - The purpose of the present work was to investigate the mechanisms by which glutathione depletion induced by treatment with buthionine sulfoximine (BSO) led within 24-30 h to PC 12 cells apoptosis. Our results showed that treatment by relatively low concentrations (10-30 MUM) of deferoxamine (DFx), a natural iron specific chelator, almost completely shielded the cells from BSO-induced toxicity and that DFx still remained protective when added up to 9-12h after BSO treatment. On the other hand, phosphopeptides derived from milk casein and known to carry iron across cell membranes, markedly potentiated the toxic action of BSO when loaded with iron but were ineffective in sodium form. Kept for 24 h in serum free medium, the cells underwent a decrease in glutathione content after BSO treatment, but remained viable. However, these BSO-pre-treated cells showed a rapid (90-120 min) decrease in cell viability when incubated with low doses of iron, whereas a great proportion of them remained viable in the presence of higher concentrations of copper and zinc. We also observed in PC 12 cells an early (4-8 h) and transient increase in the expression of ferritin subunits following BSO addition. Taken together these results suggest that BSO-induced glutathione depletion leads to an alteration of cellular iron homeostasis, which may contribute to its toxicity. PMID- 23680050 TI - Toxic risks and nutritional benefits of traditional diet on near visual contrast sensitivity and color vision in the Brazilian Amazon. AB - BACKGROUND: Visual functions are known to be sensitive to toxins such as mercury (Hg) and lead (Pb), while omega-3 fatty acids (FA) and selenium (Se) may be protective. In the Tapajos region of the Brazilian Amazon, all of these elements are present in the local diet. OBJECTIVE: Examine how near visual contrast sensitivity and acquired color vision loss vary with biomarkers of toxic exposures (Hg and Pb) and the nutrients Se and omega-3 FA in riverside communities of the Tapajos. METHODS: Complete visuo-ocular examinations were performed. Near visual contrast sensitivity and color vision were assessed in 228 participants (>=15 years) without diagnosed age-related cataracts or ocular pathologies and with near visual acuity refracted to at least 20/40. Biomarkers of Hg (hair), Pb (blood), Se (plasma), and the omega-3 FAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in plasma phospholipids were measured. Multiple linear regressions were used to examine the relations between visual outcomes and biomarkers, taking into account age, sex, drinking and smoking. RESULTS: Reduced contrast sensitivity at all spatial frequencies was associated with hair Hg, while %EPA, and to a lesser extent %EPA+DHA, were associated with better visual function. The intermediate spatial frequency of contrast sensitivity (12 cycles/degree) was negatively related to blood Pb and positively associated with plasma Se. Acquired color vision loss increased with hair Hg and decreased with plasma Se and %EPA. CONCLUSIONS: These findings suggest that the local diet of riverside communities of the Amazon contain toxic substances that can have deleterious effects on vision as well as nutrients that are beneficial for visual function. Since remediation at the source is a long process, a better knowledge of the nutrient content and health effects of traditional foods would be useful to minimize harmful effects of Hg and Pb exposure. PMID- 23680051 TI - [Serum microRNA-21 usefulness in inflammatory pathology of the colon]. AB - BACKGROUND: MicroRNAs are 20-22 nucleotide molecular structures with post transcriptional activity that are involved in the immune response, as well as in the inflammatory pathways of different cells and tissues. AIMS: We present herein a prospective study in which serum microRNA-21 expression was determined in patients diagnosed with acute appendicitis as a model of bowel inflammation. MATERIAL AND METHODS: A prospective cohort study of patients diagnosed with acute appendicitis was conducted. Serum microRNA-21 was analyzed through the PCR of blood samples taken from the patients prior to surgery. MicroRNA-21 values were compared with the analytic variables (leukocytes, hemoglobin, hematocrit, platelets, prothrombin activity, glucose, urea, and creatinine) and the anatomopathologic variables (normal appendix, phlegmonous, gangrenous, and perforated acute appendicitis). RESULTS: A total of 60 patients with acute appendicitis diagnosis were consecutively included in the study from June to October 2009. Sixty-six percent of the patients were men (40 men and 20 women), with a mean age of 26.2+/-14.8 years. The mean absolute level of microRNA-21 was 24.8+/-0.93, whereas the mean microRNA-21 gene expression was 1.04+/-0.28. No correlation between the analytic and anatomopathologic parameters evaluated was observed (P=.47). CONCLUSIONS: It is necessary to continue to search for the most appropriate microRNAs, so that their determination in serum can lead to greater precision in establishing the diagnosis and outcome of inflammatory disorders of the bowel. PMID- 23680052 TI - Comparative evaluation of esophageal Barrett's epithelium through esophageal capsule endoscopy and methylene blue chromoendoscopy. AB - BACKGROUND: Patients presenting with Barrett's esophagus (BE) should be under life-long surveillance in an attempt to detect cancer in its early stages. Esophageal capsule endoscopy (ECE) is a new technique that enables a noninvasive evaluation of the esophagus. AIMS: To evaluate ECE effectiveness compared with methylene blue (MB) chromoendoscopy for the detection of esophageal lesions in which there was suspicion of cancer, the length and pattern of BE, and the presence of hiatal hernia. MATERIAL AND METHODS: Twenty-one patients with BE who underwent Nissen fundoplication and had a follow-up period of more than five years were prospectively enrolled in the study. The patients underwent ECE and chromoendoscopy with MB performed by different physicians who were blinded to each of the procedures. RESULTS: ECE sensitivity, negative predictive value, and accuracy were 100%, 100%, and 79%, respectively, for the detection of esophageal lesions suspected of cancer. ECE accuracy in assessing BE length was 89% and in the evaluation of finger-like projections, circumferential BE, and mixed BE was 74%, 79%, and 74%, respectively. In relation to hiatal hernia detection, ECE sensitivity was 43% and its accuracy was 74%. CONCLUSIONS: ECE appears to be a good method for detecting lesions in which there is suspicion of esophageal cancer and it had modest results in regard to the accurate identification of BE length and pattern. ECE is not a good method for detecting hiatal hernia. Further studies are needed in order to define the definitive role of ECE in BE monitoring. PMID- 23680054 TI - Strategies for obtaining unpublished drug trial data: a qualitative interview study. AB - BACKGROUND: Authors of systematic reviews have difficulty obtaining unpublished data for their reviews. This project aimed to provide an in-depth description of the experiences of authors in searching for and gaining access to unpublished data for their systematic reviews, and to give guidance on best practices for identifying, obtaining and using unpublished data. METHODS: This is a qualitative study analyzing in-depth interviews with authors of systematic reviews who have published Cochrane reviews or published systematic reviews outside of The Cochrane Library. We included participants who 1) were the first or senior author of a published systematic review of a drug intervention, 2) had expertise in conducting systematic reviews, searching for data, and assessing methodological biases, and 3) were able to participate in an interview in English. We used non random sampling techniques to identify potential participants. Eighteen Cochrane authors were contacted and 16 agreed to be interviewed (89% response rate). Twenty-four non-Cochrane authors were contacted and 16 were interviewed (67% response rate). RESULTS: Respondents had different understandings of what was meant by unpublished data, including specific outcomes and methodological details. Contacting study authors was the most common method used to obtain unpublished data and the value of regulatory agencies as a data source was underappreciated. Using the data obtained was time consuming and labor intensive. Respondents described the collaboration with other colleagues and/or students required to organize, manage and use the data in their reviews, generally developing and using templates, spreadsheets and computer programs for data extraction and analysis. Respondents had a shared belief that data should be accessible but some had concerns about sharing their own data. Respondents believed that obtaining unpublished data for reviews has important public health implications. There was widespread support for government intervention to ensure open access to trial data. CONCLUSIONS: Respondents uniformly agreed that the benefit of identifying unpublished data was worth the effort and was necessary to identify the true harms and benefits of drugs. Recent actions by government, such as increased availability of trial data from the European Medicines Agency, may make it easier to acquire critical drug trial data. PMID- 23680058 TI - [Anticholinergic syndrome due to dexchlorpheniramine as a cause of urinary retention]. PMID- 23680060 TI - Cellular uptake and localization of inhaled gold nanoparticles in lungs of mice with chronic obstructive pulmonary disease. AB - BACKGROUND: Inhalative nanocarriers for local or systemic therapy are promising. Gold nanoparticles (AuNP) have been widely considered as candidate material. Knowledge about their interaction with the lungs is required, foremost their uptake by surface macrophages and epithelial cells. METHODS: Scnn1b-Tg and Wt mice inhaled a 21-nm AuNP aerosol for 2 h. Immediately (0 h) or 24 h thereafter, bronchoalveolar lavage (BAL) macrophages and whole lungs were prepared for stereological analysis of AuNP by electron microscopy. RESULTS: AuNP were mainly found as singlets or small agglomerates of <= 100 nm diameter, at the epithelial surface and within lung-surface structures. Macrophages contained also large AuNP agglomerates (> 100 nm). At 0 h after aerosol inhalation, 69.2+/-4.9% AuNP were luminal, i.e. attached to the epithelial surface and 24.0+/-5.9% in macrophages in Scnn1b-Tg mice. In Wt mice, 35.3+/-32.2% AuNP were on the epithelium and 58.3+/-41.4% in macrophages. The percentage of luminal AuNP decreased from 0 h to 24 h in both groups. At 24 h, 15.5+/-4.8% AuNP were luminal, 21.4+/-14.2% within epithelial cells and 63.0+/-18.9% in macrophages in Scnn1b-Tg mice. In Wt mice, 9.5+/-5.0% AuNP were luminal, 2.2+/-1.6% within epithelial cells and 82.8+/-0.2% in macrophages. BAL-macrophage analysis revealed enhanced AuNP uptake in Wt animals at 0 h and in Scnn1b-Tg mice at 24 h, confirming less efficient macrophage uptake and delayed clearance of AuNP in Scnn1b-Tg mice. CONCLUSIONS: Inhaled AuNP rapidly bound to the alveolar epithelium in both Wt and Scnn1b-Tg mice. Scnn1b-Tg mice showed less efficient AuNP uptake by surface macrophages and concomitant higher particle internalization by alveolar type I epithelial cells compared to Wt mice. This likely promotes AuNP depth translocation in Scnn1b-Tg mice, including enhanced epithelial targeting. These results suggest AuNP nanocarrier delivery as successful strategy for therapeutic targeting of alveolar epithelial cells and macrophages in COPD. PMID- 23680059 TI - Effect of thiazolidinediones and insulin on cognitive outcomes in ACCORD-MIND. AB - OBJECTIVE: To examine the relationship of cognitive performance to exposure to insulin (INS) and thiazolidinediones (TZD) in the ACCORD-MIND cohort. METHODS: Participants (55-80years) with type 2 diabetes (T2D), hemoglobin A1c (HbA1c) >7.5% (>58mmol/mol), and a high risk of cardiovascular events were randomly assigned to receive intensive control targeting HbA1c to <6.0% (42mmol/mol) or a standard strategy targeting HbA1c to 7.0%-7.9% (53-63mmol/mol). The Digit Symbol Substitution Test (DSST) was assessed at baseline and at 20 and 40months. Exposure to INS was calculated as average daily dose/kg of body weight; exposure to rosiglitazone (ROS) was calculated as days of ROS prescription in the intervals preceding the 20- and 40-month DSSTs. RESULTS: At baseline, INS use was associated with reduced DSST performance, but not after controlling for comorbidities and lab values. There was no relationship between use of a TZD and DSST performance on at baseline. ROS but not INS exposure was associated with greater decline in DSST performance over 40months in subjects randomized to the intensive but not the standard group. CONCLUSIONS: Exposure to a TZD may increase cognitive decline in some patients with T2D. However, these results may be confounded by unexplained differences between participants. PMID- 23680061 TI - Chlorella-induced psychosis. PMID- 23680062 TI - A case of ziprasidone associated with acutely worsened diabetes mellitus. PMID- 23680063 TI - Development of novel catalytically active polymer-metal-nanocomposites based on activated foams and textile fibers. AB - In this paper, we report the intermatrix synthesis of Ag nanoparticles in different polymeric matrices such as polyurethane foams and polyacrylonitrile or polyamide fibers. To apply this technique, the polymer must bear functional groups able to bind and retain the nanoparticle ion precursors while ions should diffuse through the matrix. Taking into account the nature of some of the chosen matrices, it was essential to try to activate the support material to obtain an acceptable value of ion exchange capacity. To evaluate the catalytic activity of the developed nanocomposites, a model catalytic reaction was carried out in batch experiments: the reduction of p-nitrophenol by sodium borohydride. PMID- 23680064 TI - Prevalence of human immunodeficiency virus/hepatitis C virus co-infection in Brazil and associated factors: a review. AB - The hepatitis C virus and human immunodeficiency virus share the same transmission routes, which makes co-infection an unfavorable condition for the natural history of both viral diseases. In this context, it should be highlighted that the knowledge of the extent of co-infection and associated risk factors is a vital tool for prevention and control over infectious diseases. The aim of this study was to review the literature, seeking to examine the prevalence of human immunodeficiency virus/hepatitis C virus co-infection reported in studies conducted in Brazil, and identify the main risk factors associated with co infection. The electronic search was conducted in the Medline, Lilacs and SciELO databases. The following keywords were used: human immunodeficiency virus and Hepatitis C or hepatitis C virus and Brazil. The search led to 376 articles, of which 69 were selected for data extraction. We excluded animal studies, reports or case series, review articles, letters to the editor, other types of hepatitis and those studies in which co-infected patients were intentionally selected for comparison to single infected individuals. As a result, 40 articles were reviewed. The majority of the population in these studies was male (71%) and young adults, with a mean age of 26.7 years. The prevalence of hepatitis C virus co-infection among individuals living with human immunodeficiency virus in the studies conducted in Brazil ranged from 3.3% (serum samples) to 82.4% (drug users), with an average of 20.3%. The findings reveal that the prevalence of human immunodeficiency virus/hepatitis C virus co-infection is highly variable, depending on the characteristics of the study population. Risk factors associated with human immunodeficiency virus/hepatitis C virus co-infection were injection drug use and blood transfusion. PMID- 23680065 TI - Adherence to antiretroviral prophylaxis during early infancy in Latin America. PMID- 23680067 TI - Adolescents' ability to select healthy food using two different front-of-pack food labels: a cross-over study. AB - OBJECTIVE: To compare, in adolescents, two models of front-of-pack Guideline Daily Amounts (GDA) labels in terms of (i) friendliness and acceptance and (ii) the ability to choose a diet that closely follows the nutritional recommendations. DESIGN: A randomized cross-over study was designed to compare two simplified front-of-pack GDA nutrition labels. SETTING: A Spanish secondary school. SUBJECTS: Eighty-one healthy adolescents aged between 14 and 16 years were recruited. Participants were randomly exposed to two experimental non-real food-choice conditions using multiple-traffic-light or monochrome nutritional labels. Participants had to choose options from a closed menu for 5 d on the basis of the experimental front-of-pack labelling. For each meal, three food options with different nutritional compositions were given to the participants. The contents of total energy and fat, saturated fat, sugar and salt of the chosen options were calculated. RESULTS: There were no significant differences in baseline sociodemographic and anthropometric characteristics between participants regardless of the experimental condition in which they started. There were no carry-over effects between the experimental sequences. It was observed that when participants used the multiple-traffic-light GDA system they chose significantly less total energy (mean -123.1 (sd 211.0) kJ (-29.4 (sd 50.4) kcal), P < 0.001), sugar (-4.5 (sd 4.6) g, P < 0.001), fat (-2.1 (sd 4.5) g, P = 0.006), saturated fat (-1.0 (sd 1.9) g, P = 0.002) and salt (-0.4 (sd 0.5) g, P < 0.001) than when they used the monochrome GDA system. CONCLUSIONS: Compared with the monochrome GDA front-of-pack nutritional label, the multiple-traffic-light system helped adolescents to differentiate between healthier and less healthy food, theoretically making it possible for them to choose a diet closer to dietary recommendations. PMID- 23680066 TI - Does enrollment status in community-based insurance lead to poorer quality of care? Evidence from Burkina Faso. AB - INTRODUCTION: In 2004, a community-based health insurance (CBI) scheme was introduced in Nouna health district, Burkina Faso, with the objective of improving financial access to high quality health services. We investigate the role of CBI enrollment in the quality of care provided at primary-care facilities in Nouna district, and measure differences in objective and perceived quality of care and patient satisfaction between enrolled and non-enrolled populations who visit the facilities. METHODS: We interviewed a systematic random sample of 398 patients after their visit to one of the thirteen primary-care facilities contracted with the scheme; 34% (n = 135) of the patients were currently enrolled in the CBI scheme. We assessed objective quality of care as consultation, diagnostic and counselling tasks performed by providers during outpatient visits, perceived quality of care as patient evaluations of the structures and processes of service delivery, and overall patient satisfaction. Two-sample t-tests were performed for group comparison and ordinal logistic regression (OLR) analysis was used to estimate the association between CBI enrollment and overall patient satisfaction. RESULTS: Objective quality of care evaluations show that CBI enrollees received substantially less comprehensive care for outpatient services than non-enrollees. In contrast, CBI enrollment was positively associated with overall patient satisfaction (aOR = 1.51, p = 0.014), controlling for potential confounders such as patient socio-economic status, illness symptoms, history of illness and characteristics of care received. CONCLUSIONS: CBI patients perceived better quality of care, while objectively receiving worse quality of care, compared to patients who were not enrolled in CBI. Systematic differences in quality of care expectations between CBI enrollees and non-enrollees may explain this finding. One factor influencing quality of care may be the type of provider payment used by the CBI scheme, which has been identified as a leading factor in reducing provider motivation to deliver high quality care to CBI enrollees in previous studies. Based on this study, it is unlikely that perceived quality of care and patient satisfaction explain the low CBI enrollment rates in this community. PMID- 23680068 TI - A comparison of proximal humeral cancellous bone of great apes and humans. AB - The shoulder is the most mobile joint in the primate body, and is involved in both locomotor and manipulative activities. The presumed functional sensibility of trabecular bone can offer a way of decoding the activities to which the forelimbs of fossil primates were subjected. We examine the proximal humeral trabecular architecture in a relatively closely related group of similarly sized hominids (Pongo pygmaeus, Pan troglodytes, and Homo sapiens), in order to evaluate the effect of diverging habitual motion behaviors of the shoulder complex in a coherent phylogenetic group. In order to characterize and compare the humeral trabecular architectures of the three species, we imaged a large sample by high-resolution computed tomography (HrCT) and quantified their trabecular architectures by standard bone 3D morphometric parameters. Univariate statistical analysis was performed, showing significant differences among the species. However, univariate statistics could not highlight the structural particularity in the cancellous bone of each species. A principal component analysis also showed clear separation of the three taxa and enabled a structural characterization of the humeral trabecular bone of each species. We conclude that the differences in the architectural setup of the three hominids likely reflect multiple differences in their habitual activity patterns of their shoulder joint, although individual structural features are difficult to relate to specific loading conditions. PMID- 23680069 TI - The time has come for an Australian Centre for Disease Control. PMID- 23680070 TI - Th1 and Th2 cytokine profiles induced by hepatitis C virus F protein in peripheral blood mononuclear cells from chronic hepatitis C patients. AB - Th1 and Th2 cytokine response has been confirmed to be correlated with the pathogenesis of HCV infection. The aim of the study is to investigate the Th1 and Th2 cytokine profiles induced by HCV alternate reading frame protein (F protein) in chronic hepatitis C patients. We assessed the immune responses specific to HCV F protein in 55 chronic HCV patients. IFN-gamma, IL-2, IL-4 and IL-5 secretion by peripheral blood mononuclear cells (PBMC) post F protein stimulation were compared among HCV patients and healthy donors. Finally, the associations between HCV F protein and HLA class II alleles were explored. We found that the seroprevalence of anti-F antibodies in HCV-related hepatocellular carcinoma (HCC) patients was significantly higher than that of patients without HCC, but such a significant difference in humoral immune responses to F protein was not observed in HCV 1b-infected- and non-HCV 1b-infected-patients. Additionally, the PBMC proliferation of HCC patients was significantly lower than that of patients without HCC. Furthermore, F protein stimulation of PBMCs from F-seropositive patients resulted in Th2 biased cytokine responses (significantly decreased IFN gamma and/or IL-2 and significantly increased IL-4 and/or IL-5 levels) that reportedly may contribute to HCC progression and pathogenesis. However, no significant difference in the association between HCV F protein and HLA DRB1*0201, 0301, 0405, 1001 and HLA-DQB1*0201, 0401, 0502, 0602 was observed in this study. These findings suggest that F protein may contribute to the HCV associated bias in Th1/Th2 responses of chronic hepatitis C patients including the progress of HCC pathogenesis. PMID- 23680072 TI - Development of a comprehensive real-time PCR assay for dystrophin gene analysis and prenatal diagnosis of Chinese families. AB - BACKGROUND: To develop a comprehensive method to analyze deletions or duplications of the dystrophin gene in both patients and carriers of Duchenne muscular dystrophy (DMD), likewise applied to prenatal diagnosis. METHODS: A total of thirty Chinese families were recruited, composed of 29 DMD affected males and 38 female relatives containing four pregnant women. Deletions were previously screened by multiplex PCR. A comprehensive real-time PCR assay using SYBR Green I dye was performed for the initial detection of duplications in patients with a seven-exon primer set, carrier detection for female relatives and prenatal diagnosis for the 4 of them. The results were later confirmed by multiple ligation-dependent probe amplification (MLPA) and linkage analysis. RESULTS: Three out of 4 duplications were first discovered by real-time PCR. Carrier status was ascertained in 22 and rejected in the remaining sixteen female relatives. Furthermore, 4 fetuses were diagnosed as two normal females, one normal male and one female carrier, respectively. CONCLUSIONS: Our real-time PCR assay is useful in duplication screen with a detection rate of >70%, as well as rapid and reliable in both carrier detection and prenatal diagnosis of DMD families with known deletions and duplications. PMID- 23680071 TI - Determination of optimal cutoff value to accurately identify glucose-6-phosphate dehydrogenase-deficient heterozygous female neonates. AB - BACKGROUND: Conventional screening tests to assess G6PD deficiency use a low cutoff value of 2.10 U/gHb which may not be adequate for detecting females with heterozygous deficiency. The aim of present study was to determine an appropriate cutoff value with increased sensitivity in identifying G6PD-deficient heterozygous females. METHODS: G6PD activity analysis was performed on 51,747 neonates using semi-quantitative fluorescent spot test. Neonates suspected with G6PD deficiency were further analyzed using quantitatively enzymatic assay and for common G6PD mutations. The cutoff values of G6PD activity were estimated using the receiver operating characteristic curve. RESULTS: Our results demonstrated that using 2.10 U/g Hb as a cutoff, the sensitivity of the assay to detect female neonates with G6PD heterozygous deficiency was 83.3%, as compared with 97.6% using 2.55 U/g Hb as a cutoff. The high cutoff identified 21% (8/38) of the female neonates with partial G6PD deficiency which were not detected with 2.10 U/g Hb. Our study found that high cutoffs, 2.35 and 2.55 U/g Hb, would increase assay's sensitivity to identify male and female G6PD deficiency neonates, respectively. CONCLUSIONS: We established a reliable cutoff value of G6PD activity with increased sensitivity in identifying female newborns with partial G6PD deficiency. PMID- 23680073 TI - T helper and regulatory T cell cytokine profile in active, stable and narrow band ultraviolet B treated generalized vitiligo. AB - BACKGROUND: Vitiligo is a T cell mediated autoimmune depigmenting disease. Altered cytokine concentrations have been suggested in the pathogenesis of vitiligo. METHODS: T helper and regulatory T cell cytokines (IL-2, IFN-gamma, IL 10, IL-13, IL-17 and TGF-beta) have been estimated by ELISA and their clinical correlation was determined. The study had 3 groups: group I with 80 vitiligo patients (60 active and 20 stable), group II with 25 narrow band ultraviolet B treated vitiligo and group III with 70 healthy controls. RESULTS: Significant difference was found in the serum interleukin (IL)-10, IL-13, IL-17A and TGF beta1 concentrations among 3 groups (P<0.05). In group I, serum IL-2, IL-17A concentrations were significantly increased and TGF-beta1 concentrations were decreased in active vitiligo compared to stable vitiligo (P<0.05). Concentrations of IL-2, IL-10 and IL-13 (rho=-0.307, rho=-0.407, rho=-0.351 and P<0.05; respectively) were negatively- and TGF-beta1 concentrations were positively correlated (rho=0.799, P=0.001) with disease duration. Interleukin-13 concentrations were negatively- and serum TGF-beta1 concentrations were positively-correlated (rho=-0.326, rho=0.244 and P<0.05; respectively) with percentage of body surface area involvement. CONCLUSIONS: Increased concentrations of serum IL-10, IL-13, and IL-17A and decreased concentrations of TGF-beta1 suggested altered cell-mediated immunity that may facilitate the melanocyte cytotoxicity in vitiligo. PMID- 23680074 TI - Health care performance comparison using a disease-based approach: the EuroHOPE project. AB - This article describes the methodological challenges associated with disease based international comparison of health system performance and how they have been addressed in the EuroHOPE (European Health Care Outcomes, Performance and Efficiency) project. The project uses linkable patient-level data available from national sources of Finland, Hungary, Italy, The Netherlands, Norway, Scotland and Sweden. The data allow measuring the outcome and the use of resources in uniformly-defined patient groups using standardized risk adjustment procedures in the participating countries. The project concentrates on five important disease groups: acute myocardial infarction (AMI), ischemic stroke, hip fracture, breast cancer and very low birth weight and preterm infants (VLBWI). The essentials of data gathering, the definition of the episode of care, the developed indicators concerning baseline statistics, treatment process, cost and outcomes are described. The preliminary results indicate that the disease-based approach is attractive for international performance analyses, because it produces various measures not only at country level but also at regional and hospital level across countries. The possibility of linking hospital discharge register to other databases and the availability of comprehensive register data will determine whether the approach can be expanded to other diseases and countries. PMID- 23680075 TI - Randomized clinical trial examining duration of voucher-based reinforcement therapy for cocaine abstinence. AB - BACKGROUND: This is the first study to systematically manipulate duration of voucher-based reinforcement therapy (VBRT) to see if extending the duration increases abstinence during and following VBRT. METHODS: We randomized cocaine dependent methadone-maintained adults to Standard (12 weeks; n=62) or Extended (36 weeks; n=68) VBRT and provided escalating voucher amounts contingent upon urinalysis verification of cocaine abstinence. Urinalysis was scheduled at least every 2 weeks during the 48-week study and more frequently during VBRT (3/week) and 12 weeks of Aftercare (2/week). RESULTS: Extended VBRT produced longer durations of continuous cocaine abstinence during weeks 1-24 (5.7 vs 2.7 weeks; p=0.003) and proportionally more abstinence during weeks 24-36 (X(2)=4.57, p=.03, OR=2.18) compared to Standard VBRT. Duration of VBRT did not directly predict after-VBRT abstinence; but longer continuous abstinence during VBRT predicted abstinence during Aftercare (p=0.001) and during the last 12 weeks of the study (p<0.001). Extended VBRT averaged higher monthly voucher costs compared to Standard VBRT ($96 vs $43, p<.001); however, the average cost per week of abstinence attained was higher in the Standard group ($8.06 vs $5.88, p<.001). Participants in the Extended group with voucher costs exceeding $25 monthly averaged 20 weeks of continuous abstinence. CONCLUSIONS: Greater abstinence occurred during Extended VBRT, but providing a longer duration was not by itself sufficient to maintain abstinence after VBRT. However, if abstinence can be captured and sustained during VBRT, then providing longer durations may help increase the continuous abstinence that predicts better long-term outcomes. PMID- 23680076 TI - Association between nicotine replacement therapy use in pregnancy and smoking cessation. AB - BACKGROUND: There is an urgent need to find better ways of helping pregnant smokers to stop. Randomized controlled trials (RCTs) have not detected an effect of nicotine replacement therapy (NRT) for smoking cessation in pregnancy. This may be because of inadequate dosing because of faster nicotine metabolism in this group. In England, many pregnant smokers use single form and combination NRT (patch plus a faster acting form). This correlational study examined whether the latter is associated with higher quit rates. METHODS: Routinely collected data from 3880 pregnant smokers attempting to stop in one of 44 Stop Smoking Services in England. The outcome measure was 4-week quit rates, verified by expired-air carbon monoxide level<10 ppm. Outcome was compared between those not using medication versus using single form NRT (patch or one of the faster acting forms), or combination NRT. Potential confounders were intervention setting (specialist clinic, home visit, primary care, other), intervention type (one-to one, group, drop-in, other), months pregnant, age, ethnicity and occupational group in multi-level logistic regressions. RESULTS: After adjustment, combination NRT was associated with higher odds of quitting compared with no medication (OR=1.93, 95% CI=1.13-3.29, p=0.016), whereas single NRT showed no benefit (OR=1.06, 95% CI=0.60-1.86, p=0.84). CONCLUSIONS: Use of a combination of nicotine patch and a faster acting form may confer a benefit in terms of promoting smoking cessation during pregnancy. While this conclusion is based on correlational data, it lends support to continuing this treatment option pending confirmation by an RCT. PMID- 23680077 TI - A qualitative study into the difficulties experienced by healthcare decision makers when reading a Cochrane diagnostic test accuracy review. AB - BACKGROUND: Cochrane reviews are one of the best known and most trusted sources of evidence-based information in health care. While steps have been taken to make Cochrane intervention reviews accessible to a diverse readership, little is known about the accessibility of the newcomer to the Cochrane library: diagnostic test accuracy reviews (DTARs). The current qualitative study explored how healthcare decision makers, who varied in their knowledge and experience with test accuracy research and systematic reviews, read and made sense of DTARs. METHODS: A purposive sample of clinicians, researchers and policy makers (n = 21) took part in a series of think-aloud interviews, using as interview material the first three DTARs published in the Cochrane library. Thematic qualitative analysis of the transcripts was carried out to identify patterns in participants' 'reading' and interpretation of the reviews and the difficulties they encountered. RESULTS: Participants unfamiliar with the design and methodology of DTARs found the reviews largely inaccessible and experienced a range of difficulties stemming mainly from the mismatch between background knowledge and level of explanation provided in the text. Experience with systematic reviews of interventions did not guarantee better understanding and, in some cases, led to confusion and misinterpretation. These difficulties were further exacerbated by poor layout and presentation, which affected even those with relatively good knowledge of DTARs and had a negative impact not only on their understanding of the reviews but also on their motivation to engage with the text. Comparison between the readings of the three reviews showed that more accessible presentation, such as presenting the results as natural frequencies, significantly increased participants' understanding. CONCLUSIONS: The study demonstrates that authors and editors should pay more attention to the presentation as well as the content of Cochrane DTARs, especially if the reports are aimed at readers with various levels of background knowledge and experience. It also raises the question as to the anticipated target audience of the reports and suggests that different groups of healthcare decision-makers may require different modes of presentation. PMID- 23680078 TI - Modeling mutant phenotypes and oscillatory dynamics in the Saccharomyces cerevisiae cAMP-PKA pathway. AB - BACKGROUND: The cyclic AMP-Protein Kinase A (cAMP-PKA) pathway is an evolutionarily conserved signal transduction mechanism that regulates cellular growth and differentiation in animals and fungi. We present a mathematical model that recapitulates the short-term and long-term dynamics of this pathway in the budding yeast, Saccharomyces cerevisiae. Our model is aimed at recapitulating the dynamics of cAMP signaling for wild-type cells as well as single (pde1Delta and pde2Delta) and double (pde1Deltapde2Delta) phosphodiesterase mutants. RESULTS: Our model focuses on PKA-mediated negative feedback on the activity of phosphodiesterases and the Ras branch of the cAMP-PKA pathway. We show that both of these types of negative feedback are required to reproduce the wild-type signaling behavior that occurs on both short and long time scales, as well as the the observed responses of phosphodiesterase mutants. A novel feature of our model is that, for a wide range of parameters, it predicts that intracellular cAMP concentrations should exhibit decaying oscillatory dynamics in their approach to steady state following glucose stimulation. Experimental measurements of cAMP levels in two genetic backgrounds of S. cerevisiae confirmed the presence of decaying cAMP oscillations as predicted by the model. CONCLUSIONS: Our model of the cAMP-PKA pathway provides new insights into how yeast respond to alterations in their nutrient environment. Because the model has both predictive and explanatory power it will serve as a foundation for future mathematical and experimental studies of this important signaling network. PMID- 23680080 TI - Epidemiology of uncontrolled epilepsy in the Al-Kharga District, New Valley, Egypt. AB - BACKGROUND: Despite advances in treating epilepsy, uncontrolled epilepsy continues to be a major clinical problem. Therefore, this work aimed to study the epidemiology of uncontrolled epilepsy in Al-Kharga District, New Valley. METHODS: This study was carried out in 3 stages via door-to-door screening of the total population (62,583 persons). All suspected cases of epilepsy were subjected to case ascertainment, conventional ElectroEncephaloGraphy (EEG), and the Stanford Binet Intelligence Scale. Patients who had been receiving suitable anti-epileptic drugs (AEDs) over the previous 6 months and were having active seizures were considered uncontrolled, according to Ohtsuka et al.(23) The patients underwent serum AED level estimation, video EEG monitoring, and brain MRIs. Fifty age- and gender-matched patients with controlled epilepsy were chosen for statistical analysis and compared with true intractable patients. RESULTS: A total of 437 patients with epilepsy were identified, 30.7% of whom (n=134/437) were uncontrolled, with a prevalence of 2.1/1000. A total of 52.2% of uncontrolled patients (n=70/134) were inappropriately treated, while 47.8% (n=64/134) were compliant with appropriate treatments. Video monitoring EEG of compliant uncontrolled patients demonstrated that 78.1% patients (n=50/64) had definite epilepsy, while 21.9% (n=14/64) had psychogenic non-epileptic seizures (PNES). A logistic regression analysis revealed that status epilepticus, focal seizures, and mixed seizure types were risk factors for intractability. PMID- 23680081 TI - Extramembrane control of ion channel peptide assemblies, using alamethicin as an example. AB - Ion channels allow the influx and efflux of specific ions through a plasma membrane. Many ion channels can sense, for example, the membrane potential (the voltage gaps between the inside and the outside of the membrane), specific ligands such as neurotransmitters, and mechanical tension within the membrane. They modulate cell function in response to these stimuli. Researchers have focused on developing peptide- and non-peptide-based model systems to elucidate ion-channel protein functions and to create artificial sensing systems. In this Account, we employed a typical peptide that forms ion channels,alamethicin, as a model to evaluate our methodologies for controlling the assembly states of channel-forming molecules in membranes. As alamethicin self-assembles in membranes, it prompts channel formation, but number of peptide molecules in these channels is not constant. Using planar-lipid bilayer methods, we monitored the association states of alamethicin in real time. Many ligand-gated, natural-ion channel proteins have large extramembrane domains. As these proteins interact with specific ligands, those conformational alterations in the extramembrane domains are transmitted to the transmembrane, pore-forming domains to open and close the channels. We hypothesized that if we conjugated suitable extramembrane segments to alamethicin, ligand binding to the extramembrane segments could alter the structure of the extramembrane domains and influence the association states or association numbers of alamethicin in the membranes. We could then assess those changes by using single-channel current recording. We found that we could modulate channel assembly and eventual ion flux with attached leucine-zipper extramembrane peptide segments. Using conformationally switchable leucine-zipper extramembrane segments that respond to Fe(3+), we fabricated an artificial Fe(3+) sensitive ion channel; a decrease in the helical content of the extramembrane segment led to an increase in the channel current. When we added a calmodulin C terminus segment, we formed a channel that was sensitive to Ca(2+). This result demonstrated that we could prepare artificial channels that were sensitive to specific ligands by adding appropriate extramembrane segments from natural protein motifs that respond to external stimuli. In conclusion, our research points to the possibility of creating tailored sensor or signal transduction systems through the conjugation of a conformationally switchable extramembrane peptide/protein segment to a suitable transmembrane peptide segment. PMID- 23680079 TI - Anti-inflammatory, antioxidant, and antimicrobial activities of Cocos nucifera var. typica. AB - BACKGROUND: Teas from the husk fiber of Cocos nucifera are used in the folk medicine to treat arthritis and other inflammatory processes. Some works show that some varieties have biological activities. However, one of the main variety of the species, C. nucifera var. typica, known in Brazil as "gigante", was not studied yet. Thus, this study evaluates if this variety has the anti-inflammatory and antimicrobial activities already reported in other varieties. METHODS: C. nucifera aqueous crude extract (10, 50, and 100 mg/kg) and the reference drugs morphine (1 mg/kg) and acetylsalicylic acid (100 mg/kg) were evaluated in models of inflammation (formalin-induced licking and subcutaneous air pouch). The antioxidant activity was evaluated by 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) photometric assay and compared with those of the standards (quercetin, rutin, and ascorbic acid). The extract was also screened against Candida albicans, Escherichia coli, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus (MRSA), in the agar diffusion method. The minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) were determined by the broth micro-dilution assay. Activities of combinations of the extract and antibiotics (methicillin or vancomycin) against MRSA were evaluated using checkerboard assays. RESULTS: The extract significantly inhibited the time that the animals spent licking the formalin-injected paws (second phase). The extract also inhibited the inflammatory process induced by subcutaneous carrageenan injection by reducing cell migration, protein extravasation, and TNF alpha production. Additionally, the extract showed an antioxidant potential in vitro as good as standards in their antioxidant activity. The extract was active only against S. aureus and MRSA. MIC and the bactericidal concentrations were identical (1,024 MUg/ml). The extract and methicillin acted synergistically against the clinical MRSA isolate, whereas an indifferent effect was detected when the extract was combined with vancomycin. CONCLUSIONS: The extract exhibits anti-inflammatory activity through the inhibition of the cell migration. The mixture of extract constituents and methicillin could lead to the development of a new combination antibiotic against MRSA infections. PMID- 23680082 TI - Drive for muscularity and muscularity-oriented disordered eating in men: the role of set shifting difficulties and weak central coherence. AB - Set shifting difficulties and weak central coherence are information-processing biases associated with thinness-oriented eating and body image pathology in women. However, little is known about the relationship between these processing biases and muscularity-oriented eating and body image pathology. We investigated whether set shifting and central coherence were uniquely related to the drive for muscularity and muscularity-oriented disordered eating in a sample of 91 male undergraduates. Participants completed the Wisconsin Card Sort Test, the Matching Familiar Figures Task, the Drive for Muscularity scale, and a modified Eating Disorders Examination-Questionnaire. Results indicated that set shifting difficulties and weak central coherence were both uniquely positively associated with the drive for muscularity, and that set shifting difficulties were uniquely positively associated with muscularity-oriented disordered eating. Results are discussed with regard to the male experience of body image and eating pathology, and in regard to muscle dysmorphia. PMID- 23680083 TI - Screening for diabetes and hypertension in a rural low income setting in western Kenya utilizing home-based and community-based strategies. AB - BACKGROUND: The burdens of hypertension and diabetes are increasing in low- and middle-income countries (LMICs). It is important to identify patients with these conditions early in the disease process. The goal of this study, therefore, is to compare community- versus home-based screening for hypertension and diabetes in Kenya. METHODS: This was a feasibility study conducted by the Academic Model Providing Access to Healthcare (AMPATH) program in Webuye, a town in western Kenya. Home-based (door-to-door) screening occurred in March 2010 and community based screening in November 2011. HIV counselors were trained to screen for diabetes and hypertension in the home-based screening with local district hospital based staff conducting the community-based screening. Participants >18 years old qualified for screening in both groups. Counselors referred all participants with a systolic blood pressure (SBP) >= 160 mmHg and/or a random blood glucose >= 7 mmol/L (126 mg/dL) to a local clinic for follow-up. Differences in likelihood of screening positive between the two strategies were compared using Fischer's Exact Test. Logistic regression models were used to identify factors associated with the likelihood of following-up after a positive screening. RESULTS: There were 236 participants in home-based screening: 13 (6%) had a SBP >= 160 mmHg, and 54 (23%) had a random glucose >= 7 mmol/L. There were 346 participants in community-based screening: 35 (10%) had a SBP >= 160 mmHg, and 27 (8%) had a random glucose >= 7 mmol/L. Participants in community-based screening were twice as likely to screen positive for hypertension compared to home-based screening (OR=1.93, P=0.06). In contrast, participants were 3.5 times more likely to screen positive for a random blood glucose >= 7 mmol/L with home based screening (OR=3.51, P<0.01). Rates for following-up at the clinic after a positive screen were low for both groups with 31% of patients with an elevated SBP returning for confirmation in both the community-based and home-based group (P=1.0). Follow-up after a random glucose was also low with 23% returning in the home-based group and 22% in the community-based group (P=1.0). CONCLUSION: Community- or home-based screening for diabetes and hypertension in LMICs is feasible. Due to low rates of follow-up, screening efforts in rural settings should focus on linking cases to care. PMID- 23680085 TI - Optical properties of GaP/GaNP core/shell nanowires: a temperature-dependent study. AB - Recombination processes in GaP/GaNP core/shell nanowires (NWs) grown on Si are studied by employing temperature-dependent continuous wave and time-resolved photoluminescence (PL) spectroscopies. The NWs exhibit bright PL emissions due to radiative carrier recombination in the GaNP shell. Though the radiative efficiency of the NWs is found to decrease with increasing temperature, the PL emission remains intense even at room temperature. Two thermal quenching processes of the PL emission are found to be responsible for the degradation of the PL intensity at elevated temperatures: (a) thermal activation of the localized excitons from the N-related localized states and (b) activation of a competing non-radiative recombination (NRR) process. The activation energy of the latter process is determined as being around 180 meV. NRR is also found to cause a significant decrease of carrier lifetime. PMID- 23680084 TI - Standardization of human stem cell pluripotency using bioinformatics. AB - The study of cell differentiation, embryonic development, and personalized regenerative medicine are all possible through the use of human stem cells. The propensity for these cells to differentiate into all three germ layers of the body with the potential to generate any cell type opens a number of promising avenues for studying human development and disease. One major hurdle to the development of high-throughput production of human stem cells for use in regenerative medicine has been standardization of pluripotency assays. In this review we discuss technologies currently being deployed to produce standardized, high-quality stem cells that can be scaled for high-throughput derivation and screening in regenerative medicine applications. We focus on assays for pluripotency using bioinformatics and gene expression profiling. We review a number of approaches that promise to improve unbiased prediction of utility of both human induced pluripotent stem cells and embryonic stem cells. PMID- 23680086 TI - Paraurosomoida indiensis gen. nov., sp. nov., an oxytrichid (Ciliophora, Hypotricha) from Kyongnosla Alpine Sanctuary, including note on non-oxytrichid Dorsomarginalia. AB - Paraurosomoida indiensis gen. nov., sp. nov. was isolated from a soil sample collected from Kyongnosla Alpine Sanctuary in the Eastern Himalayas. The present study reports the morphology, morphogenesis, and molecular phylogeny inferred from 18S rDNA sequence. The study is based on live and protargol-impregnated specimens. Paraurosomoida indiensis is very flexible, measures about 90 * 25 MUm in life and possesses citrine cortical granules randomly distributed singly and in small linear groups. Paraurosomoida indiensis has undulating membranes nearly in Oxytricha pattern; only 11 frontal-ventral cirri due to lack of all pretransverse ventral and transverse cirri; one dorsomarginal row and three bipolar dorsal kineties. Divisional morphogenesis resembles oxytrichids involving six parental cirri in primordia formation. Anlagen V and VI for both proter and opisthe are formed from two primary primordia originating from disaggregated cirri V/4 and V/3 respectively. Three dorsal kineties develop from within row anlagen without a kinety 3 fragmentation. Molecular analyses consistently place P. indiensis with soft bodied oxytrichids. PMID- 23680087 TI - The use of the international classification of functioning, disability and health (ICF) in indigenous healthcare: a systematic literature review. AB - INTRODUCTION: The International Classification of Functioning, Disability and Health (ICF) was endorsed by the World Health Organisation (WHO) in 2001 to obtain a comprehensive perspective of health and functioning of individuals and groups. Health disparities exist between Indigenous and non-Indigenous Australians and there is a need to understand the health experiences of Indigenous communities from Indigenous Australian's perspectives in order to develop and implement culturally appropriate and effective intervention strategies to improve Indigenous health. This systematic review examines the literature to identify the extent and context of use of the ICF in Indigenous healthcare, to provide the foundation on which to consider its potential use for understanding the health experiences of Indigenous communities from their perspective. METHODS: The search was conducted between May and June 2012 of five scientific and medical electronic databases: MEDLINE, Web of Science, CINAHL, Academic Search Complete and PsychInfo and six Indigenous-specific databases: AIATSIS, APAIS-health, ATSI-health, health and society, MAIS-ATSIS and RURAL. Reference lists of included papers were also searched. Articles which applied the ICF within an Indigenous context were selected. Quantitative and qualitative data were extracted and analysed by two independent reviewers. Agreement was reached by consensus. RESULTS: Five articles met the inclusion criteria however two of the articles were not exclusively in an Indigenous context. One article applied the ICF in the context of understanding the health experience and priorities of Indigenous people and a second study had a similar focus but used the revised version of the International Classification of Impairments, Disability and Handicap (ICIDH-2), the predecessor to the ICF. Four of the five papers involved Indigenous Australians, and one of the paper's participants were Indigenous (First Nation) Canadians. CONCLUSION: Literature referring to the use of the ICF with Indigenous populations is limited. The ICF has the potential to help understand the health and functioning experience of Indigenous persons from their perspective. Further research is required to determine if the ICF is a culturally appropriate tool and whether it is able to capture the Indigenous health experience or whether modification of the framework is necessary for use with this population. PMID- 23680088 TI - Obesity is associated with higher long-term mortality after aortic valve replacement with small prosthesis. AB - OBJECTIVE: Although many studies have evaluated the impacts of obesity on various medical treatments, it is not known whether obesity is related to late mortality with implantation of small aortic prosthesis. This study evaluated the effect of obesity on late survival of patients after aortic valve replacement (AVR) with implantation of small aortic prosthesis (size <= 21 mm). METHODS: From January 1998 to December 2008, 536 patients in our institution who underwent primary AVR (307 patients with smaller prostheses) survived the 30 days after surgery. Patients were categorised as normal weight if body mass index (BMI) was <= 25 kg/m(2), as overweight if BMI 25-30 kg/m(2), and as obese if BMI >= 30 kg/m(2). Data were collected at the third-month (M), sixth-M, first-year (Y), third-Y, fifth-Y, and eighth-Y after operation. RESULTS: By multivariable analysis, obesity was a significant independent factor of late mortality (hazard ratio [HR]: 1.59; p=0.006). The obese and overweight groups of patients exhibited lower survival (p<0.001) and a higher proportion in NYHA class III/IV (p<0.01) compared with the normal group. Lower EOAI and higher left ventricular mass index were found in the obese and overweight groups, but we saw no significant variance in LVEF among the three groups. CONCLUSIONS: Obesity was associated with increased late mortality of patients after AVR with implantation of small aortic prosthesis. Being obese or and overweight may also affect the NYHA classification, even in the longer term. PMID- 23680089 TI - Concurrent sexual partnerships among young adults in Cape Town, South Africa: how is concurrency changing? AB - BACKGROUND: The current debate about the role of concurrent sexual partnerships in the spread of HIV is influenced by limited or weak empirical data on concurrency. There is still uncertainty about the most basic statistics and little is known about how concurrency is changing. METHODS: Longitudinal data (n=2958) with repeated concurrency measures were employed to examine the prevalence of individual concurrency (someone has other partners during their most recent sexual partnership) and perceived partner concurrency (someone perceives his or her partner to have other partners) by population group and gender in 2005 and 2009. Individual fixed-effects logit regression models were created to examine factors associated with changes in individual concurrency among Black men and women. RESULTS: The prevalence of individual concurrency increased among Black men who reported having had sex (from 33% in 2005 to 39% in 2009), remained constant among Black women (14%), decreased among Coloured (mixed race) men (from 16% to 8%) and remained low among Coloured women (2% in 2005 and 1% in 2009). Overall, a small decrease in perceived partner concurrency was observed. Changes in individual concurrency were positively associated with changes in perceived partner concurrency among men and women. Among Black women, decreases in household income and finding employment increased the odds of reporting a positive change in individual concurrency. CONCLUSIONS: Race and gender differences in concurrency should be taken into account in future research and HIV prevention initiatives. High and increasing levels of concurrency within most recent partnerships among Black men highlight this group as a potential focus for such efforts. PMID- 23680090 TI - Plasma mercury levels in Hong Kong residents: in relation to fish consumption. AB - Mercury exposure is of particular concern since mercury is a neurotoxin and the developing fetus is most sensitive to its adverse effect. Human blood is routinely used as an indicator for the evaluation of human exposure to Hg. To investigate Hg species in human plasma for Hong Kong residents and the relationship between fish consumption and Hg species in plasma, 151 plasma samples were analyzed for Hg species. The mean values of total Hg (THg) and methyl-mercury (MeHg) concentration in plasma were 0.62 and 0.28 MUg/L, respectively. No significant differences were observed between females and males as well as among age groups. Fish consumption rate was significantly positively correlated with MeHg concentrations in plasma, which demonstrated that plasma could be a biomarker for human MeHg exposure. Two methods were used to estimate human MeHg exposure. One was based on fish MeHg content and fish consumption rate (EDI(Fish)), another was employed by converting MeHg concentration in blood to MeHg exposure amount (EDI(Blood)). A significant positive correlation was observed between EDI(Blood) and EDI(Fish), and no significant difference was found between EDI(Blood) and EDI(Fish). These results demonstrated that fish consumption was the major source of MeHg for humans. PMID- 23680091 TI - A new method for detection and discrimination of Pepino mosaic virus isolates using high resolution melting analysis of the triple gene block 3. AB - Diagnostic methods distinguished different Pepino mosaic virus (PepMV) genotypes but the methods do not detect sequence variation in particular gene segments. The necrotic and non-necrotic isolates (pathotypes) of PepMV share a 99% sequence similarity. These isolates differ from each other at one nucleotide site in the triple gene block 3. In this study, a combination of real-time reverse transcription polymerase chain reaction and high resolution melting curve analysis of triple gene block 3 was developed for simultaneous detection and differentiation of PepMV pathotypes. The triple gene block 3 region carrying a transition A -> G was amplified using two primer pairs from twelve virus isolates, and was subjected to high resolution melting curve analysis. The results showed two distinct melting curve profiles related to each pathotype. The results also indicated that the high resolution melting method could readily differentiate between necrotic and non-necrotic PepMV pathotypes. PMID- 23680092 TI - An updated TaqMan real-time PCR for canine and feline parvoviruses. AB - Canine parvovirus type 2 (CPV-2) emerged in late 1970s from the feline panleukopenia virus (FPLV) and developed, since then, into novel genetic and antigenic variants (CPV-2a, -2b and -2c). Canine and feline parvoviruses cause an acute enteric disease in their hosts, with high level of viral shedding. In this study, a quantitative TaqMan PCR for detection and quantitation of canine and feline parvoviruses in serum and fecal samples was developed. The primers were designed based upon the entire GenBank content for CPV and FPLV. A standard curve was generated, and validation tests were performed using 10-fold serial dilutions of CPV-2 virus in CPV/FPLV-negative feces and CPV/FPLV-negative serum samples. As a result, the 100% detection limit of the PCR was 18 copies of the viral genome per MUl of serum and fecal sample. All canine parvovirus types as well as FPLV were detected. In conclusion, the real-time PCR represents an upgraded and useful tool to identify and quantify canine and feline parvoviruses in different sample matrices. PMID- 23680093 TI - HPV Direct Flow CHIP: a new human papillomavirus genotyping method based on direct PCR from crude-cell extracts. AB - HPV Direct Flow CHIP is a newly developed test for identifying 18 high-risk and 18 low-risk human papillomavirus (HPV) genotypes. It is based on direct PCR from crude-cell extracts, automatic flow-through hybridization, and colorimetric detection. The aim of this study was to evaluate the performance of HPV Direct Flow CHIP in the analysis of 947 samples from routine cervical screening or the follow-up of abnormal Pap smears. The specimens were dry swab samples, liquid based cytology samples, or formalin-fixed paraffin-embedded tissues. The genotype distribution was in agreement with known epidemiological data for the Spanish population. Three different subgroups of the samples were also tested by Linear Array (LA) HPV Genotyping Test (n=108), CLART HPV2 (n=82), or Digene Hybrid Capture 2 (HC2) HPV DNA Test (n=101). HPV positivity was 73.6% by HPV Direct Flow CHIP versus 67% by LA, 65.9% by HPV Direct Flow CHIP versus 59.8% by CLART, and 62.4% by HPV Direct Flow CHIP versus 42.6% by HC2. HPV Direct Flow CHIP showed a positive agreement of 88.6% with LA (k=0.798), 87.3% with CLART (k=0.818), and 68.2% with HC2 (k=0.618). In conclusion, HPV Direct Flow CHIP results were comparable with those of the other methods tested. Although further investigation is needed to compare the performance of this new test with a gold-standard reference method, these preliminary findings evidence the potential value of HPV Direct Flow CHIP in HPV vaccinology and epidemiology studies. PMID- 23680094 TI - Visual detection of Potato Leafroll virus by loop-mediated isothermal amplification of DNA with the GeneFinderTM dye. AB - The most common virus affecting potatoes in the field worldwide is Potato Leafroll virus (PLRV), belonging to the family Luteoviridae, genius Plerovirus. There are several molecular methods to detect PLRV including polymerase chain reaction (PCR), Multiplex AmpliDet RNA and double antibody sandwich ELISA (DAS ELISA). But these techniques take a long time for 3h to two days, requiring sophisticated tools. The aim of this study was to reduce the time required to detect PLRV, using a newly designed loop-mediated isothermal amplification (LAMP) technique requiring only an ordinary water bath or thermoblock. PLRV RNA was extracted from overall 80 infected naturally potato leaves. A set of six novel primers for the LAMP reaction was designed according to the highly conserved sequence of the viral coat protein (CP) gene. LAMP was carried out under isothermal conditions, applying the Bst DNA polymerase enzyme; the LAMP products were detected visually using the GeneFinderTM florescence dye. A positive result using the GeneFinderTM dye was a color change from the original orange to green. Results confirmed LAMP with GeneFinderTM provides a rapid and safe assay for detection of PLRV. Since with other molecular methods, equipping laboratories with a thermocycler or expensive detector systems is unavoidable, this assay was found to be a simple, cost-effective molecular method that has the potential to replace other diagnostic methods in primary laboratories without the need for expensive equipment or specialized techniques. It can also be considered as a reliable alternative viral detection system in further investigations. PMID- 23680095 TI - A quick look at biochemistry: carbohydrate metabolism. AB - In mammals, there are different metabolic pathways in cells that break down fuel molecules to transfer their energy into high energy compounds such as adenosine 5'-triphosphate (ATP), guanosine-5'-triphosphate (GTP), reduced nicotinamide adenine dinucleotide (NADH2), reduced flavin adenine dinucleotide (FADH2) and reduced nicotinamide adenine dinucleotide phosphate (NADPH2). This process is called cellular respiration. In carbohydrate metabolism, the breakdown starts from digestion of food in the gastrointestinal tract and is followed by absorption of carbohydrate components by the enterocytes in the form of monosaccharides. Monosaccharides are transferred to cells for aerobic and anaerobic respiration via glycolysis, citric acid cycle and pentose phosphate pathway to be used in the starvation state. In the normal state, the skeletal muscle and liver cells store monosaccharides in the form of glycogen. In the obesity state, the extra glucose is converted to triglycerides via lipogenesis and is stored in the lipid droplets of adipocytes. In the lipotoxicity state, the lipid droplets of other tissues such as the liver, skeletal muscle and pancreatic beta cells also accumulate triacylglycerol. This event is the axis of the pathogenesis of metabolic dysregulation in insulin resistance, metabolic syndrome and type 2 diabetes. In this paper a summary of the metabolism of carbohydrates is presented in a way that researchers can follow the biochemical processes easily. PMID- 23680096 TI - Health-related quality of life questionnaires in lung cancer trials: a systematic literature review. AB - BACKGROUND: Lung cancer is one of the leading causes of cancer deaths. Treatment goals are the relief of symptoms and the increase of overall survival. With the rising number of treatment alternatives, the need for comparable assessments of health-related quality of life (HRQoL) parameters grows. The aim of this paper was to identify and describe measurement instruments applied in lung cancer patients under drug therapy. METHODS: We conducted a systematic literature review at the beginning of 2011 using the electronic database Pubmed. RESULTS: A total of 43 studies were included in the review. About 17 different measurement instruments were identified, including 5 generic, 5 cancer-specific, 4 lung cancer-specific and 3 symptom-specific questionnaires. In 29 studies at least 2 instruments were used. In most cases these were cancer and lung cancer-specific ones. The most frequently used instruments are the EORTC QLQ-C30 and its lung cancer modules LC13 or LC17. Only 5 studies combined (lung) cancer-specific questionnaires with generic instruments. CONCLUSIONS: The EORTC-C30 and EORTC LC13 are the most frequently used health-related quality of life measurement instruments in pharmacological lung cancer trials. PMID- 23680097 TI - Opinions on Kampo and reasons for using it--results from a cross-sectional survey in three Japanese clinics. AB - BACKGROUND: Traditional Japanese Medicine (Kampo) is often used in Japan, but very little data on its users are available. We investigated who uses Kampo, the reasons and opinions for its use. METHODS: Questionnaire survey in three Japanese outpatient clinics offering Kampo in different settings: Kampo only, Kampo and traditional Chinese medicine, Kampo and Western medicine. Before seeing the doctor, patients were asked about socio-demographic data, medical history, experience with Kampo, general health-related opinions and behaviours, opinions about Western medicine and Kampo, and reasons for Kampo utilization. Descriptive statistics and predictors for Kampo use were calculated. RESULTS: A total of 354 questionnaires were completed. Participants were 50.97 +/- 15.60 (mean +/- SD) years of age, 68% were female. Of all patients, 73% (n = 202) were using Kampo currently and 84% (297) had taken Kampo before. Questions on general health related opinions and behaviour revealed a strong environmental awareness. The most frequent indications for earlier Kampo use were: common cold (36%), gastrointestinal complaints (30%), oversensitivity to cold ("Hi'e-sho"; 29%), stress/anxiety (21%), and shoulder stiffness (20%). Kampo users suffered more often from chronic illnesses (OR 2.88 [1.48-5.58]). Beliefs in underlying philosophy (Wu Xing (adjusted OR 3.08, [1.11-8.55]), Ying and Yang (OR 2.57 [1.15 5.73], a holistic way of seeing the patient (OR 2.17 [1.53-3.08]), and in Kampo efficacy (OR 2.62 [1.66-4.13]) were positively associated with Kampo use. So was, interestingly, conviction of the efficacy of Western medicine (OR 1.87 [1.28 2.74]). Half of the patients had a general preference for a combination of Kampo and Western treatment. CONCLUSIONS: Most patients visiting a clinic that also provided Kampo had previous experience with Kampo. Usage was associated with beliefs in philosophical Kampo concepts and its efficacy. PMID- 23680098 TI - A study on dispersion and characterisation of alpha-mangostin loaded pH sensitive microgel systems. AB - BACKGROUND: alpha-Mangostin was extracted with methanol from the rind of mangosteen fruit and purified by using silica gel column chromatography technique. The compound is characterised using infrared, (13)C and (1)H NMR as well as UV-vis spectroscopy. The alpha-mangostin dispersion in colloidal systems was studied by incorporating it with an ionic microgel, poly (N Isopropylacrylamide)-co-2VP at different pH. RESULT: The DLS result showed the size of microgel-alpha-mangostin mixture declined from 548 nm to 200 nm upon the increment of the pH. Moreover, it was found the morphology of loaded compound depended largely on the nature of the continuous phase of the microgel system. Interestingly, by manipulating the pH, alpha-mangostin tends to form crystal at extremely low pH and transforms into spherical shapes at pH 6. CONCLUSION: This research shows different structures of the alpha-mangostin particle that are attributed by adjusting the pH using microgel systems as a template. PMID- 23680099 TI - Investigations for neonatal seizures. AB - Seizures during the neonatal period are always medical emergencies. Apart from the need for rapid anticonvulsive treatment, the underlying condition is often not immediately obvious. In the search for the correct diagnosis, a thorough history, clinical examination, laboratory work-up, neurophysiological and neuroradiological investigations are all essential. A close collaboration between neonatologists, neuropaediatricians, laboratory specialists, neurophysiologists and radiologists facilitates the adequate care of the infant. PMID- 23680100 TI - Fabrication of nanostructured ZnO film as a hole-conducting layer of organic photovoltaic cell. AB - We have investigated the effect of fibrous nanostructured ZnO film as a hole conducting layer on the performance of polymer photovoltaic cells. By increasing the concentration of zinc acetate dihydrate, the changes of performance characteristics were evaluated. Fibrous nanostructured ZnO film was prepared by sol-gel process and annealed on a hot plate. As the concentration of zinc acetate dihydrate increased, ZnO fibrous nanostructure grew from 300 to 600 nm. The obtained ZnO nanostructured fibrous films have taken the shape of a maze-like structure and were characterized by UV-visible absorption, scanning electron microscopy, and X-ray diffraction techniques. The intensity of absorption bands in the ultraviolet region was increased with increasing precursor concentration. The X-ray diffraction studies show that the ZnO fibrous nanostructures became strongly (002)-oriented with increasing concentration of precursor. The bulk heterojunction photovoltaic cells were fabricated using poly(3-hexylthiophene-2,5 diyl) and indene-C60 bisadduct as active layer, and their electrical properties were investigated. The external quantum efficiency of the fabricated device increased with increasing precursor concentration. PMID- 23680101 TI - Determinants of unequal HIV care access among people living with HIV in Peru. AB - BACKGROUND: Equity in access to health care among people living with HIV (PLHA) has not been extensively studied in Peru despite the fact there is significant social diversity within this group. We aimed to assess the extent to which health care provision to PLHA, including ARVT, was equitable and, if appropriate, identify factors associated with lower access. METHODS: We conducted a survey among adult PLHA in four cities in Peru, recruited through respondent-driven sampling (RDS), to collect information on socio-demographic characteristics, social network size, household welfare, economic activity, use of HIV-related services including ARV treatment, and health-related out-of-pocket expenses. RESULTS: Between September 2008 and January 2009, 863 individuals from PLHA organizations in four cities of Peru were enrolled. Median age was 35 (IQR = 29 41), and mostly male (62%). Overall, 25% reported to be gay, 11% bisexual and 3% transgender. Most PLHA (96%) reported access to some kind of HIV-related health service, and 84% were receiving those services at a public facility. Approximately 85% of those reporting access to care were receiving antiretroviral treatment (ARV), and 17% of those not in treatment already had indication to start treatment. Among those currently on ARV, 36% percent reported out-of-pocket expenses within the last month. Transgender identity and age younger than 35 years old, were associated with lower access to health care. CONCLUSIONS: Our findings contribute to a better social and demographic characterization of the situation of PLHAs, their access to HIV care and their source of care, and provide an assessment of equity in access. In the long term, it is expected that HIV care access, as well as its social determinants, will impact on the morbidity and mortality rates among those affected by the HIV/AIDS epidemic. HIV care providers and program managers should further characterize the barriers to healthcare access and develop strategies to resolve them by means of policy change, for the benefit of the health service users and as part of the national response to the HIV/AIDS epidemic within a human rights framework. PMID- 23680102 TI - Regenerating the injured kidney with human umbilical cord mesenchymal stem cell derived exosomes. AB - Transplantation of adult stem cells is being used to facilitate repair or regeneration of damaged or diseased tissues. However, in many cases, the therapeutic effects of the injected stem cells are mediated by factors secreted by stem cells and not by differentiation of the transplanted stem cells. Recent reports have identified a class of microvesicles, termed exosomes, released by stem cells that are able to confer therapeutic effects on injured renal and cardiac tissue. In this issue of Stem Cell Research & Therapy, Zhou and colleagues demonstrate the ability of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs), but not non-stem cell-derived exosomes, to improve acute kidney injury induced by cisplatin in rats. The authors demonstrate that hucMSC exosomes can reduce cisplatin-mediated renal oxidative stress and apoptosis in vivo and increase renal epithelial cell proliferation in culture. These results suggest that stem cell-derived exosomes, which are easy to isolate and safer to use than the parental stem cells, could have significant clinical utility. PMID- 23680103 TI - The functional coding variant Asn107Ile of the neuropeptide S receptor gene (NPSR1) influences age at onset of obsessive-compulsive disorder. AB - Neuropeptide S (NPS) is a novel central acting neuropeptide that modulates several brain functions. NPS has shown strong anxiolytic-like effects and interactions with other central transmitter systems, including serotonin and glutamate. A coding variation (Asn107Ile) of the NPS receptor gene (NPSR1) was associated with panic disorder and schizophrenia. Based on these encouraging findings, the present study aimed at exploring a potential role of NPSR1 in obsessive-compulsive disorder (OCD). A sample of 232 OCD patients was successfully genotyped for the NPSR1 Asn107Ile variant (rs324981). Age at onset was taken into account to address the heterogeneity of the OCD phenotype. The NPSR1 genotype significantly affected age at onset of the OCD patients, with a mean age at onset approximately 4 yr earlier in homozygous carriers of the low functioning Asn107 variant compared to patients with at least one Ile107 variant (p=0.032). Case-control analyses with 308 healthy control subjects reveal a highly significant association of the Asn107 variant with early onset OCD (odds ratio=2.36, p=0.0004) while late onset OCD or the OCD group as a whole were unrelated to the NPSR1 genotype. Based on our association finding relating NPSR1 genotype to early onset OCD, we suggest a differential role of the NPS system in OCD. In particular, the early onset OCD subtype seems to be characterized by a genetically driven low NPS tone, which might affect other OCD-related transmitter systems, including the serotonin and glutamate systems. In agreement with preclinical research, we suggest that NPS may be a promising pharmacological candidate with anti-obsessional properties. PMID- 23680105 TI - Thrombin split products (prothrombin fragment 1 + 2) in urine in patients with suspected deep vein thrombosis admitted for radiological verification. AB - INTRODUCTION: The appearance of prothrombin fragment 1 + 2 (F1 + 2) in urine has been associated with postoperative hypercoagulability and thromboembolism. We wanted to assess if F1 + 2 was released in urine (uF1 + 2) in patients with procoagulant disorders, and if higher levels were found in patients with radiological verified deep vein thrombosis (DVT). MATERIALS AND METHODS: Consecutive patients were interviewed on comorbidities and medications. An unselected total cohort (n = 534) and a control cohort (n = 177) were analysed. A urine sample (10 ml) was collected and snap frozen before levels of uF1 + 2 were measured with an ELISA kit. Visualisation of DVT was done with compression ultrasound, supplied with venography when feasible. All patients were followed up for 3-6 months. RESULTS: DVT was diagnosed in 108/534 patients. Statistical significant higher uF1 + 2 levels were found in patients with DVT (p < 0.001), in DVT positive patients with ongoing malignancy (p = 0.034) and in pregnant women compared to the control cohort (p < 0.001). Non-significant increased urine concentrations were found in DVT positive vs. DVT negative patients with infections and traumas. CONCLUSIONS: Levels of uF1 + 2 was associated with DVT both in the total cohort and in the control cohort as well as in most patients with coexisting conditions. PMID- 23680104 TI - The novel BH3 alpha-helix mimetic JY-1-106 induces apoptosis in a subset of cancer cells (lung cancer, colon cancer and mesothelioma) by disrupting Bcl-xL and Mcl-1 protein-protein interactions with Bak. AB - BACKGROUND: It has been shown in many solid tumors that the overexpression of the pro-survival Bcl-2 family members Bcl-2/Bcl-xL and Mcl-1 confers resistance to a variety of chemotherapeutic agents. We designed the BH3 alpha-helix mimetic JY-1 106 to engage the hydrophobic BH3-binding grooves on the surfaces of both Bcl-xL and Mcl-1. METHODS: JY-1-106-protein complexes were studied using molecular dynamics (MD) simulations and the SILCS methodology. We have evaluated the in vitro effects of JY-1-106 by using a fluorescence polarization (FP) assay, an XTT assay, apoptosis assays, and immunoprecipitation and western-blot assays. A preclinical human cancer xenograft model was used to test the efficacy of JY-1 106 in vivo. RESULTS: MD and SILCS simulations of the JY-1-106-protein complexes indicated the importance of the aliphatic side chains of JY-1-106 to binding and successfully predicted the improved affinity of the ligand for Bcl-xL over Mcl-1. Ligand binding affinities were measured via an FP assay using a fluorescently labeled Bak-BH3 peptide in vitro. Apoptosis induction via JY-1-106 was evidenced by TUNEL assay and PARP cleavage as well as by Bax-Bax dimerization. Release of multi-domain Bak from its inhibitory binding to Bcl-2/Bcl-xL and Mcl-1 using JY-1 106 was detected via immunoprecipitation (IP) western blotting.At the cellular level, we compared the growth proliferation IC50s of JY-1-106 and ABT-737 in multiple cancer cell lines with various Bcl-xL and Mcl-1 expression levels. JY-1 106 effectively induced cell death regardless of the Mcl-1 expression level in ABT-737 resistant solid tumor cells, whilst toxicity toward normal human endothelial cells was limited. Furthermore, synergistic effects were observed in A549 cells using a combination of JY-1-106 and multiple chemotherapeutic agents. We also observed that JY-1-106 was a very effective agent in inducing apoptosis in metabolically stressed tumors. Finally, JY-1-106 was evaluated in a tumor bearing nude mouse model, and was found to effectively repress tumor growth. Strong TUNEL signals in the tumor cells demonstrated the effectiveness of JY-1 106 in this animal model. No significant side effects were observed in mouse organs after multiple injections. CONCLUSIONS: Taken together, these observations demonstrate that JY-1-106 is an effective pan-Bcl-2 inhibitor with very promising clinical potential. PMID- 23680106 TI - Locally advanced prostate cancer: current controversies and optimisation opportunities. AB - Prostate cancer is the most common malignancy in men worldwide. The rate of patients presenting with locally advanced prostate cancer has declined in recent decades, mainly due to prostate-specific antigen screening, but the management of these patients still remains controversial. Current literature suggests that the standard of care for these patients is a combination approach with radiation therapy and androgen deprivation therapy. However, there remain many unresolved issues, including the role of dose-escalated radiation therapy, the additional benefit of surgery and the role of systemic therapy, both standard chemotherapeutic agents and novel agents. Furthermore, in the era of personalised medicine, additional research is needed to evaluate the role of biomarkers to better predict the risk of local and systemic relapse in this population. PMID- 23680107 TI - Equine influenza--a global perspective. AB - To date, equine influenza outbreaks have been reported all over the world with the exception of a small number of island nations including New Zealand and Iceland. Influenza is endemic in Europe and North America and is considered to be of potentially major economic significance to the equine industry worldwide. The importation of subclinically infected vaccinated horses, and inadequate quarantine procedures have resulted in several major outbreaks in susceptible populations for example, in Australia (2007) when more than 76,000 horses on over 10,000 properties were reported as infected. This review summarises the current understanding of, and recent research on, equine influenza, including epidemiology, pathogenesis, clinical characteristics, laboratory diagnosis, management and prevention. Recent advances in diagnostic techniques are discussed as are the merits of different vaccination regimes. PMID- 23680108 TI - Expression and activity of recombinant proaerolysin derived from Aeromonas hydrophila cultured from diseased channel catfish. AB - Aerolysin is one of the putative toxins in extracellular products (ECP) produced by Aeromonas hydrophila, an important pathogen of catfish. To better understand the molecular mechanism and mode of action of this toxin, proaerolysin-coding gene was cloned from the genomic DNA of an A. hydrophila strain, cultured from diseased channel catfish, and heterologously expressed in E. coli. Functional recombinant proaerolysin was obtained, revealing some unique properties. The purified recombinant proaerolysin was inactive but could be activated by treatment with furin, trypsin, and ECP although different treatments produced different cleavage profiles and resulted in differential hemolytic and cytotoxic activities. The highest activity was observed from aerolysin processed by furin while treatment of proaerolysin with trypsin and ECP resulted in reduced activities. The unprocessed proaerolysin, though not hemolytic in vitro, had the same cytopathic effect on cultured walking catfish gill cells as the furin processed had. In in vivo assay, the recombinant proaerolysin was found to be lethal to catfish when injected via intraperitoneal (IP) route. The lethal toxicity was acute and dose-dependent, as observed in IP injection of live A. hydrophila. This is the first recombinant proaerolysin confirmed to be a virulence factor; the recombinant protein could be used to further evaluate virulence, pathogenicity and antigenicity associated with A. hydrophila infection. PMID- 23680109 TI - Mycoplasma hyopneumoniae: from disease to vaccine development. AB - Mycoplasma hyopneumoniae is the etiological agent of swine enzootic pneumonia (EP), a disease that affects swine production worldwide. Vaccination is the most cost-effective strategy for the control and prevention of the disease. Despite efforts to control M. hyopneumoniae infection, significant economic losses in pig production continue to occur. The results of genome-based research have the potential to help understand the biology and pathogenesis of M. hyopneumoniae, and contribute to the development of more effective vaccines and diagnostic tests. In this review, the characteristics of M. hyopneumoniae related to pathogenesis and control measures will be discussed. Special emphasis will be placed on vaccination strategies that have been proposed with the use of reverse vaccinology approaches. PMID- 23680110 TI - Surrogate endpoints: can size of effect mitigate perplexity? PMID- 23680112 TI - A survey to examine patient awareness, knowledge, and perceptions regarding the risks and consequences of surgical site infections. AB - We surveyed patients to determine awareness and knowledge regarding risks and consequences of and prevention of surgical site infection (SSI), and we found that 26% of respondents thought that education for SSI prevention could be improved and that 16% could not recall discussing SSI risks and prevention with a health care worker at all. Only 60% of patients recalled receiving an informational flyer in the hospital. Our results show that better educational and engagement interventions incorporating patient preferences are needed to promote awareness and patient engagement regarding SSI prevention. PMID- 23680113 TI - Appearance of osteolysis with melorheostosis: redefining the disease or a new disorder? A novel case report with multimodality imaging. AB - We present a case report of melorheostosis with the novel radiographic finding of underlying cortical resorption. A number of radiographic patterns of melorheostosis have been described; however, the combination of new bone formation and resorption of the original cortex appears unique. Although the presence of underlying lysis has been postulated in published studies, direct radiographic evidence of bony resorption in melorheostosis has not been reported. These findings can be subtle and might go unnoticed using standard imaging. An in depth review of the radiographic features is presented, including multimodality imaging with magnetic resonance imaging and computed tomography. PMID- 23680114 TI - Modified Evans peroneus brevis lateral ankle stabilization for balancing varus ankle contracture during total ankle replacement. AB - Lateral ankle instability is frequently encountered when performing total ankle replacement and remains a challenge. In the present techniques report, I have described a modification of the Evans peroneus brevis tendon lateral ankle stabilization harvested through limited incisions using simple topographic anatomic landmarks. The harvested peroneus brevis is then transferred either to the anterior distal tibia concomitantly with total ankle replacement or through the tibia when performed after total ankle replacement and secured with plate and screw fixation. This modified Evans peroneus brevis tendon is useful in providing lateral ankle stability during or after primary and revision total ankle replacement. PMID- 23680111 TI - Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: a re-analysis of meta-analyses of individual patients' data. AB - BACKGROUND: The gold standard endpoint in clinical trials of chemotherapy and radiotherapy for lung cancer is overall survival. Although reliable and simple to measure, this endpoint takes years to observe. Surrogate endpoints that would enable earlier assessments of treatment effects would be useful. We assessed the correlations between potential surrogate endpoints and overall survival at individual and trial levels. METHODS: We analysed individual patients' data from 15,071 patients involved in 60 randomised clinical trials that were assessed in six meta-analyses. Two meta-analyses were of adjuvant chemotherapy in non-small cell lung cancer, three were of sequential or concurrent chemotherapy, and one was of modified radiotherapy in locally advanced lung cancer. We investigated disease-free survival (DFS) or progression-free survival (PFS), defined as the time from randomisation to local or distant relapse or death, and locoregional control, defined as the time to the first local event, as potential surrogate endpoints. At the individual level we calculated the squared correlations between distributions of these three endpoints and overall survival, and at the trial level we calculated the squared correlation between treatment effects for endpoints. FINDINGS: In trials of adjuvant chemotherapy, correlations between DFS and overall survival were very good at the individual level (rho(2)=0.83, 95% CI 0.83-0.83 in trials without radiotherapy, and 0.87, 0.87-0.87 in trials with radiotherapy) and excellent at trial level (R(2)=0.92, 95% CI 0.88-0.95 in trials without radiotherapy and 0.99, 0.98-1.00 in trials with radiotherapy). In studies of locally advanced disease, correlations between PFS and overall survival were very good at the individual level (rho(2) range 0.77-0.85, dependent on the regimen being assessed) and trial level (R(2) range 0.89-0.97). In studies with data on locoregional control, individual-level correlations were good (rho(2)=0.71, 95% CI 0.71-0.71 for concurrent chemotherapy and rho(2)=0.61, 0.61 0.61 for modified vs standard radiotherapy) and trial-level correlations very good (R(2)=0.85, 95% CI 0.77-0.92 for concurrent chemotherapy and R(2)=0.95, 0.91 0.98 for modified vs standard radiotherapy). INTERPRETATION: We found a high level of evidence that DFS is a valid surrogate endpoint for overall survival in studies of adjuvant chemotherapy involving patients with non-small-cell lung cancers, and PFS in those of chemotherapy and radiotherapy for patients with locally advanced lung cancers. Extrapolation to targeted agents, however, is not automatically warranted. FUNDING: Programme Hospitalier de Recherche Clinique, Ligue Nationale Contre le Cancer, British Medical Research Council, Sanofi Aventis. PMID- 23680115 TI - Particular catastrophic antiphospholipid syndrome, on the sole surgical site after breast reduction. AB - A 20-year-old woman treated with vitamin K antagonist for antiphospholipid syndrome (APS) (pulmonary embolisms at age 15) was admitted for breast reduction after bridging therapy. At 2 days post-surgery haematomas appeared on the surgical site and anticoagulant therapy was withheld. She developed a skin and breast necrosis leading to the diagnosis of catastrophic APS. Despite medical treatment (anticoagulant therapy, corticosteroids and intravenous immunoglobulins) and surgery, necrosis continued. After 2 weeks of negative pressure wound therapy (V.A.C.((r)) TherapyTM) the patient improved, mammary tissues were alive, well vascularised and budding. Breast reconstruction was then initiated. Artificial dermis graft (MatriDerm((r)) 2 mm) was applied, and 3 weeks later the apposition of split-thickness skin graft on it. Six months later, results of the surgery were good and the patient was satisfied. PMID- 23680116 TI - Radiation-induced craniofacial deformities: a new classification and management algorithm. AB - Little is written about the spectrum of late radiation-induced craniofacial abnormalities and the guidelines for treating these abnormalities. The clinical records of 13 patients (eight males and five females) who received childhood craniofacial radiation between birth and 11 years of age and who subsequently had reconstructive surgery were reviewed. Eleven patients had their irradiation at the age from 1 to 5 years. The other two patients received their treatment at a relatively older age (9 and 11 years). Their deformities ranged from isolated soft-tissue deficiency with no or minimal bony deficiency to cases having osseous deformities with or without soft-tissue deficiency but still the normal or near normal craniofacial form can be obtained with surgical intervention and the outermost extreme of the deformity is the patients whose normal or near-normal craniofacial form and function cannot be regained even with much sophisticated surgeries. Our new classification is based on two factors: the tissue component of the deformity and the possibility of regaining a normal or near-normal craniofacial form and function with the planned surgical intervention. Based on this classification, a new treatment algorithm was created. PMID- 23680117 TI - Off-resonance magnetoresistance spike in irradiated ultraclean 2D electron systems. AB - : We report on the theoretical studies of a recently discovered strong radiation induced magnetoresistance spike obtained in ultraclean two-dimensional electron systems at low temperatures. The most striking feature of this spike is that it shows up on the second harmonic of the cyclotron resonance. We apply the radiation-driven electron orbits model in the ultraclean scenario. Accordingly, we calculate the new average advanced distance by the electron in a scattering event which will define the unexpected resonance spike position. Calculated results are in good agreement with experiments. PMID- 23680118 TI - Involvement of N-methyl-D-aspartate glutamate receptor and nitric oxide in cardiovascular responses to dynamic exercise in rats. AB - Dynamic exercise evokes sustained cardiovascular responses, which are characterized by arterial pressure and heart rate increases. Although it is well accepted that there is central nervous system mediation of cardiovascular adjustments during exercise, information on the role of neural pathways and signaling mechanisms is limited. It has been reported that glutamate, by acting on NMDA receptors, evokes the release of nitric oxide through activation of neuronal nitric oxide synthase (nNOS) in the brain. In the present study, we tested the hypothesis that NMDA receptors and nNOS are involved in cardiovascular responses evoked by an acute bout of exercise on a rodent treadmill. Moreover, we investigated possible central sites mediating control of responses to exercise through the NMDA receptor-nitric oxide pathway. Intraperitoneal administration of the selective NMDA glutamate receptor antagonist dizocilpine maleate (MK-801) reduced both the arterial pressure and heart rate increase evoked by dynamic exercise. Intraperitoneal treatment with the preferential nNOS inhibitor 7 nitroindazole reduced exercise-evoked tachycardiac response without affecting the pressor response. Moreover, treadmill running increased NO formation in the medial prefrontal cortex (MPFC), bed nucleus of the stria teminalis (BNST) and periaqueductal gray (PAG), and this effect was inhibited by systemic pretreatment with MK-801. Our findings demonstrate that NMDA receptors and nNOS mediate the tachycardiac response to dynamic exercise, possibly through an NMDA receptor-NO signaling mechanism. However, NMDA receptors, but not nNOS, mediate the exercise evoked pressor response. The present results also provide evidence that MPFC, BNST and PAG may modulate physiological adjustments during dynamic exercise through NMDA receptor-NO signaling. PMID- 23680119 TI - Riluzole attenuates excitatory amino acid transporter type 3 activity in Xenopus oocytes via protein kinase C inhibition. AB - This study aimed to evaluate the effect of riluzole on the activity of excitatory amino acid transporter type 3 (EAAT3), a neuronal glutamate transporter, and to investigate the role of protein kinase C (PKC) in this effect. EAAT3 expression was induced in Xenopus oocytes by injecting EAAT3 mRNA. Using the two-electrode voltage clamping method, membrane currents were recorded before, during, and after applying l-glutamate (30 MUM) in the absence and presence of prior incubation with riluzole (0.3-100 MUM). To study the effect of PKC on the riluzole-induced change in EAAT3 activity, oocytes were preincubated with 100 MUM phorbol-12-myristate-13-acetate (PMA), a PKC activator, or PKC inhibitors (2 uM staurosporine and 100 uM chelerythrine) before the recording. Responses were quantified by integrating current traces and are reported in microCoulombs (MUC). Riluzole reduced EAAT3 activity in a concentration-dependent manner (0.3-100 MUM). Treatment of oocytes with PMA significantly increased the baseline and riluzole-reduced EAAT activity (P<0.05). In addition, treatment of oocytes with PKC inhibitors reduced basal transporter currents, but did not show a further significant decrease in the riluzole-reduced EAAT3 activity. These results suggest that riluzole reduces EAAT3 activity through PKC inhibition. PMID- 23680120 TI - Relationship between testicular sperm extraction and varicocelectomy in patients with varicocele and nonobstructive azoospermia. AB - OBJECTIVE: To evaluate the effect of varicocelectomy on sperm retrieval at testicular sperm extraction (TESE) and at spermiograms in patients with nonobstructive azoospermia. MATERIALS AND METHODS: An observational study was conducted from April 2008 to December 2011. The study included men with a clinical diagnosis of nonobstructive azoospermia with a history of clinical unilateral varicocele (only grade III). After providing consent, the patients were treated with 2 different strategies according to the timing of varicocelectomy: group 1, varicocelectomy before microsurgical TESE (3 months); and group 2, varicocelectomy during microsurgical TESE. At 6 months after varicocelectomy, we evaluated the semen analysis findings for all patients. All patients underwent subinguinal microsurgical varicocelectomy. We also evaluated the percentage of sperm retrieval during TESE. RESULTS: During the study period, 35 patients were enrolled. Group 1 included 19 patients and group 2, 16 patients. The sperm retrieval rate during the spermiograms was significantly greater in group 1 (57.8%) than in group 2 (37.5%). The percentage of sperm retrieval during TESE between the 2 groups was significantly greater in group 1 (57.8%) than in group 2 (27%; P <.05). CONCLUSION: Our results have suggested that varicocele repair significantly increases the sperm retrieval rate in patients with clinical varicocele and nonobstructive azoospermia at both TESE and spermiogram. PMID- 23680121 TI - Human 4F5 single-chain Fv antibody recognizing a conserved HA1 epitope has broad neutralizing potency against H5N1 influenza A viruses of different clades. AB - Influenza A viruses present a significant threat to public health worldwide. High affinity human scFv antibodies against a conserved epitope can potentially provide immunity to diverse viruses and protect against future pandemic viruses. A library of phage-displayed human scFv containing 6.0*10(8) members was generated from lymphocytes of H5N1 virus vaccinated individuals. Using the recombinant H5N1 virus hemagglutinin ectodomain (HA1), 4F5 scFv was identified with neutralizing activity against both clade 2 and 9 H5N1 viruses. In embryonated chicken eggs, the antiviral activity of 4F5 scFv conferred a 100% survival rate and at least a 62.5% survival rate against different clades of H5N1 viruses by pre-treatment and post-treatment, respectively. 4F5 scFv belongs to the VH-3-43 family according to the IMGT database, and a peptide (76)WLLGNP(81) containing half of an alpha-helix in HA1 was identified as the binding pocket. The conserved binding epitope of this novel broadly neutralizing scFv may become key in the design and implementation of vaccines or RNA interference against H5N1 viruses. PMID- 23680123 TI - Separation of cognitive domains to improve prediction of progression from mild cognitive impairment to Alzheimer's disease. AB - Addressing causes of heterogeneity in cognitive outcomes is becoming more critical as Alzheimer's disease (AD) research focuses on earlier disease. One of the causes of this heterogeneity may be that individuals with deficiencies in different cognitive domains may perform similarly on a neuropsychological (NP) test for very different reasons. Tatsuoka and colleagues have applied a Bayesian model in order to integrate knowledge about cognitive domains relevant to each NP test with the observed outcomes from the Alzheimer's Disease Neuroimaging Initiative (ADNI) mild cognitive impairment data. This approach resulted in better prediction of AD diagnosis than more traditional approaches. PMID- 23680122 TI - "Leaner and less fit" children have a better cardiometabolic profile than their "heavier and more fit" peers: the Healthy Growth Study. AB - BACKGROUND AND AIMS: To examine differences in cardiometabolic risk factors between children of different BMI and fitness levels. METHODS AND RESULTS: From a representative sample of 1222 boys and 1188 girls, aged 9-13 years, anthropometric, body composition, physical activity, cardiorespiratory fitness, biochemical and blood pressure data was collected. The prevalence of overweight and obesity was 29.9% and 11.8% respectively. In both genders, plasma HDL cholesterol concentration was higher in the 'leaner and less fit' group (lowest quartile of BMI and lowest quartile of fitness) compared to the 'heavier and more fit' (highest quartile of BMI and highest quartile of fitness) and intermediate (all other children) groups (p < 0.05). Furthermore, the 'leaner and less fit' groups in both genders had lower triacylglycerol concentration, total-to-HDL cholesterol ratio, HOMA-IR, insulin and systolic blood pressure levels compared to the 'heavier and more fit' and/or intermediate groups. Similar trends were observed for hypertension in boys and insulin resistance for both genders. Finally, the effect size of being 'leaner and less fit' on serum levels of cardiometabolic risk indices was mainly small to medium (i.e. Cohen's d 0.2-0.5). CONCLUSION: Leaner and less fit boys and girls had better cardiometabolic risk profiles than their heavier and more fit peers, probably suggesting a higher importance of leanness over fitness in children from a cardiometabolic health benefit perspective. PMID- 23680124 TI - Diagnosis of latent tuberculosis infection among HIV-infected clients in Far North Queensland: use of an interferon-gamma release assay. AB - Latent Mycobacterium tuberculosis infection is a significant risk for those infected with HIV. We examined the use of an interferon-gamma release assay for the diagnosis of latent tuberculosis among HIV-infected clients attending two sexual health services in Far North Queensland. Of 240 clients tested, 19 returned a positive result (7.9%, 95% confidence interval (CI): 4.5-11.3%) and three were indeterminate (1.3%, 95% CI: -0.2%-2.7%). Low CD4 count was found to be significantly associated with an indeterminate test result (P=0.004). However, we found no significant association between test results and client demographics, self-reported prior tuberculosis infection, Bacille Calmette-Guerin vaccine status or selected tuberculosis risk factors (P-values=0.2-0.9). PMID- 23680125 TI - Enantioselective hydrolyzation and photolyzation of dufulin in water. AB - BACKGROUND: Dufulin is a novel, highly effective antiviral agent that activatives systemic acquired resistance of plants. This compound is widely used in China to prevent and control viral diseases in tobacco, vegetable and rice. Dufulin can treat plants infected by the tobacco mosaic virus and the cucumber mosaic virus. However, the achiral analysis and residue determination of dufulin remain underdeveloped because of its high enantioselectivity rates and high control costs. The enantioselectivity of an antiviral compound is an important factor that should be considered when studying the effect of chiral pesticides on the environment. The enantioselective degradation of dufulin in water remains an important objective in pesticide science. RESULTS: The configuration of dufulin enantiomers was determined in this study based on its circular dichroism spectra. The S-(+)-dufulin and R-(-)-dufulin enantiomers were separated and identified using an amylose tris-(3,5-dimethylphenylcarbamate) chiral column by normal phase high-performance liquid chromatography. The degradation of the rac-dufulin racemate and its separate enantiomers complied with first-order reaction kinetics and demonstrated acceptable linearity. The enantioselective photolysis of rac dufulin allowed for the faster degradation of R-(-)-dufulin, as compared with S (+)-dufulin. However, S-(+)-dufulin was hydrolyzed faster than its antipode. CONCLUSION: The photolysation and hydrolyzation of dufulin in water samples normally complied with the first-order kinetics and demonstrated acceptable linearity (R2>0.66). A preferential photolysation of the R-(-)-enantiomer was observed in water samples. Moreover, the S-(+)-enantiomer was hydrolyzed faster than its antipode. PMID- 23680126 TI - Antiprotozoal and antimycobacterial activities of Persea americana seeds. AB - BACKGROUND: Persea americana seeds are widely used in traditional Mexican medicine to treat rheumatism, asthma, infectious processes as well as diarrhea and dysentery caused by intestinal parasites. METHODS: The chloroformic and ethanolic extracts of P. americana seeds were prepared by maceration and their amoebicidal, giardicidal and trichomonicidal activity was evaluated. These extracts were also tested against Mycobacterium tuberculosis H37Rv, four mono resistant and two multidrug resistant strains of M. tuberculosis as well as five non tuberculosis mycobacterium strains by MABA assay. RESULTS: The chloroformic and ethanolic extracts of P. americana seeds showed significant activity against E. histolytica, G. lamblia and T. vaginalis (IC50 <0.634 MUg/ml). The chloroformic extract inhibited the growth of M. tuberculosis H37Rv, M. tuberculosis MDR SIN 4 isolate, three M. tuberculosis H37Rv mono-resistant reference strains and four non tuberculosis mycobacteria (M. fortuitum, M. avium, M. smegmatis and M. absessus) showing MIC values <=50 MUg/ml. Contrariwise, the ethanolic extract affected only the growth of two mono-resistant strains of M. tuberculosis H37Rv and M. smegmatis (MIC <=50 MUg/ml). CONCLUSIONS: The CHCl3 and EtOH seed extracts from P. americana showed amoebicidal and giardicidal activity. Importantly, the CHCl3 extract inhibited the growth of a MDR M. tuberculosis isolate and three out of four mono-resistant reference strains of M. tuberculosis H37Rv, showing a MIC = 50 MUg/ml. This extract was also active against the NTM strains, M. fortuitum, M. avium, M. smegmatis and M. abscessus, with MIC values <50 MUg/ml. PMID- 23680128 TI - Oxidized eicosapentaenoic acids more potently reduce LXRalpha-induced cellular triacylglycerol via suppression of SREBP-1c, PGC-1beta and GPA than its intact form. AB - Dietary polyunsaturated fatty acids (PUFA), especially eicosapentaenoic acid (EPA), improve lipid metabolism and contribute to the prevention of vascular diseases such as atherosclerosis. However, EPA in the diet is easily oxidized at room temperature and several types of oxidized EPA (OEPA) derivatives are generated. To compare the efficiencies of OEPAs on lipid metabolism with EPA, human hepatocellular liver carcinoma cell line (HepG2) was treated with EPA or OEPAs and their effects on lipid metabolism related genes were studied. OEPAs more potently suppressed the expression of sterol-responsive element-binding protein (SREBP)-1c, a major transcription factor that activates the expression of lipogenic genes, and its downstream target genes than did EPA under conditions of lipid synthesis enhanced by T0901317, a synthetic liver X receptor (LXR) agonist. Furthermore, PGC-1beta, a coactivator of both LXRalpha and SREBP-1, was markedly down-regulated by OEPAs compared with EPA. The treatment of OEPAs also significantly down-regulated the expression of glycerol-3-phosphate acyltransferase (GPA), the initiating enzyme in triacylglycerol (TG) synthesis, more than EPA. Therefore, the advantageous effects of OEPAs on cardiovascular diseases might be due to their SREBP-1c, PGC-1beta and GPA mediated ameliorating effects. PMID- 23680127 TI - Efficacy and safety of active negative pressure peritoneal therapy for reducing the systemic inflammatory response after damage control laparotomy (the Intra peritoneal Vacuum Trial): study protocol for a randomized controlled trial. AB - BACKGROUND: Damage control laparotomy, or abbreviated initial laparotomy followed by temporary abdominal closure (TAC), intensive care unit resuscitation, and planned re-laparotomy, is frequently used to manage intra-abdominal bleeding and contamination among critically ill or injured adults. Animal data suggest that TAC techniques that employ negative pressure to the peritoneal cavity may reduce the systemic inflammatory response and associated organ injury. The primary objective of this study is to determine if use of a TAC dressing that affords active negative pressure peritoneal therapy, the ABThera Open Abdomen Negative Pressure Therapy System, reduces the extent of the systemic inflammatory response after damage control laparotomy for intra-abdominal sepsis or injury as compared to a commonly used TAC method that provides potentially less efficient peritoneal negative pressure, the Barker's vacuum pack. METHODS/DESIGN: The Intra-peritoneal Vacuum Trial will be a single-center, randomized controlled trial. Adults will be intraoperatively allocated to TAC with either the ABThera or Barker's vacuum pack after the decision has been made by the attending surgeon to perform a damage control laparotomy. The study will use variable block size randomization. On study days 1, 2, 3, 7, and 28, blood will be collected. Whenever possible, peritoneal fluid will also be collected at these time points from the patient's abdomen or TAC device. Luminex technology will be used to quantify the concentrations of 65 mediators relevant to the inflammatory response in peritoneal fluid and plasma. The primary endpoint is the difference in the plasma concentration of the pro-inflammatory cytokine IL-6 at 24 and 48 h after TAC dressing application. Secondary endpoints include the differential effects of these dressings on the systemic concentration of other pro-inflammatory cytokines, collective peritoneal and systemic inflammatory mediator profiles, postoperative fluid balance, intra-abdominal pressure, and several patient important outcomes, including organ dysfunction measures and mortality. DISCUSSION: Results from this study will improve understanding of the effect of active negative pressure peritoneal therapy after damage control laparotomy on the inflammatory response. It will also gather necessary pilot information needed to inform design of a multicenter trial comparing clinical outcomes among patients randomized to TAC with the ABThera versus Barker's vacuum pack. TRIAL REGISTRATION: ClinicalTrials.gov identifier http://www.clicaltrials.gov/ct2/show/NCT01355094. PMID- 23680129 TI - The dual role of mesenchymal stem cells in tumor progression. AB - Mesenchymal stem cells (MSCs) have attracted increasing interest in the field of oncology because of their inherent capacity to migrate and home tumor tissues. The remarkable tropism of MSCs for tumor microenvironments has been exploited in order to use these cells as cellular vehicles to deliver gene therapies or anticancer agents. At functional levels, these cells display chemotactic properties similar to those of immune cells in response to tissue insult and inflammation and secrete a broad range of bioactive biomolecules with an impact on tumor development and a progression through direct actions on tumor cells and the stromal microenvironment. However, the exact contribution of such interactions in tumor progression has not yet been fully clarified, and some concerns remain regarding whether MSCs exert a tumor-suppressive effect or, on the contrary, favor tumor growth. The article by Keramidas and colleagues in this issue of Stem Cell Research & Therapy provides an interesting contribution to this hot topic. PMID- 23680130 TI - A small jab - a big effect: nonspecific immunomodulation by vaccines. AB - Recent epidemiological studies have shown that, in addition to disease-specific effects, vaccines against infectious diseases have nonspecific effects on the ability of the immune system to handle other pathogens. For instance, in randomized trials tuberculosis and measles vaccines are associated with a substantial reduction in overall child mortality, which cannot be explained by prevention of the target disease. New research suggests that the nonspecific effects of vaccines are related to cross-reactivity of the adaptive immune system with unrelated pathogens, and to training of the innate immune system through epigenetic reprogramming. Hence, epidemiological findings are backed by immunological data. This generates a new understanding of the immune system and about how it can be modulated by vaccines to impact the general resistance to disease. PMID- 23680131 TI - Robustness of amplicon deep sequencing underlines its utility in clinical applications. AB - We investigated the robustness of amplicon deep sequencing to study its utility in routine clinical applications offering patient-specific individualized assays for molecular disease characterization and monitoring. Amplicons were designed targeting RUNX1, CEBPA, CBL, NRAS, KRAS, DNMT3A, EZH2, and TP53 using different PCR amplification strategies and Roche GS FLX Titanium and Illumina MiSeq sequencing platforms. Thirty-three patients with leukemia were selected as an exemplary cohort representing heterogeneous cancer specimens. Both standard two primer amplification and four-primer microfluidics PCRs yielded highly linear characteristics in detecting molecular alterations in series of dilution experiments. By fitting a linear mixed-effects model to the logarithmized data, a slope beta of -1.000 (95% CI, +/-0.046) was obtained for two-primer assays and of -0.998 (95% CI, +/-0.105) was obtained for four-primer assays, which represented a near-perfect decrease of the mutation load. Furthermore, data are presented on technical precision, limit of detection, and occurrence of small subclones in TP53- and RUNX1-mutated patients to identify clonal disease progression and residual disease. We demonstrate that, depending on the local sequence context for each amplicon, the limit of detection of the assay cannot be lower than a range of 0.25% to 3.5%. In conclusion, amplicon deep sequencing enabled the assessment of mutations in a highly robust manner and across a broad range of relative frequencies of mutations. This assay detects residual disease or identifies mutations with predictive relevance to direct treatment strategies. PMID- 23680132 TI - Development of a genomic DNA reference material panel for myotonic dystrophy type 1 (DM1) genetic testing. AB - Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG triplet repeat in the 3' untranslated region of the DMPK gene that encodes a serine-threonine kinase. Patients with larger repeats tend to have a more severe phenotype. Clinical laboratories require reference and quality control materials for DM1 diagnostic and carrier genetic testing. Well-characterized reference materials are not available. To address this need, the Centers for Disease Control and Prevention-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the genetic testing community, the National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members, and the Coriell Cell Repositories, has established and characterized cell lines from patients with DM1 to create a reference material panel. The CTG repeats in genomic DNA samples from 10 DM1 cell lines were characterized in three clinical genetic testing laboratories using PCR and Southern blot analysis. DMPK alleles in the samples cover four of five DM1 clinical categories: normal (5 to 34 repeats), mild (50 to 100 repeats), classical (101 to 1000 repeats), and congenital (>1000 repeats). We did not identify or establish Coriell cell lines in the premutation range (35 to 49 repeats). These samples are publicly available for quality control, proficiency testing, test development, and research and should help improve the accuracy of DM1 testing. PMID- 23680133 TI - Surgical management of an aberrant left subclavian artery originating from a left patent ductus arteriosus in a dog with a right aortic arch and abnormal branching. AB - An increase in the availability of advanced imaging modalities has led to improved recognition of cardiovascular anomalies. Computed tomography angiography (CTA) provides a non-invasive means of acquiring 3D images with a relatively short acquisition time thereby providing essential information in regards to patient anatomy and procedure planning. The dog in this report had a right aortic arch and abnormal branching with an aberrant left subclavian artery originating from the ampulla of a left patent ductus arteriosus (PDA) that was detected with CTA. The PDA was creating a volume overload to the left side of the heart as well as contributing to the vascular ring and compression of the esophagus. Therefore, ligation and transection instead of a minimally invasive catheter-based procedure was required. This aortic arch anomaly and surgical management have not been previously reported in dogs. PMID- 23680134 TI - Hybrid cutting balloon dilatation for treatment of cor triatriatum sinister in a cat. AB - A hybrid surgical approach and balloon dilatation were performed successfully in a cat with cor triatriatum sinister and clinical signs of congestive heart failure. Left lateral thoracotomy was used to access the heart and cutting balloon followed by standard balloon dilatation were utilized to dilate the perforation in the anomalous left atrial membrane. Clinical signs resolved completely after dilation of the anomalous left atrial membrane. Based upon the outcome of this case, balloon dilatation appears to be a viable treatment option for cats affected with cor triatriatum sinister. PMID- 23680135 TI - Balloon valvuloplasty of congenital mitral stenosis. AB - Radiographic, echocardiographic, fluoroscopic, and angiographic images from 2 dogs with severe congenital mitral valve stenosis that underwent cardiac catheterization and balloon valvuloplasty are presented. Both dogs displayed systolic doming of the mitral valve leaflets, increased diastolic pressure gradient across the left atrium and ventricle, and decreased mitral inflow E to F slope. Balloon valvuloplasty was performed on both dogs using atrial transeptal puncture. PMID- 23680137 TI - [Travel queries in an international vaccination center]. PMID- 23680136 TI - [Morbidity and drug consumption. Comparison of results between the National Health Survey and electronic medical records]. AB - OBJECTIVE: To compare the prevalence of disease and drug consumption obtained by using the National Health Survey (NHS) with the information provided by the electronic medical records (EMR) in primary health care and the Pharmaceutical Consumption Registry in Aragon (Farmasalud) in the adult population in the province of Zaragoza. METHODS: A cross-sectional study was performed to compare the prevalence of diseases in the NHS-2006 and in the EMR. The prevalence of drug consumption was obtained from the NHS-2006 and Farmasalud. Estimations using each database were compared with their 95% confidence intervals (95% CI) and the results were stratified by gender and age groups. The comparability of the databases was tested. RESULTS: According to the NHS, a total of 81.8% of the adults in the province of Zaragoza visited a physician in 2006. According to the EMR, 61.4% of adults visited a primary care physician. The most prevalent disease in both databases was hypertension (NHS: 21.5%, 95% CI: 19.4-23.9; EMR: 21.6%, 95% CI: 21.3-21.8). The greatest differences between the NHS and EMR was observed in the prevalence of depression, anxiety, and other mental illnesses (NHS: 10.9%; EMR: 26.6%). The most widely consumed drugs were analgesics The prevalence of drug consumption differed in the two databases, with the greatest differences being found in pain medication (NHS: 23.3%; Farmasalud: 63.8%) and antibiotics (NHS: 3.4%; Farmasalud: 41.7%). These differences persisted after we stratified by gender and were especially important in the group aged more than 75 years. CONCLUSIONS: The prevalence of morbidity and drug consumption differed depending on the database employed. The use of different databases is recommended to estimate real prevalences. PMID- 23680138 TI - Effects of common mental disorders and physical conditions on role functioning in Spain. AB - OBJECTIVE: To examine the effects of common mental disorders and physical conditions on role functioning in Spain. METHODS: Cross-sectional study of the general adult population of Spain (n = 2,121). Non-psychotic mental disorders were assessed with the Composite International Diagnostic Interview (CIDI 3.0) and physical conditions with a checklist. The role functioning dimension of the WHO-Disability Assessment Schedule (WHODAS) was used to asses the number of days in the past month in which respondents were fully or partially limited to perform daily activities. Generalized linear models were used to estimate individual level associations of specific conditions and role functioning, controlling for co-morbidity. Societal level estimates were calculated using population attributable risk proportions (PARP). RESULTS: Mental disorders and physical conditions showed similar number of days with full role limitation (about 20 days per year); in contrast mental disorders were responsible for twice as many days with partial role limitation than physical conditions (42 vs 21 days, respectively). If the population were entirely unexposed to mental and physical conditions, days with full limitation would be reduced by 73% and days with partial limitation by 41%. CONCLUSIONS: Common health conditions in Spain are associated with considerably more days with role limitation than other Western countries. There is need of mainstreaming disability in the Spanish public health agenda in order to reduce role limitation among individuals with common conditions. PMID- 23680139 TI - Connecting with an old partner in a new way. AB - In this issue of Cancer Cell, Hao and colleagues report a non-canonical interaction between the insulin receptor substrate 1 and certain oncogenic variants of the p110alpha catalytic subunit of phosphoinositide 3-kinase (PI3K). A cell-penetrant peptide that disrupts this interaction downregulates PI3K signaling and inhibits tumor growth in mice. PMID- 23680140 TI - A new mode of RAF autoregulation: a further complication in the inhibitor paradox. AB - ERK pathway activation in cells expressing wild-type BRAF is a well-reported, clinically-relevant adverse effect of the otherwise impressive response of BRAF(V600E)-mutated melanomas to RAF inhibitors. In this issue of Cancer Cell, Holderfield and colleagues show that RAF autoinhibition underpins this paradox, further complicating therapeutic strategies centered around RAF. PMID- 23680141 TI - EZH2: an epigenetic gatekeeper promoting lymphomagenesis. AB - In this issue of Cancer Cell, Beguelin and colleagues highlight EZH2 as an essential regulator for B cell activation and report an addiction of germinal center-derived neoplasms to EZH2 activity. This reversible process is specifically targetable and hence presents high translational value for lymphoma therapy. PMID- 23680142 TI - Luring BRCA1 to the scene of the crime. AB - To preserve genome stability, BRCA1 must be recruited to sites of DNA damage, where BRCA1 facilitates repair of double-strand DNA breaks (DSBs). In this issue of Cancer Cell, Li and Yu report that BRCA1 recruitment involves a novel interaction between its partner protein BARD1 and poly(ADP-ribose) chains at the DSB. PMID- 23680143 TI - Chromoplexy: a new category of complex rearrangements in the cancer genome. AB - Widespread structural alterations of cancer genomes are increasingly observed in a broad spectrum of tumors. In a recent issue of Cell, Baca and colleagues describe large chains of rearrangements that coordinately affect multiple chromosomes in prostate cancer. This phenomenon of chromoplexy may define cancer subtypes and drive punctuated tumor evolution. PMID- 23680144 TI - Releasing the block: setting differentiation free with mutant IDH inhibitors. AB - Hotspot mutations in IDH1 and IDH2 cause a differentiation block that can promote tumorigenesis. Two recent papers reported that small molecules targeting mutant IDH1 or mutant IDH2 release this differentiation block and/or impede tumor growth, providing a proof-of-concept that mutant IDHs are therapeutically targetable and that their effects are reversible. PMID- 23680145 TI - Tumor cell dissemination: emerging biological insights from animal models and cancer patients. AB - Circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) are increasingly recognized for their potential utility in disease monitoring and therapeutic targeting. The clinical application of CTC/DTC requires better understanding of the biological mechanisms behind tumor dissemination, the survival of DTCs, and their activation to aggressive growth from dormancy. Recent research using animal models of DTCs and CTCs have provided novel insights into these processes. Here, we discuss these findings in the context of results obtained from the clinical analyses of CTCs and DTCs, which demonstrate that the animal models mimic, in many aspects, the complex situation in patients. PMID- 23680146 TI - RAF inhibitors activate the MAPK pathway by relieving inhibitory autophosphorylation. AB - ATP competitive inhibitors of the BRAF(V600E) oncogene paradoxically activate downstream signaling in cells bearing wild-type BRAF (BRAF(WT)). In this study, we investigate the biochemical mechanism of wild-type RAF (RAF(WT)) activation by multiple catalytic inhibitors using kinetic analysis of purified BRAF(V600E) and RAF(WT) enzymes. We show that activation of RAF(WT) is ATP dependent and directly linked to RAF kinase activity. These data support a mechanism involving inhibitory autophosphorylation of RAF's phosphate-binding loop that, when disrupted either through pharmacologic or genetic alterations, results in activation of RAF and the mitogen-activated protein kinase (MAPK) pathway. This mechanism accounts not only for compound-mediated activation of the MAPK pathway in BRAF(WT) cells but also offers a biochemical mechanism for BRAF oncogenesis. PMID- 23680147 TI - Oncogenic ERBB3 mutations in human cancers. AB - The human epidermal growth factor receptor (HER) family of tyrosine kinases is deregulated in multiple cancers either through amplification, overexpression, or mutation. ERBB3/HER3, the only member with an impaired kinase domain, although amplified or overexpressed in some cancers, has not been reported to carry oncogenic mutations. Here, we report the identification of ERBB3 somatic mutations in ~11% of colon and gastric cancers. We found that the ERBB3 mutants transformed colonic and breast epithelial cells in a ligand-independent manner. However, the mutant ERBB3 oncogenic activity was dependent on kinase-active ERBB2. Furthermore, we found that anti-ERBB antibodies and small molecule inhibitors effectively blocked mutant ERBB3-mediated oncogenic signaling and disease progression in vivo. PMID- 23680148 TI - Mutant p53 prolongs NF-kappaB activation and promotes chronic inflammation and inflammation-associated colorectal cancer. AB - The tumor suppressor p53 is frequently mutated in human cancer. Common mutant p53 (mutp53) isoforms can actively promote cancer through gain-of-function (GOF) mechanisms. We report that mutp53 prolongs TNF-alpha-induced NF-kappaB activation in cultured cells and intestinal organoid cultures. Remarkably, when exposed to dextran sulfate sodium, mice harboring a germline p53 mutation develop severe chronic inflammation and persistent tissue damage, and are highly prone to inflammation-associated colon cancer. This mutp53 GOF is manifested by rapid onset of flat dysplastic lesions that progress to invasive carcinoma with mutp53 accumulation and augmented NF-kappaB activation, faithfully recapitulating features frequently observed in human colitis-associated colorectal cancer (CAC). These findings might explain the early appearance of p53 mutations in human CAC. PMID- 23680149 TI - In vivo RNAi screen for BMI1 targets identifies TGF-beta/BMP-ER stress pathways as key regulators of neural- and malignant glioma-stem cell homeostasis. AB - In mouse and human neural progenitor and glioblastoma "stem-like" cells, we identified key targets of the Polycomb-group protein BMI1 by combining ChIP-seq with in vivo RNAi screening. We discovered that Bmi1 is important in the cellular response to the transforming growth factor-beta/bone morphogenetic protein (TGF beta/BMP) and endoplasmic reticulum (ER) stress pathways, in part converging on the Atf3 transcriptional repressor. We show that Atf3 is a tumor-suppressor gene inactivated in human glioblastoma multiforme together with Cbx7 and a few other candidates. Acting downstream of the ER stress and BMP pathways, ATF3 binds to cell-type-specific accessible chromatin preloaded with AP1 and participates in the inhibition of critical oncogenic networks. Our data support the feasibility of combining ChIP-seq and RNAi screens in solid tumors and highlight multiple p16(INK4a)/p19(ARF)-independent functions for Bmi1 in development and cancer. PMID- 23680152 TI - SnapShot: melanoma. PMID- 23680153 TI - One-qubit quantum gates in a circular graphene quantum dot: genetic algorithm approach. AB - The aim of this work was to design and control, using genetic algorithm (GA) for parameter optimization, one-charge-qubit quantum logic gates sigmax, sigmay, and sigmaz, using two bound states as a qubit space, of circular graphene quantum dots in a homogeneous magnetic field. The method employed for the proposed gate implementation is through the quantum dynamic control of the qubit subspace with an oscillating electric field and an onsite (inside the quantum dot) gate voltage pulse with amplitude and time width modulation which introduce relative phases and transitions between states. Our results show that we can obtain values of fitness or gate fidelity close to 1, avoiding the leakage probability to higher states. The system evolution, for the gate operation, is presented with the dynamics of the probability density, as well as a visualization of the current of the pseudospin, characteristic of a graphene structure. Therefore, we conclude that is possible to use the states of the graphene quantum dot (selecting the dot size and magnetic field) to design and control the qubit subspace, with these two time-dependent interactions, to obtain the optimal parameters for a good gate fidelity using GA. PMID- 23680150 TI - EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. AB - The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B cells and targeted by somatic mutations in B cell lymphomas. Here, we find that EZH2 deletion or pharmacologic inhibition suppresses GC formation and functions. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GC B cell (GCB)-type diffuse large B cell lymphomas (DLBCLs) are mostly addicted to EZH2 but not the more differentiated activated B cell (ABC)-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting. PMID- 23680151 TI - Function of BRCA1 in the DNA damage response is mediated by ADP-ribosylation. AB - Carriers of BRCA1 germline mutations are predisposed to breast and ovarian cancers. Accumulated evidence shows that BRCA1 is quickly recruited to DNA lesions and plays an important role in the DNA damage response. However, the mechanism by which BRCA1 is recruited to DNA damage sites remains elusive. BRCA1 forms a Ring-domain heterodimer with BARD1, a major partner of BRCA1 that contains tandem BRCA1 C-terminus (BRCT) motifs. Here, we identify the BRCTs of BARD1 as a poly(ADP-ribose) (PAR)-binding module. The binding of the BARD1 BRCTs to PAR targets the BRCA1/BARD1 heterodimer to DNA damage sites. Thus, our study uncovers a PAR-dependent mechanism of rapid recruitment of BRCA1/BARD1 to DNA damage sites. PMID- 23680154 TI - The application of MR imaging in the detection of hip involvement in patients with ankylosing spondylitis. AB - OBJECTIVE: To investigate the changes in hip MR imaging, evaluate the frequency of hip involvement and compare the value of clinical symptoms, radiographs, and MR imaging in the detection of hip involvement in patients with ankylosing spondylitis (AS). METHODS: Anteroposterior radiographs of the pelvis, MR imaging of the hip and clinical evaluation were undertaken in 58 patients with definite AS. All patients were followed up 3 years. Annual radiographs and clinical evaluation were carried out. The imaging data were independently assessed by two experienced radiologists who were blinded to patient identity and clinical characteristics. Based on the Bath Ankylosing Spondylitis Radiology Hip Index (BASRI-hip) scoring system, BASRI-hip scores >= 2 were defined as radiological hip involvement. On MR imaging, both acute and chronic inflammatory changes were considered positive signs for hip involvement. Symptomatic hip involvement was defined as current or past pain or limitation of the hip movement. The statistical analysis was performed using the chi(2) test for comparison of sensitivity among clinical symptoms, radiographs, and MR imaging in the detection of hip involvement and the Student's t-test for comparison of disease duration between with and without hip involvement. A P value <0.05 was considered to be statistically significant. For interpreting MRI and radiographs, the percentage of agreement between the two assessors and the kappa coefficients were calculated. RESULTS: On MR imaging, positive changes were detected in 86 (74.1%) hips among 116 hips in all 58 patients. Joint effusion was observed in 73 (62.9%) hips; 23 out of 27 patients who underwent fat-saturated contrast-enhanced T1 weighted sequences had abnormal synovial enhancement in bilateral hips. The other abnormal MR findings included subchondral bone marrow edema in 35 (30.2%) hips, enthesitis in 22 (19.0%) hips, fatty accumulation of the bone marrow in 28 (24.1%) hips, bone erosive destruction in 32 (27.6%) hips, and joint-space narrowing in 4 (3.4%) hips. Based on the BASRI-hip scoring system, 68, 24, 18, 6 and 0 hips had no, suspicious, mild, moderate or severe damage on conventional radiographs of the pelvis, respectively. Thirty-five hips in 20 patients had current or past pain or limitation. The proportion of hip involvement according to MR imaging, radiographs, and clinical symptoms was 74.1% (86/116), 20.7% (24/116), and 30.2% (35/116), respectively. MR imaging yielded higher values than radiographs and clinical symptoms in the detection of hip involvement in patients with AS (chi(2)=66.45 and 44.93, P <0.05). Interreader reliability for interpretation of findings was acceptable for both MRI and radiographs. During follow-up, radiological hip involvement were found in 10 hips with BASRI-hip scores <= 1 at baseline and clinical symptoms appeared in 15 sides of the original asymptomatic hip. On baseline MR imaging, inflammatory changes were seen in all hips which appeared symptoms and/or radiological involvement both at baseline and during follow-up. CONCLUSION: The proportion of hip involvement is much higher than that suggested by radiographic changes and clinical symptoms. MR imaging is superior to conventional radiographs and clinical symptoms in the detection of hip involvement. Joint effusion and synovial enhancement caused by synovitis are the commonest hip findings on MR imaging in patients with AS. PMID- 23680155 TI - Analysis of the thoracic aorta using a semi-automated post processing tool. AB - OBJECTIVE: To evaluates a semi-automated method for Thoracic Aortic Aneurysm (TAA) measurement using ECG-gated Dual Source CT Angiogram (DSCTA). METHODS: This retrospective HIPAA compliant study was approved by our IRB. Transaxial maximum diameters of outer wall to outer wall were studied in fifty patients at seven anatomic locations of the thoracic aorta: annulus, sinus, sinotubular junction (STJ), mid ascending aorta (MAA) at the level of right pulmonary artery, proximal aortic arch (PROX) immediately proximal to innominate artery, distal aortic arch (DIST) immediately distal to left subclavian artery, and descending aorta (DESC) at the level of diaphragm. Measurements were performed using a manual method and semi-automated software. All readers repeated their measurements. Inter-method, intra-observer and inter-observer agreements were evaluated according to intraclass correlation coefficient (ICC) and Bland-Altman plot. The number of cases with manual contouring or center line adjustment for the semi-automated method and also the post-processing time for each method were recorded. RESULTS: The mean difference between semi-automated and manual methods was less than 1.3mm at all seven points. Strong inter-method, inter-observer and intra-observer agreement was recorded at all levels (ICC >= 0.9). The maximum rate of manual adjustment of center line and contour was at the level of annulus. The average time for manual post-processing of the aorta was 19 +/- 0.3 min, while it took 8.26 +/- 2.1 min to do the measurements with the semi-automated tool (Vitrea version 6.0.0.1 software). The center line was edited manually at all levels, with most corrections at the level of annulus (60%), while the contour was adjusted at all levels with highest and lowest number of corrections at the levels of annulus and DESC (75% and 0.07% of the cases), respectively. CONCLUSION: Compared to the commonly used manual method, semi-automated measurement of vessel dimensions is feasible in the thoracic aorta with the advantage of reduced post-processing time. PMID- 23680156 TI - Association of carotid atherosclerotic plaque features with acute ischemic stroke: a magnetic resonance imaging study. AB - BACKGROUND AND PURPOSE: It remains unclear whether direct vessel wall imaging can identify carotid high-risk lesions in symptomatic subjects and whether carotid plaque characteristics are more effective indicators for cerebral infarct severity than stenosis. This study sought to determine the associations of carotid plaque characteristics by MR imaging with stenosis and acute cerebral infarct (ACI) sizes on diffusion weighted imaging (DWI). MATERIALS AND METHODS: One hundred and fourteen symptomatic patients underwent carotid and brain MRI. ACI volume was determined from symptomatic internal carotid artery territory on DWI images. Ipsilateral carotid plaque morphological and compositional characteristics, and stenosis were also determined. The relationships between carotid plaque characteristics, stenosis and ACIs size were then evaluated. RESULTS: In carotid arteries with 30-49% stenosis, 86.7% and 26.7% were found to have lipid-rich necrotic core (LRNC) and intraplaque hemorrhage, respectively. Furthermore, 45.8% of carotid arteries with 0-29% stenosis developed LRNCs. Carotid morphological measurements, such as % wall volume, and the LRNC size were significantly associated with ipsilateral ACIs volume before and after adjustment for significant demographic factors (age and LDL) or stenosis in patients with carotid plaque (all p<0.05). CONCLUSIONS: A substantial number of high-risk plaques characterized by vessel wall imaging exist in carotid arteries with lower grade stenosis. In addition, carotid plaque characteristics, particularly the % wall volume and LRNC size, are independently associated with cerebral infarction as measured by DWI lesions. Our findings indicate that characterizing atherosclerotic plaque by MR vessel wall imaging might be useful for stratification of plaque risk and infarction severity. PMID- 23680157 TI - Protective effect of a Butea monosperma (Lam.) Taub. flowers extract against skin inflammation: antioxidant, anti-inflammatory and matrix metalloproteinases inhibitory activities. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Butea monosperma (Lam.) Taubert (Syn. Butea frondosa; family Fabaceae) is a common plant of the Indian continent (Das et al., 2011; Sharma and Deshwal, 2011). The brightly orange flowers of this plant are widely used in traditional medicine and more particularly for inflammatory disease. AIM OF THE STUDY: In vitro anti-inflammatory mechanism of a hydroethanolic extract of B. monosperma flowers (BME) and more specifically of an enriched fraction in butrin and isobutrin (BI) was studied using cell culture of Normal Human Keratinocyte, cells involved in the skin inflammatory. MATERIALS AND METHODS: Dried and crushed B. monosperma flowers were extracted with Ethanol/H2O (70/30 v/v). The butrin/isobutrin fraction was obtained by centrifugal Partition Chromatography (CPC). Experiments were conducted on UV-B treated normal human epidermis keratinocytes, cells involved in the skin inflammatory response. To evaluate extract anti-inflammatory activity, cytokines IL-1beta, IL-6, IL-8, prostaglandin E2 and metalloproteinases MMP-1, -2, -9 and -10 were measured in the cells supernatant. RESULTS: Our data clearly showed that hydroalcoholic B. monosperma flower extract was able to decrease the secretion of IL-1beta, IL-6 and IL-8 pro-inflammatory cytokines of -32, -33 and -18% respectively. Interestingly, Prostaglandin E2 production and the secretion of MMP-1, -2, -9 and -10 were also inhibited. Same results were observed in presence of enriched fraction in butrin and isobutrin and confirmed the participation of these molecules in the anti-inflammatory activity. CONCLUSION: These results explain the anti-inflammatory activity of B. monosperma and confirm the interest to use it in traditional Indian medicine. Moreover, its metalloproteinases inhibitory activities coupled with its anti-inflammatory action also give anti-aging property to this plant. PMID- 23680158 TI - Antiplasmodial and anti-inflammatory activities of Canthium henriquesianum (K. Schum), a plant used in traditional medicine in Burkina Faso. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Canthium henriquesianum (K. Schum) is traditionally used in Burkina Faso for the treatment of malaria, but has not been properly investigated, yet. The aim of this study was to characterize in vitro the antiplasmodial and the anti-inflammatory activity of extracts from Canthium henriquesianum (K. Schum). In parallel, extracts of Gardenia sokotensis (Hutch) and Vernonia colorata (Willd), also traditionally used together in Burkina Faso and already reported with antimalarial activity, were compared. MATERIALS AND METHODS: Plant extracts were tested in vitro for antimalarial activity against chloroquine susceptible (D10) and resistant (W2) strains of Plasmodium falciparum using the lactate dehydrogenase assay. Cell cytotoxicity was assessed on human dermal fibroblast (HDF) by the MTT assay. The selectivity index (SI) was used as the ratio of the activity against the parasites compared to the toxicity of the plant extract against HDF. In vitro cytokine production was assessed by ELISA technique. RESULTS: Canthium henriquesianum aqueous extract had a moderate antimalarial activity (IC50<50 ug/ml) with a good selectivity index (SI=HDF/D10>7). Canthium henriquesianum diisopropyl ether extract was the most potent inhibitor of parasite growth with an IC50 9.5 ug/ml on W2 and 8.8 ug/ml on D10 and limited toxicity (SI>2). Gardenia sokotensis and Vernonia colorata aqueous extracts were shown to be significantly less active (IC50>=50 ug/ml) with substantial toxicity. In addition, when the production of IL-1beta and TNFalpha by lipopolysaccharide (LPS) or hemozoin (malaria pigment) stimulated human THP-1 monocytes was assayed, it was found that the extract of Canthium henriquesianum induced a dose-dependent inhibition of IL-1beta, but not of TNFalpha production, thus confirming its traditional use as antipyretic. By NMR analysis, the chromone was identified as the mostly represented compound in the diisopropyl ether extract of Canthium henriquesianum. Chromone however, was less active as antimalarial than the crude extract and it did not inhibit cytokine production at not toxic doses, indicating that other molecules in the total extracts contribute to the antiplasmodial and anti-inflammatory activity. CONCLUSION: Canthium henriquesianum seems to possess antimalarial activity in vitro and the ability to inhibit the production of the pyrogenic cytokine IL-1beta. PMID- 23680159 TI - The water permeability of lens aquaporin-0 depends on its lipid bilayer environment. AB - Aquaporin-0 (AQP0), the primary water channel in lens fiber cells, is critical to lens development, organization, and function. In the avascular lens there is thought to be an internal microcirculation associated with fluid movement. Although AQP0 is known to be important in fluid fluxes across membranes, the water permeability of this channel has only been measured in Xenopus oocytes and in outer lens cortical membranes, but not in inner nuclear membranes, which have an increased cholesterol/phospholipid ratio. Here we measure the unit water permeability of AQP0 in different proteoliposomes with cholesterol/phospholipid ratios and external pHs similar to those found in the cortex and nucleus of the lens. Osmotic stress measurements were performed with proteoliposomes containing AQP0 and three different lipids mixtures: (1) phosphatidylcholine (PC) and phosphatidylglycerol (PG), (2) PC, PG, with 40 mol% cholesterol, and (3) sphingomyelin (SM), PG, with 40 mol% cholesterol. At pH 7.5 the unit permeabilities of AQP0 were 3.5 +/- 0.5 * 10(-14) cm(3)/s (mean +/- SEM), 1.1 +/- 0.1 * 10(-14) cm(3)/s, and 0.50 +/- 0.04 * 10(-14) cm(3)/s in PC:PG, PC:PG:cholesterol, and SM:PG:cholesterol, respectively. For lipid mixtures at pH 6.5, corresponding to conditions found in the lens nucleus, the AQP0 permeabilities were 1.5 +/- 0.4 * 10(-14) cm(3)/s and 0.76 +/- 0.03 * 10(-14) cm(3)/s in PC:PG:cholesterol and SM:PG:cholesterol, respectively. Thus, although AQP0 unit permeability can be modified by changes in pH, it is also sensitive to changes in bilayer lipid composition, and decreases with increasing cholesterol and SM content. These data imply that AQP0 water permeability is regulated by bilayer lipid composition, so that AQP0 permeability would be significantly less in the lens nucleus than in the lens cortex. PMID- 23680161 TI - Effect of light on the activity of motor cortex neurons during locomotion. AB - The motor cortex plays a critical role in accurate visually guided movements such as reaching and target stepping. However, the manner in which vision influences the movement-related activity of neurons in the motor cortex is not well understood. In this study we have investigated how the locomotion-related activity of neurons in the motor cortex is modified when subjects switch between walking in the darkness and in light. Three adult cats were trained to walk through corridors of an experimental chamber for a food reward. On randomly selected trials, lights were extinguished for approximately 4s when the cat was in a straight portion of the chamber's corridor. Discharges of 146 neurons from layer V of the motor cortex, including 51 pyramidal tract cells (PTNs), were recorded and compared between light and dark conditions. It was found that while cats' movements during locomotion in light and darkness were similar (as judged from the analysis of three-dimensional limb kinematics and the activity of limb muscles), the firing behavior of 49% (71/146) of neurons was different between the two walking conditions. This included differences in the mean discharge rate (19%, 28/146 of neurons), depth of stride-related frequency modulation (24%, 32/131), duration of the period of elevated firing ([PEF], 19%, 25/131), and number of PEFs among stride-related neurons (26%, 34/131). 20% of responding neurons exhibited more than one type of change. We conclude that visual input plays a very significant role in determining neuronal activity in the motor cortex during locomotion by altering one, or occasionally multiple, parameters of locomotion-related discharges of its neurons. PMID- 23680160 TI - Light levels, refractive development, and myopia--a speculative review. AB - Recent epidemiological evidence in children indicates that time spent outdoors is protective against myopia. Studies in animal models (chick, macaque, tree shrew) have found that light levels (similar to being in the shade outdoors) that are mildly elevated compared to indoor levels, slow form-deprivation myopia and (in chick and tree shrew) lens-induced myopia. Normal chicks raised in low light levels (50 lux) with a circadian light on/off cycle often develop spontaneous myopia. We propose a model in which the ambient illuminance levels produce a continuum of effects on normal refractive development and the response to myopiagenic stimuli such that low light levels favor myopia development and elevated levels are protective. Among possible mechanisms, elevation of retinal dopamine activity seems the most likely. Inputs from intrinsically-photosensitive retinal ganglion cells (ipRGCs) at elevated light levels may be involved, providing additional activation of retinal dopaminergic pathways. PMID- 23680162 TI - Functional inactivation of orexin 1 receptors in the cerebellum disrupts trace eyeblink conditioning and local theta oscillations in guinea pigs. AB - The cerebellum plays an essential role in motor learning. Recently, orexins, the newfound lateral hypothalamic neuropeptides, have been found to excite Purkinje cells in the cerebellar cortex and neurons in the deep cerebellar nuclei (DCN). However, little is known about their roles in cerebellum-dependent motor learning. Therefore, the present study was designed to investigate the functional significance of hypothalamic orexinergic system during trace eyeblink conditioning, a tractable behavioral model system of cerebellum-dependent motor learning. It was revealed that the orexin 1 receptors (OXR1) were specifically localized on the soma of Purkinje cells and large DCN neurons. Furthermore, interfering with the endogenous orexins' effects on the cerebellum via the selective OXR1 antagonist SB-334867 disrupted the timing rather than the acquisition of trace conditioned eyeblink responses. In addition to the behavioral effects, the SB-334867 prevented the increase in peak amplitude of cerebellar theta oscillations with learning. These results suggest that the endogenous orexins may modulate motor learning via the activation of cerebellar OXR1. PMID- 23680163 TI - Biases in rhythmic sensorimotor coordination: effects of modality and intentionality. AB - Sensorimotor biases were examined for intentional (tracking task) and unintentional (distractor task) rhythmic coordination. The tracking task involved unimanual tracking of either an oscillating visual signal or the passive movements of the contralateral hand (proprioceptive signal). In both conditions the required coordination patterns (isodirectional and mirror-symmetric) were defined relative to the body midline and the hands were not visible. For proprioceptive tracking the two patterns did not differ in stability, whereas for visual tracking the isodirectional pattern was performed more stably than the mirror-symmetric pattern. However, when visual feedback about the unimanual hand movements was provided during visual tracking, the isodirectional pattern ceased to be dominant. Together these results indicated that the stability of the coordination patterns did not depend on the modality of the target signal per se, but on the combination of sensory signals that needed to be processed (unimodal vs. cross-modal). The distractor task entailed rhythmic unimanual movements during which a rhythmic visual or proprioceptive distractor signal had to be ignored. The observed biases were similar as for intentional coordination, suggesting that intentionality did not affect the underlying sensorimotor processes qualitatively. Intentional tracking was characterized by active sensory pursuit, through muscle activity in the passively moved arm (proprioceptive tracking task) and rhythmic eye movements (visual tracking task). Presumably this pursuit afforded predictive information serving the coordination process. PMID- 23680164 TI - Dual-task performance is differentially modulated by rewards and punishments. AB - Dual-task situations play a pivotal role in daily life and are subject to a research in cognitive psychology and neuroscience. From a neuroscience perspective, the response selection bottleneck may be partly constituted by the dopaminergic system. The dopaminergic system plays a pivotal role in reward and punishment effects. In the current study we therefore investigated the effects of rewards and punishments as a potential modulator of dual-tasking processes. We examined dual-task performance in the psychological refractory period (PRP) paradigm, where the task order was either predictable, or unpredictable. Three groups were tested; a punishment group (N=14), a reward group (N=18) and a control group (N=16). The results show that in the punishment condition, dual task performance is increased relative to controls (i.e., faster RTs). In the reward condition performance decreased relative to controls. The effects observed were of moderate to high effect sizes. However, the effects were only evident when task performance was unpredictable. These divergent effects of rewards and punishments on dual-tasking may be explained by the differential involvement of different dopamine receptors in rewards and punishments, and their effects on the amount and flexibility of task goals in working memory. PMID- 23680165 TI - Intranasal infusion of melanocortin receptor four (MC4R) antagonist to rats ameliorates development of depression and anxiety related symptoms induced by single prolonged stress. AB - Brain melanocortinergic systems and specifically melanocortin receptor four (MC4R) are implicated in modulation of anxiety- and depressive-like behavior induced by mild or moderate stress. Here we examine whether blockage of central MC4Rs with HS014 before severe traumatic stress may protect against development of anxiety and depression co-morbid with post-traumatic stress disorder (PTSD). Male rats were treated intranasally (IN) with vehicle or varied doses of HS014, 30min prior to single prolonged stress (SPS) animal model of PTSD. IN administration of 100MUg HS014 pre-SPS improved despair behavior in forced swim (FS) immediately after immobilization stress part of SPS protocol. During all 4 intervals of 20min FS these rats spent less time immobile than rats given vehicle or 3.5ng HS014. This dose of HS014 also had a long-term beneficial effect manifested as reduction of immobility time in forced swim test performed after SPS. However, both HS014 doses were effective in ameliorating development of anxiety-like behavior after traumatic stress. Thus, rats given IN HS014 prior to SPS exhibited less open arms (OA) visits in elevated plus maze (EPM), spent longer time in OA and less in closed arms, had lower anxiety index, higher risk assessment and more head dips over borders in OA. They also spent longer time in the center of the open field and defecated less. Reduced grooming behavior in EPM was observed with 100MUg HS014. This is the first study revealing pronounced resilience effects of HS014 on development of behavioral symptoms co-morbid with PTSD. PMID- 23680166 TI - Increased prevalence of chronic obstructive pulmonary disease in a general population. AB - BACKGROUND: Prevalence of COPD is increasing worldwide, and there is need for regularly updated estimates of COPD prevalence and risk factors. METHODS: In the Norwegian Hordaland County Cohort Study (HCCS), 1664 subjects aged 35-90 yrs answered questionnaires and performed spirometry in 2003-05. We estimated COPD prevalence and analysed risk factors for COPD with logistic regression. RESULTS: In a previous study phase, prevalence of GOLD-defined COPD was 7%. Eight years later, corresponding prevalence was 14%. Seventy % of the subjects experienced respiratory symptoms. Only 1 out of 4 had a physician's diagnosis. Significant risk factors for COPD were sex, age, smoking habits and pack-years. Men had 1.7 (OR, 95% CI 1.2, 2.3) higher odds for COPD than women. Subjects above 65 yrs had 10.3 (OR, 95% CI 6.4, 16.5) times higher odds for COPD than subjects below 40 yrs. Heavy smokers had 4.2 (OR, 95% CI 2.6, 6.7) times higher odds for COPD than subjects with <10 pack-years. When compared with the previous study phase, age and smoking status had roughly the same associations with COPD prevalence. Educational level and male gender, on the other hand, had less effect on COPD prevalence in 2005 than in 1997, while pack years were more important in 2005 than in 1997. CONCLUSIONS: Prevalence of GOLD defined COPD has increased from 7% to 14% in nine years. Although the risk factors remain the same, the strength of associations vary. There is still substantial under diagnosis in COPD, and better disease awareness and diagnostic routines are needed. PMID- 23680167 TI - Illuminating luminal B: QSOX1 as a subtype-specific biomarker. AB - Breast cancer is a complex and heterogeneous disease that affects about one out of every eight women. In the last decade, several advancements have been made that have increased our understanding of breast cancer and have allowed us to more accurately diagnose and treat this disease in a more targeted manner. For example, gene expression profiling enabled the classification of breast cancers into four main subtypes - basal-like, HER2+ (human epidermal growth factor receptor 2-positive), luminal A and luminal B - and this classification is used to direct the use of targeted therapies such as tamoxifen or trastuzumab. The luminal subtypes are generally characterized as being estrogen receptor-positive and targetable with anti-hormone therapies. However, whereas luminal A cancers have a good prognosis, luminal B cancers are associated with early relapse following endocrine therapy and a prognosis that is similar to that of the aggressive basal subtype. It is thus imperative that luminal B cancers be better characterized so that therapeutic targets and biomarkers for this disease type can be realized. In the previous issue of Breast Cancer Research, Katchman and colleagues address this need by demonstrating that quiescin sulfydryl oxidase 1 (QSOX1), a secreted enzyme involved in post-translational modifications, is associated with poor prognosis in patients with luminal B breast cancer. The authors further determined that this protein promotes breast cancer proliferation and invasion. Collectively, these studies suggest that QSOX1 is a predictive biomarker for luminal cancers and that it may be a useful target for elusive luminal B disease. PMID- 23680168 TI - The impact of living with HIV: differences in experiences of stigma for heterosexual and homosexual people living with HIV in Australia. AB - Background HIV in Australia has been closely aligned with the gay community and continues to disproportionately affect members of this community. Although heterosexual transmission remains low, recently there has been an increase in new HIV diagnoses attributable to heterosexual sex. This highlights the need to address the health and social consequences for heterosexual people living with HIV (PLHIV). This subanalysis of a larger study compared the experiences of stigma, health and wellbeing of a sample of gay and heterosexual PLHIV. METHODS: Data were drawn from a study of experiences of stigma among PLHIV in Australia. All 49 participants who reported being heterosexual were included, as were 49 participants randomly selected from the 611 gay participants. The samples were compared on perceived HIV stigma, HIV treatment-related stigma, perceived negative reactions of others, HIV status disclosure, and health and wellbeing measures. RESULTS: The findings illustrate that heterosexual PLHIV have more negative experiences in terms of both general HIV stigma and treatment-related stigma than gay PLHIV. The heterosexual PLHIV also perceived greater negative reactions in relation to their HIV status by different people in their social environment and were less likely to access treatment than the gay PLHIV. There were no differences between the two groups in any of the health and wellbeing measures. CONCLUSIONS: This study shows that in the Australian context, heterosexual PLHIV may feel more stigmatised than gay PLHIV. In view of lower HIV treatment uptake in heterosexual PLHIV, addressing HIV-related stigma could contribute to increasing access to HIV treatment. PMID- 23680169 TI - Potential benefits of satiety to the consumer: scientific considerations. AB - Foods and dietary patterns that enhance satiety may provide benefit to consumers. The aim of the present review was to describe, consider and evaluate research on potential benefits of enhanced satiety. The proposal that enhanced satiety could only benefit consumers by a direct effect on food intake should be rejected. Instead, it is proposed that there is a variety of routes through which enhanced satiety could (indirectly) benefit dietary control or weight-management goals. The review highlights specific potential benefits of satiety, including: providing appetite control strategies for consumers generally and for those who are highly responsive to food cues; offering pleasure and satisfaction associated with low-energy/healthier versions of foods without feeling 'deprived'; reducing dysphoric mood associated with hunger especially during energy restriction; and improved compliance with healthy eating or weight-management efforts. There is convincing evidence of short-term satiety benefits, but only probable evidence for longer-term benefits to hunger management, possible evidence of benefits to mood and cognition, inadequate evidence that satiety enhancement can promote weight loss, and no evidence on which consumers would benefit most from satiety enhancement. The appetite-reducing effects of specific foods or diets will be much more subtle than those of pharmaceutical compounds in managing hunger; nevertheless, the experience of pharmacology in producing weight loss via effects on appetite suggests that there is potential benefit of satiety enhancement from foods incorporated into the diet to the consumer. PMID- 23680170 TI - Treatment provider is most predictive of ED dismissal in minimally-injured trauma patients: a retrospective review. AB - BACKGROUND: Secondary triage protocols have been described in the literature as physiologic (first-tier) criteria and mechanism-related (second-tier) criteria to determine the level of trauma activation. There is debate as to the efficiency of triage decisions based on mechanism of injury which may result in overtriage and overuse of limited trauma resources. Our institution developed and implemented an advanced three-tier trauma alert system in which stable patients presenting with blunt traumatic mechanism of injury would be evaluated by the emergency department (ED) physician rather than the trauma surgeon. The American College of Surgeons Committee on Trauma (ACSCOT) requires that operational changes be monitored and evaluated for patient safety and performance. The primary aim of this study was to evaluate the process, as well as outcomes, of patient care pre and post implementation of the new triage protocol. The secondary aim was to determine predictor variables that were associated with ED dismissal. METHODS: A retrospective blinded pre/post process change implementation explicit chart review was conducted to compare process and outcomes of minimally injured trauma patients who were field triaged by mechanism of injury. Generalized linear modeling was performed to determine which predictor variables were associated with ED dismissal. RESULTS: There were no significant differences in minutes to physician evaluation, CT scan, OR/ICU disposition, readmission rates, safety or quality. Significant differences only occurred in time to chest x-ray, length of stay in ED, and ED dismissal rates. Trauma surgeon and ED physician patient groups did not differ on ISS, age, or sex. The only significant predictor for ED dismissal was treatment provider, with ED physicians 3.6 times more likely to dismiss the patient from the emergency department. CONCLUSIONS: ED physicians provided compble care as measured by safety, timeliness, and quality in minimally injured patients triaged to our trauma center based only on mechanism of injury. Moreover, ED physicians were more likely to dismiss patients from the ED. A three tiered internal triaging protocol can redirect resource usage to reduce the burden on the trauma service. This may be increasingly beneficial in trauma models in which the trauma surgeons also serve as critical care intensivists. PMID- 23680171 TI - Prevalence of sexual abuse of male high school students in Addis Ababa, Ethiopia. AB - BACKGROUND: Sexual abuse of boys is a neglected problem in many developing countries including Ethiopia. As a result, its prevalence, contributing factors and circumstance in which sexual abuse occurs are largely unknown. The objective of this study is to determine the prevalence and factors associated with sexual abuse of male high school students in Addis Ababa city administration. METHODS: A cross-sectional descriptive study involving 884 randomly selected students of nine high schools in Addis Ababa was conducted in March 2009. A pre-tested questionnaire was used to collect data. Analysis of the data was made using SPSS for windows version 15. RESULTS: This study indicates the life time prevalence of rape and sexual harassment of boys in Addis Ababa were 4.3%, and 68.2%, respectively. The chance of experiencing sexual coercion was higher among students who live alone (AOR = 2.87; 95% CI; 1.07, 7.66) and among students who live with others (AOR =1.80; 95% CI = 1.04, 3.11) than those living with both parents. Similarly, the odds of experiencing rape in their life time was higher among students who live with others (AOR=2.20; 95% CI; 1.04, 4.68) than those who live with their parents. CONCLUSIONS: Sexual abuse of male students is not uncommon in Addis Ababa. It is higher in those living alone or not living with their parents. Due attention is needed by schools, parents and other concerned bodies. Designing a program to fight against sexual abuse should include young school boys. PMID- 23680172 TI - MicroRNA-146 inhibits pro-inflammatory cytokine secretion through IL-1 receptor associated kinase 1 in human gingival fibroblasts. AB - BACKGROUND: Although various microRNAs (miRNAs) regulate immune and inflammatory responses, the function of miRNAs in periodontitis has not been clearly illuminated. In this study, we measured miRNA-146 (miRNA-146a and miRNA-146b-5p) expression and explored its regulatory function in the inflammatory response in human gingival fibroblasts (HGFs). METHODS: miRNA-146a and miRNA-146b-5p expression was measured by performing real-time polymerase chain reaction in HGFs after Porphyromonas gingivalis (p.g) lipopolysaccharide (LPS) stimulation. After the HGFs were transfected with miRNA-146a and miRNA-146b-5p inhibitor, the expression levels of interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were measured by enzyme-linked immunosorbent assay (ELISA). Meanwhile, IL-1 receptor-associated kinase 1 (IRAK1) and TNF receptor-associated factor 6 (TRAF6) were detected by western blot and quantitative PCR. A luciferase assay was used to detect whether miRNA-146 could directly bind to the 3'-UTR of IRAK1. RESULTS: The expression levels of miRNA 146a and miRNA-146b-5p significantly increased in the P.g LPS-stimulated HGFs compared to the non-stimulated HGFs. The inhibition of miRNA-146a and miRNA-146b 5p resulted in increased IL-1beta, IL-6 and TNF-alpha secretion. The mRNA and protein levels of IRAK1, but not TRAF6, also increased. We further found that miRNA-146a and miRNA-146b-5p directly bound to the IRAK1 3'-UTR. CONCLUSION: Our data suggest that miRNA-146 inhibits pro-inflammatory cytokine secretion through IRAK1 in HGFs, which indicates that miRNA-146 functions as a negative regulator of periodontal inflammation. PMID- 23680173 TI - Part two: Against the motion. External diameter for AAA size. AB - Aneurysm diameter measurement is quick and easy, but suffers from the pitfalls of being "too rough and ready". When semi-automated segmentation took 7-10 minutes to estimate volume, it was not a practical tool for busy, routine clinical practice. Today, the availability of automatic segmentation in seconds is bound to make volume measurement, along with 3D ultrasonography, the tools of the future. There can be no debate. PMID- 23680174 TI - Mucosal healing with oral tacrolimus is associated with favorable medium- and long-term prognosis in steroid-refractory/dependent ulcerative colitis patients. AB - BACKGROUND: Oral administration of tacrolimus is an effective remission induction therapy for steroid-refractory/dependent ulcerative colitis (UC). AIM: This study aimed to evaluate the short- as well as medium- and long-term effectiveness of tacrolimus therapy. METHODS: The medical records of 51 patients treated with tacrolimus for UC at our hospital between July 2009 and December 2011 were reviewed retrospectively. Clinical remission and improvement were defined as a Lichtiger score of 4 or less and as a Lichtiger score of <=10 and a reduction in the score of >=3 compared with the baseline score, respectively. Endoscopic findings were evaluated based on the endoscopic activity index and Mayo endoscopic score. RESULTS: The clinical effectiveness combining clinical remission and improvement was observed in 62.7% of the patients at 3 months. Thirty-six patients underwent colonoscopy at 3 months, and 12 (33.3%) and 10 patients (27.8%) showed Mayo endoscopic scores of 0 and 1, respectively. On Kaplan-Meier analysis, the overall percentage of event-free survivors, who did not require colectomy nor switching to other induction therapy such as infliximab, was 73.0% at 6 months, 49.9% at 1 year, and 37.8% at 2 years. Patients with a Mayo endoscopic score of 0-1 at 3 months showed significantly better medium- and long-term prognosis than those with a score of 2-3 (p<0.01). All adverse events, including infections in 2 patients, were reversible. CONCLUSIONS: Tacrolimus therapy was effective for inducing clinical and endoscopic remission of steroid-refractory/dependent UC. Endoscopic improvement was associated with favorable medium- and long-term prognosis. PMID- 23680175 TI - US-guided application of Nd:YAG laser in porcine pancreatic tissue: an ex vivo study and numerical simulation. AB - BACKGROUND: Laser ablation (LA) with a neodymium-doped yttrium aluminum garnet (Nd:YAG) laser is a minimally invasive approach able to achieve a high rate of complete tissue necrosis. In a previous study we described the feasibility of EUS guided Nd:YAG pancreas LA performed in vivo in a porcine model. OBJECTIVE: To establish the best laser setting of Nd:YAG lasers for pancreatic tissue ablation. A secondary aim was to investigate the prediction capability of a mathematical model on ablation volume. DESIGN: Ex vivo animal study. SETTING: Hospital animal laboratory. SUBJECTS: Explanted pancreatic glands from 60 healthy farm pigs. INTERVENTION: Laser output powers (OP) of 1.5, 3, 6, 10, 15, and 20 W were supplied. Ten trials for each OP were performed under US guidance on ex vivo healthy porcine pancreatic tissue. MAIN OUTCOME MEASUREMENTS: Ablation volume (Va) and central carbonization volume (Vc) were measured on histologic specimens as the sum of the lesion areas multiplied by the thickness of each slide. The theoretical model of the laser-tissue interaction was based on the Pennes equation. RESULTS: A circumscribed ablation zone was observed in all histologic specimens. Va values grow with the increase of the OP up to 10 W and reach a plateau between 10 and 20 W. The trend of Vc values rises constantly until 20 W. The theoretical model shows a good agreement with experimental Va and Vc for OP between 1.5 and 10 W. LIMITATIONS: Ex vivo study. CONCLUSION: Volumes recorded suggest that the best laser OP could be the lowest one to obtain similar Va with smaller Vc in order to avoid the risk of thermal injury to the surrounding tissue. The good agreement between the two models demonstrates the prediction capability of the theoretical model on laser-induced ablation volume in an ex vivo animal model and supports its potential use for estimating the ablation size at different laser OPs. PMID- 23680176 TI - Prospective randomized comparison of short-access mother-baby cholangioscopy versus direct cholangioscopy with ultraslim gastroscopes. AB - BACKGROUND: Mother-baby technologies, the criterion standard for cholangioscopy, have several limitations. A novel, short-access, mother-baby (SAMBA) system may improve this technique. Direct cholangioscopy (DC) was recently developed as an alternative to mother-baby cholangioscopy. OBJECTIVE: Comparison of success rates with SAMBA and DC. DESIGN: Single-center, randomized, controlled trial. SETTING: Academic tertiary-care referral center. PATIENTS: Sixty patients with suspected cholangiopathies randomized to either SAMBA (n = 30) or DC (n = 30). INTERVENTION: Cholangioscopy under deep sedation. MAIN OUTCOME MEASUREMENTS: Technical success rate of diagnostic or therapeutic procedure. RESULTS: A total of 24 and 21 diagnostic procedures were performed in the SAMBA and DC groups, respectively. There were no significant differences in the overall technical success rates between SAMBA (90.0%) and DC (86.7%) (P = 1.0). There was better correlation between the endoscopic prediction and histologic findings in DC (P = .013). Procedure times were shorter in DC (P < .03). In patients without significant stenoses, SAMBA allowed intrahepatic bile duct exploration in all cases, compared with 10.5% of cases in DC (P < .01). No differences regarding adverse event rates between the groups occurred (10.0% both groups). LIMITATIONS: Small sample size. Heterogeneous indications for cholangioscopy. DC requires advanced skills of the endoscopist. The study is not replicable. CONCLUSION: SAMBA and DC offer high technical success rates for diagnostic and therapeutic interventions. The advantages of DC consist of superior imaging, shorter total procedure time, and a wider working channel for adequate tissue sampling. SAMBA is better than DC with regard to intraductal stability and accessibility of the intrahepatic bile ducts. PMID- 23680177 TI - Early diagnosis and management of delayed bleeding in the submucosal tunnel after peroral endoscopic myotomy for achalasia (with video). PMID- 23680178 TI - A phase II study of endoscopic submucosal dissection for superficial esophageal neoplasms (KDOG 0901). AB - BACKGROUND: Most previous studies of endoscopic submucosal dissection (ESD) for superficial esophageal neoplasms were retrospective; prospective studies are scant. OBJECTIVE: To prospectively assess the efficacy and safety of ESD for superficial esophageal neoplasms. DESIGN: Phase II study. SETTING: University hospital. PATIENTS: Fifty-two patients (median age 68 years; 48 men) who had a histologic diagnosis of superficial esophageal cancer without metastasis on CT or high-grade intraepithelial neoplasia (HGIN) were enrolled from April 2009 through November 2011. INTERVENTION: ESD was used to treat 56 lesions. All procedures were done by 4 endoscopists who each had previously performed ESD in more than 100 patients with gastric tumors. MAIN OUTCOME MEASUREMENTS: The primary endpoint was the R0 resection rate, and secondary endpoints were the safety and the rate of accurately diagnosing tumor depth on endoscopic examination. RESULTS: The median treatment time was 69 minutes (24-168 minutes). The histopathologic diagnosis was squamous cell carcinoma in 49 lesions, HGIN in 5, and tubular adenocarcinoma in 2. The en bloc resection rate and R0 resection rate were 100% and 94.6%, respectively. The rates of adverse events during ESD and after ESD were 22.2% and 53.8%, respectively, but most events were mild. One patient (1.9%) had mediastinal emphysema without perforation. The rate of accurately diagnosing tumor depth on endoscopic examination was 76.8%. LIMITATIONS: Single-center, nonrandomized study. CONCLUSION: Our study showed that ESD was an effective and relatively safe treatment for superficial esophageal neoplasms. ESD may be a useful treatment option for superficial esophageal neoplasms in hospitals with endoscopists who are experts in performing ESD for gastric tumors. ( CLINICAL TRIAL REGISTRATION NUMBER: UMIN000002047.). PMID- 23680179 TI - Epithelialized omental patch masquerading as a duodenal lipoma. PMID- 23680180 TI - Interventional chromoendoscopy. PMID- 23680182 TI - The effect of lactose-isomaltulose-containing growing-up milks on cognitive performance of Indonesian children: a cross-over study. AB - Glycaemic response to dietary carbohydrates might have an impact on cognitive performance. The present study investigated the effects of growing-up milks (GUM) with isomaltulose and extra minerals and vitamins or lower protein content on cognitive parameters in children aged 5-6 years. In a blinded, partly randomised, controlled, cross-over study, four GUM were provided, each taken over 14 d (2 * 200 ml/d): standard (Std) GUM; Std GUM+5 g isomaltulose (Iso-5 GUM); Iso-5 GUM with 26 % less protein (Iso-5 LP GUM); Std GUM with 2.5 g isomaltulose and extra Mg, Zn, Se, D3, B1, B2, B12, folic acid and choline (Iso-2.5 GUM). At test days, when GUM replaced breakfast, repeated (0, 60, 120 and 180 min post-dose) cognitive tasks were performed (picture presentation, simple reaction time, digit vigilance, choice reaction time, spatial and numeric working memory and picture recognition). Task performance of all subjects (n 50) worsened over the morning. Best performance was seen on isomaltulose GUM, most notably at 180 min. Iso-2.5 GUM showed best performance on several parameters of attention and memory, Iso-5 GUM performed best on parameters of memory and Iso-5 LP GUM was positively associated with parameters of attention but less with memory. Std GUM showed only a benefit on one attention and one memory task. Thus, isomaltulose-enriched GUM positively affected parameters of attention and memory at 180 min post-dose when compared with Std GUM. Extra minerals and vitamins seem beneficial, whereas lowering protein content might improve attention in particular. PMID- 23680181 TI - Challenges for consent and community engagement in the conduct of cluster randomized trial among school children in low income settings: experiences from Kenya. AB - BACKGROUND: There are a number of practical and ethical issues raised in school based health research, particularly those related to obtaining consent from parents and assent from children. One approach to developing, strengthening, and supporting appropriate consent and assent processes is through community engagement. To date, much of the literature on community engagement in biomedical research has concentrated on community- or hospital-based research, with little documentation, if any, of community engagement in school-based health research. In this paper we discuss our experiences of consent, assent and community engagement in implementing a large school-based cluster randomized trial in rural Kenya. METHODS: Data collected as part of a qualitative study investigating the acceptability of the main trial, focus group discussions with field staff, observations of practice and authors' experiences are used to: 1) highlight the challenges faced in obtaining assent/consent; and 2) strategies taken to try to both protect participant rights (including to refuse and to withdraw) and ensure the success of the trial. RESULTS: Early meetings with national, district and local level stakeholders were important in establishing their co-operation and support for the project. Despite this support, both practical and ethical challenges were encountered during consenting and assenting procedures. Our strategy for addressing these challenges focused on improving communication and understanding of the trial, and maintaining dialogue with all the relevant stakeholders throughout the study period. CONCLUSIONS: A range of stakeholders within and beyond schools play a key role in school based health trials. Community entry and information dissemination strategies need careful planning from the outset, and with on-going consultation and feedback mechanisms established in order to identify and address concerns as they arise. We believe our experiences, and the ethical and practical issues and dilemmas encountered, will be of interest for others planning to conduct school-based research in Africa. TRIAL REGISTRATION: National Institute of Health NCT00878007. PMID- 23680183 TI - Evidence of apoptosis in Raillietina echinobothrida induced by methanolic extracts of three traditional medicinal plants of Northeast India. AB - The therapeutic benefits of medicinal plants in terms of anthelmintic properties are known since time immemorial in India, particularly among natives of the Northeast India. However, only sporadic and scarce reports on scientific validation of these plants are available. The present study was conducted on the cestode Raillietina echinobothrida, to establish whether the anthelmintic activity of Potentilla fulgens, Alpinia nigra and Millettia pachycarpa was mediated by apoptosis or not. Light microscopic observation following MTT assay revealed the highest percentage of inhibition of viability among the worms by methanol extract of M. pachycarpa (89.33%), followed by A. nigra (65%) and P. fulgens (37%). Ultrastructural observations revealed swelling of mitochondria, disruption of mitochondrial membrane, vacuolization of mitochondria, appearance of apoptotic bodies in the cytoplasm, disintegration of nuclear membrane and nucleolus were very common throughout the tegument. DAPI stained specimens showed typical morphology of apoptosis, like nuclear condensation and fragmentation in the extracts treated parasites. A decrease in mitochondrial membrane potential was also recorded in the treated groups. Confirmatory TUNEL assay and DNA fragmentation assay of the extracts treated parasites also confirmed the apoptotic nature of cell death and is concluded to be responsible for paralysis and death of the parasite. PMID- 23680184 TI - Entamoeba histolytica antigenic protein detected in pus aspirates from patients with amoebic liver abscess. AB - Entamoeba histolytica is a causative agent of amoebic liver abscess (ALA) and is endemic in many underdeveloped countries. We investigated antigenic E. histolytica proteins in liver abscess aspirates using proteomics approach. Pus samples were first tested by real-time PCR to confirm the presence of E. histolytica DNA and the corresponding serum samples tested for E. histolytica specific IgG by a commercial ELISA. Proteins were extracted from three and one pool(s) of pus samples from ALA and PLA (pyogenic liver abscess) patients respectively, followed by analysis using isoelectric focussing, SDS-PAGE and Western blot. Unpurified pooled serum samples from infected hamsters and pooled human amoebic-specific IgG were used as primary antibodies. The antigenic protein band was excised from the gel, digested and analysed by MALDI-TOF/TOF and LC MS/MS. The results using both primary antibodies showed an antigenic protein band of ~14kDa. Based on the mass spectrum analysis, putative tyrosine kinase is the most probable identification of the antigenic band. PMID- 23680185 TI - Activation of the nuclear receptor FXR enhances hepatocyte chemoprotection and liver tumor chemoresistance against genotoxic compounds. AB - The success of pharmacological treatments in primary liver cancers is limited by the marked efficacy of mechanisms of chemoresistance already present in hepatocytes. The role of the nuclear receptor FXR is unclear. Although, in non treated liver tumors, its expression is reduced, the refractoriness to anticancer drugs is high. Moreover, the treatment with cisplatin up-regulates FXR. The aim of this study was to investigate whether FXR is involved in stimulating chemoprotection/chemoresistance in healthy and tumor liver cells. In human hepatocytes, the activation of FXR with the agonist GW4064 resulted in a significant protection against cisplatin-induced toxicity. In human hepatoma Alexander cells, with negligible endogenous expression of FXR, GW4064 also protected against cisplatin-induced toxicity, but only if they were previously transfected with FXR/RXR. Investigation of 109 genes potentially involved in chemoresistance revealed that only ABCB4, TCEA2, CCL14, CCL15 and KRT13 were up regulated by FXR activation both in human hepatocytes and FXR/RXR-expressing hepatoma cells. In both models, cisplatin, even in the absence of FXR agonists, such as bile acids and GW4064, was able to up-regulate FXR targets genes, which was due to FXR-mediated trans-activation of response elements in the promoter region. FXR-dependent chemoprotection was also efficient against other DNA damaging compounds, such as doxorubicin, mitomycin C and potassium dichromate, but not against non-genotoxic drugs, such as colchicine, paclitaxel, acetaminophen, artesunate and sorafenib. In conclusion, ligand-dependent and independent activation of FXR stimulates mechanisms able to enhance the chemoprotection of hepatocytes against genotoxic compounds and to reduce the response of liver tumor cells to certain pharmacological treatments. PMID- 23680186 TI - Inhibition of 14-3-3 binding to Rictor of mTORC2 for Akt phosphorylation at Ser473 is regulated by selenoprotein W. AB - 14-3-3 reduces cell proliferation by inhibiting the activity of proteins involved in the signaling pathway that includes Akt kinase. Activation of Akt is enhanced by activating the mammalian target of rapamycin complex 2 (mTORC2). 14-3-3 is also a negative regulator of the mTORC2/Akt pathway, by interacting with a component of mTORC2. Recently, we reported that selenoprotein W (SelW) regulated the interaction between 14-3-3 and its target protein, CDC25B. Here, we show that the binding of Rictor, a component of mTORC2, to 14-3-3, is regulated by the interaction of 14-3-3 with SelW. When SelW was down-regulated, mTORC2-dependent phosphorylation of Akt at Ser473 was decreased. However, the phosphorylation of Thr308 was not affected. The interaction of Rictor with 14-3-3 was increased in SelW-knockdown cells, as compared to control cells. SelW-knockdown cells were also more sensitive to DNA damage induced by etoposide, than control cells. This phenomenon was due to the decreased phosphorylation of Akt at Ser473. We also found that ectopic expression of SelW(U13C) reduced the interaction between Rictor and 14-3-3, leading to Akt phosphorylation at Ser473. Taken together, these findings demonstrate that SelW activates the mTORC2/Akt pathway for Akt phosphorylation at Ser473, by interrupting the binding of Rictor to 14-3-3. PMID- 23680187 TI - Brain modifications after acute alcohol consumption analyzed by resting state fMRI. AB - Resting-state functional magnetic resonance imaging (fMRI) is a recent breakthrough in neuroimaging research able to describe "in vivo" the spontaneous baseline neuronal activity characterized by blood oxygen level dependent (BOLD) signal fluctuations at slow frequency (0.01-0.1Hz) that, in the absence of any task, forms spatially distributed functional connectivity networks, called resting state networks (RSNs). The aim of this study was to investigate, in the young and healthy population, the changing of the RSNs after acute ingestion of an alcohol dose able to determine a blood concentration (0.5g/L) that barely exceeds the legal limits for driving in the majority of European Countries. Fifteen healthy volunteers underwent two fMRI sessions using a 1.5T MR scanner before and after alcohol oral consumption. The main sequence acquired was EPI 2D BOLD, one per each session. To prevent the excessive alcohol consumption the subjects underwent the estimation of blood rate by breath test and after the stabilization of blood alcohol level (BAL) at 0.5g/L the subjects underwent the second fMRI session. Functional data elaboration was carried out using the probabilistic independent component analysis (PICA). Spatial maps so obtained were further organized, with MELODIC multisession temporal concatenation FSL option, in a cluster representing the group of pre-alcohol sessions and the group of post-alcohol sessions, followed by the dual regression approach in order to evaluate the increase or decrease in terms of connectivity in the RSNs between the two sessions at group level. The results we obtained reveal that acute consumption of alcohol reduces in a significant way the BOLD signal fluctuations in the resting brain selectively in the sub-callosal cortex (SCC), in left temporal fusiform cortex (TFC) and left inferior temporal gyrus (ITG), which are cognitive regions known to be part of the reward brain network and the ventral visual system. PMID- 23680189 TI - Facile approach to prepare multi-walled carbon nanotubes/graphene nanoplatelets hybrid materials. AB - A facile approach was developed to prepare multi-walled carbon nanotubes/graphene nanoplatelets hybrid materials through covalent bond formation. First, poly(acryloyl chloride) was grafted onto oxidized multi-walled carbon nanotubes through the reaction between the acyl chloride groups of poly and the hydroxyl groups of oxidized multi-walled carbon nanotubes. Second, the remaining acyl chloride groups of poly were allowed to react with the hydroxyl groups of hydroxylated graphene nanoplatelets. Scanning electron microscopy and transmission electron microscopy data showed that the multi-walled carbon nanotubes and graphene nanoplatelets were effectively connected with each other. And Fourier transform infrared spectroscopy data indicated the formation of covalent bonds between carbon nanotubes and graphene nanoplatelets. Conformational changes were monitored by Raman spectroscopy. This novel kind of carbon hybrid materials may have the potential application in a wide field, especially in increasing the toughness and strength of the matrix resin. PMID- 23680188 TI - Small RNAs: a new frontier in mosquito biology. AB - The discovery of small non-coding RNAs has revolutionized our understanding of regulatory networks governing multiple functions in animals and plants. However, our knowledge of mosquito small RNAs is limited. We discuss here the state of current knowledge regarding the roles of small RNAs and their targets in mosquitoes, and describe the ongoing efforts to understand the role of the RNA interference (RNAi) pathway in mosquito antiviral immunity and transposon silencing. Providing a clear picture into the role of small RNAs in mosquito vectors will pave the way to the utilization of these small molecules in developing novel control approaches that target mosquito immunity and/or reproductive events. Elucidation of the functions of small RNAs represents a new frontier in mosquito biology. PMID- 23680190 TI - Factors associated with vitamin D deficiency in a population of 2044 HIV-infected patients. AB - BACKGROUND AND AIMS: The high prevalence of vitamin D deficiency in HIV-infected patients has been demonstrated but there are still controversies regarding to the role of antiretroviral therapy (ART) in this setting. The aims of this study was to validate factors associated with vitamin D deficiency in a large cohort of HIV infected patients. METHODS: A retrospective analysis of 2044 consecutive patients from December 2005 to March 2011 was conducted. Factors independently associated with vitamin D deficiency (<30 ng/ml and <10 ng/ml) were analyzed. Vitamin D levels were compared according to CD4 count, viral load and ART modalities. RESULTS: vitamin D was <30 ng/ml in 89.2% and <10 ng/ml in 32.4%. The median value was 13.8 ng/ml (4-102). Winter season, female sex, heterosexual acquisition of HIV, the need of second lines (complex and sequential treatment modalities) and a longer duration of ART were independently associated with vitamin D deficiency (<30 ng/ml). CD4 count <200/MUl, advanced stages of disease and the current efavirenz use were independently associated with severe vitamin D deficiency (<10 ng/ml). Median vitamin D levels was 14.1 ng/dl when CD4 >=200/MUl, 11.5 ng/dl when CD4<200 (p = 0.0003). The ART modalities had a significant influence on vitamin D concentrations, the highest vitamin D level was observed in the absence of treatment. CONCLUSIONS: In HIV-infected patients, vitamin D deficiency is associated with ART modalities and duration. The most severe vitamin D deficiencies are associated with low CD4 count, the use of efavirenz and advanced stages of disease severity. PMID- 23680191 TI - Dissecting plant iron homeostasis under short and long-term iron fluctuations. AB - A wealth of information on the different aspects of iron homeostasis in plants has been obtained during the last decade. However, there is no clear road-map integrating the relationships between the various components. The principal aim of the current review is to fill this gap. In this context we discuss the lack of low affinity iron uptake mechanisms in plants, the utilization of a different uptake mechanism by graminaceous plants compared to the others, as well as the roles of riboflavin, ferritin isoforms, nitric oxide, nitrosylation, heme, aconitase, and vacuolar pH. Cross-homeostasis between elements is also considered, with a specific emphasis on the relationship between iron homeostasis and phosphorus and copper deficiencies. As the environment is a crucial parameter for modulating plant responses, we also highlight how diurnal fluctuations govern iron metabolism. Evolutionary aspects of iron homeostasis have so far attracted little attention. Looking into the past can inform us on how long-term oxygen and iron-availability fluctuations have influenced the evolution of iron uptake mechanisms. Finally, we evaluate to what extent this homeostastic road map can be used for the development of novel biofortification strategies in order to alleviate iron deficiency in human. PMID- 23680192 TI - Production of bioelectricity, bio-hydrogen, high value chemicals and bioinspired nanomaterials by electrochemically active biofilms. AB - Microorganisms naturally form biofilms on solid surfaces for their mutual benefits including protection from environmental stresses caused by contaminants, nutritional depletion or imbalances. The biofilms are normally dangerous to human health due to their inherited robustness. On the other hand, a recent study suggested that electrochemically active biofilms (EABs) generated by electrically active microorganisms have properties that can be used to catalyze or control the electrochemical reactions in a range of fields, such as bioenergy production, bioremediation, chemical/biological synthesis, bio-corrosion mitigation and biosensor development. EABs have attracted considerable attraction in bioelectrochemical systems (BESs), such as microbial fuel cells and microbial electrolysis cells, where they act as living bioanode or biocathode catalysts. Recently, it was reported that EABs can be used to synthesize metal nanoparticles and metal nanocomposites. The EAB-mediated synthesis of metal and metal semiconductor nanocomposites is expected to provide a new avenue for the greener synthesis of nanomaterials with high efficiency and speed than other synthetic methods. This review covers the general introduction of EABs, as well as the applications of EABs in BESs, and the production of bio-hydrogen, high value chemicals and bio-inspired nanomaterials. PMID- 23680193 TI - Flux analysis and metabolomics for systematic metabolic engineering of microorganisms. AB - Rational engineering of metabolism is important for bio-production using microorganisms. Metabolic design based on in silico simulations and experimental validation of the metabolic state in the engineered strain helps in accomplishing systematic metabolic engineering. Flux balance analysis (FBA) is a method for the prediction of metabolic phenotype, and many applications have been developed using FBA to design metabolic networks. Elementary mode analysis (EMA) and ensemble modeling techniques are also useful tools for in silico strain design. The metabolome and flux distribution of the metabolic pathways enable us to evaluate the metabolic state and provide useful clues to improve target productivity. Here, we reviewed several computational applications for metabolic engineering by using genome-scale metabolic models of microorganisms. We also discussed the recent progress made in the field of metabolomics and (13)C metabolic flux analysis techniques, and reviewed these applications pertaining to bio-production development. Because these in silico or experimental approaches have their respective advantages and disadvantages, the combined usage of these methods is complementary and effective for metabolic engineering. PMID- 23680194 TI - E-professionalism at the dermatology office: new challenges to confidentiality in the era of social networking. PMID- 23680195 TI - Internet dermatology resources. PMID- 23680196 TI - Physician Global Assessment (PGA) and Psoriasis Area and Severity Index (PASI): why do both? A systematic analysis of randomized controlled trials of biologic agents for moderate to severe plaque psoriasis. PMID- 23680197 TI - Novel systemic drugs for psoriasis: mechanism of action for apremilast, a specific inhibitor of PDE4. PMID- 23680198 TI - Reply: To PMID 22459360. PMID- 23680199 TI - Add Pittsburgh teledermatology "with a twist" to the map! PMID- 23680200 TI - Methotrexate for the treatment of cutaneous dermatomyositis. PMID- 23680201 TI - Cantharidin therapy: practice patterns and attitudes of health care providers. PMID- 23680202 TI - Investigation of molluscum contagiosum virus, orf and other parapoxviruses in lymphomatoid papulosis. PMID- 23680203 TI - Successful treatment of alopecia totalis with hydroxychloroquine: report of 2 cases. PMID- 23680204 TI - What's new in pediatric dermatology?: part I. Diagnosis and pathogenesis. AB - The field of pediatric dermatology has been rich in new developments. Part I of this continuing medical education article will focus on new diagnoses and new insights into the etiology and pathogenesis of pediatric skin disorders. Insights into the pathogenesis of atopic dermatitis, new forms of contact dermatitis, recently recognized mimickers of port wine stains, associations with infantile hemangiomas, the concept of genetic diseases being classified by common pathways (RASopathies), newly recognized genetic discoveries in mosaic disorders, the recognition of cystic fibrosis being associated with aquagenic wrinkling of the palms, new forms of epidermolysis bullosa, and genital ulcers in non-sexually active adolescent girls will be discussed. PMID- 23680205 TI - What's new in pediatric dermatology?: part II. Treatment. AB - The field of pediatric dermatology has been rich in new developments. Part II of this continuing medical education article will focus on new therapeutic modalities for several entities encountered in pediatric dermatology. The treatment of atopic dermatitis, exciting advances in the use of propranolol and other beta-blockers for the use of infantile hemangiomas, the use of rapamycin for vascular anomalies, the use of biologics in children, the central nervous system risks of general anesthesia in young children, side effects in the use of isotretinoin, the treatment of tinea capitis, treatment of herpes simplex infections, and the use of technologies such as texting and social media in medicine will be discussed. PMID- 23680208 TI - A de novo SOX10 mutation in a patient with Waardenburg syndrome type IV. PMID- 23680209 TI - Disseminated keratotic spicules: a rare manifestation in multiple myeloma and successful response to lenalidomide. PMID- 23680210 TI - Pityriasis rosea-like eruption associated with lamotrigine. PMID- 23680211 TI - Effectiveness of topical maxacalcitol for acquired perforating disorder. PMID- 23680212 TI - Tumor necrosis factor inhibition and glucose homeostasis. PMID- 23680213 TI - Pasteurella multocida cellulitis in a 15-year-old male with chronic lymphedema. PMID- 23680214 TI - Acquired perforating dermatosis associated with natalizumab. PMID- 23680215 TI - Acute treatment of generalized pustular psoriasis of von Zumbusch with single dose infliximab. PMID- 23680216 TI - Localized myxedema of thyroid disease. PMID- 23680217 TI - Dermoscopy of a Sister Mary Joseph nodule. PMID- 23680218 TI - Bullous pemphigoid associated with chronic renal allograft rejection. PMID- 23680219 TI - Red fingers syndrome in a patient with pseudolymphoma. PMID- 23680220 TI - Carcinomatous lymphangitis in lymphoepithelial carcinoma of the parotid. PMID- 23680221 TI - Bullae and psoriasiform hyperkeratosis after treatment with golimumab. PMID- 23680222 TI - Introduction of routine polymerase chain reaction testing for Neisseria gonorrhoeae in a community laboratory. AB - We introduced polymerase chain reaction (PCR) testing for Neisseria gonorrhoeae (NG) on the Cobas 4800 CT/NG assay for all samples received with a Chlamdyia trachomatis request in March 2012. From 1 March 2012 to 30 June 2012, all PCR positive/culture-negative specimens had additional testing at another assay. A total of 40053 tests were performed. The estimated specificity and positive predictive value were 99.9% and 97.1%, respectively; thus routine additional testing is not required. PMID- 23680223 TI - Overdiagnosis in breast cancer screening: the importance of length of observation period and lead time. AB - BACKGROUND: Overdiagnosis in breast cancer screening is a controversial topic. One difficulty in estimation of overdiagnosis is the separation of overdiagnosis from lead time that is the advance in the time of diagnosis of cancers, which confers an artificial increase in incidence when a screening programme is introduced. METHODS: We postulated a female population aged 50-79 with a similar age structure and age-specific breast cancer incidence as in England and Wales before the screening programme. We then imposed a two-yearly screening programme; screening women aged 50-69, to run for twenty years, with exponentially distributed lead time with an average of 40 months in screen-detected cancers. We imposed no effect of the screening on incidence other than lead time. RESULTS: Comparison of age- and time-specific incidence between the screened and unscreened populations showed a major effect of lead time, which could only be adjusted for by follow-up for more than two decades and including ten years after the last screen. From lead time alone, twenty-year observation at ages 50-69 would confer an observed excess incidence of 37%. The excess would only fall below 10% with 25 years or more follow-up. For the excess to be nullified, we would require 30 year follow-up including observation up to 10 years above the upper age limit for screening. CONCLUSION: Studies using shorter observation periods will overestimate overdiagnosis by inclusion of cancers diagnosed early due to lead time among the nominally overdiagnosed tumours. PMID- 23680224 TI - Efficacy of dehydroepiandrosterone to improve ovarian response in women with diminished ovarian reserve: a meta-analysis. AB - Women with diminished ovarian reserve often respond poorly to controlled ovarian stimulation resulting in retrieval of fewer oocytes and reduced pregnancy rates. It has been proposed that pre-IVF Dehydroepiandrosterone (DHEA) adjuvant therapy may improve ovarian response and pregnancy rates in women with diminished ovarian reserve. This meta-analysis aims to investigate efficacy of DHEA as an adjuvant to improve ovarian response and IVF outcome in women with diminished ovarian reserve. Electronic databases were searched under the following terms: (DHEA) and (diminished ovarian reserve) and/or (poor response). Studies were included if they reported at least one of the following outcomes; clinical pregnancy rate, number of oocytes retrieved, miscarriage rate. We identified 22 publications determining effects of DHEA in clinical trials. Only 3 controlled studies were eligible for meta-analysis. There was no significant difference in the clinical pregnancy rate and miscarriage rates between women pre-treated with DHEA compared to those without DHEA pre-treatment (RR 1.87, 95% CI 0.96-3.64; and RR 0.59, 95% CI 0.21-1.65, respectively). The number of oocytes retrieved (WMD -1.88, 95% CI 2.08, 1.67; P < 0.001) was significantly lower in the DHEA group. In conclusion, based on the limited available evidence from a total of approximately 200 IVF cycles, there are insufficient data to support a beneficial role of DHEA as an adjuvant to controlled ovarian stimulation in IVF cycle. Well-designed, randomised controlled trials as well as more exact knowledge about DHEA mechanisms of action are needed to support use of DHEA in standard practice for poor-responders. PMID- 23680225 TI - The face of appearance-related social pressure: gender, age and body mass variations in peer and parental pressure during adolescence. AB - BACKGROUND: Appearance-related social pressure plays an important role in the development of a negative body image and self-esteem as well as severe mental disorders during adolescence (e.g. eating disorders, depression). Identifying who is particularly affected by social pressure can improve targeted prevention and intervention, but findings have either been lacking or controversial. Thus the aim of this study is to provide a detailed picture of gender, weight, and age related variations in the perception of appearance-related social pressure by peers and parents. METHODS: 1112 German students between grades 7 and 9 (mean age: M = 13.38, SD = .81) filled in the Appearance-Related Social Pressure Questionnaire (German: FASD), which considers different sources (peers, parents) as well as various kinds of social pressure (e.g. teasing, modeling, encouragement). RESULTS: Girls were more affected by peer pressure, while gender differences in parental pressure seemed negligible. Main effects of grade-level suggested a particular increase in indirect peer pressure (e.g. appearance related school and class norms) from early to middle adolescence. Boys and girls with higher BMI were particularly affected by peer teasing and exclusion as well as by parental encouragement to control weight and shape. CONCLUSION: The results suggest that preventive efforts targeting body concerns and disordered eating should bring up the topic of appearance pressure in a school-based context and should strengthen those adolescents who are particularly at risk - in our study, girls and adolescents with higher weight status. Early adolescence and school transition appear to be crucial periods for these efforts. Moreover, the comprehensive assessment of appearance-related social pressure appears to be a fruitful way to further explore social risk-factors in the development of a negative body image. PMID- 23680226 TI - Ultra-early tranexamic acid after subarachnoid hemorrhage (ULTRA): study protocol for a randomized controlled trial. AB - BACKGROUND: A frequent complication in patients with subarachnoid hemorrhage (SAH) is recurrent bleeding from the aneurysm. The risk is highest within the first 6 hours after the initial hemorrhage. Securing the aneurysm within this timeframe is difficult owing to logistical delays. The rate of recurrent bleeding can also be reduced by ultra-early administration of antifibrinolytics, which probably improves functional outcome. The aim of this study is to investigate whether ultra-early and short-term administration of the antifibrinolytic agent tranexamic acid (TXA), as add-on to standard SAH management, leads to better functional outcome. METHODS/DESIGN: This is a multicenter, prospective, randomized, open-label trial with blinded endpoint (PROBE) assessment. Adult patients with the diagnosis of non-traumatic SAH, as proven by computed tomography (CT) within 24 hours after the onset of headache, will be randomly assigned to the treatment group or the control group. Patients in the treatment group will receive standard treatment with the addition of a bolus of TXA (1 g intravenously) immediately after randomization, followed by continuous infusion of 1 g per 8 hours until the start of aneurysm treatment, or a maximum of 24 hours after the start of medication. Patients in the control group will receive standard treatment without TXA. The primary outcome measure is favorable functional outcome, defined as a score of 0 to 3 on the modified Rankin Scale (mRS), at 6 months after SAH. Primary outcome will be determined by a trial nurse blinded for treatment allocation. We aim to include 950 patients in 3 years. DISCUSSION: The strengths of this study are: 1. the ultra-early and short-term administration of TXA, resulting in a lower dose as compared to previous studies, which should reduce the risk for delayed cerebral ischemia (DCI), an important risk factor in the long-term treatment with antifibrinolytics; 2. the power calculation is based on functional outcome and calculated with use of recent study results of our own population, supported by data from prominent studies; and 3. the participation of several specialized SAH centers, and their referring hospitals, in the Netherlands with comparative treatment protocols. TRIAL REGISTRATION: Nederlands Trial Register (Dutch Trial Registry) number NTR3272. PMID- 23680227 TI - Zoned Out: "NIMBYism", addiction services and municipal governance in British Columbia. AB - In Canada, Provincial Governments have jurisdiction over delivery of healthcare including harm reduction services and Methadone Maintenance Therapy (MMT). While policy directives and funding come from the provincial capital, individuals' access to these services happens in neighbourhoods and municipalities spread out across the province. In some cases, public health objectives targeted at people living with addictions and the rights to equitable access to healthcare are at odds with the vision that residents, business associations and other interest groups have for their neighbourhood or city. This paper looks at the cases of four British Columbia municipalities, Mission, Surrey, Coquitlam and Abbotsford, where local governments have used zoning provisions to restrict access to harm reduction services and drug substitution therapies including MMT. This paper will contextualize these case studies in a survey of zoning and bylaw provisions related to harm reduction and MMT across British Columbia, and examine the interplay between municipal actions and public discourses that affect access to healthcare for people living with addictions. Finally, this paper will explore possible legal implications for municipalities that use their zoning and permitting powers to restrict access to health care for people with addictions, as well as public engagement strategies for healthcare advocates that have the potential to reduce resistance to health services for people living with addictions in communities across the province. PMID- 23680228 TI - Performance and determinants of routine immunization coverage within the context of intensive polio eradication activities in Uttar Pradesh, India: Social Mobilization Network (SM Net) and Core Group Polio Project (CGPP). AB - BACKGROUND: Studies that have looked at the effect of polio eradication efforts in India on routine immunization programs have provided mixed findings. One polio eradication project, funded by US Agency for International Development (USAID) and carried out by the CORE Group Polio Project (CGPP) in the state of Uttar Pradesh of India, has included the strengthening of routine immunization systems as a core part of its polio eradication strategy. This paper explores the performance of routine immunization services in the CGPP intervention areas concurrent with intensive polio eradication activities. The paper also explores determinants of routine immunization performance such as caretaker characteristics and CGPP activities to strengthen routine immunization services. METHODS: We conduct secondary data analysis of the latest project household immunization survey in 2011 and compare these findings to reports of past surveys in the CGPP program area and at the Uttar Pradesh state level (as measured by children's receipt of DPT vaccinations). This is done to judge if there is any evidence that routine immunization services are being disrupted. We also model characteristics of survey respondents and respondents' exposure to CGPP, communication activities against their children's receipt of key vaccinations in order to identify determinants of routine immunization coverage. RESULTS: Routine immunization coverage has increased between the first survey (2005 for state level estimates, 2008 for the CGPP program) and the latest (2011 for both state level and CGPP areas), as measured by children's receipt of DPT vaccination. This increase occurred concurrent with polio eradication efforts intensive enough to result in interruption of transmission. In addition, a mothers' exposure to specific communication materials, her religion and education were associated with whether or not her children receive one or more doses of DPT. CONCLUSIONS: A limitation of the analysis is the absence of a controlled comparison. It is possible routine immunization coverage would have increased even more in the absence of polio eradication efforts. At the same time, however, there is no evidence that routine immunization services were disrupted by polio eradication efforts. Targeted health communications are helpful in improving routine immunization performance. Strategies to address other determinants of routine immunization, such as religion and education, are also needed to maximize coverage. PMID- 23680229 TI - Abstracts of scientific papers 18th world congress on disaster and emergency medicine. PMID- 23680230 TI - No association between the intake of marine n-3 PUFA during the second trimester of pregnancy and factors associated with cardiometabolic risk in the 20-year-old offspring. AB - The intake of marine n-3 PUFA has been shown to decrease the risk of CVD in a number of studies. Since the development of CVD is often a lifelong process, marine n-3 PUFA intake early in life may also affect the development of later CVD. The aim of the present study was to investigate the association between maternal intake of marine n-3 PUFA during the second trimester of pregnancy and factors associated with cardiometabolic risk in the 20-year-old offspring. The study was based on the follow-up of the offspring of a Danish pregnancy cohort who participated in a study conducted from 1988 to 1989. A total of 965 pregnant women were originally included in the cohort and detailed information about the intake of marine n-3 PUFA during the second trimester was collected. In 2008-9, the offspring were invited to participate in a clinical examination including anthropometric, blood pressure (BP) and short-term heart rate variability measurements. Also, a fasting venous blood sample was drawn from them. Multiple linear regression modelling, using the lowest quintile of marine n-3 PUFA intake as the reference, was used to estimate the association with all outcomes. A total of 443 offspring participated in the clinical examination. No association between the intake of marine n-3 PUFA during the second trimester of pregnancy and offspring adiposity, glucose metabolism, BP or lipid profile was found. In conclusion, no association between the intake of marine n-3 PUFA during the second trimester of pregnancy and the factors associated with cardiometabolic risk in the 20-year-old offspring could be detected. PMID- 23680231 TI - Efficacy of coating activated carbon with milk proteins to prevent binding of bacterial cells from foods for PCR detection. AB - Foods contaminated with pathogens are common sources of illness. Currently, the most common and sensitive rapid detection method involves the PCR. However, food matrices are complex and contain inhibitors that limit the sensitivity of the PCR. The use of coated activated carbon can effectively facilitate the removal of PCR inhibitors without binding targeted bacterial cells from food samples. With the use of activated carbon coated with milk proteins, a cell recovery at pH 7.0 of 95.7%+/-2.0% was obtained, compared to control uncoated activated carbon, which yielded a cell recovery of only 1.1%+/-0.8%. In addition, the milk protein coated activated carbon was able to absorb similar amounts of soluble compounds as uncoated activated carbon, with the exception of bovine hemoglobin. This suggests that the use of milk proteins to coat activated carbon may therefore serve as a suitable replacement for bentonite in the coating of activated carbon, which has previously been used for the removal of PCR inhibitors from food. PMID- 23680232 TI - Application of probabilistic neural network in bacterial identification by biochemical profiles. AB - An algorithm of Probabilistic Neural Network (PNN) for bacterial identification based on the probability matrix of API 20E system as a case study is reported. The PNN shows the correct identification of all the taxa belonging to the training and test sets and possesses merits over the conventional methods. PMID- 23680233 TI - Recovery of soil unicellular eukaryotes: an efficiency and activity analysis on the single cell level. AB - Eukaryotic unicellular organisms are an important part of the soil microbial community, but they are often neglected in soil functional microbial diversity analysis, principally due to the absence of specific investigation methods in the special soil environment. In this study we used a method based on high-density centrifugation to specifically isolate intact algal and yeast cells, with the aim to analyze them with flow cytometry and sort them for further molecular analysis such as deep sequencing. Recovery efficiency was tested at low abundance levels that fit those in natural environments (10(4) to 10(6) cells per g soil). Five algae and five yeast morphospecies isolated from soil were used for the testing. Recovery efficiency was between 1.5 to 43.16% and 2 to 30.2%, respectively, and was dependent on soil type for three of the algae. Control treatments without soil showed that the majority of cells were lost due to the method itself (58% and 55.8% respectively). However, the cell extraction technique did not much compromise cell vitality because a fluorescein di-acetate assay indicated high viability percentages (73.3% and 97.2% of cells, respectively). The low abundant algae and yeast morphospecies recovered from soil were cytometrically analyzed and sorted. Following, their DNA was isolated and amplified using specific primers. The developed workflow enables isolation and enrichment of intact autotrophic and heterotrophic soil unicellular eukaryotes from natural environments for subsequent application of deep sequencing technologies. PMID- 23680234 TI - A high throughput method for enrichment of natural killer cells and lymphocytes and assessment of in vitro cytotoxicity. AB - In vitro assessment of lymphocyte and natural killer (NK) cell cytotoxicity typically employs density gradient centrifugation and magnetic cell separation to isolate effector cells, and chromium release to assess cytotoxicity. In order to improve the rapidity and scalability of in vitro cytotoxicity assessment, we evaluated the efficacy of a protocol utilizing tetrameric antibody complexes and SepMateTM isolation tubes to negatively select NK cells (TACs/Sep), and calcein AM release to measure cytotoxicity. We compared the efficiency and accuracy of this protocol to a conventional approach employing density gradient centrifugation and magnetically labeled antibodies (DG/MACS) to isolate NK cells and chromium release to measure cytotoxicity. The TACs/Sep method significantly decreased the time required for NK cell isolation (1h vs. 4h), but resulted in higher red blood cell contamination. NK cell activation marker expression (including CD94, NKG2D, NKp30, NKp46, DNAM-1, 2B4, KIR2DL1/S1, KIR2DL2/L3, intracellular granzyme B, and perforin) was similar when comparing NK cells isolated by the TACs/Sep or DG/MACS methods, but the TACs/Sep method induced higher expression of CD16. In vitro cytotoxicity against HT29 colon cancer and K562 leukemia cells was not affected by the isolation method. Lastly, by combining the TACs/Sep NK cell isolation method with calcein-acetoxymethyl diacetylester (calcein-AM) release, the time required to assess in vitro cytotoxicity was reduced by 33% (4h) compared to protocols employing DG/MACS and chromium release. Altogether, these results provide the foundation for the development of a rapid, high throughput functional assay, and make it practical for the multiplexing of downstream applications, such as flow cytometric analysis and enzyme-linked immunosorbent assays (ELISAs). PMID- 23680235 TI - AXM mutagenesis: an efficient means for the production of libraries for directed evolution of proteins. AB - Affinity maturation is an important part of the recombinant antibody development process. There are several well-established approaches for generating libraries of mutated antibody genes for affinity maturation, but these approaches are generally too laborious or expensive to allow high-throughput, parallel processing of multiple antibodies. Here, we describe a scalable approach that enables the generation of libraries with greater than 10(8) clones from a single Escherichia coli transformation. In our method, a mutated DNA fragment is produced using PCR conditions that promote nucleotide misincorporation into newly synthesized DNA. In the PCR reaction, one of the primers contains at least three phosphorothioate linkages at its 5' end, and treatment of the PCR product with a 5' to 3' exonuclease is used to preferentially remove the strand synthesized with the non-modified primer, resulting in a single-stranded DNA fragment. This fragment then serves as a megaprimer to prime DNA synthesis on a uracilated, circular, single-stranded template in a Kunkel-like mutagenesis reaction that biases nucleotide base-changes between the megaprimer and uracilated DNA sequence in favor of the in vitro synthesized megaprimer. This method eliminates the inefficient subcloning steps that are normally required for the construction of affinity maturation libraries from randomly mutagenized antibody genes. PMID- 23680236 TI - Cassandra's prophecy: a public heath perspective. AB - A public health approach to informing women about age-related fertility decline is best targeted indirectly through professionals. PMID- 23680238 TI - Cephalothin susceptibility testing as class representative for oral cephalosporins: is it time to move on? AB - Based on current epidemiologic and resistance trends, we propose reconsideration of the use of cephalothin susceptibility to predict susceptibility to oral narrow spectrum cephalosporins among Enterobacteriaceae, particularly in predicting cephalexin susceptibility for urinary tract isolates. PMID- 23680239 TI - Transport time for blood culture bottles: underlying factors and its consequences. AB - In the present study we investigated transport times for blood cultures from three tertiary-care hospitals to Karolinska University Laboratory and identified predictors of long transport times. Concomitantly, consequences of delayed incubation on total detection time (TDT) were analyzed by in vitro sepsis models. A total of 909 blood cultures were studied. The median (interquartile range) transport time was 9 (3-15) h. The hospital accommodating the microbiology laboratory had the shortest transport time compared to the other two hospitals (P < 0.0001). Samples taken between 16:00-24:00 had longer transport times compared to samples taken between 8:00-16:00 and 24:00-08:00 (P < 0.0001). In vitro experiments showed that TDT was longer for samples pre-incubated at room temperature (RT) for 19 h compared to the ones pre-incubated for 2 h or 9.5 h (P < 0.0001). In conclusion, off-site location, time of sampling and number of transports per day were related to, and predictors of transport time. PMID- 23680240 TI - Detection of Clostridium difficile toxins A, B and binary toxin with slow off rate modified aptamers. AB - Rapid and accurate diagnostic tests for Clostridium difficile infections (CDI) are crucial for management of patients with suspected CDI and for infection control. Enzyme immunoassays for detection of the toxins are routinely used but lack adequate sensitivity. We generated slow off-rate modified aptamers (SOMAmerTM reagents) via in vitro selection (SELEX) that bind toxins A, B and binary toxin with high affinity and specificity. Using SOMAmers alone or in conjunction with antibodies, we have developed toxin assays with a 1 pmol/L (300 pg/mL) limit of detection and a 3 log dynamic range. SOMAmers proved useful as capture or detection agents in equilibrium solution binding radioassays, pull down capture assays, dot blots, and plate- or membrane-based sandwich assays, thus represent a promising alternative to antibodies in diagnostic applications. SOMAmers detected toxins A, B and binary toxin in culture supernatants from toxigenic C. difficile, including a BI/NAP1 strain and historic strains. PMID- 23680241 TI - Periodontal disease and type 1 diabetes mellitus: associations with glycemic control and complications: an Indian perspective. AB - AIM: To evaluate the frequency of periodontal disease in a group of patients with type 1 diabetes mellitus and its relationship with diabetic metabolic control, duration and complications. MATERIALS AND METHODS: A comparison was made of periodontal parameters (plaque index, bleeding index, pocket depth and attachment loss) in a group of diabetic patients versus a group of non-diabetics (n=20). Statistical analysis was performed to evaluate the relationship between periodontal parameters and degree of metabolic control, the duration of the disease and the appearance of complications. RESULTS: Diabetics had greater bleeding index (p<0.001), probing pocket depth (p<0.001) and clinical attachment level (p=0.001). Patients diagnosed for diabetes for shorter duration of time (4 7 years) showed bleeding index-disease severity correlation to be 1.760 +/- 0.434. CONCLUSION: Patients with type 1 diabetes have increased periodontal disease susceptibility. Periodontal inflammation is greatly increased in subjects with longer disease course, poor metabolic control and diabetic complications. PMID- 23680242 TI - Prevalence and risk factors of microalbuminuria in type 2 diabetes mellitus outpatients at University Sains Malaysia Hospital. AB - BACKGROUND AND OBJECTIVE: Microalbuminuria is early stage of diabetic nephropathy as well as a marker of cardiovascular disease. The objective of this study is to determine the prevalence of microalbuminuria and associated risk factors among type 2 diabetic outpatients, attending a diabetic clinic in University Sains Malaysia Hospital (HUSM). PATIENTS AND METHODS: Prospective study design was used in the data collection process. The study sample consists of 1066 type 2 diabetes mellitus outpatients who fit the inclusion criteria. All the patients were recruited from the diabetic outpatient clinics from HUSM. The study period was from January till December 2008. Microalbuminuria was diagnosed if the urinary albumin excretion more than 30 mg/g of creatinine. RESULTS: A total of 1661 patients were included in this study. Microalbuminuria was diagnosed in 273 (25.4%) patients. Multivariate logistic regression analysis indicated that microalbuminuria was positively associated with duration of hypertension (P=0.044), HbA1c (P=0.004), systolic blood pressure (<0.001), creatinine clearance (P=0.007) and the presence of neuropathy (P=0.004). CONCLUSION: High prevalence of microalbuminuria was in type 2 diabetic outpatients. Predictive factors for microalbuminuria were duration of hypertension, HbA1c, systolic blood pressure, creatinine clearance and the presence of neuropathy. The study suggests the need to screen for microalbuminuria early and the active management of modifiable risk factors in particular, hyperglycemia, hypertension and creatinine clearance, to reduce the burden of end-stage renal disease in the future. PMID- 23680243 TI - Pregnancy outcome and glycemic control in women with type 1 diabetes: a retrospective comparison between CSII and MDI treatment. AB - AIM: Present study was aimed to evaluate glycemic control and maternal-fetal outcome in pregnant type 1 diabetic patient treated with continuous subcutaneous insulin infusion (CSII) or multiple daily injections of insulin (MDI). PATIENTS AND METHODS: A retrospective observational study included thirty-four pregnant type 1 diabetic patients. Patients were divided into two group, CSII treated group (n=14) and MDI treated group (n=20). The HbA1c level and maternal-fetal outcome were evaluated in both the treatment group. Outcome parameters such as glycemic control (HbA1c), hypoglycemic events, time and mode of delivery and labor results (abortion, premature labor, perinatal mortality, neonatal weight, Apgar score, neonatal hypoglycaemia, presence of congenital abnormalities) were analyzed. RESULTS: Pregnancy outcome and glycemic control in pregnant type 1 diabetic patients treated with CSII and MDI were evaluated and compared. Two groups were compared for their epidemiological parameters, although patients on CSII treatment had longer duration of diabetes compared to MDI treated group. Reduction in HbA1c level was higher in CSII treated patients at first (CSII: 0.9% vs MDI: 0.46%), second (CSII: 1.58% vs MDI: 0.78%) and third trimester (CSII: 1.74% vs MDI: 1.09%) of pregnancy compared to MDI treated patients. Duration of pregnancy and new born baby weight were founded similar in both group. Moreover, the rate of abortion, preterm labor, cesarean section and hypoglycemia in new born were founded less in CSII treated group compared to MDI treated group and Apgar score was significantly (p<0.05) higher in CSII treated group compared to MDI treated group. CONCLUSION: Results of present study revealed that the CSII gives better glycemic control and pregnancy outcome in pregnant type 1 diabetic patients compared to MDI treatment. CSII also decreases the daily insulin requirement compared MDI. PMID- 23680244 TI - Comparison of DEXA-derived body fat measurement to two race-specific bioelectrical impedance equations in healthy Indians. AB - AIM: Prevalence of obesity is increasing in Asian Indians. Reliable, precise and convenient methods to estimate body composition are required. This study aimed to test the accuracy of bioelectrical impedance analysis (BIA) estimates of body composition among Asian Indians according to two BIA equations--one developed for Asians, the other for Caucasians. METHODS: Two hundred apparently healthy Asian Indians (100 males, 100 females; mean age 36.6 +/- 7.6 years; mean BMI 16.6-46.7 kg/m(2)) underwent BIA assessment of fat mass (FM), fat free mass (FFM) and percentage body fat (%BF) using Tanita Multi-Frequency Body Composition Analyzer MC-180MA (Tanita Corporation, Tokyo, Japan). One set of BIA values was automatically calculated by the analyzer (Caucasian figures), the other set by Tanita (Japanese Asian figures). Results were compared to dual X-ray absorptiometry (DEXA) as the standard measure. RESULTS: A moderate level of relative agreement was found between the DEXA-derived measurement of %BF and the estimate from both the Caucasian (r(2)=0.75; p<0.001) and Asian equation (r(2)=0.7; p<0.001). Despite this, the level of absolute agreement was poor, with large bias and wide limits of agreement. According to the Caucasian equation the mean difference between methods was -8.3 +/- 3.9 (95% limits of agreement -20.10 to 9.40), for the Asian equations mean difference was -5.4 +/- 4.3 (95% limits of agreement -20.63 to 11.41). INTERPRETATION AND CONCLUSIONS: When compared to DEXA, the current Asian and Caucasian Tanita formulae significantly under estimate the %BF of Asian Indians. PMID- 23680237 TI - Personalized medicine in psychiatry: problems and promises. AB - The central theme of personalized medicine is the premise that an individual's unique physiologic characteristics play a significant role in both disease vulnerability and in response to specific therapies. The major goals of personalized medicine are therefore to predict an individual's susceptibility to developing an illness, achieve accurate diagnosis, and optimize the most efficient and favorable response to treatment. The goal of achieving personalized medicine in psychiatry is a laudable one, because its attainment should be associated with a marked reduction in morbidity and mortality. In this review, we summarize an illustrative selection of studies that are laying the foundation towards personalizing medicine in major depressive disorder, bipolar disorder, and schizophrenia. In addition, we present emerging applications that are likely to advance personalized medicine in psychiatry, with an emphasis on novel biomarkers and neuroimaging. PMID- 23680245 TI - Morphofunctional characteristics of the foot in patients with diabetes mellitus and diabetic neuropathy. AB - AIMS: To determine the structural and biomechanical characteristics associated with the conditions diabetes mellitus and diabetic neuropathy. METHODS: Observational study of 788 patients conducted between February 2007 and February 2009, which included subjects with and without diabetes mellitus who had no active ulcer at enrollment. Demographic variables and the general and specific history of diabetes mellitus were recorded. The patient's foot type according to the Foot Posture Index, joint mobility and deformity were recorded. RESULTS: No associations were found between the different foot types (neutral, pronated and supinated) and the structural and demographic variables at a general level, except for the pronated foot that was associated with a higher body mass index, longer suffering from diabetes and the presence of neuropathy [p<0.001, OR (95% CI): 6.017 (4.198-8.624); p<0.001, OR (95% CI): 1.710 (1.266-2.309); p=0.010, OR (95% CI): 0.759 (0.615-0.937), respectively]. CONCLUSIONS: The confluence of risk factors such as neuropathy, body mass index, duration of diabetes and limited joint mobility in patients with diabetes mellitus and pronated foot may be a high risk anthropometric pattern for developing associated complications such as Charcot foot. A prospective analysis of these patients is required to define the risk for developing Charcot neuroarthropathy. PMID- 23680246 TI - A study evaluating prevalence of hypertension and risk factors affecting on blood pressure control among type 2 diabetes patients attending teaching hospital in Malaysia. AB - INTRODUCTION: Hypertension is extremely common disease found in patients with diabetes mellitus. Eighty to 90% of patients with type 2 diabetes mellitus will develop hypertension, and about 20% of hypertensive patients develop diabetes. The aim of this study was designed to assess the prevalence of hypertension and factors affecting the control of hypertension among type 2 diabetic patients. MATERIALS AND METHODS: A total of 1077 type 2 diabetes mellitus patients were included in this study who attended at diabetes clinic of Universiti Sains Malaysia (USM) teaching hospital in Kelantan. All these patients were prospectively followed from January to December 2008. Logistic regression analysis was used to assess the independent effect of variables on hypertension. RESULTS: The prevalence of hypertension (BP>130/80 or on medication for high blood pressure) was 92.7%. A total 471 (47.2%) patients had achieved blood pressure targets <= 130/80 mmHg. The logistic regression indicated that hypertension was positively associated with age (P=0.040), BMI (P=0.027), HbA1c (P=0.046), and level of education (P=0.039). CONCLUSION: Hypertension is a common co-morbidity among diabetic patients. Hypertension was not controlled to the recommended levels of blood pressure in about one-half (52.8%) of diabetes patients. Age, BMI, HbA1c and level of education are factors affecting on hypertension. PMID- 23680247 TI - A novel endocrinology-based wellness program to reduce medication expenditures and improve glycemic outcomes. AB - AIMS: The purpose of this study was to determine the difference in diabetes related medication expenditures as a result of a 16-week lifestyle intervention program. Medical expenditures for patients with diabetes are twice as high compared to patients without this condition. Secondary objectives were changes in HbA1C, BMI, weight, body fat, and program satisfaction. METHODS: The Wellness Life! Program includes educational sessions focused on nutrition, fitness, and behavioral therapy. Medication costs were based on Average Wholesale Prices, tabulated from the 2010 Red Book. RESULTS: A total of 36 patients (49-80 years old) enrolled, of which 27 patients have diabetes mellitus (Type 2=26, Type 1=1). Mean 30-day anti-diabetic medication costs decreased by $142.92. Clinical mean parameters improved in both the overall group and the diabetic subgroup, respectively: HbA1C (%) -0.69, -0.82; weight (lbs) -16.94, -17.11; BMI -2.73, 2.88; and body fat (%) -1.71, -1.79. Participants were generally satisfied with the program. CONCLUSIONS: Employing a multidisciplinary wellness program within an endocrinology practice can reduce anti-diabetic medication expenses; however, long term follow-up is needed to determine if medication reductions and improved clinical parameters persist. PMID- 23680248 TI - Relationship between socioeconomic status and metabolic syndrome among Nigerian adults. AB - The study determined the diastolic and systolic pressure, anthropometric parameters, serological parameters comprising fasting blood glucose (FBG), triglyceride (TG) and high density lipoprotein cholesterol (HDL-C) as well as the socio-economic status (SES) of inhabitants of Ilora with a view to providing information on impact of SES on metabolic syndrome (MetS). One hundred participants (54 males and 46 females) whose ages ranged from 30 and 70 years, participated in the study. Participants were recruited from the three wards of the town using multi-stage random sampling procedure. Subjects' weights, height, blood pressure, waist circumference (WC) were measured using standard instruments. Fasting blood glucose (FBG) was measured using a glucometer on participants' blood samples taken after at least 8h of fasting. Serum triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) were analyzed using enzyme colometric assay kits in the laboratory. SES of the participants was determined by using a questionnaire, which sought information on annual income, occupation and education. Participants who had MetS were determined using the new International Diabetes Foundation definition of MetS. Both descriptive and inferential statistics were used to analyze the data. The mean scores for the males and females systolic blood pressure (SBP) were 123.20 +/- 20.72 mmHg and 117.78 +/- 14.64 mmHg, and the diastolic blood pressure (DBP), 78.63 +/- 11.72 mmHg and 75.98 +/- 13.06 mmHg, respectively. The mean of serological variables scores for the males and females, respectively, were FBG (4.95 +/- 0.81 mmol/L and 4.84 +/- 1.36 mmol/L), TG (1.28 +/- 0.75 mmol/L and 1.35 +/- 1.05 mmol/L), HDL-C (1.26 +/- 0.21 mmol/L and 2.32 +/- 7.34 mmol/L). The mean SES scores for the males and females were 14.35 +/- 4.75 and 13.13 +/- 4.66, respectively. The prevalence of MetS was 43.5% in females and 9.3% in males. Significant differences were found in SBP and FBG across the three SES groups (F=3.148 and 3.862, respectively, p<0.05). The high SES group was found to have significantly higher SBP and FBG than the low and middle SES groups. There were significant correlations between SES scores and SBP (r=0.255; p<0.05), FBG (r=0.270; p<0.01), and BMI (r=0.210; p<0.05). Also, significant relationships were found between weight and TG (r=0.282; p<0.05), waist circumference (WC) and FBG (r=0.264; p<0.05), and WC and TG (r=0.414; p<0.01). The study concluded that SES has significant relationship with metabolic syndrome components such as SBP and fasting blood glucose among adult population in Nigeria. PMID- 23680249 TI - Pattern and predictors of dyslipidemia in patients with type 2 diabetes mellitus. AB - Dyslipidemia is a major risk factor for macro-vascular complications in patients with type 2 diabetes mellitus (T2DM). Present study explored pattern and predictors of dyslipidemia in Bangladeshi T2DM patients. The cross-sectional study is conducted among 366 consecutive eligible T2DM patients aged >30 years, BIRDEM diabetic hospital, during July-to-December 2010. Physical examination, diabetic profile, lipid profile and serum createnine was performed. Adjusted odds ratio and confidence limit were generated through binary logistic regression. Most frequent form (59.3%) of dyslipidemia is low HDL. Duration of T2DM is significantly correlated with TC (P<0.05), HDL (P<0.05) and LDL (P<0.05) in both male and female. Glycemic control in terms of HbA1c >7% appeared as predictor of dyslipidemia (P<0.01). Duration T2DM is associated with increased risk of having higher TC (P<0.05), LDL (P<0.05) and lower HDL (P<0.01) and does not seem to affect triglyceride (P>0.05). T2DM with comorbid hypertension seems to predict hyper tri-glyceridemia and lower HDL. Both TC-HDL ratio and LDL-HDL ratio appeared as good predictor of all four parameters of dyslipidemia (P<0.01). The characteristic features of diabetic dyslipidemia are low HDL, high triglyceride and LDL cholesterol level. Low HDL level is the most frequent type of abnormality. Poor glycemic control, prolonged duration, coexisting hypertension predicts dyslipidemia in T2DM. PMID- 23680250 TI - The diabetic foot infections: biofilms and antimicrobial resistance. AB - AIM: To study the difference in antimicrobial resistance profile among biofilm producing and non-producing microorganisms isolated from diabetic foot ulcer in a tertiary care hospital in North India. METHODOLOGY: We performed a prospective study on 162 DFU in patients treated in a multidisciplinary based diabetes and endocrinology center of JNMCH, AMU, Aligarh, India during the period of December 2008-March 2011. Detailed history and physical examination was carried out for every subject. Patient's profile, grade of DFU, co-morbidities and complications, laboratory data and final outcome were collected. Standard methods of sample collection and identification of microorganism were adopted. Risk factors for biofilm producing infections were determined by univariate analysis with 95% of CI. P value <0.05 were considered as significant. RESULTS: The overall biofilm producing infection rate among DFU was 67.9%. On univariate analysis, significant risk factors for biofilm producing infection were male sex [P=0.015, OR 2.35, RR 1.71], duration of diabetes [P<0.006, OR 4.0, RR 2.7], duration of ulcer >1 month [P<0.02, OR 2.26, RR 1.72], size of ulcer >4 cm(2) [P<0.05, OR 2.03, RR 1.54], Grade II ulcer [P<0.06, OR 1.87, RR 1.63], necrotic ulcer [P<0.002, OR 5.79, RR 3.59], previous antibiotic use [P<0.007, OR 4.24, RR 2.74], subcutaneous infection [P<0.06, OR 1.87, RR 1.63], HbA1c >7% [P<0.04, OR 3.19, RR1.87] and polymicrobial infection [P<0.001, OR 6.64, RR 3.21] were significant risk factors. CONCLUSIONS: Treating the DFU by shifting from the planktonic model of microbiology to the biofilm model was recommended. With this new scientific approaches along with coordination of clinical and laboratory efforts, education, and research, it is possible to imagine overcoming much of biofilm disease. PMID- 23680251 TI - Paraoxonase 1: a better atherosclerotic risk predictor than HDL in type 2 diabetes mellitus. AB - INTRODUCTION: Type 2 diabetes mellitus is a state of glycative stress and oxidative stress. Lower level of serum PON 1 has been correlated to higher morbidity and mortality related to cardiovascular complications in type 2 diabetes mellitus. OBJECTIVES: To estimate and compare the serum PON 1 levels in type 2 diabetes mellitus and controls and to predict which one is the better atherosclerotic risk predictor among HDL and PON 1 in T2DM patients. MATERIALS AND METHODS: An observational analytical case-control study was conducted with a sample size of 30 in two groups like group I (30 cases of type 2 diabetes mellitus diagnosed by ADA 2010 criteria) and group II (30 age and sex matched controls). Human serum paroxonase 1 levels were measured by ELISA. RESULTS: Both HDL and PON 1 were negatively correlated with the various atherogenic indices (AIP, AC, CRI I, CRI II) but the strength of negative correlation is always greater for PON 1. In multiple linear regression analysis, we found that the regression coefficient (beta) is always higher for PON 1 than for HDL while taking the atherogenic indices as outcome variable. CONCLUSION: PON 1 can be a better predictor than HDL for atherosclerotic risk in type 2 diabetes mellitus. PMID- 23680252 TI - Ferroportin Q248H mutation, hyperferritinemia and atypical type 2 diabetes mellitus in South Kivu. AB - BACKGROUND: The ferroportin Q248H mutation is relatively common in sub-Saharan Africa. No previous study examined its relationship with atypical diabetes mellitus (DM) in this area. OBJECTIVE: To determine the potential interactions between ferroportin Q248H mutation, hyperferritinemia and DM in South Kivu (RDC). METHODOLOGY: Presence of ferroportin Q248H mutation and iron status were investigated in diabetic patients (n=179, age (mean) 57.7 years, CRP (median) 0.16 mg/L) and non-diabetic subjects (n=86, age 44.5 years, CRP 0.07 mg/L) living in the city of Bukavu. Hyperferritinemia was considered for values greater than 200 and 300 MUg/L in women and in men, respectively. RESULTS: The prevalence of ferroportin Q248H mutation [12.1%] was non-significantly higher in diabetics than non-diabetics [14.0% vs. 8.1%, p=0.17]. Similarly, hyperferritinemia frequency was higher in diabetic patients with Q248H mutation [44.0% vs. 14.3%, p=0.16] and in mutation carriers [37.0% vs 16.5%, p=0.001] than in the control groups, respectively. The association between Q248H mutation and DM was nevertheless not significant [adjusted OR 1.70 (95% CI: 0.52-5.58), p=0.37], whereas hyperferritinemia [OR 2.72 (1.24-5.98), p=0.01] showed an independent effect after adjustment for age and metabolic syndrome. CONCLUSIONS: The present work suggests a potential association between abnormal iron metabolism, ferroportin Q248H mutation and atypical DM in Africans, which may be modulated by environmental factors. PMID- 23680253 TI - Alopecia due to common metabolic diseases. AB - Alopecia is an important condition presenting with excessive hair loss. The problem of alopecia is important concern in trichology. Sometimes, alopecia can be due to complicated etiologies. The good examples are metabolic diseases. In this article, the authors will present the details of alopecia due to some important metabolic diseases. Special focus is made on diagnosis and treatment. PMID- 23680254 TI - HbA1c and iron deficiency: a review. AB - Conditions that affect erythrocyte turnover influence HbA1c concentrations and the International Expert Committee has warned clinicians to be aware of any conditions that could affect the turnover of red blood cells. Although many forms of anemia are associated with lowering of HbA1c, iron deficiency has been shown to shift HbA1c slightly upward. The exact mechanism through which iron deficiency anemia affects HbA1c levels, however still remains unclear. The explanations provided above are merely speculations, warranting further studies to confirm and elucidate the role of these factors. As little work has been done in this field so future and large scale studies are required which may address HbA1c enhancing effect and the mechanism of increased HbA glycation in iron deficiency properly. PMID- 23680255 TI - Intramural left atrial hematoma complicating catheter ablation for atrial fibrillation. PMID- 23680256 TI - 3-Dimensional transesophageal echocardiography-guided closure of a Gerbode shunt due to CorMatrix patch dehiscence. PMID- 23680258 TI - Cellulase activity mapping of Trichoderma reesei cultivated in sugar mixtures under fed-batch conditions. AB - BACKGROUND: On-site cellulase production using locally available lignocellulosic biomass (LCB) is essential for cost-effective production of 2nd-generation biofuels. Cellulolytic enzymes (cellulases and hemicellulases) must be produced in fed-batch mode in order to obtain high productivity and yield. To date, the impact of the sugar composition of LCB hydrolysates on cellulolytic enzyme secretion has not been thoroughly investigated in industrial conditions. RESULTS: The effect of sugar mixtures (glucose, xylose, inducer) on the secretion of cellulolytic enzymes by a glucose-derepressed and cellulase-hyperproducing mutant strain of Trichoderma reesei (strain CL847) was studied using a small-scale protocol representative of the industrial conditions. Since production of cellulolytic enzymes is inducible by either lactose or cellobiose, two parallel mixture designs were performed separately. No significant difference between inducers was observed on cellulase secretion performance, probably because a common induction mechanism occurred under carbon flux limitation. The characteristics of the enzymatic cocktails did not correlate with productivity, but instead were rather dependent on the substrate composition. Increasing xylose content in the feed had the strongest impact. It decreased by 2-fold cellulase, endoglucanase, and cellobiohydrolase activities and by 4-fold beta-glucosidase activity. In contrast, xylanase activity was increased 6-fold. Accordingly, simultaneous high beta-glucosidase and xylanase activities in the enzymatic cocktails seemed to be incompatible. The variations in enzymatic activity were modelled and validated with four fed-batch cultures performed in bioreactors. The overall enzyme production was maintained at its highest level when substituting up to 75% of the inducer with non-inducing sugars. CONCLUSIONS: The sugar substrate composition strongly influenced the composition of the cellulolytic cocktail secreted by T. reesei in fed-batch mode. Modelling can be used to predict cellulolytic activity based on the sugar composition of the culture feeding solution, or to fine tune the substrate composition in order to produce a desired enzymatic cocktail. PMID- 23680257 TI - Effects of resistin on porcine ovarian follicle steroidogenesis in prepubertal animals: an in vitro study. AB - BACKGROUND: Resistin was first reported to be an adipocyte-specific hormone, but recent studies have indicated a connection between resistin and reproductive function. However, it is not yet known if resistin is expressed by the ovary and if it can affect steroidogenesis in ovarian follicles from prepubertal pigs. METHODS: In this study, using real time PCR, immunoblotting, and ELISA, we quantified resistin expression and concentration in maturing ovarian follicles (small, 3-4 mm; medium, 4-5 mm; large, 6-7 mm) collected from prepubertal pigs. In addition, the dose-responsive effects of recombinant human resistin (0.1, 1, 10, and 100 ng/ml) on steroid hormone (i.e., progesterone [P4], androstendione [A4], testosterone [T], and estradiol [E2]) secretion in culture medium and steroidogenic enzyme (i.e., CYP11A1, 3betaHSD, CYP17A1, 17betaHSD, and CYP19A1) expression in ovarian follicles were determined. RESULTS: We observed that resistin gene and protein expression increased significantly (P < 0.05) during follicular growth, with large follicles expressing the highest level of this adipokine. Recombinant resistin also increased P4, A4, and T secretion by up regulating the steady state levels of CYP11A1, 3betaHSD, CYP17A1, and 17betaHSD. Recombinant resistin had no effects on E2 secretion and CYP19A1 expression in ovarian follicles. CONCLUSION: Our results show resistin expression in ovarian follicles from prepubertal pigs for the first time. We also show that recombinant resistin stimulates steroidogenesis in ovarian follicles by increasing the expression of CYP11A1, 3betaHSD, CYP17A1, and 17betaHSD. The presence of resistin in the porcine ovary and its direct effects on steroidogenesis suggest that resistin is a new regulator of ovary function in prepubertal animals. PMID- 23680259 TI - Clinical review: Predictive value of neutrophil gelatinase-associated lipocalin for acute kidney injury in intensive care patients. AB - Neutrophil gelatinase-associated lipocalin (NGAL) may be an early marker of acute kidney injury (AKI), but elevated NGAL occurs in a wide range of systemic diseases. Because intensive care patients have high levels of comorbidity, our objective was to conduct a systematic review of the literature to evaluate the value of plasma and urinary NGAL to predict AKI in these patients. We conducted a systematic electronic literature search of MEDLINE through PubMed, EMBASE, and Cochrane Library for all English language research publications evaluating the predictive value of plasma or urinary NGAL (or both) for AKI in adult intensive care patients. Two authors independently extracted data by using a standardized extraction sheet including study characteristics, type of NGAL measurements, and type of outcome measures. The primary summary measure was area under receiver operating characteristic curve (AuROC) for NGAL to predict study outcomes. Eleven studies with a total of 2,875 (range of 20 to 632) participants were included: seven studies assessed urinary NGAL and six assessed plasma NGAL. The included studies varied in design, including observation period from NGAL sampling to AKI follow-up (range of 12 hours to 7 days), definition of baseline creatinine value, and urinary NGAL quantification method (normalizing to urinary creatinine or absolute concentration). AuROC values for the prediction of AKI ranged from 0.54 to 0.98. Five studies reported AuROC for use of renal replacement therapy ranging from 0.73 to 0.89, and four studies reported AuROC for mortality ranging from 0.58 to 0.83. There were no differences in the predictive values of urinary and plasma NGAL. The heterogeneity in study design and results made it difficult to evaluate the value of NGAL to predict AKI in intensive care patients. NGAL seems to have reasonable value in predicting use of renal replacement therapy but not mortality. PMID- 23680260 TI - Ethno-medicinal study of plants used for treatment of human and livestock ailments by traditional healers in South Omo, Southern Ethiopia. AB - BACKGROUND: Plants have traditionally been used for treatment of human and livestock ailments in Ethiopia by different ethnic and social groups. However, this valuable source of knowledge is not adequately documented, which impedes their widespread use, evaluation and validation. Here, we recorded indigenous knowledge and standard practices for human and livestock disease control, of three ethnic groups (Aari, Maale and Bena-Tsemay) in South Omo Zone of Southern Nations, Nationalities and Peoples Regional State, Ethiopia. METHODS: A cross sectional study was carried out using a semi-structured questionnaire to document knowledge of 50 traditional healers (40 male and 10 female) in medicinal plant use for treatment of human and livestock ailments. Descriptive statistics were used to analyze and summarize the ethno-botanical data. RESULTS: Ninety-one plants, with claimed medicinal properties against a total of 34 human and livestock ailments, were reported and botanically identified as belonging to 57 genera and 33 plant families. Most of the plant species reported belonged to one of seven major families: Lamiaceae, Solanaceae, Menispermiaceae, Fabaceae, Asteraceae, Plumbaginaceae and Geraniaceae. Woody plants (shrubs 21% and trees 29%) were the major growth form used, whilst roots (40%) and leaves (35%) were the major plant parts used in the study areas. Healers mostly practice oral administration of plant preparations (65%). Multiple medicinal plants were cited against particular ailments, and mixing of two or more different medicinal plants (14.3%) against a single ailment was also commonly reported. CONCLUSION: This study showed that traditional medicine, mainly involving the use of medicinal plants, is playing a significant role in meeting the primary healthcare needs of the three ethnic groups. Acceptance of traditional medicine and limited access to modern healthcare facilities could be considered as the main factors for the continuation of the practice. Documented knowledge of the traditional healers can be used to support the country's human and livestock health care system and improve lives and livelihoods. Information generated will be used in future studies to validate bioactivity of selected medicinal plants used by traditional healers, so to increase their acceptability in health care systems both nationally and internationally. PMID- 23680261 TI - Successful Unrelated Cord Blood Stem Cell Transplantation in an X-linked Chronic Granulomatous Disease Patient with Disseminated BCG-induced Infection. AB - A 19-month-old boy with chronic granulomatous disease (CGD) received umbilical cord blood transplantation (UCBT) from an unrelated donor after experiencing a life-threatening disseminated Bacillus Calmette-Guerin infection. After busulfan and cyclophosphamide conditioning, we performed a 5/6-matched UCBT. Engraftment and mixed chimerism was 100% in peripheral blood, and 100% of his neutrophils had normal oxidative burst activity on day 17. The patient is now 3 years old, free from infection, and growing well. To our knowledge, this is the second case of CGD treated with UCBT in Taiwan. His successful outcome illustrates that UCBT in a patient with CGD should be considered early if a human leukocyte antigen matched donor is not available or the patient has just recovered from a severe infection. PMID- 23680262 TI - Nasopharyngeal carriage and antimicrobial susceptibility pattern of Streptococcus pneumoniae among pediatric outpatients at Gondar University Hospital, North West Ethiopia. AB - BACKGROUND: Pneumonia caused by Streptococcus pneumoniae is the leading cause of death among children in Ethiopia. S. pneumoniae nasopharyngeal carriage can result in endogenous infections and bacterial spread in the community. S. pneumoniae drug resistance is rapidly increasing worldwide. The aim of the study was to assess the nasopharyngeal carriage and antimicrobial susceptibility pattern of S. pneumoniae among pediatric outpatients. METHODS: A cross-sectional study was conducted on children aged <=10 years from February to May of 2012. Data on potential risk factors were gathered using an interview-based questionnaire. Nasopharyngeal specimens were collected with a sterile plastic cotton tip swab. Bacteria were characterized by colony appearance, Gram staining, and optochin susceptibility and bile solubility tests. An antimicrobial susceptibility test was performed using the disk diffusion method. A logistic regression analysis was used to examine the possible risk factors. All tests with p value less than 0.05 were considered statistically significant. RESULTS: Of the 234 children screened, 41.03% carried S. pneumoniae. Age-related downward trend for S. pneumoniae carriages (50.9% in <3-year-olds, 40.7% in 3- to 5-year-olds, 40.0% in 5- to <8-year-olds, and 33.3% in 8- to 10-year-olds) were observed. Children living with siblings < 5 years old (p = 0.003) and in a house having one room (p = 0.004) were associated with higher S. pneumoniae carriage. S. pneumoniae showed 33.2% resistance to erythromycin and tetracycline, 29.2% to cotrimoxazole, 14.6% to chloramphenicol and ciprofloxacin, and 10.4% to penicillin. CONCLUSION: The S. pneumoniae carriage rate was higher among younger children. High antimicrobial resistance of S. pneumoniae against erythromycin, tetracycline, and cotrimoxazole was observed. Being in the young age group and living with younger children are risk factors for pneumococcal carriage. PMID- 23680263 TI - Prognosis and monitoring of leishmaniasis in dogs: a working group report. AB - This review presents the consensus opinion of the Canine Leishmaniasis Working Group on the prognosis and monitoring of leishmaniasis in dogs. While the prognosis for both exposed and infected dogs is considered to be favourable, this changes if infection progresses to overt disease. For clinically affected animals undergoing treatment, the prognosis is dictated by the severity of the signs (and in particular the severity of renal dysfunction) when therapy is initiated; assessing the degree of proteinuria is useful in this context. Approximately 75% of dogs without evidence of renal involvement live for >4years if adequately treated. Monitoring the response to treatment includes ongoing clinical and clinicopathological assessment, as well as quantifying serological responses and the parasite load in the patient. PMID- 23680264 TI - Evaluation of three intervention strategies to reduce the transmission of Salmonella Typhimurium in pigs. AB - Despite current control measures, Salmonella in pigs remains a major public health concern. In this in vivo study, the effect of three intervention strategies on Salmonella Typhimurium transmission in pigs was evaluated. The first intervention was feed supplemented with coated calcium-butyrate (group A); the second comprised oral vaccination with a double-attenuated Salmonella Typhimurium strain (group B), and the third was acidification of drinking water with a mixture of organic acids (group C). After challenge at 8 weeks of age, animals were individually sampled for 6 weeks (blood once per week; faeces twice per week) and then were euthanased at 14 weeks of age. Post-mortem ileum, caecum, ileocaecal lymph nodes, and tonsils were sampled, along with ileal, caecal and rectal contents, and tested for the presence of Salmonella spp. Transmission was quantified by calculating an 'adjusted' reproduction ratio 'Ra' and its 95% confidence interval (CI). The proportion of pigs that excreted Salmonella spp. via the faeces was significantly higher in group C (58%, P<0.0001) and the positive control group (41%, P=0.03), compared to group B (15%), and the proportion in group C was also significantly higher than in group A (23%, P=0.01). Group A had the lowest proportion of positive post-mortem samples (18%), followed by group B (31%), the positive control group (41%) and group C (64%) (P<0.03). The highest transmission was seen in the positive control group and group C (Ra=+infinity with 95% CI [1.88; +infinity]), followed by group B (Ra=2.61 [1.21; 9.45]) and A (Ra=1.76 [1.02; 9.01]). The results of this study suggest that vaccination and supplementation of the feed with coated calcium butyrate limited Salmonella transmission in pigs and might be useful control measures. PMID- 23680265 TI - Co-infection by Escherichia coli O157 and gastrointestinal strongyles in sheep. AB - This research investigated the prevalence of gastrointestinal (GI) strongyles and Escherichia coli O157 in naturally infected sheep, as well as the possible correlation between the pathogens examined. A total of 314 sheep, randomly selected from 21 farms located in southern Italy, were examined. GI strongyles and E. coli O157 were detected by using the FLOTAC double technique and culture media, respectively. GI strongyles were detected on 19/21 farms (90.5%) and E. coli O157 on 12/21 (57.4%). At the animal level, GI strongyles were detected from 193/314 (61.5%) sheep analysed, whereas E. coli O157 was isolated from 20/314 (6.4%) sheep. Statistical analysis performed at animal-level showed a negative correlation between E. coli O157 and GI strongyle EPGs (Spearman's rho=-0.128; P=0.03). Caution should be exercised in interpreting the research findings because a number of different confounding factors possibly influenced the trend of negative correlation between the two pathogenic agents investigated. Further studies, including molecular diagnostics, production data and multivariable analytical approaches, are needed to assess the actual impact of multiple pathogen infections in grazing sheep and other livestock species. PMID- 23680266 TI - Understanding parasitic infection in sheep to design more efficient animal selection strategies. AB - Modern livestock breeding practices provide new opportunities for producing animals that are adapted to their production environment and are free of disease. Using current knowledge of biology and by seeking 'the desired outcome' animal selection strategies can be designed that deliver more precisely defined results so maximising genetic gain and minimising risk. This review briefly describes the evolution of genetic selection in livestock and considers some of the positive and negative aspects of selection practices over time. The selection of sheep to withstand gastro-intestinal nematode parasitism is used as an example to explain how developments in selection strategy have improved genetic progress for complex traits. Re-evaluation of the understanding of the outcomes of selection for parasite resistance is used here to examine whether a more sophisticated approach is desirable, and to propose a number of additional phenotype measurement strategies that could complement and improve the quality of information used for animal selection. Finally some ideas are presented for creating a situation where a designed, highly defined breeding objective might be used to increase precision and reduce risk. This may become possible via research to adapt or develop tools for more sophisticated phenotypic evaluation, to discover biological processes integral to desired breed changes, and to define desired animal types which match economic and societal expectations. PMID- 23680267 TI - Primary healthcare providers' views on improving sexual and reproductive healthcare for adolescents in Bolivia, Ecuador, and Nicaragua. AB - OBJECTIVES: To elicit the views of primary healthcare providers from Bolivia, Ecuador, and Nicaragua on how adolescent sexual and reproductive health (ASRH) care in their communities can be improved. METHODS: Overall, 126 healthcare providers (46 from Bolivia, 39 from Ecuador, and 41 from Nicaragua) took part in this qualitative study. During a series of moderated discussions, they provided written opinions about the accessibility and appropriateness of ASRH services and suggestions for its improvement. The data were analyzed by employing a content analysis methodology. RESULTS: Study participants emphasized managerial issues such as the prioritization of adolescents as a patient group and increased healthcare providers' awareness about adolescent-friendly approaches. They noted that such an approach needs to be extended beyond primary healthcare centers. Schools, parents, and the community in general should be encouraged to integrate issues related to ASRH in the everyday life of adolescents and become 'gate openers' to ASRH services. To ensure the success of such measures, action at the policy level would be required. For example, decision-makers could call for developing clinical guidelines for this population group and coordinate multisectoral efforts. CONCLUSIONS: To improve ASRH services within primary healthcare institutions in three Latin American countries, primary healthcare providers call for focusing on improving the youth-friendliness of health settings. To facilitate this, they suggested engaging with key stakeholders, such as parents, schools, and decision-makers at the policy level. PMID- 23680268 TI - Semi-continuous anaerobic co-digestion of orange peel waste and residual glycerol derived from biodiesel manufacturing. AB - The manufacturing of orange juice generates high volumes of orange peel waste which should not be deposited in landfill according to current recommendations. Furthermore, glycerol is a compound co-generated in biodiesel manufacturing, but the volume generated is higher than the current demand for pure glycerol. The anaerobic co-digestion of orange peel waste with residual glycerol could reduce the inhibitory effect of some compounds and provide a correct nutrient balance. Under mesophilic temperature and semi-continuous conditions, a mixture of orange peel waste-residual glycerol of 1:1 (in COD) operated favorably for organic loads up to 2.10 g VS/L. At higher organic loads, the accumulation of volatile fatty acids (VFA) and a decrease in the pH caused process destabilization. The methane yield coefficient was quite constant, with a mean value of 330+/-51 mL(STP)/g VSadded, while the organic loading rate (OLR) reached a mean value of 1.91+/-0.37 kgVS/m3 d (17.59+/-2.78 kgmixture/m3 d) and the hydraulic retention time (HRT) varied in a range of 8.5-30.0 d. PMID- 23680269 TI - Mercury leaching characteristics of waste treatment residues generated from various sources in Korea. AB - In this study, mercury (Hg) leaching characteristics of the waste treatment residues (fly ash, bottom ash, sludge, and phosphor powder) generated from various sources (municipal, industrial, medical waste incinerators, sewage sludge incinerator, oil refinery, coal-fired power plant, steel manufacturing plant, fluorescent lamp recycler, and cement kiln) in Korea were investigated. First, both Hg content analysis and toxicity characteristic leaching procedure (TCLP) testing was conducted for 31 collected residue samples. The Hg content analysis showed that fly ash from waste incinerators contained more Hg than the other residue samples. However, the TCLP values of fly ash samples with similar Hg content varied widely based on the residue type. Fly ash samples with low and high Hg leaching ratios (RL) were further analyzed to identify the major factors that influence the Hg leaching potential. Buffering capacity of the low-RL fly ash was higher than that of the high-RL fly ash. The Hg speciation results suggest that the low-RL fly ashes consisted primarily of low-solubility Hg compounds (Hg2Cl2, Hg(0) or HgS), whereas the high-RL fly ashes contain more than 20% high-solubility Hg compounds (HgCl2 or HgSO4). PMID- 23680270 TI - [Does impact factor influence the ethics of the instructions provided to journal authors?]. AB - OBJECTIVE: Verify whether a journal's impact factor is a mechanism that modifies the ethical requirements described in the instructions provided to authors of articles published in Brazilian medical journals. METHODS: 48 selected journals were divided into two groups: impact-factor (n=24), and no-impact-factor (n=24). The number of ethical requirements was compared between both groups based on a specific research protocol, ranging from zero to six points, analyzing the presence of an approval by a research ethics committee; reference to the fact that the research follows the precepts of the Declaration of Helsinki and the rules of Resolution 196/96; use of an informed consent; information about the authors' conflicts of interest; and a request for registration of clinical trials in the Brazilian Clinical Trials Registry. RESULTS: The average score of the impact-factor group was significantly higher than that of the no-impact-factor group (3.12 +/- 1.03 vs. 2.08 +/- 1.64, p=0.0121). When each ethical requirement was compared between the groups, there was significant difference only between the requirement of an informed consent and the disclosure of conflicts of interest (p < 0.05). CONCLUSION: The impact factor is a determinant factor on the ethics included in the instructions to authors of articles in scientific journals, showing that higher-quality journals seek better-designed articles that are conscientious at the beginning of the research. PMID- 23680271 TI - Serum magnesium and proton-pump inhibitors use: a cross-sectional study. AB - OBJECTIVE: The aim of this study was to evaluate the association of serum magnesium levels with proton pump inhibitors (PPIs) use and other factors. METHODS: This was a cross-sectional study of 151 patients admitted with acute diseases in the Internal Medicine Division of the Hospital de Clinicas de Porto Alegre, after the exclusion of conditions that are commonly associated with hypomagnesemia: diarrhea; vomiting; chronic alcohol use; severely uncompensated diabetes mellitus; and chronic use of laxatives, diuretics or other drugs causing magnesium deficiency. RESULTS: All patients had normal serum magnesium levels. Serum albumin and creatinine levels were positively associated with serum magnesium levels, after adjusting for confounders. There was no difference between mean serum magnesium levels of PPI users and non-users, nor between men and women; there was also no correlation among age, serum phosphorus, and potassium levels with serum magnesium levels. Limitations of this study include the absence of an instrument for measuring adherence to PPI use and the sample size. CONCLUSION: The association of PPI use and hypomagnesemia is uncommon. Congenital defects in the metabolism of magnesium may be responsible for hypomagnesemia in some patients using this drug class. PMID- 23680272 TI - [Digital signature of medical reports: an issue still not resolved]. PMID- 23680273 TI - [Venous thromboprophylaxis in medical patients: an application review]. AB - OBJECTIVE: Routine thromboprophylaxis, despite its well-known effectiveness and the fact that venous thromboembolism is a potentially avoidable condition, is not fully established in clinical practice. The objectives of the present study were to determine how often thromboprophylaxis is used and the presence of thromboembolism risk factors, and to verify the appropriateness of its use in medical inpatients, assuming a long-standing national guideline as a parameter. METHODS: This was a retrospective cross-sectional study, involving inpatients with medical conditions in the adult general ward of a university hospital. The review was based on a defined guideline. RESULTS: 146 patients were included in the review. At least one risk factor for venous thromboembolism was found in 94.5%. In 130 (89%) patients, prophylactic heparin was indicated, and some kind of heparin was prescribed in 73.3%. Regarding the adequacy of prophylaxis, 53.4% of prescriptions were correct regarding prophylaxis indication and dose; 24% had incorrect dose or frequency of use; 19.2% had no prophylaxis prescription, although it was indicated; and in five cases (3.4%), the drug was prescribed, even though it was not indicated. CONCLUSION: Thromboprophylaxis is underused in this population, and an inappropriate dose was prescribed in 50% of cases. Therefore, future studies and interventions should include an educational program started from the emergency department care, an essential step to bring evidence closer to clinical practice. PMID- 23680274 TI - [Food taboos in medicine: a hypothesis for pathophysiology regarding harmful food]. PMID- 23680275 TI - Prediction of chronic critical illness in a general intensive care unit. AB - OBJECTIVE: To assess the incidence, costs, and mortality associated with chronic critical illness (CCI), and to identify clinical predictors of CCI in a general intensive care unit. METHODS: This was a prospective observational cohort study. All patients receiving supportive treatment for over 20 days were considered chronically critically ill and eligible for the study. After applying the exclusion criteria, 453 patients were analyzed. RESULTS: There was an 11% incidence of CCI. Total length of hospital stay, costs, and mortality were significantly higher among patients with CCI. Mechanical ventilation, sepsis, Glasgow score <15, inadequate calorie intake, and higher body mass index were independent predictors for CCI in the multivariate logistic regression model. CONCLUSIONS: CCI affects a distinctive population in intensive care units with higher mortality, costs, and prolonged hospitalization. Factors identifiable at the time of admission or during the first week in the intensive care unit can be used to predict CCI. PMID- 23680276 TI - Atopic dermatitis in adults: clinical and epidemiological considerations. AB - OBJECTIVE: Atopic dermatitis (AD) is a chronic inflammatory disease causing intense pruritus, and with typical clinical features. There are few epidemiological studies concerning AD in adults, as well as little information about its prognostic. The aim of this study was to evaluate the clinical and epidemiological course of adults with AD. METHODS: 80 patients aged above 18 years (mean age=29 years) were selected (30 males and 50 females) and interviewed about hospitalization, systemic corticoid usage, age of AD onset, and personal and/or familial history of atopy. Disease severity was evaluated through the Scoring Atopic Dermatitis (SCORAD) tool. Laboratory examination included IgE serum levels and eosinophil blood count. RESULTS: 71 out of 80 patients referred association with respiratory symptoms (18 had asthma, 17 had rhinitis, and 36 had both conditions); nine out of 80 patients denied any respiratory disease. AD patients were divided in mild (n=25), moderate (n=30), and severe (n=25); 56% had one or more hospitalizations due to AD. A positive association was found between IgE serum levels, eosinophil blood count, and disease severity. CONCLUSION: Adult AD represents a clinical challenge that needs to be better characterized, since it can be misdiagnosed and interferes with the patient's social and personal life. The association of skin and respiratory atopic disease is frequent, and laboratory parameters such as circulating IgE levels and eosinophil blood count may be helpful to assess disease severity. PMID- 23680277 TI - Use of methylphenidate among medical students: a systematic review. AB - OBJECTIVE: To review the effects of methylphenidate on cognitive enhancement, memory, and performance in medical students. METHODS: A review of four databases (LILACS, PubMed, ScienceDirect, and SciELO), analyzing the title and abstract of all articles published between 1990 and 2012 in English, Portuguese, and Spanish. Selected articles were read in entirety, including in the review those that met the established criteria. RESULTS: The prevalence of use among medical students reached 16%, with no gender difference. Most students began using the drug after entering the university, and the reasons cited to justify it are related to enhancing academic performance. CONCLUSION: There is no evidence in the literature that the use of methylphenidate is beneficial in terms of memory or learning. The drug simply increases wakefulness and alertness, reducing the time of sleep. PMID- 23680278 TI - Erythema and nipple retraction: a sign of concern. PMID- 23680279 TI - Postmenopausal osteoporosis, breast cancer, and aromatase inhibitor. PMID- 23680280 TI - Neck circumference as an independent predictive contributor to cardio-metabolic syndrome. AB - BACKGROUND: The predictive potentials of neck circumference (NC) for cardio metabolic risks remain uncertain. The aim of this study was to investigate whether NC independently contributes to the prediction of cardio-metabolic risks beyond body mass index (BMI), waist circumference (WC) and waist to hip ratio (WHpR) in a large Chinese population. METHODS: A total of 4201 participants (2508 men and 1693 women) aged 20-85 were recruited from the Health Examination Centre between May 2009 and April 2010, anthropometric indices, biochemical and clinical parameters were measured. Receiver operating characteristic, partial correlation and logistic regression analyses were employed to evaluate the association of the anthropometric indices to cardio-metabolic risks separately by gender. RESULTS: Neck circumference was positively correlated with SBP and DBP (r=0.250 and 0.261), fasting blood glucose (FBP) (r=0.177), TG (r=0.240), TC (r=0.143) and LDL C (r=0.088) and negatively correlated with HDL-C (r=-0.202) in males (all P<0.01). Similar results were found in females with the exception of TC. The AUCs of NC for metabolic abnormalities ranged from 0.558 (Increased LDL-C) to 0.683 (MS-rf) in men and 0.596 (Increased LDL-C) to 0.703 (MS-rf) in women (P<0.01). The NC of >=37 cm for men and >=33 cm for women were the best cut-off points for metabolic syndrome. The adjusted ORs (95% CIs) of NC in men and women respectively were 1.29 (1.12-1.48) and 1.44 (1.20-1.72) for metabolic syndrome risk factors (MS-rf), 1.15 (1.01-1.32) and 1.22 (1.03-1.46) for high BP, 1.16 (1.02-1.33) and 1.42 (1.18-1.71) for increased TG, and 1.26 (1.06-1.50) and 1.32 (1.06-1.65) for increased FBP; the adjusted OR of NC in women for decreased HDL-C was 1.29 (1.10-1.51). CONCLUSIONS: Neck circumference was significantly associated with cardio-metabolic risk factors and independently contributed to the prediction of cardio-metabolic risks beyond the classical anthropometric indices in adults of China. PMID- 23680281 TI - Th17 lymphocyte levels are higher in patients with ruptured than non-ruptured lumbar discs, and are correlated with pain intensity. AB - BACKGROUND: Th17 lymphocytes have important roles in inflammation and autoimmune disease. Research on relationship between Th17 lymphocytes and pain associated with lumbar disc herniation (LDH) is limited. The purpose of this study was to examine the association of pain and Th17 lymphocyte and interleukin (IL)-17 levels in patients with herniated and non-herniated lumbar discs. METHODS: Thirty four patients with single lumbar intervertebral disc herniation (median age, 44 years), and 17 healthy adults (median age, 37 years) were enrolled. Patients were divided into 2 groups depending on their magnetic resonance imaging (MRI) results and visual observations during surgery (group P, non-ruptured disc, n=15; group E, ruptured disc, n=19). Patients received posterior or transforaminal lumbar interbody fusion. Preoperative pain intensity was recorded using a visual analogue scale (VAS) score. The percentage of Th17 lymphocytes and IL-17 and prostaglandin E2 (PGE2) levels in peripheral blood were determined. Disc tissue was examined by immunohistochemistry for Th17 and IL-17 expression. RESULTS: Preoperative VAS pain scores were significantly higher in group E than group P (8.32+/-1.04 vs. 6.33+/-2.68, respectively, p=0.009). Similarly, PGE2 level was greater in group E than group P (3.75+/-1.41pg/ml vs. 2.63+/-0.89pg/ml, respectively, p=0.011). Compared to healthy controls (1.05+/-0.19%), the percentage of Th17 cells was significantly greater in group P (1.52+/-0.62%, p=0.031), and the percentage in group E (2.99+/-1.09%, p<0.001) was significantly greater than in group P. The IL-17 expressions were similar. VAS pain score was positively correlated with Th17 proportion (r=0.489, p=0.003), and IL-17 concentration (r=0.458, p=0.007). PGE2 was also positively correlated with Th17 proportion (r=0.539, p=0.001), and IL-17 concentration (r=0.500, p=0.003). The expression of IL-17 was higher in the cells of group E and group P compared with normal tissue (p<0.001). CONCLUSIONS: Immune system activation is responsible, at least in part, for the pain experienced by patients with LDH, and increased levels of Th17 lymphocytes and IL-17 contribute to the pain. PMID- 23680282 TI - Understanding post-hospital morbidity associated with immobilisation of cervical spine fractures in older people using geriatric medicine assessment techniques: A pilot study. AB - INTRODUCTION: There is a paucity of research into the outcomes and complications of cervical spine immobilisation (hard collar or halothoracic brace) in older people. AIMS: To identify morbidity and mortality outcomes using geriatric medicine assessment techniques following cervical immobilisation in older people with isolated cervical spine fractures. PATIENTS AND METHODS: We identified participants using an injury database. We completed a questionnaire measuring pre admission medical co-morbidities and functional independence. We recorded the surgical plan and all complications. A further questionnaire was completed three months later recording complications and functional independence. RESULTS: Sixteen patients were recruited over a three month period. Eight were immobilised with halothoracic brace, 8 with external hard collar. Three deaths occurred during the study. Lower respiratory tract infection was the most common complication (7/16) followed by delirium (6/16). Most patients were unable to return home following the acute admission, requiring sub-acute care on discharge. The majority of patients were from home prior to a fall, 6/16 were residing there at 3 months. Most participants had an increase in their care needs at 3 months. There was no difference in the type or incidence of complications between the different modes of immobilisation. CONCLUSIONS: Geriatric medicine assessment techniques identified the morbidity and functional impairment associated with cervical spine immobilisation. This often results in a prolonged length of stay in supported care. This small pilot study recommends a larger study over a longer period using geriatric medicine assessment techniques to better define the issues. PMID- 23680283 TI - Implementing the National Hip Fracture Database: An audit of care. AB - BACKGROUND: Hip fractures are common injuries in the elderly, with significant associated morbidity and mortality rates. The National Hip Fracture Database (NHFD) was implemented to audit care according to national standards thus improving its clinical and cost-effectiveness. PATIENTS AND METHODS: We retrospectively examined the care pathway for all hip fractures after its introduction at our centre over 1 year, with an audit of care according to the BOA-BGS 'Blue Book' guidelines. Data between the first (period 1: initial audit) and second (period 2: re-audit) six months of the study period were compared. RESULTS: There were 372 patients (28% male, 72% female) in total with 190 in period 1 and 182 in period 2. For all patients, the median age was 85 years (range 33-101) and the median time to surgery was 24.5h (1-519.3), with 251 (67.5%) within 36h. Surgical delay was mainly due to lack of theatre space (37.6%) and medical reasons (54.7%). The median length of stay was 11 days (2-92) and the inpatient mortality rate was 6.2% (23). When comparing the two study periods, there were significantly more patients undergoing falls (p<0.01) and bone protection (p<0.01) assessments in period 2. Lack of theatre space was a significantly less common (p<0.01), with a significantly shorter median time to surgery (p=0.01) and length of stay (p<0.01) in period 2. More patients were discharged to rehabilitation units and the mortality rate was non-significantly lower in period 2 (7.4% vs. 5%). The best practice tariff was met in 45.3% and 70.3% (p<0.001) of patients in periods 1 and 2 respectively providing a total income of L95230.00 (GBP). CONCLUSIONS: Implementing the NHFD has led to an improvement the quality of hip fracture care according to national guidelines. More patients were assessed by an orthogeriatrician, with a shorter time to surgery and length of stay following re-audit. There is potential for an improvement in mortality rates as well as significant financial income for hospitals. PMID- 23680284 TI - Mediterranean diet adherence during pregnancy and risk of wheeze and eczema in the first year of life: INMA (Spain) and RHEA (Greece) mother-child cohort studies. AB - Maternal diet during pregnancy might influence the development of childhood allergic disorders. The aim of the present study was to evaluate the impact of Mediterranean diet (MD) adherence during pregnancy on wheeze and eczema in the first year of life in two population-based mother-child cohorts in Spain and Greece. We studied 1771 mother-newborn pairs from the Spanish multi-centre 'INMA' (INfancia y Medio Ambiente) study (Gipuzkoa, Sabadell and Valencia) and 745 pairs from the 'RHEA' study in Crete, Greece. The symptoms of wheeze and eczema were based on the criteria of the International Study of Asthma and Allergies in Childhood. Maternal diet during pregnancy was assessed by FFQ and MD adherence was evaluated through an a priori score. Multivariate log-binomial regression models were used to adjust for several confounders in each cohort and summary estimates were obtained by a meta-analysis. MD adherence was not associated with the risk of wheeze and eczema in any cohort, and similar results were identified in the meta-analysis approach. High meat intake (relative risk (RR) 1.22, 95 % CI 1.00, 1.49) and 'processed' meat intake (RR 1.18, 95 % CI 1.02, 1.37) during pregnancy were associated with an increased risk of wheeze in the first year of life, while a high intake of dairy products was significantly associated with a decreased risk of infantile wheeze (RR 0.83, 95 % CI 0.72, 0.96). The results of the present study show that high meat intake during pregnancy may increase the risk of wheeze in the first year of life, while a high intake of dairy products may decrease it. PMID- 23680285 TI - Metal-dependent activity of Fe and Ni acireductone dioxygenases: how two electrons reroute the catalytic pathway. AB - Two virtually identical acireductone dioxygenases, ARD and ARD', catalyze completely different oxidation reactions of the same substrate, 1,2-dihydroxy-3 keto-5-(methylthio)pentene, depending exclusively on the nature of the bound metal. Fe(2+)-dependent ARD' produces the alpha-keto acid precursor of methionine and formate and allows for the recycling of methionine in cells. Ni(2+)-dependent ARD instead produces methylthiopropionate, CO, and formate, and exits the methionine salvage cycle. This mechanistic difference has not been understood to date but has been speculated to be due to the difference in coordination of the substrate to Fe(2+)versus Ni(2+): forming a five-membered ring versus a six membered ring, respectively, thus exposing different carbon atoms for the attack by O2. Here, using mixed quantum-classical molecular dynamics simulations followed by the density functional theory mechanistic investigation, we show that, contrary to the old hypothesis, both metals preferentially bind the substrate as a six-membered ring, exposing the exact same sites to the attack by O2. It is the electronic properties of the metals that are then responsible for the system following different reaction paths, to yield the respective products. We fully explain the puzzling metal-induced difference in functionality between ARD and ARD' and, in particular, propose a new mechanism for ARD'. All results are in agreement with available isotopic substitution and other experimental data. PMID- 23680286 TI - Use of optical imaging to progress novel therapeutics to the clinic. AB - There is an undisputed need for employment and improvement of robust technology for real-time analyses of therapeutic delivery and responses in clinical translation of gene and cell therapies. Over the past decade, optical imaging has become the in vivo imaging modality of choice for many preclinical laboratories due to its efficiency, practicality and affordability, while more recently, the clinical potential for this technology is becoming apparent. This review provides an update on the current state of the art in in vivo optical imaging and discusses this rapidly improving technology in the context of it representing a translation enabler or indeed a future clinical imaging modality in its own right. PMID- 23680287 TI - Enzymatically in situ shell cross-linked micelles composed of 4-arm PPO-PEO and heparin for controlled dual drug delivery. AB - We report a controlled dual drug delivery system using heparinized 4-arm poly(propylene oxide) (PPO)-poly(ethylene oxide) (PEO) micelles (cHTM) that are sterically stabilized by enzymatic shell cross-linking (SCL). Tyramine (TA) was chemically conjugated to 4-arm PPO-PEO (Tetronic) and heparin, resulting in Tetronic-TA (Tet-TA) and heparin-TA (Hep-TA), respectively. To prepare a series of cHTM, different amounts of Hep-TA were added to a micellar solution of Tet-TA, followed by addition of horseradish peroxidase (HRP) and hydrogen peroxide (H2O2) to trigger SCL between TA groups at the micellar surfaces. Increasing the feed amount of Hep-TA led to increased heparin content of cHTM, thereby resulting in increased micelle size with more negatively charged surfaces. All SCL micelles were found to be highly stable over 4weeks, showing negligible changes in their sizes and zeta potentials. Dual drug-loaded cHTM containing indomethacin (IMC) and basic fibroblast growth factor (bFGF) were prepared via a one-pot procedure. With favorable IMC loading, the loading efficiencies of bFGF into cHTM were much higher than those in the controls due to the presence of heparin on the micellar surface. After bFGF was added to IMC loaded cHTM the surface of HTM became less negative with an increase in size, suggesting successful binding of positively charged bFGF to heparinized micelle surfaces. In vitro release data clearly showed more sustained release of IMC and bFGF as compared with non-cross-linked micelles. Based on these results, we suggest that cHTM can be used as a new drug delivery platform for controlled dual drug release. PMID- 23680288 TI - A permeation enhancer for increasing transport of therapeutic macromolecules across the intestine. AB - Delivery of therapeutic macromolecules is limited by the physiological limitations of the gastrointestinal tract including poor intestinal permeability, low pH and enzymatic activity. Several permeation enhancers have been proposed to enhance intestinal permeability of macromolecules; however their utility is often hindered by toxicity and limited potency. Here, we report on a novel permeation enhancer, Dimethyl palmitoyl ammonio propanesulfonate (PPS), with excellent enhancement potential and minimal toxicity. PPS was tested for dose- and time dependent cytotoxicity, delivery of two model fluorescent molecules, sulforhodamine-B and FITC-insulin in vitro, and absorption enhancement of salmon calcitonin (sCT) in vivo. Caco-2 studies revealed that PPS is an effective enhancer of macromolecular transport while being minimally toxic. TEER measurements in Caco-2 monolayers confirmed the reversibility of the effect of PPS. Confocal microscopy studies revealed that molecules permeate via both paracellular and transcellular pathways in the presence of PPS. In vivo studies in rats showed that PPS enhanced relative bioavailability of sCT by 45-fold after intestinal administration. Histological studies showed that PPS does not induce damage to the intestine. PPS is an excellent permeation enhancer which provides new opportunities for developing efficacious oral/intestinal delivery systems for therapeutic macromolecules. PMID- 23680289 TI - Clinical research in Finland in 2002 and 2007: quantity and type. AB - BACKGROUND: Regardless of worries over clinical research and various initiatives to overcome problems, few quantitative data on the numbers and type of clinical research exist. This article aims to describe the volume and type of clinical research in 2002 and 2007 in Finland. METHODS: The research law in Finland requires all medical research to be submitted to regional ethics committees (RECs). Data from all new projects in 2002 and 2007 were collected from REC files and the characteristics of clinical projects (76% of all submissions) were analyzed. RESULTS: The number of clinical projects was large, but declining: 794 in 2002 and 762 in 2007. Drug research (mainly trials) represented 29% and 34% of the clinical projects; their total number had not declined, but those without a commercial sponsor had. The number of different principal investigators was large (630 and 581). Most projects were observational, while an experimental design was used in 43% of projects. Multi-center studies were common. In half of the projects, the main funder was health care or was done as unpaid work; 31% had industry funding as the main source. There was a clear difference in the type of research by sponsorship. Industry-funded research was largely drug research, international multi-center studies, with randomized controlled or other experimental design. The findings for the two years were similar, but a university hospital as the main research site became less common between 2002 and 2007. CONCLUSIONS: Clinical research projects were common, but numbers are declining; research was largely funded by health care, with many physicians involved. Drug trials were a minority, even though most research promotion efforts and regulation concerns them. PMID- 23680290 TI - Immigrants do not transmit tuberculosis more than indigenous patients in Catalonia (Spain). AB - BACKGROUND: Immigrants may not transmit tuberculosis (TB) more than indigenous patients. The objective was to study the prevalence of TB infection among contacts of immigrant and indigenous TB patients and the risk factors associated with latent TB infection. METHODS: Contacts of TB cases recorded in 2005 and 2006 were surveyed using a standardized Health Department questionnaire. Infections were diagnosed using the tuberculin skin test (TST) (cut-off >= 5 mm). The risk of infection was determined by multivariate logistic regression and the adjusted odds ratios (aOR) with the 95% confidence intervals (CI) were calculated. RESULTS: The study of contacts was completed in 1329 cases of TB. The prevalence of infection was 32.3% (3038/9406) in all contacts, 41.4% in contacts of immigrant cases and 29.2% in contacts of indigenous cases. In the multivariate analysis, immigrant index cases were not associated with an increased risk (aOR = 0.9; 95%CI: 0.8-1.0). The prevalence of TST conversion was 10.0% (296/2969) in all contacts, 11.2% in immigrant contacts and 9.7% in indigenous contacts (p = 0.158). CONCLUSIONS: Immigrants do not transmit TB more than indigenous TB patients. Infections which may have occurred in the countries of origin of immigrants were detected by the systematic study of contacts. PMID- 23680291 TI - Bio-crossroads: the 15th European Congress of Biotechnology, Istanbul, September 2012. PMID- 23680292 TI - Vulnerability of fourth ventricle choroid plexus in sudden unexplained fetal and infant death syndromes related to smoking mothers. AB - The human choroid plexuses in the ventricular system represent the main source of cerebrospinal fluid secretion and constitute a major barrier interface that controls the brain's environment. The present study focused on the choroid plexus of the fourth ventricle, the main cavity of the brainstem containing important nuclei and/or structures mediating autonomic vital functions. In serial sections of 84 brainstems of subjects aged from 17 gestational weeks to 8 postnatal months of life, the deaths due to both known and unknown causes, we examined the cytoarchitecture and the developmental steps of the fourth ventricle choroid plexus to determine whether this structure shows morphological and/or functional alterations in unexplained perinatal deaths (Sudden Infant Death Syndrome and Sudden Intrauterine Unexplained Death Syndrome). High incidence of histological and immunohistochemical alterations (prevalence of epithelial dark cells, the presence of cystic cells in the stroma, decreased number of blood capillaries, hyperexpression of Substance P and apoptosis) were prevalently observed in unexplained death victims (p<0.05 vs. controls). A significant correlation was found between maternal smoking in pregnancy and choroidal neuropathological parameters (p<0.01). This work underscores the negative effects of prenatal exposure to nicotine on the development of the autonomic nervous system, and in particular of the fourth ventricle choroid plexus that is a very vulnerable structure in the developing CSF-brain system. PMID- 23680293 TI - Exploring haemodynamics of haemodialysis using extrema points analysis model. AB - BACKGROUND: Haemodialysis is a form of renal replacement therapy used to treat patients with end stage renal failure. It is becoming more appreciated that haemodialysis patients exhibit higher rates of multiple end organ damage compared to the general population. There is also a strong emerging evidence that haemodialysis itself causes circulatory stress. We aimed at examining haemodynamic patterns during haemodialysis using a new model and test that model against a normal control. METHODS: We hypothesised that blood pressures generated by each heart beat constantly vary between local peaks and troughs (local extrema), the frequency and amplitude of which is regulated to maintain optimal organ perfusion. We also hypothesised that such model could reveal multiple haemodynamic aberrations during HD. Using a non-invasive cardiac output monitoring device (Finometer(r)) we compared various haemodynamic parameters using the above model between a haemodialysis patient during a dialysis session and an exercised normal control after comparison at rest. RESULTS: Measurements yielded 29,751 data points for each haemodynamic parameter. Extrema points frequency of mean arterial blood pressure was higher in the HD subject compared to the normal control (0.761Hz IQR 0.5-0.818 vs 0.468Hz IQR 0.223-0.872, P < 0.0001). Similarly, extrema points frequency of systolic blood pressure was significantly higher in haemodialysis compared to normal. In contrary, the frequency of extrema points for TPR was higher in the normal control compared to HD (0.947 IQR 0.520-1.512 vs 0.845 IQR 0.730-1.569, P < 0.0001) with significantly higher amplitudes. CONCLUSION: Haemodialysis patients potentially exhibit an aberrant haemodynamic behaviour characterised by higher extrema frequencies of mean arterial blood pressure and lower extrema frequencies of total peripheral resistance. This, in theory, could lead to higher variation in organ perfusion and may be detrimental to vulnerable vascular beds. PMID- 23680294 TI - The relationship between parent health literacy and pediatric emergency department utilization: a systematic review. AB - BACKGROUND: Low health literacy in parents can potentially impact understanding of a child's diagnosis and treatment course. No reviews have addressed parent health literacy in the emergency department (ED), the relationship between parent health literacy and child ED utilization, or the impact of low literacy interventions on child ED utilization. OBJECTIVE: To systematically evaluate the peer-reviewed literature pertaining to parental health literacy and ED utilization. The following key questions were addressed: question (Q) 1) What is the prevalence of low health literacy, as estimated by validated health literacy measures, of parents in the ED? Q2) Is parent low health literacy related to ED use for children? Q3) Do low literacy interventions targeting parents likely to have low health literacy affect ED use for children? DATA SOURCES: The authors reviewed 483 unduplicated titles and abstracts published between 1980 and May 2012 using PubMed and CINAHL, with 117 retained for full review and 17 included in the final analytic review. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS: All included articles had a valid measure of parent health literacy and a Q1) descriptive measurement of the population, Q2) ED utilization, or Q3) utilized a low literacy educational intervention. STUDY APPRAISAL AND SYNTHESIS METHODS: One author extracted data verified by a second author. Studies were rated for quality by both authors. RESULTS: Q1) A median of 30% (interquartile range 22-36%) of parents in the ED possesses low health literacy. Q2) Studies investigating the relationship between health literacy and ED yielded mixed results. Q3) Seven of 8 low literacy interventions were associated with a reduction in ED use. Random effects pooled odds ratios from 6 studies showed intervention effectiveness (odds ratio 0.35; 95% CI 0.15-0.81). LIMITATIONS: No intervention studies measured health literacy, limiting the ability to determine whether the low literacy intervention targeted health literacy. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Roughly 1 in 3 parents of children presenting to the ED have low health literacy. Importantly, interventions targeting parents likely to have low health literacy have an impact in reducing ED utilization. PMID- 23680296 TI - Incidence of enuresis and encopresis among children with attention deficit/hyperactivity disorder in a population-based birth cohort. AB - OBJECTIVE: This study reports the incidence of enuresis and encopresis among children with attention-deficit/hyperactivity disorder (ADHD) versus those without ADHD. METHODS: Subjects included 358 children (74.5% boys) with research identified ADHD from a 1976 to 1982 population-based birth cohort (n = 5718) and 729 (75.2% boys) non-ADHD control subjects from the same birth cohort, matched by gender and age. All subjects were retrospectively followed from birth until a diagnosis of enuresis or encopresis was made or last follow-up before 18 years of age. The complete medical record for each subject was reviewed to obtain information on age of initial diagnosis of an elimination disorder, frequency and duration of symptoms, and identification of exclusionary criteria specified by DSM-IV, with confirmation of the diagnosis by expert consensus. RESULTS: Children with ADHD were 2.1 (95% confidence interval [CI], 1.3-3.4; P = .002) times more likely to meet DSM-IV criteria for enuresis than non-ADHD controls; they were 1.8 (95% CI, 1.2-2.7; P = .006) times more likely to do so than non-ADHD controls when less stringent criteria for a diagnosis of enuresis were employed. Though not significant, children with ADHD were 1.8 (95% CI, 0.7-4.6; P = .23) times more likely to meet criteria for encopresis than non-ADHD controls. The relative risk was 2.0 (95% CI, 1.0-4.1; P = .05) when a less stringent definition for encopresis was utilized. CONCLUSIONS: Children with ADHD are more likely than their peers without ADHD to develop enuresis with a similar trend for encopresis. PMID- 23680295 TI - Parental and home environmental facilitators of sugar-sweetened beverage consumption among overweight and obese Latino youth. AB - OBJECTIVE: To explore parental and home environmental facilitators of sugar sweetened beverage (SSB) and water consumption among obese/overweight Latino youth. METHODS: Semistructured interviews were conducted with 55 overweight/obese Latino youth aged 10 to 18 and 55 parents, recruited from school-based clinics and a school in one West Coast district. All youth consumed SSBs regularly and lived in a home where SSBs were available. We used qualitative methods to examine key themes around beliefs about SSBs and water, facilitators of SSB and water consumption, and barriers to reducing SSB consumption. RESULTS: A few parents and youth believed that sports drinks are healthy. Although nearly all thought that water is healthy, most parents and about half of youth thought that tap water is unsafe. About half of parent-child dyads had discordant beliefs regarding their perceptions of tap water. About half of parents believed that homemade culturally relevant drinks (eg, aguas frescas), which typically contain sugar, fruit, and water, were healthy because of their "natural" ingredients. Participants cited home availability as a key factor in SSB consumption. About half of parents set no rules about SSB consumption at home. Among those with rules, most parent-child pairs differed on their beliefs about the content of the rules, and youth reported few consequences for breaking rules. CONCLUSIONS: Obesity programs for Latino youth should address misconceptions around water and should discuss culturally relevant drinks and sports drinks as potential sources of weight gain. Health care providers can help parents set appropriate rules by educating about the risks of keeping SSBs at home. PMID- 23680297 TI - Seroprevalence of Toxoplasma gondii in slaughtered horses and donkeys in Liaoning province, northeastern China. AB - BACKGROUND: Toxoplasma gondii is an important zoonotic pathogen infecting humans and almost all warm-blooded animals. The most common sources of human infection are ingestion of tissue cysts in raw or undercooked meat. However, limited information is available about T. gondii infection in horses and donkeys in China. In the present study, we report the seroprevalence of T. gondii infection in horses and donkeys in Liaoning province, northeastern China. METHODS: Serum samples were collected from 711 and 738 slaughtered horses and donkeys, respectively, in 13 regions of Liaoning province. The modified agglutination test (MAT) was used to test the specific antibodies to T. gondii. RESULTS: In this study, 178 of 711 (25.0%) horses were seropositive for T. gondii with titers of 1:25 in 81, 1:50 in 62, 1:100 in 33, and 1:200 in 2, and seroprevalence of T. gondii infection from 13 regions ranged from 8.2% to 37.0%. Antibodies to T. gondii were found in 174 of 738 (23.6%) donkeys with titers of 1:25 in 66, 1:50 in 54, 1:100 in 49, and 1:200 in 5, and seroprevalence varied in 13 different regions, ranging from 9.1% to 32.6%. CONCLUSIONS: The results of the present study indicated that the rate of infection with T. gondii in horses and donkeys is a little high in Liaoning province, northeastern China in comparison to other surveys in China, which suggests that consumption of horse and donkey meat in this area may represent a potential source for human infection with T. gondii. PMID- 23680298 TI - Cell cycle-dependent localization of CHK2 at centrosomes during mitosis. AB - BACKGROUND: Centrosomes function primarily as microtubule-organizing centres and play a crucial role during mitosis by organizing the bipolar spindle. In addition to this function, centrosomes act as reaction centers where numerous key regulators meet to control cell cycle progression. One of these factors involved in genome stability, the checkpoint kinase CHK2, was shown to localize at centrosomes throughout the cell cycle. RESULTS: Here, we show that CHK2 only localizes to centrosomes during mitosis. Using wild-type and CHK2-/- HCT116 human colon cancer cells and human osteosarcoma U2OS cells depleted for CHK2 with small hairpin RNAs we show that several CHK2 antibodies are non-specific and cross react with an unknown centrosomal protein(s) by immunofluorescence. To characterize the localization of CHK2, we generated cells expressing inducible GFP-CHK2 and Flag-CHK2 fusion proteins. We show that CHK2 localizes to the nucleus in interphase cells but that a fraction of CHK2 associates with the centrosomes in a Polo-like kinase 1-dependent manner during mitosis, from early mitotic stages until cytokinesis. CONCLUSION: Our findings demonstrate that a subpopulation of CHK2 localizes at the centrosomes in mitotic cells but not in interphase. These results are consistent with previous reports supporting a role for CHK2 in the bipolar spindle formation and the timely progression of mitosis. PMID- 23680300 TI - Determinants of neonatal death with emphasis on health care during pregnancy, childbirth and reproductive history. AB - OBJECTIVE: To identify risk factors for neonatal mortality, focusing on factors related to assistance care during the prenatal period, childbirth, and maternal reproductive history. METHODS: This was a case-control study conducted in Maceio, Northeastern Brazil. The sample consisted of 136 cases and 272 controls selected from official Brazilian databases. The cases consisted of all infants who died before 28 days of life, selected from the Mortality Information System, and the controls were survivors during this period, selected from the Information System on Live Births, by random drawing among children born on the same date of the case. Household interviews were conducted with mothers. RESULTS: The logistic regression analysis identified the following as determining factors for death in the neonatal period: mothers with a history of previous children who died in the first year of life (OR=3.08), hospitalization during pregnancy (OR=2.48), inadequate prenatal care (OR=2.49), lack of ultrasound examination during prenatal care (OR=3.89), transfer of the newborn to another unit after birth (OR=5.06), admittance of the newborn at the ICU (OR=5.00), and low birth weight (OR=2.57). Among the socioeconomic conditions, there was a greater chance for neonatal mortality in homes with fewer residents (OR=1.73) and with no children younger than five years (OR=10.10). CONCLUSION: Several factors that were associated with neonatal mortality in this study may be due to inadequate care during the prenatal period and childbirth, and inadequate newborn care, all of which can be modified. PMID- 23680299 TI - Clinical review: Helmet and non-invasive mechanical ventilation in critically ill patients. AB - Non-invasive mechanical ventilation (NIV) has proved to be an excellent technique in selected critically ill patients with different forms of acute respiratory failure. However, NIV can fail on account of the severity of the disease and technical problems, particularly at the interface. The helmet could be an alternative interface compared to face mask to improve NIV success. We performed a clinical review to investigate the main physiological and clinical studies assessing the efficacy and related issues of NIV delivered with a helmet. A computerized search strategy of MEDLINE/PubMed (January 2000 to May 2012) and EMBASE (January 2000 to May 2012) was conducted limiting the search to retrospective, prospective, nonrandomized and randomized trials. We analyzed 152 studies from which 33 were selected, 12 physiological and 21 clinical (879 patients). The physiological studies showed that NIV with helmet could predispose to CO2 rebreathing and increase the patients' ventilator asynchrony. The main indications for NIV were acute cardiogenic pulmonary edema, hypoxemic acute respiratory failure (community-acquired pneumonia, postoperative and immunocompromised patients) and hypercapnic acute respiratory failure. In 9 of the 21 studies the helmet was compared to a face mask during either continous positive airway pressure or pressure support ventilation. In eight studies oxygenation was similar in the two groups, while the intubation rate was similar in four and lower in three studies for the helmet group compared to face mask group. The outcome was similar in six studies. The tolerance was better with the helmet in six of the studies. Although these data are limited, NIV delivered by helmet could be a safe alternative to the face mask in patients with acute respiratory failure. PMID- 23680301 TI - Temporal trends of overall mortality and hospital morbidity due to diarrheal disease in Brazilian children younger than 5 years from 2000 to 2010. AB - OBJECTIVE: To verify the temporal trends of the indicators of overall mortality and hospital morbidity due to diarrheal disease in children younger than 1 year and between 1 and 4 years, according to the region of Brazil, between 2000 and 2010. METHOD: This was an ecological study of temporal series. Data on hospital admission authorization, mean length of stay, and mean value of the authorization were obtained from the Hospital Information System. The number of infant deaths was obtained from the Mortality Information System; information on live births and the general population were obtained from the Information System on Live Births and Demographic Censuses, respectively. These data were available at the website of the informatics department of the Brazilian Unified Health System/Ministry of Health RESULTS: Mortality due to diarrheal disease in Brazil showed a downwards trend in both age groups. Regarding hospitalization, there was a slight downwards trend in children younger than 1 year and a non-significant upwards trend between 1-4 years, with a shorter hospital stay and lower mean value of hospital stay, regardless of age and region. The North and Northeast had the highest mortality rates and the highest percentage of hospitalizations in children younger than 1 year. The Midwest had the highest mean annual reduction in hospital stay. CONCLUSION: Currently, the indicators of overall mortality and hospital morbidity due to diarrhea in Brazilian children are generally lower, but decreasing slowly. PMID- 23680302 TI - An evaluation of marginal fit of three-unit fixed dental prostheses fabricated by direct metal laser sintering system. AB - OBJECTIVES: This in vitro study aimed to evaluate and compare marginal fit of three-unit fixed dental prostheses (FDPs) fabricated using a newly developed direct metal laser sintering (DMLS) system with that of three-unit FDPs by a conventional lost wax technique (LW) method. METHODS: Ten cobalt-chromium alloy three-unit FDPs using DMLS system and another ten nickel-chromium alloy FDPs using LW method were fabricated. Marginal fit was examined using a light-body silicone. After setting, the silicon film was cut into four parts and the thickness of silicon layer was measured at 160* magnification using a digital microscope to measure absolute marginal discrepancy (AMD), marginal gap (MG) and internal gap (IG). A repeated measure ANOVA for statistical analysis was performed using the SPSS statistical package version 12.0 (alpha=0.05). RESULTS: The mean values of AMD, MG, and IG were significantly larger in the DMLS group than in the LW group (p<0.001). Means of AMD, MG and IG in the first molars were 83.3, 80.0, and 82.0MUm in the LW group; and 128.0, 112.0, and 159.5MUm in the DMLS group, respectively. No significant difference between measurements for premolars and molars was found (p>0.05). SIGNIFICANCE: The marginal fit of the DMLS system appeared significantly inferior compared to that of the conventional LW method and slightly larger than the acceptable range. For clinical application further improvement of DMLS system may be required. PMID- 23680303 TI - Gendered constructions of the impact of HIV and AIDS in the context of the HIV positive seroconcordant heterosexual relationship. AB - INTRODUCTION: This article explores the complex, dynamic and contextual frameworks within which men working in a mining community and their live-in long term partners or spouses (termed "couples" in this study) respond to the introduction of HIV into their heterosexual relationships; the way in which partners adopt gendered positions in enabling them to make sense of their illness; how they negotiate their respective masculine and feminine roles in response to the need for HIV-related lifestyle changes; as well as the gendered nature of partner support in relation to antiretroviral therapy (ARV) adherence. METHODS: We conducted an in-depth qualitative study with a sample of 12 HIV positive seroconcordant heterosexual couples in a South African mining organization. Transcripts based on semi-structured couple's interviews were analyzed using an inductive emergent thematic analytical method. RESULTS: The findings present compelling evidence that the impact of HIV and AIDS is mitigated, in the main, by the nature of the dyadic relationship. Where power and agency were skewed in accordance with traditional gender scripts, the impact of HIV and AIDS was deleterious in terms of negotiating disclosure, meeting expectations of care and support, and promoting treatment adherence. As a corollary, the study also revealed that where the relational dynamic evidenced a more equitable distribution of power, the challenge of negotiating illness was embraced in a way that strengthened the couples' affiliation in profound ways, manifested not simply in a reduction in risk behaviours, but in both partner's courage to re-visit sensitive issues related to managing their relationship in the context of a debilitating illness. CONCLUSIONS: Gendered positioning (by self and others) was found to play a crucial role in the way couples experienced HIV and ARV treatment, and underscored the positive role of a couples-counselling approach in the negotiation of the illness experience. However, as part of a broader social project, the findings highlight the need to address the shortcomings of a public health discourse on illness normalization that reifies and reinforces skewed gender relations. In essence, the findings make a compelling case for targeting couples as the primary unit of analysis and intervention in HIV and AIDS praxis, not only to enhance treatment and prevention outcomes, but to impact on and potentially transform the lived identity of such relationships, in AIDS-affected communities. We recommend early intervention with couples in terms of couples HIV testing, risk-reduction counselling and gender based interventions giving couples opportunities to revisit and challenge their prevailing gendered identities. We note, however, that these efforts will be undermined in the long term, if the structural drivers of HIV risk and vulnerability, contained within macro-level social, economic and cultural practices, are not simultaneously addressed. PMID- 23680304 TI - Catabolic flexibility of mammalian-associated lactobacilli. AB - Metabolic flexibility may be generally defined as "the capacity for the organism to adapt fuel oxidation to fuel availability". The metabolic diversification strategies used by individual bacteria vary greatly from the use of novel or acquired enzymes to the use of plasmid-localised genes and transporters. In this review, we describe the ability of lactobacilli to utilise a variety of carbon sources from their current or new environments in order to grow and survive. The genus Lactobacillus now includes more than 150 species, many with adaptive capabilities, broad metabolic capacity and species/strain variance. They are therefore, an informative example of a cell factory capable of adapting to new niches with differing nutritional landscapes. Indeed, lactobacilli naturally colonise and grow in a wide variety of environmental niches which include the roots and foliage of plants, silage, various fermented foods and beverages, the human vagina and the mammalian gastrointestinal tract (GIT; including the mouth, stomach, small intestine and large intestine). Here we primarily describe the metabolic flexibility of some lactobacilli isolated from the mammalian gastrointestinal tract, and we also describe some of the food-associated species with a proven ability to adapt to the GIT. As examples this review concentrates on the following species - Lb. plantarum, Lb. acidophilus, Lb. ruminis, Lb. salivarius, Lb. reuteri and Lb. sakei, to highlight the diversity and inter relationships between the catabolic nature of species within the genus. PMID- 23680306 TI - DNA barcoding and elucidation of cryptic aphid species (Hemiptera: Aphididae) in India. AB - Rapid, precise and timely identification of invasive pest insects such as aphids is important and a challenge worldwide due to their complex life cycles, parthenogenetic reproduction, sex and colour morphs. In this respect, DNA barcoding employing a 658 bp fragment of 5' region of the mitochondrial cytochrome oxidase I (CO-I) gene is an effective tool in addressing the above. In the present study, we employed CO-I for discriminating 142 individuals representing 32 species of aphids from India. Sequence analyses revealed that the intraspecific and interspecific distances ranged from zero to 3.8% and 2.31 to 18.9%, respectively. In addition, the study also showed for the first time the prevalence of three cryptic species, namely Brevicoryne brassicae (Linnaeus), Hyperomyzus carduellinus (Theobald) and Brachycaudus helichrysi (Kaltenbach) from India. Our work has clearly demonstrated that DNA barcoding is an efficient and accurate method for identification of aphid species (including cryptic species), an approach that potentially could play an important role in formulating viable pest management strategies, more especially biocontrol. PMID- 23680305 TI - Matrix-based gene delivery for tissue repair. AB - Scaffolds for tissue repair must provide structural and biochemical cues to initiate the complex cascade of events that lead to proper tissue formation. Incorporating genes into these scaffolds is an attractive alternative to protein delivery since gene delivery can be tunable to any DNA sequence and genes utilize the cells' machinery to continuously produce therapeutic proteins, leading to longer lasting transgene expression and activation of autocrine and paracrine signaling that are not activated with bulk protein delivery. In this review, we discuss the importance of scaffold design and the impact of its design parameters (e.g. material, architecture, vector incorporation, biochemical cue presentation) on transgene expression and tissue repair. PMID- 23680307 TI - The predictive value of endorectal 3 Tesla multiparametric magnetic resonance imaging for extraprostatic extension in patients with low, intermediate and high risk prostate cancer. AB - PURPOSE: We determined the positive and negative predictive values of multiparametric magnetic resonance imaging for extraprostatic extension at radical prostatectomy for different prostate cancer risk groups. MATERIALS AND METHODS: We evaluated a cohort of 183 patients who underwent 3 Tesla multiparametric magnetic resonance imaging, including T2-weighted, diffusion weighted magnetic resonance imaging and dynamic contrast enhanced sequences, with an endorectal coil before radical prostatectomy. Pathological stage at radical prostatectomy was used as standard reference for extraprostatic extension. The cohort was classified into low, intermediate and high risk groups according to the D'Amico criteria. We recorded prevalence of extraprostatic extension at radical prostatectomy and determined sensitivity, specificity, positive predictive value and negative predictive value of multiparametric magnetic resonance imaging for extraprostatic extension in each group. Univariate and multivariate analyses were performed to identify predictors of extraprostatic extension at radical prostatectomy. RESULTS: The overall prevalence of extraprostatic extension at radical prostatectomy was 49.7% ranging from 24.7% to 77.1% between low and high risk categories. Overall staging accuracy of multiparametric magnetic resonance imaging for extraprostatic extension was 73.8%, with sensitivity, specificity, positive predictive value and negative predictive value of 58.2%, 89.1%, 84.1% and 68.3%, respectively. Positive predictive value of multiparametric magnetic resonance imaging for extraprostatic extension was best in the high risk cohort with 88.8%. Negative predictive value was highest in the low risk cohort with 87.7%. With an odds ratio of 10.3 multiparametric magnetic resonance imaging is by far the best preoperative predictor of extraprostatic extension at radical prostatectomy. CONCLUSIONS: For adequate patient counseling, knowledge of predictive values of multiparametric magnetic resonance imaging for extraprostatic extension is of utmost importance. High negative predictive value, important for decisions on nerve sparing strategies at radical prostatectomy, is only reached in low risk subjects. PMID- 23680308 TI - Expanded criteria to identify men eligible for active surveillance of low risk prostate cancer at Johns Hopkins: a preliminary analysis. AB - PURPOSE: At our institution the eligibility criteria used to enroll patients in active surveillance are clinical stage T1, prostate specific antigen density less than 0.15 ng/ml, biopsy Gleason score 6 or less, 2 or fewer positive biopsy cores and 50% or less involvement of any biopsy core. We hypothesized that these criteria may be excessively strict, precluding many men from active surveillance. MATERIALS AND METHODS: We studied pathological outcomes in men treated with radical prostatectomy between 1995 and 2012 who met 4 or more of the 5 active surveillance criteria. Outcomes included a definition of significant tumor (pathological Gleason 7 or greater, or nonorgan confined). We compared adverse pathology rates between men who met all 5 vs 4 of 5 active surveillance criteria. RESULTS: Of 8,261 men 1,890 (22.9%) met all active surveillance eligibility criteria and 2,133 (25.8%) met 4. Men with values exceeding prostate specific antigen density and biopsy Gleason criteria were at increased risk for adverse pathological outcomes. Clinical stage greater than T1 was not associated with adverse pathological findings. The risk of significant tumors in men with clinical stage T2 lesions, 3 or fewer positive biopsy cores and less than 60% core involvement was comparable to that of men who met all active surveillance criteria. CONCLUSIONS: Prostate specific antigen density greater than 0.15 ng/ml and biopsy Gleason score 7 or greater are strongly associated with adverse pathological findings at radical prostatectomy. Our findings suggest that active surveillance criteria should be expanded to include men with clinical stage T2 lesions and a greater number of positive biopsy cores of low grade. Based on these preliminary findings, we are in the process of reassessing active surveillance eligibility criteria using more detailed pathological analysis. PMID- 23680309 TI - The association of depression, anxiety and nocturia: a systematic review. AB - PURPOSE: This systematic review focuses on the relationship between nocturia and depression/anxiety. Our objective is to provide an overview of current data on the epidemiology, pathophysiology and patient management implications of the association between nocturia and depression/anxiety. MATERIALS AND METHODS: We queried PubMed(r), Web of Science(r) and EmbaseTM in July 2012 to identify abstracts, and original, review and editorial articles on nocturia and mood disorders, specifically depression and anxiety. The search was done using the key words "nocturia," "depression" and "anxiety." We complied with the Assessment of Multiple Systemic Reviews (AMSTAR) instrument. We retrieved a total of 500 records, including 95, 81 and 324 from PubMed, Web of Science and Embase, respectively. RESULTS: Cross-sectional (level 3) data indicated that nocturia and depression/anxiety are strongly associated. One prospective study contended that depression leads to nocturia in a unidirectional relationship. Nocturia poses a greater risk for depression in men vs women. Results conflict on the effect of serotonin reuptake inhibitors on nocturia. CONCLUSIONS: The results of this systematic review suggest a bidirectional association between depression and nocturia. The relationship between anxiety and nocturia is less clear. Practicing clinicians should consider administering a brief self-administered scale to assess for depression in patients with nocturia. PMID- 23680310 TI - Upper tract imaging surveillance is not effective in diagnosing upper tract recurrence in patients followed for nonmuscle invasive bladder cancer. AB - PURPOSE: We evaluated the usefulness of routine upper tract imaging in patients followed for nonmuscle invasive bladder cancer. MATERIALS AND METHODS: A retrospective review of patients treated for nonmuscle invasive bladder cancer between 2000 and 2006 was conducted. Kaplan-Meier curves were calculated to determine upper tract urothelial carcinoma-free probability for stage Ta and T1 disease. Bladder cancer stage was included as a time dependent covariate. Descriptive statistics were used to report rates of imaging studies used and the efficacy in diagnosing upper tract urothelial carcinoma. RESULTS: Of 935 patients treated and followed for nonmuscle invasive bladder cancer 51 were diagnosed with upper tract urothelial carcinoma. Median followup was 5.5 years. The 5-year upper tract urothelial carcinoma-free probability among patients with Ta and T1 disease was 98% and 93%, respectively. The 10-year upper tract urothelial carcinoma-free probability among patients with Ta and T1 disease was 94% and 88%, respectively. Only 15 (29%) patients were diagnosed on routine imaging while the others were diagnosed after symptoms developed. Overall 3,074 routine imaging scans were conducted for an overall efficacy of 0.49%. CONCLUSIONS: Upper tract recurrence is a lifelong risk in patients with bladder cancer, but most cases will be missed on routine upper tract imaging. The majority of upper tract urothelial carcinoma can be diagnosed using a combination of thorough history taking, physical examination, urine cytology and sonography, indicating that routine surveillance imaging may not be the most efficient way to detect upper tract recurrence. PMID- 23680311 TI - Endoscopic vascular targeted photodynamic therapy with the photosensitizer WST11 for benign prostatic hyperplasia in the preclinical dog model. AB - PURPOSE: Vascular targeted photodynamic therapy with WST11 (TOOKAD(r) Soluble) is in phase III clinical trials of an interstitial transperineal approach for focal therapy of prostate cancer. We investigated the safety and efficacy of the endourethral route in the context of benign prostatic hyperplasia in the dog model. MATERIALS AND METHODS: An optical laser fiber was positioned in the prostatic urethra of 34 dogs, including 4 controls. It was connected to a 753 nm diode laser at 200 mW/cm fluence, delivering 200 to 300 J. WST11 (5 to 15 mg/kg) was infused intravenously in 2 modes, including continuous, starting 5 to 15 minutes before and during illumination, or a bolus 5 to 10 minutes before illumination. Prostate ultrasound, cystourethrogram, urodynamics and histopathology were performed. Followup was 1 week to 1 year. RESULTS: Endourethral WST11 vascular targeted photodynamic therapy was uneventful in all except 1 dog, which experienced urinary retention but reached the 1-week end point. All prostates except those in controls showed hemorrhagic lesions. They consisted of 2 levels of concentric alterations, including periurethral necrosis with endothelial layer destruction and adjacent inflammation/atrophy with normal blood vessels. Prostatic urethral width increased as early as 6 weeks after treatment, while prostatic volume decreased, reaching 25% by 18 to 26 weeks. A parallel decrease in urethral pressure at 6 weeks lasted up to 1 year. CONCLUSIONS: We confirmed the vascular effect of endourethral WST11 vascular targeted photodynamic therapy. To our knowledge we report for the first time that the resulting periurethral necrosis led to significant, sustained widening of the prostatic urethra, accompanied by long-term improvement in urodynamic parameters. These findings support future clinical applications of this minimally invasive approach to benign prostatic hyperplasia. PMID- 23680315 TI - A proportionate response to H7N9. PMID- 23680314 TI - Evaluation of early cerebral metabolic, perfusion and microstructural changes in HCV-positive patients: a pilot study. AB - BACKGROUND & AIMS: The aim of the study was to evaluate early metabolic perfusion, and microstructural cerebral changes in patients with the hepatitis C virus (HCV) infection and normal appearing brain on plain MR using advanced MR techniques, as well as to assess correlations of MR measurements with the liver histology activity index (HAI). METHODS: Fifteen HCV-positive patients and 18 control subjects underwent single voxel MR spectroscopy (MRS), perfusion weighted imaging (PWI), and diffusion tensor imaging (DTI), using a 1.5T MR unit. MRS metabolite ratios (NAA/Cr, Cho/Cr, mI/Cr) were calculated. PWI values of relative cerebral blood volume (rCBV) were assessed from 8 areas including several cortical locations, basal ganglia, and fronto-parietal white matter. DTI fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were obtained from 14 white matter tracts. RESULTS: Compared to controls, HCV-positive patients showed significantly (p < 0.05) lower NAA/Cr ratios within frontal and parietal white matters, lower rCBV values within frontal and temporo-parietal cortices, decreased FA values, as well as increased ADC values in several white matter tracts. We also found elevated rCBV values in basal ganglia regions. The increase in mI/Cr and Cho/Cr ratio was correlated with a higher HAI score. CONCLUSIONS: The results of advanced MR techniques indicate neurotoxicity of HCV reflected by neuronal impairment within white matter, cortical hypoperfusion, and disintegrity within several white matter tracts. Hyperperfusion in basal ganglia may be an indicator of brain inflammation in HCV patients. Our findings may suggest a biologic link between HCV-related liver disease and cerebral dysfunction. PMID- 23680316 TI - Inverted intercostal hernia of soft tissue of the chest wall: multi-detector computed tomography findings. PMID- 23680317 TI - Endobronchial lipoma: a rare cause of bronchial occlusion. AB - Endobronchial lipoma is a rare benign neoplasm of the tracheobronchial tree. Despite its benign nature, associated endoluminal polypoid growth can cause bronchial occlusion. In this paper, we present the consequences of a late diagnosis of this condition. PMID- 23680318 TI - Limited evidence for the safety of beta-blockers for cocaine-associated chest pain. PMID- 23680319 TI - Acute neck infections in children: who is likely to undergo surgical drainage? AB - BACKGROUND: Superficial neck infections including lymphadenitis and abscesses are commonly encountered in pediatric emergency departments (PEDs). It is often unclear which patients are likely to develop an abscess that necessitates surgical drainage. In evaluating these patients, computed tomography (CT) and ultrasound are often used to identify/confirm abscess formation. The criteria for determining the need for imaging studies are not well defined. DESIGN/METHODS: All visits to the study PED were examined in 2009 to 2010. Visits with the diagnosis of cervical lymphadenitis or abscess were identified. Records were retrospectively reviewed to determine the duration of symptoms, fever, previous antibiotic therapy, prior PED visit, size of neck swelling, fluctuance on physical examination, white blood cell count, and results of CT and/or ultrasound obtained in the PED. Data were analyzed to determine which of these characteristics were more likely to be associated with an abscess that was operatively drained. RESULTS: A total of 768 patients were evaluated for neck infections. One hundred twelve (14%) of these pediatric patients underwent abscess drainage in the operating room. Two hundred eighty-nine patients underwent a neck CT and/or ultrasound, of which 119 were positive for abscess. Factors associated with surgical drainage included fluctuance (odds ratio [OR], 18.92; 95% confidence interval [CI], 3.66-31.37), previous emergency department visit (OR, 2.79; 95% CI, 1.34-5.84), and age less than 4 years (OR, 3.01; 95% CI, 1.15-9.87). A recursive partitioning model stratified patients' risk for going to the operating room. Patients without fluctuance and with no prior emergency department visit, along with no prior antibiotic use, have less than 4% chance of having an abscess that necessitates surgical drainage. CONCLUSIONS: Pediatric patients who are more likely to have a neck infection that necessitates surgical drainage can be stratified based on clinical characteristics. This knowledge may allow physicians to better predict the resource needs including hospital admission and emergent imaging for neck infection. PMID- 23680320 TI - Safety of beta-blockers in the acute management of cocaine-associated chest pain. PMID- 23680321 TI - Renal infarction secondary to ketamine abuse. AB - Renal infarction is an uncommon condition that resulted from inadequate perfusion of the kidney and is easily missed diagnosed due to its nonspecific clinical presentations. Major risk factors for renal infarction are atrial fibrillation, previous embolism, and ischemic and valvular heart disease. Progressive decrease in renal function or even death can occur if renal infarction is not diagnosed accurately and promptly. Ketamine abuse may cause variable urinary tract injury. However, renal infarction caused by ketamine abuse has never been reported. To our knowledge, this is the first documented case of renal infarction following nasal insufflation of ketamine. PMID- 23680322 TI - Initial middle latency auditory evoked potentials index helps to predict resuscitated outcomes in patients with cardiac arrest. AB - INTRODUCTION: We speculated that initial middle latency auditory evoked potentials index (MLAEPi) can indicate cerebral function and predict the restoration of spontaneous circulation (ROSC), postresuscitation survival or of neurologic outcomes among patients with cardiac arrest. METHODS: This prospective study included 61 patients with cardiac arrest who received basic life support and did not achieve ROSC until arrival at the emergency center between September 2010 and September 2011. All patients were then administered advanced cardiac life support at the emergency department. Initial MLAEPi was immediately measured using an MLAEP monitor (aepEX plus; Audiomex, Glasgow, Scotland, UK) during the first cycle of advanced cardiac life support. Prediction of the ROSC, survival, and good outcome were investigated. RESULTS: Sixteen patients achieved ROSC (ROSC group), and 45 did not achieve ROSC at the scene (non-ROSC group). The initial MLAEPi was significantly higher in the ROSC than in the non-ROSC group (33 vs 28, P < .01). Four survivors in the ROSC group were classified as good outcomes (Cerebral Performance Category 1 and 2). Initial MLAEPi in survivors were significantly higher than that in nonsurvivors (43 vs 29, P < .01). The receiver operating characteristic curves for the initial MLAEPi with area under the curves was 0.75 (95% confidence interval [CI], 0.62-0.88; P < .01) for ROSC, 0.94 (95% CI, 0.88-1.00; P < 0.01) for survival, and 0.96 (95% CI, 0.89-1.03; P < .01) for a good outcome, respectively. CONCLUSIONS: Initial MLAEPi represented by simple numerical values upon presentation at emergency facilities could predict ROSC, survival, and neurologic outcomes among patients with cardiac arrest. PMID- 23680323 TI - Methylene blue for refractory anaphylaxis--is it a magic bullet? The authors' response. PMID- 23680324 TI - Emergency cricothyroidotomies for trauma: further considerations. PMID- 23680325 TI - Painful, pigmented lymphadenopathy secondary to decorative tattooing. AB - Pigmented lymph nodes are traditionally associated with melanoma and metastatic malignancy. This report describes the case of 22-year-old white man, who presented with painful right groin lymphadenopathy. Groin ultrasound and computed tomography confirmed an enlarged (2 cm) right inguinal lymph node. Elective excision of this lymph node was conducted due to unresolving pain, and a pigmented node was retrieved. Although a suspicious finding, histologic examination demonstrated black pigment infiltration from a decorative tattoo on the right leg. Unresolving, painful, pigmented lymphadenopathy can result from decorative tattooing. Selective excision of the affected lymph node and histologic examination result in symptom resolution and can aide in appropriate diagnosis. PMID- 23680326 TI - Repeated pulse intramuscular injection of pralidoxime chloride in severe acute organophosphorus pesticide poisoning. AB - OBJECTIVE: This study aimed to clarify the efficacy of 2 therapies for patients with severe acute organophosphorus pesticide poisoning, including atropine adverse effects, the length of intensive care unit (ICU) stay, complications, and mortality. METHODS: A retrospective cohort study of 152 cases collected from May 2008 to November 2012 at 2 urban university hospitals was conducted. Patients admitted to the hospital for organophosphate poisoning were divided into 2 groups with different therapeutic regimens: group A was administered a repeated pulse intramuscular injection of pralidoxime chloride, and group B received the same initial dosage of atropine and pralidoxime chloride, but pralidoxime chloride intravenous therapy was administered for only 3 days, regardless of the length of atropine therapy. Subsequently, atropine adverse effects, length of ICU stay, complications, and mortality were statistically analyzed and compared between the 2 groups. RESULTS: The total dose of atropine was 57.40 +/- 15.14 mg in group A and 308.26 +/- 139.16 mg in group B; group A received less atropine than did group B (P = .001). The length of ICU stay in group A was reduced (P = .025), and group A had fewer atropine adverse effects (P = .002). However, there was no significant difference in the mortality or complication rate between the 2 groups (P > .05). CONCLUSION: In patients with severe poisoning, group A used less atropine, had fewer atropine adverse effects, and had a shorter ICU stay. We suggest that therapy should be started as early as possible using a sufficient amount of pralidoxime chloride started intramuscularly in combination with atropine and that the drugs should not be prematurely discontinued. PMID- 23680327 TI - Putamen hemorrhage occurred simultaneously with Stanford type A acute aortic dissection: a case report. AB - This case report describes a 60-year-old man found unresponsive on the road. He was later admitted to our emergency department (ED) with consciousness disturbance and decorticate rigidity. Computed tomographic imaging revealed coexisting left putamen hemorrhage and Stanford type A acute aortic dissection. Decompressive craniectomy and hematoma evacuation were performed, but he died during his second hospital day. Morbid anatomy proved aortic dissection from the ascending aorta to left common iliac artery with pericardial effusion up to 500 mL. Brain hemorrhage and acute aortic dissection share several risk factors including hypertension and atherosclerosis, but few cases have been reported with brain hemorrhage and aortic dissection occurring simultaneously. Diagnosis for aortic dissection is difficult, especially when the patient has consciousness disturbance because of brain hemorrhage. Consequently, coexistence of these 2 conditions might be missed frequently in emergency settings. Therefore, wider knowledge of this case is important to inform others to suspect and investigate aortic dissection in cases of brain hemorrhage. PMID- 23680328 TI - A new algorithm in the Chest Pain Unit using the high-sensitivity troponin T. PMID- 23680329 TI - Wandering spleen presenting as small bowel obstruction. PMID- 23680330 TI - Direct evaluation of the effect of filtering the chest compression artifacts on the uninterrupted cardiopulmonary resuscitation time. AB - OBJECTIVES: Filtering the cardiopulmonary resuscitation (CPR) artifact has been a major approach to minimizing interruptions to CPR for rhythm analysis. However, the effects of these filters on interruptions to CPR have not been evaluated. This study presents the first methodology for directly quantifying the effects of filtering on the uninterrupted CPR time. METHODS: A total of 241 shockable and 634 nonshockable out-of-hospital cardiac arrest records (median duration, 150 seconds) from 248 patients were analyzed. Filtering and rhythm analysis were commenced after 1 minute of CPR, and the end point for CPR was established at the time of the first shock diagnosis. Kaplan-Meier curves were used to compute the probability of interrupting CPR as a function of time. The probabilities of delivering 2 minutes of uninterrupted CPR for the shockable and nonshockable rhythms were compared with the 2-minute cycles of uninterrupted CPR recommended by the guidelines. RESULTS: For the nonshockable rhythms, the probabilities of delivering at least 2 and 3 minutes of uninterrupted CPR were 58% (95% confidence interval, 54%-62%) and 48% (44%-52%), respectively. These are the probabilities of reducing and substantially reducing the frequency of CPR interruptions for rhythm analysis. For the shockable rhythms, the probability of avoiding unnecessary CPR prolongation beyond 2 minutes was 100% (99%-100%). CONCLUSIONS: Filtering reduces the frequency of CPR interruptions for rhythm analysis in less than 60% of nonshockable rhythms. New strategies to increase the probability of prolonging CPR for nonshockable rhythms should be defined and evaluated using the methodology proposed in this study. PMID- 23680331 TI - Hantavirus infection in North America: a clinical review. AB - The recent outbreak of hantavirus in Yosemite National Park has attracted national attention, with 10 confirmed cases of hantavirus cardiopulmonary syndrome and thousands of more people exposed. This article will review the epidemiology, presentation, workup, and treatment for this rare but potentially lethal illness. The possibility of infection with hantavirus deserves consideration in patients with severe respiratory symptoms with rodent exposure or rural/wilderness travel. Accurate diagnosis requires a high index of suspicion. Hantavirus cardiopulmonary syndrome presents as a vague prodrome of fever, cough, myalgias, chills, and nausea followed by a rapidly worsening respiratory phase. Presumptive diagnosis can be made based on pulmonary interstitial edema on chest radiographs in association with leukocytosis, thrombocytopenia, and hemoconcentration. Suspected cases should be confirmed with a reference laboratory and reported to the appropriate public health authorities. Although treatment is primarily supportive, aggressive fluid administration should be avoided due to the risk of pulmonary edema. The cardiopulmonary phase of the disease can progress rapidly with catastrophic decompensation in as little as a few hours. Patients require rapid intensive care unit admission for monitoring, mechanical ventilation, vasoactive agents, and possibly extracorporeal mechanical ventilation. Emergency physicians should be aware of outbreaks and vigilant for hantavirus exposures, especially during the summer and early fall months. PMID- 23680332 TI - Human T47D-ERbeta breast cancer cells with tetracycline-dependent ERbeta expression reflect ERalpha/ERbeta ratios in rat and human breast tissue. AB - T47D-ERbeta breast cancer cells with tetracycline-dependent ERbeta expression and constant ERalpha expression can be used to investigate effects of varying ERalpha/ERbeta ratios on estrogen-induced cellular responses. This study defines conditions at which ERalpha/ERbeta ratios in T47D-ERbeta cells best mimic ERalpha/ERbeta ratios in breast and other estrogen-sensitive tissues in vivo in rat as well as in human. Protein and mRNA levels of ERalpha and ERbeta were analyzed in T47D-ERbeta cells exposed to a range of tetracycline concentrations and compared to ERalpha and ERbeta levels found in breast, prostate, and uterus from rat and human origin. The ERalpha/ERbeta ratio in T47D-ERbeta cells exposed to >150ng/ml tetracycline is comparable to the ratio found in rat mammary gland and in human breast tissue. The ERalpha/ERbeta ratio of other estrogen-sensitive rat and human tissues can also be mimicked in T47D-ERbeta cells. The ERalpha/ERbeta ratio found in MCF-7 and native T47D breast cancer cell lines did not reflect ratios in analyzed rat and human tissues, which further supports the use of T47D-ERbeta cells as model for estrogen-responsive tissues. Using 17beta estradiol and the T47D-ERbeta cells under the conditions defined to mimic various tissues it could be demonstrated how these different tissues vary in their proliferative response. PMID- 23680333 TI - Hypertension in adolescence is not an independent risk factor for renal cancer: a cohort study of 918,965 males. AB - BACKGROUND: Hypertension has been repeatedly linked to renal cell cancer, independent of overweight and anti-hypertensive drug use, but its role remains unclear, especially within the growing group of relatively young-middle aged renal cancer patients. In order to delineate the role of hypertension in early onset renal cancer, we examined the association of blood pressure measured at age 17 with the incidence of renal cancer. METHODS: Sociodemographic and medical data of 918,965 adolescent males examined for fitness for military service from 1967 to 2005 were linked to the National Cancer Registry in this nationwide population based cohort study (12,910,585 person years) to obtain cancer incidence. A single measurement of blood pressure at age 17 was stratified as optimal (<120/80), normal (>= 120/80 < 130/85), high normal (>= 130/85 < 140/90), or high (>= 140/90). We used Cox proportional hazards modeling to estimate the hazard ratio of the blood pressure categories for renal cancer, adjusted for year of birth, body mass index, origin of parents, and height. We also assessed the role of a clinical diagnosis of persistent hypertension (n = 4223, based on multiple measurements). RESULTS: Of those who had their blood pressure recorded, 90 examinees developed renal cancer. In a multivariable model, the higher categories of blood pressure were associated with a decreased risk of renal cancer (hazard ratio, 0.32; 95% confidence interval, 0.12-0.84; P = .021 for blood pressure >= 140/90 vs < 120/80). Furthermore, there was no evidence of increased risk for those with an established diagnosis of hypertension (hazard ratio, 1.28; 95% confidence interval, 0.17-9.50; P = .81). CONCLUSIONS: It is unlikely that hypertension in adolescents carries an increased risk for renal cancer. PMID- 23680334 TI - Safety and blood pressure trajectory of short-term withdrawal of antihypertensive medications in older adults: experience from a clinical trial sample. AB - BACKGROUND: The short-term safety of and blood pressure changes after withdrawing hypertension treatment in older adults in preparation for clinical trials have not been well established. METHODS: Participants were enrolled in a clinical trial and antihypertensive medications were tapered over 3 weeks (week 1: reduction by 25%-50%; week 2: 50%-75%, week 3: off). Blood pressure was measured at the initial visit and after stopping all antihypertensive therapy (personnel) and twice a day during the taper phase (provided monitor). Trend analyses and linear models were used to assess changes in blood pressure. RESULTS: All participants (n = 53, mean age = 71 years, total of 1158 readings) successfully tapered their medications with no symptoms. Only 2% of the readings exceeded 180/100 mm Hg, but none were consecutive. Blood pressure gradually increased with an overall increase of 12/6 mm Hg, 95% confidence interval (4/1, 21/11). The daily increase in blood pressure was 0.2 mm Hg (standard error = 0.1) in both the systolic and diastolic blood pressure. Increases in systolic and diastolic blood pressure were comparable for all antihypertensive classes (P > .05 for all). CONCLUSION: Short-term (<3-4 weeks) withdrawal of antihypertensive therapy in older adults with hypertension is safe and is associated with mild increases in blood pressure. PMID- 23680335 TI - Field transmission intensity of Schistosoma japonicum measured by basic reproduction ratio from modified Barbour's model. AB - BACKGROUND: Schistosomiasis japonica, caused by infection with Schistosoma japonicum, is still recognized as a major public health problem in the Peoples' Republic of China. Mathematical modelling of schistosomiasis transmission has been undertaken in order to assess and project the effects of various control strategies for elimination of the disease. Seasonal fluctuations in transmission may have the potential to impact on the population dynamics of schistosomiasis, yet no model of S. japonicum has considered such effects. In this paper, we characterize the transmission dynamics of S. japonicum using a modified version of Barbour's model to account for seasonal variation (SV), and investigate the effectiveness of the control strategy adopted in Liaonan village of Xingzi county, Jiangxi Province. METHODS: We use mathematical tools for stability analysis of periodic systems and derive expressions for the basic reproduction ratio of S. japonicum in humans; we parameterise such expressions with surveillance data to investigate the conditions for persistence or elimination of the disease in the study village. We perform numerical simulations and parametric sensitivity analysis to understand local transmission conditions and compare values of the basic reproductive ratio with and without seasonal fluctuations. RESULTS: The explicit formula of the basic reproduction ratio for the SV-modified Barbour's model is derived. Results show that the value of the basic reproduction ratio, R0, of Liaonan village, Xingzi county is located between 1.064 and 1.066 (very close to 1), for schistosomiasis transmission during 2006 to 2010, after intensification of control efforts. CONCLUSIONS: Our modified version of the Barbour model to account for seasonal fluctuations in transmission has the potential to provide better estimations of infection risk than previous models. Ignoring seasonality tends to underestimate R0 values albeit only marginally. In the absence of simultaneous R0 estimations for villages not under control interventions (such villages do not currently exist in China), it is difficult to assess whether control strategies have had a substantial impact on levels of transmission, as the parasite population would still be able to maintain itself at an endemic level, highlighting the difficulties faced by elimination efforts. PMID- 23680336 TI - Health care for children and youth in the United States: 13 years of evidence. PMID- 23680337 TI - The challenge of reaching adolescents to promote health care. PMID- 23680338 TI - The little organization that could and the seventh competency: the 2012 APPD presidential address. PMID- 23680339 TI - Annual report on health care for children and youth in the United States: trends in racial/ethnic, income, and insurance disparities over time, 2002-2009. AB - OBJECTIVE: To examine trends in children's health access, utilization, and expenditures over time (2002-2009) by race/ethnicity, income, and insurance status/expected payer. METHODS: Data include a nationally representative random sample of children in the United States in 2002-2009 from the Medical Expenditure Panel Survey (MEPS) and a nationwide sample of pediatric hospitalizations in 2005 and 2009 from the Healthcare Cost and Utilization Project (HCUP). RESULTS: The percentage of children with private insurance coverage declined from 65.3% in 2002 to 60.6% in 2009. At the same time, the percentage of publicly insured children increased from 27.0% in 2002 to 33.1% in 2009. Fewer children reported being uninsured in 2009 (6.3%) compared to 2002 (7.7%). The most significant progress was for Hispanic children, for whom the percentage of uninsured dropped from 15.0% in 2002 to 10.3% in 2009. The uninsured were consistently the least likely to have access to a usual source of care, and this disparity remained unchanged in 2009. Non-Hispanic whites were most likely to report a usual source of care in both 2002 and 2009. The percentage of children with a doctor visit improved for whites and Hispanics (2009 vs 2002). In contrast, black children saw no improvement during this time period. Between 2002 and 2009, children's average total health care expenditures increased from $1294 to $1914. Average total expenditures nearly doubled between 2002 and 2009 for white children with private health insurance. Among infants, hospitalizations for pneumonia decreased in absolute number (41,000 to 34,000) and as a share of discharges (0.8% to 0.7%). Fluid and electrolyte disorders also decreased over time. Influenza appeared only in 2009 in the list of top 15 diagnoses with 11,000 hospitalization cases. For children aged 1 to 17, asthma hospitalization increased in absolute number (from 119,000 to 134,000) and share of discharges (6.6% to 7.6%). Skin infections appeared in the top 15 categories in 2009, with 57,000 cases (3.3% of total). CONCLUSIONS: Despite significant improvement in insurance coverage, disparities by race/ethnicity and income persist in access to and use of care. Hispanic children experienced progress in a number of measures, while black children did not. Because racial/ethnic and socioeconomic disparities are often reported as single cross-sectional studies, our approach is innovative and improves on prior studies by examining population trends during the time period 2002-2009. Our study sheds light on children's disparities during the most recent economic crisis. PMID- 23680340 TI - Associations between frequency of bullying involvement and adjustment in adolescence. AB - OBJECTIVE: To examine whether infrequent bullying perpetration and victimization (once or twice a month) are associated with elevated levels of internalizing and externalizing problems and to assess evidence for a minimum frequency threshold for bullying involvement. METHODS: The analytic sample included 128,681 6th, 9th, and 12th graders who completed the 2010 Minnesota Student Survey. Logistic regression and general linear models examined the association between bullying frequency and adjustment correlates including emotional distress, self-harm, physical fighting, and substance use while controlling for demographic characteristics. Gender and grade were included as moderators. RESULTS: Infrequent bullying perpetration and victimization were associated with increased levels of all adjustment problems relative to those who did not engage in bullying in the past 30 days. Grade moderated many of these findings, with perpetration frequency being more strongly related to substance use, self-harm, and suicidal ideation for 6th graders than 12th graders, whereas victimization frequency was associated with self-harm more strongly for 12th graders than 6th graders. Evidence for minimum thresholds for bullying involvement across all outcomes, grades, and bullying roles was inconsistent. CONCLUSIONS: Infrequent bullying involvement may pose risks to adolescent adjustment; thus, clinicians and school personnel should address even isolated instances of bullying behavior. Researchers should reexamine the use of cut points in bullying research in order to more fully understand the nature of bullying in adolescence. These data indicate the need for prevention and intervention programs that target diverse internalizing and externalizing problems for bullies and victims, regardless of bullying frequency. PMID- 23680342 TI - Health status, emotional/behavioral problems, health care use, and expenditures in overweight/obese US children/adolescents. AB - OBJECTIVE: To examine the association of overweight/obesity with health, health care utilization, and expenditures in a national sample of 10- to 17-year-old children and adolescents. METHODS: Secondary analysis of 2005 to 2009 Medical Expenditure Panel Survey data (n = 17,224). Outcome measures included suboptimal health, emotional/behavioral problems, health care utilization, and expenditures. RESULTS: Overweight and obese children and adolescents had greater risk of suboptimal health (adjusted risk ratio [ARR], 1.4 and 1.7; P < .01), use of prescriptions (ARR, both 1.1; P = .01), and emergency department visits (ARR, 1.2 and 1.1; P = .01); overweight children/adolescents had lower mean out-of-pocket expenditures (~$100, P < .01); and obese children/adolescents had greater risk of emotional/behavioral problems (ARR, 1.2; P < .01) and specialist visits (ARR, 1.1; P = .01). The most common specialty referral among obese children/adolescents was psychiatry. Overweight and obesity were not associated with office visits or total expenditures. A greater proportions of children and adolescents with suboptimal health and emotional/behavioral problems had health care expenditures, and those with suboptimal health were more likely to have out of-pocket expenditures. CONCLUSIONS: Pediatric overweight and obesity affect child and adolescent health status, emotional/behavioral problems, and specific domains of health care utilization, but do not appear to be associated with total health care expenditures. Out-of-pocket expenditures are lower among overweight children and adolescents. These findings highlight the need for early intervention in overweight children/adolescents, when health care expenditures may not be greater, and suggest that it may prove useful to pay special attention to the health status and emotional/behavioral problems of overweight and obese children/adolescents in weight-management interventions. PMID- 23680341 TI - Use of active ingredient information for low socioeconomic status parents' decision-making regarding cough and cold medications: role of health literacy. AB - OBJECTIVE: Parent administration of multiple medications with overlapping active ingredients places children at risk for overdose. We sought to examine how parents use active ingredient information as part of the process of selecting a cough/cold medication for their child and how health literacy plays a role. METHODS: Experimental study of parents of children presenting for care in an urban public hospital pediatric clinic. Parents were asked to determine which of 3 cough/cold medications could be given to relieve a child's cold symptoms, as part of a scenario in which they had already given a dose of acetaminophen; only 1 did not contain acetaminophen. Primary dependent variable: correct selection of cough/cold medication by using active ingredient as the rationale for choice. Primary independent variable: parent health literacy (Newest Vital Sign test). RESULTS: Of 297 parents, 79.2% had low health literacy (Newest Vital Sign score 0 3); 35.4% correctly chose the cough/cold medication that did not contain acetaminophen. The proportion of those who made the correct choice was no different than expected from chance alone (Goodness of fit test; chi(2) = 2.1, P = .3). Only 7.7% chose the correct medication and used active ingredient as the rationale. Those with adequate literacy skills were more likely to have selected the correct medication and rationale (25.8% vs 3.0% (P = .001); adjusted odds ratio 11.1 (95% confidence interval 3.6-33.7), after we adjusted for sociodemographics, including English proficiency and education. CONCLUSIONS: Many parents, especially those with low health literacy, do not use active ingredient information as part of decision-making related to administering multiple medications. PMID- 23680343 TI - Electronic medical record adoption in hospitals that care for children. AB - OBJECTIVE: Hospitals that care for children face unique barriers in electronic medical records (EMR) use that may affect their ability to meaningfully use EMR. The purpose of this study was to investigate hospitals that care for children, both freestanding and adult hospitals with children's services, to determine progress toward advanced stages of EMR use. METHODS: The American Hospital Association survey described hospitals across the United States. Healthcare Information and Management Systems Society 2006 and 2010 databases identified hospitals' EMR use. EMR stage was classified according to previous studies. Multivariable analysis was used to determine independent predictors of EMR use. RESULTS: The analysis included 2794 hospitals. During the study time frame, a significant increase occurred for hospitals moving into any stage of EMR in adult hospitals with children's services (47% to 75%; P < .001), while improvements for freestanding children's hospitals were modest at best (46% to 59%; P = .3). Conversely, freestanding children's hospitals had the largest gain in advance stage 3 adoption (6% to 39%; P < .001) compared to adult hospitals with children's services (6% to 23%; P < .001). Freestanding children's hospitals were less likely to use pharmacy information systems but more likely to use computerized provider order entry. CONCLUSIONS: In 2010, freestanding children's hospitals had the highest percentage use of advanced stage EMR (39%), but the lowest improvements in percentage of hospitals entering into any stage of adoption over the study period. This trend created a digital divide among freestanding children's hospitals that may improve with pediatric-specific electronic medication management products. PMID- 23680344 TI - Correlates of patient portal enrollment and activation in primary care pediatrics. AB - OBJECTIVE: To identify the demographic, practice site, and clinical predictors of patient portal enrollment and activation among a pediatric primary care population. METHODS: We conducted a cross-sectional analysis of the primary care database of an academic children's hospital that introduced a patient portal in December 2007. RESULTS: We analyzed data for 84,015 children. Over a 4-year period, 38% enrolled in the portal; of these, 26% activated the account. The adjusted odds of portal enrollment was lower for adolescents, Medicaid recipients, low-income families, Asian or other race, and Hispanic ethnicity, and higher for patients with more office encounters, and presence of autism on the problem list. Once enrolled, the odds of portal activation [adjusted odds ratio (95% confidence interval)] was decreased for: Medicaid [0.55 (0.50-0.61)] and uninsured [0.79 (0.64-0.97)] (vs private insurance), black [0.53 (0.49-0.57)] and other [0.80 (0.71-0.91)] (vs white race), Hispanic ethnicity [0.77 (0.62-0.97)], and increased for: infant age [1.26 (1.15-1.37)] (vs school age), attendance at a resident continuity practice site [1.91 (1.23-2.97)], living further away from the practice (vs under 2 miles)[4.5-8.8 miles: 1.14 (1.02-1.29); more than 8.8 miles: 1.19 (1.07-1.33)], having more office encounters (vs 1-3) [4-7 encounters: 1.40 (1.24-1.59); 8-12 encounters: 1.58 (1.38-1.81); 13+ encounters: 2.09 (1.72 2.55)], and having 3 or more items on the problem list (vs 0) [1.19 (1.07-1.33)]. CONCLUSIONS: Sociodemographic disparities exist in patient portal enrollment/activation in primary care pediatrics. Attendance at a resident continuity practice site, living farther away from the practice, having more office encounters, and having more problem list items increased the odds of portal activation. PMID- 23680345 TI - Car seat safety for preterm neonates: implementation and testing parameters of the infant car seat challenge. AB - BACKGROUND: The American Academy of Pediatrics (AAP) recommends that all preterm neonates undergo a period of observation in a car safety seat before discharge, known as the Infant Car Seat Challenge (ICSC), to monitor for respiratory immaturity and the risk of adverse cardiopulmonary events in the upright position. However, no universal guidelines exist to define appropriate cutoffs for failure of the ICSC. We sought to evaluate regional neonatal intensive care unit (NICU) implementation of the ICSC and to evaluate variation in failure criteria. METHODS: We contacted level II and III nurseries/NICUs in New York/New England (n = 119) to determine if each performed ICSCs, their inclusion criteria, duration of testing, and failure criteria. RESULTS: We contacted 119 institutions and had an 87% response rate (n = 103). Of the institutions that responded, 89% (n = 89) perform ICSCs. Of these 89 with current protocols, 17% did not follow AAP guidelines to test all neonates born <37 weeks' gestation, and 45% did not follow guidelines for test duration. Despite wide variation, most units use thresholds for bradycardia of <80 bpm and desaturation of <90% to determine failure. CONCLUSIONS: Despite AAP guidelines, implementation of ICSCs for preterm neonates is not universal in the region studied. Variation in definition of ICSC failure means that neonates are receiving differential care, not on the basis of their clinical characteristics, but on which institution performs the test. We propose standardizing the test to all infants born at <37 weeks' gestation to a duration of at least 90 minutes, along with a failure threshold for bradycardia of <80 bpm for >10 seconds, and for saturation <90% for >10 seconds. PMID- 23680346 TI - Primary care spatial density and nonurgent emergency department utilization: a new methodology for evaluating access to care. AB - OBJECTIVE: To determine the spatial and demographic characteristics of pediatric patients who make nonurgent visits (NUVs) to an urban pediatric emergency department (ED). We hypothesized that the rate of NUVs would be inversely associated with the spatial density of primary care providers (PCPs). METHODS: A retrospective, cross-sectional analysis was conducted for all visits to Washington, DC's principal pediatric ED between 2003 and 2006. NUVs were defined by a unique algorithm combining resource allocation, ambulatory-sensitive diagnoses, and billing data. Multivariate linear regression analysis was used to determine the association of PCP density and demographic variables on the spatial rate of NUVs. RESULTS: Over the 4-year period, 35.1% (52,110) of the 148,314 ED visits by Washington, DC, residents were nonurgent. NUVs were most associated with neighborhood median household income <$40,000 and low spatial density of PCPs. For every 1-unit increase in PCP density, the spatial rate of NUVs decreased by 9%. The odds of a visit being nonurgent were significantly higher for African Americans and Hispanics than for whites (odds ratio [OR] 2.4, 95% confidence interval [CI] 2.19-2.64; and OR 2.6, 95% CI 2.36-2.86, respectively), for patients using public insurance versus private (OR 1.46, 95% CI 1.42-1.50), and for patients age <5 years (OR 2.66, 95% CI 2.60-2.72). CONCLUSIONS: Low spatial density of primary care is strongly associated with nonurgent ED utilization. Improving spatial distribution of primary care may decrease ED misuse and improve access to the medical home. PMID- 23680347 TI - Effects of different discount levels on healthy products coupled with a healthy choice label, special offer label or both: results from a web-based supermarket experiment. AB - BACKGROUND: Two strategies commonly recommended to improve population diets include food labels and food taxes/subsidies. The aim of this study was to examine the effects of both strategies separately and in combination. FINDINGS: An experiment with a 3x3 factorial design was conducted, including: three levels of price reduction (10%; 25%; and 50%) x three labels ('special offer', 'healthy choice' and 'special offer & healthy choice') on healthy foods defined following the Choices front-of-pack nutrition label. N=109 participants completed the experiment by conducting a typical weekly shop for their household at a three dimensional web-based supermarket. Data were analysed using analysis of covariance. Participants receiving a 50% price discount purchased significantly more healthy foods for their household in a typical weekly shop than the 10% discount (+8.7 items; 95%CI=3.8-13.6) and the 25% discount group (+7.7 items; 95%CI=2.74 - 12.6). However, the proportion of healthy foods was not significantly higher and the discounts lead to an increased amount of energy purchased. No significant effects of the labels were found. CONCLUSION: This study brings some relevant insights into the effects of price discounts on healthier foods coupled with different labels and shows that price effects over shadowed food labels. However, price discounts seem to have ambiguous effects; they do encourage the purchase of healthy products, but also lead to increased energy purchases. More research is needed to examine how pricing strategies can work in directing consumers towards interchanging unhealthier options for healthier alternatives. PMID- 23680348 TI - Using allometric procedures to substantiate the plastochrone method for eelgrass leaf growth assessments. AB - Estimation of leaf productivity in eelgrass (Zostera marina L.) is crucial for evaluating the ecological role of this important seagrass species. Although leaf marking techniques are widely used to obtain estimates of leaf productivity, the accuracy of these assessments, has been questioned mainly because these fail to account for leaf growth below the reference mark and also because they apparently disregard the contribution of mature leaf tissues to the growth rate of leaves. On the other hand, the plastochrone method is a simpler technique that has been considered to effectively capture growth in a more realistic way, thereby providing more accurate assessments of both above- and below-ground productivities. But since the actual values of eelgrass growth rates are difficult to obtain, the worth of the plastochrone method has been largely vindicated because it produces assessments that overestimate productivity as compared to estimates obtained by leaf marking. Additionally, whenever eelgrass leaf biomass can be allometrically scaled in terms of matching leaf length in a consistent way, the associated leaf growth rates can be also projected allometrically. In this contribution, we used that approach to derive an authentication of the plastochrone method and formally demonstrate that, as has been claimed to occur for leaf marking approaches, the plastochrone method itself underestimates actual values of eelgrass leaf growth rates. We also show that this unavoidable bias is mainly due to the inadequacy of single-leaf biomass assessments in providing a proxy for the growth of all leaf tissue in a shoot over a given interval. Moreover, the derived formulae give conditions under which assessments of leaf growth rates using the plastochrone method would systematically underestimate matching values obtained by leaf marking procedures. And, assessments of leaf growth rates obtained by using the present data show that plastochrone method estimations underestimated corresponding proxies obtained allometrically (27%), or through leaf marking (35%). Allometric projection is recommended as a simpler and more effective procedure to reduce the bias in eelgrass leaf productivity estimations that associates to the use of plastochrone methods. PMID- 23680349 TI - Experimental study on the mechanical strain of corneal collagen. AB - Currently, investigations of biomechanical properties of the fibrous tunic are becoming even more topical, especially for diagnosis of corneal ectatic disease, as well as correct interpretation of intraocular pressure (IOP) parameters, particularly in patients with prior surgery on cornea. The study principle is based on the ability of substances to change optical anisotropy depending on mechanical strain applied to them. An experimental set-up was constructed which allows assessment of polarization degree of light which is emitted during luminescence of strained collagen. The study was performed on 18 corneoscleral discs of chinchilla rabbit eyes at 15 and 50mm Hg pressure, among them in 6 cases before and after making radial incisions, and in 6 cases before and after conducting the mechanical cornea abrasions that were asymmetrical by depth until reaching the local zone of iatrogenic keratectasia. Corneal collagen mechanical strain mappings were formed on 3 experimental models (intact cornea, cornea post radial keratotomy and keratectasia) under intra-chamber pressure of 15 and 50mm Hg. Corneal collagen mechanical strain is evenly allocated in the intact cornea. After radial keratotomy the main mechanical loading was concentrated over the middle part of corneal periphery, particularly in the bottom of keratotomic incisions. The increased intra-chamber pressure made the strain rise in those models. Upon cornea abrasion the main straining is distributed within the thinning zone, and the increase of intra-chamber pressure only increases the load over residual stroma. A new principle of corneal biomechanical properties investigation based on assessment of degree of light polarization emitted during luminescence of strained collagen, has been proposed and experimentally tested. PMID- 23680350 TI - Torsional stiffness and strength of the proximal tibia are better predicted by finite element models than DXA or QCT. AB - Individuals with spinal cord injury experience a rapid loss of bone mineral below the neurological lesion. The clinical consequence of this bone loss is a high rate of fracture around regions of the knee. The ability to predict the mechanical competence of bones at this location may serve as an important clinical tool to assess fracture risk in the spinal cord injury population. The purpose of this study was to develop, and statistically compare, non-invasive methods to predict torsional stiffness (K) and strength (Tult) of the proximal tibia. Twenty-two human tibiae were assigned to either a "training set" or a "test set" (11 specimens each) and mechanically loaded to failure. The training set was used to develop subject-specific finite element (FE) models, and statistical models based on dual energy x-ray absorptiometry (DXA) and quantitative computed tomography (QCT), to predict K and Tult; the test set was used for cross-validation. Mechanical testing produced clinically relevant spiral fractures in all specimens. All methods were accurate and reliable predictors of K (cross-validation r(2)>=0.91; error<=13%), however FE models explained an additional 15% of the variance in measured Tult and illustrated 12-16% less error than DXA and QCT models. Given the strong correlations between measured and FE predicted K (cross-validation r(2)=0.95; error=10%) and Tult (cross-validation r(2)=0.91; error=9%), we believe the FE modeling procedure has reached a level of accuracy necessary to answer clinically relevant questions. PMID- 23680351 TI - Diarrhoea in children: identifying the cause and burden. PMID- 23680352 TI - Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study. AB - BACKGROUND: Diarrhoeal diseases cause illness and death among children younger than 5 years in low-income countries. We designed the Global Enteric Multicenter Study (GEMS) to identify the aetiology and population-based burden of paediatric diarrhoeal disease in sub-Saharan Africa and south Asia. METHODS: The GEMS is a 3 year, prospective, age-stratified, matched case-control study of moderate-to severe diarrhoea in children aged 0-59 months residing in censused populations at four sites in Africa and three in Asia. We recruited children with moderate-to severe diarrhoea seeking care at health centres along with one to three randomly selected matched community control children without diarrhoea. From patients with moderate-to-severe diarrhoea and controls, we obtained clinical and epidemiological data, anthropometric measurements, and a faecal sample to identify enteropathogens at enrolment; one follow-up home visit was made about 60 days later to ascertain vital status, clinical outcome, and interval growth. FINDINGS: We enrolled 9439 children with moderate-to-severe diarrhoea and 13,129 control children without diarrhoea. By analysing adjusted population attributable fractions, most attributable cases of moderate-to-severe diarrhoea were due to four pathogens: rotavirus, Cryptosporidium, enterotoxigenic Escherichia coli producing heat-stable toxin (ST-ETEC; with or without co-expression of heat labile enterotoxin), and Shigella. Other pathogens were important in selected sites (eg, Aeromonas, Vibrio cholerae O1, Campylobacter jejuni). Odds of dying during follow-up were 8.5-fold higher in patients with moderate-to-severe diarrhoea than in controls (odd ratio 8.5, 95% CI 5.8-12.5, p<0.0001); most deaths (167 [87.9%]) occurred during the first 2 years of life. Pathogens associated with increased risk of case death were ST-ETEC (hazard ratio [HR] 1.9; 0.99-3.5) and typical enteropathogenic E coli (HR 2.6; 1.6-4.1) in infants aged 0 11 months, and Cryptosporidium (HR 2.3; 1.3-4.3) in toddlers aged 12-23 months. INTERPRETATION: Interventions targeting five pathogens (rotavirus, Shigella, ST ETEC, Cryptosporidium, typical enteropathogenic E coli) can substantially reduce the burden of moderate-to-severe diarrhoea. New methods and accelerated implementation of existing interventions (rotavirus vaccine and zinc) are needed to prevent disease and improve outcomes. FUNDING: The Bill & Melinda Gates Foundation. PMID- 23680353 TI - Clinical review: Brain-body temperature differences in adults with severe traumatic brain injury. AB - Surrogate or 'proxy' measures of brain temperature are used in the routine management of patients with brain damage. The prevailing view is that the brain is 'hotter' than the body. The polarity and magnitude of temperature differences between brain and body, however, remains unclear after severe traumatic brain injury (TBI). The focus of this systematic review is on the adult patient admitted to intensive/neurocritical care with a diagnosis of severe TBI (Glasgow Coma Scale score of less than 8). The review considered studies that measured brain temperature and core body temperature. Articles published in English from the years 1980 to 2012 were searched in databases, CINAHL, PubMed, Scopus, Web of Science, Science Direct, Ovid SP, Mednar and ProQuest Dissertations & Theses Database. For the review, publications of randomised controlled trials, non randomised controlled trials, before and after studies, cohort studies, case control studies and descriptive studies were considered for inclusion. Of 2,391 records identified via the search strategies, 37 were retrieved for detailed examination (including two via hand searching). Fifteen were reviewed and assessed for methodological quality. Eleven studies were included in the systematic review providing 15 brain-core body temperature comparisons. The direction of mean brain-body temperature differences was positive (brain higher than body temperature) and negative (brain lower than body temperature). Hypothermia is associated with large brain-body temperature differences. Brain temperature cannot be predicted reliably from core body temperature. Concurrent monitoring of brain and body temperature is recommended in patients where risk of temperature-related neuronal damage is a cause for clinical concern and when deliberate induction of below-normal body temperature is instituted. PMID- 23680356 TI - WITHDRAWN: Addition of amifostine to CHOP regimen significantly reduced toxicity in patients with aggressive non-Hodgkin's lymphoma without affecting the long term survival: Results of a phase II trial. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.5144/1658 3876.2012.152. The duplicate article has therefore been withdrawn. PMID- 23680354 TI - ZNF469 frequently mutated in the brittle cornea syndrome (BCS) is a single exon gene possibly regulating the expression of several extracellular matrix components. AB - Brittle cornea syndrome (BCS; MIM 229200) is an autosomal recessive generalized connective tissue disorder caused by mutations in ZNF469 and PRDM5. It is characterized by extreme thinning and fragility of the cornea that may rupture in the absence of significant trauma leading to blindness. Keratoconus or keratoglobus, high myopia, blue sclerae, hyperelasticity of the skin without excessive fragility, and hypermobility of the small joints are additional features of BCS. Transcriptional regulation of extracellular matrix components, particularly of fibrillar collagens, by PRDM5 and ZNF469 suggests that they might be part of the same pathway, the disruption of which is likely to cause the features of BCS. In the present study, we have performed molecular analysis of a cohort of 23 BCS affected patients on both ZNF469 and PRDM5, including those who were clinically reported previously [1]; the clinical description of three additional patients is reported in detail. We identified either homozygous or compound heterozygous mutations in ZNF469 in 18 patients while, 4 were found to be homozygous for PRDM5 mutations. In one single patient a mutation in neither ZNF469 nor PRDM5 was identified. Furthermore, we report the 12 novel ZNF469 variants identified in our patient cohort, and show evidence that ZNF469 is a single exon rather than a two exon gene. PMID- 23680355 TI - Development of a checklist to assess the quality of reporting of knowledge translation interventions using the Workgroup for Intervention Development and Evaluation Research (WIDER) recommendations. AB - BACKGROUND: Influenced by an important paper by Michie et al., outlining the rationale and requirements for detailed reporting of behavior change interventions now required by Implementation Science, we created and refined a checklist to operationalize the Workgroup for Intervention Development and Evaluation Research (WIDER) recommendations in systematic reviews. The WIDER recommendations provide a framework to identify and provide detailed reporting of the essential components of behavior change interventions in order to facilitate replication, further development, and scale-up of the interventions. FINDINGS: The checklist was developed, applied, and improved over the course of four systematic reviews of knowledge translation (KT) strategies in a variety of healthcare settings conducted by Scott and associates. The checklist was created as one method of operationalizing the work of the WIDER in order to facilitate comparison across heterogeneous studies included in these systematic reviews. Numerous challenges were encountered in the process of creating and applying the checklist across four stages of development. The resulting improvements have produced a 'user-friendly' and replicable checklist to assess the quality of reporting of KT interventions in systematic reviews using the WIDER recommendations. CONCLUSIONS: With journals, such as Implementation Science, using the WIDER recommendations as publication requirements for evaluation reports of behavior change intervention studies, it is crucial to find methods of examining, measuring, and reporting the quality of reporting. This checklist is one approach to operationalize the WIDER recommendations in systematic review methodology. PMID- 23680357 TI - CpG island hypermethylation-associated silencing of microRNAs promotes human endometrial cancer. AB - BACKGROUND: Endometrial cancer (EC) is the most common gynecologic malignancy, but the molecular events involved in the development and progression of EC remain unclear. This study aimed to explore epigenetic modification of genes and miRNAs involved in EC development. METHODS: Ishikawa and AN3CA cells were treated with 5'-Aza-2-deoxycytidine or histone deacetylase inhibitor. The expression of miRNAs and related genes were detected by PCR and Western blot. Promoter methylation was detected by bisulfite specific PCR sequencing. The proliferation, colony formation, cell cycle progression, migration and invasion of EC cells were evaluated by MTT, soft agar assay, flow cytometry, wound healing and invasion assay, respectively. RESULTS: Aberrant expression of miRNAs including miR-200b, miR-130a/b, miR-625 and miR-222 was associated with tumorigenesis and metastasis in endometrial cancer. Silencing of miR-130b induced E-cadherin expression, while ectopic expression of miR-130b and knockdown of DICER1 increased the expression of Vimentin, zeb2, N-cadherin, Twist and Snail in EC cells. Furthermore, 5'-Aza-2 deoxycytidine and Histone deacetylase (HDAC) inhibitor inhibited the proliferation, colony formation, migration and invasion of EC cells, accompanied by reduced MMP secretion. CONCLUSIONS: Our study provides the first description of epigenetic modification of epithelial mesenchymal transition associated genes and miRNAs in EC cells, which are extensively involved in the regulation of gene expression and subsequent accumulation of malignant features of EC cells. PMID- 23680358 TI - Mechanisms and effectiveness of prebiotics in modifying the gastrointestinal microbiota for the management of digestive disorders. AB - The gastrointestinal microbiota is a complex ecosystem with each human individual hosting at least 160 different bacterial strains. Our understanding of its role is rapidly expanding as a result of the molecular microbiological techniques that can accurately characterise its composition and 'omics' technologies that measure its metabolic activity. Since 1995, extensive research has investigated the prebiotic concept, which describes how supplementation of some non-digestible oligosaccharides can stimulate the growth and/or activity of specific genera including bifidobacteria. However, the vast majority of studies are in healthy human subjects, with few undertaken in patients with disorders relevant to clinical nutrition. Marked alterations of the luminal microbiota have been demonstrated in patients with digestive disorders, highlighting mechanisms through which they might be involved in their pathogenesis, including higher clostridia in patients who develop diarrhoea during enteral nutrition and the influence of bifidobacteria on intestinal dendritic cell phenotype in Crohn's disease. The impact of prebiotics on the intestinal microbiota of healthy people has not been consistently replicated in patients with digestive disorders. For example, a number of studies show that inulin/oligofructose do not increase bifidobacteria in enteral nutrition and Crohn's disease. Indeed, in Crohn's disease and irritable bowel syndrome there is evidence that some prebiotics in high doses worsen functional symptoms. Unlike healthy human subjects, patients experience a number of issues that may alter their gastrointestinal microbiota (disease, antibiotics and inflammation) and the use of microbiota modifying therapies, such as prebiotics, do not always elicit the same effects in patients as they do in healthy people. PMID- 23680359 TI - Numerical investigation of the effect of cannula placement on thrombosis. AB - Despite the rapid advancement of left ventricular assist devices (LVADs), adverse events leading to deaths have been frequently reported in patients implanted with LVADs, including bleeding, infection, thromboembolism, neurological dysfunction and hemolysis. Cannulation forms an important component with regards to thrombus formation in assisted patients by varying the intraventricular flow distribution in the left ventricle (LV). To investigate the correlation between LVAD cannula placement and potential for thrombus formation, detailed analysis of the intraventricular flow field was carried out in the present study using a two way fluid structure interaction (FSI), axisymmetric model of a passive LV incorporating an inflow cannula. Three different cannula placements were simulated, with device insertion near the LV apex, penetrating one-fourth and mid way into the LV long axis. The risk of thrombus formation is assessed by analyzing the intraventricular vorticity distribution and its associated vortex intensity, amount of stagnation flow in the ventricle as well as the level of wall shear stress. Our results show that the one-fourth placement of the cannula into the LV achieves the best performance in reducing the risk of thrombus formation. Compared to cannula placement near the apex, higher vortex intensity is achieved at the one-fourth placement, thus increasing wash out of platelets at the ventricular wall. One-fourth LV penetration produced negligible stagnation flow region near the apical wall region, helping to reduce platelet deposition on the surface of the cannula and the ventricular wall. PMID- 23680360 TI - Radiation dose in repeated CT guided radiofrequency ablations. AB - OBJECTIVE: To calculate the cumulative effective and skin doses in patients that underwent repeated CT guided radiofrequency ablations (RFA). MATERIALS AND METHODS: From all patients that had undergone RFA during a five years period those which had three or more RFAs were selected. Using the CT images DICOM data, the dose length product (DLP), effective dose (E), skin dose profiles as well as the peak skin dose (PSD) were calculated, using appropriate methods and software developed for this purpose. For each patient, cumulative DLP and E were also calculated from the sum of the respective figures of each individual procedure. To calculate PSD, the skin dose profiles of each procedure were overlaid on the same Z-axis scale using anatomical landmarks for reference and the skin doses to each point were summed up. RESULTS: Five patients were studied; four had undergone 3 RFAs and one 10 RFAs. Cumulative DLP, E and PSD ranges were 5.6-22.3 Gy cm, 0.08-0.36 Sv and 0.8-3.4 Gy, respectively. Median E and PSD values per RFA were 35 mSv and 0.4 Gy, respectively. For comparison purposes it must be noted that in this CT department a routine abdomen-pelvis scan results to an E of about 10 mSv. CONCLUSIONS: Patients that undergo repeated RFAs are exposed to considerably high radiation exposure levels. When these patients are in the final stage of malignant diseases, stochastic effects may not be of major concern. However, optimization of the exposure factors and monitoring of these patients to avoid skin injuries are required. PMID- 23680361 TI - Performance and limitations of positron emission tomography (PET) scanners for imaging very low activity sources. AB - Emerging applications for positron emission tomography (PET) may require the ability to image very low activity source distributions in the body. The performance of clinical PET scanners in the regime where activity in the field of view is <1 MBq has not previously been explored. In this study, we compared the counting rate performance of two clinical PET/CT scanners, the Siemens Biograph Reveal 16 scanner which is based on lutetium oxyorthosilicate (LSO) detectors and the GE Discovery-ST scanner which is based on bismuth germanate (BGO) detectors using a modified National Electrical Manufacturers Association (NEMA) NU 2-2007 protocol. Across the activity range studied (2-100 kBq/mL in a 5.5 mL line source in the NEMA scatter phantom), the BGO-based scanner significantly outperformed the LSO-based scanner. This was largely due to the effect of background counts emanating from naturally occurring but radioactive (176)Lu within the LSO detector material, which dominates the observed counting rate at the lowest activities. Increasing the lower energy threshold from 350 keV to 425 keV in an attempt to reduce this background did not significantly improve the measured NECR performance. The measured singles rate due to (176)Lu emissions within the scanner energy window was also found to be dependent on temperature, and to be affected by the operation of the CT component, making approaches to correct or compensate for the background more challenging. We conclude that for PET studies in a very low activity range, BGO-based scanners are likely to have better performance because of the lack of significant background. PMID- 23680362 TI - Co-stimulatory molecules as targets for treatment of lupus. AB - Co-stimulatory molecules help to regulate interactions between T cells and antigen-presenting cells and may play an important role in the pathogenesis of lupus. Both work in murine models and some early studies in human lupus support further examination of these molecules as therapeutic targets. Complexities of lupus clinical trial variables may have hampered progress in this area but recent developments in the field may make interventional trials more feasible in the near future. To date biologics which provide direct blockade of interactions between CD40 and CD154, B7RP-1 and ICOS, and CD80 or CD86 with CD28 have been assessed in multicenter clinical trials. These data will be reviewed and critiqued. PMID- 23680363 TI - Multilayered coating on titanium for controlled release of antimicrobial peptides for the prevention of implant-associated infections. AB - Prevention of bacterial colonization and formation of a bacterial biofilm on implant surfaces has been a challenge in orthopaedic surgery. The treatment of implant-associated infections with conventional antibiotics has become more complicated by the emergence of multi-drug resistant bacteria. Antimicrobial eluting coatings on implants is one of the most promising strategies that have been attempted. This study reports a controlled release of an antimicrobial peptide (AMP) from titanium surface through a non-cytotoxic multilayered coating. Three layers of vertically oriented TiO2 nanotubes, a thin layer of calcium phosphate coating and a phospholipid (POPC) film were impregnated with a potent broad-spectrum AMP (HHC-36). The coating with controlled and sustained release of AMP was highly effective against both Gram-positive (Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa) bacteria. No cytotoxicity to osteoblast like cells (MG-63) was observed. Moderate platelet activation and adhesion on the implant surface with no observable activation in solution, and very low red blood cell lysis was observed on the implant. This multi-layer assembly can be a potential approach to locally deliver AMPs to prevent peri-implant infection in orthopaedics without being toxic to host cells. PMID- 23680364 TI - Discarded human kidneys as a source of ECM scaffold for kidney regeneration technologies. AB - In the United States, more than 2600 kidneys are discarded annually, from the total number of kidneys procured for transplant. We hypothesized that this organ pool may be used as a platform for renal bioengineering and regeneration research. We previously showed that decellularization of porcine kidneys yields renal extracellular matrix (ECM) scaffolds that maintain their basic components, support cell growth and welfare in vitro and in vivo, and show an intact vasculature that, when such scaffolds are implanted in vivo, is able to sustain physiological blood pressure. The purpose of the current study was to test if the same strategy can be applied to discarded human kidneys in order to obtain human renal ECM scaffolds. The results show that the sodium dodecylsulfate-based decellularization protocol completely cleared the cellular compartment in these kidneys, while the innate ECM framework retained its architecture and biochemical properties. Samples of human renal ECM scaffolds stimulated angiogenesis in a chick chorioallantoic membrane assay. Importantly, the innate vascular network in the human renal ECM scaffolds retained its compliance. Collectively, these results indicate that discarded human kidneys are a suitable source of renal scaffolds and their use for tissue engineering applications may be more clinically applicable than kidneys derived from animals. PMID- 23680365 TI - Direct conversion of fibroblasts into neural progenitor-like cells by forced growth into 3D spheres on low attachment surfaces. AB - Many stem cells grow into three-dimensional (3D) spheres or colonies, such as neural progenitor cells (NPCs) and embryonic stem cells (ESCs). Sphere morphology helps maintaining the stemness of stem cells. Our previous study demonstrated that forced growth of RT4 and HEK293 cells into 3D sphere on low attachment surface could induce stem cell properties. The close relationship between 3D sphere morphology and stem cell stemness drives us to hypothesize that 3D sphere formation induces fibroblasts reprogramming. The key gene Sox2 for reprogramming fibroblasts into NPCs was found to be overexpressed in 3D sphere cultured mouse fibroblasts. These cells exhibited similar morphological and molecular features to NPCs in vitro, were capable of differentiating into neurons, astrocytes and oligodendrocytes, and could generate long-term expandable neurospheres while maintaining differentiation capability. When engrafted into hippocampus of adult rat brain, the 3D sphere cells differentiated into neural cells. Thus, NPCs can be generated from fibroblasts directly through a physical approach without introducing exogenous reprogramming factors. PMID- 23680366 TI - Variation of the effect of calcium phosphate enhancement of implanted silk fibroin ligament bone integration. AB - In this article, low crystallinity hydroxyapatite (LHA) is developed and utilized to modify silk fibroin scaffolds which are applied to repair bone/ligament defects successfully. It can promote osteogenesis which is authenticated through in vitro and in vivo tests. The scaffold is an efficient carrier, supporting cell proliferation and differentiation. Meanwhile, cytocompatibility and osteoblastic gene expressions (RUNX2 and osteocalcin, for example) of rabbit's bone marrow derived mesenchymal stem cells (MSCs) are significantly boosted on LHA/silk scaffold. Further, for animal trial, almost 60% of bone volume and 80% of original mechanical strength are recovered after 4 months' bone/ligament regeneration in bone tunnel of rabbit model, where significant amount of bone tissue regeneration is also confirmed by data of histological evaluation and micro computed tomography (MU-CT). Hence, the invented scaffold is applicable for ligament/bone regeneration in future lager animal and clinical trials. PMID- 23680367 TI - Hyaluronan-modified core-shell liponanoparticles targeting CD44-positive retinal pigment epithelium cells via intravitreal injection. AB - Retinal inflammation, a common process of posterior ocular diseases, may lead to severe vision loss or even blindness. Retinal pigment epithelium (RPE) cells are generally considered as the therapeutic target of inflammation pathogenesis. However, the lack of retina-specific distribution for general intravitreous drug delivery systems makes the anti-inflammation treatment inefficient. In the present study, a hyaluronan (HA)-modified core-shell liponanoparticles (HA-LCS NPs) was designed to improve the treatment efficiency by increasing RPE-targeted distribution. Our in vitro RPE cell uptake study showed that a higher HA grafting density (5.8%) and a higher molecular weight (200-400 kDa) modification of HA improved the intracellular uptake of HA-LCS-NPs. In addition, in vivo distribution evaluation in experimental autoimmune uveitis (EAU) rats revealed that HA-LCS-NPs could specifically target RPE cells through the interaction between the CD44 receptor and the HA ligand, while chitosan nanoparticles (CS NPs) were limited to the vitreous cavity and the core-shell liponanoparticles (LCS-NPs) only reached the inner layers of the retina. At 7 d post-injection, approximately 75% of the fluorescence of HA-LCS-NPs still remained in the RPE/choroid. In conclusion, HA-LCS-NPs might present a promising intraocular drug delivery system to achieve RPE-targeted distribution and prolonged intraocular residence. PMID- 23680368 TI - Enhanced reconstruction of long bone architecture by a growth factor mutant combining positive features of GDF-5 and BMP-2. AB - Non healing bone defects remain a worldwide health problem and still only few osteoinductive growth factors are available for clinical use in bone regeneration. By introducing BMP-2 residues into growth and differentiation factor (GDF)-5 we recently produced a mutant GDF-5 protein BB-1 which enhanced heterotopic bone formation in mice. Designed to combine positive features of GDF 5 and BMP-2, we suspected that this new growth factor variant may improve long bone healing compared to the parent molecules and intended to unravel functional mechanisms behind its action. BB-1 acquired an increased binding affinity to the BMP-IA receptor, mediated enhanced osteogenic induction of human mesenchymal stem cells versus GDF-5 and higher VEGF secretion than BMP-2 in vitro. Rabbit radius defects treated with a BB-1-coated collagen carrier healed earlier and with increased bone volume compared to BMP-2 and GDF-5 according to in vivo micro-CT follow-up. While BMP-2 callus often remained spongy, BB-1 supported earlier corticalis and marrow cavity formation, showing no pseudojoint persistence like with GDF-5. Thus, by combining positive angiogenic and osteogenic features of GDF 5 and BMP-2, only BB-1 restored a natural bone architecture within 12 weeks, rendering this promising growth factor variant especially promising for long bone regeneration. PMID- 23680369 TI - The effect of human hair keratin hydrogel on early cellular response to sciatic nerve injury in a rat model. AB - Peripheral nerve injuries requiring surgery can be repaired by autograft, the clinical "gold standard", allograft, or nerve conduits. Most published clinical studies show the effectiveness of nerve conduits in small size defects in sensory nerves. Many preclinical studies suggest that peripheral nerve regeneration through conduits can be enhanced and repair lengths increased with the use of a biomaterial filler in the conduit lumen. We have previously shown that a luminal hydrogel filler derived from human hair keratin (HHK) can improve electrophysiological and histological outcomes in mouse, rabbit, and non-human primate nerve injury models, but insight into potential mechanisms has been lacking. Based on the premise that a keratin biomaterial (KOS) hydrogel provides an instantaneous structural matrix within the lumen, the current study compares the cellular behavior elicited by KOS hydrogel to Matrigel (MAT) and saline (SAL) conduit fillers in a 1 cm rat sciatic nerve injury model at early stages of regeneration. While there was little difference in initial cellular influx, the KOS group showed earlier migration of dedifferentiated Schwann cells (SC) from the proximal nerve end compared to the other groups. The KOS group also showed faster SC dedifferentiation and myelin debris clearance, and decreased macrophage infiltration during Wallerian degeneration of the distal nerve tissue. PMID- 23680370 TI - Quality improvement using the AUC: is it this easy? PMID- 23680371 TI - In hot blood: quantifying the arterial input function. PMID- 23680372 TI - Imaging for improving therapy: a stop on the way to improve outcomes? PMID- 23680373 TI - Detection and imaging of cardiac allograft vasculopathy. AB - Cardiac allograft vasculopathy (CAV) is an important cause of morbidity and mortality among cardiac transplant recipients. CAV occurs in approximately 30% of patients by 5 years and 50% by 10 years, and is a major cause of graft loss and death. Early detection of CAV is important because it may allow alterations in medical therapy before progression to the stage that revascularization is required. This has led to routine screening for CAV in transplant recipients, traditionally by invasive coronary angiography (ICA). Recent advances in imaging technology, specifically intravascular ultrasound, now also permit detection of subangiographic CAV. Noninvasive stress testing and multislice coronary computed tomography angiography have been investigated as noninvasive alternatives to routine ICA. However, currently available noninvasive tests remain limited with respect to their sensitivity and specificity for CAV. Given the multiple available diagnostic modalities, no consensus definition for the classification of CAV has been widely accepted, although new guidelines that rely heavily on ICA have recently been published by the International Society of Heart and Lung Transplantation. This review summarizes imaging modalities that are utilized in the diagnosis and surveillance of CAV and explores newer imaging techniques that may play a future role. PMID- 23680374 TI - Great vessel and coronary artery anatomy in transposition and other coronary anomalies: a universal descriptive and alphanumerical sequential classification. AB - In patients with transposition of the great arteries, the identification of coronary anatomy is fundamental to optimal surgical outcome. A number of classifications describing the coronary vessels' origin and course in transposition of the great arteries have been published. However, all are limited to operative or pathological case series. They are often alphanumeric classifications that do not lend themselves to clinical practice; they do not consider certain important anatomical variations that may increase surgical morbidity and mortality, nor do they fully delineate coronary anatomy or define the relationship to adjacent structures seen with cardiovascular computed tomography. Using cardiovascular computed tomography for illustrative purposes, we propose and validate a universal sequential descriptive classification and an associated alphanumeric classification that may be used for all coronary anomalies with or without associated congenital heart disease. PMID- 23680375 TI - Morphological assessment of RVOT: CT and CMR imaging. PMID- 23680376 TI - RV form and function: a piston pump, vortex impeller, or hydraulic ram? PMID- 23680377 TI - Renal GLUT1 reduction depends on angiotensin-converting enzyme inhibition in diabetic hypertensive rats. AB - AIMS: Angiotensin-converting enzyme (ACE) inhibitors are used in diabetic kidney disease to reduce systemic/intra-glomerular pressure. The objective of this study was to investigate whether reducing blood pressure (BP) could modulate renal glucose transporter expression, and urinary markers of diabetic nephropathy in diabetic hypertensive rats treated with ramipril or amlodipine. MAIN METHODS: Diabetes was induced in spontaneously-hypertensive rats (~210 g) by streptozotocin (50mg/kg). Thirty days later, animals received ramipril 15 MUg/kg/day (R, n=10), or amlodipine 10mg/kg/day (A, n=8,) or water (C, n=10) by gavage. After 30-day treatment, body weight, glycaemia, urinary albumin and TGF beta1 (enzyme-linked immunosorbent assay) and BP (tail-cuff pressure method) were evaluated. Kidneys were removed for evaluation of renal cortex glucose transporters (Western blotting) and renal tissue ACE activity (fluorometric assay). KEY FINDINGS: After treatments, body weight (p=0.77) and glycaemia (p=0.22) were similar among the groups. Systolic BP was similarly reduced (p<0.001) in A and R vs. C (172.4 +/- 3.2; 1867 +/- 3.7 and 202.2 +/- 4.3 mmHg; respectively). ACE activity (C: 0.903 +/- 0.086; A: 0.654 +/- 0.025, and R: 0.389 +/- 0.057 mU/mg), albuminuria (C: 264.8 +/- 15.4; A: 140.8 +/- 13.5 and R: 102.8 +/- 6.7 mg/24h), and renal cortex GLUT1 content (C: 46.81 +/- 4.54; A: 40.30 +/- 5.39 and R: 26.89 +/- 0.79 AU) decreased only in R (p<0.001, p<0.05 and p<0.001; respectively). SIGNIFICANCE: We concluded that the blockade of the renin angiotensin system with ramipril reduced early markers of diabetic nephropathy, a phenomenon that cannot be specifically related to decreased BP levels. PMID- 23680378 TI - Acute effects of cocaine, morphine and their combination on bioenergetic function and susceptibility to oxidative stress of rat liver mitochondria. AB - AIMS: Cocaine and heroin are frequently co-abused in a combination known as speedball. Despite the relevance of the liver in the metabolism and detoxification of these drugs, little is known about the impact of speedball on liver function. MAIN METHODS: In this work, we evaluated the effects of cocaine, morphine and morphine+cocaine (Mor+Coc) combination (1:1) in isolated rat liver mitochondria, upon glutamate/malate or succinate energization, on bioenergetics and oxidative stress-related parameters by using Clark O2, Ca(2+), TPP(+) and pH electrodes and by measuring thiobarbituric acid reactive substances (TBARS) and H2O2 production. KEY FINDINGS: Cocaine and Mor+Coc at the higher concentrations (1mM) similarly increased O2 consumption at state 2, state 4 and state oligomycin. In these conditions, maximum respiration was decreased only upon glutamate/malate energization, suggesting an involvement of complex I. Morphine (1mM) only increased state 2 respiration. Cocaine and Mor+Coc induced a similar decrease in maximum mitochondrial membrane potential and in ADP-induced depolarization, whereas morphine had no effect. The drugs and their combination similarly decreased mitochondrial ATPase activity and had no effect on Ca(2+) induced permeability transition. Morphine and Mor+Coc prevented lipid peroxidation, since in these conditions there was a decrease in O2 consumption and in TBARS upon ADP/Fe(2+) stimulus, and a decrease in H2O2 formation, suggesting an antioxidant effect. Interestingly, heroin did not share morphine antioxidant properties. SIGNIFICANCE: Our results show that the sequential direct exposure of liver mitochondria to morphine and cocaine does not alter the effects observed in the presence of each drug alone. PMID- 23680379 TI - Palmitate induces apoptosis in mouse aortic endothelial cells and endothelial dysfunction in mice fed high-calorie and high-cholesterol diets. AB - AIMS: Obesity is associated with hypertriglyceridemia and elevated circulating free fatty acids (FFA), resulting in endothelial dysfunction. Endoplasmic reticulum (ER) stress has been implicated in many of these processes. To determine if ER stress participates in palmitate-induced apoptosis, we investigated the effects of diet-induced obesity and palmitate on mouse aortic endothelial cells (MAEC) in vivo and in vitro. MAIN METHODS: Male C57BL/6 mice were fed standard chow diets (SCD) or high-calorie and high-cholesterol diets (HCD) for 3 months. Insulin resistance was detected, and the serum, including proinflammatory indices and markers of endothelial function, was also analyzed. The ultrastructure and apoptosis of the endothelial cells in the thoracic aorta were observed. The primary MAEC were separated and treated with palmitate at different concentrations or different times respectively to observe any changes in cellular proliferation, intracellular reactive oxygen species (ROS) levels and apoptosis. Finally, the ER stress markers C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78) were analyzed. KEY FINDINGS: HCD-fed obese mice became inflammation-activated and insulin-resistant. Swollen mitochondria, expanded ER and apoptosis in the endothelial cells of the thoracic aorta were observed in HCD-fed mice. Palmitate inhibited cell proliferation, increased production of ROS and induced apoptosis in MAEC. CHOP was overexpressed and shifted into the nucleus (mainly), while the expression of GRP78 was upregulated in the palmitate-treated MAEC. SIGNIFICANCE: Our results indicate that diet induced obesity results in endothelial dysfunction in vivo, and that oxidative and ER stress may be involved in apoptosis induced by the palmitate in vitro. PMID- 23680380 TI - Altered oxytocinergic hypothalamus systems in sepsis. AB - Sepsis is known to affect neuroendocrine circuits: injections of lipopolysaccaride are potent stimulators of oxytocin secretion from the posterior lobe, acute sepsis leads to uterus contractions and spontaneous abort. Here, we report changes in expression and distribution of hypothalamic oxytocin in rats that had been subjected to caecal ligation and puncture which led to acute sepsis. Septic animals showed loss of oxytocin immunostaining in perikarya of the supraoptic and paraventricular nuclei and an increase of oxytocin positive fibres, suggesting a shift of oxytocin pools into the axonal compartment. Immunostaining of the posterior lobe revealed reduction of oxytocin in septic rats. Magnocellular neurons in supraoptic- and to a lesser extent in paraventricular nuclei showed nuclear immunoreactivity for the protooncogene c Fos, indicating stimulation of transcriptional activity upon sepsis. Contrary to magnocellular oxytocin immunoreactivity, we observed increased oxytocin immunoreactivity in cell bodies and processes of periventricular nucleus and in perivascular neurons. Oxytocin neurons in other regions of the hypothalamus and the preoptic region did not appear to be affected by acute sepsis. Our findings suggest a differential activation of neurohypophyseal and cerebrospinal fluid contacting oxytocin systems while centrally projecting oxytocin neurons may not be affected. Systemic oxytocin levels may serve as additional diagnostic marker for sepsis. PMID- 23680381 TI - Polysaccharide-based nucleic acid nanoformulations. AB - Therapeutic application of nucleic acids requires their encapsulation in nanosized carriers that enable safe and efficient intracellular delivery. Before the desired site of action is reached, drug-loaded nanoparticles (nanomedicines) encounter numerous extra- and intracellular barriers. Judicious nanocarrier design is highly needed to stimulate nucleic acid delivery across these barriers and maximize the therapeutic benefit. Natural polysaccharides are widely used for biomedical and pharmaceutical applications due to their inherent biocompatibility. At present, there is a growing interest in applying these biopolymers for the development of nanomedicines. This review highlights various polysaccharides and their derivatives, currently employed in the design of nucleic acid nanocarriers. In particular, recent progress made in polysaccharide assisted nucleic acid delivery is summarized and the specific benefits that polysaccharides might offer to improve the delivery process are critically discussed. PMID- 23680382 TI - Use of black carp (Mylopharyngodon piceus) in biological control of intermediate host snails of fish-borne zoonotic trematodes in nursery ponds in the Red River Delta, Vietnam. AB - BACKGROUND: The risks of fish-borne zoonotic trematodes (FZT) to human health constitute an important problem in Vietnam. The infection of humans with these trematodes, such as small liver trematodes (Clonorchis sinensis and Opisthorchis viverrini), intestinal trematodes (Heterophyidae) and others is often thought to be linked to fish culture in areas where the habit of eating raw fish is common. Juvenile fish produced in nurseries are often heavily infected with FZT and since fishes are sold to aquaculture facilities for growth, control of FZT in these fishes should be given priority. Controlling the first intermediate host (i.e., freshwater gastropods), would be an attractive approach, if feasible. The black carp, Mylopharyngodon piceus, is a well-known predator of freshwater snails and is already used successfully for biological control of snails in various parts of the world including Vietnam. Here we report the first trials using it for biological control of intermediate host snails in nursery ponds stocked with 1 week old fry (10-12 mm in length) of Indian carp, Labeo rohita. METHODS: Semi field and field experiments were set up to test the effect of black carp on snail populations. In the semi-field experiment a known quantity of snails was initially introduced into a pond which was subsequently stocked with black carp. In the field trial in nursery ponds, density of snails was estimated prior to a nursing cycle and at the end of the cycle (after 9 weeks). RESULTS: The results showed that black carp affect the density of snail populations in both semi-field and field conditions. The standing crop of snails in nursery ponds, however, was too high for 2 specimens to greatly reduce snail density within the relatively short nursing cycle. CONCLUSIONS: We conclude that the black carp can be used in nursery ponds in Northern Vietnam for snail control. Juvenile black carp weighing 100 - 200 g should be used because this size primarily prey on intermediate hosts of FZT and other studies have shown that it does not prey on fish fry of other species. It may be necessary to use a high stocking density of black carp or to reduce snail density in the nursery ponds using other measures (e.g. mud removal) prior to stocking fry in order for the black carp to keep the density of intermediate host snails at a very low level. PMID- 23680383 TI - [A fatal mixing household cleaners]. PMID- 23680384 TI - ["The only thing worse than being talked about is not being talked about" (Oscar Wilde): reply]. PMID- 23680386 TI - Quantification of selected synthetic cannabinoids and Delta9-tetrahydrocannabinol in oral fluid by liquid chromatography-tandem mass spectrometry. AB - An LC-MS/MS method for the quantification of the synthetic cannabinoids JWH-200, JWH-250, JWH-073, JWH-018, HU-211, CP 47,497 and CP 47,497-C8, and THC in oral fluid was developed and validated. Samples (0.5 mL) were extracted using Strata X cartridges (Phenomenex). Chromatographic separation was achieved with a SunfireTM IS column (20*2.1 mm, 3.5 MUm) (Waters Corp.), with formic acid 0.1% and acetonitrile as mobile phase. A different chromatographic gradient was applied for the separation of the analytes depending on the ionization mode employed, with a total chromatographic run of 14 min. Detection was performed in a Quattro MicroTM API ESCI (Waters Corp.), using electrospray in the positive mode (ESI+) for JWH-200, JWH-250, JWH-073, JWH-018 and THC, and ESI- for HU-211, CP 47,497, and CP 47,497-C8. Validation of the method included the assessment of selectivity, linearity (0.1-2.5 to 200 ng/mL), limits of detection (0.025-1 ng/mL) and quantification (0.1-2.5 ng/mL), imprecision (%CV<=14.4%), accuracy (91.8-109.7% of target concentration), extraction recovery (65.4-105.6%) and Quantisal recovery (56.1-66.7%), and matrix effect (neat oral fluid: -56.0% to 38.5%; oral fluid in Quantisal buffer: -15.1% to -71.7%). The application of this method to oral fluid samples from roadside testing will provide unique information on the use of these new synthetic drugs by Spanish drivers. PMID- 23680387 TI - In situ derivatization of metals and organometallics using borate reagents in gas chromatographic speciation studies. AB - Development of sensitive and selective analytical methods is required for trace metal and metalloids speciation analysis, including their alkyl-, phenyl- or other organometallic species. Gas chromatography is one of the most suitable techniques for effective separation of the above compounds however it requires that the analytes are volatile or semi-volatile. Today very popular derivatization methods make use of borate reagents for in situ derivatization of elements like Hg, Pb, Sn, Se, As, etc. Tetrahydroborates are suitable for hydride generation and alkylborates for alkylation of the inorganic ions of the above elements, as well as of several partially alkylated ones. This almost immediate reaction can be done in aqueous solutions and produces fully alkylated products of higher volatility suitable for separation by gas chromatography and measured by various detectors. The number of papers published in this field is constantly high, including many applications to various types of matrices, like biological, environmental, industrial, food, polymers, etc. For this reason, many articles of the last two decades are reviewed in this paper and emphasis is given to the use of borate reagents and the relative microreactions for selected elements. PMID- 23680385 TI - Neural control of sexually dimorphic behaviors. AB - All sexually reproducing animals exhibit gender differences in behavior. Such sexual dimorphisms in behavior are most obvious in stereotyped displays that enhance reproductive success such as mating, aggression, and parental care. Sexually dimorphic behaviors are a consequence of a sexually differentiated nervous system, and recent studies in fruit flies and mice reveal novel insights into the neural mechanisms that control these behaviors. In the main, these include a diverse array of novel sex differences in the nervous system, surprisingly modular control of various stereotyped dimorphic behavioral routines, and unanticipated sensory and central modulation of mating. We start with a brief overview to provide the appropriate conceptual framework so that the advances made by the newer studies discussed subsequently can be fully appreciated. We restrict our review to reporting progress in understanding the basis of mating and aggression in fruit flies and mice. PMID- 23680388 TI - Recent development and applications of dispersive liquid-liquid microextraction. AB - Dispersive liquid-liquid microextraction (DLLME) is a modern sample pretreatment technique that is regarded as consilient with the current trends of modern analytical chemistry. DLLME is simple, inexpensive, environmentally friendly, and could offer high enrichment factors from a wide gap between acceptor and donor phases. As a consequence, DLLME has attracted considerable attention from researchers and, based on the numerous publications concerning DLLME, has been generally accepted in separation science since the technique's invention in 2006. However, several innate weaknesses of DLLME, which restrict the technique's use in certain fields, have led to various attempts or suggestions to improve this technique. The present review focuses on the recent advances made in DLLME; the selected papers that are discussed in this work represent modifications that fall into three main categories (exploration of new extraction solvents, disperser solvents and combination with other techniques). The recent applications of DLLME in environmental, food and biological samples are also summarised, covering almost all of the publications related to the technology from the beginning. In addition, the feasibility of future trends of DLLME is discussed. PMID- 23680389 TI - The better the story, the bigger the serving: narrative transportation increases snacking during screen time in a randomized trial. AB - BACKGROUND: Watching television and playing video games increase energy intake, likely due to distraction from satiety cues. A study comparing one hour of watching TV, playing typical video games, or playing motion-controlled video games found a difference across groups in energy intake, but the reasons for this difference are not clear. As a secondary analysis, we investigated several types of distraction to determine potential psychosocial mechanisms which may account for greater energy intake observed during sedentary screen time as compared to motion-controlled video gaming. METHODS: Feelings of enjoyment, engagement (mental immersion), spatial presence (the feeling of being in the game), and transportation (immersion in a narrative) were investigated in 120 young adults aged 18 - 35 (60 female). RESULTS: Only narrative transportation was associated with total caloric intake (rho = .205, P = .025). Transportation was also higher in the TV group than in the gaming groups (P = .002) and higher in males than in females (P = .003). Transportation mediated the relationship between motion controlled gaming (as compared to TV watching) and square root transformed energy intake (indirect effect = -1.34, 95% confidence interval -3.57, -0.13). No other distraction-related variables were associated with intake. CONCLUSIONS: These results suggest that different forms of distraction may differentially affect eating behavior during screen time, and that narrative appears to be a particularly strong distractor. Future studies should further investigate the effects of narrative on eating behavior. PMID- 23680390 TI - Kallistatin - the score beats the marker. PMID- 23680392 TI - Dietary lipid modification for mild and severe dyslipidaemias. AB - The aim of this review is to place a historical perspective on linking dyslipidaemia with atherosclerosis and emphasises previous knowledge about the impact on the lipoprotein profile and health in persons with mild dyslipidaemia and in those with defined genetic disorders. CVD is becoming the leading cause of death and disability in developed and developing countries and is strongly related to lifestyle factors that influence plasma lipoprotein concentrations. It is established that risk of complications from atherosclerosis increases with increasing LDL and decreasing HDL and that there is potentiation of risk when these and other risk factors co-exist. High-fat diets used for losing body mass may increase risk through dyslipidaemia. Pharmaceutical modulation of the lipoproteins has lowered risk powerfully but residual risk persists, possibly relating to existing disease as well as progression relating in many instances to dietary lipids. The impact of various dietary lipids is reviewed as they relate to the conventional lipoprotein profile in persons who do not have significant metabolic defects, as well as the impact on inherited metabolic disease such as familial hypercholesterolaemia, hypertriglyceridaemia and phytosterolaemia. For most persons with dyslipidaemias a significant benefit will be seen on the lipid profile by adopting a low saturated fat diet with less cholesterol intake. PMID- 23680391 TI - An FE investigation simulating intra-operative corrective forces applied to correct scoliosis deformity. AB - BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a deformity of the spine, which may require surgical correction by attaching a rod to the patient's spine using screws implanted in the vertebral bodies. Surgeons achieve an intra operative reduction in the deformity by applying compressive forces across the intervertebral disc spaces while they secure the rod to the vertebra. We were interested to understand how the deformity correction is influenced by increasing magnitudes of surgical corrective forces and what tissue level stresses are predicted at the vertebral endplates due to the surgical correction. METHODS: Patient-specific finite element models of the osseoligamentous spine and ribcage of eight AIS patients who underwent single rod anterior scoliosis surgery were created using pre-operative computed tomography (CT) scans. The surgically altered spine, including titanium rod and vertebral screws, was simulated. The models were analysed using data for intra-operatively measured compressive forces - three load profiles representing the mean and upper and lower standard deviation of this data were analysed. Data for the clinically observed deformity correction (Cobb angle) were compared with the model-predicted correction and the model results investigated to better understand the influence of increased compressive forces on the biomechanics of the instrumented joints. RESULTS: The predicted corrected Cobb angle for seven of the eight FE models were within the 5 degrees clinical Cobb measurement variability for at least one of the force profiles. The largest portion of overall correction was predicted at or near the apical intervertebral disc for all load profiles. Model predictions for four of the eight patients showed endplate-to-endplate contact was occurring on adjacent endplates of one or more intervertebral disc spaces in the instrumented curve following the surgical loading steps. CONCLUSION: This study demonstrated there is a direct relationship between intra-operative joint compressive forces and the degree of deformity correction achieved. The majority of the deformity correction will occur at or in adjacent spinal levels to the apex of the deformity. This study highlighted the importance of the intervertebral disc space anatomy in governing the coronal plane deformity correction and the limit of this correction will be when bone-to-bone contact of the opposing vertebral endplates occurs. PMID- 23680393 TI - Validation of suitable endogenous control genes for quantitative PCR analysis of microRNA gene expression in a rat model of endometrial cancer. AB - BACKGROUND: MicroRNAs are small RNA molecules that negatively regulate gene expression by translational inhibition or mRNA cleavage. The discovery that abnormal expression of particular miRNAs contributes to human disease, including cancer, has spurred growing interest in analysing expression profiles of these molecules. Quantitative polymerase chain reaction is frequently used for quantification of miRNA expression due to its sensitivity and specificity. To minimize experimental error in this system an appropriate endogenous control gene must be chosen. An ideal endogenous control gene should be expressed at a constant level across all samples and its expression stability should be unaffected by the experimental procedure. RESULTS: The expression and validation of candidate control genes (4.5S RNA(H) A, Y1, 4.5S RNA(H) B, snoRNA, U87 and U6) was examined in 21 rat cell lines to establish the most suitable endogenous control for miRNA analysis in a rat model of cancer. The stability of these genes was analysed using geNorm and NormFinder algorithms. U87 and snoRNA were identified as the most stable control genes, while Y1 was least stable. CONCLUSION: This study identified the control gene that is most suitable for normalizing the miRNA expression data in rat. That reference gene will be useful when miRNAs expression are analyzed in order to find new miRNA markers for endometrial cancer in rat. PMID- 23680394 TI - Distribution and sources of organochlorine pesticides in agricultural soils from central China. AB - There is little information on the organochlorine pesticides (OCPs) residues in agricultural soils of Wuhan, the largest city in central China. Surface soil samples were collected from agricultural soils in Wuhan and analyzed to determine twenty-one OCPs. According to the measured concentrations and detection frequencies, dichlorodiphenyltrichloroethanes (DDTs), hexachlorocyclohexanes (HCHs), heptachlor (HEPT), hexachlorobenzene (HCB) and aldrin were the predominant compounds in soil. DDTs accounted for 77.10% of total OCPs, followed by HCHs (7.83%), aldrin (4.21%), HEPTs (2.82%) and HCB (1.53%). The total DDT concentrations ranged from nd to 1198.0ngg(-1) and the main contaminated areas were distributed in Hannan and Xinzhou districts of Wuhan. The total HCH concentrations ranged from nd to 100.58ngg(-1) in soil and relatively higher levels were observed in soil samples from Huangpi and Hannan districts. Source analysis showed that OCPs residues except heptachlor originated mainly from historical application, besides slight recent introduction at some sites. Based on the China National Soil Quality Standard, DDT pollution in most samples of Wuhan agricultural soils could be considered as no and low contamination, while the level of HCHs was classified as no pollution. Our study indicated that there existed potential exposure risk of OCPs in Wuhan agricultural soils although the use of OCPs has been banned. PMID- 23680395 TI - Prediction of contacts from correlated sequence substitutions. AB - Recent work has led to a substantial improvement in the accuracy of predictions of contacts between amino acids using evolutionary information derived from multiple sequence alignments. Where large numbers of diverse sequence relatives are available and can be aligned to the sequence of a protein of unknown structure it is now possible to generate high-resolution models without recourse to the structure of a template. In this review we describe these exciting new techniques and critically assess the state-of-the-art in contact prediction in the light of these. While concentrating on methods, we also discuss applications to protein and RNA structure prediction as well as potential future developments. PMID- 23680396 TI - Dose-volumetric parameters and prediction of severe acute esophagitis in patients with locally-advanced non small-cell lung cancer treated with neoadjuvant concurrent hyperfractionated-accelerated chemoradiotherapy. AB - BACKGROUND: To identify dose-volume parameters predictive for severity of acute esophagitis (CTC > grade 2) in locally-advanced non small-cell lung cancer (LA NSCLC) patients treated with neoadjuvant concurrent hyperfractionated-accelerated chemoradiotherapy (HA-CRT) a retrospective analysis was performed. 88 patients were treated with HA-CRT followed by radical surgery. Predictive power of absolute oesophageal length, absolute and relative oesophageal volume included in the 95%-isodose, patient- and tumor-related factors for severity of acute esophagitis was assessed. FINDINGS: A total of 82 patients (93%) developed radiation-induced acute esophagitis. Grade 1 was documented in 1 (1%), grade 2 in 55 (67%), grade 3 in 23 (28%) and grade 4 in 3 (4%) patients, respectively. Absolute oesophageal volume included in the 95%-isodose (42.8 Gy) achieved 13.5 cm3 (range: 3 - 29 cm3). Of the tested variables in univariate analysis, absolute oesophageal volume included in the 95%-Isodose was found to be the only significant variable (p = 0.03) predicting severe acute esophagitis (CTC > grade 2). For this volume a gradation scale of the likelihood of severity was built. CONCLUSION: Increase of absolute oesophageal volume included in the 95%-isodose correlates with severity of acute esophagitis in LA-NSCLC patients treated with neo-adjuvant concurrent HA-CRT. PMID- 23680397 TI - [Comment on the study "Intracranial dural arteriovenous fistulae. Experience after 81 cases and literature review", by Paredes et al]. PMID- 23680398 TI - The role of prestimulus activity in visual extinction. AB - Patients with visual extinction following right-hemisphere damage sometimes see and sometimes miss stimuli in the left visual field, particularly when stimuli are presented simultaneously to both visual fields. Awareness of left visual field stimuli is associated with increased activity in bilateral parietal and frontal cortex. However, it is unknown why patients see or miss these stimuli. Previous neuroimaging studies in healthy adults show that prestimulus activity biases perceptual decisions, and biases in visual perception can be attributed to fluctuations in prestimulus activity in task relevant brain regions. Here, we used functional MRI to investigate whether prestimulus activity affected perception in the context of visual extinction following stroke. We measured prestimulus activity in stimulus-responsive cortical areas during an extinction paradigm in a patient with unilateral right parietal damage and visual extinction. This allowed us to compare prestimulus activity on physically identical bilateral trials that either did or did not lead to visual extinction. We found significantly increased activity prior to stimulus presentation in two areas that were also activated by visual stimulation: the left calcarine sulcus and right occipital inferior cortex. Using dynamic causal modelling (DCM) we found that both these differences in prestimulus activity and stimulus evoked responses could be explained by enhanced effective connectivity within and between visual areas, prior to stimulus presentation. Thus, we provide evidence for the idea that differences in ongoing neural activity in visually responsive areas prior to stimulus onset affect awareness in visual extinction, and that these differences are mediated by fluctuations in extrinsic and intrinsic connectivity. PMID- 23680399 TI - Prefrontal vulnerabilities and whole brain connectivity in aging and depression. AB - Studies exploring the underpinnings of age-related neurodegeneration suggest fronto-limbic alterations that are increasingly vulnerable in the presence of disease including late life depression. Less work has assessed the impact of this specific vulnerability on widespread brain circuitry. Seventy-nine older adults (healthy controls=45; late life depression=34) completed translational tasks shown in non-human primates to rely on fronto-limbic networks involving dorsolateral (Self-Ordered Pointing Task) or orbitofrontal (Object Alternation Task) cortices. A sub-sample of participants also completed diffusion tensor imaging for white matter tract quantification (uncinate and cingulum bundle; n=58) and whole brain tract-based spatial statistics (n=62). Despite task associations to specific white matter tracts across both groups, only healthy controls demonstrated significant correlations between widespread tract integrity and cognition. Thus, increasing Object Alternation Task errors were associated with decreasing fractional anisotropy in the uncinate in late life depression; however, only in healthy controls was the uncinate incorporated into a larger network of white matter vulnerability associating fractional anisotropy with Object Alternation Task errors using whole brain tract-based spatial statistics. It appears that the whole brain impact of specific fronto-limbic vulnerabilities in aging may be eclipsed in the presence of disease-specific neuropathology like that seen in late life depression. PMID- 23680400 TI - Low expression of LOC285194 is associated with poor prognosis in colorectal cancer. AB - BACKGROUND: The long non-coding RNAs (lncRNAs) study has gradually become one of the hot topics in the field of RNA biology. One lncRNA which has attracted attention is LOC285194, a lncRNA demonstrated the potential tumor-suppressor role in osteosarcoma. The aim of this study was to examine the expression of LOC285194 in colorectal cancer (CRC) patients and to investigate the relationship between this lncRNA levels and existing clinicopathologic parameters and patient survival. METHODS: The expression of LOC285194 was detected by quantitative real time polymerase chain reaction in pairs of tumorous and adjacent normal tissues of 81 colorectal cancer patients with a follow-up of 5 years, as well as in three colorectal cancer cell lines and normal intestinal mucous cell line. Then, we analyzed the potential relationship between this lncRNA levels in tumor tissues and existing clinicopathological features of CRC, and clinical outcome. RESULTS: The relative expression levels of LOC285194 was significantly lower in tumor tissues (p<0.001) and colorectal cancer cell lines compared with adjacent normal tissues and normal intestinal mucous cell line. In addition, low expression of LOC285194 was correlated with larger tumor size (p=0.015), higher tumor stage (p=0.034), and more distant metastasis (p=0.046). Kaplan-Meier analysis indicated that patients with low LOC285194 expression had a poor disease free survival (p=0.010). Moreover, multivariate analysis showed that decreased expression of LOC285194 was an independent predictor of disease-specific survival. CONCLUSION: Our data indicate that LOC285194 might be a novel prognostic indicator in colorectal cancer and may be a potential target for diagnosis and gene therapy. PMID- 23680401 TI - Providing open access data online to advance malaria research and control. AB - BACKGROUND: To advance research on malaria, the outputs from existing studies and the data that fed into them need to be made freely available. This will ensure new studies can build on the work that has gone before. These data and results also need to be made available to groups who are developing public health policies based on up-to-date evidence. The Malaria Atlas Project (MAP) has collated and geopositioned over 50,000 parasite prevalence and vector occurrence survey records contributed by over 3,000 sources including research groups, government agencies and non-governmental organizations worldwide. This paper describes the results of a project set up to release data gathered, used and generated by MAP. METHODS: Requests for permission to release data online were sent to 236 groups who had contributed unpublished prevalence (parasite rate) surveys. An online explorer tool was developed so that users can visualize the spatial distribution of the vector and parasite survey data before downloading it. In addition, a consultation group was convened to provide advice on the mode and format of release for data generated by MAP's modelling work. New software was developed to produce a suite of publication-quality map images for download from the internet for use in external publications. CONCLUSION: More than 40,000 survey records can now be visualized on a set of dynamic maps and downloaded from the MAP website on a free and unrestricted basis. As new data are added and new permissions to release existing data come in, the volume of data available for download will increase. The modelled data output from MAP's own analyses are also available online in a range of formats, including image files and GIS surface data, for use in advocacy, education, further research and to help parameterize or validate other mathematical models. PMID- 23680402 TI - Pelvic fracture rates in community-living people with and without disability and in residents of nursing homes. AB - OBJECTIVES: There are limited data on the epidemiology of pelvic fractures. The purpose of this study was to calculate incidence rates of pelvic fractures leading to hospital admission and to compare incidence rates between residents of nursing homes and community-dwelling persons with and without care need. METHODS: Data were retrieved from a database of the largest health insurance company in Bavaria, Germany. Between 2004 and 2009, 10,170 pelvic fractures were observed in 751,101 women and 491,098 men. Age- and gender-specific incidence rates were calculated. Incidence rates were further stratified by setting (nursing home versus community) and functional status (no care need versus care need for those in the community). In addition, the average cumulative risk for a pelvic fracture at different ages was calculated. RESULTS: The incidence rate increased from 0.54 and 0.38 per 1000 person-years in women and men aged 65 to 69 years to 9.35 and 4.45 per 1000 person-years in women and men aged 90 years and older, respectively. Persons living in a nursing home or living at home with care need had considerably higher incidence rates than community-dwelling older persons without care need. The average cumulative risk at the age of 65 years for an incident pelvic fracture until the age of 90 years was 6.9% in women and 2.8% in men. CONCLUSION: The incidence of pelvic fractures leading to hospital admission is higher in women than in men and rises dramatically with increasing age. Persons with care need have a particularly high risk for pelvic fracture. PMID- 23680404 TI - Assessment of menstrual cycle length in cynomolgus monkeys as a female fertility endpoint of a biopharmaceutical in a 6 month toxicity study. AB - According to ICH S6(R1), mating studies are not practical for assessing effects on female fertility of biopharmaceuticals that are pharmacologically active only in non-human primates (NHPs). Instead, fertility should be assessed by evaluating histopathology and organ weights of the reproductive tract in studies of at least 3 months dosing duration using sexually mature NHPs. An assessment of the menstrual cycle in females can be included if there is cause for concern based on pharmacological mode of action or relevant findings in previous studies. However, many factors unrelated to the molecule under evaluation can impact cycle length and thus affect data interpretation. Assessment of a monoclonal antibody in a 6 month repeat dose toxicity study is used as an example in this manuscript to review potential sources of background variability, identify strategies to minimize its impact and recommend optimal ways to collect, present and analyze menstrual cycle data. Experimental variables include the amount of time required for menses to normalize following the transport of animals to the testing facility, stress-related effects on the cycle length due to socialization issues with new cagemates, and the normal background irregularity of cycle length in NHPs. Study related procedures (i.e., animal handling for dosing, blood draws, body weights, ECGs, etc.) did not affect cycle lengths in this study. We show that introducing a number of key experimental control procedures to minimize cycle variability can enable a robust assessment of the effects of a biotherapeutic on menstrual cycling within a chronic toxicity study in NHPs. PMID- 23680403 TI - Molecular mechanism of metal-independent decomposition of lipid hydroperoxide 13 HPODE by halogenated quinoid carcinogens. AB - Halogenated quinones are a class of carcinogenic intermediates and newly identified chlorination disinfection by-products in drinking water. 13 Hydroperoxy-9,11-octadecadienoic acid (13-HPODE) is the most extensively studied endogenous lipid hydroperoxide. Although it is well known that the decomposition of 13-HPODE can be catalyzed by transition metal ions, it is not clear whether halogenated quinones could enhance its decomposition independent of metal ions and, if so, what the unique characteristics and similarities are. Here we show that 2,5-dichloro-1,4-benzoquinone (DCBQ) could markedly enhance the decomposition of 13-HPODE and formation of reactive lipid alkyl radicals such as pentyl and 7-carboxyheptyl radicals, and the genotoxic 4-hydroxy-2-nonenal (HNE), through the complementary application of ESR spin trapping, HPLC-MS, and GC-MS methods. Interestingly, two chloroquinone-lipid alkoxyl conjugates were also detected and identified from the reaction between DCBQ and 13-HPODE. Analogous results were observed with other halogenated quinones. This represents the first report that halogenated quinoid carcinogens can enhance the decomposition of the endogenous lipid hydroperoxide 13-HPODE and formation of reactive lipid alkyl radicals and genotoxic HNE via a novel metal-independent nucleophilic substitution coupled with homolytic decomposition mechanism, which may partly explain their potential genotoxicity and carcinogenicity. PMID- 23680405 TI - The relationship between developmental toxicity and aromatic-ring class profile of high-boiling petroleum substances. AB - In response to the US EPA HPV Challenge Program, this study was conducted to: (1) evaluate the relationship between PAC content and the developmental toxicity of high-boiling petroleum substances (HBPS) and (2) develop mathematical models to predict the developmental toxicity of similar untested substances based on their aromatic ring class (ARC) profiles. For this investigation, 68 developmental toxicity studies were reviewed. The ARC models relied on data from 21 rat dermal developmental toxicity studies conducted with similar experimental designs to ensure a consistent data set for comparison. The most sensitive general endpoints of developmental toxicity (i.e., decreased fetal survival and growth) were chosen for modeling. The ARC models demonstrated a strong correlation between the predicted vs. observed values for specific sensitive endpoints of these developmental toxicities (percent resorptions, r=0.99; live fetuses per litter, r=0.98; fetal body weight, r=0.94). Such associations provide a promising approach for predicting the developmental toxicity of untested HBPS. Efforts to corroborate the ARC models using test substances that were not used to build the ARC models produced mixed results, and further development and refinement of the ARC models is recommended before they can be reliably applied to all HBPS. PMID- 23680406 TI - Sociodemographic characteristics of mother's population and risk of preterm birth in Chile. AB - BACKGROUND: Preterm birth is a global problem in Perinatal and infant Health. Currently is gaining a growing attention. Rates of preterm birth have increased in most countries, producing a dramatic impact on public health. Factors of diverse nature have been associated to these trends. In Chile, preterm birth has increased since 90. Simultaneously, the advanced demographic transition has modified the characteristics of woman population related to maternity. The principal objective of this study is to analyze some sociodemographic characteristics of the maternal population over time, and their possible association to rates of preterm birth. The second aim is to identify groups of mothers at high risk of having a preterm child. METHODS: This population-based study examined all liveborn singletons in Chile from 1991 to 2008; divided in three periods. Preterm birth rates were measured as % births <37 weeks of gestation. Logistic regression assessed the risk of preterm birth associated with mother's age, parity, and marital status, expressed as crude and adjusted odds ratios. RESULTS: Over time, rates of preterm birth increased in overall population, especially during the third period (2001-2008). In the same time, characteristics of maternal population changed: significant increase of extreme reproductive ages, significant decrease in parity and increase in mothers living without a partner. Risk of preterm birth remained higher in groups of mothers: <18 and >38 years of age; without a partner; primiparas and grandmultiparas. However, global increase in preterm birth was not explained by the modification of socio demographics characteristics of maternal population. CONCLUSIONS: Some socio demographic characteristics remained associated with preterm birth over time. These associations allowed identifying five groups of mothers at higher risk to have a preterm child in the population. Increase in overall preterm birth affected all women, even those considered at "low sociodemographic risk" and the contribution of more recent period (2001-2008) to this increase is greater. Then, studied factors couldn't explain the increase in preterm birth. Further research will have to consider other factors affecting maternal population that could explain the observed trend of preterm birth. PMID- 23680407 TI - Do positive or negative stressful events predict the development of new brain lesions in people with multiple sclerosis? AB - BACKGROUND: Stressful life events have long been suspected to contribute to multiple sclerosis (MS) disease activity. The few studies examining the relationship between stressful events and neuroimaging markers have been small and inconsistent. This study examined whether different types of stressful events and perceived stress could predict the development of brain lesions. METHOD: This was a secondary analysis of 121 patients with MS followed for 48 weeks during a randomized controlled trial comparing stress management therapy for MS (SMT-MS) to a waitlist control (WLC). Patients underwent magnetic resonance imaging (MRI) scans every 8 weeks. Every month, patients completed an interview measure assessing stressful life events and self-report measures of perceived stress, anxiety and depressive symptoms, which were used to predict the presence of gadolinium-enhancing (Gd+) and T2 lesions on MRI scans 29-62 days later. Participants classified stressful events as positive or negative. Negative events were considered 'major' if they involved physical threat or threat to the patient's family structure, and 'moderate' otherwise. RESULTS: Positive stressful events predicted decreased risk for subsequent Gd+ lesions in the control group [odds ratio (OR) 0.53 for each additional positive stressful event, 95% confidence interval (CI) 0.30-0.91] and less risk for new or enlarging T2 lesions regardless of group assignment (OR 0.74, 95% CI 0.55-0.99). Across groups, major negative stressful events predicted Gd+ lesions (OR 1.77, 95% CI 1.18-2.64) and new or enlarging T2 lesions (OR 1.57, 95% CI 1.11-2.23) whereas moderate negative stressful events, perceived stress, anxiety and depressive symptoms did not. CONCLUSIONS: Major negative stressful events predict increased risk for Gd+ and T2 lesions whereas positive stressful events predict decreased risk. PMID- 23680408 TI - Wnt/beta-catenin signaling may be involved with the maturation, but not the differentiation, of insulin-producing cells. AB - Wnt/beta-catenin signaling (WNT) has widespread roles during stem cell differentiation. Whether WNT suppresses or promotes insulin-producing cell (IPC) differentiation and function is still not known. In this study, we investigated the role of WNT signaling during human adipose-derived stem cell (hADSC) differentiation into IPCs. Western blot analysis revealed that several key components of WNT were dynamically regulated in a 12-day IPC differentiation assay. Specifically, protein levels of Wnt1, beta-catenin, and GSK3beta steadily increased from day 0 to day 9 and rapidly decreased by day 12 of differentiation. Similarly, endonuclear beta-catenin levels peaked at day 9 and then, fell to pre differentiation levels. The expression of two WNT pathway targets, TCF-1 and cyclin D1, closely followed the same pattern of regulation, confirming that WNT signaling was transiently activated during IPC differentiation. Interestingly, the inhibition of WNT signaling did not block IPC differentiation; instead, it resulted in the upregulation of IPC-specific markers, including PDX-1, insulin, IRS-1, and IRS-2. Notably, another IPC marker, glucokinase, remained downregulated since it is a direct target of WNT signaling. Next, we examined the effect of maintaining active WNT signaling from day 9 to day 12 of IPC differentiation. Differentiating cells were treated with Wnt1 on day 9, when WNT signaling is typically turned off, and subjected to gene expression analysis on day 12. Remarkably, Wnt1 treatment resulted in reduced expression of IPC-specific markers. Taken together, these data indicate that WNT may not be necessary for IPC differentiation but may be involved in IPC maturation. PMID- 23680409 TI - Sex and severe sepsis. AB - Epidemiological studies document that males are more prone than females to develop severe sepsis and this is confirmed by Sakr and colleagues in the previous issue of Critical Care. However, the impact of gender on prognosis of severe sepsis is a matter of debate. Sakr and colleagues report a higher mortality in septic females than in males. This puzzling result might be explained by confounding factors such as age, nosocomial infections, follow-up period, and case mix. The impact of sexual hormones in older females is less relevant. Treatments aimed at modifying sexual hormone profile are promising but need to be tested in future trials. PMID- 23680410 TI - Detection of the FCGR3a polymorphism using a real-time polymerase chain reaction assay. AB - The fragment crystallizable (Fc) region of the immunoglobulin G, low affinity III A receptor (FCGR3a, also known as CD16) belongs to the Fc gamma receptor family (FCGR), which plays an important role in immunoinflammatory processes. It is a low affinity, transmembrane receptor that is mainly expressed in monocytes, natural killer cells, and macrophages. It has been implicated in various inflammatory conditions, and recently a polymorphism (rs396991) in this gene has been shown to influence response to rituximab (anti-CD20) therapy in various disorders. We evaluated two molecular methods to genotype this polymorphism. Archived, formalin-fixed, paraffin-embedded samples from 26 biopsies of diffuse large B-cell lymphoma were retrieved and DNA was extracted. The samples were tested for the FCGR3a polymorphism using real-time polymerase chain reaction (PCR) followed by melt curve analysis or by a standard TaqMan allelic discrimination assay using the ABI 7500 FAST real-time PCR instrument. With the TaqMan allelic discrimination assay, we found that 16 cases were the wild type genotype, homozygous phenylalanine (F/F), for the FCGR3a receptor, whereas two cases had the homozygous valine (V/V) polymorphism and eight cases were heterozygous with a V/F genotype. Results with the real-time PCR followed by melt curve analysis were similar for 25 cases; however, four samples did not have sufficient DNA for the melt curve analysis method, and the result from one sample was discordant. The new TaqMan assay offers several advantages over previously published assays, such as faster turnaround time and ease of interpretation. These performance characteristics make it highly suitable for use in a clinical laboratory. PMID- 23680411 TI - Endemic characteristics of infantile visceral leishmaniasis in the People's Republic of China. AB - BACKGROUND: Visceral leishmaniasis (VL) was once a severe parasitic disease in China. Thanks to the great efforts of integrated control, VL was eliminated in most epidemic areas, except for certain western provinces (autonomous region) at the end of 1950s. From then on, VL gained less attention and has seemed to spread, especially in the last 15 years. Infants are the most important population threatened by VL. However, there have been few studies on the endemic characteristics of infantile VL in China. METHODS: Infantile VL cases were collected from the online National Infectious Diseases Reporting System (NIDRS). Statistical description and inference was used to reveal the endemic characteristics in gender, age group, time and regionalism. Spatial analysis was carried out to explore the high risk area for infantile VL in China. RESULTS: A total of 1093 infantile VL cases were reported from 2006 to 2012. There was no statistically significant difference in gender over time. The minimum, maximum and mean age of these cases was 1.1, 35.9 and 13.8 months, respectively. Among them 86.92% were under 2 years of age, and there was a statistically significant difference among age groups over time. An incidence peak appeared in 2008-2009, most cases were distributed in the months September to December, and there was a tail-raising effect in the coming two months of the next year. More than 98% of cases were reported in Xinjiang Uygur Autonomous Region, Gansu Province and Sichuan Province, accounting for 61.02%, 32.75% and 4.57%, respectively. A total of 56 counties reported infantile VL cases, with the cumulative incidence ranging from 0.02 to 24.57%. There were two main zones of high endemicity for infantile VL in China. The monthly incidence clearly coincides with the number of towns where infantile VL cases were reported. Three fatalities were reported during the study period, the case fatality rate was 2.750/00. CONCLUSIONS: The endemic situation of infantile VL is serious, and there are several active foci of infantile VL prevalence in China. VL has emerged as a severe threat to infants of endemic regions in China. PMID- 23680412 TI - Involvement of shared resources in time judgment and sequence reasoning tasks. AB - Previous research suggests that time perception is supported by the same attentional resources involved in sequence processing. The present experiment was designed to clarify this connection by examining the relation between timing and reasoning tasks that involved either sequencing or non-sequencing judgments. For the timing task, subjects produced a series of 5-s intervals. For the reasoning tasks, subjects judged whether pairs of statements describing common actions either (a) were presented in the correct temporal order (sequencing), or (b) described similar actions or objects (similarity). Subjects performed the timing and reasoning tasks both separately and concurrently in a series of 3-minute trials. Comparisons of single-task and dual-task performance assessed interference patterns between concurrent tasks. Both reasoning tasks interfered with timing by making temporal productions longer and more variable. Timing had differential effects on the two reasoning tasks. Concurrent timing caused sequencing judgments to become slower, less accurate, and less sensitive relative to sequencing-only conditions. In contrast, similarity judgments were either unaffected or affected to a lesser degree by the concurrent timing task. These results support the notion that timing and sequencing are closely related processes that rely on the same set of cognitive resources or mechanisms. PMID- 23680413 TI - Pulmonary nocardiosis in an immunocompetent patient with COPD: the role of defective innate response. AB - OBJECTIVES: Pulmonary nocardiosis is an uncommon opportunistic infection affecting mainly immunocompromised patients. We herein present a case of nocardiosis without profound underlying immunodeficiency. BACKGROUND: A female, 84-years' old patient with stage IV chronic obstructive pulmonary disease (COPD) is presented. No profound causes of immunodeficiency existed, such as HIV infection, diabetes mellitus, malignancy, alcoholism, chemotherapy or previous corticosteroid intake. The patient recovered after treatment with trimethoprim/sulfamethoxazole for 6 months. RESULTS: One year after infection resolution, stimulation of the patient's blood monocytes with Nocardia antigens revealed defective production of tumor necrosis factor-alpha, interleukin (IL)-6 and IL-17. CONCLUSION: We provide preliminary evidence for a link between defective innate immune responses and predisposition for Nocardia infections. Further studies must be conducted in order to fully investigate this mechanism of infection acquisition. PMID- 23680414 TI - Surgical treatment of recurrent stress urinary incontinence in women: a systematic review and meta-analysis of randomised controlled trials. AB - CONTEXT: Recurrent stress urinary incontinence (R-SUI) represents a management dilemma; however, only a limited number of randomised controlled trials (RCTs) have assessed the various surgical procedures used for its treatment. OBJECTIVE: To assess the effectiveness and complications of various surgical procedures for the treatment of female R-SUI. EVIDENCE ACQUISITION: A prospective peer-reviewed protocol was prepared a priori. A systematic literature review of all published RCTs comparing surgical procedures for treatment of R-SUI was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta analysis statement. Data were analysed using RevMan 5. EVIDENCE SYNTHESIS: We conducted a literature search from 1945 to February 2013. Data were available for a total of 350 women in 10 RCTs with a mean follow-up of 18.1 mo. Meta-analysis was possible for the comparison of retropubic tension-free vaginal tape (RP-TVT) versus transobturator tension-free vaginal tape (TO-TVT) in five RCTs (n = 135). There was no statistically significant difference between RP-TVT and TO-TVT in the patient-reported improvement (odds ratio [OR]: 0.84, 95% confidence interval [CI], 0.41-1.69) or objective cure/improvement (OR: 1.75; 95% CI, 0.86-3.54). One RCT showed a trend towards a higher rate of patient-reported and objective cure/improvement with the inside-out TO-TVT compared with the outside-in; however, it was not statistically significant (OR: 3.00; 95% CI, 0.85-10.57, and OR: 3.32; 95% CI, 0.96-11.41, respectively). There was no significant difference between Burch colposuspension and RP-TVT (one RCT) in patient-reported improvement (OR: 0.33; 95% CI, 0.01-8.57) or objective cure/improvement (OR: 0.52; 95% CI, 0.13-2.05). CONCLUSIONS: This meta-analysis shows no evidence of a significant difference in patient-reported and objective cure/improvement rates between RP-TVT and TO-TVT in the surgical treatment of women with R-SUI. However, due to the relatively low number of patients, the analysis might be underpowered. This review highlights the poor level of evidence in this field and the need for well-designed clinical trials to address this important clinical dilemma. PMID- 23680415 TI - Prospective analysis of human leukocyte functional tests reveals metal sensitivity in patients with hip implant. AB - BACKGROUND: The aim of the study was to examine the reactivity of peripheral human leukocytes to various metal ions prior and following hip replacement in order to investigate implant-induced metal sensitivity. METHODS: Three patient groups were set up: (1) individuals without implants and no history of metal allergy (7 cases), (2) individuals without implants and known history of metal allergy (7 cases), and (3) patients undergoing cementless hip replacement (40 cases). Blood samples were taken in groups 1 and 2 at three different occasions; in group 3, prior and 3, 6, 12, 24, and 36 months after surgery. Peripheral leukocytes were separated and left either untreated or challenged with Ti, NiCl2, CoCl2, CrCl3, and phytohemagglutinin. Cell proliferation, cytokine release, and leukocyte migration inhibition assays were performed. Metal-induced reactivity was considered when all three assays showed significant change. Skin patch tests were also carried out. RESULTS: Both skin patch tests and leukocyte functional tests were negative in group 1, and both were positive in group 2. In group 3, after 6 months, 12% of the patients showed reactivity to the tested metals except for NiCl2. Following the 36-month period, 18% of group three became sensitive to metals (including all the earlier 12%). In contrast, patch tests were negative at each time point in group 3. CONCLUSIONS: Orthopedic implant material may induce metal reactivity after implantation in a manner where susceptibility is yet to be elucidated. Leukocyte triple assay technique might be a useful tool to test implant material-related sensitivity. PMID- 23680416 TI - Substantia nigra echogenicity is correlated with nigrostriatal impairment in Machado-Joseph disease. AB - BACKGROUND: Several studies have demonstrated increased substantia nigra (SN) echogenicity in Parkinson's disease (PD) and Machado-Joseph disease (MJD). Pathological substrate of PD is characterized by dopaminergic nigrostriatal cell loss, also found in MJD. Also, SN hyperechogenicity might be associated with nigrostriatal dysfunction in PD, when comparing dopamine transporter binding with SN echogenicity. The present study aimed to correlate the SN echogenic size and striatal dopamine transporter density in MJD patients. METHODS: We performed TCS in 30 subjects and SPECT with [(99m)Tc]-TRODAT-1 in 18 subjects with MJD. Fifteen healthy subjects matched for age and gender formed a control group. TCS and [(99m)Tc]-TRODAT-1 SPECT findings from both MJD patients and control subjects were compared. RESULTS: There were no differences regarding age (p = 0.358) or gender (p = 0.566) between groups (MJD versus control group). Mean DAT binding potentials and SN echogenicity were significantly different between groups. There was a significant negative correlation with regard to the SN echogenic size and the ipsilateral striatal TRODAT-1 uptake: the higher the SN echogenicity, the lower the DAT uptake in the ipsilateral cerebral hemisphere. CONCLUSION: Increase in SN echogenic size likely correlates with presynaptic dopaminergic nigrostriatal dysfunction in MJD, suggesting a concurrent in vivo pathophysiological mechanism. PMID- 23680417 TI - Delusional misidentification syndrome and other unusual delusions in advanced Parkinson's disease. AB - BACKGROUND: Unusual delusional syndromes are rare protean diseases with speculative etiopathogenic mechanisms. METHODS: Seven consecutive patients with advanced PD were evaluated over a 15-year period at the Movement Disorders Unit in the Neurology Service, Hospital de Clinicas, Federal University of Parana, and the Parana State Parkinson's Patients Association. RESULTS: We describe advanced Parkinson's disease patients presenting with unusual delusional syndromes, including cases of Ekbom, Othello, Capgras' and Diogenes syndromes, reduplicative paramnesia and mirrored-self misidentification. CONCLUSION: There are a few isolated reports of unusual neuropsychiatric disorders in patients with PD. We believe that these syndromes associated with advanced PD in elderly patients presenting with cognitive impairment and polypharmacy are probably often underestimated. Neurologists should be aware for these rare and treatable conditions. PMID- 23680418 TI - Co-occurring chronic conditions and healthcare expenditures associated with Parkinson's disease: a propensity score matched analysis. AB - BACKGROUND: The objective of this study was to ascertain co-occurring chronic conditions and expenditures associated with Parkinson's disease among elderly individuals (age >= 65 years). METHODS: A retrospective, cross-sectional matched case-control design with data from Medical Expenditure Panel Survey (MEPS), a nationally representative survey of households in the United States was used. Elderly with Parkinson's disease (N = 350) were compared to a matched control group (N = 1050) based on propensity scores. Ordinary Least Squares regressions on logged dollars were performed to understand the association between Parkinson's disease and expenditures. All analyses accounted for the complex survey design of the MEPS and were conducted in SAS 9.3. RESULTS: Among elderly, the average total expenditures were $15,404 for those with Parkinson's disease and $13,333 for those without Parkinson's disease. Results from regressions revealed that elderly with Parkinson's disease had 109% greater total expenditure compared to those without Parkinson's disease, when only demographic and socioeconomic variables were entered in the model. When co-occurring chronic conditions were additionally included in the model, those with Parkinson's disease had 84% greater expenditures compared to those without Parkinson's disease. CONCLUSIONS: Excess expenditures associated with Parkinson's disease are partially driven by co-occurring conditions among individuals with Parkinson's disease. PMID- 23680419 TI - Motor outcomes during hospitalization in Parkinson's disease patients: a prospective study. AB - BACKGROUND: Retrospective studies suggest that many Parkinson's disease patients have a worsening of their motor status during hospitalization. We aimed to quantify this prospectively, and study possible contributing factors. METHODS: Over one year we included all consecutive Parkinson's disease patients, newly admitted to a Dutch teaching hospital. We analyzed complications, interventions, and medication distribution. At inclusion and at discharge we assessed the motor status with the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III). RESULTS: 48% of 46 admitted patients had complications, mainly confusion/delirium (24%) and infections (15%). At discharge 28% of the patients had a worse motor function with a mean increase of more than 5 points on the UPDRS-III. Medication errors occurred in 39%. This is the most important risk factor (p < 0.000) for motor function deterioration, followed by infections during hospitalization, and not being in control of own Parkinson's disease medication. 24% of patients were allowed to take control of their own Parkinson's disease medication, none of these patients did deteriorate. CONCLUSIONS: This prospective study shows that a substantial part of hospitalized PD patients has a significant worse motor function at discharge mainly due to medication errors and infections. Quality of care could be improved by addressing preventable errors and allow patients to take control of their own Parkinson's disease medication. PMID- 23680420 TI - A novel bedside task to tap inhibitory dysfunction and fronto-striatal atrophy in Parkinson's disease. AB - BACKGROUND: Given the heterogeneity of mild cognitive deficits in non-demented Parkinson's disease (PD), sensitive and anatomically specific behavioural measures are crucial when evaluating cognition in this patient group. Inhibitory dysfunction is one such deficit increasingly being recognised in non-demented PD; however, few clinical measures exist to detect it and its associated fronto striatal pathology. METHODS: In 50 non-demented PD patients and 27 controls we employ a novel measure, the Excluded Letter Fluency (ELF) test, to objectively assess inhibitory dysfunction. ELF results were also contrasted with an established inhibitory measure (Hayling Test) and covaried against grey matter atrophy via voxel-based morphometry analysis in a subset of patients. RESULTS: The findings show that patients made significantly more rule-break errors than controls on the ELF and this measure was more sensitive than the Hayling in detecting inhibitory dysfunction, classifying over 76% of patients in logistic regression analysis. Importantly, ELF rule-break errors correlated with grey matter atrophy in known inhibitory-control regions (orbitofrontal cortex, inferior frontal gyrus and ventral striatum). CONCLUSIONS: The ELF is a brief bedside task that efficiently detects inhibitory dysfunction in non-demented PD. The utility of this novel behavioural measure is further substantiated by its anatomical specificity for fronto-striatal inhibitory control regions. PMID- 23680421 TI - Applause sign in clinically overlapping diseases: a case of TDP-43 proteinopathy. PMID- 23680422 TI - Sternutatory reflex induced by periocular needle insertion in patients receiving chronic botulinum toxin injections. PMID- 23680424 TI - Effects of walking speed on asymmetry and bilateral coordination of gait. AB - The mechanisms regulating the bilateral coordination of gait in humans are largely unknown. Our objective was to study how bilateral coordination changes as a result of gait speed modifications during over ground walking. 15 young adults wore force sensitive insoles that measured vertical forces used to determine the timing of the gait cycle events under three walking conditions (i.e., usual walking, fast and slow). Ground reaction force impact (GRFI) associated with heel strikes was also quantified, representing the potential contribution of sensory feedback to the regulation of gait. Gait asymmetry (GA) was quantified based on the differences between right and left swing times and the bilateral coordination of gait was assessed using the phase coordination index (PCI), a metric that quantifies the consistency and accuracy of the anti-phase stepping pattern. GA was preserved in the three different gait speeds. PCI was higher (reduced coordination) in the slow gait condition, compared to usual-walking (3.51% vs. 2.47%, respectively, p=0.002), but was not significantly affected in the fast condition. GRFI values were lower in the slow walking as compared to usual walking and higher in the fast walking condition (p<0.001). Stepwise regression revealed that slow gait related changes in PCI were not associated with the slow gait related changes in GRFI. The present findings suggest that left-right anti phase stepping is similar in normal and fast walking, but altered during slow walking. This behavior might reflect a relative increase in attention resources required to regulate a slow gait speed, consistent with the possibility that cortical function and supraspinal input influences the bilateral coordination of gait. PMID- 23680426 TI - Cognitive and postural precursors of motion sickness in adolescent boxers. AB - Athletic head trauma (both concussive and sub-concussive) is common among adolescents. Concussion typically is followed by motion sickness-like symptoms, by changes in cognitive performance, and by changes in standing body sway. We asked whether pre-bout body sway would differ between adolescent boxers who experienced post-bout motion sickness and those who did not. In addition, we asked whether pre-bout cognitive performance would differ as a function of adolescent boxers' post-bout motion sickness. Nine of nineteen adolescent boxers reported motion sickness after a bout. Pre-bout measures of cognitive performance and body sway differed between boxers who reported post-bout motion sickness and those who did not. The results suggest that susceptibility to motion sickness like symptoms in adolescent boxers may be manifested in characteristic patterns of body sway and cognitive performance. It may be possible to use pre-bout data to predict susceptibility to post-bout symptoms. PMID- 23680425 TI - Effect of age on the ability to recover from a single unexpected underfoot perturbation during gait: kinematic responses. AB - A sudden underfoot perturbation can present a serious threat to balance during gait, but little is known about how humans recover from such perturbations or whether their response is affected by age. We tested the hypothesis that age would not affect the stepping responses to a nominal 10 degree inversion or eversion of the stance foot during gait. Twenty-three healthy young (22.7+/-3.35 yrs) and 18 healthy old adults (68.0+/-7.19 yrs) performed 60 walking trials along a 6-m level walkway at a normal gait speed. In 16 of these trials, a single medial (MP) or lateral (LP) perturbation was randomly administered once under the left or right foot. Recovery step width (SW), step length (SL), trunk kinematics and walking speed were measured optoelectronically. Repeated-measures analysis of variance and post hoc t-tests were used to test the hypotheses. The results show that a MP or LP altered the recovery SL (p=0.005) and age affected the number of recovery steps (p=0.017), as well as the first recovery SW and SL (p=0.013 and p=0.031, respectively). Both MP and LP caused young adults to have wider SW (p<0.02) and shorter SL (p<0.005) without changing trunk movement during their first recovery step. Older adults, however, significantly changed lateral trunk inclination during the first recovery step, decreased their fourth recovery SL (p<0.001). We conclude that young adults adjust the step kinematics of as many as four recovery steps following this perturbation, a response that was delayed and significantly weaker in older adults who instead exhibited an immediate torso inclination consistent with a hip response strategy. PMID- 23680427 TI - The effects of walking speed and prosthetic ankle adapters on upper extremity dynamics and stability-related parameters in bilateral transtibial amputee gait. AB - Bilateral transtibial amputee (BTA) gait has been investigated less and is not as well understood compared to that of their unilateral counterparts. Relative to able-bodied individuals, BTAs walk with reduced self-selected speeds, increased step width, hip-hiking, and greater metabolic cost. The clinically observed upper body motions of these individuals have not been quantified, but appear substantially different from able-bodied ambulators and may impact upright balance. Therefore, the objective of this study was to characterize the upper extremity kinematics of BTAs during steady-state walking. We measured medial lateral ground reaction forces, step width and extrapolated center-of-mass (XCoM) trajectory, and observed effects of walking speed and increased prosthetic ankle range-of-motion (ROM) on these parameters. Significantly, BTAs display greater lateral trunk flexion ROM and shoulder abduction than able-bodied individuals when walking at similar speeds, and the inclusion of prosthetic adaptors for increasing passive ankle ROM slightly reduced step width. Overall, exaggerated lateral trunk flexion ROM was invariant with step width. Results suggest that lateral trunk motion is useful for shifting the body center-of-mass laterally onto the leading stance limb while simultaneously unloading the trailing limb. However, exaggerated lateral trunk flexion may introduce an unstable scenario if the XCoM is displaced beyond the lateral base-of-support. Further studies would be useful to identify if either prostheses that assist limb advancement and/or gait training may be effective in reducing this lateral sway while still maintaining efficient ambulation. PMID- 23680428 TI - Effects of cognitive enrichment on behavioural and physiological reactions of pigs. AB - Cognitive enrichment, a special form of environmental enrichment, addresses the cognitive abilities of animals in captivity. Through cognitive interaction with the environment, the animals regain a certain control over their environment, and essential resources, such as food or water, act as a reward for successful coping. It is assumed that this process has important implications for animal welfare, especially in the intensive housing systems of farm animals. This study investigates the effects of cognitive enrichment on welfare-relevant behaviour (agonistic interactions and behavioural reactivity in a repeated open-field test) and autonomic control (heart rate variability during feeding, resting and in a repeated open-field test) in domestic pigs. A total of forty-eight pigs, Sus scrofa, were housed in groups of four. In six replicates, an experimental group was compared with a conventionally fed control group. The pigs in the experimental group were confronted with a cognitive challenge that was integrated into their familiar housing environment. Pigs were rewarded with food after they successfully mastered the discrimination of an individual acoustical signal followed by an operant task. The pigs in both groups reacted with sympathetic arousal to feeding announcement (increased heart rate (HR)). During feeding, the experimental pigs' HR decreased, and heart rate variability (HRV) increased, while the control pigs' HR stayed highly elevated and HRV decreased. These results are supported by a considerably larger number of agonistic interactions during feeding in the control group. During resting, the basal HRV of the experimental pigs increased (during operant conditioning) compared to the control. In the repeated open-field test, the experimental pigs displayed less locomotion and elimination as well as more contact with the wall and an unknown object compared to the control group. We conclude that cognitive enrichment leads to relaxed feeding and evokes longer lasting positive emotions. Moreover, the pigs displayed more explorative and less fearful behaviour in stressful situations. These findings support the use of cognitive enrichment to improve animal welfare. PMID- 23680429 TI - Differential effects of central ghrelin on fatty acid metabolism in hypothalamic ventral medial and arcuate nuclei. AB - Fatty acid metabolism is an important pathway involved in the hypothalamus mediated control of food intake. Previous studies using whole hypothalamic tissue lysates have shown that fatty acid metabolism plays a key role in ghrelin's effect on feeding. Here, we report site-specific effects of central ghrelin on fatty acid metabolism in two critical hypothalamic nuclei, the ventral medial nucleus (VMN) and the arcuate nucleus (Arc). Intracerebroventricular administration of ghrelin to rats activates AMP-activated protein kinase in both the VMN and the Arc, while ghrelin treatment has a site-specific effect on fatty acid metabolic pathways in these two nuclei. In the VMN, central ghrelin increases the phosphorylation level of ACC, indicating the decrease in activity, and decreases the level of malonyl-CoA (the product of ACC). Malonyl-CoA is an inhibitor of carnitine palmitoyltransferase-1 (CPT-1) that is a key enzyme in mitochondrial fatty acid oxidation. Consistent with this action of malonyl-CoA on CPT-1, central ghrelin treatment increases the activity of CPT-1 in the VMN. In contrast, in the Arc, neither malonyl-CoA level nor CPT-1 activity is affected following central ghrelin. Taken together, our data suggest ghrelin exerts differential effects on fatty acid metabolic pathways in the VMN and the Arc. PMID- 23680430 TI - Enhanced voluntary wheel running in GPRC6A receptor knockout mice. AB - GPRC6A is an amino acid-sensing receptor highly expressed in the brain and in skeletal muscle. Although recent evidence suggests that genetically engineered GPRC6A receptor knockout (KO) mice are susceptible to develop subtle endocrine and metabolic disturbances, the underlying disruptions in energy metabolism are largely unexplored. Based on GPRC6A's expression pattern and ligand preferences, we hypothesize that the receptor may impact energy metabolism via regulating physical activity levels. Thus, in the present study, we exposed GPRC6A receptor KO mice and their wild-type (WT) littermates to voluntary wheel running and forced treadmill exercise. Moreover, we assessed energy expenditure in the basal state, and evaluated the effects of wheel running on food intake, body composition, and a range of exercise-induced central and peripheral biomarkers. We found that adaptation to voluntary wheel running is affected by GPRC6A, as ablation of the receptor significantly enhances wheel running in KO relative to WT mice. Both genotypes responded to voluntary exercise by increasing food intake and improving body composition to a similar degree. In conclusion, these data demonstrate that the GPRC6A receptor is involved in regulating exercise behaviour. Future studies are highly warranted to delineate the underlying molecular details and to assess if these findings hold any translational value. PMID- 23680431 TI - Influence of the PROP bitter taste phenotype and eating attitudes on energy intake and weight status in pre-adolescents: a 6-year follow-up study. AB - The PROP bitter-taste phenotype is a marker for food preferences and eating behavior, and may associate with differences in body weight in children. Previous work has shown that PROP status in combination with eating attitudes are better predictors of weight status in preadolescents, than either factor alone. However, no studies have examined the role of PROP phenotypes in body weight change in children over time. The primary objective of this study was to investigate current weight status and change in weight status in children from preschool (baseline) to preadolescence as a function of eating attitudes and PROP phenotype. Other measures included self-reported food intakes and physical activity by activity monitor. Seventy-three lean (BMI percentile=57.7+/-3.2%) children with mean age=10.3+/-0.5yrs, participated in the follow up. There were no group differences in energy intake, current BMI-percentile or change in BMI percentile from baseline by PROP phenotype in either boys or girls. However, there was a trend for non-taster girls to show a downward shift in BMI-percentile at follow up. Hierarchical regression analysis revealed that baseline BMI percentile and physical activity energy expenditure were the strongest predictors of current weight (28.5% variance),followed by child restraint, the taster*gender interaction, and the maternal BMI*maternal emotional eating interaction, accounting for 7.1%, 6.0% and 4.8% of variance in the model, respectively. These findings suggest that PROP status and eating attitudes are modest predictors of weight status in preadolescent children. PMID- 23680432 TI - Contextual control of flavor neophobia. AB - The role of context in the retrieval of learned information has been widely analyzed in the associative learning domain. However, evidence about the effect of context on flavor memory retrieval is more limited. We have carried out four experiments with rats testing for possible interactions between neophobia habituation and the context in which flavors are presented, by manipulating prior experience with contexts. Our results point to the relevance of context familiarity for the establishment and recovery of a safe taste memory trace. More specifically, the use of the animals' home cages as experimental context favored neophobia habituation (Experiments 1A and 2), reduced dopamine levels induced by administration of the dopamine D1-like receptor antagonist SCH-23390 disrupted neophobia habituation when tested in presence of a new context (Experiment 1B), and testing in the animal's home cage increases the amount of flavor consumed, even when such flavor had a previous history of aversive conditioning (Experiment 3). We propose that exploring context without aversive consequences generates a safe memory trace of such context that becomes in the basis of increased flavor consumption. PMID- 23680433 TI - 'Food addiction' and its association with a dopaminergic multilocus genetic profile. AB - BACKGROUND: Our objective was to employ a novel genetic methodology - whereby functional variants of the dopamine pathway were aggregated to reflect a polygenic liability - in the study of food addiction. We anticipated that the composite index of elevated dopamine signaling (a multilocus genetic profile score [MLGP]) would distinguish those with a designation of food addiction (according to the Yale Food Addiction Scale [YFAS] criteria), and age and weight equivalent controls. Our second aim was to assess whether this index was positively associated with eating-related sub-phenotypes of food addiction (e.g. binge eating and food cravings). METHODS: Adults (n=120) recruited from the community were solicited for an overeating/overweight study. Eating-behavior questionnaires were completed and a blood sample was taken for genotyping. RESULTS AND CONCLUSIONS: The YFAS identified 21 participants with food addiction. As predicted, the MLGP score was higher in those with YFAS-diagnosed food addiction, and it correlated positively with binge eating, food cravings, and emotional overeating. We then tested a multiple-mediation model proposing that reward-driven overeating facilitates the relationship between the MLGP score and food addiction. The model was statistically significant, supporting the view that the relationship between a composite genetic index of dopamine signaling and food addiction is mediated by certain aspects of reward-responsive overeating. PMID- 23680434 TI - Evaluation of the 2011 long-lasting, insecticide-treated net distribution for universal coverage in Togo. AB - BACKGROUND: Malaria remains a substantial public health problem in Togo. An integrated child health campaign was conducted in Togo in October 2011. This campaign included a component of free distribution of 2,799,800 long-lasting, insecticide-treated nets (LLINs) to households throughout Togo. This distribution marked the first effort in Togo at universal LLIN coverage and was not targeted specifically to children under five years and pregnant women, but to all household members. This study reports the results of the LLIN distribution campaign in terms of bed net possession and utilization. METHODS: A representative household survey was implemented during the rainy season nine months after the LLIN distribution component of the campaign. Some 6,015 households selected through two stages of probability proportion to size stratified random sampling were interviewed using a brief questionnaire that included a demographic section with questions on the number of household members and sleeping spaces, and a campaign participation section with questions used to evaluate non-LLIN aspects of the campaign. A net roster listed all nets and their characteristics, and a household roster listed all members and visitors with information about bed net use. The questions addressed different aspects of bed net and LLIN possession and utilization. Crude weighted frequencies, percentages, and t- tests of association were calculated using the Stata 12.0 Survey features. RESULTS: Possession of at least one bed net and/or LLIN increased from 41.3% to 96.7% (P <0.001). Household possession of at least one campaign LLIN was 93.3%. Report LLIN among pregnant women was 77.5% and 79.3% for children under five. For the general population LLIN use was 68.3%. CONCLUSIONS: Due to the gap in LLIN possession and use and the significant number of individuals reporting a lack of nets as a reason for non-use, additional national LLIN distribution campaigns with a stronger educational component need to be implemented in order increase the use of available LLINs and to reach and maintain universal coverage of LLINs in Togo. The LLIN distribution campaign focusing on universal coverage of the general population in Togo was more successful at increasing LLIN possession and use of children under five years and pregnant women than other campaigns focusing only on these target groups. PMID- 23680435 TI - Improvements in white matter micro-structural integrity of right uncinate fasciculus and left fronto-occipital fasciculus of remitted first-episode medication-naive panic disorder patients. AB - OBJECTIVE: We designed this study to investigate neural correlates of white matter micro-structural integrity of remitted patients with first-episode, medication-naive and very late-onset panic disorder. METHOD: Twenty-one remitted patients with panic disorder completed treatment course with treatment of escitalopram (dose range around 10-15 mg/d). Twenty-one healthy controls were also enrolled into this study. Patients and controls all received 3-Tesla magnetic resonance imaging diffusion tensor imaging scanning at baseline and 6th week. We utilized FDT (FMRIB's Diffusion Toolbox v2.0) function of FSL (FMRIB Software Library) to calculate fractional anisotropy (FA). We compared FA values of patients and controls at baseline and 6th week to estimate the changes of FA of remitted patient group and inter-scan bias of controls. FA outputs of remitted patients and controls were compared by independent t test. RESULTS: We found increased FA in some regions of right uncinate fasciculus and left fronoto occipital fasciculus after remission in patient group (corrected p<0.05). Reduced FA of other regions of right uncinate fasciculus was still observed in remitted patients when they were compared to the control group. CONCLUSION: Subtle changes of white matter micro-structural integrity after remission might represent neural correlates of treatment effects for first-episode, medication-naive and very late onset panic disorder. PMID- 23680436 TI - Association of genetic variation in CACNA1C with bipolar disorder in Han Chinese. AB - BACKGROUND: A growing body of evidence highlights the existence of shared genetic susceptibility to both major depressive disorder (MDD) and bipolar disorder (BD), suggesting some potential genetic overlap between the disorders. Genome-wide association studies have identified consistent association of single nucleotide polymorphisms of the alpha-1 C subunit of the L-type voltage-gated calcium channel gene (CACNA1C) with MDD and BD, suggesting CACNA1C as a promising candidate gene for susceptibility to mood disorders. In the present study, we tested the association of CACNA1C with MDD and BD in Han Chinese. METHODS: We genotyped three potentially functional polymorphisms in 635 MDD patients, 286 BD patients and 730 normal, control patients. RESULTS: The genotype frequencies of SNP rs1051375 showed statistically significant differences between the BD and control groups (P=0.005). At the allele level, the difference of G allele frequency of rs1051375 between BD patients and control subjects was also significant (P=0.011; OR=1.30, 95% CI: 1.06-1.58). We found that GG genotype of rs1051375 carriers had a lower age at onset than those with the AG or AA genotype, and the mean+/-standard deviation ages at onset of GG, AG and AA carriers were 24.04+/-4.22, 25.76+/-4.75 and 25.78+/-4.33 years, respectively. Neither genotype nor allele frequencies of the three polymorphisms were found to be significantly different between the MDD patients and control subjects. LIMITATIONS: The relative small sample size in BD group should be considered a limitation of this study. CONCLUSIONS: Our initial findings support a potential association of CACNA1C as a genetic risk factor for BD susceptibility. PMID- 23680437 TI - Immunohistochemical analysis of the expression of MAGE-A and NY-ESO-1 cancer/testis antigens in diffuse large B-cell testicular lymphoma. AB - BACKGROUND: Primary testicular lymphoma (PTL) is a rare and lethal disease. The most common histological subtype is diffuse large B-cell lymphoma (DLBCL). Standard treatments are frequently ineffective. Thus, the development of novel forms of therapy is urgently required. Specific immunotherapy generating immune responses directed against antigen predominantly expressed by cancer cells such as cancer-testis antigens (CTA) may provide a valid alternative treatment for patients bearing PTL, alone or in combination with current therapies. METHODS: Three monoclonal antibodies (mAbs), 77B recognizing MAGE-A1, 57B recognizing an epitope shared by multiple MAGE-A CTA (multi-MAGE-A specific) and D8.38 recognizing NY-ESO-1/LAGE-1 were used for immunohistochemical staining of 27 PTL, including 24 DLBCL. RESULTS: Expression of MAGE-A1 was infrequently detectable in DLBCL specimens (12.50%), whereas multi-MAGE-A and NY-ESO-1/LAGE-1 specific reagents stained the cytoplasms of tumor cells in DLBCL specimens with higher frequencies (54.17% and 37.50%, respectively) with different expression levels. CONCLUSIONS: These results suggest that MAGE-A and NY-ESO-1/LAGE-1, possibly in combination with other CTA, might be used as targets for specific immunotherapy in DLBCL. PMID- 23680438 TI - Factors associated with newly diagnosed tic disorders among children in Taiwan: a 10-year nationwide longitudinal study. AB - Increased attention has been paid to tic disorders clinically, yet relatively few studies have probed potential factors that account for the occurrence of tic disorders in the general population. In this study, we used data derived from the Taiwan's National Health Insurance Research Database to examine an array of factors related to the diagnosis of tic disorders and to further probe gender heterogeneity in clinical manifestation. Poisson regression analyses were applied to model the effects of birth cohort, period, and age, separately, on tic disorders. A total of 880 newly diagnosed tic disorders were identified from 2002 to 2009 among 100,516 youngsters in the study dataset who were born between 1997 and 2005. The results showed that a significant increase in the adjusted incidence rate ratio (IRR) was observed when age increased, with the highest adjusted IRR found at age 8-9 years. Compared to the time period from 2002 to 2005, an elevated IRR was found in the time period from 2006 to 2009 (adjusted IRR: 1.37; 95% CI: 1.05-1.80). Boys tended to be more likely to receive their initial diagnosis from psychiatrists and have higher comorbid attention deficit/hyperactivity disorder (ADHD), as compared with their girl counterparts. In conclusion, the findings indicate that the effects of age and period, respectively, influence the occurrence of newly diagnosed tic disorders. Gender difference and higher frequent comorbid ADHD in boys than in girls were observed in this study. PMID- 23680439 TI - Flexibility as the key for somatic health: From mind wandering to perseverative cognition. AB - Mind wandering (MW) has been defined as the brain's default mode of operation. It is a common experience, however, that this process can become maladaptive, and take the form of repetitive thoughts. We aimed to compare the cardiac and cognitive correlates of perseverative cognition (PC) and MW. Seventy-three healthy participants were engaged in two recall interviews designed to draw their attention to a neutral and a personally relevant negative episode. After each interview, participants performed a 20-min tracking task with thought probe while the electrocardiogram was continuously recorded. Perseverative cognition was associated with higher levels of cognitive inflexibility (slower reaction times, highest intrusiveness, efforts to inhibit), autonomic rigidity (low heart rate variability), and mood worsening compared to being focused on task or MW. Results suggest that MW fails to serve its adaptive function, and turns into a risk factor for health whenever it becomes a rigid and inflexible pattern (PC). PMID- 23680440 TI - Changes in Streptococcus pneumoniae serotype distribution in invasive disease and nasopharyngeal carriage after the heptavalent pneumococcal conjugate vaccine introduction in Bogota, Colombia. AB - BACKGROUND: In Bogota, the Heptavalent Conjugate Vaccine (PCV7) was introduced into childhood immunization schedule since 2009. The aim of this study was to assess the changes in serotype distribution and penicillin susceptibility of Streptococcus pneumoniae isolates recovered from nasopharyngeal samples and invasive disease among children living in Bogota, before and after PCV7 introduction. METHODS: Nasopharyngeal swabs were collected from healthy children aged between 12 and 18 months of age before (years 2005-2006) and after (2011) PCV7 introduction. Identification of S. pneumoniae was performed by multiplex PCR. Serotype was determined by PCR and Quellung reaction. Susceptibility to penicillin, ceftriaxone, trimethoprim-sulfamethoxazole, chloramphenicol, tetracycline and erythromycin was evaluated. In addition, distribution of serotypes and antimicrobial susceptibility before and after vaccine introduction among invasive isolates recovered from children <=2 years old living in Bogota was analyzed. RESULTS: Prevalence of pneumococcal nasopharyngeal carriage declined from 55.7% (137/246) in unvaccinated to 44.2% (87/197) (p=0.01) in vaccinated children. The proportion of children carrying PCV7 serotypes decreased from 23.6% (58/246) to 7.6% (15/197) (p<0.001). The decrease was counterbalanced by an increase in the proportion of non-PCV7 serotypes. The most prevalent among emerging serotypes were 15A, 15B, 15C, 11A and 35B. Among IPD isolates, PCV7 serotypes decreased from 69.1% (235/340) in 2005/2009 to 38.0% (32/84) in 2010/2011 (p<0.001). The increase of non-PCV7 serotypes was significant. Resistance to penicillin among invasive isolates recovered from meningitis decreased from 41.1% (30/73) in the pre-vaccine period to 14.2% (2/14) in post vaccine period (p=0.02). CONCLUSIONS: A decrease in the prevalence of pneumococcal nasopharyngeal carriage following the introduction of PCV7 vaccine, have been overshadowed by an important surge in the prevalence of non-PCV7 serotypes. Systematic surveillance combining nasopharyngeal carriage surveys and IPD detection could help in evaluating the impact of conjugate vaccines. PMID- 23680441 TI - High-dose vitamin A supplementation administered with vaccinations after 6 months of age: sex-differential adverse reactions and morbidity. AB - BACKGROUND: WHO recommends vitamin A supplementation (VAS) at vaccination contacts after six months of age. The effect of this recommendation on mortality has not been evaluated. METHODS: We tested the effect of VAS at vaccination contacts on mortality in a randomised trial in Guinea-Bissau. In a subgroup within this trial we studied adverse reactions to VAS and whether VAS modified known adverse reactions to live and inactivated vaccines and general morbidity during the first month after supplementation overall and by sex. Children aged 6 17 months were randomised to VAS or placebo at the day of vaccination (day 0). We interviewed the caretaker, assessed the fontanel and measured temperature and local reaction at the injection site at home visits on day 1, 2, 3, 7, 14, 21, and 31. We defined systemic adverse reactions to inactivated and live vaccines as fever on day 1 and 2 and on 4-14 respectively. Clinical symptoms associated with increased intracranial pressure (ICP) on day 1 were considered possible adverse reactions to VAS. RESULTS: In 1673 children VAS had no overall effect on clinical symptoms associated with increased ICP (Relative Risk(RR)=1.07 (95%CI: 0.85 1.35)). However, VAS was associated with such clinical symptoms in boys RR=1.38 (1.00-1.91)) but not in girls (p=0.03 for interaction between VAS and sex). VAS had no effect on fever after inactivated vaccines. VAS had no overall effect on fever after live vaccines (RR=0.86 (0.53-1.39)), but tended to reduce the prevalence of fever in boys (RR=0.58 (0.30-1.14)), but not in girls (RR=1.37 (0.66-2.84)) (p=0.09 for interaction between VAS and sex). VAS was associated with increased local reactions to measles vaccine in both sexes (RR=3.65 (1.20 11.12)). CONCLUSION: Adverse reactions were rare, mild and transient and may not in their own right cause concern. However, VAS caused sex-differential adverse reactions and may have sex-differential effects on adverse reactions to vaccines. PMID- 23680442 TI - Distribution of carried pneumococcal clones in UK children following the introduction of the 7-valent pneumococcal conjugate vaccine: a 3-year cross sectional population based analysis. AB - The success of Streptococcus pneumoniae (pneumococcus) in both colonisation and disease is associated with the increased prevalence of genetic clones expressing virulence factors that assist host invasion. We studied the distribution of pneumococcal clones in paediatric carriage as part of an ongoing longitudinal study of pneumococcal carriage in children less than 5 years of age. Across three years, 87 different sequence types (STs) were found amongst 310 pneumococci. A decline in PCV-7 related STs was observed during the study period. STs 62, 199, 433 and 1692 increased after the implementation of PCV-7 and were related to increases in serotypes 11A, 19A, 22F, and to serotype 6C, respectively. Overall, a strong correlation was observed between ST and serotype. Thirteen STs contained multiple serotypes and 74 STs were associated with only one serotype. On-going molecular epidemiological surveillance of pneumococcal carriage is warranted during the implementation of pneumococcal conjugate vaccines. PMID- 23680443 TI - The acoustic reflection method for the assessment of paediatric upper airways. AB - The acoustic reflection method (ARM) is based on the analysis of the reflection of an acoustic wave in the airway, allowing the calculation of its longitudinal cross-sectional area profile and airway resistance. The ARM represents a simple, quick and totally non invasive tool for the investigation of the upper airways, requiring minimal cooperation, which makes this technique particularly suitable for children. Normal values of the minimal cross sectional area of the upper airways in children have been recently published. The ARM has shown its utility in the investigation of the nasal cavity in healthy and diseased children and of the upper airways in children with various diseases such as mucopolysaccharidosis and cystic fibrosis. This simple, rapid, and inexpensive technique seems promising for the non-invasive investigation of the whole upper airway during wakefulness in children, both in health and disease, and may constitute a complementary or alternative method to explore and follow children with anomalies of the upper airways. PMID- 23680444 TI - A class of pyrrole derivatives endowed with analgesic/anti-inflammatory activity. AB - We report the synthesis and bio-pharmacological evaluation of a class of pyrrole derivatives featuring a small appendage fragment (carbaldehyde, oxime, nitrile) on the central core. Compound 1c proved to be extremely effective in vivo, showing an interesting anti-nociceptic profile that is comparable to reference compounds already marketed, hence representing a great stimulus for a further improvement of this class of molecules. PMID- 23680445 TI - Falcipain-2 inhibition by suramin and suramin analogues. AB - Falcipain-2 is a cysteine protease of the malaria parasite Plasmodium falciparum that plays a key role in the hydrolysis of hemoglobin, a process that is required by intraerythrocytic parasites to obtain amino acids. In this work we show that the polysulfonated napthylurea suramin is capable of binding to falcipain-2, inhibiting its catalytic activity at nanomolar concentrations against both synthetic substrates and the natural substrate hemoglobin. Kinetic measurements suggest that the inhibition occurs through an noncompetitive allosteric mechanism, eliciting substrate inhibition. Smaller suramin analogues and those with substituted methyl groups also showed inhibition within the nanomolar range. Our results identify the suramin family as a potential starting point for the design of falcipain-2 inhibitor antimalarials that act through a novel inhibition mechanism. PMID- 23680446 TI - The utility of surgical lung biopsy in cancer patients with acute respiratory distress syndrome. AB - BACKGROUND: This retrospective study evaluated the utility and safety of surgical lung biopsy (SLB) in cancer patients with acute respiratory distress syndrome (ARDS). METHODS: All cases of critically ill patients with cancer and diagnosed with ARDS who underwent SLB in a tertiary care hospital from January 2002 to July 2009 were reviewed. Clinical data including patient baseline characteristics, surgical complications, pathological findings, treatment alterations, and survival outcomes were retrospectively collected and analyzed. RESULTS: A total of 16 critically ill patients with cancer diagnosed with ARDS who underwent SLB were enrolled. The meantime from ARDS onset to SLB was 3.0 +/- 1.5 days. All SLB specimens offered a pathological diagnosis, and specific diagnoses were made in 9 of 16 patients. Biopsy findings resulted in a change in therapy in 11 of 16 patients. Overall, the SLB surgical complication rate was 19% (3/16). SLB did not directly cause the observed operative mortality. The ICU mortality rate was 38% (6/16). Patients who switched therapies after SLB had a trend toward decreased mortality than patients without a change in therapy (27% versus 60%; P = 0.299). CONCLUSIONS: In selected critically ill cancer patients with ARDS, SLB had a high diagnostic yield rate and an acceptable surgical complication rate. PMID- 23680447 TI - Congenital heart disease and coronary atherosclerosis: a looming concern? PMID- 23680448 TI - TSH receptor antibodies have predictive value for breast cancer - retrospective analysis. AB - BACKGROUND: Associations between breast cancer and thyroid disorders are reported in numerous studies. Relationships between thyroperoxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb) and breast cancer have been previously demonstrated. However, no analysis has been performed concerning an association between thyrotropin (TSH) receptor antibodies (TSHRAb) and breast cancer. The aim of the study was to evaluate the prevalence of breast cancer or benign breast tumors in patients with Graves' disease and to analyze a possible relationship between Graves' disease and these two groups of breast diseases with emphasis to epidemiology and laboratory findings. PATIENTS AND METHODS: Clinical and laboratory details of 2003 women hospitalized for endocrine disorders were retrospectively analyzed, using an unpaired Student's t-test, logistic regression analysis, chi2 test of independence or the two-sided ratio comparison test. RESULTS: The coexistence of Graves' disease and breast cancer was statistically significant. We observed TSHRAb and TgAb more frequently in patients with breast cancer. We found that TSHRAb is the only variable possessing predictive value for breast cancer. CONCLUSIONS: The strong relationship between Graves' disease and breast cancer is proposed. We suggest that TSHRAb could be described as a positive determinant of breast cancer. The present data call attention to the usefulness of screening for breast cancer in long-term follow-up of patients with autoimmune thyroid disorders, especially of those with Graves' disease. Similarly, screening for autoimmune thyroid disorders should be performed in patients with nodular breast disease. Additionally, the article draws ideas for further research in order to develop targeted treatment for more successful outcome in patients with breast cancer. PMID- 23680449 TI - Determinants of male participation in reproductive healthcare services: a cross sectional study. AB - BACKGROUND: The role of male's participation in reproductive healthcare is now well-recognized. The present study investigated the role of men in some selected reproductive health issues, characterizing their involvement, including factors influencing their participation in reproductive healthcare services. METHODS: This study was conducted in the working areas of urban and rural implemented by NGOs. The sample-size was determined scientifically. The systematic sampling procedure was used for selecting the sample. The study included 615 men aged 25 45 years. Bivariate analysis was performed between male's involvement as the dependent variable with several independent variables. Logistic regression analysis was applied to assess the effects of risk factors on the participation of men in reproductive health care services. RESULTS: The mean age of the respondents was little over 34 years while their mean years of schooling was 3.7, and their mean monthly income was about Tk 3,400 (US$ 1 = Tk 70) at the time of the study. Rickshaw-pulling and driving was the main occupation of the respondents from the urban while farming were main occupation in the rural area respectively. About two-thirds of the respondents discussed reproductive health issues with their wives and accompanied them to healthcare facilities. The current contraceptive-use rate was 63% among the men who attended the evening clinics. Results of bivariate analysis showed a significant association with education, occupation, income, access to media, and number of living children. Results of logistic regression analysis showed that secondary to higher education level, number of living children, paid employment status, long marital duration, and access to media were important correlates of males' involvement in reproductive healthcare services. CONCLUSIONS: The results imply that a greater integration of reproductive healthcare matters with the Millennium Development Goals and increasing perception of men through enrollment in various components of reproductive activities will produce synergistic effects. PMID- 23680450 TI - Anticipating the use of future things: towards a framework for prospective use analysis in innovation design projects. AB - Anticipation of future product use is a persistent issue in User-Centered Design. In this paper, we argue that one obstacle to early integration of use analysis in innovation design is overreliance on retrospective use analysis, i.e. that which is based on clear references to existing products or activities. In contrast, innovation design projects are full of uncertainty, leading to a need for prospective analysis. After having described some limitations of prospective use analysis, we contend that creativity tools may be used to assist the anticipation of future product use, by allowing designers to approach the variability of situations of future use in a structured manner rather than by "muddling through". We illustrate the expected benefits of this approach with two case studies, and describe some prospects for future research and practice in ergonomics. PMID- 23680452 TI - Iron overload of hematological origin: validation of a screening procedure for cardiac overload by MRI in routine clinical practice. AB - PURPOSE: Screening for cardiac iron overload is generally done by magnetic resonance imaging (MRI) and demonstrated by a shortening of the myocardial T2* below 20 ms at 1.5 Tesla. This measurement was validated with a specific sequence and the CMRTools((r)) calculation software (reference technique). The objective of this study was to validate the use of sequences and software programs that are available in routine clinical practice to screen for iron overload. MATERIAL AND METHODS: First, a phantom of 11 tubes with a T2* between 4 and 33 ms was tested at three sites that had MRI machines of different brands. Second, the myocardial T2* values of 75 patients were measured in routine clinical practice using two methods. The first method used the reference sequence specially installed in the machines associated with the CMRTool software. The second method used the standard acquisition sequences available in the machines followed by calculation on a computer spreadsheet. RESULTS: In the phantom, the mean of the differences in T2* between each machine was 0.6 ms. Thirteen patients had a lowered T2* value with the reference technique. Three cases were poorly classified using the routine technique and corresponded with false positives of low overload (T2* between 18 and 20 ms). CONCLUSION: Screening for myocardial iron overload can be done by MRI by using sequences and calculation software available in routine clinical practice during the same examination as the one for the evaluation of hepatic iron overload. PMID- 23680451 TI - New insights on the function of SCF ubiquitin E3 ligases in the lung. AB - Recent developments in pulmonary cell biology have shown that the maintenance of protein concentrations, proteostasis, is an integral process of all biologic systems. The balance of available protein is the sum total of three key elements of cell metabolism: production by transcription and translation, compartmentalization through processing and sorting, and proteolytic degradation of proteins at any stage of their life-span. Considerable advances are constantly made in each of these three essential fields, and our appreciation for the diversity of mechanisms of protein degradation has expanded greatly in the last decade. The ubiquitin proteasome system (UPS) has emerged as the predominant protein degradation pathway in eukaryotes, with the large cullin-RING family of E3 ligases responsible for ubiquitination of a broad array of proteins to be degraded. The Skip-Cullin-F-box (SCF) ubiquitin E3 ligase superfamily is the largest family of cullin-RING ligases, with interchangeable F-box proteins orchestrating the trafficking proteins for ubiquitination and degradation. We will discuss the best characterized and most recent developments in the role of this intriguing family of proteins in normal physiology and disorders of the lungs. PMID- 23680453 TI - Cluster reduction and compensatory lengthening in the acquisition of possessive s. AB - Previous research shows that two-year-olds' third person singular -s and plural s are produced more accurately in utterance-final compared to utterance-medial position. However, only the third person singular is affected by coda complexity. This study explores these effects with possessive -s. Acoustic analysis of twelve two-year-olds' elicited imitations examined the use of simple versus complex codas (e.g. Sue's vs. Doug's ) both utterance-medially and utterance-finally. Morpheme production was surprisingly robust across contexts, though coda clusters were often simplified to a lengthened -s morpheme utterance-medially (e.g., Dou's [daz]). The findings raise many questions about the development of speech planning processes across populations. PMID- 23680454 TI - Fulani show decreased susceptibility to Plasmodium falciparum infection versus Mossi: data from a community-wide screening and treatment of asymptomatic carriers in Burkina Faso. AB - BACKGROUND: The Fulani ethnic group is known to have a lower susceptibility to Plasmodium falciparum infection than the Mossi. METHODS: This commentary describes data from a recent cluster-randomized trial of community-wide screening and treatment of asymptomatic carriers of P. falciparum in 18 villages in Sapone, Burkina Faso. RESULTS: The Fulani groups had a lower proportion of asymptomatic carriers at any occasion, a lower density of asexual forms and gametocytes of P. falciparum at baseline, and, in children under five years of age, lower rates of symptomatic malaria episodes per person-year than the Mossi. DISCUSSION AND CONCLUSION: These data confirm previously reported differences in P. falciparum susceptibility between Fulani and Mossi. PMID- 23680455 TI - Antioxidants: friends or foe in prevention or treatment of cancer: the debate of the century. AB - There are a number of intrinsic (e.g. oncogenes) and extrinsic (e.g. radiation and inflammation) factors, which may arise in reactive oxygen species (ROS), resulting in DNA instability and then cancer. In this situation, initial cancerous cells would balance the harmful effects of ROS by switching on the protective effects in a longstanding manner. In normal conditions, ROS have an important role in signal transduction and gene transcription, nevertheless, ROS may act as a trigger for carcinogenesis via persistent DNA injuries as well as mutations in p53 such as conditions observed in skin, hepatocellular, and colon cancers. Some compounds like paclitaxel are able to attack cancer cells through generation of ROS or interfering with ROS metabolism, while there are a few anti angiogenesis compounds without toxicity such as endostatin, which act as anti neoplastic only together with another chemotherapeutic drug. Furthermore, some anti-cancer agents like piperlongumine bind to the active sites of several key cellular antioxidants including glutathione S transferase and carbonyl reductase 1 only in the cancer cells. Although the natural antioxidants can alone or in combination with the diet provide some benefits for chemoprevention, their position in cancer therapy, especially initial stages of carcinogenesis is breaking down. On the other hand antioxidants can promote the survival of detached cells from extra cellular medium playing dual activities with respect to tumorigenesis through inhibition of tumorigenesis by preventing oxidative injuries to DNA and otherwise maintenance of tumor by promoting cell survival via metabolic rescue. Hopefully, more details of antioxidant and anti-neoplastic mechanisms become clear day by day, which have made researchers renew the strategy for designing cancer prevention or treatment. PMID- 23680456 TI - Exposure to As, Cd and Pb-mixture impairs myelin and axon development in rat brain, optic nerve and retina. AB - Arsenic (As), lead (Pb) and cadmium (Cd) are the major metal contaminants of ground water in India. We have reported the toxic effect of their mixture (metal mixture, MM), at human relevant doses, on developing rat astrocytes. Astrocyte damage has been shown to be associated with myelin disintegration in CNS. We, therefore, hypothesized that the MM would perturb myelinating white matter in cerebral cortex, optic nerve (O.N.) and retina. We observed modulation in the levels of myelin and axon proteins, such as myelin basic protein (MBP), proteolipid protein, 2'-, 3'-cyclic-nucleotide-3'-phosphodiesterase, myelin associated glycoprotein and neurofilament (NF) in the brain of developing rats. Dose and time-dependent synergistic toxic effect was noted. The MBP- and NF immunolabeling, as well as luxol-fast blue (LFB) staining demonstrated a reduction in the area of intact myelin-fiber, and an increase in vacuolated axons, especially in the corpus-callosum. Transmission electron microscopy (TEM) of O.N. revealed a reduction in myelin thickness and axon-density. The immunolabeling with MBP, NF, and LFB staining in O.N. supported the TEM data. The hematoxylin and eosin staining of retina displayed a decrease in the thickness of nerve-fiber, plexiform-layer, and retinal ganglion cell (RGC) count. Investigating the mechanism revealed a loss in glutamine synthetase activity in the cerebral cortex and O.N., and a fall in the brain derived neurotrophic factor in retina. An enhanced apoptosis in MBP, NF and Brn3b-containing cells justified the diminution in myelinating axons in CNS. Our findings for the first time indicate white matter damage by MM, which may have significance in neurodevelopmental-pediatrics, neurotoxicology and retinal-cell biology. PMID- 23680457 TI - Does long-term creatine supplementation impair kidney function in resistance trained individuals consuming a high-protein diet? AB - BACKGROUND: The aim of this study was to determine the effects of creatine supplementation on kidney function in resistance-trained individuals ingesting a high-protein diet. METHODS: A randomized, double-blind, placebo-controlled trial was performed. The participants were randomly allocated to receive either creatine (20 g/d for 5 d followed by 5 g/d throughout the trial) or placebo for 12 weeks. All of the participants were engaged in resistance training and consumed a high-protein diet (i.e., >= 1.2 g/Kg/d). Subjects were assessed at baseline (Pre) and after 12 weeks (Post). Glomerular filtration rate was measured by 51Cr-EDTA clearance. Additionally, blood samples and a 24-h urine collection were obtained for other kidney function assessments. RESULTS: No significant differences were observed for 51Cr-EDTA clearance throughout the trial (Creatine: Pre 101.42 +/- 13.11, Post 108.78 +/- 14.41 mL/min/1.73m2; Placebo: Pre 103.29 +/ 17.64, Post 106.68 +/- 16.05 mL/min/1.73m2; group x time interaction: F = 0.21, p = 0.64). Creatinine clearance, serum and urinary urea, electrolytes, proteinuria, and albuminuria remained virtually unchanged. CONCLUSIONS: A 12-week creatine supplementation protocol did not affect kidney function in resistance trained healthy individuals consuming a high-protein diet; thus reinforcing the safety of this dietary supplement. TRIAL REGISTRATION: ClinicalTrials.gov NCT01817673. PMID- 23680458 TI - Transplantation of human neuro-epithelial-like stem cells derived from induced pluripotent stem cells improves neurological function in rats with experimental intracerebral hemorrhage. AB - Specific targeted therapy for intracerebral hemorrhage (ICH), which has high disability and case-fatality rate, is currently not available. Induced pluripotent stem cells (iPSCs) generated from somatic cells of ICH patients have therapeutic potential for individualized cerebral protection. While, whether ICH patient-originated iPSCs could differentiate into neuro-epithelial-like stem (NES) cells and whether such NES cells could improve functional recovery in the hemorrhage-injured brain are unclear. Here, we showed that fibroblasts from an ICH patient can be efficiently reprogrammed to iPSCs by lentiviral vectors carrying defined transcription factors (OCT4, SOX2, KLF4, and c-MYC). These iPSCs have the typical morphology, surface antigens, capability of self-renewal and differentiating into cell types of all three embryonic germ layers that are similar to human embryonic stem cells (hESCs). Using defined serum-free neural differentiation medium, we induced the iPSCs differentiate into NES cells. Subsequently, the NES cells from ICH patient-originated iPSCs were transplanted into the perihematoma of rats with experimental ICH injury. Intriguingly, recovery of neurological dysfunction in experimental ICH rats was observed post NES cells graftage. Transplanted NES cells migrated to the surrounding area of hematoma, survived and differentiated into neuron-like cells. Our study demonstrates that the transplantation of human iPS-originated NES cells is an effective approach of treating ICH injury and the improvement of neural function is partially due to neuronal replacement and regeneration. PMID- 23680460 TI - Sex and regional differences in effects of chronic intermittent ethanol exposure on subsequent excitotoxic challenges in hippocampal slice cultures. AB - The organotypic hippocampal slice culture technique was used to study how the effects of repeated ethanol withdrawal might differ between males and females at the cellular level, including potential modulation of subsequent insults. A chronic intermittent ethanol (CIE) exposure paradigm was employed, with 3 days of exposure followed by 24 h withdrawal for 3 cycles. Slices were next exposed to corticosterone (CORT) or pentylenetetrazol (PTZ) for 24 h then imaged for propidium iodide (PI) signal intensities. There were sex-selective responses in the CA1 region and dentate gyrus of the hippocampal slice cultures to treatment with CIE and/or CORT or PTZ. The 50 mM CIE alone generally did not increase the PI signal, but enhanced sensitivity to the toxic effects of CORT (particularly for females) and PTZ (particularly for males). In contrast, 100 mM CIE elicited a toxic response that was greater in females than males, and was exacerbated by exposure to PTZ. These data showed that hippocampal sexual dimorphism influences sensitivity to ethanol and other toxic chemicals even in an immature state. Low dose CIE may attenuate harm from additional challenges in a hippocampal sex- and region-selective manner. These findings add to the growing evidence of important neurobiological sex differences in responses to chronic ethanol exposure and withdrawal. PMID- 23680459 TI - Alpha-synuclein overexpression induced mitochondrial damage by the generation of endogenous neurotoxins in PC12 cells. AB - Alpha-synuclein is one of the important components of Lewy body which involved in neuropathology of Parkinson's disease (PD). The relationship between alpha synuclein and cell death is still unclear. In the study, PC12 cell, stably over expressing alpha-synuclein model was used, and we investigated the level of intracellular oxidative stress, dopamine and endogenous neurotoxin. The results showed that the level of oxidative stress and intracytoplasmic dopamine (DA) was increased in cells over expressing alpha-synuclein compared with normal PC12 cells. Simultaneously, additional generation of endogenous neurotoxins 1-methyl-4 phenyl-1,2,3,4-tetrahydroisoquinoline (salsolinol) and 1(R),2(N)-dimethyl-6,7 dihydroxy-1,2,3,4-tetrahydroisoquinolin (NM-salsolinol) was detected and this phenomenon was exacerbated after exposed to H2O2 for 24 h, but mitigated when treated with dopamine synthesis inhibitors. The presence of endogenous neurotoxins exacerbated alpha-synuclein induced mitochondrial damage. These results suggest that the endogenous neurotoxins may become a bridge between alpha synuclein and cell death. PMID- 23680461 TI - Establishment and evaluation of an experimental animal model of high altitude cerebral edema. AB - The aim of our study was to develop a model of high altitude cerebral edema (HACE) using an acute, hypobaric hypoxia environment combined with exhaustive exercise. Forty healthy male Sprague-Dawley rats were randomly divided into a plains control group (PC group) and a plateau altitude hypoxia group (AH group). After 2 days of treadmill adaptation under normoxic conditions, the AH group was housed in hypobaric conditions (simulating 4000 m above sea level) for 2 days while performing exhaustive exercise. The simulated altitude was then increased to 8000 m for 3 days of simple hypobaric hypoxia exposure. Compared with the PC group, the AH group showed significantly greater (P<0.01) water content and Evans blue staining in their brain tissue. Furthermore, the hippocampal formation was seriously damaged, and the number of pyramidal cells decreased. In addition, the brain structure was altered into a loose state with notable edema, which was demonstrated by the leakage of lanthanum nitrate particles from brain microvessels into the surrounding tissue through widened tight junctions. Some neurons and glial cell organelles were swollen and some nerve fibers were demyelinated as well. We have shown that acute hypobaric hypoxia exposure with exhaustive exercise increases the permeability of the blood-brain barrier and leads to cerebral edema, making this a valid animal model of HACE. PMID- 23680462 TI - Smoothened controls cyclin D2 expression and regulates the generation of intermediate progenitors in the developing cortex. AB - Translocation of the Smoothened to the cell membrane is critical for sonic hedgehog activity. However, the biological importance of Smoothened itself has not been fully studied. To address this issue, we disabled Smoothened specifically in the dorsal telencephalon. Birth-date analysis and layer marker expression patterns revealed the slightly impaired development of the superficial layer neurons in the embryos of Emx1-Cre; Smoothened(fl/-) conditional knockout mice. Further analysis of the mutant embryos revealed a decrease in the number of intermediate progenitor cells. In the knockout mice, the expression of cyclin D2, but not cyclin D1 or cyclin E, was reduced in the dorsal telencephalon. In addition, the projections of dopaminergic neurons were affected during development, and the number of activated astrocytes was increased in the neocortex of the mutant mice. Our data suggest that Smoothened signaling, acting through cyclin D2, is critical for the proper development and maturation of the neocortex. PMID- 23680463 TI - Changes in posture associated with postural control impairment induced by ankle plantarflexor fatigue during unipedal quiet standing. AB - The aim of the present study was to investigate changes in joint angles and limb positions accompanying postural control impairments induced by fatigue of the ankle plantarflexor muscles and vision removal. Thirteen subjects performed unipedal standing tasks with and without vision before and after isometric fatigue of the plantarflexor muscles. Results indicated that to compensate for the negative effects of fatigue and vision removal on postural control, participants increased flexion at the ankle, knee and back while the free lower limb and the pelvis moved backward and the upper limbs forward. These strategies could be performed to increase the role of non-fatigued muscles and optimize the use of all the joints implicated in unipedal standing. PMID- 23680464 TI - Phosphatidylinositol 4-phosphate 5-kinase beta regulates growth cone morphology and semaphorin 3A-triggered growth cone collapse in mouse dorsal root ganglion neurons. AB - Growth cone motility and morphology, which are critical for axon guidance, are controlled through intracellular events such as actin cytoskeletal reorganization and vesicular trafficking. The membrane phospholipid phosphatidylinositol 4,5 bisphosphate [PI(4,5)P2] has been implicated in regulation of these cellular processes in a diverse range of cell types. The main kinases involved in the production of PI(4,5)P2 are the type I phosphatidylinositol 4-phosphate 5-kinase (PIP5K) family, which consist of three isozymes, alpha, beta and gamma. Here, we demonstrate the involvement of PIP5Kbeta in growth cone dynamics. Overexpression of a lipid kinase-deficient mutant of PIP5Kbeta (PIP5Kbeta-KD) in mouse dorsal root ganglion (DRG) neurons stimulated axon elongation and increased growth cone size, whereas wild-type PIP5Kbeta tended to show opposite effects. Furthermore, PIP5Kbeta-KD inhibited growth cone collapse of DRG neurons induced by semaphorin 3A (Sema3A). These results provide evidence that PIP5Kbeta negatively regulates axon elongation and growth cone size and is involved in the cellular signaling pathway for Sema3A-triggered repulsion in DRG neurons. PMID- 23680465 TI - Reduced sense of agency in chronic schizophrenia with predominant negative symptoms. AB - Self-disturbances in schizophrenia have been regarded as a fundamental vulnerability marker for this disease, and have begun to be studied from the standpoint of an abnormal "sense of agency (SoA)" in cognitive neuroscience. To clarify the nature of aberrant SoA in schizophrenia, it needs to be investigated in various clinical subtypes and stages. The residual type of chronic schizophrenia with predominant negative symptoms (NS) has never been investigated for SoA. Accordingly, we investigated SoA by an original agency attribution task in NS-predominant schizophrenia, and evaluated the dynamic interplay between the predictive and postdictive components of SoA in the optimal cue integration framework. We studied 20 patients with NS-predominant schizophrenia, and compared with 30 patients with paranoid-type schizophrenia and 35 normal volunteers. NS predominant schizophrenia showed markedly diminished SoA compared to normal controls and paranoid-type schizophrenia, indicating a completely opposite direction in agency attribution compared with excessive SoA demonstrated in paranoid-type schizophrenia. Reduced SoA was detected in experimental studies of schizophrenia for the first time. According to the optimal cue integration framework, these results indicate that there was no increase in compensatory contributions of the postdictive processes despite the existence of inadequate predictions, contrary to the exaggerated postdictive component in paranoid-type schizophrenia. PMID- 23680466 TI - Affecting coping: does neurocognition predict approach and avoidant coping strategies within schizophrenia spectrum disorders? AB - According to various diathesis-stress models of schizophrenia, life stress plays a defining role in the onset and course of schizophrenia-spectrum disorders. In this regard, individual differences in coping strategies and affective traits, variables related to the management and experience of stress, may play a large role in susceptibility to the disorder and symptom exacerbation. Furthermore, it has been posited that cognitive deficits may limit an individuals' ability to effectively respond to stressful situations. We investigated the relationships between attention, immediate memory, trait negative affect (NA), trait positive affect (PA) and specific coping strategies within three groups: chronic schizophrenia patients (n=27), psychometrically-defined schizotypy (n=89), and schizotypy demographically-matched controls (n=26). As hypothesized affective traits displayed predictable relationships with specific coping strategies, such that NA was associated with the greater use of avoidant coping strategies within the schizophrenia and schizotypy group, while PA was associated with greater use of approach coping styles within all groups. The schizotypy group reported significantly higher levels of NA and also greater use of avoidant coping strategies than both the control and schizophrenia group. As expected group differences were found in trait affect, coping strategies, and cognitive functioning. Importantly, these group differences remained significant even when demographic variables were entered as covariates. Contrary to our expectations, cognitive functioning displayed only a few tenuous relationships with coping strategies within the schizophrenia and schizotypy groups. Overall, results support the notion that affective traits and not cognitive functioning is the best predictor of approach and avoidant coping strategies. PMID- 23680467 TI - The sense of coherence as a predictor of the scope and impact of stigma experiences among people with mental illness. AB - This study explored the role of the sense of coherence (SOC) in predicting the scope and impact of stigma experiences in 229 patients with schizophrenia or affective disorders. Findings revealed that SOC significantly predicted lower levels of stigma, accounting for 13% of the variance in stigma experiences and 4% of the variance in stigma impact, over and above that explained by background characteristics, diagnosis and the psychiatric symptoms of the participants. PMID- 23680468 TI - Lipid peroxidation markers in adult attention deficit hyperactivity disorder: new findings for oxidative stress. AB - Malondialdehyde (MDA) is a reliable marker of lipid peroxidation where paraoxonase and arylesterase are two enzymes against it. Although increased MDA has been previously shown in adults with attention deficit/hyperactivity disorder (A-ADHD), levels of paraoxonase and arylesterase enzymes have not been studied yet. We aimed to determine the status of both MDA level and paraoxonase and arylesterase enzyme activities in A-ADHD patients. A total of 35 adults with ADHD diagnosis according to Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV) criteria and 29 healthy volunteers were included in the study. Serum MDA, paraoxonase and arylesterase levels of the participants were measured. The disease severity of the patients was determined by using Turgay's Adult Attention Deficit Disorder/Attention Deficit Hyperactivity Disorder (ADD/ADHD) DSM IV Based Diagnostic Screening and Rating Scale. The serum MDA level of patients was significantly higher than that of healthy control subjects, whereas their paraoxonase and arylesterase levels were significantly lower. There was no correlation between the levels of biochemical parameters (MDA, paraoxonase and arylesterase) and the disease severity. Sub-types of A-ADHD were similar in terms of these biochemical parameters. Increased lipid peroxidation, a part of oxidative stress, in adults with ADHD appears to be unbuffered by antioxidant enzymes, namely paraoxonase and arylesterase. PMID- 23680469 TI - Increased levels of CD34+ cells are associated in patients with abdominal aortic aneurysms compared with patients with peripheral vascular disease. AB - BACKGROUND: Circulating progenitor cells are integral to vascular health and effectively predict vascular reactivity. CD34 is a known marker of circulating progenitor cells. Few studies have examined the role of CD34+ cells in abdominal aortic aneurysm (AAA) disease and peripheral vascular disease (PVD). The aim of this study was to compare the percentage of CD34+ cells between patients with AAA versus PVD. MATERIALS AND METHODS: We collected peripheral whole blood from AAA or PVD patients. The blood was stained with fluorescently labeled antibodies against CD34 or isotype controls. We collected data using a flow cytometer and analyzed them. We also recorded risk factors such as hypertension, diabetes, total cholesterol, serum white blood cells, serum creatinine, body mass index, blood pressure, statin use, current smoking status, coronary artery disease, cerebral vascular accident, and chronic obstructive pulmonary disease. RESULTS: We enrolled 24 patients in this study (AAA, n = 12; PVD, n = 12). The AAA patients had a greater percentage of CD34+ cells compared with PVD patients. (r = 0.84; P = 0.016). There were no significant risk factors differences between AAA and PVD patients. CONCLUSIONS: Based on CD34+ cell counts, AAA is a less severe vascular disease than PVD. Whether CD34+ cells can serve as a biomarker for risk stratification or a potential therapy warrants further study. PMID- 23680470 TI - Radiochemical synthesis and in vivo evaluation of [18F]AZ11637326: an agonist probe for the alpha7 nicotinic acetylcholine receptor. AB - INTRODUCTION: The alpha-7 nicotinic acetylcholine receptor (alpha7 nAChR) is key in brain communication and has been implicated in the pathophysiology of diseases of the central nervous system. A positron-emitting radioligand targeting the alpha7 nAChR would enable better understanding of a variety of neuropsychiatric illnesses, including schizophrenia and Alzheimer's disease, and could enhance the development of new drugs for these and other conditions. We describe our attempt to synthesize an alpha7 nAChR-selective radiotracer for positron emission tomography (PET). METHODS: We prepared the high-affinity (K(d) = 0.2 nM) alpha7 nAChR agonist, 5'-(2-[(18)F]fluorophenyl)spiro[1-azabicyclo-[2.2.2]octane]-3,2' (3'H)furo[2,3-b]pyridine, [(18)F]AZ11637326, in two steps, a nucleophilic fluorination followed by decarbonylation. We studied [(18)F]AZ11637326 in rodents, including mice lacking alpha7 nAChR, and in non-human primates. RESULTS: [(18)F]AZ11637326 was synthesized in a non-decay-corrected radiochemical yield of 3% from the end of synthesis (90 min) with a radiochemical purity >90% and average specific radioactivity of 140GBq/MUmol (3,781 mCi/MUmol). Modest rodent brain uptake was observed (2-5% injected dose per gram of tissue, depending on specific activity), with studies comparing CD-1 and alpha7 nAChR null mice indicating an element of target-specific binding. Blocking studies in non-human primates did not reveal specific binding within the brain. CONCLUSION: Despite the high affinity and target selectivity of AZ11637326 for alpha7 nAChR in vitro and encouraging rodent studies, receptor-mediated binding could not be demonstrated in non-human primates. Further structural optimization of compounds of this class will be required for them to serve as suitable radiotracers for PET. PMID- 23680471 TI - Building a transplantation physician workforce for growing need: recruitment starts during residency. PMID- 23680472 TI - Mortality rates of human metapneumovirus and respiratory syncytial virus lower respiratory tract infections in hematopoietic cell transplantation recipients. AB - Human metapneumovirus (HMPV), a common respiratory virus, can cause severe disease in pre- and post-hematopoietic cell transplantation (HCT) recipients. We conducted a retrospective cohort analysis in HCT patients with HMPV (n = 23) or respiratory syncytial virus (n = 23) detected in bronchoalveolar lavage samples by reverse transcription PCR between 2006 and 2011 to determine disease characteristics and factors associated with outcome. Mortality rates at 100 days were 43% for both HMPV and respiratory syncytial virus lower respiratory tract disease. Steroid therapy, oxygen requirement >2 L or mechanical ventilation, and bone marrow as cell source were significant risk factors for overall and virus related mortality in multivariable models, whereas the virus type was not. The presence of centrilobular/nodular radiographic infiltrates was a possible protective factor for mechanical ventilation. Thus, HMPV lower respiratory tract disease is associated with high mortality in HCT recipients. Earlier detection in combination with new antiviral therapy is needed to reduce mortality among HCT recipients. PMID- 23680473 TI - Of mice and men. PMID- 23680474 TI - Repetitive hyperbaric oxygen treatment attenuates complete Freund's adjuvant induced pain and reduces glia-mediated neuroinflammation in the spinal cord. AB - Hyperbaric oxygen (HBO) therapy is reported to attenuate pain in both clinical pain conditions and animal pain models, but the underlying mechanism remains to be investigated. Here, we show that 7 daily 60-minute HBO (100% oxygen, 2 atmosphere absolute) treatments effectively and persistently inhibited heat hyperalgesia, mechanical allodynia, and paw edema induced by peripheral injection of complete Freund's adjuvant (CFA). Five daily 60-minute HBO treatments also produced a prolonged reversal effect of the ongoing inflammatory pain. Furthermore, such an HBO treatment reduced CFA-induced activation of glial cells, phosphorylation of mitogen-activated protein kinases, and production of a variety of proinflammatory cytokines (tumor necrosis factor alpha [TNF-alpha], interleukin-1 beta [IL-1beta], and interleukin-6 [IL-6]) and chemokines (monocyte chemoattractant protein-1 [MCP-1], keratinocyte-derived chemokine [KC], and IFN gamma-inducible protein 10 [IP-10]) in the spinal cord. HBO treatment also decreased lipopolysaccharide-induced mRNA expression of these cytokines and chemokines in primary cultures of astrocytes and microglia. In addition, the mRNA expressions of IL-1beta, IL-6, MCP-1, KC, and IP-10 in the inflamed paw skin were decreased by HBO. Taken together, these data suggest that HBO treatment is an effective therapy for inflammatory pain in animals. The inhibition of the neuroinflammation that is mediated by glial cells and inflammatory mediators may, at least in part, contribute to the antinociceptive effect of HBO therapy. PERSPECTIVE: Our results suggest that repetitive HBO treatment attenuates CFA induced pain and reduces glial activation and inflammatory mediators' production. These findings provide evidence of the antinociception effect of HBO on inflammatory pain and characterize some of the underlying mechanisms. PMID- 23680475 TI - Splenectomy increases the survival time of heart allograft via developing immune tolerance. AB - BACKGROUND: The spleen is an active lymphoid organ. The effect of splenectomy on the immune response remains unclear. This study investigated whether splenectomy can induce immune tolerance and has a beneficial role in cardiac allograft. METHODS: Wistar rats were used for heart donors. The Sprague-Dawley (SD) rats designated as the recipients of heart transplantation (HT) were randomly assigned into four groups: sham, splenectomy, HT, splenectomy + HT. The survival of transplanted hearts was assessed by daily checking of abdominal palpation. At various time points after transplantation, the transplanted hearts were collected and histologically examined; the level of CD4+CD25+ T regulatory lymphocytes (Tregs) and rate of lymphocyte apoptosis (annexin-v+ PI+ cells) in the blood were analyzed by using flow cytometric method. RESULTS: 1) Splenectomy significantly prolonged the mean survival time of heart allografts (7 +/- 1.1 days and 27 +/- 1.5 days for HT and splenectomy + HT, respectively; n = 12-14/group, HT vs. splenectomy + HT, p < 0.001); 2) Splenectomy delayed pathological changes (inflammatory cell infiltration, myocardial damage) of the transplanted hearts in splenectomy + HT rats; 3) The level of CD4+CD25+ Tregs in the blood of splenectomized rats was significantly increased within 7 days (2.4 +/- 0.5%, 4.9 +/- 1.3% and 5.3 +/- 1.0% for sham, splenectomy and splenectomy + HT, respectively; n = 15/group, sham vs. splenectomy or splenectomy + HT, p < 0.05) after splenectomy surgery and gradually decreased to baseline level; 4) Splenectomy increased the rate of lymphocyte apoptosis (day 7: 0.3 +/- 0.05%, 3.9 +/- 0.9% and 4.1 +/- 0.9% for sham, splenectomy and splenectomy + HT, respectively; n = 15/group, sham vs. splenectomy or splenectomy + HT, p < 0.05) in a pattern similar to the change of the CD4+CD25+ Tregs in the blood. CONCLUSIONS: Splenectomy inhibits the development of pathology and prolongs the survival time of cardiac allograft. The responsible mechanism is associated with induction of immune tolerance via elevating CD4+CD25+ Tregs and increasing lymphocyte apoptosis. PMID- 23680476 TI - Sex, gender and immunosenescence: a key to understand the different lifespan between men and women? PMID- 23680477 TI - Novel agents for chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is a heterogeneous group of B-cell neoplasm. CLL is typically sensitive to a variety of cytotoxic agents, but relapse frequently occurs with conventional approaches. The treatment of CLL is evolving rapidly with the introduction of novel drugs, such as bendamustine, ofatumumab, lenalidomide, ibrutinib, idelalisib, veltuzumab, XmAb5574, navitoclax, dasatinib, alvespimycin, and TRU-016. This review summarizes the most current clinical experiences with these agents in the treatment of CLL. PMID- 23680478 TI - Intense FDG uptake on PET/CT in the upper and lower respiratory system indicative of Wegener's granulomatosis. AB - Wegener's granulomatosis (WG) is an uncommon systemic vasculitis, which involves the upper and lower respiratory tracts and the kidneys. Because the patients generally present with clinical manifestations that are similar to common diseases, WG may be initially misdiagnosed as infection or malignancy. We report the case of a 55-year-old male presenting with weight loss, cough, hemoptysis, low-grade fever, and pulmonary nodules detected on the thoracic CT scan. Malignancy was initially suspected, so a PET/CT was performed. It demonstrated intense FDG uptake in the upper and lower respiratory system. The diagnosis of WG was based on PET findings, elevated serum levels of inflammatory markers, and the presence of c-ANCA. We consider that the knowledge of FDG-PET/CT findings may help to make an easier and earlier diagnosis of WG. PMID- 23680479 TI - Age-related bone deterioration is diminished by disrupted collagen sensing in integrin alpha2beta1 deficient mice. AB - Collagen binding integrins are of essential importance in the crosstalk between cells and the extracellular matrix. Integrin alpha2beta1 is a major receptor for collagen I, the most abundant protein in bone. In this study we show for the first time that integrin alpha2 deficiency is linked to collagen type I expression in bone. Investigating the femurs of wild type and integrin alpha2beta1 deficient mice, we found that loss of integrin alpha2 results in altered bone properties. Histomorphometric analysis of integrin alpha2 long bones displayed more trabecular network compared to wild type bones. During age related bone loss the integrin alpha2beta1 deficient bones retain trabecular structure even at old age. These findings were supported by functional, biomechanical testing, wherein the bones of integrin alpha2beta1 deficient mice do not undergo age-related alteration of biomechanical properties. These results might be explained by the increased presence of collagen in integrin alpha2beta1 deficient bone. Collagen type I could be detected in higher quantities in the integrin alpha2beta1 deficient bones, forming abnormal, amorphous fibrils. This was linked to higher expression levels of collagen type I and other bone formation related proteins as alkaline phosphatase of integrin alpha2beta1 deficient osteoblasts. Osteoclasts of integrin alpha2beta1 deficient mice did not show any differences. Consequently these results indicate that the absence of integrin alpha2beta1 alleviates the effects of age related bone degradation through over-expression of collagen type I and demonstrate a molecular mechanism how collagen binding integrins might directly impact bone aging. PMID- 23680480 TI - Drug-eluting balloons: the path is made by walking. PMID- 23680481 TI - A case of coronary-vertebral subclavian steal syndrome. PMID- 23680482 TI - Giant left ventricular aneurysm after myocardial infarction. PMID- 23680483 TI - Transient ST-segment elevation and chest pain following percutaneous mitral valvuloplasty. AB - Transient ST-segment elevation occurring in the context of percutaneous cardiac interventions has not been fully characterized. We present a case of an inferior ST-segment elevation associated with angina and hypotension following percutaneous mitral valvuloplasty. Coronary angiography during ST elevation found no abnormalities and no myocardial necrosis was documented. Thus, as the Inoue balloon had been reinflated and overinflated, we suggest that mechanical myocardial compression might be responsible for the transmural transient ischemia observed in some cardiac percutaneous procedures involving balloons or closure devices. PMID- 23680485 TI - Pharmaceutical pictograms: a model for development and testing for comprehension and utility. AB - BACKGROUND: With concerns about the medication literacy skills of patients comes the need to develop various types of information materials that will enhance understanding and drug use. OBJECTIVES: To review pictogram development projects and to propose a model for pharmaceutical pictogram development and testing for comprehension and use. METHODS: Previous efforts in developing specific types of pictograms in engineering and safety as well as in health care and pharmacy are collected and summarized in terms of level of comprehension and recall. The impact of pictogram-enhanced medication information materials on knowledge acquisition, information retention, and adherence is assessed. RESULTS AND CONCLUSIONS: Pictograms are a key component in re-designing medication information to improve comprehension, recall, and adherence. Many types of pictograms still produce low levels of comprehension and the impact of pictograms on medication knowledge is inconsistent. Prior training through patient counseling on the intended meaning and use of pictograms greatly increases their effectiveness. A model for the development and testing of pictograms and pictogram sequences for comprehension and use in medication information is presented and discussed. PMID- 23680484 TI - Genetic characterization of moaB mutants of Escherichia coli. AB - The moaABCDE operon of Escherichia coli encodes enzymes essential for the biosynthesis of the molybdenum cofactor (Moco). However, the role of the moaB gene within this operon has remained enigmatic. Here, we have investigated the effect of moaB defects on two phenotypes diagnostic for Moco-deficiency: chlorate resistance and sensitivity to the base analog 6-N-hydroxylaminopurine (HAP). We found that transposon insertions in moaB caused partial Moco-deficiency associated with chlorate-resistance, but not for HAP-sensitivity. On the other hand, in-frame deletions of moaB, or moaB overexpression, had no effect on either phenotype. Our combined data are consistent with the lack of any role for MoaB in Moco biosynthesis in E. coli. PMID- 23680486 TI - Mechanisms underlying global stereopsis in fovea and periphery. AB - To better understand the pooling properties underlying global stereopsis we examined the relationship between carrier luminance spatial frequency and modulator disparity spatial frequency. Thresholds for detecting global sinusoidal disparity corrugations of spatially band-pass noise were measured as a function of modulator disparity spatial frequency for both centrally and peripherally located stimuli using a standard 2-IFC task. We found a characteristic relationship that depended on modulator disparity spatial frequency. At high modulator disparity spatial frequencies (>1c/d), there is an optimal ratio of around 2.6, whereas at low modulator disparity spatial frequencies, there is an optimal absolute carrier luminance spatial frequency (i.e., 3c/d). In the periphery, vision is restricted to modulator disparity spatial frequencies below 1c/d and, as a consequence, following the above rule, there is an optimum absolute carrier luminance spatial frequency that reduces in spatial frequency with increasing eccentricity. This finding is consistent with there being more than one channel processing global stereo that is subsequently confirmed using a 2*2 AFC detection/discrimination paradigm. Furthermore, because of the different carrier/modulator relationships in central and peripheral vision, peripheral global stereo cannot be simply related to central global stereo by a scaling factor and thus cannot be simply due to cortical magnification, as originally thought. PMID- 23680487 TI - Visible light-driven CdSe nanotube array photocatalyst. AB - Large-scale CdSe nanotube arrays on indium tin oxide (ITO) glass have been synthesized using ZnO nanorod template. The strong visible light absorption in CdSe, its excellent photoresponse, and the large surface area associated with the tubular morphology lead to good visible light-driven photocatalytic capability of these nanotube arrays. Compared to freestanding nanoparticles, such one-piece nanotube arrays on ITO make it very convenient for catalyst recycling after their usage. PMID- 23680488 TI - Intakes of calcium, vitamin D, and dairy servings and dental plaque in older Danish adults. AB - BACKGROUND: To investigate whether intakes of calcium and dairy-servings within recommendations were associated with plaque score when allowing for vitamin D intakes. METHODS: In this cross-sectional study, including 606 older Danish adults, total dietary calcium intake (mg/day) was classified as below vs. within recommendations and dairy intake as <3 vs. >=3 servings/ d. Dental plaque, defined as the percentage of tooth surfaces exhibiting plaque, was classified as < median vs. >=median value (9.5%). Analyses were stratified by lower and higher (>=6.8 MUg/d) vitamin D intake. FINDINGS: Intakes of calcium (OR = 0.53; 95% CI = 0.31-0.92) and dairy servings (OR = 0.54; 95% CI = 0.33-0.89) within recommendations were significantly associated with lower plaque score after adjustments for age, gender, education, intakes of alcohol, sucrose and mineral supplements, smoking, diseases, number of teeth, visits to the dentist, use of dental floss/tooth pick and salivary flow, among those with higher, but not lower, vitamin D intake. CONCLUSION: Intakes of calcium dairy-servings within recommendations were inversely associated with plaque, among those with higher, but not lower, vitamin D intakes. Due to the cross-sectional nature of the study, it is not possible to infer that this association is causal. PMID- 23680489 TI - N-acylated glucosamines for bone and joint disorders: effects of N-butyryl glucosamine on ovariectomized rat bone. AB - The benefit of glucosamine (GlcN) in bone and joint disorders remains controversial. N-acetylation and other N-acylations of GlcN alter its biological properties fundamentally. We have shown previously that N-butyryl glucosamine (GlcNBu) preserved strikingly the subchondral bone structure in a destructive arthritis rat model. Here, we examine whether GlcNBu preserves bone in the ovariectomized (OVX) rat, a model for postmenopausal osteoporosis. Rats were randomized into 4 groups: group 1, sham OVX glucose (Glc) fed; group 2, sham OVX GlcNBu fed; group 3, OVX Glc fed; and group 4, OVX GlcNBu fed. A single, oral, 200-mg/kg dose of GlcNBu or Glc was administered daily for 6 months. Bone mineral content (BMC) and bone mineral density, and biomechanical properties of the femurs and spines were determined by standardized techniques. Two-way analysis of variance with a Bonferroni post hoc test was used for statistical analysis. Ovariectomy in group 3 resulted either in significant or highly significant effects in a number of the tests. For spinal BMCs the interaction between GlcNBu and OVX was significant. For the femurs, this interaction was also seen in energy to failure, and ultimate displacement and ultimate strain tests. In general, ovariectomy was necessary to show significant preventive effects of GlcNBu on mineral content and some biomechanical properties. We conclude that GlcNBu feeding in the OVX rat preserves bone mineral and some biomechanical properties. Translationally, GlcNBu can be positioned between nutriceuticals and pharmaceuticals for the prevention and treatment of osteoporosis. Advantages include low production costs and a favorable safety profile. PMID- 23680490 TI - Inhibition of phagocytosis and lysosomal acidification suppresses neurotoxic prion peptide-induced NALP3 inflammasome activation in BV2 microglia. AB - Prion diseases are neurodegenerative disorders characterized by the accumulation of misfolded prion protein. In a previous study, we showed that neurotoxic prion peptide (PrP106-126) induced NALP3 inflammasome activation in mouse primary and immortalized microglia. In the present work, we examined the relevance of phagocytosis and lysosomal acidification to the activation of the NALP3 inflammasome in PrP106-126-stimulated microglia. Our results showed that the inhibition of phagocytosis or lysosomal acidification significantly reduced IL 1beta and IL-18 production, downregulated NALP3 and ASC expression, and decreased the expression of proinflammatory factors. We concluded that phagocytosis and lysosomal acidification are necessary for PrP106-126-induced NALP3 activation in BV2 cells. PMID- 23680491 TI - Neck dissection with the harmonic scalpel in patients with squamous cell carcinoma of the oral cavity. AB - Our purpose was to evaluate the use of the Harmonic scalpel in neck dissections. MATERIAL AND METHODS: We conducted a randomized prospective intervention study to compare the Harmonic scalpel (32 patients) with the conventional technique (31 patients). RESULTS: Operative time was lowered by 64 min (p < 0.001) and 7.5 min (p = 0.367); blood lost during surgery was lowered by 80.5 ml (p < 0.001) and 76.6 ml (p < 0.001); the length of time the drains were kept in place was lowered by 1.3 days (p < 0.001) and 1.5 days (p < 0.01); and the volume of drainage was lower by 228.7 ml (p < 0.001) and 187.6 ml (p < 0.01) in selective and comprehensive neck dissections respectively in patients treated with the Harmonic scalpel. CONCLUSIONS: The Harmonic scalpel shortens operative time in selective dissections. It reduces blood loss during surgery; time drains are kept in place and the amount of drainage in comprehensive and selective neck dissections. PMID- 23680492 TI - DNA asymmetry and cell fate regulation in stem cells. AB - The semi-conservative nature of DNA replication has suggested that identical DNA molecules within chromatids are inherited by daughter cells after cell division. Numerous reports of non-random DNA segregation in prokaryotes and eukaryotes suggest that this is not always the case, and that epigenetic marks on chromatids, if not the individual DNA strands themselves, could have distinct signatures. Their selective distribution to daughter cells provides a novel mechanism for gene and cell fate regulation by segregating chromatids asymmetrically. Here we highlight some examples and potential mechanisms that can regulate this process. We propose that cellular asymmetry is inherently present during each cell division, and that it provides an opportunity during each cell cycle for moderating cell fates. PMID- 23680493 TI - The human microbiome is a source of therapeutic drug targets. AB - It was appreciated early in drug discovery that the microbiota play an important role in the efficacy of therapeutic compounds. Indeed, the first antibiotic sulfa drugs were shown in the 1940s to be transformed by the bacteria that encode what we now call the intestinal microbiome. Here we briefly review the roles symbiotic bacteria play in the chemistry of human health, and we focus on the emerging appreciation that specific enzyme targets expressed by microbial symbiotes can be selectively disrupted to achieve clinical outcomes. We conclude that components of the microbiome should be considered 'druggable targets,' and we suggest that our rapidly evolving understanding of the chemical biology of mammalian-microbial symbiosis will translate into improved human health. PMID- 23680495 TI - Viral endomyocardial infection in the 1st year post transplant is associated with persistent inflammation in children who have undergone cardiac transplant. AB - BACKGROUND: Viral genome in cardiac allograft has been associated with early graft loss in children who have undergone cardiac transplant from unknown mechanisms. METHODS: This study is a retrospective review of children who have undergone cardiac transplant at a single institution from 1/2004 to 5/2008. Patients underwent cardiac catheterisations with endomyocardial biopsies to evaluate for rejection--graded on Texas Heart Institute scale--and the presence of virus by polymerase chain reaction. Patients with virus identified during the first year post transplant were compared at 1 year post transplant with virus free patients. RESULTS: The cohort comprised 59 patients, and the median age at transplant was 5.1 years. Viral genomes were isolated from 18 (31%) patients. The PCR + group had increased inflammation on endomyocardial biopsies, with a median score of 4 (ISHLT IR) versus 1 (ISHLT 1R) in the PCR--group (p = 0.014). The PCR + group had a similar cardiac index (median 3.7 ml/min/m(2)), pulmonary capillary wedge pressure (median 10 mmHg), and pulmonary vascular resistance index (median 1.7 U m(2)) comparatively. PCR + patients were more likely to have experienced an episode of rejection (p = 0.004). CONCLUSIONS: Children who developed viral endomyocardial infections after a cardiac transplant have increased allograft inflammation compared with virus-free patients. However, the haemodynamic profile is similar between the groups. The ongoing subclinical inflammation may contribute to the early graft loss associated with these patients. PMID- 23680496 TI - The effect of customised and sham foot orthoses on plantar pressures. AB - BACKGROUND: The effectiveness of foot orthoses has been evaluated in many clinical trials with sham foot orthoses used as the control intervention in at least 10 clinical trials. However, the mechanical effects and credibility of sham orthoses has been rarely quantified. This study aimed to: (i) compare the effects on plantar pressures of three sham foot orthoses to a customised foot orthosis, and (ii) establish the perceived credibility and the expected benefit of each orthotic condition. METHODS: Thirty adults aged between 18 and 51 participated in this study. At 0 and 4 weeks, plantar pressure data were collected for the heel, midfoot and forefoot using the pedar((r))-X in-shoe system for the following five randomly assigned conditions: (i) shoe alone, (ii) customised foot orthosis, (iii) contoured polyethylene sham foot orthosis, (iv) contoured EVA sham foot orthosis, and (v) flat EVA sham foot orthosis. At the initial data collection session, each participant completed a Credibility/Expectancy Questionnaire (CEQ) to determine the credibility and expected benefit of each orthotic condition. RESULTS: Compared to the shoe alone at week 0, the contoured polyethylene sham orthosis was the only condition to not significantly effect peak pressure at any region of the foot. In contrast, the contoured EVA sham orthosis, the flat EVA sham orthosis and the customised orthosis significantly reduced peak pressure at the heel. At the medial midfoot, all sham orthoses provided the same effect as the shoe alone, which corresponded to effects that were significantly different to the customised orthosis. There were no differences in peak pressure between conditions at the other mask regions, the lateral midfoot and forefoot. When the conditions were compared at week 4, the differences between the conditions were generally similar to the findings observed at week 0. With respect to credibility and expected benefit, all orthotic conditions were considered the same with the exception of the contoured polyethylene sham orthosis, which was perceived as being less credible and less likely to provide benefits. CONCLUSION: The findings of this study indicate that all of the sham orthoses tested provided the same effect on plantar pressures at the midfoot and forefoot as a shoe alone. However, the contoured EVA sham orthosis and the flat EVA sham orthosis significantly reduced peak pressure under the heel, which was similar to the customised orthosis. In contrast, the contoured polyethylene sham orthosis had no significant effect on plantar pressure and was comparable to the shoe alone at all regions of the foot. Hence, lower plantar pressures were found under the heel with some sham orthoses, but not with others. Importantly, participants perceived the polyethylene sham orthosis - the sham that had no effect on plantar pressure to be the least credible orthosis and the least likely to provide benefits. This may be critical for the design of future clinical trials as it may introduce confounding effects that produce inaccurate results. These findings provide some evidence for the mechanical effects, treatment credibility and expected benefit of sham foot orthoses, which should be considered when they are used as a control intervention in a clinical trial. PMID- 23680494 TI - A disintegrin and metalloproteinase-12 (ADAM12): function, roles in disease progression, and clinical implications. AB - BACKGROUND: A disintegrin and metalloproteinase-12 (ADAM12) is a member of the greater ADAM family of enzymes: these are multifunctional, generally membrane bound, zinc proteases for which there are forty genes known (21 of these appearing in humans). ADAM12 has been implicated in the pathogenesis of various cancers, liver fibrogenesis, hypertension, and asthma, and its elevation or decrease in human serum has been linked to these and other physiological/pathological conditions. SCOPE: In this review, we begin with a brief overview of the ADAM family of enzymes and protein structure. We then discuss the role of ADAM12 in the progression and/or diagnosis of various disease conditions, and we will conclude with an exploration of currently known natural and synthetic inhibitors. MAJOR CONCLUSION: ADAM12 has potential to emerge as a successful drug target, although targeting the metalloproteinase domain with any specificity will be difficult to achieve due to structural similarity between the members of the ADAM and MMP family of enzymes. Overall, more research is required to establish ADAM12 being as a highly desirable biomarker and drug target of different diseases, and their selective inhibitors as potential therapeutic agents. GENERAL SIGNIFICANCE: Given the appearance of elevated levels of ADAM12 in various diseases, particularly breast cancer, our understanding of this enzyme both as a biomarker and a potential drug target could help make significant inroads into both early diagnosis and treatment of disease. PMID- 23680497 TI - The effects of risk perception and flight experience on airline pilots' locus of control with regard to safety operation behaviors. AB - The primary objective of this paper was to integrate two research traditions, social cognition approach and individual state approach, and to understand the relationships between locus of control (LOC), risk perception, flight time, and safety operation behavior (SOB) among Chinese airline pilots. The study sample consisted of 193 commercial airline pilots from China Southern Airlines Ltd. The results showed that internal locus of control directly affected pilot safety operation behavior. Risk perception seemed to mediate the relationship between locus of control and safety operation behaviors, and total flight time moderated internal locus of control. Thus, locus of control primarily influences safety operation behavior indirectly by affecting risk perception. The total effect of internal locus of control on safety behaviors is larger than that of external locus of control. Furthermore, the safety benefit of flight experience is more pronounced among pilots with high internal loci of control in the early and middle flight building stages. Practical implications for aviation safety and directions for future research are also discussed. PMID- 23680498 TI - Animal models of pain: best behavioral analysis for better translational research. PMID- 23680499 TI - All that is obvious is not clear: what is the origin of throbbing pain in migraine? PMID- 23680500 TI - Is the pie-crusting technique safe for MCL release in varus deformity correction in total knee arthroplasty? AB - Established for lateral release in TKA, the pie-crusting technique has not been studied for the medial collateral ligament (MCL). In cadaveric knees the MCL was release with a pie-crusting technique in one and traditional technique in the contralateral knee. Along with a control group, each MCL was subjected to mechanical testing. The stiffness, force and stress required to cause ligament elongation were less in the pie-crusting group (p < 0.05) compared to the control group, but were not statistically different than the traditional group. The pie crusting group demonstrated a characteristic "stair-step" failure mode at the joint line, whereas the traditional group failed elastically at the tibial insertion. MCL pie-crusting is likely technique dependent since failure occurs within the ligament itself and further study is warranted. PMID- 23680501 TI - One-component revision of failed hip resurfacing from adverse reaction to metal wear debris. AB - This study assessed the results of 90 one-component revisions for failed hip resurfacing due to adverse reaction to metal wear debris (76 acetabular, 14 femoral). Patients with a femoral head size 40-45 mm (n=33) received a two-piece titanium meshed shell with a cross-linked polyethylene liner and patients with femoral head size 46-54 mm (n=43) received metal-on-metal components. Patients with femoral head size>45 mm who wished a metal-polyethylene bearing received a dual mobility femoral prosthesis. The mean follow-up was 61 months and the procedure was successful in 97% of the patients. Three failures required re revision; there was one deep infection. There were no dislocations. One-component revision is a reasonable alternative to revision to total hip arthroplasty. PMID- 23680502 TI - Revision total joint arthroplasty: the epidemiology of 63,140 cases in New York State. AB - Recent evidence suggests a substantial rise in the number of revision total joint arthroplasty (TJA) procedures performed. The New York State SPARCS inpatient database was utilized to identify revision total shoulder, knee, and hip arthroplasty procedures between 1993 and 2010. Yearly incidence and related epidemiology were analyzed. A total of 1,806 revision TSA, 26,080 revision TKA, and 35,254 revision THA cases were identified. The population-based incidence of these procedures increased 288%, 246%, and 44% respectively (P<0.001). Revision burden for hip arthroplasty decreased from 16.1% in 2001 to 11.5% in 2010 (P<0.001). The rates of revision TSAs and TKAs increased at a substantially faster rate than that of revision THAs. Revision burden for hip arthroplasty steadily has decreased since 2001. PMID- 23680503 TI - Supracondylar periprosthetic fractures of the knee in the elderly patients: a comparison of treatment using allograft-implant composites, standard revision components, distal femoral replacement prosthesis. AB - The following study is a review of 3 different treatment methods for treating comminuted distal periprosthetic femur fractures in 23 patients over the age of 70 (average age 80, range 70-90). Reconstruction techniques included 7 allograft prosthesis composite (APC), 9 revision systems (RSA), and 7 distal femur endoprosthesis (DFR). Operative time and blood loss were found to be significantly less in RSA and DFR patients compared to the APC patients. Hospital stay was shortest for the DFR patients. No significant difference was found in the 6-week or 6-month Knee Society Scores. Our preliminary results demonstrate that in experienced hands, distal femur endoprosthesis should be considered in patients with advanced age and poor bone quality who require early mobilization. PMID- 23680504 TI - Current status of modern fully porous coated metal-on-metal hip resurfacing arthroplasty. AB - Between March 2007 and July 2010, 1000 consecutive fully porous coated hip resurfacing arthroplasties (HRA) were performed by a single surgeon in 871 patients. The average length of follow-up was 3 +/- 1 years. Three cases (0.3%) in three patients showed adverse wear related failures. Another 17 (1.7%) failures were identified at the time of this study. Using any failure of any component as the endpoint, the survivorship rate was 98.8% at two years and 97.4% at five years. Excluding the failed cases, all components were radiographically stable; there was only one partial femoral radiolucency seen. The clinical and radiological outcomes of this fully porous coated hip resurfacing were comparable to, if not better than, those reported by others using hybrid fixation methods at five years post-operatively. PMID- 23680505 TI - The impact of leg length discrepancy on clinical outcome of total hip arthroplasty: comparison of four measurement methods. AB - In a single-surgeon series of 119 patients with unilateral primary uncemented total hip arthroplasty, four leg-length discrepancy measurement methods (absolute, relative, trochanteric, standardized-trochanteric) were analyzed for their impact on WOMAC score, Oxford Hip Score and self-perceived leg-length discrepancy. After adjustment for age, gender and BMI, postoperative WOMAC scores correlated only with clinical absolute measurements of leg elongation (P=0.05). Self-perceived leg-length discrepancy corresponded best to the clinically measured relative leg-length discrepancy (11 mm perceived vs. 7 mm unperceived; P=0.04) while there was no significant correspondence with radiographic measurements or leg elongation magnitudes. Within the <10 mm range of mean postoperative leg length discrepancy in the studied series, its impact on the overall clinical satisfaction was detectable but not considerable. PMID- 23680506 TI - Impact of a hospital-level intervention to reduce heart disease overreporting on leading causes of death. AB - INTRODUCTION: The quality of cause-of-death reporting on death certificates affects the usefulness of vital statistics for public health action. Heart disease deaths are overreported in the United States. We evaluated the impact of an intervention to reduce heart disease overreporting on other leading causes of death. METHODS: A multicomponent intervention comprising training and communication with hospital staff was implemented during July through December 2009 at 8 New York City hospitals reporting excessive heart disease deaths. We compared crude, age-adjusted, and race/ethnicity-adjusted proportions of leading, underlying causes of death reported during death certification by intervention and nonintervention hospitals during preintervention (January-June 2009) and postintervention (January-June 2010) periods. We also examined trends in leading causes of death for 2000 through 2010. RESULTS: At intervention hospitals, heart disease deaths declined by 54% postintervention; other leading causes of death (ie, malignant neoplasms, influenza and pneumonia, cerebrovascular disease, and chronic lower respiratory diseases) increased by 48% to 232%. Leading causes of death at nonintervention hospitals changed by 6% or less. In the preintervention period, differences in leading causes of death between intervention and nonintervention hospitals persisted after controlling for race/ethnicity and age; in the postintervention period, age accounted for most differences observed between intervention and nonintervention hospitals. Postintervention, malignant neoplasms became the leading cause of premature death (ie, deaths among patients aged 35-74 y) at intervention hospitals. CONCLUSION: A hospital-level intervention to reduce heart disease overreporting led to substantial changes to other leading causes of death, changing the leading cause of premature death. Heart disease overreporting is likely obscuring the true levels of cause-specific mortality. PMID- 23680507 TI - Community-based participatory research: its role in future cancer research and public health practice. AB - The call for community-based participatory research approaches to address cancer health disparities is increasing as concern grows for the limited effectiveness of existing public health practice and research in communities that experience a disparate burden of disease. A national study of participatory research projects, Research for Improved Health, funded by the National Institutes of Health (2009 2013), identified 64 of 333 projects focused on cancer and demonstrated the potential impact participatory approaches can have in reducing cancer disparities. Several projects highlight the success of participatory approaches to cancer prevention and intervention in addressing many of the challenges of traditional practice and research. Best practices include adapting interventions within local contexts, alleviating mistrust, supporting integration of local cultural knowledge, and training investigators from communities that experience cancer disparities. The national study has implications for expanding our understanding of the impact of participatory approaches on alleviating health disparities and aims to enhance our understanding of the barriers and facilitators to effective community-based participatory research. PMID- 23680508 TI - Smoke-free rules and secondhand smoke exposure in homes and vehicles among US adults, 2009-2010. AB - INTRODUCTION: An increasing number of US states and localities have implemented comprehensive policies prohibiting tobacco smoking in all indoor areas of public places and worksites. However, private settings such as homes and vehicles remain a major source of exposure to secondhand smoke (SHS) for many people. This study assessed the prevalence and correlates of voluntary smoke-free rules and SHS exposure in homes and vehicles among US adults. METHODS: We obtained data from the 2009-2010 National Adult Tobacco Survey, a landline and cellular-telephone survey of adults aged 18 years or older residing in the 50 US states or the District of Columbia. We calculated national and state estimates of smoke-free rules and past-7-day SHS exposure in homes and vehicles and examined national estimates by sex, age, race/ethnicity, and education. RESULTS: The national prevalence of voluntary smoke-free home rules was 81.1% (state range, 67.9% 92.9%), and the prevalence of household smoke-free vehicle rules was 73.6% (state range, 58.6%-85.8%). Among nonsmokers, the prevalence of SHS exposure was 6.0% in homes (state range, 2.4%-13.0%) and 9.2% in vehicles (state range, 4.8%-13.7%). SHS exposure among nonsmokers was greatest among men, younger adults, non Hispanic blacks, and those with a lower level of education. CONCLUSION: Most US adults report having voluntary smoke-free home and vehicle rules; however, millions of people remain exposed to SHS in these environments. Disparities in exposure also exist among certain states and subpopulations. Efforts are needed to warn about the dangers of SHS and to promote voluntary smoke-free home and vehicle rules. PMID- 23680509 TI - Cooperative strategies to develop effective stroke and heart attack awareness messages in rural american Indian communities, 2009-2010. AB - INTRODUCTION: National initiatives to improve the recognition of heart attack and stroke warning signs have encouraged symptomatic people to seek early treatment, but few have shown significant effects in rural American Indian (AI) communities. METHODS: During 2009 and 2010, the Montana Cardiovascular Health Program, in collaboration with 2 tribal health departments, developed and conducted culturally specific public awareness campaigns for signs and symptoms of heart attack and stroke via local media. Telephone surveys were conducted before and after each campaign to evaluate the effectiveness of the campaigns. RESULTS: Knowledge of 3 or more heart attack warning signs and symptoms increased significantly on 1 reservation from 35% at baseline to 47% postcampaign. On the second reservation, recognition of 2 or more stroke signs and symptoms increased from 62% at baseline to 75% postcampaign, and the level of awareness remained at 73% approximately 4 months after the high-intensity campaign advertisements ended. Intent to call 9-1-1 did not increase in the heart attack campaign but did improve in the stroke campaign for specific symptoms. Recall of media campaigns on both reservations increased significantly from baseline to postcampaign for both media outlets (ie, radio and newspaper). CONCLUSION: Carefully designed, culturally specific campaigns may help eliminate disparities in the recognition of heart attack and stroke warning signs in AI communities. PMID- 23680510 TI - Intra- and inter-molecular hydrogen bonds, conformation and vibrational characteristics of hydrazo-group in 5-nitro-2-(2-phenylhydrazinyl)pyridine and its 3-, 4- or 6-methyl isomers. AB - Syntheses of 5-nitro-2-(2-phenylhydrazinyl)pyridine (5-nitro-2 phenylhydrazopyridine), 3-methyl-5-nitro-2-(2-phenylhydrazinyl)pyridine (3-methyl 5-nitro-2-phenylhydrazopyridine), 4-methyl-5-nitro-2-(2-phenylhydrazinyl)pyridine (4-methyl-5-nitro-2-phenylhydrazopyridine) and 6-methyl-5-nitro-2-(2 phenylhydrazinyl)pyridine (6-methyl-5-nitro-2-phenylhydrazopyridine) have been described. Their IR and Raman spectra have been measured and analyzed in terms of DFT quantum chemical calculations. The 6-311G(2d,2p) basis set with the B3LYP functional has been used to discuss the optimized structure and vibrational spectra. The vibrational characteristics of the hydrazo-bond have been reported with their relation to the inter- and intra-molecular hydrogen bonds formed in the studied systems. The role and influence of substitution position of the methyl chromophore on the structure and vibrational data have been discussed. PMID- 23680511 TI - Spectral and thermal characterization of 3-acetyl-5-azophenyl-4-hydroxy-6-methyl pyran-2-one and its metal complexes. AB - Five chelates of 3-acetyl-5-azophenyl-4-hydroxy-6-methyl-pyran-2-one (phenylazo dehydroacetic acid) with Cr(III), Fe(III), Ni(II), Cu(II) and Zn(II) have been synthesized and characterized by elemental analysis, magnetic susceptibility measurements, electronic, (1)H NMR, FAB mass, IR-spectral and thermal (TG/DTG) analytical techniques. In the present work it has been found that oxygen of the deprotonated OH group and one of the azo-nitrogens of the ligand take part in coordination. The Cr(III), Fe(III) and Ni(II) complexes were found to be having octahedral geometry and the Cu(II) and Zn(II) tetrahedral. PMID- 23680512 TI - Electron paramagnetic resonance studies of gamma-irradiated DL-alanine ethyl ester hydrochloride, L-theanine and L-glutamic acid dimethyl ester hydrochloride. AB - The electron paramagnetic resonance (EPR) of gamma irradiated powders of DL alanine ethyl ester hydrochloride, L-theanine and L-glutamic acid dimethyl ester hydrochloride were investigated at room temperature. The observed paramagnetic species were attributed to the CH3CHCOOC2H5, -CH2CHCOOH and -CH2CHCOOCH3 radicals, respectively. Hyperfine structure constants and g-values were determined for these three radicals. Some spectroscopic properties and suggestions concerning the possible structure of the radicals were also discussed. PMID- 23680513 TI - Theoretical studies of the electronic spectrum of tellurium monosulfide. AB - Ab initio based multireference singles and doubles configuration interaction (MRDCI) study including spin-orbit coupling is carried out to explore the electronic structure and spectroscopic properties of tellurium monosulfide (TeS) molecule by employing relativistic effective core potentials (RECP) and suitable Gaussian basis sets of the constituent atoms. Potential energy curves correlating with the lowest and second dissociation limit are constructed and spectroscopic constants (T(e), r(e), and omega(e)) of several low-lying bound Lambda-S electronic states up to 3.68 eV of energy are computed. The binding energies and electric dipole moments (MU(e)) of the ground and the low-lying excited Lambda-S states are also computed. The effects of the spin-orbit coupling on the electronic spectrum of the species are studied in details and compared with the available data. The transition probabilities of some dipole-allowed and spin forbidden transitions are computed and radiative lifetimes of some excited states at lowest vibrational level are estimated from the transition probability data. PMID- 23680514 TI - Profile measurement of concave spherical mirror and a flat mirror using a high speed nanoprofiler. AB - Ultraprecise aspheric mirrors that offer nanofocusing and high coherence are indispensable for developing third-generation synchrotron radiation and X-ray free-electron laser sources. In industry, the extreme ultraviolet (wavelength: 13.5 nm) lithography used for high-accuracy aspheric mirrors is a promising technology for fabricating semiconductor devices. In addition, ultraprecise mirrors with a radius of curvature of less than 10 mm are needed in many digital video instruments. We developed a new type of nanoprofiler that traces the normal vector of a mirror's surface. The principle of our measuring method is that the normal vector at each point on the surface is determined by making the incident light beam on the mirror surface and the reflected beam at that point coincide, using two sets of two pairs of goniometers and one linear stage. From the acquired normal vectors and their coordinates, the three-dimensional shape is calculated by a reconstruction algorithm. The characteristics of the measuring method are as follows: the profiler uses the straightness of laser light without using a reference surface. Surfaces of any shape can be measured, and there is no limit on the aperture size. We calibrated this nanoprofiler by considering the system error resulting from the assembly error and encoder scale error, and evaluated the performance at the nanometer scale. We suppressed the effect of random errors by maintaining the temperature in a constant-temperature room within +/-0.01 degrees C. We measured a concave spherical mirror with a radius of curvature of 400 mm and a flat mirror and compared the results with those obtained using a Fizeau interferometer. The profiles of the mirrors were consistent within the range of system errors. PMID- 23680516 TI - A rare cause for a neonatal cystic abdominal mass. AB - Intrauterine ovarian torsion is a rare event, but it is a possible cause for unilateral ovarian aplasia. Most commonly the ovary undergoes autolysis after torsion so that no tissue or remnants can be discovered on the involved side. We report a rare case of unilateral intrauterine torsion followed by autoamputation and abdominal reimplantation resulting in an intra-abdominal complex cystic mass with a review of the literature. PMID- 23680517 TI - Barbed versus standard suture: a randomized trial for laparoscopic vaginal cuff closure. AB - STUDY OBJECTIVE: To compare closure times, cuff healing, and postoperative dyspareunia between barbed and traditional sutures during laparoscopic total hysterectomy. DESIGN: A randomized clinical trial (Canadian Task Force classification I). SETTING: A university hospital. PATIENTS: Sixty-three women undergoing total laparoscopic hysterectomy. INTERVENTIONS: Total laparoscopic hysterectomy was performed using standard techniques. The vaginal cuff closure method was randomized to barbed suture (Quill; Angiotech Pharmaceuticals, Inc., Vancouver, Canada) or standard suture (Vicryl; Ethicon Inc., Somerville, NJ). The time required for cuff closure was documented. Patients were examined postoperatively to assess cuff healing, and a standardized sexual function questionnaire was administered preoperatively and at 3 months postoperatively. MEASUREMENTS AND MAIN RESULTS: The mean vaginal cuff closure time was 10.4 minutes versus 9.6 minutes in the barbed versus standard suture group (p = .51). Cuff healing appeared similar between the 2 groups. Rates of dyspareunia, partner dyspareunia, and sexual function were similar in both groups at 3 months postoperatively. Vaginal cuff closure times were significantly faster among attendings compared with residents/fellows (7.1 vs. 12.8 minutes, respectively; p < .0001). The study was designed to have a statistical power of 80% to detect a difference of 5 minutes in cuff closure time between the 2 groups (alpha level of 0.05). CONCLUSION: Laparoscopic vaginal cuff closure times are similar when using barbed sutures and braided sutures. PMID- 23680518 TI - Cesarean scar defects: an underrecognized cause of abnormal uterine bleeding and other gynecologic complications. AB - The gynecologic sequelae due to deficient uterine scar healing after cesarean section are only recently being identified and described. These include conditions such as abnormal bleeding, pelvic pain, infertility, and cesarean scar ectopic pregnancy, as well as a potentially higher risk of complications and difficulties during gynecologic procedures such as uterine evacuation, hysterectomy, endometrial ablation, and insertion of an intrauterine device. The proposed mechanism of abnormal uterine bleeding is a pouch or "isthmocele" in the lower uterine segment that causes delayed menstrual bleeding. The prevalence of symptomatic or clinically relevant cesarean scar defects (CSDs) ranges from 19.4% to 88%. Possible risk factors for CSD include number of cesarean sections, uterine position, labor before cesarean section, and surgical technique used to close the uterine incision. There are no accepted guidelines for the diagnostic criteria of CSD. We propose that a CSD be defined on transvaginal ultrasound or saline infusion sonohysterography as a triangular hypoechoic defect in the myometrium at the site of the previous hysterotomy. We also propose a classification system to aid in standardized classification for future research. Surgical techniques for repair of CSD include laparoscopic excision, resectoscopic treatment, vaginal revision, and endometrial ablation. PMID- 23680515 TI - Neural melanocortin receptors in obesity and related metabolic disorders. AB - Obesity is a global health issue, as it is associated with increased risk of developing chronic conditions associated with disorders of metabolism such as type 2 diabetes and cardiovascular disease. A better understanding of how excessive fat accumulation develops and causes diseases of the metabolic syndrome is urgently needed. The hypothalamic melanocortin system is an important point of convergence connecting signals of metabolic status with the neural circuitry that governs appetite and the autonomic and neuroendocrine system controling metabolism. This system has a critical role in the defense of body weight and maintenance of homeostasis. Two neural melanocortin receptors, melanocortin 3 and 4 receptors (MC3R and MC4R), play crucial roles in the regulation of energy balance. Mutations in the MC4R gene are the most common cause of monogenic obesity in humans, and a large literature indicates a role in regulating both energy intake through the control of satiety and energy expenditure. In contrast, MC3Rs have a more subtle role in energy homeostasis. Results from our lab indicate an important role for MC3Rs in synchronizing rhythms in foraging behavior with caloric cues and maintaining metabolic homeostasis during periods of nutrient scarcity. However, while deletion of the Mc3r gene in mice alters nutrient partitioning to favor accumulation of fat mass no obvious role for MC3R haploinsufficiency in human obesity has been reported. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. PMID- 23680519 TI - Laparoscopic-assisted uterovaginal anastomosis for uterine cervix atresia with vaginal aplasia using a silicone stent lined with acellular porcine small intestinal submucosa graft inserted using a 16F Foley catheter. AB - Herein is reported a novel technique for cervical reconstruction of congenital cervicovaginal atresia. The patient was a 16-year-old girl with congenital atresia of the cervix and vagina, didelphic uterus, and right hematosalpinx. At laparoscopic-assisted creation of a neocervix, a silicone stent was inserted using a 16F Foley catheter and lined with an acellular porcine small intestinal submucosa graft under ultrasound guidance. At 3-month clinical follow-up after placement of the stent, the patient had regular menstrual flow. The neocervix was completely mucosalized on the inner surface at 4 months after surgery. There were no complications related to the silicone stent or the cervical stent. Cervical reconstruction using a vaginal mucosa-lined silicone stent is accessible and effective, and provides an alternative option to preserve reproductive potential in patients with cervicovaginal atresia. PMID- 23680520 TI - Surgical outcome of extraperitoneal paraaortic lymph node dissections compared with transperitoneal approach in gynecologic cancer patients. AB - STUDY OBJECTIVE: To evaluate the surgical outcome of extraperitoneal paraaortic lymph node dissection compared with the traditional transperitoneal approach. DESIGN: Retrospective review (Canadian Task Force classification III). SETTING: University hospital. PATIENTS: Women with gynecologic malignancies admitted to our hospital between 2007 and 2011 who underwent laparoscopic paraaortic lymphadenectomy. INTERVENTIONS: Indication, diagnosis, and outcome according to type of surgery were evaluated. MEASUREMENTS AND MAIN RESULTS: Of 47 patients who underwent laparoscopic paraaortic lymphadenectomy because of gynecologic indications, 28 patients underwent extraperitoneal paraaortic lymph node dissection and 19 underwent the same procedure via the classic transperitoneal technique. The most frequent indication for extraperitoneal lymph node dissection was cervical cancer (71.4%), and for the transperitoneal technique was endometrial cancer (47.4%). The mean (SD) duration of surgery was 211 (38) minutes in the transperitoneal approach group, and 173 (51) minutes in the extraperitoneal lymphadenectomy group (p = .009). No significant differences between groups were found in the number of lymph nodes removed (15 [5.9] nodes in the extraperitoneal group vs 17.4 [8.6] in the transperitoneal group; p = .25). However, a higher rate of positive nodes was observed in the extraperitoneal group than in the transperitoneal group (42.8% vs 36.2%, respectively [p = .001]), and a significantly shorter stay in the intensive care unit in the extraperitoneal group (0.59 [0.5] vs 1.1 [0.5] days, respectively; p = .02). No significant differences in complication rate were found between groups. CONCLUSIONS: Extraperitoneal paraaortic lymph node dissection is a minimally invasive procedure that is an excellent and safe approach to the paraaortic area, with a low complication rate, sufficient number of lymph nodes, and short hospital stay. It seems to be a good alternative to the classic transperitoneal approach. PMID- 23680522 TI - What is in a name? The need for strict diagnostic criteria in computerized tomographic angiography of anomalous coronary artery originating from the opposite aortic sinus. PMID- 23680521 TI - WAVE1 gene silencing via RNA interference reduces ovarian cancer cell invasion, migration and proliferation. AB - OBJECTIVE: Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) has been implicated in cancer cell migration and invasion. We have previously shown that the overexpression of WAVE1 in epithelial ovarian cancer (EOC) tissues is associated with a poor prognosis. However, the mechanism of WAVE1 regulating the malignant behaviors in EOC remains unclear. METHODS: In the present study, we knocked down WAVE1 expression in SKOV3 and OVCAR-3 cells through RNA interference to detect the cell biology and molecular biology changes. Moreover, western-blot was used to investigate the underlying mechanism of WAVE1 regulating the proliferative and invasive malignant behaviors in ovarian cancer cells. RESULTS: The down-regulation of WAVE1 had a significant effect on cell morphological changes. WAVE1 silencing decreased cell migration, cell invasion, cell adhesion, colony formation and cell proliferation in vitro. In addition, we found that down-regulation of WAVE1 inhibited malignant behaviors in vivo. Furthermore, our study also indicated that the PI3K/AKT and p38MAPK signaling pathways might contribute to WAVE1 promotion of ovarian cancer cell proliferation, migration, and invasion. CONCLUSIONS: WAVE1 might promote the proliferative and invasive malignant behaviors through the activation of the PI3K/AKT and p38MAPK signaling pathways in EOC. PMID- 23680523 TI - Pediatric transoral robotic surgery for oropharyngeal malignancy: a case report. AB - The treatment of oropharyngeal malignancy is associated with numerous functional morbidities. Transoral robotic surgery has been used with increased frequency in adult oropharyngeal malignancy. The benefits include decreased surgical morbidity and improved functional outcomes. Use of transoral robotic has been limited in children. This case represents our experience with a 17-month old child who was diagnosed with a high-grade undifferentiated sarcoma of the soft palate. She was able to be successfully treated with transoral robotic surgery as a part of her multimodal therapy, representing the first case of transoral robotic surgery for an oropharyngeal malignancy in a young child. PMID- 23680524 TI - A solitary tonsil can cause severe obstructive sleep apnea. AB - Hypertrophy of the tonsils and adenoids is the most common cause of pediatric obstructive sleep apnea. Bilateral tonsillectomy, most commonly performed with adenoidectomy, is the accepted treatment for obstructive sleep apnea. We report the unusual case of a child who underwent unilateral tonsillectomy and adenoidectomy at another institution and subsequently presented to us with persistent severe obstructive sleep apnea and a diagnosis of attention deficit hyperactivity disorder. The adenoids were not obstructing the choanae. The remaining tonsil was removed and the patient's sleep apnea resolved. This is the first objectively documented report of a solitary tonsil causing severe obstructive sleep apnea (using polysomnography) that resolved after removal of the remaining tonsil. PMID- 23680525 TI - Decreased nitrite levels in erythrocytes of children with beta thalassemia/hemoglobin E. AB - Nitrite anion is bioactive nitric oxide (NO) species circulating in blood, and represents the NO bioavailability and endothelial function. In this study, we aimed to investigate the nitrite levels and the correlation with hemolysis and severity in beta-thalassemia/hemoglobin E (beta-thal/HbE). 38 Children (12.0+/ 1.9 years of age) with a diagnosis of mild, moderate and severe beta-thalassemia were enrolled in the study. The blood nitrite levels and potential plasma NO consumption were measured by the chemiluminescence method. The nitrite levels in whole blood and erythrocytes of the severe thalassemia subjects were lower than those of the control subjects. At day 7 after transfusion of packed erythrocytes, the nitrite levels in erythrocytes increased. The plasma hemoglobin and NO consumption increased in the severe thalassemia subjects. The nitrite levels in erythrocytes inversely correlated with plasma hemoglobin, lactate dehydrogenase activity, potential NO consumption, and lipid peroxidation. Our studies demonstrate the decreased NO bioavailability in thalassemia, which could result from endothelial dysfunction, the increased potential NO consumption in plasma by cell-free hemoglobin and oxidative stress. PMID- 23680526 TI - The NPY intergeniculate leaflet projections to the suprachiasmatic nucleus transmit metabolic conditions. AB - The intergeniculate leaflet (IGL) is classically known as the area of the Thalamic Lateral Geniculate Complex providing the suprachiasmatic nucleus (SCN) non-photic information. In the present study we investigated whether this information might be related to the metabolic state of the animal. The following groups of male Wistar rats were used for analysis of neuropeptide Y (NPY) and c Fos in the IGL and SCN. (1) Fed ad libitum. (2) Fasted for 48 h. (3) Fasted for 48 h followed by refeeding for 3 h. (4) Monosodium glutamate-lesioned and 48 h fasted. (5) Electrolytic lesion in the IGL and 48 h fasted. The results were quantified by optical densitometry. Neuronal tracers were injected in two brain areas that receive metabolic information from the periphery, the arcuate nucleus (ARC) and Nucleus of the Tractus Solitarius to investigate whether there is an anatomical relationship with the IGL. Lesion studies showed the IGL, and not the ARC, as origin of most NPY projections to the SCN. Fasting induced important changes in the NPY expression in the IGL, coinciding with similar changes of NPY/glutamate decarboxylase projections of the IGL to the SCN. These changes revealed that the IGL is involved in the transmission of metabolic information to the SCN. In fasted animals IGL lesion resulted in a significant increase of c-Fos in the SCN as compared to intact fasted animals demonstrating the inhibitory influence of the IGL to the SCN in fasting conditions. When the animal after fasting was refed, an increase of c-Fos in the SCN indicated a removal of this inhibitory input. Together these observations show that in addition to increased inhibitory IGL input during fasting, the negative metabolic condition also results in increased excitatory input to the SCN via other pathways. Consequently the present observations show that at least part of the non-photic input to the SCN, arising from the IGL contains information about metabolic conditions. PMID- 23680527 TI - [Progressive binocular diplopia]. PMID- 23680528 TI - [Situs ambiguous or heterotaxy]. PMID- 23680529 TI - Predictors of the change in bilirubin levels over twelve weeks of treatment with atazanavir. PMID- 23680530 TI - Differences in IgE mediated basophil degranulation induced by proteic fractions from whole flea body extract in patients with papular urticaria by flea bite and healthy controls. AB - BACKGROUND: Papular urticaria by flea bite (PUFB) is a chronic inflammatory disease in children. The aim of this study was to assess the functional activity of IgE to protein fractions from flea body extract, through basophil degranulation in PUFB patients and controls. METHODS: Basophil degranulation, measured by overexpression of CD63 surface molecules, was evaluated by flow cytometry in samples from patients and controls. Cell stimulation was performed with three fractions with different molecular weight from flea body extract using a Basotest(r) modified protocol. Mann-Whitney U-test was used for comparisons. RESULTS: Specific IgE from PUFB patients and healthy controls induced basophil degranulation to flea body extract with no significant differences between them (16.2 +/- 3.1% vs 13.6 +/- 2.8% p = 0.77). However, when flea extract was analyzed in fractions with proteins ranging different molecular weights, significant differences were observed on the response from patients compared with controls to <50 kD (14.9 +/- 5.1% vs 9.7 +/- 2.1% p = 0.0058) and 50-100 kD proteic fractions (8.3 +/- 3.2% vs 2.8 +/- 1.6% p = 0.0021). CONCLUSION: In this study, was established that the differential response by IgE, in PUFB, depends from the molecular weight of the antigens contained in the flea extract. These antigens may be related to 30-35 kD proteins previously described as major allergens. PMID- 23680531 TI - Non-invasive cardiac output monitoring during catheter interventions in patients with cavopulmonary circulations. AB - INTRODUCTION: Functionally univentricular hearts palliated with superior or total cavopulmonary connection result in circulations in series. The absence of a pre pulmonary pump means that cardiac output is more difficult to adjust and control. Continuous monitoring of cardiac output is crucial during cardiac catheter interventions and can provide new insights into the complex physiology of these lesions. MATERIALS AND METHODS: The Icon cardiac output monitor was used to study the changes in cardiac output during catheter interventions in 15 patients (median age: 6.1 years, range: 4.8-15.3 years; median weight: 18.5 kg, range: 15 63 kg) with cavopulmonary circulations. A total of 19 interventions were undertaken in these patients and the observed changes in cardiac output were recorded and analysed. RESULTS: Cardiac output was increased with creation of stent fenestrations after total cavopulmonary connection (median increase of 22.2, range: 6.7%-28.6%) and also with drainage of significant pleural effusions (16.7% increase). Cardiac output was decreased with complete or partial occlusion of fenestrations (median decrease of 10.6, range: 7.1%-13.4%). There was a consistent increase in cardiac output with stenting of obstructive left pulmonary artery lesions (median increase of 7.7, range: 5%-14.3%, p = 0.007). CONCLUSIONS: Icon provides a novel technique for the continuous, non-invasive monitoring of cardiac output. It provides a further adjunct for monitoring of physiologically complex patients during catheter interventions. These results are consistent with previously reported series involving manipulation of fenestrations. This is the first report identifying an increase in cardiac output with stenting of obstructive pulmonary arterial lesions. PMID- 23680532 TI - How does the introduction of a pain and sedation management guideline in the paediatric intensive care impact on clinical practice? A comparison of audits pre and post guideline introduction. AB - Despite the use of guidelines to inform practice for pain and sedation management there are few evaluations of the effect of their introduction on clinical practice. Previous evaluations of the protocols and guidelines used to manage pain and sedation in the paediatric intensive care unit (PICU) report increases in pain and sedation medication administration post guideline introduction. In most reported cases the guideline was accompanied by a treatment algorithm. To our knowledge there is no published data on the effect of introducing a guideline without a treatment algorithm on pain and analgesia administration. PURPOSE: To evaluate the impact the introduction of a pain and sedation guideline will have on clinical practice. METHODS: A 19 bed PICU was audited for one month prior to the introduction of a guideline and one month post. FINDINGS: The proportion of patients receiving oral Clonidine increased (p=0.001) and the administration of Ketamine, particularly via bolus (p=0.003), reduced after the introduction of the guideline. The use of a validated pain tool to assess pain increased by 25% and communication of management plans increased by 25%. The documentation of the use of boluses increased by 36%. CONCLUSION: The introduction of a clinical practice guideline for pain and sedation management in PICU contributes to changes in medication administration, use of validated pain assessments, improved documentation of boluses and communication of management plans. PMID- 23680533 TI - Clinical components and associated behavioural aspects of a complex healthcare intervention: multi-methods study of selective decontamination of the digestive tract in critical care. AB - BACKGROUND: This study sought to identify and describe the clinical and behavioural components (e.g. the what, how, when, where and by whom) of 'selective decontamination of the digestive tract' (SDD) as routinely implemented in the care of critically ill patients. METHODS: Multi-methods study, consisting of semi-structured observations of SDD delivery, interviews with clinicians and documentary analysis, conducted in two ICUs in the UK that routinely deliver SDD. Data were analysed within-site to describe clinical and behavioural SDD components and synthesised across-sites to describe SDD in context. RESULTS: SDD delivery involved multiple behaviours extending beyond administration of its clinical components. Not all behaviours were specified in relevant clinical documentation. Overall, SDD implementation and delivery included: adoption (i.e. whether to implement SDD), operationalisation (i.e. implementing SDD into practice), provision (i.e. delivery of SDD) and surveillance (i.e. monitoring the ecological effects). Implementation involved organisational, team and individual level behaviours. Delivery was perceived as easy by individual staff, but displayed features of complexity (including multiple interrelated behaviours, staff and contexts). CONCLUSIONS: This study is the first to formally outline the full spectrum of clinical and behavioural aspects of SDD. It identified points in the delivery process where complex behaviours occur and outlined how SDD can be interpreted and applied variably in practice. This comprehensive specification allows greater understanding of how this intervention could be implemented in units not currently using it, or replicated in research studies. It also identified strategies required to adopt SDD and to standardise its implementation. PMID- 23680535 TI - Assessment of people with cognitive impairment and hip fracture: a systematic review and meta-analysis. AB - This study systematically assesses the literature pertaining to the diagnostic test accuracy of assessment instruments to evaluate patients following hip fracture surgery who present with cognitive impairment. A systematic review and meta-analysis was performed. Studies assessing the reliability, validity, sensitivity or specificity of assessment tools for patients following hip fracture who were cognitively impaired were included. An assessment of published (MEDLINE, EMBASE, CINHAL, AMED, Cochrane library, PEDro) and unpublished/trial registry (OpenGrey, the WHO International Clinical Trials Registry Platform, Current Controlled Trials, the UK National Research Register Archive) databases were undertaken. Methodological quality of the literature was assessed using the QUADAS-2 appraisal tool. Nine studies including 690 participants, with a mean age of 82.1 years were included. The literature demonstrated a high risk of bias for study methodology, but low risk of bias for applicability. Two assessment domains were recognized: pain and delirium. For pain, the Facial Action Coding System (FACS) and DOLOPLUS-2 tools possessed strong inter-rater reliability and internal consistency, with the FACS demonstrating concurrent validity with other pain scales. For delirium, the Delirium Rating Scale-Revisited-98 (DRS-R-98) demonstrated high inter-rater reliability and sensitivity and specificity, with the NEECHAM Confusion Scale possessing high internal consistency. To conclude, there is a paucity of literature assessing the reliability, validity and diagnostic test accuracy of instruments to assess people with cognitive impairment following hip fracture surgery. Based on the current available data, delirium may be best assessed using the NEECHAM Confusion Scale or DRS-R-98. Pain is most accurately evaluated using the FACS. PMID- 23680534 TI - Microneedles for intradermal and transdermal drug delivery. AB - The formidable barrier properties of the uppermost layer of the skin, the stratum corneum, impose significant limitations for successful systemic delivery of broad range of therapeutic molecules particularly macromolecules and genetic material. Microneedle (MN) has been proposed as a strategy to breach the stratum corneum barrier function in order to facilitate effective transport of molecules across the skin. This strategy involves use of micron sized needles fabricated of different materials and geometries to create transient aqueous conduits across the skin. MN, alone or with other enhancing strategies, has been demonstrated to dramatically enhance the skin permeability of numerous therapeutic molecules including biopharmaceuticals either in vitro, ex vivo or in vivo experiments. This suggested the promising use of MN technology for various possible clinical applications such as insulin delivery, transcutaneous immunisations and cutaneous gene delivery. MN has been proved as minimally invasive and painless in human subjects. This review article focuses on recent and future developments for MN technology including the latest type of MN design, challenges and strategies in MNs development as well as potential safety aspects based on comprehensive literature review pertaining to MN studies to date. PMID- 23680536 TI - The association between energy cost of walking and physical function in older adults. AB - To assess the association between energy cost of walking and self-report of function, independent of comorbidity and gait speed, in older adults with mobility limitations. This cross-sectional observational study was conducted within an ambulatory clinical research training center. Forty-two older adults, age 65 and older, with slow and variable gait participated. Function was assessed using the Late Life Function and Disability Index-Basic Lower Extremity Subscale, while energy cost of walking was derived by standardizing the mean oxygen consumption recorded during physiological steady state by gait speed. Comorbidity and gait speed were collected as co-variates. Pearson's r correlation coefficient and regression analyses were used to assess the relationship between energy cost and function. Energy cost of walking was significantly correlated with self reported function (Pearson's r=-0.50, p<0.001); furthermore, energy cost of walking explained an additional 17% (p=0.002) of the variance in self-reported function above and beyond the variance explained by comorbidity and gait speed combined. Energy cost of walking is emerging as another significant factor related to functional performance among older adults, even after controlling for comorbidity and gait speed - robust variables known for their strong contributions to function. Knowledge of and attention to the efficiency of how one moves (high energy cost of walking) may enhance rehabilitation efforts to further reduce "functional burden" in older adults. PMID- 23680537 TI - Sentinel node biopsy for squamous cell carcinoma of the oral cavity and oropharynx: a diagnostic meta-analysis. AB - BACKGROUND: The aim of the study was to systematically assess the accuracy of a sentinel lymph node biopsy (SLNB) in cT1/T2N0 oral cavity and oropharyngeal squamous cell carcinoma patients. METHODS: We searched electronic databases, including EMBASE and MEDLINE (Pubmed) up to November 7 2012, by combining oral cancer keywords with sentinel node biopsy keywords. We included diagnostic accuracy studies which used neck dissection as a reference test for the sentinel node biopsy. Study characteristics and measures of accuracy were extracted. Diagnostic accuracy was calculated from 2 * 2 tables. RESULTS: 21 Studies (847 patients) could be included. Most of these patients had oral cavity squamous cell carcinoma (OCSCC). The pooled data showed an overall sensitivity of 0.93 [95% CI 0.90-0.95]. Subgroup analysis showed no significant differences in subgroups. CONCLUSION: The high sensitivity of SLNB supports a role in the diagnostic work up of OCSCC. PMID- 23680538 TI - Acute limb ischemia: role of preoperative and postoperative duplex in differentiating acute embolic from thrombotic ischemia. AB - BACKGROUND: Acute limb ischemia (ALI) represents an emergency in which delayed intervention results in significant morbidity, and potentially, death. PURPOSE: To assess the role of duplex in differentiating embolic from thrombotic ALI. METHODS AND MATERIALS: We prospectively recruited 57 patients; with 62 non traumatic ALI. We measured the diameter at the occluded site (dO) and the corresponding contralateral healthy side (dC). The absolute (?) and percent change (?%) between the two diameters were calculated as: (dO-dC) and [(?/dC)*100] respectively. According to the reference standard (contrast angiography or surgery), limbs were classified into embolic (E-group:37 limbs) and thrombotic (T-group:25 limbs) groups. Postoperative duplex was done in 34 patients after embolectomy and the absolute (?P) and percent change (?P%) between the postoperative (dP) and preoperative (dO) diameters at the occlusion were calculated as: (dP-dO) and [(?P/dO)*100] respectively. RESULTS: The baseline clinical characteristics were similar between both groups. However, in the E group, (?%) was 21.96+/-17.53% vs. -11.03+/-16.16% in the T-group, (p<0.001). A cutoff value of >1.41% for (?%) had 100% sensitivity and 76% specificity for the diagnosis of embolic vs. thrombotic occlusion with AUC 0.95 (95% CI: 0.901-0.999, p<0.00l). Postoperatively (?P%) was -11.8+/-8.2% with a significant negative correlation found between (?) and (?P); Spearman's coefficient (rho)=-0.912, P<0.001. CONCLUSIONS: A cut off value of 1.41% as percent dilatation or diminution in the diameter of occluded artery is the most important duplex sign for predicting embolic or thrombotic ALI respectively. Postoperative reduction in the diameter of occluded artery after embolectomy confirms this sign. PMID- 23680539 TI - Future challenges for parasitology: vector control and 'One health' in Europe: the veterinary medicinal view on CVBDs such as tick borreliosis, rickettsiosis and canine leishmaniosis. AB - The medical as well as the veterinary importance of parasitic arthropods or ectoparasites in general terms, is characterized by the primary or secondary impact on the health of humans and companion animals alike. The parasitic arthropods addressed here are those ectoparasites belong to the class of insects, such as fleas and sand flies, or the subclass of acarids, such as ticks. These parasitic arthropods interact intensively with their hosts by blood feeding. Fleas, sand flies and ticks hold the vector capacity to transmit pathogens such as virus, bacteria or protozoa to cats, dogs and humans. The diseases caused by these pathogens are summarized under the terms canine vector-borne diseases (CVBD), feline vector-borne diseases (FVBD) or metazoonoses. In small animal practice, it is important to understand that the transmitted pathogen may either lead to a disease with clinical signs, or more often to asymptomatic, clinically healthy, or silent infections. Blocking of the vector-host interactions, the blood feeding and subsequently the transmission of pathogens during blood feeding is a key element of CVBD control. The focus of this review is on the current knowledge of the epidemiology of parasitic vectors and three important CVBDs they transmit; rickettsiosis, tick borreliosis and canine leishmaniosis from a European perspective, and how veterinary medicine may contribute to the challenges of CVBDs and their control. Prevention of CVBDs is fundamentally based on ectoparasite control. Ectoparasite management in cats and dogs is important not only for the health and well-being of the individual companion animal but for public health in general and is therefore a perfect example of the 'One health' approach. PMID- 23680540 TI - Cryptosporidium parvum: determination of ID50 and the dose-response relationship in experimentally challenged dairy calves. AB - The objectives were to determine the median infective dose (ID50) of Cryptosporidium parvum and to describe the dose-response relationship including associated clinical illness in experimentally challenged dairy calves. Within the first 24h of life, 27 test calves were experimentally challenged with C. parvum oocysts and 3 control calves were sham dosed. Test calves received 1 of 8 possible doses (25, 50, 100, 500, 1 * 10(3), 1 * 10(4), 1 * 10(5), and 1 * 10(6) oocysts). All 27 test calves developed diarrhea. Fecal oocyst shedding occurred in 25 (92.6%) test calves and in 0 control calves. The 2 non-shedding test calves both received 25 oocysts. There was an inverse relationship between dose and time to onset of fecal oocyst shedding (P=0.005). There was no relationship found between dose and duration (P=0.2) or cessation (P=0.3) of fecal oocyst shedding. In addition, there was not a significant relationship between log-dose and the log-peak oocysts (P=0.2) or log-total oocysts (P=0.5) counted/g of feces across the dose groups. There was a positive dose-response relationship between log-dose and diarrhea (P=0.01). However, when controlling for other factors, such as onset and cessation of fecal oocyst shedding, dose was not a significant predictor of diarrhea (P=0.5). Onset and cessation of fecal oocyst shedding were found to be the best predictors of diarrhea (P=0.0006 and P=0.04, respectively). The ID50 for fecal oocyst shedding was 5.8 oocysts, for diarrhea was 9.7 oocysts, and for fecal oocyst shedding with diarrhea was 16.6 oocysts. Given that the ID50 of C. parvum is far less than would be excreted into the environment by a naturally infected calf, prevention and control of cryptosporidiosis is a formidable challenge. PMID- 23680541 TI - Development of a multiplex real time PCR to differentiate Sarcocystis spp. affecting cattle. AB - Cattle are intermediate hosts of Sarcocystis cruzi, Sarcocystis hirsuta and Sarcocystis hominis which use canids, felids or primates as definitive hosts (DH), respectively, and in addition of Sarcocystis sinensis from which the DH is unknown. The aims of the present study were to develop and optimize a multiplex real time PCR for a sensitive and specific differentiation of Sarcocystis spp. affecting cattle and to estimate the prevalence of Sarcocystis spp. in Argentinean cattle. The 18S rRNA genes from individual sarcocysts were amplified and cloned to serve as controls. For the amplification of bovine Sarcocystis spp. a total of 3 primers were used in combination with specific individual probes. Each assay was evaluated and optimized individually and subsequently combined in a multiplex assay (BovSarcoMultiplex real time PCR). The analytical specificity of the multiplex assay was assessed using 5 ng of DNA of heterologous Sarcocystis spp. and other apicomplexan parasites, and no positive reactions were observed other than for the species the PCR targeted. The analytical sensitivity ranged between 0.0125 and 0.125 fg of plasmid DNA (equivalent to the DNA of 2-20 plasmid DNA copies) or resembling DNA of 0.1-0.3 bradyzoites. A total of 380 DNA loin samples from Argentina were tested and 313, 29, 14 and 2 were positive for S. cruzi, S. sinensis, S. hirsuta and S. hominis, respectively. S. sinensis was the most prevalent species among thick walled Sarcocystis spp. in Argentinean cattle. Mixed infections were detected in 8.9% of all samples. Diagnostic sensitivity and specificity for the BovSarcoMultiplex real time PCR relative to previous microscopic examination for thin and thick-walled cyst were 91.5% and 41.7%, 36.3% and 95.9% respectively. Improved DNA extraction methods may allow to further increase the specific and sensitive detection of Sarcocystis spp. in meat samples. PMID- 23680542 TI - Hierarchical model for evaluating pyrantel efficacy against strongyle parasites in horses. AB - Anthelmintic resistance is an increasing challenge for the control of equine parasites. The fecal egg count reduction test (FECRT) is the practical gold standard method for evaluating reduction in anthelmintic efficacy, but the interpretation is complicated due to high levels of variability. A hierarchical statistical model was described for analysis of FECRT data from multiple farms to evaluate the role of biological factors in determining the strongyle efficacy of pyrantel pamoate in a study performed in Denmark. The model was then used to describe two notions of farm efficacy, namely conditional and marginal efficacy. The median of the lower prediction limits was used to describe a robust classification rule. The performance of the methodology was evaluated using Monte Carlo simulations. The field study was performed on 64 Danish horse farms of different breeds. Of 1644 horses, 614 had egg counts >= 200 eggs per gram (EPG) and were treated. Individual coprocultures were performed for identification of Strongylus vulgaris from all horses pre-treatment. Thirty-one farms (48.4%) were positive for S. vulgaris, but pyrantel efficacy was unaffected by the presence of this parasite in the statistical model. Further, there were no significant effects of age, gender, or interactions between these, while the pre-treatment egg count was negatively associated with the egg count reduction. The statistical model classified 81.3%, 10.9%, and 7.8% of farms as no signs of resistance (NR), suspect resistance (SR), and resistance (RE), respectively. In comparison, arithmetic calculations classified 68.8%, 17.2%, and 14.1% in the same categories. Using 10,000 simulated data sets, the methodology provided a classification of farms into different efficacy categories with a false discovery of reduced farm efficacy rate equaling 8.74%. In addition, model-classification was unaffected by presence of single outlier horses in a separate simulation study. PMID- 23680543 TI - Chronic bovine besnoitiosis: intra-organ parasite distribution, parasite loads and parasite-associated lesions in subclinical cases. AB - Bovine besnoitiosis caused by Besnoitia besnoiti is a chronic and debilitating disease. The most characteristic clinical signs of chronic besnoitiosis are visible tissue cysts in the scleral conjunctiva and the vagina, thickened skin and a generally poor body condition. However, many seropositive animals remain subclinically infected, and the role that these animals may play in spreading the disease is not known. The aim of the present study was to assess the intra-organ parasite distribution, the parasite load and the parasite-associated lesions in seropositive but subclinically infected animals. These animals were seropositive at the time of several consecutive samplings, had visible tissue cysts in the past and, at time of slaughter, had detectable specific anti-Besnoitia spp. antibody levels, but they did not show evident clinical signs at culling. Thus, histopathological, immunohistochemical and molecular analyses of several samples from the respiratory tract, reproductive tract, other internal organs and skin from six cows were performed. The tissue cysts were located primarily in the upper respiratory tract, i.e., in the rhinarium and larynx/pharynx (four cows), followed by the distal genital tract (vulva/vagina) and the skin of the neck (three and two cows, respectively, out of the four cows with cysts in the respiratory tract). We were unable to detect any parasites in the two remaining cows. Cysts were associated with a significant non-purulent inflammatory infiltrate consisting predominantly of T lymphocytes and activated monocytes/macrophages in two cows. The parasite burden, estimated by quantitative real-time PCR, was very low. It is noteworthy that the only animal that showed a recent increase in the antibody titre had the highest parasite burden and the most conspicuous inflammatory reaction against the cysts. In conclusion, although these cows no longer displayed any visible signs of besnoitiosis, they remained infected. Therefore, cows without visible signs of disease may still be able to transmit the parasite. PMID- 23680544 TI - A novel lophine-based fluorescence probe and its binding to human serum albumin. AB - The binding of a lophine-based fluorescence probe, 4-[4-(4-dimethylaminophenyl)-5 phenyl-1H-imidazol-2-yl]benzoic acid methyl ester (DAPIM) with human serum albumin (HSA) was investigated by fluorescence spectroscopy under physiological conditions. While DAPIM shows extreme low fluorescence in aqueous solution, DAPIM binding with HSA emits strong fluorescence at 510nm. The binding constant and binding number determined by Scatchard plot was 3.65*10(6)M(-1) and 1.07, respectively. Competitive binding between DAPIM and other ligands such as warfarin, valproic acid, diazepam and oleic acid, were also studied fluorometrically. The results indicated that the primary binding site of DAPIM to HSA is site II at subdomain IIIA. DAPIM can be a useful fluorescence probe for the characterization of drug-binding sites. In addition to the interaction study, because the fluorescence intensity of DAPIM increased in proportion to HSA concentration, its potential in HSA assay for serum sample was also evaluated. PMID- 23680545 TI - Cobalt as chemical modifier to improve chromium sensitivity and minimize matrix effects in tungsten coil atomic emission spectrometry. AB - Cobalt is used as chemical modifier to improve sensitivity and minimize matrix effects in Cr determinations by tungsten coil atomic emission spectrometry (WCAES). The atomizer is a tungsten filament extracted from microscope light bulbs. A solid-state power supply and a handheld CCD-based spectrometer are also used in the instrumental setup. In the presence of 1000 mg L(-1) Co, WCAES limit of detection for Cr (lambda=425.4 nm) is calculated as 0.070 mg L(-1); a 10-fold improvement compared to determinations without Co modifier. The mechanism involved in such signal enhancement is similar to the one observed in ICP OES and ICP-MS determinations of As and Se in the presence of C. Cobalt increases the population of Cr(+) by charge transfer reactions. In a second step, Cr(+)/e(-) recombination takes place, which results in a larger population of excited-state Cr atoms. This alternative excitation route is energetically more efficient than heat transfer from atomizer and gas phase to analyte atoms. A linear dynamic range of 0.25-10 mg L(-1) and repeatability of 3.8% (RSD, n=10) for a 2.0 mg L( 1) Cr solution are obtained with this strategy. The modifier high concentration also contributes to improving accuracy due to a matrix-matching effect. The method was applied to a certified reference material of Dogfish Muscle (DORM-2) and no statistically significant difference was observed between determined and certified Cr values at a 95% confidence level. Spike experiments with bottled water samples resulted in recoveries between 93% and 112%. PMID- 23680546 TI - Interpolation in the standard additions method. AB - The standard additions method (SAM) has traditionally been performed by using extrapolation. This practice is suboptimal because predictions are affected by even slight departures of calibration points from a straight line. Despite this, most textbooks and papers in analytical chemistry still refer exclusively to extrapolation. In contrast, the use of interpolation is recommended in this paper as a way to get predictions on the central part of the regression line and thus minimize the bias in the prediction and the variance associated with the analytical result. Several scenarios were studied, with concentration errors simulated in different calibration solutions. It was found that translational effects due to variations at the central part of the calibration caused the lowest disturbances on the predicted concentrations. The differences between the interpolated and extrapolated predictions can be as large as +/-30%. The confidence interval associated with the extrapolation result is wider than that due to interpolation by as much as 100%. It is shown that commonly used equations underestimate the correct confidence intervals. Both, absence of bias and improved precision, are of relevance in quality assurance, method validation and error propagation. PMID- 23680547 TI - Nanoporous platinum-cobalt alloy for electrochemical sensing for ethanol, hydrogen peroxide, and glucose. AB - Nanoporous platinum-cobalt (NP-PtCo) alloy with hierarchical nanostructure is straightforwardly fabricated by dealloying PtCoAl alloy in a mild alkaline solution. Selectively etching Al resulted in a hierarchical three-dimensional network nanostructure with a narrow size distribution at 3 nm. The as-prepared NP PtCo alloy shows superior performance toward ethanol and hydrogen peroxide (H2O2) with highly sensitive response due to its unique electrocatalytic activity. In addition, NP-PtCo also exhibits excellent amperometric durability and long-term stability for H2O2 as well as a good anti-interference toward ascorbic acid, uric acid, and dopamine. The hierarchical nanoporous architecture in PtCo alloy is also highly active for glucose sensing electrooxidation and sensing in a wide linear range. The NP-PtCo alloy holds great application potential for electrochemical sensing with simple preparation, unique catalytic activity, and high structure stability. PMID- 23680548 TI - A new strategy based on cholesterol-functionalized iron oxide magnetic nanoparticles for determination of polycyclic aromatic hydrocarbons by high performance liquid chromatography with cholesterol column. AB - This study reported for the first time the use of cholesterol-functionalized magnetic nanoparticles (Fe3O4@SiO2@Chol) for the determination of polycyclic aromatic hydrocarbons (PAHs) in traditional Chinese medicine samples (TCMs) by high performance liquid chromatography (HPLC) coupled with fluorescence detection. The method was efficient, environmentally friendly, and fast. The solvent consumption of the proposed column is only half of the conventional column but with higher efficiency. Influencing factors, including sorbent amount, desorption solvent, sample volume and extraction time, were investigated in detail. Under the optimum conditions, good linearity (R(2)>0.991) was obtained over the range of 5-400 ng g(-1), with limits of detection (LOD) 0.75, 0.50, 1.0, 0.56, 0.60, 0.84 and 0.80 ng g(-1) for anthracene, fluoranthene, pyrene, chrysene, benzo[a]anthracene, benzo(b)fluoranthene and benzo(k)fluoranthene, respectively. PMID- 23680549 TI - Identification of isomeric disaccharides in mixture by the 1-phenyl-3-methyl-5 pyrazolone labeling technique in conjunction with electrospray ionization tandem mass spectrometry. AB - 1-Phenyl-3-methyl-5-pyrazolone (PMP) labeling technique has hitherto proved to be a convenient and sensitive method for separating and detecting oligosaccharides. However, the detailed fragmentation of the derivatives by tandem mass spectrometry has been reported limitedly and no characteristic fragment ions for isomers have been detected. In this study, eight disaccharide isomers were labeled with PMP and analyzed by positive ion electrospray ionization multi-stage tandem mass spectrometry (ESI-MS(n)). In comparison with the native disaccharides, PMP labeled disaccharides gave rise to more fragment ions in the tandem mass spectra. The distinctive diagnostic fragment ions formed from cleavage of C-C bonds have been detected in the fragmentation of PMP-labeled disaccharide linkage isomers, allowing unambiguous assignment of the position of the glycosidic linkages. This feature is particularly useful for the structural determination of unknown isomeric disaccharides mixed together. In addition, the anomeric configurations can also be easily assigned based on the relative abundance ratios of the selected ion pairs. To verify the feasibility of the method used in the analysis of natural product, water soluble Panax Ginseng extract has been further investigated to identify its unknown disaccharides. The results confirmed that the PMP labeling technique in conjunction with ESI-MS(n) could offer a powerful and convenient tool for differentiation of structurally closely related isomers, even the unknown mixtures of isomeric disaccharides with different linkage types. PMID- 23680550 TI - An accurate and reliable analysis of trimethylamine using thermal desorption and gas chromatography-time of flight mass spectrometry. AB - Trimethylamine (TMA) is well-known for manifesting the odor of rotting fish and urine. The analysis of TMA in environmental samples generally suffers from low reproducibility and poor sensitivity. In this study, a technique for the quantitative analysis of gas phase TMA was developed using thermal desorption (TD)-gas chromatography (GC)-time of flight mass spectrometry (TOF-MS). This new approach yielded good linearity (R(2)=0.9930), precision (RSE=1.59%), and high sensitivity with the method detection limit (MDL) of 51 pg, i.e., detection of 0.021 ppb of TMA at 1L sample (limit of detection (LOD): 5.32 pg (0.002 ppb). This method was tested against gas samples collected from two representative sources of TMA: (1) rotten thornback fish and (2) cat urine-soaked clay. The concentration of TMA in these samples, when analyzed after treatment at varying dilution ratios, averaged 293+/-29.7 ppm (RSE=3.82%) and 74.1+/-5.78 ppb (RSE=3.19%), respectively. The feasibility of this approach, when tested with TD GC-Quadruple (Q) MS, showed a good compatibility with moderately reduced sensitivity. The results of this study demonstrated that one can achieve highly reliable and reproducible analysis of TMA from environmental samples when using thermal desorption (for pretreatment) and detection (by the TOF or Q-MS system). PMID- 23680551 TI - An integrated strategy for in vivo metabolite profiling using high-resolution mass spectrometry based data processing techniques. AB - An ongoing challenge of drug metabolite profiling is to detect and identify unknown or low-level metabolites in complex biological matrices. Here we present a generic strategy for metabolite detection using multiple accurate-mass-based data processing tools via the analysis of rat samples of two model drug candidates, AZD6280 and AZ12488024. First, the function of isotopic pattern recognition was proved to be highly effective in the detection of metabolites derived from [(14)C]-AZD6280 that possesses a distinct isotopic pattern. The metabolites revealed using this approach were in excellent qualitative correlation to those observed in radiochromatograms. Second, the effectiveness of accurate mass based untargeted data mining tools such as background subtraction, mass defect filtering, or a data mining package (MZmine) used for metabolomic analysis in detection of metabolites of [(14)C]-AZ12488024 in rat urine, feces, bile and plasma samples was examined and a total of 33 metabolites of AZ12488024 were detected. Among them, at least 16 metabolites were only detected by the aid of the data mining packages and not via radiochromatograms. New metabolic pathways such as S-oxidation and thiomethylation reactions occurring on the thiazole ring were proposed based on the processed data. The results of these experiments also demonstrated that accurate mass-based mass defect filtering (MDF) and data mining techniques used in metabolomics are complementary and can be valuable tools for delineating low-level metabolites in complex matrices. Furthermore, the application of distinct multiple data-mining algorithms in parallel, or in tandem, can be effective for rapidly profiling in vivo drug metabolites. PMID- 23680552 TI - Targeted analysis with benchtop quadrupole-orbitrap hybrid mass spectrometer: application to determination of synthetic hormones in animal urine. AB - Sensitive and unequivocal determination of analytes/contaminants in complex matrices is a challenge in the field of food safety control. In this study, various acquisition modes (Full MS/AIF, Full MS+tMS/MS, Full MS/dd MS/MS and tSIM/ddMS/MS) and parameters of a quadrupole-orbitrap hybrid mass spectrometer (Q Exactive) were studied in detail. One of the main conclusions has been that, reducing the scan range for Full MS (using the quadrupole) and targeted modes give higher signal-to-noise (S/N) ratios and thereby better detection limits for analytes in matrix. The use of Q Exactive in a complex case, for the confirmatory analysis of hormones in animal urine is presented. A targeted SIM data dependent MS/MS (tSIM/ddMS/MS) acquisition method for determination of eight synthetic hormones (trenbolone, 17alpha ethinylestradiol, zeranol, stanozolol, dienestrol, diethylstilbestrol, hexestrol, taleranol) and a naturally occurring hormone (zearalenone) in animal urine were optimized to have sensitive precursors from targeted SIM mode and trigger MS/MS scans over the entire chromatograph peak. The method was validated according to EC/657/2002. CCalpha (decision limit) for the analytes ranged between 0.11 MUg L(-1) and 0.69 MUg L(-1) and CCbeta (detection capability) ranged between 0.29 MUg L(-1) and 0.90 MUg L(-1). PMID- 23680553 TI - Enhancement of sensitivity of paper-based sensor array for the identification of heavy-metal ions. AB - Paper-based microfluidic devices have been widely investigated in recent years. Among various detection techniques, colorimetric method plays a very important role in paper-based microfluidic devices. The limitation, however, is also clear: they generally require highly sensitive indicators. In this work, we have developed a novel enrichment-based paper test for the discrimination of heavy metal ions. Comparing to regular paper-based microfluidic devices, enrichment based technique showed largely improved sensitivity. Combining with eight pyridylazo compounds and array technologies-based pattern-recognition, we have obtained the discrimination capability of eight different heavy-metal ions at same concentration as low as 50 MUM using our enrichment-based pyridylazo compounds array paper. Identification of the heavy-metal ions was readily achieved using a standard chemometric approach. This method can be, of course, used for other analytes as well. PMID- 23680554 TI - Polymerized hemin as an electrocatalytic platform for peroxynitrite's oxidation and detection. AB - Peroxynitrite (ONOO(-)) constitutes a major cytotoxic agent, implicated in a host of pathophysiological conditions, thereby stimulating a tremendous interest in evaluating its role as an oxidant in vivo. Some of the detection methods for peroxynitrite include oxidation of fluorescent probes, EPR spectroscopy, chemiluminescence, immunohistochemistry, and probe nitration; however, these are more difficult to apply for real-time quantification due to their inherent complexity. The electrochemical detection of peroxynitrite is a simpler and more convenient technique, but the best of our knowledge there are only few papers to date studying its electrochemical signature, or reporting amperometric microsensors for peroxynitrite. Recently, we have reported the use of layered composite films of poly(3,4-ethylenedioxythiophene) (PEDOT) and hemin (iron protoporphyrin IX) as a platform for amperometric measurement of peroxynitrite. The main goal herein is to investigate the intrinsic catalytic role of hemin electropolymerized thin films on carbon electrodes in oxidative detection of peroxynitrite. The electrocatalytic oxidation of peroxynitrite is characterized by cyclic voltammetry. The catalytic current increased as a function of peroxynitrite's concentration, with a peak potential shifting positively with peroxynitrite's concentration. The catalytic efficiency decreased as the scan rate increased, and the peak potential of the catalytic oxidation was found to depend on pH. We show that optimized hemin-functionalized carbon electrodes can be used as simple platforms for peroxinitrite detection and quantification. We report dose-response amperometry as an electroanalytical determination of this analyte on hemin films and we contrast the intrinsic hemin catalytic role with its performance in the case of the PEDOT-hemin as a composite matrix. Finally, we include some work extending the use of simple hemin films for peroxynitrite determination on carbon microfiber electrodes in a flow system. PMID- 23680555 TI - Fluorescent detection of protein kinase based on zirconium ions-immobilized magnetic nanoparticles. AB - We report here an affinity separation-based fluorometric method for monitoring the activity and inhibition of protein kinase. In this assay, when the fluorescein isothiocyanate (FITC) labeled substrate peptides (S-peptide) are phosphorylated by kinase, the product peptides (P-peptide) will be adsorbed and concentrated onto the surface of Zr(4+)-immobilized nitrilotriacetic acid-coated magnetic nanoparticles (Zr-NTA MNPs) through the chelation of Zr(4+) and phosphate groups. After magnetic separation, the fluorescence intensity of the homogeneous solution changes dramatically. Hence the fluorescence response allows this MNPs-based method to easily probe kinase activity by a spectrometer. The feasibility of the method has been demonstrated by sensitive measurement of the activity of cAMP-dependent protein kinase (PKA) with a low detection limit (0.5 mU MUL(-1)). Moreover, the system is successfully applied to estimate the IC50 value of PKA inhibitor H-89 and detect the Forskolin/3-isobutyl-1-methylxanthine (IBMX) stimulated activation of PKA in cell lysate. Additionally, Zr-NTA MNPs are reusable by stripping Zr(4+) ions from NTA-coated MNPs and rechelating again. This method, which relies on the surface-functionalized MNPs, presents a promising candidate for simple and cost-effective assay of kinase activity and inhibitor screening. PMID- 23680556 TI - Electrochemical immunosensor based on nanoporpus gold loading thionine for carcinoembryonic antigen. AB - Nanoporous gold (NPG) has recently received considerable attention in analytical electrochemistry because of its good conductivity and large specific surface area. A facile layer-by-layer assembly technique fabricated NPG was used to construct an electrochemical immunosensor for carcinoembryonic antigen (CEA). NPG was fabricated on glassy carbon (GC) electrode by alternatively assembling gold nanoparticles (AuNPs) and silver nanoparticles (AgNPs) using 1,4 benzenedimethanethiol as a cross-linker, and then AgNPs were dissolved with HNO3. The thionine was absorbed into the NPG and then gold nanostructure was electrodeposited on the surface through the electrochemical reduction of gold chloride tetrahydrate (HAuCl4). The anti-CEA was directly adsorbed on gold nanostructure fixed on the GC electrode. The linear range of the immunosensor was from 10 pg mL(-1) to 100 ng mL(-1) with a detection limit of 3 pg mL(-1) (S/N=3). The proposed immunosensor has high sensitivity, wide linear range, low detection limit, and good selectivity. The present method could be widely applied to construct other immunosensors. PMID- 23680557 TI - Highly sensitive capillary electrophoresis-mass spectrometry for rapid screening and accurate quantitation of drugs of abuse in urine. AB - The combination of capillary electrophoresis (CE) and mass spectrometry (MS) is particularly well adapted to bioanalysis due to its high separation efficiency, selectivity, and sensitivity; its short analytical time; and its low solvent and sample consumption. For clinical and forensic toxicology, a two-step analysis is usually performed: first, a screening step for compound identification, and second, confirmation and/or accurate quantitation in cases of presumed positive results. In this study, a fast and sensitive CE-MS workflow was developed for the screening and quantitation of drugs of abuse in urine samples. A CE with a time of-flight MS (CE-TOF/MS) screening method was developed using a simple urine dilution and on-line sample preconcentration with pH-mediated stacking. The sample stacking allowed for a high loading capacity (20.5% of the capillary length), leading to limits of detection as low as 2 ng mL(-1) for drugs of abuse. Compound quantitation of positive samples was performed by CE-MS/MS with a triple quadrupole MS equipped with an adapted triple-tube sprayer and an electrospray ionization (ESI) source. The CE-ESI-MS/MS method was validated for two model compounds, cocaine (COC) and methadone (MTD), according to the Guidance of the Food and Drug Administration. The quantitative performance was evaluated for selectivity, response function, the lower limit of quantitation, trueness, precision, and accuracy. COC and MTD detection in urine samples was determined to be accurate over the range of 10-1000 ng mL(-1) and 21-1000 ng mL(-1), respectively. PMID- 23680558 TI - Determination of weight distribution ratios of Pa(V) and Np(V) with some extraction chromatography resins and the AG1-X8 resin. AB - Literature data on distribution ratios (Dw) of Np(V) and Pa(V) for the AG1-X8 resin are scarce whereas those related on resin capacity factors (k') values for TEVA, TRU and U/TEVA resins are absent. Therefore, batch extraction experiments for Pa(V) and Np(V) from HCl and HNO3 media were realized, at tracer scale, with AG1-X8 and EIChroM resins (TEVA, TRU and U/TEVA). Based on the new Dw and k' values obtained in this study, a new protocol for Pa/Np separation has been developed leading to a better separation factor of 10(5) and a chemical yield of 97+/-3% and 99+/-1% for Pa and Np, respectively. A separation of (231)Pa from uranium matrix was successfully tested. PMID- 23680559 TI - Ethical perspectives on pain. PMID- 23680560 TI - Common misconceptions about opioid use for pain management at the end of life. PMID- 23680561 TI - Drug seeking or pain crisis? Responsible prescribing of opioids in the emergency department. PMID- 23680562 TI - Use of narcotics contracts. PMID- 23680563 TI - Undergraduate medical education on pain management across the globe. PMID- 23680564 TI - Physicians' responsibility to understand patients' pain. PMID- 23680565 TI - Long-term opioid treatment. PMID- 23680566 TI - Objectifying chronic pain: from the patient to diagnostic metrics. PMID- 23680567 TI - Fighting prescription drug abuse with federal and state law. PMID- 23680568 TI - Pain and ethnicity. PMID- 23680569 TI - Chronic pain patients and the biomedical model of pain. PMID- 23680570 TI - Pain and the paintbrush: the life and art of Frida Kahlo. PMID- 23680571 TI - Medicinal cannabis and painful sensory neuropathy. PMID- 23680572 TI - Src/p38 MAPK pathway in spinal microglia is involved in mechanical allodynia induced by peri-sciatic administration of recombinant rat TNF-alpha. AB - Our previous work has shown that peri-sciatic administration of recombinant rat TNF-alpha (rrTNF) induces mechanical allodynia and up-regulation of TNF-alpha in the spinal dorsal horn of rats; however, the underlying mechanisms remain unknown. In the current study, we found that the levels of phosphorylated Src family kinases (p-SFKs) and phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) were significantly increased in bilateral lumbar spinal dorsal horn on day 3 after rrTNF administration. Double immunofluorescence staining revealed that p-SFKs and p-p38 MAPK were nearly restricted to the microglia. Intrathecal delivery of SFKs inhibitor PP2 or p38 MAPK inhibitor SB203580, started 30 min before rrTNF administration and given once daily thereafter for 7 days, blocked mechanical allodynia in bilateral hind paws and increase of TNF-alpha expression in the spinal dorsal horn. Moreover, PP2 inhibited the up-regulation of p-p38 MAPK induced by rrTNF. We also found that intrathecal injection of TNF-alpha neutralization antibody alleviated mechanical allodynia in bilateral hind paws and suppressed up-regulation of p-SFKs and p-p38 MAPK. These results suggest that activation of the SFKs/p38 MAPK pathway in microglia and subsequent TNF-alpha expression in the spinal dorsal horn may contribute to the mechanical hyperalgesic state induced by peri-sciatic administered rrTNF. PMID- 23680573 TI - Chronic methamphetamine treatment induces oxytocin receptor up-regulation in the amygdala and hypothalamus via an adenosine A2A receptor-independent mechanism. AB - There is mounting evidence that the neuropeptide oxytocin is a possible candidate for the treatment of drug addiction. Oxytocin was shown to reduce methamphetamine self-administration, conditioned place-preference, hyperactivity and reinstatement in rodents, highlighting its potential for the management of methamphetamine addiction. Thus, we hypothesised that the central endogenous oxytocinergic system is dysregulated following chronic methamphetamine administration. We tested this hypothesis by examining the effect of chronic methamphetamine administration on oxytocin receptor density in mice brains with the use of quantitative receptor autoradiographic binding. Saline (4ml/kg/day, i.p.) or methamphetamine (1mg/kg/day, i.p.) was administered daily for 10 days to male, CD1 mice. Quantitative autoradiographic mapping of oxytocin receptors was carried out with the use of [(125)I]-vasotocin in brain sections of these animals. Chronic methamphetamine administration induced a region specific upregulation of oxytocin receptor density in the amygdala and hypothalamus, but not in the nucleus accumbens and caudate putamen. As there is evidence suggesting an involvement of central adenosine A2A receptors on central endogenous oxytocinergic function, we investigated whether these methamphetamine-induced oxytocinergic neuroadaptations are mediated via an A2A receptor-dependent mechanism. To test this hypothesis, autoradiographic oxytocin receptor binding was carried out in brain sections of male CD1 mice lacking A2A receptors which were chronically treated with methamphetamine (1mg/kg/day, i.p. for 10 days) or saline. Similar to wild-type animals, chronic methamphetamine administration induced a region-specific upregulation of oxytocin receptor binding in the amygdala and hypothalamus of A2A receptor knockout mice and no genotype effect was observed. These results indicate that chronic methamphetamine use can induce profound neuroadaptations of the oxytocinergic receptor system in brain regions associated with stress, emotionality and social bonding and that these neuroadaptations are independent on the presence of A2A receptors. These results may at least partly explain some of the behavioural consequences of chronic methamphetamine use. PMID- 23680574 TI - Antidepressant-like activity of 2-(4-phenylpiperazin-1-yl)-1, 8-naphthyridine-3 carboxylic acid (7a), a 5-HT3 receptor antagonist in behaviour based rodent models: evidence for the involvement of serotonergic system. AB - The present study was designed to investigate the putative antidepressant-like activity of 7a, a 5-HT3 receptor antagonist, (although indirect evidence of 5-HT3 antagonism) with an optimal log P (3.35) and pA2 value (7.6) greater than ondansetron (pA2--6.6) using behavioural tests battery of depression. Acute treatment of 7a (0.5-2 mg/kg, i.p.) in mice produced antidepressant-like effects in forced swim test (FST) and tail suspension test (TST) without affecting the baseline locomotion in actophotometer test in mice. Moreover, the combination of a sub-effective dose of 7a (0.25 mg/kg, i.p.) and fluoxetine (5 mg/kg, i.p.) produced an anti-immobility effect in mouse FST. Pretreatment of mice with p chlorophenylalanine methyl ester (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin (5-HT) synthesis, for 4 consecutive days) and 1-(m-Chlorophenyl) biguanide (mCPBG, 10 mg/kg, i.p., a 5-HT3 receptor agonist) prevented the anti immobility effects of 7a (2 mg/kg, i.p.) in the mouse FST. In addition, 7a (0.5-2 mg/kg, i.p.) treatment also potentiated the 5-hydroxytryptophan (5-HTP) and pargyline induced head twitch response in mice. Furthermore, sub-chronic treatment (14 days) with 7a (0.5-2 mg/kg, i.p.) and paroxetine (10 mg/kg, i.p.) significantly attenuated the behavioural anomalies induced by bilateral olfactory bulbectomy in rats in a modified open field paradigm. These results suggest that the antidepressant-like action of 7a may be mediated by an interaction with the serotonergic system and this molecule should be further investigated as an alternative therapeutic approach for the treatment of depression. PMID- 23680575 TI - Only repeated administration of the serotonergic agonist 8-OH-DPAT improves place learning of rats subjected to fimbria-fornix transection. AB - Serotonergic agonists may act neuroprotectively against brain injury. This study addressed the therapeutic potential of 8-hydroxy-2-di-n-propylamino-tetralin (8 OH-DPAT), a selective 5-HT1A/7 receptor agonist, after mechanical brain injury, and evaluated its effects in terms of acquisition of an allocentric place learning task in a water maze. Rats were divided into 6 experimental groups, three of which were subjected to bilateral transection of fimbria-fornix (FF), while three groups were given control surgery (Sham). After surgery, within both the lesioned, and sham-operated animals, respectively, one group was administered a single dose of saline, one group was given a single dose (0.5 mg/kg/b.w.) of 8 OH-DPAT, and one group was treated with daily administration of 8-OH-DPAT (0.5 mg/kg/b.w.) for eight days. The acquisition of the water maze based place learning task started on the 8th day post-surgery and continued for 20 days. The results show that the lesioned group subjected to repeated administration of 8-OH DPAT demonstrated a significantly improved acquisition of the place learning task compared to the vehicle injected lesion group. In contrast, the lesioned group treated with a single administration displayed impaired performance compared to the baseline lesion group. There were no significant effects of the 8-OH-DPAT administration in the sham control groups. We conclude that only the repeated stimulation of the 5-HT1A/7 system was associated with beneficial, recovery enhancing effects. PMID- 23680576 TI - Treatment with group psychotherapy for chronic psychogenic nonepileptic seizures. AB - Although there have been a number of psychotherapy trials for chronic psychogenic nonepileptic seizures, evidence-based treatment options are limited. We developed an eclectic group psychotherapy which combines psychoeducation and behavioral and psychoanalytic techniques. Nine patients completed 12 weeks of psychotherapy. Patients were interviewed with SCID-I. They also filled in the following measures at the beginning and end of the therapy: Beck Depression Inventory, Dissociative Experiences Scale, Spielberger State-Trait Anxiety Scale, SF-36 Life Quality Scale, and Toronto Alexithymia Scale. Seizure frequency was assessed before and after the therapy and on follow-up visits at the fourth, sixth, ninth, and twelfth months. After one year of follow-up, the decrease in seizure frequency was highly significant (p<0.001). In addition, we observed significant improvements in the mental health subscale of the SF-36 (p=0.03) and the state (p=0.006) and trait (p=0.02) subscales of the Spielberger State-Trait Anxiety Scale at the end of the therapy. These results suggest that group psychotherapy might be a treatment option for chronic psychogenic nonepileptic seizures. PMID- 23680577 TI - Management of allergy and anaphylaxis during oral surgery. AB - Minor and major allergic reactions occur during oral and maxillofacial treatment. Immediate diagnosis and pharmacologic intervention are imperative. Signs and symptoms may be variable. The early administration of epinephrine is critical. PMID- 23680578 TI - Engaging a wider public health workforce for the future: a public health practitioner in residence approach. AB - This paper outlines and assesses a project that sought to use a studio residency (a public health practitioner in residence) as a vehicle to introduce public health issues and concepts into the curricula of a studio cohort of fifth and sixth year architecture students. The practitioner delivered workshops, group tutorials and one-to-one guidance on individual design projects whose aim was to improve the health and well-being of the local population. Students reported being enthused by the practitioner and developed a broader understanding of their role as future architects in the promotion and protection of the health of the public. The public health practitioner in residence model may offer an exciting way of educating and inspiring the future wider public health workforce in the built environment design focused professions. Such an approach could transform the way in which such professionals construct their societal role in terms of their future impact on population health and their contribution as members of the wider public health workforce. PMID- 23680579 TI - Agency problems, ethical challenges and governance attributes in different models of physician-patient interaction within the assisted reproduction setting. PMID- 23680581 TI - Opioid withdrawal syndrome after treatment with low-dose extended-release oxycodone and naloxone in a gastric cancer patient with portal vein thrombosis. PMID- 23680582 TI - Ontario hospitals are not using palliative care performance indicators in their balanced scorecards. PMID- 23680583 TI - Evaluation of right ventricular function in patients with tetralogy of Fallot using the myocardial performance index and isovolumic acceleration: a comparison with cardiac magnetic resonance imaging. AB - BACKGROUND: Assessment of right ventricular function is a key point in the follow up of operated patients with tetralogy of Fallot. Cardiac magnetic resonance assessment of right ventricular function is considered the gold standard. However, this technique is expensive, has limited availability, and requires significant expertise to acquire and interpret the images. Myocardial performance index and isovolumic acceleration have recently been studied for the assessment of right ventricular function and are shown to be simple yet powerful tools for assessing patients with right ventricular dysfunction of various origins. METHODS: In this study, the integrity of myocardial performance index and isovolumic acceleration obtained by tissue Doppler imaging echocardiography to quantify right ventricular function was assessed in 31 patients operated for tetralogy of Fallot. Myocardial performance index and isovolumic acceleration measurements were compared with the parameters derived by cardiac magnetic resonance imaging. RESULTS: In this study, a significant correlation has not been detected between cardiac magnetic resonance-originated right ventricular ejection fraction, pulmonary regurgitation fraction and myocardial performance index, isovolumic acceleration obtained by tissue Doppler imaging echocardiography from the lateral tricuspid annulus of the right ventricle. CONCLUSION: We have concluded that when evaluated separately, myocardial performance index and isovolumic acceleration obtained from tissue Doppler imaging echocardiography can be used in the long-term follow-up of patients who have been operated for tetralogy of Fallot, but that they do not show correlation with cardiac magnetic resonance-originated right ventricle ejection fraction and pulmonary regurgitation fraction. PMID- 23680584 TI - Editorial comment. PMID- 23680580 TI - Creating computable algorithms for symptom management in an outpatient thoracic oncology setting. AB - CONTEXT: Adequate symptom management is essential to ensure quality cancer care, but symptom management is not always evidence based. Adapting and automating national guidelines for use at the point of care may enhance use by clinicians. OBJECTIVES: This article reports on a process of adapting research evidence for use in a clinical decision support system that provided individualized symptom management recommendations to clinicians at the point of care. METHODS: Using a modified ADAPTE process, panels of local experts adapted national guidelines and integrated research evidence to create computable algorithms with explicit recommendations for management of the most common symptoms (pain, fatigue, dyspnea, depression, and anxiety) associated with lung cancer. RESULTS: Small multidisciplinary groups and a consensus panel, using a nominal group technique, modified and subsequently approved computable algorithms for fatigue, dyspnea, moderate pain, severe pain, depression, and anxiety. The approved algorithms represented the consensus of multidisciplinary clinicians on pharmacological and behavioral interventions tailored to the patient's age, comorbidities, laboratory values, current medications, and patient-reported symptom severity. Algorithms also were reconciled with one another to enable simultaneous management of several symptoms. CONCLUSION: A modified ADAPTE process and nominal group technique enabled the development and approval of locally adapted computable algorithms for individualized symptom management in patients with lung cancer. The process was more complex and required more time and resources than initially anticipated, but it resulted in computable algorithms that represented the consensus of many experts. PMID- 23680585 TI - Evaluation of four biodegradable, injectable bone cements in an experimental drill hole model in sheep. AB - Four cement applications were tested in this investigation. Two dicalcium phosphate dihydrate (DCPD-brushite) hydraulic cements, an apatite hydraulic fiber loaded cement, and a calcium sulfate cement (Plaster of Paris) were implanted in epiphyseal and metaphyseal cylindrical bone defects in sheep. The in vivo study was performed to assess the biocompatibility and bone remodeling of four cement formulations. After time periods of 2, 4, and 6 months, the cement samples were clinically and histologically evaluated. Histomorphometrically, the amount of new bone formation, fibrous tissue, and bone marrow and the area of remaining cement were measured. In all specimens, no signs of inflammation were detectable either macroscopically or microscopically. Cements differed mainly in their resorption time. Calcium sulfate was already completely resorbed at 2 months and showed a variable amount of new bone formation and/or fibrous tissue in the original drill hole over all time periods. The two DCPD cements in contrast were degraded to a large amount at 6 months, whereas the apatite was almost unchanged over all time periods. PMID- 23680586 TI - Metabolic profiling reveals that time related physiological changes in mammalian cell perfusion cultures are bioreactor scale independent. AB - Metabolic profiling was used to characterize the time course of cell physiology both in laboratory- and manufacturing-scale mammalian cell perfusion cultures. Two independent experiments were performed involving three vials from the same BHK cell bank, used to inoculate three laboratory-scale bioreactors, from which four manufacturing-scale cultures were initiated. It was shown that metabolomic analysis can indeed enhance the prime variable dataset for the monitoring of perfusion cultures by providing a higher resolution view of the metabolic state. Metabolic profiles could capture physiological state shifts over the course of the perfusion cultures and indicated a metabolic "signature" of the phase transitions, which was not observable from prime variable data. Specifically, the vast majority of metabolites had lower concentrations in the middle compared to the other two phases. Notably, metabolomics provided orthogonal (to prime variables) evidence that all cultures followed this same metabolic state shift with cell age, independently of bioreactor scale. PMID- 23680587 TI - Isocyanate exposure assessment combining industrial hygiene methods with biomonitoring for end users of orthopedic casting products. AB - Previous studies have suggested a potential risk to healthcare workers applying isocyanate-containing casts, but the authors reached their conclusions based on immunological or clinical pulmonology test results alone. We designed a study to assess potential exposure to methylene diphenyl diisocyanate (MDI) among medical personnel applying orthopedic casts using two different application methods. Air, dermal, surface, and glove permeation sampling methods were combined with urinary biomonitoring to assess the overall risk of occupational asthma to workers handling these materials. No MDI was detected in any of the personal and area air samples obtained. No glove permeation of MDI was detected. A small proportion of surface (3/45) and dermal wipe (1/60) samples were positive for MDI, but were all from inexperienced technicians. Urinary metabolites of MDI [methylenedianiline (MDA)] were detected in three of six study participants prior to both a 'dry' and 'wet' application method, five of six after the dry method, and three of six after the wet method. All MDA results were below levels noted in worker or general populations. Our conclusion is that the risk of MDI exposure is small, but unquantifiable. Because there is some potential risk of dermal exposure, medical personnel are instructed to wear a minimum of 5-mil-thick (5 mil = 0.005 inches) nitrile gloves and avoid contact to unprotected skin. This could include gauntlets, long sleeves, and/or a laboratory coat. PMID- 23680588 TI - Toluene diisocyanate emission to air and migration to a surface from a flexible polyurethane foam. AB - Flexible polyurethane foam (FPF) is produced from the reaction of toluene diisocyanate (TDI) and polyols. Because of the potential for respiratory sensitization following exposure to TDI, concerns have been raised about potential consumer exposure to TDI from residual 'free TDI' in FPF products. Limited and conflicting results exist in the literature concerning the presence of unreacted TDI remaining in FPF as determined by various solvent extraction and analysis techniques. Because residual TDI results are most often intended for application in assessment of potential human exposure to TDI from FPF products, testing techniques that more accurately simulated human contact with foam were designed. To represent inhalation exposure to TDI from polyurethane foam, a test that measured the emission of TDI to air was conducted. For simulation of human dermal exposure to TDI from polyurethane foam, a migration test technique was designed. Emission of TDI to air was determined for a representative FPF using three different emission test cells. Two were commercially available cells that employ air flow over the surface of the foam [the Field and Laboratory Emission Cell (FLEC(r)) and the Micro-Chamber/Thermal ExtractionTM cell]. The third emission test cell was of a custom design and features air flow through the foam sample rather than over the foam surface. Emitted TDI in the air of the test cells was trapped using glass fiber filters coated with 1-(2-methoxyphenyl) piperazine (MP), a commonly used derivatizing agent for diisocyanates. The filters were subsequently desorbed and analyzed by liquid chromatography/mass spectrometry. Measurement of TDI migration from representative foam was accomplished by placing glass fiber filters coated with MP on the outer surfaces of a foam disk and then compressing the filters against the disk using a clamping apparatus for periods of 8 and 24 h. The sample filters were subsequently desorbed and analyzed in the same manner as for the emission tests. Although the foam tested had detectable levels of solvent-extractable TDI (56ng TDI g(-1) foam for the foam used in emissions tests; 240-2800ng TDI g(-1) foam for the foam used in migration tests), no TDI was detected in any of the emission or migration tests. Method detection limits (MDLs) for the emissions tests ranged from 0.03 to 0.5ng TDI g(-1) foam (0.002-0.04ng TDI cm(-2) of foam surface), whereas those for the migration tests were 0.73ng TDI g(-1) foam (0.16ng TDI cm(-2) of foam surface). Of the three emission test methods used, the FLEC(r) had the lowest relative MDLs (by a factor of 3-10) by virtue of its high chamber loading factor. In addition, the FLEC(r) cell offers well-established conformity with emission testing standard methods. PMID- 23680590 TI - Influence of electromagnetic interference on AED function in metro stations. PMID- 23680589 TI - IRON-HF study: a randomized trial to assess the effects of iron in heart failure patients with anemia. AB - BACKGROUND: Anemia in heart failure patients and has been associated with increased morbi-mortality. Previous studies have treated anemia in heart failure patients with either erythropoietin alone or combination of erythropoietin and intravenous (i.v.) iron. However, the effect of i.v. or oral (p.o.) iron supplementation alone in heart failure patients with anemia was virtually unknown. AIM: To compare, in a double-blind design, the effects of i.v. iron versus p.o. iron in anemic heart failure patients. METHODS: IRON-HF study was a multicenter, investigator initiated, randomized, double-blind, placebo controlled trial that enrolled anemic heart failure patients with preserved renal function, low transferrin saturation (TSat) and low-to-moderately elevated ferritin levels. Interventions were Iron Sucrose i.v. 200 mg, once a week, for 5 weeks, ferrous sulfate 200 mg p.o. TID, for 8 weeks, or placebo. Primary endpoint was variation of peak oxygen consumption (peak VO2) assessed by ergospirometry over 3 month follow-up. RESULTS: Eighteen patients had full follow-up data. There was an increment of 3.5 ml/kg/min in peak VO2 in the i.v. iron group. There was no increment in peak VO2 in the p.o. iron group. Patients' ferritin and TSat increased significantly in both treated groups. Hemoglobin increased similarly in all groups. CONCLUSION: I.v. iron seems to be superior in improving functional capacity of heart failure patients. However, correction of anemia seems to be at least similar between p.o. iron and i.v. iron supplementation. PMID- 23680592 TI - Prognostic factors in patients with proven or possible vasospastic angina who underwent coronary spasm provocation test. PMID- 23680591 TI - Simvastatin reduces wasting and improves cardiac function as well as outcome in experimental cancer cachexia. AB - BACKGROUND: Chronic inflammation is common in cancer cachexia (CC) and directly involved in the atrophy seen in this condition. Recently, several groups have described a form of cardiomyopathy in CC animal models. Hence, we investigated the effect of simvastatin with its known anti-inflammatory and cardioprotective effects in a rat model of CC. METHODS: Juvenile Wister Han rats (weight approx. 200 g) were inoculated with Yoshida AH-130 hepatoma cells and treated once daily with 0.1, 1, 10 or 20 mg/kg/d simvastatin or placebo for 14 days. Body weight and body composition (NMR) were assessed at baseline and at the end of the study. Cardiac function was analysed by echocardiography at baseline and day 11. RESULTS: Tumour-bearing, placebo-treated rats lost 47.9+/-3.8 g of their initial body weight. Treatment with 0.1, 1, 10 or 20 mg/kg/d simvastatin significantly reduced wasting by 39.6%, 47.6%, 28.5% and 35.4%, respectively (all p<0.05 vs. placebo). This was mainly due to reduced atrophy of lean mass, i.e. muscle mass. Cardiac function was significantly improved, e.g. cardiac output (untreated sham: 78.9 mL/min) was severely impaired in tumour-bearing rats (42.4 mL/min) and improved by 1, 10 or 20 mg/kg/d simvastatin (62.2, 59.0 and 57.0 mL/min, respectively, all p<0.05 vs. placebo). Most importantly, 10 or 20 mg/kg/d simvastatin reduced mortality (HR:0.16, 95%CI:0.04-0.76, p=0.021 and HR:0.16, 95%CI:0.03-0.72, p=0.017 vs placebo, respectively). CONCLUSION: Simvastatin attenuated loss of body weight as well as muscle mass and improved cardiac function leading to improved survival in this CC model. Simvastatin may be beneficial in a clinical setting to treat CC. PMID- 23680593 TI - Cardiomyocyte-specific overexpression of human stem cell factor protects against myocardial ischemia and reperfusion injury. AB - BACKGROUND: Cardiomyocyte-specific overexpression of human membrane-associated stem cell factor (hSCF) improves cardiac function post-myocardial infarction. However, whether hSCF overexpression protects the heart from ischemia and reperfusion (I/R) injury is unknown. We aimed to investigate the effects of cardiomyocyte-specific overexpression of hSCF on cardiac injury after acute myocardial I/R and related cellular and molecular signaling mechanisms. METHODS AND RESULTS: Wild-type (WT) and hSCF/tetracycline transactivator (tTA) transgenic mice (hSCF/tTA) were subjected to myocardial ischemia for 45 min followed by 3 h of reperfusion. Infarct size and myocardial apoptosis were decreased in hSCF/tTA compared to WT mice (P<0.05). Furthermore, these cardioprotective effects in the hSCF/tTA mice were abrogated by doxycycline, which turned off hSCF overexpression, and by a PI3 kinase inhibitor LY294002. Myocardial expression of insulin-like growth factor (IGF)-1 and hepatocyte growth factor (HGF), which are upstream activators of Akt signaling, was significantly increased in hSCF/tTA compared to WT mice after I/R (P<0.05), and was associated with higher number of c-kit(+) cardiac stem cells (CSCs) (P<0.05). Inhibition of c-kit signaling by ACK2 treatment abolished these protective effects in hSCF/tTA mice. CONCLUSIONS: Cardiomyocyte-specific overexpression of hSCF protects the heart from I/R injury. The cardioprotective effects of hSCF overexpression are mediated by increased c kit(+) CSCs, enhanced growth factor expression and activation of Akt signaling pathway. PMID- 23680594 TI - Vegetable and fruit intake protects from chronic heart failure. PMID- 23680595 TI - Heart rate impact on the reproducibility of heart rate variability analysis. PMID- 23680596 TI - Local inhibition of ornithine decarboxylase reduces vascular stenosis in a murine model of carotid injury. AB - OBJECTIVES: Polyamines are organic polycations playing an essential role in cell proliferation and differentiation, as well as in cell contractility, migration and apoptosis. These processes are known to contribute to restenosis, a pathophysiological process often occurring in patients submitted to revascularization procedures. We aimed to test the effect of alpha difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, on vascular cell pathophysiology in vitro and in a rat model of carotid arteriotomy induced (re)stenosis. METHODS: The effect of DFMO on primary rat smooth muscle cells (SMCs) and mouse microvascular bEnd.3 endothelial cells (ECs) was evaluated through the analysis of DNA synthesis, polyamine concentration, cell viability, cell cycle phase distribution and by RT-PCR targeting cyclins and genes belonging to the polyamine pathway. The effect of DFMO was then evaluated in arteriotomy injured rat carotids through the analysis of cell proliferation and apoptosis, RT PCR and immunohistochemical analysis of differential gene expression. RESULTS: DFMO showed a differential effect on SMCs and on ECs, with a marked, sustained anti-proliferative effect of DFMO at 3 and 8 days of treatment on SMCs and a less pronounced, late effect on bEnd.3 ECs at 8 days of DFMO treatment. DFMO applied perivascularly in pluronic gel at arteriotomy site reduced subsequent cell proliferation and preserved smooth muscle differentiation without affecting the endothelial coverage. Lumen area in DFMO-treated carotids was 49% greater than in control arteries 4 weeks after injury. CONCLUSIONS: Our data support the key role of polyamines in restenosis and suggest a novel therapeutic approach for this pathophysiological process. PMID- 23680597 TI - Amiodarone plus Flecainide combination therapy in patients with Amiodarone refractory paroxysmal atrial fibrillation. PMID- 23680598 TI - Activity and crystal structure of human thymine DNA glycosylase mutant N140A with 5-carboxylcytosine DNA at low pH. AB - The mammalian thymine DNA glycosylase (TDG) excises 5-carboxylcytosine (5caC) when paired with a guanine in a CpG sequence, in addition to mismatched bases. Here we present a complex structure of the human TDG catalytic mutant, asparagine 140 to alanine (N140A), with a 28-base pair DNA containing a G:5caC pair at pH 4.6. TDG interacts with the carboxylate moiety of target nucleotide 5caC using the side chain of asparagine 230 (N230), instead of asparagine 157 (N157) as previously reported. Mutation of either N157 or N230 residues to aspartate has minimal effect on G:5caC activity while significantly reducing activity on G:U substrate. Combination of both the asparagine-to-aspartate mutations (N157D/N230D) resulted in complete loss of activity on G:5caC while retaining measurable activity on G:U, implying that 5caC can adopt alternative conformations (either N157-interacting or N230-interacting) in the TDG active site to interact with either of the two asparagine side chain for 5caC excision. PMID- 23680599 TI - The role of ATM and DNA damage in neurons: upstream and downstream connections. AB - ATM (ataxia-telangiectasia mutated) is a large protein kinase whose best-known function is as a participant in the process of DNA damage repair, specifically lesions that result in double strand breaks. In the cells of the nervous system, however, the symptoms of children with ataxia-telangiectasia and the phenotypes of mice with engineered mutations in their ATM gene argue for a broader range of protein functions. ATM is now appreciated to play a role in vesicle dynamics as well as in the maintenance of the epigenetic code of histone modifications. Finally, the decline of ATM levels with age suggest that late onset neurodegenerative diseases may owe part of their pathogenesis to deficits in ATM signaling. Evidence from the location of HDAC4 in the hippocampal pyramidal cells of the Alzheimer's disease brain supports this hypothesis. These multiple functions of the ATM protein are in keeping with the complex multi-system nature of the symptoms of ataxia-telangiectasia and encourage us to look beyond DNA damage for the full understanding of the disease and its consequences. PMID- 23680600 TI - Arginine-rich hydrophobic polyethylenimine: potent agent with simple components for nucleic acid delivery. AB - Conjugation of various arginine-rich peptide sequences to vectors based on 10 kDa polyethylenimine (PEI) and its hydrophobic derivative (hexanoate-PEI) was investigated as a strategy for improving pDNA and siRNA transfection activities. Six different arginine-histidine (RH) sequences and two arginine-serine (RS) sequences with a range of R/H ratios were designed and coupled to PEI and hexanoate-PEI. All arginine-rich peptide derivatives of PEI significantly enhanced luciferase gene expression compared to PEI 10 kDa alone. Hexanoate-PEI derivatives exhibited higher transfection activity than underivatized PEI vectors. Improved transfection activity may have resulted at least in part from use of higher vector/DNA ratios made possible by reduced cytotoxicity of vectors, and to use of vectors with higher molecular weights. Vectors that were the most efficient in pDNA delivery and transfection were also the most effective in siRNA delivery and protein expression knock down. PMID- 23680601 TI - Rotating-shield brachytherapy for cervical cancer. AB - In this treatment planning study, the potential benefits of a rotating shield brachytherapy (RSBT) technique based on a partially-shielded electronic brachytherapy source were assessed for treating cervical cancer. Conventional intracavitary brachytherapy (ICBT), intracavitary plus supplementary interstitial (IS+ICBT), and RSBT treatment plans for azimuthal emission angles of 180 degrees (RSBT-180) and 45 degrees (RSBT-45) were generated for five patients. For each patient, high-risk clinical target volume (HR-CTV) equivalent dose in 2 Gy fractions (EQD2) (alpha/beta = 10 Gy) was escalated until bladder, rectum, or sigmoid colon tolerance EQD2 values were reached. External beam radiotherapy dose (1.8 Gy * 25) was accounted for, and brachytherapy was assumed to have been delivered in 5 fractions. IS+ICBT provided a greater HR-CTV D90 (minimum EQD2 to the hottest 90%) than ICBT. D90 was greater for RSBT-45 than IS+ICBT for all five patients, and greater for RSBT-180 than IS+ICBT for two patients. When the RSBT 45/180 plan with the lowest HR-CTV D90 that was greater than the D90 the ICBT or IS+ICBT plan was selected, the average (range) of D90 increases for RSBT over ICBT and IS+ICBT were 16.2 (6.3-27.2)and 8.5 (0.03-20.16) Gy, respectively. The average (range) treatment time increase per fraction of RSBT was 34.56 (3.68 70.41) min over ICBT and 34.59 (3.57-70.13) min over IS+ICBT. RSBT can increase D90 over ICBT and IS+ICBT without compromising organ-at-risk sparing. The D90 and treatment time improvements from RSBT depend on the patient and shield emission angle. PMID- 23680603 TI - Nurturing in Delhi! Editor: Dr. PN Taneja; Years 1970 - 1972. PMID- 23680602 TI - Improving quality of pediatric care in India a call for action. PMID- 23680604 TI - Updated national guidelines for pediatric tuberculosis in India, 2012. PMID- 23680605 TI - Propranolol therapy for infantile hemangioma. AB - CONTEXT: There has been widespread interest surrounding the use of beta-blockers (i.e. propranolol, timolol, nadolol, acebutolol) in the treatment of infantile hemangiomas (IH). OBJECTIVE: To review literature evaluating treatment of IH with propranolol. EVIDENCE ACQUISITION: We conducted a literature search on PubMed and investigated for case reports, case series, and controlled trials by using search terms including hemangioma and propranolol. RESULTS: Data suggest that beta blockers are efficacious in cutaneous, orbital, subglottic, and hepatic hemangiomas and assist in the resolution of ulcerated hemangiomas. Improvement has also been documented in children with PHACE syndrome. Propranolol produces favorable results in children who do not respond to steroids and with no long term adverse effects. Propranolol should be administered with caution due to rare but serious side effects including hypoglycemia, wheezing, hypotension, and bradycardia. Additionally, recurrence of lesions following the cessation of treatment has been documented. CONCLUSIONS: Although large-scale randomized controlled trials must be conducted in order to further evaluate the safety and the possible role of propranolol in the treatment of IH, the reviewed literature suggests that propranolol carries promise as a potential replacement for corticosteroids as first-line therapy or as a part of a multimodal approach. PMID- 23680606 TI - Neonatal cholestasis with ductal paucity and steatosis. PMID- 23680607 TI - Pseudohypoaldosteronism type 1: management issues. AB - We report a newborn girl with life-threatening hyperkalemia and salt wasting crisis due to severe autosomal recessive multiple target organ dysfunction pseudohypoaldosteronism type 1 (MTOD PHA1). She was aggressively managed with intravenous fluids, potassium-lowering agents, high-dose sodium chloride supplementation and peritoneal dialysis. Genetic analysis revealed a homozygous mutation of the alpha- ENaC (epithelial Na(+) channel) gene. She had a stormy clinical course with refractory hyperkalemia and prolonged hospitalization. Eventually, she succumbed to pneumonia and septicemia at 4 months of age. This is probably the first case of PHA1 confirmed by genetic analysis from India. PMID- 23680608 TI - Nasal hemophilic pseudotumor: favorable response to radiotherapy. AB - Hemophilic pseudotumors are rare but dangerous complications of Hemophilia. We hereby report a 3-year-old boy with Hemophilia B, presenting with nasal pseudotumor, showing favorable response to radiotherapy after unsuccessful treatment with factor IX replacement therapy. The diagnosis and treatment of this rare condition is also reviewed. PMID- 23680609 TI - Hypokalemic periodic paralysis and distal renal tubular acidosis associated with renal morphological changes. AB - We report an unusual case of 5-yrs-old girl presenting with recurrent episodic weakness with documented hypokalemia, polyuria and failure to thrive. The child was finally diagnosed as having distal renal tubular acidosis. Imaging studies revealed associated hypoechoic spaces in renal medulla. Long term treatment with alkali and maintenance of normokalemia lead to regression of these morphological changes. PMID- 23680610 TI - Editorial policies of MEDLINE indexed Indian journals on clinical trial registration. AB - 30 MEDLINE indexed Indian journals publishing clinical trials were identified and their editorial policies on trial registration were assessed. Trial registration number was required in 9 journals (30%).16 journals (53.33%) encouraged adherence to the CONSORT Statement, while 22 (73.33%) mentioned ICMJE Guidelines. PMID- 23680612 TI - Tachycardia - Treatment issues! PMID- 23680611 TI - Clinical response to antibiotics among children with bloody diarrhea. AB - WHO recommends ciprofloxacin as the drug of choice for bloody diarrhea. We retrospectively analyzed antibiotic response in 100 children with bloody diarrhea admitted between 2006-2010. Cotrimoxazole (n=55) had higher chance of attaining improved appetite and normal activity in 48 h, hospitalization of <3d, blood disappearance in <=5d and not requiring a second antibiotic compared to others (n=45). Older antimicrobials should be tried in all possible situations. PMID- 23680613 TI - Prolonged sedation following administration of oral midazolam. PMID- 23680614 TI - Camphor poisoning: personal experience. PMID- 23680615 TI - Hair dye poisoning [paraphenylenediamine, Super vasamol 33]. PMID- 23680616 TI - ADEM following malaria. PMID- 23680617 TI - EBV-reactivation and post-transplant lymphoproliferative disorder treated with rituximab. PMID- 23680618 TI - Psoas abscess: primary or secondary? PMID- 23680619 TI - Workplace based assessments: a complement to the quarter model. PMID- 23680620 TI - Reply: To PMID 23255699. PMID- 23680621 TI - Understanding non-financial conflicts of interest. PMID- 23680622 TI - Recurrent hemarthrosis : an unusual cause. PMID- 23680623 TI - Active tuberculosis with Takayasu arteritis. PMID- 23680624 TI - Professional support framework: improving access to professional support for professionals. AB - From an organisational point of view, professional support is an important aspect of clinical governance and a tool for maximising service delivery quality. As a key factor in staff retention and recruitment, access to professional support is also regarded as an important tool for facilitating workforce growth in a competitive health workforce market. While some work units provide appropriate professional support such as in-service, professional supervision is a key challenge for a large organisation employing many health professionals to ensure equitable and relevant access to finite professional support resources. The goal of this paper is to describe the Professional Support Program designed and implemented by Queensland Health. This program seeks to support professionals who may not previously have had optimal engagement in professional support and to enhance the quality of professional support activities available. Evaluation indicates that the Professional Support Program has been successful in facilitating participation in, and quality of professional support activities. PMID- 23680626 TI - Cytoskeletal roles in cardiac ion channel expression. AB - The cytoskeleton and cardiac ion channel expression are closely linked. From the time that newly synthesized channels exit the endoplasmic reticulum, they are either traveling along the microtubule or actin cytoskeletons or likely anchored in the plasma membrane or in internal vesicular pools by those scaffolds. Molecular motors, small GTPases and even the dynamics of the cytoskeletons themselves influence the trafficking and expression of the channels. In some cases, the functioning of the channels themselves has profound influences on the cytoskeleton. Here we provide an overview of the current state of knowledge on the involvement of the actin and microtubule cytoskeletons in the trafficking, targeting and expression of cardiac ion channels and a few channels expressed elsewhere. We highlight, also, some of the many questions that remain about these processes. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Herve. PMID- 23680625 TI - T cell antigen receptor activation and actin cytoskeleton remodeling. AB - T cells constitute a crucial arm of the adaptive immune system and their optimal function is required for a healthy immune response. After the initial step of T cell-receptor (TCR) triggering by antigenic peptide complexes on antigen presenting cell (APC), the T cell exhibits extensive cytoskeletal remodeling. This cytoskeletal remodeling leads to the formation of an "immunological synapse" [1] characterized by regulated clustering, segregation and movement of receptors at the interface. Synapse formation regulates T cell activation and response to antigenic peptides and proceeds via feedback between actin cytoskeleton and TCR signaling. Actin polymerization participates in various events during the synapse formation, maturation, and eventually its disassembly. There is increasing knowledge about the actin effectors that couple TCR activation to actin rearrangements [2,3], and how defects in these effectors translate into impairment of T cell activation. In this review we aim to summarize and integrate parts of what is currently known about this feedback process. In addition, in light of recent advancements in our understanding of TCR triggering and translocation at the synapse, we speculate on the organizational and functional diversity of microfilament architecture in the T cell. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Herve. PMID- 23680627 TI - Comparison of efficacy and safety of laser in situ keratomileusis using 2 femtosecond laser platforms in contralateral eyes. AB - PURPOSE: To compare the efficacy, predictability, and refractive outcomes of laser in situ keratomileusis (LASIK) using 2 femtosecond platforms for flap creation. SETTING: Multisurgeon single center. DESIGN: Clinical trial. METHODS: Bilateral femtosecond LASIK was performed using the Wavelight Allegretto Eye-Q 400 Hz excimer laser system. The Visumax femtosecond platform (Group 1) was used to create the LASIK flap in 1 eye, while the Intralase femtosecond platform (Group 2) was used to create the LASIK flap in the contralateral eye. The preoperative, 1-month, and 3-month postoperative visual acuities, refraction, and contrast sensitivity in the 2 groups were compared. RESULTS: The study enrolled 45 patients. Three months after femtosecond LASIK, 79.5% of eyes in Group 1 and 82.1% in Group 2 achieved an uncorrected distance visual acuity of 20/20 (P=.808). The mean efficacy index was 0.97 in Group 1 and 0.98 in Group 2 at 3 months (P=.735); 89.7% of eyes in Group 1 and 84.6% of eyes in Group 2 were within +/- 0.50 diopter of emmetropia at 3 months (P=.498). No eye in either group lost more than 2 lines of corrected distance visual acuity. The mean safety index at 3 months was 1.11 in Group 1 and 1.10 in Group 2 (P=.570). CONCLUSION: The results of LASIK with both femtosecond lasers were similar, and both platforms produced efficacious and predictable LASIK outcomes. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23680628 TI - Comparison of the efficacy of povidone-iodine 1.0%, 5.0%, and 10.0% irrigation combined with topical levofloxacin 0.3% as preoperative prophylaxis in cataract surgery. AB - PURPOSE: To compare the efficacy of povidone-iodine 1.0%, 5.0%, and 10.0% in combination with topical levofloxacin 0.3% in reducing the preoperative conjunctival bacterial load before cataract surgery. SETTING: Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany. DESIGN: Randomized clinical trial. METHODS: This study enrolled patients scheduled for cataract surgery between July 2010 and January 2011. All patients received topical levofloxacin 0.3% 4 times on the preoperative day and were randomly assigned to these study groups: Group 1 (povidone-iodine 1.0%), Group 2 (povidone-iodine 5.0%), and Group 3 (povidone-iodine 10.0%). In all groups, the conjunctiva was flush irrigated with 10 mL of povidone-iodine of the respective concentration. Conjunctival specimens were obtained at 4 timepoints: baseline (no-surgery eye), before povidone-iodine irrigation, after povidone-iodine irrigation, and at the end of surgery. All specimens were inoculated onto blood and chocolate agars and into thioglycolate broth. RESULTS: The study was completed by 271 patients. In the control smear (no-surgery eye), no significant difference in positive cultures was found. After 10 mL povidone-iodine irrigation, a considerable reduction in the conjunctival bacterial load occurred in all groups. The difference in positive cultures was statistically significant between Group 1 and Group 3 (P=.024) and between Group 2 and Group 3 (P=.029). Coagulase-negative Staphylococcus was the most commonly isolated bacteria in all groups. CONCLUSION: Povidone-iodine 10.0% was more effective than povidone-iodine 1.0% and 5.0% in decreasing the conjunctival bacterial load before surgery. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23680629 TI - Determination of the nature and origin of the metallic foreign particles appearing on the iris after phacoemulsification. AB - PURPOSE: To determine the nature and the origin of metallic foreign particles appearing on the iris after phacoemulsification surgery. SETTING: P.D. Hinduja Hospital and Medical Research Centre, Mumbai, Maharashtra, India. DESIGN: Case series. METHODS: Metallic foreign particles were observed on the iris surface and the pupillary border on the first postoperative visit after phacoemulsification. One metallic particle, which was stuck to the iris surface, was removed intraoperatively and sent for metal analysis along with the phaco needle, the wrench used to tighten the phaco needle to the phaco handpiece, and the anterior chamber maintainer used during phacoemulsification. The composition of the elements was studied by scanning electron microscopy (SEM) to determine the origin of the metallic particle. RESULTS: Foreign particles were seen in 11 eyes. On SEM, 3 elements (carbon, magnesium, and silicone) were common in the metal particle and 4 elements (carbon, magnesium, silicone, and titanium) on the wrench. The elements in the phaco needle (titanium) and anterior chamber maintainer (manganese, iron, and nickel) did not match those in the metal particle. CONCLUSION: The metal contents of the metallic particle extracted from the eye matched some of the constituent metals of the wrench that was used to tighten the phaco needle on the handpiece just before surgery. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23680630 TI - Corneal cell response after flap creation using a mechanical microkeratome or a 200 kHz femtosecond laser. AB - PURPOSE: To compare the inflammatory cell response within the corneal flap interface created by a mechanical microkeratome and a femtosecond laser. SETTING: Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany. DESIGN: Experimental in vitro study. METHODS: Corneoscleral buttons of 12 enucleated human eyes not suitable for transplantation were put into organ culture. Corneal flaps were created using a 200 kHz femtosecond laser (Visumax) (femtosecond group) or a mechanical microkeratome (Amadeus) (microkeratome group). Flaps were not lifted after treatment. In 2 corneas, no treatment was performed (control group). Corneas were kept in organ culture for 12 hours thereafter. To evaluate cell-mediated immune reaction, immunofluorescent staining for leucocytes (cluster of differentiation 45) and specifically for dendritic cells (human leukocyte antigen-DR) was performed in every group. A terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was used to determine apoptosis reaction. RESULTS: The ratio of dendritic cells in the femtosecond group compared with the microkeratome group was 1.2 (P=.02), the ratio of leucocytes was 1.4 (P=.06), and the ratio of apoptotic cells was 1.0 (P=.59). There was no marked significant difference in the distribution of inflammatory cell reaction. The control group showed neither specific inflammatory reaction nor apoptosis. CONCLUSION: This in vitro series of human corneas showed similar inflammatory tissue reaction after femtosecond laser assisted and microkeratome-assisted flap creation (P<.05). FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23680631 TI - Visual and optical outcomes of a diffractive multifocal toric intraocular lens. AB - PURPOSE: To evaluate the visual and wavefront outcomes after cataract surgery with implantation of a diffractive multifocal toric intraocular lens (IOL). SETTING: Two clinical centers, Lisbon, Portugal. DESIGN: Case series. METHODS: This study comprised patients with cataract and corneal astigmatism between 0.75 diopter (D) and 2.50 D who had phacoemulsification with implantation of an Acrysof IQ Restor toric IOL. Over a 3-month follow-up, the main outcome measures were uncorrected distance visual acuity (UDVA), uncorrected intermediate visual acuity (UIVA) at 80 cm, uncorrected near visual acuity (UNVA) at 40 cm, spherical equivalent (SE) refraction, residual astigmatism, rotational stability of the IOL, higher-order aberrations, and the presence of dysphotopic phenomena. RESULTS: The study included 38 eyes (19 patients). The mean UDVA was 0.07 logMAR +/- 0.10 (SD), the mean UIVA was 0.16 +/- 0.10 logMAR, and the mean UNVA was 0.02 +/- 0.09 logMAR. Predictability of refractive results was very good, with an SE refraction within +/- 0.50 D of the attempted spherical correction in 33 eyes (87%). The mean toric IOL axis rotation was 2.97 +/- 2.33 degrees. One eye required a second surgery to align the IOL axis. Ocular aberrometry and dysphotopic phenomena results were similar to those published for the nontoric version of the toric IOL. CONCLUSION: Implantation of the diffractive multifocal toric IOL in patients with cataract and corneal astigmatism provided excellent distance, intermediate, and near visual outcomes; predictability of the refractive results; rotational stability; and good optical performance, allowing all patients to achieve complete spectacle independence. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23680632 TI - Evaluation of corneal thickness using a Scheimpflug-Placido disk corneal analyzer and comparison with ultrasound pachymetry in eyes after laser in situ keratomileusis. AB - PURPOSE: To evaluate the repeatability and reproducibility of corneal thickness measurements in post-laser in situ keratomileusis (LASIK) eyes using a rotating Scheimpflug camera combined with a Placido disk corneal topographer (Sirius) and compare the results with those of ultrasound (US) pachymetry. SETTING: Eye Hospital of Wenzhou Medical College, Wenzhou, China. DESIGN: Comparative evaluation of a diagnostic test or technology. METHODS: Patients were examined 3 times with the Scheimpflug-Placido topographer by 2 examiners. The central pupil corneal thickness (CTpupil), apical corneal thickness (CTapex), and thinnest corneal thickness (CTthinnest) were recorded. After noncontact examinations, US pachymetry was used to obtain the central corneal thickness (CCT). RESULTS: The Scheimpflug-Placido topographer showed high intraoperator repeatability as indicated by a test-retest repeatability of less than 8.5 MUm for CTpupil, CTapex, and CTthinnest, The coefficients of variation (CoV) were less than 0.7%, and the intraclass correlation coefficient was higher than 0.99. Excellent results were also obtained for interoperator reproducibility. All CoVs were less than 0.5%. The 95% limits of agreement between the Scheimpflug-Placido measurement and the US pachymetry measurements were narrow (-16.62 to 12.44 MUm for CTpupil versus US pachymetry CCT; -17.49 to 12.16 MUm for CTapex versus US pachymetry CCT; -18.59 to 10.90 MUm for CTthinnest versus US pachymetry CCT). CONCLUSIONS: The Scheimpflug-Placido topographer showed excellent intraoperator repeatability and interoperator reproducibility of CTpupil, CTapex, and CTthinnest measurements in post-LASIK eyes. The CCT measurements obtained using the device were in high agreement with those obtained by US pachymetry, suggesting that the 2 devices are interchangeable. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23680633 TI - Corneal inlay implantation in a young pseudophakic patient. AB - We describe the surgical correction of a 32-year-old pseudophakic patient with the Kamra corneal inlay. To our knowledge, this is the youngest patient to have such a procedure. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 23680635 TI - D1-D2 dopamine receptor synergy promotes calcium signaling via multiple mechanisms. AB - The D(1) dopamine receptor (D(1)R) has been proposed to form a hetero-oligomer with the D(2) dopamine receptor (D(2)R), which in turn results in a complex that couples to phospholipase C-mediated intracellular calcium release. We have sought to elucidate the pharmacology and mechanism of action of this putative signaling pathway. Dopamine dose-response curves assaying intracellular calcium mobilization in cells heterologously expressing the D(1) and D(2) subtypes, either alone or in combination, and using subtype selective ligands revealed that concurrent stimulation is required for coupling. Surprisingly, characterization of a putative D(1)-D(2) heteromer-selective ligand, 6-chloro-2,3,4,5-tetrahydro-3 methyl-1-(3-methylphenyl)-1H-3-benzazepine-7,8-diol (SKF83959), found no stimulation of calcium release, but it did find a broad range of cross-reactivity with other G protein-coupled receptors. In contrast, SKF83959 appeared to be an antagonist of calcium mobilization. Overexpression of G(qalpha) with the D(1) and D(2) dopamine receptors enhanced the dopamine-stimulated calcium response. However, this was also observed in cells expressing G(qalpha) with only the D1R. Inactivation of Gi or Gs with pertussis or cholera toxin, respectively, largely, but not entirely, reduced the calcium response in D(1)R and D(2)R cotransfected cells. Moreover, sequestration of G(betagamma) subunits through overexpression of G protein receptor kinase 2 mutants either completely or largely eliminated dopamine-stimulated calcium mobilization. Our data suggest that the mechanism of D(1)R/D(2)R-mediated calcium signaling involves more than receptor-mediated G(q) protein activation, may largely involve downstream signaling pathways, and may not be completely heteromer-specific. In addition, SKF83959 may not exhibit selective activation of D(1)-D(2) heteromers, and its significant cross reactivity to other receptors warrants careful interpretation of its use in vivo. PMID- 23680636 TI - An unusual pattern of ligand-receptor interactions for the alpha7 nicotinic acetylcholine receptor, with implications for the binding of varenicline. AB - The alpha7 nicotinic acetylcholine receptor shows broad pharmacology, complicating the development of subtype-specific nicotinic receptor agonists. Here we use unnatural amino acid mutagenesis to characterize binding to alpha7 by the smoking cessation drug varenicline (Chantix; Pfizer, Groton, CT), an alpha4beta2-targeted agonist that shows full efficacy and modest potency at the alpha7 receptor. We find that unlike binding to its target receptor, varenicline does not form a cation-pi interaction with TrpB, further supporting a unique binding mode for the cationic amine of nicotinic agonists at the alpha7 receptor. We also evaluate binding to the complementary face of the receptor's binding site by varenicline, the endogenous agonist acetylcholine, and the potent nicotine analog epibatidine. Interestingly, we find no evidence for functionally important interactions involving backbone NH and CO groups thought to bind the canonical agonist hydrogen bond acceptor of the nicotinic pharmacophore, perhaps reflecting a lesser importance of this pharmacophore element for alpha7 binding. We also show that the Trp55 and Leu119 side chains of the binding site's complementary face are important for the binding of the larger agonists epibatidine and varenicline, but dispensable for binding of the smaller, endogenous agonist acetylcholine. PMID- 23680637 TI - Organic cation transporter 1 (OCT1/mOct1) is localized in the apical membrane of Caco-2 cell monolayers and enterocytes. AB - Organic cation transporters (OCTs) are members of the solute carrier 22 family of transporter proteins that are involved in absorption, distribution, and excretion of organic cations. OCT3 is localized in the apical (AP) membrane of enterocytes, but the literature is ambiguous about OCT1 (mOct1) localization, with some evidence suggesting a basolateral (BL) localization in human and mouse enterocytes. This is contrary to our preliminary findings showing AP localization of OCT1 in Caco-2 cell monolayers, an established model of human intestinal epithelium. Therefore, this study aims at determining the localization of OCT1 (mOct1) in Caco-2 cells, and human and mouse enterocytes. Functional studies using OCT1-specific substrate pentamidine showed transporter-mediated AP but not BL uptake in Caco-2 cells and human and mouse intestinal tissues. OCT1 inhibition decreased AP uptake of pentamidine by ~50% in all three systems with no effect on BL uptake. A short hairpin RNA-mediated OCT1 knockdown in Caco-2 cells decreased AP uptake of pentamidine by ~50% but did not alter BL uptake. Immunostaining and confocal microscopy in all three systems confirmed AP localization of OCT1 (mOct1). Our studies unequivocally show AP membrane localization of OCT1 (mOct1) in Caco-2 cells and human and mouse intestine. These results are highly significant as they will require reinterpretation of previous drug disposition and drug-drug interaction studies where conclusions were drawn assuming BL localization of OCT1 in enterocytes. Most importantly, these results will require revision of the regulatory guidance for industry in the United States and elsewhere because it has stated that OCT1 is basolaterally localized in enterocytes. PMID- 23680638 TI - Candida orthopsilosis fungemias in a Spanish tertiary care hospital: incidence, epidemiology and antifungal susceptibility. AB - BACKGROUND: Few studies exist on prevalence of fungemia by Candida orthopsilosis, with variable results. AIMS: To study the incidence, epidemiology and antifungal susceptibility of C. orthopsilosis strains isolated from fungemias over two years at a tertiary hospital. METHODS: Candidemia episodes between June 2007 and June 2009 in a university hospital (Puerta del Mar, Cadiz, Spain) were studied. The strains initially identified as Candida parapsilosis were genotypically screened for C. parapsilosis sensu stricto, C. orthopsilosis and Candida metapsilosis, and their antifungal susceptibility was evaluated. RESULTS: In this period 52 cases of candidemia were documented. Of the 19 strains originally identified as C. parapsilosis, 13 were confirmed as C. parapsilosis sensu stricto and 6 as C. orthopsilosis. Of the 52 isolates, the most frequent species were Candida albicans (30.8%), C. parapsilosis sensu stricto (25%), C. orthopsilosis, Candida tropicalis and Candida glabrata in equal numbers (11.5%). C. orthopsilosis isolates were susceptible to amphotericin B, caspofungin, voriconazole and fluconazole, with no significant differences in MIC values with C. parapsilosis sensu stricto. The source of isolates of C. orthopsilosis were neonates (50%) and surgery (50%), and 100% were receiving parenteral nutrition; however C. parapsilosis sensu stricto was recovered primarily from patients over 50 years (69.2%) and 46.1% were receiving parenteral nutrition. CONCLUSIONS: These findings show that C. orthopsilosis should be considered as human pathogenic yeast and therefore its accurate identification is important. Despite our small sample size our study suggests that a displacement of some epidemiological characteristics previously attributed to C. parapsilosis to C. orthopsilosis may be possible. PMID- 23680640 TI - Cloning and characterising an unusual perforin from chicken (Gallus gallus). AB - In mammals the 67 kDa pore-forming protein perforin is essential to the granule exocytosis pathway used by cytotoxic lymphocytes to eliminate virally infected and malignant cells. There is indirect evidence that this pathway exists in lower vertebrates such as teleost fish and birds, although in genome databases for the chicken and other bird species the perforin gene is incomplete and no full length expressed sequence tag has been reported. We present here the full gene and transcript sequence of chicken perforin. The inferred protein product contains an extended C-terminus that is at least 90 amino acids longer than any mammalian perforin, which is also evident in partial genomic sequences from other birds. To determine whether this extension is present in the translated protein, we raised two polyclonal antisera. The antisera identified a protein of just less than 80 kDa in both transfected COS-1 cells and concanavalin A stimulated chicken splenocytes, indicating that the extended C-terminus is present in the mature protein. Our findings confirm that perforin exists in birds, and show that it is considerably longer than perforin of non-avian vertebrates. PMID- 23680642 TI - Mitochondrial OXPHOS function is unaffected by chronic azithromycin treatment. AB - BACKGROUND: Certain antibiotics may cause unwanted side effects due to the similarity of the mitochondrial translation system to the prokaryotic one. Children with cystic fibrosis (CF) are vulnerable to recurrent respiratory tract infections and azithromycin, a translation targeted antibiotic, is often used chronically to treat CF patients. No major clinical side effects were found with chronic treatment. However, mitochondrial function was not previously assessed. We evaluated oxidative phosphorylation (OXPHOS) in lymphocytes from children with CF receiving chronic azithromycin treatment using an improved ATP production assay. METHOD: Enzymatic activities of respiratory chain complexes II-IV and ATP production were measured in lymphocytes. RESULTS: Relative to controls and to CF patients without azithromycin treatment, no significant difference in mitochondrial respiratory chain complexes II-IV was detected, and ATP production with pyruvate, glutamate and succinate, did not disclose any differences between the groups. CONCLUSION: We suggest that chronic treatment with azithromycin does not significantly affect OXPHOS function. PMID- 23680641 TI - Menopausal hormone therapy and risk of endometrial cancer. AB - Endometrial cancer is clearly a hormonally responsive tumor, with a critical role played by estrogens unopposed by progestins. Numerous epidemiologic studies have shown substantial risk increases associated with use of unopposed estrogens, especially among thin women. This risk, however, can be reduced if progestins are added to the therapy. The manner in which progestins are prescribed is a critical determinant of risk. Most studies show that women who have ever used progestins continuously (>25 days/months) are at somewhat reduced risk relative to non-users (meta-analysis relative risk, RR, based on observational studies=0.78, 95 confidence intervals, CI, 0.72-0.86). The reduced risk in greatest among heavy women. In contrast, women who have ever used progestins sequentially for <10 days each month are at increased risk, with meta-analysis results showing on overall RR of 1.76 (1.51-2.05); in contrast, progestins given for 10-24 days/month appear unrelated to risk (RR=1.07, 0.92-1.24). These risks were based on varying patterns of usage, with little information available regarding how endometrial cancer risk is affected by duration of use, type and/or dose of estrogen or progestin, or mode of administration. Effects may also vary by clinical characteristics (e.g., differences for Type I vs. II tumors). Further resolution of many of these relationships may be dependent on pooling data from multiple studies to derive sufficient power for subgroups of users. With changing clinical practices, it will be important for future studies to monitor a wide range of exposures and to account for divergent effects of different usage patterns. This article is part of a Special Issue entitled 'Menopause'. PMID- 23680643 TI - The effects of the myostatin g+6723G>A mutation on carcass and meat quality of lamb. AB - This study evaluated the effects of the myostatin g+6723G>A mutation on carcass and meat quality traits of lamb (AA: n=5; AG: n=8; GG: n=9). Dressing percentage was positively affected by the mutation with homozygotes for the mutation having the highest yield. Regarding carcass composition, there was a significant increase in the proportional weights of the loin and hindquarter muscles. Objective meat quality traits of the M. longissimus lumborum (LL) and M. semimembranosus (SM) were not significantly affected. For the SM, toughness (shear force and compression) tended to be lowest for homozygotes for the mutation. The myostatin g+6723G>A mutation did not affect sensory meat quality traits of grilled steaks for the LL, but resulted in a significant improvement in eating quality for the SM. Given the number of animals in this study, the robustness of the outcome of this study with regard to the effects on meat quality and its causes requires further investigation. PMID- 23680644 TI - Alanine-scanning mutagenesis of WH2 domains of VopF reveals residues important for conferring lethality in a Saccharomyces cerevisiae model. AB - VopF, the type III effector molecule, has been implicated in the pathogenesis of non-O1, non-O139 strains of Vibrio cholerae. It is a protein of 530 amino acids, comprises of one formin homology 1-like (FH1-like) domain and three WASP homology 2 (WH2) domains. Previous works have demonstrated that WH2 domains are crucial for VopF function as a modulator of cellular actin homeostasis. Furthermore, domain deletion analysis also suggests that VopF variant constituted with only WH2 domain 3 is more efficient in restricting the growth of budding yeast than its congeners containing either only domain 1 or domain 2. Interestingly, a good degree of sequence diversity is present within each WH2 domain of VopF. In order to ascertain the importance of different amino acids in each WH2 domain, a systemic alanine scanning mutagenesis was employed. Using a yeast model system, the alanine derivatives of each amino acid of WH2 domain 1 and 3 of VopF were examined for growth restricting activity. Taken together, our mutagenesis results reveal the identification of critical residues of WH2 domain 1 and 3 of VopF. PMID- 23680645 TI - Update of the spectrum of GJB2 gene mutations in Tunisian families with autosomal recessive nonsyndromic hearing loss. AB - Hearing loss is the most frequent sensory disorder. It affects 3 in 1000 newborns. It is genetically heterogeneous with 60 causally-related genes identified to date. Mutations in GJB2 gene account for half of all cases of non syndromic deafness. The aim of this study was to determine the relative frequency of GJB2 allele variants in Tunisia. In this study, we screened 138 patients with congenital hearing loss belonging to 131 families originating from different parts of Tunisia for mutations in GJB2 gene. GJB2 mutations were found in 39% of families (51/131). The most common mutation was c.35delG accounting for 35% of all cases (46/131). The second most frequent mutation was p.E47X present in 3.8% of families. Four identified mutations in our cohort have not been reported in Tunisia; p.V37I, c.235delC, p.G130A and the splice site mutation IVS1+1G>A (0.76%). These previously described mutations were detected only in families originating from Northern and not from other geographical regions in Tunisia. In conclusion we have confirmed the high frequency of c.35delG in Tunisia which represents 85.4% of all GJB2 mutant alleles. We have also extended the mutational spectrum of GJB2 gene in Tunisia and revealed a more pronounced allelic heterogeneity in the North compared to the rest of the country. PMID- 23680639 TI - Viruses and antiviral immunity in Drosophila. AB - Viral pathogens present many challenges to organisms, driving the evolution of a myriad of antiviral strategies to combat infections. A wide variety of viruses infect invertebrates, including both natural pathogens that are insect restricted, and viruses that are transmitted to vertebrates. Studies using the powerful tools in the model organism Drosophila have expanded our understanding of antiviral defenses against diverse viruses. In this review, we will cover three major areas. First, we will describe the tools used to study viruses in Drosophila. Second, we will survey the major viruses that have been studied in Drosophila. And lastly, we will discuss the well-characterized mechanisms that are active against these diverse pathogens, focusing on non-RNAi mediated antiviral mechanisms. Antiviral RNAi is discussed in another paper in this issue. PMID- 23680647 TI - Kinetic analysis of inhibition of glucoamylase and active site mutants via chemoselective oxime immobilization of acarbose on SPR chip surfaces. AB - We here report a quantitative study on the binding kinetics of inhibition of the enzyme glucoamylase and how individual active site amino acid mutations influence kinetics. To address this challenge, we have developed a fast and efficient method for anchoring native acarbose to gold chip surfaces for surface plasmon resonance studies employing wild type glucoamylase and active site mutants, Y175F, E180Q, and R54L, as analytes. The key method was the chemoselective and protecting group-free oxime functionalization of the pseudo-tetrasaccharide-based inhibitor acarbose. By using this technique we have shown that at pH 7.0 the association and dissociation rate constants for the acarbose-glucoamylase interaction are 10(4)M(-1)s(-1) and 10(3)s(-1), respectively, and that the conformational change to a tight enzyme-inhibitor complex affects the dissociation rate constant by a factor of 10(2)s(-1). Additionally, the acarbose presenting SPR surfaces could be used as a glucoamylase sensor that allowed rapid, label-free affinity screening of small carbohydrate-based inhibitors in solution, which is otherwise difficult with immobilized enzymes or other proteins. PMID- 23680646 TI - Structural characterization and expression analysis of a beta-thymosin homologue (Tbeta) in disk abalone, Haliotis discus discus. AB - Repertoires of proteins and small peptides play numerous physiological roles as hormones, antimicrobial peptides, and cellular signaling factors. The beta thymosins are a group of small acidic peptides involved in processes such as actin sequestration, neuronal development, wound healing, tissue repair, and angiogenesis. Recent characterization of the beta thymosins as immunological regulators in invertebrates led to our identification and characterization of a beta-thymosin homologue (Tbeta) from Haliotis discus discus. The cDNA possessed an ORF of 132 bp encoding a protein of 44 amino acids with a molecular mass of 4977 Da. The amino acid sequence shows high identity with another molluskan beta thymosin and has a characteristic actin binding motif (LKKTET) and glutamyl donors. Phylogenetic analysis showed a close relationship with molluskan homologues, as well as its distinct identity and common ancestral origin. Genomic analysis revealed a 3 exon-2 intron structure similar to the other homologues. In silico promoter analysis also revealed significant transcription factor binding sites, providing evidence for the expression of this gene under different cellular conditions, including stress or pathogenic attack. Tissue distribution profiling revealed a ubiquitous presence in all the examined tissues, but with the highest expression in mantle and hemocyte. Immune challenge with lipopolysaccharide, poly I:C and Vibrio parahemolyticus induced beta-thymosin expression in gill and hemocytes, affirming an immune-related role in invertebrates. PMID- 23680648 TI - Medullary sponge kidney. AB - PURPOSE OF REVIEW: After it was first described in 1939, medullary sponge kidney (MSK) received relatively little attention. This was because it was believed to have a low prevalence and because it was considered a benign condition. Studies in recent years have been changing these convictions however, hence the present review. RECENT FINDINGS: Insight has been obtained on the genetic basis of this disease, supporting the hypothesis that MSK is due to a disruption at the 'ureteric bud-metanephric mesenchyme' interface. This explains why so many tubular defects coexist in this disease, and particularly a distal tubular acidification defect of which the highly prevalent metabolic bone disease is one very important consequence. In addition to the typical clinical phenotype of recurrent stone disease, other clinical profiles have now been recognized, that is, an indolent, almost asymptomatic MSK, and a rare form characterized by intractable, excruciating pain. SUMMARY: Findings suggest the need for a more comprehensive clinical characterization of MSK patients. The genetic grounds for the condition warrant further investigation, and reliable methods are needed to diagnose MSK. PMID- 23680649 TI - Clinical assessment of phosphorus status, balance and renal handling in normal individuals and in patients with chronic kidney disease. AB - PURPOSE OF REVIEW: The concepts of steady state, external balance, total body status and internal distribution are not always appreciated or even considered in clinical practice. The current tests available for clinical assessment of phosphorus physiology and pathophysiology are valid in some aspects, but also have many limitations. The purpose of this review is to clarify the above concepts and discuss the utility of the currently available tests to assess phosphorus disorders. RECENT FINDINGS: Both epidemiologic and preclinical data have shown that disturbances in mineral metabolism contribute significantly to the morbidity and mortality in chronic kidney disease. There are also emerging data supporting the notion that phosphotoxicity may exist even in individuals with normal renal function. In chronic kidney disease (CKD), hyperphosphatemia is a relative late event and is a suboptimal indicator of phosphorus balance and status. The judicious use of plasma and urine chemistry and hormonal biomarkers such as fibroblast growth factor 23 should be considered. SUMMARY: There is a dire need to increase awareness of what physiologic parameters should be monitored in terms of phosphorus pathophysiology. Although the current available tests in the clinical armamentarium are not ideal, understanding their implications and limitations will improve patient care and motivate practitioners and investigators to develop better tests. PMID- 23680650 TI - Effects of homogenization technique and introduction of interfaces in a multiscale approach to predict the elastic properties of arthropod cuticle. AB - In this paper the mechanical response of the arthropod cuticle is evaluated by means of a multiscale approach including interface effects. The cuticle's elastic behavior is modeled at the nano and the micro scales by mean-field homogenization techniques. With respect to the work of Nikolov et al. (2011), the idea has been extended to study, at different scales of the structure, the effect of the used homogenization technique as well as the interface effect on the global elastic properties. First results revealed the sensitivity of the used homogenization technique on the global predicted elastic properties of the arthropod cuticle. To account for the interface between the fillers and the matrix of the composite structure of the arthropod cuticle, interphases are assumed at different scales of the structure with the same shape and topological orientation as the fillers. The approaches are based on few parameters directly related to the mechanical properties, the volume fraction and the morphology of the interphase. Results of the predicted elastic properties using the multiscale model including interphases are in good agreement with the experimental results. We show that the introduction of interphases leads to an improvement of the global elastic response in comparison to the multiscale model without interphases. PMID- 23680652 TI - Evaluation of extraprostatic disease in the staging of prostate cancer by F-18 choline PET/CT: can PSA and PSA density help in patient selection? AB - OBJECTIVE: The aim of our study was to evaluate the accuracy of F-18 choline positron emission tomography/computed tomography (PET/CT) in assessing the presence of extraprostatic disease during staging of prostate cancer, in relation to prostate-specific antigen (PSA) and PSA density, a PSA derivative that is useful for improving risk stratification in prostate cancer patients. METHODS: F 18 choline PET/CT was performed in 45 patients for early staging of biopsy-proven prostate cancer. None of the examined patients had received therapy before the examination. In all of them a transrectal ultrasonography had been performed earlier to calculate the prostate volume and PSA density. The mean PSA value was 25.5 (+/-38.1) ng/ml, whereas the mean PSA density was 0.70 (+/-0.88). RESULTS: Results of F-18 choline PET/CT were related to PSA and PSA density. PET/CT was positive for extraprostatic disease in 18/45 patients (40%) (mean PSA and PSA density were, respectively, 44.08 ng/ml and 1.08); PET/CT was negative for extraprostatic disease in 27/45 patients (60%) (mean PSA and PSA density were, respectively, 13.12 ng/ml and 0.4). PET/CT was positive in 13/18 patients (72%) with a PSA cutoff value greater than or equal to 18 ng/ml and in 5/21 (24%) with a PSA value less than 18 ng/ml (P=0.0017). PET/CT was positive in 16/18 patients (89%) with PSA density greater than or equal to 0.31 and in 2/18 (11%) with PSA density lower than 0.31 (P=0.0234). CONCLUSION: The possibility of detecting extraprostatic disease of prostate cancer with F-18 choline PET/CT is related to PSA and PSA density. In particular, F-18 choline PET/CT should be recommended only in patients with a PSA value of at least 18 ng/ml, whereas a PSA density of at least 0.31 ng/ml is more probably associated with distant metastases. PMID- 23680651 TI - Measurements of mechanical anisotropy in brain tissue and implications for transversely isotropic material models of white matter. AB - White matter in the brain is structurally anisotropic, consisting largely of bundles of aligned, myelin-sheathed axonal fibers. White matter is believed to be mechanically anisotropic as well. Specifically, transverse isotropy is expected locally, with the plane of isotropy normal to the local mean fiber direction. Suitable material models involve strain energy density functions that depend on the I4 and I5 pseudo-invariants of the Cauchy-Green strain tensor to account for the effects of relatively stiff fibers. The pseudo-invariant I4 is the square of the stretch ratio in the fiber direction; I5 contains contributions of shear strain in planes parallel to the fiber axis. Most, if not all, published models of white matter depend on I4 but not on I5. Here, we explore the small strain limits of these models in the context of experimental measurements that probe these dependencies. Models in which strain energy depends on I4 but not I5 can capture differences in Young's (tensile) moduli, but will not exhibit differences in shear moduli for loading parallel and normal to the mean direction of axons. We show experimentally, using a combination of shear and asymmetric indentation tests, that white matter does exhibit such differences in both tensile and shear moduli. Indentation tests were interpreted through inverse fitting of finite element models in the limit of small strains. Results highlight that: (1) hyperelastic models of transversely isotropic tissues such as white matter should include contributions of both the I4 and I5 strain pseudo-invariants; and (2) behavior in the small strain regime can usefully guide the choice and initial parameterization of more general material models of white matter. PMID- 23680653 TI - Investigation of analog charge multiplexing schemes for SiPM based PET block detectors. AB - Reducing the number of output channels in pixelated positron emission tomography (PET) detectors is an effective way to minimize cost and complexity while minimizing the impact on detector performance. This paper compares the system performance of two multiplexing schemes by using both simulation and experimental studies, with respect to spatial, time and energy resolutions. Simulations were performed using the SPICE environment to investigate differences in resulting flood histograms and rising edge slopes. Experiments were performed using lutetium-yttrium oxyorthosilicate (LYSO) crystals coupled to a SensL ArraySL-4 silicon photomultiplier (SiPM) connected to interchangeable circuit boards containing the two multiplexing schemes of interest. Three crystal configurations were tested: a single crystal element (3*3*20 mm(3)), 2*2 array (crystal pitch: 2*2) and 6*6 array (crystal pitch: 2.1*2.1*20 mm(3)). Good agreement was found between the simulations and experiment results. It is found that the capacitive multiplexing is able to achieve an improved time resolution of good uniformity (average of 1.11 +/- 0.01 ns and 1.90 +/- 0.03 ns for the arrays, respectively) and crystal separation, compared to the resistive multiplexing (average of 1.95 +/- 0.03 ns and 3.33 +/- 0.10 ns). On the other hand, the resistive multiplexing demonstrates slightly improved energy resolution (11 +/- 0.1% and 22 +/- 0.6%, compared to 12 +/- 0.1% and 24 +/- 0.4% for the capacitive array), which is believed to be caused by the RC circuit formed between the splitting capacitors and the input impedance of amplifiers. The relevancy of this work to the PET block detector design using SiPM arrays is also discussed, including light sharing, edge compression and gain variation among SiPM pixels. PMID- 23680655 TI - Neurodegenerative disorder FTDP-17-related tau intron 10 +16C -> T mutation increases tau exon 10 splicing and causes tauopathy in transgenic mice. AB - Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is a neurodegenerative disorder caused by mutations in the tau gene. Many mutations identified in FTDP-17 have been shown to affect tau exon 10 splicing in vitro, which presumably causes pathologic imbalances in exon 10(-) [3-repeat (3R)] and exon 10(+) [4-repeat (4R)] tau expression and leads to intracellular inclusions of hyperphosphorylated tau in patient brains. However, no reports have investigated this theory using model mice with a tau intronic mutation. Herein, we generated new transgenic mice harboring the tau intron 10 +16C -> T mutation. We prepared a transgene construct containing intronic sequences required for exon 10 splicing in the longest tau isoform cDNA. Although mice bearing the construct without the intronic mutation showed normal developmental changes of the tau isoform from 3R tau to equal amounts of 3R and 4R tau, mice with the mutation showed much higher levels of 4R tau at the adult stage. 4R tau was selectively recovered in insoluble brain fractions in their old age. Furthermore, these mice displayed abnormal tau phosphorylation, synapse loss and dysfunction, memory impairment, glial activation, tangle formation, and neuronal loss in an age dependent manner. These findings provide the first evidence in a mouse model that a tau intronic mutation-induced imbalance of 3R and 4R tau could be a cause of tauopathy. PMID- 23680654 TI - Failure of fibrotic liver regeneration in mice is linked to a severe fibrogenic response driven by hepatic progenitor cell activation. AB - Failure of fibrotic liver to regenerate after resection limits therapeutic options and increases demand for liver transplantation, representing a significant clinical problem. The mechanism underlying regenerative failure in fibrosis is poorly understood. Seventy percent partial hepatectomy (PHx) was performed in C57Bl/6 mice with or without carbon tetrachloride (CCl4)-induced liver fibrosis. Liver function and regeneration was monitored at 1 to 14 days thereafter by assessing liver mass, alanine aminotransferase (ALT), mRNA expression, and histology. Progenitor (oval) cell mitogen tumor necrosis factor like weak inducer of apoptosis (TWEAK) and TWEAK-neutralizing antibody were used to manipulate progenitor cell proliferation in vivo. In fibrotic liver, hepatocytes failed to replicate efficiently after PHx. Fibrotic livers showed late (day 5) peak of serum ALT (3542 +/- 355 IU/L compared to 93 +/- 65 IU/L in nonfibrotic livers), which coincided with progenitor cell expansion, increase in profibrogenic gene expression and de novo collagen deposition. In fibrotic mice, inhibition of progenitor activation using TWEAK-neutralizing antibody after PHx resulted in strongly down-regulated profibrogenic mRNA, reduced serum ALT levels and improved regeneration. Failure of hepatocyte-mediated regeneration in fibrotic liver triggers activation of the progenitor (oval) cell compartment and a severe fibrogenic response. Inhibition of progenitor cell proliferation using anti-TWEAK antibody prevents fibrogenic response and augments fibrotic liver regeneration. Targeting the fibrogenic progenitor response represents a promising strategy to improve hepatectomy outcomes in patients with liver fibrosis. PMID- 23680656 TI - Control of the human osteopontin promoter by ERRalpha in colorectal cancer. AB - Colorectal cancer is the second leading cause of death from cancer. Osteopontin (OPN) is a component of tumor extracellular matrix identified as a key marker of cancer progression. The estrogen-related receptor alpha (ERRalpha) has been implicated in endocrine-related cancer development and progression, possibly through modulation of cellular energy metabolism. Previous reports that ERRalpha regulates OPN expression in bone prompted us to investigate whether ERRalpha controls OPN expression in human colorectal cancer. Using a tissue microarray containing 83 tumor-normal tissue pairs of colorectal cancer samples, we found that tumor epithelial cells displayed higher staining for ERRalpha than normal mucosa, in correlation with elevated OPN expression. In addition, knocking down endogenous ERRalpha led to reduced OPN expression in HT29 colon cancer cells. Promoter analysis, inhibition of ERRalpha activity, and expression and mutation of potential ERRalpha response elements in the proximal promoter of human OPN showed that ERRalpha and its obligate co-activator, peroxisome proliferator activated receptor gamma co-activator-1 alpha, positively control human OPN promoter activity. Furthermore, chromatin immunoprecipitation experiments confirmed in vivo occupancy of the OPN promoter by ERRalpha in HT29 cells, suggesting that OPN is a direct target of ERRalpha in colorectal cancer. These findings suggest an additional mechanism by which ERRalpha participates in the development and progression of colorectal cancer, further supporting the relevance of targeting ERRalpha with antagonists as anticancer agents. PMID- 23680657 TI - Syncytial knots (Tenney-Parker changes) in the human placenta: evidence of loss of transcriptional activity and oxidative damage. AB - Syncytiotrophoblast is the multinucleated epithelium of the placenta. Although many nuclei are dispersed within the syncytioplasm, others are aggregated into specializations referred to as true and false syncytial knots, and syncytial sprouts. Nuclei within true knots display highly condensed chromatin and are thought to be aged and effete. True knots increase in frequency with gestational age. Excessive formation (Tenney-Parker change) is associated with placental pathology, and a knotting index is used to assess severity. However, this index is potentially confounded by the creation of artifactual appearances (false knots) through tangential sectioning. In addition, knots must be distinguished from syncytial sprouts, which are markers of trophoblast proliferation. Here, we distinguish between sprouts, true knots, and false knots using serial sections and perform IHC for proliferating cell nuclear antigen, upstream binding factor, RNA polymerase II, and 8-oxo-deoxyguanosine as markers of recent incorporation, transcriptional activity, and oxidative damage. Villous explants were exposed to hydrogen peroxide to test the relationship between transcriptional activity and oxidative damage. Sprouts and false knots were found to contain recently incorporated and transcriptionally active nuclei. By contrast, most nuclei within true knots are negative for transcriptional markers but positive for 8-oxo deoxyguanosine. In vitro, we observed a negative correlation between transcriptional activity and oxidative damage. These findings demonstrate that true knots contain effete damaged nuclei and provide IHC markers for their identification. PMID- 23680659 TI - A comparative study of the hovering efficiency of flapping and revolving wings. AB - Direct numerical simulations are used to explore the hovering performance and efficiency for hawkmoth-inspired flapping and revolving wings at Reynolds (Re) numbers varying from 50 to 4800. This range covers the gamut from small (fruit fly size) to large (hawkmoth size) flying insects and is also relevant to the design of micro- and nano-aerial vehicles. The flapping wing configuration chosen here corresponds to a hovering hawkmoth and the model is derived from high-speed videogrammetry of this insect. The revolving wing configuration also employs the wings of the hawkmoth but these are arranged in a dual-blade configuration typical of helicopters. Flow for both of these configurations is simulated over the range of Reynolds numbers of interest and the aerodynamic performance of the two compared. The comparison of these two seemingly different configurations raises issues regarding the appropriateness of various performance metrics and even characteristic scales; these are also addressed in the current study. Finally, the difference in the performance between the two is correlated with the flow physics of the two configurations. The study indicates that viscous forces dominate the aerodynamic power expenditure of the revolving wing to a degree not observed for the flapping wing. Consequently, the lift-to-power metric of the revolving wing declines rapidly with decreasing Reynolds numbers resulting in a hovering performance that is at least a factor of 2 lower than the flapping wing at Reynolds numbers less than about 100. PMID- 23680658 TI - Inhibition of Janus activated kinase-3 protects against myocardial ischemia and reperfusion injury in mice. AB - Recent studies have documented that Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) pathway can modulate the apoptotic program in a myocardial ischemia/reperfusion (I/R) model. To date, however, limited studies have examined the role of JAK3 on myocardial I/R injury. Here, we investigated the potential effects of pharmacological JAK3 inhibition with JANEX-1 in a myocardial I/R model. Mice were subjected to 45 min of ischemia followed by varying periods of reperfusion. JANEX-1 was injected 1 h before ischemia by intraperitoneal injection. Treatment with JANEX-1 significantly decreased plasma creatine kinase and lactate dehydrogenase activities, reduced infarct size, reversed I/R-induced functional deterioration of the myocardium and reduced myocardial apoptosis. Histological analysis revealed an increase in neutrophil and macrophage infiltration within the infarcted area, which was markedly reduced by JANEX-1 treatment. In parallel, in in vitro studies where neutrophils and macrophages were treated with JANEX-1 or isolated from JAK3 knockout mice, there was an impairment in the migration potential toward interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), respectively. Of note, however, JANEX-1 did not affect the expression of IL-8 and MCP-1 in the myocardium. The pharmacological inhibition of JAK3 might represent an effective approach to reduce inflammation-mediated apoptotic damage initiated by myocardial I/R injury. PMID- 23680661 TI - [Decrease in allogenic transfusions due to the spread of use of postoperative retransfusion systems in knee replacement surgery]. AB - OBJECTIVES: Surgical teams have several tools in order to reduce the need for postoperative allogenic transfusion. Postoperative autotransfusion of unwashed shed blood has become common practice for total knee replacement surgery since 2006 in our hospital. This study was designed to evaluate if this practice has reduced allogenic blood transfusions. MATERIAL AND METHODS: A retrospective study comparing two cohorts, group 2004 with patients operated on for total knee replacement during the year 2004, before the use of the retransfusion system, and group 2008, patients operated on in the year 2008, with regular use of the retransfusion system. Gender, preoperative and postoperative haemoglobin levels, total amount of calculated erythrocytes lost, reinfusion of shed blood and allogenic blood transfusion during hospital stay were recorded. RESULTS: Both groups were similar as regards gender, preoperative and postoperative hemoglobin levels, and total amount of erythrocytes lost. The proportion of transfused patients was significantly lower in group 2008 versus group 2004 (20.18% versus 42.19%), with a relative risk of being transfused of 0.47 and a NNT of 4.54. P=.0017. CONCLUSIONS: In our hospital the use of postoperative retransfusion systems has reduced the proportion of transfused patients during hospitalization for total knee replacement surgery, although this result cannot be generalized due to the lack of a fixed transfusion trigger. PMID- 23680662 TI - Flagellin/Toll-like receptor 5 response was specifically attenuated by keratan sulfate disaccharide via decreased EGFR phosphorylation in normal human bronchial epithelial cells. AB - Bacterial or viral infection of the airway plays a critical role in the pathogenesis and exacerbation of chronic obstructive pulmonary disease (COPD) which is expected to be the 3rd leading cause of death by 2020. The induction of inflammatory responses in immune cells as well as airway epithelial cells is observed in the disease process. There is thus a pressing need for the development of new therapeutics. Keratan sulfate (KS) is the major glycosaminoglycans (GAGs) of airway secretions, and is synthesized by epithelial cells on the airway surface. Here we report that a KS disaccharide, [SO3(-) 6]Galbeta1-4[SO3(-)-6]GlcNAc, designated as L4, suppressed the production of Interleukin-8 (IL-8) stimulated by flagellin, a Toll-like receptor (TLR) 5 agonist, in normal human bronchial epithelial (NHBE) cells. Such suppressions were not observed by other L4 analogues, N-acetyllactosamine or chondroitin-6 sulfate disaccharide. Moreover, treatment of NHBE cells with L4 inhibited the flagellin-stimulated phosphorylation of epidermal growth factor receptor (EGFR), the down stream signaling pathway of TLRs in NHBE cells. These results suggest that L4 specifically blocks the interaction of flagellin with TLR5 and subsequently suppresses IL-8 production in NHBE cells. Taken together, L4 represents a potential molecule for prevention and treatment of airway inflammatory responses to bacteria infections, which play a critical role in exacerbation of COPD. PMID- 23680663 TI - Enigma homolog 1 promotes myogenic gene expression and differentiation of C2C12 cells. AB - The Enigma homolog (ENH) gene generates several splicing variants. The initially identified ENH1 possesses one PDZ and three LIM domains, whereas ENH2~4 lack the latter domains. The splicing switch from ENH1 to LIM-less ENHs occurs during development/maturation of skeletal and heart muscles. We examined for the roles of ENH splicing variants in muscle differentiation using C2C12 cells. Cells stably expressing ENH1 exhibited significantly higher MyoD and myogenin mRNA levels before differentiation and after 5 days in low serum-differentiating medium than mock-transfected cells. ENH1-stable transformants also retained the ability to exhibit elongated morphology with well-extended actin fibers following differentiation. In contrast, cells stably expressing ENH3 or ENH4 did not show myotube-like morphology or reorganization of actin fibers following culture in the differentiating medium. Transient overexpression of ENH1 using adenovirus supported the increased expression of muscle marker mRNAs and the formation of well-organized stress fibers, whereas ENH4 overexpression prevented these morphological changes. Furthermore, specific suppression of ENH1 expression by RNAi caused a significant reduction in MyoD mRNA level and blocked the morphological changes. These results suggest that ENH1 with multiple protein protein interaction modules is essential for differentiation of striated muscles, whereas ectopic expression of LIM-less ENH disrupts normal muscle differentiation. PMID- 23680664 TI - Nanosecond pulsed electric field stimulation of reactive oxygen species in human pancreatic cancer cells is Ca(2+)-dependent. AB - The cellular response to 100 ns pulsed electric fields (nsPEF) exposure includes the formation of transient nanopores in the plasma membrane and organelle membranes, an immediate increase in intracellular Ca(2+), an increase in reactive oxygen species (ROS), DNA fragmentation and caspase activation. 100 ns, 30 kV/cm nsPEF stimulates an increase in ROS proportional to the pulse number. This increase is inhibited by the anti-oxidant, Trolox, as well as the presence of Ca(2+) chelators in the intracellular and extracellular media. This suggests that the nsPEF-triggered Ca(2+) increase is required for ROS generation. PMID- 23680665 TI - Neuronal nitric oxide synthase is phosphorylated in response to insulin stimulation in skeletal muscle. AB - Type 2 Diabetes (T2DM) is the seventh leading cause of death in the United States, and is quickly becoming a global pandemic. T2DM results from reduced insulin sensitivity coupled with a relative failure of insulin secretion. Reduced insulin sensitivity has been associated with reduced nitric oxide synthase (NOS) activity and impaired glucose uptake in T2DM skeletal muscle. Upon insulin stimulation, NO synthesis increases in normal adult skeletal muscle, whereas no such increase is observed in T2DM adults. Endothelial NOS is activated by phosphorylation in the C-terminal tail in response to insulin. Neuronal NOS (nNOS), the primary NOS isoform in skeletal muscle, contains a homologous phosphorylation site, raising the possibility that nNOS, too, may undergo an activating phosphorylation event upon insulin treatment. Yet it remains unknown if or how nNOS is regulated by insulin in skeletal muscle. Data shown herein indicate that nNOS is phosphorylated in response to insulin in skeletal muscle and that this phosphorylation event occurs rapidly in C2C12 myotubes, resulting in increased NO production. In vivo phosphorylation of nNOS was also observed in response to insulin in mouse skeletal muscle. These results indicate, for the first time, that nNOS is phosphorylated in skeletal muscle in response to insulin and in association with increased NO production. PMID- 23680666 TI - Magnetic resonance imaging features of pathologically proven cerebral sparganosis. AB - OBJECTIVE: The purpose of this study was to identify characteristic magnetic resonance imaging (MRI) features of cerebral sparganosis, a rare parasitic disease caused by the plerocercoid larva of Spirometra mansoni. METHODS: This retrospective study reviewed medical records, computed tomography (CT) and MRI scans and pathological specimens from patients with pathologically proven cerebral sparganosis. The location, signal intensity and contrast enhancement characteristics of the lesions were assessed. RESULTS: Records of 12 patients (seven male and five female; age range 8-35 years) were reviewed. A total of 13 lesions were identified: of the 10 patients with supratentorial lesions, nine had a single lesion and one had bilateral hemispheric lesions. Two patients had a single lesion in the ependyma of the 4(th) ventricle. All lesions were iso hypointense on T1-weighted images, slightly hypointense on T2-weighted images and surrounded by extensive oedema. Ten of the 13 lesions demonstrated a 'string knots sign', characterized by a tangled string in a knot-like shape on contrast enhanced MRI. CONCLUSION: A string-knots sign enhancement pattern in cortical subcortical regions should suggest the diagnosis of cerebral sparganosis. PMID- 23680667 TI - Quantitative computed tomography assessment of bone mineral density after 2 years' oral bisphosphonate treatment in postmenopausal osteoarthritis patients who underwent total knee arthroplasty. AB - OBJECTIVES: To identify the effects of two years' oral bisphosphonate (alendronate) treatment in patients who underwent total knee arthroplasty (TKA); to determine whether significant responses seen after the first year of treatment changed during the second year. Additionally, the study tried to identify factors relating to bone mineral density (BMD) changes. METHODS: This was a prospective 2 year follow-up study of a previous 1-year report of postmenopausal women with knee osteoarthritis who underwent primary unilateral or staged bilateral TKA, after which they received 70 mg alendronate orally once-weekly. BMD was measured using quantitative computed tomography (QCT) on lumbar vertebrae at baseline (pre TKA) and at 12 and 24 months. Factors associated with BMD changes were determined by regression analysis. RESULTS: Sixty-one patients entered the second year and continued treatment for >= 24 months. Mean vertebral QCT BMDs at baseline and after 12 and 24 months' alendronate treatment were 71.8 mg/ml (41.9-97.5 mg/ml), 69.3 mg/ml (31.4-103.9 mg/ml), and 72.7 mg/ml (33.1-136.1 mg/ml), respectively. Patients undergoing bilateral TKA and who had more severe OA at baseline (bilateral severe [grade 4] OA) had a lower BMD response after 2 years' bisphosphonate treatment, compared with patients with less severe unilateral knee OA who underwent unilateral TKA. Improvements were, however, seen compared with year 1 levels. Low BMI was associated with BMD nonresponse. CONCLUSIONS: Patients with bilateral severe OA (grade 4) requiring bilateral knee replacement are at greater risk of nonresponse after 2 years' oral alendronate treatment. A longer duration of treatment may be necessary in these patients. PMID- 23680668 TI - Beneficial effects of nebivolol and hydrochlorothiazide combination in spontaneously hypertensive rats. AB - OBJECTIVE: This study examined the combined effect of nebivolol (NEB) and hydrochlorothiazide (HCTZ) on cardiovascular function in spontaneously hypertensive rats (SHR). METHODS: SHR normotensive male rats were randomly assigned to five groups (n = 8 per group): (i) SHR control group; (ii) NEB 2 mg/kg per day group; (iii) HCTZ 10 mg/kg per day group; (iv) NEB 2 mg/kg per day + HCTZ 10 mg/kg per day group; (v) Eight age-matched Wistar-Kyoto normotensive male rats served as the control group. All groups were treated orally for 8 weeks. RESULTS: The combination of NEB + HCTZ synergistically reduced systolic blood pressure and heart rate compared with either monotherapy. HCTZ increased water intake, which is a sign of diuresis. NEB reduced plasma angiotensin II concentration, which was increased in SHR and after HCTZ treatment. NEB + HCTZ increased plasma nitric oxide (NO) concentration and NO synthase activity, which were both reduced in SHR. NEB + HCTZ normalized femoral arterial vasorelaxation induced by acetylcholine, which was impaired in SHR. CONCLUSIONS: The combination of NEB + HCTZ provided a number of beneficial and additive effects due to the synergistic characteristics of both drugs, in an experimental rat model of hypertension. PMID- 23680669 TI - Temporomandibular dysfunction syndrome: a prospective study of 255 consecutive patients. AB - OBJECTIVE: To determine the relationship between temporomandibular dysfunction syndrome (TMDS), sex and pain severity. METHODS: Data were collected prospectively from consecutive patients with TMDS. Patients were divided into four subgroups according to signs and symptoms: myofascial pain; intra-articular disorders; extra-articular disorders; degenerative disorders. Intergroup sex distribution differences were evaluated, the pain severity between the four subgroups was compared, and the rates of bruxism and inco-ordination were measured. A visual analogue scale was used to rate the pain. RESULTS: A total of 255 patients with TMDS were included in the study. A significantly higher rate of extra-articular disorders was found in male patients. Bruxism was found to be significantly more common in females than in males. There was no significant difference in the prevalence of inco-ordination based on sex. The overall pain score was higher in females than in males, but there was no significant difference. The pain score was significantly higher in patients in the degenerative disorders subgroup, compared with other subgroups. CONCLUSIONS: There was no relationship between TMDS and pain and sex. Pain scores were significantly higher in the degenerative disorders subgroup, compared with other subgroups. PMID- 23680670 TI - Structure determination of the exopolysaccharide of Lactobacillus fermentum TDS030603-a revision. AB - The highly viscous neutral exopolysaccharide, produced in large amounts by Lactobacillus fermentum TDS030603 in MRS broth and in a chemically defined medium supplemented with glucose, was investigated by GLC(-EIMS) monosaccharide and methylation analysis, periodate oxidation, MALDI-TOF mass spectrometry, and 1D/2D NMR spectroscopy. The GLC(-EIMS) analyses showed that the EPS contained d-glucose and d-galactose in an averaged molar ratio of 2.6:1.0, consisting of terminal d Glcp, 3-substituted d-Glcp, 2,3-disubstituted d-Glcp, and 6-substituted d-Galp in an averaged molar ratio of 1.3:1.0:1.1:1.1, with a trace of terminal d-Galp (0.1). Combined with the NMR data of the EPS (previously reported constituent analysis: terminal Glcp, 3-substituted Glcp, 2,3-disubstituted Glcp, and 6 substituted Galp in an averaged molar ratio of 1.2:1.1:1.0:1.1) and oligosaccharides isolated after partial acid hydrolysis, a branched tetrasaccharide repeating unit, with some heterogeneity in the side chain, having the following structure is proposed: [fromula see text]. PMID- 23680671 TI - The orphan nuclear receptor small heterodimer partner negatively regulates pancreatic beta cell survival and hyperglycemia in multiple low-dose streptozotocin-induced type 1 diabetic mice. AB - The small heterodimer partner (SHP; NR0B2) regulates the transcription of a variety of target genes and controls a variety of physiological functions in various tissues. However, the role of SHP in beta cell has not been fully determined yet. We used SHP knockout (SHP KO) mice to investigate the role of SHP in multiple low-dose streptozotocin (MLDS)-induced diabetes. Blood glucose and insulin levels were measured until 20 days, and intraperitoneal glucose tolerance and glucose-stimulated insulin secretion tests were performed. The expression of apoptotic genes and beta cell markers were detected by quantitative realtime polymerase chain reaction, immunostaining and western blot analysis. SHP KO mice showed significantly lower blood glucose, higher insulin levels, and enhanced glucose tolerance compared with wild type (WT) mice after MLDS treatment. Moreover, beta cell mass and pancreatic insulin content were remarkably increased in SHP KO mice. In the response to glucose stimulation, islets of SHP KO showed increased insulin secretion via up-regulation of beta cell enriched transcription factors compared to WT mice after streptozotocin (STZ) treatment. In quantification for beta cell apoptosis at day 1 post STZ treatment, the SHP KO mice showed significantly increased anti-apoptotic gene expression and decreased release of apoptotic markers cytochrome c, smac/diablo, and only a few apoptotic beta cells were found in SHP KO pancreas through inactivation of caspase-3, compared to those of WT. These data demonstrate that SHP deficiency ameliorates hyperglycemia and preserves islet function by inhibiting apoptosis of pancreatic beta cells and up-regulating of their enriched transcriptional factors. PMID- 23680672 TI - Deubiquitinases in skeletal muscle atrophy. AB - The ubiquitin proteasome system plays a critical role in skeletal muscle atrophy. A large body of research has revealed that many ubiquitin ligases are induced and play an important role in mediating the wasting. However, relatively little is known about the roles of deubiquitinases in this process. Although it might be expected that deubiquitinases would be downregulated in atrophying muscles to promote ubiquitination and degradation of muscle proteins, this has not to date been demonstrated. Instead several deubiquitinases are induced in atrophying muscle, in particular USP19 and USP14. USP19, USP2 and A20 are also implicated in myogenesis. USP19 has been most studied to date. Its expression is increased in both systemic and disuse forms of atrophy and can be regulated through a p38 MAP kinase signaling pathway. In cultured muscle cells, it decreases the expression of myofibrillar proteins by apparently suppressing their transcription indicating that the ubiquitin proteasome system may be activated in skeletal muscle to not only increase protein degradation, but also to suppress protein synthesis. Deubiquitinases may be upregulated in atrophy in order to maintain the pool of free ubiquitin required for the increased overall conjugation and degradation of muscle proteins as well as to regulate the stability and function of proteins that are essential in mediating the wasting. Although deubiquitinases are not well studied, these early insights indicate that some of these enzymes play important roles and may be therapeutic targets for the prevention and treatment of muscle atrophy. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. PMID- 23680673 TI - Fibroblast growth factor 2 inhibits bone morphogenetic protein 9-induced osteogenic differentiation of mesenchymal stem cells by repressing Smads signaling and subsequently reducing Smads dependent up-regulation of ALK1 and ALK2. AB - Understanding the interactions between growth factors and bone morphogenic proteins (BMPs) signaling remains a crucial issue to optimize the use of mesenchymal stem cells (MSCs) and BMPs in bone tissue engineering. BMP9 is highly capable of promoting osteogenic differentiation of MSCs. Fibroblast growth factor 2 (FGF2) is abundantly secreted during the healing process of fractures or in surgery bone sites. Herein, we explore the detail effect of FGF2 on BMP9-induced osteogenic differentiation of MSCs. It was found that FGF2 inhibited BMP9-induced osteogenic differentiation by blocking BMP9-induced Smads signaling and subsequently reducing Smads dependent up-regulation of ALK1 and ALK2 in MSCs. This effect was rescued by exogenous expression of ALK1 and ALK2, which are proved to be receptors for BMP9. Our results discovered a clue to explain the mechanism involved in the inhibitory effect of FGF2 on BMP9-induced osteogenic differentiation of MSCs. This crosstalk between FGF2 and BMP9 should be emphasized in the future use of BMP9 in therapeutic purpose of fracture repair. PMID- 23680674 TI - Lung inflammation caused by adenosine-5'-triphosphate is mediated via Ca2+/PKCs dependent COX-2/PGE2 induction. AB - Up-regulation of cyclooxygenase (COX)-2 and prostaglandin E2 (PGE2) are implicated in lung inflammation. Adenosine 5'-triphosphate (ATP) has been shown to act via activation of P2 purinoceptors, leading to COX-2 expression in various inflammatory diseases. The mechanisms of ATP-induced COX-2 expression and PGE2 release remain unclear. We showed that pretreatment with the inhibitors of P2 receptors (PPADS and Suramin), Gq protein (GPA2A), phosphatidylcholine phospholipase C (PC-PLC; D609), phosphoinositide-phospholipase C (PI-PLC; ET-18 OCH3), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII; KN62), protein kinase C (PKC; Go6976, Ro-318220, GF109203X, and rottlerin), MEK1/2 (PD98059), p38 MAPK (SB202190), and nuclear factor-kappaB (NF-kappaB; Bay11-7082) and the intracellular calcium chelator (BAPTA/AM) or transfection with siRNAs of these molecules and cPLA2 reduced ATPgammaS-induced COX-2 expression or PGE2 production in A549 cells. In addition, ATPgammaS-induced elevation of intracellular Ca(2+) concentration was attenuated by PPADS, Suramin, D609, or ET-18-OCH3. ATPgammaS induced p38 MAPK, p42/p44 MAPK, and NF-kappaB p65 activation were inhibited by Go6976, Ro-318220, GF109203X, or rottlerin. ATPgammaS also induced cPLA2 phosphorylation and activity, which were reduced via inhibition of P2 receptors, PKCs, p38 MAPK, and p42/p44 MAPK. ATPgammaS-induced cPLA2 expression was inhibited by SB202190, PD98059, or Bay11-7082. In the in vitro study, we established that ATPgammaS induced PGE2 generation via a cPLA2/COX-2-dependent pathway. In the in vivo study, we found that ATPgammaS induced COX-2 mRNA expression in the lungs and leukocyte (mainly eosinophils and neutrophils) count in bronchoalveolar lavage (BAL) fluid in mice via a P2 receptors-dependent signaling pathway. We concluded that ATPgammaS may induce lung inflammation via a cPLA2/COX-2/PGE2-dependent pathway. PMID- 23680675 TI - Upregulation of Toll-like receptor 2 gene expression by acetylation of AP-2 alpha in THP-1 cells, a human monocytic cell line. AB - Human Toll-like receptor 2 (TLR2) is a receptor for a variety of microbial products and mediates activation signals in cells of the innate immune system. Therefore, it is of great interest to investigate the molecular mechanisms that control the expression of TLR2. In this study, using real-time PCR and western blot assays, we show that trichostatin A (TSA), which is a histone deacetylase inhibitor, upregulates the expression of both TLR2 mRNA and protein in the human THP-1 cell line. A luciferase activity analysis of the truncated TLR2 promoter indicated that the region from -230 to -140 in the TLR2 promoter was sensitive to TSA. Moreover, using electrophoresis mobility shift and chromatin immunoprecipitation assays, we identified an AP-2 alpha (AP-2alpha) responsive element at position -184 and found that the binding of AP-2alpha to this element was enhanced by TSA under in vitro and in vivo conditions. Immunoprecipitation and western blot analyses showed that the levels of acetylated AP-2alpha were increased in THP-1 cells after TSA treatment, and this increase is consistent with the increased binding affinity to the AP-2alpha responsive elements. In summary, these data define a mechanism through which AP-2alpha acetylation and increased promoter access induce the expression of the TLR2 gene. This mechanism may provide insight into a regulatory mode of TLR2 expression and the molecular foundations of certain immunological diseases. PMID- 23680676 TI - Cytotoxicity of TiO2 nanoparticles and their detoxification in a freshwater system. AB - In the current study, two aspects concerning (i) the cytotoxicity potential of TiO2 nanoparticles (NPs) toward freshwater algal isolate Scenedesmus obliquus and (ii) the potential detoxification of NPs by the microalgae were assessed under light (UV-illumination) and dark conditions at low exposure levels (<=1 MUg/mL), using sterile freshwater as the test medium. The statistically significant reduction in cell viability, increase in reactive oxygen species production and membrane permeability (light vs. dark) suggested photo-induced toxicity of TiO2 NPs. The electron micrographs demonstrated adsorption of the NPs onto the cell surface and substantiated their internalization/uptake. The fluorescence micrographs and the confocal laser scanning (CLSM) images suggested the absence of a definite/intact nucleus in the light treated cells pointing toward the probable genotoxic effects of NPs. In a separate three cycle experiment, a continuous decrease in the cytotoxicity was observed, whereas, at the end of each cycle only fresh algae were added to the supernatant containing NPs from the previous cycle. The decreasing concentrations of the NPs in the subsequent cycles owing to agglomeration-sedimentation processes exacerbated by the algal interactions played a crucial role in the detoxification. In addition, the exo polymeric substances produced by the cells could have rendered the available NPs less reactive, thereby, enhancing the detoxification effects. PMID- 23680677 TI - Using transcriptomic profiles in the diatom Phaeodactylum tricornutum to identify and prioritize stressors. AB - The transcriptomic profile of the marine diatom, Phaeodactylum tricornutum, exposed to several ecologically relevant stressors, was used to develop toxicity identification evaluation (TIE)-like gene expression assays. Algal growth inhibition was measured by flow cytometry to determine exposure concentrations that elicited a sublethal toxic response. P. tricornutum was exposed to concentrations of copper (2 MUg L-1), cadmium (5 MUg L-1), silver (20 MUg L-1), simazine (75 MUg L-1), the water accommodated fraction (WAF) of weathered crude oil (5 mg L-1), 50 MUg L-1 ammonia, a decreased salinity treatment (150/00), and a mixture exposure of ammonia, decreased salinity and cadmium (10 MUg L-1). Analysis of the gene expression via microarray indicated that unique transcriptomic signals were generated for each of the individual treatments. Transcriptomic profiles of ammonia and the mixture treatment overlapped substantially. Photosynthesis related transcripts were altered in the simazine (herbicide) treatment. A transcript involved in degrading hydrocarbons, dioxygenase, had increased abundance after crude oil exposure. Overall, transcriptomic responses in the different treatments were associated with stress responses, membrane transport, transcription and translation and could be linked to contaminant mode of action. The transcriptomic profiles were used to design real-time (quantitative) polymerase chain reaction (qPCR) assays that would link changes in transcript abundance to a particular stressor in a TIE-based approach. At least one transcript for each contaminant tested (copper, cadmium, silver, salinity and ammonia) responded exclusively to that contaminant. With further development of additional transcriptomic markers for each contaminant, this new approach has potential to enhance traditional toxicology bioassays by providing additional lines of evidence to identify biologically relevant stressors within a contaminated ecosystem based on changes in the transcriptomic profile. PMID- 23680678 TI - Boron doped diamond ultramicroelectrodes: a generic platform for sensing single nanoparticle electrocatalytic collisions. AB - Boron doped diamond (BDD) disk ultramicroelectrodes have been used to sense single nanoparticle (NP) electrocatalytic collision events. BDD serves as an excellent support electrode due to its electrocatalytic inactivity and low background currents and thus can be used to detect the electroactivity of a wide range of colliding NPs, with high sensitivity. In particular, single NP collisions for hydrazine oxidation at Au and Pt NPs were shown to be markedly different. PMID- 23680679 TI - Effects of early exercise engagement on vascular risk in patients with transient ischemic attack and nondisabling stroke. AB - The objective of this study was to conduct a randomized, parallel-group clinical trial assessed the efficacy of a health-enhancing physical activity program (exercise and education) on vascular risk factors and aerobic fitness in patients who have experienced a transient ischemic attack (TIA) or nondisabling stroke. Sixty patients (69+/-11 years) completed a baseline (BL) vascular risk stratification and aerobic fitness examination (cycle test) within 2 weeks of symptom onset. Subjects were then randomized to either an 8-week, twice weekly exercise program or to a usual-care control (CON) group. Postintervention (PI) assessments were completed immediately after the intervention and at 3-month follow-up. A series of primary (systolic blood pressure [SBP]) and secondary (vascular risk factors like total cholesterol [TC], high-density lipoproteins, etc.; Framingham risk score; peak oxygen uptake) outcome measures were assessed. Significantly greater reductions in SBP (mean change+/-SD; -10.4+/-9.2 mm Hg) and TC (-.53+/-.90 mmol/L) were observed between BL and PI assessments for the exercise group compared with the CON group (-1.9+/-15.4 mm Hg and -.08+/-.59 mmol/L, respectively) (P<.05). These improvements were maintained between the PI and the 3-month follow-up assessment (P>.05). Significant improvements in aerobic fitness were also observed and maintained at the 3-month follow-up assessment after regular exercise participation (P<.05). The early engagement in exercise resulted in significant improvements in vascular risk factors and fitness in those diagnosed with TIA. As these beneficial effects were maintained up to 3 months after completing the exercise program, exercise should be considered a useful additive treatment strategy for newly diagnosed TIA patients. Future research should examine the long-term efficacy of such programs. PMID- 23680680 TI - Stroke awareness in the Saudi community living in Riyadh: prompt public health measures must be implemented. AB - BACKGROUND: Stroke is very prevalent in the Kingdom of Saudi Arabia, approaching 43.8 per 100,000 people. Stroke outcome is known to be affected by the level of stroke awareness in the community. We conducted this study to assess the level of stroke awareness in the Saudi population. METHODS: A validated survey of 11 questions was used to assess the level of stroke awareness among the Saudi population. The survey was distributed in a 1-month period to every adult Saudi citizen visiting 10 shopping centers, 10 large supermarkets, 4 hospitals, and 2 universities. RESULTS: Two thousand eight hundred sixty-two people completed the questionnaire (a 78% response rate). One thousand eight hundred forty-four people (64%) were able to define stroke correctly. One thousand four hundred twenty eight people (49.9%) named mass media as the source of their knowledge. One thousand three hundred one (45.9%) believe stroke and brain death share the same pathologic mechanism and outcome, particularly those <40 years of age (P < .05). Six hundred twenty-two (21.7%) of the respondents correctly chose >=5 risk factors and made <=1 error. Five hundred twenty-seven (18.4%) of the participants in this study were able to correctly identify >=3 symptoms of the list and make <=1 error. CONCLUSIONS: There is an alarming deficit in the level of stroke awareness in the Saudi population. Urgent public health measures to correct this deficiency are promptly needed. PMID- 23680681 TI - Predictors of acute stroke mimics in 8187 patients referred to a stroke service. AB - BACKGROUND: Some patients seen by a stroke team do not have cerebrovascular disease but a condition that mimics stroke. The purpose of this study was to determine the rate and predictors of stroke mimics in a large sample. METHODS: This is an analysis of data from consecutive patients seen by the National Institutes of Health Stroke Program over 10 years. Data were collected prospectively as a quality improvement initiative. Patients with a cerebrovascular event or a stroke mimic were compared with the Student t or Pearson chi-square test as appropriate, and logistic regression was done to identify independent predictors. RESULTS: The analysis included 8187 patients: 30% had a stroke mimic. Patients with a stroke mimic were younger, and the proportion of patients with a stroke mimic was higher among women, patients without any risk factors, those seen as a code stroke or who arrived to the emergency department via personal vehicle, and those who had the onset of symptoms while inpatients. The proportion of patients with a stroke mimic was marginally higher among African-Americans than Caucasians. Factors associated with the greatest odds of having a stroke mimic in the logistic regression were lack of a history of hypertension, atrial fibrillation or hyperlipidemia. CONCLUSIONS: One third of the patients seen by a stroke team over 10 years had a stroke mimic. Factors associated with a stroke mimic may be ascertained by an emergency physician before calling the stroke team. PMID- 23680682 TI - Early mobilization after acute stroke. AB - BACKGROUND: Treatment in stroke units reduces mortality and disability compared with treatment in general medical wards. Early mobilization is considered one element of stroke unit care contributing to this benefit. There are uncertainties regarding the effect of this approach on different groups of acute stroke patients. In this study, we compared the proportions of patients having a modified Rankin Scale score <=2 assessed 3 months poststroke in patients mobilized within 24 hours versus between 24 to 48 hours of hospitalization, and explored whether other factors were associated with good outcome. METHODS: Patients hospitalized within 24 hours of stroke onset were enrolled in this prospective, randomized, controlled trial with blinded outcome assessment. They were assigned to 2 groups; 1 that was mobilized within 24 hours of admittance and 1 that was mobilized 24 to 48 hours after admittance. Binary logistic regression was performed to analyze predictors of good outcome, with stepwise elimination of nonsignificant variables in the multivariate model. Candidate variables were mobilization within 24 hours of admittance, age, sex, stroke risk factors, and National Institutes of Health Stroke Scale score on admittance. RESULTS: Twenty seven patients were mobilized within 24 hours of hospitalization and 25 between 24 and 48 hours. The median times to first mobilization were 7.5 hours (interquartile range 2.5-16.3) and 30.0 hours (interquartile range 25.5-38.0), respectively. Fifty-five percent of patients had a good outcome. None of the candidate variables had a significant association with good outcome. CONCLUSIONS: Neither time to mobilization nor any other candidate variable was associated with good outcome 3 months poststroke. PMID- 23680683 TI - Predictors of functional dependency after stroke in Nigeria. AB - BACKGROUND: The factors impacting poststroke functional dependency have not been adequately explored in sub-Saharan Africa. This study examined the risk factors for functional dependency in a group of Nigerian African stroke survivors. METHODS: One hundred twenty-eight stroke survivors attending a tertiary general hospital in southwestern Nigeria were consecutively recruited and assessed for functional dependency using the modified Rankin Scale (mRS). Stroke was diagnosed according to the World Health Organization criteria. Candidate independent variables assessed included the demographic and clinical characteristics of survivors, cognitive dysfunction, and a diagnosis of major depressive disorder. Variables with significant relationship to functional dependency were entered into a logistic regression model to identify factors that were predictive of functional dependency among the stroke survivors. RESULTS: In all, 60.9% of the stroke survivors were functionally dependent (mRS scores>=3), with mean+/-SD mRS scores of 2.71+/-1.01. Female sex (P=.003; odds ratio [OR] 3.08; 95% confidence interval [CI] 1.47-6.44), global cognitive dysfunction (P=.002; OR 5.04; 95% CI 1.79-14.16), and major depressive disorder (P<.0001; OR 3.06; 95% CI 1.92-4.87) were strongly associated with functional dependency in univariate analysis. Major depressive disorder was an independent predictor of functional dependency in multivariate analysis (P<.0001; OR 6.89; 95% CI 2.55-18.6; R2=0.19). CONCLUSIONS: Depression, female sex, and cognitive dysfunction were strongly associated with poorer functioning after stroke. Interventions aimed at depression and cognitive dysfunction after stroke may improve functional independence in stroke survivors. PMID- 23680684 TI - Subarachnoid hemorrhage after resuscitation from out-of-hospital cardiac arrest. AB - BACKGROUND: This study was undertaken to retrospectively investigate clinical features of subarachnoid hemorrhage (SAH) with cardiopulmonary arrest in patients achieving return of spontaneous circulation (ROSC) in order to explore the possibility of long-term survival. METHODS: Of 143 SAH patients with cardiopulmonary arrest in our hospital between April 2004 and June 2012, data on 59 (41%) patients who attained ROSC were analyzed to determine the predictive factors for neurologic recovery and outcome. Recovery of brainstem reflexes and improvement of Glasgow Coma Scale (GCS) motor score were noted (postresuscitation neurologic restorative assessment, grade I) in 5, and 2 of these patients survived. RESULTS: By-grade analysis of patient background characteristics revealed a significantly shorter duration of cardiac arrest (P = .001) and a significantly smaller adrenaline dose (P = .011) for grade I patients. A logistic analysis of 1-week survival data revealed significant differences in duration of cardiac arrest (P = .022) and adrenaline dose (P = .019), with odds ratios of 0.89 and 0.25, respectively. Cox regression analysis of mortality data revealed significant differences in the duration of cardiac arrest (P = .012), adrenaline dose (P < .0001), and location of ROSC (P = .016), with hazard ratios of 1.03, 1.43, and 1.98, respectively. CONCLUSIONS: Cardiac arrest caused by SAH is a disease state with a grave prognosis, but there is the possibility of a good survival outcome when the administration of a small dose of adrenaline results in the rapid recovery of brainstem reflexes. PMID- 23680685 TI - Cryptogenic stroke and the left atrial septal pouch: a case report. AB - The left atrial septal pouch (LASP) is an anatomic variant of the interatrial septum and may be a nidus for thromboembolism. We present the case of a 49 year old man without known vascular risk factors who experienced bi-hemispheric strokes over the course of 10 days, suggestive of multiple emboli. Transesophageal echocardiography revealed a prominent LASP. We suggest that presence of LASP was a likely cause of stroke in this patient and that further study of a possible association between LASP and ischemic stroke in younger individuals may be warranted. PMID- 23680686 TI - Factors associated with prognosis of eating and swallowing disability after stroke: a study from a community-based stroke care system. AB - BACKGROUND: The long-term prognosis of eating and swallowing disability has not been fully clarified. As community-based stroke care systems have developed in Japan, these data have become available. METHODS: We examined changes in nutritional intake using data acquired from a community-based stroke care system. There were 334 stroke patients who were discharged from our acute care hospital and transferred to rehabilitation hospitals with tube feeding. We examined the relationship between the initial bedside swallowing assessment and the method of nutrition delivery at discharge from a rehabilitation hospital. We also calculated the functional independent measure (FIM) to examine the relationship between activities of daily living and nutritional intake. RESULTS: There were 291 patients on oral intake and 43 on enteral feeding at discharge from a rehabilitation hospital. Patients with enteral feeding were older than patients with oral intake (69.4 +/- 11.4 v 75.2 +/- 9.9 years; P = .0016). The enteral feeding group also had lower FIM gain (27.5 +/- 28.3 v 16.5 +/- 23.5; P = .0161) and FIM efficiency (1.10 +/- 1.24 v 0.65 +/- 1.26; P = .0270) at the acute care hospital. CONCLUSIONS: Age, FIM gain, and FIM efficacy in the acute care hospital reliably predicted the long-term prognosis of eating and swallowing disability. PMID- 23680687 TI - Postoperative dural arteriovenous fistula in a patient with Cowden disease: a case report. AB - We report the case of a 37-year-old male with Cowden disease that caused a gradual neurological deficit because of rupture of a brain stem cavernous hemangioma. Removal of the hemangioma and hematoma was performed with an infrafacial triangle approach. Nine months after the operation, magnetic resonance imaging showed abnormal vessels on the cerebellar surface. Digital subtraction angiography showed a dural arteriovenous fistula (dAVF) from part of the meningeal artery to the ectatic inferior vermian vein with cortical reflux. After embolization, surgical obliteration of the dAVF was performed. Surgical findings showed neovascularization in the thickened dura, in which dural vessels shunted to cerebellar vessels through adhesion between the dura mater and cerebellar surface. Therefore, the thickened dura was removed with the cerebellar surface. This case suggests that postoperative angiogenesis may cause arteriovenous fistula in patients with Cowden disease. PMID- 23680688 TI - Long-term adherence to national guidelines for secondary prevention of ischemic stroke: a prospective cohort study in a public hospital in Chile. AB - BACKGROUND: Clinical guidelines for the secondary prevention of ischemic stroke have been developed, but their publication is insufficient to make them effective. Our aim was to investigate adherence to Chilean guidelines, its associated variables, and to determine prognosis at follow-up. METHODS: We prospectively included all consecutive patients discharged with a diagnosis of ischemic stroke from Valparaiso Regional Hospital between July 15, 2007 and January 15, 2008. Patient follow-up was performed at 5, 10, and 15 months using a standardized questionnaire. We used the Chi-square and Fisher exact tests to compare discrete variables and multivariate logistic regression analysis to adjust for potential confounding factors. A Cox regression model was fitted. RESULTS: We included 156 patients; 128 patients (82%) completed follow-up. Adherence to oral anticoagulation decreased significantly compared to all other medications during follow-up (P = .004). This was not associated with any of the studied variables. Adherence to antihypertensives, statins, and hypoglycemic medications remained >65% without a significant variation. Patients with cardioembolic stroke had greater mortality (P = .003) and recurrence rates. CONCLUSIONS: The observed significant decrease in adherence to oral anticoagulation in patients with cardioembolic stroke suggests a need for the implementation of specific strategies to achieve the desired secondary prevention goals in these patients. Future research into the evaluation of other factors that could be associated with the lack of adherence to these guidelines, measurements of therapeutic goals, and new therapeutic strategies that are easier to use and that are associated with less risk could improve the prognosis of these patients. PMID- 23680689 TI - The spectrum of aphasia subtypes and etiology in subacute stroke. AB - BACKGROUND: Aphasia is one of the most common stroke syndrome presentations, yet little is known about the spectrum of different subtypes or their stroke mechanisms. Yet, subtypes and etiology are known to influence the prognosis and recovery. AIM: Our aim is to analyze aphasia subtypes and etiology in a large subacute stroke population. METHODS: Consecutive patients from a dedicated cognitive stroke registry were accrued. A validated cognitive screening examination was administered during the first month of stroke presentation, which enabled a diagnosis of 14 different aphasic subtypes. The evolution from one subtype to another in the acute and subacute period, at times, resulted in more than 1 subtype being diagnosed. Etiology of stroke was determined by the modified Trial of Org 10172 in Acute Stroke Treatment criteria that included intracerebral hemorrhage. Exclusions included dementia, chronic medical illness, substance abuse, and severe depression. RESULTS: Of 2389 stroke patients, after exclusions (n=593), aphasias numbered 625 (625 of 1796; 34.8%), and the subtype frequencies included Broca aphasia (n=170; 27.2%), anomic aphasia (n=165; 26.4%), global aphasia (n=119; 19.04%), and subcortical aphasia (n=57; 9.12%). Less frequent subtypes (total n=40; 6.7%) included transcortical aphasia (n=11), Wernicke aphasia (n=10), conduction aphasia (n=7), aphemia (n=3), semantic aphasia (n=3), crossed aphasia (n=3), pure word deafness (n=2), and foreign accent syndrome (n=1). Aphasia subtypes and etiologies had some significant associations (chi square: 855.8, P value<.0001). Bonferroni-adjusted P values revealed that anomic aphasia had a significant association with small-vessel disease (SVD) (odds ratio [OR]=2.0254, 95% confidence interval [CI]: 1.3820-2.9681), and global aphasia patients mostly had cardioembolic (CE) causes (OR=2.3589, 95% CI: 1.5506-3.5885) and less likely SVD (OR=.2583, 95% CI: .1444-.4654). Other notable inferences were included. Wernicke aphasia was caused by either CE (6 of 12; 50%) or hemorrhage (4 of 12; 33.3%) in a combined 83% of cases. Subcortical aphasia was because of SVD in 36% (31 of 85) or because of hemorrhage in 32% (27 of 85) yielding a combined 68% of cases. Sixty percent of transcortical aphasias as a group were because of either large-vessel disease (7 of 20; 35%) or hemorrhage (5 of 20; 25%). Alternatively, a diagnosis of Broca aphasia could be because of any of the etiological categories. CONCLUSIONS: (1) Aphasias are a heterogeneous entity in subtype and etiology; (2) Broca, global, anomic, and subcortical aphasias accounted for the vast majority of aphasia subtypes; (3) SVD, cardioembolism, and hemorrhage are significantly associated with certain signature aphasic syndromes; and (4) determination of aphasia subtype can assist with etiology, prognosis, influence aphasia therapy, and provide the basis for future randomized controlled trials with pharmacological therapy or behavioral therapy. PMID- 23680691 TI - Breast cancer phenotype, nodal status and palpability may be useful in the detection of overdiagnosed screening-detected breast cancers. AB - BACKGROUND: Breast cancer remains the leading cause of female cancer death despite improvements in treatment and screening. Screening is often criticized for leading to overdiagnosis and overtreatment. However, few have attempted to identify overdiagnosed cases. PATIENTS AND METHODS: A large, consecutive series of patients treated for primary operable, screening-detected, breast cancer (n = 1610). Details from pathology and clinical reports, treatment and follow-up were available from our prospectively managed database. Univariate and multivariate Cox proportional models were used to study the prognostic variables in screening detected breast cancers for distant metastatic and breast cancer-specific survival. RESULTS: We included 1610 patients. The mean/median follow-up was 6.0/6.0 years. Univariate analysis: tumor size, palpability, breast cancer phenotype and nodal status were predictors of distant metastasis and breast cancer-specific death. Multivariate analysis: palpability, breast cancer phenotype and nodal status remained independent prognostic variables. Palpability differed by breast cancer phenotype. CONCLUSION: Screening-detected breast cancer is associated with excellent outcome. Palpability, nodal status and breast cancer phenotype are independent prognostic variables that may select patients at increased risk for distant metastatic relapse and breast cancer-specific death. Overdiagnosed cases reside most likely in the nonpalpable node negative subgroup with a Luminal A phenotype. PMID- 23680690 TI - Racial and socioeconomic disparities in access to mechanical revascularization procedures for acute ischemic stroke. AB - BACKGROUND: Mechanical revascularization procedures performed for treatment of acute ischemic stroke have increased in recent years. Data suggest association between operative volume and mortality rates. Understanding procedural allocation and patient access patterns is critical. Few studies have examined these demographics. METHODS: Data were collected from the 2008 Nationwide Inpatient Sample database. Patients hospitalized with ischemic stroke and the subset of individuals who underwent mechanical thrombectomy were characterized by race, payer source, population density, and median wealth of the patient's zip code. Demographic data among patients undergoing mechanical thrombectomy procedures were examined. Stroke admission demographics were analyzed according to thrombectomy volume at admitting centers and patient demographics assessed according to the thrombectomy volume at treating centers. RESULTS: Significant allocation differences with respect to frequency of mechanical thrombectomy procedures among stroke patients existed according to race, expected payer, population density, and wealth of the patient's zip code (P < .0001). White, Hispanic, and Asian/Pacific Islander patients received endovascular treatment at higher rates than black and Native American patients. Compared with the white stroke patients, black (P < .001), Hispanic (P < .001), Asian/Pacific Islander (P < .001), and Native American stroke patients (P < .001) all demonstrated decreased frequency of admission to hospitals performing mechanical thrombectomy procedures at high volumes. Among treated patients, blacks (P = .0876), Hispanics (P = .0335), and Asian/Pacific Islanders (P < .001) demonstrated decreased frequency in mechanical thrombectomy procedures performed at high-volume centers when compared with whites. While present, socioeconomic disparities were not as consistent or pronounced as racial differences. CONCLUSIONS: We demonstrate variances in endovascular acute stroke treatment allocation according to racial and socioeconomic factors in 2008. Efforts should be made to monitor and address potential disparities in treatment utilization. PMID- 23680692 TI - Circulating levels of immune and inflammatory markers and long versus short survival in early-stage lung cancer. AB - BACKGROUND: Some patients diagnosed with early-stage lung cancer and treated according to standard care survive for only a short period of time, while others survive for years for reasons that are not well understood. Associations between markers of inflammation and survival from lung cancer have been observed. MATERIALS AND METHODS: Here, we investigate whether circulating levels of 77 inflammatory markers are associated with long versus short survival in stage I and II lung cancer. Patients who had survived either <79 weeks (~1.5 years) (short survivors, SS) or >156 weeks (3 years) (long survivors, LS) were selected from a retrospective population-based study. Logistic regression was used to calculate adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs). The false discovery rate was calculated to adjust for multiple testing. RESULTS: A total of 157 LS and 84 SS were included in this analysis. Thirteen markers had adjusted OR on the order of 2- to 5-fold when comparing the upper and lower quartiles with regard to the odds of short survival versus long. Chemokine CCL15 [chemokine (C-C motif) ligand 15] was the most significant marker associated with increased odds of short survival (ORs = 4.93; 95% CI 1.90-12.8; q value: 0.042). Smoking and chronic obstructive pulmonary disease were not associated with marker levels. CONCLUSIONS: Our results provide some evidence that deregulation of inflammatory responses may play a role in the survival of early-stage lung cancer. These findings will require confirmation in future studies. PMID- 23680693 TI - A Graph Cut Approach to Image Segmentation in Tensor Space. AB - This paper proposes a novel method to apply the standard graph cut technique to segmenting multimodal tensor valued images. The Riemannian nature of the tensor space is explicitly taken into account by first mapping the data to a Euclidean space where non-parametric kernel density estimates of the regional distributions may be calculated from user initialized regions. These distributions are then used as regional priors in calculating graph edge weights. Hence this approach utilizes the true variation of the tensor data by respecting its Riemannian structure in calculating distances when forming probability distributions. Further, the non-parametric model generalizes to arbitrary tensor distribution unlike the Gaussian assumption made in previous works. Casting the segmentation problem in a graph cut framework yields a segmentation robust with respect to initialization on the data tested. PMID- 23680694 TI - Sex-dependent changes in brain CB1R expression and functionality and immune CB2R expression as a consequence of maternal deprivation and adolescent cocaine exposure. AB - Early life stress has been associated with several psychiatric disorders, including drug addiction. Actually, maternal deprivation (MD) alters the endocannabinoid system, which participates in motivation and reward for drugs, including cocaine. At youth, the rate of cocaine abuse is alarmingly increasing. Herein, we have investigated the consequences of MD and/or adolescent cocaine exposure in brain CB1Rs and CB2Rs in immune tissues. Control and maternally deprived (24h on postnatal day, pnd, 9) male and female Wistar rats were administered cocaine (8mg/kg/day) or saline during adolescence (pnd 28-42). At adulthood, [(3)H]-CP-55,940 autoradiographic binding was employed for the analysis of CB1R density and CP-55,940-stimulated [(35)S]-GTPgammaS binding for CB1R functionality; CB2R expression was analyzed by Western blotting. Sex differences in CB1R expression and functionality were found, and MD induced important and enduring sex-dependent changes. In addition, the plastic changes induced by adolescent cocaine administration in brain CB1Rs were differentially influenced by early life events. MD increased spleen CB2R expression while adolescent cocaine administration attenuated this effect; cocaine exposure also diminished CB2R expression in bone marrow. Present findings provide evidence for changes in brain CB1R expression and functionality and immune CB2R expression as a consequence of early life stress and adolescent cocaine exposure, and indicate functional interactions between both treatments, which in many regions differ between males and females. PMID- 23680695 TI - Tissue distribution of dioxin-like compounds: potential impacts on systemic relative potency estimates. AB - Relative effect potencies (REPs) for dioxins and dioxin-like compounds based on tissue concentration or internal dose ((systemic)REPs) can be considered of high relevance for human risk assessment. Within the EU-project SYSTEQ, (systemic)REPs for 1,2,3,7,8-pentachlorodibenzodioxin (PeCDD), 2,3,4,7,8, pentachlorodibenzofuran (4-PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PCB 126), 2,3',4,4',5-pentachlorobiphenyl (PCB 118) and 2,3,3',4,4',5-hexachlorobiphenyl (PCB 156) were calculated based on a plasma, adipose tissue or liver concentration in Sprague Dawley rats and C57bl/6 mice three days after a single oral dose. Compound-specific distribution as well as differences in accumulation and elimination can influence the tissue concentration and thereby the relative potency estimate of a congener. Here, we show that distribution patterns are generally similar for the tested congeners between the SYSTEQ dataset and other studies using either a single dose or subchronic dosing. Furthermore, the responding concentration for TCDD in single dose studies is comparable to the responding concentrations reported in subchronic studies. In contrast with data for laboratory rodents, available distribution data for humans in the general population display little or no hepatic sequestration. Because hepatic sequestration due to CYP1A2 protein binding may affect the amount of congener that is bioavailable for the AhR to produce hepatic responses, estimates of relative potencies between congeners with differing degrees of hepatic sequestration based on hepatic responses may be misleading for application to human risk assessment. Therefore, extra-hepatic concentration in blood serum/plasma or adipose tissue together with a biological extra-hepatic response might give a more accurate prediction of the relative potency of a congener for human responses under environmental conditions. PMID- 23680696 TI - Hydrogen cyanide concentrations in the breath of adult cystic fibrosis patients with and without Pseudomonas aeruginosa infection. AB - Elevated concentrations of hydrogen cyanide (HCN) have been detected in the headspace of Pseudomonas aeruginosa (PA) cultures and in the breath of children with cystic fibrosis (CF) and PA infection. The use of mouth-exhaled breath HCN as a marker of PA infection in adults is more difficult to assess as some without PA infection generate HCN in their mouths. The analysis of breath exhaled via the nose, thereby avoiding volatile compounds produced in the mouth, will demonstrate elevated concentrations of HCN in adult CF patients chronically infected with PA. Using selected ion flow mass spectrometry (SIFT-MS), the mouth and the nose exhaled breaths of 20 adult CF patients; 10 with chronic PA infection and 10 free from PA infection, were analysed for HCN. Acetone and ethanol were also measured as controls. SIFT-MS allows direct sampling and analysis of single breath exhalations, obviating the need to collect samples into bags or onto traps, which can compromise samples. HCN was detected in the mouth-exhaled breath of patients in both groups and in the nose-exhaled breath of patients with chronic PA infection. The difference in median (IQR) nose-exhaled HCN between the groups is statistically significant (11 (0.8-18) ppbv versus 0 (0-3.2) ppbv, p = 0.03). The concentrations of acetone and ethanol in nose-exhaled and mouth-exhaled breath are in keeping with previous studies. HCN in nose-exhaled breath is a biomarker of chronic airway infection with PA in adults with CF. Its application as a non invasive diagnostic test for early PA infection warrants further investigation. PMID- 23680697 TI - Toll-like receptor 4 signaling pathway mediates proinflammatory immune response to cobalt-alloy particles. AB - Metal orthopedic implant debris-induced osteolysis of hip bone is a major problem in patients with prosthetic-hips. Although macrophages are the principal targets for implant-wear debris, the receptor(s) and mechanisms underlying these responses are not fully elucidated. We examined whether the TLR4 pathway mediates immune response to metal-on-metal (MoM) implant-generated wear particles. Human monocytes (THP-1) were exposed to Co-alloy particles at increasing particle:cell ratio for 24 h. Challenge with particles caused up-regulation of IL-1beta, TNF alpha and IL-8, and mediated degradation of cytosolic I-kappaB and nuclear translocation of NF-kappaB. Blocking antibodies against TLR4 or gene silencing of MyD88 and IRAK-1 prevented particle-induced I-kappaB/NF-kappaB activation response and markedly inhibited IL-8 release. Particle-mediated IL-8 response was not observed in TLR4-negative HEK293T cells; whereas transfection-based TLR4 overexpression in HEK293T enabled particle-sensitivity, as observed by I-kappaB degradation and IL-8 expression in response to particles. Results demonstrate that Co-alloy particles trigger immune response via the TLR4-MyD88-dependent signaling pathway. PMID- 23680698 TI - Translating the evidence for gene association with depression into mouse models of depression-relevant behaviour: current limitations and future potential. AB - Depression is characterised by high prevalence and complex, heterogeneous psychopathology. At the level of aetio-pathology, considerable research effort has been invested to identify specific gene polymorphisms associated with increased depression prevalence. Genome-wide association studies have not identified any risk polymorphisms, and candidate gene case-control studies have identified a small number of risk polymorphisms. It is increasingly recognised that interaction between genotype and environmental factors (G*E), notably stressful life events, is the more realistic unit of depression aetio-pathology, with G*E evidence described for a small number of risk polymorphisms. An important complementary approach has been to describe genes exhibiting brain region-specific expression changes in depression. Mouse models of depression informed by the human evidence allow for the study of causality, but to-date have also yielded limited insights into depression aetio-pathology. This review of the translational evidence integrates human and mouse research approaches and evidence. It also makes specific recommendations in terms of how future research in human and mouse should be designed in order to deliver evidence for depression aetio-pathology and thereby to inform the development of novel and improved antidepressant treatments. PMID- 23680699 TI - Finding a way in: a review and practical evaluation of fMRI and EEG for detection and assessment in disorders of consciousness. AB - Diagnoses and assessments of cognitive function in disorders of consciousness (DOC) are notoriously prone to error due to their reliance on behavioural measures. As a result, researchers have turned to functional neuroimaging and electrophysiological techniques with the goal of developing more effective methods of detecting awareness and assessing cognition in these patients. This article reviews functional magnetic resonance imaging (fMRI) and electroenchphalography (EEG)-based studies of cognition and consciousness in DOC, including assessment of basic sensory, perceptual, language, and emotional processing; studies for detection of conscious awareness; paradigms for the establishment of communication in the absence of behaviour; and functional connectivity studies. The advantages and limitations of fMRI and EEG-based measures are examined as research and clinical tools in this population and an explanation offered for the rediscovery of the unique advantages of EEG in the study of DOC. PMID- 23680700 TI - Towards a neuroscience of empathy: ontogeny, phylogeny, brain mechanisms, context and psychopathology. AB - Empathy allows individuals to share the affective states of others, predict others' actions, and stimulate prosocial behavior. Whilst the proximate mechanisms of empathy, modulated in part by neuropeptides such as oxytocin, control the ways we interact with our social environment, the ultimate causes seem to have arisen along with the mechanisms involved in mammalian parental care. The conceptual boundaries of empathy, however, have been blurred by definitional inaccuracies of mechanisms that can be regarded as phylogenetic precursors or physiological prerequisites for empathy, including mimicry and emotion contagion. Contextual factors such as early experiences with primary care givers (attachment), current mood states and other environmental contingencies are capable of modulating empathy. Moreover, evidence suggests that there is also a "dark side" of empathy, namely envy and schadenfreude (gloating) that are elicited by social comparison, competition and ingroup-outgroup distinction. This review aims at clarifying some of the open definitional questions related to empathy, and emphasizing the need for considering contextual factors in the study of empathy in both normal and abnormal psychology. PMID- 23680701 TI - Effects of diabetes on hippocampal neurogenesis: links to cognition and depression. AB - Diabetes often leads to a number of complications involving brain function, including cognitive decline and depression. In addition, depression is a risk factor for developing diabetes. A loss of hippocampal neuroplasticity, which impairs the ability of the brain to adapt and reorganize key behavioral and emotional functions, provides a framework for understanding this reciprocal relationship. The effects of diabetes on brain and behavioral functions in experimental models of type 1 and type 2 diabetes are reviewed, with a focus on the negative impact of impaired hippocampal neurogenesis, dendritic remodeling and increased apoptosis. Mechanisms shown to regulate neuroplasticity and behavior in diabetes models, including stress hormones, neurotransmitters, neurotrophins, inflammation and aging, are integrated within this framework. Pathological changes in hippocampal function can contribute to the brain symptoms of diabetes-associated complications by failing to regulate the hypothalamic pituitary-axis, maintain learning and memory and govern emotional expression. Further characterization of alterations in neuroplasticity along with glycemic control will facilitate the development and evaluation of pharmacological interventions that could successfully prevent and/or reverse the detrimental effects of diabetes on brain and behavior. PMID- 23680703 TI - A genetic variant in ERCC2 is associated with gastric cancer prognosis in a Chinese population. AB - Endogenous and exogenous factors can induce DNA damage, leading to increased risk of cancer. Nucleotide excision repair (NER) is considered as the most versatile DNA repair pathway to deal with a variety of different DNA lesions. ERCC1 and ERCC2 are the two important proteins in NER pathway. In this study, we investigated the association of three functional single nucleotide polymorphisms (SNPs) (ERCC1 rs11615, ERCC2 rs13181 and ERCC2 rs1799793) with the clinical outcome of 940 gastric cancer patients in a Chinese population. Multiplex SNaPshot technology was used to genotype these three SNPs. Our results revealed that individuals with ERCC2 rs13181TG/GG genotypes had a decreased risk of death compared with those with TT genotype [log-rank P = 0.008; adjusted hazard ratio = 0.68, 95% confidence interval = 0.51-0.91] and this protective effect was more pronounced among the subgroups of patients with tumour size <= 5 cm (0.59, 0.39 0.89), non-cardia gastric tumour (0.69, 0.48-0.98), no lymph node metastasis (0.55, 0.32-0.96), no distant metastasis (0.70, 0.52-0.95) and chemotherapy (0.39, 0.21-0.72). We conclude that ERCC2 rs13181 polymorphism could play different roles in the overall survival of gastric cancer. Further larger studies should be conducted to validate our findings. PMID- 23680702 TI - Using conditioned place preference to identify relapse prevention medications. AB - Stimuli, including contexts, which predict the availability or onset of a drug effect, can acquire conditioned incentive motivational properties. These conditioned properties endure after withdrawal, and can promote drug-seeking which may result in relapse. Conditioned place preference (CPP) assesses the associations between drugs and the context in which they are experienced. Here, we review the potential utility of CPP procedures in rodents and humans to evaluate medications that target conditioned drug-seeking responses. We discuss the translational potential of the CPP procedure from rodents to humans, and review findings with FDA-approved treatments that support the use of CPP to develop relapse-reduction medications. We also discuss challenges and methodological questions in applying the CPP procedure to this purpose. We argue that an efficient and valid CPP procedure in humans may reduce the burden of full clinical trials with drug-abusing patients that are currently required for testing promising treatments. PMID- 23680705 TI - The shortcomings of radiologic staging for rectal cancer and the impact on the treatment plan. PMID- 23680706 TI - Sphincter preservation in anal cancer: a brief review. AB - Management of anal cancer is a challenge. The goal of treatment is to eradicate tumor without sacrificing the anal sphincters. The idea of organ preservation emerged following the discovery of a high complete response rate from preoperative combined chemoradiation (CRT) prior to abdominoperineal resection.CRT is widely accepted as the standard therapy for treating anal squamous cell cancer. The combination of external beam radiotherapy with interstitial brachytherapy increases the dose to the tumor volume and decreases dose to normal tissues. The current goal is to avoid colostomy, and surgery has become a salvage or secondary therapy. In this article, we review the non surgical management of anal cancer with special emphasis on CRT, role of intensity modulated radiation therapy and brachytherapy. PMID- 23680707 TI - The accuracy of multi-detector row computerized tomography in staging rectal cancer compared to endoscopic ultrasound. AB - BACKGROUND/AIM: Our aim was to evaluate the diagnostic accuracy of multi-detector row computerized tomography (MDCT) in staging of rectal cancer by comparing it to rectal endoscopic ultrasound (EUS). MATERIALS AND METHODS: We prospectively included all patients with rectal cancer referred to our gastroenterology unit for staging of rectal cancer from December 2007 until February 2011, 53 patients whose biopsy had proven rectal cancer underwent both MDCT scan of the pelvis and rectal EUS. Both imaging modalities were compared and the agreement between T- and N-staging of the disease was assessed. RESULTS: We staged 62 patients with rectal cancer during the study period. Of these, 53 patients met the inclusion criteria and were evaluated (25 women and 28 men). The mean age was 57.79 +/- 14.99 years (range 21-87). MDCT had poor accuracy compared with EUS in T-staging with a low degree of agreement (kappa = 0.26), while for N-staging MDCT had a better accuracy and a moderate degree of agreement with EUS (kappa = 0.45). CONCLUSIONS: MDCT has a poor accuracy for predicting tumor invasion compared to EUS for T-staging while it has moderate accuracy for N-staging. PMID- 23680708 TI - Do probiotics improve eradication response to Helicobacter pylori on standard triple or sequential therapy? AB - BACKGROUND: The standard triple therapy for the eradication of Helicobacter pylori consists of a combination of a proton pump inhibitor at a standard dose together with two antibiotics (amoxicillin 1000 mg plus either clarithromycin 500 mg or metronidazole 400 mg) all given twice daily for a period of 7-14 days. Recent reports have shown a dramatic decline in the rate of H. pylori eradication utilizing standard triple therapy from 95% down to 70-80%. AIMS: Our study was designed to evaluate the effect of adding a probiotic as an adjuvant to common regimens used for H. pylori eradication. MATERIALS AND METHODS: An open label randomized observational clinical study was designed to test three different regimens of H. pylori eradication treatment: Standard triple therapy with a concomitant probiotic added at the same time (n = 100), starting the probiotic for 2 weeks before initiating standard triple therapy along with the probiotic (n = 95), and the third regimen consists of the probiotic given concomitantly to sequential treatment (n = 76). The three arms were compared to a control group of patients treated with the traditional standard triple therapy (n = 106). RESULTS: The eradication rate for the traditional standard therapy was 68.9%, and adding the probiotic "Bifidus infantis" to triple therapy, led to a successful rate of eradication of 83% (P < 0.001). Pre-treatment with 2 weeks of B. infantis before adding it to standard triple therapy increased the success rate of eradication to 90.5%. Similar improvement in eradication rate was noted when B. infantis was added as an adjuvant to the sequential therapy leading to an eradication rate of 90.8%. CONCLUSION: Adding B. infantis as an adjuvant to several therapeutic regimens commonly used for the eradication of H. pylori infection significantly improves the cure rates. PMID- 23680709 TI - Pepsin and bile acid concentrations in sputum of mustard gas exposed patients. AB - BACKGROUND/AIM: Gastro-esophageal reflux has been suggested to be associated with several pulmonary complications such as asthma, and post-transplant bronchiolitis obliterans (BO). Pepsin or bile salts in the sputum is shown to be an optimal molecular marker of gastric contents macro/micro aspiration. In this study, we investigated sputum pepsin as a marker of micro-aspiration in sulfur mustard (SM) exposed cases compared to healthy controls. MATERIALS AND METHODS: In a case controlled study, 26 cases with BO and 12 matched healthy controls were recruited and all cases were symptomatic and their exposure to SM was previously documented during Iran-Iraq conflict. Pepsin levels in sputum and total bile acids were measured using enzymatic assay. The severity of respiratory disorder was categorized based upon the spirometric values. RESULT: The average concentration of pepsin in sputum was higher in the case group (0.29 +/- 0.23) compared with healthy subjects (0.13 +/- 0.07; P +/- 0.003). Moreover, the average concentration of bile acids in the sputum cases was not significantly different in comparison to the controls ( P = 0.5). CONCLUSION: Higher pepsin concentrations in sputum of SM exposed patients compared with healthy control subjects indicate the occurrence of significantly more gastric micro-aspiration in SM exposed patients. PMID- 23680710 TI - Anti-inflammatory efficiency of Ankaferd blood stopper in experimental distal colitis model. AB - BACKGROUND/AIM: Ankaferd blood stopper (ABS) is a herbal extract that enhances mucosal healing. In this study, we aimed to investigate the efficiency of ABS in the treatment of experimental distal colitis. MATERIALS AND METHODS: Twenty one male albino rats were divided into three groups: Sham control (Group 1), colitis induced by acetic acid and treated with saline (Group 2), colitis induced by acetic acid and treated with ABS (Group 3). At end of the 7 th day of induction, all the rats were lightly anesthetized with intramuscular ketamine (8 mg/kg) and thereafter laparotomy and total colectomy were performed. The distal colon segment was assessed macroscopically and microscopically. In addition malondialdehyde (MDA), superoxide dismutase (SOD) and nitric oxide (NO) levels of the colonic tissue and changes in body weight were measured. RESULTS: The MDA and NO levels of the colonic tissues and weight loss were significantly higher in Group 2 compared to Group 1 and Group 3. Microscopic and macroscopic damage scores were significantly higher in Group 2 and Group 3 than Group 1 (P: 0.001, P: 0.004, respectively). Although the microscopic and macroscopic damage scores in Group 3 were slightly lower than Group 2, the difference was not statistically significant. The SOD levels of the colonic tissues were not different between the three groups. CONCLUSION: Weight alterations and high-levels of the colonic tissue MDA and NO suggested that ABS might have anti-inflammatory effects on experimental distal colitis. However, this suggestion was not supported by histopathological findings. PMID- 23680712 TI - Acute abdomen associated with retroperitoneal gas. PMID- 23680711 TI - Oxidative stress markers in intestinal mucosa of Tunisian inflammatory bowel disease patients. AB - BACKGROUND / AIMS: Inflammatory bowel diseases (IBDs), Crohn's disease (CrD) and ulcerative colitis (UC), are chronic gastrointestinal inflammatory disorders. The precise etiology of IBD remains unclear, and it is thought that interactions among various factors, including, genetic factors, the host immune system and environmental factors, cause disruption of intestinal homeostasis, leading to dysregulated inflammatory responses of the gut. As inflammation is intimately related to formation of reactive intermediates, including, reactive oxygen species, oxidative stress has been proposed as a mechanism underlying the pathophysiology of IBD. The purpose of this study is to examine the lipid peroxidation, protein oxidation and anti-oxidative profile in Tunisian IBD. MATERIALS AND METHODS: Malondialdehyde (MDA), conjugated dienes (CD), protein thiol levels, as well as the catalase (CAT) activity were evaluated in intestinal biopsies of 17 patients affected by IBD (12 CrD and 5 UC) and 12 healthy control individuals. RESULTS: Oxidative stress was confirmed in these two types of disease biopsies as compared to controls. MDA and CD levels were significantly increased in both UC and CrD patients' biopsies as compared to controls' biopsies ( P < 0.001). CAT activity was similar in UC and CrD biopsies' and was not significantly increased in IBD patients' biopsies compared with controls' biopsies ( P > 0.05). Anon-significant decrease in thiol (SH) level was observed in both UC and CrD patients' biopsies compared with controls' biopsies ( P > 0.05). CONCLUSION: Increased levels of MDA and CD in IBD patients' biopsies underline the implication of oxidative stress in the physiopathology of IBD. PMID- 23680713 TI - Esophageal carcinoma: are modern targeted therapies shaking the rock? AB - PURPOSE OF REVIEW: Our current review aims to outline recent progress in the development of modern targeted therapeutic regimens for esophageal cancer. RECENT FINDINGS: Esophageal cancers demonstrate marked molecular heterogeneity. Modern technology increasingly allows us to identify subgroups of patients whose tumors fit particular molecular profiles. Tumor-based human epidermal growth factor receptor 2 (HER-2) analysis has become a standard part of the work-up for patients with tumors of the esophagogastric junction. The anti-HER-2 antibody, trastuzumab, when added to a chemotherapeutic regimen combining a fluoropyrimidine and platinum, provides a survival benefit for those patients with HER-2 overexpression and/or amplification. Despite large coordinated efforts to establish the efficacy of additional targeted therapeutics, to this point minimal additional benefit has been realized in affecting prominent molecular targets, such as vascular endothelial growth factor and epidermal growth factor receptor, in esophageal cancer. Multiple targets of interest remain under investigation with some early encouraging data. These targets include mammalian target of rapamycin, c-MET, insulin like growth factor 1 receptor and cytotoxic T lymphocyte antigen 4. Additional improvements in therapy may stem from improved patient selection for combinations of standard cytotoxic regimens, such as platinum-based regimens. SUMMARY: Targeted therapeutics have yielded early benefit, but further progress will require a deeper understanding of this disease, improved identification of subpopulations who may derive greater benefit, and continued multicenter efforts to conduct the necessary clinical investigations. PMID- 23680714 TI - Advanced unresectable hepatocellular carcinoma: new biologics as fresh ammunition or clues to disease understanding? AB - PURPOSE OF REVIEW: Hepatocellular carcinoma (HCC) is a prevalent malignancy associated with a guarded prognosis. At present, sorafenib is the only approved systemic therapy for patients with advanced disease. The effect of sorafenib on overall survival is modest and limited in time by the occurrence of drug resistance. RECENT FINDINGS: Together with the increasing knowledge of molecular pathways involved in HCC, targeted molecules have been developed and tested in first and second line following sorafenib. These include antiangiogenic drugs, as well as biologicals inhibiting cell proliferation and survival. Recent phase III trials investigated sunitinib, linifanib, brivanib and erlotinib, but none of them were found superior to sorafenib. New findings in mechanisms of drug resistance create opportunities in the treatment of sorafenib-refractory disease, with cMET inhibition as the most promising approach. This article reviews the pathways involved in HCC and their targets as well as potential strategies for drug development in the future. SUMMARY: Advanced HCC has been the subject of intensive clinical research following the success of sorafenib. Despite many failures, some agents show promising results in phase II trials. Targeting new pathways, using multidrug regimens and tailoring treatment guided by predictive markers should allow new successes. PMID- 23680715 TI - Response to Dr Uparkar and Dr Kaul. PMID- 23680716 TI - Validation of a new photogrammetric technique to monitor the treatment effect of Botulinum toxin in synkinesis. AB - AIMS: To validate a new photogrammetric technique for quantifying eye surface area and using this to quantify the degree of improvement in symmetry in patients with oral-ocular synkinesis following Botulinum toxin injection. STUDY DESIGN: Feasibility study and retrospective outcomes analysis METHODS: Ten patients' photographs were chosen from a photographic database. Their eye surface areas were measured independently by two raters using a graphics tablet. One rater repeated the procedure after 15 days. Bland-Altman plots were computed, ascertaining inter-rater and intra-rater variability. The eye surface areas of 19 patients were then derived from photographs taken before and after Botulinum toxin injections. Paired t-tests were used to analyse the significance of the difference in pre- and post-treatment symmetry. RESULTS: Ninety per cent of eye surface areas derived from the two raters were within a coefficient of variation of 0.1 (95% CI: 0.05-0.15). Similarly, 90% of eye surface areas derived from one rater had a coefficient of variation of 0.08 (95% CI: 0.04-0.12). Botulinum toxin significantly reduced synkinesis resulting from lip puckering, Mona Lisa smiling and Hollywood smiling (P<0.05). CONCLUSIONS: We have proposed a clinically valid tool for quantifying the effects of Botulinum toxin treatment for oral-ocular synkinesis. We recommend this method be used to monitor the response of such patients when receiving Botulinum toxin treatment. PMID- 23680718 TI - Laser barrage anterior to ridge in threshold ROP-caveat. PMID- 23680717 TI - Ocular prostheses in the last century: a retrospective analysis of 8018 patients. AB - PURPOSE: To analyze the clinical characteristics of patients with ocular prosthesis to assess the causes of eye loss in the different genders and age groups, and their incidence over the years. METHODS: We retrospectively examined the rates of ocular prosthesis application and related causes in the period from 1927 to 2011 in a referral center in Rome, Italy, and compared them over time. We also compared the results within the population in terms of age and gender. RESULTS: Of 8018 ocular prosthesis wearers, 63% were males and 37% were females, with a mean age of 29 years. The most frequent cause of ocular prosthesis application was a traumatic event (54%), with work-related eye injuries being the most frequent single cause of ocular trauma reported. Other frequent causes were end-stage ocular diseases, tumors, and malformations, without significant differences in gender. Tumors and malformations showed a slight increasing trend over time, while end-stage ocular diseases and work-related injuries remained unchanged, and other traumatic events decreased. CONCLUSION: The constantly high frequency of ocular prosthesis application for work-related injuries and end stage ocular diseases suggests that preventive measures for these events have not been addressed accordingly, and might represent a neglected public-health issue. PMID- 23680720 TI - [Reply to: How can we increase the number of scientific publications in general and gastrointestinal surgery?]. PMID- 23680719 TI - Radiation-dose response of glycophorin A somatic mutation in erythrocytes associated with gene polymorphisms of p53 binding protein 1. AB - Information on individual variations in response to ionizing radiation is still quite limited. Previous studies of atomic-bomb survivors revealed that somatic mutations at the glycophorin A (GPA) gene locus in erythrocytes were significantly elevated with radiation exposure dose, and that the dose response was significantly higher in survivors with subsequent cancer development compared to those without cancer development. Noteworthy in these studies were great inter individual differences in GPA mutant fraction even in persons with similar radiation doses. It is hypothesized that persistent GPA mutations in erythrocytes of atomic-bomb survivors are derived from those in long-lived hematopoietic stem cell (HSC) populations, and that individual genetic backgrounds, specifically related to DNA double-strand break repair, contribute to individual differences in HSC mutability following radiation exposure. Thus, we examined the relationship between radiation exposure, GPA mutant fraction in erythrocytes, and single nucleotide polymorphisms (SNPs) of the key gene involved in DNA double strand break repair, p53 binding protein 1 (53BP1). 53BP1 SNPs and inferred haplotypes demonstrated a significant interaction with radiation dose, suggesting that radiation-dose response of GPA somatic mutation is partly dependent on 53BP1 genotype. It is also possible that 53BP1 plays a significant role in DNA double strand break repair in HSCs following radiation exposure. PMID- 23680723 TI - Cancer networks and beyond: interpreting mutations using the human interactome and protein structure. AB - Over recent years, with the advances in next-generation sequencing, a large number of cancer mutations have been identified and accumulated in public repositories. Coupled to this is our increased ability to generate detailed interactome maps that help to enrich our knowledge of the biological implications of cancer mutations. As a result, network analysis approaches have become an invaluable tool to predict and interpret mutations that are associated with tumour survival and progression. Our understanding of cancer mechanisms is further enhanced by mapping protein structure information to such networks. Here we review the current methodologies for annotating the functional impacts of cancer mutations, which range from analysis of protein structures to protein protein interaction network studies. PMID- 23680724 TI - Metabolic network modeling approaches for investigating the "hungry cancer". AB - Metabolism is the functional phenotype of a cell, at a given condition, resulting from an intricate interplay of various regulatory processes. The study of these dynamic metabolic processes and their capabilities help to identify the fundamental properties of living systems. Metabolic deregulation is an emerging hallmark of cancer cells. This deregulation results in rewiring of the metabolic circuitry conferring an exploitative metabolic advantage for the tumor cells which leads to a distinct benefit in survival and lays the basis for unbound progression. Metabolism can be considered as a thermodynamic open-system in which source substrates of high value are being processed through a well established interconnected biochemical conversion system, strictly obeying physiochemical principles, generating useful intermediates and finally resulting in the release of byproducts. Based on this basic principle of an input-output balance, various models have been developed to interrogate metabolism elucidating its underlying functional properties. However, only a few modeling approaches have proved computationally feasible in elucidating the metabolic nature of cancer at a systems level. Besides this, statistical approaches have been set up to identify biochemical pathways being more relevant for specific types of tumor cells. In this review, we are briefly introducing the basic statistical approaches followed by the major modeling concepts. We have put an emphasis on the methods and their applications that have been used to a greater extent in understanding the metabolic remodeling of cancer. PMID- 23680725 TI - Synthesis and characterization of multi-functional linear-dendritic block copolymer for intracellular delivery of antitumor drugs. AB - A novel amphiphilic linear-dendritic block copolymer, semi-polyamidoamine-b poly(D,L-lactic acid) (PALA) was synthesized and evaluated for its potential as a drug delivery system in this study. PALA was self-assembled in aqueous solution to form nanomicelles with low critical micelle concentration; antitumor drug docetaxel (DTX) was successfully encapsulated into micelles. The prepared micelles demonstrated pH-induced charge conversion and dimension changes. In vitro drug release suggested susceptibility of DTX-loaded micelles to acidic microenvironment. Hemolysis and cytotoxicity testing also indicated in vitro biocompatibility of PALA. Pharmacokinetic study in rats proved that DTX-loaded PALA micelles enhanced the AUC of DTX and prolonged drug clearance in comparison to conventional DTX injection (Taxotere((r))). It was concluded that self assembled micelles from linear-dendritic block copolymer PALA demonstrated potential for intracellular delivery of anticancer molecules, and that its safety and efficacy in chemotherapy should be further studied. PMID- 23680726 TI - Novel alternatives to reduce powder retention in the dry powder inhaler during aerosolization. AB - Dry powder inhalers (DPIs) are used predominantly for the treatment of pulmonary diseases by delivering drugs directly into the lungs. The drug delivery efficiency is typically low and there is significant drug retention inside the DPI. An innovative 'green' initiative aimed at minimizing drug wastage via channeling the residual drug into the useful inhaled therapeutic fraction was pioneered. Drug retention could be minimized via coating the drug capsule and delivery device with pharmaceutically acceptable force-control agents. This coating reduces the adhesion between the drug particles and the internal surfaces of the DPI, which in turn increases the fine particle dose by as much as 300%. PMID- 23680727 TI - Drug precipitation inhibitors in supersaturable formulations. AB - Use of supersaturable formulations has been demonstrated as an effective approach to improve solubility and oral absorption of poorly water-soluble compounds. In supersaturable formulations, drug concentration exceeds the equilibrium solubility when the formulations are exposed to the gastrointestinal fluids and drug might precipitate before being absorbed, resulting in delayed response, and reduced efficacy or compromised bioavailability. Polymer based drug precipitation inhibitors have been used to inhibit or retard such precipitation. In this manner one can maintain a drug in the supersaturated concentration for an extended period of time, leading to significantly improved bioavailability of the poorly water-soluble drugs. This review article discusses different types of precipitation inhibitors, working hypotheses, and case studies with improved oral bioavailability. PMID- 23680728 TI - Influence of the insertion of a cationic peptide on the size and shape of nanoliposomes: a light scattering investigation. AB - Nanoliposomes are widely used for drug delivery in the human body. Cell penetrating peptides are amphiphilic peptides inserting in the lipid bilayer of these lipid vesicles to induce the fusion with target cells. Separation by size exclusion chromatography coupled with the analysis by light scattering detectors provides both the hydrodynamic radius and the radius of gyration of all the liposomes in a sample. In this paper, the influence of the insertion of a cationic peptide, K2LA12, on the size and shape of anionic liposomes has been studied by this approach. The results obtained highlighted an increase in size and a slight deformation of the lipid vesicles depending on the concentration of peptides incorporated into the lipid bilayers. PMID- 23680729 TI - Stabilization of bovine insulin against agitation-induced aggregation using RNA aptamers. AB - Stabilization of monomeric insulin is a primary requirement for preserving the efficacy of the final formulation. Degraded and/or aggregated protein as well as the presence of any of the conventional excipients can result in immunogenic or anaphylactic reactions, and reduced bioavailability of the protein drug. The aim of this work was to select novel RNA-based stabilizers of bovine insulin which would recognize and bind to the monomeric protein and help retain its bioactivity. RNA aptamers were selected by an in vitro selection method. They were screened for their ability to inhibit insulin fibrillation using agitation as a stress condition. The in vitro activity of insulin was determined by phosphorylation of downstream proteins in the cell. In vivo bioactivity was determined in a diabetic rat model. RNA aptamers, which bound to insulin with very low dissociation constants and high specificity, were selected. These sequences were aligned and consensus regions were found. The RNA sequences had no effect on the signalling cascade initiated by insulin. The bioactivity of insulin, as measured by its ability to lower plasma glucose level in a diabetic rat model, also remained unchanged. RNA aptamers are a novel class of protein stabilizers which have the ability to disrupt protein-protein interactions and hence inhibit protein aggregation. Their non-toxic and non-immunogenic nature makes such formulations safe for use. PMID- 23680730 TI - Gastro-floating tablets of cephalexin: preparation and in vitro/in vivo evaluation. AB - Gastro-floating tablets of cephalexin were developed to prolong the residence time in major absorption sites. Gastro-floating tablets were prepared and optimized using hydroxypropyl methylcellulose (HPMC K100M) as matrix and sodium bicarbonate as a gas-forming agent. The properties of the tablets in terms of floating lag time, floating time and in vitro release were evaluated. Furthermore, in vivo pharmacokinetic study in fed and fasted beagle dogs was performed. The gastro-floating tablets had short floating lag time and exhibited a satisfactory sustained-release profile in vitro. Compared with conventional capsules, the gastro-floating tablets presented a sustained-release behavior with a relative bioavailability of 99.4%, while the reference sustained-release tablets gave a relative bioavailability of only 39.3%. Meanwhile, the food had significant effect on the pharmacokinetics of sustained-release tablets. It was concluded that the gastro-floating tablets had a sustained-release effect in vitro and in vivo, as well as desired pharmacokinetic properties in both fed and fasted conditions. PMID- 23680731 TI - Enhanced brain distribution and pharmacodynamics of rivastigmine by liposomes following intranasal administration. AB - Alzheimer's disease (AD) is a common progressive neurodegenerative disorder associated with cholinergic neurons degeneration. The blood-brain barrier (BBB) not only provides protection for the brain but also hinders the treatment and diagnosis of this neurological disease, because the drugs must cross BBB to reach the lesions. The present work was aimed at formulating rivastigmine liposomes (Lp) and cell-penetrating peptide (CPP) modified liposomes (CPP-Lp) to improve rivastigmine distribution in brain and proceed to enhance pharmacodynamics by intranasal (IN) administration and minimize side effects. The results revealed that Lp especially the CPP-Lp can enhance the permeability across the BBB by murine brain microvascular endothelial cells model in vitro. IN administration of rivastigmine solution and rivastigmine liposomes demonstrated the capacity to improve rivastigmine distribution and adequate retention in CNS regions especially in hippocampus and cortex, which were the regions most affected by AD, than that of IV administration. Importantly, the lagging but intense inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities were relative to the extended release, absorption and retention. In addition, there was very mild nasal toxicity of liposomal formulations. The data suggest that rivastigmine liposomes especially CPP-Lp improve the brain delivery and enhance pharmacodynamics which respect to BBB penetration and nasal olfactory pathway into brain after IN administration, and simultaneously decrease the hepatic first pass metabolism and gastrointestinal adverse effects. PMID- 23680733 TI - 3D hydrodynamics and shear rates' variability in the United States Pharmacopeia Paddle Dissolution Apparatus. AB - The 3D hydrodynamics and shear rates distributions within the United States Pharmacopeia Apparatus 2 have been investigated in this paper. With the help of a CFD package, several geometric modifications to the device were evaluated in this study. Specially, we examine the influence of impeller clearance, blade diameter, shape of the vessel base and shape of the lower part of blade. Increasing the impeller clearance was observed to exacerbate the heterogeneity in shear and would likely result in greater variability in dissolution measurements. Use of moderate blade diameter and dished bottom were observed to reduce shear heterogeneity in the regions where tablets are most likely to visit during testing. The comparative analysis shows better reproducibility and accelerated dissolution rates with the modified vessel shape, the dished bottom can enhance mixing near the vessel base when compared with the flat bottom. Increasing length of the lower edge of the paddle was observed to generate high radial pumping and to enlarge the dead zone located at the center of the vessel base. PMID- 23680732 TI - Electrospun chitosan-based nanofiber mats loaded with Garcinia mangostana extracts. AB - The aim of this study was to prepare electrospun chitosan-based nanofiber mats and to incorporate the fruit hull of Garcinia mangostana (GM) extracts into the mats. Chitosan-ethylenediaminetetraacetic acid/polyvinyl alcohol (CS-EDTA/PVA) was selected as the polymers. The GM extracts with 1, 2 and 3 wt% alpha-mangostin were incorporated into the CS-EDTA/PVA solution and electrospun to obtain nanofibers. The morphology and diameters of the mats were analyzed using scanning electron microscopy (SEM). The mechanical and swelling properties were investigated. The amount of GM extracts was determined using high-performance liquid chromatography (HPLC). The antioxidative activity, antibacterial activity, extract release and stability of the mats were evaluated. In vivo wound healing tests were also performed in Wistar rats. The results indicated that the diameters of the fibers were on the nanoscale and that no crystals of the extract were observed in the mats at any concentration. The mats provided suitable tensile strength and swelling properties. All of the mats exhibited antioxidant and antibacterial activity. During the wound healing test, the mats accelerated the rate of healing when compared to the control (gauze-covered). The mats maintained 90% of their content of alpha-mangostin for 3 months. In conclusion, the chitosan-based nanofiber mats loaded with GM extracts were successfully prepared using the electrospinning method. These nanofiber mats loaded with GM extracts may provide a good alternative for accelerating wound healing. PMID- 23680734 TI - Characterization and in vitro permeation study of microemulsions and liquid crystalline systems containing the anticholinesterase alkaloidal extract from Tabernaemontana divaricata. AB - The aims of the present study were to characterize the microstructure and study the skin permeation enhancement of formulations containing the alkaloidal extract from Tabernaemontana divaricata. The extract was loaded in the formulations composed of Zingiber cassumunar oil, Triton X-114, ethanol and water with the oil:surfactant ratios of 1:5 and 2:5. The formulations were characterized by photon correlation spectroscopy, polarizing light microscopy, differential scanning calorimetry, and viscosity measurement. A reverse micellar phase, w/o microemulsions, liquid crystalline systems, liquid crystal in microemulsion systems and coarse emulsions were formed along the aqueous dilution line of both oil:surfactant ratios. Formulations with the ratio of 1:5 containing 0.1 MUg/ml extract showed a significantly higher acetylcholinesterase inhibition than those with the ratio of 2:5. The skin of stillborn piglet was used in the permeation study. The liquid crystalline and microemulsion systems significantly increased the transdermal delivery of the extract within 24h. It was concluded that the alkaloidal extract from T. divaricata stem loaded in liquid crystalline or microemulsion systems comprising Z. cassumunar oil/Triton X-114/ethanol/water may act as an alternative percutanous formulations for enhancing the acetylcholine level in Alzheimer's patients. PMID- 23680735 TI - Quantitative analysis of the layer separation risk in bilayer tablets using terahertz pulsed imaging. AB - Layer separation is a critical defect in many bilayer tablets. Despite its importance for product quality, few studies have investigated its root cause. We evaluated bilayer tablets with varying layer separation tendencies using terahertz pulsed imaging (TPI) in comparison with other analytical methods such as tensile strength measurements, friability testing, scanning electron microscopy (SEM), and X-ray computed tomography (XRCT). The layer separation risk was determined by friability testing and shown to be correlated with the final compression pressure used for bilayer tablet fabrication. TPI could nondestructively detect cracks between the component layers that lead to layer separation. The adhesion integrity of the interface was quantified by the interface index, a unique value derived from the time-domain terahertz waveform. The interface index showed good correlation to the layer separation tendency and could distinguish interface quality among seven batches of bilayer tablets. In contrast, SEM and XRCT detected structural defects but could not distinguish batches with high or low layer separation risk. TPI revealed the relationship between compression pressure and interface quality. Thus, TPI can aid in quality control by providing a precise estimate of the layer separation risk and robust quality of bilayer tablet development with better understanding of layer separation. PMID- 23680736 TI - Practical approach to management of inpatient hyperglycemia in select patient populations. AB - Hospitalized patients frequently transition between various levels of care and changing clinical situations. Optimal management of hospitalized patients with hyperglycemia includes awareness of situations that may significantly affect glucose and/or insulin metabolism. A review of published clinical trials reveals practical approaches to the management of hyperglycemia in select patient populations that may prove useful for the hospital clinician. We outline approaches to the management of hyperglycemia in hospitalized patients receiving glucocorticoids, patients with severe or end-stage renal disease undergoing hemo- or peritoneal dialysis, and patients receiving total parenteral or enteral feeding, in addition to patients transitioning from intravenous insulin infusion to subcutaneously administered insulin. Key considerations underlying these management methods include a proactive approach, frequent blood glucose monitoring, daily review of blood glucose patterns, and daily reassessment of the insulin regimen and associated orders. PMID- 23680738 TI - Hepatopulmonary syndrome and portopulmonary hypertension. AB - Hepatopulmonary syndrome and portopulmonary hypertension are 2 of many diseases that affect the lungs in patients with liver disease. The 2 vascular conditions are often confused. We review both hepatopulmonary syndrome and portopulmonary hypertension to better understand their pathophysiologies, clinical presentations, tools to aid in differentiating and diagnosing the disease states, treatment options, and influences on patient prognosis. We also consider patient viability for liver transplantation. PMID- 23680737 TI - Carotid artery intima-media thickness and the renin-angiotensin system. AB - Carotid artery intima-media thickness (IMT) is a biomarker for cardiovascular disease that also predicts the risk of cardiovascular mortality. Angiotensin converting enzyme (ACE) inhibition is a unique therapeutic modality because it both treats hypertension and improves arterial health and cardiovascular disease outcomes. Controversy exists regarding the role of ACE inhibitors and angiotensin receptor blockers (ARBs) in IMT regression. Our article provides an update on how ACE inhibitors and ARBs could play a role in decreasing IMT. PMID- 23680739 TI - Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. AB - INTRODUCTION: Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of patients with type 2 diabetes mellitus (T2DM). Our randomized, double-blind, placebo-controlled, phase 3 study (www.clinicaltrials.gov: NCT01106651) evaluated the efficacy and safety of canagliflozin therapy in older subjects (aged 55-80 years) with T2DM inadequately controlled on their current regimen of blood glucose-lowering agents (any approved oral or injectable treatment). METHODS: Subjects (N = 716) aged 55 to 80 years (mean, 63.6 years) with glycated hemoglobin (HbA1c) levels >= 7.0% to <= 10.0% were randomized. Seven hundred fourteen received canagliflozin 100 mg or 300 mg or placebo (1:1:1) daily. The prespecified primary endpoint was change from baseline in HbA1c level at week 26. Prespecified secondary endpoints included proportion of subjects achieving HbA1c levels < 7.0%, change from baseline in fasting plasma glucose (FPG) level and systolic blood pressure (BP), and percent change from baseline in body weight, triglyceride levels, and high density lipoprotein cholesterol (HDL-C) level. Adverse events (AEs) were reported throughout the study. RESULTS: At week 26, treatment with canagliflozin 100 mg and 300 mg significantly reduced HbA1c levels compared with placebo (-0.60%, 0.73%, -0.03%, respectively; P < 0.001); more subjects achieved HbA1c levels < 7.0% with both canagliflozin doses compared with placebo (P < 0.001). Both canagliflozin doses significantly reduced body weight, FPG level, and systolic BP, and increased HDL-C level compared with placebo (P < 0.001); low-density lipoprotein cholesterol level was increased with both canagliflozin doses compared with placebo. The overall AE incidence was slightly higher with canagliflozin 300 mg than with canagliflozin 100 mg or placebo (78.0%, 72.2%, 73.4%, respectively). Serious AE and AE-related discontinuation rates were low across groups. Both canagliflozin doses were associated with higher rates than placebo of genital mycotic infections, urinary tract infections, and osmotic diuresis-related AEs (ie, pollakiuria, polyuria). Documented hypoglycemia rates were modestly higher with both canagliflozin doses compared with placebo. CONCLUSION: Canagliflozin improved glycemic control, reduced body weight and systolic BP, and was generally well tolerated in older subjects with T2DM who were on background therapy with a variety of blood glucose-lowering agents. PMID- 23680740 TI - Update in perioperative medicine 2012. AB - Perioperative medicine is an increasing area of research focus that brings together internists, anesthesiologists, surgeons, and hospitalists. A medical team approach to ensure the best possible patient outcomes has fostered collaborative strategies across areas of patient care. We review 8 seminal articles in the field of perioperative medicine. Each article was published in either 2011 or 2012 and adds to care strategies in the areas of perioperative cardiac medicine, pulmonary care, blood transfusion decision making, and medication management. PMID- 23680741 TI - Combination therapy with DPP-4 inhibitors and insulin in patients with type 2 diabetes mellitus: what is the evidence? AB - As type 2 diabetes mellitus (T2DM) progresses, most patients will require insulin replacement therapy. Whether oral antidiabetic drug (OAD) therapy should be retained when initiating insulin is still debated. While the rationale to keep metformin with insulin is strong (mostly as an insulin-sparing agent to limit weight gain), the evidence is less clear for other OADs. In particular, the question now comes up what the expected benefit could be of combining the newer agents, such as the dipeptidyl peptidase-4 (DPP-4) inhibitors with insulin. Additionally, when metformin is no longer a treatment option, as in the case of patients with severe renal impairment, insulin is often used as monotherapy, with little evidence of benefit in maintaining other OADs. In this specific situation, it is also of interest to evaluate the potential benefit of combined treatment with a DPP-4 inhibitor and insulin. Among the classic limitations of insulin therapy in patients with T2DM, hypoglycemia remains a major barrier to glycemic control, along with weight gain exacerbation. The oral DPP-4 inhibitors improve glycemic control by increasing the sensitivity of the islet cells to glucose, and thus are not associated with an increased risk for hypoglycemia and are weight neutral. In addition to the expected benefits associated with limiting insulin dose and regimen complexity, the specific advantages the DPP-4 inhibitor drug class on hypoglycemia and weight gain could justify combining DPP-4 inhibitors with insulin; additionally, a DPP-4 inhibitor may be of special value to decrease glycemic excursions that are not properly addressed by basal insulin therapy and metformin use, even after optimizing titration of the basal insulin. However, given the common original perception that treatment with DPP-4 inhibitors may be less beneficial with increasing disease progression because of the loss of beta cell function, the potential relevance of these agents in the setting of advanced T2DM treated with insulin was not necessarily anticipated. Promising data from studies on the use of these new agents in insulin-treated patients with T2DM have started to emerge. Our article provides a comprehensive overview of the currently available evidence from controlled randomized clinical trials and we discuss the potential role of DPP-4 inhibitors in the this setting. Further clinical experience will allow to fully assess the positioning of these agents in insulin treated T2DM populations. PMID- 23680742 TI - Management of acute ischemic stroke. AB - Stroke is one of the most common causes of morbidity and mortality in hospitalized patients in the United States. A proper understanding of stroke mechanisms helps to guide specific case management. The only therapy approved by the US Food and Drug Administration for the management of acute ischemic stroke is initiation of intravenous recombinant tissue plasminogen activator within 3 hours of symptom onset. Other treatment options include intra-arterial recombinant tissue plasminogen activator, mechanical thrombectomy, clot retrieval, or a combination of these approaches. In this article, we provide an evidence-based review of the diagnostic approach for acute ischemic stroke, including recognizing common stroke mimics. We detail the initial medical management of acute stroke and the medical and surgical therapeutic interventions for patients who have sustained acute ischemic stroke. PMID- 23680743 TI - Improving clinician performance of inpatient venous thromboembolism risk assessment and prophylaxis. AB - Clinicians are aware of the importance of thromboprophylaxis, and that the application of measures to prevent venous thromboembolism (VTE) occurrence in hospitalized patients must be improved. To enhance clinician execution of appropriate steps to reduce the risk of inpatient VTE, a performance improvement (PI) continuing medical education (CME) initiative consisting of 3 independent tracks for hospitalized patients-patients who are medically ill, patients receiving oncology treatment, and patients undergoing major orthopedic surgery was designed and implemented. After a baseline chart review of select evidenced based performance measures for VTE risk stratification and prevention, participants identified >= 1 area of personal improvement. Participants then engaged in a period of self-improvement and reassessed their performance with a second chart review. After participating in the PI CME activity, clinician participants in the medically ill track increased their documentation of VTE risk assessments upon patient admission from baseline (56% vs 93%, n = 250; P < 0.001) and their prescription of low-molecular-weight heparin, low-dose unfractionated heparin, or fondaparinux (72% vs 88%, n = 250; P < 0.001). Orthopedic-track participants were significantly more likely to prescribe 15 to 35 days of VTE prophylaxis after total hip arthroplasty or hip fracture surgery upon patient discharge compared with baseline (51%, n = 123 vs 61%, n = 107; P < 0.001). Oncology-track participants demonstrated a nonsignificant trend for assessing and documenting bleeding risk after participation in the PI CME activity (56% vs 68%, n = 80; P = 0.143). Improvements in evidence-based strategies to reduce the risk of inpatient VTE were associated with PI CME participation. Although areas for improvement remain, increased participant identification and use of prophylactic measures can reduce the risk of VTE in hospitalized patients. PMID- 23680744 TI - Pleiotropic effects of thiazolidinediones: implications for the treatment of patients with type 2 diabetes mellitus. AB - Thiazolidinediones (TZDs) are insulin-sensitizing antidiabetes agents that act through the peroxisome proliferator-activated receptor-gamma to cause a durable improvement in glycemic control in patients with type 2 diabetes mellitus. Although less well recognized, TZDs also exert a protective effect on beta-cell function. In addition to their beneficial effects on glucose homeostasis, TZDs especially pioglitazone-exert a number of other pleiotropic effects that make them ideal agents as monotherapy or in combination with other oral agents, glucagon-like peptide-1 analogs, or insulin. Pioglitazone improves endothelial dysfunction, reduces blood pressure, corrects diabetic dyslipidemia, and reduces circulating levels of inflammatory cytokines and prothrombotic factors. Pioglitazone also redistributes fat and toxic lipid metabolites in muscle, liver, beta cells, and arteries, and deposits the fat in subcutaneous adipocytes where it cannot exert its lipotoxic effects. Consistent with these antiatherogenic effects, pioglitazone reduced major adverse cardiac event endpoints (ie, mortality, myocardial infarction, and stroke) in the Prospective Pioglitazone Clinical Trial in Macrovascular Events and in a meta-analysis of all other published pioglitazone trials. Pioglitazone also mobilizes fat out of the liver, improving liver function and histologic abnormalities in patients with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Pioglitazone also reduces proteinuria, all-cause mortality, and cardiovascular events in patients with type 2 diabetes mellitus with a reduced glomerular filtration rate. These benefits must be weighed against the side effects of the drug, including weight gain, fluid retention, atypical fractures, and, possibly, bladder cancer. When low doses of pioglitazone are used (eg, 7.5-30 mg/d) with gradual titration, and physician recognition of the potential side effects are applied, the risk-to benefit ratio is very favorable. Despite having similar effects on glycemic control, pioglitazone and rosiglitazone appear to have different effects on cardiovascular outcomes. Rosiglitazone has been associated with an increased risk of myocardial infarction, and its use in the United States is restricted because of cardiovascular safety concerns. PMID- 23680745 TI - [The contribution of high-impact clinical journals to science: the case of The Lancet]. PMID- 23680746 TI - [Reactions to institutional violence: patient strategies for facing infringements of the right to health in Brazil]. AB - In this article we identify evidences of inequalities, prejudices and discrimination in the access and utilization of public health services belonging to the Brazilian Unified Health Care System, considering them to be institutional violence and a negation of rights, in order to look at the reactions of the subjects victimized by this process. This research study utilized different methodologies, articulating participant observation, semi-structured interviews, focus groups and dramatization. The results highlight the trajectory in seeking health care as the main expression of inequalities, strengthened by structural factors such as the precarious condition of health care services, which potentiate power asymmetries, and the presence of discrimination derived from stigmas and prejudices. Most patients' reactions to the situation of institutional violence seek an individual solution to the problem, often reaffirming the conditions that generate rights violations. Few patients' reactions question the systemic conditions that determine the continued discrimination. PMID- 23680747 TI - [Old age in primary school readers: a journey through the end of the 19th century to the start of the 21st century in Argentina]. AB - This article presents the content (discourse) analysis of messages transmitted by primary school readers in the period between 1880 to 2012. This study allowed us to explore the image of old age and aging that society has and passes on to new generations as well as the role assigned to this generational group. The historical periods that provide the context for the data were defined according to the continuity of or the turning points in the social values transmitted in the reading materials. The role assigned to elderly people and the image of old age that the Argentine society passed on and continues to pass on to younger generations demonstrate that each period described has its own model of aging. PMID- 23680748 TI - [Treatment for cancer pain at the end of life: a case study in a palliative care service in the Autonomous City of Buenos Aires]. AB - Cancer pain relief has been defined as a worldwide public health challenge in the last decades and has recently been included in public debates as a human rights issue. However, barriers to the provision of adequate pain management continue to exist. This article analyzes the cancer pain treatment provided in a palliative care setting in the Autonomous City of Buenos Aires, focusing on how professionals and patients implement and negotiate the terms and adherence to the pain treatment. Based on a qualitative approach that triangulates data from semi structured interviews and from ethnographic observations, the article addresses the way pain is measured and assessed and the strategies of health professionals in establishing pain treatment protocols. The article also describes the rhetoric regarding the right to pain relief developed by health professionals through their practice and discusses the limitations of that rhetoric. PMID- 23680749 TI - [The origin and quality of water for human consumption: the health of the population residing in the Matanza-Riachuelo river basin area in Greater Buenos Aires]. AB - The aim of this study is to analyze the origin and quality of water used for consumption in a sample of households in Matanza-Riachuelo river basin area in Greater Buenos Aires, Argentina. The results of drinking water by source indicated that 9% of water samples from the public water system, 45% of bottled water samples and 80% of well water samples were not safe for drinking due to excess content of coliforms, Escherichia coli or nitrates. Individuals living in households where well water is the main source of drinking water have a 55% higher chance of suffering a water-borne disease; in the cases of diarrheas, the probability is 87% higher and in the case of dermatitis, 160% higher. The water for human consumption in this region should be provided by centralized sources that assure control over the quality of the water. PMID- 23680750 TI - [Self-care, adherence and uncertainty: biomedical treatments and patients' experiences regarding chronic migraine pain]. AB - Based in the social sciences, this text explores and analyzes the particularities of migraine treatments using a relational approach, articulating the statements of professionals with the experiences and practices of patients in health services and their everyday care trajectories to manage pain. This qualitative research study utilized semi-structured interviews with neurologists and patients in a public hospital in the Autonomous City of Buenos Aires. A number of processes were observed by which biomedicine assigns part of the responsibility for the course of the disease to the patient through the logic of self-care. Patients must make changes in their ways of life in order to prevent headaches from appearing. Nevertheless, as the efficacy of these modifications is unclear, daily life is filled with uncertainty and charged with the mandate to follow care guidelines, which are valued not only professionally but also socially. PMID- 23680751 TI - [Sociodemographic determinants of access to breast cancer screening in Mexico: a review of national surveys]. AB - The aim of this article is to identify factors affecting access to breast cancer screening in Mexico according to the sociodemographic characteristics of the women, using three nationally-representative surveys. Descriptive statistics were performed and multiple classification analysis techniques were used. The dependent variables were that the women had realized: 1) breast self-examination, 2) clinical breast examination, or 3) mammography; the covariates were: age group, education level, type of locality (urban/rural), marital status, number of children, enrollment in social security and socioeconomic status. A low level of screening use was detected and gaps were observed between different groups of women according to sociodemographic characteristics. In general women of lower economic strata, without enrollment in social security and with lower educational levels, showed fewer detection practices than the national average. PMID- 23680752 TI - [Health statistics aren't born in a cabbage patch: Jesuits, political arithmetic, stigmergy and oligopticons]. AB - By analyzing the content and network of production of a map from 1751, created by the circular mission of the Jesuits in Chiloe (an archipelago located off the southern coast of Chile), that contains birth, death and population data, this article discusses the role that health statistics play historically, philosophically, technically and sociologically. In doing so, the article seeks to comprehend the genesis of a process of production of data and references in order to debate what health statistics are composed of, what ends they are used for, what their connection is to the formation of collectives and the differential conditions of possibility that exist for producing statistics. We attempt to develop hypotheses that demonstrate statistics as a hybrid articulation between diverse elements, epistemological, biopolitical, historical and philosophical in nature, with facets at once religious and demographic, ontological and ethnic, scientific and governmental. PMID- 23680754 TI - Trypanocidal activity of 1,3,7-trihydroxy-2-(3-methylbut-2-enyl)-xanthone isolated from Kielmeyera coriacea. AB - This work evaluated the activity and ultrastructural and morphological alterations induced by the xanthone 1,3,7-trihydroxy-2-(3-methylbut-2-enyl) xanthone (C23) isolated from Kielmeyera coriacea against Trypanosoma cruzi. This xanthone had inhibitory activity against the three forms of this protozoan and did not induce toxicity in mammalian cells. The best activity of this xanthone was against the intracellular amastigote form. Additionally, the mitochondrion was the main target of this compound, reflected by electronic microscopy and rhodamine 123 assays. Our MitoSOX assay results also indicated that C23 increased O2(-) production in mitochondrion. C23 might be a promising chemotherapeutic agent against T. cruzi because its trypanocidal action involves the disruption of mitochondrion, a specific target of Trypanosomatides. PMID- 23680755 TI - Current ophthalmologic treatment strategies for acute and chronic Stevens-Johnson syndrome and toxic epidermal necrolysis. AB - PURPOSE OF REVIEW: To review the newer, effective ophthalmologic treatments for acute Stevens-Johnson syndrome (SJS) as well as the emerging treatment options for patients with chronic, severe ocular surface damage from the disease. RECENT FINDINGS: Amniotic membrane transplantation (AMT) applied to the eyes and eyelids in the acute phase of SJS can prevent the devastating scarring and visual problems that characterize the chronic phase of the disease. The severity of ocular inflammation in the acute phase does not always correlate to the severity of skin and systemic involvement. Thus, it is crucial that all patients with SJS be evaluated by an ophthalmologist familiar with the current management of the disease, the potential urgency of the situation and the option of AMT. Although challenging, the severe, chronic ocular problems of SJS can be at least partially alleviated with autologous serum drops, mucous membrane grafting to replace scarred tarsal conjunctiva, specialized contact lenses (PROSE), conjunctival replacement surgery (COMET), limbal stem cell transplantation and kerotoprostheses. SUMMARY: Early AMT is an effective treatment of acute SJS. Emerging treatments offer increased hope for those who have already suffered damage from SJS, but emphasis on the prevention of damage in the acute phase is most crucial. PMID- 23680756 TI - Hormones and dry eye syndrome: an update on what we do and don't know. AB - PURPOSE OF REVIEW: Dry eye syndrome (DES) prevalence is large and its relationship with hormonal diseases is becoming clearer, although more complex. This review provides insight to this association as well as clarifying what remains unanswered about how to interpret and treat findings common to both DES and hormonal diseases. RECENT FINDINGS: Several sex hormone-related diseases are associated with DES. Hormone replacement therapy to correct such conditions has conflicting outcomes based on epidemiologic studies and clinical trials. Thyroid associated diseases are frequently involved in DES and must be investigated in cases where the cause of the ocular disease is undetermined. Diabetes mellitus is one of the major causes of DES, whereas correcting the metabolic imbalance minimizes its ocular symptomology. Gene therapy to treat DES-related hormonal diseases is a promising option based on animal studies. SUMMARY: Diagnosis and management of hormonal diseases can minimize the ocular surface damage and severity of DES. Clinical care of DES includes patient evaluation of hormonal status. Future research requires clarification of the underlying disease mechanisms and identifying novel strategies to reprogram the endocrine system rather than chronic medication usage. PMID- 23680757 TI - Updated practical intraocular lens power calculation after refractive surgery. AB - PURPOSE OF REVIEW: Since its introduction in the 1980s, more than 40 million people worldwide have undergone some form of kerato-refractive surgery. Many of these individuals are now candidates for cataract surgery and pose the challenge of attaining first-rate refractive outcomes in nonvirgin eyes. Numerous approaches have been developed to estimate intraocular lens (IOL) power in eyes postrefractive surgery. This review highlights the most practical, relevant options for accurate IOL power determination in these cases. RECENT FINDINGS: With refined techniques and advances in instrumentation, more accurate assessments of true corneal power and thus, IOL power, are possible in postrefractive eyes. Optical coherence tomography and other corneal tomography instruments have markedly improved accuracy in this process. However, when expensive, modern equipments are not readily available, and online IOL calculators such as the American Society of Cataract and Refractive Surgery (ASCRS) calculator have become efficient, reliable options. Recent evidence confirms the accuracy of these online calculators. SUMMARY: Emerging literature supports the use of methods that do not rely on prior refractive data in IOL power determination. Online IOL calculators provide user-friendly, efficient options that greatly facilitate accurate IOL power determination for cataract surgery in eyes that have undergone prior kerato-refractive surgery. PMID- 23680758 TI - Descemet's membrane endothelial keratoplasty surgery: update on the evidence and hurdles to acceptance. AB - PURPOSE OF REVIEW: Descemet's stripping endothelial keratoplasty (DSEK) is the most popular treatment for endothelial dysfunction, but Descemet's membrane endothelial keratoplasty (DMEK) now provides better vision with lower risk of immunologic rejection. Although DMEK is more challenging, advances in instrumentation and techniques are reducing the learning curve. RECENT FINDINGS: In contrast to DSEK, which includes posterior donor stroma, DMEK consists merely of donor endothelium and Descemet's membrane, so DMEK does not create a stromal interface and induces significantly less posterior surface aberrations, resulting in better vision. Furthermore, multiple centers report remarkably low (<1%) cumulative probability of immunologic graft rejection episodes through 2 years after DMEK. Initially, the biggest challenges were tissue loss in preparation and ensuring attachment. Subsequent improvements have reduced complication rates to levels experienced with DSEK. DMEK/DSEK hybrids and 'thin' DSEK also can provide better vision than standard DSEK; randomized controlled comparisons with DMEK are needed. SUMMARY: DMEK provides an anatomically exact replacement of dysfunctional host endothelium and has set new benchmarks for rejection risk and visual outcomes following endothelial replacement. DMEK is providing new insights into how different corneal layers contribute to immunogenicity and immune tolerance and into the key factors that limit vision after endothelial keratoplasty. PMID- 23680759 TI - Topical chemotherapy for ocular surface squamous neoplasia. AB - PURPOSE OF REVIEW: Ocular surface squamous neoplasia (OSSN) is an umbrella term for a spectrum of epithelial dysplasias of the cornea, conjunctiva, and limbus. Treatment for OSSN has historically been surgery, but nonsurgical interventions have been increasingly adopted. Advantages of medical treatments include the ability to treat the entire ocular surface and prevention of surgical complications. RECENT FINDINGS: The primary medical treatments for OSSN include mitomycin C, 5-fluorouracil, and interferon alpha2b. Mitomycin C has been shown in studies to be highly effective but has short-term and long-term side-effects that may be intolerable. 5-Fluorouracil and interferon alpha2b have been found to be similar in efficacy to mitomycin, with interferon being extremely well tolerated in the majority of patients. Most recently, other chemotherapeutic agents have been tried for OSSN including antivascular endothelial growth factor agents and vitamin A. The data regarding these latter treatment strategies are still limited. SUMMARY: An understanding of the recent literature, with respect to the efficacy, advantages, and disadvantages of the various therapies for OSSN will allow us to tailor treatment to each patient. PMID- 23680760 TI - Topography-guided laser refractive surgery. AB - PURPOSE OF REVIEW: Topography-guided laser refractive surgery regularizes the front corneal surface irregularities to achieve the desired refractive outcome. This is particularly applicable in highly aberrated corneas, where wavefront aberrometry is often not possible. This article aims to review the recently published results of topography-guided ablations in normal regular corneas, highly aberrated corneas, and its application in conjunction with collagen cross linking (CXL) in cases of keratectasia. RECENT FINDINGS: Topography-guided laser ablation is increasingly used with good efficacy and safety outcomes in highly aberrated corneas with irregular astigmatism. These include eyes with refractive surgery complications including postlaser in-situ keratomileusis ectasia, decentered ablation, small optical zones, asymmetrical astigmatism, and postradial keratectomy astigmatism. Further indications are for postkeratoplasty astigmatism and keratoconus. Simultaneous topography-guided ablations with CXL in keratectasia have been promising, both in addressing the surface irregularities and progressive nature of the conditions. SUMMARY: Topography-guided laser refractive surgery is proving to be effective and well tolerated in the visual rehabilitation of highly aberrated eyes, with increasing predictability based on the recent research. PMID- 23680761 TI - Scheimpflug imaging for laser refractive surgery. AB - PURPOSE OF REVIEW: To review the principles and clinical applications of Scheimpflug corneal and anterior segment imaging with special relevance for laser refractive surgery. RECENT FINDINGS: Computerized Scheimpflug imaging has been used for corneal and anterior segment tomography (CASTm) in different commercially available instruments. Such approach computes the three-dimensional image of the cornea and anterior segment, enabling the characterization of elevation and curvature of the front and back surfaces of the cornea, pachymetric mapping, calculation of the total corneal refractive power and anterior segment biometry. CASTm represents a major evolution for corneal and anterior segment analysis, beyond front surface corneal topography and single point central corneal thickness measurements. This approach enhances the diagnostic abilities for screening ectasia risk as well as for planning, evaluating the results, managing complications of refractive procedures, and selecting intraocular lens power, type, and design. In addition, dynamic Scheimpflug imaging has been recently introduced for in-vivo corneal biomechanical measurements and has also been used for anterior segment imaging of femtocataract surgery. SUMMARY: Scheimpflug imaging has an important role for laser refractive surgery with different applications, which continuously improve due to advances in technology. PMID- 23680763 TI - The availability and quality across Europe of outpatient care for difficult-to engage patients with severe mental illness: a survey among experts. AB - BACKGROUND: As many patients with severe mental illness (SMI) who have complex needs are difficult to engage, outreach mental health services are needed to engage them into treatment. The extent to which these services exist in large European cities is unknown. METHODS: Experts in 29 European countries were sent a structured questionnaire containing two case vignettes of difficult-to-engage patients (a first-episode psychosis patient and a homeless chronic schizophrenia patient). The type and quality of outpatient care was assessed and related to several national indices. RESULTS: The questionnaire was returned by experts from 22 countries (76%) representing 92% of the EU population. Six countries (21%) had a systematic method for detecting difficult-to-engage patients. The most important route whereby such patients entered the mental health system was through informal care; the most important reasons for entering it were the level of psychiatric symptoms, nuisance and violence. Assertive outreach was available in nine countries (41%), with coverage ranging from a few teams (sometimes for a specific target group) to most of the country. The case vignettes showed that outpatient care for these difficult-to-engage patients varied widely. In seven (30%) of the 22 countries, a hospital would take no action if such patients who had been admitted voluntarily discharged themselves prematurely. On a scale of 0 10, the experts' mean scores regarding the quality of outpatient care for patients with SMI in general were 5.2 (SD = 1.9) and 3.2 (SD = 2.2) in difficult to-engage ones. Explorative analyses showed that the quality of outpatient care for difficult-to-engage patients was associated with gross national income and the number of psychiatrists per capita. CONCLUSIONS: Outpatient mental health services for difficult-to-engage SMI patients varied widely among European countries; experts judged their overall quality to be poor. It is now important to achieve consensus on a minimum European standard for the quality of care for such patients. PMID- 23680764 TI - Causal attribution of mental illness in South-Eastern Nigeria. AB - BACKGROUND: Understanding of mental illness in sub-Saharan Africa has remained under-researched in spite of the high and increasing neuropsychiatric burden of disease in the region. AIMS: This study investigated the causal beliefs that the Igbo people of south-eastern Nigeria hold about schizophrenia, with a view to establishing the extent to which the population makes psychosocial, biological and supernatural attributions. METHOD: Multi-stage sampling was used to select participants (N = 200) to which questionnaires were administered. RESULTS: Mean comparison of the three causal models revealed a significant endorsement of supernatural causation. Logistic regressions revealed significant contributions of old age and female gender to supernatural attribution; old age, high education and Catholic religious denomination to psychosocial attributions; and high education to biological attributions. CONCLUSIONS: It is hoped that the findings would enlighten, augment literature and enhance mental health care service delivery. PMID- 23680765 TI - Rapid Sonogashira cross-coupling of iodoferrocenes and the unexpected cyclo oligomerization of 4-ethynylphenylthioacetate. AB - A systematic study into the Sonogashira cross-coupling of 1,1'-diiodoferrocene (fcI2) confirms that the Pd(0)-P((t)Bu)3 system provides a remarkable rate increase over Pd(0)-(PPh3)2. Attempts to couple 4-ethynylphenylthioacetate (2) with fcI2 instead produced a novel cyclic trimer of the former, from syn addition of S-Ac across C=C. PMID- 23680767 TI - The use of next-generation sequencing in clinical diagnosis of familial hypercholesterolemia. AB - PURPOSE: Familial hypercholesterolemia is a common Mendelian disorder associated with early-onset coronary heart disease that can be treated by cholesterol lowering drugs. The majority of cases in the United Kingdom are currently without a molecular diagnosis, which is partly due to the cost and time associated with standard screening techniques. The main purpose of this study was to test the sensitivity and specificity of two next-generation sequencing protocols for genetic diagnosis of familial hypercholesterolemia. METHODS: Libraries were prepared for next-generation sequencing by two target enrichment protocols; one using the SureSelect Target Enrichment System and the other using the PCR-based Access Array platform. RESULTS: In the validation cohort, both protocols showed 100% specificity, whereas the sensitivity for short variant detection was 100% for the SureSelect Target Enrichment and 98% for the Access Array protocol. Large deletions/duplications were only detected using the SureSelect Target Enrichment protocol. In the prospective cohort, the mutation detection rate using the Access Array was highest in patients with clinically definite familial hypercholesterolemia (67%), followed by patients with possible familial hypercholesterolemia (26%). CONCLUSION: We have shown the potential of target enrichment methods combined with next-generation sequencing for molecular diagnosis of familial hypercholesterolemia. Adopting these assays for patients with suspected familial hypercholesterolemia could improve cost-effectiveness and increase the overall number of patients with a molecular diagnosis. PMID- 23680766 TI - Changes in plasma and urine globotriaosylceramide levels do not predict Fabry disease progression over 1 year of agalsidase alfa. AB - PURPOSE: Globotriaosylceramide concentrations were assessed as potential predictors of change from baseline after 12 months by estimated glomerular filtration rate and left-ventricular mass index using pooled data from three randomized, placebo-controlled agalsidase alfa trials and open-label extensions of patients with Fabry disease. METHODS: Males (aged 18 years or older) with Fabry disease received agalsidase alfa (0.2 mg/kg every other week for 12 months). A backward-elimination approach evaluated potential predictors (baseline estimated glomerular filtration rate and left-ventricular mass index; age at first dose; baseline and change from baseline at 12 months of globotriaosylceramide (urine, plasma); urine protein excretion; and systolic and diastolic blood pressure). Subgroups included patients randomized to placebo or agalsidase alfa (double-blind phase), then to agalsidase alfa (open-label extensions; placebo->agalsidase alfa or agalsidase alfa->agalsidase alfa, respectively) and stage 2/3 chronic kidney disease patients. RESULTS: Baseline estimated glomerular filtration rate, age at first dose, baseline urine globotriaosylceramide excretion, and baseline and change from baseline urine protein excretion significantly predicted change from baseline estimated glomerular filtration rate in the analysis population (N = 73; all P<0.05), although not in all subgroups. Change from baseline urine and plasma globotriaosylceramide (baseline and change from baseline) concentrations did not predict change from baseline estimated glomerular filtration rate. No predictors of left-ventricular mass index were significant. CONCLUSION: Changes in globotriaosylceramide concentrations do not appear to be useful biomarkers for prediction of Fabry disease-related changes in estimated glomerular filtration rate or left-ventricular mass index. PMID- 23680769 TI - A novel technique of modified continuous blanket suture for amniotic membrane fixation in severe ocular surface diseases. AB - The purpose of this article is to demonstrate a novel technique using modified continuous blanket suture (MCBS) to fix the amniotic membrane (AM) in different severe ocular surface disease lesions. The MCBS techniques were used to fix the AMs of 5 representative patients with different ocular surface lesions related to severe ocular surface diseases. In all cases, stable adherence of the AM was maintained until the epithelialization of the ocular surface was completed. No early detachment, dissolution, or dislocation of the AM patch was observed. During follow-up, all patients acquired a smooth and acceptable ocular surface without any persistent epithelial defect, infection, or ulceration. The MCBS method achieved good AM fixation on the ocular surface in cases of severe ocular surface lesions and could prevent the early detachment of the AM and promote the epithelialization of the ocular surface. PMID- 23680770 TI - What's new in Shock? June 2013. PMID- 23680771 TI - Quality of cardiopulmonary resuscitation affects cardioprotection by induced hypothermia at 34 degrees C against ischemia/reperfusion injury in a rat isolated heart model. AB - In this study, we aimed to compare the effects of low- and high-quality cardiopulmonary resuscitation (CPR) on cardioprotection by induced hypothermia (IH) at 34 degrees C and examine whether extracellular signal-regulated kinase or endothelial nitric oxide synthase mediates this cardioprotection. Left ventricle infarct sizes were evaluated in six groups of rat hearts (n = 6) following Langendorff perfusion and triphenyltetrazolium chloride staining. Controls underwent 30 min of global ischemia at 37 degrees C, followed by 10 min of simulated low- or high-quality CPR reperfusion and 90 min of reperfusion at 75 mmHg. The IH groups underwent IH at 34 degrees C during reperfusion. The U0126 group received U0126 (60 MUM)-an extracellular signal-regulated kinase inhibitor during reperfusion at 34 degrees C. The L-NIO (N-(1-iminoethyl)-L-ornithine dihydrochloride) group received L-NIO (2 MUM)-an endothelial nitric oxide synthase inhibitor-5 min before global ischemia at 37 degrees C to the end of reperfusion at 34 degrees C. Infarct size did not significantly differ between the control and IH groups receiving low-quality CPR. However, IH with high quality CPR reduced the infarct size from 47.2% +/- 10.2% to 26.0% +/- 9.4% (P = 0.005). U0126 reversed the IH-induced cardioprotection (45.9% +/- 9.4%, P = 0.010), whereas L-NIO had no significant effect. Cardiopulmonary resuscitation quality affects IH-induced cardioprotection. Extracellular signal-regulated kinase may mediate IH-induced cardioprotection. PMID- 23680772 TI - Receptor-selective vasopressin analogs: a new push for "decatecholaminization"? PMID- 23680773 TI - Humane end points in experimental models of septic shock: a must, not a superfluous nightmare for researchers! PMID- 23680774 TI - Isolated mitochondria infusion mitigates ischemia-reperfusion injury of the liver in rats: mitotracker probes and mitochondrial membrane potential. PMID- 23680775 TI - Isolated mitochondria infusion mitigates ischemia-reperfusion injury of the liver in rats: reply. PMID- 23680778 TI - NSAIDs and fracture healing. AB - PURPOSE OF REVIEW: Published data raise concerns about the use of nonselective NSAIDs and selective cyclo-oxygenase (COX)-2 inhibitors as anti-inflammatory or analgesic drugs in patients after a recent fracture or who are undergoing (uncemented) arthroplasty or osteotomy. However, clinical reports on the effect of COX-2 inhibition on fracture healing in humans have been variable and inconclusive. This review gives an overview of the published data and an advice when to avoid NSAIDs. RECENT FINDINGS: Prostaglandins play an important role as mediators of inflammation and COX are required for their production. Inflammation is an essential step in the fracture healing process in which prostaglandin production by COX-2 is involved. Data from animal studies suggest that NSAIDs, which inhibit COX-2, can impair fracture healing due to the inhibition of the endochondral ossification pathway. Animal data suggest that the effects of COX-2 inhibitors are dependent on the timing, duration, and dose, and that these effects are reversible. SUMMARY: These animal data, together with the view of limited scientifically robust clinical evidence in humans, indicate that physicians consider only short-term administration of COX-2 inhibitors or other drugs in the pain management of patients who are in the phase of fracture or other bone defect healing. COX-2-inhibitors should be considered a potential risk factor for fracture healing, and therefore to be avoided in patients at risk for delayed fracture healing. PMID- 23680779 TI - Treatment of spondyloarthropathy: the potential for agents other than TNF inhibitors. AB - PURPOSE OF REVIEW: Inhibitors of tumor necrosis factor (TNF) have demonstrated dramatic clinical efficacy in patients with spondyloarthropathy (SpA). However, not all patients respond, and some patients who initially improve, subsequently lose response. Therefore, there is still an unmet clinical need for additional therapies. Herein we describe the recent data on newer treatments for SpA patients. RECENT FINDINGS: Treatments targeting various cytokines, cell surface molecules, and signaling molecules have been assessed. The effects of taregeting B cells with rituximab, T-cell costimulation with abatacept, and interleukin (IL) 6 with tocilizumab have been disappointing in ankylosing spondylitis (AS). Abatacept appears to have a modest effect in patients with psoriatic arthritis (PsA). Targeting IL-17 with secukinumab, IL-12/23 with ustekinumab, and phosphodiesterase 4 (PDE4) with apremilast may prove to be promising treatments for SpA. SUMMARY: There are several newer therapies that may emerge for SpA, particularly those targeting IL-17, IL-23/IL-12, and PDE4. PMID- 23680780 TI - Periplasmic expression optimization of VEGFR2 D3 adopting response surface methodology: antiangiogenic activity study. AB - Vascular endothelial growth factor (VEGF) is one of the most significant mediators of angiogenesis, which interacts with a specific membrane receptor: VEGF receptor 2 (VEGFR2). Studies elsewhere have shown that, a VEGF-blocker can regulate several vital processes of tumor promotion. However, there is no literature evidence of investigation on antiangiogenic ability of single domain 3 of VEGFR-2 (VEGFR2 D3), as the key domain in signal transduction of VEGF. In this article, we aimed at developing an efficient method for producing soluble form of this receptor as therapeutic applications. The optimization of the production of soluble VEGFR2 D3 in Escherichia coli was firstly done by testing the periplasmic expression in different expression systems using three osmotic shock methods. To enhance the yield, vital factors were selected from nine factors by Plackett Burman design and the level of each viral factor was optimized via a response surface methodology based central composite design. After purification and identification of the protein, the bioactivity assays: quantitative ELISA, VEGF induced proliferation and in vivo chick chorioallantoic membrane assay were employed in our study. The outcome showed that, E. coli Rosetta-gami (DE3)/pET22b VEGFR2 D3 was the most effective expression system. Furthermore, the inducing time, peptone and glycerol concentration affected the periplasmic expression of VEGFR2 D3 significantly. The corresponding level was also optimized. The bioactivity assay studies showed VEGFR2 D3 could suppress both VEGF stimulated cell proliferation in vitro and neovascularization in vivo. We have therefore provided a novel antiangiogenic drug candidate relating to VEGF-VEGFR2 pathway. PMID- 23680781 TI - Metabolic adaptation allows Amacr-deficient mice to remain symptom-free despite low levels of mature bile acids. AB - Bile acids play multiple roles in the physiology of vertebrates; they facilitate lipid absorption, serve as signaling molecules to control carbohydrate and lipid metabolism, and provide a disposal route for cholesterol. Unexpectedly, the alpha methylacyl-CoA racemase (Amacr) deficient mice, which are unable to complete the peroxisomal cleavage of C27-precursors to the mature C24-bile acids, are physiologically asymptomatic when maintained on a standard laboratory diet. The aim of this study was to uncover the underlying adaptive mechanism with special reference to cholesterol and bile acid metabolism that allows these mice to have a normal life span. Intestinal cholesterol absorption in Amacr-/- mice is decreased resulting in a 2-fold increase in daily cholesterol excretion. Also fecal excretion of bile acids (mainly C27-sterols) is enhanced 3-fold. However, the body cholesterol pool remains unchanged, although Amacr-deficiency accelerates hepatic sterol synthesis 5-fold. Changes in lipoprotein profiles are mainly due to decreased phospholipid transfer protein activity. Thus Amacr deficient mice provide a unique example of metabolic regulation, which allows them to have a normal lifespan in spite of the disruption of a major metabolic pathway. This metabolic adjustment can be mainly explained by setting cholesterol and bile acid metabolism to a new balanced level in the Amacr-deficient mouse. PMID- 23680782 TI - UV and dark-triggered repetitive release and encapsulation of benzophenone-3 from biocompatible ZnO nanoparticles potential for skin protection. AB - The present study reports a UV and dark-triggered highly intelligent drug delivery system for skin protection. ZnO nanoparticles (NPs), a UV filter, were synthesized and characterized to be the carrier for benzophenone-3 (Bp-3), a UV absorption medicine, by varying the molar ratio of ZnO NPs to Bp-3 ranging from 300 : 1 to 20 : 1. The drug release under three cycles of UV and dark stimulation (each for two hours) and its cytotoxicity to human keratinocyte cells and skin fibroblasts were investigated. SEM studies showed the diameter of ZnO was around 30 to 40 nm, which assembled into loose and large NPs ranging from 500 to 1400 nm. Contact angle tests showed ZnO NPs switched to a more hydrophilic and back to a more hydrophobic state under two hours of UV and dark exposure. The optimized encapsulation efficiency and loading capacity of Bp-3 were 53.68 +/- 0.13% and 133.61 +/- 0.20% when the molar ratio of ZnO NPs to Bp-3 was 150 : 1 and 80 : 1. The Bp-3 was almost completely released from ZnO NPs under 2 hours of UV radiation and was mostly encapsulated in after 2 hours of dark stay in three cycles of UV and dark exposure. The Bp-3 loaded ZnO NPs showed low cytotoxicity to human keratinocyte cells and human skin fibroblasts. Overall, a UV and dark triggered repetitively on-demand drug delivery system biocompatible to skin cells and potential for skin protection from UV radiation was developed. PMID- 23680783 TI - The separation anxiety hypothesis of panic disorder revisited: a meta-analysis. AB - OBJECTIVE: Evidence suggests that childhood separation anxiety disorder may be associated with a heightened risk for the development of other disorders in adulthood. The authors conducted a meta-analysis to examine the relationship between childhood separation anxiety disorder and future psychopathology. METHOD: PubMed, PsycINFO, and Embase were searched for studies published through December 2011. Case-control, prospective, and retrospective cohort studies comparing children with and without separation anxiety disorder with regard to future panic disorder, major depressive disorder, any anxiety disorder, and substance use disorders were included in the analysis. Effects were summarized as pooled odds ratios in a random-effects model. RESULTS: Twenty-five studies met all inclusion criteria (14,855 participants). A meta-analysis of 20 studies indicated that children with separation anxiety disorder were more likely to develop panic disorder later on (odds ratio=3.45; 95% CI=2.37-5.03). Five studies suggested that a childhood diagnosis of separation anxiety disorder increases the risk of future anxiety (odds ratio=2.19; 95% CI=1.40-3.42). After adjusting for publication bias, the results of 14 studies indicated that childhood separation anxiety disorder does not increase the risk of future depression (odds ratio=1.06; 95% CI=0.78-1.45). Five studies indicated that childhood separation anxiety disorder does not increase the risk of substance use disorders (odds ratio=1.27; 95% CI=0.80-2.03). Of the subgroup analyses performed, differences in comparison groups and sample type significantly affected odds ratio sizes. CONCLUSIONS: A childhood diagnosis of separation anxiety disorder significantly increases the risk of panic disorder and any anxiety disorder. These results support a developmental psychopathology conceptualization of anxiety disorders. PMID- 23680784 TI - DIANA-microT web server v5.0: service integration into miRNA functional analysis workflows. AB - MicroRNAs (miRNAs) are small endogenous RNA molecules that regulate gene expression through mRNA degradation and/or translation repression, affecting many biological processes. DIANA-microT web server (http://www.microrna.gr/webServer) is dedicated to miRNA target prediction/functional analysis, and it is being widely used from the scientific community, since its initial launch in 2009. DIANA-microT v5.0, the new version of the microT server, has been significantly enhanced with an improved target prediction algorithm, DIANA-microT-CDS. It has been updated to incorporate miRBase version 18 and Ensembl version 69. The in silico-predicted miRNA-gene interactions in Homo sapiens, Mus musculus, Drosophila melanogaster and Caenorhabditis elegans exceed 11 million in total. The web server was completely redesigned, to host a series of sophisticated workflows, which can be used directly from the on-line web interface, enabling users without the necessary bioinformatics infrastructure to perform advanced multi-step functional miRNA analyses. For instance, one available pipeline performs miRNA target prediction using different thresholds and meta-analysis statistics, followed by pathway enrichment analysis. DIANA-microT web server v5.0 also supports a complete integration with the Taverna Workflow Management System (WMS), using the in-house developed DIANA-Taverna Plug-in. This plug-in provides ready-to-use modules for miRNA target prediction and functional analysis, which can be used to form advanced high-throughput analysis pipelines. PMID- 23680785 TI - Catalytic site identification--a web server to identify catalytic site structural matches throughout PDB. AB - The catalytic site identification web server provides the innovative capability to find structural matches to a user-specified catalytic site among all Protein Data Bank proteins rapidly (in less than a minute). The server also can examine a user-specified protein structure or model to identify structural matches to a library of catalytic sites. Finally, the server provides a database of pre calculated matches between all Protein Data Bank proteins and the library of catalytic sites. The database has been used to derive a set of hypothesized novel enzymatic function annotations. In all cases, matches and putative binding sites (protein structure and surfaces) can be visualized interactively online. The website can be accessed at http://catsid.llnl.gov. PMID- 23680788 TI - Stimuli-responsive plasmonic core-satellite assemblies: i-motif DNA linker enabled intracellular pH sensing. AB - We report stimuli-responsive core-satellite assemblies of binary gold nanoparticles, linked by i-motif DNA, for live cell plasmonic imaging of pH changes in the endocytic pathway. PMID- 23680786 TI - Real-time detection of DNA topological changes with a fluorescently labeled cruciform. AB - Topoisomerases are essential cellular enzymes that maintain the appropriate topological status of DNA and are the targets of several antibiotic and chemotherapeutic agents. High-throughput (HT) analysis is desirable to identify new topoisomerase inhibitors, but standard in vitro assays for DNA topology, such as gel electrophoresis, are time-consuming and are not amenable to HT analysis. We have exploited the observation that closed-circular DNA containing an inverted repeat can release the free energy stored in negatively supercoiled DNA by extruding the repeat as a cruciform. We inserted an inverted repeat containing a fluorophore-quencher pair into a plasmid to enable real-time monitoring of plasmid supercoiling by a bacterial topoisomerase, Escherichia coli gyrase. This substrate produces a fluorescent signal caused by the extrusion of the cruciform and separation of the labels as gyrase progressively underwinds the DNA. Subsequent relaxation by a eukaryotic topoisomerase, human topo IIalpha, causes reintegration of the cruciform and quenching of fluorescence. We used this approach to develop a HT screen for inhibitors of gyrase supercoiling. This work demonstrates that fluorescently labeled cruciforms are useful as general real time indicators of changes in DNA topology that can be used to monitor the activity of DNA-dependent motor proteins. PMID- 23680790 TI - Verb aspect and problem solving. AB - Verb aspect conveys the temporal flow of an action, such as whether it is on going or complete. If language guides how situation models are to be constructed, then verb aspect could influence cognition that would use situation models, as in solving insight problems. In this study, verb aspect within the insight problem was manipulated to determine if the imperfective aspect (was accepting) or perfective aspect (accepted) influenced people's solution rates. Results revealed that solution rates for problems that depended on the way an action was being done within the problem were better when the imperfective aspect was used. For problems that did not focus on the action of the sentence, solution rates were better when the perfective aspect was used. The language used to convey problems can influence the ease which people are able to arrive at a solution. PMID- 23680787 TI - Noninvasive cardiac monitoring in pregnancy: impedance cardiography versus echocardiography. AB - OBJECTIVE: The objective of this study was to report thoracic impedance cardiography (ICG) measurements and compare them with echocardiography (echo) measurements throughout pregnancy and in varied maternal positions. METHOD: A prospective cohort study involving 28 healthy parturients was performed using ICG and echo at three time points and in two maternal positions. Pearson's correlations, Bland-Altman plots and paired t-tests were used for statistical analysis. RESULT: Significant agreements between many but not all ICG and echo contractility, flow and resistance measurements were demonstrated. Differences in stroke volume (SV) due to maternal position were also detected by ICG in the antepartum (AP) period. Significant trends were observed by ICG for cardiac output and thoracic fluid content (TFC; P<0.025) with advancing pregnancy stages. CONCLUSION: ICG and echo demonstrate significant correlations in some but not all measurements of cardiac function. ICG has the ability to detect small changes in SV associated with maternal position change. ICG measurements reflected maximal cardiac contractility in the a AP period yet reflected a decrease in contractility and an increase in TFC in the postpartum period. PMID- 23680791 TI - Individual differences in the perception of biological motion: links to social cognition and motor imagery. AB - Biological motion perception is often claimed to support social cognition, and to rely upon embodied representations and motor imagery. Are people with higher levels of social traits or more vivid motor imagery better at biological motion perception? We administered four experiments measuring sensitivity in using (global) form and (local) motion cues in biological motion, plus well-established measures of social cognition (e.g., empathy) and motor imagery (e.g., kinesthetic motor imagery). This first systematic investigation of individual variability in biological motion processing demonstrated significant relationships between these domains, along with a dissociation. Sensitivity for using form cues in biological motion processing was correlated with social (and not the imagery) measures; sensitivity for using motion cues was correlated with motor imagery (and not the social) measures. These results could not be explained by performance on non biological control stimuli. We thus show that although both social cognition and motor imagery predict sensitivity to biological motion, these skills likely tap into different aspects of perception. PMID- 23680792 TI - What counts in grammatical number agreement? AB - Both notional and grammatical number affect agreement during language production. To explore their workings, we investigated how semantic integration, a type of conceptual relatedness, produces variations in agreement (Solomon & Pearlmutter, 2004). These agreement variations are open to competing notional and lexical grammatical number accounts. The notional hypothesis is that changes in number agreement reflect differences in referential coherence: More coherence yields more singularity. The lexical-grammatical hypothesis is that changes in agreement arise from competition between nouns differing in grammatical number: More competition yields more plurality. These hypotheses make opposing predictions about semantic integration. On the notional hypothesis, semantic integration promotes singular agreement. On the lexical-grammatical hypothesis, semantic integration promotes plural agreement. We tested these hypotheses with agreement elicitation tasks in two experiments. Both experiments supported the notional hypothesis, with semantic integration creating faster and more frequent singular agreement. This implies that referential coherence mediates the effect of semantic integration on number agreement. PMID- 23680793 TI - Experiencing ownership over a dark-skinned body reduces implicit racial bias. AB - Previous studies have investigated how existing social attitudes towards other races affect the way we 'share' their bodily experiences, for example in empathy for pain, and sensorimotor mapping. Here, we ask whether it is possible to alter implicit racial attitudes by experimentally increasing self-other bodily overlap. Employing a bodily illusion known as the 'Rubber Hand Illusion', we delivered multisensory stimulation to light-skinned Caucasian participants to induce the feeling that a dark-skinned hand belonged to them. We then measured whether this could change their implicit racial biases against people with dark skin. Across two experiments, the more intense the participants' illusion of ownership over the dark-skinned rubber hand, the more positive their implicit racial attitudes became. Importantly, it was not the pattern of multisensory stimulation per se, but rather, it was the change in the subjective experience of body ownership that altered implicit attitudes. These findings suggest that inducing an overlap between the bodies of self and other through illusory ownership is an effective way to change and reduce negative implicit attitudes towards outgroups. PMID- 23680794 TI - Hydrogen trapping in delta-Pu: insights from electronic structure calculations. AB - Density functional theory calculations have been performed to provide details of the structural and charge-transfer details related to the solid solution of hydrogen in (delta)-plutonium. We follow the Flanagan model that outlines the process by which hydrogen interacts with a metal to produce hydride phases, via a sequence of surface, interstitial and defect-bound (trapped) states. Due to the complexities of the electronic structure in plutonium solid-state systems, we take the pragmatic approach of adopting the 'special quasirandom structure' to disperse the atomic magnetic moments. We find that this approach produces sound structural and thermodynamic properties in agreement with the available experimental data. In delta-Pu, hydrogen has an exothermic binding energy to all of the states relevant in the Flanagan model, and, furthermore, is anionic in all these states. The charge transfer is maximized (i.e. most negative for hydrogen) in the hydride phase. The pathway from surface to hydride is sequentially exothermic, in the order surface < interstitial < grain boundary < vacancy < hydride (hydride being the most exothermic state). Thus, we find that there is no intermediate state that involves an endothermic increase in energy, consistent with the general experimental observations that the hydriding reaction in plutonium metal can proceed with zero apparent activation barrier. PMID- 23680795 TI - Structure-based non-canonical amino acid design to covalently crosslink an antibody-antigen complex. AB - Engineering antibodies to utilize non-canonical amino acids (NCAA) should greatly expand the utility of an already important biological reagent. In particular, introducing crosslinking reagents into antibody complementarity determining regions (CDRs) should provide a means to covalently crosslink residues at the antibody-antigen interface. Unfortunately, finding the optimum position for crosslinking two proteins is often a matter of iterative guessing, even when the interface is known in atomic detail. Computer-aided antibody design can potentially greatly restrict the number of variants that must be explored in order to identify successful crosslinking sites. We have therefore used Rosetta to guide the introduction of an oxidizable crosslinking NCAA, l-3,4 dihydroxyphenylalanine (l-DOPA), into the CDRs of the anti-protective antigen scFv antibody M18, and have measured crosslinking to its cognate antigen, domain 4 of the anthrax protective antigen. Computed crosslinking distance, solvent accessibility, and interface energetics were three factors considered that could impact the efficiency of l-DOPA-mediated crosslinking. In the end, 10 variants were synthesized, and crosslinking efficiencies were generally 10% or higher, with the best variant crosslinking to 52% of the available antigen. The results suggest that computational analysis can be used in a pipeline for engineering crosslinking antibodies. The rules learned from l-DOPA crosslinking of antibodies may also be generalizable to the formation of other crosslinked interfaces and complexes. PMID- 23680799 TI - Survey of Enterobacteriaceae contamination of table eggs collected from layer flocks in Australia. AB - In the present study, eggs from commercial caged layer flocks at different stages of lay in Australia were collected. Enterobacteriaceae populations from eggshell surface and eggshell pore were enumerated and these populations characterized using API(r) Rapid 20E strips. The eggshell surface, eggshell pore and egg internal content samples were also processed for the isolation of Salmonella and these isolates were tested for the presence or absence of several virulence genes (prgH, sopB, spiC, orfL, invA, sifA, sitC, misL). Results indicated that there was no significant difference in total Enterobacteriaceae count on the eggs of the flock from early, mid or late lay flocks. Enterobacteriaceae isolates were of 11 different genera which included: Cedecea, Citrobacter, Enterobacter, Escherichia, Klebsiella, Kluyvera, Leclercia, Pantoea, Salmonella, Serratia and Yersinia. Out of all 153 identified Enterobacteriaceae isolates, the Escherichia genus was reported most frequently (60.78%). Results also indicated that overall there were 4.51% (14/310) Salmonella positive pooled samples. In this study, 14 Salmonella strains were isolated, serotyping confirmed that 12 out of them were Salmonella Infantis and the 2 others were Salmonella enterica subsp. enterica serovar 4,12:d: Polymerase chain reaction results indicated that all Salmonella Infantis isolates harboured invA, misL, orfL, prgH, sifA, sitC, sopB and spiC genes which suggests that Salmonella Infantis strains isolated from eggshell surface may have the capacity to invade and survive in macrophages. PMID- 23680800 TI - Efficacy and putative mode of action of native and commercial antagonistic yeasts against postharvest pathogens of pear. AB - Putative mechanisms of action associated with the biocontrol capacity of four yeast strains (Cryptoccocus albidus NPCC 1248, Pichia membranifaciens NPCC 1250, Cryptoccocus victoriae NPCC 1263 and NPCC 1259) against Penicillium expansum and Botrytis cinerea were studied by means of in vitro and in situ assays. C. albidus(YP), a commercial yeast was also evaluated for comparative purposes. The yeast strains exhibited a variety of different mechanisms including: wound colonization, germination inhibition, biofilm formation, secretion of killer toxins, competition for nutrient and secretion of hydrolytic enzymes (protease, chitinase and glucanase). The relationship between strains (and their associated antagonist mechanisms) and in situ antagonist activity was also evaluated. Results indicate that mechanisms such as production of hydrolytic enzymes, the ability for colonization of wounds, production of killer toxin and inhibition of germination are the most important for biocontrol activity. Our study indicate that multiple modes of action may explain why P. membranifaciens NPCC 1250 and C. victoriae NPCC 1263 provided excellent control of postharvest pears disease. PMID- 23680797 TI - Animal models of enteroaggregative Escherichia coli infection. AB - Enteroaggregative Escherichia coli (EAEC) has been acknowledged as an emerging cause of gastroenteritis worldwide for over two decades. Epidemiologists are revealing the role of EAEC in diarrheal outbreaks as a more common occurrence than ever suggested before. EAEC induced diarrhea is most commonly associated with travelers, children and immunocompromised individuals however its afflictions are not limited to any particular demographic. Many attributes have been discovered and characterized surrounding the capability of EAEC to provoke a potent pro-inflammatory immune response, however cellular and molecular mechanisms underlying initiation, progression and outcomes are largely unknown. This limited understanding can be attributed to heterogeneity in strains and the lack of adequate animal models. This review aims to summarize current knowledge about EAEC etiology, pathogenesis and clinical manifestation. Additionally, current animal models and their limitations will be discussed along with the value of applying systems-wide approaches such as computational modeling to study host-EAEC interactions. PMID- 23680801 TI - Phylogenetic affinities of Phobetinus to other pirate spider genera (Araneae: Mimetidae) as indicated by spinning field morphology. AB - Spinnerets from Phobetinus sagittifer and an undescribed Phobetinus species were examined by scanning electron microscopy to gain a better understanding of this genus' relationships to other genera in the family Mimetidae. Consistent with placement of Phobetinus in Mimetinae, females possessed two synapomorphies of this subfamily; enlarged cylindrical silk gland spigots with domed shafts and a single cylindrical spigot per posterior lateral spinneret (PLS). Spinning field features overall suggest Phobetinus is most closely related to Mimetus, followed by Australomimetus, then Ero. A possible synapomorphy of a clade including Mimetus and Phobetinus is a pair of modified piriform silk gland spigots on each anterior lateral spinneret of adult males located adjacent to the secondary major ampullate silk gland tartipore. These spigots were present in P. sagittifer; however, similarly positioned spigots in the undescribed species were not obviously modified (i.e., wider or with larger openings relative to the other piriform spigots). Close affinity to Mimetus was also indicated by tartipore accommodated PLS aciniform silk glands in both Phobetinus species. These have been consistently observed in Mimetus, but not in Australomimetus or Ero. Somatic and genitalic drawings of P. sagittifer are provided to aid identification and similarities are noted between male pedipalps of Mimetus and Phobetinus. PMID- 23680802 TI - Comparative morphology of selected characters of the Pentatomidae foreleg (Hemiptera, Heteroptera). AB - Heteropteran legs are very diverse within and among taxa, and such variation is frequently correlated with life habits. Structural modifications are commonly present in the legs of the Pentatomoidea but are poorly studied. Using scanning electron microscopy, the tibia and pretarsal microstructure of 82 species of Pentatomidae (Heteroptera), three species of Scutelleridae, and ten species of Thyreocoridae were described, focusing on the pretarsal structure, the foretibial apparatus, and the foretibial comb. The Pentatomidae, the Scutelleridae, and the Thyreocoridae have uniform pretarsal structures. Variation can be found in the length of the parempodial setae and in the shape of the parempodial projections. The foretibial combs of the Pentatomidae, the Thyreocoridae, and the Scutelleridae are described for the first time, and we have demonstrated that there is low structural variation in the foretibial comb complex of the studied species. The setae organization and distribution on the foretibial apparatus is uniform in the families studied. However, the Asopinae (Pentatomidae) bear a foretibial apparatus that is uniquely organized. The taxonomic and phylogenetic relevance of the pretarsal traits, the foretibial apparatus, and the foretibial comb are discussed. PMID- 23680803 TI - Energetics of C-N coupling reactions on Pt(111) and Ni(111) surfaces from application of density-functional theory. AB - We applied density-functional theory (DFT) with the projector-augmented-wave method (PAW) to investigate systematically the energetics of C-N coupling reactions on Pt(111) and Ni(111)surfaces. Our approach includes several steps: the adsorption of reactants and products (CHx, NHy and CHxNHy, x = 0-3, y = 0-2), movement of molecular fragments on the surface, and then C-N coupling. According to our calculations, the energies (ignoring the conventional negative sign) of adsorption of CHx and NHy on Pt(111)/Ni(111) surfaces decrease in the order C > CH > CH2 > CH3 and N > NH > NH2, with values 7.41/6.91, 6.97/6.52, 4.58/4.39, 2.19/2.01 eV and 5.10/5.49, 4.12/4.79, 2.75/2.87 eV, respectively. Regarding the adsorption energies among CHxNHy, the adsorption energy of CNH2 species is the highest on the Pt(111) surface, whereas on the Ni(111) surface CH3N is the most stable. The C-N coupling barriers differ on the two metallic surfaces despite the structures of initial, transition and final states being similar. On the Pt(111) surface, the coupling reaction of CH2 + NH2 has the smallest barrier, whereas CH + NH2 is the most favorable on the Ni(111) surface. The detailed local density of states (LDOS) and electron-localization functions (ELF) were investigated to rationalize the calculated outcomes. PMID- 23680804 TI - A ballistic quantum ring Josephson interferometer. AB - We report the realization of a ballistic Josephson interferometer. The interferometer is made from a quantum ring etched in a nanofabricated two dimensional electron gas confined in an InAs-based heterostructure laterally contacted to superconducting niobium leads. The Josephson current flowing through the structure shows oscillations with h/e flux periodicity when threading the loop with a perpendicular magnetic field. This periodicity, in sharp contrast with the h/2e one observed in conventional dc superconducting quantum interference devices, confirms the ballistic nature of the device in agreement with theoretical predictions. This system paves the way for the implementation of interferometric Josephson pi-junctions, and for the investigation of Majorana fermions. PMID- 23680805 TI - The clinical utility of gene expression testing on the diagnostic evaluation of patients presenting to the cardiologist with symptoms of suspected obstructive coronary artery disease: results from the IMPACT (Investigation of a Molecular Personalized Coronary Gene Expression Test on Cardiology Practice Pattern) trial. AB - Accurate, noninvasive evaluation for obstructive coronary artery disease (CAD) remains challenging and inefficient. In this study, 171 patients presenting with stable chest pain and related symptoms without a history of CAD were referred to 6 cardiologists for evaluation. In the prospective cohort of 88 patients, the cardiologist's diagnostic strategy was evaluated before and after gene expression score (GES) testing. The GES is a validated, quantitative blood-based diagnostic test measuring peripheral blood cell expression levels of 23 genes to determine the likelihood of obstructive CAD (at least 1 vessel with >= 50% angiographic coronary artery stenosis). The objective of the study was to measure the effect of the GES on diagnostic testing using a pre/post study design. There were 83 prospective patients evaluable for study analysis, which included 57 (69%) women, mean age 53 +/- 11 years, and mean GES 12.5 +/- 9. Presenting symptoms were classified as typical angina, atypical angina, and noncardiac chest pain in 33%, 60%, and 7% of patients (n = 27, 50, and 6), respectively. After GES, changes in diagnostic testing occurred in 58% of patients (n = 48, P < 0.001). Of note, 91% (29/32) of patients with decreased testing had low GES (<= 15), whereas 100% (16/16) of patients with increased testing had elevated GES (P < 0.001). A historical cohort of 83 patients, matched to the prospective cohort by clinical factors, had higher diagnostic test use compared with the post-GES prospective cohort (P < 0.001). In summary, the GES showed clinical utility in the evaluation of patients with suspected obstructive CAD presenting to the cardiologist's office. PMID- 23680806 TI - Mission: Lifeline STEMI networks geospatial information systems (GIS) maps. PMID- 23680807 TI - Characteristics of hospital observation services: a society of cardiovascular patient care survey. AB - INTRODUCTION: Little is known about the setting in which observation services are provided, or how observation patients are managed in settings such as accredited cardiovascular patient care centers. OBJECTIVE: To describe the characteristics of observation services in accredited Cardiovascular Patient Care hospitals, or those seeking accreditation. METHODS: This is a cross-sectional survey of hospitals either accredited by the Society of Cardiovascular Patient Care, or considering accreditation in 2010. The survey was a web-based free service linked to an e-mail sent to Cardiovascular Patient Care coordinators at the respective institutions. The survey included 17 questions which focused on hospital characteristics and observation services, specifically management, settings, staffing, utilization, and performance data. RESULTS: Of the 789 accredited hospitals, 91 hospitals (11.5%) responded to the survey. Responding hospitals had a median of 250 inpatient beds (interquartile range [IQR] 277), 32.5 emergency department (ED) beds or hall spots, with an average annual ED census of 41,660 (IQR 30,149). These hospitals had an average of 8 (IQR 9) observation unit beds whose median length of stay (LOS) was 19 hours (IQR 8.1), with a discharge rate of 89.1% (IQR 15). There was an average of 1 observation bed to 3.8 ED beds. Observation units were most commonly administered by emergency medicine (48.5%), but staffed by a broad spectrum of specialties. Nonemergency medicine units had longer LOSs, which were not significant. Most common conditions were chest pain and abdominal pain. CONCLUSIONS: Accredited chest pain centers have observation units whose LOSs and discharge rates are comparable to prior studies with utilization patterns that may serve as benchmarks for similar hospitals. PMID- 23680808 TI - A quality improvement project for reducing cardiac computed tomography radiation dose in a community-based, multihospital setting. AB - Radiation associated with computed tomography coronary angiography (CTCA) is a persistent concern. Strategies for reducing radiation exposure have been described, primarily in academic settings. We developed a standard protocol for CTCA acquisition focused on radiation reduction strategies in a community-based, multihospital setting and hypothesized that the protocol would be effective at reducing radiation in this setting. The protocol included the use of body mass index based tube voltage adjustment and routine use of prospective electrocardiographic gating with either dose modulation or step-and-shoot acquisition. Data on radiation exposure were collected retrospectively and compared by nonparametric testing. Some hospitals failed to routinely record radiation exposure data; only 2 facilities had data available from both before and after the intervention for direct comparison. Data were acquired from 124 subjects, 41 from the standard of care group and 83 scanned under the new protocol. In hospital A, radiation was significantly reduced by 61% from 20.5 +/- 4.6 millisieverts (mSv) to 7.9 +/- 4.8 mSv (P < 0.001). Within the new protocol group for hospital A, radiation was lower with step-and-shoot (4.0 +/- 1.5 mSv) as compared to dose modulation (10.2 +/- 4.2 mSv, P < 0.001). In hospital B, which already employed step-and-shoot acquisition, radiation dose was reduced 16% from 9.3 +/- 3.0 mSv to 7.9 +/- 2.2 mSv (P < 0.017) by applying body mass index based tube voltage adjustment alone. In conclusion, a minimal investment in institutional resources can result in a reduction in radiation exposure from CTCA, even in a community-based, multihospital setting. Some facilities do not routinely record radiation exposure data. PMID- 23680810 TI - Avoidable utilization of the chest pain observation unit: evaluation of very-low risk patients. AB - BACKGROUND: Very-low-risk patients treated in a chest pain observation unit (CPOU) may threaten efficient care delivery. To optimize the efficiency of CPOU evaluations, it is necessary to quantify the avoidable CPOU utilization rate, examine physician variability, and determine patient and physician characteristics associated with avoidable CPOU utilization. METHODS: Consecutive chest pain patients were evaluated in an Emergency Department-based CPOU. Patients were risk stratified based on the American College of Cardiology/American Heart Association framework, age, and electrocardiogram findings. Very-low-risk was defined as age <35, physician assessment of low-risk, and normal or nondiagnostic electrocardiogram. Patients identified as very-low risk were considered avoidable CPOU evaluations. Individual physicians' avoidable CPOU utilization rates were calculated. Patients were followed for 30-day major adverse cardiac events, defined as the composite of death, acute myocardial infarction, and coronary revascularization. RESULTS: Over 33 months, the registry included 1731 chest pain patients. The study definition of avoidable CPOU evaluations was met by 174 patients (10.1%, 95% confidence interval: 8.7-11.6%). The median rate of physician's avoidable CPOU utilization was 10% (interquartile range: 5.9-13.6%) and varied from 1.9% to 18.4%. None of the patients with an avoidable CPOU evaluation had a major adverse cardiac events within 30 days. Physician predictors of avoidable CPOU utilization included recent residency graduation (<5 years), part-time status, and moderate or high rates of CPOU use. CONCLUSIONS: Approximately 10% of CPOU evaluations were avoidable. Wide variability exists among physicians regarding their individual rates of avoidable CPOU utilization. This variability could represent an opportunity to improve the efficiency of CPOU care delivery. PMID- 23680809 TI - The "rule of halves" does not apply in Peru: awareness, treatment, and control of hypertension and diabetes in rural, urban, and rural-to-urban migrants. AB - OBJECTIVE: To determine the awareness, treatment, and control of hypertension and diabetes by migration status. DESIGN: Cross-sectional study, secondary analyses of the PERU MIGRANT study. PATIENTS: Rural, rural-to-urban migrants, and urban participants. MAIN OUTCOME MEASURES: Awareness, treatment, and control of hypertension and diabetes mellitus were calculated using weights to account for participant's group size. RESULTS: Of 205 of the 987 (weighted prevalence 24.1%, 95% confidence interval: 21.1%-27.1%) participants identified as hypertensive, 48.3% were aware of their diagnosis, 40% of them were receiving treatment, and 30.4% of those receiving treatment were controlled. Diabetes was present in 33 of the 987 (weighted prevalence 4.6%, 95% confidence interval: 3.1%-6%), and diabetes awareness, treatment, and control were 71.1%, 40.6%, and 7.7%, respectively. Suboptimal control rates, defined as those not meeting blood pressure or glycaemia targets among those with the condition, were 95.1% for hypertension and 97% for diabetes. Higher awareness, treatment, and control rates, for both hypertension and diabetes, were observed in rural-to-urban migrants and urban participants compared with rural participants. However, treatment rates were much lower among migrants compared with the urban group. CONCLUSIONS: These results identify major unmet needs in awareness, treatment, and control of hypertension and diabetes. Particular challenges are lack of awareness of both hypertension and diabetes in rural areas, and poor levels of treatment and control among people who have migrated from rural into urban areas. PMID- 23680811 TI - 2013 ACCF/AHA key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes and coronary artery disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Acute Coronary Syndromes and Coronary Artery Disease Clinical Data Standards). PMID- 23680812 TI - Paul A. Cibis, MD: a pioneer of modern vitreoretinal surgery. AB - Paul Anton Cibis (1911-1965) was one of the pioneers of modern vitreoretinal surgery. He reasoned that the pathology of complex retinal detachments was intravitreal fibrosis and concluded that the optimum surgery was the injection of liquid silicone oil into the vitreous cavity to dissect fibrous membranes from the retinal surface and use the silicone for retinal tamponade. Prior to the invention of pars plana vitrectomy, such surgery was innovative, even daring. These surgical techniques were an important advance in directly operating on the vitreous in retinal detachment surgery. However, Cibis' contributions to vitreoretinal surgery only occupied the last 10 years of his tragically short life. Prior to his practice in retinal surgery, he made contributions to basic research in physiologic optics, local retinal adaptation, and the effect of ionizing radiation and atomic energy on the globe. PMID- 23680813 TI - Screening miRNA and their target genes related to tetralogy of Fallot with microarray. AB - Our aim is to screen miRNAs and genes related to tetralogy of Fallot and construct a co-expression network based on integrating miRNA and gene microarrays. We downloaded the gene expression profile GSE35490 (miRNA) and GSE35776 (mRNA) of tetralogy of Fallot from the Gene Expression Omnibus database, which includes eight normal and 15 disease samples from infants, and screened differentially expressed miRNAs and genes between normal and disease samples (cut off: p < 0.05; FDR < 0.05; and log FC > 2 or log FC < -2); in addition, we downloaded human miRNA and their targets, which were collected in the miRNA targets prediction database TargetScan, and selected ones that also appeared in our differentially expressed miRNAs and their predicted targets (score >0.9) and then made a relationship of diff_miRNAs and diff_genes of our results. Finally, we uploaded all the diff_target genes into String, constructed a co-expression network regulated by diff_miRNAs, and performed functional analysis with the software DAVID. Comparing normal and disease lesion tissue, we got 32 and 875 differentially expressed miRNAs and genes, respectively, and found hsa-miR-124 with 34 diff_target genes and hsa-miR-138 with two diff_target genes. Then we constructed a co-expression network that contains 231 pairs of genes. Genes in the network were enriched into 14 function clusters, and the most significant one is protein localisation. We screened the tetralogy of Fallot-related hsa-miR-124 and hsa-miR-138 with their direct and indirect differentially expressed target genes, and found that protein localisation is the significant cause affecting tetralogy of Fallot. Our approach may provide the groundwork for a new therapy approach to treating tetralogy of Fallot. PMID- 23680815 TI - Engineering electrodeposited ZnO films and their memristive switching performance. AB - We report the influence of zinc oxide (ZnO) seed layers on the performance of ZnO based memristive devices fabricated using an electrodeposition approach. The memristive element is based on a sandwich structure using Ag and Pt electrodes. The ZnO seed layer is employed to tune the morphology of the electrodeposited ZnO films in order to increase the grain boundary density as well as construct highly ordered arrangements of grain boundaries. Additionally, the seed layer also assists in optimizing the concentration of oxygen vacancies in the films. The fabricated devices exhibit memristive switching behaviour with symmetrical and asymmetrical hysteresis loops in the absence and presence of ZnO seed layers, respectively. A modest concentration of oxygen vacancy in electrodeposited ZnO films as well as an increase in the ordered arrangement of grain boundaries leads to higher switching ratios in Ag/ZnO/Pt devices. PMID- 23680816 TI - Selective and sensitive chromogenic detection of cyanide and HCN in solution and in gas phase. AB - Two triphenylmethane based chemodosimeters for selective and chromogenic sensing of cyanide anions in aqueous environments and of hydrogen cyanide in gas phase were prepared and studied. PMID- 23680818 TI - Hydroxyapatite/poly-L-lactide acid screws have better biocompatibility and femoral burr hole closure than does poly-L-lactide acid alone. AB - Hydroxyapatite (HA)/poly-l-lactide(PLLA) composite biomaterials are available for orthopedic applications, but bioresorption and cell-mediated inflammation in bone cortex are unknown. We conducted an 84-month follow-up study with Beagle dogs that were subjected to implants with either PLLA (left femur) or HA/PLLA (right femur). Histological and radiographic analysis showed that HA/PLLA screws induced significant increases in HA content from 36 months onward and complete burr hole closure at 60 months, whereas PLLA screws did not. Moreover, PLLA screws induced more severe fibrous tissue and histiocyte infiltration. HA/PLLA screws promote earlier burr hole replacement and have superior biocompatibility compared to PLLA screws. PMID- 23680817 TI - Antidepressant medication augmented with cognitive-behavioral therapy for generalized anxiety disorder in older adults. AB - OBJECTIVE Generalized anxiety disorder is common among older adults and leads to diminished health and cognitive functioning. Although antidepressant medications are efficacious, many elderly individuals require augmentation treatment. Furthermore, little is known about maintenance strategies for older people. The authors examined whether sequenced treatment combining pharmacotherapy and cognitive-behavioral therapy (CBT) boosts response and prevents relapse in older adults with generalized anxiety disorder. METHOD Participants were individuals at least 60 years of age with generalized anxiety disorder (N=73) who were recruited from outpatient clinics at three sites. Participants received 12 weeks of open label escitalopram and were then randomly assigned to one of four conditions: 16 weeks of escitalopram (10-20 mg/day) plus modular CBT, followed by 28 weeks of maintenance escitalopram; escitalopram alone, followed by maintenance escitalopram; escitalopram plus CBT, followed by pill placebo; and escitalopram alone, followed by placebo. RESULTS Escitalopram augmented with CBT increased response rates on the Penn State Worry Questionnaire but not on the Hamilton Anxiety Rating Scale compared with escitalopram alone. Both escitalopram and CBT prevented relapse compared with placebo. CONCLUSIONS This study demonstrates effective strategies for treatment of generalized anxiety disorder in older adults. The sequence of antidepressant medication augmented with CBT leads to worry reduction in the short-term. Continued medication prevents relapse, but for many individuals, CBT would allow sustained remission without requiring long-term pharmacotherapy. PMID- 23680819 TI - Topographical and chemical effects of electrochemically assisted deposited hydroxyapatite coatings on osteoblast-like cells. AB - A recently commercialised hydroxyapatite electrochemically assisted chemical deposition technique (BoneMaster) has been shown to induce increased bone apposition; whether this response is caused by the surface topography or chemistry is unknown. An in-vitro examination using human osteoblast-like cells was performed on a series of BoneMaster-coated surfaces. The chemistry was separated from the topography using a thin gold coating; Thermanox coverslips were used as a control. BoneMaster surfaces showed significantly greater alkaline phosphatase activity and osteocalcin production compared with controls; however, no difference was found between the gold-coated and uncoated BoneMaster samples, indicating topography is the main contributing factor. PMID- 23680821 TI - Analysis of designed beta-hairpin peptides: molecular conformation and packing in crystals. AB - The crystal structures of several designed peptide hairpins have been determined in order to establish features of molecular conformations and modes of aggregation in the crystals. Hairpin formation has been induced using a centrally positioned (D)Pro-Xxx segment (Xxx = (L)Pro, Aib, Ac6c, Ala; Aib = alpha aminoisobutyric acid; Ac6c = 1-aminocyclohexane-1-carboxylic acid). Structures of the peptides Boc-Leu-Phe-Val-(D)Pro-(L)Pro-Leu-Phe-Val-OMe (1), Boc-Leu-Tyr-Val (D)Pro-(L)Pro-Leu-Phe-Val-OMe (2, polymorphic forms labeled as 2a and 2b), Boc Leu-Val-Val-(D)Pro-(L)Pro-Leu-Val-Val-OMe (3), Boc-Leu-Phe-Val-(D)Pro-Aib-Leu-Phe Val-OMe (4, polymorphic forms labeled as 4a and 4b), Boc-Leu-Phe-Val-(D)Pro-Ac6c Leu-Phe-Val-OMe (5) and Boc-Leu-Phe-Val-(D)Pro-Ala-Leu-Phe-Val-OMe (6) are described. All the octapeptides adopt type II' beta-turn nucleated hairpins, stabilized by three or four cross-strand intramolecular hydrogen bonds. The angle of twist between the two antiparallel strands lies in the range of -9.8 degrees to -26.7 degrees . A detailed analysis of packing motifs in peptide hairpin crystals is presented, revealing three broad modes of association: parallel packing, antiparallel packing and orthogonal packing. An attempt to correlate aggregation modes in solution with observed packing motifs in crystals has been made by indexing of crystal faces in the case of three of the peptide hairpins. The observed modes of hairpin aggregation may be of relevance in modeling multiple modes of association, which may provide insights into the structure of insoluble polypeptide aggregates. PMID- 23680822 TI - [Magnetic resonance imaging with high field strengths: a lot helps a lot?]. PMID- 23680820 TI - Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme. AB - BACKGROUND: To examine the efficacy of valproic acid (VPA) given either with or without levetiracetam (LEV) on seizure control and on survival in patients with glioblastoma multiforme (GBM) treated with chemoradiation. METHODS: A retrospective analysis was performed on 291 patients with GBM. The efficacies of VPA and LEV alone and as polytherapy were analyzed in 181 (62%) patients with seizures with a minimum follow-up of 6 months. Cox-regression survival analysis was performed on 165 patients receiving chemoradiation with temozolomide of whom 108 receiving this in combination with VPA for at least 3 months. RESULTS: Monotherapy with either VPA or LEV was instituted in 137/143 (95.8%) and in 59/86 (68.6%) on VPA/LEV polytherapy as the next regimen. Initial freedom from seizure was achieved in 41/100 (41%) on VPA, in 16/37 (43.3%) on LEV, and in 89/116 (76.7%) on subsequent VPA/LEV polytherapy. At the end of follow-up, seizure freedom was achieved in 77.8% (28/36) on VPA alone, in 25/36 (69.5%) on LEV alone, and in 38/63 (60.3%) on VPA/LEV polytherapy with ongoing seizures on monotherapy. Patients using VPA in combination with temozolomide showed a longer median survival of 69 weeks (95% confidence interval [CI]: 61.7-67.3) compared with 61 weeks (95% CI: 52.5-69.5) in the group without VPA (hazard ratio, 0.63; 95% CI: 0.43-0.92; P = .016), adjusting for age, extent of resection, and O(6) DNA methylguanine-methyltransferase promoter methylation status. CONCLUSIONS: Polytherapy with VPA and LEV more strongly contributes to seizure control than does either as monotherapy. Use of VPA together with chemoradiation with temozolomide results in a 2-months' longer survival of patients with GBM. PMID- 23680824 TI - [Working in the magnetic field of ultrahigh field MRI]. AB - Development of magnetic resonance imaging (MRI) device technology continues to increase the static magnetic flux densities applied and consequently leads to considerably increased occupational exposure. This has already made it necessary to review limits of occupational exposure and to postpone European legal regulations for occupational exposure to electromagnetic fields. This raises the question whether and if so which adverse health effects and health risks might be associated with occupational exposure to MRI ultra-high static magnetic fields. Based on a survey on interaction mechanisms recommendations and safety rules are presented to help minimize adverse health effects of emerging ultra-high field MRI. PMID- 23680825 TI - [Contrast in static images in clinical magnetic resonance imaging : Part 1: Contrast properties of tissue]. AB - In comparison to roentgen-based radiological examination techniques, magnetic resonance imaging (MRI) provides a wide variety of tissue contrast. This can be utilized for better detection and characterization of pathological findings. The basis of image contrast in MRI is the chemical and physical properties of the hydrogen atoms in tissue, in particular in their chemical bonds in water and lipid molecules and in the environment in which the hydrogen-containing molecules are contained. This environment is mainly determined by the composition of substances, viscosity and temperature as well as the microscopic geometrical conditions in tissue. Part 1 of this advanced education article describes those contrast mechanisms which are most commonly utilized in static clinical standard examinations of various organ systems. PMID- 23680827 TI - Modeling contaminant transport and remediation at an acrylonitrile spill site in Turkey. AB - The August 1999 earthquake in Turkey damaged three acrylonitrile (AN) storage tanks at a plant producing synthetic fiber by polymerization. A numerical modeling study was carried out to analyze the groundwater flow and contaminant (AN) transport at the spill site. This study presents the application of a numerical groundwater model to determine the hydrogeological parameters of the site, where such data were not available during the field surveys prior to the simulation studies. The two- and three-dimensional transient flow and transport models were first calibrated using the first 266days of observed head and concentration data and then verified using the remaining 540-day observed data set. Off-site migration of the contaminant plume was kept under control within the site boundaries owing to the favorable geology of the site, the characteristics of the local groundwater flow regime and the pumping operations. As expected, the applied pump-and-treat system was effective at high-permeability zones, but not fully effective at low-permeability zones. The results of long term simulations for unconfined aquifer showed that the size of the plume in the high permeability zone shrank significantly due to the dilution by natural recharge. However, in the low permeability zone, it was not significantly affected. The study showed that accurate and sufficient data regarding the source characteristics, concentration and groundwater level measurements, groundwater pumping rates and their durations at each of the extraction points involved in the pump-and-treat system along with the hydrogeological site characterization are the key parameters for successful flow and transport model calibrations. PMID- 23680828 TI - Anterior release generates more thoracic rotation than posterior osteotomy: a biomechanical study of human cadaver spines. AB - STUDY DESIGN: Biomechanical testing of human cadaveric spines. OBJECTIVE: To determine the effect of anterior and posterior anatomic structures on the rotational stability of the thoracic spine. SUMMARY OF BACKGROUND DATA: Historically, large and/or stiff spinal deformities were treated with anterior release to facilitate correction. However, anterior release increases risks and requires a 2-part procedure. Recently, large or rigid deformities have been treated with a single posterior procedure using pedicle screws and spinal osteotomies. No study has yet evaluated the effect of anterior release or posterior osteotomy on thoracic spinal column rotation. METHODS: Thoracolumbar spines were obtained from cadavers and segmented into upper, middle, and lower specimens. Specimens were cyclically loaded with a +/-5 N.m moment in axial rotation for 10 cycles. Specimens were tested intact and then retested after sectioning or removal of each structure to simulate those removed during anterior release and posterior osteotomy. The total increases in axial rotation after posterior and anterior resections were calculated using a 3-dimensional motion capture camera system. For each ligament resection, the absolute and percent change in degrees of rotation was calculated from comparison with the intact specimen. The median data points were compared to account for outliers. RESULTS: Resection of anterior structures was more efficacious than resection of posterior structures. An 8.8% to 71.9% increase in the amount of axial rotation was achieved by a posterior release, whereas resection of anterior structures led to a 141% to 288% increase in rotation. The differences between the anterior and posterior resections at all levels tested (T2-T3, T6-T7, and T10-T11) were significant (P < 0.05). CONCLUSION: Anterior release generated significantly more thoracic rotation than posterior osteotomy in biomechanical testing of human cadaver spines. LEVEL OF EVIDENCE: N/A. PMID- 23680830 TI - Decompression and Coflex interlaminar stabilization compared with decompression and instrumented spinal fusion for spinal stenosis and low-grade degenerative spondylolisthesis: two-year results from the prospective, randomized, multicenter, Food and Drug Administration Investigational Device Exemption trial. AB - STUDY DESIGN: Prospective, randomized, multicenter, Food and Drug Administration Investigational Device Exemption trial. OBJECTIVE: To evaluate the safety and efficacy of Coflex interlaminar stabilization compared with posterior spinal fusion in the treatment of 1- and 2-level spinal stenosis and degenerative spondylolisthesis. SUMMARY OF BACKGROUND DATA: Long-term untoward sequelae of lumbar fusion for stenosis and degenerative spondylolisthesis have led to the search for motion-preserving, less-invasive alternatives. METHODS: Three hundred twenty-two patients (215 Coflex and 107 fusions) from 21 sites in the United States were enrolled between 2006 and 2010. Subjects were randomized to receive laminectomy and Coflex interlaminar stabilization or laminectomy and posterolateral spinal fusion with spinal instrumentation in a 2:1 ratio. Overall device success required a 15-point reduction in Oswestry Disability Index, no reoperations, no major device-related complications, and no postoperative epidural injections. RESULTS: Patient follow-up at minimum 2 years was 95.3% and 97.2% in the Coflex and fusion control groups, respectively. Patients taking Coflex experienced significantly shorter operative times (P < 0.0001), blood loss (P < 0.0001), and length of stay (P < 0.0001). There was a trend toward greater improvement in mean Oswestry Disability Index scores in the Coflex cohort (P = 0.075). Both groups demonstrated significant improvement from baseline in all visual analogue scale back and leg parameters. Patients taking Coflex experienced greater improvement in Short-Form 12 physical health outcomes (P = 0.050) and equivalent mental health outcomes. Coflex subjects experienced significant improvement in all Zurich Claudication Questionnaire outcomes measures compared with fusion (symptom severity [P = 0.023]; physical function [P = 0.008]; satisfaction [P = 0.006]). Based on the Food and Drug Administration composite for overall success, 66.2% of Coflex and 57.7% of fusions succeeded (P = 0.999), thus demonstrating noninferiority. The overall adverse event rate was similar between the groups, but Coflex had a higher reoperation rate (10.7% vs. 7.5%, P = 0.426). At 2 years, fusions exhibited increased angulation (P = 0.002) and a trend toward increased translation (P = 0.083) at the superior adjacent level, whereas Coflex maintained normal operative and adjacent level motion. CONCLUSION: Coflex interlaminar stabilization is a safe and efficacious alternative, with certain advantages compared with lumbar spinal fusion in the treatment of spinal stenosis and low-grade spondylolisthesis. LEVEL OF EVIDENCE: 1. PMID- 23680829 TI - Extracellular signal-regulated kinase inhibition modulates rat annulus fibrosus cell response to interleukin-1. AB - STUDY DESIGN: Rat annulus fibrosus (AF) cells were activated with interleukin-1 (IL-1) with or without extracellular signal-regulated kinase (ERK) inhibition. Factors associated with the anabolic/catabolic balance of the disc were determined. OBJECTIVE: To clarify the role of ERK pathway in AF cells response to IL-1. SUMMARY OF BACKGROUND DATA: IL-1 plays an important role in intervertebral disc degeneration. ERK is an important inflammatory pathway that plays a crucial role in the expression of inflammatory and catabolic genes induced by IL-1 in chondrocytes. However, the role of the ERK pathway in AF cells response to IL-1 has not been fully investigated. METHODS: Rat AF cells in monolayer culture were exposed to IL-1, with or without ERK inhibition; ribonucleic acid was isolated for real time polymerase chain reaction analysis of gene expression, conditioned media analyzed for nitrite, prostaglandin E-2, and IL-6, Western blot was performed to detect the changes of protein expression. RESULTS: ERK specific inhibitor U0126 significantly inhibited IL-1-induced ERK activation. IL-1 dependent upregulation of iNOS, IL-6, Cox-2, (MMP)-3, and MMP-13 was significantly reduced by ERK inhibition. The decreased gene expression of collagen I, collagen II, collagen IX, and IGF-1 induced by IL-1 was also reversed by U0126. Gene expression of ADAMTS-4, ADAMTS-5, and TGF-b were not affected by IL-1 or ERK inhibition. IL-1 moderately upregulated aggrecan and TIMP-1 expression, ERK inhibition had no significant effect on aggrecan expression but decreased TIMP-1 expression in the presence of IL-1. ERK inhibition reversed the changes of protein expression of MMP-3, MMP-13, TIMP-1, aggrecan and collagen II induced by IL-1. IL-1-induced nitric oxide, prostaglandin E-2, and IL-6 accumulation were also reduced by ERK inhibition. CONCLUSION: These results suggest that IL-1 induces an imbalance between anabolic and catabolic events in AF cells, ERK inhibition could provide some protection against the adverse effects of IL-1. LEVEL OF EVIDENCE: N/A. PMID- 23680831 TI - En bloc vertebral column derotation provides spinal derotation but no additional effect on thoracic rib hump correction as compared with no derotation in adolescents undergoing surgery for idiopathic scoliosis with total pedicle screw instrumentation. AB - STUDY DESIGN: A comparative review of 2 cohorts with prospective data collection. OBJECTIVE: To compare clinical and radiographical parameters in patients with adolescent idiopathic scoliosis undergoing surgery, using total pedicle screw instrumentation with and without en bloc vertebral column derotation (DVR). SUMMARY OF BACKGROUND DATA: All pedicle screw instrumentations with or without DVR are an effective surgical method for adolescent idiopathic scoliosis correction. However, there are limited data comparing pedicle screw instrumentation alone with pedicle screws with DVR on clinical and radiographical outcomes. METHODS: We followed 72 consecutive children and adolescents (14 males, mean age at surgery: 14.7 [range, 9.0-18.0] years; 6 juveniles, 66 adolescents) operated for a structural thoracic idiopathic scoliosis (Lenke 1-4, or 6) using all pedicle screw construct in a prospective manner for a minimum of 2 years. Of them, 24 had pedicle screw instrumentation with apical monoaxial screws without derotation (N-DVR) and 48 with en bloc DVR. RESULTS: Preoperatively, the mean (SD) main thoracic curve was 56 degrees +/- 9 degrees and 57 degrees +/- 11 degrees and was corrected to 16 degrees +/- 6 degrees in both groups at 2-year follow-up (not significant). Thoracic rib hump averaged 12.3 degrees +/- 3.6 degrees versus 14.2 degrees +/- 5.0 degrees (P = 0.075) preoperatively and 7.2 degrees +/- 3.8 degrees versus 8.3 degrees +/- 3.7 degrees at 2-year follow up in the N-DVR and in the DVR both groups, respectively (P = 0.30). Correction of spinal rotation in the main thoracic curve as assessed by the Upsani score was significantly better in the DVR group than in the N-DVR group at 6 months (P = 0.038) and 2-year follow-up (P = 0.039). Thoracic kyphosis reduced from a mean of 23 degrees +/- 18 degrees to 20 degrees +/- 9 degrees in the N-DVR group but remained unchanged in the DVR group (P = 0.11 between groups at 2-year follow up). CONCLUSION: En bloc DVR has a significant effect on radiographical spinal column derotation and may help prevent flattening of thoracic kyphosis, but this derotation is not reflected by better thoracic rib hump correction at 2-year follow-up. LEVEL OF EVIDENCE: 2. PMID- 23680832 TI - ISSLS Prize winner: The anatomy of failure in lumbar disc herniation: an in vivo, multimodal, prospective study of 181 subjects. AB - STUDY DESIGN: A prospective multimodal study including clinical, radiological, serial postcontrast magnetic resonance imaging, intraoperative findings, and histopathological study. OBJECTIVE: To document in vivo, the site of anatomical failure in lumbar disc herniation (LDH). SUMMARY OF BACKGROUND DATA: Although in vitro mechanical disruption studies have implicated both the endplate junction (EPJ) and the annulus fibrosus (AF) as the site of failure in LDH, there are no in vivo human studies to document the exact anatomy of failure. METHODS: One hundred eighty-one consecutive patients requiring microdiscectomy at a single level formed the study group. The status of the endplate and AF in the operated level (study discs) and the other discs (control) were evaluated by plain radiograph, thin slice computed tomographic scan, plain and contrast magnetic resonance imaging, intraoperative examination, and histopathological analysis. RESULTS: LDH due to EPJ failure (EPJF- type I herniation) was more common (117; 65%) than annulus fibrosis rupture. Herniated discs had a significantly higher incidence of EPJF than control discs (P < 0.0001). The EPJF was evident radiologically as vertebral corner defect in 30 patients, rim avulsion in 46, frank bony avulsions in 24, and avulsion at both upper and lower EP in 4. Thirteen discs with normal EP radiologically had cartilage or bone avulsion intraoperatively. Sixty-four discs (35%) had intact EP of which annular high intensity zone was found in 21 (11%), suggesting a disruption of AF (type II herniation). Postcontrast magnetic resonance image of 20 patients showed dye leak at the EPJ proving EPJF as main cause of LDH. CONCLUSION: Our study provides the first in vivo evidence that LDH in humans is more commonly the result of EPJF than AF rupture and offers clinical validation of previous in vitro mechanical disruption studies. Future research must focus on the EPJ as a primary area of interest in LDH. LEVEL OF EVIDENCE: N/A. PMID- 23680833 TI - Does the presence of dystrophic features in patients with type 1 neurofibromatosis and spinal deformities increase the risk of surgery? AB - STUDY DESIGN: Retrospective chart and radiographical review. OBJECTIVE: To present the demographics of patients with scoliosis and neurofibromatosis type 1 (NF-1), to record the incidence of dystrophic features, and to determine whether the presence of dystrophic features increase the risk of surgery in patients with NF-1 and associated spinal pathology. SUMMARY OF BACKGROUND DATA: The most common of the osseous complications of NF-1 is spinal deformity, occurring in 10% to 30% of individuals with NF-1. Many of these patients will eventually require surgery for curve progression, which makes study of demographics and identification of features predicting the need for surgery essential in this patient population. METHODS: A retrospective review was performed in patients with NF-1 and spinal deformities, followed in a multidisciplinary neurofibromatosis center. A subset of 56 patients with complete radiographical evaluation was reviewed for identification of risk factors for spine surgery. RESULTS: One hundred thirty-one patients from a population of 694 patients with NF-1 (19%) had scoliosis. Mean age at diagnosis of scoliosis was 9 years (range; 1-17 yr). Scoliosis and need for surgery were equally distributed between males and females. In the group of 56 patients, 63% had 3 or more dystrophic features. The presence of 3 or more dystrophic features was the strongest predictor of the need for surgery (odds ratio = 14.34; P < 0.001). Individual features most predictive of need for surgery were the presence of vertebral scalloping (odds ratio = 13.19; P < 0.001) followed by the presence of dural ectasia (odds ratio = 6.38; P = 0.005). Patients with no dystrophic features were unlikely to progress to need for surgery. CONCLUSION: Scoliosis and need for surgery were equally distributed between males and females. The presence of 3 or more dystrophic features was highly predictive of the need for surgery, with the most significant individual predictors being vertebral scalloping and dural ectasia. A combination of radiographical and MRI features can be used to predict need for spinal surgery. LEVEL OF EVIDENCE: 3. PMID- 23680834 TI - Subarachnoid hemorrhage and acute hydrocephalus as a complication of C1 lateral mass screws. AB - STUDY DESIGN: Case report. OBJECTIVE: To present a previously unreported complication of subarachnoid hemorrhage and hydrocephalus after C1 lateral mass screw insertion. To inform spine specialists of this potential postoperative complication. SUMMARY OF BACKGROUND DATA: Damage to the carotid artery, vertebral artery, hypoglossal nerve and dural tears are all recognized complications. Acute hydrocephalus as a result of subarachnoid hemorrhage is not previously reported. METHODS: A 63-year-old female with a traumatic C1 ring and C2 peg fracture underwent C1-C2 fixation. During insertion of the C1 lateral mass screws there was significant hemorrhage from the C1-C2 venous plexus. Three days postoperatively, she developed headache, confusion, and became drowsy. RESULTS: Computed tomographic scan of the brain revealed hydrocephalus and intraventricular blood that was managed with an external ventricular drain. CONCLUSION: The case of acute hydrocephalus due to intraventricular hemorrhage from C1 lateral mass screw placement has not previously been reported. Surgeons performing the procedure should consider the diagnosis if patients display signs of raised intracranial pressure postoperatively. LEVEL OF EVIDENCE: N/A. PMID- 23680835 TI - Hydatid cyst of paravertebral muscle mimicking disc herniation. AB - STUDY DESIGN: Case report. OBJECTIVE: To present a case of primary hydatid cyst in the lumbar subcutaneous tissue affecting posterior paravertebral muscle and mimicking disc herniation. SUMMARY OF BACKGROUND DATA: Cystic hydatid disease is a rare but significant parasitic disease in endemic areas. Musculoskeletal or soft tissue hydatidosis accounts for about 0.5% to 5% of all echinococcal infections in endemic areas and is almost secondary to the hepatic or pulmonary disease. Primary lumbar subcutaneous hydatid cyst affecting paravertebral muscle and extending to neural foramina is a very rare condition even in endemic areas. METHODS: A 25-year-old-female patient was admitted with swelling and pain in the right lumbar region for 3 months. The pain was reflecting in the right gluteal region and the right leg. Lumbar extension and right lateral flexion was painful and straight leg raising test was positive at right side. There was a mild hypoesthesia at L5 dermatome. According to the magnetic resonance image that the clinician obtained for initial diagnosis of lumbar disc herniation, we found multi-cystic masses located at the right paravertebral muscle at the level of L3 L5 which extended to L4-L5 neural foramina and at subcutaneous tissue at the right gluteal region. RESULTS: The patient was operated for the purpose of removal of cysts. Postoperatively, diagnosis of hydatid cyst was confirmed by histopathology. CONCLUSION: By this case, we emphasize that cystic hydatid disease should be taken into consideration in the differential diagnosis of low back pain and could mimic disc herniation. LEVEL OF EVIDENCE: N/A. PMID- 23680836 TI - Antithrombotic effects of aspirin on 1- or 2-level lumbar spinal fusion surgery: a comparison between 2 groups discontinuing aspirin use before and after 7 days prior to surgery. AB - STUDY DESIGN: Retrospective clinical analysis. OBJECTIVE: To study proper discontinuation date of aspirin in spinal fusion surgery. SUMMARY OF BACKGROUND DATA: It is thought that excess bleeding can be normalized if aspirin intake is discontinued approximately 7 days before surgery; however, the average life span of a platelet is generally regarded to be 7 to 10 days. METHODS: From January 2004 to December 2009, a single surgeon performed 182 cases of 1- or 2-level lumbar fusion surgical procedures. Patients who were aspirin users (n = 86) were divided into 2 groups according to the number of days prior to surgery that they discontinued their aspirin use: the aspirin 1 group discontinued their aspirin use 3 to 7 days before surgery and the aspirin 2 group discontinued their aspirin use 7 to 10 days before surgery. Ninety-six patients who did not use aspirin before surgery were selected for the control group. We retrospectively compared the several hematological parameters among the 2 aspirin groups and the control group. RESULTS: Both the total amount of drained blood and the duration of indwelling of the drainage catheter were significantly less in the control group than in the aspirin 1 group in patients who underwent either type of 1-level fusion surgery. However, those were not significantly different between aspirin 2 group and control group in patients who underwent either type of 1-level fusion surgery. Only drainage catheter was significantly less in the control group than in the aspirin 1 group in patients who underwent 2-level fusion surgery. CONCLUSION: Only the aspirin 1 group, wherein patients discontinued aspirin use 3 to 7 days before surgery, showed a greater drained blood and drainage catheter than the control group. If aspirin was discontinued 7 days or longer before surgery, there was no difference in the study parameters, compared with the control group. LEVEL OF EVIDENCE: 3. PMID- 23680837 TI - Experience with 161 cases of anterior exposure of the thoracic and lumbar spine in an acute care surgery model: impact of exposure level and underlying pathology on morbidity. AB - STUDY DESIGN: Retrospective chart review. OBJECTIVE: To evaluate the outcomes of anterior exposure of the thoracic and lumbar spine by an acute care surgery service. SUMMARY OF BACKGROUND DATA: Spine surgeons typically require an "approach surgeon" to provide anterior exposure of the thoracic and lumbar spine. We hypothesized that a dedicated acute care surgery service can perform those operations with acceptable morbidity and mortality. METHODS: A retrospective review of 161 trauma and nontrauma patients was performed. All cases were performed at a level I trauma center with a dedicated acute care surgery service. In-hospital morbidity and mortality were evaluated. A brief description of the operative techniques used by our group is also provided. RESULTS: Of the 161 patients, 59 (37%) were trauma patients. Ninety-three patients (58%) had anterolateral retroperitoneal exposure of the thoracic and lumbar spine. Sixty eight patients (42%) had anterior retroperitoneal midline exposure of the lumbar and lumbosacral spine. Total morbidity was 9.3% (7.4% for trauma patients and 1.8% for non trauma patients). Morbidity was highest in patients who had anterolateral exposure of the thoracic and lumbar spine (6.8%). Morbidity in patients who had midline exposure of L4 to S1 was 0%. Total mortality was 1.2% (3.3% for trauma patients and 0% for nontrauma patients). The acute care surgery service gained 3141 physician work relative value units (RVU) by performing those operations. CONCLUSION: Anterior exposure of the thoracic and lumbar spine both for trauma and nontrauma related indications can be performed with acceptable morbidity and mortality by a dedicated acute care surgery service. Morbidity and mortality were higher in trauma patients and in those who underwent thoracolumbar procedures. Patients who had midline exposure of L4 to S1 for degenerative disc disease had the lowest morbidity. LEVEL OF EVIDENCE: 4. PMID- 23680838 TI - Should we cross the cross-links? AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To assess critically if cross-links are necessary adjuvants in posterior spinal constructs. SUMMARY OF BACKGROUND DATA: Although numerous biomechanical studies are available in the literature, there has been no clinical study that has evaluated the need for cross-links in clinical situations. METHODS: The spinal constructs of patients of varied etiology who underwent surgery between July 2007 and July 2011 without the usage of cross-links were evaluated. The immediate postoperative erect radiographs were compared with the erect radiographs at the last follow-up by 2 independent observers (spine fellows not involved in the management of the patients) critically for any rotational instability using the Nash-Moe technique of assessment of vertebral rotation as well as for any "parallelogram effect." The intraobserver and interobserver reliability was analyzed. RESULTS: There were 208 cases included in the study during the study period that satisfied the criteria. The total number of motion segments fused was 707 ranging from 1 to 15 involving various etiologies. The average follow-up was 15 months (12-36 mo). Barring one patient with a thoracolumbar fracture with rotational instability (AO [Arbeitsgemeinschaft fur Osteosynthesefragen] type C) who had undergone a short segment fixation, none of the cases demonstrated any rotational instability in the follow-up radiographs. Interestingly, the rotational instability (parallelogram effect) in that patient got corrected spontaneously once anterior reconstruction was performed. The intraobserver reliability was 100% and the interobserver reliability was 92.83%. This variability was in assessing the grade of vertebral rotation only; none of the levels had a change in rotation irrespective of variation in grade assessment in the final postoperative radiograph. CONCLUSION: This study concludes that use of cross-links in clinical practice may be avoidable. The derivations from biomechanical studies do not translate into clinical advantages. Eliminating the usage of cross-links reduces the operative time as well as the overall total hospital costs (a single cross link may cost anywhere between $1500 and $2000 and surgeons tend to use single or multiple cross-links). Additionally, prominence of implants, corrosion, infection, implant failure, and pseudarthrosis are the other complications attributed to cross-links in the literature that can be eliminated by preventing their incorporation in spinal constructs. LEVEL OF EVIDENCE: N/A. PMID- 23680839 TI - Prevalence and motion characteristics of degenerative cervical spondylolisthesis in the symptomatic adult. AB - STUDY DESIGN: Retrospective analysis of kinetic magnetic resonance images. OBJECTIVE: To define the prevalence of degenerative cervical spondylolisthesis in symptomatic patients and to analyze the motion characteristics and influence on the spinal canal at the affected level. SUMMARY OF BACKGROUND DATA: When compared with lumbar spondylolisthesis, there are few studies evaluating cervical spondylolisthesis, and the prevalence and motion characteristics of cervical spondylolisthesis are not well defined. METHODS: Four hundred sixty-eight symptomatic patients underwent upright cervical kinetic magnetic resonance images in neutral, flexion, and extension positions. Segmental displacement and intervertebral angles were measured in 3 positions using computer analysis software. Spondylolisthesis was defined as the vertebral displacement more than 2 mm, and graded based on the magnitude into 2 groups at each level: grade 1 (2-3 mm), grade 2 (>3 mm). Instability was defined as segmental translational motion exceeding 3 mm. RESULTS: Grade 1 and 2 spondylolisthesis at a minimum of 1 level were observed with a prevalence of 16.4% and 3.4% of all patients, respectively. The most affected levels were C4-C5 (6.2%) and C5-C6 (6.0%) followed by C3-C4 (3.6%) and C6-C7 (3.0%). Translational motion was greater in levels with grade 1 as compared with segments without spondylolisthesis, but there was no difference in angular motion between the 3 groups. Translational instability was observed with a prevalence of 16.7% in grade 2, 4.3% in grade 1, and 3.4% in segments without spondylolisthesis. Space available for the cord at the affected level was decreased and spinal cord compression grade was higher in grade 1 and grade 2 as compared with levels without spondylolisthesis. CONCLUSION: Cervical spondylolisthesis of at least 2 mm was observed in 20% of patients and was most common at C4-C5 and C5-C6. The presence of spondylolisthesis was associated with increased translational motion and decreased segmental spinal canal diameter. LEVEL OF EVIDENCE: N/A. PMID- 23680840 TI - Late maternal hypothyroidism alters the expression of Camk4 in neocortical subplate neurons: a comparison with Nurr1 labeling. AB - Maternal thyroid hormones (THs) are essential for normal offspring's neurodevelopment even after onset of fetal thyroid function. This is particularly relevant for preterm children who are deprived of maternal THs following birth, are at risk of suffering hypothyroxinemia, and develop attention deficit/hyperactivity disorder. Expression of neocortical Ca(2+)/calmodulin kinase IV (Camk4), a genomic target of thyroid hormone, and nuclear receptor related 1 protein (Nurr1), a postnatal marker of cortical subplate (SP) cells, was studied in euthyroid fetuses and in pups born to dams thyroidectomized in late gestation (LMH group, a model of prematurity), and compared with control and developmentally hypothyroid pups (C and MMI groups, respectively). In LMH pups, the extinction of heavy Camk4 expression in an SP was 1-2 days delayed postnatally compared with C pups. The heavy Camk4 and Nurr1 expression in the SP was prolonged in MMI pups, whereas heavy Camk4 and Nurr1 expression in layer VIb remains at P60. The abnormal expression of Camk4 in the cortical SP and in layer VIb might cause altered cortical connectivity affecting neocortical function. PMID- 23680842 TI - Development of layer 1 neurons in the mouse neocortex. AB - Layer 1 of the neocortex harbors a unique group of neurons that play crucial roles in synaptic integration and information processing. Although extensive studies have characterized the properties of layer 1 neurons in the mature neocortex, it remains unclear how these neurons progressively acquire their distinct morphological, neurochemical, and physiological traits. In this study, we systematically examined the dynamic development of Cajal-Retzius cells and gamma-aminobutyric acid (GABA)-ergic interneurons in layer 1 during the first 2 postnatal weeks. Cajal-Retzius cells underwent morphological degeneration after birth and gradually disappeared from layer 1. The majority of GABAergic interneurons showed clear expression of at least 1 of the 6 distinct neurochemical markers, including Reelin, GABA-A receptor subunit delta (GABAARdelta), neuropeptide Y, vasoactive intestinal peptide (VIP), calretinin, and somatostatin from postnatal day 8. Furthermore, according to firing pattern, layer 1 interneurons can be divided into 2 groups: late-spiking (LS) and burst spiking (BS) neurons. LS neurons preferentially expressed GABAARdelta, whereas BS neurons preferentially expressed VIP. Interestingly, both LS and BS neurons exhibited a rapid electrophysiological and morphological development during the first postnatal week. Our results provide new insights into the molecular, morphological, and functional developments of the neurons in layer 1 of the neocortex. PMID- 23680841 TI - Speech-specific tuning of neurons in human superior temporal gyrus. AB - How the brain extracts words from auditory signals is an unanswered question. We recorded approximately 150 single and multi-units from the left anterior superior temporal gyrus of a patient during multiple auditory experiments. Against low background activity, 45% of units robustly fired to particular spoken words with little or no response to pure tones, noise-vocoded speech, or environmental sounds. Many units were tuned to complex but specific sets of phonemes, which were influenced by local context but invariant to speaker, and suppressed during self-produced speech. The firing of several units to specific visual letters was correlated with their response to the corresponding auditory phonemes, providing the first direct neural evidence for phonological recoding during reading. Maximal decoding of individual phonemes and words identities was attained using firing rates from approximately 5 neurons within 200 ms after word onset. Thus, neurons in human superior temporal gyrus use sparse spatially organized population encoding of complex acoustic-phonetic features to help recognize auditory and visual words. PMID- 23680843 TI - Effects of RNA interference-mediated knock-down of hypoxia-inducible factor-alpha on respiratory burst activity of the Pacific oyster Crassostrea gigas hemocytes. AB - In mammals, hypoxia-inducible factor-1 alpha (HIF-1alpha) is known to play important roles not only in oxygen homeostasis but also in innate immune responses. In this study, to assess the functional role of HIF-alpha in respiratory burst activity of Crassostrea gigas hemocytes, oysters were injected with HIF-alpha- or green fluorescent protein (GFP)-targeted-long double-stranded RNAs (dsRNAs), and at 1, 3, and 7 days post-injection, knock-down of C. gigas HIF alpha expression and production of reactive oxygen species (ROS) were analyzed. Expression of HIF-alpha in mantle, gill, and hemocytes of C. gigas was clearly down-regulated by injection of the HIF-alpha-targeted-long dsRNA, but was not inhibited by the GFP-targeted-long dsRNA, indicating that HIF-alpha expression was suppressed through sequence-specific and systemic RNA interference (RNAi). Respiratory burst activity of hemocytes was significantly increased by administration of GFP-targeted-long dsRNA. However, knock-down of HIF-alpha expression led to significant decrease of chemiluminescence (CL) response of C. gigas hemocytes at 3 and 7 days post-administration of HIF-alpha-targeted-long dsRNA, indicating the critical role of HIF-alpha in activation of respiratory burst activity of oyster hemocytes. PMID- 23680844 TI - Evolutionary analysis of TLR9 genes reveals the positive selection of extant teleosts in Perciformes. AB - The innate immune system can recognize non-self through pattern recognition receptors. Toll-like receptors were the best-known members of these receptors, and they could sense, recognize, and bind pathogen-associated molecular patterns. TLRs played an important role in innate immune system and were conserved in both invertebrate and vertebrate lineages. Thereinto, TLR9 could detect unmethylated CpG motifs in dsDNA and was expected to undergo coevolution with its microbial ligands. It was known that aquatic and terrestrial organisms dwelled in different environments which contained different pathogens, and they had to adapt to their local environmental conditions. Therefore, we collected TLR9 genes from invertebrate to vertebrate to further explore whether the huge differences between aquatic and terrestrial environments affected the TLR9s evolution between aquatic and terrestrial organisms. Molecular evolution analysis detected positively selected sites in the ancestral lineages of vertebrates, teleosts, and Perciformes but not in the ancestral lineage of mammals. In PAML, site model revealed that extant mammalian TLR9 genes underwent positive selection. However, the positive selection of extant teleosts appeared primarily in Perciformes in which there were 14 positively selected sites. Among these sites, two of them were located on the amino acid insertions of the leucine-rich repeats which could create DNA binding sites, three were found on the convex surface which might possibly affect the flexibility of the TLR solenoids, and six were located on the beta-face of concave surface which contained the ligand-binding sites of the TLR solenoids. In other ML methods, we also found three sites under selection that coincided with the codons identified by M8 and these sites were all located in LRRs. The diverse aquatic and terrestrial environments might possess different pathogens to make the living organisms adapt to their local environmental conditions. The positive selection on LRRs in TLR9s of Perciformes might be associated with the adaptation to the rapidly evolving pathogens in the water. PMID- 23680845 TI - Sh3glb1/Bif-1 and mitophagy: acquisition of apoptosis resistance during Myc driven lymphomagenesis. AB - Evasion of apoptosis, which enables cells to survive and proliferate under metabolic stress, is one of the hallmarks of cancer. We have recently reported that SH3GLB1/Bif-1 functions as a haploinsufficient tumor suppressor to prevent the acquisition of apoptosis resistance and malignant transformation during Myc driven lymphomagenesis. SH3GLB1 is a membrane curvature-inducing protein that interacts with BECN1 though UVRAG and regulates the post-Golgi trafficking of membrane-integrated ATG9A for autophagy. At the premalignant stage, allelic loss of Sh3glb1 enhances Myc-induced chromosomal instability and results in the upregulation of anti-apoptotic proteins, including MCL1 and BCL2L1. Notably, we found that Sh3glb1 haploinsufficiency increases mitochondrial mass in overproliferated prelymphomatous EMU-Myc cells. Moreover, loss of Sh3glb1 suppresses autophagy-dependent mitochondrial clearance (mitophagy) in PARK2/Parkin-expressing mouse embryonic fibroblasts (MEFs) treated with the mitochondrial uncoupler CCCP. Interestingly, PARK2-expressing Sh3glb1-deficient cells accumulate ER-associated immature autophagosome-like structures after treatment with CCCP. Taken together, we propose a model of mitophagy in which SH3GLB1 together with the class III phosphatidylinositol 3-kinase complex II (PIK3C3CII) (PIK3R4-PIK3C3-BECN1-UVRAG) regulates the trafficking of ATG9A containing Golgi-derived membranes (A9(+)GDMs) to damaged mitochondria for autophagosome formation to counteract oncogene-driven tumorigenesis. PMID- 23680846 TI - Electrocatalytic oxidation and selective determination of an opioid analgesic methadone in the presence of acetaminophen at a glassy carbon electrode modified with functionalized multi-walled carbon nanotubes: application for human urine, saliva and pharmaceutical samples analysis. AB - For the first time, electrocatalytic oxidation and selective determination of methadone (Mtd), as a long-acting opioid, in the presence of acetaminophen (Ac) has been investigated at a glassy carbon electrode modified with functionalized multi-walled carbon nanotubes. This simple and sensitive electrochemical sensor was fabricated through the drop-casting of functionalized multi-walled carbon nanotubes (fMWCNT) on the surface of a glassy carbon electrode (GCE). The electrocatalytic oxidations of Ac and Mtd are both individually and simultaneously investigated at the surface of the fMWCNT modified glassy carbon electrode (fMWCNT/MGCE) through using cyclic and differential pulse voltammetric studies. The fMWCNT/MGCE offered a considerable enhancement in the anodic peak current of Ac and Mtd associated with separating their overlapping voltammetric responses with potential difference of 290 mV. The catalytic peak currents obtained from differential pulse voltammetry of Ac and Mtd increased linearly with their concentration at the ranges of 0.45-90.0 MUM and 0.5-100.0 MUM, respectively, and the detection limits for Ac and Mtd were sequentially 0.35 MUM and 0.28 MUM. Furthermore, this electrochemical sensor was successfully implemented for the quantitative determination of Ac and Mtd in human urine, saliva and pharmaceutical samples using standard addition method and the obtained results were found to be satisfactory. PMID- 23680847 TI - Collective behavior of block copolymer thin films within periodic topographical structures. AB - We perform a systematic study of the effect of adjacent nanostructures on the confinement of block copolymers (BCP) within pre-patterned trenches in 100 nm thick SiO2 films. Asymmetric PS-b-PMMA BCP with a styrene fraction of 0.71, Mn = 67100 are used. When deposited in the form of thin film, these BCP naturally self organize upon annealing and form a PS matrix with hexagonally packed PMMA cylinders perpendicularly oriented with respect to the substrate. An accurate study of the confinement of this BCP thin film within isolated trenches is performed as a function of their width (80-260 nm). In this specific configuration the confinement of the BCP thin film within the pre-patterned structures has only been partially achieved. The effect of adjacent trenches on the arrangement of the BCP thin film is investigated using parallel trenches periodically distributed on the surface. The effective confinement of the BCP film is strongly modified by the periodicity of the pre-patterned structures. PMID- 23680848 TI - Thermoelectric properties of Zn-doped Ca5In2Sb6. AB - The Zintl compound Ca5Al2Sb6 is a promising thermoelectric material with exceptionally low lattice thermal conductivity resulting from its complex crystal structure. In common with the Al analogue, Ca5In2Sb6 is naturally an intrinsic semiconductor with a low p-type carrier concentration. Here, we improve the thermoelectric properties of Ca5In2Sb6 by substituting Zn(2+) on the In(3+) site. With increasing Zn substitution, the Ca5In(2-x)Zn(x)Sb6 system exhibits increased p-type carrier concentration and a resulting transition from non-degenerate to degenerate semiconducting behavior. A single parabolic band model was used to estimate an effective mass in Ca5In2Sb6 of m* = 2m(e), which is comparable to the Al analogue, in good agreement with density functional calculations. Doping with Zn enables rational optimization of the electronic transport properties and increased zT in accordance with a single parabolic band model. The maximum figure of merit obtained in optimally Zn-doped Ca5In2Sb6 is 0.7 at 1000 K. While undoped Ca5In2Sb6 has both improved electronic mobility and reduced lattice thermal conductivity relative to Ca5Al2Sb6, these benefits did not dramatically improve the Zn-doped samples, leading to only a modest increase in zT relative to optimally doped Ca5Al2Sb6. PMID- 23680849 TI - Management of urinary tract infection in a tertiary children's hospital before and after publication of the NICE guidelines. AB - INTRODUCTION: The UK National Institute for Health and Clinical Excellence (NICE) introduced guidelines for the diagnosis, treatment and management of urinary tract infection (UTI) in children and adolescents in August 2007. AIM: The primary aim was to determine whether publication of NICE guidelines was associated with a change in the use of diagnostic imaging investigations in patients with a documented first UTI in a tertiary children's hospital. Secondary aims were to describe the epidemiology, microbiology, prescription of prophylactic antibiotics and follow-up for these children, and the incidence of structural renal tract abnormalities, vesicoureteric reflux and renal uptake defects identified. METHODS: Retrospective review of the case notes of patients presenting to Princess Margaret Hospital, Perth, Western Australia with a first UTI over a 4-year period (August 2005-2009). Details of demographics, radiological investigations, microbiology and follow-up were obtained. Data for subjects presenting before and after 31 August 2007 were compared. RESULTS: Data from 659 subjects, median age 6 (range 0-186) months were analysed. Compared with the pre-NICE period, there was no change in the proportion of patients undergoing renal USS in the 2 years following publication of the guidelines. There was a decrease in the proportion undergoing MCUG (p<0.0001) and receiving antibiotic prophylaxis (p<0.0001) and an increase in the proportion undergoing DMSA (p<0.001). CONCLUSIONS: Practice changed following publication of the NICE guidelines. While the reduction in MCUG requests and prescription of antibiotic prophylaxis is in line with NICE guidelines, the increase in DMSA requests is contrary to the recommendations. PMID- 23680850 TI - The association between caesarean section and childhood obesity revisited: a cohort study. AB - BACKGROUND: The mode of delivery has recently gained attention as another potential perinatal risk factor for childhood obesity but results are conflicting. OBJECTIVE: To examine whether caesarean section is independently associated with childhood obesity after adjusting for a broad range of confounding factors. METHODS: The current study used a population-based survey in Grade 5 students linked to a provincial perinatal registry in the Canadian province of Nova Scotia. Associations between caesarean section and childhood overweight and obesity at age 10/11 years were examined using multiple logistic regression. RESULTS: Of the 4298 students who participated in the 2003 Children's Lifestyle and School Performance Study (response rate 51.1%), 3426 (80%) could be linked with information in the Atlee Perinatal Database, and 2988 mother-child pairs (70%) had complete information on the exposure and outcome. Compared to vaginal delivery, caesarean section was associated with offspring obesity (OR) 1.49, 95% CI 1.10 to 2.00) in the univariate analysis. After adding maternal prepregnancy weight to the multiple regression model, the OR for obesity dropped from 1.48 to 1.20 (95% CI 0.87 to 1.65). When caesarean section with and without labour were considered separately, we found no statistically significant associations relative to the vaginal delivery group (OR 1.24, 95% CI 0.84 to 1.82 and OR 1.03, 95% CI 0.58 to 1.84). CONCLUSION: Our results do not support a causal association between caesarean section and childhood obesity. Maternal prepregnancy weight was an important confounder in the association between caesarean delivery and childhood obesity and needs to be considered in future studies. PMID- 23680851 TI - Should critically ill children with acute respiratory failure be treated with surfactant? PMID- 23680853 TI - Morphology control of ceria nanocrystals for catalytic conversion of CO2 with methanol. AB - This paper describes the synthesis of ceria catalysts with octahedron, nanorod, nanocube and spindle-like morphologies via a template-free hydrothermal method. The surface morphologies, crystal plane and physical-chemical structures were investigated via field-emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD) and temperature-programmed desorption of ammonia and carbon dioxide (NH3-TPD and CO2-TPD). The catalytic performance over these ceria catalysts with different exposed planes were tested for dimethyl carbonate (DMC) synthesis from CO2 and methanol. The results showed that the spindle-like CeO2 showed the highest DMC yields, followed by nano-rods, nano cubes and nano-octahedrons. A synergism among the exposed (111) plane, defect sites, and acid-basic sites was proposed to be crucial to obtaining the high reactivity of DMC formation. PMID- 23680852 TI - In vitro effects of bisphenol A on the quality parameters, oxidative stress, DNA integrity and adenosine triphosphate content in sterlet (Acipenser ruthenus) spermatozoa. AB - Among endocrine disruptors, the xenoestrogen bisphenol A (BPA) deserves particular attention due to widespread human exposure. Besides hormonal effects, BPA has been suspected to be responsible for adverse effect on reproductive ability of various species. In the present study the effect of BPA on the quality parameters, oxidative stress, the DNA integrity and intracellular ATP content of sterlet (Acipenser ruthenus) spermatozoa were investigated in vitro. Fish spermatozoa were exposed to concentrations of BPA possibly occurring in nature (0.5, 1.75, 2.5, 5 and 10MUg/L) for 2h. Results revealed that BPA significantly decreased spermatozoa motility and velocity of spermatozoa at concentration of BPA 2.5-10MUg/L. Significant positive correlation (r=0.713, P<0.05) was found between percent motile spermatozoa and ATP content. Oxidative stress was observed at concentrations 1.75-10MUg/L, as reflected by significantly higher levels of protein and lipid oxidation and superoxide dismutase activity. Intracellular ATP content of spermatozoa decreased with increasing concentrations of BPA. A dramatic increase in DNA fragmentation expressed as percent tail DNA (2.2%+/ 0.46) and Olive tail moment (0.37+/-0.09 arbitrary units) was recorded at concentrations of 1.75MUg/L and above. The present study confirms that concentrations of BPA that can be encountered in nature are capable to induce oxidative stress, leading to impaired sperm quality, DNA fragmentation and intracellular ATP content. PMID- 23680854 TI - Psychodynamic therapy and cognitive-behavioral therapy in social anxiety disorder: a multicenter randomized controlled trial. AB - OBJECTIVE Various approaches to cognitive-behavioral therapy (CBT) have been shown to be effective for social anxiety disorder. For psychodynamic therapy, evidence for efficacy in this disorder is scant. The authors tested the efficacy of psychodynamic therapy and CBT in social anxiety disorder in a multicenter randomized controlled trial. METHOD In an outpatient setting, 495 patients with social anxiety disorder were randomly assigned to manual-guided CBT (N=209), manual-guided psychodynamic therapy (N=207), or a waiting list condition (N=79). Assessments were made at baseline and at end of treatment. Primary outcome measures were rates of remission and response, based on the Liebowitz Social Anxiety Scale applied by raters blind to group assignment. Several secondary measures were assessed as well. RESULTS Remission rates in the CBT, psychodynamic therapy, and waiting list groups were 36%, 26%, and 9%, respectively. Response rates were 60%, 52%, and 15%, respectively. CBT and psychodynamic therapy were significantly superior to waiting list for both remission and response. CBT was significantly superior to psychodynamic therapy for remission but not for response. Between-group effect sizes for remission and response were small. Secondary outcome measures showed significant differences in favor of CBT for measures of social phobia and interpersonal problems, but not for depression. CONCLUSIONS CBT and psychodynamic therapy were both efficacious in treating social anxiety disorder, but there were significant differences in favor of CBT. For CBT, the response rate was comparable to rates reported in Swedish and German studies in recent years. For psychodynamic therapy, the response rate was comparable to rates reported for pharmacotherapy and cognitive-behavioral group therapy. PMID- 23680855 TI - Land use, climate and transport of nutrients: evidence emerging from the Lake Vico Case Study [corrected]. AB - Soil erosion is a Europe-wide problem, causing both loss of soil fertility and pollution due to nutrient transport into water bodies. This process is particularly important in the Mediterranean area, where the climate, characterised by long periods of drought followed by intense precipitation, favours soil erosion. Research carried out in this field has amply described this process, showing that climate and land use/land cover (LU/LC) are the two main factors regulating this phenomenon. However, the interaction between these factors is complex and experimental research is needed to understand the nutrient loads deriving from different land uses. This paper shows the results of a long term monitoring project carried out in the Lake Vico basin (central Italy), using high resolution data and runoff samples to determine the phosphorus (P) export from four different LU/LC classes resulting from the same climatic event. The results highlight the fundamental role that LU/LC plays in terms of phosphorus load. Furthermore, the results appear to indicate that the maximum rainfall registered for 30' (I 30, max), rather than the total quantity of precipitation, has the greatest effect on levels of erosion, and consequently on the migration of nutrients rather than the total quantity of precipitation can affect on erosion and therefore the migration of nutrients. These data could contribute to scientific planning support for land management choices aimed at controlling water pollution from non-point pollution sources. PMID- 23680858 TI - Improving the performance of quantum dot-sensitized solar cells by using TiO2 nanosheets with exposed highly reactive facets. AB - We demonstrated CdS quantum dot-sensitized solar cells (QDSSCs) based on anatase TiO2 nanosheets with exposed {001} and {100} facets. Under the illumination of one Sun (AM 1.5 G, 100 mW cm(-2)), the photovoltaic conversion efficiencies were 2.29% for a QDSSC based on {001}-TiO2 nanosheets, 2.18% for a QDSSC based on {100}-TiO2 nanosheets, and 1.46% for a QDSSC based on commercial Degussa P25. It was found that the exposed highly reactive facets of TiO2 nanosheets had a remarkable influence on the QDSSCs due to their better adsorption abilities for QDs, leading to the high short current density and the enhanced photovoltaic performance. PMID- 23680856 TI - Phylogenetic evidence for recent diversification of obligate coral-dwelling gobies compared with their host corals. AB - The rich diversity of coral reef organisms is supported, at least in part, by the diversity of coral reef habitat. Some of the most habitat specialised fishes on coral reefs are obligate coral-dwelling gobies of the genus Gobiodon that inhabit a range of coral species, mostly of the genus Acropora. However, the role of this specialised pattern of habitat use in the evolution of coral-dwelling gobies is not well understood. Diversification of coral-dwelling gobies may be driven by the diversification of their host corals (cospeciation), or alternatively, diversification of these fishes may have occurred independently of the diversification of host corals. The cospeciation hypothesis assumes similar timing in evolution of the gobies and their host corals. We used four genes for each group and the available fossil records to reconstruct and date phylogenies for 20 species of Gobiodon from the Indo-Pacific and the Red Sea, and for 28 species of the coral genus Acropora. Our results indicate that Gobiodon diversified mostly in the last ~5My, whereas Acropora corals have consistently diversified since the Eocene, making the hypothesis of cospeciation untenable. The fully resolved molecular phylogeny of the genus Gobiodon is in part at odds with previous analyses incorporating morphological data and indicates that some morphological traits form paraphyletic clades within Gobiodon. Our phylogeny supports a hypothesis in which Gobiodon diversified in the Indo-Pacific Ocean and then radiated recently, with multiple new variants found in the Red Sea. PMID- 23680857 TI - Identification of volatile compounds produced by the bacterium Burkholderia tropica that inhibit the growth of fungal pathogens. AB - It has been documented that bacteria from the Burkholderia genera produce different kinds of compounds that inhibit plant pathogens, however in Burkholderia tropica, an endophytic diazotrophic and phosphate-solubilizing bacterium isolated from a wide diversity of plants, the capacity to produce antifungal compounds has not been evaluated. In order to expand our knowledge about Burkholderia tropica as a potential biological control agent, we analyzed 15 different strains of this bacterium to evaluate their capacities to inhibit the growth of four phytopathogenic fungi, Colletotrichum gloeosporioides, Fusarium culmorum, Fusarium oxysporum and Sclerotium rolffsi. Diverse analytical techniques, including plant root protection and dish plate growth assays and gas chromatography-mass spectroscopy showed that the fungal growth inhibition was intimately associated with the volatile compounds produced by B. tropica and, in particular, two bacterial strains (MTo293 and TTe203) exhibited the highest radial mycelial growth inhibition. Morphological changes associated with these compounds, such as disruption of fungal hyphae, were identified by using photomicrographic analysis. By using gas chromatography-mass spectroscopy technique, 18 volatile compounds involved in the growth inhibition mechanism were identified, including alpha-pinene and limonene. In addition, we found a high proportion of bacterial strains that produced siderophores during growth with different carbon sources, such as alanine and glutamic acid; however, their roles in the antagonism mechanism remain unclear. PMID- 23680860 TI - Probing deep into the interaction of a fluorescent chalcone derivative and bovine serum albumin (BSA): an experimental and computational study. AB - In the present manuscript, a novel fluorescent chalcone derivative is synthesized and its photophysical properties are fully characterized. The designed fluorophore is applied as a probe to study protein-dye interactions with bovine serum albumin. Circular dichroism gave interesting results on the thermodynamics of the interaction. NMR spectroscopy, especially relaxation measurements, revealed the atoms in the chalcone derivative that interacts with the protein upon binding. Molecular docking calculations indicate that the most favourable binding sites are near the two tryptophan residues. Furthermore, ab initio and DFT calculations offer insights into the reactivity and physicochemical properties of this novel fluorophore. PMID- 23680859 TI - [Stress incontinence in elderly women]. AB - Stress incontinence is one of the major challenges in geriatric medicine. This is becoming more apparent in routine urology practice with the demographic changes in the population. A thorough diagnosis for a correct treatment of stress incontinence is as important in elderly women as it is in younger patients. This includes assessing the risk factors of incontinence and obesity, parturition, pelvic surgery and changes in hormone levels are risk factors usually found in elderly women. These are the main reasons why this patient group is most frequently affected. Treatment options do not differ significantly from these of younger women. Lifestyle modification, weight loss and supervised pelvic floor training are the mainstays of conservative therapy and surgical treatment should only be considered after these options have been exhausted. In these cases minimally invasive surgical techniques offer clear advantages especially for elderly often multimorbid women. PMID- 23680861 TI - Defibrotide: properties and clinical use of an old/new drug. AB - The drug named defibrotide (DFT) has been studied for many years. It has been shown to possess many activities: profibrinolytic, antithrombotic-thrombolytic, antiischemic (heart, liver, kidney, skin, brain), antishock, antiatherosclerotic, antirejection and anti-angiogenic. The previously displayed activities, as antithrombotic, profibrinolytic and anti-inflammatory, suggested its use in vascular disorders, as in the treatment of peripheral obliterative arterial disease and in thrombophlebitis. Some years after, the use of DFT in hepatic veno occlusive disease has been also proposed. Even if DFT was considered for long time a multi-target drug, now it could be considered on the whole as a drug able to protect endothelium against activation. The present work reviews the more important experimental and clinical studies performed to detect DFT effects. PMID- 23680862 TI - Vanadium complexes having [VO]2+, [VO]3+ and [VO2]+ cores with hydrazones of 2,6 diformyl-4-methylphenol: synthesis, characterization, reactivity, and catalytic potential. AB - The Schiff bases H3dfmp(L)2 obtained by the condensation of 2,6-diformyl-4 methylphenol and hydrazones [L = isonicotinoylhydrazide (inh), nicotinoylhydrazide (nah) and benzoylhydrazide (bhz)] are prepared and characterized. By reaction of [V(IV)O(acac)2] and the H3dfmp(L)2 in methanol the V(IV)O-complexes [V(IV)O{Hdfmp(inh)2}(H2O)] (1), [V(IV)O{Hdfmp(nah)2}(H2O)] (2) and [V(IV)O{Hdfmp(bhz)2}(H2O)] (3) were obtained. Upon their aerial oxidation in methanol [V(V)O(OMe)(MeOH){Hdfmp(inh)2}] (4), [V(V)O(OMe)(MeOH){Hdfmp(nah)2}] (5) and [V(V)O(OMe)(MeOH){Hdfmp(bhz)2}] (6) were isolated. In the presence of KOH, oxidation of 1-3 results in the formation of [V(V)O2{H2dfmp(inh)2}]n.5H2O (7), K[V(V)O2{Hdfmp(nah)2}] (8) and K[V(V)O2{Hdfmp(bhz)2}] (9). All compounds are characterized in the solid state and in solution, namely by spectroscopic techniques (IR, UV-Vis, EPR, (1)H, (13)C and (51)V NMR), and DFT is also used to calculate the V(IV) hyperfine coupling constants of V(IV)-compounds and (51)V NMR chemical shifts of several V(V)-species and assign them to those formed in solution. Single crystal X-ray analysis of [V(V)O(OMe)(MeOH){Hdfmp(bhz)2}] (6) and [V(V)O2{H2dfmp(inh)2}]n.5H2O (7) confirm the coordination of the ligand in the dianionic (ONO(2-)) enolate tautomeric form, one of the hydrazide moieties remaining non-coordinated. In the case of 7 the free N(pyridine) atom of the inh moiety coordinates to the other vanadium center yielding a polynuclear complex in the solid state. It is also demonstrated that the V(V)O2-complexes are catalyst precursors in the oxidative bromination of styrene by H2O2, therefore acting as functional models of vanadium dependent haloperoxidases. Plausible intermediates involved in the catalytic process are established by UV-Vis, (51)V NMR and DFT studies. PMID- 23680863 TI - Surgical treatment of lamellar macular hole secondary to epiretinal membrane. AB - BACKGROUND: To examine the surgical results of lamellar macular hole (LMH) secondary to epiretinal membrane (ERM). METHODS: A 3-year retrospective review was performed of patients with LMH secondary to ERM that underwent ERM and internal limiting membrane (ILM) peeling. The main outcome measures included best corrected visual acuity (BCVA) and postoperative macular structure. The results were compared with cases of idiopathic ERM with similar baseline demographic characteristics. RESULTS: Thirty eyes in 30 patients were collected. The mean BCVA improvement was 3.4 Snellen lines after a mean follow-up period of 16.9 months. Optical coherence tomography (OCT) showed improved macular contour in 27 cases. Patients with intravitreal gas tamponade exhibited a higher percentage of restoration of macular contour than those without (P = 0.016). Final BCVA was correlated with an intact photoreceptor inner segment-outer segment (IS-OS) junction (P = 0.03). The degree of visual improvement is less than that observed in idiopathic ERM patients. CONCLUSION: In LMH secondary to ERM with significant visual decrease, ERM and ILM peeling may improve BCVA. Postoperative gas tamponade is associated with better restoration of macular configuration. Final BCVA is related to an intact photoreceptor IS-OS junction rather than to the normalization of the macular contour. PMID- 23680864 TI - Upregulation of TGF-beta1 in experimental proliferative vitreoretinopathy is accompanied by epithelial to mesenchymal transition. AB - BACKGROUND: Proliferative vitreoretinopathy (PVR) is characterized by epithelial to mesenchymal transition (EMT) of retinal pigment epithelium (RPE) cells and consecutive formation of fibrous membranes, leading to retinal redetachment. Transforming growth factor beta (TGF-beta) has been suggested to play an important role in this process, but the role of TGF-beta isoforms is unknown. METHODS: In pigmented rabbits (n = 14), PVR was induced by cryopexy and a full thickness limbus-parallel incision. PVR was evaluated by indirect ophthalmoscopy. Concentrations of TGF-beta isoforms were determined by multiplex bead assay analysis in aqueous humor (AH) and vitreous samples. EMT marker vimentin was analyzed by western blot. Masson's-trichrome, haematoxilin and eosine (H&E), and immunohistochemical analysis for EMT marker alpha SMA were performed on cross sections of eyes. RESULTS: PVR was induced in all treated eyes. The number of quadrants affected by PVR was 1 (n = 5), 2 (n = 2), 3 (n = 2), 4 (n = 5). Vimentin and alpha SMA were expressed during PVR development. During PVR development, both TGF-beta1 levels (AH: p = 0.001; vitreous: p = 0.002) and TGF beta2 levels increased (AH: p = 0.027; vitreous: p = 0.02), while TGF-beta3 was not detected at any timepoint. The increase was more pronounced for TGF-beta1 than for TGF- beta2 (AH: p = 0.002; vitreous: p = 0.0005), and only TGF-beta1 correlated with the amount of PVR (p = 0.024, r = 0,723). CONCLUSIONS: Development of PVR membranes was accompanied by a pronounced upregulation of TGF beta1, rather than TGF-beta2. Therefore TGF-beta1 could be a promising target for inhibition of PVR. PMID- 23680865 TI - The acute sick and injured patients: an overview of the emergency department patient population at a Norwegian University Hospital Emergency Department. AB - OBJECTIVES: There is a lack of knowledge of the emergency department (ED) population in Norway; hence, the aim of this study was to describe the ED patient population at a Norwegian University Hospital. MATERIALS AND METHODS: Prospective data of all ED patients admitted to the main ED over a period of 2 months were collected. The patients' presenting complaint was registered using the International Classification of Primary Care-2 (ICPC-2). RESULTS: A total of 3163 patients arrived in the ED during the study period. The majority (71%) of patients presented with a complaint that was defined as a symptom in ICPC-2. The most common symptoms were abdominal pain (13%), chest pain (13%), and dyspnea (9%). The complaints of the remaining patients (29%) were primarily traumas, infections, and other diagnoses. CONCLUSION: ED patients have a diverse spectrum of presenting complaints and the majority of patients present with symptoms rather than a defined medical diagnosis. PMID- 23680866 TI - Synthesis and receptor binding studies of novel 4,4-disubstituted arylalkyl/arylalkylsulfonyl piperazine and piperidine-based derivatives as a new class of sigma1 ligands. AB - This study presents the synthesis and biological evaluation of a new series of arylalkyl/arylalkylsulfonyl piperazine and piperidine-based derivatives as sigma receptor ligands. It was found that a number of halogen substituted sulfonamides display relatively high and low affinities to sigma1 and sigma2 receptors, respectively. The sigma1 affinities and subtype selectivities of four piperidine derivatives were also found to be generally comparable to those of piperazine analogues. Compared to sigma1-Rs compounds with n = 0 and 2, those with n = 1 proved to have optimal length of carbon chain by exhibiting higher affinities. Within this series, the 4-benzyl-1-(3-iodobenzylsulfonyl)piperidine sigma ligand was identified with 96-fold sigma1/sigma2 selectivity ratio (Kisigma1 = 0.96 +/- 0.05 nM and Kisigma2 = 91.8 +/- 8.1 nM). PMID- 23680867 TI - Combined use of WT1 and flow cytometry monitoring can promote sensitivity of predicting relapse after allogeneic HSCT without affecting specificity. AB - Either WT1 or leukemia-associated aberrant immune phenotypes (LAIPs) was one of the minimal residual disease (MRD) parameters used to predict leukemia relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We first evaluated the clinical value of various positive MRD standards for accurately indicating relapse based on WT1 and FCM data in adult patients with acute leukemia (AL). In total, 824 AL patients treated with allo-HSCT were enrolled in this study. We compared the sensitivity and specificity of diverse, multiple criteria MRD prognostic standards based on WT1 and FCM assays. Higher sensitivity was achieved without a loss of specificity when MRDco+, which was defined as two consecutive WT10.6+ or FCM+ or both WT10.6+ and FCM+ in the same sample within a year posttransplantation, was used as the positive MRD standard. Similar results were observed, even in 484 patients who had both abnormal WT1 and LAIPs values before transplant. A multivariate analysis showed that MRDco+ was an independent risk factor for leukemia relapse after transplant in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). The combined use of FCM and WT1 monitoring could distinguish between patients with low and high risks of relapse. Various positive MRD standards were useful for guiding intervention. PMID- 23680868 TI - Azathioprine-associated pure red cell aplasia in renal transplant recipients: a report of two cases. PMID- 23680869 TI - Intravoxel incoherent motion imaging for assessment of bone marrow infiltration of monoclonal plasma cell diseases. AB - Modern imaging techniques have demonstrated that monoclonal plasma cell diseases infiltrate the bone marrow in a diffuse, focal, mixed pattern. While focal lesions can be easily counted and measured, the diffuse lesions of the infiltration are hard to assess. We therefore investigated 31 patients with monoclonal plasma cell diseases of all stages with intravoxel incoherent motion imaging of the same region of the pelvis from where afterwards a biopsy was obtained. We found a significant correlation between plasma cell percentage in bone marrow histology and the imaging parameters "apparent diffusion coefficient" and the diffusion coefficient D. Furthermore, those parameters correlated with other factors of disease activity, e.g., monoclonal protein, hemoglobin, and immunoparesis. In summary, we found that the non-invasively acquired imaging parameters correlated with the degree of plasma cell infiltration in the bone marrow. PMID- 23680870 TI - Lenalidomide monotherapy in relapsed primary cutaneous diffuse large B cell lymphoma-leg type. PMID- 23680871 TI - Nano-silica fabricated with silver nanoparticles: antifouling adsorbent for efficient dye removal, effective water disinfection and biofouling control. AB - A nano-silica-AgNPs composite material is proposed as a novel antifouling adsorbent for cost-effective and ecofriendly water purification. Fabrication of well-dispersed AgNPs on the nano-silica surface, designated as NSAgNP, has been achieved through protein mediated reduction of silver ions at ambient temperature for development of sustainable nanotechnology. The coated proteins on AgNPs led to the formation of stable NSAgNP and protected the AgNPs from oxidation and other ions commonly present in water. The NSAgNP exhibited excellent dye adsorption capacity both in single and multicomponent systems, and demonstrated satisfactory tolerance against variations in pH and dye concentration. The adsorption mainly occurred through electrostatic interaction, though pi-pi interaction and pore diffusion also contributed to the process. Moreover, the NSAgNP showed long-term antibacterial activity against both planktonic cells and biofilms of Gram-negative Escherichia coli and Pseudomonas aeruginosa. The antibacterial activity of AgNPs retarded the initial attachment of bacteria on NSAgNP and thus significantly improved the antifouling properties of the nanomaterial, which further inhibited biofilm formation. Scanning electron and fluorescence microscopic studies revealed that cell death occurred due to irreversible damage of the cell membrane upon electrostatic interaction of positively charged NSAgNP with the negatively charged bacterial cell membrane. The high adsorption capacity, reusability, good tolerance, removal of multicomponent dyes and E. coli from the simulated contaminated water and antifouling properties of NSAgNP will provide new opportunities to develop cost effective and ecofriendly water purification processes. PMID- 23680872 TI - Modifying mesoporous silica nanoparticles to avoid the metabolic deactivation of 6-mercaptopurine and methotrexate in combinatorial chemotherapy. AB - Mesoporous silica nanoparticles with amino and thiol groups (MSNSN) were prepared and covalently modified with methotrexate and 6-mercaptopurine to form 6-MP-MSNSN MTX. In the presence of DTT, 6-MP-MSNSN-MTX gradually releases 6-MP. In rat plasma, 6-MP-MSNSN-MTX effectively inhibits the metabolic deactivation of 6-MP and MTX. 6-MP-MSNSN-MTX could be an agent for long-acting chemotherapy. PMID- 23680874 TI - Cu impedance-based detection of superparamagnetic nanoparticles. AB - A novel method for superparamagnetic nanoparticle detection using copper impedance as the sensing property is presented. The increase of impedance produced by the proximity of the nanoparticles in the copper is comparable to that of classical magnetoimpeditive materials. A physical interpretation of the detection in terms of the induction of eddy currents in the copper element by the oscillating magnetic moments of the particles is proposed. Experimental research has been done to support this hypothesis, namely, analyses of the influence of the driving current frequency and amplitude, and of the geometry and size of the sensing conductor. The ability of copper to quantify the number of nanoparticles was successfully verified, evidencing the great potential of this new method. PMID- 23680873 TI - Alterations in brain structures related to taste reward circuitry in ill and recovered anorexia nervosa and in bulimia nervosa. AB - OBJECTIVE: The pathophysiology of anorexia nervosa remains obscure, but structural brain alterations could be functionally important biomarkers. The authors assessed taste pleasantness and reward sensitivity in relation to brain structure, which may be related to food avoidance commonly seen in eating disorders. METHOD: The authors used structural MR imaging to study gray and white matter volumes in women with current restricting-type anorexia nervosa (N=19), women recovered from restricting-type anorexia nervosa (N=24), women with bulimia nervosa (N=19), and healthy comparison women (N=24). RESULTS: All eating disorder groups exhibited increased gray matter volume of the medial orbitofrontal cortex (gyrus rectus). Manual tracing confirmed larger gyrus rectus volume, and volume predicted taste pleasantness ratings across all groups. Analyses also indicated other morphological differences between diagnostic categories. Antero-ventral insula gray matter volumes were increased on the right side in the anorexia nervosa and recovered anorexia nervosa groups and on the left side in the bulimia nervosa group relative to the healthy comparison group. Dorsal striatum volumes were reduced in the recovered anorexia nervosa and bulimia nervosa groups and predicted sensitivity to reward in all three eating disorder groups. The eating disorder groups also showed reduced white matter in right temporal and parietal areas relative to the healthy comparison group. The results held when a range of covariates, such as age, depression, anxiety, and medications, were controlled for. CONCLUSION: Brain structure in the medial orbitofrontal cortex, insula, and striatum is altered in eating disorders and suggests altered brain circuitry that has been associated with taste pleasantness and reward value. PMID- 23680875 TI - Protective effect of a new biomaterial against the development of experimental osteoarthritis lesions in rabbit: a pilot study evaluating the intra-articular injection of alginate-chitosan beads dispersed in an hydrogel. AB - OBJECTIVE: This study aimed to evaluate the structural benefit of a new biomaterial composed of alginate-chitosan (AC) beads dispersed in a hydrogel (H) derived from chitosan on the development of osteoarthritis (OA) in rabbit. DESIGN: OA was induced by the surgical transection of the anterior cruciate ligament in rabbits. Animals received a single intra-articular injection (900 MUl) of AC beads in H hydrogel, H hydrogel alone or saline a week after surgery. OA development was followed by X-rays. Blood samples were collected throughout the study to measure biological markers (Prostaglandins E2 - PGE2 and C reactive protein - CRP). Macroscopic observation and histological evaluation of articular cartilage and synovial membrane were performed 6 weeks after surgery. RESULTS: AC beads in H hydrogel prevented from the development of OA based on the reduction of the Kellgren & Lawrence (K&L) score. It also significantly reduced the histological score of cartilage lesion severity. This effect was homogenous on every joint compartment. It was due to a significant effect on cartilage structure and cellularity scores. The injection of AC beads in H hydrogel also tended to reduce the synovial membrane inflammation. No significant variation of biological markers was noted. CONCLUSIONS: The present pilot study provides interesting and promising results for the use of AC beads in H hydrogel in animal. It indeed prevented the development of OA cartilage lesions without inflammatory signs. The potencies of this biomaterial to protect OA joint should be further documented. It could then represent a new alternative for viscosupplementation in human OA management. PMID- 23680876 TI - Categorization of two-photon microscopy images of human cartilage into states of osteoarthritis. AB - OBJECTIVE: The degeneration of articular cartilage is part of the clinical syndrome of osteoarthritis (OA) and one of the most common causes of pain and disability in middle-aged and older people(1). However, the objective detection of an initial state of OA is still challenging. In order to categorize cartilage into states of OA, an algorithm is presented which offers objective categorization on the basis of two-photon laser-scanning microscopy (TPLSM) images. METHODS: The algorithm is based on morphological characteristics of the images and results in a topographical visualization. This paper describes the algorithm and shows the result of a categorization of human cartilage samples. RESULTS: The resulting map of the analysis of TPLSM images can be divided into areas which correspond to the grades of the Outerbridge-Categorization. The algorithm is able to differentiate the samples in coincidence with the macroscopic impression. CONCLUSION: The method is promising for early OA detection and categorization. In order to achieve a higher benefit for the physician the method must be transferred to an endoscopic setup for an application in surgery. PMID- 23680877 TI - OARSI recommended performance-based tests to assess physical function in people diagnosed with hip or knee osteoarthritis. AB - OBJECTIVES: To recommend a consensus-derived set of performance-based tests of physical function for use in people diagnosed with hip or knee osteoarthritis (OA) or following joint replacement. METHODS: An international, multidisciplinary expert advisory group was established to guide the study. Potential tests for consideration in the recommended set were identified via a survey of selected experts and through a systematic review of the measurement properties for performance-based tests. A multi-phase, consensus-based approach was used to prioritize and select performance-based tests by applying decision analysis methodology (1000Minds software) via online decision surveys. The recommended tests were chosen based on available measurement-property evidence, feasibility of the tests, scoring methods and expert consensus. RESULTS: Consensus incorporated the opinions of 138 experienced clinicians and researchers from 16 countries. The five tests recommended by the advisory group and endorsed by Osteoarthritis Research Society International (OARSI) were the 30-s chair-stand test, 40 m fast-paced walk test, a stair-climb test, timed up-and-go test and 6 min walk test. The first three were recommended as the minimal core set of performance-based tests for hip or knee OA. CONCLUSION: The OARSI recommended set of performance-based tests of physical function represents the tests of typical activities relevant to individuals diagnosed with hip or knee OA and following joint replacements. These tests are complementary to patient-reported measures and are recommended as prospective outcome measures in future OA research and to assist decision-making in clinical practice. Further research should be directed to expanding the measurement-property evidence of the recommended tests. PMID- 23680878 TI - Correlation of meniscal T2* with multiphoton microscopy, and change of articular cartilage T2 in an ovine model of meniscal repair. AB - OBJECTIVE: To correlate meniscal T2* relaxation times using ultra-short echo time (UTE) magnetic resonance imaging (MRI) with quantitative microscopic methods, and to determine the effect of meniscal repair on post-operative cartilage T2 values. DESIGN: A medial meniscal tear was created and repaired in the anterior horn of one limb of 28 crossbred mature ewes. MR scans for morphological evaluation, meniscal T2* values, and cartilage T2 values were acquired at 0, 4 and 8 months post-operatively for the Tear and Non-Op limb. Samples of menisci from both limbs were analyzed using multiphoton microscopy (MPM) analysis and biomechanical testing. RESULTS: Significantly prolonged meniscal T2* values were found in repaired limbs than in control limbs, P < 0.0001. No regional differences of T2* were detected for either the repaired or control limbs in the anterior horn. Repaired limbs had prolonged cartilage T2 values, primarily anteriorly, and tended to have lower biomechanical force to failure at 8 months than Non-Op limbs. MPM autofluorescence and second harmonic generation data correlated with T2* values at 8 months (rho = -0.48, P = 0.06). CONCLUSIONS: T2* mapping is sensitive to detecting temporal and zonal differences of meniscal structure and composition. Meniscal MPM and cartilage T2 values indicate changes in tissue integrity in the presence of meniscal repair. PMID- 23680880 TI - The authors' reply. PMID- 23680879 TI - The layered structure of the articular surface. AB - OBJECTIVE: Articular cartilage is roughly separated into three areas: the tangential, middle, and deep zones. The structure and molecular components of an additional important zone, the most superficial zone (MSZ), which directly faces the joint cavity, have yet to be conclusively elucidated. The purpose of the present study was to use multiple methods to study the MSZ in order to determine its structure. MATERIALS AND METHODS: Knees from 16 pigs (age, 6 months) were used. Full-thickness cartilage specimens were harvested from the femoral groove. The MSZ was observed using light microscopy, transmission electron microscopy (TEM), and scanning electron microscopy (SEM) in combination with histochemical and immunohistochemical methods. RESULTS: The combined findings from the three different observational methods indicate that the MSZ is subdivided into three layers. Among these three layers, collagen subtypes I, II, and III are present in the innermost (third) layer of the MSZ. Beneath the third layer, type II collagen is the predominant type, with small amounts of type III collagen. This layer beneath the third layer is considered to be the tangential layer. CONCLUSIONS: Our observations indicate that the MSZ is subdivided into three layers. Further analysis of the molecular components in each layer may improve our understanding of the structure of the articular surface. PMID- 23680881 TI - Huge left ventricular diverticulum simulating athlete's heart, a multimodality imaging study. PMID- 23680882 TI - Pulsatile external compression of coronary arteries. PMID- 23680883 TI - Milk Alkali syndrome: an electrocardiographic masquerader for non-hypothermic Osborn phenomenon. PMID- 23680884 TI - On the 50th anniversary of the first description of a multistage exercise treadmill test: re-visiting the birth of the 'Bruce protocol'. PMID- 23680885 TI - Remote monitoring after recent hospital discharge in patients with heart failure: a systematic review and network meta-analysis. AB - CONTEXT: Readmission to hospital for heart failure is common after recent discharge. Remote monitoring (RM) strategies have the potential to deliver specialised care and management and may be one way to meet the growing needs of the heart failure population. OBJECTIVE: To determine whether RM strategies improve outcomes for adults who have been recently discharged (<28 days) following an unplanned admission due to heart failure. STUDY DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Fourteen electronic databases (including MEDLINE, EMBASE and PsycINFO) were searched to January 2012, and supplemented by hand-searching relevant articles. STUDY SELECTION: All randomised controlled trials (RCTs) or observational cohort studies with a contemporaneous control group were included. RM interventions included home telemonitoring (TM) (including implanted monitoring devices) with medical support provided during office hours or 24/7 and structured telephone support (STS) programmes delivered via human-to-human contact (HH) or human-to-machine interface (HM). DATA EXTRACTION: Data were extracted and validity was assessed independently by two reviewers. RESULTS: Twenty-one RCTs that enrolled 6317 patients were identified (11 studies evaluated STS (10 of which were HH, while 1 was HM), 9 studies assessed TM, and 1 study assessed both STS and TM). No trial of implanted monitoring devices met the inclusion criteria. Compared with usual care, although not reaching statitistical significance, RM trended to reduce all-cause mortality for STS HH (HR: 0.77, 95% credible interval (CrI): 0.55, 1.08), TM during office hours (HR: 0.76, 95% CrI: 0.49, 1.18) and TM24/7 (HR: 0.49, 95% CrI: 0.20, 1.18). Exclusion of one trial that provided better-than-usual support to the control group rendered each of the above comparisons statistically significant. No beneficial effect on mortality was observed with STS HM. Reductions were also observed in all-cause hospitalisations for TM interventions but not for STS interventions. Care packages generally improved health-related quality-of-life and were acceptable to patients. CONCLUSIONS: STS HH and TM with medical support provided during office hours showed beneficial trends, particularly in reducing all-cause mortality for recently discharged patients with heart failure. Where 'usual' care is less good, the impact of RM is likely to be greater. PMID- 23680886 TI - Congenital heart disease and rheumatic heart disease in Africa: recent advances and current priorities. AB - Africa has one of the highest prevalence of heart diseases in children and young adults, including congenital heart disease (CHD) and rheumatic heart disease (RHD). We present here an extensive review of recent data from the African continent highlighting key studies and information regarding progress in CHD and RHD since 2005. Main findings include evidence that the CHD burden is underestimated mainly due to the poor outcome of African children with CHD. The interest in primary prevention for RHD has been recently re-emphasised, and new data are available regarding echocardiographic screening for subclinical RHD and initiation of secondary prevention. There is an urgent need for comprehensive service frameworks to improve access and level of care and services for patients, educational programmes to reinforce the importance of prevention and early diagnosis and a relevant research agenda focusing on the African context. PMID- 23680887 TI - Recent advances in the epidemiology, pathogenesis and prognosis of acute heart failure and cardiomyopathy in Africa. AB - This review addresses recent advances in the epidemiology, pathogenesis and prognosis of acute heart failure and cardiomyopathy based on research conducted in Africa. We searched Medline/PubMed for publications on acute decompensated heart failure and cardiomyopathy in Africa for the past 5 years (ie, 1 January 2008 to 31 December 2012). This was supplemented with personal communications with colleagues from Africa working in the field. A large prospective registry has shown that acute decompensated heart failure is caused by hypertension, cardiomyopathy and rheumatic heart disease in 90% of cases, a pattern that is in contrast with the dominance of coronary artery disease in North America and Europe. Furthermore, acute heart failure is a disease of the young with a mean age of 52 years, occurs equally in men and women, and is associated with high mortality at 6 months (~18%), which is, however, similar to that observed in non African heart failure registries, suggesting that heart failure has a dire prognosis globally, regardless of aetiology. The molecular genetics of dilated cardiomyopathy, hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy in Africans is consistent with observations elsewhere in the world; the unique founder effects in the Afrikaner provide an opportunity for the study of genotype-phenotype correlations in large numbers of individuals with cardiomyopathy due to the same mutation. Advances in the understanding of the molecular mechanisms of peripartum cardiomyopathy have led to promising clinical trials of bromocriptine in the treatment of peripartum heart failure. The key challenges of management of heart failure are the urgent need to increase the use of proven treatments by physicians, and the control of hypertension in primary care and at the population level. PMID- 23680888 TI - Recent advances in the epidemiology, outcome, and prevention of myocardial infarction and stroke in sub-Saharan Africa. AB - The early part of the new millennium witnessed reports of a growing burden of cardiovascular disease in Sub-Saharan Africa (SSA). However the contribution of ischemic heart disease and stroke to this increasing burden relative to that caused by hypertensive heart disease, cardiomyopathy and rheumatic heart disease was not clear. Over the last decade, data from the continent has begun to clarify this issue and suggests three main points. The burden of ischemic heart disease relative to other causes of heart disease remains low particularly in the black Africans majority. Stroke caused predominantly by hypertension is now a major cause of disability and premature death. Third, the burden of risk factors for atherosclerosis is increasing rapidly in most urban and some rural regions. A concerted effort to understand the primary drivers of this increase in cardiac risk factors is required to prevent a future epidemic of atherosclerosis and its sequelae. PMID- 23680889 TI - Recent advances in HIV-associated cardiovascular diseases in Africa. AB - The last decade has witnessed major advances in our understanding of the epidemiology and pathophysiology of HIV-related cardiovascular disease in sub Saharan Africa. In this review, we summarise these and discuss clinically relevant advances in diagnosis and treatment. In the Heart of Soweto Study, 10% of patients with newly diagnosed cardiovascular disease were HIV positive, and the most common HIV-related presentations were cardiomyopathy (38%), pericardial disease (13%) and pulmonary arterial hypertension (8%). HIV-related cardiomyopathy is more common with increased immunosuppression and HIV viraemia. With adequate antiretroviral therapy, the prevalence is low. Contributing factors such as malnutrition and genetic predisposition are under investigation. In other settings, pericardial disease is the most common presentation of HIV-related cardiovascular disease (over 40%), and over 90% of pericardial effusions are due to Mycobacterium tuberculosis (TB) pericarditis. HIV-associated TB pericarditis is associated with a greater prevalence of myopericarditis, a lower rate of progression to constriction, and markedly increased mortality. The role of steroids is currently under investigation in the form of a randomised controlled trial. HIV-associated pulmonary hypertension is significantly more common in sub Saharan Africa than in developed countries, possibly as a result of interactions between HIV and other infectious agents, with very limited treatment options. It has recently been recognised that patients with HIV are at increased risk of sudden death. Infection with HIV is independently associated with QT prolongation, which is more marked with hepatitis C co-infection and associated with a 4.5-fold higher than expected rate of sudden death. The contribution of coronary disease to the overall burden of HIV-associated cardiovascular disease is still low in sub-Saharan Africa. PMID- 23680890 TI - New insights on diabetes mellitus and obesity in Africa-Part 2: prevention, screening and economic burden. AB - Evidence has been accumulating on the importance of the rising burden of diabetes mellitus on the African continent at an increasingly higher pace. In the first paper of this series of two companion papers, recent evidence on the prevalence, pathogenesis and comorbidities of obesity and diabetes mellitus in Africa were summarised. In this second paper, we focus on recent developments pertaining to the prevention, screening and the economic burden of diabetes and obesity on the continent. There are indications that awareness on diabetes and chronic diseases at large has increased in Africa in recent times. However, the care for diabetes largely remains suboptimal in most countries, which are not adequately prepared to face the prevention and control of diabetes, as the costs of caring for the condition pose a tremendous challenge to most local economies. Moreover, translation strategies to prevent and control diabetes and obesity, on the continent, are still to be evaluated. PMID- 23680891 TI - New insights on diabetes mellitus and obesity in Africa-part 1: prevalence, pathogenesis and comorbidities. AB - Evidence continues to accumulate on the rising burden of diabetes mellitus at a higher pace in Africa. In a series of two papers, we sought to summarise recent evidence on diabetes and obesity in Africa based on a systematic review of studies published between January 2002 and October 2012. This first paper on the prevalence, pathogenesis and comorbidities shows that the increase in diabetes prevalence has paralleled that of obesity in Africa. Recent surveys on diabetes and obesity have been largely suboptimal. Hence, the need for more representative and robust continent-wide prevalence figures, which may be somehow achieved through pooling of existing data. Prospective studies linking environmental risk factors to disease occurrence and outcomes remain scarce, and genetic factors for diabetes or obesity have not been extensively assessed. The health consequences of diabetes are manifold, and include a complex interaction with other conditions like HIV infection and sickle cell disease/trait. PMID- 23680892 TI - The 10 'Best Buys' to combat heart disease, diabetes and stroke in Africa. PMID- 23680893 TI - Recent advances in the epidemiology, diagnosis and treatment of endomyocardial fibrosis in Africa. AB - Endomyocardial fibrosis (EMF) continues to be an important and disabling disease in many parts of Africa, although its prevalence has declined in some parts of the continent. Increased access to medical care in general and increased availability of echocardiography in some parts of the continent have led to recognition of the disease in areas in which the disease had not been previously reported, and this has given new insights into its natural history. However, the early manifestations of EMF continue to elude clinicians and researchers, and no progress has been made in defining its aetiology. Advances have, however, been made in establishing the epidemiology and improving clinical diagnosis and management, through modern medical therapy and improved surgical techniques. Research is still required to define clinical, biological and echocardiographic markers of early stages of EMF, so that advances in the knowledge of its pathogenesis and pathophysiology can be made. This will hopefully determine preventive measures and avoid the burden of this debilitating condition in this continent. PMID- 23680894 TI - Recent advances in recombinant protein production: BAC-based expression vectors, the bigger the better. AB - Designing appropriate expression vectors is one of the critical steps in the generation of stable cell lines for recombinant protein production. Conventional expression vectors are severely affected by the chromatin environment surrounding their integration site into the host genome, resulting in low expression levels and transgene silencing. In the past, a new generation of expression vectors and different strategies was developed to overcome the chromatin effects. Bacterial artificial chromosomes (BACs) are cloning vectors capable of accommodating up to 350 Kb. Thus, BACs can carry a whole eukaryotic locus with all the elements controlling the expression of a gene; therefore, BACs harbor their own chromatin environment. Expression vectors based on BACs containing open/permissive chromatin loci are not affected by the chromatin surrounding their integration site in the host cell genome. Consequently, BAC-based expression vectors containing the appropriate loci confer predictable and high levels of expression over time. These properties make BAC-based expression vectors a very attractive tool applied to the recombinant protein production field. PMID- 23680895 TI - Physiologic corticosterone oscillations regulate murine hematopoietic stem/progenitor cell proliferation and CXCL12 expression by bone marrow stromal progenitors. AB - The role of corticosterone (Cort), the immune system's major stress hormone, in the regulation of hematopoietic stem and progenitor cells (HSPCs) and their dynamic bone marrow (BM) microenvironment is currently unknown. We report that corticotropin-releasing factor receptor 1 (CRFR1) mutant mice with chronically low Cort levels showed aberrant HSPC regulation, having higher HSPC numbers and upregulation of the chemokine CXCL12, phenotypes that were restored by Cort supplementation. Expanded stromal progenitors known to support HSPCs were also observed in these low-Cort-containing mice. A similar phenotype was induced in wild-type (WT) mice by Metyrapone, a Cort synthesis inhibitor. Conversely, high Cort exposure induced HSPC apoptosis, reduced long-term BM repopulation and decreased stromal progenitor cell numbers. We documented circadian oscillations of Cort in WT BM but not in CRFR1 mutant mice, leading to diminished circadian BM CXCL12 fluctuations and increased number of circulating HSPCs in these mice. Finally, low Cort induced expansion of stromal progenitors, CXCL12 expression, HSPC proliferation and BM repopulation capacity, involving Notch1 signaling. This was associated with upregulation of the Notch ligand, Jagged1, in BM myeloid cells. Our results suggest that daily physiologic Cort oscillations are critical for balanced HSPC proliferation and function involving Notch1 signaling and their supportive BM microenvironment. PMID- 23680896 TI - Intrinsic left atrial histoanatomy as the basis for reentrant excitation causing atrial fibrillation/flutter in rats. AB - BACKGROUND: Although the pulmonary veins are accepted as preferential trigger sites for paroxysmal atrial fibrillation/flutter (AF/AFL), the intrinsic basis for reentrant excitation is undetermined in persistent AF/AFL. OBJECTIVE: To identify histoanatomic substrates for reentrant AF/AFL in rats. METHODS: Spatiotemporal patterns of impulse propagation were visualized optically on the posterior surface of the atria in di-4-ANEPPS-stained Langendorff-perfused rat heart/lung preparations. The relevant histology was also analyzed. RESULTS: Burst (S1-S2) pacing at the right atrium provoked AF/AFL in 15 of 19 hearts, and most cases developed by organized reentrant excitation through the coronary sinus (CS) and left atrial (LA) roof, with nonorganized irregular propagation in 3 cases. The reentrant circuit developed along 2 pathways of propagation: a slower pathway at the LA roof (conduction velocity, 42.4 +/- 16.6 cm/s) and a faster pathway along the CS (conduction velocity, 53.3 +/- 9.2 cm/s). Upon extra stimulus (S2) after consecutive S1 pacing, the impulse at the roof propagated retrogradely from the CS, resulting in reentrant propagation anchored by the atrial septum and posterior LA. Histologic quantification revealed significantly lower myocardial density in the posterior LA and the septum than elsewhere in the atria. Moreover, myocytes in the LA roof, than in the CS, were of lower density, more randomly arranged in the direction of conduction, and characterized by more disorganized distribution of connexin 43 over the entire cell membrane, which is consistent with the slower impulse propagation there. CONCLUSION: The intrinsic histoanatomic heterogeneity in the LA would constitute a pro-reentrant substrate responsible for perpetuating AF/AFL. PMID- 23680897 TI - Resting heart rate and risk of sudden cardiac death in the general population: influence of left ventricular systolic dysfunction and heart rate-modulating drugs. AB - BACKGROUND: Higher levels of resting heart rate (HR) have been associated with sudden cardiac death (SCD) but mechanisms are poorly understood. We hypothesized that severe left ventricular systolic dysfunction (LVSD) and HR-modulating drugs explain the HR-SCD relationship. OBJECTIVE: To evaluate the relationship between HR, severe LVSD, HR-modulating drugs, and SCD in the community by using a case control approach. METHODS: From the ongoing Oregon Sudden Unexpected Death Study, SCD cases (n = 378) aged >=35 years and with electrocardiogram-documented resting HR were compared to 378 age- and gender-matched control subjects with coronary artery disease (mean age 68 +/- 13 years; 69% man). Associations with SCD were assessed by using multivariable logistic regression. RESULTS: Mean resting HR was significantly higher among SCD cases compared to controls (7.5 beats/min difference; P < .0001). HR was a significant determinant of SCD after adjustment for significant comorbidities and medications (odds ratio for 10 beats/min increase 1.26; 95% confidence interval 1.14-1.38; P < .0001). After considering LVSD, resting HR was slightly attenuated but remained significantly associated with SCD (P = .005). In addition to diabetes and digoxin as well as pulmonary and renal disease, LVSD was also independently associated with SCD (odds ratio 1.79; 95% confidence interval 1.11-2.87; P = .02). CONCLUSIONS: Contrary to expectations, the significant relationship between increased resting HR and SCD persisted even after adjustment for LVSD and HR-modulating drugs. These findings suggest a potential role for additional novel interventions/therapies that modulate autonomic tone. PMID- 23680898 TI - Catheter ablation of atrial fibrillation supported by novel nonfluoroscopic 4D navigation technology. AB - BACKGROUND: The MediGuide technology (MGT) represents a novel sensor-based electromagnetic 4-dimensional (4D) navigation system allowing real-time catheter tracking in the environment of prerecorded X-ray loops. OBJECTIVE: To report on our clinical experience in atrial fibrillation (AF) ablation with recently available MGT-enabled ablation catheters. METHODS: The MGT was used in addition to a conventional 3D mapping system in 80 patients with AF (age 61 +/- 10 years; 47 men; 40 with persistent AF), who underwent circumferential pulmonary vein isolation and voltage mapping with and without substrate modification. Short native right anterior oblique/left anterior oblique loops were used as background movies for the nonfluoroscopic placement of sensor-equipped diagnostic catheters into the coronary sinus and the right ventricle. After single transseptal puncture, selective angiograms of the pulmonary veins were used as background movies for near nonfluoroscopic left atrial reconstruction. Computed tomography registration as well as mapping/ablation was performed by using the new open irrigated MGT-enabled ablation catheter. RESULTS: MGT application was not associated with a change in established workflow. Large parts of the procedure (mean entire duration 167 +/- 47 minutes) could be done without additional fluoroscopy, whereas median residual fluoroscopy duration of 4.6 (interquartile range: 2.9, 7.1) minutes was mainly used for the acquisition of background loops, transseptal puncture, occasional verification of transseptal sheath position, and manipulation of the circular mapping catheter. Three (4%) minor complications occurred. CONCLUSIONS: The MGT integrates easily into the workflow of standard AF ablation and allows for high-quality nonfluoroscopic 4D catheter tracking. This results in low radiation exposure for patients and staff without complicating the workflow of the procedure. PMID- 23680899 TI - Separation of phenylpropanoid glycosides from a Chinese herb by HSCCC. AB - An effective high-speed counter-current chromatography method was established for the preparative isolation and purification of two phenylpropanoid glycosides from the Tibetan medicinal plant Pedicularis longiflora Rudolph. var. tubiformis (Klotz). Tsoong. With a two-phase solvent system composed of chloroform-n-butanol methanol-water (4:3:4:5, v/v), 40 mg of an extract of Pedicularis longiflora Rudolph. var. tubiformis (Klotz). Tsoong was separated to yield 20 mg of verbascoside and 18 mg of isoacteoside, with purity values of 97 and 98%, respectively. The chemical structures of these two components were identified by proton and carbon nuclear magnetic resonance. In addition, the antioxidant activity of the two phenylpropanoid glycosides was evaluated by 2,2-diphenyl-1 picrylhydrazyl (DPPH)-high-performance liquid chromatography, and the results showed that the two components exhibited strong antioxidant DPPH radical scavenging activity, with IC50 values of 15.6 and 18.9 ug/mL, respectively. PMID- 23680900 TI - New determination method for sulfonation degree of phthalic anhydride by RP-HPLC. AB - A novel method was developed to monitor the reaction process and evaluate the sulfonation level in the sulfonation of phthalic anhydride by reversed-phase high performance liquid chromatography (RP-HPLC). The product peak was identified in chromatograms through product analysis and by comparing its retention time with that of standard compounds. By comparing the hydrolysis and alcoholysis methods, optimized pretreatment of the sample was found for RP-HPLC. Based on the determined percentages of phthalic anhydride and sulfonated phthalic anhydride in the mixture, the degree of sulfonation was calculated. When the sulfonation degree of phthalic anhydride was in the range of 2.8-71%, the recovery of 97-104% was achieved, and the procedure was rapid and accurate. PMID- 23680901 TI - The chemical fate of paroxetine metabolites. Dehydration of radicals derived from 4-(4-fluorophenyl)-3-(hydroxymethyl)piperidine. AB - Quantum chemical calculations have been used to model reactions which are important for understanding the chemical fate of paroxetine-derived radicals in the environment. In order to explain the experimental observation that the loss of water occurs along the (photo)degradation pathway, four different mechanisms of radical-induced dehydrations have been considered. The elimination of water from the N-centered radical cation, which results in the formation of an imine intermediate, has been calculated as the most feasible process. The predicted energy barrier (DeltaG = 98.5 kJ mol(-1)) is within the barrier limits set by experimental measurements. All reaction intermediates and transition state structures have been calculated using the G3(MP2)-RAD composite procedure, and solvent effects have been determined using a mixed (cluster/continuum) solvation model. Several new products, which comply with the available experimental data, have been proposed. These structures could be relevant for the chemical fate of antidepressant paroxetine, but also for biologically and environmentally related substrates. PMID- 23680902 TI - Biomarker validation of recent unprotected sexual intercourse in a prospective study of young women engaged in sex work in Phnom Penh, Cambodia. AB - BACKGROUND: Accurate measurement of unprotected sex is essential in HIV prevention research. Since 2001, the 100% Condom Use Program targeting female sex workers (FSWs) has been a central element of the Cambodian National HIV/AIDS Strategy. We sought to assess the validity of self-reported condom use using the rapid prostate-specific antigen (PSA) test among Cambodian FSWs. METHODS: From 2009 to 2010, we enrolled 183 FSWs in Phnom Penh in a prospective study of HIV risk behavior. Prostate-specific antigen test results from the OneStep ABAcard were compared with self-reported condom use in the past 48 hours at quarterly follow-up visits. RESULTS: Among women positive for seminal fluid at the first follow-up visit, 42% reported only protected sex or no sex in the detection period. Discordant results were more likely among brothel and street-based FSW versus entertainment (56% vs. 17%), recent (last 3 months) amphetamine-type stimulant (ATS) users (53% vs. 20%), and those with 5 or more partners in the past month (58% vs. 13%). In multivariable regression models, positive PSA results were associated with recent ATS use (adjusted risk ratio [ARR], 1.5; 95% confidence interval [CI], 1.1-2.2), having a nonpaying last sex partner (ARR, 1.7; CI, 1.2-2.5), and sex work venue (ARR, 3.0; CI, 1.4-6.5). Correspondingly, women with a nonpaying last sex partner were more likely to report unprotected sex (ARR, 1.5; CI, 1.1-2.2), but no associations were found with sex work venue or ATS use. CONCLUSIONS: Results confirm the questionable validity of self reported condom use among FSW. The PSA biomarker assay is an important monitoring tool in HIV/sexually transmitted infection research including prevention trials. PMID- 23680903 TI - Molecular epidemiology of beta-lactamase-producing Neisseria gonorrhoeae strains in Manaus, AM, Brazil. AB - We report new sequence types of 14 penicillinase-producing Neisseria gonorrhoeae, isolated from sexually transmitted disease clinic attendees in Manaus, Brazil. They were characterized by WI/WII/WIII groups, susceptibility testing and Multi Antigen Sequencing Typing/Mutilocus Sequence Typing protocols. Twelve were classified as WII/III and 2 as WI and were presented resistance to penicillin and tetracycline. New alleles for por and AroE genes and novel sequence types were identified, revealing molecular characteristics not described previously. ST1590 is the common ancestor after eBURST analysis, and these findings represent an important contribution of molecular epidemiology approach in gonococci's research in Amazonas. PMID- 23680904 TI - Does perception of relationship type impact sexual health risk? AB - A sample of 327 men (age, 16-36 years) responded to self-completed questionnaires, which included questions regarding their most recent female sexual partner and specific behaviors pertaining to that partner. Analyses showed significant differences in several variables including condom use and sexually transmitted infection history, among the different relationship types. PMID- 23680905 TI - Secondary syphilis presenting as a generalized lymphadenopathy: clinical mimicry of malignant lymphoma. AB - The diagnosis of syphilis remains challenging. The absence of classical features of the disease, such as the rash of secondary syphilis or genital lesion, may pose diagnostic difficulties. In this article, we report a case of secondary syphilis in which the clinical syndrome and pattern of fluorodeoxyglucose uptake mimicked malignant lymphoma. This case highlights the importance of thorough history taking including sexual contact. Clinicians should be alert for syphilis underlying unexplained lymphadenopathy, even in the absence of typical rash or genital lesion. PMID- 23680906 TI - Association of sexually transmitted infections with high-risk human papillomavirus types: a survey with 802 female sex workers in china. AB - A cross-sectional study that investigated the association between cervical infection of Chlamydia trachomatis, Neisseria gonorrhoeae, or Mycoplasma genitalium and infection with high-risk types of human papillomavirus among female sex workers in China found that the presence of cervical C. trachomatis or M. genitalium infection was independently associated with infection with certain high-risk types of specific high-risk human papillomavirus among this population. PMID- 23680907 TI - Clinician perspectives on management of adolescents with pelvic inflammatory disease using standardized patient scenarios. AB - National survey data designed to delineate clinician perspectives on the indications to hospitalize adolescents for pelvic inflammatory disease indicate that clinicians endorse care consistent with the Centers for Disease Control and Prevention sexually transmitted diseases treatment guidelines but that there is less agreement on the social factors that may impair an adolescent's ability to self-care in the outpatient setting. PMID- 23680908 TI - Association of Chlamydia trachomatis infection and herpes simplex virus type 2 serostatus with genital human papillomavirus infection in men: the HPV in men study. AB - BACKGROUND: Studies in women indicate that some sexually transmitted infections promote human papillomavirus (HPV) persistence and carcinogenesis. Little is known about this association in men; therefore, we assessed whether Chlamydia trachomatis (CT) infection and herpes simplex virus type 2 (HSV-2) serostatus are associated with genital HPV prevalence, an early event in HPV-related pathogenesis. METHODS: Genital exfoliated cells, first-void urine, and blood from 3971 men recruited in the United States, Mexico, and Brazil were tested for HPV, CT, and HSV-2 antibodies, respectively. Multivariable logistic regression was used to assess the association of CT infection and HSV-2 serostatus with 4 HPV outcomes (any, oncogenic, nononcogenic only, and multiple infections). RESULTS: A total of 64 (1.6%) men were CT positive, and 811 (20.4%) men were HSV-2 seropositive. After adjustment for potential confounders, CT was associated with any HPV (adjusted odds ratio [aOR], 2.19; 95% confidence interval [CI], 1.13 4.24), oncogenic HPV (aOR, 3.10; 95% CI, 1.53-6.28), and multiple HPV (aOR, 3.43; 95% CI, 1.69-6.95) prevalence. Herpes simplex virus type 2 serostatus was associated with any HPV (aOR, 1.25; 95% CI, 1.02-1.52), nononcogenic HPV only (aOR, 1.38; 95% CI, 1.08-1.75), and multiple HPV (aOR, 1.33; 95% CI, 1.06-1.68) prevalence. In analyses stratified by sexual behavior, CT infection was significantly associated with HPV detection among men reporting 2 or more recent sexual partners, whereas HSV-2 serostatus was significantly associated with HPV detection in men reporting 0 to 5 lifetime sexual partners. CONCLUSION: In this population, CT infection and HSV-2 serostatus were associated with prevalent genital HPV infection. Future prospective studies should investigate whether these infections influence HPV acquisition and/or persistence. PMID- 23680909 TI - Penile herpes simplex virus type 1 infection presenting two and a half years after Jewish ritual circumcision of an infant. AB - The association between Jewish ritual circumcision and genital herpes simplex virus type 1 infection has been well described. We report a case of genital herpes that first presented at the age of 21/2 years. We believe that the infection was acquired asymptomatically through direct orogenital suction performed during circumcision in the newborn period. PMID- 23680910 TI - Synthesis of the bismuth oxyhalide solid solutions with tunable band gap and photocatalytic activities. AB - Three series of BiOM(x)R(1-x) (M, R = Cl, Br, I) solid solutions were systematically synthesized through a low-temperature precipitation. These solid solutions were characterized by XRD, FESEM, TEM, EDS, UV-vis spectra, nitrogen sorption/desorption, and PL. The tunable band gaps of the as-prepared solid solutions were realized via only changing the molar ratio of two halide ions. Meanwhile, the influence of citric acid in the formations of controllable morphological structures was discussed to study the growth mechanism of solid solutions. The photocatalytic activities of the bismuth oxyhalide solid solutions have also been investigated by the degradation of Rhodamine-B (RhB) under visible light irradiation. The optimized solid solutions possess higher photocatalytic activity than pure ones [BiOM (M = Cl, Br, I)] due to the broadened range of visible light response and the reduced recombination rate of electron-holes pairs. The results show that the synthesis of BiOM(x)R(1-x) (M, R = Cl, Br, I) solid solutions have profound significance for the design of the novel photocatalyst materials. PMID- 23680911 TI - A novel program for treating patients with trimorbidity: hepatitis C, serious mental illness, and active substance use. AB - BACKGROUND: Advances in hepatitis C virus (HCV) treatment have yielded improved virological response rates, and yet, many individuals with psychiatric illness still fail to receive HCV therapy. Concerns about safety, adherence, and efficacy of HCV treatment are compounded and treatment is further deferred when substance use is also present. This is especially problematic given the disproportionately high rates of both mental health issues and substance use among individuals living with HCV. OBJECTIVE: This study sought to examine HCV treatment outcomes in clients with serious mental illness (SMI) and with high rates of active substance use who were participating in a community-based HCV treatment program. PATIENTS AND METHODS: A retrospective chart review of 129 clients was carried out. Patients were classified as having an SMI if they had a history of bipolar disorder, psychotic disorder, past suicide attempt or mental health related hospitalization. RESULTS: Fifty-one patients were defined as having an SMI. Among the 46 patients with SMI and a detectable HCV viral load, HCV antiviral therapy was initiated in nine (19.6%). A relapse or an increase in substance use was common (77.8% or n=7), as was the requirement for adjustment or initiation of psychotropic medications (66.7% or n=6) during HCV antiviral therapy. Despite these barriers, rates of adherence to antiviral therapy were high and overall sustained virological response rates were comparable with published trials. CONCLUSION: This study is the first to report HCV treatment outcomes in a population in which SMI and active polysubstance use was prevalent and suggests that with appropriate models of care, clients with trimorbidity can be treated safely and effectively. PMID- 23680912 TI - Sustained virological response based on the week 4 response in hepatitis C virus genotype 1 patients treated with peginterferons alpha-2a and alpha-2b, plus ribavirin. AB - BACKGROUND: It is unclear whether the magnitude of reduction in hepatitis C virus (HCV) RNA between baseline and week 4 of peginterferon-ribavirin treatment influences the probability of achieving a sustained virological response (SVR) in patients without a rapid virological response (RVR). METHODS: Data of 151 genotype 1 chronic hepatitis C patients treated with 48 weeks of peginterferon alpha-2a (group 1, n=86) and peginterferon alpha-2b (group 2, n=65), plus ribavirin, were evaluated retrospectively. Patients of each group were further divided into those who had RVR and those who did not. Patients without an RVR were then subdivided into four discrete categories on the basis of the magnitude of decrease in HCV RNA from baseline to week 4: those with a >=3 log10 drop, those with a >=2 log10 but <3 log10 drop, those with a >=1 log10 but <2 log10 drop, and those with a <1 log10 drop. The proportion of SVR was calculated for each category. RESULTS: Overall, 80 and 88.2% of RVR patients and 41.2 and 39.6% of non-RVR patients achieved an SVR in group 1 and group 2, respectively. Among non-RVR patients, the SVR rates were 75, 50, 16.7, and 11.1% in group 1 (trend test P=0.001) and 63.6, 42.9, 30, and 23.1% in group 2 (trend test P=0.038) in those with a drop in HCV RNA level of >=3 log10, >=2 log10, >=1 log10, and <1 log10 at week 4, respectively. CONCLUSION: Patients with a >=3 log10 drop in HCV RNA at week 4 have a high probability of achieving an SVR when treated with either peginterferon alpha-2a-ribavirin or peginterferon alpha-2b-ribavirin. PMID- 23680913 TI - Amorfrutin B is an efficient natural peroxisome proliferator-activated receptor gamma (PPARgamma) agonist with potent glucose-lowering properties. AB - AIMS/HYPOTHESIS: The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is an important gene regulator in glucose and lipid metabolism. Unfortunately, PPARgamma-activating drugs of the thiazolidinedione class provoke adverse side effects. As recently shown, amorfrutin A1 is a natural glucose lowering compound that selectively modulates PPARgamma. In this study we aimed to characterise, in vitro, a large spectrum of the amorfrutins and similar molecules, which we isolated from various plants. We further studied in vivo the glucose-lowering effects of the so far undescribed amorfrutin B, which featured the most striking PPARgamma-binding and pharmacological properties of this family of plant metabolites. METHODS: Amorfrutins were investigated in vitro by binding and cofactor recruitment assays and by transcriptional activation assays in primary human adipocytes and murine preosteoblasts, as well as in vivo using insulin-resistant high-fat-diet-fed C57BL/6 mice treated for 27 days with 100 mg kg(-1) day(-1) amorfrutin B. RESULTS: Amorfrutin B showed low nanomolar binding affinity to PPARgamma, and micromolar binding to the isotypes PPARalpha and PPARbeta/delta. Amorfrutin B selectively modulated PPARgamma activity at low nanomolar concentrations. In insulin-resistant mice, amorfrutin B considerably improved insulin sensitivity, glucose tolerance and blood lipid variables after several days of treatment. Amorfrutin B treatment did not induce weight gain and furthermore showed liver-protecting properties. Additionally, amorfrutins had no adverse effects on osteoblastogenesis and fluid retention. CONCLUSIONS/INTERPRETATION: The application of plant-derived amorfrutins or synthetic analogues thereof constitutes a promising approach to prevent or treat complex metabolic diseases such as insulin resistance or type 2 diabetes. PMID- 23680914 TI - Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice. AB - AIMS/HYPOTHESIS: Mutations in BSCL2/seipin cause Berardinelli-Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterised by near absence of adipose tissue and severe insulin resistance. We aimed to determine how seipin deficiency alters glucose and lipid homeostasis and whether thiazolidinediones can rescue the phenotype. METHODS: Bscl2 (-/-) mice were generated and phenotyped. Mouse embryonic fibroblasts (MEFs) were used as a model of adipocyte differentiation. RESULTS: As observed in humans, Bscl2 (-/-) mice displayed an early depletion of adipose tissue, with insulin resistance and severe hepatic steatosis. However, Bscl2 (-/-) mice exhibited an unexpected hypotriglyceridaemia due to increased clearance of triacylglycerol-rich lipoproteins (TRL) and uptake of fatty acids by the liver, with reduced basal energy expenditure. In vitro experiments with MEFs demonstrated that seipin deficiency led to impaired late adipocyte differentiation and increased basal lipolysis. Thiazolidinediones were able to rescue the adipogenesis impairment but not the alteration in lipolysis in Bscl2 (-/-) MEFs. In vivo treatment of Bscl2 (-/-) mice with pioglitazone for 9 weeks increased residual inguinal and mesenteric fat pads as well as plasma leptin and adiponectin concentrations. Pioglitazone treatment increased energy expenditure and improved insulin resistance, hypotriglyceridaemia and liver steatosis in these mice. CONCLUSIONS/INTERPRETATION: Seipin plays a key role in the differentiation and storage capacity of adipocytes, and affects glucose and lipid homeostasis. The hypotriglyceridaemia observed in Bscl2 (-/-) mice is linked to increased uptake of TRL by the liver, offering a new model of liver steatosis. The demonstration that the metabolic complications associated with BSCL can be partially rescued with pioglitazone treatment opens an interesting therapeutic perspective for BSCL patients. PMID- 23680915 TI - Impact of impaired insulin secretion and insulin resistance on the incidence of type 2 diabetes mellitus in a Japanese population: the Saku study. AB - AIMS/HYPOTHESIS: To assess the impact of impaired insulin secretion (IIS) and insulin resistance (IR) on type 2 diabetes incidence in a Japanese population. METHODS: This 4 year cohort study included 3,059 participants aged 30-69 without diabetes at baseline who underwent comprehensive medical check-ups between April 2006 and March 2007 at Saku Central Hospital. Based on their insulinogenic index and HOMA-IR values, participants were classified by the criteria of the Japan Diabetes Society into four categories: normal; isolated IIS (i-IIS); isolated IR (i-IR); and IIS plus IR. They were followed up until March 2011. The incidence of type 2 diabetes was determined from fasting and 2 h post-load plasma glucose concentrations and from receiving medical treatment for diabetes. RESULTS: At baseline, 1,550 individuals (50.7%) were classified as normal, 900 (29.4%) i-IIS, 505 (16.5%) i-IR, and 104 (3.4%) IIS plus IR. During 10,553 person-years of follow-up, 219 individuals developed type 2 diabetes, with 126 (57.5%) having i IIS at baseline. Relative to the normal group, the multivariable-adjusted HRs for type 2 diabetes in the i-IIS, i-IR and IIS plus IR groups were 8.27 (95% CI 5.33, 12.83), 4.90 (95% CI 2.94, 8.17) and 16.93 (95% CI 9.80, 29.25), respectively. The population-attributable fractions of type 2 diabetes onset due to i-IIS, i IR, and IIS plus IR were 50.6% (95% CI 46.7%, 53.0%), 14.2% (95% CI 11.8%, 15.6%) and 12.9% (95% CI 12.3%, 13.2%), respectively. CONCLUSIONS/INTERPRETATION: Compared with IR, IIS had a greater impact on the incidence of type 2 diabetes in a Japanese population. PMID- 23680916 TI - Prediction of mortality and macrovascular complications in type 2 diabetes: validation of the UKPDS Outcomes Model in the Casale Monferrato Survey, Italy. AB - AIMS/HYPOTHESIS: The United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model can be used to estimate the lifetime occurrence of major diabetes-related complications in order to calculate health economic outcomes. The aim of the study was to assess the performance of the model by comparing the predicted and observed mortality and the incidence of macrovascular complications in an Italian population-based cohort with type 2 diabetes. METHODS: We used data from the Casale Monferrato Survey, a cohort enrolled in 1988 and surveyed in 1991 (n = 1,967) to assess the prevalence of cardiovascular risk factors. In 2000, a new survey included all the members of the original cohort who were still alive (n = 860), and in addition all individuals identified with a new diagnosis of type 2 diabetes since 1993 (n = 2,389). We compared the mortality predicted by the model for the 1991 survey over the subsequent 17-year period with the observed risk. The following outcomes were analysed in the 2000 survey: myocardial infarction (MI), other ischaemic heart disease, stroke, congestive heart failure (CHF) and amputation. RESULTS: For all-cause mortality, the predictions from the model at 5 and 10 years (23% and 47%, respectively) were identical to the observed risks. At 15 years, the risk of death was slightly overestimated (an estimate of 67% vs 64% observed, 95% CI 61%, 66%). The performance of the model was best for patients with a recent history of disease (duration <6 years). Among the complications, the predicted cumulative incidences of MI and CHF were very close to those observed. CONCLUSIONS/INTERPRETATION: External validation is essential to assess the accuracy of simulation models. The UKPDS Outcomes Model satisfactorily predicted a set of actual incidences of mortality and complications in an Italian diabetes cohort up to a duration of approximately 12 years. The longer term performance of such models should be carefully evaluated. PMID- 23680917 TI - An oral cavity carcinoma nomogram to predict benefit of adjuvant radiotherapy. AB - IMPORTANCE: After surgical resection for oral cavity squamous cell carcinoma, adjuvant radiotherapy may be recommended for patients at higher risk for locoregional recurrence, but it can be difficult to predict whether a particular patient will benefit. OBJECTIVE: To construct a model to predict which patients with oral cavity squamous cell carcinoma would benefit from adjuvant radiotherapy. DESIGN AND SETTING: We constructed several types of survival models using a set of 979 patients with oral cavity squamous cell carcinoma. Covariates were age, sex, tobacco use, stage, grade, margins, and subsite. The best performing model was externally validated on a set of 431 patients. PARTICIPANTS: The model was based on a set of 979 patients with oral cavity squamous cell carcinoma, including 563 from Memorial Sloan Kettering Cancer Center, New York, New York, and 416 from the Hospital AC Camargo, Sao Paulo, Brazil. The validation set consisted of 431 patients from Princess Margaret Hospital, Toronto, Ontario, Canada. MAIN OUTCOME AND MEASURE: The primary outcome measure of interest was locoregional recurrence-free survival. RESULTS: The lognormal model showed the best performance per the Akaike information criterion. An online nomogram was built from this model that estimates locoregional failure-free survival with and without postoperative radiotherapy. CONCLUSIONS AND RELEVANCE: A web-based nomogram can be used as a decision aid for adjuvant treatment decisions for patients with oral cavity squamous cell carcinoma. PMID- 23680918 TI - Tobacco use by sexual identity among young adults in the United States. AB - INTRODUCTION: National surveillance data are needed for the lesbian, gay, bisexual, and transgender population, a group which has been shown to have unique health needs. METHODS: This study uses data from Legacy's Young Adult Cohort Study, a nationally representative sample collected in the summer of 2011 to examine patterns of tobacco use by sexual identity. RESULTS: Homosexual and bisexual past 30-day cigarette use (35% and 27%, respectively) was higher than heterosexual past 30-day cigarette use (18%; p = .004). The prevalence of any current tobacco use among heterosexuals was 22% compared with 35% in homosexuals and 31% in bisexuals (p = .04). Prevalence of dual use was 30% among heterosexuals, 43% among homosexuals, and 35% among bisexuals. High school education (OR = 4.27), current alcohol use (OR = 12.64), and current other drug use (OR = 9.67) were significant predictors of current cigarette use among lesbian, gay, and bisexual respondents. Strong predictors of other tobacco product use were Black race (OR = 6.95), current alcohol use (OR = 11.70), and current other drug use (OR = 7.42). CONCLUSIONS: Prevalence estimates for tobacco use were higher among young adults who self-identify as sexual minorities compared with those who identify as heterosexuals. Tobacco use is strongly associated with alcohol and other drug use in this population. This study highlights the significant disparities in tobacco use behaviors among sexual minority populations and the critical need to conduct surveillance among these groups. PMID- 23680919 TI - The Gordian knot of clinical research in anxiety disorders: some answers, more questions. PMID- 23680920 TI - Distribution of the anticancer drugs doxorubicin, mitoxantrone and topotecan in tumors and normal tissues. AB - PURPOSE: Pharmacokinetic analyses estimate the mean concentration of drug within a given tissue as a function of time, but do not give information about the spatial distribution of drugs within that tissue. Here, we compare the time dependent spatial distribution of three anticancer drugs within tumors, heart, kidney, liver and brain. METHODS: Mice bearing various xenografts were treated with doxorubicin, mitoxantrone or topotecan. At various times after injection, tumors and samples of heart, kidney, liver and brain were excised. RESULTS: Within solid tumors, the distribution of doxorubicin, mitoxantrone and topotecan was limited to perivascular regions at 10 min after administration and the distance from blood vessels at which drug intensity fell to half was ~25-75 MUm. Although drug distribution improved after 3 and 24 h, there remained a significant decrease in drug fluorescence with increasing distance from tumor blood vessels. Drug distribution was relatively uniform in the heart, kidney and liver with substantially greater perivascular drug uptake than in tumors. There was significantly higher total drug fluorescence in the liver than in tumors after 10 min, 3 and 24 h. Little to no drug fluorescence was observed in the brain. CONCLUSIONS: There are marked differences in the spatial distributions of three anticancer drugs within tumor tissue and normal tissues over time, with greater exposure to most normal tissues and limited drug distribution to many cells in tumors. Studies of the spatial distribution of drugs are required to complement pharmacokinetic data in order to better understand and predict drug effects and toxicities. PMID- 23680921 TI - Assessment of the absorption, metabolism and excretion of [14C]pasireotide in healthy volunteers using accelerator mass spectrometry. AB - PURPOSE: Pasireotide (SOM230) is a multireceptor-targeted somatostatin analog designed to have a broader somatostatin receptor binding profile than other currently available somatostatin analogs. The purpose of this study was to evaluate the absorption, metabolism and excretion of pasireotide in healthy male subjects (N = 4) following a single, subcutaneous (sc), 600 MUg dose of [14C]pasireotide. METHODS: Blood, plasma, urine and feces were collected for 240 h post-dose and analyzed for total 14C and metabolite profile by accelerator mass spectrometry (AMS) or high-performance liquid chromatography-AMS. Parent drug levels were analyzed by radioimmunoassay. RESULTS: [14C]pasireotide was rapidly absorbed, with a mean peak plasma 14C concentration of 16.6 +/- 5.28 ngEq/mL at 0.5 h in plasma. The parent drug to total 14C AUC(0-24h) ratio was 1.08, indicating that little metabolite was present in plasma up to 24 h post-dose. In pooled plasma samples (0-12 h), only unchanged [14C]pasireotide was detected. Unchanged [14C]pasireotide accounted for approximately 84 % of total excretion (feces and urine). Approximately 56 % of the administered radioactive dose was recovered within 240 h, eliminated primarily in feces (48.3 +/- 8.16 %) and minimally in urine (7.63 +/- 2.03 %). No serious adverse events were reported. CONCLUSIONS: A single dose of [14C]pasireotide 600 MUg sc administered to healthy male subjects was rapidly absorbed and excreted in its unchanged form primarily via the hepatic route. PMID- 23680923 TI - Statistical analysis of the spatial distribution of radionuclides in soils around a coal-fired power plant in Spain. AB - Coal-fired power-plants (CFPP) can be a source of contamination because the coal contains trace amounts of natural radionuclides, such as (40)K and (238)U, (232)Th and their decay products. These radionuclides can be released as fly ash from the CFPP and deposited from the atmosphere on the nearby top soils, therefore modifying the natural radioactivity background levels, and subsequently increasing the total radioactive dose received for the nearby population. In this paper, an area of 64 km(2) around the CFPP of Velilla del Rio Carrion (Spain) has been studied by collecting 67 surface soil samples and measuring the activities of one artificial and six natural radionuclides by gamma spectrometry. The found results are similar to the background natural levels and ranged from 0 to 209 for (137)Cs, 11 to 50 for (238)U, 14 to 67 for (226)Ra, 29 to 380 for (210)Pb, 15 to 68 for (232)Th, 17 to 78 for (224)Ra, 97 to 790 for (40)K (all values in Bq kg( 1)). Besides the classical radiochemical tools, Analysis of Variance (ANOVA), Principal Component Analysis (PCA), Hierarchical Clustering Analysis (HCA), and kriging mapping have been used to the experimental dataset, allowing us to find the existence of two different models of spatial distribution around the CFPP. The first, followed by (238)U, (226)Ra, (232)Th, (224)Ra and (40)K can be assigned to 'natural background radioactivity', whereas the second model, followed by (210)Pb and (137)Cs, is based on 'atmospheric fallout radioactivity'. The main conclusion of this work is that CFPP has not influence on the radioactivity levels measured in the studied area, with has a mean annual outdoor effective dose E = 71 +/- 22 MUSv, very close to the average UNSCEAR value of 70 MUSv, thus confirming the almost non-existent radioactive risk posed by the presence of the CFPP. PMID- 23680924 TI - Cross-linked lysozyme crystal templated synthesis of Au nanoparticles as high performance recyclable catalysts. AB - Bio-nanomaterials fabricated using a bioinspired templating technique represent a novel class of composite materials with diverse applications in biomedical, electronic devices, drug delivery, and catalysis. In this study, Au nanoparticles (NPs) are synthesized within the solvent channels of cross-linked lysozyme crystals (CLLCs) in situ without the introduction of extra chemical reagents or physical treatments. The as-prepared AuNPs-in-protein crystal hybrid materials are characterized by light microscopy, transmission electron microscopy, x-ray diffraction, and Fourier-transform infrared spectroscopy analyses. Small AuNPs with narrow size distribution reveal the restriction effects of the porous structure in the lysozyme crystals. These composite materials are proven to be active heterogeneous catalysts for the reduction of 4-nitrophenol to 4 aminophenol. These catalysts can be easily recovered and reused at least 20 times because of the physical stability and macro-dimension of CLLCs. This work is the first to use CLLCs as a solid biotemplate for the preparation of recyclable high performance catalysts. PMID- 23680925 TI - Genomic analysis of bacteriophage PBECO4 infecting Escherichia coli O157:H7. AB - Escherichia coli O157:H7 is a human pathogen. We isolated a novel bacteriophage infecting this bacterium from a sewage water treatment facility. Phage PBECO4 belongs to the family Myoviridae, having an isometric head and a contractile tail. It has a linear double-stranded DNA genome of 348,113 base pairs in length with a GC content of 34.09 %. Whole-genome sequencing revealed that PBECO4 is distantly related to enterobacteria phage vB_KleM_RaK2, with 10 % similarity, and Cronobacter phage vB_CsaM_GAP32 with 6 % similarity. Five hundred fifty-one putative open reading frames (ORFs) and six tRNA genes were found. Eight ORFs are related to genes encoding structural proteins, nine to DNA packaging, two to DNA lysis activity, and 42 to replication and regulation. Four hundred ninety ORFs have not been functionally annotated. PMID- 23680926 TI - The complete genome sequence of Lamium mild mosaic virus, a member of the genus Fabavirus. AB - Lamium mild mosaic virus (LMMV) is the only one of the five members of the genus Fabavirus for which there are no nucleotide sequence data. In this study, the complete genome sequence of LMMV was determined and compared with the available complete genome sequences of other members of the genus Fabavirus. The genome was the largest of the genus but maintained the typical organization, with RNA 1 of 6080 nucleotides (nt), RNA 2 of 4065 nt, and an unusually long 3' untranslated region in RNA 2 of 603 nt. Phylogenetic analysis of the amino acid sequences of the protease-polymerase (Pro-Pol) region and the two coat proteins confirmed that LMMV belongs to a distinct species within the genus Fabavirus. PMID- 23680927 TI - Cooperative enhancement of optical nonlinearities in a porphyrin derivative bearing a pyrimidine chromophore at the periphery. AB - A novel porphyrin derivative bearing one D-pi-A-pi-D pyrimidine chromophore at the periphery was designed, prepared, and studied using the Z-scan technique, the results showing that this compound exhibits enhanced nonlinear optical (NLO) absorption, refraction and optical limiting responses. The significant NLO properties can be ascribed to an effective combination of distinct nonlinear mechanisms. PMID- 23680928 TI - Improving the bioactivity of Zn(II)-curcumin based complexes. AB - New Zn(II)-curcumin based heteroleptic complexes (1-5) have been synthesized and fully characterized, with the aim to improve the bioactivity of the precursor derivative [(bpy-9)Zn(curc)Cl] (A), a potentially intercalating antitumor agent recently reported. Some structural changes have been made starting from the reference complex A, in order to introduce new functionalities, such as electrostatic and/or covalent interactions. In particular, keeping the same N,N chelating ligand, namely bpy-9, two completely different Zn(II) species have been obtained: a tetracoordinated Zn(II) cation with tetrafluoroborate as counterion (1) and a dimeric neutral complex in which the sulfate anion acts as a bridging group through two Zn(II) centres (2). Moreover, by changing the N,N chelating unit, [(L(n))Zn(curc)Cl] complexes (3-5), in which the Zn(II) ion shows the same pentacoordination seen in the precursor complex A, have been obtained. The antitumour activity of all new Zn(II) complexes was tested in vitro against the human neuroblastoma cell line SH-SY5Y in a biohybrid membrane system and the results indicate that all species exhibit strong cytotoxic activity. In particular the ionic tetrafluoroborate Zn(II) complex, 1, and the neutral phenanthroline based Zn(II) derivative, 4, show the strongest growth inhibition, being even more effective than the model complex A. Both complexes have a dose dependent anti-proliferative effect on cells as demonstrated by the decrease of viability and the increase of Annexin V and PI-positive cells with the increase of their concentration. Cells treated with complexes 1 and 4 undergo apoptosis that involves the activation of JNK, caspase 3 and MMP changes. Finally, complex 1 is more effective in the induction of caspase-3 activation demonstrating its ability to trigger the execution-phase of cell apoptosis. PMID- 23680929 TI - Racial differences and income disparities are associated with poor outcomes in kidney transplant recipients with lupus nephritis. AB - BACKGROUND: An analysis of income and racial/ethnic disparities on renal transplant outcomes in recipients with lupus nephritis (LN) has not been reported. We analyzed the United States Renal Data System database to assess the impact of these disparities on graft loss and death in the LN and non-LN cohorts. METHODS: We identified 4214 patients with LN as the cause of end-stage renal disease in a retrospective cohort of 150,118 patients first transplanted from January 1, 1995 to July 1, 2006. We merged data on median household income from the United States Census based on the ZIP code. RESULTS: In multivariate Cox regression analyses, African-Americans (AF) recipients with LN (vs. non-AF) had an increased risk of graft loss (adjusted hazard ratio [AHR], 1.39; 95% confidence interval [CI], 1.21-1.60) and death (AHR, 1.33; 95% CI, 1.09-1.63). Furthermore, there were significant associations of lower-income quintiles with higher risk for graft loss and death among AF with LN. In comparison, among non AF recipients with LN, income levels did not predict risk for transplant outcomes. The racial disparity for both graft loss and death outcomes among AF with LN was greater than among AF without LN (AHR, 1.32; 95% CI, 1.29-1.36 for graft loss and AHR, 1.02; 95% CI, 0.99-1.05 for death). CONCLUSIONS: AF kidney transplant recipients with LN were at increased risk for graft loss and death compared with non-AF. Income levels were associated with the risk of graft loss and death in AF but not in non-AF recipients with LN. PMID- 23680930 TI - Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study. AB - BACKGROUND: Osteoarthritis is the most prevalent joint disease and a frequent cause of joint pain, functional loss, and disability. Osteoarthritis often becomes chronic, and conventional treatments have demonstrated only modest clinical benefits without lesion reversal. Cell-based therapies have shown encouraging results in both animal studies and a few human case reports. We designed a pilot study to assess the feasibility and safety of osteoarthritis treatment with mesenchymal stromal cells (MSCs) in humans and to obtain early efficacy information for this treatment. METHODS: Twelve patients with chronic knee pain unresponsive to conservative treatments and radiologic evidence of osteoarthritis were treated with autologous expanded bone marrow MSCs by intra articular injection (40*10 cells). Clinical outcomes were followed for 1 year and included evaluations of pain, disability, and quality of life. Articular cartilage quality was assessed by quantitative magnetic resonance imaging T2 mapping. RESULTS: Feasibility and safety were confirmed, and strong indications of clinical efficacy were identified. Patients exhibited rapid and progressive improvement of algofunctional indices that approached 65% to 78% by 1 year. This outcome compares favorably with the results of conventional treatments. Additionally, quantification of cartilage quality by T2 relaxation measurements demonstrated a highly significant decrease of poor cartilage areas (on average, 27%), with improvement of cartilage quality in 11 of the 12 patients. CONCLUSIONS: MSC therapy may be a valid alternative treatment for chronic knee osteoarthritis. The intervention is simple, does not require hospitalization or surgery, provides pain relief, and significantly improves cartilage quality. PMID- 23680931 TI - Renal transplant imaging using magnetic resonance angiography with a nonnephrotoxic contrast agent. AB - BACKGROUND: In renal allograft recipients presenting with graft dysfunction, it is critical to determine the patency of the transplant vasculature to guide clinical management. Conventional modalities such as Doppler ultrasound, contrast enhanced computed tomography, magnetic resonance angiography (MRA), and noncontrast MRA are each of limited use because of technical factors and toxicity of standard contrast agents. The purpose of this study was to retrospectively review our institutional experience with renal transplant MRA using ferumoxytol (a nonnephrotoxic medication) as a contrast agent and evaluate its use in the assessment of allograft vascular patency in patients with graft dysfunction, either delayed or slow graft function within hours to days after kidney transplantation or acute kidney injury weeks to months after kidney transplantation. METHODS: Sixteen kidney transplant recipients were retrospectively identified who underwent ferumoxytol-enhanced MRA after a nondiagnostic ultrasound for kidney dysfunction after transplantation. Image evaluation was performed by two radiologists, and clinical follow-up data were collected. RESULTS: In 1 of 16 subjects, MRA with ferumoxytol demonstrated complete arterial occlusion of an allograft. In 2 of 16 subjects, MRA detected moderate to severe anastomotic stenoses, which were confirmed at catheter angiography and successfully treated, resulting in the improvement of graft function. In 13 of 16 subjects, MRA demonstrated normal graft vasculature, and an alternative cause of allograft dysfunction was ultimately confirmed. CONCLUSIONS: Our study suggests that ferumoxytol-enhanced MRA may be a novel, safe method to accurately detect graft artery abnormalities in renal transplant recipients without the risk of nephrotoxicity, when transplant ultrasound is nondiagnostic. PMID- 23680932 TI - Mucosal pH, dental findings, and salivary composition in pediatric liver transplant recipients. AB - BACKGROUND: Oral health and dental maintenance have become part of the standard of care for pediatric liver transplant recipients. These individuals tend to suffer particularly from dental problems, such as gingival enlargement, gingivitis, poor oral hygiene, dental hypoplasia, and caries. Saliva composition influences oral hygiene and disease states. We investigated saliva composition and its association with the oral health of young recipients of liver transplants. METHODS: In 70 patients, 36 liver transplant recipients (ages 2-23 years) and 34 healthy controls (ages 4-21 years), we measured the following variables: (a) oral hygiene, (b) gingival inflammation, (c) caries status, (d) dental calculus formation, (e) oral mucosal pH, and (f) salivary protein composition. RESULTS: Lower mean decayed, missing, and filled teeth index (P=0.0038), higher mean gingival index (P=0.0001), and higher mean calculus score (P=0.003) were found in the transplanted study group compared with the control. The mean mucosal pH for seven intraoral sites was higher in the transplant group (P=0.0006). The median salivary albumin concentration was significantly lower in the transplant group (P=0.01), as was the median salivary albumin/total protein ratio (P=0.0002). CONCLUSIONS: In post-liver transplant pediatric recipients, low incidence of caries, together with high incidence of dental calculus, could be attributed to elevated oral mucosal pH. Salivary albumin and immunoglobulin A levels were relatively low in these patients. Clinicians should pay particular attention to the oral health and dental care of liver transplanted children. PMID- 23680934 TI - Enhancing of intensity of fluorescence by DEP manipulations of polyaniline-coated Al2O3 nanoparticles for immunosensing. AB - A novel modification of low-cost Al2O3 nanoparticles (Al2O3 NPs) for antibody protein immunosensing is proposed. The modified NPs are utilized to enhance the intensity of fluorescence in a dielectrophoretic (DEP) chip with a microelectrode array. The surface of the Al2O3 NPs is modified by ionic polyaniline (PANDB) rather than the conventional silane (3-aminopropyltrimethoxysilane) to conjugate the antibody on the outer shell. After the PANDB-Al2O3 NPs is functionalized to form probes, a DEP chip with a vertical non-uniform electric field that is produced by top and bottom electrodes condenses and immobilizes the nanoprobes on the surface of the electrodes by positive DEP force for immunosensing of the fluorescent protein. Additionally, each microelectrode array can be individually controlled with/without DEP manipulation using a computer program. Experimental results indicate that PANDB-based nanoprobes provide more rapid and sensitive immunosensing than those having undergone conventional silane modification. During immunosensing, fluorescence intensity can be doubled by the application of extra DEP force. The individual control of NPs on the microelectrode array has great potential for applications in multi-antibody arrays in a single chip for immunosensing. PMID- 23680935 TI - A new insight into electrochemical microRNA detection: a molecular caliper, p19 protein. AB - microRNA (miRNA) has drawn a great attention in biomedical research due to its functions on biological processes. Detection of miRNAs is a big challenge since the amount present in real samples is very low and the length of them is short. In this study, for the first time an electrochemical biosensor for detection of mir21 using the oxidation signal of protein 19 (p19) as a molecular caliper was designed. The proposed method enables detection of mir21 in direct, rapid, sensitive, inexpensive and label-free way. Binding specificity of the p19 to 20 23 base pair length double stranded RNA (dsRNA) and direct/water-mediated intermolecular contacts between the fusion protein and miRNA allows detection of miRNA-antimiRNA hybrid structure. The detection of mir21 was achieved in picomole sensitivity through the changes of intrinsic p19 oxidation signals observed at +0.80 V with Differential Pulse Voltammetry (DPV) and the specifity of the designed sensor was proved by control studies. PMID- 23680933 TI - Macrophage folate receptor-targeted antiretroviral therapy facilitates drug entry, retention, antiretroviral activities and biodistribution for reduction of human immunodeficiency virus infections. AB - Macrophages serve as vehicles for the carriage and delivery of polymer-coated nanoformulated antiretroviral therapy (nanoART). Although superior to native drug, high drug concentrations are required for viral inhibition. Herein, folate modified ritonavir-boosted atazanavir (ATV/r)-encased polymers facilitated macrophage receptor targeting for optimizing drug dosing. Folate coating of nanoART ATV/r significantly enhanced cell uptake, retention and antiretroviral activities without altering cell viability. Enhanced retentions of folate-coated nanoART within recycling endosomes provided a stable subcellular drug depot. Importantly, up to a five-fold enhanced plasma and tissue drug levels followed folate-coated formulation injection in mice. Folate polymer encased ATV/r improves nanoART pharmacokinetics bringing the technology one step closer to human use. FROM THE CLINICAL EDITOR: This team of authors describes a novel method for macrophage folate receptor-targeted antiretroviral therapy. Atazanvir entry, retention, and antiretroviral activities were superior using the presented method, and so was its biodistribution, enabling a more efficient way to address human immunodeficiency virus infections, with a hoped for clinical application in the near future. PMID- 23680936 TI - A new quantitative experimental approach to investigate single cell adhesion on multifunctional substrates. AB - Cell adhesion is fundamental for the organization of cells in multicellular organisms since it has a key role in several physiological functions that drive tissue formation and development. A better knowledge of the affections that influence the adhesion capability of cells in several pathologies, such as cancer diseases or multiple sclerosis could enable the development of new therapeutical strategies. Whereas the optimal control of cell adhesion and growth on new technological materials is a primary issue in modern tissue engineering, few techniques are able to provide quantitative and reliable results on cell adhesion. We present a method that enables the investigation of cell adhesion at the single cell level and provides the capability to test the adhesion of a single cell on multifunctional substrates. To reach this goal we applied single cell force spectroscopy (SCFS) on custom designed patterns of molecules prepared on a rigid substrate by using a cantilever based molecule deposition tool, and we tested the adhesion of Chinese Hamster Ovary cells and Human Embrionic Kidney cells on two polyelectrolytes that are widely used as adhesive factors for cells growth: Polyethylenimine and Poly-D-Lysine. Our results confirm the common hypothesis on the mechanism of adhesion promotion by protonated molecules. Optimizations of the experimental settings of SFCS experiment are introduced here. The presented technique offers the unique opportunity to be extended to the study of cell adhesion on an unlimited number molecular species. PMID- 23680937 TI - Isokinetic eccentric resistance training prevents loss in mechanical muscle function after running. AB - The aim of the study was to verify whether 8 weeks of resistance training employing maximal isokinetic eccentric (IERT) knee extensor actions would reduce the acute force loss observed after high-intensity treadmill running exercise. It was hypothesized that specific IERT would induce protective effects against muscle fatigue and ultrastructural damages, preventing or reducing the loss in mechanical muscle function after running. Subjects were tested before and after IERT protocol for maximal isometric, concentric and eccentric isokinetic knee extensor strength (60 degrees and 180 degrees s(-1)). In a second session, subjects performed treadmill running (~35 min) and the previously mentioned measurements were repeated immediately after running. Subsequently, subjects were randomized to training (n = 12) consisting of 24 sessions of maximal IERT knee extensors actions at 180 degrees s(-1), or served as controls (n = 8). The effects of acute running-induced fatigue and training on isokinetic and isometric peak torque, and rate of force development (RFD) were investigated. Before IERT, running-induced eccentric torque loss at 180 degrees s(-1) was -8 %, and RFD loss was -11 %. Longitudinal IERT led to reduced or absent acute running-induced losses in maximal IERT torque at 180 degrees s(-1) (+2 %), being significantly reduced compared to before IERT (p < 0.05), however, RFD loss remained at -11 % (p > 0.05). In conclusion, IERT yields a reduced strength loss after high intensity running workouts, which may suggest a protective effect against fatigue and/or morphological damages. However, IERT may not avoid reductions in explosive muscle actions. In turn, this may allow more intense training sessions to be performed, facilitating the adaptive response to running training. PMID- 23680938 TI - Is urinary specific gravity a useful simple marker of fluid depletion in athletes? PMID- 23680939 TI - Authors' response. Comparison between blood and urinary fluid balance indices during dehydrating exercise and the subsequent hypohydration when fluid is not restored. PMID- 23680940 TI - Mediterranean diet, cognitive function, and dementia: a systematic review. AB - BACKGROUND: Adherence to a Mediterranean diet has been associated with lower risk of various age-related diseases including dementia. Although narrative reviews have been published, no systematic review has synthesized studies on the association between Mediterranean diet adherence and cognitive function or dementia. METHODS: We conducted a systematic review of 11 electronic databases (including Medline) of published articles up to January 2012. Reference lists, selected journal contents, and relevant websites were also searched. Study selection, data extraction, and quality assessment were performed independently by two reviewers using predefined criteria. Studies were included if they examined the association between a Mediterranean diet adherence score and cognitive function or dementia. RESULTS: Twelve eligible papers (11 observational studies and one randomized controlled trial) were identified, describing seven unique cohorts. Despite methodological heterogeneity and limited statistical power in some studies, there was a reasonably consistent pattern of associations. Higher adherence to Mediterranean diet was associated with better cognitive function, lower rates of cognitive decline, and reduced risk of Alzheimer disease in nine out of 12 studies, whereas results for mild cognitive impairment were inconsistent. CONCLUSIONS: Published studies suggest that greater adherence to Mediterranean diet is associated with slower cognitive decline and lower risk of developing Alzheimer disease. Further studies would be useful to clarify the association with mild cognitive impairment and vascular dementia. Long-term randomized controlled trials promoting a Mediterranean diet may help establish whether improved adherence helps to prevent or delay the onset of Alzheimer disease and dementia. PMID- 23680941 TI - Perfluorooctanoate and neuropsychological outcomes in children. AB - BACKGROUND: In animal studies, perfluorinated compounds affect fetal growth, development, viability, and postnatal growth. The limited epidemiologic findings on child neurobehavioral development are mixed. METHODS: We recruited and evaluated 320 children who participated in the C8 Health Project, a 2005-2006 survey in a Mid-Ohio Valley community highly exposed to perfluorooctanoate (PFOA) through contaminated drinking water. We examined associations among estimated in utero PFOA exposure, measured childhood PFOA serum concentration, and subsequent performance on neuropsychological tests 3-4 years later at ages 6-12 years. We assessed Intelligence Quotient (IQ) reading and math skills, language, memory and learning, visual-spatial processing, and attention. All multivariable linear regression models were adjusted for age, sex, home environment, test examiner, and maternal IQ. Models with measured childhood PFOA were additionally adjusted for child body mass index. RESULTS: Children in the highest as compared with lowest quartile of estimated in utero PFOA had increases in Full Scale IQ (beta 4.6, 95% confidence interval [CI] = 0.7-8.5) and decreases in characteristics of attention deficit/hyperactivity disorder as measured by the Clinical Confidence Index of Connors' Continuous Performance Test-II (beta -8.5, 95% CI = -16.1 to 0.8). There were negligible associations between PFOA and reading or math skills or neuropsychological functioning. CONCLUSION: These results do not suggest an adverse association between the levels of PFOA exposure experienced by children in this cohort and their performance on neuropsychological tests. PMID- 23680942 TI - GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine. AB - A single dose of the short-acting NMDA antagonist ketamine produces rapid and prolonged antidepressant effects in treatment-resistant patients with major depressive disorder (MDD), which are thought to occur via restoration of synaptic connectivity. However, acute dissociative side effects and eventual fading of antidepressant effects limit widespread clinical use of ketamine. Recent studies in medial prefrontal cortex (mPFC) show that the synaptogenic and antidepressant like effects of a single standard dose of ketamine in rodents are dependent upon activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling pathway together with inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3), which relieves its inhibitory in influence on mTOR. Here, we found that the synaptogenic and antidepressant-like effects of a single otherwise subthreshold dose of ketamine were potentiated when given together with a single dose of lithium chloride (a nonselective GSK-3 inhibitor) or a preferential GSK 3beta inhibitor; these effects included rapid activation of the mTORC1 signaling pathway, increased inhibitory phosphorylation of GSK-3beta, increased synaptic spine density/diameter, increased excitatory postsynaptic currents in mPFC layer V pyramidal neurons, and antidepressant responses that persist for up to 1 week in the forced-swim test model of depression. The results demonstrate that low, subthreshold doses of ketamine combined with lithium or a selective GSK-3 inhibitor are equivalent to higher doses of ketamine, indicating the pivotal role of the GSK-3 pathway in modulating the synaptogenic and antidepressant responses to ketamine. The possible mitigation by GSK-3 inhibitors of the eventual fading of ketamine's antidepressant effects remains to be explored. PMID- 23680944 TI - New research with diets and epilepsy. AB - The ketogenic diet is not a new treatment for the treatment of epilepsy, but the degree of literature now available seems to have given it a new lease of life. Over the past 12 years, there has been more scientific data on both benefits and effect of the ketogenic diet. Data demonstrate a clear benefit in efficacy. We also have a clearer idea in utilization, type of diet to use, and in whom. Questions however remain and further work is required, not least in recognizing likely candidates and in simplifying administration. PMID- 23680943 TI - Effect of serotonin on paired associative stimulation-induced plasticity in the human motor cortex. AB - Serotonin modulates diverse brain functions. Beyond its clinical antidepressant effects, it improves motor performance, learning and memory formation. These effects might at least be partially caused by the impact of serotonin on neuroplasticity, which is thought to be an important foundation of the respective functions. In principal accordance, selective serotonin reuptake inhibitors enhance long-term potentiation-like plasticity induced by transcranial direct current stimulation (tDCS) in humans. As other neuromodulators have discernable effects on different kinds of plasticity in humans, here we were interested to explore the impact of serotonin on paired associative stimulation (PAS)-induced plasticity, which induces a more focal kind of plasticity, as compared with tDCS, shares some features with spike timing-dependent plasticity, and is thought to be relative closely related to learning processes. In this single-blinded, placebo controlled, randomized crossover study, we administered a single dose of 20 mg citalopram or placebo medication and applied facilitatory- and excitability diminishing PAS to the left motor cortex of 14 healthy subjects. Cortico-spinal excitability was explored via single-pulse transcranial magnetic stimulation elicited MEP amplitudes up to the next evening after plasticity induction. After citalopram administration, inhibitory PAS-induced after-effects were abolished and excitatory PAS-induced after-effects were enhanced trendwise, as compared with the respective placebo conditions. These results show that serotonin modulates PAS-induced neuroplasticity by shifting it into the direction of facilitation, which might help to explain mechanism of positive therapeutic effects of serotonin in learning and medical conditions characterized by enhanced inhibitory or reduced facilitatory plasticity, including depression and stroke. PMID- 23680945 TI - A novel topical rapamycin cream for the treatment of facial angiofibromas in tuberous sclerosis complex. AB - Facial angiofibromas are dermatological manifestations of tuberous sclerosis complex, a neurocutaneous disorder characterized by excess cell growth and proliferation. Oral rapamycin has been used to treat visceral tuberous sclerosis related tumors; however, the side effect profile of this medicine precludes its routine use in patients lacking significant internal involvement. The authors formulated a novel rapamycin cream that is easy to compound and apply, does not cause local or systemic side effects, and results in a dramatic improvement of facial angiofibromas. PMID- 23680947 TI - Skin biopsy: a new tool to diagnose sarcoglycanopathy. AB - Muscular dystrophies are progressive, genetic disorders of muscle degeneration. The current gold standard for diagnosis is muscle biopsy or genetic studies. Muscle biopsy is an invasive procedure and genetic testing facilities are available only in a few centers. Thus, a diagnostic test that is easily available, simpler, and less invasive is desirable. Over the past 2 decades, skin biopsy has been evolving as a suitable option. Two cases of sarcoglycanopathy are described here, which have been correctly diagnosed by skin biopsy. Muscle biopsy has been used as the gold-standard diagnostic method. Skin biopsy can substitute for muscle biopsy as the preliminary diagnostic tool directing appropriate molecular testing. However, these results require validation in studies with an adequate sample size. This holds promise for the future when repeated biopsies will be required for evaluating protein rescue in trials of novel treatment options in these disorders. PMID- 23680946 TI - Ketogenic diets and pain. AB - Ketogenic diets are well established as a successful anticonvulsant therapy. Based on overlap between mechanisms postulated to underlie pain and inflammation, and mechanisms postulated to underlie therapeutic effects of ketogenic diets, recent studies have explored the ability for ketogenic diets to reduce pain. Here we review clinical and basic research thus far exploring the impact of a ketogenic diet on thermal pain, inflammation, and neuropathic pain. PMID- 23680948 TI - Treatment of diabetes and diabetic complications with a ketogenic diet. AB - Accumulating evidence suggests that low-carbohydrate, high-fat diets are safe and effective to reduce glycemia in diabetic patients without producing significant cardiovascular risks. Most of these studies have been carried out specifically restricting carbohydrates, which tends to lead to increased protein intake, thus reducing the ketosis. However, diets that limit protein as well as carbohydrates, entailing a composition very high in fat, appear even more effective to reduce glucose and whole-body glucose metabolism in humans. In animal models, low carbohydrate, high-protein diets do not produce ketosis or reduce glycemia but rather cause obesity. However, limiting both protein and carbohydrates as in a classic ketogenic diet remarkably reduces blood glucose in animal models of type 1 and type 2 diabetes and reverses diabetic nephropathy. Future studies should assess if ketogenic diets would be effective to reverse diabetic complications in humans. PMID- 23680949 TI - Learning curve for transoral robotic surgery: a 4-year analysis. AB - IMPORTANCE: As new institutions incorporate transoral robotic surgery (TORS) into their everyday practice, it is helpful to have a timeline reference of expected goals to follow as their experience increases. This article evaluates a single tertiary care academic institution's experience with TORS for head and neck tumors and reports its 4-year learning curve. OBJECTIVE: To evaluate a single institution's experience with TORS over a 4-year period and report treatment trends and clinical outcomes. DESIGN: Prospective case study. SETTING: A single tertiary care academic institution. PARTICIPANTS: A total of 168 patients underwent TORS for tumors of the head and neck at University of Alabama at Birmingham between March 2007 and September 2011. The total group was subdivided into 4 consecutive groups (42 patients each). Patients were monitored throughout their hospital stay and up to 4.5 years postoperatively (mean follow-up duration, 14 months). INTERVENTION: Transoral robotic surgery. MAIN OUTCOMES AND MEASURES: Data points were collected and compared over time, including feasibility, operative time, tumor type, stage, subsite, length of intubation, need for tracheostomy, feeding tube use, hospital stay, margin status, neck dissection performed, and postoperative complications. RESULTS: Significant decreases in operative time, length of intubation, and hospital stay were seen as TORS experience increased. Overall, the mean operative time decreased by 47% (group 4, 86 minutes; group 1, 183 minutes). Total mean intubation time decreased by 87% (group 1, 12.9 hours; group 4, 1.7 hours) and mean hospital stay decreased from 3.0 days to 1.4 days. There was not a significant difference between groups in number of cases unable to be performed robotically (7-9 per group), tumor stage (majority T1/T2), tumor subsite (majority oropharynx), positive margin status (2 5 per group), number of salvage cases performed (7-9 per group), and number of tracheostomies (2-4 per group) or feeding tubes (22-25 per group) required. CONCLUSIONS AND RELEVANCE: This is the first multiyear prospective study to document a single institution's TORS experience over time and demonstrate particular areas of expected improvement as case number increases. PMID- 23680951 TI - Travelling around the world with interventional cardiology. PMID- 23680950 TI - Degradation dynamics of emamectin benzoate on cabbage under subtropical conditions of Punjab, India. AB - Emamectin benzoate (Proclaim 5 SG) was applied to cabbage at 8.5 and 17 g a.i. ha 1, during the head initiation stage. A high performance liquid chromatography (HPLC) analytical method, for the determination of emamectin benzoate in cabbage, was developed. Average recoveries of emamectin benzoate ranged from 92 % to 96 % at different fortification levels (0.05, 0.25 and 0.50 mg kg-1). The initial deposits, 0.11 and 0.21 mg kg-1 of emamectin benzoate at 8.5 and 17 g a.i. ha-1, dissipated below the determination limit of 0.05 mg kg-1 in 3 and 5 days, respectively. PMID- 23680952 TI - The devil is in the details: further steps towards surgical standards with Mitral Clip management? PMID- 23680953 TI - North American view on the European Sentinel Registry of the Transcatheter Valve Implantation pilot study. PMID- 23680954 TI - Building bridges for tomorrow: the EAPCI and YOUNG Interventionalists. PMID- 23680955 TI - Highlights from The Experts "Live", 4th annual congress of the Euro CTO Club, London 2012. PMID- 23680956 TI - Emerging indications, in-hospital and long-term outcome of balloon aortic valvuloplasty in the transcatheter aortic valve implantation era. AB - AIMS: The introduction of transcatheter aortic valve implantation (TAVI) has generated a renewed interest in the treatment of high-risk patients with severe aortic stenosis. This study describes the indications and long-term outcome of balloon aortic valvuloplasty (BAV) in recent years. METHODS AND RESULTS: Between 2000 and 2010, 415 consecutive patients at our institution underwent BAV. The number of BAV per year increased sharply after the introduction of TAVI. Patients were 77.5+/-10.9 years old and showed important comorbidities (average logistic EuroSCORE=23.9+/-15.3%). We identified four cohorts according to the indications: 1) bridge for TAVI (B-TAVI; n=162); 2) bridge for aortic valve replacement (B AVR, n=97); 3) cardiogenic shock (n=23); 4) palliation (n=133). Baseline characteristics were significantly different among groups. In-hospital mortality was 5.1%, and occurred predominantly in patients who underwent BAV in the setting of cardiogenic shock (56.5% vs. around 2% in the other subgroups). Other major events were stroke (0.5%), major vascular complications (2.2%), and life threatening bleedings (1.5%). The cumulative one-year and two-year mortality rates were 33.2% and 57.4%, respectively, with the highest incidence in the shock group (70.7% and 80.4%) and the lowest in the B-AVR group (21.7% and 38.4%). Rehospitalisation for heart failure was 26.3% at one-year and 47.2% at two-year follow-up. CONCLUSIONS: The number of BAV is increasing, mainly due to increased referral of high-risk patients and to the emerging indication of bridge for TAVI. In this complex population, BAV is relatively safe but two-year survival remains poor, and more effective and definitive treatments should be pursued in a timely fashion. PMID- 23680957 TI - AngioJet rheolytic thrombectomy in patients presenting with high-risk pulmonary embolism and cardiogenic shock: a feasibility pilot study. AB - AIMS: Pulmonary embolism (PE) associated with haemodynamic instability has exceedingly high mortality. While intravenous thrombolysis is considered the therapy of choice, percutaneous mechanical thrombectomy may represent an alternative treatment. METHODS AND RESULTS: The impact of AngioJet(r) rheolytic thrombectomy (RT) in PE associated with cardiogenic shock was assessed in a single-centre prospective pilot study. Ten consecutive PE patients in cardiogenic shock were included in the study. Six patients had thrombolysis contraindications, eight were intubated before the RT procedure and six had experienced cardiac arrest prior to the RT procedure. The RT procedure was technically successful in all cases. The Miller index improved from 25 to 20 (p=0.002). The shock index decreased from 1.22 to 0.9 (p=0.129). Thrombolytic agents were administered during or after the procedure in four patients because of progressive clinical deterioration. Seven patients died in the first 24 hours: two from multi-organ failure, one from post-anoxic cerebral oedema, and four from progressive right heart failure. The three survivors had favourable outcomes at one year. CONCLUSIONS: This study suggests that the AngioJet(r) RT procedure may be safely performed in PE patients with cardiogenic shock. However, despite angiographic and haemodynamic improvements, the procedure does not appear to influence the dismal prognosis of these high-risk patients. PMID- 23680958 TI - Direct comparison between coronary computed tomography and invasive angiography for calculation of SYNTAX score. AB - AIMS: We aimed to test the feasibility of calculating SYNTAX score from coronary computed tomographic angiography (CCTA) compared to from invasive coronary angiography (ICA). METHODS AND RESULTS: SYNTAX score was independently and blindly calculated from CCTA and from ICA in 104 patients, age 57+/-10, with significant (>50%) stenoses in 1.7+/-0.7 vessels. The level of agreement was assessed by Cohen's kappa. Agreement between ICA and CCTA for conventional vessel based analysis (presence of >50% stenosis per vessel) was substantial with kappa=0.66 and sensitivity, specificity and accuracy of 74%, 90% and 80%, respectively. The mean SYNTAX score was 14.2+/-10.0 by ICA and 10.3+/-6.9 by CCTA, with a significant underestimation of 3.9+/-8.2 by CCTA (p<0.001). Weighted kappa was 0.33, indicating only fair agreement. When only good quality CCTA were included, kappa improved to 0.56. Analysis of the cause of the bias showed ICA to identify more lesions per patient (2.2+/-1.3 vs. 1.7+/-1.0, p<0.001), while the mean score per lesion was not different (6.4 vs. 5.9, p=ns). CONCLUSIONS: CCTA, despite having a good agreement with ICA by conventional vessel-based analysis, showed only fair agreement for the calculation of SYNTAX score, and cannot be currently used as a substitute for diagnostic ICA for this purpose. PMID- 23680959 TI - Bioresorbable drug-eluting magnesium-alloy scaffold: design and feasibility in a porcine coronary model. AB - AIMS: Among three versions of bioresorbable magnesium scaffolds featuring different paclitaxel-elution kinetics, we determined the best-performing scaffold and compared it with established, paclitaxel-eluting, permanent stents TAXUS Liberte and eucaTAX. METHODS AND RESULTS: Drug-elution kinetics in magnesium scaffolds were modulated by varying the composition of their bioresorbable poly(lactide-co-glycolide) coating loaded with paclitaxel. A 50:50 ratio of lactide to glycolide, or an 85:15 ratio and either high- or low-molecular-weight polymer was applied in the "50/50", "85/15H", and "85/15L" scaffolds, respectively. Seventy-three magnesium scaffolds (25 50/50, 24 85/15H, 24 85/15L) and 36 control stents (18 TAXUS Liberte, 18 eucaTAX) were implanted in coronary arteries of 50 Yucatan mini-pigs. Angiography, histomorphometry, and histopathology data were acquired at 28, 90 and 180 days. The best-performing magnesium scaffold, 85/15H, was equivalent to TAXUS Liberte and superior to eucaTAX regarding late luminal loss, intimal area, fibrin score, and endothelialisation. Intimal inflammation score was higher in 85/15H than in the control stents at 28 days, but this effect disappeared at later time points. CONCLUSIONS: By selecting suitable paclitaxel-elution kinetics, it was feasible to develop a bioresorbable magnesium scaffold whose efficacy and healing characteristics in a porcine coronary model are comparable with those of established paclitaxel-eluting permanent metallic stents. PMID- 23680960 TI - Advanced three-dimensional quantitative coronary angiographic assessment of bifurcation lesions: methodology and phantom validation. AB - AIMS: Validation of new three-dimensional (3-D) bifurcation quantitative coronary angiography (QCA) software. METHODS AND RESULTS: Cardiovascular Angiography Analysis System (CAAS 5v10) allows 3-D angiographic reconstructions based on two or more 2-D projection images. Measurements for minimal lumen diameter (MLD), reference vessel diameter (RVD), percent diameter stenosis (DS) and bifurcation angle (BA) were validated against precision manufactured phantom bifurcations. Length measurements were validated against angiographic measurement catheters inserted into a plexiglas bifurcation phantom. In 3-D reconstructions based on two 2-D images, acquired at variable rotation and angulation, accuracy and precision (mean difference +/- SD) of the 11-segment model for MLD, RVD and DS were 0.013+/-0.131 mm, -0.052+/-0.039 mm and -1.08+/-5.13%, respectively; inter observer variability was 0.141 mm, 0.058 mm and 5.42%, respectively. Adding the antero-posterior (optimal) projection to these basic reconstructions resulted in reduced variability (0.101 mm, 0.041 mm and 3.93% for MLD, RVD and DS, p<0.01 for all) and showed a trend towards improved precision (0.109 mm, 0.031 mm and 4.26%, respectively, p>0.05 for all). In basic reconstructions, accuracy and precision for BA was -1.3+/-5.0 degrees , whereas inter-observer variability was 7.5 degrees ; respective measures for length were 0.15+/-0.26 mm and 0.54 mm. Adding the antero-posterior projection resulted in decreased precision (0.47 mm, p<0.01) and increased variability (1.03 mm, p<0.01) for length measurements; precision (5.4 degrees ) and variability (7.9 degrees ) for BA did not change significantly (p>0.30). CONCLUSIONS: Advances in the methodology of 3-D reconstruction and quantitative analysis for bifurcation lesions translated into highly accurate, precise and reproducible measures of diameter, length and BA. PMID- 23680961 TI - Relation of angiographic side branch calibre to myocardial mass: a proof of concept myocardial infarct index. AB - Elevation of biomarkers and ischaemia after coronary stenting of a bifurcation is not uncommon due to side branch (SB) occlusion. Hence, it is important to understand the relation between the lumen calibre of the SB and the myocardial mass affected. The objective of this proof of concept perspective is to provide a formulation for the relation between the SB calibre and perfused myocardial mass based on experimentally-validated scaling laws. A lumen calibre-mass scaling law provides a nearly linear relation between cross-sectional area of SB and the myocardial mass at risk. It is clinically known that the larger the diameter of the SB the more myocardial mass is at risk. The present analysis formulates this notion quantitatively and provides a simple relation where the %infarct can be determined directly from the angiographic cross-sectional area of SB. This relation can help guide the decision for bifurcation stenting where the SB may be at risk for occlusion. This brief proof of concept perspective provides a basis for future human studies that may demarcate the calibre (and hence myocardial mass) in relation to cardiac biomarkers as a cut-off for treatment of SB. PMID- 23680962 TI - Visualisation of a coronary stent presenting late mechanical failure in an aberrant left circumflex artery with coronary computed tomography angiography and optical coherence tomography. PMID- 23680963 TI - Structural polymorphism in self-assembled networks of a triphenylene based macrocycle. AB - Understanding and controlling the structural polymorphism in self-assembled networks of functional molecules merit special attention. In this contribution, we describe the concentration controlled structural evolution in self-assembled monolayers of a large triangular discotic macrocycle at the liquid-solid interface. Scanning tunneling microscopy (STM) reveals that the adlayers formed by an alkoxy substituted cyclo-tris(7,9-triphenylenylene) macrocycle exhibit concentration dependent 2D phase behavior at the 1,2,4-trichlorobenzene/HOPG interface. The self-assembled network evolves from high-density linear packing which is formed at relatively high concentrations to a low-density porous pattern at lower concentrations. A trimeric hexagonal phase exists at intermediate concentrations examined. The transformation of the trimeric hexagonal phase to the linear phase could be monitored by recording time-dependent STM images. The self-assembly behavior is affected significantly by the choice of the organic solvent where an amorphous network is formed along with high-density linear packing at the 1-phenyloctane/HOPG interface. The results presented here provide detailed insight into the polymorphism phenomenon exhibited by an organic semiconductor and furnish general guidelines to control the morphology of thin films of such technologically important materials. PMID- 23680966 TI - Racial and ethnic differences in outcomes in older patients with acute ischemic stroke. AB - BACKGROUND: Little is known as to whether long-term outcomes of acute ischemic stroke (AIS) vary by race/ethnicity. Using the American Heart Association Get With The Guidelines-Stroke registry linked with Medicare claims data set, we examined whether 30-day and 1-year outcomes differed by race/ethnicity among older patients with AIS. METHODS AND RESULTS: We analyzed 200 900 patients with AIS >65 years of age (170 694 non-Hispanic whites, 85.0%; 20 514 non-Hispanic blacks, 10.2%; 6632 Hispanics, 3.3%; 3060 non-Hispanic Asian Americans, 1.5%) from 926 US centers participating in the Get With The Guidelines-Stroke program from April 2003 through December 2008. Compared with whites, other racial and ethnic groups were on average younger and had a higher median score on the National Institutes of Health Stroke Scale. Whites had higher 30-day unadjusted mortality than other groups (white versus black versus Hispanic versus Asian=15.0% versus 9.9% versus 11.9% versus 11.1%, respectively). Whites also had higher 1-year unadjusted mortality (31.7% versus 28.6% versus 28.1% versus 23.9%, respectively) but lower 1-year unadjusted all-cause rehospitalization (54.7% versus 62.5% versus 60.0% versus 48.6%, respectively). After risk adjustment, Asian American patients with AIS had lower 30-day and 1-year mortality than white, black, and Hispanic patients. Relative to whites, black and Hispanic patients had higher adjusted 1-year all-cause rehospitalization (black: adjusted odds ratio, 1.28 [95% confidence interval, 1.21-1.37]; Hispanic: adjusted odds ratio, 1.22 [95% confidence interval, 1.11-1.35]), whereas Asian patients had lower odds (adjusted odds ratio, 0.83 [95% confidence interval, 0.74-0.94]). CONCLUSIONS: Among older Medicare beneficiaries with AIS, there were significant differences in long-term outcomes by race/ethnicity, even after adjustment for stroke severity, other prognostic variables, and hospital characteristics. PMID- 23680965 TI - Regional density of cardiologists and rates of mortality for acute myocardial infarction and heart failure. AB - BACKGROUND: Cardiologists are distributed unevenly across regions of the United States. It is unknown whether patients in regions with fewer cardiologists have worse outcomes after hospitalization for acute myocardial infarction (AMI) or heart failure (HF). METHODS AND RESULTS: Using Medicare administrative claims data from 2010, we examined the relationship between regional density of cardiologists and risk of death after hospitalization for AMI and HF using hospitalizations for pneumonia as a comparison. We defined density as the number of cardiologists divided by population aged>=65 years within hospital referral regions, categorized into quintiles. Among 171 126 admissions for AMI, 352 853 admissions for HF, and 343 053 admissions for pneumonia, we tested associations between density of cardiologists and 30-day and 1-year mortality for each condition. We used 2-level hierarchical logistic regression models that adjusted for characteristics of patients and hospital referral regions. Patients hospitalized for AMI (odds ratios [OR], 1.13; 95% confidence interval [CI], 1.06 1.21) and HF (OR, 1.19; 95% CI, 1.12-1.27) in the lowest quintile of density had modestly higher 30-day mortality risk compared with patients in the highest quintile, unlike patients hospitalized for pneumonia (OR, 1.02; 95% CI, 0.96 1.09). Patients hospitalized for AMI (OR, 1.06; 95% CI, 1.00-1.12) and HF (OR, 1.09; 95% CI, 1.04-1.13) in the lowest quintile had slightly higher 1-year mortality risk, unlike patients hospitalized for pneumonia (OR, 1.00; 95% CI, 0.95-1.05). CONCLUSIONS: Patients hospitalized for AMI and HF in regions with a low density of cardiologists experienced modestly higher 30-day and 1-year mortality risk, unlike patients with pneumonia. PMID- 23680964 TI - How plants LINC the SUN to KASH. AB - Linkers of the nucleoskeleton to the cytoskeleton (LINC) complexes formed by SUN and KASH proteins are conserved eukaryotic protein complexes that bridge the nuclear envelope (NE) via protein-protein interactions in the NE lumen. Revealed by opisthokont studies, LINC complexes are key players in multiple cellular processes, such as nuclear and chromosomal positioning and nuclear shape determination, which in turn influence the generation of gametes and several aspects of development. Although comparable processes have long been known in plants, the first plant nuclear envelope bridging complexes were only recently identified. WPP domain-interacting proteins at the outer NE have little homology to known opisthokont KASH proteins, but form complexes with SUN proteins at the inner NE that have plant-specific properties and functions. In this review, we will address the importance of LINC complex-regulated processes, describe the plant NE bridging complexes and compare them to opisthokont LINC complexes. PMID- 23680967 TI - Programming nanostructured soft biological surfaces by atomic layer deposition. AB - Here, we present the first successful attempt to programme the surface properties of nanostructured soft biological tissues by atomic layer deposition (ALD). The nanopatterned surface of lotus leaf was tuned by 3-125 nm TiO2 thin films. The lotus/TiO2 composites were studied by SEM-EDX, XPS, Raman, TG-DTA, XRR, water contact angle and photocatalysis measurements. While we could preserve the superhydrophobic feature of lotus, we managed to add a new property, i.e. photocatalytic activity. We also explored how surface passivation treatments and various ALD precursors affect the stability of the sensitive soft biological tissues. As we were able to gradually change the number of nanopatterns of lotus, we gained new insight into how the hollow organic nanotubes on the surface of lotus influence its superhydrophobic feature. PMID- 23680968 TI - Quinoline-based fluorescent zinc sensors with enhanced fluorescence intensity, Zn/Cd selectivity and metal binding affinity by conformational restriction. AB - Two cyclohexanediamine-based tetrakisquinoline derivatives, N,N,N',N'-tetrakis(2 quinolylmethyl)-trans-1,2-cyclohexanediamine (TQDACH) and N,N,N',N'-tetrakis(1 isoquinolylmethyl)-trans-1,2-cyclohexanediamine (1-isoTQDACH), have been prepared and their zinc-induced fluorescent response was investigated. In DMF-H2O (1 : 1) solution, TQDACH exhibits increase of fluorescence at 455 nm in the presence of 1 eq. of zinc ion (lambda(ex) = 317 nm, phi = 0.010). Similarly, 1-isoTQDACH exhibited fluorescence enhancement upon binding with zinc (lambda(ex) = 325 nm, lambda(em) = 352 and 475 nm, phi = 0.032). The fluorescence intensity ratio induced by cadmium relative to zinc (I(Cd)/I(Zn)) for these 1,2 cyclohexanediamine probes is lower than those for the corresponding ethylenediamine derivatives, TQEN and 1-isoTQEN. Crystal structures of the zinc and cadmium complexes of TQDACH and 1-isoTQDACH reveal the superior metal binding ability of the 1,2-cyclohexanediamine and isoquinoline moieties in comparison to ethylenediamine and quinoline. The conformational restriction afforded by the 1,2 cyclohexanediamine skeleton upon zinc binding leads to enhanced fluorescence intensity and strong metal binding affinity. PMID- 23680970 TI - What are the optimal treatment courses for geriatric anxiety, and how do we find out? PMID- 23680969 TI - The randomized shortened dental arch study: oral health-related quality of life. AB - OBJECTIVES: Although the shortened dental arch (SDA) concept is a widely accepted strategy to avoid overtreatment, little is known on its impact on oral health related quality of life (OHRQoL). This multicenter randomized controlled trial aimed to investigate the OHRQoL for removable partial dental prostheses (RPDP) with molar replacement versus the SDA concept. MATERIAL AND METHODS: In both groups, missing anterior teeth were replaced with fixed dental prosthesis. Two hundred fifteen patients with bilateral molar loss in at least one jaw were included. The Oral Health Impact Profile (OHIP-49) was completed before; 6 weeks (baseline), 6 months, and 12 months after treatment; and thereafter annually until 5 years. RESULTS: Of the initial cohort, 81 patients were assigned to the RPDP group and 71 to the SDA group (age, 34 to 86 years). Before treatment, the median OHIP score was similar in both groups (RPDP, 38.0; SDA, 40.0; n.s.). Results indicate marked improvements in OHRQoL in both groups between pretreatment and baseline (RPDP, 27.0; SDA, 19.0; p <= 0.0001) which continued in the RPDP group until the 1-year follow-up (p = 0.0002). These significant reductions in OHIP scores are reflected in its subscales. No further differences were seen within and between groups during the remainder observation period. CONCLUSION: Both treatments show a significant improvement in OHRQoL which continued in the RPDP group until the 1-year follow-up. No significant differences were seen between groups. CLINICAL RELEVANCE: For improving OHRQoL, it is not necessary to replace missing molars with a RPDP. PMID- 23680971 TI - Disinfection of rigid nasal endoscopes following in vitro contamination with Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa, and Haemophilus influenzae. AB - IMPORTANCE: If not adequately cleaned, rigid nasal endoscopes (RNEs) have the potential to cause iatrogenic cross-contamination. OBJECTIVE: To test the efficacy of various disinfection methods in reducing bacterial load on RNEs in vitro. DESIGN AND SETTING: In vitro model. INTERVENTIONS: Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa, and Haemophilus influenzae contamination was separately induced on RNEs in vitro. Two experimental sets were completed. The RNEs were disinfected using the following protocols: 30-second scrub with antimicrobial soap (ABS) and water, 30-second scrub with 70% isopropyl alcohol (IA), 30-second scrub with ABS followed by 30-second scrub with IA, 30 second scrub with germicidal cloth, isolated 5-minute soak in an enzymatic soap solution, 5- and 10-minute soaks in ortho-phthalaldehyde, 0.55%, solution (Cidex OPA), and isolated 30-second rinse with tap water, all with 30-second precleaning and postcleaning rinses with tap water. Two sets of experiments (experiment sets A and B) were carried out with a 30-second tap water rinse after inoculation of each RNE. This was followed by immediate cleaning in set A and a 1-hour air-dry delay in set B. Otherwise there were no differences in the disinfection protocols between sets for each method noted. MAIN OUTCOMES AND MEASURES: Effectiveness of various disinfection protocols in cleaning rigid nasal endoscopes experimentally inoculated with bacteria commonly found in the upper aerodigestive tract. Positive cultures following disinfection indicated ineffective or incomplete disinfection. RESULTS: Most cleaning methods were effective in eliminating S aureus, S pneumoniae, and H influenzae from the scopes following experimental contamination. Continued growth of P aeruginosa was found after all of the disinfection trials in experiment set A with the exception of a 10-minute immersion in Cidex OPA, and in set B except for the 10-minute Cidex OPA immersion and ABS plus IA trials. CONCLUSIONS AND RELEVANCE: Most cleaning methods used in our trials appear to properly disinfect RNEs after in vitro inoculation with S aureus, S pneumoniae, and H influenzae. However, it appears that disinfectants may be less effective in cleaning rigid scopes experimentally inoculated with P aeruginosa. There is a paucity of published data regarding cross-contamination during rigid nasal endoscopy, and these results should guide future studies and to some extent practice to avoid iatrogenic spread of contamination. PMID- 23680972 TI - Simulated degradation of biochar and its potential environmental implications. AB - A simulated oxidation technique was used to examine the impacts of degradation on the surface properties of biochar and the potential implications of the changes in biochar properties were discussed. To simulate the short- and long-term environmental degradation, mild and harsh degradation were employed. Results showed that after mild degradation, the biochar samples showed significant reductions in surface area and pore volumes. After harsh degradation, the biochar samples revealed dramatic variations in their surface chemistry, surface area, pore volumes, morphology and adsorption properties. The results clearly indicate that changes of biochar surface properties were affected by biochar types and oxidative conditions. It is suggested that biochar surface properties are likely to be gradually altered during environmental exposure. This implies that these changes have potential effects for altering the physicochemical properties of biochar amended soils. PMID- 23680973 TI - Arsenic K-edge X-ray absorption near-edge spectroscopy to determine oxidation states of arsenic of a coastal aquifer-aquitard system. AB - Determination of oxidation states of solid-phase arsenic in bulk sediments is a valuable step in the evaluation of its bioavailability and environmental fate in deposits, but is difficult when the sediments have low arsenic contents and heterogeneous distribution of arsenic species. As K-edge X-ray absorption near edge spectroscopy (XANES) was used to determine quantitatively the oxidation states of arsenic in sediments collected from different depths of boreholes in the Pearl River Delta, China, where the highest aquatic arsenic concentration is 161.4 MUg/L, but the highest solid arsenic content only 39.6 mg/kg. The results demonstrated that XANES is efficient in determining arsenic oxidation states of the sediments with low arsenic contents and multiple arsenic species. The study on the high-resolution vertical variations of arsenic oxidation states also indicated that these states are influenced strongly by groundwater activities. With the help of geochemical data, solid arsenic speciation, toxicity and availability were further discussed. PMID- 23680974 TI - Immunologic mechanism of Patchouli alcohol anti-H1N1 influenza virus may through regulation of the RLH signal pathway in vitro. AB - Patchouli alcohol (PA) is a kind of methanol extracted from traditional Chinese medicine Pogostemonis Herba. Our research aimed to observe the anti-influenza virus role of PA in vitro. 16HBE (human respiratory epithelial cell) was infected by H1N1 (A/FM1/1/47) to set the cell model. Then the 16HBE was co-cultivated with three kinds of immune cells: dendritic cells, macrophages, and monocytes, PA (the concentration is 10 MUg/mL) was added as a treatment intervention for 24 h. The immune cells and the supernate were collected for RT-PCR and ELISA detection related to RLH (RIG-1-like helicases) pathway. Results showed that the IL-4 and IFN-gamma in supernate were increased after H1N1 infection, and the PA treatment suppressed the expression of cytokines and the mRNA of RLH pathway. PA anti influenza virus may through regulate the RLH singal pathway. PMID- 23680975 TI - Two rep genes in small cryptic plasmid pKST21 of Escherichia coli. AB - The complete nucleotide sequence of a small cryptic plasmid pKST21 from Escherichia coli was determined. This plasmid is 1,460 bp long with an overall GC content of 51 %. Based on sequence analysis, the presence of two segments with different average GC density was observed. The segment with higher GC content revealed 98-90 % similarity to several small plasmids of E. coli and to pCR1 from Gram-positive Corynebacterium renale. Plasmid pKST21 possesses two conversely oriented open reading frames encoding proteins with a high degree of amino acid identity to Rep proteins involved in replication. ORF1 encodes replication protein similar to RepA protein of Bartonella tribocorum or Bacillus cereus plasmids or to the putative plasmid Rep protein from ecologically close Selenomonas ruminantium. ORF2 similarly encodes a replication protein, which shares 97 % homology with Rep protein from C. renale. Genetic diversity observed in plasmid pKST21 indicates a mosaic structure of the plasmid with different segments acquired from different sources. Deletion analysis showed that both fragments carrying the repA and repB genes are necessary for the replication of pKST21 in E. coli. The presence of plasmid with the same gene composition was revealed in 14 % of tested E. coli isolates from the rumen of sheep. All these strains produced identical ERIC-PCR profiles indicating isogenic origin of the strain and lack of horizontal gene transfer of pKST21 plasmid. PMID- 23680976 TI - Block allograft for reconstruction of alveolar bone ridge in implantology: a systematic review. AB - PURPOSE: The aim of this study was to evaluate the literature regarding clinical efficacy and predictability of block allograft for restoration of vertical and/or horizontal bone defects. MATERIALS AND METHODS: A literature search was conducted in PubMed/MEDLINE and Cochrane databases about studies reporting the use of block allografts. The review included studies published in English from 1960 to 2011 and excluded single-case reports and articles that did not use block allograft stabilized by fixation screws. RESULTS: The search revealed 567 articles, but only 14 were included, which were conducted in humans with a total of 194 patients treated with block allografts, totalizing 253 blocks. CONCLUSIONS: Although a high success rate has been reported for the bone allograft survival, this systematic review demonstrated low level of scientific evidence articles with short follow-up time and diversified methodology with difficult possibilities to compare their results. PMID- 23680977 TI - A method for obtaining a three-dimensional geometric model of dental implants for analysis via the finite element method. AB - PURPOSE: The aim of the study was to present a methodology of development of a virtual 3-dimensional dental implant model for analyses via the finite element method. MATERIALS AND METHODS: A set, consisting of a dental implant and abutment, was embedded in acrylic resin for subsequent metallographic grinding and polishing. After the evidentiation of the internal geometry of the implant, the specimen was treated in a sputter for observation using scanning electron microscopy (SEM). The SEM image was transported to computer-aided design software by which all details of the implant were measured. With the measures obtained, the geometry was reproduced with 3-dimensional modeling software. Finally, the model was imported into finite element method analysis software with which it was discretized, generating a mesh. RESULTS: A model with the accurate geometry of the implant was developed. A mesh of 297,600 elements and 490,045 nodes was generated. An aleatory acceleration simulation was performed to test the mesh, and no errors were identified. CONCLUSION: The developed methodology generated a precise dental implant model, which can be applied in different finite element method simulations. PMID- 23680978 TI - Local tissue ischemia is not necessary for suture-induced adhesion formation. AB - BACKGROUND: We investigated the hypothesis that local tissue ischemia is responsible for suture-induced adhesion formation. METHODS: A total of 160 interrupted sutures were placed in the parietal peritoneum of 20 Wistar rats. The animals were randomized into an ischemia group, where the sutures were pulled tight and a non-ischemia group, where the sutures were tied as loose loops with air knots to avoid any local ischemia. The midline laparotomy was closed with a running suture. On postoperative day 10, adhesions to the sutures were counted. RESULTS: There was no statistically significant difference in the number of adhesions forming to sutures with local ischemia (n = 66/80) versus sutures without local ischemia (n = 69/80). CONCLUSION: We conclude that local tissue ischemia is not necessary for suture-induced adhesion formation and propose an additional mechanical mechanism to explain how suture knots can predispose to adhesiogenesis. PMID- 23680980 TI - Protein engineering of oxidosqualene-lanosterol cyclase into triterpene monocyclase. AB - A computational modeling/protein engineering approach was applied to probe H234, C457, T509, Y510, and W587 within Saccharomyces cerevisiae oxidosqualene lanosterol cyclase (ERG7), which spatially affects the C-10 cation of lanosterol formation. Substitution of Trp587 to aromatic residues supported the "aromatic hypothesis" that the pi-electron-rich pocket is important for the stabilization of electron-deficient cationic intermediates. The Cys457 to Gly and Thr509 to Gly mutations disrupted the pre-existing H-bond to the protonating Asp456 and the intrinsic His234 : Tyr510 H-bond network, respectively, and generated achilleol A as the major product. An H234W/Y510W double mutation altered the ERG7 function to achilleol A synthase activity and generated achilleol A as the sole product. These results support the concept that a few-ring triterpene synthase can be derived from polycyclic cyclases by reverse evolution, and exemplify the power of computational modeling coupled with protein engineering both to study the enzyme's structure-function-mechanism relationships and to evolve new enzymatic activity. PMID- 23680979 TI - Scoring of human acute pancreatitis: state of the art. AB - BACKGROUND: Acute pancreatitis remains as one of the most difficult and challenging digestive disorder to predict in terms of clinical course and outcome. Every case has an individual course and therefore acute pancreatitis remains challenging and fascinating. Due to this variability, many different scoring systems have evolved during the last decades. Every scoring system has advantages and disadvantages. Not every scoring system is capable of assessing the clinical time course of the disease, some are only suitable for the time of initial presentation. AIM: This paper will give an overview on the development of different widely used scoring systems and their performance in assessing severity and prognosis of acute pancreatitis. CONCLUSION: Severity assessment means objective quantification of overall severity of illness. Early and reliable stratification of severity is required to decide best treatment of the individual patient, preparation for possible evolving complications or for referral to specialist centers. No single scoring system is able to cover the entire range of problems associated with treatment and assessment of acute pancreatitis. In our clinical experience, we recommend hematocrit upon admission, daily sequential organ failure assessment score and procalcitonin, C-reactive protein on day 3 and CT severity index beyond the first week. These scoring tools together with close clinical follow-up of the patient ultimately lead to an optimized treatment of this challenging disease. PMID- 23680981 TI - Preparation of thermostable PBO/graphene nanocomposites with high dielectric constant. AB - In this study, poly(p-phenylene benzobisoxazole) (PBO)/graphene composites were prepared using PBO and poly(4,6-dihydroxymetaphenylenediamine terephthalamide) (PHA)-modified graphene oxide (GO-PHA). PHA is the precursor of PBO. GO-PHA was obtained via chemical coupling reaction of amino-terminated PHA and acyl-chloride functionalized GO. Partially reduced graphene nanosheets and benzoxazole rings were formed after heating. GO-PHA could be stably dispersed in methane sulfonic acid (MSA), which facilitated its uniform distribution in the PBO matrix. The PBO/graphene nanocomposites were obtained by the dissolution of GO-PHA and PBO in MSA. The thermogravimetric analysis results showed that the PBO/graphene composites had good thermal stability below 400 degrees C. The dielectric constant of the composites increased as the amount of GO-PHA increased, and the percolation threshold was f(c) = 0.037. The nanocomposite had a dielectric constant of 15.8, which was approximately five times larger than that of pure PBO polymer. PMID- 23680982 TI - Measuring mRNA copy number in individual Escherichia coli cells using single molecule fluorescent in situ hybridization. AB - We present a protocol for measuring the absolute number of mRNA molecules from a gene of interest in individual, chemically fixed Escherichia coli cells. A set of fluorescently labeled oligonucleotide probes is hybridized to the target mRNA, such that each mRNA molecule is decorated by a known number of fluorescent dyes. Cells are then imaged using fluorescence microscopy. The copy number of the target mRNA is estimated from the total intensity of fluorescent foci in the cell, rather than from counting discrete 'spots' as in other currently available protocols. Image analysis is performed using an automated algorithm. The measured mRNA copy number distribution obtained from many individual cells can be used to extract the parameters of stochastic gene activity, namely the frequency and size of transcription bursts from the gene of interest. The experimental procedure takes 2 d, with another 2-3 d typically required for image and data analysis. PMID- 23680983 TI - Evaluation of the pathogenesis and treatment of Mycobacterium marinum infection in zebrafish. AB - Mycobacterium marinum-infected zebrafish are used to study tuberculosis pathogenesis, as well as for antitubercular drug discovery. The small size of zebrafish larvae coupled with their optical transparency allows for rapid analysis of bacterial burdens and host survival in response to genetic and pharmacological manipulations of both mycobacteria and host. Automated fluorescence microscopy and automated plate fluorimetry (APF) are coupled with facile husbandry to facilitate large-scale, repeated analysis of individual infected fish. Both methods allow for in vivo screening of chemical libraries, requiring only 0.1 MUmol of drug per fish to assess efficacy; they also permit a more detailed evaluation of the individual stages of tuberculosis pathogenesis. Here we describe a 16-h protocol spanning 22 d, in which zebrafish larvae are infected via the two primary injection sites, the hindbrain ventricle and caudal vein; this is followed by the high-throughput evaluation of pathogenesis and antimicrobial efficacy. PMID- 23680984 TI - Creation of recombinant antigen-binding molecules derived from hybridomas secreting specific antibodies. AB - This protocol describes the design and development of recombinant monovalent antigen-binding molecules derived from monoclonal antibodies through rapid identification and cloning of the functional variable heavy (VH) and variable light (VL) genes and the design and cloning of a synthetic DNA sequence optimized for expression in recombinant bacteria. Typically, monoclonal antibodies are obtained from mouse hybridomas, which most often result from the fusion of B lymphocytes from immunized mice with murine myeloma cells. The protocol described here has previously been exploited for the successful development of multiple antibody-based molecules targeting a wide range of biomolecular targets. The protocol is accessible for research groups who may not be specialized in this area, and should permit the straightforward reverse engineering of functional, recombinant antigen-binding molecules from hybridoma cells secreting functional IgGs within 50 working days. Furthermore, convenient strategies for purification of antibody fragments are described. PMID- 23680985 TI - Chronic obstructive pulmonary disease self-management activation research trial (COPD-SMART): design and methods. AB - BACKGROUND: Treatment of COPD requires multiple pharmacological and non pharmacological intervention strategies. One target is physical inactivity because it leads to disability and contributes to poor physical and mental health. Unfortunately, less than 1% of eligible patients have access to gold standard pulmonary rehabilitation. METHODS: A single-site parallel group randomized trial was designed to determine if a self-management lifestyle physical activity intervention would improve physical functioning and dyspnea. During the first six weeks after enrollment patients receive COPD self-management education delivered by a health coach using a workbook and weekly telephone calls. Patients are then randomized to usual care or the physical activity intervention. The 20 week physical activity intervention is delivered by the health coach using a workbook supported by alternating one-on-one telephone counseling and computer assisted telephone calls. Theoretical foundations include social cognitive theory and the transtheoretical model. RESULTS: Primary outcomes include change in Chronic Respiratory Questionnaire (CRQ) dyspnea domain and 6 minute walk distance measured at 6-, 12-, and 18-months after randomization. Secondary outcomes include other CRQ domains (fatigue, emotion, and mastery), SF 12, and health care utilization. Other measures include process outcomes and clinical characteristics. CONCLUSIONS: This theory driven self-management lifestyle physical activity intervention is designed to reach patients unable to complete center-based pulmonary rehabilitation. Results will advance knowledge and methods for dissemination of a potentially cost-effective program for patients with COPD. PMID- 23680987 TI - The syntheses and characterizations of vanadium complexes with 1,2 dihydroxyanthraquinone and the structure-effect relationship in their in vitro anticancer activities. AB - [V(V)O2(O2C14H6O2)(C5N2H12)](C5N2H13)(CH3OH) (1) and {Na[V(V)O(O2C14H6O2)2][(CH3)2NCHO]}n (2) have been synthesized by the reaction of V2O5 and NaVO3 with aromatic 1,2-diol (1,2-dihydroxyanthraquinone), and their molecular and crystal structures have been determined by X-ray diffraction. MTT assay tests of the V(V)O2L(A)L(B) and V(V)OL2 complexes against cancer cells have revealed that, when L is catechol, VOL2 showed broad-spectrum, high anticancer activities which were proportional to their concentration; however when L is naphthol or alizarin, VOL2 displayed little effect towards the cancer cells; moreover, complex 1 in the coordination model of V(V)O2L(A)L(B) showed specifically higher inhibition (88.65%) against HCT-8 than the clinical anticancer drug Fu-5 (69.97%). The results revealed that both the V(V) and the ligands cannot influence the inhibition against cancer cells individually. The mechanism of the broad-spectrum anticancer activities of VOL2 when L is catechol ligand might originate from the redox activities of V(V)/V(IV) which regulate the concentration of ROS (reactive oxygen species). N-Methylpiperazine formed as a by product in complex 1 was confirmed by (1)H NMR and its formation mechanism catalyzed by V2O5 has been deduced. PMID- 23680986 TI - Experience Corps: a dual trial to promote the health of older adults and children's academic success. AB - BACKGROUND: As the population ages, older adults are seeking meaningful, and impactful, post-retirement roles. As a society, improving the health of people throughout longer lives is a major public health goal. This paper presents the design and rationale for an effectiveness trial of Experience CorpsTM, an intervention created to address both these needs. This trial evaluates (1) whether senior volunteer roles within Experience CorpsTM beneficially impact children's academic achievement and classroom behavior in public elementary schools and (2) impact on the health of volunteers. METHODS: Dual evaluations of (1) an intention-to-treat trial randomizing eligible adults 60 and older to volunteer service in Experience CorpsTM, or to a control arm of usual volunteering opportunities, and (2) a comparison of eligible public elementary schools receiving Experience CorpsTM to matched, eligible control schools in a 1:1 control:intervention school ratio. OUTCOMES: For older adults, the primary outcome is decreased disability in mobility and Instrumental Activities of Daily Living (IADL). Secondary outcomes are decreased frailty, falls, and memory loss; slowed loss of strength, balance, walking speed, cortical plasticity, and executive function; objective performance of IADLs; and increased social and psychological engagement. For children, primary outcomes are improved reading achievement and classroom behavior in Kindergarten through the 3rd grade; secondary outcomes are improvements in school climate, teacher morale and retention, and teacher perceptions of older adults. SUMMARY: This trial incorporates principles and practices of community-based participatory research and evaluates the dual benefit of a single intervention, versus usual opportunities, for two generations: older adults and children. PMID- 23680989 TI - Surgical management of osteochondritis dissecans of the knee in the paediatric population: a systematic review addressing surgical techniques. AB - PURPOSE: Several case series have been published exploring a variety of surgical treatments for osteochondritis dissecans (OCD) in patients 18 years and younger, but a systematic review is currently lacking. This systemic review identifies the various surgical techniques reported in the literature for treating OCD and assesses the effectiveness of these treatments based on functional outcomes and radiographic healing. METHODS: A search of the EMBASE and MEDLINE databases was performed to identify clinical studies reporting outcomes of surgical management of OCD in the knee. A quality assessment of the included articles was conducted independently by 2 reviewers using a quality assessment tool developed by Yang et al. RESULTS: A total of 25 papers including 470 patients aged <=18 years (516 lesions) met the eligibility criteria and were reviewed. Surgical techniques for stable lesions included (arthroscopic and open) transarticular drilling, either alone (41%) or with bioabsorbable pin fixation (3%), extra-articular drilling (29%) and fixation with bioabsorbable screws (4%) or bone pegs (4%). For unstable lesions, surgical techniques included (arthroscopic and open) fixation with bioabsorbable pins (9%), metal screws (4%), bone pegs (4 %), osteochondral plugs (3%) or bioabsorbable screws (2%), as well as transarticular drilling with bioabsorbable pin fixation (3%) and drilling with metal screw fixation (2%). CONCLUSION: The most common techniques were transarticular drilling for stable lesions and bioabsorbable pin fixation for unstable lesions. The key findings were that the vast majority of lesions healed postoperatively, regardless of technique, and that high-quality trials are required to more appropriately compare the effectiveness of techniques. LEVEL OF EVIDENCE: Systematic review, Level IV. PMID- 23680990 TI - Neonatal outcomes of intrauterine nonylphenol exposure--a longitudinal cohort study in Taiwan. AB - BACKGROUND: Nonylphenol (NP) is an environmental hormone with proven estrogenic effects. Although its adverse effects on animals are well documented, the effects of NP exposure on humans remain unclear, and those on the human foetus are completely unknown. This study explores the effects of intrauterine NP exposure on neonates. METHODS: A cohort of pregnant women was established in a medical centre in northern Taiwan. Urine samples from the first, second, and third trimesters of gestation were collected. Urinary NP concentration was measured by high-performance liquid chromatography coupled with fluorescent detection. Neonatal outcomes were evaluated immediately after delivery. A mixed-effects model using a generalised estimating equation was applied to assess the association between gestational age, maternal body weight, and maternal NP concentration throughout the three trimesters. A multivariable regression model was used to determine the association between maternal NP level in urine in each trimester and neonatal outcomes. RESULTS: In total, 162 singleton pregnant women completed this study through delivery. The geometric mean of creatinine-adjusted urinary NP concentrations were 4.27 MUg/g, 4.21 MUg/g, and 4.10 MUg/g in the first, second, and third trimesters, respectively. Pregnant women whose urinary NP concentrations were above the median in the second trimester had low maternal weight gain (beta=-1.55 kg, p=0.02) and short neonatal body length (beta=-0.47 cm, p=0.04). Women with an above-median urinary NP concentration had an odds ratio of having a small for gestational age (SGA) neonate of 7.81 (p<0.05). CONCLUSIONS: This study indicates that maternal high NP exposure in the second trimester is associated with SGA, decreased foetal body length at birth, and low maternal weight gain. The effects of this endocrine-disrupting substance on pregnant women and foetuses should be a concern during gestation. PMID- 23680991 TI - Relationship status acceptance, alcohol use, and the perpetration of verbal aggression among males mandated to treatment for intimate partner violence. AB - Forty substance using, male offenders of intimate partner violence completed measures of alcohol use and relationship status acceptance during a pretreatment screening session. They also completed a measure of verbal aggression after each month of a 12-week intervention program. Treatment length, heavy episodic drinking, and relationship status acceptance were used to assess the frequency of verbal aggression at each of the four assessment periods in a repeated measures ANCOVA. Main effects were detected for both alcohol and acceptance variables such that greater verbal aggression was observed among participants with a recent history of heavy episodic drinking and failure to accept the status of the relationship with their female victim. The interaction between time in treatment and relationship status acceptance was significant and showed that participants who accepted their relationship status reported low verbal aggression across measurement occasions while those who did not accept their relationship status reported high initial verbal aggression that decreased over treatment. PMID- 23680992 TI - Trinets encode tree-child and level-2 phylogenetic networks. AB - Phylogenetic networks generalize evolutionary trees, and are commonly used to represent evolutionary histories of species that undergo reticulate evolutionary processes such as hybridization, recombination and lateral gene transfer. Recently, there has been great interest in trying to develop methods to construct rooted phylogenetic networks from triplets, that is rooted trees on three species. However, although triplets determine or encode rooted phylogenetic trees, they do not in general encode rooted phylogenetic networks, which is a potential issue for any such method. Motivated by this fact, Huber and Moulton recently introduced trinets as a natural extension of rooted triplets to networks. In particular, they showed that [Formula: see text] phylogenetic networks are encoded by their trinets, and also conjectured that all "recoverable" rooted phylogenetic networks are encoded by their trinets. Here we prove that recoverable binary level-2 networks and binary tree-child networks are also encoded by their trinets. To do this we prove two decomposition theorems based on trinets which hold for all recoverable binary rooted phylogenetic networks. Our results provide some additional evidence in support of the conjecture that trinets encode all recoverable rooted phylogenetic networks, and could also lead to new approaches to construct phylogenetic networks from trinets. PMID- 23680993 TI - Analytical aspects of the Brownian motor effect in randomly flashing ratchets. AB - The muscle contraction, operation of ATP synthase, maintaining the shape of a cell are believed to be secured by motor proteins, which can be modelled using the Brownian ratchet mechanism. We consider the randomly flashing ratchet model of a Brownian motor, where the particles can be in two states, only one of which is sensitive the applied spatially periodic potential (the mathematical setting is a pair of weakly coupled reaction-diffusion and Fokker-Planck equations). We prove that this mechanism indeed generates unidirectional transport by showing that the amount of mass in the wells of the potential decreases/increases from left to right. The direction of transport is unambiguously determined by the location of each minimum of the potential with respect to the so-called diffusive mean of its adjacent maxima. The transport can be generated not only by an asymmetric potential, but also by a symmetric potential and asymmetric transition rates, and as a consequence of the general result we derive explicit conditions when the latter happens. When the transitions are localized on narrow active sites in the protein conformation space, we find a more explicit characterization of the bulk transport direction, and infer that some common preconditions of the motor effect are redundant. PMID- 23680994 TI - Northern excess in adolescent male firearm suicides: a register-based regional study from Finland, 1972-2009. AB - There are more firearms in Northern Finland as compared to Southern Finland, and a positive association between suicide rates and the number of firearms in a given region has been demonstrated in previous literature. Accordingly, the authors compared firearm suicide rates of Finnish adolescent (under 18 years) males in the two geographic regions. Young adult (18-24 years) and adult (25-44 years) males were used as reference groups. National data on cases of suicide in Northern and Southern Finland between 1972 and 2009 were obtained from Statistics Finland. Firearm suicides (n=5,423) were extracted according to ICD classification (ICD-8/9: E955, ICD-10: X72-X75). The distribution of types of firearms (hunting gun, handgun, other) employed in suicides was also investigated. The adolescent male firearm suicide rate in Northern Finland was almost three times higher than that observed in Southern Finland, while there was no difference in rates of suicide by other methods. A northern excess in firearm suicide rates was also found among young adult and adult males. Hunting guns were the most common type of firearms employed in young male suicides, and their use was especially common in Northern Finland. Our results indicate that the use of firearms plays a major role in explaining the northern excess in young Finnish male suicide rates, and emphasize a need to advance suicide prevention according to specific regional characteristics. PMID- 23680995 TI - Hypnosedative prescribing in outpatient psychiatry. AB - The objective of this study was to describe hypnosedative (HS) prescribing patterns in a typical sample of psychiatric outpatients. Prescription information was extracted from the clinical records of all current outpatients at two New Zealand public mental health centres. This included the type and duration of HS use and documentation of a clinical review of longstanding (>3 months) use, patient sex, age and ICD10 diagnoses. One-third of the patients (35.2%) were prescribed at least one HS; this was longstanding in two-thirds (69%). One in 10 had a coprescription of more than one HS drug. HS use was related to female sex and diagnosis, being more common among patients with nonpsychotic than psychotic disorders and very infrequent in patients on clozapine. In most longstanding cases, a clinical review had been documented. The logistic regression confirmed female sex, diagnosis and clozapine all as independent predictors of HS prescription. HS prescribing in psychiatric illness is more common than in the general population, often longstanding, with polypharmacy being common. The frequent use of antipsychotic drugs as HSs is of concern, given their side-effect profile. As there are risks involved with longstanding HS use, a better rationale for the role of medication in the management of sleep problems in psychiatric disorders is needed. PMID- 23680996 TI - Practical management of schizophrenia: the role of long-acting Antipsychotics. AB - The management of schizophrenia remains a clinical challenge, despite improvements in drug therapy, the availability of psychosocial treatments and family and community interventions. High rates of impaired adherence play a substantive role in promoting poor outcomes. Long-acting injectable (LAI) antipsychotics have been developed with the aim of enhancing treatment adherence and improving the long-term treatment outcomes of schizophrenia. Second generation LAIs combine the favourable features of an atypical antipsychotic with the improved pharmacokinetic profile of a long-acting formulation (e.g., improved bioavailability and assured medication delivery). Therefore, LAI antipsychotics may have clinical utility as a potential treatment strategy in many patients. Second-generation LAIs minimise the risk of relapse, improve global outcomes, and may contribute to helping patients improve their level of recovery. Given the relatively recent introduction of these agents, and the promising results of current clinical trials it is anticipated that future well conducted studies will lend support to the more widespread use of these agents in a broader range of patients. PMID- 23680997 TI - Application of multiple artificial neural networks for the determination of the optical properties of turbid media. AB - We determined the optical properties of turbid media from simulated spatially resolved reflectance (SRR) curves using an artificial neural network (ANN). In order to improve the performance of our method, multiple ANNs were applied for this problem. First, Monte Carlo (MC) simulations were performed using random optical properties which are relevant for biological tissue. For a better performance of the ANN in respect of SRR measurements, the exact setup geometry was taken into account for the MC simulations. Second, the performed simulations were classified into different categories according to their shape. Third, multiple ANNs which were adjusted to these categories, were used to solve the inverse problem, i.e., the determination of the optical properties from SRR curves. Finally, these ANNs were applied to determine the optical properties of simulated SRR curves out of the range 0.5 mm(-1) < MU(s)(') < 5 mm(-1) and 0.0001 mm(-1) < MU(a)<1 mm(-1). The average relative error was 2.9% and 6.1% for the reduced scattering coefficient MUs' and for the absorption coefficient MU(a), respectively. PMID- 23680999 TI - Preparing residents for future practice: report of a curriculum for electronic patient-doctor communication. AB - OBJECTIVES: Patients frequently use secure web portals to access their medical record and communicate with their doctors, though few institutions currently train residents for electronic communication. We sought to develop a curriculum for secure messaging between patients and resident physicians, and to assess resident attitudes before and after the curriculum. METHODS: In 2011, we developed a curriculum for patient-doctor secure messaging using a web-based patient portal within an internal medicine residency programme. We asked all residents to perform a self-assessment of skills, and report attitudes toward electronic communication at the beginning and end of the experience (9 months apart). We enrolled residents who practiced at the hospital-based clinic site into the patient portal, and recorded usage statistics. RESULTS: The completed survey response rate was 108/159 (68%). At baseline, 57% of residents had used traditional email with patients, and most residents felt that the portal would increase work for providers but benefit patients. Postintervention questionnaires demonstrated no significant changes among all respondents, but residents who used the portal perceived improvements in care. Most residents were concerned about professional liability. More residents felt comfortable writing electronic messages to patients after the curriculum (80% to 91%, p=0.01). CONCLUSIONS: Implementing a patient web portal and secure messaging in a residency clinic is feasible and may improve the work and educational experience of trainees. Residents were initially sceptical of secure messaging being an additional burden to their work, but this was not realised among residents who used the portal. PMID- 23681000 TI - Pacemaker-related reversible right heart failure. PMID- 23680998 TI - Building a synapse: a complex matter. AB - L-glutamate is the primary neurotransmitter at excitatory synapses in the vertebrate CNS and at arthropod neuromuscular junctions (NMJs). However, the molecular mechanisms that trigger the recruitment of glutamate receptors at the onset of synaptogenesis and promote their stabilization at postsynaptic densities remain poorly understood. We have reported the discovery of a novel, evolutionary conserved molecule, Neto, essential for clustering of ionotropic glutamate receptors (iGluRs) at Drosophila NMJ. Neto is the first auxiliary subunit described in Drosophila and is the only non-channel subunit absolutely required for functional iGluRs. Here we review the role of Drosophila Neto in synapse assembly, its similarities with other Neto proteins and a new perspective on how glutamatergic synapses are physically assembled and stabilized. PMID- 23681001 TI - A facile and efficient pretreatment of corncob for bioproduction of butanol. AB - The present study developed a combined ball milling-aqueous swelling (CBMAS) pretreatment to accelerate the hydrolysis of corncob. The enzymatic hydrolysis of microcrystalline cellulose carried out in the plates and flasks indicated that the response of enzymatic hydrolysis to CBMAS was quite evident. The fermentable reducing sugars of hydrolysates from CBMAS-pretreated corncob was 59.8 g/L, which was 1.3 and 1.7 folds higher than those from diluted acid and alkaline pretreated corncob hydrolysates, respectively. Simultaneous CBMAS pretreatment and enzymatic hydrolysis was also conducted, reducing the processing time from 66 h to 28 h. The enzymatic hydrolysates from CBMAS-pretreated corncob could be directly utilized as the substrate for butanol fermentation without detoxication. Under the optimal conditions, fermentable sugars in the corncob hydrolysate were completely consumed to generate 9.52 g/L butanol. PMID- 23681002 TI - Promiscuity of a modular polyketide synthase towards natural and non-natural extender units. AB - Combinatorial biosynthesis approaches that involve modular type I polyketide synthases (PKSs) are proven strategies for the synthesis of polyketides. In general however, such strategies are usually limited in scope and utility due to the restricted substrate specificity of polyketide biosynthetic machinery. Herein, a panel of chemo-enzymatically synthesized acyl-CoA's was used to probe the promiscuity of a polyketide synthase. Promiscuity determinants were dissected, revealing that the KS is remarkably tolerant to a diverse array of extender units, while the AT likely discriminates between extender units that are native to the producing organism. Our data provides a clear blueprint for future enzyme engineering efforts, and sets the stage for harnessing extender unit promiscuity by employing various in vivo polyketide diversification strategies. PMID- 23681003 TI - Measurements of ligand bias and functional affinity. PMID- 23681004 TI - Inflammatory disorders: targeting TRAFs tames inflammation. PMID- 23681005 TI - G protein-coupled receptors: pioneering Frizzled family receptor structure solved. PMID- 23681006 TI - Quantifying biased agonism: understanding the links between affinity and efficacy. PMID- 23681007 TI - The most transformative drugs of the past 25 years: a survey of physicians. AB - Strategic and legislative efforts to catalyse pharmaceutical innovation may be hampered by a lack of consensus over what characterizes an innovative drug. To help clarify this issue, we conducted an extensive survey on transformative drug development, involving ~180 expert physicians based at 30 leading US academic medical centres, covering 15 medical specialties. In an iterative Delphi process, the survey participants narrowed a list of all new drugs approved in their fields in the past 25 years and reached consensus over those that they considered to be most transformative, which are presented in this article. Participants were also asked how various factors affected their opinion; they most often invoked the effectiveness and superiority of the drugs over existing alternatives when identifying transformative drug innovation. PMID- 23681008 TI - Analgesia: a new player in neuropathic pain pathogenesis. PMID- 23681009 TI - Noble metal catalyzed preparation of Ni2P/alpha-Al2O3. AB - Noble metal (Ru, Pd, and Pt) catalyzed preparation of Ni2P/alpha-Al2O3 was proved by XRD characterization. As is known from H2-TPR experiments, Pd exhibits superior catalytic activity over Ru and Pt. These noble metal catalysts can be uniformly deposited on nickel phosphate precursors, and generate spillover hydrogen. Such a surface catalytic effect promotes the preparation of Ni2P/alpha Al2O3, without avoiding the formation of the minor phase Ni12P5. They can also be homogeneously dispersed in nickel phosphate precursors, and boost bulk diffusion of oxygen during reduction process, this is termed the "bulk catalytic effect". It is feasible to produce pure phase Ni2P by the latter preparation method using 0.05 wt% Pd or 0.1 wt% Ru at 768 K. The bulk catalytic effect may be considered as a meaningful option for developing catalytic materials. PMID- 23681011 TI - An exonuclease III protection-based electrochemical method for estrogen receptor assay. AB - Estrogen receptor (ER), expressed in approximately 80% of primary breast cancer cells, has proven to be a valuable predictive factor of the disease. Herein, by making use of the specific binding of ER to its DNA response elements, we propose an Exonuclease III (Exo III) protection-based electrochemical method for detecting ER proteins. In this assay, the presence of ER can protect the duplex DNA molecules immobilized on an electrode surface from Exo III-catalyzed digestion, resulting in an increased electrochemical signal. Experimental results have revealed that the proposed method can allow the quantification of ER in the range of 0.5 to 100 nM with a satisfactory detection limit of 0.38 nM. Furthermore, since this approach can also be employed to detect ER directly in nuclear extracts, it may be of great use in biomedical applications in the future. PMID- 23681013 TI - Peripheral blood miR-328 expression as a potential biomarker for the early diagnosis of NSCLC. AB - Lung cancer is often diagnosed at an advanced stage, with subsequently poor prognosis. There are no biomarkers available to facilitate early diagnosis or to discriminate between benign and malignant nodules. MicroRNAs (miRNAs) are stable molecules that can be found and measured in peripheral blood, thus representing potential diagnostic biomarkers. We evaluated 100 individuals comprising 86 patients with predominantly early-stage non-small cell lung cancer (NSCLC) and 24 healthy donors. RNA was extracted from peripheral blood samples and the expression of a panel of miRNAs was analyzed by Real-Time PCR method. Expression levels of miR-328, miR-18a, miR-339 and miR-140 were significantly higher in NSCLC patients than in healthy donors (p < 0.05). In particular, miR-328 showed good diagnostic accuracy in discriminating between patients with early NSCLC and healthy donors (AUC ROC 0.82, 95% CI 0.72-0.92), with 70% sensitivity and 83% specificity at the best relative expression cut-off of 300. Moreover, miR-339 was a good discriminant between healthy donors and late-stage NSCLC patients (AUC ROC 0.79, 95% CI 0.68-0.91). In conclusion, miR-328 represents a potential diagnostic biomarker of NSCLC, especially for the identification of early-stage tumors. Its role in discriminating between benign and malignant nodules detected by spiral CT warrants further investigation. PMID- 23681014 TI - Auditory distraction eliminates retrieval induced forgetting: implications for the processing of unattended sound. AB - The Retrieval-Induced Forgetting (RIF) paradigm includes three phases: (a) study/encoding of category exemplars, (b) practicing retrieval of a sub-set of those category exemplars, and (c) recall of all exemplars. At the final recall phase, recall of items that belong to the same categories as those items that undergo retrieval practice, but that did not undergo retrieval practice themselves, is impaired. The received view is that this is because retrieval of target category-exemplars (e.g., "Tiger" in the category Four-legged animal) requires inhibition of nontarget category-exemplars (e.g., "Dog" and "Lion") that compete for retrieval. Here, we used the RIF paradigm to investigate whether ignoring auditory items during the retrieval-practice phase modulates the inhibitory process. In two experiments, RIF was present when retrieval practice was conducted in quiet and when it was conducted in the presence of spoken words that were drawn from a different category to that from which the targets for retrieval practice were selected. In contrast, RIF was abolished when words that were either identical to, or merely semantically related to, the retrieval practice words were presented as background speech. The results suggest that the act of ignoring speech can reduce inhibition of the non-practiced category exemplars, thereby eliminating RIF, but only when the spoken words are competitors for retrieval (i.e., belong to the same semantic category as the to be-retrieved items). PMID- 23681015 TI - Participant sexual orientation matters: new evidence on the gender bias in face recognition. AB - Research participants' sexual orientation is not consistently taken into account in experimental psychological research. We argue that it should be in any research related to participant or target gender. Corroborating this argument, an example study is presented on the gender bias in face recognition, the finding that women correctly recognize more female than male faces. In contrast, findings with male participants have been inconclusive. An online experiment (N = 1,147) was carried out, on purpose over-sampling lesbian and gay participants. Findings demonstrate that the pro-female gender bias in face recognition is modified by male participants' sexual orientation. Heterosexual women and lesbians as well as heterosexual men showed a pro-female gender bias in face recognition, whereas gay men showed a pro-male gender bias, consistent with the explanation that differences in face expertise develop congruent with interests. These results contribute to the growing evidence that participant sexual orientation can be used to distinguish between alternative theoretical explanations of given gender correlated patterns of findings. PMID- 23681012 TI - Methylated DNA and microRNA in body fluids as biomarkers for cancer detection. AB - Epigenetic alterations including DNA methylation and microRNAs (miRNAs) play important roles in the initiation and progression of human cancers. As the extensively studied epigenetic changes in tumors, DNA methylation and miRNAs are the most potential epigenetic biomarkers for cancer diagnosis. After the identification of circulating cell-free nuclear acids, increasing evidence demonstrated great potential of cell-free epigenetic biomarkers in the blood or other body fluids for cancer detection. PMID- 23681016 TI - Eye movements of older and younger readers when reading unspaced text. AB - Older and younger readers read normal and unspaced text as their eye movements were monitored. A high or low frequency word was embedded in each sentence. Global analyses yielded large effects of spacing with unspaced text leading to much longer reading times for both groups, but the older readers had much more difficulty with unspaced text than younger readers. Local analyses of the target word revealed large main effects due to age, spacing, and frequency. In general, the older readers had more difficulty with the unspaced text than younger readers and some reasons why they did so are suggested. PMID- 23681010 TI - Plant defense against insect herbivores. AB - Plants have been interacting with insects for several hundred million years, leading to complex defense approaches against various insect feeding strategies. Some defenses are constitutive while others are induced, although the insecticidal defense compound or protein classes are often similar. Insect herbivory induce several internal signals from the wounded tissues, including calcium ion fluxes, phosphorylation cascades and systemic- and jasmonate signaling. These are perceived in undamaged tissues, which thereafter reinforce their defense by producing different, mostly low molecular weight, defense compounds. These bioactive specialized plant defense compounds may repel or intoxicate insects, while defense proteins often interfere with their digestion. Volatiles are released upon herbivory to repel herbivores, attract predators or for communication between leaves or plants, and to induce defense responses. Plants also apply morphological features like waxes, trichomes and latices to make the feeding more difficult for the insects. Extrafloral nectar, food bodies and nesting or refuge sites are produced to accommodate and feed the predators of the herbivores. Meanwhile, herbivorous insects have adapted to resist plant defenses, and in some cases even sequester the compounds and reuse them in their own defense. Both plant defense and insect adaptation involve metabolic costs, so most plant-insect interactions reach a stand-off, where both host and herbivore survive although their development is suboptimal. PMID- 23681017 TI - American College of Radiology (ACR) and American Society for Radiation Oncology (ASTRO) Practice Guideline for the Performance of Stereotactic Radiosurgery (SRS). AB - American College of Radiology and American Society for Radiation Oncology Practice Guideline for the Performance of Stereotactic Radiosurgery (SRS). SRS is a safe and efficacious treatment option of a variety of benign and malignant disorders involving intracranial structures and selected extracranial lesions. SRS involves a high dose of ionizing radiation with a high degree of precision and spatial accuracy. A quality SRS program requires a multidisciplinary team involved in the patient management. Organization, appropriate staffing, and careful adherence to detail and to established SRS standards is important to ensure operational efficiency and to improve the likelihood of procedural success. A collaborative effort of the American College of Radiology and American Society for Therapeutic Radiation Oncology has produced a practice guideline for SRS. The guideline defines the qualifications and responsibilities of all the involved personnel, including the radiation oncologist, neurosurgeon, and qualified medical physicist. Quality assurance is essential for safe and accurate delivery of treatment with SRS. Quality assurance issues for the treatment unit, stereotactic accessories, medical imaging, and treatment-planning system are presented and discussed. Adherence to these practice guidelines can be part of ensuring quality and patient safety in a successful SRS program. PMID- 23681018 TI - A response to Sher et al, "Cost-effectiveness analysis of SBRT versus IMRT for low-risk prostate cancer". PMID- 23681019 TI - One-step cloning of intron-containing hairpin RNA constructs for RNA interference via isothermal in vitro recombination system. AB - Hairpin RNA-based RNA interference (hpRNAi) has become a powerful tool for exploring gene function in reverse genetics. Although, several methods are available for making constructs that express hpRNAi, multiple time-consuming cloning steps are usually involved. Here, we introduce an efficient and flexible hpRNAi vector construction method via the isothermal in vitro recombination system (IR-hpRNAi). For an IR-hpRNAi reaction, two PCR products of a target gene sequence are generated, which containS complementary ends (~20 bp) to each other and to the ends of linearized vector, are fused in a way of head-to-head or tail to-tail into the vector. This IR-hpRNAi method offers two options to construct the RNAi vectors. Using this method, we created a IR-hpRNAi construct for the Arabidopsis PDS3 gene,and verified the silencing effect via Agrobacterium mediated transformation. The IR-hpRNAi system rules out the requirement of engineering restriction enzyme cutting sites in target DNA fragments, and is ligation-independent. Thus, this method has advantages over the other hpRNAi construction methods. PMID- 23681020 TI - Validation of an adapted arabic version of fibromyalgia syndrome impact questionnaire. AB - Fibromyalgia (FM) is the most common chronic pain syndrome encountered in medical practice, affecting females more than males, and the estimated prevalence of FM in Egypt is 1.3 %. The aim was to translate and adapt the Fibromyalgia Impact Questionnaire (FIQ) into Arabic and assess reliability and validity. The Arabic version of Fibromyalgia Impact Questionnaire (FIQ-A) was adapted following the forward/backward translation approach. Fifty-one female patients with FM were studied to assess psychometric properties of the FIQ-A. Reliability was analyzed by the correlation coefficient between test and retest. Internal consistency was checked by the Cronbach's alpha coefficient. Construct validity was assessed comparing FIQ-A with Health Assessment Questionnaire (HAQ), Health Assessment Questionnaire of Fibromyalgia (FHAQ), The Medical Outcome Survey Short-Form-36 (SF-36), and the Total Visual Analog Scale (TVAS) for FM symptom, and feasibility was assessed by the time taken in completing the FIQ-A and the proportion of patients completed the questionnaire. Patients studied were 33.2 +/- 9.8 years old. Translation was concordant. Adaptation affected 4 sub-items of physical function. Test-retest correlation coefficient was 0.89 for total FIQ-A and Cronbach's alpha was 0.76. Excellent to good statistically significant correlations (p < 0.05) were found between the FIQ-A items and HAQ, FHAQ, and SF 36. The FIQ-A is a reliable, valid for measuring health status and physical function in Arabic-speaking FM patients. PMID- 23681021 TI - Evidence of cryptic genetic lineages within Aedes notoscriptus (Skuse). AB - Aedes notoscriptus (Skuse), a mosquito from the southwest Pacific region including Australia, has been implicated as a vector of arboviruses, but its status as a species is unclear. To investigate the taxonomic situation, we assessed genetic variation and phylogenetic relationships among Ae. notoscriptus from the east coast of Australia, Western Australia and New Zealand. Phylogenetic analyses of DNA sequence data from mitochondrial markers indicate that Ae. notoscriptus is a complex of divergent genetic lineages, some of which appear geographically restricted, while others are widespread in eastern Australia. Samples from New Zealand and Western Australia were related to populations from one southern Australian lineage. Nuclear markers show no evidence of genetic isolation by geographic distance in the overall sample of mosquitoes, but strong isolation by distance is obvious within two of the lineages, supporting their status as isolated gene pools. The morphological character of wing centroid size variation is also associated with genetic lineage. These findings point to the possibility that Ae. notoscriptus is a complex of species, highlighting the need to understand physiological and ecological differences that may influence future control strategies. PMID- 23681022 TI - Whole-genomic analysis of G3P[23], G9P[23] and G3P[13] rotavirus strains isolated from piglets with diarrhea in Thailand, 2006-2008. AB - Group A rotavirus (RVA) is the most common cause of severe acute viral gastroenteritis in humans and animals worldwide. This study characterized the whole genome sequences of porcine RVAs, 2 G3P[23] strains (CMP40/08 and CMP48/08), 1 G9P[23] strain (CMP45/08), and 1 G3P[13] strain (CMP29/08). These strains were collected from diarrheic piglets less than 7weeks of age in 4 pig farms in Chiang Mai, Thailand, in 2008. The VP7-VP4-VP6-VP1-VP2-VP3-NSP1-NSP2 NSP3-NSP4-NSP5 genes of CMP40/08 and CMP48/08 strains were assigned as G3-P[23] I5-R1-C1-M1-A8-N1-T1-E1-H1 genotypes based on their nucleotide sequences and phylogenetic analyses. The CMP29/08 strain was different from the CMP40/08 and CMP48/08 strains only in the VP4 gene, since it was assigned as P[13] genotype. Furthermore, the VP7 gene of the CMP45/08 strain was classified as genotype G9, and the NSP3 gene as T7 genotype. The finding of this study supports the porcine origin of T7 genotype, although the NSP3 gene of this strain was similar to the bovine UK strain at the highest nucleotide sequence identity of 92.6%. Whole genome sequence analysis of the porcine RVAs indicated that multiple inter genotypic and intra-genotypic reassortment events had occurred among the porcine RVAs circulating in this studied area. Interestingly, the VP7 gene of the CMP45/08 strain, and the VP1, NSP2, and NSP4 genes of all four porcine RVAs strains described in this study revealed much similarity to those of two porcine like human RVA strains (RVA/Human-tc/THA/Mc323/1989/G9P[19] and RVA/Human tc/THA/Mc345/1989/G9P[19]) detected in Thailand in 1989. The present study provided important information on the evolution of porcine RVA. PMID- 23681023 TI - Limited intra-genetic diversity in Dientamoeba fragilis housekeeping genes. AB - Dientamoeba fragilis is a common intestinal parasite of unsettled clinical significance. Differences in clinical outcome of parasitic infections may reflect parasite genetic diversity, and so tools to study intra-genetic diversity that could potentially reflect differences in clinical phenotypes are warranted. Here, we show that genetic analysis of three D. fragilis housekeeping genes enables clear distinction between the two known genotypes, but that integration of housekeeping genes in multi-locus sequencing tools for D. fragilis may have limited epidemiological and clinical value due to no further added genetic resolution. PMID- 23681026 TI - The early history of the cochlear implant: a retrospective. AB - IMPORTANCE: Histories of cochlear implant (CI) technology have often been inaccurate owing to the confusion of terms and anatomical situations or to biased reporting. This retrospective, published shortly after the death of inventor William F. House-and more than 50 years after placement of the first CI-offers a precise account of the early experimental period. OBJECTIVE: To clarify the first steps in the development of the CI, ie, an electrical stimulating device partially inserted into the cochlea. EVIDENCE REVIEW: Literature review based on published data, oral history material, interviews, and written contact with protagonists. FINDINGS: The first CI was implanted by William House and John Doyle of Los Angeles, California, in 1961. In 1964, Blair Simmons and Robert White of Stanford University, Stanford, California, placed a 6-channel electrode through the promontory and vestibule directly into the modiolus. The next step in the development of the CI was its clinical trial on a cohort of patients. Robin Michelson, Robert Schindler, and Michael Merzenich at the University of California, San Francisco, conducted these experiments in 1970 and 1971. In 1973, the first international conference on the "electrical stimulation of the acoustic nerve as a treatment for profound sensorineural deafness in man" was organized in San Francisco. At the same time, Claude Henry Chouard in France and Graeme Clark in Australia began their research. The final step in the establishment of CI as a clinically feasible technology involved the independent evaluation of implant users. The first such evaluation-the result of a 1975 request from the National Institutes of Health-was published in 1977 by Robert Bilger and coworkers at the University of Pittsburgh, Pittsburgh, Pennsylvania. CONCLUSIONS AND RELEVANCE: Inspired by French experiments with electrode implantation at the VIII nerve, the initial practical development of the CI is nonetheless a Californian story, divided between the House group at Los Angeles and teams at Stanford University and UCSF. PMID- 23681027 TI - The significance of cochlear implant history. PMID- 23681028 TI - Analysis of the 3-dimensional fluid-attenuated inversion-recovery (3D-FLAIR) sequence in idiopathic sudden sensorineural hearing loss. AB - IMPORTANCE: The unpredictability of idiopathic sudden sensorineural hearing loss (ISSNHL) presents a challenge to preventive care. Our study confirms the potentially important role of the 3-T magnetic resonance imaging (MRI), and in particular of the 3-dimensional fluid-attenuated inversion-recovery (3D-FLAIR) sequence, in the diagnosis and prognosis of ISSNHL to guide medical treatment. OBJECTIVE: To confirm the diagnostic, clinical, and prognostic role of 3D-FLAIR MRI in patients with idiopathic sudden sensorineural hearing loss (ISSNHL). DESIGN, SETTING, AND PATIENTS: Retrospective study in a tertiary referral center with a consecutive sample of 23 patients diagnosed as having unilateral ISSNHL from January 2010 to March 2011. EXPOSURES: Patients underwent 3D-FLAIR MRI at 3 T to evaluate ISSNHL, and the MRI images were compared with those belonging to a random group of 20 age-matched healthy patients. MAIN OUTCOMES AND MEASURES: Precontrast and postcontrast high-intensity 3D-FLAIR MRI findings in patients with ISSNHL and the correlation with clinical findings. RESULTS: Thirteen patients showed high-intensity signals in the affected inner ear on precontrast and postcontrast 3D-FLAIR MRI (57%). From the analysis of different MRI sequences, we posited 3 radiologic patterns likely correlated with mild hemorrhage, acute inflammation, and presence or absence of blood-labyrinth or nerve barrier (BLB) breakdown. Hypersignal on 3D-FLAIR MRI was positively associated with pretreatment hearing loss (P = .04) and presence of vertigo (P = .04). A strict correlation also existed between distribution of the signal (vestibule, semicircular canals) and clinical features (vertigo) (P = .04). CONCLUSIONS AND RELEVANCE: Use of 3D-FLAIR MRI at 3 T may contribute to the elucidation of pathologic conditions in the inner ears of patients with ISSNHL and provide new radiologic indicators (mild hemorrhage, acute inflammation, presence or absence of BLB breakdown) that might assume the role of prognostic factors. PMID- 23681029 TI - Hemispheric dominance and cell phone use. AB - IMPORTANCE: A thorough understanding of why we hold a cell phone to a particular ear may be of importance when studying the impact of cell phone safety. OBJECTIVE: To determine if there is an obvious association between sidedness of cell phone use and auditory hemispheric dominance (AHD) or language hemispheric dominance (LHD). It is known that 70% to 95% of the population are right-handed, and of these, 96% have left-brain LHD. We have observed that most people use their cell phones in their right ear. DESIGN: An Internet survey was e-mailed to individuals through surveymonkey.com. The survey used a modified Edinburgh Handedness Inventory protocol. Sample questions surveyed which hand was used to write with, whether the right or left ear was used for phone conversations, as well as whether a brain tumor was present. SETTING: General community. PARTICIPANTS: An Internet survey was randomly e-mailed to 5000 individuals selected from an otology online group, patients undergoing Wada testing and functional magnetic resonance imaging, as well as persons on the university listserv, of which 717 surveys were completed. MAIN OUTCOME AND MEASURE: Determination of hemispheric dominance based on preferred ear for cell phone use. RESULTS: A total of 717 surveys were returned. Ninety percent of the respondents were right handed, and 9% were left handed. Sixty-eight percent of the right handed people used the cell phone in their right ear, 25% in the left ear, and 7% had no preference. Seventy-two of the left-handed respondents used their left ear, 23% used their right ear, and 5% had no preference. Cell phone use averaged 540 minutes per month over the past 9 years. CONCLUSIONS AND RELEVANCE: An association exists between hand dominance laterality of cell phone use (73%) and our ability to predict hemispheric dominance. Most right-handed people have left brain LHD and use their cell phone in their right ear. Similarly, most left handed people use their cell phone in their left ear. Our study suggests that AHD may differ from LHD owing to the difference in handedness and cell phone ear use. Literature suggests a possible relationship between cell phone use and cancer. The fact that few tumors were identified in this population does not rule out an association. PMID- 23681030 TI - Dexamethasone for the prevention of recurrent laryngeal nerve palsy and other complications after thyroid surgery: a randomized double-blind placebo-controlled trial. AB - IMPORTANCE: Recurrent laryngeal nerve dysfunction and hypoparathyroidism are well recognized, important complications of thyroid surgery. The duration of convalescence after noncomplicated thyroid operation may depend on several factors, of which pain and fatigue are the most important. Nausea and vomiting occur mainly on the day of operation. Glucocorticoids are well known for their analgesic, anti-inflammatory, immune-modulating and antiemetic effects. However, there is little information in the literature on the use of steroids in thyroid surgery, and the information that is available is conflicting. OBJECTIVE: To investigate whether preoperative dexamethasone could improve surgical outcome in patients undergoing thyroid surgery. DESIGN: A randomized double-blind placebo controlled trial. A 30-day follow-up for morbidity was performed in all cases. SETTING: All patients were hospitalized in a public hospital. PARTICIPANTS: From June 2008 through August 2011, 328 patients were randomized to receive either intravenous dexamethasone, 8 mg, administered 90 minutes before skin incision, or saline solution (placebo). INTERVENTIONS: Intravenous dexamethasone, 8 mg. MAIN OUTCOMES AND MEASURES: The primary end points were temporary or permanent recurrent laryngeal nerve palsy. Transient and definitive hypoparathyroidism, pain and fatigue scores, nausea, and the number of vomiting episodes were also registered. Preoperatively and at several times during the first 24 postoperative hours, we measured C-reactive protein, interleukin 6, and interleukin 1beta levels. RESULTS: In the dexamethasone group, the rate of temporary recurrent laryngeal nerve palsy (4.9%) was significantly lower compared with the placebo group (8.4%) (P = .04). Also, postoperative transient biochemical hypoparathyroidism occurred more frequently in the placebo group (37.0%) than in the dexamethasone group (12.8%). Dexamethasone use significantly reduced postoperative levels of C-reactive protein (P = .01) and interleukin 6 and interleukin 1beta (P = .02), fatigue (P = .01), and overall pain during the first 24 postoperative hours (P = .04), as well as the total analgesic (ketorolac tromethamine) requirement (P = .04). Dexamethasone use also reduced nausea and vomiting on the day of operation (P = .045). CONCLUSIONS AND RELEVANCE: Preoperative administration of dexamethasone, 8 mg, reduced postoperative temporary recurrent laryngeal nerve palsy and hypoparathyroidism rates and reduced pain, fatigue, nausea, and vomiting after thyroid surgery. However, these data require further analysis in randomized prospective studies. TRIAL REGISTRATION clinicaltrials.gov Identifier:NCT01690806. PMID- 23681031 TI - Inclusion of extracapsular spread in the pTNM classification system: a proposal for patients with head and neck carcinoma. AB - IMPORTANCE: The inclusion of data about the presence of metastatic neck nodes with extracapsular spread (ECS) in the neck dissection improves the prognostic classification of patients with head and neck squamous cell carcinoma (HNSCC). OBJECTIVE: To evaluate the prognostic capacity of ECS in patients with HNSCC, and to analyze the usefulness of including this information in the pathological classification of patients treated with a neck dissection. DESIGN: Retrospective unicenter study performed from 1985 through 2007. SETTING: Tertiary referral center. PARTICIPANTS: A total of 1190 patients with HNSCC treated with a neck dissection. INTERVENTION: Unilateral or bilateral neck dissection . MAIN OUTCOMES AND MEASURES: Adjusted survival and local, regional, and distant metastases-free survival. Patients were classified according to a recursive partitioning analysis (RPA) method, considering pN category and number of neck nodes with ECS as the independent variables. RESULTS: Five-year adjusted survival for patients without metastatic nodes in the neck dissection (pN0) was 85.5%, for patients with neck node metastases without ECS (pN+/ECS-) it was 62.5%, and for patients with neck node metastases with ECS (pN+/ECS+) it was 29.9%. There were significant differences in survival between patients with pN0 lesions and pN+/ECS- (P < .001), and between patients with pN+/ECS- and those with pN+/ECS+ (P < .001). According to the RPA method, we propose classifying patients according to 4 categories: category I, pN0 lesions; category II, pN1/ECS+ or pN+/ECS-; category III, pN2-3/1 node and ECS+; and category IV, pN2-3/2 or more nodes and ECS+. The RPA-derived classification achieved a better prognostic discrimination than the pTNM classification. CONCLUSIONS AND RELEVANCE: The inclusion of information about ECS in the neck dissection improved the prognostic classification of patients with HNSCC in relation to the pTNM classification. PMID- 23681032 TI - Use of adjuvant intralesional bevacizumab for aggressive respiratory papillomatosis in children. AB - IMPORTANCE: Juvenile recurrent respiratory papillomatosis (RRP) can be an aggressive disease process necessitating frequent trips to the operating room with multiple anesthetics for tumor debulking and airway preservation. Adjuvant therapy, such as that which is reported in this article, may help reduce the number of operative procedures affected children need each year and therefore may also affect their overall quality of life (QOL). OBJECTIVE: To describe our experience with intralesional bevacizumab (Avastin) treatment for children with severe RRP by comparing median number of surgical procedures per year, median duration of time between procedures, Derkay staging, and voice QOL before and after bevacizumab treatment. DESIGN: Prospective, consecutive case series. SETTING: Tertiary care aerodigestive center. PARTICIPANTS: Ten children, aged 18 months to 18 years, with severe RRP necessitating more than 4 operative interventions in 1 year whose parents (or legal guardians) consented to intralesional bevacizumab treatment. INTERVENTIONS: Intralesional bevacizumab administered at concentration of 2.5 mg/mL for 3 consecutive injections (with 532 nm pulsed KTP [potassium titanyl phosphate] laser when necessary) at intervals of 2 to 3 weeks. MAIN OUTCOME MEASURES: Time between surgical procedures, number of procedures per year, Derkay staging, total Pediatric Voice-Related Quality of Life (PVRQOL) score, Emotional PVRQOL score, and Physical PVRQOL score defined by comparing the year leading up to first of 3 bevacizumab injections with the year following the third bevacizumab injection. RESULTS: The median duration of time between surgical procedures increased by 5.9 weeks after bevacizumab (P = .002). The median number of procedures per year decreased by 4 (P = .002). Derkay staging decreased by 6 (P = .03). The median total PVRQOL score increased by 25.5 (P = .02), the median Emotional PVRQOL score increased by 11.3 (P = .047), and the median Physical PVRQOL score increased by 14.3 (P = .047). CONCLUSIONS AND RELEVANCE: Intralesional bevacizumab treatment may increase duration of time between surgical procedures and decrease number of procedures per year, while improving voice QOL. PMID- 23681033 TI - Real-time subglottic stenosis imaging using optical coherence tomography in the rabbit. AB - IMPORTANCE: Subglottic stenosis (SGS) is a severe, acquired, potentially life threatening disease that can be caused by endotracheal tube intubation. Newborns and neonates are particularly susceptible to SGS owing to the small caliber of their airway. OBJECTIVE: To demonstrate optical coherence tomography (OCT) capabilities in detecting injury and scar formation using a rabbit model. Optical coherence tomography may provide a noninvasive, bedside or intensive care unit modality for the identification of early airway trauma with the intention of preventing progression to SGS and can image the upper airway through an existing endotracheal tube coupled with a small fiber-optic probe. DESIGN: Rabbits underwent suspension laryngoscopy with induction of of SGS via epithelial injury. This model was used to test and develop our advanced, high-speed, high-resolution OCT imaging system using a 3-dimensional microelectromechanical systems-based scanning device integrated with a fiber-optic probe to acquire high-resolution anatomic images of the subglottic epithelium and lamina propria. SETTING: All experiments were performed at the Beckman Laser Institute animal operating room. INTERVENTION OR EXPOSURE: Optical coherence tomography and endoscopy was performed with suspension laryngoscopy at 6 different time intervals and compared with conventional digital endoscopic images and histologic sections. Fifteen rabbits were killed at 3, 7, 14, 21, and 42 days after the induction of SGS. The laryngotracheal complexes were serially sectioned for histologic analysis. MAIN OUTCOME AND MEASURE: Histologic sections, endoscopic images, and OCT images were compared with one another to determine if OCT could accurately delineate the degree of SGS achieved. RESULTS: The rabbit model was able to reliably and reproducibly achieve grade I SGS. The real-time OCT imaging system was able to (1) identify multiple structures in the airway; (2) delineate different tissue planes, such as the epithelium, basement membrane, lamina propria, and cartilage; and (3) detect changes in each tissue plane produced by trauma. Optical coherence tomography was also able demonstrate a clear picture of airway injury that correlated with the endoscopic and histologic images. With subjective review, 3 patients had high correlation between OCT and histologic images, 10 demonstrated some correlation with histologic images, and 2 showed little to no correlation with histologic images. CONCLUSIONS AND RELEVANCE: Optical coherence tomography, coupled with a fiber-optic probe, identifies subglottic scarring and can detect tissue changes in the rabbit airway to a depth of 1 mm. This technology brings us 1 step closer to minimally invasive subglottic airway monitoring in the intubated neonate, with the ultimate goal of preventing SGS and better managing the airway. PMID- 23681034 TI - Blood loss during endoscopic sinus surgery with propofol or sevoflurane: a randomized clinical trial. AB - IMPORTANCE: Total intravenous anesthesia (TIVA) with propofol has been associated with reduced operative time, decreased perioperative risks, and decreased intraoperative blood loss compared with inhalational anesthesia (IA). During endoscopic sinus surgery (ESS), reduced bleeding from the mucosal surfaces could improve visualization of the anatomy and decrease the risk of serious complications. OBJECTIVE: To compare blood loss during ESS between patients receiving TIVA with propofol and those receiving IA with sevoflurane. DESIGN, SETTING, AND PARTICIPANTS: Prospective, randomized study of 33 patients undergoing ESS in an academic medical center. INTERVENTIONS: Patients received either TIVA or IA. MAIN OUTCOMES AND MEASURES: The primary outcome was rate of blood loss in milliliters per hour. The secondary outcomes included the quality of visibility measured by the surgeon's numeric rating score, ease of anesthesia as measured by the anesthesiologist's numeric rating score, and total blood loss. RESULTS: The mean (SEM) blood loss per hour in the TIVA group was 78.5 (14) mL/h, and in the IA group it was 80.3 (17) mL/h (P = .93). A post hoc subgroup analysis found that in patients with a Lund-Mackay score of 12 or lower, the propofol TIVA group had a lower rate of blood loss compared with the sevoflurane IA group (mean blood loss, approximately 18 mL/h vs approximately 99 mL/h). The anesthesiologist's numeric rating score was significantly higher (indicating greater ease of performance) in the IA group than in the TIVA group. There was no statistically significant difference in the surgical numeric rating score between the 2 groups. CONCLUSIONS AND RELEVANCE: In this comparative study, our results did not show any difference in blood loss and surgical conditions between the TIVA and IA groups. Even further study is not likely to show a difference in blood loss between TIVA and IA during ESS. PMID- 23681035 TI - Surgical approaches to the thyroid gland: which is the best for you and your patient? PMID- 23681036 TI - Modern thyroidectomy and the tailored surgical approach. PMID- 23681037 TI - Radiology quiz case 1: suspected arachnoid cyst of the right cerebellopontineangle. PMID- 23681039 TI - Radiology quiz case 2: hypoglossal nerve schwannoma of the submandibularspace. PMID- 23681041 TI - Pathology quiz case 1: hyalinzed spindle cell tumor with giant rosettes(HSCTGR). PMID- 23681043 TI - Pathology quiz case 2: extranodal Rosai-Dorfman disease (RDD)of the maxillary sinus. PMID- 23681045 TI - Pathology quiz case 3: Wegener granulomatosis. PMID- 23681047 TI - Intra-vaginal diazepam for high-tone pelvic floor dysfunction: a randomized placebo-controlled trial. AB - INTRODUCTION AND HYPOTHESIS: Intra-vaginal diazepam suppositories are commonly prescribed as a treatment option for high-tone pelvic floor myalgia. This triple blinded placebo-controlled randomized trial sought to determine if 10 mg diazepam suppositories improve resting pelvic floor electromyography (EMG) compared with placebo. METHODS: Women >=18 years of age with hypertonic pelvic floor muscles on examination, confirmed by resting EMG >=2.0 microvolts (MUv), administered vaginal suppositories containing either diazepam or placebo for 28 consecutive nights. Outcomes included vaginal surface EMG (four measurements), the Female Sexual Function Index (FSFI), the Short Form Health Survey 12 (SF-12), four visual analog scales (VAS), the Patient Global Impression of Severity (PGI-S), and the Patient Global Impression of Improvement (PGI-I). A priori sample size calculation indicated that 7 subjects in each group could detect a 2-MUv difference in resting EMG tone with 90% power. RESULTS: Twenty-one subjects were enrolled. The mean age was 36.1 (SD 13.9) years, mean body mass index was 28.56 (SD 9.4), and the majority (85.7%) was Caucasian. When evaluating response to therapy, no difference was seen in any of the resting vaginal EMG assessments at any time point within subjects or between groups, nor was an interaction found. Additionally, no differences were noted in any of the validated questionnaires. CONCLUSIONS: When used nightly over 4 weeks, 10 mg of vaginal diazepam was not associated with improvement in resting EMG parameters or subjective outcomes compared with placebo. This suggests such that therapy alone may be insufficient in treating high-tone pelvic floor dysfunction. PMID- 23681048 TI - Passive monitors to measure hydrogen sulfide near concentrated animal feeding operations. AB - Hydrogen sulfide (H2S) is one of many airborne pollutants emitted by concentrated animal feeding operations (CAFOs). However, few studies have characterized ambient H2S levels near these facilities, largely due to the lack of low-cost, reliable, and easily transportable instrumentation available to researchers. We determined intermediate environmental H2S exposure near CAFOs using Radiello passive monitors. First, a laboratory study was performed to determine the accuracy of the device. Next, a total of eight passive H2S monitors were deployed bi-weekly in close proximity (<40 m) to a medium-sized swine confinement for seven months in order to determine the temporal and spatial variability of H2S. Finally, we measured H2S concentrations across two rural Iowa counties to characterize ambient exposure near thirteen CAFOs and two schools. The value of the temperature-adjusted H2S passive diffusion rate provided by the supplier was 29% larger than the 24 h rate determined experimentally. Concentrations of H2S measured near the medium-sized confinement were varied and ranged from 0.2 to 48.6 ppb depending on the sampling period and proximity to a lagoon on the property. Two-week concentrations near the schools were low (<1 ppb), while concentrations near the thirteen CAFOs ranged from 0.1 to 42.9 ppb. The passive monitors were effective in measuring H2S concentrations near a swine CAFO as long as they were exposed for a sufficient period of time (two weeks). Radiello passive monitors are a promising new device in measuring intermediate H2S exposure in rural populations. Measured values in excess of an Iowa state limit of 30 ppb (24 h average) suggest that enforcement actions are needed to mitigate H2S migration from swine CAFOs. PMID- 23681049 TI - Resistance exercise combined with essential amino acid supplementation improved walking ability in elderly people. AB - We investigated the effects of resistance exercise combined with essential amino acid supplementation on psoas major muscle (PMM) hypertrophy and walking ability in elderly individuals. Twenty-nine healthy elderly individuals were assigned to 3 groups: (1) E (exercise), (2) A3 (exercise combined with 3.0 g of essential amino acid supplementation), and (3) A6 (exercise combined with 6.0 g of essential amino acid supplementation). To evaluate walking ability, the participants underwent the following 3 types of tests: the (1) 10-meter walk (10 W), (2) 10-meter walk involving crossing of obstacles (10-W + O), and (3) 6 minute walk (6M-W) tests. The 6-month training program resulted in significant PMM hypertrophy in all groups independent of amino acid supplementation. The extent of hypertrophy in the participants who took amino acids was dose dependent, although the differences were not significant. Groups A3 and A6 demonstrated improvements in the 10-W and 10-W + O tests, whereas no improvement was observed in group E, regardless of PMM hypertrophy. Furthermore, group A6 showed an improvement in the 6M-W test. These results suggest that our training program causes PMM hypertrophy, whereas the training program combined with essential amino acid supplementation improves walking ability. PMID- 23681050 TI - Oscillation of oxygenation in skeletal muscle at rest and in light exercise. AB - The aim of the present study was to compare the frequency of oxygenation determined in the vastus lateralis by near-infrared spectroscopy (NIRS) in light exercise with that at rest. A subject rested in a recumbent position for 5 min and changed body position to a sitting position on a cycle ergometer for 9 min. Then exercise with low intensity (work rate of 60% of maximal oxygen uptake) was carried out for 30 min. Total hemoglobin and myoglobin (THb/Mb) suddenly decreased after the start of exercise and gradually increased for 6 min. Oxygenated hemoglobin and myoglobin (Hb/MbO2) suddenly decreased and returned to a steady-state after the start of exercise. The difference between Hb/MbO2 and THb/Mb showed a sudden decrease and then a steady-state. This difference was analyzed by fast Fourier transform. The peak frequencies of the power spectrum density (PSD) were 0.0169 +/- 0.0076 Hz at rest and 0.0117 +/- 0.0042 Hz in exercise. The peak frequency of PSD was significantly decreased in exercise. In exercise, the range of frequencies was expanded. It is concluded that there are oscillations at rest as well as in exercise and that the frequency of peak PSD becomes lower in exercise than at rest. PMID- 23681051 TI - Whole body vibration as a safe exercise training method induces no impaired alterations on rat plasma antioxidant biomarkers. AB - Whole body vibration (WBV) has been regarded as an exercise training method and as a non-pharmacological supportive treatment option appearing to be efficient in chronic disease conditions, such as bone disorders and for cardio-respiratory fitness. Since, data on the safety and efficacy of vibration on oxidative stress parameters are lacking, it was decided to assess the effects of WBV on the plasma antioxidant biomarkers in adult male Wistar rat model. METHODS: Male Wistar rats weighing 140-180 g, were divided into control and vibration group. Vibration training consisted of vertical sinusoidal whole body vibration for 8 weeks, followed by blood collection. RESULTS: The vibrated rats weighed more than the control group (1353.0 +/- 21.0 vs. 157.0 +/- 36.0g, P < 0.048). The plasma Cu and Zn concentrations, vitamin C, uric acid, the activities of antioxidant enzymes, total antioxidant capacity, and malondialdehyde (MDA) levels were similar in the vibration group. No major differences was observed for selected plasma antioxidant parameters . DISCUSSION: The potential effects of physiological responses of WBV on several physiological systems are without deteriorations concerning plasma antioxidant status. PMID- 23681052 TI - Apes communicate about absent and displaced objects: methodology matters. AB - Displaced reference is the ability to refer to an item that has been moved (displaced) in space and/or time, and has been called one of the true hallmarks of referential communication. Several studies suggest that nonhuman primates have this capability, but a recent experiment concluded that in a specific situation (absent entities), human infants display displaced reference but chimpanzees do not. Here, we show that chimpanzees and bonobos of diverse rearing histories are capable of displaced reference to absent and displaced objects. It is likely that some of the conflicting findings from animal cognition studies are due to relatively minor methodological differences, but are compounded by interpretation errors. Comparative studies are of great importance in elucidating the evolution of human cognition; however, greater care must be taken with methodology and interpretation for these studies to accurately reflect species differences. PMID- 23681053 TI - Processing ordinality and quantity: ERP evidence of separate mechanisms. AB - We report an event-related potential (ERP) experiment of ordinal processing exploring the relationship between ordinal and numerical information. ERPs were recorded from healthy adults while making ordered/non-ordered judgments on 3 non symbolic numerical stimuli (arrays of dots). Three main variables were manipulated: (1) Ordinality (ordered vs. non-ordered groups of dots), tapping the quick "gist" estimation of ordinality. (2) Direction (ascending vs. descending order), tapping the symbolic, culturally influenced aspect of ordinality, and (3) Ratio between the group of dots, tapping the processing of the basic numerosity information. Behavioral results showed independent effects for each variable, replicating our previous findings with this paradigm. ERP effects differentiated between three cognitive processes for estimating ordinality, processing numerosity, and direction. This differentiation was found both in terms of timing and topography: Order estimation was associated with early scalp parietal and lateral occipital positivity (80-130ms) originating in the left Middle Temporal Gyrus; numerical ratio was associated with a later scalp medial posterior positivity (130-200ms); and direction was associated with a late and widespread scalp right frontal and scalp right parietotemporal positivity and a corresponding scalp left frontal and scalp left parietotemporal negativity (300 600ms). A theoretical model is suggested, stressing an early and basic ordinal specific mechanism. PMID- 23681054 TI - Environmental tobacco smoke and airway obstruction in children with sickle cell anemia. AB - BACKGROUND: The contribution of environmental tobacco smoke (ETS) exposure to pulmonary morbidity in children with sickle cell anemia (SCA) is poorly understood. We tested the hypothesis that children with SCA and ETS exposure would have an increased prevalence of obstructive lung disease and respiratory symptoms compared with children with SCA and no ETS exposure. METHODS: Parent reports of ETS and respiratory symptom frequency were obtained for 245 children with SCA as part of a multicenter prospective cohort study. One hundred ninety six children completed pulmonary function testing. Multivariable regression models were used to evaluate the associations between ETS exposure at different time points (prenatal, infant [birth to 2 years], preschool [2 years to first grade], and current) and lung function and respiratory symptoms. RESULTS: Among the 245 participants, a high prevalence of prior (44%) and current (29%) ETS exposure was reported. Of the 196 children who completed pulmonary function testing, those with parent-reported infant and current ETS exposure were more likely to have airway obstruction (defined as an FEV1/FVC ratio below the lower limit normal) compared with unexposed children (22.0% vs 3.1%, P < .001). Those with ETS exposure also had a lower forced expiratory flow, midexpiratory phase/FVC ratio (0.82 vs 0.97, P = .001) and were more likely to have evidence of bronchodilator responsiveness (23% vs 11%, P = .03). Current and prior ETS exposure and in utero smoke exposure were associated with increased frequency of respiratory symptoms. CONCLUSIONS: ETS exposure is associated with evidence of lower airway obstruction and increased respiratory symptoms in SCA. PMID- 23681055 TI - A novel multi-component reaction to imidazo[4,5-g]-quinazolines. AB - The trace impurities discovered after extended storage of a 5-amino- benzimidazole library were determined as imidazo[4,5-g]quinazoline derivatives by extensive spectroscopic data analysis. The formation of this highly aromatic heterocyclic ring involved a novel multi-component reaction, using which several novel compounds were prepared. Its mechanism was deduced as a cascade of chemical transformations, including the formation of a Schiff's base, intramolecular hetero-Diels-Alder reaction, defluorination and dehydrogenation. PMID- 23681056 TI - Virtual screening and structure-based discovery of indole acylguanidines as potent beta-secretase (BACE1) inhibitors. AB - Proteolytic cleavage of amyloid precursor protein by beta-secretase (BACE1) is a key step in generating the N-terminal of beta-amyloid (Abeta), which further forms into amyloid plaques that are considered as the hallmark of Alzheimer's disease. Inhibitors of BACE1 can reduce the levels of Abeta and thus have a therapeutic potential for treating the disease. We report here the identification of a series of small molecules bearing an indole acylguanidine core structure as potent BACE1 inhibitors. The initial weak fragment was discovered by virtual screening, and followed with a hit-to-lead optimization. With the aid of co crystal structures of two discovered inhibitors (compounds 19 and 25) with BACE1, we explored the SAR around the indole and aryl groups, and obtained several BACE1 inhibitors about 1,000-fold more potent than the initial fragment hit. Accompanying the lead optimization, a previously under-explored sub-site opposite the flap loop was redefined as a potential binding site for later BACE1 inhibitor design. PMID- 23681057 TI - Four new citrinin derivatives from a marine-derived Penicillium sp. fungal strain. AB - Four new citrinin derivatives, including two citrinin dimers and two citrinin monomer derivatives, were isolated and identified from a marine-derived fungal strain Penicillium sp. ML226 along with six known related compounds. Their structures were elucidated by spectroscopic and chemical methods. The new compounds showed modest cytotoxic activity against HepG-2 cell line and weak antimicrobial activity against Staphylococcus aureus. PMID- 23681058 TI - Production of flavours and fragrances via bioreduction of (4R)-(-)-carvone and (1R)-(-)-myrtenal by non-conventional yeast whole-cells. AB - As part of a program aiming at the selection of yeast strains which might be of interest as sources of natural flavours and fragrances, the bioreduction of (4R) (-)-carvone and (1R)-(-)-myrtenal by whole-cells of non-conventional yeasts (NCYs) belonging to the genera Candida, Cryptococcus, Debaryomyces, Hanseniaspora, Kazachstania, Kluyveromyces, Lindnera, Nakaseomyces, Vanderwaltozyma and Wickerhamomyces was studied. Volatiles produced were sampled by means of headspace solid-phase microextraction (SPME) and the compounds were analysed and identified by gas chromatography-mass spectroscopy (GC-MS). Yields (expressed as % of biotransformation) varied in dependence of the strain. The reduction of both (4R)-(-)-carvone and (1R)-(-)-myrtenal were catalyzed by some ene-reductases (ERs) and/or carbonyl reductases (CRs), which determined the formation of (1R,4R)-dihydrocarvone and (1R)-myrtenol respectively, as main flavouring products. The potential of NCYs as novel whole-cell biocatalysts for selective biotransformation of electron-poor alkenes for producing flavours and fragrances of industrial interest is discussed. PMID- 23681059 TI - Synthesis and characterization of oil-chitosan composite spheres. AB - Oil-chitosan composite spheres were synthesized by encapsulation of sunflower seed oil in chitosan droplets, dropping into NaOH solution and in situ solidification. Hydrophilic materials (i.e., iron oxide nanoparticles) and lipophilic materials (i.e., rhodamine B or epirubicin) could be encapsulated simultaneously in the spheres in a one step process. The diameters of the prepared spheres were 2.48 +/- 0.11 mm (pure chitosan spheres), 2.31 +/- 0.08 mm (oil-chitosan composites), 1.49 +/- 0.15 mm (iron-oxide embedded oil-chitosan composites), and 1.69 +/- 0.1 mm (epirubicin and iron oxide encapsulated oil chitosan composites), respectively. Due to their superparamagnetic properties, the iron-oxide embedded oil-chitosan composites could be guided by a magnet. A lipophilic drug (epirubicin) could be loaded in the spheres with encapsulation rate measured to be 72.25%. The lipophilic fluorescent dye rhodamine B was also loadable in the spheres with red fluorescence being observed under a fluorescence microscope. We have developed a novel approach to an in situ process for fabricating oil-chitosan composite spheres with dual encapsulation properties, which are potential multifunctional drug carriers. PMID- 23681060 TI - Anti-infective potential of marine invertebrates and seaweeds from the Brazilian coast. AB - This manuscript describes the evaluation of anti-infective potential in vitro of organic extracts from nine sponges, one ascidian, two octocorals, one bryozoan, and 27 seaweed species collected along the Brazilian coast. Antimicrobial activity was tested against Staphylococcus aureus (ATCC 25923), Enterococcus faecalis (ATCC 29212), Pseudomonas aeruginosa (ATCC 27853), Escherichia coli (ATCC 25922) and Candida albicans (ATCC 10231) by the disk diffusion method. Antiprotozoal activity was evaluated against Leishmania braziliensis (MHOM/BR/96/LSC96-H3) promastigotes and Trypanosoma cruzi (MHOM/BR/00/Y) epimastigotes by MTT assay. Activity against intracellular amastigotes of T. cruzi and L. brasiliensis in murine macrophages was also evaluated. Antiviral activity was tested against Herpes Simplex Virus type 1 (HSV-1, KOS strain) by the plaque number reduction assay (IC50). Cytotoxicity on VERO cells was evaluated by the MTT assay (CC50). The results were expressed as SI = CC50/IC50. The most promising antimicrobial results were obtained against S. aureus and C. albicans with Dragmacidon reticulatum. Among the seaweeds, only Osmundaria obtusiloba showed moderate activity against P. aeruginosa. Concerning antiprotozoal activity, Bugula neritina, Carijoa riseii, Dragmaxia anomala and Haliclona (Halichoclona) sp. showed the most interesting results, mainly against extracellular promastigote forms of L. braziliensis (66, 35.9, 97.2, and 43.6% inhibition, respectively). Moreover, six species of seaweeds Anadyomene saldanhae, Caulerpa cupressoides, Canistrocarpus cervicornis, Dictyota sp., Ochtodes secundiramea, and Padina sp. showed promising results against L. braziliensis (87.9, 51.7, 85.9, 93.3, 99.7, and 80.9% inhibition, respectively), and only Dictyota sp. was effective against T. cruzi (60.4% inhibition). Finally, the antiherpes activity was also evaluated, with Haliclona (Halichoclona) sp. and Petromica citrina showing the best results (SI = 11.9 and SI > 5, respectively). All the active extracts deserve special attention in further studies to chemically characterize the bioactive compounds, and to perform more refined biological assays. PMID- 23681061 TI - Peptide-LNA oligonucleotide conjugates. AB - Although peptide-oligonucleotide conjugates (POCs) are well-known for nucleic acids delivery and therapy, reports on internal attachment of peptides to oligonucleotides are limited in number. To develop a convenient route for preparation of internally labeled POCs with improved biomedical properties, peptides were introduced into oligonucleotides via a 2'-alkyne-2'-amino-LNA scaffold. Derivatives of methionine- and leucine-enkephalins were chosen as model peptides of mixed amino acid content, which were singly and doubly incorporated into LNA/DNA strands using highly efficient copper(i)-catalyzed azide-alkyne cycloaddition (CuAAC) "click" chemistry. DNA/RNA target binding affinity and selectivity of the resulting POCs were improved in comparison to LNA/DNA mixmers and unmodified DNA controls. This clearly demonstrates that internal attachment of peptides to oligonucleotides can significantly improve biomolecular recognition by synthetic nucleic acid analogues. Circular dichroism (CD) measurements showed no distortion of the duplex structure by the incorporated peptide chains while studies in human serum indicated superior stability of the POCs compared to LNA/DNA mixmers and unmodified DNA references. Molecular modeling suggests strong interactions between positively charged regions of the peptides and the negative oligonucleotide backbones which leads to clamping of the peptides in a fixed orientation along the duplexes. PMID- 23681064 TI - Radio-UHPLC: a tool for rapidly determining the radiochemical purity of technetium-99m radiopharmaceuticals? AB - Determining the radiochemical purity (RCP) of technetium-99m ((99m)Tc) radiopharmaceuticals using the method described in the package insert is a time consuming process, requiring particular attention in order to achieve accurate RCP results. The purpose of this study was to evaluate whether radio-ultra high performance liquid chromatography (radio-UHPLC) may be an alternative method for RCP testing of (99m)Tc-tetrofosmin, (99m)Tc-MAG3 and (99m)Tc-sestamibi. Results obtained using radio-UHPLC were in excellent agreement with the standard method, with total analysis time being reduced to less than 3 min. PMID- 23681062 TI - Molecular genetic testing and the future of clinical genomics. AB - Genomic technologies are reaching the point of being able to detect genetic variation in patients at high accuracy and reduced cost, offering the promise of fundamentally altering medicine. Still, although scientists and policy advisers grapple with how to interpret and how to handle the onslaught and ambiguity of genome-wide data, established and well-validated molecular technologies continue to have an important role, especially in regions of the world that have more limited access to next-generation sequencing capabilities. Here we review the range of methods currently available in a clinical setting as well as emerging approaches in clinical molecular diagnostics. In parallel, we outline implementation challenges that will be necessary to address to ensure the future of genetic medicine. PMID- 23681063 TI - Mechanisms and models of somatic cell reprogramming. AB - Conversion of somatic cells to pluripotency by defined factors is a long and complex process that yields embryonic-stem-cell-like cells that vary in their developmental potential. To improve the quality of resulting induced pluripotent stem cells (iPSCs), which is important for potential therapeutic applications, and to address fundamental questions about control of cell identity, molecular mechanisms of the reprogramming process must be understood. Here we discuss recent discoveries regarding the role of reprogramming factors in remodelling the genome, including new insights into the function of MYC, and describe the different phases, markers and emerging models of reprogramming. PMID- 23681065 TI - Quantitative assessment of the coronary microvasculature: new tools for the black box. PMID- 23681066 TI - Prognostic value of the Index of Microcirculatory Resistance measured after primary percutaneous coronary intervention. AB - BACKGROUND: Most methods for assessing microvascular function are not readily available in the cardiac catheterization laboratory. The aim of this study is to determine whether the Index of Microcirculatory Resistance (IMR), measured at the time of primary percutaneous coronary intervention, is predictive of death and rehospitalization for heart failure. METHODS AND RESULTS: IMR was measured immediately after primary percutaneous coronary intervention in 253 patients from 3 institutions with the use of a pressure-temperature sensor wire. The primary end point was the rate of death or rehospitalization for heart failure. The prognostic value of IMR was compared with coronary flow reserve, TIMI myocardial perfusion grade, and clinical variables. The mean IMR was 40.3+/-32.5. Patients with an IMR >40 had a higher rate of the primary end point at 1 year than patients with an IMR <=40 (17.1% versus 6.6%; P=0.027). During a median follow-up period of 2.8 years, 13.8% experienced the primary end point and 4.3% died. An IMR >40 was associated with an increased risk of death or rehospitalization for heart failure (hazard ratio [HR], 2.1; P=0.034) and of death alone (HR, 3.95; P=0.028). On multivariable analysis, independent predictors of death or rehospitalization for heart failure included IMR >40 (HR, 2.2; P=0.026), fractional flow reserve <=0.8 (HR, 3.24; P=0.008), and diabetes mellitus (HR, 4.4; P<0.001). An IMR >40 was the only independent predictor of death alone (HR, 4.3; P=0.02). CONCLUSIONS: An elevated IMR at the time of primary percutaneous coronary intervention predicts poor long-term outcomes. PMID- 23681068 TI - ALS-associated mutations in FUS disrupt the axonal distribution and function of SMN. AB - Mutations in the RNA binding protein fused in sarcoma/translated in liposarcoma (FUS/TLS) cause amyotrophic lateral sclerosis (ALS). Although ALS-linked mutations in FUS often lead to a cytosolic mislocalization of the protein, the pathogenic mechanisms underlying these mutations remain poorly understood. To gain insight into these mechanisms, we examined the biochemical, cell biological and functional properties of mutant FUS in neurons. Expression of different FUS mutants (R521C, R521H, P525L) in neurons caused axonal defects. A protein interaction screen performed to explain these phenotypes identified numerous FUS interactors including the spinal muscular atrophy (SMA) causing protein survival motor neuron (SMN). Biochemical experiments showed that FUS and SMN interact directly and endogenously, and that this interaction can be regulated by FUS mutations. Immunostaining revealed co-localization of mutant FUS aggregates and SMN in primary neurons. This redistribution of SMN to cytosolic FUS accumulations led to a decrease in axonal SMN. Finally, cell biological experiments showed that overexpression of SMN rescued the axonal defects induced by mutant FUS, suggesting that FUS mutations cause axonal defects through SMN. This study shows that neuronal aggregates formed by mutant FUS protein may aberrantly sequester SMN and concomitantly cause a reduction of SMN levels in the axon, leading to axonal defects. These data provide a functional link between ALS-linked FUS mutations, SMN and neuronal connectivity and support the idea that different motor neuron disorders such as SMA and ALS may be caused, in part, by defects in shared molecular pathways. PMID- 23681067 TI - Dual AAV therapy ameliorates exercise-induced muscle injury and functional ischemia in murine models of Duchenne muscular dystrophy. AB - Neuronal nitric oxide synthase (nNOS) membrane delocalization contributes to the pathogenesis of Duchenne muscular dystrophy (DMD) by promoting functional muscle ischemia and exacerbating muscle injury during exercise. We have previously shown that supra-physiological expression of nNOS-binding mini-dystrophin restores normal blood flow regulation and prevents functional ischemia in transgenic mdx mice, a DMD model. A critical next issue is whether systemic dual adeno associated virus (AAV) gene therapy can restore nNOS-binding mini-dystrophin expression and mitigate muscle activity-related functional ischemia and injury. Here, we performed systemic gene transfer in mdx and mdx4cv mice using a pair of dual AAV vectors that expressed a 6 kb nNOS-binding mini-dystrophin gene. Vectors were packaged in tyrosine mutant AAV-9 and co-injected (5 * 10(12) viral genome particles/vector/mouse) via the tail vein to 1-month-old dystrophin-null mice. Four months later, we observed 30-50% mini-dystrophin positive myofibers in limb muscles. Treatment ameliorated histopathology, increased muscle force and protected against eccentric contraction-induced injury. Importantly, dual AAV therapy successfully prevented chronic exercise-induced muscle force drop. Doppler hemodynamic assay further showed that therapy attenuated adrenergic vasoconstriction in contracting muscle. Our results suggest that partial transduction can still ameliorate nNOS delocalization-associated functional deficiency. Further evaluation of nNOS binding mini-dystrophin dual AAV vectors is warranted in dystrophic dogs and eventually in human patients. PMID- 23681070 TI - Determination of elemental tissue composition following proton treatment using positron emission tomography. AB - Positron emission tomography (PET) has been suggested as an imaging technique for in vivo proton dose and range verification after proton induced-tissue activation. During proton treatment, irradiated tissue is activated and decays while emitting positrons. In this paper, we assessed the feasibility of using PET imaging after proton treatment to determine tissue elemental composition by evaluating the resultant composite decay curve of activated tissue. A phantom consisting of sections composed of different combinations of (1)H, (12)C, (14)N, and (16)O was irradiated using a pristine Bragg peak and a 6 cm spread-out Bragg peak (SOBP) proton beam. The beam ranges defined at 90% distal dose were 10 cm; the delivered dose was 1.6 Gy for the near monoenergetic beam and 2 Gy for the SOBP beam. After irradiation, activated phantom decay was measured using an in room PET scanner for 30 min in list mode. Decay curves from the activated (12)C and (16)O sections were first decomposed into multiple simple exponential decay curves, each curve corresponding to a constituent radioisotope, using a least squares method. The relative radioisotope fractions from each section were determined. These fractions were used to guide the decay curve decomposition from the section consisting mainly of (12)C + (16)O and calculate the relative elemental composition of (12)C and (16)O. A Monte Carlo simulation was also used to determine the elemental composition of the (12)C + (16)O section. The calculated compositions of the (12)C + (16)O section using both approaches (PET and Monte Carlo) were compared with the true known phantom composition. Finally, two patients were imaged using an in-room PET scanner after proton therapy of the head. Their PET data and the technique described above were used to construct elemental composition ((12)C and (16)O) maps that corresponded to the proton activated regions. We compared the (12)C and (16)O compositions of seven ROIs that corresponded to the vitreous humor, adipose/face mask, adipose tissue, and brain tissue with ICRU 46 elemental composition data. The (12)C and (16)O compositions of the (12)C + (16)O phantom section were estimated to within a maximum difference of 3.6% for the near monoenergetic and SOBP beams over an 8 cm depth range. On the other hand, the Monte Carlo simulation estimated the corresponding (12)C and (16)O compositions in the (12)C + (16)O section to within a maximum difference of 3.4%. For the patients, the (12)C and (16)O compositions in the seven ROIs agreed with the ICRU elemental composition data, with a mean (maximum) difference of 9.4% (15.2%). The (12)C and (16)O compositions of the phantom and patients were estimated with relatively small differences. PET imaging may be useful for determining the tissue elemental composition and thereby improving proton treatment planning and verification. PMID- 23681071 TI - Histologic features associated with metastatic potential in invasive adenocarcinomas of the lung. AB - INTRODUCTION: The International Association for the Study of Lung Cancer (IASLC) recently reclassified adenocarcinomas of the lung on the basis of histologic patterns. However, there is lack of consensus about a grading system for these tumors. We studied a series of invasive lung adenocarcinomas and correlated histologic features with lymph node and distant metastases. A series of invasive lung carcinomas resected over a 5-year period were retrospectively reviewed and classified by the IASLC system. The proportion of each histologic subtype was estimated at 5% increments, and cytologic features were blindly recorded and subsequently correlated with lymph node and distant metastases. The 125 tumors were classified on the basis of the predominant pattern as lepidic predominant (LPA) (n=9), acinar (n=71), solid (n=23), papillary (n=11), and mucinous (n=11). The acinar pattern was heterogeneous, in that a cribriform subgroup (n=34) was significantly more likely to demonstrate lymph node metastases compared with a tubular subgroup (n=37) and had a higher mitotic rate, rate of necrosis, vascular invasion, and prominent nucleoli. Mucinous tumors were LPA (n=3), tubular (n=4), and cribriform predominant (n=4). The rate of lymph node metastasis was greatest in the solid type (P=0.02). The rate of distant metastasis was greatest in the mucinous and solid groups (P<0.02). Mitotic activity (>= 1/HPF), desmoplasia >20% of the tumor, prominent nucleoli, and vascular invasion, along with a solid growth pattern >= 20%, were independently associated with metastatic potential and considered poor prognostic histologic features. A 3-tiered grading system separated tumors into well differentiated (predominantly LPA, papillary, and tubular patterns), moderately differentiated (predominantly cribriform tumors), and poorly differentiated (>= 20% solid growth pattern). Tumors in the well differentiated group were elevated to moderately differentiated if there were poor prognostic histologic features. Using this system, there was a stepwise increase in the rate of lymph node metastasis (P<0.0001) and distant metastasis (P=0.0004) from well-differentiated, moderately differentiated, to poorly differentiated tumors, the rate being 40, 46, and 39, respectively. Application of the IASLC classification in this series resulted in a predominance of acinar adenocarcinomas. To stratify tumors into clinically relevant grades, grading by pattern (tubular, cribriform, solid), mitotic activity, and nuclear features is useful. PMID- 23681069 TI - Structural asymmetry of anterior insula: behavioral correlates and individual differences. AB - The current study investigated behavioral correlates of structural asymmetry of the insula, and traditional perisylvian language regions, in a large sample of young adults (N=200). The findings indicated (1) reliable leftward surface area asymmetry of the anterior insula, (2) association of this asymmetry with divided visual field lateralization of visual word recognition, and (3) modulation of the correlation of structural and linguistic asymmetry by consistency of hand preference. Although leftward asymmetry of cortical surface area was observed for the anterior insula, pars opercularis and triangularis, and planum temporale, only the anterior insula asymmetry was associated with lateralized word recognition. We interpret these findings within the context of recent structural and functional findings about the human insula. We suggest that leftward structural lateralization of earlier developing insular cortex may bootstrap asymmetrical functional lateralization even if the insula is only a minor component of the adult language network. PMID- 23681072 TI - Ovarian transitional cell carcinoma represents a poorly differentiated form of high-grade serous or endometrioid adenocarcinoma. AB - Ovarian transitional cell tumors include Brenner tumors (BTs) and transitional cell carcinoma (TCC; non-BTs) according to the most recent World Health Organization classification. However, it remains a matter of debate whether TCC represents a distinct entity or a morphologic variant of high-grade serous adenocarcinoma (HG-SC). The purpose of this study was to resolve the above question by clarifying the morphologic, immunohistochemical, and molecular features of TCC. We reviewed 488 cases of epithelial ovarian carcinomas and reclassified them on the basis of the most recent World Health Organization classification with the modifications proposed by Kobel and colleagues, and 35 cases of TCC were identified; 25 and 6 TCCs were admixed with HG-SC and endometrioid adenocarcinoma (EC), respectively, and the remaining 4 cases were pure TCC. TCC components were not observed in any clear cell carcinomas or mucinous adenocarcinomas. Only 2 cases of malignant BT were identified. In addition to TCCs, malignant BTs, and related adenocarcinomas, benign and borderline BTs were included in the following immunohistochemical and molecular analyses. Immunohistochemically, pure TCCs, TCCs admixed with HG-SC, and pure HG SCs were characterized by frequent aberrant p53 expression (diffuse or null pattern) and WT1+/ER+/PR+/IMP2+ immunophenotype, whereas BTs, including benign, borderline, and malignant BTs, were characterized by lack of aberrant p53 expression and WT1-/ER-/PR-/IMP2- immunophenotype. In contrast to the BTs, pure ECs and TCCs admixed with EC showed an ER+/PR+ immunophenotype. Nearly all the tumors with a TP53 gene mutation by molecular analysis showed aberrant p53 staining patterns. In conclusion, TCC is not a distinct entity but a poorly differentiated form of serous or EC, as (1) most TCCs coexist with HG-SC (mostly) or EC (occasionally), and (2) the immunophenotype and molecular features are similar to those of HG-SC or EC but different from those of BTs. PMID- 23681073 TI - Napsin A expression in anaplastic, poorly differentiated, and micropapillary pattern thyroid carcinomas. AB - Napsin A is a sensitive and specific marker for pulmonary adenocarcinoma versus squamous cell carcinoma. However, studies have shown that napsin A is also positive in approximately 5% of papillary thyroid carcinomas. The prevalence of napsin A in more aggressive types of thyroid carcinoma is unknown. Napsin A positivity in metastatic thyroid carcinoma, especially in conjunction with thyroid transcription factor-1 (TTF-1), could be misdiagnosed as lung adenocarcinoma. We investigated napsin A, TTF-1, and PAX8 expression in 26 anaplastic, 16 poorly differentiated, and 2 micropapillary pattern thyroid carcinomas. A focal micropapillary component was also present in 3 poorly differentiated and 3 anaplastic thyroid carcinomas. Four of 26 (15%) anaplastic, 2/16 (13%) poorly differentiated, and 2/2 (100%) micropapillary pattern thyroid carcinomas were napsin A positive. Three of the 6 cases (50%) with a focal micropapillary component were napsin A positive (1 of these 3 cases was positive only in the micropapillary component). All napsin A-positive cases were also positive for TTF-1, and all but 1 micropapillary pattern carcinoma were also PAX8 positive. In 1 case, napsin A was positive in the micropapillary component, but PAX8 was only positive in the adjacent poorly differentiated carcinoma. In summary, a minority of anaplastic and poorly differentiated thyroid carcinomas are napsin A positive. More importantly, napsin A expression is more common in carcinomas with a micropapillary component, a pattern shared in common with some lung adenocarcinomas. PAX8 may be diagnostically useful to distinguish these napsin A-positive thyroid carcinomas from lung adenocarcinomas, which are PAX8 negative. PMID- 23681075 TI - Signet ring cell colorectal carcinoma: a distinct subset of mucin-poor microsatellite-stable signet ring cell carcinoma associated with dismal prognosis. AB - We evaluated a consecutive series of signet ring cell colorectal carcinomas in an attempt to correlate the histopathologic pattern of infiltration with molecular alterations and prognosis. Of the 4760 primary colorectal carcinomas surgically resected between the years 2002 and 2012, 53 (1%) were composed of >50% signet ring cells. Of the 53 signet ring cell carcinomas, 40 (75%) were composed of >50% extracellular mucin with signet ring cells floating within pools of mucin and were subclassified as mucin-rich signet ring cell carcinomas. Thirteen (25%) carcinomas were characterized by diffusely infiltrating carcinomas with minimal to no extracellular mucin and were subclassified as mucin-poor signet ring cell carcinomas. All 13 mucin-poor signet ring cell carcinomas were either stage III or IV, whereas many cases of mucin-rich signet ring cell carcinoma were stage I or II (17 cases) (P=0.005). Compared with mucin-rich tumors, mucin-poor signet ring cell carcinomas more frequently demonstrated adverse histologic features such as lymphatic invasion (13/13, 100% vs. 22/40, 55%; P=0.002), venous invasion (6/13, 46% vs. 3/40, 8%; P=0.004), and perineural invasion (11/13, 85% vs. 9/40, 23%; P=0.0001). Twenty-three of 53 (43%) signet ring cell carcinomas demonstrated high levels of microsatellite instability (MSI-H). Twenty-two of 23 (96%) MSI-H signet ring cell carcinomas were mucin rich; only 1 MSI-H signet ring carcinoma was mucin poor (P=0.0033). Mucin-poor signet ring cell carcinoma had significantly reduced overall and recurrence-free survival compared with mucin rich signet ring cell carcinomas (P=0.0035 and 0.0001, respectively), even when adjusting for tumor stage. Mucin-poor signet ring cell carcinoma had a higher propensity for peritoneal dissemination (5/13, 38%) compared with mucin-rich signet ring cell carcinoma (5/40, 12.5%), although this was not statistically significant (P=0.052). Finally, MSI-H and microsatellite-stable signet ring cell carcinomas had similar overall and recurrence-free survival (P=0.2266 and 0.1055, respectively), even when adjusting for tumor stage. In conclusion, we identified a unique subset of signet ring cell colorectal carcinoma with diffuse infiltration and minimal to no extracellular mucin (mucin-poor signet ring cell carcinoma), which lacks MSI-H and has a dismal prognosis with an aggressive clinical course often with peritoneal dissemination. Further, our results confirm that MSI does not affect survival in colorectal signet ring cell carcinomas. PMID- 23681074 TI - Most nonparotid "acinic cell carcinomas" represent mammary analog secretory carcinomas. AB - Acinic cell carcinoma (ACC) is a low-grade salivary gland malignancy characterized by serous acinar differentiation. Most ACCs arise in the parotid gland, but ACCs have been reported to originate in nonparotid salivary glands where serous acini are less abundant. Given the recent discovery of mammary analog secretory carcinoma (MASC)-a salivary malignancy that histologically mimics ACC-a retrospective reevaluation of nonparotid ACCs is warranted. The surgical pathology archives of The Johns Hopkins Hospital were searched for all ACCs arising outside of the parotid gland. For each case, the histologic slides were reviewed; immunohistochemical analysis (mammaglobin, S100 protein) was performed; and confirmatory ETV6 breakapart fluorescence in situ hybridization assay was completed. Demographic and clinical data were obtained from the medical records. Fourteen extraparotid tumors diagnosed as ACC were identified. Eleven of 14 (79%) tumors harbored the ETV6 translocation (oral cavity=9 of 11; submandibular gland=2 of 2). The translocation-positive tumors occurred in 7 women and 4 men ranging in age from 20 to 86 years (mean, 56 y) and usually presented as painless masses. Immunohistochemistry for mammaglobin and S100 was positive in all 11 translocation-positive tumors but negative in the 3 translocation-negative tumors. Histologically, the translocation-positive tumors exhibited uniform cells with vacuolated cytoplasm, microcystic/cystic and papillary architecture, and intraluminal secretions; however, the presence of basophilic cytoplasmic granules was conspicuously absent. Basophilic cytoplasmic granules, indicative of true serous acinar differentiation, were present in the 3 translocation-negative tumors. Of the translocation-positive tumors, only 1 locally recurred, and none metastasized. Most alleged ACCs of nonparotid origin actually represent misclassified MASCs. The impact of diagnostic error is mitigated by the low-grade nature of MASC that, like ACCs, do not appear to be clinically aggressive. PMID- 23681076 TI - Primary myoepithelioma of bone: a report of 8 cases. AB - The clinical and pathologic features of 8 primary myoepitheliomas of bone were analyzed. There were 5 female and 3 male patients who ranged in age from 16 to 49 (mean, 33.5) years. Three tumors arose in the ilium, 2 in the tibia, and 1 each in the maxilla, sacrum, and L1 vertebral body. Microscopically, the tumors had a solid, lobulated, reticular, or storiform growth pattern and were predominantly composed of spindle-shaped cells arranged in intersecting fascicles with eosinophilic cytoplasm. The round to polygonal epithelioid cells were arranged randomly or formed small clusters and contained variable amounts of eosinophilic or clear cytoplasm. Immunohistochemically, all the tumors were positive for vimentin and S100 protein, and 7 were positive for epithelial membrane antigen. No tumors were positive for keratin (AE1.3/CAM5.2). Smooth muscle actin was positive in 3 tumors and negative in 4, whereas desmin was negative in all 7 tumors tested. Nuclear staining for p63 was negative in 3 tested tumors. Staining for GFAP and CD34 was performed on 4 and 5 tumors, respectively, and all showed no expression. Fluorescence in situ hybridization for EWSR1 rearrangement was performed in 7 tumors. Five tumors (71%) showed the presence of EWSR1 gene rearrangement, and 2 were negative. Cytogenetic studies conducted on 1 tumor showed 46,XY,t(1;22)(q21;q12) associated with EWSR1-PBX1 fusion. Surgical procedures included curettage in 3 patients, resection in 3 patients, and 2 patients only had an open biopsy. Follow-up information was available for 4 patients; all remain free of disease with no recurrence. Although experience with primary myoepithelioma of bone is limited, histologically, banal tumors appear to behave in a benign manner, and conservative surgery appears to be sufficient treatment. Immunohistochemical and molecular analyses are helpful in their accurate identification. PMID- 23681077 TI - Perineural invasion in T1 oral squamous cell carcinoma indicates the need for aggressive elective neck dissection. AB - Observation or elective neck dissection (END) for cN0 neck remains controversial for the treatment of T1-2 oral squamous cell carcinoma (OSCC). Perineural invasion (PNI) has been recognized as a poor prognostic factor for OSCC. However, its significance in T1 OSCC remains unclear. A detailed histologic reevaluation of PNI was carried out in 307 patients with T1-2 OSCC who received surgical treatment between June 2001 and January 2009. We found that the presence of PNI correlated with cervical lymph node metastasis in both T1 and T2 OSCC, with a lower PNI-positive rate in T1 (17.1% vs. 36.6%; P<0.001). Importantly, observation for cN0 neck was used twice as often in T1 than in T2 patients (47.4% vs. 22.8%; P<0.001). Although patients with T1 OSCC achieved significantly better outcomes, PNI correlated with neck recurrence and poor disease-specific survival (DSS) only in T1 (P<0.001 and P<0.0001) but not in T2 patients (P=0.399 and 0.1478). Of the 146 patients with T1 OSCC, PNI independently predicted cervical lymph node metastasis, neck recurrence, and poor DSS. END significantly reduced neck recurrence of T1 OSCC in PNI-positive (P=0.001) but not in PNI-negative (P=0.114) patients. In addition, END improved the 5-year DSS of T1 OSCC more in PNI-positive than in PNI-negative patients (16.2% vs. 5.4%). Our results indicate that PNI independently predicts a poor prognosis in T1 OSCC patients who are potentially curable but tend to be treated conservatively. For its efficacy in improving treatment outcomes, aggressive END is indicated for T1 OSCC patients at the presence of PNI. PMID- 23681078 TI - Adrenal cortical adenoma: the fourth component of the Carney triad and an association with subclinical Cushing syndrome. AB - The Carney triad is the combination of gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma. Herein, we describe the clinical, imaging, pathologic, and follow-up findings from 14 patients for a fourth component of the syndrome, adrenal adenoma. The adrenal neoplasm was asymptomatic and usually a late finding. Results of adrenocortical function tests were normal. Computed tomography revealed low-density adrenal masses that were consistent with adenomas. Bilateral lesions were present in 4 patients. In 13 of the 14 patients who underwent surgery, resected adrenal glands and biopsy specimens featured 1 or more circumscribed, yellow tumors, up to 3.5 cm in diameter, composed of well differentiated polygonal cells with clear vacuolated cytoplasm and a smaller component of eosinophilic cells. The extratumoral cortex had combinations of normal histologic features, discrete clear cell micronodules, zonal clear cell hypertrophy, and marked atrophy. The lesion in the 14th patient was different, grossly and microscopically resembling the usual sporadic cortisol-secreting adenoma. After the tumor was excised, the patient required glucocorticoid support. None of the tumors recurred or metastasized. Fourteen additional patients had unilateral or bilateral adrenal tumors consistent with adenomas detected by imaging studies. PMID- 23681079 TI - LC3 and p62 as diagnostic markers of drug-induced autophagic vacuolar cardiomyopathy: a study of 3 cases. AB - Autophagic vacuolar cardiomyopathy is an underrecognized, but potentially fatal, complication of treatment with chloroquine (CQ) and its derivative hydroxychloroquine (HCQ), which are used as therapy for malaria and common connective tissue disorders. Currently, the diagnosis of autophagic vacuolar cardiomyopathy is established through an endomyocardial biopsy and requires electron microscopy, which is not widely available and has a significant potential for sampling error. Recently, we have reported that immunohistochemistry for autophagic markers LC3 and p62 can replace electron microscopy in the diagnosis of HCQ-induced and colchicine-induced autophagic vacuolar skeletal myopathies. In the current study, we use 3 cases of CQ-induced or HCQ-induced cardiomyopathy and 1 HCQ-treated control case to show that the same two markers can be used to diagnose autophagic vacuolar cardiomyopathies by light microscopy. CQ-induced or HCQ-induced autophagic vacuolar cardiomyopathy is not universally fatal, but successful treatment requires early detection. By lowering the barriers to diagnosis, the application of these immunohistochemical markers will decrease the number of misdiagnosed patients, thus increasing the likelihood of favorable clinical outcomes. PMID- 23681080 TI - Human papillomavirus is not an etiologic agent of urothelial inverted papillomas. AB - Inverted papilloma of the urinary bladder is rare, accounting for <1% of all bladder neoplasms. Although there is general consensus that inverted papilloma is benign in nature, little is known about its pathogenesis. Some have suggested that human papillomavirus (HPV) plays an etiologic role in the development of this neoplasm. These claims have not been adequately substantiated, and there is controversy as to the role of HPV in other urinary bladder neoplasms as well. To further investigate a possible etiologic role of HPV in urothelial neoplasia, we evaluated 27 inverted papillomas of the urinary bladder for the presence of HPV. Both immunohistochemical and in situ hybridization (ISH) studies for HPV and immunohistochemical analysis for p16, a surrogate marker for HPV infection, were used to assess HPV infection status. In the urinary bladder inverted papillomas of these 27 patients (age range, 35 to 78 y; M:F ratio, 11:1), no HPV was detected by HPV immunohistochemistry or by ISH. Immunoreactivity to p16 was detected in 11/27 (41%) of the cases. Expression of p16 is seen inconsistently within these neoplasms and does not correlate with the presence of HPV antigens or genes by immunohistochemistry or ISH, respectively. Therefore, p16 is not a reliable surrogate marker for HPV infection in urothelial inverted papilloma. Our findings indicate the absence of HPV in urothelial inverted papillomas. HPV testing should not be used as a diagnostic adjunct for inverted papilloma cases. PMID- 23681081 TI - Effects of CPAP on clinical variables and autonomic modulation in children during an asthma attack. AB - Continuous positive airway pressure (CPAP) causes changes in alveolar and intrathoracic pressure and the activation of pulmonary stretch receptors affects the balance of the autonomic nervous system. The acute effects of CPAP on autonomic modulation have been demonstrated in different diseases, but no studies have been carried out addressing CPAP in patients with asthma. The hypothesis tested in the present study is that CPAP can produce an autonomic effect beyond a mechanical effect of bronchial dilatation in children with asthma. The results demonstrated improvements in clinical variables and an increase in vagal tone with the administration of CPAP during an asthma attack, as demonstrated by a diminished respiratory rate and a reduction in signs of respiratory distress. Regarding autonomic modulation, an increase in parasympathetic variables was found, indicating non-cholinergic activation stemming from the persistent increase in peak flow. PMID- 23681083 TI - Internet use among older adults: association with health needs, psychological capital, and social capital. AB - BACKGROUND: Previous studies have identified socioeconomic status and health status as predictors of older adults' computer and Internet use, but researchers have not examined the relationships between older adults' health needs and psychological capital (emotional well-being and self-efficacy) and social capital (social integration/ties and support networks) to different types of Internet use. OBJECTIVE: This study examined (1) whether older adults' health conditions and psychological and social capital differentiate Internet users from nonusers, and (2) whether the Internet users differed in their types of Internet use on the basis of their health conditions and psychological and social capital. METHODS: Data for this study came from the National Health and Aging Trends Study, which is based on a nationally representative sample of US Medicare beneficiaries aged 65 years and older. The sample for this study were those who resided in the community in their own or others' homes (N=6680). Binary logistic regression analysis was used to compare health needs, psychological capital, and social capital among (1) any type of Internet users and nonusers, (2) Internet users who engaged in health-related tasks and Internet users who did not, (3) Internet users who engaged in shopping/banking tasks and Internet users who did not, and (4) Internet users only used the Internet for email/texting and all other Internet users. RESULTS: Depressive and anxiety symptoms, measures of psychological capital, were negatively associated with Internet use among older adults (odds ratio [OR] 0.83, 95% CI 0.70-0.98, P=.03 and OR 0.79, 95% CI 0.65 0.97, P=.03, respectively), whereas most measures of social capital were positively associated with Internet use. Having more chronic medical conditions and engaging in formal volunteering increased the odds of Internet use for health related tasks by 1.15 (95% CI 1.08-1.23, P<.001) and 1.28 (95% CI 1.05-1.57, P=.02), respectively, but anxiety symptoms decreased the odds (OR 0.74, 95% CI 0.55-0.99, P=.05). Religious service attendance was negatively associated with Internet use for shopping/banking activities (OR 0.75, 95% CI 0.62-0.91, P=.01). Anxiety symptoms increased the odds of using the Internet only for emails/texting (OR 1.75, 95% CI 1.12-2.75, P=.02), but formal volunteering decreased the odds (OR 0.63, 95% CI 0.43-0.92, P=.02). Other correlates of Internet use solely for emails/texting were older age (80-84 years and >=85 years), a black or "other" racial/ethnic background, a high school education or less than high school, and lower income. CONCLUSIONS: The findings point to the importance of social capital in facilitating older adults' learning and adoption of Internet technology. Older adults who used the Internet for email/texting purposes only were the most socially and economically disadvantaged group of Internet users. Computer/Internet training for older adults and computer/Internet use for various purposes need to consider the significant role their social capital can play. PMID- 23681084 TI - Generation and validation of a normative, age-specific reference curve for lumbar spine trabecular bone score (TBS) in French women. AB - Age-related changes in lumbar vertebral microarchitecture are evaluated, as assessed by trabecular bone score (TBS), in a cohort of 5,942 French women. The magnitude of TBS decline between 45 and 85 years of age is piecewise linear in the spine and averaged 14.5%. TBS decline rate increases after 65 years by 50%. INTRODUCTION: This study aimed to evaluate age-related changes in lumbar vertebral microarchitecture, as assessed by TBS, in a cohort of French women aged 45-85 years. METHODS: An all-comers cohort of French Caucasian women was selected from two clinical centers. Data obtained from these centers were cross-calibrated for TBS and bone mineral density (BMD). BMD and TBS were evaluated at L1-L4 and for all lumbar vertebrae combined using GE-Lunar Prodigy densitometer images. Weight, height, and body mass index (BMI) also were determined. To validate our all-comers cohort, the BMD normative data of our cohort and French Prodigy data were compared. RESULTS: A cohort of 5,942 French women aged 45 to 85 years was created. Dual-energy X-ray absorptiometry normative data obtained for BMD from this cohort were not significantly different from French prodigy normative data (p = 0.15). TBS values at L1-L4 were poorly correlated with BMI (r = -0.17) and weight (r = -0.14) and not correlated with height. TBS values obtained for all lumbar vertebra combined (L1, L2, L3, L4) decreased with age. The magnitude of TBS decline at L1-L4 between 45 and 85 years of age was piecewise linear in the spine and averaged 14.5%, but this rate increased after 65 years by 50%. Similar results were obtained for other region of interest in the lumbar spine. As opposed to BMD, TBS was not affected by spinal osteoarthrosis. CONCLUSION: The age-specific reference curve for TBS generated here could therefore be used to help clinicians to improve osteoporosis patient management and to monitor microarchitectural changes related to treatment or other diseases in routine clinical practice. PMID- 23681085 TI - The efficacy of calcium supplementation alone in elderly Thai women over a 2-year period: a randomized controlled trial. AB - Supplementation with elemental calcium 500 mg/day alone for 2 years is able to decrease bone turnover and is effective in retarding bone loss at lumbar spine and slowing bone loss at femoral neck in elderly Thai women who had low dietary calcium intake. INTRODUCTION: Most elderly Thais have a total dietary calcium intake of less than the recommended amount. The aim of the study was to investigate the effect of calcium supplementation on bone mineral density and biochemical indices of bone remodeling in Thai postmenopausal women. METHODS: Four hundred and four healthy postmenopausal women 60 years old or older without osteoporosis were recruited and conducted in a randomized, double-blinded, placebo-controlled trial. They were randomly given elementary calcium 500 mg/day or placebo for 2 years. Dietary calcium intake was calculated from the nutrient compositional analysis of the 3-day food records. Serum 25 hydroxyvitamin D was measured by radioimmunoassay and bone turnover markers were determined by electrochemiluminescence immunoassay. RESULTS: The age of the subjects was 65.8 +/- 4.4 years. All baseline characteristics of the subjects in the calcium supplemented group and the placebo group were not statistically different. At the end of the study, significant decreases in serum C-terminal telopeptide of type I collagen and serum total procollagen type I amino terminal propeptide in the calcium-supplemented group were observed, while there was no change in the placebo group. In addition, plasma parathyroid hormone decreased, although not significantly, only in the calcium-supplemented group. Percent changes from baseline of lumbar spine (L2-L4) bone mineral density increased 2.76% in the calcium-supplemented group and 0.87% in the placebo group, whereas the percent changes from baseline of femoral neck decreased 0.21% in the calcium-supplemented group and 0.90% in the placebo group. CONCLUSIONS: Calcium supplementation is necessary for the decrease of bone turnover and prevention of bone loss in Thai elderly women. PMID- 23681082 TI - Clinical consequences of altered chemoreflex control. AB - Control of ventilation dictates various breathing patterns. The respiratory control system consists of a central pattern generator and several feedback mechanisms that act to maintain ventilation at optimal levels. The concept of loop gain has been employed to describe its stability and variability. Synthesizing all interactions under a general model that could account for every behavior has been challenging. Recent insight into the importance of these feedback systems may unveil therapeutic strategies for common ventilatory disturbances. In this review we will address the major mechanisms that have been proposed as mediators of some of the breathing patterns in health and disease that have raised controversies and discussion on ventilatory control over the years. PMID- 23681086 TI - Bone mass and density in preadolescent boys with and without Down syndrome. AB - Preadolescent boys with Down syndrome at 7-10 years of age have lower bone mass and density in the pelvis than age-matched children without Down syndrome. However, bone mass and density of total body less head and lumbar spine are not different between these two groups. INTRODUCTION: This study aimed to assess bone mineral content (BMC) and density (BMD) in preadolescent boys with and without Down syndrome (DS) at 7-10 years of age. METHODS: Eleven preadolescent boys with DS and eleven age-matched children without DS participated in this study. Dual energy X-ray absorptiometry was used to measure BMC and BMD in whole body and lumbar spine. Both BMC and BMD of total body less head (TBLH) and lumbar spine (vertebrae L2-L4) were compared between the two groups, with and without adjusting for physical characteristics such as bone area, body height, and total lean mass. Two bone mineral apparent density (BMAD) variables were calculated to estimate volumetric BMD in the lumbar spine. RESULTS: Both BMC and BMD in the pelvis were lower in the DS group, after adjusting for physical characteristics. However, with and without adjusting for physical characteristics, the two groups were not different in BMC and BMD of the arms, legs, and TBLH from the whole body scan and in BMC, BMD, and BMAD of the lumbar spine from the lumbar spine scan. CONCLUSIONS: These findings indicate that the pelvis may be the first site to show the significant difference in BMC and BMD between preadolescent boys with and without DS. It also suggests that significantly lower BMC and BMD in whole body and lumbar spine, which is usually observed in young adults with DS, may not occur before adolescence. PMID- 23681087 TI - Ankle fractures have features of an osteoporotic fracture. AB - We report the bone attenuation of ankle joint measured on computed tomography (CT) and the cause of injury in patients with ankle fractures. The results showed age- and gender-dependent low bone attenuation and low-energy trauma in elderly females, which suggest the osteoporotic features of ankle fractures. INTRODUCTION: This study was performed to investigate the osteoporotic features of ankle fracture in terms of bone attenuation and cause of injury. METHODS: One hundred ninety-four patients (mean age 51.0 years, standard deviation 15.8 years; 98 males and 96 females) with ankle fracture were included. All patients underwent CT examination, and causes of injury (high/low-energy trauma) were recorded. Mean bone attenuations of the talus, medial malleolus, lateral malleolus, and distal tibial metaphysis were measured on CT images. Patients were divided into younger age (<50 years) and older age (>=50 years) groups, and mean bone attenuation and causes of injury were compared between the two groups in each gender. RESULTS: Proportion of low-energy trauma was higher in the older age group than in the younger age group, but the difference was only significant in female gender (p = 0.011). The older age group showed significantly lower bone attenuation in the talus, medial malleolus, lateral malleolus, and distal tibial metaphysis than the younger age group in both genders. The older age group showed more complex pattern of fractures than the younger age group. With increasing age, bone attenuations tended to decrease and the difference of bone attenuation between the genders tended to increase in the talus, medial malleolus, lateral malleolus, and distal tibial metaphysis. CONCLUSIONS: Ankle fracture had features of osteoporotic fracture that is characterized by age- and gender-dependent low bone attenuation. Ankle fracture should not be excluded from the clinical and research interest as well as from the benefit of osteoporosis management. PMID- 23681089 TI - Pseudoarthrosis in atypical femoral fracture: case report. AB - Atypical femoral fractures can be subsequent to a long-term biphosphonates treatment; they have a high frequency of delayed healing. The authors describe a femoral pseudoarthrosis of an atypical fracture treated with intramedullary nailing in a female after prolonged alendronate therapy. Atypical femoral fractures can be subsequent to a long-term biphosphonates treatment even if, in the literature, there is no clarity on the exact pathogenetic mechanism. The Task Force of the American Society for Bone and Mineral Research described the major and minor features to define atypical fractures and recommends that all the five major features must be present while minor features are not necessary. Another controversial aspect regarding the atypical femoral fractures is the higher frequency of the delayed healing that can be probably related to a suppressed bone turnover caused by a prolonged period of bisphosphonates treatment. This concept could be corroborated by the Spet Tc exam. In the case of a pseudoarthrosis, there is not a standardization of the treatment. In this report, the authors describe a femoral pseudoarthrosis of an atypical fracture treated with intramedullary nailing in a female after prolonged alendronate therapy; the patient was studied with clinical, bioumoral end SPECT-Tc exam of both femurs. Many studies show the relationship between bisphosphonates and the presence of atypical fractures. These fractures should be monitored more closely due to the risk of nonunion and they require considering an initial treatment with pharmacological augmentation to reduce the complications for the patient and the health care costs. PMID- 23681088 TI - Bisphosphonate use and subsequent hip fracture in South Korea. AB - We determined the incidence of second hip fracture and evaluated whether compliant and persistent users of bisphosphonate had a lower incidence of second hip fracture after prior hip fracture, from a national claim registry. INTRODUCTION: Bisphosphonate is prescribed worldwide for the primary prevention of osteoporotic fracture. However, the association between adherent use of bisphosphonate and prevention of second hip fracture is unclear. Our purpose was to determine whether the adherent use of bisphosphonate was associated with a decreased risk of second hip fracture in South Korea, using a nationwide database. METHODS: From 2007 to 2011, first and second hip fractures were identified using the ICD-10 and procedure code form from the nationwide database of the Health Insurance Review and Assessment Service. Compliant use of bisphosphonate was defined as a patient medication possession ratio of 80 or more. Persistent users were defined patients with a refill gap of 30 days or less. We compared the incidence of second hip fracture in compliant and persistent users and non-users. RESULTS: Among 59,782 patients with first hip fracture, in this study, 1,336 second hip fracture occurred after the initial hip fracture during the study period. The mean age at the first hip fracture was 75.4 years (range, 50 to 100 years). The cumulative 1-year, 2-year, and 3-year incidence of second hip fracture was 1.0% (552/59,782), 1.9% (1,123/59,782), and 2.2% (1,336/59,782), respectively. After multivariate analysis, compliant and persistent use of bisphosphonate was significantly independent protectors for second hip fracture (HR, 0.595; 95% CI, 0.400-0.885; HR, 0.433; 95% CI, 0.327 0.573, respectively). CONCLUSIONS: Compliant and persistent use of bisphosphonate decreases the risk of second hip fracture, in terms of secondary prevention. PMID- 23681090 TI - Spatial distribution and vertical migration of (137)Cs in soils of Belgrade (Serbia) 25 years after the Chernobyl accident. AB - In this study, the specific activity of (137)Cs was determined by gamma-ray spectrometry in 72 surface soil samples and 11 soil profiles collected from the territory of Belgrade 25 years after the Chernobyl accident. Based on the data obtained the external effective gamma dose rates due to (137)Cs were assessed and geographically mapped. The influence of pedogenic factors (pH, specific electrical conductivity, cation exchange capacity, organic matter content, soil particle size and carbonate content) on the spatial and vertical distribution of (137)Cs in soil was estimated through Pearson correlations. The specific activity of (137)Cs in surface soil samples ranged from 1.00 to 180 Bq kg(-1), with a mean value of 29.9 Bq kg(-1), while in soil profiles they ranged from 0.90 to 58.0 Bq kg(-1), with a mean value of 15.3 Bq kg(-1). The mean external effective gamma dose at 1 m above the ground due to (137)Cs in the soil was calculated to be 1.96 nSv h(-1). Geographic mapping of the external effective gamma dose rates originating from (137)Cs revealed much higher dose rates in southern parts of Belgrade city and around the confluence of the Sava and Danube. Negative Pearson correlation coefficients were found between pH, cation exchange capacity and (137)Cs specific activity in surface soil. There were positive correlations between organic matter and (137)Cs specific activity in surface soil; and between specific electrical conductivity, organic matter, silt content and (137)Cs specific activity in soil profiles. PMID- 23681092 TI - An easy to deploy street light control system based on wireless communication and LED technology. AB - This paper presents an intelligent streetlight management system based on LED lamps, designed to facilitate its deployment in existing facilities. The proposed approach, which is based on wireless communication technologies, will minimize the cost of investment of traditional wired systems, which always need civil engineering for burying of cable underground and consequently are more expensive than if the connection of the different nodes is made over the air. The deployed solution will be aware of their surrounding's environmental conditions, a fact that will be approached for the system intelligence in order to learn, and later, apply dynamic rules. The knowledge of real time illumination needs, in terms of instant use of the street in which it is installed, will also feed our system, with the objective of providing tangible solutions to reduce energy consumption according to the contextual needs, an exact calculation of energy consumption and reliable mechanisms for preventive maintenance of facilities. PMID- 23681091 TI - 3D preoperative planning in the ER with OsiriX(r): when there is no time for neuronavigation. AB - The evaluation of patients in the emergency room department (ER) through more accurate imaging methods such as computed tomography (CT) has revolutionized their assistance in the early 80s. However, despite technical improvements seen during the last decade, surgical planning in the ER has not followed the development of image acquisition methods. The authors present their experience with DICOM image processing as a navigation method in the ER. The authors present 18 patients treated in the Emergency Department of the Hospital das Clinicas of the University of Sao Paulo. All patients were submitted to volumetric CT. We present patients with epidural hematomas, acute/subacute subdural hematomas and contusional hematomas. Using a specific program to analyze images in DICOM format (OsiriX((r))), the authors performed the appropriate surgical planning. The use of 3D surgical planning made it possible to perform procedures more accurately and less invasively, enabling better postoperative outcomes. All sorts of neurosurgical emergency pathologies can be treated appropriately with no waste of time. The three-dimensional processing of images in the preoperative evaluation is easy and possible even within the emergency care. It should be used as a tool to reduce the surgical trauma and it may dispense methods of navigation in many cases. PMID- 23681093 TI - Mobile monitoring and reasoning methods to prevent cardiovascular diseases. AB - With the recent technological advances, it is possible to monitor vital signs using Bluetooth-enabled biometric mobile devices such as smartphones, tablets or electric wristbands. In this manuscript, we present a system to estimate the risk of cardiovascular diseases in Ambient Assisted Living environments. Cardiovascular disease risk is obtained from the monitoring of the blood pressure by means of mobile devices in combination with other clinical factors, and applying reasoning techniques based on the Systematic Coronary Risk Evaluation Project charts. We have developed an end-to-end software application for patients and physicians and a rule-based reasoning engine. We have also proposed a conceptual module to integrate recommendations to patients in their daily activities based on information proactively inferred through reasoning techniques and context-awareness. To evaluate the platform, we carried out usability experiments and performance benchmarks. PMID- 23681094 TI - Using a fiber loop and fiber bragg grating as a fiber optic sensor to simultaneously measure temperature and displacement. AB - This study integrated a fiber loop manufactured by using commercial fiber (SMF 28, Corning) and a fiber Bragg grating (FBG) to form a fiber optic sensor that could simultaneously measure displacement and temperature. The fiber loop was placed in a thermoelectric cooling module with FBG affixed to the module, and, consequently, the center wavelength displacement of FBG was limited by only the effects of temperature change. Displacement and temperature were determined by measuring changes in the transmission of optical power and shifts in Bragg wavelength. This study provides a simple and economical method to measure displacement and temperature simultaneously. PMID- 23681095 TI - Study on a real-time BEAM system for diagnosis assistance based on a system on chips design. AB - As an innovative as well as an interdisciplinary research project, this study performed an analysis of brain signals so as to establish BrainIC as an auxiliary tool for physician diagnosis. Cognition behavior sciences, embedded technology, system on chips (SOC) design and physiological signal processing are integrated in this work. Moreover, a chip is built for real-time electroencephalography (EEG) processing purposes and a Brain Electrical Activity Mapping (BEAM) system, and a knowledge database is constructed to diagnose psychosis and body challenges in learning various behaviors and signals antithesis by a fuzzy inference engine. This work is completed with a medical support system developed for the mentally disabled or the elderly abled. PMID- 23681096 TI - The good, the bad and the ugly - TFH cells in human health and disease. AB - Antibody production is an important feature of the vertebrate immune system. Antibodies neutralize and clear pathogens, thereby protecting against infectious diseases. Such humoral immunity has great longevity, often persisting for the host's lifetime. Long-lived humoral immunity depends on help provided by CD4(+) T cells, namely T follicular helper (TFH) cells, which support the differentiation of antigen-specific B cells into memory and plasma cells. TFH cells are stringently regulated, as aberrant TFH cell activity is involved in immunopathologies such as autoimmunity, immunodeficiencies and lymphomas. The elucidation of the mechanisms that regulate TFH cell differentiation, function and fate should highlight targets for novel therapeutics. PMID- 23681098 TI - Mucosal immunology: TLRs get rhythm. PMID- 23681097 TI - The plasticity and stability of regulatory T cells. AB - Regulatory T (TReg) cells are crucial for the prevention of fatal autoimmunity in mice and humans. Forkhead box P3 (FOXP3)(+) TReg cells are produced in the thymus and are also generated from conventional CD4(+) T cells in peripheral sites. It has been suggested that FOXP3(+) TReg cells might become unstable under certain inflammatory conditions and might adopt a phenotype that is more characteristic of effector CD4(+) T cells. These suggestions have caused considerable debate in the field and have important implications for the therapeutic use of TReg cells. In this article, Nature Reviews Immunology asks several experts for their views on the plasticity and stability of TReg cells. PMID- 23681099 TI - Tolerance: the origins of colonic TReg cells. PMID- 23681100 TI - Natural killer cells: adaptive control of NK cells. PMID- 23681102 TI - Implantable cardioverter-defibrillators in patients with COPD. AB - BACKGROUND: COPD is a common comorbidity in heart failure. The efficacy of implantable cardioverter-defibrillator (ICD) therapy has not been determined in patients with heart failure and COPD. METHODS: We examined the incidence of ICD shocks and mortality in 628 consecutive patients who underwent defibrillator implantation at the Minneapolis Veterans Affairs Medical Center from 2006 to 2010. RESULTS: The mean age of the patients was 67 +/- 10 years, and 99% were men. Patients with COPD (n = 246 [39%]) were functionally more limited (P < .0001) and more likely to have an ICD for primary prevention of sudden death (P = .04) than those without COPD. Over a median 4.1 years (interquartile range [IQR] 2.2-5.7) of follow-up, patients with COPD had a higher incidence of appropriate shocks than those without COPD (29% vs 17%; P < .0001), whereas the incidence of inappropriate shocks was similar (9% vs 10%, P = .61). In multivariable analysis, COPD was associated with a twofold increase in the odds of an appropriate ICD shock (95% CI, 1.3-2.9; P = .001). Incidence of ICD shocks did not vary with severity of COPD. Although all-cause mortality was higher in patients with COPD than in those without COPD (29% vs 21%, P = .029), 1-year mortality (5.3% vs 2.6%, P = .08) and the average time from first appropriate ICD shock to death was comparable (median, 2.3 [IQR, 1.2-4.4] vs 2.8 [IQR, 1.4-5.3] years; P = .29). CONCLUSIONS: Patients with COPD have a higher incidence of ICD shocks than those without COPD and appear to benefit from ICD therapy. PMID- 23681101 TI - The history of Toll-like receptors - redefining innate immunity. AB - The discovery of Toll-like receptors (TLRs) was an important event for immunology research and was recognized as such with the awarding of the 2011 Nobel Prize in Physiology or Medicine to Jules Hoffmann and Bruce Beutler, who, together with Ralph Steinman, the third winner of the 2011 Nobel Prize and the person who discovered the dendritic cell, were pioneers in the field of innate immunity. TLRs have a central role in immunity - in this Timeline article, we describe the landmark findings that gave rise to this important field of research. PMID- 23681105 TI - Lemon peel and Limoncello liqueur: a proteomic duet. AB - Combinatorial peptide ligand libraries (CPLLs) have been adopted for investigating the proteomes of lemon peels and pulp, of a home-made alcoholic infusion of peels and of a very popular Italian liqueur called "Limoncello", stated to be an infusion of the flavedo (the outer, yellow skin of lemons). The aim of this study was not only to perform the deepest investigation so far of the lemon peel proteome but also to assess the genuineness of the commercial liqueur via a three-pronged attack. First, different extraction techniques have been used for the characterization of the peel (and additionally of the pulp) proteome, secondly a home-made infusion has been analysed and finally the proteome of the commercial drink was checked. The peel (the flavedo, not the underlying layer called albedo) proteome has been evaluated via prior capture with CPLLs at different pH values (2.2 and 7.2). Via mass spectrometry analysis of the recovered fractions, after elution of the captured populations in 4% boiling SDS, we could identify a total of 1011 unique gene products in the peel extracts and 674 in the pulp, 264 proteins in the home-made infusion and just 8 proteins (and protein fragments), together with 12 peptides, in one Italian Limoncello produced in the Sorrento Region, thus proving the genuineness of this product. On the contrary, cheaper Limoncellos were devoid of any protein/peptide, casting doubts on their production from vegetable extracts. This could be the starting point for investigating the genuineness and natural origin of commercial drinks in order to protect consumers from adulterated products. PMID- 23681108 TI - In memoriam. PMID- 23681104 TI - Taurine ameliorates neurobehavioral, neurochemical and immunohistochemical changes in sporadic dementia of Alzheimer's type (SDAT) caused by intracerebroventricular streptozotocin in rats. AB - Oxidative loads in the brain are involved in age related impairments like learning and memory as well as neurodegeneration. Taurine, the most abundant free amino acid in humans has many potential health benefits through its anti-oxidant and anti-inflammatory properties. Therefore, we investigated the neuroprotective potential of taurine on oxidative stress, neuronal loss and memory impairments in streptozotocin model of cognitive impairments in rats. The cognitive impairment was developed by giving single intracerebroventricular (ICV) injection of streptozotocin (STZ) 3 mg/kg body weight bilaterally. An increased latency and path length was observed in ICV-STZ group animals as compared to sham group animals and these were inhibited significantly in STZ group pre-treated with taurine (50 mg/kg body weight orally once daily for 15 days). Moreover, the significantly depleted content of GSH and elevated level of thiobarbituric acid reactive substances (TBARS) in ICV-STZ group animals were protected significantly with pre-treatment of taurine. The activity of antioxidant enzymes, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, catalase, and superoxide dismutase was decreased in STZ group as compared to sham group and pre treatment of STZ group with taurine has protected their activities significantly. Furthermore, the increased activity of acetylcholine esterase and decreased expression of choline acetyl transferase were attenuated by the pre-treatment of taurine. Taurine also protected the morphology of the hippocampal pyramidal neurons. This study concludes that the prophylactic intervention of taurine may be used to prevent the deterioration of cognitive functions and neurobehavioral activities, often associated with the generation of free radicals. PMID- 23681109 TI - Do novel oral anticoagulants do better than standard therapy in the treatment of deep vein thrombosis? AB - The focus of DVT treatment is the prevention of recurrence and thrombus migration by treatment with anticoagulants. The aim is to improve outcomes by reducing clot burden and by preventing thrombus propagation, in order to prevent PE and the development of long-term complication. Actually, initial therapy is parenteral anticoagulation, mainly with low molecular weight heparin followed by a vitamin K antagonist (VKA) for triggered and idiopathic DVT. The long term treatment suggestion with a VKA is for sure the most challenging therapeutic scenario, showing all the disadvantages of VKA especially in the onset phase when therapeutic levels of VKA are difficult to achieve. The difference between VKAs and NOACs is the fact, that NOACs target a specific factor in the coagulation cascade. At time now two pathways have been chosen for treatment options, the direct inhibition of active sites of thrombin and factor Xa. Routine monitoring is not required and the drugs can be administered in fixed doses, which should increase patient adherence to long term treatment. At time now, four novel anticoagulants are called to be options for DVT treatment. Rivaroxaban, apixaban and edoxaban are direct FXa inhibitors, whereas dabigtran etexilate is a direct thrombin inhibitor. PMID- 23681110 TI - Pressure dependent photolysis quantum yields for CH3C(O)CH3 at 300 and 308 nm and at 298 and 228 K. AB - The quantum yield of formation of CH3 and CH3CO in the pulsed laser photo excitation of acetone at 300 and 308 nm was investigated at several pressures (60 to 740 Torr) and at either 298 or 228 K. The organic radicals generated were monitored indirectly following conversion (by reaction with Br2) to Br atoms, which were detected by resonance fluorescence. The photolysis of Cl2 in back-to back experiments at the same wavelength and under identical experimental conditions served as chemical actinometer. The pressure and temperature dependent quantum yields obtained with this method are in good agreement with previous literature values and are reproduced using the parameterisation developed by Blitz et al. The Br formation kinetics deviated from that expected from reactions of CH3 and CH3CO alone and Br atoms were still observed at high yield even when the quantum yield of formation of CH3 and CH3CO was low. This is explained by the reactive quenching of thermalized triplet acetone (T1) by Br2. High yields of T1 (>80%) at the highest pressure in this study indicate that any dissociation from the first excited singlet state (S1) occurs in competition with intersystem crossing, and that physical quenching of S1 to the electronic ground (S0) is not a major process at these wavelengths. The rate coefficient for reaction of T1 with Br2 was found to be ~3 * 10(-10) cm(3) molecule(-1) s(-1), independent of pressure or temperature. PMID- 23681111 TI - Structural and electronic properties of a large-scale Moire pattern of hexagonal boron nitride on Cu(111) studied with density functional theory. AB - Hexagonal boron nitride (h-BN) adsorbed on metal surfaces shows great promise for applications in nanoscience. Depending on the nature of the substrate, effects such as an extended corrugation of the monolayer can be observed and utilized, e.g. for the patterning of adsorbed molecules. Here we present an in-depth computational study of the structural and electronic properties of a 6 nm Moire pattern formed by a rotated layer of h-BN on a Cu(111) surface. In contrast to related systems, the h-BN layer undergoes only minute structural changes upon adsorption. Nevertheless, the projected density of states at various atoms in the cell and the electrostatic potential above the surface are periodically modulated, leading to the experimentally observed electronic corrugation. We rationalize this observation with the variation in adsorption registry resulting in periodic changes of the lateral, rather than vertical, h-BN-Cu distances. PMID- 23681112 TI - Galectin-1 (GAL-1) expression is a useful tool to differentiate between small cell osteosarcoma and Ewing sarcoma. AB - Galectin-1 (GAL-1) is frequently expressed in osteosarcomas. Although a valuable diagnostic marker to differentiate between chondroblastic osteosarcomas and conventional chondrosarcomas, it has not been tested in the Ewing sarcoma family of tumors (ESFTs). We studied by immunohistochemistry GAL-1 expression in 43 osteosarcomas, 23 chondrosarcomas, and 217 genetically confirmed ESFTs using a tissue microarray. GAL-1 was expressed in 78 % of osteosarcomas, 33 % of chondrosarcomas, and 8 % of ESFTs. Osteoblastic and small cell osteosarcoma subtypes expressed GAL-1 in a high percentage of cells when compared with the other histological subtypes, whereas two chondroblastic osteosarcomas were negative. GAL-1 was mainly expressed in high-grade chondrosarcomas (grade III). ESFTs were rarely positive (8 %), and this was not related to the histological subtype nor to the clinical outcome. Although GAL-1 expression distinguishes chondroblastic osteosarcomas from conventional chondrosarcomas and is usually negative in conventional chondrosarcomas, the final diagnosis needs to incorporate histopathology since some chondroblastic osteosarcomas fail to express GAL-1, while high-grade chondrosarcomas are GAL-1 positive. Since GAL-1 is frequently expressed in osteogenic tumors, including small cell osteosarcoma, but rarely positive in ESFTs, its expression seems a valuable tool for distinguishing between these lesions. GAL-1 immunoexpression is not indicative of prognosis in ESFT. PMID- 23681113 TI - Specific lymph node involvement in scleromyxedema: a new diagnostic entity for hypermetabolic lymphadenopathy. AB - Scleromyxedema is a generalized skin disease mostly associated with monoclonal gammopathy. In its chronic course, it can lead to systemic disorders related to mucin deposits in organs. We describe here specific lymph node involvement, hitherto not reported in scleromyxedema. A 68-year-old man with a 1-year history of micropapular eruption and skin sclerosis involving the neck, trunk, hands, and face was diagnosed with scleromyxedema associated with IgG kappa monoclonal gammopathy. Enlarged mediastinal lymph nodes found on thoracic X-ray and computed tomography scan were hypermetabolic on positron emission tomography. Lymph node biopsy showed partial nodal infiltration by numerous fibroblasts surrounded by mucin and collagen deposits, the same being observed on the skin biopsy. Lymph node and skin lesions both improved after intravenous immunoglobulin and corticosteroid treatment. Lymph node involvement in scleromyxedema should be considered in the etiological diagnosis of hypermetabolic, enlarged lymph nodes, especially if monoclonal gammopathy is associated. PMID- 23681114 TI - Differential expression of E-cadherin, beta-catenin, and Lewis x between invasive hydatidiform moles and post-molar choriocarcinomas. AB - Trophoblast cell adhesion and migration are carefully coordinated during normal placental development. We have compared the expression of three adhesion molecules, E-cadherin, beta-catenin, and Lewis x, by immunohistochemistry during normal trophoblast differentiation, and in hydatidiform moles and choriocarcinomas. Both E-cadherin and beta-catenin were expressed in normal placenta cytotrophoblast, and this expression decreased with trophoblast maturation. E-cadherin was mainly localized along the contact between cytotrophoblast and syncytiotrophoblast, which indicates its role in the differentiation of the syncytial layer. Lewis x disappeared progressively during differentiation of normal villous vessels, and was expressed in molar pregnancies. Interestingly, whereas choriocarcinomas were not, or poorly, stained, invasive hydatidiform moles (invHMs) strongly expressed Lewis x in vascular structures. This observation correlated well with E-cadherin and beta catenin expression and suggests that these three markers are associated with the invasive transformation. The presence of robust endothelial structures in invHMs could also explain their ability to maintain organized villous architecture (contrary to metastatic choriocarcinomas) during their invasion of extrauterine tissues such as the lung or the brain after dissemination through the blood flow. In our hands, Lewis x appeared to be a new, reliable marker that can be used to clearly distinguish invHMs from choriocarcinomas. PMID- 23681115 TI - Longitudinal fundus and retinal studies with SD-OCT: a comparison of five mouse inbred strains. AB - Spectral domain optical coherence tomography (SD-OCT) has recently been established as a method for in vivo imaging of fundus and retina in the mouse. It enables more effective studies of retinal diseases including investigations of etiopathologic mechanisms. In order to learn more about longitudinal fundus development and to enable recognition of disease-associated irregularities, we performed confocal scanning laser ophthalmoscopy (cSLO) and SD-OCT measurements in the inbred strains C57BL/6J, C3HeB/FeJ, FVB/NCrl, BALB/cByJ, and 129S2/SvJ when they were between 2 and 6 months of age. In general, cSLO and SD-OCT data did not reveal sex-specific or unilateral differences. C3HeB/FeJ and FVB/NCrl mice showed diffuse choroidal dysplasia. Choroidal vein-like structures appeared as dark fundus stripes in C3HeB/FeJ. In FVB/NCrl, fundus fleck accumulation was found. In contrast, only minor time-dependent changes of fundus appearance were observed in C57BL/6J, BALB/cByJ, and 129S2/SvJ. This was also found for individual fundic main blood vessel patterns in all inbred strains. Vessel numbers varied between 6 and 13 in C57BL/6J. This was comparable in most cases. We further found that retinae were significantly thicker in C57BL/6J compared to the other strains. Total retinal thickness generally did not change between 2 and 6 months of age. As a conclusion, our results indicate lifelong pathologic processes in C3HeB/FeJ and FVB/NCrl that affect choroid and orbital tissues. Inbred strains with regular retinal development did not reveal major time dependent variations of fundus appearance, blood vessel pattern, or retinal thickness. Consequently, progressive changes of these parameters are suitable indicators for pathologic outliers. PMID- 23681116 TI - Dosimetric accuracy assessment of a treatment plan verification system for scanned proton beam radiotherapy: one-year experimental results and Monte Carlo analysis of the involved uncertainties. AB - During one year of clinical activity at the Italian National Center for Oncological Hadron Therapy 31 patients were treated with actively scanned proton beams. Results of patient-specific quality assurance procedures are presented here which assess the accuracy of a three-dimensional dose verification technique with the simultaneous use of multiple small-volume ionization chambers. To investigate critical cases of major deviations between treatment planning system (TPS) calculated and measured data points, a Monte Carlo (MC) simulation tool was implemented for plan verification in water. Starting from MC results, the impact of dose calculation, dose delivery and measurement set-up uncertainties on plan verification results was analyzed. All resulting patient-specific quality checks were within the acceptance threshold, which was set at 5% for both mean deviation between measured and calculated doses and standard deviation. The mean deviation between TPS dose calculation and measurement was less than +/-3% in 86% of the cases. When all three sources of uncertainty were accounted for, simulated data sets showed a high level of agreement, with mean and maximum absolute deviation lower than 2.5% and 5%, respectively. PMID- 23681117 TI - Daily dynamics of leaf and soil-to-branch hydraulic conductance in silver birch (Betula pendula) measured in situ. AB - Daily dynamics of leaf (K(L)) and soil-to-branch hydraulic conductance (KS-B) was investigated in silver birch (Betula pendula Roth.) using evaporative flux method in situ: water potential drop was measured with a pressure chamber and evaporative flux was estimated as sap flux density measured with sap flow gauges. Canopy position had a significant (P < 0.001) effect on both K(L) and K(S-B). Upper-canopy leaves exhibited 1.7 and soil-to-branch pathway 2.3 times higher hydraulic efficiency than those for lower-canopy. K(L) varied significantly with time of day: K(L) for both upper- and lower-canopy leaves was lowest in the morning and rose gradually achieving maximal values in late afternoon (4.75 and 3.38 mmol m-2 s-1 MPa-1, respectively). Relevant environmental factors affecting K(L) were photosynthetic photon flux density (Q(P)), air relative humidity (RH) and air temperature (T(A)). K(S-B) started rising in the morning and reached maximum in the lower canopy (1.44 mmol m-2 s-1 MPa-1) at 1300 h and in the upper canopy (2.52 mmol m-2 s-1 MPa-1) at 1500 h, decreasing afterwards. Environmental factors controlling K(S-B) were Psi(S) and Q(P). The diurnal patterns of K(L) reflect a combination of environmental factors and endogenous rhythms. The temporal pattern of K(S-B) refers to daily up- and down-regulation of hydraulic conductance of water transport pathway from soil-root interface to leaves with respect to changing irradiance. PMID- 23681118 TI - Early rehabilitation prevents disability after earthquake: A letter to international rehabilitation colleagues. PMID- 23681119 TI - Flumequine enhances the in vivo mutagenicity of MeIQx in the mouse liver. AB - The combined effects of various carcinogens found in food products are a concern for human health. In the present study, the effects of flumequine (FL) on the in vivo mutagenicity of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in the liver were investigated. Additionally, we attempted to clarify the underlying mechanisms through comprehensive gene analysis using a cDNA microarray. Male gpt delta mice were fed a diet of 0.03 % MeIQx, 0.4 % FL, or 0.03 % MeIQx + 0.4 % FL for 13 weeks. The effects of cotreatment with phenobarbital (PB) were also examined. Treatment with MeIQx alone increased gpt and Spi(-) mutant frequencies, and cotreatment with FL, but not with PB, further exacerbated these effects, despite the lack of in vivo genotoxicity in mice treated with FL alone. FL caused an increase in Cyp1a2 mRNA levels and a decrease in Ugt1b1 mRNA levels, suggesting that the enhancing effects of FL may be due in part to modification of MeIQx metabolism by FL. Moreover, FL induced an increase in hepatocyte proliferation accompanied by hepatocellular injury. Increases in the mRNA levels of genes encoding cytokines derived from Kupffer cells, such as Il1b and Tnf, and cell cycle-related genes, such as Ccnd1 and Ccne1, suggested that FL treatment increases compensatory cell proliferation. Thus, the present study clearly demonstrated the combined effects of 2 different types of carcinogens known as contaminants in foods. PMID- 23681122 TI - CAPITO--a web server-based analysis and plotting tool for circular dichroism data. AB - MOTIVATION: Circular dichroism (CD) spectroscopy is one of the most versatile tools to study protein folding and to validate the proper fold of purified proteins. Here, we aim to provide a readily accessible, user-friendly and platform-independent tool capable of analysing multiple CD datasets of virtually any format and returning results as high-quality graphical output to the user. RESULTS: CAPITO (CD Anaylsis and Plotting Tool) is a novel web server-based tool for analysing and plotting CD data. It allows reliable estimation of secondary structure content utilizing different approaches. CAPITO accepts multiple CD datasets and, hence, is well suited for a wide application range such as the analysis of temperature or pH-dependent (un)folding and the comparison of mutants. AVAILABILITY: http://capito.nmr.fli-leibniz.de. CONTACT: cwiede@fli leibniz.de or mago@fli-leibniz.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23681121 TI - DrugMap Central: an on-line query and visualization tool to facilitate drug repositioning studies. AB - SUMMARY: Systematic studies of drug repositioning require the integration of multi-level drug data, including basic chemical information (such as SMILES), drug targets, target-related signaling pathways, clinical trial information and Food and Drug Administration (FDA)-approval information, to predict new potential indications of existing drugs. Currently available databases, however, lack query support for multi-level drug information and thus are not designed to support drug repositioning studies. DrugMap Central (DMC), an online tool, is developed to help fill the gap. DMC enables the users to integrate, query, visualize, interrogate, and download multi-level data of known drugs or compounds quickly for drug repositioning studies all within one system. AVAILABILITY: DMC is accessible at http://r2d2drug.org/DMC.aspx. CONTACT: STWong@tmhs.org. PMID- 23681123 TI - TANGO: a generic tool for high-throughput 3D image analysis for studying nuclear organization. AB - MOTIVATION: The cell nucleus is a highly organized cellular organelle that contains the genetic material. The study of nuclear architecture has become an important field of cellular biology. Extracting quantitative data from 3D fluorescence imaging helps understand the functions of different nuclear compartments. However, such approaches are limited by the requirement for processing and analyzing large sets of images. RESULTS: Here, we describe Tools for Analysis of Nuclear Genome Organization (TANGO), an image analysis tool dedicated to the study of nuclear architecture. TANGO is a coherent framework allowing biologists to perform the complete analysis process of 3D fluorescence images by combining two environments: ImageJ (http://imagej.nih.gov/ij/) for image processing and quantitative analysis and R (http://cran.r-project.org) for statistical processing of measurement results. It includes an intuitive user interface providing the means to precisely build a segmentation procedure and set up analyses, without possessing programming skills. TANGO is a versatile tool able to process large sets of images, allowing quantitative study of nuclear organization. AVAILABILITY: TANGO is composed of two programs: (i) an ImageJ plug in and (ii) a package (rtango) for R. They are both free and open source, available (http://biophysique.mnhn.fr/tango) for Linux, Microsoft Windows and Macintosh OSX. Distribution is under the GPL v.2 licence. CONTACT: thomas.boudier@snv.jussieu.fr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23681124 TI - ACCUSA2: multi-purpose SNV calling enhanced by probabilistic integration of quality scores. AB - SUMMARY: Direct comparisons of assembled short-read stacks are one way to identify single-nucleotide variants. Single-nucleotide variant detection is especially challenging across samples with different read depths (e.g. RNA-Seq) and high-background levels (e.g. selection experiments). We present ACCUSA2 to identify variant positions where nucleotide frequency spectra differ between two samples. To this end, ACCUSA2 integrates quality scores for base calling and read mapping into a common framework. Our benchmarks demonstrate that ACCUSA2 is superior to a state-of-the-art SNV caller in situations of diverging read depths and reliably detects subtle differences among sample nucleotide frequency spectra. Additionally, we show that ACCUSA2 is fast and robust against base quality score deviations. AVAILABILITY: ACCUSA2 is available free of charge to academic users and may be obtained from https://bbc.mdc-berlin.de/software. CONTACT: christoph.dieterich@mdc-berlin.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23681125 TI - MEME-LaB: motif analysis in clusters. AB - SUMMARY: Genome-wide expression analysis can result in large numbers of clusters of co-expressed genes. Although there are tools for ab initio discovery of transcription factor-binding sites, most do not provide a quick and easy way to study large numbers of clusters. To address this, we introduce a web tool called MEME-LaB. The tool wraps MEME (an ab initio motif finder), providing an interface for users to input multiple gene clusters, retrieve promoter sequences, run motif finding and then easily browse and condense the results, facilitating better interpretation of the results from large-scale datasets. AVAILABILITY: MEME-LaB is freely accessible at: http://wsbc.warwick.ac.uk/wsbcToolsWebpage/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23681126 TI - Simple adaptations of surgical technique to critically reduce the risk of postoperative sternal complications in patients receiving bilateral internal thoracic arteries. AB - OBJECTIVES: Limited blood supply to the thoracic chest wall is a known risk factor for sternal wound complications after CABG. Therefore, bilateral internal thoracic arteries are still rarely utilized despite their proven superior graft patency. The aim of our study was to analyse whether modification of the surgical technique is able to limit the risk of sternal wound complications in patients receiving bilateral internal thoracic artery grafting. METHODS: All 418 non emergent CABG patients receiving bilateral internal thoracic artery CABG procedures (BITA) from January 2001 to January 2012 were analysed for sternal wound complications. Surgical technique together with known risk factors and relevant comorbidity were analysed for their effect on the occurrence of sternal wound complications by means of multivariate logistic regression analysis. RESULTS: Sternal wound complications occurred in 25 patients (5.9%), with a sternal dehiscence rate of 2.4% (10 patients). In multivariate analysis, diabetes (odds ratio [OR]: 4.8, 95% CI: 1.9-11.7, P=0.001), but not obesity (OR: 1.6, 95% CI: 0.7-4.2, P=0.28) or chronic obstructive pulmonary disease (OR: 2.2, 95% CI: 0.87-5.6, P=0.1) was a relevant comorbid condition for sternal complications. Skeletonization of ITA grafts (OR: 0.17, 95% CI: 0.06-0.5, P=0.001) and the augmented use of sternal wires (OR: 0.24, 95% CI: 0.06-0.95, P=0.04) were highly effective in preventing sternal complications. The use of platelet-enriched fibrin glue (PRF) sealant, however, was associated with more superficial sternal infections (OR: 3.7, 95% CI: 1.3-10.5, P=0.02). CONCLUSIONS: Adjusted for common risk factors, skeletonization of BITA grafts together with augmented sternal wires is effective in preventing sternal complications. The use of PRF sealant, however, increased the risk for superficial wound complications. PMID- 23681127 TI - Antioxidant effects of Lactobacillus plantarum via activation of transcription factor Nrf2. AB - The present study was undertaken to investigate antioxidant and hypolipidemic effects, as well as its molecular mechanism of wild Lactobacillus plantarum FC225 isolated from fermented cabbages. The scavenging activities of superoxide anion radical, 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and hydroxyl radical were enhanced by FC225 treatment. The strain FC225 also attenuated hyperlipidemic status, decreased lipid peroxidation, plasma cholesterol, triglyceride and low density lipoprotein cholesterol levels in high fat diet-fed mice. Meanwhile, FC225 therapy could significantly elevate the activities of superoxidase dismutase and glutathione peroxidase, and decrease the content of malondialdehyde (MDA) in liver homogenates, whereas there was no change in catalase activity in high fat diet-fed mice. In addition, compared with the control group, FC225 markedly elevated the gene expression of nuclear factor erythroid 2-related factor 2 (Nrf2), which was in parallel with the increased value of CD4+/CD8+ ratio in the FC225-treated hyperlipidemic mice. The results demonstrated that the strain FC225 confers hypolipidemic and antioxidant protective effects which may be attributable to Nrf2 signal pathway mediated antioxidant enzyme expression. PMID- 23681128 TI - Which patients could benefit the most from bioresorbable vascular scaffold implant: from clinical trials to clinical practice. AB - Bioresorbable scaffold technology has evol-ved over the last few years with a number of devices either available or under clinical and preclinical investigation. The absence of a permanent metallic segment in the treated vessel wall has the potential of addressing some of the issues still encountered with metallic drug-eluting stents (DES) despite improvements in stent platform, polymer and drug elution. To date however, the use of bioresorbable vascular scaffolds (BVS) has largely been restricted to patients recruited into clinical trials with a relatively small number of "real-world" patients treated with these devices. Here we explore the issue of BVS use in "real-world" patients and try to identify, on the basis of our experience, the subset of patients that could benefit the most. PMID- 23681129 TI - New St. Jude Medical PorticoTM transcatheter aortic valve: features and early results. AB - Patients with symptomatic aortic valve disease who are inoperable or have high surgery-related risks may be treated with transcatheter aortic valve implantation devices. With this method increasingly applied, device innovations are aimed at achieving improved procedural results and therapeutic outcome. This paper describes the innovations implemented in the St. Jude Medical PorticoTM system for transcatheter aortic valve implantation, the application of this system and initial clinical experience. PMID- 23681130 TI - Recent developments in renal denervation. AB - Renal denervation is a novel catheter based approach that has been shown to effectively lower blood pressure in patients with resistant hypertension. Small studies have shown additional benefits in patients being treated for hypertension, such as improvements in insulin sensitivity, sleep apnoea and arrhythmias. More recently, it has been used for the first time for the treatment of sympathetic overactivation in patients with chronic systolic heart failure. Currently renal denervation therapy uses electrode-tipped catheters which deliver radio frequency energy to sympathetic afferent and efferent nerves running close to the lumen of the renal arteries. Further trials are on-going to assess the utility of this novel therapy in disease states beyond resistant hypertension. PMID- 23681131 TI - Saving the patient with post-ACS cardiogenic shock. AB - The adoption of early revascularization as the preferred strategy in all ST elevation myocardial infarctions (STEMI) and high risk acute coronary syndromes (ACS) without ST elevation resulted in a considerable reduction in the incidence of post-ACS cardiogenic shock (CS) however the incidence of CS on hospital arrival has not changed. In-hospital and 30 day mortality from CS remains excessively high in facilities with coronary revascularization capabilities. Trials investigating the incremental value of either intra-aortic counter pulsation (IACP) or advanced MCS did not demonstrate a meaningful mortality reduction. Mortality remains 45-60% and depends on clinical characteristics of the patient, timely and successful revascularization and advanced MCS in suitable candidates. Most CS survivors demonstrate satisfactory functional capacity and quality of life. The authors propose the "Guthrie classification" for post-ACS CS. This classification promotes better characterization of CS patients enrolled in clinical trials and registries. It also allows the clinician to better define the goals and benefits of therapy for the CS subjects. The precise pathophysiology of post-ACS CS remains poorly understood at the biochemical and cellular level. Uncovering and modifying these processes remains key to any fundamental change in post-ACS CS outcomes. PMID- 23681132 TI - MitraClip Registries: what have we learned recently. AB - MitraClip therapy is emerging as an alternative treatment for primary and secondary mitral regurgitation in high risk patients. A randomized trial has shown safety in selected patients, with efficacy non inferior to surgery in elderly patients with functional mitral regurgitation. Following commercialization, MitraClip therapy is offered to patients very different from the profile of those enrolled in the randomized trial. Several registries are on the way and provide useful preliminary information related to real-world experience with percutaneous mitral valve repair with the MitraClip system. PMID- 23681134 TI - Early vascular healing with biodegradable polymer coated sirolimus-eluting coronary stent implantation: assessed by optical coherence tomography results at 4-month follow-up. AB - AIM: The aim of this study was to evaluate the strut apposition and neointimal coverage of Supralimus-Core stent struts at 4 months after implantation using optical coherence tomography (OCT). METHODS: The Supralimus-Core OCT study is a retrospective, single-center study evaluating strut apposition and neointimal coverage with OCT at 4 months after stent implantation. A total of 12 patients, who had 15 stents implanted were included in the study. The OCT was obtained using a C7-XR FD-OCT (frequency-domain OCT) intravascular imaging system. Strut apposition, neointimal hyperplasia (NIH) thickness and stent coverage on each stent strut were evaluated. RESULTS: A total of 2870 struts and 1950 frames were analyzed from 15 stents. Average stent length was 29.3 mm. Average reference vessel diameter was 2.64 mm. Among 12 patients, 3 (25.0%) patients were with diabetes, 4 (26.7%) type B2 and 10 (66.7%) type C lesions. The apposed and covered struts were 2787 (97.11%), whereas malapposed and covered struts were 3 (0.10%), apposed and uncovered 49 (1.71%) and malapposed and uncovered 31 (1.08%). Mean NIH thickness was 155.1+/-55.2 um. CONCLUSION: The present study suggests that Supralimus-Core stent has a favorable vascular healing pattern at 4 months after stent implantation in terms of stent-strut coverage and strut apposition. This information indicates that the Supralimus-Core stent is a promising solution for decreasing late stent restenosis and preventing stent thrombosis. PMID- 23681133 TI - Circulating endothelial progenitor cells are inversely correlated with in-stent restenosis in patients with non-ST-segment elevation acute coronary syndromes treated with EPC-capture stents (JACK-EPC trial). AB - AIM: Aim of the study was to evaluate the association between circulating endothelial progenitor cells (EPCs) and angiographic outcomes after implantation of GenousTM stent in patients with non-ST-segment elevation acute coronary syndromes (ACS) (NSTE-ACS) undergoing urgent percutaneous coronary intervention (PCI). METHODS: Sixty patients treated with EPC-capture stent (N.=30) or bare metal stents (BMS) (N.=30) receiving 80 mg atorvastatin and dual antiplatelet therapy (DAT) for 12 months. Restenosis was assessed after 6 months by quantitative coronary angiography (QCA) and major acute coronary events (MACE) evaluated after 6 and 12 months. INCLUSION CRITERIA: de novo lesion >70% in native vessel, diameter 2.5-4 mm, lesion length <30 mm. EXCLUSION CRITERIA: diabetes, previous revascularization, significant left main stenosis, chronic total occlusions (CTO) and multivessel disease. RESULTS: Majority of patients in EPC-capture stent and BMS groups presented with NSTEMI (73.3% and 70%, respectively). Mean stent length was 20.1+/-8 and 19.9+/-10 mm, diameter 3+/-0.97 and 3.1+/-0.88 mm in respective groups. The binary restenosis was significantly lower in GenousTM (13 vs. 26.6%, P=0.04). Risk of MACE after 6 and 12 months were comparable in both groups. There was no stent thrombosis. Numbers of circulating EPCs were significantly approximately 2-fold higher during the ACS than after 6 months. Mobilization of EPCs during acute ischemia was significantly lower in patients who developed restenosis after 6 months (3 vs. 4.5 cells/MUL, P=0.002) and it was negatively correlated with late-loss after 6 months (R=-0.42; P<0.03). CONCLUSION: Use of GenousTM stents in NSTE-ACS is associated with lower restenosis rate than BMS at 6 months. There was no ST through 1 year. The number of circulating EPCs is inversely correlated with in-stent late loss (LL). PMID- 23681135 TI - Mesoglycan treatment in Raynaud phenomenon: a case series. AB - AIM AND METHODS: Raynaud's phenomenon (RP) is a common clinical disorder without cure or gold standard therapy. Mesoglycan is an well-balanced extract of glycosaminoglycans active on endothelial layers at microcirculatory level. Herein we investigated for the first time the efficacy and tolerability of mesoglycan on vasospastic attacks and videocapillaroscopy patterns in 25 consecutive patients with primary or secondary RP. RESULTS AND CONCLUSION: During 12 months of add-on therapy, mesoglycan obtained a remarkable and significant reduction in the frequency of Raynaud attacks and an improvement of the capillaroscopy abnormalities in most patients, without important adverse effects, revealing a good convenience in the management if this condition. PMID- 23681136 TI - Long term clinical outcomes in DES implantation for unprotected left main disease. AB - AIM: Generate a long term follow-up and evaluate the impact of clinical and procedural characteristics on long term events in percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation for unprotected left main coronary artery (ULMCA) disease. METHODS: Ninety-seven consecutive patients who underwent PCI with DES, either sirolimus (SES) or paclitaxel-eluting stent (PES), for de novo lesions in ULMCA were analyzed. No patients were excluded. Mean follow-up was 3 years (range 1-6.7 years). RESULTS: Technical and procedural success rate were 100% and 95.9%. According to the Academic Research Consortium definitions, cardiac death occurred in 6.1% of patients, reinfarction, target vessel revascularization (TVR) and target lesion revascularization (TLR) occurred in 6.1%, 17.5% and 4.2% of patients respectively. Definite stent thrombosis (ST) incidence was 1%, whereas possible ST occurred in 4.2% of patients. Postdilation was performed in 49.5% of patients and was, among all clinical and procedural characteristics, the only factor at multivariate analysis significantly related to lower MACE (25% vs. 46.9%, P=0.024, CI: 0.202 to 0.889) and TVR (8.3% vs. 26.5%, P=0.03 CI: 0.096-0.895). CONCLUSION: Long term follow-up in PCI of ULMCA disease shows favorable clinical results. Stent postdilation seems to have a protective role in DES PCI for ULMCA disease. PMID- 23681137 TI - What's new in transapical aortic valve implantation: clinical experience with second generation devices. AB - Within 10 years after transcatheter aortic valve implantation (TAVI) was first accomplished for treatment of calcified aortic stenosis, this new technology has rapidly evolved to become clinical routine. Today it may be considered standard treatment for inoperable patients with superior outcomes compared to best medical therapy. Furthermore, it represents an alternative therapeutic option compared to surgical aortic valve replacement in high-risk patients. According to current international guidelines and expert consensus statements, TAVI should be performed as a joint effort by an interdisciplinary heart team to ensure input from multiple skill sets for optimal patient outcome. Major safety concerns include neurologic complications, acute kidney injury, access site complications, procedure-related conduction disturbances, paravalvular leakage valve durability. At present, only one device for transapical TAVI is in widespread clinical use: the Edwards Sapien transcatheter valve (Edwards Lifesciences, Irvine, CA, USA). Recently, however, a number of second generation devices for transapical TAVI have been developed in order to address some of the limitations of first generation valves. In this paper, current data on second generation devices for transapical TAVI will be reviewed and ongoing trials discussed. PMID- 23681138 TI - Rare cardiomyopathies: diagnostic features. AB - Cardiomyopathies (CM) are an important and heterogeneous group of diseases affecting the myocardium. They can induce mechanical and/or electrical disorders and are due to a variety of causes, they frequently are genetic. However, since their high number and their clinical complexity, the identification is still a challenge. Echocardiography is a very useful tool in the assessment of CM. In this review we aim to define the typical clinical features and to discuss the main diagnostic tool, above all echocardiography that can help physicians in the correct assessment of CM. PMID- 23681139 TI - Why interventional cardiologists may be the most suitable specialists for the endovascular management of peripheral artery disease. AB - Peripheral artery disease has a major morbidity and mortality burden worldwide, and its impact is going to increase even further given the obesity and diabetes pandemic. Whereas medical therapy and open surgical therapy (e.g. bypass, endarterectomy, and aneurysmectomy) remain mainstays in the management of peripheral artery disease, endovascular (i.e. percutaneous or transcatheter) therapy is gaining ever increasing success among patients and physicians alike. However, endovascular interventions can be performed by cardiologists, radiologists, vascular surgeons and, possibly, others as well. Are all these specialists similarly likely to perform endovascular procedures in a safe and effective fashion? Can we identify a subset of specialists ideally equipped to perform endovascular interventions in the best manner? We indeed make the case in this article for the possible superiority of interventional cardiologists, for their background, training and clinical experience, in performing endovascular procedures. PMID- 23681140 TI - Successful bilateral carotid artery stenting via radial artery. PMID- 23681141 TI - Critical ischemia of the left arm caused by thoracic outlet syndrome (TOS): case report and review of the literature. PMID- 23681142 TI - Unilateral acid aspiration augments the effects of ventilator lung injury in the contralateral lung. AB - BACKGROUND: Mechanical ventilation is necessary during acute respiratory distress syndrome, but it promotes lung injury because of the excessive stretch applied to the aerated parenchyma. The authors' hypothesis was that after a regional lung injury, the noxious effect of mechanical ventilation on the remaining aerated parenchyma would be more pronounced. METHODS: Mice, instilled with hydrochloric acid (HCl) in the right lung, was assigned to one of the following groups: mechanical ventilation with tidal volumes (VT) 25 ml/kg (HCl-VILI25, n = 12), or VT 15 ml/kg (HCl-VILI15, n = 9), or spontaneous breathing (HCl-SB, n = 14). Healthy mice were ventilated with VT 25 ml/kg (VILI25, n = 11). Arterial oxygenation, lung compliance, bronchoalveolar lavage inflammatory cells, albumin, and cytokines concentration were measured. RESULTS: After 7 h, oxygenation and lung compliance resulted lower in HCl-VILI25 than in VILI25 (P < 0.05, 210 +/- 54 vs. 479 +/- 83 mmHg, and 32 +/- 3.5 vs. 45 +/- 4.1 ul/cm H2O, mean +/- SD, respectively). After right lung injury, the left lung of HCl-VILI25 group received a greater fraction of the VT than the VILI25 group, despite an identical global VT. The number of total and polymorphonuclear cells in bronchoalveolar lavage resulted significantly higher in HCl-VILI25, compared with the other groups, in not only the right lung, but also in the left lung. The albumin content in the left lung resulted higher in HCl-VILI25 than in VILI25 (224 +/- 85 vs. 33 +/- 6 ug/ml; P < 0.05). Cytokines levels did not differ between groups. CONCLUSION: Aggressive mechanical ventilation aggravates the preexisting lung injury, which is noxious for the contralateral, not previously injured lung, possibly because of a regional redistribution of VT. PMID- 23681143 TI - Effect of perioperative intravenous lidocaine administration on pain, opioid consumption, and quality of life after complex spine surgery. AB - BACKGROUND: The authors tested the primary hypothesis that perioperative IV lidocaine administration during spine surgery (and in the postanesthesia care unit for no more than 8 h) decreases pain and/or opioid requirements in the initial 48 postoperative hours. Secondary outcomes included major complications, postoperative nausea and vomiting, duration of hospitalization, and quality of life. METHODS: One hundred sixteen adults having complex spine surgery were randomly assigned to perioperative IV lidocaine (2 mg.kg.h) or placebo during surgery and in the postanesthesia care unit. Pain was evaluated with a verbal response scale. Quality of life at 1 and 3 months was assessed using the Acute Short-form (SF) 12 health survey. The authors initially evaluated multivariable bidirectional noninferiority on both outcomes; superiority on either outcome was then evaluated only if noninferiority was established. RESULTS: Lidocaine was significantly superior to placebo on mean verbal response scale pain scores (P < 0.001; adjusted mean [95% CI] of 4.4 [4.2-4.7] and 5.3 [5.0-5.5] points, respectively) and significantly noninferior on mean morphine equivalent dosage (P = 0.011; 55 [36-84] and 74 [49-111] mg, respectively). Postoperative nausea and vomiting and the duration of hospitalization did not differ significantly. Patients given lidocaine had slightly fewer 30-day complications than patients given placebo (odds ratio [95% CI] of 0.91 [0.84-1.00]; P = 0.049). Patients given lidocaine had significantly greater SF-12 physical composite scores than placebo at 1 (38 [31-47] vs. 33 [27-42]; P = 0.002) and 3 (39 [31-49] vs. 34 [28 44]; P = 0.04) months, postoperatively. CONCLUSION: IV lidocaine significantly improves postoperative pain after complex spine surgery. PMID- 23681144 TI - Automated alerting and recommendations for the management of patients with preexisting hypoxia and potential acute lung injury: a pilot study. AB - BACKGROUND: Acute lung injury (ALI) is associated with high mortality. Low tidal volume (Vt) ventilation has been shown to reduce mortality in ALI patients in the intensive care unit. Anesthesiologists do not routinely provide lung-protective ventilation strategies to patients with ALI in the operating room. The authors hypothesized that an alert, recommending lung-protective ventilation regarding patients with potential ALI, would result in lower Vt administration. METHODS: The authors conducted a randomized controlled trial on anesthesia providers caring for patients with potential ALI. Patients with an average or last collected ratio of partial pressure of arterial oxygen to inspired fraction of oxygen less than 300 were randomized to providers being sent an alert with a recommended Vt of 6 cc/kg predicted body weight or conventional care. Primary outcomes were Vt/kg predicted body weight administered to patients. Secondary outcomes included ventilator parameters, length of postoperative ventilation, and death. RESULTS: The primary outcome was a clinically significant reduction in mean Vt from 508-458 cc (P = 0.033), with a reduction in Vt when measured in cc/kg predicted body weight from 8 to 7.2 cc/kg predicted body weight (P = 0.040). There were no statistically significant changes in other outcomes or adverse events associated with either arm. CONCLUSIONS: Automated alerts generated for patients at risk of having ALI resulted in a statistically significant reduction in Vt administered when compared with a control group. Further research is required to determine whether a reduction in Vt results in decreased mortality and/or postoperative duration of mechanical ventilation. PMID- 23681145 TI - miR-21 contributes to xenon-conferred amelioration of renal ischemia-reperfusion injury in mice. AB - BACKGROUND: MicroRNAs participate in the regulation of numerous physiological and disease processes. The in vivo role of microRNAs in anesthetics-conferred organoprotection is unknown. METHODS: Mice were exposed for 2 h to either 70% xenon, or 70% nitrogen, 24 h before the induction of renal ischemia-reperfusion injury. The role of microRNA, miR-21, in renal protection conferred by the delayed xenon preconditioning was examined using in vivo knockdown of miR-21 and analysis of miR-21 target pathways. RESULTS: Xenon preconditioning provided morphologic and functional protection against renal ischemia-reperfusion injury (n = 6), characterized by attenuation of renal tubular damage, apoptosis, and oxidative stress. Xenon preconditioning significantly increased the expression of miR-21 in the mouse kidney. A locked nucleic acid-modified anti-miR-21, given before xenon preconditioning, knocked down miR-21 effectively, and exacerbated subsequent renal ischemia-reperfusion injury. Mice treated with anti-miR-21 and ischemia-reperfusion injury showed significantly higher serum creatinine than antiscrambled oligonucleotides-treated mice, 24 h after ischemia-reperfusion (1.37 +/- 0.28 vs. 0.81 +/- 0.14 mg/dl; n = 5; P < 0.05). Knockdown of miR-21 induced significant up-regulation of programmed cell death protein 4 and phosphatase and tensin homolog deleted on chromosome 10, two proapoptotic target effectors of miR-21, and resulted in significant down-regulation of phosphorylated protein kinase B and increased tubular cell apoptosis. In addition, xenon preconditioning up-regulated hypoxia-inducible factor-1alpha and its downstream effector vascular endothelial growth factor in a time-dependent manner. Knockdown of miR-21 resulted in a significant decrease of hypoxia inducible factor-1alpha. CONCLUSIONS: These results indicate that miR-21 contributes to the renoprotective effect of xenon preconditioning. PMID- 23681146 TI - Long term geological record of a global deep subsurface microbial habitat in sand injection complexes. AB - There is extensive evidence from drilling into continental margins for microbial colonization of a deep biosphere. However it is difficult to prove deep biosphere activity in the geological record, where evidence for life is dominated by the remains of organic matter buried after deposition at the surface. Nevertheless we propose that natural injections of sand into muddy strata at continental margins represent an excellent habitat opportunity for deep microbial activity down to several kilometres' present day depth. Sulphur isotope data for iron sulphides precipitated soon after injection indicate consistent microbial sulphate reduction through the geological record. The complexes are favourable sites for colonization, because high permeability and extensive sand/mud interface allow ready availability of electron donors and nutrients. The measured examples of iron sulphide in injected sands extend back to the Proterozoic, and show that injected sand complexes have been a long-term environment for deep subsurface microbial colonization. PMID- 23681147 TI - Assessment of early bronchiectasis in young children with cystic fibrosis is dependent on lung volume. AB - OBJECTIVE: The aim of this study was to determine whether assessment of early CT scan-detected bronchiectasis in young children with cystic fibrosis (CF) depends on lung volume. METHODS: This study, approved by the hospital ethics committee, included 40 young children with CF from a newborn screened population contributing paired volume-controlled inspiratory and expiratory volumetric chest CT scans acquired under general anesthesia while clinically stable. Bronchiectasis was assessed with a semiquantitative CT scan score in inspiration and expiration, and the sensitivity of the expiratory CT scan to detect bronchiectasis was compared with the inspiratory CT scan by sensitivity and intraclass correlation coefficient analysis and Bland-Altman plots. Matched inspiratory and expiratory airway-vessel measurements were obtained in a subset of 10 children, and the relationship between lung volume and airway:vessel ratio after adjusting for age and vessel size was examined with the use of a linear regression model with generalized estimating equations. The number of visible airways in inspiration and expiration was compared in all 40 children by Wilcoxon signed rank test. RESULTS: Expiratory scans had poor sensitivity (0.46) to detect bronchiectasis, underestimating disease extent (P < .001). Airway:vessel ratios were consistently higher in inspiration, independent of age and vessel size (P < .001), with significantly more airways visible in inspiration than in expiration, independent of age (median, 71 vs 28, respectively; P < .001). CONCLUSIONS: In young children with CF, radiologic assessment of early bronchiectasis with chest CT scan depends on lung volume; thus, expiratory scans may not be appropriate for evaluating bronchiectasis in this population. Lung volume during CT image acquisition should be standardized to evaluate airway dimensions in young children. PMID- 23681148 TI - Basic surgical skills training in United Kingdom foundation year doctors: can we do more? AB - OBJECTIVE: Recent changes to the structure of medical training have placed increasing pressure on foundation year 1 (FY1) doctors to decide upon careers earlier. The deadline for application to core surgical training (CST) at the start of the foundation year 2 (FY2) may deter doctors from pursuing careers in surgery due to insufficient experience and confidence in its practical aspects. We piloted a four-week basic surgical skills (BSS) programme near the start of the FY1 year to a small cohort of FY1s and assessed its impact on confidence in basic surgical competencies and attitudes to a career in surgery. METHODS: FY1 doctors at Whipps Cross University Hospital (WXUH) were selected to participate in a four week BSS programme within three months of starting their posts. We devised the BSS programme based on relevant key competencies in the Intercollegiate Surgical Curriculum Programme (ISCP). Using questionnaires we assessed confidence in basic surgical skills, competencies and attitudes to surgery before, immediately after and at 8 months after completion of the course and compared this with non-participating FY1s. RESULTS: Out of 31 FY1 doctors, 14 (4 males, 10 females) participated in the BSS programme and 17 (10 males, 7 females) were non-participants (control group). Using the Mann-Whitney test, there was a statistically significant increase in confidence at 8 month follow-up of course participants (versus control group) in tying knots (p = 0.0112), suturing skills (p = 0.0455) performing fine needle aspiration (FNA) cytology (p = 0.0017), obtaining tru-cut biopsy samples (p = 0.0031), suturing lacerations in accident and emergency (A&E) (p = 0.0009), incising and draining abscesses (p = 0.0034), performing skin closure (p = 0.0042), surgical sharps handling (p = 0.0402) and surgical instrument handling (p = 0.0066). Course participants were significantly more likely than non-participants to receive additional training in BSS from senior members of the team (p = 0.0076). Importantly, they also demonstrated a statistically significant increase in interest in a career in surgery at 8 month follow-up in comparison to non-participants (p = 0.0016). CONCLUSIONS: A structured, challenging BSS teaching programme early on during the FY1 year increases confidence in key surgical skills and competencies and can increase interest in surgery as a career. PMID- 23681149 TI - A descriptive cost analysis study of cases of right iliac fossa pain. AB - Patients with suspected appendicitis comprise a large proportion of general surgical workload. The resulting healthcare burden is significant when one considers that investigations, observation and surgical procedures are often needed. As no previous study has examined the cost of managing patients with suspected appendicitis, we performed a cost analysis study of management of cases of right iliac fossa (RIF) pain in University Hospital Limerick. Patients who were admitted with right iliac fossa pain from 1st April 2011 to 4th May 2011 were identified prospectively. After discharge, patients' medical records were reviewed. Costing data collected comprised details on length of stay, number and type of radiological investigations, number and type of blood investigations, medications administered and operations performed. Costs for radiological investigations were obtained from casemix data. Blood investigation costs were obtained from relevant laboratories. Medication costs were obtained from the pharmacy department. Operation costs were based on the cost of equipment combined with cost relating to operating theatre time and recovery unit time. Due to unavailability of data on Irish public hospital bed-day cost, a private hospital provided cost details on this aspect. 94 patients (M = 33, F = 61) were admitted with RIF pain during this time period. 62 underwent surgery. There were 53 appendicectomies performed with 42 (79%) positive for appendicitis on histological analysis. Blood test, radiology, pharmacy, operative and bed-day costs were ?1857, ?6252, ?3517, ?184,191 and ?152,706 respectively. The total estimated cost was ?348,525 (?3708 average per patient). There is a high cost associated with managing suspected appendicitis in Ireland. Strategies to reduce cost include reducing unnecessary admissions and unnecessary operations. Reducing LOS may be another potentially valuable cost saving method. It is imperative that resources are channelled into the provision of accurate costing structures. PMID- 23681150 TI - How reliable is secondary risk stratification with stimulated thyroglobulin in patients with differentiated thyroid carcinoma? Results from a retrospective study. AB - OBJECTIVE: Primary risk factors in patients with differentiated thyroid carcinoma (DTC) are well established. In our institution, secondary risk stratification has been performed with stimulated Thyroglobulin (sTg; TSH > 30 mIU/l) within six months after primary therapy since 2001. In this study, we evaluated the predictive value of sTg for long-term disease-free survival (DFS). PATIENTS, METHODS: Data of 202 consecutive patients with DTC were analyzed retrospectively. Median follow-up time was 6.4 years (12 months to 16.2 years). Patients were staged according to Union International Contre le Cancer (UICC) criteria. Primary risk stratification was carried out according to European Thyroid Association criteria. Initially, 134 patients (66%) were classified as low-risk and 68 patients (34%) as high-risk. The influence of established risk factors and sTg on DFS was analyzed at three different time points, up to 36 months after initial therapy. RESULTS: In total, 169 (84%) of all patients remained in complete remission after surgery followed by radioiodine-therapy. Six patients (3%) developed tumour recurrence after initial complete remission. Primary risk factors for persistent disease were male sex, follicular or oncocytic tumour, primary tumour > 4 cm in diameter, initial lymph node involvement, initial metastatic disease and microscopic or macroscopic residual tumor. sTg <= 0.3 ng/ml measured within six months after initial therapy was a highly significant predictor (p <= 0.001) for lasting DFS, 99% of patients with sTg <= 0.3 ng/ml were in complete remission 36 months after initial therapy. CONCLUSIONS: A stimulated Tg <= 0.3 ng/ml within six months after initial therapy is a reliable predictor for long-term disease-free survival independent of primary risk stratification. PMID- 23681151 TI - 18F-FDG PET/CT findings in patients with Kikuchi disease. AB - PURPOSE: Kikuchi disease (KD) is a benign and self-limited syndrome characterized by cervical lymphadenopathy. This study evaluated 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) findings in patients with KD and analyzed their imaging features. PATIENTS, MATERIAL, METHODS: We evaluated the FDG PET/CT findings of 22 patients (14 men, 8 women) with KD, ranging in age from 9 to 73 years. All patients had been diagnosed based on the pathological findings of biopsy. We examined the locations, metabolic activity and size of hypermetabolic lymph nodes (LNs) on FDG PET/CT imaging with medical history including laboratory results. RESULTS: Among the 22 patients, we identified 619 hypermetabolic LNs which had maximum standard uptake value (SUVmax) above 3.0. The 16 patients were studied with FDG PET/CT to identify the cause of fever, another 5 patients for their neck masses, and the remaining patient for his left inguinal mass. Hypermetabolic LNs were noted in neck (18 bilaterally, 2 right, 1 left) of 21 patients, axilla of 10, mediastinum of 9, abdomen of 17, pelvis of 6, and inguinal area of 3. The SUVmax of FDG uptake in affected LNs by patient base analysis were 6.2-29.4. Of the 619 hypermetabolic LNs identified, 440 LNs (71.1%) were less than 10 mm in their short axis determined by CT, and were occasionally aggregated. No patient showed solid organ hypermetabolic lesion in FDG PET/CT. CONCLUSION: Kikuchi disease could present multiple hypermetabolic LNs in body on FDG PET/CT. Based on the physical findings, consideration of the generalized distribution of the relatively small-sized hypermetabolic LNs, FDG PET/CT may be useful as a diagnostic tool in cases of Kikuchi disease. PMID- 23681152 TI - Evaluation of hybrid PET/CT gastrography in gastric cancer. AB - AIM: With the recent advances in multidetector-row CT, a fusion of functional PET with three dimensional (3D) CT gastrography may provide enhanced diagnostic capability and help surgeons during preoperative planning. The diagnostic value of hybrid PET/CT gastrography was compared with that of conventional PET/CT alone in gastric cancer staging. PATIENTS, METHODS: Patients with gastric cancer (n = 101) confirmed by endoscopic biopsy specimens underwent conventional PET/CT and regional PET with contrast enhanced CT, followed by gastrectomy with lymphadenectomy at our institution from November 2007 to November 2008. These images were fused into a hybrid PET/CT gastrography using the cardiac IQ fusion software. Conventional PET/CT and hybrid PET/CT gastrography were evaluated for staging of gastric cancer. After gastrectomy, these were compared with pathologic reports respectively. RESULTS: Gastric cancer was diagnosed as 50 early gastric cancer (EGC) and 51 advanced gastric cancer (AGC) on pathologic examination. In EGC, hybrid PET/CT gastrography and PET/CT identified 36 (72%) and 7 (14%) tumours, respectively. Hybrid PET/CT gastrography correctly delineated the subtype of 25 EGC. In AGC, all 51 (100%) tumours were identified on the hybrid PET/CT gastrography compared to 39 (76.5%) tumours on PET/CT. Hybrid PET/CT gastrography correctly classified the morphology of 42 AGC using the Bormann classification. Additionally, depth of invasion was correctly presented in 38 of 51 AGC. Hybrid PET/CT gastrography for regional lymph node (LN) metastasis in the EGC and AGC showed the sensitivity of 75% and 83.9%, and specificity 90.5% and 55%, respectively. CONCLUSION: Hybrid PET/CT gastrography is the more intuitive and comprehensive method for the preoperative evaluation of gastric cancer than conventional PET/CT. PMID- 23681153 TI - PET/ultrasound fusion for differentiation of Vox implant silicone particles from recurrent cancer. PMID- 23681154 TI - Respiratory syncytial virus infection in children with severe motor and intellectual disabilities. AB - Children with severe motor intellectual disabilities (SMID) are at high risk of death from acute viral lower respiratory tract infections (LRTI). Although respiratory syncytial virus (RSV) is the most common cause of viral LRTI in children, there have been a few reports on the relationship between SMID and the severity of RSV-LRTI. The aim of the present study is to assess the influence of RSV-LRTI in children with SMID. A case-control study composed of children with SMID (n = 18) and previously healthy children (n = 43) less than 16 years old hospitalized for RSV-LRTI was performed during five consecutive RSV seasons. The clinical presentation and the laboratory data in the SMID group were compared with those in the non-SMID group. In the bivariate analysis, the median age of the SMID group was higher than that of the non-SMID group (p = 0.002). Children with SMID had an increased risk for ventilation support (p = 0.057). The count of neutrophils in the SMID group was significantly increased (p = 0.012), whereas the proportion of bacterial co-infection was lower than that in the non-SMID group (p = 0.005). Multivariate logistic analysis showed that SMID was associated with longer oxygen usage [>7 days: odds ratio (OR) 5.309, p = 0.033]. The present study revealed that children with SMID were prone to developing hypoxia by RSV LRTI. The strategies for the treatment and prevention of RSV infection need to be improved in SMID children. PMID- 23681156 TI - Hiring into advanced practice positions: the nurse practitioner versus physician assistants debate. AB - Nurse practitioners (NPs) and physician assistants (PAs) have long been part of the care model at our institution. Over the years, however, we have demonstrated a preference for NPs based on the belief that they can better meet our patients' needs. A recent evaluation of our care model led us to question these preferential hiring practices. After carefully examining NP and PA education and licensure requirements, scope of practice, and roles at our institution, we concluded that similarities between the roles far outweighed the differences and that our preferential hiring practices should be replaced by an individualized approach, in which advanced practice positions are filled by whichever candidate best meets the role requirements. This inclusive and analytic approach may be a useful model for other nurse leaders considering the NP/PA question. PMID- 23681155 TI - Differential effects of beta-mercaptoethanol on CdSe/ZnS and InP/ZnS quantum dots. AB - The small thiol beta-mercaptoethanol (BME) has been used as an anti-blinking reagent for CdSe/ZnS quantum dots (QDs), although its effects on QD photoluminescence are complex. It acts as an antioxidant as well as a hole scavenger on both CdSe and CdTe, which leads to changes in emission intensity and lifetime that vary qualitatively according to BME concentration, time of incubation, and pH of the solution. Because the band edge energies of InP/ZnS are shifted from those of CdTe and CdSe, it may be expected that thiols including BME might be unable to trap holes from these QDs. In this study, we use steady-state and time-resolved emission spectroscopy with physical fitting models combined with blinking analysis to compare the effects of different concentrations of BME on CdSe/ZnS vs. InP/ZnS QDs over time. We also find excellent correspondence between simple physical model parameters and blinking off times, a finding that will be useful for all blinking studies involving semiconductor nanoparticles. BME alters blinking in InP/ZnS QDs with a single ZnS shell, but not those with double thickness shells. The effects are similar to those seen with CdSe/ZnS, despite very different effects of BME on steady-state spectra, and highly pH dependent. PMID- 23681157 TI - Fostering itself increases nicotine self-administration in young adult male rats. AB - RATIONALE: In gestational exposure studies, a fostered group is frequently used to control for drug-induced maternal effects. However, fostering itself has varying effects depending on the parameters under investigation OBJECTIVES: This study was designed to assess whether maternal behavior contributed to enhanced acquisition (higher number of bar presses compared to controls) of nicotine self administration (SA) displayed by offspring with gestational nicotine and ethanol (Nic+EtOH) exposure. METHODS: Offspring were exposed to Nic+EtOH throughout full gestation, that is, gestational days (GD) GD2-20 and during postnatal days 2-12 (PN2-12), the rodent third trimester equivalent of human gestation during which rapid brain growth and synaptogenesis occur. Young adult (PN60) male offspring acquired operant nicotine SA, using a model of unlimited (i.e., 23 h) access to nicotine. RESULTS: Gestational drug treatments did not alter litter parameters (body weight, volume distribution, crown-rump length, and brain weight) or postnatal growth of the offspring. Fostering increased locomotor activity to a novel environment on PN45 regardless of gestational treatment group. Surprisingly, fostering per se significantly increased the SA behavior of drug naive pair-fed controls, so that their drug-taking behavior resembled the enhanced nicotine SA observed in non-fostered offspring exposed to Nic+EtOH during gestation. In contrast, fostering did not change the SA behavior of the Nic+EtOH group. CONCLUSIONS: Fostering is shown to be its own experimental variable, ultimately increasing the acquisition of nicotine SA in control, drug naive offspring. As such, the current dogma that fostering is required for our gestationally drug-exposed offspring is contraindicated. PMID- 23681159 TI - The effects of acute abstinence from smoking and performance-based rewards on performance monitoring. AB - RATIONALE: Abstinence from smoking disrupts performance in multiple cognitive domains, and such cognitive effects may serve to maintain smoking behavior. Rather than having specific effects on a narrow domain of processing, abstinence may disrupt more general cognitive control processes and/or motivation. OBJECTIVES: The present study tested the prediction that overnight abstinence from smoking would disrupt a general performance monitoring system indexed via the error-related negativity (ERN). A secondary aim was to determine the extent to which performance-based monetary rewards improved the ERN among smokers and whether the effect of the reward was diminished during abstinence. METHODS: The ERN was assessed during a flanker task among 25 heavy, non-treatment-seeking smokers both when smoking as usual and after overnight abstinence; reward and no reward trial blocks occurred within each session. RESULTS: As predicted, mean ERN amplitude was reduced during abstinence. The ERN was enhanced by reward; this effect did not vary with smoking abstinence. CONCLUSION: This study provides novel data which suggest that acute abstinence from smoking disrupts a neurophysiological index of a general performance monitoring system that is involved in a range of cognitive functions. The ERN may be a useful complement to narrow-band cognitive studies of abstinence and interventions designed to target cognition in addiction. Because the ERN was concurrently sensitive to abstinence and performance-based incentives, it may be particularly useful for examining the interplay of cognition and motivation in smoking and smoking cessation. PMID- 23681160 TI - Ecstasy use and depression: a 4-year longitudinal study among an Australian general community sample. AB - RATIONALE: Longitudinal, population-based studies can better assess the relationship of ecstasy use with depression. OBJECTIVES: We examined whether change in ecstasy use was associated with change in depressive symptoms/probable depression over a 4-year period, among a large Australian sample. METHODS: The Personality and Total Health project is a longitudinal general community study of Australians from Canberra and Queanbeyan. Data from the youngest cohort when aged 24-30 (N = 2, 128) and 4 years later (N = 1, 977) was included. The Goldberg depression scale and the Brief Patient Health Questionnaire measured depressive symptoms and probable depression, respectively. Multilevel growth models also considered demographics, psychosocial characteristics, and other drug use. RESULTS: Ecstasy use was not associated with long-term depressive symptoms or greater odds of depression in multivariate analyses. Users had more self-reported depressive symptoms when using ecstasy compared to not using. However, differences between people who had and had not ever used ecstasy largely accounted for this. Other factors were more important in the prediction of depression. CONCLUSIONS: It would be premature to conclude that ecstasy use is not related to the development of long-term depressive symptoms, given the relatively low level of ecstasy and other drug use in this community sample. Results showed that other factors need to be considered when investigating ecstasy use and depression. PMID- 23681158 TI - Central nervous system effects of prenatal selective serotonin reuptake inhibitors: sensing the signal through the noise. AB - RATIONALE: Women are increasingly prescribed selective serotonin reuptake inhibitors (SSRIs) during pregnancy, with potential implications for neurodevelopment. Whether prenatal SSRI exposure has an effect on neurodevelopment and behavior in the offspring is an important area of investigation. OBJECTIVES: The aim of this paper was to review the existing preclinical and clinical literature of prenatal SSRI exposure on serotonin related behaviors and markers in the offspring. The goal is to determine if there is a signal in the literature that could guide clinical care and/or inform research. RESULTS: Preclinical studies (n = 4) showed SSRI exposure during development enhanced depression-like behavior. Half of rodent studies examining anxiety-like behavior (n = 13) noted adverse effects with SSRI exposure. A majority of studies of social behavior (n = 4) noted a decrease in sociability in SSRI exposed offspring. Human studies (n = 4) examining anxiety in the offspring showed no adverse effects of prenatal SSRI exposure. The outcome of one study suggested that children with autism were more likely to have a mother who was prescribed an SSRI during pregnancy. CONCLUSIONS: Preclinical findings in rodents exposed to SSRIs during development point to an increase in depression- and anxiety-like behavior and alteration in social behaviors in the offspring, though both the methods used and the findings were not uniform. These data are not robust enough to discourage use of SSRIs during human pregnancy, particularly given the known adverse effects of maternal mental illness on pregnancy outcomes and infant neurodevelopment. Future research should focus on consistent animal models and prospective human studies with larger samples. PMID- 23681161 TI - Serotonin depletion counteracts sex differences in anxiety-related behaviour in rat. AB - BACKGROUND: Numerous studies suggest (1) that a major physiological role of brain serotonin-containing neurons is to modulate sex steroid-driven behaviour such as sex and aggression, (2) that sex steroids influence brain serotonergic neurotransmission and (3) that brain serotonergic neurotransmission displays sexual dimorphism. Such observations indicate that an important task for brain serotonin is to either enhance or counteract sex differences in behaviour. METHODS: To test this hypothesis, we explored the effect of short-term serotonin depletion on the behaviour of adult male and female rats in a behavioural paradigm in which males and females have been shown to behave differently, i.e. the elevated plus maze. RESULTS: Two rounds of testing of untreated Wistar rats confirmed the previous observation that females make more entries into open arms (round 1, p = 0.001; round 2, p = 0.008) and spend more time on these arms (round 1, p <= 0.001; round 2, p = 0.006) than males; in addition, males displayed fewer entries into closed arms upon habituation, i.e. at the second round (p <= 0.001) than did females. Administration of the tryptophan hydroxylase inhibitor para chloro-phenylalanine, at a regimen (300 mg/kg/day for 3 days), markedly reducing brain content of serotonin, enhanced entries upon open arms (p = 0.01) and time spent on open arms (p = 0.004) in males but exerted no such effects in females (p = 0.9 and p = 0.9, respectively); moreover, it reduced entries into closed arms in females (p <= 0.001) but not in males (p = 0.1). CONCLUSIONS: Serotonin depletion abolishing the sex differences observed at baseline supports the theory that serotonin aids to uphold certain sex differences in behaviour. PMID- 23681163 TI - Determination of reliable reference genes for multi-generational gene expression analysis on C. elegans exposed to abused drug nicotine. AB - RATIONAL: More research has recently been focused on multigenerational toxicogenomics impacts. Such studies rely on behavioral as well as genetic and epigenetic analyses using various biotechniques. Of these technologies, quantitative reverse transcriptase PCR is considered as a mature discovery and validation tool. Nevertheless, the interpretation of the resulting gene expression necessitates the establishment of reliable internal controls for normalization. No study has been performed to identify reliable reference genes in multigenerational settings. OBJECTIVES: The primary aim was to evaluate the stability of 16 reference gene candidates in Caenorhabditis elegans exposed to nicotine and their two subsequent generations for determining the most reliable reference genes for multigenerational study. METHODS: We exposed C. elegans to nicotine in the F0 generation and investigated the relative stabilities of 16 housekeeping genes in L4 larvae across three generations (F0, F1, and F2) using five statistical approaches (geNorm, ?Ct method, NormFinder, BestKeeper, and RefFinder). RESULTS: geNorm shows that CDC-42 and Y45F10D.4 were the most stable reference genes. Based on NormFinder, TBA-1, EIF3.C, ARP-6, CDC-42, and MDH2 may serve as the top reliable reference genes. Comparative ?Ct method ranked TBA-1, CDC-42, EIF3.C, ARP-6, and Y45F10D.4 as the most stable reference genes. BestKeeper shows that Y45F10D.4, F35G12.2, TBA-1, CDC-42, and CSQ-1were better reference genes. Overall, TBA-1, CDC-42, EIF3.C, ARP-6, and Y45F10D.4 were the most reliable reference genes for mutigenerational nicotine-exposed study. CONCLUSIONS: Of the 16 tested gene candidates, TBA-1 and CDC-42 were the two most stable reference genes for performing reliable gene expression normalization in the multigenerational impact of nicotine exposure. PMID- 23681162 TI - Cocaine self-administration behavior in inbred mouse lines segregating different capacities for inhibitory control. AB - RATIONALE: Various dimensions of impulsivity have been linked to substance abuse and dependence, both as consequences of, and as predisposing factors to addiction. With respect to the latter, they may be quantitative indicators of liability for substance use disorders (SUD) and aid in determining underlying genetic influences. We have previously determined that inhibitory control over impulsive responding, as measured by a reversal learning task, is heritable and under substantial genetic control, however their role as explaining variables for aspects of SUD have not been well explored. OBJECTIVE: The aim of this study was to test for an association between genetically determined differences in inhibitory control and addiction-related phenotypes, such that phenotypes of poor inhibitory control would predict propensity for elevated operant drug-seeking and -taking behaviors. METHODS: Mice from BxD strains with either good reversal learning (GRL) or poor reversal learning (PRL) ability were tested for intravenous cocaine self-administration under FR1, FR2, and FR5 reinforcement schedules. Additionally, locomotor responses to experimenter-delivered cocaine were assessed. RESULTS: Compared to GRL strains, PRL strains acquired self administration behavior more rapidly and administered cocaine at greater rates under all schedules of reinforcement, without any differences in discrimination index. In addition, PRL mice also exhibited increased responding during time-out periods. PRL strains also showed larger locomotor responses to 10 or 20 mg/kg injections of cocaine. CONCLUSIONS: These studies demonstrate that heritable strain differences in inhibitory control do influence drug self-administration, thus suggest that genetically driven impulsivity of this type may predispose susceptibility to drug abuse and addiction. PMID- 23681164 TI - Pharmacological treatments prescribed to people with autism spectrum disorder (ASD) in primary health care. AB - RATIONALE: Autism spectrum disorders (ASDs) affect 1 % of children, having significant impact on health and social outcomes. Psychotropic medication use by individuals with ASD in the USA increased over time, and polypharmacy occurred in >50 % of those prescribed. In the UK, no psychotropic drugs are approved in ASDs, and little is known about patterns of pharmacological treatment in the ASD population and associated co-morbidities. METHODS: We used The Health Improvement Network, a nationally representative primary care database, to assess the prevalence of ASD diagnoses, psychotropic drug prescribing and neuropsychiatric co-morbidities of 0-24 year olds between 1992 and 2008. RESULTS: ASD prevalence increased 65-fold from 0.01 % (1992) to 0.50 % (2008). Psychotropic drugs were prescribed to 29 % (1,619/5,651) of the ASD cohort; the most prescribed drugs were sleep medication (9.7 % of prescribed patients), psychostimulants (7.9 %) and antipsychotics (7.3 %). More patients were given psychostimulants and sleep medications over time from 1.5-6.3 % and 2.2-5.9 % respectively. Thirty-seven per cent of the cohort had >= 1 record of a neuropsychiatric co-morbidity, the most common being developmental difficulties and learning disabilities (12.6 %), behavioural, conduct and personality disorders (11.1 %) and attention deficit hyperactivity disorder (7.5 %). CONCLUSIONS: British physicians are more conservative in prescribing practice than American colleagues. However, use of psychostimulants and antipsychotics is much higher in those with ASD than in the general population. Polypharmacy was seen in 34 % of prescribed patients in 2008. Additional studies examining use, efficacy, and long-term safety of antipsychotics and psychostimulants in autistic individuals are warranted. PMID- 23681167 TI - Abnormal processing of deontological guilt in obsessive-compulsive disorder. AB - Guilt plays a significant role in the occurrence and maintenance of obsessive compulsive disorder (OCD). Two major types of guilt have been identified: one deriving from the transgression of a moral rule (deontological guilt DG), another (altruistic guilt AG), relying on the assumption of having compromised a personal altruistic goal. Clinical evidence suggests that OCD patients are particularly sensitive to DG, but not AG. In this functional magnetic resonance imaging (fMRI) study, we investigated brain response of OCD patients while processing DG and AG stimuli. A previously validated fMRI paradigm was used to selectively evoke DG and AG, and anger and sadness, as control emotions in 13 OCD patients and 19 healthy controls. Patients' behavioral results showed a prominent attitude to experience guilt, compared to controls, while accomplishing task. fMRI results revealed that patients have reduced activation in the anterior cingulate (ACC) and frontal gyrus when experiencing guilt, regardless of its specific type (DG or AG). When separately considering each type of guilt (against each of its control), patients showed decreased activation in the ACC, the insula and the precuneus, for DG. No significant differences were observed between groups when processing AG, anger or sad stimuli. This study provides evidence for an abnormal processing of guilt, and specifically DG, in OCD patients. We suggest that decreased activation may reflect patients' cerebral efficiency, which derives from their frequent exposure to guilty feelings ("neural efficiency hypothesis"). In conclusion, our study confirms a selective abnormal processing of guilt, and specifically DG, in OCD. PMID- 23681166 TI - Cocaine potentiates MDMA-induced oxidative stress but not dopaminergic neurotoxicity in mice: implications for the pathogenesis of free radical-induced neurodegenerative disorders. AB - RATIONALE: The drugs of abuse 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy") and cocaine both increase the generation of free radicals, and in the case of MDMA, this increase in oxidative stress is involved in the dopaminergic neurotoxicity produced by the drug in mice. Oxidative stress processes are also involved in the pathogenesis of several neurodegenerative diseases. OBJECTIVES: We aimed to determine the consequences of the combined administration of MDMA and cocaine on oxidative stress and dopaminergic neurotoxicity. METHODS: Mice received MDMA (20 mg/kg, i.p.; two doses separated by 3 h) followed by cocaine 1, 3, 6, or 24 h after the second MDMA dose. Mice were killed between 1 h and 7 days after cocaine injection. RESULTS: MDMA decreased dopamine transporter density and dopamine concentration 7 days later. Cocaine did not alter this neurotoxicity. MDMA produced an increase in the concentration of 2,3-dihydroxybenzoic acid in striatal microdialysis samples and an increase in lipid peroxidation in the striatum which were potentiated by cocaine. MDMA and cocaine given together also increased nitrate and 3-nitrotyrosine levels compared with either drug given alone. On the other hand, MDMA increased superoxide dismutase activity and decreased catalase activity, changes which were prevented by cocaine administration. In addition, cocaine administration produced an increase in glutathione peroxidase (GPx) activity in both saline-treated and MDMA-treated mice. CONCLUSIONS: Cocaine potentiates MDMA-induced oxidative stress but does not produce an increase in the neurotoxicity produced by MDMA, and this lack of potentiation may involve an increase in GPx activity. PMID- 23681168 TI - Identification of tumor differentiation factor (TDF) in select CNS neurons. AB - Identification of central nervous system (CNS) molecules elucidates normal and pathological brain function. Tumor differentiation factor (TDF) is a recently found protein secreted by the pituitary into the blood. TDF mRNA was detected in brain; not heart, placenta, lung, liver, skeletal muscle, or pancreas. However, TDF has an unclear function. It is not known whether TDF is expressed only by pituitary or by other brain regions. It is also not known precisely where TDF is expressed in the brain or which cells produce TDF. Database searching revealed that this molecule shares no homology with any known protein. Therefore, we investigated the distribution of TDF in the rat brain using immunohistochemistry (IHC) and immunofluorescence (IF). TDF protein was detected in pituitary and most other brain regions. Double-staining for TDF and glial fibrillary acidic protein (GFAP), an astrocyte marker, showed no co-localization. Double-staining for TDF with NeuN, a neuronal marker, showed co-localization. Not all NeuN positive cells were positive for TDF. Western blotting (WB) using NG108 neuroblastoma and GS9L astrocytoma cell lysate revealed TDF immunoreactivity in cultured neuroblastoma, not astrocytoma. These data suggest that TDF is localized in neurons, not in astrocytes. This is the first report of any cellular localization of TDF. TDF may have specific roles as a pituitary-derived hormone and in the CNS, and appears to be produced by distinct CNS neurons, not astroglia. PMID- 23681169 TI - Molecular composition of extracellular matrix in the vestibular nuclei of the rat. AB - Previous studies have demonstrated that the molecular and structural composition of the extracellular matrix (ECM) shows regional differences in the central nervous system. By using histochemical and immunohistochemical methods, we provide here a detailed map of the distribution of ECM molecules in the vestibular nuclear complex (VNC) of the rat. We have observed common characteristics of the ECM staining pattern in the VNC and a number of differences among the individual vestibular nuclei and their subdivisions. The perineuronal net (PNN), which is the pericellular condensation of ECM, showed the most intense staining for hyaluronan, aggrecan, brevican and tenascin-R in the superior, lateral and medial vestibular nuclei, whereas the HAPLN1 link protein and the neurocan exhibited moderate staining intensity. The rostral part of the descending vestibular nucleus (DVN) presented a similar staining pattern in the PNN, with the exception of brevican, which was negative. The caudal part of the DVN had the weakest staining for all ECM molecules in the PNN. Throughout the VNC, versican staining in the PNN, when present, was distinctive due to its punctuate appearance. The neuropil also exhibited heterogeneity among the individual vestibular nuclei in ECM staining pattern and intensity. We find that the heterogeneous distribution of ECM molecules is associated in many cases with the variable cytoarchitecture and hodological organization of the vestibular nuclei, and propose that differences in the ECM composition may be related to specific neuronal functions associated with gaze and posture control and vestibular compensation. PMID- 23681170 TI - Response surface methodology as optimization strategy for reduction of reactive carbonyl species in foods by means of phenolic chemistry. AB - Response surface methodology (RSM) was utilized to investigate the dose-response relationships of a phenolic mixture (catechin, genistein and daidzein) as a pre thermal processing technique to reduce reactive carbonyl species (RCSs; glyoxal, methylglyoxal and 3-deoxyglucosone) in ultra-high temperature (UHT) bovine milk. A modified derivatization technique for RCSs was developed to overcome quantitative error caused by interference from the phenolic compounds. For the statistical analysis, a Box-Behnken 3-factor (catechin, genistein and daidzein) 3 level (0.17, 0.645 and 1.12 mM) design was employed. In general, all phenolic mixtures were able to reduce RCSs in UHT milk; some compositions reported RCSs levels at or below levels reported in pasteurized milk. Predictive models with no significant lack of fit (p > 0.05), high R(2)-values (0.886-0.979) and good predictive power were developed. ANOVA analysis of the glyoxal levels indicated that only linear effects of each phenolic compound had a significant effect (p < 0.05) meaning that no significant interactions between the different phenolic compounds influenced glyoxal levels. Linear, cross product and quadratic effects of factors were reported (p < 0.05) for methylglyoxal, indicating more complicated interactions between the phenolic compounds. Both linear and quadratic effects were also reported (p < 0.05) for 3-deoxyglucosone. Overall, based on canonical analysis, catechin seemed to be the most influential factor for the reduction of RCSs in UHT milk. In summary, RSM provided a basis to understand phenolic structure-reactivity and to optimize the composition of a tertiary mixture of phenolic compounds for reduction of RCSs in UHT milk. PMID- 23681165 TI - Noradrenergic versus dopaminergic modulation of impulsivity, attention and monitoring behaviour in rats performing the stop-signal task: possible relevance to ADHD. AB - RATIONALE: Deficient response inhibition is a prominent feature of many pathological conditions characterised by impulsive and compulsive behaviour. Clinically effective doses of catecholamine reuptake inhibitors are able to improve such inhibitory deficits as measured by the stop-signal task (SST) in humans and other animals. However, the precise therapeutic mode of action of these compounds in terms of their relative effects on dopamine (DA) and noradrenaline (NA) systems in prefrontal cortical and striatal regions mediating attention and cognitive control remains unclear. OBJECTIVES: We sought to fractionate the effects of global catecholaminergic manipulations on SST performance by using receptor-specific compounds for NA or DA. The results are described in terms of the effects of modulating specific receptor subtypes on various behavioural measures such as response inhibition, perseveration, sustained attention, error monitoring and motivation. RESULTS: Blockade of alpha2 adrenoceptors improved sustained attention and response inhibition, whereas alpha1 and beta1/2 adrenergic receptor antagonists disrupted go performance and sustained attention, respectively. No relevant effects were obtained after targeting DA D1, D2 or D4 receptors, while both a D3 receptor agonist and antagonist improved post-error slowing and compulsive nose-poke behaviour, though generally impairing other task measures. CONCLUSIONS: Our results suggest that the use of specific pharmacological agents targeting alpha2 and beta noradrenergic receptors may improve existing treatments for attentional deficits and impulsivity, whereas DA D3 receptors may modulate error monitoring and perseverative behaviour. PMID- 23681172 TI - Practical considerations for image-based PSF and blobs reconstruction in PET. AB - Iterative reconstructions in positron emission tomography (PET) need a model relating the recorded data to the object/patient being imaged, called the system matrix (SM). The more realistic this model, the better the spatial resolution in the reconstructed images. However, a serious concern when using a SM that accurately models the resolution properties of the PET system is the undesirable edge artefact, visible through oscillations near sharp discontinuities in the reconstructed images. This artefact is a natural consequence of solving an ill conditioned inverse problem, where the recorded data are band-limited. In this paper, we focus on practical aspects when considering image-based point-spread function (PSF) reconstructions. To remove the edge artefact, we propose to use a particular case of the method of sieves (Grenander 1981 Abstract Inference New York: Wiley), which simply consists in performing a standard PSF reconstruction, followed by a post-smoothing using the PSF as the convolution kernel. Using analytical simulations, we investigate the impact of different reconstruction and PSF modelling parameters on the edge artefact and its suppression, in the case of noise-free data and an exactly known PSF. Using Monte-Carlo simulations, we assess the proposed method of sieves with respect to the choice of the geometric projector and the PSF model used in the reconstruction. When the PSF model is accurately known, we show that the proposed method of sieves succeeds in completely suppressing the edge artefact, though after a number of iterations higher than typically used in practice. When applying the method to realistic data (i.e. unknown true SM and noisy data), we show that the choice of the geometric projector and the PSF model does not impact the results in terms of noise and contrast recovery, as long as the PSF has a width close to the true PSF one. Equivalent results were obtained using either blobs or voxels in the same conditions (i.e. the blob's density function being the same as the voxel-based PSF). From a practical point-of-view, the method can be used to perform fast reconstructions based on very simple models (compared to sinogram-based PSF modelling), producing artefact-free images with a better compromise between noise and spatial resolution than images reconstructed without or with under-estimated PSF. Besides, the method inherently limits the spatial resolution in the reconstructed images to the intrinsic one of the PET system. PMID- 23681171 TI - Semihydrogenated BN sheet: a promising visible-light driven photocatalyst for water splitting. AB - Based on first principles calculations, we predict semihydrogenated graphitic BN (sh-BN) sheet is a potential metal-free visible-light driven photocatalyst for water splitting. The ground state of sh-BN is a strip-like antiferromagnetic semiconductor with a band gap suitable for visible-light absorption. The redox potentials of water splitting are all located inside the band gap and the probability densities of valence and conduction bands are distributed apart spatially leading to a well-separation of photogenerated electrons and holes. PMID- 23681173 TI - Functional studies and proteomics in platelets and fibroblasts reveal a lysosomal defect with increased cathepsin-dependent apoptosis in ATP1A3 defective alternating hemiplegia of childhood. AB - Alternating hemiplegia of childhood (AHC) is a rare syndrome with repeated hemiplegic episodes, paroxysmal events and global neurological impairment. Recently, heterozygous de novo ATP1A3 missense mutations have been identified in AHC patients, but the underlying pathogenesis mechanism remains unknown. Mutation analysis of ATP1A3 in 9 unrelated AHC cases revealed mostly D801N or E815K variants. As platelets represent a good cellular model to study defects in neuropathologies, morphological and functional experiments were performed in these subjects. Platelets from the AHC patients presented with structural and functional abnormalities of granules positive for the lysosomal marker CD63. Similar structural granule abnormalities were detected in patients' fibroblasts. Proteomic analysis of platelets and fibroblasts showed a total of 93 differentially expressed proteins in AHC mainly involved in metabolism. Interestingly, 7 of these proteins were detected in both cell types, including the lysosomal protein cathepsin. AHC fibroblasts revealed significantly increased levels of activated cathepsin B, which induces a stronger activation of apoptosis. Our study is the first to link ATP1A3 defects in AHC to a platelet and fibroblast lysosomal defect with evidence of increased apoptosis. Further studies are needed to define how this lysosomal defect is related to decreased ATPase activity. Biological Significance Only recently, the genetic cause of AHC was identified as heterozygous ATP1A3 mutations, but the underlying pathophysiological mechanism still remains unknown. By performing functional, morphological and proteomic studies in AHC patients we found a structural and functional granule defect in AHC platelets and fibroblasts that was specifically found in granules positive for the lysosomal marker CD63. In particular, proteomics identified several differentially expressed proteins in fibroblasts and platelets from AHC cases that are predicted to have an important role in cell function and maintenance, a pathway typically attributed to lysosomes. The lysosomal protein cathepsin was found to be differentially expressed in both platelets and fibroblasts of AHC patients, inducing a stronger activation of mainly the intrinsic apoptosis. Despite the precise mechanism for the increased lysosomal cathepsin B-dependent apoptosis detected in AHC in relation to impaired ATP1A3 deserves further studies, we could here show some evidence for a defective regulation of apoptosis in AHC, a disease that still has no biochemical or neuroradiological parameters for diagnosis. PMID- 23681174 TI - Texas 3-step decellularization protocol: looking at the cardiac extracellular matrix. AB - The extracellular matrix (ECM) is a critical tissue component, providing structural support as well as important regulatory signaling cues to govern cellular growth, metabolism, and differentiation. The study of ECM proteins, however, is hampered by the low solubility of ECM components in common solubilizing reagents. ECM proteins are often not detected during proteomics analyses using unbiased approaches due to solubility issues and relatively low abundance compared to highly abundant cytoplasmic and mitochondrial proteins. Decellularization has become a common technique for ECM protein-enrichment and is frequently used in engineering studies. Solubilizing the ECM after decellularization for further proteomic examination has not been previously explored in depth. In this study, we describe testing of a series of protocols that enabled us to develop a novel optimized strategy for the enrichment and solubilization of ECM components. Following tissue decellularization, we use acid extraction and enzymatic deglycosylation to facilitate re-solubilization. The end result is the generation of three fractions for each sample: soluble components, cellular components, and an insoluble ECM fraction. These fractions, developed in mass spectrometry-compatible buffers, are amenable to proteomics analysis. The developed protocol allows identification (by mass spectrometry) and quantification (by mass spectrometry or immunoblotting) of ECM components in tissue samples. BIOLOGICAL SIGNIFICANCE: The study of extracellular matrix (ECM) proteins in pathological and non-pathological conditions is often hampered by the low solubility of ECM components in common solubilizing reagents. Additionally, ECM proteins are often not detected during global proteomic analyses due to their relatively low abundance compared to highly abundant cytoplasmic and mitochondrial proteins. In this manuscript we describe testing of a series of protocols that enabled us to develop a final novel optimized strategy for the enrichment and solubilization of ECM components. The end result is the generation of three fractions for each sample: soluble components, cellular components, and an insoluble ECM fraction. By analysis of each independent fraction, differences in protein levels can be detected that in normal conditions would be masked. These fractions are amenable to mass spectrometry analysis to identify and quantify ECM components in tissue samples. The manuscript places a strong emphasis on the immediate practical relevance of the method, particularly when using mass spectrometry approaches; additionally, the optimized method was validated and compared to other methodologies described in the literature. PMID- 23681175 TI - An X-ray absorption spectroscopic study of the effect of bond covalency on the electronic structure of Gd2Ti(2-x)Sn(x)O7. AB - The titanate and stannate pyrochlore-type oxides have been investigated because of their potential applications in different fields. Pyrochlore-type oxides exhibit a wide variety of properties such as fast ionic conduction, resistance to radiation induced structural damage, and ferro- and antiferro-magnetism. These properties mainly depend on the metal-oxygen bonding interactions and electronic structure of the materials, both of which can change with composition. The Gd2Ti(2-x)Sn(x)O7 (0 <= x <= 2) system was synthesized by the ceramic method and investigated by X-ray absorption near edge spectroscopy (XANES), which allows for the examination of the effect of substitution on bonding and the electronic structure of materials. Examination of metal K- and L3-edge XANES spectra from the Gd2Ti(2-x)Sn(x)O7 system allowed for the elucidation of how the metal-oxygen bond covalency effects the electronic structure of these materials with increasing Sn content. The ionic character of the Ti-O and Gd-O bonds increases while the Sn-O bond becomes more covalent as x increases in the formula, and resulted in changes in energy and/or line shape of the spectra. This study shows that the bonding interactions between metal and oxygen vary strongly with composition, which may affect the fast ionic conduction and resistance to radiation induced structural damage that has been previously reported for these materials. It was also observed in this study that the intensity of the intersite hybrid peaks found in the pre-edge region of the Ti K-edge XANES spectra resulting from excitations of 1s electrons into next-nearest neighbour Ti 3d states decreased significantly with increasing Sn incorporation. PMID- 23681176 TI - [Suture-free amniotic membrane transplantation]. AB - Amniotic membrane transplantation has been used very successfully in ophthalmology since the 1940s for treatment of surface disorders. Over the course of the years the indications for use have been continuously extended. In contrast the operative technique is predominantly invasive, i.e. the amniotic membrane is surgically sutured onto the surface of the eye. In order to avoid surgical trauma the authors have developed a device which allows the amniotic membrane to be stretched in a ring and the amniotic ring can then be placed suture-free on the eye surface. The authors are hopeful that the biological principle of the amniotic membrane can be better utilized by uncomplicated repetitive application. PMID- 23681178 TI - [Multiple bilateral masses of the choroid]. PMID- 23681177 TI - [Treatment of retinal arterial branch occlusion with transluminal Nd:YAG laser embolectomy]. AB - BACKGROUND: There is currently no effective therapy for retinal artery branch occlusion (RABO). Transluminal Nd:YAG embolectomy (TYE) was developed to achieve rapid reperfusion; however, it is still a subject of controversy. A Nd:YAG laser is focused on the occluded vessel, the vessel wall is ruptured and the embolism dislocates to the vitreous humor through the opening in the artery. METHOD: We retrospectively examined the results of five patients treated with TYE. RESULTS: The age of the patients was 26-75 years (mean age 58 years, median 68 years). Initial visual acuity was hand movements to 1.0 and all patients had visual field defects. Treatment was performed between 4 and 30 h from the onset of symptoms. Visual acuity improved markedly in two cases the next day (hand movements to 0.8 and 0.4 to 1.0) and final visual acuity was between 0.8 and 1.25. All treatments led to vitreous hemorrhage but only one patient required surgical treatment. The range of follow-up was 4-42 months. CONCLUSIONS: The results are in accordance with those published in the literature. It can be concluded that TYE is a fast, easy and readily available method that should be taken into account especially in cases with low initial visual acuity. PMID- 23681179 TI - [BOON (Bonn ophthalmology online network). Concept of an integrative databank for monitoring patients under intravitreal therapy]. AB - BACKGROUND: Previous studies have proven that long-lasting success in the therapy of neovascular age-related macular degeneration (AMD) and other neovascular retinal diseases depends on monthly follow-up examinations to assess visual acuity and retinal morphology. MATERIALS AND METHODS: The interactive database Bonn ophthalmology online network (BOON) offers a platform for patient monitoring, increasing control reliability and providing a tool for permanent communication between treating centers and referring ophthalmologists. The BOON data-based project started in 2009 at the department of ophthalmology at Bonn University and ten referring ophthalmology practices. It was programmed to communicate diagnostic findings, images and patient appointments online. In order to react promptly the system gave immediate notice if patients had missed a follow-up appointment or the condition had worsened. Patients were recruited in 2009 and 2010 and were followed for 1 year. Each patient had an electronic master file with several registers in which, besides personal data, precise diagnostic findings, imaging and reports were quickly and easily entered by means of detailed check box and drop-down menus. Each follow-up was registered and an alert email was sent to the referring physician in cases of missed appointments or disease progression. RESULTS AND CONCLUSIONS: The BOON database supports the requirements for a fast and detailed communication between treating and referring physicians in the treatment of patients with AMD as well as other retinal diseases. It was programmed to support data exchange and monthly control visits and thus a better patient management. Results will show whether this helps to enhance long-term treatment success in neovascular diseases. PMID- 23681180 TI - [Defect covering of a perforated corneal ulcer with bovine pericardium transplant]. AB - An 89-year-old patient presented in an emergency situation with a perforated corneal ulcer of neurotrophic genesis. An operative treatment with a Tutopatch(r) was performed. In the course of treatment a reorganization of the Tutopatch(r) into corneal tissue resulted and a subsequent satisfactory defect covering with maintenance of visual acuity. Tutopatch(r) represents a good alternative for covering perforated corneal ulcers. PMID- 23681181 TI - [Unclear parapapillary tumor in childhood]. PMID- 23681182 TI - Controlled 3D-coating of the pores of highly ordered mesoporous antiferromagnetic Co3O4 replicas with ferrimagnetic Fe(x)Co(3-x)O4 nanolayers. AB - The controlled filling of the pores of highly ordered mesoporous antiferromagnetic Co3O4 replicas with ferrimagnetic FexCo3-xO4 nanolayers is presented as a proof-of-concept toward the integration of nanosized units in highly ordered, heterostructured 3D architectures. Antiferromagnetic (AFM) Co3O4 mesostructures are obtained as negative replicas of KIT-6 silica templates, which are subsequently coated with ferrimagnetic (FiM) FexCo3-xO4 nanolayers. The tuneable magnetic properties, with a large exchange bias and coercivity, arising from the FiM/AFM interface coupling, confirm the microstructure of this novel two phase core-shell mesoporous material. The present work demonstrates that ordered functional mesoporous 3D-materials can be successfully infiltrated with other compounds exhibiting additional functionalities yielding highly tuneable, versatile, non-siliceous based nanocomposites. PMID- 23681183 TI - Treatment outcomes of saddle nose correction. AB - IMPORTANCE: Many valuable classification schemes for saddle nose have been suggested that integrate clinical deformity and treatment; however, there is no consensus regarding the most suitable classification and surgical method for saddle nose correction. OBJECTIVES: To present clinical characteristics and treatment outcome of saddle nose deformity and to propose a modified classification system to better characterize the variety of different saddle nose deformities. DESIGN, SETTING, AND PARTICIPANTS: The retrospective study included 91 patients who underwent rhinoplasty for correction of saddle nose from April 1, 2003, through December 31, 2011, with a minimum follow-up of 8 months. Saddle nose was classified into 4 types according to a modified classification. MAIN OUTCOME AND MEASURE: Aesthetic outcomes were classified as excellent, good, fair, or poor. RESULTS: Patients underwent minor cosmetic concealment by dorsal augmentation (n = 8) or major septal reconstruction combined with dorsal augmentation (n = 83). Autologous costal cartilages were used in 40 patients (44%), and homologous costal cartilages were used in 5 patients (6%). According to postoperative assessment, 29 patients had excellent, 42 patients had good, 18 patients had fair, and 2 patients had poor aesthetic outcomes. No statistical difference in surgical outcome according to saddle nose classification was observed. Eight patients underwent revision rhinoplasty, owing to recurrence of saddle, wound infection, or warping of the costal cartilage for dorsal augmentation. CONCLUSIONS: We introduce a modified saddle nose classification scheme that is simpler and better able to characterize different deformities. Among 91 patients with saddle nose, 20 (22%) had unsuccessful outcomes (fair or poor) and 8 (9%) underwent subsequent revision rhinoplasty. Thus, management of saddle nose deformities remains challenging. LEVEL OF EVIDENCE: 4. PMID- 23681184 TI - Reply: Comment on 'Quiescence and yH2AX in neuroblastoma are regulated by ouabain/Na,K-ATPase': ouabain and cancer. PMID- 23681185 TI - Comment on 'Quiescence and gammaH2AX in neuroblastoma are regulated by ouabain/Na,K-ATPase': ouabain and cancer. PMID- 23681186 TI - Does the 'Liverpool Care Pathway' facilitate an improvement in quality of care for dying cancer patients? AB - BACKGROUND: The Liverpool Care Pathway for the Dying Patient (LCP) aims to transfer hospice principles of care for dying patients to other health-care sectors. This post-bereavement survey explored the LCP's effectiveness in improving quality of care for cancer patients. METHODS: Postal self-completion questionnaires were sent to 778 next-of-kin to consecutive deceased patients who had died an 'expected' cancer death in a hospice and acute tertiary hospital. RESULTS: Following exclusions (n=53), 255 of the 725 next-of-kin agreed to participate (35.2% response rate). Overall hospice participants reported the best quality of care, and hospital participants, for whom care was not supported by the LCP, reported the worst quality of care. Multivariate analysis showed the hospice was an independent predictor for patients being treated with dignity (OR 8.46) and receiving adequate family support (OR 7.18) (P<0.0001). Care supported by the LCP and the hospital specialist palliative care team were both associated with good family support, but neither was an independent predictor. CONCLUSIONS: From the bereaved relatives' perspective, within the hospital, the LCP is effective in improving specific aspects of care, such as symptom control for dying patients. Further improvement is required, however, to attain the hospice standard of care. PMID- 23681187 TI - Telomerase reverse transcriptase inhibition stimulates cyclooxygenase 2 expression in cancer cells and synergizes with celecoxib to exert anti-cancer effects. AB - BACKGROUND: Telomerase and telomerase reverse transcriptase (hTERT) confer cancer cells sustained proliferation and survival potentials. Targeting telomerase or hTERT is a novel anti-cancer strategy. However, telomerase/hTERT inhibition alone has minimal clinical efficacy. We explored the relationship between hTERT and cyclooxygenase 2 (COX2) and evaluated synergistic anti-cancer effects of targeting both hTERT and COX2. METHODS: hTERT was depleted in gastric and cervical cancer cells using small interfering RNA (siRNA) and analysed for COX2 expression using quantitative PCR and immunoblotting. Viable cells and apoptotic cells in gastric cancer cells treated with hTERT siRNA or/and the COX2 inhibitor celecoxib were measured using Trypen blue exclusion and flow cytometry. The in vivo anti-cancer effect of hTERT depletion or/and celecoxib was evaluated using mouse xenograft models. RESULTS: Knocking down hTERT expression in cancer cells led to robust increases in mRNA and protein levels of COX2. The COX2 promoter activity increased substantially in hTERT-depleted cells. hTERT depletion led to the activation of p38 mitogen-activated protein kinase responsible for the stimulation of COX2 gene transcription. hTERT depletion or celecoxib alone did not affect cancer cell survival, whereas their combination synergistically killed them both in vitro and in vivo. CONCLUSION: hTERT induces COX2 expression and simultaneously targeting hTERT and COX2 synergistically kills cancer cells. PMID- 23681189 TI - Class, race and ethnicity and information avoidance among cancer survivors. AB - BACKGROUND: Information seeking may increase cancer survivors' ability to make decisions and cope with the disease, but many also avoid cancer information after diagnosis. The social determinants and subsequent communication barriers that lead to avoidance have not been explored. The purpose of this study is to examine the influence of social determinants on information avoidance among cancer survivors. METHODS: We examined how health information avoidance is associated with structural and individual factors in a mail-based survey of 519 cancer survivors. Factor analysis was conducted to determine barriers to obtaining cancer information, and multivariable logistic regression models by gender were run to analyze social determinants of avoidance from an intersectional approach. RESULTS: Participants who were younger, female, had greater debt and lower income, and had difficulty finding suitable information were more likely to avoid information. The probability of information avoidance increased when survivors reported barriers to information use or comprehension. CONCLUSION: These results indicate that survivors' information avoidance may be driven, in part, by social determinants, particularly among those at the intersection of multiple social status categories. Customized strategies are needed that maximize the likelihood that information will be used by vulnerable groups such as those from a lower socioeconomic position. PMID- 23681188 TI - The impact of comorbidity and stage on prognosis of Danish melanoma patients, 1987-2009: a registry-based cohort study. AB - BACKGROUND: Comorbid conditions may play an important role in the prognosis of melanoma patients but have received little attention. METHODS: Using data from Danish registries, we identified patients diagnosed with melanoma from 1987 to 2009. We estimated the prevalence of comorbidity and calculated mortality rate ratios and interaction risks between melanoma and comorbidity. For every melanoma patient, 10 individuals were selected for comparison. Individuals in the comparison cohort were matched to their corresponding melanoma patients on age, gender, and exact prevalent comorbidities. RESULTS: We included 23 476 patients, 81% of whom had no comorbidity. Higher prevalence of comorbidity was associated with more advanced cancer stage. The standardised mortality rate increased with increasing level of comorbidity in both cohorts and was consistently higher among melanoma patients. Melanoma and comorbidity interacted to increase the mortality rate. The highest proportional excess was seen in melanoma patients with comorbidity score 3, in whom interaction accounted for 77 deaths per 1000 person years (40% of the total rate). We stratified by cancer stage and found that the interaction was markedly concentrated in patients with distant metastases. CONCLUSION: Interaction between melanoma and comorbidity was primarily concentrated in patients with distant metastases, which raises the possibility that comorbidity is associated with delay of melanoma diagnosis, advanced cancer stage, and less aggressive melanoma treatment. PMID- 23681190 TI - Protection of vascular endothelium by aspirin in a murine model of chronic Chagas' disease. AB - Chronic Chagas' disease affects 10-30 % of patients infected with Trypanosoma cruzi, and it mainly manifests as cardiomyopathy. Important pathophysiological mechanisms involved in the cardiac lesions include activation of the endothelium and induced microvascular alterations. These processes involve the production of endothelial adhesion molecules and thromboxane A2, which are involved in inflammatory cell recruitment and platelet aggregation, respectively. Cyclooxygenase inhibitors such as aspirin decrease thromboxane production and alter the course of Chagas' disease, both in the acute and chronic phases. We studied the effects of the administration of low and high doses of aspirin during the early phase of T. cruzi infection, following microvascular damage in the context of a chronic murine model of Chagas' disease. The effects of both schedules were assessed at 24 and 90 days postinfection by evaluating parasitemia, mortality, and cardiac histopathological changes as well as the expression of ICAM, VCAM, and E-selectin in cardiac tissue. Thromboxane A2, soluble ICAM, and E-selectin blood levels were also measured. While aspirin did not affect parasitemia or mortality in the infected mice, it decreased both cardiac inflammatory infiltrates and thromboxane levels. Additionally, at 90 days postinfection, aspirin normalized sICAM and sE-selectin levels. Considering the improved endothelial function induced by aspirin, we propose the possibility of including this drug in clinical therapy to treat chronic Chagas' disease. PMID- 23681191 TI - An antigenic domain of the Leishmania amazonensis nucleoside triphosphate diphosphohydrolase (NTPDase 1) is associated with disease progression in susceptible infected mice. AB - An antigenic conserved B domain was previously identified within nucleoside triphosphate diphosphohydrolases (NTPDases) of plants and parasites. Now, the r potDomain B, a 6* His-tag polypeptide belonging to the conserved B domain from the potato apyrase, and synthetic peptides LbB1LJ and LbB2LJ derived from the B domain from Leishmania NTPDase 1 were used as molecular tools for studies of the Leishmania amazonensis NTPDase 1. Widespread subcellular location of the specific NTPDase 1 was detected by Western blots of promastigote fractions and ultrastructural immunocytochemical microscopy using immune sera raised against these biomolecules. In addition, the L. amazonensis-infected BALB/c mice were evaluated at 12 to 120 days after infection, which progresses showing typical nodular lesion. High antibody reactivity with either r-potDomain B, LbB1LJ, or LbB2LJ was found in L. amazonensis-infected BALB/c mice indicating the antigenicity of the B domain from NTPDase 1 isoform. The IgG1 antibody reactivity significantly increased at 90-120 days postinfection, 18- to 24-fold when compared to the 12th day, and remained elevated even at 120th after infection, coinciding with the most active stage of the disease. In contrast, significantly higher IgG2a antibody reactivity with each biomolecule was observed at 40th day, about two- to fourfold higher than those found at 12th or 20th day, and decreased along 120-day period. Apparently, the conserved B domain is capable to induce IgG2a production in early disease stages. All together, these results suggest that r-potDomain B or synthetic peptides could be molecular starting points in experimental protocols of immunotherapy and/or vaccination for leishmaniasis. PMID- 23681192 TI - The first case of Demodex gatoi in Austria, detected with fecal flotation. AB - Feline demodicosis is a rare parasitic condition caused by three different species of mites (Demodex cati, Demodex gatoi, and an unnamed species). D. gatoi inhabits the superficial skin layer (stratum corneum) and is easily transmitted between individual cats. A 2-year-old female spayed Cornish Rex was presented with alopecia and pruritus. The dermatological examination revealed bilateral alopecia and excoriations on trunk, limbs, and belly. The second cat in the household, a 3-year-old female spayed Thai, showed no clinical signs. Superficial and deep skin scrapings were performed and cellophane tapes applied, and living D. gatoi mites could be detected in both cats. Oral ivermectin (0.25 mg/kg every other day) was subscribed. Feces were collected from both cats and fecal flotation with sugar and zinc solutions performed. When compared to skin scrapings and cellophane tapes, D. gatoi was detected more frequently and in higher numbers in fecal samples. Our findings suggest that D. gatoi can be efficiently diagnosed with coproscopy, particularly in asymptomatic carrier animals. DNA was extracted from the flotation liquid, and a PCR protocol for the species verification was designed. A fragment targeting a 325-bp DNA fragment of the D. gatoi mitochondrial 16S rDNA gene was amplified with a 100% similarity to the D. gatoi entry in GenBank(r) (GI 421920216). We report the first finding of D. gatoi in Austria and propose fecal flotation as a valuable tool for mite detection. Fecal flotation liquid is suitable for DNA extraction and PCR-based species verification of D. gatoi. PMID- 23681194 TI - Activity assessment of Tunisian olive leaf extracts against the trophozoite stage of Acanthamoeba. AB - The olive tree (Olea europaea, Oleaceae) has historically provided huge economic and nutritional benefits to the Mediterranean basin. In fact, olive leaf extracts have also been used by native people of this area in folk medicine to treat fever and other diseases such as malaria. Recently, several studies have focused on the extraction of high-added-value compounds from olive leaves. However, no previous studies have been developed in order to evaluate the activity of these extracts against Acanthamoeba. In the present work, olive leaf extracts from five different Tunisian varieties of olive trees (Chemlali Tataouine, Zarrazi, Toffehi, Dhokkar, and Limouni) were obtained by using three different solvents, and their activity against the trophozoite stage of Acanthamoeba castellanii Neff was screened. The IC50/96 h (50% parasite growth inhibition) was chosen as the appropriate and comparable data to give as previously described. It could be observed that the amoebicidal activity was dose dependent. Trophozoite growth was inhibited by all the tested extracts with IC50 ranging from 8.234 +/- 1.703 MUg/ml for the alcoholic mixture of the Dhokkar extract to 33.661 +/- 1.398 MUg/ml for the methanolic extract of the Toffehi variety. The activity in fact was affected especially by the tested variety and not by the solvent extraction, the Dhokkar variety being the most active one as mentioned above. PMID- 23681195 TI - Influence of food substrates on the development of the blowflies Calliphora vicina and Calliphora vomitoria (Diptera, Calliphoridae). AB - The blowflies Calliphora vicina and Calliphora vomitoria are among the first colonizers of human remains in Europe. Laboratory development studies with immature stages of these blowflies for postmortem interval (PMI) calculations are generally performed on different media such as processed food substrates or liver of various animals. The question arises whether these media per se influence the development of larvae and thus PMI calculations? In this systematic approach, the effects of an assortment of food substrates on the development of the larvae were analyzed. C. vomitoria showed much better growth on processed substrates such as beef, pork, turkey, and mixed minced meats than on unprocessed substrates such as beef and pork liver and turkey steak. Beef liver even impeded full development of the species and resulted in death of all individuals. C. vomitoria was therefore categorized as a specialist. Even though mixed minced meat yielded low pupariation rates for C. vicina, the species showed, otherwise, comparable growth rates on all substrates tested and was thus considered to be a generalist. These findings emphasize the importance of parameters besides temperature on the development rates of forensically important fly larvae. PMID- 23681193 TI - Protein kinases of Toxoplasma gondii: functions and drug targets. AB - Toxoplasma gondii is an important opportunistic parasite that infects almost all warm-blooded animals, causing congenital neurological and ocular diseases, especially in immunocompromised humans. The available therapeutic drugs are hypersensitive and toxic, and no vaccine is available to block the transmission of this parasite. Safer and more effective drugs are thus urgently needed to treat toxoplasmosis. Protein kinases (PKs) play crucial roles in the proliferation, differentiation, and pathogenesis of T. gondii. T. gondii calcium dependent protein kinase 1 and cGMP-dependent protein kinase are associated with cell invasion; mitogen-activated protein kinase 1 and cAMP-dependent protein kinase are involved in stress response and conversion from tachyzoite to bradyzoite; casein kinase 1 and cdc2 cyclin-dependent kinase control cell cycle. Rhoptry kinases, the T. gondii-specific PKs, are involved in host manipulation. Because of their difference in structure and function from that of mammalian PKs, T. gondii PKs are promising drug targets. In this review, we describe the functions of T. gondii protein kinases and their inhibitors as potential drugs against T. gondii. PMID- 23681196 TI - Evaluation of a possible direct effect by casein phosphopeptides on paracellular and vitamin D controlled transcellular calcium transport mechanisms in intestinal human HT-29 and Caco2 cell lines. AB - Intestinal cells are continuously exposed to food whose components are able to modulate some of their physiological functions. Among the bioactive food derivatives are casein phosphopeptides (CPPs), coming from the in vitro or in vivo casein digestion, which display the ability to form aggregates with calcium ions and to increase the uptake of the minerals in differentiated intestinal human HT-29 and Caco2 cells. Since extracellular calcium is a known inactivator of the TRPV6 channel, which is also involved in the colon cancer progression, the present study aims to determine a possible modulation by CPPs of the molecular structures responsible for paracellular and/or transcellular calcium absorption in these two cell lines. The paracellular calcium transport was determined by TEER measurements in Caco2 cells and by Lucifer Yellow flow in HT-29 cells. The possible modulation of transcellular calcium absorption machinery by CPPs was investigated by determining the mRNA expression for both the TRPV6 calcium channel and the VDR receptor in 1,25(OH)2D3 pre-treated undifferentiated/differentiated cells. The results obtained point out that: (i) CPPs do not affect paracellular calcium absorption; (ii) 1,25(OH)2D3 increases the TRPV6 mRNA expression in both types of cells. In the case of HT-29 cells this is the first determination of the presence of the TRPV6 channel; (iii) CPPs per se are not able to affect the VDR and TRPV6 mRNA expression; (iv) CPP administration does not affect the TRPV6 mRNA expression in 1,25(OH)2D3 pre treated HT-29 cells and Caco2 cells. Unlike peptides coming from the digestion of cheese whey protein digest, the digestion of milk casein produces peptides with no effects on TRPV6 calcium channel expression, though the same peptides are able to determine a calcium uptake by the intestinal cells. PMID- 23681197 TI - Genetic and environmental sources of individual religiousness: the roles of individual personality traits and perceived environmental religiousness. AB - In the current study, we examined the genetic and environmental sources of the links between individual religiousness and individual personality traits, perceived parental religiousness, and perceived peer religiousness. Data from 870 individuals (incl. 394 twin pairs) were analyzed. Variance in individual religiousness was significantly influenced by genetic effects, environmental influences shared by twins reared together, and individual-specific environmental influences. Individual religiousness showed significant associations with age, sex, specific personality traits (e.g., agreeableness, openness to values), and perceived religiousness of important social interaction partners, such as parents, best friends, and spouses. The links to personality traits were relatively small and primarily genetically mediated. The associations between individual religiousness and parental religiousness were substantial and mediated by shared environmental effects. These links significantly decreased across age accompanying a significant decrease of shared environmental influences on individual religiousness. The correlations between individual religiousness and perceived religiousness of spouses and best friends were relatively moderate but increased with age. These associations were mediated by genetic as well as nonshared environmental sources accompanying an increase of nonshared environmental influences on individual religiousness with age. The results suggest that inter-individual differences in religiousness are due to multiple sources. PMID- 23681198 TI - Treatment of the skin manifestations of hereditary hemorrhagic telangiectasia with pulsed dye laser. AB - Hereditary hemorrhagic telangiectasia (HHT) is a familial disorder, in which variably sized arteriovenous malformations develop in the skin, respiratory tract, central nervous system, and gastrointestinal and urogenital tracts. Bleeding is a major problem in the abnormal vessels, primarily in the nose and internal lesions. Skin lesions, in contrast, do not generally bleed spontaneously but pose a significant cosmetic concern. The lesions are characteristically small caliber vessels located in the dermis. As such, they are ideal targets for vascular lesions. Eight patients with cutaneous facial lesions of HHT were treated by pulsed dye laser. All patients exhibited excellent (75-100%) clearance after a mean of 2.6 treatments (range 1-8). In comparison, a control group of patients with non-HHT facial telangiectasia required a mean of 1.9 (range 1-5; p < 0.05) treatments. No adverse events were reported in either group. The study confirms the safety and efficacy of PDL in the management of the cutaneous lesions of HHT. PMID- 23681199 TI - Bioanalytical separation and preconcentration using ionic liquids. AB - Ionic liquids (ILs) are novel solvents that display a number of unique properties, such as negligible vapor pressure, thermal stability (even at high temperatures), favorable viscosity, and miscibility with water and organic solvents. These properties make them attractive alternatives to environmentally unfriendly solvents that produce volatile organic compounds. In this article, a critical review of state-of-the-art developments in the use of ILs for the separation and preconcentration of bioanalytes in biological samples is presented. Special attention is paid to the determination of various organic and inorganic analytes--including contaminants (e.g., pesticides, nicotine, opioids, gold, arsenic, lead, etc.) and functional biomolecules (e.g., testosterone, vitamin B12, hemoglobin)--in urine, blood, saliva, hair, and nail samples. A brief introduction to modern microextraction techniques based on ILs, such as dispersive liquid-liquid microextraction (DLLME) and single-drop microextraction (SDME), is provided. A comparison of IL-based methods in terms of their limits of detection and environmental compatibilities is also made. Finally, critical issues and challenges that have arisen from the use of ILs in separation and preconcentration techniques are also discussed. PMID- 23681200 TI - Mass spectrometry for the characterisation of nanoparticles. AB - Mass spectrometry (MS) has gained much importance in recent years as a powerful tool for reliable analytical characterisation of nanoparticles (NPs). The outstanding capabilities of different MS-based techniques including elemental and molecular detection and their coupling with different separation techniques and mechanisms are outlined herein. Examples of highly valuable elemental and molecular information for a more complete characterisation of NPs are given. Some selected applications illustrate the analytical potential of MS for NP sizing and quantitative assessment of the size distribution as well. PMID- 23681201 TI - Hard X-ray nanoprobe investigations of the subtissue metal distributions within Daphnia magna. AB - The unique potential of nanoscale elemental imaging of major/minor and trace level elemental distributions within thin biological tissue sections of the ecotoxicological model organism Daphnia magna is demonstrated by synchrotron radiation nano-X-ray fluorescence (nano-XRF). The applied highly specialized sample preparation method, coupled with the high spatial resolution (~180 nm) and high X-ray photon flux (6 * 10(11) photons/s) available at the European Synchrotron Radiation Facility (ESRF) ID22NI beamline proved to be critical for the high-quality visualization of (trace-)metal distributions on the submicron level within the target structures of interest. These include the branchial sacs on the thoracic appendages (epipodites) of D. magna, which are osmoregulatory regions where ion exchange occurs. For the main element of interest (Zn), detection limits of 0.7 ppm (3 ag) was reached in fast-scanning mode using an acquisition time of 0.3 s/pixel. As demonstrated, synchrotron radiation nano-XRF revealed the elemental distributions of Ca, Fe, and Zn within this osmoregulatory region on the submicron scale, aiding the exploration of possible detoxification mechanisms of Zn within D. magna at the subtissue level. PMID- 23681202 TI - Multi-channel PMMA microfluidic biosensor with integrated IDUAs for electrochemical detection. AB - A novel multi-channel poly(methyl methacrylate) (PMMA) microfluidic biosensor with interdigitated ultramicroelectrode arrays (IDUAs) for electrochemical detection was developed. The focus of the development was a simple fabrication procedure and the realization of a reliable large IDUA that can provide detection simultaneously to several microchannels. As proof of concept, five microchannels are positioned over a large single IDUA where the channels are parallel with the length of the electrode finger. The IDUAs were fabricated on the PMMA cover piece and bonded to a PMMA substrate containing the microfluidic channels using UV/ozone-assisted thermal bonding. Conditions of device fabrication were optimized realizing a rugged large IDUA within a bonded PMMA device. Gold adhesion to the PMMA, protective coatings, and pressure during bonding were optimized. Its electrochemical performance was studied using amperometric detection of potassium ferri and ferro hexacyanide. Cumulative signals within the same chip showed very good linearity over a range of 0-38 MUM (R(2) = 0.98) and a limit of detection of 3.48 MUM. The bonding of the device was optimized so that no cross talk between the channels was observed which otherwise would have resulted in unreliable electrochemical responses. The highly reproducible signals achieved were comparable to those obtained with separate single-channel devices. Subsequently, the multi-channel microfluidic chip was applied to a model bioanalytical detection strategy, i.e., the quantification of specific nucleic acid sequences using a sandwich approach. Here, probe-coated paramagnetic beads and probe-tagged liposomes entrapping ferri/ferro hexacyanide as the redox marker were used to bind to a single-stranded DNA sequence. Flow rates of the non-ionic detergent n-octyl-beta-D-glucopyranoside for liposome lysis were optimized, and the detection of the target sequences was carried out coulometrically within 250 s and with a limit of detection of 12.5 MUM. The robustness of the design and the reliability of the results obtained in comparison to previously published single channel designs suggest that the multi-channel device offers an excellent opportunity for bioanalytical applications that require multianalyte detection and high-throughput assays. PMID- 23681204 TI - High polarization of nuclear spins mediated by nanoparticles at millikelvin temperatures. AB - Nuclear magnetic resonance (NMR) techniques are extensively used in many areas of basic and clinical research, as well as in diagnostic medicine. However, NMR signals are intrinsically weak, and this imposes substantial constraints on the amounts and concentrations of materials that can be detected. The signals are weak because of the low energies characteristic of NMR and the resulting very low (typically 0.0001-0.01%) polarization of the nuclear spins. Here, we show that exposure to very low temperatures and high magnetic fields, in conjunction with nanoparticle-mediated relaxation enhancement, can be used to generate extremely high nuclear polarization levels on a realistic timescale; with copper nanoparticles at 15 mK and 14 T, (13)C polarization grew towards its equilibrium level of 23% with an estimated half-time of about 60 hours. This contrasts with a (13)C half-time of at least one year in the presence of aluminium nanoparticles. Cupric oxide nanoparticles were also effective relaxation agents. Our findings lead us to suspect that the relaxation may be mediated, at least in part, by the remarkable magnetic properties that some nanoparticle preparations can display. This methodology offers prospects for achieving polarization levels of 10-50% or more for many nuclear species, with a wide range of potential applications in structural biology and medicine. PMID- 23681203 TI - 11-Nor-9-carboxy-?9-tetrahydrocannabinol quantification in human oral fluid by liquid chromatography-tandem mass spectrometry. AB - Currently, ?9-tetrahydrocannabinol (THC) is the analyte quantified for oral fluid cannabinoid monitoring. The potential for false-positive oral fluid cannabinoid results from passive exposure to THC-laden cannabis smoke raises concerns for this promising new monitoring technology. Oral fluid 11-nor-9-carboxy-?9 tetrahydrocannabinol (THCCOOH) is proposed as a marker of cannabis intake since it is not present in cannabis smoke and was not measureable in oral fluid collected from subjects passively exposed to cannabis. THCCOOH concentrations are in the picogram per milliliter range in oral fluid and pose considerable analytical challenges. A liquid chromatography-tandem mass spectrometry (LCMSMS) method was developed and validated for quantifying THCCOOH in 1 mL Quantisal collected oral fluid. After solid phase extraction, chromatography was performed on a Kinetex C18 column with a gradient of 0.01% acetic acid in water and 0.01% acetic acid in methanol with a 0.5-mL/min flow rate. THCCOOH was monitored in negative mode electrospray ionization and multiple reaction monitoring mass spectrometry. The THCCOOH linear range was 12-1,020 pg/mL (R(2) > 0.995). Mean extraction efficiencies and matrix effects evaluated at low and high quality control (QC) concentrations were 40.8-65.1 and -2.4-11.5%, respectively (n = 10). Analytical recoveries (bias) and total imprecision at low, mid, and high QCs were 85.0-113.3 and 6.6-8.4% coefficient of variation, respectively (n = 20). This is the first oral fluid THCCOOH LCMSMS triple quadrupole method not requiring derivatization to achieve a <15 pg/mL limit of quantification. The assay is applicable for the workplace, driving under the influence of drugs, drug treatment, and pain management testing. PMID- 23681205 TI - Validation of the A&D BP UB-542 wrist device for home blood pressure measurement according to the European Society of Hypertension International Protocol revision 2010. AB - OBJECTIVE: The objective of this study was to determine the accuracy of the A&D BP UB-542 wrist device for home blood pressure (BP) measurement according to the International Protocol of the European Society of Hypertension (ESH). METHODS: Device evaluation was carried out in 33 patients. The mean age was 50.9+/-10.1 years, the mean systolic BP was 141.6+/-22.8 mmHg (range 92 : 189), the mean diastolic BP was 89.2+/-11.4 mmHg (range 62 : 120), the mean arm circumference was 28.8+/-3.2 cm (range 23-35), and the mean wrist circumference was 17.1+/-1.4 cm (range 14-19.5). The protocol requirements were followed precisely. RESULTS: The device passed all requirements, fulfilling the standards of the protocol. On average, the device overestimated the systolic BP by 1.8+/-7.2 mmHg and diastolic BP by 1.6+/-5.7 mmHg. CONCLUSION: These data show that the A&D BP UB-542 wrist device met the requirements for validation by the International Protocol and can be recommended for clinical use in the adult population. PMID- 23681206 TI - Validation of the fully automated A&D TM-2656 blood pressure monitor according to the British Hypertension Society Protocol. AB - OBJECTIVE: The present study aimed to evaluate the accuracy of the fully automated oscillometric upper-arm blood pressure monitor TM-2656 according to the British Hypertension Society (BHS) Protocol 1993. METHODS: We recruited individuals until there were 85 eligible participants and their blood pressure could meet the blood pressure distribution requirements specified by the BHS Protocol. For each individual, we sequentially measured the systolic and diastolic blood pressures using a mercury sphygmomanometer (two observers) and the TM-2656 device (one supervisor). Data analysis was carried out according to the BHS Protocol. RESULTS: The device achieved grade A. The percentage of blood pressure differences within 5, 10, and 15 mmHg was 62, 85, and 96%, respectively, for systolic blood pressure, and 71, 93, and 99%, respectively, for diastolic blood pressure. The average (+/-SD) of the device-observer differences was -2.1+/ 7.8 mmHg (P<0.0001) and -1.1+/-5.8 mmHg (P<0.0001) for systolic and diastolic blood pressures, respectively. CONCLUSION: The A&D upper-arm blood pressure monitor TM-2656 has passed the requirements of the BHS Protocol, and can thus be recommended for blood pressure measurement. PMID- 23681207 TI - Episodic future thought: contributions from working memory. AB - The ability to imagine hypothetical events in one's personal future is thought to involve a number of constituent cognitive processes. We investigated the extent to which individual differences in working memory capacity contribute to facets of episodic future thought. College students completed simple and complex measures of working memory and were cued to recall autobiographical memories and imagine future autobiographical events consisting of varying levels of specificity (i.e., ranging from generic to increasingly specific and detailed events). Consistent with previous findings, future thought was related to analogous measures of autobiographical memory, likely reflecting overlapping cognitive factors supporting both past and future thought. Additionally, after controlling for autobiographical memory, residual working memory variance independently predicted future episodic specificity. We suggest that when imagining future events, working memory contributes to the construction of a single, coherent, future event depiction, but not to the retrieval or elaboration of event details. PMID- 23681208 TI - The HATCH and CHA2DS 2-VASc scores. Prognostic value in pulmonary vein isolation. AB - AIMS: The HATCH score describes the risk of paroxysmal atrial fibrillation (Afib) progression, while the CHA2DS2vasc score depicts the risk of thromboembolic events in patients with Afib. We hypothesized that both scores may predict failure of Afib ablation. METHODS AND RESULTS: In all, 449 consecutive patients (65.5 % male, mean age 61.7 +/- 10.1 years) who presented to our institution for Afib ablation were investigated. A HATCH score of 0, 1, 2, 3, and >= 4 was found in 19.6, 50.3, 9.8, 15.6, and 4.6 % of the patients, respectively. A CHA2DS2vasc score of 0, 1, 2, 3, 4, 5, and > 5 was found in 10.7, 20.9, 25.1, 20.6, 15.0, 4.7, and 3.0 % of the patients, respectively (mean CHA2DS2vasc score, 2.4 +/- 1.5). After 618 procedures (1.38 +/- 0.55/patient), 84.3 % of patients were free of any atrial arrhythmia after a mean follow-up of 12.7 +/- 7.1 months. The freedom of Afib after a single ablation procedure ranged between 50.7 and 60.3 % in patients with HATCH scores between 0 and 3 and dropped to 30.0 % in patients with a HATCH score greater than 3 (p = 0.041). The freedom of Afib after 1.38 procedures per patient ranged between 79.5 % and 88.4 % in patients with a HATCH score between 0 and 3 and was lower with a score of 4 or more (66.7 %, p = 0.064). Pulmonary vein isolation was equally successful in patients with a CHA2DS2vasc score of 5 or lower, but less effective in patients with a score greater than 5 (p = 0.013). CONCLUSION: Pulmonary vein isolation is equally effective in patients with a low-to-moderate risk of disease progression and thromboembolic risk. However, the success rate seems to decrease in patients with high sores. PMID- 23681209 TI - Percutaneous versus surgical closure of atrial septal defects in children and adolescents. AB - BACKGROUND: There is a scarcity of data comparing percutaneous and surgical closure of the secundum atrial septal defect (ASD). OBJECTIVES: Assessment of safety and efficacy of both methods of treatment in a referral center affiliated with the Ministry of Health. METHODS: Observational, prospective, non-randomized study of two cohorts of children and adolescents younger than 14 years, treated by catheterization or surgery. Data was collected prospectively in the percutaneous group (A) and retrospectively in the surgical group (B). RESULTS: A total of 75 patients (pts) were enrolled in group A from April 2009 to October 2011 and 105 pts were treated in group B from January 2006 to January 2011. Age was older and weight was higher in group B and the ASD diameter was similar in both groups. Technical success was achieved in all procedures and there were no deaths. Complications (most minor) occurred in 68% of group B and 4% of A (p < 0.001). Rates of total occlusion or non-significant residual shunts were similar in both groups. Median hospitalization time was 1.2 days in group A and 8.4 days in group B (p < 0.001). CONCLUSION: Both treatment modalities are safe and effective, showing excellent outcomes. However, the percutaneous treatment has lower morbidity and shorter in-hospital stay length. These observations support the concept that percutaneous treatment of atrial septal defects should be regarded as the method of choice to manage selected patients with this condition. PMID- 23681210 TI - Questioning the prevalence of left ventricular hypertrophy considered as reference in the study by its authors. PMID- 23681211 TI - A recent evaluation of ventricular repolarization in diabetic patients. PMID- 23681212 TI - Immunocompromised patient with multiple cardiac masses. PMID- 23681213 TI - Idiopathic hypereosinophilic syndrome presenting as severe Loeffler's endocarditis. PMID- 23681214 TI - Apical ballooning syndrome during diagnostic coronary angiography. PMID- 23681215 TI - Maximum oxygen consumption measurement: valuable biological marker in health and in sickness. PMID- 23681216 TI - Ipsilateral opposite-side aspiration in resistant pneumothorax after CT image guided lung biopsy: complementary role after simple needle aspiration. AB - BACKGROUND: The goal of this study was to evaluate the efficacy of ipsilateral opposite-side aspiration, a new method to overcome resistant pneumothorax after failure of a simple aspiration. The patient position is reversed (from prone to supine or vice versa) and the aspiration repeated. METHODS: Between January 1, 2010, and April 3, 2012, 129 consecutive, CT image-guided, percutaneous needle biopsies of lung nodules were performed in 127 patients (75 men, 52 women; mean age, 67.8 years; range, 26-88 years). Two patients underwent repeated biopsies. The mean lesion diameter was 38 mm (range, 8-110 mm). Core biopsy and fine-needle aspiration (FNA) were performed in 126 procedures; in three cases, only FNA was performed. In the cases with symptomatic minimal pneumothorax and in all patients with pneumothorax > 10 mm, immediate, simple, manual aspiration was performed. Ipsilateral opposite-side aspiration was performed when simple aspiration failed. RESULTS: Among 129 CT image-guided biopsies, pneumothorax was detected by CT scan in 54 (42%); 51 (39%) were detected during the biopsy. Delayed pneumothorax occurred in two patients (1.55%). Manual aspiration to treat pneumothorax was performed in 27 of 129 procedures (21%). Simple aspiration was successful in 20 of these 27 cases (74%). Ipsilateral opposite-side aspiration was accomplished in the remaining seven cases (26%) and was successful in six cases (86%). Two of 129 procedures (1.55%) required chest tube placement. CONCLUSIONS: Immediate, simple, percutaneous aspiration of iatrogenic pneumothorax was successful in 74% of patients needing treatment. Our proposed new method of ipsilateral opposite-side aspiration offers a solution for patients who remain with resistant pneumothorax after simple aspiration. PMID- 23681217 TI - Including oxygen enhancement ratio in ion beam treatment planning: model implementation and experimental verification. AB - We present a method for adapting a biologically optimized treatment planning for particle beams to a spatially inhomogeneous tumor sensitivity due to hypoxia, and detected e.g., by PET functional imaging. The TRiP98 code, established treatment planning system for particles, has been extended for including explicitly the oxygen enhancement ratio (OER) in the biological effect calculation, providing the first set up of a dedicated ion beam treatment planning approach directed to hypoxic tumors, TRiP-OER, here reported together with experimental tests. A simple semi-empirical model for calculating the OER as a function of oxygen concentration and dose averaged linear energy transfer, generating input tables for the program is introduced. The code is then extended in order to import such tables coming from the present or alternative models, accordingly and to perform forward and inverse planning, i.e., predicting the survival response of differently oxygenated areas as well as optimizing the required dose for restoring a uniform survival effect in the whole irradiated target. The multiple field optimization results show how the program selects the best beam components for treating the hypoxic regions. The calculations performed for different ions, provide indications for the possible clinical advantages of a multi-ion treatment. Finally the predictivity of the code is tested through dedicated cell culture experiments on extended targets irradiation using specially designed hypoxic chambers, providing a qualitative agreement, despite some limits in full survival calculations arising from the RBE assessment. The comparison of the predictions resulting by using different model tables are also reported. PMID- 23681218 TI - Polyethyleneimine incorporated metal-organic frameworks adsorbent for highly selective CO2 capture. AB - A series of polyethyleneimine (PEI) incorporated MIL-101 adsorbents with different PEI loadings were reported for the first time in the present work. Although the surface area and pore volume of MIL-101 decreased significantly after loading PEI, all the resulting composites exhibited dramatically enhanced CO2 adsorption capacity at low pressures. At 100 wt% PEI loading, the CO2 adsorption capacity at 0.15 bar reached a very competitive value of 4.2 mmol g( 1) at 25 degrees C, and 3.4 mmol g(-1) at 50 degrees C. More importantly, the resulting adsorbents displayed rapid adsorption kinetics and ultrahigh selectivity for CO2 over N2 in the designed flue gas with 0.15 bar CO2 and 0.75 bar N2. The CO2 over N2 selectivity was up to 770 at 25 degrees C, and 1200 at 50 degrees C. We believe that the PEI based metal-organic frameworks is an attractive adsorbent for CO2 capture. PMID- 23681219 TI - Octopamine modulates activity of neural networks in the honey bee antennal lobe. AB - Neuronal plasticity allows an animal to respond to environmental changes by modulating its response to stimuli. In the honey bee (Apis mellifera), the biogenic amine octopamine plays a crucial role in appetitive odor learning, but little is known about how octopamine affects the brain. We investigated its effect in the antennal lobe, the first olfactory center in the brain, using calcium imaging to record background activity and odor responses before and after octopamine application. We show that octopamine increases background activity in olfactory output neurons, while reducing average calcium levels. Odor responses were modulated both upwards and downwards, with more odor response increases in glomeruli with negative or weak odor responses. Importantly, the octopamine effect was variable across glomeruli, odorants, odorant concentrations and animals, suggesting that the octopaminergic network is shaped by plasticity depending on an individual animal's history and possibly other factors. Using RNA interference, we show that the octopamine receptor AmOA1 (homolog of the Drosophila OAMB receptor) is involved in the octopamine effect. We propose a network model in which octopamine receptors are plastic in their density and located on a subpopulation of inhibitory neurons in a disinhibitory pathway. This would improve odor-coding of behaviorally relevant, previously experienced odors. PMID- 23681220 TI - Social signals increase monoamine levels in the tegmentum of juvenile Mexican spadefoot toads (Spea multiplicata). AB - Monoamines are important neuromodulators that respond to social cues and that can, in turn, modify social responses. Yet we know very little about the ontogeny of monoaminergic systems and whether they contribute to the development of social behavior. Anurans are an excellent model for studying the development of social behavior because one of its primary components, phonotaxis, is expressed early in life. To examine the effect of social signals on monoamines early in ontogeny, we presented juvenile Mexican spadefoot toads (Spea multiplicata) with a male mating call or no sound and measured norepinephrine, epinephrine, dopamine, serotonin, and a serotonin metabolite, across the brain using high-pressure liquid chromatography. Our results demonstrate that adult-like monoaminergic systems are in place shortly after metamorphosis. Perhaps more interestingly, we found that mating calls increased the level of monoamines in the juvenile tegmentum, a midbrain region involved in sensory-motor integration and that contributes to brain arousal and attention. We saw no such increase in the auditory midbrain or in forebrain regions. We suggest that changes in monoamine levels in the juvenile tegmentum may reflect the effects of social signals on arousal state and could contribute to context-dependent modulation of social behavior. PMID- 23681221 TI - Anti-TNF-alpha therapy for renal amyloid as a complication of Crohn's disease. PMID- 23681222 TI - Facial nuclear degeneration on MRI in bulbar onset amyotrophic lateral sclerosis. PMID- 23681223 TI - BECN1 and BIM interactions with MCL-1 determine fludarabine resistance in leukemic B cells. AB - The purine analog fludarabine (Fd) is an essential therapeutic for chronic lymphocytic leukemia (CLL). Innate or acquired resistance to Fd is a significant clinical problem and is largely mediated by increased expression of BCL-2 family members. The antiapoptotic BCL-2 family proteins inhibit both apoptosis and autophagy, therefore, downregulation of antiapoptotic BCL-2 family proteins and enhanced autophagy must coexist in cells dying in response to an apoptosis inducing therapeutic. However, in the drug-resistant cells that have an increased dependence on antiapoptotic proteins, whether autophagy is also inhibited remains unclear. Here, we examined the role of the BCL-2 family in regulating cell death and autophagy in leukemic cell lines and their derivative isogenic Fd-resistant (FdR) cells. MCL-1 degradation following Fd treatment freed the proapoptotic effectors BIM and BECN1, thus leading to cell death-associated autophagy in Fd sensitive cells. However, in FdR cells, low BIM expression and BECN1 sequestration by MCL-1 prevented cell death. Consistently, in sensitive cells inhibition of apoptosis using siBIM and of both the early-phase autophagy nucleation steps by siBECN1, shATG7 or 3-methyladenine and the late-phase autophagy by shLAMP2, significantly reduced Fd-induced cell death. Paradoxically, FdR cells were addicted to basal autophagy, which was dependent on AMP-activated protein kinase (AMPK) but not BECN1. Moreover, in FdR cells, inhibition of autophagy by shLAMP2, but not siBECN1, enhanced cell death. The BH3-mimetic obatoclax released BIM and BECN1 from MCL-1 in Fd-sensitive and BECN1 from MCL-1 in FdR cells, and was effective at killing both Fd-sensitive and - resistant leukemic cells, including primary CLL cells. Therefore, a differential regulation of autophagy through BECN1 and AMPK signaling in Fd-sensitive and - resistant cells determines the different possible outcomes of autophagy inhibition. These findings suggest effective means to overcome Fd resistance by induction of BIM dependent apoptosis and activation of BECN1-dependent autophagy. PMID- 23681224 TI - Activation of executioner caspases is a predictor of progression-free survival in glioblastoma patients: a systems medicine approach. AB - Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. GBM cells are highly resistant to apoptosis induced by antitumor drugs and radiotherapy resulting in cancer progression. We assessed whether a systems medicine approach, analysing the ability of tumor cells to execute apoptosis could be utilized to predict the response of GBM patients to treatment. Concentrations of the key proapoptotic proteins procaspase-3, procaspase-9, Smac and Apaf-1 and the antiapopotic protein XIAP were determined in a panel of GBM cell lines and GBM patient tumor resections. These values were used as input for APOPTO-CELL, a systems biological based mathematical model built to predict cellular susceptibility to undergo caspase activation. The modeling was capable of accurately distinguishing between GBM cells that die or survive in response to treatment with temozolomide in 10 of the 11 lines analysed. Importantly the results obtained using GBM patient samples show that APOPTO-CELL was capable of stratifying patients according to their progression-free survival times and predicted the ability of tumor cells to support caspase activation in 16 of the 21 GBM patients analysed. Calculating the susceptibility to apoptosis execution may be a potent tool in predicting GBM patient therapy responsiveness and may allow for the use of APOPTO-CELL in a clinical setting. PMID- 23681225 TI - Modeling cell-in-cell structure into its biological significance. AB - Although cell-in-cell structure was noted 100 years ago, the molecular mechanisms of 'entering' and the destination of cell-in-cell remain largely unclear. It takes place among the same type of cells (homotypic cell-in-cell) or different types of cells (heterotypic cell-in-cell). Cell-in-cell formation affects both effector cells and their host cells in multiple aspects, while cell-in-cell death is under more intensive investigation. Given that cell-in-cell has an important role in maintaining homeostasis, aberrant cell-in-cell process contributes to the etiopathology in humans. Indeed, cell-in-cell is observed in many pathological processes of human diseases. In this review, we intend to discuss the biological models of cell-in-cell structures under physiological and pathological status. PMID- 23681226 TI - Many faces of DAMPs in cancer therapy. AB - A new concept of immunogenic cell death (ICD) has recently been proposed. The immunogenic characteristics of this cell death mode are mediated mainly by molecules called 'damage-associated molecular patterns' (DAMPs), most of which are recognized by pattern recognition receptors. Some DAMPs are actively emitted by cells undergoing ICD (e.g. calreticulin (CRT) and adenosine triphosphate (ATP)), whereas others are emitted passively (e.g. high-mobility group box 1 protein (HMGB1)). Recent studies have demonstrated that these DAMPs play a beneficial role in anti-cancer therapy by interacting with the immune system. The molecular pathways involved in translocation of CRT to the cell surface and secretion of ATP from tumor cells undergoing ICD are being elucidated. However, it has also been shown that the same DAMPs could contribute to progression of cancer and promote resistance to anticancer treatments. In this review, we will critically evaluate the beneficial and detrimental roles of DAMPs in cancer therapy, focusing mainly on CRT, ATP and HMGB1. PMID- 23681227 TI - IP3R2 levels dictate the apoptotic sensitivity of diffuse large B-cell lymphoma cells to an IP3R-derived peptide targeting the BH4 domain of Bcl-2. AB - Disrupting inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)/B-cell lymphoma 2 (Bcl-2) complexes using a cell-permeable peptide (stabilized TAT-fused IP3R derived peptide (TAT-IDP(S))) that selectively targets the BH4 domain of Bcl-2 but not that of B-cell lymphoma 2-extra large (Bcl-Xl) potentiated pro-apoptotic Ca(2+) signaling in chronic lymphocytic leukemia cells. However, the molecular mechanisms rendering cancer cells but not normal cells particularly sensitive to disrupting IP3R/Bcl-2 complexes are poorly understood. Therefore, we studied the effect of TAT-IDP(S) in a more heterogeneous Bcl-2-dependent cancer model using a set of 'primed to death' diffuse large B-cell lymphoma (DL-BCL) cell lines containing elevated Bcl-2 levels. We discovered a large heterogeneity in the apoptotic responses of these cells to TAT-IDP(S) with SU-DHL-4 being most sensitive and OCI-LY-1 being most resistant. This sensitivity strongly correlated with the ability of TAT-IDP(S) to promote IP3R-mediated Ca(2+) release. Although total IP3R-expression levels were very similar among SU-DHL-4 and OCI-LY-1, we discovered that the IP3R2-protein level was the highest for SU-DHL-4 and the lowest for OCI-LY-1. Strikingly, TAT-IDP(S)-induced Ca(2+) rise and apoptosis in the different DL-BCL cell lines strongly correlated with their IP3R2-protein level, but not with IP3R1-, IP3R3- or total IP3R-expression levels. Inhibiting or knocking down IP3R2 activity in SU-DHL-4-reduced TAT-IDP(S)-induced apoptosis, which is compatible with its ability to dissociate Bcl-2 from IP3R2 and to promote IP3-induced pro-apoptotic Ca(2+) signaling. Thus, certain chronically activated B-cell lymphoma cells are addicted to high Bcl-2 levels for their survival not only to neutralize pro-apoptotic Bcl-2-family members but also to suppress IP3R hyperactivity. In particular, cancer cells expressing high levels of IP3R2 are addicted to IP3R/Bcl-2 complex formation and disruption of these complexes using peptide tools results in pro-apoptotic Ca(2+) signaling and cell death. PMID- 23681228 TI - Stemness and inducing differentiation of small cell lung cancer NCI-H446 cells. AB - Small cell lung cancer (SCLC) accounts for nearly 15% of human lung cancers and is one of the most aggressive solid tumors. The SCLC cells are thought to derive from self-renewing pulmonary neuroendocrine cells by oncogenic transformation. However, whether the SCLC cells possess stemness and plasticity for differentiation as normal stem cells has not been well understood thus far. In this study, we investigated the expressions of multilineage stem cell markers in the cancer cells of SCLC cell line (NCI-H446) and analyzed their clonogenicity, tumorigenicity, and plasticity for inducing differentiation. It has been found that most cancer cells of the cell line expressed multilineage stem cell markers under the routine culture conditions and generated single-cell clones in anchorage-dependent or -independent conditions. These cancer cells could form subcutaneous xenograft tumors and orthotopic lung xenograft tumors in BALB/C-nude mice. Most cells in xenograft tumors expressed stem cell markers and proliferation cell nuclear antigen Ki67, suggesting that these cancer cells remained stemness and highly proliferative ability in vivo. Intriguingly, the cancer cells could be induced to differentiate into neurons, adipocytes, and osteocytes, respectively, in vitro. During the processes of cellular phenotype conversions, autophagy and apoptosis were two main metabolic events. There is cross-talking between autophagy and apoptosis in the differentiated cancer cells. In addition, the effects of the inhibitor and agonist for Sirtuin1/2 on the inducing osteogenic differentiation indicated that Sirtuin1/2 had an important role in this process. Taken together, these results indicate that most cancer cells of NCI-H446 cell line possess stemness and plasticity for multilineage differentiation. These findings have potentially some translational applications in treatments of SCLC with inducing differentiation therapy. PMID- 23681229 TI - Loss of connective tissue growth factor as an unfavorable prognosis factor activates miR-18b by PI3K/AKT/C-Jun and C-Myc and promotes cell growth in nasopharyngeal carcinoma. AB - Connective tissue growth factor (CTGF) has different roles in different types of cancer. However, the involvement and molecular basis of CTGF in tumor progression and prognosis of human nasopharyngeal carcinoma (NPC) have almost never been reported. In this study, we observed that downregulated CTGF expression was significantly associated with NPC progression and poor prognosis. Knockdown of CTGF markedly elevated the ability of cell proliferation in vivo and in vitro. Subsequently, we discovered that the reduction of CTGF increased the expression of miR-18b, an oncomir-promoting cell proliferation. Further, we discovered that attenuated CTGF-mediated upregulation of miR-18b was dependent on the increased binding of transcription factors Jun proto-oncogene (C-Jun) and v-Myc myelocytomatosis viral oncogene homolog (C-Myc) to miR-18b promoter region via phosphoinositide 3-kinase (PI3K)/AKT pathway. Finally, we further found that miR 18b directly suppressed the expression of CTGF in NPC. In clinical fresh specimens, miR-18b was widely overexpressed and inversely correlated with CTGF expression in NPC. Our studies are the first to demonstrate that reduced CTGF as an unfavorable prognosis factor mediates the activation of miR-18b, an oncomir directly suppresses CTGF expression, by PI3K/AKT/C-Jun and C-Myc and promotes cell growth of NPC. PMID- 23681230 TI - SIRT1 activation enhances HDAC inhibition-mediated upregulation of GADD45G by repressing the binding of NF-kappaB/STAT3 complex to its promoter in malignant lymphoid cells. AB - We explored the activity of SIRT1 activators (SRT501 and SRT2183) alone and in combination with panobinostat in a panel of malignant lymphoid cell lines in terms of biological and gene expression responses. SRT501 and SRT2183 induced growth arrest and apoptosis, concomitant with deacetylation of STAT3 and NF kappaB, and reduction of c-Myc protein levels. PCR arrays revealed that SRT2183 leads to increased mRNA levels of pro-apoptosis and DNA-damage-response genes, accompanied by accumulation of phospho-H2A.X levels. Next, ChIP assays revealed that SRT2183 reduces the DNA-binding activity of both NF-kappaB and STAT3 to the promoter of GADD45G, which is one of the most upregulated genes following SRT2183 treatment. Combination of SRT2183 with panobinostat enhanced the anti-growth and anti-survival effects mediated by either compound alone. Quantitative-PCR confirmed that the panobinostat in combination with SRT2183, SRT501 or resveratrol leads to greater upregulation of GADD45G than any of the single agents. Panobinostat plus SRT2183 in combination showed greater inhibition of c Myc protein levels and phosphorylation of H2A.X, and increased acetylation of p53. Furthermore, EMSA revealed that NF-kappaB binds directly to the GADD45G promoter, while STAT3 binds indirectly in complexes with NF-kappaB. In addition, the binding of NF-kappaB/STAT3 complexes to the GADD45G promoter is inhibited following panobinostat, SRT501 or resveratrol treatment. Moreover, the combination of panobinostat with SRT2183, SRT501 or resveratrol induces a greater binding repression than either agent alone. These data suggest that STAT3 is a corepressor with NF-kappaB of the GADD45G gene and provides in vitro proof-of concept for the combination of HDACi with SIRT1 activators as a potential new therapeutic strategy in lymphoid malignancies. PMID- 23681231 TI - Neuropeptide Y receptors activation protects rat retinal neural cells against necrotic and apoptotic cell death induced by glutamate. AB - It has been claimed that glutamate excitotoxicity might have a role in the pathogenesis of several retinal degenerative diseases, including glaucoma and diabetic retinopathy. Neuropeptide Y (NPY) has neuroprotective properties against excitotoxicity in the hippocampus, through the activation of Y1, Y2 and/or Y5 receptors. The principal objective of this study is to investigate the potential protective role of NPY against glutamate-induced toxicity in rat retinal cells (in vitro and in an animal model), unraveling the NPY receptors and intracellular mechanisms involved. Rat retinal neural cell cultures were prepared from newborn Wistar rats (P3-P5) and exposed to glutamate (500 MUM) for 24 h. Necrotic cell death was evaluated by propidium iodide (PI) assay and apoptotic cell death using TUNEL and caspase-3 assays. The cell types present in culture were identified by immunocytochemistry. The involvement of NPY receptors was assessed using selective agonists and antagonists. Pre-treatment of cells with NPY (100 nM) inhibited both necrotic cell death (PI-positive cells) and apoptotic cell death (TUNEL-positive cells and caspase 3-positive cells) triggered by glutamate, with the neurons being the cells most strongly affected. The activation of NPY Y2, Y4 and Y5 receptors inhibited necrotic cell death, while apoptotic cell death was only prevented by the activation of NPY Y5 receptor. Moreover, NPY neuroprotective effect was mediated by the activation of PKA and p38K. In the animal model, NPY (2.35 nmol) was intravitreally injected 2 h before glutamate (500 nmol) injection into the vitreous. The protective role of NPY was assessed 24 h after glutamate (or saline) injection by TUNEL assay and Brn3a (marker of ganglion cells) immunohistochemistry. NPY inhibited the increase in the number of TUNEL-positive cells and the decrease in the number of Brn3a-positive cells induced by glutamate. In conclusion, NPY and NPY receptors can be considered potential targets to treat retinal degenerative diseases, such as glaucoma and diabetic retinopathy. PMID- 23681232 TI - GADD45beta mediates p53 protein degradation via Src/PP2A/MDM2 pathway upon arsenite treatment. AB - Growth arrest and DNA-damage-inducible, beta (GADD45beta) has been reported to inhibit apoptosis via attenuating c-Jun N-terminal kinase (JNK) activation. We demonstrated here that GADD45beta mediated its anti-apoptotic effect via promoting p53 protein degradation following arsenite treatment. We found that p53 protein expression was upregulated in GADD45beta-/- cells upon arsenite exposure as compared with those in GADD45beta+/+ cells. Further studies showed that GADD45beta attenuated p53 protein expression through Src/protein phosphatase 2A/murine double minute 2-dependent p53 protein-degradation pathway. Moreover, we identified that GADD45beta-mediated p53 protein degradation was crucial for its anti-apoptotic effect due to arsenite exposure, whereas increased JNK activation was not involved in the increased cell apoptotic response in GADD45beta-/- cells under same experimental conditions. Collectively, our results demonstrate a novel molecular mechanism responsible for GADD45beta protection of arsenite-exposed cells from cell death, which provides insight into our understanding of GADD45beta function and a unique compound arsenite as both a cancer therapeutic reagent and an environmental carcinogen. Those novel findings may also enable us to design more effective strategies for utilization of arsenite for the treatment of cancers. PMID- 23681234 TI - Recruitment of CCR6-expressing Th17 cells by CCL20 secreted from plasmin stimulated macrophages. AB - In the present study, monocyte-derived human macrophages were differentiated from buffy coats. Naive CD4+ T-cells enriched from peripheral blood mononuclear cells using anti-CD4 magnetic beads and the autoMACS separation system were polarized under T-helper 17 (Th17)-promoting conditions for 6 days to get Th17 cells. The frequency of Th17 cell differentiation and the expression of C-C chemokine receptor type 6 (CCR6) on Th17 cells were investigated by flow cytometry. Plasmin triggered induction of macrophage inflammatory protein-3alpha/C-C chemokine ligand 20 (CCL20) genes in macrophages was assessed by reverse transcription polymerase chain reaction, and secreted protein levels were measured by enzyme linked immunosorbent assay. Th17 cell migration induced by CCL20 secreted from plasmin-stimulated macrophages was tested in vitro by chemotaxis using a transwell system. These results demonstrate that plasmin triggers the expression of chemokine CCL20 messenger RNA and the release of CCL20 protein in human monocyte-derived macrophages, which critically depend on the proteolytic activity of plasmin and activation of p38 mitogen-activated protein kinase and nuclear factor-kappaB signaling pathways. Expression of CCR6 was detected on 87.23 +/- 8.6% of Th17 cells in vitro. Similar to chemotaxis triggered by recombinant human CCL20, supernatants collected from plasmin-stimulated macrophage-induced chemotactic migration of Th17 cells, which could be inhibited by an anti-CCL20 neutralizing antibody. These results suggest that plasmin generated in inflamed tissues might elicit production of chemokine CCL20 by human macrophages leading to the recruitment of CCR6 positive Th17 cells to the inflammatory sites. PMID- 23681233 TI - Hypoxia counteracts taxol-induced apoptosis in MDA-MB-231 breast cancer cells: role of autophagy and JNK activation. AB - Cancer cell resistance against chemotherapy is still a heavy burden to improve anticancer treatments. Autophagy activation and the development of hypoxic regions within the tumors are known to promote cancer cell resistance. Therefore, we sought to evaluate the role of autophagy and hypoxia on the taxol-induced apoptosis in MDA-MB-231 breast cancer cells. The results showed that taxol induced apoptosis after 16 h of incubation, and that hypoxia protected MDA-MB-231 cells from taxol-induced apoptosis. In parallel, taxol induced autophagy activation already after 2 h of incubation both under normoxia and hypoxia. Autophagy activation after taxol exposure was shown to be a protective mechanism against taxol-induced cell death both under normoxia and hypoxia. However, at longer incubation time, the autophagic process reached a saturation point under normoxia leading to cell death, whereas under hypoxia, autophagy flow still correctly took place allowing the cells to survive. Autophagy induction is induced after taxol exposure via mechanistic target of rapamycin (mTOR) inhibition, which is more important in cells exposed to hypoxia. Taxol also induced c-Jun N-terminal kinase (JNK) activation and phosphorylation of its substrates B-cell CLL/lymphoma 2 (Bcl2) and BCL2-like 1 (BclXL) under normoxia and hypoxia very early after taxol exposure. Bcl2 and BclXL phosphorylation was decreased more importantly under hypoxia after long incubation time. The role of JNK in autophagy and apoptosis induction was studied using siRNAs. The results showed that JNK activation promotes resistance against taxol-induced apoptosis under normoxia and hypoxia without being involved in induction of autophagy. In conclusion, the resistance against taxol-induced cell death observed under hypoxia can be explained by a more effective autophagic flow activated via the classical mTOR pathway and by a mechanism involving JNK, which could be dependent on Bcl2 and BclXL phosphorylation but independent of JNK-induced autophagy activation. PMID- 23681235 TI - Autoantibody against angiotensin AT1 receptor from preeclamptic patients enhances collagen-induced human platelet aggregation. AB - Hypercoagulability, platelet activation, and thrombocytopenia are the chief characteristics of preeclampsia, but their responsible underlying molecular mechanisms remain obscure. Recent studies have demonstrated that the autoantibody against angiotensin II type 1 receptor (AT1-AA) constitutes a novel risk factor for preeclampsia. However, the role of AT1-AA in platelet activation and hypercoagulability in preeclampsia has never been investigated. In the present study, we determined whether AT1-AA promotes platelet aggregation in vitro, and dissected the potential underlying mechanisms. AT1-AA was detected by enzyme linked immunosorbent assay. After immunoglobulin G fractions purified from the preeclamptic patient positive sera were added to platelets isolated from healthy volunteers, platelet aggregation and intracellular Ca(2+) levels were detected. AT1-AA significantly enhanced in vitro collagen-induced platelet aggregation, an effect blocked by the AT1 receptor antagonist losartan. Additionally, AT1-AA increased and maintained collagen-induced cytosolic calcium concentration throughout the experiment. We demonstrated for the first time that AT1-AA significantly promotes collagen-induced platelet aggregation through angiotensin type 1 receptor activation in vitro, potentially via increased intracellular Ca(2+) concentration, supporting AT1-AA as a potential contributor to the hypercoagulable state of preeclampsia. PMID- 23681236 TI - Microarray partition using a recycled marker pen and neutral balsam. PMID- 23681237 TI - Exceptions that prove the rules in neuro-ophthalmology. PMID- 23681238 TI - Spontaneous cerebrospinal fluid otorrhea and rhinorrhea in idiopathic intracranial hypertension patients. AB - BACKGROUND: Spontaneous cerebrospinal fluid (CSF) leakage may occur in patients with normal or increased intracranial pressure (ICP). We describe herein spontaneous CSF leakage as a result of chronic increased ICP in 4 patients with idiopathic intracranial hypertension (IIH). Although rhinorrhea previously has been described in IIH patients, to our knowledge this is the first report of otorrhea in these patients. METHODS: Four patients with spontaneous CSF leakage were examined between 2001 and 2011; 3 presented with rhinorrhea and 1 with otorrhea. Clinical settings and manifestations were analyzed. RESULTS: All patients were found to have IIH. Three had been diagnosed with IIH several years earlier and had been noncompliant with their medical treatment, whereas in 1 patient, CSF rhinorrhea was the presenting symptom of IIH. CONCLUSION: CSF leak is a rare complication in IIH patients. We have shown that rhinorrhea can be the presenting sign in these patients and that rhinorrhea and otorrhea can be a late sign of the disease. PMID- 23681239 TI - Macular hole: a rare complication of ocular bartonellosis. AB - A 37-year-old woman presented with an anterior optic neuropathy related to Bartonella henselae. Twenty-nine days after symptom onset, a partial thickness macular hole developed in the involved eye. Fundus photography and optical coherence tomography confirmed the conversion to a full-thickness macular hole in 2 months. Macular hole as a complication of cat scratch disease is a rare entity, with 2 prior reported cases in children. The development of a macular hole following cat scratch disease can appear without the clinical picture of multiple white chorioretinal lesions, macular star, or vitritis. PMID- 23681240 TI - Variable ptosis after botulinum toxin type a injection with positive ice test mimicking ocular myasthenia gravis. AB - We describe a patient who received cosmetic botulinum toxin type A injections to the brow and subsequently developed unilateral ptosis that was variable during examination and was transiently improved after the ice pack test. Ptosis gradually resolved spontaneously over approximately 3 months. This is the third patient to have variable ptosis documented after botulinum toxin type A injection to the brow and the second to have a positive ice test. The ice test is not completely specific for myasthenia gravis but may, at times, improve ptosis resulting from other defects at the neuromuscular junction. Wound botulism now is much more common because of illicit drug use, and the ice test also might be positive in this setting. PMID- 23681241 TI - Drug-related mitochondrial optic neuropathies. AB - BACKGROUND: There is a group of optic neuropathies of either genetic or acquired origin characterized by similar clinical manifestations with preferential involvement of the papillomacular bundle (PMB). PMB fibers are most susceptible to injury as they are small, unmyelinated, and have high-energy demands. These optic neuropathies share a presumed common pathophysiology of mitochondrial dysfunction. EVIDENCE ACQUISITION: A variety of medications cause optic neuropathy by interfering with mitochondrial function. The evidence linking these therapeutic agents as a cause of mitochondrial optic neuropathy (MON) is well established in some and less certain in others. The differential diagnosis includes other optic nerve disorders producing bilateral, symmetric visual loss, including certain nutritional deficiencies, toxins, and genetic diseases. RESULTS: Ethambutol, chloramphenicol, linezolid, erythromycin, streptomycin, and antiretroviral drugs can cause drug-related MON. In many cases, drug toxicity is dose and duration dependent, and discontinuation of the drug in a timely manner can lead to significant visual recovery. CONCLUSIONS: Mitochondrial optic neuropathies are increasingly recognized as a spectrum of conditions that reach a similar end point by compromising a common pathway of mitochondrial dysfunction. Clinicians should be aware of drugs that can cause a MON. Prompt recognition of this association is critical in preventing irreversible, profound visual loss. PMID- 23681243 TI - Optic nerve sheath fenestration vs cerebrospinal diversion procedures: what is the preferred surgical procedure for the treatment of idiopathic intracranial hypertension failing maximum medical therapy? PMID- 23681242 TI - A case of extraocular muscle enlargement causing diplopia: thinking beyond thyroid eye disease. PMID- 23681244 TI - Are we there yet? Is neuro-ophthalmology at the cusp of a paradigm shift? Lessons from leber hereditary optic neuropathy. PMID- 23681246 TI - Neuro-ophthalmology in Malawi. PMID- 23681247 TI - Neuro-ophthalmology in Korea. PMID- 23681250 TI - Mandibular osteotomies and distraction osteogenesis: evolution and current advances. AB - IMPORTANCE: Although a number of mandibular and occlusal problems may be addressed by orthodontic treatment alone, dentofacial osteotomies are often needed to achieve desired functional or cosmetic results. With the increased popularity of mandibular distraction osteogenesis in recent years, the role of the facial plastic and reconstructive surgeon is crucial in the multidisciplinary care of patients with such problems. OBJECTIVE: To review the history and evolution of mandibular osteotomies and distraction osteogenesis and to discuss indications, advantages, disadvantages, and recent advances of these techniques. EVIDENCE REVIEW: Medline and PubMed searches without date limits, confined to publications in English, German, and French languages were used to search for terms mandibular advancement, mandibular osteotomy, orthognathic surgery, mandibular distraction osteogenesis, prognathism, and retrognathism in the respective languages. References not found on the sources noted were found in print form in the New York Medical College Library when needed. Particular techniques, as originally described or relating to mandibular osteotomies and mandibular distraction osteogenesis, were critically reviewed. FINDINGS: The goal of surgical mandibular modification procedures is to correct a variety of craniofacial abnormalities for both functional and aesthetic purposes. Multiple techniques of both mandibular osteotomy and distraction osteogenesis have been shown to be effective. Their effectiveness and utility is primarily determined by the specific craniofacial defect and desired outcome, as well as surgeon preference and patient compliance. CONCLUSIONS: While mandibular osteotomy has evolved tremendously, distraction osteogenesis continues to grow as a leading method of surgical correction for a variety of craniofacial defects. Current research shows significant strides in making distraction more effective and efficient to use for both the surgeon and the patient. With the growing popularity of these procedures, the up-to-date knowledge of the facial plastic and reconstructive surgeon in these advances is of utmost importance. PMID- 23681251 TI - El Greco's portrait of a lady. PMID- 23681252 TI - Staff and youth views on autonomy and emancipation from residential care: a participatory research study. AB - The use of participatory approaches in designing services is still relatively uncommon. In this study, we helped design a service to support the transition of youth from residential care to independent living by exploring the perspectives of staff and of youth regarding: (a) the concept and development of autonomy; and (b) key factors in developing this type of service. We gathered the data through 10 interviews with staff (n=10) and 4 focus groups with youth (n=21), and subjected the data to a thematic content analysis. Staff defined autonomy as self regulation and self-care, and identified three paths to foster autonomy--a sense of normality, meaningful relationships, and planning for emancipation. The staff and youth identified the following important aspects in designing the service: achieving normality (e.g. limited number of residents), promoting youth capacity (e.g. skill-building activities), providing social support (e.g. trust and respect between residents), and assuring guidance and boundaries (e.g. supervision of youth). PMID- 23681254 TI - Detection of an aging-related increase in advanced glycation end products in fast and slow-twitch skeletal muscles in the rat. AB - Glycation, a non-enzymatic addition of reducing sugars to epsilon-amino groups of proteins, is a post-translational modification that results in the formation of irreversible advanced glycation end products (AGEs). Ageing related decline in myofibrillar protein function is effected by a number of structural and functional modifications including glycation. Functional properties of skeletal muscles, such as maximum velocity of unloaded shortening, are known to be profoundly affected by ageing at the motor unit, cellular and tissue levels. However, the contribution of protein modifications to a decline in muscle function is not well understood. In this study we measured AGEs of intracellular and sarcolemmal proteins, using an anti-AGE antibody in soleus (SOL) and extensor digiotorum longus (EDL) muscles of male and female rats of five different age groups. Using a fluorescent secondary antibody to visualize AGEs in the confocal microscope, we found that myosin is glycated in both fiber types in all age groups; an ageing related increase in AGEs was observed in both intracellular and sarcolemmal regions in all age groups, with the exception of sarcolemma of SOL (unchanged) and EDL (reduced) in female rats; the greatest concentration of AGEs was found intracellularly in the SOL of the oldest age group (27-30) of females. While an ageing related decline in motor properties can be partially attributed to the observed increase in myofibrillar protein glycation, our results also indicate that intracellular and the less well studied sarcolemmal protein modification likely contribute to an aging-related decline in muscle function. Further studies are required to establish a link between the observed ageing related increase in glycation and muscle function at the motor unit, cellular and tissue levels. PMID- 23681253 TI - Transgenic mouse models for ADHD. AB - Attention-deficit hyperactivity disorder (ADHD) is a developmental disorder characterized by symptoms of inattention, impulsivity and hyperactivity that adversely affect many aspects of life. Whereas the etiology of ADHD remains unknown, growing evidence indicates a genetic involvement in the development of this disorder. The brain circuits associated with ADHD are rich in monoamines, which are involved in the mechanism of action of psychostimulants and other medications used to treat this disorder. Dopamine (DA) is believed to play a major role in ADHD but other neurotransmitters are certainly also involved. Genetically modified mice have become an indispensable tool used to analyze the contribution of genetic factors in the pathogenesis of human disorders. Although rodent models cannot fully recapitulate complex human psychiatric disorders such as ADHD, transgenic mice offer an opportunity to directly investigate in vivo the specific roles of novel candidate genes identified in ADHD patients. Several knock-out and transgenic mouse models have been proposed as ADHD models, mostly based on targeting genes involved in DA transmission, including the gene encoding the dopamine transporter (DAT1). These mutant models provided an opportunity to evaluate the contribution of dopamine-related processes to brain pathology, to dissect the neuronal circuitry and molecular mechanisms involved in the antihyperkinetic action of psychostimulants and to evaluate novel treatments for ADHD. New transgenic models mouse models targeting other genes have recently been proposed for ADHD. Here, we discuss the recent advances and pitfalls in modeling ADHD endophenotypes in genetically altered animals. PMID- 23681255 TI - Building risk-on-a-chip models to improve breast cancer risk assessment and prevention. AB - Preventive actions for chronic diseases hold the promise of improving lives and reducing healthcare costs. For several diseases, including breast cancer, multiple risk and protective factors have been identified by epidemiologists. The impact of most of these factors has yet to be fully understood at the organism, tissue, cellular and molecular levels. Importantly, combinations of external and internal risk and protective factors involve cooperativity thus, synergizing or antagonizing disease onset. Models are needed to mechanistically decipher cancer risks under defined cellular and microenvironmental conditions. Here, we briefly review breast cancer risk models based on 3D cell culture and propose to improve risk modeling with lab-on-a-chip approaches. We suggest epithelial tissue polarity, DNA repair and epigenetic profiles as endpoints in risk assessment models and discuss the development of 'risks-on-chips' integrating biosensors of these endpoints and of general tissue homeostasis. Risks-on-chips will help identify biomarkers of risk, serve as screening platforms for cancer preventive agents, and provide a better understanding of risk mechanisms, hence resulting in novel developments in disease prevention. PMID- 23681256 TI - Managing complex research datasets using electronic tools: a meta-analysis exemplar. AB - Meta-analyses of broad scope and complexity require investigators to organize many study documents and manage communication among several research staff. Commercially available electronic tools, for example, EndNote, Adobe Acrobat Pro, Blackboard, Excel, and IBM SPSS Statistics (SPSS), are useful for organizing and tracking the meta-analytic process as well as enhancing communication among research team members. The purpose of this article is to describe the electronic processes designed, using commercially available software, for an extensive, quantitative model-testing meta-analysis. Specific electronic tools improved the efficiency of (a) locating and screening studies, (b) screening and organizing studies and other project documents, (c) extracting data from primary studies, (d) checking data accuracy and analyses, and (e) communication among team members. The major limitation in designing and implementing a fully electronic system for meta-analysis was the requisite upfront time to decide on which electronic tools to use, determine how these tools would be used, develop clear guidelines for their use, and train members of the research team. The electronic process described here has been useful in streamlining the process of conducting this complex meta-analysis and enhancing communication and sharing documents among research team members. PMID- 23681258 TI - The detailed characterization of electrochemically switchable molecular assemblies on silicon electrodes. AB - In this paper we explore a multi-step synthetic strategy toward fabrication of monolayer-modified Si(100) electrodes that can be electrochemically switched. The synthetic scheme is modular and benefits from an established intramolecular lactonization scheme of benzoquinone analogs. A redox-tagged pendant group can be released from the surface such as to allow for in situ monitoring of the switch process. We show that this model system can be used to elucidate chemical and structural events for a surface dynamic system that is rapidly gaining popularity. The influence of polarization times, overpotentials and semiconductor doping type on the kinetic of the switch event is also investigated. In both basic and acidic aqueous electrolytes the release of suitable redox-active markers is found to require unexpectedly large cathodic overpotentials. The release event is accompanied by minor oxidation of the electrode surface and the switched constructs can be regenerated by chemical means with no appreciable deterioration of surface quality. PMID- 23681257 TI - Severity of acute kidney injury and two-year outcomes in critically ill patients. AB - BACKGROUND: The association between levels of acute kidney injury (AKI) during ICU admission and long-term mortality are not well defined. METHODS: We examined medical records of adult patients admitted to a large tertiary medical center with no history of end-stage renal disease who survived 60 days from ICU admission between 2001 and 2007. Demographic, clinical, physiologic, and date of death data were extracted. RESULTS: Among 15,048 patients, 12,399 (82.4%) survived 60 days from ICU admission and comprised the study population. AKI did not develop in 5,663 (45.7%) during ICU admission, whereas progressively severe levels of AKI as defined by Acute Kidney Injury Network (AKIN) criteria AKIN 1, AKIN 2, and AKIN 3 developed in 4,589 (37.0%), 1,613 (13.0%), and 534 (4.3%), respectively. Only 42.5% of patients with AKIN 3 survived 2 years from ICU admission. Patients with AKIN 3 had a 61% higher mortality risk 2 years from ICU discharge compared with patients in whom AKI did not develop. Patients with AKIN 1 and AKIN 2 had similar increased mortality risk 2 years from ICU admission (hazard ratio, 1.26 and 1.28, respectively). The level of estimated glomerular filtration rate on ICU discharge and chronic kidney disease were associated with long-term mortality. CONCLUSIONS: Patients in whom AKI develops during ICU admission have significantly increased risks of death that extend beyond their high ICU mortality rates. These increased risks of death continue for at least 2 years after the index ICU admission. PMID- 23681259 TI - Simple pathological examination technique for detection of cancer located at the surgical margin of the stomach. AB - BACKGROUND: The technique for examining surgical resection margins described in the Japanese Classification of Gastric Carcinoma is based on the examination of continuous infiltration by the primary tumor, and discontinuous lesions such as multiple cancers are not examined. However, examining lesions-particularly cancers-at the resection margins is important for the prevention of cancers in the remaining stomach that result from cancer remnants (remnant gastric cancer). METHODS: The clinical usefulness of a simple pathological examination technique for detecting cancer located at the surgical margin of the stomach was studied. A specimen 5-8 mm wide was resected from the surgical cut margin along the entire circumference of the stomach. When the pathological margin was positive for cancer, the surgical margin was also examined, and cases that were positive for cancer were regarded as marginally positive. RESULTS: Of the 1,498 patients with early gastric cancer who were examined using this method, 17 (1.1 %) were marginally positive for multiple cancers, and 8 of these 17 patients (57 %) had microcancers <5 mm in diameter. CONCLUSION: This method is simple and useful for detecting cancer involving the surgical margin, which occurs at a rate of 1.1 %, making it possible to prevent remnant gastric cancer by reoperation. PMID- 23681260 TI - Single-incision laparoscopic total gastrectomy with D1+beta lymph node dissection for proximal early gastric cancer. AB - Single-incision laparoscopic distal gastrectomy for early gastric cancer has recently been reported by a few centers in Korea and Japan. In this technical report, we describe the world's first pure single-incision laparoscopic total gastrectomy with D1+beta lymph node dissection for proximal early gastric cancer. PMID- 23681261 TI - Thyroid consensuses: guidelines for clinical practice. PMID- 23681262 TI - Highlights of the new consensuses on thyroid diseases of the Brazilian Society of Endocrinology and Metabolism. PMID- 23681263 TI - The Brazilian consensus for the clinical approach and treatment of subclinical hypothyroidism in adults: recommendations of the thyroid Department of the Brazilian Society of Endocrinology and Metabolism. AB - INTRODUCTION: Subclinical hypothyroidism (SCH), defined as elevated concentrations of thyroid stimulating hormone (TSH) despite normal levels of thyroid hormones, is highly prevalent in Brazil, especially among women and the elderly. Although an increasing number of studies have related SCH to an increased risk of coronary artery disease and mortality, there have been no randomized clinical trials verifying the benefit of levothyroxine treatment in reducing these risks, and the treatment remains controversial. OBJECTIVE: This consensus, sponsored by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism and developed by Brazilian experts with extensive clinical experience with thyroid diseases, presents these recommendations based on evidence for the clinical management of SCH patients in Brazil. MATERIALS AND METHODS: After structuring the clinical questions, the search for evidence in the literature was initially performed in the MedLine-PubMed database and later in the Embase and SciELO - Lilacs databases. The strength of evidence was evaluated according to the Oxford classification system and established based on the experimental design used, considering the best available evidence for each question and the Brazilian experience. RESULTS: The topics covered included SCH definition and diagnosis, natural history, clinical significance, treatment and pregnancy, and the consensus issued 29 recommendations for the clinical management of adult patients with SCH. CONCLUSION: Treatment with levothyroxine was recommended for all patients with persistent SCH with serum TSH values > 10 mU/L and for certain patient subgroups. PMID- 23681264 TI - Congenital hypothyroidism: recommendations of the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism. AB - Congenital hypothyroidism (CH) is the most common congenital endocrine disorder, with an incidence of 1:2,000 to 1:4,000 live births and it is a leading preventable mental retardation. Neonatal Screening Programs allow early identification of the disease and the adequate treatment of affected children can avoid the complications related to deprivation of the hormone. Most cases of primary congenital hypothyroidism (85%) are due to thyroid dysgenesis (ectopia, hypoplasia or agenesis) while the remaining result from defects in hormone synthesis. Affected children (> 95%) usually have no symptoms suggesting the disease at birth. The most frequent symptoms and signs are prolonged neonatal jaundice, hoarse cry, lethargy, slow movements, constipation, macroglossia, umbilical hernia, large fontanelle, hypotonia and dry skin. Around the world, various strategies are used for the screening of the CH. In Brazil, screening for CH is mandatory by law and usually done by serum TSH in dried blood collected from the heel. The recommended age for performing this test is after 48 hours of life until the 4th day. Diagnostic confirmation is required dosing TSH and free T4 or total T4 in serum. PMID- 23681265 TI - The clinical use of thyroid function tests. AB - Laboratory tests are essential for accurate diagnosis and cost-effective management of thyroid disorders. When the clinical suspicion is strong, hormonal levels just confirms the diagnosis. However, in most patients, symptoms are subtle and unspecific, so that only biochemical tests can detect the disorder. The objective of this article is to do a critical analysis of the appropriate use of the most important thyroid function tests, including serum concentrations of thyrotropin (TSH), thyroid hormones and antithyroid antibodies. Through a survey in the MedLine database, we discuss the major pitfalls and interferences related to daily use of these tests and recommendations are presented to optimize the use of these diagnostic tools in clinical practice. PMID- 23681266 TI - The Brazilian consensus for the diagnosis and treatment of hyperthyroidism: recommendations by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism. AB - INTRODUCTION: Hyperthyroidism is characterized by increased synthesis and release of thyroid hormones by the thyroid gland. Thyrotoxicosis refers to the clinical syndrome resulting from excessive circulating thyroid hormones, secondary to hyperthyroidism or due to other causes. This article describes evidence-based guidelines for the clinical management of thyrotoxicosis. OBJECTIVE: This consensus, developed by Brazilian experts and sponsored by the Department of Thyroid Brazilian Society of Endocrinology and Metabolism, aims to address the management, diagnosis and treatment of patients with thyrotoxicosis, according to the most recent evidence from the literature and appropriate for the clinical reality of Brazil. MATERIALS AND METHODS: After structuring clinical questions, search for evidence was made available in the literature, initially in the database MedLine, PubMed and Embase databases and subsequently in SciELO - Lilacs. The strength of evidence was evaluated by Oxford classification system was established from the study design used, considering the best available evidence for each question. RESULTS: We have defined 13 questions about the initial clinical approach for the diagnosis and treatment that resulted in 53 recommendations, including the etiology, treatment with antithyroid drugs, radioactive iodine and surgery. We also addressed hyperthyroidism in children, teenagers or pregnant patients, and management of hyperthyroidism in patients with Graves' ophthalmopathy and various other causes of thyrotoxicosis. CONCLUSIONS: The clinical diagnosis of hyperthyroidism usually offers no difficulty and should be made with measurements of serum TSH and thyroid hormones. The treatment can be performed with antithyroid drugs, surgery or administration of radioactive iodine according to the etiology of thyrotoxicosis, local availability of methods and preferences of the attending physician and patient. PMID- 23681267 TI - Transcriptome sequencing of neonatal thymic epithelial cells. AB - In order to gain novel insights into thymus biology, we analysed the whole transcriptome of cortical and medullary thymic epithelial cells (cTECs and mTECs) and of skin epithelial cells (ECs). Consistent with their ability to express ectopic genes, mTECs expressed more genes than other cell populations. Out of a total of 15,069 genes expressed in TECs, 25% were differentially expressed by at least 5-fold in cTECs vs. mTECs. Genes expressed at higher levels in cTECs than mTECs regulate numerous cell functions including cell differentiation, cell movement and microtubule dynamics. Many positive regulators of the cell cycle were overexpressed in skin ECs relative to TECs. Our RNA-seq data provide novel systems-level insights into the transcriptional landscape of TECs, highlight substantial divergences in the transcriptome of TEC subsets and suggest that cell cycle progression is differentially regulated in TECs and skin ECs. PMID- 23681268 TI - Patient and prescriber determinants for the choice between amoxicillin and broader-spectrum antibiotics: a nationwide prescription-level analysis. AB - OBJECTIVES: Bacterial resistance to antibiotics, driven by antibiotic consumption, imposes a major threat to the effective treatment of bacterial infections. In addition to reducing the amount of antibiotics prescribed, avoiding broad-spectrum antibiotics could extend the lifetime of the current arsenal of antibiotic substances. Therefore, we documented prescriber and patient characteristics associated with the choice between amoxicillin and broader spectrum alternatives (co-amoxiclav or moxifloxacin) in recent years in Belgium. METHODS: Complete reimbursement claims data (2002-09) for antibiotic prescriptions in outpatient care, including patient and prescriber characteristics, were collected for both young children (1-5 years) and the adult population (30-60 years). A backwards selection procedure within generalized estimating equations retained the most relevant determinants. RESULTS: The age, gender and social category of the patient were found to be predictive of the extent to which amoxicillin was prescribed instead of the broader-spectrum alternatives, with female patients generally taking a higher proportion of amoxicillin than male patients. The age category of 40-44-year-old prescribers exhibited a preference for broad-spectrum antibiotics compared with both younger and older age groups. Significant interactions between the region and the prescriber's qualification (general practitioner or paediatrician) on the choice of antibiotic for children were found. CONCLUSIONS: Patient (age, gender and social category) and prescriber characteristics (age, gender, region and qualification) had an influence on whether amoxicillin or the alternative broad spectrum antibiotics were prescribed. These findings should help policy makers to better target future campaigns to promote prudent prescribing of antibiotics. PMID- 23681269 TI - Protective effect of procysteine on Acinetobacter pneumonia in hyperoxic conditions. AB - OBJECTIVES: Ventilator-associated pneumonia (VAP) is an important cause of morbidity and mortality in critical care settings. Acinetobacter has become a leading cause of VAP. In particular, the appearance and spread of multidrug resistant Acinetobacter is of great concern. In this study, we examined the effect of the antioxidant procysteine on Acinetobacter murine pneumonia in hyperoxic conditions in order to simulate VAP. METHODS: Acinetobacter was administered intranasally to BALB/c mice kept in hyperoxic conditions. At designated timepoints, bacterial number, cytokine production and histopathological findings in the lungs were examined. The effects of procysteine on survival rates, lung bacterial burdens and the phagocytic activities of alveolar macrophages were evaluated. RESULTS: Drastic decreases in survival were observed when the infected mice were kept in hyperoxic conditions (P < 0.001). Significant differences in pulmonary bacterial number and neutrophil accumulation were observed between mice kept in hyperoxic or normoxic conditions on day 3. Although all mice infected with Acinetobacter spp. and kept in hyperoxic conditions died by day 3, procysteine treatment significantly improved survival (60% survival on day 7, P < 0.01). Procysteine treatment decreased the lung bacterial burden on days 2 and 3. Finally, improved uptake of FITC-labelled beads by alveolar macrophages from mice treated with procysteine and kept in hyperoxic conditions was noted. CONCLUSIONS: These results suggest that hyperoxia increases mortality in mice with Acinetobacter pneumonia and that procysteine improves survival by increasing the phagocytic activity of alveolar macrophages in mice kept in hyperoxic conditions. PMID- 23681270 TI - Complete sequencing of an IncFII NDM-1 plasmid in Klebsiella pneumoniae shows structural features shared with other multidrug resistance plasmids. PMID- 23681271 TI - Antibiotic prescription practices for pneumonia, skin and soft tissue infections and urinary tract infections throughout the US Veterans Affairs system. AB - OBJECTIVES: Currently used metrics for antibiotic utilization are not linked to a diagnosis and may be difficult to interpret. We aimed to describe patterns and variation in antibiotic management of three common infectious disease diagnoses in Veterans Affairs Medical Centers (VAMCs). METHODS: This descriptive retrospective cohort study included all veterans discharged between 2007 and 2009 after an acute care admission to a VAMC and a principal ICD-9-CM code for pneumonia (PNEU), skin and soft-tissue infections (SSTI), urinary tract infections (UTI) or non-infectious disease-related diagnoses (NON_INF). Systemic antibiotic use was assessed based on barcode medication administration data. A treatment period was defined as a time of uninterrupted inpatient antibiotic therapy with no gaps of >1 calendar day. RESULTS: Over the study period there were 1.44 million discharges with an acute care admission to 128 VAMCs included in the study. Of the discharges, 58 118 had a primary ICD-9-CM diagnosis classifiable as PNEU, 36 797 as SSTI, 30 223 as UTI and 1 243 098 as NON_INF. Empirical antibiotic use during the first 2 hospital days was frequent for all infectious disease diagnoses. Type of empirical coverage varied among facilities for all conditions, as did treatment durations. Roughly half of all empirical courses of therapy where the patient was still hospitalized on day 4 did not exhibit any change to the antibiotic regimen. CONCLUSIONS: There is substantial variation in the management of common infectious diseases with regard to choice of empirical agents and duration of therapy. Diagnosis-specific antibiotic use metrics may prove useful for antibiotic stewardship programmes. PMID- 23681272 TI - The national burden of infections after prostate biopsy in England and Wales: a wake-up call for better prevention--authors' response. PMID- 23681273 TI - Greater insulin resistance indicates decreased diurnal variation in the QT interval in patients with type 2 diabetes. AB - Circadian variations in the QT interval (QT) and QT dispersion are decreased in patients with type 2 diabetes because of cardioneuropathy. Insulin resistance has been recently identified as an independent determinant of QT prolongation in normoglycemic women. However, the relationship between QT prolongation and the degree of insulin resistance as well as circadian variation remains unclear in diabetic patients. This study was designed to assess the relationship between insulin resistance and the circadian variation in QT measurements in patients with type 2 diabetes. In 14 patients with diabetes, QT, corrected QT (QTc), QT dispersion, QTc dispersion, and RR interval (RR) were analyzed using 12-lead Holter monitoring and commercial software. The degree of diurnal variation in each measurement was defined as the amplitude between the maximum and mean values on curves fitted using the mean cosinor method (A_QT, A_QTc, A_QT dispersion, A_QTc dispersion, and A_RR). The cosine curve was fitted to all measured values in each QT measurement and RR for 24 h. Insulin resistance (glucose infusion rate (GIR)) was measured using the euglycemic hyperinsulinemic glucose clamp method. The maximum QT, QTc, QT dispersion, and QTc dispersion were >450 ms. GIR was significantly correlated with A_QT only (r = 0.59, P < 0.05). GIR was not correlated with other variables, and was dependent only on the circadian variation in QT. PMID- 23681274 TI - Spinal injection therapy for low back pain. PMID- 23681275 TI - Oxidative effect of several intravenous iron complexes in the rat. AB - The objective of this study was to compare the oxidative stress induced in rat internal organs by the administration of the following clinically used intravenous (IV) iron (Fe) containing compounds: iron sucrose (IS), iron dextran (ID), ferric carboxymaltose and ferumoxytol. Groups of six adult rats received 1 mg/kg of each compound weekly for 5 doses. Seven days following the last dose, animals were euthanized and tissue samples of heart, lung, liver, and kidney were obtained, washed in warmed saline and frozen under liquid nitrogen and stored at 80 degrees C for analysis for nitrotyrosine (NT) and dinitro phenyl (DNP) as markers of oxidative stress. All tissues showed a similar pattern of oxidative stress. All Fe products stimulated an increase in the tissue concentration of both NT and DNP. In general, DNP was stimulated significantly less than NT except for IS. DNP was stimulated to an equal degree except for ID where NT was significantly higher than the NT concentrations in all other Fe compounds. ID produced over 10-fold the concentration of NT than any other Fe. IV Fe compounds present a risk of oxidative stress to a variety of internal organs. However, we found that IS was the least damaging and ID was the worst. PMID- 23681276 TI - Building the crossroad between inpatient/outpatient rehabilitation and lifelong community-based fitness for people with neurologic disability. AB - The length of stay in inpatient and outpatient rehabilitation after an injury or illness has declined in recent years, exposing those with newly acquired neurologic disability to a risk of significant postrehabilitation health decline. Following a short stay in outpatient rehabilitation, individuals with neurologic disability have few, if any, options to continue their physical recovery after discharge, thus further increasing their risk for functional decline and secondary conditions. Professionals who work in community-based fitness facilities have the potential to assist therapists in extending the recovery process and preventing this decline. The focus of this article was to address a conceptual framework for better understanding how rehabilitation and health/fitness professionals can work together to help with this growing need. To that end, the antecedents to and effects of postrehabilitation health decline are discussed, followed by the introduction of a theoretical model illustrating a therapist-to-trainer system that facilitates the use of community-based fitness facilities by individuals with neurologic disabilities to continue their recovery postrehabilitation. Finally, a thorough description of an exemplary existing community-based inclusive fitness program is presented, followed by examples of select disability groups using these programs for continued recovery.Video Abstract available (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A45) for more insights from the authors. PMID- 23681278 TI - [Nutritional therapy in acute pancreatitis]. AB - Acute pancreatitis is a frequent clinical entity in the West. About 80% of patients with acute pancreatitis develop edematous pancreatitis, while 20% develop necrotizing pancreatitis: The latter is a potentially life-threatening disease. In this case, early enteral nutrition has been shown to improve the course of the disease. Usually, gastric enteral nutrition with a polymeric formula via a nasogastric tube is possible; only in a minority of patients is jejunal feeding necessary owing to the high gastric residual volume. An elemental formula is useful for patients with significant intestinal maldigestion. If enteral feeding is not feasible within 5-7 days, (additional) parenteral nutrition has to be considered. Individualized--primary enteral--nutritional support is an essential part of a multimodal therapy in severe acute pancreatitis and it improves clinical outcome. PMID- 23681277 TI - [Nutrition and liver failure]. AB - In the critically ill liver patient, nutrition support is not very different from that given for other illnesses. In hyperacute liver failure, nutrition support is of less importance than in the other subtypes of acute liver failure that take a more protracted course. Nasoenteral tube feeding using a polymeric standard formula should be the first-line approach, while parenteral nutrition giving glucose, fat, amino acids, vitamins, and trace elements is initiated when enteral nutrition is insufficient or impracticable. In chronic liver disease, notably cirrhosis, there is frequently protein malnutrition indicating a poor prognosis and requiring immediate initiation of nutrition support. Enteral nutrition ensuring an adequate provision of energy and protein should be preferred. Particular care should be taken to avoid refeeding syndrome and to treat vitamin and trace element deficiency. PMID- 23681279 TI - Exploring culture-specific differences in beliefs about causes, kinship and the heritability of major depressive disorder: the views of Anglo-Celtic and Chinese Australians. AB - The aim of this study was to explore cultural differences in causal attributions and beliefs about heritability of major depressive disorder (MDD). Face-to-face interviews with Anglo-Celtic- and Chinese-Australians community members with a family history of MDD were conducted and subjected to a rigorous qualitative analysis, using the computer software NVivo. Sixteen Anglo-Celtic-Australians and 16 Chinese-Australians were interviewed. Both groups believed that a combination of genetic and environmental factors contributed to MDD, that stress was an important cause of MDD, and that coping factors were significant moderators of the impact of stress on MDD. Both cultural groups believed that the causes of MDD affecting multiple family members included a shared family environment and a "contagion effect", in addition to genetics. Unique to the Chinese-Australian group was the beliefs that parental pressures to exceed academically contributed to MDD; this cultural group also reported beliefs that depression was due to God's will or alternatively fate, which in turn was related to attributions to feng shui and auspicious dates. This study documented key culture-specific differences in beliefs about causes and inheritance of MDD; such differences have major implications for clinician-patient communication about genetic risk associated with having a family history of MDD. PMID- 23681280 TI - Does a duty of disclosure foster special treatment of genetic research participants? AB - The principle that research participants not receive enhanced care compared to non-participants may be challenged by a duty to disclose genetic research results, especially where care is otherwise inaccessible. Autism researchers' attitudes toward providing enhanced care to study participants were analyzed quantitatively using descriptive and multivariate analyses of survey data and qualitatively through thematic analysis of interview data. Approximately half of survey respondents (n = 168, RR = 44 %) agreed they should provide additional knowledge (52 %) or services (48 %) to study participants that may not be available to non-participants. Qualitatively (n = 23), respondents were motivated by the notion of reciprocity but highlighted tensions when research enables access to expertise and therapeutic resources that are otherwise difficult to obtain. For researchers, feeling obliged to report research results may be in conflict with the obligation to avoid special treatment of research participants; this may in turn threaten principles of voluntariness, autonomy, and justice. PMID- 23681281 TI - Usefulness of ventricular endocardial electric reconstruction from body surface potential maps to noninvasively localize ventricular ectopic activity in patients. AB - As radio frequency (RF) catheter ablation becomes increasingly prevalent in the management of ventricular arrhythmia in patients, an accurate and rapid determination of the arrhythmogenic site is of important clinical interest. The aim of this study was to test the hypothesis that the inversely reconstructed ventricular endocardial current density distribution from body surface potential maps (BSPMs) can localize the regions critical for maintenance of a ventricular ectopic activity. Patients with isolated and monomorphic premature ventricular contractions (PVCs) were investigated by noninvasive BSPMs and subsequent invasive catheter mapping and ablation. Equivalent current density (CD) reconstruction (CDR) during symptomatic PVCs was obtained on the endocardial ventricular surface in six patients (four men, two women, years 23-77), and the origin of the spontaneous ectopic activity was localized at the location of the maximum CD value. Compared with the last (successful) ablation site (LAS), the mean and standard deviation of localization error of the CDR approach were 13.8 and 1.3 mm, respectively. In comparison, the distance between the LASs and the estimated locations of an equivalent single moving dipole in the heart was 25.5 +/- 5.5 mm. The obtained CD distribution of activated sources extending from the catheter ablation site also showed a high consistency with the invasively recorded electroanatomical maps. The noninvasively reconstructed endocardial CD distribution is suitable to predict a region of interest containing or close to arrhythmia source, which may have the potential to guide RF catheter ablation. PMID- 23681282 TI - Microfluidic cytometer for high-throughput measurement of photosynthetic characteristics and lipid accumulation in individual algal cells. AB - Commercially viable algal biofuel production requires discovery of new strains, genetic engineering for higher productivity and optimization of growth conditions. To accelerate research in these areas, we developed a microfluidic cytometer that measures forward light scatter, chlorophyll fluorescence induction and lipophilic stain fluorescence at a rate of 100 cells s(-1). The chlorophyll fluorescence data is processed in real-time to measure the fluorescence-based maximum quantum yield, reported as Fv/Fm, to quantify the photochemical energy conversion of each cell. To demonstrate instrument performance, Fv/Fm measurements are obtained for unstressed (nutrient-replete) and stressed (nutrient-limited) cultures of the marine diatom Phaeodactylum tricornutum and are correlated to values obtained in bulk samples using traditional pulse amplitude-modulating fluorometry. We then use the cytometer to characterize unstressed and stressed P. tricornutum and show that lipid content (as measured by Nile Red fluorescence) is inversely correlated with Fv/Fm. We believe these findings to be the first time that both photosynthetic efficiency and lipid accumulation have been simultaneously evaluated at the single cell level, and that in doing so, the diversity within these populations was revealed. PMID- 23681283 TI - An HDAC inhibitor enhances cancer therapeutic efficiency of RNA polymerase III promoter-driven IDO shRNA. AB - Histone deacetylase (HDAC) inhibitors are used in treating certain human malignancies. Our laboratories demonstrated their capability in enhancing antitumor effect of DNA vaccine driven by an RNA polymerase II (RNA pol II) promoter. However, it is unknown whether HDAC inhibitors enhance the therapeutic short hairpin RNA (shRNA) expressed by an RNA polymerase III (RNA pol III) promoter. We investigated whether HDAC inhibitors augmented antitumor effect of indoleamine 2,3 dioxygenase (IDO) shRNA. HDAC inhibitor OSU-HDAC42 and suberoylanilide hydroxamic acid enhanced RNA pol III-driven U6 and H1 promoter activity in three different cell types in vitro: 293, NIH3T3 and dendritic cell line DC2.4. Subcutaneous injection of OSU-HDAC42 enhanced U6 and H1 promoter activity on abdominal skin of mice in vivo. Combination of IDO shRNA and OSU HDAC42 increased antitumor effect of IDO shRNA in MBT-2 murine bladder tumor model. IDO shRNA induced tumor-infiltrating CD8+ and CD4+ T cells, whereas OSU HDAC42 treatment induced tumor-infiltrating CD4+ T cells. Combination of OSU HDAC42 and IDO shRNA further induced tumor-infiltrating natural killer cells and enhanced interferon-gamma in lymphocytes, but suppressed interleukin (IL)-4 expression of lymphocytes. In addition, OSU-HDAC42 treatment did not alter mRNA expression of IL-12 and tumor necrosis factor-alpha. In conclusion, HDAC inhibitor OSU-HDAC42 may serve as adjuvant of the therapeutic shRNA expressed by an RNA pol III promoter. PMID- 23681284 TI - Effects of amine organic groups as lattice in ZSM-5 on the hydrolysis of dimethyl ether. AB - The effects of doping amine to ZSM-5 on its catalytic activity for hydrolysis of dimethyl ether (DME) have been studied theoretically using Density Functional Theory with the embedded cluster ONIOM(M06/6-31G(d,p):UFF) model. Doping by amine to ZSM-5 yields two new active centers, namely the protonated Z[NH2] and non protonated Z[NH] amine sites in addition to the normal Bronsted acid Z[OH] site. The reaction has two possible stepwise and concerted channels. The stepwise channel consists of two elementary steps; (i) the demethylation followed by (ii) the hydrolysis while the concerted channel involves in the demethylation and hydrolysis in a single step. We found that the reaction favors to proceed via the concerted channel at all three active centers. The results predict that the Z[OH] shows the best catalytic performance for the studied reaction. The Z[NH2] is not catalytically active due to the activation barriers are extremely high for both stepwise and concerted pathways. The demethylation step is energetically favorable over the Z[NH] site, however, the product methylamonium surface intermediate is too stable to be further converted to methanol. PMID- 23681285 TI - Association of aldosterone synthase (CYP11B2) gene -344T/C polymorphism with the risk of primary chronic glomerulonephritis in the Polish population. AB - INTRODUCTION: We evaluate whether angiotensinogen AGT M235T (rs699), angiotensin converting enzyme ACE (I/D) (rs4646994) and aldosterone synthase CYP11B2 -344C/T (rs1799998) polymorphisms can be genetic risk factors of chronic glomerulonephritis (GN) in the Polish population. MATERIALS AND METHODS: The study was conducted in 140 patients with primary chronic GN: mesangial proliferative GN (MesPGN) (n = 49), IgA nephropathy (IgAN) (n = 31), membranous nephropathy (MN) (n = 27), focal segmental glomerulosclerosis (FSGS) (n = 25), membranoproliferative GN (MPGN) (n = 4), and minimal change disease (MCD) (n = 4), and controls (n = 187). Genotypes were determined by HRM curve analysis for AGT M235T, by PCR and agarose gel separation for ACE (I/D), and by PCR-RFLP for CYP11B2 -344C/T. RESULTS: We found a significant association of the CYP11B2 344C/T polymorphism in the recessive model with all subtypes of GN (OR = 1.925 (95% CI = 1.152-3.219, p = 0.0118, p(corr) = 0.0354)). We also observed that the CYP11B2 -344C/T polymorphism in the recessive model may also be an independent significant risk factor of IgAN (OR = 2.743 (95% CI = 1.219-6.172, p = 0.0122, p(corr) = 0.0366)), FSGS (OR = 2.895 (95% CI = 1.200-6.985, p = 0.0145, p(corr) = 0.0435)), and all proliferative GNs (MesPGN, IgAN, MPGN) (OR = 2.171 (95% CI = 1.211-3.894, p = 0.0084, p(corr) = 0.0252)). CONCLUSION: Our results suggest that the CYP11B2 -344C/T polymorphism might be an independent risk factor of IgAN, FSGS and all proliferative chronic GNs. PMID- 23681286 TI - Alkali and alkaline-earth metal borohydride hydrazinates: synthesis, structures and dehydrogenation. AB - Four new borohydride hydrazinates, including NaBH4.NH2NH2, LiBH4.1/2NH2NH2, LiBH4.1/3NH2NH2 and Mg(BH4)2.3NH2NH2, were synthesized. NaBH4.NH2NH2 and Mg(BH4)2.3NH2NH2 possess monoclinic and trigonal structures, respectively, while LiBH4.1/2NH2NH2 and LiBH4.1/3NH2NH2 exhibit orthorhombic and monoclinic structures. The effects of composition on the dehydrogenation of hydrazinates were investigated. It is demonstrated that cations with high Pauling electronegativity hold hydrazine strongly in the vicinity of borohydride and result in direct dehydrogenation at elevated temperatures. Specifically, Mg(BH4)2 hydrazinates can directly generate hydrogen upon heating it under a flow of Ar; on the other hand, the Li and Na counterparts lost part or all of the hydrazine components under the same condition. In addition, reducing NH2NH2 content in the complexes leads to improved dehydrogenation properties. Mechanistic investigation of Mg(BH4)2 hydrazinates using isotopic labelling indicates that hydrogen desorption is via homogeneous dissociation of N-N bond of NH2NH2 followed by the establishment of B-N bond and combination of H(delta+) (N) and H(delta-) (B). PMID- 23681287 TI - Contrasting patterns of survival and dispersal in multiple habitats reveal an ecological trap in a food-caching bird. AB - A comprehensive understanding of how natural and anthropogenic variation in habitat influences populations requires long-term information on how such variation affects survival and dispersal throughout the annual cycle. Gray jays Perisoreus canadensis are widespread boreal resident passerines that use cached food to survive over the winter and to begin breeding during the late winter. Using multistate capture-recapture analysis, we examined apparent survival and dispersal in relation to habitat quality in a gray jay population over 34 years (1977-2010). Prior evidence suggests that natural variation in habitat quality is driven by the proportion of conifers on territories because of their superior ability to preserve cached food. Although neither adults (>1 year) nor juveniles (<1 year) had higher survival rates on high-conifer territories, both age classes were less likely to leave high-conifer territories and, when they did move, were more likely to disperse to high-conifer territories. In contrast, survival rates were lower on territories that were adjacent to a major highway compared to territories that did not border the highway but there was no evidence for directional dispersal towards or away from highway territories. Our results support the notion that natural variation in habitat quality is driven by the proportion of coniferous trees on territories and provide the first evidence that high-mortality highway habitats can act as an equal-preference ecological trap for birds. Reproductive success, as shown in a previous study, but not survival, is sensitive to natural variation in habitat quality, suggesting that gray jays, despite living in harsh winter conditions, likely favor the allocation of limited resources towards self-maintenance over reproduction. PMID- 23681288 TI - Suicide in lung cancer: who is at risk? AB - BACKGROUND: Suicide rates among patients with lung cancer are higher than the general population. This study aims to identify patient and disease characteristics associated with suicide in patients with lung cancer. METHODS: We conducted an analysis of subjects with primary lung cancer diagnosed between 1973 and 2008 recorded in the Surveillance, Epidemiology and End Results database. RESULTS: From 871,230 people diagnosed with lung cancer, 1,184 cases of suicide were identified. The rate of suicide did not change considerably over time, with 8.83 compared with 7.17 suicides per 10,000 person-years in 1973 to 1979 and 2000 to 2009, respectively. The standardized mortality ratio (SMR) of the entire cohort was 4.95, with an SMR of 13.4 within 3 months of a cancer diagnosis. Despite most subgroups having a higher SMR than the general population, a wide variation in suicide risk was seen among different subgroups, including histologic type (SMR 1.58 vs 7.28 in bronchoalveolar and small cell carcinoma, respectively). The highest SMRs were found in patients with the following characteristics: male, older age, higher-grade tumor, and metastatic disease, and in patients who did not receive or refused treatment. Despite the higher SMR among patients with metastatic disease, > 50% of suicides occurred in those with locoregional and potentially curable disease. CONCLUSIONS: Patients with lung cancer have a higher risk for suicide compared with the general US population, especially within 3 months of diagnosis. Despite the higher SMR among patients with a poorer prognosis, a concerning proportion of suicides occurs in potentially curable patients, highlighting the need for effective screening strategies to avoid this preventable cause of death. PMID- 23681289 TI - High plasma concentrations of asymmetric dimethylarginine inhibit ischemic cardioprotection in hypercholesterolemic rats. AB - A low concentration of nitric oxide associated with a high concentration of asymmetric dimethylarginine (ADMA) can explain the lack of ischemic cardioprotection observed in the presence of hypercholesterolemia. The objective of the present study was to evaluate the effect of hypercholesterolemia on ischemic pre- and postconditioning and its correlation with plasma concentrations of ADMA. Male Wistar rats (6-8 weeks old) fed a 2% cholesterol diet (n = 21) for 8 weeks were compared to controls (n = 25) and were subjected to experimental myocardial infarction and reperfusion, with ischemic pre- and postconditioning. Total cholesterol and ADMA were measured in plasma before the experimental infarct and the infarct area was quantified. Weight, total cholesterol and plasma ADMA (means +/- SE; 1.20 +/- 0.06, 1.27 +/- 0.08 and 1.20 +/- 0.08 vs 0.97 +/- 0.04, 0.93 +/- 0.05 and 0.97 +/- 0.04 uM) were higher in animals on the hypercholesterolemic diet than in controls, respectively. Cardioprotection did not reduce infarct size in the hypercholesterolemic animals (pre: 13.55% and post: 8% compared to 7.95% observed in the group subjected only to ischemia and reperfusion), whereas infarct size was reduced in the animals on a normocholesterolemic diet (pre: 8.25% and post: 6.10% compared to 12.31%). Hypercholesterolemia elevated ADMA and eliminated the cardioprotective effects of ischemic pre- and postconditioning in rats. PMID- 23681290 TI - BAFF promotes regulatory T-cell apoptosis and blocks cytokine production by activating B cells in primary biliary cirrhosis. AB - Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology. A number of questions regarding its etiology are unclear. CD4+CD25+ regulatory T cells (Tregs) play a critical role in self-tolerance and, for unknown reasons, their relative number is reduced in PBC patients. B-cell-activating factor (BAFF) is a key survival factor during B cell maturation and its concentration is increased in peripheral blood of PBC patients. It has been reported that activated B cells inhibit Treg cell proliferation and there are no BAFF receptors on Tregs. Therefore, we speculated that excessive BAFF may result in Treg reduction via B cells. To prove our hypothesis, we isolated Tregs and B cells from PBC and healthy donors. BAFF and IgM concentrations were then analyzed by ELISA and CD40, CD80, CD86, IL-10, and TGF-beta expression in B cells and Tregs were measured by flow cytometry. BAFF up regulated CD40, CD80, CD86, and IgM expression in B cells. However, BAFF had no direct effect on Treg cell apoptosis and cytokine secretion. Nonetheless, we observed that BAFF-activated B cells could induce Treg cell apoptosis and reduce IL-10 and TGF-beta expression. We also showed that BAFF-activated CD4+ T cells had no effect on Treg apoptosis. Furthermore, we verified that bezafibrate, a hypolipidemic drug, can inhibit BAFF-induced Treg cell apoptosis. In conclusion, BAFF promotes Treg cell apoptosis and inhibits cytokine production by activating B cells in PBC patients. The results of this study suggest that inhibition of BAFF activation is a strategy for PBC treatment. PMID- 23681291 TI - When the left hand does not know what the left hand is doing: response mode affects mental rotation of hands. AB - Mentally simulating a movement is known to share temporal and kinematic characteristics with the execution of the same movement, and this is thought to be reflected in the sharing of neural resources between the two activities. A powerful method of implicitly facilitating such mental simulation (or motor imagery) in individuals is to present them with a picture of a hand and ask them to identify its laterality (i.e. left or right). The mental rotation undertaken in order to complete this hand laterality recognition task (HLRT) provides an effective form of motor imagery, and the task has become an influential tool in clinical and experimental studies. However, performance on the task is modified by numerous factors, and there is a suggestion that the method of response demanded by different versions of the task may have a modulating effect. Here, we compared performance on the HLRT when responding verbally or manually in a group of unimpaired right-handed participants. For manual responses, we also compared performance when participants responded unimanually, using the index and middle fingers of their dominant or non-dominant hand. Performance was poorer for the manual compared to the verbal condition both in terms of accuracy and response time. Furthermore, for manual responses, the requirement to make a response with a specific limb selectively disrupted the ability to recognise an image of the corresponding limb. The disruption is considered to reflect difficulty in concurrently planning two actions with the same limb (manual response and mental rotation). Implications for the interpretation of existing and future studies are discussed. PMID- 23681292 TI - Segmental trunk control acquisition and reaching in typically developing infants. AB - This study explored the influence of an external support at the thoracic and pelvic level of the trunk on the success of reaching, postural stability and reaching kinematics while infants reached for a toy. Seventeen infants (4-6 months) were clustered into two groups according to their trunk control assessed with the Segmental Assessment of Trunk Control. Major differences were seen between groups with pelvic support, whereas with thoracic support, all infants showed similar quality reaching behaviors. With the external pelvic support, infants who had acquired trunk control in the lumbar region were more accurate in their reaching movements (less movement time, improved straightness of reach, less movement units and increased path length per movement unit) and were more stable (decreased trunk and head displacement) during a reach than infants who had only acquired trunk control in the thoracic region. These results support the hypothesis that trunk control influences the quality of reaching behavior. PMID- 23681293 TI - Signal-related contributions to stopping-interference effects in selective response inhibition. AB - In our ability to selectively inhibit a subset of concurrent response tendencies, referred to as selective response inhibition, stopping-interference (SI) effects have been found and attributed to global inhibitory processes. In the standard stop-signal paradigm, the stop signal might not only signal stopping but also produce other effects simply by virtue of being an additional signal. Therefore, we investigated whether previously observed SI effects reflect not only selective response inhibition but also other effects caused by the appearance of the stop signal. In Experiment 1, we controlled for the possible extra influences of the stop signal and still found SI effects, allowing a more confident attribution of SI effects to global inhibitory processes. Furthermore, the extra signal affected the motor system, as revealed by a reduction in SI effects on response force after the improved control. Using the lateralized readiness potential, Experiment 2 showed that the extra signal affected relatively central motor processing. The findings thus advance our knowledge about the distinction between signal-related and motor-inhibitory effects in stop-signal tasks. PMID- 23681294 TI - Dopamine, norepinephrine, and the management of sensorimotor bindings: individual differences in updating of stimulus-response episodes are predicted by DAT1, but not DBH5'-ins/del. AB - Evidence suggests that the flexibility of managing (creating and updating) stimulus-response bindings is driven by the dopaminergic system. Given that striatal dopamine (DA) plays a crucial role in the updating of working memory, the present study tested whether individual differences in the efficiency of updating stimulus-response episodes (event files) are predicted by differences in genetic predisposition related to the efficiency of the striatal dopaminergic pathway. In view of contrasting claims that stimulus-response binding is related to norepinephrine, we also considered genetic predispositions regarding noradrenergic pathways. In a sample of 100 healthy adults, we studied whether the degree to which stimulus-response bindings affect ongoing performance is predicted by polymorphisms of the dopamine transporter gene (DAT1, associated with striatal DA levels) and DBH5'-ins/del (strongly correlated with dopamine beta-hydroxylase, the enzyme catalyzing the dopamine-norepinephrine conversion). The performance of 9-repeat carriers of the DAT1 gene was more affected by stimulus-response bindings than the performance of 10/10 homozygotes was, while DBH5'-ins/del polymorphism was not related to performance. This outcome pattern suggests a crucial role of the nigrostriatal dopaminergic pathway in the flexible management of stimulus-response episodes, whereas norepinephrine does not seem to play a role. PMID- 23681295 TI - Adaptation of lift forces in object manipulation through action observation. AB - The ability to predict accurately the weights of objects is essential for skilled and dexterous manipulation. A potentially important source of information about object weight is through the observation of other people lifting objects. Here, we tested the hypothesis that when watching an actor lift an object, people naturally learn the object's weight and use this information to scale forces when they subsequently lift the object themselves. Participants repeatedly lifted an object in turn with an actor. Object weight unpredictably changed between 2 and 7 N every 5th to 9th of the actor's lifts, and the weight lifted by the participant always matched that previously lifted by the actor. Even though the participants were uninformed about the structure of the experiment, they appropriately adapted their lifting force in the first trial after a weight change. Thus, participants updated their internal representation about the object's weight, for use in action, when watching a single lift performed by the actor. This ability presumably involves the comparison of predicted and actual sensory information related to actor's actions, a comparison process that is also fundamental in action. PMID- 23681296 TI - The influence of motor cortical stimulus intensity on the relaxation rate of human lower limb muscles. AB - Transcranial magnetic stimulation (TMS) allows an in vivo assessment of the rate of muscle relaxation during a voluntary contraction. It is unknown if this method can be applied to lower limb muscles, and the effect of stimulus intensity on relaxation rate has not been investigated in any muscle group. The present study sought to address these unknowns. A secondary aim was to test the sensitivity of the method to a change in muscle length by comparing the relaxation rate of the plantar flexor muscles with the gastrocnemius at short and long lengths. Seven subjects performed 21 maximal voluntary isometric contractions (MVCs) of the dorsiflexors (DF) and plantar flexors with a knee angle of either 90 degrees or 180 degrees (PF90 and PF180, respectively). TMS intensity ranged from 40 to 100% stimulator output in intervals of 10%. Relaxation rates increased with stimulus intensity but were equivalent to maximal output at 50 (DF and PF90) or 60% (PF180). MVC torque was greater, and the rate of relaxation was faster for PF180 compared to PF90. The main findings are that TMS can be used to measure relaxation rates of lower limb muscles, and these rates are robust provided the stimulus intensity is above a critical threshold. The dependency of plantar flexor relaxation rate on the length of the fast-twitch gastrocnemius fibers reinforces published temperature and fatigue data which show that the method is sensitive to the contractile properties of the muscle fibers which are actively contributing to torque production. PMID- 23681297 TI - Role of 5-HT2C receptors in the enhancement of c-Fos expression induced by a 5 HT2B/2C inverse agonist and 5-HT 2 agonists in the rat basal ganglia. AB - Some non-selective serotonin2C (5-HT2C) agonists or inverse agonists enhance the product of the proto-oncogene c-Fos within the basal ganglia, a group of brain regions involved in motor behavior and in the ability of these drugs to promote abnormal movements. The role of 5-HT2C receptors in these effects is unclear. The 5-HT2C antagonist SB243,213 (1 mg/kg), which enhanced Fos per se in the striatum and the subthalamic nucleus (STN) only, was used to study the implication of 5 HT2C receptors. The agonists Ro 60-0175 (3 mg/kg) and m-CPP (1 mg/kg) and the inverse agonist SB206,553 (10 mg/kg) enhanced Fos expression in the STN and faintly in the entopeduncular nucleus (EPN, the internal globus pallidus in primate). The effects of these drugs differed mainly in the striatum regarding the magnitude (m-CPP > Ro 60-0175> SB243,213 > SB206,553) or the striatal quadrants (faint to no labeling in lateral striatum) and in the substantia nigra. None of these compounds enhanced Fos expression by themselves in the globus pallidus or in the EPN when combined with SB243,213. Their Fos effect in the STN was reduced significantly by SB243,213 only in the case of m-CPP. In the ventromedial striatum, SB243,213 reduced the effects of m-CPP while SB206,553 reduced the effects of SB243,213. The results show that opposite pharmacological agents alter similarly Fos expression in the EPN or the STN. Although some of the effects of 5-HT agents are related to targets other than 5-HT2C receptors, the study confirms the existence of multiple 5-HT2C receptor-dependent controls recruited by these drugs upon basal ganglia activity. PMID- 23681299 TI - Successful arterial reconstruction and colectomy to treat severe visceral arterial disease with concomitant colon cancer. PMID- 23681298 TI - Evaluation of lateral spinal hemisection as a preclinical model of spinal cord injury pain. AB - Operant escape from nociceptive thermal stimulation of 13 Long-Evans rats was compared before and after lateral spinal hemisection, to determine whether this lesion configuration provides an appropriate preclinical model of the hyperalgesia that can be associated with human spinal cord injury. Escape from 44 degrees C and from 47 degrees C stimulation was not affected following sham spinal surgery but was significantly reduced over 20 weeks of postoperative testing following lateral spinal hemisection. This result is opposite to previous reports of enhanced reflex withdrawal in response to thermal stimulation of rats following lateral spinal hemisection. In addition, the latency of reflexive lick/guard responses to 44 degrees C was increased and the duration of lick/guard responding was decreased in the present study (hyporeflexia). Thus, previous assessments of simple withdrawal reflexes have described a hyperreflexia following lateral spinal hemisection that was not replicated by lick/guard testing, and postoperative escape responding revealed hypoalgesia rather than the increased pain sensitivity expected in a model of chronic pain. PMID- 23681300 TI - Endoscopic pilonidal sinus treatment (E.P.Si.T.). AB - We present a new video-assisted minimally invasive technique for the treatment of pilonidal disease (E.P.Si.T: endoscopic pilonidal sinus treatment). Between March and November 2012, we operated on 11 patients suffering from pilonidal disease. Surgery is performed under local or spinal anesthesia using the Meinero fistuloscope. The external opening is excised and the fistuloscope is introduced through the small hole. Anatomy is identified, hair and debris are removed and the entire area is ablated under direct vision. There were no significant complications recorded in the patient cohort. The pain experienced during the postoperative period was minimal. At 1 month postoperatively, the external opening(s) were closed in all patients and there were no cases of recurrence at a median follow-up of 6 months. All patients were admitted and discharged on the same day as surgery and commenced work again after a mean time period of 4 days. Aesthetic results were excellent. The key feature of the E.P.Si.T. technique is direct vision, allowing a good definition of the involved area, removal of debris and cauterization of the inflamed tissue. PMID- 23681301 TI - Systematic review and meta-analysis of published, randomized, controlled trials comparing suture anastomosis to stapled anastomosis for ileostomy closure. AB - The objective of this article is to systematically analyze the randomized, controlled trials comparing the effectiveness of suture anastomosis (SUA) versus stapled anastomosis (STA) in patients undergoing ileostomy closure. Randomized, controlled trials comparing the effectiveness of SUA versus STA in patients undergoing ileostomy closure were analyzed using RevMan((r)), and combined outcomes were expressed as odds risk ratio (OR) and standardized mean difference (SMD). Four randomized, controlled trials that recruited 645 patients were retrieved from electronic databases. There were 327 patients in the STA group and 318 patients in the SUA group. There was significant heterogeneity among included trials. Operative time (SMD -1.02; 95 % CI -1.89, -0.15; z = 2.29; p < 0.02) was shorter following STA compared to SUA. In addition, risk of small bowel obstruction (OR 0.54; 95 % confidence interval (CI), 0.30, 0.95; z = 2.13; p < 0.03) was lower in the STA group. Risk of anastomotic leak (OR 0.87; 95 % CI 0.12, 6.33; z = 0.14; p = 0.89), surgical site infection, reoperation and readmission were similar following STA and SUA in patients undergoing ileostomy closure. Length of hospital stay was also similar between STA and SUA groups. In ileostomy closure, STA was associated with shorter operative time and lower risk of postoperative small bowel obstruction. However, STA and SUA were similar in terms of anastomotic leak, surgical site infection, readmission, reoperations and length of hospital stay. PMID- 23681302 TI - Transperineal ultrasonography as a complementary diagnostic tool in identifying acute perianal sepsis. AB - BACKGROUND: Successful anal fistula care in complex cases can be assisted by specialized imaging which accurately defines the site of the internal fistula opening and the fistula type. There are currently limited data concerning the clinical indications for and accuracy of transperineal ultrasound (TP-US) in acute perianal sepsis. The aims of this study were to compare the anatomical interpretation of TP-US images with magnetic resonance imaging (MRI) and surgical findings in an unselected patient cohort presenting with acute perianal sepsis. METHODS: Sixty-seven consecutive patients with acute anorectal sepsis referred from the surgical department were examined using TP-US and Gadolinium-enhanced MRI with both examiners blinded to the surgical results. Fistulae were categorized by the Parks' classification of fistula type. RESULTS: Thirty-six abscesses were detected by MRI, 38 by TP-US and 30 by surgical examination. Operatively discordant cases showed only ischiorectal panniculitis. TP-US was more accurate in the diagnosis of superficial sepsis and MRI in the diagnosis of deep-seated perirectal infection. TP-US and MRI show concordance with operative findings in fistula diagnosis with a tendency for TP-US to overdiagnose trans sphincteric fistulae and MRI to over diagnose extra-sphincteric fistulae. Comparison of TP-US with MRI showed good agreement for perianal abscess diagnosis (tau = 0.82) and for fistula diagnosis (tau = 0.68). For fistulae, TP-US showed moderate agreement with surgery (tau = 0.43) with only fair agreement between MRI and surgery (tau = 0.29). CONCLUSIONS: Transperineal ultrasound complements other imaging modalities in the anatomical diagnosis of acute perianal abscesses and fistulae. It has specific advantages over other techniques and is accurate in the detection of superficially located perirectal sepsis showing concordance with MRI and surgical findings. PMID- 23681303 TI - Evo-devo of the mammary gland. AB - We propose a new scenario for mammary evolution based on comparative review of early mammary development among mammals. Mammary development proceeds through homologous phases across taxa, but evolutionary modifications in early development produce different final morphologies. In monotremes, the mammary placode spreads out to form a plate-like mammary bulb from which more than 100 primary sprouts descend into mesenchyme. At their distal ends, secondary sprouts develop, including pilosebaceous anlagen, resulting in a mature structure in which mammary lobules and sebaceous glands empty into the infundibula of hair follicles; these structural triads (mammolobular-pilo-sebaceous units or MPSUs) represent an ancestral condition. In marsupials a flask-like mammary bulb elongates as a sprout, but then hollows out; its secondary sprouts include hair and sebaceous anlagen (MPSUs), but the hairs are shed during nipple formation. In some eutherians (cat, horse, human) MPSUs form at the distal ends of primary sprouts; pilosebaceous components either regress or develop into mature structures. We propose that a preexisting structural triad (the apocrine-pilo sebaceous unit) was incorporated into the evolving mammary structure, and coupled to additional developmental processes that form the mammary line, placode, bulb and primary sprout. In this scenario only mammary ductal trees and secretory tissue derive from ancestral apocrine-like glands. The mammary gland appears to have coopted signaling pathways and genes for secretory products from even earlier integumentary structures, such as odontode (tooth-like) or odontode derived structures. We speculate that modifications in signal use (such as PTHrP and BMP4) may contribute to taxonomic differences in MPSU development. PMID- 23681305 TI - Laboratory screening markers in gastroenterology--state of the art. AB - INTRODUCTION: Screening tests for gastrointestinal diseases acceptable for population with a high sensitivity and high specificity can now be offered by clinical laboratories. This paper summarizes major recent advances in this area of laboratory medicine. METHODS: Relevant articles published within the last 5 years in the NLM (National Library of Medicine) PubMed - Medline database covering the three gastrointestinal diseases - colorectal cancer, coeliac disease, and atrophic gastritis were included for this overview. RESULTS: In Europe, colorectal cancer (CRCA) is the second most frequent malignant disease. Quantitative immunochemical analysis of the stool for haemoglobin provides the best screening test to date, with both sensitivity and specificity approaching 95%. Even though coeliac disease (CD) affects approximately 1% of the general population, it remains largely unrecognised. Recommended methods for screening currently involve the detection of IgA and IgG antibodies against tissue transglutaminase and deamidated gliadin peptide. Evaluations of screening are now discussed for other diseases of the gastrointestinal tract - such as chronic atrophic gastritis (CAG), and inflammatory bowel disease (IBD). Detection of infection by Helicobacter pylori and stomach-specific plasmatic biomarkers, especially pepsinogen I/II ratio, could help with the prevention of gastric carcinomas. The use of faecal calprotectin as a screening test could substantially reduce the number of invasive methods necessary for the diagnostic work-up of patients with IBD. CONCLUSIONS: Screening tests for CRCA and CD have been used worldwide for many years. Screening strategies for gastrointestinal diseases are suggested in the text, based on recent basic science, clinical papers as well as our own experience. PMID- 23681306 TI - Class I and III antiarrhythmic drugs for prevention of sudden cardiac death and management of postmyocardial infarction arrhythmias. A review. AB - BACKGROUND: The aim of the present paper is to review the evolution of concepts regarding the use of Class I and III antiarrhythmic drugs (AADs) in myocardial infarction over the past four decades. METHODS: Results of animal experiments carried out by the authors and papers published between 1970 and 2012 in journals and the PubMed search system were used. RESULTS: Animal experiments carried out as early as the 1970s showed that Class IB and IC AADs lose their antiarrhythmic effect and electrically destabilize ventricles in the very early phase of myocardial ischemic focus formation. The cause of this is interaction between Class IB and IC AADs as well as Class III AADs with sympathetic neural activation (SNA) of the heart in the early phase of myocardial ischemia. Given the extremely high and uneven distribution of noradrenaline in tissue, SNA results in dispersion of the depolarization and repolarization processes in the ventricles. The clinical sequels of the interaction between the effects of AADs and SNA are as follows: the antiarrhythmic effect of AADs is restored in AMI once SNA has resolved; membrane-destabilization of the ventricles can be restored any time in the presence of randomly occurring SNA not only due to increasing myocardial ischemia but, also, as a result of psychological stress (emotions), and any pre existing structural heart disease will enhance the pro-fibrillatory effect of a randomly occurring SNA. CONCLUSIONS: Despite the above risks, AADs continue to play an irreplaceable role in suppressing post-myocardial arrhythmias and in preventing sudden cardiac death following ICD placement. The risk of AADs' proarrhythmic effect in SNA can be reduced by combining them with beta-blockers. The last recourse when attempting to suppress malignant ventricular tachyarrhythmias is left sympathetic denervation of the heart. PMID- 23681307 TI - Association between GSTM1 and CYP1A1 polymorphisms and survival in oral cancer patients. AB - AIMS: Cancer patient's inherited genotype may influence his or her survival, but evidence for the role of these genetic differences in oral cancer survival has not yet been explored. METHODS: The authors evaluated polymorphisms in the GSTM1 and CYP1A1 genes for associations with overall survival in 100 oral squamous cell carcinoma (OSCC) treated patients and 100 controls who were followed up for survival within 2 years of the date of completion of their treatment. Overall survival was evaluated in Kaplan-Meier survival functions and Cox proportional hazards models. RESULTS: After adjustment for stage and histology, GSTM1null genotype was associated with shorter survival among OSCC patients, compared with GSTM1 present genotype. There was no association between CYP1A1 C genotype and survival in the overall study population. CONCLUSION: The study indicated a potential role for GSTM1 polymorphism in predicting the clinical outcomes of treated oral carcinoma patients. PMID- 23681308 TI - Omission of adjuvant radiation therapy in elderly patients with low risk breast cancer undergoing breast-conserving surgery--two center experience. AB - INTRODUCTION: Breast cancer is, now often diagnosed in patients older than 70 years due to longer life expectancy. The usual treatment is mastectomy to obviate radiotherapy or breast-conserving surgery followed by radiotherapy. The aim of this study was to investigate the need for adjuvant radiotherapy in older patients and the consequences of omitting radiotherapy following conservative surgery. METHODS: An extensive database search was made of patients who had been treated for breast cancer at the Department of Oncology, University Hospital Olomouc and the Atlas Hospital in Zlin (2004-2008). We identified 738 patients of whom 190 patients (25.7%) were older than 70 years of age. These were followed up for progression-free and overall survival. The cause of death was checked for breast cancer relapse. RESULTS: In total only 9 patients undergoing breast saving surgery were ultimately identified. No patient had confirmed local recurrence during the follow up period: Two patients have died due to distant metastasis without local relapse and one patient has died for reasons other than breast cancer. CONCLUSION: Omitting radiotherapy after breast saving surgery provides an opportunity for women to undergo breast saving surgery and avoid 7 weeks of radiotherapy. This could significantly improve patient quality of life. In our of many years experience and from published randomized data, this procedure is safe for a select group of patients 70 years of age and older. PMID- 23681309 TI - The anticancer activity of alpha-tomatine against mammary adenocarcinoma in mice. AB - AIM: To evaluate the anticancer effect of alpha-tomatine (i.p.) either alone or in combination with doxorubicin (i.v.) in a mouse tumour model. METHODS: We studied the effect of repeated alpha-tomatine (0.1 - 9 mg/kg) and/or doxorubicin (2 mg/kg) on the growth and mitotic activity of the solid Ehrlich tumour in vivo, as well as on the survival of the tumour-bearing mice. RESULTS: Monotherapy with alpha-tomatine had a significant dose-dependent anticancer effect which peaked at 1 mg/kg. This was shown by both slowed tumour growth and reduced tumour cell proliferation. We also provide the first evidence that the combination alpha tomatine (1 mg/kg) and doxorubicin (2 mg/kg) had a synergistic effect and significantly prolonged the survival of the mice. Neither alpha-tomatine nor doxorubicin influenced the infiltration of tumours with CD3+ lymphocytes; nor were we able to find an in vivo modulation of the key molecules of two regulatory pathways reported in vitro as the principal anti-cancer mechanisms of alpha tomatine, i.e. iNOS and phosphorylated ERK2. However, alpha-tomatine still led to intracellular DNA inhibition and protein synthesis in Ehrlich tumour cells in a short-term culture ex vivo with IC50 values of 8.7 and 6.6 uM. CONCLUSIONS: The results suggest that TauOmicronMU, especially in combination with doxorubicin, may be a promising agent for the treatment of malignant solid tumours. Despite growing knowledge of the mechanisms of TauOmicronMU action in cancer cells, most aspects remain unclear. Parallel organ toxicity, especially potential liver effects, requires careful attention when performing in vivo studies in the future. PMID- 23681310 TI - Evaluating and comparing algorithms for respiratory motion prediction. AB - In robotic radiosurgery, it is necessary to compensate for systematic latencies arising from target tracking and mechanical constraints. This compensation is usually achieved by means of an algorithm which computes the future target position. In most scientific works on respiratory motion prediction, only one or two algorithms are evaluated on a limited amount of very short motion traces. The purpose of this work is to gain more insight into the real world capabilities of respiratory motion prediction methods by evaluating many algorithms on an unprecedented amount of data. We have evaluated six algorithms, the normalized least mean squares (nLMS), recursive least squares (RLS), multi-step linear methods (MULIN), wavelet-based multiscale autoregression (wLMS), extended Kalman filtering, and epsilon-support vector regression (SVRpred) methods, on an extensive database of 304 respiratory motion traces. The traces were collected during treatment with the CyberKnife (Accuray, Inc., Sunnyvale, CA, USA) and feature an average length of 71 min. Evaluation was done using a graphical prediction toolkit, which is available to the general public, as is the data we used. The experiments show that the nLMS algorithm-which is one of the algorithms currently used in the CyberKnife-is outperformed by all other methods. This is especially true in the case of the wLMS, the SVRpred, and the MULIN algorithms, which perform much better. The nLMS algorithm produces a relative root mean square (RMS) error of 75% or less (i.e., a reduction in error of 25% or more when compared to not doing prediction) in only 38% of the test cases, whereas the MULIN and SVRpred methods reach this level in more than 77%, the wLMS algorithm in more than 84% of the test cases. Our work shows that the wLMS algorithm is the most accurate algorithm and does not require parameter tuning, making it an ideal candidate for clinical implementation. Additionally, we have seen that the structure of a patient's respiratory motion trace has strong influence on the outcome of prediction. Further work is needed to determine a priori the suitability of an individual's respiratory behaviour to motion prediction. PMID- 23681312 TI - Recent advances in microfluidic techniques for single-cell biophysical characterization. AB - Biophysical (mechanical and electrical) properties of living cells have been proven to play important roles in the regulation of various biological activities at the molecular and cellular level, and can serve as promising label-free markers of cells' physiological states. In the past two decades, a number of research tools have been developed for understanding the association between the biophysical property changes of biological cells and human diseases; however, technical challenges of realizing high-throughput, robust and easy-to-perform measurements on single-cell biophysical properties have yet to be solved. In this paper, we review emerging tools enabled by microfluidic technologies for single cell biophysical characterization. Different techniques are compared. The technical details, advantages, and limitations of various microfluidic devices are discussed. PMID- 23681311 TI - Vagal nerve stimulation in children under 12 years old with medically intractable epilepsy. AB - OBJECTIVE: This study aims to assess the efficacy and safety of vagal nerve stimulation (VNS) in children less than 12 years old operated on at the University Hospital Wales. METHOD: Retrospective review of patients undergoing VNS insertion, over a 3-year period, was undertaken. All children had a minimum follow-up period of 2 years. Sixteen patients were identified via the paediatric epilepsy surgery database. A case note review and telephone evaluation was conducted. Seizure frequency using the McHugh classification was the primary outcome measure, with anti-epileptic drug (AED) use as a secondary outcome measure. RESULTS: There were 10 males and 6 females. The mean time with epilepsy prior to surgery was 5.7 years and the mean age at the time of surgery was 7.6 years. Overall, nine (56 %) children experienced a reduction in their seizure frequency of 50 % or more. Of these, four (25 %) had a reduction of more than 80 %. Seven children (44 %) had no reduction in their seizure frequency, although two of these patients reported benefit regarding seizure control and post-ictal recovery. The VNS system was removed in two patients due to infection and no benefit, respectively. Half of the cohort (50 %) reduced the number of anti epileptic drugs post-surgery, and there was an overall mean reduction of AED of 0.5. CONCLUSION: This study suggests that VNS is a safe and effective adjuvant therapy in children under 12 years old, with over half reporting significant benefit. Further studies are needed to enable preoperative selection of patients in order to maximise the potential benefit. PMID- 23681313 TI - Electronic structures and magnetic properties of MoS2 nanostructures: atomic defects, nanoholes, nanodots and antidots. AB - Developing approaches to effectively induce and control the magnetic states is critical to the use of magnetic nanostructures in quantum information devices but is still challenging. Here MoS2-based nanostructures including atomic defects, nanoholes, nanodots and antidots are characterized with spin-polarized density functional theory. The S-vacancy defect is more likely to form than the Mo vacancy defect due to the form of Mo-Mo metallic bonds. Among different shaped nanoholes and nanodots, triangle ones associated with ferromagnetic characteristic are most energetically favorable, and exhibit unexpected large spin moments that scale linearly with edged length. In particular, S-terminated triangle nanodots show strong spin anisotropy around the Fermi level with a substantial collective characteristic of spin states at edges, enabling it to a desired spin-filtering structure. However, in the antidot, the net spin, coupled order and stability of spin states can be engineered by controlling type and distance of internal nanoholes. Based on the analysis of the spin coupled mechanism, a specific antidot structure, the only S-terminated antidot, was determined to exhibit a large net spin with long-range ferromagnetic coupling above room temperature. Given the recent achievement of graphene- and BN-based nanohole, nanodot and antidot structures, we believe that our calculated results are suitable for experimental verification and implementation opening a new path to explore MoS2-based magnetic nanostructures. PMID- 23681314 TI - IPHEN--a real-time network for phenological monitoring and modelling in Italy. AB - This paper aims to describe the Italian PHEnology Network (IPHEN), a cooperative project started in 2006 with the aim of producing nationwide maps of analysis and forecast of plants phenological stages mainly used to satisfy the needs of agriculture, health and environmental care. Iphen is a data processing system composed of the following main segments (a) collection of atmospheric and phenological data, (b) processing of data with suitable phenological and geo statistical models and (c) phenological maps of analysis and forecast. In more detail, IPHEN maps of analysis (featuring phenological stages reached at the date of processing) are produced with models based on a Normal Heat Hours approach which weighs hourly air temperature effectiveness for plant phenological progression applied to national grids of hourly temperature derived from the operational agro-meteorological network of CRA-CMA. A correction scheme based on phenological surveys provided by volunteer observers is applied to the first guess maps of analysis to obtain final maps. Forecast maps (prediction of the days of occurrence of relevant phenological stages) are produced on the basis of GFS model medium range forecasts and climatic data. Freeware IPHEN maps for grapevine, common and Arizona cypress, black elder, olive and locust trees are broadcasted weekly on the CRA-CMA website. The positive operational results of IPHEN are testified by 150 maps broadcasted during the 2011 season for the above mentioned species. The system performances and reliability have been analysed focusing on the analysis of phenological simulation errors and on the sensitivity of phenological maps to anomalous atmospheric circulation patterns. The error analysis shows that phenological models are characterized by advances/delays that justify the adoption of an observation based correction scheme. The sensitivity analysis highlights that the system is responsive to the effects of circulation blocking systems leading to phenological advances and delays. PMID- 23681315 TI - Design and synthesis of Pd-MnO2 nanolamella-graphene composite as a high performance multifunctional electrocatalyst towards formic acid and methanol oxidation. AB - One great challenge in the development of portable fuel cell systems is to explore novel electrocatalysts with better performance and lower costs. Here we report a facile strategy to fabricate a ternary nanocomposite based on Pd/MnO2 nanolamella-graphene sheets (Pd/MNL/GS) and demonstrate its application as a multifunctional catalyst for both the direct formic acid fuel cell (DFAFC) and direct methanol fuel cell (DMFC). The developed route rationally utilizes graphene as both a green reducing agent in the synthesis of MnO2 nanolamella and a superior supporting material for growing and supporting Pd nanoparticles (NPs). Whether for formic acid oxidation or methanol oxidation, the as-prepared Pd/MNL/GS hybrid has extremely large electrochemically active surface area (ECSA) values and exhibits significantly high forward peak current densities, both of which are nearly 3 times greater than those of the Pd/GS catalyst and 6 times the Pd/Vulcan XC-72 catalyst, revealing that metal Pd can be effectively utilized in the presence of promoter components (MNL and GS). Therefore, such a ternary composite with a sophisticated 2D configuration may bring new design opportunities of high-performance energy conversion devices in the future. PMID- 23681316 TI - Vaccination perceptions and barriers of school employees: a pilot study. AB - Schools are where vaccine-preventable diseases can spread. Vaccination of school children has been studied; however, data are lacking on the vaccination status, perceptions, and barriers to vaccination for school employees. We surveyed school employees' vaccination perceptions, awareness of current vaccination status, and potential barriers to vaccinations. Adult vaccination knowledge is lacking in the school employee population. School employees were unaware of their vaccination status for diseases such as measles and pertussis. Most subjects believed vaccinations were safe and effective, although they believed vaccinations were more important for children than adults. Many believed vaccine mandates should exist for school employees. Knowledge gaps regarding adult vaccines can be positively influenced by school nurses. Gaps may be especially important to bridge regarding adults working in the school setting, an environment ideal for the spreading of communicable diseases. PMID- 23681318 TI - [Epidemiology and public policies]. AB - The present essay deals with the relation between epidemiology and public policies, highlighting the epidemiology position in the public health field, analyzing the impact of public policies over epidemiological profile and contributions from epidemiology to the lay down, implementation and evaluation of public health policies. In the first title, the essay debates the links between the epidemiology and public health field, the social determinants and political action framework proposed by the WHO's Commission on Social Determinants of Health, and different approaches of health policies. In the second title the essay analyses the reduction of child stunting in Brazil as an example of public policies that impact epidemiological profile. The third title presents three strategic topics for the application of public health policies: reduction of social inequalities in health, health promotion and regulation of products and services that have impact over health. The fourth title discusses the possibilities and difficulties to combine the epidemiological knowledge in the lay down, implementation and evaluation of public policies and, finally, material examples of such relation between epidemiology and public policies are presented. PMID- 23681317 TI - Clinical impact of a 6-week preoperative very low calorie diet on body weight and liver size in morbidly obese patients. AB - BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) may be a technically challenging surgical technique when features such as thick abdominal wall and increased liver volume are present. Very low calorie diets in the form of liquid meal replacements given 6 weeks prior to surgery have proven to decrease liver volume. The aim of our study was to assess the effect of a 6-week preoperative low calorie/regular diet on liver volume and body weight in morbidly obese patients. METHODS: A pilot study was carried out in 20 morbidly obese patients with an 800-kcal diet for 6 weeks. They were followed weekly to ensure proper compliance. CT scan was used for determining liver volume every 2 weeks in order to assess the impact of the diet. Baseline values were taken as controls for every patient as tied measures. Statistical analysis was suitable to variable scaling and performed using SPSS v. 20.0. Parametric and non-parametric test for tied measures were done. Any p value lesser than 0.05 or 5% was considered as statistically significant. RESULTS: Twenty patients adhered to the diet intervention for 6 weeks prior to LRYGB. Median +/- SD age was 34.5 +/- 11.5 years and 17 were female (85%). Heart rate and blood pressure did not vary across the study. Initial median +/- SD BMI was 46.02 +/- 5.29 kg/m2 (range 38.7-54.8). Repeated and tied measurements across the 6 weeks of treatment within individuals resulted statistically significant for reducing BMI (p < 0.0001). CT scan assessed liver volume initially as a control and in weeks 2, 4 and 6. Parametric and non-parametric assessment for multiple measurements also showed statistical significance among these values (p < 0.0001). Diet tolerability was additionally evaluated with a questionnaire showing more than 80% of acceptability with discrete rates of nausea (15%) and diarrhoea (15%). CONCLUSIONS: Based on our results, we demonstrated that a very low calorie diet with home ingredients is capable for effectively reducing body weight and liver size in morbidly obese patients. This relatively short intervention (4 to 6 weeks) was accomplished in all our patients with a high frequency of compliance and a low rate of secondary effects. PMID- 23681319 TI - [Spontaneous and voluntary fetal losses in Brazil in 1999-2000: a study of associated factors]. AB - Despite its illegality in Brazil, about 31% of all pregnancies end in abortion. Most abortions are performed by unskilled personnel and under unsafe conditions, resulting in increased female mortality. This study used data from a cross sectional representative sample of 3,047 puerperal women, in 1999-2000, part of a national multicenter study on the prevalence of syphilis in Brazil. Of these, 1,838 women with at least one previous pregnancy before the reference pregnancy were included in the analysis. The outcomes studied were voluntary prior fetal loss, spontaneous prior fetal loss, and no prior fetal loss. The analysis was carried out using multinomial logistic regression. The results indicated a high number of fetal losses per woman (up to six); and 31% of the losses were voluntary. The absence of prenatal care, history of STD in the reference pregnancy, and absence of living children were factors that increased the odds of fetal loss. For voluntary fetal loss, being non-white, having more than one partner in the previous year, and an early age at first sexual intercourse also increased the odds of fetal loss. These data confirm the public health relevance of abortion in Brazil. Characteristics related to women's vulnerability should be considered in family planning programs in order to reduce the number of abortions and their consequences. Counseling must also be provided, targeting women with a previous abortion. PMID- 23681320 TI - [Ten years of HIV-AIDS epidemic in more than 60 years in Federal District- Brazil]. AB - INTRODUCTION: The progressive increase in number of HIV/AIDS cases in old age brings the necessity of studies about the specificities of this phenomenon by region. OBJECTIVE: To identify the epidemiology in AIDS cases diagnosed in Distrito Federal - Brasil, in individuals aged > 60 years old. METHODS: We conducted a time serie study with secondary data from SINAN/AIDS for the period January 1999 to December 2009. RESULTS: In this period, 4,258 new cases of AIDS were of whom 89 (2.0%) are elderly. Although a small percentage, the annual growth was continuous. The most frequent exposure category was heterosexual, the age group most affected was 60 and 69 years, with 71 (79.8%) cases; the proportion of cases man/woman has changed over the years, in 1999 was 1:1 and in 2006, 0,7:1. CONCLUSION: The HIV/AIDS epidemic among the elderly can be seen stable on the Distrito Federal. PMID- 23681321 TI - [Detection of high risk human papillomavirus by hybrid capture II(r) according cytological findings in women treated for squamous intraepithelial lesions of the cervix, period 2006/2010]. AB - OBJECTIVE: To determinate the frequency of high risk human papillomavirus (HR HPV) by hybrid capture II (r) (CH II(r)), according cytology results in women treated for squamous intraepithelial lesions of the cervix (SIL). MATERIAL AND METHODS: A descriptive cross-sectional study of a series of cases that included 122 women treated, 79 (75%) for low grade SIL (LSIL) and 43 (35%) for high grade SIL (HSIL) attending at the HPV Laboratory at the Health Sciences Research Institute (IICS), National University of Asuncion (UNA), for post-treatment control during period 2006/2010. RESULTS: A total of 28% (34/122) of women treated for SIL were positive for HR-HPV, detecting viral infection in 20% of women with no SIL (NSIL) (22/108), in 83% of women with LSIL (10/12) and in 100% of women with HSIL (2/2). Of 34 women positive for HR-HPV, 10 women (29%) had high values (100 pg / mL or more) of relative viral load, detecting an increase of positive cases with severity of the lesion (28% NSIL, 30% LSIL, 50% HSIL). CONCLUSION: HR-HPV detection by CH II(r) and high relative viral load values especially in women with NSIL could help to identify treated women at risk of developing recurrence, thereby contributing to strengthening the cervical cancer prevention program. PMID- 23681322 TI - [Alcohol consumption pattern and coronary heart disease risk in metropolitan Sao Paulo: analyses of GENACIS Project]. AB - OBJECTIVES: To examine the association between patterns of drinking and coronary heart disease (CHD) risk in a populational sample. METHODS: A population-based cross-sectional study carried out from January 2006 to June 2007, in Metropolitan Sao Paulo, Brazil, in conjunction with the international collaborative GENACIS project (Gender, Alcohol, and Culture: an International Study), with PAHO support. The subjects (1,501; 609 men, 892 women) of this study were residents of randomly chosen households aged 30 years and above who consented to provide information. The dependent variable was cardiac risk as assessed by the WHO Rose Angina Questionnaire. Logistic Regression analysis was used and the data were adjusted for Body Mass Index (BMI) and smoking. RESULTS: The response rate was 75%. Being female, older, African-American, a current smoker, and having a greater BMI were associated with higher risk of coronary heart disease. Lifetime abstainers (OR = 2.22) and former drinkers (OR = 2.42) had greater CHD risk than those who consumed up to 19g pure alcohol per day, with no binge. Among those who had binged weekly or more there was a tendency toward higher risk (OR = 3.95, p = .09). CONCLUSIONS: Our findings suggest a lower risk for CHD among moderate drinkers. It is important, in studies which were investigating cardiac risk, assess heavy alcohol use, since it can change that risk. Also, effective public policies are needed to reduce harmful drinking and related morbidity in Brazil. PMID- 23681323 TI - [Bolsa-Familia Program: diet quality of adult population in Curitiba, Parana]. AB - This study evaluated the quality of diet of the population receiving the Bolsa Familia Program in Curitiba, state of Parana, Brazil. It was a population-based cross-sectional study, conducted from July 2006 to July 2007. 747 beneficiaries were interviewed from 19 years of age, of both genders. A 24 hour-recall was implemented in order to assess the quality of the diet and the Healthy Eating Index (HEI) was used as a parameter for the classification of the group in consumption levels. Descriptive statistics were used to describe the diet quality of the studied population. Wald test and ANOVA test were performed to compare the means of the index according to the socio-economic variables, considering a significance level of 5%. The sample comprised 91.4% of women and 8.6% of men. The average age of the population was 36.4 +/- 13.3 years, with 75% having completed elementary school. The mean HEI was 51 points, which features a diet that needs improvement. The population has a monotonous diet with an adequate intake of legumes, but low for fruits, vegetables and dairy products. Comparing the categories of diet quality of individuals, all components, except sodium, showed statistically different median score (p < 0.01). Studies that evaluate the quality of the diet are essential to support the implementation of nutrition education programs targeted to the core of the problem in the populations studied. PMID- 23681324 TI - [Falls and fractures among older adults living in long-term care]. AB - OBJECTIVE: To investigate the prevalence of falls and fractures over the past 12 months and associated factors among older adults living in long-term care. METHODS: Census of all long-term care located in the city of Pelotas, Brazil, in 2008. Falls over the past 12 months were assessed using the following question: "Over the last 12 months, have you fallen?" For those who replied positively, another question was asked: "In any of these falls, have you fractured a bone?" Sex, age, schooling, disability relating to basic activities of daily living, type of financing of the long-term care and hospital admissions were the independent variables. We used chi-square tests for heterogeneity and linear trend in the unadjusted analysis, and Poisson regression with robust variance in the adjusted one. RESULTS: Within the 24 long-term care studied, we collected data for 466 individuals. The prevalence of falls in the past year was 38.9% (95%CI 34.5; 43.4). Among those who have fallen, 19.2% had fractures. Femur (hip) was the most frequent site fractured (43.4%), followed by wrist (10%). In the adjusted analysis, older age, disability for 1-5 basic activities of daily living, living in public institutions and hospital admissions in the last year were associated with higher risk of falls. CONCLUSION: The high prevalence of falls and fractures highlights the fragility of the individuals living in long term care. Special attention should be paid to older adults and those with hospital admissions in the last year. PMID- 23681325 TI - [Notification of healthcare associated infections based on international criteria performed in a reference neonatal progressive care unity in Belo Horizonte, MG]. AB - OBJECTIVE: To describe occurrence of Healthcare Related Infections in a neonatal unit of public reference service in Belo Horizonte-MG, based on international criteria. METHODS: This is a descriptive study, performed by active searching, in the Progressive Care Unit Neonatal Hospital das Clinicas, Federal University of Minas Gerais (HC / UFMG), from 2008 to 2009. Notification of infections was based on National Healthcare Safety Network (NHSN) criteria. The database and analysis were performed in a internal program. RESULTS: A total of 325 episodes of infection in newborns were notified and overall incidence density of infections was 22.8/1,000 patient-days, with a rate of 36.7% of newborns. Sepsis was the main infection (62.5%) reported. The incidence density of infections was higher in neonates weighing lower than 750g (42.4/1,000 patient-days). There were 18.15 episodes of central venous catheter related sepsis/1,000 central venous catheter day and 19.29 umbilical catheter related sepsis /1,000 umbilical catheter-days. Microorganisms were isolated in 122 (37.5%) cases of reported infections, mainly defined as Staphylococcus coagulase negative and Staphylococcus aureus (51 cases). Mortality and lethality rates were 4.3% and 17,12%, respectively. CONCLUSION: The use of standardized criteria for reporting infections is necessary for the construction of indicators in neonatology, which are scarce in the country and highlight the need for evaluation of national criteria proposed by National Agency of Sanitary Surveillance (ANVISA). PMID- 23681326 TI - [Male mortality in three Brazilian state capitals, 1979-2007]. AB - INTRODUCTION: In Brazil, there is a higher male mortality in almost all ages and causes. The objective is to estimate and describe the trend in male mortality, between 1979/2007, in three State Capitals (Sao Paulo, Rio de Janeiro and Porto Alegre). METHODS: The study populations refer to the residents in the three cities, in 1979/1981, 1990/1992, 1999/2001 and 2005/2007, and their deaths. The data source was Health Information System of the Brazilian Ministry of Health. Overall (crude/standardized) and specific mortality coefficients were calculated. RESULTS: Up to 24 years, men predominate in the population; after, it has been observed higher female participation and gender ratios ever lower. This fact is associated with high male mortality and the intense involvement of young men with external causes. Throughout the series, these causes were responsible for large risk estimates of male death. In 2005/2007, this group was the leading cause of death in men until the age 40-44 years. In the following age groups, deaths by circulatory system diseases are the main cause. CONCLUSION: These capitals show features of a developing city, with reduced fertility, increased longevity and consequent trend to an aging population. Estimates of the men high risk of dying make clear their vulnerability. The intensity with these events occur demand actions that will reduce the mortality rates of preventable diseases and the men's risky behaviors. It is necessary that men adopt healthier lifestyles habits, thus increasing life expectancy and reducing the gender differences in mortalities. PMID- 23681327 TI - [Knowledge, attitudes and practices on tuberculosis in prisons and public health services]. AB - OBJECTIVE: To analyze the knowledge, attitudes and practices about TB in a prison and in public health services (PHS). METHODS: A cross sectional study was carried out and KAP (knowledge, attitudes and practices) questionnaire was applied to 141 prisoners, 115 prison's employees and 158 PHS workers. Epi-Info version 6.04 was used for comparison of proportions with statistic significance at p < 0.05. RESULTS: Mistaken concepts on TB were observed among the three searched groups. PHS also showed basic errors on TB knowledge thus pointing out imperfections on training. CONCLUSION: KAP revealed efficient for data collection of general knowledge items but was limited on practices and attitudes and so its use as the only tool for data collection about knowledge, attitudes and practices on TB is not advisable. It is suggested its regular use to aid educational activities and considering the high prevalence of TB among prisoners, it is noted the need to involve the Departments of Health in the supervision of educational activities in the prison system. PMID- 23681328 TI - [Factors that influence outpatient service user satisfaction in a low-income population: a population-based study]. AB - AIM: To measure the prevalence of overall satisfaction with the previous medical consultation and their associated factors, among adults aged 20 years or more, in a city located in southern Brazil. METHODS: A cross-sectional population-based study was performed in Porto Alegre, RS, Brazil, from July to December 2009. Systematic sampling was used with a probability proportional to the size of each of the 121 census tracts in the area studied. Overall satisfaction with the previous consultation was evaluated with a standardized questionnaire. Crude analysis was performed using the chi-square test, while the adjusted analysis used Poisson regression with robust variance. Results were expressed as prevalence ratios. RESULTS: Among the 3,700 eligible individuals, 3,391 answered the survey. Of those, 64.8% (1677) reported having had their previous medical consultation in the three months prior to the interview. Regarding the overall satisfaction with the previous consultation, 63.7% reported being satisfied and 23.2% were very satisfied. Adjusted analysis showed that those who went to private/health plan-affiliated services were 1.15 times more likely to be satisfied than those going to public services. Easy consultation booking and being well treated by receptionist and physician were directly related with a higher level of satisfaction. The length of time waiting was inversely associated with satisfaction both in the crude and adjusted analyses. CONCLUSION: The present study revealed a high prevalence of satisfaction with medical consultations and a significant positive association between satisfaction and the location of consultation (health plan-affiliated or private services). PMID- 23681329 TI - [Trends and diversity in the empirical use of Karasek's demand-control model (job strain): a systematic review]. AB - INTRODUCTION: Karasek's demand-control model has been used to investigate association between job strain and health outcomes. However, different instruments and definitions have been utilized to assess the exposure 'high strain at work', which makes difficult the comparison of results across studies. OBJECTIVE: To describe the measurement instruments and the definitions adopted for the exposure variable 'job strain', according to the demand-control model, by observational studies published until 2010. METHODS: Systematic review of observational studies published until December 2010, addressing the exposure 'job strain', measured according to the demand-control model and used the JCQ or its derivatives, since explicit. RESULTS: Among 877 selected abstracts, 496 (57%) met the inclusion criteria. It identified a trend towards the increasing production literature on the subject. Most studies were sectional; found no relevant differences among study populations of men and women. Sweden, USA, Japan and Canada accounted for 57% of publications, mostly including more than 1000 participants and diverse occupations. Cardiovascular outcomes and their risk factors were the most studied (45%), followed by those related to mental health (25%). In 71% of the studies used the Job Content Questionnaire (from 2 to 49 items) and 19% of the total, the Swedish version (Demand-Control Questionnaire Swedish). Quadrants of the demand-control exposure were used in 51% of the work, but with different cutoff points; scores of the two dimensions were analyzed separately in 27%, and its ratio in 14% of the total. Social support at work was assessed in 44% of the studies. CONCLUSION: Karasek's model should continue to raise epidemiological studies and we hope that researchers face these theoretical and methodological issues outstanding. PMID- 23681330 TI - Television viewing and abdominal obesity in women according to smoking status: results from a large cross-sectional population-based study in Brazil. AB - OBJECTIVE: To investigate the associations between television viewing and abdominal obesity (AO) in Brazilian women, according to smoking status. METHODS: Data of 13,262 adult women (18-49 years) from the 2006's Demographic Health Survey, a cross-sectional household study with complex probabilistic sample and national representativeness, were analyzed. AO, defined as waist circumference >= 80.0 cm, was the outcome. Television viewing frequency (>= 5 times/week, 1-4 times/week, < 1 time/week) was the main exposure variable, and smoking status (yes or no) the main co-variable. Prevalence ratios were estimated using Poisson regression models separately for smokers and non-smokers. RESULTS: A statistically significant interaction term was observed between smoking status and television viewing (p < 0.05). Prevalence of AO among smokers who reported television viewing >= 5 times/week amounted to 59.0%, higher than the 35.0% for those with < 1 time/week television viewing (p-value = 0.020). The values for non smokers were 55.2% and 55.7%, respectively. Smokers with television viewing >= 5 times/week were 1.7 times (95% CI: 1.1 - 2.5) more likely to pre-sent AO, compared to those who reported a frequency < 1 time/week. There was no significant association among non-smokers. CONCLUSIONS: Television viewing >= 5 times/week may increase the prevalence of AO among women who smoke. More detailed information on media use, as hours per day, may offer better estimates. PMID- 23681331 TI - [Prevalence and factors associated to malnutrition and excess weight among under five year-olds in the six largest cities of Maranhao]. AB - Prevalences of malnutrition and overweight among children under five years and its association with socioeconomic, demographic and health indicators were estimated for the six largest municipalities of Maranhao, in 2006/2007. By means of a household survey, a sample of 1214 children under five years of age was randomly selected. Two-stage cluster sampling was used, representing the six municipalities of Maranhao with over one hundred thousand inhabitants. Standardized questionnaire was administered to mothers or guardians and trained personnel measured weight and height or length. For classification of malnutrition cutoff points of <-2z scores for weight-for-age, weight-for length/height and length/height-for-age were used. Overweight was considered when weight for height was > +2 z score, following World Health Organization guidelines. By weight-for-age malnutrition prevalence was 4.5, by length/height for-age 8.5% were stunted and by the weight-for-length/height 3.9% were malnourished (wasting), while 6.7% were overweight. Children of families headed by women had lower prevalence of malnutrition (prevalence ratio=0.4). Socioeconomic variables were not associated with malnutrition or overweight. Participation in money transfer programs from the government was not associated with malnutrition or overweight. The prevalence of malnutrition was low, but being overweight was more prevalent than malnutrition. Social inequality was not detected in relation to malnutrition in children under five years of age, suggesting a favorable trend towards greater equity. PMID- 23681332 TI - [Validity of self-reported height, weight and body mass index in the adult population of Brasilia, Brazil]. AB - OBJECTIVE: To assess the validity of self-reported weight, height and body mass index (BMI) estimates from adults in Brasilia and to identify factors associated to differences between measured and self-reported values. METHODS: In a cluster sampling 250 households were selected and weight and height were measured in all adults after an interview. Bland & Altman (B&A) was used to determined agreement between measured and self-reported parameters. The multiple analysis of variance was used to determine the associated factors. Sensitivity and specificity were used for excess weight (BMI >= 25 kg/m2). RESULTS: Interviews and measurements were done in 469 individuals. B&A showed bias (difference between measured and self-reported values) was not significant for weight (- 0.17 kg, p = 0.1) and significant for height (- 1 cm, p < 0.001). The limits of agreement (LA) were wide: from +/- 4 kg for weight and - 6 cm to 4 cm for height. BMI presented a non significant bias of - 0.06 kg/m2 (p = 0.08) and LA of - 1.5 to + 1.4 kg/m2. Men with a BMI < 25 kg/m2 overestimated weight, while overweight or obese men underestimated it (p < 0.01). Men older than 60y of age (p = 0.037) and women with less than 12y of study (p < 0.01) overestimated height. The sensitivity and specificity to detect excess weight were for men and women, respectively: 94%, 88% and 90%, 98%. Sensitivity to detect excess weight was 77% for 60 or over years old women and 75% for women between 9 to 11 years of study, while. specificity was 78% for men between 30 e 39 years old. CONCLUSION: In Brasilia, self-reported height can be used for subgroups of women with more than 12y of study and men under 60y of age. Men with adequate BMI over estimate their weight when compared to overweight and obese men. Self-reported measures can be used for excess weight population follow-up. PMID- 23681333 TI - [Within-person variance of the energy and nutrient intake in adolescents: data adjustment in epidemiological studies]. AB - OBJECTIVE: The aim of this paper is to calculate within-person variance component of the energy and nutrient intake that can be useful to adjust intake distribution from adolescents when is available only a single 24-hour recall for each participant. It will also give an example of its use in the intake distribution adjustment in adolescents from another sample. METHODS: It was used 24 hour recall from 215 adolescents living in Sao Paulo, Brazil. The variance components were estimated using the Software for Intake Distribution Estimation (PC-SIDE). It was made a model for each nutrient and sex of which were included covariates for day and month of intake and weight variable as well. RESULTS: The within-person variance component ranged from 0.55 for mono saturated fat (female) up to 0.96 for folate (male). I was found higher values regarding to macronutrient and energy for males. In the example of the use of the variance component, it was estimated the distribution of intake of vitamin B6 with less bias, when compared to the distribution with no adjustment. CONCLUSION: These results can be used to estimate habitual energy and nutrient intake for adolescent population when it is only a single dietary measurement. PMID- 23681334 TI - [Factors associated with breastfeeding in two municipalities with low human development index in Northeast Brazil]. AB - OBJECTIVE: To determine the duration of breastfeeding and to identify factors associated with exclusive / predominant breastfeeding in children under two years old. METHODS: This is a cross-sectional study conducted from March to June 2005 in the municipalities of Gameleira and Sao Joao do Tigre, located in the interior of Pernambuco and Paraiba States. The sample comprised 504 children under two years (280 residents in Gameleira and 224 in Sao Joao do Tigre). Survival analysis was used to estimate the median duration of survival time of breastfeeding and the associations with socioeconomic conditions, factors related to mothers and children and health care. RESULTS: The duration of exclusive and exclusive/predominant breastfeeding and breastfeeding were of 19, 79 and 179 days in Gameleira and 23, 91 and 169 days in Sao Joao do Tigre, respectively. Mothers with better socioeconomic conditions, as represented by education, sanitation, and possession of consumer goods, had a higher median duration of exclusive/ predominant breastfeeding in both towns. Prenatal care represented by higher number of attendance, earlier onset and feeding and breastfeeding advice had a positive influence on breastfeeding duration. CONCLUSIONS: Breastfeeding duration was lower than the recommendation. Despite the families precarious living conditions, a better socioeconomic status and prenatal care were protective factors for exclusive/ predominant breastfeeding duration in these areas. PMID- 23681335 TI - Ecological aspects of phlebotomine fauna (Diptera, Psychodidae) of Serra da Cantareira, Greater Sao Paulo Metropolitan region, state of Sao Paulo, Brazil. AB - Human cases of American cutaneous leishmaniasis (ACL) have been recorded in Serra da Cantareira, in the Greater Sao Paulo Metropolitan Region, where two conservation units are situated, the Parque Estadual da Cantareira and the Parque Estadual Alberto Lofgren. The present study aimed to identify the sandfly fauna and some of its ecological aspects in these two parks and their surrounding area to investigate Leishmania sp. vectors. The captures were undertaken monthly from January to December 2009, from 6:00 p.m. to 6:00 a.m., with automatic light traps installed in forests and peridomicile areas and with modified black/white Shannon traps in the peridomicile. A total of 12 species and 5,436 sandflies were captured: with automatic light traps (141), Shannon traps (5,219) and attempting to bite the researchers while they were conducting the collection in Shannon traps (76). Pintomyia fischeri and Migonemyia migonei were the most abundant species. Pi. fischeri predominated in all three kinds of captures (49%, 88.8% and 65.8%, respectively). Mg. migonei was the second most prevalent in Shannon traps (10.0%) and attempting to bite the researchers (22.4%). Pi. fischeri females were significantly more attracted to black and those of Mg. migonei to white Shannon traps. A positive and significant correlation was observed between the numbers of Pi. fischeri and the mean of minimum relative humidity values on the fifteen days prior to capture, while there was a negative and significant correlation between the relative humidity on the capture day and the two most abundant species. The anthropophilia and high frequencies of Pi. fischeri and Mg. migonei suggest that both species may be transmitting ACL agents in this region. PMID- 23681336 TI - [Test-retest reliability of the Work Ability Index (WAI) in nursing workers]. AB - This paper assesses the test retest reliability of the Work Ability Index (WAI) in nursing workers. A self-administered questionnaire was applied twice to a group of 80 workers (nurses and nursing aides/assistants) at a public hospital in Rio de Janeiro, Brazil within an interval from seven to fifteen days. The reliability was estimated using quadratic weighted kappa statistics, interclass correlation coefficient (ICC) and the Bland and Altman plot. Eighty-one percent of participants were women aged between from 22 to 67 years (mean =39.1; SD=10.8 years); 36.3% had completed higher education. The global score of the WAI presented ICC= 0.79 (IC95% 0.67 to 0.86) and weighted kappa=0.69 (CI95% 0.50 to 0.80) for categorical WAI (classified as low, moderate, good and excellent). The quadratic weighted kappa of the WAI items ranged from 0.39 to 0.82 and the Bland and Altman plot did not show a systematic pattern. The agreement between the test and retest measures shows an acceptable degree of reliability, suggesting the adequacy of the assessment process among nursing workers. PMID- 23681337 TI - [Health Index applied to the city of Araraquara, SP: an instrument to accompaniment the primary care]. AB - The improvement of the process of evaluation and monitoring of the Primary Care Attention has been yearned by the managers of the different spheres in the context of the Unified System Health - UHS. Thus, in the order to identify the conditions of the health assistance in the city of Araraquara/SP, based on the particular features presented in the inscribe areas of each unit of health. It was adopted by means of a composed indicator aiming to favor a broader view which contemplates the emergency of phenomena from a more including vision. It was used the methodology developed in the Index of Health of Drumond Jr, whose final value of the Index is gotten by the average of the values of the components of each health district. To the components originally adopted - Coefficient of Infant Mortality, Coefficient of Tuberculosis Incidence, Coefficient of Mortality by External Causes and Coefficient of Precocious Mortality by Chronic Diseases - was still added in this study, the Tax of Alphabetization and the Monthly Nominal Average Income of Responsible People for the Domiciles. The 24 Units of Health had been classified according to values obtained in the relation among its components. The results point intra-urban differentials in relation to the majority of the components and lower values for the Health Units located at the periphery of the city. Knowing this fact municipal administration is of fundamental importance to progress in improving the process of evaluation of primary care in the county. PMID- 23681338 TI - [Situation of the municipalities of Sao Paulo state in relation to the purchase of products directly from family farms for the National School Feeding Program (PNAE)]. AB - INTRODUCTION: In 2009, Law 11,947 was passed, which provides for the care of school meals and consolidates the linkage of family farming with the National School Feeding Program (PNAE), by stipulating that at least 30% of the total financial resources granted by the Federal Government to the states and municipalities should be used for the acquisition of food directly from family farmers and rural entrepreneurs family or their organizations. OBJECTIVE: To characterize the situation of the municipalities of Sao Paulo state in relation to the acquisition of products directly from family farmers after approval of Law 11,947. METHOD: The diagnosis was carried out in the months of June to August 2011 by institutions linked to the Intersectoral School Feeding State Commission (CEIA). For the survey, a questionnaire was used and telephone interviews were conducted with representatives of the 645 municipal districts. RESULTS: It was possible to obtain the following information for a total of 613 municipalities: 47% (288) had already made local purchases at least once in all its stages. Of the 325 municipalities that do not conducted the process at all stages, 57% had not published a public call; 37% published but had not signed the purchase contract; 2% published a call, signed the contract but had not received the products; and 4% published at least one call, received the products but had not yet paid the farmers. CONCLUSION: The results show that approximately 50% of the municipalities evaluated are in a positive situation in relation to the local procurement for PNAE. However, the number of municipalities that did not publish the public call or not signed the contract is still important and deserves attention of the sectors involved. PMID- 23681339 TI - Self-powered flexible and transparent photovoltaic detectors based on CdSe nanobelt/graphene Schottky junctions. AB - Flexible and transparent electronic and optoelectronic devices have attracted more and more research interest due to their potential applications in developing portable, wearable, low-cost, and implantable devices. We have fabricated and studied high-performance flexible and transparent CdSe nanobelt (NB)/graphene Schottky junction self-powered photovoltaic detectors for the first time. Under 633 nm light illumination, typical photosensitivity and responsivity of the devices are about 1.2 * 10(5) and 8.7 A W(-1), respectively. Under 3500 Hz switching frequency, the response and recovery times of them are about 70 and 137 MUs, respectively, which, to the best of our knowledge, are the best reported values for nanomaterial based Schottky junction photodetectors up to date. The detailed properties of the photodetectors, such as the influences of incident light wavelength and light intensity on the external quantum efficiency and speed, are also investigated. Detailed discussions are made in order to understand the observed phenomena. Our work demonstrates that the self-powered flexible and transparent CdSe NB/graphene Schottky junction photovoltaic detectors have a bright application prospect. PMID- 23681340 TI - Higher gait variability is associated with decreased parietal gray matter volume among healthy older adults. AB - The objectives of this study were to examine the association of stride time variability (STV) with gray and white matter volumes in healthy older adults, and to determine the specific location of any parenchymal loss associated with higher STV. A total of 71 participants (mean age 69.0 +/- 0.8 years; 59.7 % female) were included in this study. All participants had a 1.0 Tesla 3D T1-weighted MRI of the brain to measure gray and white matter volumes. STV was measured at steady state self-selected walking speed using an electronic footswitch system. We found an association between higher STV and lower gray matter volume in the right parietal lobe (e.g., angular gyrus, Brodmann area 39, cluster corrected pFWE = 0.035). There were no significant associations between STV and higher gray matter volume or change in white matter volume. To the best of our knowledge this study is the first to identify a significant association of higher STV with lower right parietal gray matter volume in healthy older adults. PMID- 23681341 TI - Risk factors for recurrence after lung cancer resection as estimated using the survival tree method. AB - BACKGROUND: Patients with lung cancer often present with recurrence, even after resection. The identification of risk factors for recurrence after resection is useful. METHODS: Among 1,338 patients with lung cancer who underwent a complete resection, 277 developed recurrences post surgery. Data regarding the TNM factors, histologic subtype, and presence/absence of vessel invasion were analyzed retrospectively using the survival tree method to identify groups with a high risk of recurrence after resection. RESULTS: The results revealed that the T factor, the N factor, and lymphatic (ly) and blood (v) vessel invasion were related to the risk of recurrence, and six combinations of these factors were identified using the survival tree method: group A: v = 0, T <= 1b, ly = 0; group B: v = 0, T <= 1b, ly >= 1; group C: v = 0, T >= 2a; group D: v >= 1, N <= 1, T <= 2b; group E: v >= 1, N <= 1, T >= 3; and group F: v >= 1, N >= 2. The six groups were then further classified into three groups: a low-risk group (group A), a moderate-risk group (groups B, C, and D), and a high-risk group (groups E and F). The 5-year recurrence-free survival rate was approximately 98% for the low-risk group, 75% for the moderate-risk group, and 30% for the high-risk group. CONCLUSIONS: Combining the T, N, v, and ly factors allowed the precise identification of a group with a high risk of recurrence after resection. PMID- 23681343 TI - Well-dispersed Co3O4/Co2MnO4 nanocomposites as a synergistic bifunctional catalyst for oxygen reduction and oxygen evolution reactions. AB - Co3O4/Co2MnO4 nanocomposites, derived from a single-source CoMn-layered double hydroxide precursor, exhibit excellent bifunctional oxygen electrode activities for both oxygen reduction and evolution reactions, which can be attributed to the large specific surface area and well-dispersed heterogeneous structure of the nanocomposites. PMID- 23681344 TI - The relationship between geriatric depression and health-promoting behaviors among community-dwelling seniors. AB - BACKGROUND: People older than 65 years old account for about 10.9% of Taiwan's total population; it is also known that the older adults experience a higher incidence of depression. Public health nurses play an important role in promoting community health. Policymaking for community healthcare should reflect the relationship between health-promoting behavior and depression in community dwelling seniors. Therefore, the encouragement of healthy aging requires strategic planning by those who provide health promotion services. OBJECTIVE: This study was designed to elicit the health-promoting behaviors of community seniors and investigate the relationship between geriatric depression and health promoting behaviors among seniors who live in rural communities. METHODS: We used a cross-sectional, descriptive design and collected data using a demographic information datasheet, the Health Promotion for Seniors and Geriatric Depression Scale short forms. RESULTS: The study included 427 participants. Most were women; mean age was 75.8 years. Most were illiterate; roughly half engaged in a limited number of health-promoting activities. The Geriatric Depression Scale score was negatively associated with health-promoting behavior. Social participation, health responsibility, self-protection, active lifestyle, and total Health Promotion for Seniors score all reached statistical significance. Multivariate analysis indicated that geriatric depression and physical discomfort were independent predictors of health-promoting behavior after controlling the confounding factors. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Participants practiced less than the recommended level of health-promoting behaviors. We found a negative correlation between the geriatric depression score and health promoting behavior. Results can be referenced to develop strategies to promote healthy aging in the community, especially with regard to promoting greater social participation and increased activity for community-dwelling older adults experiencing depression. PMID- 23681345 TI - Disability assessment: the efficacy of multimedia interactive nurse education. AB - BACKGROUND: Nearly 3% of the population in Taiwan is classified as disabled. Disability assessment directly relates to long-term care quality and resource allocation. PURPOSE: The purpose of this study was to explore the effects of a multimedia interactive DVD on enhancing nurse knowledgeand disability assessment skills. METHODS: The study was a quasi-experimental design. The experimental group received multimedia interactive DVD, and the control group received conventional classroom education. The study gathered data using scales assessing knowledge related to disability assessment and case studies. Scales were implemented before and after multimedia interactive DVD interventions at weeks 2 and 4. In-depth interviews with voice recording were used to collect qualitative data to elicit differences in perception between the experimental and control groups. RESULTS: This study found significant improvements in the experimental group in terms of disability assessment knowledge and case study assessment skills. These improvements lasted through at least 1-month posttest. Analysis of interview data for the experimental group showed that the multimedia interactive DVD provided a more flexible approach to learning than classroom education and improved participant self-confidence to conduct disability assessments. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The study showed the effectiveness of the developed multimedia interactive DVD in significantly improving the disability assessment confidences of nurses. Study findings can be used as a reference guide for continuing educational efforts in long-term care settings. PMID- 23681342 TI - Phenotypic conservation in patients with X-linked retinitis pigmentosa caused by RPGR mutations. AB - IMPORTANCE: For patients with X-linked retinitis pigmentosa and clinicians alike, phenotypic variability can be challenging because it complicates counseling regarding patients' likely visual prognosis. OBJECTIVE: To evaluate the clinical findings from patients with X-linked retinitis pigmentosa with 13 distinct RPGR mutations and assess for phenotypic concordance or variability. DESIGN: Retrospective medical record review of data collected from 1985 to 2011. SETTING: Kellogg Eye Center, University of Michigan. PATIENTS: A total of 42 patients with X-linked retinitis pigmentosa with mutations in RPGR. Age at first visit ranged from 4 to 53 years, with follow-up ranging from 1 to 11 visits (median follow-up time, 5.5 years; range, 1.4-32.7 years, for 23 patients with >1 visit). MAIN OUTCOMES AND MEASURES: Clinical data assessed for concordance included visual acuity (VA), Goldmann visual fields (GVFs), and full-field electroretinography (ERG). Electroretinography phenotype (cone-rod vs rod-cone dysfunction) was defined by the extent of photopic vs scotopic abnormality. Qualitative GVF phenotype was determined by the GVF pattern, where central or peripheral loss suggested cone or rod dysfunction, respectively. Goldmann visual fields were also quantified and compared among patients. RESULTS: Each mutation was detected in 2 or more related or unrelated patients. Five mutations in 11 patients displayed strong concordance of VA, while 4 mutations in 16 patients revealed moderate concordance of VA. A definitive cone-rod or rod-cone ERG pattern consistent among patients was found in 6 of 13 mutations (46.2%); the remaining mutations were characterized by patients demonstrating both phenotypes or who had limited data or nonrecordable ERG values. Concordant GVF phenotypes (7 rod-cone pattern vs 4 cone-rod pattern) were seen in 11 of 13 mutations (84.6%). All 6 mutations displaying a constant ERG pattern within the mutation group revealed a GVF phenotype consistent with the ERG findings. CONCLUSIONS AND RELEVANCE: While VA and ERG phenotypes are concordant in only some patients carrying identical mutations, assessment of GVF phenotypes revealed stronger phenotypic conservation. Phenotypic concordance is important for establishing proper counseling of patients diagnosed as having X-linked retinitis pigmentosa, as well as for establishing accurate patient selection and efficacy monitoring in therapeutic trials. PMID- 23681346 TI - Quality of life patterns and survival among older people. AB - BACKGROUND: As the numbers and proportions of elderly people in the global population increase, quality of life (QOL) within this group becomes an important research issue. Undertaking cross-national comparisons of elderly people can provide a better understanding of QOL patterns. PURPOSE: This study examines QOL patterns using a harmonization data set from two longitudinal studies of the older people in the United Kingdom (UK) and Taiwan and explores the relationship between clusters of older people and mortality hazards in these countries. METHODS: Data were derived from the 1989 wave of the Nottingham Longitudinal Study of Activity and Ageing and the Survey of Health and Living Status of the Elderly in Taiwan. Cluster analysis was used to observe QOL patterns in the older people and their profiles. Cox regression analysis was used to test for the presence of clusters associated with mortality hazards. RESULT: Fifteen subgroups were extracted from cluster analysis of the Nottingham Longitudinal Study of Activity and Ageing sample (n = 690), and 20 groups were generated from cluster analysis of the Survey of Health and Living Status of the Elderly in Taiwan data set (n = 1,438). Cox regression analyses revealed a relationship between mortality risk and certain clusters over a 14-year period in the U.K. and Taiwan. CONCLUSIONS: Using cluster analyses to group the older people according to shared characteristics identified different QOL levels across these profiles both in the UK and Taiwan. The author also identified differences in the same profile levels between the two countries. It is important to explore the relationship between clusters and mortality hazards because clusters reflect important QOL factors affecting mortality risk. PMID- 23681347 TI - The impacts of widowhood, chronic disease, and physical function on mortality among older people. AB - BACKGROUND: Age-related physical and mental health is well documented. The numbers of widows and widowers are rising in Taiwan. Thus, it is worthwhile to consider factors affecting survival rates after the death of a spouse. PURPOSE: This study examined the impacts of widowhood, chronic disease, and physical function on mortality risk among the older people in Taiwan. METHODS: A panel data design was applied to investigate the hazard ratio of mortality among the older people. Subject data were obtained from the 2003 Survey of Health and Living Status of the Middle Aged and Elderly in Taiwan and linked to the 2003 2007 national death registry data. Cox proportional hazard models were used to examine the relationships between survival rates and factors including status as a widower or widow, chronic disease, and physical function disability. RESULTS: After controlling for potentially confounding variables, survival analysis indicated a relatively higher mortality risk among the widowed compared with those whose spouses were still alive. Of these, widowers showed a higher mortality risk than widows. In addition, incidence of tumor and stroke significantly influenced mortality among both married men and women. Bronchitis, pneumonia, and other respiratory disease significantly raised the risk of mortality for married men but not for married women. Moreover, physical function variables were significant predictive factors related to mortality hazard, with instrumental activities of daily living showing the strongest predictive relationship. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The study confirmed that widowhood, chronic disease, and physical function were strongly associated with mortality hazard in older people. Therefore, greater attention should be paid to these factors to reduce elderly mortality risk. Research results should be useful in developing welfare strategies for this group. PMID- 23681348 TI - Illness representations and coping processes of Taiwanese patients with early stage chronic kidney disease. AB - BACKGROUND: Chronic kidney disease (CKD) is a public health problem worldwide with an increasing incidence and prevalence and high cost. The role of illness perceptions in understanding health-related behavior has received little attention in patients with early-stage CKD. PURPOSE: This qualitative study aimed to describe the illness representation and coping process experience of patients with early-stage CKD in Taiwan. METHODS: A qualitative content analysis approach was used to analyze semistructured, open-ended, one-on-one interviews with 15 patients with early-stage CKD. Purposive sampling was used to recruit patients diagnosed with early-stage CKD from the nephrology departments of two medical centers in Taiwan. Trustworthiness of the study was evaluated using four criteria suggested by Lincoln and Guba. RESULTS: Six themes emerged from the analysis: experiencing early symptoms, self-interpreting the causes of having CKD, realizing CKD as a long-term disease, believing CKD could be controlled by following doctors' orders, anticipating the consequences of having CKD, and adopting coping strategies to delay the progress of CKD. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Findings from this study compared with previous studies reveal that education can effectively change patient illness representations as an approach to improve coping behavior. This finding offers healthcare professionals insight into the health education necessary to assess patient illness representation to provide culturally sensitive interventions. PMID- 23681349 TI - Correlations among social support, depression, and anxiety in patients with type 2 diabetes. AB - BACKGROUND: Social support is related to patient self-care and health status. Patients' psychosocial issues play an important role in diabetes care. PURPOSE: This study investigates correlations among social support, depression, and anxiety in patients with diabetes. METHODS: A cross-sectional study design and purposive sampling were used. One hundred eleven patients with type-2 diabetes were recruited from three regional teaching hospitals in northern, central, and southern Taiwan, respectively. Questionnaires used included the social support and psychological referral inventory, Beck depression inventory, and Beck anxiety inventory. RESULTS: Approximately 12.6% of the study population had depression, and 27.0% had anxiety. Depression and anxiety were positively correlated (r = .65, p < .01), whereas depression was negatively correlated with the sum of disease control types (r = -0.26, p < .01) and social support (r = -0.27, p <.01). The sum of disease control types and social support were the most important explanatory factors for depression in patients, explaining 45.5% of variance. Anxiety was correlated positively with age (r = .26, p < .01), total number of complications (r = .31, p < .01), and depression (r = .65, p < .01). Anxiety correlated negatively with weight (r = -0.20, p < .05) and sum of disease control types (r = -0.25, p < .05). The above variables were important explanatory factors for anxiety, accounting for 15.2% of variance. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Psychological factors, such as depression and anxiety, are common symptoms in patients with diabetes. If social support can be strengthened in these patients, then psychological factors can be improved. Professional care providers should focus on reducing the patient depression and anxiety levels, strengthening social support, and providing referrals to psychology-related professionals. PMID- 23681350 TI - Smoking in korean-chinese middle school students: prevalence and risk factors. AB - BACKGROUND: Cigarette smoking is rising among Chinese adolescents, and adolescent smoking is a crucial public health issue. Despite the number of studies that have explored the prevalence and various aspects of adolescent smoking in China, we know of no data currently available on smoking behavior among Korean-Chinese adolescents. PURPOSE: This article studies the prevalence of smoking and factors affecting smoking behavior among Korean-Chinese adolescents. METHODS: Data were collected from six Korean-Chinese middle schools in the Yanbian region of Jilin, China. The differences in data from three groups (never-smokers, ever-smokers, and current smokers) were analyzed using chi2 tests and analysis of variance. Logistic regression was used to analyze the factors affecting smoking behavior. RESULTS: Among the 2,116 participants, 7.3% of the boys and 3.7% of the girls were ever-smokers, and 7.2% of the boys and 0.8% of the girls were current smokers. Differences among groups in terms of gender, number of friends currently smoking, parental smoking behavior, academic performance, alcohol consumption, and intention not to smoke were all significant (p < .001, .05). Compared with never-smoking and ever-smoking students, currently smoking students perceived a significantly less antismoking environment (p = .000). The smoking rate was 2.24 times higher in boys than girls and was 11.57 times higher in students who had three smoking friends compared with those who had no smoking friends. CONCLUSION: The findings may help develop more effective intervention approaches to prevent adolescent smoking. Preventive programs should involve smoking parents by increasing the value they place on their children's nonsmoking behavior and equipping them to help deter adolescent smoking. PMID- 23681351 TI - Development and validation of the postpartum sleep quality scale. AB - BACKGROUND: Postpartum sleep disorders are a significant problem for postnatal women. Although factors predisposing postnatal women to sleep disorders have been identified, few sleep quality assessment instruments adequately address these factors. PURPOSE: This study aimed to develop a Postpartum Sleep Quality Scale (PSQS) and test its psychometric properties. METHODS: Sixteen PSQS items were generated from clinical practice, a literature review, and expert recommendations. Two hundred two postpartum women were recruited from a medical center and an obstetric clinic in southern Taiwan in 2010-2011 to assess the internal consistency, test-retest reliability, construct validity, and convergent validity of the developed PSQS. RESULTS: Item analysis removed two of the initial PSQS items. The resultant 14-item PSQS showed good internal consistency (alpha = .81) and acceptable 5-day test-retest reliability (r = .81). Construct validity was confirmed using exploratory factor analysis, which extracted and defined "Infant night care-related daytime dysfunction" and "Physical symptoms-related sleep inefficiency" as the two main categories of postpartum sleep quality. These two factors explained 44.49% of total variance, with factor loadings between .43 and .76. Significant correlation (r = .67) with the Pittsburgh Sleep Quality Index showed convergent validity. CONCLUSION: The 14-item PSQS is a reliable, valid, and useful scale for measuring postpartum sleep quality and examining intervention protocols in Taiwanese postpartum women with sleep disturbance. PMID- 23681352 TI - The effect of glutathione treatment on the biochemical and immunohistochemical profile in streptozotocin-induced diabetic rats. AB - This study investigated the possible role of glutathione (GSH) in diabetic complications and its biochemical safety in experimental diabetic rats. Serum biochemical parameters and the histology of the pancreas were investigated. Seven rats were separated as controls. To create the diabetes in rats, 45 mg/kg single dose streptozotocin (STZ) was administered i.p. The treatment was continued for 1 month. STZ was administered to the diabetes + GSH group, then reduced GSH, dissolved in isotonic salt solution (200 mg/kg), was applied i.p. two times a week. The GSH group received i.p. GSH. Serum biochemical parameters were determined by autoanalyzer. Immunohistochemical procedures were used to determine the percentage of the insulin-immunoreactive beta-cell area in the islets of Langerhans. The biochemical parameters changed to different degrees or did not change. Pancreatic cells of the control and GSH groups were healthy, but in the diabetic and GSH-treated diabetic groups we found damage in different numbers. The results from these analyses show that GSH supplementation can exert beneficial effects on pancreatic cells in STZ-induced diabetic rats and can safely be used for therapy in and protection from diabetes and complications of diabetes. PMID- 23681353 TI - Protective effects of the flavonoid-rich fraction from rhizomes of Smilax glabra Roxb. on carbon tetrachloride-induced hepatotoxicity in rats. AB - Hepatoprotective agents could prevent tissue damage and reduce morbidity and mortality rates; such agents may include folkloric or alternative treatments. The present study evaluated the protective effects of the flavonoid-rich fraction from rhizomes of Smilax glabra Roxb. (SGF) on carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. Sprague-Dawley male rats were orally treated with SGF daily and received CCl4 intraperitoneally twice a week for 4 weeks. Our results showed that SGF at doses of 100, 300 and 500 mg/kg significantly reduced the elevated activities of serum aminotransferases (ALT and AST), alkaline phosphatase and lactate dehydrogenase and the level of hepatic thiobarbituric acid-reactive substances compared to the CCl4-treated group. Moreover, SGF treatment was also found to significantly increase the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione-S transferase and glutathione compared with CCl4-induced intoxicated liver. Histopathologic examination revealed that CCl4-induced hepatic damage was markedly reversed by SGF. The results suggest that SGF has hepatoprotective and antioxidant properties in CCl4-induced liver injury in rats. PMID- 23681354 TI - Early white matter changes in childhood multiple sclerosis: a diffusion tensor imaging study. AB - BACKGROUND AND PURPOSE: Loss of integrity in nonlesional white matter occurs as a fundamental feature of multiple sclerosis in adults. The purpose of our study was to evaluate DTI-derived measures of white matter microstructure in children with MS compared with age- and sex-matched controls by using tract-based spatial statistics. MATERIALS AND METHODS: Fourteen consecutive pediatric patients with MS (11 female/3 male; mean age, 15.1 +/- 1.6 years; age range, 12-17 years) and age- and sex-matched healthy subjects (11 female/3 male; mean age, 14.8 +/- 1.7 years) were included in the study. After we obtained DTI sequences, data processing was performed by using tract-based spatial statistics. RESULTS: Compared with healthy age- and sex-matched controls, children with multiple sclerosis showed a global decrease in mean fractional anisotropy (P <= .001), with a concomitant increase in mean (P < .001), radial (P < .05), and axial diffusivity (P < .001). The most pronounced fractional anisotropy value decrease in patients with MS was found in the splenium of the corpus callosum (P < .001). An additional decrease in fractional anisotropy was identified in the right temporal and right and left parietal regions (P < .001). Fractional anisotropy of the white matter skeleton was related to disease duration and may, therefore, serve as a diagnostic marker. CONCLUSIONS: The microstructure of white matter is altered early in the disease course in childhood multiple sclerosis. PMID- 23681355 TI - Bone involvement in atypical teratoid/rhabdoid tumors of the CNS. AB - SUMMARY: Destruction of the bony structures of the skull is rare in primary tumors of the CNS. In low-grade gliomas, modeling of the skull is caused by slow growth and chronic pressure. Bony destruction is exceptional even in highly malignant gliomas. Atypical teratoid/rhabdoid tumors of the CNS are highly malignant neoplasms diagnosed with an increasing frequency, mainly in young children. On imaging, these tumors exhibit distinct though not specific morphologic features including peripheral cysts, bleeding residues, and a distinct bandlike, wavy pattern of enhancement. A combination of these single characteristics together with a predilection for young age is suggestive of an atypical teratoid/rhabdoid tumor. We present 5 children with an atypical teratoid/rhabdoid tumor affecting the adjacent bone. These 5 patients were collected in our imaging data base for childhood atypical teratoid/rhabdoid tumor consisting of 91 children at the time of this evaluation and thus representing 6.6%. The mean age of children with bone involvement (4.8 years) was above the average age (2 years) of all children in the data base. We add this rare feature to the list of typical features in MR imaging and CT morphology of atypical teratoid/rhabdoid tumor. PMID- 23681356 TI - Neuroradiologic features in X-linked alpha-thalassemia/mental retardation syndrome. AB - BACKGROUND AND PURPOSE: X-linked alpha-thalassemia/mental retardation syndrome (Mendelian Inheritance in Man, 301040) is one of the X-linked intellectual disability syndromes caused by mutations of the ATRX gene and characterized by male predominance, central hypotonic facies, severe cognitive dysfunction, hemoglobin H disease (alpha-thalassemia), genital and skeletal abnormalities, and autistic and peculiar behavior. More than 200 patients in the world, including >70 Japanese patients, have been diagnosed with ATR-X syndrome. MATERIALS AND METHODS: We reviewed the brain MRI and/or CT findings of 27 Japanese patients with ATR-X with ATRX mutations retrospectively. RESULTS: The findings were categorized into 5 types: 1) nonspecific brain atrophy (17/27); 2) white matter abnormalities, especially around the trigones (11/27); 3) widespread and scattered white matter abnormalities (1/27); 4) delayed myelination (4/27); and 5) severe and rapidly progressive cortical brain atrophy (1/27). CONCLUSIONS: This is the first report on a comprehensive study of brain MRI/CT findings of ATR X syndrome. Our findings suggest that the ATRX protein seems to be involved in normal myelination. The classification will require revisions in the near future, but it will be helpful in establishing the relationship between ATRX mutation and brain development and understanding the ATRX protein function in the brain. PMID- 23681357 TI - Environmental impact assessment and eco-friendly decision-making in civil structures. AB - This study develops two useful procedures in performing an environmental-impact assessment. One is the advanced life-cycle assessment (LCA) method, which effectively tracks the flow of materials and considers the recycling and demolition of a civil structure. The other is an eco-friendly decision-making procedure, which may effectively apply when determining the prototype of a civil structure. The advanced LCA method differs from traditional LCA procedure, as it classifies the input material prior to the impact assessment. Classification work is performed to establish independent life-cycle stages for each material. The processes of recycling and demolition are appropriately added to the life-cycle stages. The impact assessment is performed separately for the materials, and results are aggregated at the end of the analysis. The eco-friendly decision making procedure enables designers to choose an economical, and environmentally friendly, alternative during the planning phase of the construction project. This procedure rationally amalgamates economical value and environmental effects into a single indicator. The life cycle cost (LCC) of a structure can be analysed by using conventional LCC tools, whereas the environmental impact is estimated by LCA. The results from LCC and LCA are then integrated by using either a CO2 conversion method or an analytical hierarchy process (AHP). The CO2 conversion method presents the result as a monetary value, whereas the AHP presents the result as a non-dimensional value. A practical example using a steel box girder bridge and a pre-stressed concrete (PSC) box-girder bridge is also given in order to aid the understanding of the presented procedure. PMID- 23681358 TI - Land use impact on water quality: valuing forest services in terms of the water supply sector. AB - The aim of this paper is to quantify the impact of the forest on raw water quality within the framework of other land uses. On the basis of measurements of quality parameters that were identified as being the most problematic (i.e., pesticides and nitrates), we modeled how water quality is influenced by land uses. In order to assess the benefits provided by the forest in terms of improved water quality, we used variations of drinking water prices that were determined by the operating costs of water supply services (WSS). Given the variability of links between forests and water quality, we chose to cover all of France using data observed in each administrative department (France is divided into 95 departements), including a description of WSS and information on land uses. We designed a model that describes the impact of land uses on water quality, as well as the operation of WSS and prices. This bioeconomic model was estimated by the generalized method of moments (GMM) to account for endogeneity and heteroscedasticity issues. We showed that the forest has a positive effect on raw water quality compared to other land uses, with an indirect impact on water prices, making them lower for consumers. PMID- 23681359 TI - Erectile dysfunction may be the first clinical sign of insulin resistance and endothelial dysfunction in young men. AB - OBJECTIVES: The purpose of this study is to investigate the possible underlying pathogenesis of erectile dysfunction (ED) without well-known etiology in young men under the age of 40 years. METHODS: 192 patients and 33 normal controls were enrolled. ED was evaluated by using the International Index of Erectile Function 5 (IIEF-5) questionnaire. Traditional cardiovascular risk factors, hormone levels, and vascular parameters were measured. Insulin resistance (IR) was measured by homeostasis model assessment (HOMA). RESULTS: Patients with ED had significantly higher levels of systolic blood pressure (SBP), high-sensitivity C reactive protein (Hs-CRP), high Insulin resistance index (HOMA-IR) and carotid intima-media thickness (IMT), compared with controls. The brachial artery endothelium-dependent flow-mediated vasodilation (FMD) values were significantly lower in ED patients. By multivariate logistic regression analysis, FMD, SBP, Hs CRP and HOMA-IR were significantly associated with ED. In receiver-operating characteristic (ROC) analysis, FMD was a significant predictor of ED (area under the curve (AUC) 0.933, p < 0.001). The cutoff value of FMD <10.4 % had sensitivity of 81.3 % and specificity of 100 %. HOMA-IR was also proven to be predictor of ED (AUC of HOMA-IR 0.759, p < 0.001). CONCLUSIONS: ED may be the first clinical sign of endothelial dysfunction and a clinical marker of cardiovascular and metabolic diseases. Subclinical endothelial dysfunction and insulin resistance may be the underlying pathogenesis of ED in young patients without well-known etiology. Measurement of FMD, HOMA-IR can improve our ability to predict and treat ED, as well as subclinical cardiovascular disease early in young men. PMID- 23681361 TI - The bis-phenanthridinium system flexibility and position of covalently bound uracil finely tunes the interaction with polynucleotides. AB - A series of structurally similar bis-phenanthridinium derivatives, some with uracil at different positions, revealed different interactions with various polynucleotides. The uniform binding of mononucleotides to all studied compounds by "cyclobisintercaland" binding type indicated that compound-polynucleotide interaction selectivity was the consequence of polynucleotide secondary structure and not direct nucleobase recognition. Although affinity and fluorimetric response of all studied compounds toward ds-DNA/RNA was similar, the thermal denaturation and ICD signal-based sensing was highly sensitive to polynucleotide basepair composition and secondary structure. In particular, for the specific poly rAH(+)-poly rAH(+) double helix MD parameters are newly developed and used for analysis of its complexes. The highly sensitive orientation of phenanthridinium as well as the role of the uracil substituent, both binding interactions finely tuned by the steric and binding properties of the DNA/RNA ligand interaction site, offer novel structural information about binding and steric properties of particular DNA-RNA systems. PMID- 23681360 TI - Outcome of percutaneous coronary intervention with drug-eluting stents in unprotected left main versus non-left main native coronary artery disease: results from the prospective multicenter German DES.DE registry. AB - BACKGROUND: Unprotected left main coronary artery (ULMCA) disease is considered an indication for surgical revascularization. However, refined percutaneous coronary intervention (PCI) technology and modern drug-eluting stents (DES) render the ULMCA a target for interventional treatment. METHODS AND RESULTS: Between October 2005 and September 2009, 374 patients receiving DES in ULMCA and 18,678 patients receiving DES in non-left main coronary arteries (nLMCA) with no previous coronary artery bypass graft surgery, were registered at 130 DES.DE sites. The composite of death, myocardial infarction (MI), and stroke defined as major adverse cardiac and cerebrovascular events (MACCE) and target vessel revascularization (TVR) were defined as primary endpoints. Baseline clinical and descriptive morphology of coronary artery disease revealed more comorbidities and more complex anatomies in the ULMCA group. At 1-year follow-up, the ULMCA group suffered from higher rates of overall death (5.6 versus 2.3 %; p < 0.0001), stroke (2.0 versus 0.8 %; p < 0.05), MACCE (8.6 versus 4.9 %; p < 0.01); whereas rates for definite/probable stent thrombosis (2.4 versus 1.6 %; p = 0.29), TVR (14.2 versus 10.8 %; p = 0.06) and MI (1.3 versus 1.9 %; p = 0.44) were not statistically different. These results persisted even after adjustment for different baseline characteristics, except MACCE that was no longer statistically significant. CONCLUSION: Data collected in DES.DE revealed that ULMCA PCI with DES result in similar TVR rates as compared to PCI in nLMCA. Moreover, modern DES have not offset the higher comorbidity index and higher procedure-related complication rate with PCI of ULMCA lesions. PMID- 23681362 TI - An uncommon cause of abdominal pain after endoscopic retrograde cholangiopancreatography. PMID- 23681363 TI - An efficient proteomic approach to analyze agriculture crop biomass. AB - While a plant cell wall is formed by a complex of various components, including polysaccharides and structural proteins, its composition and representation may vary during cell growth. Currently, plant research targets the proteins participating in wall loosening. Multiple classes of enzymes, including various hemicellulases and cellulases, are required for plant material degradation to achieve the maximum decomposition. Identifying the set of proteins involved in the breakdown of cell-wall polymers is important to understand plant material conversion into suitable products. The objective of this study was to describe a method which can be used to carry out proteomics analysis of complex plant samples and identify enzymes degrading biomass. For this purpose we used proteomic techniques including gel electrophoresis, high pressure liquid chromatography combinated with mass spectrometry followed by data evaluation using databases searching. Results show that more than 50 % of these activities correspond to enzymes with proteolytic function. This study was focused primarily on enzymes able to breakdown the lignocellulosic and hemicellulosic parts that are very important for the material conversion into required products of degradation. PMID- 23681365 TI - Reactive surface area of the Li(x)(Co(1/3)Ni(1/3)Mn(1/3))O2 electrode determined by MU(+)SR and electrochemical measurements. AB - The self-diffusion coefficient of Li(+) ions (D(Li)) in the positive electrode material Li(x)(Co(1/3)Ni(1/3)Mn(1/3))O2 has been estimated by muon-spin relaxation (MU(+)SR) using powder samples with x = 1-0.49, which were prepared by an electrochemical reaction in a Li-ion battery. Here, since the implanted muons sense a slight change in the internal magnetic field due to Li-diffusion, MU(+)SR provides an intrinsic D(Li) through the temperature dependence of the nuclear field fluctuation rate (nu) [Sugiyama et al., Phys. Rev. Lett., 2009, 103, 147601]. Both D(Li) at 300 K and activation energy (E(a)) were estimated to be ~2.9 * 10(-12) cm(2) s(-1) and 0.074 eV for the x = 1 sample, ~11.0 * 10(-12) cm(2) s(-1) and 0.097 eV for x = 0.70, and ~8.9 * 10(-12) cm(2) s(-1) and 0.062 eV for x = 0.49, assuming that the diffusing Li(+) ions mainly jump from a regular occupied site to a regular vacant site. The estimated D(Li) was smaller by roughly one order of magnitude than those for Li(x)CoO2 in the whole x range measured. Furthermore, by making comparison with D(Li) obtained by electrochemical measurements, the reactive surface area of the Li(x)(Co(1/3)Ni(1/3)Mn(1/3))O2 electrode in a liquid electrolyte was found to strongly depend on x particularly at x > 0.8. PMID- 23681364 TI - A Phase II study of polyclonal anti-TNF-alpha (AZD9773) in Japanese patients with severe sepsis and/or septic shock. AB - Because tumor necrosis factor-alpha (TNF-alpha) induces many of the pathophysiological signs and symptoms observed in sepsis, it is a potential therapeutic target for treatment. The primary objective of this study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple intravenous (i.v.) infusions of two doses of AZD9773 in Japanese patients with severe sepsis and/or septic shock. In this Phase II, double-blind, placebo-controlled, dose-escalation study (ClinicalTrials.gov Identifier: NCT01144624), Japanese patients were randomized to two successive treatment cohorts (cohort 1, loading/maintenance doses of 250/50 U/kg or placebo; cohort 2, loading/maintenance doses of 500/100 U/kg or placebo) for a 5-day treatment period, then a follow-up period to day 29. Twenty patients were enrolled (AZD9773 cohort 1, n = 7; AZD9773 cohort 2, n = 7; placebo, n = 6), and all completed the study. Most treatment-emergent adverse events (TEAEs) were mild or moderate and none led to discontinuation. The most common TEAEs in the AZD9773 cohorts were pleural effusion (64.3%) and peripheral edema (28.6%). Pharmacokinetic data demonstrated an approximately proportional increase in concentration with increasing dose. Treatment with AZD9773 led to a decrease in TNF-alpha concentrations, which was more discernible in the AZD9773 cohort 2; TNF-alpha concentrations generally decreased with time in patients receiving placebo. A similar pattern of response was observed with interleukin-6 (IL-6) and IL-8. AZD9773 was generally well tolerated with dose-proportional pharmacokinetics in Japanese patients with severe sepsis/septic shock. PMID- 23681366 TI - [Consequences of pneumonectomy in the early and late phases]. AB - Pneumonectomy can represent the appropriate surgical treatment option in advanced or centrally localized non-small cell lung cancer (NSCLC). A satisfactory oncologic tumor surgery can be reached in these cases although pneumonectomy is associated with a significantly higher mortality and morbidity than less extensive resection of the lung parenchyma.The aim of this article is a systematic review and the presentation of possible postoperative consequences of pneumonectomy in the early and late phases, which depend not only on the underlying disease but are also primarily affected by the state and function of the remaining contralateral lung parenchyma. Cardiopulmonary complications, especially pneumonia, pulmonary embolism, cardiac arrhythmia or myocardial infarction lead to increased 30-day mortality in the early postoperative period. Moreover, advanced ages over 70 years can be identified as a significant risk factor for poor quality of life after pneumonectomy. PMID- 23681367 TI - [No advantage for routine drainage after pancreatic resection]. PMID- 23681368 TI - [Laparoscopic vs open rectal carcinoma surgery: short-term results of the COLOR II trial]. PMID- 23681369 TI - [Hand-sewn vs mechanical esophagogastric anastomosis after esophagus resection]. PMID- 23681370 TI - Risk of subsequent primary tumor development in melanoma patients. AB - Incidence of subsequent malignant tumor development in 740 patients with primary cutaneous melanoma verified between 2006 and 2010 at the Semmelweis University was studied retrospectively and was compared to data of sex and age matched Hungarian population. The follow-up period was 1499 person-years for the whole group from the diagnosis of index melanoma with an average of 2 years. Standardized incidence rate (SIR) was established as the ratio of observed and expected values. The risk of all subsequent malignancies was 15- and 10-fold higher in males (SIR: 15.42) and in females (SIR: 10.55) with melanoma, than in the general population. The increased cancer risk resulted mainly from the significantly higher skin tumor development: SIR values were 160.39 and 92.64 for additional invasive melanoma and 342.28 and 77.04 for subsequent in situ melanoma in males and females, respectively. Non-melanoma skin cancers also notably contributed to the higher risk, the SIR was elevated in both genders to the same extent (males: 17.12, females: 17.55). The risk was also significantly higher for extracutaneous tumor development like chronic lymphocytic leukemia, colon and kidney cancer (both genders), non-Hodgkin's lymphoma, cervical cancer (females), and bladder carcinoma (males). These data underline the importance of patient education and the necessity of frequent medical follow up, including a close-up dermatological screening of melanoma survivors for further malignancies. PMID- 23681372 TI - The second year of the Join Action Group in the administration of the National Network ABEn. PMID- 23681371 TI - Twenty-four hour efficacy with preservative free tafluprost compared with latanoprost in patients with primary open angle glaucoma or ocular hypertension. AB - AIM: To compare 24 h intraocular pressure (IOP) control obtained with preservative free (PF) tafluprost 0.0015% versus branded preservative containing latanoprost 0.005% administered as first choice monotherapy in patients with primary open angle glaucoma (POAG) or ocular hypertension (OHT). METHODS: This prospective, observer-masked, crossover study included consecutive newly diagnosed patients with POAG or OHT, and baseline IOP between 24 and 33 mm Hg. Qualifying patients underwent baseline untreated 24 h IOP monitoring in habitual positions, with Goldmann tonometry at times 10:00, 14:00, 18:00 and 22:00, and Perkins supine tonometry at times 02:00 and 06:00. They were then randomised to either latanoprost or tafluprost, administered in the evening, for 3 months and then switched to the opposite therapy for another 3 months. 24 h monitoring was repeated at the end of each treatment period. RESULTS: 38 patients completed the study. Mean untreated 24 h IOP (24.9 mm Hg) was significantly reduced with both prostaglandins (p<0.001). Tafluprost demonstrated similar mean 24 h efficacy compared with latanoprost (17.8 vs 17.7 mm Hg; p=0.417). Latanoprost demonstrated significantly better 24 h trough IOP (15.9 vs 16.3 mm Hg; p=0.041) whereas tafluprost provided significantly lower 24 h IOP fluctuation (3.2 vs 3.8 mm Hg; p=0.008). No significant difference existed between the two prostaglandins for any adverse event. CONCLUSIONS: PF tafluprost achieved similar 24 h IOP reduction to branded latanoprost. The current study highlights the importance of complete assessment of efficacy over 24 h. CLINICAL TRIALS REGISTRATION: NCT01162603. PMID- 23681373 TI - [Quality of working life and burnout among nursing staff in Intensive Care Units]. AB - This descriptive-correlational and cross-sectional study aimed to evaluate the quality of working life (QWL) and the presence of burnout among nursing professionals working at Intensive Care Units. The sample was composed of 53 nursing professionals from a university hospital located in the city of Londrina PR, Brazil. Three instruments were used for data collection: socio-demographic and professional characterization, Visual Analogue Scale for QWL and Maslach Burnout Inventory. Data was collected from April to August, 2009. Among the participants, most were auxiliary nurses (52.8%), women (66.0%) and married (67.9%). The average age was of 42.4 years. Regarding assessment of QWL, the average score obtained for the total sample was 71.1 (SD=15.5), showing that workers were satisfied with their QWL. The average for Emotional Exhaustion, Depersonalization and Personal Accomplishment dimensions was 11.4 (SD=7.7), 4.6 (SD=4.1) and 25.0 (SD=5.9), respectively. The QWL for the total sample showed significant association only with Emotional Exhaustion (p=0.000). PMID- 23681374 TI - [Factorial analysis of correspondence of the social representations about nurse nocturnal work]. AB - The study aimed to apprehend the Social Representations of nurses on nocturnal work. It was based on the Theory of Social Representations with qualitative and quantitative approaches. The free evocations of 25 nurses in a public hospital in Salvador-Bahia were collected, that underwent the Factorial Analysis of Correspondence (FAC). The FAC revealed on the opposition game demonstrated, in Factor 1, opposition between shifts service and, in Factor 2, age x length of service. Seized on the semantic universe of nurses the nocturnal work is a Responsibility Work, Hard Work, Initiative Work and Financial Need. The nurses refer to the nocturnal work through representations that give normative character, prescribing attitudes and behaviors socially constructed and accepted as from the category itself, emphasizing the historical development of the profession. Those results indicate the need for strategies that contribute to the development of policies for managing people, considering the specificity, subjectivity and complexity of nocturnal work. PMID- 23681375 TI - [Conceptions of nursing staff about the exposure to physical and chemical risks in hospital environment]. AB - This study aimed to identify how the nursing team realizes the chemical and physical risks to which it is exposed in the hospital environment. This is a descriptive study, based on an exploratory field research, of quantitative source. Data were collected through a questionnaire administered to 33 professional nursing staff of a general hospital in the northwestern region of the state of Rio Grande do Sul, in the first half of 2011 and were analyzed using descriptive statistics. The workers noticed chemical and physical risks they are exposed and reported to recognize them, however, after the analysis of the responses, we identified knowledge deficit about the scientific conception of physical risk. The continuing health education can be a strategy to update workers on occupational risks. PMID- 23681376 TI - [Embracement in an emergency service: users' perception]. AB - The objective was to understand how users of an emergency service see the nursing action in the user embracement. Interviews were carried out with 382 service users from October 2008 to March 2009. We randomly approached subjects that were assessed in the embracement and they directed to the emergency ward. It was verified that even though most users (34.5%) reported having being assisted by the nursing team, few reported having been guided by some professional of the embracement team (49.2%). The major difficulties experienced by users referred to the lack of information on care and respect in the assistance. We emphasize the importance of more nursing activities in user embracement, understanding it as an activity not restricted to a service entrance. PMID- 23681377 TI - [Communication between users and health workers in Family Health committees]. AB - Communication problems in social network forums related to health are currently of interest. This study analyzed the communication between users and health workers in the board of Family Health. This is a qualitative study, in which the Habermas' Theory of Communicative Action was the theoretical framework used. Data collected revealed two intertwined dimensions: estrangements and approximations between users and health workers. In relation to estrangements, asymmetrical relationships are highlighted, characterized by coercion and manipulation on the part of the health workers, which are practices that harm the participation of users. On the other hand, moments of interaction and fights for rights addressed during approximations between users and health workers are also present. Finally, we argue that communication in the committees of Family Health present potentialities and limitations and should be discussed, especially through permanent health education. PMID- 23681378 TI - [Influence of communication in the hospital accreditation process]. AB - The research objective was to examine the perspective of professionals, the major communication barriers experienced during the Accreditation process in a medium sized private hospital in Belo Horizonte. This is a qualitative study involving 34 health professionals from different categories. The survey results showed that the shortage of information, lack of objectivity, integrity and explicitness in the transfer of knowledge favors the rupture of the provision of quality services. The organizational communication is an effective tool to support major changes in companies, as it is the scope of hospital accreditation. Articulating the change in a concise manner, with focus on the communication, can be achieved the quality standard. PMID- 23681379 TI - [Socio-demographic profile and lifestyle of workers of a metallurgical industry]. AB - This is a cross-sectional study, carried out in a metallurgical industry in the state of Sao Paulo, Brazil, aiming to identify the demographic profile, health aspects such as body mass index, hours of sleep, smoking, alcohol consumption and lifestyle of the workers. We interviewed 182 workers who answered a questionnaire with socio-demographic, lifestyle and health. The majority was male (75.8%), with a mean age of 33.8 years, did leisure activities (88.5%) and did overtime (72.5%). Physical activity was referred by 55% of the workers, 17.6% smoked and 59.3% reported drinking alcohol. The investigation of health and work aspects is important in order to implement prevention and protection measures related to work and the personal life of each worker. PMID- 23681380 TI - [Worker with physical disability: weaknesses and disorders self referred]. AB - This study aimed to investigate weaknesses and disorders experienced by workers with physical disabilities in their work environment. It is a descriptive case study, with qualitative approach. Data were collected from eight workers with physical disabilities and analyzed using thematic analysis. Most of the subjects surveyed reported having encountered difficulties in finding employment and mentioned the prejudice and obstacles to accessibility. Most of them do not identify risks for disease in the workplace. People with disabilities should have knowledge about their rights and about the occupational hazards they are exposed, in order to facilitate means for consolidating a society increasingly inclusive and to promote healthy ambience. Health professionals should make a profound reflection on the subject, so that can collaborate for the healthy inclusion of people with disabilities in their jobs. PMID- 23681382 TI - [Accountability of the other: discourses of nurses of the Family Health Strategy on the occurrence of dengue]. AB - The aim of this investigation was to know, from the discourse of Family Health Strategy nurses, what are the behaviors of the population in relation to dengue, to improve communication between professionals and the population. A qualitative study was conducted with nurses in the Family Health Strategy of six selected cities, and the data were analyzed by the technique of the Collective Subject Discourse. The results showed four central ideas about the population's behavior, to who nurses attribute important part of the responsibility for the occurrence of dengue. The conclusion is that the discourse of nurses is very close to common sense, generalizing inadequate behaviors. Thus, it is necessary to implement specific actions to change behaviors and keep them in the long term. PMID- 23681381 TI - [Occupational risks of a shoe industry from the workers' perspective]. AB - This is a qualitative and descriptive study, which aimed to identify the occupational risks of a shoe industry, as well as the preventive measures taken against those risks, from the workers' perspective. The sample consisted of fifteen workers. Data were collected through semi-structured interviews and analyzed according to content analysis. The ethical aspects were respected and the research was approved by the Committee of Ethics in Research of the Northwest Regional University of Rio Grande do Sul. The results showed that the workers are aware of the risks of their work process, made use of safety measures for personal protection, and the company offers safety devices, informing and performing periodical visits to the sectors, aiming to develop educational actions. PMID- 23681383 TI - Quality of life of primary caregivers of spinal cord injury survivors. AB - The aim of this study was to analyze quality of life of caregivers who are relatives of patients with spine cord injury (SCI). Fourteen women (seven caregivers and seven controls) were evaluated by the Medical Outcomes Study 36 - Item Short-Form Health Survey (SF-36) and the Caregiver Burden Scale (CBS) Questionnaires. The data from both questionnaires were compared using the Mann Whitney U testing procedure for differences between caregivers and controls (p<0.05). The results from SF-36 were not statistically significant between groups, however, for the CBS data, there were significant differences between groups (p>0.05), characterized by the percentage difference of 62%, 66.7%, 55%, 50%, 57% and 63% for tension, isolation, disappointment, emotional involvement, environment and overall score, respectively. The CBS questionnaire was more adequate for verifying quality of life of caregivers of SCI patients, and caregiving may have a negative impact on their quality of life. PMID- 23681384 TI - [Alcohol and alcoholism: attitudes of nursing students]. AB - This is a descriptive exploratory study that aimed to verify nursing students' attitudes facing to the alcoholic drinks, alcoholism and alcoholics, according to their position in face of an attitudes scale items. For data collection, it was used the Scale of Attitudes to alcohol, alcoholism and alcoholic, applied to 144 nursing students. The results showed a tendency to negative attitudes of these students in face of alcoholism, alcoholic person and alcoholic drinks, since most participants were placed in category indifferent or disagree with the positive items, agreeing with negative scale items. We conclude that this trend of negative attitudes is connected to insufficient attention given to the subject during the nurses' education, being verified the need for greater importance to be given to this problem. PMID- 23681385 TI - [Awkward bodies, but not forgotten: representations of women and men about their wounded bodies]. AB - In this qualitative study, which aimed to capture and analyze the representations of the body injured, it were collected, through in-depth interviews, the discourses of eighteen adults, with chronic wounds, users of an outpatient service of a public hospital in the city of Salvador-BA, that cares of wounded individuals. From the analysis of the statements, through Thematic Content Analysis, emerged the following categories, related to the wounded body: It is a strange that promotes suffering; It is constantly watched; It is rejected; It is a prisoner; It is vulnerable to violence; It requires special care, and It is a body in grief. Such representations are anchored in negative images and suffering, and reveal that, very different from the idealized body, the wounded body promotes mixed feelings and self-deprecating. The results showed that people with chronic wounds consider their own bodies as awkward; they experience negative feelings about their image, and mobilize alternatives for self-care and personal presentation, distinct from those activated before chronic state. PMID- 23681386 TI - [HIV seropositive women and their partners facing the decision of a pregnancy]. AB - The purpose of this qualitative, descriptive exploratory study is to investigate the reasons why HIV seropositive women and their partners make the decision of becoming pregnant despite the risk of vertical transmission, contamination or reinfection of the partner. The subjects of this study were six pregnant women. Data collection was done through a semi-structured questionnaire which was organized in the NVIVO 2.0 software and interpreted through theme-based content analysis. Through this analysis three themes emerged: Pregnancy planning; Knowledge of HIV/AIDS transmission and treatment; Living in the context of HIV/AIDS. The relevance of this study resides on the fact that the desire of the couple in becoming parents remains, despite of the awareness regarding the risks of vertical transmission and contamination. PMID- 23681387 TI - [Adolescence and sexuality: sexual scripts from the social representations]. AB - This study aimed to identify the social representations of adolescents about sexuality, from their personal experiences. The research, of a qualitative and representational nature, was carried out with thirteen teenagers in a unit of education for young and adults. It has, as instrument for data collection, a semi structured interview and focus group meetings. It was observed the coexistence of questions regarding sexuality and its relation to the sexual act itself; absence of dialogue between parents and children about this theme; and incipient school approach, with limitations of the contents about condom use. In this study, the social representations are anchored in sexuality as sexual act, objectified through social and sexual scripts, which gives teens a practical knowledge about themselves. PMID- 23681388 TI - [Mothering the surgical newborn: foundations for nursing care]. AB - The study aimed to understand the phenomenon of mothering in the presence of a neonatal surgery. This is a qualitative study, applying the life story method, engaging eighteen women-mothers of newborn undergoing surgery. The data, collected between July and August 2009, pointed to the emergence of two units of meaning: Separation, removal and rejection in the face of neonatal surgery and Experiencing a 'different' way of mothering'. Mothering in the presence of a neonatal surgery is a time of transition and adaptation against the unexpected, and what is normal and normative. Occurs in different ways, and may go through phases of rejection and separation and has focused on surgery and procedures performed. The construction of models to support women and family is essential for them to cope and adapt to the experience of neonatal surgery. PMID- 23681389 TI - [Social interactions of preschool children with Down syndrome during extracurricular activities]. AB - The aim of this research was to identify the process of social interaction of children with Down Syndrome (DS) during extracurricular activities in the regular early childhood education in Ribeirao Preto-SP, Brazil. Six children aged 3-6 years participated in this study. There were two recordings of each child in situations of social interaction during extracurricular activities, and analyzed by 15 behaviors, divided into two categories of social skills: interpersonal and self-expression. The results demonstrate that, in the interpersonal skill category, the higher occurrence was the behavior "occurs interaction with other children". In the self-expression skills category, only the behaviors "smiles" and "imitates other children" have significant occurrence. The behaviors more frequently identified in this study permit to understand that the school environment is a facilitator for the interaction of child with DS with the typical developmental children, allowing him/her to develop the expected social skills. PMID- 23681390 TI - [National Policy of Humanization and education of health care professionals: integrative review]. AB - The National Policy of Humanization aims at innovations in health production, management and care with emphasis on permanent education for workers in the Unified Public Health System and training of university students in the health care field. This study aimed to know, through an integrative review of the literature, the scientific production about the National Policy of Humanization and education of health care professionals, from 2002 to 2010. Ten articles were analyzed in thematic strand through three axes: humanization and users caring, humanization and the work process, humanization and training. The articles point to the need to overcome the biological conception, valuing cultural aspects of users. The work process is marked by the devaluation of workers and by users deprived of their rights. The training of health professionals is grounded in health services where the prevailing standards are practices that hinder innovative attitudes. PMID- 23681391 TI - [Elderly maltreatment: integrative review of the literature]. AB - The study aimed to identify, through an integrative literature review, scientific knowledge, produced between 2005 and 2009 about the mistreatment of the elderly. It was selected sixteen studies in the data banks LILACS, SciELO and BDENF. Of the sixteen studies, 56.25% comprised original articles. The journal that published the most was the Public Health Journal (25%), being the majority of the studies from the Southeast (56.25%). The survey revealed that the physical violence was prevalent among the elderly; the home was the environment where aggression occurs more frequently; and family members were the main aggressors. Among the elderly attacked, it was observed that women are the victims most affected. These findings raise the development of other researches that might clarify the multiple dimensions of violence against the elderly. PMID- 23681392 TI - [Problematization of teamwork in nursing: experience report]. AB - This is a report of experience in relation to teamwork, from the observation of the reality of clinical clerkship in nursing. It was held group dynamics with the nursing staff of the surgical clinic of a public hospital in Sao Paulo, with participation by eight nursing assistants and was used as a theoretical basis, the methodology of Curriculum, aimed at understanding reality it to intervene and transform it. Deficiency was observed in these participants self-criticism, as pointed out the problem in terms of teamwork always due to lack of cooperation of other colleagues, rather than the attitudes. This strategy has contributed significantly to the reflection of behaviors, attitudes, values and beliefs essential to nursing education. PMID- 23681393 TI - Introduction to statistical modelling 2: categorical variables and interactions in linear regression. AB - In the first article in this series we explored the use of linear regression to predict an outcome variable from a number of predictive factors. It assumed that the predictive factors were measured on an interval scale. However, this article shows how categorical variables can also be included in a linear regression model, enabling predictions to be made separately for different groups and allowing for testing the hypothesis that the outcome differs between groups. The use of interaction terms to measure whether the effect of a particular predictor variable differs between groups is also explained. An alternative approach to testing the difference between groups of the effect of a given predictor, which consists of measuring the effect in each group separately and seeing whether the statistical significance differs between the groups, is shown to be misleading. PMID- 23681395 TI - Successful desensitization to low-dose methotrexate. PMID- 23681394 TI - Persistent antiphospholipid antibodies do not contribute to adverse pregnancy outcomes. AB - OBJECTIVE: To determine whether women with persistent aPL (>12 weeks apart on at least two separate occasions) without a history of thrombosis or adverse pregnancy outcome had the same adverse pregnancy outcomes as those with obstetric APS or unmatched controls. METHODS: This was a case-control study between 2005 and 2011 where we identified 73 women with persistent aPL and coincidentally the same number with obstetric APS. Unmatched controls were identified from low-risk clinics (ratio 1:4). Women with multiple pregnancies, fetal anomalies, SLE, thrombotic APS and other thrombophilias were excluded. RESULTS: Cases and controls were demographically similar, with the exception of younger controls with fewer medical comorbidities. aPL profiles were similar between aPL and APS. In women with aPL, risk of APS-type complications (odds ratio 1.3; 95% CI 0.6, 2.9) and birthweight distribution (median birthweight on a customized centile was 50.8, interquartile range 26.4-68.9; P < 0.05) were similar to controls. These findings persisted even after adjustment for maternal age and medical comorbidities. CONCLUSION: Women with persistent aPL on aspirin had pregnancy outcomes that were similar to controls. These data suggest that in the absence of other risk factors, women with aPL do not need intense antenatal surveillance or modified management in pregnancy. PMID- 23681397 TI - Easy probability estimation of the diagnosis of early axial spondyloarthritis by summing up scores. AB - OBJECTIVES: Several sets of criteria for the diagnosis of axial SpA (including non-radiographic axial spondyloarthritis) have been proposed in the literature in which scores were attributed to relevant findings and the diagnosis requests a minimal sum of these scores. To quantitatively estimate the probability of axial SpA, multiplying the likelihood ratios of all relevant findings was proposed by Rudwaleit et al. in 2004. The objective of our proposal is to combine the advantages of both, i.e. to estimate the probability by summing up scores instead of multiplying likelihood ratios. METHODS: An easy way to estimate the probability of axial spondyloarthritis is to use the logarithms of the likelihood ratios as scores attributed to relevant findings and to use the sum of these scores for the probability estimation. RESULTS: A list of whole-numbered scores for relevant findings is presented, and also threshold sum values necessary for a definite and for a probable diagnosis of axial SpA as well as a threshold below which the diagnosis of axial spondyloarthritis can be excluded. In a diagram, the probability of axial spondyloarthritis is given for sum values between these thresholds. CONCLUSION: By the method proposed, the advantages of both, the easy summing up of scores and the quantitative calculation of the diagnosis probability, are combined. Our method also makes it easier to estimate which additional tests are necessary to come to a definite diagnosis. PMID- 23681398 TI - Glycosylation status of serum in inflammatory arthritis in response to anti-TNF treatment. AB - OBJECTIVE: Glycosylation is the most common post-translational modification and is altered in disease. The typical glycosylation change in patients with inflammatory arthritis (IA) is a decrease in galactosylation levels on IgG. The aim of this study is to evaluate the effect of anti-TNF therapy on whole serum glycosylation from IA patients and determine whether these alterations in the glycome change upon treatment of the disease. METHODS: Serum samples were collected from 54 IA patients before treatment and at 1 and 12 months after commencing anti-TNF therapy. N-linked glycans from whole serum samples were analysed using a high-throughput hydrophilic interaction liquid chromatography based method. RESULTS: Glycosylation on the serum proteins of IA patients changed significantly with anti-TNF treatment. We observed an increase in galactosylated glycans from IgG, also an increase in core-fucosylated biantennary galactosylated glycans and a decrease in sialylated triantennary glycans with and without outer arm fucose. This increase in galactosylated IgG glycans suggests a reversing of the N-glycome towards normal healthy profiles. These changes are strongly correlated with decreasing CRP, suggesting a link between glycosylation changes and decreases in inflammatory processes. CONCLUSION: Glycosylation changes in the serum of IA patients on anti-TNF therapy are strongly associated with a decrease in inflammatory processes and reflect the effect of anti-TNF on the immune system. PMID- 23681396 TI - Predictors of self-reported health-related quality of life in systemic lupus erythematosus. AB - OBJECTIVE: The Medical Outcomes Short Form-36 Survey (SF-36) has been widely used as a measure of health-related quality of life (HRQOL) in different populations. SLE patients have consistently reported lower scores compared with the general population. The objective of our study was to identify predictors of HRQOL using SF-36 among patients with SLE enrolled in a 2-year randomized controlled trial (RCT). METHODS: We analysed 200 SLE patients enrolled in the Lupus Atherosclerosis Prevention Study (LAPS), an RCT of atorvastatin vs placebo, who completed SF-36 at qualifying, 12- and 24-month (final) visits. RESULTS: At baseline, mean SF-36 domain scores were lower than those of age- and gender matched population norms. There was no statistical difference reported between Physical Component Summary (PCS), Mental Component Summary and eight domain scores in the atorvastatin vs placebo group at 2 years. In multiple regression analyses, African American patients reported significantly lower scores in Physical Functioning compared with Caucasians. The presence of FM was significantly associated with lower scores in physical functioning, role physical, bodily pain, general health, vitality, social functioning and lower overall mean PCS scores. The Physician's Global Assessment of disease activity was associated with multiple SF-36 domains in univariate analysis. CONCLUSION: This longitudinal study confirmed lower scores reported across all SF-36 domains. No one explanatory variable was independently associated with all domain scores. FM was independently associated with poorer HRQOL in most domains, underscoring the need for effective treatments for FM in SLE. PMID- 23681400 TI - Severity and management of drug-drug interactions in acute geriatric patients. AB - BACKGROUND: Previous studies have investigated the prevalence of drug-drug interactions (DDIs) among the elderly in different care settings, but data describing the frequency and management of DDIs among acute geriatric patients appear to be absent. OBJECTIVE: The aim of this study was to investigate the severity and interdisciplinary management of DDIs in patients admitted to an acute geriatric ward. METHODS: The study was conducted at Oslo University Hospital, Norway, over a period of 19 weeks in 2010/11. On admission and daily during the hospital stay, prescribed medications were reviewed by pharmacists to identify DDIs with the aid of web-based databases. DDIs defined to be of potential clinical relevance, i.e., those classified as "major" (generally avoid) or "moderate" (precautions recommended), were following assessments by pharmacists presented at interdisciplinary meetings with geriatricians and nurses, and discussed in relation to the possible implementation of monitoring actions or changes in prescribing. The odds for prescribing changes were compared in relation to DDI type ("pharmacokinetic" vs. "pharmacodynamic") and severity ("major" vs. "moderate"). The project group retrospectively assessed the possible causal relationships between hospitalizations and DDIs. RESULTS: The pharmacists identified 245 DDIs of major (n = 13) or moderate (n = 232) severity in 80 (63.5 %) of the 126 patients included on admission and/or during hospitalization. In 94 of 162 cases where the pharmacists alerted the geriatricians (58.0 %), prescribing changes or monitoring actions were implemented. Prescribing changes (n = 38) were performed significantly more often for major than for moderate DDIs [odds ratio (OR) 3.8; 95 % confidence interval (CI) 1.2-12.2, p = 0.03], and significantly more often for pharmacokinetic than for pharmacodynamic DDIs (OR 4.9; 95 % CI 2.2-10.9, p < 0.01). For 28 of 126 patients (22.2 %), a causal relationship between hospitalizations and DDIs was assessed as "possible". CONCLUSIONS: The present study shows that acute geriatric patients are frequently exposed to DDIs for which active management is recommended in order to avoid unfavorable clinical outcomes. The integration of pharmacists into interdisciplinary teams could prevent potentially severe DDIs in the elderly. PMID- 23681399 TI - Imatinib in very elderly patients with chronic myeloid leukemia in chronic phase: a retrospective study. AB - BACKGROUND: A large number of chronic myeloid leukemia (CML) patients are treated with imatinib mesylate outside of clinical trials, which may not be representative of common clinical practice. The age of CML patients enrolled within controlled clinical studies is lower with respect to patients included in population-based registries. PATIENTS AND METHODS: To describe the safety and tolerability of imatinib in very elderly CML patients in chronic phase, 211 chronic-phase CML patients aged >75 years were retrospectively analyzed using data collected from 31 institutions in Italy. RESULTS: The median age at imatinib start was 78.6 years [interquartile range (IR) 76.3-81.4], median time from diagnosis to imatinib start was 1.2 months (IR 0.5-3.7). The starting dose of imatinib was 400 mg/day in 144 patients (68.2 %), >400 mg/day in 4 patients (2.0 %), and <400 mg/day in 63 patients (29.8 %); overall, 94 patients (44.5 %) needed a dose reduction and 27 (12.7 %) discontinued imatinib for toxicity. Grade 3-4 hematologic and extrahematologic toxicities were observed in 40 (18.9 %) and 45 (21.3 %) patients, respectively. After a median observation of 29.8 months (IR 13.0-55.6), 203/211 patients had at least 6 months of observation on imatinib or discontinued before and were evaluable for response and outcome; of them, 183 patients (90.2 %) achieved a complete hematologic response (CHR). Among these 183 patients in CHR, 14 refused any other karyotypic or molecular evaluation, 24 achieved CHR only, and 145 (71.4 %) achieved a cytogenetic response (CyR) of any grade, which was complete (CCyR) in 129 (63.5 %). Among the 129 patients with CCyR, 95 (46.7 %) achieved a major molecular response (MMolR). By multivariate regression analysis, late chronic phase (p = 0.001) and grade 3-4 extrahematologic toxicity (p = 0.007) maintained a negative independent prognostic impact for CCyR, while late chronic phase (p = 0.026), grade 3-4 extrahematologic toxicity (p = 0.007), and lower initial dose of imatinib (p = 0.044) maintained a negative independent prognostic impact for MMolR. The 2-year and 4-year overall survival were 92.6 % (95 % CI 88.7-96.5) and 78.0 % (95 % CI 71.2-84.8), respectively. CONCLUSIONS: Results from this large cohort of patients show that no upper age limit should be applied for the administration of imatinib to patients with chronic-phase CML; the very elderly, including those with concomitant severe diseases, should be offered this treatment. The role of a reduced starting dose of imatinib warrants further studies. PMID- 23681401 TI - Neuropsychiatric symptoms in patients with dementias associated with cortical Lewy bodies: pathophysiology, clinical features, and pharmacological management. AB - Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are synucleinopathies that lead to neurodegeneration and dementia. Although they result in symptoms common to Alzheimer's disease, they are associated with early emergence of parkinsonism and high frequency of neuropsychiatric symptoms, most commonly hallucinations and delusions. This review summarizes the current understanding of the underlying biology of neuropsychiatric symptoms in DLB and PDD and the evidence base for treatment to address them. Disruption to cholinergic and serotonergic neurotransmission and synapse activity are highlighted as primary pathological factors in neuropsychiatric symptoms, particularly loss of key neurotransmitter functions, alterations to neuronal receptors in the serotonergic pathway, and regionally specific structural changes that are linked to specific symptoms. Review of options for pharmacological treatment of neuropsychiatric symptoms suggests that the best evidence for the value of treatment is for cholinesterase inhibitors, with an indication that people with visual hallucinations are particularly likely to benefit. Evidence for the benefits of antipsychotics other than clozapine is limited, and there are serious safety concerns about the use of antipsychotics in these patients. Evidence to support other pharmacological interventions is very preliminary. Nonpharmacological approaches based on person-centered care and cholinesterase inhibitors should be considered as the first-line treatment for neuropsychiatric symptoms except in extreme cases. PMID- 23681402 TI - Evolution of sites of recurrence after early breast cancer over the last 20 years: implications for patient care and future research. AB - Improvements in adjuvant therapy have led to a sustained fall in recurrences after early breast cancer. The differential reduction in local and systemic recurrences is poorly understood. This study aimed to explore changes in the distribution of loco-regional and distant recurrences in clinical trials reported over the last 20 years. We also aimed to determine the relative impact of adjuvant chemotherapy and endocrine therapy. MEDLINE search for adjuvant, phase III randomized breast cancer clinical studies between January 1990 and March 2011 was performed. Neoadjuvant, single agent biologics and studies that did not report the proportion of loco-regional and distant recurrences were excluded. The change in the frequency of recurrences was assessed as the nonparametric correlation between the number of loco-regional recurrences as a proportion of all recurrences and time. Studies were weighted by sample size. The differential effect of chemotherapy and endocrine therapy was also assessed. Fifty-three randomized clinical trials with a total of 86,598 patients were included in the analysis. Between 1990 and 2011, the proportion of loco-regional recurrences has decreased from approximately 30 to 15 % (Spearman's rho = -0.40, p < 0.001). There was no interaction between type of surgery (mastectomy vs. lumpectomy), administration of adjuvant radiation therapy and menopausal status and the correlation of loco-regional recurrences and time. Chemotherapy regimen showed a larger negative correlation compared with endocrine therapy ( rho = 0.49 vs. rho = 0.24). Advances in treatment of early breast cancer have differentially reduced the proportion of loco-regional recurrences compared with distant recurrences. In recent trials, loco-regional recurrences account for less than 10-15 % of all recurrences. These falling event rates may affect patient care, especially when deciding on treatments influencing loco-regional control. This change may also impact on the design of clinical trials assessing loco-regional therapy such as surgery and/or local radiation therapy. PMID- 23681404 TI - Di 2-ethylhexylphtalate in the aquatic and terrestrial environment: a critical review. AB - Phthalates are being increasingly used as softeners-plasticizers to improve the plasticity and the flexibility of materials. Amongst the different plasticizers used, more attention is paid to di (2-ethylhexylphtalate) (DEHP), one of the most representative compounds as it exhibits predominant effects on environment and human health. Meanwhile, several questions related to its sources; toxicity, distribution and fate still remain unanswered. Most of the evidence until date suggests that DEHP is an omnipresent compound found in different ecological compartments and its higher hydrophobicity and low volatility have resulted in significant adsorption to solids matrix. In fact, there are important issues to be addressed with regard to the toxicity of this compound in both animals and humans, its behavior in different ecological systems, and the transformation products generated during different biological or advanced chemical treatments. This article presents detailed review of existing treatment schemes, research gaps and future trends related to DEHP. PMID- 23681403 TI - Cognitive function in older women with breast cancer treated with standard chemotherapy and capecitabine on Cancer and Leukemia Group B 49907. AB - Cognitive changes in older women receiving chemotherapy are poorly understood. We examined self-reported cognitive function for older women who received adjuvant chemotherapy on Cancer and Leukemia Group B (CALGB) 49907. CALGB 49907 randomized 633 women aged >=65 with stage I-III breast cancer to standard adjuvant chemotherapy (cyclophosphamide-methotrexate-5-fluorouracil or doxorubicin cyclophosphamide) versus capecitabine. We examined self-reported cognitive function in 297 women (CALGB 361002) who enrolled on the quality of life substudy and had no gross impairment on cognitive screening. Women were evaluated using an 18-item instrument at six time points (baseline through 24 months). At each time point for each patient, we calculated a cognitive function score (CFS) defined as the mean response of items 1-18 and defined impairment as a score >1.5 standard deviations above the overall average baseline score. Differences in scores by patient characteristics were evaluated using a Kruskal-Wallis test. A linear mixed-effects model was used to assess CFSs by treatment over time. Among 297 women, the median age was 71.5 (range 65-85) and 73 % had performance status of 0. Baseline depression and fatigue were reported in 6 and 14 % of patients, respectively. The average CFS at baseline was 2.08 (corresponding to "normal ability"), and baseline cognitive function did not differ by treatment regimen (p = 0.350). Over 24 months, women reported minimal changes at each time point and insignificant differences by treatment arm were observed. In a healthy group of older women, chemotherapy was not associated with longitudinal changes in self reported cognitive function. PMID- 23681405 TI - Impacts of informal trails on vegetation and soils in the highest protected area in the Southern Hemisphere. AB - There is limited recreation ecology research in South America, especially studies looking at informal trails. Impacts of informal trails formed by hikers and pack animals on vegetation and soils were assessed for the highest protected area in the Southern Hemisphere, Aconcagua Provincial Park. The number of braided trails, their width and depth were surveyed at 30 sites along the main access route to Mt Aconcagua (6962 m a.s.l.). Species composition, richness and cover were also measured on control and trail transects. A total of 3.3 ha of alpine meadows and 13.4 ha of alpine steppe were disturbed by trails. Trails through meadows resulted in greater soil loss, more exposed soil and rock and less vegetation than trails through steppe vegetation. Trampling also affected the composition of meadow and steppe vegetation with declines in sedges, herbs, grasses and shrubs on trails. These results highlight how visitor use can result in substantial cumulative damage to areas of high conservation value in the Andes. With unregulated use of trails and increasing visitation, park agencies need to limit the further spread of informal trails and improve the conservation of plant communities in Aconcagua Provincial Park and other popular parks in the region. PMID- 23681406 TI - Bilateral central retinal artery occlusion and vein occlusion complicated by severe choroidopathy in systemic lupus erythematosus. AB - Severe retinal vascular occlusions resulting in blindness is a rare occurrence in patients with systemic lupus erythematosus (SLE). Herein, we report a case of a 33-year-old female who developed combined central retinal artery occlusion, retinal vein occlusion, and choroidopathy and rapidly became completely blind in both eyes within a week. The electroretinogram revealed a severely attenuated a wave and b-wave, indicating a profound dysfunction of both choroidal and retinal circulation, respectively. The current case demonstrates objectively the functional impact of severe choroidopathy in SLE for the first time. Patients with unilateral blindness due to combined retinal/choroidal vascular obstructions should be monitored carefully to ensure adequate anticoagulant therapy in an attempt to guard the vision in the fellow eye. PMID- 23681407 TI - Accuracy in radiographic assessment of pelvic ring fracture deformity: analysis of current methods. AB - OBJECTIVES: To our knowledge, measuring pelvic ring displacement on plain radiographs has not been scientifically evaluated. This study aims to assess the validity and reliability of existing measurement systems utilizing plain radiographs. METHODS: A Sawbones model, validated as part of this study, was fractured in a controlled fashion to simulate known pelvic ring fracture patterns. Computed tomographic scans with 2- and 3-dimensional reconstructions of intact and injury models were obtained to measure the "true" displacement of anterior and posterior disrupted surfaces. The computed tomographic data set was used to create computer-reconstructed radiographs (CRR) simulating standard anteroposterior, inlet and outlet views. Currently described measurement techniques were utilized by 8 senior orthopaedic residents and 3 fellowship trained orthopaedic trauma surgeons on the computer-reconstructed radiograph of each model. These measurements were than assessed for interobserver reliability and validity. RESULTS: Average observer measurements of anterior symphysis diastasis and vertical translation had good validity and reliability with each having an average confidence interval of 4.6 mm. The observer measurements of sacroiliac (SI) joint displacement were significantly less reliable with average confidence interval of 5.8 mm. Kappa correlation calculations for whether the SI joint was displaced more than 1 cm showed an overall agreement of 0.702 and kappa coefficient of 0.404. CONCLUSIONS: Computer-reconstructed radiographic, and thus plain radiographic, assessments of deformity at the SI joint have poor reliability and accuracy. Clinicians should recognize these limitations when measuring pelvic displacement of the SI joint and cautiously interpret clinical results of treatment of SI joint injuries where displacement is measured on plain radiographs. PMID- 23681408 TI - Biomechanical analysis of trochanteric fracture fixations using a Y-shaped locking plate. AB - OBJECTIVES: Clinical evidence suggests that the use of Y-shaped locking plates with anterior and lateral locking screws provide improved primary fixation stability over the use of straight locking plates in the treatment of greater trochanter (GT) fractures. However, it remains unclear how the use of cable cerclages, in replacement or addition to the locking screws, would impact the primary fixation stability. METHODS: Nine surgical fixations were tested on a dynamic test bench through 27 sawbones experiments. These fixations on the GT and bone shaft (BS) included locking screws alone, cable cerclages alone, or 7 combinations of both. Migrations, defined as the remaining movements of the unloaded GT fragment, were measured for all 9 fixations submitted to dynamic stair climbing cycling after an experimental plan. RESULTS: Under dynamic stair climbing conditions: (1) Y-shaped locking plates fixed by locking screws alone (vs cable cerclages alone) significantly reduced GT migrations, (2) adding cable cerclages to screws provided no significant reduction of migrations, and (3) cable cerclages alone can be used on the BS but is not recommended on the GT. CONCLUSIONS: Y-shaped locking plates with anterior and lateral locking screws improved primary stability of GT fractures over fixation with cable cerclages. Cable cerclages provided acceptable primary stability when screw fixations were unachievable but on the BS only. PMID- 23681409 TI - Direct reduction technique for superomedial dome impaction in geriatric acetabular fractures. AB - The treatment of acetabular fractures in the elderly patients remains challenging. The "Gull Sign," which was recently described, was 100% predictive of failure of reduction and/or fixation. However, we believe that adequate reduction can be achieved and lead to good functional outcomes. Our technique differs from classic methods because it uses an anterior intrapelvic approach (the modified Stoppa) to obtain direct reduction of the impacted fragments. Access to the impacted superomedial dome is achieved by mobilizing the quadrilateral fragment, thus allowing direct visualization of the impacted articular surface. After reduction, definitive fixation is obtained with 3.5-mm cortical screws positioned in the subchondral bone directly over the Gull fragment. Our technique was performed in 9 patients, with a mean follow-up of 2.8 years. The quality of reduction was within 3 mm in 7 patients (78%). The overall conversion rate to total hip arthroplasty was 33%. All patients undergoing total hip arthroplasty either had initial malreduction or suffered an early loss of reduction. Other complications included 1 case of heterotopic ossification (Brooker type II) and 1 case of deep vein thrombosis. There were no infections. The average Harris Hip Score was 81. Good reduction of superior medial dome impaction can be obtained and maintained in the well-selected geriatric patient. We believe that, appropriately used, this direct reduction technique can be an important adjunct to surgeons dealing with this troublesome fracture. PMID- 23681410 TI - Long-term outcome after operative treatment of traumatic patellar dislocation in adolescents. AB - OBJECTIVES: Retrospective evaluation of the long-term outcomes after surgical treatment of traumatic patellar dislocations in adolescents and identification of possible predictive factors of poor outcomes. DESIGN: Retrospective clinical study. SETTING: University Clinic, Level I Trauma Center. PATIENTS: All 33 adolescents, with a mean age of 14.8 years, who were treated surgically after traumatic patellar dislocation between 1994 and 2006, were involved in this study. INTERVENTION: Mini-open medial reefing and arthroscopic lateral release. MAIN OUTCOME MEASUREMENTS: The clinical outcome was evaluated with the visual analogue scale, the Lysholm score, the Kujala score, and the Tegner activity level scale. On preoperative radiographs and magnetic resonance imaging scans, trochlear dysplasia and patella alta were assessed. The variables analyzed were sex, associated osteochondral injuries, the number of redislocations before surgery, and the number of redislocations after surgery. RESULTS: At the mean follow-up of 9.8 years, the mean Lysholm score was 82.6, the mean Kujala score was 84.4, the mean Tegner activity level was 4.8, and the mean visual analogue scale was 0.2. We found no significant differences in the subgroups regarding functional outcomes. Fifteen patients with patella alta and 4 patients with trochlear dysplasia were assessed radiologically. Redislocations after surgery were observed in 4 patients, 2 of them were female patients who exhibited quadriceps angles requiring tibial tubercle osteotomy to be performed after maturation. CONCLUSIONS: The techniques of mini-open medial reefing and lateral release demonstrate a good functional long-term outcome and effectively prevent recurrent instability. The major predictive factor for poor outcomes and redislocations is an inadequately addressed pathology. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 23681411 TI - Pediatric orthopaedic injuries requiring hospitalization: epidemiology and economics. AB - OBJECTIVE: This study aimed to identify the 10 most frequent pediatric orthopaedic injuries requiring hospitalization in the United States, the major causes of these injuries, and their economic burden to health care cost. METHODS: The 2006 Kids' Inpatient Database (KID) (age range, 0-20 years) was used to determine the 10 most frequent pediatric orthopaedic injuries requiring hospitalization. The injuries were identified by ICD-9-CM codes 800.0-999.9 and external cause of injury codes (E-codes). Discharges were weighted to produce national estimates according to average age at admission, hospital charges, and length of stay. RESULTS: The 2 populations accounting for the highest total hospitalization charges (USD) for pediatric orthopaedic injury were young children with femur fractures (11 years of age, 20%, $32 441 per visit) and adolescents with vertebral fractures (17 years of age, 8%, $53 992 per visit). But the most common injuries requiring hospitalization were femur (11 years of age; 20%) and humerus (8 years of age; 18%) fractures. The most costly injuries, vertebral and pelvic injuries, were largely related to motor vehicle accidents (11.7% and 14.4%, respectively). In contrast, humerus and radius fractures had a high rate of playground-related injuries (21.9% and 11.3%, respectively). None of the causes accounted for more than 25% of the total incidence for the 10 most common injuries identified in this study. CONCLUSIONS: Identification of the patients responsible for the majority of the hospitalization charges for pediatric injuries will enable institutions to better plan their budgets on the basis of the local incidence. PMID- 23681412 TI - Magnetic resonance imaging for the evaluation of ligamentous injury in the pelvis: a prospective case-controlled study. AB - OBJECTIVES: Management of external rotation pelvic ring disruptions is based on which ligaments are disrupted within the pelvis. We hypothesized that magnetic resonance imaging (MRI) can evaluate the ligaments of the pelvic ring and differentiate injured from uninjured pelves. DESIGN: Prospective cohort study. SETTING: Level I trauma center. PATIENTS: Twenty-one patients with 25 acute external rotation injuries of the hemipelvis; control group of 26 patients without pelvic ring injury. INTERVENTION: All patients underwent the same MRI protocol reviewed by 1 musculoskeletal radiologist. MAIN OUTCOME MEASURES: Integrity of 5 structures: sacrospinous, sacrotuberous, anterior sacroiliac, and posterior sacroiliac ligaments and pelvic floor musculature. RESULTS: Visualization of sacrospinous, sacrotuberous, anterior sacroiliac, and posterior sacroiliac ligaments, and pelvic floor musculature was possible for 91%, 100%, 98%, 91%, and 100%, respectively, of all studied structures. No injuries were identified in control group patients in contrast to ligament injury observed with all injured pelves (0% versus 100%; P < 0.0001). Observed relationship of ligament injury to pelvic injury type generally agreed with the Young-Burgess classification system, with the important exception that patients with anterior posterior compression type II injuries had damage to the sacrospinous ligament in only 50% of the cases. CONCLUSIONS: Ligamentous anatomy and injury about the pelvic ring appears to be easily evaluated with MRI, arguing that there may be a role for this imaging modality in managing these cases. Tearing of the sacrospinous ligament is variable among anterior-posterior compression type II injuries, arguing that the injury pattern can be subdivided into those with and without sacrospinous ligament tears. LEVEL OF EVIDENCE: Diagnostic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 23681413 TI - Transcortical screw fixation of the olecranon shows equivalent strength and improved stability compared with tension band fixation. AB - OBJECTIVES: Currently, the standard for 21-B3.1 olecranon fracture fixation is the tension band wire construct described by the AO foundation. Although this technique effectively repairs displaced olecranon fractures and osteotomies, it is associated with a high rate of secondary surgery for implant removal due to hardware "back out," prominence, and discomfort. The senior author of this study has used transcortical screw fixation for olecranon fractures and osteotomies to avoid hardware discomfort but has been unable to find literature documenting the strength of this method. Accordingly, we compared the strength and stability of transcortical screw fixation with tension band fixation of simple transverse olecranon fractures under cyclical loading. METHODS: Eighteen fourth-generation synthetic biomechanical testing ulnas underwent a transverse olecranon osteotomy and were repaired by tension banding or screw fixation. Two 4.0 mm partially threaded screws inserted across the fracture gap into the anterior cortex of the ulna achieved screw fixation. Ulnas were tested in 2 ways as follows: (1) cyclic loading that simulated pushing up from a chair; and (2) single cycle loading to failure. Fracture displacement was recorded using a transducer that was placed on the posterior surface of the ulna. RESULTS: Differences between screw fixation and tension banding in the peak displacement during cyclic loading and single cycle load to failure were not significant. Screw fixation did show significantly less "trough" displacement (resting position between cycles) during cyclic loading indicating less plastic deformation. CONCLUSIONS: In a synthetic bone model of simple transverse olecranon fractures, screw fixation provided equivalent strength and less plastic deformation as compared with tension banding. PMID- 23681415 TI - Defining the lateral and accessory views of the patella: an anatomic and radiographic study with implications for fracture treatment. AB - OBJECTIVE: The majority of orthopaedic surgeons rely on a lateral fluoroscopic image to assess reduction during patella fracture osteosynthesis. However, a comprehensive radiographic description of the lateral view of the patella has not been performed previously, and no accessory views to better visualize specific anatomic features have been developed. The purpose of this study was to provide a detailed anatomic description of all radiographic features of the true lateral of the patella, describe reproducible accessory views for assessing specific features of the patella, and demonstrate their utility in a fracture model. METHODS: Twelve cadaver knee specimens free of patellofemoral pathology were used, and imaging was performed using standard C-arm fluoroscopy. For each specimen, a true lateral radiographic projection of the patella was obtained and distinct features were noted. Next, an arthrotomy was made and steel wire was contoured and fixed to various anatomic regions of the patella so as to obliterate the radiographic densities on the true lateral projection, thus confirming their anatomic correlation. Ideal views of the lateral and medial facets themselves were determined using radiographic markers and varying amounts of internal or external rotation of the specimen. Last, a transverse osteotomy was created in each patella and the ability of the true lateral and accessory views to detect malreduction was assessed. RESULTS: The true lateral projection of the patella was obtained with the limb in neutral alignment. Constant radiographic features of the lateral view of the patella include the articular tangent, a secondary articular density of variable length, and a dorsal cortical density. The articular tangent was produced by the central ridge between the medial and lateral facets in all specimens. The secondary articular density was created by a confluence of the edge of the lateral and edge of the medial facets in 5 patellas, a confluence of the edge of the lateral facet and the intersection of the odd and medial facets in 6 patellas, and the edge of the lateral facet alone in 1 patella. The edge of the lateral facet gave a constant contribution to the appearance of the secondary articular density in all cases. A distinct accessory view of the tangent of the lateral facet could be seen with an average of 17 degrees of patella external rotation (range, 12-35 degrees), and the tangent of the medial facet with an average of 26.5 degrees of internal rotation (range, 15-45 degrees). These accessory views were better able to visualize malreduction than the single lateral projection in a fracture model in all specimens. CONCLUSIONS: Described here is a comprehensive description of the true lateral radiographic view of the patella and accessory views. These views can be used in the evaluation of minimally displaced patella fractures if a computerized tomography is not desired to better assess the true amount of displacement and when assessing intraoperative reduction during patella fracture osteosynthesis. PMID- 23681416 TI - Measurement of activities of daily living in patients with COPD: a systematic review. AB - BACKGROUND: The objectives of this systematic review were to synthesize the literature on measures of activities of daily living (ADLs) that have been used in individuals with COPD and to provide an overview of the psychometric properties of the identified measures and describe the relationship of the disease-specific instruments with other relevant outcome measures for individuals with COPD and health-care use. METHODS: Studies that included a measure of ADLs in individuals with COPD were identified using electronic and hand searches. Two investigators performed the literature search. One investigator reviewed the study title, abstract, and full text of the articles to determine study eligibility and performed the data extraction and tabulation. In cases of uncertainty, a second reviewer was consulted. RESULTS: A total of 679 articles were identified. Of those, 116 met the inclusion criteria. Twenty-seven ADLs instruments were identified, of which 11 instruments were respiratory disease specific, whereas 16 were generic. Most instruments combined instrumental ADLs (IADLs) with basic ADLs (BADLs). The majority of the instruments were self reported; only three instruments were performance based. Twenty-one studies assessed psychometric properties of 16 ADLs instruments in patients with COPD. CONCLUSIONS: Although several ADLs instruments were identified, psychometric properties have only been reported in a few. Selection of the most appropriate measure should focus on the target construct (BADLs or IADLs or both), type of test (disease-specific vs generic and self-reported vs performance-based), depth of information obtained, and psychometric properties of the instruments. Given the relevance of ADLs to the lives of patients with COPD, its assessment should be more frequently incorporated as a clinical outcome in their management. PMID- 23681417 TI - Metal nanoparticle-loaded hierarchically assembled ZnO nanoflakes for enhanced photocatalytic performance. AB - We have demonstrated an environmentally friendly and template-free aqueous synthesis of hierarchically assembled 3D ZnO nanoflakes. The ZnO nanoflakes self assembled to expose highly interconnected networks of well-defined catalytic active {0001} facets. Well dispersed Pt, Ag and Au metal nanoparticles were loaded to form hybrid ZnO nanoflakes for enhanced photocatalytic activity. The enhanced photocatalytic activity may be attributed to the synergetic effects of well-structured ZnO crystal facets, high metal nanoparticles dispersity, enhanced light absorption and charge-transfer kinetics which leads to high photocatalytic degradation. PMID- 23681418 TI - Electrogenerated polypyridyl ruthenium hydride and ligand activation for water reduction to hydrogen and acetone to iso-propanol. AB - The complex [Ru(tpy)(bpy)(S)](2+) (tpy = 2,2':6',2''-terpyridine, bpy = 2,2' bipyridine, S = solvent) is an electrocatalyst for water or proton reduction to hydrogen and for reduction of acetone to iso-propanol in CH3CN. Electrocatalysis is initiated by sequential 1e(-) reductions at the tpy and bpy ligands followed by addition of water to give a ruthenium hydride intermediate. Significant rate enhancements for hydrogen evolution are observed with added weak acids, such as H2PO4(-), for the latter, with a rate enhancement of 10(4) compared to water. The reactivity of the in situ electrogenerated hydride toward hydride transfer is promoted by ligand reduction. PMID- 23681419 TI - Fetal left and right ventricle myocardial performance index: defining normal values for the second and third trimesters--single tertiary center experience. AB - Myocardial performance index (MPI), or Tei index, has become a commonly used parameter for the noninvasive, Doppler-derived assessment of global systolic and diastolic performance of the heart in both adults and children. Normal values have been established in adults and children; however, limited data exist in fetal hearts. The aim of this study was to further elucidate normal values of fetal left (LV) and right ventricle (RV) MPI values in second- and third trimester fetuses and compare these values with other previously published data. This was a retrospective study to measure MPI in healthy fetuses. After Institutional Review Board approval, 2000 fetal echocardiography studies (FES) were acquired during a period of 4 years. Demographic parameters examined included gestational age (GA), maternal age (MA), and indication for fetal echocardiography. Fetuses with congenital heart disease, arrhythmias, or significant noncardiac fetal anomalies were excluded. The following echocardiography parameters were collected: LV ejection time (LVET), mitral valve close-to-open time (MVCO), RVET, tricuspid valve CO (TVCO), and fetal heart rate. For simplicity, LV and RV MPI values were calculated as follows: LV MPI = MVCO - LVET/LVET and RV MPI = TVCO - RVET/RVET. Four hundred twenty FES met the study criteria. LV MPI was evaluated in 230 and 190 FES in the second and third trimester, respectively. Of the 420 FES, 250 (150 in the second trimester and 100 in the third trimester) had all of the measurements required for RV MPI calculation. MA ranged between 16 and 49 years. Indications for FES included diabetes mellitus (N = 140; 33 %), suspected fetal anomalies on routine obstetrical ultrasound (N = 80; 20 %), autoimmune disorder (N = 60; 14 %), family history of CHD (N = 76; 18 %), medication exposure (N = 22; 5 %), increase nuchal thickness (N = 13; 3 %), and other indications (N = 29; 6 %). Averaged LV and RV MPI values were 0.464 +/- 0.08 and 0.466 +/- 0.09, respectively. Further analysis based on gestational period showed slightly greater LV and RV MPI values during the third compared with the second trimester, i.e., 0.48 and 0.49, respectively, with no statistically significant difference. There was no significant association of LV and RV MPI with heart rate. To our knowledge, this is the first study to establish normal values of fetal MPI based on a large fetal population from a single tertiary center. LV and RV MPI values were independent of GA and fetal heart rate. MPI is a useful parameter for the assessment of global cardiac function in the fetus and demonstrates good reproducibility with narrow interobserver and intraobserver variability. Its usefulness should be studied in fetal hearts with complex congenital anomalies. PMID- 23681420 TI - Active surveillance of sudden cardiac death in young athletes by periodic Internet searches. AB - The authors hypothesized that prospective, systematic Internet searches could identify occurrences of sudden cardiac death (SCD) in athletes and would be useful for establishing a system of active surveillance. Weekly advanced Google searches of the Internet were conducted for cases of SCD in young athletes during a 12-month period (2007-2008). Athletes ages 11-30 years who collapsed during a game, practice, or within an hour of exercise were included in the study. Individuals with known histories of cardiac issues and events occurring outside the United States were excluded. Verification of SCD was by autopsy reports and death certificates from county coroner offices and vital record agencies. Initially, 71 events were identified. Verification for the cause of death by coroner reports was possible in 45 cases, 43 (96 %) of which were confirmed to be SCDs. A total of 69 individuals 11-30 years of age (mean 17 +/- 5 years) died suddenly of cardiovascular causes while participating in 15 different organized sports and a variety of nonorganized physical activities. The most common cause of death was hypertrophic cardiomyopathy (30 %), followed by coronary artery anomalies (9 %), and myocarditis (9 %). The incidence of athlete SCD, the types of sports involved, and the cardiac causes of death in our study were comparable with those of previous reports. Readily available Internet searches have the potential to be a powerful tool for identifying occurrences of athlete SCD. An active surveillance system using Google searches followed by coroner report verification can provide important epidemiologic and clinical information. PMID- 23681421 TI - Celiac disease and autoimmunity: review and controversies. AB - Celiac disease (CD) is an autoimmune condition affecting the small intestine, triggered by the ingestion of gluten, the protein fraction of wheat, barley, and rye. There is a strong linkage between CD and HLA-DQ2 and HLA-DQ8 haplotypes. Multiple case reports and small series suggest concordance between CD and other autoimmune disorders. This paper provides a brief overview of the pathogenesis of CD and reviews the literature regarding associations between CD and other autoimmune diseases, including the potential effects of gluten-free diet therapy on the prevention or amelioration of associated diseases. PMID- 23681424 TI - Association of ocular and oculodermal melanocytosis with the rate of uveal melanoma metastasis: analysis of 7872 consecutive eyes. AB - IMPORTANCE: Ocular/oculodermal (oculo[dermal]) melanocytosis is a congenital periocular pigmentary condition that can lead to the development of uveal melanoma, estimated at 1 in 400 affected patients. In this study, patients with melanocytosis who developed uveal melanoma were found to have double the risk for metastasis compared with those without melanocytosis. OBJECTIVE: To determine the relationship of oculo(dermal) melanocytosis to the prognosis of patients with uveal melanoma. DESIGN, SETTING, AND PATIENTS: Retrospective chart review of 7872 patients with uveal melanoma treated at the Ocular Oncology Service, Wills Eye Institute, from August 25, 1970, through August 27, 2008. EXPOSURES: Enucleation, plaque radiotherapy, local resection, or thermotherapy. MAIN OUTCOMES AND MEASURES: Metastasis and death. RESULTS: Of 7872 patients with uveal melanoma, oculo(dermal) melanocytosis was present in 230 (3%). The melanocytosis involved the sclera (92%), iris (17%), choroid (12%), eyelid (8%), and temporal fossa (1%). Eyes with melanoma and oculo(dermal) melanocytosis had a relative risk for metastasis 1.6 times greater compared with those with no melanocytosis (P < .001). Metastasis of uveal melanoma was 2.8 times higher in patients with iris melanocytosis (P < .001), 2.6 times higher with choroidal melanocytosis (P = .02), and 1.9 times higher with scleral melanocytosis (P < .001). By Kaplan-Meier estimates, metastasis in patients with oculo(dermal) melanocytosis vs no melanocytosis was 2% vs 1.8% at 1 year, 27% vs 15% at 5 years, and 48% vs 24% at 10 years (P < .001). By multivariable analysis, the factors predictive of metastasis in patients harboring uveal melanoma associated with oculo(dermal) melanocytosis were increased tumor thickness (P = .001) and the presence of subretinal fluid (P = .05), and the only factor predictive of death was increased tumor thickness (P = .009). CONCLUSIONS AND RELEVANCE Patients with uveal melanoma associated with oculo(dermal) melanocytosis have double the risk for metastasis compared with those with no melanocytosis. All patients with oculo(dermal) melanocytosis should undergo ophthalmic examination and imaging on a twice-yearly basis because this could help with the early detection of melanoma. PMID- 23681423 TI - MiR-17-92 cluster: an apoptosis inducer or proliferation enhancer. AB - Study of the non-coding RNA roles in the regulation of adaptive immune responses through T cells could be the basis of novel therapeutic applications. MicroRNAs (miRNAs) are a class of short non-coding RNAs that control the cell's functions and destination. To investigate the role of miRNAs in T cell activation, herein the expressions of miR-17-92 cluster and its paralogs were studied in naive CD4(+)T cells that were activated by anti-CD2, -CD3, -CD28 microbeads and induced with or without IL-2. Proliferation and apoptosis rate of the cultured cells were determined by BrdU incorporation assay (ELISA) and propidium iodide staining, respectively. In continuation the expressions of eight miRNAs of the mentioned clusters were analyzed quantitatively. In addition their potential targets were predicted using multiple algorithms; as a confirmation, the transcription of PIK3R3 (a putative target of modulated miRNAs) was evaluated. Stimulation index (SI) of activated cells was decreased on day 6; whereas, the IL-2 induced cells showed increase in SI in the assay time. Evaluation of eight members of the aforementioned cluster showed upregulation of miR-92a-2* (~15 times) in IL-2 un induced (activated) cells relative to the IL-2 induced cells. In silico investigations revealed that the suggested miRNAs targeted genes that were involved in cell proliferation, survival, and apoptosis. Transcriptional analysis of PIK3R3 illustrated decrease in activated cells relative to IL-2 induced cells. According to our findings, it seems that multiple members of miR-17-92 families in activated CD4(+)T cells inhibited negative regulators of IL-2 such as DUSP, PTPN, and SOCS families after IL-2 induction. According to our findings, it seems that multiple genes of cell proliferation-related families such as MAPK, E2F, AKT, STAT, and JAK as well as PIK3R3 are inhibited by miR-17-92 cluster in activated cells. As FASL is a putative target of over-expressed miRNAs in activated cell, antigen-induced cell death (AICD) might be occurred in FASL independent manner. Altogether this study suggested that clonal expansion through IL-2 signaling pathway does not depend on the members of miR-17-92 family; while, it appears that AICD in activated CD4(+)T cells without IL-2 induction is affected by these miRNA clusters. PMID- 23681426 TI - Improved dosage form of the combined alendronate and calcitriol (Maxmarvil(r)) on the absorption of alendronate in Korean postmenopausal women. AB - Alendronate is one of the most potent anti-osteoporotic agents for postmenopausal osteoporosis. However, high doses of alendronate cause esophageal irritation, myalgia, gastrointestinal discomfort and decrease of serum calcium level. Recently, Maxmarvil(r) was developed as an enteric-coated tablet containing alendronate (5 mg) and calcitriol (0.5 MUg) to minimize these side effects of alendronate. In the present study, we evaluated the pharmacokinetic profile and examined the incidence of unfavorable effects after oral administration of Maxmarvil(r) in Korean healthy postmenopausal women without a previous history of fracture. In the in vitro dissolution test, alendronate was not released from Maxmarvil(r) in pH 1.2 phosphate buffer solution but released in pH 6.0 and 6.8 phosphate buffer solutions and completely dissolved in 30 min. After oral administration of Maxmarvil(r), three out of 18 (16.7%) women showed mild adverse effects; two myalgia and one upper gastrointestinal discomfort without heartburn. Most of these complaints disappeared during the study without additional treatment. The peak (Umax) and the average (Uave) urinary excretion rate of alendronate and the time to reach Umax (Tmax) were 2.94 MUg/h, 0.901 MUg/h and 6.77 h, respectively. The total cumulative urinary excretion of alendronate (Ae0 24 h) was 21.6 MUg (0.432% of oral alendornate), which was similar to the reported values. Taken together, enteric-coated Maxmarvil(r) is less harmful for the esophagus and gastrointestinal mucosa, shows the same pharmacokinetic profile to conventional alendronate (70 mg) and improves the tolerability of medication in clinical practice. PMID- 23681428 TI - [Primary cutaneous aspergillosis in an extremely low birth weight preterm infant]. AB - A small hyperpigmented nodule 4 mm in diameter with a smaller satellite lesion was noted on the left hip 5 weeks after spontaneous birth of an otherwise unharmed 490 g female infant at 23 + 5 weeks of gestation. The mother had been treated with antibiotics for a clinically suspected amniotic infection syndrome. Aspergillus fumigatus was identified in both repeated swabs of the lesions and culture of the resected tissue. The infant received liposomal amphotericin B (3 mg/kg/day) for 8 days. No new lesions were noted thereafter. There was no evidence for a primary immunodeficiency. PMID- 23681425 TI - Precise evaluation of liver histology by computerized morphometry shows that steatosis influences liver stiffness measured by transient elastography in chronic hepatitis C. AB - BACKGROUND: Liver stiffness evaluation (LSE) by Fibroscan is now widely used to assess liver fibrosis in chronic hepatitis C. Liver steatosis is a common lesion in chronic hepatitis C as in other chronic liver diseases, but its influence on LSE remains unclear. We aimed to precisely determine the influence of steatosis on LSE by using quantitative and precise morphometric measurements of liver histology. METHODS: 650 patients with chronic hepatitis C, liver biopsy, and LSE were included. Liver specimens were evaluated by optical analysis (Metavir F and A, steatosis grading) and by computerized morphometry to determine the area (%, reflecting quantity) and fractal dimension (FD, reflecting architecture) of liver fibrosis and steatosis. RESULTS: The relationships between LSE and liver histology were better described using morphometry. LSE median was independently linked to fibrosis (area or FD), steatosis (area or FD), activity (serum AST), and IQR/LSE median. Steatosis area >=4.0 % induced a 50 % increase in LSE result in patients with fibrosis area <9 %. In patients with IQR/LSE median <=0.30, the rate of F0/1 patients misclassified as F >= 2 by Fibroscan was, respectively for steatosis area <4.0 and >=4.0 %: 12.6 vs 32.4 % (p = 0.003). Steatosis level did not influence LSE median when fibrosis area was >=9 %, and consequently did not increase the rate of F <= 3 patients misclassified as cirrhotic. CONCLUSION: A precise evaluation of liver histology by computerized morphometry shows that liver stiffness measured by Fibroscan is linked to liver fibrosis, activity, and also steatosis. High level of steatosis induces misevaluation of liver fibrosis by Fibroscan. PMID- 23681429 TI - Outbreak of acute Chagas disease associated with oral transmission in the Rio Negro region, Brazilian Amazon. AB - INTRODUCTION: Chagas disease is considered as emerging in the Brazilian Amazon, usually occurring in acute outbreaks. METHODS: We describe 17 cases of acute Chagas disease in Rio Negro, Amazonas. RESULTS: There were 15 males (average age, 31.3 years), all positive for Trypanosoma cruzi in fresh blood smear examination, and 14 positive by xenodiagnosis and PCR. The top clinical manifestations were fever, asthenia, abdominal pain, and palpitations. Electrocardiograms featured low-voltage QRS, anterosuperior divisional block, and right bundle branch block associated with anterosuperior divisional block. CONCLUSIONS: All patients had consumed acai products from Monte Alegre in the rural area around Santa Izabel do Rio Negro, Brazil. PMID- 23681430 TI - HIV, hepatitis B and C, and syphilis prevalence and coinfection among sex workers in Southern Brazil. AB - INTRODUCTION: Sex workers (SWs) are vulnerable to HIV, hepatitis, and syphilis coinfection. METHODS: A cross-sectional study was conducted in Tubarao, Laguna, and Imbituba, Southern Brazil. We surveyed 147 SWs using face-to-face interviews and blood sampling for serological evaluation. RESULTS: Prevalence of hepatitis B (HBV) was 23.1%, syphilis 19.7%, hepatitis C (HCV) 8.8%, and HIV 8.8%. Of 13 HIV infected patients, 3 were co-infected with HCV, 4 with syphilis, and 5 with HBV. CONCLUSIONS: SWs had high HIV infection rates, and coinfection with viral hepatitis and syphilis. PMID- 23681431 TI - Parity and influence of abiotic factors on Anopheles in the Manso dam, State of Mato Grosso, Brazil. AB - INTRODUCTION: This study examined the parity of Anopheles mosquitoes and the influence of abiotic factors on the distribution of these mosquitoes in the Manso dam, Mato Grosso, Brazil. METHODS: The anophelines were captured using the Human Attraction Technique for 12 h, while recording the temperature and relative humidity. Parity was determined by examining the conditions of the fi laments. RESULTS: Anopheles darlingi and Anopheles triannulatus accounted for 98.5% of the anophelines, with 88% of these being parous. CONCLUSIONS: Sudden variations in weather could be the cause of shifts from the total absence of mosquitoes to the appearance of females in abundance over a three-day period. PMID- 23681432 TI - Development of duplex-PCR for identification of Aeromonas species. AB - INTRODUCTION: The number of reports of intestinal infections caused by Aeromonas spp. has increased significantly in recent years. In most clinical laboratories, identification of these bacteria is carried out by general phenotypic tests that sometimes do not accurately differentiate Aeromonas and Vibrio. METHODS: A duplex polymerase chain reaction (PCR) was developed directed to 2 targets identifying Aeromonas spp. pathogenic to humans. RESULTS: The duplex-PCR results were reproducible and specific for Aeromonas spp. pathogenic to humans. CONCLUSIONS: This method will allow differentiation between Vibrio and Aeromonas spp. in patients with in cholera-like symptoms and can also be used in water quality monitoring. PMID- 23681433 TI - Evaluation of CD4+CD25+ T lymphocyte response time kinetics in patients with chronic Chagas disease after in vitro stimulation with recombinant Trypanosoma cruzi antigens. AB - INTRODUCTION: CD4+CD25+ T lymphocytes have been implicated in the regulation of host inflammatory response against Trypanosoma cruzi, and may be involved in the clinical course of the disease. METHODS: Peripheral blood mononuclear cells from patients with chronic Chagas disease were cultured in the presence of T. cruzi recombinant antigens and assayed for lymphocytes at distinct time points. RESULTS: It was possible to differentiate clinical forms of chronic Chagas disease at days 3 and 5 according to presence of CD4+CD25+ T cells in cell cultures. CONCLUSIONS: Longer periods of cell culture proved to be potentially valuable for prospective evaluations of CD4+CD25+ T lymphocytes in patients with chronic Chagas disease. PMID- 23681434 TI - HIV incidence in Asia: a review of available data and assessment of the epidemic. AB - Rates of new HIV infections in Asia are poorly characterized, likely resulting in knowledge gaps about infection trends and the most important areas to target for interventions. We conducted a systematic review of peer-reviewed English language publications and conference abstracts on HIV incidence in thirteen countries - Bangladesh, Cambodia, China, India, Indonesia, Laos, Malaysia, Myanmar, Philippines, Singapore, Taiwan, Thailand, and Vietnam. We obtained data on HIV incidence rate, incidence estimation method, population, and risk factors for incident infection. Our search yielded 338 unique incidence estimates from 70 published articles and 41 conference abstracts for eight countries. A total of 138 (41%) were obtained from prospective cohort studies and 106 (31%) were from antibody-based tests for recent infection. High HIV incidence rates were observed among commercial sex workers (0.4-27.8 per 100 person-years), people who inject drugs (0.0-43.6 per 100 person-years) and men who have sex with men (0.7-15.0 per 100 person-years). Risk factors for incident HIV infection include brothel-based sex work and cervicitis among commercial sex workers; young age, frequent injection use and sharing needles or syringes among people who inject drugs; multiple male sexual partners, receptive anal intercourse and syphilis infection among men who have sex with men. In the countries with available data, incidence rates were highest in key populations and varied widely by incidence estimation method. Established surveillance systems that routinely monitor trends in HIV incidence are needed to inform prevention planning, prioritize resources, measure impact, and improve the HIV response in Asia. PMID- 23681435 TI - Vaccinating HIV patients: focus on human papillomavirus and herpes zoster vaccines. AB - Vaccination has been one of our most powerful tools to decrease morbidity and mortality from infectious diseases in the last century. It is critical to understand the evolving safety and efficacy data for vaccines in HIV-infected individuals as the number of people living with HIV in the United States and globally continues to increase. The quadrivalent human papillomavirus vaccine and the herpes zoster vaccine are newly licensed in the general population, and several studies have recently been published on the safety and efficacy of these vaccines in HIV populations. This manuscript reviews recent data for the vaccines most commonly administered in HIV patients and incorporates these data into our body of knowledge about the safety and efficacy of vaccines in this population. In addition, patient factors that predict response for each vaccine are discussed. Given the great burden of human papillomavirus and herpes zoster in HIV patients, we discuss the benefits and the challenges of vaccinating HIV patients with the human papillomavirus and herpes zoster vaccines. This review provides information that clinicians need to make real-time decisions in the absence of large-scale trials in the HIV population. PMID- 23681436 TI - Clinical perspective on drug-drug interactions with the non-nucleoside reverse transcriptase inhibitor rilpivirine. AB - Rilpivirine (TMC278) is a non-nucleoside reverse transcriptase inhibitor approved in combination with other antiretrovirals for the treatment of HIV-1 infection in treatment-naive adults (Edurant((r)) 25 mg once daily; Complera((r)) [USA]/Eviplera((r)) [EU] once daily single-tablet regimen). Rilpivirine should be administered with a meal to optimize bioavailability. Its solubility is pH dependent. Rilpivirine is primarily excreted via the feces with negligible renal elimination. Rilpivirine is predominantly metabolized by cytochrome P450 3A4. There is no clinically relevant effect of age, gender, bodyweight, race, estimated glomerular filtration rate, or hepatitis B/C coinfection status on rilpivirine pharmacokinetics in adults. Drug-drug interactions were investigated with cytochrome P450 3A substrates, inducers and inhibitors, drugs altering intragastric pH, antiretrovirals, and other often coadministered drugs. Rilpivirine 25 mg once daily does not have a clinically relevant effect on exposure of coadministered drugs. Coadministration with cytochrome P450 3A inhibitors (ketoconazole, ritonavir-boosted protease inhibitors, telaprevir) results in increased rilpivirine plasma concentrations, but these are not considered clinically relevant; no dose adjustments are required. Coadministration of rilpivirine with cytochrome P450 3A inducers (e.g. rifampin, rifabutin) or compounds increasing gastric pH (e.g. omeprazole, famotidine) results in decreased rilpivirine plasma concentrations, which may increase the risk of virologic failure and resistance development. Therefore, strong cytochrome P450 3A inducers and proton-pump inhibitors are contraindicated. Histamine-2 receptor antagonists and antacids can be coadministered with rilpivirine, provided doses are temporally separated. No dose adjustments are required when rilpivirine is coadministered with: acetaminophen, phosphodiesterase type 5 inhibitors (sildenafil, etc.), atorvastatin (and other statins), oral contraceptives (ethinyl estradiol, norethindrone), chlorzoxazone (cytochrome P450 2E1 substrate), methadone, digoxin, tenofovir disoproxil fumarate, didanosine and other nuceos(t)ide reverse transcriptase inhibitors, and HIV integrase inhibitors (raltegravir, dolutegravir, GSK1265744). PMID- 23681437 TI - Human papillomavirus, anal cancer, and screening considerations among HIV infected individuals. AB - Invasive anal cancer has become an important cause of non AIDS-related cancer among HIV-infected individuals. Human papillomavirus is the main etiological agent. This review explains the pathophysiologic role of human papillomavirus in the development of invasive anal cancer, summarizes recent epidemiological trends of invasive anal cancer, and reviews the evidence to address common clinical questions posed when screening for anal cancer in HIV-infected patients. The effect of highly active antiretroviral therapy on human papillomavirus oncogenesis is still unclear, but given the increased clinical burden of invasive anal cancer among HIV-infected patients, many clinics have implemented screening programs for anal cancer and its precursors. Despite the availability of several modalities for treatment of precursors of anal cancer, evidence that current treatment modalities favorably alter the natural history of human papillomavirus oncogenesis in the anal and perianal regions is still inconclusive. However, there is sufficient evidence to state that the accuracy of anal cancer screening procedures (cytology and high-resolution anoscopy directed biopsy) is comparable to the accuracy of those used in screening for cervical cancer precursors. Studies that systematically assess the efficacy of these anal cancer screening programs in reducing the incidence of and morbidity and mortality from invasive anal cancer among HIV-infected patients are needed. PMID- 23681438 TI - Mechanosensitivity and compositional dynamics of cell-matrix adhesions. AB - Cells perceive information about the biochemical and biophysical properties of their tissue microenvironment through integrin-mediated cell-matrix adhesions, which connect the cytoskeleton with the extracellular matrix and thereby allow cohesion and long-range mechanical connections within tissues. The formation of cell-matrix adhesions and integrin signalling involves the dynamic recruitment and assembly of an inventory of proteins, collectively termed the 'adhesome', at the adhesive site. The recruitment of some adhesome proteins, most notably the Lin11-, Isl1- and Mec3-domain-containing proteins, depends on mechanical tension generated by myosin II-mediated contractile forces exerted on cell-matrix adhesions. When exposed to force, mechanosensitive adhesome proteins can change their conformation or expose cryptic-binding sites leading to the recruitment of proteins, rearrangement of the cytoskeleton, reinforcement of the adhesive site and signal transduction. Biophysical methods and proteomics revealed force ranges within the adhesome and cytoskeleton, and also force-dependent changes in adhesome composition. In this review, we provide an overview of the compositional dynamics of cell-matrix adhesions, discuss the most prevalent functional domains in adhesome proteins and review literature and concepts about mechanosensing mechanisms that operate at the adhesion site. PMID- 23681440 TI - Response: 'Antibody crossreactivity between the tumour suppressor PHLPP1 and the proto-oncogene beta-catenin'. PMID- 23681439 TI - Introns of plant pri-miRNAs enhance miRNA biogenesis. AB - Plant MIR genes are independent transcription units that encode long primary miRNA precursors, which usually contain introns. For two miRNA genes, MIR163 and MIR161, we show that introns are crucial for the accumulation of proper levels of mature miRNA. Removal of the intron in both cases led to a drop-off in the level of mature miRNAs. We demonstrate that the stimulating effects of the intron mostly reside in the 5'ss rather than on a genuine splicing event. Our findings are biologically significant as the presence of functional splice sites in the MIR163 gene appears mandatory for pathogen-triggered accumulation of miR163 and proper regulation of at least one of its targets. PMID- 23681441 TI - One world, one health. Humans, animals and the environment are inextricably linked--a fact that needs to be remembered and exploited in our modern approach to health. PMID- 23681443 TI - The balance of brains--corruption and migration. Corruption could be an important factor for emigration and immigration decisions by highly skilled professionals. PMID- 23681444 TI - MicroRNA and autophagy--C. elegans joins the crew. PMID- 23681442 TI - The DLK signalling pathway--a double-edged sword in neural development and regeneration. AB - Dual leucine zipper kinase (DLK), a mitogen-activated protein kinase kinase kinase, controls axon growth, apoptosis and neuron degeneration during neural development, as well as neurodegeneration after various insults to the adult nervous system. Interestingly, recent studies have also highlighted a role of DLK in promoting axon regeneration in diverse model systems. Invertebrates and vertebrates, cold- and warm-blooded animals, as well as central and peripheral mammalian nervous systems all differ in their ability to regenerate injured axons. Here, we discuss how DLK-dependent signalling regulates apparently contradictory functions during neural development and regeneration in different species. In addition, we outline strategies to fine-tune DLK function, either alone or together with other approaches, to promote axon regeneration in the adult mammalian central nervous system. PMID- 23681445 TI - Your decisions are what you eat. Metabolic state can have a serious impact on risk-taking and decision-making in humans and animals. PMID- 23681446 TI - Homo artefaciens. PMID- 23681447 TI - Effects of stretching on performances involving stretch-shortening cycles. AB - BACKGROUND: Alongside its role in athletic conditioning, stretching has commonly been integrated in warm-up routines prior to athletic performance. Numerous studies have reported detrimental acute effects on strength following stretching. Consequently, athletes have been recommended to discontinue stretching as part of warm-ups. In contrast, studies indicate that chronic stretching performed as a separate bout from training or competition may enhance performance. However, the influence of stretching on complex performances has received relatively little attention. OBJECTIVE: The purpose of this study was to review both the acute and chronic effects of stretching on performances involving the stretch-shortening cycle (SSC). METHODS: A systematic search for literature was undertaken (January 2006-December 2012) in which only randomized controlled trials (RCTs) or studies with repeated measures designs were included. The Physiotherapy Evidence Database (PEDro) rating scale was used for quality assessment of the evidence. RESULTS: The review included 43 studies, from which conflicting evidence emerged. Approximately half of the studies assessing the acute effect of static stretching reported a detrimental effect on performance, while the remainder found no effect. In contrast, dynamic stretching showed no negative effects and improved performance in half of the trials. The effect size associated with static and dynamic stretching interventions was commonly low to moderate, indicating that the effect on performance might be limited in practice. Factors were identified that might have contributed to the conflicting results reported across studies, such as type of SSC performance and carrying out dynamic activity between the stretching bout and performance. Few studies since 2006 have addressed the chronic effect of stretching on functional and sports performance. Although negative effects were not reported, robust evidence of the overall beneficial effects within current bibliographic databases remains elusive. Plausible mechanisms for the observed effects from stretching are discussed, as well as possible factors that may have contributed to contradictory findings between studies. LIMITATIONS: Considerable heterogeneity in study design and methods makes comparison between studies challenging. No regression analysis of the contribution of different predictors to variation between trials had previously been performed. Hence, predictors had to be selected on the basis of a qualitative analysis of the predictors that seemed most influential, as well as being identified in previous narrative reviews. CONCLUSION: Different types of stretching have differential acute effects on SSC performances. The recommended volume of static stretching required to increase flexibility might induce a negative acute effect on performances involving rapid SSCs, but the effect sizes of these decrements are commonly low, indicating that the acute effect on performance might be limited in practice. No negative acute effects of dynamic stretching were reported. For athletes that require great range of motion (ROM) and speed in their sport, long-term stretching successfully enhances flexibility without negatively affecting performance. Acute dynamic stretching may also be effective in inducing smaller gains in ROM prior to performance without any negative effects being observed. PMID- 23681448 TI - Could targeted exercise programmes prevent lower limb injury in community Australian football? AB - BACKGROUND: Australian football is a popular sport in Australia, at both the community and elite levels. It is a high-speed contact sport with a higher incidence of medically treated injuries when compared with most other organized sports. Hamstring injuries, ligament injuries to the knee or ankle, hip/groin injuries and tendinopathies are particularly common and often result in considerable time lost from sport. Consequently, the prevention of lower limb injuries is a priority for both community and elite Australian football organizations. There is considerable literature available on exercise programmes aimed at reducing lower limb injuries in Australian football and other running related sports. The quality and outcomes of these studies have varied considerably, but indicate that exercise protocols may be an effective means of preventing lower limb injuries. Despite this, there has been limited high-quality and systematic evaluation of these data. OBJECTIVE: The aim of this literature review is to systematically evaluate the evidence about the benefits of lower limb injury prevention exercise protocols aimed at reducing the most common severe lower limb injuries in Australian football. METHODS: The Cochrane Central Register of Controlled Trials, the Cochrane Bone Joint and Muscle Trauma Group Specialized Register, MEDLINE and other electronic databases were searched, from January 1990 to December 2010. Papers reporting the results of randomized controlled trials (RCTs), quasi-RCTs, cohort and case-control studies were extracted. Primary outcomes were injury reduction or risk factor identification and/or modification. Secondary outcomes were adherence to any trialled interventions, injury severity and adverse effects such as secondary injuries and muscle soreness. The methodological quality of extracted manuscripts was assessed and results were collated. RESULTS: Forty-seven papers were identified and reviewed of which 18 related to hamstring injury, eight related to knee or ankle ligament injury, five related to tendon injury and four were hip or groin injury related. Another 12 papers targeted general lower limb injuries. Most (n = 27 [57%]) were observational studies, investigating injury risk factors. Twenty reported the results of intervention trials. Of these, 15 were efficacy trials reporting the effects of an intervention in reducing injury rates, four were biomechanical interventions in which the impact of the intervention on a known injury risk factor was assessed and one reported changes in injury risk factors as well as injury rates. The strength of the evidence base for exercise programmes for lower limb injury prevention was found to be limited, primarily due to the research methods employed, low adherence to interventions by the study participants and a lack of statistical power. Limited evidence obtained from a small number of RCTs suggests that balance and control exercises might be efficacious in preventing ankle ligament injuries and a programme involving a combination of balance and control exercises, eccentric hamstring, plyometrics and strength exercises could be efficacious in preventing all lower limb injuries. CONCLUSIONS: Overall, the evidence for exercise programmes as an efficacious lower limb injury prevention strategy is predominantly restricted to studies addressing injury aetiology and mechanisms. The findings of this review highlight the need to develop and test interventions in well designed population based trials with an emphasis on promoting intervention uptake and adherence and, hence, intervention effectiveness. The results of this review can inform the development of the components of a future lower limb injury prevention exercise protocol for community-level Australian football. PMID- 23681451 TI - Intense generation of respirable metal nanoparticles from a low-power soldering unit. AB - Evidence of intense nanoparticle generation from a low power (45W) flux soldering unit is presented. This is a familiar device often used in daily life, including home repairs and school electronic laboratories. We demonstrate that metal containing nanoparticles may reach high concentrations (ca. 10(6) particles/cm(3)) within the breathing range of the operator, with initial size distributions centered at 35-60nm The morphological and chemical analysis of nanoparticle agglomerates collected on TEM grids and filters confirms their multiparticle structure and the presence of metals. PMID- 23681449 TI - Genes for elite power and sprint performance: ACTN3 leads the way. AB - The ability of skeletal muscles to produce force at a high velocity, which is crucial for success in power and sprint performance, is strongly influenced by genetics and without the appropriate genetic make-up, an individual reduces his/her chances of becoming an exceptional power or sprinter athlete. Several genetic variants (i.e. polymorphisms) have been associated with elite power and sprint performance in the last few years and the current paradigm is that elite performance is a polygenic trait, with minor contributions of each variant to the unique athletic phenotype. The purpose of this review is to summarize the specific knowledge in the field of genetics and elite power performance, and to provide some future directions for research in this field. Of the polymorphisms associated with elite power and sprint performance, the alpha-actinin-3 R577X polymorphism provides the most consistent results. ACTN3 is the only gene that shows a genotype and performance association across multiple cohorts of elite power athletes, and this association is strongly supported by mechanistic data from an Actn3 knockout mouse model. The angiotensin-1 converting enzyme insertion/deletion polymorphism (ACE I/D, registered single nucleotide polymorphism [rs]4646994), angiotensinogen (AGT Met235Thr rs699), skeletal adenosine monophosphate deaminase (AMPD1) Gln(Q)12Ter(X) [also termed C34T, rs17602729], interleukin-6 (IL-6 -174 G/C, rs1800795), endothelial nitric oxide synthase 3 (NOS3 -786 T/C, rs2070744; and Glu298Asp, rs1799983), peroxisome proliferator-activated receptor-alpha (PPARA Intron 7 G/C, rs4253778), and mitochondrial uncoupling protein 2 (UCP2 Ala55Val, rs660339) polymorphisms have also been associated with elite power performance, but the findings are less consistent. In general, research into the genetics of athletic performance is limited by a small sample size in individual studies and the heterogeneity of study samples, often including athletes from multiple-difference sporting disciplines. In the future, large, homogeneous, strictly defined elite power athlete cohorts need to be established though multinational collaboration, so that meaningful genome-wide association studies can be performed. Such an approach would provide unbiased identification of potential genes that influence elite athletic performance. PMID- 23681452 TI - Alveolar soft part sarcoma-radiologic patterns in children and adolescents. AB - BACKGROUND: Alveolar soft part sarcoma is a rare but highly malignant tumour and little is known about its radiologic pattern in children. OBJECTIVE: To describe the radiologic features of alveolar soft part sarcoma in children and adolescents. MATERIALS AND METHODS: We retrospectively analysed the clinical and imaging data of six children age 7-17 years at diagnosis, with histologically or genetically proven alveolar soft part sarcoma. RESULTS: The tumours were located deep within muscles of the limbs (n = 4), in chest wall muscle (n = 1) and in the orbit (n = 1). High-flow feeding arteries, large drainage veins and intense enhancement were consistent findings by all imaging modalities. At MRI, all tumours demonstrated high signal intensity on T2-weighted images and high or iso intense signal on T1-W imaging compared to muscle. In tumours larger than 70 mm in one dimension (n = 3/6), large vessels converging toward the tumour centre led to a highly vascularised central stellar area pattern. Five children demonstrated synchronous (n = 4/5) and metachronous (n = 1/5) lung metastases. CONCLUSION: Alveolar soft part sarcoma should be suggested when a highly vascularised, intramuscular mass demonstrating large feeding and drainage vessels converging toward a central stellar area is seen in children, especially if synchronous lung metastases are present. PMID- 23681456 TI - [The history of the concept of "worker health" in the field of collective health: the case of Brazil]. PMID- 23681455 TI - Sleep disorders in US military personnel: a high rate of comorbid insomnia and obstructive sleep apnea. AB - BACKGROUND: Sleep disturbances are among the most common symptoms of military personnel who return from deployment. The objective of our study was to determine the presence of sleep disorders in US military personnel referred for evaluation of sleep disturbances after deployment and examine associations between sleep disorders and service-related diagnoses of depression, mild traumatic brain injury, pain, and posttraumatic stress disorder (PTSD). METHODS: This was a cross sectional study of military personnel with sleep disturbances who returned from combat within 18 months of deployment. Sleep disorders were assessed by clinical evaluation and polysomnogram with validated instruments to diagnose service related illnesses. RESULTS: Of 110 military personnel included in our analysis, 97.3% were men (mean age, 33.6 +/- 8.0 years; mean BMI, 30.0 +/- 4.3 kg/m2), and 70.9% returned from combat within 12 months. Nearly one-half (47.3%) met diagnostic criteria for two or more service-related diagnoses. Sleep disorders were diagnosed in 88.2% of subjects; 11.8% had a normal sleep evaluation and served as control subjects. Overall, 62.7% met diagnostic criteria for obstructive sleep apnea (OSA) and 63.6% for insomnia. The exclusive diagnoses of insomnia and OSA were present in 25.5% and 24.5% of subjects, respectively; 38.2% had comorbid insomnia and OSA. Military personnel with comorbid insomnia and OSA were significantly more likely to meet criteria for depression (P < .01) and PTSD (P < .01) compared with control subjects and those with OSA only. CONCLUSIONS: Comorbid insomnia and OSA is a frequent diagnosis in military personnel referred for evaluation of sleep disturbances after deployment. This diagnosis, which is difficult to treat, may explain the refractory nature of many service-related diagnoses. PMID- 23681457 TI - [From local studies to a regional perspective: pooled analysis of secondary data in a collaborative project on vulnerabilities associated with drug use in Argentina, Brazil and Uruguay (1998-2004)]. AB - This paper develops the methodological principles of pooled analysis design, using it to study situations of vulnerability among drug users at a regional level. Data from thirteen cross-sectional studies carried out in Argentina, Brazil and Uruguay between 1998 and 2004 were integrated. A critical review of the concept of data matrix which identifies four structural components, allowed us to: define the units of analysis spanning the different original populations; identify a core of common variables (social and demographic characteristics, drug use, sexual practices, serology of blood-borne and sexually transmitted diseases) with their respective values; examine the indicators, dimensions and procedures used to measure the variables; and establish their compatibility with a thematic and comparative analysis of data collection tools. The main result was a new data matrix with 3,534 cases. Multidisciplinary collaboration between teams and institutions from the three countries made it possible to maximize the available sources in order to analyze characteristics of the local contexts and of the overall regional. PMID- 23681458 TI - [Analysis of the reasons for abandoning the follow-up and treatment process in women with pre-cancerous cervical lesions in the province of Jujuy: implications for health management]. AB - Adequate follow-up and treatment of women with high-grade squamous intraepithelial lesion (HSIL) and cancer is key in reducing cervical cancer mortality. This research study aims to analyze the magnitude of abandonment in the follow-up and treatment process, as well as the reasons for this abandonment, in women with HSIL who received care in public health services in the province of Jujuy in 2010. Secondary sources were analyzed and women were interviewed in their homes. The abandonment rate within the study population was 23.5%. Among these women, 40.5% mentioned organizational problems in the health care system as a reason for abandoning and 30.9% mentioned subjective reasons. Our results have been used in the reorganization of the follow-up and treatment process being carried out in the province. PMID- 23681459 TI - [Decentralization and equity: public health expenditure in the municipalities of the Province of Buenos Aires]. AB - In this paper we analyze the degree of equity in access to the public health care system in the Province of Buenos Aires (Argentina). Through a quantitative retrospective study, we analyze the inequalities in the distribution of the total public health expenditure per capita. This variable is used as a proxy for the ability of the inhabitants of each jurisdiction to access health care services. The results indicate the existence of large disparities in the levels of expenditure devoted to the population without health coverage. Moreover, the existence of greater health care needs (estimated using infant mortality rates and percentage of homes with basic needs unmet) does not translate into higher levels of public expenditure. Finally, we detect a positive association between the relative wealth of municipalities (measured by the gross geographic product per capita) and the public health expenditure per capita. PMID- 23681460 TI - [First debates regarding the legalization of drug use in Argentina at the start of the 20th century: the proposal of Dr. Leopoldo Bard and its sociohistorical context]. AB - This paper analyzes the discourses of Argentine doctor and public health professional Leopoldo Bard using three texts on drug abuse published between 1923 and 1933. These texts embody the debates of the time regarding the role of the State, public policies at the national and regional level and, particularly, the US influence in Argentina exerted through the figure of Dr. Bard. The legislative measures and policies of that time, undoubtedly of a repressive character, were key in the State's advances into the private sphere and in the increasing importance of professional organizations in the definition of the material and symbolic borders of the socially acceptable, including those related to drug use. The multiple purposes these policies seem to satisfy are also highlighted: at the local level they enable other forms of repressing conflicts arising from immigration, while at the international level they appease US requirements. PMID- 23681461 TI - [Notes on childhood and theory: a Latin American approach]. AB - This work seeks to introduce and examine different historically relevant theories and propose certain frameworks that allow for the development of a Latin American theoretical approach based in a new discourse regarding childhood and adolescence. In order to undertake the creation of this Latin American approach, understanding the category of childhood as a social and historical construction, the work draws upon the contributions of structuralism (in particular, childhood as a permanent category, its relational dimension with regards to adulthood and its historical and intercultural dimension) and Foucault and Deleuze's concept of the society of control associated with the category of domination, an essential aspect of Latin American thought. The text was presented as a speech in the V World Congress for the Rights of Children and Adolescents held in San Juan, Argentina, from October 15-19, 2012. PMID- 23681462 TI - [The fight against polio: a social-medical alliance, Buenos Aires, 1943]. AB - The present article analyzes the emergence of a volunteer-based social assistance organization that played an active role in the health care provided for poliomyelitis in Argentina: Asociacion para la Lucha contra la Paralisis Infantil (Association for the Fight against Child Paralysis). This institution was created in Buenos Aires in 1943 by a group of women from upper and middle class social sectors. In a context of biomedical uncertainty, the organization mobilized material and symbolic resources to respond to the need for rehabilitation of the permanent physical conditions the disease provoked in its victims. Using as a source the institutional memories of the organization, the article demonstrates how doctors and philanthropists formed a social-medical alliance and developed a fundamental interest in practicing a form of treatment sustained in a framework that united Christian ideas with medical and rehabilitative innovations. PMID- 23681463 TI - [The Universidad de Buenos Aires in the 1970s: analysis of the press release expressing solidarity with Rodolfo Puiggros]. AB - This article reconstructs the historical context surrounding the emission of a press release by authorities of the Universidad de Buenos Aires, expressing their solidarity with historian and university rector Rodolfo Puiggros after his resignation. In his term, Puiggros attempted to fuse the institution's scientific and technological plans with the new development model initiated by Hector Campora and the Peronist movement in 1973. The article makes reference to the project of university transformation promoted by Puiggros, combining the ideological traditions of Marxism, reformism, and nationalism. A few key points, useful for analyzing the reasons behind Puiggros's resignation, are presented, and the arguments highlighted within this press release, published by Office of Media and Communications on October 5, 1973, are discussed. PMID- 23681464 TI - [Training, teaching and research for a policy of national reconstruction in the health field. 1973]. AB - This text reproduces a speech given by Dr. Mario Testa on June 28, 1973 in the main hall of the Faculty of Medicine of the Universidad de Buenos Aires. The words of introduction preceding the text, written by Testa himself, provide the context of not only the historical moment the university was experiencing, just days after Rodolfo Puiggros took office as the rector within the university's political overhaul, but also the meaning given to the project of pedagogical renovation. This project proposed redefining the relationship between the university and society, originating such projects such as the Instituto de Medicina del Trabajo (Institute of Occupational Medicine), the Instituto de la Madre y el Nino (Mother and Child Institute) and the Instituto de Patologia Regional (Regional Pathology Institute) in the Faculty of Medicine; the Centro de Produccion de Medicamentos de Base (the Center for Basic Drug Production) in the Faculty of Pharmacy and Biochemistry; and the Centro de Erradicacion de Villas de Emergencia (Center for the Eradication of Shantytowns) in the Faculty of Architecture, among many others. Republishing these words, spoken almost 40 years ago, is a way of continuing to put into discussion the type of education and training health professionals receive with public funds. PMID- 23681466 TI - Patrolling your blind spots: introspection and public catharsis in a medical school faculty development course to reduce unconscious bias in medicine. AB - Cultural competence education has been criticized for excessively focusing on the culture of patients while ignoring how the culture of medical institutions and individual providers contribute to health disparities. Many educators are now focusing on the role of bias in medical encounters and searching for strategies to reduce its negative impact on patients. These bias-reduction efforts have often been met with resistance from those who are offended by the notion that "they" are part of the problem. This article examines a faculty development course offered to medical school faculty that seeks to reduce bias in a way that avoids this problem. Informed by recent social-psychological research on bias, the course focuses on forms of bias that operate below the level of conscious awareness. With a pedagogical strategy promoting self-awareness and introspection, instructors encourage participants to discover their own unconscious biases in the hopes that they will become less biased in the future. By focusing on hidden forms of bias that everyone shares, they hope to create a "safe-space" where individuals can discuss shameful past experiences without fear of blame or criticism. Drawing on participant-observation in all course sessions and eight in-depth interviews, this article examines the experiences and reactions of instructors and participants to this type of approach. We "lift the hood" and closely examine the philosophy and strategy of course founders, the motivations of the participants, and the experience of and reaction to the specific pedagogical techniques employed. We find that their safe-space strategy was moderately successful, largely due to the voluntary structure of the course, which ensured ample interest among participants, and their carefully designed interactive exercises featuring intimate small group discussions. However, this success comes at the expense of considering the multidimensional sources of bias. The specific focus on introspection implies that prior ignorance, not active malice, is responsible for biased actions. In this way, the individual perpetrators of bias escape blame for their actions while the underlying causes of their behavior go unexplored or unaccounted for. PMID- 23681467 TI - The function and muscle strength recovery of shoulder after humeral diaphysis fracture following plating and intramedullary nailing. AB - OBJECTIVE: To evaluate the shoulder function and shoulder girdle muscle strength of humeral diaphysis fractures postoperatively following intramedullary nailing (IMN) and open reduction internal fixation (ORIF). METHODS: Fifty cases of humeral diaphysis fractures were randomly allocated into two groups. Antegrade IMN and ORIF were, respectively, performed in group I and II. Union status, functional scoring, range of motion, muscle strength of shoulder girdle including external/internal rotation and abduction/adduction strength were recorded at 18 months after surgery. Statistical package for social sciences 13.0 was used for analysis. RESULTS: Group I had lower functional score than group II (P < 0.05). Both groups had approximately 50 % of muscle strength loss on injured side. In group II, the internal rotation strength loss was significantly greater compared to group I (P < 0.01). The total side to side (internal plus external) range of rotation (ROR) lack and external ROR lack of involved shoulder was significantly greater in group I (P = 0.005 and 0.049). The range of abduction lack was also significantly greater in group I. CONCLUSIONS: Both surgically treated groups had significant loss of muscle strength of shoulder girdle when measured at 18 months postoperatively. There was greater loss of rotation strength in ORIF group than the IMN group. However, IMN had lower functional scores and a decreased range of motion postoperatively. The assumption that rotator cuff damage caused by nailing leads to weaker abduction strength than plating was not supported. PMID- 23681468 TI - Pigmented villo-nodular synovitis and giant-cell tumor of tendon sheaths: a binational retrospective study. AB - AIM: Pigmented villonodular synovitis is rare. Thus, we initiated a retrospective multi-center study regarding symptoms, location, type of disease, type of surgery, number of recurrences, use of adjuvant therapies and functional outcome. RESULTS: Ten centers contributed. Data from 173 patients were sampled. The disease was seen predominantly in joints, less frequently in tendon sheaths and bursae. Patients with articular lesions suffered mainly from the diffuse type. In tendon sheaths, the relation "diffuse versus nodular" was nearly 50 % each, in bursae most often the nodular type was found. Anatomically, mostly the knee was affected. Institutions with more than 20 patients had a lower rate of recurrence than those with less than 20 cases. Regarding the knee, there were less recurrences in joints treated with open synovectomy than in those treated arthroscopically. CONCLUSIONS: Since the rate of recurrence has been rather high, the use of adjuvant treatments (radiosynoviorthesis or radiotherapy) is recommended. In our study, the rate of their application was quite low. Patients who received an adjuvant therapy after primary surgery did not show any recurrence. In 14 % of patients in whom an adjuvant therapy had been used, after at least one recurrence, further recurrences were observed. Functional results were excellent in 84 % of patients. LEVEL OF EVIDENCE: Prognostic multi-center study, Level III. PMID- 23681469 TI - Clinical and radiographic results of Bryan cervical total disc replacement: 4 year outcomes in a prospective study. AB - INTRODUCTION: Early results have indicated that the Bryan cervical total disc replacement (TDR) favorably compares to anterior cervical decompression and fusion, while it is associated with fewer complications and higher levels of satisfaction. In this study, we sought to prospectively report the midterm outcomes of the Bryan TDR. PATIENTS AND METHODS: A total of 20 patients had performed their 4-year follow-up visit and had been assessed clinically and radiologically. Clinical outcomes (JOA, VAS, NDI, SF-36) and ROM measurements were investigated preoperatively and at 1 and 6 months, and 1, 2 and 4 years after operation. Complications were also investigated. Occurrences of heterotopic ossifications (HOs) and adjacent-level degeneration (ALD) radiographic changes were detected from 4-year follow-up X-rays. RESULTS: The mean JOA score, VAS score for arm and neck, NDI score and SF-36 score for PCS and MCS were reduced significantly at each postoperative time point when compared with the preoperative condition. The range of movement of the cervical spine, functional spinal unit, treated segment and the adjacent segment temporarily decreased at the early assessment, but all recovered to preoperative levels over a 6-month to 4-year time period. HO was evident in 6 of the 23 operated segments, which did not restrict the movement of the prosthesis. No obvious ALD was found on MRI. There were no cases of prosthesis migration, subsidence, loosening or wear. CONCLUSION: The midterm outcomes demonstrated that the Bryan TDR maintains favorable clinical and radiological results, with preservation of movement and satisfactory clinical outcome. There were no serious complications or cases of prosthetic wear or failure. The long-term benefits are yet to be examined. PMID- 23681470 TI - Surgeons save bones: an algorithm for orthopedic surgeons managing secondary fracture prevention. AB - Postmenopausal osteoporosis has a big impact on health care budget worldwide, which are expected to double by 2050. In spite of severe medical and socioeconomic consequences from fragility fractures, there are insufficient efforts in optimizing osteoporotic treatment and prevention. Undertreatment of osteoporosis is a well known phenomenon, particularly in elderly patients. Treatment rates remain low across virtually all patient, provider, and hospital level characteristics, even after fragility fractures. In-hospital initiation is one of the options to increase treatment rates and improve osteoporosis management. However, multiple factors contribute to the failure of initiating appropriate treatment of osteoporosis in patients with fragility fractures. These include a lack of knowledge in osteoporosis and an absence of a comprehensive treatment guideline among family physicians and orthopedic surgeons. Furthermore, orthopedic surgeons are hardly willing to accept their responsibility for osteoporosis treatment due to the fact that they are usually not familiar with the initiation of specific drug treatments. The presented algorithm offers trauma surgeons and orthopedic surgeons a safe and simple guided pathway of treating osteoporosis in postmenopausal women appropriately after fragility fractures based on the current literature. From our point of view, this algorithm is useful for almost all cases and the user can expect treatment recommendations in more than 90 % of all cases. Nevertheless, some patients may require specialized review by an endocrinologist. The proposed algorithm may help to increase the rate of appropriate osteoporosis treatment hence reducing the rates of fragility fractures. PMID- 23681471 TI - Associations among family history of cancer, cancer screening and lifestyle behaviors: a population-based study. AB - PURPOSE: Some cancers are largely preventable through modification of certain behavioral risk factors and preventive screening, even among those with a family history of cancer. This study examined the associations between (1) family cancer history and cancer screening, (2) family history and cancer preventive lifestyle behaviors, and (3) cancer screening and lifestyle behaviors. METHODS: Data were from the 2009 California Health Interview Survey (n = 12,603). Outcomes included screening for breast cancer (BC) and colorectal cancer (CRC) and six cancer preventive lifestyle behaviors, based on World Cancer Research Fund recommendations. Multivariate logistic regression analyses, stratified by gender and race-ethnicity, examined associations. Predicted probabilities of cancer screening by family cancer history, race-ethnicity, and sex were computed. RESULTS: Family history of site-specific cancer-CRC for men and women, and BC for women-was associated with higher probability of cancer screening for most groups, especially for CRC, but was largely unrelated to other lifestyle behaviors. In the few cases in which family history was significantly associated with lifestyle for example, physical activity among White and Latino males, smoking among White and Asian females-individuals with a family history had lower odds of adherence to recommendations than those with no family history. Greater overall adherence to lifestyle recommendations was associated with higher odds of up-to-date CRC screening among White and Asian males, and lower odds among Asian females (no significant association with BC screening); this relationship did not vary by family cancer history. CONCLUSION: The fact that family history of cancer is not associated with better lifestyle behaviors may reflect shared behavioral risks within families, or the lack of knowledge about how certain lifestyle behaviors impact personal cancer risk. Findings can inform interventions aimed at lifestyle behavioral modification for individuals at increased cancer risk due to family history. PMID- 23681472 TI - Coffee consumption and the risk of overall and fatal prostate cancer in the NIH AARP Diet and Health Study. AB - PURPOSE: Evidence on the association between coffee consumption and prostate cancer risk is inconsistent; furthermore, few studies have examined the relationship between coffee consumption and fatal prostate cancer. The aim of this study was to investigate whether coffee intake is associated with the risk of overall and fatal prostate cancer. METHODS: We conducted a prospective analysis among 288,391 men in the National Institutes of Health AARP Diet and Health Study who were between 50 and 71 years old at baseline in 1995-1996. Coffee consumption was assessed at baseline. Cox proportional hazards models were used to calculate the age- and multivariable-adjusted hazard ratios (HR)s and 95 % confidence intervals (CIs). RESULTS: Over 11 years of follow-up, 23,335 cases of prostate cancer were ascertained, including 2,927 advanced and 917 fatal cases. Coffee consumption was not significantly associated with prostate cancer risk. The multivariable-adjusted HRs (95 % CI), comparing those who drank six or more cups per day to nondrinker, were as follows: 0.94 (0.86-1.02), p trend = 0.08 for overall prostate cancer, 1.13 (0.91-1.40), p trend = 0.62 for advanced prostate cancer, and 0.79 (0.53-1.17), p trend = 0.20 for fatal prostate cancer. The findings remained nonsignificant when we stratified by prostate-specific antigen testing history or restricted to nonsmokers. CONCLUSIONS: We found no statistically significant association between coffee consumption and the risk of overall, advanced, or fatal prostate cancer in this cohort, though a modest reduction in risk could not be excluded. PMID- 23681473 TI - Extensive spinal cord ischemia following endovascular repair of an infrarenal abdominal aortic aneurysm: a rare complication. AB - Postoperative paraplegia secondary to spinal cord ischemia (SCI) is an extremely rare and devastating complication of endovascular repair in abdominal aortic aneurysm (AAA) surgery. The reported incidence is only 0.21 % worldwide. This case of postoperative paraplegia occurred in a 60-year-old man immediately following endovascular repair of an infrarenal AAA. Postoperative magnetic resonance imaging showed multiple foci of SCI involvement from C5 to L1. However, neither cerebral spinal fluid drainage nor steroid therapy was effective; he was eventually admitted with no improvement in his neurological status. The mechanism remains multifactorial until now and needs more attention in perioperative management. We report the first case involved in the most significantly extensive SCI after endovascular repair of an infrarenal AAA. PMID- 23681474 TI - Induction of COX-2 expression by Helicobacter pylori is mediated by activation of epidermal growth factor receptor in gastric epithelial cells. AB - Chronic infection of the gastric mucosa by Helicobacter pylori is associated with an increased risk of developing gastric cancer; however, the vast majority of infected individuals never develop this disease. One H. pylori virulence factor that increases gastric cancer risk is the cag pathogenicity island, which encodes a bacterial type IV secretion system. Cyclooxygenase-2 (COX-2) expression is induced by proinflammatory stimuli, leading to increased prostaglandin E2 (PGE2) secretion by gastric epithelial cells. COX-2 expression is increased in gastric tissue from H. pylori-infected persons. H. pylori also activates the epidermal growth factor receptor (EGFR) in gastric epithelial cells. We now demonstrate that H. pylori-induced activation of COX-2 in gastric cells is dependent upon EGFR activation, and that a functional cag type IV secretion system and direct bacterial contact are necessary for full induction of COX-2 by gastric epithelial cells. PGE2 secretion is increased in cells infected with H. pylori, and this induction is dependent on a functional EGFR. Increased apoptosis in response to H. pylori occurs in cells treated with a COX-2 inhibitor, as well as COX-2-/- cells, indicating that COX-2 expression promotes cell survival. In vivo, COX-2 induction by H. pylori is significantly reduced in mice deficient for EGFR activation compared with wild-type mice with a fully functional receptor. Collectively, these findings indicate that aberrant activation of the EGFR-COX-2 axis may lower the threshold for carcinogenesis associated with chronic H. pylori infection. PMID- 23681475 TI - Paradoxical regulation of ChAT and nNOS expression in animal models of Crohn's colitis and ulcerative colitis. AB - Morphological and functional changes in the enteric nervous system (ENS) have been reported in inflammatory bowel disease. We examined the effects of inflammation on the expression of choline acetyltransferase (ChAT) and nNOS in the muscularis externae of two models of colonic inflammation, trinitrobenzene sulfonic acid (TNBS)-induced colitis, which models Crohn's disease-like inflammation, and DSS-induced colitis, which models ulcerative Colitis-like inflammation. In TNBS colitis, we observed significant decline in ChAT, nNOS, and protein gene product (PGP) 9.5 protein and mRNA levels. In DSS colitis, ChAT and PGP9.5 were significantly upregulated while nNOS levels did not change. The nNOS dimer-to-monomer ratio decreased significantly in DSS- but not in TNBS-induced colitis. No differences were observed in the percentage of either ChAT (31 vs. 33%)- or nNOS (37 vs. 41%)-immunopositive neurons per ganglia or the mean number of neurons per ganglia (55 +/- 5 vs. 59 +/- 5, P > 0.05). Incubation of the distal colon muscularis externae in vitro with different types of inflammatory mediators showed that cytokines decreased ChAT and nNOS expression, whereas H2O2, a component of oxidative stress, increased their expression. NF-kappaB inhibitor MG-132 did not prevent the IL-1beta-induced decline in either ChAT or nNOS expression. These findings showed that TNBS- and DSS-induced inflammation differentially regulates the expression of two critical proteins expressed in the colonic myenteric neurons. These differences are likely due to the exposure of the myenteric plexus neurons to different combinations of Th1-type inflammatory mediators and H2O2 in each model. PMID- 23681477 TI - Amphiphilic aminoclay-RGO hybrids: a simple strategy to disperse a high concentration of RGO in water. AB - The aqueous dispersion of graphene or reduced graphene oxide (RGO) is very much important to realize the full potential of these materials in many fields. Herein we present a simple route to prepare highly water dispersible aminoclay-RGO (AC RGO) hybrids by the in situ condensation of aminoclay over graphene oxide (GO) followed by reduction with hydrazine hydrate. The resultant hybrids are stable in aqueous media even at concentrations up to 7.5 mg RGO per mL. To the best of our knowledge this is the highest concentration of an aqueous dispersion of RGO. Significantly, the hybrids are amphiphilic in nature and show simultaneous adsorption of Cytochrome C through hydrophobic interaction and DNA through electrostatic interaction. This strategy opens up new possibilities for the prospect of RGO in catalysis and biomedical applications. PMID- 23681476 TI - Pancreatitis activates pancreatic apelin-APJ axis in mice. AB - Pancreatitis is classified into acute pancreatitis (AP) and chronic pancreatitis (CP). Apelin, a small regulatory peptide, is the endogenous ligand for the APJ receptor. Apelin and APJ are expressed in the pancreas. The aims of this study were to examine whether apelin influences the inflammatory and fibrosis responses to pancreatitis in mice and to identify mechanisms behind apelin's activities. Supramaximal cerulein induction of AP or CP caused significant (P < 0.05) elevations in pancreatic apelin and APJ expression. Levels declined during the recovery phases. In apelin gene-knockout mice with pancreatitis, pancreatic neutrophil invasion and myeloperoxidase activity were enhanced significantly, and apelin treatment suppressed both. Apelin exposure reduced CP-induced elevations of extracellular matrix-associated proteins. Apelin inhibited PDGF-simulated connective tissue growth factor production and proliferation of pancreatic stellate cells (PSCs). Serum granulocyte colony-stimulating factor and keratinocyte cytokine levels were higher in apelin gene-knockout than wild-type mice with pancreatitis. Apelin reduced AP- and CP-induced elevations in pancreatic NF-kappaB activation. Together, these findings imply that the pancreatic apelin-APJ system functions to curb the inflammatory and fibrosis responses during pancreatitis. Furthermore, findings suggest that apelin reduces inflammation and fibrosis by reducing neutrophil recruitment and PSC activity. Inhibition of neutrophil invasion may be mediated by reduced keratinocyte cytokine and granulocyte colony-stimulating factor secretion. Apelin-induced reductions in PSC proliferation and connective tissue growth factor production are putative mechanisms underlying apelin's inhibition of extracellular matrix production. The apelin-associated changes in NF-kappaB binding may be linked to apelin's regulation of pancreatic inflammatory and fibrosis responses during pancreatitis. PMID- 23681478 TI - Association of socio-economic status and dietary habits with early childhood caries among 3- to 5-year-old children of Belgaum city. AB - AIM: To ascertain if there were any association of socio-demographic factors and dietary habits with early childhood caries (ECC). METHODS: A cross-sectional study was conducted on 1,250 children 3-5 years of age. A self-designed validated questionnaire was prepared comprising two parts, one pertaining to socio demographic data and the other related to a 3-day diet diary. Socio-economic stratification was based on Kuppuswamy's classification. Diet history was obtained via a 3-day diet diary completed by the parents. A calibrated examiner conducted the oral examinations of the preschool children. Dental caries was assessed by using WHO criteria. Chi-square test and logistic regressions described the strength of the associations. RESULTS: The prevalence rate of ECC was 63.17 %. Significant associations were obtained between ECC and age of the child, number of siblings in the family, mother's education, sucrose exposure in between meals, sucrose exposure at meals, total frequency of sucrose exposure, and total sweet score. However, non-significant association of ECC was observed with socio-economic status. CONCLUSION: Many of the socio-demographic and dietary factors were significantly associated with ECC. It would be appropriate to plan health education strategies for parents and care takers by inculcating socio demographic factors with emphasis on reduced sucrose intake. ECC should be regarded as a serious public health problem. PMID- 23681479 TI - Electrophysiological and morphological characterization of cells in superficial layers of rat presubiculum. AB - The presubiculum (PrS) plays critical roles in spatial information processing and memory consolidation and has also been implicated in temporal lobe epileptogenesis. Despite its involvement in these processes, a basic structure function analysis of PrS cells remains far from complete. To this end, we performed whole-cell recording and biocytin labeling of PrS neurons in layer (L)II and LIII to examine their electrophysiological and morphological properties. We characterized the cell types based on electrophysiological criteria, correlated their gross morphology, and classified them into distinct categories using unsupervised hierarchical cluster analysis. We identified seven distinct cell types: regular-spiking (RS), irregular-spiking (IR), initially bursting (IB), stuttering (Stu), single-spiking (SS), fast-adapting (FA), and late-spiking (LS) cells, of which RS and IB cells were common to LII and LIII, LS cells were specific to LIII, and the remaining types were identified exclusively in LII. Recorded neurons were either pyramidal or nonpyramidal and, except for Stu cells, displayed spine-rich dendrites. The RS, IB, and IR cells appeared to be projection neurons based on extension of their axons into LIII of the medial entorhinal area (MEA) and/or angular bundle. We conclude that LII and LIII of PrS are distinct in their neuronal populations and together constitute a more diverse population of neurons than previously suggested. PrS neurons serve as major drivers of circuits in superficial (LII-III) entorhinal cortex (ERC) and couple neighboring structures through robust afferentation, thereby substantiating the PrS's critical role in the parahippocampal region. PMID- 23681480 TI - A Guide for Health Professionals Working with Aboriginal Peoples: Cross Cultural Understanding. PMID- 23681481 TI - Intrachoroidal cavitation in North Carolina macular dystrophy. PMID- 23681482 TI - A regulatory gene (ECO-orf4) required for ECO-0501 biosynthesis in Amycolatopsis orientalis. AB - ECO-0501 is a novel linear polyene antibiotic, which was discovered from Amycolatopsis orientalis. Recent study of ECO-0501 biosynthesis pathway revealed the presence of regulatory gene: ECO-orf4. The A. orientalis ECO-orf4 gene from the ECO-0501 biosynthesis cluster was analyzed, and its deduced protein (ECO orf4) was found to have amino acid sequence homology with large ATP-binding regulators of the LuxR (LAL) family regulators. Database comparison revealed two hypothetical domains, a LuxR-type helix-turn-helix (HTH) DNA binding motif near the C-terminal and an N-terminal nucleotide triphosphate (NTP) binding motif included. Deletion of the corresponding gene (ECO-orf4) resulted in complete loss of ECO-0501 production. Complementation by one copy of intact ECO-orf4 restored the polyene biosynthesis demonstrating that ECO-orf4 is required for ECO-0501 biosynthesis. The results of overexpression ECO-orf4 on ECO-0501 production indicated that it is a positive regulatory gene. Gene expression analysis by reverse transcription PCR of the ECO-0501 gene cluster showed that the transcription of ECO-orf4 correlates with that of genes involved in polyketide biosynthesis. These results demonstrated that ECO-orf4 is a pathway-specific positive regulatory gene that is essential for ECO-0501 biosynthesis. PMID- 23681484 TI - [Praise for the 80th birthday of Prof. Dr. Harald Tscherne]. PMID- 23681485 TI - [Sequelae after complex trauma of the knee joint]. PMID- 23681486 TI - [Posttraumatic limitations in range of movement of the knee joint]. AB - Limitations of range of movement of the knee joint are frequent sequelae of complex knee trauma. The subjective outcome is significantly compromised by loss of movement of the knee joint. This article discusses the osseous and soft tissue factors contributing to loss of movement of the knee joint after trauma. Indications and techniques of arthrolysis, posterior capsulotomy, periarticular osteotomy, tuberosity shift, patella tendon lengthening, vastus intermedius resection and quadricepsplasty are discussed. In summary complex revision surgery is often indicated to improve function of the knee and quality of life of the patients. PMID- 23681487 TI - [Intracondylar segment osteotomy: correction of intra-articular malalignment after fracture of the tibial plateau]. AB - Intracondylar deformities after tibial plateau fractures are intra-articular deformities which present within the medial and/or lateral knee compartments. They exist either isolated or in combination with other extra-articular deformities and/or ligament problems. These deformities are complex problems and difficult to treat. While many treatment concepts exist for extra-articular deformities there is limited information available for intra-articular or even intracondylar deformities. Selecting the appropriate procedure for the approach, osteotomy, management of bone defects and cartilage damage is crucial. The authors describe the analysis, planning, treatment and clinical outcome for these rare but difficult problems and present step by step details of the surgical technique. PMID- 23681488 TI - GABAergic tonic inhibition is regulated by developmental age and epilepsy in the dentate gyrus. AB - gamma-Aminobutyric acid (GABA) spillover from synaptic cleft activates extrasynaptic GABAA receptor and results in a tonic inhibition, which induces a background inhibitory effect to stabilize the membrane potential of the neuronal cells. However, the role of tonic inhibition and how it can be regulated during brain development and epileptic state remain elusive. By whole-cell patch-clamp recording on the granule cell in the dentate gyrus, we recorded tonic conductance to investigate the level of tonic inhibition in these two critical periods. According to our observation, an age-dependent increase in tonic conductance was observed. Furthermore, a change in tonic inhibition was also found in a chronic epileptic animal model, indicating that the alteration in tonic inhibition after epilepsy induction persists for a long duration to modulate neuronal activities. The present results show that tonic inhibition is altered during brain development and a chronic epileptic condition, indicating a role of the tonic inhibitory effect in both the critical periods. PMID- 23681489 TI - Complete photochromic structural changes in ruthenium(II)-diimine complexes, based on control of the excited states by metalation. AB - The thermal and photochemical reactions of a newly synthesized complex, [Ru(II)(TPA)(tpphz)](2+) (1; TPA=tris(2-pyridylmethyl)amine, tpphz=tetrapyrido[3,2-a:2',3'-c:3'',2''-h: 2''',3'''-j]phenazine), and its derivatives have been investigated. Heating a solution of complex 1 (closed form) and its derivatives in MeCN caused the partial dissociation of one pyridylmethyl moiety of the TPA ligand and the resulting vacant site on the Ru(II) center was occupied by a molecule of MeCN from the solvent to give a dissociated complex, [Ru(II)(eta(3)-TPA)(tpphz)(MeCN)](2+) (1', open form), and its derivatives, respectively, in quantitative yields. The thermal dissociation reactions were investigated on the basis of kinetics analysis, which indicated that the reactions proceeded through a seven-coordinate transition state. Although the backwards reaction was induced by photoirradiation of the MLCT absorption bands, the photoreaction of complex 1' reached a photostationary state between complexes 1 and 1' and, hence, the recovery of complex 1 from complex 1' was 67%. Upon protonation of complex 1 at the vacant site of the tpphz ligand, the efficiency of the photoinduced recovery of complex 1+H(+) from complex 1'+H(+) improved to 83%. In contrast, dinuclear MU-tpphz complexes 2 and 3, which contained the Ru(II)(TPA)(tpphz) unit and either a Ru(II)(bpy)2 or Pd(II)Cl2 moiety on the other coordination edge of the tpphz ligand, exhibited 100% photoconversion from their open forms into their closed forms (2'->2 and 3'->3). These results are the first examples of the complete photochromic structural change of a transition metal complex, as represented by complete interconversion between its open and closed forms. Scrutinization by performing optical and electrochemical measurements allowed us to propose a rationale for how metal coordination at the vacant site of the tpphz ligand improves the efficiency of photoconversion from the open form into the closed form. It is essential to lower the energy level of the triplet metal-to-ligand charge-transfer excited state ((3)MLCT*) of the closed form relative to that of the triplet metal-centered excited state ((3)MC*) by metal coordination. This energy-level manipulation hinders the transition from the (3)MLCT* state into the (3)MC* state in the closed form to block the partial photodissociation of the TPA ligand. PMID- 23681490 TI - Changes in soil bacterial community structure with increasing disturbance frequency. AB - Little is known of the responsiveness of soil bacterial community structure to disturbance. In this study, we subjected a soil microcosm to physical disturbance, sterilizing 90 % of the soil volume each time, at a range of frequencies. We analysed the bacterial community structure using 454 pyrosequencing of the 16S rRNA gene. Bacterial diversity was found to decline with the increasing disturbance frequencies. Total bacterial abundance was, however, higher at intermediate and high disturbance frequencies, compared to low and no-disturbance treatments. Changing disturbance frequency also led to changes in community composition, with changes in overall species composition and some groups becoming abundant at the expense of others. Some phylogenetic groups were found to be relatively more disturbance-sensitive or tolerant than others. With increasing disturbance frequency, phylogenetic species variability (an index of community composition) itself became more variable from one sample to another, suggesting a greater role of chance in community composition. Compared to the tightly clustered community of the original undisturbed soil, in all the aged disturbed soils the lists of most abundant operational taxonomic units (OTUs) in each replicate were very different, suggesting a possible role of stochasticity in resource colonization and exploitation in the aged and disturbed soils. For example, colonization may be affected by whichever localized concentrations of bacterial populations happen to survive the last disturbance and be reincorporated in abundance into each pot. Overall, it appears that the soil bacterial community is very sensitive to physical disturbance, losing diversity, and that certain groups have identifiable 'high disturbance' vs. 'low disturbance' niches. PMID- 23681493 TI - Introduction to this issue: international perspectives on preventive detention. PMID- 23681494 TI - Understanding the experience of patients with chronic obstructive pulmonary disease who access specialist palliative care: a qualitative study. AB - BACKGROUND: Palliative care for people with life-limiting non-malignant disease is increasingly prioritised. People with end-stage chronic obstructive pulmonary disease are among a key group of non-cancer patients likely to benefit from specialist palliative care, but it remains uncertain whether the needs of this group are met by existing services. AIM: To evaluate the experiences of patients with chronic obstructive pulmonary disease who accessed specialist palliative care. DESIGN: Data from semi-structured interviews were analysed using a hermeneutic phenomenological approach. SETTING/PARTICIPANTS: Eight patients accessing specialist palliative care within one city in North West England. RESULTS: Perceived benefits of specialist palliative care included reduced frequency of hospital admission, improved physical and psychological symptoms, reduced social isolation and a broadened physical environment. Participants were mainly aware of their poor prognosis, but discussion of referral to palliative care sometimes caused distress owing to the historical associations between dying and hospice care. Following engagement with services, participants' perceptions changed: palliative care was associated with social inclusion and opportunities to engage in reciprocal and altruistic social action. Negative associations were replaced by uncertainty and anxiety about the prospect of discharge. CONCLUSIONS: Much within existing services works well for people with chronic obstructive pulmonary disease, but opportunities to enhance palliative care for this underserved group remain. Future research might focus on prospectively evaluating the impact of key components of palliative care on core patient-centred outcomes. Additionally, work must be done to raise awareness of the benefits of specialist palliative care for non-cancer patients, as negative associations can form a barrier to access. PMID- 23681491 TI - Neurovascular function and sudorimetry in health and disease. AB - In this review of thermoregulatory function in health and disease, we review the basic mechanisms controlling skin blood flow of the hairy and glabrous skin and illustrate the major differences in blood flow to glabrous skin, which is, in essence, sympathetically mediated, while hairy skin is dependent upon neuropeptidergic signals, nitric oxide, and prostaglandin, among others. Laser Doppler methods of quantification of blood flow--in response to iontophoresis of acetylcholine or heat--and nociceptor-mediated blood flow have relatively uniformly demonstrated an impaired capacity to increase blood flow to the skin in diabetes and in its forerunners, prediabetes and the metabolic syndrome. This reduced capacity is likely to be a significant contributor to the development of foot ulcerations and amputations in diabetes, and means of increasing blood flow are clearly needed. Understanding the pathogenic mechanisms is likely to provide a means of identifying a valuable therapeutic target. Thermoregulatory control of sweating is intimately linked to the autonomic nervous system via sympathetic C fibers, and sweat glands are richly endowed with a neuropeptidergic innervation. Sweating disturbances are prevalent in diabetes and its precursors, and quantification of sweating may be useful as an index of diagnosis of somatic and, probably, autonomic dysfunction. Moreover, quantifying this disturbance in sweating by various methods may be useful in identifying the risk of progression from prediabetes to diabetes, as well as responses to therapeutic intervention. We now have the technological power to take advantage of this physiological arrangement to better understand, monitor, and treat disorders of small nerve fibers and the somatic and autonomic nervous system (ANS). Newer methods of sudomotor function testing are rapid, noninvasive, not technically demanding, and accessible to the outpatient clinic. Whether the potential applications are screening for diabetes, following poorly controlled diabetes subjects during alteration of their treatment regimen, or simply monitoring somatic and autonomic function throughout the course of treatment, sudorimetry can be an invaluable tool for today's clinicians. PMID- 23681495 TI - Comprehensive VTE prevention program incorporating mandatory risk assessment reduces the incidence of hospital-associated thrombosis. AB - BACKGROUND: VTE is a common complication of hospitalization and is associated with significant morbidity and mortality. The use of appropriate thromboprophylaxis can significantly reduce the risk of VTE but remains underutilized. In England, a comprehensive approach to VTE prevention was launched in 2010. This study aimed to evaluate the impact of the implementation of the national program in a single center. METHODS: A prospective quality improvement program was established at King's College Hospital NHS Foundation Trust in 2010. The multidisciplinary thrombosis team launched mandatory documented VTE risk assessment and updated thromboprophylaxis guidance. Root cause analysis of hospital-associated thrombosis (HAT) was implemented to identify system failures, enable outcome measurement, and facilitate learning to improve VTE prevention practice. The key outcomes were the incidence of HAT and the proportion of events preventable with appropriate thromboprophylaxis. RESULTS: Documented VTE risk assessment improved from <40% to > 90% in the first 9 months. Four hundred twenty-five episodes of HAT were identified over 2 years. A significant reduction in the incidence of HAT was observed following sustained achievement of 90% risk assessment (risk ratio, 0.88; 95% CI, 0.74-0.98; P = .014). The proportion of HAT attributable to inadequate thromboprophylaxis fell significantly from 37.5% to 22.4% (P = .005). CONCLUSIONS: Mandatory VTE risk assessment can significantly reduce preventable HAT and thereby improve patient safety. PMID- 23681496 TI - Pregnancy outcomes amongst thalassemia traits. AB - OBJECTIVE: To compare the pregnancy outcome between pregnancies affected and not affected by thalassemia trait. METHODS: A retrospective case-control cohort study was conducted on singleton pregnant women who attended antenatal care and delivered at Songklanagarind Hospital. All of the participating thalassemia trait pregnant women were diagnosed based on hemoglobin typing and/or DNA analysis. A ratio of around 1-1 was used to compare their pregnancy outcomes with normal pregnant women. RESULTS: Seven hundred thirty-nine thalassemia trait and 799 normal pregnant women were included in the study. All of the women were Thai nationals living in the Southern Region of Thailand and nearly all of them had spontaneously conceived. Maternal complication rates of gestational diabetes, preterm birth, antepartum bleeding, postpartum bleeding, shoulder dystocia and puerperal morbidity, and the rates of neonatal complications: macrosomia, fetal weight <2,000 g, intrauterine growth restriction (IUGR), stillbirth, low Apgar score (<7) at 1 and 5 min and NICU admission, were not significantly different between the two groups. The rate of pre-eclampsia, however, was significantly different, with RRs of 1.73 (CI 1.01-3.00). CONCLUSION: The thalassemia trait condition did not affect the risk of gestational diabetes, postpartum hemorrhage, stillbirth, preterm birth and puerperal morbidity. However, pre-eclampsia should be warranted especially among nulliparous and high-BMI pregnant women. PMID- 23681497 TI - The evidence on surgical interventions for low back disorders, an overview of systematic reviews. AB - PURPOSE: Many systematic reviews have been published on surgical interventions for low back disorders. The objective of this overview was to evaluate the available evidence from systematic reviews on the effectiveness of surgical interventions for disc herniation, spondylolisthesis, stenosis, and degenerative disc disease (DDD). An earlier version of this review was published in 2006 and since then, many new, better quality reviews have been published. METHODS: A comprehensive search was performed in the Cochrane database of systematic reviews (CDSR), database of reviews of effectiveness (DARE) and Pubmed. Two reviewers independently performed the selection of studies, risk of bias assessment, and data extraction. Included are Cochrane reviews and non-Cochrane systematic reviews published in peer-reviewed journals. The following conditions were included: disc herniation, spondylolisthesis, and DDD with or without spinal stenosis. The following comparisons were evaluated: (1) surgery vs. conservative care, and (2) different surgical techniques compared to one another. The methodological quality of the systematic reviews was evaluated using AMSTAR. We report (pooled) analyses from the individual reviews. RESULTS: Thirteen systematic reviews on surgical interventions for low back disorders were included for disc herniation (n = 6), spondylolisthesis (n = 2), spinal stenosis (n = 4), and DDD (n = 4). Nine (69 %) were of high quality. Five reviews provided a meta analysis of which two showed a significant difference. For the treatment of spinal stenosis, intervertebral process devices showed more favorable results compared to conservative treatment on the Zurich Claudication Questionnaire [mean difference (MD) 23.2 95 % CI 18.5-27.8]. For degenerative spondylolisthesis, fusion showed more favorable results compared to decompression for a mixed aggregation of clinical outcome measures (RR 1.40 95 % CI 1.04-1.89) and fusion rate favored instrumented fusion over non-instrumented fusion (RR 1.37 95 % CI 1.07-1.75). CONCLUSIONS: For most of the comparisons, the included reviews were not significant and/or clinically relevant differences between interventions were identified. Although the quality of the reviews was quite acceptable, the quality of the included studies was poor. Future studies are likely to influence our assessment of these interventions. PMID- 23681498 TI - A comprehensive multimodal pain treatment reduces opioid consumption after multilevel spine surgery. AB - PURPOSE: Major spine surgery with multilevel instrumentation is followed by large amount of opioid consumption, significant pain and difficult mobilization in a population of predominantly chronic pain patients. This case-control study investigated if a standardized comprehensive pain and postoperative nausea and vomiting (PONV) treatment protocol would improve pain treatment in this population. METHODS: A new regimen with acetaminophen, NSAIDs, gabapentin, S ketamine, dexamethasone, ondansetron and epidural local anesthetic infusion or patient controlled analgesia with morphine, was introduced in a post-intervention group of 41 consecutive patients undergoing multilevel (median 10) instrumented spinal fusions and compared with 44 patients in a pre-intervention group. RESULTS: Compared to patients in the pre-intervention group, patients treated according to the new protocol consumed less opioid on postoperative day (POD) 1 (P = 0.024) and 2 (P = 0.048), they were mobilized earlier from bed (P = 0.003) and ambulation was earlier both with and without a walking frame (P = 0.027 and P = 0.027, respectively). Finally, patients following the new protocol experienced low intensities of nausea, sedation and dizziness on POD 1-6. CONCLUSIONS: In this study of patients scheduled for multilevel spine surgery, it was demonstrated that compared to a historic group of patients receiving usual care, a comprehensive and standardized multimodal pain and PONV protocol significantly reduced opioid consumption, improved postoperative mobilization and presented concomitant low levels of nausea, sedation and dizziness. PMID- 23681499 TI - Sacrococcygeal sinus angle: as a new anatomic landmark for the posterior approach of presacral lesions. AB - PURPOSE: We have discussed the importance of sacrococcygeal sinus angle (SSA), which is a new anatomical landmark in the surgery of presacral lesions. Because of its anatomical structure, the sacrum limits the surgical exposure like a compact barrier for the posterior surgical approach. The main aim of this paper is to explain the anatomical description and clinical importance of SSA in the surgery of presacral lesions. METHODS: Three groups were designated, consisting of ten patients in each group, as early childhood (group 1), late childhood (group 2) and adulthood (group 3). Patients were selected randomly. The degree of SSA measurement was performed between the line tangent to the anterior margin of the first sacral vertebra and the line from the promontorium to the tip of the coccyx. The measurement of SSA was performed on patients' lumbosacral magnetic resonance images. When the SSA forms a triangle via a parallel line starting from the inferior tip of the sacrum and running parallel to the ground, the area of the triangle also covers the field of view of the presacral region. In addition, the sacral region needed to be resected for maximum exposure is also within this area. RESULTS: The mean SSA was measured to be 53.9 +/- 11.4 degrees in group 1, 77.8 +/- 11.2 degrees in group 2 and 74.5 +/- 12.5 degrees in group 3. Intergroup comparisons revealed a significant difference between group 1 and the other two groups statistically. It was found that the SSA was 20 degrees less in group 1 as compared to the other age groups (p = 0.0005). The area of a triangle is calculated using the sine area formula, and according to this formula the area of a triangle increases when the degree of the angle increases, thus comprising larger part of the sacrum. This condition requires more and wide sacral resection to obtain maximum exposure in the presacral zone. CONCLUSIONS: We have observed that the SSA is significantly smaller during early childhood compared with the other age groups. This feature provides an anatomical superiority in this age group for the posterior approach in the surgical treatment of presacral masses. PMID- 23681500 TI - Coronary CT angiography using the second-generation 320-detector row CT: assessment of image quality and radiation dose in various heart rates compared with the first-generation scanner. AB - To assess the image quality and radiation dose reduction in various heart rates in coronary CT angiography using the second-generation 320-detector row CT compared with the first-generation CT. Ninety-six patients were retrospectively included. The first 48 patients underwent coronary CT angiography with the first generation 320-detector row CT, while the last 48 patients underwent with the second-generation CT. Subjective image quality was graded using a 4-point scale (4, excellent; 1, unable to evaluate). Image noise and contrast-to-noise ratio were also analyzed. Subgroup analysis was performed based on the heart rate. The mean effective dose was derived from the dose length product multiplied by a conversion coefficient for the chest (kappa = 0.014 mSv * mGy(-1) * cm(-1)). The overall subjective image quality score showed no significant difference (3.66 vs 3.69, respectively, p = 0.25). The image quality score of the second-generation group tended to be higher than that of the first-generation group in the 66- to 75-bpm subgroup (3.36 vs 3.53, respectively, p = 0.07). No significant difference was observed in image noise and contrast-to-noise ratio. The overall radiation dose reduced by 24 % (3.3 vs 2.5 mSv, respectively, p = 0.03), and the reduction was substantial in patients with higher heart rate (66- to 75-bpm, 4.3 vs 2.2 mSv, respectively, p = 0.009; >75 bpm, 8.2 vs 3.7 mSv, respectively, p = 0.005). The second-generation 320-detector row CT could maintain the image quality while reducing the radiation dose in coronary CT angiography. The dose reduction was larger in patients with higher heart rate. PMID- 23681501 TI - Gadobutrol in the central nervous system at three doses: results from a phase II, randomized, multicenter trial. AB - PURPOSE: To investigate the efficacy and safety of three doses of gadobutrol and determine the minimum effective dose for contrast-enhanced MRI of the central nervous system (CNS). MATERIALS AND METHODS: This was a Phase II, multicenter, double-blind, parallel-group controlled study in subjects referred for contrast enhanced MRI of the CNS. Subjects were randomized to receive gadobutrol 0.03, 0.1, or 0.3 mmol/kg body weight, and underwent unenhanced, gadobutrol-enhanced, and comparator-enhanced MRI scans. Three blinded readers assessed the images. Primary efficacy variables were number of lesions detected, border delineation, contrast enhancement, and internal morphology. RESULTS: Of the 229 randomized subjects, 173 were evaluated for efficacy. Clinically meaningful improvements in lesion border delineation, contrast enhancement, and internal morphology were observed for 0.1 mmol/kg gadobutrol. Pair-wise comparisons of a composite score of the four primary variables showed the 0.1 mmol/kg dose to be statistically superior to the 0.03 mmol/kg dose (P = 0.003). The 0.3 mmol/kg dose showed no statistically significant difference with the 0.1 mmol/kg dose. Twenty-two (9.8%) subjects reported at least one treatment-emergent adverse event (TEAE). No TEAE was reported at an incidence >3.5%. CONCLUSION: The 0.1 mmol/kg dose of gadobutrol was effective and well tolerated for contrast-enhanced MRI of the CNS. PMID- 23681502 TI - Benefits of combining inspiratory muscle with 'whole muscle' training in children with cystic fibrosis: a randomised controlled trial. AB - BACKGROUND: The purpose of this study (randomised controlled trial) was to assess the effects of an 8-week combined 'whole muscle' (resistance+aerobic) and inspiratory muscle training (IMT) on lung volume, inspiratory muscle strength (PImax) and cardiorespiratory fitness (VO2 peak) (primary outcomes), and dynamic muscle strength, body composition and quality of life in paediatric outpatients with CF (cystic fibrosis, secondary outcomes). We also determined the effects of a detraining period. METHODS: Participants were randomly allocated with a block on gender to a control (standard therapy) or intervention group (initial n=10 (6 boys) in each group; age 10+/-1 and 11+/-1 years). The latter group performed a combined programme (IMT (2 sessions/day) and aerobic+strength exercises (3 days/week, in-hospital)) that was followed by a 4-week detraining period. All participants were evaluated at baseline, post-training and detraining. RESULTS: Adherence to the training programme averaged 97.5%+/-1.7%. There was a significant interaction (group*time) effect for PImax, VO2peak and five repetition maximum strength (leg-press, bench-press, seated-row) (all (p<0.001), and also for %fat (p<0.023) and %fat-free mass (p=0.001), with training exerting a significant beneficial effect only in the intervention group, which was maintained after detraining for PImax and leg-press. CONCLUSION: The relatively short-term (8-week) training programme used here induced significant benefits in important health phenotypes of paediatric patients with CF. IMT is an easily applicable intervention that could be included, together with supervised exercise training in the standard care of these patients. PMID- 23681503 TI - Testing for boosting at the Paralympic games: policies, results and future directions. AB - BACKGROUND: 'Boosting' is defined as the intentional induction of autonomic dysreflexia (AD) by athletes with a spinal cord injury (SCI) at or above the level of T6 for the purpose of improving sports performance. Boosting has been shown to confer up to a 9.7% improvement in race time. Additionally, to compete in a hazardous dysreflexic state, whether intentional or unintentional, would present an extreme health risk to the athlete. For these reasons, the International Paralympic Committee strictly bans the practice of boosting, and has developed a protocol to test for its presence. METHODS: Testing was performed at three major international Paralympic events. Education regarding the dangers of AD was provided to athletes and team staff. Testing was conducted on athletes from the relevant sport classes: Athletics (wheelchair racing classes T51/T52/T53) and Handcycling (H1). Key parameters included the athlete's demographics (gender, country of origin), classification and blood pressure measurements. An extremely elevated blood pressure was considered to be a proxy maker for AD, and a systolic blood pressure of >=180 mm Hg was considered a positive test. RESULTS: A total of 78 tests for the presence of AD were performed during the three games combined. No athlete tested positive. The number of athletes tested, by classification, was: 6 in Athletics T51, 47 in Athletics T52, 9 in Athletics T53 and 16 in Handcycling H1. Of those tested, the average systolic and diastolic blood pressures were 135 mm Hg (range 98-178) and 82 mm Hg (range 44-112), respectively. All athletes were compliant with testing. No athletes were withdrawn from competition due to the presence of AD. DISCUSSION: Testing for the presence of AD in paralympic athletes with SCI prior to competition has been carried out for the first time at three major international paralympic competitions. There have been no positive tests thus far. Knowledge gained during these early testing experiences will be used to guide ongoing refinement of the testing protocol and the development of further educational initiatives. PMID- 23681504 TI - Efficacy and safety of certolizumab pegol for Crohn's disease: a systematic review and meta-analysis. AB - INTRODUCTION: The authors performed a systematic review and meta-analysis of data from randomized controlled trials (RCTs) to evaluate the efficacy and safety of certolizumab pegol. METHODS: The authors searched PubMed, MEDLINE via Medscape, BioMed Central, Google Scholar, China National Knowledge Infrastructure (CNKI), the Cochrane library, and the Directory of Open Access Journals. The outcomes of interest were response and remission rates and the treatment-related toxicity rate. RESULTS: A total of five RCTs, involving 1,891 participants, were included. The meta-analysis revealed that certolizumab significantly increased the overall (induction + maintenance therapy) response [odds ratio (OR) 1.565, 95% CI 1.056 2.321, P = 0.026] and remission rates (OR 1.626, 95% CI 1.297-2.038, P < 0.001) compared with placebo. Certolizumab significantly increased the response and remission rates when given as maintenance therapy (OR 2.171, 95% CI 1.644-2.866, P < 0.001 and OR 1.888, 95% CI 1.390-2.565, P < 0.001), but not as induction therapy (OR 1.234, 95% CI 0.912-1.671, P = 0.173 and OR 1.361, 95% CI 0.974 1.901, P = 0.071). Certolizumab (induction + maintenance therapy) did not significantly increase the treatment-related toxicity rate compared with placebo (OR 0.985, 95% CI 0.799-1.214, P = 0.887). CONCLUSION: Certolizumab may be an efficacious treatment for Crohn's disease as maintenance therapy and appears to have a favorable safety profile. PMID- 23681505 TI - Efficacy and safety of lisdexamfetamine dimesylate in children with attention deficit/hyperactivity disorder and recent methylphenidate use. AB - INTRODUCTION: Lisdexamfetamine dimesylate (LDX) is a long-acting prodrug stimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). Post hoc subgroup analyses were performed from two studies in children with ADHD to compare the efficacy of LDX in participants who had received prior methylphenidate (MPH) treatment with that of the overall study populations. METHODS: Study 1 (7-week; open-label design) and study 2 (randomized, double blind, placebo-controlled, crossover, laboratory school design) enrolled children aged 6-12 years with ADHD and baseline ADHD Rating Scale IV (ADHD-RS-IV) total score >=28. Both studies excluded children whose prestudy ADHD treatment provided effective control of ADHD symptoms with an acceptable safety profile. Post hoc efficacy analyses were performed in children who had received MPH within 6 months of study enrollment. Efficacy measures included the following scales: ADHD-RS-IV, Clinical Global Impressions-Improvement (CGI-I), Expression and Emotion Scale for Children (EESC), Behavior Rating Inventory of Executive Function (BRIEF), Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP), and Permanent Product Measure of Performance (PERMP). RESULTS: In studies 1 and 2, 83/318 (26%) and 67/129 (52%) participants, respectively, had received MPH within 6 months and were not adequately controlled on current medication with acceptable tolerability; most of these participants had received long-acting MPH. In prior MPH participants, efficacy assessments demonstrated improvements from baseline (study 1) and versus placebo (study 2) that were comparable with those seen in the respective overall study population. Safety profiles were consistent with long-acting stimulant use. CONCLUSION: In two studies, children who had received prior MPH treatment improved during treatment with LDX and experienced similar improvements in their symptoms as the overall study populations. For children with ADHD who were previously treated with MPH, LDX may, therefore, be an efficacious treatment option. PMID- 23681506 TI - Hsp90 facilitates accurate loading of precursor piRNAs into PIWI proteins. AB - PIWI-interacting RNAs (piRNAs) defend the genome against transposon activity in animal gonads. The Hsp90 chaperone machinery has been implicated in the piRNA pathway, but its exact role remains obscure. Here, we examined the effect of 17-N allylamino-17-demethoxygeldanamycin (17-AAG), an Hsp90-specific inhibitor, on the piRNA pathway. In the silkworm ovary-derived BmN4 cells, 17-AAG treatment reduced the level of piRNAs and PIWI proteins. In vitro, the 5'-nucleotide preference upon precursor piRNA loading was compromised by 17-AAG, whereas 3'-end trimming and 2'-O-methylation were unaffected. Our data highlight a role of Hsp90 in accurate loading of precursor piRNAs into PIWI proteins. PMID- 23681507 TI - The spliceosome catalyzes debranching in competition with reverse of the first chemical reaction. AB - Splicing of nuclear pre-mRNA occurs via two steps of the transesterification reaction, forming a lariat intermediate and product. The reactions are catalyzed by the spliceosome, a large ribonucleoprotein complex composed of five small nuclear RNAs and numerous protein factors. The spliceosome shares a similar catalytic core structure with that of fungal group II introns, which can self splice using the same chemical mechanism. Like group II introns, both catalytic steps of pre-mRNA splicing can efficiently reverse on the affinity-purified spliceosome. The spliceosome also catalyzes a hydrolytic spliced-exon reopening reaction as observed in group II introns, indicating a strong link in their evolutionary relationship. We show here that, by arresting splicing after the first catalytic step, the purified spliceosome can catalyze debranching of lariat intron-exon 2. The debranching reaction, although not observed in group II introns, has similar monovalent cation preferences as those for splicing catalysis of group II introns. The debranching reaction is in competition with the reverse Step 1 reaction influenced by the ionic environment and the structure of components binding near the catalytic center, suggesting that the catalytic center of the spliceosome can switch between different conformations to direct different chemical reactions. PMID- 23681508 TI - Uncertainty reduction as a measure of cognitive load in sentence comprehension. AB - The entropy-reduction hypothesis claims that the cognitive processing difficulty on a word in sentence context is determined by the word's effect on the uncertainty about the sentence. Here, this hypothesis is tested more thoroughly than has been done before, using a recurrent neural network for estimating entropy and self-paced reading for obtaining measures of cognitive processing load. Results show a positive relation between reading time on a word and the reduction in entropy due to processing that word, supporting the entropy reduction hypothesis. Although this effect is independent from the effect of word surprisal, we find no evidence that these two measures correspond to cognitively distinct processes. PMID- 23681511 TI - [Endovascular treatment of thoracic aneurisms: indications, techniques and results]. AB - CLINICAL ISSUE OF THORACIC ANEURYSMS: Aneurysms are among the most common diseases affecting the thoracic aorta, with a continuous increase in incidence over the recent decades. The main cause of thoracic aneurysms is atherosclerosis, which, due to the frequent lack of major symptoms and the potentially lethal complications such as ruptured aortic aneurysm, remains a challenge in clinical practice. STANDARD RADIOLOGICAL METHODS: CT angiography remains the imaging method of choice for acute aortic aneurysms, with MR angiography being increasingly used for follow-up imaging. THRESHOLD FOR TREATMENT: In the ascending aorta a diameter larger than 5-5.5 cm (descending aorta 6.5 cm) is regarded as the threshold for treatment. THORACIC ENDOVASCULAR AORTIC REPAIR: The continuous evolution of aortic stent grafting (i.e., thoracic endovascular aortic repair [TEVAR]) since Parodi, Palmaz and Dake has led to a steep rise in stent grafting procedures in recent years. PRACTICAL RECOMMENDATIONS: Particularly in elderly patients with multiple comorbidities, TEVAR is a valuable, less invasive option compared to open surgical repair. PMID- 23681510 TI - Organ selective regulation of sympathetic outflow by the brain Angiotensin system. AB - Angiotensin II (Ang II) has actions on the sympathetic nervous system both as a circulating hormone acting on the circumventricular organs and also as a neurotransmitter/ neuromodulator acting within the brain. Administration of Ang II into the cerebral ventricles has diverse effects on sympathetic nerve activity (SNA), causing an increase in cardiac and splanchnic and a decrease in renal SNA. Similar contrasting effects on cardiac and renal SNA are seen with administration of hypertonic saline, which is thought to act centrally through angiotensinergic pathways. In heart failure there is compelling evidence that central angiotensinergic mechanisms contribute to the increases in cardiac and renal SNA, which have numerous detrimental effects. Although there is evidence that Ang II regulates sympathetic activity, and contributes to excess SNA in disease, the exact sites in the brain at which Ang II acts to selectively control SNA to individual organs are not well defined. PMID- 23681512 TI - [Endoleaks - when is treatment necessary?]. AB - Currently the majority of infrarenal abdominal aortic aneurysm repairs are endovascular procedures using a stent graft. This method continues to be questioned due to an up to 50 % incidence of endoleaks, i.e. the postinterventional persistence of blood flow outside the graft and within the aneurysm sac, potentially bearing the risk of a further increase of the aneurysm diameter and aneurysm rupture. Currently a total of five different endoleak types can be distinguished. Multiphase computed tomography (CT) is the standard imaging method for the detection and classification of endoleaks or alternatively contrast-enhanced ultrasound can be used. The different types of endoleak have very different therapeutic implications. In direct endoleaks (types I and III) the systemic blood pressure is directly transferred to the aneurysm wall which carries a high risk of rupture and in general an immediate intervention is indicated. Indirect endoleaks (types II, IV and V) take a more benign course and in the majority of cases treatment is only necessary when further aneurysm expansion occurs. PMID- 23681513 TI - [Do we need hybrid operating theaters?: a critical appraisal]. AB - CLINICAL ISSUE: Infrastructural improvements with a combination of interventional and open surgical procedures. STANDARD TREATMENT: Separate performance of interventional and open surgical procedures. TREATMENT INNOVATIONS: Implementation of hybrid operating rooms. DIAGNOSTIC WORK-UP: Intraoperative high quality digital subtraction angiography. PERFORMANCE: Best hygienic conditions Intraoperative improved image quality Improved patient management Increased patient safety Broadening of indications ACHIEVEMENTS: Major improvement from a medical standpoint Different implications from a management perspective Economic aspects challenging PRACTICAL RECOMMENDATIONS: Exact planning of all aspects and effects is necessary. PMID- 23681514 TI - [Intramammary lesion in a 23-year-old female patient]. PMID- 23681515 TI - [Indications for contrast media]. PMID- 23681516 TI - Do childhood cancer survivors with physical performance limitations reach healthy activity levels? AB - BACKGROUND: The extent to which physical performance limitations affect the ability of childhood cancer survivors to reach healthy activity levels is unknown. Therefore this study aims to describe the effect of different types of limitations on activity levels in survivors. PROCEDURE: Within the Swiss Childhood Cancer Survivor Study we sent a questionnaire to all survivors (>=16 years) registered in the Swiss Childhood Cancer Registry, who survived >5 years and were diagnosed 1976-2005 aged <16 years. We measured healthy activity levels using international guidelines and assessed different kinds of performance limitations (visual impairment, weight and endurance problems, cardiorespiratory, musculoskeletal, and neurological problems, pain and fatigue syndromes). RESULTS: The sample included 1,560 survivors (75% response rate), of whom 209 (13.5%) reported they have performance limitations. Forty-two percent of survivors with limitations reached healthy activity levels, compared to 57% of survivors without limitations. Least active were survivors with vision impairments (25% active), weight and endurance problems (27.3%), cardiorespiratory problems (36.4%), and musculoskeletal problems (43.1%). After adjusting for socio-demographic variables and type of cancer, we found that survivors with limitations were 1.4 (95%CI 1.0 2.0; P = 0.047) times more likely to be inactive. CONCLUSIONS: Although many survivors with physical performance limitations maintain healthy activity levels, there is room for improvement. Adapted and targeted physical activity counseling for survivors with performance limitations might help them to raise level of activity and pursue a healthy lifestyle. PMID- 23681518 TI - Analyzing plant signaling phospholipids through 32Pi-labeling and TLC. AB - Lipidomic analyses through LC-, GC-, and ESI-MS/MS can detect numerous lipid species based on headgroup and fatty acid compositions but usually miss the minor phospholipids involved in cell signaling because of their low chemical abundancy. Due to their high turnover, these signaling lipids are, however, readily picked up by labeling plant material with (32)P-orthophosphate and subsequent analysis of the lipid extracts by thin layer chromatography. Here, protocols are described for suspension-cultured tobacco BY-2 cells, young Arabidopsis seedlings, Vicia faba roots, and Arabidopsis leaf disks, which can easily be modified for other plant species and tissues. PMID- 23681519 TI - Analysis of D3-,4-,5-phosphorylated phosphoinositides using HPLC. AB - Detection of polyphosphoinositides (PPIs) is difficult due to their low chemical abundancy. This problem is further complicated by the fact that PPIs are present as various, distinct isomers, which are difficult, if not impossible, to separate by conventional thin layer chromatography (TLC) systems. PPIs in plants include PtdIns3P, PtdIns4P, PtdIns5P, PtdIns(3,5)P 2, and PtdIns(4,5)P 2. Here, a protocol is described analyzing plant PPIs using (32)P-orthophosphorus pre labeled material. After extraction, lipids are deacylated and the resulting glycerophosphoinositol polyphosphates (GroPInsPs) separated by HPLC using a strong anion-exchange column and a shallow salt gradient. Alternatively, PPIs are first separated by TLC, the lipids reisolated, deacylated, and the GroPInsPs then separated by HPLC. PMID- 23681520 TI - Mass measurement of polyphosphoinositides by thin-layer and gas chromatography. AB - Phosphoinositides derive from the phospholipid, phosphatidylinositol (PtdIns), by phosphorylation of the inositol ring in the lipid head group. The determination of phosphoinositide species is a particular challenge, because the structurally similar inositolphosphate-head groups must be analyzed as well as the lipid associated fatty acids. The method presented in this chapter consists of two steps: First phosphoinositides are separated by thin-layer chromatography (TLC) according to their characteristic head groups and the individual lipids are isolated. Second, the fatty acids associated with each isolated lipid are analyzed using a gas-chromatograph (GC). The combination of these two classical methods for lipid analysis, TLC and GC, provides a cost-efficient and reliable alternative to lipidomics approaches requiring more extensive instrumentation. PMID- 23681521 TI - Measurement of inositol (1,4,5) trisphosphate in plant tissues by a competitive receptor binding assay. AB - The phosphoinositide signaling pathway is important for plant responses to many different stresses. As part of the responses to a stimulus, InsP3 levels may increase rapidly and transiently. The receptor binding assay for InsP3 described here is easy to use and an ideal method to monitor and compare InsP3 levels in multiple samples from large scale experiments. The method is based on competitive binding of InsP3 to the mammalian brain InsP3 specific receptor protein. This chapter describes a protocol for extracting and neutralizing plant samples and performing the receptor binding assay (using a commercially available kit). The protocol described has been used effectively to monitor InsP3 levels in plant tissues of different origin and in response to different stresses. PMID- 23681522 TI - Quantification of diacylglycerol by mass spectrometry. AB - Diacylglycerol (DAG) is an important intermediate of lipid metabolism and a component of phospholipase C signal transduction. Quantification of DAG in plant membranes represents a challenging task because of its low abundance. DAG can be measured by direct infusion mass spectrometry (MS) on a quadrupole time-of-flight mass spectrometer after purification from the crude plant lipid extract via solid phase extraction on silica columns. Different internal standards are employed to compensate for the dependence of the MS and MS/MS signals on the chain length and the presence of double bonds in the acyl moieties. Thus, using a combination of single MS and MS/MS experiments, quantitative results for the different molecular species of DAGs from Arabidopsis can be obtained. PMID- 23681523 TI - Distinguishing phosphatidic acid pools from de novo synthesis, PLD, and DGK. AB - In plants, phosphatidic acid (PA) functions as a metabolic precursor in the biosynthesis of glycerolipids, but it also acts as a key signaling lipid in the response to environmental stress conditions (Testerink and Munnik, J Exp Bot 62:2349-2361, 2011). In vivo (32)P-radiolabeling assays have shown the level of PA to increase within seconds/minutes of exposure to a stimulus. This response can be due to the activity of diacylglycerol kinase (DGK) and/or phospholipase D (PLD). A method is described to investigate which of the pathways is responsible for PA accumulation under a particular stress condition. First, a differential (32)P-radiolabeling protocol is used to discriminate (32)P-PA pools that are rapidly labeled versus those requiring long prelabeling times, reflecting DGK and PLD activities, respectively. Second, to specifically monitor the contribution of PLD, a transphosphatidylation assay is applied, which makes use of the artificial lipid phosphatidylbutanol as an in vivo marker of PLD activity. PMID- 23681524 TI - Use of phospholipase A2 for the production of lysophospholipids. AB - Biological lipid extracts often contain small amounts of lysophospholipids (LPLs). Since different functions are emerging for LPLs in lipid metabolism and signalling, there is need for a reliable and cost-effective method for their identification. For this purpose, authentic LPL standards have to be synthesized from phosphoglycerides by PLA2 digestion in vitro. PLA2 specifically hydrolyzes the fatty acid ester linkage in the sn-2-position of phospholipids to liberate sn 2-linked fatty acids and the corresponding LPL. Due to this specificity, the reaction is also useful to analyze the positional distribution of fatty acids within membrane phospholipids. This chapter describes the in vitro generation of LPLs from diacyl-phosphoglycerides and their TLC analysis. PMID- 23681526 TI - Lipidomic analysis of plant membrane lipids by direct infusion tandem mass spectrometry. AB - Plant phospholipids and glycolipids can be analyzed by direct infusion electrospray ionization triple-quadrupole mass spectrometry. A biological extract is introduced in solvent by continuous infusion into the mass spectrometer's electrospray ionization source, where ions are produced from the lipids. For analysis of membrane lipids, a series of precursor and neutral loss scans, each specific for lipids containing a common head group, are obtained sequentially. The mass spectral data are processed and combined, using the Web application LipidomeDB Data Calculation Environment, to create a lipid profile. PMID- 23681525 TI - Analysis and quantification of plant membrane lipids by thin-layer chromatography and gas chromatography. AB - Galactolipids represent the predominant membrane lipid class in plants. In general, galactolipids are restricted to plastids, but during phosphate deficiency, they also accumulate in extraplastidial membranes. Two groups of plants can be distinguished based on the presence of a specific fatty acid, hexadecatrienoic acid (16:3), in chloroplast lipids. Plants that contain galactolipids with 16:3 acids are designated "16:3-plants"; the other group of plants which lack 16:3 contain mostly 18:3 in their galactolipids ("18:3 plants"). The methods in this chapter describe the extraction of membrane lipids from whole leaves, or from subcellular fractions, and their analysis via thin layer chromatography (TLC) with different staining methods. Furthermore, a protocol for membrane lipid quantification is presented starting with the separation via TLC, transmethylation of the isolated lipids to fatty acid methyl esters, and their quantitative analysis via gas chromatography (GC). PMID- 23681527 TI - Detection and quantification of plant sphingolipids by LC-MS. AB - Sphingolipids generate signals in plants in response to a variety of biotic and abiotic stresses. Measuring these signaling compounds is complicated by the heterogeneity of structures within the sphingolipid family and the comparatively low concentration of their metabolites in plant tissues. To date, the only method with the sensitivity, dynamic range, and specificity to measure all sphingolipids in a plant extract is liquid chromatography coupled to mass spectrometry. The drawback of this method is the cost of the hardware, the expertise in mass spectrometry required to critically assess the outcome and the lack of suitable standards for accurate quantitative analysis. The goal of this chapter is to assist researchers in setting up experiments to measure sphingolipids and explain some of the pitfalls and solutions along the way. PMID- 23681529 TI - Analysis of fatty acid amide hydrolase activity in plants. AB - N-Acylethanolamines (NAEs) are fatty acid derivatives amide-linked to ethanolamine. NAEs vary in chain lengths and numbers of double bonds and generally reflect the fatty acids found in membrane lipids in the tissues in which they reside. NAEs are present naturally in trace amounts and occur in a wide range of organisms including plants, animals, and microbes. Some NAE types are known to be involved in the endocannabinoid signaling system of vertebrates, and in plants they may play important regulatory roles in several physiological processes, such as root growth, seedling development, stress responses, and pathogen interactions. The biological effects of NAEs are terminated through their hydrolysis into the ethanolamine and free fatty acid by a membrane enzyme known as the fatty acid amide hydrolase (FAAH). Thus, FAAH represents an important target to better understand the function of these lipid mediators in numerous cellular processes. FAAH has been extensively characterized in mammalian and plant systems, and they share a conserved Ser-Ser-Lys catalytic mechanism. Here we describe procedures and experimental conditions to assay and characterize recombinant and endogenous FAAH enzymatic activity derived from plant tissues. PMID- 23681528 TI - Analysis of defense signals in Arabidopsis thaliana leaves by ultra-performance liquid chromatography/tandem mass spectrometry: jasmonates, salicylic acid, abscisic acid. AB - Defense signaling compounds and phytohormones play an essential role in the regulation of plant responses to various environmental abiotic and biotic stresses. Among the most severe stresses are herbivory, pathogen infection, and drought stress. The major hormones involved in the regulation of these responses are 12-oxo-phytodienoic acid (OPDA), the pro-hormone jasmonic acid (JA) and its biologically active isoleucine conjugate (JA-Ile), salicylic acid (SA), and abscisic acid (ABA). These signaling compounds are present and biologically active at very low concentrations from ng/g to MUg/g dry weight. Accurate and sensitive quantification of these signals has made a significant contribution to the understanding of plant stress responses. Ultra-performance liquid chromatography (UPLC) coupled with a tandem quadrupole mass spectrometer (MS/MS) has become an essential technique for the analysis and quantification of these compounds. PMID- 23681530 TI - Ionization behavior of polyphosphoinositides determined via the preparation of pH titration curves using solid-state 31P NMR. AB - Detailed knowledge of the degree of ionization of lipid titratable groups is important for the evaluation of protein-lipid and lipid-lipid interactions. The degree of ionization is commonly evaluated by acid-base titration, but for lipids localized in a multicomponent membrane interface this is not a suitable technique. For phosphomonoester-containing lipids such as the polyphosphoinositides, phosphatidic acid, and ceramide-1-phosphate, this is more conveniently accomplished by (31)P NMR. Here, we describe a solid-state (31)P NMR procedure to construct pH titration curves to determine the degree of ionization of phosphomonoester groups in polyphosphoinositides. This procedure can also be used, with suitable sample preparation conditions, for other important signaling lipids. Access to a solid-state, i.e., magic angle spinning, capable NMR spectrometer is assumed. The procedures described here are valid for a Bruker instrument, but can be adapted for other spectrometers as needed. PMID- 23681531 TI - Phosphatidylinositol synthase activity from plant membrane fractions and from E. coli-expressed recombinant peptides. AB - Phosphatidylinositol (PtdIns) synthase is a lipid-synthesizing enzyme responsible for the synthesis of the phospholipid, PtdIns. Its enzymatic properties have been studied in in vitro assays using either membrane-enriched fractions or the purified protein in reconstituted lipid vesicles as a source of enzyme. More recently the specificities in terms of substrate preferences have also been studied using the recombinant protein expressed in Escherichia coli. This chapter deals with the purification of membranes as a source of PtdIns synthase before focusing on the in vitro assays of the enzymatic activities of the protein and, briefly, on the analysis of the product. PMID- 23681532 TI - Phosphatidylinositol 4-kinase and phosphatidylinositol 4-phosphate 5-kinase assays. AB - Inositol lipid kinases are perhaps the easiest and most straightforward enzymes in the phosphoinositide pathway to analyze. In addition to monitoring lipid kinase-specific activity, lipid kinase assays can be used to quantify the inositol lipids present in isolated membranes (Jones et al., Methods Mol Biol 462:75-88, 2009). The lipid kinase assays are based on the fact that the more negatively charged phosphorylated lipid products are readily separated from their lipid substrates by thin layer chromatography. We have summarized our current protocols and identified important considerations for working with inositol lipids including different methods for substrate delivery when using recombinant proteins. PMID- 23681533 TI - Assaying inositol and phosphoinositide phosphatase enzymes. AB - One critical aspect of phosphoinositide signaling is the turnover of signaling molecules in the pathway. These signaling molecules include the phosphatidylinositol phosphates (PtdInsPs) and inositol phosphates (InsPs). The enzymes that catalyze the breakdown of these molecules are thus important potential regulators of signaling, and in many cases the activity of such enzymes needs to be measured and compared to other enzymes. PtdInsPs and InsPs are broken down by sequential dephosphorylation reactions which are catalyzed by a set of specific phosphatases. Many of the phosphatases can act on both PtdInsP and InsP substrates. The protocols described in this chapter detail activity assays that allow for the measurement of PtdInsP and InsP phosphatase activities in vitro starting with native or recombinant enzymes. Three different assays are described that have different equipment requirements and allow one to test a range of PtdInsP and InsP phosphatases that act on different substrates. PMID- 23681534 TI - Determination of phospholipase C activity in vitro. AB - Measurement of phospholipase C (PLC) activity in vitro is a valuable biochemistry technique easily applicable in samples from different organisms. It quantifies the enzymatic activity of a key protein involved in critical developmental functions in organisms such as plants, animals, and bacteria. A protocol is described which assays the formation of two main products of the PLC hydrolysis reaction on radioactively labeled phospholipid substrates. PMID- 23681535 TI - Assaying nonspecific phospholipase C activity. AB - Plant nonspecific phospholipase C (NPC) is a recently described enzyme which plays a role in membrane rearrangement during phosphate starvation. It is also involved in responses of plants to brassinolide, abscisic acid (ABA), elicitors, and salt. The NPC activity is decreased in cells treated with aluminum. In the case of salt stress, the molecular mechanism of NPC action is based on accumulation of diacylglycerol (DAG) by hydrolysis of phospholipids and conversion of DAG, the product of NPC activity, to phosphatidic acid (PA) that participates in ABA signaling pathways. Here we describe a step-by-step protocol, which can be used to determine in situ or in vitro NPC activity. Determination is based on quantification of fluorescently labeled DAG as a product of cleavage of the fluorescently labeled substrate lipid, phosphatidylcholine. High-performance thin-layer chromatography is used for separation of fluorescent DAG. The spot is visualized with a laser scanner and the relative amounts of fluorescent DAG are quantified using imaging software. PMID- 23681536 TI - Assaying different types of plant phospholipase D activities in vitro. AB - Over the past decade, tremendous progress has been made toward understanding the physiological functions of individual members of the diverse phospholipase D (PLD) family of enzymes in plants. For instance, the involvement of plant PLD members has been shown or suggested in a wide variety of the cellular and physiological processes such as regulating stomatal opening and closure; signaling plant responses to drought, salt, and other abiotic and biotic stresses; organizing microtubule and actin cytoskeletal structures; promoting pollen tube growth; cycling phosphorus; signaling nitrogen availability; regulating N-acylethanolamine stress signaling; and remodeling membrane phospholipids in plant responses to phosphate deprivation and during and after freezing. There are at least a dozen PLDs in Arabidopsis that can be separated into six classes, phospholipases Dalpha, Dbeta, Dgamma, Ddelta, Depsilon, and Dzeta, based on their molecular and enzymatic characteristics. Several of the classes have distinguishing enzymatic properties that can be used to discriminate among the various classes. Here we provide four variations of in vitro PLD activity assays using choline-labeled phosphatidylcholine to distinguish, to the extent possible, among the different PLD classes. PMID- 23681537 TI - Measuring PLD activity in vivo. AB - Phospholipase D (PLD) hydrolyzes structural phospholipids like phosphatidylcholine (PC) and phosphatidylethanolamine (PE) into phosphatidic acid (PA) and free choline/ethanolamine. In plants, this activity can be stimulated by a wide variety of biotic and abiotic stresses (Li et al., Biochim Biophys Acta 1791:927-935, 2009; Testerink and Munnik, J Exp Bot 62(7):2349-2361, 2011). This chapter describes a protocol for the measurement of PLD activity in vivo. The protocol takes advantage of a unique property of PLD, i.e., its ability to substitute a primary alcohol, such as 1-butanol, for water in the hydrolytic reaction. This transphosphatidylation reaction results in the formation of phosphatidylbutanol (PBut), which is a specific and unique reporter for PLD activity. The assay is highly sensitive for detecting PLD activity in vivo, following stimulation of intact plant cells, seedlings, and tissues, being a valuable method for studying the regulation of plant PLD activity in vivo. PMID- 23681538 TI - Assaying plant phosphatidic acid phosphatase activity. AB - Phosphatidic acid phosphatase (PAP; EC 3.1.3.4) catalyzes the dephosphorylation of phosphatidic acid (PA) to produce diacylglycerol (DAG) and inorganic phosphate. In seed plants, PA plays pivotal roles both as a precursor to membrane lipids and as a signaling molecule. As more information on the roles of PAP in plants becomes available and the importance of PAP is revealed, protocols for assaying plant PAP activity are of interest to an increasing audience. This chapter describes procedures to assay plant PAP activity that are based on recent publications. PMID- 23681539 TI - Assay of phospholipase A activity. AB - Phospholipases of the A type constitute a large family of esterases that catalyze the hydrolysis of the fatty acid ester bonds in phospholipids and thus generate lysophospholipids and fatty acids. Both products or their metabolites are important signal molecules in the cellular adaptation to stress, developmental processes and several diseases in plants and animals. The assay of PLA activity has been much promoted by the availability of phospholipid substrates with fluorophores at one or two fatty acids. The double labeled compounds display an increase of fluorescence due to the escape from intramolecular quenching or FRET. They thus allow the sensitive monitoring of PLA activity even without a separation of the hydrolysis products. This chapter is focused on the proper use of fluorescent (BODIPY) labelled substrates for assays of PLA activity in cells and subcellular fractions by fluorimetric analysis and classical or confocal microscopy. PMID- 23681540 TI - Lipid-binding analysis using a fat blot assay. AB - Protein-lipid interactions play an important role in lipid metabolism, membrane trafficking and cell -signaling by regulating protein localization, activation, and function. The Fat Blot assay is a relatively simple and inexpensive method to examine these interactions using nitrocellulose membrane-immobilized lipids. The assay is adapted from the method by Dowler et al. (Sci STKE 129:pl6, 2002) and provides qualitative and quantitative information on the relative affinity with which a protein binds to a particular lipid. To perform a Fat Blot assay, serial dilutions of different phospholipids are spotted onto a nitrocellulose membrane. These membranes are then incubated with a lipid-binding protein possessing a GST (or other epitope) tag. The membranes are washed and the protein, which is bound to the membrane by virtue of its interaction with the lipid's head group, is detected by immunoblotting with an antibody against GST (or other epitope). The procedure only requires a few micrograms of protein and is quick, simple and cheap to perform. PMID- 23681541 TI - Liposome-binding assays to assess specificity and affinity of phospholipid protein interactions. AB - Protein-lipid interactions play an important role in cellular protein relocation, activation and signal transduction. The liposome-binding assay is a simple and inexpensive method to examine protein-lipid binding in vitro. The phospholipids used for liposome production are dried and hydrated. Subsequent extrusion of the phospholipid mixture ensures the production of large unilamellar vesicles (LUV) filled with raffinose. Those LUVs can be easily separated from the aqueous solution by centrifugation. By incubating a protein of interest with the LUVs and subsequent centrifugation steps, the bound protein fraction can be determined using Western Blot or Coomassie staining. This technique enables analysis of protein-lipid binding affinity and specificity. PMID- 23681542 TI - Lipid affinity beads: from identifying new lipid binding proteins to assessing their binding properties. AB - Lipid affinity beads can be used to identify novel proteins with lipid binding capacity or to determine binding prerequisites of known lipid-binding proteins. Here we describe several applications for which this tool can be used and which considerations have to be taken into account. In addition to a precise protocol, several suggestions are made for experimental setups to facilitate identification of in vivo lipid binding targets. PMID- 23681543 TI - Using genetically encoded fluorescent reporters to image lipid signalling in living plants. AB - The discovery of the green fluorescent protein has revolutionized cell biology as it allowed researchers to visualize dynamic processes in living cells. The fusion of fluorescent protein variants with lipid binding domains that bind to specific phospholipids have been very instrumental in investigating the role of these molecules in living plants. Here, we describe the use of these reporters to image lipids in living Arabidopsis seedlings using fluorescence microscopy. PMID- 23681544 TI - Imaging changes in cytoplasmic calcium using the Yellow Cameleon 3.6 biosensor and confocal microscopy. AB - Changes in the concentration of cytoplasmic calcium, [Ca(2+)]cyt are central regulators in many cellular signal transduction pathways including many lipid mediated regulatory networks. Given this central role that [Ca(2+)] has during plant growth, monitoring spatial and temporal [Ca(2+)] dynamics can reveal a critical component of cellular physiology. Here, we describe the measurement of [Ca(2+)]cyt in Arabidopsis root cells using plants expressing Yellow Cameleon 3.6 (YC 3.6). YC3.6 is a Ca(2+)-sensitive biosensor where the intensity of its fluorescence resonance energy transfer (FRET) signal changes as the Ca(2+) level within the cell rises and falls. The FRET from this calcium reporter can be visualized using confocal microscopy and the resultant images converted to a quantitative map of the levels of Ca(2+) using an approach called ratio analysis. PMID- 23681545 TI - Neuromonitoring in thyroidectomy: a meta-analysis of effectiveness from randomized controlled trials. AB - Neuromonitoring in thyroid surgery has been employed to make nerve identification easier and decrease the rates of laryngeal nerve injuries. Several individual randomized controlled trials (RCTs) have been published, which did not identify statistical differences in the rates of recurrent laryngeal nerve (RLN) or external branch of the superior laryngeal nerve (EBSLN) injuries. The objective of this report is to perform meta-analysis of the combined results of individual studies to measure the frequency of RLN and EBSLN injuries in patients who underwent thyroidectomy with routine neuromonitoring in comparison with common practice of search and identification. RCTs comparing routine neuromonitoring versus no use in patients who underwent elective partial or total thyroidectomy were evaluated. Outcomes measured were temporary and definitive palsy of the RLN and EBSLN. A systematic review and meta-analysis was done using random effects model. GRADE was used to classify quality of evidence. Six studies with 1,602 patients and 3,064 nerves at risk were identified. Methodological quality assessment showed high risk of bias in most items. Funnel plot did not reveal publication bias. The risk difference for temporary RLN palsy, definitive RLN palsy, temporary EBSLN palsy, and definitive EBSLN palsy were -2% (95% confidence interval -5.1 to 1); 0% (-1 to 1); -9% (-15 to -2) and -1% (-4 to 2), respectively. Quality was rated low or very low in most outcomes due to methodological flaws. Meta-analysis did not demonstrate a statistically significant decrease in the risk of temporary or definitive RLN injury and definitive EBSLN injury with the use of neuromonitoring. The neuromonitoring group had a statistically significant decrease in the risk of temporary EBSLN injury. PMID- 23681546 TI - Are there pollination syndromes in the Australian epacrids (Ericaceae: Styphelioideae)? A novel statistical method to identify key floral traits per syndrome. AB - BACKGROUND AND AIMS: Convergent floral traits hypothesized as attracting particular pollinators are known as pollination syndromes. Floral diversity suggests that the Australian epacrid flora may be adapted to pollinator type. Currently there are empirical data on the pollination systems for 87 species (approx. 15 % of Australian epacrids). This provides an opportunity to test for pollination syndromes and their important morphological traits in an iconic element of the Australian flora. METHODS: Data on epacrid-pollinator relationships were obtained from published literature and field observation. A multivariate approach was used to test whether epacrid floral attributes related to pollinator profiles. Statistical classification was then used to rank floral attributes according to their predictive value. Data sets excluding mixed pollination systems were used to test the predictive power of statistical classification to identify pollination models. KEY RESULTS: Floral attributes are correlated with bird, fly and bee pollination. Using floral attributes identified as correlating with pollinator type, bird pollination is classified with 86 % accuracy, red flowers being the most important predictor. Fly and bee pollination are classified with 78 and 69 % accuracy, but have a lack of individually important floral predictors. Excluding mixed pollination systems improved the accuracy of the prediction of both bee and fly pollination systems. CONCLUSIONS: Although most epacrids have generalized pollination systems, a correlation between bird pollination and red, long-tubed epacrids is found. Statistical classification highlights the relative importance of each floral attribute in relation to pollinator type and proves useful in classifying epacrids to bird, fly and bee pollination systems. PMID- 23681547 TI - The two faces of potent antitumor duocarmycin-based drugs: a structural dissection reveals disparate motifs for DNA versus aldehyde dehydrogenase 1 affinity. PMID- 23681548 TI - Bioaccumulation and neurotoxicity of dithiopyridine herbicide in the brain of freshwater fish, Cyprinus carpio. AB - The freshwater carp, Cyprinus carpio, was exposed to 0.5 mg (30% of median lethal concentration (LC50)), 1.0 mg (60% of LC50), and 1.6 mg (LC50) of dithiopyridine herbicide per liter for acute (24 h) and 1/10 of LC50 (0.2 mg/L/day) for sublethal (1, 3, 7, 14, and 21 days) experiments. The herbicide bioaccumulation was significantly affected by the acute exposure levels and the experimental periods and was positively correlated with them. One-way analysis of variance revealed that the acute and sublethal exposure to the herbicide as well as the experimental periods caused significant reduction in the concentrations of catecholamines (dopamine (DA) and norepinephrine (NE)), elevation of acetylcholine (ACh), and was associated with a marked decrease in the activity of acetylcholinesterase (AChE). In comparison with the corresponding controls, most levels of the DA and NE and the activity of AChE were significantly decreased, whereas the concentration of ACh was markedly elevated, during acute and sublethal exposure. In the acute and sublethal experiments, the herbicide accumulated in the brain was inversely proportional to the levels of DA and NE and the activity of AChE but has a direct correlation with the concentration of ACh. In addition, the brain's AChE activity was negatively correlated with ACh content during the acute (r = -0.94) and sublethal (r = -0.78) experiments. PMID- 23681549 TI - p?TubHA4C, a new versatile vector for constitutive expression in Drosophila. AB - Several vectors for gene expression are available in Drosophila, a hub for genetics and genomics innovation. However, the vectors for ubiquitous expression have a complex structure, including coding exons, that makes in-frame cloning of cDNAs very complicated. In this report we describe a new Drosophila expression vector (p?TubHA4C) for ubiquitous expression of coding sequences under the control of a minimal 0.9 kb promoter of alpha1 tubulin (alpha1t). This plasmid was designed to include optimized multiple cloning sites (polylinker) to provide flexibility in cloning strategies. We also added the option of double labeling the expressed proteins with two C-terminal tags, the viral epitope hemagglutinin and a synthetic tetracysteine (4C) tag that binds small fluorescent compounds. This dual tag allows both in situ and biochemical detection of the desired protein. In particular, the new 4C tag technology combines easy fluorescent labeling with small arsenical compounds in live or fixed cells and tissues, while producing minimal alterations to the tagged protein due to its small size. To demonstrate the potent and ubiquitous expression under the control of the ?Tub promoter, bacterial lacZ was expressed and monitored in cell culture and transgenic flies. We found that the modified 0.9 kb DeltaTub promoter induced similar expression levels to the intact 2.6 kb alpha1t promoter, supporting the inclusion of all critical regulatory elements in the new and flexible ?TubHA4C vector. PMID- 23681550 TI - Cloning and characterization of a novel apolipoprotein gene, apolipoprotein AV, in tree shrews. AB - Apolipoprotein AV (apoAV) modulates plasma triglyceride levels, which is an independent risk factor for cardiovascular disease. ApoAV is also involved in atherosclerosis lesion formation. In order to systematically evaluate the apolipoprotein-related gene profile in tree shrew, a model for its insusceptibility to atherosclerosis, we performed apoAV cloning and characterization. The full-length cDNA of apoAV was identified using SMART-RACE. ApoAV cDNA sequence revealed two transcripts, 1,948 and 1,397 base pairs, due to alternative polyadenylation. These two transcripts share the same open reading frame (ORF), which encodes a 369-amino acid protein with high identity to human apoAV (75 %), including a 23-amino acid N-terminal signal peptide. ApoAV is expressed exclusively in the liver. Mature apoAV was expressed in E. coli BL21(DE3) and purified by Ni-chelated resin. Lipoprotein lipase activity was significantly stimulated by this recombinant protein. The full-length ORF of apoAV was cloned into pDsRed-monomer-N1 vector with a red fluorescent protein tag and was primarily localized in cytoplasm of hepG2 cells. The successful cloning, expression and localization of apoAV in tree shrew has laid down the foundation for further investigation on its structure and functions. PMID- 23681552 TI - Effect of hydrogen peroxide on human tendon allograft. AB - Bacterial contamination of tendon allografts at the completion of processing has historically been about 2 %, with tendons that are found to be culture positive being discarded. Treatment of tendon allograft with hydrogen peroxide at the beginning of tissue processing may reduce bacterial contamination, however, the potential side effects of hydrogen peroxide treatment include hydrolysis of the collagen and this may alter the mechanical properties of the graft. Pairs of human tendons were used. One was washed in 3 % hydrogen peroxide for 5 min and the untreated tendon was used as a control. The ultimate tensile strength of the tendons was determined using a material testing machine. A freeze clamp technique was used to hold the tendons securely at the high loads required to cause tendon failure. There was no statistical difference in the ultimate tensile strength between the treated and untreated tendons. Mean strength ranged from Extensor Hallucis Longus at 588 Newtons to Tibialis Posterior at 2,366 Newtons. Hydrogen peroxide washing may reduce bacterial contamination of tendon allograft and does not affect the strength of the tendon. PMID- 23681551 TI - Heterologous expression of rice calnexin (OsCNX) confers drought tolerance in Nicotiana tabacum. AB - Calnexin (CNX) is an integral membrane protein of endoplasmic reticulum (ER) and is a critical component of ER quality control machinery. It acts as a chaperone and ensures proper folding of newly synthesised glycoproteins. CNX shares a considerable homology with its luminal counterpart calreticulin (CRT). Together, they constitute CNX/CRT cycle which is imperative for proper folding of nascent proteins. CNX deficient organisms develop severe complications because of improper folding of proteins and consequently ER stress. CNX maintains calcium homeostasis by binding to the Ca(2+) which is a central node in various signaling pathways. Phosphorylation of cytoplasmic tail of CNX controls the sarco endoplasmic reticulum calcium ATPase and thus the movement of Ca(2+) in and out of its store-house, i.e. ER. Our studies on Oryza sativa CNX (OsCNX) reveal constitutive expression at various developmental stages and various tissues, thereby proving its requirement throughout the plant development. Further, its expression under various stress conditions gives an insight of the crosstalk existing between ER stress and abiotic stress signaling. This was confirmed by heterologous expression of OsCNX (OsCNX-HE) in tobacco and the OsCNX-HE lines were observed to exhibit better germination under mannitol stress and survival under dehydration stress conditions. The dehydration tolerance conferred by OsCNX appears to be ABA-dependent pathway. PMID- 23681554 TI - Root endophyte Piriformospora indica DSM 11827 alters plant morphology, enhances biomass and antioxidant activity of medicinal plant Bacopa monniera. AB - Unorganized collections and over exploitation of naturally occurring medicinal plant Bacopa monniera is leading to rapid depletion of germplasm and is posing a great threat to its survival in natural habitats. The species has already been listed in the list of highly threatened plants of India. This calls for micropropagation based multiplication of potential accessions and understanding of their mycorrhizal associations for obtaining plants with enhanced secondary metabolite contents. The co-cultivation of B. monniera with axenically cultivated root endophyte Piriformospora indica resulted in growth promotion, increase in bacoside content, antioxidant activity and nuclear hypertrophy of this medicinal plant. PMID- 23681553 TI - Status epilepticus: an update. AB - Status epilepticus (SE) still results in significant mortality and morbidity. Whereas mortality depends mainly on the age of the patient as well as the cause, morbidity is often due to the myriad of complications that occur during prolonged admission to an intensive care environment. Although SE is a clinical diagnosis in most cases (convulsant), its treatment requires support by continuous electroencephalographic recording to ensure cessation of potential nonconvulsive elements of SE. Treatment has recently changed to incorporate four stages and must be initiated at the earliest possible time. PMID- 23681557 TI - CD2AP is associated with end-stage renal disease in patients with type 1 diabetes. AB - CD2-associated protein (CD2AP) is essential for podocyte function. CD2AP mutations have been found in patients with focal segmental glomerulosclerosis, a disease histologically resembling diabetic nephropathy and often progressing to end-stage renal disease (ESRD). We hypothesised that variations in the CD2AP gene may contribute to susceptibility to glomerular injury in diabetes and investigated if single-nucleotide polymorphisms (SNPs) in CD2AP are associated with diabetic nephropathy in patients with type 1 diabetes. The discovery cohort consisted of 2,251 Finnish patients with type 1 diabetes. SNPs were selected from the HapMap database to cover the CD2AP gene. The associations between genotyped SNPs and diabetic nephropathy or ESRD were analysed with the chi-squared test and logistic regression. Three SNPs were selected for replication in cohorts from Denmark, Italy, the United Kingdom and Ireland. None of the 15 successfully genotyped SNPs were associated with diabetic nephropathy when compared to patients with normal albumin excretion rate. However, when genotype frequencies in patients with ESRD were compared with all other patients, two CD2AP SNPs, rs9369717 and rs9349417, were found to be associated with ESRD. The meta-analysis of the original and two additional European cohorts resulted in significant p values <0.01 for these SNPs. A third SNP, rs6936632, was suggestively associated with ESRD in the Finnish patients and in the meta-analysis of four cohorts. CD2AP gene variants may contribute to susceptibility to ESRD in patients with type 1 diabetes. PMID- 23681558 TI - A 7-year follow-up retrospective, international, multicenter study of insulin pump therapy in children and adolescents with type 1 diabetes. AB - We evaluated the long-term glycemic control in children with type 1 diabetes, using continuous subcutaneous insulin infusion (CSII) for at least 5 years in three diabetes centers from three different countries: Canada, Italy and Spain. This was an observational retrospective multicenter cohort study. Subjects were included if they were followed at one of the participating centers, had type 1 diabetes, age 5-20 years at time of data collection and used CSII for more than 5 years. Data collected included gender, age, disease duration, age at CSII initiation, body mass index (BMI), hemoglobin A1c (HbA1c), insulin requirement and serious adverse events (SAE) at baseline and every 12 months during follow up. One hundred fifteen patients were included in the study (55% males), aged 5 20 years (mean: 13.5 +/- 3.8 years), with mean diabetes duration of 6.3 +/- 3.4 years, using CSII for mean of 6.9 +/- 1.2 years (range 5-12 years.). HbA1c significantly improved after 1 year of CSII treatment and during follow-up (p = 0.02). When HbA1c was compared between countries, a difference was observed, with slightly lower values in Italy than in Canada and Spain (p = 0.04). When evaluated by gender, HbA1c was similar at baseline, but significantly improved only in males during all follow-up (p = 0.004). No significant differences were observed for BMI, insulin requirement or SAE. Insulin pump therapy is safe and effective in the pediatric population, although in this study, the major benefit in HbA1c was seen in males. The use of advanced pump features was associated with greater improvement in HbA1c. PMID- 23681560 TI - A framework for modeling the interaction of syntactic processing and eye movement control. AB - We explore the interaction between oculomotor control and language comprehension on the sentence level using two well-tested computational accounts of parsing difficulty. Previous work (Boston, Hale, Vasishth, & Kliegl, 2011) has shown that surprisal (Hale, 2001; Levy, 2008) and cue-based memory retrieval (Lewis & Vasishth, 2005) are significant and complementary predictors of reading time in an eyetracking corpus. It remains an open question how the sentence processor interacts with oculomotor control. Using a simple linking hypothesis proposed in Reichle, Warren, and McConnell (2009), we integrated both measures with the eye movement model EMMA (Salvucci, 2001) inside the cognitive architecture ACT-R (Anderson et al., 2004). We built a reading model that could initiate short "Time Out regressions" (Mitchell, Shen, Green, & Hodgson, 2008) that compensate for slow postlexical processing. This simple interaction enabled the model to predict the re-reading of words based on parsing difficulty. The model was evaluated in different configurations on the prediction of frequency effects on the Potsdam Sentence Corpus. The extension of EMMA with postlexical processing improved its predictions and reproduced re-reading rates and durations with a reasonable fit to the data. This demonstration, based on simple and independently motivated assumptions, serves as a foundational step toward a precise investigation of the interaction between high-level language processing and eye movement control. PMID- 23681559 TI - Regional mapping of gas uptake by blood and tissue in the human lung using hyperpolarized xenon-129 MRI. AB - PURPOSE: To develop a breathhold acquisition for regional mapping of ventilation and the fractions of hyperpolarized xenon-129 (Xe129) dissolved in tissue (lung parenchyma and plasma) and red blood cells (RBCs), and to perform an exploratory study to characterize data obtained in human subjects. MATERIALS AND METHODS: A three-dimensional, multi-echo, radial-trajectory pulse sequence was developed to obtain ventilation (gaseous Xe129), tissue, and RBC images in healthy subjects, smokers, and asthmatics. Signal ratios (total dissolved Xe129 to gas, tissue-to gas, RBC-to-gas, and RBC-to-tissue) were calculated from the images for quantitative comparison. RESULTS: Healthy subjects demonstrated generally uniform values within coronal slices, and a gradient in values along the anterior-to posterior direction. In contrast, images and associated ratio maps in smokers and asthmatics were generally heterogeneous and exhibited values mostly lower than those in healthy subjects. Whole-lung values of total dissolved Xe129 to gas, tissue-to-gas, and RBC-to-gas ratios in healthy subjects were significantly larger than those in diseased subjects. CONCLUSION: Regional maps of tissue and RBC fractions of dissolved Xe129 were obtained from a short breathhold acquisition, well tolerated by healthy volunteers and subjects with obstructive lung disease. Marked differences were observed in spatial distributions and overall amounts of Xe129 dissolved in tissue and RBCs among healthy subjects, smokers and asthmatics. PMID- 23681561 TI - Highly active, thermally stable, ethylene-polymerisation pre-catalysts based on niobium/tantalum-imine systems. AB - The reactions of MCl5 or MOCl3 with imidazole-based pro-ligand L(1)H, 3,5-tBu2-2 OH-C6H2-(4,5-Ph2-1H-)imidazole, or oxazole-based ligand L(2)H, 3,5-tBu2-2-OH-C6H2 (1H-phenanthro[9,10-d])oxazole, following work-up, afforded octahedral complexes [MX(L(1,2))], where MX=NbCl4 (L(1), 1a; L(2), 2a), [NbOCl2(NCMe)] (L(1), 1b; L(2), 2b), TaCl4 (L(1), 1c; L(2), 2c), or [TaOCl2(NCMe)] (L(1), 1d). The treatment of alpha-diimine ligand L(3), (2,6-iPr2C6H3N=CH)2, with [MCl4(thf)2] (M=Nb, Ta) afforded [MCl4(L(3))] (M=Nb, 3a; Ta, 3b). The reaction of [MCl3(dme)] (dme=1,2-dimethoxyethane; M=Nb, Ta) with bis(imino)pyridine ligand L(4), 2,6-[2,6 iPr2C6H3N=(Me)C]2C5H3N, afforded known complexes of the type [MCl3(L(4))] (M=Nb, 4a; Ta, 4b), whereas the reaction of 2-acetyl-6-iminopyridine ligand L(5), 2-[2,6 iPr2C6H3N=(Me)C]-6-Ac-C5H3N, with the niobium precursor afforded the coupled product [({2-Ac-6-(2,6-iPr2C6H3N=(Me)C)C5H3N}NbOCl2)2] (5). The reaction of MCl5 with Schiff-base pro-ligands L(6)H-L(10)H, 3,5-(R(1))2-2-OH-C6H2CH=N(2-OR(2) C6H4), (L(6)H: R(1)=tBu, R(2)=Ph; L(7)H: R(1)=tBu, R(2)=Me; L(8)H: R(1)=Cl, R(2)=Ph; L(9)H: R(1)=Cl, R(2)=Me; L(10)H: R(1)=Cl, R(2)=CF3) afforded [MCl4(L(6 10))] complexes (M=Nb, 6a-10a; M=Ta, 6b-9b). In the case of compound 8b, the corresponding zwitterion was also synthesised, namely [Ta(-)Cl5(L(8)H)(+)].MeCN (8c). Unexpectedly, the reaction of L(7)H with TaCl5 at reflux in toluene led to the removal of the methyl group and the formation of trichloride 7c [TaCl3(L(7 Me))]; conducting the reaction at room temperature led to the formation of the expected methoxy compound (7b). Upon activation with methylaluminoxane (MAO), these complexes displayed poor activities for the homogeneous polymerisation of ethylene. However, the use of chloroalkylaluminium reagents, such as dimethylaluminium chloride (DMAC) and methylaluminium dichloride (MADC), as co catalysts in the presence of the reactivator ethyl trichloroacetate (ETA) generated thermally stable catalysts with, in the case of niobium, catalytic activities that were two orders of magnitude higher than those previously observed. The effects of steric hindrance and electronic configuration on the polymerisation activity of these tantalum and niobium pre-catalysts were investigated. Spectroscopic studies ((1)H NMR, (13)C NMR and (1)H-(1)H and (1)H (13)C correlations) on the reactions of compounds 4a/4b with either MAO(50) or AlMe3/[CPh3](+)[B(C6F5)4](-) were consistent with the formation of a diamagnetic cation of the form [L(4)AlMe2](+) (MAO(50) is the product of the vacuum distillation of commercial MAO at +50 degrees C and contains only 1 mol% of Al in the form of free AlMe3). In the presence of MAO, this cationic aluminium complex was not capable of initiating the ROMP (ring opening metathesis polymerisation) of norbornene, whereas the 4a/4b systems with MAO(50) were active. A parallel pressure reactor (PPR)-based homogeneous polymerisation screening by using pre-catalysts 1b, 1c, 2a, 3a and 6a, in combination with MAO, revealed only moderate-to-good activities for the homo-polymerisation of ethylene and the co-polymerisation of ethylene/1-hexene. The molecular structures are reported for complexes 1a-1c, 2b, 5, 6a, 6b, 7a, 8a and 8c. PMID- 23681562 TI - Combining two biomarkers, IDH1/2 mutations and 1p/19q codeletion, to stratify anaplastic oligodendroglioma in three groups: a single-center experience. AB - IDH1/2 mutations and 1p/19q codeletion occur frequently in anaplastic gliomas and are prognostic factors. We combined these two biomarkers to stratify patients treated for anaplastic oligodendroglioma (AO). 43 consecutive WHO AO were selected. We combined immunohistochemistry (IHC) with the monoclonal antibody mIDH1R132H and DNA sequencing of IDH1 and IDH2 genes. Fluorescence in situ hybridization was carried out to evaluate 1p/19q codeletion. These biomarkers were correlated with progression-free survival (PFS) and overall survival (OS). IDH1/IDH2 mutations occurred in 23/43 (54 %) patients: 20/43 IDH1-R132H mutation in IHC, 2/43 IDH1-R132G mutation and 1/43 IDH2-R172K mutation identified by DNA sequencing. 1p/19q codeletion was detected for 23/43 patients. With median follow up of 19 months (range 1.4-128), median PFS and OS were 22 and 35 months respectively. IDH1/IDH2 mutations were strongly associated with improved PFS and OS: 5-year PFS was 86 versus 6 % and 5-year OS was 91 versus 9 % for patients with IDH1/IDH2 mutations versus wild-type IDH respectively. In multivariate analyses, IDH1/IDH2 mutations and 1p/19q loss were independent prognostic factors. Three groups with distinct prognostic features were identified: patients with IDH1/2 mutations and 1p/19q loss (median PFS, median OS not reached), patients with IDH1/2 mutations or 1p/19q loss (median PFS: 22 months, median OS: 30 months), and patients without IDH1/2 mutations nor 1p/19q loss with a bad prognosis (median PFS: 8.6 months, median OS: 9.9 months). Combining two biomarkers, IDH1/2 and 1p/19q codeletion, makes it possible to stratify AO in three groups with very distinct prognostic features. PMID- 23681563 TI - Compartmental absorption modeling and site of absorption studies to determine feasibility of an extended-release formulation of an HIV-1 attachment inhibitor phosphate ester prodrug. AB - BMS-663068 is a phosphonooxymethyl ester prodrug under development for the treatment of HIV/AIDS. The prodrug is designed to overcome the solubility-limited bioavailability of the active moiety, BMS-626529. BMS-663068 is not absorbed from the gastrointestinal (GI) tract and requires enzymatic conversion by alkaline phosphatase to BMS-626529 immediately before absorption. In the light of the known short in vivo half-life of BMS-626529, compartmental absorption modeling was used to predict the potential feasibility of extended-release (ER) delivery to achieve target Cmax :Cmin ratios. To further refine the model with respect to colonic absorption, the regional absorption of BMS-626529 following delivery of BMS-663068 to upper and lower GI sites was characterized through a site of absorption study in human subjects. A refined model was subsequently applied to guide the development of ER tablet formulations. Comparisons of results from the refined model to the in vivo human pharmacokinetic data for three selected ER formulations demonstrate the utility of the model in predicting feasibility of ER delivery and in directing formulation development. PMID- 23681564 TI - Accurate prediction of collapse temperature using optical coherence tomography based freeze-drying microscopy. AB - The objective of this study was to assess the feasibility of developing and applying a laboratory tool that can provide three-dimensional product structural information during freeze-drying and which can accurately characterize the collapse temperature (Tc ) of pharmaceutical formulations designed for freeze drying. A single-vial freeze dryer coupled with optical coherence tomography freeze-drying microscopy (OCT-FDM) was developed to investigate the structure and Tc of formulations in pharmaceutically relevant products containers (i.e., freeze drying in vials). OCT-FDM was used to measure the Tc and eutectic melt of three formulations in freeze-drying vials. The Tc as measured by OCT-FDM was found to be predictive of freeze-drying with a batch of vials in a conventional laboratory freeze dryer. The freeze-drying cycles developed using OCT-FDM data, as compared with traditional light transmission freeze-drying microscopy (LT-FDM), resulted in a significant reduction in primary drying time, which could result in a substantial reduction of manufacturing costs while maintaining product quality. OCT-FDM provides quantitative data to justify freeze-drying at temperatures higher than the Tc measured by LT-FDM and provides a reliable upper limit to setting a product temperature in primary drying. PMID- 23681565 TI - Critical factors in the measurement of tablet film coatings using terahertz pulsed imaging. AB - The present work gives an insight into some key measurement and signal processing considerations in terahertz pulsed imaging (TPI). TPI is increasingly used for the measurement of the spatial variation of coating thickness on coated solid dosage forms. The potential of TPI for the assessment of coating thickness distributions and the use in process development is described in recent literature. However, some critical factors need to be taken into account when working with this technique. These are (1) the signal processing of the raw data, (2) the influence of the composition of the sample matrix on the TPI signals and subsequent coating analysis, (3) signal distortions that can occur at tablet edges or areas with defects, and (4) the refractive index as a key parameter in the quantification of layer thickness. In this paper, we will highlight to what extent these factors impact on the qualitative and quantitative analysis of TPI data and how artifacts and misinterpretation of data can be avoided to ensure fully quantitative and robust measurements. PMID- 23681568 TI - Molecular methods for the study of signal transduction in plants. AB - Novel and improved analytical methods have led to a rapid increase in our understanding of the molecular mechanism underlying plant signal transduction. Progress has been made both at the level of single-component analysis and in vivo imaging as well as at the systems level where transcriptomics and particularly phosphoproteomics afford a window into complex biological responses. Here we review the role of the cyclic nucleotides cAMP and cGMP in plant signal transduction as well as the discovery and biochemical and biological characterization of an increasing number of complex multi-domain nucleotide cyclases that catalyze the synthesis of cAMP and cGMP from ATP and GTP, respectively. PMID- 23681569 TI - Recombinant expression and functional testing of candidate adenylate cyclase domains. AB - Adenylate cyclases (ACs) are enzymes capable of converting adenosine-5' triphosphate to cyclic 3', 5'--adenosine monophosphate (cAMP). In animals and lower eukaryotes, ACs and their product cAMP have firmly been established as important signalling molecules with important roles in several cellular signal transduction pathways. However, in higher plants, the only annotated and experimentally confirmed AC is a Zea mays pollen protein capable of generating cAMP. Recently a number of candidate AC-encoding genes in Arabidopsis thaliana have been proposed based on functionally assigned amino acids in the catalytic center of annotated and/or experimentally tested nucleotide cyclases in lower and higher eukaryotes. Here we detail the cloning and recombinant expression of functional candidate AC domains using, as an example, the A. thaliana pentatricopeptide repeat-containing protein (AtPPR-AC; At1g62590). Through a complementation test, in vivo adenylate cyclase activity of candidate recombinant molecules can be prescreened and promising candidates can subsequently be further evaluated in an in vitro AC immunoassay. PMID- 23681570 TI - Quantification of cyclic dinucleotides by reversed-phase LC-MS/MS. AB - Cyclic dinucleotides such as bis-(3',5')-cyclic dimeric adenosine monophosphate (c-di-AMP) and bis-(3',5')-cyclic dimeric guanosine monophosphate (c-di-GMP) represent important second messengers in bacteria. Although their synthesis has not been described in plants so far, they may be involved in the regulation of bacterial phytopathogen-plant interactions as well as rhizobium plant symbiosis. Here, we describe a sensitive and specific quantification method for c-di-AMP and c-di-GMP by HPLC-coupled tandem mass spectrometry. Additional linear dinucleotide metabolites and mononucleotides, as well as cyclic mononucleotides, can be simultaneously determined by this method. PMID- 23681571 TI - Determination of ADP-ribosyl cyclase activity, cyclic ADP-ribose, and nicotinic acid adenine dinucleotide phosphate in tissue extracts. AB - Cyclic ADP-ribose (cADPR) is a novel second messenger that releases calcium from intracellular stores. Although first shown to release calcium in the sea urchin egg, cADPR has been shown since to be active in a variety of cells and tissues, from plant to human. cADPR stimulates calcium release via ryanodine receptors although the mechanism is still not completely understood. cADPR is produced enzymatically from NAD by ADP-ribosyl cyclases; several of these proteins have been identified including one isolated from Aplysia californica, two types found in mammals (CD38 and CD157), and three forms in sea urchin. A cyclase activity has been measured in extracts from Arabidopsis thaliana although the protein is still unidentified. Nicotinic acid adenine dinucleotide phosphate (NAADP) is another novel messenger that releases calcium from internal stores and is produced by these same enzymes by an exchange reaction. NAADP targets lysosomal stores whereas cADPR releases calcium from the endoplasmic reticulum. Due to their importance in cell signaling, cADPR and NAADP have been the focus of numerous investigations over the last 25 years. This chapter describes several assay methods for the measurements of cADPR and NAADP concentration and cyclase activity in extracts from cells. PMID- 23681572 TI - In vivo imaging of cGMP in plants. AB - The cyclic nucleotide 3',5'-cyclic guanyl monophosphate (cGMP) has been implicated in the regulation of important plant processes. To unravel its physiological role further, accurate recording of dynamic changes in cGMP concentration is necessary. Fluorescent sensors based on biological molecules for "live imaging" are ideal for this since they have high specificity, a sensitivity that is in the range of biologically relevant concentrations, high spatial and dynamic resolution, and measurements with such sensors are nondestructive. In this chapter we describe the use of the cGMP FlincG sensor in plant materials that either transiently or stably express this sensor. PMID- 23681573 TI - Characterization of heterologously expressed transporter genes by patch- and voltage-clamp methods: application to cyclic nucleotide-dependent responses. AB - The application of patch- and voltage-clamp methods to study ion transport can be limited by many -hurdles: the size of the cells to be patched and/or stabbed, the subcellular localization of the molecule of interest, and its density of expression that could be too low even in their own native environment. Functional expression of genes using recombinant DNA technology not only overcomes those hurdles but also affords additional and elegant investigations such as single point mutation studies and subunit -associations/regulations. In this chapter, we give a step-by-step description of two electrophysiological methods, patch clamp and two-electrode voltage clamp (TEVC), that are routinely used in combination with heterologous gene expression to assist researchers interested in the identification and characterization of ion transporters. We describe how to (1) obtain and maintain the cells suitable for the use with each of the above mentioned methods (i.e., HEK-293 cells and yeast spheroplasts to use with the patch-clamp methodology and Xenopus laevis oocytes with TEVC), (2) transfect/inject them with the gene of interest, and (3) record ion transport activities. PMID- 23681574 TI - Noninvasive microelectrode ion flux estimation technique (MIFE) for the study of the regulation of root membrane transport by cyclic nucleotides. AB - Changes in ion permeability and subsequently intracellular ion concentrations play a crucial role in intracellular and intercellular communication and, as such, confer a broad array of developmental and adaptive responses in plants. These changes are mediated by the activity of plasma-membrane based transport proteins many of which are controlled by cyclic nucleotides and/or other signaling molecules. The MIFE technique for noninvasive microelectrode ion flux measuring allows concurrent quantification of net fluxes of several ions with high spatial (MUm range) and temporal (ca. 5 s) resolution, making it a powerful tool to study various aspects of downstream signaling events in plant cells. This chapter details basic protocols enabling the application of the MIFE technique to study regulation of root membrane transport in general and cyclic nucleotide mediated transport in particular. PMID- 23681575 TI - Calcium imaging of the cyclic nucleotide response. AB - Calcium (Ca(2+)) is a key component of the signalling network by which plant cells respond to developmental and environmental signals. A change in guard cell cytosolic free Ca(2+)([Ca(2+)]cyt) is an early event in the response of stomata to both opening and closing stimuli, and cyclic nucleotide-mediated Ca(2+) signalling has been implicated in the regulation of stomatal aperture. A range of techniques have been used to measure [Ca(2+)]cyt in plant cells. Here we describe a potential method for imaging cyclic nucleotide-induced changes in [Ca(2+)]cyt in guard cells using the cameleon ratiometric Ca(2+) reporter protein. PMID- 23681576 TI - Identification and quantitation of signal molecule-dependent protein phosphorylation. AB - Phosphoproteomics is a fast-growing field that aims at characterizing phosphorylated proteins in a cell or a tissue at a given time. Phosphorylation of proteins is an important regulatory mechanism in many cellular processes. Gel free phosphoproteome technique involving enrichment of phosphopeptide coupled with mass spectrometry has proven to be invaluable to detect and characterize phosphorylated proteins. In this chapter, a gel-free quantitative approach involving (15)N metabolic labelling in combination with phosphopeptide enrichment by titanium dioxide (TiO2) and their identification by MS is described. This workflow can be used to gain insights into the role of signalling molecules such as cyclic nucleotides on regulatory networks through the identification and quantification of responsive phospho(proteins). PMID- 23681577 TI - Comparative gel-based phosphoproteomics in response to signaling molecules. AB - The gel-based proteomics approach is a valuable technique for studying the characteristics of proteins. This technique has diverse applications ranging from analysis of a single protein to the study of the total cellular proteins. Further, protein quality and to some extent distribution can be first assessed by means of one-dimensional gel electrophoresis and then more informatively, for comparative analysis, using the two-dimensional gel electrophoresis technique. Here, we describe how to take advantage of the availability of fluorescent dyes to stain for a selective class of proteins on the same gel for the detection of both phospho- and total proteomes. This enables the co-detection of phosphoproteins as well as total proteins from the same gel and is accomplished by utilizing two different fluorescent stains, the ProQ-Diamond, which stains only phosphorylated proteins, and Sypro Ruby, which stains the entire subset of proteins. This workflow can be applied to gain insights into the regulatory mechanisms induced by signaling molecules such as cyclic nucleotides through the quantification and subsequent identification of responsive phospho- and total proteins. PMID- 23681578 TI - An affinity pull-down approach to identify the plant cyclic nucleotide interactome. AB - Cyclic nucleotides (CNs) are intracellular second messengers that play an important role in mediating physiological responses to environmental and developmental signals, in species ranging from bacteria to humans. In response to these signals, CNs are synthesized by nucleotidyl cyclases and then act by binding to and altering the activity of downstream target proteins known as cyclic nucleotide-binding proteins (CNBPs). A number of CNBPs have been identified across kingdoms including transcription factors, protein kinases, phosphodiesterases, and channels, all of which harbor conserved CN-binding domains. In plants however, few CNBPs have been identified as homology searches fail to return plant sequences with significant matches to known CNBPs. Recently, affinity pull-down techniques have been successfully used to identify CNBPs in animals and have provided new insights into CN signaling. The application of these techniques to plants has not yet been extensively explored and offers an alternative approach toward the unbiased discovery of novel CNBP candidates in plants. Here, an affinity pull-down technique for the identification of the plant CN interactome is presented. In summary, the method involves an extraction of plant proteins which is incubated with a CN-bait, followed by a series of increasingly stringent elutions that eliminates proteins in a sequential manner according to their affinity to the bait. The eluted and bait-bound proteins are separated by one-dimensional gel electrophoresis, excised, and digested with trypsin after which the resultant peptides are identified by mass spectrometry techniques that are commonplace in proteomics experiments. The discovery of plant CNBPs promises to provide valuable insight into the mechanism of CN signal transduction in plants. PMID- 23681579 TI - Structural and functional characterization of receptor kinases with nucleotide cyclase activity. AB - There has been an increase in the identification and characterization of plant receptor kinases possessing nucleotide cyclase activity. This has necessitated the development of robust methodologies for the structural and functional characterization of this biologically important family of proteins. Here we outline some of the techniques that can be effectively used in the characterization of this bifunctional family of proteins. PMID- 23681580 TI - Computational identification of candidate nucleotide cyclases in higher plants. AB - In higher plants guanylyl cyclases (GCs) and adenylyl cyclases (ACs) cannot be identified using BLAST homology searches based on annotated cyclic nucleotide cyclases (CNCs) of prokaryotes, lower eukaryotes, or animals. The reason is that CNCs are often part of complex multifunctional proteins with different domain organizations and biological functions that are not conserved in higher plants. For this reason, we have developed CNC search strategies based on functionally conserved amino acids in the catalytic center of annotated and/or experimentally confirmed CNCs. Here we detail this method which has led to the identification of >25 novel candidate CNCs in Arabidopsis thaliana, several of which have been experimentally confirmed in vitro and in vivo. We foresee that the application of this method can be used to identify many more members of the growing family of CNCs in higher plants. PMID- 23681581 TI - Identification of cyclic nucleotide gated channels using regular expressions. AB - Cyclic nucleotide-gated channels (CNGCs) are nonselective cation channels found in plants, animals, and some bacteria. They have a six-transmembrane/one-pore structure, a cytosolic cyclic nucleotide-binding domain, and a cytosolic calmodulin-binding domain. Despite their functional similarities, the plant CNGC family members appear to have different conserved amino acid motifs within corresponding functional domains than animal and bacterial CNGCs do. Here we describe the development and application of methods employing plant CNGC-specific sequence motifs as diagnostic tools to identify novel candidate channels in different plants. These methods are used to evaluate the validity of annotations of putative orthologs of CNGCs from plant genomes. The methods detail how to employ regular expressions of conserved amino acids in functional domains of annotated CNGCs and together with Web tools such as PHI-BLAST and ScanProsite to identify novel candidate CNGCs in species including Physcomitrella patens. PMID- 23681582 TI - Inferring biological functions of guanylyl cyclases with computational methods. AB - A number of studies have shown that functionally related genes are often co expressed and that computational based co-expression analysis can be used to accurately identify functional relationships between genes and by inference, their encoded proteins. Here we describe how a computational based co-expression analysis can be used to link the function of a specific gene of interest to a defined cellular response. Using a worked example we demonstrate how this methodology is used to link the function of the Arabidopsis Wall-Associated Kinase-Like 10 gene, which encodes a functional guanylyl cyclase, to host responses to pathogens. PMID- 23681583 TI - Identification and characterization of cyclic nucleotide phosphodiesterases. AB - Cyclic nucleotide phosphodiesterases regulate cellular levels of small molecule second messengers that control important biological processes in all kingdoms of life. Identifying and characterizing these enzymes is necessary for basic research and pharmaceutical applications. Here, we describe the use of thin layer chromatography to analyze cellular extracts or purified proteins for cyclic nucleotide phosphodiesterase activity. PMID- 23681584 TI - Detection of reactive oxygen species downstream of cyclic nucleotide signals in plants. AB - Cyclic nucleotides act in plant cell signal transduction cascades by activating cyclic nucleotide gated cation-conducting ion channels (CNGCs). Activation of CNGCs results in inward cation (including Ca(2+)) conductance across the plasma membrane. Elevation of cytosolic Ca(2+) is an early step in numerous plant cell signal transduction cascades, including plant immune responses to pathogens. CNGC involvement, along with cyclic nucleotides cAMP and cGMP, in pathogen defense programs is one relatively well-studied area of cyclic nucleotide signaling in plants. During plant immune responses, CNGC-dependent Ca(2+) elevations lead to a signaling cascade that results in the generation of defense molecules such as hydrogen peroxide and nitric oxide, and induction of defense gene expression. This pathogen defense response is discussed, and methods to detect some of the downstream signaling steps in the pathway are presented. PMID- 23681585 TI - Measurement of nitric oxide in plant tissue using difluorofluorescein and oxyhemoglobin. AB - Nitric oxide (NO) is now well established as a signalling molecule in plants, regulating various physiological processes ranging from development to responses to pathogens and changes in the physical environment. Various methods for the detection of NO in plant tissue have been described, and all of these methods have serious limitations that impact their utility for accurate detection of NO in plant tissues. Despite such limitations, both difluorofluorescein diacetate and oxyhemoglobin present convenient and relatively easy approaches for measuring NO in plant tissue and their utility can be enhanced by including appropriate controls to address some of the limitations that these two methods have. This chapter provides methods for measuring or detecting NO production in plant tissue using either difluorofluorescein diacetate or oxyhemoglobin. PMID- 23681586 TI - Infrared gas analysis technique for the study of the regulation of photosynthetic responses. AB - Homeostatic maintenance of physiological and biochemical processes is a key requirement for survival and adaptive responses of multicellular organisms such as plants. These important processes are in part mediated by various plant enzymes and hormones, many of which are in part, controlled by cyclic nucleotides and/or other signalling molecules. Infrared gas analysis (IRGA) technique is one of the modern methods which allows for rapid and accurate measurements of cyclic nucleotide mediated photosynthetic responses to plant hormones, and thus makes it a powerful and useful tool to study aspects of downstream cell signalling events in plants. In this chapter the basic protocols enabling the use of the IRGA technique to study signalling molecules, such as cyclic nucleotides on photosynthetic responses, are outlined. PMID- 23681587 TI - Poplar genetic engineering: promoting desirable wood characteristics and pest resistance. AB - Worldwide biomass demand for industrial applications, especially for production of biofuels, is increasing. Extended cultivation of fast growing trees such as poplars may contribute to satisfy the need for renewable resources. However, lignin, which constitutes about 20-30% of woody biomass, renders poplar wood recalcitrant to saccharification. Genetic engineering of the enzymes of the lignification pathway has resulted in drastic decreases in lignin and greatly improved the carbohydrate yield for ethanol fermentation. While uncovering key enzymes for lignification facilitated rapid biotechnological progress, knowledge on field performance of low-lignin poplars is still lagging behind. The major biotic damage is caused by poplar rust fungi (Melampsora larici-populina), whose defense responses involve lignification and production of phenolic compounds. Therefore, manipulation of the phenylpropanoid pathway may be critical and should be tightly linked with new strategies for improved poplar rust tolerance. Emerging novel concepts for wood improvement are discussed. PMID- 23681588 TI - Bacteria-mediated bisphenol A degradation. AB - Bisphenol A (BPA) is an important monomer in the manufacture of polycarbonate plastics, food cans, and other daily used chemicals. Daily and worldwide usage of BPA and BPA-contained products led to its ubiquitous distribution in water, sediment/soil, and atmosphere. Moreover, BPA has been identified as an environmental endocrine disruptor for its estrogenic and genotoxic activity. Thus, BPA contamination in the environment is an increasingly worldwide concern, and methods to efficiently remove BPA from the environment are urgently recommended. Although many factors affect the fate of BPA in the environment, BPA degradation is mainly depended on the metabolism of bacteria. Many BPA-degrading bacteria have been identified from water, sediment/soil, and wastewater treatment plants. Metabolic pathways of BPA degradation in specific bacterial strains were proposed, based on the metabolic intermediates detected during the degradation process. In this review, the BPA-degrading bacteria were summarized, and the (proposed) BPA degradation pathway mediated by bacteria were referred. PMID- 23681590 TI - Improvement of sludge digestate biodegradability by thermophilic bioaugmentation. AB - The sludge digestate stabilized by mesophilic anaerobic digestion was further degraded through thermophilic anaerobic digestion using 0-10 % (v/v) of thermophilic, proteolytic Coprothermobacter proteolyticus, and/or methanogenic granular sludge. The results demonstrated that the temperature shift to thermophilic condition promoted abiotic solubilization of proteins and reactivated the fermentative bacteria and methanogens indigenous in the sludge digestate, resulting in a final methane yield of 6.25 mmol-CH4/g-volatile suspended solid (VSS) digestate. The addition of C. proteolyticus accelerated the hydrolysis and fermentation of proteins and polysaccharides in the digestate during the early stage of thermophilic anaerobic digestion and stimulated methane production by syntrophic cooperation with methanogenic granular sludge. In the treatment with granular sludge and inoculated with 10 % (v/v) of C. proteolyticus, a final methane yield of 7 mmol-CH4/g-VSS digestate was obtained, and 48.4 % proteins and 27.0 % polysaccharides were degraded. The dissolved proteins were contributed by abiotic factor, C. proteolyticus, and indigenous digestate bacteria, respectively, by around 16, 28, and 56 %. PMID- 23681589 TI - Bioethanol production by heterologous expression of Pdc and AdhII in Streptomyces lividans. AB - Two genes from Zymomonas mobilis that are responsible for ethanol production, pyruvate decarboxylase (pdc) and alcohol dehydrogenase II (adhII), were heterologously expressed in the Gram-positive bacterium Streptomyces lividans TK24. An examination of carbon distribution revealed that a significant portion of carbon metabolism was switched from biomass and organic acid biosynthesis to ethanol production upon the expression of pdc and adhII. The recombinant S. lividans TK24 produced ethanol from glucose with a yield of 23.7% based on the carbohydrate consumed. The recombinant was able to produce ethanol from xylose, L arabinose, mannose, L-rhamnose, galactose, ribose, and cellobiose with yields of 16.0, 25.6, 21.5, 33.6, 30.6, 14.6, and 33.3%, respectively. Polymeric substances such as starch and xylan were directly converted to ethanol by the recombinant with ethanol yields of 18.9 and 8.8%, respectively. The recombinant S. lividans TK24/Tpet developed in this study is potentially a useful microbial resource for ethanol production from various sources of biomasses, especially microalgae. PMID- 23681591 TI - Biomolecular assembly of thermoresponsive superlattices of the tobacco mosaic virus with large tunable interparticle distances. PMID- 23681592 TI - Thermoresponsive biodegradable PEG-PCL-PEG based injectable hydrogel for pulsatile insulin delivery. AB - An injectable biodegradable hydrogel was prepared for temperature-responsive pulsatile release of insulin. Triblock copolymer of poly(ethylene glycol) poly(epsilon-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE) was prepared by ring opening bulk copolymerization and characterized using FT-IR, (1) HNMR, and gel permeation chromatography. Aqueous solution of PECE formed an injectable hydrogel, which was solution at room temperature and transformed into gel at 37 degrees C. The temperature-responsive sol-gel transition and crystallinity of PECE hydrogel was studied and compared with pluronic, a well-studied nonbiodegradable injectable hydrogel. In vitro release study revealed that insulin release profile of PECE was similar to pluronic, and its viscosity was 1/30(th) of pluronic sol at 10,000 s(-1) shear rate. Release behavior of insulin from PECE hydrogels followed Fickian diffusion of first order. Insulin retained its secondary structure after release as confirmed by circular dichroism spectrum. A threefold increase in Fickian diffusion coefficient was evidenced when temperature was increased from 34 to 40 degrees C because of crystalline melting of PCL part of PECE. Pulsatile release of insulin showed a correlation coefficient of 0.90 with the change of temperature. PMID- 23681593 TI - Exercise capacity affects quality of life in patients with pulmonary hypertension. AB - BACKGROUND: The objective of this prospective study was to evaluate the impact of exercise capacity, mental disorders, and hemodynamics on quality-of-life (QoL) parameters in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: Sixty-three patients with invasively diagnosed PAH (n = 48) or CTEPH (n = 15) underwent a broad panel of assessments, including cardiopulmonary exercise testing (CPET), 6-minute walking distance (6-MWD), World Health Organization functional class (WHO-FC), and assessment of hemodynamics. QoL was evaluated by the 36-item Medical Outcome Study Short Form Health Survey Questionnaire (SF-36). Exercise capacity, hemodynamics, age, gender, and mental disorders (anxiety and depression) were assessed for association with QoL subscores by uni- and multivariate regression analyses. RESULTS: Exercise capacity, WHO-FC, oxygen therapy, symptoms of right heart failure, right atrial pressure, and mental disorders were significantly associated with QoL (p < 0.05). In the stepwise backward selection multivariate analysis, depression remained an independent parameter in seven of eight subscales of the SF-36. Furthermore, peak oxygen uptake (peakVO2) during CPET, 6 MWD, anxiety, long-term oxygen therapy, right heart failure, and age remained independent factors for QoL. Hemodynamic parameters at rest did not independently correlate with any domain of the SF-36 QoL subscores. CONCLUSIONS: Mental disorders, exercise capacity, long-term oxygen therapy, right heart failure, and age play important role in the quality of life in patients with PAH and CTEPH. PMID- 23681594 TI - Genetic and functional diversity of fluorescent Pseudomonas from rhizospheric soils of wheat crop. AB - Wheat rhizospheric soils were collected from different part of northern and eastern Indo-Gangetic plains, which is being irrigated from water of Ganga River. Isolation of fluorescent Pseudomonas species was carried out from the soil samples collected. The percentage of isolates positive for indolic compound, P solubilisation, siderophore production and ACC deaminase activity were 64.0, 38.6, 63.5, and 19.7, respectively. A total of 543 isolates were randomly selected for studies based on the genus specific confirmation by the Pseudomonas specific primer. Among the 543 isolates, 26 different clusters were formed from 16S rDNA-RFLP whereas 27 clusters were generated by the rpoB-RFLP with similarity percent ranging from 3 to 100%. 16S rDNA sequencing showed 9 different species of Pseudomonas whereas, rpoB sequencing showed 13 different species of Pseudomonas. Phylogenetic analysis based on 16S rDNA gene sequences generated 15 branches showing the more than 70% of boot strap value, whereas 18 branches in the rpoB based phylogenetic tree were supported by bootstrap values above 70%. Diversity indices based on rpoB were higher than the ribosomal RNA gene. PMID- 23681596 TI - Impaired structural and functional development of cerebellum following gestational exposure of deltamethrin in rats: role of reelin. AB - Reelin is an extracellular matrix molecule that is involved in the normal development of the cerebellar lamination, Bergmann glial fibres alignment, Purkinje cell monolayer arrangement and granule cell migration. In this study, we have examined the effects of maternal exposure of deltamethrin (DLT), a type II pyrethroid insecticide, on the structural and functional development of rat cerebellum during postnatal life. DLT (0.75 mg/kg body weight, intraperitoneally dissolved in dimethylsulphoxide) was administered in timed pregnant rats during two different gestational time periods, i.e. gestational days of 7-10 and 11-14, respectively. In DLT exposed rats, a significant overexpression of reelin was observed in the cells of the external granule cell layer (EGL) and internal granule cell layer along with an ectopic expression of reelin in the EGL as well as in the migrating granule cells just below the EGL, revealing an arrest of granule cell migration in this zone. Mis-orientation and hypertrophy of the Bergmann glial fibres further hampered the journey of the granule cells to their final destination. Possibly reelin overexpression also caused misalignment of the Purkinje cells and inhibited the neurite growth leading to a significant decrease in the spine density, main dendritic length and width of the dendritic arbour. Thus, it is proposed that the DLT exerts its neurotoxic effects possibly via the intracellular accumulation and low release of reelin leading to an impaired granule cell and Purkinje cell migration, inhibition of neurite outgrowth and reduced spine density. Such impaired cerebellar development leads to motor coordination deficits. PMID- 23681597 TI - In vivo kinematics of the thumb carpometacarpal joint during three isometric functional tasks. AB - BACKGROUND: The thumb carpometacarpal (CMC) joint is often affected by osteoarthritis--a mechanically mediated disease. Pathomechanics of the CMC joint, however, are not thoroughly understood due to a paucity of in vivo data. QUESTIONS/PURPOSES: We documented normal, in vivo CMC joint kinematics during isometric functional tasks. We hypothesized there would be motion of the CMC joint during these tasks and that this motion would differ with sex and age group. We also sought to determine whether the rotations at the CMC joint were coupled and whether the trapezium moved with respect to the third metacarpal. METHODS: Forty-six asymptomatic subjects were CT-scanned in a neutral position and during three functional tasks (key pinch, jar grasp, jar twist), in an unloaded and a loaded position. Kinematics of the first metacarpal, third metacarpal, and the trapezium were then computed. RESULTS: Significant motion was identified in the CMC joint during all tasks. Sex did not have an effect on CMC joint kinematics. Motion patterns differed with age group, but these differences were not systematic across the tasks. Rotation at the CMC joint was generally coupled and posture of the trapezium relative to the third metacarpal changed significantly with thumb position. CONCLUSIONS: The healthy CMC joint is relatively stable during key pinch, jar grasp, and jar twist tasks, despite sex and age group. CLINICAL RELEVANCE: Our findings indicate that directionally coupled motion patterns in the CMC joint, which lead to a specific loading profile, are similar in men and women. These patterns, in addition to other, nonkinematic influences, especially in the female population, may contribute to the pathomechanics of the osteoarthritic joint. PMID- 23681598 TI - Primary gastrointestinal stromal tumor of the liver: report of a case. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. They can occur anywhere in the gastrointestinal tract, and rarely outside the digestive tract. We herein report a case of primary gastrointestinal stromal tumor that was resected from the liver of a 56-year-old male, which is the sixth description of a primary hepatic gastrointestinal stromal tumor. The tumor was shown to be completely limited within the liver by radiological, intraoperative and pathological examinations. The pathological results demonstrated an intermediate risk gastrointestinal stromal tumor, and immunohistochemical expression of CD117 was positive. Although rare, we suggested that GISTs should be considered in the differential diagnosis of hepatic nodules, and that not all hepatic gastrointestinal stromal tumors should automatically be considered to be metastases from a primary gastrointestinal site. PMID- 23681599 TI - Duodenal ulcer penetration into the superior mesenteric artery after percutaneous transluminal angioplasty and stent placement for acute mesenteric ischemia: report of a case. AB - A 78-year-old male presented with the chief complaints of abdominal pain and vomiting. Contrast-enhanced computed tomography and abdominal angiography showed occlusion of the superior mesenteric artery due to thrombosis, and emergency percutaneous transluminal angioplasty and stent placement were carried out. Two months later, stent thrombosis developed, and a second stent was placed. Eight months later, he complained of general fatigue and anorexia. Gastrointestinal endoscopy revealed a duodenal ulcer at the third portion close to the superior mesenteric artery. Thirteen days after conservative management, duodenal ulcer penetration into the superior mesenteric artery with subsequent air embolism developed, and the patient died of multiple organ failure. PMID- 23681600 TI - Bowline knot of a monofilament suture eliminates C-loop formation in intracorporeal ligation. AB - We describe how we developed a new method of tying an intracorporeal suture of monofilament material using a bowline knot, which eliminates the troublesome C loop formation for winding the thread on the rod. The winding-forceps point to the site of suturing, and the needle end of the thread is placed under the rod of the forceps during the knot tying. This position allows for easy winding of the line even when the forceps-angle is as narrow as 10 degrees because the winding forceps and suture line are in parallel. This method resolves the problems of C loop formation with a narrow forceps-angle. Thus, our bowline method of knot tying provides an easy, secure, and rapid intracorporeal ligation requiring a short learning curve, as an alternative to the conventional C-loop method. PMID- 23681601 TI - Whole-body MR angiography: first experiences with the new TimCT technology with single contrast injection. AB - PURPOSE: To assess image quality, presence of artifacts, arterial stenosis, and interobserver agreement of Tim-CT in assessment of the arterial system using contrast-enhanced whole-body-MRA (CE-Wb-MRA) with a single contrast-medium injection in patients with arteriosclerosis. MATERIALS AND METHODS: The retrospective study included 18 patients (mean age, 68 years). A total of 468 arteries were evaluated. CE-Wb-MRA was performed using Tim-CT technology on a 1.5 Tesla (T) MRI after injecting a single dose of Vasovist. Evaluations were independently performed by two radiologists. The arterial system was divided into seven anatomic locations. Each radiologist assessed the image quality, degree of artifacts, and arterial stenosis in different locations. RESULTS: All Wb-MRA examinations were technically successful. Image quality: 28.42% arteries were excellent, 29.17% were good, 22.54% were satisfactory, 9.40% were poor, and 5.13% of insufficient quality. Occurrence of artifacts: 37.25% were free of artifacts, 49.44% minimal artifacts not affecting diagnosis, and 13.31% strong artifacts not permitting a diagnosis. A total of 60.00% arteries showed no stenosis, 8.76% were <=50% stenotic, 5.17% were 51-75% stenotic, 4.38% were 76-99%, and 8.54% total occlusion. The interobserver agreement was good for supra-aortic, pelvic, and upper and lower leg regions. CONCLUSION: CE-Wb-MRA using the TimCT technology and with a single contrast injection is a feasible tool for whole-body MRA. PMID- 23681602 TI - The association between family and friend integration and physical activity: results from the NHIS. AB - BACKGROUND: Social integration predicts morbidity and mortality, but its relationships with specific health behaviors that could explain this relationship, such as physical activity, have not been established. Additionally, studies associating social integration with health have not distinguished between sources of social contact (family vs. friends), which could be differentially related to health. PURPOSE: The purpose of this study was to examine the association between social integration and physical activity and to explore differences in family and friend social integration. METHOD: Data came from the 2001 wave of the National Health Interview Survey. Adult participants (N = 33,326) indicated levels of social integration by reporting whether they had seen and/or called friends and/or family in the past 2 weeks and also reported their weekly minutes of physical activity. Logistic regression was used to determine odds of meeting physical activity (PA) guidelines (>= 150 min/week) and odds of inactivity (0 min/week) based on levels of social integration. RESULTS: Greater integration predicted higher odds of meeting PA guidelines and lower odds of inactivity after controlling for sociodemographic variables. This association was stronger and dose-dependent for integration with friends, whereas moderate family contact predicted greater activity than high levels of family contact. CONCLUSION: Those who are more socially integrated, particularly with friends rather than family, are also more physically active, which could partially explain the link between social integration and morbidity and mortality. Future studies examining this association should distinguish between sources of integration and explore why and how contact with friends vs. family is differentially associated with health behaviors. PMID- 23681603 TI - Immunological insights from patients undergoing surgery on ipilimumab for metastatic melanoma. AB - BACKGROUND: The tumor microenvironment after treatment with ipilimumab is not well described. Furthermore, the safety of surgery for patients being treated with ipilimumab for metastatic melanoma has not been well reported. This study analyzed the safety of surgery and the immune phenotype of tumors resected while on ipilimumab. METHODS: From our prospective melanoma database, we identified patients undergoing surgery for any indication within 30 days of receiving a dose of induction ipilimumab or while on maintenance ipilimumab therapy. Surgical toxicity was graded 1-5 by the Clavien classification. Tumor-infiltrating lymphocytes were classified by flow cytometry and compared with peripheral blood. RESULTS: 23 patients were identified who underwent 34 operations a median of 27 weeks after initiation of ipilimumab (1-123 weeks). Subcutaneous resections were the most frequent, followed by intra-abdominal and nodal procedures. Grade 1 or 2 wound complications were seen in 22% of patients. No Grade 3-5 complications were seen. Analysis of the T cell infiltrate and matched peripheral blood from ten patients showed an elevated % of CD4+FOXP3+ T-regulatory cells and a 2.8-fold lower ratio of CD8+/CD4+FOXP3+ in the tumor compared with blood (p=0.02). In addition, all CD8+ T cells had a higher expression of PD-1 in the tumor, compared with peripheral blood. CONCLUSIONS: Surgery for patients on ipilimumab is safe. This study highlights the immunosuppressive phenotype in tumors not responding to immunotherapy. The high percentage of T-regulatory cells and low T-effector cells in progressive tumors suggests a possible mechanism of immune escape. PMID- 23681604 TI - Update on the American Board of Surgery subspecialty certificate in Complex General Surgical Oncology. PMID- 23681606 TI - Substrate-dependent stereospecificity of Tyl-KR1: an isolated polyketide synthase ketoreductase domain from Streptomyces fradiae. AB - The stereospecificity of an enzymatic reaction depends on the way in which a substrate and its enantiomer bind to the active site. These binding modes cannot be easily predicted. We have studied the stereospecificity and stereoselectivity of the ketoreductase domain Tyl-KR1 of the tylactone polyketide synthase from Streptomyces fradiae by analysing the stereochemical outcome of the reduction of five different keto ester substrates. The absolute configuration of the Tyl-KR1 reduction products was determined by using vibrational circular dichroism (VCD) spectroscopy combined with quantum chemical calculations. The conversion of only one of the tested substrates, 2-methyl-3-oxovaleric acid N-acetylcysteamine thioester, afforded the expected anti-(2R,3R) configuration of the alpha-methyl beta-hydroxyl ester product, representing the stereochemistry observed for the physiological polyketide product tylactone. For all other substrates, which were modified with respect to the type of ester and/or the chain length (C4 instead of C5), the opposite configuration (anti-(2S,3S)) was obtained with significant enantio- and diastereoselectivity. Inversion of both stereocentres suggests completely different binding modes invoked by only minor modifications of the substrate structure. PMID- 23681605 TI - Increased noradrenaline levels in the rostral pons can be reversed by M1 antagonist in a rat model of post-traumatic stress disorder. AB - The dysregulation of hypothalamic-pituitary-adrenal axis and noradrenergic, serotonergic and glutamatergic systems are thought to be involved in the pathophysiology of post-traumatic stress disorder. The effect of selective M1 muscarinic receptor antagonist, pirenzepine on anxiety indices was investigated by using elevated plus maze, following exposure to trauma reminder. Upon receiving the approval of ethics committee, Sprague-Dawley rats were exposed to dirty cat litter (trauma) for 10 min and 1 week later, the rats confronted to a trauma reminder (clean litter). The rats also received intraperitoneal pirenzepine (1 or 2 mg/kg/day) or saline for 8 days. Noradrenaline (NA) concentration in the rostral pons was analyzed by HPLC with electrochemical detection. The anxiety indices of the rats subjected to the trauma reminder were increased when compared to control rats (p < 0.05). Pirenzepine treatment in traumatized rats displayed similar anxiety indices of non-traumatized rats treated with physiological saline. Although freezing time was prolonged with pirenzepine in traumatized groups the change was not found statistically significant. The NA level was 1.5 +/- 0.1 pg/mg in non-traumatized rats and increased to 2.4 +/- 0.2 pg/mg in traumatized rats. Bonferroni post hoc test revealed that the NA content of the rostral pons of the traumatized rats treated with physiological saline was significantly higher than the content of other groups (p < 0.01). We conclude that NA content in the rostral pons increases in respect to confrontation to a trauma reminder which can be reversed by M1 antagonist pirenzepine indicating the roles of M1 receptors. PMID- 23681608 TI - Moving from basic toward systems pharmacodynamic models. AB - Building upon many classical foundations of pharmacology, a diverse array of mechanistic pharmacokinetic-pharmacodynamic (PK/PD) models have emerged based on mechanisms of drug action and primary rate-limiting or turnover processes in physiology. An array of basic models can be extended to handle various complexities including tolerance and can readily be employed as building blocks in assembling enhanced PK/PD or small systems models. Our corticosteroid models demonstrate these concepts as well as elements of horizontal and vertical integration of molecular to whole-body processes. The potential advantages and challenges in moving PK/PD toward systems models are described. PMID- 23681607 TI - Usp18 deficient mammary epithelial cells create an antitumour environment driven by hypersensitivity to IFN-lambda and elevated secretion of Cxcl10. AB - The theory of cancer immunoediting refers to mechanisms by which the immune system can suppress or promote tumour progression. A major challenge for the development of novel cancer immunotherapies is to find ways to exploit the immune system's antitumour activity while concomitantly reducing its protumour activity. Using the PyVmT model of mammary tumourigenesis, we show that lack of the Usp18 gene significantly inhibits tumour growth by creating a tumour-suppressive microenvironment. Generation of this antitumour environment is driven by elevated secretion of the potent T-cell chemoattractant Cxcl10 by Usp18 deficient mammary epithelial cells (MECs), which leads to recruitment of Th1 subtype CD4(+) T cells. Furthermore, we show that Cxcl10 upregulation in MECs is promoted by interferon-lambda and that Usp18 is a novel inhibitor of interferon-lambda signalling. Knockdown of the interferon-lambda specific receptor subunit IL-28R1 in Usp18 deficient MECs dramatically enhances tumour growth. Taken together, our data suggest that targeting Usp18 may be a viable approach to boost antitumour immunity while suppressing the protumour activity of the immune system. PMID- 23681609 TI - Newly modified Stoppa approach for acetabular fractures. AB - PURPOSE: We present our experience of using a newly modified Stoppa approach combined with a lateral approach to the iliac crest in patients with acetabular fractures in reference to fracture reduction and fixation, technical aspects, and the incidence of complications. METHODS: We used a consecutive group of 29 adult patients with acetabular fractures treated operatively with a newly modified Stoppa approach between 2009 and 2011. The newly modified Stoppa approach was performed to fix the acetabular fractures with main anterior displacement and the anterior and lateral parts of the pelvis. This approach was combined with a lateral approach on the iliac crest for fractures of the iliac wing. RESULTS: All the patients were followed up for at least 1.5 years. Of the 29 patients, ten anterior column, two associated both column, seven anterior column with posterior hemi-transverse, four transverse, and six T-type fractures. The average blood loss was 950 mL, and average operative time was 155 minutes. Anatomic or satisfactory reduction was achieved in 96 % of the acetabular fractures. Two patients had mild symptoms of the lateral femoral cutaneous nerve and improved within three months. CONCLUSIONS: The newly modified Stoppa approach provides excellent visualization to the anterior column, quadrilateral surface and permits good postoperative results for treatment of acetabular fractures. We considered this technique as a viable alternative for the ilioinguinal approach when exposure of the anterior acetabulum is needed. PMID- 23681610 TI - Biocomposites reinforced by fibers or tubes as scaffolds for tissue engineering or regenerative medicine. AB - As a dynamic and hierarchically organized composite, native extracellular matrix (ECM) not only supplies mechanical support, which the embedded cells need, but also regulates various cellular activities through interaction with them. On the basis of the ECM-mimetic principle, good biocompatibility and appropriate mechanical properties are the two basic requirements that the ideal scaffolds for the tissue engineering or regenerative medicine need. Some fibers and tubes have been shown effective to reinforce scaffolds for tissue engineering or regenerative medicine. In this review, three parts, namely properties affected by the addition of fibers or tubes, scaffolds reinforced by fibers or tubes for soft tissue repair, and scaffolds reinforced by fibers or tubes for hard tissue repair are stated, which shows that tissue repair or regeneration efficacy was enhanced significantly by fiber or tube reinforcement. In addition, it indicates that these reinforcing agents can improve the biocompatibility and biodegradation of the scaffolds in most cases. However, there are still some concerns, such as the homogeneousness in structure or composition throughout the reinforced scaffolds, the adhesive strength between the matrix and the fibers or tubes, cytotoxicity of nanoscaled reinforcing agents, etc., which were also discussed in the conclusion and perspectives part. PMID- 23681611 TI - Catalytic enantioselective intermolecular desymmetrization of 3-substituted oxetanes. PMID- 23681612 TI - Isolation and maintenance of cortical neural progenitor cells in vitro. AB - Neural progenitor cells (NPCs) or neural stem cells are important tools for investigating central nervous system (CNS) development. NPCs can be used in therapeutic strategies and for characterizing differentiation mechanisms. Here, we describe methods for isolating and culturing embryonic NPCs. PMID- 23681613 TI - Neural induction with a dopaminergic phenotype from human pluripotent stem cells through a feeder-free floating aggregation culture. AB - Pluripotent stem cells are promising potential sources for cell replacement therapy and are useful research tools for exploring disease mechanisms. Neural cells are one of the cell types that have been most efficiently differentiated through several established protocols. This chapter describes the feeder-free floating aggregation culture system for the induction of dopaminergic neurons. This method is simple and highly efficient for the production of dopaminergic neurons. It has several advantages for application in clinical usage in comparison to the other protocols using either feeder cells or Matrigel. PMID- 23681614 TI - Nucleoside analog labeling of neural stem cells and their progeny. AB - Nucleoside analog pulse labeling is an important technique which can assess the birthdate, cell cycle maintenance, or cycling rates of cells during development. This method has evolved over several decades of use and is now applied to a multitude of tissue subtypes and systems. The methodology in this chapter covers the classic uses for analog pulse labeling as well as their use in conjunction with the newly characterized technique of in utero electroporation (IUE). PMID- 23681615 TI - Culture of dissociated hippocampal neurons. AB - Hippocampal neurons consist mainly of pyramidal neuron and granule cell, and dissociated hippocampal neurons are a good tool to investigate the molecular and cellular mechanism of neuronal development and neuronal degenerative disease in the central neuronal system (CNS). Here, we describe a general procedure of dissociated hippocampal neuron culture. PMID- 23681616 TI - Culturing mouse cerebellar granule neurons. AB - The cerebellum plays an important role in motor control, motor skill acquisition, memory and learning among other brain functions. In rodents, cerebellar development continues after birth, characterized by the maturation of granule neurons. Cerebellar granule neurons (CGNs) are the most abundant neuronal type in the central nervous system, and they provide an excellent model for investigating molecular, -cellular, and physiological mechanisms underlying neuronal development as well as neural circuitry linked to behavior. Here we describe a procedure to isolate and culture CGNs from postnatal day 6 mice. These cultures can be used to examine numerous aspects of CGN differentiation, electrophysiology, and function. PMID- 23681617 TI - Preparation of primary cultured dopaminergic neurons from mouse brain. AB - Dopaminergic neurons are involved in a variety of normal brain functions; degenerations of these neurons cause diseases in human. Investigation of how dopaminergic neurons respond to extracellular signals and molecular mechanisms regulating dopaminergic neuron survival and death often requires reliable, reproducible, and high-quality primary cultures of dopaminergic neurons. Here, we described methods to dissect and culture these neurons from embryonic mesencephalon of mouse brain. We utilize coverslips made from Aclar film to maximize the number of surviving dopaminergic neuron in the culture and immunocytochemistry of tyrosine hydroxylase (TH) to identify dopaminergic neuron. PMID- 23681618 TI - Culturing astrocytes from postnatal rats. AB - The use of cultures has informed us of functions and regulation of astrocytes that were previously unknown. This chapter details the methods that result in such cultures. PMID- 23681619 TI - Culturing oligodendrocyte lineage cells from neonatal rats. AB - The use of enriched oligodendrocyte lineage cell cultures has yielded insight into functions of these cells and regulatory mechanisms. This chapter details methods that result in such cultures. PMID- 23681620 TI - Isolation and culture of Schwann cells. AB - Primarily cultured Schwann cells are essential for the investigation of molecular mechanisms regulating proliferation, survival, differentiation, and myelination of Schwann cell and for the development of efficient transplantation for regeneration of injured spinal cord or peripheral nervous system. Here we describe a basic protocol for isolation and purification of primary Schwann cell from neonatal rat or mouse and discuss some modifications adapted to the culturing from adult nerves and optional methods for Schwann cell enrichment. PMID- 23681621 TI - DNA transfection: calcium phosphate method. AB - The calcium phosphate transfection is a widely used method for introducing foreign DNA plasmids into cells. Mechanisms underlying this transfection method are not yet defined; however, DNA-calcium phosphate precipitates are internalized by the cells and DNA is efficiently expressed in almost all cell types. The cost efficiency and simplicity of this method allows for use in primary neuronal cultures, despite issues of neurotoxicity. Here, we describe an optimized calcium phosphate transfection method for the delivery of DNA plasmid into primary dissociated neuronal cultures. PMID- 23681622 TI - The gene-gun approach for transfection and labeling of cells in brain slices. AB - Biolistic transfection and diolistic labeling are techniques in which subcellular sized particles, coated with DNA and lipophilic dyes, respectively, are propelled into cells. The gene-gun approach is particularly applicable for use on ex vivo organized tissue such as brain slices, where cells are not accessible for transfection with methods used in dissociated cell preparations. This simple and rapid method results in targeting of individual cells in a Golgi-like manner, allowing investigating structural and functional aspects of neuronal development. PMID- 23681623 TI - Lentiviral vector production, titration, and transduction of primary neurons. AB - Lentiviral vectors have become very useful tools for transgene delivery. Based on their ability to transduce both dividing and nondividing cells and to produce long-term transgene expression, lentiviruses have found numerous applications in the biomedical sciences, including developmental neuroscience. This protocol describes how to prepare lentiviral vectors by calcium phosphate transfection and to concentrate viral particles by ultracentrifugation. Functional vector titers can then be determined by methods such as fluorescence-activated cell sorting or immunostaining. Effective titers in the range of 10(8)-10(9) infectious units/ml can be routinely obtained using these protocols. Finally, we describe the infection of primary neuronal cultures with lentiviral vectors resulting in 85-90 % cell transduction using appropriate multiplicities of infection. PMID- 23681624 TI - In ovo electroporation in embryonic chick spinal cords. AB - The developing spinal cord is a well-established model system widely used to study the signaling pathways and genetic programs that control neuronal/glial differentiation and neural circuit assembly. This is largely due to the relatively simple organization (compared to other CNS regions) and experimental accessibility of the neural tube, particularly in the chick embryo. In vivo transfection of cells within the developing chick neural tube using in ovo electroporation has emerged as a rapid and powerful experimental technique in that (1) transfected factors can be functionally tested in a spatially and temporally controlled manner and (2) the chick embryo provides a physiologically relevant in vivo environment to conduct biochemical studies such as dual-channel luciferase assay, co-immunoprecipitation (co-IP), and Chromatin Immunoprecipitation (ChIP). In this chapter, we will take an in-depth look at the in ovo electroporation system in embryonic chicken spinal cord. In the following chapter, we will continue by examining the use of in ovo electroporation in the dual-channel luciferase assay as an example of its biochemical application. PMID- 23681625 TI - Gene transfer in developing chick embryos: in ovo electroporation. AB - In ovo electroporation is a popular technique to study gene function during development. This technique enables precise temporal and spatial genetic manipulation with the added advantages of being quick and inexpensive. In this chapter the transient transfection of a construct into the neural tube of a chicken embryo via in ovo electroporation is described. Modifications of this basic technique and methods to -analyze the resulting electroporated embryos such as qPCR and microarray are also discussed. PMID- 23681626 TI - In utero electroporation in mice. AB - In utero electroporation has been extensively used to study a variety of developmental questions in the developing brain. This protocol aims to provide the basic knowledge for a beginner to get familiar with the technique. Basically, by electroporating a DNA construct into a subpopulation of progenitor cells in the ventricular zone of embryonic brain, the progenitor cells carrying the DNA will undergo neurogenesis, migration, and final differentiation to become mature neurons positioned in distinct cortical layers according to their birth date. In addition, by controlling the direction of electroporation, a specific cortical area can be targeted. Thus, in utero electroporation allows gene modification in a specific cortical layer in a specific cortical area. PMID- 23681627 TI - General introduction to in situ hybridization protocol using nonradioactively labeled probes to detect mRNAs on tissue sections. AB - In situ hybridization (ISH) is a type of hybridization that uses a labeled complementary DNA or RNA strand (i.e., probe) to localize a specific DNA or RNA sequence in a portion or section of tissue (In Situ) or in the entire tissue (whole mount ISH). Localization of endogenous transcripts is a desirable approach for confirming expression patterns. This is distinct from immunohistochemistry, which usually localizes proteins in tissue sections. DNA ISH can be used to determine the structure of chromosomes. However, RNA ISH (hybridization histochemistry) is used to measure and localize mRNAs and other transcripts within tissue sections or whole mounts. RNA-RNA hybrids approach may offer increased sensitivity, which is more stable than that of DNA-RNA hybrids. Here we describe the efficient ISH protocol for nonradioactive (i.e., in direct methods using digoxigenin (DIG) system) RNA probes, and it can be performed in less than 3 days. PMID- 23681628 TI - Immunofluorescence staining with frozen mouse or chick embryonic tissue sections. AB - Immunofluorescence (IF), a form of immunohistochemistry (IHC) with specific applications, is commonly used for both basic research and clinical studies, including diagnostics, and involves visualizing the cellular distribution of target molecules (e.g., proteins, DNA, and small molecules) using a microscope capable of exciting and detecting fluorochrome compounds that emit light at specific, largely nonoverlapping wavelengths. The procedure for carrying out IF varies according to the tissue type and methods for processing and preparing tissue (e.g., fixative used to preserve tissue morphology and antigenicity). The protocol presented here provides a general guideline for multichannel IF staining using frozen embryonic mouse or chicken tissue sectioned on a cryostat. In general, the procedure involves the following: (1) fixing freshly dissected tissues in a 4 % paraformaldehyde solution buffered in the physiological pH range, (2) cryopreservation of tissue in a 30 % sucrose solution, (3) embedding and sectioning tissue in Optimal Cutting Temperature (OCT) matrix compound, (4) direct or indirect detection of the target antigen/s using fluorochrome conjugated antibodies. PMID- 23681629 TI - beta-Galactosidase staining of lacZ fusion proteins in whole tissue preparations. AB - The lacZ gene product, beta-galactosidase, has classically been used as a reporter of gene expression. beta-Galactosidase activity can be detected using a chromogenic substrate, X-gal, which leaves an intense blue precipitate when cleaved by the enzyme. Insertion of the lacZ coding DNA targeted into a specific gene creates a beta-galactosidase-tagged fusion protein that is expressed under the endogenous promoter. Analysis of the hybrid protein takes advantage of the chromogenic detection system, as the distribution and relative abundance of the expressed protein can be efficiently visualized. PMID- 23681630 TI - Chromatin immunoprecipitation assay of brain tissues using Percoll gradient purified nuclei. AB - Protein-DNA interactions are critical to maintain genome stability, DNA replication, chromosome -segregation and to regulate gene expression. Chromatin immunoprecipitation (ChIP) is a powerful technique to study these interactions within living neurons and nervous tissue. In particular, ChIP analysis of chromatin in which protein-DNA interactions are first fixed in situ provides a valuable approach to identify specific transcription factor-DNA interactions and their regulation in the developing nervous system. Here we describe a procedure utilizing Percoll gradient purification of nuclei from fresh brain tissue pre fixed with formaldehyde for ChIP analysis. This purification protocol provides an enrichment of neuronal nuclei in high yield. We also illustrate the suitability of chromatin prepared from Percoll-purified brain nuclei for ChIP analysis of regulated transcription factor interactions with neuronal gene promoters. PMID- 23681631 TI - In vivo dual luciferase reporter assay with chick neural tube in ovo electroporation system. AB - Luciferase reporter systems are widely employed to provide a quantitative readout of gene expression for studies of transcriptional regulation, translation efficiency, and cell signaling. The most common application of luciferase involves transient transfections into cells in vitro or in vivo. In both cases, the normal variability inherent in transfection approaches can introduce significant errors into the data that makes comparison between separate experiments problematic. The dual luciferase reporter assay system (DLR, Promega, WI, USA) is designed to control for this technical issue by using a co transfection approach with two separate reporter proteins that emit at distinct wavelengths: one from firefly (Photinus pyralis) and the second from Renilla (Renilla reniformis). By normalizing experimental luciferase readings to an internal control transfected under the same conditions, these problems can be largely negated. Here, we describe a method for applying this technique to an in vivo system, the developing chick embryo neural tube. This system provides a physiologically relevant context for functional studies in a spatially and/or temporally controlled manner. PMID- 23681632 TI - Growth cone collapse assay. AB - Growth cone collapse is an easy and efficient test for detecting and characterizing axon guidance activities secreted or expressed by cells. It can also be used to dissect signaling pathways by axon growth inhibitors and to isolate therapeutic compounds that promote axon regeneration. Here, we describe a growth cone collapse assay protocol used to study signal transduction mechanisms of the repulsive axon guidance molecule ephrin-A5 in hippocampal neurons. PMID- 23681633 TI - The stripe assay: studying growth preference and axon guidance on binary choice substrates in vitro. AB - Stripe assays are frequently used for studying binary growth decisions of cells and axons towards surface-bound molecules in vitro. In particular in the fields of neurodevelopment and axon guidance, stripe assays have become a routine tool. Several variants of the stripe assay have been developed since its introduction by Bonhoeffer and colleagues in 1987 (Development 101:685-696, 1987). In all variants, however, the principle is the generation of a structured binary growth substrate, consisting of two sets of cues, arranged in alternating stripes. There are two major classes of stripe assays, mainly distinguished by the source material used for stripe pattern manufacturing: membrane stripe assays, where the stripe patterns are generated with membrane fractions isolated from tissue or cells, and stripe assays with purified proteins, also called modified stripe assays. In this chapter we describe in detail the classical membrane stripe assay, the commonly used modified stripe assay employing purified proteins, and a novel stripe assay for high-affinity interacting proteins, like receptor/ligand pairs. PMID- 23681634 TI - Microcontact printing of substrate-bound protein patterns for cell and tissue culture. AB - Patterned distributions of signalling molecules play fundamental roles during embryonic development. Several attempts have been made to reproduce these patterns in vitro. In order to study substrate-bound or membrane proteins, microcontact printing (MUCP) is a suitable method for tethering molecules on various surfaces. Here, we describe three MUCP variants to produce patterns down to feature sizes of about 300 nm, which are highly variable with respect to shape, protein spacing, and density. Briefly, the desired pattern is etched into a silicon master, which is then used as a master for the printing process. Each variant offers certain advantages and the method of choice depends on the desired protein and the biological question. PMID- 23681635 TI - Semiautomated analysis of dendrite morphology in cell culture. AB - Quantifying dendrite morphology is a method for determining the effect of biochemical pathways and extracellular agents on neuronal development and differentiation. Quantification can be performed using Sholl analysis, dendrite counting, and length quantification. These procedures can be performed on dendrite-forming cell lines or primary neurons grown in culture. In this protocol, we describe the use of a set of computer programs to assist in quantifying many aspects of dendrite morphology, including changes in total and localized arbor complexity. PMID- 23681636 TI - Monitoring synaptic plasticity by imaging AMPA receptor content and dynamics on dendritic spines. AB - Time-lapse imaging techniques are widely used to monitor dendritic spine dynamics, a measurement of synaptic plasticity. However, it is challenging to follow the dynamics of spines over an extended period in vivo during development or in deep brain structures that are beyond the reach of traditional microscopes. Here, we describe an AMPA receptor-based optical approach to monitor recent history of synaptic plasticity. This method allows the identification of spines that have recently acquired synaptic AMPA receptors in a single imaging session, so that synaptic plasticity that occurs in vivo in a variety of conditions can be simply imaged in an ex vivo preparation. PMID- 23681637 TI - Morphological analysis of neuromuscular junctions by immunofluorescent staining of whole-mount mouse diaphragms. AB - Immunofluorescence or IF is a technique allowing the visualization of a specific protein or antigen in cells or tissues by binding a specific antibody chemically conjugated with a fluorescence dye. Immunofluorescent staining is widely used in life science research, particularly for neuroscience. Here, we describe the immunofluorescent staining of whole-mount neonatal mouse diaphragms to study the morphological patterns of the neuromuscular junction (NMJ) by using of presynaptic neuronal marker-neurofilament (NF) and synaptophysin antibodies; postsynaptic acetylcholine receptors (AChRs) were labeled with Alexa Fluor 594 conjugated alpha-bungarotoxin (alpha-BTX). Immunofluorescence-stained diaphragms were examined under a confocal microscope. PMID- 23681638 TI - Routine histology techniques for the developing and adult central nervous system. AB - The preparation of tissue for histological study is a multi-step process in which potential loss of quality and the introduction of artifacts can occur during each step. Knowledge of the process and the potential pitfalls at each step will serve the investigator well. Here I describe the most basic histologic techniques, worked out so long ago they are often absent from current literature. PMID- 23681639 TI - Cryosectioning. AB - Cryosectioning, the sectioning of frozen specimens, has been an important histological tool for more than a century and continues to be extensively utilized today. However, the ability to produce high-quality sections is often a difficult process requiring extensive patience and experience. In this chapter, we have detailed an effective method for the embedding, mounting, and sectioning of frozen tissues, as well as have provided suggestions in producing high-quality sections. PMID- 23681640 TI - The Golgi-Cox method. AB - One of the best neurohistologic methods to reveal the cytoarchitecture of the brain and detailed morphology of neurons with unsurpassed clarity has been the Golgi staining. It is based on the principle of metallic impregnation of neurons, allowing visualization in their entirety including cell soma, axons, dendrites, and spines. In this chapter, we describe the Golgi-Cox protocol standardized in our laboratory that can be used to study experimental effects of different genetic manipulations on spatial distribution of neurons, dendrite density, spine number and morphology to elucidate gene functions during development and in adult brain. PMID- 23681641 TI - Neuroanatomical tract-tracing using biotinylated dextran amine. AB - Biotinylated dextran amine (BDA) is a highly efficient and powerful marker for bidirectional tracing of nerve pathways in a wide variety of species at the light and electron microscopic level. The BDA tract-tracing method can readily be combined with other anterograde or retrograde tracers for multiple neuroanatomical labeling studies to map the neuronal connectivity, or with immunocytochemistry for neurotransmitters and their receptors to reveal details of synaptic specializations within the multisynaptic neuronal circuits. Here, we describe an experimental protocol for anterograde and retrograde tracing using BDA. By applying BDA 10 kDa as an anterograde tracer, we demonstrate the existence of a direct bilateral nigro-trigeminal pathway in the rat. PMID- 23681642 TI - Retrograde tracing technique for neonatal animals. AB - Tract tracing is a fundamental technique in neuroanatomy for examining fiber connections in the nervous system. After the introduction of horseradish peroxidase 40 years ago, many tracing substances have been used for neuroanatomical studies on various nervous systems. Here, we described retrograde tracing techniques using multiple fluorescent tracers, which make it possible to detect axonal collaterals. This technique is useful to study the development of axonal trajectories, as well as regenerative and compensatory mechanisms of animals that undergo neural damage at early stages. PMID- 23681643 TI - ACC deaminase and IAA producing growth promoting bacteria from the rhizosphere soil of tropical rice plants. AB - Beneficial plant-associated bacteria play a key role in supporting and/or promoting plant growth and health. Plant growth promoting bacteria present in the rhizosphere of crop plants can directly affect plant metabolism or modulate phytohormone production or degradation. We isolated 355 bacteria from the rhizosphere of rice plants grown in the farmers' fields in the coastal rice field soil from five different locations of the Ganjam district of Odisha, India. Six bacteria producing both ACC deaminase (ranging from 603.94 to 1350.02 nmol alpha ketobutyrate mg(-1) h(-1) ) and indole acetic acid (IAA; ranging from 10.54 to 37.65 MUM ml(-1) ) in pure cultures were further identified using polyphasic taxonomy including BIOLOG((R)) , FAME analysis and the 16S rRNA gene sequencing. Phylogenetic analyses of the isolates resulted into five major clusters to include members of the genera Bacillus, Microbacterium, Methylophaga, Agromyces, and Paenibacillus. Seed inoculation of rice (cv. Naveen) by the six individual PGPR isolates had a considerable impact on different growth parameters including root elongation that was positively correlated with ACC deaminase activity and IAA production. The cultures also had other plant growth attributes including ammonia production and at least two isolates produced siderophores. Study indicates that presence of diverse rhizobacteria with effective growth-promoting traits, in the rice rhizosphere, may be exploited for a sustainable crop management under field conditions. PMID- 23681644 TI - Faciobrachial dystonic seizures arise from cortico-subcortical abnormal brain areas. PMID- 23681645 TI - Laminar infarcts in clinical routine: a prospective analysis in standard stroke unit patients. AB - The present study aimed to investigate prospectively the frequency of laminar infarcts (LI) within a standard stroke unit population. Laminar infarcts follow neuroanatomical borders rather than the vascular architecture. The LI are rarely noticed in clinical routine because they are typically not detected by computed tomography. As there is a lack of systemic studies about this specific infarct pattern, little is known about their frequency, clinical characteristics or pathophysiological mechanisms. Consecutive acute ischemic stroke unit patients were prospectively enrolled during a 12 month period. The LI were defined as ischemic lesions following the gyral anatomy of the cerebral cortex. The clinical assessment included a standardized questionnaire, clinical syndromes and standard diagnostic results. There were 491 consecutive ischemic stroke patients enrolled (243 female, mean age 75 +/- 12 years). The MRI revealed no laminar lesion crossing vascular territories and 28 patients with LI non-crossing vascular territories (7 %). According to the TOAST classification, 61 % of LI were classified as stroke of undetermined etiology (TOAST V) including 46 % with completed evaluation (TOAST Vb). In contrast to these findings, only 20 % of the whole study cohort with non-laminar infarcts were classified as TOAST V. The results indicate that LI are rare. In clinical routine, patients with LI require particular attention. Within the TOAST classification, this specific infarct pattern seems to be underrepresented. PMID- 23681646 TI - Adult-onset autosomal dominant leukodystrophy without early autonomic dysfunctions linked to lamin B1 duplication: a phenotypic variant. AB - The early presentation of autonomic dysfunctions at the disease onset has been considered the mandatory clinical feature in adult-onset autosomal dominant leukodystrophy, which is a rarely recognised leukodystrophy caused by duplication of the lamin B1 gene. We report the first family with adult-onset autosomal dominant leukodystrophy and lamin B1 duplication, without the distinguishing early-appearing autonomic dysfunctions. Subjects from three consecutive generations of a multi-generational Serbian family affected by adult-onset autosomal dominant leukodystrophy underwent clinical, biochemical, neurophysiological, neuroradiological, and genetic studies. The patients atypically exhibited late autonomic dysfunctions commencing at the disease end stages in some. Genetic findings of lamin B1 duplication verified adult-onset autosomal dominant leukodystrophy, which was supported also by neuroimaging studies. Exclusively, proton magnetic spectroscopy of the brain revealed a possibility of neuro-axonal damage in the white matter lesions, while magnetic resonance imaging of the spinal cord excluded spinal myelin affection as a required finding in this leukodystrophy. The detection of lamin B1 duplication, even when autonomic dysfunctions do not precede the other symptoms of the disease, proves for the first time that lamin B1-duplicated adult-onset autosomal dominant leukodystrophy may have a phenotypic variant with delayed autonomic dysfunctions. Prior to this report, such a phenotype had been speculated to represent an entity different from lamin B1-duplicated leukodystrophy. Hereby we confirm the underlying role of lamin B1 duplication, regardless of the autonomic malfunction onset in this disorder. It is the only report on adult-onset autosomal dominant leukodystrophy from Southeastern Europe. PMID- 23681648 TI - Persistent hiccups as sole manifestation of right cortical infarction without apparent brainstem lesion. PMID- 23681647 TI - Initial cognitive dip after subthalamic deep brain stimulation in Parkinson disease. AB - Although many studies have shown no significant change in global cognitive function after subthalamic brain stimulation (STN DBS) in patients with Parkinson disease (PD) and have concluded that STN DBS is generally safe from a cognitive standpoint, some studies have reported a decline in global cognitive function after STN DBS. Interestingly, in some studies, the decline in cognitive function appears to be greater during the initial short period after surgery (within 6 or 12 months after surgery) than the decline thereafter. To this end, we examined whether the rate of change in global cognitive function during the initial 6 months after STN DBS was different from the mean 6-month change that occurred between 6 and 36 months after surgery. Thirty-six PD patients who underwent bilateral STN DBS and were followed for more than 3 years were included. Change in Mini-Mental Status Examination (MMSE) score during the first 6 months after surgery was compared with the 6-month MMSE score change between 6 and 36 months after surgery. Mean MMSE change during the first 6 months after surgery was significantly greater than the mean 6-month MMSE change between 6 to 36 months after surgery. The levodopa equivalent daily dose at baseline and the score for Stroop Color-word test at baseline were significantly associated with the decline in MMSE score during the first 6 months after surgery. Our result showed that decline in global cognitive function was faster in the first 6 months after surgery, compared with that after 6 months. PMID- 23681649 TI - Determinants and normal values of ascending aortic diameter by age, gender, and race/ethnicity in the Multi-Ethnic Study of Atherosclerosis (MESA). AB - PURPOSE: To determine the normal size and wall thickness of the ascending thoracic aorta (AA) and its relationship with cardiovascular risk factors in a large population-based study. MATERIALS AND METHODS: The mean AA luminal diameter was measured in 3573 Multi-Ethnic Study of Atherosclerosis (MESA) participants (age: 45-84 years), using gradient echo phase contrast cine MRI. Multiple linear regression models were used to evaluate the associations between risk factors and AA diameter. The median and upper normal limit (95th percentile) was defined in a "healthy" subgroup as well as AA wall thickness. RESULTS: The upper limits of body surface area indexed AA luminal diameter for age categories of 45-54, 55-64, 65-74, and 75-84 years are 21, 22, 22, and 28 mm/m(2) in women and 20, 21, 22, 23 mm/m(2) in men, respectively. The mean AA wall thickness was 2.8 mm. Age, gender, and body surface area were major determinants of AA luminal diameter (~+1 mm/10 years; ~+1.9 mm in men than women; ~+1 mm/ 0.23 m(2) ; P < 0.001). The AA diameter in hypertensive subjects was +0.9 mm larger than in normotensives (P < 0.001). CONCLUSION: AA diameter increases gradually with aging for both genders among all race/ethnicities. The normal value of AA diameter is provided. PMID- 23681650 TI - Survival analysis of patients with chondrosarcomas of the pelvis. AB - BACKGROUND: Studies for patients with pelvic chondrosarcomas are limited. This study determines the outcome of patients with pelvic chondrosarcomas, and whether there is any association with tumors' grade, type, stage, margins and pelvic location. MATERIALS AND METHODS: We retrospectively studied 215 patients with pelvic chondrosarcomas. All patients had biopsy and histological diagnosis of their tumors followed by limb salvage or amputation. We staged patients using the Musculoskeletal Tumor Society system. We performed a univariate and multivariate analysis of the survival to death, local recurrence and metastasis with respect to grade, type (central vs. peripheral), stage, margins, and pelvic location, and the survival to death of patients with and without local recurrence. RESULTS: Grade was the most important univariate and multivariate predictor of the survival of the patients. Dedifferentiation was associated with significantly lower overall survival. Peripheral chondrosarcomas predicted survival only in the univariate analysis. Surgical margins predicted local recurrence only in the multivariate analysis. Periacetabular location was associated with lower survival to death and local recurrence. The occurrence of local recurrence compromises the overall survival. CONCLUSION: Grade was the most important predictor of the overall survival of patients with chondrosarcomas of the pelvis. PMID- 23681651 TI - Pulsatile perfusion bioreactor system for durability testing and compliance estimation of tissue engineered vascular grafts. AB - The aim of the study was to design, construct, and test a bioreactor for the conditioning of tissue-engineered vascular grafts under physiological pressure, flow, and environmental conditions and up to supra-physiological pulse frequencies (5 Hz) as the first step towards durability testing. The system also allows the calculation of the compliance of vascular grafts as an indicator of tissue development. The system relies on the combination of a pulse-free pump and a linear magnetic actuator applying pressure pulses with controllable profile and frequency. The compliance estimation is based on the accurate measurement of the vessel's diameter by means of an optical micrometre. Software-based interface enables the control of a magnetic actuator and data acquisition to monitor the conditions of the system. Porcine carotid arteries were tested in the bioreactor for up to 4 weeks at different pulse frequencies. The tissue was analysed by means of histology and immunohistochemistry. Physiological pressures (~80 and 120 mmHg for diastolic and systolic phase, respectively) were generated in the system at frequencies between 1 and 5 Hz. The environmental conditions within the bioreactor were monitored and online determination of the compliance of the arteries was achieved under sterile conditions. Conditioning of the grafts resulted in the abundant production of ECM proteins. In conclusion, we developed a bioreactor for the conditioning of tissue engineered vascular grafts under controlled pressure conditions. The system is suitable to perform durability tests at supra-physiological pulse rates and physiological pressure levels under continuous monitoring of environmental variables (pH, pO2, pCO2, and temperature) and compliance. PMID- 23681652 TI - Unbiased about chromosome segregation: give me a mechanism and I will make you "immortal". PMID- 23681653 TI - Unbiased segregation of yeast chromatids in Saccharomyces cerevisiae. AB - The budding yeast Saccharomyces cerevisiae is characterized by asymmetric cell division and the asymmetric inheritance of spindle components during normal vegetative growth and during certain specialized cell divisions. There has been a longstanding interest in the possibility that yeast chromosomes segregate non randomly during mitosis and that some of the differences between mother and daughter cells could be explained by selective chromatid segregation. This review traces the history of the experiments to determine if there is biased chromatid segregation in yeast. The special aspects of spindle morphogenesis and behavior in yeast that could accommodate a mechanism for biased segregation are discussed. Finally, a recent experiment demonstrated that yeast chromatids segregate randomly without mother-daughter bias in a common laboratory strain grown under routine laboratory conditions. PMID- 23681654 TI - Adult hair follicle stem cells do not retain the older DNA strands in vivo during normal tissue homeostasis. AB - Tissue stem cells have been proposed to segregate the chromosomes asymmetrically (in a non-random manner), thereby retaining preferentially the older "immortal" DNA strands bearing the stemness characteristics into one daughter cell, whereas the newly synthesized strands are segregated to the other daughter cell that will commit to differentiation. Moreover, this non-random segregation would protect the stem cell genome from accumulating multiple mutations during repeated DNA replication. This long-standing hypothesis remains an active subject of study due to conflicting results for some systems and lack of consistency among different tissue stem cell populations. In this review, we will focus on work done in the hair follicle, which is one of the best-understood vertebrate tissue stem cell system to date. In cell culture analysis of paired cultured keratinocytes derived from hair follicle, stem cells suggested a non-random segregation of chromosome with respect to the older DNA strand. In vivo, the hair follicle stem cells appear to self-renew and differentiate at different phases of their homeostatic cycle. The fate decisions occur in quiescence when some stem cells migrate out of their niche and commit to differentiation without self-renewal. The stem cells left behind in the niche self-renew symmetrically and randomly segregate the chromosomes at each division, making more stem cells. This model seems to apply to at least a few other vertebrate tissue stem cells in vivo. PMID- 23681655 TI - Random chromosome segregation in mouse intestinal epithelial stem cells. AB - The mammalian intestinal epithelium is endowed with a high cell turnover sustained by a few stem cells located in the bottoms of millions of crypts. Until recently, it was generally assumed that the extreme sensitivity to DNA damaging agents leading to cell death and the asymmetric mode of chromosome segregation of intestinal epithelial stem cells prevented the illicit survival of mutated stem cells and guarded against mistakes leading to aneuploidy and neoplastic transformation. Recent evidence points instead to a pool of mutipotent self renewing stem cells capable of repairing DNA by homologous recombination significantly more efficiently than other crypt cells. Furthermore, the equilibrium between cell division and differentiation is achieved at the level of the cell population obeying to a random mode of chromosome segregation and a predominantly symmetric mode of cell division. This review summarizes the experimental findings on the mode of cell division adopted by intestinal epithelial stem cells. PMID- 23681656 TI - Sorting DNA with asymmetry: a new player in gene regulation? AB - In recent years, our views on how DNA and genes are organised and regulated have evolved significantly. One example is provided by reports that single DNA strands in the double helix could carry distinct forms of information. That chromatids carrying old and nascently replicated DNA strands are recognised by the mitotic machinery, then segregated in a concerted way to distinct daughter cells after cell division is remarkable. Notably, this phenomenon in several cases has been associated with the cell fate choice of resulting daughter cells. Here, we review the evidence for asymmetric or template DNA strand segregation in mammals with a focus on skeletal muscle. PMID- 23681657 TI - Nonrandom sister chromatid segregation of sex chromosomes in Drosophila male germline stem cells. AB - Sister chromatids are the product of DNA replication, which is assumed to be a very precise process. Therefore, sister chromatids should be exact copies of each other. However, reports have indicated that sister chromatids are segregated nonrandomly during cell division, suggesting that sister chromatids are not the same, although their DNA sequences are the same. Researchers have speculated that stem cells may retain template strands to avoid replication-induced mutations. An alternative proposal is that cells may segregate distinct epigenetic information carried on sister chromatids. Recently, we found that Drosophila male germline stem cells segregate sister chromatids of X and Y chromosomes with a strong bias. We discuss this finding in relation to existing models for nonrandom sister chromatid segregation. PMID- 23681660 TI - DNA abandonment and the mechanisms of uniparental inheritance of mitochondria and chloroplasts. AB - For most eukaryotic organisms, the nuclear genomes of both parents are transmitted to the progeny following biparental inheritance. For mitochondria and chloroplasts, however, uniparental inheritance (UPI) is frequently observed. The maternal mode of inheritance for mitochondria in animals can be nearly absolute, suggesting an adaptive advantage for UPI. In other organisms, however, the mode of inheritance for mitochondria and chloroplasts can vary greatly even among strains of a species. Here, I review the data on the transmission of organellar DNA (orgDNA) from parent to progeny and the structure, copy number, and stability of orgDNA molecules. I propose that UPI is an incidental by-product of DNA abandonment, a process that lowers the metabolic cost of orgDNA repair. PMID- 23681661 TI - Unbiased segregation of fission yeast chromosome 2 strands to daughter cells. AB - The base complementarity feature (Watson and Crick in Nature 171(4356):737-738, 1953) and the rule of semi-conservative mode of DNA replication (Messelson and Stahl in Proc Natl Acad Sci U S A 44:671-682, 1958) dictate that two identical replicas of the parental chromosome are produced during replication. In principle, the inherent strand sequence differences could generate nonequivalent daughter chromosome replicas if one of the two strands were epigenetically imprinted during replication to effect silencing/expression of developmentally important genes. Indeed, inheritance of such a strand- and site-specific imprint confers developmental asymmetry to fission yeast sister cells by a phenomenon called mating/cell-type switching. Curiously, location of DNA strands with respect to each other at the centromere is fixed, and as a result, their selected segregation to specific sister chromatid copies occurs in eukaryotic cells. The yeast system provides a unique opportunity to determine the significance of such biased strand distribution to sister chromatids. We determined whether the cylindrical-shaped yeast cell distributes the specific chromosomal strand to the same cellular pole in successive cycles of cell division. By observing the pattern of recurrent mating-type switching in progenies of individual cells by microscopic analyses, we found that chromosome 2 strands are distributed by the random mode in successive cell divisions. We also exploited unusual "hotspot" recombination features of this system to investigate whether there is selective segregation of strands such that oldest Watson-containing strands co-segregate in the diploid cell at mitosis. Our data suggests that chromosome 2 strands are segregated independently to those of the homologous chromosome. PMID- 23681659 TI - Organelle asymmetry for proper fitness, function, and fate. AB - During cellular division, centrosomes are tasked with building the bipolar mitotic spindle, which partitions the cellular contents into two daughter cells. While every cell will receive an equal complement of chromosomes, not every organelle is symmetrically passaged to the two progeny in many cell types. In this review, we highlight the conservation of nonrandom centrosome segregation in asymmetrically dividing stem cells, and we discuss how the asymmetric function of centrosomes could mediate nonrandom segregation of organelles and mRNA. We propose that such a mechanism is critical for insuring proper cell fitness, function, and fate. PMID- 23681662 TI - A CO-FISH assay to assess sister chromatid segregation patterns in mitosis of mouse embryonic stem cells. AB - Sister chromatids contain identical DNA sequence but are chiral with respect to both their helical handedness and their replication history. Emerging evidence from various model organisms suggests that certain stem cells segregate sister chromatids nonrandomly to either maintain genome integrity or to bias cellular differentiation in asymmetric cell divisions. Conventional methods for tracing of old vs. newly synthesized DNA strands generally lack resolution for individual chromosomes and employ halogenated thymidine analogs with profound cytotoxic effects on rapidly dividing cells. Here, we present a modified chromosome orientation fluorescence in situ hybridization (CO-FISH) assay, where identification of individual chromosomes and their replication history is achieved in subsequent hybridization steps with chromosome-specific DNA probes and PNA telomere probes. Importantly, we tackle the issue of BrdU cytotoxicity and show that our method is compatible with normal mouse ES cell biology, unlike a recently published related protocol. Results from our CO-FISH assay show that mitotic segregation of mouse chromosome 7 is random in ES cells, which contrasts previously published results from our laboratory and settles a controversy. Our straightforward protocol represents a useful resource for future studies on chromatid segregation patterns of in vitro-cultured cells from distinct model organisms. PMID- 23681658 TI - Asymmetric distribution of histones during Drosophila male germline stem cell asymmetric divisions. AB - It has long been known that epigenetic changes are inheritable. However, except for DNA methylation, little is known about the molecular mechanisms of epigenetic inheritance. Many types of stem cells undergo asymmetric cell divisions to generate self-renewed stem cells and daughter cells committed for differentiation. Still, whether and how stem cells retain their epigenetic memory remain questions to be elucidated. During the asymmetric division of Drosophila male germline stem cell (GSC), our recent studies revealed that the preexisting histone 3 (H3) are selectively segregated to the GSC, whereas newly synthesized H3 deposited during DNA replication are enriched in the differentiating daughter cell. We propose a two-step model to explain this asymmetric histone distribution. First, prior to mitosis, preexisting histones and newly synthesized histones are differentially distributed at two sets of sister chromatids. Next, during mitosis, the set of sister chromatids that mainly consist of preexisting histones are segregated to GSCs, while the other set of sister chromatids enriched with newly synthesized histones are partitioned to the daughter cell committed for differentiation. In this review, we apply current knowledge about epigenetic inheritance and asymmetric cell division to inform our discussion of potential molecular mechanisms and the cellular basis underlying this asymmetric histone distribution pattern. We will also discuss whether this phenomenon contributes to the maintenance of stem cell identity and resetting chromatin structure in the other daughter cell for differentiation. PMID- 23681663 TI - Selective tracking of template DNA strands after induction of mitosis with unreplicated genomes (MUGs) in Drosophila S2 cells. AB - According to the "immortal" DNA strand hypothesis (Cairns Nature 255:197-200, 1975), stem cells would keep their template strands in order to prevent the accumulation of mutations, which could occur during DNA replication. Despite the growing number of studies that attempt to test this hypothesis, the conclusions remain highly controversial. In the base of this controversy lie the current limitations of available methodology to selectively and faithfully track the fate of template DNA strands throughout and upon cell division. Here, we developed a method that allows the unequivocal tracking of single chromatids containing template DNA strands in Drosophila S2 cells in culture. This method consists in the induction of mitosis with unreplicated genomes (MUGs) in which cells are allowed to enter mitosis without prior DNA replication. This is achieved by RNAi mediated knockdown of Double parked, a conserved protein required for the initiation of DNA replication and post-replication checkpoint response. The advantages of this system when compared with MUGs generated in mammalian cells is the preservation of chromatid morphology, the ease of loss-of-function studies and the possibility of in vivo applications. Altogether, this approach allows for the readily visualization and tracking of template DNA strands by simply monitoring cells stably expressing GFP-fusions with either Histone H2B or the centromeric Histone variant CID/CENP-A by time-lapse fluorescence microscopy. This might be useful for the dissection of the molecular mechanism behind asymmetric DNA strand segregation. PMID- 23681665 TI - Structural studies of the chemical constituents of Tithonia tagetiflora Desv. (Asteraceae). AB - Tithonia tagetiflora Desv. (Asteraceae) is a widespread plant in Vietnam, and the species of Tithonia are known as plants containing many biologically active compounds. However, T. tagetiflora's chemical composition remains mostly unknown. Therefore, we now report the structural elucidation of two new sesquiterpene lactones, 8-angeloyloxy-2,14-epoxygermacra-4,10(1),11(13)-trien-6,12-olide (1) and 6-angeloyloxy-1-hydroxy-3,4-epoxygermacra-9,11(13)-dien-8,12-olide (2), together with three known compounds, including two norisoprenoids, (6S,9S) vomifoliol or (6R,9R)-vomifoliol (3) and (6S,9S)-roseoside (4), and one glutinane type triterpene, epi-glutinol (5), from the leaves of T. tagetiflora. Their structures are established by 1D and 2D NMR spectroscopy, as well as ESI-MS analysis and comparison with literature data. PMID- 23681664 TI - Plasma-assisted heparin conjugation on electrospun poly(L-lactide) fibrous scaffolds. AB - Heparin conjugation on poly(L-lactide) fibrous scaffolds fabricated by electrospinning was accomplished by surface functionalization with amine (-NH2) groups using a sequential treatment with Ar-NH3 and H2 plasmas. The density of the incorporated -NH2 groups was determined by combining a chemical derivatization method with X-ray photoelectron spectroscopy. The time of Ar-NH3 plasma treatment significantly affected the N/C, -NH2 /N, and -NH2 /C fractions, whereas the plasma power, Ar-NH3 gas composition, and time of H2 plasma treatment only influenced the -NH2 /N and -NH2 /C fractions. Scaffold surface functionalization by -NH2 groups significantly increased the amount of covalently bonded heparin compared to a hydrolysis method. The function of immobilized heparin was confirmed by the decrease of platelet attachment during the exposure of the scaffolds to blood from Sprague-Dawley rats. In vitro experiments with bovine aorta endothelial cells demonstrated that heparin conjugation enhanced cell infiltration through the fibrous scaffolds, regardless of the amount of covalently immobilized heparin. PMID- 23681666 TI - Convergent synthesis of (-)-quinocarcin based on the combination of Sonogashira coupling and gold(I)-catalyzed 6-endo-dig hydroamination. AB - The total synthesis of the pentacyclic tetrahydroisoquinoline alkaloid quinocarcin, which possesses intriguing structural and biological features, has been achieved through a gold(I)-catalyzed regioselective hydroamination reaction. It is noteworthy that the regioselectivity of the intramolecular hydroamination of an unsymmetrical alkyne could be completely switched through substrate control. Other key features of this synthesis include the highly stereoselective synthesis of 2,5-cis-pyrrolidine through the intramolecular amination of the bromoallene and the Lewis acid mediated ring opening of dihydrobenzofuran. PMID- 23681667 TI - Strongly luminescent gold(III) complexes with long-lived excited states: high emission quantum yields, energy up-conversion, and nonlinear optical properties. PMID- 23681668 TI - A TSPO ligand is protective in a mouse model of multiple sclerosis. AB - Local production of neurosteroids such as progesterone and allopregnanolone confers neuroprotection in central nervous system (CNS) inflammatory diseases. The mitochondrial translocator protein (TSPO) performs a rate-limiting step in the conversion of cholesterol to pregnenolone and its steroid derivatives. Previous studies have shown that TSPO is upregulated in microglia and astroglia during neural inflammation, and radiolabelled TSPO ligands such as PK11195 have been used to image and localize injury in the CNS. Recent studies have shown that modulating TSPO activity with pharmacological ligands such as etifoxine can initiate the production of neurosteroids locally in the injured CNS. In this study, we examined the effects of etifoxine, a clinically available anxiolytic drug, in the development and progression of mouse experimental autoimmune encephalomyelitis (EAE), an experimental model for multiple sclerosis (MS). Our results showed that etifoxine attenuated EAE severity when administered before the development of clinical signs and also improved symptomatic recovery when administered at the peak of the disease. In both cases, recovery was correlated with diminished inflammatory pathology in the lumbar spinal cord. Modulation of TSPO activity by etifoxine led to less peripheral immune cell infiltration of the spinal cord, and increased oligodendroglial regeneration after inflammatory demyelination in EAE. Our results suggest that a TSPO ligand, e.g. etifoxine, could be a potential new therapeutic option for MS with benefits that could be comparable to the administration of systemic steroids but potentially avoiding the detrimental side effects of long-term direct use of steroids. PMID- 23681669 TI - Endorectal MRI and MR spectroscopic imaging of prostate cancer: developing selection criteria for MR-guided focal therapy. AB - PURPOSE: To investigate criteria that can identify dominant treatable prostate cancer foci with high certainty at endorectal magnetic resonance imaging (MRI) and MR spectroscopic (MRS) imaging, and thus facilitate selection of patients who are radiological candidates for MR-guided focal therapy. MATERIALS AND METHODS: We retrospectively identified 88 patients with biopsy-proven prostate cancer who underwent endorectal MRI and MRS imaging prior to radical prostatectomy with creation of histopathological tumor maps. Two independent readers noted the largest tumor foci at MRI, if visible, and the volume of concordant abnormal tissue at MRS imaging, if present. A logistic random intercept model was used to determine the association between clinical and MR findings and correct identification of treatable (over 0.5 cm3) dominant intraprostatic tumor foci. RESULTS: Readers 1 and 2 identified dominant tumor foci in 50 (57%) and 58 (65%) of 88 patients; 42 (84%) and 48 (83%) of these were dominant treatable lesions at histopathology, respectively. Within the statistical model, the volume of concordant spectroscopic abnormality was the only factor that predicted correct identification of a dominant treatable lesion on T2-weighted images (odds ratio=1.75; 95% confidence interval=1.08 to 2.82; P value=0.02). In particular, all visible lesions on T2-weighted imaging associated with at least 0.54 cm3 of concordant spectroscopic abnormality were correctly identified dominant treatable tumor foci. CONCLUSION: Patients with dominant intraprostatic tumor foci seen on T2-weighted MRI and associated with at least 0.54 cm3 of concordant MRS imaging abnormality may be radiological candidates for MR-guided focal therapy. PMID- 23681671 TI - Survival of Respiratory Viruses on Fresh Produce. AB - In addition to enteric viruses of fecal origin, emerging zoonotic viruses such as respiratory coronaviruses and influenza viruses may potentially be transmitted via contaminated foods. The goal of this study was to determine the recovery efficiencies and the survival of two respiratory viruses, namely, adenovirus 2 (Ad2) and coronavirus 229E (CoV229E), on fresh produce in comparison to the enteric poliovirus 1 (PV1). Adenovirus was recovered with efficiencies of 56.5, 31.8, and 34.8 % from lettuce, strawberries, and raspberries, respectively. Coronavirus was recovered from lettuce with an efficiency of 19.6 % yet could not be recovered from strawberries. Poliovirus was recovered with efficiencies of 76.7 % from lettuce, but only 0.06 % from strawberries. For comparison purposes, the survival of Ad2, CoV229E, and PV1 was determined for periods up to 10 days on produce. The enteric PV1 survived better than both respiratory viruses on lettuce and strawberries, with only <=1.03 log10 reductions after 10 days of storage at 4 degrees C compared to CoV229E not being recovered after 4 days on lettuce and reductions of 1.97 log10 and 2.38 log10 of Ad2 on lettuce and strawberries, respectively, after 10 days. Nevertheless, these respiratory viruses were able to survive for at least several days on produce. There is therefore the potential for transfer to the hands and subsequently to the mucosa via rubbing the eyes or nose. In addition, some respiratory coronaviruses (e.g., severe acute respiratory syndrome coronavirus) and adenoviruses are also capable of replication in the gut and there is thus some potential for acquisition through the consumption of contaminated produce. PMID- 23681672 TI - Preoperative carcinoembryonic antigen as an outcome predictor in colon cancer. AB - OBJECTIVE: Several reports have shown that certain pre-operative CEA intervals can be predictive of long-term outcomes and have subsequently implied that preoperative CEA may be useful to assess the risk of recurrence or death as a continuous number for individual cases. This analysis assesses if this hypothesis is valid after correction for confounders. METHODS: All colon cancer patients operated on at Massachusetts General Hospital from 2004 through 2011 were considered for retrospective review. Association between outcomes and preoperative CEA was measured in intervals and as a linear relationship. RESULTS: Of the 1,071 patients operated for colon adenocarcinoma, 621 (57.9%) had a preoperative CEA drawn and were included in the analysis. In models using intervals, preoperative CEA did show association with (disease-free) survival, but this was shown to be chiefly a surrogate for metastatic presentation. In linear approaches adjusted for metastatic presentation, CEA loses all correlations with metastatic disease (P = 0.84), survival (P = 0.11), survival duration (P = 0.42) and disease-free interval (P = 0.94). CONCLUSIONS: Extrapolating the predictive value of certain preoperative CEA intervals to a continuous approach for use in a case-for-case basis is unjustified. Preoperative CEA may be a useful risk estimator but has limited significance for predictions of long-term outcomes in individual cases. PMID- 23681673 TI - MiADMSA protects arsenic-induced oxidative stress in human keratinocyte 'HaCaT' cells. AB - Arsenic toxicity may lead to skin manifestations and arsenic accumulation in keratinised tissue. Thus human keratinocytes has been extensively used to study dermal effects of arsenic exposure. The present study was aimed to investigate time and dose-dependent effects of arsenic using HaCaT cell line. Another major focus of the study was to evaluate if treatment with monoisoamyl dimercaptosuccinic acid (MiADMSA) offers protection against arsenic-induced oxidative stress and apoptotic cell death using HaCaT cells. HaCaT cell lines were incubated to three different concentrations of arsenic (10, 30 and 50 MUM) for 24 h to identify the toxic dose by measuring oxidative stress variables. Later, MiADMSA pre-incubation for an hour preceded arsenic exposure (30 MUM). We evaluated cell morphology, lactate dehydrogenase, glutathione linked enzyme and antioxidant enzyme activities to measure oxidative stress status, while MTT assay and caspase 9 and 3 levels were determined for cell viability and apoptotic status. The present study suggests arsenic-induced toxicity in a concentration dependant manner. Arsenic also caused a significant increase in lactate dehydrogenase accompanied by an elevated antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase and caspase activity). Interestingly, pre-treatment of cell with MiADMSA elicited significant protection against arsenic-induced oxidative stress and apoptotic cell death. The present findings are of clinical relevance and suggest MiADMSA to be a promising candidate in protecting skin against arsenic-induced toxic effects, which need further exploration using in vivo experimental models. PMID- 23681670 TI - Fungal communities in the garden chamber soils of leaf-cutting ants. AB - Leaf-cutting ants modify the properties of the soil adjacent to their nests. Here, we examined whether such an ant-altered environment impacts the belowground fungal communities. Fungal diversity and community structure of soil from the fungus garden chambers of Atta sexdens rubropilosa and Atta bisphaerica, two widespread leaf-cutting ants in Brazil, were determined and compared with non nest soils. Culture-dependent methods revealed similar species richness but different community compositions between both types of soils. Penicillium janthinellum and Trichoderma spirale were the prevalent isolates in fungus chamber soils and non-nest soils, respectively. In contrast to cultivation methods, analyses of clone libraries based on the internal transcribed spacer (ITS) region indicated that richness of operational taxonomic units significantly differed between soils of the fungus chamber and non-nest soils. FastUnifrac analyses based on ITS sequences further revealed a clear distinction in the community structure between both types of soils. Plectania milleri and an uncultured Clavariaceae fungus were prevalent in fungus chamber soils and non nest soils, respectively. FastUnifrac analyses also revealed that fungal community structures of soil from the garden chambers markedly differed among ant species. Our findings suggest that leaf-cutting ants affect fungal communities in the soil from the fungus chamber in comparison to non-nest soils. PMID- 23681674 TI - SeMet inhibits IL-1beta-induced rheumatoid fibroblast-like synoviocytes proliferation and the production of inflammatory mediators. AB - Previous studies demonstrated that Se has anti-inflammatory activities and that it plays an important role in maintaining normal cartilage metabolism. Nevertheless, little is known about the effects of Se on the production of inflammatory mediators in rheumatoid fibroblast-like synoviocytes (FLSs). The objective of this study was to determine the effects of Se on the interleukin 1beta (IL-1beta)-induced proliferation of FLSs and production of matrix metalloproteinases (MMPs) and inflammatory mediators by FLSs. In this study, the proliferation of FLSs was assessed using the MTT assay after cultured with/without the presence of IL-1beta and SeMet. Human FLSs were pretreated with SeMet (0.5 MUM) and subsequently stimulated with IL-1beta (5 ng/ml) for 24 h. Production of NO and PGE2 were evaluated by the Griess reaction and ELISA. Gene expression of MMP-3, MMP-13, iNOS, and COX-2 was measured by real-time PCR. MMP-3 and MMP-13 proteins in culture medium were determined using cytokine-specific ELISA. Western immunoblotting was used to analyze the iNOS and COX-2 protein production in the culture medium and the activity of phosphorylation of P38 MAPK pathways. We found that SeMet significantly inhibits IL-1beta-induced proliferation of FLSs. SeMet also inhibited the production of PGE2 and NO induced by IL-1beta. SeMet significantly decreased IL-1beta-stimulated gene expression and production of MMP-3, MMP-13, iNOS, and COX-2 in human FLSs. In addition, we found SeMet partly inhibited the IL-1beta-induced activation of p38 MAPK pathways. The present report is first to demonstrate that SeMet inhibits IL-1beta induced expression of MMPs and production of inflammatory factors in cultured FLSs, indicating that SeMet may be a potential agent in the treatment of rheumatoid arthritis. PMID- 23681675 TI - Clinical features in patients with pulmonary embolism at a community hospital: analysis of 4 years of data. AB - The aim of this study is to assess the various clinical features, risk factors, and electrocardiographic (EKG) findings associated with acute pulmonary embolism (PE). Knowledge gained from the study may enable health care providers in diagnosis of PE, thus allowing them to carry out appropriate diagnostic testing and treatment after recognition of this potentially lethal disease. PE is common but frequently under-diagnosed clinical problem, associated with potentially fatal outcomes. Clinical presentation is highly variable, non-specific and most patients have an underlying identifiable risk factor. The presentation of PE can easily be confused with other cardio-pulmonary or systemic disorders. Prompt diagnosis of this potentially deadly disease is of utmost importance. Knowledge of salient features associated with PE may enable health care providers in diagnosis of PE, thus allowing them to carry out appropriate diagnostic testing and treatment after its recognition. We performed a single-center, cross sectional descriptive study including all inpatient and emergency department encounters >=18 years of age diagnosed with PE at our institution, a 300-bed inner city community hospital, during the dates January 2007 to December 2010. All patients were diagnosed with multi-detector 64-slice spiral computed tomography angiography. Using a standardized form, we performed simultaneous retrospective chart review to collect the necessary data required for the study. PE was confirmed in 334 patients during the 4 years study period. Mean age of subjects was 65.8 years (+/-16.4, range 22-98). Females represented 54 % of study subjects. Dyspnea, chest pain, and cough were present in 72, 38, and 19 % of the patients, respectively. Dyspnea was the only presenting symptom in 29 %. Tachypnea, hypoxia, tachycardia, and signs of DVT were present in 39, 35, 33, and 29 %, respectively. Cancer was most common risk factor present in 27 %, followed by prior history of venous thromboembolism (DVT or PE), immobilization, and surgery in 19, 15, and 15, respectively. EKG interpretation revealed normal sinus rhythm in 53 %, sinus tachycardia in 31 %, S1Q3T3 pattern in 6 %, and atrial fibrillation (AF) in 6 %.We also noted that 8 % of elderly patients had new onset AF at the time of diagnosis of PE. Diagnosis of PE remains a challenging task due to its variable presentation. Many of the classical features associated with this potentially fatal disease are often missing. This data re-emphasizes a wide spectrum of clinical presentation and non-specificity of symptoms of PE. Clinical suspicion of PE is a critical step and of paramount importance for further objective investigations, which would assist in the diagnosis and appropriate timely management of PE. PMID- 23681676 TI - Discrepant ratios of arterial versus venous thrombosis in hemophilia A as compared with hemophilia B. AB - The occurrence of thrombosis in patients with congenital bleeding disorders represents an exceptional event. Hemophilia A and hemophilia B patients have been showed to present both arterial and venous thrombosis (85 cases of arterial thrombosis and 34 cases of venous thrombosis). The great majority of arterial thrombosis are myocardial infarction or other acute coronary syndromes, whereas the majority of venous thrombosis are deep vein thrombosis and/or pulmonary embolisms. However there are discrepancies in the proportion of arterial and venous thrombosis seen in hemophilia A versus hemophilia B. The ratio of arterial versus venous thrombosis in hemophilia A is 3.72 whereas that for hemophilia B is 1.12. This indicates that arterial thrombosis is more frequent in hemophilia A as compared to hemophilia B and the opposite is true for venous thrombosis. The potential significance of this discrepancy is discussed. PMID- 23681677 TI - Parent training for children born premature: a pilot study examining the moderating role of emotion regulation. AB - The aim of the current study was to examine the moderating effect of emotion regulation on treatment efficacy following a parent-training intervention, parent child interaction therapy, for young children born preterm. In this pilot randomized controlled trial, 28 young children who were born preterm (i.e., <37 weeks gestation) and presented with elevated levels of externalizing behavior problems were randomly assigned to an immediate treatment or waitlist control group. Observers masked to treatment condition coded an index of emotion regulation (i.e., global regulation) during a videotaped 10-min parent-child interaction at the initial baseline assessment. Treatment efficacy was assessed using a parent-report questionnaire of child disruptive behavior. Results demonstrated that global regulation significantly interacted with treatment condition in predicting change in child disruptive behavior. Specifically, higher levels of distress at baseline were associated with greater improvements in child disruptive behavior following the intervention. These findings are discussed in the context of the differential susceptibility hypothesis and highlight the importance of considering children's emotion regulation skills in the course of psychosocial treatment for young children born premature. PMID- 23681679 TI - Strategies for expanding colorectal cancer screening at community health centers. AB - Community health centers are uniquely positioned to address disparities in colorectal cancer (CRC) screening as they have addressed other disparities. In 2012, the federal Health Resources and Services Administration, which is the funding agency for the health center program, added a requirement that health centers report CRC screening rates as a standard performance measure. These annually reported, publically available data are a major strategic opportunity to improve screening rates for CRC. The Patient Protection and Affordable Care Act enacted provisions to expand the capacity of the federal health center program. The recent report of the Institute of Medicine on integrating public health and primary care included an entire section devoted to CRC screening as a target for joint work. These developments make this the ideal time to integrate lifesaving CRC screening into the preventive care already offered by health centers. This article offers 5 strategies that address the challenges health centers face in increasing CRC screening rates. The first 2 strategies focus on improving the processes of primary care. The third emphasizes working productively with other medical providers and institutions. The fourth strategy is about aligning leadership. The final strategy is focused on using tools that have been derived from models that work. CA Cancer J Clin 2013. (c) 2013 American Cancer Society, Inc. PMID- 23681678 TI - Rasagiline prevents apoptosis induced by PK11195, a ligand of the outer membrane translocator protein (18 kDa), in SH-SY5Y cells through suppression of cytochrome c release from mitochondria. AB - Rasagiline protects neuronal cells from cell death caused by various lines of insults. Its neuroprotective function is due to suppression of mitochondrial apoptosis signaling and induction of neuroprotective genes, including Bcl-2 and neurotrophic factors. Rasagiline inhibits the mitochondrial membrane permeabilization, an initial stage in apoptosis, but the mechanism has been elusive. In this paper, it was investigated how rasagiline regulates mitochondrial death cascade in apoptosis induced in SH-SY5Y cells by PK11195, a ligand of the outer membrane translocator protein of 18 kDa. Rasagiline prevented release of cytochrome c (Cyt-c), and the following caspase 3 activation, ATP depletion and apoptosis, but did not inhibit the mitochondrial membrane potential collapse, in contrast to Bcl-2 overexpression. Rasagiline stabilized the mitochondrial contact site and suppressed Cyt-c release into cytoplasm, which should be the critical point for the regulation of apoptosis. Monoamine oxidase was not associated with anti-apoptotic activity of rasagiline in PK11195-induced apoptosis. PMID- 23681680 TI - The inherent cost-effectiveness of family physicians. PMID- 23681681 TI - Family physicians' perceptions on how they deliver cost-effective care: a qualitative study from the Residency Research Network of Texas (RRNeT). AB - BACKGROUND AND OBJECTIVES: The aim of our study was to deepen our understanding of the factors that may explain the observational literature that more primary care physicians in an area contribute to better population health outcomes and lower health care costs. METHODS: This study used in-depth, qualitative interviewing of family physicians in both urban and rural, academic, and private practices. Interviews were initiated with a series of grand tour questions asking subjects to give examples and personal narratives demonstrating cost effectiveness and cost inefficiencies in their own practices. An iterative open coding approach was used to analyze transcripts to search for unifying themes and sub-themes until consensus among investigators was achieved. RESULTS: Thirty eight respondents gave examples of how their decision-making approaches resulted in improved patient outcomes and lower costs. Family physicians' cost-effective care was founded on two themes-characteristic attitudes and skills of the physicians themselves and a thorough knowledge of the whole patient. Family physicians also felt their approaches to gathering information and then making diagnostic and treatment decisions resulted in fewer tests and fewer treatments ordered overall. Family physicians also delivered care in less expensive facilities and generated lower overall charges for physician fees. CONCLUSIONS: Family physicians perceived that their approaches to patient care result in medical decision making priorities and care delivery processes that contribute to more cost-effective health care. These outcomes were achieved less by providing preventive services and strictly adhering to guidelines but rather by how they individualized the management of new symptoms and chronic conditions. PMID- 23681682 TI - Patient-provider communication about diabetes self-care activities. AB - BACKGROUND AND OBJECTIVES: Controlling diabetes requires sustained self management on the part of patients. Health care providers can support patients' self-care efforts through communication and problem solving. We conducted this study to determine the frequency with which self-care activities were discussed during office visits for follow-up care of diabetes and how much time was spent on these discussions. METHODS: Audio recordings of 28 patient encounters in five primary care clinics were analyzed. We determined the frequency of self-care discussions and the amount of time devoted to these discussions. RESULTS: Self care was discussed in all 28 encounters. Median encounter times for each clinic ranged from 19.8 to 37.6 minutes, with self-care discussions taking from 0.1 to 17.2 minutes. Median discussion time devoted to all self-care activities was 5.2 minutes, representing 23.5% of a visit of median length. Blood sugar testing was discussed longer than the other activities. The least time was devoted to eye and foot examinations. Discussions were usually initiated by providers and did not differ in length according to who initiated the discussion. CONCLUSIONS: Patients with diabetes regularly discussed self-care activities during follow-up visits at family medicine clinics. Providers varied in their capacity to incorporate self care planning into routine medical care for patients with diabetes. Interventions are needed that help improve goal-setting and documentation. Documentation of self-care discussions will be important for meeting Meaningful Use criteria. PMID- 23681684 TI - Integrative medicine at academic health centers: a survey of clinicians' educational backgrounds and practices. AB - BACKGROUND AND OBJECTIVES: Integrative medicine is a relatively new field that seeks to combine conventional and nonconventional approaches to patient care. Many academic health centers have now established integrative medicine clinics, yet little is known about the clinicians who practice at them. We used a nationwide survey to characterize the backgrounds, clinical practices, and involvement in research and education of clinicians who practice integrative medicine at academic health centers. METHODS: Participants included clinicians (MDs, DOs, PAs, and nurse practitioners) who practice at 30 different integrative medicine clinics that are affiliated with academic health centers. RESULTS: Completed surveys from 136 of 162 clinicians were received (84% response rate). The integrative therapies that clinicians most often reported providing themselves were breathing exercises (66%), herbal medicine prescribing (61%), meditation (44%), and functional medicine (34%). The integrative therapies that clinicians most often referred their patients for were acupuncture (96%), massage (92%), yoga (85%), and meditation (79%). Respondents reported spending a mean of 20% of their time training medical students, and 63% had participated in research in the past year. CONCLUSIONS: This survey provides the first national assessment of clinicians practicing integrative medicine at academic health centers. These clinicians use a wide variety of complementary and alternative therapies and appear involved in the research and education missions of their academic health centers. PMID- 23681683 TI - Pilot trial of a licensed practical nurse intervention for hypertension and depression. AB - BACKGROUND AND OBJECTIVES: Depression is a risk factor for hypertension, and risk of depression is increased substantially in patients with hypertension. Our objective was to examine whether an intervention carried out by Licensed Practical Nurses (LPNs) integrating depression treatment into care for hypertension improved blood pressure control and depressive symptoms. METHODS: In all, 60 patients ages 41 to 92 years with hypertension and depressive symptoms at a large primary care practice in Philadelphia were randomly assigned to an integrated care intervention carried out by LPNs (n=30) or usual care (n=30). Intervention and control groups did not differ statistically on baseline measures. Outcomes assessed at baseline and 12 weeks included standard laboratory procedures to measure blood pressure control and the Patient Health Questionnaire (PHQ-9) to assess depression. RESULTS: Patients in the integrated care intervention had lower diastolic blood pressure (intervention 74.2 mmHg versus usual care 82.0 mmHg) and fewer depressive symptoms (PHQ-9 mean scores, intervention 2.4 versus usual care 7.1) compared with patients in the usual care group at 12 weeks after adjustment for baseline values. Patients in the integrated care intervention also had lower systolic blood pressure (intervention 130.0 mmHg versus usual care 140.6 mmHg) compared with patients in the usual care group at 12 weeks although the results approached but did not reach conventional levels of statistical significance. CONCLUSION: Training existing primary care practice office staff will facilitate implementation in real world practices with limited resources and competing demands. PMID- 23681685 TI - Patient portal implementation: resident and attending physician attitudes. AB - BACKGROUND AND OBJECTIVES: Electronic patient portals are increasingly common, but there is little information regarding attitudes of faculty and residents at academic medical centers toward them. METHODS: The primary objective was to investigate attitudes toward electronic patient portals among primary care residents and faculty and changes in faculty attitudes after implementation. The study design included a pre-implementation survey of 39 general internal medicine and family medicine residents and 43 generalist faculty addressing attitudes and expectations of a planned patient portal and also a pre- and post-implementation survey of general internal medicine and family medicine faculty physicians. The survey also addressed email communication with patients. RESULTS: Prior to portal implementation, residents reported receiving much less e-mail from patients than faculty physicians; 68% and 9% of residents and faculty, respectively, reported no email exchange in a typical month. Residents were less likely to agree with allowing patients to view selected parts of their medical record on-line than faculty physicians (57% and 81%, respectively). Physicians who participated in the portal's pilot implementation had expected workload to increase (64% agreed), but after implementation, 87% of those responding were neutral or disagreed that workload had increased. After implementation, only 33% believed quality of care had improved compared to 55% who had expected it to improve prior to implementation. CONCLUSIONS: Residents and faculty physicians need to be prepared for a changing environment of electronic communication with patients. Some positive and negative expectations of physicians toward enhanced electronic access by patients were not borne out by experience. PMID- 23681686 TI - Family medicine training in China. AB - BACKGROUND AND OBJECTIVES: In 2010, six ministries of the Chinese government jointly issued a plan for building team-based primary care led by family physicians, prompting the creation of new models of family medicine training across the country. The purpose of this paper is to describe examples of existing family physician training models in China, to present advantages and disadvantages of the various models, and to present a specific model of family medicine residency training implemented at the Zhejiang University Medical School affiliated Sir Run Run Shaw Hospital in collaboration with the Michigan State University-affiliated Genesys Regional Medical Center. PMID- 23681687 TI - Brief intervention effective in reducing weight bias in medical students. AB - BACKGROUND: Medical students are exposed to a growing number of obese patients in clinical encounters. Many medical students harbor negative attitudes and stereotypes regarding obese patients, which lead to negative interpersonal behaviors. This study pilot tested the effectiveness of an educational intervention in reducing bias toward obese patients. METHODS: Second- and third year medical students (n=64) watched a 17- minute video, "Weight Bias in Health Care," and participated in interactive discussion to share experiences with encountering obese patients. The Beliefs About Obese Persons (BAOP), Attitudes Toward Obese Persons (ATOP), and Fat Phobia Scales (FPS) were administered before and after intervention. Change in mean scores from before to after the intervention was tested for statistical significance using the paired samples t test. General linear models were used to examine associations of subject characteristics with mean scores for each scale. RESULTS: The intervention increased beliefs that genetic and environmental factors play an important role in the cause of obesity as opposed to lack of personal control (mean BAOP increased from 16.53 to 19.27). It also decreased students' negative stereotypes regarding obese patients (mean FPS decreased from 3.65 to 3.45). There were independent associations of subject characteristics with post-intervention ATOP scores, with more positive attitudes in younger, male, and white participants. CONCLUSIONS: Implementing a short educational intervention was effective in improving medical students' beliefs and stereotypes regarding obese patients. This widely accessible and easily replicable program can serve as a model and springboard for further development of educational interventions to reduce weight bias among medical students. PMID- 23681692 TI - An indispensable academic home. PMID- 23681688 TI - Evaluation of prenatal and pediatric group visits in a residency training program. AB - BACKGROUND: It is well established that group visits offer an appropriate alternative to individual care with respect to efficiency, clinical effectiveness, and patient and provider satisfaction and are feasible in the training setting. The purpose of this paper is to describe resident educational outcomes from participation in prenatal and well-child group visits over the last 6 years. METHODS: We surveyed the 48 physicians who graduated from the University of North Carolina Family Medicine Residency from 2006 through 2011 regarding their current scope of practice, the number of group visits they experienced, and the educational value of group visits. RESULTS: Thirty-four (71%) of graduates responded. Twelve respondents (35%) include prenatal care in their current practice, 29 (85%) include pediatric care, and five (15%) include group visits. As residents, all respondents participated in group visits. Respondents most valued what they learned in group visits from patient questions, from the exposure to a bolus of patients at the same stage of development, and from faculty role modeling. CONCLUSIONS: Group visits are a potentially valuable adjunct to the standard training experience, with benefits for learning efficiency, scope of practice, and the promotion of patient-centered care that can be carried forward into practice. PMID- 23681693 TI - Financing of primary care graduate medical education: the need for evidence. PMID- 23681694 TI - Total syntheses of (-)-transtaganolide A, (+)-transtaganolide B, (+) transtaganolide C, and (-)-transtaganolide D and biosynthetic implications. PMID- 23681695 TI - A novel bidirectional continuous perfusion bioreactor for the culture of large sized bone tissue-engineered constructs. AB - This works reports the development and preliminary assessment of a new bioreactor for culturing large-sized three-dimensional constructs in bone tissue engineering. The bidirectional continuous perfusion bioreactor (BCPB) promotes mechanical stimulation of cells through the creation of shear forces induced by flow perfusion. The main innovation consists in the possibility of culturing scaffolds of large dimensions that can be suitable for the regeneration of critical sized defects. The functionality of BCPB was preliminarily evaluated by culturing starch-polycaprolactone scaffolds/goat bone marrow stromal cells for 14 and 21 days. Cylindrical blocks were stacked (42 mm thick). Static culture was used as controls. The samples were collected for DNA, alkaline phosphatase (ALP), scanning electron microscopy (SEM), and histological analysis. The results showed higher ALP levels in the bioreactor cultures than those obtained under static conditions. The number of cells in constructs cultured in the bioreactor showed lower values compared to static cultures, suggesting that static conditions tend to privilege the metabolic path way for cellular proliferation while dynamic conditions tend to privilege the metabolic path for osteogenic differentiation. SEM observations show that, the migration and cell distribution was observed in the bioreactor. These results demonstrate the feasibility and the benefit of culturing constructs in BCPB. PMID- 23681696 TI - Using Baltimore HIV behavioral surveillance data for local HIV prevention planning. AB - In response to the National HIV/AIDS Strategy (NHAS) and as part of CDC's Enhanced Comprehensive HIV Prevention Plan (ECHPP) project, Maryland developed a comprehensive local HIV prevention plan for the Baltimore-Towson Metropolitan Statistical Area and identified a series of priority HIV prevention and service goals. The current project sought to: (1) determine how well National HIV Behavioral Surveillance (NHBS) indicators were aligned with NHAS/ECHPP-informed local HIV prevention goals (2) facilitate on-going NHBS data utilization to inform on-going local HIV prevention and service planning, and (3) build a foundation for future NHBS data utilization in local HIV decision-making. Project activities identified key HIV-related indicators in NHBS that are directly or indirectly related to local HIV priorities as informed by NHAS/ECHPP, which can be used for HIV prevention planning in the Baltimore area. Areas for enhancing NHBS and local data collection to further inform HIV prevention priorities are highlighted. PMID- 23681697 TI - Syndemic and other risk factors for unprotected anal intercourse among an online sample of Belgian HIV negative men who have sex with men. AB - Men who have sex with men (MSM) are confronted with different health problems. Next to a higher HIV prevalence and a higher reporting of depressive symptoms and other mental health problems, there is also evidence of substance dependence and sexual compulsivity occurring simultaneously. Using a sample of 591 HIV-negative Belgian MSM, we examine the relationships between depressive symptoms and other risk factors of unprotected anal intercourse (UAI) practice with casual partners. These risk factors include depressive symptoms, sexual behavioural indicators, individual risk perception of UAI, intrapersonal factors measured by the sexual sensation seeking scale, substance use, sources of social support and social norming regarding condom use and finally the location where or media through which men find sex partners. Our findings show that multifactorial, intertwined factors contribute to the explanation of UAI among MSM at risk for HIV infection. These findings underline the need for an integrated sexual health approach for MSM. PMID- 23681699 TI - Can physician's self-estimates be used as a valid instrument to determine prescription frequencies of anti-psoriatic drugs? Comparison of the results of a cross-sectional study using self-estimates with actual prescription behavior documented in a cohort study. AB - PURPOSE: Physicians' self-estimates of their own prescription behavior can be used as a tool to gather information on prescription frequencies. Self-estimates as a tool for health-care research on prescription frequencies need to be validated as a suitable method before it can be used widely. METHODS: We performed a cross-sectional study inviting all dermatologists in Berlin and Brandenburg to give self-estimates of their own prescription behavior of anti psoriatic drugs. The results were compared with the results from a consecutive 8 months cohort study with the same participants documenting their actual treatment choices during every visit of a psoriasis patient on a standardized documentation sheet. Differences between self-estimates and documented prescription patterns were analyzed with respect to systemic anti-psoriatic drugs and UV treatment. RESULTS: Fifty-one dermatologists participated. They documented an average of 91 patient visits each. Absolute differences between the self-estimates and the documented actual prescription behavior ranged from -2.5% to 1.4% for systemic treatments. For psoralen plus ultravioloet A (PUVA) treatment, the absolute difference was 3.3% and for ultraviolet B (UVB) 4.7%. CONCLUSIONS: Self-estimates were surprisingly exact. Self-estimates may be suggested as one tool to assess prescription frequencies, but further studies are needed to confirm their validity. PMID- 23681698 TI - Brain microvessel cross-presentation is a hallmark of experimental cerebral malaria. AB - Cerebral malaria is a devastating complication of Plasmodium falciparum infection. Its pathogenesis is complex, involving both parasite- and immune mediated events. CD8(+) T cells play an effector role in murine experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA (PbA) infection. We have identified a highly immunogenic CD8 epitope in glideosome-associated protein 50 that is conserved across rodent malaria species. Epitope-specific CD8(+) T cells are induced during PbA infection, migrating to the brain just before neurological signs manifest. They are functional, cytotoxic and can damage the blood-brain barrier in vivo. Such CD8(+) T cells are also found in the brain during infection with parasite strains/species that do not induce neuropathology. We demonstrate here that PbA infection causes brain microvessels to cross-present parasite antigen, while non-ECM-causing parasites do not. Further, treatment with fast-acting anti-malarial drugs before the onset of ECM reduces parasite load and thus antigen presentation in the brain, preventing ECM death. Thus our data suggest that combined therapies targeting both the parasite and host antigen presenting cells may improve the outcome of CM patients. PMID- 23681700 TI - An adenosine kinase in apoplastic location is involved in Magnaporthe oryzae cold acclimation. AB - Cold acclimation is an important process to increase freezing tolerance for over winter survival in many organisms. The apoplastic area is very important in cold acclimation. Two-dimensional electrophoresis was used to identify apoplastic proteins involved in the cold acclimation process of the filamentous fungus Magnaporthe oryzae, and nine protein spots showed at least 1.5-fold increase during cold treatment. These proteins were further analyzed by matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry. One of these proteins was identified to be an adenosine kinase (MoAK), an ortholog of the adenosine kinase from Saccharomyces cerevisiae. The MoAK gene showed significantly increased in transcription level. Microscopic analyses showed that an MoAK::GFP fusion protein was localized in the apoplastic region. The MoAk protein showed anti-freezing activity when expressed in yeast. These results indicated that cold acclimation is crucial for fungal freezing tolerance and MoAK played an important role in this process in M. oryzae. PMID- 23681701 TI - Relationship between proprioception at the knee joint and gait ataxia in HSAN III. AB - BACKGROUND: Hereditary sensory and autonomic neuropathy type III features marked ataxic gait that progressively worsens over time. We assessed whether proprioceptive disturbances can explain the ataxia. METHODS: Proprioception at the knee joint was assessed using passive joint angle matching in 18 patients and 14 age-matched controls; 5 patients with cerebellar ataxia were also studied. Ataxia was quantified using the Brief Ataxia Rating Score, which ranged from 7 to 26 of 30. RESULTS: Neuropathy patients performed poorly in judging joint position: mean absolute error was 8.7 degrees +/- 1.0 degrees , and the range was very wide (2.8 degrees -18.1 degrees ); conversely, absolute error was only 2.7 degrees +/- 0.3 degrees (1.6 degrees -5.5 degrees ) in the controls and 3.0 degrees +/- 0.2 degrees (2.1 degrees -3.4 degrees ) in the cerebellar patients. This error was positively correlated to the degree of ataxia in the neuropathy patients but not the cerebellar patients. CONCLUSIONS: These results suggest that poor proprioceptive acuity at the knee joint is a major contributor to the ataxic gait associated with hereditary sensory and autonomic neuropathy type III. PMID- 23681702 TI - Changes in fine structure of pericytes and novel desmin-immunopositive perivascular cells during postnatal development in rat anterior pituitary gland. AB - Pericytes are perivascular cells associated with capillaries. We previously demonstrated that pericytes, identified by desmin immunohistochemistry, produce type I and III collagens in the anterior pituitary gland of adult rats. In addition, we recently used desmin immunoelectron microscopy to characterize a novel type of perivascular cell, dubbed a desmin-immunopositive perivascular cell, in the anterior pituitary. These two types of perivascular cells differ in fine structure. The present study attempted to characterize the morphological features of pituitary pericytes and novel desmin-immunopositive perivascular cells during postnatal development, in particular their role in collagen synthesis. Desmin immunostaining revealed numerous perivascular cells at postnatal day 5 (P5) and P10. Transmission electron microscopy showed differences in the fine structure of the two cell types, starting at P5. Pericytes had well developed rough endoplasmic reticulum and Golgi apparatus at P5 and P10. The novel desmin-immunopositive perivascular cells exhibited dilated cisternae of rough endoplasmic reticulum at P5-P30. In addition, during early postnatal development in the gland, a number of type I and III collagen-expressing cells were observed, as were high expression levels of these collagen mRNAs. We conclude that pituitary pericytes and novel desmin-immunopositive perivascular cells contain well-developed cell organelles and that they actively synthesize collagens during the early postnatal period. PMID- 23681703 TI - Characterization of the spatial and temporal expression of the OsSSII-3 gene encoding a key soluble starch synthase in rice. AB - BACKGROUND: Starch, the major component of rice grain, consists of amylose and amylopectin. SSIIa, a key soluble starch synthase involved in the biosynthesis of rice amylopectin, is a major factor that controls the gelatinization temperature of rice grain. Extensive work has been done and impressive progress has been made in elaborating the function of the gene encoding SSIIa (OsSSII-3). However, the systematic expression analysis of OsSSII-3 is still rare. RESULTS: In the present study, we performed a comprehensive expression analysis of OsSSII-3 in both the developing seeds and other tissues of indica rice 9311 by using quantitative real time PCR. The results showed that the gene was dominantly expressed in the developing seeds. In addition, the promoter sequence of OsSSII-3 was cloned and fused with the GUS reporter gene and its expression was carefully monitored in the transgenic rice. The data from both histochemical and fluorometric analyses showed that the OsSSII-3 promoter was capable of driving the target gene to have an endosperm-specific expression, which may be due to the existing of several endosperm-specific motifs in the promoter, including the -300 elements, AACA motifs and GCN4 motifs. This result was quite consistent with that of the endogenous transcription analysis of OsSSII-3. CONCLUSION: This study not only advanced our understanding of the spatial and temporal expression characteristics of OsSSII-3, but also provided a valuable promoter for future application in generating elite rice varieties with high nutritional or medicinal value. PMID- 23681705 TI - Synthesis of highly fluorescent diquinaldinatoalumino silole derivatives. PMID- 23681707 TI - Mechanisms of plant growth promotion and disease suppression by Pseudomonas aeruginosa strain 2apa. AB - A new Pseudomonas strain, designated as 2apa was isolated from tomato rhizosphere and identified as a member of species Pseudomonas aeruginosa based on its morphology, conventional, biochemical, cell wall fatty acid methyl ester analysis, and 16S rRNA gene sequence analysis. The strain 2apa was positive for root colonization, indole acetic acid (IAA), salicylic acid and siderophore production and inhibited the growth of wide range of microorganisms. Antimicrobial substances produced by this strain with further purification and structure elucidation proved to be phenazine. Under laboratory and greenhouse conditions the strain promoted plant growth and suppressed a wide range of foliar and root pathogens in tomato. The protection offered by strain 2apa to foliar pathogens is considered as induced systemic resistance and was further confirmed by enhanced accumulation of phenolics, elicitation of lipoxygenas activity, and jasmonic acid levels. The broad-spectrum antimicrobial and induced systemic resistance exhibiting strain P. aeruginosa 2apa can be used as an effective biological control candidate against devastating fungal and bacterial pathogens, which attack both root and foliar portions of tomato plant. Production of other functional traits such as IAA and siderophore may enhance its potential as biofertilizer. PMID- 23681709 TI - Continuous gas-phase hydroaminomethylation using supported ionic liquid phase catalysts. PMID- 23681704 TI - Progress in stem cell therapy for major human neurological disorders. AB - Human neurological disorders such as Alzheimer's disease (AD), Parkinson's disease, stroke or spinal cord injury are caused by the loss of neurons and glial cells in the brain or spinal cord in the Central Nervous System (CNS). Stem cell technology has become an attractive option to investigate and treat these diseases. Several types of neurons and glial cells have successfully been generated from stem cells, which in some cases, have ameliorated some dysfunctions both in animal models of neurological disorders and in patients at clinical level. Stem cell-based therapies can be beneficial by acting through several mechanisms such as cell replacement, modulation of inflammation and trophic actions. Here we review recent and current remarkable clinical studies involving stem cell-based therapy for AD and stroke and provide an overview of the different types of stem cells available nowadays, their main properties and how they are developing as a possible therapy for neurological disorders. PMID- 23681710 TI - Characterization of a bovine viral diarrhea virus originated from cattle in Gansu Province, China. AB - A bovine viral diarrhea disease virus (BVDV) GS-4 was isolated in Western China form dairy cattle with respiratory disease. Genomic comparison analysis with the 5' half genome sequence encompassing the coding region of N(pro), capsid, and envelope glycoproteins showed that the GS-4 should be classified into BVDV-1b1, which is considered as one of the predominant subgenotypes found in China. This classification was confirmed by phylogenetic analysis based on E2 coding region. PMID- 23681711 TI - [Neuroimaging of bipolar disorders]. AB - During recent years, marked progress has been made both in structural and functional neuroimaging of affective disorders. Structural changes in the limbic system, prefrontal cortex and subcortical regions including their fascicular connections appear to correlate with affective disorders in most, but not all studies. Especially for bipolar disorder, there still is a considerable heterogeneity among the results. Functional neuroimaging (fMRI, SPECT, PET) underlines the importance of paralimbic, cortical and subcortical structures in mood regulation; however, the methodology of these studies is still in its infancy meaning that the results of these studies are not always reproducible. However, in summary it can be expected that with improving methodology functional neuroimaging will play an increasing role in affective, including bipolar, disorders in the near future. PMID- 23681708 TI - Systemic ceramide accumulation leads to severe and varied pathological consequences. AB - Farber disease (FD) is a severe inherited disorder of lipid metabolism characterized by deficient lysosomal acid ceramidase (ACDase) activity, resulting in ceramide accumulation. Ceramide and metabolites have roles in cell apoptosis and proliferation. We introduced a single-nucleotide mutation identified in human FD patients into the murine Asah1 gene to generate the first model of systemic ACDase deficiency. Homozygous Asah1(P361R/P361R) animals showed ACDase defects, accumulated ceramide, demonstrated FD manifestations and died within 7-13 weeks. Mechanistically, MCP-1 levels were increased and tissues were replete with lipid laden macrophages. Treatment of neonates with a single injection of human ACDase encoding lentivector diminished the severity of the disease as highlighted by enhanced growth, decreased ceramide, lessened cellular infiltrations and increased lifespans. This model of ACDase deficiency offers insights into the pathophysiology of FD and the roles of ACDase, ceramide and related sphingolipids in cell signaling and growth, as well as facilitates the development of therapy. PMID- 23681712 TI - [Bipolar disorders--psychoeducation in the context of neurobiological knowledge and optimised treatment]. PMID- 23681713 TI - [Psychotherapeutic interventions in bipolar disorders--treatment programmes, their contents and effectiveness]. AB - Cognitive-behavioural interventions combined with pharmacotherapy have gained importance in the treatment of bipolar disorders. Based on the vulnerability stress instability model psychoeducational, cognitive-behavioural, interpersonal and family interventions are provided. This paper gives an overview of treatment programmes and their foci. They include providing knowledge about the illness and its treatment, modifying dysfunctional cognitions and symptom management as well as relapse prevention by promoting a stable life style. There are several English and German-based randomised controlled follow-up studies in English-speaking countries which provide support for the efficacy of combined treatment. Since 2004 German-based manualised treatment programmes have become available and have been shown to be clinically feasible and promising. PMID- 23681714 TI - [Differential diagnosis of and pharmacotherapy for bipolar disorder]. AB - Bipolar disorders constitute a group of frequent, chronic psychiatric illnesses with a most severe impact on the patient's life. The course can be very individual and heterogeneous, the best known and most frequent manifestations include the classical bipolar I and bipolar II disorders. However, in Germany even typical bipolar I disorders are underdiagnosed and, consequently, undertreated. This is true despite the fact that the number of pharmacological treatment options has rapidly increased during recent years, both in the field of anticonvulsants and atypical antipsychotics. This supplies us today with new therapeutic strategies, not only for acute mania, but also for bipolar depression and maintenance treatment, and it is feasible to assume that there will be more options available within the next few years. PMID- 23681715 TI - [Cognitive-psychoeducational group programme for bipolar disorder: pilot study with two-year follow-up]. AB - 52 patients with bipolar disorder were treated with psychopharmacotherapy and a cognitive psychoeducational group programme that was established at the Department of Psychiatry and Psychotherapy of the Ludwig Maximilian University, Munich, Germany. The programme covers psychoeducation, identifying and coping with depressive and manic symptoms, relapse prevention and establishing a stable life style. 96 % rated the group to be helpful and felt well informed about their illness. There were significant gains in knowledge (F = 25,714, p < 0.001) and improvements in the severity of the illness (CGI; F = 68,255, p < 0.001) post treatment. With regard to sociodemographic and clinical variables, only the level of work qualification showed a differential treatment response: patients with higher qualifications had a more favourable course of the illness (F = 4,125, p = 0.048). At one and two year follow-up 25 % and, respectively, 30 % of the sample had to be readmitted. A higher number of previous hospitalisations (p = 0.010) and male sex (p = 0.031) turned out to be significant predictors of relapse (R2 = 0.358, p = 0.004) at two year follow-up. This disorder-specific group programme represents a key component of treatment offering emotional support for patients and their relatives. Patients are to be involved in the treatment process and need information about the illness, its psychosocial and pharmacological treatment as well as help in learning practical skills to improve their living with the disease. Being integrated and committed to a supporting network may increase their quality of life. PMID- 23681716 TI - [The challenge of treating bipolar outpatients]. AB - The course of bipolar illness comprises a wide range, which may vary between one single episode once every five years and a severe ultra rapid cycling course with mood changes within days. Even with optimal pharmacological treatment the functional outcome in bipolar patients is still poor. Underlying pathomechanisms are not fully understood yet. This article addresses three possible illness specific-aspects: cognitive defects, high relapse frequency and poor adherence. Causes as well as therapeutic interventions for these therapeutic pitfalls are summarised. PMID- 23681717 TI - [De-escalation and atypical antipsychotics in the treatment of acute mania]. AB - Agitation is a severe clinical state which represents a therapeutic challenge and often forms part of manic or mixed episodes. Therapeutic options for acute mania have been limited for many years to lithium and typical antipsychotics. Besides anticonvulsants, atypical antipsychotics have been increasingly introduced in the last decade after proving their efficacy in this indication. To avoid intramuscular administration and excessive sedation, a therapeutic contact to the often agitated patient is required. De-escalation techniques can be helpful in this respect but also reduce aggressive behaviour on the ward, improve compliance, reduce relapse rates and lead to a better outcome in the long-term course of the illness. Therefore, a basic knowledge about de-escalation techniques in acute manic patients is an important clinical tool which will be critically reviewed. Furthermore, the efficacy and tolerability of atypical antipsychotics in acute mania, such as olanzapine, zotepine, risperidone, quetiapine, ziprasidone, aripiprazole, paliperidone and asenapine are discussed. PMID- 23681718 TI - The motives of intergenerational transfer to the elderly parents in China: consequences of high medical expenditure. AB - The support for the elderly is facing big challenges with the problem of population aging. Transfers from adult children could partly insure elderly parents against low income and high medical expenditure. There are two main motives for transfers in the literature, namely altruism and exchange. By using data from a new household survey of people aged 45 years and above in China, we estimate the transfer derivatives with the adjustment of medical expenditure in elderly parents' income. We find a large negative impact of adjusted income on transfers at the lower end of income distribution, which is consistent with the altruistic motive. Evidence on the exchange motive is found only for sons, but not for daughters. In addition, there is evidence on the 'exchange-for-service' motive, which interprets transfer as a payment to parents' family services, such as taking care of grandchildren. PMID- 23681719 TI - Current controversies on the role of behavior therapy in Tourette syndrome. AB - Comprehensive behavioral intervention for tics (CBIT) is a safe and effective treatment for managing the tics of Tourette syndrome (TS). In contrast to most current medications used for the treatment of tics, the efficacy of CBIT has been demonstrated in 2 relatively large, multisite trials. It also shows durability of benefit over time. Similar to psychopharmacological intervention, skilled practitioners are required to implement the intervention. Despite concerns about the effort required to participate in CBIT, patients with TS and parents of children with TS appear willing to meet the requirements of the CBIT program. Efforts are under way to increase the number of trained CBIT providers in the United States. Based on available evidence, recent published guidelines suggest that CBIT can be considered a first-line treatment for persons with tic disorders. (c) 2013 Movement Disorder Society. PMID- 23681720 TI - [Role of whole-body ultrasound in severe pre-eclampsia and post-partum hemorrhage]. AB - PURPOSE: Management of severe pre-eclamptic patients is a challenge for the staff on obstetrical wards. We demonstrate that ultrasound applied to several organs performed at a patient's bedside gave the information required for the patient's management, without the need to transfer her to the radiology department or to call external consultants. CLINICAL FEATURES: A 29-yr-old severely pre-eclamptic patient with HELLP syndrome (hemolysis, cytolysis, thrombopenia) presented, in the post-partum period, with an occult uterine hemorrhage diagnosed with bedside abdominal/pelvic ultrasound. Ultrasound was also used to insert a central venous catheter. After undergoing a hysterectomy to control hemorrhage and receiving activated factor VII, the patient recovered uneventfully. Hemodynamic management was optimized non-invasively using pulmonary and cardiac ultrasound, when the patient developed hemorrhagic shock followed by pulmonary edema. Volume replacement was guided by cardiac ultrasound findings, and we were able to detect incipient interstitial pulmonary edema and follow its course using pulmonary ultrasound. CONCLUSION: Practitioners must be aware of the role of whole-body ultrasound in the diagnosis and treatment of complex, multi-organ conditions such as pre-eclampsia. Moreover, ultrasound helps in the management of global hemodynamics. The training of anesthesiologists in a variety of ultrasound techniques should be encouraged. PMID- 23681721 TI - Unrecognized tamponade diagnosed pre-induction by focused echocardiography. AB - PURPOSE: We report a case of unrecognized cardiac tamponade diagnosed pre induction by focused transthoracic echocardiography (TTE). The value of focused perioperative TTE, the anesthetic implications of Churg-Strauss syndrome, and the diagnosis of cardiac tamponade are discussed. CLINICAL FEATURES: A 58-yr-old man with a history of severe asymptomatic aortic stenosis presented for elective endoscopic sinus surgery for intractable nasal polyps with recurrent sinusitis. His cardiologist and cardiac surgeon had recommended proceeding with surgery, as aortic valve replacement was not indicated because he was asymptomatic. Prior to induction, a focused TTE was performed by anesthesia in order to document the degree of aortic stenosis, baseline ventricular function, and baseline volume status. This provided a baseline for comparison in case the patient's hemodynamic status should deteriorate intraoperatively. Unexpectedly, the TTE examination revealed cardiac tamponade. After confirmation of the diagnosis by cardiology, urgent pericardiocentesis was performed. A diagnosis of Churg-Strauss syndrome was ultimately made, and the patient was treated with high-dose prednisone therapy. CONCLUSION: Focused TTE has significant clinical utility for the diagnosis and assessment of hemodynamically significant cardiac conditions, particularly in the complex patient where clinical examination is challenging and echocardiographic findings can have immediate management implications. PMID- 23681722 TI - Towards a myriad of peptaibiotics. PMID- 23681723 TI - The comprehensive peptaibiotics database. AB - Peptaibiotics are nonribosomally biosynthesized peptides, which - according to definition - contain the marker amino acid alpha-aminoisobutyric acid (Aib) and possess antibiotic properties. Being known since 1958, a constantly increasing number of peptaibiotics have been described and investigated with a particular emphasis on hypocrealean fungi. Starting from the existing online 'Peptaibol Database', first published in 1997, an exhaustive literature survey of all known peptaibiotics was carried out and resulted in a list of 1043 peptaibiotics. The gathered information was compiled and used to create the new 'The Comprehensive Peptaibiotics Database', which is presented here. The database was devised as a software tool based on Microsoft (MS) Access. It is freely available from the internet at http://peptaibiotics-database.boku.ac.at and can easily be installed and operated on any computer offering a Windows XP/7 environment. It provides useful information on characteristic properties of the peptaibiotics included such as peptide category, group name of the microheterogeneous mixture to which the peptide belongs, amino acid sequence, sequence length, producing fungus, peptide subfamily, molecular formula, and monoisotopic mass. All these characteristics can be used and combined for automated search within the database, which makes The Comprehensive Peptaibiotics Database a versatile tool for the retrieval of valuable information about peptaibiotics. Sequence data have been considered as to December 14, 2012. PMID- 23681724 TI - Recent results in alamethicin research. PMID- 23681725 TI - Unprecedented 17-residue peptaibiotics produced by marine-derived Trichoderma atroviride. AB - In the course of investigations on marine-derived toxigenic fungi, five strains of Trichoderma atroviride were studied for their production of peptaibiotics. While these five strains were found to produce classical 19-residue peptaibols, three of them exhibited unusual peptidic sodium-adduct [M + 2 Na](2+) ion peaks at m/z between 824 and 854. The sequencing of these peptides led to two series of unprecedented 17-residue peptaibiotics based on the model Ac-XXX-Ala-Ala-XXX-XXX Gln-Aib-Aib-Aib-Ala/Ser-Lxx-Aib-Pro-XXX-Aib-Lxx-[C(129) ]. The C-terminus of these new peptides was common to all of them, and its elemental formula C5 H9 N2 O2 was established by HR-MS. It could correspond to the cyclized form of N(delta) -hydroxyornithine which has already been observed at the C-terminus of various peptidic siderophores. The comparison of the sequences of 17- and 19-residue peptides showed similarities for positions 1-16. This observation seems to indicate a common biosynthesis pathway. Both new 17-residue peptaibiotics and 19 residue peptaibols exhibited weak in vitro cytotoxicities against KB cells. PMID- 23681727 TI - Sequences of metanicins, 20-residue peptaibols from the ascomycetous fungus CBS 597.80. AB - Four linear 20-residue peptaibols, named metanicins (MTCs) A-D, were isolated from submerged cultures of the ascomycetous fungus CBS 597.80. Structure elucidation was performed by a combination of fast-atom-bombardment mass spectrometry (FAB-MS), electrospray ionization MS, Edman degradation of isolated fragments, and amino acid analysis by ion-exchange and gas chromatography, and enantioselective HPLC. The sequences of MTC A(B) are (amino acid exchange in B and C in parentheses): Ac-Aib-Ala-Aib-Ala-Aib-Ala-Gln-Aib-Val-Aib-Gly-Leu-Aib-Pro Val-Aib-Aib(D-Iva)-Gln-Gln-Pheol and of MTC C(D) Ac-Aib-Ala-Aib-Ala-Aib-Ala-Gln Aib-Val-Aib-Gly-Leu-Aib-Pro-Val-Aib-Aib(D-Iva)-Gln-Gln-Pheol (Ac, acetyl; Aib, alpha-aminoisobutyric acid; Iva, isovaline; Pheol, L-phenylalaninol). The peptides are related, and some of the sequences are identical, to other 20 residue peptaibols isolated from Trichoderma species. MTCs show moderate activities against Micrococcus luteus, Enterococcus faecalis, and Staphylococcus aureus, and very low activities against Bacillus subtilis. The producer has originally been identified and deposited as Metarhizium anisopliae var. anisopliae CBS 597.80. Although this identification has been withdrawn by Centralbureau voor Schimmelcultures (CBS) in the meantime, the accession number will be retained - independently from any taxonomic revisions. PMID- 23681726 TI - Screening the biosphere: the fungicolous fungus Trichoderma phellinicola, a prolific source of hypophellins, new 17-, 18-, 19-, and 20-residue peptaibiotics. AB - To investigate the significance of antibiotics for the producing organism(s) in the natural habitat, we screened a specimen of the fungicolous fungus Trichoderma phellinicola (syn. Hypocrea phellinicola) growing on its natural host Phellinus ferruginosus. Results revealed that a particular group of non-ribosomal antibiotic polypeptides, peptaibiotics, which contain the non-proteinogenic marker amino acid, alpha-aminoisobutyric acid, was biosynthesized in the natural habitat by the fungicolous producer and, consequently, released into the host. By means of liquid chromatography coupled to electrospray high-resolution time-of flight mass spectrometry, we detected ten 20-residue peptaibols in the specimen. Sequences of peptaibiotics found in vivo were independently confirmed by analyzing the peptaibiome of an agar plate culture of T. phellinicola CBS 119283 (ex-type) grown under laboratory conditions. Notably, this strain could be identified as a potent producer of 39 new 17-, 18-, and 19-residue peptaibiotics, which display the same building scheme as the 20-residue peptaibols found in the specimen. Two of the 19-residue peptaibols are tentatively assigned to carry tyrosinol, a novel C-terminal residue, as deduced from high-resolution tandem mass-spectrometry data. For the new peptaibiotics produced by T. phellinicola, the name 'hypophellin(s)', based on the teleomorph name, is introduced. PMID- 23681728 TI - The sequences of the eleven-residue peptaibiotics: suzukacillins-B. AB - The filamentous fungus designated 'Trichoderma viride' strain 63 C-1 simultaneously produces suzukacillins (SZs), two microheterogeneous groups of peptaibols, under submerged culture conditions. Both groups are readily distinguishable by TLC: the major group is designated SZ-A, whereas the minor group with a higher Rf value is named SZ-B. The peptide mixture was obtained from a MeOH extract of the mycelium. SZ-B was separated from SZ-A by Sephadex LH-20 column chromatography. Although it provided one single spot on silica-gel TLC plates, 15 individual peptides could be separated by C8 reversed-phase (RP) HPLC, and their sequences were determined by HPLC/QqTOF-ESI-HRMS. Fourteen peptides exhibit the C-terminal sequence Pro(6) -Lxx-Lxx-Aib-Pro-Vxxol/Lxxol(11) , which is common for eleven-residue peptaibols. The remaining peptide is tentatively assigned as a ten-residue sequence, in which the C-terminal 1,2-amino alcohol is deleted, thus terminating in free proline. Nine of the peptides carry an Ac-Aib residue at the N-terminus, very frequently found in eleven-residue peptaibols. Four peptides comprise the rare Ac-Ala N-terminus, and for two peptides, N terminal Ac-D-Iva residues were identified. One peptide contains a C-terminal residue of yet undetermined structure. Comparison with previously reported eleven residue peptaibol sequences reveals that eight of the peptides represent new sequence analogs. PMID- 23681729 TI - Peptaibol antiamoebin I: spatial structure, backbone dynamics, interaction with bicelles and lipid-protein nanodiscs, and pore formation in context of barrel stave model. AB - Antiamoebin I (Aam-I) is a membrane-active peptaibol antibiotic isolated from fungal species belonging to the genera Cephalosporium, Emericellopsis, Gliocladium, and Stilbella. In comparison with other 16-amino acid-residue peptaibols, e.g., zervamicin IIB (Zrv-IIB), Aam-I possesses relatively weak biological and channel-forming activities. In MeOH solution, Aam-I demonstrates fast cooperative transitions between right-handed and left-handed helical conformation of the N-terminal (1-8) region. We studied Aam-I spatial structure and backbone dynamics in the membrane-mimicking environment (DMPC/DHPC bicelles)(1) ) by heteronuclear (1) H,(13) C,(15) N-NMR spectroscopy. Interaction with the bicelles stabilizes the Aam-I right-handed helical conformation retaining significant intramolecular mobility on the ms-MUs time scale. Extensive ms-MUs dynamics were also detected in the DPC and DHPC micelles and DOPG nanodiscs. In contrast, Zrv-IIB in the DPC micelles demonstrates appreciably lesser mobility on the MUs-ms time scale. Titration with Mn(2+) and 16 doxylstearate paramagnetic probes revealed Aam-I binding to the bicelle surface with the N-terminus slightly immersed into hydrocarbon region. Fluctuations of the Aam-I helix between surface-bound and transmembrane (TM) state were observed in the nanodisc membranes formed from the short-chain (diC12 : 0) DLPC/DLPG lipids. All the obtained experimental data are in agreement with the barrel-stave model of TM pore formation, similarly to the mechanism proposed for Zrv-IIB and other peptaibols. The observed extensive intramolecular dynamics explains the relatively low activity of Aam-I. PMID- 23681730 TI - Spin-echo electron paramagnetic resonance (EPR) spectroscopy of a pore-forming (Lipo)peptaibol in model and bacterial membranes. AB - This review compiles the unusual structural and dynamic peculiarities of trichogin GA IV and its analogs in lipid bilayers. Different electron spin echo (ESE) spectroscopic techniques were employed to study a set of spin-labeled analogs of trichogin GA IV in model and natural membranes. Pulsed electron electron double resonance (PELDOR) method enabled the elucidation of the peptide conformation, while the ESE envelope modulation (ESEEM) technique was applied to study the insertion of the site-specifically spin-labeled peptide into the core of the membrane. The latter technique was also used to examine the water accessibility for peptide-attached spin labels at different levels of membrane depth. Finally, it will be shown that measurement of the ESE decays at different temperatures reveals molecular information on the mobility of the transmembrane lipopeptide aggregate. The experimental results are discussed in terms of the antibiotic and toxic activities of trichogin GA IV. PMID- 23681731 TI - Structural characterization of the short peptaibols trichobrachins by molecular dynamics methods. AB - A structural characterization was carried out by molecular-dynamics methods for eight trichobrachin peptides, to identify the conformational features of these short peptaibols. For all peptides, the backbone and side-chain conformations were investigated, different secondary structures, such as type-I and -III beta turns as well as beta-bend ribbon spirals, were determined in certain tetrapeptide units of the molecules, and the preferred rotamers of the side chains of amino acids were identified. Furthermore, the end-to-end and residue?residue distances were examined, as well as the fluctuations of backbone atoms were studied. Based on these results, the peptides were compared to one another. Our theoretical study indicated that trichobrachins could be characterized by typical structural properties, and both conformational similarities and dissimilarities were observed between these peptaibols. In summary, this structural investigation supplied a characterization of the various conformational features of eight trichobrachin peptides. PMID- 23681732 TI - 3D structure, dynamics, and activity of synthetic analog of the peptaibiotic trichodecenin I. AB - In this contribution, we report on the conformational preferences of synthetic analogs of the antimicrobial peptide trichodecenin I in solution. This 6-amino acid residue long peptide is characterized by a single, strongly helicogenic Aib residue in the central part of the sequence and is rich in the conformationally mobile Gly residues. It has been reported that, in CHCl3 solution and in the crystal state, this peptaibiotic adopts a non-helical, multiple beta-turn conformation, whereas a 310 /alpha-helical structure was obtained from an X-ray diffraction study on a trichodecenin I analog (TDT4W6) containing the fluorescent Trp residue in position 6 (replacing Ile) and an equally helicogenic TOAC residue in position 4 (replacing Aib). In this work, we applied spectroscopic techniques and molecular-dynamics calculations, in particular, on the fluorescent TDT4W6 trichodecenin I analog with the aim at investigating its 3D-structural and dynamical features in solution. Our results revealed that TDT4W6 can be described by an ensemble of conformers quickly interconverting in the nanosecond time scale. The most populated cluster has a conformation similar to the NMR structure of native trichodecenin I in CHCl3 . However, also helical-like conformers are present, even if poorly populated and less stable under the analytical conditions. PMID- 23681733 TI - Spectroscopically labeled peptaibiotics. Synthesis and properties of selected trichogin GA IV analogs bearing a side-chain-monofluorinated aromatic amino acid for (19) F-NMR analysis. AB - We prepared by solid-phase methods, chromatographically purified, and characterized three analogs of the ten-amino acid-residue, membrane-active, lipopeptaibiotic trichogin GA IV, each containing a single (4 fluorophenyl)alanine in position 3, 7, or 10, where it replaces the hydrophobic residue Leu(3) , Leu(7) , or Ile(10) , respectively. We incorporated the fluorine probe based on the observation that the (19) F-NMR technique has been extensively utilized to analyze peptide?membrane interactions in biological systems. A detailed conformational investigation in solution, including a membrane-mimetic environment, was performed on these compounds using FT-IR absorption, CD, and 2D NMR, combined with molecular-dynamics calculations. The experimentally observed, mixed 310 /alpha-helical structures unequivocally show that the principal conformational features of trichogin GA IV are preserved in all three analogs. Analogies and differences between the behavior of the natural lipopeptaibiotic and those of the peptides characterized by the side-chain monofluorinated aromatic amino acid were found in membrane-permeabilization experiments and antimicrobial assays. The results of a preliminary solution (19) F-NMR study support the view that the (19) F label is an excellent reporter for changes in the helical environment of the peptide. PMID- 23681734 TI - Attempts toward the synthesis of the peptaibol antiamoebin by using the 'azirine/oxazolone method'. AB - The two segments, 1-9 and 10-16, of the peptaibol antibiotic antiamoebin I, i.e., the nonapeptide Ac-Phe-Aib-Aib-Aib-D,L-Iva-Gly-Leu-Aib-Aib-OH (15) and the heptapeptide Z-Hyp-Gln-D,L-Iva-Hyp-Aib-Pro-Pheol (34), have been prepared as mixtures of the epimers containing D,L-Iva. All alpha,alpha-disubstituted alpha amino acids were introduced by the 'azirine/oxazolone method', in which amino or peptide acids are coupled with the corresponding 2H-azirin-3-amines, followed by selective hydrolysis of the terminal amide bond. The amino acids Hyp and Gln were introduced as Z-protected(4) ) (2S,4R)-4-(tert-butoxy)proline (19) and methyl N [bis(4-methoxyphenyl)methyl]glutamine (26). Coupling of peptide segments was achieved via the 'mixed anhydride' method, the DCC/HOBt or TBTU/HOBt strategy. The crystal structure of the segment 6-9 was determined by X-ray crystallography and displayed the presence of a beta-turn conformation. PMID- 23681735 TI - Conformational properties of secondary amino acids: replacement of pipecolic acid by N-methyl-l-alanine in efrapeptin C. AB - The efrapeptins, a family of naturally occurring peptides with inhibitory activities against ATPases, contain several alpha,alpha-disubstituted alpha-amino acids such as alpha-aminoisobutyric acid (Aib) or isovaline (Iva) besides pipecolic acid (Pip), beta-Ala, Leu, Gly, and a C-terminal heterocyclic residue. Secondary alpha-amino acids such as proline are known to stabilize discrete conformations in peptides. A similar influence is ascribed to N-alkyl alpha-amino acids. We synthesized two efrapeptin C analogs with replacement of Pip by N methyl-L-alanine (MeAla) using a combination of solid- and solution-phase techniques in a fragment-condensation strategy to compare the conformational bias of both secondary amino acids. The solution conformation was investigated by vibrational circular dichroism (VCD) to probe whether the analogs adopt a 310 helical conformation. The MeAla-containing analogs [MeAla(1,3) ]efrapeptin C and [MeAla(1,3,11) ]efrapeptin C inhibit ATP hydrolysis by the A3 B3 complex of A1 A0 -ATP synthase from Methanosarcina mazei Go1. PMID- 23681736 TI - Bis(4,6-dimethoxy-1,3,5-triazin-2-yl) ether as coupling reagent for peptide synthesis. AB - Bis(4,6-dimethoxy-1,3,5-triazin-2-yl) ether (4) was prepared by treatment of 2 hydroxy-4,6-dimethoxy-1,3,5-triazine with 2-chloro-4,6-dimethoxy-1,3,5-triazine in 61% yield. Ether 4, isoelectronic with pyrocarbonates, was found capable to activate carboxylic acids in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) to yield, under mild reaction conditions, superactive triazine esters. Versatility of this new coupling reagent was confirmed by condensation of lipophilic and sterically hindered carboxylic acids with amines in 71-98% yield, and by synthesis of peptides, including those containing Aib-Aib sequence, in solution with high yield and high enantiomeric purity. PMID- 23681737 TI - Nitramines with varying sensitivities: functionalized dipyrazolyl-N nitromethanamines as energetic materials. AB - 1,3-Dichloro-2-nitro-2-azapropane is an excellent precursor to dense energetic functionalized dipyrazolyl-N-nitromethanamines. This new family of energetic compounds was fully characterized by using (1)H, (13)C, and (15)N NMR and IR spectroscopy, differential scanning calorimetry, elemental analysis, and impact sensitivity tests. Additionally, single-crystal X-ray structuring was done for 3 and 5.CH3CN, which gave insight into structural characteristics. The experimentally determined densities of 2-9 fall between 1.69 and 1.90 g cm(-3). Heats of formation and detonation properties were calculated by using Gaussian 03 and EXPLO5 programs, respectively. The influence of different energetic moieties on the structural and energetic properties was established theoretically. PMID- 23681738 TI - Genetic and phenoptypic differentiation of zebra mussel populations colonizing Spanish river basins. AB - Zebra mussel populations in Ebro and Mijares Rivers (northern Spain) were analyzed to study the mechanisms by which this aquatic species deals with pollution. Variability analyses of mitochondrial cytochrome oxidase I gene and of one nuclear microsatellite were performed for ten populations from the Ebro River and one from the Mijares River. Comparison of these results with those from five additional European populations indicated that the Spanish populations constitute a homogeneous gene pool. Transcriptome analyses of gill samples from a subset of the Spanish populations showed changes on expression levels that correlated with variations in general fitness and loads of heavy metals. The less polluted upstream Ebro populations showed overexpression of mitochondrial and cell proliferation-related genes compared to the more polluted, downstream Ebro populations. Our data indicate that heavy metals were the main factors explaining these transcriptomic patterns, and that zebra mussel is resilient to pollutants (like mercury and organochlorine compounds) proved to be extremely toxic to vertebrates. We propose that zebra mussel populations sharing a common gene pool may acclimate to different levels and forms of pollution through modulations in their transcriptomic profile, although direct selection on genes showing differential expression patterns cannot be ruled out. PMID- 23681739 TI - Integrated ecotoxicological assessment of marine sediments affected by land-based marine fish farm effluents: physicochemical, acute toxicity and benthic community analyses. AB - An integrated ecotoxicological assessment of marine sediments affected by land based marine fish farm effluents was developed using physicochemical and benthic community structure analyses and standardised laboratory bioassays with bacteria (Vibrio fischeri), amphipods (Ampelisca brevicornis) and sea urchin larvae (Paracentrotus lividus). Intertidal sediment samples were collected at five sites of the Rio San Pedro (RSP) creek, from the aquaculture effluent to a clean site. The effective concentration (EC50) from bacterial bioluminescence and A. brevicornis survival on whole sediments and P. lividus larval developmental success on sediment elutriates were assessed. Numbers of species, abundance and Shannon diversity were the biodiversity indicators measured in benthic fauna of sediment samples. In parallel, redox potential, pH, organic matter and metal levels (Cd, Cu, Ni, Pb and Zn) in the sediment and dissolved oxygen in the interstitial water were measured in situ. Water and sediment physicochemical analysis revealed the exhibition of a spatial gradient in the RSP, evidenced by hypoxia/anoxia, reduced and acidic conditions, high organic enrichment and metal concentrations at the most contaminated sites. Whereas, the benthic fauna biodiversity decreased the bioassays depicted decreases in EC50, A. brevicornis survival, P. lividus larval success at sampling sites closer to the studied fish farms. This study demonstrates that the sediments polluted by fish farm effluents may lead to alterations of the biodiversity of the exposed organisms. PMID- 23681740 TI - Ethical considerations for experiments involving elite athletes and "doping". PMID- 23681741 TI - Reply to Schumacher et al. PMID- 23681742 TI - Scientific research using elite athletes: WADA point of view. PMID- 23681743 TI - Molecular discrimination and identification of Acetobacter genus based on the partial heat shock protein 60 gene (hsp60) sequences. AB - BACKGROUND: To identify the Acetobacter species using phenotypic and genotypic (16S rDNA sequence analysis) technique alone is inaccurate. The aim of this study was to use the hsp60 gene as a target for species discrimination in the genus Acetobacter, as well as to develop species-specific polymerase chain reaction and mini-sequencing methods for species identification and differentiation. RESULTS: The average sequence similarity for the hsp60 gene (89.8%) among type strains was significantly less than that for the 16S rRNA gene (98.0%), and the most Acetobacter species could be clearly distinguished. In addition, a pair of species-specific primer was designed and used to specifically identify Acetobacter aceti, Acetobacter estunensis and Acetobacter oeni, but none of the other Acetobacter strains. Afterwards, two specific single-nucleotide polymorphism primers were designed and used to direct differentiate the strains belonging to the species A. aceti by mini-sequencing assay. CONCLUSION: The phylogenetic relationships in the Acetobacter genus can be resolved by using hsp60 gene sequencing, and the species of A. aceti can be differentiated using novel species-specific PCR combined with the mini-sequencing technology. PMID- 23681744 TI - A novel glucoamylase activated by manganese and calcium produced in submerged fermentation by Aspergillus phoenicis. AB - This study investigates the production of glucoamylase from Aspergillus phoenicis in Machado Benassi (MB) medium using 1% maltose as carbon source. The maximum amylase activity was observed after four days of cultivation, on static conditions at 30 degrees C. Glucoamylase production was induced by maltose and inhibited by different glucose concentrations. The optimum of temperature and pH were 60-65 degrees C, and 4.5 or 5.0 to sodium acetate and Mcllvaine buffers, respectively. It was observed that the enzyme was totally stable at 30-65 degrees C for 1 h, and the pH range was 3.0-6.0. The enzyme was mainly activated by manganese (176%), and calcium (130%) ions. The products of starch hydrolysis were analyzed by thin layer chromatography and after 3 h, only glucose was detected, characterizing the amylolytic activity as a glucoamylase. PMID- 23681745 TI - ERBB4 confers metastatic capacity in Ewing sarcoma. AB - Metastatic spread is the single-most powerful predictor of poor outcome in Ewing sarcoma (ES). Therefore targeting pathways that drive metastasis has tremendous potential to reduce the burden of disease in ES. We previously showed that activation of the ERBB4 tyrosine kinase suppresses anoikis, or detachment-induced cell death, and induces chemoresistance in ES cell lines in vitro. We now show that ERBB4 is transcriptionally overexpressed in ES cell lines derived from chemoresistant or metastatic ES tumours. ERBB4 activates the PI3K-Akt cascade and focal adhesion kinase (FAK), and both pathways contribute to ERBB4-mediated activation of the Rac1 GTPase in vitro and in vivo. ERBB4 augments tumour invasion and metastasis in vivo, and these effects are blocked by ERBB4 knockdown. ERBB4 expression correlates significantly with reduced disease-free survival, and increased expression is observed in metastatic compared to primary patient-matched ES biopsies. Our findings identify a novel ERBB4-PI3K-Akt-FAK Rac1 pathway associated with aggressive disease in ES. These results predict that therapeutic targeting of ERBB4, alone or in combination with cytotoxic agents, may suppress the metastatic phenotype in ES. PMID- 23681746 TI - Enhanced morphinan alkaloid production in hairy root cultures of Papaver bracteatum by over-expression of salutaridinol 7-o-acetyltransferase gene via Agrobacterium rhizogenes mediated transformation. AB - Papaver bracteatum is an important medicinal plant valued for its high content of thebaine and an alternative to P. somniferum for benzylisoquinoline alkaloid production. Salutaridinol 7-o-acetyltransferase (SalAT) is a key gene in morphinan alkaloids biosynthesis pathway. Over expression of SalAT gene was used for metabolic engineering in P. bracteatum hairy root cultures. Transcript level of the salutaridinol 7-o-acetyltransferase gene in transgenic hairy root lines increased up to 154 and 128 % in comparison with hairy roots without SalAT over expression and wild type roots, respectively. High performance liquid chromatography analysis showed that the transgenic hairy roots relatively improved levels of thebaine (1.28 % dry weight), codeine (0.02 % dry weight) and morphine (0.03 % dry weight) compared to those hairy roots without SalAT over expression. This suggests that P. bracteatum hairy roots expressing the SalAT gene could be potentially used for the production of valuable morphinan alkaloids. PMID- 23681747 TI - Stepwise evolution of DNA-programmable nanoparticle superlattices. PMID- 23681748 TI - Chromosomal distribution of schizophrenia susceptibility loci. AB - In order to find the chromosomal distribution of polymorphic loci associated with the schizophrenia risk, the present study was carried out. Meta-analysis studies with information of genetic polymorphisms and schizophrenia risk were identified and used for the present study. There were 39 loci associated with schizophrenia risk. Statistical analysis revealed that the schizophrenia susceptible loci distributed non-randomly on human chromosomes. Human chromosome segments 6p21.1 p22.3 (P < 0.001) bear significantly higher number of susceptible loci. PMID- 23681749 TI - Pramipexole reduces phosphorylation of alpha-synuclein at serine-129. AB - alpha-Synuclein is a central component of the pathogenesis of Parkinson's disease (PD). Phosphorylation at serine-129 represents an important post-translational modification and constitutes the major form of the protein in Lewy bodies. Several kinases have been implicated in the phosphorylation of alpha-synuclein. The targeting of kinase pathways as a potential to influence the pathogenesis of PD is an important focus of attention, given that mutations of specific kinases (LRRK2 and PINK1) are causes of familial PD. Pramipexole (PPX) is a dopamine agonist developed for the symptomatic relief of PD. Several in vitro and in vivo laboratory studies have demonstrated that PPX exerts neuroprotective properties in model systems of relevance to PD. The present study demonstrates that PPX inhibits the phosphorylation of alpha-synuclein and that this is independent of dopamine receptor activation. PPX blocks the increase in phosphorylated alpha synuclein induced by inhibition of the ubiquitin proteasomal system. The phosphorylation of alpha-synuclein occurs in part at least through casein kinase 2, and PPX in turn reduces the phosphorylation of this enzyme, thereby inhibiting its activity. Thus, PPX decreases the phosphorylation of alpha-synuclein, and this mechanism may contribute to its protective properties in PD models. PMID- 23681750 TI - Development of somites, muscle, and skeleton is independent of signals from the Wolffian duct. AB - BACKGROUND: In the vertebrate embryo, skeletal muscle and the axial skeleton arise from the somites. Patterning of the somites into the respective somite compartments, namely dermomyotome, myotome, and sclerotome, depends on molecular signals from neighboring structures, including surface ectoderm, neural tube, notochord, and lateral plate mesoderm. A potential role of the intermediate mesoderm, notably the Wolffian or nephric duct, in somite development is poorly understood. RESULTS: We studied somite compartmentalization as well as muscular and skeletal development after surgical ablation of the early Wolffian duct anlage, which lead to loss of the Wolffian duct and absence of the mesonephros, whereas Pax2 expression in the nephrogenic mesenchyme was temporarily maintained. We show that somite compartments, as well as the somite derivatives, skeletal muscle and the cartilaginous skeleton, develop normally in the absence of the Wolffian duct. CONCLUSIONS: Our results indicate that development of the musculoskeletal system is independent of the Wolffian duct as a signaling center. PMID- 23681751 TI - Dill seed extract improves abnormalities in lipid metabolism through peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activation in diabetic obese mice. AB - Dill, a small annual herb, is widely used as a flavoring agent in dishes including salads. It has been demonstrated that dill extract and its essential oil show hypolipidemic effects in rats. However, the mechanism of these effects has not been elucidated yet. We found that dill seed extract (DSE) activated peroxisome proliferator-activated receptor-alpha (PPAR-alpha), an indispensable regulator for hepatic lipid metabolism, by luciferase assay. Thus, we performed DSE feeding experiments using diabetic obese model KK-Ay mice to examine the effects of DSE on PPAR-alpha activation in vivo. A 4-week feeding of DSE contained in a high-fat diet decreased plasma triacylglyceride and glucose levels and increased the mRNA expression levels of fatty acid oxidation-related genes in the liver. In addition, the DSE feeding as well as bezafibrate (a PPAR-alpha potent agonist) feeding increased oxygen consumption rate and rectal temperature. These results indicate that DSE suppresses high-fat diet-induced hyperlipidemia through hepatic PPAR-alpha activation. PMID- 23681752 TI - Evaluation of the bioefficacy of a stabilized form of human growth hormone (SP hGH). AB - Protein aggregation is a major obstacle in maintaining the stability of therapeutic proteins. In previous studies, fusion between a stabilizing peptide (SP) and human growth hormone (hGH) resulted in improved solubility and stability compared with hGH alone, although the bioactivity of the protein was not confirmed in vivo. In this study, we evaluated the bioefficacy of hGH and SP-hGH in vivo using a mouse model. Subcutaneous injections of 30 MUg of hGH or SP-hGH were administered to 8-month-old female mice, twice a week for 14 weeks. Neither hGH nor SP-hGH significantly affected body weight or blood glucose levels compared with control mice. Interestingly, abdominal fat was significantly reduced in SP-hGH-treated mice compared with hGH-treated mice. While total cholesterol, HDL, and LDL levels were slightly higher in both groups, TG levels were significantly reduced in both SP-hGH and hGH-treated mice compared with control mice. IGF-1 levels in the liver were increased in both the SP-hGH and hGH groups, thereby inducing liver cell proliferation. These results suggest that SP fusion with hGH attained similar or improved bioefficacy compared with hGH alone. PMID- 23681753 TI - Anti-atherogenic effects of 17beta-estradiol. AB - Estrogens are secreted primarily by the ovaries and placenta, by the testes in men and also produced by peripheral steroidogenic conversion. The 3 major naturally occurring estrogens are: 17beta-estradiol (E2), estrone and estriol, of which E2 is the predominant and most active. The actions of E2 are mediated by at least 3 different receptors - the classical ERs (ERalpha and ERbeta) and G protein coupled receptor 30 (GPR30). E2 signaling in cardiomyocytes involves ERalpha- and ERbeta-independent pathways, and treatment with the E2 receptor antagonists (Selective Estrogen Receptor Modulators- SERMs), which are agonists of GPR30, inhibits cardiac cell growth. Effects of E2 in preventing endothelial dysfunction, a prerequisite of atherosclerosis, are well recognized. Atherosclerosis involves interaction between the cells of the arterial wall endothelial cells (EC) and vascular smooth muscle cell (VSMC), as well as migration of macrophages into wall tunica media. It is predominantly developed at sites with abnormally high shear stress, such as bifurcations or branching of arteries, initiated by an injury to the endothelium and exposure to atherogenic lipids and toxins, such as those contained in tobacco smoke or infectious agents. Animal studies have shown effects of E2 in preventing atherosclerosis, inflammation and endothelial or vascular dysfunction. Gender differences along this pathogenic pathway have been also described. We review the data from the available animal and human studies, which focus on anti-atherogenic effects of E2. These studies represent evidence, albeit indirect, for an inhibitory effect of E2 on the progression of coronary artery atherosclerosis. PMID- 23681755 TI - Chelation-assisted cross-coupling of anilines through in situ activation as diazonium salts with boronic acids under ligand-, base-, and salt-free conditions. AB - We describe the coupling of anilines with aryl boronic acids, under ligand-, base , and salt-free conditions at room temperature. This new reaction proceeds through the formation of an aryl palladium alkoxo complex, which allows the transmetalation step with aryl boronic acids without any external base. Importantly, this sustainable procedure generates only environmentally friendly byproducts such as tBuOH, H2O, N2, and B(OH)3. The reaction mechanism has been deeply investigated through experimental and theoretical studies. PMID- 23681754 TI - Vascular risk factors and neuropsychiatric symptoms in Alzheimer's disease: the Cache County Study. AB - OBJECTIVE: Knowledge of potentially modifiable risk factors for neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) is important. This study longitudinally explores modifiable vascular risk factors for NPS in AD. METHODS: Participants enrolled in the Cache County Study on Memory in Aging with no dementia at baseline were subsequently assessed over three additional waves, and those with incident (new onset) dementia were invited to join the Dementia Progression Study for longitudinal follow-up. A total of 327 participants with incident AD were identified and assessed for the following vascular factors: atrial fibrillation, hypertension, diabetes mellitus, angina, coronary artery bypass surgery, myocardial infarction, cerebrovascular accident, and use of antihypertensive or diabetes medicines. A vascular index (VI) was also calculated. NPS were assessed over time using the Neuropsychiatric Inventory (NPI). Affective and Psychotic symptom clusters were assessed separately. The association between vascular factors and change in NPI total score was analyzed using linear mixed model and in symptom clusters using a random effects model. RESULTS: No individual vascular risk factors or the VI significantly predicted change in any individual NPS. The use of antihypertensive medications more than four times per week was associated with higher total NPI and Affective cluster scores. CONCLUSIONS: Use of antihypertensive medication was associated with higher total NPI and Affective cluster scores. The results of this study do not otherwise support vascular risk factors as modifiers of longitudinal change in NPS in AD. PMID- 23681756 TI - Mapping and significance of the mRNA methylome. AB - Internal methylation of eukaryotic mRNAs in the form of N6-methyladenosine (m(6)A) and 5-methylcytidine (m(5)C) has long been known to exist, but progress in understanding its role was hampered by difficulties in identifying individual sites. This was recently overcome by high-throughput sequencing-based methods that mapped thousands of sites for both modifications throughout mammalian transcriptomes, with most sites found in mRNAs. The topology of m(6)A in mouse and human revealed both conserved and variable sites as well as plasticity in response to extracellular cues. Within mRNAs, m(5)C and m(6)A sites were relatively depleted in coding sequences and enriched in untranslated regions, suggesting functional interactions with post-transcriptional gene control. Finer distribution analyses and preexisting literature point toward roles in the regulation of mRNA splicing, translation, or decay, through an interplay with RNA binding proteins and microRNAs. The methyltransferase (MTase) METTL3 'writes' m(6)A marks on mRNA, whereas the demethylase FTO can 'erase' them. The RNA:m(5)C MTases NSUN2 and TRDMT1 have roles in tRNA methylation but they also act on mRNA. Proper functioning of these enzymes is important in development and there are clear links to human disease. For instance, a common variant of FTO is a risk allele for obesity carried by 1 billion people worldwide and mutations cause a lethal syndrome with growth retardation and brain deficits. NSUN2 is linked to cancer and stem cell biology and mutations cause intellectual disability. In this review, we summarize the advances, open questions, and intriguing possibilities in this emerging field that might be called RNA modomics or epitranscriptomics. PMID- 23681758 TI - [Updated inventory of mosquitoes (Diptera: Culicidae) of the island of La Reunion, Indian Ocean]. AB - A literature analysis coupled with new entomological surveys conducted between 2009 and 2012 led to changes in the list of mosquito species present on the island of La Reunion. Using morphological criteria, Orthopodomyia arboricollis is replaced by Or. reunionensis. On the basis of morphometrical and genetic criteria, Culex univittatus is replaced by Cx. neavei. Cx. poicilipes, which was already reported missing 40 years ago, has not been found again. Anopheles arabiensis is confirmed as the only species of the Gambiae complex present on the island. Thus, twelve species are currently known. For each of them, elements of taxonomic, biological and medical interest are listed. An. arabiensis is a major vector of human Plasmodium (last case of indigenous malaria in 1967). In the Indian Ocean, Aedes albopictus and Ae. aegypti both are competent for transmitting dengue and chikungunya viruses. In Africa, Cx. quinquefasciatus transmits Wuchereria bancrofti and Cx. neavei transmits the Sindbis virus; both species also transmit the West Nile virus. Cx. tritaeniorhynchus is the major vector of Japanese Encephalitis virus in Asia. Two species are endemic (Ae. dufouri and Or. reunionensis), the ten other ones are also found in Madagascar and on the African continent (An. coustani, An. arabiensis, Ae. fowleri, Cx. tritaeniorhynchus, Cx. neavei, Cx. insignis, Lutzia tigripes), with three of them having also a cosmopolitan distribution (Ae. aegypti, Ae. albopictus and Cx. quinquefasciatus). Among the twelve recorded taxa, eight species are anthropophilic, three are supposedly zoophilic and one is a predatory species. No new invasive anthropophilic species did settle on the island. Updated identification keys of larval and adult stages are proposed. PMID- 23681757 TI - Evaluation of [(18)F]-CP18 as a PET imaging tracer for apoptosis. AB - PURPOSE: We identified and validated [(18)F]-CP18, a DEVD (the caspase 3 substrate recognition motif) containing substrate-based compound as an imaging tracer for caspase-3 activity in apoptotic cells. PROCEDURES: CP18 was radiolabeled with fluorine-18 using click chemistry. The affinity and selectivity of CP18 for caspase-3 were evaluated in vitro. The biodistribution and metabolism pattern of [(18)F]-CP18 were assessed in vivo. [(18)F]-CP18 positron emission tomography (PET) scans were performed in a dexamethasone-induced thymic apoptosis mouse model. After imaging, the mice were sacrificed, and individual organs were collected, measured in a gamma counter, and tested for caspase-3 activity. RESULTS: In vitro enzymatic caspase-3 assay demonstrated specific cleavage of CP18. In vivo, [(18)F]-CP18 is predominantly cleared through the kidneys and urine, and is rapidly eliminated from the bloodstream. There was a sixfold increase in caspase activity and a fourfold increase of [(18)F]-CP18 retention in the dexamethasone-induced thymus of treated versus control mice. CONCLUSIONS: We report the use [(18)F]-CP18 as a PET tracer for imaging apoptosis. Our data support further development of this tracer for clinical PET applications. PMID- 23681759 TI - [Comparison of the efficacy and safety of praziquantel administered in single dose of 40 versus 60 mg/kg for treating urinary schistosomiasis in Mauritania]. AB - During the last twenty years, praziquantel (PZQ) was the drug of choice for the treatment of schistosomiasis in the majority of national programs. However, a lower rate of cure had been significantly noted on the left bank of the Senegal River. To explain this unusual rate of cure, the assumption of a possible resistance to the drug as well as under-dosing was considered. With an aim of testing this hypothesis of underdosing, we compared the amount of a single dose of 60 mg/kg of PZQ versus the standardized dose of 40 mg/kg used in curing urinary schistosomiasis in Mauritania. One hundred and fifty-one children aged from 10 to 19 years, including 77 in the group of 60 mg/kg and 74 in the group of 40 mg/ kg, were included in the study. The rates of cure were respectively 64.8% for 60 mg/kg and 67.5% for 40 mg/kg three weeks after the administration of the treatment without statistically significant difference. For the majority of the patients, the drug was well tolerated and no serious adverse events were noted; however, clinical signs in the form of abdominal pain associated or not with diarrhea and vomiting were noted. Praziquantel remains an effective and well tolerated drug: the amount of 40 mg/kg of body weight can still be maintained for the treatment of schistosomiasis in Mauritania. PMID- 23681760 TI - Development of a new fluorescence immunochromatography strip for detection of chloramphenicol residues in chicken muscles. AB - BACKGROUND: Chloramphenicol (CAP), an antimicrobial drug that is widely used in animal feed, would have a negative effect on human health due to its low elimination rate and relatively high residue in animal food. It is important to develop a rapid and economic method to determine CAP in animal food to ensure that human health is not affected. RESULTS: A new fluorescence immunochromatography strip was developed and established for the detection of CAP residue in chicken muscles for the first time. A CAP-bovine serum albumin conjugate, monoclonal antibody and polyclonal antibody against CAP were applied to constitute a fluorescence immunochromatography strip. The fluorescence intensity was detected by a charge-coupled device scanner and transformed to a digital value. The CAP linearity working range was from 0.1 ng mL(-1) to 20 ng mL(-1) with a limit of detection of 0.1 ng mL(-1) within 10 min. The performance of the strip assay was compared with a commercial ELISA kit and the correlation coefficient was 0.99, which indicated that the new strip assay had a good quantification ability for CAP. CONCLUSION: The fluorescence immunochromatography strip was successfully applied to the detection of CAP residues in chicken samples. To our knowledge, it is the first report regarding the development of a fluorescence immunochromatography method for screening CAP in animal samples. PMID- 23681761 TI - Visualization of single proteins from stripped native cell membranes: a protocol for high-resolution atomic force microscopy. AB - Atomic force microscopy (AFM) proved to be able to obtain high-resolution three dimensional images of single-membrane proteins, isolated, crystallized, or included in reconstructed model membranes. The extension of this technique to native systems, such as the protein immersed in a cell membrane, needs a careful manipulation of the biological sample to meet the experimental constraints for high-resolution AFM imaging. In this article, a general protocol for sample preparation is presented, based on the mechanical stretch of the cell membrane. The effectiveness for AFM imaging has been tested on the basis of an integrated optical and AFM approach and the proposed method has been applied to cells expressing cystic fibrosis transmembrane conductance regulator, a channel involved in cystic fibrosis, showing the possibility to identify and analyze single proteins in the plasma membrane. PMID- 23681762 TI - Many-body dispersion interactions in molecular crystal polymorphism. PMID- 23681763 TI - Genetic and functional characterization of culturable plant-beneficial actinobacteria associated with yam rhizosphere. AB - Actinobacteria were isolated from the rhizosphere of yam plants from agricultural fields from Yeoju, South Korea and analyzed for their genetic and plant beneficial functional diversity. A total of 29 highly occurring actinobacterial isolates from the yam rhizosphere were screened for various plant-beneficial traits such as antimicrobial activity on fungi and bacteria; biocontrol traits such as production of siderophore, protease, chitinase, endo-cellulase, and beta glucanase. The isolates were also screened for plant growth-promoting (PGP) traits such as auxin production, phosphate solubilization, 1-aminocyclopropane-1 carboxylic acid (ACC) deaminase activity, and in vitro Arabidopsis growth promotion. 16S rDNA sequence-based phylogenetic analysis was carried out on the actinobacterial isolates to determine their genetic relatedness to known actinobacteria. BOX-PCR analysis revealed high genetic diversity among the isolates. Several isolates were identified to belong to the genus Streptomyces and a few to Kitasatospora. The actinobacterial strains exhibited high diversity in their functionality and were identified as novel and promising candidates for future development into biocontrol and PGP agents. PMID- 23681764 TI - 4-Hydroxyderricin and xanthoangelol from Ashitaba (Angelica keiskei) suppress differentiation of preadiopocytes to adipocytes via AMPK and MAPK pathways. AB - SCOPE: Adipocytes differentiation is deeply involved in the onset of obesity. 4 Hydroxyderricin (4HD) and xanthoangelol (XAG) are the chalcones that are derived from Ashitaba (Angelica keiskei). In this study, we demonstrated the inhibitory effects of these chalcones on adipocytes differentiation. METHODS AND RESULTS: 4HD and XAG suppressed intracellular lipid accumulation by Oil red O staining at 5 MUM without cytotoxicity. They inhibited adipocytes differentiation accompanied by down-expression of adipocyte-specific transcription factors, CCAAT/enhancer binding protein-beta (C/EBP-beta), C/EBP-alpha, and peroxisome proliferator activated receptor gamma (PPAR-gamma) using RT-PCR and Western blotting analysis. To obtain insights into the underlying mechanism, the activation of AMP-activated protein kinase (AMPK) and mitogen-activated protein kinase pathways was investigated. These two chalcones promoted phosphorylation of AMPK and acetyl CoA carboxylase during differentiation of 3T3-L1 adipocytes accompanied by a decrease in glycerol-3-phosphate acyl transferase-1 and an increase in carnitine palmitoyltransferase-1 mRNA expression. These chalcones also promoted phosphorylation of extracellular signal-regulated kinases and Jun aminoterminal kinases, but not p38. Moreover, the inhibitors for AMPK and extracellular signal regulated kinases abolished the chalcones-caused down-expression of C/EBP-beta, C/EBP-alpha, and PPAR-gamma. Treatment with Jun aminoterminal kinases inhibitor abolished the down-expression of C/EBP-alpha and PPAR-gamma, but not C/EBP-beta. CONCLUSION: 4HD and XAG inhibit adipocytes differentiation through AMPK and mitogen-activated protein kinase pathways, resulting in the down-expression of adipocyte-specific transcription factors. PMID- 23681765 TI - Measuring the exposome: a powerful basis for evaluating environmental exposures and cancer risk. AB - Advances in laboratory sciences offer much in the challenge to unravel the complex etiology of cancer and to therefore provide an evidence-base for prevention. One area where improved measurements are particularly important to epidemiology is exposure assessment; this requirement has been highlighted through the concept of the exposome. In addition, the ability to observe genetic and epigenetic alterations in individuals exposed to putative risk factors also affords an opportunity to elucidate underlying mechanisms of carcinogenesis, which in turn may allow earlier detection and more refined molecular classification of disease. In this context the application of omics technologies to large population-based studies and their associated biobanks raise exciting new avenues of research. This review considers the areas of genomics, transcriptomics, epigenomics and metabolomics and the evidence to date that people exposed to well-defined factors (for example, tobacco, diet, occupational exposures, environmental pollutants) have specific omics profiles. Although in their early stages of development these approaches show promising evidence of distinct exposure-derived biological effects and indicate molecular pathways that may be particularly relevant to the carcinogenic process subsequent to environmental and lifestyle exposures. Such an interdisciplinary approach is vital if the full benefits of advances in laboratory sciences and investments in large-scale prospective cohort studies are to be realized in relation to cancer prevention. PMID- 23681766 TI - Hydroxylated phenylacetamides derived from bioactive benzoxazinoids are bioavailable in humans after habitual consumption of whole grain sourdough rye bread. AB - SCOPE: Understanding relationships between dietary whole grain and health is hindered by incomplete knowledge of potentially bioactive metabolites derived from these foods. We aimed to discover compounds in urine correlated with changes in amounts of whole grain rye consumption. METHODS AND RESULTS: After a wash-out period, volunteers consumed 48-g whole grain rye foods per day for 4 wk and then doubled their intake for a further 4 wk. Samples of 24-h urines were analyzed by flow infusion electrospray MS followed by supervised multivariate data analysis. Urine samples from participants who reported high intakes of rye flakes, rye pasta, or total whole grain rye products could not be discriminated adequately from their wash-out samples. However, discrimination was seen in urine samples from participants who reported high whole grain sourdough rye bread consumption. Accurate mass analysis of explanatory signals followed by fragmentation identified conjugates of the benzoxazinoid lactam 2-hydroxy-1,4-benzoxazin-3-one and hydroxylated phenyl acetamide derivatives. Statistical validation showed sensitivities of 84-96% and specificities of 70-81% (p values < 0.05) for elevated concentrations of these signals after preferential whole grain sourdough rye bread consumption. CONCLUSION: Several potentially bioactive alkaloids have been identified in humans consuming fermented whole grain sourdough rye bread. PMID- 23681767 TI - Identification of Daqingye and Banlangen including crude drugs and decoction dregs from three plant species by normal light and fluorescence microscopy. AB - Daqingye and Banlangen are commonly used Chinese medicinal materials derived from the leaves and roots of Isatis indigotica Fort., respectively, which clinical effects have been confirmed by many studies in recent years. However, many problems have arisen concerning the quality and identity of materials sold in the market under these two names. Thus, the identification of Daqingye and Banlangen has drawn public attention. In this work, transverse sections of Daqingye and Banlangen from I. indigotica Fort. and two easily confused species, namely Baphicacanthus cusia (Nees) Bremek. and Clerodendrum cyrtophyllum Turcz., were investigated with normal light and fluorescence microscopy. The distinguishing features were 7-9 vascular bundles, cystoliths and nonglandular hairs in the leaves of I. indigotica, B. cusia, and C. cyrtophyllum, respectively. The Banlangen could be distinguished according to the characteristics of parenchymous cells, cystoliths, and stone cells. Moreover, the fluorescence features of Daqingye and Banlangen investigated in this study can provide direct points for differentiating those samples. Importantly, whether the crude drugs were decocted could be easily identified by their different fluorescence features, which can ensure their quality in clinical application. This is the first report to distinguish the three species that are commonly found in the market sold as Daqingye and Banlangen by normal light and fluorescence microscopy. This work indicates that the combination of normal light and fluorescence microscopy could be powerful, convenient, and economical for authenticating Daqingye and Banlangen from the three species, including crude drugs and decoction dregs. PMID- 23681768 TI - A detective story in drug discovery: elucidation of a screening artifact reveals polymeric carboxylic acids as potent inhibitors of RNA polymerase. AB - Chasing the active impurity: In the validation of a screening hit it was discovered that a polymeric trace impurity was responsible for the biological activity. Such a side product can be formed with similar compounds. During the investigations it was discovered that the negatively charged macromolecule interacts very efficiently with the protein surface of E. coli RNAP via electrostatic interactions. PMID- 23681769 TI - The mechanisms of EGFR in the regulation of axon regeneration. AB - To understand the relationship between epidermal growth factor receptor (EGFR) and axon regeneration and the mechanisms of how EGFR regulates the neuronal intrinsic regenerative ability, we evaluated the levels of mRNA and protein of EGFR,total mammalian target of rapamycin (mTOR), p-mTOR(Ser2448) , total Akt and p-Akt(Ser473) in rats of different developmental stage by using Western blot and real-time polymerase chain reaction analysis. Axon protein tau and neuron proteins beta-tubulin/neurofilament (NF) were assessed to evaluate the extent of the axon regeneration in cultured neuron cells. Expressions of EGFR,total mTOR, p mTOR(Ser2448) , total Akt and p-Akt(Ser473) in cultured neuron cells were also detected using Western blot analysis. Our results showed that the expressions of EGFR and mTOR dropped off with the ageing of the rats, and Ser473 phosphorylation of Akt and Ser2448 phosphorylation of mTOR were highly expressed in foetal and newborn rats but decreased obviously in adult rats. tau, beta-tubulin and NF were upregulated when EGFR was overexpressed and down-regulated after EGFR was blocked. The phosphorylation of mTOR and Akt was apparently elevated when EGFR was overexpressed and decreased when EGFR was blocked, which suggested that EGFR has the potential to regulate the neuronal intrinsic regeneration and mTOR and PI3K/Akt pathway activation may have an important role in it. PMID- 23681770 TI - Devising the optimal preclinical oncology curriculum for undergraduate medical students in the United States. AB - A third of women and a near majority of men in the United States will be diagnosed with cancer in their lifetimes. To prepare future physicians for this reality, we have developed a preclinical oncology curriculum that introduces second-year medical students to essential concepts and practices in oncology to improve their abilities to appropriately care for these patients. We surveyed the oncology and education literature and compiled subjects important to students' education including basic science and clinical aspects of oncology and addressing patients' psychosocial needs. Along with the proposed curriculum content, scheduling, independent learning exercises, and case studies, we discuss practical considerations for curriculum implementation based on experience at our institution. Given the changing oncology healthcare landscape, all (new) physicians must competently address their cancer patients' needs, regardless of chosen specialty. A thorough and logically organized cancer curriculum for preclinical medical students should help achieve these aims. This new model curriculum, with accompanying strategies to evaluate its efforts, is essential to update how medical students are educated about cancer. PMID- 23681771 TI - Reflections on palliative care. PMID- 23681772 TI - Heavy metal accumulation by poplar in calcareous soil with various degrees of multi-metal contamination: implications for phytoextraction and phytostabilization. AB - The object of this study was to assess the capacity of Populus alba L. var. pyramidalis Bunge for phytoremediation of heavy metals on calcareous soils contaminated with multiple metals. In a pot culture experiment, a multi-metal contaminated calcareous soil was mixed at different ratios with an uncontaminated, but otherwise similar soil, to establish a gradient of soil metal contamination levels. In a field experiment, poplars with different stand ages (3, 5, and 7 years) were sampled randomly in a wastewater-irrigated field. The concentrations of cadmium (Cd), Cu, lead (Pb), and zinc (Zn) in the poplar tissues and soil were determined. The accumulation of Cd and Zn was greatest in the leaves of P. pyramidalis, while Cu and Pb mainly accumulated in the roots. In the pot experiment, the highest tissue concentrations of Cd (40.76 mg kg(-1)), Cu (8.21 mg kg(-1)), Pb (41.62 mg kg(-1)), and Zn (696 mg kg(-1)) were all noted in the multi-metal-contaminated soil. Although extremely high levels of Cd and Zn accumulated in the leaves, phytoextraction using P. pyramidalis may take at least 24 and 16 years for Cd and Zn, respectively. The foliar concentrations of Cu and Pb were always within the normal ranges and were never higher than 8 and 5 mg kg( 1), respectively. The field experiment also revealed that the concentrations of all four metals in the bark were significantly higher than that in the wood. In addition, the tissue metal concentrations, together with the NH4NO3-extractable concentrations of metals in the root zone, decreased as the stand age increased. P. pyramidalis is suitable for phytostabilization of calcareous soils contaminated with multiple metals, but collection of the litter fall would be necessary due to the relatively high foliar concentrations of Cd and Zn. PMID- 23681773 TI - Efficiency of lipopeptide biosurfactants in removal of petroleum hydrocarbons and heavy metals from contaminated soil. AB - This study describes the potential application of lipopeptide biosurfactants in removal of petroleum hydrocarbons and heavy metals from the soil samples collected from industrial dumping site. High concentrations of heavy metals (like iron, lead, nickel, cadmium, copper, cobalt and zinc) and petroleum hydrocarbons were present in the contaminated soil samples. Lipopeptide biosurfactant, consisting of surfactin and fengycin was obtained from Bacillus subtilis A21. Soil washing with biosurfactant solution removed significant amount of petroleum hydrocarbon (64.5 %) and metals namely cadmium (44.2 %), cobalt (35.4 %), lead (40.3 %), nickel (32.2 %), copper (26.2 %) and zinc (32.07 %). Parameters like surfactant concentration, temperature, agitation condition and pH of the washing solution influenced the pollutant removing ability of biosurfactant mixture. Biosurfactant exhibited substantial hydrocarbon solubility above its critical micelle concentration. During washing, 50 % of biosurfactant was sorbed to the soil particles decreasing effective concentration during washing process. Biosurfactant washed soil exhibited 100 % mustard seed germination contradictory to water washed soil where no germination was observed. The results indicate that the soil washing with mixture of lipopeptide biosurfactants at concentrations above its critical micelle concentration can be an efficient and environment friendly approach for removing pollutants (petroleum hydrocarbon and heavy metals) from contaminated soil. PMID- 23681774 TI - Response to comment on "identification of substances with potential for long range transport as possible substances of very high concern". PMID- 23681775 TI - Statin use and risk of hepatocellular carcinoma. AB - The objective of this study was to explore the association between statins use and risk of developing hepatocellular carcinoma (HCC). We used the research database of the Taiwan National Health Insurance program to conduct a population based case-control study. Cases were 3,480 patients with newly diagnosed HCC identified during 2000 and 2009. Controls were 13,920 subjects without HCC and frequency matched for age, sex and duration of observational period of cases (i.e., the duration between year of being enrolled in the insurance program and index year of cases). Six commercially available statins, including simvastatin, lovastatin, fluvastatin, atorvastatin, pravastatin, and rosuvastatin, were analyzed. The adjusted odds ratio [OR] of HCC was 0.72 [95% (CI) 0.59-0.88] for the group with stains use, when compared to the group with non-use of statins. In sub-analysis, simvastatin (OR 0.69, 95% CI 0.50-0.94), lovastatin (OR 0.52, 95% CI 0.36-0.76) and atorvastatin (OR 0.70, 95% CI 0.53-0.93) were associated with significant reduction in odds of HCC. Statins use correlates with 28% decreased risk of HCC. Individual statins, including simvastatin, lovastatin and atorvastatin, are associated with reduced risk of HCC. PMID- 23681776 TI - Early life exposures and the risk of adult glioma. AB - Exposure to common infections in early life may stimulate immune development and reduce the risk for developing cancer. Birth order and family size are proxies for the timing of exposure to childhood infections with several studies showing a reduced risk of glioma associated with a higher order of birth (and presumed younger age at infection). The aim of this study was to examine whether birth order, family size, and other early life exposures are associated with the risk of glioma in adults using data collected in a large clinic-based US case-control study including 889 glioma cases and 903 community controls. A structured interviewer-administered questionnaire was used to collect information on family structure, childhood exposures and other potential risk factors. Logistic regression was used to calculate odds ratios (OR) and corresponding 95% confidence intervals (CI) for the association between early life factors and glioma risk. Persons having any siblings were at significantly lower risk for glioma when compared to those reporting no siblings (OR=0.64; 95% CI 0.44-0.93; p=0.020). Compared to first-borns, individuals with older siblings had a significantly lower risk (OR=0.75; 95% CI 0.61-0.91; p=0.004). Birth weight, having been breast fed in infancy, and season of birth were not associated with glioma risk. The current findings lend further support to a growing body of evidence that early exposure to childhood infections reduces the risk of glioma onset in children and adults. PMID- 23681779 TI - Electroactive explosives: nitrate ester-functionalized 1,2,4,5-tetrazines. PMID- 23681777 TI - Staufen-mediated mRNA decay. AB - Staufen1 (STAU1)-mediated mRNA decay (SMD) is an mRNA degradation process in mammalian cells that is mediated by the binding of STAU1 to a STAU1-binding site (SBS) within the 3'-untranslated region (3'-UTR) of target mRNAs. During SMD, STAU1, a double-stranded (ds) RNA-binding protein, recognizes dsRNA structures formed either by intramolecular base pairing of 3'-UTR sequences or by intermolecular base pairing of 3'-UTR sequences with a long-noncoding RNA (lncRNA) via partially complementary Alu elements. Recently, STAU2, a paralog of STAU1, has also been reported to mediate SMD. Both STAU1 and STAU2 interact directly with the ATP-dependent RNA helicase UPF1, a key SMD factor, enhancing its helicase activity to promote effective SMD. Moreover, STAU1 and STAU2 form homodimeric and heterodimeric interactions via domain-swapping. Because both SMD and the mechanistically related nonsense-mediated mRNA decay (NMD) employ UPF1; SMD and NMD are competitive pathways. Competition contributes to cellular differentiation processes, such as myogenesis and adipogenesis, placing SMD at the heart of various physiologically important mechanisms. PMID- 23681778 TI - Tau proteins expressions in advanced breast cancer and its significance in taxane containing neoadjuvant chemotherapy. AB - Tau is a microtubule-associated protein and expressed in normal breast epithelial cells and breast cancer. Tau expression in breast cancer may be important for chemotherapy optimization. This study is to investigate the expression of Tau in advanced breast cancer and its significance in taxane-containing neoadjuvant chemotherapy. Levels of Tau protein in advanced breast cancer were detected immunohistochemically. The chemotherapeutic efficacy indexes in Tau(-) group, which includes the remission rate, Miller-Payne pathological reactive grade, and pathologic complete response rate, were improved compared with that in Tau(+) group. There was difference in the efficacy indexes among ER+ subgroups but not among ER- patients. In addition, Tau expression was positively correlated (r = 0.32, P < 0.00). In multivariate analysis, when age, clinical stage, postoperative lymph node metastasis, ER, PR, HER2, Ki-67, TP53, or Tau status were included, postoperative lymph node metastasis and Tau-negative status were identified as independent predictors of pathologic complete response. In conclusion, negative Tau protein expression may be an effective predictor for taxane-containing neoadjuvant chemotherapy, especially in ER+ subgroups. Further study on the molecular mechanism and utility of Tau for individualizing adjuvant chemotherapy is warranted. PMID- 23681780 TI - The effect of balloon-occluded transvenous obliteration of gastric varices and gastrorenal shunts on the hepatic synthetic function: a comparison between Child Pugh and model for end-stage liver disease scores. AB - PURPOSE: To evaluate the effect of balloon-occluded transvenous obliteration (BRTO) on the model for end-stage liver disease (MELD) and the Child-Pugh (C-P) score and their individual components. METHODS: A retrospective review of patients undergoing only BRTO without transjugular intrahepatic portosystemic shunt was performed (08, 2007 to 06, 2010). Pre- and post-BRTO MELD and C-P scores were calculated. The post-BRTO MELD and C-P score samplings were categorized as (1) immediate (within 14 days), (2) early (14-90 days), and (3) delayed (90-180 days) post-BRTO. The C-P and MELD scores and their individual components before and after (various sample intervals) were compared. RESULTS: A total of 29 consecutive successful BRTO procedures were found and assessed. In all, 26 had immediate post-BRTO sampling (average 1.8 days after BRTO), 13 (57%) had an early post-BRTO sampling (average 47 days from BRTO), and 10 (38%) had a delayed post-BRTO sampling (average 121 days from BRTO). The bilirubin rises significantly (P = .007) within days after BRTO, but synthetic function improves significantly between 1.5 and 4.0 months post-BRTO (international normalized ration: P = .02, bilirubin: P = .027, and albumin: P = .012). However, 31% (N = 8/ 26) of the patients had worsening ascites with or without hydrothorax. The MELD score significantly improved circa 4 months post-BRTO (from 14.1 to 10.7, P = .0008). However, the C-P score did not change significantly (from 7.6 to 6.7, P = .063). CONCLUSION: The BRTO has a positive effect on the hepatic synthetic function. However, there is a high incidence of post-BRTO ascites (31% of the patients). As a result, the MELD score appears to be a more sensitive gauge for hepatic synthetic function compared to the C-P score for patients undergoing BRTO. PMID- 23681781 TI - Stable expression of human VDR in murine VDR-null cells recapitulates vitamin D mediated anti-cancer signaling. AB - Mammary tumor cells derived from vitamin D receptor (VDR) knock-out (KO) mice were engineered to stably express wild-type (WT) or mutated VDR for characterization of the mechanisms by which 1,25-dihydroxyvitamin D (1,25D), the VDR ligand, mediates growth regulation. Although KO cells were completely resistant to 1,25D, introduction of WT human VDR restored gene expression and growth inhibition in response to 1,25D and a variety of structural analogs. Pdgfb, Vegfa, and Nfkbi were identified as genomic targets of both human and murine VDR signaling in this cell model. KO cells expressing hVDRs containing point mutations (W286R, R274L) that reduce or abolish ligand binding did not exhibit changes in gene expression or growth in response to physiological doses of 1,25D but did respond to higher doses and more potent analogs. KO cells expressing hVDR with the G46D point mutation, which abrogates VDR binding to DR3 response elements, exhibited partial growth inhibition in response to 1,25D and synthetic vitamin D analogs, providing proof of principle that VDR signaling through alternative genomic or non-genomic mechanisms contributes to vitamin D mediated growth effects in transformed cells. We conclude that the 1,25D-VDR signaling axis that triggers anti-cancer effects is highly conserved between the murine and human systems despite differences in VDR protein, cofactors, and target genes and that these actions are not solely mediated via canonical VDRE signaling. PMID- 23681782 TI - Population pharmacokinetics of belimumab following intravenous administration in patients with systemic lupus erythematosus. AB - The population pharmacokinetics (PK) of belimumab were characterized in 1,603 patients with systemic lupus erythematosus receiving belimumab 1, 4, 10, or 20 mg/kg doses in Phase 1-3 trials. Belimumab PK were well described with a linear two-compartment model, with clearance from the central compartment (CL). Belimumab exposure was approximately dose-proportional. The estimated population terminal half-life was 19.4 days and steady-state volume of distribution (Vss) was 5.29 L for the currently approved 10 mg/kg dose used in the Phase 3 trials, with an estimated CL of 215 mL/day. No effects of age, sex, race, disease activity, co-medications, or baseline characteristics on belimumab PK were found to alter exposure in a manner requiring dose adjustment. An association observed between increasing baseline proteinuria and increasing CL may be clinically relevant in nephropathy with very high proteinuria levels. No evidence of target mediated clearance was observed. Clinically relevant effects of body size (increased CL and V1 with increased body weight, and reduced V1 with increased body mass index) have been accounted for in current weight-normalized belimumab dosing. PMID- 23681783 TI - Influence of gallium-doped zinc-oxide thickness on polymer light-emitting diode luminescence efficiency. AB - Conducting atomic force microscopy and scanning surface potential microscopy were used to study the local electrical properties of gallium-doped zinc oxide (GZO) films prepared by pulsed laser deposition (PLD) on a polyimide (PI) substrate. For a PLD deposition process time of 8 min, the root-mean-square roughness, coverage percentage of the conducting regions, and mean work function on the GZO surface were 2.33 nm, 96.6%, and 4.82 eV, respectively. When the GZO/PI substrate was used for a polymer light-emitting diode (PLED), the electroluminescence intensity increased by nearly 20% compared to a standard PLED, which was based on a commercial-ITO/glass substrate. PMID- 23681784 TI - Filling knowledge gaps that distinguish the safety profiles of nano versus bulk materials. PMID- 23681788 TI - [Internet presence of neurologists, psychiatrists and medical psychotherapists in private practice]. AB - OBJECTIVE: The world wide web provides new options to physicians in terms practice marketing, information brokerage, and process optimization. This study explores prevalence and content of homepages of neurologists, psychiatrists and medical psychotherapists in private practice. METHODS: Through the legal bodies of physicians in private practice in six northern German states neurologists, psychiatrists and medical psychotherapists were identified. According to a standardized and operationalized criteria catalogue, homepages were rated. RESULTS: 1804 physicians were identified, 352 (19.5 %) had operated a homepage. Higher frequencies of homepages found for male physicians (vs. female physicians), practice centres (vs. single practices) and urban practices (vs. rural practices). In average, practices reached 18.8 (+/- 5.3) of 42 points; contact data and accessibility information were generally available; information as to qualification and specialization was provided more infrequently. Legal specifications were not considered in more than every second homepage, interactive elements like online appointment of follow-up prescription were only rarely offered. CONCLUSIONS: Only every fifth neurological or psychiatric practice operates an own homepage, higher competition (urban area) and higher professionalization (practice centres) seem to act as promotors. The legal framework has to be focused, and patient needs should be taken into account. PMID- 23681789 TI - [Psychometric properties of the Autism-Checklist (ACL) in adults with intellectual disability]. AB - OBJECTIVE: To determine the validity of the Autism-Checklist (ACL) in adults with intellectual disability (ID) who are suspected of having autism spectrum disorder. METHODS: In 154 adults with ID the results of the ACL were compared to the results of the final diagnostic classification obtained by a multiprofessional case conference for autism. Psychometric properties of the ACL were evaluated. RESULTS: The internal consistency as indicated by Cronbach's alpha was 0.81. The ACL sum score highly correlated with established screening measures such as the Social Communication Questionnaire (SCQ: Spearman's rho = 0.620) and the Pervasive Developmental Disorder in Mental Retardation Scale (PDD MRS: Spearman's rho = 0.490). ROC Analysis revealed an area under the curve of 0.859. The ACL classification complied with the final diagnostic classification in 80.5 % and Cohen's kappa revealed a moderate agreement of 0.596. Sensitivity/specificity of the ACL were 90.7 %/67.6 %, respectively. Interrater intertime reliability was good (Cohen's kappa = 0.702; Spearman = 0.549; n = 53). In 19 patients (22 %) a diagnosis of ASD had been given prior to referral. CONCLUSION: The ACL is a suitable measure for adults with ID and suspicion of autism spectrum disorders. PMID- 23681790 TI - [Antipsychotic polypharmacy in high-utilising patients with schizophrenia]. AB - OBJECTIVES: Although guidelines usually recommend monotherapy, in clinical practice, antipsychotic polypharmacy is common especially with chronically ill patients. We therefore assessed the current practice of antipsychotic polypharmacy in "high-utilising" patients with schizophrenia in Germany. METHODS: Antipsychotic medication was assessed using a representative sample of 638 patients with schizophrenia from two multi-centre studies. RESULTS: Antipsychotic combination treatment was administered to 43.9 % of the patients. Combination treatment not including clozapine was apparent in 36.2 %. CONCLUSIONS: Antipsychotic polypharmacy is prevalent in the treatment of patients with schizophrenia showing high service use also when excluding such combinations with clozapine. Differences between the study samples indicate possible influences linked with therapy resistance or treatment setting. PMID- 23681791 TI - [Implementing models of cross-sectoral mental health care (integrated health care, regional psychiatry budget) in Germany: systematic literature review]. AB - OBJECTIVE: Cross-sectoral integrated health-care and the regional psychiatry budget are two models of cross-sectoral health care (comprising in-patient and out-patient care) in Germany. Both models of financing were created in order to overcome the so-called fragmentation in German health care. The regional psychiatry budget is a specific solution for psychiatric services whereas integrated health care models can be developed for all areas of health care. The purpose of this overview is to elucidate both the current state of implementation of these models and the results of evaluation research. METHODS: Systematic literature review, additional manual search. RESULTS: 28 journal articles and 38 websites referring to 21 projects were identified. The projects are highly heterogenuous in terms of size, included populations and services, aims, and steering-function (concerning the different pathways of care). CONCLUSIONS: The projects yield innovative models of mental health care capable of competing with the co-existing traditional financing systems of in-patient and out-patient services. The future of mental health care organisation in Germany is currently open and under political discussion. PMID- 23681792 TI - Tendon mechanobiology: experimental models require mathematical underpinning. AB - Mathematical and computational modeling is in demand to help address current challenges in mechanobiology of musculoskeletal tissues. In particular for tendon, the high clinical importance of the tissue, the huge mechanical demands placed on it and its ability to adapt to these demands, require coupled, multiscale models incorporating complex geometrical and microstructural information as well as time-based descriptions of cellular activity and response.This review introduces the information sources required to develop such multiscale models. It covers tissue structure and biomechanics, cell biomechanics, the current understanding of tendon's ability in health and disease to update its properties and structure and the few already existing multiscale mechanobiological models of the tissue. Finally, a sketch is provided of what such models could achieve ideally, pointing out where experimental data and knowledge are still missing. PMID- 23681793 TI - Value-based healthcare in Lynch syndrome. AB - Lynch syndrome (LS), one of the most frequent forms of hereditary colorectal cancer (CRC), is caused by a defect in one of the mismatch repair (MMR) genes. Carriers of MMR defects have a strongly increased risk of developing CRC and endometrial cancer. Over the last few years, value-based healthcare has been introduced as an approach to the cost-effective delivery of measurable patient value over complete cycles of care. This requires all involved stakeholders to formulate and validate 'patient value' for Lynch syndrome, as well as to identify targets and associated costs. The aim of this study was to develop a value-based care model for Lynch syndrome that can determine patient value and associated costs, and to design a coordinated care pathway from existing guidelines. All specialists in our hospital involved in the management of LS patients evaluated the care delivered to these patients at their department and formulated outcome measures relevant to patient value. Patients were then invited to complete a questionnaire that assessed the importance of these measures on a scale of 1-10. Six high-value outcomes were identified: (1) prevention of cancer or detection of early stage cancer (2) rapid results from MMR gene mutation testing (3) rapid investigation of the colon and uterus (4) no/little pain during colonoscopy and gynaecologic examination/biopsy (5) the offer of psychological help and (6) registration with the Dutch Lynch syndrome registry. A total of 38 (59 %) out of 62 patients completed the questionnaire. The relevance of all outcomes was confirmed by the patients and mean scores varied from 7.2 to 9.9. Patients underscored the relevance of both proper patient education and the efficiency of surveillance during their care cycle. Value-based care delivery for Lynch syndrome includes the implementation of six parameters related to prevention and early detection of cancer, a short cycle time and registration to ensure continuation of care. Estimated costs are 3320 for the first cycle of care ( 3550 including gynaecologic surveillance) and approximately 720 per subsequent annual cycle ( 950 including gynaecologic surveillance). PMID- 23681794 TI - Low-background, highly sensitive DNA biosensor by using an electrically neutral cobalt(II) complex as the redox hybridization indicator. AB - An electrically neutral cobalt complex, [Co(GA)2(phen)] (GA = glycollic acid, phen = 1,10-phenathroline), was synthesized and its interactions with double stranded DNA (dsDNA) were studied by using electrochemical methods on a glassy carbon electrode (GCE). We found that [Co(GA)2(phen)] could intercalate into the DNA duplex through the planar phen ligand with a high binding constant of 6.2(+/ 0.2)*10(5) M(-1). Surface studies showed that the cobalt complex could electrochemically accumulate within the modified dsDNA layer, rather than within the single-stranded DNA (ssDNA) layer. Based on this feature, the complex was applied as a redox-active hybridization indicator to detect 18-base oligonucleotides from the CaMV35S promoter gene. This biosensor presented a very low background signal during hybridization detection and could realize the detection over a wide kinetic range from 1.0*10(-14) M to 1.0*10(-8) M, with a low detection limit of 2.0 fM towards the target sequences. The hybridization selectivity experiments further revealed that the complementary sequence, the one base-mismatched sequence, and the non-complementary sequence could be well distinguished by the cobalt-complex-based biosensor. PMID- 23681795 TI - Associations of three common polymorphisms in CD95 and CD95L promoter regions with gastric cancer risk. AB - There are many studies performed to assess the associations of CD95 A670G and G1377A polymorphisms with gastric cancer, and the association of CD95L T844C polymorphism with gastric cancer risk, but the data are remaining controversial. To get a comprehensive assessment of the association above, we performed a meta analysis of published studies. PubMed, Embase, Web of Science, and Wanfang Medicine databases were searched for eligible studies. There were eight studies including 3,790 subjects on CD95 A670G polymorphism, eight studies including 4,563 subjects on CD95 G1377A polymorphism, and eight studies including 4,563 subjects on CD95L T844C polymorphism. Overall, CD95 G1377A polymorphism was associated with a significantly increased risk of gastric cancer (for AA versus GG: odds ratio (OR) = 1.24, 95 % confidence interval (95 % CI) = 1.02-1.52, P = 0.030; for AA versus GG + GA: OR = 1.27, 95 % CI = 1.05-1.53, P = 0.012). However, there were no associations of CD95 A670G and CD95L T844C polymorphisms with gastric cancer. Subgroup analysis by ethnicity found similar associations in Asians, but the associations in Caucasians were still unclear owing to the lack of relevant data. Therefore, the outcomes of this meta-analysis show that there is a significant association between CD95 G1377A polymorphism and risk of gastric cancer. PMID- 23681796 TI - XRCC1 Arg194Trp polymorphism is associated with oral cancer risk: evidence from a meta-analysis. AB - Previous studies show that X-ray cross-complementing group 1 (XRCC1) Arg194Trp may result in variations in host's repair efficiency of DNA damage, and this repair deficit may eventually cause individual susceptibility to oral cancer. However, published data regarding the association between XRCC1 Arg194Trp polymorphism and oral cancer risk were contradictory. The aim of this study was to derive a more precise estimation of the association of XRCC1 Arg194Trp polymorphism with oral cancer by performing a meta-analysis. Odds ratios (ORs) and 95 % confidence intervals (95 % CIs) were used to assess the strength of the association. Finally, a meta-analysis of nine eligible studies including 1,281 cases and 1,966 controls was performed. Overall, there was a significant association between XRCC1 Arg194Trp polymorphism and oral cancer risk (for Trp versus Arg: OR = 1.41, 95 % CI 1.08-1.83, P = 0.01; for TrpTrp versus ArgArg: OR = 1.50, 95 % CI 1.00-2.30, P = 0.05; for TrpTrp/ArgTrp versus ArgArg: OR = 1.49, 95 % CI 1.14-1.94, P = 0.003). After excluding those studies containing patients with oral leukoplakia, there was still an obvious association between XRCC1 Arg194Trp polymorphism and oral cancer risk (for TrpTrp/ArgTrp versus ArgArg: OR = 1.40, 95 % CI 1.14-1.71, P = 0.001). Subgroup analysis by ethnicity suggested that there was an obvious association between XRCC1 Arg194Trp polymorphism and oral cancer risk in Asians under three genetic models. In conclusion, the results from this meta-analysis suggest that XRCC1 Arg194Trp polymorphism is associated with oral cancer risk, especially in Asians. PMID- 23681797 TI - Association between microsomal epoxide hydrolase 1 polymorphisms and susceptibility to esophageal cancer: a meta-analysis. AB - Microsomal epoxide hydrolase 1 (EPHX1) plays an important role in the detoxification of carcinogenic polycyclic aromatic hydrocarbons. EPHX1 Tyr113His and His139Arg polymorphisms have been reported to have some impacts on the EPHX1 activity. Previous case-control studies assessing the associations between EPHX1 polymorphisms and esophageal cancer risk reported conflicting results. To quantitatively summarize the associations of EPHX1 Tyr113His and His139Arg polymorphisms with esophageal cancer risk, a systemic review and meta-analysis of published studies were performed. Published literatures from PubMed, Embase, and China National Knowledge Infrastructure databases were searched. The strength of the associations between EPHX1 polymorphisms and esophageal cancer risk was estimated by the pooled odds ratios (ORs) with its 95 % confidence interval (95 %CI). This meta-analysis yielded nine case-control studies, which included nine studies for Tyr113His polymorphism (1,291 cases and 2,120 controls) and seven studies for His139Arg polymorphism (899 cases and 1,615 controls). Overall, meta analysis showed that EPHX1 Tyr113His polymorphism was not associated with esophageal cancer risk under all genetic models. Meta-analysis of these seven studies for EPHX1 His139Arg polymorphism showed that EPHX1 His139Arg polymorphism was also not associated with esophageal cancer risk under all genetic models. However, subgroup analysis by ethnicity further showed that there was an obvious association between EPHX1 His139Arg polymorphism and decreased risk of esophageal cancer in Caucasians (ArgArg versus HisArg/HisHis: OR = 0.52, 95 %CI 0.27-0.97, P = 0.041). This meta-analysis suggests that EPHX1 His139Arg polymorphism is associated with decreased risk of esophageal cancer in Caucasians. In addition, more studies with large samples are needed to get a more precise estimation on the associations mentioned above. PMID- 23681799 TI - C282Y polymorphism in the HFE gene is associated with risk of breast cancer. AB - The C282Y and H63D polymorphisms in the HFE gene have been implicated in susceptibility of breast cancer, but a number of studies have reported inconclusive results. The aim of this study is to investigate the association between the C282Y and H63D polymorphisms in the HFE gene and breast cancer risk by meta-analysis. We searched PubMed and Embase databases, covering all related studies until March 2, 2013. Statistical analysis was performed using STATA 10.0. A total of 7 studies including 1,720 cases and 18,296 controls for HFE C282Y polymorphism and 5 studies including 942 cases and 1,571 controls for HFE H63D polymorphism were included in the meta-analysis. The results showed that HFE C282Y polymorphism was significantly associated with increased risk of breast cancer under homozygotes vs. wild-type model (OR = 2.06, 95%CI = 1.19-3.58) and recessive model (OR = 1.98, 95%CI = 1.14-3.44) but not under heterozygotes vs. wild-type model (OR = 0.97, 95%CI = 0.70-1.35), dominant model (OR = 1.00, 95%CI = 0.72-1.40) and multiplicative model (OR = 1.04, 95%CI = 0.76-1.42). However, we did not find any association between HFE H63D polymorphism and breast cancer risk under all genetic models. This current meta-analysis suggested that C282Y polymorphism rather than H63D might be associated with increased risk of breast cancer. PMID- 23681798 TI - Regulatory T cells in chronic lymphocytic leukemia: implication for immunotherapeutic interventions. AB - Identification of regulatory T cells (Tregs) has led to breaking the dichotomy of the Th1/Th2 axis in the immunopathology of several diseases such as autoimmune diseases and cancer. Despite the presence of extensive information about immunobiology of Tregs in pathogenesis of autoimmune diseases, little is known about the frequency and function of these cells in hematologic malignancies, particularly chronic lymphocytic leukemia (CLL). Recent data have demonstrated increased frequency and intact functional capacity of CD4(+) Tregs in CLL patients. However, the precise role of these cells in the immunopathology of CLL is not well known. While targeting Tregs in cancer diseases seems to be an interesting immunotherapeutic approach, such therapeutic interventions in CLL might be deleterious due to suppression of the tumor-specific adaptive and innate immune responses. Thus, the precise biological and regulatory functions of all Tregs subsets should be carefully investigated before planning any immunotherapeutic interventions based on targeting of Tregs. In this communication, we review the recent data published on immunobiology of Tregs in CLL and discuss about the possibility of targeting Tregs in CLL. PMID- 23681800 TI - Numblike regulates proliferation, apoptosis, and invasion of lung cancer cell. AB - Numblike (Numbl), a conserved homolog of Drosophila Numb, has been proved to be implicated in early development of the nervous system. A recent study also showed that Numbl played an important role in tumorigenesis and invasion by suppressing NF-kappaB activation. However, the biological role of Numbl remains unknown in lung cancer up to now. To address the expression of Numbl in the lung cancer cell, four lung cancer cell lines (metastatic cell lines NCI-H292, 95-D, and non metastatic cell lines A549, HCC827) and non-cancerous human bronchial epithelial cells were used to detect the protein expression of Numbl by western blotting. The results in this study indicated that the expression of Numbl was downregulated in human lung cancer cell lines, especially in metastatic cell lines. To investigate the role of Numbl in lung cancer cell proliferation, apoptosis, and invasion, we generated human lung cancer 95-D cell lines in which Numbl was either overexpressed or depleted. Subsequently, the effects of Numbl on the cell viability, cycle, apoptosis, and invasion properties in 95-D cells were determined with MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] assay, flow cytometry analysis, and Transwell invasion assays. The results indicated that Numbl could decrease cell viability, suppress cell proliferation and invasion, and promote cell apoptosis. In addition, we investigated the effects of Numbl on the expression of the following proteins: TRAF6 (tumor necrosis factor receptor-associated factor 6), p-p65 (phosphor-NF kappaB), cyclin D1, caspase-3, and matrix metalloproteinase 9 (MMP9). Results showed that Numbl could decrease the expression of TRAF6, p-p65, cyclin D1, and MMP9 and increase the expression of caspase-3. All these results suggested that Numbl might be involved in the inhibition of growth, proliferation, and invasion of 95-D cells, as well as the potentiation of apoptosis of 95-D cells by abrogating TRAF6-induced activation of NF-kappaB. PMID- 23681801 TI - Quality of life estimate in stomach, colon, and rectal cancer patients in a hospital in China. AB - The objective of this study was to investigate the outcome and coping patterns of patients with stomach, colon, and rectal cancer in a hospital in China. Health related quality of life was assessed in 118 stomach, colon, and rectal cancer patients in Chinese People's Liberation Army General Hospital, Beijing, China, using the generic version of the European Organization for Research and Treatment of Cancer Quality of Life (QOL) Questionnaire Core 30 Items, Self-rated Anxiety Scores (SAS), Self-rated Depression Scores (SDS), Medical Coping Modes of Questionnaire (MCMQ), and Social Support Requirement Scale (SSRS) questionnaires. The overall QOL was 50.7 +/- 6.5, 48.1 +/- 7.7, and 47.6 +/- 6.4, respectively, for stomach, colon, and rectal cancer groups. Correlations between QOL and SAS and SDS in stomach cancer patients were significantly higher than observed in the cohort of colon or rectal cancer patients (Spearman coefficient of 0.366 and 0.129, respectively). Cluster analysis of MCMQ data revealed four identifiable patterns (resign, confront, avoid-confront, and avoid-resign) of coping in the study group. Subjective support was significantly higher than objective support (p < 0.05); however, extent of using the support was significantly lower than either objective (p < 0.05) or subjective support (p < 0.01). SAS and SDS were negatively correlated to SSRS scores (p < 0.01 and p < 0.05, respectively). Stomach, colon, and rectal cancer patients had anxiety and depression stemming from their cancer diagnosis and postdiagnosis treatment, and sex dependency was prevalent in SSRS response. Coping patterns were reliable indicators of psychosocial side effects in patients with stomach, colon, and rectal cancers. PMID- 23681803 TI - Ataxia-telangiectasia group D complementing gene (ATDC) upregulates matrix metalloproteinase 9 (MMP-9) to promote lung cancer cell invasion by activating ERK and JNK pathways. AB - Although the expression pattern and biological functions of ataxia-telangiectasia group D complementing gene (ATDC) had been implicated in several types of cancer, the roles and potential mechanisms of ATDC in lung cancer cell invasion are still ambiguous. In this study, we used gain- and loss-of-function analyses to explore the roles and potential mechanisms of ATDC in lung cancer cell invasion. siRNA knockdown of ATDC impaired cell invasion in A549 and H1299 cell lines, and its overexpression promoted cell invasion in HBE cell line. ATDC may contribute to the invasive ability of lung cancer cells by promoting the expression of invasion related matrix metalloproteinase 9 (MMP-9). In addition, ATDC increased activating protein 1 (AP-1) reporter luciferase activity and the protein and mRNA levels of c-Jun and c-Fos. We further demonstrated that the roles of ATDC on cell invasion, MMP-9 upregulation, and AP-1 activation were dependent on extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) pathway activation, and ERK inhibitor U0126 or JNK inhibitor SP600125 blocked these effects of ATDC. These results suggested that ATDC upregulates MMP-9 to promote lung cancer cell invasion by activating ERK and JNK pathways. PMID- 23681802 TI - Matrix metalloproteinases in cancer: their value as diagnostic and prognostic markers and therapeutic targets. AB - Biomarkers are used as tools in cancer diagnostics and in treatment stratification. In most cancers, there are increased levels of one or several members of the matrix metalloproteinases (MMPs). This is a family of proteolytic enzymes that are involved in many phases of cancer progression, including angiogenesis, invasiveness, and metastasis. It has therefore been expected that MMPs could serve as both diagnostic and prognostic markers in cancer patients, but despite a huge number of studies, it has been difficult to establish MMPs as cancer biomarkers. In the present paper, we assess some of the challenges associated with MMP research as well as putative reasons for the conflicting data on the value of these enzymes as diagnostic and prognostic markers in cancer patients. We also review the prognostic value of a number of MMPs in patients with lung, colorectal, breast, and prostate cancers. The review also discusses MMPs as potential target molecules for therapeutic agents and new strategies for development of such drugs. PMID- 23681804 TI - DLC-1 is a candidate biomarker methylated and down-regulated in pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive malignancies in humans, and its prognosis is generally poor even after surgery. Many advances have been made to understand the pathogenesis of PDA; however, the molecular mechanisms that lead to pancreatic carcinogenesis are still not clearly understood. The aims of this study were to investigate the relationship between DLC-1 methylation status and clinicopathological characteristics of PDA patients and evaluate the role of DLC-1 methylation status in PDA. The expression of DLC-1 mRNA in PDA tissues was analyzed by real-time PCR. The methylation status of DLC 1 was analyzed by methylation-specific polymerase chain reaction (MSP). Furthermore, we determined the prognostic importance of DLC-1 methylation status in PDA patients. Our results showed that the expression level of DLC-1 mRNA in PDA tissues was lower than that in non-cancerous tissues. The rate of DLC-1 promoter methylation was significantly higher in PDA tissues than in adjacent non cancerous tissues (p < 0.001). Downregulation of DLC-1 was strongly correlated with promoter methylation (P = 0.003). The presence of DLC-1 methylation in PDA tissue samples was significantly correlated with clinical stage (P = 0.005), histological differentiation (P = 0.05), and lymph node metastasis (P = 0.006). Kaplan-Meier survival analysis showed that DLC-1 methylation status was inversely correlated with overall survival of the PDA patients. Further, Cox multivariate analysis indicated that DLC-1 methylation status was an independent prognostic factor for the overall survival rate of PDA patients. In conclusion, our data suggest that downregulation of DLC-1 may be explained by DNA methylation; DLC-1 may be a biomarker for PDA. PMID- 23681805 TI - Metabolite profiling using liquid chromatography/quadrupole time-of-flight mass spectrometry for the identification of a suitable marker and target matrix of griseofulvin use in bovines. AB - RATIONALE: Griseofulvin is an antifungal agent with potential for misuse in food producing animals. Little is known about its metabolism in ruminants and hence what are suitable marker residues and target matrices for monitoring purposes. METHODS: Tissues harvested from cattle treated with the antifungal agent griseofulvin were screened using liquid chromatography coupled to positive and negative electrospray ionization (ESI) quadrupole time-of-flight mass spectrometry (qToFMS) operated in ToF mode. RESULTS: Twenty-five possible metabolites were detected across all tissue types, but two isomeric compounds with accurate masses corresponding to loss of a methyl group from parent griseofulvin were considered to be the best candidate markers. Data from fragmentation experiments enabled a tentative assignment of the structures of the two compounds as 4-demethylgriseofulvin and 6-demethylgriseofulvin. These assignments were confirmed by matching the product ion spectra of incurred residues to those of custom synthesized reference standards. CONCLUSIONS: 4 Demethyl- and 6-demethylgriseofulvin have been identified as potential marker compounds of griseofulvin use in cattle. Liver was identified as the target matrix. Hair was shown to have potential for non-invasive testing. PMID- 23681806 TI - Measurement of apo(a) kinetics in human subjects using a microfluidic device with tandem mass spectrometry. AB - RATIONALE: Apolipoprotein(a) [apo(a)] is the defining protein component of lipoprotein(a) [Lp(a)], an independent risk factor for cardiovascular disease. The regulation of Lp(a) levels in blood is poorly understood in part due to technical challenges in measuring Lp(a) kinetics. Improvements in the ability to readily and reliably measure the kinetics of apo(a) using a stable isotope labeled tracer is expected to facilitate studies of the role of Lp(a) in cardiovascular disease. Since investigators typically determine the isotopic labeling of protein-bound amino acids following acid-catalyzed hydrolysis of a protein of interest [e.g., apo(a)], studies of protein synthesis require extensive protein purification which limits throughput and often requires large sample volumes. We aimed to develop a rapid and efficient method for studying apo(a) kinetics that is suitable for use in studies involving human subjects. METHODS: Microfluidic device and tandem mass spectrometry were used to quantify the incorporation of [(2)H3]-leucine tracer into protein-derived peptides. RESULTS: We demonstrated that it is feasible to quantify the incorporation of [(2)H3]-leucine tracer into a proteolytic peptide from the non-kringle repeat region of apo(a) in human subjects. Specific attention was directed toward optimizing the multiple reaction monitoring (MRM) transitions, mass spectrometer settings, and chromatography (i.e., critical parameters that affect the sensitivity and reproducibility of isotopic enrichment measurements). The results demonstrated significant advantages with the use of a microfluidic device technology for studying apo(a) kinetics, including enhanced sensitivity relative to conventional micro-flow chromatography, a virtually drift-free elution profile, and a stable and robust electrospray. CONCLUSIONS: The technological advances described herein enabled the implementation of a novel method for studying the kinetics of apo(a) in human subjects infused with [(2)H3]-leucine. PMID- 23681807 TI - Electrospray tandem mass spectrometry analysis of methylenedioxy chalcones, flavanones and flavones. AB - RATIONALE: Several methylenedioxy chalcones, flavanones and flavones substituted with mono-, di- and trimethoxy groups have been used in the treatment of proliferative conditions like cancer and inflammatory diseases. The application of these flavonoids in biology requires an analytical method to ensure a detailed knowledge of their structures after drug metabolism. METHODS: Electrospray ionization mass (ESI-MS) and tandem mass (ESI-MS/MS) spectra were acquired using a Q-TOF 2 instrument. Fragmentation patterns and their pathways were analyzed by CID-MS(2-3) spectra acquired in a LXQ linear ion trap mass spectrometer using standard isolation and excitation procedures (activation q value of 0.25, activation time of 30 ms). ESI-MS and ESI-MS(n) conditions: spray voltage 5 kV, nitrogen 8.00 sheath gas flow rate (arb), heated capillary temperature 275 degrees C, capillary voltage 10.99 V; tube lens voltage 75.01 V. RESULTS: The ESI MS/MS spectra of chalcones were nearly identical to their corresponding isomeric flavanones with (0,alpha)A(+)/(1,3)A(+) and (0,1')B(+)/(1,4)B(+) cleavages. Other common losses are of (*)CH3, H2O, HCHO and C2H2O. The characteristic loss of C2H2O and absence of a (0,alpha)B(+)/(1,3)B(+) product ion allows to distinguish between the 2- or 4-methoxy-substituted chalcones and flavanones. Common losses of (*)CH3, (*)CH3 and (*)H, and C2H2O2 characteristic for the presence of methylenedioxy groups were observed in flavones. CONCLUSIONS: The substitution pattern on the B-ring leads to distinct base peak formation in the flavones. In addition, differentiation of isomers with methoxy substituents in ortho and para positions of the B-ring was achieved using MS/MS in chalcones and flavanones. This method will be helpful for identification of these compounds in biological mixtures. PMID- 23681808 TI - Transmission mode direct analysis in real time mass spectrometry for fast untargeted metabolic fingerprinting. AB - RATIONALE: Untargeted metabolic fingerprinting is a discovery tool to better understand biochemical processes involved in detecting and characterizing disease states and responses to environmental stressors. Although current mass spectrometric (MS) methods are very powerful, there is a clear need for more rapid, high-throughput MS approaches for metabolomics studies. METHODS: A rapid metabolic fingerprinting method for human blood sera that utilizes a new transmission mode direct analysis in real time (TM-DART) sampling technique coupled with quadrupole time of flight mass spectrometry (QTOFMS) is presented. In this approach, the sample is deposited directly on a stainless steel mesh that is held in the ionization region by a custom-built module. As a result, the DART plasma gas stream interacts with the sample in a flow-through fashion, which maximizes the interaction between the sample and ionizing species and minimizes variance in sample positioning. RESULTS: The optimization of TM-DART parameters directly affecting metabolite desorption and ionization, such as sample position and ionizing gas desorption temperature, was critical in achieving high sensitivity and detecting a broad mass range of metabolites. Ramping the ionizing gas desorption temperature further enhanced analysis by adding a simple separation dimension to this ambient approach. In terms of reproducibility, TM DART compared favorably with traditional probe mode (PM-) DART analysis, with coefficients of variation as low as 16%. The longer-lasting TM-DART signals enabled the acquisition of metabolite full scan and product ion accurate mass spectra in a single experiment, resulting in greater confidence in metabolite identification. CONCLUSIONS: TM-DART MS proved to be a powerful analytical technique for rapid metabolome analysis of human blood sera. PMID- 23681809 TI - Rapidly formed quinalphos complexes with transition metal ions characterized by electrospray ionization mass spectrometry. AB - RATIONALE: Electrospray ionization tandem mass spectrometry (ESI-MS/MS) offers the unique opportunity to characterize complexes of the organophosphorus pesticide (OP) quinalphos (PA-Q) with transition metal ions immediately formed after contact. This study complements research looking at longer term kinetics of quinalphos hydrolysis in the presence of transition metal ions and gives insights into the structural features of the initial complex formation in solution. (Hydrolysis reaction: PA-Q + H2 O -> PA-OH + HQ, where PA-OH is the diethyl phosphate product and HQ is hydroxyquinoxaline.) METHODS: Low micromolar PA-Q solutions with an approximately 3-fold molar excess of transition metal ions were immediately analyzed after mixing. Fragmentation of the transition metal ion complexes with PA-Q was accomplished in two different ways: first, in-source fragmentation by elevating the declustering potential and second, low-energy collision-induced dissociation (CID). RESULTS: For Ag(+), the [PA-Q - Ag(+)] and respective Ag(+) -containing degradation product ions are readily observed. For Cu(2+), we observed the [PA-Q + Cu(2+) + NO3(-)] complex ion with weak intensity and strong signals from both the [2PA-Q + Cu(+)] and the [PA-Q + Cu(+)] ions, the latter two attributable to charge-state reduction in the gas phase from Cu(II) to Cu(I), indicating that PA-Q fulfills specific structural requirements of the formed complex for charge-state reduction during transition from solution to the gas phase. For Hg(2+), the [PA-Q + Hg(2+) + (PA-OH - H)(-)] ion was the largest observed species containing one Hg(2+) ion. No 1:1 species ([PA-Q] or other degradation products:Hg(2+)) was observable. CONCLUSIONS: ESI-MS/MS of complexes formed from PA-Q and transition metal ions is a formidable technique to probe initial formation of these complexes in solution. Previous work from other groups established structural requirements that enable charge-state reduction from Cu(II) to Cu(I) in ligand complexes during transition into the gas phase, and these rules allow us to propose structural features of PA-Q complexes with copper ions in solution. PMID- 23681810 TI - Continuous-flow liquid microjunction surface sampling probe connected on-line with high-performance liquid chromatography/mass spectrometry for spatially resolved analysis of small molecules and proteins. AB - RATIONALE: A continuous-flow liquid microjunction surface sampling probe extracts soluble material from surfaces for direct ionization and detection by mass spectrometry. Demonstrated here is the on-line coupling of such a probe with high performance liquid chromatography/mass spectrometry (HPLC/MS) enabling extraction, separation and detection of small molecules and proteins from surfaces in a spatially resolved (~0.5 mm diameter spots) manner. METHODS: A continuous-flow liquid microjunction surface sampling probe was connected to a six-port, two-position valve for extract collection and injection to an HPLC column. A QTRAP(r) 5500 hybrid triple quadrupole linear ion trap equipped with a Turbo VTM ion source operated in positive electrospray ionization (ESI) mode was used for all experiments. The system operation was tested with the extraction, separation and detection of propranolol and associated metabolites from drug dosed tissues, caffeine from a coffee bean, cocaine from paper currency, and proteins from dried sheep blood spots on paper. RESULTS: Confirmed in the tissue were the parent drug and two different hydroxypropranolol glucuronides. The mass spectrometric response for these compounds from different locations in the liver showed an increase with increasing extraction time (5, 20 and 40 s). For on-line separation and detection/identification of extracted proteins from dried sheep blood spots, two major protein peaks dominated the chromatogram and could be correlated with the expected masses for the hemoglobin alpha and beta chains. CONCLUSIONS: Spatially resolved sampling, separation, and detection of small molecules and proteins from surfaces can be accomplished using a continuous-flow liquid microjunction surface sampling probe coupled on-line with HPLC/MS detection. PMID- 23681811 TI - Online methodology for determining compound-specific hydrogen stable isotope ratios of trichloroethene and 1,2-cis-dichloroethene by continuous-flow isotope ratio mass spectrometry. AB - RATIONALE: Carbon and chlorine compound-specific isotope analysis (CSIA) is utilized in chlorinated solvent contamination studies of soil and groundwater contaminated sites. However, in field studies, hydrogen CSIA has been used only in non-chlorinated volatile organic compound (VOC) investigations, due to low conversion yields into hydrogen gas and poor reproducibility. Therefore, it is important to develop hydrogen CSIA methodology for soil and subsurface contamination studies. METHODS: A new analytical method for determining compound specific hydrogen stable isotope ratios is presented. The isotopic ratios were measured by gas chromatography/isotope ratio mass spectrometry (GC/IRMS) coupled with a chromium reduction system. The method was used to determine the delta(2) H values of trichloroethene (TCE) and 1,2-cis-dichloroethene (cis-DCE). RESULTS: The accuracy of the method was verified by conducting comparison measurements of standards by the conventional offline technique and the new method. The precision of the new analytical method (better than +/-7 0/00) is better than that obtained from the offline method. The quantification limits of the headspace-solid-phase microextraction (SPME) are 400 ug/L and 200 ug/L for TCE and cis-DCE, respectively. The quantification limits can be improved by adopting a more efficient pre-concentration system such as purge-and-trap or thermal adsorption. CONCLUSIONS: This analytical method will facilitate the use of hydrogen CSIA on chlorinated solvents, which can be beneficial in multi-isotope approaches (coupling delta(2)H values with delta(13)C and/or delta(37)Cl values) in field site investigations where source identifications and contaminant behaviours are questioned. PMID- 23681812 TI - Simultaneous determination of natural-abundance delta15N values and quantities of individual amino acids in proteins from milk of lactating women and from infant hair using gas chromatography/isotope ratio mass spectrometry. AB - RATIONALE: In isotope tracer experiments used in nutritional studies, it is frequently desirable both to determine the (15)N/(14)N ratios of target compounds and to quantify these compounds. This report shows how this can be achieved in a single chromatographic run for protein amino acids using an isotope ratio mass spectrometer. METHODS: Protein hydrolysis by acidic digestion was used to release amino acids, which were then derivatized as their N-pivaloyl-O-isopropyl esters. Suitable conditions for sample preparation were established for both hair and milk proteins. The N-pivaloyl-O-isopropyl esters of amino acids were separated by gas chromatography (GC) on a 60 m ZB-WAX column linked via a combustion interface to an isotope ratio mass spectrometer. The (15)N/(14)N ratios were obtained from the m/z 28, 29 and 30 peak intensities and the quantities from the Area All (Vs) integrated peak areas. RESULTS: It is shown from a five-point calibration curve that both parameters can be measured reliably within the range of 1.0 to 2.0 mg/mL for the major amino acids derived from the hydrolysis of human maternal milk or hair samples. The method was validated in terms of inter-day and inter user repeatability for both parameters for 14 amino acids. The amino acid percentage composition showed a good correlation with literature values. The method was applied to determine the variability in a population of lactating mothers and their infants. CONCLUSIONS: It has been established that delta(15)N values can be simultaneously determined for a complex mixture of amino acids at variable concentrations. It is shown that the percentage composition obtained correlates well with that obtained by calculation from the protein composition or from literature values. This procedure should provide a significant saving in analysis time, especially in those cases where the GC run-time is necessarily long. It allows the satisfactory determination of the variation within a sample population. PMID- 23681814 TI - Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for the characterization of functionalized carbon nanotubes. AB - RATIONALE: Functionalization of carbon nanotubes (CNTs) generates complex systems that require the development of suitable characterization protocols. New techniques have been explored, and existing analytical and spectroscopic methods to characterize functionalized CNTs have been adapted. Presently, chemical characterization of functionalized CNTs (f-CNTs) remains a difficult task. METHODS: Matrix-assisted laser desorption/ionization (MALDI) analysis is performed on f-MWCNT samples prepared via grafting or absorption of anti-oxidant (AO) molecules on both MWCNT-COOH and MWCNT-OH. Covalently functionalized MWCNTs were subjected to thermal degradation and/or hydrolysis reaction before analysis, whereas MWCNTs with a physical adsorption of the functionalizing molecules were directly spotted in the target sample. Noteworthy, in our approach f-MWCNTs constitute at the same time analyte and MALDI matrix. RESULTS: The identification of functionalizing AO molecules is ascertained after degradation or hydrolysis reactions in both MWCNT-COOH and MWCNT-OH grafted samples. Absorbed AO molecules, as well as organic impurities derived from grafting reactions, are also revealed by MALDI MS without any preliminary cleavage reaction. CONCLUSIONS: A simple MALDI-TOF mass spectrometry method permits to obtain the unambiguous discrimination between grafted or adsorbed functionalized molecules onto the surface of MWCNTs. PMID- 23681813 TI - The use of a xylosylated plant glycoprotein as an internal standard accounting for N-linked glycan cleavage and sample preparation variability. AB - RATIONALE: Traditionally, free oligosaccharide internal standards are used to account for variability in glycan relative quantification experiments by mass spectrometry. However, a more suitable internal standard would be a glycoprotein, which could also control for enzymatic cleavage efficiency, allowing for more accurate quantitative experiments. METHODS: Hydrophobic, hydrazide N-linked glycan reagents (both native and stable-isotope labeled) are used to derivatize and differentially label N-linked glycan samples for relative quantification, and the samples are analyzed by a reversed-phase liquid chromatography chip system coupled online to a Q-Exactive mass spectrometer. The inclusion of two internal standards, maltoheptaose (previously used) and horseradish peroxidase (HRP) (novel), is studied to demonstrate the effectiveness of using a glycoprotein as an internal standard in glycan relative quantification experiments. RESULTS: HRP is a glycoprotein containing a xylosylated N-linked glycan, which is unique from mammalian N-linked glycans. Thus, the internal standard xylosylated glycan could be detected without interference to the sample. Additionally, it was shown that differences in cleavage efficiency can be detected by monitoring the HRP glycan. In a sample where cleavage efficiency variation is minimal, the HRP glycan performs as well as maltoheptaose. CONCLUSIONS: Because the HRP glycan performs as well as maltoheptaose but is also capable of correcting and accounting for cleavage variability, it is a more versatile internal standard and will be used in all subsequent biological studies. Because of the possible lot-to-lot variation of an enzyme, differences in biological matrix, and variable enzyme activity over time, it is a necessity to account for glycan cleavage variability in glycan relative quantification experiments. PMID- 23681815 TI - Stable isotope probing of amino sugars--a promising tool to assess microbial interactions in soils. AB - RATIONALE: Bacteria and fungi are key protagonists of litter degradation in soils. Often they have to share common substrates, which has led to special interactions between both microbial groups. Due to the historical classification of bacteriology and mycology as two separate fields of microbial research, the understanding of their interactions in soils is scares, while it is crucial for a better understanding of nutrient recycling and carbon sequestration in soils. Therefore, a new approach to investigate fungal-bacterial interactions is proposed using stable isotope probing of their amino sugar biomarkers. METHODS: An agricultural soil, under different microbial inhibition treatments, was incubated for 21 days with (13)C-labeled plant residues. Residue respiration was determined by measuring the isotopic composition and concentration of the produced CO2, using an isotope ratio mass spectrometer coupled to a trace gas preparation unit. At several time points, amino sugars were extracted, after hydrolysis, from the incubated microcosms. Subsequently, (13)C-isotopic composition and concentration of the individual amino sugars was determined using liquid chromatography/isotope ratio mass spectrometry. RESULTS: When the bacterial community was inhibited, fungi showed an increased capacity to metabolize added plant residues indicating an antagonistic effect of bacteria towards fungi. Furthermore, the fungal community was able to take benefit of a larger portion of the residue, which indicates that this antagonism was at least partially due to interference competition. On the other hand, the inhibition of the fungal community appeared to have a very negative effect on the capacity of bacteria to metabolize added plant residues. Therefore, the bacterial community could be considered as playing a parasitic type role towards fungi during litter degradation. CONCLUSIONS: This newly developed methodology proved to be very useful for elucidating microbial interactions during plant residue degradation. PMID- 23681816 TI - Structural elucidation of a new sildenafil analogue using high-resolution Orbitrap mass spectrometry. AB - RATIONALE: One new phosphodiesterase type 5 (PDE-V) inhibitor, propoxyphenyl homohydroxysildenafil (PP-HHS), has been isolated from one health supplement, and analyzed using high-resolution Orbitrap mass spectrometry. High-resolution mass spectrometry (HRMS) is useful to elucidate unknown substances at low concentrations. METHODS: Two isolated compounds, propoxyphenyl thiohomohydroxysildenafil (PP-THHS) and propoxyphenyl homohydroxysildenafil (PP HHS), were infused into the Thermo Fischer Scientific LTQ Orbitrap XLTM hybrid FTMS system at a flow rate of 3 MUL per min. The high-resolution MS(2) spectra were acquired using different high-energy collision dissolution (HCD) mode; 40 V for PPT-HHS and 45 V for PP-HHS. The accurate mass measurement was assisted with the aid of Mass Frontier software, version 5.0. RESULTS: The fragmentation pattern of PP-HHS in the MS(2) spectrum is very similar to that of PP-THHS except the product ions at m/z 519, 501, 325, 299 and 283 are less than PP-THHS by 16 m/z units. This is a result of the replacement of sulfur atom by oxygen at the thiolactam moiety. All the mass errors are below 5.0 ppm. CONCLUSIONS: High resolution Orbitrap mass spectrometry is an alternative method to determine unknown compounds like PDE-V inhibitor analogues unambiguously by analyzing the product ions at high mass accuracy. PP-HHS is an unapproved drug and no pharmacological study has been reported. Hence, it could be harmful to unknowing consumers with undesirable side effects. PMID- 23681817 TI - Comparative metabolism and stability of andrographolide in liver microsomes from humans, dogs and rats using ultra-performance liquid chromatography coupled with triple-quadrupole and Fourier transform ion cyclotron resonance mass spectrometry. AB - RATIONALE: Andrographolide (AP) is a major active anti-inflammatory compound extracted from Andrographis paniculata Nees. The metabolism stability of AP is one of the key factors for its further development as a new drug candidate. In order to clarify the biotransformation of AP among species, a comparative investigation of its in vitro metabolic pathways in human, dog and rat liver microsomes was carried out. METHODS: In the present study, the in vitro metabolic profiles of AP using pooled human (HLMs), dog (DLMs) and rat (RLMs) liver microsomes were studied. The in vitro biotransformation including phase I and phase II incubation systems and metabolic stabilities of AP were studied for the first time. Ultra-performance liquid chromatography (UPLC) coupled with Fourier transform ion cyclotron resonance (FTICR) and tandem mass spectrometry (MS/MS) was used for identification of metabolites and quantification of AP. RESULTS: Eight phase I and five phase II metabolites resulted from dehydration, deoxygenation, hydrogenation and glucuronidation were tentatively identified by accurate mass measurement and MS/MS fragmentation behavior. A dehydration reaction was detected in all these incubation systems. Deoxy-AP and the related glucuronide metabolites were observed in HLMs only. Besides, the metabolic stabilities of AP in the three liver microsomes showed that the in vitro intrinsic clearance (CLint) of RLMs was much higher than that of HLMs and DLMs. CONCLUSIONS: A qualitative and semi-quantitative method was developed for the identification and metabolic stabilities of AP. The general metabolic profiles between three species were clarified. Significant species differences indicated a more cautious strategy for further pharmacokinetics research of AP in animal models. PMID- 23681819 TI - Octacoordinate metal carbonyls of scandium and yttrium: theoretical calculations and experimental observation. AB - RATIONALE: The transition metal carbonyls are among the most important complexes in coordination chemistry. The maximum coordination number in these complexes is seven. Because the cations Sc(+) and Y(+) have empty second outermost d orbital subshells, they can possibly bond eight CO ligands, forming the 18-electron d(10)s(2)p(6) noble gas configuration. The aim of this study is to determine whether the octacoordinate metal carbonyls of Sc(+) and Y(+) exist. METHODS: The structures and bonding of M(CO)n(+) (M = Sc and Y, n = 7-9) were studied using Density Functional Theory (DFT) calculations with the functionals of B3LYP and BP86. The cationic complexes from laser ablation of Sc and Y in CO gas were analyzed by time-of-flight mass spectrometry. RESULTS: The structures of M(CO)n(+) (M = Sc and Y, n = 7-9) and the bond dissociation energies for the last CO ligand in M(CO)n(+) (M = Sc and Y, n = 8 and 9) were obtained using DFT calculations. The products in the experiment for both metals include the series MO(CO)n(+), MO(H2O)(CO)n(+) and M(CO)n(+) (M = Sc or Y). The intensities of the MO(CO)n(+) and MO(H2O)(CO)n(+) ions change gradually with the number of CO ligands, while most M(CO)n(+) ions are very weak except for three intense ones, Sc(CO)7(+), Sc(CO)8(+) and Y(CO)8(+). CONCLUSIONS: Comparisons between the theoretical calculations and the experimental observations indicate that eight CO ligands are chemically bonded on the central atom in the singlet state of Sc(CO)8(+) ((1)A1 state of D(4d) symmetry) and the singlet and triplet states of Y(CO)8(+) ((1)A1 state of D(4d) symmetry and (3)A(1g) state of O(h) symmetry). The (1)A1 states of both Sc(CO)8(+) and Y(CO)8(+) have the 18-electron d(10)s(2)p(6) noble gas configuration. In M(CO)9(+) (M = Sc or Y), the ninth CO is weakly adsorbed on the external shell. PMID- 23681820 TI - alpha-Cyano-4-hydroxycinnamic acid, sinapinic acid, and ferulic acid as matrices and alkylating agents for matrix-assisted laser desorption/ionization time-of flight mass spectrometric analysis of cysteine-containing peptides. PMID- 23681818 TI - Comparison of high-performance liquid chromatography/tandem mass spectrometry and high-performance liquid chromatography/photo-diode array detection for the quantitation of carotenoids, retinyl esters, alpha-tocopherol and phylloquinone in chylomicron-rich fractions of human plasma. AB - RATIONALE: Bioavailability of essential lipophilic micronutrients and carotenoids is of utmost interest for human health, as the consumption of these compounds may help alleviate major nutritional deficiencies, cardiovascular disease, and cancer. High-performance liquid chromatography/photo-diode array detection (HPLC PDA) and high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) were compared for the quantitative analysis of alpha- and beta carotene, beta-cryptoxanthin, lutein, lycopene, alpha-tocopherol, phylloquinone, and several retinyl esters from chylomicron-containing triglyceride rich lipoprotein (TRL) fractions of human plasma obtained from two clinical trials. METHODS: After selecting an efficient extraction method for the analytes, both the HPLC/PDA and the HPLC/MS/MS methods were developed and several parameters validated using an HP 1200 series HPLC system interfaced with a HP 1200 series diode-array detector (Agilent Technologies, Santa Clara, CA, USA) and a QTRAP 5500 (AB Sciex, Foster City, CA, USA) via an atmospheric pressure chemical ionization (APCI) probe operated in positive ion mode. RESULTS: For lycopene, alpha- and beta-carotene, HPLC/MS/MS was up to 37 times more sensitive than HPLC PDA. PDA detection was shown to be up to 8 times more sensitive for lutein. MS/MS signals were enhanced by matrix components for lutein and beta-cryptoxanthin, as determined by referencing to the matrix-independent PDA signal. In contrast, matrix suppression was observed for retinyl palmitate, alpha-carotene, and beta carotene. Both detectors showed similar suitability for alpha-tocopherol, lycopene and retinyl palmitate (representing ~73% of total retinyl esters). MS/MS exclusively allowed the quantitation of minor retinyl esters, phylloquinone, and (Z)-lycopene isomers. CONCLUSIONS: HPLC/MS/MS was more sensitive than HPLC-PDA for six of the eight analytes and represents a powerful tool for the analysis of chylomicron samples and potentially other biological samples of limited sample size. When internal standards are available for the target carotenoid, employing MS/MS detection may reduce the necessary blood sample volume, which is particularly advantageous for minimizing risk and discomfort to human subjects during clinical studies. PMID- 23681821 TI - Collision-induced dissociation study of isosilychristin, a constituent of silymarin. PMID- 23681822 TI - Photoinduced curling of organic molecular crystal nanowires. PMID- 23681823 TI - Variability of histamine pharmacodynamic response in children with allergic rhinitis. AB - Histamine iontophoresis with laser Doppler monitoring (HILD) is a robust and dynamic surrogate for histamine microvasculature response. We characterized histamine pharmacodynamics in children using HILD. HILD was performed in 54 children with allergic rhinitis. A non-compartmental analysis and non-linear mixed-effects model with a linked effect PK/PD model was used to provide estimates for area under the effect curve (AUEC), maximal response over baseline (EffmaxNT), and time of EffmaxNT (Tmax). Data were placed in sub-groups by visualization of time vs. response relationships. ANOVA and regression analyses were used for sub-group comparisons. Three histamine response phenotypes were identified. One group demonstrated a hyper-responsive phenotype (higher Tmax, EffmaxNt and AUEC, P < .01). AUEC and EffmaxNT were more strongly associated in this group (r(2) = 0.86) than the entire cohort (r(2) = 0.64). These data demonstrate a hyper-responsive histamine phenotype via HILD. This finding is important to future pharmacologic studies of antihistamines. PMID- 23681824 TI - Evolutionary systems biology: what it is and why it matters. AB - Evolutionary systems biology (ESB) is a rapidly growing integrative approach that has the core aim of generating mechanistic and evolutionary understanding of genotype-phenotype relationships at multiple levels. ESB's more specific objectives include extending knowledge gained from model organisms to non-model organisms, predicting the effects of mutations, and defining the core network structures and dynamics that have evolved to cause particular intracellular and intercellular responses. By combining mathematical, molecular, and cellular approaches to evolution, ESB adds new insights and methods to the modern evolutionary synthesis, and offers ways in which to enhance its explanatory and predictive capacities. This combination of prediction and explanation marks ESB out as a research manifesto that goes further than its two contributing fields. Here, we summarize ESB via an analysis of characteristic research examples and exploratory questions, while also making a case for why these integrative efforts are worth pursuing. PMID- 23681825 TI - Heme-related gene expression signatures of meat intakes in lung cancer tissues. AB - Lung cancer causes more deaths worldwide than any other cancer. In addition to cigarette smoking, dietary factors may contribute to lung carcinogenesis. Epidemiologic studies, including the environment and genetics in lung cancer etiology (EAGLE), have reported increased consumption of red/processed meats to be associated with higher risk of lung cancer. Heme-iron toxicity may link meat intake with cancer. We investigated this hypothesis in meat-related lung carcinogenesis using whole genome expression. We measured genome-wide expression (HG-U133A) in 49 tumor and 42 non-involved fresh frozen lung tissues of 64 adenocarcinoma EAGLE patients. We studied gene expression profiles by high-versus low meat consumption, with and without adjustment by sex, age, and smoking. Threshold for significance was a false discovery rate (FDR) <= 0.15. We studied whether the identified genes played a role in heme-iron related processes by means of manually curated literature search and gene ontology-based pathway analysis. We found that gene expression of 232 annotated genes in tumor tissue significantly distinguished lung adenocarcinoma cases who consumed above/below the median intake of fresh red meats (FDR = 0.12). Sixty-three (~ 28%) of the 232 identified genes (12 expected by chance, P-value < 0.001) were involved in heme binding, absorption, transport, and Wnt signaling pathway (e.g., CYPs, TPO, HPX, HFE, SLCs, and WNTs). We also identified several genes involved in lipid metabolism (e.g., NCR1, TNF, and UCP3) and oxidative stress (e.g., TPO, SGK2, and MTHFR) that may be indirectly related to heme-toxicity. The study's results provide preliminary evidence that heme-iron toxicity might be one underlying mechanism linking fresh red meat intake and lung cancer. PMID- 23681826 TI - Laparoscopy-assisted vs. open total gastrectomy for advanced gastric cancer: long term outcomes and technical aspects of a case-control study. AB - BACKGROUND AND OBJECTIVES: An increasing number of studies comparing laparoscopy assisted distal gastrectomy and conventional open distal gastrectomy have been reported; the technical feasibility and clinical efficacy have been confirmed. However, few data are available to compare laparoscopy-assisted total gastrectomy (LATG) and open techniques for the treatment of advanced gastric cancer (AGC). The aim of this study is to compare the oncologic efficacy and long-term outcomes of LATG vs. open total gastrectomy (OTG) for AGC and to provide our experiences regarding these surgical difficulties as well. METHODS: Using data from a clinical database of all operations performed in our department by a special surgical team, we retrospectively analysed data from 117 cases of LATG and matched OTG performed between January 2004 and December 2010. This analysis was a case-control study in which patients in the two groups were matched according to tumour location, age, gender, BMI and TNM stage via a propensity score matching method. Patient clinical characteristics, lymph node retrieval, early postoperative complications, recurrence and long-term outcomes were compared. RESULTS: The demographics, preoperative data and characteristics of the tumour were similar in both groups. No significant differences were found in the LATG group compared with the OTG group with regard to the number of retrieved lymph nodes or distance from the proximal margin. Operating time was longer in the LATG group than in the OTG group (292.8 +/- 49.5 vs. 242.1 +/- 47.4, p < 0.05). Significant differences were found between LATG and OTG with regard to blood loss, postoperative hospitalisation and times of analgesic injection. The early postoperative complication rates in the LATG group were significantly lower than in the OTG group (11.1 vs. 16.3 %, p < 0.05). Operative mortality was zero in both groups. During a median follow-up of 61.2 (range, 6-84) months, the overall 5-year survival rates in the LATG group and OTG group were 49.3 and 46.5 %, respectively; there was no significant difference between the two groups (p = 0.756). CONCLUSION: Our results suggest that LATG is technically feasible for advanced gastric cancer patients and can yield good short- and long-term oncologic outcomes as compared with conventional OTG. PMID- 23681827 TI - A place for ultrastructural analysis of platelets in cerebral ischemic research. AB - It is well known that estrogen is neuroprotective through various mechanisms which suggest that sex hormone levels, thrombotic mechanisms, and inflammatory processes are strongly interconnected in predicting the outcome and consequences of cerebral ischemia. Because platelet ultrastructure is altered in conditions like thrombosis and associated with stroke, the question arises whether ultrastructural analyses of platelet morphology may provide further insight into the role of estrogen during ischemic insult. In the current study, a hyperglycemic modification to the two-vessel occlusion model for inducing experimental cerebral ischemia was employed, in order to correlate neural tissue integrity levels between three experimental groups to corresponding platelet ultrastructure so as to determine whether there is an association between cerebral ischemia and the presence of inflammatory or necrotic platelet ultrastructure. It is apparent in the results that under the influence of estrogen in cyclic or intact females, there is lesser neural tissue damage as well as a reduced degree of inflammation evident in platelet activation morphology when compared to males and acyclic or ovariectomized females. It is unmistakable that neural injury is closely shadowed, if not preceded, by inflammatory changes in the coagulation system, particularly manifested in platelet ultrastructure. It is therefore suggested that platelets may indeed be used successfully to follow the progression of events of cerebral ischemia and possibly assist in the assessment of treatment strategies and their effects on hemostasis. PMID- 23681828 TI - Enhanced photocatalytic performances of CeO2/TiO2 nanobelt heterostructures. AB - CeO2 /TiO2 nanobelt heterostructures are synthesized via a cost-effective hydrothermal method. The as-prepared nanocomposites consist of CeO2 nanoparticles assembled on the rough surface of TiO2 nanobelts. In comparison with P25 TiO2 colloids, surface-coarsened TiO2 nanobelts, and CeO2 nanoparticles, the CeO2 /TiO2 nanobelt heterostructures exhibit a markedly enhanced photocatalytic activity in the degradation of organic pollutants such as methyl orange (MO) under either UV or visible light irradiation. The enhanced photocatalytic performance is attributed to a novel capture-photodegradation-release mechanism. During the photocatalytic process, MO molecules are captured by CeO2 nanoparticles, degraded by photogenerated free radicals, and then released to the solution. With its high degradation efficiency, broad active light wavelength, and good stability, the CeO2 /TiO2 nanobelt heterostructures represent a new effective photocatalyst that is low-cost, recyclable, and will have wide application in photodegradation of various organic pollutants. The new capture photodegradation-release mechanism for improved photocatalysis properties is of importance in the rational design and synthesis of new photocatalysts. PMID- 23681829 TI - Potentials for food waste minimization and effects on potential biogas production through anaerobic digestion. AB - Several treatment alternatives for food waste can result in both energy and nutrient recovery, and thereby potential environmental benefits. However, according to the European Union waste management hierarchy, waste prevention should be the prioritized strategy to decrease the environmental burdens from all solid waste management. The aim of the present study was therefore to investigate the potential for food waste minimization among Swedish households through an investigation of the amount of avoidable food waste currently disposed of. A further aim was to investigate the effect on the national biogas production potential through anaerobic digestion of food waste, considering minimization potentials. A method for waste composition analyses of household food waste, where a differentiation between avoidable and unavoidable food waste is made, was used in a total of 24 waste composition analyses of household waste from Swedish residential areas. The total household food waste generation reached 3.4 kg (household and week)(-1), on average, of which 34% is avoidable. The theoretical methane (CH4) potential in unavoidable food waste reached 442 Ndm(3) (kg VS)(-1) or 128 Nm(3) tonne(-1) wet waste, while the measured (mesophilic CH4 batch tests) CH4 production reached 399 Ndm(3) (kg VS)(-1), which is lower than several previous assessments of CH4 production from household food waste. According to this study the combination of a decrease in food waste generation-in case of successful minimization-and decreased CH4 production from unavoidable food waste will thus result in lower total potential energy recovery from household food waste through anaerobic digestion CH4 potential than previously stated. PMID- 23681830 TI - Consensus on hypotonia via Delphi process. AB - OBJECTIVES: To generate consensus on the assessment of hypotonia in the pediatric population, more specifically with respect to the clinical characteristics and first line tests and methods to be used to assess these characteristics. METHODS: Consensus methodology was used. A sample of experts was recruited based on specific inclusion criteria. A two-round Delphi process was conducted electronically, which was based on a prior literature appraisal and survey amongst a cohort of clinicians. An a priori threshold margin error of 70 +/- 5 % was pre-determined, with Cronbach's alpha measuring the level of internal consistency. RESULTS: The 2-round iteration was useful in establishing consensus on clinical characteristics and tests /methods in the assessment of low muscle tone in the pediatric population (2-5 y age band). Twenty-four clinical characteristics, organized into 11 clusters were determined as relevant for inclusion. For each characteristic, one test (as a first line assessment method) had been identified with consensus after two rounds. Additionally, consensus on the importance of collateral sources was determined. The ranking order of importance of characteristics however revealed variations. CONCLUSIONS: The results of this study have displayed that Delphi, if executed with available guidelines, may be a useful technique in moving towards consensus on issues that may be contentious and have assisted in providing initial data to move towards consensus on the assessment of hypotonia in children. PMID- 23681831 TI - Neonatal meningitis and sepsis by Chryseobacterium indologenes: a rare and resistant bacterium. AB - Early neonatal meningitis with non-fermenting Gram negative bacilli (NFGNB) is rare, and whenever it occurrs, inanimate environment is usually implicated as the source. The authors report a case of neonatal meningitis and sepsis with Chryseobacterium indologenes, a rare non fermenting Gram negative bacterium with unusual antimicrobial susceptibility. Despite resistance to all the beta lactams, carbapenems and aminoglycosides, therapy with ciprofloxacin led to a favorable outcome. PMID- 23681832 TI - Irritant contact dermatitis due to "Kajal". PMID- 23681833 TI - Gamma interferon receptor defect presenting as recurrent tuberculosis. AB - Failure of response to therapy in childhood tuberculosis may be due to resistance, paradoxical response or immunodeficiency. Interferon-gamma (IFNgamma) plays a major role during host defense against Mycobacterium tuberculosis (Mtb). An 8-y-old boy presented with fever, hepatosplenomegaly and parotid abscess. He had been earlier treated for BCG adenitis in infancy and at 5 y for TB osteomyelitis of iliac bone and recovered. Investigations confirmed disseminated Mycobacterium Avium Intracellulare infection. He was investigated for immunodeficiency because of recurrent mycobacterial disease and a partial defect of gamma-interferon receptor was identified. He required a 2 y course of therapy with a 7 drug regimen and recovered. The authors report this case because of its rarity and to highlight the need to consider gamma-interferon receptor defect in the presence of recurrent tuberculosis (TB) and also review the options for therapy. PMID- 23681834 TI - A rare case of MRI negative pituitary germinoma. PMID- 23681835 TI - A clinical pharmacokinetic study comparing two azelastine hydrochloride nasal formulations in a single-dose design. AB - Azelastine hydrochloride is a potent second-generation antihistamine, available in Europe and the USA as a nasal spray formulation for the treatment of allergic rhinitis symptoms. GlaxoSmithKline (GSK) Consumer Healthcare has developed a new nasal formulation of azelastine hydrochloride. The present study was aimed at comparing the clinical pharmacokinetic profiles and assessing the bioequivalence of the new formulation of azelastine hydrochloride with a marketed reference nasal spray product. This was a randomized, two-way crossover, two-stage, single dose pharmacokinetic study with 2 weeks washout between the two treatment periods. A dosage of 0.28 mg of the test and reference products was administered as a single dose to healthy volunteers according to the crossover design. Twenty three subjects (15 subjects from stage 1 and 8 subjects from stage 2) were enrolled in the study. Adjusted mean values for AUC0-t were 1,526.8 h pg/mL for the test drug and 1,441.5 h pg/mL for the reference drug; for C max the values were 61.59 pg/mL for the test drug and 58.21 pg/mL for the reference drug. The 94.12 % CI of geometric mean ratios (test/reference) were 0.99-1.13 and 0.95-1.18 for AUC0-t and C max. This met the predefined criteria for bioequivalence between test and reference drugs. Secondary pharmacokinetic parameters for azelastine and for the metabolite desmethyl azelastine, AUC(0-infinity) and t max, were numerically similar between the two study treatments. Both test and reference azelastine hydrochloride formulations were well tolerated at single dose. This study demonstrated the bioequivalence between the new azelastine hydrochloride nasal spray formulation and the marketed reference Allergodil((r)) after single dose administration. PMID- 23681837 TI - Rhodium(I)-catalyzed enantioselective hydrogenation of substituted acrylic acids with sterically similar beta,beta-diaryls. PMID- 23681836 TI - Increased elimination of paclitaxel by magnesium isoglycyrrhizinate in epithelial ovarian cancer patients treated with paclitaxel plus cisplatin: a pilot clinical study. AB - Magnesium isoglycyrrhizinate (MI) has been complementarily used for restoring the hepatic impairments caused by taxol plus platinum based chemotherapies in China. Due to the hepatic dependence of paclitaxel elimination, this pilot clinical study aimed to investigate the influence of MI on the pharmacokinetics of paclitaxel in epithelial ovarian cancer patients. During the standard chemotherapy of intravenous paclitaxel (125 mg/m(2) infused over a 3-h period) and intraperitoneal cisplatin (60 mg/m(2)) for patients with FIGO stage II epithelial ovarian cancer, 9 each of total 18 patients were respectively treated with intravenous MI (100 mg) or vehicle control for 4 days. Plasma paclitaxel was analyzed by HPLC and the pharmacokinetic parameters were calculated with non compartmental analysis. The hematological, hepatic and renal status was monitored before and 3 days after paclitaxel administration. It was observed the terminal t 1/2 and MRT of paclitaxel were significantly (p = 0.002 and 0.001) reduced by MI, respectively, from 11.0 +/- 2.2 and 5.6 +/- 1.0 h to 7.7 +/- 1.7 and 4.0 +/- 0.3 h. Hematological toxicity indicated by platelet count and hepatic events marked with ALT, AST and gamma-GT were significant in both groups. In spite of the insignificance of decreased system exposure of paclitaxel and recovered hepatic function by MI, they did correlate with each other. It was therefore deduced that the liver toxicities of paclitaxel plus cisplatin chemotherapy potentially decrease hepatic elimination and increase system exposure of paclitaxel, and the recovery of liver function by MI helps to restore hepatic clearance of paclitaxel. The clinical significance of this pharmacokinetic interaction requires further studies with larger population size. PMID- 23681838 TI - [Muscle activation during therapeutic climbing exercises]. AB - BACKGROUND: Therapeutic climbing exercises are employed for the treatment of shoulder- and knee-joint injuries. However, there is a void in the literature regarding muscle activation levels during the performance of these exercises. Thus, the purpose of this study was to investigate differences in muscle activation during therapeutic climbing exercises depending on the degree of task difficulty. PARTICIPANTS/MATERIAL AND METHODS: A sample of 10 healthy subjects (sex: 4 females, 6 males; age: 27 +/- 3 years; climbing experience: 5 +/- 3 years) performed three shoulder girdle (i. e., wide shoulder pull, narrow shoulder pull, shoulder row) and two leg extensor (i. e., ascending frontal, ascending sidewards) exercises. Electromyographic (EMG) data were recorded on the right side for eleven muscles and then normalised using the maximum voluntary contractions for each muscle. RESULTS: With increasing task difficulty, muscle activity in all but one muscle (i. e., m. trapezius ascendens) increased significantly for the three shoulder girdle exercises. For the two leg extensor exercises, an increase in task difficulty produced a tendency towards yet not significantly higher muscle activity. CONCLUSION: Shoulder row was the most effective therapeutic climbing exercise in the ability to activate muscles while showing the highest EMG signals. The absence of significant differences in muscle activity between the two leg extensor exercises indicates their equivalent use for muscle activation during therapy. PMID- 23681839 TI - Three-dimensional fetal echocardiography for prediction of postnatal surgical approach in double outlet right ventricle: a pilot study. AB - OBJECTIVES: To examine the feasibility of reconstructing three-dimensional (3D) echocardiographic views in fetuses with double outlet right ventricle, which might enhance prognostication with respect to the postnatal surgical approach. METHODS: This was a retrospective blinded observational study. Our database was reviewed from January 2007 to June 2011 to identify fetuses with usual atrial arrangement, concordant atrioventricular connections, double outlet right ventricle and relatively balanced left and right ventricular size. Six fetuses, in which there was an intention to treat, were included. RESULTS: In all six cases, we identified important features, including location of the ventricular septal defect and its relation to the atrioventricular valves and great arteries. The postnatal surgical approach was predicted accurately in each case. CONCLUSION: In this group of fetuses with double outlet right ventricle, detailed evaluation by 3D fetal echocardiography enhanced visualization of the anatomy, leading to accurate prediction of the type of surgical repair. Prospective validation in a large cohort of fetuses is warranted. PMID- 23681840 TI - Evaluation of radionuclide concentrations and associated radiological hazard indexes in building materials used in Egypt. AB - Radionuclide concentrations of 226Ra, 232Th and 40K in different types of building materials used in Egypt were measured using gamma-ray spectroscopy. The results showed relatively moderate radionuclide concentrations for all samples except granite, which showed extremely high concentrations of 78.75 +/- 2.36, 2.82 +/- 0.11 and 2.37 +/- 0.07 kBq kg-1 for 226Ra, 232Th and 40K, respectively. The radiological hazard indexes of radium equivalent activity (Raeq), external hazard index (Hex) and internal hazard index (Hin), due to the presence of those radionuclides in the investigated building materials, were calculated. The released radon from the selected samples was measured using the AlphaGUARD radon monitor in order to use its value to calculate the radon emanation coefficient and the radon exhalation rate. The alpha equivalent dose (dose from indoor radon generated from building materials) was calculated using the measured values of the radium concentration and the radon emanation coefficient. PMID- 23681841 TI - Uptake kinetics and nanotoxicity of silica nanoparticles are cell type dependent. AB - In this study, it is shown that the cytotoxic response of cells as well as the uptake kinetics of nanoparticles (NPs) is cell type dependent. We use silica NPs with a diameter of 310 nm labeled with perylene dye and 304 nm unlabeled particles to evaluate cell type-dependent uptake and cytotoxicity on human vascular endothelial cells (HUVEC) and cancer cells derived from the cervix carcinoma (HeLa). Besides their size, the particles are characterized concerning homogeneity of the labeling and their zeta potential. The cellular uptake of the labeled NPs is quantified by imaging the cells via confocal microscopy in a time dependent manner, with subsequent image analysis via a custom-made and freely available digital method, Particle_in_Cell-3D. We find that within the first 4 h of interaction, the uptake of silica NPs into the cytoplasm is up to 10 times more efficient in HUVEC than in HeLa cells. Interestingly, after 10 or 24 h of interaction, the number of intracellular particles for HeLa cells by far surpasses the one for HUVEC. Inhibitor studies show that these endothelial cells internalize 310 nm SiO2 NPs via the clathrin-dependent pathway. Remarkably, the differences in the amount of taken up NPs are not directly reflected by the metabolic activity and membrane integrity of the individual cell types. Interaction with NPs leads to a concentration-dependent decrease in mitochondrial activity and an increase in membrane leakage for HUVEC, whereas HeLa cells show only a reduced mitochondrial activity and no membrane leakage. In addition, silica NPs lead to HUVEC cell death while HeLa cells survive. These findings indicate that HUVEC are more sensitive than HeLa cells upon silica NP exposure. PMID- 23681842 TI - Effect of including cancer mortality on the cost-effectiveness of aspirin for primary prevention in men. AB - BACKGROUND: Recent data suggest that aspirin may be effective for reducing cancer mortality. OBJECTIVE: To examine whether including a cancer mortality-reducing effect influences which men would benefit from aspirin for primary prevention. DESIGN: We modified our existing Markov model that examines the effects of aspirin among middle-aged men with no previous history of cardiovascular disease or diabetes. For our base case scenario of 45-year-old men, we examined costs and life-years for men taking aspirin for 10 years compared with men who were not taking aspirin over those 10 years; after 10 years, we equalized treatment and followed the cohort until death. We compared our results depending on whether or not we included a 22 % relative reduction in cancer mortality, based on a recent meta-analysis. We discounted costs and benefits at 3 % and employed a third party payer perspective. MAIN MEASURE: Cost per quality-adjusted life year (QALY) gained. KEY RESULTS: When no effect on cancer mortality was included, aspirin had a cost per QALY gained of $22,492 at 5 % 10-year coronary heart disease (CHD) risk; at 2.5 % risk or below, no treatment was favored. When we included a reduction in cancer mortality, aspirin became cost-effective for men at 2.5 % risk as well (cost per QALY, $43,342). Results were somewhat sensitive to utility of taking aspirin daily; risk of death after myocardial infarction; and effects of aspirin on stroke, myocardial infarction, and sudden death. However, aspirin remained cost-saving or cost-effective (< $50,000 per QALY) in probabilistic analyses (59 % with no cancer effect included; 96 % with cancer effect) for men at 5 % risk. CONCLUSIONS: Including an effect of aspirin on cancer mortality influences the threshold for prescribing aspirin for primary prevention in men. If such an effect is real, many middle-aged men at low cardiovascular risk would become candidates for regular aspirin use. PMID- 23681843 TI - Putting the pieces together: necrolytic migratory erythema and the glucagonoma syndrome. AB - Glucagonomas are slow-growing, rare pancreatic neuroendocrine tumors. They may present with paraneoplastic phenomena known together as the "glucagonoma syndrome." A hallmark sign of this syndrome is a rash known as necrolytic migratory erythema (NME). In this paper, the authors describe a patient with NME and other features of the glucagonoma syndrome. The diagnosis of this rare tumor requires an elevated serum glucagon level and imaging confirming a pancreatic tumor. Surgical and medical treatment options are reviewed. When detected early, a glucagonoma is surgically curable. It is therefore imperative that clinicians recognize the glucagonoma syndrome in order to make an accurate diagnosis and refer for treatment. PMID- 23681844 TI - Opioid prescribing: can the art become more science? PMID- 23681846 TI - Isolated median neuropathy as the first symptom of leprosy. AB - INTRODUCTION: Focal peripheral neuropathy of the median nerve is mainly caused by a traumatic event or pressure, but it may also be produced by systemic illnesses. Among the latter, leprosy is a rare cause. METHODS: Six cases of isolated median neuropathy as the first sign of leprosy were selected from patients with an exclusively neurological complaint as the initial symptom. The patients, evaluated at the National Leprosy Reference Center in Rio de Janeiro, Brazil, followed routine and specialized procedures. RESULTS: Three of the patients had pure neural leprosy, and 3 had skin lesions. Clinical median nerve function impairment was confirmed by neurophysiological testing and histopathology. Both mononeuritis and mononeuritis multiplex were observed. CONCLUSIONS: This case series demonstrates an additional form of presentation of leprosy, which, if not diagnosed and treated in time, may lead to permanent disability. PMID- 23681847 TI - Cdc20 turnover rate: a key determinant in cancer patient response to anti-mitotic therapies? PMID- 23681848 TI - Concise review: two negative feedback loops place mesenchymal stem/stromal cells at the center of early regulators of inflammation. AB - Recent data demonstrated that MSCs can be activated by proinflammatory signals to introduce two negative feedback loops into the generic pathway of inflammation. In one loop, the activated MSCs secrete PGE2 that drives resident macrophages with an M1 proinflammatory phenotype toward an M2 anti-inflammatory phenotype. In the second loop, the activated MSCs secrete TSG-6 that interacts with CD44 on resident macrophages to decrease TLR2/NFkappa-B signaling and thereby decrease the secretion of proinflammatory mediators of inflammation. The PGE2 and TSG-6 negative feedback loops allow MSCs to serve as regulators of the very early phases of inflammation. These and many related observations suggest that the MSC like cells found in most tissues may be part of the pantheon of cells that protect us from foreign invaders, tissue injury, and aging. PMID- 23681850 TI - Cyclooxygenase-2 expression in lung in patients with congenital heart malformations and pulmonary arterial hypertension. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a cause of morbidity in patients with congenital heart disease (CHD). It has been hypothesized that prostanoides participate in the development of PAH. The aim of this study was to show the potential expression of cyclooxygenase-2 (COX-2) in patients with CHD and PAH. PATIENTS AND METHODS: We included patients with isolated left-to-right shunts undergoing lung biopsy before or concomitantly with cardiac surgery between 2004 and 2009.For determination of COX-2 expression, histological and immunohistochemistry analyses as well as quantitative polymerase chain reaction (qPCR) were performed. RESULTS: We were able to show COX-2 protein overexpression in the lung tissue of children with CHD and PAH. Furthermore, we showed an increase in COX-1 gene expression and an even stronger induction of COX-2 by using qPCR and immunohistochemistry. CONCLUSIONS: We examined the expression of COX-2 in lung tissue from patients with CHD and PAH. We showed that COX-2 is expressed in diseased lung tissue, indicating a relationship between COX-2 and vascular remodeling in pulmonary arteries in CHD. PMID- 23681849 TI - Assessing health-related quality of life in patients with heart failure: a systematic, standardized comparison of available measures. AB - To systematically evaluate available health-related quality of life (HRQL) instruments for use in patients with heart failure (HF). Seven HF-specific HRQL questionnaires and associated studies of their metric properties were identified by systematic review: the Chronic Heart Failure Assessment Tool, the Cardiac Health Profile congestive heart failure, the Chronic Heart Failure Questionnaire (CHFQ), the Kansas City Cardiomyopathy Questionnaire (KCCQ), the Left Ventricular Disease Questionnaire (LVDQ), the Minnesota Living with Heart Failure Questionnaire (MLHFQ), and the Quality of Life in Severe Heart Failure Questionnaire. Each instrument was assessed by four experts using a standardized tool for evaluating patient-reported outcomes (EMPRO; scores from 0 to 100). Four questionnaires were given adequate scores (median >50) for the attribute "conceptual model." The LVDQ had the highest rated median for "reliability" (72.8). The CHFQ, the KCCQ, and the MLHFQ all got reasonable scores for "validity" (from 54.4 to 76.4). The reviewers rated the KCCQ the highest in terms of "sensitivity to change" (median 94.4). Only the CHFQ (50.0) and the KCCQ (72.2) received adequate scores for the "interpretability" attribute. The most highly rated instruments based on the overall EMPRO score were the KCCQ (64.4) and the MLHFQ (60.7), followed by the CHFQ (59.2). Based on the first systematic and reliable expert-based evaluation of available HF-specific HRQL questionnaires, the evidence seems to support the choice of the KCCQ, the MLHFQ, and the CHFQ over the others, which require further research on metric properties. PMID- 23681851 TI - Rapid screening for potential epitopes reactive with a polycolonal antibody by solution-phase H/D exchange monitored by FT-ICR mass spectrometry. AB - The potential epitopes of a recombinant food allergen protein, cashew Ana o 2, reactive to polyclonal antibodies, were mapped by solution-phase amide backbone H/D exchange (HDX) coupled with Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). Ana o 2 polyclonal antibodies were purified in the serum from a goat immunized with cashew nut extract. Antibodies were incubated with recombinant Ana o 2 (rAna o 2) to form antigen:polyclonal antibody (Ag:pAb) complexes. Complexed and uncomplexed (free) rAna o 2 were then subjected to HDX MS analysis. Four regions protected from H/D exchange upon pAb binding are identified as potential epitopes and mapped onto a homologous model. PMID- 23681852 TI - A MASSive laboratory tour. An interactive mass spectrometry outreach activity for children. AB - It is imperative to fascinate young children at an early stage in their education for the analytical sciences. The exposure of the public to mass spectrometry presently increases rapidly through the common media. Outreach activities can take advantage of this exposure and employ mass spectrometry as an exquisite example of an analytical science in which children can be fascinated. The presented teaching modules introduce children to mass spectrometry and give them the opportunity to experience a modern research laboratory. The modules are highly adaptable and can be applied to young children from the age of 6 to 14 y. In an interactive tour, the students explore three major scientific concepts related to mass spectrometry; the building blocks of matter, charged particle manipulation by electrostatic fields, and analyte identification by mass analysis. Also, the students carry out a mass spectrometry experiment and learn to interpret the resulting mass spectra. The multistage, inquiry-based tour contains flexible methods, which teach the students current-day research techniques and possible applications to real research topics. Besides the scientific concepts, laboratory safety and hygiene are stressed and the students are enthused for the analytical sciences by participating in "hands-on" work. The presented modules have repeatedly been successfully employed during laboratory open days. They are also found to be extremely suitable for (early) high school science classes during laboratory visit-focused field trips. PMID- 23681855 TI - The third immigrant disease. PMID- 23681856 TI - Scientific publishing needs disruption. PMID- 23681854 TI - Delimiting species using single-locus data and the Generalized Mixed Yule Coalescent approach: a revised method and evaluation on simulated data sets. AB - DNA barcoding-type studies assemble single-locus data from large samples of individuals and species, and have provided new kinds of data for evolutionary surveys of diversity. An important goal of many such studies is to delimit evolutionarily significant species units, especially in biodiversity surveys from environmental DNA samples. The Generalized Mixed Yule Coalescent (GMYC) method is a likelihood method for delimiting species by fitting within- and between-species branching models to reconstructed gene trees. Although the method has been widely used, it has not previously been described in detail or evaluated fully against simulations of alternative scenarios of true patterns of population variation and divergence between species. Here, we present important reformulations to the GMYC method as originally specified, and demonstrate its robustness to a range of departures from its simplifying assumptions. The main factor affecting the accuracy of delimitation is the mean population size of species relative to divergence times between them. Other departures from the model assumptions, such as varying population sizes among species, alternative scenarios for speciation and extinction, and population growth or subdivision within species, have relatively smaller effects. Our simulations demonstrate that support measures derived from the likelihood function provide a robust indication of when the model performs well and when it leads to inaccurate delimitations. Finally, the so-called single-threshold version of the method outperforms the multiple threshold version of the method on simulated data: we argue that this might represent a fundamental limit due to the nature of evidence used to delimit species in this approach. Together with other studies comparing its performance relative to other methods, our findings support the robustness of GMYC as a tool for delimiting species when only single-locus information is available. PMID- 23681857 TI - Prevalence of use of complementary and alternative medicine (CAM) by patients/consumers in the UK: systematic review of surveys. AB - This systematic review aimed to estimate the prevalence of use of complementary and alternative medicine (CAM) in the UK. Five databases were searched for English language, peer-reviewed surveys published between 1 January 2000 and 7 October 2011. In addition, relevant book chapters and files from our own departmental records were searched by hand. Eighty-nine surveys were included, with a total of 97,222 participants. Most studies were of poor methodological quality. Across surveys on CAM in general, the average one-year prevalence of use of CAM was 41.1% and the average lifetime prevalence was 51.8%. In methodologically sound surveys, the equivalent rates were 26.3% and 44%, respectively. In surveys with response rates >70%, average one-year prevalence was nearly threefold lower than in surveys with response rates between 21% and 50%. Herbal medicine was the most popular CAM, followed by homeopathy, aromatherapy, massage and reflexology. Many patients and consumers in the UK use CAM; healthcare professionals should therefore responsibly advise their patients about the use of CAM. PMID- 23681858 TI - Doctors and others: reflections on the first Francis Report. PMID- 23681859 TI - Erectile dysfunction in general medicine. AB - Erectile dysfunction (ED) affects millions of men worldwide with implications that go far beyond sexual activity. ED is now recognised as an early marker of cardiovascular disease, diabetes mellitus (DM) and depression. The risk factors that are associated with ED (sedentary lifestyle, obesity, smoking, hypercholesterolaemia and the metabolic syndrome) are very similar to those for cardiovascular disease (CVD). Arguably, the awareness of ED as a symptomatic entity in the post-ViagraTM age is on the rise. Nevertheless, ED is commonly missed when evaluating patients in the hospital setting, either because of lack of consideration or awareness, or through simple embarrassment (of both clinician and patient). This article provides an overview of the aetiology, assessment and importance of ED and hopes to promote its consideration in day-to-day clinical practice. PMID- 23681860 TI - Fever of unknown origin as the first manifestation of colonic pathology. AB - Fever of unknown origin (FUO) is an entity caused by more than 200 diseases. Haematologic neoplasms are the most common malignant cause of FUO. Fever as a first symptom of colonic tumour pathology, both benign and malignant, is a rare form of presentation. Our work is a descriptive study of a series of 23 patients with colonic tumoral pathology who presented with fever of unknown origin. The mean age was 67.6 years; 56.5% of patients were men and 43.5% were women. Primary malignant neoplasia was the most common diagnosis. Blood cultures were positive in 45% of the samples. Coagulase-negative staphylococci were the most common cause of bacteraemia. Nine of 10 faecal occult blood tests performed were positive. Fever secondary to colon neoplasms, both benign and malignant, usually presents with a bacteraemic pattern, with positive results for blood-culture tests in a high percentage of cases. PMID- 23681861 TI - Are patients admitted to emergency departments with regular supraventricular tachycardia (SVT) treated appropriately? AB - Regular supraventricular tachycardia (SVT) is frequently encountered in clinical practice. Guidelines are available from the National Service Framework (NSF) for the treatment of patients attending emergency departments (ED) with SVT. These recommend a thyroid-function test (TFT) and arrhythmia electrocardiography (ECG), and referral to a heart-rhythm specialist on discharge. Hospital admission is rarely required. In our multicentre study, we examined the implementation of these guidelines among patients attending the ED with SVT. Only 34% of patients had specialist referrals, with an average wait of 50.3 days (the majority of delays resulted from referral requests from general practitioners). A history of previous SVT, the mode of tachycardia termination, patient age and/or comorbidities were similar for the 27 (23.5%) patients who were admitted overnight. Of these, 15 (13%) of the total 115 patients who attended ED with regular SVT were referred for Holter monitoring despite having ECGs demonstrating arrhythmia. Low referral rates, unnecessary investigations and admissions indicate a need for improvement for better patient care and to minimise healthcare costs. We have formulated a standard operating procedure, which will be available via the College of Emergency Medicine website. PMID- 23681862 TI - Importance of the correct diagnosis of opioid-induced respiratory depression in adult cancer patients and titration of naloxone. AB - Opioids can induce respiratory depression by invoking a centrally mediated decrease in involuntary respiratory rate, which in severe cases can cause a decrease in oxygen saturation. If respiratory depression is opioid induced, both low respiratory rate and low oxygen saturation will be present. If this is the case, oxygenation, rousing by verbal and physical stimulation and decreasing the opioid dose should be tried first. Naloxone, an opioid antagonist, should be avoided if at all possible but, if essential, titrate slowly to respiratory function administering 20-100 ug intravenously every two minutes. If used as a bolus for a patient on long-term opioids for chronic cancer pain, then refractory pain and symptomatic opioid withdrawal can result. PMID- 23681863 TI - Legionella pneumonia cases over a five-year period: a descriptive, retrospective study of outcomes in a UK district hospital. AB - As the recent outbreaks in Edinburgh and Camarthen, UK, have shown, Legionella pneumonia (LP) remains a significant public health problem, which is not only confined to those who have travelled abroad. In both outbreaks and sporadic cases, diagnosis can go unrecognised. We reviewed the demographics, comorbidities, diagnosis, treatment and clinical outcome of LP cases over five years in a district general hospital in northwest England. Over half of LP cases were UK acquired and 'classic' clinical features were common. Clinical criteria for diagnosing LP were confirmed, but few sputum samples were sent to reference laboratories, limiting further essential epidemiological mapping of UK cases. Following current UK community-acquired pneumonia guidance would have missed nearly one quarter of LP cases in our series, potentially leading to further morbidity and mortality. PMID- 23681864 TI - Managing hyperglycaemic emergencies: an illustrative case and review of recent British guidelines. AB - Diabetic ketoacidosis and hyperosmolar hyperglycaemic syndrome are important hyperglycaemic emergencies seen in patients with diabetes. Occasionally, differentiation between the two conditions can be difficult. We present the case of a patient whose hyperglycaemic emergency was managed in a way that could have adversely influenced the outcome. We also discuss important aspects of the new Joint British Diabetes Societies Guidelines on the management of hyperglycaemic emergencies. PMID- 23681865 TI - Now I know what I don't know: how to reform the foundation years to fit 21st century medicine. AB - The two-year Foundation Programme was introduced in the UK as a structured way to deal with the lack of training, support and difficulties with career progression associated with the old senior house office (SHO) grade. Although it provides a clear curriculum and structure for career progression, there is growing dissatisfaction among participants about the difference between the aspirations of the Foundation Programme and the realities of working as a foundation doctor. In particular, the erosion of the traditional team structure, difficulties with the system of assessment and a feeling that the career structure is now too rigid has led to a situation where doctors are being forced to choose their specialty training too early and often with little experience in the specialty. To what extent is the Foundation Programme fit for purpose? This will be considered together with suggestions for future reform. PMID- 23681866 TI - Performance at MRCP(UK): when should trainees sit examinations? AB - This paper analyses candidate performance in the three components of the MRCP(UK) examination to establish when they are most likely to pass. Using data from the 2010 and 2011 MRCP(UK) examinations, pass rates of candidates who gained their primary medical qualification (PMQ) in 2005 or later were analysed. Results from a total of 22,827 candidates were included in the study: 12,517 (54.8%) from Part 1, 5,545 (24.3%) from Part 2 written and 4,765 (20.9%) from the Part 2 practical assessment of clinical examination skills (PACES). The results show that candidates are more likely to pass Part 1 and Part 2 written 12-24 months after graduation and to pass Part 2 PACES 25-36 months after graduation. When we consider the training programme for physicians in the UK, successful candidates are likely to be in foundation programmes or early core or specialty training when they achieve success. At the moment, some candidates are dissuaded from taking the examination during their foundation programme, but our data show that their likelihood of success is highest during this period of training. The analysis also shows that for candidates who fail their first attempt, delaying their next attempt by one diet significantly increases the likelihood of them passing at their next attempt. PMID- 23681867 TI - Recent advancements in the drug treatment of endocrine diseases. AB - Recent years have seen several advances in the management of endocrine diseases. These include novel drugs developed as a consequence of better understanding of the pathophysiology of endocrine conditions, as well as improved delivery methods for existing drugs. In this article, we summarise recent studies evaluating several drugs used in the treatment of endocrine disorders. PMID- 23681868 TI - Endocrine disease in pregnancy. AB - Endocrine disease is common in pregnancy. Most pre-existing endocrine conditions, if well controlled, have little impact on maternal or fetal morbidity. Uncontrolled endocrine conditions in pregnancy, whether poorly controlled pre conception or newly diagnosed, are associated with a variety of adverse fetal outcomes and maternal morbidity. Also, transplacental transfer of maternal antibodies can have adverse fetal or neonatal consequences. The initial diagnosis of many conditions is hindered by the overlap of symptoms that occur in normal pregnancy and those that suggest specific endocrine pathologies, and also by the changes in reference ranges for common biochemical measurements that occur as a result of physiological changes in pregnancy. This article summarises the common endocrine disorders in pregnancy and describes how pregnancy can alter their investigation, treatment and ongoing management, as well as the potential effects on the fetus. PMID- 23681869 TI - Hypertension - a clinical update for physicians. PMID- 23681870 TI - Neutropenic sepsis: management and complications. PMID- 23681871 TI - Myeloproliferative neoplasms. AB - The myeloproliferative neoplasms that are associated with the JAK2 mutation are a heterogeneous group of disorders. The additional mutations that result in the clinical phenotype are still the subject of research. As more than one mutation is involved, and as JAK2 has a necessary physiological role (unlike BCR-ABL), the development of targeted therapy remains a challenge. Although new drugs are being developed, treatment at present is predominantly with agents that have been in use for many years. An understanding of the need to control the thrombotic risk has, however, led to improved survival rates such that ET and PV can be seen as chronic diseases. PMID- 23681872 TI - Anaemia of chronic disease. PMID- 23681873 TI - Uses and abuses of fresh-frozen plasma for the prophylaxis of bleeding. PMID- 23681874 TI - Uses and abuses of fresh frozen plasma for the treatment of bleeding. PMID- 23681877 TI - Not your typical pneumonia. PMID- 23681878 TI - Recurrent thrombosis despite a therapeutic international normalised ratio. PMID- 23681879 TI - Emphysematous pyelonephritis. PMID- 23681880 TI - Sustainability of MBPhD programmes. PMID- 23681881 TI - The virtual bronchoscopy simulator - a young physician's view. PMID- 23681882 TI - Community-acquired pneumonia and welding. PMID- 23681883 TI - Tissue and organ donation guidance. PMID- 23681884 TI - Bone protection in chronic obstructive pulmonary disease (COPD) patients requiring regular intermittent glucocorticoid therapy. PMID- 23681885 TI - Neuromuscular ultrasound in common entrapment neuropathies. AB - Neuromuscular ultrasound involves the use of high-resolution ultrasound to image the peripheral nervous system of patients with suspected neuromuscular diseases. It complements electrodiagnostic studies well by providing anatomic information regarding nerves, muscles, vessels, tendons, ligaments, bones, and other structures that cannot be obtained with nerve conduction studies and electromyography. Neuromuscular ultrasound has been studied extensively over the past 10 years and has been used most often in the assessment of entrapment neuropathies. This review focuses on the use of neuromuscular ultrasound in 4 of the most common entrapment neuropathies: carpal tunnel syndrome, ulnar neuropathy at the elbow and wrist, and fibular neuropathy at the knee. PMID- 23681886 TI - Structural representative of the protein family PF14466 has a new fold and establishes links with the C2 and PLAT domains from the widely distant Pfams PF00168 and PF01477. AB - The domain of unknown function (DUF) YP_001302112.1, a protein secreted by the human intestinal microbita, has been determined by NMR and represents the first structure for the Pfam PF14466. Its NMR structure is classified as a new fold, which, nonetheless, shows limited similarities with representatives of the PLAT/LH2 domains from PF01477 and the C2 domains from PF00168, both of which bind Ca(2+) for their physiological functions. Further experiments revealed affinity of YP_001302112.1 for Ca(2+), and the NMR structure in the presence of CaCl2 was better defined than that of the apo-protein. Overall, these NMR structures establish a new connection between structural representatives from two widely different Pfams that include the calcium-binding domain of a sialidase from Vibrio cholerae and the alpha-toxin from Clostridium perfrigens, whereby these two proteins have only 7% sequence identity. Furthermore, it provides information toward the functional annotation of YP_001302112.1, based on its capacity to bind Ca(2+), and thus adds to the structural and functional coverage of the protein sequence universe. PMID- 23681887 TI - Blunted feelings: alexithymia is associated with a diminished neural response to speech prosody. AB - How we perceive emotional signals from our environment depends on our personality. Alexithymia, a personality trait characterized by difficulties in emotion regulation has been linked to aberrant brain activity for visual emotional processing. Whether alexithymia also affects the brain's perception of emotional speech prosody is currently unknown. We used functional magnetic resonance imaging to investigate the impact of alexithymia on hemodynamic activity of three a priori regions of the prosody network: the superior temporal gyrus (STG), the inferior frontal gyrus and the amygdala. Twenty-two subjects performed an explicit task (emotional prosody categorization) and an implicit task (metrical stress evaluation) on the same prosodic stimuli. Irrespective of task, alexithymia was associated with a blunted response of the right STG and the bilateral amygdalae to angry, surprised and neutral prosody. Individuals with difficulty describing feelings deactivated the left STG and the bilateral amygdalae to a lesser extent in response to angry compared with neutral prosody, suggesting that they perceived angry prosody as relatively more salient than neutral prosody. In conclusion, alexithymia may be associated with a generally blunted neural response to speech prosody. Such restricted prosodic processing may contribute to problems in social communication associated with this personality trait. PMID- 23681889 TI - Unexpected co-arctation of aorta detected by transesophageal echocardiography during patent ductus arteriosus ligation. AB - In the presence of a large patent ductus arteriosus (PDA), aortic co-arctation (CoA) cannot be diagnosed clinically because PDA masks the clinical features. This condition impedes the identification of CoA by transthoracic echcocardiography. However, the closure of PDA can result in a severe clinical condition that causes a patient with undiagnosed CoA to suffer from shock and multi-organ failure. In this article, a case of PDA was presented, in which transesophageal echocardiography provided full information that could be used as reference to identify and define CoA during PDA ligation surgery. PMID- 23681888 TI - Inflammation and liver tumorigenesis. AB - Inflammation has been considered as one of the hallmarks of cancer, and chronic hepatitis is a major cause of liver cancer. This review will focus on the pathogenic role of inflammation in hepatocarcinogenesis and will discuss recent advances in understanding the chronic hepatitis-liver cancer link based on hot spots in liver cancer research, including cellular interaction, cytokines, microRNA and stem cells. All of these mechanisms should be taken into consideration because they are crucial for the development of more efficacious therapeutic strategies for preventing and treating human chronic hepatitis and hepatocellular carcinoma. PMID- 23681890 TI - Progress on molecular biomarkers and classification of malignant gliomas. AB - Gliomas are the most common primary intracranial tumors in adults. Anaplastic gliomas (WHO grade III) and glioblastomas (WHO grade IV) represent the major groups of malignant gliomas in the brain. Several diagnostic, predictive, and prognostic biomarkers for malignant gliomas have been reported over the last few decades, and these markers have made great contributions to the accuracy of diagnosis, therapeutic decision making, and prognosis of patients. However, heterogeneity in patient outcomes may still be observed, which highlights the insufficiency of a classification system based purely on histopathology. Great efforts have been made to incorporate new information about the molecular landscape of gliomas into novel classifications that may potentially guide treatment. In this review, we summarize three distinctive biomarkers, three most commonly altered pathways, and three classifications based on microarray data in malignant gliomas. PMID- 23681891 TI - Present status and progress of neoadjuvant chemoradiotherapy for esophageal cancer. AB - Trimodality based on neoadjuvant chemoradiotherapy (nCRT) followed by surgery is gaining popularity as a treatment strategy for locally advanced esophageal cancer. In this review, we summarize the role of nCRT and the recommended nCRT regimens based on clinical trials and meta-analyses. We analyze the relationship of nCRT with pathologic complete response (pCR) and then identify potential predictive markers of response. Compared with surgery alone and neoadjuvant chemotherapy followed by surgery, trimodality provides longer survival and has the advantage of local control compared with definitive chemoradiotherapy. The standard regimen is a platinum-based regimen with a radiation dose range of 41.4 50.4 Gy by conventional fractionation. Evidence shows that patients with pCR tend to live longer than non-responders, indicating that pCR is a significant prognostic factor for patients with esophageal cancer. Individualized medicine requires predictive markers of individual patients based on their own genes. Currently, no definite marker is proved to be sufficiently sensitive and specific for use in clinical practice, although 18-fluorodeoxyglucose positron emission tomography shows promise in predicting response to nCRT. PMID- 23681893 TI - HPAEC-PAD method for the analysis of alkaline hydrolyzates of Haemophilus influenzae type b capsular polysaccharide. AB - A gradient method has been devised for the rapid analysis of alkaline hydrolyzates of Haemophilus influenzae type b (Hib) capsular polysaccharide-based vaccines by high-performance anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD). As compared with published procedures, peak shape and sensitivity were significantly improved with this approach, analysis time was short and there was little interference from impurities. The limits of detection and quantification were established with a purified reference polysaccharide. We propose this method as a practical alternative for the analysis of minute amounts of Hib polysaccharide, which can be lower than with the conventional approaches. PMID- 23681892 TI - Molecular classification of non-small-cell lung cancer: diagnosis, individualized treatment, and prognosis. AB - Non-small-cell lung cancer (NSCLC) is the most common cause of premature death among the malignant diseases worldwide. The current staging criteria do not fully capture the complexity of this disease. Molecular biology techniques, particularly gene expression microarrays, proteomics, and next-generation sequencing, have recently been developed to facilitate effectively its molecular classification. The underlying etiology, pathogenesis, therapeutics, and prognosis of NSCLC based on an improved molecular classification scheme may promote individualized treatment and improve clinical outcomes. This review focuses on the molecular classification of NSCLC based on gene expression microarray technology reported during the past decade, as well as their applications for improving the diagnosis, staging and treatment of NSCLC, including the discovery of prognostic markers or potential therapeutic targets. We highlight some of the recent studies that may refine the identification of NSCLC subtypes using novel techniques such as epigenetics, proteomics, or deep sequencing. PMID- 23681894 TI - Dynamic Vascular Pattern (DVP), a quantification tool for contrast enhanced ultrasound. AB - Contrast-enhanced ultrasound (CEUS) is widely applied in tumour diagnosis, especially for focal liver lesions (FLL), due to its high sensitivity and specificity. According to the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) CEUS guidelines (2012) and non-liver guidelines (2011), the majority of tumours, regardless of location, show specific CEUS enhancement patterns that can distinguish benign from malignant lesions. However, even experienced clinicians evaluating FLL may find occasional irregularities in these patterns, due to particular FLL pathologies, that make a definitive diagnosis difficult. Hence, there is a need to train physicians to utilize contrast enhancement kinetics to aid in the correct interpretation of data from CEUS examinations in patients with divergent liver tumour pathologies. Here we report on a CEUS quantitation software, SonoLiver(r), to verify and improve diagnostic accuracy in the characterization of suspicious liver lesions through the analysis of dynamic vascular patterns (DVP). PMID- 23681896 TI - [Treatment of a postoperative rectal stenosis with a self-expanding biodegradable polydioxanone stent]. AB - Rectal stricture is a serious although infrequent complication of transanal endoscopic microsurgery (TEM). In some cases, these strictures may be refractory to treatment by endoscopic balloon dilatation. Biodegradable stents might improve the outcome by providing an extended period of dilatation. Moreover, these stents can remain in place without the need to remove them. In the presented case, a biodegradable polidioxanone stent originally developed to treat benign oesophageal stenoses was used to treat a patient suffering from rectal stricture following a TEM. PMID- 23681895 TI - [How safe is sedation in gastrointestinal endoscopy? A multicentre analysis of 388,404 endoscopies and analysis of data from prospective registries of complications managed by members of the Working Group of Leading Hospital Gastroenterologists (ALGK)]. AB - BACKGROUND: Gastrointestinal endoscopies are increasingly being carried out with sedation. All of the drugs used for sedation are associated with a certain risk of complications. Data currently available on sedation-associated morbidity and mortality rates are limited and in most cases have substantial methodological limitations. The aim of this study was to record severe sedation-associated complications in a large number of gastrointestinal endoscopies. METHODS: Data on severe sedation-associated complications were collected on a multicentre basis from prospectively recorded registries of complications in the participating hospitals (median documentation period 27 months, range 9 - 129 months). RESULTS: Data for 388,404 endoscopies from 15 departments were included in the study. Severe sedation-associated complications occurred in 57 patients (0.01 %). Forty one percent of the complications and 50 % of all complications with a fatal outcome (10/20 patients) occurred during emergency endoscopies. In addition, it was found that 95 % of the complications and 100 % of all fatal complications affected patients in ASA class >= 3. CONCLUSIONS: Including nearly 400,000 endoscopies, this study represents the largest prospective, multicenter record of the complications of sedation worldwide. The analysis shows that sedation is carried out safely in gastrointestinal endoscopy. The morbidity and mortality rates are much lower than previously reported in the literature in similar groups of patients. Risk factors for the occurrence of serious complications include emergency examinations and patients in ASA class >= 3. PMID- 23681897 TI - Manifestation of an abdominal immune reconstitution inflammatory syndrome associated with a nontuberculous mycobacterial infection - a case report. AB - Immune reconstitution inflammatory syndrome (IRIS) is an inflammatory reaction in HIV-infected patients after initiation of antiretroviral therapy. It results from restored immunity to specific infectious or non-infectious antigens. We describe the case of a 47-year-old female patient who presented with an unspecific painful pressure in the abdomen and weight loss that was diagnosed as intra-abdominal (unmasking) IRIS due to nontuberculous mycobacterial infection (Mycobacterium avium complex). Antiretroviral therapy had been initiated six months earlier when pneumocystis pneumonia led to the diagnosis of HIV infection with a viral load of 123 000 copies/ml and a CD 4 cell count of 6/ul. Although IRIS is a known complication after initiation of antiretroviral therapy in HIV-infected patients this case with a rare site of manifestation and symptoms that are common in all day gastroenterological clinic highlights a differential diagnosis that requires a high index of suspicion and the need for the careful use of diagnostic tools. PMID- 23681898 TI - [The PEG-dilemma - pleading for an ethically responsible medical treatment]. AB - Within the 32 years of its existence our attitude towards artificial enteral nutrition via PEG-tubes has changed in a fundamental way: in our modern understanding nutrition via PEG is supportive, early, preventive, and in many cases temporary. PEG-feeding is not an alternative but a possible supplement to normal oral food intake and requires an individual medical indication as well as an ethical justification. This does not follow standardised algorithmic thinking but is decided on an individual base taking personal wishes, resources, and needs of the individual patient into account. Nutrition via PEG-tube is not a terminal basic or even symbolic treatment at the end of life. The present dilemma of the PEG is that the public discussion primarily focus one-sided on the problems of PEG-placement in multimorbid, elderly, and/or demented patients or patients in end-stage tumour diseases where indeed PEG-placement is neither medically nor ethically justified - we still place PEG-tubes to often in the wrong patients! On the other hand we still consider supportive and in many cases temporary nutrition via PEG too rare and even too late in those patients which clearly could benefit from an early, supportive, and preventive PEG-treatment on the base of our present evidence-based scientific knowledge - we still consider PEG-treatment not adequately and in most cases too late in the right patients! Placing a PEG-tube is not the second last step before death and physicians have to accept the ethically given limits of medical treatment by realizing our modern understanding of the benefits and limits of supportive artificial nutrition via PEG. PMID- 23681899 TI - [Colorectal cancer: screening and surveillance in inflammatory bowel diseases - consensus of the working group for inflammatory bowel diseases of the Austrian Society of Gastroenterology and Hepatology]. AB - Patients with ulcerative colitis and Crohn's colitis are at increased risk of colorectal cancer (CRC). This risk is dependent on the duration and extent of disease, inflammatory activity and possible additional risk factors. Thus, the aim is to reduce this risk and to detect dysplastic and malignant lesions at an early stage. The working group for Inflammatory Bowel Diseases (IBD) of the Austrian Society of Gastroenterology and Hepatology (OGGH) has developed consensus statements on the following topics: risk of colorectal cancer, screening and surveillance, procedure of surveillance colonoscopy, dysplasia and its management, and chemoprevention. This consensus is intended to increase awareness of the increased risk of CRC in IBD and to support a standardised approach in cancer prevention. PMID- 23681900 TI - CD44/cellular prion protein interact in multidrug resistant breast cancer cells and correlate with responses to neoadjuvant chemotherapy in breast cancer patients. AB - Multidrug resistance (MDR) is one of the most important factors leading to chemotherapeutic failure in patients with breast cancer. The invasive/metastatic ability of MDR cells is strengthened compared with their parental cells. However, the mechanisms underlying MDR have not been fully elucidated. We found that CD44 and the cellular prion protein (PrPc) were both overexpressed in MDR cells (MCF7/Adr and H69AR). Subsequently, we chose the human breast cancer cell line MCF7/Adr, which is resistant to adriamycin, for further research. We discovered that PrPc physically and functionally interacted with CD44. The knockdown of CD44 or PrPc by siRNA in MCF7/Adr cells inhibited cell migration, invasion and proliferation in vitro. However, when the MCF7/Adr cells transfected with CD44 siRNA were incubated with 10 times the peak plasma concentration (PPC) of taxol, their invasive ability was again enhanced. In the breast-carcinoma tissue samples, a significant correlation between the CD44 expression and the PrPc expression was observed in the postneoadjuvant-chemotherapy (NAC) cases. Moreover, in Group 2, which was unresponsive to NAC, the CD44 and PrPc expression levels were significantly increased in the post-NAC cases compared with the pre NAC cases using the paired-samples t-test. These data indicate that the CD44/PrPc interaction enhances the malignancy of breast cancer cells and affects the responses to neoadjuvant chemotherapy in breast cancer patients. Therefore, blocking the CD44/PrPc interaction may improve outcomes in chemorefractory breast cancer patients. PMID- 23681902 TI - Sleeping too little too late: a comment on Loft and Cameron. PMID- 23681901 TI - Very small embryonic-like stem cells from the murine bone marrow differentiate into epithelial cells of the lung. AB - The view that adult stem cells are lineage restricted has been challenged by numerous reports of bone marrow (BM)-derived cells giving rise to epithelial cells. Previously, we demonstrated that nonhematopoietic BM cells are the primary source of BM-derived lung epithelial cells. Here, we tested the hypothesis that very small embryonic like cells (VSELs) are responsible for this engraftment. We directly compared the level of BM-derived epithelial cells after transplantation of VSELs, hematopoietic stem/progenitor cells, or other nonhematopoietic cells. VSELs clearly had the highest rate of forming epithelial cells in the lung. By transplanting VSELs from donor mice expressing H2B-GFP under a type 2 pneumocyte specific promoter, we demonstrate that this engraftment occurs by differentiation and not fusion. This is the first report of VSELs differentiating into an endodermal lineage in vivo, thereby potentially crossing germ layer lineages. Our data suggest that Oct4+ VSELs in the adult BM exhibit broad differentiation potential. PMID- 23681903 TI - Predicting sputum eosinophilia in exacerbations of COPD using exhaled nitric oxide. AB - Fractional exhaled nitric oxide (FENO) may be a pulmonary biomarker in chronic obstructive pulmonary disease (COPD). In this prospective study, the relationship between FENO and airway inflammation was assessed in COPD exacerbations. FENO and lung function were measured, and sputum was collected from 49 ex-smoking COPD patients, first at the time of hospital admission and again at discharge following treatment. There was a significant positive correlation between the percentage of sputum eosinophils and FENO concentrations, both at exacerbation (r = 0.593, p < 0.001) and discharge (r = 0.337, p = 0.044). The increase in forced expiratory volume in one second (FEV(1)) after treatment was greater in patients with sputum eosinophilia (DeltaFEV(1) 0.35 +/- 0.12 vs. 0.13 +/- 0.04 L, p = 0.046), and FENO was a strong predictor of sputum eosinophilia (area under the receiver operating characteristic curve, 0.89). The optimum cut point was 19 parts per billion (sensitivity: 90 %; specificity: 74 %). Our data suggest that FENO is a good surrogate marker of eosinophilic inflammation in COPD patients with exacerbations. PMID- 23681904 TI - Adenosine signaling inhibits CIITA-mediated MHC class II transactivation in lung fibroblast cells. AB - Efficient antigen presentation by major histocompatibility complex (MHC) molecules represents a critical process in adaptive immunity. Class II transactivator (CIITA) is considered the master regulator of MHC class II (MHC II) transcription. Previously, we have shown that CIITA expression is upregulated in smooth muscle cells deficient in A2b adenosine receptor. Here, we report that treatment with the adenosine receptor agonist adenosine-5'N-ethylcarboxamide (NECA) attenuated MHC II transcription in lung fibro-blast cells as a result of CIITA repression. Further analysis revealed that NECA preferentially abrogated CIITA transcription through promoters III and IV. Blockade with a selective A2b receptor antagonist MRS-1754 restored CIITA-dependent MHC II transactivation. Forskolin, an adenylyl cyclase activator, achieved the same effect as NECA. A2b signaling repressed CIITA transcription by altering histone modifications and recruitment of key factors on the CIITA promoters in a STAT1-dependent manner. MRS-1754 blocked the antagonism of transforming growth factor beta (TGF-beta) in CIITA induction by interferon gamma (IFN-gamma), alluding to a potential dialogue between TGF-beta and adenosine signaling pathways. Finally, A2b signaling attenuated STAT1 phosphorylation and stimulated TGF-beta synthesis. In conclusion, we have identified an adenosine-A2b receptor-adenylyl cyclase axis that influences CIITA-mediated MHC II transactivation in lung fibroblast cells and as such have provided invaluable insights into the development of novel immune-modulatory strategies. PMID- 23681905 TI - A chemical lift-off process: removing non-specific adsorption in an electrochemical Epstein-Barr virus immunoassay. AB - Upon contact of sensor surfaces with complex biological samples containing a variety of different proteins, non-specific adsorption hampers the high-sensitive detection of the analyte in question. To substantially decrease the impact of non specific adsorption at thiol-based self-assembled monolayers, a chemical lift-off process is introduced. A sequence of local hydrolysis of isooctyl 3 mercaptopropionate, covalent binding of an antigen against the Epstein-Barr virus (EBV), stepwise incubation with a serum sample possibly containing the EBV antibody and an enzyme-labeled anti-human antibody is completed with a lift-off by integral hydrolysis of the remaining ester groups at the self-assembled monolayer. The cleavage of the ester removes any non-specifically bound protein during a following stringent washing step. The substantial improvement of the detection limit of an electrochemical immunoassay against EBV using native recombinant antigens, their immobilization after local deprotection using a scanning electrochemical microscope (SECM) and the local read-out using the generator-collector mode of SECM with redox cycling amplification demonstrates the successful application of the proposed lift-off procedure. PMID- 23681906 TI - Inhaled, dual release liposomal ciprofloxacin in non-cystic fibrosis bronchiectasis (ORBIT-2): a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: The delivery of antipseudomonal antibiotics by inhalation to Pseudomonas aeruginosa-infected subjects with non-cystic fibrosis (CF) bronchiectasis is a logical extension of treatment strategies successfully developed in CF bronchiectasis. Dual release ciprofloxacin for inhalation (DRCFI) contains liposomal ciprofloxacin, formulated to optimise airway antibiotic delivery. METHODS: Phase II, 24-week Australian/New Zealand multicentre, randomised, double-blind, placebo-controlled trial in 42 adult bronchiectasis subjects with >=2 pulmonary exacerbations in the prior 12 months and ciprofloxacin-sensitive P aeruginosa at screening. Subjects received DRCFI or placebo in three treatment cycles of 28 days on/28 days off. The primary outcome was change in sputum P aeruginosa bacterial density to the end of treatment cycle 1 (day 28), analysed by modified intention to treat (mITT). Key secondary outcomes included safety and time to first pulmonary exacerbation-after reaching the pulmonary exacerbation endpoint subjects discontinued study drug although remained in the study. RESULTS: DRCFI resulted in a mean (SD) 4.2 (3.7) log10 CFU/g reduction in P aeruginosa bacterial density at day 28 (vs -0.08 (3.8) with placebo, p=0.002). DRCFI treatment delayed time to first pulmonary exacerbation (median 134 vs 58 days, p=0.057 mITT, p=0.046 per protocol). DRCFI was well tolerated with a similar incidence of systemic adverse events to the placebo group, but fewer pulmonary adverse events. CONCLUSIONS: Once-daily inhaled DRCFI demonstrated potent antipseudomonal microbiological efficacy in adults with non CF bronchiectasis and ciprofloxacin-sensitive P aeruginosa. In this modest-sized phase II study, DRCFI was also well tolerated and delayed time to first pulmonary exacerbation in the per protocol population. PMID- 23681907 TI - From manual curation to visualization of gene families and networks across Solanaceae plant species. AB - High-quality manual annotation methods and practices need to be scaled to the increased rate of genomic data production. Curation based on gene families and gene networks is one approach that can significantly increase both curation efficiency and quality. The Sol Genomics Network (SGN; http://solgenomics.net) is a comparative genomics platform, with genetic, genomic and phenotypic information of the Solanaceae family and its closely related species that incorporates a community-based gene and phenotype curation system. In this article, we describe a manual curation system for gene families aimed at facilitating curation, querying and visualization of gene interaction patterns underlying complex biological processes, including an interface for efficiently capturing information from experiments with large data sets reported in the literature. Well-annotated multigene families are useful for further exploration of genome organization and gene evolution across species. As an example, we illustrate the system with the multigene transcription factor families, WRKY and Small Auxin Up regulated RNA (SAUR), which both play important roles in responding to abiotic stresses in plants. Database URL: http://solgenomics.net/ PMID- 23681908 TI - Does an NSAID a day keep satellite cells at bay? AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely consumed by athletes worldwide, despite growing evidence for a negative influence on the adaptation of skeletal muscle to exercise, at least in young healthy individuals. This review focuses on the potential of NSAIDs to alter the activity of satellite cells, the muscle stem cell responsible for repair and maintenance of skeletal muscle. The signaling pathways that are potentially modified by NSAID exposure are also considered. Growth factors as well as inflammatory cells and connective tissue appear to be key factors in the response of muscle under conditions where cyclooxygenase and prostaglandin activity are blocked through NSAID ingestion or infusion. Discrepancies in the literature regarding the response of young and old individuals are addressed, where it appears that the elderly may benefit from NSAID ingestion, although this clearly requires further study. The long-term implications for the muscle of the apparent inhibitory effect of NSAIDs on satellite cells in younger individuals are not clear, and it is possible these may first become apparent with chronic use in athletes training at a high level or with advancing age. Reports of the potential for NSAIDs to alter prostaglandin and growth factor signaling provide a basis for further study of the mechanism of NSAID action on satellite cells. PMID- 23681909 TI - The frequency response of cerebral autoregulation. AB - The frequency-response of pressure autoregulation is not well delineated; therefore, the optimal frequency of arterial blood pressure (ABP) modulation for measuring autoregulation is unknown. We hypothesized that cerebrovascular autoregulation is band-limited and delineated by a cutoff frequency for which ABP variations induce cerebrovascular reactivity. Neonatal swine (n = 8) were anesthetized using constant minute ventilation while positive end-expiratory pressure (PEEP) was modulated between 6 and 0.75 cycles/min (min(-1)). The animals were hemorrhaged until ABP was below the lower limit of autoregulation (LLA), and PEEP modulations were repeated. Vascular reactivity was quantified at each frequency according to the phase lag between ABP and intracranial pressure (ICP) above and below the LLA. Phase differences between ABP and ICP were small for frequencies of >2 min(-1), with no ability to differentiate cerebrovascular reactivity between ABPs above or below the LLA. For frequencies of <2 min(-1), ABP and intracranial pressure (ICP) showed phase shift when measured above LLA and no phase shift when measured below LLA [above vs. below LLA at 1 min(-1): 156 degrees (139-174 degrees ) vs. 30 degrees (22-50 degrees ); P < 0.001 by two way ANOVA for both frequency and state of autoregulation]. Data taken above LLA fit a Butterworth high-pass filter model with a cutoff frequency at 1.8 min(-1) (95% confidence interval: 1.5-2.2). Cerebrovascular reactivity occurs for sustained ABP changes lasting 30 s or longer. The ability to distinguish intact and impaired autoregulation was maximized by a 60-s wave (1 min(-1)), which was 100% sensitive and 100% specific in this model. PMID- 23681910 TI - Five days of head-down-tilt bed rest induces noninflammatory shedding of L selectin. AB - Head-down-tilt bed rest (HDTBR) is a popular model, simulating alterations of gravitation during space missions. The aim of this study was to obtain a better insight into the complexly orchestrated regulations of HDTBR-induced immunological responses, hypothesizing that artificial gravity can mitigate these HDTBR-related physiological effects. This crossover-designed 5 days of HDTBR study included three protocols with no, or daily 30 min of centrifugation or 6 * 5 min of centrifugation. Twelve healthy, male participants donated blood pre HDTBR, post-HDTBR, and twice during HDTBR. Cellular immune changes were assessed either by enumerative and immune cell phenotyping assays or by functional testing of responses to either recall antigens or receptor-dependent activation by chemotactic agents N-formyl-methionyl-leucyl-phenylalanine (fMLP) and with TNF alpha. The expression of the adhesion molecule L-selectin (CD62L) on the surface of granulocytes and its shedding into plasma samples were measured. In parallel, other humoral factor, such as interleukin-6 and interleukin-8, parameters of endothelial damage (glycocalyx) were determined. Hematocrit and hemoglobin were significantly increased during HDTBR. Although immune functional tests did not indicate a change in the immune performance, the expression of CD62L on resting granulocytes was significantly shed by 50% during HDTBR. Although the latter is normally associated to an activation of inflammatory innate immune responses and during interaction of granulocytes with the endothelium, CD62L shedding was, however, not related either to a systemic inflammatory alteration or to shedding of the endothelial glycocalyx during bed rest. This suggests a noninflammatory or "mechanical" shedding related to fluid shifts during head-down intervention and not to an acute inflammatory process. PMID- 23681912 TI - Inflammation: sustaining the balance to optimize recovery of skeletal muscle, connective tissue, and exertional injuries. PMID- 23681911 TI - Heightened muscle inflammation susceptibility may impair regenerative capacity in aging humans. AB - The regenerative response of skeletal muscle to mechanically induced damage is impaired with age. Previous work in our laboratory suggests this may result from higher proinflammatory signaling in aging muscle at rest and/or a greater inflammatory response to damage. We, therefore, assessed skeletal muscle proinflammatory signaling at rest and 24 h after unaccustomed, loaded knee extension contractions that induced modest muscle damage (72% increase in serum creatine kinase) in a cohort of 87 adults across three age groups (AGE40, AGE61, and AGE76). Vastus lateralis muscle gene expression and protein cell signaling of the IL-6 and TNF-alpha pathways were determined by quantitative PCR and immunoblot analysis. For in vitro studies, cell signaling and fusion capacities were compared among primary myoblasts from young (AGE28) and old (AGE64) donors treated with TNF-alpha. Muscle expression was higher (1.5- to 2.1-fold) in AGE76 and AGE61 relative to AGE40 for several genes involved in IL-6, TNF-alpha, and TNF-like weak inducer of apoptosis signaling. Indexes of activation for the proinflammatory transcription factors signal transducer and activator of transcription-3 and NF-kappaB were highest in AGE76. Resistance loading reduced gene expression of IL-6 receptor, muscle RING finger 1, and atrogin-1, and increased TNF-like weak inducer of apoptosis receptor expression. Donor myoblasts from AGE64 showed impaired differentiation and fusion in standard media and greater NF-kappaB activation in response to TNF-alpha treatment (compared with AGE28). We show for the first time that human aging is associated with muscle inflammation susceptibility (i.e., higher basal state of proinflammatory signaling) that is present in both tissue and isolated myogenic cells and likely contributes to the impaired regenerative capacity of skeletal muscle in the older population. PMID- 23681913 TI - Slow breathing as a means to improve orthostatic tolerance: a randomized sham controlled trial. AB - Endogenous oscillations in blood pressure (BP) and cerebral blood flow have been associated with improved orthostatic tolerance. Although slow breathing induces such responses, it has not been tested as a therapeutic strategy to improve orthostatic tolerance. With the use of a randomized, crossover sham-controlled design, we tested the hypothesis that breathing at six breaths/min (vs. spontaneous breathing) would improve orthostatic tolerance via inducing oscillations in mean arterial BP (MAP) and cerebral blood flow. Sixteen healthy participants (aged 25 +/- 4 yr; mean +/- SD) had continuous beat-to-beat measurements of middle cerebral artery blood velocity (MCAv), BP (finometer), heart rate (ECG), and end-tidal carbon dioxide partial pressure during an incremental orthostatic stress test to presyncope by combining head-up tilt with incremental lower-body negative pressure. Tolerance time to presyncope was improved (+15%) with slow breathing compared with spontaneous breathing (29.2 +/- 5.4 vs. 33.7 +/- 6.0 min; P < 0.01). The improved tolerance was reflected in elevations in low-frequency (LF; 0.07-0.2 Hz) oscillations of MAP and mean MCAv, improved metrics of dynamic cerebrovascular control (increased LF phase and reduced LF gain), and a reduced rate of decline for MCAv (-0.60 +/- 0.27 vs. 0.99 +/- 0.51 cm.s(-1).min(-1); P < 0.01) and MAP (-0.50 +/- 0.37 vs. -1.03 +/- 0.80 mmHg/min; P = 0.01 vs. spontaneous breathing) across time from baseline to presyncope. Our findings show that orthostatic tolerance can be improved within healthy individuals with a simple, nonpharmacological breathing strategy. The mechanisms underlying this improvement are likely mediated via the generation of negative intrathoracic pressure during slow and deep breathing and the related beneficial impact on cerebrovascular and autonomic function. PMID- 23681914 TI - Exercise-inducible factors to activate lipolysis in adipocytes. AB - We examined the effects of exercise training on the levels of lipid droplet (LD) associated and mitochondria-related proteins in diet-induced obese (DIO) rats. Furthermore, we assessed putative factors induced by exercise to activate lipolysis in differentiated 3T3-L1 adipocytes. DIO Wistar male rats (age 20 wk) were divided into sedentary control (SED, n = 7) and exercise training (EX, n = 7) groups. EX animals were subjected to treadmill running (25 m/min, 1 h/day, 5 days/wk) for 6 wk. Epididymal fat was dissected and used for protein analyses. 3T3-L1 adipocytes were incubated with media containing hydrogen peroxide (H2O2), sodium-lactate, caffeine, AICAR, or SNAP (NO donor) for 6 h, or 1 mM H2O2 for 15 min, followed by incubation with normal media for up to 24 h total. Protein expression levels and lipolytic activities were biochemically assayed. Epididymal fat significantly decreased in EX animals compared with SED animals. Levels of cytochrome c oxidase (COx), perilipin, hormone sensitive lipase (HSL), and adipose triglyceride lipase (ATGL) proteins in epididymal fat pads of EX animals were significantly increased compared with those in SED animals. In 3T3-L1 cells, glycerol or fatty acid release was significantly increased by all treatments. Lactate or SNAP significantly increased PGC-1alpha expression, and H2O2 significantly increased COx protein levels compared with controls. Expression of perilipin, HSL, ATGL, or comparative gene identification (CGI)-58 was significantly increased by all treatments. By increasing lipolytic activity in adipocytes, the exercise-inducible factors are attractive therapeutic effectors against LD-associated metabolic diseases. PMID- 23681915 TI - Economy and rate of carbohydrate oxidation during running with rearfoot and forefoot strike patterns. AB - It continues to be argued that a forefoot (FF) strike pattern during running is more economical than a rearfoot (RF) pattern; however, previous studies using one habitual footstrike group have found no difference in running economy between footstrike patterns. We aimed to conduct a more extensive study by including both habitual RF and FF runners. The purposes of this study were to determine whether there were differences in running economy between these groups and whether running economy would change when they ran with the alternative footstrike pattern. Nineteen habitual RF and 18 habitual FF runners performed the RF and FF patterns on a treadmill at 3.0, 3.5, and 4.0 m/s. Steady-state rates of oxygen consumption (Vo2, ml.kg(-1).min(-1)) and carbohydrate contribution to total energy expenditure (%CHO) were determined by indirect calorimetry for each footstrike pattern and speed condition. A mixed-model ANOVA was used to assess the differences in each variable between groups and footstrike patterns (alpha = 0.05). No differences in Vo2 or %CHO were detected between groups when running with their habitual footstrike pattern. The RF pattern resulted in lower Vo2 and %CHO compared with the FF pattern at the slow and medium speeds in the RF group (P < 0.05) but not in the FF group (P > 0.05). At the fast speed, a significant footstrike pattern main effect indicated that Vo2 was greater with the FF pattern than with the RF pattern (P < 0.05), but %CHO was not different (P > 0.05). The results suggest that the FF pattern is not more economical than the RF pattern. PMID- 23681916 TI - Neurophysiological techniques to detect early small-fiber dysfunction in transthyretin amyloid polyneuropathy. AB - INTRODUCTION: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is characterized by early selective involvement of small nerve fibers. Initial clinical diagnosis is complicated by psychosocial factors. We evaluated diagnostic accuracy of sural sensory nerve action potentials, plantar sympathetic skin response (SSR), and cortical laser-evoked potentials (LEP) to dorsal foot stimulation in the early diagnosis of TTR-FAP. METHODS: Sixty-three subjects with TTR-FAP (Val30Met) mutation were split into 2 groups (asymptomatic carriers and early-symptomatic patients) and compared with 33 healthy controls. RESULTS: The diagnostic accuracy of plantar SSR amplitude and LEP N2 latency was similar; all had very high specificity (94 to 97%) but low sensitivity (22 to 32%) in distinguishing controls from carriers and early-symptomatic patients. No control had abnormal results on both tests. CONCLUSIONS: Plantar SSR and LEPs have similar diagnostic performance in detecting small-fiber dysfunction in early TTR FAP; we propose that both tests should be used to investigate this population. Muscle Nerve 49: 181-186, 2014. PMID- 23681917 TI - Determination of leakage from antibody adsorbent: composition analysis and pH effect. AB - To study the leakage at different solution pH values, IgG Sepharose 6FF(r), a commercially available immunoadsorbent, was used as a model. The leaked substance consists of three parts: (1) ligands and its fragments; (2) ligands plus matrix fragments in which ligands are chemically attached to the adsorbent matrix; and (3) matrix fragments. Buffer solution pH values had a great effect on both the kinetics and the amount of ligand leakage. Cross-linking of the adsorbent matrix could reduce both matrix leakage and antibody leakage at pH 3.0, but its effect was limited at pH 11.0 for ligand leakage. PMID- 23681920 TI - Watertight dural closure in brain surgery: a simple model for training. AB - BACKGROUND: To avoid cerebrospinal fluid leaks and related possible complications, the dura mater should be meticulously closed after craniotomy procedures. Several techniques for duraplasty and different material for watertight closure have been described. OBJECTIVE: To describe a device to be used for the training of neurosurgical procedures of duraplasty. TECHNICAL REPORT: A plastic dummy with a balloon was developed to test the efficacy of the watertight closure of the dura. The technical notes to reproduce the method have been described. CONCLUSION: The described model represents a new, simple, effective and affordable device to be used for neurosurgical training in the procedures of duraplasty and to test the efficacy of watertight closures. PMID- 23681918 TI - Triplex-forming oligonucleotides targeting c-MYC potentiate the anti-tumor activity of gemcitabine in a mouse model of human cancer. AB - Antimetabolite chemotherapy remains an essential cancer treatment modality, but often produces only marginal benefit due to the lack of tumor specificity, the development of drug resistance, and the refractoriness of slowly proliferating cells in solid tumors. Here, we report a novel strategy to circumvent the proliferation-dependence of traditional antimetabolite-based therapies. Triplex forming oligonucleotides (TFOs) were used to target site-specific DNA damage to the human c-MYC oncogene, thereby inducing replication-independent, unscheduled DNA repair synthesis (UDS) preferentially in the TFO-targeted region. The TFO directed UDS facilitated incorporation of the antimetabolite, gemcitabine (GEM), into the damaged oncogene, thereby potentiating the anti-tumor activity of GEM. Mice bearing COLO 320DM human colon cancer xenografts (containing amplified c MYC) were treated with a TFO targeted to c-MYC in combination with GEM. Tumor growth inhibition produced by the combination was significantly greater than with either TFO or GEM alone. Specific TFO binding to the genomic c-MYC gene was demonstrated, and TFO-induced DNA damage was confirmed by NBS1 accumulation, supporting a mechanism of enhanced efficacy of GEM via TFO-targeted DNA damage induced UDS. Thus, coupling antimetabolite chemotherapeutics with a strategy that facilitates selective targeting of cells containing amplification of cancer relevant genes can improve their activity against solid tumors, while possibly minimizing host toxicity. PMID- 23681919 TI - KIT receptor gain-of-function in hematopoiesis enhances stem cell self-renewal and promotes progenitor cell expansion. AB - The KIT receptor tyrosine kinase has important roles in hematopoiesis. We have recently produced a mouse model for imatinib resistant gastrointestinal stromal tumor (GIST) carrying the Kit(V558Delta) and Kit(T669I) (human KIT(T670I) ) mutations found in imatinib-resistant GIST. The Kit(V558Delta;T669I/+) mice developed microcytic erythrocytosis with an increase in erythroid progenitor numbers, a phenotype previously seen only in mouse models of polycythemia vera with alterations in Epo or Jak2. Significantly, the increased hematocrit observed in Kit(V558Delta;T669I/+) mice normalized upon splenectomy. In accordance with increased erythroid progenitors, myeloerythroid progenitor numbers were also elevated in the Kit(V558Delta;T669I/+) mice. Hematopoietic stem cell (HSC) numbers in the bone marrow (BM) of Kit(V558Delta;T669I/+) mice were unchanged in comparison to wild-type mice. However, increased HSC numbers were observed in fetal livers and the spleen and peripheral blood of adult Kit(V558Delta;T669I/+) mice. Importantly, HSC from Kit(V558Delta;T669I/+) BM had a competitive advantage over wild-type HSC. In response to 5-fluorouracil treatment, elevated numbers of dividing Lin(-) Sca(+) cells were found in the Kit(V558Delta;T669I/+) BM compared to wild type. Our study demonstrates that signaling from the Kit(V558Delta;T669I/+) receptor has important consequences in hematopoiesis enhancing HSC self-renewal and resulting in increased erythropoiesis. PMID- 23681921 TI - Chemometric approach for fast analysis of prometryn in human hair by GC-MS. AB - A method for the fast analysis of a specific component in complex samples by GC MS was developed and used for the quantitative determination of prometryn in hair samples. In this method, the tedious and time-consuming sample pretreatment for purification was avoided, and a short capillary column and fast temperature program were employed to speed up the analysis. Although the measured total ion chromatogram is composed of overlapping peaks with interference and background noise, the signal of prometryn can be extracted by chemometric methods. Window independent component analysis was used to extract the mass spectrum and a non negative immune algorithm was employed to obtain the chromatographic profile of the interesting component from the measured data. Due to the complexity of the matrix, a standard addition method was adopted for the quantification. The applicability of the method was validated with spiked samples, and the recoveries were in the range of 99-105%. PMID- 23681922 TI - Heat shock protein 70 and albuminuria in patients with type 2 diabetes: a matched case control study. AB - Here, we aimed to study serum heat shock protein (HSP) 70 levels in diabetic patients with and without albuminuria. We performed a 1:1 matched case control study on 40 diabetic patients with albuminuria as cases and 40 age, sex, body mass index matched diabetic patients without albuminuria (normoalbuminuria) as controls. Normoalbuminuria was defined as urinary albumin excretion rate <15 mg/12 h, and albuminuria was defined as urinary albumin excretion rate between 100-400 mg/12 h. Patients with albuminuria had a higher HSP70 than controls (0.83 +/- 0.50 vs. 0.63 +/- 0.06; p = 0.02), while they did not differ in any other studied variables. In ten of the studied pairs, the controls had higher HSP70 levels than cases (reverse relationship). Patients in the "direct relationship group" had higher HbA1c values than the patients in the "reverse relationship group" (8.9 +/- 0.3 vs. 7.3 +/- 0.6, p = 0.04). Cases in the reverse pairs had a lower low density lipoprotein cholesterol levels than their controls. The odds ratio of HSP70 in the prediction of albuminuria was (28.69 (3.2-250.1), p = 0.002). In conclusion, we have shown an increased HSP70 levels in diabetic patients with albuminuria. PMID- 23681923 TI - Heart rate variability indices for very short-term (30 beat) analysis. Part 2: validation. AB - Heart rate variability (HRV) analysis over shorter periods may be useful for monitoring dynamic changes in autonomic nervous system activity where steady state conditions are not maintained (e.g. during drug administration, or the start or end of exercise). This study undertakes a validation of 70 HRV indices that have previously been identified as possible for short-term use. The indices were validated over 10 * 30 beat windows using PhysioNet databases with physiological states of rest, active, exercising, sleeping, and meditating (N from 12 to 20). Baseline 95 % confidence intervals of the median were established with bootstrap resampling (10,000x). Statistical significance was assessed using the overlap of 95 % confidence intervals. Thirty-one indices could differentiate between resting and at least one physiological state using 30 beat windows. All respiratory sinus arrhythmia indices and Poincare plot indices were strongly correlated to time domain measures (SDNN or RMSSD). Spectral indices using the Lomb-Scargle algorithm were able to correctly identify paradoxical shifts in power with meditation and reduced power in exercise. Some less-known indices gave interesting results: PolVar20 identified the higher sympathetic activity of exercise with the largest positive magnitude. These indices should now be considered for rigorous gold standard tests with pharmacological blockade. PMID- 23681924 TI - Validation of the new Complior sensor to record pressure signals non-invasively. AB - The Complior device (Alam Medical, France) has contributed to the rise of arterial stiffness as a measure of cardiovascular risk. In its latest version (Complior Analyse) the sensor records pressure instead of distension waveforms thus allowing the measurement of central pressure and pulse wave analysis. The aim of our study was to verify that the new sensor measures pressure waveforms accurately in both time and frequency domain. Invasive and non-invasive signals were recorded simultaneously at the radial artery and compared in the frequency and time domain in haemodynamically stable intensive care unit patients. Twelve patients entered the study (8 men, 4 women, mean age 69 +/- 17 years). Heart rate was 90 +/- 15 bpm, systolic blood pressure 133 +/- 19 mmHg and diastolic blood pressure 68 +/- 15 mmHg. There was no statistical difference in the amplitude of harmonics between the invasive signal and Complior signal. When superimposing waveforms in the time domain, there was a small difference in the form factor (4.2 +/- 2.8 %) and in the absolute area between the 2 waveforms (3.3 +/- 1.7 mmHg.s(-1)). These differences were of the same magnitude as the beat-to-beat variation of the form factor (3.3 %) and of the absolute area (3.1 mmHg.s(-1)), respectively. The second systolic peak was detectable in 4 subjects, with no statistical difference between invasive and non-invasive values. The new pressure sensor of the Complior Analyse device recorded pressure waveforms accurately and could be used to perform pressure wave analysis. PMID- 23681925 TI - Clinical study results from a randomized controlled trial of cognitive behavioural guided self-help in patients with partially remitted depressive disorder. AB - OBJECTIVES: Cognitive behavioural guided self-help has been shown to be effective in mild and moderate depressive disorder. It is not known, however, if it is effective in individuals with partially remitted depressive disorder, which is a serious clinical problem in up to 50-60% of treated patients. This study is the first one to examine the clinical benefit of this intervention in this patient population. DESIGN: For the purpose of this study, a single-blind, randomized controlled design was used. METHOD: We randomized 90 individuals with partially remitted depressive disorder either to cognitive behavioural guided self-help plus psychopharmacotherapy (n = 49) or psychopharmacotherapy alone (n = 41). They were clinically assessed at regular intervals with ratings of depressive symptoms and stress-coping strategies over a 3-week run-in period and a 6-week treatment period. RESULTS: After 6 weeks, intention-to-treat analysis (n = 90) showed that patients treated with cognitive behavioural guided self-help plus psychopharmacotherapy did not have significantly lower scores on the Hamilton Rating Scale of Depression (17-item version; HRSD-17) and on the Beck Depression Inventory (BDI) compared to patients treated with psychopharmacotherapy alone. When negative stress-coping strategies were considered, there was a significant difference between the two groups at the end of treatment with respect to the BDI but not to the HRSD-17. CONCLUSIONS: Guided self-help did not lead to a significant reduction in symptom severity in patients with partially remitted depressive disorder after a 6-week intervention. However, the intervention leads to a reduction of negative stress-coping strategies. PRACTITIONER POINTS: Cognitive behavioural guided self-help did not significantly improve depressive symptoms measured with the Hamilton Rating Scale of Depression (17-item version; HRSD-17) in patients with partially remitted depressive disorder. Improvements were found in reducing negative stress-coping strategies for those allocated to the cognitive behavioural guided self-help, which significantly improved Beck Depression Inventory but not HRSD-17. These findings suggest that cognitive behavioural guided self-help may offer some assistance in managing negative stress-coping strategies. PMID- 23681926 TI - Conserved epitopes dominate cross-CD8+ T-cell responses against influenza A H1N1 virus among Asian populations. AB - Novel strains of influenza A viruses (IAVs) have emerged with high infectivity and/or pathogenicity in recent years, causing worldwide concern. T cells are correlated with protection in humans through cross-reactive immunity against heterosubtypes of IAV. However, the different hierarchical roles of IAV-derived epitopes with distinct levels of polymorphism in the cross-reactive T-cell responses against IAV remain elusive. In this study, immunodominant epitopes scattered throughout the entire proteome of 2009 pandemic influenza A H1N1 virus and seasonal IAVs were synthesized and divided into different pools depending on their conservation. The overall profile of the IAV-specific CD8(+) T-cell immunity was detected by utilizing these peptide pools and also individual peptides. A dominant role of the conserved peptide-specific T-cell immunity was illuminated within the anti-IAV responses, while the CD8(+) T-cell responses against the variable epitopes were lower than the conserved peptides. As previously demonstrated within a Caucasian population, we determined that GL9 specific T cells, which also utilize Vbeta 17 TCR (BV19), play a pivotal role in IAV-specific T-cell immunity within an HLA-A2(+) Asian population. Our study objectively reveals the different predominant roles of T-cell epitopes among IAV specific cross-reactive cellular immunity. This may guide the development of vaccines with cross-T-cell immunogenicity against heterosubtypes of IAV. PMID- 23681927 TI - Knowledge on the line: manipulating beliefs about the magnitudes of symbolic numbers affects the linearity of line estimation tasks. AB - It has been suggested that differences in performance on number-line estimation tasks are indicative of fundamental differences in people's underlying representations of numerical magnitude. However, we were able to induce logarithmic-looking performance in adults for magnitude ranges over which they can typically perform linearly by manipulating their familiarity with the symbolic number formats that we used for the stimuli. This serves as an existence proof that individuals' performances on number-line estimation tasks do not necessarily reflect the functional form of their underlying numerical magnitude representations. Rather, performance differences may result from symbolic difficulties (i.e., number-to-symbol mappings), independently of the underlying functional form. We demonstrated that number-line estimates that are well fit by logarithmic functions need not be produced by logarithmic functions. These findings led us to question the validity of considering logarithmic-looking performance on number-line estimation tasks as being indicative that magnitudes are being represented logarithmically, particularly when symbolic understanding is in question. PMID- 23681928 TI - Don't just repeat after me: retrieval practice is better than imitation for foreign vocabulary learning. AB - Second language (L2) instruction programs often ask learners to repeat aloud words spoken by a native speaker. However, recent research on retrieval practice has suggested that imitating native pronunciation might be less effective than drill instruction, wherein the learner is required to produce the L2 words from memory (and given feedback). We contrasted the effectiveness of imitation and retrieval practice drills on learning L2 spoken vocabulary. Learners viewed pictures of objects and heard their names; in the imitation condition, they heard and then repeated aloud each name, whereas in the retrieval practice condition, they tried to produce the name before hearing it. On a final test administered either immediately after training (Exp. 1) or after a 2-day delay (Exp. 2), retrieval practice produced better comprehension of the L2 words, better ability to produce the L2 words, and no loss of pronunciation quality. PMID- 23681929 TI - Grasping the invisible: semantic processing of abstract words. AB - The problem of how abstract word meanings are represented has been a challenging one. In the present study, we extended the semantic richness approach (e.g., Yap, Tan, Pexman, & Hargreaves in Psychonomic Bulletin & Review 18:742-750, 2011) to abstract words, examining the effects of six semantic richness variables on lexical-semantic processing for 207 abstract nouns. The candidate richness dimensions were context availability (CA), sensory experience rating (SER), valence, arousal, semantic neighborhood (SN), and number of associates (NoA). The behavioral tasks were lexical decision (LDT) and semantic categorization (SCT). Our results showed that the semantic richness variables were significantly related to both LDT and SCT latencies, even after lexical and orthographic factors were controlled. The patterns of richness effects varied across tasks, with CA effects in the LDT, and SER and valence effects in the SCT. These results provide new insight into how abstract meanings may be grounded, and are consistent with a dynamic, multidimensional framework for semantic processing. PMID- 23681931 TI - In vivo bio-safety evaluations and diagnostic/therapeutic applications of chemically designed mesoporous silica nanoparticles. AB - The remarkable progress of nanotechnology and its application in biomedicine have greatly expanded the ranges and types of biomaterials from traditional organic material-based nanoparticles (NPs) to inorganic biomaterials or organic/inorganic hybrid nanocomposites due to the unprecedented advantages of the engineered inorganic material-based NPs. Colloidal mesoporous silica NPs (MSNs), one of the most representative and well-established inorganic materials, have been promoted into biology and medicine, and shifted from extensive in vitro research towards preliminary in vivo assays in small-animal disease models. In this comprehensive review, the recent progresses in chemical design and engineering of MSNs-based biomaterials for in vivo biomedical applications has been detailed and overviewed. Due to the intrinsic structural characteristics of elaborately designed MSNs such as large surface area, high pore volume and easy chemical functionalization, they have been extensively investigated for therapeutic, diagnostic and theranostic (concurrent diagnosis and therapy) purposes, especially in oncology. Systematic in vivo bio-safety evaluations of MSNs have revealed the evidences that the in vivo bio-behaviors of MSNs are strongly related to their preparation prodecures, particle sizes, geometries, surface chemistries, dosing parameters and even administration routes. In vivo pharmacokinetics and pharmacodynamics further demonstrated the effectiveness of MSNs as the passively and/or actively targeted drug delivery systems (DDSs) for cancer chemotherapy. Especially, the advance of nano-synthetic chemistry enables the production of composite MSNs for advanced in vivo therapeutic purposes such as gene delivery, stimuli-responsive drug release, photothermal therapy, photodynamic therapy, ultrasound therapy, or anti-bacteria in tissue engineering, or as the contrast agents for biological and diagnostic imaging. Additionally, the critical issues and potential challenges related to the chemical design/synthesis of MSNs-based "magic bullet" by advanced nano-synthetic chemistry and in vivo evaluation have been discussed to highlight the issues scientists face in promoting the translation of MSNs-based DDSs into clinical trials. PMID- 23681932 TI - Eating disorders with and without comorbid depression and anxiety: similarities and differences in a clinical sample of children and adolescents. AB - OBJECTIVE: This study aimed to describe and compare the demographic and clinical characteristics of children and adolescents with an eating disorder (ED) and comorbid depression or anxiety. METHOD: Data were drawn from intake assessments of children and adolescents at a specialist ED clinic. Demographic characteristics (e.g. age and gender) and clinical characteristics (e.g. body mass, binge eating and purging) were compared between 217 ED participants without comorbidity, 32 with comorbid anxiety, 86 with comorbid depression and 36 with comorbid anxiety and depression. RESULTS: The groups with comorbid depression had more complex and severe presentations compared with those with an ED and no comorbid disorder and those with comorbid anxiety alone, especially in regard to binge eating, purging, dietary restraint and weight/shape concerns. DISCUSSION: Depression and anxiety were differentially related to clinical characteristics of EDs. The findings have implications for understanding the relations between these disorders and their potential to impact outcome of ED treatments. PMID- 23681930 TI - The 6-minute walk test and other endpoints in Duchenne muscular dystrophy: longitudinal natural history observations over 48 weeks from a multicenter study. AB - INTRODUCTION: Duchenne muscular dystrophy (DMD) subjects >=5 years with nonsense mutations were followed for 48 weeks in a multicenter, randomized, double-blind, placebo-controlled trial of ataluren. Placebo arm data (N = 57) provided insight into the natural history of the 6-minute walk test (6MWT) and other endpoints. METHODS: Evaluations performed every 6 weeks included the 6-minute walk distance (6MWD), timed function tests (TFTs), and quantitative strength using hand-held myometry. RESULTS: Baseline age (>=7 years), 6MWD, and selected TFT performance are strong predictors of decline in ambulation (Delta6MWD) and time to 10% worsening in 6MWD. A baseline 6MWD of <350 meters was associated with greater functional decline, and loss of ambulation was only seen in those with baseline 6MWD <325 meters. Only 1 of 42 (2.3%) subjects able to stand from supine lost ambulation. CONCLUSION: Findings confirm the clinical meaningfulness of the 6MWD as the most accepted primary clinical endpoint in ambulatory DMD trials. PMID- 23681933 TI - Facile polymer functionalization of hydrothermal-carbonization-derived carbons. AB - A simple and efficient polymer grafting onto hydrothermal carbonization (HTC) derived materials is described. The method pertains to the Diels-Alder cycloaddition reaction of furan moieties present on the surface of a HTC material with the maleimide groups stemming from a maleimide protected poly(ethylene glycol) (Me-PEG-MI) by a retro Diels-Alder reaction. The precursor polymer, HTC material, and final product are characterized. Successful grafting is confirmed by elemental analysis, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, and dispersion studies. PMID- 23681934 TI - Brief intervention to preteens and adolescents to create smoke-free homes and cotinine results: a randomized trial. AB - BACKGROUND: Little research has focused on brief and practical strategies for addressing environmental tobacco smoke exposure through interventions focused explicitly on creating a smoke-free home. METHODS: We used a two-group (intervention and control groups) repeated-measures randomized controlled trial design. Families were randomized to the intervention (n = 176) or control (n = 176) condition after the baseline interview, with outcome assessments for reported and urine cotinine measures at 2 (post-intervention), 6 (follow-up) and 12 (follow-up) months. RESULTS: Baseline urinary cotinine levels of both groups were not statistically significantly different (P > 0.05); however, post intervention urinary cotinine levels were significantly different at 2, 6 and 12 months after start of the study (P < 0.001). CONCLUSION: As a physician-based brief intervention, our intervention was effective. Clinical providers might offer feedback and brief interventions to preteens and adolescents. Because of the ease of intervention on delivery, this intervention has the potential to have significant impact if widely disseminated. PMID- 23681935 TI - Psychometric properties of the primary care behavioral health screen. AB - The Primary Care Behavioral Health Screen (PCBHS) is a self-report instrument developed to screen for behavioral health problems in primary care settings. The present paper describes development of the PCBHS and reports findings from item analyses and studies examining the instrument's convergent validity and test retest reliability. Results suggest the PCBHS is a useful and valid method for screening a variety of behavioral health problems in a busy primary care practice. Recommendations for further research on the PCBHS are provided. PMID- 23681936 TI - Contribution of ADAMTS1 as a tumor suppressor gene in human breast carcinoma. Linking its tumor inhibitory properties to its proteolytic activity on nidogen-1 and nidogen-2. AB - The extracellular protease ADAMTS1 (A disintegrin and metalloprotease with thrombospondin repeats 1) has been described as an anti-angiogenic molecule and its role as a putative tumor protective molecule has also been suggested. Here, we have used a tumor xenograft model to determine the role of ADAMTS1 in tumor growth and angiogenesis. Increasing levels of the protease led to the complete inhibition of tumor growth. In an attempt to elucidate the mechanism of action of this protease, we focused our attention on its proteolytic activity on nidogens, one of the main components of the vascular basement membrane. The increased expression of ADAMTS1 was accompanied by increased proteolysis of nidogen-1 and 2 and their almost complete removal from vascular structures, together with major morphological alterations of tumor blood vessels and a decreased vessel density. The clinical relevance of this work is supported by our observations that ADAMTS1 expression is decreased in breast tumor specimens when compared with healthy tissue. Our studies also reveal that the cleavage of nidogen-1 and -2 is partially inhibited in human tumor samples. Moreover, the deposition of both nidogens surrounding vascular structures is drastically altered, implying a possible reduction in the maintenance of vessel integrity. Our studies reflect the requirement to explore the functional interactions between proteases and specific substrates in cancer biology. PMID- 23681937 TI - Research on benzene, toluene and dimethylbenzene detection based on a cataluminescence sensor. AB - We present a sensitive and quick way to determine benzene, toluene and dimethylbenzene (BTEX) in air, applying a cataluminescence (CTL) sensor based on a nano-sized composite material, gamma-Al2O3/PtO2. The factors that affect the sensor's performance were studied, including the sensing material, temperature, rate of air carrier and wavelength. It was shown that when Pt accounted for 0.2% of the sensing material, the rate of the air carrier that carries target gas was 450 mL/min, the determination wavelength was 400 nm and temperature was 236 degrees C, this sensor showed the best CTL intensity to BTEX. In addition, the CTL intensity had a high linear relation with the concentration of BTEX, with a linear range from 0.5 to 100 mL/m(3), and a detection limit 0.22 mL/m(3). This nano-sized material had a quick response within 1.5 s, short recovery time within 1 min and a long lifetime, showing good potential for a variety of applications. PMID- 23681938 TI - Novel solvent-free microwave-assisted extraction coupled with low-density solvent based in-tube ultrasound-assisted emulsification microextraction for the fast analysis of organophosphorus pesticides in soils. AB - A novel and rapid solventless microwave-assisted extraction coupled with low density solvent-based in-tube ultrasound-assisted emulsification microextraction has been developed for the efficient determination of nine organophosphorus pesticides in soils by GC analysis with microelectron capture detection. A specially designed, homemade glass tube inbuilt with a scaled capillary tube was used as an extraction device to collect and measure the separated extractant phase easily. Parameters affecting the efficiencies of the developed method were thoroughly investigated. From experimental results, the following conditions were selected for the extraction of organophosphorus pesticides from 1.0 g of soil sample to 5 mL of aqueous solution under 226 W of microwave irradiation for 2.5 min followed by ultrasound-assisted emulsification microextraction with 20 MUL toluene for 30 s and then centrifugation at 3200 rpm for 3 min. Detections were linear in the range of 0.25-10 ng/g with detection limits between 0.04 and 0.13 ng/g for all target analytes. The applicability of the method to real samples was assessed on agricultural contaminated soils and the recoveries ranged between 91.4 and 101.3%. Compared to other methods, the present method was shown to be highly competitive in terms of sensitivity, cost, eco-friendly nature, and analysis speed. PMID- 23681939 TI - Functional transplantation of salivary gland cells differentiated from mouse early ES cells in vitro. AB - Atrophy or hypofunction of the salivary gland because of aging or disease causes hyposalivation and has an effect on the quality of life of patients, for example not only dry mouth but deterioration in mastication/deglutition disorder and the status of oral hygiene. Currently conducted therapies for atrophy or hypofunction of the salivary gland in clinical practice are only symptomatic treatments with drugs and artificial saliva, and therefore it is preferable to establish a radical therapy. At this time, as a fundamental investigation, by co-culturing mouse early ES (mEES-6) cells with human salivary gland-derived fibroblasts (hSG fibro), differentiation of mEES-6 cells to salivary gland cells has been attempted. Also, the possibility of cell engraftment was examined. After identifying the cells which were co-cultured with GFP-transfected mEES-6 cells and hSG-fibro, the cells were transplanted into the submandibular gland of SCID mice, and the degree of differentiation into tissues was examined. The possibility of tissue functional reconstitution from co-cultured cells in a three dimensional culture system was examined. Our results confirmed that the co cultured cells expressed salivary gland-related markers and had an ability to generate neo-tissues by transplantation in vivo. Moreover, the cells could reconstitute gland structures in a three-dimensional culture system. By co culture with hSG-fibro, mEES-6 cells were successfully differentiated into salivary gland cells which were transplantable and have tissue neogenetic ability. PMID- 23681941 TI - Fluorogenic probing of specific recognitions between sugar ligands and glycoprotein receptors on cancer cells by an economic graphene nanocomposite. AB - Economical nanocomposites based on pi-stacking of N-acetyl glycosyl rhodamine B to graphene oxide (GO) are simply prepared. These "sweet" GO-materials are proven to be admirable for the fluorogenic recognition of specific intercellular sugar based ligand-glycoprotein receptor interactions of interest. PMID- 23681940 TI - SMA valiant trial: a prospective, double-blind, placebo-controlled trial of valproic acid in ambulatory adults with spinal muscular atrophy. AB - INTRODUCTION: An open-label trial suggested that valproic acid (VPA) improved strength in adults with spinal muscular atrophy (SMA). We report a 12-month, double-blind, cross-over study of VPA in ambulatory SMA adults. METHODS: There were 33 subjects, aged 20-55 years, included in this investigation. After baseline assessment, subjects were randomized to receive VPA (10-20 mg/kg/day) or placebo. At 6 months, patients were switched to the other group. Assessments were performed at 3, 6, and 12 months. The primary outcome was the 6-month change in maximum voluntary isometric contraction testing with pulmonary, electrophysiological, and functional secondary outcomes. RESULTS: Thirty subjects completed the study. VPA was well tolerated, and compliance was good. There was no change in primary or secondary outcomes at 6 or 12 months. CONCLUSIONS: VPA did not improve strength or function in SMA adults. The outcomes used are feasible and reliable and can be employed in future trials in SMA adults. PMID- 23681942 TI - Synthesis and biological evaluation of pyrazoline derivatives bearing an indole moiety as new antimicrobial agents. AB - 1-(p-Methylphenyl)-3,5-diaryl-2-pyrazoline derivatives (2a-f) were synthesized via the treatment of 1-(1H-indol-3-yl)-3-aryl-2-propen-1-ones (1a-f) with p methylphenylhydrazine hydrochloride in hot acetic acid. The structures of these compounds were elucidated by IR, 1H NMR, and mass spectral data and elemental analysis. These compounds were investigated for their antimicrobial activity. Brine-Shrimp lethality assay was carried out to determine the toxicity of the compounds. Compound 2e, which is the pyrazoline derivative bearing the 2,5 dichlorophenyl moiety, can be identified as the most promising agent against Klebsiella pneumoniae (ATCC 13883) and Candida glabrata (ATCC 36583) due to its inhibitory effects on K. pneumoniae and C. glabrata with a MIC value of 100 ug/mL as a non-toxic agent (LC50 > 1000 ug/mL). PMID- 23681943 TI - Photoacoustic and photothermal detection of circulating tumor cells, bacteria and nanoparticles in cerebrospinal fluid in vivo and ex vivo. AB - Circulating cells, bacteria, proteins, microparticles, and DNA in cerebrospinal fluid (CSF) are excellent biomarkers of many diseases, including cancer and infections. However, the sensitivity of existing methods is limited in their ability to detect rare CSF biomarkers at the treatable, early-stage of diseases. Here, we introduce novel CSF tests based on in vivo photoacoustic flow cytometry (PAFC) and ex vivo photothermal scanning cytometry. In the CSF of tumor-bearing mice, we molecularly detected in vivo circulating tumor cells (CTCs) before the development of breast cancer brain metastasis with 20-times higher sensitivity than with current assays. For the first time, we demonstrated assessing three pathways (i.e., blood, lymphatic, and CSF) of CTC dissemination, tracking nanoparticles in CSF in vivo and their imaging ex vivo. In label-free CSF samples, we counted leukocytes, erythrocytes, melanoma cells, and bacteria and imaged intracellular cytochromes, hemoglobin, melanin, and carotenoids, respectively. Taking into account the safety of PAFC, its translation for use in humans is expected to improve disease diagnosis beyond conventional detection limits. PMID- 23681945 TI - Anionic polysaccharides as templates for the synthesis of conducting polyaniline and as structural matrix for conducting biocomposites. AB - A green chemoenzymatic pathway for the synthesis of conducting polyaniline (PANI) composites is presented. Laccase-catalyzed polymerization in combination with anionic polysaccharides is used to produce polysaccharide/PANI composites, which can be processed into flexible films or coated onto cellulose surfaces. Different polysaccharide templates are assessed, including kappa-carrageenan, native spruce O-acetyl galactoglucomannan (GGM), and TEMPO-oxidized cellulose and GGM. The resulted conducting biocomposites derived from natural materials provide a broad range of potential applications, such as in biosensors, electronic devices, and tissue engineering. PMID- 23681944 TI - Relationship between sleep disturbance and depression, anxiety, and functioning in college students. AB - BACKGROUND: Sleep disturbance (SD) has complex associations with depression, both preceding and following the onset and recurrence of depression. We hypothesized that students with depressive symptoms with SD would demonstrate a greater burden of comorbid psychiatric symptoms and functional impairment compared to students with depressive symptoms without SD. METHODS: During a mental health screening, 287 undergraduate students endorsed symptoms of depression (Beck Depression Inventory [BDI] >= 13) and filled out the following self-report measures: demographic questionnaire, BDI, Anxiety Symptom Questionnaire-intensity and frequency (ASQ), Beck Hopelessness Scale (BHS), Beck Anxiety Inventory (BAI), Quality of Life Enjoyment and Satisfaction Questionnaire (QLESQ), and the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ). SD was measured using the BDI sleep item #16 dichotomized (score 0: no SD; or score > 0: some SD). RESULTS: Students with depressive symptoms and SD (n = 220), compared to those without SD (n = 67), endorsed significantly more intense and frequent anxiety and poorer cognitive and physical functioning. Students with depressive symptoms with and without SD did not significantly differ in depressive severity, hopelessness, or quality of life. CONCLUSIONS: College students with depressive symptoms with SD may experience a greater burden of comorbid anxiety symptoms and hyperarousal, and may have impairments in functioning, compared to students with depressive symptoms without SD. These findings require replication. PMID- 23681946 TI - Bis(2-hydroxy-3-isopropyl-6-methyl-benzaldehyde)ethylenediamine: a novel cation sensor. AB - Novel substituted phenol-based new symmetrical bis(2-hydroxy-3-isopropyl-6-methyl benzaldehyde)ethylenediamine (1) has been designed and synthesized. The compound 1 fluorometrically recognized Cu(2+) ion in CH3OH/H2O (90:10, v/v) by exhibiting an increase in emission upon complexation. In addition, Cu(2+) gave rise to a change in colour of the solution of compound 1, which was clearly visible to the naked eye under UV irradiation. The association constant (K) of compound 1 with Cu(2+) ion was computed with the Benesi-Hildebrand plot and Scatchard plot at 43,000 M(-1) and 43,011 M(-1) respectively. PMID- 23681948 TI - Lean laboratories: laboratory medicine needs to learn from other industries how to deliver more for less. PMID- 23681947 TI - Synthesis, photo-physical and DFT studies of ESIPT inspired novel 2-(2',4' dihydroxyphenyl) benzimidazole, benzoxazole and benzothiazole. AB - Novel ESIPT inspired benzimidazole, benzoxazole and benzothiazole were synthesized from 2,4-dihydroxy benzoic acid and 1,2-phenelenediamine, 2 aminophenol, and 2-aminothiophenol respectively. The synthesized 2-(2',4' dihydroxyphenyl) benzimidazole, benzoxazole and benzothiazole are fluorescent and the emission characteristic are very sensitive to the micro-environment. They show a single absorption and dual emission with large Stokes shift originating from excited state intramolecular proton transfer. The absorption-emission characteristics of all these compounds are studied as a function of pH. The change in the electronic transition, energy levels, and orbital diagrams of synthesized compounds were investigated by the molecular orbital calculation and were correlated with the experimental spectral emission. Experimental absorption and emission wavelengths are in good agreement with those predicted using the Density Functional Theory (DFT) and Time-Dependent Density Functional Theory (TD DFT) [B3LYP/6-31G(d)]. PMID- 23681949 TI - Audit of the practice of sputum smear examination for patients with suspected pulmonary tuberculosis in Fiji. AB - BACKGROUND: In Fiji, patients with suspected pulmonary tuberculosis (PTB) currently submit three sputum specimens for smear microscopy for acid-fast bacilli, but there is little information about how well this practice is carried out. METHODS: A cross-sectional retrospective review was carried out in all four TB diagnostic laboratories in Fiji to determine among new patients presenting with suspected PTB in 2011: the quality of submitted sputum; the number of sputum samples submitted; the relationship between quality and number of submitted samples to smear-positivity; and positive yield from first, second and third samples. RESULTS: Of 1940 patients with suspected PTB, 3522 sputum samples were submitted: 997 (51.4%) patients submitted one sample, 304 (15.7%) patients submitted two samples and 639 (32.9%) submitted three samples. Sputum quality was recorded in 2528 (71.8%) of samples, of which 1046 (41.4%) were of poor quality. Poor quality sputum was more frequent in females, inpatients and children (0-14 years). Good quality sputum and a higher number of submitted samples positively correlated with smear-positivity for acid-fast bacilli. There were 122 (6.3%) patients with suspected PTB who were sputum smear positive. Of those, 89 had submitted three sputum samples: 79 (89%) were diagnosed based on the first sputum sample, 6 (7%) on the second sample and 4 (4%) on the third sample. CONCLUSION: This study shows that there are deficiencies in the practice of sputum smear examination in Fiji with respect to sputum quality and recommended number of submitted samples, although the results support the continued use of three sputum samples for TB diagnosis. Ways to improve sputum quality and adherence to recommended guidelines are needed. PMID- 23681950 TI - Highly efficient differentiation of functional hepatocytes from human induced pluripotent stem cells. AB - Human induced pluripotent stem cells (hiPSCs) hold great potential for use in regenerative medicine, novel drug development, and disease progression/developmental studies. Here, we report highly efficient differentiation of hiPSCs toward a relatively homogeneous population of functional hepatocytes. hiPSC-derived hepatocytes (hiHs) not only showed a high expression of hepatocyte-specific proteins and liver-specific functions, but they also developed a functional biotransformation system including phase I and II metabolizing enzymes and phase III transporters. Nuclear receptors, which are critical for regulating the expression of metabolizing enzymes, were also expressed in hiHs. hiHs also responded to different compounds/inducers of cytochrome P450 as mature hepatocytes do. To follow up on this observation, we analyzed the drug metabolizing capacity of hiHs in real time using a novel ultra performance liquid chromatography-tandem mass spectrometry. We found that, like freshly isolated primary human hepatocytes, the seven major metabolic pathways of the drug bufuralol were found in hiHs. In addition, transplanted hiHs engrafted, integrated, and proliferated in livers of an immune-deficient mouse model, and secreted human albumin, indicating that hiHs also function in vivo. In conclusion, we have generated a method for the efficient generation of hepatocytes from induced pluripotent stem cells in vitro and in vivo, and it appears that the cells function similarly to primary human hepatocytes, including developing a complete metabolic function. These results represent a significant step toward using patient/disease-specific hepatocytes for cell-based therapeutics as well as for pharmacology and toxicology studies. PMID- 23681951 TI - Transplantation of CD15-enriched murine neural stem cells increases total engraftment and shifts differentiation toward the oligodendrocyte lineage. AB - Neural stem cell (NSC) transplantation is a promising therapeutic approach for neurological diseases. However, only a limited number of cells can be transplanted into the brain, resulting in relatively low levels of engraftment. This study investigated the potential of using a cell surface marker to enrich a primary NSC population to increase stable engraftment in the recipient brain. NSCs were enriched from the neonatal mouse forebrain using anti-CD15 (Lewis X antigen, or SSEA-1) in a "gentle" fluorescence-activated cell sorting protocol, which yielded >98% CD15-positive cells. The CD15-positive cells differentiated into neurons, astrocytes, and oligodendrocytes in vitro, after withdrawal of growth factors, demonstrating multipotentiality. CD15-positive cells were expanded in vitro and injected bilaterally into the ventricles of neonatal mice. Cells from enriched and unenriched donor populations were found throughout the neuraxis, in both neurogenic and non-neurogenic regions. Total engraftment was similar at 7 days postinjection, but by 28 days postinjection, after brain organogenesis was complete, the survival of donor cells was significantly increased in CD15-enriched grafts over the unenriched cell grafts. The engrafted cells were heterogeneous in morphology and differentiated into all three neural lineages. Furthermore, in the CD15-enriched grafts, there was a significant shift toward differentiation into oligodendrocytes. This strategy may allow better delivery of therapeutic cells to the developing central nervous system and may be particularly useful for treating diseases involving white matter lesions. PMID- 23681952 TI - Patterns of cortical reorganization in the adult marmoset after a cervical spinal cord injury. AB - In the present study, we used microelectrode recordings of multiunit responses to evaluate patterns of the reactivation of somatosensory cortex after sensory loss produced by spinal cord lesions in the common marmoset (Callithrix jacchus). These New World monkeys have become a popular model in studies of cortical organization and function. Primary somatosensory cortex and adjoining somatosensory areas can become extensively deactivated by lesions of somatosensory afferents as they ascend in the dorsal columns of the cervical spinal cord. Six to 7 weeks after complete lesions of the cuneate fasciculus subserving the forelimb at cervical levels 5-6, the hand region in contralateral areas 3b and 1 was reactivated by inputs from the forelimb, but excluded representations of some or all digits. In a similar manner, recording sites from the forelimb region of areas 2-5 responded to parts of the forelimb but not to digits after an extensive lesion of the contralateral cuneate fasciculus at C5 C6. Lesions that damaged only the gracile fasciculus or a small percentage of the cuneate fasciculus did not produce changes in the gross hand representation in contralateral areas 3b, 3a, 1, and 2. Finally, a complete but lower lesion of the cuneate fasciculus at C8 produced some abnormalities in the reactivation, but the digits were represented. The results indicate that areas 3a, 3b, 1, and 2-5 of the somatosensory cortex are extensively reactivated after large, apparently complete lesions of the contralateral cuneate fasciculus, but afferents from the digits may not contribute to their reactivation. PMID- 23681953 TI - Spectrofluorimetric analysis of gemifloxacin mesylate in pharmaceutical formulations. AB - A simple, rapid and highly sensitive spectrofluorimetric method was developed for determination of gemifloxacin mesylate (GFX) in tablets. The method is based on measuring the native fluorescence of GFX in isopropanol at 400 nm after excitation at 272 nm. The fluorescence-concentration plot was rectilinear over the range of 0.01-0.50 ug/mL with a lower detection limit of 1.19 ng/mL and quantification limit of 3.6 ng/mL. The method was fully validated and successfully applied to the determination of GFX tablets with an average percentage recovery of 99.65 +/- 0.532. The method was extended to the stability study of GFX. The drug was exposed to acidic, alkaline, oxidative and photolytic degradation according to International Conference on Harmonization guidelines. The rate of GFX degradation was found at its highest in acidic conditions, and in its lowest in the neutral one. However, it was stable under dry heat and photolytic degradation conditions. PMID- 23681955 TI - Clinically insignificant effect of supplemental vitamin C on serum urate in patients with gout: a pilot randomized controlled trial. AB - OBJECTIVE: Studies in human volunteers have shown that vitamin C reduces serum urate (SU) levels. The aim of this study was to determine the effects of vitamin C on SU levels in patients with gout. METHODS: Patients with gout and an SU level >0.36 mmoles/liter (6 mg/dl) were recruited. Twenty patients already taking allopurinol were randomized to receive an increase in the dose of allopurinol or to commence taking vitamin C (500 mg/day). Twenty patients who had not been taking allopurinol were randomized to start receiving either allopurinol (up to 100 mg/day) or vitamin C (500 mg/day). Levels of plasma ascorbate, creatinine, and SU were measured on day 0 and week 8. RESULTS: There was no significant difference in the baseline SU level or estimated glomerular filtration rate (eGFR) between those who received vitamin C and those who did not (for SU, mean +/- SEM 0.50 +/- 0.11 mmoles/liter [8.4 +/- 1.8 mg/dl] versus 0.50 +/- 0.09 mmoles/liter [8.4 +/- 1.5 mg/dl]; for eGFR, mean +/- SEM 65.5 +/- 3.5 ml/minute/1.73 m(2) versus 67.9 +/- 4.6 ml/minute/1.73 m(2) ). Among the randomized patients, 30% in the vitamin C group and 25% in the no vitamin C control group were receiving diuretics. In the patients receiving vitamin C, there was a significant increase between day 0 and week 8 in the plasma ascorbate level. The reduction in SU level over 8 weeks was significantly less in those patients receiving vitamin C compared to those who started or increased the dose of allopurinol (mean reduction 0.014 mmoles/liter [0.23 mg/dl] versus 0.118 mmoles/liter [1.9 mg/dl]; P < 0.001). CONCLUSION: A modest dosage of vitamin C (500 mg/day) for 8 weeks had no clinically significant urate-lowering effects in patients with gout, despite the fact that plasma ascorbate levels increased. These results differ from previous findings in healthy control subjects with hyperuricemia. The uricosuric effect of modest-dose vitamin C appears to be small in patients with gout, when administered as monotherapy or in combination with allopurinol. PMID- 23681954 TI - Twenty-four-hour ambulatory blood pressure reduction with a perindopril/amlodipine fixed-dose combination. AB - BACKGROUND: Most hypertensive patients need more than one agent to achieve blood pressure (BP) control. The fixed dose combinations can provide effective 24-h BP control, which is essential in hypertension management. AIMS: The primary objectives of the PErindopril/Amlodipine Reduction of blood pressure Level (PEARL) ABPM substudy were to assess the effect of a perindopril/amlodipine fixed dose combination on mean 24-h BP, daytime BP, and nighttime BP in a subgroup of PEARL patients. Secondary objectives included assessment of office BP, metabolic parameters (blood glucose and lipids), heart rate, and safety and tolerability. METHODS: PEARL was a 3-month observational study with a perindopril/amlodipine fixed-dose combination for treatment of outpatients with essential hypertension uncontrolled by prior treatment (office BP >=140/90 mmHg or >=130/80 mmHg in those at high/very high cardiovascular risk). In this ABPM substudy of PEARL, treatment efficacy was assessed by 24-h ABPM. At inclusion, previous angiotensin converting enzyme (ACE) inhibitors and/or calcium channel blockers (CCBs) were replaced by a perindopril/amlodipine fixed-dose combination at a dosage (5/5, 5/10, 10/5, or 10/10 mg) chosen by the physician and uptitrated at month 1, if required. ABPM and office BP measurements were assessed at inclusion, month 1, and month 3. Metabolic effects, heart rate, and adverse events were also monitored. RESULTS: Mean age of the 262 ABPM patients (144 males) was 60.4 +/- 11.7 years, and mean baseline office brachial systolic BP/diastolic BP was 159.8 +/- 16.0/94.3 +/- 10.3 mmHg. After 3 months, the perindopril/amlodipine fixed dose combination reduced mean 24-h ambulatory BP from 146.1/84.3 to 127.6/75.9 mmHg (p < 0.001). Mean office BP decreased to 131.1/80.0 mmHg (p < 0.001). Results were consistent in subgroups, defined by cardiovascular comorbidities or previous treatments. Favorable metabolic and heart rate effects were observed, and no serious adverse events were reported. CONCLUSIONS: Further effective, safe, and sustained 24-h ambulatory BP and office BP reductions were obtained by switching from ACE inhibitors and/or CCBs to a perindopril/amlodipine fixed-dose combination in outpatients with uncontrolled essential hypertension in a practice setting. For this type of patient, the use of a perindopril/amlodipine fixed-dose combination can be considered an effective and safe option to normalize BP. PMID- 23681956 TI - Materials for bioresorbable radio frequency electronics. AB - Materials, device designs and manufacturing approaches are presented for classes of RF electronic components that are capable of complete dissolution in water or biofluids. All individual passive/active components as well as system-level examples such as wireless RF energy harvesting circuits exploit active materials that are biocompatible. The results provide diverse building blocks for physically transient forms of electronics, of particular potential value in bioresorbable medical implants with wireless power transmission and communication capabilities. PMID- 23681957 TI - Nonfitting protein-ligand interaction scoring function based on first-principles theoretical chemistry methods: development and application on kinase inhibitors. AB - Targeted therapy is currently a hot topic in the fields of cancer research and drug design. An important requirement for this approach is the development of potent and selective inhibitors for the identified target protein. However, current ways to estimate inhibitor efficacy rely on empirical protein-ligand interaction scoring functions which, suffering from their heavy parameterizations, often lead to a low accuracy. In this work, we develop a nonfitting scoring function, which consists of three terms: (1) gas-phase protein ligand binding enthalpy obtained by the eXtended ONIOM hybrid method based on an integration of density functional theory (DFT) methods (XYG3 and omegaB97X-D) and the semiempirical PM6 method, (2) solvation free energy based on DFT-SMD solvation model, and (3) entropy effect estimated by using DFT frequency analysis. The new scoring function is tested on a cyclin-dependent kinase 2 (CDK2) inhibitor database including 76 CDK2 protein inhibitors and a p21 activated kinase 1 (PAK1) inhibitor database including 20 organometallic PAK1 protein inhibitors. From the results, good correlations are found between the calculated scores and the experimental inhibitor efficacies with the square of correlation coefficient R(2) of 0.76-0.88. This suggests a good predictive power of this scoring function. To the best of our knowledge, this is the first high level theory-based nonfitting scoring function with such a good level of performance. This scoring function is recommended to be used in the final screening of lead structure derivatives. PMID- 23681958 TI - Amorphous Cu-In-S nanoparticles as precursors for CuInSe2 thin-film solar cells with a high efficiency. AB - CuInSe2 (CISe) absorber layers for thin-film solar cells were fabricated through the selenization of amorphous Cu-In-S nanoparticles, which were prepared by using a low-temperature colloidal process within one minute without any external heating. Two strategies for obtaining highly dense CISe absorber films were used in this work; the first was the modification of nanoparticle surface through chelate complexation with ethanolamine, and the second strategy utilized the lattice expansion that occurred when S atoms in the precursor particles were replaced with Se during selenization. The synergy of these two strategies allowed formation of highly dense CISe thin films, and devices fabricated using the absorber layer demonstrated efficiencies of up to 7.94% under AM 1.5G illumination without an anti-reflection coating. PMID- 23681959 TI - CROI 2013: Basic science review. AB - The 20th Conference on Retroviruses and Opportunistic Infections was held in Atlanta, Georgia, and featured strong coverage in several basic science categories. Presentations on viral reservoir and cure research covered a variety of topics, including approaches to gauge viral reservoir size in patients on suppressive antiretroviral therapy, approaches to reactivate latently infected cells, and the role of residual replication in viral persistence under antiretroviral therapy. Research on viral restriction factors remains a strong feature of the conference, and presentations on the impact of viral restrictions on the establishment of viral reservoirs, as well as strategies that harness the antiviral potential of cellular restrictions, generated a lot of interest. Several studies on the nature of proviral latency left us with the sobering message that elimination of the latent viral pool is going to be an even greater challenge than previously suspected. PMID- 23681960 TI - CROI 2013: New tools to understand transmission dynamics and prevent HIV infections. AB - New tools to track HIV incidence and identify transmission networks are providing insights about the leading edge of new HIV infections globally. Phylogenetic analyses point to the continued global nature of HIV transmission patterns and the challenges to reducing HIV infections through targeted antiretroviral programs alone. New methods for measuring acute infection and HIV incidence using cross-sectional surveys are proving useful in tracking the impact of prevention programs at the population level. Globally, men who have sex with men, and young men and women continue to be at highest risk of HIV acquisition; the US South also bears a disparate burden of new HIV infections and poor HIV-related outcomes. The use of injectable hormonal contraception may increase HIV acquisition risk; new, effective contraceptive methods and contraceptive counseling are needed, as simply removing this strategy could lead to a net increase in deaths due to unintended pregnancies. Another preexposure prophylaxis efficacy trial failed to show protection, likely because of poor adherence by women in the trial. Fortunately, new strategies are being developed that could substantially reduce new infections globally, such as methods to increase adherence and the use of long-acting antiretroviral agents. PMID- 23681961 TI - CROI 2013: Complications of HIV disease, viral hepatitis, and antiretroviral therapy. AB - Studies with direct-acting antivirals (DAAs) for hepatitis C virus (HCV) monoinfection and HIV coinfection were highlighted at the 2013 Conference on Retroviruses and Opportunistic Infections (CROI). In HCV monoinfected patients, several interferon alfa-sparing, all-oral regimens demonstrated cure rates of greater than 90% with 12 weeks of treatment, including for hard-to-treat patients. Cure rates of 75% were attained in HIV/HCV coinfected patients with the addition of the investigational HCV protease inhibitor (PI) simeprevir to peginterferon alfa and ribavirin. Drug-drug interaction data to inform safe coadminstration of antiretroviral therapy with DAA-based HCV treatment were presented. There was continued emphasis on pathogenesis, management, and prevention of the long-term complications of HIV disease and its therapies, including cardiovascular disease, renal disease, alterations in bone metabolism, and vitamin D deficiency, along with a growing focus on biomarkers to predict development of end-organ disease. Understanding the elevated risk for non-AIDS defining malignancies in the HIV-infected population and optimal management was a focal point of this year's data. Finally, the conference provided important information on tuberculosis coinfection and cryptococcal meningitis. PMID- 23681962 TI - CROI 2013: Advances in antiretroviral therapy. AB - The 20th Conference on Retroviruses and Opportunistic Infections (CROI) presented important highlights of advances in antiretroviral therapy. Investigators emphasized new approaches to finding a cure for HIV infection, with a special focus on an infant who received combination antiretroviral therapy at 30 hours of age and may have achieved a functional cure in the absence of continued antiretroviral therapy. Challenges and opportunities for sustainable antiretroviral therapy under the Patient Protection and Affordable Care Act (PPACA) were discussed, and investigators around the globe examined attrition through the cascade of care for HIV disease and its implications. Knowledge of barriers to antiretroviral therapy in resource-limited settings (RLSs) continues to expand, as do innovative strategies for improving antiretroviral therapy access and uptake in these settings. Encouraging results from expanded prevention of mother-to-child transmission programs, including option B+, were presented. Prevalence of transmitted (primary) drug resistance appears to be increasing in the United States, and new detection techniques may increase access to resistance testing in RLSs. PMID- 23681963 TI - An ultrasensitive chemiluminescent method for the tanshinol borneol ester determination and its pharmacokinetic analysis. AB - Tanshinol borneol ester (DBZ), a chemical combination of danshensu and borneol, is an experimental drug that exhibits efficacious anti-ischemic activity in animal models. In this work, an ultrasensitive chemiluminescence (CL) method for the determination of DBZ was established based on the inhibitory effect of DBZ on the CL signal produced from the reaction between potassium permanganate and luminol in alkaline solution. The CL intensity responded linearly to the concentration of DBZ in the range 2.0 * 10(-10) to 4.0 * 10(-8) g/mL with a detection limit of 7 * 10(-11) g/mL. The relative standard deviation (RSD) was 3.8% for 4.0 * 10(-9) g DBZ (n = 11). The proposed method showed characteristics of high sensitivity, simple device and quick. In addition, this proposed method had been applied satisfactorily to the analysis of DBZ in blood. The pharmacokinetics of DBZ in rat has also been studied using the CL method. PMID- 23681967 TI - Pharmacokinetics and pharmacodynamics of recombinant human angiotensin-converting enzyme 2 in healthy human subjects. AB - BACKGROUND AND OBJECTIVES: Angiotensin-converting enzyme 2 (ACE2) converts angiotensin II (Ang1-8) to angiotensin 1-7 (Ang1-7), a functional antagonist of Ang1-8, with vasodilatory, antiproliferative, antiangiogenic, and anti inflammatory properties. In conditions with an unbalanced renin-angiotensin aldosterone system with elevated Ang1-8, administration of ACE2 has shown promising effects in a variety of animal models. Enhancing ACE2 activity by exogenous administration of ACE2 might also be beneficial in human diseases with pathologically elevated Ang1-8. As a first step we performed a first-in-man study to determine pharmacokinetics, pharmacodynamics, safety, and tolerability of recombinant ACE2 in healthy volunteers. METHODS: Recombinant human ACE2 (rhACE2) was administered intravenously to healthy human subjects in a randomized, double blind, placebo-controlled, single-dose, dose-escalation study followed by an open label multiple-dose study. ACE2 concentrations were determined by quantifying ACE2 activity and ACE2 content in plasma samples. Concentrations of the angiotensin system effector peptides Ang1-8, Ang1-7, and Ang1-5 were determined using a liquid chromatography-tandem mass spectrometry method. RESULTS: Single rhACE2 doses of 100-1,200 MUg/kg caused a dose-dependent increase of systemic exposure with biphasic elimination and a dose-independent terminal half-life of 10 h. In all single-dose cohorts, Ang1-8 decreased within 30 min postinfusion, angiotensin 1-7 (Ang1-7) either increased (100 and 200 MUg/kg doses), decreased, or remained unchanged (400-1,200 MUg/kg doses), whereas angiotensin 1-5 (Ang1-5) transiently increased for all doses investigated. With the exception of the lowest rhACE2 dose, the decrease in Ang1-8 levels lasted for at least 24 h. Repeated dosing (400 MUg/kg for 3 or 6 days) caused only minimal accumulation of ACE2, and Ang1-8 levels were suppressed over the whole application period. CONCLUSIONS: Administration of rhACE2 was well tolerated by healthy human subjects. Exposure was dose dependent with a dose-independent terminal elimination half-life in the range of 10 h. Despite marked changes in angiotensin system peptide concentrations, cardiovascular effects were absent, suggesting the presence of effective compensatory mechanisms in healthy volunteers. PMID- 23681969 TI - Dual surface-functionalized Janus nanocomposites of polystyrene/Fe3O4@SiO2 for simultaneous tumor cell targeting and stimulus-induced drug release. AB - Folic acid (FA) and doxorubicin (DOX) are coupled separately onto Fe3 O4 @SiO2 and polystyrene surfaces of a unique polystyrene/Fe3 O4 @SiO2 Janus structure. This super-paramagnetic, dual-functionalized Janus nanocomposite enables effective tumor cell targeting and internalization via the folate receptor, and induces significant cancer cell death by controlled, stimulus-induced drug release under acidic conditions in endosomal compartments. PMID- 23681970 TI - Microclimatic challenges in global change biology. AB - Despite decades of work on climate change biology, the scientific community remains uncertain about where and when most species distributions will respond to altered climates. A major barrier is the spatial mismatch between the size of organisms and the scale at which climate data are collected and modeled. Using a meta-analysis of published literature, we show that grid lengths in species distribution models are, on average, ca. 10 000-fold larger than the animals they study, and ca. 1000-fold larger than the plants they study. And the gap is even worse than these ratios indicate, as most work has focused on organisms that are significantly biased toward large size. This mismatch is problematic because organisms do not experience climate on coarse scales. Rather, they live in microclimates, which can be highly heterogeneous and strongly divergent from surrounding macroclimates. Bridging the spatial gap should be a high priority for research and will require gathering climate data at finer scales, developing better methods for downscaling environmental data to microclimates, and improving our statistical understanding of variation at finer scales. Interdisciplinary collaborations (including ecologists, engineers, climatologists, meteorologists, statisticians, and geographers) will be key to bridging the gap, and ultimately to providing scientifically grounded data and recommendations to conservation biologists and policy makers. PMID- 23681971 TI - Unraveling cellulose microfibrils: a twisted tale. AB - Molecular dynamics (MD) simulations of cellulose microfibrils are pertinent to the paper, textile, and biofuels industries for their unique capacity to characterize dynamic behavior and atomic-level interactions with solvent molecules and cellulase enzymes. While high-resolution crystallographic data have established a solid basis for computational analysis of cellulose, previous work has demonstrated a tendency for modeled microfibrils to diverge from the linear experimental structure and adopt a twisted conformation. Here, we investigate the dependence of this twisting behavior on computational approximations and establish the theoretical basis for its occurrence. We examine the role of solvent, the effect of nonbonded force field parameters [partial charges and van der Waals (vdW) contributions], and the use of explicitly modeled oxygen lone pairs in both the solute and solvent. Findings suggest that microfibril twisting is favored by vdW interactions, and counteracted by both intrachain hydrogen bonds and solvent effects at the microfibril surface. PMID- 23681972 TI - Role of the trochlear nerve in eye abduction and frontal vision of the red-eared slider turtle (Trachemys scripta elegans). AB - Horizontal head rotation evokes significant responses from trochlear motoneurons of turtle that suggests they have a functional role in abduction of the eyes like that in frontal-eyed mammals. The finding is unexpected given that the turtle is generally considered lateral-eyed and assumed to have eye movements instead like that of lateral-eyed mammals, in which innervation of the superior oblique muscle by the trochlear nerve (nIV) produces intorsion, elevation, and adduction (not abduction). Using an isolated turtle head preparation with the brain removed, glass suction electrodes were used to stimulate nIV with trains of current pulses. Eyes were monitored via an infrared camera with the head placed in a gimble to quantify eye rotations and their directions. Stimulations of nIV evoked intorsion, elevation, and abduction. Dissection of the superior oblique muscle identified lines of action and a location of insertion on the eye, which supported kinematics evoked by nIV stimulation. Eye positions in alert behaving turtles with their head extended were compared with that when their heads were retracted in the carapace. When the head was retracted, there was a reduction in interpupillary distance and an increase in binocular overlap. Occlusion of peripheral fields by the carapace forces the turtle to a more frontal-eyed state, perhaps the reason for the action of abduction by the superior oblique muscle. These findings support why trochlear motoneurons in turtle respond in the same way as abducens motoneurons to horizontal rotations, an unusual characteristic of vestibulo-ocular physiology in comparison with other mammalian lateral-eyed species. PMID- 23681973 TI - A collaborative approach to perinatal and infant mental health service delivery in Australia. AB - OBJECTIVE: The objective of this paper is to report on the development and implementation of a community-based perinatal and infant mental health day program for mothers with psychiatric illness. The program was initiated through interagency collaboration between adult mental health, infant mental health and community child health services in Queensland, Australia in response to calls for an integrated approach that could be delivered state-wide if successful. Preliminary results of the program's evaluation are provided. METHOD: A pre-post survey design was used to assess the influence the program had on maternal mental and emotional well-being and the maternal-infant relationship. Twenty-one women receiving treatment for perinatal mental illness gave consent to attend the 6 week day program integrating three currently separate and discrete services: adult mental health, infant mental health and community child health. RESULTS: Clinically and statistically significant improvements were observed for maternal mental health, and parent-infant relationships following the program. CONCLUSIONS: These findings support interagency collaboration between adult mental health, infant mental health and community child health services to deliver services to women with mental illness with newborns and their families. The utility of using a collaborative approach in a community setting endorses more comprehensive and longer-term evaluation of effectiveness and cost benefit. PMID- 23681974 TI - Reversible capture of SO2 through functionalized ionic liquids. AB - Emission of SO2 in flue gas from the combustion of fossil fuels leads to severe environmental problems. Exploration of green and efficient methods to capture SO2 is an interesting topic, especially at lower SO2 partial pressures. In this work, ionic liquids (ILs) 1-(2-diethylaminoethyl)-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([Et2 NEMim][Tf2 N]) and 1-(2 diethylaminoethyl)-3-methylimidazolium tetrazolate ([Et2 NEMim][Tetz]) were synthesized. The performances of the two ILs to capture SO2 were studied under different conditions. It was demonstrated that the ILs were very efficient for SO2 absorption. The [Et2 NEMim][Tetz] IL designed in this work could absorb 0.47 g(SO2)g(IL)(-1) at 0.0101 MPa SO2 partial pressure, which is the highest capacity reported to date under the same conditions. The main reason for the large capacity was that both the cation and the anion could capture SO2 chemically. In addition, the IL could easily be regenerated, and the very high absorption capacity and rapid absorption/desorption rates were not changed over five repeated cycles. PMID- 23681975 TI - Analytic derivatives for the XYG3 type of doubly hybrid density functionals: Theory, implementation, and assessment. AB - We present a theoretical development of the equations required to perform an analytic geometry optimization of a molecular system using the XYG3 type of doubly hybrid (xDH) functionals. In contrast to the well-established B2PLYP type of DH functionals, the energy expressions in the xDH functionals are constructed by using density and orbital information from another standard Kohn-Sham (KS) functional (e.g., B3LYP) for doing the self-consistent field calculations. Thus, the xDH functionals are nonvariational in both the hybrid density functional part and the second-order perturbation part, each of which requires formally to solve a coupled-perturbed KS equation. An implementation is reported here which combines the two parts by defining a total Lagrangian such that only a single set of the Z-vector equations need to be solved. The computational cost with our implementation is of the same order as those for the conventional Moller-Plesset theory to the second order (MP2) and B2PLYP. Systematic test calculations are provided for covalently bonded molecules as well as compounds involving the intramolecular nonbonded interactions for the main group elements. Satisfactory performance of the xDH functionals demonstrates that the extra computer time on top of the conventional KS procedure is well-invested, in particular, when the standard KS functionals and MP2 as well, are problematic. PMID- 23681976 TI - A novel phosphorescence sensor for Co2+ ion based on Mn-doped ZnS quantum dots. AB - N-acetyl-L-cysteine-capped Mn-doped ZnS quantum dots (QDs) were prepared by hydrothermal methods. It could emit phosphorescence at 583 nm with the excitation wavelength at 315 nm. The phosphorescence intensity of QDs could be quenched dramatically by increasing the concentration of Co(2+) ion. The novel phosphorescence sensor based on N-acetyl-L-cysteine-capped QDs was developed for detecting Co(2+) ion with a linear dynamic range of 1.25 * 10(-6) -3.25 * 10(-5) m. The limit of detection and RSD were 6.0 * 10(-8) m and 2.3%, respectively. Interference experiments showed excellent selectivity over numerous cations such as alkali, alkaline earth and transitional metal ions. The possible quenching mechanism was also examined by phosphorescence decays. The proposed phosphorescence method was further applied to the trace determination of Co(2+) ion in tap and pond water samples with recoveries of 97.75-103.32%. PMID- 23681977 TI - Circulating endothelial cell kinetics and their potential predictive value during mobilization procedure. AB - OBJECTIVE: Circulating endothelial cells (CECs) in patients with hematological malignancies are assessed as a noninvasive marker of angiogenesis. The aim of this study was to evaluate the numbers of CECs and their subsets during mobilization of hematopoietic stem cells. PATIENTS AND METHODS: Thirty-eight patients were enrolled to the study (19 females and 19 males) at median age of 56.5 years. The group consisted of patients with multiple myeloma (26), lymphoma (10), and acute myeloid leukemia (2). Blood samples were collected before chemotherapy (0), 1 day after chemotherapy (Cht+1), on the day G-CSF commenced (G0), after 1 day of G-CSF (G+1), and on the day of the first apheresis. CECs were evaluated by four-color flow cytometry. Circulating progenitor cells were defined as CD45-/CD34+/CD31+/CD133+. Apoptotic CECs (ApoCECs) were defined as CD146+/AnnexinV+. RESULTS: Median (Me) CECs number was 10.5/ul and it decreased after chemotherapy (Me = 8.3/ul, P < 0.001 when compared with baseline). Based on the number of aphereses needed to obtain 2 * 10(6)/kg CD34+ cells, patients were divided into "highly efficient" (one apheresis) and "poorly efficient" mobilizers (two or more aphereses). Median ApoCEC at Day G+1 was lower in highly efficient than in poorly efficient mobilizers (Me = 3.1/ul vs. Me = 5.1/ul, P = 0.02). ApoCEC at Day G+1 correlated with the number of aphereses (r = 0.48, P = 0.03). In multivariate analysis, ApoCEC at Day G+1 was an independent factor for successful mobilization during one apheresis. CONCLUSIONS: CECs and their subsets change significantly during mobilization of HSCs. ApoCECs measured at the time of G-CSF commencement can predict the efficacy of HSC collection. PMID- 23681980 TI - Methodological issues in meta-analysis of diagnostic accuracy studies. PMID- 23681979 TI - Blocking LINGO-1 as a therapy to promote CNS repair: from concept to the clinic. AB - LINGO-1 is a leucine-rich repeat and Ig domain-containing, Nogo receptor interacting protein, selectively expressed in the CNS on both oligodendrocytes and neurons. Its expression is developmentally regulated, and is upregulated in CNS diseases and injury. In animal models, LINGO-1 expression is upregulated in rat spinal cord injury, experimental autoimmune encephalomyelitis, 6 hydroxydopamine neurotoxic lesions and glaucoma models. In humans, LINGO-1 expression is increased in oligodendrocyte progenitor cells from demyelinated white matter of multiple sclerosis post-mortem samples, and in dopaminergic neurons from Parkinson's disease brains. LINGO-1 negatively regulates oligodendrocyte differentiation and myelination, neuronal survival and axonal regeneration by activating ras homolog gene family member A (RhoA) and inhibiting protein kinase B (Akt) phosphorylation signalling pathways. Across diverse animal CNS disease models, targeted LINGO-1 inhibition promotes neuron and oligodendrocyte survival, axon regeneration, oligodendrocyte differentiation, remyelination and functional recovery. The targeted inhibition of LINGO-1 function presents a novel therapeutic approach for the treatment of CNS diseases. PMID- 23681981 TI - Stable acid-responsive electrospun biodegradable fibers as drug carriers and cell scaffolds. AB - Acid-responsive electrospun fibers are fabricated by introducing sodium bicarbonate into PLLA fibers using an emulsion method. This novel electrospun fibrous scaffold exhibits a rapid acid-responsive controlled drug release (early stage) and stable three-dimensional (3D) structure as a tissue engineering scaffold (late stage) for cell growth. PMID- 23681983 TI - Upregulation of insulin-like growth factor and interleukin 1beta occurs in neurons but not in glial cells in the cochlear nucleus following cochlear ablation. AB - One of the main mechanisms used by neurons and glial cells to promote repair following brain injury is to upregulate activity-dependent molecules such as insulin-like growth factor 1 (IGF-1) and interleukin-1beta (IL-1beta). In the auditory system, IGF-1 is crucial for restoring synaptic transmission following hearing loss; however, whether IL-1beta is also involved in this process is unknown. In this study, we evaluated the expression of IGF-1 and IL-1beta within neurons and glial cells of the ventral cochlear nucleus in adult rats at 1, 7, 15, and 30 days following bilateral cochlear ablation. After the lesion, significant increases in both the overall mean gray levels of IGF-1 immunostaining and the mean gray levels within cells of the cochlear nucleus were observed at 1, 7, and 15 days compared with control animals. The expression and distribution of IL-1beta in the ventral cochlear nucleus of ablated animals was temporally and spatially correlated with IGF-1. We also observed a lack of colocalization between IGF-1 and IL-1beta with either astrocytes or microglia at any of the time points following ablation. These results suggest that the upregulation of IGF-1 and IL-1beta levels within neurons-but not within glial cells-may reflect a plastic mechanism involved in repairing synaptic homeostasis of the overall cellular environment of the cochlear nucleus following bilateral cochlear ablation. PMID- 23681984 TI - Urbanization and its effects on personality traits: a result of microevolution or phenotypic plasticity? AB - Human-altered environmental conditions affect many species at the global scale. An extreme form of anthropogenic alteration is the existence and rapid increase of urban areas. A key question, then, is how species cope with urbanization. It has been suggested that rural and urban conspecifics show differences in behaviour and personality. However, (i) a generalization of this phenomenon has never been made; and (ii) it is still unclear whether differences in personality traits between rural and urban conspecifics are the result of phenotypic plasticity or of intrinsic differences. In a literature review, we show that behavioural differences between rural and urban conspecifics are common and taxonomically widespread among animals, suggesting a significant ecological impact of urbanization on animal behaviour. In order to gain insight into the mechanisms leading to behavioural differences in urban individuals, we hand raised and kept European blackbirds (Turdus merula) from a rural and a nearby urban area under common-garden conditions. Using these birds, we investigated individual variation in two behavioural responses to the presence of novel objects: approach to an object in a familiar area (here defined as neophilia), and avoidance of an object in a familiar foraging context (defined as neophobia). Neophilic and neophobic behaviours were mildly correlated and repeatable even across a time period of one year, indicating stable individual behavioural strategies. Blackbirds from the urban population were more neophobic and seasonally less neophilic than blackbirds from the nearby rural area. These intrinsic differences in personality traits are likely the result of microevolutionary changes, although we cannot fully exclude early developmental influences. PMID- 23681985 TI - Graph classification using signal-subgraphs: applications in statistical connectomics. AB - This manuscript considers the following "graph classification" question: Given a collection of graphs and associated classes, how can one predict the class of a newly observed graph? To address this question, we propose a statistical model for graph/class pairs. This model naturally leads to a set of estimators to identify the class-conditional signal, or "signal-subgraph," defined as the collection of edges that are probabilistically different between the classes. The estimators admit classifiers which are asymptotically optimal and efficient, but which differ by their assumption about the "coherency" of the signal-subgraph (coherency is the extent to which the signal-edges "stick together" around a common subset of vertices). Via simulation, the best estimator is shown to be not just a function of the coherency of the model, but also the number of training samples. These estimators are employed to address a contemporary neuroscience question: Can we classify "connectomes" (brain-graphs) according to sex? The answer is yes, and significantly better than all benchmark algorithms considered. Synthetic data analysis demonstrates that even when the model is correct, given the relatively small number of training samples, the estimated signal-subgraph should be taken with a grain of salt. We conclude by discussing several possible extensions. PMID- 23681986 TI - 3D facial landmark detection under large yaw and expression variations. AB - A 3D landmark detection method for 3D facial scans is presented and thoroughly evaluated. The main contribution of the presented method is the automatic and pose-invariant detection of landmarks on 3D facial scans under large yaw variations (that often result in missing facial data), and its robustness against large facial expressions. Three-dimensional information is exploited by using 3D local shape descriptors to extract candidate landmark points. The shape descriptors include the shape index, a continuous map of principal curvature values of a 3D object's surface, and spin images, local descriptors of the object's 3D point distribution. The candidate landmarks are identified and labeled by matching them with a Facial Landmark Model (FLM) of facial anatomical landmarks. The presented method is extensively evaluated against a variety of 3D facial databases and achieves state-of-the-art accuracy (4.5-6.3 mm mean landmark localization error), considerably outperforming previous methods, even when tested with the most challenging data. PMID- 23681987 TI - A branch-and-bound approach to correspondence and grouping problems. AB - Data correspondence/grouping under an unknown parametric model is a fundamental topic in computer vision. Finding feature correspondences between two images is probably the most popular application of this research field, and is the main motivation of our work. It is a key ingredient for a wide range of vision tasks, including three-dimensional reconstruction and object recognition. Existing feature correspondence methods are based on either local appearance similarity or global geometric consistency or a combination of both in some heuristic manner. None of these methods is fully satisfactory, especially in the presence of repetitive image textures or mismatches. In this paper, we present a new algorithm that combines the benefits of both appearance-based and geometry-based methods and mathematically guarantees a global optimization. Our algorithm accepts the two sets of features extracted from two images as input, and outputs the feature correspondences with the largest number of inliers, which verify both the appearance similarity and geometric constraints. Specifically, we formulate the problem as a mixed integer program and solve it efficiently by a series of linear programs via a branch-and-bound procedure. We subsequently generalize our framework in the context of data correspondence/grouping under an unknown parametric model and show it can be applied to certain classes of computer vision problems. Our algorithm has been validated successfully on synthesized data and challenging real images. PMID- 23681988 TI - A general framework for tracking multiple people from a moving camera. AB - In this paper, we present a general framework for tracking multiple, possibly interacting, people from a mobile vision platform. To determine all of the trajectories robustly and in a 3D coordinate system, we estimate both the camera's ego-motion and the people's paths within a single coherent framework. The tracking problem is framed as finding the MAP solution of a posterior probability, and is solved using the reversible jump Markov chain Monte Carlo (RJ MCMC) particle filtering method. We evaluate our system on challenging datasets taken from moving cameras, including an outdoor street scene video dataset, as well as an indoor RGB-D dataset collected in an office. Experimental evidence shows that the proposed method can robustly estimate a camera's motion from dynamic scenes and stably track people who are moving independently or interacting. PMID- 23681989 TI - Automatic relevance determination in nonnegative matrix factorization with the beta-divergence. AB - This paper addresses the estimation of the latent dimensionality in nonnegative matrix factorization (NMF) with the beta-divergence. The beta-divergence is a family of cost functions that includes the squared euclidean distance, Kullback Leibler (KL) and Itakura-Saito (IS) divergences as special cases. Learning the model order is important as it is necessary to strike the right balance between data fidelity and overfitting. We propose a Bayesian model based on automatic relevance determination (ARD) in which the columns of the dictionary matrix and the rows of the activation matrix are tied together through a common scale parameter in their prior. A family of majorization-minimization (MM) algorithms is proposed for maximum a posteriori (MAP) estimation. A subset of scale parameters is driven to a small lower bound in the course of inference, with the effect of pruning the corresponding spurious components. We demonstrate the efficacy and robustness of our algorithms by performing extensive experiments on synthetic data, the swimmer dataset, a music decomposition example, and a stock price prediction task. PMID- 23681990 TI - Clustering dynamic textures with the hierarchical em algorithm for modeling video. AB - Dynamic texture (DT) is a probabilistic generative model, defined over space and time, that represents a video as the output of a linear dynamical system (LDS). The DT model has been applied to a wide variety of computer vision problems, such as motion segmentation, motion classification, and video registration. In this paper, we derive a new algorithm for clustering DT models that is based on the hierarchical EM algorithm. The proposed clustering algorithm is capable of both clustering DTs and learning novel DT cluster centers that are representative of the cluster members in a manner that is consistent with the underlying generative probabilistic model of the DT. We also derive an efficient recursive algorithm for sensitivity analysis of the discrete-time Kalman smoothing filter, which is used as the basis for computing expectations in the E-step of the HEM algorithm. Finally, we demonstrate the efficacy of the clustering algorithm on several applications in motion analysis, including hierarchical motion clustering, semantic motion annotation, and learning bag-of-systems (BoS) codebooks for dynamic texture recognition. PMID- 23681991 TI - Color invariants for person reidentification. AB - We revisit the problem of specific object recognition using color distributions. In some applications--such as specific person identification--it is highly likely that the color distributions will be multimodal and hence contain a special structure. Although the color distribution changes under different lighting conditions, some aspects of its structure turn out to be invariants. We refer to this structure as an intradistribution structure, and show that it is invariant under a wide range of imaging conditions while being discriminative enough to be practical. Our signature uses shape context descriptors to represent the intradistribution structure. Assuming the widely used diagonal model, we validate that our signature is invariant under certain illumination changes. Experimentally, we use color information as the only cue to obtain good recognition performance on publicly available databases covering both indoor and outdoor conditions. Combining our approach with the complementary covariance descriptor, we demonstrate results exceeding the state-of-the-art performance on the challenging VIPeR and CAVIAR4REID databases. PMID- 23681992 TI - Discovering motion primitives for unsupervised grouping and one-shot learning of human actions, gestures, and expressions. AB - This paper proposes a novel representation of articulated human actions and gestures and facial expressions. The main goals of the proposed approach are: 1) to enable recognition using very few examples, i.e., one or k-shot learning, and 2) meaningful organization of unlabeled datasets by unsupervised clustering. Our proposed representation is obtained by automatically discovering high-level subactions or motion primitives, by hierarchical clustering of observed optical flow in four-dimensional, spatial, and motion flow space. The completely unsupervised proposed method, in contrast to state-of-the-art representations like bag of video words, provides a meaningful representation conducive to visual interpretation and textual labeling. Each primitive action depicts an atomic subaction, like directional motion of limb or torso, and is represented by a mixture of four-dimensional Gaussian distributions. For one--shot and k-shot learning, the sequence of primitive labels discovered in a test video are labeled using KL divergence, and can then be represented as a string and matched against similar strings of training videos. The same sequence can also be collapsed into a histogram of primitives or be used to learn a Hidden Markov model to represent classes. We have performed extensive experiments on recognition by one and k-shot learning as well as unsupervised action clustering on six human actions and gesture datasets, a composite dataset, and a database of facial expressions. These experiments confirm the validity and discriminative nature of the proposed representation. PMID- 23681993 TI - Hierarchical object parsing from structured noisy point clouds. AB - Object parsing and segmentation from point clouds are challenging tasks because the relevant data is available only as thin structures along object boundaries or other features, and is corrupted by large amounts of noise. To handle this kind of data, flexible shape models are desired that can accurately follow the object boundaries. Popular models such as active shape and active appearance models (AAMs) lack the necessary flexibility for this task, while recent approaches such as the recursive compositional models make model simplifications to obtain computational guarantees. This paper investigates a hierarchical Bayesian model of shape and appearance in a generative setting. The input data is explained by an object parsing layer which is a deformation of a hidden principal component analysis (PCA) shape model with Gaussian prior. The paper also introduces a novel efficient inference algorithm that uses informed data-driven proposals to initialize local searches for the hidden variables. Applied to the problem of object parsing from structured point clouds such as edge detection images, the proposed approach obtains state-of-the-art parsing errors on two standard datasets without using any intensity information. PMID- 23681994 TI - Higher order partial least squares (HOPLS): a generalized multilinear regression method. AB - A new generalized multilinear regression model, termed the higher order partial least squares (HOPLS), is introduced with the aim to predict a tensor (multiway array) Y from a tensor X through projecting the data onto the latent space and performing regression on the corresponding latent variables. HOPLS differs substantially from other regression models in that it explains the data by a sum of orthogonal Tucker tensors, while the number of orthogonal loadings serves as a parameter to control model complexity and prevent overfitting. The low dimensional latent space is optimized sequentially via a deflation operation, yielding the best joint subspace approximation for both X and Y. Instead of decomposing X and Y individually, higher order singular value decomposition on a newly defined generalized cross-covariance tensor is employed to optimize the orthogonal loadings. A systematic comparison on both synthetic data and real world decoding of 3D movement trajectories from electrocorticogram signals demonstrate the advantages of HOPLS over the existing methods in terms of better predictive ability, suitability to handle small sample sizes, and robustness to noise. PMID- 23681995 TI - Joint albedo estimation and pose tracking from video. AB - The albedo of a Lambertian object is a surface property that contributes to an object's appearance under changing illumination. As a signature independent of illumination, the albedo is useful for object recognition. Single image-based albedo estimation algorithms suffer due to shadows and non-Lambertian effects of the image. In this paper, we propose a sequential algorithm to estimate the albedo from a sequence of images of a known 3D object in varying poses and illumination conditions. We first show that by knowing/estimating the pose of the object at each frame of a sequence, the object's albedo can be efficiently estimated using a Kalman filter. We then extend this for the case of unknown pose by simultaneously tracking the pose as well as updating the albedo through a Rao Blackwellized particle filter (RBPF). More specifically, the albedo is marginalized from the posterior distribution and estimated analytically using the Kalman filter, while the pose parameters are estimated using importance sampling and by minimizing the projection error of the face onto its spherical harmonic subspace, which results in an illumination-insensitive pose tracking algorithm. Illustrations and experiments are provided to validate the effectiveness of the approach using various synthetic and real sequences followed by applications to unconstrained, video-based face recognition. PMID- 23681996 TI - Learning full pairwise affinities for spectral segmentation. AB - Segmenting a single image into multiple coherent groups remains a challenging task in the field of computer vision. Particularly, spectral segmentation which uses the global information embedded in the spectrum of a given image's affinity matrix is a major trend in image segmentation. This paper focuses on the problem of efficiently learning a full range of pairwise affinities gained by integrating local grouping cues for spectral segmentation. We first construct a sparse multilayer graph whose nodes are both the pixels and the oversegmented regions obtained by an unsupervised segmentation algorithm. By applying the semi supervised learning strategy to this graph, the intra and interlayer affinities between all pairs of nodes can be estimated without iteration. These pairwise affinities are then applied into the spectral segmentation algorithms. In this paper, two types of spectral segmentation algorithms are introduced: $(K)$-way segmentation and hierarchical segmentation. Our algorithms provide high-quality segmentations which preserve object details by directly incorporating the full range connections. Moreover, since our full affinity matrix is defined by the inverse of a sparse matrix, its eigendecomposition can be efficiently computed. The experimental results on the BSDS and MSRC image databases demonstrate the superiority of our segmentation algorithms in terms of relevance and accuracy compared with existing popular methods. PMID- 23681997 TI - Learning to track and identify players from broadcast sports videos. AB - Tracking and identifying players in sports videos filmed with a single pan-tilt zoom camera has many applications, but it is also a challenging problem. This paper introduces a system that tackles this difficult task. The system possesses the ability to detect and track multiple players, estimates the homography between video frames and the court, and identifies the players. The identification system combines three weak visual cues, and exploits both temporal and mutual exclusion constraints in a Conditional Random Field (CRF). In addition, we propose a novel Linear Programming (LP) Relaxation algorithm for predicting the best player identification in a video clip. In order to reduce the number of labeled training data required to learn the identification system, we make use of weakly supervised learning with the assistance of play-by-play texts. Experiments show promising results in tracking, homography estimation, and identification. Moreover, weakly supervised learning with play-by-play texts greatly reduces the number of labeled training examples required. The identification system can achieve similar accuracies by using merely 200 labels in weakly supervised learning, while a strongly supervised approach needs a least 20,000 labels. PMID- 23681998 TI - Low-rank matrix approximation with manifold regularization. AB - This paper proposes a new model of low-rank matrix factorization that incorporates manifold regularization to the matrix factorization. Superior to the graph-regularized nonnegative matrix factorization, this new regularization model has globally optimal and closed-form solutions. A direct algorithm (for data with small number of points) and an alternate iterative algorithm with inexact inner iteration (for large scale data) are proposed to solve the new model. A convergence analysis establishes the global convergence of the iterative algorithm. The efficiency and precision of the algorithm are demonstrated numerically through applications to six real-world datasets on clustering and classification. Performance comparison with existing algorithms shows the effectiveness of the proposed method for low-rank factorization in general. PMID- 23681999 TI - Nonparametric illumination correction for scanned document images via convex hulls. AB - A scanned image of an opened book page often suffers from various scanning artifacts known as scanning shading and dark borders noises. These artifacts will degrade the qualities of the scanned images and cause many problems to the subsequent process of document image analysis. In this paper, we propose an effective method to rectify these scanning artifacts. Our method comes from two observations: that the shading surface of most scanned book pages is quasi concave and that the document contents are usually printed on a sheet of plain and bright paper. Based on these observations, a shading image can be accurately extracted via convex hulls-based image reconstruction. The proposed method proves to be surprisingly effective for image shading correction and dark borders removal. It can restore a desired shading-free image and meanwhile yield an illumination surface of high quality. More importantly, the proposed method is nonparametric and thus does not involve any user interactions or parameter fine tuning. This would make it very appealing to nonexpert users in applications. Extensive experiments based on synthetic and real-scanned document images demonstrate the efficiency of the proposed method. PMID- 23682000 TI - Parsing facades with shape grammars and reinforcement learning. AB - In this paper, we use shape grammars (SGs) for facade parsing, which amounts to segmenting 2D building facades into balconies, walls, windows, and doors in an architecturally meaningful manner. The main thrust of our work is the introduction of reinforcement learning (RL) techniques to deal with the computational complexity of the problem. RL provides us with techniques such as Q learning and state aggregation which we exploit to efficiently solve facade parsing. We initially phrase the 1D parsing problem in terms of a Markov Decision Process, paving the way for the application of RL-based tools. We then develop novel techniques for the 2D shape parsing problem that take into account the specificities of the facade parsing problem. Specifically, we use state aggregation to enforce the symmetry of facade floors and demonstrate how to use RL to exploit bottom-up, image-based guidance during optimization. We provide systematic results on the Paris building dataset and obtain state-of-the-art results in a fraction of the time required by previous methods. We validate our method under diverse imaging conditions and make our software and results available online. PMID- 23682001 TI - Toward open set recognition. AB - To date, almost all experimental evaluations of machine learning-based recognition algorithms in computer vision have taken the form of "closed set" recognition, whereby all testing classes are known at training time. A more realistic scenario for vision applications is "open set" recognition, where incomplete knowledge of the world is present at training time, and unknown classes can be submitted to an algorithm during testing. This paper explores the nature of open set recognition and formalizes its definition as a constrained minimization problem. The open set recognition problem is not well addressed by existing algorithms because it requires strong generalization. As a step toward a solution, we introduce a novel "1-vs-set machine," which sculpts a decision space from the marginal distances of a 1-class or binary SVM with a linear kernel. This methodology applies to several different applications in computer vision where open set recognition is a challenging problem, including object recognition and face verification. We consider both in this work, with large scale cross-dataset experiments performed over the Caltech 256 and ImageNet sets, as well as face matching experiments performed over the Labeled Faces in the Wild set. The experiments highlight the effectiveness of machines adapted for open set evaluation compared to existing 1-class and binary SVMs for the same tasks. PMID- 23682002 TI - Writer adaptation with style transfer mapping. AB - Adapting a writer-independent classifier toward the unique handwriting style of a particular writer has the potential to significantly increase accuracy for personalized handwriting recognition. This paper proposes a novel framework of style transfer mapping (STM) for writer adaptation. The STM is a writer-specific class-independent feature transformation which has a closed-form solution. After style transfer mapping, the data of different writers are projected onto a style free space, where the writer-independent classifier needs no change to classify the transformed data and can achieve significantly higher accuracy. The framework of STM can be combined with different types of classifiers for supervised, unsupervised, and semi-supervised adaptation, where writer-specific data can be either labeled or unlabeled and need not cover all classes. In this paper, we combine STM with the state-of-the-art classifiers for large-category Chinese handwriting recognition: learning vector quantization (LVQ) and modified quadratic discriminant function (MQDF). Experiments on the online Chinese handwriting database CASIA-OLHWDB demonstrate that STM-based adaptation is very efficient and effective in improving classification accuracy. Semi-supervised adaptation achieves the best performance, while unsupervised adaptation is even better than supervised adaptation. On handwritten text data, semi-supervised adaptation achieves error reduction rates 31.95 and 25.00 percent by LVQ and MQDF, respectively. PMID- 23682003 TI - A scalable formulation of probabilistic linear discriminant analysis: applied to face recognition. AB - In this paper, we present a scalable and exact solution for probabilistic linear discriminant analysis (PLDA). PLDA is a probabilistic model that has been shown to provide state-of-the-art performance for both face and speaker recognition. However, it has one major drawback: At training time estimating the latent variables requires the inversion and storage of a matrix whose size grows quadratically with the number of samples for the identity (class). To date, two approaches have been taken to deal with this problem, to 1) use an exact solution that calculates this large matrix and is obviously not scalable with the number of samples or 2) derive a variational approximation to the problem. We present a scalable derivation which is theoretically equivalent to the previous nonscalable solution and thus obviates the need for a variational approximation. Experimentally, we demonstrate the efficacy of our approach in two ways. First, on labeled faces in the wild, we illustrate the equivalence of our scalable implementation with previously published work. Second, on the large Multi-PIE database, we illustrate the gain in performance when using more training samples per identity (class), which is made possible by the proposed scalable formulation of PLDA. PMID- 23682004 TI - Enhanced FK506 production in Streptomyces tsukubaensis by rational feeding strategies based on comparative metabolic profiling analysis. AB - FK506, a widely used immunosuppressant, is produced by industrial fermentation processes using various Streptomyces species. However, the low titer becomes a bottleneck for its application and industrialization. It urgently required a full understanding of the biological mechanisms for FK506 overproduction. Towards this end, comparative metabolomics approach was employed to analyze metabolite concentrations difference of Streptomyces tsukubaensis cultivated in two media with low and high productivities. Initially, 98 intracellular metabolites were identified and 13 metabolites involved in five pathways were determined to be directly correlated with FK506 biosynthesis. Then in-depth analysis elucidated how those key factors exerted influence on FK506 biosynthesis. Many previously unreported metabolites were shown to play an important role in FK506 biosynthesis and provided potential regulation points for external manipulation. Based on such key information, rationally designed feeding strategy was carried out. Results showed that the FK506 yield increased from 251 to 405 mg/L, whereas, by-products FK520 and 37,38-dihydro-FK506 decreased by 31% and 39%, respectively, compared with the values of control. To our knowledge, it is the first study to apply the comparative metabolomics method to identify key metabolites to promote the FK506 production. The strategies developed here can easily be extended to titer improvement of other important microbial natural products and process optimization. PMID- 23682005 TI - Does vaccine dose predict response to the monovalent pandemic H1N1 influenza a vaccine in children with acute lymphoblastic leukemia? A single-centre study. AB - BACKGROUND: Vaccination against influenza is an important strategy in preventing severe infection among children with acute lymphoblastic leukemia (ALL). Successful vaccination depends on both vaccine and host-related factors. We conducted a study on factors predicting the immunogenicity of the monovalent pandemic H1N1 (pH1N1) influenza A vaccine in children with ALL. METHODS: Children with ALL in our hospital were recruited and received two doses of the inactivated split-virion AS03-adjuvanted vaccine. The serological response was measured before each vaccine dose (Day 0 and 28) and 3 months after the second dose. Antibody titres were measured using a hemagglutination-inhibition assay. Seroconversion was defined as a >=fourfold increase in antibody titre and a post vaccination titre >=1:40. RESULTS: Pre and post-vaccination titres were available from 45 children with ALL after one dose of the vaccine and 39 children after two doses. The seroconversion rate was 11.1% after one dose and 25.6% after the second dose. Univariate analysis demonstrated a significantly higher (P = 0.01) seroconversion rate among children who received the adult dose (0.5 ml) of the vaccine and a trend towards increased seroconversion (P = 0.07) by multivariate analysis. Factors including age, gender, lymphocyte count, treatment phase and regimen did not significantly affect the seroconversion rate. Children who received the adult dose demonstrated a significantly greater magnitude of serological response after both one dose (P = 0.04) and two doses (P = 0.001). CONCLUSIONS: These data suggest that the immunogenicity of the pH1N1 vaccine among children with ALL is improved by repeated and adult doses of the vaccine. PMID- 23682006 TI - Higher doses of CD34+ progenitors are associated with improved overall survival without increasing GVHD in reduced intensity conditioning allogeneic transplant recipients with clinically advanced disease. AB - OBJECTIVE: The influence of CD34+ cell dose on the outcome of allogeneic peripheral blood stem cell (PBSC) transplantation after reduced intensity conditioning (RIC) remains controversial. The impact of the number of CD34+ hematoprogenitors infused on transplant outcome and on the incidence of graft versus host disease (GVHD) was analyzed. MATERIALS AND METHODS: Data of 138 patients with advanced hematological diseases who received an allogeneic PBSC transplant after RIC were analyzed. Donors were mobilized with granulocyte colony stimulating factor and underwent one to three apheresis procedures. Incidence of acute and chronic GVHD and overall and event-free survival (OS and EFS) was determined. RESULTS: The median number of CD34+ cells infused was 5.57 * 10(6) kg(-1) (range: 1.1-15.6). There was no relationship between CD34+ cell dose and neutrophil or platelet engraftment. Patients receiving >=5 * 10(6) kg(-1) CD34+ cells had a 63.1% 5-year OS when compared with 48.2% for those receiving a lower number (P = 0.024). At 5-year follow-up, there was no significant difference in EFS between the groups (44% vs. 42.8%, P = 0.426). No relationship between CD34+ cell dose and acute GVHD was found (P = 0.1). Relapse rate was the same in patients with and without acute GVHD (P = 0.117). A nonsignificant improvement on OS and EFS in patients who developed chronic GVHD was found (P = 0.57 and 0.41). CONCLUSION: A CD34+ cell dose >=5 * 10(6) kg(-1) was associated with a significantly higher OS, but no improved EFS in high-risk patients. The number of CD34+ progenitors infused had no influence on the incidence of acute or chronic GVHD. PMID- 23682007 TI - Age independent first trimester screening for Down syndrome: improvement in test performance. AB - OBJECTIVE: The aim of this study was to compare screening performance for Down syndrome of the absolute risk (AR) method to the first trimester combined test (FCT) at different maternal ages. METHODS: There was a retrospective analysis of 32,448 FCT. AR was defined as final risk divided by maternal age risk. RESULTS: The likelihood of receiving a true prediction was comparable between both methods in all age groups. With the AR method, two extra Down syndrome cases were detected in women <30 years, three cases were missed in women >=36 years, and the likelihood of receiving a false prediction decreased overall (OR 0.82, CI 0.77 0.87; P < 0.0001), in women aged 36-40 years (0.45, CI 0.41-0.51; P < 0.0001), in women aged 41-45 years (0.18, CI 0.13-0.26; P < 0.0001) and increased in women aged <=25 years (2.12, CI 1.52-2.96; P < 0.004). CONCLUSIONS: The AR method results in a significant decreased likelihood of receiving a false prediction with a comparable likelihood of receiving a true prediction. Thus, fewer invasive diagnostic tests will be performed. It will take away the misunderstanding about differences in screening performance for women of different ages. This might lead to a higher uptake of first trimester screening resulting in a more efficient screening policy. PMID- 23682008 TI - Descriptive analysis of a staff injury-reduction intervention in a human services setting for children and youth with intellectual and developmental disabilities. AB - Clinical safety is a dominant concern for human services organizations serving people with intellectual and developmental disabilities (IDD) and high-risk challenging behaviors. This article is a descriptive analysis of components that comprised an injury-reduction intervention among direct-care staff at a specialized school. Using a behavior-based safety approach, intervention was associated with fewer staff injuries and more weeks without injury reports. The article focuses on systems-level strategies and recommendations for future research and practice. PMID- 23682009 TI - Measuring psychotropic drug exposures in register-based studies--validity of a dosage assumption of one unit per day in older Finns. AB - Pharmacoepidemiological studies provide valuable information on the relationships between psychotropic drug use and adverse outcomes in older people. To minimize the influence of misclassification bias in pharmacoepidemiological studies, more emphasis should be given to methodological aspects of exposure assessment. This study evaluated the validity of a dosage assumption of one unit per day for measuring legend duration of psychotropic drug exposures among older people. Using data from the Finnish Prescription Register, the study analysed 62,320 psychotropic drug prescriptions dispensed for people aged >= 75 years (n = 52,729) in September 2009. The proportions of prescriptions in which the prescribed dose deviated from one unit per day were assessed for categories and subcategories of psychotropic drugs. The prescription was considered misclassified (a) if the prescribed drug was intended for "as needed" use, (b) if the prescription included a dose range, or (c) if the prescribed dose was below or above one unit per day. Among antidepressants, less than every fourth (23.7%) prescription was misclassified. The proportions of misclassification varied substantially across subcategories, being 13.1% for selective serotonin reuptake inhibitors (SSRIs), 25.3% for other antidepressants and 53.8% for tricyclic antidepressants. Of the benzodiazepine and antipsychotic prescriptions, 79.9% and 57.6%, respectively, were misclassified. In conclusion, the dosage assumption of one unit per day is valid for measuring the legend duration of SSRI and other antidepressant exposures among older people. Among other psychotropic drugs, the dosage assumption is likely to lead to severe exposure misclassification. PMID- 23682010 TI - Indexed effective orifice area is a significant predictor of higher mid- and long term mortality rates following aortic valve replacement in patients with prosthesis-patient mismatch. AB - Prosthesis-patient mismatch (PPM) is defined as a too-small effective orifice area (EOA) of an inserted prosthetic relative to body size, resulting in an abnormally high postoperative gradient. It is unclear, however, whether residual stenosis after aortic valve replacement (AVR) has a negative impact on mid- and long-term survivals. We searched electronic databases, including PubMed, Embase, Medline and the Cochrane controlled trials register, through October 2012, to identify published full-text English studies on the association between PPM and mortality rates. A significant PPM was defined as an indexed EOA (iEOA)<0.85 cm2/m2, and severe PPM as an iEOA<0.65 cm2/m2. Two reviewers independently assessed the studies for inclusion and extracted data. Fourteen observational studies, involving 14 874 patients, met our final inclusion criteria. Meta analysis demonstrated that PPM significantly increased mid-term (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.19-1.69) and long-term (OR 1.52, 95% CI 1.26 1.84) all-cause mortalities. Subgroup analysis showed that PPM was associated with higher mid- and long-term mortality rates only in younger and predominantly female populations. Risk-adjusted sensitivity analysis showed that severe PPM was associated with reduced survival (adjusted hazard ratio [HR] 1.50, 95% CI 1.24 1.80), whereas moderate PPM was not (adjusted HR 0.96, 95% CI 0.86-1.07). Regardless of severity, however, PPM had a negative effect on survival in patients with impaired ejection fraction (adjusted HR 1.26, 95% CI 1.09-1.47). PPM (iEOA<0.85 cm2/m2) after AVR tended to be associated with increased long-term all-cause mortality in younger patients, females and patients with preoperative left ventricular dysfunction. Severe PPM (iEOA<0.65 cm2/m2) was a significant predictor of reduced long-term survival in all populations undergoing AVR. PMID- 23682011 TI - Left ventricular rupture without obstructive coronary artery disease. PMID- 23682012 TI - The incidental finding of a pseudoaneurysm after mitral valve surgery, on computed tomography. PMID- 23682013 TI - Microwell chips for selection of bio-macromolecules that increase the differentiation capacities of mesenchymal stem cells. AB - Microwell chips (25 mm * 25 mm) are fabricated to select proper substrates for growing three-dimensional (3D) spheroids from mesenchymal stem cells (MSCs). Different bio-macromolecules and their combinations are immobilized on the chip by air plasma treatment and by polyelectrolyte interaction. Only a small number of MSCs (~10(5) ) are needed for each chip. The expression level of N-cadherin, a cell-adhesion molecule, is used as an indicator for cell-cell interactions. MSC spheroids expressing the highest N-cadherin level also show the greatest osteogenic potential. The microwell chip may be used as an efficient platform to screen bio-macromolecules that enhance the differentiation potential of MSCs. PMID- 23682014 TI - Coordination-based molecular assemblies of oligofurans and oligothiophenes. AB - Molecular assemblies (MAs) of oligofurans and oligothiophenes were formed from solutions on various substrates. These films were obtained by alternating deposition of organic chromophores (oligofurans or oligothiophenes) and a palladium salt. These coordination-based MAs were characterized by UV/Vis spectroscopy, spectroscopic ellipsometry, atomic force microscopy (AFM), X-ray reflectivity (XRR), X-ray photoelectron spectroscopy (XPS), and electrochemistry. The MAs exhibit similar electrochemical behavior and their growth and structure are apparently not affected when different organic template layers are used. The density of the MAs is a function of the structure of the molecular component. The oligothiophene density is approximately 50% higher than that observed for the oligofuran-based assemblies. The optical and electrochemical properties of the MAs scale linearly with their thickness. The UV/Vis data indicate that upon increasing the film thickness, there is no significant conjugation between the metal-separated organic chromophores. DFT calculations confirmed that the HOMO LUMO gap of the surface-bound oligofuran and oligothiophene metal oligomers do not change significantly upon increasing their chain length. However, electrochemical measurements indicate that the susceptibility of the MAs towards oxidation is dependent on the number of chromophore units. PMID- 23682015 TI - Migration of bone marrow-derived cells into the central nervous system in models of neurodegeneration. AB - Microglia are the brain-resident macrophages tasked with the defense and maintenance of the central nervous system (CNS). The hematopoietic origin of microglia has warranted a therapeutic potential for the hematopoietic system in treating diseases of the CNS. However, migration of bone marrow-derived cells (BMDC) into the CNS is a marginal event under normal, healthy conditions. A busulfan-based chemotherapy regimen was used for bone marrow transplantation in wild-type mice before subjecting them to a hypoxic-ischemic brain injury or in APP/PS1 mice prior to the formation of amyloid plaques. The cells were tracked and analyzed throughout the development of the pathology. The efficacy of a preventive macrophage colony-stimulating factor (M-CSF) treatment was also studied to highlight the effects of circulating monocytes in hypoxic-ischemic brain injury. Such an injury induces a strong migration of BMDC into the CNS, without the need for irradiation. These migrating cells do not replace the entire microglial pool but rather are confined to the sites of injury for several weeks, suggesting that they could perform specific functions. M-CSF showed neuroprotective effects as a preventive treatment. In APP/PS1 mice, the formation of amyloid plaques was sufficient to induce the entry of cells into the parenchyma, though in low numbers. This study confirms that BMDC infiltrate the CNS in animal models for stroke and Alzheimer's disease and that peripheral cells can be targeted to treat affected regions of the CNS. PMID- 23682016 TI - Staff expectations and views of cognitive behaviour therapy (CBT) for adults with intellectual disabilities. AB - BACKGROUND: The role of support workers and other professionals in the psychotherapeutic process has been commented upon but not as yet been systematically investigated. METHOD: To explore their views and expectations of cognitive behaviour therapy (CBT) for adults with intellectual disabilities, eleven paid support workers and professionals were recruited and interviewed before the CBT sessions commenced for their service users and nine took part in the second interview that took place after nine sessions. RESULTS: Thematic Analysis of the interview transcripts indicates that staff members do not perceive CBT as a long-term solution for psychological problems have little knowledge of CBT and do not feel included in the process. Nevertheless, after nine sessions, most participants reported improved psychological well-being for their service users and expressed a wish for longer-term involvement of the therapist. CONCLUSIONS: The results suggest that for CBT to be effective in the longer term, the therapist is required to consider a wider systemic approach including staff training and supervision, staff and management consultancy and creating a delicate balance between confidentiality and sharing the psychological formulation with 'significant others' to ensure maintenance and generalisation of improved psychological well-being. PMID- 23682018 TI - Body fluid and tissue analysis using filter paper sampling support prior to LC MS/MS: application to fatal overdose with colchicine. AB - Because of the various matrices available for forensic investigations, the development of versatile analytical approaches allowing the simultaneous determination of drugs is challenging. The aim of this work was to assess a liquid chromatography-tandem mass spectrometry (LC-MS/MS) platform allowing the rapid quantification of colchicine in body fluids and tissues collected in the context of a fatal overdose. For this purpose, filter paper was used as a sampling support and was associated with an automated 96-well plate extraction performed by the LC autosampler itself. The developed method features a 7-min total run time including automated filter paper extraction (2 min) and chromatographic separation (5 min). The sample preparation was reduced to a minimum regardless of the matrix analyzed. This platform was fully validated for dried blood spots (DBS) in the toxic concentration range of colchicine. The DBS calibration curve was applied successfully to quantification in all other matrices (body fluids and tissues) except for bile, where an excessive matrix effect was found. The distribution of colchicine for a fatal overdose case was reported as follows: peripheral blood, 29 ng/ml; urine, 94 ng/ml; vitreous humour and cerebrospinal fluid, < 5 ng/ml; pericardial fluid, 14 ng/ml; brain, < 5 pg/mg; heart, 121 pg/mg; kidney, 245 pg/mg; and liver, 143 pg/mg. Although filter paper is usually employed for DBS, we report here the extension of this alternative sampling support to the analysis of other body fluids and tissues. The developed platform represents a rapid and versatile approach for drug determination in multiple forensic media. PMID- 23682017 TI - Warfarin pharmacogenomics in children. AB - Warfarin is the most commonly used oral anticoagulant worldwide. Warfarin has a narrow therapeutic index, requiring frequent monitoring of the INR to achieve therapeutic anticoagulation. The role of pharmacogenomics in warfarin disposition and response has been well established in adults, but remains unclear for pediatric patients. In this review, we focus on the important CYP2C9 and VKORC1 variants involved in warfarin response, our current understanding of warfarin disposition and pharmacogenomics, and recent warfarin pharmacogenetic studies in pediatric patients. Finally, we discuss the need for future pediatric studies and the clinical implications of developing pharmacogenetic-based dosing algorithms in children. PMID- 23682019 TI - Ischemia-reperfusion injury of the isolated diabetic rat heart: effect of the antioxidant stobadine. AB - The etiology of diabetic complications is strongly associated with increased oxidative stress. The aim of the present study was to evaluate the effect of the potent antioxidant stobadine (STB) on global ischemia-reperfusion cardiac injury in the rat model of diabetes mellitus (DM). Diabetes was induced by multiple low doses of streptozotocin. The effect of STB was compared with that of a high dose of alpha-lipoic acid (ALA). All experiments were performed on isolated Langendorff-perfused hearts 10 weeks after streptozotocin administration. Diabetic hearts showed to be more resistant to ischemia-reperfusion than the control hearts, as shown by the reduced number of reperfusion dysrhythmias. The effect of the therapy with ALA (100 mg/kg i.p., 5 times a week during 8 weeks) was comparable to that of STB (25 mg/kg i.p., 5 times a week during 8 weeks) resulting in lowering the heart rate and coronary flow as well as the number of serious reperfusion dysrhythmias. Though the protective effect of STB on the reperfusion-induced dysrhythmias was comparable with that of ALA, both substances failed to enhance functional recovery of the diabetic rat heart. PMID- 23682020 TI - Hydroxyl radicals' production and ECG parameters during ischemia and reperfusion in rat, guinea pig and rabbit isolated heart. AB - Ischemic and reperfusion injury is a serious condition related to numerous biochemical and electrical abnormalities of the myocardium. It has been repeatedly studied in various animal models. In this study, the production of hydroxyl radicals and electrophysiological parameters were compared in three species. Rat, guinea pig and rabbit isolated hearts were perfused according to Langendorff under strictly identical conditions. The heart rate and arrhythmia were monitored during ischemia and reperfusion periods at defined time intervals; the production of hydroxyl radical was determined by HPLC as 2.5-dihydroxybenzoic acid (2.5-DHBA) formed by salicylic acid hydroxylation. Relationship between arrhythmias and production of 2.5-DHBA was studied. The inter-species differences were observed in timing of arrhythmias onset and their severity, and in the production of 2.5-DHBA in both ischemia and reperfusion. The most considerable changes were observed in rats, where arrhythmias appeared early and with highest severity during ischemia on one side and the regular rhythm was restored early and completely during reperfusion. The corresponding changes in the production of 2.5-DHBA were observed. It can be concluded that rat isolated heart is the most suitable model for evaluation of ischemia/reperfusion injury under given experimental conditions. PMID- 23682021 TI - Mesenchymal stem cells in prostate cancer have higher expressions of SDF-1, CXCR4 and VEGF. AB - Our previous study found that the activity of PCa-MSCs, which could stimulate the cell proliferation of RM-1, was significantly different compared to BMMSCs. Our results indicated that it could be mediated in part by growth factors/chemokines, which were involved in the different activity between two kinds of MSCs (PCa-MSCs and BMMSCs). Normal MSCs (BMMSCs) were isolated from the femur, tibia of the normal mice; prostate tumor MSCs (PCa-MSCs) were obtained from the mice implanted with prostate tumor. Analysis of the expression of SDF-1, CXCR4, VEGF,bFGF and vWF of two kinds of MSCs were examined by ELISA, Realtime-PCR and Western blotting. The expressions of SDF-1 and CXCR4 in PCa-MSCs were higher compared to BMMSCs. Expressions of bFGF and vWF were higher in PCa-MSCs yet the difference did not reach statistical significance. The expression of VEGF was significantly higher in PCa-MSCs. Our data showed that activity of PCa-MSCs was significantly improved compared with BMMSCs, which seemed to have an intrinsic, cell-specific capacity localized to PCa. It could be induced by some factors or chemokines such as SDF-1, CXCR4, and VEGF. The possible role of PCa-MSCs in the process of PCa development needed further clarification. PMID- 23682022 TI - Effect of TiO2 nanoparticles on emotional behavior and biochemical parameters in adult Wistar rats. AB - The rapidly developing field of nanotechnology is becoming a potential source for human exposure to nanoparticles. Titanium dioxide (TiO2) nanoparticles have been widely produced in industrial processes for several years. The aim of this study was to investigate the effects of TiO2 nanoparticles on plasmatic biochemical parameters and the emotional behavior in adult Wistar rats. Rats were treated by intraperitoneal injection of TiO2 nanoparticles (20-30 nm) at a dose of 25 mg/kg. For toxicity evaluation of nanoparticles sample, body weight, organ coefficient, blood biochemistry panel assay (AST, ALT, LDH, uric acid, creatinine, and glucose content) and emotional behavior parameters were determined. Sub-acute TiO2 nanoparticles treatment decreased the body weight, but increased the relative brain weight. Biochemical assessment in plasma samples showed that TiO2 nanoparticles injection increased uric acid concentration and AST activity in rats. However, the same treatment decreased the creatinine level, but had no effect on glucose concentration, ALT and LDH activity. The emotional behavior of control and treated rats was tested in elevated plus-maze. Interestingly, our results showed that TiO2-treated rats spent more time in the secured closed arms and entered the anxiogenic open arms less frequently than control. Our results suggest that TiO2 nanoparticles intoxication could altered biochemical parameters related to changes in organ function and leads to emotional behavior impairment of rats. PMID- 23682023 TI - 3T3-L1 adipocytes possess anandamide- and epinephrine-responsive machinery for MDM2 distribution to the plasma membrane. AB - The effects of biomolecules on peripheral tissues and their responsive machinery are not well understood. We examined MDM2 level in the plasma membrane (PM) and total MDM2 level of 3T3-L1 adipocytes treated with biomolecular anandamide, epinephrine, and other agents for 15 min. We also examined biomolecular responses in cells treated with mithramycin A, a binding inhibitor, or cells exposed to cooling and cell viability. Immunoblotting revealed that PM MDM2 level increased and total MDM2 level was not altered following treatment with anandamide, epinephrine, capsaicin, CL316243, and aluminum fluoride. PM MDM2 distribution caused by a biomolecular concentration was maintained by treatment with mithramycin A and exposure of cells to 28 degrees C or 32 degrees C but not to 18 degrees C, and PM MDM2 levels after treatment with high concentrations of biomolecules were altered upon exposure to the inhibitor and mild hypothermia. These conditions did not decrease cell viability. Our findings indicate that 3T3 L1 adipocytes possess molecular machinery that responds differentially to anandamide and epinephrine under the inhibitor treatment and cool temperature conditions and that is sensitive to other agents (which mimic biomolecular responses); these machineries can induce subcellular alterations in molecular interactions. We provide information helpful for clarifying biomolecular responsive machinery present in 3T3-L1 adipocytes. PMID- 23682024 TI - Long-term effect of prazosin and losartan administration on blood pressure, heart, carotid artery, and acetylcholine induced dilation of cardiovascular system of young Wistar rats and SHR. AB - The long-term effects of prazosin and losartan administration on blood pressure, trophicity of the heart and carotid arteries, and responses of the cardiovascular system to acetylcholine, were studied in Wistar rats and spontaneously hypertensive rats (SHRs). Four-week-old rats were treated with prazosin (10 mg/kg b.w./day in tap water) or losartan (20 mg/kg b.w./day in tap water) for 5-6 weeks. BP was measured by plethysmographic method. Ten animals of each group were subjected to in vivo studies and subsequent to morphological investigations. The right jugular vein was cannulated for administration of acetylcholine (0.1, 1, and 10 ug). After perfusion with a glutaraldehyde fixative (120 mmHg), the carotid arteries were embedded in Durcupan ACM, and the inner diameter (ID), wall thickness (WT) (tunica intima and media), cross sectional area (CSA) (tunica intima and media), and WT/ID ratio were calculated. In Wistar rats and SHRs, prazosin and losartan administration produced a decrease in the blood pressure and trophicity of the heart. In Wistar rats, both drugs decreased the WT, CSA, and the WT/ID ratio. In addition, these drugs increased the circumferential stress of the artery without affecting the ID. In contrast, in the SHRs, only losartan administration produced these effects. Importantly, both the drugs improved the responses to acetylcholine in SHRs. PMID- 23682025 TI - The long-term administration of Orai 1 antagonist possesses antitussive, bronchodilatory and anti-inflammatory effects in experimental asthma model. AB - The best-studied store-operated Ca2+ channels (SOCs), Ca2+ release activated Ca2+ (CRAC) channels, are activated by depleting endoplasmic reticulum Ca2+ pool and mediate Ca2+ influx vitally important for Ca2+ restoration and many cellular function. CRAC channels were identified on immune and airway smooth muscle (ASM) cells. Emerging evidence points to its involvement in allergic airways diseases. This article evaluated therapeutic potency of CRAC antagonist in experimental animal model of allergic asthma. Allergic asthma, induced by repetitive exposure of guinea pigs to ovalbumine, was followed by 14 days therapy by CRAC antagonist (3-fluoropyridine-4-carboxylic acid, FPCA). In vivo changes of specific airways resistance (sRaw) evaluated bronchodilatory effect of FPCA and salbutamol. The method of citric acid-induced cough reflex assessed antitussive activity of FPCA and codeine. The measurement of exhaled NO (ENO), expression of inducible NO synthase (iNOS) by RT-PCR and immunohistochemical staining of airways tissue verified anti-inflammatory effect of FPCA. Long-term administration of FPCA resulted in significant cough suppression and bronchodilation, both comparable to the effect of control drugs. FPCA significantly decreased ENO and iNOS expression, which together with immunohistochemical analysis validated its anti inflammatory effect. Presented data confirmed CRAC channels as a promising target for treatment of respiratory diseases associated with allergic inflammation. PMID- 23682026 TI - Effects of caloric restriction on oxidative stress parameters. AB - Moderate caloric restriction prolongs lifespan. Changes in oxidative stress and hormesis may be involved in this process. The aim of this study is to examine the effects of different levels of chronic caloric restriction (CR) and acute fasting on stress response and oxidative stress parameters in rat liver and plasma. Forty two rats were divided into groups: control group, calorie-restricted groups with intake of 80-90%, 60-70%, 40-50%, 20-30% of daily caloric needs and acute fasting group. To determine alanine aminotransferase (ALT), aspartate aminotransferase (AST) and superoxide dismutase (SOD) activity, concentration of corticosterone, nitrites and nitrates (NOx), malondialdehyde (MDA) and glutathione (GSH), liver samples and blood were collected. Increase in plasma corticosterone concentration and AST and ALT activity was found in severe CR. Ingestion 40-50% daily caloric needs or less increased liver MDA and NOx concentration and decreased SOD activity. Ingestion 60-70% daily caloric needs increased Mn-SOD activity, GSH and NOx. In acute fasting group and group taking 20-30% daily caloric needs, GSH was significantly lower than in control group. Severe CR and acute fasting increase oxidative damage and decrease antioxidative capacity of hepatocytes. Moderate CR increases antioxidative capacity of hepatocytes due to increase in Mn-SOD activity and GSH concentration, which might have a role in anti-aging and hormetic mechanism of CR. PMID- 23682027 TI - Secure preventive detention in Germany: incapacitation or treatment intervention? AB - Secure preventive detention of dangerous offenders has been a major source of debate in German law and practice. Unlike the other two custodial measures of correction and security in the Penal Code (confinement in a psychiatric hospital and in a detoxification clinic), it has served mainly as incapacitation. Judgments by the German Federal Constitutional Court and the European Court of Human Rights challenged this traditional concept of secure preventive detention, which led to a redefinition of the measure. It is now conceived as an offending behavior treatment measure in a secure environment. This article reports on the background of this development and analyzes its implications. PMID- 23682028 TI - The newest member of the VEGF family. AB - In this issue of Blood, Singh et al establish the existence of a new soluble isoform of vascular endothelial growth factor receptor 3 (sVEGFR-3), which is synthesized and secreted by corneal epithelial cells; they show that sVEGFR-3 modulates lymphangiogenesis by impounding vascular endothelial growth factor (VEGF) C and rendering it unable to activate its cognate receptors, thereby maintaining the natural alymphatic disposition of the cornea. PMID- 23682029 TI - Jump-starting the T cells in CLL. AB - In this issue of Blood, Shanafelt and colleagues demonstrate that T-cell immune synapse function can be increased in chronic lymphocytic leukemia (CLL), both by reducing tumor burden with immunochemotherapy and by lenalidomide. PMID- 23682030 TI - Gimme a brake: HPK1 regulates LFA-1 and neutrophil traction. AB - In this issue of Blood, Jakob et al report that hematopoietic progenitor kinase 1 (HPK1) participates during signaling of neutrophil recruitment by acting as a regulator of the adhesiveness of the b2-integrin lymphocyte function-associated antigen 1 (LFA-1) during acute inflammation. PMID- 23682031 TI - SHPing in different directions in platelet production. AB - In this issue of Blood, Mazharian and colleagues characterize Shp1 and Shp2 conditional knockout (KO) murine models, underscoring the role of these phosphatases not only on platelet function but also on megakaryocyte development and platelet counts and size. PMID- 23682033 TI - Characterization of CTX-M-type extended-spectrum beta-lactamase in clinical clones of Escherichia coli in Southwest China. AB - The rapid and widespread dissemination of CTX-M-type extended-spectrum beta lactamases (ESBLs) Escherichia coli in most of the provinces in China has been previously characterized; however, these enzymes have been rarely reported among minority regions. A prospective study using 180 E. coli clones from three hospitals in the minority district of Dali Bai was conducted between January 2009 and June 2010 to characterize the profiles of bla(CTX-M) -producing E. coli. Overall, 87 of the isolates (48.3%) encoded the resistance phenotypes of ESBLs. Among these 87 isolates, 56 (64.4%) exconjugants were successfully obtained. The genotypes of bla(CTX-M) were evaluated by PCR and DNA sequencing. In total, 22 and 53 E. coli isolates possessed CTX-M cluster 1 and CTX-M cluster 9, respectively. Five bla(CTX-M) subtypes were detected, namely, bla(CTX-M3) (n = 12), bla(CTX-M15) (n = 4), bla(CTX-M22) (n = 2), bla(CTX-M14) (n = 41), and bla(CTX-M9) (n = 8). The broth microdilution method was performed to determine the minimal inhibitory concentration of 13 antibiotics. Most CTX-M producers were multiply resistant to both beta-lactam and non-beta-lactam antibiotics. Imipenem showed excellent activity, and only one isolate harboring bla(CTX-M14+CTX-M3) exhibited resistance to it. In conclusion, there seems to be great concern regarding the distribution and drug resistance of CTX-M ESBL-producing E. coli. PMID- 23682034 TI - Rescue of easily shocked mutant seizure sensitivity in Drosophila adults. AB - Genetic factors that influence seizure susceptibility can act transiently during the development of neural circuits or might be necessary for the proper functioning of existing circuits. We provide evidence that the Drosophila seizure sensitive mutant easily shocked (eas) represents a neurological disorder in which abnormal functioning of existing neural circuits leads to seizure sensitivity. The eas(+) gene encodes for the protein Ethanolamine Kinase, involved in phospholipid biosynthesis. We show that induction of eas(+) in adult mutant flies rescues them from seizure sensitivity despite previously known developmental defects in brain morphology. Additionally, through cell-type-specific rescue, our results suggest a specific role for eas(+) in excitatory rather than inhibitory neural transmission. Overall, our findings emphasize an important role for proper phospholipid metabolism in normal brain function and suggest that certain classes of epilepsy syndromes could have the potential to be treated with gene therapy techniques. PMID- 23682035 TI - Mental health care Monitor Older adults (MEMO): monitoring patient characteristics and outcome in Dutch mental health services for older adults. AB - Information on which older adults attend mental health care and whether they profit from the care they receive is important for policy-makers. To assess this information in daily practice, the "Mental health care Monitor Older adults" (MEMO) was developed in the Netherlands. The aim of this paper is to describe MEMO and the older adults who attend outpatient mental health care regarding their predisposing and enabling characteristics and need for care. In MEMO all patients referred to the division of old age psychiatry of the participating mental health care organisations are assessed at baseline and monitored at 4, 8 and 12-month follow-up. Primary outcomes are mental and social functioning, consumer satisfaction, and type of treatment provided (MEMO Basic). Over the years, MEMO Basic is repeated. In each cycle, additional information on specific patient groups is added (e.g. mood disorders). Data collection is supported by a web-based system for clinicians, including direct feedback to monitor patients throughout treatment. First results at baseline showed that the majority of patients that entered the division of old age psychiatry was female (69%), had low education (83%), lived alone (53%), was depressed (42%) and had a comorbid condition (82%). It seemed that older immigrants were not sufficiently reached. The current study is the first in the Netherlands to evaluate patient characteristics and outcome in mental health care provided for older adults in day-to-day practice. If MEMO works out successfully, the method should be extended to other target groups. PMID- 23682036 TI - Degradable and biocompatible poly(N,N-dimethylaminoethyl methacrylate-co caprolactone)s as DNA transfection agents. AB - This study describes the synthesis of a set of novel, degradable block copolymers for DNA transfection, and analyzes their physicochemical and biological properties. PEO macro-azoinitiators are used for the free radical copolymerization of DMAEMA and MDO, resulting in a series of different quaternized or non-quaternized block copolymers. All of the polymers show little cytotoxicity and full degradability, and thus, based on their favorable properties, may represent promising vectors for in vivo applications. Marked differences in DNA complexation efficacies and biological activities are observed, and one of the poly(PEG-co-(MDO-co-DMAEMA))s is identified as optimal for DNA transfection. PMID- 23682037 TI - Shape-persistent (Pt-salphen)2 phosphorescent coordination frameworks: structural insights and selective perturbations. AB - The development of molecular frameworks derived from binuclear platinum(II) aromatic Schiff base (salphen) complexes and their supramolecular chemistry have been undertaken. A series of axially rotating (Pt-salphen)2 luminophores, tethered in a cofacial manner by a rigid linker (xanthene, 1; dibenzofuran, 2; biphenylene, 3), was synthesized in which the O(salphen) groups are potentially amenable for guest-binding. The molecular structures of 1 and 3 have been determined by X-ray crystallography, revealing intra- and intermolecular pi stacking interactions, as well as contrasting syn (1) and anti (3) configurations, for the (Pt-salphen)2 moiety. All complexes are luminescent in solution at room temperature. Their photophysical and solvatochromic properties have been examined, and the emissions are assigned to mixed triplet O(p)/Pt(d) >pi*(diimine) excited states. The red-shifted fluid emissions and lower quantum yields of 1 and 3, relative to 2, are ascribed to enhanced intramolecular pi stacking interactions. Photophysical changes and selective responses to metal ions (particularly Pb(2+)) have been investigated by using various spectroscopic methods and DFT calculations, and through comparative studies with control complexes. A plausible binding mechanism is proposed based on occupation of the O(salphen)-binding cavity, which induces perturbation of intramolecular pi-pi interactions, and hence the self-quenching and emission properties, of the (Pt salphen)2 unit. PMID- 23682038 TI - Validity of CBCL-derived PTSD and dissociation scales: further evidence in a sample of neglected children and adolescents. AB - There is growing evidence that child neglect is an important risk factor for posttraumatic stress disorder (PTSD) and dissociation. Considering that the Child Behavior Checklist (CBCL) is a widely used measure, the possibility of using validated CBCL-derived trauma symptoms scales could be particularly useful to better understand how trauma symptoms develop among neglected children and adolescents. This study examined the factor structure of three CBCL-derived measures of PTSD and dissociation (namely, PTSD scale, Dissociation scale, and PTSD/Dissociation scale) in a sample of 239 neglected children and adolescents aged 6 to 18 years using the latest version of CBCL (CBCL 6-18). Evidence of convergent validity of these scales was also examined for participants aged 12 and under using two well-validated measures of PTSD and Dissociation: the Trauma Symptoms Checklist for Young Children and the Child Dissociation Checklist. Findings suggest that CBCL-derived measures of trauma symptoms, especially PTSD and Dissociations scales, may be of heuristic value in the study of trauma symptomatology in neglected samples. Factor structure and evidence of convergent validity were supported for these two scales. Results also provide further support to the well-established assumption that PTSD and dissociation are two related but different constructs. PMID- 23682039 TI - Seasonal variation in semen quality in China. AB - In this study, we assessed the effect of seasonal variation on the semen quality in Chinese by using the average highest temperature (AHT) of the ejaculation day for partitioning season periods. A total of 13 635 semen samples were collected and analysed according to the AHT of the ejaculation day. Semen volume, sperm concentration and the percentage of spermatozoa with normal morphology in midsummer (AHT > 30 degrees C) were significantly lower than those in other periods of the year. Sperm motility with AHT 10-20 degrees C in winter and spring was significantly higher than that in other seasons. The percentage of head defects spermatozoa with AHT < 10 degrees C in winter was significantly lower than that in other periods. We observed that there was a significant effect of season on the semen parameters. Highest environment temperature of the day may be a determining factor for the seasonal variations in semen quality. PMID- 23682040 TI - Influenza: marketing vaccine by marketing disease. PMID- 23682041 TI - Comparison of comfort and image quality with two endorectal coils in MRI of the prostate. AB - PURPOSE: To prospectively evaluate comfort and image quality of prostate MRI using two different endorectal (ER) coils. MATERIALS AND METHODS: Thirty consecutive patients were prospectively randomized to receive prostate MRI using either a prostate endocoil (PEC) or colorectal endocoil (CEC). Patients and operators were surveyed with regard to endocoil placement. Four Body MRI trained radiologists rated image quality for each examination and additional selected blinded coronal T2 weighted images. RESULTS: Average patient discomfort (on a 0 10 pain scale) was greater with the PEC (5.0 for PEC and 2.7 for CEC) with a statistically significant difference (P < 0.03). Ability to identify the neurovascular bundle (NVB) was 5.8 times more likely to be rated excellent with the CEC compared with the PEC (P < 0.003). Image quality with CEC was 3.5 times more highly rated (P < 0.04). In particular, signal-to-noise ratio (SNR) with the CEC was 3.0 times more highly rated than with the PEC (P < 0.05). CONCLUSION: The smaller CEC was better tolerated by patients than the traditional PEC, and resulted in at least equivalent, and in some instances improved image quality. This may result in fewer aborted cases and lead to decreased procedural intolerance to endorectal coil MRI. PMID- 23682042 TI - Syncope in children caused by hair grooming: clinical characteristics in 12 new cases. PMID- 23682043 TI - Diagnostic accuracy studies: how to report and analyse inconclusive test results. PMID- 23682044 TI - Government welfare cuts are hitting children, says BMA. PMID- 23682045 TI - BMA disputes government line that evidence for rolling out NHS 111 was robust. PMID- 23682046 TI - Government's plan to raise dementia diagnoses gets mixed response. PMID- 23682047 TI - OFSTED style ratings for hospitals are not specific enough for patient procedures, Francis says. PMID- 23682048 TI - Under-5 child mortality falls by almost 40% over 20 years in countries with worst record, WHO says. PMID- 23682049 TI - Autopsies using MRIs in babies and infants could help improve uptake rates. PMID- 23682050 TI - Assisted suicide for the dying would reduce suffering, says Falconer. PMID- 23682051 TI - Number of organ donations to strangers trebled last year. PMID- 23682052 TI - Vermont governor agrees to sign bill on physician assisted suicide. PMID- 23682053 TI - Americans should lower salt intake but not too much, review says. PMID- 23682054 TI - Cochrane researchers continue to face challenges over access to data on flu drugs. PMID- 23682055 TI - Effects of distraction on negative behaviors and salivary alpha-amylase under mildly stressful medical procedures for brief inpatient children. AB - Inconsistent results have been reported on the effects of distraction on negative emotions during medical procedures in infants. These differing results may be attributable to the fact that the effects are apparent under a mildly stressful medical procedure. A total of 17 infants, 18 preschoolers, and 15 school-aged children who were hospitalized were administered, monitoring for vital signs, a mildly stressful medical procedure, by a nurse in a uniform with attractive character designs as a distractor. Consistent with the hypothesis, participating infants showed fewer negative behaviors and lower salivary alpha-amylase levels when distracted. The results support the efficacy of distraction in infants under a mildly stressful medical procedure. PMID- 23682056 TI - Another body project: the thin ideal, motherhood, and body dissatisfaction among Mexican women. AB - In this article, we examine the bodily experiences of Mexican women, to investigate their acceptance of the thin ideal and resulting body dissatisfaction. We conducted semi-structured individual interviews with 30 adult participants in Mexico City. Interviewees accepted the thin body ideal, but experiencing their bodies as signifiers of motherhood protected them from body dissatisfaction. Instead of a personal body project, they engaged in a project of caring for their children's bodies. We suggest that health campaigns directed to adult women should consider the relational aspects of their lives. PMID- 23682057 TI - Approach/avoidance motivation, message framing and skin cancer prevention: a test of the congruency hypothesis. AB - The congruency hypothesis posits that approach-orientated individuals are persuaded to engage in prevention behaviours by positively framed messages; conversely, negatively framed messages are more persuasive in encouraging those who are avoidance-orientated. A 2 (frame: loss vs gain) * 2 (motivation: avoidance vs approach) design examined the effects of skin cancer information on sun-protective intentions and free sunscreen sample requests among 533 young adults. Gain-framed messages had the strongest effect on sun-protective intentions for approach-oriented individuals, whereas loss-framed messages had the strongest effect on avoidance-oriented individuals. Message framing effects on precautionary sun behaviour intentions were moderated by motivational differences. PMID- 23682058 TI - Applying Leventhal's self-regulatory model to pregnancy: evidence that pregnancy related beliefs and emotional responses are associated with maternal health outcomes. AB - This study explored whether women's beliefs about, and emotional responses to, pregnancy could account for variations in maternal mental and physical health outcomes, using the self-regulatory model as a theoretical framework. Women in the last trimester of pregnancy (N=408) completed an online survey including measures of representations of pregnancy, coping, and physical and mental health. Results revealed that representations of pregnancy accounted for up to 30 and 39 per cent of the variance in indicators of physical and mental health, respectively. Findings suggest that beliefs about pregnancy may have important implications for maternal health. PMID- 23682059 TI - Predictors of weight variation and weight gain in peri- and post-menopausal women. AB - This research encompasses a community sample of 497 women in peri- and post menopause and uses structural equation modelling to investigate the structural models of weight variation and weight gain. Variables such as body shape concerns, depression, stress and life events are explored. Weight gain (from pre menopause to current menopausal status) was observed in 69 per cent of participants. The predictors of weight gain were lower education level (beta = .146, p = .017), less or no physical exercise (beta = -.111, p = .021), having a recent psychological problem (beta = .191, p < .001), transition from peri- to post-menopause (beta = .147, p = .013) and more frequent body shape concerns (beta = .313, p < .001). Prevention of weight gain in pre-menopause is recommended; risk groups should be targeted considering the predictors of weight increase. PMID- 23682060 TI - Body talk among undergraduate women: why conversations about exercise and weight loss differentially predict body appreciation. AB - Undergraduate women (N = 143) completed self-reports on exercise behavior, body orientation, body appreciation, and body-related talk. Results showed that conversations about weight loss/dieting and conversations about exercise differentially predicted body appreciation. Importantly, multiple regression analyses showed that the relationship between talk type and body appreciation was explained by the object-process dichotomy: Conversations about exercise oriented women to consider what their bodies can do which, in turn, predicted appreciation of one's body. In contrast, the relationship between conversations about weight loss/dieting and body appreciation was mediated by negative attitudes about one's body but not by an object orientation. PMID- 23682061 TI - Exploring positive adjustment in people with spinal cord injury. AB - This study explored adjustment in people with spinal cord injury; data from four focus groups are presented. Thematic analysis revealed four themes, managing goals and expectations, comparison with others, feeling useful and acceptance, showing participants positively engaged in life, positively interpreted social comparison information and set realistic goals and expectations. These positive strategies show support for adjustment theories, such as the Cognitive Adaptation Theory, the Control Process Theory and Response Shift Theory. These results also provide insight into the adjustment process of a person with spinal cord injury and may be useful in tailoring support during rehabilitation. PMID- 23682062 TI - Emotional intelligence, personality, and gender as factors in disordered eating patterns. AB - We examined the hypotheses that proposing higher levels of emotional intelligence (ability test and self-report) and lower neuroticism, extraversion, and agreeableness associate with lower levels of disordered eating. In a correlational study, 126 Israeli college students completed two measures of emotional intelligence, a brief five-factor personality test, demographic data questionnaires, and questionnaires assessing food preoccupation, namely, the Body Weight, Image and Self-Esteem Scale and the Appearance Schema Inventory. Results suggested that ability emotional intelligence is associated with disordered eating beyond gender and personality. Self-reported emotional intelligence did not associate with any of the outcomes after controlling for personality. Implications and applications are briefly discussed. PMID- 23682063 TI - Predictors of recent HIV testing among male street laborers in urban Vietnam. AB - This study assessed the prevalence of and factors associated with HIV testing among male street laborers. In a cross-sectional survey, social mapping was done to recruit and interview 450 men aged 18-59 years in Hanoi. Although many of these men engaged in multiple risk behaviors for HIV, only 19.8 percent had been tested for HIV. A modified theoretical model provided better fit than the conventional Information-Motivation-Behavioral Skills model, as it explained much more variance in HIV testing. This model included three Information-Motivation Behavioral components and four additional factors, namely, the origin of residence, sexual orientation, the number of sexual partners, and the status of condom use. PMID- 23682064 TI - Changes in self-rated health and subjective social status over time in a cohort of healthcare personnel. AB - As part of a prospective cohort study of 1354 female and 347 male healthcare personnel, we examined the stability of subjective social status over ~7 months and the prospective association between subjective social status and self-rated health status. Most (82%) subjective social status ratings were stable (within +/ 1 point). Lower baseline subjective social status among healthcare personnel was associated with more subsequent reports of fatigue and headache and worsening global self-rated health status. Healthcare personnel who placed themselves on the bottom half of the subjective social status ladder were four times more likely to experience a decline in global self-rated health status and half as likely to improve to excellent self-rated health status. PMID- 23682065 TI - Vulnerable discipline: experiences of male competitive bodybuilders. AB - The aim was to understand experiences of male competitive bodybuilders from a non pathologizing perspective. Six male Norwegian competitive bodybuilders were interviewed. The interviews were analysed using a meaning condensation procedure resulting in five themes: being proud of capacity for discipline, seeing a perfectionist attitude as a necessary evil, experiencing recognition within the bodybuilding community, being stigmatized outside the bodybuilding community and going on stage to display a capacity for willpower and discipline. We suggest that bodybuilders may be stigmatized for breaking social norms: by their distinctive appearance, by the way they handle suspected drug use and by challenging gender norms. PMID- 23682066 TI - The role of skin cancer knowledge in sun-related behaviours: a systematic review. AB - Skin cancer is the most commonly diagnosed cancer in many Western countries. This systematic review provides a comprehensive overview of the relationship between skin cancer knowledge and sun-protective, exposure and tanning behaviours in the general population. A total of 34 studies, published in peer-reviewed journals over three decades, were reviewed and synthesised. Sun-protective behaviour was positively associated with skin cancer knowledge in most cases. Findings were inconsistent regarding other sun-related behaviours. Heterogeneity in measurement compromised the capacity to definitively link knowledge and sun-related behaviours. There is a need for development and utilisation of a standardised skin cancer knowledge scale, and guidelines are suggested. PMID- 23682067 TI - Being healthy or looking good? The effectiveness of health versus appearance focused arguments in two-sided messages. AB - Two experimental studies test the effectiveness of health versus appearance related arguments in two-sided messages. The first study shows that two-sided messages to discourage suntanning are more effective when using appearance focused instead of health-focused arguments. Study 2 elaborates on the underlying mechanism and extends the generalization of the results of the first study, by investigating two-sided messages to promote physical exercise. The results show that for health-motivated consumers, a health-focused message is more effective, whereas for appearance-motivated consumers, an appearance-focused message is more effective. This matching effect is mediated by argument relevance. PMID- 23682068 TI - Multiple-goal management: an examination of simultaneous pursuit of a weight-loss goal with another goal. AB - This study investigated the characteristics contributing to successful goal attainment of a weight-loss and a non-weight-loss goal simultaneously. Weight loss and non-weight-loss goals, self-efficacy, persistence, temptations, intergoal interference and facilitation were measured via an online questionnaire (N=103, Mage=25.36+/-6.9, 80% women). Weight-loss self-efficacy, persistence, temptations and intergoal facilitation significantly predicted weight-loss goal attainment. Those who were more successful in attaining both their goals simultaneously had higher self-efficacy and persistence and experienced less temptation towards both goals. This study provides an insight into the characteristics necessary for successful simultaneous management of a weight-loss goal with another goal. PMID- 23682069 TI - MPs told about practical difficulties of full data disclosure. PMID- 23682070 TI - Is neural activation within the rescued penumbra impeded by selective neuronal loss? AB - After stroke, penumbral salvage determines clinical recovery. However, the rescued penumbra may be affected by selective neuronal loss, as documented both histopathologically in animals and using the validated in vivo positron emission tomography marker (11)C-flumazenil in humans. However, whether the non-infarcted penumbra is capable of neuronal activation, and how selective neuronal loss may interfere, is unknown. Here we prospectively mapped the topographical relationships between functional magnetic resonance imaging responses and non infarcted penumbra, and tested the hypothesis that the former do take place in the latter, but only in its subsets spared selective neuronal loss. Seven patients (mean age 74 years; three thrombolysed) with first-ever acute anterior circulation stroke, presence of penumbra on computed tomography perfusion performed within 6 h of onset, and substantial deficit on admission but good outcome at 1-3 months (National Institute of Health Stroke Score range 6-13 and 0 1, respectively, P = 0.001), were studied. At follow-up, patients underwent structural magnetic resonance imaging to map the infarct, functional magnetic resonance imaging (three tasks selected to probe the right or left hemisphere), and (11)C-flumazenil positron emission tomography generating binding potential maps. Patients with significant carotid or middle-cerebral artery disease or impaired vasoreactivity were excluded. Following image coregistration, the non infarcted penumbra comprised all acutely ischaemic voxels (identified on acute computed tomography perfusion using previously validated thresholds) not part of the final infarct. To test our hypotheses, the overlap between functional magnetic resonance imaging activation clusters and non-infarcted penumbra was mapped, and binding potential values then computed both within and outside this overlap. In addition, the overlap between functional magnetic resonance imaging activation clusters and areas of significantly reduced binding potential (determined using Statistical Parametric Mapping against 16 age-matched control subjects) was assessed in each patient. An overlap between non-infarcted penumbra and functional magnetic resonance imaging clusters was present in seven of seven patients, substantial in four. Binding potential was significantly reduced in the whole non-infarcted penumbra (P < 0.01) but not within the functional magnetic resonance imaging overlap. Clusters with significantly reduced binding potential showed virtually no overlap with functional magnetic resonance imaging activation compared with 12 age-matched controls (P = 0.04).The results from this proof of principle study suggest that 1-3 months after stroke the non-infarcted penumbra is capable of neuronal activation, consistent with its established role in recovery of neurological functions. However, although the non-infarcted penumbra as a whole was affected by selective neuronal loss, activations tended to occur within portions spared selective neuronal loss, suggesting the latter impedes neuronal activation. Although its clinical correlates are still elusive, selective neuronal loss may represent a novel therapeutic target in the aftermath of ischaemic stroke. PMID- 23682071 TI - The chemopreventive efficacies of nonsteroidal anti-inflammatory drugs: the relationship of short-term biomarkers to long-term skin tumor outcome. AB - The ultraviolet B (UVB) component of sunlight, which causes DNA damage and inflammation, is the major cause of nonmelanoma skin cancer (NMSC), the most prevalent of all cancers. Nonsteroidal anti-inflammatory drugs (NSAID) and coxibs have been shown to be effective chemoprevention agents in multiple preclinical trials, including NMSC, colon, and urinary bladder cancer. NSAIDs, however, cause gastrointestinal irritation, which led to the recent development of nitric oxide (NO) derivatives that may partially ameliorate this toxicity. This study compared the efficacy of several NSAIDs and NO-NSAIDs on UV-induced NMSC in SKH-1 hairless mice and determined whether various short-term biomarkers were predictive of long term tumor outcome with these agents. Naproxen at 100 (P = 0.05) and 400 ppm (P < 0.01) in the diet reduced tumor multiplicity by 26% and 63%, respectively. The NO naproxen at slightly lower molar doses shows similar activities. Aspirin at 60 or 750 ppm in the diet reduced tumor multiplicity by 19% and 50%, whereas the equivalent doses (108 and 1,350 ppm) were slightly less effective. Sulindac at 25 and 150 ppm in the diet, doses far below the human equivalent dose was the most potent NSAID with reductions of 50% and 94%, respectively. In testing short-term biomarkers, we found that agents that reduce UV-induced prostaglandin E2 synthesis and/or inhibit UV-induced keratinocyte proliferation yielded long-term tumor efficacy. PMID- 23682072 TI - Characterization of raloxifene glucuronidation: potential role of UGT1A8 genotype on raloxifene metabolism in vivo. AB - Raloxifene is a second-generation selective estrogen receptor modulator used for the prevention and treatment of osteoporosis and the prevention of breast cancer in postmenopausal women. Raloxifene is extensively metabolized by glucuronidation to form raloxifene-6-glucuronide (ral-6-Gluc) and raloxifene-4'-glucuronide (ral 4'-Gluc). The goal of the present study was to determine whether functional polymorphisms in active UGTs could play a role in altered raloxifene glucuronidation in vivo. Using homogenates from HEK293 UGT-overexpressing cell lines, raloxifene was shown to be glucuronidated primarily by the hepatic UGTs 1A1 and 1A9 and the extra-hepatic UGTs 1A8 and 1A10; no detectable raloxifene glucuronidation activity was found for UGT2B enzymes. Functional UGT1A1 transcriptional promoter genotypes were significantly (Ptrend = 0.005) associated with ral-6-Gluc formation in human liver microsomes, and, consistent with the decreased raloxifene glucuronidation activities observed in vitro with cell lines overexpressing UGT1A8 variants, the UGT1A8*2 variant was significantly (P = 0.023) correlated with total raloxifene glucuronide formation in human jejunum homogenates. While ral-4'-Gluc exhibited 1:100th the anti-estrogenic activity of raloxifene itself as measured by binding to the estrogen receptor, raloxifene glucuronides comprised about 99% of the circulating raloxifene dose in raloxifene treated subjects, with ral-4'-Gluc comprising ~70% of raloxifene glucuronides. Plasma ral-6-Gluc (Ptrend = 0.0025), ral-4'-Gluc (Ptrend = 0.001), and total raloxifene glucuronides (Ptrend = 0.001) were increased in raloxifene-treated subjects who were predicted slow metabolizers [UGT1A8 (*1/*3)] versus intermediate metabolizers [UGT1A8 (*1/*1) or UGT1A8 (*1/*2)] versus fast metabolizers [UGT1A8 (*2/*2). These data suggest that raloxifene metabolism may be dependent on UGT1A8 genotype and that UGT1A8 genotype may play an important role in overall response to raloxifene. PMID- 23682073 TI - Folic acid prevents the initial occurrence of sporadic colorectal adenoma in Chinese older than 50 years of age: a randomized clinical trial. AB - Colorectal adenoma (CRA) is the precursor lesion of colorectal cancer (CRC). Several agents have been shown to be effective in the chemoprevention of CRA recurrence, but there has been little research on its primary prevention. Participants older than 50 years with no adenomas were recruited for our study and randomized to receive either 1 mg/day folic acid supplement or treatment without folic acid. After 3 years of follow-up, plasma folate and colonoscopy were evaluated. Seven hundred ninety-one participants (91.98%) completed the study. CRA occurred in 64 (14.88%) participants in the folic acid group and 132 (30.70%) in the control group [unadjusted risk ratio (RR), 0.49; 95% confidence interval (CI), 0.37-0.63; P < 0.01]; left-sided adenoma (unadjusted RR, 0.54; 95% CI, 0.38-0.76; P = 0.001) and advanced CRA (unadjusted RR, 0.36; 95% CI, 0.16 0.81; P = 0.01) were most common. There was no significance difference in the occurrence of three or more adenomas (unadjusted RR, 0.70; 95% CI, 0.36-1.77; P = 0.38) or right-sided adenoma (unadjusted RR, 0.55; 95% CI, 0.30-1.00; P = 0.07) between the two groups. Participants with low plasma folate may have a high risk of CRA. In conclusion, primary prevention with 1 mg/day folic acid supplementation could reduce the incidence of CRA, especially left-sided and advanced disease in those with no previous adenomas. People with differing baseline plasma folate levels should be given individualized treatment. Those with low plasma folate should be encouraged to take adequate supplements; plasma folate should be elevated to an effective therapeutic level, which may reduce the incidence of CRA. PMID- 23682074 TI - Metabolic syndrome and mammographic density in Mexican women. AB - Metabolic syndrome has been associated with an increased risk of breast cancer; however, little is known about the association between metabolic syndrome and percent mammographic density, a strong predictor of breast cancer. We analyzed cross-sectional data from 789 premenopausal and 322 postmenopausal women in the Mexican Teacher's Cohort (ESMaestras). Metabolic syndrome was defined according to the harmonized definition. We measured percent density on mammograms using a computer-assisted thresholding method. Multivariable linear regression was used to estimate the association between density and metabolic syndrome, as well as its components by state (Jalisco, Veracruz) and menopausal status (premenopausal, postmenopausal). Among premenopausal women in Jalisco, women with metabolic syndrome had higher percent density than those without after adjusting for potential confounders including BMI [difference = 4.76; 95% confidence interval (CI), 1.72-7.81]. Among the metabolic syndrome components, only low high-density lipoprotein levels (<50 mg/dL) were associated with significantly higher percent density among premenopausal women in Jalisco (difference = 4.62; 95% CI, 1.73 7.52). Metabolic syndrome was not associated with percent density among premenopausal women in Veracruz (difference = -2.91; 95% CI, -7.19 to 1.38), nor among postmenopausal women in either state. Metabolic syndrome was associated with higher percent density among premenopausal women in Jalisco, Mexico, but was not associated with percent density among premenopausal women in Veracruz, Mexico, or among postmenopausal women in either Jalisco or Veracruz. These findings provide some support for a possible role of metabolic syndrome in mammographic density among premenopausal women; however, results were inconsistent across states and require further confirmation in larger studies. PMID- 23682076 TI - Progesterone enhances calcitriol antitumor activity by upregulating vitamin D receptor expression and promoting apoptosis in endometrial cancer cells. AB - Human studies suggest that progesterone and calcitriol may prove beneficial in preventing or inhibiting oncogenesis, but the underlying mechanism is not fully understood. The current study investigates the effects of progesterone, calcitriol, and their combination on immortalized human endometrial epithelial cells and endometrial cancer cells and identifies their targets of action. Combination treatment with both agents enhanced vitamin D receptor expression and inhibited cell proliferation through caspase-3 activation and induction of G0-G1 cell-cycle arrest with associated downregulation of cyclins D1 and D3 and p27 induction. We used mass spectrometry-based proteomics to measure protein abundance differences between calcitriol-, progesterone-, or combination-exposed endometrial cells. A total of 117 proteins showed differential expression among these three treatments. Four proteins were then selected for validation studies: histone H1.4 (HIST1H1E), histidine triad nucleotide-binding protein 2 (HINT2), IFN-induced, double-stranded RNA-activated protein kinase (EIF2AK2), and Bcl-2 associated X protein (BAX). Abundance levels of selected candidates were low in endometrial cancer cell lines versus the immortalized endometrial epithelial cell line. All four proteins displayed elevated expression in cancer cells upon exposure to calcitriol, progesterone, or the combination. Further BAX analysis through gain- or loss-of-function experiments revealed that upregulation of BAX decreased cell proliferation by changing the BAX:BCL-2 ratio. Knockdown of BAX attenuated progesterone- and calcitriol-induced cell growth inhibition. Our results showed that progesterone and calcitriol upregulate the expression of BAX along with other apoptosis-related proteins, which induce inhibition of endometrial cancer cell growth by apoptosis and cell-cycle arrest. PMID- 23682075 TI - Effect of zileuton and celecoxib on urinary LTE4 and PGE-M levels in smokers. AB - COX-2 and 5-lipoxygenase (5-LO) use arachidonic acid for the synthesis of eicosanoids that have been implicated in carcinogenesis and cardiovascular disease. The ability of celecoxib, a selective COX-2 inhibitor, to redirect arachidonic acid into the 5-LO pathway can potentially reduce its efficacy as a chemopreventive agent and increase the risk of cardiovascular complications. Levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E4 (LTE4), biomarkers of the COX and 5-LO pathways, are elevated in smokers. Here, we investigated the effects of zileuton, a 5-LO inhibitor, versus zileuton and celecoxib for 6 +/- 1 days on urinary PGE-M and LTE4 levels in smokers. Treatment with zileuton led to an 18% decrease in PGE-M levels (P = 0.03); the combination of zileuton and celecoxib led to a 62% reduction in PGE-M levels (P < 0.001). Levels of LTE4 decreased by 61% in subjects treated with zileuton alone (P < 0.001) and were unaffected by the addition of celecoxib. Although zileuton use was associated with a small overall decrease in PGE-M levels, increased PGE-M levels were found in a subset (19 of 52) of subjects. Notably, the addition of celecoxib to the 5-LO inhibitor protected against the increase in urinary PGE-M levels (P = 0.03). In conclusion, zileuton was an effective inhibitor of 5-LO activity resulting in marked suppression of urinary LTE4 levels and possible redirection of arachidonic acid into the COX-2 pathway in a subset of subjects. Combining celecoxib and zileuton was associated with inhibition of both the COX-2 and 5-LO pathways manifested as reduced levels of urinary PGE-M and LTE4. PMID- 23682077 TI - How long will it take to reduce gastric cancer incidence by eradicating Helicobacter pylori infection? AB - Helicobacter pylori (H. pylori) is the most important risk factor for the development of gastric cancer. The objective of this article is to estimate how the number of clinically diagnosed cases caused by H. pylori would reduce in the years after the eradication of the infection from a population. It is assumed that the eradication of H. pylori will prevent the start of some new gastric tumors, but those that have passed the "point of no return" will continue to develop until diagnosed clinically. The observed reduction in the number of clinically diagnosed cases of gastric cancer will depend on the form and parameters of the distribution of the time t taken for tumor to develop into a clinical case after passing the "point of no return." This analysis assumes that the time t follows normal and log-normal distributions with means 5, 10, and 15 years. If the mean value of time t were 5 years, H. pylori caused cases should be almost eliminated after 10 years, whereas if the mean were 10 years, the number of cases should be halved. If the mean were 15 years, the reduction would only be about 15% after 10 years. The eradication of H. pylori from a population will reduce the incidence of gastric cancer, but the follow-up time needed to show and evaluate the reduction may be longer than that that has been used in studies published so far. PMID- 23682080 TI - Reninoma: a rare cause of curable hypertension. AB - A 25-year-old lady presented with hypertensive encephalopathy. She also had chronic refractory hypertension for the past 7 years. Workup revealed persistent hypokalaemia with metabolic alkalosis suggesting hyperaldosteronism. Hyperaldosteronic states such as renal artery stenosis, Conn's syndrome and Liddle's syndrome were ruled out. Her plasma renin activity was high. Contrast enhanced CT of the abdomen showed a 1.9*2 cm heterogeneously enhancing lesion in the anterior aspect of the right kidney suggesting a possibility of reninoma. The benign tumour was resected by a nephron-sparing surgery. Histopathology suggested a juxtaglomerular cell tumour. Anti-hypertensive drugs were completely withdrawn postoperatively. PMID- 23682078 TI - Identification of putative immunologic targets for colon cancer prevention based on conserved gene upregulation from preinvasive to malignant lesions. AB - The length of time required for preinvasive adenoma to progress to carcinoma, the immunogenicity of colorectal cancer (CRC), and the identification of high-risk populations make development and testing of a prophylactic vaccine for the prevention of CRC possible. We hypothesized that genes upregulated in adenoma relative to normal tissue, which maintained increased expression in CRC, would encode proteins suitable as putative targets for immunoprevention. We evaluated existing adenoma and CRC microarray datasets and identified 160 genes that were >=2-fold upregulated in both adenoma and CRC relative to normal colon tissue. We further identified 23 genes that showed protein overexpression in colon adenoma and CRC based on literature review. Silencing the most highly upregulated genes, CDH3, CLDN1, KRT23, and MMP7, in adenoma and CRC cell lines resulted in a significant decrease in viability (P < 0.0001) and proliferation (P < 0.0001) as compared to controls and an increase in cellular apoptosis (P < 0.05 for CDH3, KRT23). Results were duplicated across cell lines representing microsatellite instability, CpG island methylator, and chromosomal instability phenotypes, suggesting immunologic elimination of cells expressing these proteins could impact the progression of all CRC phenotypes. To determine whether these proteins were immunogens, we interrogated sera from early stage CRC patients and controls and found significantly elevated CDH3 (P = 0.006), KRT23 (P = 0.0007), and MMP7 (P < 0.0001) serum immunoglobulin G in cases as compared to controls. These data show a high throughput approach to the identification of biologically relevant putative immunologic targets for CRC and identified three candidates suitable for vaccine development. PMID- 23682079 TI - HACEK-induced endocarditis. AB - A 61-year-old patient with diabetes had a bio-prosthetic aortic valve replacement 3 years before admission. He complained of lethargy, night sweats, decreased appetite and erratic blood glucose with no weight loss. He had splinter haemorrhage and a systolic ejection murmur at the aortic area. Chest and abdominal examination revealed no abnormality. The erythrocyte sedimentation rate and C reactive protein were raised. He had several sets of blood cultures and he was started on empirical vancomycin, rifampicin and gentamicin. Transthoracic echocardiography showed vegetation on the base of the anterior mitral leaflet, which was confirmed by a trans-oesophageal echocardiography. Blood culture was positive for Haemophilus aphrophilus, and he was started on ceftriaxone for 6 weeks instead of vancomycin and rifampicin and continued gentamicin for 2 weeks. Follow-up echocardiography showed no evidence of vegetations. The patient recovered completely and he was discharged home. PMID- 23682081 TI - Intussusception in a 7-week-old baby. AB - A 7-week-old baby presented to a district general hospital with a history of pallor, lethargy, vomiting and high pitched cry. She had vomited three times at home. It was reported that the last vomitus had a greenish tinge to it. In hospital, she had a non-bilious vomit. There was no history of fever, constipation or diarrhoea. Her birth history and medical history were unremarkable. She was noted to be pale, lethargic and quiet on examination. Her vital signs were unremarkable. She had a soft scaphoid abdomen on examination. No masses were palpable. Investigations for sepsis were done and antibiotics started. Results of all the investigations were normal apart from mildly raised blood glucose and neutrophilia. Later on she passed a small amount of blood per rectum. Examination revealed a palpable mass in the epigastrium. An abdominal x ray was suggestive of intestinal obstruction. Intussusception was confirmed on ultrasound. The intussusception was successfully reduced following surgery. PMID- 23682082 TI - Conservative management of a ruptured mycotic aneurysm. AB - Mycotic aneurysms are a well-recognised complication of infective endocarditis. In contrast to many sequelae of endocarditis, they can present late in the course of the disease, despite adequate treatment. We discuss the case of an 82-year-old patient who was successfully treated for Enterococcus faecalis endocarditis, but presented late with a hypotensive collapse. CT imaging demonstrated a ruptured mycotic aneurysm. He underwent laparotomy, but the decision was made to treat conservatively to protect the vascular supply to the bowel. The patient subsequently made a full recovery. PMID- 23682083 TI - Multilobed cystic dilation of the ventriculus terminalis (CDVT). AB - The cystic dilation of ventriculus terminalis (CDVT) is a rare anatomical variant in adulthood. In this report we describe a new case of an adult with multilobed CDVT, causing low-back pain and subjective disturbances in walking. A myelotomy with fenestration of the cyst was performed with a good clinical and radiological outcome. PMID- 23682084 TI - Presacral tumours: a rare case of a dermoid cyst in a paediatric patient. AB - Presacral tumours are considered very rare tumours with their incidence being around 1:40 000. Presacral dermoid tumours, part of the family of presacral tumours, usually present in the female adult population. They are benign tumours arising from all the three germ cell layers. Presentation in a paediatric population, defined as an individual under the age of 18 years, is extremely rare. A 15-year-old girl presented with abdominal pain present for 5 years diagnosed as a somatisation disorder. Upon further investigation with abdominal CT and MRI a diagnosis of a presacral mass was made. A laparoscopic-assisted transabdominal excision of the mass was performed and histopathology confirmed the radiological suspicion of a presacral dermoid cyst. As there are no reports of a presacral dermoid cysts being excised and reported in the paediatric surgical literature, we hope to highlight this pathology as a potential cause of abdominal pain in the paediatric population. PMID- 23682085 TI - An unusual cause of Grey Turner's sign. AB - A woman in her late 70s presented to the acute general surgical take with a 3-day history of worsening right leg pain and swelling. She had undergone right revision total hip arthroplasty 20 months previously and reported chronic postoperative right thigh pain attributed to a femoral deep venous thrombosis for which she had been warfarinised. On examination, Grey Turner's sign (bruising of the flanks indicating retroperitoneal haemorrhage) was present, as well as a large tender mass in the right iliac fossa and pitting oedema throughout the right lower limb. Urgent CT scan with intravenous contrast revealed a right retroperitoneal haematoma secondary to a right acetabular screw protruding into the right external iliac vein. The patient was successfully managed with warfarin reversal and surgical removal of the relevant acetabular screw. At 2-month follow up, the patient's symptoms continue to resolve. PMID- 23682086 TI - Retrograde jejunogastric intussusception with jejunojejunal intussusception (double telescoping). AB - A 55-year-old woman presented with features of gastric outlet obstruction not responding to conservative treatment at a peripheral hospital. She had gastric surgery 15 years before. On examination, there was a globular mass palpable in the epigastrium. Ultrasound and endoscopy findings were suggestive of retrograde jejunogastric intussusception. After initial resuscitation, emergency laparotomy was undertaken which revealed a jejunogastric intussusception at the previous retrocolic gastrojejunostomy site. After manual reduction of the intussuscepted loop by gentle traction, another segment of the jejunum was seen to be telescoping within this loop. On reduction, this jejunal loop was seen to measure around 20 cm and the apex of the intussusceptum was found to be gangrenous and perforated. Resection of the involved segment was done followed by a Roux-en-y anastomosis to restore the continuity. PMID- 23682087 TI - Aceclofenac-induced acute tubulointerstitial nephritis in a patient with diabetes. AB - We describe a case of a 40-year-old lady diabetic and hypertensive, who presented with increasing fatigue and decreased physical endurance attributable to deterioration in renal function. The renal biopsy revealed drug-induced acute tubulointerstitial nephritis and the chronology of the events suggested the aetiology to be a recent intake of aceclofenac for knee pain. The patient improved with oral corticosteroids and the renal functions returned to baseline in 3 weeks. We did not come across a case of aceclofenac-induced acute tubulointerstitial nephritis on extensive electronic search of literature. This is probably the first case report of acute tubulointerstitial nephritis associated with the use of aceclofenac, a newer potent non-steroidal anti inflammatory drug. PMID- 23682088 TI - Adrenal gland non-Hodgkin's lymphoma in a patient with pulmonary adenocarcinoma. AB - Although primary neoplasms of adrenal gland are uncommon, adrenal metastases are frequently encountered in patients with malignancy, and lung is the most common primary tumour site. Among primary tumours of the adrenal gland non-Hodgkin's lymphoma (NHL) is a very rare entity. We describe a case of a 79-year-old man with a previous diagnosis of adenocarcinoma of the lung who presented after 2 years with a unilateral adrenal gland mass. A solitary metastasis from pulmonary carcinoma was suspected and a laparoscopic adrenalectomy was performed. Histological examination revealed a diffuse large B-cell NHL. The patient was treated with CHOP regimen plus rituximab and a total remission was achieved. After an 8-month follow-up the patient was free of disease. This is the first reported case of a rare non-synchronous tumoral combination involving lung and adrenal gland, emphasising at the incidental discovery of the NHL during a procedure performed for a pulmonary adenocarcinoma. PMID- 23682089 TI - Simultaneous bilateral spontaneous hydropneumothorax: a rare presentation of bilateral malignant pleural mesothelioma. AB - This is a case of a 69-year-old man with a history of asbestos exposure who presented with acute shortness of breath. His chest x-ray showed bilateral hydropneumothorax. Further investigations including CT chest and video-assisted thoracoscopic surgery revealed bilateral pleural thickening and histology confirmed epithelioid mesothelioma. This case highlights the need for clinicians to be aware of atypical presentations of malignant pleural mesothelioma as well as the importance of considering underlying secondary causes such as malignancy in the older patient presenting with spontaneous pneumo/hydropneumothorax. PMID- 23682090 TI - Primary squamous cell carcinoma of the parotid gland: a rare entity. AB - Primary squamous cell carcinoma of the parotid gland is a rare aggressive malignancy. It is a rapidly advancing lesion which, if not recognised and treated early, results in high morbidity and mortality. Despite radical surgery and adjuvant radiotherapy, prognosis of this cancer continues to be poor. Careful clinical and histological examination is mandatory to differentiate this tumour from metastatic squamous cell carcinoma and other primary malignancies of the parotid. The authors hereby report the case of a 50-year-old male patient who presented with a progressively increasing, painless mass in parotid region of 6 months duration. An initial fine-needle aspiration cytology and subsequent histopathological examination confirmed that the tumour was squamous cell carcinoma. As no other primary source could be demonstrated in the patient, a final diagnosis of primary squamous cell carcinoma of parotid was offered. Currently the patient is on regular follow-up without any signs of recurrence. PMID- 23682091 TI - Superior mesenteric arteriovenous fistula embolisation complicated by bowel ischaemia. AB - Superior mesenteric arteriovenous fistulas are rare, especially when iatrogenic in origin. Management of these fistulas can be surgical or endovascular. Endovascular embolisation is the preferred modality with a low rate of complications. Among the reported complications, bowel ischaemia is considered an unlikely occurrence. We report a case of a complex iatrogenic arterioportal fistula that was managed by endovascular embolisation and controlled through both its inflow and outflow, and was later complicated by bowel ischaemia. PMID- 23682092 TI - Aortic valve tethering: embryonic remnant of a common origin? AB - A 14-year-old asymptomatic girl without relevant medical history was referred to our department for heart murmur evaluation. The echocardiogram showed cardiac chambers with normal size and function. Noteworthy was the presence of an apparently fibrous tissue joining the ventricular surfaces of the aortic non coronary and right coronary leaflets with the anterior mitral leaflet. Both valves were slightly thickened and there was a mild anterior mitral valve 'billowing' causing an eccentric mild-to-moderate regurgitant jet. During systole, tethering of this tissue caused the incomplete opening of both mentioned aortic leaflets, causing a turbulent flow with no significant gradient across the valve. During diastole, moderate eccentric aortic regurgitation jet was noted, probably related to incomplete coaptation at the insertion point of this anomalous tissue. We speculate that this finding may represent the remnant of some tissue during heart development that abnormally persisted in this young lady. PMID- 23682093 TI - Active haemorrhage of a renal allograft detected on portable ultrasound. AB - Function of a renal allograft relies on the integrity of its vascular anatomy. Renal biochemistry, ultrasound and percutaneous biopsy are used in combination to determine allograft function. Biopsy is not without risk, and in this case study we demonstrate a rare but a potentially life-threatening complication of renal allograft biopsy. PMID- 23682094 TI - Unilateral renal artery stenosis with renal atrophy in a patient with metastatic papillary thyroid carcinoma treated with sorafenib. AB - Tyrosine kinase inhibitors (TKIs) have been recently introduced for treatment of different malignancies. Various cardiovascular toxicities have been reported with TKIs with hypertension being the most common adverse cardiovascular event. We report a case of a 60-year-old woman who developed left renal artery stenosis associated with renal atrophy in the context of metastatic papillary thyroid carcinoma treated with sorafenib. Renal atrophy was noticed during serial imaging studies to monitor cancer therapy. Clinically, she was asymptomatic without significant change in blood pressure. The glomerular filtration rate dropped from 88 ml/min/1.73 m(2) at baseline to 56 ml/min/1.73 ml/min and partially recovered to 71 ml/min/1.73 m(2) after renal artery stenting. To our knowledge, this will be the first known case of renal artery stenosis associated with TKI use. Physicians may need to investigate the possibility of developing renal artery stenosis in patients with unexplained worsening in kidney functions while on TKIs. PMID- 23682095 TI - Bone quality, as measured by trabecular bone score, in patients with primary hyperparathyroidism. AB - OBJECTIVE: In primary hyperparathyroidism (PHPT), vertebral fractures (VFx) occur regardless of bone mineral density (BMD) and may depend on decreased bone quality. Trabecular bone score (TBS) is a texture measurement acquired during a spinal dual-energy X-ray absorptiometry (DXA). Recently, TBS has been proposed as an index of bone micro-architecture. DESIGN: We studied 92 PHPT patients (74 females, age 62.1+/-9.7 years) and 98 control subjects. In all patients at baseline, in 20 surgically treated patients and in 10 conservatively treated patients after 24 months, TBS, spinal (lumbar spine (LS)) and femoral (total hip (TH) and femoral neck (FN)) BMD were assessed by DXA and VFx by spinal radiograph. RESULTS: PHPT patients had lower TBS (-2.39+/-1.8) and higher VFx prevalence (43.5%) than controls (-0.98+/-1.07 and 8.2% respectively, both P<0.0001). TBS was associated with VFx (odds ratio 1.4, 95% CI 1.1-1.9, P=0.02), regardless of LS-BMD, age, BMI and gender, and showed a better compromise between sensitivity (75%) and specificity (61.5%) for detecting VFx than LS-BMD, TH-BMD and FN-BMD (31 and 75%, 72 and 44.2%, and 64 and 65% respectively). In surgically treated patients, TBS, LS-BMD, TH-BMD and FN-BMD increased (+47+/-44.8,+29.2+/ 34.1,+49.4+/-48.7 and +30.2+/-39.3% respectively, all P<0.0001). Among patients treated conservatively, TBS decreased significantly in those (n=3) with incident VFx (-1.3+/-0.3) compared with those without (-0.01+/-0.9, P=0.048), while BMD changes were not statistically different (LS 0.3+/-1.2 vs -0.8+/-0.9 respectively, P=0.19; TH 0.4+/-0.8 vs -0.8+/-1.4 respectively, P=0.13 and FN 0.4+/-0.9 vs -0.8+/-1.4 respectively, P=0.14). CONCLUSIONS: In PHPT, bone quality, as measured by TBS, is reduced and associated with VFx and improves after surgery. PMID- 23682096 TI - Efficacy and safety of LB03002, a once-weekly sustained-release human GH for 12 month treatment in Korean children with GH deficiency. AB - PURPOSE: The purpose of this study was to investigate the efficacy and safety of LB03002, a sustained-release human GH (SR-hGH), compared with that of daily rhGH for 12 months in children with GH deficiency (GHD). METHODS: A total of 73 children with GHD were screened and 63 eligible subjects were randomized in a 1:1 ratio of LB03002 (SR-hGH) to daily rhGH treatment group. LB03002 was administered once weekly at a dose of 0.5 mg/kg while daily rhGH was administered for 6 consecutive days with equally divided doses to make a total of 0.21 mg/kg per week. Treatments were given for 12 months by s.c. injections. Injection site reactions and adverse events were investigated throughout the study period. RESULTS: The mean (S.D.) height velocity (HV) SHOWED a clinically significant increase after the 6-month treatment: 3.00 (1.15) cm/year at screening to 9.78 (1.98) cm/year at 6 months in the LB03002 group; 2.39 (1.63) cm/year at screening to 10.56 (2.65) cm/year at 6 months in the daily rhGH group. The increased HV at 12 months was still maintained in both the groups: 9.06 (1.63) cm/year at 12 months in the LB03002 group; 9.72 (2.32) cm/year at 12 months in the daily rhGH group. Most of the adverse drug reactions were mild and tolerable. No subjects were withdrawn due to adverse events. CONCLUSION: Weekly injection of LB03002 at a dose of 0.5 mg/kg per week was confirmed to have comparable efficacy to daily injection of rhGH at a dose of 0.21 mg/kg per week. Both formulations were well tolerated. PMID- 23682097 TI - Exercise-induced headache. PMID- 23682098 TI - 7-month-old male with scrotal swelling. PMID- 23682099 TI - Carrots and sticks. PMID- 23682100 TI - Photo quiz: A 38-year-old man with uveitis, cholestasis, and rash. PMID- 23682101 TI - Reply to "Mistaken identity of Brucella infection". PMID- 23682102 TI - Calibration technologies for correct determination of Epstein-Barr Virus, human herpesvirus 6 (HHV-6), and HHV-8 antiviral drug susceptibilities by use of real time-PCR-based assays. PMID- 23682103 TI - Reply to "Calibration technologies for correct determination of Epstein-Barr Virus, human herpesvirus 6 (HHV-6), and HHV-8 antiviral drug susceptibilities by use of real-time-PCR-based assays". PMID- 23682106 TI - The effects on student health of interventions modifying the school environment: systematic review. AB - BACKGROUND: Owing to the limited effectiveness of traditional health education curricula in schools, there is increasing interest in interventions aiming to promote young people's health by modifying the school environment. Existing systematic reviews cannot determine whether environmental intervention is effective because they examine interventions combining environmental modifications and traditional health education. This gap is significant because school-environment interventions are complex to implement and may be sidelined in underfunded and attainment-focused school systems without evidence to support such an approach. This systematic review examined the effectiveness of school environment interventions without health-education components on student health and inequalities. METHODS: This was a systematic review of experimental/quasi experimental studies of school-environment interventions. Sixteen databases were searched, eliciting 62 329 references which were screened, with included studies quality assessed, data extracted and narratively synthesised. RESULTS: Sixteen reports of 10 studies were included, all from the USA and the UK. Five evaluations of interventions aiming to develop a stronger sense of community and/or improve relationships between staff and students suggested potential benefits particularly regarding violence and aggression. Two trials of interventions enabling students to advocate for changes in school catering and physical activity reported benefits for physical activity but not diet. Three evaluations of improvements to school playgrounds offered weak evidence of effects on physical activity. CONCLUSIONS: School environment interventions show the potential to improve young people's health particularly regarding violence, aggression and physical activity. Further trials are required to provide a stronger and more generalisable evidence base. PMID- 23682107 TI - Does physical activity during pregnancy adversely influence markers of the metabolic syndrome in adult offspring? A prospective study over two decades. AB - BACKGROUND: It is unknown whether physical activity during pregnancy (PA) has long-term impact on the metabolic profile of the offspring. We investigated associations of PA with markers of the metabolic syndrome (MS) in 20y old offspring. METHODS: Longitudinal study where 965 pregnant women during 1988-1989 had four dimensions of PA assessed by questionnaires in gestation week 30: PA at work; leisure time PA, daily amount of walking-biking and sport participation. The following MS markers were assessed in the offspring (n=439): body mass index (BMI), waist circumference, blood pressure, homeostasis model assessment insulin resistance as well as fasting plasma glucose, triglycerides, cholesterol (high density lipoprotein (HDL), low-density lipoprotein and total cholesterol), insulin and leptin levels. RESULTS: Walking-biking PA in pregnancy is associated with unchanged or subtle, adverse changes of distinct MS markers among offspring including lower levels of HDL cholesterol (ratio 0.95 (95% CI 0.92 to 0.98) per 1 h increment in walking-biking), a higher diastolic blood pressure (difference 1.12 (95% CI 0.03 to 2.20) mm Hg/1 h increment) and a higher BMI (ratio 1.03 (95% CI 1.01 to 1.05) per 1 h increment). In separate analyses in males, these associations persisted and additional adverse associations were found for triglycerides, systolic blood pressure, waist circumference and leptin. No associations were detected with other measures of PA. CONCLUSIONS: The study did not substantiate any protective effects of PA in pregnancy. In contrast, data suggested that high amounts of daily walking-biking in pregnancy may have adverse effects on levels of HDL cholesterol, diastolic blood pressure and BMI in young adult offspring. PMID- 23682108 TI - Interleukin-13 induces collagen type-1 expression through matrix metalloproteinase-2 and transforming growth factor-beta1 in airway fibroblasts in asthma. AB - Airway remodelling is a feature of asthma that contributes to loss of lung function. One of the central components of airway remodelling is subepithelial fibrosis. Interleukin (IL)-13 is a key T-helper 2 cytokine and is believed to be the central mediator of allergic asthma including remodelling, but the mechanism driving the latter has not been elucidated in human asthma. We hypothesised that IL-13 stimulates collagen type-1 production by the airway fibroblast in a matrix metalloproteinase (MMP)- and transforming growth factor (TGF)-beta1-dependent manner in human asthma as compared to healthy controls. Fibroblasts were cultured from endobronchial biopsies in 14 subjects with mild asthma and 13 normal controls that underwent bronchoscopy. Airway fibroblasts were treated with various mediators including IL-13 and specific MMP-inhibitors. IL-13 significantly stimulated collagen type-1 production in asthma compared to normal controls. Inhibitors of MMP-2 significantly attenuated collagen production in asthma but had no effect in normal controls. IL-13 significantly increased total and active forms of TGF-beta1, and this activation was blocked using an MMP-2 inhibitor. IL-13 activated endogenous MMP-2 in asthma patients as compared to normal controls. In an ex vivo model, IL-13 potentiates airway remodelling through a mechanism involving TGF-beta1 and MMP-2. These effects provide insights into the mechanism involved in IL-13-directed airway remodelling in asthma. PMID- 23682109 TI - Slow-growing lung cancer as an emerging entity: from screening to clinical management. AB - The current paradigm is that untreated lung cancer is invariably and rapidly fatal, therefore the medical community normally dismisses the idea that a patient could live with such a disease for years without any therapy. Yet evidence from lung cancer screening research and from recent clinical series suggests that, although rarely recognised in routine practice, slow-growing lung cancers do exist and are more common than previously thought. Here, current evidence is reviewed and clinical cases are illustrated to show that slow-growing lung cancer is a real clinical entity, and the reasons why management protocols developed in the screening setting may also be useful in clinical practice are discussed. Features suggesting that a lung cancer may be slow-growing are described and appraised, areas of uncertainty are examined, modern management options for early stage disease are evaluated and the influence that all this knowledge might have on our clinical decision-making is weighed. Further research directed at developing appropriate guidelines for these peculiar but increasingly common patients is warranted. PMID- 23682111 TI - Mapping the future for pulmonary fibrosis: report from the 17th International Colloquium on Lung and Airway Fibrosis. AB - Pulmonary fibrosis is the ultimate outcome of various interstitial lung diseases, many of which have a dismal prognosis. Pulmonary fibrosis, therefore, represents a critical unmet medical need. Progress in research over the past 30 years has been encouraging. This work, which has been funded by governments, charitable trusts, industries and patient groups, has resulted in clinical trials testing novel drugs, giving hope to patients. In late September 2012, representatives from academia, industry and funding agencies met at the 17th International Colloquium on Airway and Lung Fibrosis to discuss state-of-the-art knowledge of pulmonary fibrosis. This manuscript summarises the outcomes of the meeting, highlighting the most relevant results and discoveries. It also attempts to provide a roadmap for future studies. It is hoped that such a roadmap may help interested parties to generate new research, which will be vital to continued progress. We are encouraged by the commitment expressed by all participants at this meeting and the shared vision of promoting future progress through international collaboration, the pooling of valuable resources, and the involvement of a new generation of physicians and scientists. PMID- 23682110 TI - Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. AB - Idiopathic pulmonary fibrosis is a progressive, fatal disease. This prospective, randomised, double-blind, multicentre, parallel-group, placebo-controlled phase II trial (NCT00903331) investigated the efficacy and safety of the endothelin receptor antagonist macitentan in idiopathic pulmonary fibrosis. Eligible subjects were adults with idiopathic pulmonary fibrosis of <3 years duration and a histological pattern of usual interstitial pneumonia on surgical lung biopsy. The primary objective was to demonstrate that macitentan (10 mg once daily) positively affected forced vital capacity versus placebo. Using a centralised system, 178 subjects were randomised (2:1) to macitentan (n=119) or placebo (n=59). The median change from baseline up to month 12 in forced vital capacity was -0.20 L in the macitentan arm and -0.20 L in the placebo arm. Overall, no differences between treatments were observed in pulmonary function tests or time to disease worsening or death. Median exposures to macitentan and placebo were 14.5 months and 15.0 months, respectively. Alanine and/or aspartate aminotransferase elevations over three times upper limit of normal arose in 3.4% of macitentan-treated subjects and 5.1% of placebo recipients. In conclusion, the primary objective was not met. Long-term exposure to macitentan was well tolerated with a similar, low incidence of elevated hepatic aminotransferases in each treatment group. PMID- 23682112 TI - Membrane and capillary components of lung diffusion and pro-angiogenic cells in infants. AB - Angiogenesis is a critical determinant of alveolarisation, which increases alveolar surface area and pulmonary capillary blood volume in infants; however, our understanding of this process is very limited. The purpose of our study was to measure the pulmonary membrane diffusion capacity (DM) and pulmonary capillary blood volume (VC) components of the diffusing capacity of the lung for carbon monoxide (DLCO) in healthy infants and toddlers, and evaluate whether these components were associated with pro-angiogenic circulating haematopoietic stem/progenitor cells (pCHSPCs) early in life. 21 healthy subjects (11 males), 3 25 months of age, were evaluated. DLCO was measured under normoxic and hyperoxic conditions, and DM and VC were calculated. From 1 mL venous blood, pCHSPCs were quantified by multiparametric flow cytometry. DM and VC increased with increasing body length; however, membrane resistance as a fraction of total resistance to pulmonary diffusion remained constant with somatic size. In addition, DLCO and VC, but not DM, increased with an increasing percentage of pCHSPCs. The parallel increase in the membrane and vascular components of pulmonary diffusion is consistent with alveolarisation during this period of rapid lung growth. In addition, the relationship between pCHSPCs and VC suggest that pro-angiogenic cells may contribute to this vascular process. PMID- 23682113 TI - Iron-dependent modifications of the flower transcriptome, proteome, metabolome, and hormonal content in an Arabidopsis ferritin mutant. AB - Iron homeostasis is an important process for flower development and plant fertility. The role of plastids in these processes has been shown to be essential. To document the relationships between plastid iron homeostasis and flower biology further, a global study (transcriptome, proteome, metabolome, and hormone analysis) was performed of Arabidopsis flowers from wild-type and triple atfer1-3-4 ferritin mutant plants grown under iron-sufficient or excess conditions. Some major modifications in specific functional categories were consistently observed at these three omic levels, although no significant overlaps of specific transcripts and proteins were detected. These modifications concerned redox reactions and oxidative stress, as well as amino acid and protein catabolism, this latter point being exemplified by an almost 10-fold increase in urea concentration of atfer1-3-4 flowers from plants grown under iron excess conditions. The mutant background caused alterations in Fe-haem redox proteins located in membranes and in hormone-responsive proteins. Specific effects of excess Fe in the mutant included further changes in these categories, supporting the idea that the mutant is facing a more intense Fe/redox stress than the wild type. The mutation and/or excess Fe had a strong impact at the membrane level, as denoted by the changes in the transporter and lipid metabolism categories. In spite of the large number of genes and proteins responsive to hormones found to be regulated in this study, changes in the hormonal balance were restricted to cytokinins, especially in the mutant plants grown under Fe excess conditions. PMID- 23682114 TI - Growth and nodulation of symbiotic Medicago truncatula at different levels of phosphorus availability. AB - Medicago truncatula is an important model plant for characterization of P deficiency on leguminous plants at the physiological and molecular levels. Growth optimization of this plant with regard to P supply is the first essential step for elucidation of the role of P in regulation of nodulation. Hence, a study was carried out to address the growth pattern of M. truncatula hydroponically grown at different gradual increases in P levels. The findings revealed that M. truncatula had a narrow P regime, with an optimum P level (12 MUM P) which is relatively close to the concentration that induces P toxicity. The accumulated P concentration (2.7 mg g(-1) dry matter), which is normal for other crops and legumes, adversely affected the growth of M. truncatula plants. Under P deficiency, M. truncatula showed a higher symbiotic efficiency with Sinorhizobium meliloti 2011 in comparison with S. meliloti 102F51, partially as a result of higher electron allocation to N2 versus H(+). The total composition of free amino acids in the phloem was significantly affected by P deprivation. This pattern was found to be almost exclusively the result of the increase in the asparagine level, suggesting that asparagine might be the shoot-derived signal that translocates to the nodules and exerts the down-regulation of nitrogenase activity. Additionally, P deprivation was found to have a strong influence on the contents of the nodule carbon metabolites. While levels of sucrose and succinate tended to decrease, a higher accumulation of malate was observed. These findings have provided evidence that N2 fixation of M. truncatula is mediated through an N feedback mechanism which is closely related to nodule carbon metabolism. PMID- 23682115 TI - ARA7(Q69L) expression in transgenic Arabidopsis cells induces the formation of enlarged multivesicular bodies. AB - Arabidopsis thaliana ARA7 (AtRabF2b), a member of the plant Rab5 small GTPases functioning in the vacuolar transport pathway, localizes to pre-vacuolar compartments (PVCs), known as multivesicular bodies (MVBs) in plant cells. Overexpression of the constitutively active GTP-bound mutant of ARA7, ARA7(Q69L), induces the formation of large ring-like structures (1-2 um in diameter). To better understand the biology of these ARA7(Q69L)-induced ring-like structures, transgenic Arabidopsis cell lines expressing ARA7(Q69L) tagged with green fluorescent protein (GFP) under the control of a heat shock-inducible promoter were generated. In these transgenic cells, robust ring-like structures were formed after 4 h of heat shock induction. Transient co-expression, confocal imaging, and immunogold electron microscopy (immunogold-EM) experiments demonstrated that these GFP-ARA7(Q69L)-labelled ring-like structures were distinct from the Golgi apparatus and trans-Golgi network, but were labelled with an antibody against an MVB marker protein. In addition, live cell imaging and detailed EM analysis showed that the GFP-ARA7(Q69L)-induced spherical structures originated from the homotypic fusion of MVBs. In summary, it was demonstrated that GFP-ARA7(Q69L) expression is an efficient tool for studying PVC/MVB-mediated protein trafficking and vacuolar degradation in plant cells. PMID- 23682116 TI - A wheat PI4K gene whose product possesses threonine autophophorylation activity confers tolerance to drought and salt in Arabidopsis. AB - Phosphoinositides are involved in regulation of recruitment and activity of signalling proteins in cell membranes. Phosphatidylinositol (PI) 4-kinases (PI4Ks) generate PI4-phosphate the precursor of regulatory phosphoinositides. No type II PI4K research on the abiotic stress response has previously been reported in plants. A stress-inducible type II PI4K gene, named TaPI4KIIgamma, was obtained by de novo transcriptome sequencing of drought-treated wheat (Triticum aestivum). TaPI4KIIgamma, localized on the plasma membrane, underwent threonine autophosphorylation, but had no detectable lipid kinase activity. Interaction of TaPI4KIIgamma with wheat ubiquitin fusion degradation protein (TaUDF1) indicated that it might be hydrolysed by the proteinase system. Overexpression of TaPI4KIIgamma revealed that it could enhance drought and salt stress tolerance during seed germination and seedling growth. A ubdkgamma7 mutant, identified as an orthologue of TaPI4KIIgamma in Arabidopsis, was sensitive to salt, polyethylene glycol (PEG), and abscisic acid (ABA), and overexpression of TaPI4KIIgamma in the ubdkgamma7 mutant compensated stress sensitivity. TaPI4KIIgamma promoted root growth in Arabidopsis, suggesting that TaPI4KIIgamma might enhance stress resistance by improving root growth. Overexpression of TaPI4KIIgamma led to an altered expression level of stress-related genes and changes in several physiological traits that made the plants more tolerant to stress. The results provided evidence that overexpression of TaPI4KIIgamma could improve drought and salt tolerance. PMID- 23682117 TI - Composition and structure of photosystem I in the moss Physcomitrella patens. AB - Recently, bryophytes, which diverged from the ancestor of seed plants more than 400 million years ago, came into focus in photosynthesis research as they can provide valuable insights into the evolution of photosynthetic complexes during the adaptation to terrestrial life. This study isolated intact photosystem I (PSI) with its associated light-harvesting complex (LHCI) from the moss Physcomitrella patens and characterized its structure, polypeptide composition, and light-harvesting function using electron microscopy, mass spectrometry, biochemical, and physiological methods. It became evident that Physcomitrella possesses a strikingly high number of isoforms for the different PSI core subunits as well as LHCI proteins. It was demonstrated that all these different subunit isoforms are expressed at the protein level and are incorporated into functional PSI-LHCI complexes. Furthermore, in contrast to previous reports, it was demonstrated that Physcomitrella assembles a light-harvesting complex consisting of four light-harvesting proteins forming a higher-plant-like PSI superstructure. PMID- 23682118 TI - Transcriptional repression of BODENLOS by HD-ZIP transcription factor HB5 in Arabidopsis thaliana. AB - In Arabidopsis thaliana, the phytohormone auxin is an important patterning agent during embryogenesis and post-embryonic development, exerting effects through transcriptional regulation. The main determinants of the transcriptional auxin response machinery are AUXIN RESPONSE FACTOR (ARF) transcription factors and AUXIN/INDOLE-3-ACETIC ACID (AUX/IAA) inhibitors. Although members of these two protein families are major developmental regulators, the transcriptional regulation of the genes encoding them has not been well explored. For example, apart from auxin-linked regulatory inputs, factors regulating the expression of the AUX/IAA BODENLOS (BDL)/IAA12 are not known. Here, it was shown that the HOMEODOMAIN-LEUCINE ZIPPER (HD-ZIP) transcription factor HOMEOBOX PROTEIN 5 (HB5) negatively regulates BDL expression, which may contribute to the spatial control of BDL expression. As such, HB5 and probably other class I HD-ZIP proteins, appear to modulate BDL-dependent auxin response. PMID- 23682120 TI - Highly efficient, in vivo optimized, archaeal endonuclease for controlled RNA splicing in mammalian cells. AB - ARCHAEA-ExPRESs is an mRNA modification technology that makes use of components derived from the Archaeon Methanocaldococcus jannaschii, namely the tRNA splicing endonuclease (MJ-EndA) and its natural substrate, the bulge-helix-bulge (BHB) structure (1). These components can perform both cis- and trans-splicing in cellular and animal models and may provide a convenient way to modulate gene expression using components independent of cellular regulatory networks. To use MJ-EndA in stable expression mammalian systems, we developed variants characterized by high efficiency and sustainable in vivo activity. The MJ-EndA variants were created by the introduction of proper localization signals followed by mutagenesis and direct selection in mammalian cells. Of note, enzyme selection used an in vivo selection method based on puromycin resistance conferred to cells by BHB-mediated intron splicing from an out-of-frame puromycin N-acetyl transferase (PAC) gene. This approach yielded several endonuclease variants, the best of which showed 40-fold higher activity compared to the parental enzyme and stable processing of 30% of the target mRNA. Notably, these variants showed complete compatibility with long-term expression in mammalian cells, suggesting that they may be usefully applied in functional genomics and genetically modified animal models. PMID- 23682119 TI - Small GTPase Sar1 is crucial for proglutelin and alpha-globulin export from the endoplasmic reticulum in rice endosperm. AB - Rice seed storage proteins glutelin and alpha-globulin are synthesized in the endoplasmic reticulum (ER) and deposited in protein storage vacuoles (PSVs). Sar1, a small GTPase, acts as a molecular switch to regulate the assembly of coat protein complex II, which exports secretory protein from the ER to the Golgi apparatus. To reveal the route by which glutelin and alpha-globulin exit the ER, four putative Sar1 genes (OsSar1a/b/c/d) were cloned from rice, and transgenic rice were generated with Sar1 overexpressed or suppressed by RNA interference (RNAi) specifically in the endosperm under the control of the rice glutelin promoter. Overexpression or suppression of any OsSar1 did not alter the phenotype. However, simultaneous knockdown of OsSar1a/b/c resulted in floury and shrunken seeds, with an increased level of glutelin precursor and decreased level of the mature alpha- and beta-subunit. OsSar1abc RNAi endosperm generated numerous, spherical, novel protein bodies with highly electron-dense matrixes containing both glutelin and alpha-globulin. Notably, the novel protein bodies were surrounded by ribosomes, showing that they were derived from the ER. Some of the ER-derived dense protein bodies were attached to a blebbing structure containing prolamin. These results indicated that OsSar1a/b/c play a crucial role in storage proteins exiting from the ER, with functional redundancy in rice endosperm, and glutelin and alpha-globulin transported together from the ER to the Golgi apparatus by a pathway mediated by coat protein complex II. PMID- 23682121 TI - Adenosine regulates bone metabolism via A1, A2A, and A2B receptors in bone marrow cells from normal humans and patients with multiple myeloma. AB - Multiple myeloma (MM) is characterized by osteolytic bone lesions with uncoupled bone remodeling. In this study, we examined the effects of adenosine and its receptors (A1R, A2AR, A2BR, and A3R) on osteoblast and osteoclast differentiation of cells derived from patients with MM and healthy control subjects. Mesenchymal stem cells and bone marrow-derived mononuclear cells were isolated from bone marrow and differentiated into osteoblasts and osteoclasts, respectively. A1R antagonist rolofylline and A2BR agonist BAY60-6583 inhibit osteoclast differentiation of cells from patients with MM in a dose-dependent manner, as shown by TRAP staining (IC50: 10 and ~10 nM, respectively). BAY60-6583 and dipyridamole, a nucleoside transport inhibitor, stimulate osteoblast differentiation of cells from patients with MM, as measured by ALP activity at d 14 and Alizarin Red staining at d 21 (by 1.57+/-0.03- and 1.71+/-0.45-fold, respectively), which can be blocked by A2BR antagonist MRS1754. Consistently, real-time PCR showed a significant increase of mRNA of osteocalcin and osterix at d 14. The effect of adenosine and its receptors is consistent in patients with MM and healthy subjects, suggesting an intrinsic mechanism that is important in both MM bone metabolism and normal physiology. Furthermore, the effect of dipyridamole on osteoblast differentiation is diminished in both A2BR- and CD39-knockout mice. These results indicate that adenosine receptors may be useful targets for the treatment of MM-induced bone disease. PMID- 23682122 TI - Dysfunction of the autophagy/lysosomal degradation pathway is a shared feature of the genetic synucleinopathies. AB - The past decade has witnessed huge advances in our understanding of the genetics underlying Parkinson's disease. Identifying commonalities in the biological function of genes linked to Parkinson's provides an opportunity to elucidate pathways that lead to neuronal degeneration and eventually to disease. We propose that the genetic forms of Parkinson's disease largely associated with alpha synuclein-positive neuropathology (SNCA, LRRK2, and GBA) are brought together by involvement in the autophagy/lysosomal pathway and that this represents a unifying pathway to disease in these cases. PMID- 23682123 TI - Vascular endothelial growth factor is important for brown adipose tissue development and maintenance. AB - Vascular endothelial growth factor (VEGF) is critical for angiogenesis, but also has pleiotropic effects on several nonvascular cells. Our aim was to investigate the role of VEGF in brown adipose tissue (BAT). We show that VEGF expression increases 2.5-fold during differentiation of cultured murine brown adipocytes and that VEGF receptor-2 is phosphorylated, indicating VEGF signaling. VEGF increased proliferation in brown preadipocytes in vitro by 70%, and blockade of VEGF signaling using anti-VEGFR2 antibody DC101 increased brown adipocyte apoptosis, as determined by cell number and activation of caspase 3. Systemic VEGF neutralization in mice, accomplished by adenoviral expression of soluble Flt1, resulted in 7-fold increase in brown adipocyte apoptosis, mitochondrial degeneration, and increased mitophagy compared to control mice expressing a null adenovirus. Absence of the heparan sulfate-binding VEGF isoforms, VEGF164 and VEGF188, resulted in abnormal BAT development in mice at E15.5, with fewer brown adipocytes and lower mitochondrial protein compared to wild-type littermates. These results suggest a role for VEGF in brown adipocytes and preadipocytes to promote survival, proliferation, and normal mitochondria and development. PMID- 23682124 TI - Sphingomyelin regulates the transbilayer movement of diacylglycerol in the plasma membrane of Madin-Darby canine kidney cells. AB - Diacylglycerol (DAG) is a key component in lipid metabolism and signaling. Previous model membrane studies using DAG analogs suggest their rapid membrane transbilayer movement. However, little is known about the DAG distribution and dynamics in cell membranes. Using live-cell fluorescence microscopy, we monitored the transbilayer movement of DAG with the yellow fluorescent protein-tagged C1AB domain from protein kinase C-gamma (EYFP-C1AB), which selectively binds DAG. When HeLa cells were treated with Bacillus cereus phospholipase C (Bc-PLC) to produce DAG on the outer leaflet of the plasma membrane, intracellularly expressed EYFP C1AB probe accumulated at the plasma membrane, indicating the transbilayer movement of the outer leaflet DAG to the inner leaflet. This Bc-PLC-induced translocation of EYFP-C1AB probe to the plasma membrane was not observed in the sphingolipid-enriched plasma membrane of Madin-Darby canine kidney cells, but was recovered after cell treatment with sphingomyelinase or preincubation with an inhibitor of sphingolipid biosynthesis. The inhibitory effect of sphingomyelin (SM) on the transbilayer movement of DAG was reproduced in model membranes using a fluorescent short-chain DAG analog. These results demonstrate that the SM content on the outer leaflet regulates the transbilayer movement of DAG in the plasma membrane, thus providing new insights into the dynamics of DAG in cell pathophysiology. PMID- 23682125 TI - Genetic population structure of US atlantic coastal striped bass (Morone saxatilis). AB - Genetic population structure of anadromous striped bass along the US Atlantic coast was analyzed using 14 neutral nuclear DNA microsatellites. Young-of-the year and adult striped bass (n = 1114) were sampled from Hudson River, Delaware River, Chesapeake Bay, North Carolina, and South Carolina. Analyses indicated clear population structure with significant genetic differentiation between all regions. Global multilocus F ST was estimated at 0.028 (P < 0.001). Population structure followed an isolation-by-distance model and temporal sampling indicated a stable population structure more than 2 years at all locations. Significant structure was absent within Hudson River, whereas weak but significant genetic differences were observed between northern and southern samples in Chesapeake Bay. The largest and smallest effective striped bass population sizes were found in Chesapeake Bay and South Carolina, respectively. Coalescence analysis indicated that the highest historical gene flow has been between Chesapeake Bay and Hudson River populations, and that exchange has not been unidirectional. Bayesian analysis of contemporary migration indicated that Chesapeake Bay serves as a major source of migrants for Atlantic coastal regions from Albemarle Sound northward. In addition to examining population genetic structure, the data acquired during this project were capable of serving as a baseline for assigning fish with unknown origin to source region. PMID- 23682126 TI - Reply to Eisenhut. PMID- 23682127 TI - T-helper cell 2-driven immunity in pregnancy as a determinant of antiplasmodial antibody half-life through regulation of Fc-receptor-mediated clearance. PMID- 23682131 TI - Good and bad news about latest outcomes for smoking. PMID- 23682128 TI - 5'-AMP impacts lymphocyte recirculation through activation of A2B receptors. AB - Natural hibernation consists of torpid phases with metabolic suppression alternating with euthermic periods. Induction of torpor holds substantial promise in various medical conditions, including trauma, major surgery, and transplantation. Torpor in mice can be induced pharmacologically by 5'-AMP. Previously, we showed that during natural torpor, the reduction in body temperature results in lymphopenia via a reduction in plasma S1P. Here, we show that during torpor induced by 5'-AMP, there is a similar reduction in the number of circulating lymphocytes that is a result of their retention in secondary lymphoid organs. This lymphopenia could be mimicked by engagement of A(2B)Rs by a selective A(2B)R agonist (LUF6210) in the absence of changes in temperature and prevented by A(2B)R antagonists during 5'-AMP-induced torpor. In addition, forced cooling of mice led to peripheral blood lymphopenia, independent of A(2B)R signaling. The induction of torpor using 5'-AMP impacted the migration of lymphocytes within and between secondary lymphoid organs. During torpor, the homing into LNs was impaired, and two-photon intravital microscopy revealed that cell motility was decreased significantly and rapidly upon 5'-AMP administration. Furthermore, the S1P plasma concentration was reduced by 5'-AMP but not by LUF6210. S1P plasma levels restored upon arousal. Likely, the reduced migration in LNs combined with the reduced S1P plasma level substantially reduces lymphocyte egress after injection of 5'-AMP. In conclusion, 5'-AMP induces a state of pharmacological torpor in mice, during which, lymphopenia is governed primarily by body temperature-independent suppression of lymphocyte egress from LNs. PMID- 23682129 TI - Regulation of the osterix (Osx, Sp7) promoter by osterix and its inhibition by parathyroid hormone. AB - Osterix (Osx, Sp7) is a zinc-finger transcription factor belonging to the specificity protein (Sp) family expressed in cells of the osteoblast lineage in the developing skeleton where it regulates expression of a number of osteoblastic genes. We previously reported inhibition of osterix mRNA and protein by parathyroid hormone (PTH) stimulation of cAMP in osteoblasts. We here show that Osx expression in osteoblasts is regulated by Sp proteins as demonstrated by mithramycin A inhibition of Osx mRNA and OSX protein levels. Mutation of putative transcription factor binding sites within the Osx promoter demonstrated a tandem repeat sequence that selectively binds OSX but not other Sp factors expressed in osteoblasts (Sp1, Sp3, or Tieg (Klf10)). Mutation of either or both the repeat sequences inhibited 90% of the promoter activity and also abrogated some of the PTH-mediated inhibition of the promoter. Previous studies have shown growth factor regulation of Osx expression by MAPK proteins, particularly p38 phosphorylation of OSX that increases its transcriptional activity. PTH stimulation of osteoblasts inhibits MAPK components (ERK, JNK, and p38) but inhibition of Osx mRNA and protein expression by PTH was selectively mimicked by p38 inhibition and expression of constitutively active MKK6, which stimulates p38, blocked PTH inhibition of OSX. Together, our studies suggest that OSX autoregulation is a major mechanism in osteoblasts and that PTH stimulation inhibits osterix by inhibition of p38 MAPK regulation of OSX. PMID- 23682132 TI - Studying the connection between exercise and cancer risk reduction. PMID- 23682135 TI - Full Genome Sequence of an Avian Influenza H5N1 Virus Isolated from the Environment in Hunan Province, China. AB - We isolated an avian influenza virus A/environment/Hunan/3/2011(H5N1) from a body of water in Hunan, China. The nucleotide sequence of the virus shares 95% homology with H5N1 from the east Asia region. Phylogenetic analysis indicates that its HA gene belongs to clade 2.3.2.1 and that other internal genes present different recombination features. PMID- 23682134 TI - Survival benefit with radium-223 dichloride in a mouse model of breast cancer bone metastasis. AB - BACKGROUND: Bone metastases are associated with increased morbidity and poor prognosis in breast cancer patients. Radium-223 dichloride is a calcium mimetic that localizes to bone, providing targeted therapy for skeletal metastasis. METHODS: We investigated the mode of action of radium-223 dichloride using breast cancer cell, osteoclast, and osteoblast cultures as well as a mouse model of breast cancer bone metastasis. A single dose of radium-223 dichloride was used in three different settings mimicking the prevention or treatment of bone metastasis. Disease progression was monitored using fluorescence and radiographic imaging and histological analyses. The effect of radium-223 dichloride alone and in combination with doxorubicin or zoledronic acid on survival of mice was analyzed by Kaplan-Meier methods. All statistical tests used were two-sided. RESULTS: Radium-223 dichloride incorporated into bone matrix and inhibited proliferation of breast cancer cells and differentiation of osteoblasts and osteoclasts (all P values < .001) in vitro. In an established bone metastasis setting, radium-223 dichloride prevented tumor-induced cachexia (0/14 vs 7/14 control mice) and decreased osteolysis by 56% and tumor growth by 43% (all P values < .05). Radium-223 dichloride induced double-strand DNA breaks in cancer cells in vivo. Finally, radium-223 dichloride extended survival as a monotherapy (29.2 days, 95% confidence interval [CI] = 26.6 to 31.8 days, P = .039) and in combination with zoledronic acid (31.4 days, 95% CI = 28.8 to 34.0 days, P = .004) or doxorubicin (31.5 days, 95% CI = 29.5 to 33.5 days, P < .001) compared to the vehicle group (24.9 days, 95% CI = 23.4 to 26.4 days). Similar but even more pronounced effects were observed when radium-223 dichloride was administered in a preventive or micrometastatic setting. CONCLUSIONS: Our findings strongly support the development of radium-223 dichloride for the treatment of breast cancer patients with or at high risk of developing bone metastases. PMID- 23682136 TI - Genome Sequence of Ex-Afghanistan Crimean-Congo Hemorrhagic Fever Virus SCT Strain, from an Imported United Kingdom Case in October 2012. AB - Crimean-Congo hemorrhagic fever (CCHF) virus is a serious human pathogen causing severe hemorrhagic disease with a fatality rate of up to approximately 30%. We have determined the viral genomic sequence from an isolate that caused a fatal case of imported CCHF in the United Kingdom in October 2012. PMID- 23682137 TI - Complete Closed Genome Sequences of Mannheimia haemolytica Serotypes A1 and A6, Isolated from Cattle. AB - Mannheimia haemolytica is a respiratory pathogen affecting cattle and related ruminants worldwide. M. haemolytica is commonly associated with bovine respiratory disease complex (BRDC), a polymicrobial multifactorial disease. We present the first two complete closed genome sequences of this species, determined using an automated assembly pipeline requiring no manual finishing. PMID- 23682138 TI - Genome Sequences of Two Emerging Non-O157 Shiga Toxin-Producing Escherichia coli Strains. AB - Shiga toxin-producing Escherichia coli (STEC) causes severe illness in humans, including hemorrhagic colitis and hemolytic uremic syndrome. A parallel evolutionary model was proposed in which E. coli strains of distinct phylogenies independently integrate Shiga toxin-encoding genes and evolve into STEC. We report the draft genomes of two emerging non-O157 STEC strains. PMID- 23682139 TI - Draft Genome Sequence of the Steroid Degrader Rhodococcus ruber Strain Chol-4. AB - The whole-genome shotgun sequence of Rhodococcus ruber strain Chol-4 is presented here. This organism was shown to be able to grow using many steroids as the sole carbon and energy sources. These sequence data will help us to further explore the metabolic abilities of this versatile degrader. PMID- 23682140 TI - Complete genome sequence of west nile virus isolated from alappuzha district, kerala, India. AB - West Nile virus belongs to the Flaviviridae family, transmitted by vector mosquitoes. Here, we reported the complete genome sequence of West Nile virus isolated from human samples during an acute encephalitis outbreak in Kerala, India. Phylogenetic analysis revealed that the virus genome clusters into genetic lineage 1, clade 1a. PMID- 23682141 TI - Complete Nucleotide Sequence of Canine Distemper Virus CDV-PS, Isolated from Dogs in China. AB - A new strain of canine distemper virus, CDV-PS, has been isolated from dogs in China, and its complete genome has been sequenced and analyzed. The phylogenetic analysis suggests that CDV-PS belongs to the Asia-1 cluster and has low identity to the vaccine strain. PMID- 23682142 TI - Draft Genome Sequences of Two Pairs of Human Intestinal Bifidobacterium longum subsp. longum Strains, 44B and 1-6B and 35B and 2-2B, Consecutively Isolated from Two Children after a 5-Year Time Period. AB - We report the genome sequences of four isolates of a human gut symbiont, Bifidobacterium longum. Strains 44B and 35B were isolated from two 1-year-old infants, while 1-6B and 2-2B were isolated from the same children 5 years later. The sequences permit investigations of factors enabling long-term colonization of bifidobacteria. PMID- 23682143 TI - Complete Genome Sequence of Xanthomonas citri subsp. citri Strain Aw12879, a Restricted-Host-Range Citrus Canker-Causing Bacterium. AB - Xanthomonas citri subsp. citri causes citrus canker. The Asiatic strain has a broad host range, whereas the Wellington variant has a restricted host range. Here, we present the complete genome of X. citri subsp. citri strain A(W)12879. This study lays the foundation to further characterize the mechanisms for virulence and host range of X. citri. PMID- 23682144 TI - Complete Genome Sequence of Marinobacter sp. BSs20148. AB - Marinobacter sp. BSs20148 was isolated from marine sediment collected from the Arctic Ocean at a water depth of 3,800 m. Here we report the complete genome sequence of Marinobacter sp. BSs20148. This genomic information will facilitate the study of the physiological metabolism, ecological roles, and evolution of the Marinobacter species. PMID- 23682145 TI - Genome Sequence of Bacillus subtilis MB73/2, a Soil Isolate Inhibiting the Growth of Plant Pathogens Dickeya spp. and Rhizoctonia solani. AB - Bacillus subilis MB73/2 is a Gram-positive bacterium isolated in Poland from a meadow soil sample. When tested in vitro, the strain shows strong antagonism toward plant pathogens-the soft rot-causing bacteria Dickeya spp. and the crown rot fungus Rhizoctonia solani. Here, we present the genome sequence of MB73/2. PMID- 23682146 TI - Draft Genome Sequence of Cesiribacter andamanensis Strain AMV16T, Isolated from a Soil Sample from a Mud Volcano in the Andaman Islands, India. AB - Here we report the 4.75-Mb genome of Cesiribacter andamanensis strain AMV16(T), isolated from a soil sample from a mud volcano in the Andaman Islands, India. PMID- 23682147 TI - Draft Genome Sequence of Curtobacterium flaccumfaciens Strain UCD-AKU (Phylum Actinobacteria). AB - Here we present the draft genome of an actinobacterium, Curtobacterium flaccumfaciens strain UCD-AKU, isolated from a residential carpet. The genome assembly contains 3,692,614 bp in 130 contigs. This is the first member of the Curtobacterium genus to be sequenced. PMID- 23682148 TI - Complete Genome Sequence of the gamma-Hexachlorocyclohexane-Degrading Bacterium Sphingomonas sp. Strain MM-1. AB - gamma-Hexachlorocyclohexane (gamma-HCH) is a man-made chlorinated insecticide that has caused serious environmental problems. Here, we report the complete genome sequence of the gamma-HCH-degrading bacterium Sphingomonas sp. strain MM 1, which consists of one chromosome and five plasmids. All the specific lin genes that are almost identical to those of Sphingobium japonicum UT26 for the conversion of gamma-HCH to beta-ketoadipate are dispersed on four out of the five plasmids. PMID- 23682149 TI - Draft Genome Sequence of the Serratia marcescens Strain VGH107, a Taiwanese Clinical Isolate. AB - Serratia marcescens, a member of the family Enterobacteriaceae, is the causative agent of various types of wound infections. We report a high-quality draft genome sequence of S. marcescens strain VGH107, which was isolated from a patient with an infection from a snakebite wound. PMID- 23682150 TI - Complete Genome Sequence of a Novel Reassortant H3N6 Avian Influenza Virus Isolated from Domestic Green-Winged Teal. AB - An avian influenza virus strain, A/domestic green-winged teal/Hunan/2036/2007(H3N6) (DGW-T2036), was isolated from healthy domestic green winged teals (Anas crecca) in Hunan Province, South China. All eight gene segments of the isolate were sequenced. Genomic analysis demonstrated that this H3N6 virus is a novel reassortant avian influenza virus with a gene constellation originating from multiple ancestors. PMID- 23682151 TI - Genome Sequences of Two Morphologically Distinct and Thermophilic Bacillus coagulans Strains, H-1 and XZL9. AB - Two thermophilic Bacillus coagulans strains, H-1 and XZL9, both of which were isolated from soils, have different morphological properties. Strain XZL9 but not H-1 is an efficient pentose-utilizing producer of important platform compounds, such as l-lactic acid and 2,3-butanediol. Here we announce the 2.86- and 3.43-Mb sequences of their genomes. PMID- 23682152 TI - Draft Genome Sequence of Pseudomonas veronii Strain 1YdBTEX2. AB - Pseudomonas veronii strain 1YdBTEX2 was isolated from a benzene-contaminated site. Here we report the draft genome sequence of 1YdBTEX2 and its genes associated with aromatic metabolism. The broad catabolic potential of this strain is consistent with the environment from which it was isolated. PMID- 23682153 TI - Draft Genome Sequence of the Tyramine Producer Enterococcus durans Strain IPLA 655. AB - We here report a 3.059-Mbp draft assembly for the genome of Enterococcus durans strain IPLA 655. This dairy isolate provides a model for studying the regulation of the biosynthesis of tyramine (a toxic compound). These results should aid our understanding of tyramine production and allow tyramine accumulation in food to be reduced. PMID- 23682154 TI - A divergent P element and its associated MITE, BuT5, generate chromosomal inversions and are widespread within the Drosophila repleta species group. AB - The transposon BuT5 caused two chromosomal inversions fixed in two Drosophila species of the repleta group, D. mojavensis and D. uniseta. BuT5 copies are approximately 1-kb long, lack any coding capacity, and do not resemble any other transposable element (TE). Because of its elusive features, BuT5 has remained unclassified to date. To fully characterize BuT5, we carried out bioinformatic similarity searches in available sequenced genomes, including 21 Drosophila species. Significant hits were only recovered for D. mojavensis genome, where 48 copies were retrieved, 22 of them approximately 1-kb long. Polymerase chain reaction (PCR) and dot blot analyses on 54 Drosophila species showed that BuT5 is homogeneous in size and has a widespread distribution within the repleta group. Thus, BuT5 can be considered as a miniature inverted-repeat TE. A detailed analysis of the BuT5 hits in D. mojavensis revealed three partial copies of a transposon with ends very similar to BuT5 and a P-element-like transposase encoding region in between. A putatively autonomous copy of this P element was isolated by PCR from D. buzzatii. This copy is 3,386-bp long and possesses a seven-exon gene coding for an 822-aa transposase. Exon-intron boundaries were confirmed by reverse transcriptase-PCR experiments. A phylogenetic tree built with insect P superfamily transposases showed that the D. buzzatii P element belongs to an early diverging lineage within the P-element family. This divergent P element is likely the master transposon mobilizing BuT5. The BuT5/P element partnership probably dates back approximately 16 Ma and is the ultimate responsible for the generation of the two chromosomal inversions in the Drosophila repleta species group. PMID- 23682155 TI - Effect of dietary restriction and exercise on lower extremity tissue compartments in obese, older women: a pilot study. AB - BACKGROUND: Accumulating evidence suggests that both dietary restriction and exercise (DR + E) should be incorporated in weight loss interventions to treat obese, older adults. However, more information is needed on the effects to lower extremity tissue composition-an important consideration for preserving mobility in older adults. METHODS: Twenty-seven sedentary women (body mass index: 36.3+/ 5.4kg/m(2); age: 63.6+/-5.6 yrs) were randomly assigned to 6 months of DR + E or a health education control group. Thigh and calf muscle, subcutaneous adipose tissue (SAT), and intermuscular adipose tissue (IMAT) size were determined using magnetic resonance imaging. Physical function was measured using a long-distance corridor walk and knee extension strength. RESULTS: Compared with control, DR + E significantly reduced body mass (-6.6+/-3.7kg vs control: -0.05+/-3.5kg; p < .01). Thigh and calf muscle volumes responded similarly between groups. Within the DR + E group, adipose tissue was reduced more in the thigh than in the calf (p < .04). Knee extension strength was unaltered by DR + E, but a trend toward increased walking speed was observed in the DR + E group (p = .09). Post hoc analyses showed that reductions in SAT and IMAT within the calf, but not the thigh, were associated with faster walking speed achieved with DR + E (SAT: r = 0.62; p = .01; IMAT: r = -0.62; p = .01). CONCLUSIONS: DR + E preserved lower extremity muscle size and function and reduced regional lower extremity adipose tissue. Although the magnitude of reduction in adipose tissue was greater in the thigh than the calf region, post hoc analyses demonstrated that reductions in calf SAT and IMAT were associated with positive adaptations in physical function. PMID- 23682156 TI - Obesity and life expectancy among long-lived Black adults. AB - BACKGROUND: In samples of African Americans and the elderly adults, obesity is often not found to be a risk factor for mortality. These data contradict the evidence linking obesity to chronic disease in these groups. Our objective was to determine whether obesity remains a risk factor for mortality among long-lived black adults. METHODS: The Adventist Health Study 2 is a large prospective cohort study of Seventh-day Adventist church members who are encouraged by faith-based principles to avoid tobacco, alcohol, and meat consumption. We conducted an attained age survival analysis of 22,884 U.S. blacks of the cohort-half of whom attained an age of 58-108 years during the follow-up (adult life expectancy of 84 years in men, 89 years in women). RESULTS: Women in the highest body mass index quintile (>33.8) experienced a significant 61% increase (hazard ratio [95% CI] = 1.62 [1.23, 2.11] relative to the middle quintile) in mortality risk and a 6.2 year (95% CI = 2.8-10.2 years) decrease in life expectancy. Men in the highest body mass index quintile (>30.8) experienced a significant 87% increase (hazard ratio [95% CI] = 1.87 [1.28, 2.73] relative to the middle quintile) in mortality risk and 5.9-year (95% CI = 2.1- 9.5 years) decrease in life expectancy. Obesity (>30) was a significant risk factor relative to normal weight (18.5-24.9) in never-smokers. Instantaneous hazards indicated excess risk from obesity was evident through at least age 85 years. The nonobese tended to follow plant-based diets and exercise vigorously. CONCLUSIONS: Avoiding obesity promotes gains in life expectancy through at least the eighth decade of life in black adults. Evidence for weight control through plant-based diets and active living was found in long-lived nonobese blacks. PMID- 23682157 TI - Relationship between wealth and age trajectories of walking speed among older adults: evidence from the English Longitudinal Study of Ageing. AB - BACKGROUND: Slow walking speed is associated with higher risk of accidents, disability, and mortality in older adults, with people in more disadvantaged socioeconomic positions being at higher risk. We explore the relationship between wealth and age trajectories of walking speed among older adults. METHODS: Data come from three waves (2002-2003 to 2006-2007) of the English Longitudinal Study of Ageing. We use latent growth curve models and aging-vector graphs to explore individual changes and average population age trajectories of walking speed by wealth among 7,225 individuals aged 60 and older. RESULTS: For someone aged 71 in the poorest wealth quintile, the baseline mean walking speed was 0.75 m/s, which decreased to 0.71 m/s 4 years later, whereas that of a person in the richest wealth quintile was 0.91 m/s, which decreased to 0.82 m/s. Although the decline in walking speed was faster among people in the richest wealth (net of covariates), the gaps in walking speed between richest and poorest did not close. Even after accounting for covariates, people in the richest wealth only reached critical values (0.60 m/s) of walking speed at the age of 90, whereas people in the poorest wealth reached that level 6 years earlier. CONCLUSIONS: Our findings showed continuing gaps in physical functioning by wealth, even among people with the same health, psychosocial, and demographic conditions. As wealth reflects both past and current socioeconomic status, the implications of our findings are that reducing socioeconomic inequalities at all stages of the life course may have a positive impact on functioning in old age. PMID- 23682158 TI - Validation of the Iconographical Falls Efficacy Scale in cognitively impaired older people. AB - BACKGROUND: This study evaluated psychometric properties of the Iconographical Falls Efficacy Scale (Icon-FES) to measure fear of falling in cognitively impaired older people. Icon-FES uses pictures as visual cues to prompt responses. METHODS: A total of 50 community-dwelling older people with moderate cognitive impairment were assessed on Icon-FES, Falls Efficacy Scale-International, and various physical and cognitive measures. RESULTS: Overall structure and measurement properties of Icon-FES, as evaluated with item response theory, were good. Internal consistency was high (Cronbach's alpha = 0.97). Distribution was near normal, indicating absence of floor and ceiling effects. Icon-FES construct validity was supported by its relation with Falls Efficacy Scale-International (r = .68, p < .001) and its ability to discriminate between groups relating to fall risk factors (gender, balance, falls). Scores were not affected by different levels of cognitive functioning, as assessed with the Mini-Mental State Examination and Trail Making Test. CONCLUSIONS: Icon-FES is the first measure of fear of falling that compensates for reduced abstract abilities by using pictures to match the verbal descriptions. This study supports its feasibility, reliability, and validity to assess fear of falling in people with moderate cognitive impairment or dementia living in the community. Compared with Falls Efficacy Scale-International, Icon-FES was better at identifying participants with higher fall risk and did not show a floor effect likely due to a greater range of physically challenging activities. PMID- 23682159 TI - Body composition explains sex differential in physical performance among older adults. AB - BACKGROUND: Older women have higher percent body fat, poorer physical function, lower strength, and higher rates of nonfatal chronic conditions than men. We sought to determine whether these differences explained physical performance differences between men and women. METHODS: Physical performance was assessed in the Health, Aging and Body Composition study in 2,863 men and women aged 70-79 with a composite 0-4 point score consisting of chair stands, standing balance including one-leg stand, and 6-m usual and narrow walk tests. Total body composition was measured by dual x-ray absorptiometry, thigh composition by computed tomography, and knee extensor strength by isokinetic dynamometer. Analysis of covariance estimated least square mean performance scores for men and women. RESULTS: Men had higher performance scores than women (least square means: 2.33+/-0.02 vs 2.03+/-0.02, p < .0001), adjusted for race, study site, age, and height. Body composition measures (total body fat and thigh muscle area, muscle density, subcutaneous fat, and intermuscular fat) accounted for differences between men and women (least square means: 2.15+/-0.02 vs 2.17+/-0.02, p = .53). Higher strength in men partly explained the sex difference (least square means: 2.28+/-0.02 vs 2.12+/-0.02, p < .0001). Strength attenuated the association of thigh muscle mass with performance. Chronic health conditions did not explain the sex difference. CONCLUSIONS: In a well-functioning cohort, poorer physical function in women compared with men can be explained predominantly by their higher fat mass, but also by other body composition differences. The higher proportion of body fat in women may put them at significant biomechanical disadvantage for greater disability in old age. PMID- 23682160 TI - Young little mice express a premature cardiovascular aging phenotype. AB - To investigate the effect of growth hormone and insulin-like growth factor 1 deficiency on the aging mouse arterial system, we compared the hemodynamics in young (4 months) and old (30 months) growth hormone-releasing hormone receptor null dwarf (Little) mice and their wild-type littermates. Young Little mice had significantly lower peak and mean aortic velocity and significantly higher aortic impedance than young wild-type mice. However, unlike the wild-type mice, there were no significant changes in arterial function with age in the Little mice. Aortic pulse wave velocity estimated using characteristic impedance increased with age in the wild-type mice, but it changed minimally in the Little mouse. We therefore conclude that arterial function in Little mice expresses a premature aging phenotype at young age and may neither enhance nor reduce their longevity. PMID- 23682162 TI - Objective assessment of activity, energy expenditure, and functional limitations in older men: the Osteoporotic Fractures in Men study. AB - BACKGROUND: The relationship between objectively assessed activity, energy expenditure, and the development of functional limitations is unknown. METHODS: Energy expenditure and activity levels were measured objectively using the multisensor SenseWear Pro Armband worn for greater than or equal to 5 days in 1,983 MrOS men (aged >= 78.3 years) free of functional limitations. Validated algorithms calculated energy expenditure; standard cut points defined moderate or greater activity (>= 3.0 METS); and sedentary behavior (time awake <= 1.5 METS). Self-reported functional limitation was determined at the activity assessment and 2.0 years later as inability to perform instrumental activities of daily living (managing money, managing medications, shopping, housework, and meal preparation) and activities of daily living (climb stairs, walk two to three blocks, transfer, or bathe). RESULTS: Each standard deviation decrease in total energy expenditure (420.6 kcal/day) increased the likelihood of inability to perform an instrumental activity of daily living (multivariate odds ratio [mOR]: 1.61, 95% CI: 1.30-2.00) or activity of daily living (mOR: 1.35, 95% CI: 1.12-1.63). Each standard deviation decrease in moderate or greater activity (61.1 minutes/day) increased the likelihood of inability to perform an instrumental activity of daily living (mOR: 1.47, 95% CI: 1.22-1.78) or activity of daily living (mOR: 1.36, 95% CI: 1.14-1.61). Each standard deviation increase in minutes of sedentary behavior (105.2 minutes/day) increased the likelihood of inability to perform an instrumental activity of daily living (mOR: 1.20, 95% CI: 1.03-1.40) or activity of daily living (mOR: 1.17, 95% CI: 1.01-1.35). CONCLUSION: Older men with lower total energy expenditure, lower moderate activity, or greater sedentary time were more likely to develop a functional limitation. PMID- 23682161 TI - Rapamycin extends life and health in C57BL/6 mice. AB - Target of rapamycin inhibition by rapamycin feeding has previously been shown to extend life in genetically heterogeneous mice. To examine whether it similarly affected mouse health, we fed encapsulated rapamycin or a control diet to C57BL/6Nia mice of both sexes starting at 19 months of age. We performed a range of health assessments 6 and 12 months later. Rapamycin feeding significantly reduced mTOR activity in most but not all tissues. It also reduced total and resting metabolic rate during the light (inactive) phase of the light:dark cycle in females only but had no effect on spontaneous activity or metabolism during the dark (active) phase of either sex. Males only had less fragmented sleep when fed rapamycin, whereas stride length and rotarod performance were improved in both sexes. Survival was also improved by this late-life rapamycin feeding, and some pathological lesions were delayed. We found no adverse health consequences associated with rapamycin treatment. PMID- 23682164 TI - Frontal plane instability following rapid voluntary stepping: effects of age and a concurrent cognitive task. AB - BACKGROUND: Quick step execution may prevent falls when balance is lost. Lateral steps often emerge as a consequence of frontal plane instability arising after the first rapid step. In this study, we suggest a new analysis, focusing on the variability of the frontal plane fluctuations of center of pressure (CoP), that is, mediolateral instability, and their changes over time during and immediately following rapid voluntary stepping in older and younger adults in single- and dual-task conditions. This may be useful in understanding age-related alterations in the locomotor control system. METHODS: Seventeen older adults, who live independently in the community, and 16 younger adults performed rapid forward voluntary stepping under single- and dual-task conditions. The average mediolateral CoP fluctuations, that is, the average distance the CoP travels from side to side in the frontal plane over time, standard deviation, and the coefficient of variation of mediolateral CoP fluctuation were extracted and calculated from CoP data during and immediately following rapid voluntary stepping using a force plate. RESULTS: We found an age-related increase in the coefficient of variation that represents the variability of frontal plane fluctuations and no significant differences in the average and standard deviations of frontal plane fluctuations. Cognitive task had no influence on measures of frontal plane fluctuations in both age groups. CONCLUSION: The study showed frontal plane instability during and immediately following rapid stepping in older persons. This may be a factor contributing to lateral balance loss and the large number of lateral falls seen in the older population. PMID- 23682165 TI - Benefits of having friends in older ages: differential effects of informal social activities on well-being in middle-aged and older adults. AB - OBJECTIVES: It has been considered a fact that informal social activities promote well-being in old age, irrespective of whether they are performed with friends or family members. Fundamental differences in the relationship quality between family members (obligatory) and friends (voluntary), however, suggest differential effects on well-being. Further, age-related changes in networks suggest age-differential effects of social activities on well-being, as older adults cease emotionally detrimental relationships. METHOD: Longitudinal representative national survey study with middle-aged (n = 2,830) and older adults (n = 2,032). Age-differential effects of activities with family members and friends on changes in life satisfaction, positive affect (PA), and negative affect (NA) were examined in latent change score models. RESULTS: In the middle aged group, activities with friends and families increased PA and life satisfaction and were unrelated to NA. In the older age group, family activities increased both PA and NA and were unrelated to changes in life satisfaction, but activities with friends increased PA and life satisfaction and decreased NA. DISCUSSION: Social activities differentially affect different facets of well being. These associations change with age. In older adults, the effects of social activities with friends may become more important and may act as a buffer against negative effects of aging. PMID- 23682163 TI - Lower levels of circulating progenitor cells are associated with low physical function and performance in elderly men with impaired glucose tolerance: a pilot substudy from the VA Enhanced Fitness trial. AB - BACKGROUND: Aging is marked by a decline in physical function. Although the biological underpinnings for this remain unclear, loss of regenerative capacity has been proposed as one cause of the loss of physical function that occurs over time. The quantity of circulating progenitor cells (CPCs) may be one reflection of regenerative capability. We sought to determine whether certain specific CPC subpopulations were associated with physical function. METHODS: Baseline CPCs were measured in 129 randomized participants in the Enhanced Fitness clinical trial based on the cell surface markers CD34, CD133, CD146, and CD14 and aldehyde dehydrogenase (ALDH) activity. Physical function was assessed using usual and rapid gait speed, 6-minute walk distance, chair stand time, and balance time. RESULTS: Low counts of early angiogenic CPCs identified as CD34(+), CD34(+)CD133(+), and ALDH-bright (ALDH(br)) cells were associated with low usual gait speed (p < .005, p < .001, and p < .007), rapid gait speed (p < .001, p < .003, and p < .001), and 6-minute walking distance (all comparisons p < .001), and longer time required to complete five chair stands (p < .006, p < .002, and p < .004). CPC counts of mature endothelial or monocytic markers were not associated with physical function. CONCLUSIONS: The numbers of CD34(+) and ALDH(br) CPCs are significantly lower in patients with impaired physical function. Further studies are needed to determine the underlying causes for this association. PMID- 23682166 TI - Campylobacter jejuni carbon starvation protein A (CstA) is involved in peptide utilization, motility and agglutination, and has a role in stimulation of dendritic cells. AB - Campylobacter jejuni is the most frequent cause of severe gastroenteritis in the developed world. The major symptom of campylobacteriosis is inflammatory diarrhoea. The molecular mechanisms of this infection are poorly understood compared to those of less frequent disease-causing pathogens. In a previous study, we identified C. jejuni proteins that antibodies in human campylobacteriosis patients reacted with. One of the immunogenic proteins identified (Cj0917) displays homology to carbon starvation protein A (CstA) from Escherichia coli, where this protein is involved in the starvation response and peptide uptake. In contrast to many bacteria, C. jejuni relies on amino acids and organic acids for energy, but in vivo it is highly likely that peptides are also utilized, although their mechanisms of uptake are unknown. In this study, Biolog phenotype microarrays have been used to show that a DeltacstA mutant has a reduced ability to utilize a number of di- and tri-peptides as nitrogen sources. This phenotype was restored through genetic complementation, suggesting CstA is a peptide uptake system in C. jejuni. Furthermore, the DeltacstA mutant also displayed reduced motility and reduced agglutination compared to WT bacteria; these phenotypes were also restored through complementation. Murine dendritic cells exposed to UV-killed bacteria showed a reduced IL-12 production, but the same IL-10 response when encountering C. jejuni DeltacstA compared to the WT strain. The greater Th1 stimulation elicited by the WT as compared to DeltacstA mutant cells indicates an altered antigenic presentation on the surface, and thus an altered recognition of the mutant. Thus, we conclude that C. jejuni CstA is important not only for peptide utilization, but also it may influence host pathogen interactions. PMID- 23682167 TI - Actinobaculum schaalii causing epididymitis in an elderly patient. AB - Actinobaculum schaalii is a Gram-positive coccoid rod that causes various infections in humans and is easily overlooked in cultures. A. schaalii has long been thought to be of low prevalence and limited invasive potential, causing benign cystitis in elderly patients with underlying urological conditions. Here, we report the first case of epididymitis caused by this bacterium. PMID- 23682168 TI - Genetic evidence of paleolithic colonization and neolithic expansion of modern humans on the tibetan plateau. AB - Tibetans live on the highest plateau in the world, their current population size is approximately 5 million, and most of them live at an altitude exceeding 3,500 m. Therefore, the Tibetan Plateau is a remarkable area for cultural and biological studies of human population history. However, the chronological profile of the Tibetan Plateau's colonization remains an unsolved question of human prehistory. To reconstruct the prehistoric colonization and demographic history of modern humans on the Tibetan Plateau, we systematically sampled 6,109 Tibetan individuals from 41 geographic populations across the entire region of the Tibetan Plateau and analyzed the phylogeographic patterns of both paternal (n = 2,354) and maternal (n = 6,109) lineages as well as genome-wide single nucleotide polymorphism markers (n = 50) in Tibetan populations. We found that there have been two distinct, major prehistoric migrations of modern humans into the Tibetan Plateau. The first migration was marked by ancient Tibetan genetic signatures dated to approximately 30,000 years ago, indicating that the initial peopling of the Tibetan Plateau by modern humans occurred during the Upper Paleolithic rather than Neolithic. We also found evidences for relatively young (only 7-10 thousand years old) shared Y chromosome and mitochondrial DNA haplotypes between Tibetans and Han Chinese, suggesting a second wave of migration during the early Neolithic. Collectively, the genetic data indicate that Tibetans have been adapted to a high altitude environment since initial colonization of the Tibetan Plateau in the early Upper Paleolithic, before the last glacial maximum, followed by a rapid population expansion that coincided with the establishment of farming and yak pastoralism on the Plateau in the early Neolithic. PMID- 23682169 TI - Spotlight Thailand. AB - Thailand is a Buddhist country located on the mainland of southeast Asia, where 3 generation homes are still common. Care of older adults is primarily a family responsibility. Recent policy changes mean that all Thais are now eligible for services through the national health care system. Almost half the population has no retirement pension, leaving responsibility for support of older adults largely to extended family. Long-term care is becoming a serious concern as the population ages, women move into the workforce, and family size decreases. Thai researchers have focused on issues related to health and nutrition, income security, housing, general population aging, local and community care and services, information and education, and quality of life. There is currently no formal long-term care system. PMID- 23682170 TI - Effect of ecological walking training in sedentary elderly people: act on aging study. AB - PURPOSE OF THE STUDY: This study aims to investigate the effects of a walking program on aerobic endurance and function in a sample of sedentary elderly people. DESIGN AND METHODS: For this study, 126 sedentary individuals were recruited: 63 individuals (mean age = 74.1+/-6.0 years) for the control group and 63 (mean age = 72.0+/-4.5 years) for the intervention group. The intervention consisted of walking training including balance exercises and lower limb strength activities twice a week for 4 months. We collected baseline and post-test measurements of aerobic endurance, lower limb strength, and mobility. We also measured aerobic endurance at increments of 4, 8, and 12 weeks between the baseline and the post-test. We used analyses of covariance with baseline value, gender, age, and body mass index scores as covariates (p < . 05) and calculated the effect size for the effects of the intervention. The changeover time of aerobic endurance was also analyzed with the repeated analysis of variance (p < .05). RESULTS: The intervention group showed steady and significant improvements with respect to the 6-min walk (aerobic endurance) from 447.89 m (SD 73.87) to 561.51 m (SD 83.96), as well as the 30-s chair stand (lower limb strength) from 10 (SD 3) to 13 (SD 3) number of times and the Timed Up and Go Test (mobility) from 8.53 s (SD 2.86) to 7.13 s (SD 1.76) at the post-test, whereas the control group showed significant decrease in all measurements. IMPLICATION: These results underline that an ecological walking training program can be used to improve physical functioning among sedentary elderly people. PMID- 23682171 TI - Venous thromboembolism in major lower limb orthopedic surgery. PMID- 23682173 TI - Role of autologous chondrocyte transplantation in articular cartilage defects: An experimental study. AB - INTRODUCTION: Injuries of articular cartilage (AC) have very limited potential to heal, because they are avascular and this may subsequently lead to secondary arthrosis. Autologous cultured chondrocytes transplantation is can be used to create hyaline or hyaline-like repair in a cartilage defect area. The purpose of this study was to repair artificially created full-thickness AC defects in 20 rabbit knee joints with autologous cultured chondrocytes. MATERIALS AND METHODS: An AC defect of 3 mm was created on the lateral condyle of both tibiae. The defect was filled with autologous chondrocytes cultured in vitro and fixed with fibrin, at a later stage on the left side. The right knee acted as a control. The rabbits were sacrificed after 3, 6, and 12 weeks of transplantation and the reparative tissues were analyzed macroscopically and histologically. RESULTS: Histological scores of the cultured autologous chondrocyte transplanted knees were significantly better than the control knees at 3, 6, and 12 weeks following the transplantation. Integration of repaired tissue with adjacent cartilage, hyaline characteristics of repaired tissue, maturity of cartilage, and cellularity increases with duration and is significant in chondrocytes transplanted defects compared to control. The histological scores also become better with increasing duration of followup. CONCLUSION: Transplantation of autologous chondrocytes cultured in vitro and fixed with fibrin is effective in repairing AC defects. PMID- 23682172 TI - Current concepts and controversies on adolescent idiopathic scoliosis: Part I. AB - Adolescent idiopathic scoliosis is the most common spinal deformity encountered by General Orthopaedic Surgeons. Etiology remains unclear and current research focuses on genetic factors that may influence scoliosis development and risk of progression. Delayed diagnosis can result in severe deformities which affect the coronal and sagittal planes, as well as the rib cage, waistline symmetry, and shoulder balance. Patient's dissatisfaction in terms of physical appearance and mechanical back pain, as well as the risk for curve deterioration are usually the reasons for treatment. Conservative management involves mainly bracing with the aim to stop or slow down scoliosis progression during growth and if possible prevent the need for surgical treatment. This is mainly indicated in young compliant patients with a large amount of remaining growth and progressive curvatures. Scoliosis correction is indicated for severe or progressive curves which produce significant cosmetic deformity, muscular pain, and patient discontent. Posterior spinal arthrodesis with Harrington instrumentation and bone grafting was the first attempt to correct the coronal deformity and replace in situ fusion. This was associated with high pseudarthrosis rates, need for postoperative immobilization, and flattening of sagittal spinal contour. Segmental correction techniques were introduced along with the Luque rods, Harri Luque, and Wisconsin systems. Correction in both coronal and sagittal planes was not satisfactory and high rates of nonunion persisted until Cotrel and Dubousset introduced the concept of global spinal derotation. Development of pedicle screws provided a powerful tool to correct three-dimensional vertebral deformity and opened a new era in the treatment of scoliosis. PMID- 23682174 TI - A comparison of 3D scapular kinematics between dominant and nondominant shoulders during multiplanar arm motion. AB - BACKGROUND: Generally, the scapular motions of pathologic and contralateral normal shoulders are compared to characterize shoulder disorders. However, the symmetry of scapular motion of normal shoulders remains undetermined. Therefore, the aim of this study was to compare 3dimensinal (3D) scapular motion between dominant and nondominant shoulders during three different planes of arm motion by using an optical tracking system. MATERIALS AND METHODS: Twenty healthy subjects completed five repetitions of elevation and lowering in sagittal plane flexion, scapular plane abduction, and coronal plane abduction. The 3D scapular motion was measured using an optical tracking system, after minimizing reflective marker skin slippage using ultrasonography. The dynamic 3D motion of the scapula of dominant and nondominant shoulders, and the scapulohumeral rhythm (SHR) were analyzed at each 10 degrees increment during the three planes of arm motion. RESULTS: There was no significant difference in upward rotation or internal rotation (P > 0.05) of the scapula between dominant and nondominant shoulders during the three planes of arm motion. However, there was a significant difference in posterior tilting (P = 0.018) during coronal plane abduction. The SHR was a large positive or negative number in the initial phase of sagittal plane flexion and scapular plane abduction. However, the SHR was a small positive or negative number in the initial phase of coronal plane abduction. CONCLUSIONS: Only posterior tilting of the scapula during coronal plane abduction was asymmetrical in our healthy subjects, and depending on the plane of arm motion, the pattern of the SHR differed as well. These differences should be considered in the clinical assessment of shoulder pathology. PMID- 23682175 TI - Arthroscopic management of recalcitrant stiffness following rotator cuff repair: A retrospective analysis. AB - BACKGROUND: Rotator cuff repair surgery is one of the most commonly performed procedures in the world but limited literature exists for guidance of optimal management of post-operative arthrofibrosis following cuff repair. The purpose of this study is to report the results of arthroscopic capsular release, lysis of adhesions, manipulation under anesthesia, and aggressive physical therapy in patients with recalcitrant postoperative stiffness after rotator cuff repair. MATERIALS AND METHODS: Twenty-nine patients who had recalcitrant arthrofibrosis following either an arthroscopic (62%), open (28%), or mini-open (10%) rotator cuff repair were included in study. The average age at the time of index cuff repair surgery was 49.8 years (range 24-70 years). Sixteen patients (55%) were involved in worker's compensation claims. The mean time from the date of index operation to lysis of adhesions was 9.7 months (range 4.2-36.2 months), and the mean time from lysis of adhesion to most recent follow-up 18.2 months (range 4.1 43.7 months). Post-operative evaluation was performed using American Shoulder and Elbow Surgeons Score (ASES), Visual Analog Score (VAS), Single Assessment Numeric Evaluation (SANE), and Simple Shoulder Test (SST) on 18 (62%), while range of motion (ROM), dynamometer strength testing, and Constant-Murley Scoring were performed on 13 (45%). Statistical analysis was performed using a Student's t test. RESULTS: Prior to arthroscopic lysis of adhesions, mean forward active elevation (FE) was 103.8 degrees , (range 60-145 degrees (SD 26.3) and external rotation at the side (ERS) was 25.3 degrees , (range 5-70 degrees SD 15.1 degrees ). Post-operatively, at the most recent follow-up, FE was significantly improved to 158.3 degrees , (range 110-180 degrees SD 22.3 degrees ), and ERS improved to 58.9 degrees , (range 15-90 degrees SD 18.6 degrees ) in both cases. Involvement in a worker's compensation claim resulted in a lower ASES, VAS, and SANE score, but there was no statistically significant difference in motion. CONCLUSION: Arthroscopic capsular release, lysis of adhesions, and manipulation under anesthesia is a safe, reliable method of treating persistent stiffness following rotator cuff repair. PMID- 23682176 TI - Outcome of locking compression plates in humeral shaft nonunions. AB - BACKGROUND: Nonunion of diaphyseal fractures of the humerus are frequently seen in clinical practice (incidence of up to 15% in certain studies) and osteosynthesis using dynamic compression plates, intra medullary nails and Ilizarov fixators have been reported previously. Locking compression plates (LCP) are useful in the presence of disuse osteoporosis, segmental bone loss and cortical defects that preclude strong fixation. We report a prospective followup study of the outcome of the use of LCP for humeral nonunion following failed internal fixation in which implants other than LCP had been used. MATERIALS AND METHODS: Twenty four patients with nonunion of humeral shaft fractures following failed internal fixation were included in the study. The mean followup period was 3.4 years (range: 2.4 to 5.7 years) and the minimum followup period was 2 years. Mean age of the patients was 41.04 years (range: 24 to 57 years). All 24 patients underwent osteosynthesis using LCP and autologous bone grafting (cortico cancellous iliac crest graft combined with or without fibular strut graft). Main outcome measurements included radiographic assessment of fracture union and pre and postoperative functional evaluation using the modified Constant and Murley scoring system. RESULTS: 23 out of 24 fractures united following osteosynthesis. Average time to union was 16 weeks (range: 10 to 28 weeks). Complications included delayed union (n = 2), transient radial nerve palsy (n = 2) and persistent nonunion (n = 1). Functional evaluation using the Constant and Murley score showed excellent results in 11, good in 10, fair in two and poor outcome in one patient. CONCLUSIONS: Locking compression plating and cancellous bone grafting is a reliable option for achieving union in humeral diaphyseal nonunion with failed previous internal fixation and results in good functional outcome in patients with higher physiological demands. PMID- 23682177 TI - Open reduction and locking plate fixation of displaced proximal humerus fractures. AB - BACKGROUND: Treatment of proximal humerus fractures is controversial and various operative modalities have been tried in the literature. The aim of the present study was to evaluate functional outcome and complication rate after open reduction and internal fixation of displaced proximal humerus fractures by proximal humerus locking plate. MATERIALS AND METHODS: 52 patients with displaced proximal humerus fractures treated with proximal humerus locking plate between May 2008 and October 2010 were included in the study. Fractures were classified according to Neer's classification into displaced 2-part, 3-part, and 4-part fractures. Patients were followed for a minimum period of 1 year. 11 patients had less than 1 year of followup and were not considered in the evaluation of final results. Forty one patients were considered for final evaluation. Functional evaluation was done according to the Constant-Murley scoring system. Constant score was compared between 2-part, 3-part, and 4-part fractures at final up and also between young (<=60 yrs) and old (>60 yrs). RESULTS: 11 patients had 2-part fractures, 22 patients had 3-part fractures, and 19 patients had 4-part fractures. The mean followup period was 15.21 +/- 2.59 months. 65.8% (n = 27) patients had good to excellent result, 19.5% (n = 8) had fair, and 14.7% (n = 6) had poor result. Constant scores for 2-part (79.83 +/- 6.95) and 3-part fractures (74.22 +/- 12.53) were significantly superior to those of 4-part fractures (61.09 +/- 14.29) (P value = 0.002 and 0.018, respectively). Difference between 2-part and 3-part fractures was not significant (P value = 0.623). There was no significant difference between younger (<=60) and older patients (>60). Complications encountered in this series were varus malreduction in 17% (n = 7), screw perforation in 10% (n = 4), plate impingement in 12% (n = 5), infection in 2% (n = 1), and nonunion in 2% (n = 1) of cases. CONCLUSION: Proximal humerus locking plate gives reliable fixation for 2-part and 3-part fractures. Its use in more complicated fracture patterns of 4-part fractures is associated with poor clinical outcome. PMID- 23682178 TI - Comparative study of extended versus short term thromboprophylaxis in patients undergoing elective total hip and knee arthroplasty in Indian population. AB - BACKGROUND: Postoperative thromboprophylaxis with low molecular weight heparin (LMWH) for an extended period of 4 weeks is now preferred over short term thromboprophylaxis in patients undergoing total hip/knee arthroplasty (THA/TKA). However, most of the data demonstrating the efficacy and safety of extended thromboprophylaxis and short term thromboprophylaxis is from clinical trials done in the West. In India, the data of the incidence of venous thromboembolism (VTE) following THA/TKA has been conflicting and the duration has not been clearly defined. The aim of the study was to evaluate and compare the efficacy of extended thromboprophylaxis over short term thromboprophylaxis in Indian patients undergoing elective THA/TKA surgeries. MATERIALS AND METHODS: A prospective arm of 197 consecutive patients undergoing elective THA/TKA surgeries who were administered extended thromboprophylaxis for 4 weeks was compared with a historical group of 795 patients who were administered short term thromboprophylaxis for only 7-11 days. In both groups, LMWH (enoxaparin) was used in a dose of 40 mg subcutaneously, in addition to mechanical thromboprophylaxis. Primary efficacy endpoint was objectively confirmed venous thromboembolism (VTE). The presence of DVT was confirmed by a combination of pretest scoring, D-dimer, and Color Doppler Flow Imaging (CDFI) of deep veins of the legs, and pulmonary thromboembolism (PTE) was confirmed by ventilation perfusion (V/Q) scan or pulmonary angiography. Fisher's exact test and t test were used for the statistical analysis. The baseline confounding factors were compared between the two groups using t test for comparing the means for continuous data and Fisher's exact test for categorical data. RESULTS: In the prospective arm, only 1 patient developed symptomatic PTE compared to 26 (3.27%) cases of VTE (20 cases of PTE and 6 cases of DVT) in the retrospective group. CONCLUSION: Extended thromboprophylaxis (for 4 weeks) was found to be more effective than short term thromboprophylaxis in minimizing the risk of postoperative VTE in patients who underwent THA/TKA. PMID- 23682179 TI - Thromboprophylaxis in routine arthroscopy of knee. AB - BACKGROUND: Thromboprophylaxis in arthroscopy is controversial. Recent literature has shown variable rates of deep vein thrombosis following routine arthroscopic knee surgery; however, it is unknown if current practice reflects the literature. We have conducted a cross sectional survey to provide insight into the practice patterns perceived risks, benefits and barrier in the use of thromboprophylaxis. MATERIALS AND METHODS: A 19 item survey was created regarding surgeons' use of thromboprophylaxis in their patients undergoing routine knee arthroscopy. E-mail surveys were sent out to members of the Canadian Orthopaedic Association. RESULTS: Seventy-seven responses were obtained; of which 58.2% (n=45) of surgeons stated that they had a clinical interest in sports medicine, and 37.3% (n=29) had completed a fellowship in sports medicine or arthroscopy. Fifty five surgeons (71.6%) performed more than 40 arthroscopies per year. Prolonged surgical time was the only risk factor that would significantly increase their use of prophylaxis. Practice patterns surrounding the use of thromboprophylaxis were otherwise quite variable. CONCLUSIONS: Our survey reveals that opinions and practice patterns surrounding the use of thromboprophylaxis following routine knee arthroscopy are diverse. This survey points out the need for larger well designed studies for concise guidelines. PMID- 23682180 TI - Four quadrant parallel peripheral screw fixation for displaced femoral neck fractures in elderly patients. AB - BACKGROUND: The treatment options for displaced femoral neck fracture in elderly are screw fixation, hemiarthroplasty and total hip arthroplasty based primarily on age of the patient. The issues in screw fixation are ideal patient selection, optimal number of screws, optimal screw configuration and positioning inside the head and neck of femur. The problems of screw fixation may be loss of fixation, joint penetration, avascular necrosis of femoral head, nonunion, prolonged rehabilitation period and the need for second surgery in failed cases. We hereby present results of a modified screw fixation technique in femoral neck fractures in patients >=50 years of age. MATERIALS AND METHODS: Patients >=50 years of age (range 50-73 years) who sustained displaced femoral neck fracture and fulfilled the inclusion criteria were enrolled in this prospective study. They were treated with closed reduction under image intensifier control and cannulated cancellous screw fixation. Accurate anatomical reduction was not aimed and a cross sectional contact area of >75% without varus was accepted as good reduction. Four screws were positioned in four quadrants of femoral head and neck, as parallel and as peripheral as possible. Radiological and functional results were evaluated periodically. Sixty four patients who could complete a minimum followup of two years were analyzed. RESULTS: Radiologically, all fractures healed after mean duration of 10 weeks (range 8-12 weeks). There was no avascular necrosis. Nonanatomical healing was observed in 45 cases (70%). All patients except one had excellent functional outcome and could do cross-legged sitting and squatting. Chondrolysis with progressive head resorption was seen in one case, which was converted to total hip arthroplasty. CONCLUSION: Closed reduction and cannulated cancellous screw fixation gives satisfactory functional results in large group of elderly patients. The four quadrant parallel peripheral (FQPP) screw fixation technique gives good stability, allows controlled collapse, avoids fixation failure and achieves predictable bone healing in displaced femoral neck fracture in patients >=50 years of age. PMID- 23682181 TI - Autologous bone plugs in unilateral total knee arthroplasty. AB - BACKGROUND: The purpose of this study was to compare blood loss, declines in hemoglobin (HgB) and hematocrit (HcT) levels, and required homologous transfusions for patients who either had the femoral intramedullary defect left open or filled with an autologous bone plug during total knee arthroplasty (TKA). We hereby present our results of autologous bone plugs in unilateral TKA. MATERIALS AND METHODS: A retrospective chart review was performed on 55 patients diagnosed with osteoarthritis (OA) who had undergone unilateral TKA. Twenty six patients had the femoral defect filled with an autologous bone plug and 29 did not. Lateral releases and patella replacements were not performed. Drained blood was reinfused when appropriate. RESULTS: MEAN BLOOD LOSS AND MEAN BLOOD REINFUSED WERE SIMILAR FOR THE PLUGGED (LOSS: 960.8 +/- 417.3 ml; reinfused: 466.7 +/- 435.9 mL) and unplugged groups (loss: 1065.9 +/- 633.5 ml, P = 0.38; reinfused: 528.4 +/- 464.8 ml, P = 0.61). Preoperative HgB (14.3 +/- 1.4 g/dL, P = 0.93) and HcT levels (42.2 +/- 4.6%, P = 0.85) were similar across plug conditions. HgB and HcT levels declined similarly for the plugged (2.7 +/- 1.2 g/dl and 7.9 +/- 4.0%) and unplugged groups (3.0 +/- 0.9 g/dl, P = 0.16 and 9.0 +/- 2.6%, P = 0.16), respectively. Of patients, one in the plugged group and none in the unplugged group required homologous transfusions (P = 0.5). CONCLUSION: The autologous bone plug does not appear to reduce the need for homologous blood transfusions following unilateral TKA. PMID- 23682182 TI - Functional outcome of Schatzker type V and VI tibial plateau fractures treated with dual plates. AB - BACKGROUND: Dual plate fixation in comminuted bicondylar tibial plateau fractures remains controversial. Open reduction and internal fixation, specifically through compromised soft tissues, has historically been associated with major wound complications. Alternate methods of treatment have been described, each with its own merits and demerits. We performed a retrospective study to evaluate the functional outcome of lateral and medial plate fixation of Schatzker type V and VI fractures through an anterolateral approach, and a medial minimally invasive approach or a posteromedial approach. MATERIALS AND METHODS: We treated 46 tibial plateau fractures Schatzker type V and VI with lateral and medial plates through an anterolateral approach and a medial minimal invasive approach over an 8 years period. Six patients were lost to followup. Radiographs in two planes were taken in all cases. Immediate postoperative radiographs were assessed for quality of reduction and fixation. The functional outcome was evaluated according to the Oxford Knee Score criteria on followup. RESULTS: Forty patients (33 men and 7 women) who completed the followup were included in the study. There were 20 Schatzker type V fractures and 20 Schatzker type VI fractures. The mean duration of followup was 4 years (range 1-8 years). All patients had a satisfactory articular reduction defined as <=2 mm step-off or gap as assessed on followup. All patients had a good coronal and sagittal plane alignment, and articular width as assessed on supine X-rays of the knee in the anteroposterior (AP) and lateral views. The functional outcome, as assessed by the Oxford Knee Score, was excellent in 30 patients and good in 10 patients. All patients returned to their pre-injury level of activity and employment. There were no instances of deep infection. CONCLUSIONS: Dual plate fixation of severe bicondylar tibial plateau fractures is an excellent treatment option as it provides rigid fixation and allows early knee mobilization. Careful soft tissue handling and employing minimal invasive techniques minimizes soft tissue complications. PMID- 23682183 TI - Tru-cut biopsy as the initial method of tissue diagnosis in bone tumors with soft tissue extension. AB - BACKGROUND: Tru-cut biopsy in suspected bone tumors can be performed even in less specialized centers. Tru-cut biopsy has been proved as safe with more than 90% accuracy. However, its usefulness was not widely studied in general hospitals where Tru-cut biopsy is performed by orthopedic surgeons. This study was conducted to find out the accuracy and adequacy of Tru-cut biopsy performed by an orthopedic surgeon not trained in musculoskeletal oncology, in a general hospital. MATERIALS AND METHODS: A study was conducted through a prospectively collected database using a uniform protocol. All patients who had a malignant appearing bone lesion with a palpable soft tissue mass were included in the current study. Fifty such consecutive cases underwent Tru-Cut biopsy by orthopedic residents or registrars who were aware of the principles of Tru-cut biopsy and the recommendations of Musculoskeletal Tumor Society. When an open biopsy or a resection of the tumor was subsequently performed, the histological diagnosis was compared for accuracy with the diagnosis of needle biopsy. We evaluated adequacy of sample obtained and accuracy of diagnosis in terms of sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: Seventy seven cases were initially enrolled. Out of which 18 were excluded and 59 patients were biopsied. Out of which 50 were analysed. Only 4 out of 50 biopsied specimens were inadequate resulting in an adequacy rate of 92%. Among 46 cases, which were analyzed for diagnostic accuracy, 84.78% had true positive result, 8.69% had true negative, and 6.52% had false-negative report. The sensitivity and specificity of Tru-cut biopsy in our series was 92.85% and 100%, respectively, with positive predictive value of 100% and negative predictive value of 57.14%. CONCLUSIONS: Tru-cut biopsy can be recommended as an initial method of tissue diagnosis in musculoskeletal tumors with soft tissue extension. PMID- 23682184 TI - Cerebrotendinous xanthomatosis. AB - Cerebrotendinous xanthomatosis is a rare autosomal recessive lipid storage disorder affecting the biosynthetic pathway of bile acids, leading to increased cholestanol formation and its accumulation in various tissues. Patients can present with tendon xanthomas, gait abnormalities, osteoporosis with or without a pathological fracture, diminished vision, intractable diarrhoea, seizures, ataxia, psychosis, and mental retardation. We report a 20-year-old man who presented with multiple recurrent tendon swellings and seizures. The earlier diagnosis and treatment helps in preventing the devastating neurological sequalae of this sinister condition. Treatment with chenodeoxycholic acid is crucial in preventing the progression of this rare disorder. PMID- 23682185 TI - Unusual presentation of a radial neck fracture in a child. AB - Fracture of the radial neck are uncommon injuries. In children, they may present as radial neck fractures, a components of forearm fracture dislocations, or as isolated fracture dislocations. Here, we present an unusual and previously undescribed variant of radial neck fracture with dislocation of the radial head to the medial side and ulnar nerve injury. The fracture dislocation was openly reduced and fixed with a small fragment plate. The fracture healed with some loss of rotational movements. At short followup of 6 months patient had useful elbow function but ulnar nerve did not recover. PMID- 23682186 TI - Desmoplastic fibroma of ulna: Excision and reconstruction of olecranon with a fibular graft. AB - Desmoplastic fibroma is a rare, well differentiated, locally aggressive fibrous tumor usually arising from soft tissues, and rarely from bones. Involvement of forearm bones is extremely unusual. We present a large desmoplastic fibroma of right ulna in a 15-year-old male. The tumor was excised with a wide margin, and the bony defect was reconstructed with nonvascular autologous fibular graft. Reconstruction of the olecranon process was attempted using the fibular head and the remaining olecranon. At 2-years followup, there was no recurrence, flexion extension arc of the elbow joint was 40 degrees -130 degrees and there was no restriction of activities of daily living. PMID- 23682187 TI - Ulnar buttress arthroplasty after enbloc resection of a giant cell tumor of the distal ulna. AB - Enbloc resection with or without ulnar stump stabilization is the recommended treatment for giant cell tumors (GCT) of the distal ulna. A few sporadic reports are available where authors have described various procedures to prevent ulnar stump instability and ulnar translation of carpal bones. We report a GCT of the distal ulna in a 43-year-old male which was resected enbloc. The distal radioulnar joint was reconstructed by fixing an iliac crest graft to the distal end of the radius (ulnar buttress arthroplasty) and the ulnar stump was stabilized with extensor carpi ulnaris tenodesis. After a followup at three years, there was no evidence of tumor recurrence or graft resorption; the patient had a normal range of movement of the wrist joint and the functional outcome was excellent as per the score of Ferracini et al. PMID- 23682188 TI - A retrospective analysis of medial open wedge high tibial osteotomy for varus osteoarthritic knee. PMID- 23682189 TI - Author's reply. PMID- 23682190 TI - Outcome of one-stage treatment of developmental dysplasia of hip in older children. PMID- 23682191 TI - Author reply. PMID- 23682192 TI - The epidemiology of clinical malaria among African children. AB - There is a resurgence of interest in the clinical epidemiology of malaria among African children. This renewed interest follows fifty years of failure to eradicate infection in Africa and redirected efforts toward disease control and prevention. We have a poor understanding of the mechanisms by which clinical immunity is acquired; however, several recent studies have provided new insights into how fast clinical protection is acquired under the varied transmission intensities common to Africa. What is clear is that the frequency with which individuals encounter infection from birth will determine the speed with which they become clinically immune and the patterns of severe pathology they are likely to experience. There remains doubt and concerns over the long-term consequences of reducing natural parasite exposure in several areas of Africa. New field studies are urgently required to tackle these issues so that control may be guided by an improved understanding of malaria as a disease that can lead to death. PMID- 23682193 TI - CCL: an algorithm for the efficient comparison of clusters. AB - The systematic comparison of the atomic structure of solids and clusters has become an important task in crystallography, chemistry, physics and materials science, in particular in the context of structure prediction and structure determination of nanomaterials. In this work, an efficient and robust algorithm for the comparison of cluster structures is presented, which is based on the mapping of the point patterns of the two clusters onto each other. This algorithm has been implemented as the module CCL in the structure visualization and analysis program KPLOT. PMID- 23682194 TI - Development and applications of a new neutron single-crystal diffractometer based on a two-dimensional large-area curved position-sensitive detector. AB - A new single-crystal neutron diffractometer based on a large-area curved two dimensional position-sensitive detector (C-2DPSD) has been developed. The diffractometer commissioning is almost complete, together with development of the measurement methodology and the raw data processing software package, the Reciprocal Analyzer, and the instrument is now ready to be launched for users. Position decoding of the C-2DPSD is via a delay-line readout method with an effective angular range of 110 * 54 degrees in the horizontal and vertical directions, respectively, with a nominal radius of curvature of 530 mm. The diffractometer is equipped with a Ge(311) mosaic monochromator and two supermirror vacuum guide paths, one before and one after the monochromator position. The commissioning incorporates corrections and calibration of the instrument using an NaCl crystal, various applications such as crystallographic and magnetic structure measurements, a crystallinity check on large crystals, and a study on the composition or dopant content of a mixed crystal of (Tm x Yb1-x )Mn2O5. The installation of the diffractometer and the measurement method, the calibration procedure and results, the raw data treatment and visualization, and several applications using the large C-2DPSD-based diffractometer are reported. PMID- 23682195 TI - The current approach to initial crystallization screening of proteins is under sampled. AB - Protein crystallization conditions that resulted in crystal structures published by scientists at the MRC Laboratory of Molecular Biology (MRC-LMB, Cambridge, UK) have been analysed. It was observed that the more often a crystallization reagent had been used to formulate the initial conditions, the more often it was found in the reported conditions that yielded diffraction quality crystals. The present analysis shows that, despite the broad variety of reagents, they have the same impact overall on the yield of crystal structures. More interestingly, the correlation implies that, although the initial crystallization screen may be considered very large, it is an under-sampled combinatorial approach. PMID- 23682196 TI - Automatic processing of macromolecular crystallography X-ray diffraction data at the ESRF. AB - The development of automated high-intensity macromolecular crystallography (MX) beamlines at synchrotron facilities has resulted in a remarkable increase in sample throughput. Developments in X-ray detector technology now mean that complete X-ray diffraction datasets can be collected in less than one minute. Such high-speed collection, and the volumes of data that it produces, often make it difficult for even the most experienced users to cope with the deluge. However, the careful reduction of data during experimental sessions is often necessary for the success of a particular project or as an aid in decision making for subsequent experiments. Automated data reduction pipelines provide a fast and reliable alternative to user-initiated processing at the beamline. In order to provide such a pipeline for the MX user community of the European Synchrotron Radiation Facility (ESRF), a system for the rapid automatic processing of MX diffraction data from single and multiple positions on a single or multiple crystals has been developed. Standard integration and data analysis programs have been incorporated into the ESRF data collection, storage and computing environment, with the final results stored and displayed in an intuitive manner in the ISPyB (information system for protein crystallography beamlines) database, from which they are also available for download. In some cases, experimental phase information can be automatically determined from the processed data. Here, the system is described in detail. PMID- 23682197 TI - An electrically assisted device for protein crystallization in a vapor-diffusion setup. AB - A new easy-to-use device has been designed and implemented for electric field induced protein crystallization in a vapor-diffusion configuration. The device not only controls crystal nucleation by means of the electrical current, but also favors crystal growth owing to its vapor-diffusion setup. Crystallization was conducted in the presence of an internal electric field and direct current. The proteins investigated were lysozyme, as model protein, and 2TEL-lysozyme (a synthetic protein consisting of two tandem alpha helix motifs connected to a lysozyme moiety). Lysozyme crystals that grew attached to the cathode were larger than those grown attached to the anode or in the absence of an electric current. On the other hand, crystals of 2TEL-lysozyme qualitatively showed a better X-ray diffraction pattern when grown in the presence of an electric current. PMID- 23682198 TI - Synthesis, Redox Properties, and Conformational Analysis of Vicinal Disulfide Ring Mimics. AB - A vicinal disulfide ring (VDR) results from disulfide bond formation between two adjacent cysteine residues. This 8-membered ring is a rare motif in protein structures and is functionally important to those few proteins that posses it. This article focuses on the construction of strained and unstrained VDR mimics, discernment of the preferred conformation of these mimics, and the determination of their respective disulfide redox potentials. PMID- 23682199 TI - Benzamide synthesis by direct electrophilic aromatic substitution with cyanoguanidine. AB - Cyanoguanidine is an inexpensive commodity chemical and it is found to be a useful reagent for the direct Friedel-Crafts carboxamidation of arenes. The reaction works best in an excess of Bronsted superacid, an observation suggesting the involvement of a superelectrophilic intermediate. Theoretical calculations indicate that the most stable diprotonated species involves protonation at the guanidine and cyano nitrogen atoms. PMID- 23682201 TI - Development of Pinhole-Free Amorphous Aluminum Oxide Protective Layers for Biomedical Device Applications. AB - This paper describes synthesis of ultrathin pinhole-free insulating aluminum oxide layers for electronic device protection in corrosive liquid environments, such as phosphate buffered saline (PBS) or clinical fluids, to enable emerging biomedical applications such as biomolecular sensors. A pinhole-free 25-nm thick amorphous aluminum oxide layer has been achieved using ultra-high vacuum DC magnetron reactive sputtering of aluminum in oxygen/argon plasma followed by oxygen plasma post-processing. Deposition parameters were optimized to achieve the best corrosion protection of lithographically defined device structures. Electrochemical deposition of copper through the aluminum oxide layers was used to detect the presence (or absence) of pinholes. FTIR, XPS, and spectroscopic ellipsometry were used to characterize the material properties of the protective layers. Electrical resistance of the copper device structures protected by the aluminum oxide layers and exposed to a PBS solution was used as a metric to evaluate the long-term stability of these device structures. PMID- 23682202 TI - Does the amount of school choice matter for student engagement? AB - School choice may increase student engagement by enabling students to attend schools that more closely match their needs and preferences. But this effect on engagement may depend on the characteristics of the choices available. Therefore, we consider how the amount of educational choice of different types in a local educational marketplace affects student engagement using a large, national population of 8th grade students. We find that more choice of regular public schools in the elementary and middle school years is associated with a lower likelihood that students will be severely disengaged in eighth grade, and more choices of public schools of choice has a similar effect but only in urban areas. In contrast, more private sector choice does not have such a general beneficial effect. PMID- 23682200 TI - Partial cooperative unfolding in proteins as observed by hydrogen exchange mass spectrometry. AB - Many proteins do not exist in a single rigid conformation. Protein motions, or dynamics, exist and in many cases are important for protein function. The analysis of protein dynamics relies on biophysical techniques that can distinguish simultaneously existing populations of molecules and their rates of interconversion. Hydrogen exchange (HX) detected by mass spectrometry (MS) is contributing to our understanding of protein motions by revealing unfolding and dynamics on a wide timescale, ranging from seconds to hours to days. In this review we discuss HX MS-based analyses of protein dynamics, using our studies of multi-domain kinases as examples. Using HX MS, we have successfully probed protein dynamics and unfolding in the isolated SH3, SH2 and kinase domains of the c-Src and Abl kinase families, as well as the role of inter- and intra-molecular interactions in the global control of kinase function. Coupled with high resolution structural information, HX MS has proved to be a powerful and versatile tool for the analysis of the conformational dynamics in these kinase systems, and has provided fresh insight regarding the regulatory control of these important signaling proteins. HX MS studies of dynamics are applicable not only to the proteins we illustrate here, but to a very wide range of proteins and protein systems, and should play a role in both classification of and greater understanding of the prevalence of protein motion. PMID- 23682203 TI - More IMPATIENT: A Gridding-Accelerated Toeplitz-based Strategy for Non-Cartesian High-Resolution 3D MRI on GPUs. AB - Several recent methods have been proposed to obtain significant speed-ups in MRI image reconstruction by leveraging the computational power of GPUs. Previously, we implemented a GPU-based image reconstruction technique called the Illinois Massively Parallel Acquisition Toolkit for Image reconstruction with ENhanced Throughput in MRI (IMPATIENT MRI) for reconstructing data collected along arbitrary 3D trajectories. In this paper, we improve IMPATIENT by removing computational bottlenecks by using a gridding approach to accelerate the computation of various data structures needed by the previous routine. Further, we enhance the routine with capabilities for off-resonance correction and multi sensor parallel imaging reconstruction. Through implementation of optimized gridding into our iterative reconstruction scheme, speed-ups of more than a factor of 200 are provided in the improved GPU implementation compared to the previous accelerated GPU code. PMID- 23682204 TI - A Guide for Health Professionals Working with Aboriginal Peoples: Executive Summary. AB - OBJECTIVE: to provide Canadian health professionals with a network of information and recommendations regarding Aboriginal health. OPTIONS: health professionals working with Aboriginal individuals and communities in the area of women's health care. OUTCOMES: improved health status of Aboriginal peoples in Canada. Appropriateness and accessibility of women's health services for Aboriginal peoples.Improved communication and clinical skills of health professionals in the area of Aboriginal health.Improved quality of relationship between health professionals and Aboriginal individuals and communities.Improved quality of relationship between health care professionals and Aboriginal individuals and communities. EVIDENCE: recommendations are based on expert opinion and a review of the literature. Published references were identified by a Medline search of all review articles, randomized clinical control trials, meta-analyses, and practice guidelines from 1966 to February 1999, using the MeSH headings "Indians, North American or Eskimos" and "Health." Subsequently published articles were brought to the attention of the authors in the process of writing and reviewing the document. Ancillary and unpublished references were recommended by members of the SOGC Aboriginal Health Issues Committee and the panel of expert reviewers. VALUES: information collected was reviewed by the principal author. The social, cultural, political, and historic context of Aboriginal peoples in Canada, systemic barriers regarding the publication of information by Aboriginal authors, the diversity of Aboriginal peoples in Canada, and the need for a culturally appropriate and balanced presentation were carefully considered in addition to more traditional scientific evaluation. The majority of information collected consisted of descriptive health and social information and such evaluation tools as the evidence guidelines of the Canadian Task Force on the Periodic Health exam were not appropriate. BENEFITS COSTS AND HARMS: utilization of the information and recommendations by Canadian health professionals will enhance understanding, communication, and clinical skills in the area of Aboriginal health. The resulting enhancement of collaborative relationships between Aboriginal peoples and their women's health providers may contribute to health services that are more appropriate, effective, efficient, and accessible for Aboriginal peoples in Canada. The educational process may require an initial investment of time from the health professional. RECOMMENDATIONS: Recommendations were grouped according to four themes: sociocultural context, health concerns, cross-cultural understanding, and Aboriginal health resources. Health professionals are encouraged to learn the appropriate names, demographics, and traditional geographic territories and language groups of the various Aboriginal groups in Canada. In addition, sensitivity to the impact of colonization and current socioeconomic challenges to the health status of Aboriginal peoples is warranted. Health services for Aboriginal peoples should take place as close to home as possible. Governmental obligations and policies regarding determination are recognized. With respect to health concerns, holistic definitions of health, based on Aboriginal perspectives, are put forward. Aboriginal peoples continue to experience a disproportionate burden of health problems. Health professionals are encouraged to become familiar with several key areas of morbidity and mortality. Relationships between Aboriginal peoples and their care providers need to be based on a foundation of mutual respect. Gaps and barriers in the current health care system for Aboriginal peoples are identified. Health professionals are encouraged to work with Aboriginal individuals and communities to address these gaps and barriers. Aboriginal peoples require culturally appropriate health care, including treatment in their own languages when possible. This may require interpreters or Aboriginal health advocates. Health professionals are encouraged to recognize the importance of family and community roles, and to respect traditional medicines and healers. Health professionals can develop their sensitivities towards Aboriginal peoples by participating in workshops, making use of educational resources, and by spending time with Aboriginal peoples in their communities. Aboriginal communities and health professionals are encouraged to support community-based, community-directed health services and health research for Aboriginal peoples. In addition, the education of more Aboriginal health professionals is essential. The need for a preventative approach to health programming in Aboriginal communities is stressed. VALIDATION: recommendations were reviewed and revised by the SOGC Aboriginal Health Issues Committee, a panel of expert reviewers, and the SOGC Council. In addition, this document was also reviewed and supported by the Assembly of First Nations, Canadian Institute of Child Health, Canadian Paediatric Society, College of Family Physicians of Canada, Congress of Aboriginal Peoples, Federation of Medical Women of Canada, Inuit Tapirisat of Canada, Metis National Council, National Indian and Inuit Community Health Representatives Organization, and Pauktuutit Inuit Women's Association. SPONSOR: Society of Obstetricians and Gynaecologists of Canada. PMID- 23682205 TI - A Guide for Health Professionals Working with Aboriginal Peoples: The Sociocultural Context of Aboriginal Peoples in Canada. PMID- 23682206 TI - Rigid Structure from Motion from a Blind Source Separation Perspective. AB - We present an information theoretic approach to define the problem of structure from motion (SfM) as a blind source separation one. Given that for almost all practical joint densities of shape points, the marginal densities are non Gaussian, we show how higher-order statistics can be used to provide improvements in shape estimates over the methods of factorization via Singular Value Decomposition (SVD), bundle adjustment and Bayesian approaches. Previous techniques have either explicitly or implicitly used only second-order statistics in models of shape or noise. A further advantage of viewing SfM as a blind source problem is that it easily allows for the inclusion of noise and shape models, resulting in Maximum Likelihood (ML) or Maximum a Posteriori (MAP) shape and motion estimates. A key result is that the blind source separation approach has the ability to recover the motion and shape matrices without the need to explicitly know the motion or shape pdf. We demonstrate that it suffices to know whether the pdf is sub-or super-Gaussian (i.e., semi-parametric estimation) and derive a simple formulation to determine this from the data. We provide extensive experimental results on synthetic and real tracked points in order to quantify the improvement obtained from this technique. PMID- 23682207 TI - A 13-bit Noise Shaping SAR-ADC with Dual-Polarity Digital Calibration. AB - We present a new noise shaping method and a dual polarity calibration technique suited for successive approximation register type analog to digital converters (SAR-ADC). Noise is pushed to higher frequencies with the noise shaping by adding a switched capacitor. The SAR capacitor array mismatch has been compensated by the dual-polarity digital calibration with minimum circuit overhead. A proof-of concept prototype SAR-ADC using the proposed techniques has been fabricated in a 0.5-MUm standard CMOS technology. It achieves 67.7 dB SNDR at 62.5 kHz sampling frequency, while consuming 38.3MUW power with 1.8 V supply. PMID- 23682208 TI - Using Consumer Input to Tailor Evidence-Based Parenting Interventions to the Needs of Grandparents. AB - Grandparents provide a significant amount of child care to their grandchildren. However, there is limited research investigating whether grandparents would view a parenting program developed specifically for them as useful. Our study adopted a consumer focused perspective to program design and examined the challenges encountered by grandparents in their role as an informal child care provider. Focus groups were conducted with fourteen grandparents (11 females, 3 males) aged 45-76 years (M = 60.14) the majority of whom provided 11-20 h of care per week to their grandchild. A thematic analysis indicated that grandparents have difficulty managing the relationship with the parents and remembering effective parenting strategies. In addition, grandparents also indicated wanting further strategies to cope with the stressors associated with the role, particularly surrounding feelings of frustration and guilt. These results suggest that grandparents could benefit from a parenting program and this paper argues that an existing evidence based parenting program should be modified. In terms of implications for program design the inclusion of a module centered on improving grandparent-parent communication and partner support may buffer potential conflict and tension that can arise in co-parenting situations. PMID- 23682209 TI - Epidemiological study of orthopedic injuries in hemodialysis patients in Taiwan: a fixed cohort survey, 2004-2008. AB - BACKGROUND: The burden of chronic kidney disease (CKD) is a growing concern worldwide. The prevalence of hemodialysis in Taiwan is the highest in the world, and this may increase the prevalence of orthopedic fractures. The aim of this study was to explore the incidences of various orthopedic injuries and the related risk factors. METHODS: A nationwide prospective study based on the Taiwan National Health Insurance dataset was conducted during 2004-2008. A total of 82,491 CKD patients were selected as the fixed cohort population. The International Classification of Diseases 9-CM diagnosis codes and treatment codes were identified as the inclusion criteria for orthopedic injury. RESULTS: A total of 82,491 Taiwanese people with CKD were identified in 2004, and 4915 orthopedic injuries occurred during the 5-year follow-up period. The cumulative incidences of orthopedic injuries were 42.560/00 for lower limb fractures, and 12.930/00, 3.270/00, and 1.640/00 for upper limb fractures, vertebrae fractures, and joint dislocations, respectively. All three types of orthopedic fractures were more common in the oldest age stratum (>=65 years old). In the CKD patients, the risk ratio of osteoporosis was 3.47 (95% confidence interval, 3.10-3.89) for all orthopedic injuries. Patients of advanced age, the female gender, and those with high comorbidity were also at significant risk of sustaining orthopedic fractures. CONCLUSION: The results from this Taiwanese CKD cohort support the strong influence of aging and osteoporosis on all kinds of orthopedic injuries. The postponing of osteoporosis may need to be taken into consideration for the prevention of orthopedic injury among CKD patients undergoing hemodialysis. PMID- 23682210 TI - Effects of regenerative radioelectric asymmetric conveyer treatment on human normal and osteoarthritic chondrocytes exposed to IL-1beta. A biochemical and morphological study. AB - PURPOSE: Osteoarthritis (OA) is a degenerative disease characterized by a progressive loss of articular cartilage extracellular matrix and is due to functional impairments occurring in chondrocytes. In previous works, we highlighted that Regenerative Tissue Optimization (TO-RGN) treatment with radioelectric asymmetric conveyer (REAC) technology influenced the gene expression profiles controlling stem cell differentiation and the pluripotency of human skin-derived fibroblasts in vitro. Since interleukin-1 beta signaling has been implicated in the induction and progression of this disease (through metalloproteinase-3 synthesis and nitric oxide production), we investigated whether REAC TO-RGN might influence the biochemical and morphological changes induced by interleukin-1 beta in normal and OA chondrocytes. METHODS: The induction of metalloproteinase-3 and proteoglycan synthesis was evaluated by a solid-phase enzyme-amplified sensitivity immunoassay, and nitric oxide production was evaluated with the Griess method. Ultrastructural features were observed by transmission electron microscopy. RESULTS: REAC TO-RGN treatment decreased nitric oxide and metalloproteinase-3 production in normal and OA chondrocytes, while inducing an increase in proteoglycan synthesis. OA chondrocytes were more affected by REAC TO-RGN treatment than were normal chondrocytes. Ultrastructural changes confirmed that REAC TO-RGN may counteract the negative effects of interleukin-1 beta incubation. CONCLUSION: The results of this in vitro study suggest that REAC TO-RGN treatment may represent a new, promising approach for the management of OA. PMID- 23682211 TI - Walking Stroop carpet: an innovative dual-task concept for detecting cognitive impairment. AB - BACKGROUND: Several studies have reported the potential value of the dual-task concept during locomotion in clinical evaluation because cognitive decline is strongly associated with gait abnormalities. However, current dual-task tests appear to be insufficient for early diagnosis of cognitive impairment. METHODS: Forty-nine subjects (young, old, with or without mild cognitive impairment) underwent cognitive evaluation (Mini-Mental State Examination, Frontal Assessment Battery, five-word test, Stroop, clock-drawing) and single-task locomotor evaluation on an electronic walkway. They were then dual-task-tested on the Walking Stroop carpet, which is an adaptation of the Stroop color-word task for locomotion. A cluster analysis, followed by an analysis of variance, was performed to assess gait parameters. RESULTS: Cluster analysis of gait parameters on the Walking Stroop carpet revealed an interaction between cognitive and functional abilities because it made it possible to distinguish dysexecutive cognitive fragility or decline with a sensitivity of 89% and a specificity of 94%. Locomotor abilities differed according to the group and dual-task conditions. Healthy subjects performed less well on dual-tasking under reading conditions than when they were asked to distinguish colors, whereas dysexecutive subjects had worse motor performances when they were required to dual task. CONCLUSION: The Walking Stroop carpet is a dual-task test that enables early detection of cognitive fragility that has not been revealed by traditional neuropsychological tests or single-task walking analysis. PMID- 23682212 TI - A longitudinal study of risk factors for community-based home help services in Alzheimer's disease: the influence of cholinesterase inhibitor therapy. AB - BACKGROUND: To investigate the long-term effects of cholinesterase inhibitor (ChEI) therapy and the influence of sociodemographic and clinical factors on the use of community-based home help services (HHS) by patients with Alzheimer's disease (AD). METHODS: This 3-year, prospective, multicenter study included 880 AD patients treated with donepezil, rivastigmine, or galantamine in a routine clinical setting. At baseline and every 6 months, the patients were assessed with several rating scales, including the Mini-Mental State Examination, Instrumental Activities of Daily Living (IADL), and Physical Self-Maintenance Scale. Doses of ChEI and amounts of HHS per week were recorded. Cox regression models were used to predict the time to HHS, and multiple linear regression was used to predict the volume of HHS used. RESULTS: During the study, 332 patients (38%) used HHS. Factors that both postponed HHS use and predicted lower amounts of HHS were higher doses of ChEIs, better IADL ability, and living with family. Men, younger individuals, and those with a slower IADL decline showed a longer time to HHS, whereas female sex, a lower cognitive status, or more medications at baseline predicted fewer hours of HHS. CONCLUSIONS: Higher doses of ChEI might reduce the use of HHS, possibly reducing the costs of community-based care. Female spouses provide more informal care than do male spouses, so the likelihood of using HHS is greater among women with AD. The "silent group" of more cognitively impaired and frail elderly AD patients receives less HHS, which might precipitate institutionalization. PMID- 23682213 TI - A comparison of cardiovascular risk factors for ten antipsychotic drugs in clinical practice. AB - It is well known that abdominal obesity, dyslipidemia, and insulin resistance are highly prevalent in patients receiving maintenance treatment with antipsychotics, but there is limited knowledge about the association between cardiovascular risk factors and treatment with antipsychotic drugs. In this naturalistic study we investigated a sample of 809 antipsychotic-treated patients from Swedish psychosis outpatient teams. Cardiovascular risk factors (eg, metabolic syndrome, homeostasis model assessment of insulin resistance, and low-density lipoprotein values) were measured, and their associations to current antipsychotic pharmacotherapy were studied. Ten antipsychotic drugs were compared in a stepwise logistic regression model. For the patients, the presence of the components of metabolic syndrome ranged from 35% for hyperglycemia to 64% for elevated waist circumference. Hypertriglyceridemia was associated with clozapine (odds ratio [OR] = 1.81, 95% confidence interval [CI] 1.08-3.04), reduced high-density lipoprotein with both clozapine and olanzapine (OR = 1.73, 95% CI 1.01-2.97; and OR = 2.03, 95% CI 1.32-3.13), hypertension with perphenazine (OR = 2.00, 95% CI 1.21-3.59), and hyperglycemia inversely with ziprasidone (OR = 0.21, 95% CI 0.05 0.89) and positively with haloperidol (OR = 2.02, 95% CI 1.18-3.48). There were no significant relationships between any of the antipsychotic drugs and increased waist circumference, homeostasis model assessment of insulin resistance, or low density lipoprotein levels. In conclusion, treatment with antipsychotic drugs is differentially associated with cardiovascular risk factors, even after adjusting for waist circumference, sex, age, and smoking. PMID- 23682214 TI - Differences between bipolar and unipolar depression on Rorschach testing. AB - BACKGROUND: The bipolar-unipolar distinction in patients with a major depressive episode is the most important issue related to the diagnosis and treatment of mood disorders, but remains unresolved. This study was undertaken to compare bipolar and unipolar depression on Rorschach testing using the Comprehensive System with reference to healthy Japanese controls. METHODS: Patients with bipolar or unipolar depression who had undergone the Rorschach test for routine clinical purposes were followed up naturalistically for a long period. Based on diagnostic confirmation after long-term follow-up, scores on this test for patients with bipolar and unipolar depression were compared with those published elsewhere for healthy Japanese controls. RESULTS: The bipolar depression group showed significantly higher scores or positive findings in five variables of the Rorschach test, ie, WSum6, DR2 > 0, (CF + C) > FC + 2, PureC > 1, and Populars > 7, as assessed using the Comprehensive System, than did the unipolar depression group and healthy controls. These scores did not differ between the unipolar depression and control groups. CONCLUSION: The results of this study show thought disorder or cognitive slippage and marked laxness in modulating emotion in bipolar depression, indicating the psychopathological characteristics of bipolar disorder. PMID- 23682216 TI - A HIERARCHICAL FUNCTIONAL DATA ANALYTIC APPROACH FOR ANALYZING PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS. AB - Ordinary differential equation (ODE) based models find application in a wide variety of biological and physiological phenomena. For instance, they arise in the description of gene regulatory networks, study of viral dynamics and other infectious diseases, etc. In the field of toxicology, they are used in physiologically based pharmacokinetic (PBPK) models for describing absorption, distribution, metabolism and excretion (ADME) of a chemical in-vivo. Knowledge about the model parameters is important for understanding the mechanism of action of a chemical and are often estimated using non-linear least squares methodology. However, there are several challenges associated with the usual methodology. Using functional data analytic methodology, in this article we develop a general framework for drawing inferences on parameters in models described by a system of differential equations. The proposed methodology takes into account variability between and within experimental units. The performance of the proposed methodology is evaluated using a simulation study and data obtained from a benzene inhalation study. We also describe a R-based software developed towards this purpose. PMID- 23682218 TI - Current status and standards for establishment of hemodialysis units in Korea. AB - The number of hemodialysis patients and dialysis facilities is increasing each year, but there are no surveillance programs validating that the services and equipment of each hemodialysis unit meet specified safety and quality standards. There is a concern that excessive competition and illegal activities committed by some dialysis facilities may violate patients' right to health. Contrastingly, developed countries often have their own survey program to provide initial certification and monitoring to ensure that these clinics continue to meet basic requirements. Because hemodialysis units provide renal replacement therapy to critical patients suffering from severe chronic renal failure, appropriate legal regulation is important for the provision of initial certification and maintenance of facility, equipment, and human resource quality. Therefore, several standards providing minimum requirements for the area of hemodialysis unit, equipment for emergency care, physician and nurse staffs, water purification and quality management are urgently needed. PMID- 23682217 TI - Diagnosis and therapy of multiple myeloma. AB - Many advances in the treatment of multiple myeloma have been made due to the use of transplantation and the introduction of novel agents including thalidomide, lenalidomide, and bortezomib. The first step is recognizing the symptoms and starting prompt treatment. Different strategies should be selected for young and elderly subjects. Young patients are commonly eligible for transplantation, which is now considered the standard approach for this setting, and various inductions therapies containing novel agents are available before transplantation. Elderly patients are usually not eligible for transplantation, and gentler approaches with new drugs combinations are used for their treatment. PMID- 23682219 TI - Procalcitonin as a biomarker of infectious diseases. AB - Traditional biomarkers, including C-reactive protein, leukocytes, erythrocyte sedimentation rate, and clinical signs and symptoms, are not sufficiently sensitive or specific enough to guide treatment decisions in infectious febrile diseases. Procalcitonin (PCT) is synthesized by a large number of tissues and organs in response to invasion by pathogenic bacteria, fungi, and some parasites. A growing body of evidence supports the use of PCT as a marker to improve the diagnosis of bacterial infections and to guide antibiotic therapy. Clinically, PCT levels may help guide the need for empirical antibiotic therapy, source control for infections, and duration of antibiotic therapy. The aim of this review is to summarize the current evidence for PCT in different infections and clinical settings, and to discuss the reliability of this marker in order to provide physicians with an overview of the potential for PCT to guide antibiotic therapy. PMID- 23682220 TI - Can the liver tell us about the heart? An old story revisited. PMID- 23682221 TI - beta-Cell dysfunction and insulin resistance in gestational glucose intolerance. PMID- 23682222 TI - Design of precise third-line therapy for gastric cancer: target or chemotherpy? PMID- 23682223 TI - Serum bilirubin as a prognostic marker in patients with acute decompensated heart failure. AB - BACKGROUND/AIMS: Several prognostic markers for heart failure (HF) have been determined but the importance of liver function tests (LFTs) remains unknown. The aim of this study was to determine the prognostic significance, if any, of abnormal LFTs in acute decompensated HF. METHODS: All adult patients (> 18 years of age) who were admitted to a community hospital with a diagnosis of acute decompensated HF during the period January 2008 to December 2009 were identified. Exclusion criteria included acute coronary syndrome, active hepatobiliary disease, renal failure (serum creatinine >= 2 mg/dL), and malignancy. The primary end point was readmission secondary to acute exacerbation of HF. The Cox proportional hazard model was used for statistical analyses. RESULTS: Univariate analysis showed that serum total bilirubin (TB, p < 0.01), serum B-type natriuretic peptide (p < 0.05), ejection fraction (EF, p < 0.05), and heart rate (p < 0.05) were significant predictors of hospital readmission secondary to acute decompensated HF. Multivariate analysis showed that high serum TB (> 1.3 mg/dL) on admission was an independent predictor (p < 0.05) of hospital readmission secondary to HF. The 'at-risk' group-patients with serum TB > 1.3 mg/dL and/or EF < 35% on admission-had a readmission rate that was 87% +/- 20% (p < 0.05) higher than those with neither criterion. CONCLUSIONS: In patients with acute decompensated HF, elevated serum TB on admission with or without low EF (< 35%) predicts a worse prognosis and early future readmission, secondary to HF. PMID- 23682224 TI - Insulin secretion and insulin resistance in Korean women with gestational diabetes mellitus and impaired glucose tolerance. AB - BACKGROUND/AIMS: The aim was to compare the insulin sensitivity and secretion index of pregnant Korean women with normal glucose tolerance (NGT), gestational impaired glucose tolerance (GIGT; only one abnormal value according to the Carpenter and Coustan criteria), and gestational diabetes mellitus (GDM). METHODS: A cross-sectional study was performed with 1,163 pregnant women with positive (1-hour plasma glucose >= 7.2 mmol/L) in a 50-g oral glucose challenge test (OGCT). The 100-g oral glucose tolerance test (OGTT) was used to stratify the participants into three groups: NGT (n = 588), GIGT (n = 294), and GDM (n = 281). RESULTS: The GDM group had higher homeostasis model assessment of insulin resistance and lower insulin sensitivity index (ISOGTT), quantitative insulin sensitivity check index, homeostasis model assessment for estimation of index beta-cell secretion (HOMA-B), first and second phase insulin secretion, and insulin secretion-sensitivity index (ISSI) than the NGT group (p <= 0.001 for all). Moreover, the GIGT group had lower ISOGTT, HOMA-B, first and second phase insulin secretion, and ISSI than the NGT group (p < 0.001 for all). Among the GIGT subjects, the 1-hour plasma glucose abnormal levels group showed significantly greater weight gain during pregnancy and higher values in the 50-g OGCT than the other two groups. Moreover, the 1-hour and 2-hour abnormal levels groups had poorer insulin secretion status than the 3-hour abnormal levels group. CONCLUSIONS: Korean women with GDM show impairments of both insulin secretion and insulin sensitivity. In addition, GIGT is associated with both beta-cell dysfunction and insulin resistance. PMID- 23682225 TI - Third-line docetaxel chemotherapy for recurrent and metastatic gastric cancer. AB - BACKGROUND/AIMS: To determine the efficacy and toxicity of docetaxel as a third line therapy for patients with relapsed gastric cancer who have undergone modified oxaliplatin-fluorouracil (m-FOLFOX)-4 and modified irinotecan fluorouracil (m-FOLFIRI) regimens. METHODS: We analyzed 33 patients who had been histologically diagnosed with adenocarcinoma of the stomach and who had progressed after m-FOLFOX-4 and m-FOLFIRI regimens. Patients were treated with cycles of 75 mg/m(2) docetaxel on day 1 every 3 weeks. RESULTS: The median age of the patients was 56.0 years (range, 31.0 to 74.0), and 73% of the patients (24/33) had an Eastern Cooperative Oncology Group performance status of 0 or 1. All patients were evaluated in terms of tumor response: five (15%), nine (27%), and 19 (58%) patients experienced a partial response, stable disease, and progressive disease, respectively. The median time to progression was 2.1 months (95% confidence interval [CI], 1.63 to 2.58), and overall survival was 4.7 months (95% CI, 3.20 to 6.20), from the start of the docetaxel regimen. Assessing patients' toxicity profiles, the median number of cycles was 2.0 (range, 1.0 to 12.0). The major hematologic toxicities included grade 3 to 4 neutropenia (19/33, 58%), grade 3 to 4 thrombocytopenia (2/33, 6%), and grade 3 to 4 anemia (5/33, 15%). Neutropenic fever developed in three patients (3/33, 9%). The nonhematological toxicities were nausea and vomiting (10/33, 30%), abdominal pain (4/33, 12%), skin rash (1/33, 3%), and fluid retention (3/33, 9%). CONCLUSIONS: Docetaxel is a feasible third-line therapy regimen for patients with advanced gastric cancer after m-FOLFIRI and m-FOLFOX-4 regimens. PMID- 23682226 TI - A comparison of the BISAP score and serum procalcitonin for predicting the severity of acute pancreatitis. AB - BACKGROUND/AIMS: The bedside index of severity in acute pancreatitis (BISAP) is a new, convenient, prognostic multifactorial scoring system. As more data are needed before clinical application, we compared BISAP, the serum procalcitonin (PCT), and other multifactorial scoring systems simultaneously. METHODS: Fifty consecutive acute pancreatitis patients were enrolled prospectively. Blood samples were obtained at admission and after 48 hours and imaging studies were performed within 48 hours of admission. The BISAP score was compared with the serum PCT, Ranson's score, and the acute physiology and chronic health examination (APACHE)-II, Glasgow, and Balthazar computed tomography severity index (BCTSI) scores. Acute pancreatitis was graded using the Atlanta criteria. The predictive accuracy of the scoring systems was measured using the area under the receiver-operating curve (AUC). RESULTS: The accuracy of BISAP (>= 2) at predicting severe acute pancreatitis was 84% and was superior to the serum PCT (>= 3.29 ng/mL, 76%) which was similar to the APACHE-II score. The best cutoff value of BISAP was 2 (AUC, 0.873; 95% confidence interval, 0.770 to 0.976; p < 0.001). In logistic regression analysis, BISAP had greater statistical significance than serum PCT. CONCLUSIONS: BISAP is more accurate for predicting the severity of acute pancreatitis than the serum PCT, APACHE-II, Glasgow, and BCTSI scores. PMID- 23682227 TI - Relationship between bronchial anthracofibrosis and endobronchial tuberculosis. AB - BACKGROUND/AIMS: Various pulmonary diseases may be associated with bronchial anthracofibrosis (BAF). Our aim was to identify a relationship between BAF and endobronchial tuberculosis (EBTB). METHODS: In total, 156 patients, diagnosed with EBTB using bronchoscopy, between June 1999 and May 2008, were included. Clinical and bronchoscopic findings between patients with BAF (n = 72, BAF group) and without BAF (n = 84, non-BAF) were analyzed retrospectively. RESULTS: The crude odds ratio (OR) of BAF for EBTB was 8.88 (95% confidence interval, 6.37 to 12.37). On multivariate analysis, adjusting for age, history of biomass smoke exposure, and comorbidities, the most significant independent factor for EBTB was a history of biomass smoke exposure (adjusted OR, 17.471; adjusted p < 0.001). EBTB was more frequent in the right lung, particularly the right middle lobar bronchus, in the BAF group. Actively caseating, edematous-hyperemic, and ulcerative were the major types, with 77 (49%), 33 (21%), and 31 cases (20%), respectively. The BAF group had more ulcerative type, while the non-BAF group had more actively caseating type. The duration of EBTB treatment was similar between the groups. No significant difference was observed in the development of complications during treatment and posttreatment bronchostenosis between the groups. CONCLUSIONS: These findings suggest that BAF may be a risk factor for EBTB and affect the location and morphological type at the time of EBTB development. PMID- 23682228 TI - Low glibenclamide concentrations affect endoplasmic reticulum stress in INS-1 cells under glucotoxic or glucolipotoxic conditions. AB - BACKGROUND/AIMS: beta-Cell apoptosis caused by increased endoplasmic reticulum (ER) stress is an important pathogenic component of type 2 diabetes mellitus. In theory, sulfonylureas, used for the treatment of diabetes, can contribute to ER stress. We assessed changes in ER stress in pancreatic beta-cells under glucotoxic or glucolipotoxic conditions using low concentrations of the sulfonylurea, glibenclamide (GB). METHODS: Low concentrations of GB (10 or 100 nM) were added to INS-1 cells cultured under glucotoxic or glucolipotoxic conditions. The degree of viability, level of apoptosis and levels of markers associated with ER stress were measured. RESULTS: Apoptosis decreased in response to low concentrations of GB under glucolipotoxic but not glucotoxic conditions. Most ER stress markers decreased upon the addition of GB. Under glucotoxic conditions, changes in the levels of ER stress markers were not consistent. However, all decreased significantly under glucolipotoxic conditions. CONCLUSIONS: Low concentrations of GB exerted antiapoptotic effects through the attenuation of ER stress under glucolipotoxic conditions. PMID- 23682229 TI - Clinical characteristics and outcomes in renal transplant recipients with renal cell carcinoma in the native kidney. AB - BACKGROUND/AIMS: We investigated the incidence and clinical characteristics of renal cell carcinoma (RCC) in the native kidney of renal transplant recipients. METHODS: Between 1991 and 2010, 1,425 patients underwent kidney transplantation at our institution. We retrospectively evaluated the clinical features and outcomes in renal transplant patients with RCC in the native kidney after renal transplantation. RESULTS: The patients included three males and two females with a mean age of 63 years (range, 52 to 74). The incidence of RCC was 0.35%. The median interval between renal transplantation and RCC occurrence was 16.2 years (range, 9 to 20). All of our patients with RCC had developed renal cysts either before (n = 3) or after (n = 2) renal transplantation. The mean duration of dialysis was 12 months (range, 2 to 39). Of the five patients, four underwent dialysis treatment for less than 8 months. All the RCCs were low grade at the time of diagnosis. Four patients underwent radical nephrectomy, and one patient refused the operation. The four patients who underwent radical nephrectomy showed no evidence of local recurrence or distant metastasis during the median follow-up of 2.9 years. However, the patient who did not undergo surgery developed spinal metastasis from the RCC 6 years later. CONCLUSIONS: This study suggests that the follow-up period is an important factor for the development of RCC in renal transplant recipients, and more vigorous screening with a longer follow-up period is required in renal transplant recipients. PMID- 23682230 TI - A case of hemophagocytic syndrome in a patient with fulminant ulcerative colitis superinfected by cytomegalovirus. AB - Hemophagocytic syndrome (HPS) is an uncommon hematological disorder that manifests as fever, splenomegaly, and jaundice, with hemophagocytosis in the bone marrow and other tissues pathologically. Secondary HPS is associated with malignancy and infection, especially viral infection. The prevalence of cytomegalovirus (CMV) infection in ulcerative colitis (UC) patients is approximately 16%. Nevertheless, HPS in UC superinfected by CMV is very rare. A 52-year-old female visited the hospital complaining of abdominal pain and hematochezia for 6 days. She was diagnosed with UC 3 years earlier and had been treated with sulfasalazine, but had stopped her medication 4 months earlier. On admission, her spleen was enlarged. The peripheral blood count revealed pancytopenia and bone marrow aspiration smears showed hemophagocytosis. Viral studies revealed CMV infection. She was treated successfully with ganciclovir. We report this case with a review of the related literature. PMID- 23682231 TI - Synephrine-containing dietary supplement precipitating apical ballooning syndrome in a young female. AB - Apical ballooning syndrome (ABS) is a unique reversible cardiomyopathy that is frequently precipitated by emotional or physical stress. In addition, the few drugs reported to precipitate ABS were either illegal or strictly controlled for medical use. This paper reports a case of ABS precipitated by a dietary supplement. Our case accentuates the potential risk of dietary supplements containing synephrine, which is uncontrolled and available to the general public. Therefore, the Korea Food and Drug Administration should regulate these dietary supplements, and warn healthcare workers and the general public of the potential hazards of the indiscriminate abuse of dietary supplements. PMID- 23682232 TI - A case of mediastinal ectopic thyroid presenting with a paratracheal mass. AB - Mediastinal ectopic thyroid is a very rare condition, with few reported cases in the literature and no reported cases in Korea. This report describes an asymptomatic 65-year-old man with a right paratracheal mass compressing the superior vena. Additionally, the epidemiology, clinical manifestation, diagnosis, and management of mediastinal ectopic thyroids are discussed. A mediastinal ectopic thyroid should be considered in the differential diagnosis of all mediastinal masses. Surgical excision is recommended for both the diagnosis and treatment of this condition, because of its potential for malignancy and compression of mediastinal structures. This case demonstrates the clinical importance of mediastinal etopic thyroid. PMID- 23682233 TI - A case of ruptured renal cortical arteriovenous malformation of the right testicular vein in hemorrhagic fever with renal syndrome. AB - Hemorrhagic fever with renal syndrome (HFRS) is an acute viral disease characterized by fever, hemorrhage, and renal failure. Among the various hemorrhagic complications of HFRS, the spontaneous rupture of an arteriovenous malformation of the testicular vessels with a retroperitoneal hematoma is a rare finding. Here, we report a case of HFRS complicated by a massive retroperitoneal hematoma that was treated with transcatheter arterial embolization. PMID- 23682234 TI - Spontaneous coronary artery dissection diagnosed by intravascular ultrasound and followed up by cardiac computed tomography. PMID- 23682235 TI - The renoprotective effects of pentoxifylline: beyond its role in diabetic nephropathy. PMID- 23682236 TI - Successful treatment of recurrent follicular B-cell lymphoma with clarithromycin, prednisolone, and cyclophosphamide. PMID- 23682237 TI - A case of polymyositis associated with Hashimoto's thyroiditis. PMID- 23682238 TI - A duodenal lipoma with a long stalk. PMID- 23682239 TI - Hemorrhagic cholecystitis presenting as obstructive jaundice. PMID- 23682241 TI - Emergency Department Screening for Adolescent Mental Health Disorders: The Who, What, When, Where, Why and How It Could and Should Be Done. AB - Mental health problems are a significant cause of morbidity and mortality among pediatric populations. Screening for these problems can result in earlier identification and increase treatment and improve outcomes for these children and adolescents. The emergency department (ED) is an ideal site for such screening. Pediatric ED patients are known to be at higher risk for mental health problems. For many, an ED visit is one of the few opportunities to identify and intervene with these children and adolescents. A number of brief, efficient screening instruments have been developed for the ED setting. Screening for mental health problems is both feasible and acceptable to ED patients, parents, and caregivers. PMID- 23682243 TI - Fragment-based Quantum Mechanical/Molecular Mechanical Simulations of Thermodynamic and Kinetic Process of the Ru2+-Ru3+ Self-Exchange Electron Transfer. AB - A fragment-based fractional number of electron (FNE) approach, is developed to study entire electron transfer (ET) processes from the electron donor region to the acceptor region in condensed phase. Both regions are described by the density fragment interaction (DFI) method while FNE as an efficient ET order parameter is applied to simulate the electron transfer process. In association with the QM/MM energy expression, the DFI-FNE method is demonstrated to describe ET processes robustly with the Ru2+-Ru3+ self-exchange ET as a proof-of-concept example. This method allows for systematic calculations of redox free energies, reorganization energies, and electronic couplings, and the absolute ET rate constants within the Marcus regime. PMID- 23682244 TI - A Guide for Health Professionals Working with Aboriginal Peoples: Aboriginal Health Resources. PMID- 23682242 TI - Primary Sclerosing Cholangitis: Current and Future Management Strategies. AB - Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease. The etiology of this disorder is unknown and there are no effective medical therapies. PSC is associated with inflammatory bowel disease and an increased risk for hepatobiliary and colorectal malignancies. The aim of this review is to highlight the clinical features and diagnostic approach to patients with suspected PSC, characterize associated comorbidities, review screening strategies for PSC associated malignancies and review contemporary and future therapies. PMID- 23682245 TI - Undiagnosed Bipolar Disorders in Patients with Major Depressive Episode: Iran's part of a Multicenter Cross-Sectional Study. AB - OBJECTIVE: Bipolar spectrum disorders may often go undiagnosed or unrecognized. The aim of this study was to determine the proportion of bipolar disorder symptoms in Iranian patients with a major depressive episode. METHODS: 313 patients with a current DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders 4th ed. Text rev.) diagnosed with a major depressive episode entered this cross-sectional study. Thirty two items revised Hypomania/ mania Symptoms Checklist (HCL-32) was used to determine the frequency of bipolar episodes. RESULTS: Considerable proportion of patients (53.9%) previously diagnosed as major depressive disorder fulfilled the criteria for bipolar disorder by Bipolarity Specifier. The Bipolarity Specifier additionally identified significant association for manic / hypomanic states during antidepressants therapy (p<0.0003) and current mixed mood symptoms (p<0.0001). CONCLUSION: Bipolar symptoms meeting the criteria for bipolar disorders in depressed patients who have not been previously diagnosed with bipolar disorder are frequent. Current DSM criteria may not be sufficient to diagnose more subtle or atypical forms of bipolar disorders. PMID- 23682246 TI - Effects of Chronic Illness on the Quality of Life in Psychiatric out patients of the Iraq - Iran War. AB - OBJECTIVE: Quality of life measures can provide an important source of medical information for promoting the health status of chronically ill patients. The purpose of the present study was to evaluate health related quality of life in psychiatric veterans of the Iraq- Iran war of the 1980s. METHODS: They were out patients diagnosed with various psychiatric symptoms. The present study used a cross sectional design, in which 971 psychiatric veterans were selected by Systematic-randomized sampling and evaluated using the SF36 questionnaire. RESULTS: Findings revealed that veterans who suffered from one or more chronic conditions/illnesses reported significantly more bodily pain and significantly less vitality, mental and general health compared to those veterans without chronic conditions. Moreover, specific aspects of poor quality of life were more salient in specific chronic conditions/illnesses than others. CONCLUSION: Based on these findings, chronic conditions, especially respiratory problems, can have a detrimental effect on the quality of life in psychiatric war veterans. PMID- 23682247 TI - Feigned symptoms among defendants claiming psychiatric problems: Survey of 45 Malingerers. AB - OBJECTIVE: In many jurisdictions, psychiatric problems are intended for commutation. Therefore, a forensic psychiatrist has an important role in detection of malingering. While several studies evaluate diagnostic tests, it is less known what symptoms are more likely to be imitated by malingerers. METHOD: In a prospective study 45 malingerers, who were diagnosed according to interviews by two forensic psychiatrists, from defendants with a judicial order for evaluation of mental status and criminal responsibility during a period of eighteen months were examined in legal medicine center of Tehran. Participants were assessed in another interview to determine symptoms. Dichotomous symptoms in felony and misdemeanor groups were analyzed using fisher's exact test. The level of statistical significance was set at P < 0.05. RESULTS: Thirty-eight malingerers were charged with misdemeanors and seven with felonies. Behavioral symptoms were most frequently faked by 35 participants (77.8%). Participants charged with criminal accusation had a significantly lower mean age (P=0.032) and a higher level of education (P=0.008) than other non-criminal defendants. A statistically significant increase in memory function problems was demonstrated in the misdemeanor group (P=0.040). With regard to dual symptom imitation, statistically significant correlations were observed between thought content and perceptual symptoms (P=0.048) for felonies and mood & affect and thought process symptoms (P=0.034), mood & affect and behavioral symptoms (P=0.000) and cognitive function and behavioral symptoms (P=0.039) for misdemeanors. In general, many simulators attempted to mimic simple symptoms of behavioral disorders. Probably felony offenses need less accurate programming; therefore, their rates are higher in older, less educated participants. CONCLUSION: This study demonstrated that differences between presenting symptoms among different offenses may not be useful in detection of malingering,; however, unusual dual symptom imitations may be useful, particularly when standard tests are not performed. PMID- 23682248 TI - Job Burnout among Iranian Elementary School Teachers of Students with Autism: a Comparative Study. AB - OBJECTIVE: Teachers often experience burnout and challenges during their active career. Different studies have shown that those directly involved with teaching children with special needs are more subject to burnout. Due to advance screening tools, more children with autism are now diagnosed and involved in special education. The aim of the present study was to investigate the professional burnout in teachers of children with autism compared to teachers of other children with special needs. METHODS: Casual Comparative study design was used for this research. Three self-reported measures (Maslach Burnout Inventory, Job Descriptive Index, and General Health Questionnaire) were distributed; clustered sampling selection was conducted to select participants. Ninety three female teachers (32 teachers of children with autism, 30 teachers in schools for deaf and 31 for teachers of children with mental retardation) from 12 schools located in 4 districts of Tehran were selected. Pearson's and Spearman's correlation statistical tests, analysis of variances and regression were used to analyze the results. RESULTS: Results of the current study revealed a significant difference in criterion validity between the three groups of teachers The three groups were different in terms of general health (p=0.010), emotional exhaustion (p=0.005) and depersonalization (p<0.001); however considering other variables no significant differences were observed. Comparison between groups showed that the average scores of teachers of children with autism were significantly higher than teachers of deaf and hard of hearing and mentally retarded children in general health, fatigue, and depersonalization variables. No significant differences were observed in average scores of teachers for mentally retarded and deaf children. CONCLUSIONS: Female teachers' of children with autism are experiencing significantly higher levels of burnout and general mental health problems compared to teachers of children with other disabilities requiring special education. PMID- 23682249 TI - Psychometric properties of the adolescent health concern inventory: the persian version. AB - OBJECTIVE: It is important to consider the health concerns of adolescents before developing and implementing public health promotion or health education curriculum programs aimed at ameliorating priority health problems experienced by adolescents. The aim of this study was to test the psychometric properties of the original Adolescent Health Concern Inventory (AHCI) for use with an Iranian population. METHODS: This was a methodological study in which 50 adolescents with age range of 14-18 years were selected using convenience sampling. The translation and cultural adaptation process of The AHCI followed recognized and established guidelines. The face and content validity was established by analyzing feedback solicited from teenagers and professionals with expertise in health, sociology and psychology. Reliability was examined using test-retest and Cronbach's alpha for internal consistency reliability. Kappa and McNemar tests were used to examine test-retest reliability for each item. RESULTS: Minor cultural differences were identified and resolved during the translation process and determining the validity of the checklist. Results from Kappa and McNemar tests indicate a high degree of test-retest reliability. Internal consistency reliability as measured by Cronbach's alpha for the subscales were between 0.68 and 0.87 with total instrument reliability of 0.96 indicating considerable overall reliability. CONCLUSION: The Persian version of the AHCI appears valid and reliable. Hence, it can be used for filling a gap in identifying the adolescents' health concerns in the research and community settings and school health education programs in Iran to design appropriate interventions. PMID- 23682250 TI - Iranian medical students' perception of psychiatry: before and after a psychiatry clerkship. AB - OBJECTIVE: We aimed to compare the medical students' attitude towards psychiatry before and after psychiatry clerkship, and to examine the association of choosing psychiatry as a future career with some personal characteristics. METHOD: In a self-controlled, quasi-experimental study, all of the medical students entering the psychiatry clerkship in three major medical schools of Iran located in Tehran (Tehran, Shahid Beheshti, and Iran University of Medical Sciences) were asked to participate anonymously in the study on the first and the last 3-days of their psychiatry clerkship. From 346 invited 4th-5th year medical students, 225 (65%) completed anonymous self-report questionnaires before and after a 4-week psychiatry clerkship. RESULTS: Positive response to choose psychiatry as a career was seen in 13.3% and 18.3% before and after psychiatry rotation, respectively. However, the difference was not statistically significant; about one-quarter of the students were turned on to psychiatry and 25% were discouraged during the clerkship. Individual pair wise comparisons revealed significant improvements only in two out of 13 measured aspects of psychiatry. Seventeen out of 38 (47.7%) students who identified psychiatry as the career of choice or strong possibility reported that one of their family members or close friends' mental illness had an impact on their choice. Those students who considered psychiatry as the strong possibility claimed that they are more interested in humanities (OR = 2.96; 95% CI: 1.17, 7.49), and playing a musical instrument (OR = 2.53; 95% CI: 1.15, 5.57). CONCLUSION: It may be concluded that exposure to psychiatry clerkship could influence medical students' opinion about psychiatry positively, or negatively. Personal characteristics and individual interests of students may play an important role in choosing psychiatry as their future career. PMID- 23682252 TI - Frequency of latent and smear positive tuberculosis in chronic psychotic disorders. AB - OBJECTIVE: Screening is one of the ways to combat Tuberculosis (TB) and should be mostly concentrated on groups showing some symptoms of the disease. Tuberculosis can be transferred from person to person in laboratories, prisons and psychiatry hospitals. The purpose of this study was to survey pulmonary TB in patients with schizophrenia in Rasht. METHODS: In this descriptive-cross sectional, Two hundred fifty seven consecutive patients with chronic psychotic disorder hospitalized in psychotic hospitals underwent purified protein derivative (PPD) test. PPD test was done with the unit 5T which was injected subcutaneously on anterior surface and at the top of left forearm. The results of the test were interpreted by the pen technique method and based on transverse diameter of induration of about 48 72 hrs. Induration size due to hypersensitivity to PPD more than 10mm was considered positive. Patients with positive PPD test underwent complementary sputum smear. Data were analyzed using chi- square and T test. RESULTS: The mean age of patients was 45+/-10 years; 75.5% were male, 74.7% were single, 10.5% married, 7.8% divorced, and 68.1% were smokers. These patients suffered from chronic psychotic disorder at the mean time of 15+/-7.9 years. In 74 patients (28%) positive PPD test were recorded, but active pulmonary TB was not found in complementary experiments of PPD sample. Based on data analysis, only age and gender showed a significant relationship with the results of the PPD test (P < 0.05). CONCLUSIONS: This study showed that patients with positive PPD test are much more than the normal population, but active pulmonary TB was not observed in our samples. Since these patients are in clinical and closed places, more programs for screening are required. PMID- 23682251 TI - Reality Testing in Children with Childhood-Onset Schizophrenia and Normal Children: A Comparison using the Ego Impairment Index on the Rorschach. AB - OBJECTIVE: The aim of this study was to examine reality testing in schizophrenic children and compare it with normal children using minus responses subcomponent in ego impairment index of the Rorschach test. METHODS: In a descriptive design, 20 accidentally sampled children, including 10 schizophrenic and 10 normal children, were recruited in to two groups and were compared in terms of reality testing subcomponent of Ego Impairment Index (EII). After initial interview, the Rorschach inkblot test was administered on the two groups, and Distorted Quality responses (FQ-) were calculated. The results were then analyzed by independent t test and Cohen's d for effect size. RESULTS: The result of independent t-test revealed that the mean of minus responses in schizophrenic children was significantly higher than that of normal children. In addition, the usefulness of the Rorschach ego impairment index (EII) in evaluating reality testing in schizophrenic children was confirmed. In addition, it was found that defect in reality testing is one of the prominent characteristics of schizophrenic children. CONCLUSION: The higher minus responses in schizophrenic children indicate that schizophrenic children have weaker functioning in reality testing compared with normal children. PMID- 23682253 TI - Verbal Fluency Performance in Patients with Non-demented Parkinson's Disease. AB - OBJECTIVE: While Parkinson's disease (PD) has traditionally been defined by motor symptoms, many researches have indicated that mild cognitive impairment is common in non-demented PD patients. The purpose of this study was to compare verbal fluency performance in non-demented Parkinson's disease patients with healthy controls. METHOD: In this cross-sectional study thirty non-demented Parkinson's disease patients and 30 healthy controls, matched by age, gender and education, were compared on verbal fluency performance. Verbal fluency was studied with a Phonemic Fluency task using the letters F, A, and S, a semantic fluency task using the categories animals and fruits. The independent t-test was used for data analysis. RESULTS: Overall, participants generated more words in the semantic fluency task than in the phonemic fluency task. Results revealed significant differences between patients and controls in semantic fluency task (p<.05). In addition, PD patients showed a significant reduction of correctly generated words in letter fluency task. The total number of words produced was also significantly lower in the PD group (p<.05). CONCLUSION: Verbal fluency disruption is implied in non-demented PD patients in association with incipient cognitive impairment. PMID- 23682254 TI - Delirium associated with donepezil in a patient with Alzheimer's disease: a case report. AB - Donepezil, a member of the acetylcholinesterase inhibitor family, is approved for management of cognitive impairments as well as behavioral complications in patients with neurodegenerative Alzheimer's disease. Generally, donepezil is regarded as a safe medication in patients with Alzheimer's disease although there have been reports of several minor adverse events including gastrointestinal disturbances. Herein we describe a patient with Alzheimer's disease who demonstrated delirious behavior upon treatment with donepezil. PMID- 23682256 TI - Anthelmintics Resistance; How to Overcome it? AB - Many parasitic helminthes of veterinary importance have genetic features that favor development of anthelmintic resistance, this becoming a major worldwide constrain in livestock production. The development of anthelmintic resistance poses a large threat to future production and welfare of grazing animals. Development of variable degrees of resistance among different species of gastrointestinal nematodes has been reported for all the major groups of anthelmintic drugs. It has been observed that frequent usage of the same group of anthelmintic; use of anthelmintics in sub-optimal doses, prophylactic mass treatment of domestic animals and frequent and continuous use of a single drug have contributed to the widespread development of anthelmintic resistance in helminthes. The degree and extent of this problem especially with respect to multidrug resistance in nematode populations is likely to increase. Maintaining parasites in refugia and not exposed to anthelmintics, seems to be a key point in controlling and delaying the development of resistance, because the susceptible genes are preserved. Targeted selective treatments attract the interest of scientists towards this direction. Additionally, adoption of strict quarantine measures and a combination drug strategy are two important methods of preventing of anthelmintic resistance. Experience from the development of anthelmintic resistance suggests that modern control schemes should not rely on sole use of anthelmintics, but employ other, more complex and sustainable recipes, including parasite resistant breeds, nutrition, pasture management, nematode-trapping fungi, antiparasitic vaccines and botanical dewormers. Most of them reduce reliance on the use of chemicals and are environmental friendly. Finally, if new anthelmintic products are released, an important question will be raised about how they should be used. It is suggested that slowing the development of resistance to a new class are likely to be gained by releasing it in combination with one or more of the older anthelmintic classes, especially where efficacy of the older active(s) remains high. PMID- 23682255 TI - Efficacy of Pyrimethamine/Sulfadoxine versus Chloroquine for the Treatment of Uncomplicated Falciparum Malaria in Children Aged Under 5 Years. AB - The children aged under 5 years from vast African areas badly suffer from falciparum malaria and many of them die of this disease. Therapeutic efficacy of anti-malaria drugs, especially pyrimethamine-sulfadoxine (PS) and chloroquine (CQ) to falciparum malaria is frequently evaluated and reported in recent 10 years. Unfortunately, to date, these widespread materials and researches have not been systematically collected and analyzed. In our study, two investigators were employed to widely and independently gather researches on efficacy of PS vs. CQ mono-therapy of falciparum malaria in children aged below 5 years in unpublished and published databases. Meta-analyses were conducted in categories of PS group and CQ group respectively. Pooled OR of PS vs. CQ was 0.11 (95%CI, 0.05-0.24). PS showed higher therapeutic efficacy to falciparum malaria in less-than-5-year children than CQ. Random model was chosen to analyze for the heterogeneity existence between different studies. Subgroup analyses were performed, but heterogeneity was still presented. Heterogeneity might be caused by different resistance of falciparum malaria to PS and CQ in different settings. Malaria type associated with parasite species, basic information of PS and CQ, and PS & CQ resistant malaria control measures were demonstrated and discussed respectively in detail in this article. PMID- 23682257 TI - Ficolin-A Enhances Inhibition of the C-Terminal 19 kDa Region of Merozoite Surface Protein-1 of Plasmodium berghei Using Test In Vivo. AB - BACKGROUND: Malaria remains a serious public health problem with significant morbidity and mortality. This study was conducted to identify whether ficolin-A could play an active role of against malaria infection. METHODS: The function of ficolin-A was analyzed in mouse model. The open reading frame of ficolin-A was cloned from the liver of new born C57BL/6 mice by RT-PCR and then inserted into the expression vector of eukaryon to construct pVAX1-ficolin-A plasmid. Meanwhile, the open reading frame of the 19-kDa fragment of merozoite surface protein-1 of Plasmodium berghei (MSP119) was cloned and then the expression vector of eukaryon, pVAX1- MSP119 was constructed. Both recombinant vectors were used in the mouse model of infection by Plasmodium berghei. RESULTS: pVAX1 ficolin-A alone could not significantly suppress parasite density and prolong survival time of infection mice; however, when injected pVAX1-ficolin-A and pVAX1 MSP119 together, the percent of invasion by Plasmodium was decreased (from 43.78% to 22.23% at 10 day after infection, compared to vector) and the survival time was prolonged significantly in the infection mouse model (P=0.01). CONCLUSION: Ficolin-A can enhance the immunoprotection of MSP119, it implies ficolin-A may be used as immunoenhancer in the study of vaccine defending malaria. PMID- 23682258 TI - Brain Tissue Cysts in Infected Mice with RH-Strain of Toxoplasma gondii and Evaluation of BAG1 and SAG1 Genes Expression. AB - BACKGROUND: Toxoplasma gondii is an obligate intracellular parasite that infects humans at high prevalence rates. The virulent RH strain of T. gondii is generally considered to have lost its cyst forming capacity. This study performed to obtain tissue cysts in mice infected with tachyzoites of RH strain treated with sulfadiazine (SDZ). It provides the opportunity to analyze the conversion of tachyzoite to bradyzoite stage of the RH strain, followed by stage-specific gene expression analyzing. METHODS: Two groups of Swiss-Webster and BALB/c mice were infected subcutaneously with 10(4) tachyzoites of T. gondii, RH strain and given SDZ (300 mg/l) with NaHCO3 (5 g(-1)) in drinking water from day1 to day 14 post infection (p.i). The infected mice were sacrificed on day 50 post infection. Their brains were removed and the numbers of tissue cysts were microscopically counted. Total RNA was extracted from brains and cDNA synthesis was carried out. Finally, RT-PCR (Reverse transcription PCR) was used to detect the expression of bradyzoite (BAG1) and tachyzoite (SAG1) specific genes during tachyzoite / bradyzoite stage conversion. RESULTS: Sixty five percent of all infected mice were survived. Cysts were detectable in mice brain (45%) on day 50 p.i. Also RT PCR of the brain samples was positive for SAG1 and BAG1. CONCLUSION: It seems that conversion of tachyzoites to bradyzoites in brain of mice undergoing SDZ was not completed until 50 days after inoculation. PMID- 23682259 TI - Genotyping of Hydatid Cyst Isolated from Human and Domestic Animals in Ilam Province, Western Iran Using PCR-RFLP. AB - BACKGROUND: Hydatidosis or cystic hydatid disease is one of the most important diseases in human and animals. Identification of strains is important for improvement of control and prevention of disease. The aim of this study was to determine the strains isolated from human and domestic animals in Ilam Province, Iran, using PCR-RFLP method. METHODS: Respectively, 30 and 4 animal and human hydatid cysts were collected from different slaughterhouses and hospitals of the province. Protoscolices were separated and their DNA genome was extracted by extraction kit. rDNA-ITS1 of each isolated samples was duplicated by BD1(Forward) and 4s (Reverse) Primers. PCR products were studied by electrophoresis and then were digested using TaqI, HpaII, RsaI and AluI restriction enzymes. RFLP products were studied using electrophoresis on 1% agar gel. RESULT: A fragment of 1000bp was produced from amplification of rDNA-ITS1 of protoscolices using PCR method. After digestion of PCR product by AluI enzyme, 200bp and 800bp, by RsaI, 655bp and 345bp and by HpaII 700bp and 300bp sizes were obtained. TaqI enzyme had no change in fragment size and it remained 1000bp. Considering the method, Ilam strains was specified as E. granulosus sensu stricto (G1-G3). CONCLUSIONS: Although sheep strain (G1) is dominated in human and different animal in Iran and the world, but more efforts should be done to clarify the true genotype of Ilam strains specified as E. granulosus sensu stricto (G1-G3). PMID- 23682260 TI - Microscopy and serological assessment for heartworm infection in cats in makati, Philippines showing clinical signs of dirofilariosis. AB - BACKGROUND: The sole published data on feline heartworm infection in the Philippines was reported four decades ago. The study therefore endeavoured to assess and provide an update on the current status of heartworm infection in domesticated feline species using serologic and parasitological examination methods. METHODS: A total of 46 males and 54 females cats showing clinical signs of dirofilariosis from Makati City, Philippines were subjected to two antigen based test kits and a microfilaria concentration method. RESULTS: The most commonly observed clinical sign was coughing while exercise intolerance was seldom seen. Age groups ranging from 1 to 4 years old exhibited majority of the clinical signs whereas the 8.1 to 12 years category had the least. The results from the different detection methods employed revealed that none of the animals were positive for circulating microfilaria and no detectable levels of heartworm antigens were obtained. CONCLUSION: The presence of associated clinical signs is not an outright indicator of feline dirofilariosis and may be indicative of the rarity of heartworm infection in cats in Makati, Philippines. PMID- 23682261 TI - Double-Stranded RNA Viral Infection in Tehran Trichomonas vaginalis Isolates. AB - BACKGROUND: Trichomonas vaginalis is a pathogenic protozoon and may be contaminated with dsRNA virus called Trichomonas vaginalis virus (TVV). The viral infection is an important factor for its pathogenesis and sensitivity to metronidazole. The presence of TVV is associated with qualitative and quantitative expression of cysteine proteinases and surface immunogenic; P270. The purpose of this study was to determine TVV frequency in T. vaginalis clinical isolates in Tehran, Iran. METHODS: The 46 T. vaginalis isolates were collected from Tehran Province and cultured in TYI-S-33 culture medium. Viral RNA was extracted and RT-PCR was done. RESULTS: Of 46 T. vaginalis isolates, 8 isolates (17.39%) were infected with TVV-1. There was not any association between patient age and TVV- infected T. vaginalis. There were 17.39% viral infection in T. vaginalis isolates which was lower than that reported by other researchers. CONCLUSION: This is the first report on T. vaginalis isolates infection by TVV-1 in Iran. PMID- 23682262 TI - Potential Use of Biomphalaria alexandrina Snail Antigens for Serodiagnosis of Schistosomiasis Mansoni by Immunoblot Analysis. AB - BACKGROUND: The aim of this study was to evaluate the possible use of Biomphalaria alexandrina snail antigens in diagnosis of schistosomiasis mansoni using enzyme linked immunolectrotransfere blot (EITB). METHODS: S. mansoni adult worm crude antigens (AWA), feet and visceral humps of B. alexandrina and Bulinus truncatus were used. Hyperimmune mice sera (HIS) versus each antigen were prepared for diagnosis of S. mansoni using western blot (WB). RESULTS: Snail foot antigens were more specific in antibodies detection than visceral hump antigens. Three of five polypeptides of B. alexandrina foot antigen identified by S. mansoni HIS showed specific positive reactivity. These polypeptides were at MW of 31/32 and 43 kDa. While, only one of the six polypeptides of B. alexandrina hepatopancrease antigen identified by S. mansoni HIS, at a MW of 43 kDa was specific. Similarly, 2 polypeptides at MW of 44 and 55 kDa were specific in detection of anti- S. haematobium antibodies. However, the antigenically active polypeptide of B. truncatus hepatopancrease antigen had no specific reactivity towards anti-S. haematobium antibodies. CONCLUSION: B. alexandrina foot antigens were the most specific of the tested snail antigens in diagnosis of schistosomiasis mansoni. PMID- 23682263 TI - The Ultrastructural Effects of Sulfachloropyrazine on Toxoplasma gondii Tachyzoites. AB - BACKGROUND: Toxoplasmosis is one of the most common parasitic infections of humans and other mammals. This study was aimed to understand the mechanism of action of veterinary medicine-sulfachloropyrazine (SPZ, 99.97%) against Toxoplasma gondii. METHODS: T. gondii tachyzoites were soaked in PBS (as a control) or SPZ (250 mg/mL) for 2 h at 37 degrees C. After being processed, any ultrastructural changes of the tachyzoites that had occurred were observed by Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM). RESULTS: The tachyzoites from control groups with a uniform size had a smooth surface and intact cell or nuclear membranes. In addition, an oval-shaped nucleus, conoids and micronemes were also observed. By contrast, many parasites from the SPZ-treated groups were detrimentally affected by the treatment. Some appeared to be of the vacuolization in their cytoplasm, with the substantial reduction in the number of dense granules and the blur of some organelles. CONCLUSION: The morphology and ultrastructure of tachyzoites can be affected significantly by SPZ, which might kill the parasite by inhibiting its energy metabolism, inducing apoptosis and damaging its structure. The study provides an experimental basis for further study on the mechanism of SPZ against T. gondii. PMID- 23682264 TI - Helminth Parasites of Rhombomys opimus from Golestan Province, Northeast Iran. AB - BACKGROUND: The aim of the study was to determine the helminthic species occurring in great gerbil Rhombomys opimus collected from Maraveh Tappeh, Golestan Province, northeast Iran. METHODS: During 2010-2011, a total of 77 R. opimus were captured from rural areas of Maraveh Tappeh, Golestan Province, using Sherman live traps and examined for infectivity with any larva or adult stages of helminthic parasites. RESULTS: Overall, 63 R. opimus (81.8%) were found infected with different helminthic species. The rate of infectivity with each species was as follows: Trichuris rhombomidis 31.2%, Trichuris muris 32.5%, Trichuris spp. 10.4%, Syphacia muris 2.6%, Dipetalonema viteae (Acanthocheilonema viteae) 37.7%, Skrjabinotaenia lobata 15.6%, Hymenolepis (=Rodentolepis) nana fraterna 5.2%, and Taenia endothoracicus larva 1.3%. CONCLUSION: R. opimus is host for several species of cestodes and nematodes in the study area. The high rate of infectivity with D. viteae indicates the susceptibility of these gerbils to this filarial nematode. Synchronous infections occurred up to four species of helminthes in one host. PMID- 23682265 TI - Geographical distribution of leishmania species of human cutaneous leishmaniasis in fars province, southern iran. AB - BACKGROUND: The goal of this study was to know the identity of Leishmania species responsible of cutaneous leishmaniasis (CL) in Fars Province, southern Iran. METHODS: Five counties of Shiraz, Firouz Abad, Ghir-Karzin, Farashband and Larestan were prospected. Forty-four patients exhibiting cutaneous lesions were selected. Samples collected on skin lesions were examined both microscopically (after Giemsa staining) and molecularly (after PCR-RFLP). RESULTS: On the 44 examined patients, 39 exhibit Leishmania sp. by microscopical examination, all confirmed by PCR. For five patients with negative microscopical examination, PCR was positive for three of them. Among these 42 positive samples, 3 (7%) were infected by L. tropica and 39 (93%) by L. major. CONCLUSIONS: Leishmania major is the most prevalent species in prospected area and L. tropica occurs in Shiraz and Ghir-Karzin counties. PMID- 23682266 TI - Influence of Fasciola hepatica on Serum Biochemical Parameters and Vascular and Biliary System of Sheep Liver. AB - BACKGROUND: The aim of this study was to evaluate the functional capacity of the liver based on the activity of specific enzymes and bilirubin in serum and also to investigate the influence of mechanical and toxic effects of Fasciola hepatica on the structures of the blood vessels and biliary tract in the sheep liver. METHODS: Blood samples and liver of 63 indigenous sheep of Pramenka breed, slaughtered in the period from March to December 2009 were used. Based on parasitological findings in the liver, all animals were divided into two groups: control (n = 34) and infected group (n = 29). For investigation and description of pathological changes in sheep liver, naturally infected with F. hepatica, corrosion cast technique was used. RESULTS: Biochemical analysis of tested parameters showed a significant elevation (P<=0.05) of serum gamma-glutamyl transferase (GGT), total bilirubin (TBIL) and direct bilirubin (DBIL) in infected sheep group comparing with the control group. No significant differences were observed for activity of aspartate aminotranferase (AST) between groups. Vascular and biliary systems of the liver were found to be affected. CONCLUSION: Results of biochemical analysis are consistent with pathological findings and measuring of tested parameters could be used in early diagnosis of sheep fasciolosis and to test the effectiveness of anthelmintic therapy. Corrosion cast technique is very useful for investigation of pathological changes and neoangiogenesis of vascular and biliary system in sheep liver, caused by mechanical and toxic effects of F. hepatica. PMID- 23682267 TI - Evaluation of Cross Immunity and Histopathological Findings in Experimentally Infected BALB/c Mice with Neospora caninum and Besnoitia caprae. AB - BACKGROUND: Caprine besnoitiosis is an economically important disease of goats. Neospora caninum, another coccidian parasite of worldwide distribution, infects several animal species and is a major cause of abortion in cattle. Combined infections of N. caninum and Besnoitia caprae can occur in geographical areas endemic for both species of parasite in goats. This experiment was conducted to investigate the possible cross-immunity between these two infections in experimentally infected BALB/c mice. METHODS: Forty BALB/c mice were divided into four equal groups. The mice of Groups 1 and 4 were inoculated with 1*10(6) live virulent tachyzoites of N. caninum (NC-1), while animals of Groups 2 and 3 were inoculated with sterile tissue culture medium. Each mouse in Groups 1 and 2 was challenged 28 days later with 1*10(6) live virulent bradyzoites of B. Caprae (BC 1). RESULTS: Following the challenge, the mice in Groups 1 and 2 showed 100% morbidity and 100% mortality within 9 days post infection, while all the animals of Groups 3 and 4 remained alive. The dead animals were necropsied. The survivors (mice in Group 3 and 4) were euthanized 9 days after inoculation and the gross and histopathological lesions in different organs were investigated. CONCLUSION: Immunization and challenge experiments with lethal dose of B. caprae in the highly susceptible BALB/c mice showed no cross-protection between N. caninum and B. caprae. PMID- 23682268 TI - Differential Detection of Echinococcus Spp. Copro-DNA by Nested-PCR in Domestic and Wild Definitive Hosts in Moghan Plain, Iran. AB - BACKGROUND: Despite Echinococcus granulosus, there are merely two old reports of E. multilocularis infection among Iranian canids of Moghan Plain, the only area known endemic for the species. We detected specific DNA markers in fecal samples by PCR (Copro-PCR) for differential diagnosis of Echinococcus species in living canids. METHODS: Totally 144 fecal samples from domestic dogs, red foxes and a golden jackal were examined for genus-specific Echinococcus coproantigens using ELISA. Forty two positive or ambiguous samples were further examined for Echinococcus species-specific DNA markers by two different set of nested-PCR. RESULTS: Twenty five out of 144 (17.4%) animals were contaminated with E. granulosus including 14 (23.7%) domestic dogs, 10 (11.9%) red foxes and one (100%) golden jackal. But none of them harboured E. multilocularis species specific Copro-DNA. The overall prevalence of E. granulosus and E. multilocularis infections in canids of the area was estimated to be 17.4% and 0.0%, respectively. There was a significant relation between the results of Copro-PCR and CA-ELISA. CONCLUSION: The lack of E. multilocularis infection, compared to previous reports may be due to the differences in used diagnostic methods and/or recently limited territories of wild canids and altered their food resources in this particular area. PMID- 23682269 TI - Cloning, Nucleotide Sequencing and Bioinformatics Study of NcSRS2 Gene, an Immunogen from Iranian Isolate of Neospora caninum. AB - BACKGROUND: Neosporosis is caused by an obligate intracellular parasitic protozoa Neospora caninum which infect variety of hosts. NcSRS2 is an immuno-dominant antigen of N. caninum which is considered as one of the most promising targets for a recombinant or DNA vaccine against neosporosis. As no study has been carried out to identify the molecular structure of N. caninum in Iran, as first step, we prepared a scheme to identify this gene in this parasite in Iran. METHODS: Tachyzoite total RNA was extracted and cDNA was synthesized and NcSRS2 gene was amplified using cDNA as template. Then the PCR product was cloned into pTZ57R/T vector and transformed into E. coli (DH5alpha strain). Finally, the recombinant plasmid was extracted from transformed E. coli and sequenced. Bioinformatics analysis also carried out. RESULTS: The PCR product of NcSRS2 gene was sequenced and recorded in GenBank. The deduced amino acid sequence of NcSRS2 in current study was compared with other N. caninum NcSRS2 and showed some identities and differences. CONCLUSION: NcSRS2 gene of N. caninum successfully cloned in pTZ57R/T. Recombinant plasmid was confirmed by sequencing, colony PCR and enzymatic digestion. It is ready to express recombinant protein for further studies. PMID- 23682270 TI - Evaluation of the leishmanicidal and cytotoxic potential of essential oils derived from ten colombian plants. AB - BACKGROUND: The leishmanicidal and cytotoxic activity of ten essential oils obtained from ten plant specimens were evaluated. METHODS: Essential oils were obtained by the steam distillation of plant leaves without any prior processing. Cytotoxicity was tested on J774 macrophages and leishmanicidal activity was assessed against four species of Leishmania associated with cutaneous leishmaniasis. RESULTS: Seven essential oils exhibited activity against Leishmania parasites, five of which were toxic against J774 macrophages. Selectivity indices of >6 and 13 were calculated for the essential oils of Ocimum basilicum and Origanum vulgare, respectively. CONCLUSION: The essential oil of Ocimum basilicum was active against promastigotes of Leishmania and innocuous to J774 macrophages at concentrations up to 1600 ug/mL and should be further investigated for leishmanicidal activity in others in vitro and in vivo experimental models. PMID- 23682271 TI - Urea Output by L3 Teladorsagia circumcincta and some Properties of Two Urea Producing Enzymes. AB - BACKGROUND: Like several other parasites, Teladorsagia circumcincta secretes or excretes urea, but neither the rate of efflux nor the possible metabolic sources of the urea has been considered. METHODS: Parasites were maintained by passage through sheep. Urea efflux was measured using phenol/hypochlorite after treatment with urea aminohydrolase. The kinetics of creatine amidinohydrolase and arginine amidinohydrolase were characterised by coupling the reactions with urea aminohydrolase and glutamate dehydrogenase. RESULTS: Infective L3 T. circumcincta secreted or excreted urea at 25% of the rate of NH3/NH4 (+). The rate of urea efflux was about 84 pmol h(-1) (10(3) larvae)(-1) over 4 hours, corresponding to about 11 nmol h(-1) mg(-1) protein. We could not detect urea aminohydrolase activity, but urea production by both creatine amidinohydrolase and arginine amidinohydrolase could be detected. The apparent K m and V max of creatine amidinohydrolase were 1.1 mM and 48 nmol h(-1) mg(-1) protein, respectively, and the activity was greatest at pH 8. The apparent K m and V max of arginine amidinohydrolase were 0.7 mM and 62 nmol h(-1) mg(-1) protein, respectively, and the activity was greatest at pH 7.9. CONCLUSION: The activity of creatine amidinohydrolase and arginine amidinohydrolase was sufficient to account for the rate of urea secretion or excretion. PMID- 23682272 TI - Rapid epidemiological assessment of onchocerciasis in a tropical semi-urban community, enugu state, Nigeria. AB - BACKGROUND: This study was carried out in Opi-Agu a tropical semi-urban autonomous community comprising of three villages in Enugu State, Nigeria, between the months of April and June 2010. It was designed to determine the prevalence of Onchocerca volvulus infection and assess the perception of the disease among the inhabitants of this community. METHODS: A total number of 305 individuals comprising of 148 males and 157 females were examined for various manifestations of onchocerciasis symptoms using rapid epidemiological assessment (REA) method. RESULTS: Out of this number, 119 (39.02%) individuals were infected. Prevalence of infection among age groups and villages varied. Age group 41 yr and above had the highest (31.00%) prevalence, while among the villages, Ogbozalla village ranked higher (45.71%) than the other villages. Overall the prevalence of infection among the sexes revealed that males were more infected (43.24%) than the females (35.03%). Lichenified onchodermatitis (LOD) was the most prevalent (35.29%) onchocerciasis symptom among others identified in the area, while leopard skin (LS) had the lowest (20.17%) occurrence and blindness (0.00%) which is the most devastating effect of O. volvulus infection was not observed. Questionnaire responses from 410 individuals revealed that 34.8% respondent from Idi village and 28.1% from Ibeku village believed that O. volvulus infection occurs through poor personal hygiene. Bite of blackfly ranked least (10.6%) among the respondent's knowledge of the causes of onchocerciasis in Opi-Agu community. CONCLUSION: Opi-Agu community members had poor knowledge of onchocerciasis, the vector and of its etiologic organism. There is need for integration of community health education with mass chemotherapy. PMID- 23682273 TI - Seroepidemiologcal investigation of visceral leishmaniasis in stray and owned dogs in alborz province, central iran using direct agglutination test. AB - BACKGROUND: The aim of present study was to determine the seroprevalence of canine visceral leishmaniasis (CVL) among stray and owned dogs in Kouhsar district of Alborz Province, central Iran. METHODS: The study was performed from March 2011 to July 2011 using Direct Agglutination Test (DAT). Three hundred and thirty seven dogs including 257 stary and 80 owned dogs were selected by random sampling. The agreement between serological data and sex, age, life style of dogs and clinical signs were assessed by Chi-square. RESULTS: DAT showed that from 337 serum samples collected from owned and stray dogs, 12sera (3.6%) were positive. The seroprevalance was 10% (8/80) among owned dogs and 1.6% (4/257) among stray dogs. A significant difference in seroplevalance was seen between owned and stray dogs (P = 0.01). The highest seroprevalence rate (14%) was observed among the ownership dogs of 5 years old and above. Statistical analysis revealed significant relation between seroprelvalence and age (P= 0.02). There was no statistically significant relation between male (6.3%) and female (2.2%) seroprevalence (P= 0.085). CONCLUSION: This survey indicates the importance and necessity of serologic screening of visceral leishmaniasis in human and dogs in Kouhsar district. PMID- 23682274 TI - Plasmodium falciparum: Adhesion Phenotype of Infected Erythrocytes Using Classical and Mini-Column Cytoadherence Techniques. AB - BACKGROUND: Cytoadherence of Plasmodium falciparum- infected erythrocytes to host cells is an important trait for parasite survival and has a major role in pathology of malaria disease. Infections with P. falciparum usually consist of several subpopulations of parasites with different adhesive properties. This study aimed to compare relative sizes of various binding subpopulations of different P. falciparum isolates. It also investigated the adhesive phenotype of a laboratory P. falciparum line, A4, using different binding techniques. METHODS: Seven different P. falciparum isolates (ITG, A4, 3D7 and four field isolates) were cultivated to late trophozoite and schizont and then cytoadherence to cell differentiation 36 (CD36), intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule (V-CAM) and E-selectin were examined. The relative binding sizes of parasite subpopulations to human receptors were measured by mini-column cytoadherence method. The adhesion phenotype of P. falciparum-A4 line was evaluated by in vitro static, flow-based and mini-column binding assays. RESULTS: The relative binding size of ITG, A4 and 3D7 clones to a column made with CHO/ICAM-1 was 68%, 54% and 0%, respectively. The relative binding sizes of these lines to CHO/CD36 were 59.7%, 28.7% and 0%, respectively. Different field isolates had variable sizes of respective CD36 and ICAM1-binding subpopulations. A4 line had five different subpopulations each with different binding sizes. CONCLUSION: This study provided further evidence that P. falciparum isolates have different binding subpopulations sizes in an infection. Furthermore, measurement of ICAM-1 or CD36 binding subpopulations may practical to study the cytoadherence phenotypes of P. falciparum field isolates at the molecular level. PMID- 23682275 TI - Activity of Superoxide Dismutase (SOD) Enzyme in the Excretory-Secretory Products of Fasciola hepatica and F. gigantica Parasites. AB - BACKGROUND: The aim of this study was to compare superoxide dismutase (SOD) activity in Fasciola hepatica and Fasciola gigantica parasites. MATERIALS: F. gigantica and F. hepatica helminths were collected from abattoir and cultured in buffer media for 4 h at 37 degrees C. Excretory-Secretory (ES) products were collected, centrifuged and stored at -20( degrees )C. E-S protein concentration was measured by Bradford method and SOD activity was detected using RANSOD kit (Randox Lab. Crumlin, UK). Statistical t-test was conducted for analysis of results. RESULTS: Protein concentration for F. hepatica and F. gigantica were obtained 7.293 ug/ml and 19.65 ug/ml respectively and SOD activity as 0.721 U/ml and 1.189 U/ml, in that order. ES protein concentration of two species was significantly different (P<0.05), however the difference of SOD activity of two species was not significant. CONCLUSION: Two species of Fasciola have comparable SOD biochemical defense enzyme and can help us explain the parasite survival in host tissue. PMID- 23682276 TI - Leucocytozoonosis in domestic birds in southwestern iran: an ultrastructural study. AB - BACKGROUND: Leucocytozoonosis is a disease of birds caused by obligate intracellular protozoa of the genus Leucocytozoon. We determined the prevalence of Leucocytozoon spp. using light and transmission electron microscopy in domestic birds in southwest of Iran. METHODS: A total of 825 blood smears from 275 birds were examined for presence of infection. The structure morphology of Leucocytozoon spp. was studied using light and electron microscopy. RESULTS: Forty-four (16.0%) of the birds were positives for Leucocytozoon. The detected parasite were found in 14 chickens (5.1%), 12 geese (4.3%), 10 ducks (3.6%), and 8 turkeys (2.9%). The majority of the records were from the northeastern regions. CONCLUSION: Leucocytozoonosis are distributed in the Lorestan province bird population and electron microscopy can resolve the problem to distinguish between similar species of Leucocytozoon. PMID- 23682277 TI - Improving urine sample efficacy as a convenient alternative for invasive samples in molecular diagnosis of toxoplasmosis. AB - BACKGROUND: Diagnosis of some diseases is difficult due to invasive sampling. Urine has been candidate as a non-invasive and convenient alternative. It has many advantages and easy accessibility but some technical ills should be removed. Finding a suitable extraction method for improving urine DNA quantity and quality in altering invasive specimens for molecular diagnosis of some infectious diseases, was the main object of present research. METHOD: Toxoplasmosis was selected as an experimental model, regarding the congenital and ocular forms, its abundance and requirement to invasive sample for diagnosis. Samples prepared by adding some defined Toxoplasma gondii (RH strain) tachyzoites to normal urine. Several urine DNA extraction and purification methods comparatively were tested for finding the best one. The amount of extracted DNA assessed using Nanodrope spectrophotometer and a multiplex semi-nested PCR were designed for evaluating the results. RESULTS: Urine samples with known number of tachyzoites were purified comparatively by five better methods. The results reviled that Cinnagen kit performed with more efficacies. It works well up to 1-5tachyzoites ul(-1) of urine. The amount and quality of extracted DNA of more than 100 urine samples with defined tachyzoites were analyzed using a nested PCR method. Finally methods were enough sensitive to detect one tachyzoite DNA in final PCR reaction. CONCLUSION: This method was enough eligible and sensitive to perform molecular tests for different purposes of instance detecting toxoplasmosis by urine sample as a convenience and non invasive method; although it is better to perform some more experiments using patients samples comparing gold methods. PMID- 23682278 TI - Bone marrow negative visceral leishmaniasis in an adolescent male. AB - Visceral Leishmaniasis or Kala Azar is endemic in certain regions of India. In endemic areas, the constellation of fever, progressive weight loss, weakness, pronounced splenomegaly, anemia, leukopenia, and hypergammaglobulinemia is highly suggestive of visceral leishmaniasis. Demonstration of the parasite in liver, splenic or bone marrow aspirates is confirmatory. We present a case in which Leishmania donovani (LD) bodies were demonstrated on splenic aspirate. We were unable to demonstrate LD bodies on bone marrow aspiration. PMID- 23682279 TI - Aortopathy in Congenital Heart Disease in Adults: Aortic Dilatation with Decreased Aortic Elasticity that Impacts Negatively on Left Ventricular Function. AB - Bicuspid aortic valve and/or coarctation of the aorta are consistently associated with ascending aortic and para-coarctation medial abnormalities. Medial abnormalities in the ascending aorta are prevalent in other types of patients with a variety of forms congenital heart disease (CHD), such as single ventricle, persistent truncus arteriosus, transposition of the great arteries, hypoplastic left heart syndrome, tetralogy of Fallot. These abnormalities encompass a wide age range, and may predispose to dilatation, aneurysm, and rupture that necessitates aortic valve and root surgery. This dilatation can develop in CHD patients without stenotic region. These CHDs exhibit ongoing dilatation of the aortic root and reduced aortic elasticity and increased aortic stiffness that may relate to intrinsic properties of the aortic root. The concept of aortic dilatation is shifting a paradigm of aortic dilatation, as so called post stenotic dilatation, to primary intrinsic aortopahy. These aortic dilatation and increased stiffness can induce aortic aneurysm, rupture of the aorta and aortic regurgitation, but also provoke left ventricular hypertrophy, reduced coronary artery flow and left ventricular failure. We can recognize this association of aortic pathophysiological abnormality, aortic dilation and aorto-left ventricular interaction as a new clinical entity: "aortopathy". PMID- 23682280 TI - Acute stent thrombosis and heparin induced thrombocytopenia: another manifestation of kounis syndrome? PMID- 23682281 TI - Spatial and temporal expression, and statin responsiveness of galectin-1 and galectin-3 in murine atherosclerosis. AB - BACKGROUND AND OBJECTIVES: Existing data on the spatiotemporal expression patterns of a variety of galectins in murine atherosclerosis are limited. We investigated the expression levels of galectins, and their in vivo spatiotemporal expression patterns and statin responsiveness in the inflamed atherosclerotic plaques of apolipoprotein E (apoE)(-/-) mice. MATERIALS AND METHODS: Galectins expression patterns in aortic atherosclerotic plaques and serum galectin-3 levels were investigated in 26-week-old apoE(-/-) (n=6) and C57BL/6 mice (n=9). To investigate the spatial and temporal patterns of galectin-1 and galectin-3 in plaques, high-cholesterol diet-fed 26-week-old (n=12) and 36-week-old apoE(-/-) mice (n=6) were sacrificed and their aortas were examined for galectins' expression using immunoblot analysis and immunohistochemical stain. 36-week-old apoE(-/-) mice were treated with atorvastatin (n=3, 0.57 mg/kg/day) for the evaluation of its effect on aortic galectins' expression. RESULTS: Immunoblot analyses showed that galectin-1 and galectin-3 were the predominant galectins expressed in murine atherosclerosis. The serum galectin-3 level was significantly higher in apoE(-/-) mice (p<0.001). While galectin-1 was weakly expressed in both intimal plaques and the media of atherosclerotic aortas, galectin-3 was heavily and exclusively accumulated in intimal plaques. Galectin-3 distribution was colocalized with plaque macrophages' distribution (r=0.66). As the degree of plaque extent and inflammation increased, the intraplaque galectin-3 expression levels proportionally elevated (p<0.01 vs. baseline), whereas galectin-1 expression had not elevated (p=0.14 vs. baseline). Atorvastatin treatment markedly reduced intraplaque galectin-3 and macrophage signals (p<0.001 vs. baseline), whereas it failed to reduce galectin-1 expression in the aortas. CONCLUSION: Galectin-3 is the predominant gal and is colocalized with macrophages within atherosclerotic plaques. Intraplaque galectin-3 expression reflects the degree of plaque inflammation. PMID- 23682283 TI - The Brachial Ankle Pulse Wave Velocity is Associated with the Presence of Significant Coronary Artery Disease but Not the Extent. AB - BACKGROUND AND OBJECTIVES: Arterial stiffness is well known as an important risk factor for cardiovascular disease. At our institution, we assessed the association between arterial stiffness, as determined by brachial ankle pulse wave velocity (baPWV), and the extent of coronary artery disease (CAD), as detected by conventional coronary angiography (CAG) in patients who visited the outpatient clinic for angina without any previous history of heart disease. In addition, we evaluated if the level of baPWV could predict the revascularization as a clinical outcome. SUBJECTS AND METHODS: On a retrospective basis, we analyzed the data of 651 consecutive patients who had undergone baPWV and elective CAG for suspected CAD between June 2010 and July 2011, at a single cardiovascular center. RESULTS: The baPWV was one of the statistically meaningful predictors of significant CAD (diameter of stenosis >50%) in addition to male gender, age, the level of high density lipoprotein-cholesterol, and hemoglobin A1c in multivariate analysis. However, baPWV was not the significant predictor of revascularization. When the extent of CAD was classified into following 4 groups; no significant CAD, 1-, 2- and 3-vessel disease, there was significant difference of baPWV between the significant and non-significant CAD group, but there was no difference of baPWV among the 3 significant CAD groups, although there was a trend toward the positive correlation. CONCLUSION: Although baPWV was an independent predictor of significant CAD, it was neither associated significantly with the extent of CAD nor with the risk of revascularization. Therefore, baPWV has a limited value for portending the severity of CAD in patients with chest pain. PMID- 23682282 TI - Intravascular ultrasound-guided percutaneous coronary intervention improves the clinical outcome in patients undergoing multiple overlapping drug-eluting stents implantation. AB - BACKGROUND AND OBJECTIVES: Stented segment length is a predictive factor for restenosis and stent thrombosis still in the drug-eluting stent (DES) era, and the benefit of routine intravascular ultrasound (IVUS) is still unclear. The aim of the present study was to investigate whether IVUS-guided percutaneous coronary intervention (PCI) improved the vascular outcomes as compared with conventional PCI in the treatment of diffuse coronary artery disease. SUBJECTS AND METHODS: From our registry database from January 2006 to May 2009, we identified 85 consecutive patients with de novo coronary lesions treated with at least 64 mm of multiple, overlapping DES. The 2-year rate of major adverse cardiovascular events (MACE), defined as the composite of cardiovascular death, non-fatal myocardial infarction, target lesion revascularization (TLR), or stent thrombosis, was compared according to the use of IVUS. RESULTS: The 2-year MACE rate was lower in the IVUS-guided group than that of the angiography-guided group (8% vs. 33.3%, p=0.005). The incidence of TLR was lower in patients with IVUS use than in those without IVUS use (0% vs. 27.8%, p<0.001). On Cox proportional hazard analysis, no IVUS use {hazard ratio (HR) 5.917, 95% confidence interval (CI) 1.037-33.770, p=0.045} and age (HR 1.097, 95% CI 1.006-1.138, p=0.032) were unfavorable predictors for the 2-year MACE. CONCLUSION: The use of IVUS may improve the effectiveness and safety of multiple overlapping drug-eluting stenting for long, diffuse coronary lesions. PMID- 23682284 TI - Bedside-Friendly Prediction for Presence of Post-Myocardial lnfarction Systolic Dysfunction Using Multimarker Panel: Integrating Salivary Diagnostics into Clinical Practice. AB - BACKGROUND AND OBJECTIVES: We investigated if a combination of plasma or salivary interleukin-2 (IL-2), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF alpha), transforming growth factor-beta (TGF-beta), and troponin can improve estimation of the pretest probability of the left ventricular systolic dysfunction (LVSD). SUBJECTS AND METHODS: Eighty patients with newly-diagnosed myocardial infarction (MI) were echocardiographically examined for LVSD (ejection fraction <=40%). Measurements included traditional MI risk factors, plasma and salivary concentrations of troponin, IL-2, IL-6, TNF-alpha, and TGF-beta. With the LVSD as the outcome variable, we developed logistic regression models, starting with a basic model incorporating traditional risk factors and consecutively adding salivary and plasma biomarkers. Models were compared using several criteria, including (but not limited to) C statistic (discrimination) and net reclassification improvement index (NRI). RESULTS: APART FROM TROPONIN, PLASMA, AND SALIVARY VALUES OF THE BIOMARKERS WERE CORRELATED: spearman's rho was 0.19 (p=0.088) for troponin, 0.36 (p=0.001) for IL-2, 0.74 (p<0.001) for IL-6, 0.61 (p<0.001) for TNF-alpha, and 0.65 (p<0.001) for TGF-beta. The predictive performances of the basic model for estimating the pretest probability of the presence of LVSD considerably improved when cytokines were added (salivary added: C-statistic from 0.77 to 0.82 and NRI 77%; plasma added: C-statistic to 0.80 and NRI 134%). CONCLUSION: Multiple biomarkers added diagnostic value to the standard risk factors for predicting the presence of post-MI LVSD. PMID- 23682286 TI - Three-dimensional angiography-guided percutaneous transluminal angioplasty for distal aorta and bi-iliac chronic total occlusion. AB - Percutaneous recanalization of chronic total occlusions (CTOs) in peripheral arteries, especially TASC D classification including the distal aorta and both iliac arteries is still technically challenging. The conventional technique using standard guidewires and catheters guided by computed tomography and angiography can achieve a limited initial success, depending on lesion characteristics and operator's experience. A special imaging technique using 3-dimensional rotational angiography and spatio-temporal reconstruction with endoview for a better examination of the proximal stump, exact obstruction location, and distal stump direction in a stumpless lesion can be indispensable for successful intervention. We report a successful revascularization case of stumpless distal aorta and bi iliac CTO guided by this specialized imaging technique. PMID- 23682285 TI - Subclinical renal insufficiency range of estimated glomerular filtration rate and microalbuminuria are independently associated with increased arterial stiffness in never treated hypertensives. AB - BACKGROUND AND OBJECTIVES: Microalbuminuria (MAU) and decreased estimated glomerular filtration rate (eGFR) are risk factors for cardiovascular disease (CVD) in patients with hypertension. However, in hypertensive patients with normal or minimally reduced eGFR (>=60 mL/min/1.73 m(2)) and with normo- or MAU, the value of combined estimation of eGFR and urine microalbumin for the risk assessment has not been widely reported. We evaluated the association between arterial stiffness and the combined estimation of eGFR and urine microalbumin. SUBJECTS AND METHODS: Subjects with never treated hypertension and normal or minimally reduced eGFR were evaluated (n=491, 50.1+/-10.4 years). eGFR was calculated by the simplified Modification of Diet in Renal Disease formula. Urinary albumin-to-creatinine ratio (UACR) was assessed with spot urine. Arterial stiffness was assessed with heart-femoral pulse wave velocity (hfPWV). All subjects were divided into four groups; group 1, eGFR >=90 mL/min/1.73 m(2) (normal eGFR) and normo-albuminuria (NAU); group 2, eGFR 89.9-60 mL/min/1.73 m(2) (minimally reduced eGFR) and NAU; group 3, normal eGFR and MAU; group 4, minimally reduced eGFR and MAU. RESULTS: Group 1 had the lowest hfPWV (964.6+/ 145.4; group 2, 1013.5+/-168.9; group 3, 1058.2+/-238.0; group 4, 1065.8+/-162.9 cm/sec). Analysis adjusting age, sex, body mass index, heart rate and mean arterial pressure showed significantly lower hfPWV of group 1 compared to group 2 (p=0.032) and 3 (p=0.007). Multiple regression analysis showed a significant association of hfPWV with logUACR {beta=0.096, 95% confidence interval (CI) 8.974 60.610, p=0.008} and eGFR (beta=-0.069, 95% CI -1.194 - -0.005, p=0.048). CONCLUSION: Minimally reduced eGFR or MAU is independently associated with increased arterial stiffness, indicating greater CVD risk. PMID- 23682287 TI - Percutaneous Transluminal Angioplasty of Contralateral Iliac and Superficial Femoral Arteries via Graft Vessel in a Patient with FemoroFemoral Bypass Graft. AB - Peripheral arterial disease represents a significant problem, particularly among the elderly population. There has been great progress made in the treatment of peripheral arterial disease in recent years. Percutaneous transluminal angioplasty (PTA) has been employed as a method of treatment for patients with a variety of peripheral arterial disease. We report our experience with PTA of contralateral common iliac and superficial femoral arteries via graft vessel in a patient with femorofemoral bypass due to ipsilateral iliac artery occlusion. PMID- 23682288 TI - A case of successful bare metal stenting for aortic coarctation in an adult. AB - Aortic coarctation is a correctable hypertensive disease. For safety reasons and due to the invasiveness of surgical techniques, percutaneous interventions have become drastically more popular in recent times. In elderly patients with aortic coarctation who are at risk of an aortic wall aneurysm and rupture, covered stents are preferred but in younger patients, bare metal stenting may be sufficient for long-term safety. Herein we present a 47-year-old typical aortic coarctation patient who was successfully treated with a bare metal stent. PMID- 23682289 TI - A case demonstrating a percutaneous closure using the amplatzer duct occluder for paravalvular leakage after tricuspid valve replacement. AB - There has been a dramatic increase in the number and type of procedures performed in the field of cardiac intervention in the past decade. Percutaneous intervention is becoming an increasingly recognized modality for the management of prosthetic paravalvular leakages (PVLs) in severely symptomatic non-surgical candidates. Herein, we report our experience of percutaneous closure using the Amplatzer duct occluder for a PVL in a patient who underwent tricuspid valve replacement. PMID- 23682290 TI - A Retrograde Approach to Coronary Ostial Stenosis after a Bentall Procedure in a Patient with Behcet's Disease. AB - We describe a case of chronic total occlusion of the right coronary artery ostium 5 months after a repeated Bentall procedure in a patient with Behcet's disease. In this patient, an antegrade approach to delivering the guidewire during percutaneous coronary intervention was not successful. Coronary angiography revealed the existence of collateral blood supply from the left coronary artery. Using a retrograde approach, a guidewire was successfully advanced from the distal left circumflex artery through the collateral vessel and into the posterolateral branch of the right coronary artery. After the guidewire crossed over the occluded right coronary artery ostium and was snared into the ascending aorta, antegrade access for balloon and stent delivery succeeded. PMID- 23682291 TI - Right coronary artery to left ventricular fistula associated with infective endocarditis of the mitral valve. AB - A 27-year-old man with bacterial endocarditis of the mitral valve and embolic episodes was bound to have a large right coronary artery fistula communicating with the left ventricle, immediately inferior to the posterior mitral annulus. The perforation of the posterior leaflet and coronary arteriovenous fistula was identified using two-dimensional Doppler echocardiography. The diagnosis was confirmed by coronary angiography, and the patient underwent a successful operation. PMID- 23682292 TI - Various expressions of coronary Doppler patterns of myocardial bridging. PMID- 23682293 TI - Human ESC/iPSC-based "Omics" and Bioinformatics for Translational Research. AB - The establishment of human embryonic stem cell lines (hESCs) created the basis for new approaches in regenerative medicine and drug discovery. Despite the potential of hESCs for cell based therapies, ethical controversies limit their use. These obstacles could be overcome by induced pluripotent stem cells (iPSCs) that are generated by reprogramming somatic cells. Before iPSCs can be used for clinical applications, however, they must be thoroughly analyzed for aberrations in the genome, epigenome, transcriptome, and proteome. Here, we review how 'omics' technologies can be employed for a quantitative and definitive assessment of these cells. PMID- 23682294 TI - Improving learning about familial risks using a multicomponent approach: the GRACE program. AB - AIM: To enhance learning (knowledge, attitudes and practices) about the importance of family health history (FHH) information and familial risks. METHODS: A pre-post design with one group was employed in this study. Five learning sessions were conducted with a community-based sample (n = 75) recruited from five counties in Texas, USA. Each learning session included: a short online video; enactive instructions on how to use the online Surgeon General FHH tool; and a presentation on how to assess familial risks. Participants completed the pre-post knowledge, attitudes and practices questionnaires and the study's satisfaction survey, and participated in a short focus group interview. RESULTS: Participants' average age was 48.1 +/- 13.3 years. Over half of the participants (79%) were female, and 55% described themselves as non-Hispanic White. Our findings showed significant changes (p < 0.05) in participants' specific knowledge about factors that affect their familial risks. Similarly, significant changes (p < 0.05) in participants' attitudes toward familial risks assessment for common disease complications and confidence in controlling these risks have been documented. Participants' reported a high level of satisfaction in using online FHH tools, yet no significant change (p > 0.05) was detected in their reported practices regarding sharing FHH information with their providers or relatives. Focus group interviews revealed that participants were uncertain about providers' or relatives' reactions to sharing FHH information. CONCLUSION: Using different learning styles may have a significant impact on improving knowledge and attitudes about familial risks. PMID- 23682296 TI - Discord of Measurements in Assessing Depression among African Americans with Cancer Diagnoses. AB - OBJECTIVE: This study examined the level of agreement among the Center for Epidemiologic Studies-Depression Scale (CES-D), Hamilton Rating Scale for Depression (HAM-D), Beck Depression Inventory (BDI-II), and Observers' Rating on assessing depression of African American adults with cancer. METHODS: 75 breast and prostate cancer patients (57 African Americans and 18Whites) were interviewed and administered the depression measures. Nonparametric tests were performed to examine the level of measurement agreement by group and the symptom items of CES D, HAM-D and BDI-II to which African American patients responded differently across measures. RESULTS: The four measures showed agreement on approximately 75% of the cases in both racial groups. However, the difference between measures in identifying depressive cases is marked. The item analysis indicated that most measurement disagreements about African American patients occurred on two items: self-report of depression and sleeping disturbance. CONCLUSION: Measurement discord may be explained by African American's reporting behavior that varies from a self-reported measure to an interviewer-administrated measure of depression. African American patients showed a reluctance to use the word "depression" and a tendency to report sleep disturbance. The findings suggest that accurately assessing depression in these patients requires a consideration of their culturally shaped life experiences. PMID- 23682295 TI - Large-scale sequencing and the natural history of model human RNA viruses. AB - RNA virus exploration within the field of medical virology has greatly benefited from technological developments in genomics, deepening our understanding of viral dynamics and emergence. Large-scale first-generation technology sequencing projects have expedited molecular epidemiology studies at an unprecedented scale for two pathogenic RNA viruses chosen as models: influenza A virus and dengue. Next-generation sequencing approaches are now leading to a more in-depth analysis of virus genetic diversity, which is greater for RNA than DNA viruses because of high replication rates and the absence of proofreading activity of the RNA dependent RNA polymerase. In the field of virus discovery, technological advancements and metagenomic approaches are expanding the catalogs of novel viruses by facilitating our probing into the RNA virus world. PMID- 23682297 TI - Clinical utility of magnetic resonance spectroscopy to enhance diagnosis of HIV associated mild neurocognitive disorder. PMID- 23682298 TI - Analytical Ultracentrifugation as a Tool for Studying Protein Interactions. AB - The last two decades have led to significant progress in the field of analytical ultracentrifugation driven by instrumental, theoretical, and computational methods. This review will highlight key developments in sedimentation equilibrium (SE) and sedimentation velocity (SV) analysis. For SE, this includes the analysis of tracer sedimentation equilibrium at high concentrations with strong thermodynamic non-ideality, and for ideally interacting systems the development of strategies for the analysis of heterogeneous interactions towards global multi signal and multi-speed SE analysis with implicit mass conservation. For SV, this includes the development and applications of numerical solutions of the Lamm equation, noise decomposition techniques enabling direct boundary fitting, diffusion deconvoluted sedimentation coefficient distributions, and multi-signal sedimentation coefficient distributions. Recently, effective particle theory has uncovered simple physical rules for the co-migration of rapidly exchanging systems of interacting components in SV. This has opened new possibilities for the robust interpretation of the boundary patterns of heterogeneous interacting systems. Together, these SE and SV techniques have led to new approaches to study macromolecular interactions across the entire the spectrum of affinities, including both attractive and repulsive interactions, in both dilute and highly concentrated solutions, which can be applied to single-component solutions of self-associating proteins as well as the study of multi-protein complex formation in multi-component solutions. PMID- 23682300 TI - A Simulation Framework to Investigate in vitro Viral Infection Dynamics. AB - Virus infection is a complex biological phenomenon for which in vitro experiments provide a uniquely concise view where data is often obtained from a single population of cells, under controlled environmental conditions. Nonetheless, data interpretation and real understanding of viral dynamics is still hampered by the sheer complexity of the various intertwined spatio-temporal processes. In this paper we present a tool to address these issues: a cellular automata model describing critical aspects of in vitro viral infections taking into account spatial characteristics of virus spreading within a culture well. The aim of the model is to understand the key mechanisms of SARS-CoV infection dynamics during the first 24 hours post infection. Using a simulated annealing algorithm we tune free parameters with data from SARS-CoV infection of cultured lung epithelial cells. We also interrogate the model using a Latin Hypercube sensitivity analysis to identify which mechanisms are critical to the observed infection of host cells and the release of measured virus particles. PMID- 23682301 TI - Post-docetaxel options for further survival benefit in metastatic castration resistant prostate cancer: Questions of choice. AB - There are currently two medical treatments approved in Canada that offer survival benefits for patients with metastatic castration-resistant prostate cancer that progresses on or after docetaxel-based chemotherapy, and evidence is accumulating on the efficacy of further interventions in this setting. The current and emerging strategies are based on a variety of mechanisms (cytotoxicity, hormonal inhibition, radiopharmacy and immunotherapy) and there is nothing to suggest that patients will be unable to benefit from several or even all of these agents when used sequentially. Given the possibility of multiple lines of treatment for patients whose disease progresses on or after docetaxel, the challenge for clinicians will be to determine the optimum treatment pathway for each individual. That challenge is already being faced, albeit on a limited scale, now that both cabazitaxel (chemotherapy) and abiraterone (hormonal agent) are available for use post-docetaxel. PMID- 23682302 TI - Optimal management of patients receiving cabazitaxel-based chemotherapy. AB - The emergence of chemotherapy as a survival-improving treatment for metastatic castration-resistant prostate cancer has focused attention on the need for effective prevention and management of side effects. The most recent chemotherapeutic agent in this setting is cabazitaxel, licensed for use when the disease progresses on or after docetaxel-based treatment. Experience with cabazitaxel shows that, as with docetaxel, its side effects are largely predictable and manageable using methods that are already well-known to oncology teams. Patient education, clear instructions for when and how patients should seek advice, and properly implemented local policies on side effect management are essential to optimal patient care. PMID- 23682299 TI - In vivo animal stroke models: a rationale for rodent and non-human primate models. AB - On average, every four minutes an individual dies from a stroke, accounting for 1 out of every 18 deaths in the United States. Approximately 795,000 Americans have a new or recurrent stroke each year, with just over 600,000 of these being first attack [1]. There have been multiple animal models of stroke demonstrating that novel therapeutics can help improve the clinical outcome. However, these results have failed to show the same outcomes when tested in human clinical trials. This review will discuss the current in vivo animal models of stroke, advantages and limitations, and the rationale for employing these animal models to satisfy translational gating items for examination of neuroprotective, as well as neurorestorative strategies in stroke patients. An emphasis in the present discussion of therapeutics development is given to stem cell therapy for stroke. PMID- 23682303 TI - Metastatic castration-resistant prostate cancer: The emerging continuum of care. PMID- 23682304 TI - Chemotherapy for prostate cancer: Clinical practice in Canada. AB - Whereas prostate cancer was once deemed unresponsive to chemotherapy, there is now evidence that patients with metastatic castration-resistant prostate cancer can obtain a survival benefit from both first-line (docetaxel-based) and second line (cabazitaxel-based) chemotherapy. The side effects of these agents have been shown to be predictable and manageable, particularly in North American centres. However, patient selection remains a key issue, with the aim of delivering each line of treatment at a time when the individual patient remains fit and well enough to tolerate a cytotoxic regimen. Hence, it is increasingly important for urologists and oncologists to work together to ensure timely consideration of the chemotherapeutic approach before it is precluded by a decline in performance status. PMID- 23682305 TI - Women's Health Initiative Hormone Therapy Trials: New insights on Cardiovascular Disease from Additional Years of Follow up. AB - Debate and controversy surrounding the benefits and risks of menopausal hormone therapy (MHT) for prevention of cardiovascular disease has continued in the decade since the cessation of the Women's Health Initiative (WHI) hormone therapy interventions. As a result, many women and their physicians have been reluctant to turn to MHT for relief of vasomotor and other menopausal symptoms. However, several follow-up studies of WHI participants provide additional insight into clinical characteristics of women who are more likely to have favorable outcomes and lower rates of adverse events associated with MHT. This report focuses on those studies that identify characteristics and biomarkers helpful in stratifying risk for an individual. Incorporation of these factors into a benefit:risk model could assist in patient-oriented decision making regarding use of MHT. Personalizing treatment offers the potential to minimize risk and improve health outcomes. PMID- 23682306 TI - Masking Vegetable Bitterness to Improve Palatability Depends on Vegetable Type and Taste Phenotype. AB - Consumption of dark green vegetables falls short of recommendations, in part, because of unpleasant bitterness. A laboratory-based study of 37 adults was used to determine bitter and hedonic responses to vegetables (asparagus, Brussels sprouts, kale) with bitter masking agents (1.33 M sodium acetate, 10 and 32 mM sodium chloride, and 3.2 mM aspartame) and then characterized by taste phenotype and vegetable liking. In repeated-measures ANOVA, aspartame was most effective at suppressing bitterness and improving hedonic responses for all sampled vegetables. Among the sodium salts, 32 mM sodium chloride decreased bitterness for kale and sodium acetate reduced bitterness across all vegetables with a tendency to increase liking for Brussels sprouts, as release from mixture suppression increased perceived sweetness. Participants were nearly equally divided into three 6-n-propylthiouracil (PROP) phenotype groups. Those tasting the least PROP bitterness (non-tasters) reported least vegetable bitterness, and the additives produced little change in vegetable liking. Aspartame persisted as the most effective bitter blocker for the PROP tasters (medium, supertasters), improving vegetable liking for the medium tasters but too much sweetness for supertasters. The sodium salts showed some bitter blocking for PROP tasters, particularly sodium acetate, without significant gains in vegetable liking. Via a survey, adults characterized as low vegetable likers reported greater increase in vegetable liking with the maskers than did vegetable likers. These results suggest that bitter masking agents (mainly sweeteners) can suppress bitterness to increase acceptance if they are matched to perceived vegetable bitterness or to self-reported vegetable disliking. PMID- 23682307 TI - An MRI-based Attenuation Correction Method for Combined PET/MRI Applications. AB - We are developing MRI-based attenuation correction methods for PET images. PET has high sensitivity but relatively low resolution and little anatomic details. MRI can provide excellent anatomical structures with high resolution and high soft tissue contrast. MRI can be used to delineate tumor boundaries and to provide an anatomic reference for PET, thereby improving quantitation of PET data. Combined PET/MRI can offer metabolic, functional and anatomic information and thus can provide a powerful tool to study the mechanism of a variety of diseases. Accurate attenuation correction represents an essential component for the reconstruction of artifact-free, quantitative PET images. Unfortunately, the present design of hybrid PET/MRI does not offer measured attenuation correction using a transmission scan. This problem may be solved by deriving attenuation maps from corresponding anatomic MR images. Our approach combines image registration, classification, and attenuation correction in a single scheme. MR images and the preliminary reconstruction of PET data are first registered using our automatic registration method. MRI images are then classified into different tissue types using our multiscale fuzzy C-mean classification method. The voxels of classified tissue types are assigned theoretical tissue-dependent attenuation coefficients to generate attenuation correction factors. Corrected PET emission data are then reconstructed using a three-dimensional filtered back projection method and an order subset expectation maximization method. Results from simulated images and phantom data demonstrated that our attenuation correction method can improve PET data quantitation and it can be particularly useful for combined PET/MRI applications. PMID- 23682308 TI - A Bivalent Ligand Targeting the Putative Mu Opioid Receptor and Chemokine Receptor CCR5 Heterodimers: Binding Affinity versus Functional Activities. AB - Opioid substitution and antiretroviral therapies have steadily increased the life spans of AIDS patients with opioid addiction, while the adverse drug-drug interactions and persistence of HIV-associated neurocognitive disorders still require new strategies to target opioid abuse and HIV-1 comorbidities. A bivalent ligand 1 with a 21-atom spacer was thus synthesized and explicitly characterized as a novel pharmacological probe to study the underlying mechanism of opioid enhanced NeuroAIDS. The steric hindrance generated from the spacer affected the binding affinity and Ca2+ flux inhibition function activity of bivalent ligand 1 at the chemokine receptor CCR5 more profoundly than it did at the mu opioid receptor (MOR). However, the CCR5 radioligand binding affinity and the Ca2+ flux inhibition function of the ligand seemed not necessarily to correlate with its antiviral activity given that it was at least two times more potent than maraviroc alone in reducing Tat expression upon HIV-1 infection in human astrocytes. Furthermore, the ligand was also about two times more potent than the simple mixture of maraviroc and naltrexone in the same viral entry inhibition assay. Therefore bivalent ligand 1 seemed to function more effectively by targeting specifically the putative MOR-CCR5 heterodimer in the viral invasion process. The results reported here suggest that a properly designed bivalent ligand may serve as a useful chemical probe to study the potential MOR-CCR5 interaction during the progression of NeuroAIDS. PMID- 23682309 TI - Engineering and Applications of DNA-Grafting Polymer Materials. AB - The emergence of hybrid materials combining biomacromolecules and organic polymers has received broad attention based on their potential applications in chemical, biological and materials sciences. Among different coupling strategies, the grafting of oligonucleotides to organic polymers as side chains by covalent bonds provides a novel platform whereby the properties of both oligonucleotides and polymer backbone are integrated, manipulated and optimized for various applications. In this review, we give the perspective on this specific type of DNA polymer hybrid materials , using selected examples with emphasis on bioanalysis, biomedicine and stimuli-responsive materials. It is expected the success of DNA-grafting polymers will not only impact the frabication of novel bimolecule incorporated materials, but also will influence how the properties of synthetic materials are tailored using different functional groups. PMID- 23682310 TI - How Do Perfluorinated Alkanoic Acids Elicit Cytochrome P450 to Catalyze Methane Hydroxylation? An MD and QM/MM Study. AB - Recent experimental studies show that usage of perfluoro decanoic acid (PFDA), as a dummy substrate, can elicit P450BM3 to perform hydroxylation of small alkanes, such as methane (ref. 17) and propane (ref. 17 and ref. 18). To comprehend the mechanism whereby PFDA operates to potentiate P450BM3 to catalyze the hydroxylation of small alkanes, we used molecular dynamics (MD) and hybrid quantum mechanical / molecular mechanical (QM/MM) calculations. The MD results show that without the PFDA, methane escapes the active site, while the presence of PFDA can potentially induce a productive Cpd I-Methane juxtaposition for rapid oxidation. Nevertheless, when only a single methane molecule is present near the PFDA, it still escapes the pocket within less than a nanosecond. However, when three methane molecules are present in the pocket, they alternate quasi periodically such that at all times (within 10 ns), a molecule of methane is always present in the proximity of Cpd I in a reactive conformation. Our results further demonstrate that the PFDA does not exert any electrostatic catalysis, whether the PFDA is in the protonated or deprotonated forms. Taken together, we conclude that methane hydroxylation requires, in addition to PFDA, a high partial pressure of methane that will cause a high methane concentration in the active site. Further study of ethane and propane hydroxylations demonstrates that higher alkane concentration is helpful for all the three small alkanes. Thus for the smallest alkane, methane, at least three molecules are necessary whereas for the larger ethane, two molecules are needed to force one ethane to be closer to Cpd I. Finally, for propane a second molecule is helpful but not absolutely necessary; for this molecule the PFDA may well be sufficient to keep propane close to Cpd I for efficient oxidation. We therefore propose that high alkane pressure should assist small alkane hydroxylation by P450 in a manner inversely proportional to the size of the alkanes. PMID- 23682311 TI - A role for PVRL4-driven cell-cell interactions in tumorigenesis. AB - During all stages of tumor progression, cancer cells are subjected to inappropriate extracellular matrix environments and must undergo adaptive changes in order to evade growth constraints associated with the loss of matrix attachment. A gain of function screen for genes that enable proliferation independently of matrix anchorage identified a cell adhesion molecule PVRL4 (poliovirus-receptor-like 4), also known as Nectin-4. PVRL4 promotes anchorage independence by driving cell-to-cell attachment and matrix-independent integrin beta4/SHP-2/c-Src activation. Solid tumors frequently have copy number gains of the PVRL4 locus and some have focal amplifications. We demonstrate that the transformation of breast cancer cells is dependent on PVRL4. Furthermore, growth of orthotopically implanted tumors in vivo is inhibited by blocking PVRL4-driven cell-to-cell attachment with monoclonal antibodies, demonstrating a novel strategy for targeted therapy of cancer. DOI:http://dx.doi.org/10.7554/eLife.00358.001. PMID- 23682312 TI - Feeding-induced rearrangement of green leaf volatiles reduces moth oviposition. AB - The ability to decrypt volatile plant signals is essential if herbivorous insects are to optimize their choice of host plants for their offspring. Green leaf volatiles (GLVs) constitute a widespread group of defensive plant volatiles that convey a herbivory-specific message via their isomeric composition: feeding of the tobacco hornworm Manduca sexta converts (Z)-3- to (E)-2-GLVs thereby attracting predatory insects. Here we show that this isomer-coded message is monitored by ovipositing M. sexta females. We detected the isomeric shift in the host plant Datura wrightii and performed functional imaging in the primary olfactory center of M. sexta females with GLV structural isomers. We identified two isomer-specific regions responding to either (Z)-3- or (E)-2-hexenyl acetate. Field experiments demonstrated that ovipositing Manduca moths preferred (Z)-3 perfumed D. wrightii over (E)-2-perfumed plants. These results show that (E)-2 GLVs and/or specific (Z)-3/(E)-2-ratios provide information regarding host plant attack by conspecifics that ovipositing hawkmoths use for host plant selection. DOI:http://dx.doi.org/10.7554/eLife.00421.001. PMID- 23682313 TI - ER-associated mitochondrial division links the distribution of mitochondria and mitochondrial DNA in yeast. AB - Mitochondrial division is important for mitochondrial distribution and function. Recent data have demonstrated that ER-mitochondria contacts mark mitochondrial division sites, but the molecular basis and functions of these contacts are not understood. Here we show that in yeast, the ER-mitochondria tethering complex, ERMES, and the highly conserved Miro GTPase, Gem1, are spatially and functionally linked to ER-associated mitochondrial division. Gem1 acts as a negative regulator of ER-mitochondria contacts, an activity required for the spatial resolution and distribution of newly generated mitochondrial tips following division. Previous data have demonstrated that ERMES localizes with a subset of actively replicating mitochondrial nucleoids. We show that mitochondrial division is spatially linked to nucleoids and that a majority of these nucleoids segregate prior to division, resulting in their distribution into newly generated tips in the mitochondrial network. Thus, we postulate that ER-associated division serves to link the distribution of mitochondria and mitochondrial nucleoids in cells. DOI:http://dx.doi.org/10.7554/eLife.00422.001. PMID- 23682314 TI - Controlling gain one photon at a time. AB - Adaptation is a salient property of sensory processing. All adaptational or gain control mechanisms face the challenge of obtaining a reliable estimate of the property of the input to be adapted to and obtaining this estimate sufficiently rapidly to be useful. Here, we explore how the primate retina balances the need to change gain rapidly and reliably when photons arrive rarely at individual rod photoreceptors. We find that the weakest backgrounds that decrease the gain of the retinal output signals are similar to those that increase human behavioral threshold, and identify a novel site of gain control in the retinal circuitry. Thus, surprisingly, the gain of retinal signals begins to decrease essentially as soon as background lights are detectable; under these conditions, gain control does not rely on a highly averaged estimate of the photon count, but instead signals from individual photon absorptions trigger changes in gain. DOI:http://dx.doi.org/10.7554/eLife.00467.001. PMID- 23682315 TI - Stability-mediated epistasis constrains the evolution of an influenza protein. AB - John Maynard Smith compared protein evolution to the game where one word is converted into another a single letter at a time, with the constraint that all intermediates are words: WORD->WORE->GORE->GONE->GENE. In this analogy, epistasis constrains evolution, with some mutations tolerated only after the occurrence of others. To test whether epistasis similarly constrains actual protein evolution, we created all intermediates along a 39-mutation evolutionary trajectory of influenza nucleoprotein, and also introduced each mutation individually into the parent. Several mutations were deleterious to the parent despite becoming fixed during evolution without negative impact. These mutations were destabilizing, and were preceded or accompanied by stabilizing mutations that alleviated their adverse effects. The constrained mutations occurred at sites enriched in T-cell epitopes, suggesting they promote viral immune escape. Our results paint a coherent portrait of epistasis during nucleoprotein evolution, with stabilizing mutations permitting otherwise inaccessible destabilizing mutations which are sometimes of adaptive value. DOI:http://dx.doi.org/10.7554/eLife.00631.001. PMID- 23682316 TI - EBI2-mediated bridging channel positioning supports splenic dendritic cell homeostasis and particulate antigen capture. AB - Splenic dendritic cells (DCs) present blood-borne antigens to lymphocytes to promote T cell and antibody responses. The cues involved in positioning DCs in areas of antigen exposure in the spleen are undefined. Here we show that CD4(+) DCs highly express EBI2 and migrate to its oxysterol ligand, 7alpha,25-OHC. In mice lacking EBI2 or the enzymes needed for generating normal distributions of 7alpha,25-OHC, CD4(+) DCs are reduced in frequency and the remaining cells fail to situate in marginal zone bridging channels. The CD4(+) DC deficiency can be rescued by LTbetaR agonism. EBI2-mediated positioning in bridging channels promotes DC encounter with blood-borne particulate antigen. Upon exposure to antigen, CD4(+) DCs move rapidly to the T-B zone interface and promote induction of helper T cell and antibody responses. These findings establish an essential role for EBI2 in CD4(+) DC positioning and homeostasis and in facilitating capture and presentation of blood-borne particulate antigens. DOI:http://dx.doi.org/10.7554/eLife.00757.001. PMID- 23682317 TI - Make or break for mitochondria. AB - Ensuring that mitochondrial DNA is successfully divided between daughter mitochondria involves a complex series of interactions with the endoplasmic reticulum and a variety of enzymes. PMID- 23682318 TI - Influenza evolution navigates stability valleys. AB - By reconstructing how an influenza protein collected in 1968 might have evolved into one collected in 2007, researchers have obtained new insights into the interactions between genetic mutations. PMID- 23682320 TI - Twenty years of experience on stem cell transplantation in iran. AB - BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a new window to therapy of many diseases. From March 1991 through April 2011, a total of 3237 HSCT were performed in the Hematology-Oncology and Stem Cell Transplantation Research Center, affiliated to Tehran University of Medical Sciences. Here we report 20 years experience of HSCT. OBJECTIVES: Our strategy and aim include the protraction of cytogenetic and molecular biological diagnostic tests, the expansion of the first Iranian Cord Blood Bank (ICBB) and development of the first Iranian Stem Cell Donor Program (ISCDP), and improvement the researches in new therapeutic fields. PATIENTS AND METHODS: Totally, 3237 patients were undergone HSCT. Of these transplants, 2205 were allogeneic stem cell transplantation, 1016 autologous and 16 syngeneic. Among 2205 patients who were undergone allogenic-HSCT, 34 received cord blood stem cells as stem cell source for transplantation. It is important to point out that cord blood bank at our center provides reliable storage of cord blood stem cells for our patients. Stem cell transplantation was performed for treatment of various diseases such as acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic lymphoblastic leukemia, beta-thalassemia major, sickle- cell thalassemia, sickle- cell disease, multiple myeloma, myelodysplasia, mucopolysaccharidosis, paroxysmal nocturnal hemoglobinuria, non-Hodgkin's lymphoma, Hodgkin's disease, severe aplastic anemia, plasma cell leukemia, Niemann-Pick disease, Fanconi anemia, severe combined immunodeficiency, congenital neutropenia, leukocyte adhesion deficiencies, Chediak-Higashi syndrome, osteopetrosis, histiocytosis X, Hurler syndrome, amyloidosis, systemic sclerosis, breast cancer, Ewing's sarcoma, testicular cancer, germ cell tumors, neuroblastoma, medulloblastoma, renal cell carcinoma, nasopharyngeal carcinoma, ovarian cancer, Wilms' tumor, rhabdomyosarcoma, pancreatoblastoma, and multiple sclerosis. Also, we had 220 cellular therapies for post-myocardial infarction, multiple sclerosis, cirrhosis, head of femur necrosis, Diabetes Mellitus and GvHD treatment. 45 patients were undergone retransplantation in this center. RESULTS: About 78.2% of the patients (2530 of 3237) remained alive between one to 211 months after stem cell transplantation. Nearly, 21.8% (707) of our patients died after stem cell transplantation. The main causes of death were relapse, infection, hemorrhagic cystitis, graft-versus- host disease and etc. CONCLUSIONS: In Iran, HSCT has been successfully adapted in routine clinical care. Recently, new methods such as double cord blood and haploidentical transplantation have been used to treat many life-threatening diseases. PMID- 23682319 TI - Engineering of the embryonic and adult stem cell niches. AB - CONTEXT: Stem cells have the potential to generate a renewable source of cells for regenerative medicine due to their ability to self-renew and differentiate to various functional cell types of the adult organism. The extracellular microenvironment plays a pivotal role in controlling stem cell fate responses. Therefore, identification of appropriate environmental stimuli that supports cellular proliferation and lineage-specific differentiation is critical for the clinical application of the stem cell therapies. EVIDENCE ACQUISITION: Traditional methods for stem cells culture offer limited manipulation and control of the extracellular microenvironment. Micro engineering approaches are emerging as powerful tools to control stem cell-microenvironment interactions and for performing high-throughput stem cell experiments. RESULTS: In this review, we provided an overview of the application of technologies such as surface micropatterning, microfluidics, and engineered biomaterials for directing stem cell behavior and determining the molecular cues that regulate cell fate decisions. CONCLUSIONS: Stem cells have enormous potential for therapeutic and pharmaceutical applications, because they can give rise to various cell types. Despite their therapeutic potential, many challenges, including the lack of control of the stem cell microenvironment remain. Thus, a greater understanding of stem cell biology that can be used to expand and differentiate embryonic and adult stem cells in a directed manner offers great potential for tissue repair and regenerative medicine. PMID- 23682321 TI - FISH Analysis for del6q21 and del17p13 in B-cell Chronic Lymphocytic Leukemia in Iranians. AB - BACKGROUND: B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in the Western world. Major progress has been made in assessing typical chromosomal abnormalities and recognition of the correlation of these chromosomal abnormalities with laboratory features and clinical course of the disease. The most frequent genomic changes are deletions at 13q14, 11q22-23 and 17p13 and trisomy of chromosome 12. OBJECTIVES: The aim of this study was to investigate the frequency of chromosomal aberrations in B-CLL patients' peripheral blood and/or bone marrow using a molecular cytogenetic method, interphase fluorescence in situ hybridization (I-FISH) and to evaluate the correlation between these genomic changes and clinical findings. PATIENTS AND METHODS: I-FISH analyses were performed on bone marrow and blood samples of 66 B-CLL patients. RESULTS: Deletion of 17p13 was found in 11 (16.6%) and deletion 6q21 was present in 5 (7.5%). Statistical analyses were performed to investigate the correlation of these molecular-cytogenetic findings with family history, Rai staging and CD38 marker. No clear differences in distribution was noted for del17p13 and del6q21 among patients with and without family history, and no direct correlation was noted between these genomic changes and CD38 marker, but the correlation of del17p13 and Rai stage was significant. There was a high frequency of Rai stage II within del17p13 patients. CONCLUSIONS: It was demonstrated that the presence of del6q21 in B-CLL patients indicates poor prognosis and on the contrary, presence of del17p13 points at the good prognostic value of the disease. PMID- 23682322 TI - The role of vitamin C in prevention of preterm premature rupture of membranes. AB - BACKGROUND: Preterm premature rupture of membranes (PPROM) is one of the most important complications of the pregnancy and cause perinatal morbidity and mortality. History of PPROM is a risk factor of recurrent PPROM. Vitamin C plays an important role in collagen metabolism and increases resistance maintenance of the chorioamniotic membranes. OBJECTIVES: The aim of this study is to evaluate the role of vitamin C supplementation in prevention of PPROM in women with a positive history of PPROM. PATIENTS AND METHODS: This clinical trial study was performed on 170 pregnant women with the history of PPROM, with singleton pregnancy and gestational age 14 weeks in Imam-Reza Hospital, Mashhad University of Medical Sciences during 2008 to 2010. They were randomly divided into two groups. The case patients received 100 mg vitamin C daily from 14th weeks of gestation. PPROM occurrence was compared between two groups as an indicator of the protective effect of vitamin C supplements. RESULTS: PPROM occurred in 44.7% of controls and 31.8% of cases (P < 0.05). PROM occurred in 34.1% of controls and 18.8% of cases (P < 0.05). Pregnancy was terminated at term gestation in 21.2% of controls and 49.4% of cases (P < 0.05). Rupture of membranes was significantly decreased in the case group. CONCLUSIONS: Vitamin C supplementations after 14th weeks of gestation can prevent from PPROM in women with the history of PPROM. PMID- 23682323 TI - The antimicrobial effect of lactobacillus casei culture supernatant against multiple drug resistant clinical isolates of Shigella sonnei and Shigella flexneri in vitro. AB - BACKGROUNDS: Shigellosis remains an important public health problem in developing countries with S. sonnei and S. flexneri in US, Europe and in Asian countries being of importance. OBJECTIVES: This study evaluates the protective effect of Lactobacillus casei cell-free culture supernatants (CFCS) against multiple drug resistance (MDR) clinical samples of Shigella sonnei and Shigella flexneri in vitro. MATERIALS AND METHODS: S. sonnei and S .flexneri was identified by common microbiological and serological methods. Antibiogram with 18 antibiotics were tested for 34 positive cultures by disc diffusion method. The Samples showed considerable resistance to antibiotics. Antimicrobial effects of CFCS were tested against S. sonnei and S. flexneri by agar-well assay and broth micro dilution methods. In addition, the antimicrobial activity remained active treatment after adjust pH 7, adding Proteinase K and heating for L. casei. RESULTS: The results implicate that L. casei strongly inhibits the development of pathogen samples. In contrast, via the disc diffusion method 4 out of 18 antibiogram have shown complete resistance against the pathogen samples. In addition, the natures of antimicrobial properties have been tested in different conditions such as various pH, temperature and presence of proteinase K. The MIC50 (minimum inhibitory concentration) and MIC90 of CFCS of L. casei were determined, for S. sonnei were 2.25 and 10.5, for S .flexneri were 5.25 and 5.25 respectively. The results have shown a significant resistance pattern by these four antibiotics in this case. CONCLUSIONS: The data indicates that. L. casei highly resistant against to antibiotics, heat, Proteinase K and so many activities against MDR Shigella pathogenic strains . L. casei is the best probiotics candidate. PMID- 23682324 TI - Improvement of Contused Spinal Cord in Rats by Cholinergic-like Neuron Therapy. AB - BACKGROUND: Disability in spinal cord injury is an important medical problem, and cell transplantation is considered as an option for the treatment. OBJECTIVES: The purpose of this study is to use bone marrow stromal cells (BMSCs) derived cholinergic neuron-like cells (CNL) in order to ameliorate the contusion model of spinal cord injury in rats. MATERIALS AND METHODS: The CNLs were produced by pre inducing BMSCs with beta-mercaptoethanol (BME) followed by inducing with nerve growth factor (NGF). The cells were immunoreactive to neurofilament 200, NeuN, synaptophysin, synapsin, microtubule associated protein-2 and choline acetyl transferase (ChAT). The CNL were transplanted in contused rats (CR), which were sacrificed after 12 weeks. RESULTS: The results showed that BBB test showed an improvement in the CR, while the quantitative analysis showed that the improvement rate was higher in the rats treated with CNL than those treated with BMSCs only or the untreated animals, similar results were noticed in the improvement index. Immunohistochemical analysis of the tissue section prepared from the CR showed that the transplanted cells were engrafted and integrated in the traumatized spinal cord. The morphometric analysis showed that the volume density of the cavity in the CNL treated rats was significantly lower than that of the untreated ones, while the spinal tissue regeneration index was significantly higher. CONCLUSIONS: The conclusion of the study is that CNL can improve the injured spinal cord. PMID- 23682325 TI - The Effect of Additional Pleural Procedures onto Recurrence Rates on the Spontaneous Pneumothorax Surgery. AB - BACKGROUND: Spontaneous pneumothoraxes constituted 1/1000 hospital admissions. They are particularly one of life threatening health issues in combination with bilateral pneumothorax, tension pneumothorax, repertory failure or COPD. OBJECTIVES: The cases of spontaneous pneumothorax represent a significant portion of the patients profile within the chest surgery clinics. The risk of recurrent pneumothorax in post thoracoscopy is between 2% and 14%, thus the subject of cure treatment and approach is still controversial. The cases were retrospectively treated due to spontaneous pneumothorax and their reasons, treatment approaches and results were comparatively examined with the literature. PATIENTS AND METHODS: The years between 2007 and 2010, according to our hospital clinic, outpatients and accident & emergency admission records, 79 patients were admitted with a diagnosis of spontaneous pneumothorax; and the patients' age, gender, symptoms, types of pneumothorax, surgical intervention and recurrence, average length of stay, mortality and complications were retrospectively evaluated. RESULTS: Seventy of all the patients (88.6%) were male and 9 of those (13.7%) were female. The mean age was calculated as 45.50 +/- 21.07 (0-85). The patients were comprised of 41 (51.9%) with primary spontaneous pneumothorax and 38 (48.1%) with secondary spontaneous pneumothorax. 55 of the patients (69.6%) with the first attack, and 24 patients (30.4%) with post tube thoracotomy's 2nd or 3rd pneumothorax attack were admitted. Those who were accepted with post tube thoracostomy's 2nd or 3rd attack made up 2/3 of the secondary spontaneous pneumothorax patients. 57 of the patients (68.4%) were treated with the tube thoracostomy. The tube thoracostomy related complication was 6.3%, hemorrhage due to parenchymal damage and massive air leak were observed. An open surgical method to 22 of those patients and apical resection and apical pleurectomy + tetracycline pleurodesis to 16 of whom and bullae ligation and mechanical abrasion to 6 patients were applied. The recurrence of pneumothorax in post surgery was not observed for 1-3 year period Complication was not detected .Mortality, one patient (1.3%) died in post tube thoracotomy, which was a stage 4 lung cancer patient. CONCLUSIONS: Most cases for pneumothorax were consisted of the patients with the primary spontaneous pneumothorax; the patients with recurrent pneumothorax were comprised of secondary spontaneous pneumothorax patients and those of majority secondary spontaneous pneumothorax patients were observed with bullous emphysema profile. By looking at the pertinent literature, there are publications showing VATS with the recurrence rate ranging from 2% to 14% and post thoracotomy recurrence rate from 0% to 7%. We think that applying pleurectomy, mechanical abrasion and chemical pleurodesis additional to bullae ligation or apical resection in pneumothorax surgery will significantly reduce the recurrence rate. PMID- 23682326 TI - Comparing mindfulness based cognitive therapy and traditional cognitive behavior therapy with treatments as usual on reduction of major depressive disorder symptoms. AB - BACKGROUND: In this studyMindfulness and CBT were combined to investigate the enhance of psychotropic work. Both therapies have integrated acceptance-based mindfulness approaches with change-based cognitive behavioral therapies to create efficacious treatments. That is, introduce use of MBCT in active phase of treatment and chronic depression. OBJECTIVES: This study was done to evaluate efficacy of Mindfulness Based Cognitive Therapy (MBCT) and traditional Cognitive Behavior Therapy (CBT) with Treatments as usual (TAU) to reduce psychiatric symptoms in a sample of patients with Major Depressive Disorder (MDD). MATERIALS AND METHODS: 90 patients who were referred to clinics of university of Social Welfare and Rehabilitation Sciences and Tehran University Counseling Centre and met DSM-IV criteria for MDD were selected. They were randomly assigned to MBCT (n = 30), CBT (n = 30), or TAU (n = 30). They were aged between 18 and 45 years (M = 28, SD = 8), with an average of two previous depression episodes. They were interviewed through the Structured Clinical Interview for DSM-IV and self-report by Brief Symptom Inventory, pre and post treatment. Patients in MBCT and CBT group received the treatment, while TAU group continued therapy (anti depressant). RESULTS: The results indicated that MBCT and CBT groups have significant efficacy on reduction of MDD symptoms. CONCLUSIONS: MBCT appears to be as effective as CBT in the treatment of current depression. PMID- 23682327 TI - Comparison between preoperative administration of methylprednisolone with its administration before and during congenital heart surgery on serum levels of IL-6 and IL-10. AB - BACKGROUND: Steroid administration during cardiopulmonary bypass is considered to improve cardiopulmonary function by modulating inflammations caused by bypass. OBJECTIVES: This study was performed to compare effectiveness of preoperative and intraoperative methylprednisolone (MP) to preoperative methylprednisolone alone in post bypass inflammatory (IL-6) and anti-inflammatory (IL-10) factors. PATIENTS AND METHODS: Fifty pediatric patients undergoing cardiopulmonary bypass surgery from August 2011 to 2012 in the cardiac surgery department of Imam Reza Hospital, the major center for CPB, in Mashhad, Iran were randomly assigned to receive preoperative and intraoperative MP (30 mg/kg, 4 hours before bypass and in bypass prime, number 25) or preoperative MP only (30 mg/kg, number 25). Before and after bypass, four and 24 hours after bypass, serum IL-6 and IL-10 were measured by ELISA. RESULTS: In both groups, no significant difference with variation of expression for IL-6 (inflammatory factor) and IL-10 (anti inflammatory factor) in different times after bypass was observed. CONCLUSIONS: No significant difference in reducing post bypass inflammation between preoperative steroid treatment and combined preoperative and intraoperative steroid administration reported and they had the same effects. PMID- 23682329 TI - Surgery for abdominal wall pain caused by cutaneous nerve entrapment in children a single institution experience in the last 5 years. AB - BACKGROUND: Chronic abdominal pain (CAP) is a serious medical condition which needs to be approached with great attention. Chronic abdominal pain may be caused by entrapment of cutaneous branches of intercostal nerves (ACNES). OBJECTIVES: The aim of this study is the surgery for abdominal wall pain which caused by cutaneous nerve entrapment in children during last 5 years. MATERIALS AND METHODS: In all children with ACNES, we tried conservative treatment with anesthetic and steroid injections. In children who were refractory to conservative treatment, we received surgical procedure like sectioning the entrapped nerve to obtain relief. RESULTS: In 12 pediatric patients with chronic abdominal pain, we diagnosed ACNES. Each presented with abdominal pain and a positive Carnett sign. Local nerve blocks using anesthetic and steroid injections are the treatment. In all patients, we tried with local nerve block. In 3 patients, pain improvement occurs in the few minutes, and they were without pain after 5 days. In other 4 patients required a reinjection for pain recurrence. In one patients pain was gone. The maximum reinjection was 3. In other 5 patients, we did operative treatment like sectioning the entrapped nerve. CONCLUSIONS: Some children with CAP have ACNES. In all children with ACNES, we recommended local nerve blocks. If the local block in 3 times is not helping, neurectomy of the peripheral nerve is method of choice. PMID- 23682328 TI - Fixed Cut-Off for FEV1/FEV6 and FEV6 in Detection of Obstructive and Restrictive Patterns. AB - BACKGROUND: Chronic obstructive pulmonary diseases (COPD) have been defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) as irreversible conditions which are diagnosed by fixed cut-off points of FEV1/FVC. OBJECTIVE: The aim of this study was to determine the cut-off points for FEV1/FEV6 ratio and FEV6 as alternatives for FEV1/FVC and FVC in detection of airway obstruction and lung restriction, respectively. MATERIALS AND METHODS: A total of 318 Spiro metric examinations of subjects referred to Shariati hospital were analyzed. A subject was considered to have obstruction if FEV1/FVC was lower than 70%. The restriction was defined as FVC < 80% in the absence of obstruction. The Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of FEV1/FEV6 and FEV6 were calculated. RESULTS: This study shows that the current cut-off points used to detect obstruction and restriction can be replaced by FEV1/FEV6 < 71% and FEV6 < 83%, respectively. FEV1/FEV6 had sensitivity of 95.5% and specificity of 99.4%; the PPV and NPVs were 99.3% and 96.3%. The prevalence of obstruction was 49.4%. For restrictive pattern, FEV6 had sensitivity of 93%, specificity of 79.5% with PPV of 18% and NPV of 99.5%. The prevalence of restriction was 6.3%. CONCLUSIONS: The FEV1/FEV6 ratio can be used as a valid surrogate for FEV1/FVC in the diagnosis of airway obstruction, especially for screening purposes in high-risk populations for COPD. Moreover, FEV6 is an acceptable alternative for FVC in detection of restrictive pattern. PMID- 23682330 TI - Five different types of framing effects in medical situation: a preliminary exploration. AB - BACKGROUND: Considerable reports concerned the framing effect in medical situations. But quite few of them noticed to explore the differences among the various kinds of framing effects. OBJECTIVES: In the present study, five different types of framing effects were examined and the effect sizes of them were compared. MATERIALS AND METHODS: Medical decision making problems concerning medicine effect evaluation, patient's compliance, treatment and doctor options selection were established. All the problems were described in both positive and negative frames. 500 undergraduates as participants were randomly divided into ten groups. Participants from each group were asked to finish one decision making task. RESULTS: ALL THE FRAMES THAT WERE EXAMINED LEADED TO SIGNIFICANT FRAMING EFFECTS: When the Asia Disease Problem was described in a positive frame, the participants preferred the conservative frame than the risky one, while if in a negative frame, the preference reversed (P < 0.01). If the drug effect was described as "of 100 patients taking this kind of medicine, 70 patients became better", people tended to make more positive evaluations, compared with described as "of 100 patients taking this kind of medicine, 30 patients didn't become better" (P < 0.01). Doctors' advices were respectively described in a baneful or beneficial frame and the former one resulted in a better compliance (P < 0.05). If treatment options were described with a survival rate, people tended to choose risky option, while if described with a mortality rate, people tended to choose conservative option (P < 0.05). The number sized framing effect was also tested to be significant (P < 0.01). The five types of framing effects were small to big in effect size. CONCLUSIONS: Medical decision making can be affected by frame descriptions. Attentions should be paid on the standardization of description in medical practice. PMID- 23682331 TI - Application of smoothing methods for determining of the effecting factors on the survival rate of gastric cancer patients. AB - BACKGROUND: Smoothing methods are widely used to analyze epidemiologic data, particularly in the area of environmental health where non-linear relationships are not uncommon. This study focused on three different smoothing methods in Cox models: penalized splines, restricted cubic splines and fractional polynomials. OBJECTIVES: The aim of this study was to assess the effects of prognostic factors on survival of patients with gastric cancer using the smoothing methods in Cox model and Cox proportional hazards. Also, all models were compared to each other in order to find the best one. MATERIALS AND METHODS: We retrospectively studied 216 patients with gastric cancer who were registered in one referral cancer registry center in Tehran, Iran. Age at diagnosis, sex, presence of metastasis, tumor size, histology type, lymph node metastasis, and pathologic stages were entered in to analysis using the Cox proportional hazards model and smoothing methods in Cox model. The SPSS version 18.0 and R version 2.14.1 were used for data analysis. These models compared with Akaike information criterion. RESULTS: In this study, The 5 year survival rate was 30%. The Cox proportional hazards, penalized spline and fractional polynomial models let to similar results and Akaike information criterion showed a better performance for these three models comparing to the restricted cubic spline. Also, P-value and likelihood ratio test in restricted cubic spline was greater than other models. Note that the best model is indicated by the lowest Akaike information criterion. CONCLUSIONS: The use of smoothing methods helps us to eliminate non-linear effects but it is more appropriate to use Cox proportional hazards model in medical data because of its' ease of interpretation and capability of modeling both continuous and discrete covariates. Also, Cox proportional hazards model and smoothing methods analysis identified that age at diagnosis and tumor size were independent prognostic factors for the survival of patients with gastric cancer (P < 0.05). According to these results the early detection of patients at younger age and in primary stages may be important to increase survival. PMID- 23682332 TI - Epidemiology of traumatic brain injury in urmia, iran. PMID- 23682334 TI - Effect of the APOE Polymorphism and Age Trajectories of Physiological Variables on Mortality: Application of Genetic Stochastic Process Model of Aging. AB - We evaluated effects of the APOE polymorphism (carriers versus noncarriers of the e4 allele) and age trajectories of total cholesterol (CH) and diastolic blood pressure (DBP) on mortality risk in the Framingham Heart Study (original cohort). We found that long-lived carriers and noncarriers have different average age trajectories and long-lived individuals have consistently higher levels and less steep declines at old ages compared to short-lived individuals. We applied the stochastic process model of aging aimed at joint analyses of genetic and nongenetic subsamples of longitudinal data and estimated different aging-related characteristics for carriers and noncarriers which otherwise cannot be evaluated from data. We found that such characteristics differ in carriers and noncarriers: (1) carriers have better adaptive capacity than noncarriers in case of CH, whereas for DBP the opposite situation is observed; (2) mean allostatic trajectories are higher in carriers and they differ from "optimal" trajectories minimizing mortality risk; (3) noncarriers have lower baseline mortality rates at younger ages but they increase faster than those for carriers resulting in intersection at the oldest ages. Such observations strongly indicate the presence of a genetic component in respective aging-related mechanisms. Such differences may contribute to patterns of allele- and sex-specific mortality rates. PMID- 23682335 TI - The Relationship between Height and Cognitive Function among Community-dwelling Elderly: Hallym Aging Study. AB - OBJECTIVES: Height is known as an index that reflects the environment of the fetal, childhood, and adolescent periods, which affect adult health. This study was conducted to elucidate whether height is associated with cognitive impairment in community-dwelling elders in Korea. METHODS: The study subjects were recruited among community dwelling elderly individuals aged 65 or over who participated in the 2004 Hallym Aging Study. They were invited to a general hospital and were evaluated for socioeconomic status, smoking history, and various clinical measures. Cognitive function measurement was performed using the Korean-Mini Mental State Examination. Logistic regression was used to evaluate the association between height and cognitive function. RESULTS: After adjusting for potential covariates such as age and education, the smallest group was associated with higher risk of cognitive impairment compared with the tallest group among elderly men (odds ratio [OR], 4.20; 95% confidence interval [CI], 1.02-17.36), but not among elderly women (OR,1.65; 95% CI, 0.62-4.40). CONCLUSIONS: The reason for this difference according to sex may be explained by the differential effects of education on cognitive function by sex. A larger population-based prospective cohort study is needed to examine the association between height and cognitive function according to sex. PMID- 23682336 TI - Cohort study of risk factors for breast cancer in post menopausal women. AB - OBJECTIVES: The present study assessed more than 800 potential risk factors to identify new predictors of breast cancer and compare the independence and relative importance of established risk factors. METHODS: Data were collected by the Women's Health Initiative and included 147,202 women ages 50 to 79 who were enrolled from 1993 to 1998 and followed for 8 years. Analyses performed in 2011 and 2012 used the Cox proportional hazard regression to test the association between more than 800 baseline risk factors and incident breast cancer. RESULTS: Baseline factors independently associated with subsequent breast cancer at the p<0.001 level (in decreasing order of statistical significance) were breast aspiration, family history, age, weight, history of breast biopsies, estrogen and progestin use, fewer live births, greater age at menopause, history of thyroid cancer, breast tenderness, digitalis use, alcohol intake, white race, not restless, no vaginal dryness, relative with prostate cancer, colon polyps, smoking, no breast augmentation, and no osteoporosis. Risk factors previously reported that were not independently associated with breast cancer in the present study included socioeconomic status, months of breast feeding, age at first birth, adiposity measures, adult weight gain, timing of initiation of hormone therapy, and several dietary, psychological, and exercise variables. Family history was not found to alter the risk associated with other factors. CONCLUSIONS: These results suggest that some risk factors not commonly studied may be important for breast cancer and some frequently cited risk factors may be relatively unimportant or secondary. PMID- 23682337 TI - Ownership and less cost for scientists and physicians. PMID- 23682338 TI - Image fusion pitfalls for cranial radiosurgery. AB - Stereotactic radiosurgery requires imaging to define both the stereotactic space in which the treatment is delivered and the target itself. Image fusion is the process of using rotation and translation to bring a second image set into alignment with the first image set. This allows the potential concurrent use of multiple image sets to define the target and stereotactic space. While a single magnetic resonance imaging (MRI) sequence alone can be used for delineation of the target and fiducials, there may be significant advantages to using additional imaging sets including other MRI sequences, computed tomography (CT) scans, and advanced imaging sets such as catheter-based angiography, diffusor tension imaging-based fiber tracking and positon emission tomography in order to more accurately define the target and surrounding critical structures. Stereotactic space is usually defined by detection of fiducials on the stereotactic head frame or mask system. Unfortunately MRI sequences are susceptible to geometric distortion, whereas CT scans do not face this problem (although they have poorer resolution of the target in most cases). Thus image fusion can allow the definition of stereotactic space to proceed from the geometrically accurate CT images at the same time as using MRI to define the target. The use of image fusion is associated with risk of error introduced by inaccuracies of the fusion process, as well as workflow changes that if not properly accounted for can mislead the treating clinician. The purpose of this review is to describe the uses of image fusion in stereotactic radiosurgery as well as its potential pitfalls. PMID- 23682339 TI - Treatment-related brain tumor imaging changes: So-called "pseudoprogression" vs. tumor progression: Review and future research opportunities. AB - BACKGROUND: Glioblastoma multiforme (GBM) has a dismal prognosis despite aggressive therapy. Initial diagnosis and measurement of response to treatment is usually determined by measurement of gadolinium-enhanced tumor volume with magnetic resonance imaging (MRI). Unfortunately, many GBM treatment modalities can cause changes in tumor gadolinium enhancement patterns that mimic tumor progression. The lack of a definitive imaging modality to distinguish posttreatment radiographic imaging changes (PTRIC), including pseudoprogression and radiation necrosis, from true tumor progression presents a major unmet clinical need in the management of GBM patients. METHODS: The authors discuss current modalities available for differentiating PTRIC and tumor progression, describe development of an animal model of PTRIC, and consider potential molecular and cellular pathways involved in the development of PTRIC. RESULTS: An animal model using glioma cells transfected with a luciferase reporter has been developed, and after conventional GBM therapy, this animal model can be evaluated with posttreatment bioluminescence imaging and various MR tumor imaging modalities. CONCLUSIONS: Posttreatment radiographic changes that mimic tumor progression can influence clinicians to make treatment decisions that are inappropriate for the patient's actual clinical condition. Several imaging modalities have been used to try to distinguish PTRIC and true progression, including conventional MRI, perfusion MRI, MR spectroscopy, and positron emission tomography (PET); however, none of these modalities has consistently and reliably distinguished PTRIC from tumor growth. An animal model using glioma cells transfected with a luciferase reporter may enable mechanistic studies to determine causes and potential treatments for PTRIC. PMID- 23682341 TI - The impact of stereotactic radiosurgery in the management of neurofibromatosis type 2-related vestibular schwannomas. AB - Although there is an ongoing debate about the ideal management of vestibular schwannomas, radiosurgical treatment has become popular in the past decade with good to excellent results reported. Given the young age at presentation, the bilateral nature of vestibular schwanomas, the presence of other associated central nervous system tumors, patients with neurofibromatosis Type 2 (NF2) are very complex and present significant management challenges. Although results do not seem to be as good as for patients with sporadic unilateral tumors, stereotactic radiosurgery has proven a safe, attractive, and effective management modality for NF2 vestibular schwannomas. An overview of the impact stereotactic radiosurgery has had in the management of these tumors is discussed. PMID- 23682340 TI - Neuromodulation for cephalgias. AB - Headaches (cephalgias) are a common reason for patients to seek medical care. There are groups of patients with recurrent headache and craniofacial pain presenting with malignant course of their disease that becomes refractory to pharmacotherapy and other medical management options. Neuromodulation can be a viable treatment modality for at least some of these patients. We review the available evidence related to the use of neuromodulation modalities for the treatment of medically refractory craniofacial pain of different nosology based on the International Classification of Headache Disorders, 2(nd) edition (ICHD II) classification. This article also reviews the scientific rationale of neuromodulation application in management of cephalgias. PMID- 23682342 TI - Maps of the adult human hypothalamus. AB - The human hypothalamus is a small deeply located region placed at the crossroad of neurovegetative, neuroendocrine, limbic, and optic systems. Although deep brain stimulation techniques have proven that it could be feasible to modulate these systems, targeting the hypothalamus and in particular specific nuclei and white bundles, is still challenging. Our goal was to make a synthesis of relevant topographical data of the human hypothalamus, under the form of magnetic resonance imaging maps useful for mastering its elaborated structure as well as its neighborhood. As from 1.5 Tesla, Inversion-Recovery sequence allows locating the hypothalamus and most of its components. Spotting hypothalamic compartments is possible according to specific landmarks: the anterior commissure, the mammillary bodies, the preoptic recess, the infundibular recess, the crest between the preoptic and the infundibular recesses, the optical tract, the fornix, and the mammillo-thalamic bundle. The identification of hypothalamus and most of its components could be useful to allow the quantification of local pathological processes and to target specific circuitry to alleviate severe symptoms, using physical or biological agents. PMID- 23682344 TI - Multi-target neurostimulation for adequate long-term relief of neuropathic and nociceptive chronic pain components. AB - Successful treatment of chronic pain for patients with failed back surgery syndrome can be extremely complicated. These patients require careful and individualized clinical assessment, as they often present with mixed pain syndromes that involve both neuropathic and nociceptive components. The distinct types of pain involved in such cases may require combined treatments from individual interventions that are analgesically independent and specific for each type of pain involved. Neuromodulation by electric stimulation at appropriately chosen targets and combinations may be an important option to consider for such patients. We present a case of combined debilitating axial nociceptive spinal pain and bilateral neuropathic leg pain in a patient after 14 failed back operations. A combination of spinal cord stimulation (SCS) and deep brain stimulation in the periventricular gray (PVG) have successfully provided the patient with complete relief of both components of his chronic pain condition, after all other pain management options had been exhausted. By alternating activation of each implanted stimulator separately and in conjunction, we were able to demonstrate a clinically independent analgesic character for each stimulation system, each specific to a particular type of pain. The SCS provided complete relief of the neuropathic pain component, without affecting the nociceptive component at all. The PVG stimulation provided complete relief of the nociceptive component, without affecting the neuropathic component at all. In combination, there was complete relief of the total chronic pain condition. There appeared to be no overlapping or synergistic effect between the two neuromodulation systems in the patient. The patient has had prolonged complete relief from his chronic pain condition with the combined neuromodulation intervention over 22 years of follow-up. PMID- 23682343 TI - Stereotactic surgery for eating disorders. AB - EATING DISORDERS (EDS) ARE A GROUP OF SEVERELY IMPAIRED EATING BEHAVIORS, WHICH INCLUDE THREE SUBGROUPS: anorexia nervosa (AN), bulimia nervosa (BN), and ED not otherwise specified (EDNOS). The precise mechanism of EDs is still unclear and the disorders cause remarkable agony for the patients and their families. Although there are many available treatment methods for EDs today, such as family therapy, cognitive behavioral therapy, medication, psychotherapy, and so on, almost half of the patients are refractory to all current medical treatment and never fully recover. For treatment-refractory EDs, stereotactic surgery may be an alternative therapy. This review discusses the history of stereotactic surgery, the modern procedures, and the mostly used targets of stereotactic surgery in EDs. In spite of the limited application of stereotactic surgery in ED nowadays, stereotactic lesion and deep brain stimulation (DBS) are promising treatments with the development of modern functional imaging techniques and the increasing understanding of its mechanism in the future. PMID- 23682345 TI - Diagnostic yield of stereotactic needle-biopsies of sub-cubic centimeter intracranial lesions. AB - BACKGROUND: Stereotactic brain biopsies are widely used for establishing the diagnosis of intracranial lesions. Here we examine whether stereotactic biopsy of smaller brain lesions, defined for this study as being less than 1 cubic centimeter (1 cc) in volume, are associated with lowered diagnostic yield. METHODS: We conducted a retrospective analysis of 267 consecutive patients who underwent stereotactic brain biopsy between 2007 and 2011. Lesion volumes were calculated and were stratified by <1 or >1 cc. RESULTS: A total of 13 of 246 (5.2%) biopsies for lesions >1 cc resulted in nondiagnostic tissue or an incorrect diagnosis. In contrast, 5 of 21 (23.8%) biopsies for <1 cc lesions yielded nondiagnostic or incorrect diagnosis. Posthoc review of tissue from the <1 cc lesions suggests the neuropathologist's expertise in the handling and analysis of limited specimen as a critical parameter of successful diagnosis. The operative morbidities were low for both the <1 and >1 cc biopsies (0% and 1%, respectively). CONCLUSION: This study demonstrates that stereotactic cerebral biopsy of lesions less than a cubic centimeter in volume results in a lower diagnostic yield versus larger lesions (76.2% versus 94.8%). While auxiliary measures may be taken to improve diagnostic yield, these patients may be best managed in a specialized center with experienced stereotactic neurosurgeons and neuropathologists. PMID- 23682346 TI - Quantitative and Sensitive Detection of Cancer Genome Amplifications from Formalin Fixed Paraffin Embedded Tumors with Droplet Digital PCR. AB - For the analysis of cancer, there is great interest in rapid and accurate detection of cancer genome amplifications containing oncogenes that are potential therapeutic targets. The vast majority of cancer tissue samples are formalin fixed and paraffin embedded (FFPE) which enables histopathological examination and long term archiving. However, FFPE cancer genomic DNA is oftentimes degraded and generally a poor substrate for many molecular biology assays. To overcome the issues of poor DNA quality from FFPE samples and detect oncogenic copy number amplifications with high accuracy and sensitivity, we developed a novel approach. Our assay requires nanogram amounts of genomic DNA, thus facilitating study of small amounts of clinical samples. Using droplet digital PCR (ddPCR), we can determine the relative copy number of specific genomic loci even in the presence of intermingled normal tissue. We used a control dilution series to determine the limits of detection for the ddPCR assay and report its improved sensitivity on minimal amounts of DNA compared to standard real-time PCR. To develop this approach, we designed an assay for the fibroblast growth factor receptor 2 gene (FGFR2) that is amplified in a gastric and breast cancers as well as others. We successfully utilized ddPCR to ascertain FGFR2 amplifications from FFPE-preserved gastrointestinal adenocarcinomas. PMID- 23682348 TI - Palm-based diacylglycerol fat dry fractionation: effect of crystallisation temperature, cooling rate and agitation speed on physical and chemical properties of fractions. AB - Fractionation which separates the olein (liquid) and stearin (solid) fractions of oil is used to modify the physicochemical properties of fats in order to extend its applications. Studies showed that the properties of fractionated end products can be affected by fractionation processing conditions. In the present study, dry fractionation of palm-based diacylglycerol (PDAG) was performed at different: cooling rates (0.05, 0.5, 1.0, 1.5, 2.0, 2.5 and 3.0 degrees C/min), end crystallisation temperatures (30, 35, 40, 45 and 50 degrees C) and agitation speeds (30, 50, 70, 90 and 110 rpm) to determine the effect of these parameters on the properties and yield of the solid and liquid portions. To determine the physicochemical properties of olein and stearin fraction: Iodine value (IV), fatty acid composition (FAC), acylglycerol composition, slip melting point (SMP), solid fat content (SFC), thermal behaviour tests were carried out. Fractionation of PDAG fat changes the chemical composition of liquid and solid fractions. In terms of FAC, the major fatty acid in olein and stearin fractions were oleic (C18:1) and palmitic (C16:0) respectively. Acylglycerol composition showed that olein and stearin fractions is concentrated with TAG and DAG respectively. Crystallization temperature, cooling rate and agitation speed does not affect the IV, SFC, melting and cooling properties of the stearin fraction. The stearin fraction was only affected by cooling rate which changes its SMP. On the other hand, olein fraction was affected by crystallization temperature and cooling rate but not agitation speed which caused changes in IV, SMP, SFC, melting and crystallization behavior. Increase in both the crystallization temperature and cooling rate caused a reduction of IV, increment of the SFC, SMP, melting and crystallization behaviour of olein fraction and vice versa. The fractionated stearin part melted above 65 degrees C while the olein melted at 40 degrees C. SMP in olein fraction also reduced to a range of 26 to 44 degrees C while SMP of stearin fractions increased to (60-62 degrees C) compared to PDAG. PMID- 23682347 TI - Chronobiological Effects on Obesity. AB - The development of obesity is the consequence of a multitude of complex interactions between both genetic and environmental factors. It has been suggested that the dramatic increase in the prevalence of obesity over the past 30 years has been the result of environmental changes that have enabled the full realization of genetic susceptibility present in the population. Among the many environmental alterations that have occurred in our recent history is the ever increasing dyssynchrony between natural cycles of light/dark and altered patterns of sleep/wake and eating behavior associated with our "24-hour" lifestyle. An extensive research literature has established clear links between increased risk for obesity and both sleep deprivation and shift work, and our understanding of the consequences of such dyssynchrony at the molecular level is beginning to emerge. Studies linking alterations in cellular circadian clocks to metabolic dysfunction point to the increasing importance of chronobiology in obesity etiology. PMID- 23682349 TI - Eye blink correction: a test on the preservation of common ERP components using a regression based technique. AB - Eye blinks are a pervasive problem in electroencephalography research as they contaminate the brain signal. This paper tests the merits of a software tool employing the regression-based Gratton method that claims to remove the detrimental effects of the eye blink and leaves the activity of the brain. The efficacy of the correction tool was tested on five common stimulus-locked Event Related Potential (ERP) components used in a standard Go/Nogo task. Results suggested that the 'corrected' data could be predicted from data containing no eye blinks, suggesting the tool does not distort the data to great extent. This effect was found significant for all components, except for the P3. The conclusion is that this tool distorts the data at acceptable levels, yet caution should be taken when interpreting later components, like the P3. PMID- 23682350 TI - Assessing the Global Burden of Ischemic Heart Disease: Part 1: Methods for a Systematic Review of the Global Epidemiology of Ischemic Heart Disease in 1990 and 2010. AB - BACKGROUND: Ischemic heart disease (IHD) is the leading cause of death worldwide. The GBD (Global Burden of Disease, Injuries, and Risk Factors) study (GBD 2010 Study) conducted a systematic review of IHD epidemiology literature from 1980 to 2008 to inform estimates of the burden on IHD in 21 world regions in 1990 and 2010. METHODS: The disease model of IHD for the GBD 2010 Study included IHD death and 3 sequelae: myocardial infarction, heart failure, and angina pectoris. Medline, EMBASE, and LILACS were searched for IHD epidemiology studies in GBD high-income and low- and middle-income regions published between 1980 and 2008 using a systematic protocol validated by regional IHD experts. Data from included studies were supplemented with unpublished data from selected high-quality surveillance and survey studies. The epidemiologic parameters of interest were incidence, prevalence, case fatality, and mortality. RESULTS: Literature searches yielded 40,205 unique papers, of which 1,801 met initial screening criteria. Upon detailed review of full text papers, 137 published studies were included. Unpublished data were obtained from 24 additional studies. Data were sufficient for high-income regions, but missing or sparse in many low- and middle-income regions, particularly Sub-Saharan Africa. CONCLUSIONS: A systematic review for the GBD 2010 Study provided IHD epidemiology estimates for most world regions, but highlighted the lack of information about IHD in Sub-Saharan Africa and other low-income regions. More complete knowledge of the global burden of IHD will require improved IHD surveillance programs in all world regions. PMID- 23682351 TI - Inhibition of glutathione synthesis in brain endothelial cells lengthens S-phase transit time in the cell cycle: Implications for proliferation in recovery from oxidative stress and endothelial cell damage. AB - Oxidative stress-induced decrease in tissue or systemic glutathione (GSH) and damage to the vascular endothelium of the blood-brain barrier such as occurs in diabetes or stroke will have important implications for brain homeostasis. Endothelial proliferation or repair is crucial to preserving barrier function. Cell proliferation has been associated with increased intracellular GSH, but the kinetic and distribution of GSH during cell cycle is poorly understood. Here, we determined the influence of cellular GSH status on the early dynamics of nuclear to-cytosol (N-to-C) GSH distribution (6-h interval) during proliferation in a human brain microvascular endothelial cell line (IHEC). Control IHECs exhibited two peak S-phases of the cell cycle at 48 and 60 h post seeding that temporally corresponded to peak nuclear GSH levels and expression of cdk1, the S-to-G2-to-M checkpoint controller, suggesting a link between cell cycle progression and nuclear GSH. Sustained inhibition of GSH synthesis delayed S-to-G2/M cell transition; cell arrest in the S-phase was correlated with decreased total nuclear GSH and increased nuclear expressions of chk2/phospho-chk2 and GADPH. The temporal correspondence of nuclear chk2 activation and GAPDH expression with S phase prolongation is consistent with enhanced DNA damage response and extended time for DNA repair. Strikingly, when GSH synthesis was restored, cell transit time through S-phase remained delayed. Significantly, total nuclear GSH remained depressed, indicating a time lag between restored cellular GSH synthetic capacity and recovery of the nuclear GSH status. Interestingly, despite a delay in cell cycle recovery, nuclear expressions of chk2/phospho-chk2 and GAPDH resembled those of control cells. This means that restoration of nuclear DNA integrity preceded normalization of the cell cycle. The current results provide important insights into GSH control of endothelial proliferation with implications for cell repair or wound healing in recovery post-oxidative damage. PMID- 23682352 TI - Locked nucleic acid: tighter is different. AB - This viewpoint briefly reviews the impact of Locked Nucleic Acid (LNA) oligonucleotides, first described in a ChemComm paper in 1998. A number of unique applications in oligonucleotide biotechnology have been made possible by the high binding affinity and specificity of LNA, and these provide the main focus of the viewpoint. PMID- 23682353 TI - Electrochemical synthesis of p-type Zn-doped alpha-Fe2O3 nanotube arrays for photoelectrochemical water splitting. AB - A facile electrochemical method is developed to synthesize p-type Zn-doped alpha Fe2O3 nanotube arrays that demonstrate excellent photoelectrochemical properties for water splitting. PMID- 23682354 TI - Synthesis and enhanced thermal stability of albumins@alumina: towards injectable sol-gel materials. AB - A major obstacle to the introduction of bioactively-doped sol-gel based materials for medical applications has been the fact that silica - the most widely studied sol-gel material - despite being a GRAS material, which is widely used as an additive in foods and drug formulations, is still not approved by regulatory agencies for intramuscular injections. Here we point to a potential solution to this problem by shifting the weight to alumina, which is approved for injections as the most common immunization adjuvant. Towards the achievement of this goal we describe the development of protein entrapment methods tailored to alumina, and show high thermal stability of protein-dopants, using a newly developed DSC methodology for this purpose. PMID- 23682355 TI - Superior electrochemical properties of Co3O4 yolk-shell powders with a filled core and multishells prepared by a one-pot spray pyrolysis. AB - Highly crystalline Co3O4 yolk-shell powders with a filled core and various shell numbers are prepared by a simple one-pot spray pyrolysis process. Co3O4 yolk shell powders exhibited a high initial discharge capacity of 548 mA h g(-1) and retained their capacities very well, even at a high discharge rate of 10,000 mA g(-1). PMID- 23682356 TI - Tb(III) functionalized vesicles for phosphate sensing: membrane fluidity controls the sensitivity. AB - We report a modular design of vesicular chemosensors by co-embedding a Tb(III) complex and a receptor-sensitizer conjugate in phospholipid vesicles. The binding of phosphate anions to the vesicle surface in aqueous media is detected by a decrease in Tb(III) phosphorescence. The sensory response can be modulated by a variation in the membrane fluidity. PMID- 23682357 TI - Copper-catalyzed synthesis of trifluoromethyl-substituted isoxazolines. AB - A mild and efficient copper-catalyzed trifluoromethylation reaction which involves the cyclization of oximes has been developed. This method provides a convenient access to a variety of useful CF3-containing 4,5-dihydroisoxazoles by constructing a C-CF3 bond and a C-O bond in one step. PMID- 23682358 TI - Room temperature synthesis of free-standing HKUST-1 membranes from copper hydroxide nanostrands for gas separation. AB - Large scale, robust, well intergrown free-standing HKUST-1 membranes were converted from copper hydroxide nanostrand free-standing films in 1,3,5 benzenetricarboxylic acid water-ethanol solution at room temperature, and explored for gas separation. The truncated crystals are controllable and favorable for the dense intergrowth. PMID- 23682359 TI - Highly sensitive electrochemiluminescent cytosensing using carbon nanodot@Ag hybrid material and graphene for dual signal amplification. AB - Here we use functionalized carbon nanodots (C-dots) as novel electrochemiluminescence (ECL) probes and graphene nanosheets as signal amplification agents for highly sensitive and selective cancer cell detection. The ECL cytosensor shows superior cell-capture ability and exhibits a wide linear range and a low detection limit for cancer cells. PMID- 23682360 TI - A room temperature decarboxylation/C-H functionalization cascade by visible-light photoredox catalysis. AB - An elegant approach to quaternary oxindole formation has been developed through a room temperature decarboxylation/radical C-H functionalization by visible-light photoredox catalysis. PMID- 23682361 TI - Touch imprint matters.... PMID- 23682362 TI - [Clinical section - autopsy as instrument of quality assurance and continung education]. PMID- 23682363 TI - [Court decision of LG Fulda of 28 May 2009, AZ: 2 O 460/07 / court decision OLG Kassel of 27 November 2012, AZ: 14 U 134/09 - diagnostic assessment error by omission of relaparotomy]. PMID- 23682364 TI - Fingerprint changes and verification failure among patients with hand dermatitis. AB - OBJECTIVES: To determine the prevalence of fingerprint verification failure and to define and quantify the fingerprint changes associated with fingerprint verification failure. DESIGN: Case-control study. SETTING: Referral public dermatology center. PATIENTS: The study included 100 consecutive patients with clinical hand dermatitis involving the palmar distal phalanx of either thumb and 100 age-, sex-, and ethnicity-matched controls. Patients with an altered thumb print due to other causes and palmar hyperhidrosis were excluded. MAIN OUTCOME MEASURES: Fingerprint verification(pass/fail) and hand eczema severity index score. RESULTS: Twenty-seven percent of patients failed fingerprint verification compared with 2% of controls. Fingerprint verification failure was associated with a higher hand eczema severity index score (P.001). The main fingerprint abnormalities were fingerprint dystrophy (42.0%) and abnormal white lines (79.5%). The number of abnormal white lines was significantly higher among the patients with hand dermatitis compared with controls(P=.001). Among the patients with hand dermatitis, theodds of failing fingerprint verification with fingerprint dystrophy was 4.01. The presence of broad lines and long lines was associated with a greater odds of fingerprint verification failure (odds ratio [OR], 8.04; 95% CI, 3.56-18.17 and OR, 2.37; 95% CI, 1.31-4.27, respectively),while the presence of thin lines was protective of verification failure (OR, 0.45; 95% CI, 0.23-0.89). CONCLUSIONS: Fingerprint verification failure is a significant problem among patients with more severe hand dermatitis. It is mainly due to fingerprint dystrophy and abnormal white lines. TRIAL REGISTRATION: Malaysian National Medical Research Register Identifier: NMRR-11-30 8226 PMID- 23682365 TI - Laparoscopic spleen-preserving distal pancreatectomy: splenic vessel preservation compared with the Warshaw technique. AB - OBJECTIVE: To compare preservation with the division of the splenic vessels in the surgical management of laparoscopic spleen-preserving distal pancreatectomy. DESIGN: Bicentric retrospective study. SETTING: Prospectively maintained databases. PATIENTS: Between January 1997 and January 2011, 140 patients who underwent laparoscopic spleen-preserving distal pancreatectomy for benign or lowgrade malignant tumors in the body/tail of the pancreas were included. Patients treated with the attempted splenic vessel preservation were compared with patients treated with the attempted division of the splenic vessels (Warshaw technique). MAIN OUTCOME MEASURES: Operative outcomes and postoperative morbidity were evaluated. RESULTS: The outcomes of 55 patients in the splenic vessel preservation group were compared with those of 85 patients in the Warshaw technique group. The clinical characteristics were similar in both groups, except for tumor size, which was significantly greater in the Warshaw technique group (33.6 vs. 42.5 mm; P=.001). The mean operative time, mean blood loss, and rate of conversion to the open procedure did not differ between the 2 groups. The rate of successful spleen preservation was significantly improved following the splenic vessel preservation technique (96.4% vs. 84.7%; P=.03). Complications related to the spleen only occurred in the Warshaw technique group (0% vs. 10.5%; P=.03), requiring a splenectomy in 4 patients (4.7%). The mean length of stay was shorter in the splenic vessel preservation group (8.2 vs. 10.5 days; P=.01). CONCLUSIONS: The short-term benefits associated with the preservation of the splenic vessels should lead to an increased preference for this technique in selected patients undergoing laparoscopic spleen-preserving distal pancreatectomy for benign or low grade malignant tumors in the body/tail of the pancreas. PMID- 23682366 TI - Raynaud phenomenon of the nipple in breastfeeding mothers: an underdiagnosed cause of nipple pain. AB - OBJECTIVE: To elucidate the diagnostic criteria of Raynaud phenomenon of the nipple that will aid in recognizing and treating Raynaud phenomenon in breast feeding mothers with chronic deep nipple pain during lactation. DESIGN: Retrospective review of a patient database composed of 22 cases of breastfeeding mothers who fit the diagnostic criteria for Raynaud phenomenon of the nipple. SETTING: Menlo Dermatology Medical Group in Menlo Park, California, an academic affiliated, private dermatologic referral center. PATIENTS: All patients diagnosed as having Raynaud phenomenon of the nipple evaluated from January 1, 2004,through December 31, 2010. MAIN OUTCOME MEASURES: The rate of failed treatment for Candida mastitis, the rate of improvement of symptoms with nifedipine use, and the overall rate of improvement of symptoms with appropriate therapy involving treatment of Raynaud phenomenon. RESULTS: Among the 22 patients with Raynaud phenomenon of the nipple, previous treatment for Candida mastitis with oral or topical antifungals was ineffective in 20(91%). Of the 12 patients who tolerated a trial of nifedipine,10 (83%) reported decreased or resolved nipple pain. All patients experienced marked improvement of symptoms with appropriate therapy involving treatment of Raynaud phenomenon. CONCLUSIONS: Most patients were treated with antifungals before presentation without resolution of nipple pain. Nifedipine appears to be an effective medication for the treatment of Raynaud phenomenon of the nipple. With appropriate management of Raynaud phenomenon,breastfeeding mothers demonstrated improvement of nipple pain. Raynaud phenomenon of the nipple should be considered in the differential diagnosis of nipple pain during lactation. PMID- 23682367 TI - Hair care practices as a barrier to physical activity in African American women. AB - OBJECTIVE: To characterize the influence of hair style maintenance on exercise behavior in African American women. DESIGN: A 40-item survey with questions concerning hair care practices, physical activity, and the relationship between the two. SETTING: University-affiliated dermatology department at an academic medical center in Winston-Salem, North Carolina. PARTICIPANTS: A total of 123 African American women from 21 to 60 years of age were surveyed; 103 women completed the questionnaire. MAIN OUTCOME MEASURES: The statistical significance of relationships between hair care practices and physical activity was determined. RESULTS: Fifty percent of African American women surveyed have modified their hair style to accommodate exercise and nearly 40% (37.9%) avoid exercise at times owing to hair-related issues. Respondents who exercised less owing to hair concerns were 2.9 times less likely to exercise more than 150 min/wk (95% CI,0.9-9.4; P=.08). CONCLUSION: Dermatologists can discuss hair management strategies during exercise that facilitate routinely performing exercise. PMID- 23682368 TI - Opioid pain medication use after dermatologic surgery: a prospective observational study of 212 dermatologic surgery patients. AB - OBJECTIVE: To better understand postoperative opioid use after dermatologic surgery. DESIGN: Prospective observational study. SETTING: Academic dermatology department. PATIENTS: The study included 212 adults (1) who were undergoing a single skin excision (including Mohs micrographic surgery), (2) who consented to participate,and (3) who were able to be reached by telephone on postoperative day 3 or 4. Patients who did not meet these criteria and those referred to another physician for further surgical treatment or repair were excluded. MAIN OUTCOME MEASURES: The study examined(1) the incidence of opioid prescription after dermatologic surgery, (2) the percentage of prescribed opioid pain medications used in the postoperative period, and (3) patient and surgical characteristics associated with opioid pain medication prescription and use. RESULTS: Opioids were prescribed to 72 of the 212 patients(34%). Twenty-five of the 72 patients (35%) who were prescribed opioids did not use them. Forty-nine of 57 patients (86%) who filled an opioid prescription had leftover pills, and 26 of the 49 patients (53%) planned to keep them. Only maximum pain score was significantly associated with opioid use. CONCLUSIONS: Opioids were over prescribed after dermatologic surgery. Patients who had left over opioids did not dispose of them properly, which could lead to potential misuse and abuse. PMID- 23682369 TI - No-scar transanal total mesorectal excision: the last step to pure NOTES for colorectal surgery. AB - HYPOTHESIS: Because of the concerns over the operative platform, accidental organ injury, and viscerotomy closure, natural orifice transluminal endoscopic surgery (NOTES) currently remains an experimental technique. Transanal NOTES for colorectal surgery overcomes all of these issues; however, all of the reports to date have used hybrid laparoscopic techniques. We demonstrate herein the first case, to our knowledge, of pure transanal NOTES colorectal surgery. DESIGN: Case report. SETTING: University hospital. PATIENT: The patient was a 56-year-old woman with a midrectal neoplasia. INTERVENTION: Pure transanal NOTES total mesorectal excision with a coloanal anastomosis and without a diverting stoma. Using a transanal endoscopic operation device as a surgical platform, we created a viscerotomy distal to an endoluminal purse-string suture. We performed a total mesorectal excision using a "bottom-up" approach. The sigmoid colon was mobilized by a posterior, retroperitoneal approach and the colon was divided intraperitoneally. A hand-sewn, side-to-end, coloanal anastomosis was performed. Because the viscerotomy was incorporated into the anastomosis, the concerns of both accidental organ damage and viscerotomy closure were abrogated. RESULTS: The procedure was completed entirely by a transanal fashion. We successfully mobilized the rectum, mesorectum, and sigmoid colon. The specimen length was more than 20 cm. The patient required minimal analgesia and her pain was nonabdominal. CONCLUSIONS: To our knowledge, the first pure transanal NOTES total mesorectal excision with retroperitoneal sigmoid mobilization and coloanal, side-to-end anastomosis was successfully performed using what we called a peri-rectal oncologic gateway for retroperitoneal endoscopic single site surgery (PROGRESSS). This monumental case could pave the way for a new era in pure transanal NOTES for colorectal surgery. PMID- 23682370 TI - Virtual neck exploration for parathyroid adenomas: a first step toward minimally invasive image-guided surgery. AB - OBJECTIVE: To evaluate the performance of 3-dimensional (3D) virtual neck exploration (VNE) as a modality for preoperative localization of parathyroid adenomas in primary hyperparathyroidism and assess the feasibility of using augmented reality to guide parathyroidectomy as a step toward minimally invasive imageguided surgery. DESIGN: Enhanced 3D rendering methods can be used to transform computed tomographic scan images into a model for 3D VNE. In addition to a standard imaging modality, 3D VNE was performed in all patients and used to preoperatively plan minimally invasive parathyroidectomy. All preoperative localization studies were analyzed for their sensitivity, specificity, positive predictive value, and negative predictive value for the correct side of the adenoma(s) (lateralization) and the correct quadrant of the neck (localization). The 3D VNE model was used to generate intraoperative augmented reality in 3 cases. SETTING: Tertiary care center. PATIENTS: A total of 114 consecutive patients with primary hyperparathyroidism were included from January 8, 2008, through July 26, 2011. RESULTS: The accuracy of 3D VNE in lateralization and localization was 77.2% and 64.9%, respectively. Virtual neck exploration had superior sensitivity to ultrasonography (P.001), sestamibi scanning (P=.07), and standard computed tomography (P.001). Use of the 3D model for intraoperative augmented reality was feasible. CONCLUSIONS: 3-Dimensional VNE is an excellent tool in preoperative localization of parathyroid adenomas with sensitivity, specificity, and diagnostic accuracy commensurate with accepted first-line imaging modalities. The added value of 3D VNE includes enhanced preoperative planning and intraoperative augmented reality to enable less-invasive image guided surgery. PMID- 23682371 TI - Effect of nutrient supplementation on atopic dermatitis in children: a systematic review of probiotics, prebiotics, formula, and fatty acids. AB - OBJECTIVE: To identify whether nutrient supplementation with probiotics, prebiotics, formula, or fatty acids prevents the development of atopic dermatitis (AD) or reduces the severity of AD in newborns to children younger than 3 years. DATA SOURCES: We searched MEDLINE, Cochrane Central Register of Controlled Trials, and LILACS (Latin American and Caribbean Health Science Literature) from January 1, 1946, to August 27, 2012, and performed an additional manual search. STUDY SELECTION: Randomized controlled trials and cohort studies examining nutritional supplementation in prevention and amelioration of AD among children younger than 3 years. DATA EXTRACTION: Of 92 articles, 21 met inclusion criteria. DATA SYNTHESIS: In the 21 studies, a total of 6859 participants received supplements, which included infants or mothers who were either pregnant or breastfeeding;4134 infants or mothers served as controls. Nutritional supplementation was shown to be an effective method in preventing AD (11 of 17 studies) or decreasing its severity(5 of 6 studies). The best evidence lies with probiotics supplementation in mothers and infants in preventing development and reducing severity of AD. Specifically, Lactobacillus rhamnosus GG was effective in long-term prevention of AD development. gamma-Linolenic acid reduced severity of AD. Supplementation with prebiotics and black currant seed oil (gamma linolenic acid and omega-3 combination) was effective in reducing the development of AD. Conflicting findings were reported from different research groups that performed supplementation with an amino acid-based formula. CONCLUSIONS: Certain types of nutrient supplementation are beneficial in preventing AD development and reducing its severity. Future research elucidating the mechanisms underlying the actions of nutritional supplementation on AD is necessary. PMID- 23682372 TI - FFP:RBC resuscitation ratio and post-shock fluid uptake. AB - OBJECTIVE: To assess the effects of the fresh frozen plasma (FFP) to red blood cell (RBC) ratio and balanced electrolyte solution (BES) to RBC ratio during resuscitation of severely injured patients on the duration of the postoperative fluid uptake period (phase 2) as well as the fluid (BES) needs, weight gain, and hypoproteinemia in phase 2. DESIGN, SETTING, AND PATIENTS: The 316 patients were hypotensive (systolic blood pressure=81 mm Hg) and tachycardic (117/min), with an average shock time (systolic blood pressure 80 mm Hg) of 31 minutes in the operating room (OR); they received 14.2 RBC units, 854 mL of FFP, and 11.5 L of BES while in the OR. Phase 2 averaged 29.2 hours, where the patients gained 8.4 kg, had a serum albumin level of 2.6 g per day, and received 8.6 L of BES. The phase 2 time, BES needs, weight gain, and hypoproteinemia were correlated with systolic blood pressure, admission pulse rate, arterial pH, shock time, RBC, FFP, and BES; the FFP:RBC, BES:RBC, and BES: FFP ratios were given in the OR. RESULTS: Shock time had the best correlation with RBC, FFP, and BES administration in the OR as well as with phase 2 duration, BES needs, weight gain, and hypoproteinemia. There was no significant correlation with OR FFP: RBC, BES:RBC, or BES:FFP ratios and phase 2 hypoproteinemia or weight gain. The FFP:RBC ratio in the OR correlated directly with phase 2 duration and BES needs (P=.001); in contrast, the BES:RBC ratio in the OR correlated (P.001) inversely with phase 2 duration and BES needs. CONCLUSIONS: The severity of shock is best predicted by shock time and the RBC, FFP, and BES infusions in the OR. Contrary to recent reports, the FFP:RBC ratio in the OR correlates directly with duration and BES needs of phase 2, whereas the BES:RBC ratio correlates inversely with phase 2 duration and BES needs. PMID- 23682373 TI - Retraction notice to "Dynamic changes of mitochondrial fission proteins after transient cerebral ischemia in mice" [Brain res.1456 (2012) 94-99]. PMID- 23682374 TI - Retraction notice to "Secretory phospholipase A2 IIA is up-regulated by TNF-alpha and IL-1alpha/beta after transient focal cerebral ischemia in rat" [Brain res. 1134 (2007) 199-205]. PMID- 23682375 TI - Bibliography. Current world literature. Biliary tract. PMID- 23682376 TI - [A biography of Daniel Marchac, a pioneer among plastic surgeons. December 3,1936 October 15,2012]. PMID- 23682377 TI - Venous leg ulcer healing in primary care. PMID- 23682378 TI - Rallying for research. PMID- 23682379 TI - First candidate HIV vaccine to employ Sendai vector poised for trials. PMID- 23682380 TI - State laws on biosimilars may drive up plans' costs. PMID- 23682381 TI - Renewed interest in shared decision making. PMID- 23682382 TI - Comparison of sealing ability of MTA and EndoSequence Bioceramic Root Repair Material: a bacterial leakage study. AB - OBJECTIVE: To compare the sealing ability of ProRoot mineral trioxide aggregate (MTA) to the sealing ability of EndoSequence Bioceramic Root Repair Material (ES BCRR) putty using a bacterial leakage model. METHOD AND MATERIALS: Root canals of 60 single-rooted extracted teeth were enlarged to an apical diameter of 0.5 mm using EndoSequence files. The apical 3 mm of each root was sectioned at 90 degrees to the long axis of the root. An ultrasonic surgical tip was used to prepare a 3-mm deep root-end preparation in all teeth. Teeth were equally divided into four groups: Group 1, MTA; Group 2, ES-BCRR putty; Group 3, positive control, gutta-percha without sealer; Group 4, negative control, sealed with wax and nail varnish. Prepared teeth were kept moist for 48 hours to allow for initial setting of the materials. After ethylene oxide sterilization, the teeth were suspended in sterilized vials containing 3% phenol lactose broth and inoculated with Enterococcus faecalis through the occlusal access openings. The samples were observed daily for leakage to a maximum of 28 days. Chi-square and Fisher exact tests were used to compare the experimental groups and an alpha level of significance was set at P = .05. RESULTS: In the ES-BCRR group 93% of samples leaked, compared to only 20% of samples in the MTA group. There was a significant difference in leakage between the experimental groups (P < .0001). Also there were no significant differences between the negative control group and MTA group and between the positive control group and ES-BCRR group (P = 1.00). CONCLUSION: Samples in the ES-BCRR group leaked significantly more than samples in the MTA group. PMID- 23682383 TI - Abstracts of the Health Services Research & Pharmacy Practice Conference. May 9 10, 2013. Preston, United Kingdom. PMID- 23682384 TI - Partial retraction. Antigen aggregation decides the fate of the allergic immune response. PMID- 23682385 TI - Keeping baby boomer construction workers working. PMID- 23682386 TI - The expression and clinical significance of Omi/Htra2 in hepatocellular carcinoma. AB - BACKGROUND/AIMS: To investigate Omi/HtrA2 expression and its clinical significance in hepatocellular carcinoma. METHODOLOGY: We analyzed Omi/HtrA2 expression in hepatocellular carcinoma, paracancerous tissues and normal hepatic tissues by immunohistochemistry, RT-PCR and Western blot. Hypoxia-inducible factor-1alpha (HIF-1alpha) expression was also detected in hepatocellular carcinoma samples by immunohistochemistry. Meanwhile, we retrospectively analyzed the relationship between Omi/HtrA2 expression and the survival times of the patients. RESULTS: We found that Omi/HtrA2 overexpressed in hepatocellular carcinoma and was correlated with hepatocellular carcinoma differentiation, tumor size, portal vein invasion, clinical stage and lymph node metastasis. We also observed a significant inverse correlation between the expression of Omi,/HtrA2 and HIF-1alpha in hepatocellular carcinoma. The Kaplan-Meier estimates showed that patients who were Omi/HtrA2 positive had much longer survival times than those who were Omi/HtrA2 negative. Both univariate and multivariate analysis using the Cox regression model indicated that Omi/HtrA2 expression was a significant factor for prognosis. CONCLUSIONS: Hepatocellular carcinoma cells may need Omi/HtrA2 expression for apoptosis and Omi/HtrA2 might be an important prognostic marker for primary hepatocellular carcinoma. PMID- 23682387 TI - Measurement of transporter associated with antigen processing 1 and tumor necrosis factor alpha expression in hepatitis B virus-related hepatocellular carcinoma and peritumor cirrhosis tissues using tissue chip technology. AB - BACKGROUND/AIMS: The objective of this study was to explore the associations of expression of transporter associated with antigen processing 1 (TAP1) and tumor necrosis factor alpha (TNF-alpha with the occurrence and development of HBV related hepatocellular carcinoma (HCC). METHODOLOGY: The expression of TAP1 and TNF-alpha in 38 HCC, 32 peritumor liver cirrhosis and 28 normal liver tissues, were assessed by immunohistochemical assay using tissue microarray technology. RESULTS: TAP1 and TNF-alpha were negative in normal liver tissue hut positive in HCC and peritumor cirrhosis tissue. There were no significant differences in the rates of positivity for TAP1 and TNF-alpha between HCC and peritumor cirrhosis tissue (p>0.05), but there was a significant difference when rates in HCC and peritumor cirrhosis tissue were compared with those in normal liver tissue (p<0.0001, p<0.01, respectively). The degree of differentiation of HCC was correlated with TNF-alpha expression (p<0.05), but not TAP1 expression (p>0.05), CONCLUSIONS: Major histocompatibility complex class I molecules are involved in HBV-related HCC. TNF-alpha plays an important role in liver cirrhosis and in formation and development of HCC following HBV infection. TNF-alpha can be used as an indicator of the degree of differentiation of HCC. PMID- 23682388 TI - Degradable nanoscale shells could provide unique cancer treatment method. PMID- 23682389 TI - Minimal peptides can enhance nanoparticle drug delivery by inhibiting phagocytic clearance. PMID- 23682390 TI - Polyglutamte-directed coupling of nanocages for the targeted delivery of bioactive molecules to allografts and hydroxyapatite-containing implants. PMID- 23682391 TI - Sex steroid- and peptide hormone-releasing multilayered alginate microsphere: role of structure-function relationship. PMID- 23682392 TI - Abstracts of the First Global Conference on Contraception, Reproductive and Sexual Health. May 22-25, 2013. Copenhagen, Denmark. PMID- 23682393 TI - Centres worldwide review percutaneous coronary intervention vs. CABG guidelines for diabetic patients following FREEDOM study. PMID- 23682394 TI - Results from the AHA late-breaking trials on cell-based therapies. PMID- 23682395 TI - Working in Asia: the siren song of Singapore. PMID- 23682396 TI - Privacy in the digital age. PMID- 23682397 TI - Science in schools. PMID- 23682398 TI - Together we stand. PMID- 23682400 TI - Abstracts of the 50th ERA-EDTA (European Renal Association-European Dialysis and Transplant Association) Congress. May 18-21, 2013. Istanbul, Turkey. PMID- 23682402 TI - NPNG: learning to be "social". PMID- 23682401 TI - Reply to R. Bhargava et al and F.A. Greco. PMID- 23682403 TI - The role of new foam dressing technology in protection from skin breakdown. PMID- 23682405 TI - New award for research stars. PMID- 23682404 TI - SIOPE proposes amendments for EU clinical trial regulations. PMID- 23682406 TI - Chinese Government admits existence of cancer villages. PMID- 23682407 TI - Barriers to effective cancer care in Germany. PMID- 23682408 TI - Shielding Cenp-A removal in post-meiotic male cells. PMID- 23682409 TI - Findings of research misconduct. PMID- 23682410 TI - The use of the 'blind' problem in teaching epidemiology. AB - In the use of the case-study or problem-solving method of teaching epidemiology, the technique of the 'blind' problem, namely the withholding of the diagnosis of the disease until the end, presents many advantages. The student is forced to confront the purely epidemiological data without being prejudiced by his preconceived notions about the disease in question. In the study of an individual clinical case the objective is to make a diagnosis so that an accurate prognosis and specific treatment may be determined. So, in the study of an epidemic or outbreak (an epidemiological case) the objective is to establish a source of infection, a mode of spread or an aetiological factor, in order to predict a future trend and institute specific control measures. The 'blind' problem creates suspense, enhances the intellectual challenge, and permits the student and discussion leader to test a variety of hypotheses purely on the basis of the epidemiological evidence presented. An example of a localized epidemic is presented to illustrate these points. PMID- 23682411 TI - The measurement of health--a critical and selective overview. AB - The need for global and individual health status indices in addition to traditional mortality and morbidity statistics is explained. A classification model for sorting various health status indices into homogeneous groups is presented to facilitate systematic review of selected health status indices. Problems for users and authors of health status indices are briefly discussed with a view to the development of more practical indices in the future. PMID- 23682412 TI - Usefulness of community surveillance for the ascertainment of coronary heart disease and stroke. AB - In a prospective study of coronary heart disease (CHD) and stroke in Honolulu Japanese men, two methods of case ascertainment were used. The first consisted of cyclic re-examination of the cohort, and the second was based on periodic review of hospital discharge rosters, death certificates, and obituary columns (community surveillance). When a suspected case of CHD or stroke was located by either method, pertinent medical records were sought to verify it. Re-examination resulted in more complete ascertainment of CHD because it included silent myocardial infarction and angina pectoris. Community surveillance ascertained 83 per cent of all myocardial infarctions and CHD deaths combined; it was cheaper to operate and gave estimates of disease experience both in examined and unexamined men. In the first two years of this study, CHD incidence was 12 per cent lower in the examined men than in the total community. PMID- 23682413 TI - Some factors related to coronary heart disease incidence in Honolulu Japanese men: the Honolulu Heart Study. AB - Eight thousand and six Japanese men born in the years 1900-1919 participated in the baseline examination of the Honolulu Heart Study. Of the survivors, 94.6 per cent participated in a second examination two years later. All but 23 of the second exam refusers were contacted about their health. These procedures identified 101 men who had developed coronary heart disease (CHD) for the first time during this two-year interval. This incidence was associated with elevated levels of serum cholesterol, blood pressure, relative weight, uric acid, and cigarette smoking. Considered by itself, non-fasting serum triglyceride was related to CHD incidence, but in the context of other (non-lipid) characteristics this apparent association was not significant. Cigarette smoking was related to CHD other than angina pectoris (AP) but not to AP alone, while the reverse was true for glucose intolerance. In this cohort, the association between relative weight and CHD was as strong as that between serum cholesterol and CHD. PMID- 23682414 TI - The relationship of disturbing life-changes and emotions to the early development of myocardial infarction and other serious illnesses. AB - Nine thousand and ninety seven male members of the construction building workers trade union in Stockholm, aged between 41 and 61 years, were asked to complete a postal questionnaire between September and November 1972. The questionnaire was comprised of several psychosocial questions including life-change items for the preceding year. All subjects were followed up for a 12 to 15-month period with regard to death from all causes and hospitalization for myocardial infarction (MI). The urban section of the sample was also followed up for other serious illnesses. The main results were as follows: (a) The life-change measurement technique did not predict near-future MI; (b) A pre-formed discord index predominantly composed of self-rated type A behaviour and dissatisfaction variables predicted a significant number of near-future MIs; (c) One individual life-change, increased responsibility at work, predicted significantly about 10 per cent of near-future MIs; (d) Elevated life-change measures for the last year indicated increased risk of near-future neurosis onset; (e) Several questions about irritability and dissatisfaction, for example hostility in queuesor with slow persons and dissatisfaction with home life, predicted several kinds of illnesses; (f) Other variables, for example, having grown up as a late child in a large family, perception of financial state, mode of living, marital status and tobacco smoking, were important in illness prediction. PMID- 23682415 TI - Varicose veins in the South Pacific. AB - The prevalence of varicose veins has been studied in several population-based samples in the South Pacific. There is a striking gradient in the age standardized prevalence rates (0 x 8 per cent to 43 x 7 per cent) with atoll dwellers having the lowest rates, Rarotongans intermediate rates, and New Zealand Maoris and Pakehas the highest rates. The relationship between varicose veins and age, sex, height, weight, body mass and parity is examined and it is concluded that none of these factors are responsible for the observed gradient. The consumption of refined carbohydrates follows the same gradient and the possible aetiological role of this factor is discussed. PMID- 23682416 TI - Epidemiology of stomach cancer in Chile--the role of nitrogen fertilizers. AB - Chile ranks second in the world regarding age-adjusted mortality rates from stomach cancer. Analysis of death rates along its 25 provinces for a 15-year period (1957-1971) shows a peculiar geographic pattern of high and low-risk areas. Three agricultural provinces (Maule, Linares and Nuble, located south of Santiago), population 460,000, show a median rate of 50 x 1 per 100,000. In contrast, both extremes of the country, distant some 3,000 miles from one another, carry less than one-half the risk. The three northerly provinces (Tarapaca, Antofagasta and Atacama), population 652,500, show a median rate of 21 6, whereas Aysen and Magallanes in the extreme south, population 161,600, share a figure of 22.8 per 100,000. Data showing the use of nitrates throughout the country were collected for the period 1945-1972. A high correlation has been found between death rates and cumulative per capita exposure to nitrogen fertilizers. Controlling for confounding socio-economic variables, estimated by housing and infant mortality rates, the correlation holds at a significant level. A negative correlation between stomach cancer and infant mortality rates, low correlation with housing rating, and a negative correlation with lung and cervical cancer deaths were also found. The latter reinforces the lack of association with socio-economic conditions. Other major sites show a completely different pattern. The epidemiological evidence presented agrees with biochemical findings on the synthesis of nitrosamines. PMID- 23682417 TI - Natural radiation and cancer mortality in several areas of North Brittany. AB - This work deals with the relationship between natural radiation and cancer mortality in several areas of the Cotes-du-Nord departement in Brittany. Although the study area and populations were small, the results were significant, particularly for stomach cancer. It is suggested that the scope of the study should be extended to cover the whole of Brittany, and comparative studies with other granitic areas, above all in the Celtic parts of the British Isles, should be considered. PMID- 23682418 TI - Seasonal variations in the clinical of presentation of Crohn's disease and ulcerative colitis. AB - Epidemiological evidence that Crohn's disease could be a transmissible condition is limited. The case histories of 211 patients with Crohn's disease and 201 patients with ulcerative colitis have been scrutinized to ascertain whether there is a seasonal variation in the onset of symptomatic disease. Crohn's disease has a peak onset in January and July whereas ulcerative colitis has a possible peak of onset in December. A hypothesis is proposed that these findings provide epidemiological evidence, suggesting that Crohn's disease could be a transmissible condition, and that Crohn's disease and ulcerative colitis may not be aetiologically related. PMID- 23682419 TI - Mortality from lymphomas in Israel, 1950-71: the possible role of environmental factors. AB - Mortality from malignant lymphomas among the Jewish population of Israel rose during the period 1950-71. Above the age of 50 years the annual increment exceeded that in most other countries for which data are available. The rise occurred among older adults in all population groups and among children and young adults born in Africa. It was greater among native-born than among foreign-born adults. The mortality rates among foreign-born persons varied with the continent of birth. No clear-cut relationships were found with age at immigration or period since immigration. The trends for non-Hodgkin's lymphomas parallelled those for lymphomas as a whole, but those for Hodgkin's disease varied in different population groups. The findings suggest an increase in the incidence of lymphomas, more marked among native-born than among foreign-born adults, which can be speculatively attributed to environmental factors. PMID- 23682420 TI - Early results of an extensive rubella epidemic. AB - The extensive rubella epidemic which occurred in Israel in 1972, had a considerable impact on the population at risk: 1. The spread of rubella infection into the community strongly influenced the extent of legal abortions: (a) 1 x 5 as many abortions for all causes were recorded in the epidemic year, as compared to the average number recorded in the three-year pre-epidemic period; (b) about 20 per cent of all abortions were associated with a history of exposure to rubella in the first months of pregnancy. 2. The incidence of congenital rubella diagnosed up to six months from birth varies greatly: the attack rate was 11.8 per thousand live births in an area inhabited by a population whose religious belief generally prevented the practice of abortions, as opposed to a significantly lower rate of 1 x 7 per thousand in a population with a liberal approach to abortions. 3. Ten months after the epidemic subsided, the percentage of female subjects of childbearing age lacking rubella HI antibody was very similar to that found in the same age group, several years before the epidemic. PMID- 23682421 TI - Epidemiological interference. AB - Wherever intensity of disease transmission (size of virus populations) is great, there will be competition among the different viruses for soil. This competition, which is discussed here as epidemiological interference, was seen in a series of studies in West Bengal, India, and in Nepal. Competition for space led to localization of adenovirus types. Competition at different seasons led to striking variation in seasonal prevalence. Competition for soil and delay in natural immunization led to postponement of infection with childhood diseases to adulthood. Finally, the same phenomenon can explain the early continued high prevalence of poliomyelitis virus in children during the first six years of life in rural West Bengal (12). PMID- 23682422 TI - Disaster epidemiology. PMID- 23682423 TI - Popper's philosophy for epidemiologists. PMID- 23682424 TI - Effects of rotational culture on morphology, nitric oxide production and cell cycle of endothelial cells. AB - Devices for the rotational culture of cells and the study of biological reactions have been widely applied in tissue engineering. However, there are few reports exploring the effects of rotational culture on cell morphology, nitric oxide (NO) production, and cell cycle of the endothelial cells from human umbilical vein on the stent surface. This study focuses on these parameters after the cells are seeded on the stents. Results showed that covering of stents by endothelial cells was improved by rotational culture. NO production decreased within 24 h in both rotational and static culture groups. In addition, rotational culture significantly increased NO production by 37.9% at 36 h and 28.9% at 48 h compared with static culture. Flow cytometry showed that the cell cycle was not obviously influenced by rotational culture. Results indicate that rotational culture may be helpful for preparation of cell-seeded vascular grafts and intravascular stents, which are expected to be the most frequently implanted materials in the future. PMID- 23682425 TI - Reproductive performance of the Mesa silverside (Chirostoma jordani Woolman, 1894) under natural and controlled photoperiods. AB - Chirostoma jordani is a native annual species inhabiting lacustrine waters of the Central Mexico Plateau. It is widely distributed and is currently facing high environmental pressures. Five experiments were performed to study the reproductive performance of this species. Four of the experiments were conducted in 270-L indoor recirculation tanks. Two males and one female at the first stage of reproduction were included in each test. A photoperiod of 14 light hours and 10 dark hours was used. In a fifth experiment, 10 females and 15 males were kept in an outdoor 3,000-L recirculation tank under natural photoperiod. The number of spawns, fertilised eggs and 30-day-old juveniles were counted and the survival rate was calculated. The results indicated significant differences (P < 0.05) between treatments. Higher spawn numbers and greater egg production were observed under controlled photoperiod, and higher numbers of juveniles and a higher survival rate were observed under natural photoperiod. The trials exhibited different patterns of egg production during the experiment. The egg production in the natural-photoperiod trials followed a polynomial curve model. In contrast, the trials under the controlled photoperiod showed an irregular pattern of increases and decreases in egg production. PMID- 23682426 TI - Mechanisms involved in the cytotoxic effects of berberine on human colon cancer HCT-8 cells. AB - Berberine, a constituent of some traditional Chinese medicinal plants, has been reported to have cytotoxicity effects on different human cancer cell lines. There is no available information about the effects and mechanism of action of berberine on human colon cancer cell line HCT-8. In this paper, the cytotoxicity ofberberine on HCT-8 cancer cells was investigated by MTT assay, fluorescence microscopy and flow cytometry analysis. Our data revealed that berberine could significantly inhibit the growth of HCT-8 cells in a dose- and time-dependent manner. Morphology of apoptotic cells was studied with acridine orange/ethidium bromide staining. The concentrations of lactate dehydrogenase and both acid and alkaline phosphatases were significantly increased in cell supernatants after berberine treatment, suggesting cell death. Furthermore, flow cytometry analysis showed that berberine could arrest HCT-8 cells at S phase in a time-dependent manner. To further investigate the apoptotic molecular mechanism, reverse transcription-polymerase chain reaction (RT-PCR) and western blotting methods were used. The up-regulated mRNA and/or protein expressions of Fas, FasL, TNF alpha, caspase-3 and down-regulation of pro-caspase-3 suggest that the death receptor pathway may be involved in the apoptotic pathway induced by berberine. Decrease of Bcl-2 and increase of Bax in mRNA and/or protein expressions showed that the Bcl-2 family proteins were involved in berberine-induced apoptosis. We also found that berberine-induced apoptosis was associated with an upregulated expressions of p53 and prohibitin (PHB), and decreased vimentin expression. These results suggest that berberine can suppress cell growth and reduce cell survival by arresting the cell-cycle and by inducing apoptosis of HCT-8 cells. PMID- 23682427 TI - Knockdown of apoptosis-inducing factor disrupts function of respiratory complex I. AB - Recent findings suggest that apoptotic protein apoptosis-inducing factor (AIF) may also play an important non-apoptotic function inside mitochondria. AIF was proposed to be an important component of respiratory chain complex I that is the major producer of superoxide radical. The possible role of AIF is still controversial. Superoxide production could be used as a valuable measure of complex I function, because the majority of superoxide is produced there. Therefore, we employed superoxide-specific mitochondrial fluorescence dye for detection of superoxide production. We studied an impact of AIF knockdown on function of mitochondrial complex I by analyzing superoxide production in selected cell lines. Our results show that tumoral telomerase-positive (TP) AIF knockdown cell lines display significant increase in superoxide production in comparison to control cells, while a non-tumoral cell line and tumoral telomerase negative cell lines with alternative lengthening of telomeres (ALT) show a decrease in superoxide production. According to these results, we can conclude that AIF knockdown disrupts function of complex I and therefore increases the superoxide production in mitochondria. The distinct effect of AIF depletion in various cell lines could result from recently discovered activity of telomerase in mitochondria of TP cancer cells, but this hypothesis needs further investigation. PMID- 23682429 TI - Structural analysis of flagellar axonemes from inner arm dynein knockdown strains of Trypanosoma brucei. AB - Trypanosoma brucei is a protozoan flagellate that causes African sleeping sickness. Flagellar function in this organism is critical for life cycle progression and pathogenesis, however the regulation of flagellar motility is not well understood. The flagellar axoneme produces a complex beat through the precisely coordinated firing of many proteins, including multiple dynein motors. These motors are found in the inner arm and outer arm complexes. We are studying one of the inner arm dynein motors in the T. brucei flagellum: dynein-f. RNAi knockdown of genes for two components of dynein-f: DNAH10, the alpha heavy chain, and IC138, an intermediate chain, cause severe motility defects including immotility. To determine if motility defects result from structural disruption of the axoneme, we used two different flagellar preparations to carefully examine axoneme structure in these strains using transmission electron microscopy (TEM). Our analysis showed that inner arm dynein size, axoneme structural integrity and fixed central pair orientation are not significantly different in either knockdown culture when compared to control cultures. These results support the idea that immotility in knockdowns affecting DNAH10 or IC138 results from loss of dynein-f function rather than from obvious structural defects in the axoneme. PMID- 23682428 TI - A likely role for a novel PH-domain containing protein, PEPP2, in connecting membrane and cytoskeleton. AB - PH domains (pleckstrin homology) are well known to bind membrane phosphoinositides with different specificities and direct PH domain-containing proteins to discrete subcellular apartments with assistances of alternative binding partners. PH domain-containing proteins are found to be involved in a wide range of cellular events, including signalling, cytoskeleton rearrangement and vesicular trafficking. Here we showed that a novel PH domain-containing protein, PEPP2, displayed moderate phosphoinositide binding specificity. Full length PEPP2 associated with both plasma membrane and microtubules. The membrane associated PEPP2 nucleated at cell-cell contacts and the leading edge of migrating cells. Overexpression of PEPP2 increased membrane microviscosity, indicating a potential role of PEPP2 in regulating function of membrane and microtubules. PMID- 23682430 TI - Pollen viability of Polygala paniculata L. (Polygalaceae) using different staining methods. AB - Polygala paniculata L. is a medicinal plant that grows in the Brazilian Atlantic coast, known as 'barba-de-Sao-Joao', 'barba-de-bode', 'vassourinha branca', and 'mimosa'. In this study, pollen viability was estimated by three different staining methods: 2% acetic orcein, 2% acetic carmine, and Alexander's stain. The young inflorescences of twenty accessions were collected and fixed in a solution of ethanol: acetic acid (3:1) for 24 hours, then stored in ethanol 70% under refrigeration. Six slides per plant, two for each stain, were prepared by squashing, and 300 pollen grains per slide were analyzed. Pollen viability was high (> 70%) for most accessions of P. paniculata using the Alexander's stain, which proved the most adequate method to estimate pollen viability. PMID- 23682431 TI - C-terminal polymorphism of Plasmodium falciparium merozoite surface protein-1 (MSP-1) from Tak Province, Thailand. AB - This study was undertaken to ascertain the extent of polymorphism in the C terminal region of Plasmodium falciparum merozoite surface protein (MSP-1) from 119 malaria patients in Tak Province on the western border of Thailand, who were admitted to the Bangkok Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. P. falciparum infection was confirmed by microscopic examination of peripheral blood smears. Clinical manifestations were categorized into 2 groups: uncomplicated (94 cases) and complicated/severe (25 cases). A 1,040 basepair fragment of P. falciparum MSP-1 gene was compared with MSP-1 of reference strains retrieved from GenBank. The consensus sequences of MSP-1 block 16 showed it belonged to MAD20 genotype, which is the major allele of falciparum malaria from the western border of Thailand. MSP-1 block 16 amino acid fragment could be separated into 2 groups: similar and dissimilar to reference sequence. Four variations in MSP-1 block 16 were -1494K, D1510G, D1556N, and K1696I. MSP-1 block 16 diversity is not significantly associated with clinical manifestation although MAD 20 genotype is the predominant genotype in this area. The genetic data of MSP1 gene of faciparum malaria isolated from western Thai border contribute to the existing genetic database of Thai P. falciparum strain. PMID- 23682432 TI - Development of PCR-RFLP method to distinguish between Cryptosporidium parvum and C. hominis in Taiwan water samples. AB - Cryptosporidium, a protozoan pathogen that causes cryptosporidiosis has emerged as an important source of diarrheal illness among humans and animals. The current routine laboratory technique used for Cryptosporidium diagnosis is light microscopy with acid-fast staining but the technique has low efficiency and sensitivity for species-specific identification. Single PCR to amplify a 220 bp fragment of 18 S ribosomal DNA of C. parvum and C. hominis was developed. The restriction enzymes, TaqI and VspI, were used to distinguish between amplicons of human and bovine C. parvum genotype. Water samples, collected from Lo-Na, Ton-Pu, Ho-Ping, and Jen-Ai, Taiwan contained only bovine C. parvum genotype whereas in the Ton-Pu and Jen-Ai samples C. hominis was also present. Thus, the used of PCR RFLP allowed successful identification of Cryptosporidium in water samples and differentiation between human and bovine species. PMID- 23682433 TI - Growth reduction among primary schoolchildren with light trichuriasis in Malaysia treated with albendazole. AB - We studied asymptomatic primary schoolchildren in northeastern Malaysia with light to moderate trichuriasis to determine the effect of albendazole treatment on growth rates and TNF-alpha levels. Thirty-seven schoolchildren aged 6-7 years with stool samples positive for Trichuris trichiura and negative for other geohelminths and protozoa were randomized to receive albendazole 400 mg or a placebo daily for 2 days. Anthropometric parameters at baseline, 3, 6 and 12 months were compared between the 2 groups. The placebo group had a significantly greater increase in height (p = 0.04) than the albendazole treatment group. There were no significant differences in urinary TNF-alpha levels (p = 0.8) between the 2 groups and no significant changes between baseline and 1 month post-treatment levels. Further studies are needed to determine the etiology of this apparent association between the albendazole treatment group and the delay in growth rate at 6 months post-treatment. PMID- 23682434 TI - Severe pentastomiasis in children: a report of 2 cases. AB - Pentastomiasis is a type of parasitic zoonosis. Most patients with pentastomiasis are asymptomatic. We report here two pediatric patients with severe pentastomiasis (porocephaliais taiwan and armilliferiasis), and the results of their 6-year and 3-year follow-ups, respectively. The manifestations and outcomes of the two cases are described. The diagnoses were established by histopathologic and/or parasitologic examinations. After diagnosis, traditional Chinese medicine (TCM), as well as praziquantel and/or albendazole, were used for treatment. This report highlights the seriousness of pentastomiasis in children. We suggest TCM be considered as supplementary or even primary treatment of children with severe pentastomiasis. PMID- 23682435 TI - T helper (Th) 1 and Th2 cytokine expression profile in dengue and malaria infection using magnetic bead-based bio-plex assay. AB - Dengue and malaria infections are two very common vector-borne diseases annually affecting millions of people around the world. Both diseases show a variety of clinical presentations, ranging from mild symptoms of dengue fever (DF) to severe dengue hemorrhagic fever (DHF) in dengue infection, and low and high parasitemia in malaria infection. T helper (Th)1 and Th2 cytokine expressions in mild and severe forms of dengue virus type-2 (DENV-2) and Plasmodium falciparum infection, were compared to normal human sera using high throughput magnetic bead-based Bio Plex assay. A significant elevation of Th1 and Th2 cytokines expression [interleukin (IL)-2, IL-4, IL-5, IL-10, IL-13, granulocyte-macrophage colony stimulating factor (GM-CSF), interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha] was detected in DENV-2 and P. falciparum malaria infections compared with normal controls (p < 0.05). DENV-2 infection showed a slight higher expression of Th1 and Th2 cytokines in DHF than DF, except for IL-13. In P. falciparum infection, high parasitemia showed a significantly higher expression of IL-4, IL-10, GM-CSF, and TNF-alpha (p < 0.05). Both DENV-2 and P. falciparum malaria infections manifested high IL-10 expression, greatest among the cytokines examined, and in the severe forms of infection. The results of this study should lead to a better understanding of pathogenesis of dengue infection and P. falciparum malaria. PMID- 23682436 TI - Factors affecting dengue fever knowledge, attitudes and practices among selected urban, semi-urban and rural communities in Malaysia. AB - Dengue fever is a major public health problem in Malaysia. This study aimed to assess factors affecting knowledge, attitudes, and practices regarding dengue fever among a selected population in Malaysia. A descriptive, community-based, cross sectional study was conducted with 300 participants from three different geographical settings in urban, semi-urban, and rural areas within the states of Selangor and Kuala Lumpur. The questionnaire included questions on demographic data, knowledge, attitudes, and practices regarding dengue fever. Mean age of respondents was 34.4 (+/- 5.7) years, and the age ranged from 18 to 65 years. The majority of respondents were married (54.7%), Malays (72.7%) and heard about dengue fever (89.7%). Television was the common source of information about dengue fever (97.0%). Participants answered 4 out of 15 items of knowledge incorrectly. There was no significant association between knowledge score and socio-demographic factors. About one-fifth of the respondents (24%) believed that immediate treatment is not necessary for dengue fever, and the majority of them were not afraid of the disease (96.0%). Attitudes toward dengue fever were significantly associated with the level of education and employment status (p < 0.05). Practice was associated significantly with age, marital status, and geographic area (p < 0.05) and knowledge on dengue fever (p = 0.030). There is a need to increase health promotion activities through campaigns and social mobilization to increase knowledge regarding dengue fever. This would help to mold positive attitudes and cultivate better preventive practices among the public to eliminate dengue in the country. PMID- 23682437 TI - Acute hepatic failure among hospitalized Thai children. AB - We conducted a hospital-based study from June 2002 to December 2006 of Thai children aged 1-15 years with acute hepatic failure (AHF) to determine the causes and outcomes. Eleven children were included in the study. Hepatitis B virus was the cause of AHF in one child, infection-associated hemophagocytic syndrome was the cause in 1 child, Wilson's disease was the cause in 1 child and dengue fever was suspected to be the cause in 2 children. In 6 children the cause of AHF was unknown. Jaundice was reported in 9 of 11 children. Ten of 11 children had mild to moderate encephalopathy on admission. Five of 11 children died due to AHF. No liver transplantations were performed among the children in this study. Further studies into the relationship between dengue infection and AHF are needed. PMID- 23682438 TI - Economic impact of chikungunya epidemic: out-of-pocket health expenditures during the 2007 outbreak in Kerala, India. AB - The southern state of Kerala, India was seriously affected by a chikungunya epidemic in 2007. As this outbreak was the first of its kind, the morbidity incurred by the epidemic was a challenge to the state's public health system. A cross sectional survey was conducted in five districts of Kerala that were seriously affected by the epidemic, using a two-stage cluster sampling technique to select households, and the patients were identified using a syndromic case definition. We calculated the direct health expenditure of families and checked whether it exceed the margins of catastrophic health expenditure (CHE). The median (IQR) total out-of-pocket (OOP) health expenditure in the study population was USD7.4 (16.7). The OOP health expenditure did not show any significant association with increasing per-capita monthly income.The major share (47.4%) of the costs was utilized for buying medicines, but costs for transportation (17.2%), consultations (16.6%), and diagnoses (9.9%) also contributed significantly to the total OOP health expenditure. The OOP health expenditure was high in private sector facilities, especially in tertiary care hospitals. For more than 15% of the respondents, the OOP was more than double their average monthly family income. The chikungunya outbreak of 2007 had significantly contributed to the OOP expenditure of the affected community in Kerala.The OOP health expenditure incurred was high, irrespective of the level of income. Governments should attempt to ensure comprehensive financial protection by covering the costs of care, along with loss of productivity. PMID- 23682439 TI - Ocular diseases among HIV/AIDS patients in Jakarta, Indonesia. AB - We conducted a survey of ocular diseases among HIV/AIDS outpatients in Jakarta, Indonesia. This cross sectional study was conducted among 311 HIV/ AIDS patients presenting to three referral hospitals in Jakarta, Indonesia from September 2008 to May 2009. All subjects underwent ophthalmological examination, including visual acuity, intraocular pressure, eye movement, Schirmer's test and anterior and posterior segment evaluation. Most subjects (86%) were aged 20-40 years; and 77% were male. Intravenous drug use was the most common risk factor (48.9%) for HIV infection. At the time of enrollment, 85% of subjects were receiving anti retroviral therapy (ART); the median CD4+ T cell count prior to ART was 56 (0 757) cells/microl. The most common ocular manifestations were dry eye syndrome (54%), followed by toxoplasma retinochoroiditis (8.4%) and cytomegalovirus (CMV) retinitis (5.8%). Risk factors associated with ocular diseases were late HIV clinical stage (OR = 4.35 for clinical stage 4 vs 1; p = 0.001), co-infection (OR = 2.67 for 2 co-infections vs no co-infection; p = 0.009) and low CD4+ T cell count prior to ART (< 50 cells/microl vs > or = 200 cells/microl; p = 0.003). The CD4+ count at the first visit (p = 0.041) and clinical stage (p = 0.049) were associated with dry eyes. This study shows dry eyes were the most prevalent ocular disease among HIV/ AIDS patients in Jakarta. HIV clinical stage 3 or 4, co infection with tuberculosis and hepatitis C infection and a CD4+ T cell count of <50 cells/microl were risk factors for ocular disease in HIV/AIDS patients. PMID- 23682440 TI - Environmental factors affecting Burkholderia pseudomallei biofilm formation. AB - Melioidosis is highly prevalent in Northeast Thailand which is associated with high incidence of Burkholderia pseudomallei present in the soil of this region. B. pseudomallei when present in biofilm becomes resistant to numerous environmental factors and also to certain antibiotics. In this study, we examined the effects of several environmentally relevant factors (salinity, iron, manganese and temperature) on biofilm formation of four clinical ribotypes of B. pseudomallei commonly found in Northeast Thailand. The results showed that biofilm formation increased when B. pseudomallei were grown in modified Vogel and Bonner's medium containing 0.85-1.7 M NaCl or 100-500 microM iron (FeSO4). Low temperature (20 degrees C) also induced more biofilm formation than 30 degrees C or 37 degrees C. On the other hand, protease production and bacterial motility were adversely affected but not in the case of low temperature. Results from this study should be useful in the development of prevention measures or controlling B. pseudomallei biofilm formation in the environment. PMID- 23682441 TI - Total leukocyte counts and neutrophil-lymphocyte count ratios among Helicobacter pylori-infected patients with peptic ulcers: independent of bacterial CagA status. AB - Elevated leukocyte counts can be a marker of inflammation and infection. The aim of this study was to determine the total leukocyte count and neutrophil lymphocyte count ratio (NLCR) among Helicobacter pylori-infected patients with peptic ulcer disease (PU) and among asymptomatic subjects (AS) and to evaluate if there is an association between these lab values and the presence of the H. pylori virulence factor cytotoxin-associated gene A (CagA). Sixty H. pylori infected PU patients, 63 AS carriers and 32 healthy H. pylori-negative subjects (controls) were included in the study. The total white blood cell (WBC) counts and differentials were determined using standard hematological methods. The mean total WBC count, mean neutrophil count and NLCR were significantly higher among PU patients than in controls (p < 0.001, p < 0.001 and p < 0.001, respectively). Similarly, the mean WBC count, mean neutrophil count and NLCR were significantly higher among AS patients than in controls (p < 0.005, p < 0.001 and p < 0.02, respectively). The differences of mean WBC counts mean neutrophil counts and NLCR were also significantly different (p < 0.005, p < 0.001 and p < 0.001, respectively) between the PU and AS patients. There were no differences in the PU and AS patients in regard to anti-CagA positivity. These results show the CagA factor was not associated with the presence or absence of symptoms in H. pylori infected patients. PMID- 23682442 TI - Survey in Iran of clarithromycin resistance in Helicobacter pylori isolates by PCR-RFLP. AB - The aims of this study were to assess primary resistance of H. pylori strains isolated from adult patients of Ilam, Iran to antibacterial agents (amoxicillin, clarithromycin, metronidazole and tetracycline) and detection of clarithromycin, azithromycin, clarithromycin, metronidazole and tetracycline resistance by disc diffusion. Fifty biopsies were taken from gastric mucosa of the antrum and body regions of adult patients by gastroscopy, and were cultured on Helicobacter pylori selective medium. The susceptibility of H. pylori strains showed that 44, 6, 6, 4 and 16% were resistance to metronidazole, amoxicillin, tetracycline, azithromycin, and clarithromycin, respectively. Polymerase chain reaction- restriction fragment length polymorphism analysis showed that all clarithromycin resistance isolates had A2143G mutation and PCR amplicons from these strains upon digestion by BsaI restriction enzyme resulted in 319 and 106 base pair fragments. Because most of physicians in Ilam do not use amoxicillin in triple therapy of H. pylori infection, isolates showed low rate of resistance to amoxicillin. PMID- 23682443 TI - Antimicrobial susceptibility pattern of extended spectrum beta-lactamase producing gram-negative bacteria isolated from wound and urine in a tertiary care hospital, Dhaka City, Bangladesh. AB - From a total of 320 bacterial samples from wound swab and urine 169 (53%) gram negative bacteria were isolated, of which 42 (25%) extended-spectrum beta lactamase (ESBL) producers were detected by double-disk synergy test. ESBL producers were significantly more resistant against amoxiclav, Co-trimoxazole, ciprofloxacin, amikacin and gentamicin than non-ESBL producers. Among the 42 ESBL producers, 76% were positive for blaCTX-M and 43% were positive for blaOXA, with blaCTX-M predominantly (97%) observed in E. coli and blaOXA predominantly (80%) in Pseudomonas spp. Class 1 integron was found in 75% of blaCTX-M positive and 56% of blaOXA positive strains. Combinations of ESBL genes and class 1 integron were observed in 29 (69%) of the ESBL producers. The findings of this study infer that CTX-M and OXA producers are emerging in Bangladesh and we report the presence of blaOXA for the first time in Bangladesh. PMID- 23682444 TI - Community-acquired methicillin-resistant Staphylococcus aureus in a Malaysian tertiary centre. AB - Abstract. Community-acquired methicillin-resistant Staphylococcus aureus (CA MRSA) is a pathogen recognized to be distinct in both phenotype and genotype from hospital-acquired MRSA. We have identified CA-MRSA cases in Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia, including their antibiotic susceptibility patterns and genotypic characteristics. Cases were identified during January to December 2009 from routine clinical specimens, where culture and antibiotic susceptibility results yielded pauci-resistant MRSA isolates suspected as being CA-MRSA. The patients' clinical data were collected and their specimens were sent for molecular confirmation and analysis. Five cases of CA MRSA were identified, which had a multi-sensitive pattern on antibiotic susceptibility tests and were resistant to only penicillin and oxacillin. All cases were skin and soft-tissue infections, including diabetic foot with gangrene, infected scalp hematoma, philtrum abscess in a healthcare worker, thrombophlebitis complicated with abscess and infected bedsore. All five cases were confirmed MRSA by detection of mecA. SCCmec typing (ccr and mec complex) revealed SCCmec type IV for all cases except the infected bedsore case. Panton Valentine leukocidin gene was positive in all isolates. As clinical features among methicillin-sensitive Staphylococcus aureus, CA-MRSA and "nosocomial CA MRSA" are indistinct, early recognition is necessary in order to initiate appropriate antibiotics and infection control measures. Continual surveillance of pauci-resistant MRSA and molecular analysis are necessary in order to identify emerging strains as well as their epidemiology and transmission, both in the community and in healthcare setting. PMID- 23682445 TI - Treatment of Japanese patients with enteric fever using azithromycin and MIC levels for causative organisms. AB - In Japan azithromycin (AZM) has been used to treat enteric fever caused by bacteria with resistance to fluoroquinolones; however, the dose, length of treatment and effectiveness of AZM among Japanese patients with enteric fever is unclear. We studied 5 Japanese adults and 1 Japanese child with enteric fever (4 had typhoid fever and 2 had paratyphoid fever) who were treated with oral AZM. The treatment regimens were: 1,000 mg as a single or in 2 divided doses on the 1st day, followed by 500 mg as a single dose daily for 5-6 additional days, or 500 mg as a single dose daily for 10 days. The minimum inhibitory concentrations (MICs) for AZM against 5 causative organisms were investigated with an E-test. Good clinical results were observed in the 5 adult patients but treatment failure was seen in the 1 child patient with typhoid fever; no adverse reactions were found. MICs of AZM were 4 microg/ml against S. Typhi in 2 patients, 8 microg/ml against S. Typhi in 2 patients, and 32 microg/ml against S. Paratyphi A in 1 patient. Our findings indicate AZM may be a reasonable choice for treatment of Japanese adult patients with enteric fever. PMID- 23682446 TI - Development of single-strand conformational polymorphism to screen for mutations in hotspot regions of beta-globin gene of beta-thalassemia patients of Sri Lanka. AB - Beta-thalassemia is prevalent in Sri Lanka and imposes a heavy economic and social burden in the country due to the patients' life-long need for regular blood transfusion and treatment with iron chelation therapy. Thus, there is a need to develop a rapid, reliable and effective population-based presymptomatic and prenatal screening method for beta-thalassemia. Single-strand conformational polymorphism (SSCP) technique was developed as an adjunct for the previously developed allele-specific PCR (ASP) technique to screen the presence of mutations in beta-globin gene. A hotspot region of beta-globin gene containing 98% of known beta-thalassemia mutations was amplified from 24 clinically diagnosed beta thalassemia patients and two normal individuals. Two overlapping amplicons of 238 bp and 268 bp were subjected to SSCP analysis. The SSCP banding patterns of these two fragments from beta-thalassemia patients were different from the corresponding regions of normal individuals. Sequence analysis of these regions revealed the presence of 4 mutations in the form of deletion and substitution that have not been reported previously from Sri Lanka. Therefore, the SSCP protocol developed in this study together with ASP should provide an appropriate screening approach for presymptomatic and parental diagnosis of beta-thalassemia in the Sri Lankan population. PMID- 23682447 TI - Catastrophic health expenditure in an urban city: seven years after universal coverage policy in Thailand. AB - Abstract. This study explored the burden of household out-of-pocket health expenditure on urban inhabitants with different socio-economic status and health insurance schemes in Nakhon Sawan Municipality. This study employed a cross sectional survey by using a structured questionnaire. Health personnel from six primary care units interviewed a representative of the sampled households. Sampled households were selected by a two-stage random sampling technique. Descriptive statistics were used to describe general household characteristics, and Mantel-Haenszel odds ratio was used to explain the relationships between factors and catastrophic health expenditure. From 406 sampled households, there were 1,421 household members and 340 individuals who reported illness within the last month. The poor and non-poor groups reported hypertension, diabetes, and the common cold as the most common ailments. Most patients sought care at a regional hospital and then primary care units, drug stores, and private hospitals, respectively. Household out-of-pocket medical costs were most frequently paid to drug stores and to private clinics. The direct non-medical costs were mostly paid for transportation and food. Factors related to catastrohpic health expenditure were the Civil Servant Medical Benefit Scheme (CSMBS) cardholder, use of public hospital, private hospital, and clinic. Furthermore, catastrophic expenditures were related to non-medical costs and time loss for indirect cost. Catastrophic rates of the poor were 12.5 and 30.4% from direct and non-medical cost, respectively. The rates for the non-poor were lower. PMID- 23682448 TI - Where are the PA researchers? PMID- 23682449 TI - Prescribing the combination amoxicillin/clavulanate products. PMID- 23682450 TI - Return of a childhood rash with firm papules. PMID- 23682451 TI - Screening for ovarian cancer. PMID- 23682452 TI - Trauma in pregnancy: diagnosis and management of two patients in one. PMID- 23682453 TI - A 46-year-old woman with postural orthostatic tachycardia syndrome. PMID- 23682454 TI - Recurrent headaches in an older man without other neurologic symptoms. PMID- 23682455 TI - Pigmented villonodular synovitis of the left distal biceps tendon. PMID- 23682456 TI - Recurrent respiratory papillomatosis: A possible role for the HPV vaccine? PMID- 23682457 TI - Eosinophilic esophagitis: A practical primer for an atypical disease. PMID- 23682458 TI - Quick recertification series. Pneumothorax. PMID- 23682459 TI - Distinguishing three types of shoulder dislocation. PMID- 23682460 TI - Case of the month. PMID- 23682461 TI - [Prescribe a PSA test?]. PMID- 23682462 TI - [Generic drugs: any doubt no longer allowed]. PMID- 23682463 TI - [Questionable DSM-5]. PMID- 23682464 TI - [Gene therapy: where do we stand?]. AB - Gene therapy is a form of molecular medicine based on the addition of a corrected copy of a gene to the somatic cells of an individual in order to cure or to alleviate the underlying disease. This approach provides new targeted therapies for an increasing number of acquired or inherited diseases. Since its very first beginning in the 90's essentially for cancer treatment, this therapeutical approach has met unpredicted obstacles as well as true success. Recently, significant clinical benefits have been reported for several inherited diseases of the hematopoietic system but also of the retina and some cancers, widening its application provided that severe adverse events can be efficiently and stably prevented. PMID- 23682465 TI - [Miliary brain tuberculosis]. PMID- 23682466 TI - [Should we treat prostate cancer?]. PMID- 23682467 TI - [Screening for prostate cancer: why, how?]. AB - Screening for prostate cancer has been the subject of a new controversy in 2012, because of the updated and contradictory results of the two large randomized trials of prostate cancer and while the United States Preventive Services Task Force (USPSTF) recommended not use PSA in screening, because of the risk of overdiagnosis and overtreatment especially. However, this new thinking about PSA and screening may mislead the public and create a health risk. Media pressure must be an opportunity to remind the individual screening recommendations, but also to encourage innovation for better detection and better assess prostate cancer stage. New biomarkers and MRI are promising to improve screening with the PSA and DRE. The assessment of the value of PSA around 50 years is a predictor of the risk of prostate cancer and rhythm monitoring depends on the initial value and the velocity of PSA. The challenge of the coming years will be to identify patients to be treated regarding age, life expectancy and tumor aggressiveness and to identify clearly those who can benefit of active surveillance. PMID- 23682468 TI - [Populations at risk for prostate cancer]. PMID- 23682469 TI - [Prostate biopsy: a gesture without risk?]. PMID- 23682470 TI - [Gleason: what is it and what interpretation?]. PMID- 23682471 TI - [When and how to prescribe PSA?]. PMID- 23682472 TI - [New markers of prostate cancer]. PMID- 23682473 TI - [Imaging in prostate cancer]. AB - The management of prostate cancer has dramatically changed due to the progresses made in imaging, especially in MRI. MRI in indicated in the initial workup of a patient with a biopsy proven prostate carcinoma eligible to a curative treatment. Detection MRI is used in patients with increased PSA levels and negative biopsies for targeting a new series of biopsies. Lastly, MRI combined with PET allows one to schedule a salvation treatment in patients with a biological relapse of prostate cancer after treatment and a local recurrence. PMID- 23682474 TI - [Active surveillance for low-risk prostate cancer]. AB - During the last decades, incidence of prostate cancer has increased at the expense of cases at low-risk of progression. Meanwhile, the concept of active surveillance has gained widespread acceptance in order to decease the risk of overtreatment. Active surveillance is based on a strict patient monitoring to detect potential disease progression and to propose on time a radical differed treatment with no increased oncologic risk. Patients without progression can continue active surveillance avoiding potential functional consequences of radical treatment. The short and mid-term oncologic follow-up confirmed the oncologic safety of active surveillance with a rate of cumulative differed treatment approaching 30%. To date, active surveillance is recommended by several guidelines, and widely offered by urologists. The inclusion criteria remain subject to debate due to a lack of consensus. Improving the selection of low-risk prostate cancers (MRI, biomarkers) highly relevant due to a significant risk of undergrading of disease at diagnosis. Moreover, due to the slow time evolution of these low-risk cancers, a long-term confirmation of oncological results seems necessary. PMID- 23682475 TI - [The outbreak of focal therapy for localized prostate cancer management]. AB - These last years, focal therapy is emerging as an intermediate management technique between radical approaches (radical prostatectomy, external beam radiation and brachytherapy) and active surveillance to manage some early stage prostate cancer. Different energy modalities are currently being developed. Prostatic tumour destruction can be achieved with different energies: freezing effect for cryotherapy, thermal effect using focalized ultrasound for HIFU and using thermal effect of light for FLA, and activation of a photosensitizer by light for PDT. Those techniques carry a low morbidity but clinical experience is limited regarding to oncologic outcome. Prospective clinical trials are needed to highlight the full potential of this promising treatment modality. PMID- 23682476 TI - [Localized prostate cancer at high risk of progression]. AB - Localized prostate tumors have various clinical, biological and histopathological characteristics that lead to different progression profiles. High-risk prostate cancer has been classically defined by clinical examination, PSA levels and histopathological data. High-risk prostate cancer has usually a worse outcome, but classic stratification predictive of outcome for prostate cancer is a matter of debate concerning its accuracy. A great deal of scientific work have been deploy to prove that high-risk prostate cancer should be approached by teamwork including radio-hormone therapy, systemic treatment with long-term use of LH-RH and a radical prostatectomy with adequate lymph node dissection. Selection of patients is essential to define individualized therapeutic strategy and timing for every modality should come as a consensus of medical supported evidence. Accurate patient selection and multimodal treatment offer the best therapeutic option in high-risk prostate cancer. PMID- 23682477 TI - [Radical prostatectomy in prostate cancer: indications and surgical approaches]. AB - Prostate cancer is the most frequent in men: 71000 new cases were diagnosed in France in 2011. Early diagnosis allows treatments with curative intent. Risk groups by D'Amico classification system were validated to estimate progression risk after radical prostatectomy, external beam radiotherapy and brachytherapy. Radical prostatectomy is one of the reference treatments for localized prostate cancer. There are many surgical approaches: open retropubic approach, perineal, trans peritoneal or extra peritoneal laparoscopic approach, robotic assisted or not. Main surgical steps are the same between retropubic or laparoscopic approaches. Regarding oncologic (positive surgical margins rate, progression free survival) and functional results (continence and erections), no difference was reported between different surgical approaches. PMID- 23682479 TI - [Prostate brachytherapy, a validated option in specific indications]. PMID- 23682478 TI - [Radiotherapy for localized prostate cancer (with and without hormonal treatment)]. AB - External beam radiotherapy (EBRT) for non metastatic prostate cancer has evolved during the past two decades with the introduction of image-based treatment planning and technological progress. When controlled for various case selection factors and quality of treatment delivery, the outcomes among the various modalities of treatments (surgery, EBRT, brachytherapy) appear to be equivalent. Newer conformal radiotherapy (RT) methods with three-dimensional conformal RT (3D CRT) with intensity-modulated RT (IMRT) and image guided RT, have allowed radiation oncologists to improve the therapeutic ratio by lowering the dose to the surrounding critical structures while simultaneously safely escalating the dose to the disease target. This review details the practical elements of radiation dose delivery and the main guidelines for use of radiation therapy. PMID- 23682480 TI - [Castration in the treatment of locally advanced or metastatic prostate cancer]. PMID- 23682481 TI - [Chemotherapy in castrate-resistant metastatic prostate cancer]. AB - Chemotherapy is currently used in metastatic, castrate-resistant prostate cancer. The key drugs are docetaxel and cabazitaxel since two large randomized trials have shown a survival benefit for docetaxel in first-line and cabazitaxel in second-line as compared to mitoxantrone during the last decade. Docetaxel and cabazitaxel belong to the taxane family and inhibit the polymerization dynamics of microtubules during the cell cycle. These are delivered every 3 weeks in an outpatient setting. The main side effects are neutropenia, alopecia, mucositis, diarrhea and peripheral neuropathy. The prophylactic use of hematopoietic growth factor (G-CSF) in patients older than 70 years reduces the risk of febrile neutropenia. Chemotherapy is primarily used in patients with symptomatic or rapidly progressive disease. PMID- 23682482 TI - [Prostate cancer: interpretation of management guidelines]. AB - The guidelines of the urological and oncological societies reflect the different possible interpretations of evidence-based medicine, as well as the medical and economical, or even medico-legal constraints in the various countries. Essentially, the guidelines of the American Urological Association seem to be focused on the medico-legal aspects, and offer urologists a wide range of treatment options through each stage of the disease. The recommendations of the British National Institute for Health and Clinical Excellence (NICE) focus heavily on the medical and economic aspects and the risk-benefit ratio, whereas in those of the American Society of Clinical Oncology (ASCO) overall survival is the main criteria. The French and European recommendations (Association francaise d'urologie [AFU] and European Association of Urology [EAU]) are almost equivalent, except for a few minor differences, and strongly reflect the recommendations of the National Comprehensive Cancer Network (NCCN). PMID- 23682483 TI - [Treatment of acute appendicitis: history and evolution of practices]. AB - Since the princeps description of the appendectomy by Mac Burney in 1891, the treatment of appendicitis is still based on the resection of the appendix. The better quality of the pre-operative imaging leads to a significant decreased of unnecessary appendectomies during the last 30 years. The laparoscopic approach did not make a real change and is not the gold standard except in obese patient or young female. The question of an exclusive medical treatment is still a matter of debate, but it remains not recommended. PMID- 23682484 TI - [Guidelines for diagnosis of acute appendicitis in childhood]. AB - Facing a child with suspected acute appendicitis it is important to remind that a child is not a smaller adult. The main risk is to over-diagnose acute appendicitis in elder children and to misdiagnose it in preschool children and infants because it is less frequent, with early complications, and/or confusing symptoms in these age groups. Careful anamnesis and examination of the whole child--not only the belly--are mandatory. Biological findings of bacterial infection and US findings suggesting acute appendicitis are helpful. In doubtful cases the best help is offered by observation of the patient, symptoms and signs worsening necessarily in case of an acute appendicitis. PMID- 23682485 TI - [Acute appendicitis diagnosis in adults]. AB - Since the development of the new imaging techniques, such as ultrasonography and computed tomography, the attitude over acute appendicitis syndrome has drastically evolved, and the rate of negative appendectomies has noticeably decreased. These techniques allow, not only to improve the performance of the diagnosis of appendicitis, but also to assess the severity and the complications prior to surgery. Furthermore they are useful for establishing alternative diagnoses of the many diseases that may mimic acute appendicitis. PMID- 23682486 TI - [Indications for medical treatment of acute appendicitis]. AB - The acute appendicitis (AA) is an infection of the vermiform appendix and conservative antibiotic treatment is regularly mentioned since 50 years. Its success depends on the susceptibility of bacteria to empiric antibiotic therapy. The main bias of the studies comparing conservative antibiotic treatment versus appendectomy is that AA can not be proven histologically during medical treatment. However, after antibiotic conservative, 12-23% of patients are operated early after revaluation, and 11 to 15% in the first year for a total of 25% to 40% failure of conservative antibiotic treatment when proposed in first intention. In case of complicated appendicitis, severe infection and peritonitis, surgical treatment should be carried out urgently and remains the gold standard. PMID- 23682487 TI - [Surgical treatment of acute appendicitis]. PMID- 23682488 TI - [Social networks in 10 lessons: no 4. Flickr: photos to share and to "borrow"]. PMID- 23682489 TI - [Towards Uncle Sam (electronic records for physicians)]. PMID- 23682490 TI - [Reception of a victim of sexual violence]. PMID- 23682491 TI - [Acute and chronic headache]. PMID- 23682492 TI - [Colon and rectal tumors]. PMID- 23682493 TI - [Stroke diagnosis and management]. PMID- 23682494 TI - [Acute inflammatory polyradiculoneurictis. Guillain Barre syndrome]. PMID- 23682495 TI - [Pierre Menetrier. Precancerous conditions and cancer prevention]. PMID- 23682496 TI - Adding to the body of evidence. PMID- 23682497 TI - Final year student nurses' experiences of wound care: an evaluation. AB - This article reports on research to explore if pre-registration nursing students felt prepared to manage patients' skin integrity effectively on registration. Final year nursing students completing adult, child and mental health fields were invited to complete questionnaires to investigate the amount of teaching sessions delivered in university in relation to managing skin integrity during their 3 year training programme, discover if pre-registration nursing students received supplementary management of skin integrity teaching in the clinical areas, explore which member of staff in the clinical areas supported the students' learning in the area of skin integrity. Data was collected on 217 final year students (196 females and 21 males) at two higher education institutions in the north of England. The majority of respondents (n = 146; 68%) reported receiving less than 10 hours formal teaching at university on the subject of skin integrity over their 3-year courses. Of those registered on degree courses, 134 students (71%) reported receiving less than 10 hours formal teaching over their 3-year courses, compared with only 12 students (46%) registered on diploma courses. Some 198 (99%) of respondents reported that their clinical teaching was undertaken by registered nurses all or some of the time. Other health professionals were reported to provide substantially less clinical teaching; with the next largest contribution reported to be provided by specialist nurses, who provided all clinical teaching to 36 respondents (19%) and some clinical teaching to 115 respondents (59%). Some 149 respondents (70%) reported that the teaching they received had developed their knowledge and skills to maintain skin integrity for all patients. Respondents claimed that teaching received had developed their knowledge and skills, reporting an average of 16.9 hours spent in directed study; whereas those who did not claim that teaching they had received had developed their knowledge and skills reported an average of 7.6 hours spent in directed study. The results of this study suggest that diplomate nurses are likely to feel more confident and competent than their graduate counterparts, despite spending the same amount of time with mentors and their peers. PMID- 23682498 TI - Smoking and its effects on the healing process of chronic wounds. AB - Smoking has a negative impact on skin health. Numerous studies have effectively linked smoking with delayed wound healing and healing complications. Research has identified cigarette smoking affects wound healing at a cellular level. Reducing fibroblast activity and keratinocyte migration. Such is the concern around the affects that smoking has on wound healing that some question whether smoking abstinence should be a pre requisite before some surgical procedures. This article will discuss current research and clinical studies that have investigated impaired wound healing as a result of cigarette smoking. PMID- 23682499 TI - The Integrity Full Replacement Alternating Mattress. AB - The Integrity Full Replacement Alternating Mattress, manufactured and distributed by Sumed, is an innovative alternative for those users who find conventional alternating pressure mattresses uncomfortable. The mattress is designed with smaller cells than conventional alternating mattresses and this has a number of benefits for the user, in that posture within the bed is not compromised as the cells alternatively inflate and deflate, maintaining mobility and function. Furthermore, users report that the small cell size results in their experiencing far more comfort on this mattress comparered with other alternating mattresses previously tried, as they feel far less movement with the alternation. Importantly, the construction of the mattress affords significant safety to the user in the event of power failure, and this is particularly pertinent in the community setting where the user is monitored less frequently. This article discusses pressure injury prevention in the community and describes how the Integrity mattress provides a solution. PMID- 23682500 TI - Use of Urgotul SSD to reduce bacteria and promote healing in chronic wounds. AB - This product focus seeks to give an overview of the management of wound bioburden in relation to the use of antimicrobial dressings, according to recent guidelines and best practice statements. Identification of critical colonisation/localised infection and the role of biofilms is a key aspect of effective wound management. Silver antimicrobial dressings are efficient in reducing bacteria in wounds, but must be used appropriately to prevent overuse. Silver sulphadiazine has traditionally been used for the treatment of burns or Pseudomonas infection in leg ulceration, often in a cream formation. This article will be looking specifically at the effective use of Urgotul SSD in three critically colonised/non healing wounds. PMID- 23682501 TI - Interview: Julie Evans. PMID- 23682502 TI - A simple method to fabricate stabilized record bases: a modified approach using casting wax for the borders. AB - Retention and stability of a record base is often compromised in the mouth because of blockout procedures performed before adapting a record base material on a definitive cast. This article presents a technique of fabricating a stable and retentive record base, in which a definitive cast does not receive a blockout procedure so that the record base engages the facial undercuts in the cast by means of a green coloured inlay casting wax. PMID- 23682503 TI - Effect of artificial saliva and pH on shear bond strength of resin cements to zirconia-based ceramic. AB - The aim of the present study was to evaluate the effect of media with different pH on shear and strength of resin cements to zirconia-based ceramics. Sixty rectangularly shaped specimens made of a zirconia based ceramic (Cercon, Dentsply) were prepared, air-blasted with 110 microm aluminum oxide particles (Al203) and randomly assigned into three groups (n = 30). A universal resin composite (Filtek Z250, 3M/ESPE) was bonded to each specimen using one of the following three cements: Calibra (Dentsply), Panavia F2 (kurary) and Unicem (3M/ESPE). Specimens were thermal cycled and stored in one of the following three media for two weeks: water at pH = 7, saliva at pH = 7 and saliva at pH = 3.5. The mean shear bond strength of each group was analyzed using the Kruskal-Wallis test (alpha = 0.05). The modes of failure were recorded using a streomicroscope. All specimens in the Calibra groups showed premature debonding. No significant difference was found between the two other cements or different media. The failure modes in the two latter cements were predominantly adhesive. Despite the adverse effect of acidic media on the properties of restorative materials, the media did not significantly influence the bond strength of MDP-containing resin cement and a self-adhesive cement to a zirconia- based ceramic. PMID- 23682504 TI - Digital data management for CAD/CAM technology. An update of current systems. AB - Abstract - Computer-aided design/computer-aided manufacturing (CAD/CAM) technology continues to rapidly evolve in the dental community. This review article provides an overview of the operational components and methodologies used with some of the CAD/CAM systems. Future trends are also discussed. While these systems show great promise, the quality of performance varies among systems. No single system currently acquires data directly in the oral cavity and produces restorations using all materials available. Further refinements of these CAD/CAM technologies may increase their capabilities, but further special training will be required for effective use. PMID- 23682505 TI - Unilateral bounded saddles: a clinical case report on the use of a two part sectional removable partial denture. AB - An increasing proportion of the adult population is partially dentate. Dental implants, being fixed and conservative of tooth tissue could be the ideal treatment of choice however cost, systemic and localfactors may limit their use. An alternative treatment modality is therefore required fo rpatients who are not suitable candidates for dental implants, conventional removable partial dentures or bridges. This case report illustrates the use of a sectional removable partial denture to restore a unilateral bounded saddle using a Hader bar connector. PMID- 23682506 TI - A preliminary evaluation into the performance of posterior resin bonded cast metal restorations (adhesive onlays). AB - Posterior resin bonded cast metal restorations (adhesive onlays) were used in a variety of clinical scenarios including: management of tooth wear and cracked tooth, as retainers for fixed bridge work, for correction of the occlusal plane and in providing cuspal coverage following endodontic treatment. The mean length in service for the examined onlays was 42 months, with a range of 9-75 months. Two restorations in two patients failed resulting in an overall success of 94%. Patient satisfaction was high at 95%. Such restorations seem to be a viable option for managing a number of clinical scenarios. PMID- 23682507 TI - A study to evaluate the prevalence of golden proportion and RED proportion in aesthetically pleasing smiles. AB - A beautiful smile is the most striking feature in the face. However beauty is not absolute and is extremely subjective. The aim of this study is to determine the prevalence of 'Golden proportion and Recurring aesthetic dental proportion' in individuals presenting attractive smiles. 214 smile photographs of students of SDM Dental College aged 18-25 years with natural dentition were analysed for their attractiveness based on 6 predetermined criteria. Further, smiles were digitally analysed to evaluate the prevalence of Golden Proportion and Recurring Aesthetic dental proportion (RED) and obtained data was statistically analysed. RED proportion was present in 6.6% of population as opposed to golden proportion which was found in 0.6% of population. It was found that 70% RED was more prevalent than Golden Proportion in attractive as well as unattractive smiles. PMID- 23682508 TI - The effect of laser irradiation on retention of full cast crowns. AB - The objective of this work was to determine the effect on the retention force of full cast crowns cemented on short tooth preparations after preparation of dentine with an erbium, chromium: yttrium scandium gallium garnet (Er, Cr:YSGG) laser at different sub-ablative power settings. Thirty teeth were prepared for full cast crowns using a milling machine. The surface area for all preparations was measured. The surfaces of the preparations were irradiated with 0 (control), 0.25 and 0.75 W laser. The crowns were cemented with self-cure resin cement and tested for retention on a Hounsfield Tensometer machine. The 0.75 W power setting produced the highest failure load value (346.2 +/- 86.1 N) and was significantly higher than the other groups. There were no significant differences between the 0.25 W and 0 W control groups PMID- 23682509 TI - Provision of an appliance to correct mandibular deviation secondary to temporomandibular joint replacement. AB - This report outlines the provision of an appliance of novel design to correct mandibular deviation secondary to temporomandibular joint replacement. The aim of the appliance was to reduce the deviation of the mandible by guiding its path during function, thus reducing the symptoms of facial pain. A significant improvement in symptoms was noted as a result of wearing the appliance which was still evident at the 12 month review. In a patient with high levels of chronic pain associated with TMJ dysfunction, reversible minimally invasive treatment has definite advantages, particular if there is a wish to avoid further surgical intervention. PMID- 23682510 TI - Evaluation and comparison of the internal fit and marginal accuracy of base metal (nickelchromium) and zirconia copings before and after ceramic veneering: a sem study. AB - This study compares the internal fit and marginal adaptation of copy milled Zirconia copings with Nickel-Chromium (Ni-Cr) copings fabricated using a lost wax technique before and after ceramic veneering. A standardized metal master die simulating a prepared crown was fabricated and twenty impressions of the metal die were made and poured with die stone. Wax patterns were made on ten dies and cast while light cure resin patterns were made on the other ten dies for copy milling the Zirconia copings. Five specimens from each group were subjected to ceramic veneering. All the test specimens were luted on to the fresh dies, embedded in dental plaster, sectioned and image analysis done using scanning electron microscopy. Thereafter statistical analysis is done using student t test. The linear measurements for internal fit and marginal discrepancy were increased for Zirconia compared with Ni-Cr copings. The difference in the values of all the specimens of all the groups were not statistically significant (P > 0.05) except the values comparing the internal fit of Zirconia and Ni-Cr copings before ceramic veneering (P < 0.001) which was statistically significant. The internal fit and marginal adaptability of Ni-Cr copings were found to be better than the Copy milled Zirconia copings but internal fit and marginal adaptability deteriorated after ceramic veneering. PMID- 23682511 TI - Psychotherapy-lite: obesity and the role of the mental health practitioner. AB - Obesity is a chronic medical disorder that is the result of a complex interaction of genetic, environmental, neuro-endocrinological, psychosocial, and behavioral factors. There are treatment algorithms, depending on the severity of obesity, and a multi-component approach, including attention to psychological issues, is recommended regardless of the level of obesity. Cognitive-behavioral therapy is beneficial in assisting with stimulus control, self-monitoring of lifestyle changes, goal-setting, and restructuring negative and self-defeating thoughts, and psychodynamic (insight-oriented) psychotherapy is useful in assisting with conflicts regarding excessive weight, body image, relationship to food and disordered patterns of eating, and dealing with the prejudice and overt discrimination obese patients may experience. Neither therapy is particularly effective alone and either and/or both may need to be continued indefinitely to avoid inevitable weight regain. Psychological intervention before and during the difficult process of dieting, as well as before and after bariatric surgery, is essential for some vulnerable patients. Since psychological factors are neither primarily etiological nor even necessarily predominant in obesity, the mental health professional plays an important, though adjunctive--"psychotherapy-lite" role--in treating obese patients. PMID- 23682512 TI - Practice-based evidence: 45 years of psychotherapy's effectiveness in a private practice. AB - Of 2,259 patients seen during 45 years of private practice, outcome data was produced for 1,599 cases. The mean (SD) number of sessions per case was 18.82 (29.89). The dropout rate was 18.76%. Of all treated cases with outcome data 4 (0.25%) were rated as Much Worse; 11 (0.69%), Worse; 497 (31.08%), No Change from Intake; 546 (34.15%), Improved; and 541 (33.83%), Much Improved. The mean (SD) pre-/post-treatment effect size (ES) was 1.90 (1.61), the median was 1.62, and the range was from -2.91 to +15.22. Patients and parents of minors rated outcomes more positively than the therapist did. Outcome varied significantly across diagnostic categories. There was a significant, positive relationship in length of treatment and outcome. The therapist's effectiveness did not improve across the years. Years with the largest patient caseloads or the greatest proportion of patients with managed-care insurance tended to show the poorest outcomes. PMID- 23682513 TI - Prediction of attachment status from observation of a clinical intensive psychotherapy interview. AB - OBJECTIVE: The present study addresses whether it is possible to accurately determine a subject's Adult Attachment Interview (AAI) classification by observing a video-recorded clinical psychotherapy discussion that uses the principles of Intensive Short-Term Dynamic Psychotherapy (ISTDP). METHOD: A random sample of eight of the author's (Robert J. Nebrosky) private practice patients participated in an AAI administered by an experienced interviewer. The authors were blind to the results of the AAI, which were scored and classified by Erik Hesse, PHD (consultant and expert in AAI coding and classification). The authors used the Adult Attachment Clinical Rating Scale (AA-CRS), which is an adapted version of the AAI "states-of-mind scales," in conjunction with the structured ISTDP interview to obtain main classifications and subclassifications. The authors determined the pathway of unconscious anxiety according to the procedures described by Davanloo (1995, 2001) and ten Have-de Labije (2006), beginning with the structured ISTDP interview, then categorized the patient's defenses and quality of the patient's observing and attentive ego, discussed the clinican's knowledge of the patient's attachment history, and from this data drew first the major gateway of attachment using the AA-CRS. Then the authors categorized the subclassifications using the AA-CRS. RESULTS: The authors predicted seven out of eight AAI main classifications correctly, and five out of eight AAI subclassifications correctly, indicating that there was a statistically significant relationship between predicted and expected values for main classifications and subclassifications. CONCLUSIONS: The authors conclude that the systematic ISTDP inquiry at the level of the stimulus (current, past, and therapeutic relationship) and response (defence, anxiety, and impulse/feeling) and combined with the clinician's knowledge of the patient's clinical history can effectively substitute for the AAI interview and therefore, yield an experiential reference from which to explore the patient's state of mind using the Adult Attachment Clinical Rating Scale (AA-CRS). The authors speculate that the differences in subclassification could be accounted for by variations and/or differences in biographical knowledge obtained by the the clinician versus that of the AAI coder (Hesse). PMID- 23682514 TI - Controversies in psychotherapy research: epistemic differences in assumptions about human psychology. AB - It is the thesis of this paper that differences in philosophical assumptions about the subject matter and treatment methods of psychotherapy have contributed to disagreements about the external validity of empirically supported therapies (ESTs). These differences are evident in the theories that are the basis for both the design and interpretation of recent psychotherapy efficacy studies. The natural science model, as applied to psychotherapy outcome research, transforms the constitutive features of the study subject in a reciprocal manner so that problems, treatments, and indicators of effectiveness are limited to what can be directly observed. Meaning-based approaches to therapy emphasize processes and changes that do not lend themselves to experimental study. Hermeneutic philosophy provides a supplemental model to establishing validity in those instances where outcome indicators do not lend themselves to direct observation and measurement and require "deep" interpretation. Hermeneutics allows for a broadening of psychological study that allows one to establish a form of validity that is applicable when constructs do not refer to things that literally "exist" in nature. From a hermeneutic perspective the changes that occur in meaning-based therapies must be understood and evaluated on the manner in which they are applied to new situations, the logical ordering and harmony of the parts with the theoretical whole, and the capability of convincing experts and patients that the interpretation can stand up against other ways of understanding. Adoption of this approach often is necessary to competently evaluate the effectiveness of meaning based therapies. PMID- 23682515 TI - Effectiveness and cost effectiveness of Davanloo's intensive short-term dynamic psychotherapy: does unlocking the unconscious make a difference? AB - More than 20 years ago Habib Davanloo coined the term unlocking of the unconscious to describe how the psychodynamic concept of the human unconscious can become accessible using the technique of Intensive Short-Term Dynamic Psychotherapy (ISTDP). According to Davanloo, the possibility that unconscious material will be revealed is greatly increased when therapeutic efforts promote dominance of the unconscious therapeutic alliance over unconscious resistance. When these ingredients are present there is a psychic shift that allows unacceptable painful feelings to come to the surface. Toward adding further empirical support for the concept, in this article we compare outcomes between patients who experienced one or more major unlocking of the unconscious (N = 57) to those who did not experience major unlocking (N = 32) during ISTDP treatment. Significant and widespread differences were seen between these two groups, those with major unlocking had greater symptom reduction, interpersonal gains, and cost reduction for treatment. The relevance of this to clinical practice and healthcare utilization will be discussed. PMID- 23682516 TI - Efficacy of the trivalent influenza vaccination in Thai patients with hemodialysis or kidney transplant compared with healthy volunteers. AB - OBJECTIVE: To evaluate the immune response to trivalent influenza vaccination in Thai patients with hemodialysis (HD) or kidney transplant (KT) compared with healthy volunteers. MATERIAL AND METHOD: This was a cross-sectional study in Thai healthy volunteers and patients with HD and KT who received the trivalent influenza vaccine provided by the Ministry of Public Health of Thailand from 1 November 2011 to 31 December 2011. Each subject was injected intramuscularly with one dose (0.5 milliliter) of trivalent influenza vaccine containing viral strains recommended by the WHO for the 2011 influenza season (southern hemisphere). Blood samples before and 6 weeks after the vaccination were measured for immune response using a hemagglutination-inhibition antibody assay. RESULTS: Subjects consisted of 30 healthy volunteers, 30 patients with HD and 30 patients with KT Prevalence of pre-vaccination seroprotective (SP) immunity in each group (healthy volunteers, HD, KT) was as follows: against H1N1 (33.3%: 23.3%: 10.0%), H3N2 (80.0%: 26.7%: 23.3%) and B (60.0%: 20.0%: 3.30%) viral strains, respectively. Those who were seronegative (SN) before testing positive after one dose of this vaccine were as follows: H1N1 (100.0%: 73.9%: 74.1%), H3N2 (66.7%: 86.4%: 34.8%) or B (58.3%: 66. 7%: 48.3%) viral strains, respectively. The healthy group showed significantly higher SP immune response for H1N1 than the HD and KT groups (p = 0.023). The HD group had significantly higher SP immune response for H3N2 than the KT groups (p = 0.001). Immune responses for the B vaccine in all groups were not different. No major adverse event was found in any group. CONCLUSION: Immune response for H1N1 vaccine in the HD and KT groups was slightly less than that of the healthy group. Immune response for H3N2 vaccine in the KT groups was less than in the healthy and HD groups. Immune responses for B vaccine in all groups were not different. PMID- 23682517 TI - A randomized controlled trial of staple fixation versus N-butyl-2-cyanoacrylate fixation in laparoscopic inguinal hernia repair. AB - BACKGROUND: There has been paramount concern among most surgeons over complications caused by staples in the form of pubic injury and nerve entrapment leading to chronic pain in laparoscopic inguinal hernia repair OBJECTIVE: The present study aimed to compare the use of N-butyl-2-cyanoacrylate (Histoacryl) with that of staples in fixation of mesh in totally extraperitoneal laparoscopic inguinal hernia repair in terms of acute and chronic pain, complications, and recurrence within 1 year MATERIAL AND METHOD: 60 patients were allocated into 2 groups. The same protocol of general anesthesia was applied in both groups. In the staple group, Ultrapro mesh was used to cover the myopectineal orifice and was transfixed with staples. In the glue group, Histoacryl was sprayed to fix the mesh at the same area as in the staple group and also at the triangle of pain. Demographic data collected included fentanyl use, operation time, visual analogue pain score (VAS), chronic pain, complications and recurrence. RESULTS: Demographic data and complications showed no significant difference in the two groups. VAS in the staple group was significantly greater than that in the glue group after 24 hours (1.6 +/- 1.33 vs. 2.35 +/- 1.32) (p = 0.037). The incidence of chronic pain after 3 months and 1 year was higher in the staple group (33.0%, 33.0%, vs. 23.0%, 16.0%) (p = 0.390, 0.360). One patient in the staple group had a hernia recurrence eight months after the operation. CONCLUSION: N-butyl-2 cyanoacrylate might be an alternative choice of mesh fixation in TEP since overall complications and recurrence of hernia were not significantly different compared to staple fixation. PMID- 23682518 TI - Inferior vena cava diameter and collapsibility index: a practical non-invasive evaluation of intravascular fluid volume in critically-ill patients. AB - BACKGROUND: Assessment of intravascular volume status is an essential parameter for the diagnosis and management of critically-ill patients. Generally, central venous pressure (CVP), which is an invasive measure, has been recommended for this purpose. Since CVP has been associated with many complications, inferior vena cava diameter and collapsibility index (IVC-CI) were used in the present study to evaluate the intravascular volume status of critically-ill patients at Rajavithi Hospital. OBJECTIVE: To conduct a prospective, cross-sectional study to evaluate the IVC diameter as a guidance for estimating the volume status in critically-ill patients by bedside ultrasonography, focusing on correlations between CVP and lVC-Cl and lVC diameter MATERIAL AND METHOD: Critically-ill patients who had been placed with a functioning central venous catheter were prospectively enrolled. Evaluation of intravascular volume status was performed by bedside ultrasonography to measure the IVC diameters (IVCD), both end inspiratory (iIVCD) and end-expiratory (eIVCD). The IVC collapsibility indices (IVC-CI) were calculated by an equation and then were compared with the CVP values. RESULTS: Of the 70 enrolled patients, with a mean age of 63.8 +/- 1.9 years, 64.3% were intubated. The most common indication of ICU admission was sepsis with hemodynamic instability (80.0%). The volume status of patients was stratified by their CVP levels as hypovolemic 15.7%, euvolemic 32.9% and hypervolemic 51.4% which correspond with the IVC-CI of 45.69 +/- 16.16%, 31.23 +/ 16.77%, and 17.82 +/- 12.36% respectively (p < 0.001). The highest significant correlation was found between the CVP and IVC-CI (r = -0.612, p < 0.001). In addition, there was a significant correlation between CVP and iIVCD (r = 0.535, p < 0.001); and between the CVP and mean IVCD (r = 0.397, p = 0.001). CONCLUSION: The present study supported the correlation between CVP and IVC-CI. The authors conclude that the IVC-CI can provide a useful guide for noninvasive intravascular volume status assessment of critically-ill patients. PMID- 23682519 TI - Survival and prognostic factors of stage I-III breast cancer. AB - OBJECTIVE: To determine the survival duration of stage I-III breast cancer patients, and to determine prognostic factors for overall survival and disease free survival in stage I to III breast cancer patients treated with surgery and adjuvant therapy. MATERIAL AND METHOD: This retrospective cohort study was conducted by reviewing 166files of stage I-III breast cancer patients treated with surgery and adjuvant therapy in the Oncology Unit, Department of Medicine, Rajavithi Hospital from January 1st 1998 to December 31st 2007. RESULTS: There were 166 patients whose median age was 48 years. The 5-year overall survival rates for stage I, stage II and stage III were 100.0%, 89.0% and 80.8% respectively (p = 0.11). Multivariate analysis showed that pathological lymph node pN2 status was a significant poor prognostic factor for overall survival (HR = 4.32, 95% CI 1.24-15.04; p = 0.022). The one-, three- and five-year disease free survival (DFS) rates were 96.7%, 81.4% and 76.7% respectively. Multivariate analysis revealed that pathological pN2 (HR = 4.43, 95% CI 1.44-13.57; p = 0.009), pN3 (HR = 5.16, 95% CI 1.54-17.30; p = 0.008) and progesterone receptor status negative (HR = 5.53, 95% CI 1.85-16.59; p = 0.002) were poor prognostic factors for disease-free survival. CONCLUSION: The most important prognostic factor affecting disease-free survival and overall survival of stage I-III breast cancer patients was axillary lymph node metastasis. Progesterone receptor status negative influenced disease relapse. Patients with multiple unfavorable risk factors such as lymph node metastasis and progesterone receptor status negative showed poor DFS, and therefore more aggressive adjuvant chemotherapy is required for these patients. PMID- 23682520 TI - Outcomes of complete radical hysterectomy in early-stage cervical cancer patients with intra-operative detection of nodal metastases. AB - OBJECTIVE: To determine the overall 5-year survival rate and treatment-related complications in stage IB-IIA cervical cancer patients with intra-operative detection of pelvic node metastases who underwent complete radical hysterectomy and systematic lymphadenectomy. MATERIAL AND METHOD: The medical records of FIGO stage IB-IIA cervical cancer patients who underwent radical hysterectomy and pelvic lymphadenectomy in Rajavithi Hospital between January 1985 and December 2006 were retrospectively reviewed. Of the 247 node-positive stage IB-IIA cervical cancer patients, 121 patients displayed evidence of intra-operative detection and underwent complete radical hysterectomy with systematic lymphadenectomy. These 121 patients were reviewed of which 107 were in stage IB and 14 were in stage IIA. Overall 5-year survival rate and treatment-related complications were investigated. RESULTS: The median follow-up period was 117 months (range 60-312 months). Of the 121 stage IB-IIA cervical cancer PATIENTS: with intra-operative detection of pelvic node metastases who underwent complete radical hysterectomy and pelvic lymphadenectomy, the overall 5-year survival rate was 70.5%. The major treatment-related complications were intraoperative hemorrhage and post-operative bladder atony which accounted for 43.0% and 10.7%, respectively. CONCLUSION: Early-stage cervical cancer patients with intra operative detection of pelvic node metastases who underwent complete radical hysterectomy had favorable survival outcomes and manageable complications. PMID- 23682521 TI - Abnormal electroencephalography in first unprovoked seizure in Rajavithi Hospital. AB - BACKGROUND: Electroencephalography (EEG) has an important role in epilepsy diagnosis, classification of epilepsy syndrome, lesion localization, and prediction of seizure recurrence, but no study of EEG in the first unprovoked seizure had been carried out in Rajavithi Hospital prior to the current one. OBJECTIVE: The present research aimed to find the prevalence of abnormal EEG in the first unprovoked seizure and the prevalence of abnormal EEG in partial seizure and generalized seizure. MATERIAL AND METHOD: This was a retrospective study of 28 adult patients who presented with first unprovoked seizure. EEG was performed in all patients and baseline characteristics were recorded. RESULTS: Of the 28 patients with first unprovoked seizure, abnormal EEG was found in 16 patients (57.41%). 95% CI of the prevalence of abnormal EEG was 37.60-76.68%. EEG abnormalities were found in 7 patients (46.7%) who had partial seizure, and 8 patients (53.3%) who had generalized seizure. Eight patients (28.6%) had epileptiform discharges. The patients who were taking medication for underlying diseases and patients with abnormal neurological examinations were associated with a statistically significant higher risk of EEG abnormality (OR 6.43, 95% CI 1.05-39.33, p = 0.044, and OR 13.2, 95% CI 1.24-140.68, p = 0.027, respectively). CONCLUSION: Abnormal EEG was detected in more than half of the patients with first unprovoked seizure, which is comparable to previous studies. EEG should be considered for all patients with first unprovoked seizure. PMID- 23682522 TI - Recurrence rate of PSVT (paroxysmal supraventricular tachycardia) in Rajavithi emergency department. AB - BACKGROUND: PSVT (Paroxysmal Supraventricular Tachycardia) is a common heart disease, especially in young people. Although PSVT is not a life-threatening illness, its symptoms occur in a sudden onset and with increasing frequency. Because of the severity of its symptoms, it can interfere with patients' quality of life and lead to an increase in anxiety levels. The authors found that patients with PSVT tended to have recurrence of symptoms; however, there has been no previous study in Thailand of the rate of recurrent PSVT in adults. Moreover, there has been no study of the factors which precipitate PSVT cause recurrence, and result in hospitalization. OBJECTIVE: To study the rate of recurrence of PSVT within 90 days, the precipitating factors that cause PSVT and the relationship between the factors that affect recurrence of symptoms and result in admission to hospital. MATERIAL AND METHOD: This was a cross-sectional study of patients who had been diagnosed with PSVT and were treated in the emergency room at Rajavithi Hospital from 1st August 2008-31st August 2011. The primary outcome was recurrence of PSVT within 90 days and its impact on hospital admission. RESULTS: The 55 patients in the present study visited the hospital 94 times. The authors found that: 20.0% of patients had recurrence of PSVT within 90 days; 45.7% of patients had no precipitating factors; 33.0% of patients had emotional stress; and 20.0% of patients had stopped taking their medication. Patients who presented at their first visit with a heart rate of more than 200 beats per minute were more likely to have recurrence (statistically significant, HR 2.43, p = 0.017). Patients presenting with low systolic blood pressure (SBP < 90 mmHg), long duration of symptoms, structural heart disease, low serum Hematocrit concentration (Hct < 30%), serum sodium < 135 milligram, and serum potassium < 3.5 milligram were more likely to be admitted to hospital (statistically significant at p = 0.013, 0.012, 0.004, 0.001, 0.001, and 0.004 respectively). CONCLUSION: There was a high rate of recurrence of PSVT in patients in the emergency department at Rajavithi Hospital. Significant factors affecting recurrence were patients presenting with initial heart rate of over 200 beats per minute. Low systolic blood pressure, long duration of symptoms, structural heart disease, low serum Hematocrit, low serum sodium and serum potassium were associated with hospitalization. PMID- 23682523 TI - Association between hs-CRP and Hba1c in overweight type 2 diabetic female patients. AB - BACKGROUND AND OBJECTIVE: High-sensitive C-reactive protein (hs-CRP) is associated with atherosclerosis. Previous studies have shown that hs-CRP is associated with insulin resistance, type 2 diabetes and higher HbA1c levels. As type 2 diabetes is often found in overweight women, the present study investigated the relationship between hs-CRP and HbA1c levels in such patients. MATERIAL AND METHOD: This was a retrospective study of type 2 diabetic patients in Rajavithi Hospital from January 2009 until June 2011. All the subjects were females aged 40 years or more who had body mass index (BMI) of more than 25 kilograms per square metre. The patients were examined and blood was collected in order to check hs-CRP and HbA1c levels. RESULTS: Data from 75 cases, classified the patients into 2 groups by their levels of hs-CRP and risk of coronary artery disease. Of the 75 patients, 35 had hs-CRP levels less than 1 mg/L, and the remaining 40 patients had hs-CRP levels of 1 mg/ L or more, representing 46.67% and 53.33% respectively, and it was found that hs-CRP values correlated with HbA1c levels. The group with hs-CRP of less than 1 milligram per liter had a mean HbA1c of 7.36 +/- 1.23%, while the group with hs-CRP of 1 mg/L or more had a mean HbA1c of 8.77 +/- 1.78%, with statistical significance at p-value < 0.001. CONCLUSION: In the present study of patients with type 2 diabetes, the authors found that hs-CRP levels correlated with HbA1c levels. Mean HbA1c levels were significantly higher in patients who had hs-CRP levels of 1 mg/L or more (p-value < 0.001). Other factors such as age, blood pressure, BMI, LDL-C, serum creatinine were not correlated with hs-CRP level. PMID- 23682525 TI - Stability of adrenaline in ambulance and drug storage room Narenthorn Center, Rajavithi Hospital. AB - BACKGROUND: The stability and quality of Adrenaline medications were advocated 2 to be stored in temperature labeled at 2 degrees C to 8 degrees C at drug storage room. Thailand is located in a tropical area with the average room temperature within 25 degrees C. There was no previous study of adrenaline medication stability and quality in Thailand. OBJECTIVE: To assess the stability and quality of Adrenaline stored at room temperature in Ambulance and drug storage room of Narenthorn center, Rajavithi Hospital. MATERIAL AND METHOD: Forty vials of Adrenaline Bitartrade were stored at the temperature in each season for a period of 4 weeks. Half were stored in one Ambulance and the other half in a drug storage room. Samples were then analyzed for their appearance, pH and using stability indicating High Performance Liquid Chromatography (HPLC). RESULTS: The average temperature in the drug storage rooms were 30 degrees C, 28 degrees C and 27 degrees C in hot, rainy and cool seasons respectively; and 34 degrees C, 32 degrees C and 31 degrees C in Narenthorn Ambulance. The appearance of adrenaline was not changed as it was still clear. The average pH is 3.18 to 3.36. Adrenaline was found to be stable when storage in both ambulance and drug storage room. The percent drug remaining was 90 Ia% to 115 Ia%. There was no significant difference in between drug quality the two storage places (p = 0.792). No significant difference was found in the percent drug remaining between the hot and cool season. There was significant difference in the percent drug remaining between the rainy season from other seasons (p < 0.005). CONCLUSION: Even though the temperature in the drug storage room and Ambulance was higher than recommended storage temperature, adrenaline stability and quality were not changed when testing by HPLC. PMID- 23682524 TI - The results of comparisons between CT-guided and fluoroscopic-guided spinal biopsy. AB - BACKGROUND: Various methods have been described for biopsy of spinal lesions. In the past, fluoroscopes were used to guide the performance of biopsy of spinal lesions while computed tomography (CT) is now available in many hospitals. The purpose of the present study was to determine the rate of successful diagnosis of spinal biopsy by the CT-guided technique compared to the fluoroscopic-guided technique. OBJECTIVE: To compare the success rate in diagnosis of vertebral disease and ensuing complications when using CT-guided and fluoroscopy-guided biopsy MATERIAL AND METHOD: Two study groups were compared in order to establish their respective diagnostic success rates and complications. The CT-guided spinal biopsy group consisted of 10 patients (4 males, 6 females), and the fluoroscopic guided spinal biopsy group was composed of 16 patients (6 males, 10 females). RESULTS: CT-guided spinal biopsy showed a diagnostic rate of 80.0% compared to a rate of 81.3% achieved by the fluoroscopic-guided technique (p = 1.000). For thoracic vertebrae, the diagnostic rates were 100% and 62.5% respectively. The figures were not statistically significant (p = 0.491), but the CT group showed a tendency towards a higher rate of success. No complication was noted in any of the patients. CONCLUSION: CT-guided spinal biopsy in thoracic vertebrae had a higher success rate in the diagnosis of spinal lesion than the fluoroscopic guided maneuver but the results were not statistically significant. In addition, the CT-guided technique was safer for the patient. PMID- 23682526 TI - Maternal 25 hydroxyvitamin D level and its correlation in Thai gestational diabetes patients. AB - OBJECTIVE: To identify 25 hydroxyvitamin D (250HD) levels in Thai pregnant women with gestational diabetes and nongestational diabetes. MATERIAL AND METHOD: This prospective study was conducted on 197 pregnant women at Rajavithi Hospital, a tertiary care medical center in Bangkok from October 2010 to July 2011. Plasma 25 hydroxyvitamin D concentration and HbA1c level during the 75 g OGTT in gestational diabetes mellitus (GDM) and non-GDM were evaluated. The recommendations of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) were used for diagnosis of GDM in the present study. RESULTS: In the selected 197 Thai pregnant women aged from 18 to 49 years, the mean age was 32.1 years, and the mean plasma 250OHD level was 34.3 ng/dl. The percentages of patients classified as having 25OHD deficiency (< 20 ng/dl), 25OHD insufficiency and normal 25OHD were 3.1%, 22.3% and 74.6%, respectively. Among the 197 women, 70 patients (34.8%) had GDM. In the GDM group, 29 patients (41.4%) had abnormal 25OHD level of which 5.7% had 25OHD deficiency and 35.7% had 25OHD insufficiency. Among those with GDM, plasma 25OHD concentration was significantly lower than in the non-GDM subjects (32.3 +/- 10.3 vs. 35.5 +/- 6.7 ng/dl, p = 0.001). Fasting blood glucose and HbA1C independently predicted low 25OHD levels in Thai GDM subjects after applying regression model and adjusting for age, BMI, trimester and family history of DM (p = 0.031, p = 0.014 respectively). Higher pre pregnancy BMI was associated with GDM and lower 25OHD level. CONCLUSION: Thai pregnant women with GDM had lower levels of 25OHD compared to those without GDM. Only fasting plasma glucose independently predicted low 25OHD levels in GDM subjects. PMID- 23682527 TI - Effect of 4% gelofusine plus antibiotics on renal impairment and mortality in high-risk cirrhotic patients with spontaneous bacterial peritonitis. AB - BACKGROUND: Spontaneous bacterial peritonitis (SBP) increases the rates of renal impairment and mortality in cirrhotic patients. A previous study showed that cefotaxime plus albumin treatment decreased renal impairment more than antibiotic treatment alone in patients with serum bilirubin > 4 mg/dL or creatinine > 1 mg/dL. 4% Gelofusine is a colloidal volume replacement fluid used for fluid resuscitation and hemodynamic stabilization. Only one study showed that intravenous 4% gelofusine plus antibiotic could decrease the rates of renal impairment and mortality in comparison with the treatment with albumin plus antibiotic in high-risk cirrhotic patients with SBP OBJECTIVE: To evaluate the effects of 4% gelofusine plus antibiotics on renal impairment and mortality rates in high-risk cirrhotic patients with spontaneous bacterial peritonitis. MATERIAL AND METHOD: Eighteen cirrhotic patients with SBP and serum bilirubin > 4 mg/dL or creatinine > 1 mg/dL were enrolled. Ceftriaxone was given intravenously in doses of 2 g/day. Gelofusine 4% was given intravenously at 1.5 g/kg of body weight at the time of the diagnosis, followed by 1 g/kg on the 3 day. Renal impairment and mortality rates were evaluated during and after treatment. RESULTS: Five patients (27.8%) had pre-existing renal failure. Infection resolved in 15 patients (83.3%). Renal impairment developed in three patients (16.7%), and six patients (33.3%) died during hospitalization. After one month, the mortality rate was 33.3% (a total of 6 deaths). Patients with renal impairment had higher levels of plasma renin activity than those without renal impairment but the values were not statistically significant. CONCLUSION: In high-risk cirrhotic patients with spontaneous bacterial peritonitis, treatment with 4% gelofusine intravenously plus antibiotic reduced the incidence of renal impairment but did not reduce mortality in comparison with previous studies. Studies with larger sample sizes may be useful to evaluate these effects. PMID- 23682528 TI - Incidence of primary colorectal cancer from colonoscopy examinations in patients presenting with liver mass. AB - BACKGROUND: An in-patient presented with atypical primary liver mass and was suspected of having liver metastasis. One method of investigation is colonoscopy; however, there are currently no clear guidelines to indicate when this procedure should be performed. MATERIAL AND METHOD: This was a retrospective review of 6 years' data from the surgical endoscopic unit in Rajavithi Hospital. The inclusion criteria were: (1) patient presented with liver mass, (2) radiological findings (mainly from CT scan or MRI) were not typicalfor hepatocellular carcinoma (HCC), intrahepatic cholagiocarcinoma (ICGC) and other primary liver tumors. The exclusion criteria were: (1) patients did not undergo the operation in Rajavithi Hospital, (2) there was loss of patient data during the follow-up period. RESULT: A total of 1,532 cases underwent colonoscopy, of which 109 met the inclusion criteria. There were 24 cases of positive primary colorectal cancer and the incidence was 22% (95% CI 14.1-29.9), and 1 case of terminal ileum cancer. The final results after operation showed 40 cases of HCC, and 21 cases of intrahepatic cholangiocarcinoma. Risk factors for testing positive for colorectal cancer were: presenting with GI symptoms; abnormal CEA levels; and positive family history of colorectal cancer CONCLUSION: To increase the incidence of positive results for colorectal cancer and reduce unnecessary colonoscopy in patients who present with liver mass, the factors which indicate colonoscopy should be patients who present with GI symptom, abnormal CEA level, and whose family history raises concern. PMID- 23682529 TI - Comparison of outcomes for staple and conventional closure of the pharynx following total laryngectomy. AB - BACKGROUND: Closure of the wall of the pharynx is an important step in the total laryngectomy operation. An inadequate closure results in tissue contamination, wound infection, and the development of pharyngo-cutaneous fistula. OBJECTIVE: To study the outcomes of neo-pharyngeal closure after total laryngectomy by stapler compared with conventional techniques. MATERIAL AND METHOD: A retrospective descriptive study of patients undergoing total laryngectomy with either pharyngeal stapling or suturing between January 2007 and December 2011. RESULTS: Twenty-six patients had pharyngeal stapling, while another twenty-six had a conventional pharyngeal closure. The operative time was significantly less in the stapler group (p < 0.001). CONCLUSION: Pharyngeal stapling might be an alternative technique for total laryngectomy. PMID- 23682530 TI - Prevalence and factors influencing exclusive breast-feeding in Rajavithi Hospital. AB - OBJECTIVE: The aim of the present study was to identify the prevalence of exclusive breast-feeding after 2,4, and 6 months in Rajavithi Hospital. The present study evaluated the factors associated with discontinuing breast-feeding before the first two months of life in order to target early nursing interventions to encourage and support continued breast-feeding and increase the exclusive breast-feeding rate. MATERIAL AND METHOD: From September 2010 to May 2011, mothers were interviewed prior to hospital discharge from the maternity ward and follow-up phone calls were made after 2,4 and 6 months postpartum. RESULTS: The prevalence of exclusive breast-feeding after 2, 4 and 6 months was 57.9% (252 out of 435), 32.0% (139 out of 435) and 4.8% (21 out of435) respectively. At 2 months postpartum, multivariate analysis was carried out to identify whether maternal obesity and breast-feeding intervals of more than 3 hours had a statistically significant association with cessation of breast feeding. The most common reason for cessation of exclusive breast-feeding by mothers was their return to work. CONCLUSION: The prevalence of exclusive breast feeding at 2, 4, and 6 months was 57.9%, 32.0% and 4.8%, respectively. Maternal obesity, and maternal breast-feeding for intervals of more than 3 hours prior to hospital discharge were risk factors of early breast-feeding cessation at 2 months postpartum. This is an area on which we would target nursing interventions to prevent early unintended weaning. PMID- 23682531 TI - Novel COL1A1 gene mutation (R1026X) of type I osteogenesis imperfecta: A first case report. AB - A 22-year-old Thai man with blue sclera, normal height and absence of deformity sustained an open fracture at the right talus and talo-navicular dislocation while playing in a volleyball match. The patient had a history of several fractures of his elbows, wrists and ankles from minor impacts. Novel COL1A1 nonsense mutation (c. 3202 C-->T), a C to T transition at position 3,203, resulting in arginine to stop codon at codon 1026 (R102 6X) mutation in exon 42 was found, and this is the first case reported in the literature. PMID- 23682532 TI - Laparoscopic retropubic simple prostatectomy for large benign prostatic hyperplasia: first case report in Thailand. AB - BACKGROUND AND OBJECTIVE: At Rajavithi Hospital, open retropubic simple prostatectomy was started in 1985. The purpose of the present was to describe a surgical technique and early post-operative results of the first successful laparoscopic retropubic simple prostatectomy (LRSP) in Thailand. CASE REPORT: A 69-year-old Thai male presented with a chief complaint of refractory urinary retention. Digital rectal examination was performed with prostate gland of 4 finger breadths, firm consistency and smooth surface. The PSA level was 27.16 ng/ml. Transrectal ultrasound volume was 143 gm. The biopsy sample confirmed BPH and chronic prostatitis. The cystoscopy revealed prostate gland enlargement with obstruction. This patient's manifestation required surgical treatment of BPH, and the LRSP technique was chosen. The prostatic capsule was incised by monopolar scissors and the prostatic adenoma was enucleated. The prostatic capsule was closed and a 22 Fr three-way irrigating Foley catheter was inserted. The operative time was 2 hours, with estimated blood loss of 600 ml and no immediate post-operative complications. The prostate specimen weighed 169 gm. The pathologic results confirmed BPH and prostatitis. Postoperative ambulation and catheter removal was on the 2nd and the 7th day, respectively. Postoperative uroflowmetry report showed a Qmax of 15 ml/s. CONCLUSION: Operated by an experienced laparoscopic team, laparoscopic retropubic simple prostatectomy for large BPH is a feasible alternative approach to open surgery. PMID- 23682533 TI - Laparoscopic radical cystectomy with total intracorporeal ileal neobladder: first case report in Thailand. AB - BACKGROUND AND OBJECTIVE: Radical cystectomy (RC) remains the gold standard for muscle-invasive, organ-confined urothelial carcinoma (UC) of the bladder Recently, laparoscopic surgery has been used increasingly by urologists as a minimally invasive procedure to treat neoplasms of the pelvic organs. The present study aimed to report technical aspects of the experience of treating Thailand first case of RC with bilateral pelvic lymphadenectomy and ileal neobladder under the totally intracorporeal laparoscopic technique. CASE REPORT: A 67-year-old Thai male patient presented with intermediate-grade muscle- invasive UC of the bladder with negative metastatic workout. Laparoscopic radical cystectomy and pelvic lymphadenectomy were performed using 5 abdominal ports. Hemostasis was performed with bipolar forceps and vascular clips. The authors performed U-shape ileal neobladder and anastomosis using the completely intracorporeal laparoscopic technique. The operative time was 10 hours, the estimated blood loss was 1,000 ml, and there were no serious complications. The ureteric stents were removed after the 7th day, the tube drain was removed after the 10th day, and the Foley catheter was removed after the 21th day. The post-operative pathologic report indicated intermediate-grade muscle-invasive UC and free resection margin. CONCLUSION: The authors initial experience in Laparoscopic Radical cystectomy with totally intracorporeal ileal neobladder demonstrated that it was a feasible treatment modality. However more cases are required in the future to confirm its efficacy and improve laparoscopic technical performance in the treatment of organ confined UC. PMID- 23682534 TI - Fulminant type I diabetes: the first case report in Thailand. AB - Type 1 diabetes is classified as either autoimmune (type IA) or idiopathic (type IB) diabetes. Fulminant type 1 diabetes is a recently-discovered subtype of idiopathic type 1 diabetes. It is defined as diabetes with complete abrupt onset of beta cell destruction and progression to hyperglycemia and ketoacidosis within a short period of time, but with a near-normal HbA1c level. The patients often have flu-like or abdominal symptoms at onset and elevated levels of pancreatic exocrine enzymes. Their diabetes-related autoantibodies are usually negative. In the present report, the authors present a case of fulminant type 1 diabetes in a 43-year-old Thai woman who presented with sudden onset of flu-like symptoms and abdominal pain. Findings on admission included a high blood glucose level and ketoacidosis, but a prediabetes range ofHbA1c level. Autoantibodies to glutamic acid decarboxylase (GAD) were negative. This subtype of type 1 diabetes was first identified in 2000 and there have been case reports from Japan, Korea, the Philippines and the Netherlands. Nonetheless, no case had been reported in Thailand until the present study. Here the authors report the first case of fulminant type 1 diabetes in Bangkok, Thailand. PMID- 23682536 TI - There is nothing routine about the EEG. PMID- 23682535 TI - Disseminated viridians streptococcus (Streptococcus mitis) infection presenting with toxic shock-like syndrome. AB - The authors report a case of a 35-year-old man with no known underlying disease who presented with fever, cellulitis with hemorrhagic blebs on the left leg, monoarthricular left knee arthritis, multiple organ failure and septic shock. His clinical syndrome was compatible with toxic shock syndrome and his blood grew alpha hemolytic (viridians) Streptococcus mitis. To our knowledge, there are few reported cases of toxic shock syndrome cause by Streptococcus mitis in immune competent adults. PMID- 23682537 TI - Heinrich Hertz, the father of frequency. AB - Modernity stands on the shoulders of ancestors. Their historical foundations support and inspire our today. In 19th century Germany, Heinrich Rudolf Hertz was such a historical person. Hertz, a brilliant physicist, had the ability to integrate theoretical book knowledge with fundamental bench experimentation. Hertz's eclectic talents and research accomplishments ranged from drafting in architecture to meticulous manipulation of standard laboratory equipment often redesigned for his relentless curiosity (Buchwald 1994). He was the first to conclusively prove the existence of electromagnetic waves with precise experimental procedures and instrumentation he engineered to generate and detect waves (radio pulses) across space. His touchstone research verified Maxwell's theory and proved that all forms of electromagnetic radiation are propagated as waves at a finite velocity--the speed of light (Heinrich Hertz 2012). In recognition of his pivotal discoveries, Hertz's name is the universal synonym for frequency. Categorizing electroencephalographic (EEG) patterns by frequency is the primary emphasis of an EEG recording. The distribution of frequencies, amplitude, and polarity of electrocerebral potentials as recorded on the computer screen and/or graph paper result from numerous electrical fields of neuronal dipoles. Hertz's images drawn as the paper dipole remain the standard method for describing electrocerebral dipoles and the electrical fields of epileptiform activity recorded on a patient's electroencephalograph. Hertz's intended and inadvertent discoveries became the launch pad for numerous medical and media technologies. His former student Philipp Lenard won the 1905 Nobel Prize for Physics when he developed a version of the cathode tube and studied penetration by x-rays based on Herts'z cathode ray experiments in 1892. Additionally, Hertz did not pursure his ancillary discovery of the photoelectric effect in 1887. Albert Einstein would later explain features of the phenomenon and earn the Nobel Prize in physics in 1921 (Photoelectric effect 2012). The gestation of Hertz's scientific discoverries has developed the comforts and pleasures of 21st century life. The electromagnetic spectrum spans from longest wavelenght to shortest: radio waves, microwaves, infrared, optical, ultraviolet, x-ray, and gamma-rays- all measured in Hz (Electromagnetic waves 2000. PMID- 23682538 TI - Overview of using T1/T2 and 10-10 subtemporal electrode chains for localizing EEG abnormalities. AB - Evaluation of seizure activity may require the addition of T1/T2 or a subtemporal chain of electrodes based on the 10-10 measurement system. Placement of additional electrodes helps to localize seizure activity in pre-surgical patients and to reveal areas of abnormality which cannot be easily discerned with International 10-20 System of electrode placement. The addition of extra electrodes can be confusing if multiple technologists are involved with the patient's care. Extra steps such as using labeled tape can help clarify what electrodes are being used for each patient. This paper will define correct electrode placement of T1/T2 and the subtemporal chain. It will also demonstrate how to record with specific montages using these electrodes and show their usefulness in localizing abnormalities. PMID- 23682539 TI - Quality assurance and performance improvement in intraoperative neurophysiologic monitoring programs. AB - Quality assurance (QA) as it relates to intraoperative neurophysiological monitoring (IONM) can be defined as the systematic monitoring, evaluation, and modification of the IONM service to insure that desired standards of quality are being met. In practice, that definition is usually extended to include the concept that the quality of the IONM service will be improved wherever possible and, although there are some differences in the two terms, in this article the term QA will be understood to include quality improvement (QI) processes as well. The measurement and documentation of quality is becoming increasingly important to healthcare providers. This trend is being driven by pressures from accrediting agencies, payers, and patients. The essential elements of a QA program are described. A real-life example of QA techniques and management relevant to IONM providers is presented and discussed. PMID- 23682540 TI - Low frequency filtering of nasal pressure channel causes loss of flow limitation. AB - STUDY OBJECTIVES: The objective of this clinical vignette is to explore whether changes in low filter settings for respiratory waveforms have a clinically significant effect on patient management of obstructive sleep apnea (OSA). DESIGN: This is a case report. METHODS: We collected data from a continuous positive airway pressure (CPAP) titration polysomnogram (PSG) performed in our university based sleep laboratory. We reviewed the flow signal using low frequency filter settings of 0.0, 0.1, 0.3, and 0.5 Hz. RESULTS: We noted that a change in the low frequency filter for respiratory flow caused a change in the appearance of an otherwise flattened waveform indicating flow limitation to no longer appear flat. CONCLUSION: We noted that indiscriminate use of the low frequency filter for nasal pressure and flow estimate channels may lead to greater difficulty recognizing respiratory flow limitation. PMID- 23682541 TI - Motor evoked potential response latencies demonstrate moderate correlations with height and limb length in healthy young adults. AB - The purposes of this study were to determine 1) if motor evoked potential (MEP) response latencies and central motor conduction time (CMCT) are significantly correlated with lower extremity (LE) length or height, and 2) determine if MEP response latencies and CMCT are different between sexes among healthy adults. A cross-sectional, descriptive laboratory design was used. MEPs were recorded from 106 subjects (60 females, 46 males; age 20.1 +/- 2.4 years) by applying transcranial magnetic stimulation over the primary motor cortex. MEP response latencies were recorded using electromyography (EMG) responses from the tibialis anterior; CMCT was calculated from cortical and spinal-evoked MEP latencies. MEP latencies were significantly different between males (29.53 +/- 3.02 msec) and females (27.69 +/- 2.81 msec). Height accounted for greater variability (eta2 = .369 or approximately 37%) between genders and demonstrated a good-to-moderate correlation with MEP latency (r = .595, p = < .0001). Accounting for height as a confounding variable in the analyses, no significant differences between genders was observed (F1,103 = 2.45, p = .21). MEP latency should be adjusted to each subjects' height to account for the unwanted variability associated with the varied heights of subjects being tested, thereby permitting an accurate comparison and meaningful interpretation of MEPs between subjects or patients. PMID- 23682542 TI - Technical tips: the eyes and ears of artifacts in diagnostic testing. AB - Recognizing and eliminating artifacts are a daily part of my job as a neurodiagnostic technologist. Distinguishing between EEG and artifact is essential since it can impact the patient's diagnosis and treatment. I recently experienced an interesting situation that I had never previously encountered. My patient had a cochlear implant. This small device presented a challenge, but gave me the opportunity to put my troubleshooting skills to the test, and use some quick thinking to remove the artifact it created from the recording. It turns out this small device not only affected the EEG recording, but also another diagnostic test. I decided to do some research on the cochlear implant to find out how this tiny instrument affected the EEG recording as well as my patient's life, by allowing my patient to hear the world around him. PMID- 23682543 TI - Different oxygen treatment pressures alter inflammatory gene expression in human endothelial cells. AB - Hyperbaric oxygen has proven to be a useful treatment for chronic wounds. However, therapeutic conditions vary between treatment centers, and we wished to investigate the effects of different treatment pressures on cells under inflammatory conditions. Endothelial cells were exposed to a chronic wound model comprising hypoxia (2% O2 at 1 atmosphere absolute (atm abs); PO2 approximately 2 kPa) in the presence of 0.5 microg/ml lipopolysaccharide and 1 ng/ml TNF-alpha for 24 hours, then treated with normobaric oxygen (NBO2; 95%O2/5%CO2 at 1.0 atm abs; PO2 approximately 96.3 kPa), hyperbaric oxygen (HBO2) at 1.5 atm abs (1.5HBO2; 96.7%O2/3.3%CO2 at 1.5 atm abs; PO2 approximately 147 kPa), and HBO2 at 2.4 atm abs (2.4HBO2; 97.9%O2/2.1%CO2 at 2.4 atm abs; PO2 approximately 238 kPa). The mRNA expression of 92 inflammatory genes was then analyzed, and we identified changes in genes involved in adhesion molecule expression, angiogenesis and tissue remodeling, intracellular signaling, and cellular oxygen responses and redox signaling. We noted differences in expression between different treatment pressures, highlighting the need for further research into the use of different therapeutic protocols in the treatment of inflammatory conditions such as chronic wounds. PMID- 23682544 TI - Oxidative stress, antioxidant defenses and nitric oxide production following hyperoxic exposures. AB - Little data exist on the dose-response relationship between the partial pressure of inspired oxygen (PiO2) and the cellular oxidative stress response in humans. The objective of this study was to determine the effects of PiO2 on lipid peroxidation, antioxidant enzyme activity and nitric oxide (NO) production. Twelve healthy male divers breathed 100% O2 in a hyperbaric chamber for two hours at 1 (101 kPa), 1.5 (152 kPa) and 2 (203 kPa) atmospheres absolute (atm abs). Venous blood was collected pre-, within 15 minutes post-, one and two hours post hyperoxic exposures to determine changes in plasma and erythrocyte lipid peroxidation (thiobarbituric acid reactive substances-TBARS), antioxidant enzyme activity (superoxide dismutase-SOD), catalase-CAT, glutathione peroxidase-GPx), and plasma NO production (L-arginine [L-Arg], asymmetric dimethylarginine-ADMA, and nitrites). There were minor changes in TBARS and mixed responses in plasma and erythrocyte CAT and GPx activity. Plasma L-Arg increased following 1 and 1.5 atm abs exposures, yet ADMA and nitrites were unchanged. Only erythrocyte CAT and plasma GPx activity, and plasma L-Arg/ADMA demonstrated a significant PiO2 dose dependent relationship. Two-hour hyperoxic exposures at 1-2 atm abs of O2 results in mixed oxidant-antioxidant responses and unaltered NO production. Moreover, there does not appear to be a strong systemic dose-dependent oxidative stress response at these hyperoxic exposures. PMID- 23682545 TI - Nitric oxide-related endothelial changes in breath-hold and scuba divers. AB - OBJECTIVE: Scuba and breath-hold divers are compared to investigate whether endothelial response changes are similar despite different exposure(s) to hyperoxia. DESIGN: 14 divers (nine scuba and five breath-holding) performed either one scuba dive (25m/25 minutes) or successive breath-hold dives at a depth of 20 meters, adding up to 25 minutes of immersion time in a diving pool. Flow mediated dilation (FMD) was measured using echography. Peripheral post-occlusion reactive hyperemia (PORH) was assessed by digital plethysmography and plasmatic nitric oxide (NO) concentration using a nitrate/nitrite colorimetric assay kit. RESULTS: The FMD decreased in both groups. PORH was reduced in scuba divers but increased in breath-hold divers. No difference in circulating NO was observed for the scuba group. Opposingly, an increase in circulating NO was observed for the breath-hold group. CONCLUSION: Some cardiovascular effects can be explained by interaction between NO and superoxide anion during both types of diving ending to less NO availability and reducing FMD. The increased circulating NO in the breath hold group can be caused by physical exercise. The opposite effects found between FMD and PORH in the breath-hold group can be assimilated to a greater responsiveness to circulating NO in small arteries than in large arteries. PMID- 23682546 TI - Electrocardiographic aspects of deep dives in elite breath-hold divers. AB - The cardiac diving response, 12-lead electrocardiogram (ECG) and the prevalence, time of onset, and possible associations of cardiac arrhythmias were examined during deep breath-hold (BH) dives. Nine elite BH divers (33.2 +/- 3.6 years; mean +/- SD) performed one constant-weight dive of at least 75% of their best personal performance (70 +/- 7 meters for 141 +/- 22 seconds) wearing a 12-lead ECG Holter monitor. Diving parameters (depth and time), oxygen saturation (SaO2), blood lactate concentration and ventilatory parameters were also recorded. Bradycardia during these dives was pronounced (52.2 +/- 12.2%), with heart rates dropping to 46 +/- 10 beats/minute. The diving reflex was strong, overriding the stimulus of muscular exercise during the ascent phase of the dive for all divers. Classical arrhythmias occurred, mainly after surfacing, and some conduction alterations were detected at the bottom of the dives. The BH divers did not show any right shift of the QRS electrical axis during their dives. PMID- 23682547 TI - Physical exercise might influence the risk of oxygen-induced acute neurotoxicity. AB - OBJECTIVE: Hyperoxia can induce acute neurotoxicity with generalized seizures. Hyperoxia-induced reduction in cerebral blood flow velocity (CBFV) might be protective. It is unclear whether dynamic exercise during hyperoxia can overcome CBFV-reduction and thus possibly increase the risk of neurotoxicity. METHODS: We studied CBFV with both-sided transcranial Doppler with fixed transducer-position and heart rate under increasing hyperoxic conditions in nine professional military oxygen divers. The divers performed dynamic exercise on a bicycle ergometer in a hyperbaric chamber (ergometries I-III, 21kPa, 100kPa, 150kPa pO2), with continuous blood pressure (ergometries I, II), end-tidal CO2 (PetCO2; ergometry I) being measured. RESULTS: Systolic (CBFVsyst) and diastolic CBFV (CBFVdiast) readings at rest decreased with increasing pO2. During exercise, CBFVsyst and CBFVdiast significantly increased in parallel with increasing pO2, despite reduced flow velocities at rest. ERGOMETRY I: CBFVsyst increased from 65.0 +/- 11.3 cm/second at rest to 80.2 +/- 23.4cm/s during maximum workload (n.s.), diastolic from 14.5 +/- 4.1 cm/second to 15.6 +/- 7.5 cm/s (n.s.). PetCO2 increased from 43.4 +/- 7.8mmHg to 50.0 +/- 7.5mmHg. ERGOMETRY II: CBFVsyst increased from 58.2 +/- 16.5 cm/second to 99.7 +/- 17.0 cm/s (p<0.001), diastolic from 14.0 +/- 10.7 cm/second to 29.4 +/- 11.1 cm/second (p<0.01). ERGOMETRY III: CBFVsyst increased from 54.4 +/-15.0cm/second to 109.4 +/- 22.3cm/s (p<0.001), diastolic from 14.7 +/- 10.4 cm/second to 35.5 +/- 9.3 cm/second (p<0.01). INTERPRETATION: Physical exercise overrules the decrease in CBFV during hyperoxia and leads to even higher CBFV-increases with increasing pO2. A tendency towards CO2 retainment with elevated PetCOz may be causative and thus heighten the risk of oxygen-induced neurotoxicity. PMID- 23682548 TI - A prospective trial of hyperbaric oxygen for chronic sequelae after brain injury (HYBOBI). AB - OBJECTIVE: Some practitioners advocate hyperbaric oxygen (HBO2) for sequelae following brain injury. This study assessed recruitment, tolerance and safety in preparation for a randomized clinical trial. DESIGN: Prospective, open-label feasibility study. SETTING: Hyperbaric medicine department of a tertiary academic hospital. PARTICIPANTS: Participatory adult outpatients with problems from stroke (n=22), anoxia (13) or trauma (28) that occurred at least 12 months before enrollment, without contraindications to HBO2. Sixty-three participants enrolled in the study (21 females,42 males). Age was 45 +/- 16 years (18-76) and time from injury was 6.9 +/- 7.1 years (1.0-29.3). Fifty-three completed the study intervention, and 55 completed the assessment battery. METHODS: PARTICIPANTS underwent 60 daily HBO2 sessions (1.5 atm abs, 100% oxygen, 60 minutes). Assessments were conducted at baseline, after the HBO2 course, and six months later. MAIN OUTCOME MEASUREMENTS: The prime outcome was feasibility. To estimate the immediate and long-term effects of HBO2, we assessed neuropsychological measures, questionnaires, neurologic exam and physical functioning measures. Some participants also had pre- and post-HBO2 speech evaluation (n=27) and neuroimaging (n=17). RESULTS: The study met our a priori definition for feasibility for recruitment, but 44% required additional time to complete the 60 sessions (up to 105 days). HBO2-related adverse events were rare and not serious. Although many participants reported improvement in symptoms (51% memory, 51% attention/concentration, 48% balance/coordination, 45% endurance, 20% sleep) post HBO2, and 93% reported that they would participate in the study again, no standardized testing showed clinically important improvement. In the small subset of those undergoing neuroimaging, apparent improvement was observed in auditory functional MRI (8/13), MR spectroscopy (9/17) and brain perfusionby CT angiography (5/9). CONCLUSIONS: Conducting an HBO2 clinical trial in this population was feasible. Although many participants reported improvement, the lack of concurrent controls limits the strength of inferences from this trial, especially considering lack of change in standardized testing. The clinical relevance of neuroimaging changes is unknown. The findings of this study may indicate a need for caution when considering the broad application of HBO2 more than one year after brain injury due to stroke, severe TBI and anoxia, until there is more compelling evidence from carefully designed sham-controlled, blinded clinical trials. PMID- 23682549 TI - The efficacy of hyperbaric oxygen therapy in the management of chronic fatigue syndrome. AB - OBJECTIVE: Chronic fatigue syndrome (CFS) is a chronic disease with social components that ensue secondary to the incapacity of the person to fulfill work, social and family responsibilities. Currently, there is no consensus regarding its treatment. The aim of this study was to determine the efficacy of hyperbaric oxygen (HBO2) therapy in CFS. DESIGN: Sixteen patients included in the study were diagnosed with CFS according to the Fukuda criteria. Patients received 15 treatment sessions of HBO2 therapy over a period of three consecutive weeks (five days per week). The outcome measures (visual analog fatigue scale (VAFS). Fatigue Severity Scale (FSS) and Fatigue Quality of Life Score (FQLS) were assessed before the treatment and after completion of the 15 sessions. RESULTS: HBO2 therapy was well tolerated, with no complications. After treatment, patients' scores were found to have improved with respect to VAFS, FSS and FQLS (all p<0.005). CONCLUSIONS: We ,may infer that HBO2 therapy decreases the severity of symptoms and increases the life quality of CFS patients. It may be a new treatment modality for the management of CFS. However, further studies with larger sample sizes and control groups are definitely awaited. PMID- 23682550 TI - Efficacy of hyperbaric oxygen in patients with Crohn's disease: two case reports. AB - Crohn's disease is an inflammatory disease of the gastrointestinal tract, usually involving the ileum, that can lead to debilitating symptoms of abdominal pain, diarrhea and malabsorption during acute exacerbations. Because there is no known cause of the illness, treatment is based upon symptomatology and may ultimately require bowel resection if response to medical therapy is inadequate. Treatment with hyperbaric oxygen has shown promise in the reduction of inflammation associated with acute exacerbations of Crohn's disease, with alleviation of symptoms and an improvement in quality of life. We present two cases of pediatric patients with exacerbations of Crohn's disease who underwent cycles of hyperbaric oxygen therapy. Each patient was symptomatic and had no improvement despite prolonged medical therapy. Following treatment with hyperbaric oxygen, both patients showed resolution of the inflammatory lesions and improvement in conditions, allowing them to reduce drug therapy. Although the mechanisms by which hyperbaric oxygen reduce inflammation in Crohn's disease is poorly defined, this therapy seems to have offer a safe adjunct in the treatment of refractory exacerbations. PMID- 23682551 TI - Severe spinal cord decompression illness after an uneventful North Sea dive. AB - The aim of this case report is to illustrate that, even under moderate conditions, a dive can result in spinal cord decompression illness (DCI). The diver in question completed five dives with the same profile. The first four included substantial physical strain, while the final dive was for observation only, without physical strain. The spinal cord was the target organ for DCI. We discuss the roles of various diver-related risk factors and of factors related to the dive itself. Older divers have a higher risk for decompression incidents. The nature of the dive profile is a major factor in the uptake and release of inert gas. Physical exertion during pressure-exposure boosts the inert gas load, increases bubbling in tissues and raises the risk of DCI in the decompression phase of the dive. We discuss the causal involvement of such risk factors in this case, given the characteristics of the diver and the circumstances of the dive. Finally, we want to express our concern for physical fitness and smoking habits, especially for divers over the age of 40. PMID- 23682552 TI - Oxygen for the ischemic organ: Much more than an oxygen provider. PMID- 23682553 TI - Re: Adjunctive hyperbaric oxygen therapy in the treatment of thermal burns. PMID- 23682554 TI - Reply to Dr. Richard Vann in UHMS 39 (5) re: "More information on diving fatalities is needed: An appeal for publication of comprehensive investigation of case series by qualified personnel". PMID- 23682555 TI - Response to Sqn Ldr Gareth Lock re letter concerning: "More information on diving fatalities is needed: an appeal for publication of comprehensive investigation of case series by qualified personnel". PMID- 23682556 TI - A comparison of DNA extraction using AutoMate ExpressTM and EZ1 advanced XL from liquid blood, bloodstains, and semen stains. AB - In this study, DNA was extracted using an AutoMate ExpressTM and an EZ1 Advanced XL from liquid blood, fresh and aged bloodstains, and fresh and aged semen stains. Extracted DNA was quantified by real-time PCR using the D17Z1 locus. Short tandem repeat typing was performed using an AmpFlSTR((r)) Identifiler kit. The yields of DNA obtained by the AutoMate ExpressTM were higher from fresh bloodstains and fresh semen stains, almost the same from aged bloodstains and aged semen stains, but slightly lower from liquid blood compared with those obtained by the EZ1 Advanced XL. The addition of dithiothreitol or the use of PrepFilerTM lysis buffer improved the EZ1 Advanced XL results from fresh bloodstains, but not for liquid blood and aged bloodstains. Our results demonstrated that the PrepFilerTM lysis buffer is the main contributor to the higher DNA yields of the AutoMate ExpressTM for fresh bloodstains. PMID- 23682557 TI - Up-regulated expression of indoleamine 2,3-dioxygenase 1 in non-Hodgkin lymphoma correlates with increased regulatory T-cell infiltration. AB - Indoleamine 2,3-dioxygenase 1 (IDO1), which is a key enzyme in tryptophan metabolism expressed in some subsets of normal and neoplastic cells, participates in tumor-induced tolerance. However, the mechanisms involved are not clearly understood. A hypothesis suggests that IDO1 may be involved in proliferation and conversion of regulatory T cells (Tregs). In this study, we evaluated the levels of IDO1 and forkhead box P3 (FoxP3) in non-Hodgkin lymphoma (NHL) tissues and performed ex vivo experiments to investigate the role of IDO1 on T-cell tolerance in NHL. The results showed that expressions of IDO1 mRNA and protein were coincidentally higher in NHL tissues than in reactive hyperplasia of lymph node tissues. Up-regulation of IDO1 was correlated with later clinical phases, larger tumors and higher serum lactate dehydrogenase (LDH), and indicated a worse prognosis. FoxP3 mRNA and protein levels were markedly increased alongside elevated IDO1 levels. Co-culture of murine CD4 + CD25- T cells with A20 cells could initiate the conversion of CD4 + CD25+ T cells, which showed a suppressive function in the mixed lymphocyte reaction. Moreover, the potent inhibitor of IDO1, 1-methyl-l-tryptophan, attenuated the conversion of CD4 + CD25- T cells into CD4 + CD25+ FoxP3 + T cells. The results suggested that up-regulation of IDO1 in NHL tissues could induce local immune tolerance by favoring development and infiltration of FoxP3 + Tregs through the conversion of CD4 + CD25- T cells into CD4 + CD25+ FoxP3 + T cells in the tumor microenvironment. This could be a novel mechanism of NHL escape from immune control. PMID- 23682558 TI - Anti-transforming growth factor-beta therapy in patients with myelofibrosis. PMID- 23682559 TI - Uptake of HNO3 on aviation kerosene and aircraft engine soot: influences of H2O or/and H2SO4. AB - The uptake of HNO3 on aviation kerosene soot (TC-1 soot) was studied in the absence and presence of water vapor at 295 and 243 K. The influence of H2SO4 coating of the TC-1 soot surface on HNO3 uptake was also investigated. Only reversible uptake of HNO3 was observed. HONO and NO2, potential products of reactive uptake of HNO3, were not observed under any conditions studied here. The uptake of nitric acid increased slightly with relative humidity (RH). Coating of the TC-1 soot surface with sulfuric acid decreased the uptake of HNO3 and did not lead to displacement of H2SO4 from the soot surface. A limited set of measurements was carried out on soot generated by aircraft engine combustor (E soot) with results similar to those on TC-1 soot. The influence of water on HNO3 uptake on E-soot appeared to be more pronounced than on TC-1 soot. Our results suggest that HNO3 loss in the upper troposphere due to soot is not significant except perhaps in aircraft exhaust plumes. Our results also suggest that HNO3 is not converted to either NO2 or HONO upon its uptake on soot in the atmosphere. PMID- 23682560 TI - Seizure severity and health-related quality of life of adult Nigerian patients with epilepsy. AB - OBJECTIVES: There is paucity of information about the association of seizure severity and quality of life in people with epilepsy (PWE) in sub-Saharan Africa. We evaluated the relationship of seizure severity to health-related quality of life of patients with epilepsy being followed up in an outpatient neurology clinic in southwestern Nigeria. MATERIALS AND METHODS: Eighty-eight consecutive patients with epilepsy who met the recruitment criteria completed the study questionnaire in company of an eyewitness. The study questionnaire comprised of the National Hospital Seizure Severity Scale (NHS3), the Quality of Life Inventory in Epilepsy (QOLIE-31), and the Beck's Depression Inventory-II (BDI II). RESULTS: We found a minute association between seizure severity and QOLIE-31 total score (r = -0.262, P = 0.014). Increased seizure severity predicted a worse QOLIE-31 seizure worry (R(2) = 0.311, beta = -0.289; P = 0.003). Of the seven seizure severity items, generalization of seizures and presence of falls were items that predicted a worse QOLIE-31 seizure worry score and time to recover predicted a worse QOLIE-31 total score. CONCLUSIONS: Reducing seizure severity may be an alternate endpoint in epilepsy care in Nigeria (particularly difficult to control seizures) because of its practical clinical relevance in view of the fact that state-of-the-art epilepsy care is still farfetched. PMID- 23682561 TI - Strategies for moving towards equity in recruitment of rural and Aboriginal research participants. AB - INTRODUCTION: Equitable recruitment strategies, designed to ensure improved opportunities to participate in the research, are needed to include First Nations (FN) communities. The purpose of this article is to report on a set of successful strategies trialed with rural and FN communities in Canada. The strategies discussed were designed as part of a larger mixed-method study examining the effectiveness of Group Medical Visits (GMVs) on the quality of primary healthcare (PHC) in both FN reserve and northern communities in British Columbia (BC). METHODS: Community partners and the study's decision-maker partners helped to identify and recruit primary care practices and reserve communities who were offering GMVs. Eleven communities (6 rural and 5 FN reserve) within the Northern Health Authority, BC participated in the study. Participants completed a survey either in person or via telephone. Content analysis was conducted on team meeting and field notes, focusing on issues related to the data collection process. Financial analysis was conducted on monetary resources spent on recruitment efforts in the various communities. Data were recorded regarding the number of times potential participants were contacted and mode of interview. Descriptive statistics were used to examine whether there were differences by mode of data collection, gender, and FN status. Logistic regression was used to examine whether FN status remained statistically significant after controlling for sex, education, employment status, age and health status. RESULTS: Once people were contacted, participation rate was 68% with 269 (n=90 men, n=179 women) people. Of those who participated in the survey, 42% were from FN communities. Content analysis revealed two overarching categories: (1) communication and coordination of the geographically dispersed research team and participating communities was maintained using synchronous and asynchronous methods; and (2) flexibility was needed to tailor recruitment strategies. Financial resources required to achieve equitable recruitment across these communities can cost up to 17 times more than travel to sites accessible by a direct flight or car. The farther away from Prince George (BC's capital in the north), the more resources were needed to ensure equitable recruitment from a community. Community partners played a critical role in recruiting potential participants. Team members, particularly those from urban areas, require support to successfully navigate working in small northern communities. CONCLUSIONS: Achieving equity in recruitment requires flexibility, trusting partnerships within each community and regular communication among the research team. A significant portion of time and resources needs to be allocated towards travel to these communities. While achieving equity in recruiting research participants poses a number of challenges, including greater costs, research that ensures participation opportunities for rural and FN communities is likely to better inform effective strategies to meet the needs of these communities. PMID- 23682562 TI - Canadian traditionally used medicinal plants: can they play a role in antituberculosis drug development? PMID- 23682563 TI - Vitamin K: a structural basis for the design of novel neuroprotective agents? PMID- 23682565 TI - Structure-activity relationship and in vitro pharmacological evaluation of imidazo[1,2-a]pyridine-based inhibitors of 5-LO. AB - BACKGROUND: 5-LO is an important enzyme involved in the biosynthesis of leukotrienes, which are lipid mediators of immune and inflammation responses, with important roles in respiratory disease, cardiovascular disease, immune responses and certain types of cancer. Therefore, this enzyme has been investigated as a potential target for the treatment of these pathophysiological conditions. RESULTS: 5-LO inhibitory potential was investigated in intact polymorphonuclear leukocytes, a cell-free assay, in human whole blood and rodent cells to both elucidate structure-activity relationships and in vitro pharmacological evaluation. Chemical modifications for lead optimization via straight forward synthesis was used to combine small polar groups, which led to a suitable candidate (IC50 [polymorphonuclear leukocytes] = 1.15 uM, IC50 [S100] = 0.29 uM) with desired in vitro biopharmaceutical profiles in terms of solubility (451.9 ug/ml) and intrinsic clearance without demonstrating any cytotoxicity. CONCLUSION: Compound 9l is a novel, potent and selective 5-LO inhibitor with favorable preclinical drug-like properties. PMID- 23682566 TI - X-ray structures of two forms of the antibiotic oligomycin A: an inhibitor of ATP synthase. AB - BACKGROUND: Corrections to the chemical and x-ray structures of two forms of the antibiotic oligomycin A are presented: the original and best known, form (E), from Streptomyces diastatochromogenes, and a new form (C) from Streptomyces diastaticus. METHOD: The crystal structures are isomorphous, crystallizing in space group P212121, with Z = 4[C45H73O11.CH3OH] per unit cell. Oligomycin A(E) refined with R1 = 0.0734, using Cu Kalpha x-radiation; and for Oligomycin A(C) R1 = 0.0651 using Mo Kalpha x-radiation. CONCLUSION: Serious corrections to the previously published structure of oligomycin A(C) are discussed and implemented. As a supplementary study geometry optimization of side group R4 of oligomycin A(E) was undertaken and achieved by energy minimization. These additional results clearly confirm the delocalization in this region observed in both x-ray structures. This result is contrary to the generally accepted formulation. Knowledge of the correct structures is important to those involved in the study and applications of the pharmacological and biological properties of these materials. PMID- 23682567 TI - Open source drug collaborations: a rational design approach. AB - A decade ago, many biologists and legal scholars thought that open source (OS) methods would revolutionize drug discovery. These predictions were clearly disappointed. Not surprisingly, some scholars now take the opposite view that OS methods and drug discovery are inherently incompatible. This article argues for balance. Economists have observed that OS methods offer both advantages and disadvantages compared with conventional institutions. This article reviews what economists have learned regarding the strengths and weaknesses of OS methods and identifies specific drug-discovery tasks where OS methods are likely to work especially well. Successful OS collaborations should carefully focus on segments of the drug-discovery pipeline where the advantages of OS methods are particularly relevant and existing commercial methods are known to work badly. The article concludes by offering detailed suggestions for how existing OS software models can be modified and extended to conduct effective drug discovery. PMID- 23682568 TI - State-of-the-art and dissemination of computational tools for drug-design purposes: a survey among Italian academics and industrial institutions. AB - During the first edition of the Computationally Driven Drug Discovery meeting, held in November 2011 at Dompe Pharma (L'Aquila, Italy), a questionnaire regarding the diffusion and the use of computational tools for drug-design purposes in both academia and industry was distributed among all participants. This is a follow-up of a previously reported investigation carried out among a few companies in 2007. The new questionnaire implemented five sections dedicated to: research group identification and classification; 18 different computational techniques; software information; hardware data; and economical business considerations. In this article, together with a detailed history of the different computational methods, a statistical analysis of the survey results that enabled the identification of the prevalent computational techniques adopted in drug-design projects is reported and a profile of the computational medicinal chemist currently working in academia and pharmaceutical companies in Italy is highlighted. PMID- 23682569 TI - A prospective overview of the essential requirements in molecular modeling for nanomedicine design. AB - Nanotechnology has presented many new challenges and opportunities in the area of nanomedicine design. The issues related to nanoconjugation, nanosystem-mediated targeted drug delivery, transitional stability of nanovehicles, the integrity of drug transport, drug-delivery mechanisms and chemical structural design require a pre-estimated and determined course of assumptive actions with property and characteristic estimations for optimal nanomedicine design. Molecular modeling in nanomedicine encompasses these pre-estimations and predictions of pertinent design data via interactive computographic software. Recently, an increasing amount of research has been reported where specialized software is being developed and employed in an attempt to bridge the gap between drug discovery, materials science and biology. This review provides an assimilative and concise incursion into the current and future strategies of molecular-modeling applications in nanomedicine design and aims to describe the utilization of molecular models and theoretical-chemistry computographic techniques for expansive nanomedicine design and development. PMID- 23682571 TI - Glutamic acid and its derivatives: candidates for rational design of anticancer drugs. AB - Throughout the history of human civilizations, cancer has been a major health problem. Its treatment has been interesting but challenging to scientists. Glutamic acid and its derivative glutamine are known to play interesting roles in cancer genesis, hence, it was realized that structurally variant glutamic acid derivatives may be designed and developed and, might be having antagonistic effects on cancer. The present article describes the state-of-art of glutamic acid and its derivatives as anticancer agents. Attempts have been made to explore the effectivity of drug-delivery systems based on glutamic acid for the delivery of anticancer drugs. Moreover, efforts have also been made to discuss the mechanism of action of glutamic acid derivatives as anticancer agents, clinical applications of glutamic acid derivatives, as well as recent developments and future perspectives of glutamic acid drug development have also been discussed. PMID- 23682570 TI - Illuminating the lipidome to advance biomedical research: peptide-based probes of membrane lipids. AB - Systematic investigation of the lipidome will reveal new opportunities for disease diagnosis and intervention. However, lipidomic research has been hampered by the lack of molecular tools to track specific lipids of interest. Accumulating reports indicate lipid recognition can be achieved with properly constructed short peptides in addition to large proteins. This review summarizes the key developments of this area within the past decade. Select lantibiotic peptides present the best examples of low-molecular-weight probes of membrane lipids, displaying selectivity comparable to lipid-binding proteins. Designed peptides, through biomimetic approaches and combinational screening, have begun to demonstrate their potential for lipid tracking in cultured cells and even in living organisms. Biophysical characterization of these lipid-targeting peptides has revealed certain features critical for selective membrane binding, including preorganized scaffolds and the balance of polar and nonpolar interactions. The knowledge summarized herein should facilitate the development of molecular tools to target a variety of membrane lipids. PMID- 23682573 TI - Risk factors for obstetric anal sphincter injury after a successful multicentre interventional programme. AB - OBJECTIVE: To evaluate and compare the risk profile of sustaining obstetric anal sphincter injuries (OASIS) and associated risks in five risk groups (low to high), after the OASIS rate was reduced from 4.6% to 2.0% following an interventional programme. The main focus of the intervention was on manual assistance during the final part of second stage of labour. DESIGN: A multicentre interventional cohort study with before and after comparison. SETTING: Four Norwegian obstetric departments. SAMPLE: A total of 40,154 vaginal deliveries in 2003-09. METHODS: Pre-intervention and postintervention analyses. The associations of OASIS with possible risk factors were estimated using odds ratios obtained by logistic regression. MAIN OUTCOME MEASURE: Risk factors of OASIS. RESULTS: The risk of sustaining OASIS decreased by 59% (odds ratio [OR] 0.41; 95% confidence interval [95% CI] 0.36-0.46) after the intervention. Associations with obstetric risks for OASIS were largely unchanged after the intervention, including first vaginal delivery (OR 3.84; 95% CI 2.90-5.07), birthweight >= 4500 g (OR 4.42; 95% CI 2.68-7.27), forceps delivery (OR 3.54; 95% CI 1.99-6.29) and mediolateral episiotomy (OR 0.89; 95% CI 0.70-1.12). However, the highest reduction of OASIS, (65%), was observed in group 0 (low-risk) (OR 0.35; 95% CI 0.24-0.51), and a 57% (OR 0.43; 95% CI 0.35-0.52), 61% (OR 0.39; 95% CI 0.31 0.48), and 58% (OR 0.42; 95% CI 0.30-0.60) reduction in groups with one, two and three risk factors, respectively. No change was observed in the group with four risk factors. CONCLUSION: After the intervention the most significant decrease of OASIS was observed in low-risk births, although the main risk factors for OASIS remained unchanged. PMID- 23682574 TI - Conformation and activity of glucose oxidase on homogeneously coated and nanostructured surfaces. AB - Protein unfolding and loss of protein function upon surface contact is a major problem in biotechnology and biomedicine. Using glucose oxidase (GOx) as a model protein, we investigated the impact of surface chemistry, topography, and confinement on enzyme activity, conformation, and affinity. A particular focus lay on the question whether the conformation of surface-bound proteins can be stabilized by embedding nanoscale adsorption sites, here in the form of monodisperse gold nanoparticles (AuNPs), into a protein-repelling matrix material. It was found that on homogeneous surfaces, GOx activity is generally lower than that in its native state and strongly affected by surface chemistry. Loss of activity is related to an increasing amount of beta-sheets in the GOx secondary structure and a corresponding reduction of alpha-helical elements. In contrast, on AuNP surfaces, the effect of surface chemistry is negligible, and the amount of adsorbed protein only depends on particle size. The low activity of GOx on all nanostructures studied is again accompanied by an increase of beta sheet and a reduction of alpha-helical secondary structure. The major cause for protein unfolding on AuNPs thus seems to be the curvature of the surface. In addition, the data suggest that unfavorable orientation of the adsorbed enzyme also contributes to the loss of activity. PMID- 23682575 TI - Population structure of the fish pathogen Flavobacterium psychrophilum at whole country and model river levels in Japan. AB - The bacterium Flavobacterium psychrophilum is a serious problem for salmonid farming worldwide. This study investigates by multilocus sequence typing (MLST) the population structure of this pathogen in Japan where it is also a major concern for ayu, a popular game fish related to salmoniforms. A total of 34 isolates collected across the country and 80 isolates sampled in a single model river by electrofishing were genotyped. The data accounting for 15 fish species allowed identifying 35 distinct sequence types (ST) in Japan. These ST are distinct from those reported elsewhere, except for some ST found in rainbow trout and coho salmon, two fish that have been the subject of intensive international trade. The pattern of polymorphism is, however, strikingly similar across geographical scales (model river, Japan, world) in terms of the fraction of molecular variance linked to the fish host (~50%) and of pairwise nucleotide diversity between ST (~5 Kbp(-1)). These observations go against the hypothesis of a recent introduction of F. psychrophilum in Japan. Two findings were made that are important for disease control: 1) at least two independent F. psychrophilum lineages infect ayu and 2) co-infections of the same individual fish by different strains occur. PMID- 23682576 TI - Acquired racquet nails: a useful sign of hyperparathyroidism. PMID- 23682577 TI - Effects of electronic billboards on driver distraction. AB - OBJECTIVE: There is an increase in electronic advertising billboards along major roads, which may cause driver distraction due to the highly conspicuous design of the electronic billboards. Yet limited research on the impact of electronic billboards on driving performance and driver behavior is available. The Swedish Transport Administration recently approved the installation of 12 electronic billboards for a trial period along a 3-lane motorway with heavy traffic running through central Stockholm, Sweden. The aim of this study was to evaluate the effect of these electronic billboards on visual behavior and driving performance. METHOD: A total of 41 drivers were recruited to drive an instrumented vehicle passing 4 of the electronic billboards during day and night conditions. A driver was considered visually distracted when looking at a billboard continuously for more than 2 s or if the driver looked away from the road for a high percentage of time. Dependent variables were eye-tracking measures and driving performance measures. RESULTS: The visual behavior data showed that drivers had a significantly longer dwell time, a greater number of fixations, and longer maximum fixation duration when driving past an electronic billboard compared to other signs on the same road stretches. No differences were found for the factors day/night, and no effect was found for the driving behavior data. CONCLUSION: Electronic billboards have an effect on gaze behavior by attracting more and longer glances than regular traffic signs. Whether the electronic billboards attract too much attention and constitute a traffic safety hazard cannot be answered conclusively based on the present data. PMID- 23682578 TI - Specific miRNA expression profiles of non-tumor liver tissue predict a risk for recurrence of hepatocellular carcinoma. AB - AIM: It is reasonable to investigate non-tumor liver tissues to predict a risk for development of hepatocellular carcinoma (HCC). A molecular analysis of chronically damaged liver tissues may identify specific miRNA expression profiles associated with a risk for multicentric (MC) HCC. METHODS: Twenty HCC patients, who underwent a curative hepatectomy were classified into two groups: a non-MC group (no MC recurrence in more than 3 years, n = 10) and an MC group (MC recurrence within 3 years after hepatectomy, n = 10). An miRNA microarray (955 probes) was used to compare the miRNA expression patterns of the non-cancerous liver tissues between the two groups. This study identified the differentially expressed miRNA related to MC recurrence in the liver remnant. RESULTS: No differences were observed between the two groups in the liver function tests and pathological variables including both tumor factors and non-tumor liver tissues. The investigation selected 20 differentially expressed miRNA related to MC recurrence. Eighteen miRNA were downregulated, while two miRNA were upregulated in the MC group. A hierarchical clustering analysis identified a cluster that may be associated with risk of the MC recurrence of HCC. The MC recurrence-related miRNA included let-7d*, miR-328 and miR18a*, which potentially regulate K-ras gene expression. A significant inverse correlation between the miR-18a* expression and the K-ras mRNA expression was confirmed by quantitative reverse transcription polymerase chain reaction. CONCLUSION: Specific miRNA expression signatures in non-cancerous liver tissue may help to predict the risk for de novo development of HCC. PMID- 23682579 TI - Tall cell variant of papillary thyroid microcarcinoma: clinicopathologic features with BRAF(V600E) mutational analysis. AB - BACKGROUND: The tall cell variant of papillary thyroid carcinoma is an aggressive subtype that generally presents as a large tumor in the advanced stage; however, little is known about the tall cell variant of microcarcinoma (tumors measuring <1 cm). In this study, we compare the tall cell variant of microcarcinoma (microTCV) with classic papillary microcarcinomas to examine the hypothesis that, despite the small size, the microTCV may be more aggressive than the classic papillary microcarcinoma. METHODS: We identified 27 microTCV patients and compared their clinicopathologic features and BRAF(V600E) mutational status with classic papillary microcarcinomas matched by age and size. The patients with microTCV included 22 women and 5 men aged 33 to 74 years (median age, 56 years). All patients underwent total thyroidectomy; 20 patients had lymph node dissection. RESULTS: Tumor size in microTCV patients ranged from 2 mm to 10 mm (median, 7 mm). Extrathyroidal extension and lymphovascular invasion were seen in 9 (33%) and 4 (15%) tumors, respectively. Thirteen patients (48%) harbored multifocal papillary carcinomas. Metastasis to central compartment lymph nodes was seen in 8 patients and to lateral cervical nodes in 3 patients. Nine of the 25 patients (36%) presented at an advanced stage (stage III/IVA). The BRAF(V600E) mutation was detected in 25 of 27 tumors (92.6%). In contrast, age- and size matched classic papillary microcarcinomas (n=26) showed no extrathyroidal extension (p=0.002), lymphovascular invasion in 1, central compartment lymph node metastasis in 2, lateral cervical node metastasis in 1, multifocal tumors in 10 (38.5%), the BRAF(V600E) mutation in 20 (76.9%), and it infrequently presented in stage III/IVA (7.7%, p=0.02). CONCLUSIONS: The microTCV form is associated with aggressive features at presentation, and it should be differentiated from other papillary thyroid microcarcinomas. PMID- 23682580 TI - Supramolecular approaches to combining membrane transport with adhesion. AB - Cells carefully control the transit of compounds through their membranes using "gated" protein channels that respond to chemical stimuli. Connexin gap junctions, which are high conductance cell-to-cell channels, are a remarkable class of "gated" channel with multiple levels of assembly. A gap junction between adhering cells comprises two half-channels in each cell membrane that adhere to each other to form a continuous cell-to-cell channel. Each half-channel is a hexameric assembly of six protein transmembrane subunits. These gap junctions display both intramembrane assembly and intermembrane assembly, making them an attractive target for biomimetic studies. Although many examples of self assembled channels have been developed, few can also mediate intermembrane adhesion. Developing systems that combine membrane adhesion with controlled transit across the membrane would not only provide a better understanding of self assembly in and around the membrane, but would also provide a route towards smart biomaterials, targeted drug delivery and an interface with nanotechnology. This Account describes our biomimetic approaches to combining membrane adhesion with membrane transport, using both self-assembled "sticky" pores and "sticky" nanoparticles to trigger transit across membranes. This combination links both fundamental and applied research, acting as a bridge between molecular level assembly and the formation of functional biomaterials. The ultimate goal is to create complex self-assembled systems in biological or biomimetic environments that can both interface with cells and transport compounds across bilayers in response to remote chemical or electromagnetic signals. Our research in this area started with fundamental studies of intramembrane and intermembrane self assembly, building upon previously known channel-forming compounds to create self assembled channels that were switchable or able to mediate vesicle-vesicle adhesion. Subsequently, nanoparticles with a "sticky" coating were used to mediate adhesion between vesicles. Combining these adhesive properties with the unique characteristics of nanosized magnetite allowed a noninvasive magnetic signal to trigger transport of compounds out of magnetic nanoparticle-vesicle assemblies. Adding an extravesicular matrix produced new responsive biomaterials for use in tissue engineering. These biomaterials can be magnetically patterned and can deliver drugs upon receipt of a magnetic signal, allowing spatiotemporal control over cellular responses. PMID- 23682581 TI - Targeted and nontargeted wine analysis by (1)h NMR spectroscopy combined with multivariate statistical analysis. Differentiation of important parameters: grape variety, geographical origin, year of vintage. AB - The authenticity, the grape variety, the geographical origin, and the year of vintage of wines produced in Germany were investigated by (1)H NMR spectroscopy in combination with several steps of multivariate data analysis including principal component analysis (PCA), linear discrimination analysis (LDA), and multivariate analysis of variance (MANOVA) together with cross-validation (CV) embedded in a Monte Carlo resampling approach (MC) and others. A total of about 600 wines were selected and carefully collected from five wine-growing areas in the southern and southwestern parts of Germany. Simultaneous saturation of the resonances of water and ethanol by application of a low-power eight-frequency band irradiation using shaped pulses allowed for high receiver gain settings and hence optimized signal-to-noise ratios. Correct prediction of classification of the grape varieties of Pinot noir, Lemberger, Pinot blanc/Pinot gris, Muller Thurgau, Riesling, and Gewurztraminer of 95% in the wine panel was achieved. The classification of the vintage of all analyzed wines resulted in correct predictions of 97 and 96%, respectively, for vintage 2008 (n = 318) and 2009 (n = 265). The geographic origin of all wines from the largest German wine-producing regions, Rheinpfalz, Rheinhessen, Mosel, Baden, and Wurttemberg, could be predicted 89% correctly on average. Each NMR spectrum could be regarded as the individual "fingerprint" of a wine sample, which includes information about variety, origin, vintage, physiological state, technological treatment, and others. PMID- 23682582 TI - Radiosensitivity enhancement of human hepatocellular carcinoma cell line SMMC 7721 by sorafenib through the MEK/ERK signal pathway. AB - PURPOSE: Sorafenib, an oral multikinase inhibitor, is the first agent that has demonstrated an improved overall survival benefit in advanced hepatocellular carcinoma, setting a new standard for first-line treatment. However, the association between radiosensitivity and sorafenib remains unclear. The purpose of this study was to investigate whether sorafenib could enhance radiosensitivity and the possible mechanisms of sorafenib-mediated radiosensitization in human hepatocellular carcinoma cell line SMMC-7721. EXPERIMENTAL DESIGN: The cell viability of human hepatocellular carcinoma cell line SMMC-7721 was determined by the 3-(4, 5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. The radiosensitization of sorafenib in SMMC-7721 cells was evaluated by clonogenic assays, and immunofluorescence for DNA double-strand break detection, and Western blotting for protein detection. RESULTS: The MTT results clearly showed that sorafenib affected cell viability in human hepatocellular cell line SMMC-7721. Sorafenib administered 1 h before the radiation treatment resulted in radiosensitization with a sensitivity enhancement ratio (SER) of 1.65 as shown by clonogenic assays. Furthermore, sorafenib pretreatment led to decreased phosphorylation levels of extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) in SMMC-7721 cells. Interestingly, pretreatment of mitogen activated protein kinase kinases/extracellular signal-regulated kinase (MEK/ERK) signaling inhibitor U0126 had a similar effect as that of sorafenib pretreatment in hepatocellular carcinoma cells, whereas pretreatment of phosphoinositide 3 kinase/protein kinase B (PI3K/AKT) signaling inhibitor LY294002 in the same cells had no effect on radiosensitization. The group treated with sorafenib and radiation was more sensitive to irradiation alone as demonstrated by the results of the DNA double-strand break detection. CONCLUSIONS: The combination of sorafenib and radiation affected cell viability more effectively than radiation alone. Sorafenib significantly enhanced the sensitivity of SMMC-7721 cells to radiation showing significantly reduced repair of DNA double-strand breaks. The MEK/ERK signaling pathway may be a pathway responsible for the radiosensitivity enhancement of sorafenib. Our data provided experimental support for the possible combination of sorafenib with radiation for the treatment of hepatocellular carcinoma and other cancers. PMID- 23682583 TI - Conscious knowledge influences decision-making differently in substance abusers with and without co-morbid antisocial personality disorder. AB - Decision-making impairment, as measured by the Iowa Gambling Task (IGT), is a consistent finding among individuals with substance use disorder (SUD). We studied how this impairment is influenced by co-morbid antisocial personality disorder (ASPD) and conscious knowledge of the task. Three groups were investigated: SUD individuals without co-morbid ASPD (n = 30), SUD individuals with co-morbid ASPD (n = 16), and healthy controls (n = 17). Both SUD and SUD+ASPD participants had poor overall IGT performance. A block-by-block analysis revealed that SUD participants exhibited slow but steady improvement across the IGT, whereas SUD+ASPD participants exhibited initial normal improvement, but dropped off during the last 40 trials. Conscious knowledge of the task was significantly correlated to performance for controls and SUD participants, but not for SUD+ASPD participants. Our findings suggest that decision-making proceeds differently in SUD and SUD+ASPD individuals due to differences in acquisition and application of conscious knowledge. PMID- 23682584 TI - Synergistic antiangiogenic activity of tetrandrine combined with Endostar on the human umbilical vein endothelial cell model. AB - Endostar was approved for the treatment of cancer as an antiangiogenic agent with limited therapeutic effects used alone in cancer treatment. Tetrandrine (TET) has a variety of nontumor-related effects and anticancer effects, including antiangiogenic effects. This study was designed to explore the interaction of Endostar and TET. Antiproliferative effects of TET combined with Endostar on human umbilical vein endothelial cells (HUVECs) and the human colon cancer cell line LoVo were evaluated by the 3-(4,5-dimethylthiazol-2-y)-2,5 diphenylterazolium bromide (MTT) assays. The effects on HUVEC migration and tube formation of TET plus Endostar were observed by the transwell test and tube formation assay. Refer to the mechanisms of the cell proliferation inhibition effect caused by the two drugs: apoptosis assay and cell cycle analysis of HUVECs were analyzed by Annexin V-fluorescein isothiocyanate (FITC) and propidium iodide (PI) staining, followed by flow cytometry. The combination of TET and Endostar had a synergistic effect on the antiproliferation of HUVECs and LoVo cells. Further, all these antiangiogenic effects such as inhibition of cell migration, suppression of tube formation, induction of cell apoptosis, and cell cycle arrest were enhanced when HUVECs were treated with TET combined with Endostar. Thus, we identified that there was a synergistic antiangiogenic effect in vitro when combining TET with Endostar. PMID- 23682585 TI - Synthesis and evaluation of a 18F-labeled 4-ipomeanol as an imaging agent for CYP4B1 gene prodrug activation therapy. AB - We report the development of a (18)F-labeled 4-ipomeanol (4-IM), which is metabolized by the CYP4B1 enzyme, to image tumors and monitor enzyme-activating anticancer prodrugs. The fluorine-substituted derivative, 1-(3-furyl)-4-hydroxy-5 fluoro-1-pentanone (F-4-IM, 1), was synthesized from 3-furaldehyde. [(18)F]F-4-IM ([(18)F]1) was prepared in 20%-35% radiochemical yield by a fluorine-18 displacement reaction, followed by reduction and deprotection of the ketal group, and was shown to be stable (>96% at 2 hours) in human serum at 37 degrees C. The biodistribution of [(18)F]F-4-IM in normal rats was high in the lung, where CYP4B1 gene is preferentially expressed. We transduced C6-glioma cells with a retrovirus-expressing CYP4B1 (C6-CYP4B1). Evaluation of CYP4B1 expression was confirmed by reverse transcription polymerase chain reaction and MTT assay. Cell assays were carried out using C6 and C6-CYP4B, and the uptake of [(18)F]F-4-IM in these cells was compared with that in parental controls. The uptake ratio of [(18)F]F-4-IM was 2.8-fold higher in C6-CYP4B1 compared with that in parental cells at 1 hour, whereas [(3)H]4-IM was taken up at similar rates in both cell lines after 6 hours. These results suggest that [(18)F]F-4-IM could be a promising PET imaging agent with potential to be used for imaging of CYP4B1 transfected tumor cells, as well as for monitoring CYP4B1 enzyme/prodrug interactions. PMID- 23682586 TI - Management of tuberculosis and latent tuberculosis infection in human immunodeficiency virus-infected persons. AB - The syndemic of human immunodeficiency virus (HIV)/tuberculosis (TB) co-infection has grown as a result of the considerable sociogeographic overlaps between the two epidemics. The situation is particularly worrisome in countries with high or intermediate TB burden against the background of a variable HIV epidemic state. Early diagnosis of TB disease in an HIV-infected person is paramount but suffers from lack of sensitive and specific diagnostic tools. Enhanced symptom screening is currently advocated, and the wide application of affordable molecular diagnostics is urgently needed. Treatment of TB/HIV co-infection involves the concurrent use of standard antiretrovirals and antimycobacterials during which harmful drug interaction may occur. The pharmacokinetic interaction between rifamycin and antiretrovirals is a case in point, requiring dosage adjustment and preferential use of rifabutin, if available. Early initiation of antiretroviral therapy is indicated, preferably at 2 weeks after starting TB treatment for patients with a CD4 of <50 cells/MUL. Development of TB-immune reconstitution inflammatory syndrome (TB-IRIS) is however more frequent with early antiretroviral therapy. The diagnosis of TB-IRIS is another clinical challenge, and cautious use of corticosteroids is suggested to improve clinical outcome. As a preventive measure against active TB disease, the screening for latent TB infection should be widely practiced, followed by at least 6-9 months of isoniazid treatment. To date tuberculin skin test remains the only diagnostic tool in high TB burden countries. The role of alternative tests, for example, interferon-gamma release assay, would need to be better defined for clinical application. PMID- 23682588 TI - Temporary practice pause then resumption (TPPR) study design: an extension of the withdrawal study design to complementary and alternative medicine mind and body interventions (CAM-MABI). AB - Study of complementary and alternative medicine's mind and body interventions (CAM-MABI) is hindered not only by the inability to mask participants and their teachers to the study intervention but also by the major practical hurdles of long-term study of practices that can be lifelong. Two other important methodological problems are that study of newly trained practitioners cannot directly address long-term practice, and that long-term practitioners likely self select in ways that make finding appropriate controls (or a comparison group) challenging. The temporary practice pause then resumption study design (TPPR) introduced here is a new tool that extends the withdrawal study design, established in the field of drug evaluation, to the field of CAM-MABI. With the exception of the inability to mask, TPPR can address the other methodological problems noted above. Of great interest to investigators will likely be measures in practitioners of CAM-MABI that change with temporary pausing of CAM-MABI practice, followed by return of the measures to pre-pause levels with resumption of practice; this would suggest a link of the practice to measured changes. Such findings using this tool may enhance our insight into fundamental biological processes, leading to beneficial practical applications. PMID- 23682587 TI - The impact of paternity on male-infant association in a primate with low paternity certainty. AB - In multimale groups where females mate promiscuously, male-infant associations have rarely been studied. However, recent studies have shown that males selectively support their offspring during agonistic conflicts with other juveniles and that father's presence accelerates offspring maturation. Furthermore, it was shown that males invest in unrelated infants to enhance future mating success with the infant's mother. Hence, infant care might provide fitness gain for males. Here, we investigate male-infant associations in rhesus macaques (Macaca mulatta), a primate with low paternity certainty as females mate with multiple partners and males ensure paternity less efficiently through mate guarding. We combined behavioural data with genetic paternity analyses of one cohort of the semi-free-ranging population of Cayo Santiago (Puerto Rico) and recorded affiliative and aggressive interactions between focal subjects and adult males from birth to sexual maturation (0-4 years) of focal subjects. Our results revealed that 9.6% of all interactions of focal subjects involved an adult male and 94% of all male-infant interactions were affiliative, indicating the rareness of male-infant aggression. Second and most interestingly, sires were more likely to affiliate with their offspring than nonsires with unrelated infants. This preference was independent of mother's proximity and emphasized during early infancy. Male-infant affiliation rose with infant age and was pronounced between adult males and male rather than female focal subjects. Overall, our results suggest that male-infant affiliation is also an important component in structuring primate societies and affiliation directed towards own offspring presumably represent low-cost paternal care. PMID- 23682590 TI - Enabling the mission through trans-atlantic remote mentored musculoskeletal ultrasound: case report of a portable hand-carried tele-ultrasound system for medical relief missions. AB - Modern medical practice has become extremely dependent upon diagnostic imaging technologies to confirm the results of clinical examination and to guide the response to therapies. Of the various diagnostic imaging techniques, ultrasound is the most portable modality and one that is repeatable, dynamic, relatively cheap, and safe as long as the imaging provided is accurately interpreted. It is, however, the most user-dependent, a characteristic that has prompted the development of remote guidance techniques, wherein remote experts guide distant users through the use of information technologies. Medical mission work often brings specialist physicians to less developed locations, where they wish to provide the highest levels of care but are often bereft of diagnostic imaging resources on which they depend. Furthermore, if these personnel become ill or injured, their own care received may not be to the standard they have left at home. We herein report the utilization of a compact hand-carried remote tele ultrasound system that allowed real-time diagnosis and follow-up of an acutely torn adductor muscle by a team of ultrasonographers, surgeons, and physicians. The patient was one of the mission surgeons who was guided to self-image. The virtual network of supporting experts was located across North America, whereas the patient was in Lome, Togo, West Africa. The system consisted of a hand carried ultrasound, the output of which was digitized and streamed to the experts within standard voice-over-Internet-protocol software with an embedded simultaneous videocamera image of the ultrasonographer's hands using a customized graphical user interface. The practical concept of a virtual tele-ultrasound support network was illustrated through the clinical guidance of multiple physicians, including National Aeronautics and Space Administration Medical Operations remote guiders, Olympic team-associated surgeons, and ultrasound focused emergentologists. PMID- 23682589 TI - Characteristics of patients who seek care via eVisits instead of office visits. AB - PURPOSE: There is growing recognition that many physician-patient encounters do not require face-to-face contact. The availability of secure Internet portals creates the opportunity for online eVisits. Increasing numbers of health systems provide eVisits, and many health plans reimburse for eVisits. However, little is known on who chooses to seek care via an eVisit. MATERIALS AND METHODS: At four primary care practices, we used the electronic medical record to identify all eVisits and office visits for sinusitis and urinary tract infections (UTIs) between January 2010 and May 2011. From the electronic medical record we abstracted the necessary information on patient demographics. The population studied included 5,165 sinusitis visits (9% of which were eVisits) and 2,954 UTI visits (3% eVisits). RESULTS: In multivariate models controlling for other patient factors, the variables most strongly associated with a patient initiating an eVisit versus an office visit were age (18-44 years of age versus 65 years of age and older: sinusitis, odds ratio 1.65 [0.97-2.81]; UTI, 2.97 [1.03-8.62]) and longer travel distance to clinic (>10 miles from patient home to clinic versus 0 5 miles: sinusitis, odds ratio 6.54 [4.68-9.16]; UTI, odds ratio 3.25 [1.74 6.07]). Higher income was not associated with higher eVisit use. CONCLUSIONS: At these four primary care practices, eVisits accounted for almost 7% of visits for sinusitis and UTI. eVisits attract a younger patient population who might use eVisits for convenience reasons. PMID- 23682591 TI - Content and style comparison of physician communication in teledermatology and in person visits. AB - BACKGROUND: The body of research is rapidly growing regarding the use of telemedicine in patient care, including cost-effectiveness, patient access, patient outcomes, etc. Less has been done describing physician communication during different aspects of the clinical visit (i.e., education, assessment, treatment, etc.) during actual versus virtual patient visits. The purpose of this study was to evaluate dermatology healthcare providers' communication via both modalities with regard to content and style. SUBJECTS AND METHODS: In-person and teledermatology patient visits were observed, audio-recorded, and transcribed over an 8-month period. A content analysis was performed. RESULTS: The Wilcoxon rank sum test was used to compare the content differences between visit modalities for each category. A p value of 0.05 was considered as significant for all tests. There were no statistically significant differences between modalities in the average number of physician words in seven of eight communication categories: small talk, clinical assessment, psychosocial issues, patient education, patient compliance, patient treatment, and administrative issues (p value range, 0.16-0.91). As well, the same communication themes occurred in each modality to essentially the same degree. For instance, assessment and discussion of treatment occurred in 100% of in-person and teledermatology visits, as did small talk. CONCLUSIONS: This research indicates that physician providers communicate with similar style and content whether using teledermatology or in person. PMID- 23682592 TI - 14th meeting of the International Clinical Phonetics and Linguistics Association (ICPLA). PMID- 23682593 TI - The influence of the frequency of functional markers on repetitive imitation of syntactic constructions in children with specific language impairment, from their own language productions. AB - Several studies provide considerable insight into the role that frequency plays in language development. However, no study has investigated the direct relationship between frequency and grammatical acquisition in children with specific language impairment (SLI). In this study, we focus specifically on the influence of the frequency of functional words on the ability of children with SLI to produce grammatical constructions based on the children's own previous production but containing previously unused functional words. To test our hypothesis, the children were administered an imitative repetition task, tailored to their current level of language development. Results showed that children with SLI performed more poorly than language-matched children with typical language development. The difference between the two groups was more marked when the previously unused functional words were infrequent rather than frequent. Consequently, it would seem that the token frequency of functional words influences grammatical acquisition in children with SLI. The results and their implications for linguistic theories are discussed. PMID- 23682594 TI - Intervention for improving comprehension in 4-6 year old children with specific language impairment: practicing inferencing is a good thing. AB - Few studies report on therapy to improve language comprehension in children with specific language impairment (SLI). We address this gap by measuring the effect of a systematic intervention to improve inferential comprehension using dialogic reading tasks in conjunction with pre-determined questions and cues. Sixteen children with a diagnosis of SLI aged 4-6 participated in 10 weekly treatment sessions carried out by their regular therapists. Baseline and maintenance periods were also tabulated. Two experimental measures and a standardized test revealed that children's total scores and the quality of their responses post treatment were better than those obtained pre-treatment. However, perhaps due to the use of non-equivalent probes, this change could not be interpreted solely as a significant effect of intervention. These results nevertheless suggest that a systematically designed intervention focusing on the comprehension of specific types of questions requiring inferencing and using a carefully scaffolded cueing strategy can be beneficial. PMID- 23682596 TI - Induction and repair of clustered DNA lesions: what do we know so far? AB - The accumulated evidence in the literature indicates that a cluster of two or more lesions within one or two helical turns of the DNA is more challenging to repair than individual, widely dispersed lesions. The biological importance of clustered DNA lesions, especially complex double-strand breaks (DSB) and some types of non-DSB clusters (e.g., opposed bases that are oxidized), are now well known within the radiation research community. Still, many details of the induction and biological processing of complex clusters remain to be elucidated, especially in human cells. In this mini-review, we discuss recent advances in our understanding of the pathway(s) used by the mammalian cells to process and efficiently repair complex clusters other than the DSB. The effects of radiation quality and hypoxia on cluster induction and complexity are also briefly reviewed and discussed. Additional research is needed to better understand and quantify the multi-scale physiochemical and biological processes ultimately responsible for radiation-induced mutagenesis and genomic instability. New information and models to better quantify intermediate events (outcomes) related to the biological processing of non-DSB clusters are also important for ongoing efforts to assess the human health risks of terrestrial and space radiation environments and to guide the radiation therapy treatment planning process, especially for protons and carbon ions. PMID- 23682595 TI - Prevalence and risk factors of elevated blood pressure, overweight, and dyslipidemia in adolescent and young adults in rural Nepal. AB - BACKGROUND: Chronic disease begins early in life, yet population data are sparse on potential causal factors in children and young adults in South Asia. METHODS: We assessed risk factors for chronic disease in two population cohorts, aged 9-23 years, in rural Nepal. Assessed variables included short height (less than -2 z), high body mass index (BMI) (z>0.42), waist circumference (WC) >90 cm (male) or 80 cm (female) or age-adjusted child cutoff], high blood pressure (>120/80 mmHg), fasting glucose (>=100 mg/dL), glycosylated hemoglobin (HbA1c) (>7%), blood lipids [triglyceride, high-density lipoprotein cholesterol (HDL-C), and total cholesterol], diet, smoking, alcohol, and socioeconomic status (SES) factors. RESULTS: The population was stunted (46%) and few were overweight (~2%-4% with high BMI or WC). Twelve percent had high blood pressure. Plasma hypertriglyceridemia (>=150 mg/dL) affected ~8.5%, and 78% had low HDL-C concentrations <40 mg/dL (male) or <50 mg/dL (female)], while few (<=3%) had elevated total cholesterol (>=180 mg/dL), glucose, and HbA1c. Females were at higher risk than males for high blood pressure [odds ratio (OR) 1.9; 95% confidence interval (CI) 1.6-2.3] and overweight (4.2; 3.0-5.8), but had lower risk of dyslipidemia (0.7; 0.6-0.9). Ethnic plains Madheshi were less likely to be overweight (0.3; 0.2-0.4), but had greater risk of dyslipidemia (1.4; 1.1-1.7) versus those of Hill origin. Some dietary factors were significantly associated with high blood pressure or dyslipidemia, but not overweight. CONCLUSIONS: Dyslipidemia and high blood pressure are emerging health concerns among young adults in rural Nepal. PMID- 23682597 TI - Nonsuicidal self-injury disorder: an empirical investigation in adolescent psychiatric patients. AB - Nonsuicidal self-injury (NSSI) is a growing public health concern, especially among adolescents. In the current edition of the Diagnostic and Statistical Manual of Mental Disorders, NSSI is classified as a criterion of borderline personality disorder (BPD). However, a distinct NSSI disorder will now be included in DSM-5 as a "condition requiring further study." It is important to note that, at this time, there is little direct evidence supporting the DSM-5 proposal over the DSM-IV classification. To address this need, the current study examined the extent to which NSSI occurs independently of BPD and has clinical significance beyond a diagnosis of BPD in adolescent psychiatric patients. NSSI disorder was assessed based on the proposed DSM-5 criteria in 198 adolescents ages 12 to 18 (74% female; 64% Caucasian, 14% Hispanic, 10% African American, and 12% mixed/other ethnicity) from a psychiatric hospital. Major Axis I disorders, Axis II BPD, and suicide ideation and attempts were assessed with structured clinical interviews; emotion dysregulation and loneliness were measured with validated self-report questionnaires. First, results indicated that NSSI disorder occurred independently of BPD. Specifically, although there was overlap between the occurrence of BPD and NSSI disorder, this overlap was no greater than that between BPD and other Axis I disorders (e.g., anxiety and mood disorders). Second, NSSI disorder demonstrated unique associations with clinical impairment indexed by suicide ideation and attempts, emotion dysregulation, and loneliness over and above a BPD diagnosis. Taken together, findings support the classification of NSSI as a distinct and clinically significant diagnostic entity. PMID- 23682598 TI - Impact of risk factors on hypertensive disorders in pregnancy, in primiparae and multiparae. AB - BACKGROUND: Hypertensive disorders complicating pregnancy increase the risk of adverse obstetric and perinatal outcomes. AIM: To assess the impact of age, education, family history of cardiovascular disease, pre-pregnancy overweight/obesity and weight gain during pregnancy on hypertensive disorders, among primiparae and multiparae. SUBJECTS AND METHODS: In a birth cohort study, puerperae were consecutively recruited at public maternity units of Porto, Portugal (2005-2006). The study included 6952 women with singleton births and complete data. Hypertensive disorders included chronic hypertension, gestational hypertension or pre-eclampsia/eclampsia. RESULTS: Overall, hypertensive disorders affected 4.6% of single pregnancies and were associated with older age, lower education, family history of cardiovascular disease and excessive weight before and during pregnancy, similarly in primiparae and multiparae. Approximately 50% of cases among primiparae and 70% among multiparae were attributable to the joint effect of pregnancies after 34 years of age, education below 12 years, family history of cardiovascular disease and excessive weight before and during pregnancy. CONCLUSION: The risk factors explained a high proportion of hypertensive disorders during pregnancy. Excessive weight before and during pregnancy had a very large contribution. The substantial joint effect of the risk factors suggests that interventions focusing on these risk factors should be part of pre-conceptional and pre-natal care. PMID- 23682599 TI - Can we predict delivery date with obstetric ultrasound? AB - OBJECTIVE: The long-term prediction of delivery date with obstetric ultrasound. METHOD: The cervical length (CL) and the fetal vertebral, middle cerebral and umbilical resistance indices were measured in 317 pregnancies between 30 and 37 weeks. Subsequently, multivariate analysis was applied to calculate the best model for the prediction of delivery date. RESULTS: The best model included the examinations of the CL and the middle cerebral artery resistance index. In comparison with estimated delivery date (EDD) based on the last menstrual period, a small improvement was detected, particularly in earlier deliveries, however 34% of predictions still had an error of more than 5 days. CONCLUSIONS: Long-term sonographic prediction of delivery date depends mainly on the CL and improves the prediction of the EDD. However, it is still too inaccurate for clinical use. PMID- 23682600 TI - Three cases of a presumptive atypical myopathy in New Zealand horses. AB - CASE HISTORY: Three weanling Thoroughbred fillies were presented during autumn with depression, muscle rigidity and, in one case, colic symptoms and cardiovascular shock. CLINICAL FINDINGS: All fillies had abnormal physical examinations that included elevated heart rates and respiratory rates coupled with muscle rigidity through the back and rump. Biochemistry revealed markedly elevated creatinine kinase and aspartate aminotransferase which indicated a myopathy. DIAGNOSIS AND TREATMENT: All three horses were diagnosed with presumptive equine atypical myopathy. The horses received supportive therapy as per the literature available at the time regarding this condition; two responded to supportive therapy and survived, and one was euthanased due to a rapid deterioration in clinical status. PATHOLOGICAL FINDINGS: Following post mortem of one case, histology of the trapezius muscle demonstrated an acute, severe myofibre degeneration. CLINICAL RELEVANCE: Atypical myopathy and a very similar disorder termed seasonal pasture myopathy in North America are potentially fatal, pasture-related syndromes that have been described in Europe and America but have not been previously described in New Zealand. This report describes three presumptive cases of this unique syndrome in New Zealand for the first time; it outlines the characteristics of the condition; and includes recently published information regarding diagnosis and treatment. PMID- 23682601 TI - A follow-up case study of transitory developmental apraxia of speech: 'L'enfant a voyelles'. AB - It is well known that the acquisition of consonants can be a more difficult developmental process than of vowels. In this study the authors describe a case of 'transitory developmental apraxia of speech' (TDAS) in which a French-speaking child, although he acquired the whole vowel system, showed a significant delay in consonant acquisition and usage. The results of systematic observations and assessments of general cognitive and specific language functioning cover a period of 4 years (age 3:8 to 7:1l), from first clinical assessment to evidence of a good academic achievement. It is argued that this case demonstrates an unusual example of TDAS. The language deficits observed could not be attributed to oromotor, neurological, cognitive or intellectual deficits. The findings here also raise crucial questions concerning the origins of such a speech disorder and why it is transient in nature. PMID- 23682602 TI - Homonymy in phonological change. AB - This study examines the role of homonymy as a motivator of phonological change in treatment. The relative effectiveness of two treatment structures in improving the production of treated and untreated error sounds was evaluated. One treatment structure emphasized homonymous forms by comparing 1:1 a desired ambient target with its corresponding replacement error from the child's grammar, consistent with conventional minimal pair treatment (Weiner, 1981). The other treatment did not focus on homonymy, nor did it make explicit reference to a child's grammar. In line with treatment of the empty or unknown set (Gierut, 1989), two errored sounds were simply compared with each other. Differential learning was observed among the treatments such that the non-homonymous structure resulted in greater accuracies of treated sounds and in more new untreated sounds being added to the phonological system. The findings have potential implications for the status of homonymy in phonological change and in the structure of phonological treatment. PMID- 23682603 TI - A comparative analysis of phonological acquisition of consonants in the speech of 21/2-6-year-old Xhosa- and English-speaking children. AB - The articulation of 41 phonemes in the speech of 70 Xhosa-speaking children ages 21/2-6 years (10 children in each group of seven age levels 6 months apart) was studied with respect to order of acquisition, types of errors, types of substitutions, ages of phoneme acquisition, and sex variables. These variables were compared with acquisition data of 20 similar phonemes used by 70 Englishspeaking children. Results indicate Xhosa-speaking children master most phonemes at an earlier age than their English-speaking counteiparts. Xhosa speakers produce a similar number of errors on the same phonemes and make similar errors as English speakers, but Xhosa speakers make fewer errors on stops and fricatives. The data support the notion of the existence of phonological universals at least with the two groups studied. PMID- 23682604 TI - Spectral characteristics for place of articulation in the speech of young normal, moderately and profoundly hearing-impaired French Canadians. AB - A group of 10 moderately hearing-impaired children aged 7-10 years (five boys, five girls), 10 profoundly hearing-impaired children (five boys, five girls), and 10 age-matched normal control subjects (five boys, five girls), were recorded producing the six occlusives / p t k b d g / before the vowel /a/. Five productions were elicited from each child for a total of 30 potential correct productions each. LPC spectral analyses were performed at the moment of release (the burst) to determine the degree to which Blumstein and Stevens' (1979) spectral place-of-articulation features were present in the speech of these normal and hearing-impaired children, and whether there were differences between groups. A static 'centroid' analysis was also performed. Results reveal that the moderately hearing-impaired children's productions were not significantly different from those of the normal controls, but that some aspects of the profoundly hearing-impaired children's productions did differ from those of the moderately hearing-impaired and normal children. The relationship between degree of hearing loss and severity of speech production deficits is discussed. Implications of the results for remediation are also considered. PMID- 23682605 TI - Acyl-homoserine lactone quorum sensing: from evolution to application. AB - Quorum sensing (QS) is a widespread process in bacteria that employs autoinducing chemical signals to coordinate diverse, often cooperative activities such as bioluminescence, biofilm formation, and exoenzyme secretion. Signaling via acyl homoserine lactones is the paradigm for QS in Proteobacteria and is particularly well understood in the opportunistic pathogen Pseudomonas aeruginosa. Despite thirty years of mechanistic research, empirical studies have only recently addressed the benefits of QS and provided support for the traditional assumptions regarding its social nature and its role in optimizing cell-density-dependent group behaviors. QS-controlled public-goods production has served to investigate principles that explain the evolution and stability of cooperation, including kin selection, pleiotropic constraints, and metabolic prudence. With respect to medical application, appreciating social dynamics is pertinent to understanding the efficacy of QS-inhibiting drugs and the evolution of resistance. Future work will provide additional insight into the foundational assumptions of QS and relate laboratory discoveries to natural ecosystems. PMID- 23682607 TI - Epitope mapping of antibodies against ferritin heavy chain in giant cell arteritis and polymyalgia rheumatica. AB - OBJECTIVES: In a previous study we found an association between antibodies against the human ferritin heavy chain (HFC) protein and giant cell arteritis (GCA) and/or polymyalgia rheumatica (PMR), especially in GCA/PMR patients prior to glucocorticoid treatment. Antibodies against the N-terminal part of ferritin were present in 92% of untreated patients, 69% of patients with disease flare, and 13% of patients in remission. These antibodies appeared to be markers for the early detection of a disease complex usually diagnosed with considerable delay. Our aim in this study was to optimize the diagnostic test by epitope mapping of antibodies against HFC using peptide antigens in enzyme-linked immunosorbent assays (ELISAs). METHOD: We evaluated serum samples from a selected group of GCA/PMR patients in whom the sensitivity of antibodies against the N-terminal ferritin peptide was only 35%. Patients with late-onset rheumatoid arthritis (LORA), patients with fever, patients with granulomatosis with polyangiitis (GPA), patients without any autoimmune disease at age > 65 years, and blood donors served as controls. RESULTS: By combining different ELISAs we were able to increase the frequency of human ferritin peptide antibodies in GCA/PMR (p < 0.0001) without significantly altering the false-positive rate (FPR) of the diagnostic test. The frequency of antibodies against human ferritin peptide increased from 53% to 74% in GCA/PMR patients with disease flare, from 29% to 40% in GCA/PMR patients in partial remission, and from 8% to 45% in GCA/PMR patients in complete remission. CONCLUSIONS: The potential diagnostic test for GCA/PMR can be improved by combining three human ferritin peptide antibodies. PMID- 23682608 TI - Preference-for-solitude and adjustment difficulties in early and late adolescence. AB - Social withdrawal has been associated with adjustment difficulties across development. Although much is known about shyness, little is known about preference-for-solitude; even less is known about its relations with adjustment across different periods of adolescence. We examined whether preference-for solitude might be differentially associated with adjustment difficulties in early and late adolescence. Self- and parent-reports of withdrawal motivations and adjustment were collected from 234 eighth graders (113 boys; M age = 13.43) and 204 twelfth graders (91 boys; M age = 17.25). Results from structural equation modeling demonstrated that above and beyond the effects of shyness, preference for-solitude was more strongly associated with adjustment difficulties in 8th grade than in 12th grade. Preference-for-solitude was associated with greater anxiety/depression, emotion dysregulation, and lower self-esteem in 8th grade; these relations were not found in 12th grade. Although preference-for-solitude was associated with lower social competence in both 8th and 12th grades, this relation was significantly stronger in 8th grade than in 12th grade. Findings suggest preference-for-solitude has closer ties to maladjustment in early adolescence than in late adolescence. Interventions targeting preferred-solitary youth in early adolescence may be particularly fruitful. PMID- 23682606 TI - 3' cap-independent translation enhancers of plant viruses. AB - In the absence of a 5' cap, plant positive-strand RNA viruses have evolved a number of different elements in their 3' untranslated region (UTR) to attract initiation factors and/or ribosomes to their templates. These 3' cap-independent translational enhancers (3' CITEs) take different forms, such as I-shaped, Y shaped, T-shaped, or pseudoknotted structures, or radiate multiple helices from a central hub. Common features of most 3' CITEs include the ability to bind a component of the translation initiation factor eIF4F complex and to engage in an RNA-RNA kissing-loop interaction with a hairpin loop located at the 5' end of the RNA. The two T-shaped structures can bind to ribosomes and ribosomal subunits, with one structure also able to engage in a simultaneous long-distance RNA-RNA interaction. Several of these 3' CITEs are interchangeable and there is evidence that natural recombination allows exchange of modular CITE units, which may overcome genetic resistance or extend the virus's host range. PMID- 23682609 TI - Growth centiles of Pacific children living in Auckland, New Zealand. AB - BACKGROUND: Since 2000, the longitudinal Pacific Island Families study has measured the weight, height and body mass index (BMI) of 582 girls and 643 boys at 2, 4, 6 and 9 year data collection phases. AIM: To extend and record the age related distribution of weight, height and BMI measures in Pacific children aged 2-10 years and to compare the distribution to population and clinical growth charts. METHODS: Gender-specific age-related centile curves were derived using the LMS method for weight, height and BMI. The 50th centiles from the World Health Organisation growth reference for 2-5 year olds and the Centres for Disease Control (CDC) for 5-10 year olds were compared. Overweight and obesity were defined by the CDC BMI 85th and 95th centiles. RESULTS: The proportion of children whose weight and height were above the reference 50th centile increased with age. At age 10, using CDC criteria, more than 50% of the children were classified as obese and 70% were overweight. CONCLUSIONS: These charts support the need to prioritize interventions for Pacific families to address childhood obesity. These centile curves could help assess the relative growth of Pacific children and identify children for further assessment and treatment. PMID- 23682610 TI - Evaluation of the sea anemone Anthothoe albocincta as an augmentative biocontrol agent for biofouling on artificial structures. AB - Augmentative biocontrol, defined as the use of indigenous natural enemies to control pest populations, has not been explored extensively in marine systems. This study tested the potential of the anemone Anthothoe albocincta as a biocontrol agent for biofouling on submerged artificial structures. Biofouling biomass was negatively related to anemone cover. Treatments with high anemone cover (>35%) led to significant changes in biofouling assemblages compared to controls. Taxa that contributed to these changes differed among sites, but included reductions in cover of problematic fouling organisms, such as solitary ascidians and bryozoans. In laboratory trials, A. albocincta substantially prevented the settlement of larvae of the bryozoan Bugula neritina when exposed to three levels of larval dose, suggesting predation as an important biocontrol mechanism, in addition to space pre-emption. This study demonstrated that augmentative biocontrol using anemones has the potential to reduce biofouling on marine artificial structures, although considerable further work is required to refine this tool before its application. PMID- 23682612 TI - The effect of organic solvents on enzyme kinetic parameters of human CYP3A4 and CYP1A2 in vitro. AB - Abstract Enzyme kinetic parameters provide essential quantitative information about characterization of individual steps in drug metabolism. Such enzymes are located in a (partially) aqueous environment. For in vitro measurements potential lipophilic substrates regularly require organic solvents to achieve concentrations sufficient for access of the drug to the binding site of the enzyme. However, solvents may interact with the enzymes. In this study, we investigated the effects of methanol, ethanol, acetonitrile and dimethyl sulfoxide (1% to 4%) on the assessment of km, Vmax and Clint for the metabolism of midazolam via CYP3A4 to 1-hydroxymidazolam and the metabolism of caffeine to paraxanthine via CYP1A2 using expressed enzymes in vitro. The presence of acetonitrile proved the highest apparent Vmax value for paraxanthine formation but the lowest values for 1-hydroxymidazolam formation. The km value for midazolam showed no systematic effects of organic solvents, while for caffeine km was up to 8-fold lower for solvent free samples compared to solvent containing samples. The present example suggests that effects of solvents may considerably influence enzyme kinetic parameters beyond a mere change in apparent activity. These effects illustrate a difference for individual enzyme--substrate pairs, solvents, and solvent concentrations. What remains is the determination to which extent these effects compromise in vitro-in vivo extrapolations, and which solvents are most appropriate. PMID- 23682611 TI - Racial disparities in pregnancy outcomes in obese women. AB - OBJECTIVE: To estimate the effect of race on perinatal outcomes in obese women. METHODS: Retrospective cohort study of birth records linked to hospital discharge data for all live born singleton infants >=37 weeks gestation born to African American or Caucasian Missouri residents from 2000 to 2006. We excluded major congenital anomalies and women with diabetes or chronic hypertension. Obesity was defined as pre-pregnancy body mass index >=30 kg/m(2). RESULTS: There were 312 412 births meeting study criteria. 27.1% (11 776) of African-American mothers and 19.1% (49 415) of Caucasian mothers were obese. There were no differences in cesarean delivery or preeclampsia between obese African-American and obese Caucasian women. Infants of obese African-American women were significantly less likely to be macrosomic (0.9% vs. 2.2%, adjusted odds ratio [aOR] 0.5, 95% confidence interval [CI] 0.4 0.6) and more likely to be low birth weight (3.4% vs. 1.8%, aOR 1.9, 95% CI 1.7, 2.2) compared to infants of obese Caucasian women. Compared to their normal weight peers, obese Caucasian women had a greater relative risk of developing preeclampsia (aOR 3.1, 95% CI 2.9, 3.2) than obese African-American women (aOR 2.1, 95% CI 1.9, 2.4). CONCLUSION: Racial disparities impact obesity-related maternal and neonatal complications of pregnancy. PMID- 23682613 TI - Hypermethylation of TWIST1 and NID2 in tumor tissues and voided urine in urinary bladder cancer patients. AB - Bladder cancer like other cancers arises from the accumulation of many genetic and epigenetic changes that lead to the activation of proto-oncogenes or inactivation of tumor suppressor genes. We aimed to investigate the methylation patterns of Twist homolog 1 (TWIST1) and nidogen-2 (NID2) genes in bladder cancer. Fifty six histologically confirmed bladder tumor samples and paired 24 urine samples constituted the study group and was compared with 15 age- and gender-matched noncancerous individuals. DNA was purified from both tumor and urine samples. The methylation status of the two genes was analyzed by methylation-specific polymerase chain reaction (MSP) in both urinary bladder cell carcinoma samples and urine samples. Sensitivity and specificity values of the method were assessed and compared with the results of the cytology test. Methylation of TWIST1 and NID2 was detected in 98.2% and 96.4% of the tumor samples, and in 87.5% and 95.8% of the urine samples, respectively. The sensitivity of TWIST1 and NID2 genes (87.5% and 95.8% in urine samples, respectively), was higher compared with urine cytology (62.5%) for cancer detection. The sensitivity of any of the two genes was 88.8% (8/9) for low-grade cases. The sensitivity of urine cytology was 33.3% for the same low-grade cases. To be used in the early noninvasive diagnosis of bladder cancer, the combined methylation analysis of TWIST1 and NID2 genes may be a simple, noninvasive, sensitive, and specific method for detecting cancer cells in urine. PMID- 23682614 TI - Effects of oral intake of hydrogen water on liver fibrogenesis in mice. AB - AIM: Liver fibrosis is the universal consequence of chronic liver diseases. Sustained hepatocyte injury initiates an inflammatory response, thereby activating hepatic stellate cells, the principal fibrogenic cells in the liver. Reactive oxygen species are involved in liver injury and are a promising target for treating liver fibrosis. Hydrogen water is reported to have potential as a therapeutic tool for reactive oxygen species-associated disorders. This study aimed to investigate the effects of hydrogen water on liver fibrogenesis and the mechanisms underlying these effects. METHODS: C57BL/6 mice were fed with hydrogen water or control water, and subjected to carbon tetrachloride, thioacetamide and bile duct ligation treatments to induce liver fibrosis. Hepatocytes and hepatic stellate cells were isolated from mice and cultured with or without hydrogen to test the effects of hydrogen on reactive oxygen species-induced hepatocyte injuries or hepatic stellate cell activation. RESULTS: Oral intake of hydrogen water significantly suppressed liver fibrogenesis in the carbon tetrachloride and thioacetamide models, but these effects were not seen in the bile duct ligation model. Treatment of isolated hepatocyte with 1 MUg/mL antimycin A generated hydroxyl radicals. Culturing in the hydrogen-rich medium selectively suppressed the generation of hydroxyl radicals in hepatocytes and significantly suppressed hepatocyte death induced by antimycin A; however, it did not suppress hepatic stellate cell activation. CONCLUSION: We conclude that hydrogen water protects hepatocytes from injury by scavenging hydroxyl radicals and thereby suppresses liver fibrogenesis in mice. PMID- 23682615 TI - The changes in the hair cycle during gestation and the post-partum period. AB - BACKGROUND: In pregnancy, increased numbers of hair follicles remain in the anagen phase for longer periods due to hormonal changes and return to the telogen phase within 3-6 months of delivery with a sudden drop in hormone levels. This results in excessive shedding of hair known as post-partum telogen effluvium. OBJECTIVE: To determine the changes in the hair cycle during gestation and the post-partum period. METHODS: We included 116 women in this study; 28 women at the 24th week of pregnancy, 30 pregnant women at term gestation, 29 women in the 4th post-partum month, and 29 in the first post-partum year. The number of breastfeeding mothers in the post-partum period and the month in which they were examined were also recorded. The ratios of anagen and telogen were measured using Trichoscan. RESULTS: A statistically significant difference was observed between the groups in terms of the anagen and telogen ratios (P = 0.042, P = 0.042). In the inter-group comparisons, the mean anagen rate in the 4th post-partum month was significantly lower than that in the 6th and 9th month of pregnancy (P = 0.045, P = 0.038), while the average telogen rate was significantly higher (P = 0.045, P = 0.038). The mean anagen rate in the 4th post-partum month in the breastfeeding group was significantly higher than that in the non- breastfeeding group (P = 0.014), while the mean telogen rate was significantly lower (P = 0.014). There was no statistically significant difference between the two groups (the breastfeeding and non-breastfeeding groups) in terms of the mean anagen and mean telogen ratios in the first post-partum year (P = 0.385). CONCLUSION: The anagen rate increases during pregnancy and the telogen rate rises after delivery, however, there is no exaggeration in these changes in most women. PMID- 23682616 TI - Mustard seed (Sinapis Alba Linn) attenuates imiquimod-induced psoriasiform inflammation of BALB/c mice. AB - Psoriasis is a chronic inflammatory autoimmune disease with undefined etiology. All present treatments are symptomatic. The unsatisfactory outcome in the treatment of psoriasis is partially due to the poor compliance to the present therapies with more or less side-effects. As is known, drug homologous food is a popular intervention of some chronic diseases in Chinese traditional medicine. Mustard seed, consumed largely as a spice and a medicine in China, has recently been found to possess the bioactivities of anti-oxidation, anti-inflammation and anticancer. Therefore, it was supposed that mustard seed may have effects on psoriasis, and it was preliminarily validated using a BALB/c mouse model of psoriasiform inflammation induced by the topical application of imiquimod cream (Aldara) for 6 days consecutively. It was found that the forage containing 5% mustard seed obviously attenuated imiquimod-induced psoriasiform inflammation, but did not clear it completely, accompanied by reduced infiltrations of T cells, plasmacytoid dendritic cells (pDC) and macrophages in lesional skin; reduced percentages of pDC and macrophages in the composition of immunocytes of spleens; reduced content of lesion nuclear factor-kappaB p65, plasma malondialdehyde, lesion inducible nitric oxide synthase, interferon-alpha, interleukin (IL)-17 and IL-22 at mRNA and protein levels; increased activities of superoxide dismutase, catalase and glutathione peroxidase; and increased percentage of CD4(+) T cells and increased ratio of CD4(+) /CD8(+) T cells in the composition of immunocytes of spleen. These results presented herein provide a basis for mustard seed to be used as a promising intervention for psoriasis in the future. PMID- 23682617 TI - Jealousy in response to online and offline infidelity: the role of sex and sexual orientation. AB - The goal of the present study was to examine the emotional content and intensity of jealousy in response to different types of infidelity (both online and offline unfaithful partner behaviors) among Dutch heterosexuals (n = 191) and homosexuals (n = 121). Based on previous research (Dijkstra, Barelds & Groothof, 2010), participants were presented with ten jealousy-evoking situations following which the intensity of two different emotional aspects of jealousy was assessed (betrayal/anger and threat). Results showed that scenarios describing a partner having sex with someone else or falling in love with someone else primarily evoked betrayal/anger-related jealousy, whereas scenarios describing an emotional connection between a partner and someone else primarily evoked threat-related jealousy. In addition, women experienced more jealousy than men in response to scenarios in which a partner engaged in potentially extra-dyadic online (but not offline) behaviors. Finally, compared to same-sex heterosexuals, homosexuals, both male and female, responded with less intense jealousy to scenarios describing a partner having sex with someone else. Implications for the treatment of (internet) infidelity are discussed. PMID- 23682618 TI - Trajectories of change across outcomes in intensive treatment for adolescent panic disorder and agoraphobia. AB - Much remains to be learned about typical and individual growth trajectories across treatment for adolescent panic disorder with and without agoraphobia and about critical treatment points associated with key changes. The present study examined the rate and shape of change across an 8-day intensive cognitive behavioral therapy for adolescent panic disorder with and without agoraphobia (N = 56). Participants ranged in age from 12 to 17 (M = 15.14, SD = 1.70; 58.9% female, 78.6% Caucasian). Multilevel modeling evaluated within-treatment linear and nonlinear changes across three treatment outcomes: panic severity, fear, and avoidance. Overall panic severity showed linear change, decreasing throughout treatment. In contrast, fear and avoidance ratings both showed cubic change, peaking slightly at the first session of treatment, starting to decrease at the second session of treatment, and with large gains continuing then plateauing at the fourth session. Findings are considered with regard to the extent to which they may elucidate critical treatment components and sessions for adolescents with panic disorder with and without agoraphobia. PMID- 23682619 TI - Combined effect of benzalkonium chloride and ultrasound against Listeria monocytogenes biofilm on plastic surface. AB - This study was performed to evaluate the effectiveness of benzalkonium chloride combined with ultrasound in eliminating Listeria monocytogenes biofilm from polystyrene surface. The test strain of L. monocytogenes, previously classified as strong biofilm producer, was grown to form biofilm in tryptic soy broth at 20 degrees C for 6 days in polystyrene specimen containers. The biofilms formed on surface of containers were treated with ultrasound alone, benzalkonium chloride (100 and 400 mg l(-1)) alone and their combination for three different exposure times (1, 5 and 15 min) at room temperature. Sonication was performed using an ultrasound bath at a constant ultrasound frequency of 35 kHz. After treatments, levels of biofilm biomass and viable cells in biofilm were determined using crystal violet staining and XTT assays, respectively. The combined treatment of ultrasound and benzalkonium chloride resulted in significant (P < 0.05) more decrease in the level of viable cells in the L. monocytogenes biofilm compared to individual treatments of benzalkonium chloride. Our results suggest that the combination of benzalkonium chloride with ultrasound is useful approach for the elimination of L. monocytogenes biofilms from plastic surfaces. PMID- 23682620 TI - Psychometric properties of the Adolescent Sleep Hygiene Scale. AB - This study evaluated the psychometric properties of the Adolescent Sleep Hygiene Scale (ASHS), a self-report measure assessing sleep practices theoretically important for optimal sleep. Data were collected on a community sample of 514 adolescents (16-19; 17.7 +/- 0.4 years; 50% female) participating in the late adolescent examination of a longitudinal study on sleep and health. Sleep hygiene and daytime sleepiness were obtained from adolescent reports, behavior from caretaker reports, and sleep-wake estimation on weekdays from wrist actigraphy. Confirmatory factor analysis indicated the empirical and conceptually based factor structure were similar for six of the eight proposed sleep hygiene domains. Internal consistency of the revised scale (ASHSr) was alpha = 0.84; subscale alphas were: physiological: alpha = 0.60; behavioural arousal: alpha = 0.62; cognitive/emotional: alpha = 0.81; sleep environment: alpha = 0.61; sleep stability: alpha = 0.68; daytime sleep: alpha = 0.78. Sleep hygiene scores were associated positively with sleep duration (r = 0.16) and sleep efficiency (r = 0.12) and negatively with daytime sleepiness (r = -0.26). Results of extreme groups analyses comparing ASHSr scores in the lowest and highest quintile provided further evidence for concurrent validity. Correlations between sleep hygiene scores and caretaker reports of school competence, internalizing and externalizing behaviours provided support for convergent validity. These findings indicate that the ASHSr has satisfactory psychometric properties for a research instrument and is a useful research tool for assessing sleep hygiene in adolescents. PMID- 23682621 TI - Can the retinal microvasculature offer clues to cardiovascular risk factors in early life? AB - Adulthood cardiovascular diseases (CVD) burdening in adulthood have been suggested to have possible predisposition early in life. We aimed to systematically review the literatures on retinal microvasculature among paediatric population in relation to a range of environmental and systemic changes. Papers with quantitative retinal vascular assessment and epidemiological design were reviewed. CONCLUSION: This review supports the theory that major vascular diseases have pathological predisposition early in life by providing morphological evidence on retinal microcirculation in vivo. PMID- 23682622 TI - Screening of families of patients with left-sided cardiovascular anomalies. AB - BACKGROUND: There is increasing evidence of clustering of certain cardiac anomalies in some families. The frequency and echocardiographic features of such anomalies among the relatives of patients with bicuspid aortic valve (BAV) or other left-sided cardiovascular anomalies (LSCA) were evaluated. METHODS: The patients with BAV or any other LSCA and their relatives were enrolled in the study. They underwent an echocardiographic examination. The probands were assessed in three groups: BAV, BAV + coarctation of aorta (CoA), and other LSCA. Their relatives were also grouped and evaluated accordingly. The echocardiographic measurements were standardized by Z-scores. RESULTS: Eighty-six probands and 261 relatives were evaluated. The numbers of the patients in the BAV, BAV + CoA, and other LSCA group were 52, 14, and 20, respectively. Any LSCA was determined in 17 (6.5%) of the relatives. Thirteen (5%) had aortic dilatation and the remainder (1.5%) had BAV. Accordingly, BAV incidence among relatives of patients with BAV was found to be 1.9%. A second individual with an LSCA was observed in 12.8% of 86 families investigated. The frequencies of aortic stenosis, aortic regurgitation, aortic stenosis + aortic regurgitation, and aortic dilatation in the patients with BAV were found to be 37.9%, 53%, 25.8% and 48.5%, respectively. In contrast to previous reports, no enlargement was observed in the pulmonary arteries of BAV patients. CONCLUSIONS: BAV and other LSCA are of clinical significance. Because the clustering of LSCA in some families is observed, we recommend echocardiographic screening of those relatives. If this is not possible, at least it should be achieved for BAV patients. PMID- 23682623 TI - Update on genetics of essential tremor. AB - Despite the research, few advances in the etiopathogenesis on essential tremor (ET) have been made to date. The high frequency of positive family history of ET and the observed high concordance rates in monozygotic compared with dizygotic twins support a major role of genetic factors in the development of ET. In addition, a possible role of environmental factors has been suggested in the etiology of ET (at least in non-familial forms). Although several gene variants in the LINGO1 gene may increase the risk of ET, to date no causative mutated genes have been identified. In this review, we summarize the studies performed on families with tremor, twin studies, linkage studies, case-control association studies, and exome sequencing in familial ET. PMID- 23682624 TI - Serum soluble fas ligand levels in familial Mediterranean fever. AB - INTRODUCTION: Fas/FasL system plays an important role in the regulation of cell life and death, and circulating levels of sFasL have been shown to increase in some inflammatory conditions. However, there is no sufficient information about the levels of sFasL in patients with FMF. This study was designed to evaluate the serum sFasL levels in patients with FMF during attack and attack-free periods. METHODS: Twenty-five FMF patients in attack and forty-four in free-attack period, and 20 age-, sex-, and BMI-matched healthy controls were included in this study. Participants with any chronic diseases were excluded. Blood samples were obtained within the first 24 h of the attack period and between febrile attacks, and levels of WBC, ESR, Fibrinogen, hsCRP and sFasL were determined. RESULTS: The levels of traditional acute phase reactants during the attack were significantly higher than the attack-free and controls (p < 0.05). The serum sFasL levels in the FMF study groups did not differ from the control group (0.70 +/- 0.08 vs. 0.73 +/- 0.12; 0.70 +/- 0.08 vs. 0.83 +/- 0.14; 0.73 +/- 0.12 vs. 0.83 +/- 0.14, respectively, p > 0.05). Moreover, the sFasL levels during the attack were not significantly different from those in attack-free patients (0.70 +/- 0.08 vs. 0.83 +/- 0.14, p > 0.05). CONCLUSION: In this study, we demonstrated that serum sFasL levels were not markedly affected in FMF and cannot be used as a supportive marker to differentiate attacks from attack-free periods. However, further studies are needed to determine its usefulness as a marker in clinical practice. PMID- 23682625 TI - A recombinant biopolymeric platform for reliable evaluation of the activity of pH responsive amphiphile fusogenic peptides. AB - Over the past couple of decades, the sequences of several cationic and anionic pH responsive amphiphile fusogenic peptides (FPs) have been reported in the literature. Due to their endosome membrane disrupting activity, these peptides have been routinely used for enhancing the efficacy of drug/gene delivery systems. However, no accurate comparative study has been performed to establish the precise correlation between FP sequence and its impact on enhancing drug/gene delivery efficiency. Therefore, there has been no clear rationale for selecting one FP over another in the past, and it is still unclear which FP is the most suitable and efficient construct for use in drug/gene delivery system design. To address this shortcoming, we examined the use of a recombinant biopolymeric platform as a tool to assess the pH-dependent membrane disruption activity, cell toxicity and impact on gene transfer efficiency of the five most widely used cationic and anionic pH-responsive FPs, INF7, GALA, KALA, H5WYG, and RALA. We first developed specific expression methods for the production of five identical recombinant biopolymers that were different only in FP sequence in their structures. Through the use of physicochemical and biological assays, the biopolymers were characterized and compared in terms of DNA condensation ability, cell toxicity, pH-dependent cell membrane disruption activity, and gene transfer efficiency. Overall, our data suggests that, among the tested constructs, GALA is the most suitable pH-responsive FP for enhancing the efficiency of gene delivery systems due mostly to its efficient endosomolytic activity and negligible cell toxicity. Most importantly, this study demonstrates the application of an effective biopolymeric tool that facilitates reliable evaluation of the physicochemical and biological activities of any pH-responsive FP independent of its charge. Therefore, whether artificially designed or inspired by nature, the FPs can be screened for their efficacy with a higher degree of accuracy in the future. PMID- 23682626 TI - Ice particle crystallization in the presence of ethanol: an in situ study by Raman and X-ray diffraction. AB - Two distinct ethanol aqueous solution droplets ((X(EtOH))L = 8.7 wt % and 46.5 wt %) are investigated by in situ Raman spectroscopy and X-ray diffraction between 253 and 88 K. Structural changes are identified by modifications in the O-H and C H stretching modes (2800-3800 cm(-1) spectral region) during freezing and annealing events. They are attributed to the formation of ice and/or different hydrate structures in the EtOH-water system. At high initial ethanol concentration, the particle is found to be composed of a modified clathrate I (cubic structure) at 211 K on cooling and transformed into an ethanol hydrate II (monoclinic structure) on annealing between ~143 and 173 K. This latter decomposes at ~200 K and leaves an aqueous solution and ice Ih which further dissociates above ~230 K. At low initial concentration, ice first forms on cooling and the particle consists of a crystalline ice core embedded in a liquid layer of high ethanol content at ~200 K (or an amorphous layer at lower T). A new hydrate (IV) of distinct structure (orthorhombic) is observed on annealing (from 100 K) between ~123 K and ~142 K (depending on initial composition), which transforms into the ethanol hydrate II at ~160 K. The hydrate II decomposes at ~200 K, and ice Ih remains (and dissociate above ~220 K) in coexistence with the liquid layer of high ethanol content. It is proposed that the complex crystalline ice particles formed may have the potential to impact several atmospherical processes differently in comparison to the pure ice case. PMID- 23682627 TI - Pragmatic deficits and social impairment in children with ADHD. AB - BACKGROUND: Impaired social functioning has been well documented in individuals with attention-deficit/hyperactivity disorder (ADHD). Existing treatments for ADHD are effective for managing core symptoms, but have limited effectiveness at improving social skills, suggesting that social deficits in ADHD may not be directly related to core symptoms of the disorder. Language problems are also common in ADHD, with accumulating evidence of pragmatic language difficulties. Pragmatic deficits are associated with social impairment in several neurodevelopmental disorders. This study systematically examined pragmatic language functioning in children with ADHD and whether social impairment in ADHD is mediated by pragmatic deficits. METHOD: Sixty-three children (28 ADHD; 35 typically developing), ages 7-11 years, underwent a comprehensive assessment of pragmatic language, including parent ratings, standardized tests, and a narrative task. Parents also rated children's social skills on the Social Skills Improvement System. RESULTS: Children with ADHD had poorer pragmatic language skills relative to peers across all measures, even after controlling for general language abilities. Furthermore, pragmatic abilities as measured by parent ratings, mediated the relation between ADHD and social skills. CONCLUSIONS: Pragmatic language skills are impaired in many children with ADHD and may partially account for high rates of social impairment. Implications for treatment and possible prevention of social problems in children with ADHD are discussed. PMID- 23682629 TI - Removing the blinkers: moving beyond striatal dopamine in Parkinson's disease. PMID- 23682628 TI - Elective caesarean section at 38 weeks versus 39 weeks: neonatal and maternal outcomes in a randomised controlled trial. AB - OBJECTIVES: To investigate whether elective caesarean section before 39 completed weeks of gestation increases the risk of adverse neonatal or maternal outcomes. DESIGN: Randomised controlled multicentre open-label trial. SETTING: Seven Danish tertiary hospitals from March 2009 to June 2011. POPULATION: Women with uncomplicated pregnancies, a single fetus, and a date of delivery estimated by ultrasound scheduled for delivery by elective caesarean section. METHODS: Perinatal outcomes after elective caesarean section scheduled at a gestational age of 38 weeks and 3 days versus 39 weeks and 3 days (in both groups +/-2 days). MAIN OUTCOME MEASURES: The primary outcome was neonatal intensive care unit (NICU) admission within 48 hours of birth. Secondary outcomes were neonatal depression, NICU admission within 7 days, NICU length of stay, neonatal treatment, and maternal surgical or postpartum adverse events. RESULTS: Among women scheduled for elective caesarean section at 38+3 weeks 88/635 neonates (13.9%) were admitted to the NICU, whereas in the 39+3 weeks group 76/637 neonates (11.9%) were admitted (relative risk [RR] 0.86, 95% confidence interval [95% CI] 0.65-1.15). Neonatal treatment with continuous oxygen for more than 1 day (RR 0.31; 95% CI 0.10-0.94) and maternal bleeding of more than 500 ml (RR 0.79; 95% CI 0.63-0.99) were less frequent in the 39 weeks group, but these findings were insignificant after adjustment for multiple comparisons. The risk of adverse neonatal or maternal outcomes, or a maternal composite outcome (RR 1.1; 95% CI 0.79-1.53) was similar in the two intervention groups. CONCLUSIONS: This study found no significant reduction in neonatal admission rate after ECS scheduled at 39 weeks compared with 38 weeks of gestation. PMID- 23682631 TI - Uncertainty of blank correction in isotope ratio measurement. AB - Blank correction for isotope ratio measurement on small amounts of substances is often limited by presence of a blank, with an apparent isotopic composition different from that of the sample. For isotope ratios, blank correction is commonly performed either by the regression method, which works without the need for estimation of the blank, or by the subtraction method. With the subtraction method, estimation of the amount and isotope delta of the blank is required, and these estimates could be obtained either by direct, semi-indirect, or indirect measurement. Previously given expressions for the standard uncertainties of indirectly measured blank amounts and blank isotope deltas did not account for covariance between input quantities. In the present work, a previously published data set was re-evaluated, with covariance terms properly included in the calculation of uncertainties. It was shown that covariance effects may yield a significant reduction in uncertainty estimates, both for blank quantities and for blank corrected results. For series measurements on a standard material, it was also shown that the distribution of individual corrected isotope delta values around the average value was approximately normal, with its standard deviation equal to the estimated standard uncertainty of the corrected values. In most cases, it was observed that the regression and subtraction methods yield approximately the same blank corrected average values and uncertainties, regardless of method selected for estimation of blank quantities. PMID- 23682630 TI - Effect of packaging materials and storage on major volatile compounds in three Australian native herbs. AB - Lemon myrtle, anise myrtle, and Tasmanian pepper leaf are commercial Australian native herbs with a high volatile or essential oil content. Packaging of the herbs in high- or low-density polyethylene (HDPE and LDPE) has proven to be ineffective in preventing a significant loss of volatile components on storage. This study investigates and compares the effectiveness of alternate high-barrier property packaging materials, namely, polyvinylidene chloride coated polyethylene terephthalate/casted polypropylene (PVDC coated PET/CPP) and polyethylene terephthalate/polyethylene terephthalate/aluminum foil/linear low-density polyethylene (PET/PET/Foil/LLDPE), in prevention of volatile compound loss from the three native herbs stored at ambient temperature for 6 months. Concentrations of major volatiles were monitored using gas chromatography-mass spectrometry (GC MS) techniques. After 6 months of storage, the greatest loss of volatiles from lemon myrtle was observed in traditional LDPE packaging (87% loss) followed by storage in PVDC coated PET/CPP (58% loss) and PET/PET/Foil/LLDPE (loss of 23%). The volatile loss from anise myrtle and Tasmanian pepper leaf stored in PVDC coated PET/CPP and PET/PET/Foil/LLDPE packaging was <30%. This study clearly indicates the importance of selecting the correct packaging material to retain the quality of herbs with high volatile content. PMID- 23682632 TI - Modulation of the photophysical properties of curcumin in nonionic surfactant (Tween-20) forming micelles and niosomes: a comparative study of different microenvironments. AB - The modulation of the photophysical properties of curcumin inside two different types of microenvironments provided by nonionic surfactant forming micelles and vesicles (niosomes) has been investigated using steady state and time-resolved fluorescence spectroscopy. The formation of small unilamellar Tween 20/cholesterol niosomes with narrow size distribution has been successfully demonstrated by means of dynamic light scattering (DLS) and transmission electron microscopy (TEM) techniques. Our results indicate that niosomes are a better possible delivery system than the conventional surfactants forming normal micelles to suppress the level of degradation of curcumin. The enhanced fluorescence intensity along with the significant blue-shift in the emission maxima of curcumin upon encapsulation into the hydrophobic microenvironments of micelles and niosomes is a consequence of the reduced interaction of curcumin with the water molecules. We found that the more rigid and confined microenvironment of niosomes enhances the steady state fluorescence intensity along with the fluorescence lifetime of curcumin more than in micelles. The rigidity of the niosome membrane which arises basically due to the presence of cholesterol molecules increases the level of interaction between curcumin and the oxoethylene units of Tween-20 molecules. It is also possible for the hydroxyl groups of the cholesterol moieties to form intermolecular hydrogen bonds with curcumin to perturb nonradiative deactivation mechanism through excited state intramolecular hydrogen atom transfer (ESIHT). PMID- 23682633 TI - Hemophagocytic lymphohistiocytosis in adults. PMID- 23682634 TI - Driving performance in persons with mild to moderate symptoms of multiple sclerosis. AB - PURPOSE: To investigate whether driving performance is impaired in persons with mild to moderate multiple sclerosis (MS). METHOD: This study included 15 persons with MS (pwMS) and 17 healthy controls. The MS group exhibited mild to moderate impairments on the Expanded Disability Status Scale (median, Q1-Q3; 3.5, 2.5-4). The driving simulation required participants to drive in daily traffic while attending to a divided attention (DA) task. Computerized measures on the driving task included number of accidents, tickets, speed maintenance, standard deviation of lateral position, and time to collision. Response times and accuracy on the DA task were also computer generated. Additionally, pwMS completed a clinical evaluation encompassing motor, functional, visual, psychosocial and cognitive tests. RESULTS: No differences between healthy controls and pwMS were observed on all measures of the primary driving task. PwMS performed worse than healthy controls on DA response time (3.10 s, 2.87-3.68 versus 2.15 s, 2.04-2.43; p = 0.001) and accuracy (15 correct answers, 11-18 versus 24 correct answers, 22-25; p < 0.0001). Depression was significantly associated with time to collision (r = 0.77; p < 0.01). CONCLUSIONS: Subjects with mild to moderate MS are able to prioritize the driving task above the DA task. The relationship between depression and driving performance in MS merits further investigation. PMID- 23682635 TI - Salmonella enterica Typhimurium infection causes metabolic changes in chicken muscle involving AMPK, fatty acid and insulin/mTOR signaling. AB - Salmonella enterica serovar Typhimurium (Salmonella Typhimurium) infection of chickens that are more than a few days old results in asymptomatic cecal colonization with persistent shedding of bacteria. We hypothesized that while the bacterium colonizes and persists locally in the cecum it has systemic effects, including changes to metabolic pathways of skeletal muscle, influencing the physiology of the avian host. Using species-specific peptide arrays to perform kinome analysis on metabolic signaling pathways in skeletal muscle of Salmonella Typhimurium infected chickens, we have observed key metabolic changes that affected fatty acid and glucose metabolism through the 5'-adenosine monophosphate activated protein kinase (AMPK) and the insulin/mammalian target of rapamycin (mTOR) signaling pathway. Over a three week time course of infection, we observed changes in the phosphorylation state of the AMPK protein, and proteins up and down the pathway. In addition, changes to a large subset of the protein intermediates of the insulin/mTOR pathway in the skeletal muscle were altered by infection. These changes occur in pathways with direct effects on fatty acid and glucose metabolism. This is the first report of significant cellular metabolic changes occurring systemically in chicken due to a Salmonella infection. These results have implications not only for animal production and health but also for the understanding of how Salmonella infection in the intestine can have widespread, systemic effects on the metabolism of chickens without disease-like symptoms. PMID- 23682636 TI - Adherence to screening guidelines for hepatitis C among HIV-positive patients. PMID- 23682637 TI - Reply: "comment on Staphylococcus cell number discrepancy between culture-based and non-culture-based analyses: quantitative effect of face washing on cutaneous resident microbiota in female subjects who wear make-up". PMID- 23682638 TI - Simultaneous monitoring of biofilm growth, microbial activity, and inorganic deposits on surfaces with an in situ, online, real-time, non-destructive, optical sensor. AB - Deposits on surfaces in water-bearing systems, also known as 'fouling', can lead to substantial losses in the performance of industrial processes as well as a decreased product quality. Early detection and localization of such deposits can, to a considerable extent, save such losses. However, most of the surfaces that become fouled, for example, in process water pipes, membrane systems, power plants, and food and beverage industries, are difficult to access and analyses conducted on the water phase do not reveal the site or extent of deposits. Furthermore, it is of interest to distinguish biological from non-biological deposits. Although they usually occur together, different countermeasures are necessary. Therefore, sensors are required that indicate the development of surface fouling in real-time, non-destructively, and in situ, preferably allowing for discrimination between chemical and/or biological deposits. In this paper, an optical deposit sensor is presented which fulfills these requirements. Based on multiple fluorescence excitation emission matrix analysis, it detects autofluorescence of amino acids as indicators of biomass. Autofluorescence of nicotinamide adenine dinucleotide + hydrogen is interpreted as an indicator of biological activity, thus it acts as a viability marker, making the method suited for assessing the efficacy of disinfection treatments. Scattering signals from abiotic deposits such as calcium carbonate or corrosion products can clearly be distinguished from biotic substances and monitored separately. The sensor provides an early warning of fouling, allowing for timely countermeasures to be deployed. It also provides an assessment of the success of cleaning treatments and is a promising tool for integrated antifouling strategies. PMID- 23682639 TI - No effects of short-term sleep restriction, in a controlled feeding setting, on lipid profiles in normal-weight adults. AB - Short sleep has been associated with cardiovascular risk. The aim of this study was to determine the impact of short-term sleep restriction on lipid profiles and resting blood pressure factors in young, normal-weight individuals (14 men, 13 women). Participants were randomized to five nights of either habitual (9 h) or short (4 h) sleep in a cross-over design separated by a 3-week washout period. There was no sleep * day interaction on lipid profile and blood pressure. Short term sleep restriction does not alter lipid profiles and resting blood pressure in healthy, normal-weight individuals. The association between short sleep and increased cardiovascular risk reported in the epidemiological literature may be the result of long-term sleep restriction and poor lifestyle choices. PMID- 23682640 TI - Dynamic associations of negative mood and smoking across the development of smoking in adolescence. AB - Self-medication models of smoking posit that the emotional benefits of smoking reinforce and maintain cigarette use, yet research demonstrates both positive and adverse affective consequences of smoking. The current study examined longitudinal changes in adolescent mood variability and overall negative mood at various stages of smoking behavior to inform understanding of the etiology of adolescent smoking. Participants included 461 adolescents (M age = 15.67 years, SD = 0.61; 55% girls, 56.8% White) drawn from a longitudinal study of adolescent smoking. Youth provided data on smoking behavior at baseline and a 15-month follow-up wave. Ecological momentary assessments were used to measure overall levels of negative mood as well as within-person mood fluctuations (i.e., negative mood variability) at each wave. Findings revealed that smoking-mood relations vary across different stages of smoking behavior. Youth who rapidly escalated in their smoking during the study experienced improved mood regulation (for girls) and improved overall mood (for boys) as smoking increased. However, mood improvements were not observed among youth with sustained heavy use and symptoms of dependence. The current data argue for a model of smoking that accounts for changes in risk and maintenance factors at different points along the developmental trajectory of smoking, involving elements of both self medication and dependence. PMID- 23682641 TI - Reference values of oxidative stress biomarkers in healthy newborns. AB - BACKGROUND: Although oxidative stress-related diseases mostly affect neonates with extremely low birthweight, healthy preterm and term newborns may also be at risk of oxidative damage. There have been studies concerning factors that affect the level of oxidative stress biomarkers in term and preterm neonates, but there has not been a study of the reference values of oxidative stress biomarkers in healthy newborns having no risk factors. The aim of the present study was to clarify this issue. METHODS: Serum total antioxidant capacity (TAC) and total oxidant status (TOS) were assessed by Erel's method. TAC and TOS values were measured in 100 term infants, 57 boys and 43 girls, with a mean gestational age of 39 weeks and a mean birthweight of 3174 g. RESULTS: All blood samples for TAC and TOS were taken on the fifth day. The median TAC and TOS values for all male and female neonates were 1.92 mmol Trolox equivalent/L (min-max; 1.41-2.09) and 12.93 MUmol H2O2/L (min-max: 3.01-53.94), respectively. TAC and TOS values were not statistically different in male and female newborns. TAC and TOS values were not statistically different in newborns who had been delivered via a vaginal route or by cesarean section. CONCLUSION: This study can be used as a guide for the reference range of TAC and TOS values for healthy term newborns. PMID- 23682642 TI - Intermittent absent end diastolic velocity of the umbilical artery: antenatal and neonatal characteristics and indications for delivery. AB - OBJECTIVE: To check whether there is a difference in indications for delivery, antepartum and neonatal characteristics in intermittent absent end diastolic velocity (iAEDV) compared to persistent absent or reversed end diastolic velocity (pA/REDV). METHODS: A retrospective study of 109 patients with iAEDV or pA/REDV from 19 to 39 weeks. The delivery indication was classified as maternal or fetal. The primary antepartum and maternal characteristics were age, parity, AMA, chronic hypertension, PEC, thrombophilia, lupus, diabetes, smoker, placenta previa, gestational age (GA) at diagnosis of IUGR and/or SGA, GA at diagnosis of elevated S/D, iAEDV or pA/REDV, GA at delivery, minimal/absent variability day of delivery, BPP <= 6 prior to delivery. The primary neonatal outcomes were birth weight, arterial cord pH, neonatal demise, necrotizing enterocolitis, intraventricular hemorrhage and length of stay in the NICU. RESULTS: Fetuses with iAEDV were diagnosed with an elevated S/D at a later GA (29.6 vs. 27.5 weeks, p < 0.03), delivered at a later GA (31.6 vs. 29.7 weeks, p < 0.01), had a higher birth weight (1336.6 vs. 933 g, p < 0.0004), were more likely to be delivered for maternal indications (42.9% vs. 20.27%, p < 0.01), had a higher cord arterial pH (7.28 vs. 7.21, p < 0.002) and were less likely to have an arterial pH at birth <7.2 (0% vs. 34.1%, p < 0.002). CONCLUSIONS: Although fetuses with iAEDV have an improved antenatal course as compared with pA/REDV, indications for delivery are more likely to be maternal and adverse outcome is common. PMID- 23682643 TI - Misuse of journal impact factors in scientific assessment. PMID- 23682644 TI - Yes, we can---achieve adequate early postnatal growth in very preterm infants. PMID- 23682645 TI - Diagnostic reliability of sterile speculum exam for rupture of membranes. PMID- 23682646 TI - A pentaplex PCR assay for detection and characterization of Vibrio vulnificus and Vibrio parahaemolyticus isolates. AB - Vibrio parahaemolyticus and Vibrio vulnificus are the leading causes of seafood related illnesses and also can cause wound infections. These bacteria often co exist in marine and estuarine environments. However, there have been no reported protocols that can detect and characterize (i.e. pathogenic or nonpathogenic) them in a single PCR. In this study, we developed a pPCR assay with a combination of two species-specific and three pathogenic-specific PCR primers to simultaneously detect virulent (viuB in V. vulnificus and tdh/trh in V. parahaemolyticus) and nonvirulent (vvhA in V. vulnificus and tlh in V. parahaemolyticus) markers of the two species in bacterial isolates. The assay was validated by three methods. First, the pPCR was used to characterize 300 bacterial isolates consisting of seven reference strains and 293 environmental strains isolated from the Gulf of Mexico water. Results were compared with characterizations based on single-gene PCR amplifications and previously published multiplex PCR protocols. Second, 51 isolates characterized with the pPCR were analysed by 16S rRNA sequencing to confirm any false-negative/positive reaction. Finally, the effectiveness of the assay for heterogeneous bacterial samples was validated. The pPCR correctly characterized isolates from the Gulf with an efficiency of 96.6-98.7%. PMID- 23682647 TI - Defined surface immobilization of glycosaminoglycan molecules for probing and modulation of cell-material interactions. AB - As one important category of biological molecules on the cell surface and in the extracellular matrix (ECM), glycosaminoglycans (GAGs) have been widely studied for biomedical applications. With the understanding that the biological functions of GAGs are driven by the complex dynamics of physiological and pathological processes, methodologies are desired to allow the elucidation of cell-GAG interactions with molecular level precision. In this study, a microtiter plate based system was devised through a new surface modification strategy involving polydopamine (PDA) and GAG molecules functionalized with hydrazide chemical groups. A small library of GAGs including hyaluronic acid (with different molecular weights), heparin, and chondroitin sulfate was successfully immobilized via defined binding sites onto the microtiter plate surface under facile aqueous conditions. The methodology then allowed parallel studies of the GAG-modified surfaces in a high-throughput format. The results show that immobilized GAGs possess distinct properties to mediate protein adsorption, cell adhesion, and inflammatory responses, with each property showing dependence on the type and molecular weight of specific GAG molecules. The PDA-assisted immobilization of hydrazide-functionalized GAGs allows biomimetic attachment of GAG molecules and retains their bioactivity, providing a new methodology to systematically probe fundamental cell-GAG interactions to modulate the bioactivity and biocompatibility of biomaterials. PMID- 23682648 TI - Development of worker inhalation derived no effect levels for tungsten compounds. AB - Under the European Community (EC) Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), the risk to humans may be considered controlled if the estimated exposure levels to a substance do not exceed the appropriate derived no-effect level (DNEL). In order to address worker exposure, DNELs are derived for the worker population. The most significant route of exposure to workers to both soluble and sparingly soluble tungsten substances is through inhalation. In order to meet the REACH registration requirements, occupational long-term inhalation DNELs were developed according to the European Chemical Agency (ECHA) REACH guidance on characterization of dose-response for human health. The inhalation DNELlong-term for sodium tungstate, from which all other soluble tungsten substance DNELs were derived, is 3 mg sodium tungstate/m(3) (1.7 mg W/m(3)), and the inhalation DNELlong-term for tungsten blue oxide, from which all other sparingly soluble tungsten substance DNELs were derived, is 7.3 mg tungsten blue oxide/m(3) (5.8 mg tungsten/m(3)). Although derived using different methodologies and supported by different studies, the occupational inhalation DNELslong-term for soluble and sparingly soluble tungsten compounds are similar to the current National Institute for Occupational Safety and Health (NIOSH) recommended exposure level (REL) and the American Conference of Industrial Hygienists (ACGIH) threshold limit value (TLV) 8-h time weighted average (TWA) of 1 mg tungsten/m(3) for soluble tungsten compounds and 5 mg tungsten/m(3) as metal and insoluble tungsten compounds. PMID- 23682649 TI - Bacterial abundance and composition in marine sediments beneath the Ross Ice Shelf, Antarctica. AB - Marine sediments of the Ross Sea, Antarctica, harbor microbial communities that play a significant role in the decomposition, mineralization, and recycling of organic carbon (OC). In this study, the cell densities within a 153-cm sediment core from the Ross Sea were estimated based on microbial phospholipid fatty acid (PLFA) concentrations and acridine orange direct cell counts. The resulting densities were as high as 1.7 * 107 cells mL-1 in the top ten centimeters of sediments. These densities are lower than those calculated for most near-shore sites but consistent with deep-sea locations with comparable sedimentation rates. The delta13C measurements of PLFAs and sedimentary and dissolved carbon sources, in combination with ribosomal RNA (SSU rRNA) gene pyrosequencing, were used to infer microbial metabolic pathways. The delta13C values of dissolved inorganic carbon (DIC) in porewaters ranged downcore from -2.50/00 to -3.70/00, while delta13C values for the corresponding sedimentary particulate OC (POC) varied from -26.20/00 to -23.10/00. The delta13C values of PLFAs ranged between -290/00 and -350/00 throughout the sediment core, consistent with a microbial community dominated by heterotrophs. The SSU rRNA gene pyrosequencing revealed that members of this microbial community were dominated by beta-, delta-, and gamma Proteobacteria, Actinobacteria, Chloroflexi and Bacteroidetes. Among the sequenced organisms, many appear to be related to known heterotrophs that utilize OC sources such as amino acids, oligosaccharides, and lactose, consistent with our interpretation from delta13CPLFA analysis. Integrating phospholipids analyses with porewater chemistry, delta13CDIC and delta13CPOC values and SSU rRNA gene sequences provides a more comprehensive understanding of microbial communities and carbon cycling in marine sediments, including those of this unique ice shelf environment. PMID- 23682650 TI - Zinc modulates drought-induced biochemical damages in tea [Camellia sinensis (L) O Kuntze]. AB - Zinc (Zn) is an essential micronutrient that affects the growth and productivity of tea plant. Drought stress causes various biochemical and physiological damages in plants. The present study aims at understanding the role of Zn in modulating drought stress induced growth and biochemical damages in tea plant. The results of the present investigation demonstrated that drought-induced decrease in relative water content (RWC), dry mass of leaf, and antioxidants such as ascorbate and glutathione in the tested tea clones (TV-1, TV-17, and TV-29) was minimized by zinc sulfate (ZnSO4) treatment before water withholding for 7 days. Increase in phenolic content with decrease in hydrogen peroxide (H2O2) and lipid peroxidation and differential activities of enzymes such as superoxide dismutase (SOD), catalase (CAT), peroxidase (POX), polyphenol peroxidase (PPO), glutathione reductase (GR), and ascorbate peroxidase (APX) with concomitant increased Zn uptake in leaf suggested Zn modulates drought-mediated biochemical damages in tea plant. PMID- 23682651 TI - The Skin Picking Impact Scale: Factor structure, validity and development of a short version. AB - In the present study, we examined the psychometric properties of the Skin Picking Impact Scale (SPIS; Keuthen, Deckersbach, Wilhelm et al., 2001), a 10 item self report questionnaire designed to assess the psychosocial impact of skin picking disorder (SPD). Participants were 650 individuals who met criteria for SPD in an online survey. Exploratory and confirmatory factor analyses demonstrated a unitary factor structure with high internal consistency (alpha = 0.94). Consequently, we constructed an abbreviated 4-item version that retained good internal consistency (alpha = 0.87) and a robust factor structure. Both the short and the full versions demonstrated discriminant and convergent/concurrent validity. In conclusion, the findings indicate that both versions are psychometrically sound measures of SPD related psychosocial impact; however, some potential limitations of the full scale are discussed. PMID- 23682652 TI - Molecular energetics of alkyl pyrrolecarboxylates: calorimetric and computational study. AB - The pyrrole subunit plays an important role in material science as the building block of polypyrroles, an important representative class of conducting polymers, which found widely applications in the area of new materials due to their chemical, thermal, and electrical properties associated with their easiness and low cost of production, making them especially promising for commercial applications. The energetic characterization of this kind of molecules provides information concerning stability, reactivity, and biodegrability of chemical compounds in environment being, for example, helpful in choosing the most adequate method for their elimination by converting the waste into harmless compounds or even decreasing the production of toxic substances in industrial processes. This work reports a combination of calorimetric and computational determinations of several alkyl pyrrolecarboxylates (alkyl = methyl or ethyl) whose main purpose is the calculation of their standard (p degrees = 0.1 MPa) molar enthalpies of formation, in the gaseous phase, at T = 298.15 K. Experimentally, for methyl 1-pyrrolecarboxylate (M1PC), methyl 2 pyrrolecarboxylate (M2PC), and ethyl 2-pyrrolecarboxylate (E2PC), these values were derived from the standard (p degrees = 0.1 MPa) molar enthalpies of formation, in the condensed phase, DeltafHm degrees (cr,l), at T = 298.15 K, obtained by static bomb combustion calorimetry, and from the standard molar enthalpies of phase transition, Deltacr,l(g)Hm degrees , at T = 298.15 K, determined by high-temperature Calvet microcalorimetry. Standard ab initio molecular calculations, at the G3(MP2)//B3LYP level, were performed, and the standard enthalpies of formation of these three compounds were estimated. A very good agreement between the calculated and the experimental data was obtained. Thereby, we have extended these calculations to other alkyl pyrrolecarboxylates, namely, ethyl 1-pyrrolecarboxylate (E1PC), methyl 3-pyrrolecarboxylate (M3PC), and ethyl 3-pyrrolecarboxylate (E3PC), whose study was not performed experimentally. The computational analysis, at the B3LYP/6-31G(d) level of theory, of the six molecules allowed a detailed inspection and a better knowledge about their molecular structure and geometrical parameters. PMID- 23682653 TI - A novel application of infrared imaging for the diagnosis of death by fire. AB - This paper demonstrates a novel and simple technique for the diagnosis of death by fire using a digital infrared (IR) camera system. At autopsy, the inhalation of soot by a fire victim is a definite indicator proving a vital reaction during the fire. However, there can be difficulties in confirming the presence of soot because of the relative lack of soot or the similarity in color between soot and surrounding tissues. To evaluate the effectiveness of IR imaging at autopsy, we acquired internal images of the respiratory and gastrointestinal system by both an ordinary color and IR cameras. Using our method, the inhaled soot is visible as black particles or deposits, while the blood is transparent and the surrounding tissue is whitened. This technique enables the detection of normally undiscriminating soot in an ordinary color image. This is the first report suggesting the usefulness of IR imaging in forensic autopsy for the diagnosis of death by fire. PMID- 23682654 TI - P2X3 receptor: a novel 'CASKade' of signaling? PMID- 23682655 TI - Two cases of baclofen-induced encephalopathy in hemodialysis and peritoneal dialysis patients. AB - Hiccups are a spasmodic contraction of the diaphragm and usually transient phenomenon that affects nearly everyone. When hiccups develop, the patients are administrated antispastic agent, such as baclofen. Baclofen is widely used for the treatment of this spastic movement disorders. Also, baclofen is a gamma aminobutyric acid (GABA) derivative that induces presynaptic motor neuron inhibition and produces a central antispastic response. Baclofen toxicity is rare and has been reported with intrathecal pump and orally administered baclofen, particularly in patients with poor renal function. Herein, we report two cases of encephalopathy in hemodialysis and peritoneal dialysis patients who received low doses of baclofen for persistent hiccups. PMID- 23682656 TI - Understanding the biological context of NS5A-host interactions in HCV infection: a network-based approach. AB - Hepatitis C virus (HCV) is a major cause of chronic liver disease. HCV NS5A protein plays an important role in HCV infection through its interactions with other HCV proteins and host factors. In an attempt to further our understanding of the biological context of protein interactions between NS5A and host factors in HCV pathogenesis, we generated an extensive physical interaction map between NS5A and cellular factors. By combining a yeast two-hybrid assay with comprehensive literature mining, we built the NS5A interactome composed of 132 human proteins that interact with NS5A. These interactions were integrated into a high-confidence human protein interactome (HPI) with the help of the TargetMine data warehouse system to infer an overall protein interaction map linking NS5A with the components of the host cellular networks. The NS5A-host interactions that were integrated with the HPI were shown to participate in compact and well connected cellular networks. Functional analysis of the NS5A "infection" network using TargetMine highlighted cellular pathways associated with immune system, cellular signaling, cell adhesion, cellular growth and death among others, which were significantly targeted by NS5A-host interactions. In addition, cellular assays with in vitro HCV cell culture systems identified two ER-localized host proteins RTN1 and RTN3 as novel regulators of HCV propagation. Our analysis builds upon the present understanding of the role of NS5A protein in HCV pathogenesis and provides potential targets for more effective anti-HCV therapeutic intervention. PMID- 23682657 TI - Comment on Staphylococcus cell number discrepancy between culture-based and non culture-based analyses: quantitative effect of face washing on cutaneous resident microbiota in female subjects who wear make-up. PMID- 23682658 TI - Genetic approaches to neural circuits in the mouse. AB - To understand the organization and assembly of mammalian brain circuits, we need a comprehensive tool set that can address the challenges of cellular diversity, spatial complexity at synapse resolution, dynamic complexity of circuit operations, and multifaceted developmental processes rooted in the genome. Complementary to physics- and chemistry-based methods, genetic tools tap into intrinsic cellular and developmental mechanisms. Thus, they have the potential to achieve appropriate spatiotemporal resolution and the cellular-molecular specificity necessary for observing and probing the makings and inner workings of neurons and neuronal circuits. Furthermore, genetic analysis will be key to unraveling the intricate link from genes to circuits to systems, in part through systematic targeting and tracking of individual cellular components of neural circuits. Here we review recent progress in genetic tool development and advances in genetic analysis of neural circuits in the mouse. We also discuss future directions and implications for understanding brain disorders. PMID- 23682659 TI - Superior colliculus and visual spatial attention. AB - The superior colliculus (SC) has long been known to be part of the network of brain areas involved in spatial attention, but recent findings have dramatically refined our understanding of its functional role. The SC both implements the motor consequences of attention and plays a crucial role in the process of target selection that precedes movement. Moreover, even in the absence of overt orienting movements, SC activity is related to shifts of covert attention and is necessary for the normal control of spatial attention during perceptual judgments. The neuronal circuits that link the SC to spatial attention may include attention-related areas of the cerebral cortex, but recent results show that the SC's contribution involves mechanisms that operate independently of the established signatures of attention in visual cortex. These findings raise new issues and suggest novel possibilities for understanding the brain mechanisms that enable spatial attention. PMID- 23682662 TI - Neuroimaging and ADHD: fMRI, PET, DTI findings, and methodological limitations. AB - Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by pervasive and developmentally inappropriate levels of inattention, impulsivity, and hyperactivity. There is no conclusive cause of ADHD although a number of etiologic theories have been advanced. Research across neuroanatomical, neurochemical, and genetic disciplines collectively support a physiological basis for ADHD and, within the past decade, the number of neuroimaging studies concerning ADHD has increased exponentially. The current selective review summarizes research findings concerning ADHD using functional magnetic resonance imaging (fMRI), positron emission tomography (PET), and diffusion tensor imaging (DTI). Although these technologies and studies offer promise in helping to better understand the physiologic underpinnings of ADHD, they are not without methodological problems, including inadequate sensitivity and specificity for psychiatric disorders. Consequently, neuroimaging technology, in its current state of development, should not be used to inform clinical practice. PMID- 23682660 TI - From atomic structures to neuronal functions of g protein-coupled receptors. AB - G protein-coupled receptors (GPCRs) are essential mediators of signal transduction, neurotransmission, ion channel regulation, and other cellular events. GPCRs are activated by diverse stimuli, including light, enzymatic processing of their N-termini, and binding of proteins, peptides, or small molecules such as neurotransmitters. GPCR dysfunction caused by receptor mutations and environmental challenges contributes to many neurological diseases. Moreover, modern genetic technology has helped identify a rich array of mono- and multigenic defects in humans and animal models that connect such receptor dysfunction with disease affecting neuronal function. The visual system is especially suited to investigate GPCR structure and function because advanced imaging techniques permit structural studies of photoreceptor neurons at both macro and molecular levels that, together with biochemical and physiological assessment in animal models, provide a more complete understanding of GPCR signaling. PMID- 23682661 TI - Efficacy, safety and tolerability of GSK2190915, a 5-lipoxygenase activating protein inhibitor, in adults and adolescents with persistent asthma: a randomised dose-ranging study. AB - BACKGROUND: GSK2190915 is a high affinity 5-lipoxygenase-activating protein inhibitor being developed for the treatment of asthma. The objective of this study was to evaluate GSK2190915 efficacy, dose-response and safety in subjects with persistent asthma treated with short-acting beta2-agonists (SABAs) only. METHODS: Eight-week multicentre, randomised, double-blind, double-dummy, stratified (by age and smoking status), parallel-group, placebo-controlled study in subjects aged >=12 years with a forced expiratory volume in 1 second (FEV1) of 50-85% predicted. Subjects (n = 700) were randomised to receive once-daily (QD) oral GSK2190915 (10-300 mg), twice-daily inhaled fluticasone propionate 100 MUg, oral montelukast 10 mg QD or placebo. The primary endpoint was mean change from baseline (randomisation) in trough (morning pre-dose and pre-rescue bronchodilator) FEV1 at the end of the 8-week treatment period. Secondary endpoints included morning and evening peak expiratory flow, symptom-free days and nights, rescue-free days and nights, day and night-time symptom scores, day and night-time rescue medication use, withdrawals due to lack of efficacy, Asthma Control Questionnaire and Asthma Quality of Life Questionnaire scores. RESULTS: For the primary endpoint, there was no statistically significant difference between any dose of GSK2190915 QD and placebo. However, repeated measures sensitivity analysis demonstrated nominal statistical significance for GSK2190915 30 mg QD compared with placebo (mean difference: 0.115 L [95% confidence interval: 0.00, 0.23], p = 0.044); no nominally statistically significant differences were observed with any of the other doses. For the secondary endpoints, decreases were observed in day-time symptom scores and day-time SABA use for GSK2190915 30 mg QD versus placebo (p <= 0.05). No dose-response relationship was observed for the primary and secondary endpoints across the GSK2190915 dose range studied; the 10 mg dose appeared to be sub-optimal. GSK2190915 was associated with a dose-dependent reduction in urinary leukotriene E4. The profile and incidence of adverse events were similar between treatment groups. CONCLUSION: Efficacy was demonstrated for GSK2190915 30 mg compared with placebo in day-time symptom scores and day-time SABA use. No additional improvement on efficacy endpoints was gained by administration of GSK2190915 doses greater than 30 mg. GSK2190915 was well-tolerated. These results may support further studies with GSK2190915 30 mg. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01147744. PMID- 23682663 TI - Alterations in the relationship between hippocampal volume and episodic memory performance in preterm children. AB - This study examines the relationship between episodic memory and hippocampal volume (magnetic resonance imaging [MRI] volumetry) in preterm children with uncomplicated neonatal courses (<34 weeks of gestation, birth weight <2,000 g) and controls (7-11 years). To examine episodic memory performance and retrieval processes, neuropsychological tests and a recognition experiment were used. Although preterm children showed reduced hippocampal volumes relative to controls by 12%, episodic memory accuracy was not reduced. However, only in controls hippocampal volume correlated with some measures of episodic memory. Together, behavioral and MRI results indicate a minor functional specificity of the hippocampus regarding episodic memory functions in preterm children. PMID- 23682664 TI - Age, sex, and performance influence the visuospatial working memory network in childhood. AB - This study describes the influence of age, sex, and working memory (WM) performance on the visuospatial WM network. Thirty-nine healthy children (7-12 years) completed a dot location functional magnetic resonance imaging (fMRI) task. Percent signal change measured the intensity and laterality indices measured the asymmetry of activation in frontal and parietal brain regions. Old children showed greater intensity of activation in parietal regions than young children but no differences in lateralization were observed. Intensity of activation was similar across sex and WM performance groups. Girls and high WM performers showed more right-sided lateralization of parietal regions than boys and low WM performers. PMID- 23682665 TI - Exploring the development of the mirror neuron system: finding the right paradigm. AB - Due to its ability to map an observed action onto the observer's own cortical motor circuits, the mirror neuron system (MNS) has been implicated in many facets of social cognition. As such, achieving an understanding of the typical development of this intriguing brain system seems obvious. Only now, however, are studies attempting to explore the processes and principles behind the emergence of the MNS. This article critically reviews a number of experimental paradigms employed in this endeavor. We conclude by suggesting that future neuroscientific investigations should incorporate a response-stimulus procedure, whereby action execution results in, not from, novel sensory stimuli. PMID- 23682666 TI - Three-month-olds' brain responses to upright and inverted faces and cars. AB - We examined the processing of upright and inverted faces and cars in 3-month-old infants applying an event-related-potentials paradigm. The current study is the first to contrast human faces with an object category, cars, in a within-subjects design with infants. N290 amplitude was larger for inverted than upright faces, whereas no inversion effect was observed for cars. Moreover, N290 latency was enhanced for inverted faces and cars. This indicates that neural processing may already be partly face-specific in young infants. PMID- 23682667 TI - Early detection of treatment induced cardiac toxicity - can we do better? PMID- 23682668 TI - A new concept in polymeric thin-film composite nanofiltration membranes with antibacterial properties. AB - A new, thin film, biofouling resistant, nanofiltration (NF) membrane was fabricated with two key characteristics, viz. a low rate of silver (Ag) release and long-lasting antibacterial properties. In the new approach, nanoparticles were embedded completely in a polymeric thin-film layer. A comparison was made between the new thin-film composite (TFC), NF membrane and thin-film nanocomposite (TFN), and antibacterial NF membranes. Both types of NF membrane were fabricated by interfacial polymerization on a polysulphone sublayer using m phenylenediamine and trimesoyl chloride as an amine monomer and an acid chloride monomer, respectively. Energy dispersive X-ray (EDX) microanalysis demonstrated the presence of Ag nanoparticles. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) were used to study the cross-sectional and surface morphological properties of the NF membranes. Permeability and salt rejection were tested using a dead-end filtration cell. Ag leaching from the membranes was measured using inductively coupled mass spectrometry (ICP-MS). Morphological studies showed that the TFC NF membranes had better thin-film formation (a more compact structure and a smoother surface) than TFN NF membranes. Performance experiments on TFC NF membranes revealed that permeability was good, without sacrificing salt rejection. The antibacterial properties of the fabricated membranes were tested using the disk diffusion method and viable plate counts. The antibiofouling properties of the membranes were examined by measuring the quantity of bacterial cells released from the biofilm formed (as a function of the amount of biofilm present). A more sensitive surface was observed compared to that of a typical antibacterial NF membrane. The Ag leaching rates were low, which will likely result in long-lasting antibacterial and biofouling resistant properties. PMID- 23682669 TI - Abducens palsy as a clue of unexpected contralateral cerebral sinovenous thrombosis. PMID- 23682670 TI - The best way to prevent cytomegalovirus infection after liver transplantation: the debate goes on. PMID- 23682671 TI - The effect of rabbit antithymocyte globulin on human mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) possess immunomodulatory properties which are of key interest for their application in autoimmunity and transplantation. In transplantation, administration of MSCs has shown promising results in preclinical models and has recently moved to clinical trials. Therefore, it is important to study the interactions between MSCs and immunosuppressive drugs currently used in transplantation. We aimed to analyze the effect of rabbit antithymocyte globulin (rATG) MSCs. MSCs were obtained from perirenal fat of kidney donors and exposed to ranging doses of rATG (Thymoglobulin((r)) , Genzyme; 0.5-100 MUg/ml). Binding of rATG, effects on viability and susceptibility to be killed by cytotoxic lymphocytes as well as effects on their immunosuppressive potential of MSCs were tested. rATG binds dose-dependently to MSCs. This binding was associated with slightly impaired viability after 48 and 72 h when compared with nonexposed MSCs. In contrast to nontreated MSCs, rATG preexposed MSCs were susceptible to be lysed by cytokine-activated CD8(+) cytotoxic cells and NKT cells. The capacity of MSCs to suppress the proliferation of anti-CD3/CD28 activated CD4 and CD8 T cells were reduced by the presence of rATG in the culture. rATG reduces the viability and antiproliferative capacity of MSCs in a dose-dependent manner and converts them into targets for CD8 T cells and NKT cell lysis. PMID- 23682672 TI - Family demands, social support and family functioning in Taiwanese families rearing children with Down syndrome. AB - BACKGROUND: Down syndrome (DS) affects not only children but also their families. Much remains to be learned about factors that influence how families of children with DS function, especially families in non-Western populations. The purpose of this cross-sectional, correlational study was to examine how family demographics, family demands and social support relate to family functioning as well as the potential mediating effect of social support on the relationship between family demands and family functioning in Taiwanese families of children with DS. METHOD: One hundred and fifty-five parents (80 mothers and 75 fathers) from 83 families independently completed mailed questionnaires. Data were analysed using a principal component analysis and mixed linear modelling. RESULTS: Families having older children with DS, greater parental education, higher family income, fewer family demands and greater social support contributed to healthier family functioning. Social support partially mediated the effects of family demands on family functioning. CONCLUSIONS: Family demographics, family demands and social support appear to be important factors that may play a critical role in how Taiwanese families respond to the birth of a child with DS. Care of children with DS and their families is likely to be more effective if professionals working with these families are aware of factors that contribute to healthy family functioning. PMID- 23682673 TI - Massive floral display affects insect visits but not pollinator-mediated pollen transfer in Rhododendron ferrugineum. AB - Fragmentation of natural vegetation creates one of the largest threats to plant pollinator interactions. Although fragmentation impacts on plant populations have been explored in many, mainly herbaceous, species, the response of wild mass flowering species is poorly known. Here, we studied 28 heathland patches dominated by the mass-flowering shrub Rhododendron ferrugineum, each presenting different R. ferrugineum floral display sizes (total inflorescence number per patch) and patch isolation (median distance to the three nearest patches). We assessed the impacts of these two factors on (i) heathland patch visitor assemblage (considering R. ferrugineum versus surrounding community) and (ii) R. ferrugineum flower visitation rate and pollen transfer limitation (comparing seed set from emasculated to pollen-supplemented flowers). We found that diversity and abundance of bees visiting R. ferrugineum in heathland patches significantly decreased with decreasing R. ferrugineum floral display, while overall visitor density per patch and flower visitation rate increased. Moreover, a decrease in massive floral display and increase in patch isolation resulted in reduced visitor density in the surrounding community. Even in patches with few individuals, we found disproportionate visitor abundance in R. ferrugineum compared to the surrounding community. Finally, pollen transfer limitation in R. ferrugineum was neither affected by visitation rate nor by patch attributes. By disproportionally attracting pollinators from co-flowering species, and probably promoting geitonogamous pollen transfer, the mass-flowering trait appears adequate to compensate, in terms of conspecific pollen transfer, for the decrease in visitor diversity and abundance and in mate availability, which usually result from population fragmentation. PMID- 23682674 TI - Amniotic fluid nucleosome in pregnancies complicated by preterm prelabor rupture of the membranes. AB - OBJECTIVE: To determine the amniotic fluid nucleosome concentrations in pregnancies that are complicated by preterm prelabor rupture of membranes and their correlation to microbial invasion of the amniotic cavity (MIAC), histologic chorioamnionitis (HCA), and their association with neonatal outcomes. METHODS: Eighty-nine women with singleton pregnancies were included in this study. Amniotic fluid was collected, and nucleosome concentration in the amniotic fluid was determined using enzyme-linked immunosorbent assay. RESULT: There were no differences observed in the amniotic fluid nucleosome concentrations in women with or without MIAC. The presence of HCA (with chorioamnionitis: median 0.5; without chorioamnionitis: median 0.21; p = 0.01) and funisitis (with funisitis: median 0.85; without funisitis: median 0.22; p = 0.0008) was associated with higher nucleosome concentrations using crude analysis; however, this was not significant after adjusting for gestational age (p = 0.12 for both). A negative correlation was observed between amniotic fluid nucleosome concentrations and gestational age (rho = -0.52; p < 0.0001). There was no association identified between amniotic fluid nucleosome concentration and neonatal morbidity. CONCLUSIONS: Amniotic fluid nucleosome concentrations remained a stable physiologic constituent in pregnancies complicated by preterm prelabor rupture of membranes, and these concentrations were gestational age dependent. Neither MIAC nor HCA significantly affected amniotic fluid nucleosome concentrations. PMID- 23682675 TI - Women with anorexia nervosa should not be treated with estrogen or birth control pills in a bone-sparing effect. AB - Eating disorders are prevalent, serious conditions that affect mainly young women. An early and enduring sign of anorexia is amenorrhea. There is no evidence for benefits of hormone therapy in patients with anorexia; however, hormone medication and oral contraceptives are frequently prescribed for young women with anorexia as a prevention against and treatment for low bone mineral density. The use of estrogens may create a false picture indicating that the skeleton is being protected against osteoporosis. Thus the motivation to regain weight, and adhere to treatment of the eating disorder in itself, may be reduced. The most important intervention is to restore the menstrual periods through increased nutrition. Hormone and oral contraceptive therapy should not be prescribed for young women with amenorrhea and concurrent eating disorders. PMID- 23682676 TI - Extreme oxatriquinanes: structural characterization of alpha-oxyoxonium species with extraordinarily long carbon-oxygen bonds. AB - The first stable alpha-oxyoxonium species have been synthesized and characterized. Strong donation of nonbonding electrons on oxygen into the adjacent sigma*(C-O(+)) orbital was predicted by modeling to result in unheard of carbon-oxygen bond lengths. The kinetic stability of the triquinane ring system provides a platform upon which to study these otherwise elusive species, which are evocative of intermediates on the acetalization reaction pathway. Crystallographic analysis of the alpha-hydroxy and alpha-methoxy oxatriquinane triflates reveals 1.658 and 1.619 A C-O(+) bond lengths, respectively, the former of which is a new record for the C-O bond. PMID- 23682678 TI - Circulating MicroRNAs as potential biomarkers for alcoholic steatohepatitis. AB - AIMS: To investigate serum miRNA profile in alcoholic steatohepatitis (ASH), evaluate its effect as non-invasive diagnostic tool and to study its targets' function. METHODS: Microarray and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were utilized to detect serum miRNAs pattern in a rat ASH model, followed by target prediction with bioinformatics calculation. The functions and pathways of miRNAs' targets were analysed using databases of Gene Ontology and KEGG. The association between dysregulated miRNAs and genes was assessed by MiR-Gene Network. Five top dysregulated miRNAs were also verified in humans. RESULTS: Eight up-regulated and three down-regulated serum miRNAs were selected as an accurate molecular signature in distinguishing ASH from control. For up-regulated miRNAs, 122 GO and 144 KEGG pathways were significantly enriched, including apoptosis, lipid metabolic process, PPAR signalling pathway. For down-regulated miRNAs, 86 GO and 104 KEGG pathways were enriched, including fatty acid metabolism and insulin signalling pathway. Besides, Ccdc117, Gcom1, Zmynd11 and Zfp423 were found at top list as under common regulation of maximum miRNAs. Moreover, miR-214 had the highest degree of 63 among all miRNAs, followed by miR-203 and miR-539. Similarly, Stat3 and Lyn showed the highest degree of 5 among all downstream targets. All significance analysis of microarrays (SAM) revealed that five top dysregulated miRNAs showed the same tendency in humans. CONCLUSION: We have reported a unique serum miRNA pattern for non-invasive diagnosis of ASH and provided data reservoir for miRNA and downstream targets exploration. PMID- 23682677 TI - Environmental contaminant exposures and preterm birth: a comprehensive review. AB - Preterm birth is a significant public health concern, as it is associated with high risk of infant mortality, various morbidities in both the neonatal period and later in life, and a significant societal economic burden. As many cases are of unknown etiology, identification of the contribution of environmental contaminant exposures is a priority in the study of preterm birth. This is a comprehensive review of all known studies published from 1992 through August 2012 linking maternal exposure to environmental chemicals during pregnancy with preterm birth. Using PubMed searches, studies were identified that examined associations between preterm birth and exposure to five categories of environmental toxicants, including persistent organic pollutants, drinking-water contaminants, atmospheric pollutants, metals and metalloids, and other environmental contaminants. Individual studies were summarized and specific suggestions were made for future work in regard to exposure and outcome assessment methods as well as study design, with the recommendation of focusing on potential mediating toxicological mechanisms. In conclusion, no consistent evidence was found for positive associations between individual chemical exposures and preterm birth. By identifying limitations and addressing the gaps that may have impeded the ability to identify true associations thus far, this review can guide future epidemiologic studies of environmental exposures and preterm birth. PMID- 23682679 TI - Measurement of protein tyrosine phosphatase activity in single cells by capillary electrophoresis. AB - A fluorescent peptide substrate was used to measure dephosphorylation by protein tyrosine phosphatases (PTP) in cell lysates and single cells and to investigate the effect of environmental toxins on PTP activity in these systems. Dephosphorylation of the substrate by PTPN1 and PTPN2 obeyed Michaelis-Menten kinetics, with KM values of 770 +/- 250 and 290 +/- 54 nM, respectively. Dose response curves and IC50 values were determined for the inhibition of these two enzymes by the environmental toxins Zn(2+) and 1,2-naphthoquinone, as well as pervanadate. In A431 cell lysates, the reporter was a poor substrate for peptidases (degradation rate of 100 +/- 8.2 fmol min(-1) mg(-1)) but an excellent substrate for phosphatases (dephosphorylation rate of 1.4 +/- 0.3 nmol min(-1) mg(-1)). Zn(2+), 1,2-naphthoquinone, and pervanadate inhibited dephosphorylation of the reporter in cell lysates with IC50 values of 470 nM, 35 MUM, and 100 nM, respectively. Dephosphorylation of the reporter, following loading into living single cells, occurred at rates of at least 2 pmol min(-1) mg(-1). When single cells were exposed to 1,2-naphthoquinone (50 MUM), Zn(2+) (100 MUM), and pervandate (1 mM), dephosphorylation was inhibited with median values and first and third quartile values of 41 (Q1 = 0%, Q3 = 96%), 50 (Q1 = 46%, Q3 = 74%), and 53% (Q1 = 36%, Q3 = 77%), respectively, demonstrating both the impact of these toxic exposures on cell signaling and the heterogeneity of response between cells. This approach will provide a valuable tool for the study of PTP dynamics, particularly in small, heterogeneous populations such as human biopsy specimens. PMID- 23682681 TI - Abstracts of the 23rd Regional Congress of the International Society of Blood Transfusion. Amsterdam, Netherlands. June 2-5, 2013. PMID- 23682680 TI - Multifunctional nanoparticles improve therapeutic effect for breast cancer by simultaneously antagonizing multiple mechanisms of multidrug resistance. AB - For efficient reversal of multidrug resistance (MDR) in chemotherapy for breast cancer, multifunctional self-assembled nanoparticles (MSN) based on a new amphiphilic copolymer consisting of bioreducible poly[bis(2-hydroxylethyl) disulfide-diacrylate-beta-tetraethylenepentamine] and polycaprolactone (PBD-PCL) were constructed and characterized. shRNA targeting the apoptosis-inhibiting gene, Survivin, was incorporated into the nanoparticles with high RNA interference efficiency. PBD-PCL significantly inhibited the activity of P glycoprotein, one of the most well-described drug-efflux pumps, and glutathione S transferase, an important detoxification enzyme. MSN achieved colocalization of RNA and doxorubicin in tumors after intravenous administration and showed remarkable antitumor efficacy in MDR tumor-bearing mice with less side-effect than drug combination therapy. This was a new attempt to overcome MDR against three different mechanisms of MDR simutaneously: overexpression of drug efflux protein, activation of detoxification system, and blockage of apoptosis. These results indicated that the PBD-PCL-based MSN had obvious potential for therapy of breast cancer. PMID- 23682682 TI - 40-Hz square-wave stimulation requires less energy to produce muscle contraction: compared with the TASER(r) X26 conducted energy weapon. AB - Conducted energy weapons (CEWs) (including the Advanced TASER((r)) X26 model produced by TASER International, Inc.) incapacitate individuals by causing muscle contractions. In this study using anesthetized swine, the potential incapacitating effect of primarily monophasic, 19-Hz voltage imposed by the commercial CEW was compared with the effect of voltages imposed by a laboratory device that created 40-Hz square waves. Forces of muscle contraction were measured with the use of strain gauges. Stimulation with 40-Hz square waves required less pulse energy than stimulation with the commercial CEW to produce similar muscle contraction. The square-pulse stimulation, at the higher repetition rate, caused a more complete tetanus at a lower energy. Use of such a simple shape of waveform may be used to make future nonlethal weapon devices more efficient. PMID- 23682683 TI - An extension of the Coconut Cream Agar method to screen Penicillium citrinum isolates for citrinin production. AB - A simple and rapid screening method was developed for the detection of citrinin in fungal cultures using Coconut Cream Agar (CCA) described previously for detecting aflatoxin and ochratoxin A. Fifteen isolates of Penicillium citrinum were inoculated onto CCA and incubated at 25 and 30 degrees C for 10 days. All isolates produced a distinct yellow green fluorescence on CCA when the reverse side of the agar plates were viewed under long wavelength UV light. Detection was optimal at 25 degrees C after four to 5 days of incubation. Isolates positive by the CCA method also tested positive for citrinin production by the TLC agar plug method after growth on CCA, Czapek yeast extract agar and yeast extract sucrose agar. Control cultures were negative by both methods, indicating that the CCA Petri dish method was suitable for screening cultures for citrinin production. PMID- 23682685 TI - Immune thrombocytopenia -- what are the new treatment options? AB - INTRODUCTION: Primary immune thrombocytopenia (ITP) is a minor disease for many patients; however, the natural history is variable and unpredictable. Many patients who are in otherwise good health can be left untreated, especially if their platelet counts are close to 20 * 10(9)/l. The overall mortality rate for ITP is < 1%, and the morbidity and mortality associated with treatment can be worse than the disease. AREAS COVERED: ITP is not purely due to platelet destruction and in a significant proportion platelet production is sub-optimal; the review will cover the newer developments with the thrombopoietin receptor agonists (TPOrAs) of which two agents, romiplostim and eltrombopag, are now licensed and these will be placed in context to conventional treatment. EXPERT OPINION: There is an increasing understanding of the natural history of ITP and an increasing evidence-based approach to the disease and its management. Treatment should be aimed at the patient with a bleeding risk and should minimise the risk of adverse effects while maximising the chances of response. Few, if any, treatments are curative and treatment strategies need to be designed in ITP that manage patients with what can be a life-long condition with periodic relapses. PMID- 23682684 TI - Substituted 1-Phenyl-3-(pyridin-2-yl)urea negative allosteric modulators of mGlu5: discovery of a new tool compound VU0463841 with activity in rat models of cocaine addiction. AB - Cocaine is a powerful and highly addictive stimulant that disrupts the normal reward circuitry in the central nervous system (CNS), producing euphoric effects. Cocaine use can lead to acute and life threatening emergencies, and abuse is associated with increased risk for contracting infectious diseases. Though certain types of behavioral therapy have proven effective for treatment of cocaine addiction, relapse remains high, and there are currently no approved medications for the treatment of cocaine abuse. Evidence has continued to accumulate that indicates a critical role for the metabotropic glutamate receptor subtype 5 (mGlu5) in the modulation of neural circuitry associated with the addictive properties of cocaine. While the small molecule mGlu5 negative allosteric modulator (NAM) field is relatively advanced, investigation into the potential of small molecule mGlu5 NAMs for the treatment of cocaine addiction remains an area of high interest. Herein we describe the discovery and characterization of a potent and selective compound 29 (VU0463841) with good CNS exposure in rats. The utility of 29 (VU0463841) was demonstrated by its ability to attenuate drug seeking behaviors in relevant rat models of cocaine addiction. PMID- 23682686 TI - Molecular spectrum of beta-thalassemia in Fujian Province, Southeastern China. AB - To provide basic information for beta-thalassemia (beta-thal) screening, genetic counseling and prenatal diagnosis (PND), we characterized beta-thal mutations in Fujian Province, Southeastern China. A total of 16 different beta-thal gene mutations were identified from 1058 patients. Of these, the IVS-II-654 (C>T) and codons 41/42 (-TCTT) were the most prevalent, accounting for 76.3% of the total mutations. Six gene mutations, IVS-I-1 (G>T), Cap +40 to +43 (-AAAC), codon 30 (A>G), +22 (G>A), codons 54-58 (-TTATGGGCAACCC) and the initiation codon (ATG>AGG) were characterized for the first time in the Fujian population. Furthermore, the following mutations, +22 (G >A), codon 36 (-C) and codon 30 (A>G), were identified for the first time in Chinese individuals. This was the first comprehensive mutation spectrum of beta-thal mutations studied in Fujian Province, People's Republic of China (PRC). PMID- 23682687 TI - Fragmentation of allylmethylsulfide by chemical ionization: dependence on humidity and inhibiting role of water. AB - We report on a previously unknown reaction mechanism involving water in the fragmentation reaction following chemical ionization. This result stems from a study presented here on the humidity-dependent and energy-dependent endoergic fragmentation of allyl methyl sulfide (AMS) upon protonation in a proton transfer reaction-mass spectrometer (PTR-MS). The fragmentation pathways were studied with experimental (PTR-MS) and quantum chemical methods (polarizable continuum model (PCM), microhydration, studied at the MP2/6-311+G(3df,2p)//MP2/6-31G(d,p) level of theory). We report in detail on the energy profiles, reaction mechanisms, and proton affinities (G4MP2 calculations). In the discovered reaction mechanism, water reduces the fragmentation of protonated species in chemical ionization. It does so by direct interaction with the protonated species via covalent binding (C3H5(+)) or via association (AMS.H(+)). This stabilizes intermediate complexes and thus overall increases the activation energy for fragmentation. Water thereby acts as a reusable inhibitor (anticatalyst) in chemical ionization. Moreover, according to the quantum chemical (QC) results, when water is present in abundance it has the opposite effect and enhances fragmentation. The underlying reason is a concentration-dependent change in the reaction principle from active inhibition of fragmentation to solvation, which then enhances fragmentation. This amphoteric behavior of water is found for the fragmentation of C3H5(+) to C3H3(+), and similarly for the fragmentation of AMS.H(+) to C3H5(+). The results support humidity-dependent quantification efforts for PTR-MS and chemical ionization mass spectrometry (CIMS). Moreover, the results should allow for a better understanding of ion-chemistry in the presence of water. PMID- 23682689 TI - Evidence-based nephrology-rheumatology debates: a novel educational experience during nephrology fellowship training. AB - Medical educators have called for novel learning methods that supplement the traditional lecture format. Fellowship education involves didactics and pedagogic strategies using a variety of learning tools in order to improve critical thinking skills. Debating is one such tool that can enhance critical thinking skill. However, to the best of our knowledge, evidence-based debating among two different internal medicine subspecialty fields during fellowship training has never been reported. In this article, we describe an innovative educational experience for trainees using the evidence-based debate format. Two teams consisting of equal number of first- and second-year nephrology and rheumatology fellows participated in our annual interdivisional debate session. Topics that have been debated over the last three annual debate sessions include management of small vessel vasculitis and lupus nephritis. To assess the educational experience of the debate session, all fellow participants were asked to complete an anonymous on-line survey following the debate. The survey consisted of several questions using a 5-point Likert scale. All fellow participants enjoyed the debate format and found this experience to be thought-provoking and to enhance their self-directed learning. PMID- 23682688 TI - Neural correlates of the rubber hand illusion in amputees: a report of two cases. AB - One of the current challenges in the field of advanced prosthetics is the development of artificial limbs that provide the user with detailed sensory feedback. Sensory feedback from our limbs is not only important for proprioceptive awareness and motor control, but also essential for providing us with a feeling of ownership or simply put, the sensation that our limbs actually belong to ourselves. The strong link between sensory feedback and ownership has been repeatedly demonstrated with the so-called rubber hand illusion (RHI), during which individuals are induced with the illusory sensation that an artificial hand is their own. In healthy participants, this occurs via integration of visual and tactile signals, which is primarily supported by multisensory regions in premotor and intraparietal cortices. Here, we describe a functional magnetic resonance imaging (fMRI) study with two upper limb amputees, showing for the first time that the same brain regions underlie ownership sensations of an artificial hand in this population. Albeit preliminary, these findings are interesting from both a theoretical as well as a clinical point of view. From a theoretical perspective, they imply that even years after the amputation, a few seconds of synchronous visuotactile stimulation are sufficient to activate hand-centered multisensory integration mechanisms. From a clinical perspective, they show that a very basic sensation of touch from an artificial hand can be obtained by simple but precisely targeted stimulation of the stump, and suggest that a similar mechanism implemented in prosthetic hands would greatly facilitate ownership sensations and in turn, acceptance of the prosthesis. PMID- 23682690 TI - Identification of a novel splicing mutation of ECM1 in a rare lipoid proteinosis family. PMID- 23682692 TI - Transabdominal fetal ECG technique: reply to Fuchs et al. PMID- 23682691 TI - Analysis of selected sugars and sugar phosphates in mouse heart tissue by reductive amination and liquid chromatography-electrospray ionization mass spectrometry. AB - Sensitive and reliable analysis of sugars and sugar phosphates in tissues and cells is essential for many biological and cell engineering studies. However, the successful analysis of these endogenous compounds in biological samples by liquid chromatography/electrospray ionization mass spectrometry (LC/ESI-MS) is often difficult because of their poor chromatographic retention properties in reversed phase LC, the complex biological matrices, and the ionization suppression in ESI. This situation is further complicated by the existence of their multiple structural isomers in vivo. This work describes the combination of reductive amination using 3-amino-9-ethylcarbazole, with a new LC approach using a pentafluorophenyl core-shell ultrahigh performance (UP) LC column and methylphosphonic acid as an efficient tail-sweeping reagent for improved chromatographic separation. This new method was used for selected detection and accurate quantitation of the major free and phosphorylated reducing sugars in mouse heart tissue. Among the detected compounds, accurate quantitation of glyceraldehyde, ribose, glucose, glycerylaldehyde-3-phosphate, ribose-5 phosphate, glucose-6-phosphate, and mannose-6-phosphate was achieved by UPLC/multiple-reaction monitoring (MRM)-MS, with analytical accuracies ranging from 87.4% to 109.4% and CVs of <=8.5% (n = 6). To demonstrate isotope-resolved metabolic profiling, we used UPLC/quadrupole time-of-flight (QTOF)-MS to analyze the isotope distribution patterns of C3 to C6 free and phosphorylated reducing sugars in heart tissues from (13)C-labeled wild type and knockout mice. In conclusion, the preanalytical derivatization-LC/ESI-MS method has resulted in selective determination of free and phosphorylated reducing sugars without the interferences from their nonreducing structural isomers in mouse heart tissue, with analytical sensitivities in the femtomole to low picomole range. PMID- 23682693 TI - Aortic dissection in hospitalized children and young adults: a multiinstitutional study. AB - OBJECTIVE: To describe the incidence, characteristics, and outcomes of hospitalized children and young adults with aortic dissection (AD). DESIGN: Retrospective review. SETTING: The Pediatric Health Information System database, a multiinstitutional administrative database. PATIENTS: All index cases of patients <30 years old hospitalized with AD between January 2004 and June 2011. OUTCOME MEASURES: The primary outcome measure was inpatient mortality. RESULTS: Of 3 800 964 hospitalizations, AD was identified in 124 (<1%), accounting for 110 patients (69% male, P = .003) at a median age of 12.9 (interquartile range 3.9 16.8) years with a bimodal distribution in infancy and late adolescence. Associated diagnoses included congenital heart disease (CHD) (38%), trauma (24%), connective tissue disease (CTD) (16%), and isolated hypertension (HTN) (8%). Common CHD diagnoses included aortic arch (24%) and valve (21%) disease, hypoplastic left heart syndrome (10%), and transposition of the great arteries (10%). CHD patients were younger and more likely to undergo inpatient non-AD related cardiovascular procedures compared with other diagnostic groups (P < .001 for both). Marfan and Ehlers-Danlos syndrome were present in 72% and 11% of CTD patients, respectively. Overall in-hospital mortality in patients with AD was 13% compared with 1% in the database population (odds ratio 12.0, 95% confidence interval 6.9-21.1). By diagnostic category, mortality was 22% in HTN, 22% in CTD, 12% in CHD, and 4% in trauma. CONCLUSIONS: AD is rare in children and young adults but most commonly occurs in CHD and CTD and in males. AD is associated with high inpatient mortality. PMID- 23682694 TI - Leadership, accountability, and safety in health care. PMID- 23682695 TI - A review of the health effects of sexual assault on African American women and adolescents. AB - OBJECTIVE: To review the research findings for mental and physical health outcomes and health behaviors of African American women and adolescents after sexual assault. DATA SOURCES: Searches of the Cumulative Index to Nursing and Allied Health Literature, Cochrane Library, PsycINFO, and PubMed from January 2001 through May 2012 using the terms Blacks, African Americans, sexual abuse, sexual offenses, and rape. STUDY SELECTION: Criteria for inclusion included (a) results of primary research conducted in the United States and published in English, (b) African American females age 13 and older, (c) sexual assault or sexual abuse reported as distinct from other types of abuse, and (d) health status as an outcome variable. Twenty-one publications met inclusion criteria. DATA EXTRACTION: Articles were reviewed for the mental and physical health and health behavior outcomes associated with sexual assault of African American women and adolescents. DATA SYNTHESIS: Sexual assault was associated with increased risk of poor mental and physical health outcomes in the general population of women and adolescents. There was an increased risk of unhealthy behaviors (e.g., drinking, drug use, risky sexual behaviors) for all women and adolescents, with the highest risk reported for African American women and adolescents. Help seeking from family and friends demonstrated conflicting results. Cumulative effects of repeated assaults appear to worsen health outcomes. CONCLUSION: Sexual assault has significant effects on the physical and mental health and health behaviors of women and adolescents in the general population. Less evidence is available for differences among African American women and adolescents. More research is needed to understand the influence of race on women's and adolescents' responses to assault. PMID- 23682697 TI - Experiences of obstetric nurses who are present for a perinatal loss. AB - OBJECTIVE: To discover the impact of perinatal loss on obstetric nurses. DESIGN: In the parent study, obstetric nurses were provided with an open-ended statement asking them to describe in writing the experience of being present during a traumatic childbirth. For this study, a secondary qualitative analysis was performed on those cases in which a perinatal loss was described as traumatic to answer new research questions. PARTICIPANTS: A total of 464 cases were included in the parent study; 150 cases included either fetal or infant death. Of those, 91 cases had rich descriptions that we analyzed for this study. METHODS: The data were analyzed using Krippendorff's (2013) method for qualitative content analysis. Responses were clustered to allow themes to emerge. Nurses' experiences of fetal and infant loss were analyzed individually and then compared and contrasted for overarching themes. RESULTS: Six themes emerged from the fetal and infant loss experiences, with the final overarching themes from perinatal loss including getting through the shift, symptoms of pain and loss, frustrations with inadequate care, showing genuine care, recovering from traumatic experience, and never forgetting. CONCLUSION: Perinatal loss can have a lasting effect on nurses, and thus continued support may be needed. PMID- 23682696 TI - Nurse home visits improve maternal/infant interaction and decrease severity of postpartum depression. AB - OBJECTIVE: To test the efficacy of the relationship-focused behavioral coaching intervention Communicating and Relating Effectively (CARE) in increasing maternal/infant relational effectiveness between depressed mothers and their infants during the first 9 months postpartum. DESIGN: Randomized clinical trial (RCT) with three phases. METHODS: In this three-phase study, women were screened for postpartum depression (PPD) in Phase I at 6 weeks postpartum. In Phase II, women were randomly assigned to treatment or control conditions and maternal/infant interaction was video recorded at four intervals postpartum: 6 weeks, 3 months, 6 months, and 9 months. Phase III involved focus group and individual interviews with study participants. SETTING: Phase I mothers were recruited from obstetric units of two major medical centers. Phase II involved the RCT, a series of nurse-led home visits beginning at 6 weeks and ending at 9 months postpartum. Phase III focus groups were conducted at the university and personal interviews were conducted by telephone or in participants' homes. PARTICIPANTS: Postpartum mother/infant dyads (134) representative of southeastern New England, United States participated in the RCT. One hundred and twenty-five mother/infant dyads were fully retained in the 9-month protocol. RESULTS: Treatment and control groups had significant increases in quality of mother/infant interaction and decreases in depression severity. Qualitative findings indicated presence of the nurse, empathic listening, focused attention and self-reflection during data collection, directions for video-recorded interaction, and assistance with referrals likely contributed to improvements for both groups. CONCLUSIONS: Efficacy of the CARE intervention was only partially supported. Nurse attention given to the control group and the data collection process likely confounded results and constituted an unintentional treatment. Results suggest that nurse-led home visits had a positive effect on outcomes for all participants. PMID- 23682699 TI - Current resources for evidence-based practice May/June 2013. PMID- 23682698 TI - Interactive behaviors of ethnic minority mothers and their premature infants. AB - OBJECTIVE: To compare the interactive behaviors of American Indian mothers and their premature infants with those of African American mothers and their premature infants. DESIGN: Descriptive, comparative study. SETTING: Three neonatal intensive care units and two pediatric clinics in the southeast. PARTICIPANTS: Seventy-seven mother/infant dyads: 17 American Indian mother/infant dyads and 60 African American mother/infant dyads. METHODS: Videotapes of mother/infant interactions and the Home Observation for Measurement of the Environment (HOME) were used to assess the interactions of the mothers and their premature infants at 6 months corrected age. RESULTS: American Indian mothers looked more, gestured more, and were more often the primary caregivers to their infants than the African American mothers. American Indian infants expressed more positive affect and gestured more to their mothers, whereas African American infants engaged in more non-negative vocalization toward their mothers. African American mothers scored higher on the HOME subscales of provision of appropriate play materials and parental involvement with the infant. American Indian mothers scored higher on the opportunities for variety in daily living subscale. CONCLUSION: Although many of the interactive behaviors of American Indian and African American mother/infant dyads were similar, some differences did occur. Clinicians need to be aware of the cultural differences in mother/infant interactions. To optimize child developmental outcomes, nurses need to support mothers in their continuation or adoption of positive interactive behaviors. PMID- 23682700 TI - Vertical transmission of Rift Valley fever virus without detectable maternal viremia. AB - Rift Valley fever virus (RVFV) is a zoonotic bunyavirus that causes abortions in domesticated ruminants. Sheep breeds exotic to endemic areas are reportedly the most susceptible to RVFV infection. Within the scope of a risk assessment program of The Netherlands, we investigated the susceptibility of a native breed of gestating sheep to RVFV infection. Ewes were infected experimentally during the first, second, or third trimester of gestation. Mortality was high among ewes that developed viremia. Four of 11 inoculated ewes, however, did not develop detectable viremia nor clinical signs and did not seroconvert for immunoglobulin G (IgG) or IgM antibodies. Surprisingly, these ewes were found to contain viral RNA in maternal and fetal organs, and the presence of live virus in fetal organs was demonstrated by virus isolation. We demonstrate that RVFV can be transmitted vertically in the absence of detectable maternal viremia. PMID- 23682701 TI - Ontogenetic trajectories in the ornithischian endocranium. AB - Understanding ontogenetic and developmental patterns is critical for reconstructing the life history of fossil vertebrates. In dinosaurs, ontogenetic studies have nearly exclusively focused on changes in the cranial and post cranial skeleton, whereas ontogenetic changes in the endocranium have received little attention. Here, we present digital reconstructions of the brain and inner ear anatomy of two ontogenetic stages of the Jurassic ornithischian dinosaur Dysalotosaurus lettowvorbecki. Results show that the endocranial anatomy underwent considerable changes during growth, including a rostrocaudal elongation of the olfactory apparatus, a reduction in the cephalic and pontine flexure and an increase in cerebellum size. Functional elements, such as the cerebral hemispheres and the inner ear, were already well developed in early ontogenetic stages, indicating a large degree of precociality. The anisotropic pattern of size and shape changes in the endocranium further indicates that ontogenetic trajectories may be controlled by functional and environmental demands in the different growth stages in Dysalotosaurus lettowvorbecki. The occurrence of similar ontogenetic patterns in the endocranial anatomy of derived ornithopod dinosaurs suggests a more widespread distribution of this growth trajectory. PMID- 23682702 TI - Adverse pregnancy outcomes in women with nausea and vomiting of pregnancy. AB - OBJECTIVE: To examine the influence of nausea and vomiting of pregnancy (NVP) on pregnancy outcomes. METHODS: Outcomes were compared for primigravidas with a current singleton gestation enrolled at <20 weeks' gestation in a maternity risk screening and education program (n = 81 486). Patient-reported maternal characteristics and pregnancy outcomes were compared for women with and without NVP and within the NVP group for those with and without poor weight gain. RESULTS: 6.4% of women reported NVP as a pregnancy complication. Women reporting NVP were more likely to be younger, obese, single and smoke. They had higher rates of preterm delivery, pregnancy-induced hypertension and low birth weight <2500 g. Almost one-quarter of women with NVP had lower than recommended weight gain. Poor weight gain was associated with a higher incidence of adverse outcomes. Obesity, tobacco use and poor pregnancy weight gain independently increased the odds of an adverse outcome. CONCLUSION: NVP and subsequent poor weight gain may be associated with adverse pregnancy outcomes. PMID- 23682703 TI - High levels of circulating HMGB1 as a biomarker of acute liver failure in patients with viral hepatitis E. AB - BACKGROUND: Viral hepatitis E clinically ranges between acute self-limiting hepatitis (AVH) and acute liver failure (ALF). The varied clinical course of the disease possibly thought to be immune-mediated. High-mobility group box 1 (HMGB1) is a non-histone chromosomal nuclear protein with recently discovered pro inflammatory and immunomodulatory action. Its presence in abundance within hepatocytes is thought provoking in patients with hepatitis. AIM: The present study was designed to elucidate the role of circulating HMGB1 and its gene expression in patients with viral hepatitis E. METHODS: Blood samples were obtained from AVH (n = 38), ALF (n = 34) and healthy controls (HC, n = 30). The HMGB1 levels were estimated in serum by quantitative-micro-ELISA. Gene expression levels were studied in the patient's PBMCs by real-time PCR. Lymphocyte proliferation was estimated by colorimetric-MTT assay. RESULTS: Mean circulating HMGB1 levels in HC, AVH and ALF patients were found to be 12.04 +/- 2.23, 112.6 +/- 13.33 and 225.3 +/- 15.04 ng/ml respectively. The levels were significantly higher in ALF than AVH and HC (P < 0.0001). Moreover, 88.2% of ALF patients with >250 ng/ml of circulating HMGB1 had a fatal outcome. The gene expression of HMGB1 in the PBMCs of ALF and AVH patients were comparable. A positive correlation was observed between HMGB1 level and INR. A significantly low lymphocyte proliferation was observed in ALF patients (P = 0.008). CONCLUSION: Massive necrosis of hepatocytes in ALF patients might predispose to excessive accumulation of extracellular HMGB1 leading to suppression of T-cell proliferation. Therefore, it is proposed that excessive circulating HMGB1 might play an important role in immunosuppression and fulminant course of the disease following HEV infection. PMID- 23682704 TI - Anthropological measurement of the juvenile clavicle using multi-detector computed tomography--affirming reliability. AB - Currently, there is no standardized protocol for multi-detector computed tomography (MDCT) measurement of juvenile remains. Using 33 juvenile clavicles, this paper investigates a protocol to allow MDCT measurements, comparable or supplemental with traditional osteometric measurements, to be acquired for application to previously published algorithms. The results illustrate that there is no significant difference between MDCT measurements and those taken by direct osteometric methods. By presenting such a protocol, this paper takes the first steps toward validation of the process of conversion from measurement of dry juvenile bone to MDCT compatibility and allows the forensic world to take a step forward in standardizing the way MDCT is used for forensic practice. This paper assesses the limitations and potential applications of this virtual approach and offers some suggestions for where further work might progress the conversion of these new approaches into legally admissible anthropological techniques of age estimation. PMID- 23682705 TI - Comparison of culture media for the recovery of airborne yeast in wineries. AB - The direct air sampling impaction method on agar was evaluated using aerobiocollectors for the recovery of yeasts present in the winery air. Three culture media with different composition and specificity were studied. In addition, a resuscitation phase was included before the culture in the specificity medium [in the case of the Dekkera-Brettanomyces Differential Medium (DBDM) medium]. Sampling was conducted at different times of the year and in different parts of the wineries, which were different in age and design. Both the Chloramphenicol Glucose Agar (CGA) and Agar Lysine AL media recovered yeasts from the air without any prior resuscitation phase. CGA was able to recover a higher number of colony-forming units of yeasts than the other media. Consequently, to estimate the number of yeasts present in winery air, the best choice of medium would be CGA. The AL medium permitted the growth of the greatest range of genera and species. If the aim is to study the diversity of yeasts present in the air, the most suitable medium is AL. Neither CGA nor AL proved suitable for recovering yeasts of the Brettanomyces genus. The DBDM medium was the only one which provided sufficient specificity for their recovery and identification from the air, although their special characteristics made a prior protocol of resuscitation necessary. PMID- 23682706 TI - Real-time growth kinetics measuring hormone mimicry for ToxCast chemicals in T 47D human ductal carcinoma cells. AB - High-throughput screening (HTS) assays capable of profiling thousands of environmentally relevant chemicals for in vitro biological activity provide useful information on the potential for disrupting endocrine pathways. Disruption of the estrogen signaling pathway has been implicated in a variety of adverse health effects including impaired development, reproduction, and carcinogenesis. The estrogen-responsive human mammary ductal carcinoma cell line T-47D was exposed to 1815 ToxCast chemicals comprising pesticides, industrial chemicals, pharmaceuticals, personal care products, cosmetics, food ingredients, and other chemicals with known or suspected human exposure potential. Cell growth kinetics were evaluated using real-time cell electronic sensing. T-47D cells were exposed to eight concentrations (0.006-100 MUM), and measurements of cellular impedance were repeatedly recorded for 105 h. Chemical effects were evaluated based on potency (concentration at which response occurs) and efficacy (extent of response). A linear growth response was observed in response to prototypical estrogen receptor agonists (17beta-estradiol, genistein, bisphenol A, nonylphenol, and 4-tert-octylphenol). Several compounds, including bisphenol A and genistein, induced cell growth comparable in efficacy to that of 17beta estradiol, but with decreased potency. Progestins, androgens, and corticosteroids invoked a biphasic growth response indicative of changes in cell number or cell morphology. Results from this cell growth assay were compared with results from additional estrogen receptor (ER) binding and transactivation assays. Chemicals detected as active in both the cell growth and ER receptor binding assays demonstrated potencies highly correlated with two ER transactivation assays (r = 0.72; r = 0.70). While ER binding assays detected chemicals that were highly potent or efficacious in the T-47D cell growth and transactivation assays, the binding assays lacked sensitivity in detecting weakly active compounds. In conclusion, this cell-based assay rapidly detects chemical effects on T-47D growth and shows potential, in combination with other HTS assays, to detect environmentally relevant chemicals with potential estrogenic activity. PMID- 23682707 TI - Proteome analysis of the plasma protein layer adsorbed to a rough titanium surface. AB - In this study a label-free proteomic approach was used to investigate the composition of the layer of protein adsorbed to rough titanium (Ti) after exposure to human blood plasma. The influence of the protein layer on the surface free energy (SFE) of the Ti was evaluated by contact angle measurements. Ti discs were incubated with blood plasma for 180 min at 37 degrees C, and the proteins recovered were subjected to liquid chromatography coupled to tandem mass spectrometry analysis. A total of 129 different peptides were identified and assigned to 25 distinct plasma proteins. The most abundant proteins were fibronectin, serum albumin, apolipoprotein A-I, and fibrinogen, comprising 74.54% of the total spectral counts. Moreover, the protein layer increased the SFE of the Ti (p < 0.05). The layer adsorbed to the rough Ti surface was composed mainly of proteins related to cell adhesion, molecule transportation, and coagulation processes, creating a polar and hydrophilic interface for subsequent interactions with host cells. PMID- 23682708 TI - Predictors of low levels of self-efficacy among patients with chronic obstructive pulmonary disease in South Korea. AB - The aim of this study was to identify related factors of low levels of self efficacy in patients with Chronic Obstructive Pulmonary Disease (COPD). A cross sectional research design used descriptive statistics, chi(2) test, t-test, and binary logistic regression. Two hundred and forty-five patients with COPD were recruited from five hospitals in South Korea. The COPD Self-Efficacy Scale, the Bristol COPD Knowledge Questionnaire, Personal Resource Questionnaire 2000, BODE index, and the International Physical Activity Questionnaire short version were utilized to assess self-efficacy, disease-related knowledge, social support, disease severity, and physical activity, respectively. The BODE index, affect oriented coping, and duration since diagnosis of COPD were included as significant predictors of self-efficacy. These findings suggest possible screening methods to identify patients with low levels of self-efficacy and future intervention targeting for these patients would strengthen the efficiency of an intervention. PMID- 23682709 TI - The C. elegans gene pan-1 encodes novel transmembrane and cytoplasmic leucine rich repeat proteins and promotes molting and the larva to adult transition. AB - BACKGROUND: Extracellular leucine-rich repeat (eLRR) proteins are a highly diverse superfamily of membrane-associated or secreted proteins. In the membrane associated eLRR proteins, the leucine-rich repeat motifs interact with the extracellular matrix and other ligands. Characterizing their functions in animal model systems is key to deciphering their activities in various developmental processes. RESULTS: In this study, we identify pan-1 as a critical regulator of C. elegans larval development. pan-1 encodes both transmembrane and cytoplasmic isoforms that vary in the presence and number of leucine-rich repeats. RNAi experiments reveal that pan-1 is required for developmental processes that occur during the mid to late larval stages. Specifically, pan-1 loss of function causes a late larval arrest with a failure to complete development of the gonad, vulva, and hypodermis. pan-1 is also required for early larval ecdysis and execution of the molting cycle at the adult molt. We also provide evidence that pan-1 functionally interacts with the heterochronic gene lin-29 during the molting process. CONCLUSIONS: We show that PAN-1 is a critical regulator of larval development. Our data suggests that PAN-1 promotes developmental progression of multiple tissues during the transition from a larva to a reproductive adult. We further demonstrate that the activity of PAN-1 is complex with diverse roles in the regulation of animal development. PMID- 23682710 TI - Vitamin D: beyond bone. AB - In recent years, vitamin D has been received increased attention due to the resurgence of vitamin D deficiency and rickets in developed countries and the identification of extraskeletal effects of vitamin D, suggesting unexpected benefits of vitamin D in health and disease, beyond bone health. The possibility of extraskeletal effects of vitamin D was first noted with the discovery of the vitamin D receptor (VDR) in tissues and cells that are not involved in maintaining mineral homeostasis and bone health, including skin, placenta, pancreas, breast, prostate and colon cancer cells, and activated T cells. However, the biological significance of the expression of the VDR in different tissues is not fully understood, and the role of vitamin D in extraskeletal health has been a matter of debate. This report summarizes recent research on the roles for vitamin D in cancer, immunity and autoimmune diseases, cardiovascular and respiratory health, pregnancy, obesity, erythropoiesis, diabetes, muscle function, and aging. PMID- 23682711 TI - [2Fe-2S]-ferredoxin binds directly to cysteine desulfurase and supplies an electron for iron-sulfur cluster assembly but is displaced by the scaffold protein or bacterial frataxin. AB - Escherichia coli [2Fe-2S]-ferredoxin (Fdx) is encoded by the isc operon along with other proteins involved in the 'house-keeping' mechanism of iron-sulfur cluster biogenesis. Although it has been proposed that Fdx supplies electrons to reduce sulfane sulfur (S(0)) produced by the cysteine desulfurase (IscS) to sulfide (S(2-)) as required for the assembly of Fe-S clusters on the scaffold protein (IscU), direct experimental evidence for the role of Fdx has been lacking. Here, we show that Fdx (in either oxidation state) interacts directly with IscS. The interaction face on Fdx was found to include residues close to its Fe-S cluster. In addition, C328 of IscS, the residue known to pick up sulfur from the active site of IscS and deliver it to the Cys residues of IscU, formed a disulfide bridge with Fdx in the presence of an oxidizing agent. Electrons from reduced Fdx were transferred to IscS only in the presence of l-cysteine, but not to the C328S variant. We found that Fdx, IscU, and CyaY (the bacterial frataxin) compete for overlapping binding sites on IscS. This mutual exclusion explains the mechanism by which CyaY inhibits Fe-S cluster biogenesis. These results (1) show that reduced Fdx supplies one electron to the IscS complex as S(0) is produced by the enzymatic conversion of Cys to Ala and (2) explain the role of Fdx as a member of the isc operon. PMID- 23682712 TI - Synthesis of a library of "lead-like" gamma-lactams by a one pot, four-component reaction. AB - The synthesis of a pilot scale library of 116 structurally diverse gamma-lactams is reported. The library core structure emanates from a gamma-lactam forming one pot, four-component reaction of ammonium acetate, p-methoxythiophenol, p methoxybenzaldehyde, and maleic anhydride. Structural diversity then arises from amide coupling, thioaryl cleavage, N-functionalization, and heterocycle forming reactions on this core structure. Computational analysis reveals that the library contains molecular properties and shape diversity suitable for drug lead and biological probe discovery. PMID- 23682713 TI - Dialogic moments and a wicked spin on aging. PMID- 23682715 TI - Unilateral cortical hyperexcitability in congenital hydrocephalus: a TMS study. AB - INTRODUCTION: Changes in cortical excitability are considered to play an important role in promoting brain plasticity both in healthy people and in neurological diseases. Hydrocephalus is a brain development disorder related to an excessive accumulation of cerebrospinal fluid (CSF) in the ventricular system. The functional relevance of cortical structural changes described in this disease is largely unexplored in human. We investigated cortical excitability using multimodal transcranial magnetic stimulation (TMS) in a case of congenital hydrocephalus with almost no neurological signs. METHODS: A caucasian 40 years old, ambidextrous and multilingual woman affected by occult spina bifida and congenital symmetrical hydrocephalous underwent a TMS study. The intracortical and interhemispheric paired pulse paradigms were used, together with the mapping technique. RESULTS: No significant differences were found in the resting motor thresholds between the two hemispheres. Instead, the intracortical excitability curves were statistically different between the two hemispheres (with short intracortical inhibition (SICI) being strongly reduced and intracortical facilitation (ICF) enhanced in the right one), and the interhemispheric curves showed a general hyper-excitability on the right hemisphere (when conditioned by the left one) and a general hypo-excitability in the left hemisphere (when conditioned by the right one). It is noteworthy that an asymmetric right hemisphere (RH) change of excitability was observed by means of mapping technique. CONCLUSION: We hypothesize that in this ambidextrous subject, the observed RH hyper-excitability could represent a mechanism of plasticity to preserve functionality of specific brain areas possibly devoted to some special skills, such as multilingualism. PMID- 23682714 TI - Statistically enhanced spectral counting approach to TCDD cardiac toxicity in the adult zebrafish heart. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a persistent environmental pollutant and teratogen that produces cardiac toxicity in the developing zebrafish. Here we adopted a label free quantitative proteomic approach based on normalized spectral abundance factor (NSAF) to investigate the disturbance of the cardiac proteome induced by TCDD in the adult zebrafish heart. The protein expression level changes between heart samples from TCDD-treated and control zebrafish were systematically evaluated by a large scale MudPIT analysis, which incorporated triplicate analyses for both control and TCDD-exposed heart proteomic samples to overcome the data-dependent variation in shotgun proteomic experiments and obtain a statistically significant protein data set with improved quantification confidence. A total of 519 and 443 proteins were identified in hearts collected from control and TCDD-treated zebrafish, respectively, among which 106 proteins showed statistically significant expression changes. After correcting for the experimental variation between replicate analyses by statistical evaluation, 55 proteins exhibited NSAF ratios above 2 and 43 proteins displayed NSAF ratios smaller than 0.5, with statistical significance by t test (p < 0.05). The proteins identified as altered by TCDD encompass a wide range of biological functions including calcium handling, myocardium cell architecture, energy production and metabolism, mitochondrial homeostasis, and stress response. Collectively, our results indicate that TCDD exposure alters the adult zebrafish heart in a way that could result in cardiac hypertrophy and heart failure and suggests a potential mechanism for the diastolic dysfunction observed in TCDD exposed embryos. PMID- 23682716 TI - Aberrant expression of BCL11B in mycosis fungoides and its potential role in interferon-induced apoptosis. AB - BCL11B is a Kruppel-like C2H2-type zinc finger transcription factor, which has been associated with several human malignancies. Recent evidence showed that overexpressed BCL11B conferred chemoresistance to malignant T cells and that inhibiting BCL11B led to increased apoptosis, suggesting its potential pathogenic relevance in cutaneous T-cell lymphomas (CTCL), which were characterized by the resistance to chemotherapy-induced apoptosis. To investigate the expression pattern of BCL11B in different stages of mycosis fungoides (MF), quantitative reverse transcription polymerase chain reaction and immunohistochemistry were performed to compare the mRNA and protein expression among different stages of MF and benign inflammatory dermatoses (BID), respectively. BCL11B demonstrated significant upregulation in all stages of MF, compared with BID, in both mRNA expression level and protein level. In addition, BCL11B expression increased with advancing lesion tumor stage and overall disease stage. Further, to evaluate the dynamic expression of BCL11B under CTCL-directed treatment, BCL11B expression and cell apoptosis were evaluated after interferon (IFN)-alpha-2b and methotrexate treatment on CTCL cell line Hut78 cells. IFN-alpha-2b, but not methotrexate, induced BCL11B inhibition and cell apoptosis, suggesting that BCL11B may play important roles in the anti-CTCL effect of IFN-alpha-2b. In conclusion, our study demonstrated the overexpression of BCL11B in MF lesions and its potential relevance to disease progression. In addition, we provided evidence for BCL11B inhibitory approaches as a potential treatment to target chemoresistant tumor cells in advanced MF. PMID- 23682717 TI - Molecular modeling of vasopressin receptor and in silico screening of V1b receptor antagonists. AB - INTRODUCTION: G protein-coupled receptors (GPCRs) are integral membrane proteins which contain seven-transmembrane-spanning alpha-helices. GPCR-mediated signaling has been associated with various human diseases, positioning GPCRs as attractive targets in the drug discovery field. Recently, through advances in protein engineering and crystallography, the number of resolved GPCR structures has increased dramatically. This growing availability of GPCR structures has greatly accelerated structure-based drug design (SBDD) and in silico screening for GPCR targeted drug discovery. AREAS COVERED: The authors introduce the current status of X-ray crystallography of GPCRs and what has been revealed from the resolved crystal structures. They also review the recent advances in SBDD and in silico screening for GPCR-targeted drug discovery and discuss a docking study, using homology modeling, with the discovery of potent antagonists of the vasopressin 1b receptor. EXPERT OPINION: Several innovative protein engineering techniques and crystallographic methods have greatly accelerated SBDD, not only for already resolved GPCRs but also for those structures which remain unclear. These technological advances are expected to enable the determination of GPCR-fragment complexes, making it practical to perform fragment-based drug discovery. This paves the way for a new era of GPCR-targeted drug discovery. PMID- 23682718 TI - Mass spectrometry assessment of ubiquitin carboxyl-terminal hydrolase L1 partitioning between soluble and particulate brain homogenate fractions. AB - Partitioning of specific proteins between soluble and insoluble forms because of aggregation, membrane attachment, and (or) association with senile plaques and neurofibrillary tangles is a major feature of several neurodegenerative disorders, including Alzheimer's disease (AD). Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is an example of a neuron-specific protein which displays two different dimerization-dependent catalytic activities and can be farnesylated for membrane attachment, oxidized, and truncated. Decreased levels of soluble UCH L1 are inversely proportional to the number of neurofibrillary tangles. Further assessment of a link between UCH-L1 function and the pathogenesis of AD requires an analytical method to separately quantify different UCH-L1 forms. In the present study, we have developed a multiple reaction monitoring (MRM) assay to measure UCH-L1 in the high-speed supernatant and pellet of frontal cortex homogenate. The well-characterized (15)N-labeled quantification concatamer (QconCAT) carrying prototypic tryptic peptides of UCH-L1 was used as an internal standard. The composed protocol of frontal cortex processing includes solubilization and reduction/alkylation of proteins in the presence of 1% sodium dodecyl sulfate (SDS) and following with desalting/delipidation of the sample by chloroform/methanol precipitation with extra water washing of the protein pellet. The measurements were performed for frontal cortex samples from control and severe AD donors. The proposed workflow can be recommended for quantification of partitioning of other proteins of interest. PMID- 23682719 TI - Crescentic glomerulonephritis due to IgA nephropathy or propylthiouracil-induced Mpo-Anca positive vasculitis? PMID- 23682720 TI - Reply: admission CTG--what are the consequences of the current evidence? PMID- 23682721 TI - Induction of labor versus expectant management for pregnancies beyond 41 weeks. AB - OBJECTIVE: To compare the outcome following labor induction at 41 + 1 weeks of gestation and after expectant management and selective induction at 42 completed weeks. METHOD: A retrospective analysis of post-term pregnancies in a 2-year period. In the induction group, women at 41 + 1 weeks of gestation received 3 mg prostaglandin E2 (dinoprostone) in the posterior fornix, repeating the dose 6 h later. Women with a Bishop score >6 had artificial rupture of the membranes. In the expectant management group, women at more than 41 weeks gestation were checked every 2 days in the hospital. In case of abnormalities either in the fetal heart rate evaluation or in the biophysical profile, labor was induced. Labor was also induced in all cases that pregnancy exceeded 42 + 1 gestational weeks. RESULTS: A total of 438 women who met the inclusion criteria were included in the study. In all, 211 comprised the induction group, while the expectant management group consisted of 227 women. The cesarean delivery rate in the induction group was 36.5% compared to 34.4% in the expectant management group, whereas the operative vaginal delivery rate was 11.4 and 9.2% in the two groups, respectively. The vast majority of women in the expectant management group (74%) had a spontaneous onset of labor. CONCLUSION: The perinatal outcome does not differ following a policy of routine labor induction in comparison to expectant management in pregnancies beyond 41 weeks. PMID- 23682722 TI - Abiotrophia endocarditis in children with no underlying heart disease: a rare but a virulent organism. AB - Infective endocarditis is extremely rare in children with structurally normal hearts. The most common etiological agents are staphylococcal and streptococcal species. Nutritionally variant streptococci also classified as Abiotrophia species are a group of fastidious organisms that account for only 5% to 6% of all cases of culture-negative infective endocarditis. Only seven cases of Abiotrophia infective endocarditis have been previously reported in children with no underlying structural heart disease. We report two cases of Abiotrophia infective endocarditis in children without any predisposing factors. Both patients presented with nonspecific symptoms leading to delay in diagnosis. While bacteriological clearance was achieved in both cases, both had a complicated course including development of brain mycotic aneurysms, splenic infarction, renal failure, and irreversible damage to the mitral valve. Both patients required surgical removal of the native mitral valve and replacement. We also present review of seven cases with similar diagnosis published previously in literature and highlight important differences. Our cases highlight special challenges in management of Abiotrophia endocarditis in pediatric patients. As the organism may not be isolated in routine culture media, may present with atypical clinical symptoms and may have a complicated course even without antibiotic failure, a high index of suspicion should be maintained in children with subacute symptoms even with no underlying structural cardiac disease. PMID- 23682723 TI - A combined crossed beam and ab initio investigation of the gas phase reaction of dicarbon molecules (C2; X1Sigmag(+)/a3Piu) with propene (C3H6; X1A'): identification of the resonantly stabilized free radicals 1- and 3 vinylpropargyl. AB - The crossed molecular beam reactions of dicarbon, C2(X(1)Sigmag(+), a(3)Piu), with propene (C3H6; X(1)A') and with the partially deuterated D3 counterparts (CD3CHCH2, CH3CDCD2) were conducted at collision energies of about 21 kJ mol(-1) under single collision conditions. The experimental data were combined with ab initio and statistical (RRKM) calculations to reveal the underlying reaction mechanisms. Both on the singlet and triplet surfaces, the reactions involve indirect scattering dynamics and are initiated by the addition of the dicarbon reactant to the carbon-carbon double bond of propene. These initial addition complexes rearrange via multiple isomerization steps leading ultimately via atomic hydrogen elimination from the former methyl and vinyl groups to the formation of 1-vinylpropargyl and 3-vinylpropargyl. Both triplet and singlet methylbutatriene species were identified as important reaction intermediates. On the singlet surface, the unimolecular decomposition of the reaction intermediates was found to be barrier-less, whereas on the triplet surface, tight exit transition states were involved. In combustion flames, both radicals can undergo a hydrogen-atom assisted isomerization leading ultimately to the thermodynamically most stable cyclopentadienyl isomer. Alternatively, in a third body process, a subsequent reaction of 1-vinylpropargyl or 3-vinylpropargyl radicals with the propargyl radical might yield to the formation of styrene (C6H5C2H3) in an entrance barrier-less reaction under combustion-like conditions. This presents a strong alternative to the formation of styrene via the reaction of phenyl radicals with ethylene, which is affiliated with an entrance barrier of about 10 kJ mol(-1). PMID- 23682724 TI - Transgenic expression of human neutrophil peptide-1 enhances hepatic fibrosis in mice fed a choline-deficient, L-amino acid-defined diet. AB - BACKGROUND: Neutrophils infiltrate the livers of patients with nonalcoholic steatohepatitis (NASH). Human neutrophil peptides (HNPs) induce cytokine and chemokine production under inflammatory conditions, which may contribute to the progression of NASH. In this study, we focused on the effects of HNP-1 on hepatic steatosis and fibrosis in a mouse model of NASH induced by a choline-deficient, L amino acid-defined (CDAA) diet. MATERIALS & METHODS: We generated transgenic mice expressing HNP-1 under the control of a beta-actin-based promoter. HNP-1 transgenic and wild-type C57BL/6N mice were fed a CDAA diet for 16 weeks to induce hepatic steatosis and fibrosis. Serological and histological features were examined, and the effects of HNP-1 on hepatic stellate cell lines were assessed. RESULTS: HNP-1 transgenic and wild-type mice fed the CDAA diet showed no significant differences in serum alanine aminotransferase levels or the degree of hepatic steatosis based on Oil red O staining and hepatic triglyceride content. In contrast, Sirius Red and Azan staining showed significantly more severe hepatic fibrosis in HNP-1 transgenic mice compared with wild-type mice. In addition, significantly more alpha-smooth muscle actin-positive hepatic stellate cells were observed in the transgenic mice than in the wild-type mice. Finally, the proliferation of the LI90 hepatic stellate cell line increased in response to HNP-1. CONCLUSION: Our data indicate that HNP-1 enhances hepatic fibrosis in fatty liver by inducing hepatic stellate cell proliferation. Thus, neutrophil derived HNP-1 may contribute to the progression of NASH. PMID- 23682725 TI - Canonical transient receptor potential 3 channel triggers vascular endothelial growth factor-induced intracellular Ca2+ oscillations in endothelial progenitor cells isolated from umbilical cord blood. AB - Endothelial colony-forming cells (ECFCs) are the only endothelial progenitor cells (EPCs) that are capable of acquiring a mature endothelial phenotype. ECFCs are mainly mobilized from bone marrow to promote vascularization and represent a promising tool for cell-based therapy of severe ischemic diseases. Vascular endothelial growth factor (VEGF) stimulates the proliferation of peripheral blood derived ECFCs (PB-ECFCs) through oscillations in intracellular Ca(2+) concentration ([Ca(2+)]i). VEGF-induced Ca(2+) spikes are driven by the interplay between inositol-1,4,5-trisphosphate (InsP3)-dependent Ca(2+) release and store operated Ca(2+) entry (SOCE). The therapeutic potential of umbilical cord blood derived ECFCs (UCB-ECFCs) has also been shown in recent studies. However, VEGF induced proliferation of UCB-ECFCs is faster compared with their peripheral counterpart. Unlike PB-ECFCs, UCB-ECFCs express canonical transient receptor potential channel 3 (TRPC3) that mediates diacylglycerol-dependent Ca(2+) entry. The present study aimed at investigating whether the higher proliferative potential of UCB-ECFCs was associated to any difference in the molecular underpinnings of their Ca(2+) response to VEGF. We found that VEGF induces oscillations in [Ca(2+)]i that are patterned by the interaction between InsP3 dependent Ca(2+) release and SOCE. Unlike PB-ECFCs, VEGF-evoked Ca(2+) oscillations do not arise in the absence of extracellular Ca(2+) entry and after pharmacological (with Pyr3 and flufenamic acid) and genetic (by employing selective small interference RNA) suppression of TRPC3. VEGF-induced UCB-ECFC proliferation is abrogated on inhibition of the intracellular Ca(2+) spikes. Therefore, the Ca(2+) response to VEGF in UCB-ECFCs is shaped by a different Ca(2+) machinery as compared with PB-ECFCs, and TRPC3 stands out as a promising target in EPC-based treatment of ischemic pathologies. PMID- 23682726 TI - Enhanced stability of newly isolated trimeric l-methionine-N-carbamoylase from Brevibacillus reuszeri HSN1 by covalent immobilization. AB - Newly isolated and partially purified trimeric l-methionine-N-carbamoylase from Brevibacillus reuszeri HSN1 was immobilized by covalent coupling to a well-known support material, Eupergit(r) C. Approximately 80% enzyme activity yield was achieved with ~61% binding of a soluble protein from a solution containing 5 mg/mL protein. The immobilized preparation was found to be quite unstable due to a poor multisubunit covalent interaction of trimeric enzyme. Additional cross linking with polyaldehyde-dextran was done to sustain the biotechnological application of immobilized enzyme. The temperature and pH optima of immobilized enzyme were increased by 10 degrees C and 0.5 unit, respectively. The enzyme was significantly stabilized and retained ~93% enzyme activity when incubated at 60 degrees C for 60 Min, whereas free enzyme lost ~50% activity. It was recycled nine times with ~100% conversion efficiency when batch experiments were carried out at 35 degrees C, pH 7.5, for the 180 Min cycle, using 5% N-carbamoyl-l methionine as the substrate. The half-life of the immobilized preparation was determined as 23 cycles and is significant. Approximately 50% of enzyme activity was retained even after 5 months of storage at 4 degrees C, whereas free enzyme lost complete enzyme activity. Hence, we could enhance the stability of l methionine-N-carbamoylase to make it a potential biocatalyst for biotechnological production of alpha-amino acids. PMID- 23682727 TI - Uncertainty management and information seeking in cancer survivorship. AB - Uncertainty is a common experience among people coping with chronic illness. For many individuals, managing information is used as a means of coping with illness related uncertainty. In-depth interviews with 60 cancer survivors and partners were conducted. Many of the participants in this study reported feeling uncertain about the challenges awaiting them in cancer survivorship and reported experiencing various information behaviors and challenges relating to their uncertainty management. These results have important implications for health care providers and imply that continued care and information provision, after cancer treatment is complete, would facilitate adaptive survivorship. PMID- 23682728 TI - Complementary and alternative medicine for autism spectrum disorders: rationale, safety and efficacy. AB - Complementary and alternative medicine is widely used for children with autism spectrum disorder, despite uncertainty regarding efficacy. This review describes complementary and alternative practices commonly used among this population, the rationale for the use of each practice, as well as the side-effect profile and evidence for efficacy. The existing evidence base indicates that melatonin can be recommended as a treatment for sleeping disturbances associated with autism spectrum disorder, while secretin can be rejected as an efficacious treatment for broader autistic symptoms. There is insufficient evidence to draw conclusions on the efficacy of modified diets, hyperbaric oxygen therapy, immune therapy, and vitamin and fatty acid supplementation. There is a clear need for methodologically rigorous studies to provide evidence-based guidance to families and clinicians regarding complementary and alternative practices for individuals with autism spectrum disorders. PMID- 23682729 TI - Effect of hyoscine butylbromide (Buscopan(r)) on cholinergic pathways in the human intestine. AB - BACKGROUND: Hyoscine butylbromide (HBB, Buscopan((r)) ) is clinically used to treat intestinal cramps and visceral pain. Various studies, mainly on animal tissues, suggested that its antimuscarinic action is responsible for its spasmolytic effect. However, functional in vitro studies with human tissue have not been performed so far. METHODS: We wanted to provide a comprehensive study on the mode of action of HBB in human intestinal samples and investigated HBB (1 nmol L(-1) -10 MUmol L(-1)) effects on muscle activity with isometric force transducers and calcium imaging, on epithelial secretion with Ussing chamber technique and on enteric neurons using fast neuroimaging. KEY RESULTS: Hyoscine butylbromide concentration dependently reduced muscle contractions, calcium mobilization, and epithelial secretion induced by the muscarinic agonist bethanechol with IC50 values of 429, 121, and 224 nmol L(-1), respectively. Forskolin-induced secretion was not altered by HBB. Cholinergic muscarinic muscle and epithelial responses evoked by electrical nerve stimulation were inhibited by 1-10 MUmol L(-1) HBB. Moreover, HBB significantly reduced the bethanechol-induced action potential discharge in enteric neurons. Interestingly, we observed that high concentrations of HBB (10 MUmol L(-1)) moderately decreased nicotinic receptor-mediated secretion, motility, and nerve activity. CONCLUSIONS & INFERENCES: The results demonstrated the strong antimuscarinic action of HBB whereas the nicotinic antagonism at higher concentrations plays at most a moderate modulatory role. The muscle relaxing effect of HBB and its inhibition of muscarinic nerve activation likely explain its clinical use as an antispasmodic drug. Our results further highlight a so far unknown antisecretory action of HBB which warrants further clinical studies on its use in secretory disorders. PMID- 23682730 TI - Comprehensive proteomic analysis of Trypanosoma cruzi epimastigote cell surface proteins by two complementary methods. AB - Trypanosoma cruzi is a protozoan that causes Chagas' disease, a neglected infectious illness that affects millions of people, mostly in Latin America. Here, the cell surface subproteome of the T. cruzi epimastigote life form was characterized. In order to prepare samples enriched in epimastigote plasma membrane protein, two distinct methodologies were optimized and evaluated. The first methodology was based on cell surface trypsinization (Shave) of intact living cells while the second approach used biotinylation of cell surface proteins followed by streptavidin affinity chromatography isolation of the labeled proteins. Both T. cruzi subproteomes were analyzed by LC-MS/MS. The results showed that the methodologies offered comprehensive and complementary information about the parasite's plasma membrane subproteome. PMID- 23682731 TI - Clinical utility of the Neuropsychological Assessment Battery (NAB) after unilateral stroke. AB - The NAB is a comprehensive battery assessing five cognitive domains (Attention, Language, Memory, Spatial, Executive Function). Despite the advantage of co normative domain data, its clinical utility is not well established because few studies have reported full-battery findings. The aim of this study was to determine if the NAB was sensitive to well documented hemispheric differences in language and spatial skills after unilateral stroke. We compared demographically matched control participants (n = 52) and individuals after left (LHD, n = 36) or right (RHD, n = 33) hemisphere damage due to stroke on the NAB, parts of the Western Aphasia Battery, and traditional visuospatial tasks. Both stroke groups showed impaired NAB Attention, Spatial, and Executive Functions relative to controls, while the LHD group was more impaired than control and RHD groups on Language and Memory modules. LHD patients with aphasia on traditional measures performed worse than control and non-aphasic LHD patients on all NAB domains. RHD patients with spatial impairment on traditional measures performed worse than controls, but not RHD patients without spatial impairment, on the NAB Spatial domain. Findings suggest the NAB is generally comparable to traditional language and visuospatial measures, and it sufficiently detects attention and executive deficits. PMID- 23682732 TI - Fetal growth potential in Kinshasa, Dr Congo. AB - OBJECTIVES: To determine the local prediction equation of birthweight. -To establish fetal growth potential. -To seek for ability of customised birthweight to identify growth disordered neonates. METHODOLOGY: A sample of 261 mother infant couples was studied from 20 week gestation throughout term in the largest maternity of Kinshasa. Using Gardosi's model local prediction equation of birthweight and fetal growth potential were established. After calculating customised and population-based optimal birthweights, we evaluated neonatal outcomes according to both standards. RESULTS: Maternal fat mass had strong positive correlation with birthweight (p=0.003) but did not bring significant change into the prediction equation of birthweight (R(2)=0.264) probably due to its strong correlation with booking weight. The local coefficients and constant were similar to Caucasian based models. Although risk for neonatal adverse outcome was more likely to be higher with customised standards, the small number of SGAs and LGAs as well as large confidence intervals could not allow to draw strong conclusions. CONCLUSION: The value of predictive equation of birthweight of our model is similar to that of European, American, and Oceanian models, confirming, in our sub-Saharan setting too, the ability of customised birthweight to better identify growth disordered neonates according to their growth potential. PMID- 23682733 TI - Using glycinylation, a chemical derivatization technique, for the quantitation of ubiquitinated proteins. AB - The quantitation of lysine post-translational modifications (PTMs) by bottom-up mass spectrometry is convoluted by the need for analogous derivatives and the production of different tryptic peptides from the unmodified and modified versions of a protein. Chemical derivatization of lysines prior to enzymatic digestion circumvents these problems and has proven to be a successful method for lysine PTM quantitation. The most notable example is the use of deuteroacetylation to quantitate lysine acetylation. In this work, levels of lysine ubiquitination were quantitated using a structurally homologous label that is chemically similar to the diglycine (GlyGly) tag, which is left at the ubiquitination site upon trypsinolysis. The LC-MS analysis of a chemically equivalent monoglycine (Gly) tag that is analogous to the corresponding GlyGly tag proved that the monoglycine tag can be used for the quantitation of ubiquitination. A glycinylation protocol was then established for the derivatization of proteins to label unmodified lysine residues with a single glycine tag. Ubiquitin multimers were used to show that after glycinylation and tryptic digestion, the mass spectrometric response from the corresponding analogous tagged peptides could be compared for relative quantitation. For a proof of principle regarding the applicability of this technique to the analysis of ubiquitination in biological samples, the glycinylation technique was used to quantitate the increase in monoubiquitinated histone H2B that is observed in yeast which lacks the enzyme responsible for deubiquitinating H2B-K123, compared to wild-type yeast. PMID- 23682734 TI - Design and construction of supramolecular nanobeacons for enzyme detection. AB - Molecular beacons are typically water-soluble molecules that can convert specific chemical reactions or binding events into measurable optical signals, providing a noninvasive means to help understand cellular and subcellular activities at the molecular level. However, the soluble form of the current molecular beacon design often leads to their poor stability and facile degradation by nonspecific enzymes, and as a result, this undesired activation could give rise to false signals and thus poses a limitation for accurate detection of enzymatic activities. Here we report a proof-of-concept design and synthesis of a new type of supramolecular nanobeacon that is resistant to nonspecific enzymatic degradation in the self-assembled state but can be effectively cleaved by the target enzyme in the monomeric form. Our results show that the nanobeacon with a GFLG peptide linker could serve as an indicator for the presence of a lysosomal enzyme, cathepsin B. PMID- 23682736 TI - Iridium-catalyzed borylation of secondary benzylic C-H bonds directed by a hydrosilane. AB - Most functionalizations of C-H bonds by main-group reagents occur at aryl or methyl groups. We describe a highly regioselective borylation of secondary benzylic C-H bonds catalyzed by an iridium precursor and 3,4,7,8-tetramethyl-1,10 phenanthroline as the ligand. The reaction is directed to the benzylic position by a hydrosilyl substituent. This hydrosilyl directing group is readily deprotected or transformed to other functional groups after the borylation reaction, providing access to a diverse set of secondary benzylboronate esters by C-H borylation chemistry. PMID- 23682735 TI - Reduction of aromatic and heterocyclic aromatic N-hydroxylamines by human cytochrome P450 2S1. AB - Many aromatic amines and heterocyclic aromatic amines (HAAs) are known carcinogens for animals, and there is also strong evidence of some in human cancer. The activation of these compounds, including some arylamine drugs, involves N-hydroxylation, usually by cytochrome P450 enzymes (P450) in Family 1 (1A2, 1A1, and 1B1). We previously demonstrated that the bioactivation product of the anticancer agent 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203), an N-hydroxylamine, can be reduced by P450 2S1 to its amine precursor under anaerobic conditions and, to a lesser extent, under aerobic conditions [Wang, K., and Guengerich, F. P. (2012) Chem. Res. Toxicol. 25, 1740-1751]. In the study presented here, we tested the hypothesis that P450 2S1 is involved in the reductive biotransformation of known carcinogenic aromatic amines and HAAs. The N hydroxylamines of 4-aminobiphenyl (4-ABP), 2-naphthylamine (2-NA), and 2 aminofluorene (2-AF) were synthesized and found to be reduced by P450 2S1 under both anaerobic and aerobic conditions. The formation of amines due to P450 2S1 reduction also occurred under aerobic conditions but was less apparent because the competitive disproportionation reactions (of the N-hydroxylamines) also yielded amines. Further, some nitroso and nitro derivatives of the arylamines could also be reduced by P450 2S1. None of the amines tested were oxidized by P450 2S1. These results suggest that P450 2S1 may be involved in the reductive detoxication of several of the activated products of carcinogenic aromatic amines and HAAs. PMID- 23682738 TI - Relationship between Ljungan virus antibodies, HLA-DQ8, and insulin autoantibodies in newly diagnosed type 1 diabetes children. AB - Environmental factors, including viral infections, may explain an increasing and fluctuating incidence of childhood type 1 diabetes (T1D). Ljungan virus (LV) isolated from bank voles have been implicated, but it is unclear whether LV contributes to islet autoimmunity, progression to clinical onset, or both, of T1D. The aim was to test whether LV antibodies (LVAb) were related to HLA-DQ and islet autoantibodies in newly diagnosed T1D patients (n=676) and controls (n=309). Patients, 0-18 years of age, diagnosed with T1D in 1996-2005 were analyzed for LVAb, HLA-DQ genotypes, and all seven known islet autoantibodies (GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, and ZnT8QA). LVAb at 75(th) percentile, defined as cut off, was 90 (range 6-3936) U/mL and 4(th) quartile LVAb were found in 25% (170/676) of which 64% were <10 (n=108, p<0.0001), and 27% were<5 (n=45; p<0.0001) years old. The 4(th) quartile LVAb in children <10 years of age correlated to HLA DQ2/8, 8/8, and 8/X (p<0.0001). Furthermore, in the group with 4(th) quartile LVAb, 55% were IAA positive (p=0.01) and correlation was found between 4(th) quartile LVAb and IAA in children <10 years of age (p=0.035). It is concluded that 1) LVAb were common among the young T1D patients and LVAb levels were higher in the younger age groups; 2) 4(th) quartile LVAb correlated with IAA; and 3) there was a correlation between 4(th) quartile LVAb and HLA-DQ8, particularly in the young patients. The presence of LVAb supports the notion that prior exposure to LV may be associated with T1D. PMID- 23682737 TI - Essential role of NADPH oxidase-dependent reactive oxygen species generation in regulating microRNA-21 expression and function in prostate cancer. AB - AIMS: Oncogenic microRNAs (miRs) promote tumor growth and invasiveness. One of these, miR-21, contributes to carcinogenesis in prostate and other cancers. In the present study, we tested the hypothesis that NADPH oxidase-dependent reactive oxygen species (ROS) regulate the expression and function of miR-21 and its target proteins, maspin and programmed cell death 4 (PDCD4), in prostate cancer cells. RESULTS: The highly aggressive androgen receptor negative PC-3M-MM2 prostate cancer cells demonstrated high expression of miR-21 and p47(phox) (an essential subunit of NADPH oxidase). Using loss-of-function strategy, we showed that transfection of PC-3M-MM2 cells with anti-miR-21- and p47(phox) siRNA (si p47(phox)) led to reduced expression of miR-21 with concurrent increase in maspin and PDCD4, and decreased the invasiveness of the cells. Tail-vein injections of anti-miR-21- and si-p47(phox)-transfected PC-3M-MM2 cells in severe combined immunodeficient mice reduced lung metastases. Clinical samples from patients with advanced prostate cancer expressed high levels of miR-21 and p47(phox), and low expression of maspin and PDCD4. Finally, ROS activated Akt in these cells, the inhibition of which reduced miR-21 expression. INNOVATION: The levels of NADPH oxidase-derived ROS are high in prostate cancer cells, which have been shown to be involved in their growth and migration. This study demonstrates that ROS produced by this pathway is essential for the expression and function of an onco miR, miR-21, in androgen receptor-negative prostate cancer cells. CONCLUSION: These data demonstrate that miR-21 is an important target of ROS, which contributes to the highly invasive and metastatic phenotype of prostate cancer cells. PMID- 23682740 TI - Sudden unexpected death due to hemophagocytic lymphohistiocytosis syndrome. AB - The hemophagocytic lymphohistiocytosis (HLH) syndrome is a hyperimmune disorder characterized by lymphohistiocytic infiltrations, elevated cytokine levels in the blood, macrophage activation, and hemophagocytosis, frequently presenting with a febrile septic picture. This unusual disease is more common in infancy and childhood than adulthood. It is classified as primary or familial when a genetic defect is identified and secondary or acquired when triggered by certain infections, autoimmune disorders, or malignancies. If or when such patients expire, they typically do so within a hospital or under a physician's care and so such cases rarely come to the attention of forensic pathologists. We report on the unexpected deaths of two hospitalized adult cases of HLH brought to autopsy without a premortem diagnosis. Postmortem examination demonstrated marked hepatosplenomegaly and lymphadenopathy in association with hemophagocytosis. Although very uncommon HLH must be considered in infants, children, or adults who die unexpectedly with an undiagnosed septic presentation. PMID- 23682739 TI - The paradox of overnutrition in aging and cognition. AB - Populations of many countries are becoming increasingly overweight and obese, driven largely by excessive calorie intake and reduced physical activity; greater body mass is accompanied by epidemic levels of comorbid metabolic diseases. At the same time, individuals are living longer. The combination of aging and the increased prevalence of metabolic disease is associated with increases in aging related comorbid diseases such as Alzheimer's disease, cerebrovascular dementia, and sarcopenia. Here, correlative and causal links between diseases of overnutrition and diseases of aging and cognition are explored. PMID- 23682741 TI - Acetobacter strains isolated during the acetification of blueberry (Vaccinium corymbosum L.) wine. AB - Highbush blueberries (Vaccinium corymbosum L.) are known to have positive health benefits. The production of blueberry vinegar is one method to preserve this seasonal fruit and allow extended consumption. In this study, blueberry wine acetification was performed with naturally occurring micro-organisms and with an inoculated Acetobacter cerevisiae strain. Acetifications were carried out in triplicate using the Schutzenbach method. The successful spontaneous processes took up to 66% more time than the processes involving inoculation. The isolation of acetic acid bacteria (AAB) and the analysis of these AAB using molecular methods allowed the identification of the main genotypes responsible of the blueberry acetification. Although the Acet. cerevisiae strain was the predominant strain isolated from the inoculated process samples, Acetobacter pasteurianus was isolated from samples for both processes and was the only species present in the spontaneous acetification samples. To the best of our knowledge, this is the first report describing the identification and variability of AAB isolated during blueberry acetification. The isolated Acet. pasteurianus strains could be used for large-scale blueberry vinegar production or as a starter culture in studies of other vinegar production methods. PMID- 23682742 TI - External and internal shell formation in the ramshorn snail Marisa cornuarietis are extremes in a continuum of gradual variation in development. AB - BACKGROUND: Toxic substances like heavy metals can inhibit and disrupt the normal embryonic development of organisms. Exposure to platinum during embryogenesis has been shown to lead to a "one fell swoop" internalization of the shell in the ramshorn snail Marisa cornuarietis, an event which has been discussed to be possibly indicative of processes in evolution which may result in dramatic changes in body plans. RESULTS: Whereas at usual cultivation temperature, 26 degrees C, platinum inhibits the growth of both shell gland and mantle edge during embryogenesis leading to an internalization of the mantle and, thus, also of the shell, higher temperatures induce a re-start of the differential growth of the mantle edge and the shell gland after a period of inactivity. Here, developing embryos exhibit a broad spectrum of shell forms: in some individuals only the ventral part of the visceral sac is covered while others develop almost "normal" shells. Histological studies and scanning electron microscopy images revealed platinum to inhibit the differential growth of the shell gland and the mantle edge, and elevated temperature (28 - 30 degrees C) to mitigate this platinum effect with varying efficiency. CONCLUSION: We could show that the formation of internal, external, and intermediate shells is realized within the continuum of a developmental gradient defined by the degree of differential growth of the embryonic mantle edge and shell gland. The artificially induced internal and intermediate shells are first external and then partly internalized, similar to internal shells found in other molluscan groups. PMID- 23682743 TI - Community end-of-life care among Chinese older adults living in nursing homes. AB - AIM: The aim of the present study was to investigate the preference and willingness-to-pay (WTP) of older Chinese adults for community end-of-life care in a nursing home rather than a hospital. METHODS: A total of 1540 older Chinese adults from 140 nursing homes were interviewed. Four hypothetical questions were asked to explore their preferences for end-of-life care. Using a discrete choice approach, specific questions explored acceptable trade-offs between three attributes: availability of doctors onsite, attitude of the care staff and additional cost of care per month. RESULTS: Approximately 35% of respondents preferred end-of-life care in the nursing home, whereas 23% of them would consider it in a better nursing home. A good attitude of staff was the most important attribute of the care site. Respondents were willing to pay an extra cost of US$5 (HK$39) per month for more coverage of doctor's time, and US$49 (HK$379) for a better attitude of staff in the nursing home. The marginal WTP for both more coverage of doctor's time and better attitude of staff amounted to US$54 (HK$418). Respondents on government subsidy valued the cost attribute more highly, as expected, validating the hypothesis that those respondents would be less willing to pay an additional cost for end-of-life care. CONCLUSIONS: Older Chinese adults living in nursing homes are willing to pay an additional fee for community end-of-life care services in nursing homes. Both the availability of the doctor and attitudes of nursing home staff are important, with the most important attribute being the staff attitudes. Geriatr Gerontol Int 2013; 14: 273 284. PMID- 23682744 TI - Optical constants of amorphous, transparent titanium-doped tungsten oxide thin films. AB - We report on the optical constants and their dispersion profiles determined from spectroscopic ellipsometry (SE) analysis of the 20%-titanium (Ti) doped of tungsten oxide (WO3) thin films grown by sputter-deposition. The Ti-doped WO3 films grown in a wide range of temperatures (25-500 degrees C) are amorphous and optically transparent. SE data indicates that there is no significant interdiffusion at the film-substrate interface for a W-Ti oxide film growth of ~90 nm. The index refraction (n) at lambda = 550 nm vary in the range of 2.17 2.31 with a gradual increase in growth temperature. A correlation between the growth conditions and optical constants is discussed. PMID- 23682745 TI - Nutrition self-efficacy assessment: development of a questionnaire and evaluation of reliability in African-American and Latino children. AB - BACKGROUND: We aimed to develop tools that could be reliably used to evaluate self-efficacy for consuming vegetables and low-sugar foods and beverages for African American and Latino children living in inner-city communities. METHODS: A total of 112 children, aged 8-11 years, identified by a parent as being either African-American or Latino, were recruited and administered questionnaires. Internal consistency, a measure of reliability, was assessed by calculating the Cronbach's alpha of test scores. RESULTS: Cronbach's alpha exceeded the threshold of acceptability of 0.70 for the Authors' Vegetables Self-Efficacy Index, and all three Low-Sugar Self-Efficacy Indices, including the Reference Index, the Authors' Low-Sugar Food and Beverage Index, and the Low-Sugar Beverages Index. CONCLUSIONS: We present internally consistent tools that could be reliably used to evaluate self-efficacy for consuming vegetables and low-sugar foods and beverages in 8-11-year-old African-American and Latino children from low socio economic communities. PMID- 23682746 TI - Adverse reactions and alleged allergy to local anesthetics: analysis of 331 patients. AB - The aim of this study was to determine the prevalence of true local anesthetic (LA) allergy among patients referred for suspected hypersensitivity and to describe the main characteristics of adverse drug reactions (ADR) induced by LA in our population. We retrospectively analyzed the medical files of patients referred to the Department of Dermatovenereology, University Hospital Center Rijeka, Rijeka, Croatia, for the investigation of LA hypersensitivity in the period between January 2000 and December 2012. A total of 331 patients underwent skin testing and, in cases of negative results, subcutaneous exposition to LA. In patients with suspected delayed reaction, patch test was performed. Altogether, 331 patients reported 419 independent ADR occurring during 346 procedures. Most commonly, patients reported having only one ADR, but 41 (12.4%) of them had two reactions, 14 (4.2%) had three, five (1.5%) had four and in one patient (0.3%) five ADR to LA were observed. The majority of reactions occurred during dental procedures when most commonly lidocaine and articaine were used. Local reactions were reported in 44 patients, whereas 490 general symptoms occurred during 375 independent ADR in 287 patients. The most common symptoms were cardiovascular system reactions in 89 patients (18.2%). Allergic reaction was detected in three patients (0.91%). One patient showed immediate-type reaction to bupivacaine and two patients had a delayed-type reaction to lidocaine. Adverse reactions to LA are common and are mostly due to their pharmacological properties and drug combinations or psychogenic origin. Allergic accidents to LA are rare. PMID- 23682748 TI - Vibrational and theoretical studies of the structure and adsorption mode of m nitrophenyl alpha-guanidinomethylphosphonic acid analogues on silver surfaces. AB - This work presents Fourier transform Raman (FT-Raman), Fourier transform absorption infrared (FT-IR), and surface-enhanced Raman scattering (SERS) spectroscopic investigations of three m-nitrophenyl alpha-guanidinomethylphonic acids, including m-NO2PhG(cHex)P, m-NO2PhG(Morf)P, and m-NO2PhG(An)P, adsorbed onto colloidal and roughened silver surfaces. The SERS spectra were deconvoluted to determine the overlapped bands from which the specific molecular orientation can be deducted. The vibrational wavenumbers are calculated through density functional theory (DFT) at the B3LYP/6-31++G** level with the Gaussian 03, Raint, GaussSum 0.8, and GAR2PED software packages. The experimental and calculated vibrational bands are compared to those from SERS for the investigated compounds adsorbed on colloidal and roughened silver surfaces. The geometry of these molecules on the SERS-active silver surfaces is deduced from the observed changes in both the intensity and width of the Raman bands in the spectra of the bound species relative to the free species. PMID- 23682749 TI - Human factors in the development of complications of airway management: preliminary evaluation of an interview tool. AB - The 4th National Audit Project of the Royal College of Anaesthetists and the Difficult Airway Society (NAP4) analysed reports of serious events arising from airway management during anaesthesia, intensive care and the emergency department. We conducted supplementary telephone interviews with 12 anaesthetists who had reported to NAP4, aiming to identify causal factors using a method based on the Human Factors Investigation Tool (HFIT). We identified contributing human factors in all cases (median [range] 4.5 [1-10] per case). The most frequent related to: situation awareness (failures to anticipate, wrong decision) (nine cases); job factors (e.g. task difficulty; staffing, time pressure) (eight cases); and person factors (e.g. tiredness, hunger, stress) (six cases). Protective factors, such as teamwork and communication, were also revealed. The post-report HFIT interview method identified relevant human factors and this approach merits further testing as part of the investigation of anaesthetic incidents. PMID- 23682750 TI - Pulse-based non-thermal plasma (NTP) disrupts the structural characteristics of bacterial biofilms. AB - Bacterial biofilms were constructed in vitro with two pathogenic strains of Pseudomonas aeruginosa and Staphylococcus aureus using a modified, novel sequential bioreactor system. The structure and stability of bacterial biofilms were evaluated following exposure to non-thermal plasma (NTP) discharge. Mathematical software was used to determine structural changes as biofilms grew over the course of 7 days. Statistical modeling was also performed to assess the ability of NTP to affect the development of the biofilms over different periods of time. Several structural characteristics were significantly affected by NTP discharge whereas others were unaffected. Changes in the three-dimensional structure of the biofilm following introduction of NTP was not limited to one period of development. The mechanism for this phenomenon is not understood but is likely to be a dual, synergistic effect due to the composition of the reactive species and other plasma-associated molecules isolated previously in the NTP discharge used in this study. PMID- 23682751 TI - Bacterial recognition of silicon nanowire arrays. AB - Understanding how living cells interact with nanostructures is integral to a better understanding of the fundamental principles of biology and the development of next-generation biomedical/bioenergy devices. Recent studies have demonstrated that mammalian cells can recognize nanoscale topographies and respond to these structures. From this perspective, there is a growing recognition that nanostructures, along with their specific physicochemical properties, can also be used to regulate the responses and motions of bacterial cells. Here, by utilizing a well-defined silicon nanowire array platform and single-cell imaging, we present direct evidence that Shewanella oneidensis MR-1 can recognize nanoscale structures and that their swimming patterns and initial attachment locations are strongly influenced by the presence of nanowires on a surface. Analyses of bacterial trajectories revealed that MR-1 cells exhibited a confined diffusion mode in the presence of nanowires and showed preferential attachment to the nanowires, whereas a superdiffusion mode was observed in the absence of nanowires. These results demonstrate that nanoscale topography can affect bacterial movement and attachment and play an important role during the early stages of biofilm formation. PMID- 23682752 TI - Coronary sinus obstruction after atrioventricular canal defect repair. AB - The coronary sinus can become obstructed with any instrumentation at or near the ostium such as in atrioventricular canal defect repairs. This complication may lead to a wide range of consequences including dyspnea, angina, myocardial infarction, and sudden death. The following report illustrates the importance of careful perioperative echocardiographic evaluation of the coronary sinus in procedures that may affect the sinus and its ostium. PMID- 23682753 TI - Regeneration of human bone using different bone substitute biomaterials. AB - PURPOSE: The present study aimed to assess clinical and biological performances of several bone substitute biomaterials (BSBs). MATERIALS AND METHODS: The evaluation was conducted at 6 months and after several years on 295 patients undergoing sinus augmentation with 13 different BSBs; the data belonging to previously published studies have been analyzed using innovative mathematical models to evaluate the bone regenerative index (Br) and the structural density index (Ds). RESULTS: After 6 months, compared to the Ds index of native bone, the regenerated bone showed a D3 bone type; while, after several years, the regenerated bone type was D2, with an evident increase in the density of the regenerated bone over time. Moreover, the values of Br were higher for combined biomaterials indicating a fewer amount of residual particles and marrow spaces, while the values of Ds were higher for anorganic bovine bone indicating a greater new bone formation and a lesser amount of marrow spaces. After 20 years, the bone regenerated using hydroxyapatite still had a D4 bone quality. CONCLUSIONS: After 6 months of healing, the regenerated bone had a composite structure resembling poor D3 bone type, and covered approximately one-third of the space filled by BSBs. None of the evaluated biomaterials seemed to be ideal. PMID- 23682754 TI - Social influence in child care centers: a test of the theory of normative social behavior. AB - Child care centers are a unique context for studying communication about the social and personal expectations about health behaviors. The theory of normative social behavior (TNSB; Rimal & Real, 2005 ) provides a framework for testing the role of social and psychological influences on handwashing behaviors among child care workers. A cross-sectional survey of child care workers in 21 centers indicates that outcome expectations and group identity increase the strength of the relationship between descriptive norms and handwashing behavior. Injunctive norms also moderate the effect of descriptive norms on handwashing behavior such that when strong injunctive norms are reported, descriptive norms are positively related to handwashing, but when weak injunctive norms are reported, descriptive norms are negatively related to handwashing. The findings suggest that communication interventions in child care centers can focus on strengthening injunctive norms in order to increase handwashing behaviors in child care centers. The findings also suggest that the theory of normative social behavior can be useful in organizational contexts. PMID- 23682755 TI - The role of processing speed in the Brief Visuospatial Memory Test - revised. AB - The Brief Visuospatial Memory Test - Revised (BVMT-R) is a commonly used, commercialized, assessment tool to measure visuospatial learning and memory abilities across research and clinical settings. In this study we evaluated the influence of processing speed and executive functioning on BVMT-R learning, memory, and percent retention scores. A total of 141 cognitively healthy older adults completed the BVMT-R along with measures of visuoconstructional abilities (BVMT-R copy), speeded processing (Symbol Digit Modalities Test-oral), and executive function (FAS). After controlling for age and visuoconstructional abilities, hierarchical regression models showed that the processing speed measure was a unique predictor of both BVMT-R learning and memory performances, while the executive function measure was not. The visuoconstructional measure was the only unique predictor of BVMT-R percent retention. The findings suggest that, when interpreting the BVMT-R learning and memory scores of patients who exhibit speeded processing deficits, the impact of slowed processing speed on performance should be considered. PMID- 23682756 TI - Barriers and facilitators to treatment participation by adolescents in a community mental health clinic. AB - An estimated 40-60% of children in mental health treatment drop out before completing their treatment plans, resulting in increased risk for ongoing clinical symptoms and functional impairment, lower satisfaction with treatment, and other poor outcomes. Research has focused predominately on child, caregiver, and family factors that affect treatment participation in this population and relatively less on organizational factors. Findings are limited by focus on children between 3 and 14 years of age and included only caregivers' and/or therapists' perspectives. The purpose of this descriptive qualitative study was to identify organizational factors that influenced participation in treatment, with special attention to factors that contributed to dropout in adolescents. The sample included 12 adolescent-caregiver dyads drawn from two groups in a large public mental health provider database. Analysis of focus group interview data revealed several perceived facilitators and barriers to adolescent participation in treatment and provided several practical suggestions for improving treatment participation. Implications of the findings for psychiatric mental health nurses and other clinicians who provide services to families of adolescents with mental health concerns are discussed. PMID- 23682757 TI - One-pot synthesized aptamer-functionalized CdTe:Zn2+ quantum dots for tumor targeted fluorescence imaging in vitro and in vivo. AB - High quality and facile DNA functionalized quantum dots (QDs) as efficient fluorescence nanomaterials are of great significance for bioimaging both in vitro and in vivo applications. Herein, we offer a strategy to synthesize DNA functionalized Zn(2+) doped CdTe QDs (DNA-QDs) through a facile one-pot hydrothermal route. DNA is directly attached to the surface of QDs. The as prepared QDs exhibit small size (3.85 +/- 0.53 nm), high quantum yield (up to 80.5%), and excellent photostability. In addition, the toxicity of QDs has dropped considerably because of the Zn-doping and the existence of DNA. Furthermore, DNA has been designed as an aptamer specific for mucin 1 overexpressed in many cancer cells including lung adenocarcinoma. The aptamer functionalized Zn(2+) doped CdTe QDs (aptamer-QDs) have been successfully applied in active tumor-targeted imaging in vitro and in vivo. A universal design of DNA for synthesis of Zn(2+) doped CdTe QDs could be extended to other target sequences. Owing to the abilities of specific recognition and the simple synthesis route, the applications of QDs will potentially be extended to biosensing and bioimaging. PMID- 23682758 TI - Broadly applicable methodology for the rapid and dosable small molecule-mediated regulation of transcription factors in human cells. AB - Direct and selective small molecule control of transcription factor activity is an appealing avenue for elucidating the cell biology mediated by transcriptional programs. However, pharmacologic tools to modulate transcription factor activity are scarce because transcription factors are not readily amenable to small molecule-mediated regulation. Moreover, existing genetic approaches to regulate transcription factors often lead to high nonphysiologic levels of transcriptional activation that significantly impair our ability to understand the functional implications of transcription factor activity. Herein, we demonstrate that small molecule-mediated conformational control of protein degradation is a generally applicable, chemical biological methodology to obtain small molecule-regulated transcription factors that modulate transcriptional responses at physiologic levels in human cells. Our establishment of this approach allows for the rapid development of genetically encoded, small molecule-regulated transcription factors to explore the biologic and therapeutic impact of physiologic levels of transcription factor activity in cells. PMID- 23682759 TI - The relationship between serum 25-hydroxy vitamin D, parathormone and bone mineral density in Indian population. AB - OBJECTIVES: Vitamin D deficiency (VDD) is a global problem. Not all patients with VDD have clinical manifestations or secondary hyperparathyroidism. We studied the interaction between serum 25-hydroxy vitamin D (25OHD), parathormone (PTH) and bone mineral density (BMD) in Indian adolescents and adults. DESIGN: Population survey. PATIENTS: A total of 1829 adolescents and 1346 adults aged 50 years and above were analysed in this study. MEASUREMENTS: Serum biochemistry, 25OHD, PTH and BMD were estimated. Subjects were grouped according to quartiles of serum PTH. VDD was defined as severe (25OHD <= 5 ng/ml), moderate (25OHD <= 10 ng/ml) and mild (25OHD <= 20 ng/ml) and secondary hyperparathyroidism (SHPT) when serum PTH levels >65 pg/ml. RESULTS: Only 30-40% of subjects with moderate and severe VDD, respectively, had SHPT. BMD decreased from Quartile 1 to Quartile 4 of PTH at all sites among adolescents and adults, with only a marginal decline in serum 25OHD levels between these quartiles. Further, within each PTH quartile, there was no difference in BMD according to categories of VDD. Analysing BMD in the different PTH quartiles, the PTH cut-offs beyond which BMD showed a significant decline, was 35 pg/ml in adolescents and 53 pg/ml in adults. CONCLUSIONS: Less than half of the subjects with VDD have SHPT. BMD levels start to decline at PTH values currently considered to be normal. These data suggest the need to redefine SHPT in different age groups keeping in mind the relationship between PTH and BMD. This may also influence the decision to supplement subjects with VDD. PMID- 23682762 TI - Identification of cinnamic acid derivatives as novel antagonists of the prokaryotic proton-gated ion channel GLIC. AB - Pentameric ligand gated ion channels (pLGICs) mediate signal transduction. The binding of an extracellular ligand is coupled to the transmembrane channel opening. So far, all known agonists bind at the interface between subunits in a topologically conserved "orthosteric site" whose amino acid composition defines the pharmacological specificity of pLGIC subtypes. A striking exception is the bacterial proton-activated GLIC protein, exhibiting an uncommon orthosteric binding site in terms of sequence and local architecture. Among a library of Gloeobacter violaceus metabolites, we identified a series of cinnamic acid derivatives, which antagonize the GLIC proton-elicited response. Structure activity analysis shows a key contribution of the carboxylate moiety to GLIC inhibition. Molecular docking coupled to site-directed mutagenesis support that the binding pocket is located below the classical orthosteric site. These antagonists provide new tools to modulate conformation of GLIC, currently used as a prototypic pLGIC, and opens new avenues to study the signal transduction mechanism. PMID- 23682761 TI - Lumbrokinase attenuates side-stream-smoke-induced apoptosis and autophagy in young hamster hippocampus: correlated with eNOS induction and NFkappaB/iNOS/COX-2 signaling suppression. AB - Recent studies have found that cigarette smoke is epidemiologically linked to an increased risk for impaired cognitive development in adolescents. This study evaluated the influence of side stream smoke (SSS) exposure on hippocampal apoptosis and of the lumbrokinase (LK) effects on SSS induced apoptosis in young hamster hippocampus. Twenty male hamsters at six weeks of age were randomly divided into control group, SSS group (exposed to tobacco cigarettes smoke at doses of 10 cigarettes for 30 min twice a day for 1 month), and SSS hamsters with LK treatment (1.2 mg/kg, ip) for twice a week for 1 month. TUNEL assay and Western blotting were performed. The TUNEL-positive apoptotic cells, as well as Fas-dependent activity and mitochondria-dependent apoptotic pathways, such as Fas, FADD, activated caspase-8, t-Bid, activated caspase-9, and activated caspase 3, were significantly increased in the SSS-exposed hippocampus compared to the control and highly attenuated in the LK treatment group. Additionally, SSS exposure significantly increased the autophagy marker proteins, Beclin-1, ATG7, and LC3-II levels, in the hippocampus compared to those in the control group and obviously attenuated after LK treatment. LK also reduced hippocampus injury by enhancing eNOS expression and remarkably inhibited the proinflammatory NFkappaB/iNOS/COX-2 signaling activity. We found that the detrimental effects of SSS on the hippocampus are truly mediated by cell apoptosis and autophagy. However, LK reduced the hippocampus apoptosis and autophagy related injuries induced by SSS in a widespread manner. We suggest that LK presents protective effects on hippocampus apoptosis and has therapeutic potential against abnormal hippocampal function. PMID- 23682763 TI - Effect of maternal smoking during pregnancy on fetus: a cytogenetic perspective. AB - OBJECTIVE: The examination of the genotoxic, cytostatic and cytotoxic effects of smoking during pregnancy. METHOD: Lymphocyte cultures of peripheral blood were received from 20 women who smoked during pregnancy as well as umbilical cord blood of their newborns. Fluorescence Plus Giemsa staining technique was used in order to perform cytogenetic analyses for three indices, Sister Chromatid Exchanges (SCEs), Proliferation Rate Index (PRI) and Mitotic Index (MI). To reveal any underlying chromosome instability, CPT-11 was used as a positive control. RESULTS: Newborns whose mothers smoke during pregnancy had increased SCEs levels on their lymphocytes when they were exposed to the mutagenic agent CPT-11 (p < 0.01) compared with newborns lymphocytes exposed to the same agent with non-smoking mothers. Also, mothers smoking during pregnancy had increased SCE levels when their lymphocytes were exposed to CPT-11 (p < 0.01) compared with non smoking mothers whose lymphocytes were exposed to the same agent. In both groups newborns appeared as having decreased (p < 0.01) spontaneous SCEs levels compared with the corresponding SCE rates of their mothers. Decreases of PRIs and MIs are observed in mothers compared to their newborns. CONCLUSION: Smoking during pregnancy can promote cytogenetic damage in newborn's DNA, causing chromosome instability. The clinical importance of this indirect damage lies in the fact that this type of damage can act synergistically with other environmental and/or chemical mutagenic substances possibly leading to carcinogenicity. PMID- 23682764 TI - Depletion of melamine and cyanuric acid in kidney of catfish Ictalurus punctatus and trout Oncorhynchus mykiss. AB - A risk assessment conducted in 2007 identified significant knowledge gaps about tissue residues of melamine and related triazine analogs such as cyanuric acid in animals that had eaten contaminated food. The USFDA subsequently designed studies to determine residue levels in muscle, serum, and kidneys of catfish and trout given a single gavage dose of 20 mg/kg body weight (BW) of melamine, cyanuric acid, or 20 mg/kg BW of both compounds simultaneously. Renal triazines were determined by LC-MS/MS at postdose days 1, 3, 7, 14, 28 (and day 42 for trout). When dosed individually, melamine and cyanuric acid kidney residues depleted much faster than those in fish given both compounds together. Combined dose residue depletion was punctuated by extreme outliers due to the formation of persistent renal melamine cyanurate crystals. PMID- 23682765 TI - Evaluation of an innovative tool for child sexual abuse education. AB - Child sexual abuse poses a serious threat to public health and is often unreported, unrecognized, and untreated. Prevention, early recognition, and treatment are critically important to reduce long-term effects. Little data are available on effective methods of preventing child sexual abuse. The current research demonstrates a unique approach to promoting awareness and stimulating discussion about child sexual abuse. Qualitative methods have rarely been used to study child sexual abuse prevention. Qualitative inductive analyses of interviews from 20 key informants identified both positive and negative assessments with six emergent themes. The themes revealed inherent tensions in using narrative accounts to represent the complex cultural context within which child sexual abuse occurs. More research is needed, but the program shows potential as a methodology to raise awareness of child sexual abuse. PMID- 23682766 TI - Sexual abuse images in cyberspace: expanding the ecology of the child. AB - Cyberspace has added a new dimension to the ecology of children made the subjects of sexual abuse images distributed online. These images cannot be permanently removed and can continue to circulate in cyberspace forever. A review of the current literature suggests that helping professionals are not consistently aware of or do not probe possibilities of online sexual victimization in the investigation, assessment, and treatment of child sexual abuse. Nor is this issue adequately addressed in their education and training. There are gaps in the literature regarding how to identify and provide treatment for these children. New assessment and treatment targets are needed to enhance existing practice approaches. A contemporary ecological model that incorporates an explicit consideration of the cybersystem is provided as a starting point for practitioners to be aware of the possibility that images of child sexual abuse were recorded and distributed online. PMID- 23682767 TI - Parental employment status and symptoms of children abused during a recession. AB - Incidences and severity of child abuse have increased since the start of the recession. This study examined the relationship between employment status and severity of symptoms in children abused during a recession year. Participants included 154 females and 65 males between 2 and 17 years old referred to Dallas Children's Advocacy Center after surviving child sexual abuse, physical abuse, and/or neglect. We found that child abuse survivors whose mothers were unemployed showed higher symptom severity. Larger differences were found when participants were broken down by age, ethnicity, and living situation. Father's employment status did not affect symptom severity probably because many children lived with single mothers. We concluded that child abuse survivors whose mothers are unemployed have increased risk for psychological symptoms. PMID- 23682768 TI - Social service professionals' perceptions of nonoffending caregivers in child sexual abuse cases. AB - This study was designed to assess social service workers' perceptions of nonoffending caregivers in cases of child sexual abuse. Attributions of blame were examined by administering questionnaires to staff at local social service agencies. It was hypothesized that social service workers who worked in the field longer, were male, or had less education would attribute more blame to the nonoffending caregivers. The findings revealed that respondent gender was the only significant predictor of blame attribution toward nonoffending caregivers, with level of education approaching significance as a predictor. There was no relationship between attribution of blame and years in job. The findings have important contributions for informing the practice of social service professionals who work with families of child sexual abuse. PMID- 23682769 TI - Cognitive abuse within the incestuous family as a factor in the development of dissociative identity disorder. AB - The polarized nature of the ongoing controversies surrounding the genesis and validity of dissociative identity disorder pit advocates who see and work with dissociative identity disorder sufferers against skeptics who claim it to be an artificial iatrogenically produced phenomenon. This paper suggests that such a dichotomy is unwarranted and that, in fact, both sides of the argument have merit. A short description of the controversy that rages among professionals is followed by a personal-experiential review of the development of dissociative identities in the author. Using sociocognitive conceptualizations and describing the iatrogenic intrafamilial processes that led to the "choice" of dissociation as a strategy for coping with a traumatic reality, this paper shows how both sides of the conflict complement each other and suggests a new way of understanding the developmental pathway of dissociative identity disorder. PMID- 23682770 TI - Child sexual abuse survivors with dissociative amnesia: what's the difference? AB - Although the issue of dissociative amnesia in adult survivors of child sexual abuse has been contentious, many research studies have shown that there is a subset of child sexual abuse survivors who have forgotten their abuse and later remembered it. Child sexual abuse survivors with dissociative amnesia histories have different formative and therapeutic issues than survivors of child sexual abuse who have had continuous memory of their abuse. This article first discusses those differences in terms of the moderating risk factors for developing dissociative amnesia (e.g., age, ethnicity, gender, etc.) and then mediating risk factors (e.g., social support, trait dissociativity, etc.). The differences between the two types of survivors are then explored in terms of treatment issues. PMID- 23682771 TI - Tables for the metric evaluation of pair-matching of human skeletal elements. AB - A common task in forensic anthropology involves pair-matching of left and right skeletal elements. This can be achieved through visual pair-matching by evaluating similarities in morphology, and through osteometric sorting, a quantitative technique. To simplify the process of osteometric sorting, this article explains the use of a statistic (M), which captures the amount of size variation found between homologous bones from single individuals. A database of skeletal measurements for all major paired postcranial bones is used to calculate values of M from a variety of sources. The maximum value and the 90th and 95th percentiles of M are provided in tabular format, and values of M from forensic cases can be compared to these tables as an objective means for determining whether homologous bones could have originated from the same individual. This simple technique can be combined with visual pair-matching to be particularly effective in cases involving commingling of skeletons. PMID- 23682773 TI - Rate of cognitive decline in relation to sex after 60 years-of-age: a systematic review. AB - Some studies have shown differences in specific cognitive ability domains between the sexes at 60 years-of-age. However is important to analyze whether the rate of cognitive decline is also similar between the sexes after this age. The present study examined previously published literature to investigate whether cognitive decline is distinct between men and women after the age of 60 years. A systematic review was carried out with the PubMed, LILACS and PsycINFO databases (2001-2011) using the following search terms: aging, aged, cognitive function, mild cognitive impairment, mental health and cognition. We analyzed longitudinal research that used neuropsychological tests for evaluating cognitive function, showed results separated by sex and that excluded participants with dementia. Elderly women showed better performance in tests of episodic memory, whereas elderly men had a better visuospatial ability. Only one study detected distinct rates of cognitive decline in specific tests between the sexes. Despite differences observed in some domains, most of the studies showed that this rate is similar between the sexes until the age of 80 years. It is unclear whether sex influences the rate of cognitive decline after the age of 80 years. The present review observed that sex does not determine the rate of cognitive decline between 60 and 80 years-of-age. The contextual and cultural factors that involve men and women might determine a distinct decline between them, rather than sex alone. PMID- 23682772 TI - Human GGT2 does not autocleave into a functional enzyme: A cautionary tale for interpretation of microarray data on redox signaling. AB - AIMS: Human gamma-glutamyltranspeptidase 1 (hGGT1) is a cell-surface enzyme that is a regulator of redox adaptation and drug resistance due to its glutathionase activity. The human GGT2 gene encodes a protein that is 94% identical to the amino-acid sequence of hGGT1. Transcriptional profiling analyses in a series of recent publications have implicated the hGGT2 enzyme as a modulator of disease processes. However, hGGT2 has never been shown to encode a protein with enzymatic activity. The aim of this study was to express the protein encoded by hGGT2 and each of its known variants and to assess their stability, cellular localization, and enzymatic activity. RESULTS: We discovered that the proteins encoded by hGGT2 and its variants are inactive propeptides. We show that hGGT2 cDNAs are transcribed with a similar efficiency to hGGT1, and the expressed propeptides are N-glycosylated. However, they do not autocleave into heterodimers, fail to localize to the plasma membrane, and do not metabolize gamma-glutamyl substrates. Substituting the coding sequence of hGGT1 to conform to alterations in a CX3C motif encoded by hGGT2 mRNAs disrupted autocleavage of the hGGT1 propeptide into a heterodimer, resulting in loss of plasma membrane localization and catalytic activity. INNOVATION AND CONCLUSIONS: This is the first study to evaluate hGGT2 protein. The data show that hGGT2 does not encode a functional enzyme. Microarray data which have reported induction of hGGT2 mRNA should not be interpreted as induction of a protein that has a role in the metabolism of extracellular glutathione and in maintaining the redox status of the cell. PMID- 23682774 TI - Independent segmental inhibitory modulation of synaptic efficacy of the soleus H reflex. AB - Synaptic efficacy associated with muscle spindle feedback is partly regulated via depression at the Ia-motorneuron synapse through paired reflex depression (PRD) and presynaptic inhibition (PI). The purpose of this study was to examine PRD and PI of the soleus H-reflex at rest and with a background voluntary muscle contraction. The experiment was conducted on 10 healthy males with no history of neurological deficits. Soleus H-reflex and M-wave curves were elicited in three conditions: unconditioned, PRD (two consecutive H-reflexes with 100 ms interval), and PI (1.2 * MT to tibialis anterior 100 ms prior to soleus H-reflex). Each condition was tested at rest and with a 10% soleus contraction. PRD and PI both produced a pronounced inhibition to the soleus motor pool at rest, with a significant difference observed between threshold values (78.9, 89.3, and 90.4% for unconditioned, PRD, and PI reflexes, respectively). During the voluntary contraction the threshold for both inhibitory mechanisms was significantly reduced, and were not different from the unconditioned H-reflex (74.5, 78.9, and 77.0% for unconditioned, PRD, and PI reflexes, respectively). The slope of PI and the PI Hmax/Mmax ratio were significantly altered during contraction whereas no differences were observed for PRD. The results suggest these inhibitory mechanisms depend on the interaction between background voluntary activation and stimulus intensity. This behavior of these inhibitory mechanisms underscores the specificity of spinal circuitry in the control of motor behaviors. PMID- 23682776 TI - Heterogeneous reaction of NO2 on Al2O3: the effect of temperature on the nitrite and nitrate formation. AB - Although recent evidence suggests that the heterogeneous reaction of NO2 on the surface of mineral aerosol plays an important role in the atmospheric chemistry, a fundamental understanding of how temperature influences the rate and extent of nitrate formation processes remains unclear. This work presents the first laboratory study of the effect of temperature on heterogeneous reaction of NO2 on the surface of gamma-Al2O3 in the temperature range of 250-318 K at ambient pressure. From the analysis of IR spectra, nitrite was found to be an intermediate product at temperatures between 250 and 318 K. It is proved by our experiments that nitrite would convert to the bidentate nitrate as the reaction proceeded. In addition, it is interesting to find that the rate of conversion increased with decreasing temperature. Along with nitrite decrease, the initial rate of nitrate formation increased while the rate of nitrate formation in the steady region decreased with decreasing temperature. The uptake coefficients at seasonal temperatures were determined for the first time and were found to be sensitive to temperature. Finally, atmospheric implications of the role of temperature on the heterogeneous reaction of NO2 with mineral aerosol are discussed. PMID- 23682777 TI - Introduction to Special Issue on Molecular Basis for Cancer Prevention with Bioactive Food Components in Nutrition and Cancer--an International Journal. PMID- 23682778 TI - Chemopreventive and anti-cancer efficacy of silibinin against growth and progression of lung cancer. AB - The use of systemic chemotherapeutic drugs and molecular-targeted therapies in the treatment of patients with locally advanced or metastatic lung cancer has its limitations due to the associated acute and cumulative dose limiting toxicities and acquisition of drug resistance. Prevention and therapeutic intervention by dietary agents including nutraceuticals which are non-toxic, cost-effective, and physiologically bioavailable, are emerging approaches in lung cancer management. In this regard, silibinin, a natural flavonolignan, has been rigorously evaluated for the prevention and growth control of lung cancer through extensive in vitro and in vivo studies. Successful studies conducted so far, have established that silibinin is effective both alone and in combination with other agents (e.g., chemotherapeutic and epigenetic agents) in significantly inhibiting the growth of lung cancer cells. In vivo, its effects have been shown to be mediated through inhibition of proliferation, angiogenesis and epigenetic-related events. Therefore, the present review focuses on encompassing the efficacy and mechanisms of silibinin against lung cancer. PMID- 23682779 TI - Advances in prostate cancer chemoprevention: a translational perspective. AB - Chemopreventive interventions are steadily emerging as an important aspect of cancer management and control. Herein, we have discussed the major epidemiological and clinical studies advocating the role of androgen inhibitors, flavonoids and antioxidants in preventing prostate cancer (PCa). Androgen inhibitors have lately been discussed not only in treatment of PCa, but also as preventive agents especially after trials with Finasteride and Dutasteride. Flavonoids such as silibinin, green tea polyphenols, genistein, curcumin have shown great promise, but avenues to improve their bioavailability are requisite. Agents with antioxidant potentials like lycopene, selenium, and vitamin E have also been explored. Antioxidant trials have yielded mixed results or benefitted only a subgroup of population, although further studies are needed to establish them as preventive agent. Although a majority of the trials resulted in positive outcomes supporting their role as preventive agents; one should be cautious of neutral or negative results as well. For clinical applicability of these agents, we need to identify the ideal target population, time of intervention, appropriate dosage, and extent of intervention required. Incoherency of data with these agents urges for a stringent study design and thorough interpretation to accurately judge the necessity and feasibility of the preventive measures. PMID- 23682780 TI - Ocimum sanctum L (Holy Basil or Tulsi) and its phytochemicals in the prevention and treatment of cancer. AB - Ocimum sanctum L. or Ocimum tenuiflorum L, commonly known as the Holy Basil in English or Tulsi in the various Indian languages, is a important medicinal plant in the various traditional and folk systems of medicine in Southeast Asia. Scientific studies have shown it to possess antiinflammatory, analgesic, antipyretic, antidiabetic, hepatoprotective, hypolipidemic, antistress, and immunomodulatory activities. Preclinical studies have also shown that Tulsi and some of its phytochemicals eugenol, rosmarinic acid, apigenin, myretenal, luteolin, beta-sitosterol, and carnosic acid prevented chemical-induced skin, liver, oral, and lung cancers and to mediate these effects by increasing the antioxidant activity, altering the gene expressions, inducing apoptosis, and inhibiting angiogenesis and metastasis. The aqueous extract of Tulsi and its flavanoids, orintin, and vicenin are shown to protect mice against gamma radiation-induced sickness and mortality and to selectively protect the normal tissues against the tumoricidal effects of radiation. The other important phytochemicals like eugenol, rosmarinic acid, apigenin, and carnosic acid are also shown to prevent radiation-induced DNA damage. This review summarizes the results related to the chemopreventive and radioprotective properties of Tulsi and also emphasizes aspects that warrant future research to establish its activity and utility in cancer prevention and treatment. PMID- 23682781 TI - Usnic acid inhibits growth and induces cell cycle arrest and apoptosis in human lung carcinoma A549 cells. AB - Usnic acid (UA) is a secondary metabolite abundantly found in lichens. Some studies have shown the anticancer potential of UA; however, its efficacy and associated mechanisms are yet to be fully explored. Herein, we assessed the anticancer potency and associated molecular alterations by UA in human lung carcinoma A549 cells. UA treatment (25-100 MUM) for 24 and 48 h decreased total cell number by 39-67% (P < 0.01) and 68-89% (P < 0.001), respectively, and enhanced cell death by up to twofold and eightfold (P < 0.001), respectively. UA (1-10 MUM) also significantly (P < 0.001) suppressed colony formation of A549 cells. The cell growth inhibition was associated with cell cycle arrest at G0/ G1 phase. UA decreased the expression of cyclin-dependent kinase (CDK)4, CDK6, and cyclin D1 and increased the expression of CDK inhibitor (CDKI) p21/cip1 protein. While examining the cell death associated molecular changes, we observed that UA induces mitochondrial membrane depolarization and led to more than twofold increase (P < 0.01) in apoptotic cells. The apoptotic effect of UA was accompanied by enhanced poly(ADP-ribose) polymerase cleavage. This study shows that UA inhibits cell growth involving G0/G1 phase cell cycle arrest and induces cell death via mitochondrial membrane depolarization and induction of apoptosis in human lung carcinoma cells. PMID- 23682782 TI - Differential effect of grape seed extract against human non-small-cell lung cancer cells: the role of reactive oxygen species and apoptosis induction. AB - The present study examines grape seed extract (GSE) efficacy against a series of non-small-cell lung cancer (NSCLC) cell lines that differ in their Kras and p53 status to establish GSE potential as a cytotoxic agent against a wide range of lung cancer cells. GSE suppressed growth and induced apoptotic death in NSCLC cells irrespective of their k-Ras status, with more sensitivity toward H460 and H322 (wt k-Ras) than A549 and H1299 cells (mutated k-Ras). Mechanistic studies in A549 and H460 cells, selected, based on comparative efficacy of GSE at higher and lower doses, respectively, showed that apoptotic death involves cytochrome c release associated caspases 9 and 3 activation, and poly (ADP-ribosyl) polymerase cleavage, strong phosphorylation of ERK1/2 and JNK1/2, downregulation of cell survival proteins, and upregulated proapoptotic Bak expression. Importantly, GSE treatment caused a strong superoxide radical-associated oxidative stress, significantly decreased intracellular reduced glutathione levels, suggesting, for the first time, the involvement of GSE-caused oxidative stress in its apoptotic inducing activity in these cells. Because GSE is a widely-consumed dietary agent with no known untoward effects, our results support future studies to establish GSE efficacy and usefulness against NSCLC control. PMID- 23682783 TI - Prevention of familial adenomatous polyp development in APC min mice and azoxymethane-induced colon carcinogenesis in F344 Rats by omega-3 fatty acid rich perilla oil. AB - The present study explored the preventive effects of perilla oil, rich in alpha linolenic acid, in rodent models of colon tumorigenesis. Six-week-old male F344 rats were fed diets containing 5% corn oil or 10 or 20% perilla oil. Colonic aberrant crypt foci (ACF) were induced by azoxymethane (AOM) and colonic ACF were evaluated. In familial adenomatous polyposis mode, APC(min) mice fed with 20% corn oil or perilla oil for 80 days and intestines were evaluated for polyps. Multiple colonic mucosal and polyp samples were assayed for the expression and activity of cyclooxygenase COX-isoforms. Dietary perilla oil produced a dose dependent inhibition of AOM-induced colonic ACF formation (by 35-53%, P < 0.01 0.005) and reduced the number of foci with >= 4 crypts/focus (by 38-50%, P < 0.01 0.001) in F344 rats. Dietary perilla oil significantly inhibited development of small intestinal (>69%, P < 0.0001) and colon tumors (>52%, P < 0.03) in APC(min) mice. Administration of perilla oil produced lower levels of type-2 prostaglandins (38-53%) from COX-activities in polyps of APC(min) mice. These observations demonstrate that dietary perilla oil rich in omega-3 fatty acids possesses preventive activity against intestinal neoplastic lesions, both in FAP in genetically-predisposed tissues, as well as against chemically induced preneoplastic lesions in the colon. PMID- 23682784 TI - In vitro and in vivo effects of phenethyl isothiocyanate treatment on vimentin protein expression in cancer cells. AB - We have shown previously that cancer prevention by cruciferous vegetable constituent phenethyl isothiocyanate (PEITC) in a transgenic mouse model of prostate cancer is associated with induction of E-cadherin protein expression. Because suppression of E-cadherin protein concomitant with induction of mesenchymal markers (e.g., vimentin) is a biochemical hallmark of epithelial mesenchymal transition, a process implicated in cancer metastasis, we hypothesized that PEITC treatment was likely to suppress vimentin protein expression. Contrary to this prediction, exposure of human breast (MDA-MB-231) and prostate cancer cells (PC-3 and DU145) to PEITC resulted in a dose-dependent increase in vimentin protein level, which was observed as early as 6 h posttreatment and persisted for the duration of the experiment (24 h). RNA interference of vimentin resulted in a modest augmentation of PEITC-mediated inhibition of MDA-MB-231 and PC-3 cell migration as well as cell viability. Furthermore, the PEITC-induced apoptosis was moderately increased upon siRNA knockdown of vimentin protein in MDA-MB-231 and PC-3 cells. To our surprise, PEITC treatment caused a marked decrease in vimentin protein expression in breast and prostate carcinoma in vivo in transgenic mouse models, although the difference was statistically significant only in the breast carcinomas. The present study highlights the importance of in vivo correlative studies for validation of the in vitro mechanistic observations. PMID- 23682786 TI - Protective effect of topical application of alpha-tocopherol and/or N-acetyl cysteine on argemone oil/alkaloid-induced skin tumorigenesis in mice. AB - Since bioantioxidants in plasma of Epidemic Dropsy patients [a condition caused by consumption of adulterated mustard oil with argemone oil (AO)] were found to be significantly decreased, the beneficial effect of N-acetyl cysteine (NAC) and alpha-tocopherol (TOCO) against AO- or sanguinarine (SANG)-induced tumorigenicity was undertaken in mice. Topical application of TOCO and NAC either alone or in combination showed significant protection against AO/TPA- and SANG/TPA-induced skin tumorigenicity. Histopathological findings suggest that papillomatous growth in AO/TPA- and SANG/TPA-treated animals were substantially protected following topical application of TOCO or NAC. Further, treatment of TOCO and NAC either alone or in combination to AO/TPA- or SANG/TPA-induced mice significantly decreased lipid peroxidation, along with significant revival in glutathione (GSH) content and activities of tyrosinase, histidase, catalase, SOD, GSH peroxidase, and GSH reductase in skin. In vitro studies showed that TOCO and/or NAC significantly decreased the AO and SANG induced cell proliferation and activation of ERK, p38, JNK MAPKs and NF-kappaB signaling in HaCaT cells. In summary, TOCO and NAC may be useful in preventing the tumorigenic response of AO and SANG probably by acting as scavenger of free radicals and inhibiting MAPKs and NF kappaB signaling. PMID- 23682785 TI - The effect of gartanin, a naturally occurring xanthone in mangosteen juice, on the mTOR pathway, autophagy, apoptosis, and the growth of human urinary bladder cancer cell lines. AB - Garcinia mangostana, often referred to as mangosteen, is a fruit grown in Southeast Asia and has been used for centuries as a local beverage and natural medicine. Its bioactive compounds, xanthones (i.e., gartanin, alpha-mangostin, etc), have reported effects on ailments ranging from skin infections and inflammation to urinary tract infections. We demonstrate that mangosteen xanthones (i.e., gartanin and alpha-mangostin) at pharmacologically achievable concentrations inhibit the growth of cancer cell lines from different stages of human urinary bladder cancer. The growth inhibitory effects of gartanin in mouse embryonic fibroblasts are at least in part dependent on the existence of p53 or TSC1. Indeed, further studies have shown that gartanin treatment of bladder cancer cell lines T24 and RT4 resulted in a marked suppression of p70S6 and 4E BP1 expression and induction of autophagy, suggesting the inhibition of the mTOR pathway. In addition, gartanin downregulated the expression of Bcl-2 and activated the p53 pathway leading to apoptosis induction. Together, these results suggested that gartanin is a multiple targeting agent that is suitable for further study into its chemopreventive properties for human urinary bladder cancer. PMID- 23682787 TI - Anticancer activity of Phyllanthus emblica Linn. (Indian gooseberry): inhibition of transcription factor AP-1 and HPV gene expression in cervical cancer cells. AB - Plant products of Phyllanthus emblica Linn. are traditionally consumed for its immense nutritive and medicinal values. However, the molecular mechanism(s) by which it exerts it effects is less understood. In this study, we investigated mechanism of action of P. emblica fruit extract (PE) by studying its effect on activator protein-1 (AP-1) activity and human papillomavirus (HPV) transcription that are essential for tumorigenicity of cervical cancer cells. PE resulted in a dose-and time-dependent inhibition of DNA binding activity of constitutively active AP-1 in both HPV16-positive (SiHa) and HPV18-positive (HeLa) cervical cancer cells. PE-induced AP-1 inhibition was found mediated through downregulation of constituent AP-1 proteins, c-Jun, JunB, JunD, and c-Fos; however, the kinetics of their inhibition varied in both the cell types. Inhibition of AP-1 by PE was accompanied by suppression of viral transcription that resulted in growth inhibition of cervical cancer cells. Growth inhibitory activity of PE was primarily manifested through induction of apoptotic cell death. These results suggest that P. emblica exhibits its anticancer activities through inhibition of AP-1 and targets transcription of viral oncogenes responsible for development and progression of cervical cancer thus indicating its possible utility for treatment of HPV-induced cervical cancers. PMID- 23682788 TI - Celiac plexus block for treatment of pain associated with pancreatic cancer: a meta-analysis. AB - Pancreatic ductal adenocarcinoma has a high rate of neural invasion (80 to 100%) and can be associated with moderate to severe pain in pancreatic cancer. Treatment of pain with celiac plexus blockage (CPB) combined with the three-step ladder utilization of pharmaceutical analgesics following WHO guidelines is used, but the evidence in randomized controlled trials is inconsistent. This meta analysis identified and compared seven randomized control trials of pain relief from pancreatic cancer, by treatment with medical management alone to celiac plexus blockade with medical management. While no evidence of potential publication bias was detected, group size and statistical power may account for some of the inconsistent conclusions. The combined CPB groups had a significantly lower pain score at 4 weeks, but significance was not maintained at 8 weeks. The combined CPB groups required significantly less drug use compared to the combined control groups treated with pharmaceutical analgesics. PMID- 23682789 TI - Antibacterial activity and synergistic effect between watercress extracts, 2 phenylethyl isothiocyanate and antibiotics against 11 isolates of Escherichia coli from clinical and animal source. AB - To evaluate the possible in vitro interaction between natural extracts of watercress (Nasturtium officinale R. Br.) and 2-phenylethyl isothiocyanate, a natural compound derived gluconasturtiin largely present in watercress tissues, with a standard antibiotic, a synergy study was carried out against 11 isolates of extended-spectrum beta-lactamases-Escherichia coli. Aqueous and methanolic watercress extracts and 2-phenylethyl isothiocyanate were combined with the antibiotic, and a disc diffusion assay and minimum inhibitory concentration methods were used to assess the in vitro antibacterial activity. The results of this study showed that there is an increase in antibacterial activity of the antibiotic when it was combined with plants extracts and pure compounds. The most interesting result was the combination between 2-phenylethyl isothiocyanate and the antibiotic. Synergistic effects of the antibiotic with watercress extracts and 2-phenylethyl isothiocyanate suggest the potential of these plants and their natural compounds to improve the performance of the antibiotics and could be an interesting tool for antimicrobial therapy. The results led us to conclude that watercress has important pharmacological substances which can be used for developing new and effective antimicrobial agents. SIGNIFICANCE AND IMPACT OF THE STUDY: This in vitro study intends to demonstrate the potential use of watercress extracts and 2-phenylethyl isothiocyanate as antimicrobial tools against extended spectrum beta-lactamases-Escherichia coli and to determine their ability to act synergistically with commercial standard antibiotics. We intended to increase the knowledge about different clinical and pharmaceutical approaches to fight against E. coli rather than the traditional use of antibiotics. The results may be useful to those involved in the pharmaceutical, biochemical and microbiology industry and/or academic research in terms of developing alternative control measures and efficient intervention methods. PMID- 23682790 TI - Attenuated systemic microvascular function in men with coronary artery disease is associated with angina but not explained by atherosclerosis. AB - INTRODUCTION: Refractory angina is the occurrence of clinical symptoms despite maximal therapy. We investigated associations between microvascular function, atherosclerotic burden, and clinical symptoms in subjects with CAD. METHODS: Skin microvascular response to heating and ischemia was assessed in 167 male volunteers by laser Doppler fluximetry; 82 with CAD on maximal therapy and 85 with no known CAD (noCAD). CAC scores, carotid IMT, and femoral IMT were measured and symptoms were scored using the Rose angina questionnaire. RESULTS: Patients with CAD had poorer microvascular response to heating (114[95% CI 106-122]au CAD vs. 143[134-153]au no CAD; p < 0.0001) and ischemia (42[38-46]au CAD vs. 53[78 58]au. noCAD; p = 0.001). Thirty-eight percent of the noCAD group had elevated CAC scores. There were no associations between markers of atherosclerosis and microvascular function. Forty-two percent of the CAD group had refractory angina. This was associated with impaired microvascular function compared to those with elevated CAC scores but no symptoms (109 [95-124]au vs. 131[122-140]au; p = 0.008). CONCLUSIONS: Men with symptomatic CAD have poorer microvascular function compared to individuals without CAD. Microvascular function does not correlate with atherosclerosis, but is impaired in individuals with refractory angina. Microvascular dysfunction may play a role in the symptomatology of angina. PMID- 23682791 TI - National agenda for prevention of healthcare-associated infections in dialysis centers. AB - Healthcare-associated infections (HAIs) are among the leading causes of morbidity and mortality in dialysis patients. To coordinate HAI prevention efforts, the U.S. Department of Health and Human Services established the National Action Plan to Prevent Healthcare Associated Infections in End-Stage Renal Disease Facilities. This comprehensive plan prioritizes HAI prevention practices and 5 year evaluation targets based on the burden of disease, level of scientific evidence, and anticipated impact from the recommended intervention. As such, the Plan focuses primarily on interventions to reduce vascular access-related complications and infections with hepatitis B and hepatitis C virus. Over the last decade, there have been several efforts to expand HAI surveillance and prevention efforts, including coordination of HAI reporting metrics across multiple national agencies, changes in financial incentives by the Centers for Medicare & Medicaid Services (CMS), and federal funding for expansion of state based HAI prevention programs. As a result, a paradigm shift in HAI prevention has developed. Public health officials have assumed greater responsibility in reducing the burden of HAIs and healthcare providers have become more involved in HAI prevention. Since the Plan was initially drafted, several collaborative efforts in dialysis facilities have reported a reduction in HAIs through implementation of these interventions. These early successes highlight the potential impact of coordinated action to combat HAIs in dialysis settings and this National Action Plan provides evidence-based strategies on how best to achieve this. PMID- 23682792 TI - Length-dependent thermopower of highly conducting Au-C bonded single molecule junctions. AB - We report the simultaneous measurement of conductance and thermopower of highly conducting single-molecule junctions using a scanning tunneling microscope-based break-junction setup. We start with molecular backbones (alkanes and oligophenyls) terminated with trimethyltin end groups that cleave off in situ to create junctions where terminal carbons are covalently bonded to the Au electrodes. We apply a thermal gradient across these junctions and measure their conductance and thermopower. Because of the electronic properties of the highly conducting Au-C links, the thermoelectric properties and power factor are very high. Our results show that the molecular thermopower increases nonlinearly with the molecular length while conductance decreases exponentially with increasing molecular length. Density functional theory calculations show that a gateway state representing the Au-C covalent bond plays a key role in the conductance. With this as input, we analyze a series of simplified models and show that a tight-binding model that explicitly includes the gateway states and the molecular backbone states accurately captures the experimentally measured conductance and thermopower trends. PMID- 23682793 TI - Real-time interactive isosurfacing: a new method for improving marching isosurfacing algorithm output and efficiency. AB - Efficient rendering of a changing volumetric data-set is central to the development of effective medical simulations that incorporate haptic feedback. A new method referred to as real-time interactive isosurfacing (RTII) is described in this paper. RTII is an algorithm that can be applied to output from Marching Cubes-like algorithms to improve performance for real-time applications. The approach minimises processing by re-evaluating the isosurface around changing sub volumes resulting from user interactions. It includes innovations that significantly reduce mesh complexity and improve mesh quality as triangles are created from the Marching Tetrahedra isosurfacing algorithm. Rendering efficiency is further improved over other marching isosurfacing algorithm outputs by maintaining an indexed triangle representation of the mesh. The effectiveness of RTII is discussed within the context of an endoscopic sinus surgery simulation currently being developed by the authors. PMID- 23682794 TI - Applications of Fourier transform infrared spectroscopic imaging to tablet dissolution and drug release. AB - INTRODUCTION: Solid oral dosage forms are the most commonly used method for administering active pharmaceutical ingredients to patients. Understanding the mechanisms and processes of drug release is essential for improving the design of pharmaceutical tablets. AREAS COVERED: In this review, recent approaches where attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopic imaging has been applied to study tablet dissolution and drug release have been investigated. Drug release studies of model pharmaceutical systems composed of drug/polymer mixtures in the presence of aqueous solutions have been discussed, as has the subsequent combination with UV/Vis spectroscopic detection to quantify the amount of drug dissolved as a function of time. The use of a single reflection ATR accessory with a diamond crystal allows for in situ FTIR imaging of tablet compaction and dissolution. EXPERT OPINION: ATR-FTIR imaging can address the challenges of investigating the mechanisms of drug release from a range of innovative new delivery systems. Unlike standard dissolution tests, this spectroscopic imaging method obtains insight and information about changes within the tablet during dissolution. Areas where ATR-FTIR imaging has shown further potential to be particularly useful are for the study of multi-layered solid tablets, high-throughput analysis, use of microfluidic devices and for surface enhanced ATR-FTIR spectroscopy. PMID- 23682795 TI - Frequent loss of lineages and deficient duplications accounted for low copy number of disease resistance genes in Cucurbitaceae. AB - BACKGROUND: The sequenced genomes of cucumber, melon and watermelon have relatively few R-genes, with 70, 75 and 55 copies only, respectively. The mechanism for low copy number of R-genes in Cucurbitaceae genomes remains unknown. RESULTS: Manual annotation of R-genes in the sequenced genomes of Cucurbitaceae species showed that approximately half of them are pseudogenes. Comparative analysis of R-genes showed frequent loss of R-gene loci in different Cucurbitaceae species. Phylogenetic analysis, data mining and PCR cloning using degenerate primers indicated that Cucurbitaceae has limited number of R-gene lineages (subfamilies). Comparison between R-genes from Cucurbitaceae and those from poplar and soybean suggested frequent loss of R-gene lineages in Cucurbitaceae. Furthermore, the average number of R-genes per lineage in Cucurbitaceae species is approximately 1/3 that in soybean or poplar. Therefore, both loss of lineages and deficient duplications in extant lineages accounted for the low copy number of R-genes in Cucurbitaceae. No extensive chimeras of R-genes were found in any of the sequenced Cucurbitaceae genomes. Nevertheless, one lineage of R-genes from Trichosanthes kirilowii, a wild Cucurbitaceae species, exhibits chimeric structures caused by gene conversions, and may contain a large number of distinct R-genes in natural populations. CONCLUSIONS: Cucurbitaceae species have limited number of R-gene lineages and each genome harbors relatively few R-genes. The scarcity of R-genes in Cucurbitaceae species was due to frequent loss of R-gene lineages and infrequent duplications in extant lineages. The evolutionary mechanisms for large variation of copy number of R-genes in different plant species were discussed. PMID- 23682796 TI - Developing an interactive portion size assessment system (IPSAS) for use with children. AB - Novel methods of assessing dietary intake are required to reduce the participant burden in dietary surveys, improve participation rates and thereby improve the representativeness of the sample and minimise the impact of measuring dietary intake on a subject's food intake during the recording period. One method of reducing the burden placed on participants in recording dietary intake is to replace weighing of foods with estimation of portion size using tools such as food photographs. The interactive portion size assessment system (IPSAS) is an interactive portion size assessment system for use in assessing portion sizes of foods consumed by children aged 18 months to 16 years. The system is computer based and is designed to be administered during an interview for a food diary or 24-h recall. The portion sizes depicted are age-specific and based on the weights of foods served to children during the UK National Diet and Nutrition Surveys. The system displays digital images of food used to estimate the amount of each food served to the child and the amount of any food left over. Foods are categorised within the system using a three-tier structure. Twenty-seven food group icons are used with two further drop-down menus to select first the food group, then the food category and, finally, the actual food product. Each food is linked to UK food composition codes and all photographs are linked to the weight of the food depicted. Nutritional output is via a companion database. The present study describes the development of the IPSAS and the structure of the system. PMID- 23682797 TI - Effect of lifestyle modification on serum chemerin concentration and its association with insulin sensitivity in overweight and obese adults with type 2 diabetes. AB - OBJECTIVE: Chemerin, a recently identified adipokine, has been linked to adiposity, insulin resistance, metabolic syndrome risk factors and inflammation. Here, we evaluated whether a 12-week lifestyle intervention in overweight and obese adults with type 2 diabetes could significantly affect the average blood glucose and serum chemerin levels over time. DESIGN: Thirty-five overweight or obese subjects with type 2 diabetes were randomized to receive intensive lifestyle modification including supervised exercise sessions or usual care for 12 weeks. Anthropometric and clinical data were collected before the intervention and after 12 weeks. RESULTS: Lifestyle intervention induced a significant decrease in HbA1c (-1.0 +/- 0.5 vs 0.1 +/- 0.6%, P < 0.001), BMI, total body fat content, serum lipocalin-2 and chemerin levels (-8.1 +/- 21.6 vs + 8.2 +/- 15.9 ng/ml, P = 0.021) and a significant increase in VO2 max after 12 weeks compared to the usual care group. Baseline chemerin levels were positively correlated with the homoeostasis model of assessment of insulin resistance (HOMA-IR), fasting insulin and the high-sensitivity C-reactive protein (hsCRP) and negatively correlated with insulin sensitivity index (ISI). Changes in the chemerin concentration during 12 weeks were independently negatively correlated with changes in ISI and positively correlated with changes in fasting plasma glucose, total cholesterol and lipocalin-2 levels. CONCLUSIONS: A 12-week intensive lifestyle intervention significantly decreased serum chemerin level compared to usual care. Decrease in serum chemerin level was associated with improved insulin sensitivity, and this may be involved in the beneficial effects of lifestyle intervention in overweight and obese type 2 diabetic patients. PMID- 23682798 TI - The prevalence of 16p12.1 microdeletion in patients with left-sided cardiac lesions. AB - SETTING: Left-sided cardiac lesions have a birth prevalence of approximately 1 in 1000 and have been shown to be heritable in pedigree studies. A large microdeletion at 16p12.1 is associated with childhood developmental delay, and initial studies describing this deletion identified left-sided lesions as an enriched phenotype compared with a control population. OBJECTIVE: The aim of this study is to determine whether patients with left-sided cardiac lesions have an increased frequency of 16p12.1 microdeletions as compared with control populations. DESIGN: A cohort of 262 probands with left-sided lesions, including 53 with isolated aortic stenosis/bicuspid aortic valve, 83 with coarctation of the aorta with or without aortic stenosis/bicuspid aortic valve, and 126 with hypoplastic left heart syndrome were assessed for copy number variation at 16p12.1. The control cohort included 595 patients with conotruncal defects as a cardiac control and 971 healthy children. RESULTS: We detected one patient in the left-sided lesion cohort with a large duplication partially overlapping the reported 16p12.1 microdeletion, along with one patient each in the conotruncal and control cohorts with a deletion in the same region. None of these patients had dysmorphic features, extracardiac malformations, or developmental delay. CONCLUSION: In our cohort, structural variation at 16p12.1 was not identified with increased frequency in patients with left-sided lesions as compared with controls. PMID- 23682799 TI - Effective management and intrauterine treatment of congenital cytomegalovirus infection: review article and case series. AB - OBJECTIVE: Human Cytomegalovirus (CMV) infection during pregnancy is the most frequent viral cause of intrauterine infection and responsible for various cerebral and other ultrasound abnormalities of the fetus. It is the leading infectious cause of mental retardation and sensorineural deafness in affected newborns and infants. We present three cases of primary cytomegalovirus infection in pregnancy and demonstrate three different scenarios of the disease with regard to clinical outcome and therapy options. We first report on CMV related phospho- and glycoprotein-specific antibody reactivities in amnion fluid that have not been reported earlier in literature. CASE PRESENTATION: Case 1: A 33-year-old Gravida II Para I was referred for primary CMV infection at 15 weeks gestation presenting with a history of fever. HIG therapy was performed resulting in good neonatal outcome. Case 2: A 23-year-old Gravida I was referred for targeted ultrasound at 23 weeks of gestation presenting with intrauterine growth retardation, multiple fetal hepatic echodensities and thickened placenta. Termination of pregnancy was initiated. Case 3: A 29-year-old Gravida II Para I was referred for primary CMV infection at 16 weeks gestation presenting with no clinical symptoms of CMV. HIG therapy was performed, resulting in good neonatal outcome. CONCLUSION: We want to stress the potential benefit of an off label use of CMV-specific hyperimmune globulin (HIG) therapy, present an algorithm for the management of affected pregnancies and review current literature on this issue. PMID- 23682800 TI - siRNAs modified with boron cluster and their physicochemical and biological characterization. AB - RNA interference (RNAi) technology provides a powerful, yet selective, molecular tool to reduce the expression of genes in eukaryotic cells. Despite the success associated with the effective use of siRNA duplexes for gene silencing, there is a need to improve their properties. These properties, related mainly to migration through the cell membranes, stability of siRNA in vivo, and specificity of their silencing activity, can be improved by chemical modifications of siRNA backbone. In this study, we examined the physicochemical and biological properties of siRNA duplexes targeted against BACE1 gene modified at various positions with a lipophilic boron cluster (C2B10H11, CB). The lipophilicity and resistance to enzymatic degradation of the modified oligomers was higher than the unmodified counterparts. As measured in a dual fluorescence assay (BACE1-GFP/RFP), the carboranyl siRNAs (CB-siRNAs) were as active as the parent nonmodified duplexes and their toxicity toward HeLa cells was also similar. The helical structure of CB-siRNAs remained unchanged upon boron cluster introduction, as determined by CD and UV melting experiments. PMID- 23682801 TI - Novel ABCA12 missense mutation p.Phe2144Ser underlies congenital ichthyosiform erythroderma. PMID- 23682803 TI - Use of global assays to understand clinical phenotype in congenital factor VII deficiency. AB - Congenital factor VII (FVII) deficiency is characterized by genotypic variability and phenotypic heterogeneity. Traditional screening and factor assays are unable to reliably predict clinical bleeding phenotype and guide haemorrhage prevention strategy. Global assays of coagulation and fibrinolysis may better characterize overall haemostatic balance and aid in haemorrhagic risk assessment. We evaluated the ability of novel global assays to better understand clinical bleeding severity in congenital FVII deficiency. Subjects underwent central determination of factor VII activity (FVII:C) as well as clot formation and lysis (CloFAL) and simultaneous thrombin and plasmin generation (STP) global assay analysis. A bleeding score was assigned to each subject through medical chart review. Global assay parameters were analysed with respect to bleeding score and FVII:C. Subgroup analyses were performed on paediatric subjects and subjects with FVII >= 1 IU dL(-1). CloFAL fibrinolytic index (FI2 ) inversely correlated with FVII:C while CloFAL maximum amplitude (MA) and STP maximum velocity of thrombin generation (VT max) varied directly with FVII:C. CloFAL FI2 directly correlated with bleeding score among subjects in both the total cohort and paediatric subcohort, but not among subjects with FVII >= 1 IU dL(-1) . Among subjects with FVII >= 1 IU dL(-1), STP time to maximum velocity of thrombin generation and time to maximum velocity of plasmin generation inversely correlated with bleeding score. These preliminary findings suggest a novel potential link between a hyperfibrinolytic state in bleeding severity and congenital FVII deficiency, an observation that should be further explored. PMID- 23682802 TI - Interactions of the human telomere sequence with the nanocavity of the alpha hemolysin ion channel reveal structure-dependent electrical signatures for hybrid folds. AB - Human telomeric DNA consists of tandem repeats of the sequence 5'-TTAGGG-3', including a 3' terminal single-stranded overhang of 100-200 nucleotides that can fold into quadruplex structures in the presence of suitable metal ions. In the presence of an applied voltage, the alpha-hemolysin (alpha-HL) protein ion channel can produce unique current patterns that are found to be characteristic for various interactions between G-quadruplexes and the protein nanocavity. In this study, the human telomere in a complete sequence context, 5' TAGGG(TTAGGG)3TT-3', was evaluated with respect to its multiple folding topologies. Notably, the coexistence of two interchangeable conformations of the K(+)-induced folds, hybrid-1 and hybrid-2, were readily resolved at a single molecule level along with triplex folding intermediates, whose characterization has been challenging in experiments that measure the bulk solution. These results enabled us to profile the thermal denaturation process of these structures to elucidate the relative distributions of hybrid-1, hybrid-2, and folding intermediates such as triplexes. For example, at 37 degrees C, pH 7.9, in 50 mM aqueous KCl, the ratio of hybrid-1:hybrid-2:triplex is approximately 11:5:1 in dilute solution. The results obtained lay the foundation for utilizing the alpha HL ion channel as a simple tool for monitoring how small molecules and physical context shift the equilibrium between the many G-quadruplex folds of the human telomere sequence. PMID- 23682804 TI - mtDNAprofiler: a Web application for the nomenclature and comparison of human mitochondrial DNA sequences. AB - Mitochondrial DNA (mtDNA) is a valuable tool in the fields of forensic, population, and medical genetics. However, recording and comparing mtDNA control region or entire genome sequences would be difficult if researchers are not familiar with mtDNA nomenclature conventions. Therefore, mtDNAprofiler, a Web application, was designed for the analysis and comparison of mtDNA sequences in a string format or as a list of mtDNA single-nucleotide polymorphisms (mtSNPs). mtDNAprofiler which comprises four mtDNA sequence-analysis tools (mtDNA nomenclature, mtDNA assembly, mtSNP conversion, and mtSNP concordance-check) supports not only the accurate analysis of mtDNA sequences via an automated nomenclature function, but also consistent management of mtSNP data via direct comparison and validity-check functions. Since mtDNAprofiler consists of four tools that are associated with key steps of mtDNA sequence analysis, mtDNAprofiler will be helpful for researchers working with mtDNA. mtDNAprofiler is freely available at http://mtprofiler.yonsei.ac.kr. PMID- 23682806 TI - Filum terminale arteriovenous fistulas: the role of endovascular treatment. AB - OBJECT: The authors describe the clinical presentation, imaging features, and management of patients presenting with filum terminale arteriovenous fistulas (FTAVFs) and the role of transarterial treatment in their management. METHODS: The authors retrospectively reviewed data obtained in 10 patients with FTAVFs diagnosed between January 1990 and December 2011. RESULTS: Most patients (70%) were male, and the age of the population ranged from 31 to 72 years (mean 58.2 years). Clinical presentation was progressive paraparesis and sensory loss in the lower extremities in 9 cases, back pain in 7, radicular pain in 3, bowel/bladder disturbance in 5, and impotence in 1. The duration of symptoms varied between 2 and 24 months. Initial MRI studies showed intramedullary increased T2 signal, swollen cord, and dilated perimedullary veins in all patients. One patient had syringomyelia, presumably caused by venous hypertension transmitted by the perimedullary venous system. Embolization was attempted in 7 patients and was curative in 6 patients. Surgery was performed in the other 4 patients in whom embolization was unsuccessful or deemed not feasible. There was no treatment related complication in either group. Symptoms, venous congestion in the cord, and syringomyelia improved on follow-up in all patients. CONCLUSIONS: Embolization should be considered the treatment of choice for FTAVFs and can effectively treat the majority of patients presenting with an FTAVF. In a smaller group of patients in whom the angioarchitecture is unfavorable, open surgery is recommended. PMID- 23682805 TI - Translating discovery in zebrafish pancreatic development to human pancreatic cancer: biomarkers, targets, pathogenesis, and therapeutics. AB - Abstract Experimental studies in the zebrafish have greatly facilitated understanding of genetic regulation of the early developmental events in the pancreas. Various approaches using forward and reverse genetics, chemical genetics, and transgenesis in zebrafish have demonstrated generally conserved regulatory roles of mammalian genes and discovered novel genetic pathways in exocrine pancreatic development. Accumulating evidence has supported the use of zebrafish as a model of human malignant diseases, including pancreatic cancer. Studies have shown that the genetic regulators of exocrine pancreatic development in zebrafish can be translated into potential clinical biomarkers and therapeutic targets in human pancreatic adenocarcinoma. Transgenic zebrafish expressing oncogenic K-ras and zebrafish tumor xenograft model have emerged as valuable tools for dissecting the pathogenetic mechanisms of pancreatic cancer and for drug discovery and toxicology. Future analysis of the pancreas in zebrafish will continue to advance understanding of the genetic regulation and biological mechanisms during organogenesis. Results of those studies are expected to provide new insights into how aberrant developmental pathways contribute to formation and growth of pancreatic neoplasia, and hopefully generate valid biomarkers and targets as well as effective and safe therapeutics in pancreatic cancer. PMID- 23682807 TI - Treatment of intramedullary tumors: analysis of surgical morbidity and long-term results. AB - OBJECT: Surgery of intramedullary tumors is established as the treatment of choice for these challenging lesions. This study presents a detailed analysis of risk factors for surgical morbidity and data on long-term results for intramedullary tumors. METHODS: Among 1317 patients with tumors of the spinal canal treated between 1980 and 2012, 278 patients with intramedullary tumors are presented. A total of 225 of these patients underwent 246 operations for treatment of 250 tumors. The mean patient age was 41 +/- 17 years (range 3 weeks to 83 years). Patients underwent follow-up through outpatient visits and questionnaires with a mean follow-up of 41 +/- 53 months. Tumors were subdivided into 3 groups: displacing tumors (Type A, n = 162), infiltrating tumors (Type B, n = 80), and nonproliferating tumors (Type C, n = 8). A gross-total resection (GTR) was attempted for every tumor except for Type C lipomas. Participating surgeons were divided into 3 groups according to the number of operations they performed. Short-term results were determined for individual symptoms and the modified McCormick Scale, whereas tumor recurrence rates were calculated with Kaplan-Meier statistics. RESULTS: Overall, 83.3% of Type A tumors underwent GTR compared with 22.5% of Type B and none in Type C. Gross-total resection rates increased throughout the study period and correlated significantly with surgical experience. A worsened neurological state after surgery was seen in 61% of patients. This deterioration was transient in 41.5% and was a common observation after GTR. Permanent morbidity (19.5%) was lowest after GTR and correlated significantly with surgical experience and the preoperative neurological state. Further analysis showed that patients with tumors of thoracic levels, tumor hemorrhages, and malignant and recurrent tumors were at a higher risk for permanent morbidity. In the long term, tumor recurrence rates for ependymomas and benign astrocytomas correlated significantly with the amount of resection. Long term morbidity affected 3.7% with a postoperative myelopathy related to cord tethering at the level of surgery and 21.9% in form of neuropathic pain syndromes. The rate of postsurgical cord tethering could be lowered significantly by using pia sutures after tumor resection. Neuropathic pain syndromes were more common after surgery for tumors with associated syringomyelia or those located in the cervical cord. CONCLUSIONS: Intramedullary tumors should be surgically treated as soon as neurological symptoms appear. Gross-total resection is possible for the majority of benign pathologies. Cervical tumors are associated with higher GTR and lower permanent morbidity rates compared with thoracic tumors. Surgery on intramedullary tumors should be performed by neurosurgeons who deal with these lesions on a regular basis as considerable experience is required to achieve high GTR rates and to limit rates of permanent morbidity. PMID- 23682808 TI - Letter to the Editor: Thoracic fracture-dislocations. PMID- 23682809 TI - Posterior-only approach for lumbar vertebral column resection and expandable cage reconstruction for spinal metastases. AB - OBJECT: The increasing incidence of spinal metastasis, a result of improved systemic therapies for cancer, has spurred a search for an alternative method for the surgical treatment of lumbar metastases. The authors report a single-stage posterior-only approach for resecting any pathological lumbar vertebral segment and reconstructing with a medium to large expandable cage while preserving all neurological structures. METHODS: The authors conducted a retrospective consecutive case review of 11 patients (5 women, 6 men) with spinal metastases treated at 1 institution with single-stage posterior-only vertebral column resection and reconstruction with an expandable cage and pedicle screw fixation. For all patients, the indications for operative intervention were spinal cord compression, cauda equina compression, and/or spinal instability. Neurological status was classified according to the American Spinal Injury Association impairment scale, and functional outcomes were analyzed by using a visual analog scale for pain. RESULTS: For all patients, a circumferential vertebral column resection was achieved, and full decompression was performed with a posterior only approach. Each cage was augmented by posterior pedicle screw fixation extending 2 levels above and below the resected level. No patient required a separate anterior procedure. Average estimated blood loss and duration of each surgery were 1618 ml (range 900-4000 ml) and 6.6 hours (range 4.5-9 hours), respectively. The mean follow-up time was 14 months (range 10-24 months). The median survival time after surgery was 17.7 months. Delayed hardware failure occurred for 1 patient. Preoperatively, 2 patients had intractable pain with intact lower-extremity strength and 8 patients had severe intractable pain, lower extremity paresis, and were unable to walk; 4 of whom regained the ability to walk after surgery. Two patients who were paraplegic before decompression recovered substantial function but remained wheelchair bound, and 2 patients remained paraparetic after the surgery. No patients had lasting intraoperative neuromonitoring changes, and none died. Complications included 2 reoperations, 1 delayed hardware failure (cage subsidence that did not require revision), and 3 incidental durotomies (none of which required reoperation). No postoperative pneumonia, ileus, or deep venous thrombosis developed in any patient. CONCLUSIONS: A posterior-only approach for vertebral segment resection with preservation of spinal nerve roots is a viable technique that can be used throughout the entire lumbar spine. Extensive mobilization of the nerve roots is of utmost importance and allows for insertion and expansion of medium-sized, in situ expandable cages in the midline. This approach, although technically challenging, might reduce the morbidity associated with an anterior approach. PMID- 23682810 TI - Regular smoking is not associated with increased thrombin generation in young adults. PMID- 23682811 TI - Hypoosmotic and glutamate-induced swelling of bipolar cells in the rat retina: comparison with swelling of Muller glial cells. AB - Regulation of cellular volume is of great importance to avoid changes in neuronal excitability resulting from a decrease in the extracellular space volume. We compared the volume regulation of retinal glial (Muller) and neuronal (bipolar) cells under hypoosmotic and glutamate-stimulated conditions. Freshly isolated slices of the rat retina were superfused with a hypoosmotic solution (60% osmolarity; 4 min) or with a glutamate (1 mM)-containing isoosmotic solution (15 min), and the size changes of Muller and bipolar cell somata were recorded. Bipolar cell somata, but not Muller cell somata, swelled under hypoosmotic conditions and in the presence of glutamate. The hypoosmotic swelling of bipolar cell somata might be mediated by sodium flux into the cells, because it was not observed under extracellular sodium-free conditions, and was induced by activation of metabotropic glutamate receptors and sodium-dependent glutamate transporters. The glutamate-induced swelling of bipolar cell somata was mediated by sodium chloride flux into the cells induced by activation of NMDA- and non NMDA glutamate receptors, glutamate transporters, and voltage-gated sodium channels. The glutamate-induced swelling of bipolar cell somata was abrogated by adenosine and gamma-aminobutyric acid, but not by vascular endothelial growth factor and ATP. The data may suggest that Muller cells, in contrast to bipolar cells, possess endogenous mechanisms which tightly regulate the cellular volume in response to hypoosmolarity and prolonged glutamate exposure. Inhibitory retinal transmission may regulate the volume of bipolar cells, likely by inhibition of the excitatory action of glutamate. PMID- 23682812 TI - Paclitaxel, carboplatin, and trastuzumab in a neo-adjuvant regimen for HER2 positive breast cancer. AB - To evaluate a nonanthracycline-containing regimen consisting of 24 weekly administrations of paclitaxel, carboplatin, and trastuzumab as neo-adjuvant therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Patients with stage II or III breast cancer, including inflammatory disease, with HER2 overexpression (immunohistochemistry and/or fluorescent in situ hybridization) were treated with 24 weekly administrations of paclitaxel 70 mg/m(2) , carboplatin AUC = 3 mg/mL/minute, and trastuzumab 2 mg/kg (loading dose 4 mg/kg). In cycles 7, 8, 15, 16, 23, and 24, only trastuzumab was given. The primary end point was pathologic complete response (pCR) in both breast and axilla. Of 61 evaluable patients, 61% had stage II disease and 75% were node positive. The median NRI (Neoadjuvant Response Index, a measure of the degree of downstaging by chemotherapy) of all patients was 0.86. Twenty-seven (44%) had a NRI of 1.0, which corresponds to pCR in breast and lymph nodes. The most commonly reported grade 3/4 toxicities were neutropenia (72%) and thrombocytopenia (36%). Dose reduction was necessary in 51% of the patients. A weekly carboplatin paclitaxel-trastuzumab neo-adjuvant regimen is highly active in HER2-positive breast cancer with an acceptable toxicity profile. A multicenter phase 2 trial has recently reached its accrual target and will serve as a basis for a subsequent randomized phase 3 study comparing this regimen to a similar regimen preceded by anthracyclines. PMID- 23682814 TI - Time-series models for border inspection data. AB - We propose a new modeling approach for inspection data that provides a more useful interpretation of the patterns of detections of invasive pests, using cargo inspection as a motivating example. Methods that are currently in use generally classify shipments according to their likelihood of carrying biosecurity risk material, given available historical and contextual data. Ideally, decisions regarding which cargo containers to inspect should be made in real time, and the models used should be able to focus efforts when the risk is higher. In this study, we propose a dynamic approach that treats the data as a time series in order to detect periods of high risk. A regulatory organization will respond differently to evidence of systematic problems than evidence of random problems, so testing for serial correlation is of major interest. We compare three models that account for various degrees of serial dependence within the data. First is the independence model where the prediction of the arrival of a risky shipment is made solely on the basis of contextual information. We also consider a Markov chain that allows dependence between successive observations, and a hidden Markov model that allows further dependence on past data. The predictive performance of the models is then evaluated using ROC and leakage curves. We illustrate this methodology on two sets of real inspection data. PMID- 23682813 TI - Hydrogen sulfide attenuates opioid dependence by suppression of adenylate cyclase/cAMP pathway. AB - AIMS: The best-established mechanism of opioid dependence is the up-regulation of adenylate cyclase (AC)/cAMP pathway, which was reported to be negatively regulated by hydrogen sulfide (H2S), a novel endogenous neuromodulator. The present study was, therefore, designed to determine whether H2S is able to attenuate the development of opioid dependence via down-regulating AC/cAMP pathway. RESULTS: We demonstrated that application of sodium hydrosulphide (NaHS) and GYY4137, two donors of H2S, significantly alleviated naloxone-induced robust withdrawal jumping (the most sensitive and reliable index of opioid physical dependence) in morphine-treated mice. Repeated treatment with NaHS inhibited the up-regulated protein expression of AC in the striatum of morphine-dependent mice. Furthermore, NaHS also attenuated morphine/naloxone-elevated mRNA levels of AC isoform 1 and 8, production of cAMP, and phosphorylation of cAMP response element binding protein (CREB) in mice striatum. These effects were mimicked by the application of exogenous H2S or over-expression of cystathione-beta-synthase, an H2S -producing enzyme, in SH-SY5Y neuronal cells on treatment with [D-Ala(2),N-Me Phe(4),Gly(5)-ol]-Enkephalin, a selective MU-opioid receptor agonist. Blockade of extracellular-regulated protein kinase 1/2 (ERK1/2) with its specific inhibitor attenuated naloxone-induced CREB phosphorylation. Pretreatment with NaHS or stimulation of endogenous H2S production also significantly suppressed opioid withdrawal-induced ERK1/2 activation in mice striatum or SH-SY5Y cells. INNOVATION: H2S treatment is important in prevention of the development of opioid dependence via suppression of cAMP pathway in both animal and cellular models. CONCLUSION: Our data suggest a potential role of H2S in attenuating the development of opioid dependence, and the underlying mechanism is closely related to the inhibition of AC/cAMP pathway. PMID- 23682815 TI - Numerical investigation of mechanical effects caused by various fixation positions on a new radius intramedullary nail. AB - Fracture of the radius diaphysis is an unusual injury in adults. Open reduction and plate osteosynthesis has been recommended by most of the authors. However, this trend has started to change with the recent introduction of newly designed interlocking intramedullary (IM) nails. New generation of IM nails are developed in order to utilise the advantages of IM nails against plates. Because of its anatomical structure, the radius bone has a complex geometry. Therefore, the callus structure, which forms during the healing period, should not be affected from external effects, such as excessive loads or motion. In this study, effects of radial styloid process (RSP), dorsal side and ulnar notch edge fixations of a new design radius IM nail on the healing period were numerically investigated. A three-dimensional solid model of radius was obtained from computed tomography images of a volunteer and callus structure model, was placed accordingly and different fixations of implants were performed. The models were analysed under axial loads transferring from the wrist to the radius bone using finite element method. As a result of the analysis, fixation of IM nail from RSP was found to be beneficial on healing period in terms of both callus motion and emerging stresses. PMID- 23682817 TI - A 2-fold higher rate of intraventricular hemorrhage-related mortality in African American neonates and infants. AB - OBJECT: Despite the recognition of racial or ethnic differences in preterm gestation, such differences in the rate of intraventricular hemorrhage (IVH), frequently associated with preterm gestation, are not well studied. The authors performed the current study to identify racial or ethnic differences in the incidence of IVH-related mortality within the national population of the US. METHODS: Using the ICD-10 codes P52.0, P52.1, P52.2, P52.3, and P10.2 and the Multiple Cause of Death data from 2000 to 2009, the authors identified all IVH related mortalities that occurred in neonates and infants aged less than 1 year. The live births for whites and African Americans from the census for 2000-2009 were used to derive the incidence of IVH-related mortality for whites and African Americans per 100,000 live births. The IVH rate ratio (RR, 95% confidence interval [CI]) and annual percent change (APC) in the incidence rates from 2000 to 2009 were also calculated. RESULTS: A total of 3249 IVH-related mortality cases were reported from 2000 to 2009. The incidence rates of IVH were higher among African American infants (16 per 100,000 live births) than among whites (7.8 per 100,000 live births). African American infants had a 2-fold higher risk of IVH-related mortality compared with whites (RR 2.0, 95% CI 1.2-3.2). The rate of increase over the last 10 years was less in African American infants (APC 1.6%) than in white infants (APC 4.3%). CONCLUSIONS: The rate of IVH-related mortality is 2-fold higher among African American than white neonates and infants. Further studies are required to understand the underlying reasons for this prominent disparity in one of the most significant causes of infant mortality. PMID- 23682816 TI - Development and systematic oxidative stress of a rat model of chronic bronchitis and emphysema induced by biomass smoke. AB - BACKGROUND: Epidemiological research and meta-analyses of published data have shown that biomass smoke (BS) is a risk factor for chronic obstructive pulmonary disease (COPD). However, the link between BS and COPD lacks experimental confirmation. OBJECTIVES: To verify whether BS can induce pathologic changes and systemic oxidative stress, which may be relevant to the development of emphysema and chronic bronchitis in rats. METHODS: Rats were exposed to BS, cigarette smoke (CS), or clean air (sham) for 14 weeks. During the exposure, the O2, SO2, and CO levels were monitored. Pathological changes in the lungs, systemic oxidative stress, and inflammation biomarkers, together with GSTM1 and GSTP1 mRNA expression in the lung were measured. The glutamate-cysteine ligase catalytic subunit (GCLC) protein expression in the lung was measured using immunohistochemistry and western blotting. RESULTS: The O2, CO, and SO2 levels were 20.31 +/- 0.03%, 981.72 +/- 64.76, and 2.59 +/- 0.26 mg/m(3) for the BS group, respectively, while their levels in the CS group were 20.28 +/- 0.15%, 745.56 +/- 30.83, and 12.64 +/- 0.591 mg/m(3) respectively. As with the rats exposed to CS, the BS rats showed an increased number of inflammatory cells in the bronchoalveolar lavage fluid, an increased pulmonary mean linear intercept and a decreased pulmonary mean alveolar number. Characteristics of chronic bronchitis and peribronchial fibrosis were also found in the BS-exposed rat lungs. Reduced body weight, systemic oxidative stress, and increased GCLC protein expression in the lungs were observed in the rats exposed to BS and CS. CONCLUSIONS: BS can cause emphysema and chronic bronchitis similar to that caused by CS, which is accompanied by systemic oxidative stress and inflammation. PMID- 23682818 TI - Shunt infection in the first year of life. AB - OBJECT: Children younger than 1 year of age are unique in their physiology and comorbidities. Reports in the literature suggest that the risk factors for shunt infection may be different in this population compared with older children. Importantly, these infants often have other congenital malformations requiring various surgical interventions, which impose an additional risk of infection. METHODS: In the 3-year period between 2008 and 2010, 270 patients underwent initial CSF shunt placement during the 1st year of life. Clinical characteristics, hospital course, and shunt infections were prospectively recorded in the practice and hospital electronic medical record. Special attention was given to types and timing of other invasive procedures and their relationship with shunt infection. RESULTS: The average gestational age was 33.6 weeks, and the average birth weight was 2333 g. The average weight at the time of shunt insertion was 4281 g. Prior to shunt insertion, 120 patients underwent 148 surgical procedures, including ventricular access device insertion (n = 63), myelomeningocele closure (n = 37), and cardiac procedures (n = 11), among others. In the 12-month period after shunt insertion, 121 of the 270 patients underwent 135 surgical procedures, which included 79 CSF shunt revisions. Shunt infection occurred in 22 patients, and organisms were identified in 20 cases. Univariate analysis showed that of the very prematurely born infants (gestational age < 30 weeks), those who underwent preshunt cardiac surgery and any surgical procedures within 30 days after the shunt insertion were at a greater risk of shunt infection. In multivariate analysis, preshunt cardiac surgery and surgical procedures within 30 days postshunt placement were significant risk factors independent of gestational age, birth weight, and history of shunt revisions. CONCLUSIONS: The results of this study suggest that surgical procedures within 30 days after shunt insertion and preshunt cardiac surgery are associated with a greater risk of shunt infection in children in whom these devices were inserted during the 1st year of life. PMID- 23682819 TI - The role of endoscopic third ventriculostomy in the treatment of hydrocephalus. AB - OBJECT: Hydrocephalus remains a major public health problem. Conventional treatment has relied on extracranial shunting of CSF to another systemic site, but this approach is associated with a high rate of complications. Endoscopic third ventriculostomy (ETV) is a novel treatment for select forms of hydrocephalus that can eliminate the need for implantation of a lifelong ventricular shunt system. However, the indications for ETV are contested and its long-term effectiveness is not well established. METHODS: The authors selected 100 consecutive patients who underwent ETV for hydrocephalus beginning in 1994. Patients were enrolled and treated at a single institution by a single surgeon. The primary outcome was success of ETV, with success defined as no need for subsequent surgery for hydrocephalus. RESULTS: Ninety-five patients satisfied the inclusion criteria. The mean follow-up period was 5.1 years (median 4.7 years) with follow-up data available for as long as 17 years. Patients commonly presented with headache (85%), ataxia (34%), emesis (29%), and changes in vision (27%). The success rate for ETV was 75%. Twenty-one patients (22%) in the series had malfunctioning shunts preoperatively and 13 (62%) were successfully treated with ETV. Preoperative inferior bowing of the third ventricle floor on MRI was significantly associated with ETV success (p < 0.05). CONCLUSIONS: Endoscopic third ventriculostomy is an effective and durable treatment for select patients with hydrocephalus. When successful, the procedure eliminates the lifelong complications associated with implanted ventricular shunts. PMID- 23682820 TI - Percutaneous CT-guided cordotomy for the treatment of pediatric cancer pain. AB - Percutaneous cordotomy using CT guidance has been shown to be a safe and effective means of reducing pain in adults with cancer in 2 large case series. Its effectiveness in pediatric patients, however, has not been reported. Here, the authors present a case of CT-guided percutaneous cordotomy being used effectively for the treatment of unilateral limb pain in a 9-year-old boy suffering from metastatic medulloblastoma. The efficacy and minimally invasive nature of this procedure support its use in selected pediatric cases. PMID- 23682821 TI - Prevalence of and factors related to pain among elderly Japanese residents in long-term healthcare facilities. AB - AIM: We aimed to examine the pain prevalence among residents who stayed at healthcare facilities for the elderly requiring long-term care in Japan, and explore factors related to self-reported pain. METHODS: This was a cross sectional study. All residents in nine healthcare facilities in Japan were asked to participate in the present study, with the exclusion of short-term and temporary residents. Demographic data were collected from participating residents' medical records. The residents were evaluated using the Barthel Index, the Folstein Mini-Mental State Examination and Self-Rated Health measures. After/during patients underwent a body movement protocol, self-reported pain/Abbey Pain Scale scores were obtained. The chi(2) -test, t-test and logistic regression analyses were carried out to identify factors related to pain. RESULTS: Data were obtained from 246 residents. The prevalence of pain among the residents was 47.2%. Self-rated health status and history of fracture were significantly associated with self-reported pain. Logistic regression analysis showed that self-rated health status (odds ratio [OR] 0.50, 95% confidence interval (CI) 0.28-0.88), mental health diagnoses (OR 9.18, 95%CI 1.27-66.52) and respiratory diagnoses (OR 0.16; 95%CI 0.03-0.97) were associated with pain experienced by residents. CONCLUSIONS: Nearly half of the residents suffered from pain on movement. The pain of these elderly residents should be managed in order to improve their health status. PMID- 23682822 TI - Spectroscopy and photophysics of bifunctional proton donor-acceptor indole derivatives. AB - We report spectroscopic and photophysical studies of a series of selected indole derivatives in solutions and under supersonic jet isolation conditions. All the compounds can assume two rotameric forms, syn and anti. The bifunctional molecules containing both the hydrogen bond donor (indole NH group) and acceptor centers (oxygen, nitrogen, or sulfur atoms) located in separate moieties covalently linked by a single bond are compared with the compound that does not have any acceptor center, 2-(1H-pyrrol-2'-yl)-1H-indole. The former compounds (containing furan, thiazole, or thiophene moieties) were anticipated to show solvent-dependent photophysics. Contrary to the expectations, all the compounds reveal very efficient fluorescence, independent of solvent polarity and hydrogen bond donor and acceptor abilities. Laser spectroscopic studies combined with supersonic jet techniques and quantum chemical computations have been performed in order to identify the rotameric forms and to gain insight into the changes in the molecular structure accompanying electronic excitation. PMID- 23682823 TI - Manipulation and confinement of single particles using fluid flow. AB - High precision control of micro- and nanoscale objects in aqueous media is an essential technology for nanoscience and engineering. Existing methods for particle trapping primarily depend on optical, magnetic, electrokinetic, and acoustic fields. In this work, we report a new hydrodynamic flow based approach that allows for fine-scale manipulation and positioning of single micro- and nanoscale particles using automated fluid flow. As a proof-of-concept, we demonstrate trapping and two-dimensional (2D) manipulation of 500 nm and 2.2 MUm diameter particles with a positioning precision as small as 180 nm during confinement. By adjusting a single flow parameter, we further show that the shape of the effective trap potential can be efficiently controlled. Finally, we demonstrate two distinct features of the flow-based trapping method, including isolation of a single particle from a crowded particle solution and active control over the surrounding medium of a trapped object. The 2D flow-based trapping method described here further expands the micro/nanomanipulation toolbox for small particles and holds strong promise for applications in biology, chemistry, and materials research. PMID- 23682824 TI - Cellular and molecular chaperone fusion vaccines: targeting resistant cancer cell populations. AB - Molecular chaperone-based vaccines offer a number of advantages for cancer treatment. We have discussed the deployment of a vaccine prepared by gentle isolation of Hsp70 from tumour dendritic cell fusions (Hsp70 fusion vaccine). The vaccine was highly effective in triggering specific T cell immunity and in the treatment of tumour-bearing mice and the preparation was shown to retain an increased amount of tumour antigens compared to other chaperone-based isolates. This approach has the further advantage that tumour sub-populations could be used to prepare the Hsp70 fusion vaccine. Cellular fusion vaccines were made to specifically target drug-resistant cancer cells and tumour cell populations enriched in ovarian cancer stem cells (CSC). Such vaccines showed enhanced capacity to trigger T cell immunity to these resistant ovarian carcinoma populations. We have discussed the potential of using the cellular and Hsp70 fusion vaccine approaches in therapy of treatment-resistant cancer cells and its deployment in combination with ionising radiation or hyperthermia to enhance the effectiveness of both forms of therapy. PMID- 23682825 TI - Effects of aescin on testicular repairment in rats with experimentally induced varicocele. AB - This study was conducted to investigate the effects of aescin treatment in a rodent model treated with an experimentally induced varicocele. Experimental varicocele was induced by partial ligation of the left renal vein of rats. Aescin administration was performed daily for 4 weeks after the varicocele induction. Seven weeks later, a contrast-enhanced ultrasound was performed of the rats' testis to assess testicular blood flow. The animals were sacrificed, and H&E staining was then used to evaluate testicular pathological changes and polymorphonuclear leucocytes density. Cauda epididymal sperm counts and motility were evaluated. Blood was collected for the measurement of follicle-stimulating hormone, luteinising hormone and testosterone. Contrast-enhanced ultrasound showed that there were significant decreases in testicular blood flow in the aescin-treated groups compared with those in control varicocele group. Testicular oedema was detected in those rats treated with a varicocele but without aescin, while no oedema was found in the experimental group. H&E staining showed dysfunctional spermatogenesis in both cohorts; however, polymorphonuclear leucocytes density was significantly reduced in aescin-treated groups. There was an increase in sperm counts of the aescin-treated groups. Our study demonstrated that aescin could exert therapeutical effects on reversal of testicular lesions in varicocele rats. PMID- 23682826 TI - A simple and reproducible breast cancer prognostic test. AB - BACKGROUND: A small number of prognostic and predictive tests based on gene expression are currently offered as reference laboratory tests. In contrast to such success stories, a number of flaws and errors have recently been identified in other genomic-based predictors and the success rate for developing clinically useful genomic signatures is low. These errors have led to widespread concerns about the protocols for conducting and reporting of computational research. As a result, a need has emerged for a template for reproducible development of genomic signatures that incorporates full transparency, data sharing and statistical robustness. RESULTS: Here we present the first fully reproducible analysis of the data used to train and test MammaPrint, an FDA-cleared prognostic test for breast cancer based on a 70-gene expression signature. We provide all the software and documentation necessary for researchers to build and evaluate genomic classifiers based on these data. As an example of the utility of this reproducible research resource, we develop a simple prognostic classifier that uses only 16 genes from the MammaPrint signature and is equally accurate in predicting 5-year disease free survival. CONCLUSIONS: Our study provides a prototypic example for reproducible development of computational algorithms for learning prognostic biomarkers in the era of personalized medicine. PMID- 23682827 TI - Development and validation of a single-cell network profiling assay-based classifier to predict response to induction therapy in paediatric patients with de novo acute myeloid leukaemia: a report from the Children's Oncology Group. AB - Single cell network profiling (SCNP) is a multi-parameter flow cytometry technique for simultaneous interrogation of intracellular signalling pathways. Diagnostic paediatric acute myeloid leukaemia (AML) bone marrow samples were used to develop a classifier for response to induction therapy in 53 samples and validated in an independent set of 68 samples. The area under the curve of a receiver operating characteristic curve (AUC(ROC)) was calculated to be 0.85 in the training set and after exclusion of induction deaths, the AUC(ROC) of the classifier was 0.70 (P = 0.02) and 0.67 (P = 0.04) in the validation set when induction deaths (intent to treat) were included. The highest predictive accuracy was noted in the cytogenetic intermediate risk patients (AUC(ROC) 0.88, P = 0.002), a subgroup that lacks prognostic/predictive biomarkers for induction response. Only white blood cell count and cytogenetic risk were associated with response to induction therapy in the validation set. After controlling for these variables, the SCNP classifier score was associated with complete remission (P = 0.017), indicating that the classifier provides information independent of other clinical variables that were jointly associated with response. This is the first validation of an SCNP classifier to predict response to induction chemotherapy. Herein we demonstrate the usefulness of quantitative SCNP under modulated conditions to provide independent information on AML disease biology and induction response. PMID- 23682828 TI - Immune function assay (ImmuKnow) as a predictor of allograft rejection and infection in kidney transplantation. AB - BACKGROUND: The Cylex ImmuKnow (IK) assay provides a rapid and quantitative assessment of T-cell-mediated immune function. Studies have shown correlations between ImmuKnow assay and adverse events, such as immunosuppression and low or high calcineurin inhibitor trough levels. We investigated the correlation between IK changes and rejection or infection in kidney transplant patients and studied the potential application of the IK assays in optimizing individual immunosuppressive therapy. METHODS: ImmuKnow assay was used to determine dynamic intracellular ATP changes in CD4 cells in 193 samples from 42 kidney transplant patients and 25 healthy subjects. Patients were categorized into rejection, infection, and event-free groups. The IK values were assayed and analyzed between kidney transplant patients and healthy controls. RESULTS: Most IK values fell between 200 and 599 ng/mL from pre-transplantation to 30 months post transplantation. The mean IK values continuously increased throughout 30 months. Incidental allograft rejection patients had significantly higher IK values compared with the event-free patients and controls. However, infection patients had significantly lower IK values. Seven days after treatment, IK values in rejection/infection patients were different compared with the values in autograft patients, and there was a significant correlation between calcineurin inhibitor (FK506) trough levels and IK values in rejection/infection patients. Serum creatinine levels in the rejection patients were significantly higher than those in the event-free patients, and C-reactive protein levels were significantly higher in the infection patients compared with the event-free patients. CONCLUSIONS: The IK assay combined with other biomarkers can be used to identify kidney transplant patients at high risk of rejection and infection. PMID- 23682829 TI - Goal pursuit, goal adjustment, and affective well-being following lower limb amputation. AB - OBJECTIVES: This study examined the relationships between tenacious goal pursuit (TGP), flexible goal adjustment (FGA), and affective well-being in a sample of individuals with lower limb amputations. DESIGN: Cross-sectional, quantitative. METHODS: Ninety-eight patients recently admitted to a primary prosthetic rehabilitation programme completed measures of TGP, FGA, positive affect, and negative affect. RESULTS: Hierarchical regression analyses revealed that TGP and FGA accounted for a significant proportion of the variance in both positive and negative affect, controlling for sociodemographic and clinical characteristics. TGP was significantly positively associated with positive affect, while FGA was significantly negatively associated with negative affect. Moderated regression analyses indicated that the beneficial effect of FGA on negative affect was strongest at high levels of amputation-related pain intensity and low levels of TGP. DISCUSSION: TGP and FGA appear to influence subjective well-being in different ways, with TGP promoting the experience of positive affect and FGA buffering against negative affect. TGP and FGA may prove useful in identifying individuals at risk of poor affective outcomes following lower limb amputation and represent important targets for intervention in this patient group. STATEMENT OF CONTRIBUTION: What is already known on this subject? The loss of a limb has a significant impact on several important life domains. Although some individuals experience emotional distress following amputation, the majority adjust well to their limb loss, with some achieving positive change or growth as a result of their experiences. Theories of self-regulation propose that disruptions in goal attainment have negative affective consequences. The physical, social, and psychological upheaval caused by limb loss is likely to threaten the attainment of valued goals, which may leave individuals vulnerable to negative psychosocial outcomes if they do not regulate their goals in response to these challenges. According to the dual-process model of adaptive self-regulation, individuals manage discrepancies between perceived and desired goal attainment by either modifying their life situation or behaviour to fit their goals (tenacious goal pursuit [TGP]) or adjusting their goals to situational constraints (flexible goal adjustment [FGA]). Examining psychosocial adjustment to amputation from this perspective may offer some insight into the diversity of affective outcomes observed. What does this study add? Contributes to our understanding of the mechanisms underlying adjustment to acquired disability. Offers a theory-based explanation for the diversity of psychosocial outcomes observed post-amputation. Identifies important targets for interventions to enhance adjustment in this population. PMID- 23682830 TI - Alopecia areata associated with Herpes zoster. PMID- 23682831 TI - Acclimation to humidity modifies the link between leaf size and the density of veins and stomata. AB - The coordination of veins and stomata during leaf acclimation to sun and shade can be facilitated by differential epidermal cell expansion so large leaves with low vein and stomatal densities grow in shade, effectively balancing liquid- and vapour-phase conductances. As the difference in vapour pressure between leaf and atmosphere (VPD) determines transpiration at any given stomatal density, we predict that plants grown under high VPD will modify the balance between veins and stomata to accommodate greater maximum transpiration. Thus, we examined the developmental responses of these traits to contrasting VPD in a woody angiosperm (Toona ciliata M. Roem.) and tested whether the relationship between them was altered. High VPD leaves were one-third the size of low VPD leaves with only marginally greater vein and stomatal density. Transpirational homeostasis was thus maintained by reducing stomatal conductance. VPD acclimation changed leaf size by modifying cell number. Hence, plasticity in vein and stomatal density appears to be generated by plasticity in cell size rather than cell number. Thus, VPD affects cell number and leaf size without changing the relationship between liquid- and vapour-phase conductances. This results in inefficient acclimation to VPD as stomata remain partially closed under high VPD. PMID- 23682832 TI - Standardization of histological procedures for the detection of toxic substances by immunohistochemistry in Dipteran larvae of forensic importance. AB - Immunohistochemistry (IHC) technique is an alternative toxicological analysis to detect drugs in insects of forensic importance, but it requires thorough histological procedures. In this study, we tested different fixatives--phosphate buffered paraformaldehyde 4% (PP), Carnoy's fluid (CF), Kahle's solution (KS), ethanol in different concentrations, and ethanol associated to PP and CF, time of fixation and histological processes for dipteran larvae's tissue, aiming to develop a sample preparation protocol for IHC application. A suitable fixation was achieved using PP for 12 and 24 h, CF for 3 h, 70% ethanol for 19 days, and 70% ethanol/CF for 2 h/3 h. Postfixation using negative pressure, two immersions in xylene for 30 min each, and one in xylene plus paraffin for 45 min increased tissue preservation. An immunohistochemical test for cocaine detection was performed using monoclonal benzoylecgonine antibody from mouse, peroxidase conjugated anti-mouse IgG and visualized by 3,3'-diaminobenzidine method showed these histological procedures didn't compromise antigenicity. PMID- 23682833 TI - Femoral venous hemostasis in children using the technique of "figure-of-eight" sutures. AB - BACKGROUND: Structural heart interventions require the use of relatively large diameter delivery sheaths or latex nylon net balloon catheters, which results in a relatively large-diameter venous puncture point. At present, femoral venous hemostasis is achieved by manual compression. A temporary figure-of-eight subcutaneous suture has been introduced to achieve immediate postprocedural femoral venous hemostasis after using a >=24Fr sheath in an adult. This method is not well evaluated in children. METHOD: We report our experience using this technique in children treated with 7-14Fr sheaths. From May 2009 to March 2012, 104 children (ages ranging from 3 to 10 years, mean 8.1 +/- 1.6 years) with atrial septal defects (n = 86) and pulmonary valve stenosis (n = 18) underwent percutaneous transcatheter interventions. Sheath sizes used were >=7Fr (7Fr, n = 5; 8Fr, n = 29; 9Fr, n = 14; 10Fr, n = 15; 12Fr, n = 19; 14Fr, n = 22). RESULT: A total of 102 patients had immediate femoral vein hemostasis, and 2 developed a femoral vein hematoma requiring manual compression. One patient was diagnosed with a femoral artery pseudoaneurysm during hospitalization. On follow-up, there was no evidence of hematoma or thrombosis. CONCLUSION: The "figure-of-eight" suture technique is effective and safe, achieving immediate hemostasis after the use of large femoral vein sheaths in children. PMID- 23682834 TI - Reproducibility and relative validity of a brief quantitative food frequency questionnaire for assessing fruit and vegetable intakes in North-African women. AB - BACKGROUND: In the context of a rapidly increasing prevalence of noncommunicable diseases, fruit and vegetables could play a key preventive role. To date, there is no rapid assessment tool available for measuring the fruit and vegetable intakes of North-African women. The present study aimed to investigate the reproducibility and relative validity of an eight-item quantitative food frequency questionnaire that measures the fruit and vegetable intakes (FV-FFQ) of Moroccan women. METHODS: During a 1-week period, 100 women, living in the city of Rabat, Morocco (aged 20-49 years) completed the short FV-FFQ twice: once at baseline (FV-FFQ1) and once at the end of the study (FV-FFQ2). In the mean time, participants completed three 24-h dietary recalls. All questionnaires were administered by interviewers. Reproducibility was assessed by computing Spearman's correlation coefficients, intraclass correlation (ICC) coefficients and kappa statistics. Relative validity was assessed by computing Wilcoxon signed rank tests and Spearman's correlation coefficients, as well as by performing Bland-Altman plots. RESULTS: In terms of reproducibility, Spearman's correlation coefficient was 0.56; ICC coefficient was 0.68; and weighted kappa was 0.35. In terms of relative validity, compared with the three 24-h recalls, the FV-FFQ slightly underestimated mean fruit and vegetable intakes (-10.9%; P = 0.006); Spearman's correlation coefficient was 0.69; at the individual level, intakes measured by the FV-FFQ were between 0.39 and 2.19 times those measured by the 24 h recalls. CONCLUSIONS: The brief eight-item FV-FFQ is a reliable and relatively valid tool for measuring mean fruit and vegetable intakes at the population level, although this is not the case at the individual level. PMID- 23682835 TI - Melatonin and peripheral circuitries: insights on appetite and metabolism in Danio rerio. AB - Melatonin is a neuroendocrine transducer of circadian/circannual rhythms able to synchronize organism's physiological activity. On the basis of our recent findings on appetite regulation by melatonin in the zebrafish brain, the aim of this study was to evaluate melatonin's role in peripheral circuitries regulating food intake, growth, and lipid metabolism. For this purpose, the effect of two melatonin doses (100 nM and 1 MUM) administered for 10 days, via water, to adult zebrafish was evaluated at both physiological and molecular levels. The major signals controlling energy homeostasis were analyzed together. Additionally, the effect of melatonin doses on muscle metabolic resources was evaluated. The results obtained indicate that melatonin reduces food intake by stimulating molecules involved in appetite inhibition, such as leptin (LPT), in the liver and intestine and MC4R, a melanocortin system receptor, in the liver. Moreover, melatonin decreases hepatic insulin-like growth factor-I (IGF-I) gene expression, involved in growth process and other signals involved in lipid metabolism such as proliferator-activated receptors (PPARalpha, beta, and gamma) and sterol regulatory element-binding protein (SREBP). These results were correlated with lower levels of lipids in the muscles as evidenced by the macromolecular pools analyses. The findings obtained in this study could be of great interest for a better understanding of the molecular mechanisms as the basis of food intake control and, in turn, can be a useful tool for medical and aquaculture applications. PMID- 23682837 TI - Effects of conformational alteration induced by D-/L-isonucleoside incorporation in siRNA on their stability in serum and silencing activity. AB - We report here that all of the d- or l-isonucleoside (isoNA) modified siRNAs investigated showed the characteristic A-form conformation in the circular dichroism (CD) spectra compared to native siRNA. The d-isoNA modification had less influence on the thermal stability of siRNAs, but all l-isoNA modification displayed a significant tendency to decrease the thermal stability of siRNA. It was also found that the stabilities of d-/l-isoNA modified siMek1 in serum were different and d-isoNA modification was more potent, i.e., increase of serum stability of siRNA, than l-isoNA modification. When d-isoNA incorporated at position 4 and position 5 at antisense strand of siMek1 showed obvious improvement on serum stability, however, l-isoNA incorporated at positions 11 and 12 at antisense strand and position 9 at sense strand made the siMek1 duplex formed very unstable in serum. The silencing activities of modified siMek1s with d-/l-isoNA at position 1 of antisense strand also dropped dramatically; however, the modification at 3'-terminal of the sense strand with d- or l-isoNA significantly enhanced the silencing activity targeting the antisense strand as reporter and minimized the passenger strand-specific off-target effect. IsoNA modified in the seed area of siMek1, siMek1 A04D and siMek1 A05L, showed similar activity to the native one and better target selectivity. In the case of modification at the position near the cleavage area, it was found that d- or l isoNA modified sense strand at position 8, 9, or 15 of siMek1 could retain the silencing activities targeting the antisense strand as reporter. Especially, both siMek1 S15D and siMek1 S15L showed good silencing activity and high target selectivity compared to native siMek1. The effects of conformational alteration of such isoNA modification of siRNA on their stability in serum and silencing activity are discussed based on computer simulation. Systematic investigation of the relationship between modified siRNA conformation and their physical and biological properties should provide a useful guideline for chemical modification and optimization of siRNA for further clinical application. PMID- 23682836 TI - Imaging beta cell regeneration and interactions with islet vasculature in transparent adult zebrafish. AB - Blood vessel networks provide nutrients and gaseous exchange that are essential for functions. Pancreatic islet capillaries deliver oxygen to endocrine cells while transporting hormones to organs and peripheral locations throughout the body. We have developed a zebrafish diabetes model in which adult islets can be followed in vivo during beta cell regeneration while calibrating changes in beta cell mass and fasting blood glucose levels. After genetic ablation, beta cells are initially dysfunctional or dying, and blood glucose levels increase fourfold. During a 2-week period, hyperglycemia eventually normalizes as beta cell mass regenerates. We show that mCherry-fluorescent, insulin-positive beta cells re emerge in close contact with the vascular endothelium. Alterations in the dense vascular network of zebrafish islets were visualized by the expression of green fluorescent protein (GFP) in endothelial cells derived from the Fli transcription factor promoter. The rapid destruction and regeneration of beta cell mass was evaluated in the same animal over time, providing a functional model for investigating the interactions of islet cell types with vascular cells as well as the consequences of hyperglycemia on other tissues. Regenerating adult zebrafish can be utilized as vertebrate, metabolically active models for generating new insights into treatments for type 2 diabetes. PMID- 23682838 TI - Determination of reference values for urinary neutrophil gelatinase-associated lipocalin in premature infants. AB - BACKGROUND: The aim of this study is to determine the reference values of urinary neutrophil gelatinase-associated lipocalin (uNGAL) in healthy very preterm infants. METHOD: The study was performed on 30 preterm infants whose gestational ages (GA) were between 28 and 34 weeks. They were divided into three groups according to the GA as group 1: GA 28-29 weeks, group 2: 30-32 weeks and group 3: 33-34 weeks. Blood and urine samples were obtained on postnatal (PN) days 1 and 7. uNGAL was measured by ELISA. RESULTS: There were 10 preterm infants for each group. The median values of uNGAL on PN Days 1 were 19.80 (8.6-25.7) ng/ml, 9.25 (1.42-30.3) ng/ml, and 7.95 (1.60-27.8) ng/ml in group 1, group 2 and group 3, respectively. Multivariate linear regression analysis showed that uNGAL values are not associated with GA, birth weight, and gender in preterm infants on PN Days 1 and 7. CONCLUSION: Our study indicated that normal values of uNGAL concentrations in healthy very preterm infants, and older children or adults are similar preterm infants. PMID- 23682839 TI - MicroRNA profiling in the mouse hypothalamus reveals oxytocin-regulating microRNA. AB - Oxytocin (Oxt), produced in the hypothalamic paraventricular and supraoptic nuclei for transport to and release from the posterior pituitary, was originally discovered through its role in lactation and parturition. Oxt also plays important roles in the central nervous system by influencing various behaviors. MicroRNAs (miRNAs), endogenous regulators of many genes, are a class of small non coding RNAs that mediate post-transcriptional gene silencing. We performed miRNA expression profiling of the mouse hypothalamus by deep sequencing. Among the sequenced and cross-mapped small RNAs, expression of known miRNAs and unknown miRNAs candidates were analyzed. We investigated in detail one miRNA, miR-24, and found that it is a novel regulator of Oxt and controls both transcript and peptide levels of Oxt. These results provide insights into potential neurohypophysial hormone regulation mediated by miRNAs. PMID- 23682841 TI - Normal cleavage of von Willebrand factor by ADAMTS-13 in the absence of factor VIII in patients with severe hemophilia A. PMID- 23682842 TI - Thiosquaraine rotaxanes: synthesis, dynamic structure, and oxygen photosensitization. AB - Thiosquaraine dyes have sulfur atoms instead of oxygens on the central squaraine core, and they are powerful singlet oxygen photosensitizers. Stability studies show that they are susceptible to attack by nucleophiles. This problem was circumvented by preparing a mechanically interlocked thiosquaraine rotaxane. NMR studies of the rotaxane indicate an unusual dynamic molecular structure due to a nonsymmetrical coconformation. Upon irradiation with red light, the thiosquaraine rotaxane generates the same amount of singlet oxygen as the known photosensitizer methylene blue. PMID- 23682840 TI - Mn porphyrin regulation of aerobic glycolysis: implications on the activation of diabetogenic immune cells. AB - AIMS: The immune system is critical for protection against infections and cancer, but requires scrupulous regulation to limit self-reactivity and autoimmunity. Our group has utilized a manganese porphyrin catalytic antioxidant (MnTE-2-PyP(5+), MnP) as a potential immunoregulatory therapy for type 1 diabetes. MnP has previously been shown to modulate diabetogenic immune responses through decreases in proinflammatory cytokine production from antigen-presenting cells and T cells and to reduce diabetes onset in nonobese diabetic mice. However, it is unclear whether or not MnP treatment can act beyond the reported inflammatory mediators. Therefore, the hypothesis that MnP may be affecting the redox-dependent bioenergetics of diabetogenic splenocytes was investigated. RESULTS: MnP treatment enhanced glucose oxidation, reduced fatty acid oxidation, but only slightly decreased overall oxidative phosphorylation. These alterations occurred because of increased tricarboxylic acid cycle aconitase enzyme efficiency and were not due to changes in mitochondrial abundance. MnP treatment also displayed decreased aerobic glycolysis, which promotes activated immune cell proliferation, as demonstrated by reduced lactate production and glucose transporter 1 (Glut1) levels and inactivation of key signaling molecules, such as mammalian target of rapamycin, c-myc, and glucose-6-phosphate dehydrogenase. INNOVATION: This work highlights the importance of redox signaling by demonstrating that modulation of reactive oxygen species can supplant complex downstream regulation, thus affecting metabolic programming toward aerobic glycolysis. CONCLUSION: MnP treatment promotes metabolic quiescence, impeding diabetogenic autoimmune responses by restricting the metabolic pathways for energy production and affecting anabolic processes necessary for cell proliferation. PMID- 23682843 TI - Comment on basal cell carcinoma rebound after cessation of vismodegib in an individual with basal cell nevus syndrome. PMID- 23682844 TI - The Potential Impact of an Anthrax Attack on Real Estate Prices and Foreclosures in Seattle. AB - This article provides a methodology for the economic analysis of the potential consequences of a simulated anthrax terrorism attack on real estate within the Seattle metropolitan area. We estimate spatially disaggregated impacts on median sales price of residential housing within the Seattle metro area following an attack on the central business district (CBD). Using a combination of longitudinal panel regression and GIS analysis, we find that the median sales price in the CBD could decline by as much as $280,000, and by nearly $100,000 in nearby communities. These results indicate that total residential property values could decrease by over $50 billion for Seattle, or a 33% overall decline. We combine these estimates with HUD's 2009 American Housing Survey (AHS) to further predict 70,000 foreclosures in Seattle spatial zones following the terrorism event. PMID- 23682845 TI - Micro-structurally detailed model of a therapeutic hydrogel injectate in a rat biventricular cardiac geometry for computational simulations. AB - Biomaterial injection-based therapies have showed cautious success in restoration of cardiac function and prevention of adverse remodelling into heart failure after myocardial infarction (MI). However, the underlying mechanisms are not well understood. Computational studies utilised simplified representations of the therapeutic myocardial injectates. Wistar rats underwent experimental infarction followed by immediate injection of polyethylene glycol hydrogel in the infarct region. Hearts were explanted, cryo-sectioned and the region with the injectate histologically analysed. Histological micrographs were used to reconstruct the dispersed hydrogel injectate. Cardiac magnetic resonance imaging data from a healthy rat were used to obtain an end-diastolic biventricular geometry which was subsequently adjusted and combined with the injectate model. The computational geometry of the injectate exhibited microscopic structural details found the in situ. The combination of injectate and cardiac geometry provides realistic geometries for multiscale computational studies of intra-myocardial injectate therapies for the rat model that has been widely used for MI research. PMID- 23682846 TI - Development and characterization of multilamellar liposomes containing pyridostigmine. AB - Pyridostigmine has cardioprotective activity in both free and liposomal forms. This study aimed to develop and characterize liposomal formulations of pyridostigmine. For this, a spectrophotometric ultraviolet (UV) analytical method, at 270 nm, was developed and validated to quantify liposomal pyridostigmine. The method was linear in ranges from 0.02 to 0.09 mg/mL. The accuracy of this method was determined intra- and inter-day; the results of coefficient of variation were of 1.73-2.72% and 0.32-2.32%, respectively. The accuracy ranged between 99.45% and 101.12%. The method has not changed by influence of liposomal matrix and demonstrated being able to quantify pyridostigmine in liposomes. Two liposomal multilamellar formulations were developed: a constituted by dystearoyl-phosphatidylcholine (DSPC) and cholesterol (CHOL) other by dioleil-phosphatidylcholine (DOPC) and CHOL. The encapsulation efficiency was determined as 23.4% and 15.4%, respectively. Analyses of size and release of pyridostigmine from the formulations were made and the results showed that the formulations are viable for future studies in vivo. PMID- 23682847 TI - Bayes factors for testing inequality constrained hypotheses: Issues with prior specification. AB - Several issues are discussed when testing inequality constrained hypotheses using a Bayesian approach. First, the complexity (or size) of the inequality constrained parameter spaces can be ignored. This is the case when using the posterior probability that the inequality constraints of a hypothesis hold, Bayes factors based on non-informative improper priors, and partial Bayes factors based on posterior priors. Second, the Bayes factor may not be invariant for linear one to-one transformations of the data. This can be observed when using balanced priors which are centred on the boundary of the constrained parameter space with a diagonal covariance structure. Third, the information paradox can be observed. When testing inequality constrained hypotheses, the information paradox occurs when the Bayes factor of an inequality constrained hypothesis against its complement converges to a constant as the evidence for the first hypothesis accumulates while keeping the sample size fixed. This paradox occurs when using Zellner's g prior as a result of too much prior shrinkage. Therefore, two new methods are proposed that avoid these issues. First, partial Bayes factors are proposed based on transformed minimal training samples. These training samples result in posterior priors that are centred on the boundary of the constrained parameter space with the same covariance structure as in the sample. Second, a g prior approach is proposed by letting g go to infinity. This is possible because the Jeffreys-Lindley paradox is not an issue when testing inequality constrained hypotheses. A simulation study indicated that the Bayes factor based on this g prior approach converges fastest to the true inequality constrained hypothesis. PMID- 23682848 TI - In vitro approaches to investigate cytochrome P450 activities: update on current status and their applicability. AB - INTRODUCTION: Cytochromes P450 (CYPs) play a central role in the Phase I metabolism of drugs and other xenobiotics. It is estimated that CYPs can metabolize up to two-thirds of drugs present in humans. Over the past two decades, there have been numerous advances in in vitro methodologies to characterize drug metabolism and interaction involving CYPs. AREAS COVERED: This review focuses on the use of in vitro methodologies to examine CYPs' role in drug metabolism and interaction. There is an emphasis on their current development, applicability, advantages and limitations as well as the use of in silico approaches in complementing and supporting in vitro data. The article also highlights the challenges in extrapolating in vitro data to in vivo situations. EXPERT OPINION: Advances in in vitro methodologies have been made such that data can be used for in vivo prediction with comfortable degree of confidence. Improved assay designs and analytical techniques have permitted development of miniaturized assay format and automated system with improved sensitivity and throughput capacity. High-quality experimental designs and scientifically rigorous assessment/validation protocols remain crucial in developing reliable and robust in vitro models. With continued progress made in the field, in vitro methodologies will continually be employed in evaluating CYP activities in pharmaceutical industries and laboratories. PMID- 23682850 TI - Stepwise molding, etching, and imprinting to form libraries of nanopatterned substrates. AB - Herein, we describe a novel colloidal lithographic strategy for the stepwise patterning of planar substrates with numerous complex and unique designs. In conjunction with colloidal self-assembly, imprint molding, and capillary force lithography, reactive ion etching was used to create complex libraries of nanoscale features. This combinatorial strategy affords the ability to develop an exponentially increasing number of two-dimensional nanoscale patterns with each sequential step in the process. Specifically, dots, triangles, circles, and lines could be assembled on the surface separately and in combination with each other. Numerous architectures are obtained for the first time with high uniformity and reproducibility. These hexagonal arrays were made from polystyrene and gold features, whereby each surface element could be tuned from the micrometer size scale down to line widths of ~35 nm. The patterned area could be 1 cm(2) or even larger. The techniques described herein can be combined with further steps to make even larger libraries. Moreover, these polymer and metal features may prove useful in optical, sensing, and electronic applications. PMID- 23682849 TI - Application of the health belief model: development of the hearing beliefs questionnaire (HBQ) and its associations with hearing health behaviors. AB - OBJECTIVE: To develop a hearing beliefs questionnaire (HBQ) that assesses hearing beliefs within the constructs of the health belief model, and to investigate whether HBQ scores are associated with hearing health behaviors. DESIGN: A 60 item version of the questionnaire was developed and completed by 223 participants who also provided information about their hearing health behaviors (help seeking, hearing-aid acquisition, and hearing-aid use). STUDY SAMPLE: Individuals aged between 22 and 90 years recruited from a primary care waiting area at a Veterans hospital. Seventy-six percent were male, 80% were Veterans. RESULTS: A 26-item version of the HBQ with six scales was derived using factor analysis and reliability analyses. The scales measured: perceived susceptibility, perceived severity, perceived benefits, perceived barriers, perceived self-efficacy, and cues to action. HBQ scores differed significantly between individuals with different hearing health behaviors. Logistic regression analyses resulted in robust models of hearing health behaviors that correctly classified between 59% and 100% of participant hearing health behaviors. CONCLUSIONS: The HBM appears to be an appropriate framework for examining hearing health behaviors, and the HBQ is a valuable tool for assessing hearing health beliefs and predicting hearing health behaviors. PMID- 23682851 TI - Epstein-Barr virus-associated smooth muscle tumors after kidney transplantation: treatment and outcomes in a single center. AB - BACKGROUND: Epstein-Barr virus-associated smooth muscle tumors (EBV SMT) in adult kidney transplant recipients (KTR) are rare. The aims of this study are to document the clinical features, types of treatment given, and outcomes of KTR with EBV SMT in our institution. METHODS: Sixteen patients were identified from our institution's databases. Patients' survival, tumor outcome, and graft survival were compared between patients who remained on cyclosporine-based immunosuppressant and those who converted to sirolimus-based therapy. RESULTS: The median time of diagnosis was 9.4 yr after kidney transplantation, and majority of the patients had multifocal disease at the time of diagnosis. Overall, the patient survival rate was 75% over a mean follow-up period of five yr. Two patients with non-functioning allograft at the time of diagnosis of EBV SMT were excluded from the treatment outcome analysis. Comparing the sirolimus (n = 7) vs. cyclosporine groups (n = 7), patient survival rate was 100% vs. 42.9% (p = 0.08), graft survival 71.4% vs. 28.7% (p = 0.53), and disease-free status 42.9% vs. 14.3% (p = 0.73), respectively. CONCLUSION: Surgical resection in combination with decreasing immunosuppression or conversion to sirolimus appears to be effective in the treatment of EBV SMT in KTR. PMID- 23682852 TI - Altered expression of mitofusin 2 in penile tissues of diabetic rats. AB - Diabetic erectile dysfunction (ED) is a common complication in diabetes mellitus, and the efficacy of first-line therapies is not satisfactory. Recent studies revealed that corporal apoptosis was responsible for the nonresponsiveness of severe ED to phosphodiesterase type 5 inhibitors. Mitofusin 2 (Mfn2) is a versatile protein, regulating mitochondrial morphology and playing an important role in apoptosis. Several studies showed that expression of Mfn2 was decreased in STZ-induced diabetic rats' kidney, myocardium and retina, which was associated with diabetic nephropathy, cardiomyopathy and retinopathy respectively. In this study, our aim was to explore the expression of Mfn2 and apoptosis in diabetic rats' penes. We found that erectile function (ICP/MAP) elicited by electrical stimulation of cavernous nerve was markedly impaired in diabetic rats compared with the normal rats. The mRNA and protein levels of Mfn2 were found to be significantly reduced in diabetic rats' penile tissues. Compared with normal rats, the content of smooth muscle and B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) ratio were dramatically decreased, and penile apoptotic index and expression of activated-caspase-3 were dramatically increased in diabetic rats. This data indicated that repression of Mfn2 in diabetic rats' penes might be associated with excessive apoptosis in diabetes-induced severe ED. PMID- 23682853 TI - S-1 induced a durable response in metastatic extramammary Paget's disease. PMID- 23682856 TI - First indigenous transmission of Japanese Encephalitis in urban areas of National Capital Territory of Delhi, India. AB - OBJECTIVE: Until 2010, no Japanese encephalitis (JE) had been reported from Delhi. Upon report of four confirmed cases of JE in September 2011, detailed investigations were carried out to determine whether the cases were imported or indigenous. METHODS: Entomological surveys were carried out and all mosquito pools were tested for the detection of JE virus by ELISA method using specific monoclonal antibody. Human blood samples from contacts of the patients were tested by IgM-captured ELISA method. Pig's blood samples were also tested for the detection of JE virus. RESULTS: Culex tritaeniorhynchus, Culex vishnui and Culex pseudovishnui mosquitoes were found. In contrast to rural areas, their breeding habitats were different in the city. 19 pools were tested. JE virus was detected in two pools of Cx. tritaeniorhynchus females reared from field-collected larvae, indicating vertical transmission. One pool of Cx. vishnui was also positive. This is the first report for the detection of JE virus in mosquitoes from Delhi. JE IgM antibodies in five contacts/residents indicate recent infection. JE virus was also detected in pigs. CONCLUSION: Present analysis shows that of four reported JE cases, three were confirmed indigenous, indicating that the virus is multiplying in the city. Mapping of infected JE vector mosquitoes in the cities is required for preventive measures to contain further spread of the disease. PMID- 23682854 TI - Integrative genomic analysis of CREB defines a critical role for transcription factor networks in mediating the fed/fasted switch in liver. AB - BACKGROUND: Metabolic homeostasis in mammals critically depends on the regulation of fasting-induced genes by CREB in the liver. Previous genome-wide analysis has shown that only a small percentage of CREB target genes are induced in response to fasting-associated signaling pathways. The precise molecular mechanisms by which CREB specifically targets these genes in response to alternating hormonal cues remain to be elucidated. RESULTS: We performed chromatin immunoprecipitation coupled to high-throughput sequencing of CREB in livers from both fasted and re fed mice. In order to quantitatively compare the extent of CREB-DNA interactions genome-wide between these two physiological conditions we developed a novel, robust analysis method, termed the 'single sample independence' (SSI) test that greatly reduced the number of false-positive peaks. We found that CREB remains constitutively bound to its target genes in the liver regardless of the metabolic state. Integration of the CREB cistrome with expression microarrays of fasted and re-fed mouse livers and ChIP-seq data for additional transcription factors revealed that the gene expression switches between the two metabolic states are associated with co-localization of additional transcription factors at CREB sites. CONCLUSIONS: Our results support a model in which CREB is constitutively bound to thousands of target genes, and combinatorial interactions between DNA binding factors are necessary to achieve the specific transcriptional response of the liver to fasting. Furthermore, our genome-wide analysis identifies thousands of novel CREB target genes in liver, and suggests a previously unknown role for CREB in regulating ER stress genes in response to nutrient influx. PMID- 23682857 TI - Direct analyte-probed nanoextraction coupled to nanospray ionization-mass spectrometry of drug residues from latent fingerprints. AB - Here, we present a method of extracting drug residues from fingerprints via Direct Analyte-Probed Nanoextraction coupled to nanospray ionization-mass spectrometry (DAPNe-NSI-MS). This instrumental technique provides higher selectivity and lower detection limits over current methods, greatly reducing sample preparation, and does not compromise the integrity of latent fingerprints. This coupled to Raman microscopy is an advantageous supplement for location and identification of trace particles. DAPNe uses a nanomanipulator for extraction and differing microscopies for localization of chemicals of interest. A capillary tip with solvent of choice is placed in a nanopositioner. The surface to be analyzed is placed under a microscope, and a particle of interest is located. Using a pressure injector, the solvent is injected onto the surface where it dissolves the analyte, and then extracted back into the capillary tip. The solution is then directly analyzed via NSI-MS. Analyses of caffeine, cocaine, crystal methamphetamine, and ecstasy have been performed successfully. PMID- 23682858 TI - Falls and fractures in participants and excluded non-participants of a fall prevention exercise program for elderly women with a history of falls: 1-year follow-up study. AB - AIM: To evaluate the effectiveness of a strength and balance enhancing exercise intervention as a means of preventing falls in community-dwelling elderly Japanese women with a history of falls, while comparing functional fitness, fall and fracture rate in excluded subjects. METHODS: A 1-year follow-up trial was carried out on 105 participants over the age of 70 years, who were randomly assigned to the exercise or education group, and also on 91 women excluded based on the exclusion criteria. The exercise group attended a 60-min exercise class twice a week for 3 months. Falls, injuries, fractures, and functional fitness assessments were measured at baseline, post-intervention and 1-year follow up. RESULTS: During the follow up, fall rates were 19.6% in the exercise group, 40.4% in the education group and 40.8% in excluded subjects (chi(2) = 7.069, P = 0.029). Compared with the exercise group, the odds ratio (OR) for falls was greater in the education group (OR 2.78, 95% confidence interval (CI) 1.17-6.96) and excluded participants (OR 2.83, 95%CI 1.25-6.80). The OR for fractures was over fourfold greater in excluded participants (OR 4.30, 95% CI 1.02-9.70) than the exercise group. CONCLUSIONS: The exercise intervention for participants with fall history effectively decreased incidences of falls and fractures. However, fall and fracture rates in excluded people were high. Further research focusing on feasible countermeasures for falls in excluded people who are at high risk of fractures is required. PMID- 23682859 TI - An ambulance referral network improves access to emergency obstetric and neonatal care in a district of rural Burundi with high maternal mortality. AB - OBJECTIVES: In 2006, Medecins sans Frontieres (MSF) established an emergency obstetric and neonatal care (EmONC) referral facility linked to an ambulance referral system for the transfer of women with obstetric complications from peripheral maternity units in Kabezi district, rural Burundi. This study aimed to (i) describe the communication and ambulance service together with the cost; (ii) examine the association between referral times and maternal and early neonatal deaths; and (iii) assess the impact of the referral service on coverage of complicated obstetric cases and caesarean sections. METHODS: Data were collected for the period January to December 2011, using ambulance log books, patient registers and logistics records. RESULTS: In 2011, there were 1478 ambulance call outs. The median referral time (time from maternity calling for an ambulance to the time the patient arrived at the MSF referral facility) was 78 min (interquartile range, 52-130 min). The total annual cost of the referral system (comprising 1.6 ambulances linked with nine maternity units) was ? 85 586 (? 61/obstetric case transferred or ? 0.43/capita/year). Referral times exceeding 3 h were associated with a significantly higher risk of early neonatal deaths (OR, 1.9; 95% CI, 1.1-3.2). MSF coverage of complicated obstetric cases and caesarean sections was estimated to be 80% and 92%, respectively. CONCLUSION: This study demonstrates that it is possible to implement an effective communication and transport system to ensure access to EmONC and also highlights some of the important operational factors to consider, particularly in relation to minimising referral delays. PMID- 23682860 TI - Effect of storage conditions on the recrystallization of drugs in solid dispersions with crospovidone. AB - The physical stability of amorphous solid dispersions (SDs) is influenced by their storage conditions. The goal of this work was to investigate the factors affecting the recrystallization of drugs in SDs after storage under conditions of high temperature and high humidity. SDs of three drugs (dipyridamole, nifedipine and indomethacin) with different functional groups (amino, carbonyl and hydroxyl) and onset times for crystallization of the amorphous state were prepared using crospovidone (CrosPVP). All of the drugs in the SDs remained in an amorphous state at 25 degrees C/50% relative humidity (RH) in closed glass bottles for at least six months. Under conditions of high temperature (40 degrees C/75%RH/closed and 60 degrees C/open), differences in interactions between the hydrogen bond donors of the drugs and the amide carbonyl group of CrosPVP are essential factors for recrystallization of the drugs in the SDs. On the other hand, under condition of high humidity (40 degrees C/75%RH/open), in addition to the difference in the interaction between the drug and CrosPVP, the rate of increase in moisture content affects their recrystallization in SDs. PMID- 23682861 TI - Factorial invariance in multilevel confirmatory factor analysis. AB - This paper presents a procedure to test factorial invariance in multilevel confirmatory factor analysis. When the group membership is at level 2, multilevel factorial invariance can be tested by a simple extension of the standard procedure. However level-1 group membership raises problems which cannot be appropriately handled by the standard procedure, because the dependency between members of different level-1 groups is not appropriately taken into account. The procedure presented in this article provides a solution to this problem. This paper also shows Muthen's maximum likelihood (MUML) estimation for testing multilevel factorial invariance across level-1 groups as a viable alternative to maximum likelihood estimation. Testing multilevel factorial invariance across level-2 groups and testing multilevel factorial invariance across level-1 groups are illustrated using empirical examples. SAS macro and Mplus syntax are provided. PMID- 23682862 TI - Pharmacokinetic evaluation of teriflunomide for the treatment of multiple sclerosis. AB - INTRODUCTION: Teriflunomide is an immunomodulatory drug that received FDA approval for the treatment of relapsing forms of multiple sclerosis (MS) in September 2012. Its primary mode of action is inhibition of dihydroorotate dehydrogenase which inhibits the proliferation of activated T cells, but it also has a number of other actions that may be important contributors to its efficacy in MS. AREAS COVERED: This review covers a basic pathophysiology of MS and the current treatment options, including a discussion of the needs for additional treatments. The main focus of the review is the pharmacokinetics and pharmacodynamics of teriflunomide, including a brief comparison with the disease modifying antirheumatic drug leflunomide. The authors discuss the clinical efficacy and toxicity profile of teriflunomide and make some comparisons with treatments that are currently, or soon to be available. EXPERT OPINION: While teriflunomide is no more effective than a number of other agents that are used in the treatment of MS, it has a favorable side-effect profile and the convenience of once a day oral administration. As such, it is likely to be a popular agent in the treatment of MS over the next 5 years. PMID- 23682863 TI - Longitudinal Youth-At-Risk Study (LYRIKS): outreach strategies based on a community-engaged framework. AB - Schizophrenia and psychoses are debilitating disorders often leading to serious functional impairments. Early detection efforts have shifted focus to the prodromal phase and the emphasis is now on individuals at risk of developing psychosis. AIM: The Longitudinal Youth-At-Risk Study (LYRIKS) seeks to elucidate the biological markers of psychosis. This paper describes the application of a community-engaged framework to the outreach strategies of LYRIKS. It describes the outreach goals, strategies used and their impact, as well as the various challenges faced by the research team and community partners. METHODS: The target population was defined. Community organizations having close ties with the target population were identified and approached for collaboration. These included educational and healthcare institutions, and government and welfare organizations. Strategies were categorized as active or passive. Active strategies included clinical screening and recruitment, workshops, roadshows and student internships. Passive strategies included utilizing print and social media. RESULTS: Three thousand three hundred twenty-one youth were approached and 401 called the hotline to find out more about the study. Three thousand five hundred one were pre-screened; 864 were further screened using the Comprehensive Assessment of At Risk Mental State. One hundred seventy-eight and 346 were eventually recruited as subjects and controls, respectively. CONCLUSIONS: Challenges encountered included differing priorities, maintaining collaborative relationships, stigmatization and inadequate understanding of the profile of at risk youth. Future community-engaged research should be conducted more comprehensively to generate maximum benefits. PMID- 23682864 TI - Breast feeding and immunoprophylaxis efficacy of mother-to-child transmission of hepatitis B virus. AB - OBJECTIVE: This study was designed to explore if hepatitis B virus (HBV) may be transmitted via breast milk through mother-to-child transmission (MTCT), and assay the immunoprophylaxis efficacy after passive-active immunization. METHOD: From year 2008 to 2012, 67,720 pregnant women were screened and 1186 HBsAg carrier mothers and their infants aged 8-12 months were followed in multi-centers of China, among whom HBV markers (HBsAg, HBsAb, HBeAg, HBeAb and HBcAb) and HBV DNA were measured. RESULTS: HBsAg positive rate of pregnant women was 6.7% (4533/67,720) and infants' immunoprophylaxis failure rate was 3.3% (39/1186). Immunoprophylaxis failure infants were all born to mothers of HBeAg positive and HBV-DNA >6 log10 copies/ml. Among infants of HBeAg positive mothers, HBV infection rate was 9.0% and HBsAg positive rate was 8.3% in breast-feeding group versus 9.2% in formula-feeding group, P=0.761. Occurrence of perinatal HBV infection was indicated in uterus or during delivery. Different feeding patterns had no effects on HBsAb conversion of infants with the implementation of immunization. CONCLUSIONS: HBsAg prevalence rate of pregnant women enrolled was 6.7% and immunoprophylaxis failure rate of infants was 3.3%, while the infection rate reached 9.0% in infants of HBeAg positive mothers. Breast feeding did not increase the occurrence of HBV MTCT. PMID- 23682865 TI - Oxygen sensing by the carotid body: is it all just rotten eggs? AB - SIGNIFICANCE: Ventilatory responses to hypoxia are initiated by the carotid body, where inhibition of specific K(+) channels causes cell depolarization, voltage gated Ca(2+) influx, and neurotransmitter release. The identity of the upstream oxygen (O2) sensor is still controversial. RECENT ADVANCES: The activity of BKCa channels is regulated by O2, carbon monoxide (CO), and hydrogen sulfide (H2S), suggesting that integration of these signals may be crucial to the physiological response of this tissue. BKCa is colocalized with hemeoxygenase-2, an enzyme that generates CO in the presence of O2, and CO is a BKCa channel opener. Reduced CO during hypoxia results in channel closure, conferring a degree of O2 sensitivity to the BKCa channel. Conversely, H2S is a potent BKCa inhibitor. H2S is produced endogenously by cystathionine-beta-synthase and cystathionine-gamma-lyase in the rat carotid body, and its intracellular concentration is dependent upon the balance between its enzymatic generation and its mitochondrial breakdown. During hypoxia, mitochondrial oxidation of H2S in many tissues is reduced, leading to hypoxia-evoked rises in its concentration. This may be sufficient to inhibit K(+) channels and lead to carotid body excitation. CRITICAL ISSUES: Carotid body function is heavily dependent upon regulated production and breakdown of CO and H2S and integration of signals from these newly emerging gasotransmitters, in combination with several other proposed mechanisms, may refine, or even define, responses of this tissue to hypoxia. FUTURE DIRECTIONS: Since several other sensors have been postulated, the challenge of future research is to begin to integrate each in a unifying mechanism, as has been attempted for the first time herein. PMID- 23682866 TI - Dried apple enriched with mandarin juice counteracts tamoxifen-induced oxidative stress in rats. AB - The effect of a product made of dehydrated apples enriched with mandarin juice by vacuum impregnation on markers of oxidative stress (plasma antioxidant capacity, carbonyl groups (CGs), 8-hydroxydeoxyguanosine (8OHdG) and alpha-tocopherol) was tested in rats. Six groups of animals were studied: one group was fed a standard diet; two groups were supplemented with dehydrated apple either impregnated or not with mandarin juice throughout 28 days; and three groups (one unsupplemented and two supplemented) were additionally treated with tamoxifen (TAM) for 21 days used for induction of oxidative stress. The rats treated with TAM showed an increase in aminotransferases, CGs and 8OHdG. All of these effects were significantly decreased in the animals after apple snack consumption; the addition of mandarin juice into the apple mainly accounts for increased levels of alpha-tocopherol in plasma and liver. These findings suggest that the food product have a protective action against oxidative stress induced by TAM in rats. PMID- 23682868 TI - Kinetic resolution of N-acyl-thiolactams via catalytic enantioselective deacylation. AB - Methanolysis of N-acyl-thiazolidin-2-thiones and -oxazolidin-2-thiones in the presence of acyl transfer catalyst benzotetramisole (BTM) proceeds in a highly enantioselective fashion thus enabling kinetic resolution of these substrates. PMID- 23682867 TI - Neurocognition in 1-month-abstinent treatment-seeking alcohol-dependent individuals: interactive effects of age and chronic cigarette smoking. AB - BACKGROUND: Increasing age and chronic cigarette smoking are independently associated with adverse effects on multiple aspects of neurocognition in those seeking treatment for alcohol use disorders. However, the potential interactive effects of age and cigarette smoking on neurocognition in early abstinent alcohol dependent individuals (ALC) have not investigated. METHODS: Cross-sectional performances of never-smoking healthy comparison participants (nvsCOM; n = 39) and 1-month-abstinent, treatment-seeking, never-smoking (nvsALC; n = 30), former smoking (fsALC; n = 21), and actively smoking (asALC; n = 68) ALC were compared on a comprehensive neurocognitive battery. Domains of functioning evaluated were cognitive efficiency, executive functions, fine motor skills, general intelligence, learning and memory, processing speed, visuospatial functions and working memory. Participants were between 26 and 71 years of age at the time of assessment. RESULTS: asALC showed steeper age-related effects than nvsCOM on the domains of visuospatial learning, auditory-verbal memory, cognitive efficiency, executive functions, processing speed, and fine motor skills. In pairwise comparisons, fsALC and asALC performed more poorly than both nvsCOM and nvsALC on multiple domains; nvsCOM and nvsALC showed no significant differences. Domain scores for the ALC groups generally fell in the low-to-high-average range of functioning. A clinically significant level of impairment was apparent in only 25% of ALC participants on visuospatial learning, visuospatial memory, and fine motor skills domains. Measures of alcohol use or consumption were not significantly related to neurocognition in the ALC cohorts. CONCLUSIONS: The age related findings suggest that the combination of active chronic smoking and alcohol dependence in this 1-month-abstinent ALC cohort was associated with greater than normal age-related effects in multiple domains. In general, a low level of clinically significant impairment was observed in the alcohol-dependent participants. The findings from this study, in conjunction with previous research, strongly support smoking cessation interventions for those seeking treatment for alcohol and substance use disorders. PMID- 23682869 TI - Scope and limitations of the nicking enzyme amplification reaction for the synthesis of base-modified oligonucleotides and primers for PCR. AB - Enzymatic synthesis of short (10-22 nt) base-modified oligonucleotides (ONs) was developed by nicking enzyme amplification reaction (NEAR) using Vent(exo-) polymerase, Nt.BstNBI nicking endonuclease, and a modified deoxyribonucleoside triphosphate (dNTP) derivative. The scope and limitations of the methodology in terms of different nucleobases, length, sequences, and modifications has been thoroughly studied. The methodology including isolation of the modified ONs was scaled up to nanomolar amounts and the modified ONs were successfully used as primers in primer extension and PCR. Two simple and efficient methods for fluorescent labeling of the PCR products were developed, based either on direct fluorescent labeling of primers or on NEAR synthesis of ethynylated primers, PCR, and final click labeling with fluorescent azides. PMID- 23682870 TI - Clinical effects of stereotactic radiation surgery in patients with metastatic melanoma. AB - We examined the effectiveness of stereotactic radiation surgery (SRS) in 14 patients with brain metastasis in our hospital. The age of the patients ranged 45 85 years old (mean, 65). Brain metastasis was detected by neurological symptoms in seven patients and by regular imaging examination in the remaining patients. The number of metastatic lesions in the brain before SRS ranged 1-11 (median, 2). The treatment number of SRS was 1-4 times (median, 2). Six of 14 patients had neurological symptoms before SRS. Overall survival (OS) after SRS was 1.7-21.2 months (median, 8.2). The progression-free survival (PFS) after SRS was 0.9-10.5 months (median, 2.2). The result of univariate analysis showed that the application of two or more courses of SRS was significantly related to OS (P = 0.005). Single metastatic lesion (P = 0.051) and no extracranial lesion (P = 0.055) showed a slight tendency to be related to disease-free survival (DFS). Neither lactate dehydrogenase nor neurological symptoms were significantly related to OS or DFS. Although OS and DFS after SRS were not very long, the treatment of brain metastases has the potential to prevent neurological events. Repeating SRS may be accepted as a local therapy in the multimodal approach including new molecular targeting drugs for metastatic melanoma. PMID- 23682871 TI - What can and should we predict in mental health? PMID- 23682872 TI - Clinical staging for mental disorders: a new development in diagnostic practice in mental health. PMID- 23682873 TI - Suicide risk assessment: where are we now? PMID- 23682874 TI - Improved prognosis for borderline personality disorder. PMID- 23682877 TI - Everett Koop - from pariah to paragon. PMID- 23682878 TI - Challenges to a more open discussion of suicide. PMID- 23682879 TI - Suicide prevention: signposts for a new approach. PMID- 23682880 TI - Changes to the Healthy Kids Check: will we get it right? PMID- 23682881 TI - Reviewing the revisions: what are the Australian Bureau of Statistics suicide figures really telling us? PMID- 23682882 TI - The extent of alcohol advertising in Australia: an audit of bus stop advertisements. PMID- 23682883 TI - Changes in smoking intensity among Aboriginal and Torres Strait Islander people, 1994-2008. PMID- 23682884 TI - Changes in smoking intensity among Aboriginal and Torres Strait Islander people, 1994-2008. PMID- 23682885 TI - Better prepared next time: considering nutrition in an emergency response. PMID- 23682886 TI - Injury trends and mortality in adult patients with major trauma in New South Wales. PMID- 23682887 TI - Injury trends and mortality in adult patients with major trauma in New South Wales. PMID- 23682888 TI - Palliative care is everyone's business - is it yours, doctor? PMID- 23682889 TI - Philately and the diagnostic and statistical manual of mental disorders. PMID- 23682890 TI - Screening, referral and treatment for depression in patients with coronary heart disease. AB - In 2003, the National Heart Foundation of Australia position statement on "stress" and heart disease found that depression was an important risk factor for coronary heart disease (CHD). This 2013 statement updates the evidence on depression (mild, moderate and severe) in patients with CHD, and provides guidance for health professionals on screening and treatment for depression in patients with CHD. The prevalence of depression is high in patients with CHD and it has a significant impact on the patient's quality of life and adherence to therapy, and an independent effect on prognosis. Rates of major depressive disorder of around 15% have been reported in patients after myocardial infarction or coronary artery bypass grafting. To provide the best possible care, it is important to recognise depression in patients with CHD. Routine screening for depression in all patients with CHD is indicated at first presentation, and again at the next follow-up appointment. A follow-up screen should occur 2-3 months after a CHD event. Screening should then be considered on a yearly basis, as for any other major risk factor for CHD. A simple tool for initial screening, such as the Patient Health Questionnaire-2 (PHQ-2) or the short-form Cardiac Depression Scale (CDS), can be incorporated into usual clinical practice with minimum interference, and may increase uptake of screening. Patients with positive screening results may need further evaluation. Appropriate treatment should be commenced, and the patient monitored. If screening is followed by comprehensive care, depression outcomes are likely to be improved. Patients with CHD and depression respond to cognitive behaviour therapy, collaborative care, exercise and some drug therapies in a similar way to the general population. However, tricyclic antidepressant drugs may worsen CHD outcomes and should be avoided. Coordination of care between health care providers is essential for optimal outcomes for patients. The benefits of treating depression include improved quality of life, improved adherence to other therapies and, potentially, improved CHD outcomes. PMID- 23682891 TI - Trends in pre-existing mental health disorders among parents of infants born in Western Australia from 1990 to 2005. AB - OBJECTIVE: To determine the prevalence of prior and current mental health disorders in parents, including trends over time. DESIGN: retrospective population cohort study using de-identified linked health data. SETTING: Population of Western Australia. SUBJECTS: All parents of infants born in WA between 1990 and 2005. MAIN OUTCOME MEASURES: Prevalence of prior mental health disorders in parents by birth 2013 and by parent and child characteristics, including Aboriginality, maternal age, socioeconomic status and diagnostic groups. RESULTS: From 1990 to 2005, there was an increase in prevalence of prior mental health disorders in mothers, from 76 per 1000 births in 1990 to 131 per 1000 births in 2005 (3.7% increase per 2013 in the odds of children being born to mothers with a prior mental health disorder). There was also a 4.7% increase in odds per 2013 in the prevalence of mental health contacts that had taken place in the 12 months before the birth 2013 in mothers. In addition, there was an increase in prevalence of prior mental health disorders in fathers, from 56 per 1000 births in 1990 to 88 per 1000 births in 2005 (3.1% increase in odds per 2013). The diagnostic group with the highest prevalence in both mothers and fathers was substance-related disorders. CONCLUSIONS: From 1990 to 2005, there was an increase in prevalence of parents with a prior history of mental health disorders in WA. General practitioners and mental health workers can play an important role in identifying mental illness and in working with families to offer early intervention, referral and support. PMID- 23682892 TI - Socioeconomic area disparities in tobacco retail outlet density: a Western Australian analysis. AB - OBJECTIVE: To examine the association between tobacco outlet density and area socioeconomic status (SES) in Western Australia. DESIGN AND SETTING: Ecological cross-sectional study investigating the relationship between the area SES of, and the density of tobacco retail outlets in, WA suburbs and towns for the Perth metropolitan area, and at the regional and state level. SES was determined using the 2006 Australian Bureau of Statistics Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD) and classified into quartiles (very low, low, high and very high); tobacco outlet data were sourced from the WA Department of Health register of retailers licensed to sell tobacco at May 2011. MAIN OUTCOME MEASURE: Tobacco outlet density rate (per 10 000 residents). RESULTS: In WA overall, suburbs and towns with a very low IRSAD had more than four times the number of tobacco outlets compared with those with a very high IRSAD (P> < 0.001). This trend was similar when analyses were restricted to the Perth metropolitan area and to regional areas. Suburbs and towns in regional WA with a very low IRSAD had more than five times the number of tobacco outlets than those with a very high IRSAD (P> < 0.001). CONCLUSIONS: This study provides the first Australian evidence of a strong relationship between area SES and tobacco outlet density. Findings are consistent with a number of United States studies that report higher tobacco outlet densities in lower SES or minority neighbourhoods. The results underscore the importance of policy approaches to limit the number of tobacco retail licences granted, and to reduce the geographic density of outlets in more disadvantaged suburbs and towns. PMID- 23682893 TI - Improved iodine status in Tasmanian schoolchildren after fortification of bread: a recipe for national success. AB - OBJECTIVES: To examine population iodine status in Tasmania after mandatory iodine fortification of bread and assess the magnitude of difference compared with results from a period of voluntary iodine fortification. DESIGN AND SETTING: A cross-sectional urinary iodine survey of schoolchildren from classes that included fourth-grade students was conducted in Tasmania in 2011. Results were compared with surveys conducted before fortification and during a period of voluntary fortification. PARTICIPANTS: Three hundred and twenty students aged 8 13 2013s from 37 participating school classes. MAIN OUTCOME MEASURES: Median urinary iodine concentration (UIC) and proportion of UIC results < 50 ug/L. RESULTS: Median UIC in 2011 was 129 ug/L, and 3.4% of samples had a UIC under 50ug/L. This was significantly higher than during the period of voluntary fortification (129 ug/L v 108 ug/L) (P> < 0.001), which was significantly higher than before fortification (108 ug/L v 73 ug/L) (P < 0.001). There was a reduction in the proportion of samples with UIC under 50 ug/L after mandatory fortification (3.4%) compared with results from the period of voluntary fortification (9.6%) (P = 0.01), which was a further reduction compared with results from the prefortification period (17.7%) (P < 0.001). CONCLUSIONS: Iodine status in Tasmania can now be considered optimal. Mandatory iodine fortification has achieved significantly greater improvements in population iodine status compared with voluntary fortification. However, surveys of schoolchildren cannot be generalised to pregnant and breastfeeding women, who have higher iodine requirements. Measurement of iodine status in population surveys is warranted for ongoing monitoring and to justify the appropriate level of fortification of the food supply into the future. PMID- 23682894 TI - Direct-to-consumer genetic testing - clinical considerations. PMID- 23682895 TI - Direct-to-consumer genetic testing - where should we focus the policy debate? PMID- 23682896 TI - Direct-to-consumer genetic testing - a regulatory nightmare? PMID- 23682897 TI - The challenge of suicide prevention. PMID- 23682898 TI - Emphysematous cystitis due to Klebsiella pneumoniae. PMID- 23682902 TI - Respiratory virology and microbiology in intensive care units: a prospective cohort study. AB - Our aim was to determine the frequency of 12 common respiratory viruses in patients admitted to intensive care units with respiratory symptoms, evaluate the clinical characteristics and to compare the results to routine microbiological diagnostics. Throat swabs from 122 intensive care-patients >18 years with acute respiratory symptoms were collected upon admission and analysed with multiplex real-time polymerase chain reaction, for 12 community respiratory viruses. Blood and respiratory tract specimens were analysed for bacteria and fungi upon clinicians' request. Clinical and paraclinical data were collected. Viruses were detected in 19 (16%) of the 122 study patients. Five virus-positive patients (26%) had possible clinically relevant bacteria or fungi co-detected. Patients with exacerbation in COPD were associated with a viral infection (p = 0.02). Other comorbidities, clinical and paraclinical parameters, and death were independent of a viral infection or co-detection of bacteria/fungi. In conclusion, respiratory viruses were frequently detected in the patients. The investigated clinical and paraclinical parameters were not different in viral infections compared to other agents, thus respiratory viruses likely have similar impact on the clinical course as other agents. In 25% of the virus-positive patients, polymicrobial aetiology was identified. Comprehensive and sensitive diagnostic methods should be emphasized to enhance respiratory diagnostics. PMID- 23682903 TI - Citrus genus plants contain N-methylated tryptamine derivatives and their 5 hydroxylated forms. AB - The occurrence and distribution in Citrus genus plants of N-methylated derivatives of tryptamine and their 5-hydroxylated forms are reported. Tryptamine, N-methyltryptamine, N,N-dimethyltryptamine, N,N,N trimethyltryptamine, 5-hydroxytryptamine (serotonin), 5-hydroxy-N methyltryptamine, 5-hydroxy-N,N-dimethyltryptamine (bufotenine), and 5-hydroxy N,N,N-trimethyltryptamine (bufotenidine) were quantitated by LC-ESI-MS/MS. Leaves of all citrus plants examined contained N,N,N-trimethyltryptamine, a compound that we first discovered in the bergamot plant. Interestingly, we also found out that all plants examined contained 5-hydroxy-N,N-dimethyltryptamine and 5-hydroxy N,N,N-trimethyltryptamine, compounds never described so far in the Citrus genus. As N,N,N-trimethyltryptamine and 5-hydroxy-N,N,N-trimethyltryptamine possess nicotine-like activity by exerting their action on acetylcholine receptors, it is conceivable that both represent the arrival point of a biosynthetic pathway aimed to provide Citrus plants with chemical defense against aggressors. This hypothesis is supported by our finding that leaves and seeds, which are more frequently attacked by biotic agents, are the parts of the plant where the highest levels of those compounds were found. PMID- 23682904 TI - Thoracic radiculopathy following spinal cord stimulator placement: case series. AB - OBJECTIVE: The clinical entity of thoracic radiculopathy following spinal cord stimulator (SCS) placement has not been previously described. MATERIALS AND METHODS: A retrospective review of prospectively acquired data on 172 patients, having undergone thoracic SCS placement at our institution, was performed. In addition, four patients were implanted at outside institutions, and were referred for revision. We examine our early experience with placement of thoracic SCS in surgically treated patients with chronic pain and 15 associated specific postoperative radicular pain complications along respective thoracic dermatomes. We postulate that preexisting thoracic spinal pathology affords less compliance in the placement of larger paddles, and subsequent radicular pain in a band-like abdominal fashion. RESULTS: A syndrome of thoracic radiculopathy, presenting as intractable lower thoracic or abdominal wall pain occurring in the immediate postoperative period, was identified in 15 patients. These patients subsequently underwent revision surgery, with either a more extensive laminectomy to further decompress the dorsal nerve roots or lead removal, both of which resulted in near immediate relief of symptoms. CONCLUSIONS: Thoracic radiculopathy may occur following SCS paddle lead placement. This clinical syndrome is characterized by its immediate postoperative development, band-like thoracic or abdominal pain pattern, severe pain that both overwhelms the incisional pain and is refractory to medications, and absence of motor deficit. The lateral placement of paddle leads increases the risk of radicular symptoms. Preoperative thoracic spine magnetic resonance imaging may be helpful in identifying patients who may be susceptible to this syndrome. PMID- 23682905 TI - The diagnosis of symptomatic recurrent pulmonary embolism and deep vein thrombosis: guidance from the SSC of the ISTH. PMID- 23682906 TI - Knee joint passive stiffness and moment in sagittal and frontal planes markedly increase with compression. AB - Knee joints are subject to large compression forces in daily activities. Due to artefact moments and instability under large compression loads, biomechanical studies impose additional constraints to circumvent the compression position dependency in response. To quantify the effect of compression on passive knee moment resistance and stiffness, two validated finite element models of the tibiofemoral (TF) joint, one refined with depth-dependent fibril-reinforced cartilage and the other less refined with homogeneous isotropic cartilage, are used. The unconstrained TF joint response in sagittal and frontal planes is investigated at different flexion angles (0 degrees , 15 degrees , 30 degrees and 45 degrees ) up to 1800 N compression preloads. The compression is applied at a novel joint mechanical balance point (MBP) identified as a point at which the compression does not cause any coupled rotations in sagittal and frontal planes. The MBP of the unconstrained joint is located at the lateral plateau in small compressions and shifts medially towards the inter-compartmental area at larger compression forces. The compression force substantially increases the joint moment-bearing capacities and instantaneous angular rigidities in both frontal and sagittal planes. The varus-valgus laxities diminish with compression preloads despite concomitant substantial reductions in collateral ligament forces. While the angular rigidity would enhance the joint stability, the augmented passive moment resistance under compression preloads plays a role in supporting external moments and should as such be considered in the knee joint musculoskeletal models. PMID- 23682907 TI - Measuring the impacts of seclusion on psychiatry inpatients and the effectiveness of a pilot single-session post-seclusion counselling intervention. AB - Despite the accumulation of evidence demonstrating patients' accounts of trauma associated with seclusion, the use of evidence-based post-seclusion debriefing is not apparent in the published work. This study aimed to identify the impacts seclusion has on an individual using the Impact of Events - Revised (IES-R), a standardized and widely used measure of trauma symptoms, and measure the effectiveness of a post-seclusion counselling intervention in mitigating the experience of seclusion-related trauma and reducing time spent in seclusion. The study design involved a comparison of the seclusion-related trauma and time in seclusion that was experienced by consenting patients managed on the two inpatient wards of Alfred Psychiatry. To investigate the efficacy of post seclusion counselling to reduce event-related trauma as well as the use of seclusion, a brief single-session intervention was piloted comparing outcomes for patients treated on a ward implementing semistructured post-seclusion counselling and patients treated on a ward continuing with post-seclusion support as usual. A total of 31 patients consented to participate, with approximately 47% reporting trauma symptoms consistent with 'probable post-traumatic stress disorder' (IES-R total score, >33), although there was no difference in trauma experience between groups. Significantly fewer hours were spent in seclusion for patients treated on the ward piloting the post-seclusion counselling intervention. Findings, therefore, highlight not only the potential for significant trauma stemming from a seclusion event, but also the capacity for the implementation of such interventions as post-seclusion counselling to raise awareness of the need to minimize time spent in seclusion for patients. PMID- 23682908 TI - Odorant responsiveness of embryonic mouse olfactory sensory neurons expressing the odorant receptors S1 or MOR23. AB - The mammalian olfactory system has developed some functionality by the time of birth. There is behavioral and limited electrophysiological evidence for prenatal olfaction in various mammalian species. However, there have been no reports, in any mammalian species, of recordings from prenatal olfactory sensory neurons (OSNs) that express a given odorant receptor (OR) gene. Here we have performed patch-clamp recordings from mouse OSNs that express the OR gene S1 or MOR23, using the odorous ligands 2-phenylethyl alcohol or lyral, respectively. We found that, out of a combined total of 20 OSNs from embryos of these two strains at embryonic day (E)16.5 or later, all responded to a cognate odorous ligand. By contrast, none of six OSNs responded to the ligand at E14.5 or E15.5. The kinetics of the odorant-evoked electrophysiological responses of prenatal OSNs are similar to those of postnatal OSNs. The S1 and MOR23 glomeruli in the olfactory bulb are formed postnatally, but the axon terminals of OSNs expressing these OR genes may be synaptically active in the olfactory bulb at embryonic stages. The upper limit of the acquisition of odorant responsiveness for S1 and MOR23 OSNs at E16.5 is consistent with the developmental expression patterns of components of the olfactory signaling pathway. PMID- 23682909 TI - Men and women, so different, so similar: observations from cross-sex hormone treatment of transsexual subjects. AB - Sexual differentiation in mammals is largely driven by the presence of androgen in males and their absence in females. The presence of androgens induces a number of irreversible changes in males: prenatally, the genital differentiation; during puberty, the development of secondary sex characteristics - the larger facial bones, hand, feet and height in males. A large number of metabolic variables are influenced by sex hormones and consequently show difference between men and women, and this helps to explain differences in pathologies, such as cardiovascular disease, bone fractures and auto immune disease. There is some recent evidence that some sex differences in brain functions are not mediated by sex hormones, but by-products of genes located on the X and Y chromosomes. This communication reviews the results of administration of cross-sex hormone treatment to transsexual persons transitioning to the other sex. Natal males are treated with anti-androgens+oestrogens and natal females with testosterone. This provides a unique opportunity to study which metabolic functions are not irreversibly sex-differentiated but are determined by the prevailing milieu of sex steroids. The insights gained with these studies should lead to a better appreciation of the role of sex steroids in cardiovascular disease and diabetes mellitus which presently do not receive due attention. PMID- 23682911 TI - Paradigms: examples from the bacterium Xylella fastidiosa. AB - The history of advances in research on Xylella fastidiosa provides excellent examples of how paradigms both advance and limit our scientific understanding of plant pathogens and the plant diseases they cause. I describe this from a personal perspective, having been directly involved with many persons who made paradigm-changing discoveries, beginning with the discovery that a bacterium, not a virus, causes Pierce's disease of grape and other plant diseases in numerous plant species, including important crop and forest species. PMID- 23682912 TI - Virus-based transient expression vectors for woody crops: a new frontier for vector design and use. AB - Virus-based expression vectors are commonplace tools for the production of proteins or the induction of RNA silencing in herbaceous plants. This review considers a completely different set of uses for viral vectors in perennial fruit and nut crops, which can be productive for periods of up to 100 years. Viral vectors could be used in the field to modify existing plants. Furthermore, with continually emerging pathogens and pests, viral vectors could express genes to protect the plants or even to treat plants after they become infected. As technologies develop during the life span of these crops, viral vectors can be used for adding new genes as an alternative to pushing up the crop and replanting with transgenic plants. Another value of virus-based vectors is that they add nothing permanently to the environment. This requires that effective and stable viral vectors be developed for specific crops from endemic viruses. Studies using viruses from perennial hosts suggest that these objectives could be accomplished. PMID- 23682910 TI - Meningococcal carriage in the African meningitis belt. AB - A meningococcal serogroup A polysaccharide/tetanus toxoid conjugate vaccine (PsA TT) (MenAfriVac(TM) ) is being deployed in countries of the African meningitis belt. Experience with other polysaccharide/protein conjugate vaccines has shown that an important part of their success has been their ability to prevent the acquisition of pharyngeal carriage and hence to stop transmission and induce herd immunity. If PsA-TT is to achieve the goal of preventing epidemics, it must be able to prevent the acquisition of pharyngeal carriage as well as invasive meningococcal disease and whether PsA-TT can prevent pharyngeal carriage needs to be determined. To address this issue, a consortium (the African Meningococcal Carriage (MenAfriCar) consortium) was established in 2009 to investigate the pattern of meningococcal carriage in countries of the African meningitis belt prior to and after the introduction of PsA-TT. This article describes how the consortium was established, its objectives and the standardised field and laboratory methods that were used to achieve these objectives. The experience of the MenAfriCar consortium will help in planning future studies on the epidemiology of meningococcal carriage in countries of the African meningitis belt and elsewhere. PMID- 23682913 TI - Impacts of resistance gene genetics, function, and evolution on a durable future. AB - Studies on resistance gene function and evolution lie at the confluence of structural and molecular biology, genetics, and plant breeding. However, knowledge from these disparate fields has yet to be extensively integrated. This review draws on ideas and information from these different fields to elucidate the influences driving the evolution of different types of resistance genes in plants and the concurrent evolution of virulence in pathogens. It provides an overview of the factors shaping the evolution of recognition, signaling, and response genes in the context of emerging functional information along with a consideration of the new opportunities for durable resistance enabled by high throughput DNA sequencing technologies. PMID- 23682914 TI - The use and role of predictive systems in disease management. AB - Disease predictive systems are intended to be management aids. With a few exceptions, these systems typically do not have direct sustained use by growers. Rather, their impact is mostly pedagogic and indirect, improving recommendations from farm advisers and shaping management concepts. The degree to which a system is consulted depends on the amount of perceived new, actionable information that is consistent with the objectives of the user. Often this involves avoiding risks associated with costly disease outbreaks. Adoption is sensitive to the correspondence between the information a system delivers and the information needed to manage a particular pathosystem at an acceptable financial risk; details of the approach used to predict disease risk are less important. The continuing challenge for researchers is to construct tools relevant to farmers and their advisers that improve upon their current management skill. This goal requires an appreciation of growers' decision calculus in managing disease problems and, more broadly, their overall farm enterprise management. PMID- 23682915 TI - Diversity and evolution of root-knot nematodes, genus Meloidogyne: new insights from the genomic era. AB - Root-knot nematodes (RKNs) (Meloidogyne spp.) are obligate endoparasites of major worldwide economic importance. They exhibit a wide continuum of variation in their reproductive strategies, ranging from amphimixis to obligatory mitotic parthenogenesis. Molecular phylogenetic studies have highlighted divergence between mitotic and meiotic parthenogenetic RKN species and probable interspecific hybridization as critical steps in their speciation and diversification process. The recent completion of the genomes of two RKNs, Meloidogyne hapla and Meloidogyne incognita, that exhibit striking differences in their mode of reproduction (with and without sex, respectively), their geographic distribution, and their host range has opened the way for deciphering the evolutionary significance of (a)sexual reproduction in these parasites. Accumulating evidence suggests that whole-genome duplication (in M. incognita) and horizontal gene transfers (HGTs) represent major forces that have shaped the genome of current RKN species and may account for the extreme adaptive capacities and parasitic success of these nematodes. PMID- 23682916 TI - Antimicrobial defenses and resistance in forest trees: challenges and perspectives in a genomic era. AB - Molecular pathology of forest trees for a long time lagged behind parallel studies on agricultural crop pathology. Recent technological advances have significantly contributed to the observed progress in this field. The first powerful impulse was provided by the completion of the black cottonwood genome sequence in 2006. Genomes of several other important tree species will be completed within a short time. Simultaneously, application of transcriptomics and next-generation sequencing (NGS) has resulted in the rapid accumulation of a vast amount of data on molecular interactions between trees and their microbial parasites. This review provides an overview of our current knowledge about these responses of forest trees to their pathogens, highlighting the achievements of the past decade, discussing the current state of the field, and emphasizing the prospects and challenges for the near future. PMID- 23682917 TI - Quiescent and necrotrophic lifestyle choice during postharvest disease development. AB - Insidious fungal infections by postharvest pathogens remain quiescent during fruit growth until, at a particular phase during fruit ripening and senescence, the pathogens switch to the necrotrophic lifestyle and cause decay. During ripening, fruits undergo physiological processes, such as activation of ethylene biosynthesis, cuticular changes, and cell-wall loosening-changes that are accompanied by a decline of antifungal compounds, both those that are preformed and those that are inducible secondary metabolites. Pathogen infection of the unripe host fruit initiates defensive signal-transduction cascades, culminating in accumulation of antifungal proteins that limit fungal growth and development. In contrast, development of the same pathogens during fruit ripening and storage activates a substantially different signaling network, one that facilitates aggressive fungal colonization. This review focuses on responses induced by the quiescent pathogens of postharvest diseases in unripe host fruits. New genome scale experimental approaches have begun to delineate the complex and multiple networks of host and pathogen responses activated to maintain or to facilitate the transition from the quiescent to the necrotrophic lifestyle. PMID- 23682918 TI - Prevalence of depression, anxiety, stress, and anger in Turkish prisoners. AB - In Turkey, prison studies are rare and the mental health status of prisoners has not received proper attention. The purpose of this cross-sectional and descriptive study was to assess the prevalence of depression, anxiety, stress, and anger among a group of Turkish prisoners. Two self-reporting instruments (the Depression Anxiety Stress Scale-42 and Multidimensional Anger Scale) were filled out by 685 prisoners. Prisoners in the study group were found to be depressive, anxious, and stressed. Anger symptoms and aggressive behaviors were found to be at a moderate level. Prisoners with a history of being subjected to domestic violence in childhood had higher depression, anxiety, and stress scores than those without such a history. Young prisoners, those who had been previously imprisoned, with substance dependency and higher stress and anxiety levels reported more anger symptoms than others. Psychological support, together with stress and anger management programs, seems to be essential. PMID- 23682919 TI - Conjugated amplifying polymers for optical sensing applications. AB - Thanks to their unique optical and electrochemical properties, conjugated polymers have attracted considerable attention over the last two decades and resulted in numerous technological innovations. In particular, their implementation in sensing schemes and devices was widely investigated and produced a multitude of sensory systems and transduction mechanisms. Conjugated polymers possess numerous attractive features that make them particularly suitable for a broad variety of sensing tasks. They display sensory signal amplification (compared to their small-molecule counterparts) and their structures can easily be tailored to adjust solubility, absorption/emission wavelengths, energy offsets for excited state electron transfer, and/or for use in solution or in the solid state. This versatility has made conjugated polymers a fluorescence sensory platform of choice in the recent years. In this review, we highlight a variety of conjugated polymer-based sensory mechanisms together with selected examples from the recent literature. PMID- 23682920 TI - The negative impact of single prolonged stress (SPS) on bone development in mice. AB - Posttraumatic stress disorder (PTSD) disrupts hypothalamic-pituitary-adrenal (HPA) axis function. Given the established role of HPA axis hormones in regulating bone metabolism, we tested the hypothesis that traumatic stress has a negative impact on bone development. We employed a variant single prolonged stress (SPS) model in which several stressors were applied to three week old C57BL/6J mice. Compared to the controls, the stressed mice showed increased freezing behavior reminiscent of PTSD symptoms. At two weeks, bone mineral content (BMC), bone area (B area) and bone mineral density (BMD) in total body based on dual-energy X-ray absorptiometry (DXA) analysis were reduced by 10.2%, 7.0% and 3.6%, respectively. Micro-CT analysis of the metaphyseal region of the excised tibia revealed that SPS caused a deterioration of trabecular architecture with trabecular number (Tb.N), BV/TV, connectivity density (Conn-Den) decreasing 12.0%, 18.9%, 23.3% and trabecular spacing (Tb.Sp), structure model index (SMI) increasing 13.9%, 21.8%, respectively. Mechanical loading increased the cross sectional area in the mid-shaft region of the loaded right versus unloaded left tibia by 7.6% in the controls, and 10.0% in the stressed mice. Therefore, SPS applied to pre-pubertal young mice produced strong negative impact on both bone mass acquisition and trabecular architecture. Mechanical loading can be employed to increase bone size, a parameter related to bone strength, in normal as well as stressed conditions. PMID- 23682921 TI - Sum frequency generation vibrational spectroscopy of cholesterol in hybrid bilayer membranes. AB - The assignment of the vibrational spectrum of cholesterol is surprisingly incomplete for such a fundamental molecule. To improve our understanding, a new investigation of the spectra of cholesterol in the C-H stretching region has been undertaken using the surface specific technique of Sum Frequency Generation (SFG) vibrational spectroscopy and the complementary technique of Reflection Absorption Infrared Spectroscopy (RAIRS). They were used to record the spectra of monolayers of cholesterol in hybrid bilayer membranes (HBMs). In addition to cholesterol, spectra were recorded of HBMs comprising monolayers of the partially deuterated cholesterol isotopologues d6-cholesterol and d7-cholesterol, and the cholesterol analogues cholestanol and androstanol to aid assignment of the spectra. Monolayers of each of the five molecules were used to form the distal leaflet of HBMs with the proximal leaflet consisting of a monolayer of deuterated mercaptoundecanoic acid (d-MUA) self-assembled on a gold substrate. Although cholesterol has five methyl groups and eleven methylene groups, by using molecules in which certain groups were either deuterated or entirely absent, it was possible to assign vibrational bands to specific sets of methyl or methylene groups either in the alkyl chain or sterol ring system of the molecule. Analysis of the spectra showed that the alkyl chains of cholesterol are orientated away from the substrate, which is opposite to their orientation in HBMs when the proximal leaflet is a hydrophobic self-assembled monolayer of octadecane thiol (ODT) adsorbed on gold. Additionally it was shown that in the d-MUA HBM, the alpha-face of the cholesterol ring is inclined toward the layer of air above the film, and the beta-face is inclined toward the gold substrate. PMID- 23682922 TI - Commentary on Lofstedt Working Group paper. PMID- 23682923 TI - Drug absorption, distribution, metabolism and excretion considerations in critically ill adults. AB - INTRODUCTION: All critically ill patients require medication to treat organ dysfunction. However, the pharmacokinetics of drugs used to treat these patients is complex due to frequent alterations in drug absorption, distribution, metabolism, and excretion (ADME). AREAS COVERED: This review examines pharmacokinetic aspects of drug administration for adult intensive care unit (ICU) patients. Specifically, the authors examine the ADME changes that occur and which should be considered by clinicians when delivering drug therapy to critically ill patients. EXPERT OPINION: Dosage pharmacokinetics determined from single-dose or limited-duration administration studies in healthy volunteers may not apply to critically ill patients. Organ dysfunction among these patients may be due to pre-existing disease or the effects of a systemic or locoregional inflammatory response precipitated by their illness. Alterations in pharmacokinetics observed among the critically ill include altered bioavailability after enteral administration, increased volume of distribution and blood-brain barrier permeability and changes in P-glycoprotein and cytochrome P450 enzyme function. However, the effect of these changes on clinically important outcomes remains uncertain and poorly studied. Future investigations should examine not only pharmacokinetic changes among the critically ill, but also whether recognition of these changes and alterations in drug therapy directed as a consequence of their observation alters patient outcomes. PMID- 23682924 TI - Analysis for prevalence and physical linkages amongst integrons, ISEcp1, ISCR1, Tn21 and Tn7 encountered in Escherichia coli strains from hospitalized and non hospitalized patients in Kenya during a 19-year period (1992-2011). AB - BACKGROUND: We determined the prevalence and evidence for physical linkage amongst integrons, insertion sequences, Tn21 and Tn7 transposons in a collection of 1327 E. coli obtained over a 19-year period from patients in Kenya. RESULTS: The prevalence of class 1 integrons was 35%, class 2 integrons were detected in 3 isolates but no isolate contained a class 3 integron. Integron lacking the 3'-CS or those linked to sul3 gene or IS26 or those containing the ISCR1 were only detected in multidrug resistant (MDR) strains. The dfrAs were the most common cassettes and their prevalence was: - dfrA1(28%), dfrA12(20%), dfA17(9%), dfrA7(9%), and dfrA16(5%). The aadA were the second most abundant cassettes and their prevalence was: - aadA1(25%), aadA2(21%), and aadA5(14%). Other cassettes occurred in lower prevalence of below 5%. Prevalence of Tn21, ISEcp1, ISCR1 and IS26 was 22%, 10%, 15%, and 7% respectively. Majority of Tn21 containing integrons carried a complete set of transposition genes while class 2 integrons were borne on Tn7 transposon. The qnrA genes were detected in 34(3%) isolates while 19(1%) carried qnrB. All qnr genes were in MDR strains carrying integrons containing the ISCR1. Close to 88% of bla(TEM-52) were linked to IS26 while >= 80% of bla(CTX-Ms) and bla(CMYs) were linked to ISEcp1. Only a few studies have identified a bla(CTX-M-9) containing an ISEcp1 element as reported in this study. Multiple genetic elements, especially those borne on incIl, incFII, and incL/M plasmids, and their associated resistance genes were transferrable en bloc to E. coli strain J53 in mating experiments. CONCLUSIONS: This is the first detailed study on the prevalence of selected elements implicated in evolution of resistance determinants in a large collection of clinical E. coli in Africa. Proliferation of such strains carrying multiple resistance elements is likely to compromise the use of affordable and available treatment options for majority of poor patients in Africa. There is therefore a need to monitor the spread of these highly resistant strains in developing countries through proper infection control and appropriate use of antimicrobials. PMID- 23682926 TI - Interactions between reactive oxygen species generated by contractile activity and aging in skeletal muscle? AB - SIGNIFICANCE: Aging leads to a loss of skeletal muscle mass and function that causes instability, increased risk of falls, and need for residential care. This is due to a reduction in the muscle mass and strength that is primarily due caused by a decrease in the number of muscle fibers, particularly, type II fibers, and atrophy and weakening of those remaining. RECENT ADVANCES: Although increased oxidative damage was originally thought to be the key to the aging process, data now indicate that reactive oxygen species (ROS) may be one of the several components of the degenerative processes in aging. The skeletal muscle shows important rapid adaptations to the ROS generated by contractions that are attenuated in aged organisms and transgenic studies have indicated that overcoming these attenuated responses can prevent the age-related loss of muscle mass and function. CRITICAL ISSUES: Elucidation of the mechanisms by which the skeletal muscle adapts to the ROS generated to contractions and the way in which these processes are attenuated by aging is critical to the development of logical approaches to prevent age-related loss of muscle mass and function. FUTURE DIRECTIONS: Future studies are likely to focus on the redox regulation of adaptive pathways and their maintenance during aging as an approach to maintain and improve muscle function. PMID- 23682927 TI - A new method for evaluating compliance with industry self-regulation codes governing the content of alcohol advertising. AB - BACKGROUND: This study evaluated the use of a modified Delphi technique in combination with a previously developed alcohol advertising rating procedure to detect content violations in the U.S. Beer Institute Code. A related aim was to estimate the minimum number of raters needed to obtain reliable evaluations of code violations in television commercials. METHODS: Six alcohol ads selected for their likelihood of having code violations were rated by community and expert participants (N = 286). Quantitative rating scales were used to measure the content of alcohol advertisements based on alcohol industry self-regulatory guidelines. The community group participants represented vulnerability characteristics that industry codes were designed to protect (e.g., age <21); experts represented various health-related professions, including public health, human development, alcohol research, and mental health. Alcohol ads were rated on 2 occasions separated by 1 month. After completing Time 1 ratings, participants were randomized to receive feedback from 1 group or the other. RESULTS: Findings indicate that (i) ratings at Time 2 had generally reduced variance, suggesting greater consensus after feedback, (ii) feedback from the expert group was more influential than that of the community group in developing group consensus, (iii) the expert group found significantly fewer violations than the community group, (iv) experts representing different professional backgrounds did not differ among themselves in the number of violations identified, and (v) a rating panel composed of at least 15 raters is sufficient to obtain reliable estimates of code violations. CONCLUSIONS: The Delphi technique facilitates consensus development around code violations in alcohol ad content and may enhance the ability of regulatory agencies to monitor the content of alcoholic beverage advertising when combined with psychometric-based rating procedures. PMID- 23682928 TI - Tuning effect of silyl protecting groups on the glycosylation reactivity of arabinofuranosyl thioglycosides. AB - The tuning effect of silyl protecting groups on the glycosylation reactivity of arabinofuranosyl phenyl thioglycoside donors is presented. Silyl ethers on the 3 , 5-, and 3,5-positions of the arabinofuranose ring are found to have an arming effect on the donor reactivity, whereas the cyclic 3,5-acetal type protecting groups reduce the reactivity. PMID- 23682929 TI - Bilateral pallidal stimulation for "sticking-out tongue" feature in patients with primary focal tongue protrusion dystonia. AB - INTRODUCTION: Tongue protrusion dystonia can cause difficulty with speech, mastication, breathing, and swallowing. Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is a widespread therapeutic alternative for treating medically refractory dystonia. To our knowledge, detailed reports regarding DBS for tongue protrusion dystonia are rare. In this report, we describe two patients with "sticking out" tongue protrusion who had undergone bilateral GPi DBS. METHODS: Operations were performed with surface electromyographic (EMG) monitoring, microelectrode recording, and macrostimulation to identify the point at which tongue kinetic cells respond most effectively. The most effective location for active contacts was identified according to burst EMG response in the posteroventral GPi. RESULTS: Two years after DBS, total Burke, Fahn, and Marsden Dystonia Rating Scale scores of two patients were improved from 12.5 to 1 (92.0%) and from 13 to 1 (92.3%), respectively. One 58-year-old woman who lost 7 kg weight from not eating well improved enough to eat solid food and became free from choking. Another 54-year old woman who had dysarthria and mumbled could speak more fluently and would not have complained difficulty in reading any more. CONCLUSION: Stimulation on posteroventral GPi for patients with idiopathic "sticking-out" tongue movement changes EMG pattern in orofacial muscles. This fact supports a reason for modulation of unknown circuit connecting tongue-specific area in motor cortex, and basal ganglia. PMID- 23682925 TI - Inhibiting the DNA damage response as a therapeutic manoeuvre in cancer. AB - The DNA damage response (DDR), consisting of an orchestrated network of proteins effecting repair and signalling to cell cycle arrest, to allow time to repair, is essential for cell viability and to prevent DNA damage being passed on to daughter cells. The DDR is dysregulated in cancer with some pathways up-regulated and others down-regulated or lost. Up-regulated pathways can confer resistance to anti-cancer DNA damaging agents. Therefore, inhibitors of key components of these pathways have the potential to prevent this therapeutic resistance. Conversely, defects in a particular DDR pathway may lead to dependence on a complementary pathway. Inhibition of this complementary pathway may result in tumour-specific cell killing. Thus, inhibitors of the DDR have the potential to increase the efficacy of DNA damaging chemotherapy and radiotherapy and have single-agent activity against tumours with a specific DDR defect. This review describes the compounds that have been designed to inhibit specific DDR targets and summarizes the pre-clinical and clinical evaluation of these inhibitors of DNA damage signalling and repair. LINKED ARTICLES: This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8. PMID- 23682930 TI - Influence of mastication and edentulism on mandibular bone density. AB - The aim of this study was to demonstrate that external loading due to daily activities, including mastication, speech and involuntary open-close cycles of the jaw contributes to the internal architecture of the mandible. A bone remodelling algorithm that regulates the bone density as a function of stress and loading cycles is incorporated into finite element analysis. A three-dimensional computational model is constructed on the basis of computerised tomography (CT) images of a human mandible. Masticatory muscle activation involved during clenching is modelled by static analysis using linear optimisation. Other loading conditions are approximated by imposing mandibular flexure. The simulations predict that mandibular bone density distribution results in a tubular structure similar to what is observed in the CT images. Such bone architecture is known to provide the bone optimum strength to resist bending and torsion during mastication while reducing the bone mass. The remodelling algorithm is used to simulate the influence of edentulism on mandibular bone loss. It is shown that depending on the location and number of missing teeth, up to one-third of the mandibular bone mass can be lost due to lack of adequate mechanical stimulation. PMID- 23682931 TI - Decrease in antigen-specific CD63 basophil expression is associated with the development of tolerance to egg by SOTI in children. AB - BACKGROUND: In the last decade, there have been an increasing number of studies on achieving tolerance to foods by specific oral tolerance induction (SOTI). Still, the underlying mechanism of SOTI is unknown. Our aim was to describe changes in CD63 expression on basophils following in vitro Ag-specific stimulation by basophil activation test (BAT), after SOTI with egg in a pediatric population. METHODS: Ten children with persistent allergy to egg were included. Skin prick tests (SPTs) and open food challenges (OFCs) were performed before SOTI. Specific IgE determination and BAT with egg white (EW), ovomucoid (OM), and ovalbumin (OVA) were performed before and after 1 month of the buildup phase of SOTI. RESULTS: Total tolerance to egg was achieved in 9 cases and partial in one. After SOTI, there was a significant decrease in mean specific IgE levels (p < 0.05). CD63 expression also decreased (p < 0.05) in all patients. CONCLUSION: Decrease in Ag-specific basophil responsiveness is associated with the development of clinical tolerance by SOTI. PMID- 23682932 TI - Third and fourth degree perineal tears--the risk of recurrence in subsequent pregnancy. AB - OBJECTIVE: To assess the risk of recurrence of third- and fourth-degree perineal tears (34DPT) and to determine whether previous 34DPT is an independent risk factor for 34DPT in subsequent deliveries. METHOD: The study group included all women who had a vaginal delivery complicated by 34DPT (2000-2012, N = 356) and subsequently delivered again in the same medical center (N = 204). The rate of recurrence of 34DPT was compared with a control group of women who had a previous vaginal delivery not complicated by 34DPT (N = 58 581) and had a subsequent delivery in the same time period (N = 23 045). RESULTS: Women in the past-34DPT group had a higher rate of CS (18.6% versus 10.1%, p < 0.001), fetal head in occiput-posterior position (POP; 2.5% versus 0.7%, p = 0.004) and mediolateral episiotomy (25.5% versus 19.4%, p = 0.03). Women in the past-34DPT group had a higher rate of 34DPT in the subsequent delivery (2.0% versus 0.3%, p < 0.001). The rate of recurrence of 34DPT was considerably higher among women with past fourth-degree tear versus women with past third-degree tear (22.2% versus 1.0%, p < 0.001). 34DPT in previous pregnancy is independently associated with increased risk of 34DPT in subsequent delivery (OR = 4.6, 95%-CI 1.3-15.3). CONCLUSION: Women who experienced 34DPT in their previous pregnancy have an increased risk for recurrence of 34DPT in subsequent pregnancy, especially in cases of past fourth-degree tears. PMID- 23682933 TI - Effects of pomegranate seed oil on glucose and lipid metabolism-related organs in rats fed an obesogenic diet. AB - Studies conducted in mice have revealed positive effects of punicic acid (PUA). The aim of this study was to analyze the effects of PUA on fat accumulation and glycemic control in rats fed an obesogenic diet. Rats were randomly divided into two groups: control group and PUA group (diet supplemented with 0.5% PUA). No changes were observed in adipose tissue weights. The glucose tolerance test showed that the glycemic value in the PUA group had decreased significantly at the final time (120 min) (-19.3%), as had fructosamine levels (-11.1%). However, homeostasis model assessment (HOMA-IR) showed that insulin resistance did not improve. No changes were observed in the liver, skeletal muscle composition, or peroxisome proliferator-activated receptors (PPARs) activation. Low levels (mg/g tissue) of PUA (0.04 +/- 0.01 in both tissues) and higher levels of cis-9,trans 11 conjugated linoleic acid (0.31 +/- 0.08 in liver, 0.52 +/- 0.11 in muscle) were found. PUA supplementation induced hypoplasia (-16.1%) due to the antiproliferative effect on hepatocytes. In conclusion, dietary supplementation of 0.5% PUA did not lead to decreased fat accumulation in adipose tissue, liver, or skeletal muscle, or to improved glycemic control. The hypoplasia induced in liver is a negative effect that should be considered before proposing PUA as a functional ingredient. PMID- 23682934 TI - Functionalized layered double hydroxide nanoparticles conjugated with disulfide linked polycation brushes for advanced gene delivery. AB - Layered double hydroxides (LDHs) have aroused great attention as potential nanosized drug delivery carriers, but independent inorganic LDH wrapped with DNA shows very low transfection efficiency. To manipulate and control the surface properties of LDH nanoparticles is of crucial importance in the designing of LDH based drug carriers. In this work, surface-initiated atom transfer radical polymerization (ATRP) of 2-(dimethylamino)ethyl methacrylate (DMAEMA) is employed to tailor the functionality of LDH surfaces in a well-controlled manner and produce a series of well-defined novel gene delivery vectors (termed as LDH-PDs), where a flexible three-step method was first developed to introduce the ATRP initiation sites containing disulfide bonds onto LDH surfaces. In comparison the pristine LDH particles, the resultant LDH-PDs exhibited better ability to condense plasmid DNA (pDNA) and much higher levels to delivery genes in different cell lines including COS7 and HepG2 cell lines. Moreover, the LDH-PDs also could largely enhance cellular uptake. This present study demonstrates that functionalization of bioinorganic LDH with flexible polycation brushes is an effective means to produce new LDH-based gene delivery systems. PMID- 23682935 TI - Treatment delay and pathways to care in early psychosis. AB - OBJECTIVE: To examine the treatment delay associated with community and inpatient pathways into care for persons experiencing a first episode of psychosis. METHODS: A total of 104 clients entering a specialized early psychosis intervention (EPI) program and their family members were assessed for help seeking behaviours, psychiatric symptoms, level of functioning and duration of untreated psychosis (DUP). RESULTS: DUP (median = 30.5 weeks) was associated with younger age of onset, poorer engagement with the EPI program and more severe symptoms. Almost one-third of clients had four or more contacts before receiving antipsychotic medication or entering the EPI program and one in five received interventions not specifically indicated for psychosis. Referrals directly involving family members accounted for about 81% of hospital-initiated treatment (39% of all referrals) and 46% of community-initiated treatment (61% of all referrals). Community entry was associated with longer DUP, more time-seeking treatment, younger age of onset, younger age at referral, greater likelihood of receiving other medication or counselling before receiving antipsychotic medication, schizophrenia, less severe symptoms and less substance use in the previous year. Those with schizophrenia showed no differences across pathway type for time-seeking treatment, being provided interventions not specifically indicated for psychosis after onset or rates of substance use. CONCLUSIONS: Treatment delay and the provision of interventions not specifically indicated for psychosis may be increased in first-episode populations who are younger and have less severe symptoms. Improving literacy about early psychosis in both professionals and families merits greater attention. PMID- 23682936 TI - [Endoscopic management of cerebrospinal fluid fistulas and clinic outcomes]. AB - OBJECTIVES: This study aims to evaluate the efficacy of endoscopic repair of cerebrospinal fluid (CSF) fistulas. PATIENTS AND METHODS: Between January 2005 and December 2012, 10 patients (7 females, 3 males; mean age 36.1 years; range 1 to 52 years) who were diagnosed with CSF fistulas in Kocaeli University, Faculty of Medicine, Ear Nose and Throat Clinic were retrospectively analyzed. Complaints of the patients on admission and the characteristics of CSF fistulas (etiology, location, and stage) were recorded. Treatment modalities based on the characteristics of CSF fistulas and treatment outcomes were analyzed. RESULTS: The etiology of the fistula was encephalocele in six, iatrogenic trauma following functional endoscopic sinus surgery (FESS) in three, and spontaneous CSF rhinorrhea in one patient. The mean follow-up was 32.4 months (range, 12 to 84 months) postoperatively. None of the patients had recurrent disease. CONCLUSION: The endoscopic surgery is an effective modality with low morbidity and high success rate in the management of CSF fistulas. PMID- 23682937 TI - [An efficacy comparison of betahistin, trimetazidine and ginkgo biloba extract in patients with tinnitus]. AB - OBJECTIVES: This study aims to investigate the efficacy of trimetazidine, betahistine and ginkgo biloba extract in the treatment of tinnitus. PATIENTS AND METHODS: Complete clinical data of 90 patients (48 males, 42 females; mean age 52.3+/-15.1 years; range 20 to 61 years) who received betahistine, trimetazidine and ginkgo biloba extract for three months were retrospectively analyzed. The patients were divided into three groups including 30 in each group according to treatments received. Pre-treatment and post-treatment scores of tinnitus disability questionnaire were compared statistically. RESULTS: There was no statistically significant difference between pre-treatment scores of tinnitus disability questionnaire among all three groups (p>0.05), while there was a statistically significant difference among the groups following treatment (p=0.019, p<0.05). After a-three-month treatment, a decrease of 19.7+/-15.5 units in trimetazidine group, 12.2+/-12.7 units in betahistine group, and 3.80+/-5.9 units in ginkgo biloba extract group were found to be statistically significant, compared to the mean pretreatment tinnitus disability questionnaire scores (p=0.002, p<0.01). CONCLUSION: Our study results suggest that trimetazidine, betahistin and ginkgo biloba extract reduce tinnitus symptoms. However, symptomatic relief can be mostly achieved with trimetazidine treatment. PMID- 23682938 TI - [The evaluation of serum vitamin B12, folic acid and hemoglobin levels in patients with recurrent minor aphthous stomatitis]. AB - OBJECTIVES: This study aims to evaluate the serum levels of hemoglobin, vitamin B12 and folic acid in patients with recurrent minor aphthous stomatitis. PATIENTS AND METHODS: Between June 2010 and January 2012, a total of 112 patients including 57 with recurrent aphthous stomatitis (study group; 30 males 27 females; mean age 36.7+/-13.9 years; range 13 to 74 years) and 45 with chronic tinnitus patients without recurrent aphthous stomatitis (control group; 18 males 27 females; mean age 39.7+/-15.1 years; range 20 to 80 years) who were admitted to our clinic were included in this study. The serum hemoglobin, vitamin B12 and folic acid levels of the patients were measured and statistically compared. RESULTS: There was no significant difference in serum levels of hemoglobin and folic acid between the groups. Serum levels of vitamin B12 were significantly lower in the study group, compared to the control group (p<0.05). Serum levels of hemoglobin and folic acid were significantly lower in women compared to men in both groups (p<0.05). CONCLUSION: Vitamin B12 deficiency, but not lower levels of folic acid and hemoglobin, may play a role in the underlying etiology of aphthous stomatitis. Vitamin B12 supplements may be added to the treatment of recurrent aphthous stomatitis. PMID- 23682939 TI - [The relationship between operation type, adjuvant radiation therapy, spinal accessory nerve and quality of life in patients with laryngeal cancer]. AB - OBJECTIVES: In this study, we aimed to investigate the effect of operation type, adjuvant radiation therapy (RT), and preserved spinal accessory nerve on the quality of life in patients with laryngeal cancer. PATIENTS AND METHODS: A total of 191 consecutive patients (185 males, 6 females; mean age 59+/-10 years; range 42 to 79 years) who were operated due to laryngeal cancer were included. The quality of life scores were estimated using the Washington University Quality of Life Questionnaire, version IV. The patients were divided into six groups according to the operation type, the need for postoperative RT and preserved or operated spinal accessory nerve during the neck dissection. Group 1 consisted of patients with total or near total laryngectomy; group 2 consisted of those with partial laryngeal surgery; group 3 consisted of those with postoperative RT; group 4 consisted of those without postoperative RT; group 5 consisted of those with preserved 11th cranial nerve during the neck dissection, and group 6 consisted of those with non-preserved 11th cranial nerve during the neck dissection. The questionnaire scores were compared among the groups. RESULTS: The compact quality of life scores were 77.4+/-11.3 in group 1, 86.2+/-7.2 in group 2, 79.1+/-9.5 in group 3, 83.4+/-10.6 in group 4, 87.3+/-9.4 in group 5, and 79.4+/-10.8 in group 6. There was a statistically significant difference in the compact quality of life scores among the surgery groups, neck dissection groups and RT groups (p=0.018, p<0.001, p<0.001, respectively). There was no effect of preserved 11th cranial nerve on daily activity, swallowing, chewing, appearance, recreation, salivation, taste, speech, mood, and anxiety parameters. This nerve was not preserved in 71.9% of the patients who were urged to change their job due to shoulder problems. The difference was statistically significant (p<0.001). CONCLUSION: According to our study results, we concluded that partial laryngectomy improved the quality of life, rather than total or near-total laryngectomy, while postoperative RT had an adverse effect on the quality of life and preserved spinal accessory nerve during the neck dissection had a positive impact on the quality of life in patients with laryngeal cancer. PMID- 23682940 TI - Fine needle aspiration cytology of head and neck masses: a cytohistopathological correlation study with emphasis on false positives and false negatives. AB - OBJECTIVES: This study aims to evaluate the accuracy ratio of fine needle aspiration (FNA) cytology in the diagnosis of non-thyroidal head and neck masses. PATIENTS AND METHODS: Between 2000 January and 2003 December, the pathology reports of 571 patients (297 males, 274 females; mean age 45 years; range 4 to 83 years) with non-thyroidal head and neck masses who underwent FNA cytology during a four year period were retrospectively analyzed. Cytopathological and histopathological results of the samples were recorded. The smear results indicating an inconsistency were reviewed. The possible causes of the false positivity and false negativity were investigated. RESULTS: Of a total of 571 patients, 181 had a confirmed histopathological diagnosis. The overall accuracy ratio, specificity, sensitivity, negative predictive value and positive predictive value of FNA in the diagnosis of the head and neck masses were 83%, 85%, 81%, 84%, 83%, respectively. CONCLUSION: The FNA has a high accuracy, sensitivity, specificity, negative and positive predictive values in the diagnosis of head and neck masses. If the major causes of misdiagnosis including inadequate sampling and misinterpretation are avoided, the diagnostic accuracy ratio of FNA in the head and neck and will be improved. PMID- 23682941 TI - Understanding the features of posterior auricular muscle response in a facial nerve disease prototype. AB - OBJECTIVES: This study aims to compare and investigate the changes of posterior auricular muscle response (PAMR) following peripheral facial nerve palsy (PFP) with blink reflex (BR). PATIENTS AND METHODS: A total of 75 idiopathic PFP patients and age and sex-matched 38 healthy volunteers were included. Patients with PFP were classified into two groups including early (<=6 months) and late (>6 months) based on the duration of symptoms. Following clinical evaluation, PAMR and BR were recorded. A comparison was performed among the early PFP group (n=52), late PFP group (n=23) and healthy volunteers (n=38). RESULTS: We obtained PAMR in 78.9% (n=30) of healthy volunteers, in 60.9% (n=14) of late and in only 38.5% (n=20) of early PFP patients (p=0.001). No habituation was observed following repeated stimuli. The mean latencies were 9.1+/-1.6, 10.9+/-1.9 and 12.3+/-2.0 msec., respectively (p=0.000). R1 and R2 latencies were longer in the early PFP group, compared to other groups (p=0.000). CONCLUSION: Posterior auricular muscle response exhibits changes in a manner similar to R1 and R2 of BR in early and late PFP. The occurrence rate of PAMR seems to be lowest or its latency is prolonged in the early PFP. PMID- 23682942 TI - Congenital macrostomia: a case report. AB - Macrostomia is often associated with the first and second branchial arch syndrome. Depending on the involvement area, appearance may vary. In isolated cases of macrostomia, the cleft usually terminates at the medial border of the masseter muscle. The goal of macrostomia reconstruction is to achieve functional, symmetrical and accurate mouth commissure with minimal scar. In this article, we present an eight-year-old girl case with isolated bilateral macrostomia treated with vermillion-square flap method. We recommend this method for patients with mild to moderate macrostomia. PMID- 23682943 TI - Extramedullary plasmacytoma of postnasal space. AB - In this article, we present a 75-year-old male with worsened nasal obstruction on the left side. Nasal endoscopy revealed bilateral grade 2 nasal polyps and a large polyp in the left posterior choana. postnasal space could not be viewed. Urgent computed tomography and magnetic resonance imaging revealed a lesion in the postnasal space. The patient was scheduled for endoscopic excision of the postnasal space lesion and bilateral nasal polypectomy. Histopathological examination of the samples revealed benign nature of polyps and plasmacytoma for postnasal space lesion. The patient is still on radiotherapy. A thorough endoscopic examination of the nasal cavities including the postnasal space is essential in all cases of nasal polyps to avoid postnasal space lesions to be overlooked. PMID- 23682944 TI - A rapidly growing neck mass in childhood: Castleman's disease concomitant with cavernous lymphangioma in the posterior cervical region. AB - In this article, we present a 12-year-old girl case with a painless mass in the left posterior region of the neck for two weeks. Two masses were detected during surgery. Histopathologic examination revealed the hyaline vascular type of Castleman's disease for the bigger mass and cavernous lymphangioma for the smaller mass. In the light of literature data, our case was the third childhood cervical posterior triangle Castleman's disease and was the first case reported due to its concomitance with cavernous lymphangioma. PMID- 23682945 TI - Cervical cystic vagal schwannoma mimicking a type 3 second branchial cleft cyst: a case report. AB - In this article, we report a rare case of a cervical cystic vagal schwannoma mimicking a type 3 second branchial cleft cyst clinically, radiologically and cytologically. Although schwannoma is rare, it should be considered in the differential diagnosis of cystic neck masses. This article suggests that Doppler ultrasonography, computed tomography and fine needle aspiration biopsy findings may not be sufficient to provide the correct preoperative diagnosis of cystic lateral neck masses and further imaging techniques may be required. PMID- 23682946 TI - An unusual presentation of a B-cell cutaneous lymphoma mimicking as nasolabial cyst. AB - Lymphoma is a cancer of the lymphocytes which leads to solid tumors in the lymphoid organs involving lymph nodes, spleen, liver, bone marrow and skin. Primary cutaneous lymphoma, a rare subtype of non-Hodgkin's lymphoma, can be classified as cutaneous T-cell or cutaneous B-cell lymphoma. These tumors are mostly T-cell origin and mainly locate on trunk, extremities and scalp or forehead. In this article, we report a 22-year-old female case without any symptoms of non-Hodgkin's lymphoma except a sign mimicking nasolabial cyst in the nasolabial fold, who was pathologically diagnosed with cutaneous B-cell lymphoma following surgery. PMID- 23682948 TI - Primary small cell carcinoma of the urinary bladder: a case report demonstrates cytological findings in SurePath liquid-based cytology. PMID- 23682950 TI - Prevalence and viral DNA loads of three novel human polyomaviruses in skin cancers from Japanese patients. AB - Merkel cell polyomavirus (MCPyV), human polyomaviruses 6 (HPyV6) and 7 (HPyV7) are novel human polyomaviruses. This study investigated their detection rates and DNA loads in various skin cancers from Japanese patients. MCPyV, HPyV6 and HPyV7 were detected in 22.2%, 3.2% and 1.6% of squamous cell carcinomas, 18.0%, 2.0% and 4.0% of basal cell carcinomas, and 19.1%, 4.3% and 4.3% of melanomas, respectively. Quantitative real-time polymerase chain reaction showed that their DNA loads were low. These findings provide the first evidence of the prevalence of HPyV6 and HPyV7 in skin cancers in Asia. Nucleotide differences were found in the large T-sequenced region between Japanese and North American isolates: a nucleotide substitution of A to G for HPyV6; and a nucleotide substitution of T to C and the insertion of a gap for HPyV7. This suggested that two genotypes of HPyV6 and HPyV7 would be present and associated with geographical origin. PMID- 23682947 TI - Peptide dendrimer/lipid hybrid systems are efficient DNA transfection reagents: structure--activity relationships highlight the role of charge distribution across dendrimer generations. AB - Efficient DNA delivery into cells is the prerequisite of the genetic manipulation of organisms in molecular and cellular biology as well as, ultimately, in nonviral gene therapy. Current reagents, however, are relatively inefficient, and structure-activity relationships to guide their improvement are hard to come by. We now explore peptide dendrimers as a new type of transfection reagent and provide a quantitative framework for their evaluation. A collection of dendrimers with cationic and hydrophobic amino acid motifs (such as KK, KA, KH, KL, and LL) distributed across three dendrimer generations was synthesized by a solid-phase protocol that provides ready access to dendrimers in milligram quantities. In conjunction with a lipid component (DOTMA/DOPE), the best reagent, G1,2,3-KL ((LysLeu)8(LysLysLeu)4(LysLysLeu)2LysGlySerCys-NH2), improves transfection by 6 10-fold over commercial reagents under their respective optimal conditions. Emerging structure-activity relationships show that dendrimers with cationic and hydrophobic residues distributed in each generation are transfecting most efficiently. The trigenerational dendritic structure has an advantage over a linear analogue worth up to an order of magnitude. The success of placing the decisive cationic charge patterns in inner shells rather than previously on the surface of macromolecules suggests that this class of dendrimers significantly differs from existing transfection reagents. In the future, this platform may be tuned further and coupled to cell-targeting moieties to enhance transfection and cell specificity. PMID- 23682951 TI - Genome-wide association mapping of natural variation in odour-guided behaviour in Drosophila. AB - A defining goal in the field of behavioural genetics is to identify the key genes or genetic networks that shape behaviour. A corollary to this goal is the goal of identifying genetic variants that are responsible for variation in the behaviour. These goals are achieved by measuring behavioural responses to controlled stimuli, in the present case the responses of Drosophila melanogaster to olfactory stimuli. We used a high-throughput behavioural assay system to test a panel of 157 Drosophila inbred lines derived from a natural population for both temporal and spatial dynamics of odour-guided behaviour. We observed significant variation in response to the odourant 2,3-butanedione, a volatile compound present in fermenting fruit. The recent whole genome sequencing of these inbred lines allowed us to then perform genome-wide association analyses in order to identify genetic polymorphisms underlying variation in responses. These analyses revealed numerous single nucleotide polymorphisms associated with variation in responses. Among the candidate genes identified were both novel and previously identified olfaction-related genes. Further, gene network analyses suggest that genes influencing variation in odour-guided behaviour are enriched for functions involving neural processing and that these genes form a pleiotropic interaction network. We examined several of these candidate genes that were highly connected in the protein- and genetic interaction networks using RNA interference. Our results showed that subtle changes influencing nervous system function can result in marked differences in behaviour. PMID- 23682952 TI - The hazard of a scientific approach to risk: commentary on Professor Lofstedt's proposal for a European Parliamentary Working Group on Risk. PMID- 23682953 TI - Schizotypy and hemispheric asymmetry: Results from two Chapman scales, the O-LIFE questionnaire, and two laterality measures. AB - Schizotypy is a multidimensional personality construct representing the extension of psychosis-like traits into the general population. Schizotypy has been associated with attenuated expressions of many of the same neuropsychological abnormalities as schizophrenia, including atypical pattern of functional hemispheric asymmetry. Unfortunately the previous literature on links between schizotypy and hemispheric asymmetry is inconsistent, with some research indicating that elevated schizotypy is associated with relative right over left hemisphere shifts, left over right hemisphere shifts, bilateral impairments, or with no hemispheric differences at all. This inconsistency may result from different methodologies, scales, and/or sex proportions between studies. In a within-participant design we tested for the four possible links between laterality and schizotypy by comparing the relationship between two common self report measures of multidimensional schizotypy (the O-LIFE questionnaire, and two Chapman scales, magical ideation and physical anhedonia) and performance in two computerised lateralised hemifield paradigms (lexical decision, chimeric face processing) in 80 men and 79 women. Results for the two scales and two tasks did not unequivocally support any of the four possible links. We discuss the possibilities that a link between schizotypy and laterality (1) exists but is subtle, probably fluctuating, unable to be assessed by traditional methodologies used here; (2) does not exist, or (3) is indirect, mediated by other factors (e.g., stress-responsiveness, handedness, drug use) whose influences need further exploration. PMID- 23682954 TI - Enzymatic and molecular characterisation of leucine aminopeptidase of Burkholderia pseudomallei. AB - BACKGROUND: Leucine aminopeptidase (LAP) has been known to be a housekeeping protease, DNA-binding protein and repressor or activator in the operon regulation of virulence-associated genes in several bacterial species. LAP activity was consistently detected in overnight cultures of Burkholderia pseudomallei, the causative agent of melioidosis and this enzyme was partially purified and characterised in this study. The intra- and inter-species nucleotide and deduced amino acid sequence variation of LAP encoding gene (pepA) was determined. A pepA/PCR-RFLP assay was designed to facilitate the identification of major LAP sequence types amongst clinical and environmental isolates of B. pseudomallei. RESULTS: LAP activity was detected in B. pseudomallei culture supernantants by zymographic analysis. Optimum activity was at pH 9 and stable at 50[degree sign]C. Enhanced enzymatic activity was observed in the presence of metallic ions Mg2+, Ca2+, Na+ and K+. LAP activity was inhibited by EDTA, 1,10-phenanthroline, amastatin, Mn2+ and Zn2+. Sequence analysis of the complete nucleotide and deduced amino acid sequences of LAP-encoding (pepA) gene showed close genetic relatedness to B. mallei (similarity 99.7%/99.6%), but not with B. thailandensis (96.4%/96.4%). Eight pepA sequence types were identified by comparison with a 596 bp DNA fragment encompassing central regions of the pepA gene. A pepA/PCR-RFLP was designed to differentiate pepA sequence types. Based on restriction analysis with StuI and HincII enzymes of the amplified pepA gene, clinical and environmental isolates showed different predominant RFLP types. Type I was the most predominant type amongst 71.4% (65/91) of the clinical isolates, while Type II was predominant in 55.6% (5/9) of the environmental isolates. CONCLUSIONS: This study showed that LAP is a secretory product of B. pseudomallei with features similar to LAP of other organisms. Identification of major LAP sequence types of B. pseudomallei was made possible based on RFLP analysis of the pepA gene. The high LAP activity detected in both B. pseudomallei and B. thailandensis, suggests that LAP is probably a housekeeping enzyme rather than a virulence determinant. PMID- 23682955 TI - Subcapsular hematoma after ureteroscopy and laser lithotripsy. AB - BACKGROUND AND PURPOSE: Renal hematoma after ureteroscopic lithotripsy (URSL) using holmium:yttrium-aluminum-garnet (Ho:YAG) laser is a rare complication. We aimed to review our center's experience of post-URSL subcapsular hematoma. PATIENTS AND METHODS: From 2007 to 2012, 1114 URSLs using 7.5F semi-rigid ureteroscopes were performed. Patients with post-URSL symptomatic renal hematoma were reviewed. Perioperative information on patients' preoperative morbidity, renal function, stone characteristics, and degree of hydronephrosis were reviewed. Operative information, postoperative presentation of symptoms, changes in blood parameters, CT findings, and subsequent management were documented. RESULTS: Post-URSL subcapsular hematoma was diagnosed in 4 of 1114 (0.36%) patients, who ranged in age from 43 to 63 years. Preoperative imaging showed that all four patients had obstructing proximal ureteral stones ranging in size from 0.7 to 2.1 cm, and three of them had thin renal cortices. Pressure bags were not used, and Double-J ureteral stents were inserted in all cases. All four patients had the triad of loin pain, fever, and significant hemoglobin drop necessitating transfusion. Three patients presented within 2 days of URSL, and one patient presented on day 20. One patient was treated conservatively and recovered with bed rest and antibiotics. Urgent angiography was performed on one patient in view of a significant drop in hemoglobin, but no embolization was needed. One patient underwent ultrasonography-guided drainage of the hematoma, and another had an emergency open clot evacuation because of significant compression on the kidney by the hematoma. Follow-up CT scans confirmed the resolution of the hematoma in all cases. CONCLUSIONS: Post-URSL subcapsular hematoma is a rare but potentially serious complication. A high index of suspicion is needed when patients present with significant loin pain and fever after URSL for obstructing proximal ureteral stones with thin renal cortices. The management of post-URSL subcapsular hematomas needs to be customized for each patient. PMID- 23682957 TI - Letter to the editor on electronic billboards and driver distraction. PMID- 23682956 TI - Methanobactin and MmoD work in concert to act as the 'copper-switch' in methanotrophs. AB - Biological oxidation of methane to methanol by aerobic bacteria is catalysed by two different enzymes, the cytoplasmic or soluble methane monooxygenase (sMMO) and the membrane-bound or particulate methane monooxygenase (pMMO). Expression of MMOs is controlled by a 'copper-switch', i.e. sMMO is only expressed at very low copper : biomass ratios, while pMMO expression increases as this ratio increases. Methanotrophs synthesize a chalkophore, methanobactin, for the binding and import of copper. Previous work suggested that methanobactin was formed from a polypeptide precursor. Here we report that deletion of the gene suspected to encode for this precursor, mbnA, in Methylosinus trichosporium OB3b, abolishes methanobactin production. Further, gene expression assays indicate that methanobactin, together with another polypeptide of previously unknown function, MmoD, play key roles in regulating expression of MMOs. Based on these data, we propose a general model explaining how expression of the MMO operons is regulated by copper, methanobactin and MmoD. The basis of the 'copper-switch' is MmoD, and methanobactin amplifies the magnitude of the switch. Bioinformatic analysis of bacterial genomes indicates that the production of methanobactin-like compounds is not confined to methanotrophs, suggesting that its use as a metal-binding agent and/or role in gene regulation may be widespread in nature. PMID- 23682958 TI - Butalbital and driving impairment. AB - Butalbital (Fiorinal((r))), used in the treatment of migraines and muscle pain, is the most commonly encountered barbiturate in impaired driving cases. It has central nervous system (CNS) depressant properties, including sedation, drowsiness, and feelings of intoxication, which can contribute to driving impairment. Twenty-six driving under the influence cases are reviewed including results from field sobriety tests and toxicology testing. Blood samples were screened using enzyme multiplied immunoassay technique immunoassay, and the presence of butalbital was confirmed and quantified using gas chromatography/mass spectrometry, gas chromatography with flame ionization detection, or gas chromatography nitrogen/phosphorus detection. Butalbital concentrations ranged from 1.0 to 30.2 mg/L, with a mean and median of 16.0 mg/L. General impairment indicators in these cases included horizontal and vertical nystagmus, lack of convergence, poor motor coordination, and balance and speech problems, which are common to CNS depressant intoxication, similar to that associated with alcohol. These findings indicate the importance of toxicological testing for butalbital in cases where CNS depressants are indicated. PMID- 23682959 TI - The protective role of group identity: sectarian antisocial behavior and adolescent emotion problems. AB - The protective role of strength of group identity was examined for youth in a context of protracted political conflict. Participants included 814 adolescents (Mage = 13.61, SD = 1.99 at Time 1) participating in a longitudinal study in Belfast, Northern Ireland. Utilizing hierarchical linear modeling, the results show that the effect of exposure to sectarian antisocial behaviors has a stronger effect on youth emotion problems for older adolescents. The results also show that youth with higher strength of group identity reported fewer emotion problems in the face of sectarian antisocial behavior but that this buffering effect is stronger for Protestants compared to Catholics. Implications are discussed for understanding the role of social identity in postaccord societies. PMID- 23682960 TI - Supramolecular host-guest pseudocomb conjugates composed of multiple star polycations tied tunably with a linear polycation backbone for gene transfection. AB - A series of novel supramolecular pseudocomb polycations (l-PGEA-Ad/CD-PGEAs) were synthesized by tying multiple low-molecular-weight beta-cyclodextrin (CD)-cored, ethanolamine-functionalized poly(glycidyl methacrylate) (PGEA) star polymers (CD PGEAs) with an adamantine-modified linear PGEA (l-PGEA-Ad) backbone via the host guest interaction. The pseudocomb carriers were studied in terms of their DNA binding capabilities, cytotoxicities, and gene transfection efficiencies in the HepG2 and HEK293 cell lines. The pseudocomb l-PGEA-Ad/CD-PGEAs exhibited better plasmid DNA-condensing abilities than their counterparts, CD-PGEA and l-PGEA. Meanwhile, the pseudocomb carriers displayed low cytotoxicity, similar to CD-PGEA and l-PGEA. Moreover, the gene transfection efficiencies of the pseudocomb carriers were much higher than those of CD-PGEA and l-PGEA at various PGEA nitrogen/DNA phosphate molar ratios. Such supramolecular preparation of pseudocomb gene carriers could provide a flexible approach for adjusting the structure and functionality of supramolecular polymers via the proper use of non covalent interactions. PMID- 23682961 TI - Sequential and site-specific on-surface synthesis on a bulk insulator. AB - The bottom-up construction of functional devices from molecular building blocks offers great potential in tailoring materials properties and functionality with utmost control. An important step toward exploiting bottom-up construction for real-life applications is the creation of covalently bonded structures that provide sufficient stability as well as superior charge transport properties over reversibly linked self-assembled structures. On-surface synthesis has emerged as a promising strategy for fabricating stable, covalently bound molecular structure on surfaces. So far, a majority of the structures created by this method have been obtained from a rather simple one-step processing approach. But the on surface preparation of complex structures will require the possibility to carry out various reaction steps in a sequential manner as done in solution chemistry. Only one example exists in literature in which a hierarchical strategy is followed to enhance structural complexity and reliability on a metallic surface. Future molecular electronic application will, however, require transferring these strategies to nonconducting surfaces. Bulk insulating substrates are known to pose significant challenges to on-surface synthesis due to the absence of a metal catalyst and their low surface energy, frequently resulting in molecule desorption rather than reaction activation. By carefully selecting a suitable precursor molecule, we succeeded in performing a two-step linking reaction on a bulk insulating surface. Besides a firm anchoring toward the substrate surface, the reaction sites and sequential order are encoded in the molecular structure, providing so far unmatched reaction control in on-surface synthesis on a bulk insulating substrate. PMID- 23682962 TI - Sweet's syndrome associated with systemic lupus erythematosus: a case report and review of the literature. AB - A 35-year-old Japanese female patient with systemic lupus erythematosus (SLE) presented with fever, erythematous papules and nodules, and polyarthralgia. Skin biopsy of a nodule was compatible with Sweet's syndrome. The papules/nodules were well treated with an oral glucocorticoid. Thirty cases of Sweet's syndrome associated with lupus erythematosus (LE) have been reported in the published work. The mean age was 34.2 years. They showed a higher male ratio (male : female, 1:2) compared with patients with SLE (1:9) and Sweet's syndrome (1:3.7). Sweet's syndrome may occur as a manifestation of LE, and a moderate dose of an oral glucocorticoid will result in a good response. PMID- 23682963 TI - Stereoselective synthesis of the butyrolactone and the oxazoline/furan fragment of leupyrrin A(1). AB - Stereoselective syntheses of the Northern and the Southern fragments 2 and 3 of leupyrrin A1 are reported. The convergent preparation of 2 is highlighted by a zirconocene-mediated one-pot cyclization-regioselective opening of an advanced diyne while the route to 3 involves a Krische allylation and a one-pot Sharpless dihydroxylation-cyclization. Comparison of the spectroscopic data with those reported for the natural product supports a relative stereochemical assignment within these heterocycles. PMID- 23682964 TI - Impact of pubertal stage at first drink on adult drinking behavior. AB - BACKGROUND: Early alcohol use is one of the strongest predictors of later alcohol use disorders, with early use usually taking place during puberty. Many researchers have suggested drinking during puberty as a potential biological basis of the age at first drink (AFD) effect. However, the influence of the pubertal phase at alcohol use initiation on subsequent drinking in later life has not been examined so far. METHODS: Pubertal stage at first drink (PSFD) was determined in N = 283 young adults (131 males, 152 females) from an epidemiological cohort study. At ages 19, 22, and 23 years, drinking behavior (number of drinking days, amount of alcohol consumed, hazardous drinking) was assessed using interview and questionnaire methods. Additionally, an animal study examined the effects of pubertal or adult ethanol (EtOH) exposure on voluntary EtOH consumption in later life in 20 male Wistar rats. RESULTS: PSFD predicted drinking behavior in humans in early adulthood, indicating that individuals who had their first drink during puberty displayed elevated drinking levels compared to those with postpubertal drinking onset. These findings were corroborated by the animal study, in which rats that received free access to alcohol during the pubertal period were found to consume more alcohol as adults, compared to the control animals that first came into contact with alcohol during adulthood. CONCLUSIONS: The results point to a significant role of stage of pubertal development at first contact with alcohol for the development of later drinking habits. Possible biological mechanisms and implications for prevention are discussed. PMID- 23682965 TI - Peri-operative pain management in children with cerebral palsy: comparative efficacy of epidural vs systemic analgesia protocols. AB - INTRODUCTION: Selective Dorsal Rhizotomy (SDR) is the only surgical intervention with class I evidence supporting permanent reduction in spasticity for children with cerebral palsy (Paediatr Anaesth, 12, 2002, 296; Neurosurg Focus, 21, 2006, e2). Postoperatively, adequate analgesia can be difficult to achieve (J Neurosurg, 105, 2006, 8; Childs Nerv Syst, 17, 2001, 556; Pediatr Neurosurg, 43, 2007, 107; Anesth Analg, 79, 1994, 340; Reg Anesth Pain Med, 24, 1999, 438; Pediatr Anesth, 19, 2009, 1213). This study examines a novel regimen utilizing the combination of epidurally infused ropivacaine - hydromorphone and scheduled ketorolac. This regimen was compared to a protocol utilizing systemic fentanyl and diazepam. METHODS: Following IRB approval, 31 patients receiving epidural analgesia were compared with 41 patients who received systemic analgesia. All surgeries were performed by one surgeon with standardized anesthetic and nursing care. Studied outcomes included: pain scores; episodes of severe pain; nausea, itching; oxygen desaturation; and ICU admission. Data were analyzed using Mann Whitney U-test, CHI square, and Fisher exact test where indicated with P < 0.05 considered significant. RESULTS: Studied groups had similar demographics, biometrics and disease burdens. Patients in the epidural group had statistically and clinically significant reductions in peak recorded pain scores for each 4-h period in the first 24 postoperative hours. Severe pain (score >5) was markedly reduced in the epidural group with 9% of epidural patients vs. 68% of systemic patients experiencing at least one episode. Fewer epidural patients experienced oxygen desaturation during the first two postoperative days (6.5% vs. 41%, 6.5% vs. 39%). CONCLUSION: Epidural analgesia resulted in substantial improvements in pain control and safety. The data supports the superiority of a multimodal analgesia approach centered on epidural analgesia. A similar protocol should be considered following simple laminectomies or procedures associated with lower extremity muscle spasm. PMID- 23682966 TI - The gut mucosal immune system in the neonatal period. AB - Invasive sepsis in the newborn period is a major cause of childhood morbidity and mortality worldwide. The infant immune system undoubtedly differs intrinsically from the mature adult immune system. Current understanding is that the newborn infant immune system displays a range of competencies and is developing rather than deficient. The infant gut mucosal immune system is complex and displays a plethora of phenotypic and functional irregularities that may be clinically important. Various factors affect and modulate the infant gut mucosal immune system: components of the intestinal barrier, the infant gut microbiome, nutrition and the maternal-infant hybrid immune system. Elucidation of the phenotypic distribution of immune cells, their functional significance and the mucosa-specific pathways used by these cells is essential to the future of research in the field of infant immunology. PMID- 23682968 TI - Tuning the viscoelasticity of nonionic wormlike micelles with beta-cyclodextrin derivatives: a highly discriminative process. AB - We report the influence of five beta-cyclodextrin (beta-CD) derivatives, namely: randomly methylated beta-cyclodextrin (MBCD), heptakis (2,6-di-O-methyl)-beta cyclodextrin (DIMEB), heptakis (2,3,6-tri-O-methyl)-beta-cyclodextrin (TRIMEB), 2 hydroxyethyl-beta-cyclodextrin (HEBCD) and 2-hydroxypropyl-beta-cyclodextrin (HPBCD), on the self-assembly of mixtures of nonionic surfactants: polyoxyethylene cholesteryl ether (ChEO10) and monocaprylin (MCL). Mixtures of ChEO10/MCL in water form highly viscoelastic wormlike micelle solutions (WLM) over a range of concentrations; herein, the composition was fixed at 10 wt % ChEO10/3 wt % MCL. The addition of methylated beta-CDs (MBCD, DIMEB, TRIMEB) induced a substantial disruption of the solid-like viscoelastic behavior, as shown from a loss of the Maxwell behavior, a large reduction in G' and G" in oscillatory frequency-sweep measurements, and a drop of the viscosity. The disruption increased with the degree of substitution, following: MBCD < DIMEB < TRIMEB. Cryo-TEM images confirmed a loss of the WLM networks, revealing short rods and disc-like aggregates, which were corroborated by small-angle neutron scattering (SANS) measurements. Critical aggregation concentrations (CAC), measured by fluorescence spectroscopy, increased in the presence of DIMEB for both ChEO10 and MCL, suggesting the existence of interactions between methylated beta-CDs and both surfactants involved in WLM formation. Instead, hydroxyl-beta CDs had a very different effect on the WLM. HPBCD only slightly reduced the solid like behavior, without suppressing it. Quite remarkably, the addition of HEBCD reinforced the solid-like characteristics and increased the viscosity 10-fold. Cryo-TEM images confirmed the subsistence of WLM in ChEO10/MCL/HEBCD solutions, while SANS data revealed a slight elongation and thickening of the worms, and an increase of associated water molecules. CAC data showed that HPBCD had little effect on either surfactant, while HEBCD strongly affected the CAC of MCL and only slightly affected the ChEO10. For both DIMEB and HEBCD, time-resolved SANS measurements showed that morphology changes underlying these macroscopic changes occur in less than 100 ms. PMID- 23682967 TI - PPIP5K1 modulates ligand competition between diphosphoinositol polyphosphates and PtdIns(3,4,5)P3 for polyphosphoinositide-binding domains. AB - We describe new signalling consequences for PPIP5K1 (diphosphoinositol pentakisphosphate kinase type 1)-mediated phosphorylation of InsP6 and 5-InsP7 to 1-InsP7 and InsP8. In NIH 3T3 cells, either hyperosmotic stress or receptor activation by PDGF (platelet-derived growth factor) promoted translocation of PPIP5K1 from the cytoplasm to the plasma membrane. The PBD1 (polyphosphoinositide binding domain) in PPIP5K1 recapitulated that translocation. Mutagenesis of PBD1 to reduce affinity for PtdIns(3,4,5)P3 prevented translocation. Using surface plasmon resonance, we found that PBD1 association with vesicular PtdIns(3,4,5)P3 was inhibited by InsP6 and diphosphoinositol polyphosphates. However, the inhibition by PPIP5K1 substrates (IC50: 5-InsP7=5 MUM and InsP6=7 MUM) was substantially more potent than that of the PPIP5K1 products (IC50: InsP8=32 MUM and 1-InsP7=43 MUM). This rank order of ligand competition with PtdIns(3,4,5)P3 was also exhibited by the PH (pleckstrin homology) domains of Akt (also known as protein kinase B), GRP1 (general receptor for phosphoinositides 1) and SIN1 (stress-activated protein kinase-interaction protein 1). We propose that, in vivo, PH domain binding of InsP6 and 5-InsP7 suppresses inappropriate signalling ('noise') from stochastic increases in PtdIns(3,4,5)P3. That restraint may be relieved by localized depletion of InsP6 and 5-InsP7 at the plasma membrane following PPIP5K1 recruitment. We tested this hypothesis in insulin-stimulated L6 myoblasts, using mTOR (mechanistic/mammalian target of rapamycin)-mediated phosphorylation of Akt on Ser473 as a readout for SIN1-mediated translocation of mTORC (mTOR complex) 2 to the plasma membrane [Zoncu, Efeyan and Sabatini (2011) Nat. Rev. Mol. Cell Biol. 12, 21-35]. Knockdown of PPIP5K1 expression was associated with a 40% reduction in Ser473 phosphorylation. A common feature of PtdIns(3,4,5)P3-based signalling cascades may be their regulation by PPIP5K1. PMID- 23682969 TI - Recommendations for improving substance abuse treatment interventions for sexual minority substance abusers. PMID- 23682971 TI - Progress in understanding mood disorders: optogenetic dissection of neural circuits. AB - Major depression is characterized by a cluster of symptoms that includes hopelessness, low mood, feelings of worthlessness and inability to experience pleasure. The lifetime prevalence of major depression approaches 20%, yet current treatments are often inadequate both because of associated side effects and because they are ineffective for many people. In basic research, animal models are often used to study depression. Typically, experimental animals are exposed to acute or chronic stress to generate a variety of depression-like symptoms. Despite its clinical importance, very little is known about the cellular and neural circuits that mediate these symptoms. Recent advances in circuit-targeted approaches have provided new opportunities to study the neuropathology of mood disorders such as depression and anxiety. We review recent progress and highlight some studies that have begun tracing a functional neuronal circuit diagram that may prove essential in establishing novel treatment strategies in mood disorders. First, we shed light on the complexity of mesocorticolimbic dopamine (DA) responses to stress by discussing two recent studies reporting that optogenetic activation of midbrain DA neurons can induce or reverse depression-related behaviors. Second, we describe the role of the lateral habenula circuitry in the pathophysiology of depression. Finally, we discuss how the prefrontal cortex controls limbic and neuromodulatory circuits in mood disorders. PMID- 23682972 TI - Working memory for cross-domain sequences. AB - How is information from different content domains bound together into a representation of the whole sequence? Several theories predict that mixing information from different domains specifically impairs the ordering of information from different domains, whereas ordering within domains might be enhanced. In contrast, domain-general models--in which items from different domains are simply assumed to be less confusable--predict that mixing items from different domains enhances ordering, as the list items will on average be less confusable. The results of an experiment showed an overall advantage for mixed over pure lists in ordering information, supporting the domain-general viewpoint. Simulations with a representative domain-general model--the start-end model of Henson [(1998). Short-term memory for serial order: The start-end model. Cognitive Psychology, 36, 73-137]--showed that the model gave a satisfactory account of the data. Together, the data and simulations lend evidence to the idea that a domain-general mechanism is responsible for ordering stimuli from different domains, and that domain-specific effects are attributable to the relative similarity of item representations. PMID- 23682970 TI - Evaluation of vitamin C for adjuvant sepsis therapy. AB - SIGNIFICANCE: Evidence is emerging that parenteral administration of high-dose vitamin C may warrant development as an adjuvant therapy for patients with sepsis. RECENT ADVANCES: Sepsis increases risk of death and disability, but its treatment consists only of supportive therapies because no specific therapy is available. The characteristics of severe sepsis include ascorbate (reduced vitamin C) depletion, excessive protein nitration in microvascular endothelial cells, and microvascular dysfunction composed of refractive vasodilation, endothelial barrier dysfunction, and disseminated intravascular coagulation. Parenteral administration of ascorbate prevents or even reverses these pathological changes and thereby decreases hypotension, edema, multiorgan failure, and death in animal models of sepsis. CRITICAL ISSUES: Dehydroascorbic acid appears to be as effective as ascorbate for protection against microvascular dysfunction, organ failure, and death when injected in sepsis models, but information about pharmacodynamics and safety in human subjects is only available for ascorbate. Although the plasma ascorbate concentration in critically ill and septic patients is normalized by repletion protocols that use high doses of parenteral ascorbate, and such doses are tolerated well by most healthy subjects, whether such large amounts of the vitamin trigger adverse effects in patients is uncertain. FUTURE DIRECTIONS: Further study of sepsis models may determine if high concentrations of ascorbate in interstitial fluid have pro-oxidant and bacteriostatic actions that also modify disease progression. However, the ascorbate depletion observed in septic patients receiving standard care and the therapeutic mechanisms established in models are sufficient evidence to support clinical trials of parenteral ascorbate as an adjuvant therapy for sepsis. PMID- 23682973 TI - Crouching or lying-down? The reason of a (uncomfortable) delivery position. AB - Through a deep historical and cultural perspective, this article focuses on the revolution that took place in childbirth, due to the introduction of medical knowledge and surgical skills. Ranging from Greek mythology to the Sixties, this contribution analyses the social, scientific and anthropological reasons that led to the desertion of the delivery vertical position in favour of the lying down one. PMID- 23682974 TI - White-coat hypertension. AB - 1. Numerous studies have examined whether white-coat hypertension (WCHT) is associated with increased cardiovascular risk, but with definitions of WCHT that were not sufficiently robust, results have been inconsistent. The aim of the present review was to standardize the evidence by only including studies that used a definition of WCHT consistent with international guidelines. 2. Published studies were reviewed for data on vascular dysfunction, target organ damage, risk of future sustained hypertension and cardiovascular events. 3. White-coat hypertension has a population prevalence of approximately 15% and is associated with non-smoking and slightly elevated clinic blood pressure. Compared with normotensives, subjects with WCHT are at increased cardiovascular risk due to a higher prevalence of glucose dysregulation, increased left ventricular mass index and increased risk of future diabetes and hypertension. 4. In conclusion, management of a patient with WCHT should focus on cardiovascular risk factors, particularly glucose intolerance, not blood pressure alone. PMID- 23682975 TI - European Parliament Working Group on Risk: a commentary. PMID- 23682976 TI - Acid rock drainage and rock weathering in Antarctica: important sources for iron cycling in the Southern Ocean. AB - Here we describe biogeochemical processes that lead to the generation of acid rock drainage (ARD) and rock weathering on the Antarctic landmass and describe why they are important sources of iron into the Antarctic Ocean. During three expeditions, 2009-2011, we examined three sites on the South Shetland Islands in Antarctica. Two of them displayed intensive sulfide mineralization and generated acidic (pH 3.2-4.5), iron-rich drainage waters (up to 1.78 mM Fe), which infiltrated as groundwater (as Fe(2+)) and as superficial runoff (as Fe(3+)) into the sea, the latter with the formation of schwertmannite in the sea-ice. The formation of ARD in the Antarctic was catalyzed by acid mine drainage microorganisms found in cold climates, including Acidithiobacillus ferrivorans and Thiobacillus plumbophilus. The dissolved iron (DFe) flux from rock weathering (nonmineralized control site) was calculated to be 0.45 * 10(9) g DFe yr(-1) for the nowadays 5468 km of ice-free Antarctic rock coastline which is of the same order of magnitude as glacial or aeolian input to the Southern Ocean. Additionally, the two ARD sites alone liberate 0.026 and 0.057 * 10(9) g DFe yr( 1) as point sources to the sea. The increased iron input correlates with increased phytoplankton production close to the source. This might even be enhanced in the future by a global warming scenario, and could be a process counterbalancing global warming. PMID- 23682977 TI - Noyori hydrogenation: aromaticity, synchronicity, and activation strain analysis. AB - By means of density functional theory calculations, we have computationally explored the intimacies of the crucial step of Noyori hydrogrogenation reactions of multiple bonds. This process can be considered analogous to the so-called double group transfer reactions. Both kinds of transformations proceed concertedly via the simultaneous migration of two hydrogen atoms/groups in a pericyclic [sigma2s + sigma2s + pi2s] reaction through six-membered transition structures. Despite the structural resemblances of both types of saddle points, significant differences are found in terms of synchronicity and in-plane aromaticity. In addition, the activation strain model has been used to get quantitative insight into the factors which control the corresponding barrier heights. It is found that the presence of a heteroatom in the acceptor moiety is responsible for a remarkable increase of the interaction energy between the reactants which can compensate the destabilizing effect of the strain energy associated with the deformation of the initial reagents leading to low reaction barriers. PMID- 23682978 TI - Metacognitive beliefs in adolescents with an at-risk mental state for psychosis. AB - AIM: The self-regulatory executive function model suggests that metacognitive beliefs play a role in all forms of psychological disorder, including psychosis. However, our understanding of these beliefs and their relationship with symptoms in adolescents with an at-risk mental state (ARMS) for psychosis is limited. METHODS: The Metacognitions Questionnaire short form (MCQ-30) was administered to 31 adolescents with an identified ARMS. Scores were subsequently compared to a control group of 76 adolescents drawn from a community population. RESULTS: As predicted, ARMS patients scored significantly higher on metacognition subscales, with negative beliefs (F = 42.97, P = 0.001), cognitive confidence (F = 17.11, P = 0.001) and need for control (F = 22.48, P = 0.001) subscales of the MCQ-30 distinguishing them from the comparison group. CONCLUSIONS: The finding that metacognitive beliefs are significantly elevated in comparison to a community sample of adolescents is in keeping with previous adult-orientated research. Possible implications for clinical practice are discussed. PMID- 23682980 TI - Radiation exposure associated with dedicated renal mass computed tomography protocol: impact of patient characteristics. AB - BACKGROUND AND PURPOSE: Renal mass protocol CT (RMP-CT) using multiphase abdomen and pelvis CT imaging is the mainstay for diagnosis, characterization, and follow up for renal masses; however, it is associated with ionizing radiation to the patient. We sought to quantify the effective dose associated with RMP-CT and to determine how patient factors affect radiation exposure. MATERIAL AND METHODS: We retrospectively reviewed the records of 247 patients undergoing management of a small renal mass (cT1a) between 2005 and 2011 at our institution. Body mass index (BMI) was categorized as normal weight, overweight, obese, and morbidly obese (<=25, 25.1-30, 30.1-35 and >35, respectively). Effective dose of RMP-CT was calculated through the dose-length-product multiplied by a factor coefficient (0.015). Effective doses in milliSieverts (mSv) were correlated to patient characteristics. RESULTS: Patients' median age was 61 years, and median BMI was 28.7 kg/m(2); 72% were Caucasian and 56% were male. Median effective dose was 26.1 mSv (interquartile range 20.6-35.3). When stratified by BMI, the median effective doses were 18.9, 25.2, 27.7, and 36.2mSv for normal weight, overweight, obese, and morbidly obese patients, respectively. On multivariable analyses, BMI and male sex were significantly associated with increased radiation dose. CONCLUSIONS: In this series, the median effective dose for RMP-CT was 26.1 mSv. Obesity was independently associated with markedly increased radiation exposure, with morbidly obese patients being exposed to almost twice the amount of radiation compared with normal weight persons. These findings should be considered when devising management strategies in patients with a renal mass and strategies should be developed to reduce medical ionizing radiation exposure. PMID- 23682979 TI - Rationale, design and organization of the delayed antibiotic prescription (DAP) trial: a randomized controlled trial of the efficacy and safety of delayed antibiotic prescribing strategies in the non-complicated acute respiratory tract infections in general practice. AB - BACKGROUND: Respiratory tract infections are an important burden in primary care and it's known that they are usually self-limited and that antibiotics only alter its course slightly. This together with the alarming increase of bacterial resistance due to increased use of antimicrobials calls for a need to consider strategies to reduce their use. One of these strategies is the delayed prescription of antibiotics. METHODS: Multicentric, parallel, randomised controlled trial comparing four antibiotic prescribing strategies in acute non complicated respiratory tract infections. We will include acute pharyngitis, rhinosinusitis, acute bronchitis and acute exacerbation of chronic bronchitis or chronic obstructive pulmonary disease (mild to moderate). The therapeutic strategies compared are: immediate antibiotic treatment, no antibiotic treatment, and two delayed antibiotic prescribing (DAP) strategies with structured advice to use a course of antibiotics in case of worsening of symptoms or not improving (prescription given to patient or prescription left at the reception of the primary care centre 3 days after the first medical visit). DISCUSSION: Delayed antibiotic prescription has been widely used in Anglo-Saxon countries, however, in Southern Europe there has been little research about this topic. The DAP trial wil evaluate two different delayed strategies in Spain for the main respiratory infections in primary care. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, number http://NCT01363531. PMID- 23682981 TI - Presence of psychoactive substances in injured Belgian drivers. AB - OBJECTIVE: To estimate the percentage of drivers involved in a traffic crash in Belgium who have alcohol and drugs in their blood. METHODS: Blood samples of the drivers injured in a traffic crash and admitted to the emergency departments of 5 hospitals in Belgium between January 2008 and May 2010 were analyzed for ethanol (with an enzymatic method) and 22 other psychoactive substances (with ultra performance liquid chromatography with tandem mass spectrometry or gas chromatography-mass spectrometry). RESULTS: One thousand seventy-eight drivers were included in the study. Alcohol (>=0.1 g/L) was the most common substance (26.2%). A large majority of the drivers (64%) who were positive for alcohol had a blood alcohol concentration (BAC) >=1.3 g/L (legal limit in Belgium: 0.5 g/L). These high BACs were most frequent among male injured drivers. Cannabis was the most prevalent illicit drug (5.3%) and benzodiazepines (5.3%) were the most prevalent medicinal drugs. Approximately 1 percent of the drivers were positive for cocaine and amphetamines. No drivers tested positive for illicit opioids. Medicinal drugs were more likely to be found among female drivers and drivers older than 35 years, and alcohol and illicit drugs were more likely to be found among male drivers and drivers younger than 35 years. CONCLUSION: A high percentage of the injured drivers were positive for a psychoactive substance at the time of injury. Alcohol was the most common substance, with 80 percent of the positive drivers having a BAC >=0.5 g/L. Compared to a roadside survey in the same area, drivers/riders with high BACs and combinations of drugs were overrepresented. Efforts should be made to increase alcohol and drug enforcement. The introduction of a categorization and labeling system might reduce driving under the influence of medicinal drugs by informing health care professionals and patients. PMID- 23682983 TI - Thin porous alumina sheets as supports for stabilizing gold nanoparticles. AB - Thin porous alumina sheets have been synthesized using a lysine-assisted hydrothermal approach resulting in an extraordinary catalyst support that can stabilize Au nanoparticles at annealing temperatures up to 900 degrees C. Remarkably, the unique architecture of such an alumina with thin sheets (average thickness ~15 nm and length 680 nm) and rough surface is beneficial to prevent gold nanoparticles from sintering. HRTEM observations clearly showed that the epitaxial growth between Au nanoparticles and alumina support was due to strong interfacial interactions, further explaining the high sinter-stability of the obtained Au/Al2O3 catalyst. Consequently, despite calcination at 700 degrees C, the catalyst maintains its gold nanoparticles of size predominantly 2 +/- 0.8 nm. Surprisingly, catalyst annealed at 900 degrees C retained the highly dispersed small gold nanoparticles. It was also observed that a few gold particles (6-25 nm) were encapsulated by an alumina layer (thickness less than 1 nm) to minimize the surface energy, revealing a surface restructuring of the gold/support interface. As a typical and size-dependent reaction, CO oxidation is used to evaluate the performance of Au/Al2O3 catalysts. The results obtained demonstrated Au/Al2O3 catalyst calcined at 700 degrees C exhibited excellent activity with a complete CO conversion at ~30 degrees C (T100% = 30 degrees C), and even after calcination at 900 degrees C, the catalyst still achieved its T50% at 158 degrees C. In sharp contrast, Au catalyst prepared using conventional alumina support shows almost no activity under the same preparation and catalytic test conditions. PMID- 23682982 TI - S100A9 promotes human lung fibroblast cells activation through receptor for advanced glycation end-product-mediated extracellular-regulated kinase 1/2, mitogen-activated protein-kinase and nuclear factor-kappaB-dependent pathways. AB - S100A9 belongs to the S100 family of calcium-binding proteins and plays a key role in many inflammatory conditions. Recent studies have found that S100A9 was elevated significantly in the bronchoalveolar lavage fluid of idiopathic pulmonary fibrosis patients, and might be a biomarker for fibrotic interstitial lung diseases. However, the exact function of S100A9 in pulmonary fibrosis needs further studies. We performed this study to investigate the effect of S100A9 on human embryo lung fibroblast (HLF) proliferation and production of cytokines and collagen, providing new insights into the possible mechanism. S100A9 promoted proliferation of fibroblasts and up-regulated expression of both proinflammatory cytokines interleukin (IL)-6, IL-8, IL-1beta and collagen type III. S100A9 also induced HLF cells to produce alpha-smooth muscle actin (alpha-SMA) and receptor for advanced glycation end-product (RAGE). In addition, S100A9 caused a significant increase in extracellular-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) phosphorylation, while the status of p38 and c-Jun N terminal kinase (JNK) phosphorylation remained unchanged. Treatment of cells with S100A9 also enhanced nuclear factor kappa B (NF-kappaB) activation. RAGE blocking antibody pretreatment inhibited the S100A9-induced cell proliferation, cytokine production and pathway phosphorylation. S100A9-mediated cell activation was suppressed significantly by ERK1/2 MAPK inhibitor and NF-kappaB inhibitor. In conclusion, S100A9 promoted HLF cell growth and induced cells to secret proinflammatory cytokines and collagen through RAGE signalling and activation of ERK1/2 MAPK and NF-kappaB pathways. PMID- 23682984 TI - Distribution of crystalline polymer and fullerene clusters in both horizontal and vertical directions of high-efficiency bulk heterojunction solar cells. AB - In this study, we used (i) synchrotron grazing-incidence small-/wide-angle X-ray scattering to elucidate the crystallinity of the polymer PBTC12TPD and the sizes of the clusters of the fullerenes PC61BM and ThC61BM and (ii) transmission electron microscopy/electron energy loss spectroscopy to decipher both horizontal and vertical distributions of fullerenes in PBTC12TPD/fullerene films processed with chloroform, chlorobenzene and dichlorobezene. We found that the crystallinity of the polymer and the sizes along with the distributions of the fullerene clusters were critically dependent on the solubility of the polymer in the processing solvent when the solubility of fullerenes is much higher than that of the polymer in the solvent. In particular, with chloroform (CF) as the processing solvent, the polymer and fullerene units in the PBTC12TPD/ThC61BM layer not only give rise to higher crystallinity and a more uniform and finer fullerene cluster dispersion but also formed nanometer scale interpenetrating network structures and presented a gradient in the distribution of the fullerene clusters and polymer, with a higher polymer density near the anode and a higher fullerene density near the cathode. As a result of combined contributions from the enhanced polymer crystallinity, finer and more uniform fullerene dispersion and gradient distributions, both the short current density and the fill factor for the device incorporating the CF-processed active layer increase substantially over that of the device incorporating a dichlorobenzene-processed active layer; the resulting power conversion efficiency of the device incorporating the CF processed active layer was enhanced by 46% relative to that of the device incorporating a dichlorobenzene-processed active layer. PMID- 23682985 TI - Statement of retraction: Xiaowei Z, Zhenhua L, Yeqing Y, Wenjun B, Xiaofeng W, Huan S, Yongping Z. "Testosterone therapy improves psychological distress and health-related quality of life in Chinese men with symptomatic late-onset hypogonadism patients". PMID- 23682986 TI - Calcium binding to dipeptides of aspartate and glutamate in comparison with orthophosphoserine. AB - Aspartate binds calcium(II) better than glutamate with Ka = 7.0 +/- 0.9 L mol-1 for Asp and Ka = 3.0 +/- 0.8 L mol-1 for Glu, respectively, as determined using calcium-selective electrodes for aqueous solutions of ionic strength 0.20 at 25 degrees C at pH of relevance for milk products. For the mixed peptides, the affinity seems additive with Ka = 27 +/- 3 L mol-1 for Asp-Glu and 22.7 +/- 0.1 for Glu-Asp as compared to the expected 21 L mol-1. In contrast, for Asp-Asp, the affinity is less than additive with Ka = 23 +/- 5 L mol-1 as compared to the expected 49 L mol-1, whereas for Glu-Glu, the affinity is more than additive with Ka = 26 +/- 4 L mol-1 as compared to the expected 9.0 L mol-1, indicating specific structural effects for Glu-Glu. Ionic strength effects, 1.0 versus 0.20 studied, are similar for Asp and Glu with decreasing affinity for higher ionic strength, whereas the dipeptides with Glu as C-terminus are more sensitive to increasing ionic strength than with Asp as C-terminus. Despite little affinity of calcium to serine with Ka = 0.9 +/- 0.2 L mol-1, Glu has increasing affinity for calcium in the serine dipeptide Ser-Glu with Ka = 10 +/- 3 L mol-1, which becomes comparable to phosphorylated serine with Ka = 22 +/- 5 L mol-1. PMID- 23682987 TI - The compatibility of fingerprint visualization techniques with immunolabeling. AB - The chemical composition of a fingermark potentially holds a wealth of information about the fingermark donor, which can be extracted by immunolabeling. Immunolabeling can be used to detect specific components in fingermarks; however, to be applicable in the forensic field, it should be compatible with commonly used fingerprint visualization techniques. In this study, the compatibility of immunolabeling with two different fingerprint visualization techniques, magnetic powdering and ninhydrin staining, was investigated on fingermarks deposited on glass and on nitrocellulose membranes. With dermcidin as antigen of interest, immunolabeling was performed successfully on all developed fingermarks. We can conclude that immunolabeling is compatible with magnetic powdering and ninhydrin staining, which can be of great forensic value. PMID- 23682988 TI - Helping trainees to become good pediatric anesthetists. PMID- 23682989 TI - Angiokeratoma corporis diffusum in the absence of metabolic disorders: a case report and mini-review of the published work. PMID- 23682990 TI - Dimensionality of the Knee Numeric-Entity Evaluation Score (KNEES-ACL): a condition-specific questionnaire. AB - The benefit of anterior cruciate ligament (ACL) reconstruction has been questioned based on patient-reported outcome measures (PROMs). Valid interpretation of such results requires confirmation of the psychometric properties of the PROM. Rasch analysis is the gold standard for validation of PROMs, yet PROMs used for ACL reconstruction have not been validated using Rasch analysis. We used Rasch analysis to investigate the psychometric properties of the Knee Numeric-Entity Evaluation Score (KNEES-ACL), a newly developed PROM for patients treated for ACL deficiency. Two-hundred forty-two patients pre- and post ACL reconstruction completed the pilot PROM. Rasch models were used to assess the psychometric properties (e.g., unidimensionality, local response dependency, and differential item functioning). Forty-one items distributed across seven unidimensional constructs measuring impairment, functional limitations, and psychosocial consequences were confirmed to fit Rasch models. Fourteen items were removed because of statistical lack of fit and inadequate face validity. Local response dependency and differential item functioning were identified and adjusted. The KNEES-ACL is the first Rasch-validated condition-specific PROM constructed for patients with ACL deficiency and patients with ACL reconstruction. Thus, this instrument can be used for within- and between-group comparisons. PMID- 23682991 TI - Sex differences in college student adherence to NIAAA drinking guidelines. AB - BACKGROUND: Exceeding nationally recommended drinking limits puts individuals at increased risk of experiencing harmful effects due to alcohol consumption. Both weekly and daily limits exist to prevent harm due to toxicity and intoxication, respectively. It remains unclear how well college students adhere to recommended limits, and whether their drinking is sensitive to the wider sex difference in weekly versus daily drinking limits. METHODS: This study used a daily-level, academic-year-long, multisite sample to describe adherence to NIAAA daily (no more than 4 drinks per day for men, 3 drinks per day for women) and weekly (no more than 14 drinks per week for men, 7 drinks per week for women) drinking guidelines, and to test for sex differences and time effects. College students (n = 992; 58% female) reported daily drinking on a biweekly basis using web-based surveys throughout their first year of college. RESULTS: Women exceeded weekly limits more frequently (15% of weeks [14 to 17%]) than men (12% [10 to 14%]). Women and men exceeded daily drinking limits similarly often (25 and 27%, respectively). In a generalized estimating equations analysis across all 18 biweekly assessments, adjusted for covariates and a linear trend over time, women were more likely to exceed weekly guidelines compared to men. Sex differences in exceeding daily limits were not significant. Over time, rates of exceeding limits declined for daily limits but only for men for weekly limits. CONCLUSIONS: Female college students are more likely to exceed weekly alcohol intake limits than men. Furthermore, trends over time suggest that college students may be maturing out of heavy episodic drinking, but women may not mature out of harmful levels of weekly drinking. The observed disparity in risk for long-term health consequences may represent a missed opportunity for education and intervention. PMID- 23682992 TI - In vivo targeting of intratumor regulatory T cells using PEG-modified single walled carbon nanotubes. AB - Recent evidence regarding the role of regulatory T cells (Treg) in tumor development has suggested that the manipulation of Treg function selectively in the tumor microenvironment would be a desirable immunotherapy approach. Targeting intratumor immune populations would reduce side effects on peripheral healthy cells and increase antitumor efficacy of immunotherapies. However, no current approaches are available which enable selective in vivo targeting of intratumor Treg or other immune cell subpopulations. Herein, we investigated the ability of ligands against Treg-specific receptors to drive selective internalization of PEG modified single-walled carbon nanotubes (PEG-SWCNTs) into Treg residing in the tumor microenvironment. We focused our attention on the glucocorticoid-induced TNFR-related receptor (GITR), as it showed higher overexpression on intratumor vs peripheral (i.e., splenic) Treg compared to other reported Treg-specific markers (folate receptor 4, CD103, and CD39). Ex vivo investigations showed that the Treg targeting efficiency and selectivity of PEG-SWCNTs depended on incubation time, dose, number of ligands per nanotube, and targeted surface marker. In vivo investigations showed that PEG-SWCNTs armed with GITR ligands targeted Treg residing in a B16 melanoma more efficiently then intratumor non-Treg or splenic Treg. The latter result was achieved by exploiting a combination of passive tumor targeting due to enhanced tumor vascular permeability, naturally increased intratumor Treg vs effector T cell (Teff) ratio, and active targeting of markers that are enriched in intratumor vs splenic Treg. We also found that PEG-SWCNTs loaded with GITR ligands were internalized by Treg through receptor-mediated endocytosis and transported into the cytoplasm and nucleus ex vivo and in vivo. This is the first example of intratumor immune cell targeting and we hope it will pave the way to innovative immunotherapies against cancer. PMID- 23682994 TI - Electroreductive intermolecular coupling of 3-methoxycarbonylindoles with ketones. AB - The electroreductive coupling of 1-alkoxycarbonyl-3-methoxycarbonylindoles with aromatic ketones in the presence of chlorotrimethylsilane gave cis-adducts stereoselectively. The cis-adducts were readily transformed to trans-adducts by treatment with catalyst DBU. On the other hand, the electroreductive coupling of 1-methyl-3-methoxycarbonylindole with aliphatic ketones in isopropanol afforded trans-adducts exclusively. The adducts are the precursors for the synthesis of 2 substituted 3-methoxycarbonylindoles and indolines. PMID- 23682995 TI - A theoretical study of water adsorption and decomposition on low-index spinel ZnGa2O4 surfaces: correlation between surface structure and photocatalytic properties. AB - Water adsorption and decomposition on stoichiometrically perfect and oxygen vacancy containing ZnGa2O4 (100), (110), and (111) surfaces were investigated through periodic density functional theory (DFT) calculations. The results demonstrated that water adsorption and decomposition are surface-structure sensitive processes. On a stoichiometrically perfect surface, the most stable molecular adsorption that could take place involved the generation of hydrogen bonds. For dissociative adsorption, the adsorption energy of the (111) surface was more than 4 times the energies of the other two surfaces, indicating it to be the best surface for water decomposition. A detailed comparison of these three surfaces showed that the primary reason for this observation was the special electronic state of the (111) surface. When water dissociated on the (111) surface, the special Ga3c-4s and 4p hybridization states at the Fermi level had an obvious downshift to the lower energies. This large energy gain greatly promoted the dissociation of water. Because the generation of O(3c) vacancy defects on the (100) and (110) surfaces could increase the stability of the dissociative adsorption states with few changes to the energy barrier, this type of defect would make the decomposition of water molecules more favorable. However, for the (111) surface, the generation of vacancy defects could decrease the stability of the dissociative adsorption states and significantly increase their energy barriers. Therefore, the decomposition of water molecules on the oxygen vacancy defective (111) surface would be less favorable than the perfect (111) surface. These findings on the decomposition of H2O on the ZnGa2O4 surfaces can be used toward the synthesis of water-splitting catalysts. PMID- 23682996 TI - Transport Mode Selection for Toxic Gases: Rail or Road? AB - A significant majority of hazardous materials (hazmat) shipments are moved via the highway and railroad networks, wherein the latter mode is generally preferred for long distances. Although the characteristics of highway transportation make trucks the most dominant surface transportation mode, should it be preferred for hazmat whose accidental release can cause catastrophic consequences? We answer this question by first developing a novel and comprehensive assessment methodology-which incorporates the sequence of events leading to hazmat release from the derailed railcars and the resulting consequence-to measure rail transport risk, and second making use of the proposed assessment methodology to analyze hazmat transport risk resulting from meeting the demand for chlorine and ammonia in six distinct corridors in North America. We demonstrate that rail transport will reduce risk, irrespective of the risk measure and the transport corridor, and that every attempt must be made to use railroads to transport these shipments. PMID- 23682993 TI - Nox family NADPH oxidases in mechano-transduction: mechanisms and consequences. AB - SIGNIFICANCE: The majority of cells in a multi-cellular organism are continuously exposed to ever-changing physical forces. Mechano-transduction links these events to appropriate reactions of the cells involving stimulation of signaling cascades, reorganization of the cytoskeleton and alteration of gene expression. RECENT ADVANCES: Mechano-transduction alters the cellular redox balance and the formation of reactive oxygen species (ROS). Nicotine amide adenine dinucleotide reduced form (NADPH) oxidases of the Nox family are prominent ROS generators and thus, contribute to this stress-induced ROS formation. CRITICAL ISSUES: Different types and patterns of mechano-stress lead to Nox-dependent ROS formation and Nox mediated ROS formation contributes to cellular responses and adaptation to physical forces. Thereby, Nox enzymes can mediate vascular protection during physiological mechano-stress. Despite this, over-activation and induction of Nox enzymes and a subsequent substantial increase in ROS formation also promotes oxidative stress in pathological situations like disturbed blood flow or extensive stretch. FUTURE DIRECTIONS: Individual protein targets of Nox-mediated redox-signaling will be identified to better understand the specificity of Nox dependent ROS signaling in mechano-transduction. Nox-inhibitors will be tested to reduce cellular activation in response to mechano-stimuli. PMID- 23682997 TI - Friendship network position and salivary cortisol levels. AB - We employed a social network analysis approach to examine the associations between friendship network position and cortisol levels. The sample consisted of 74 first-year students (93% female, ages 22-38 years, M = 27) from a highly competitive, accelerated Nursing program. Participants completed questionnaires online, and the entire group met at one time to complete a series of sociometric nominations and donated a saliva sample. Saliva was later assayed for cortisol. Metrics derived from directed friendship nominations indexed each student's friendship network status regarding popularity, gregariousness, and degree of interconnectedness. Results revealed that (1) individuals with lower gregariousness status (i.e., lowest number of outgoing ties) had higher cortisol levels, and (2) individuals with higher popularity status (i.e., higher numbers of incoming ties) had higher cortisol levels. Popularity and gregariousness-based network status is significantly associated with hypothalamic-pituitary-adrenal axis activity. Implications for prevailing theories of the social determinants of individual differences in biological sensitivity and susceptibility to context are discussed. PMID- 23682999 TI - Diagnostic model of saliva peptide finger print analysis of primary Sjogren's syndrome patients by using weak cation exchange magnetic beads. AB - Saliva diagnostics has become an attractive field utilizing nanotechnology and molecular technologies for pSS (primary Sjogren's syndrome). However, no specific methods have been established. To refine the diagnostic power of the saliva peptide finger print for the early detection of pSS, we screened the expression spectrum of salivary peptides in pSS patients by using mass spectrometry MALDI TOF-MS (matrix-assisted laser-desorption ionization-time-of-flight MS) combined with magnetic bead. The present study was comprised 12 pSS patients and 13 healthy controls and broken down to two different phases. In the initial 'exploratory phase', we enrolled seven pSS patients with eight age- and sex matched healthy volunteers. Proteomics analysis of the unstimulated salivary samples was conducted to generate proportional peptide mass fingerprints. A diagnostic model was established. The testing cohort of the second 'validation phase' was represented by five pSS patients and five age- and sex-matched healthy controls. The diagnostic power of this diagnostic panel was then validated. The results showed seven m/z (mass-to-charge) ratio peaks with significant differences. Five peptides were up-regulated and two down-regulated in the pSS patients compared with matched healthy subjects. In the validation phase, four out of five pSS patients were diagnosed as pSS, and four of the five healthy controls were diagnosed as healthy controls, respectively. Potential biomarkers were also primarily predicted. The novel diagnostic proteomic model with m/z peaks 1068.1 Da, 1196.2 Da, 1738.4 Da, 3375.3 Da, 3429.3 Da, 3449.7 Da and 3490.6 Da is of certain value for early diagnosis of pSS. PMID- 23682998 TI - Cortical-striatal gene expression in neonatal hippocampal lesion (NVHL)-amplified cocaine sensitization. AB - Cortical-striatal circuit dysfunction in mental illness may enhance addiction vulnerability. Neonatal ventral hippocampal lesions (NVHL) model this dual diagnosis causality by producing a schizophrenia syndrome with enhanced responsiveness to addictive drugs. Rat genome-wide microarrays containing >24 000 probesets were used to examine separate and co-occurring effects of NVHLs and cocaine sensitization (15 mg/kg/day * 5 days) on gene expression within medial prefrontal cortex (MPFC), nucleus accumbens (NAC), and caudate-putamen (CAPU). Two weeks after NVHLs robustly amplified cocaine behavioral sensitization, brains were harvested for genes of interest defined as those altered at P < 0.001 by NVHL or cocaine effects or interactions. Among 135 genes so impacted, NVHLs altered twofold more than cocaine, with half of all changes in the NAC. Although no genes were changed in the same direction by both NVHL and cocaine history, the anatomy and directionality of significant changes suggested synergy on the neural circuit level generative of compounded behavioral phenotypes: NVHL predominantly downregulated expression in MPFC and NAC while NVHL and cocaine history mostly upregulated CAPU expression. From 75 named genes altered by NVHL or cocaine, 27 had expression levels that correlated significantly with degree of behavioral sensitization, including 11 downregulated by NVHL in MPFC/NAC, and 10 upregulated by NVHL or cocaine in CAPU. These findings suggest that structural and functional impoverishment of prefrontal-cortical-accumbens circuits in mental illness is associated with abnormal striatal plasticity compounding with that in addictive disease. Polygenetic interactions impacting neuronal signaling and morphology within these networks likely contribute to addiction vulnerability in mental illness. PMID- 23683000 TI - Behavior of aluminum, arsenic, and vanadium during the neutralization of red mud leachate by HCl, gypsum, or seawater. AB - Red mud leachate (pH 13) collected from Ajka, Hungary is neutralized to < pH 10 by HCl, gypsum, or seawater addition. During acid neutralization >99% Al is removed from solution during the formation of an amorphous boehmite-like precipitate and dawsonite. Minor amounts of As (24%) are also removed from solution via surface adsorption of As onto the Al oxyhydroxides. Gypsum addition to red mud leachate results in the precipitation of calcite, both in experiments and in field samples recovered from rivers treated with gypsum after the October 2010 red mud spill. Calcite precipitation results in 86% Al and 81% As removal from solution, and both are nonexchangeable with 0.1 mol L(-1) phosphate solution. Contrary to As associated with neoformed Al oxyhydroxides, EXAFS analysis of the calcite precipitates revealed only isolated arsenate tetrahedra with no evidence for surface adsorption or incorporation into the calcite structure, possibly as a result of very rapid As scavenging by the calcite precipitate. Seawater neutralization also resulted in carbonate precipitation, with >99% Al and 74% As removed from solution during the formation of a poorly ordered hydrotalcite phase and via surface adsorption to the neoformed precipitates, respectively. Half the bound As could be remobilized by phosphate addition, indicating that As was weakly bound, possibly in the hydrotalcite interlayer. Only 5-16% V was removed from solution during neutralization, demonstrating a lack of interaction with any of the neoformed precipitates. High V concentrations are therefore likely to be an intractable problem during the treatment of red mud leachates. PMID- 23683001 TI - Assessment of the environmental microbiological cross contamination following hand drying with paper hand towels or an air blade dryer. AB - AIMS: This study compared the potential for cross contamination of the surrounding environment resulting from two different hand-drying methods: paper towels and the use of an air blade dryer. METHODS AND RESULTS: One hundred volunteers for each method washed their hands and dried them using one of the two methods. Bacterial contamination of the surrounding environment was measured using settle plates placed on the floor in a grid pattern, air sampling and surface swabs. Both drying methods produced ballistic droplets in the immediate vicinity of the hand-drying process. The air blade dryer produced a larger number of droplets which were dispersed over a larger area. Settle plates showed increased microbial contamination in the grid squares which were affected by ballistic droplets. Using the settle plates counts, it was estimated that approx. 1.7 * 10(5) cfu more micro-organisms were left on the laboratory floor (total area approx. 17.15 m(2)) after 100 volunteers used an air blade dryer compared to when paper towels were used. CONCLUSIONS: The two drying methods led to different patterns of ballistic droplets and levels of microbial contamination under heavy use conditions. Whilst the increase in microbial levels in the environment is not significant if only nonpathogenic micro-organisms are spread, it may increase the risk of pathogen contamination of the environment when pathogens are occasionally present on people's hands. SIGNIFICANCE AND IMPACT OF THE STUDY: The study suggests that the risk of cross contamination from the washroom users to the environment and subsequent users should be considered when choosing a hand-drying method. The data could potentially give guidance following the selection of drying methods on implementing measures to minimise the risk of cross contamination. PMID- 23683002 TI - Impact of diabetes duration on hypoglycaemia in patients with type 2 diabetes treated with insulin glargine or NPH insulin. AB - AIM: To compare the impact of diabetes duration on hypoglycaemia in patients with type 2 diabetes mellitus (T2DM) treated with insulin glargine or NPH insulin. METHODS: A pooled analysis of 24-week patient level data from randomized controlled studies comparing once-daily insulin glargine with once-daily NPH insulin in insulin-naive adult patients with T2DM was performed, stratifying patients into quartiles by duration of diabetes: <5.8 years; 5.8 to <9.2 years; 9.2 to <14 years and >=14 years. Daytime and nocturnal hypoglycaemia events were evaluated. RESULTS: Data from 2330 patients in four randomized controlled trials were included in the analysis; 1258 treated with insulin glargine and 1072 with NPH insulin. The rates of daytime hypoglycaemia were similar for insulin glargine and NPH insulin, irrespective of disease duration. Patients with longer T2DM duration treated with glargine experienced greater glycated haemoglobin A1c (HbA1c) reductions. Rates of severe nocturnal hypoglycaemia and nocturnal hypoglycaemia [self-monitored blood glucose < 70 mg/dl (3.89 mmol/l) and < 50 mg/dl (2.78 mmol/l)] were all significantly and positively correlated with the duration of diabetes for patients treated with NPH insulin but not with insulin glargine. Despite improvements in HbA1c, rates of symptomatic nocturnal hypoglycaemia were significantly lower with insulin glargine than with NPH insulin in patients with longer T2DM duration. CONCLUSION: There is a lower risk for nocturnal hypoglycaemia with insulin glargine than with NPH insulin. When considering diabetes duration, insulin glargine (compared to NPH insulin) may be particularly beneficial in patients with a longer duration of T2DM. PMID- 23683004 TI - Broadening the early intervention paradigm: a one stop shop for youth. AB - AIM: Despite recognition of the early onset and disease burden of mental and substance use disorders in young people, poor access to services persists. A new youth outreach clinic, with principles consistent with the early intervention paradigm and intake criteria not linked to presumptive diagnostic status, was set up within an existing youth hub. The service development and early service delivery are described. METHODS: The particulars of the clinic, including location, service recipients and service delivery structure, were conceptualized and implemented. A service model based on secondary and primary consultations and up to six sessions of treatment was adopted to maximize the number of referrers and clients the clinic could service. RESULTS: Twenty referrals were received by the clinic in the first 2 months. The clients' ages ranged from 14 to 21 with just less than half under 18 years of age. Clients had complex mixes of symptomatology that fulfilled multiple diagnoses. CONCLUSIONS: The described model of service delivery can help improve accessibility, fulfil gaps in current youth mental health delivery, and build the capacity of non-tertiary level services. This is consistent with the early intervention paradigm. PMID- 23683003 TI - Tryptophan cluster protects human gammaD-crystallin from ultraviolet radiation induced photoaggregation in vitro. AB - Exposure to ultraviolet radiation (UVR) is a significant risk factor for age related cataract, a disease of the human lens and the most prevalent cause of blindness in the world. Cataract pathology involves protein misfolding and aggregation of the primary proteins of the lens, the crystallins. Human gammaD crystallin (HgammaD-Crys) is a major gamma-crystallin in the nucleus of the human lens. We report here analysis of UVR-induced damage to HgammaD-Crys in vitro. Irradiation of solutions of recombinant HgammaD-Crys with UVA/UVB light produced a rise in solution turbidity due to polymerization of the monomeric crystallins into higher molecular weight aggregates. A significant fraction of this polymerized protein was covalently linked. Photoaggregation of HgammaD-Crys required oxygen and its rate was protein concentration and UVR dose dependent. To investigate the potential roles of individual tryptophan residues in photoaggregation, triple W:F mutants of HgammaD-Crys were irradiated. Surprisingly, despite reducing UVR absorbing capacity, multiple W:F HgammaD-Crys mutant proteins photoaggregated more quickly and extensively than wild type. The results reported here are consistent with previous studies that postulated that an energy transfer mechanism between the highly conserved pairs of tryptophan residues in HgammaD-Crys could be protective against UVR-induced photodamage. PMID- 23683006 TI - Teacher, researcher, and inventor. Dr. Heinrich J. Detmers, 1833-1906. PMID- 23683007 TI - Veterinarian-client communication. PMID- 23683008 TI - Introducing the concept of veterinary family practice. PMID- 23683009 TI - What is your diagnosis? Ischemia of the spleen. PMID- 23683010 TI - What is your diagnosis? Foreign body. PMID- 23683011 TI - Animal behavior case of the month. Urine marking. PMID- 23683012 TI - Pathology in practice. Marek's disease. PMID- 23683013 TI - Evaluation of recipes of home-prepared maintenance diets for dogs. PMID- 23683014 TI - Executive summary of the 2013 U.S. Veterinary Workforce Study. PMID- 23683015 TI - Implications of the 2013 U.S. Veterinary Workforce Study and recommendations for future actions: AVMA Workforce Advisory Group. PMID- 23683016 TI - Effect of body position on indirect measurement of systolic arterial blood pressure in dogs. AB - OBJECTIVE: To determine whether a difference existed in Doppler ultrasonographic measurements of systolic arterial blood pressure (SAP) in sitting versus laterally recumbent dogs and to determine the degree of variability in measurements made in each position. DESIGN: Diagnostic test evaluation. ANIMALS: 51 healthy or sick adult dogs, without recent sedation or anesthesia and with an SAP <= 300 mm Hg. PROCEDURES: In a crossover design, SAP was measured via Doppler ultrasonography when dogs were sitting (on hind limbs with nonmeasured forelimb bearing weight) and laterally recumbent, with the cuff position at the level of the right atrium for both positions. Seven measurements were obtained per position for each dog. RESULTS: Mean +/- SD SAP was significantly higher in the sitting (172.1 +/- 33.3 mm Hg) versus recumbent (147.0 +/- 24.6 mm Hg) position, and this difference was evident for 44 of 51 (86%) dogs. The mean difference in measured SAP between the 2 positions was 25.1 +/- 28.5 mm Hg. Blood pressure measurements had a significantly higher repeatability in the recumbent position than in the sitting position. CONCLUSIONS AND CLINICAL RELEVANCE: Blood pressure measurements in dogs were significantly affected by body position, and they were higher for most dogs when sitting rather than laterally recumbent. Blood pressure measurements in the laterally recumbent body position were less variable than in the sitting position. PMID- 23683017 TI - Associations among exercise duration, lameness severity, and hip joint range of motion in Labrador Retrievers with hip dysplasia. AB - OBJECTIVE: To evaluate factors associated with lameness severity and hip joint range of motion in dogs with hip dysplasia and to assess the association between hip joint range of motion and degree of lameness. DESIGN: Prospective case series. ANIMALS: 60 client-owned Labrador Retrievers with hip dysplasia. PROCEDURES: Owners completed a questionnaire regarding their dogs' daily exercise duration and type (i.e., low impact vs high impact) and lifestyle. Range of motion of affected hip joints was measured with a transparent plastic goniometer. The presence of subluxation or luxation of hip joints as a consequence of hip dysplasia and the size of the largest osteophytes or enthesophytes of hip joints on ventrodorsal radiographic images of the pelvis were recorded. Multivariate analyses were performed to identify factors associated with lameness, loss of hip joint flexion, and loss of hip joint extension and to identify factors associated with the presence of large osteophytes. RESULTS: Exercise was associated with a decrease in the severity of lameness in dogs with hip dysplasia. The strength of this inverse relationship increased with longer exercise duration. Lameness was more severe in dogs with hip joint luxation than in dogs without luxation. Hip joint extension was 1 degrees lower for each year of age, and osteophyte or enthesophyte size was 1 mm larger with each 3-year increase in age. CONCLUSIONS AND CLINICAL RELEVANCE: Longer daily exercise duration was associated with lower lameness scores in dogs with hip dysplasia. Dogs with hip joint luxation secondary to hip dysplasia had higher lameness scores than did dogs without hip joint luxation. PMID- 23683018 TI - Metronomic administration of chlorambucil for treatment of dogs with urinary bladder transitional cell carcinoma. AB - OBJECTIVE: To determine the antitumor effects and toxicoses of metronomic oral administration of a low dose of chlorambucil in dogs with transitional cell carcinoma (TCC). DESIGN: Prospective clinical trial. ANIMALS: 31 client-owned dogs with TCC for which prior treatments had failed or owners had declined other treatments. Procedures-Chlorambucil (4 mg/m2, PO, q 24 h) was administered to dogs. Before and at scheduled times during treatment, evaluations of dogs included physical examination, CBC, serum biochemical analyses, urinalysis, thoracic and abdominal imaging including cystosonography for measurement of TCCs, and grading of toxicoses. RESULTS: 29 of 31 dogs had failed prior TCC treatment. Of the 30 dogs with available data, 1 (3%) had partial remission (>= 50% reduction in tumor volume), 20 (67%) had stable disease (< 50% change in tumor volume), and 9 (30%) had progressive disease (>= 50% increase in tumor volume or development of additional tumors); 1 dog was lost to follow-up. The median progression-free interval (time from the start of chlorambucil treatment to the day progressive disease was detected) for the dogs was 119 days (range, 7 to 728 days). The median survival time of dogs from the time of the start of chlorambucil treatment was 221 days (range, 7 to 747 days). Few toxicoses were detected; chlorambucil administration was discontinued because of toxicoses in only 1 dog. CONCLUSIONS AND CLINICAL RELEVANCE: Metronomic administration of chlorambucil was well tolerated, and 70% of dogs had partial remission or stable disease. Metronomic administration of chlorambucil may be a treatment option for dogs with TCC. PMID- 23683019 TI - Comparison of automated versus manual neutrophil counts for the detection of cellular abnormalities in dogs receiving chemotherapy: 50 cases (May to June 2008). AB - OBJECTIVE: To determine the frequency of clinically relevant abnormalities missed by failure to perform a blood smear evaluation in a specific subset of dogs receiving chemotherapy and to compare automated and manual neutrophil counts in the same population. DESIGN: Retrospective case series. ANIMALS: 50 dogs receiving chemotherapy with a total nucleated cell count > 4,000 nucleated cells/MUL. PROCEDURES: 50 blood smears were evaluated for abnormalities that have strong potential to change the medical plan for a patient: presence of blast cells, band neutrophils, nucleated RBCs, toxic change, hemoparasites, schistocytes, and spherocytes. Automated and manual neutrophil counts were compared. RESULTS: Blood smears from 10 (20%) patients had >= 1 abnormalities. Blast cells were identified on 4 (8%) blood smears, increased nucleated RBCs were identified on 5 (10%), and very mild toxic change was identified on 2 (4%). Correlation coefficient of the neutrophil counts was 0.96. Analysis revealed a slight bias between the automated and manual neutrophil counts (mean +/- SD difference, -0.43 * 10(3)/MUL +/- 1.10 * 10(3)/MUL). CONCLUSIONS AND CLINICAL RELEVANCE: In this series of patients, neutrophil count correlation was very good. Clinically relevant abnormalities were found on 20% of the blood smears. An automated CBC appears to be accurate for neutrophil counts, but a microscopic examination of the corresponding blood smear is still recommended; further studies are needed to determine whether the detection or frequency of these abnormalities would differ dependent on chemotherapy protocol, neoplastic disease, and decision thresholds used by the oncologist in the ordering of a CBC without a blood smear evaluation. PMID- 23683020 TI - Evaluation of risk factors for development of corneal ulcer after nonocular surgery in dogs: 14 cases (2009-2011). AB - OBJECTIVE: To evaluate the prevalence of and risk factors for development of corneal ulcers after nonocular surgery performed with general anesthesia in dogs. DESIGN: Retrospective case-control study. ANIMALS: 14 dogs with development of corneal ulcers after nonocular surgery and 718 control dogs. PROCEDURES: Medical records of dogs evaluated at the Veterinary Medical Teaching Hospital of Seoul National University from January 2009 to June 2011 were reviewed for assessment of risk factors for development of corneal ulcers. RESULTS: Among the 732 reviewed cases, 14 (1.9%) dogs of 6 breeds developed a corneal ulcer after nonocular surgery. Duration of anesthesia was significantly longer in dogs with ulcers than dogs without ulcers. The number of medications received and procedures performed were also significantly higher in dogs with ulcers than dogs without ulcers. Dogs with a small skull (OR, 8.59; 95% confidence interval [CI], 1.04 to 70.90) and dogs that received neurosurgery (OR, 21.12; 95% CI, 5.77 to 77.25) were more susceptible to development of corneal ulcers. Also, postoperative application of a fentanyl patch was a risk factor for development of corneal ulcers (OR, 4.53; 95% CI, 1.05 to 19.60). CONCLUSIONS AND CLINICAL RELEVANCE: Several risk factors were identified for development of corneal ulcers after nonocular surgery was performed with general anesthesia in dogs. Perioperative eye protection strategies and postoperative ophthalmic examination are needed to reduce the occurrence of corneal ulcers and their progression, especially for high-risk dogs and procedures. PMID- 23683021 TI - Prevalence of inherited disorders among mixed-breed and purebred dogs: 27,254 cases (1995-2010). AB - OBJECTIVE: To determine the proportion of mixed-breed and purebred dogs with common genetic disorders. DESIGN: Case-control study. ANIMALS: 27,254 dogs with an inherited disorder. PROCEDURES: Electronic medical records were reviewed for 24 genetic disorders: hemangiosarcoma, lymphoma, mast cell tumor, osteosarcoma, aortic stenosis, dilated cardiomyopathy, hypertrophic cardiomyopathy, mitral valve dysplasia, patent ductus arteriosus, ventricular septal defect, hyperadrenocorticism, hypoadrenocorticism, hypothyroidism, elbow dysplasia, hip dysplasia, intervertebral disk disease, patellar luxation, ruptured cranial cruciate ligament, atopy or allergic dermatitis, bloat, cataracts, epilepsy, lens luxation, and portosystemic shunt. For each disorder, healthy controls matched for age, body weight, and sex to each affected dog were identified. RESULTS: Genetic disorders differed in expression. No differences in expression of 13 genetic disorders were detected between purebred dogs and mixed-breed dogs (ie, hip dysplasia, hypo- and hyperadrenocorticism, cancers, lens luxation, and patellar luxation). Purebred dogs were more likely to have 10 genetic disorders, including dilated cardiomyopathy, elbow dysplasia, cataracts, and hypothyroidism. Mixed-breed dogs had a greater probability of ruptured cranial cruciate ligament. CONCLUSIONS AND CLINICAL RELEVANCE: Prevalence of genetic disorders in both populations was related to the specific disorder. Recently derived breeds or those from similar lineages appeared to be more susceptible to certain disorders that affect all closely related purebred dogs, whereas disorders with equal prevalence in the 2 populations suggested that those disorders represented more ancient mutations that are widely spread through the dog population. Results provided insight on how breeding practices may reduce prevalence of a disorder. PMID- 23683022 TI - Endoscopic-guided sclerotherapy for renal-sparing treatment of idiopathic renal hematuria in dogs: 6 cases (2010-2012). AB - OBJECTIVE: To describe the use of sclerotherapy for the renal-sparing treatment of idiopathic renal hematuria (IRH) in dogs and report clinical outcomes. DESIGN: Retrospective case series. ANIMALS: 6 dogs (8 renal pelvises) with IRH. PROCEDURES: Medical records of dogs that underwent sclerotherapy were reviewed. Each ureterovesicular junction was identified cystoscopically to determine the side of bleeding, and a retrograde ureteropyelogram was performed with endoscopic and fluoroscopic guidance. A ureteropelvic junction balloon was used for ureteral occlusion, and pelvis filling volumes were recorded. A povidone iodine mixture, followed by a sterile silver nitrate solution, was infused into the renal pelvis. A double-pigtail ureteral stent was placed after the procedure. Information on preprocedure and postprocedure biochemical changes, imaging parameters, and clinical outcomes was obtained. RESULTS: 6 dogs (5 males and 1 female) had sclerotherapy for unilateral (4) or bilateral (2) bleeding. Five were right-sided and 3 were left-sided. The median age and weight of dogs were 3 years and 42.4 kg (93.28 lb), respectively. Median procedure time was 150 minutes. One dog that did not have a ureteral stent placed following the procedure developed short-term signs of renal pain and pyelectasis. Cessation of macroscopic hematuria occurred in 4 of 6 dogs (median, 6 hours). Two additional dogs improved moderately. Median follow-up time was 8 months (range, 3.5 to 20.5 months). CONCLUSIONS AND CLINICAL RELEVANCE: Topical sclerotherapy for IRH was safe and effective. Local sclerotherapy for IRH in dogs could be considered a valuable and minimally invasive renal-sparing treatment over ureteronephrectomy. PMID- 23683025 TI - Evaluation of the effects of tricaine methanesulfonate on retinal structure and function in koi carp (Cyprinus carpio). AB - OBJECTIVE: To determine whether repeated exposure to clinically relevant concentrations of tricaine methanesulfonate (MS-222) would alter retinal function or induce histologically detectable retinal lesions in koi carp (Cyprinus carpio). DESIGN: Prospective, controlled, experimental study. ANIMALS: 18 healthy koi carp. PROCEDURES: 2 fish were euthanized at the start of the study, and eyes were submitted for histologic evaluation as untreated controls. Anesthesia was induced in the remaining fish with 200 mg of MS-222/L and maintained with concentrations of 125 to 150 mg/L for a total exposure time of 20 minutes daily on 1 to 13 consecutive days. On days 1, 7, and 13, electroretinography of both eyes was performed in all fish remaining in the study, and 2 fish were euthanized immediately after each procedure for histologic evaluation of the eyes. Median b wave amplitudes were compared among study days for right eyes and for left eyes via 1-way repeated-measures ANOVA with a Bonferroni correction for multiple comparisons. RESULTS: Median b-wave amplitudes on days 1, 7, and 13 were 17.7, 20.9, and 17.6 MUV, respectively, for right eyes and 15.1, 16.9, and 14.3 MUV, respectively, for left eyes. No significant differences in b-wave amplitudes were detected among study days. No histopathologic abnormalities were identified in the retinas of any fish treated with MS-222 or in control fish. CONCLUSIONS AND CLINICAL RELEVANCE: Short-term exposure of koi carp to clinically relevant concentrations of MS-222 daily for up to 13 days was not associated with changes in retinal structure or function as measured in this study. PMID- 23683023 TI - Effect of a monovalent vaccine against Leptospira borgpetersenii serovar Hardjo strain hardjobovis on fertility in Holstein dairy cattle. AB - OBJECTIVE: To determine whether vaccination with a monovalent vaccine against Leptospira borgpetersenii serovar Hardjo strain hardjobovis would improve reproductive efficiency in Holstein cattle in a commercial dairy setting. DESIGN: Randomized controlled trial. ANIMALS: 1,894 Holstein cows and heifers from a Central California dairy. PROCEDURES: Cattle were assigned to undergo SC administration of a monovalent vaccine against Leptospira borgpetersenii serovar Hardjo strain hardjobovis (n = 986) or a placebo (lactated Ringer's solution; 908). At the end of their lactation period, cows received 2 doses of the vaccine or placebo, 28 to 35 days apart, with the initial dose administered in conjunction with oxytetracycline. Heifers received the same treatments, with the second dose administered at least 2 weeks before their entrance into the heifer breeding pen. Urine and blood samples were collected from randomly selected cattle immediately before and 1 year after the trial began and submitted for fluorescent antibody and microscopic agglutination testing to identify any infecting Leptospira serovar. RESULTS: The initial herd prevalence of active infection with strain hardjobovis was 13% (6/46 tested cattle), followed by 15% (6/40) 1 year after the trial began. The odds of heifers conceiving over the period at risk for conception, regardless of vaccination, was approximately 2.8 times as high as for primiparous and pluriparous cows. Survival analysis of days from parturition to conception revealed that the vaccine protocol had no effect on the probability of conception between the vaccinated and control groups. The vaccine protocol had no impact on pregnancy loss. CONCLUSIONS AND CLINICAL RELEVANCE: The evaluated vaccination protocol against Leptospira strain hardjobovis was not effective in improving reproductive efficiency in commercial Holstein dairy cows or in decreasing urine shedding of leptospires. PMID- 23683024 TI - Immunity in heifers 12 months after vaccination with a multivalent vaccine containing a United States Leptospira borgpetersenii serovar Hardjo isolate. AB - OBJECTIVE: To evaluate immunity induced by a multivalent vaccine containing a US Leptospira borgpetersenii serovar Hardjo type hardjo bovis (LHB) isolate in heifers challenged 12 months after vaccination. DESIGN: Prospective vaccine challenge study. ANIMALS: 36 one-month old Holstein heifers. PROCEDURES: 18 heifers were vaccinated at 4 and 8 weeks of age with an inactivated vaccine containing Leptospira fractions. Additionally, 18 heifers were vaccinated at the same age with the same vaccine without any Leptospira fractions. All heifers were challenged with a US-origin LHB 12 months following booster vaccination. Urine samples were collected weekly for 8 weeks after challenge, and serum was collected at -1, 28, and 56 days after challenge for serologic testing. At 8 weeks after challenge, all heifers were necropsied, and kidney and reproductive system samples were collected for bacteriologic culture. RESULTS: 4 of 18 vaccinates had positive results of bacteriologic culture of urine samples, but only at 1 time point. All control heifers had positive results of bacteriologic culture of urine samples for at least 5 time points. Vaccinates had negative results of bacteriologic culture of kidney and reproductive system samples following necropsy, whereas all control heifers had positive results of bacteriologic culture of kidney samples and 5 of 18 had positive results of bacteriologic culture of reproductive system samples. CONCLUSIONS AND CLINICAL RELEVANCE: The vaccine administered to calves at 1 month of age prevented leptospire colonization of kidney and reproductive system tissue and significantly reduced urine shedding following challenge 12 months after vaccination. This vaccine provides an opportunity to protect calves at an early age from becoming infected and ultimately from becoming an LHB reservoir. PMID- 23683026 TI - Fall from a balcony--accidental or homicidal? Reconstruction by numerical simulation. AB - In the case presented, conflicting witness accounts and the subject's injuries were highly suspicious of an assault that might have caused the balcony fall. For the reconstruction, a simulation software, originally designed for motor vehicle accident reconstruction, was used. Three scenarios were simulated using the PC Crash multibody pedestrian model: (S1) Subject was pushed against and fell over balcony rail, (S2) subject fell off from a seated position, (S3) subject fell off from a prone position on the rail. (S1) could be ruled out due to inconsistent results in terms of landing area and minimum velocity. Realistic results were obtained for (S3) with a fall off from a prone position on the rail. After a few months, the comatose subject awoke and gave an account of what had happened being consistent with the simulation results. This case demonstrates the feasibility of multibody simulations also in cases of nontraffic incidents. PMID- 23683027 TI - Editorial comment for Kose et al. PMID- 23683029 TI - Vision and night driving abilities of elderly drivers. AB - OBJECTIVE: In this article, we review the impact of vision on older people's night driving abilities. Driving is the preferred and primary mode of transport for older people. It is a complex activity where intact vision is seminal for road safety. Night driving requires mesopic rather than scotopic vision, because there is always some light available when driving at night. Scotopic refers to night vision, photopic refers to vision under well-lit conditions, and mesopic vision is a combination of photopic and scotopic vision in low but not quite dark lighting situations. With increasing age, mesopic vision decreases and glare sensitivity increases, even in the absence of ocular diseases. Because of the increasing number of elderly drivers, more drivers are affected by night vision difficulties. Vision tests, which accurately predict night driving ability, are therefore of great interest. METHODS: We reviewed existing literature on age related influences on vision and vision tests that correlate or predict night driving ability. RESULTS: We identified several studies that investigated the relationship between vision tests and night driving. These studies found correlations between impaired mesopic vision or increased glare sensitivity and impaired night driving, but no correlation was found among other tests; for example, useful field of view or visual field. The correlation between photopic visual acuity, the most commonly used test when assessing elderly drivers, and night driving ability has not yet been fully clarified. CONCLUSIONS: Photopic visual acuity alone is not a good predictor of night driving ability. Mesopic visual acuity and glare sensitivity seem relevant for night driving. Due to the small number of studies evaluating predictors for night driving ability, further research is needed. PMID- 23683028 TI - Bioinspired fabrication of hierarchically structured, pH-tunable photonic crystals with unique transition. AB - We herein report a new class of photonic crystals with hierarchical structures, which are of color tunability over pH. The materials were fabricated through the deposition of polymethylacrylic acid (PMAA) onto a Morpho butterfly wing template by using a surface bonding and polymerization route. The amine groups of chitosan in Morpho butterfly wings provide reaction sites for the MAA monomer, resulting in hydrogen bonding between the template and MAA. Subsequent polymerization results in PMAA layers coating homogenously on the hierarchical photonic structures of the biotemplate. The pH-induced color change was detected by reflectance spectra as well as optical observation. A distinct U transition with pH was observed, demonstrating PMAA content-dependent properties. The appearance of the unique U transition results from electrostatic interaction between the NH3(+) of chitosan and the -COO(-) groups of PMAA formed, leading to a special blue-shifted point at the pH value of the U transition, and the ionization of the two functional groups in the alkali and acid environment separately, resulting in a red shift. This work sets up a strategy for the design and fabrication of tunable photonic crystals with hierarchical structures, which provides a route for combining functional polymers with biotemplates for wide potential use in many fields. PMID- 23683030 TI - Could a patient with SMC1A duplication be classified as a human cohesinopathy? AB - The disorders caused by mutations in genes encoding subunits and accessory proteins of cohesin complex are collectively termed as cohesinopathies. The best known cohesinopathy is Cornelia de Lange Syndrome (CdLS), which is a multisystem developmental disorder characterized by facial dysmorphism, limb malformations, growth and cognitive impairment. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), are responsible for ~ 70% of CdLS cases. We describe a 16-year-old boy with facial dysmorphism, growth retardation, intellectual disability, hirsutism and small hands, who has a small Supernumerary Marker Chromosome (sSMC) present in mosaic form. sSMC is composed of two duplicated segments encompassing 17 genes including SMC1A gene, at the regions Xp11.22 and Xp11.21q11.1. Clinical comparison between our patient with a previously reported individual with a SMC1A duplication and four male carriers of similar sSMC reported in databases, suggest that they all share clinical features related to cohesinopathies. Although our patient does not have the classical CdLS craniofacial phenotype, he has pre and postnatal growth retardation, intellectual disability and mild musculoskeletal anomalies, features commonly seen in patients with cohesinopathies. PMID- 23683033 TI - Impact of ozonation on naphthenic acids speciation and toxicity of oil sands process-affected water to Vibrio fischeri and mammalian immune system. AB - Oil sands process-affected water (OSPW) is the water contained in tailings impoundment structures in oil sands operations. There are concerns about the environmental impacts of the release of OSPW because of its toxicity. In this study, ozonation followed by biodegradation was used to remediate OSPW. The impacts of the ozone process evolution on the naphthenic acids (NAs) speciation and acute toxicity were evaluated. Ion-mobility spectrometry (IMS) was used to preliminarily separate isomeric and homologous species. The results showed limited effects of the ozone reactor size on the treatment performance in terms of contaminant removal. In terms of NAs speciation, high reactivity of NAs with higher number of carbons and rings was only observed in a region of high reactivity (i.e., utilized ozone dose lower than 50 mg/L). It was also found that nearly 0.5 mg/L total NAs was oxidized per mg/L of utilized ozone dose, at utilized ozone doses lower than 50 mg/L. IMS showed that ozonation was able to degrade NAs, oxidized NAs, and sulfur/nitrogenated NAs. Complete removal of toxicity toward Vibrio fischeri was achieved after ozonation followed by 28-day biodegradation period. In vitro and in vivo assays indicated that ozonation reduced the OSPW toxicity to mice. PMID- 23683032 TI - Molecular insights from dysregulation of the thiazide-sensitive WNK/SPAK/NCC pathway in the kidney: Gordon syndrome and thiazide-induced hyponatraemia. AB - Human blood pressure is dependent on balancing dietary salt intake with its excretion by the kidney. Mendelian syndromes of altered blood pressure demonstrate the importance of the distal nephron in this process and of the thiazide-sensitive pathway in particular. Gordon syndrome (GS), the phenotypic inverse of the salt-wasting Gitelman syndrome, is a condition of hyperkalaemic hypertension that is reversed by low-dose thiazide diuretics or a low-salt diet. Variants within at least four genes [i.e. with-no-lysine(K) kinase 1 (WNK1), WNK4, kelch-like family member 3 (KLHL3) and cullin 3 (CUL3)] can cause the phenotype of GS. Details are still emerging for some of these genes, but it is likely that they all cause a gain-of-function in the thiazide-sensitive Na(+) Cl(-) cotransporter (NCC) and hence salt retention. Herein, we discuss the key role of STE20/sporulation-specific protein 1 (SPS1)-related proline/alanine-rich kinase (SPAK), which functions as an intermediary between the WNKs and NCC and for which a loss-of-function mutation produces a Gitelman-type phenotype in a mouse model. In addition to Mendelian blood pressure syndromes, the study of patients who develop thiazide-induced-hyponatraemia (TIH) may give further molecular insights into the role of the thiazide-sensitive pathway for salt reabsorption. In the present paper we discuss the key features of TIH, including its high degree of reproducibility on rechallenge, possible genetic predisposition and mechanisms involving excessive saliuresis and water retention. Together, studies of Gordon syndrome and TIH may increase our understanding of the molecular regulation of sodium trafficking via the thiazide-sensitive pathway and have important implications for hypertensive patients, both in the identification of new antihypertensive drug targets and avoidance of hyponatraemic side-effects. PMID- 23683034 TI - An unusual object in the root canal of a primary tooth - a case report. AB - BACKGROUND: Children often have the habit of inserting objects into their mouth. Occasionally, these objects may be accidentally ingested. This may be frightening and stressful both for the child and the parents. In most cases, children avoid informing their parents due to the fear of being punished. CASE REPORT: This article presents a case of a foreign object embedded in the tooth of a 7-year-old boy. The parents were unaware of the presence of a foreign object in their child's tooth. CONCLUSION: The tooth was extracted and the foreign body was retrieved from the canal to avoid any complications. PMID- 23683031 TI - Bilirubin attenuates the renal tubular injury by inhibition of oxidative stress and apoptosis. AB - BACKGROUND: Bilirubin (BIL) has been recognized as an endogenous antioxidant that shows a protective effect for cardiorenal diseases. We investigated whether administration of BIL had a protective effect on cyclosporine (CsA)-induced nephropathy (CIN), and examined the effects of BIL on the oxidative stress and apoptosis. METHODS: BIL was pretreated intraperitoneally three times for a week (60 mg/kg), and CsA was injected for 4 weeks (15 mg/kg/day, subcutaneous). Proximal tubular epithelial (HK2) cells were pretreated with 0.1mg/ml of BIL for 24 hours, and then treated with 20 MUM of CsA for another 24 hours. RESULTS: CsA induced marked increases in urine kidney injury molecule-1 (Kim-1) and neutrophil gelatinase-associated lipocalin (NGAL) concentrations (P < 0.05). BIL reduced urine Kim-1 in CIN (P < 0.05), while urine NGAL exhibited a decreasing tendency. In CsA-treated rat kidneys, the protein expression of NOX4 and p22phox was reduced by BIL (P < 0.05). BIL ameliorated CsA-induced arteriolopathy, tubulointerstitial fibrosis, tubular injury, and the apoptosis examined by TUNEL assay (P < 0.01). In HK2 cells, BIL reduced intracellular reactive oxygen species in CsA-treated cells. CsA increased the protein expression of bax, cleaved caspase-9, caspase-3 and the activity of caspase-3; however, the anti-apoptotic bcl-2 protein was reduced. These changes were recovered by BIL (P < 0.05). CONCLUSIONS: The direct administration of BIL protected against CsA-induced tubular injury via inhibition of oxidative stress and apoptosis. PMID- 23683035 TI - Development of the Knee Numeric-Entity Evaluation Score (KNEES-ACL): a condition specific questionnaire. AB - Patient-related outcome measures (PROMs) are commonly used to gauge treatment effects in patients with anterior cruciate ligament (ACL) deficiency. Valid measures of specific conditions depend on relevant item content. While item content can be derived either from clinicians (face validity) or from patients, item relevance and comprehensiveness can only be confirmed by the patient (content validity). Focus group and single interviews were conducted with patients' pre- and post-ACL reconstruction in order to construct a condition specific PROM for the target patients. One hundred fifty-seven items from a previously conducted literature search were used as a basis for content genesis. Content saturation was achieved after three focus groups and seven single interviews. Thirty-eight items from the literature search were directly endorsed, and five modified items were endorsed. Twelve new item themes with verbatim content emerged. Thus, a 55-item pilot PROM consisting of six conceptual domains was assembled. We have constructed a condition-specific PROM for measurement of surgical and non-surgical treatment effects on ACL deficiency. The instrument possesses face and content validity. A pilot survey to assess the psychometric properties will be performed using Rasch measurement theory. PMID- 23683038 TI - Biodegradable shape memory nanocomposites with thermal and magnetic field responsiveness. AB - Thermal and magnetic field responsive biodegradable shape memory polymer nanocomposite was prepared with Fe3O4 nanoparticles and poly(L-lactides) (PLLA). The magnetic Fe3O4 nanoparticles with an average size of 9 nm were initially synthesized by co-precipitation method and then followed by surface modification using oleic acid. The TEM and SEM results show that the surface modified Fe3O4 nanoparticles can evenly disperse in chloroform and PLLA polymer matrix. The tensile test results show that the addition of Fe3O4 nanoparticles to a PLLA matrix greatly improved the elastic modulus, tensile strength, elongation at break, and the shape memory properties as well. Moreover, the shape recovery process of the nanocomposites driven by an alternating magnetic field was also observed. However, the shape recovery ratio and the recovery speed in an alternating magnetic field are lower than that occurred in 70 degrees C water. The lower shape recovery ratio and the recovery speed in an alternating magnetic field is attributed to the low frequency and strength of the magnetic field, which lead to small heat generated by Fe3O4 nanoparticles. PMID- 23683039 TI - Balancing mechanical strength with bioactivity in chitosan-calcium phosphate 3D microsphere scaffolds for bone tissue engineering: air- vs. freeze-drying processes. AB - The objective of this study was to evaluate the potential benefit of 3D composite scaffolds composed of chitosan and calcium phosphate for bone tissue engineering. Additionally, incorporation of mechanically weak lyophilized microspheres within those air-dried (AD) was considered for enhanced bioactivity. AD microsphere, alone, and air- and freeze-dried microsphere (FDAD) 3D scaffolds were evaluated in vitro using a 28-day osteogenic culture model with the Saos-2 cell line. Mechanical testing, quantitative microscopy, and lysozyme-driven enzymatic degradation of the scaffolds were also studied. FDAD scaffold showed a higher concentration (p < 0.01) in cells per scaffold mass vs. AD constructs. Collagen was ~31% greater (p < 0.01) on FDAD compared to AD scaffolds not evident in microscopy of microsphere surfaces. Alternatively, AD scaffolds demonstrated a superior threefold increase in compressive strength over FDAD (12 vs. 4 MPa) with minimal degradation. Inclusion of FD spheres within the FDAD scaffolds allowed increased cellular activity through improved seeding, proliferation, and extracellular matrix production (as collagen), although mechanical strength was sacrificed through introduction of the less stiff, porous FD spheres. PMID- 23683036 TI - pH-responsive hydrogels containing PMMA nanoparticles: an analysis of controlled release of a chemotherapeutic conjugate and transport properties. AB - Biopolymers composed of a pH-responsive, hydrophilic poly(methacrylic acid grafted-ethylene glycol) network polymerized in the presence of poly(methyl methacrylate) nanoparticles were designed for the oral delivery of chemotherapeutics for the treatment of colon cancer. An inulin-doxorubicin conjugate, designed to target the colon and improve doxorubicin efficacy, was loaded into these polymer carriers at an efficiency of 54%. Release studies indicated these polymer carriers minimized conjugate release in low pH conditions and released the conjugate at neutral pH conditions using a two-step pH experiment modeling the stomach and the small intestine. At lower concentration levels, the presence of the polymer carriers did not disrupt tight junctions as determined by transepithelial electrical resistance studies using Caco-2 and HT29 MTX cell lines which are an accurate model of the GI tract epithelia. Permeability values of unmodified doxorubicin and the inulin-doxorubicin conjugate in the presence of the polymer carriers were also determined using the same cell models and ranged from 1.87 to 3.80 * 10 (-6) cm/s. PMID- 23683037 TI - Synthesis of macroporous poly(dimethylsiloxane) scaffolds for tissue engineering applications. AB - Macroporous, biostable scaffolds with controlled porous architecture were prepared from poly(dimethylsiloxane) (PDMS) using sodium chloride particles and a solvent casting and particulate leaching technique. The effect of particulate size range and overall porosity on the resulting structure was evaluated. Results found 90% v/v scaffolds and particulate ranges above 100 MUm to have the most optimal open framework and porosity. Resulting hydrophobic PDMS scaffolds were coated with fibronectin and evaluated as a platform for adherent cell culture using human mesenchymal stem cells. Biocompatibility of PDMS scaffolds was also evaluated in a rodent model, where implants were found to be highly biocompatible and biostable, with positive extracellular matrix deposition throughout the scaffold. These results demonstrate the suitability of macroporous PDMS scaffolds for tissue engineering applications where strong integration with the host is desired. PMID- 23683040 TI - Reduction of inflammatory reaction in the use of purified alginate microcapsules. AB - Alginate, a polysaccharide extracted from brown seaweed, remains the most widely used biomaterial for immobilizing cells to be transplanted, because of the good viability of the encapsulated cells and the relatively ease of processing for cell encapsulation. However, the main drawback is the immune reaction in vivo. To overcome this problem, we have demonstrated a modified Korbutt method for alginate purification. After alginate microcapsules were manufactured, NIH/3T3 fibroblast cells were seeded in purified and non-purified alginate microcapsules, and the cell proliferation was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Reverse transcriptase-polymerase chain reaction was performed to assess the mRNA expression of RAW 264.7 macrophage cells for inflammation cytokines such as TNF-alpha. Purified and non-purified alginate microcapsules were implanted into Wister rats, and subsequently extracted after 1-2 weeks. Tissues surrounding the implants were harvested and underwent histological evaluation through H&E staining and immunohistochemical evaluation through ED-1 staining. In this result, contaminated materials in the purified alginate were eliminated by purification process. Thereby, density of inflammatory cell decreased about 30% more than non-purified alginate and thickness of fibrotic wall decreased about three times. In concluding, the purified alginate is anticipated to be highly potent for numerous biomaterial applications. PMID- 23683041 TI - Characterization of PEG-iron oxide hydrogel nanocomposites for dual hyperthermia and paclitaxel delivery. AB - Hyperthermia, the heating of tissue from 41 to 45 degrees C, has been shown to improve the efficacy of cancer therapy when used in conjunction with irradiation and/or chemotherapy. In this work, hydrogel nanocomposites have been developed that can control the delivery of both heat and a chemotherapeutic agent (e.g. paclitaxel). The nanocomposites studied involve a stealth, poly(ethylene glycol) (PEG)-based system comprised of PEG (n = 1000) methyl ether methacrylate and PEG (n = 400) dimethacrylate with iron oxide nanoparticles physically entrapped within the hydrogel matrices. The capability of the hydrogel nanocomposites to be heated in an alternating magnetic field was demonstrated. The heating of the hydrogel systems was dependent on the crosslinking of the hydrogel network where hydrogels with lower swelling ratios were found to heat to a greater extent than those with higher ratios. In addition, paclitaxel was shown to exhibit non Fickian release from the hydrogel systems, with the amount of drug released dependent on the hydrogel network structure. Three cell lines: M059K (glioblastoma), MDA MB 231 (breast carcinoma), and A549 (lung adenocarcinoma) were exposed to paclitaxel only, hyperthermia only, and both paclitaxel and hyperthermia to determine if a synergistic cytotoxic effect was possible for these cell lines. The efficacy of paclitaxel was greater with hyperthermia for the A549 cells; however, the M059K and MDA MB 231 did not show the same response. PMID- 23683042 TI - Preparation and characterization of OSA/CS core-shell microgel: in vitro drug release and degradation properties. AB - Cationic polymers have been widely used as drug delivery systems. Herein, an oxidized sodium alginate/chitosan (OSA/CS) core-shell microgel was prepared via water-in-oil emulsion method. Morphological properties of the resulting microgel were determined by transmission electron microscopy, hydrodynamic diameter of the microgel was characterized by dynamic light scattering. The objective of this work was to achieve the colon-specific delivery of an antiulcerative colitis drug using a fully nontoxic carrier. 5-aminosalicylic acid (5-ASA) was chosen as a model drug, which is rapidly absorbed before entering the colon, thus it is necessary to develop a colon-specific delivery system for it. The in vitro drug release profile was established in buffer solutions with 0.1 M HCl/NaCl (pH 1.2) and 0.1 M phosphate buffered saline (pH 7.4) at 37 degrees C. The results indicated that this OSA/CS core-shell microgel inhibited the release of 5-ASA in stomach to a certain extent and is degradable in physiological conditions. Due to the excellent biocompatible nature of CS and OSA, this core-shell microgel has good biocompatibility and may have potential applications in oral controlled drug delivery systems. PMID- 23683043 TI - Influence of curing agent on fibrosis around silicone implants. AB - Severe capsular contracture around silicone expander breast implants leading to pain and failure is a major clinical problem. Even though earlier studies have implicated the immunogenicity of silicone, the role of physical and chemical properties of the silicone material in excessive collagen deposition and fibrosis has been less addressed. The present study investigates whether there is any correlation between the type of curing systems i.e. addition and free radical curing and the fibrosis around silicone elastomer. The experiment carried out uses commercially available silicone ventriculo-peritoneal shunt material elastomer cured by platinum and the results are compared with results obtained in a similar study carried out by the authors using commercially available silicone tissue expander material cured by peroxide. Ultra-high molecular weight poly ethylene (UHMWPE), the standard reference for biocompatibility evaluation, was used as the control material. The materials were implanted in rat skeletal muscle for 30 and 90 days. Inflammatory cells, myofibroblasts, cytokines, and collagen deposition at the material-tissue interface were identified by haematoxylin-eosin and Masson's Trichrome stains and semi-quantitated based on immunohistochemical studies. Results indicate that even though the cellular response in the initial phase of wound healing was similar in both platinum and peroxide-cured materials, the collagen deposition in the proliferative phase was more around peroxide-cured material in comparison to the platinum-cured silicone elastomer. There is a need to look into the molecular mechanisms of this interaction and the possibility of using curing systems other than free radical peroxide in the manufacture of silicone elastomer expanders for breast prosthesis. PMID- 23683044 TI - In vitro characterization of magnetic electrospun IDA-grafted chitosan nanofiber composite for hyperthermic tumor cell treatment. AB - Magnetic nanoparticles were the thermoseeds under an alternating magnetic field and can be used to produce highly localized hyperthermia effect on deep-seated tumor. Nevertheless, effective and precisive delivery of nanoparticles to the treatment-intended site remains a challenge. In this study, Fe3O4 nanoparticles were incorporated onto the crosslinked electrospun chitosan nanofibers using chemical co-precipitation from the Fe ions adsorbed. Such magnetic nanoparticle nanofiber composites could be delivered to the treatment site precisely by surgical or endoscopic method. Iminodiacetic acid (IDA) functionality was grafted onto the chitosan with an aim to increase the amount of magnetic nanoparticles formed in the electrospun magnetic nanofiber composite. The morphology, crystalline phase as well as the magnetism characteristic of the magnetic electrospun nanofiber matrixes, was analyzed. Results have indicated that, with the incorporation of IDA functionality, more magnetic nanoparticles were formed in the electrospun chitosan nanofiber matrix. In addition, the magnetic IDA grafted chitosan nanofiber composite can effectively reduced the tumor cell proliferation under the application of magnetic field. This finding suggested the magnetic electrospun chitosan nanofiber composite can be of potential for hyperthermia treatment. PMID- 23683046 TI - Potential biosignatures in super-Earth atmospheres II. Photochemical responses. AB - Spectral characterization of super-Earth atmospheres for planets orbiting in the habitable zone of M dwarf stars is a key focus in exoplanet science. A central challenge is to understand and predict the expected spectral signals of atmospheric biosignatures (species associated with life). Our work applies a global-mean radiative-convective-photochemical column model assuming a planet with an Earth-like biomass and planetary development. We investigated planets with gravities of 1g and 3g and a surface pressure of 1 bar around central stars with spectral classes from M0 to M7. The spectral signals of the calculated planetary scenarios have been presented by in an earlier work by Rauer and colleagues. The main motivation of the present work is to perform a deeper analysis of the chemical processes in the planetary atmospheres. We apply a diagnostic tool, the Pathway Analysis Program, to shed light on the photochemical pathways that form and destroy biosignature species. Ozone is a potential biosignature for complex life. An important result of our analysis is a shift in the ozone photochemistry from mainly Chapman production (which dominates in Earth's stratosphere) to smog-dominated ozone production for planets in the habitable zone of cooler (M5-M7)-class dwarf stars. This result is associated with a lower energy flux in the UVB wavelength range from the central star, hence slower planetary atmospheric photolysis of molecular oxygen, which slows the Chapman ozone production. This is important for future atmospheric characterization missions because it provides an indication of different chemical environments that can lead to very different responses of ozone, for example, cosmic rays. Nitrous oxide, a biosignature for simple bacterial life, is favored for low stratospheric UV conditions, that is, on planets orbiting cooler stars. Transport of this species from its surface source to the stratosphere where it is destroyed can also be a key process. Comparing 1g with 3g scenarios, our analysis suggests it is important to include the effects of interactive chemistry. PMID- 23683047 TI - Natural organic matter as global antennae for primary production. AB - Humic substances (HS) are high-molecular-weight complex refractory organics that are ubiquitous in terrestrial and aquatic environments. While resistant to microbial degradation, these compounds nevertheless support microbial metabolism via oxidation or reduction of their (hydro)quinone moieties. As such, they are known to be important electron sinks for respiratory and fermentative bacteria and electron sources for denitrifying and perchlorate-reducing bacteria. HS also strongly promote abiotic reduction of Fe(III) when irradiated with light. Here, we show that HS-enhanced Fe(III) photoreduction can also drive chemolithotrophic microbial respiration by producing Fe(II), which functions as a respiratory electron donor. Due to their molecular complexity, HS absorb most of the electromagnetic spectrum and can act as broad-spectrum antennae converting radiant energy into bioavailable chemical energy. The finding that chemolithotrophic organisms can utilize this energy has important implications for terrestrial, and possibly extraterrestrial, microbial processes and offers an alternative mechanism of radiation-driven primary productivity to that of phototrophy. PMID- 23683048 TI - Carbon and hydrogen isotopic composition of methane and C2+ alkanes in electrical spark discharge: implications for identifying sources of hydrocarbons in terrestrial and extraterrestrial settings. AB - The low-molecular-weight alkanes--methane, ethane, propane, and butane--are found in a wide range of terrestrial and extraterrestrial settings. The development of robust criteria for distinguishing abiogenic from biogenic alkanes is essential for current investigations of Mars' atmosphere and for future exobiology missions to other planets and moons. Here, we show that alkanes synthesized during gas phase radical recombination reactions in electrical discharge experiments have values of delta(2)H(methane)>delta(2)H(ethane)>delta(2)H(propane), similar to those of the carbon isotopes. The distribution of hydrogen isotopes in gas-phase radical reactions is likely due to kinetic fractionations either (i) from the preferential incorporation of (1)H into longer-chain alkanes due to the more rapid rate of collisions of the smaller (1)H-containing molecules or (ii) by secondary ion effects. Similar delta(13)C(C1-C2+) and delta(2)H(C1-C2+) patterns may be expected in a range of extraterrestrial environments where gas-phase radical reactions dominate, including interstellar space, the atmosphere and liquid hydrocarbon lakes of Saturn's moon Titan, and the outer atmospheres of Jupiter, Saturn, Neptune, and Uranus. Radical recombination reactions at high temperatures and pressures may provide an explanation for the combined reversed delta(13)C(C1-C2+) and delta(2)H(C1-C2+) patterns of terrestrial alkanes documented at a number of high-temperature/pressure crustal sites. PMID- 23683049 TI - Twist1 in tumor cells and alpha-smooth muscle actin in stromal cells are possible biomarkers for metastatic giant basal cell carcinoma. AB - We previously reported a case of giant basal cell carcinoma (BCC) in a 75-year old Japanese man, who subsequently developed a pulmonary metastasis. With regard to the pathogenesis of metastasis of BCC, recently, it has been reported that high levels of expression of Twist1 and N-cadherin in primary and metastatic tumor cells, suggesting that Twist1 expression and an epithelial-mesenchymal transition (EMT) of tumor cells are important for the promotion of tumor invasion and subsequent metastasis. In this report, we identified the expressions of Twist1 in tumor cells and alpha-smooth muscle actin (alpha-SMA) in stromal cells in the primary and metastatic sites of giant BCC. These results suggest that Twist1-induced EMT of tumor cells might have been associated with distant organ metastasis in our case, and the presence of alpha-SMA-positive myofibroblasts surrounding a BCC nest can be one of hallmarks of the aggressiveness of BCC. PMID- 23683050 TI - Application potential of ATR-FT/IR molecular spectroscopy in animal nutrition: revelation of protein molecular structures of canola meal and presscake, as affected by heat-processing methods, in relationship with their protein digestive behavior and utilization for dairy cattle. AB - Protein quality relies not only on total protein but also on protein inherent structures. The most commonly occurring protein secondary structures (alpha-helix and beta-sheet) may influence protein quality, nutrient utilization, and digestive behavior. The objectives of this study were to reveal the protein molecular structures of canola meal (yellow and brown) and presscake as affected by the heat-processing methods and to investigate the relationship between structure changes and protein rumen degradations kinetics, estimated protein intestinal digestibility, degraded protein balance, and metabolizable protein. Heat-processing conditions resulted in a higher value for alpha-helix and beta sheet for brown canola presscake compared to brown canola meal. The multivariate molecular spectral analyses (PCA, CLA) showed that there were significant molecular structural differences in the protein amide I and II fingerprint region (ca. 1700-1480 cm(-1)) between the brown canola meal and presscake. The in situ degradation parameters, amide I and II, and alpha-helix to beta-sheet ratio (R_a_beta) were positively correlated with the degradable fraction and the degradation rate. Modeling results showed that alpha-helix was positively correlated with the truly absorbed rumen synthesized microbial protein in the small intestine when using both the Dutch DVE/OEB system and the NRC-2001 model. Concerning the protein profiles, R_a_beta was a better predictor for crude protein (79%) and for neutral detergent insoluble crude protein (68%). In conclusion, ATR-FT/IR molecular spectroscopy may be used to rapidly characterize feed structures at the molecular level and also as a potential predictor of feed functionality, digestive behavior, and nutrient utilization of canola feed. PMID- 23683051 TI - Synthesis of densely functionalized 3a,4-dihydro-1H-pyrrolo[1,2-b]pyrazoles via base mediated domino reaction of vinyl malononitriles with 1,2-diaza-1,3-dienes. AB - A domino reaction of vinyl malononitriles (VMs) with 1,2-diaza-1,3-dienes (DDs) produce unprecedented 3a,4-dihydro-1H-pyrrolo[1,2-b]pyrazole systems in a chemo-, regio-, and stereoselective fashion. This base promoted (DIPEA) one-pot transformation involving multiple steps constructs one new C-C bond, two C-N bonds, and two new fused heterocyclic rings with total atom economy. PMID- 23683052 TI - The relationship between oral hygiene status and obesity among preschool children in Hong Kong. AB - OBJECTIVES: To explore the association between oral hygiene status and obesity among preschool children in Hong Kong. METHODS: Three hundred and twenty-four 5 year-old children in Hong Kong were recruited. Their oral hygiene status was recorded using visible plaque index (VPI). Body height, body weight, waist circumference (WC), hip circumference and triceps skinfold thickness (TRSKF) were measured to assess general adiposity (weight/height ratio, W/H; body mass index, BMI), central adiposity (WC; waist/hip ratio, WHR) and peripheral adiposity (TRSKF). The relationships between VPI and W/H, BMI, WC, WHR and TRSKF were examined in bivariate and regression analyses. RESULTS: Fifty-six per cent of the children were considered to have high VPI (VPI >= 65.0%). Logistic regression analyses identified that W/H z-score (OR = 1.28, 95% CI = 1.01-1.61) and WC z score (OR = 1.25, 95% CI = 1.00-1.58) were associated with high VPI. No association was found after adjusted for socio-demographic status (P > 0.05). CONCLUSION: Oral hygiene status was not associated with obesity among 5-year-old children in Hong Kong after controlling for socio-demographic factors. PMID- 23683053 TI - Fabricate heterojunction diode by using the modified spray pyrolysis method to deposit nickel-lithium oxide on indium tin oxide substrate. AB - P-type lithium-doped nickel oxide (p-LNiO) thin films were deposited on an n-type indium tin oxide (ITO) glass substrate using the modified spray pyrolysis method (SPM), to fabricate a transparent p-n heterojunction diode. The structural, optical, and electrical properties of the p-LNiO and ITO thin films and the p LNiO/n-ITO heterojunction diode were characterized by field emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), UV-visible spectroscopy, Hall effect measurement, and current-voltage (I-V) measurements. The nonlinear and rectifying I-V properties confirmed that a heterojunction diode characteristic was successfully formed in the p-LNiO/n-ITO (p-n) structure. The I V characteristic was dominated by space-charge-limited current (SCLC), and the Anderson model demonstrated that band alignment existed in the p-LNiO/n-ITO heterojunction diode. PMID- 23683054 TI - Isolation and identification of a gallotannin 1,2,6-tri-O-galloyl-beta-D glucopyranose from hydroalcoholic extract of Terminalia chebula fruits effective against multidrug-resistant uropathogens. AB - AIMS: In this study, an attempt has been made to isolate and identify the bioactive compounds from hydroalcoholic extract of Terminalia chebula fruits effective against multidrug-resistant uropathogens and also to elucidate the influence of metal ions on the growth inhibitory activity of isolated compounds against the studied bacteria, if any. METHODS AND RESULTS: Bioassay-guided fractionation and extensive spectrometric analyses (FT-IR, (1) H NMR, (13) C NMR and ESI-MS) were used to isolate and characterize the bioactive compound. Growth inhibitory activities of isolated compound were studied by agar well diffusion and microbroth dilution assay methods. Checkerboard titration method was used for combination study between antibiotics and isolated compound. Influence of metal ions on growth inhibitory activity of this bioactive compound against the test isolates were also studied by INT [P-iodonitrotetrazolium violet; 2-(4 iodophenyl)-3-(4-nitrophenyl)-5-phenyltetrazolium chloride] colorimetric assay. The isolated bioactive compound 1, 2, 6-tri-O-galloyl-beta-D-glucopyranose was found to be responsible for antibacterial activity against multidrug-resistant uropathogens and showed synergy with trimethoprim and gentamicin. This antibacterial activity of bioactive compound was counteracted by the supplementation of iron in the medium. CONCLUSION: Terminalia chebula fruit extract contains bioactive compound effective against multidrug-resistant uropathogens, and this antibacterial activity may be due to its iron-complexing property. SIGNIFICANCE AND IMPACT OF THE STUDY: To the best of our knowledge, the antibacterial activity exhibited by isolated gallotannin against multidrug resistant uropathogens is first time reported by us. Besides, these promising findings may lead to the development of antimicrobial agents from T. chebula fruits for the treatment of urinary tract infections caused by these pathogens. PMID- 23683055 TI - Quantification of surface charge density and its effect on boundary slip. AB - Reduction of fluid drag is important in the micro-/nanofluidic systems. Surface charge and boundary slip can affect the fluid drag, and surface charge is also believed to affect boundary slip. The quantification of surface charge and boundary slip at a solid-liquid interface has been widely studied, but there is a lack of understanding of the effect of surface charge on boundary slip. In this paper, the surface charge density of borosilicate glass and octadecyltrichlorosilane (OTS) surfaces immersed in saline solutions with two ionic concentrations and deionized (DI) water with different pH values and electric field values is quantified by fitting experimental atomic force microscopy (AFM) electrostatic force data using a theoretical model relating the surface charge density and electrostatic force. Results show that pH and electric field can affect the surface charge density of glass and OTS surfaces immersed in saline solutions and DI water. The mechanisms of the effect of pH and electric field on the surface charge density are discussed. The slip length of the OTS surface immersed in saline solutions with two ionic concentrations and DI water with different pH values and electric field values is measured, and their effects on the slip length are analyzed from the point of surface charge. Results show that a larger absolute value of surface charge density leads to a smaller slip length for the OTS surface. PMID- 23683056 TI - Ultrasound-guided parasacral approach to the sciatic nerve block in children. AB - BACKGROUND: The parasacral (PS) approach to sciatic nerve blockade has the potential for safe and effective use in children, but has never been studied in this population. Its potential advantages include increased posterior cutaneous nerve block reliability, potential for hip joint analgesia, and decreased nerve depth, making ultrasound guidance easier. OBJECTIVE: To assess the efficacy of an ultrasound-guided PS sciatic nerve block in children. METHODS: Nineteen patients, 1-16 years old, scheduled for lower limb surgery with peripheral nerve blockade (PNB) were prospectively enrolled. A PS sciatic block was performed using both ultrasound guidance and nerve stimulation, and 0.5 ml.kg(-1) ropivacaine 0.2% (maximum 20 ml) was administered. Patient demographics, the time to perform the block, the lowest intensity of nerve stimulation, evoked response, identification of gluteal arteries, and amount of narcotic given were recorded. Postoperatively, pain scores, block success or failure, block duration, and complications were recorded. RESULTS: The block was performed using the PS approach in 95% of the cases. The success rate was 100% in the PS sciatic blocks performed. The pain scores for all patients in the first postsurgical hour were zero, except one patient that had a pain score of 3 of 10 at 30 min; his pain improved to 0 of 10 after administration of one dose of fentanyl and distraction techniques. The blocks lasted 17.3 +/- 5.4 h. No complications were identified. CONCLUSION: The PS approach is an effective option for sciatic nerve blockade to provide postoperative pain relief in children having lower extremity surgery. PMID- 23683057 TI - Benchmark Dose Analysis via Nonparametric Regression Modeling. AB - Estimation of benchmark doses (BMDs) in quantitative risk assessment traditionally is based upon parametric dose-response modeling. It is a well-known concern, however, that if the chosen parametric model is uncertain and/or misspecified, inaccurate and possibly unsafe low-dose inferences can result. We describe a nonparametric approach for estimating BMDs with quantal-response data based on an isotonic regression method, and also study use of corresponding, nonparametric, bootstrap-based confidence limits for the BMD. We explore the confidence limits' small-sample properties via a simulation study, and illustrate the calculations with an example from cancer risk assessment. It is seen that this nonparametric approach can provide a useful alternative for BMD estimation when faced with the problem of parametric model uncertainty. PMID- 23683058 TI - Intersections between interprofessional practice, cultural competency and primary healthcare. AB - The concepts of interprofessional collaborative practice (IPCP), cultural competency and primary healthcare (PHC) appear to be linked in theory and practice. This discussion article provides arguments explicating the potential linkages between IPCP and cultural competency. We argue that cultural competency is an important component of IPCP both for relationships with patients and/or communities in which providers work and between team members. Organizational structures also play an important role in facilitating IPCP and cultural competency. The integration of both IPCP and cultural competency has the potential to enhance positive health outcomes. Furthermore, we argue IPCP and cultural competency have important implications for PHC service design, given interprofessional teams are a key component of PHC systems. Linking these concepts in providing PHC services can be essential for impacting outcomes at all levels of primary healthcare, including patient, provider and systems. PMID- 23683060 TI - Team decision making: design, implementation and evaluation of an interprofessional education activity for undergraduate health science students. AB - An undergraduate health science student curriculum activity in interprofessional education (IPE) focused on team decision making was piloted. The IPE activity included a lecture, small group learning activity and an onsite observation of an interprofessional health care team (IPHCT) meeting. Measures included the Readiness for Interprofessional Learning scale, Interdisciplinary Education Perception scale and the Role Perception Questionnaires. The students completed a workbook to assess decision making capacity in IPHCTs. The results indicated that students (n = 61) were willing to share their knowledge and skills as a way of understanding clinical problems in the workplace and had professionally oriented perceptions and related affective domains. They also showed a positive role perception of their own role and that of other professions. Analysis of the workbooks revealed that students were able to identify positive and negative impacts on effective team decision making and its effects on a patient centred approach to health care. PMID- 23683061 TI - Using design to drive organizational performance and innovation in the corporate workplace: implications for interprofessional environments. AB - Learning and working are increasingly inseparable social processes characterized by a mix of routine and non-routine activities, which are meant to sustain an optimal balance of creative risk taking, idea exploration and development of professional mastery. Learning and working are embedded in broader social institutions such as universities, academic medical centers, professional organizations and business firms. The future of learning and working is witnessing a blurring of these institutional boundaries, and consequently, a spanning of disciplines and professions that have traditionally assimilated and oriented people around knowledge domains. Learning and working practices are increasingly less defined by bureaucratic controls and are, instead, more collaborative, fluid and interdisciplinary. One of the most tangible manifestations of this shift is in the spaces and places where learning and working activities happen and where people interact and organize. This article explores these learning and working paradigm shifts by discussing recent developments in the corporate workplace and exploring how such changes inform the future of interprofessional education. PMID- 23683063 TI - Cloning and characterization of luciferase from a Fijian luminous click beetle. AB - Luminous click beetle is distributed almost exclusively in Central and South America with a single genus in Melanesia. Among these click beetles, the description of Melanesian species has been fragmentary, and its luciferase gene and phylogenetic relation to other click beetles still remain uncertain. We collected a living luminous click beetle, Photophorus jansonii in Fiji. It emits green-yellow light from two spots on the pronotum and has no ventral luminous organ. Here, we cloned a luciferase gene from this insect by RT-PCR. The deduced amino acid sequence showed high identity of ~85% to the luciferases derived from other click beetle species. The luciferase of the Fijian click beetle was produced as a recombinant protein to characterize its biochemical properties. The Km for D-luciferin and ATP were 173 and 270 MUm, respectively. The luciferase was pH-insensitive and the spectrum measured at pH 8.0 showed a peak at 559 nm, which was in the range of green-yellow light as seen in the luminous spot of the living Fijian click beetle. The Fijian click beetle luciferase was assigned to the Elateridae clade by a phylogenetic analysis, but it made a clearly different branch from Pyrophorus group examined in this study. PMID- 23683062 TI - Maturation of the cytochrome cd1 nitrite reductase NirS from Pseudomonas aeruginosa requires transient interactions between the three proteins NirS, NirN and NirF. AB - The periplasmic cytochrome cd1 nitrite reductase NirS occurring in denitrifying bacteria such as the human pathogen Pseudomonas aeruginosa contains the essential tetrapyrrole cofactors haem c and haem d1. Whereas the haem c is incorporated into NirS by the cytochrome c maturation system I, nothing is known about the insertion of the haem d1 into NirS. Here, we show by co-immunoprecipitation that NirS interacts with the potential haem d1 insertion protein NirN in vivo. This NirS-NirN interaction is dependent on the presence of the putative haem d1 biosynthesis enzyme NirF. Further, we show by affinity co-purification that NirS also directly interacts with NirF. Additionally, NirF is shown to be a membrane anchored lipoprotein in P. aeruginosa. Finally, the analysis by UV-visible absorption spectroscopy of the periplasmic protein fractions prepared from the P. aeruginosa WT (wild-type) and a P. aeruginosa DeltanirN mutant shows that the cofactor content of NirS is altered in the absence of NirN. Based on our results, we propose a potential model for the maturation of NirS in which the three proteins NirS, NirN and NirF form a transient, membrane-associated complex in order to achieve the last step of haem d1 biosynthesis and insertion of the cofactor into NirS. PMID- 23683065 TI - Dipeptidyl peptidase-4 inhibitors: multitarget drugs, not only antidiabetes drugs. AB - Dipeptidyl peptidase (DPP)-4 inhibitors are a new class of antidiabetic agents that reduce blood glucose by preventing the degradation of the endogenous incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Protection by DPP-4 inhibitors of beta-cell function has been demonstrated in patients with type 2 diabetes. Because DPP-4 is an enzyme widely expressed in humans, DPP-4 inhibitors are speculated to be multitarget agents. However, other potential therapeutic benefits of DPP-4 inhibitors remain unknown. Recently, some therapeutic effects of DPP-4 inhibitors, such as immune regulation, cardiovascular protection, and anti-inflammatory effects, have been observed. This article provides a systematic and comprehensive review of current research into the newly found effects and mechanism of action of DPP-4 inhibitors in a therapeutic context. PMID- 23683064 TI - Gold nanoparticle-based activatable probe for sensing ultralow levels of prostate specific antigen. AB - It is still in high demand to develop extremely sensitive and accurate clinical tools for biomarkers of interest for early diagnosis and monitoring of diseases. In this report, we present a highly sensitive and compatible gold nanoparticle (AuNP)-based fluorescence-activatable probe for sensing ultralow levels of prostate-specific antigen (PSA) in patient serum samples. The limit of detection of the newly developed probe for PSA was pushed down to 0.032 pg/mL, which is more than 2 orders of magnitude lower than that of the conventional fluorescence probe. The ultrahigh sensitivity of this probe was attributed to the high loading efficiency of the dyes on AuNP surfaces and high fluorescence quenching unquenching abilities of the dye-AuNP pairs. The efficiency and robustness of this probe were investigated in patient serum samples, demonstrating the great potential of this probe in real-world applications. PMID- 23683066 TI - Police documentation of alcohol involvement in hospitalized injured drivers. AB - OBJECTIVE: Injured drivers with blood alcohol concentration (BAC) above the legal limit are rarely convicted of impaired driving. One explanation is that police may have difficulty recognizing alcohol intoxication in injured drivers. In this study, we compare police documentation of alcohol involvement with BAC measured on arrival at a hospital. Our objectives were to determine how often police document alcohol involvement in injured drivers with BAC >= 0.05 percent and identify factors that influence police documentation of alcohol involvement. METHODS: We included injured drivers (1999-2003) who were admitted to a British Columbia trauma center or treated in the Vancouver General Hospital emergency department. We used probabilistic linkage to obtain police collision reports. Police were considered to have indicated alcohol involvement if (1) police documented that alcohol contributed to the crash, (2) the driver received an administrative sanction for impaired driving, or (3) the driver was criminally convicted of impaired driving. The proportion of drivers for whom police indicated alcohol involvement was determined relative to age, gender, BAC levels, crash severity, and crash characteristics. Multivariate logistic regression was used to identify factors independently associated with police indication of alcohol involvement. RESULTS: Two thousand four hundred and ten injured drivers (73.5% male) were matched to a police report. Overall, 857 (35.6%) drivers tested positive for alcohol (BAC >= 0) and 736/857 (85.9%) of alcohol-positive drivers had a BAC >= 0.05 percent (the legal limit in British Columbia). Of the 736 drivers with a BAC > 0.05 percent at time of admission, police indicated alcohol involvement in 530 (72.0%). The criminal code conviction rate for impaired driving was 4.7 percent for drivers with 0.08 percent <= BAC < 0.16 percent and 13.6 percent for drivers with BAC > 0.16 percent. The following factors were associated with higher odds of police indicating alcohol involvement: (1) increasing blood alcohol levels, (2) a prior record of impaired driving, (3) involvement in a single-vehicle crash, (4) involvement in a nighttime crash, and (5) traffic violations or unsafe driving actions recorded by police. CONCLUSIONS: Police recognized and documented alcohol involvement in 72 percent of injured drivers with BAC >= 0.05 percent. Police documentation of alcohol involvement was more common at higher BAC levels, in nighttime or single-vehicle crashes, for drivers who committed traffic violations or drove unsafely, and for drivers with a prior record of impaired driving. The low conviction rate of injured impaired drivers does not appear to be due to police inability to recognize alcohol involvement. PMID- 23683067 TI - Modeling toxicity of mixtures of perfluorooctanoic acid and triazoles (triadimefon and paclobutrazol) to the benthic cladoceran Chydorus sphaericus. AB - Toxicity of perfluorooctanoic acid (PFOA) and triazoles, that is, paclobutrazol (PBZ) and triadimefon (TDF), singly and in binary mixtures was assessed on the benthic cladoceran Chydorus sphaericus. Following single exposure, toxicity of PBZ was not significantly different from that of TDF as shown by the overlapping 95% confidence intervals of their median effective concentrations: EC50(PBZ) = 0.07-0.09 mM; EC50(TDF) = 0.066-0.078 mM. PFOA was far less toxic than these triazoles: EC50(PFOA) = 0.20-0.24 mM. Assuming no interactions between PFOA and the triazoles, the toxicity of PFOA in mixtures with the triazoles estimated by the concentration addition (CA) and independent action (IA) models was significantly lower than its toxicity in single exposure. This contrasted with the results for PBZ and TDF. Based on the assumption that PFOA may interact with the triazoles, different predictions were obtained by the two models. Significant alleviation of PBZ and TDF on the toxicity of PFOA was found by the extended CA model only. According to the extended IA model, PFOA had nonsignificant effects on the toxicity of PBZ while significantly increasing the toxicity of TDF. This difference is possibly related to different modes of actions for various functional groups in PBZ and TDF. PMID- 23683068 TI - Non-response in a pharmacy and patient-based intensive monitoring system: a quantitative study on non-response bias and reasons for non-response. AB - OBJECTIVE: Worldwide pharmacists play an increasingly important role in pharmacovigilance. Lareb Intensive Monitoring (LIM) in the Netherlands is a new form of active pharmacovigilance where pharmacists play a key role. Patients using drugs which are monitored are identified in the pharmacy and invited to participate in the active monitoring. Not all invited patients participate. This study aimed to investigate non-response bias in LIM, as well as reasons for non response in order to identify barriers to participation. METHODS: The study population consisted of patients who received a first dispensation of an antidiabetic drug monitored with LIM between 1 July 2010 and 28 February 2011. Possible non-response bias was investigated by comparing age, gender and the number of drugs used as co-medication. Reasons for non-response were investigated using a postal questionnaire. KEY FINDINGS: Respondents were on average 4.5 years younger than non-respondents and used less co-medication. There were no differences regarding gender. The main reason for non-response was that information in the pharmacy was lacking. CONCLUSION: Differences between respondents and non-respondents should be taken into account when analysing and generalising data collected through LIM, as this might contribute to non-response bias. The relatively high response to the postal questionnaire, together with the answers about reasons for non-response, show that patients are willing to participate in a web-based intensive monitoring system, when they are informed and invited in the pharmacy. PMID- 23683070 TI - Fidaxomicin for treatment of clostridium difficile-associated diarrhea and its potential role for prophylaxis. AB - INTRODUCTION: Clostridium difficile has become the most important healthcare associated infection worldwide within the past decade. This is in part due to the emergence of a highly virulent epidemic strain of C. difficile as well as the relative ineffectiveness of current therapies at producing a sustained response. Fidaxomicin is a novel antibiotic that demonstrates a greater sustained response for C. difficile-associated diarrhea (CDAD) compared to existing drugs and its potential role as a prophylactic agent against C. difficile infection (CDI) is being intensely studied. AREAS COVERED: In this article, we address the emergence of CDI and the current treatment options and identify the unmet needs of the marketplace. We also summarize the pharmacodynamic and pharmacokinetic properties of fidaxomicin, and review the current literature related to the use of fidaxomicin for both treatment and prophylaxis of CDI. EXPERT OPINION: Fidaxomicin is clearly as effective in the treatment of CDAD as oral vancomycin. It has also been shown to reduce recurrent CDAD, and we hypothesize that the same properties that confer reduced recurrence make it a promising agent for prophylaxis, particularly in high-risk patients. PMID- 23683069 TI - Liraglutide suppresses postprandial triglyceride and apolipoprotein B48 elevations after a fat-rich meal in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, cross-over trial. AB - AIMS: Postprandial triglyceridaemia is a risk factor for cardiovascular disease (CVD). This study investigated the effects of steady-state liraglutide 1.8 mg versus placebo on postprandial plasma lipid concentrations after 3 weeks of treatment in patients with type 2 diabetes mellitus (T2DM). METHODS: In a cross over trial, patients with T2DM (n = 20, 18-75 years, BMI 18.5-40 kg/m2) were randomized to once-daily subcutaneous liraglutide (weekly dose escalation from 0.6 to 1.8 mg) and placebo. After each 3-week period, a standardized fat-rich meal was provided, and the effects of liraglutide on triglyceride (primary endpoint AUC(0-8h)), apolipoprotein B48, non-esterified fatty acids, glycaemic responses and gastric emptying were assessed. ClinicalTrials.gov ID: NCT00993304. FUNDING: Novo Nordisk A/S. RESULTS: After 3 weeks, mean postprandial triglyceride (AUC(0-8h) liraglutide/placebo treatment-ratio 0.72, 95% CI [0.62-0.83], p = 0.0004) and apolipoprotein B48 (AUC(0-8h) ratio 0.65 [0.58-0.73], p < 0.0001) significantly decreased with liraglutide 1.8 mg versus placebo, as did iAUC(0-8h) and C(max) (p < 0.001). No significant treatment differences were observed for non-esterified fatty acids. Mean postprandial glucose and glucagon AUC(0-8h) and C(max) were significantly reduced with liraglutide versus placebo. Postprandial gastric emptying rate [assessed by paracetamol absorption (liquid phase) and the 13C-octanoate breath test (solid phase)] displayed no treatment differences. Mean low-density lipoprotein and total cholesterol decreased significantly with liraglutide versus placebo. CONCLUSIONS: Liraglutide treatment in patients with T2DM significantly reduced postprandial excursions of triglyceride and apolipoprotein B48 after a fat-rich meal, independently of gastric emptying. Results indicate liraglutide's potential to reduce CVD risk via improvement of postprandial lipaemia. PMID- 23683071 TI - Molecular characterization of carotenoid cleavage dioxygenases and the effect of gibberellin, abscisic acid, and sodium chloride on the expression of genes involved in the carotenoid biosynthetic pathway and carotenoid accumulation in the callus of Scutellaria baicalensis Georgi. AB - Three cDNAs encoding carotenoid cleavage dioxygenases (SbCCD1, SbCCD4, and SbNCED) were isolated from Scutellaria baicalensis , an important traditional herb in Asia and North America. Amino acid sequence alignments showed that they share high identity and similarity to their orthologs in other plant species. Quantitative real-time polymerase chain reaction analysis revealed that SbCCD1 and SbCCD4 were most strongly expressed in flowers, whereas SbNCED was expressed at the highest level in roots. The expression levels of phytoene synthase (SbPSY), phytoene desaturase (SbPDS), xi-carotene desaturase (SbZDS), beta-ring carotene hydroxylase (SbCHXB), zeaxanthin epoxidase (SbZEP), SbCCD1, SbCCD4, and SbNCED in the callus of S. baicalensis varied under different concentrations of gibberellic acid (GA3) and abscisic acid (ABA). Under NaCl treatment, expression levels of all genes increased with increasing NaCl concentrations. Except for zeaxanthin, increasing GA3, ABA, and NaCl concentrations caused higher losses in the total carotenoid content. The total carotenoid content substantially decreased with increasing GA3, ABA, and NaCl concentrations, with the biggest reductions observed in the NaCl treatment. The isolation and characterization of SbCCD1, SbCCD4, and SbNCED together with the study on the effect of GA3, ABA, and NaCl on carotenoid biosynthesis will be helpful to elucidate the carotenoid biosynthesis mechanism in S. baicalensis and may set new trends in metabolic engineering of carotenoids in plants. PMID- 23683072 TI - pCGR2 copy number depends on the par locus that forms a ParC-ParB-DNA partition complex in Corynebacterium glutamicum. AB - AIMS: To characterize the par system of Corynebacterium glutamicum pCGR2 and to manipulate the par components to effectively manipulate plasmid copy number. METHODS AND RESULTS: ParB binds sequence specifically to centromere-binding sites around the parAB operon and serves as an autorepressor. A small ORF (orf4, later named parC) downstream of parAB encodes a protein with 23.7% sequence identity with ParB. ParB is also implicated in the repression of parC transcription. Nonetheless, this ParC protein does not bind to centromere-binding sites and is not essential for plasmid stability. Introduction of a frameshift mutation within ParC implicated the protein in regulation of both parAB and parC. Electrophoretic Mobility Shift Assay confirmed a previously unreported ParC-ParB-parS partition complex. ParC also interacts directly with ParB without the mediation of the centromere sites. Deletion of the par components resulted in different plasmid copy numbers. CONCLUSIONS: A previously unreported ParC-ParB-parS partition complex is formed in pCGR2, where interaction of ParC with ParB-parS may affect the level of repression by ParB. Modifying the par components and antisense RNA enables manipulation of plasmid copy number to varying degrees. SIGNIFICANCE AND IMPACT OF STUDY: Genetically manipulating the par components, in combination with deactivation of antisense RNA, is a novel approach to artificially elevate plasmid copy number. This approach can be applied for development of new genetic engineering tools. PMID- 23683073 TI - Ethical and regulatory guidelines in clinical trials of xenocorneal transplantation in Korea; the Korean xenocorneal transplantation consensus statement. AB - BACKGROUND: To establish the consensus about the conditions for undertaking clinical trials in xenocorneal transplantation in Korea, specific issues regarding the xenocorneal transplantation on ethical and regulatory aspects are addressed, and the guidelines to conduct clinical trial of the xenocorneal transplantation are proposed. METHOD AND RESULTS: Chapter 1 reviews the key ethical requirements and progress of a Korean regulatory framework for clinical trials of xenocorneal transplantation. Chapters 2-7 provide recommendations on source pigs, quality control of porcine corneal procurement, preclinical efficacy required to justify a clinical trial, strategies to prevent transmission of porcine endogenous retrovirus (PERV), patient selection for clinical trials, and informed consent in xenocorneal transplantation using either cellularized or decellularized porcine graft, which are essentially based on the International Xenotransplantation Association (IXA) islet xenotransplantation consensus statement. The consensus statement of the inclusion criteria for the patients' selection has been made by the executive board members in Korean External Eye Disease Society. CONCLUSIONS: This consensus statement will be a good initiative for Korean Food and Drug Administration to discuss final regulatory guidelines in conducting clinical trials of xenocorneal transplantation in Korea and for International Xenotransplantation Association to develop International Consensus Standards of Xenocorneal Transplantation. PMID- 23683074 TI - Plasma taurine as a predictor of poor outcome in patients with mild neurological deficits after aneurysmal subarachnoid hemorrhage. AB - OBJECT: The object of this study was to determine the relationship between plasma taurine and subarachnoid hemorrhage (SAH) outcome. METHODS: Forty patients with SAH and mild neurological deficits were included in this prospective, blinded cohort study. Plasma taurine levels were measured using high-performance liquid chromatography on admission and were correlated with patient outcomes at discharge. RESULTS: Twenty-five percent of the patients ultimately had a poor outcome. Plasma taurine concentrations at admission were increased (2-fold) in SAH patients with a favorable outcome and were further increased (6-fold) in those who had a poor outcome. Increased taurine levels identified patients who would be discharged with a poor outcome, with sensitivity and specificity values of approximately 80% and 100%, respectively, and positive and negative predictive values of approximately 90%. Delayed cerebral vasospasm showed an OR of 27.9 (95% CI 1.090-714.9) for a poor outcome, whereas an increased taurine concentration had an OR of 105 for a poor outcome (95% CI 8.3-1328.0, p < 0.001). CONCLUSIONS: Increased plasma taurine concentrations on admission predict a poor outcome in SAH. PMID- 23683075 TI - Combined chronic lymphocytic leukemia and prolactinoma: a rare occurrence in a patient presenting with pituitary apoplexy. AB - The authors describe a rare case of combined pituitary chronic lymphocytic leukemia (CLL) and prolactinoma in a 77-year-old man presenting with apoplexy. This case highlights the importance of evaluating the pituitary gland in patients with CLL who present with clinical manifestations of apoplexy as well as the need to carefully evaluate pathological specimens from the gland for the presence of lymphocytic cells in those patients. This is the first reported case of a combined CLL-prolactinoma pituitary lesion presenting with apoplexy. PMID- 23683076 TI - Benefit of cone-beam computed tomography angiography in acute management of angiographically undetectable ruptured arteriovenous malformations. AB - OBJECT: Ruptured arteriovenous malformations (AVMs) are a frequent cause of intracerebral hemorrhage (ICH). In some cases, compression from the associated hematoma in the acute setting can partially or completely occlude an AVM, making it invisible on conventional angiography techniques. The authors report on the successful use of cone-beam CT angiography (CBCT-A) to precisely identify the underlying angioarchitecture of ruptured AVMs that are not visible on conventional angiography. METHODS: Three patients presented with ICH for which they underwent examination with CBCT-A in addition to digital subtraction angiography and other imaging modalities, including MR angiography and CT angiography. All patients underwent surgical evacuation due to mass effect from the hematoma. Clinical history, imaging studies, and surgical records were reviewed. Hematoma volumes were calculated. RESULTS: In all 3 cases, CBCT-A demonstrated detailed anatomy of an AVM where no lesion or just a suggestion of a draining vein had been seen with other imaging modalities. Magnetic resonance imaging demonstrated enhancement in 1 patient; CT angiography demonstrated a draining vein in 1 patient; 2D digital subtraction angiography and 3D rotational angiography demonstrated a suggestion of a draining vein in 2 cases and no finding in the third. In the 2 patients in whom CBCT-A was performed prior to surgery, the demonstrated AVM was successfully resected without evidence of a residual lesion. In the third patient, CBCT-A allowed precise targeting of the AVM nidus using Gamma Knife radiosurgery. CONCLUSIONS: Cone-beam CT angiography should be considered in the evaluation and subsequent treatment of ICH due to ruptured AVMs. In cases in which the associated hematoma compresses the AVM nidus, CBCT-A can have higher sensitivity and anatomical accuracy than traditional angiographic modalities, including digital subtraction angiography. PMID- 23683077 TI - An uncommon accident and unusual cause of death--a fatal domestic ram attack. AB - Domestic animal attacks are not common; their fatal attacks are even rarer. Herein, a case of a 78-year-old woman attacked by a ram is presented. She sustained multiple head and chest injuries. The autopsy findings and the inspection of the scene revealed that the fatal aortic injury had been caused by direct force from the front, which subsequently caused a powerful anteroposterior chest compression, resulting in an incomplete tear by flexion and compression of the aortic arch. The aortic dissection propagated in both an ante- and retrograde direction, with intact adventitia. However, due to a rise in pressure in the formed false lumen, dissection propagated downward to the base of the heart, and further into the subepicardial adipose tissue, forming a subepicardial hematoma. This hematoma gradually compressed the proximal sections of the coronary arteries, impairing their filling, and producing a myocardial ischemia. In addition, circulation had probably been already disturbed by the right-sided pneumothorax, as well as a possible pneumomediastinum. PMID- 23683078 TI - Dermatological complications of circumcision: lesson learned from cases in a pediatric dermatology practice. AB - We discuss 11 cases of boys who presented with dermatologic complications of circumcision in an outpatient pediatric dermatology clinic. A medical practitioner had previously circumcised all patients during the newborn period. The majority of cases were found incidentally during initial thorough dermatologic examination. Late cutaneous complications included penile skin bridge, glandular adhesion of remnant foreskin, concealed penis, and a penile epidermal inclusion cyst. Minor surgical procedures under local anesthesia were performed in all but two cases. These cases should help dermatologists recognize the common late cutaneous complications of male newborn circumcision and provide insight into potential options for early intervention and management. PMID- 23683079 TI - Harms from medicines: inevitable, in error or intentional. AB - Rational therapeutics requires a balance between benefits and harms. (i) Harm may be inevitable. Some adverse drug reactions cannot be predicted or prevented. (ii) Some harm occurs in error when a medicine is wrongly formulated, prescribed, dispensed or administered. Adverse drug reactions that might have been prevented, for example, by monitoring, fall into this category. (iii) Rarely, harm is inflicted deliberately, for example, in murder by poisoning. Here I consider adverse drug reactions, errors and deliberate drug-induced harm from the perspective of a clinical pharmacologist. PMID- 23683080 TI - Outcomes of non-surgical periodontal treatment by dental hygienists in training: impact of site- and patient-level factors. AB - OBJECTIVES: To investigate the site- and patient-level factors that impact on the response to non-surgical periodontal therapy in patients with chronic periodontitis. METHODS: A retrospective evaluation of clinical outcomes following non-surgical periodontal therapy delivered by dental hygienists in training was undertaken. Case notes from 195 patients with chronic periodontitis were reviewed and clinical data pre- and post-treatment abstracted. Patients were categorized as 'responders' or 'non-responders' according to defined outcome criteria, and the relationship between clinical and demographic variables and treatment outcomes was assessed. RESULTS: Overall, there was a good response to the periodontal treatment. At deep sites (those with pretreatment probing depth >=5 mm), the mean probing depth reduction was 1.6 +/- 0.9 mm. Seventy-one (36%) patients were classified as non-responders (indicating that at least 30% of their deep sites did not improve by at least 2 mm following treatment). The non responding group contained a significantly greater proportion of smokers (28%) than the responding group (16%). Plaque scores did not differ significantly between responders or non-responders either pre- or post-treatment. Regression analyses indicated that smoking status (odds ratio, OR: 2.04), mean pretreatment probing depth (OR: 1.49) and percentage of deep sites >=5 mm at pretreatment (OR: 1.02) were significantly associated with response to treatment. CONCLUSION: This study supports the benefits of non-surgical therapy in the treatment of chronic periodontitis by dental hygienists in training. Better responses to treatment tend to be observed in non-smokers and in those with less advanced periodontitis at baseline. PMID- 23683082 TI - Frequency of FMR1 premutation carriers and rate of expansion to full mutation in a retrospective diagnostic FMR1 Korean sample. AB - Detection of female premutation (PM) carriers of fragile X syndrome may be important in that a PM allele from the mother can expand to a full mutation (FM) when transmitted to the fetus. Although the PM carrier frequency might be different in varying populations, there is a little data on the Korean population. Furthermore, the risks of expansion to FM have not been studied in Korean PM carriers. In this retrospective study, we estimated the female PM carrier frequency and the risks of expansion to FM in Korean diagnostic samples collected for FMR1 gene testing. Of 10,241 pre-conceptional or pregnant women, 13 PM [1 in 788; 95% confidence interval (CI), 1/1,250-1/455] and 75 intermediate allele carriers (1 in 137; 95% CI, 1/172-1/110) were identified. In 26 prenatal diagnoses cases, the PM allele was transmitted to the fetus in 13 pregnancies (50%), and five of these expanded to FM. All of the maternal alleles exceeding 70 repeats expanded to FM. In conclusion, the PM frequency in Korean diagnostic samples was lower than that reported in Western populations, while the risk for FM expansion in alleles exceeding 70 repeats might be higher than expected based upon previous reports. PMID- 23683081 TI - Mutational analysis of BRCA1 and BRCA2 in hereditary breast and ovarian cancer families from Asturias (Northern Spain). AB - BACKGROUND: The prevalence of BRCA1 and BRCA2 mutations in Spain is heterogeneous and varies according to geographical origin of studied families. The contribution of these mutations to hereditary breast and ovarian cancer has not been previously investigated in Asturian populations (Northern Spain). METHODS: In the present work, 256 unrelated high-risk probands with breast and/or ovarian cancer from families living in Asturias were analyzed for the presence of a BRCA1 or BRCA2 gene mutation from October 2007 to May 2012. The entire coding sequences and each intron/exon boundaries of BRCA1/2 genes were screened both by direct sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA). RESULTS: A total of 59 families (23%) were found to carry a pathogenic germ line mutation, 39 in BRCA1 and 20 in BRCA2. Twenty nine additional families (12%) carried an unknown significance variant. We detected 28 distinct pathogenic mutations (16 in BRCA1 and 12 in BRCA2), of which 3 mutations in BRCA1 (c.1674delA, c.1965C>A and c.2900_2901dupCT) and 5 in BRCA2 (c.262_263delCT, c.2095C>T, c.3263dupC, c.4030_4035delinsC, c.8042_8043delCA) had not been previously described.The novel mutations c.2900_2901dupCT in BRCA1 and c.4030_4035delinsC in BRCA2 occurred in 8 and 6 families respectively and clustered in two separated small geographically isolated areas suggesting a founder effect. These 2 mutations, together with the Galician BRCA1 mutation c.211A>G (9 families), and the common BRCA1 mutation c.3331_3334delCAAG (6 families), account for approximately 50% of all affected families. By contrast, very frequent mutations in other Spanish series such as the BRCA1 Ashkenazi founder mutation c.68_69delAG, was found in only one family. CONCLUSIONS: In this study we report the BRCA1 and BRCA2 spectrum of mutations and their geographical distribution in Asturias, which largely differ from other areas of Spain. Our findings may help design a first step recurrent mutation panel for screening high-risk breast and/or ovarian cancer families from this specific area. PMID- 23683083 TI - Dynamics of nanoscale droplets on moving surfaces. AB - We use molecular dynamics (MD) simulations to investigate the dynamic wetting of nanoscale water droplets on moving surfaces. The density and hydrogen bonding profiles along the direction normal to the surface are reported, and the width of the water depletion layer is evaluated first for droplets on three different static surfaces: silicon, graphite, and a fictitious superhydrophobic surface. The advancing and receding contact angles, and contact angle hysteresis, are then measured as a function of capillary number on smooth moving silicon and graphite surfaces. Our results for the silicon surface show that molecular displacements at the contact line are influenced greatly by interactions with the solid surface and partly by viscous dissipation effects induced through the movement of the surface. For the graphite surface, however, both the advancing and receding contact angles values are close to the static contact angle value and are independent of the capillary number; i.e., viscous dissipation effects are negligible. This finding is in contrast with the wetting dynamics of macroscale water droplets, which show significant dependence on the capillary number. PMID- 23683085 TI - Handoff checklists improve the reliability of patient handoffs in the operating room and postanesthesia care unit. AB - BACKGROUND: Ineffective communications among healthcare providers are common and increases the risk of medical errors. During the perioperative period, multiple handoffs occur within a short period of time, and failure to convey important patient information can compromise safety. We used quality improvement methodology to improve the reliability of our handoffs in the operating room and postanesthesia care unit (PACU). METHODS: Two quality improvement teams were developed to focus on the intraoperative and postanesthesia handoff processes. Key driver diagrams and 'smart aims' were developed for each process based on feedback from anesthesia and nursing staff, and handoff checklists were developed and revised using multiple plan-do-study-act cycles. Data on the reliability of the handoff processes were obtained prior to initiation of the projects and throughout the 6-month project period. RESULTS: The reliability of intraoperative anesthesia handoffs improved from 20% to 100% with use of the intraoperative handoff checklist. Similarly, with the introduction of a standardized PACU checklist, the reliability of PACU handoffs improved from 59% to greater than 90%. CONCLUSION: We utilized quality improvement methodology to develop and implement standardized checklists for handoffs of care in the operating room and PACU. Acceptance of and adherence to the standardized handoff protocols dramatically increased the quality and reliability of our handoff process. PMID- 23683086 TI - Palladium-catalyzed C-H arylation using phosphoramidate as a directing group at room temperature. AB - This communication describes the first phosphoramidate directing group for synthetically useful arylation. Remarkably, the nature of a new directing group drives selective C-H bond activation to afford diverse N-aryl phosphoramidates in good to excellent yields at room temperature. PMID- 23683087 TI - Breast image analysis for risk assessment, detection, diagnosis, and treatment of cancer. AB - The role of breast image analysis in radiologists' interpretation tasks in cancer risk assessment, detection, diagnosis, and treatment continues to expand. Breast image analysis methods include segmentation, feature extraction techniques, classifier design, biomechanical modeling, image registration, motion correction, and rigorous methods of evaluation. We present a review of the current status of these task-based image analysis methods, which are being developed for the various image acquisition modalities of mammography, tomosynthesis, computed tomography, ultrasound, and magnetic resonance imaging. Depending on the task, image-based biomarkers from such quantitative image analysis may include morphological, textural, and kinetic characteristics and may depend on accurate modeling and registration of the breast images. We conclude with a discussion of future directions. PMID- 23683088 TI - eHealth: extending, enhancing, and evolving health care. AB - eHealth holds the promise of revolutionizing health care by improving its efficiency; extending and enhancing its reach; energizing and engaging its practitioners and their patients; and in the process, democratizing, decentralizing, and even partially demystifying the practice of medicine. In emerging and developing countries, the use of eHealth and smart health-care planning has the potential to expand access to necessary treatments and prevention services that can serve as underpinnings of rapid economic development. In developed countries, the application of eHealth promises to restructure the business model of health-care delivery, while at the same time improving and personalizing the quality of care received. This article reviews the past, present, and future of eHealth in an effort to illuminate the potential of its impact. PMID- 23683089 TI - Vehicle LATCH system features associated with correct child restraint installations. AB - OBJECTIVE: Lower anchors and tethers for children (LATCH) was intended to standardize the attachment between child restraints and vehicle seats. However, LATCH implementations vary, resulting in differences in ease of attachment of child restraint connectors. Identifying vehicle characteristics associated with correct child restraint installations can provide guidance for designing vehicle LATCH systems that increase correct child restraint installations. METHODS: The LATCH system and other relevant vehicle characteristics were documented in 98 top selling 2010-2011 vehicles. These features, together with proposed LATCH usability recommendations from the International Organization for Standardization and Society of Automotive Engineers, were used to select 12 vehicles for volunteer testing with a range of LATCH system characteristics. Thirty-six volunteers were assigned to 4 groups; each group tested 3 vehicles, 4 child restraints (infant, rear-facing convertible, forward-facing convertible, and combination seat), and 2 installation methods (lower anchors and seat belt) in a split-plot experimental design. Mixed-effects logistic regression models were used to identify predictors of tight installation and correct lower anchor use. RESULTS: Vehicle survey results indicated that most vehicle manufacturers provide the minimum number of LATCH hardware locations required by regulation. Among 21 vehicles with a third row, 4 had no tether anchors and 11 had no lower anchors in the third row. Study volunteers correctly used the lower anchors in 60 percent of LATCH installations and used the top tether in 48 percent of forward-facing installations. When the tether was used, use was correct in 46 percent of trials (22% of all forward-facing installations). Only 13 percent of all trials had completely correct child restraint installation (correct use of lower anchors or seat belt, correct tether anchor use, tight seat installation, and correct installation angle). Tight installation was 3.3 times as likely with correct lower anchor use compared to trials with incorrect use. Three lower anchor characteristics were associated with rates of correct lower anchor use above 50 percent: clearance angle around the lower anchors greater than 54 degrees , attachment forces less than 178 N, and anchor depth within the seat bight of less than 2 cm. Vehicles meeting all 3 criteria were 19 times as likely to have lower anchors used correctly compared to vehicles meeting none of the criteria. No vehicle features predicted either use of tethers or correct use of tethers. CONCLUSIONS: Vehicle LATCH systems that improve lower anchor accessibility could increase the rate of correct lower anchor use, but more research is needed to understand factors associated with tether use and correct use. PMID- 23683090 TI - Screening for major diseases in community pharmacies: a systematic review. AB - OBJECTIVES: The aim of this systematic review was to assess the published evidence about the feasibility and acceptability of community pharmacy-based screening for major diseases. METHOD: Studies published between January 1990 and August 2012 involving community pharmacy-based screening interventions, published in the English language, were identified from electronic databases. Reference lists of included studies were also searched. KEY FINDINGS: Fifty studies (one randomised controlled trial, two cluster randomised studies, five non-randomised comparative studies and 42 uncontrolled studies) were included. The quality of most of these was assessed as poor. Screening was mostly opportunistic and screening tools included questionnaires or risk assessment forms, medical equipment to make physiological measurements, or a combination of both. Few studies assessed the accuracy of pharmacy-based screening tools. More than half of the screening interventions included an element of patient education. The proportion of screened individuals, identified with disease risk factors or the disease itself, ranged from 4% to 89%. Only 10 studies reported any economic information. Where assessed, patient satisfaction with pharmacy-based screening was high, but individuals who screened positive often did not follow pharmacist advice to seek further medical help. CONCLUSION: Available evidence suggests that screening for some diseases in community pharmacies is feasible. More studies are needed to compare effectiveness and cost-effectiveness of pharmacy-based screening with screening by other providers. Strategies to improve screening participants' adherence to pharmacist advice also need to be explored. This systematic review will help to inform future studies wishing to develop community pharmacy-based screening interventions. PMID- 23683091 TI - Crystallization under one-dimensional confinement in alumina nanopores of poly(trimethylene terephthalate) and its composites with single wall carbon nanotubes. AB - We report the preparation of semicrystalline polymer nanorods of PTT and of its nanocomposites with SWCNTs by infiltration of the molten polymer into disordered anodic alumina membranes. An accurate study of the crystalline orientation of these systems has been accomplished by means of X-ray microdiffraction. While polymer residual film exhibits isotropic character, edge-on lamellae are formed upon approaching the polymer/membrane interface. This effect might be due to the elongational flow that takes place in the molten state as polymer chains infiltrate the AAO membrane. At the interface, edge-on and flat-on crystalline lamellae coexist as a consequence of the strong interaction between the polymer and the AAO surface. Inside the nanopores, the confined environment induces a kinetic selection of polymer crystals which only allows the growth of crystalline lamellae with its a-axis parallel to that of the pore. In the case of PTT/SWCNT nanocomposites, this effect, in conjunction with the strong interaction between polymer and AAO surface, seems to prevail over the templating effect of the carbon nanotubes and a similar orientation to that of the neat PTT case is observed. PMID- 23683092 TI - Upper-room ultraviolet germicidal irradiation (UVGI) for air disinfection: a symposium in print. AB - Upper-room ultraviolet germicidal irradiation (UVGI) has several applications, its most important use is to reduce tuberculosis transmission in high-burden, resource-limited settings, especially those dealing with epidemics of drug resistant disease. The efficacy of upper-room (UVGI) to reduce the transmission of airborne infection in real-world settings is no longer in question. International application (dosing) guidelines are needed, as are safety standards and commissioning procedures. A recent symposium to build consensus on guidelines discussed specifications for affordable UVGI fixture designs, safety, performance, computer-aided design (CAD) for UVGI, maintenance, dosimetry, gonioradiometric measurement and innovation using germicidal LEDs. PMID- 23683093 TI - Impact of primary spherical aberration, spatial frequency and Stiles Crawford apodization on wavefront determined refractive error: a computational study. AB - PURPOSE: We tested the hypothesis that pupil apodization is the basis for central pupil bias of spherical refractions in eyes with spherical aberration. METHODS: We employed Fourier computational optics in which we vary spherical aberration levels, pupil size, and pupil apodization (Stiles Crawford Effect) within the pupil function, from which point spread functions and optical transfer functions were computed. Through-focus analysis determined the refractive correction that optimized retinal image quality. RESULTS: For a large pupil (7 mm), as spherical aberration levels increase, refractions that optimize the visual Strehl ratio mirror refractions that maximize high spatial frequency modulation in the image and both focus a near paraxial region of the pupil. These refractions are not affected by Stiles Crawford Effect apodization. Refractions that optimize low spatial frequency modulation come close to minimizing wavefront RMS, and vary with level of spherical aberration and Stiles Crawford Effect. In the presence of significant levels of spherical aberration (e.g. C(4)(0) = 0.4 MUm, 7 mm pupil), low spatial frequency refractions can induce -0.7 D myopic shift compared to high SF refraction, and refractions that maximize image contrast of a three cycle per degree square-wave grating can cause -0.75 D myopic drift relative to refractions that maximize image sharpness. DISCUSSION: Because of small depth of focus associated with high spatial frequency stimuli, the large change in dioptric power across the pupil caused by spherical aberration limits the effective aperture contributing to the image of high spatial frequencies. Thus, when imaging high spatial frequencies, spherical aberration effectively induces an annular aperture defining that portion of the pupil contributing to a well focused image. As spherical focus is manipulated during the refraction procedure, the dimensions of the annular aperture change. Image quality is maximized when the inner radius of the induced annulus falls to zero, thus defining a circular near paraxial region of the pupil that determines refraction outcome. PMID- 23683094 TI - Development and application of active films for food packaging using antibacterial peptide of Bacillus licheniformis Me1. AB - AIMS: An attempt was made to evaluate the effectiveness of partially purified antibacterial peptide (ppABP) produced by Bacillus licheniformis Me1 for food preservation by means of active packaging. METHODS AND RESULTS: The active packaging films containing ppABP were developed using two different packing materials [low-density polyethylene (LDPE) and cellulose films] by two different methods: soaking and spread coating. The activated films showed antibacterial activity against pathogens. The release study of ppABP from coated film showed that the LDPE films liberated ppABP as soon as it comes in contact with water, while gradual release of coated ppABP was observed in case of cellulose films. The activated films showed residual activity in different simulating conditions, such as pH of food and storage temperatures. The activated films demonstrated its biopreservative efficacy in controlling the growth of pathogens in cheese and paneer. CONCLUSIONS: The ppABP-activated films were found to be effective for biopreservation. The ppABP from active films got diffused into the food matrix and reduced the growth rate and maximum growth population of the target micro organism. SIGNIFICANCE AND IMPACT OF THE STUDY: Both types of ppABP-activated films can be used as a packaging material to control spoilage and pathogenic organisms in food, thereby extending the shelf life of foods. PMID- 23683095 TI - WDR19: an ancient, retrograde, intraflagellar ciliary protein is mutated in autosomal recessive retinitis pigmentosa and in Senior-Loken syndrome. AB - Autosomal recessive retinitis pigmentosa (arRP) is a clinically and genetically heterogeneous retinal disease that causes blindness. Our purpose was to identify the causal gene, describe the phenotype and delineate the mutation spectrum in a consanguineous Quebec arRP family. We performed Arrayed Primer Extension (APEX) technology to exclude ~500 arRP mutations in ~20 genes. Homozygosity mapping [single nucleotide polymorphism (SNP) genotyping] identified 10 novel significant homozygous regions. We performed next generation sequencing and whole exome capture. Sanger sequencing provided cosegregation. We screened another 150 retinitis pigmentosa (RP) and 200 patients with Senior-Loken Syndrome (SLS). We identified a novel missense mutation in WDR19, c.2129T>C which lead to a p.Leu710Ser. We found the same mutation in a second Quebec arRP family. Interestingly, two of seven affected members of the original family developed 'sub-clinical' renal cysts. We hypothesized that more severe WDR19 mutations may lead to severe ciliopathies and found seven WDR19 mutations in five SLS families. We identified a new gene for both arRP and SLS. WDR19 is a ciliary protein associated with the intraflagellar transport machinery. We are currently investigating the full extent of the mutation spectrum. Our findings are crucial in expanding the understanding of childhood blindness and identifying new genes. PMID- 23683096 TI - Answer to Dr Alexey Schamko. PMID- 23683098 TI - Objective color classification of ecstasy tablets by hyperspectral imaging. AB - The general procedure followed in the examination of ecstasy tablets for profiling purposes includes a color description, which depends highly on the observers' perception. This study aims to provide objective quantitative color information using visible hyperspectral imaging. Both self-manufactured and illicit tablets, created with different amounts of known colorants were analyzed. We derived reflectance spectra from hyperspectral images of these tablets, and successfully determined the most likely colorant used in the production of all self-manufactured tablets and four of five illicit tablets studied. Upon classification, the concentration of the colorant was estimated using a photon propagation model and a single reference measurement of a tablet of known concentration. The estimated concentrations showed a high correlation with the actual values (R(2) = 0.9374). The achieved color information, combined with other physical and chemical characteristics, can provide a powerful tool for the comparison of tablet seizures, which may reveal their origin. PMID- 23683097 TI - Repopulation of the immunosuppressed retrorsine-treated infant rat liver with human hepatocytes. AB - BACKGROUND: We previously generated humanized chimeric mice by transplanting h hepatocytes into the livers of the diseased-liver transgenic mouse model with immunodeficient background. These mice with livers mostly replaced by human (h) hepatocytes have been proved to be useful for research on drug metabolism and toxicity and on intrahepatic pathogens such as hepatitis. However, their small body size prohibited collecting sufficient biological samples and made surgical manipulation difficult, which motivated us to produce humanized larger animal(s) bearing h-hepatocytes. METHODS: Fischer 344 (F344) rats at 2 weeks of age were administrated with hepatotoxin retrorsine (RS) and then transplanted with syngeneic F344 rat (r)- or h-hepatocytes via the portal vein. The hosts were injected daily with FK506 immunosuppressant. The livers were harvested periodically for determining donor-cell replacement ratios and compared with those of the humanized chimeric mice, and liver-specific mRNA and protein expressions by immunohistochemistry and reverse-transcription PCR. RESULTS: RS treatment of infant rats inhibited hepatocyte proliferation, resulting in decreased liver weight and megalocytic changes in hepatocytes. R-hepatocytes transplanted into RS-treated rats engrafted into and repopulated the liver at ratios of 16.4 +/- 6.7% and 48.3 +/- 29.3% at 3 and 6 weeks after transplantation, respectively. H-hepatocytes also engrafted into the rat liver and showed a repopulation ratio of 2.5 +/- 1.5% at 3 weeks post-transplantation, which was comparable to the ratio in the humanized chimeric mouse model at least until 3 weeks. Propagated h-hepatocytes in the rat liver expressed hepatocyte specific mRNA and proteins at least 3 weeks after transplantation. CONCLUSIONS: Xenogeneic hepatocytes were able to engraft rat liver and grow well therein for at least 3 weeks post-transplantation in rats when immunosuppression was combined appropriately with liver injury at comparable levels to the well-characterized humanized chimeric mouse model. PMID- 23683099 TI - Method for the determination of thyreostats in milk samples using LC-MS/MS. AB - A sensitive and selective analytical method for the determination of four thyreostats (tapazol, thiouracil, methylthiouracil and propylthiouracil) in cow's milk, lamb's milk, and goat's milk was developed and validated according to 2002/657/EC criteria. Proteins in milk samples were precipitated by acetonitrile and analytes were derivatised with 3-iodobenzylbromide. Afterwards, derivatives were separated from the matrix by liquid-liquid extraction with ethyl acetate as an organic solvent and analysis was carried out using LC-MS/MS in a positive electrospray mode. The method provides, for all determined analytes, decision limits CCalpha below 1 ng ml(-1) and a detection capability CCbeta value below 1.5 ng ml(-1). The stability of analytes in sample extracts stored at various conditions was also tested and evaluated. PMID- 23683101 TI - Harry Keen and screening young adults for cardiometabolic disease. PMID- 23683100 TI - Effect of olmesartan on leukocyte recruitment in choroid-sclera complex in hypercholesterolemia model. AB - PURPOSE: Demonstrate that the blockade of angiotensin II AT-1 receptors, through the systemic administration of olmesartan, can reduce the MCP-1 expression and the resulting macrophage accumulation in the choroid and sclera of hypercholesterolemic rabbits. METHODS: Thirty-two New Zealand rabbits were divided into 3 groups: group I (GI) was fed a standard rabbit diet; group II (GII) was fed a hypercholesterolemic diet; and group III (GIII) was fed a hypercholesterolemic diet plus olmesartan. Serum levels of total cholesterol, triglyceride, HDL cholesterol, and blood glucose were determined in fasting rabbits at the beginning of the experiment and on the day of euthanasia. The choroid and sclera were submitted to morphometric analysis as well as immunohistochemical analysis with MCP-1 and RAM-11 (macrophage marker) antibodies. RESULTS: No abnormality was detected in GI. Group II and III had significant increases in choroid-sclera complex thicknesses when compared with group I (P<0.001). GII showed a significant increase in immunoreactivity for MCP 1 in relation to GI (P=0.001) and GIII (P=0.004). GII showed a significant increase in immunoreactivity for RAM-11 of the choroid-sclera complex in relation to GI (P<0.001) and GIII (P=0.034). A significant increase in immunoreactivity for RAM-11 was observed in GIII in relation to GI (P=0.008). CONCLUSION: Olmesartan reduced the MCP-1 expression and the resultant macrophage accumulation in the choroid-sclera complex of hypercholesterolemic rabbits. PMID- 23683102 TI - Professor Harry Keen, champion of people with diabetes worldwide. PMID- 23683104 TI - Systematic review of the development, implementation and availability of smart phone applications for assessing type 2 diabetes risk. PMID- 23683103 TI - Assessment of insulin action on carbohydrate metabolism: physiological and non physiological methods. AB - Carbohydrate metabolism in humans is regulated by insulin secretion from pancreatic beta-cells and glucose disposal by insulin-sensitive tissues. Insulin facilitates glucose utilization in peripheral tissues and suppresses hepatic glucose production. Any defects in insulin action predispose an individual to glucose intolerance and Type 2 diabetes mellitus. Early detection of defects in insulin action could provide opportunities to prevent or delay progression of the disease state. There are different approaches to assess insulin action. Initial methods, such as peripheral insulin concentration and simple indices, have several limitations. Subsequently, researchers developed methodologies using intravenous glucose infusion to determine glucose fluxes. However, these methodologies are limited by being non-physiological. Newer, innovative techniques that have been developed are more sophisticated and physiological. By modelling glucose kinetics using isotope dilution techniques, several robust parameters can be obtained that are physiologically relevant and sound. This brief review summarizes most of the non-physiological and physiological methodologies used to measure the variables of insulin action. PMID- 23683106 TI - Black soybean seed coat extract ameliorates hyperglycemia and insulin sensitivity via the activation of AMP-activated protein kinase in diabetic mice. AB - Black soybean seed coat has abundant levels of polyphenols such as anthocyanins (cyanidin 3-glucoside; C3G) and procyanidins (PCs). This study found that dietary black soybean seed coat extract (BE) ameliorates hyperglycemia and insulin sensitivity via the activation of AMP-activated protein kinase (AMPK) in type 2 diabetic mice. Dietary BE significantly reduced blood glucose levels and enhanced insulin sensitivity. AMPK was activated in the skeletal muscle and liver of diabetic mice fed BE. This activation was accompanied by the up-regulation of glucose transporter 4 in skeletal muscle and the down-regulation of gluconeogenesis in the liver. These changes resulted in improved hyperglycemia and insulin sensitivity in type 2 diabetic mice. In vitro studies using L6 myotubes showed that C3G and PCs significantly induced AMPK activation and enhanced glucose uptake into the cells. PMID- 23683107 TI - Substituent effects on the electrochemical, spectroscopic, and structural properties of Fischer mono- and biscarbene complexes of chromium(0). AB - A series of ten ferrocenyl, furyl, and thienyl mono- and biscarbene chromium(0) complexes were synthesized and characterized spectroscopically and electrochemically. The single crystal structure of the biscarbene complex [(CO)5Cr?C(OEt)-Fu'-(OEt)C?Cr(CO)5] (4a) was determined: C20H12Cr2O13; triclinic; P1; a = 6.2838(5), b = 12.6526(9), c = 29.1888(19) A, alpha = 89.575(2), beta = 88.030(2), gamma = 87.423(2) degrees ; Z = 4. Results from an electrochemical study in CH2Cl2 were mutually consistent with a computational study in showing that the carbene double bond of 1-6 is reduced to an anion radical, (-)Cr-C* at formal reduction potentials < -1.7 V vs FcH/FcH(+). The Cr centers are oxidized in two successive one electron transfer steps to Cr(II) via the Cr(I) intermediate. Only Cr(I) oxidation is electrochemically irreversible. Dicationic Cr(II) species formed upon two consecutive one-electron oxidation processes are characterized by a peculiar bonding situation as they are stabilized by genuine CH...Cr agostic interactions. With respect to aryl substituents, carbene redox processes occurred at the lowest potentials for ferrocene derivatives followed by furan complexes. Redox process in the thiophene derivatives occurred at the highest potentials. This result is mutually consistent with a (13)C NMR study that showed the Cr?C functionality of furyl complexes were more shielded than thienyl complexes. The NHBu carbene substituent resulted in carbene complexes showing redox processes at substantially lower redox potentials than carbenes having OEt substituents. PMID- 23683108 TI - Optimizing preservation protocols to extract high-quality RNA from different tissues of echinoderms for next-generation sequencing. AB - Transcriptomic information provides fundamental insights into biological processes. Extraction of quality RNA is a challenging step, and preservation and extraction protocols need to be adjusted in many cases. Our objectives were to optimize preservation protocols for isolation of high-quality RNA from diverse echinoderm tissues and to compare the utility of parameters as absorbance ratios and RIN values to assess RNA quality. Three different tissues (gonad, oesophagus and coelomocytes) were selected from the sea urchin Arbacia lixula. Solid tissues were flash-frozen and stored at -80 degrees C until processed. Four preservation treatments were applied to coelomocytes: flash freezing and storage at -80 degrees C, RNAlater and storage at -20 degrees C, preservation in TRIzol reagent and storage at -80 degrees C and direct extraction with TRIzol from fresh cells. Extractions of total RNA were performed with a modified TRIzol protocol for all tissues. Our results showed high values of RNA quantity and quality for all tissues, showing nonsignificant differences among them. However, while flash freezing was effective for solid tissues, it was inadequate for coelomocytes because of the low quality of the RNA extractions. Coelomocytes preserved in RNAlater displayed large variability in RNA integrity and insufficient RNA amount for further isolation of mRNA. TRIzol was the most efficient system for stabilizing RNA which resulted on high RNA quality and quantity. We did not detect correlation between absorbance ratios and RNA integrity. The best strategies for assessing RNA integrity was the visualization of 18S rRNA and 28S rRNA bands in agarose gels and estimation of RIN values with Agilent Bioanalyzer chips. PMID- 23683109 TI - Why don't we conduct replication studies in medical education? PMID- 23683110 TI - Pemetrexed for the treatment of non-small cell lung cancer. AB - INTRODUCTION: Non-small cell lung cancer (NSCLC) is a major cause of cancer related death worldwide. Although advanced NSCLC is still incurable, various anti neoplastic agents have become available for the treatment of this disease. Pemetrexed , a multi-target folate antagonist, has improved the survival of non squamous NSCLC patients. Currently, pemetrexed is approved for first-line treatment in combination with a platinum derivate, for second-line treatment as a single agent and, more recently, as maintenance treatment after first-line chemotherapy. AREAS COVERED: The authors analyzed the state of the art of pemetrexed through a review of the literature. Clinical trials and meta-analyses involving pemetrexed in NSCLC were evaluated. Pemetrexed improved survival of non squamous NSCLC in first-line, maintenance, and second-line treatments; this benefit is limited to non-squamous histology. Because pemetrexed has become part of the standard of care, current clinical trials are designed to compare it to other investigational combinations. Limited data on resectable disease are available, and additional clinical trials are being conducted. EXPERT OPINION: Pemetrexed has shown effectiveness and a favorable toxicity profile. Histology driven indications and the relationship of pemetrexed with thymidylate synthase expression suggest that a more precise definition of predictive biomarkers could be further investigated. PMID- 23683111 TI - A comparison of the assessment and management of cardiometabolic risk in patients with and without type 2 diabetes mellitus in Canadian primary care. AB - AIM: To investigate the cardiometabolic risk (CMR) assessment and management patterns for individuals with and without type 2 diabetes mellitus (T2DM) in Canadian primary care practices. METHODS: Between April 2011 and March 2012, physicians from 9 primary care teams and 88 traditional non-team practices completed a practice assessment on the management of 2461 patients >40 years old with no clinical evidence of cardiovascular disease and diagnosed with at least one of the following risk factor-T2DM, dyslipidaemia or hypertension. RESULTS: There were 1304 individuals with T2DM and 1157 without. Pharmacotherapy to manage hyperglycaemia, dyslipidaemia and hypertension was widely prescribed. Fifty-eight percent of individuals with T2DM had a glycated haemoglobin (HbA1c) <=7.0%. Amongst individuals with dyslipidaemia, median low-density lipoprotein cholesterol (LDL-C) was 1.8 mmol/l for those with T2DM and 2.8 mmol/l for those without. Amongst individuals with hypertension, 30% of those with T2DM achieved the <130/80 mmHg target, whereas 60% of those without met the <140/90 mmHg target. The composite glycaemic, LDL-C and blood pressure (BP) target outcome was achieved by 12% of individuals with T2DM. Only 17% of individuals with T2DM and 11% without were advised to increase their physical activity. Dietary modifications were recommended to 32 and 10% of those with and without T2DM, respectively. CONCLUSIONS: Patients at elevated CMR were suboptimally managed in the primary care practices surveyed. There was low attainment of recommended therapeutic glycaemic, lipid and BP targets. Advice on healthy lifestyle changes was infrequently dispensed, representing a missed opportunity to educate patients on the long-term benefits of lifestyle modification. PMID- 23683112 TI - Iron-catalyzed direct synthesis of imines from amines or alcohols and amines via aerobic oxidative reactions under air. AB - Abundant and cheap iron readily catalyzed the aerobic oxidative reactions of primary amines, secondary amines, benzylamines with anilines, and alcohols with amines by directly using air as the economic and safe oxidant, providing several direct, practical, and greener approaches for the preparation of useful imines. PMID- 23683113 TI - Vascular depression and frailty: a compound threat to longevity among older-old women. AB - OBJECTIVES: The vascular depression hypothesis posits that cerebrovascular burden contributes to the development of depression symptoms in late life. Building on work that suggests that vascular depression is a prodrome for frailty, this paper tests a theoretical framework that vascular depression symptoms are an early marker of a broader pattern of decline characterized by more frailty symptoms and shortened lifespan, and that vascular depression symptoms predict mortality through frailty. METHODS: The sample was drawn from the Health and Retirement Study and included 1361 stroke-free women over the age of 80. Data were included from six biannual waves from 1998 to 2008 (waves 4-9). A vascular depression symptomatology variable was based on Center for Epidemiological Studies Depression Scale (CES-D) scores and number of cerebrovascular risk factors (hypertension, diabetes, cardiac disease, and smoking). Frailty was measured based on wasting, slowness, weakness, fatigue, and falls. Vascular depression and frailty symptoms were modeled using slope and intercept terms. Mortality was modeled using a discrete-time survival term. RESULTS: The data supported the proposed model (RMSEA = 0.051; CFI = 0.971; X2 = 234.84, p < 0.001). Higher vascular depression symptom slope and intercept scores significantly predicted higher frailty slope and intercept scores, respectively. Frailty intercept scores significantly predicted mortality. The vascular depression symptoms indirectly predicted mortality through frailty symptoms. A second model testing the competing hypothesis - that frailty symptoms lead to vascular depression symptoms and indirectly to mortality - was not supported by the data. CONCLUSIONS: Results suggest that vascular depression symptoms are associated with a clinical trajectory that includes greater frailty and shortened remaining lifespan. PMID- 23683115 TI - Formation and properties of selenium double-helices inside double-wall carbon nanotubes: experiment and theory. AB - We report the production of covalently bonded selenium double-helices within the narrow cavity inside double-wall carbon nanotubes. The double-helix structure, characterized by high-resolution transmission electron microscopy and X-ray diffraction, is completely different from the bulk atomic arrangement and may be considered a new structural phase of Se. Supporting ab initio calculations indicate that the observed encapsulated Se double-helices are radially compressed and have formed from free Se atoms or short chains contained inside carbon nanotubes. The calculated electronic structure of Se double-helices is very different from the bulk system, indicating the possibility to develop a new branch of Se chemistry. PMID- 23683114 TI - Two-vehicle injury severity models based on integration of pavement management and traffic engineering factors. AB - OBJECTIVE: The severity of traffic-related injuries has been studied by many researchers in recent decades. However, the evaluation of many factors is still in dispute and, until this point, few studies have taken into account pavement management factors as points of interest. The objective of this article is to evaluate the combined influences of pavement management factors and traditional traffic engineering factors on the injury severity of 2-vehicle crashes. METHODS: This study examines 2-vehicle rear-end, sideswipe, and angle collisions that occurred on Tennessee state routes from 2004 to 2008. Both the traditional ordered probit (OP) model and Bayesian ordered probit (BOP) model with weak informative prior were fitted for each collision type. The performances of these models were evaluated based on the parameter estimates and deviances. RESULTS: The results indicated that pavement management factors played identical roles in all 3 collision types. Pavement serviceability produces significant positive effects on the severity of injuries. The pavement distress index (PDI), rutting depth (RD), and rutting depth difference between right and left wheels (RD_df) were not significant in any of these 3 collision types. The effects of traffic engineering factors varied across collision types, except that a few were consistently significant in all 3 collision types, such as annual average daily traffic (AADT), rural-urban location, speed limit, peaking hour, and light condition. CONCLUSIONS: The findings of this study indicated that improved pavement quality does not necessarily lessen the severity of injuries when a 2 vehicle crash occurs. The effects of traffic engineering factors are not universal but vary by the type of crash. The study also found that the BOP model with a weak informative prior can be used as an alternative but was not superior to the traditional OP model in terms of overall performance. PMID- 23683116 TI - Phase transfer of triangular silver nanoprisms from aqueous to organic solvent by an amide coupling reaction. AB - In this paper, we describe a procedure for the phase transfer of silver nanoprisms (AgNPrs) from aqueous solution to chloroform via an amide coupling reaction. AgNPrs are first modified with 16-mercaptohexadecanoic acid (MHA), and then primary or secondary amines are attached to the carboxylic acid end of the MHA ligand through a carbodiimide-mediated amide coupling step. Secondary amines, such as dicyclohexylamine and diphenylamine, are found to solubilize the nanoparticles in chloroform, whereas primary amines (e.g., butylamine and hexadecylamine) do not result in phase transfer. It is found that the AgNPrs functionalized with dicyclohexylamine show the highest stability and the least aggregation after undergoing phase transfer; in contrast, with a less nucleophilic amine, such as diphenylamine, the amide coupling reaction does not go to completion and the resultant AgNPrs are less stable and more prone to aggregation. PMID- 23683118 TI - Experiences of health and well-being among Finnish low-income fathers. AB - This article describes the everyday experiences of health and well-being among Finnish low-income fathers. The aim of study is to understand the health experiences of low-income fathers and the factors influencing the health experience and to develop nursing care in order to provide support for them. The approach is phenomenological and method is based on hermeneutical and descriptive phenomenology. The informants in this study were seven low-income Finnish fathers with children under 16 years old. Well-being of the fathers appeared as personal, realistic and bound to everyday life: income sufficient for meeting basic needs, everyday health, the pleasure and priviledge of life and the meaningfulness of the relationships in family and in community. Fathers used individual methods for maintaining the experience of well-being and they experienced the support from official sources as positive or negative. The findings of this study suggest that well-being of low-income fathers living under threat of marginalisation will be supported by care providers taking into account individual, social and economic factors, and that this support will have to be gender-sensitive, realistic and based on their everyday life. PMID- 23683117 TI - Establishment of monocular-limited photoreceptor degeneration models in rabbits. AB - BACKGROUND: Numerous rodent models of photoreceptor degeneration have been developed for the study of visual function. However, no viable model has been established in a species that is more closely related to Homo sapiens. Here, we present a rabbit model of monocular photoreceptor degeneration. METHODS: We tested 2 chemicals, verteporfin and sodium nitroprusside (SNP), for developing a 1-eye limited photoreceptor degeneration model in pigmented rabbits. After the intravenous injection of verteporfin, the retina was exposed to light from a halogen lamp for 0, 10, 30, or 60 min. Alternately, 100 MUL of various concentrations of sodium nitroprusside (0.1 mM, 0.5 mM, and 1 mM) were intravitreously injected into the rabbit eye. Retinal degeneration was evaluated by fundus photography, electroretinogram (ERG), and histological examinations. RESULTS: Fundus photographs of animals in the verteporfin- or SNP-treated groups showed evidence of retinal degeneration. The severity of this degradation depended on the duration of light exposure and the concentration of SNP administered. The degeneration was clearly limited to the light-exposed areas in the verteporfin-treated groups. Extensive retinal atrophy was observed in the SNP treated groups. The a- and b-wave amplitudes were dramatically decreased on the ERGs from SNP-treated groups. Histological examination revealed that either verteporfin or SNP induced severe photoreceptor degeneration. High-dose SNP treatment (1 mM) was also associated with inner retinal layer degeneration. CONCLUSIONS: Both SNP and verteporfin clearly caused photoreceptor degeneration without any effect on the contralateral eye. These compounds therefore represent valuable tools for the empirical investigation of visual function recovery. The findings will inform guidelines for clinical applications such as retinal prostheses, cell-based therapy, and gene therapy. PMID- 23683119 TI - Barriers to alcohol and other drug treatment use among Black African and Coloured South Africans. AB - BACKGROUND: There are racial disparities in the use of alcohol and other drug (AOD) treatment services in South Africa but little is known about the factors contributing to these disparities. This study aimed to redress this gap through identifying differences in barriers to AOD treatment use among Black African and Coloured persons from Cape Town, South Africa. The Behavioral Model of Health Services Utilization was used as an analytic framework. METHODS: A case-control design was used to compare 434 individuals with AOD problems who had accessed treatment with 555 controls who had not accessed treatment on a range of variables. Logistic regression procedures were employed to examine the unique profile of variables associated with treatment utilization for Black African and Coloured participants. RESULTS: After controlling for the influence of treatment need and predisposing factors on treatment use, several barriers to treatment were identified. Greater awareness of treatment options and fewer geographic access and affordability barriers were strongly associated with an increased likelihood of AOD treatment use for both race groups. However, Black African persons were more vulnerable to the effects of awareness and geographic access barriers on treatment use. Stigma consciousness was only associated with AOD treatment utilization for Coloured participants. CONCLUSION: Differences in barriers to AOD treatment use were found among Black African and Coloured South Africans. Targeted interventions that address the unique profile of barriers experienced by each race group are needed to improve AOD treatment use by these underserved groups. Several strategies for improving the likelihood of treatment entry are suggested. PMID- 23683120 TI - Family meetings for older adults in intermediate care settings: the impact of patient cognitive impairment and other characteristics on shared decision making. AB - BACKGROUND: Clinicians, older adults and caregivers frequently meet to make decisions around treatment and lifestyle during an acute hospital admission. Patient age, psychological status and health locus of control (HLC) influence patient preference for consultation involvement and information but overall, a shared-decision-making (SDM) approach is favoured. However, it is not known whether these characteristics and the presence of cognitive impairment influence SDM competency during family meetings. OBJECTIVE: To describe meetings between older adults, caregivers and geriatricians in intermediate care and explore patient and meeting characteristics associated with a SDM communication style. METHODS: Fifty-nine family meetings involving geriatricians, patients in an intermediate care setting following an acute hospital admission and their caregivers were rated using the OPTION system for measuring clinician SDM behaviour. The geriatric depression scale and multidimensional HLC scale were completed by patients. The mini-mental state exam (MMSE) assessed patient's level of cognitive impairment. RESULTS: Meetings lasted 38 min (SD 13) and scored 41 (SD 17) of 100 on the OPTION scale. Nine (SD 2.2) topics were discussed during each meeting, and most were initiated by the geriatrician. Meeting length was an important determinant of OPTION score, with higher SDM competency displayed in longer meetings. Patient characteristics, including MMSE, HLC and depression did not explain SDM competency. CONCLUSION: Whilst SDM can be achieved during consultations frail older patients and their caregivers, an increased consultation time is a consequence of this approach. PMID- 23683121 TI - Electric field induced morphological transitions in polyelectrolyte multilayers. AB - In this work, the morphological transitions in weak polyelectrolyte (PE) multilayers (PEMs) assembled from linear poly(ethylene imine) (LPEI) and poly(acrylic acid) (PAA) upon application of an electric field were studied. Exposure to an electric field results in the creation of a porous structure, which can be ascribed to local changes in pH from the hydrolysis of water and subsequent structural rearrangements of the weak PE constituents. Depending on the duration of application of the field, the porous transition gradually develops into a range of structures and pore sizes. It was discovered that the morphological transition of the LbL films starts at the multilayer-electrode interface and propagates through the film. First an asymmetrical structure forms, consisting of microscaled pores near the electrode and nanoscaled pores near the surface in contact with the electrolyte solution. At longer application of the field the porous structures become microscaled throughout. The results revealed in this study not only demonstrate experimental feasibility for controlling variation in pore size and porosity of multilayer films but also deepens the understanding of the mechanism of the porous transition. In addition, electrical potential is used to release small molecules from the PEMs. PMID- 23683122 TI - Analyzing the microfoundations of human violence in the DRC - intrinsic and extrinsic rewards and the prediction of appetitive aggression. AB - BACKGROUND: Civil wars are characterized by intense forms of violence, such as torture, maiming and rape. Political scientists suggest that this form of political violence is fostered through the provision of particular intrinsic and extrinsic rewards to combatants. In the field of psychology, the perpetration of this kind of cruelty is observed to be positively linked to appetitive aggression. Over time, combatants start to enjoy the fights and even the perpetration of atrocities. In this study, we examine how receiving rewards (intrinsic versus extrinsic) influence the level of appetitive aggression exhibited by former combatants. METHOD: We surveyed 95 former combatants in the eastern provinces of the Democratic Republic of the Congo. RESULTS: Linear regression analyses reveal that intrinsic as well as extrinsic rewards are linked to the former combatants' Appetitive Aggression score. However, this relationship is partly determined by the way in which combatants are recruited: While abducted combatants seem to react more strongly to extrinsic rewards, the score of those that joined voluntarily is primarily determined by intrinsic rewards. CONCLUSIONS: We conclude that receiving rewards influence the level of appetitive aggression. However, which type of rewards (intrinsic versus extrinsic) is of most importance is determined by the way combatants are recruited. PMID- 23683123 TI - A unique Y gene in the Asian malaria mosquito Anopheles stephensi encodes a small lysine-rich protein and is transcribed at the onset of embryonic development. AB - In many organisms the Y chromosome initiates sex determination and regulates male fertility and mating behaviour. However, molecular characterization of Y genes is rare outside of a few model species because it is difficult to clone and analyse repeat-rich heterochromatic Y sequences. In insects, Y genes are only well characterized in a small number of Drosophila species. Here we report the discovery of GUY1 (gene unique to the Y), a gene unique to the Y chromosome in the Asian malaria mosquito, Anopheles stephensi, using an approach that compares Illumina sequences separately obtained from male and female genomic DNA. Experimental evidence confirmed that GUY1 is a single copy gene found only on the Y chromosome. GUY1 is transcribed at the very onset of zygotic transcription and encodes a small lysine-rich protein that forms two alpha helices and shows DNA binding properties. Interestingly, three helix-loop-helix proteins are key factors that determine sex in the early embryo in Drosophila melanogaster. Single embryo analysis indicated that GUY1 is only transcribed in male embryos and that the GUY1 promoter is functional in the early embryos. GUY1 may be used as a paternally inherited molecular marker. Further investigation of GUY1 will contribute to the genetic approaches to control mosquito-borne diseases. PMID- 23683124 TI - Oxidation of tyrosine photoinduced by pterin in aqueous solution. AB - Pterins, heterocyclic compounds widespread in biological systems, accumulate in the skin of patients suffering from vitiligo, a chronic depigmentation disorder. Pterins have been previously identified as good photosensitizers under UV-A irradiation. In this work, we have investigated the ability of pterin (Ptr), the parent compound of oxidized pterins, to photosensitize the oxidation of tyrosine (Tyr) in aqueous solutions. Tyr is an important target in the study of the photodynamic effects of UV-A radiation because it is oxidized by singlet oxygen ((1)O2) and plays a key role in polymerization and cross-linking of proteins. Steady UV-A irradiation of solutions containing Ptr and Tyr led to the consumption of Tyr and dissolved O2, whereas the Ptr concentration remained unchanged. Concomitantly, hydrogen peroxide (H2O2) was produced. By combining different analytical techniques, we could establish that the mechanism of the photosensitized process involves an electron transfer from Tyr to the triplet excited state of Ptr. Mass spectrometry, chromatography and fluorescence were used to analyze the photoproducts. In particular, oxygenated and dimeric compounds were identified. PMID- 23683125 TI - Decreasing incidence of AA amyloidosis in Spain. AB - BACKGROUND: The main objectives of our study were to review all cases of amyloidosis diagnosed by renal biopsy in Spain from 1994 to 2009 and to analyse variations in the incidence over time. MATERIALS AND METHODS: We analysed all biopsies from native kidneys included in the Spanish Registry of Glomerulonephritis. A total of 120 centres provided 17 680 biopsies over 16 years. Follow-up was divided in four periods. RESULTS: We collected 653 cases of renal amyloidosis. In 438 cases (67%), amyloidosis type was specified, [AA amyloidosis, 253 cases (57.8%); AL amyloidosis, 185 cases (42.2%)]. Mean age was 60 (17.8) years; 51.4% of patients were younger than 65. Overall incidence was 3.7%. In patients < 65, AA amyloidosis was present in 66.1% and AL amyloidosis in 33.9% (P < 0.01). No differences were found in patients > 65. Patients with AA amyloidosis were younger (56.8 vs. 64.0, P < 0.01) and had worse creatinine clearance (35 vs. 57 mL/min, P < 0.01). We found a decrease in the incidence among biopsies collected during each of the 4 study periods (4.2%, 3.9%, 3.5% and 3.2%, respectively, P < 0.001). CONCLUSIONS: This is the largest series of renal amyloidosis in kidney biopsies published to date. We found amyloidosis to be decreasing slowly in Spain. This decrease affects both types and is confirmed in all cases marked in patients < 65 and in AA type. AA amyloidosis was the most frequent in our series. Patients affected by it were younger and had worse kidney function, with no differences in the level of proteinuria. PMID- 23683126 TI - Treatment with the sphingosine-1-phosphate analogue FTY 720 reduces loss of plasma volume during experimental sepsis in the rat. AB - BACKGROUND: Increased vascular leakage leading to hypovolaemia and tissue oedema is common in severe sepsis. Hypovolaemia together with oedema formation may contribute to hypoxia and result in multiorgan failure and death. To improve treatment during sepsis, a potential therapeutic target may be to reduce the vascular leakage. Substances affecting the endothelial barrier are interesting in this respect, as it is suggested that increase in vascular leakage depends on reorganisation of the endothelial cells and breakdown of the endothelial barrier. The agonist of the bioactive lipid sphingosine-1-phosphate, FTY720, has been shown to modulate the integrity of the endothelium and reduce permeability both in vitro and in vivo. The aim of the present study was to determine if FTY720 could reduce the loss of plasma volume during experimental sepsis in rats. METHODS: Sepsis was induced by ligation and incision of the caecum in the rat. Plasma volume was determined before and 4.5 h after induction of sepsis by a dilution technique using (125) I-labelled albumin. RESULTS: FTY720 in a dose of 0.2 mg/kg reduced the loss of plasma during sepsis by approximately 30% compared with vehicle, without any adverse effects on haemodynamic and physiological parameters. The increase in hematocrit and haemoglobin concentration was also found to be higher in the vehicle group. CONCLUSION: FTY720 in a dose without haemodynamic side effects reduces loss of plasma volume during experimental sepsis most likely because of reduction in permeability and may therefore be beneficial in sepsis. PMID- 23683128 TI - Papillary thyroid cancer with bilateral adrenal metastases. AB - BACKGROUND: Papillary thyroid cancer is the most common type of thyroid malignancy and has an excellent prognosis. Distant organ metastasis is rare. Bilateral adrenal metastases with iodine uptake has not been described before. PATIENT FINDINGS: A 47-year-old woman presented for evaluation because of severe right upper arm pain and weakness. Magnetic resonance imaging of the thoracic spine showed a compression fracture at the third thoracic vertebra associated with a soft tissue mass. Computed tomography (CT)-guided biopsy of the mass showed metastatic papillary thyroid carcinoma. Ultrasonography of the neck showed an enlarged right thyroid lobe with cervical lymphadenopathy. A high-resolution CT scan of the chest showed multiple bilateral pulmonary nodules. Treatment included total thyroidectomy and lymph node dissection, external beam radiation to the thoracic spine, and (131)I therapy. Initial whole body (131)I scintigraphy showed faint uptake in the right upper abdomen, interpreted as a sign of physiologic bowel activity; however, repeat whole body (131)I scintigraphy showed increased uptake in both adrenal glands, consistent with metastatic disease. Serial abdominal CT scans showed progressively enlarging bilateral adrenal masses. Despite additional treatment with (131)I, the patient's disease progressed at all metastatic sites. SUMMARY: This patient had bilateral adrenal metastases from advanced papillary thyroid cancer with distant metastasis to lung and bone at initial presentation and poor response to repeated (131)I therapy. Unilateral adrenal metastasis from thyroid cancer has been described previously in six cases; this is the first case report of bilateral adrenal metastases. CONCLUSIONS: Bilateral adrenal metastasis is rare in papillary thyroid cancer. Elevated abdominal uptake of (131)I in a high-risk patient may be a sign of abdominal metastatic disease. PMID- 23683127 TI - Inflammatory infratentorial progressive multifocal leukoencephalopathy in a patient with rheumatoid arthritis. AB - An 84-year-old man with rheumatoid arthritis (RA) treated with methotrexate, developed progressive confusion and cerebellar symptoms, and died approximately 2 months later. Neuropathological examination revealed progressive multifocal leukoencephalopathy (PML) involving the cerebellum and brainstem. The affected tissues displayed intense infiltrations by CD8+ T-cells and microglia. JC virus was localized in oligodendroglia and cerebellar granule cells. This case illustrates unusual localization of inflammatory PML in a patient with RA treated with methotrexate. PMID- 23683129 TI - The reverend: waiting for a miracle. PMID- 23683130 TI - Fighting words. PMID- 23683131 TI - The dying lone wolf. PMID- 23683132 TI - Fusarium damage in small cereal grains from Western Canada. 2. Occurrence of fusarium toxins and their source organisms in durum wheat harvested in 2010. AB - Samples of Canadian western amber durum harvested in 2010 were obtained as part of the Canadian Grain Commission Harvest Sample Program, inspected, and graded according to Canadian guidelines. A subset of Fusarium -damaged samples were analyzed for Fusarium species as well as mycotoxins associated with these species, including deoxynivalenol and other trichothecenes, moniliformin, enniatins, and beauvericin. Overall, Fusarium avenaceum and F. graminearum were the top two most frequently recovered species. Phaeosphaeria nodorum (a.k.a. Septoria nodorum ), F. culmorum , F. poae , F. acuminatum , and F. sporotrichioides were observed in samples as well. All samples analyzed for mycotoxins contained quantifiable concentrations of enniatins, whereas beauvericin, deoxynivalenol, and moniliformin were measured in approximately 75% of the samples. Concentrations in Fusarium -damaged samples ranged from 0.011 to 34.2 mg/kg of enniatins plus beauvericin, up to 4.7 mg/kg of deoxynivalenol, and up to 6.36 mg/kg of moniliformin. Comparisons of enniatins, beauvericin, and moniliformin concentrations to the occurrence of various Fusarium species suggest the existence of an infection threshold above which these emerging mycotoxins are present at higher concentrations. The current grading factor of Fusarium -damaged kernels manages concentrations of these emerging mycotoxins in grain; lower provisional grades were assigned to samples that contained the highest concentrations of enniatins, beauvericin, and moniliformin. PMID- 23683133 TI - Variability in the blood/breath alcohol ratio and implications for evidentiary purposes. AB - The breath analyzer is an indispensable tool for identifying alcohol levels among drivers. While numerous studies have shown high correlations between blood and breath alcohol concentrations, most are limited by the study design. This study seeks to assess this relationship by minimizing potential measurement bias, document time from alcohol consumption to testing, and adjusting for potential confounders. A blinded study was performed using conditions closely resembling those in the field. The Draeger 7110 MKIII IL breath analyzer was used to assess breath alcohol concentrations (BrAC). Participants were 61 healthy volunteers aged 21-37 years with body mass index <=30 and no history of alcoholism. A total of 242 valid blood/breath tests were performed in four test sets. The study results showed a high correlation coefficient between BrAC and blood alcohol concentration (BAC) levels (r = 0.983) with high sensitivity (97%) and specificity (93%). This strong association between the breath analyzer and BAC persisted even after adjustment for various stages of alcohol absorption. These results illustrate the high diagnostic sensitivity of the breath analyzer in field-tested conditions. PMID- 23683135 TI - Benzofuran derivatives: a patent review. AB - INTRODUCTION: Benzofuran moiety constitutes the core of several interesting pharmacologically active natural products. Benzofurans are among feasible potent active inhibitors against many diseases, viruses, microbes, fungus and enzymes. Several series of therapeutically important synthetic and naturally occurring benzofuran-containing compounds are reported in this chapter. AREAS COVERED: The current chapter focuses on the recent applications of benzofuran scaffolds and their wide range of biological activities during 1999 - 2012. The pharmacological areas covered included anti-inflammatory, antitumor, cytotoxic, antimicrobial, antitubercular, antioxidant, antiplasmodial, trypanocidal and insecticidal activities as well as enzyme inhibitory, HCV and HIV inhibitory activities. EXPERT OPINION: The results reported in the chapter indicate that some benzofuran derivatives may be useful as potent drugs. From the structure-activity relationship (SAR), the presence of certain functions like -OH, -OMe in the benzofuran derivatives contributed greatly in increasing the potency of their therapeutic activities when compared with standards. For example, presence of the -OH and -OMe have made some benzofuran compounds more potent HIV-RT inhibitory activity than the standard atevirdine, and more potent antitumor agent when compared with standards (fluorouracil, doxorubicin and cytarabine). In addition, the enzyme aromatase CYP19 inhibitory activity of benzofurans having -OH and -OMe were greater than that observed for the reference arimidex. PMID- 23683136 TI - Rethinking clinical reasoning. PMID- 23683134 TI - Diabetes and gout: efficacy and safety of febuxostat and allopurinol. AB - AIM: Assess influences of demographics and co-morbidities of gout patients with or without diabetes on safety and efficacy of urate-lowering agents. METHODS: Post-hoc analysis of 312 diabetic and 1957 non-diabetic gout patients [baseline serum urate levels (sUA) >=8.0 mg/dl] enrolled in a 6-month randomized controlled trial comparing urate-lowering efficacy (ULE) and safety of daily xanthine oxidase inhibitors (XOIs) febuxostat (40 mg or 80 mg) and allopurinol (200 mg or 300 mg). We compared baseline demographic, gout and co-morbid characteristics, ULE, and safety of XOI treatment in diabetic and non-diabetic gout patients. ULE was measured by the proportion of diabetic and non-diabetic patients in each treatment group achieving final visit sUA < 6.0 mg/dl. Safety was monitored throughout the trial. RESULTS: Diabetic gout patients were older, more frequently female, and had longer gout duration. Co-morbidities were more frequent among diabetic patients: cardiovascular disease; impaired renal function; hyperlipidemia; and obesity (body mass index >30 kg/m2) (p < 0.001 for all comparisons). Febuxostat 80 mg ULE exceeded that of febuxostat 40 mg or allopurinol (p < 0.050) at all levels of renal function, achieving sUA goal range in the majority of diabetic and non-diabetic patients. Diabetics and non diabetics reported self-limiting diarrhoea and URIs as the most common adverse events. CONCLUSIONS: Despite higher co-morbidity rates in diabetic patients, febuxostat and allopurinol were safe in both groups at the doses tested. Febuxostat 80 mg achieved sUA <6.0 mg/dl more often than febuxostat 40 mg or allopurinol at commonly prescribed doses. PMID- 23683137 TI - Mechanisms of reactions of open-shell, heavier group 14 derivatives with small molecules: n-pi* back-bonding in isocyanide complexes, C-H activation under ambient conditions, CO coupling, and ancillary molecular interactions. AB - The main themes of this review are the mechanisms of the reactions of germanium and tin analogues of carbenes with isocyanides, CO, ammonia, and related molecules. The treatment of Ge(Ar(Me6))2 (Ar(Me6) = C6H3-2,6(C6H2-2,4,6-Me3)2) with MeNC or Bu(t)NC afforded 1:1 complexes, but the increase in the electron density at germanium leads to C-H activation at the isocyanide methyl or tert butyl substituents. For MeNC, the initial adduct formation is followed by a migratory insertion of the MeNC carbon into a Ge-C(ipso) bond of an aryl substituent. The addition of excess MeNC led to sequential insertions of two further MeNC molecules. The third insertion led to methylisocyanide methyl group C-H activation, to afford an azagermacyclopentadienyl species. The Bu(t)NC complex (Ar(Me6))2GeCNBu(t) spontanously transforms into (Ar(Me6))2Ge(H)CN and isobutene with C-H activation of the Bu(t) substituent. The germylene Ge(Ar(Me6))(Ar(Pr(i)4)) [Ar(Pr(i)4) = C6H3-2,6(C6H3-2,6-Pr(i)2)2] reacted with CO to afford alpha-germyloxyketones. The initial step is the formation of a 1:1 complex, followed by migratory insertion into the Ge-C bond of the Ar(Pr(i)4) ligand to give Ar(Me6)GeC(O)Ar(Pr(i)4). Insertion of a second CO gave Ar(Me6)GeC(O)C(O)Ar(Pr(i)4), which rearranges to afford alpha-germyloxyketone. No reaction was observed for Sn(Ar(Me6))2 with RNC (R = Me, Bu(t)) or CO. Spectroscopic (IR) results and density functional theory (DFT) calculations showed that the reactivity can be rationalized on the basis of Ge-C (isocyanide or CO) Ge(n) -> pi* (ligand) back-bonding. The reaction of Ge(Ar(Me6))2 and Sn(Ar(Me6))2 with ammonia or hydrazines initially gave 1:1 adducts. However, DFT calculations show that there are ancillary N-H---N interactions with a second ammonia or hydrazine, which stabilizes the transition state to form germanium(IV) hydride (amido or hydrazido) products. For tin, arene elimination is favored by a buildup of electron density at the tin, as well as the greater polarity of the Sn C(ipso) bond. Germanium(IV) products were observed upon reaction of Ge(Ar(Me6))2 with acids, whereas reactions of Sn(Ar(Me6))2 with acids did not give tin(II) products. In contrast to reactions with NH3, there is no buildup of negative charge at tin upon protonation, and its subsequent reaction with conjugate bases readily affords the tin(IV) products. PMID- 23683140 TI - Fast vs. slow switching from stimulants to atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder. AB - OBJECTIVE: To compare fast versus slow switching from stimulants to atomoxetine (ATX) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). METHODS: This was a randomized, controlled, open-label study in 6-16-year old ADHD patients, previously treated with stimulants and cross-titrated (fast switch, over 2 weeks, or slow switch, over 10 weeks) to ATX because of unsatisfactory response and/or adverse events. Study duration was 14 weeks with an ATX standard target dose of 1.2 mg/kg/day. Primary measure was the change from baseline in the investigator-rated ADHD-Rating Scale (ADHD-RS) at weeks 2 and 10. Secondary measures included Global Impression of Perceived Difficulties (GIPD) and Child Health and Illness Profile-Child Edition (CHIP-CE). RESULTS: The majority of the 111 patients were male (83.8%, n=93) and mean (SD) age was 11.5 (2.38) years. Mean baseline ADHD-RS total score was 36.0 in the fast and 38.0 in the slow group. Adjusted mean change after 2 weeks was -8.1 (-10.1; -6.1) in the fast and -8.0 (-9.9;-6.0) in the slow group (p=0.927), and after 10 weeks -15.0 ( 17.4;-12.6) and -14.3 (-16.7;-12.0), respectively, (p=0.692). GIPD scores did not show differences between groups. Significant differences at week 10 were found in the CHIP-CE achievement domain favoring slow (p=0.036) and the comfort domain favoring fast cross-titration (p=0.030). No significant differences were found for adverse events, and differences for systolic blood pressure (BP) and weight were not considered clinically relevant. CONCLUSIONS: ADHD-RS and GIPD scores improved in both switching groups. No clinically relevant differences between fast and slow switching from stimulants to ATX were found. PMID- 23683139 TI - An open-label study of guanfacine extended release for traumatic stress related symptoms in children and adolescents. AB - OBJECTIVE: The purpose of this open-label pilot study was to investigate the effectiveness and tolerability of guanfacine extended release (GXR) 1-4 mg given in the evening, on the symptoms of traumatic stress (reexperiencing, avoidance, overarousal), generalized anxiety, and functional impairment in children and adolescents with a history of traumatic stress with or without posttraumatic stress disorder (PTSD). As many of our sample had associated attention deficit/hyperactivity disorder (ADHD) symptoms, we also assessed whether the presence of traumatic stress symptoms impaired the effectiveness of GXR in the treatment of comorbid ADHD symptoms. METHODS: Participants were 19 children and adolescents 6-18 years of age, with current traumatic stress symptoms. In an 8 week open-label design, each patient's scores on parent-, child-, and clinician reported symptom rating scales assessing traumatic stress symptoms, generalized anxiety, ADHD symptoms, functional impairment, and global symptom severity and improvement (n=17) were evaluated off and on GXR using chi(2) goodness-of-fit tests, paired t tests, and repeated measures analyses of variance (ANOVAs). To examine patterns of change in outcome measures across treatment, MPlus software was used to conduct linear growth curves modeled with individual-varying times of observation (i.e., random slopes). RESULTS: Using an average GXR daily dose of 1.19 mg+/-0.35 mg and an average weight-adjusted daily dose of 0.03 mg/kg+/-0.01 mg/kg, significant differences were found on all symptom severity measures. Parent reported UCLA Reaction Index scores assessing cluster B (reexperiencing), C (avoidant), and D (overarousal) symptoms significantly improved. In the presence of PTSD symptoms, children with ADHD experienced significantly improved ADHD symptom scores, suggesting that comorbidity does not attenuate an ADHD symptom response to GXR therapy. Medication was generally well tolerated. CONCLUSIONS: Within the limits of an open-label, hypothesis-generating pilot study, our results suggest that the alpha2A-adrenoceptor agonist GXR may have therapeutic effects in the treatment of PTSD symptoms in traumatically stressed children and adolescents. The effective dose may be lower than that found for ADHD. Our pilot study supports the need for further controlled research on the effects of GXR and other alpha2A-adrenoceptor agonists in pediatric disorders of traumatic stress. PMID- 23683141 TI - A meta-analysis of the consistency of atomoxetine treatment effects in pediatric patients with attention-deficit/hyperactivity disorder from 15 clinical trials across four geographic regions. AB - OBJECTIVE: Atomoxetine has been approved as a treatment for children and adolescents with attention-deficit/hyperactivity disorder (ADHD) in the United States, throughout Europe, and in other countries. This meta-analysis was to assess the consistency of the treatment effect of atomoxetine across four global geographic regions. METHODS: Data from 15 acute, double-blind, placebo-controlled trials were pooled (2 in Asia, 4 in Europe, 8 in North America, and 1 in Russia), yielding 2569 pediatric patients with ADHD. Improvements during 6-10 weeks of atomoxetine treatment were evaluated using the ADHD Rating Scale-IV or the Swanson, Nolan, and Pelham Scale-Revised. Consistency across regions was assessed by an interaction test and Higgins I(2). Consistency of one region versus other regions was assessed by effect sizes of individual regions and pairwise differences. RESULTS: Patient demographics were generally similar across regions. More patients from Asia met diagnostic criteria for ADHD inattentive subtype and fewer for combined subtype compared with patients from Europe, North America, or Russia. Asian patients had a lower mean baseline ADHD total score and mean hyperactivity/impulsivity subscore. Treatment effects showed marginal inconsistency and moderate heterogeneity among the regions (percentage of patients achieving a 40% decrease from baseline ADHD scores, atomoxetine versus placebo: Asia 39.6%, 24.0%; Europe 40.2%, 12.1%; North America 45.3%, 21.7%; Russia 54.2%, 33.3%). Inconsistency was observed primarily in Asia versus the other regions. Completion rates with atomoxetine were higher in Asia and Russia (94.4% and 94.3%, respectively) than in Europe (84.3%) or North America (80.4%). CONCLUSIONS: Atomoxetine was demonstrated as an effective treatment for ADHD in 15 clinical trials from four global regions. The current meta-analysis has revealed a degree of heterogeneity in treatment efficacy across regions, most notably in the comparison of Asian patients relative to those from the other regions. PMID- 23683142 TI - Anorexia nervosa in a 14-year-old second-generation Hispanic adolescent boy. PMID- 23683143 TI - Metal-ligand binding affinity vs reactivity: qualitative studies in Rh(I) catalyzed asymmetric ring-opening reactions. AB - Rh(I)-catalyzed asymmetric ring opening (ARO) of oxabenzonorbornadiene is used as a model system to qualitatively study reactions involving multiple metal-ligand interactions. The key feature of this approach is the use of product ee as an indicator to quickly gain important information such as the relative ligand binding affinity and relative reactivity of catalysts. PMID- 23683144 TI - Automatic and simple method for 99Tc determination using a selective resin and liquid scintillation detection applied to urine samples. AB - (99m)Tc (6.0067 h half-life) is an artificial radionuclide largely used in diagnostic medicine. Its daughter (99)Tc is a beta emitter of great concern because of its long half-life (2.111 * 10(5) years) and presumed mobile behavior in the environment. To monitor the (99)Tc in urine from treated patients, an automatic Lab-on-valve (LOV) system for separation and preconcentration of (99)Tc was developed. TEVA resin was selected since it retains pertechnetate ion selectively from diluted nitric acid solutions. After elution, (99)Tc is detected using a liquid scintillation counting (LSC) detector. The present method has been successfully applied to urine samples with low (99)Tc content (recoveries between 94-111%). The minimum detectable activity (MDA) of the developed method is 0.1 Bq or 1 Bq L(-1) (expressed as activity concentration), when preconcentrating 100 mL of sample. The high durability of the resin, together with the low amount of resin required (32 mg), the good reproducibility (RSD 2%, n = 5) and the high extraction frequency (up to 12 h(-1)) makes of the present method an inexpensive, precise and fast useful tool for monitoring (99)Tc in urine samples. PMID- 23683145 TI - Frontal impact response for pole crash scenarios. AB - OBJECTIVE: Vehicle impacts with fixed roadside structures, such as poles, constitute a significant portion of road fatalities in North America. The purpose of this study was to evaluate occupant response in pole crash scenarios and compare the current vehicle kinematic-based injury metrics to occupant-based metrics to determine whether the vehicle metrics are representative of the injury levels sustained by an occupant. METHODS: To better understand vehicle and occupant response during impact with a pole, frontal crash scenarios with 3 common pole types (a rigid pole, a rigid pole with a frangible base, and a deforming or energy-absorbing pole) were investigated at various impact velocities. A numerical model of a Hybrid III human surrogate was integrated with a numerical model of a mid-size sedan, including improvements to the vehicle and seat models, and implementation of an air bag and restraint system. The vehicle model was validated using the National Highway Traffic Safety Administration's (NHTSA) frontal crash data for varying impact velocities into a rigid wall. A numerical model of a high-energy-absorbing pole was developed and validated, along with a rigid pole and a previously developed breakaway pole, to examine the effects of pole compliance on the vehicle and occupant response. Occupant response was investigated at varying impact velocities with the poles aligned with the vehicle centerline. Offset impacts were then investigated with the energy-absorbing pole aligned with the driver-side crush structure. RESULTS: The vehicle kinematic response metrics currently used to evaluate poles were compared to the currently accepted occupant injury response metrics and it was found, in general, that the occupant-based injury criteria predicted lesser injury than the vehicle kinematic response metrics for the same impact scenario. Specifically, the occupant impact velocity provided trends that differed from all other metrics. This can be attributed in part to the improvement in vehicle safety systems not accounted for by the vehicle-based metrics. CONCLUSIONS: For the same impact scenario, the breakaway pole resulted in the lowest predicted injury metrics for the vehicle occupant but was noted to be a potential threat to pedestrians and other nearby road users. The rigid pole resulted in the highest occupant injury predictions, whereas the energy-absorbing steel pole resulted in injury metrics below the threshold values, controlled the vehicle deceleration, and detached from the base only at higher velocity impacts. Appropriate evaluation of energy-absorbing poles requires consideration of the occupant response in addition to the current kinematic criteria. PMID- 23683146 TI - Dissociation of understanding from applying others' false beliefs in remitted schizophrenia: evidence from a computerized referential communication task. AB - BACKGROUND: In research on theory of mind (ToM), false belief paradigms are commonly used. Previous studies have reported that there is heterogeneity in the magnitude of impairment on false belief tasks. Moreover, intact ability to attribute others' false beliefs has been widely reported in patients with remitted schizophrenia. Increasingly, evidence suggests that there may be different cognitive mechanisms underlying the understanding others' false beliefs versus applying one's knowledge of others' false beliefs. Since the role of psychotic symptoms in ToM impairments is an important issue in the study of ToM deficits in schizophrenia, we examined both remitted schizophrenia and non remitted schizophrenia, with the aim to investigate whether psychotic symptoms in schizophrenia are associated with deficits in understanding others' mental states or difficulties in applying this understanding. METHODS: The present study investigated 29 patients with non-remitted schizophrenia, 19 patients with remitted schizophrenia, and 22 healthy controls with a revised computerized referential communication task. The ability to understand others' false beliefs and the ability to apply others' false beliefs were measured separately. RESULTS: Patients with non-remitted schizophrenia performed significantly worse than patients with remitted schizophrenia and healthy controls on a task of understanding others' false beliefs, whereas no significant difference was found between the patients with remitted schizophrenia and healthy controls. Both the patients with non-remitted schizophrenia and patients with remitted schizophrenia performed significantly worse than healthy controls on a task of applying others' false beliefs. CONCLUSIONS: Our findings suggested a dissociation of understanding others' false beliefs from applying others' false beliefs in remitted schizophrenia. We preliminarily conclude that deficits in the ToM ability of applying knowledge of others' mental states might be state-dependent. PMID- 23683147 TI - On the reactivity of carbon supported Pd nanoparticles during NO reduction: unraveling a metal-support redox interaction. AB - Pd nanoparticles (NPs) were successfully obtained by the reduction of PdCl2 with L-ascorbic acid, whose morphology was revealed by HRTEM to be a worm-like system, formed by linked crystallite clusters with an average short-axis diameter of 5.42 nm. In situ UV-vis absorption measurements were used to monitor their formation, while XPS and XRD characterization confirmed the NPs' metallic state. A straightforward way to support the obtained Pd NPs on activated carbon (AC) was used to prepare a catalyst for NO decomposition reaction. The Pd/AC catalysts proved to be highly active in the temperature range of 323 to 673 K, and a redox mechanism is proposed, where the catalyst's active sites are oxidized by NO and reduced by carbon, emitting CO2 and enhancing their capacity to absorb and dissociate NO. PMID- 23683148 TI - Noncanonical expression of caudal during early embryogenesis in the pea aphid Acyrthosiphon pisum: maternal cad-driven posterior development is not conserved. AB - Previously we identified anterior localization of hunchback (Aphb) mRNA in oocytes and early embryos of the parthenogenetic and viviparous pea aphid Acyrthosiphon pisum, suggesting that the breaking of anterior asymmetry in the oocytes leads to the formation of the anterior axis in embryos. In order to study posterior development in the asexual pea aphid, we cloned and analysed the developmental expression of caudal (Apcad), a posterior gene highly conserved in many animal phyla. We found that transcripts of Apcad were not detected in germaria, oocytes and embryos prior to the formation of the blastoderm in the asexual (viviparous) pea aphid. This unusual expression pattern differs from that of the existing insect models, including long- and short-germ insects, where maternal cad mRNA is passed to the early embryos and forms a posterior-anterior gradient. The first detectable Apcad expression occurred in the newly formed primordial germ cells and their adjacent blastodermal cells during late blastulation. From gastrulation onward, and as in other insects, Apcad mRNA is restricted to the posteriormost region of the germ band. Similarly, in the sexual (oviparous) oocytes we were able to identify anterior localization of Aphb mRNA but posterior localization of Apcad was not detected. This suggests that cad driven posterior development is not conserved during early embryogenesis in asexual and sexual pea aphids. PMID- 23683149 TI - Home visitation program for detecting, evaluating and treating socially withdrawn youth in Korea. AB - AIM: The problems of youth social withdrawal (or hikikomori) became a hot-button social issue in Japan in the 1990s. Unfortunately, current nosology in the DSM-IV may not adequately capture the concept of socially withdrawn youth (SWY) or hikikomori. This study aimed to investigate core SWY issues, evaluate SWY's psychopathologies, and approach them therapeutically through a home visitation program. METHODS: Participants were 65 youth referred by community mental health centers and psychiatric clinics around Seoul and Kyongki-Do province. Among them, only 41 participants (31 male, 10 female, mean age 15 +/- 3.6 years) fit our SWY criteria. In addition, 248 middle and high school students in Seoul were recruited as a baseline control group. Caseworkers interviewed the SWY participants and their parents in their homes, using our structured interview manual and a number of psychiatric scales. Caseworkers also approached the participants therapeutically. RESULTS: Participants' Depression Inventory, Trait Anxiety Inventory, Social Anxiety Scale, and Internet Addiction Scale scores were significantly higher than those of baseline controls. Participants' mean number of psychotherapeutic sessions was 2.8, and the mean number of parental interview sessions was 3.4. After the therapeutic sessions, Global Assessment Functioning scores and social activities had improved somewhat in 68.3% of participants. CONCLUSION: These findings suggest that SWY is a complex phenomenon, so an individual psychopathologic process is very important for treatment. The most difficult problem in SWY treatment was therapeutic access. Hence, the home visit approach with a structured manual may be a good gateway for solving this problem. PMID- 23683150 TI - Usefulness of near-infrared spectroscopy to detect brain dysfunction in children with autism spectrum disorder when inferring the mental state of others. AB - AIMS: The purpose of this study was to examine the usefulness of near-infrared spectroscopy (NIRS) for identifying abnormalities in prefrontal brain activity in children with autism spectrum disorders (ASD) as they inferred the mental states of others. METHODS: The subjects were 16 children with ASD aged between 8 and 14 years and 16 age-matched healthy control children. Oxygenated hemoglobin concentration was measured in the subject's prefrontal brain region on NIRS during tasks expressing a person's mental state (MS task) and expressing an object's characteristics (OC task). RESULTS: There was a significant main effect of group (ASD vs control), with the control group having more activity than the ASD group. But there was no significant main effect of task (MS task vs OC task) or hemisphere (right vs left). Significant interactions of task and group were found, with the control group showing more activity than the ASD group during the MS task relative to the OC task. CONCLUSIONS: NIRS showed that there was lower activity in the prefrontal brain area when children with ASD performed MS tasks. Therefore, clinicians might be able to use NIRS and these tasks for conveniently detecting brain dysfunction in children with ASD related to inferring mental states, in the clinical setting. PMID- 23683151 TI - Repeated transcranial magnetic stimulation on dorsolateral prefrontal cortex improves performance in emotional memory retrieval as a function of level of anxiety and stimulus valence. AB - AIMS: Anxiety behavior showed a consistent attentional bias toward negative and aversive memories, induced by a right frontal cortical superiority, based on an unbalance effect between the two hemispheres. The aim of the present study was to explore the role of the left dorsolateral prefrontal cortex (DLPFC) in the memory retrieval process of positive versus negative emotional stimulus, as a function of anxiety level. METHODS: A repeated transcranial magnetic stimulation (rTMS) paradigm was used to induce cortical activation of the left DLPFC. Subjects (n = 27; age range, 21-36 years), who were divided into two different groups (high/low anxiety; State-Trait Anxiety Inventory), were required to perform a task consisting of two experimental phases: an encoding phase (lists composed of positive and negative emotional words); and a retrieval phase (old stimuli and new stimuli to be recognized). Moreover, new stimuli (distractors) semantically related or unrelated to the old stimuli were used to test a possible interference effect induced by the semantic association. RESULTS: rTMS over the left DLPFC affects memory retrieval. High-anxiety subjects benefited in greater measure from frontal left stimulation with a reduced negative bias (increased accuracy and reduced response time for the positive stimuli) and a significant increased performance for the semantically related distractors (reduced interference effect). CONCLUSION: Left DLPFC activation favors the memory retrieval of positive emotional information and might limit the unbalance effect induced by right hemispheric superiority in high levels of anxiety. PMID- 23683153 TI - Is T-helper type 2 shift schizophrenia-specific? Primary results from a comparison of related psychiatric disorders and healthy controls. AB - AIM: An imbalance between T-helper type 1 (Th1) and type 2 (Th2) cytokines has been implicated in schizophrenia, although empirical evidence is rare. The aim of this study was to examine if a Th1/Th2 imbalance occurs in schizophrenia and schizophrenia-related disorder. METHODS: Twenty-six subjects with schizophrenia, 26 subjects with schizophrenia-related disorders, and 26 healthy controls were recruited. The Human Th1/Th2 Cytokine Cytometric Bead Array Kit-II was utilized to assess serum Th1/Th2 cytokines and ratios simultaneously. MANOVA was used to detect differences among the three diagnostic groups in distinct Th1/Th2 cytokines/ratios. Pearson/Spearman correlations were used to examine the relationships between distinct Th1/Th2 cytokines/ratios and clinical/psychopathological data in schizophrenia. RESULTS: Interferon (IFN) gamma/interleukin (IL)-4, IFN-gamma/IL-10, IL-2/IL-4, and tumor necrosis factor (TNF)-alpha/IL-4 ratios were significantly decreased in schizophrenia, but not in schizophrenia-related disorders compared to healthy controls. IFN-gamma/IL-4 and IFN-gamma/IL-10 in schizophrenia subjects positively correlated with age, but not in schizophrenia-related disorder subjects or in healthy controls. CONCLUSION: A clear Th2 shift was observed in schizophrenia, but not in schizophrenia-related disorders. The Th2 shift in schizophrenia appeared to be an aberrant developmental phenomenon. PMID- 23683152 TI - Tianeptine combination for partial or non-response to selective serotonin re uptake inhibitor monotherapy. AB - AIMS: The goal of this study was to assess the efficacy and tolerability of tianeptine in combination with selective serotonin re-uptake inhibitor (SSRI) in partial responders or non-responders to SSRI monotherapy. METHODS: In this prospective, open-label, 6-week study, 150 patients with major depressive disorder who had previously not responded or partially responded to SSRI monotherapy were recruited. Tianeptine was given in combination with an SSRI for 6 weeks. RESULTS: Significant improvements were observed in the mean scores of the Hamilton Depression Rating Scale (HDRS), Montgomery-Asberg Depression Rating Scale (MADRS), and Clinical Global Impression-Severity (CGI-S). The change in the mean HDRS, MADRS, and CGI-S scores was significant from week 1. The response rates were 64.7% (HDRS) and 68.7% (MADRS), and the remission rates were 34.0% (HDRS) and 42.0% (MADRS) at week 6. Thirty-six patients (24.0%) reported adverse events that were determined by the investigator to be related to one of the study drugs. The tianeptine and SSRI combination was generally well-tolerated. CONCLUSIONS: A combination strategy with tianeptine may be an effective and well tolerated tool for patients who have failed to adequately respond to SSRI monotherapy. PMID- 23683154 TI - Awareness of deficits in Alzheimer's disease patients: analysis of performance prediction discrepancies. AB - AIM: Unawareness has been operationalized in terms of a discrepancy between the patient's self-reports and three main categories of standards: judgment of a relative, clinical assessment, and objective test performance. The purpose of this study was to develop a new measure of deficit unawareness based on multidimensional, isomorphic, simple tasks and to examine the relationship between this measure and neuropsychological tests. METHODS : Analysis was conducted on cognitive performance prediction discrepancies in a sample of Alzheimer's disease (AD) patients and a matched comparison group. RESULTS: Patients rated their cognitive functioning more highly than their performance, but their overall self-reports were lower than the overall self-reports of the comparison group. AD patients performed significantly lower than their predicted scores in all Dementia Rating Scale (DRS) domains, in contrast to comparison participants, who did not consistently perform significantly lower across domains. All unawareness scores were moderately inter-correlated, except for memory, and all unawareness scores with the exception of memory were correlated with overall neuropsychological functioning. CONCLUSION: A methodological and conceptual difficulty has been identified, and this raises the issue of the generalizability of studies with a focus on memory unawareness. The method proposed seems a good tool to assess the relationships between unawareness and several different aspects of cognitive functioning, in particular executive functioning. PMID- 23683155 TI - Symptom severity of panic disorder associated with impairment in emotion processing of threat-related facial expressions. AB - AIM: To compare emotion recognition patterns between patients with panic disorder (PD) and healthy volunteers and to analyze the correlation between the degree of emotion recognition impairment and symptom severity in patients with PD. METHODS: Twenty-four patients with PD and 20 healthy controls were tested with a facial emotional expression recognition task involving four basic emotions (i.e. happiness, sadness, anger, and fear). Emotion recognition measures included the recognition threshold, response time, response time of correctly classified emotions (response time_crt), and recognition error. An average of all four emotions for each emotion recognition measure was compared between the two groups and then a comparison of recognition measures for each specific emotion was conducted. The correlations between severity of the State-Trait Anxiety Inventory, Beck Depression Inventory (BDI), and Panic Disorder Severity Scale with emotion recognition indices were also analyzed. RESULTS: Average recognition threshold was significantly higher in the PD group compared to the control group. In the PD group, there was a non-significant trend of increase in the emotion recognition threshold for fear and the response time for anger compared with the control group. In the correlation analysis, higher trait anxiety was associated with slower response time_crt for anger and a higher BDI score was associated with slower response times and response time_crt for happiness and anger. CONCLUSION: This study suggests that symptom severity of PD might be associated with impairment in emotion processing of threat-related facial expressions. PMID- 23683156 TI - Validation of computer-administered clinical rating scale: Hamilton Depression Rating Scale assessment with Interactive Voice Response technology--Japanese version. AB - AIM: The aim of this study was to examine the reliability and validity of the Interactive Voice Response (IVR) program to rate the 17-item Hamilton Rating Scale for Depression (HAM-D) score in Japanese depressive patients. METHODS: Depression severity was assessed in 60 patients by a clinician and psychologists using HAM-D. Scoring by the IVR program was conducted on the same and the following days. Test-retest reliability, internal consistency, and concurrent validity for total HAM-D scores were examined by calculating intraclass correlation coefficient, Cronbach's alpha, and Pearson's correlation coefficient. Inter-rater consistency for each HAM-D item was examined by Cohen's kappa. RESULTS: Test-retest reliability of the IVR program was high (intraclass correlation coefficient: 0.93). Internal consistency of each total score obtained by the clinician, psychologists, and IVR program was high (Cronbach's alpha: 0.77, 0.79, 0.78, and 0.83). Regarding concurrent validity, correlation coefficients between total scores obtained by the clinician versus IVR and that by the clinician versus psychologists were high (0.81 and 0.93). The HAM-D total score rated by the clinician was 3 points lower than that of IVR. Inter-rater consistency for each HAM-D item evaluated by the clinician versus IVR was estimated to be fair (Cohen's kappa coefficient: 0.02-0.50). CONCLUSION: Our results suggest that the Japanese IVR HAM-D program is reliable and valid to assess 17-item HAM-D total score in Japanese depressive patients. However, the current program tends to overestimate depression severity, and the score of each item did not always show high agreement with clinician's rating, which warrants further improvement in the program. PMID- 23683157 TI - Association between high serum total bilirubin and post-stroke depression. AB - AIM: High serum bilirubin predicts depression in non-stroke subjects, but it is unknown whether it also predicts post-stroke depression (PSD). This study examined the association between the risk of PSD and bilirubin level. METHODS: Six hundred and thirty-five patients with acute ischemic stroke in Hong Kong were recruited. Serum total bilirubin, alanine transaminase and alkaline phosphatase levels were measured in all patients during their hospital stay. A psychiatrist gave the Structured Clinical Interview for DSM-IV to all patients 3 months after the index stroke, with 61 patients diagnosed with PSD: 27 with major depression, 24 with minor depression and 10 with dysthymia. RESULTS: In the full sample, the 25%, 50% and 75% percentile bilirubin levels were 7.0, 10.0 and 14.0 MUmol/L, respectively. Significant differences were found between the PSD and non-PSD groups in terms of bilirubin level (P = 0.006). In post-hoc comparisons, the proportion of patients with bilirubin >=14.1 MUmol/L was significantly higher in the PSD group (37.7% vs 19.7%, P = 0.001). In the final regression model, bilirubin level (>=14.1 MUmol/L) remained a significant independent predictor of PSD, with an odds ratio of 2.4. CONCLUSIONS: High bilirubin level is associated with PSD. Further investigations are needed to clarify the underlying pathophysiological link between bilirubin level and PSD. PMID- 23683158 TI - Percentage reduction of depression severity versus absolute severity after initial weeks of treatment to predict final response or remission. AB - AIM: Percentage reduction of depression severity has been used to predict both response and remission of major depression. We aimed to compare the accuracy to predict response or remission by percentage reduction of depression score or depression score after initial weeks of treatment. METHODS: The subjects were 126 depressed inpatients who received 20 mg/day fluoxetine for 6 weeks. Symptom severity was assessed using the 17-item Hamilton Depression Rating Scale (HAMD 17). Response was defined as a reduction of 50% or more of the HAMD-17. Remission was defined as a score of <=7 of the HAMD-17. At weeks 1, 2, 3 and 4, the percentages of HAMD-17 score reduction, the percentages of mood cluster score reduction, HAMD-17 scores, and mood cluster scores were regarded as potential predictors. The receiver operating characteristic curve was applied to determine the cut-off point of predictors at weeks 1, 2, 3, and 4. RESULTS: One-hundred and seven patients completed the 6-week trial. At weeks 1, 2, 3, and 4, percentages of HAMD-17 score reduction or HAMD-17 scores were the best predictors of responder or remitters, respectively. Using the percentage of HAMD-17 score reduction at each assessment as a predictor of response generated a larger area under the curve than other predictors. Conversely, applying the absolute HAMD-17 score at each assessment as a predictor of remission had the largest area under the curve. CONCLUSION: Applying percentage of reduction in depression severity during the early weeks of treatment can predict response, and it is reasonable to apply depression severity to predict remission. PMID- 23683159 TI - Affective theory of mind in patients with Parkinson's disease. AB - AIM: The aim of this study was to assess the hypothesis that patients with Parkinson's disease (PD) may have difficulties in tasks of affective theory of mind (ToM; the inference on others' feelings) especially in moderate/advanced PD stages. Difficulties of cognitive ToM have already been described in several previous studies. METHODS: Affective ToM was assessed with the Reading the Mind in the Eyes task in 35 PD patients and 35 healthy controls. Depression, global cognitive status and executive functioning were also evaluated. Patients were distinguished in early PD and moderate PD according to their scores in the Hoehn and Yahr Staging Scale. RESULTS: PD patients had more difficulties with affective ToM than healthy controls, also controlling for other variables that resulted in association with this ability. Early PD patients outperformed moderate PD patients, but this difference did not reach statistical significance when controlling for other variables. CONCLUSION: These findings confirmed that affective ToM may be impaired in PD, but any conclusion can be made on the effect of disease progression on this ability of social cognition. Therefore, longitudinal studies are needed to investigate this potential effect. PMID- 23683160 TI - Resequencing and association analysis of MIR137 with schizophrenia in a Japanese population. AB - MicroRNA may play a role in the pathophysiology of schizophrenia. A recent meta analysis of genome-wide association studies indicated a significant association between schizophrenia and a common intronic variation in MIR137HG (microRNA 137 host gene) encoding the primary microRNA-137. To explore additional risk variations for schizophrenia, we resequenced MIR137 and performed an association analysis in 1321 Japanese individuals. By resequencing, we detected four sequence variations in the 5' and 3' flanking regions. There were no significant associations between these variations and schizophrenia. Our resequencing and association analysis of MIR137 failed to find additional risk variations for schizophrenia. PMID- 23683161 TI - Identification of a patient with sporadic Creutzfeldt-Jakob disease in a psychiatric ward. PMID- 23683162 TI - Case of dementia with Lewy bodies that progressed from schizoaffective disorder. PMID- 23683163 TI - Costs and quality of life in multiple sclerosis patients with spasticity. AB - BACKGROUND: The resource use and health-related quality of life (HRQoL) of patients with multiple sclerosis (MS) spasticity are not well known. The purpose of this study was to obtain estimates of resource utilization, costs, and HRQoL, for patients with different levels of MS spasticity in southern Sweden. MATERIAL AND METHODS: Cross-sectional data on spasticity severity (using a Numerical Rating Scale, NRS), resource use and HRQoL (using EQ-5D) were collected using a patient questionnaire and chart review. Patients were recruited through a clinic in southern Sweden. The study reviews direct medical, direct non-medical and indirect costs. RESULTS: Total costs were estimated to ?114,293 per patient and year. Direct medical costs (?7898) accounted for 7% of total costs. Direct non medical costs (?68,509) accounted for 60% of total costs. Total costs increased with severity of spasticity: for patients with severe spasticity, the total cost was 2.4 times greater than those for patients with mild spasticity. HRQoL decreased as spasticity increases. CONCLUSION: The results of this study show that MS spasticity is associated with a substantial burden on society in terms of costs and HRQoL. PMID- 23683165 TI - Ocular histiocytic sarcoma in a cat. AB - A 13-year-old male neutered British blue cat presented with uveitis, hyphema, and dyscoria in the right eye. Light microscopic examination revealed that the ciliary body, iris root, drainage angle, and adjacent choroid were infiltrated by sheets of large neoplastic mononuclear and multinucleate round to polygonal cells. Neoplastic cells stained immunopositive for CD18 and HLA-DR (MHC class II) and were immunonegative for CD3, CD79a, MUM-1, CD117 (c-Kit), and S100. These findings were consistent with a histiocytic sarcoma. The cat later developed multiple cutaneous masses composed of a similar neoplastic cell population to that seen in the eye. Eight months following enucleation, the cat developed respiratory distress and was euthanized. Postmortem examination revealed multiple pulmonary tumors associated with a pleural effusion. PMID- 23683166 TI - What primary health care services should residents of rural and remote Australia be able to access? A systematic review of "core" primary health care services. AB - BACKGROUND: There are significant health status inequalities in Australia between those people living in rural and remote locations and people living in metropolitan centres. Since almost ninety percent of the population use some form of primary health care service annually, a logical initial step in reducing the disparity in health status is to improve access to health care by specifying those primary health care services that should be considered as "core" and therefore readily available to all Australians regardless of where they live. A systematic review was undertaken to define these "core" services.Using the question "What primary health care services should residents of rural and remote Australia be able to access?", the objective of this paper is to delineate those primary health care core services that should be readily available to all regardless of geography. METHOD: A systematic review of peer-reviewed literature from established databases was undertaken. Relevant websites were also searched for grey literature. Key informants were accessed to identify other relevant reference material. All papers were assessed by at least two assessors according to agreed inclusion criteria. RESULTS: Data were extracted from 19 papers (7 papers from the peer-reviewed database search and 12 from other grey sources) which met the inclusion criteria. The 19 papers demonstrated substantial variability in both the number and nature of core services. Given this variation, the specification or synthesis of a universal set of core services proved to be a complex and arguably contentious task. Nonetheless, the different primary health care dimensions that should be met through the provision of core services were developed. In addition, the process of identifying core services provided important insights about the need to deliver these services in ways that are "fit for-purpose" in widely differing geographic contexts. CONCLUSIONS: Defining a suite of core primary health care services is a difficult process. Such a suite should be fit-for-purpose, relevant to the context, and its development should be methodologically clear, appropriate, and evidence-based. The value of identifying core PHC services to both consumers and providers for service planning and monitoring and consequent health outcomes is paramount. PMID- 23683164 TI - Kinetics of O(6)-pyridyloxobutyl-2'-deoxyguanosine repair by human O(6) alkylguanine DNA alkyltransferase. AB - Tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N-nitrosonicotine (NNN) are potent carcinogens believed to contribute to the development of lung tumors in smokers. NNK and NNN are metabolized to DNA reactive species that form a range of nucleobase adducts, including bulky O(6)-[4 oxo-4-(3-pyridyl)but-1-yl]deoxyguanosine (O(6)-POB-dG) lesions. If not repaired, O(6)-POB-dG adducts induce large numbers of G -> A and G -> T mutations. Previous studies have shown that O(6)-POB-dG can be directly repaired by O(6)-alkylguanine DNA alkyltransferase (AGT), which transfers the pyridyloxobutyl group from O(6) alkylguanines in DNA to an active site cysteine residue within the protein. In the present study, we investigated the influence of DNA sequence context and endogenous cytosine methylation on the kinetics of AGT-dependent repair of O(6) POB-dG in duplex DNA. Synthetic oligodeoxynucleotide duplexes containing site specific O(6)-POB-dG adducts within K-ras and p53 gene-derived DNA sequences were incubated with recombinant human AGT protein, and the kinetics of POB group transfer was monitored by isotope dilution HPLC-ESI(+)-MS/MS analysis of O(6)-POB dG remaining in DNA over time. We found that the second-order rates of AGT mediated repair were influenced by DNA sequence context (10-fold differences) but were only weakly affected by the methylation status of neighboring cytosines. Overall, AGT-mediated repair of O(6)-POB-dG was 2-7 times slower than that of O(6)-Me-dG adducts. To evaluate the contribution of AGT to O(6)-POB-dG repair in human lung, normal human bronchial epithelial cells (HBEC) were treated with model pyridyloxobutylating agent, and O(6)-POB-dG adduct repair over time was monitored by HPLC-ESI(+)-MS/MS. We found that HBEC cells were capable of removing O(6)-POB-dG lesions, and the repair rates were significantly reduced in the presence of an AGT inhibitor (O(6)-benzylguanine). Taken together, our results suggest that AGT plays an important role in protecting human lung against tobacco nitrosamine-mediated DNA damage and that inefficient AGT repair of O(6)-POB-dG at a specific sequences contributes to mutational spectra observed in smoking induced lung cancer. PMID- 23683167 TI - Multifunctional Fe3O4@P(St/MAA)@chitosan@Au core/shell nanoparticles for dual imaging and photothermal therapy. AB - Merging different components into a single nanoparticle can exhibit profound impact on various biomedical applications including diagnostics, imaging, and therapy. However, retaining the unique properties of each component after integration has proven to be a significant challenge. Our previous research demonstrated that gold nanoshells on polystyrene spheres have potential in photohermal therapy. Here, we report a facile and green strategy to synthesize a multifunctional nanocomposite with Fe3O4 core coated gold nanoshells as dual imaging probes and photothermal agents. The as-prepared nanoparticles exhibit well-defined structure and excellent physical properties such as magnetic and plasmonic activities. Therefore, they were applied as contrast agents in magnetic resonance imaging (MRI) and dark field imaging (DFI). Besides, we demonstrated their potential application in photothermal therapy. Moreover, the obtained multifunctional nanoparticles have shown excellent biocompatibility for their low cytotoxicity and hemolyticity. PMID- 23683168 TI - Problems and hopes perceived by mothers, fathers and physicians of children receiving palliative care. AB - BACKGROUND: The quality of shared decision making for children with serious illness may depend on whether parents and physicians share similar perceptions of problems and hopes for the child. OBJECTIVE: (i) Describe the problems and hopes reported by mothers, fathers and physicians of children receiving palliative care; (ii) examine the observed concordance between participants; (iii) examine parental perceived agreement; and (iv) examine whether parents who identified specific problems also specified corresponding hopes, or whether the problems were left 'hopeless'. METHOD: Seventy-one parents and 43 physicians were asked to report problems and hopes and perceived agreement for 50 children receiving palliative care. Problems and hopes were classified into eight domains. Observed concordance was calculated between parents and between each parent and the physicians. RESULTS: The most common problem domains were physical body (88%), quality of life (74%) and medical knowledge (48%). The most common hope domains were quality of life (88%), suffering (76%) and physical body (39%). Overall parental dyads demonstrated a high percentage of concordance (82%) regarding reported problem domains and a lower percentage of concordance on hopes (65%). Concordance between parents and physicians regarding specific children was lower on problem (65-66%) and hope domains (59-63%). Respondents who identified problems regarding a child's quality of life or suffering were likely to also report corresponding hopes in these domains (93 and 82%, respectively). CONCLUSION: Asking parents and physicians to talk about problems and hopes may provide a straightforward means to improve the quality of shared decision making for critically ill children. PMID- 23683169 TI - Angiogenin outperforms VEGF, EPCs and CECs in predicting Dukes' and AJCC stage in colorectal cancer. AB - BACKGROUND: Circulating endothelial cells (CECs), endothelial progenitor cells (EPCs), Willebrand factor (vWf), soluble E-selectin, vascular endothelial growth factor (VEGF) and angiogenin are of interest in cancer vascular biology. However, few studies have looked at more than one in combination. We set out to determine which would be best in predicting the Dukes' and American Joint Committee on Cancer (AJCC) scores in colorectal cancer patients. METHODS: We recruited 154 patients with colorectal cancer, 29 healthy controls and 26 patients with benign bowel disease. CD34(+) /CD45(-) /CD146(+) CECs and CD34(+) /CD45(-) /CD309[KDR](+) EPCs were measured by flow cytometry, plasma markers by ELISA. RESULTS: All research indices were raised in colorectal cancer (P < 0.05) compared to control groups. Although CECs (P < 0.05), EPCs (P < 0.01) and angiogenin (P < 0.01) increased stepwise across the four Dukes' stages and four AJCC stages, only angiogenin remained significant in multiple regression analysis (P = 0.003 for Dukes, P = 0.01 for AJCC). Angiogenin levels were higher in Dukes' stages C and D compared to stage A, and AJCC stages 4-6 and 7-10 compared to stage 1 (all P < 0.05). Adding a second research marker to angiogenin did not markedly improve this relationship. CONCLUSION: Although we found disturbances in endotheliod cells and plasma markers of the endothelium and growth factors, only angiogenin levels were independently associated with progression of the Dukes' stage and AJCC stage, with the association with Duke's stage being stronger. We suggest that angiogenin is a potential biomarker in risk stratification for colorectal cancer, and may aid clinical decision making. PMID- 23683170 TI - Cryptococcal meningitis accompanying lymphocytic inflammation predominantly in cerebral deep white matter: a possible manifestation of immune reconstitution inflammatory syndrome. AB - Cryptococcal meningitis is rarely complicated by immune-mediated leukoencephalopathy, but the precise pathomechanism is uncertain. A 72-year-old Japanese man treated with prednisolone for Sweet disease developed a subacute progression of meningitis, which was considered as neuro-Sweet disease. A treatment by methylprednisolone rapidly improved CSF findings with a remarkable decrease in lymphocyte numbers in the blood, but the patient's consciousness still worsened after the cessation of the treatment. The patient developed cryptococcal meningitis and MRI showed abnormal intensities predominantly in the cerebral deep white matter along with the recovery of lymphocyte numbers in the blood, which resulted in death. A postmortem examination of the brain revealed degenerative lesions, especially at the cerebral white matter and cortex adjacent to the leptomeninges abundantly infiltrated by Cryptococcus neoformans. In the affected cerebral deep white matter, perivascular infiltration of lymphocytes was prominent in coexistence with reactive astrocytes and vascular proliferation, but these findings were not observed in the subcortical and cortical lesions. Cryptococcus neoformans was not present within the brain parenchyma. This is the first report of a case suggesting that cryptococcal meningitis can accompany lymphocytic inflammation predominantly in cerebral deep white matter as a possible manifestation of immune reconstitution inflammatory syndrome. PMID- 23683171 TI - Simultaneous analysis of micro-RNA and DNA for determining the body fluid origin of DNA profiles. AB - Micro-RNAs (miRNAs) can be specifically expressed in forensically relevant body fluids such as blood or saliva. The aim of the study was to develop a simultaneous extraction and analysis protocol that allows for the acquisition of a DNA profile and the identity of the body fluid using a single process. DNA and micro-RNA were extracted from blood and saliva before undergoing a cDNA synthesis step by using stem-loop reverse transcription PCR. The resulting extracts containing DNA and cDNA synthesized from body fluid-specific miRNA markers then underwent standard STR analysis using a modified ABI AmpFlSTR((r)) NGM SElectTM kit. In all samples, a full DNA profile was obtained along with additional peaks corresponding to the miRNA marker targeted. In all cases, blood samples profiled exhibited a peak indicating the presence of the blood-specific miRNA marker and the saliva sample profiled exhibited a peak indicating the presence of the saliva specific miRNA marker. PMID- 23683172 TI - Functional characterization of Nicotiana benthamiana chromomethylase 3 in developmental programs by virus-induced gene silencing. AB - DNA methylation is essential for normal developmental processes and genome stability. DNA methyltransferases are key enzymes catalyzing DNA methylation. Chromomethylase (CMT) genes are specific to the plant kingdom and encode chromodomain-containing methyltransferases. However, the function of CMT genes in plants remains elusive. In this study, we isolated and characterized a CMT gene from Nicotiana benthamiana, designated NbCMT3. Alignment of the NbCMT3 amino acid sequence with other plant CMT3s showed conservation of bromo-adjacent-homology and methyltransferase catalytic domains. We investigated the expression patterns of NbCMT3 and its function in developmental programs. NbCMT3 was expressed predominately in proliferating tissues such as apical shoots and young leaves. NbCMT3 protein showed a nuclear location, which could be related to its putative cellular functions. Knocking down NbCMT3 expression by virus-induced gene silencing revealed its vital role(s) in leaf morphogenesis. The formation of palisade cells was defective in NbCMT3-silenced plants as compared with controls. NbCMT3 has a role in developmental programs. PMID- 23683173 TI - Evaluation of corrective measures implemented for the preventive conservation of fresco paintings in Ariadne's house (Pompeii, Italy). AB - BACKGROUND: A microclimate monitoring study was conducted in 2008 aimed at assessing the conservation risks affecting the valuable wall paintings decorating Ariadne's House (Pompeii, Italy). It was found that thermohygrometric conditions were very unfavorable for the conservation of frescoes. As a result, it was decided to implement corrective measures, and the transparent polycarbonate sheets covering three rooms (one of them delimited by four walls and the others composed of three walls) were replaced by opaque roofs. In order to examine the effectiveness of this measure, the same monitoring system comprised by 26 thermohygrometric probes was installed again in summer 2010. Data recorded in 2008 and 2010 were compared. RESULTS: Microclimate conditions were also monitored in a control room with the same roof in both years. The average temperature in this room was lower in 2010, and it was decided to consider a time frame of 18 summer days with the same mean temperature in both years. In the rooms with three walls, the statistical analysis revealed that the diurnal maximum temperature decreased about 3.5 degrees C due to the roof change, and the minimum temperature increased 0.5 degrees C. As a result, the daily thermohygrometric variations resulted less pronounced in 2010, with a reduction of approximately 4 degrees C, which is favorable for the preservation of mural paintings. In the room with four walls, the daily fluctuations also decreased about 4 degrees C. Based on the results, other alternative actions are discussed aimed at improving the conservation conditions of wall paintings. CONCLUSIONS: The roof change has reduced the most unfavorable thermohygrometric conditions affecting the mural paintings, but additional actions should be adopted for a long term preservation of Pompeian frescoes. PMID- 23683174 TI - Raman second hyperpolarizability determination using computational Raman activities and a comparison with experiments. AB - Doubly vibrationally enhanced (DOVE) four-wave mixing spectroscopy, an optical analogue to 2D NMR, involves two infrared transitions and a Raman transition. The magnitude of the DOVE second hyperpolarizability gamma (or third-order susceptibility chi((3))) can be theoretically estimated if the values of the dipolar moments of the two infrared transitions and the gamma of the Raman transition are known. The Raman gamma can be measured by using the four-wave mixing interferometric method or conventional Raman spectroscopy in the presence of an internal standard. In this work, we examine if one can use the Raman activity computed from density functional theory calculation to determine the Raman gamma of selected vibrational modes of several samples including deuterated benzene, acetonitrile, tetrahydrofuran, and sodium benzoate aqueous solution. The 992 cm(-1) Raman band of benzene serves as an internal standard for organic solvents, and the 880 cm(-1) Raman band of hydrogen peroxide is for the aqueous solution sample with known gamma values. We have found that the predicted Raman gamma values from the computational Raman activities match experimental data reasonably well, suggesting a facile approach to predict the Raman gamma of interested systems. PMID- 23683175 TI - Strengthening the case for the influence of sleep on cardiovascular health in women. PMID- 23683176 TI - Perceived stress and burnout among volunteer caregivers working in AIDS care in South Africa. AB - AIMS: To conduct a quantitative investigation of stress and the relationship with burnout among AIDS care volunteers. BACKGROUND: Volunteer caregivers experience stress that could lead to burnout. Yet, very few studies quantify stress and its relationship with burnout among AIDS care volunteers. DESIGN: This study uses a cross-sectional, exploratory survey design. METHODS: Face-to-face interviews were conducted with 126 volunteer caregivers working in 13 semi-rural communities (townships) in Durban, South Africa in April 2009. All participants were women, Christian and with low levels of education. A 22-item instrument was drawn from Pearlin et al.'s role overload and role captivity scales, Van Dyk's stress factor scale and the Maslach Burnout Inventory. RESULTS: Most of the volunteers had moderate-to-high levels of stress. 'Role/work overload' 'lack of support' and 'overwhelming nature of the disease' explained most of the variance in stress. Volunteers' age and number of patients in their care were predictors of stress. Caring for only AIDS patients, lack of support, stress emanating from perceived stigma and lack of training; and the overwhelming nature of AIDS were predictors of burnout. CONCLUSION: High levels of stress could negatively impact volunteers' health and well-being and on-the-job performance. Policy makers must develop and fund home-based care models that take into account the stressors associated with AIDS care, by reducing the work load, providing ongoing psychosocial support and recruiting nurses to assist volunteers. The small non-probability sample used in this study highlights the need to treat the findings with caution. PMID- 23683177 TI - Fusarium damage in cereal grains from Western Canada. 1. Phylogenetic analysis of moniliformin-producing fusarium species and their natural occurrence in mycotoxin contaminated wheat, oats, and rye. AB - Harvest samples of common wheat (Triticum aestivum), oats (Avena sativa), and rye (Secale cereale) from producers in western Canada were analyzed for fungal infection by toxigenic Fusarium species and contamination by trichothecenes and moniliformin (MON). Fusarium graminearum and F. avenaceum were the two most frequently isolated species from samples of rye and wheat collected in 2010. F. poae and F. sporotrichioides were more commonly detected in randomly selected oat seeds. Other toxigenic Fusarium species including F. acuminatum, F. culmorum, and F. pseudograminearum as well as Phaeosphaeria nodorum (a.k.a. Septoria nodorum) were recovered primarily from fusarium-damaged kernels of wheat. Pure cultures of F. avenaceum, F. acuminatum, and other related species known to produce moniliformin were isolated from incubated seeds based on micro- and macromorphological criteria. The phylogenetic analysis inferred from partial DNA sequences of the acl1 and tef-1alpha genes revealed two major clades representing F. avenaceum and F. acuminatum, respectively. These clades comprised all Canadian isolates of the two species and a number of reference cultures studied earlier for their propensity to form moniliformin in vitro and in planta. However, some reference cultures previously reported to produce significant amounts of moniliformin formed minor phylogenetic lineages that represent rather distinct but closely related species. Concomitantly, cereal samples were analyzed for the presence of deoxynivalenol and moniliformin. These two Fusarium toxins were observed most frequently in common wheat, at concentrations up to 1.1 and 4.0 mg/kg, respectively. There was no apparent relationship between moniliformin concentrations and detection of F. avenaceum and F. acuminatum in rye and oat samples. Geographical analysis of the distribution of moniliformin and F. avenaceum and F. acuminatum across the Canadian Prairies also did not indicate a strong relationship. PMID- 23683179 TI - Certifying systematic errors in quantum experiments. AB - When experimental errors are ignored in an experiment, the subsequent analysis of its results becomes questionable. We develop tests to detect systematic errors in quantum experiments where only a finite amount of data is recorded and apply these tests to tomographic data taken in an ion trap experiment. We put particular emphasis on quantum state tomography and present three detection methods: the first two employ linear inequalities while the third is based on the generalized likelihood ratio. PMID- 23683178 TI - Melanocytomas of the central nervous system: a clinicopathological and molecular study. AB - BACKGROUND: Melanocytomas of the Central Nervous System (CNS) are rare and benign lesions. These slow-growing tumours can behave aggressively, with local recurrence. Various genetic aberrations occur in malignant melanomas and raise possible new therapeutic options. However, little information is available regarding these characteristic genetic alterations in melanocytomas of the CNS. This study was designed to better understand the clinicopathological and molecular features of melanocytomas. MATERIALS AND METHODS: Twenty cases of melanocytoma were studied by light microscopy, electron microscopy and immunohistochemistry. Clinical characteristics, therapeutic options and prognosis were analysed. BRAF, NRAS and KIT gene mutations were tested by direct DNA sequencing. RESULTS: Fourteen of twenty patients had intracranial tumours including one associated with naevus of Ota and six were spinal. Histologically, these tumours contain fusiform and epithelioid cells with little or no cellular pleomorphism and rare mitoses. Immunohistochemical and ultrastructural findings confirmed the origin of tumour cells as melanocytic. None of the melanocytomas harboured BRAF, NRAS and KIT mutations. Patients with complete resection had no tumour recurrence. Moreover, patients with incomplete tumour resection followed by radiotherapy showed a higher local control (LC) rate than incomplete resection alone (P < 0.05). CONCLUSIONS: BRAF, NRAS and KIT mutations appear to be rare, if not completely absent in melanocytomas of the CNS. The complete resection of the tumour or incomplete resection followed by radiotherapy should be considered as better therapeutic options to reduce the tumour recurrence. PMID- 23683180 TI - Many bosons in a narrow magnetic Feshbach resonance. AB - The many-boson problem in the presence of an asymptotically narrow Feshbach resonance is considered. The low energy properties are investigated using a two channel Hamiltonian. The energy spectrum of this model is shown to be bounded from below in the limit of a zero range interaction. This implies the promising possibility of achieving a strongly interacting bosonic phase in a dilute regime where the details of the actual interatomic forces are irrelevant. The integral relation between the energy and the one-body momentum distribution is derived. PMID- 23683181 TI - Topological zero-energy modes in gapless commensurate Aubry-Andre-Harper models. AB - The Aubry-Andre or Harper (AAH) model has been the subject of extensive theoretical research in the context of quantum localization. Recently, it was shown that one-dimensional quasicrystals described by the incommensurate AAH model has a nontrivial topology. In this Letter, we show that the commensurate off-diagonal AAH model is topologically nontrivial in the gapless regime and supports zero-energy edge modes. Unlike the incommensurate case, the nontrivial topology in the off-diagonal AAH model is attributed to the topological properties of the one-dimensional Majorana chain. We discuss the feasibility of experimental observability of our predicted topological phase in the commensurate AAH model. PMID- 23683182 TI - Quantum Zeno effect rationalizes the phonon bottleneck in semiconductor quantum dots. AB - Quantum confinement can dramatically slow down electron-phonon relaxation in nanoclusters. Known as the phonon bottleneck, the effect remains elusive. Using a state-of-the-art time-domain ab initio approach, we model the observed bottleneck in CdSe quantum dots and show that it occurs under quantum Zeno conditions. Decoherence in the electronic subsystem, induced by elastic electron-phonon scattering, should be significantly faster than inelastic scattering. Achieved with multiphonon relaxation, the phonon bottleneck is broken by Auger processes and structural defects, rationalizing experimental difficulties. PMID- 23683183 TI - Heat flux and entropy produced by thermal fluctuations. AB - We report an experimental and theoretical analysis of the energy exchanged between two conductors kept at different temperature and coupled by the electric thermal noise. Experimentally we determine, as functions of the temperature difference, the heat flux, the out-of-equilibrium variance, and a conservation law for the fluctuating entropy, which we justify theoretically. The system is ruled by the same equations as two Brownian particles kept at different temperatures and coupled by an elastic force. Our results set strong constraints on the energy exchanged between coupled nanosystems held at different temperatures. PMID- 23683184 TI - Record-breaking statistics for random walks in the presence of measurement error and noise. AB - We examine distance record setting by a random walker in the presence of a measurement error delta and additive noise gamma and show that the mean number of (upper) records up to n steps still grows universally as (R(n)) ~ n(1/2) for large n for all jump densities, including Levy distributions, and for all delta and gamma. In contrast, the pace of record setting, measured by the amplitude of the n(1/2) growth, depends on delta and gamma. In the absence of noise (gamma=0), the amplitude S(delta) is evaluated explicitly for arbitrary jump distributions and it decreases monotonically with increasing delta whereas, in the case of perfect measurement (delta=0), the corresponding amplitude T(gamma) increases with gamma. The exact results for S(delta) offer a new perspective for characterizing instrumental precision by means of record counting. Our analytical results are supported by extensive numerical simulations. PMID- 23683185 TI - Highly stable and finely tuned magnetic fields generated by permanent magnet assemblies. AB - Permanent magnetic materials are the only magnetic source that can be used to generate magnetic fields without power consumption or maintenance. Such stand alone magnets are very attractive for many scientific and engineering areas, but they suffer from poor temporal field stability, which arises from the strong sensitivity of the magnetic materials and mechanical support to temperature variation. In this work, we describe a highly efficient method useful to cancel the temperature coefficient of permanent magnet assemblies in a passive and accurate way. It is based on the combination of at least two units made of magnetic materials with different temperature coefficients arranged in such a way that the ratio of the fields generated by each unit matches the ratio of their effective temperature coefficients defined by both the magnetic and mechanical contributions. Although typically available magnetic materials have negative temperature coefficients, the cancellation is achieved by aligning the fields generated by each unit in the opposite direction. We demonstrate the performance of this approach by stabilizing the field generated by a dipolar Halbach magnet, recently proposed to achieve high field homogeneity. Both the field drift and the homogeneity are monitored via nuclear magnetic resonance spectroscopy experiments. The results demonstrate the compatibility of the thermal compensation approach with existing strategies useful to fine-tune the spatial dependence of the field generated by permanent magnet arrays. PMID- 23683186 TI - Scattering of cold-atom coherences by hot atoms: frequency shifts from background gas collisions. AB - Frequency shifts from background-gas collisions currently contribute significantly to the inaccuracy of atomic clocks. Because nearly all collisions with room-temperature background gases that transfer momentum eject the cold atoms from the clock, the interference between the scattered and unscattered waves in the forward direction dominates these frequency shifts. We show they are ~ 10 times smaller than in room-temperature clocks and that van der Waals interactions produce the cold-atom background-gas shift. General considerations allow the loss of the Ramsey fringe amplitude to bound this frequency shift. PMID- 23683187 TI - First long-term application of squeezed states of light in a gravitational-wave observatory. AB - We report on the first long-term application of squeezed vacuum states of light to improve the shot-noise-limited sensitivity of a gravitational-wave observatory. In particular, squeezed vacuum was applied to the German-British detector GEO 600 during a period of three months from June to August 2011, when GEO 600 was performing an observational run together with the French-Italian Virgo detector. In a second period, the squeezing application continued for about 11 months from November 2011 to October 2012. During this time, squeezed vacuum was applied for 90.2% (205.2 days total) of the time that science-quality data were acquired with GEO 600. A sensitivity increase from squeezed vacuum application was observed broadband above 400 Hz. The time average of gain in sensitivity was 26% (2.0 dB), determined in the frequency band from 3.7 to 4.0 kHz. This corresponds to a factor of 2 increase in the observed volume of the Universe for sources in the kHz region (e.g., supernovae, magnetars). We introduce three new techniques to enable the long-term application of squeezed light, and show that the glitch rate of the detector did not increase from squeezing application. Squeezed vacuum states of light have arrived as a permanent application, capable of increasing the astrophysical reach of gravitational-wave detectors. PMID- 23683188 TI - Redundancies in Nambu-Goldstone bosons. AB - We propose a simple criterion to identify when Nambu-Goldstone bosons for different symmetries are redundant. It solves an old mystery why crystals have phonons for spontaneously broken translations but no gapless excitations for equally spontaneously broken rotations. Similarly for a superfluid, the Nambu Goldstone boson for spontaneously broken Galilean symmetry is redundant with phonons. The most nontrivial example is Tkachenko mode for a vortex lattice in a superfluid, where phonons are redundant to the Tkachenko mode which is identified as the Boboliubov mode. PMID- 23683189 TI - Viability of strongly coupled scenarios with a light Higgs-like boson. AB - We present a one-loop calculation of the oblique S and T parameters within strongly coupled models of electroweak symmetry breaking with a light Higgs-like boson. We use a general effective Lagrangian, implementing the chiral symmetry breaking SU(2)(L) [Symbol: see text]SU(2)(R) -> SU(2)(L+R) with Goldstone bosons, gauge bosons, the Higgs-like scalar, and one multiplet of vector and axial-vector massive resonance states. Using a dispersive representation and imposing a proper ultraviolet behavior, we obtain S and T at the next-to-leading order in terms of a few resonance parameters. The experimentally allowed range forces the vector and axial-vector states to be heavy, with masses above the TeV scale, and suggests that the Higgs-like scalar should have a WW coupling close to the standard model one. Our conclusions are generic and apply to more specific scenarios such as the minimal SO(5)/SO(4) composite Higgs model. PMID- 23683190 TI - Evidence for the appearance of atmospheric tau neutrinos in super-Kamiokande. AB - Super-Kamiokande atmospheric neutrino data were fit with an unbinned maximum likelihood method to search for the appearance of tau leptons resulting from the interactions of oscillation-generated tau neutrinos in the detector. Relative to the expectation of unity, the tau normalization is found to be 1.42 +/- 0.35(stat)(-0.12)(+0.14)(syst) excluding the no-tau-appearance hypothesis, for which the normalization would be zero, at the 3.8sigma level. We estimate that 180.1 +/- 44.3(stat)(-15.2)(+17.8) (syst) tau leptons were produced in the 22.5 kton fiducial volume of the detector by tau neutrinos during the 2806 day running period. In future analyses, this large sample of selected tau events will allow the study of charged current tau neutrino interaction physics with oscillation produced tau neutrinos. PMID- 23683192 TI - Electrical conductivity of hot QCD matter. AB - We study the electric conductivity of hot QCD matter at various temperatures T within the off-shell parton-hadron-string dynamics transport approach for interacting partonic, hadronic or mixed systems in a finite box with periodic boundary conditions. The response of the strongly interacting system in equilibrium to an external electric field defines the electric conductivity sigma(0). We find a sizable temperature dependence of the ratio sigma(0)/T well in line with calculations in a relaxation time approach for T(c) J/psiLambda, Xi(b((-) -> J/psiXi(-) and Omega(b)(-) -> J/psiOmega(-) signals are observed and the corresponding masses are measured to be M(Lambda(b)(0))=5619.53 +/- 0.13(stat.) +/- 0.45(syst.) MeV/c(2), M(Xi(b)(-)) = 5795.8 +/- 0.9(stat.) +/- 0.4(syst.) MeV/c(2), M(Omega(b)(-)) = 6046.0 +/- 2.2(stat.) +/- 0.5(syst.) MeV/c(2) , while the differences with respect to the Lambda(b)(0) mass are M(Xi(b)(-))-M(Lambda(b)(0))=176.2 +/- 0.9(stat.) +/- 0.1(syst.) MeV/c(2), M(Omega(b)(-))-M(Lambda(b)(0))=426.4 +/- 2.2(stat.) +/- 0.4(syst.) MeV/c(2). These are the most precise mass measurements of the Lambda(b)(0), Xi(b)(-) and Omega(b)(-) baryons to date. Averaging the above Lambda(b)(0) mass measurement with that published by LHCb using 35 pb(-1) of data collected in 2010 yields M(Lambda(b)(0)) = 5619.44 +/- 0.13(stat.)+/- 0.38(syst.) MeV/c(2). PMID- 23683205 TI - 3D quasioptical theory of terahertz superradiance of an extended electron bunch moving over a corrugated surface. AB - We consider the superradiance of an extended relativistic electron bunch moving over a periodically corrugated surface for the generation of multimegawatt terahertz pulses. To study the above process we have developed a three dimensional, self-consistent, quasioptical theory of Cherenkov stimulated emission which includes a description of the formation of an evanescent wave over a corrugated surface and its excitation by rf current induced in the electron bunch. PMID- 23683206 TI - Electrostatic decay in a weakly magnetized plasma. AB - The kinematics of the electrostatic (ES) decay of a Langmuir wave into a Langmuir wave and an ion sound wave are generalized to a weakly magnetized plasma. Unlike the unmagnetized case, ES decay in a magnetized plasma is always kinematically permitted and can produce daughter Langmuir waves with very small wave numbers, which we demonstrate by quasilinear simulations. The simulations further show that ES decay in magnetized plasmas is consistent with STEREO spacecraft observations of transversely polarized Langmuir waves in the solar wind. PMID- 23683207 TI - Symmetry of spherically converging shock waves through reflection, relating to the shock ignition fusion energy scheme. AB - We examine the properties of perturbed spherically imploding shock waves in an ideal fluid through the collapse, bounce, and development into an outgoing shock wave. We find broad conservation of the size and shape of ingoing and outgoing perturbations when viewed at the same radius. The outgoing shock recovers the velocity of the unperturbed shock outside the strongly distorted core. The results are presented in the context of the robustness of the shock ignition approach to inertial fusion energy. PMID- 23683208 TI - Observation of self-similarity in the magnetic fields generated by the ablative nonlinear Rayleigh-Taylor instability. AB - Magnetic fields generated by the nonlinear Rayleigh-Taylor growth of laser-seeded three-dimensional broadband perturbations were measured in laser-accelerated planar targets using ultrafast proton radiography. The experimental data show self-similar behavior in the growing cellular magnetic field structures. These observations are consistent with a bubble competition and merger model that predicts the time evolution of the number and size of the bubbles, linking the cellular magnetic field structures with the Rayleigh-Taylor bubble and spike growth. PMID- 23683209 TI - Numerical verification of bounce-harmonic resonances in neoclassical toroidal viscosity for tokamaks. AB - This Letter presents the first numerical verification for the bounce-harmonic (BH) resonance phenomena of the neoclassical transport in a tokamak perturbed by nonaxisymmetric magnetic fields. The BH resonances were predicted by analytic theories of neoclassical toroidal viscosity (NTV), as the parallel and perpendicular drift motions can be resonant and result in a great enhancement of the radial momentum transport. A new drift-kinetic deltaf guiding-center particle code, POCA, clearly verified that the perpendicular drift motions can reduce the transport by phase-mixing, but in the BH resonances the motions can form closed orbits and particles radially drift out fast. The POCA calculations on resulting NTV torque are largely consistent with analytic calculations, and show that the BH resonances can easily dominate the NTV torque when a plasma rotates in the perturbed tokamak and therefore, is a critical physics for predicting the rotation and stability in the International Thermonuclear Experimental Reactor. PMID- 23683210 TI - Runaway breakdown and hydrometeors in lightning initiation. AB - The particular electric pulse discharges are observed in thunderclouds during the initiation stage of negative cloud-to-ground lightning. The discharges are quite different from conventional streamers or leaders. A detailed analysis reveals that the shape of the pulses is determined by the runaway breakdown of air in the thundercloud electric field initiated by extensive atmospheric showers (RB-EAS). The high amplitude of the pulse electric current is due to the multiple microdischarges at hydrometeors stimulated and synchronized by the low-energy electrons generated in the RB-EAS process. The series of specific pulse discharges leads to charge reset from hydrometeors to the free ions and creates numerous stretched ion clusters, both positive and negative. As a result, a wide region in the thundercloud with a sufficiently high fractal ion conductivity is formed. The charge transport by ions plays a decisive role in the lightning leader preconditioning. PMID- 23683211 TI - Shock-front injector for high-quality laser-plasma acceleration. AB - We report the generation of stable and tunable electron bunches with very low absolute energy spread (DeltaE ~ 5 MeV) accelerated in laser wakefields via injection and trapping at a sharp downward density jump produced by a shock front in a supersonic gas flow. The peak of the highly stable and reproducible electron energy spectrum was tuned over more than 1 order of magnitude, containing a charge of 1-100 pC and a charge per energy interval of more than 10 pC/MeV. Laser plasma electron acceleration with Ti:sapphire lasers using this novel injection mechanism provides high-quality electron bunches tailored for applications. PMID- 23683212 TI - Reaching fractional quantum Hall states with optical flux lattices. AB - We present a robust scheme by which fractional quantum Hall states of bosons can be achieved for ultracold atomic gases. We describe a new form of optical flux lattice, suitable for commonly used atomic species with ground state angular momentum J(g) = 1, for which the lowest energy band is topological and nearly dispersionless. Through exact diagonalization studies, we show that, even for moderate interactions, the many-body ground states consist of bosonic fractional quantum Hall states, including the Laughlin state and the Moore-Read (Pfaffian) state. These phases are shown to have energy gaps that are larger than temperature scales achievable in ultracold gases. PMID- 23683213 TI - Realizing fractional Chern insulators in dipolar spin systems. AB - Strongly correlated quantum systems can exhibit exotic behavior controlled by topology. We predict that the nu = 1/2 fractional Chern insulator arises naturally in a two-dimensional array of driven, dipolar-interacting spins. As a specific implementation, we analyze how to prepare and detect synthetic gauge potentials for the rotational excitations of ultracold polar molecules trapped in a deep optical lattice. With the motion of the molecules pinned, under certain conditions, these rotational excitations form a fractional Chern insulating state. We present a detailed experimental blueprint for its realization and demonstrate that the implementation is consistent with near-term capabilities. Prospects for the realization of such phases in solid-state dipolar systems are discussed as are their possible applications. PMID- 23683214 TI - Formations of dumbbell C118 and C119 inside clusters of C60 molecules by collision with alpha particles. AB - We report highly selective covalent bond modifications in collisions between keV alpha particles and van der Waals clusters of C(60) fullerenes. Surprisingly, C(119)(+) and C(118)(+) are the dominant molecular fusion products. We use molecular dynamics simulations to show that C(59)(+) and C(58)(+) ions- effectively produced in prompt knockout processes with He(2+)--react rapidly with C(60) to form dumbbell C(119)(+) and C(118)(+). Ion impact on molecular clusters in general is expected to lead to efficient secondary reactions of interest for astrophysics. These reactions are different from those induced by photons. PMID- 23683215 TI - Cavitation in amorphous solids. AB - Molecular dynamics simulations of cavitation in a Zr(50)Cu(50) metallic glass exhibit a waiting time dependent cavitation rate. On short time scales nucleation rates and critical cavity sizes are commensurate with a classical theory of nucleation that accounts for both the plastic dissipation during cavitation and the cavity size dependence of the surface energy. All but one parameter, the Tolman length, can be extracted directly from independent calculations or estimated from physical principles. On longer time scales strain aging in the form of shear relaxations results in a systematic decrease of cavitation rate. The high cavitation rates that arise due to the suppression of the surface energy in small cavities provide a possible explanation for the quasibrittle fracture observed in metallic glasses. PMID- 23683216 TI - Emergence of crystal-like atomic dynamics in glasses at the nanometer scale. AB - The vibrational dynamics of a permanently densified silica glass is compared to the one of an alpha-quartz polycrystal, the silica polymorph of the same density and local structure. The combined use of inelastic x-ray scattering experiments and ab initio numerical calculations provides compelling evidence of a transition, in the glass, from the isotropic elastic response at long wavelengths to a microscopic regime as the wavelength decreases below a characteristic length xi of a few nanometers, corresponding to about 20 interatomic distances. In the microscopic regime the glass vibrations closely resemble those of the polycrystal, with excitations related to the acoustic and optic modes of the crystal. A coherent description of the experimental results is obtained assuming that the elastic modulus of the glass presents spatial heterogeneities of an average size a ~ xi/2 pi. PMID- 23683217 TI - Tunable infrared phonon anomalies in trilayer graphene. AB - Trilayer graphene in both ABA (Bernal) and ABC (rhombohedral) stacking sequences is shown to exhibit intense infrared absorption from in-plane optical phonons. The phonon feature, lying at ~1580 cm(-1), changes strongly with electrostatic gating. For ABC-stacked graphene trilayers, we observed a large enhancement in phonon absorption amplitude, as well as softening of the phonon mode, as the Fermi level is tuned away from charge neutrality. A similar, but substantially weaker, effect is seen in samples with the more common ABA stacking order. The strong infrared response of the optical phonons and the pronounced variation with electrostatic gating and stacking order reflect the interactions of the phonons and electronic excitations in the two systems. The key experimental findings can be reproduced within a simplified charged-phonon model that considers the influence of charging through Pauli blocking of the electronic transitions. PMID- 23683218 TI - From damage percolation to crack nucleation through finite size criticality. AB - We present a unified theory of fracture in disordered brittle media that reconciles apparently conflicting results reported in the literature. Our renormalization group based approach yields a phase diagram in which the percolation fixed point, expected for infinite disorder, is unstable for finite disorder and flows to a zero-disorder nucleation-type fixed point, thus showing that fracture has a mixed first order and continuous character. In a region of intermediate disorder and finite system sizes, we predict a crossover with mean field avalanche scaling. We discuss intriguing connections to other phenomena where critical scaling is only observed in finite size systems and disappears in the thermodynamic limit. PMID- 23683219 TI - Evidence for kinetically limited thickness dependent phase separation in organic thin film blends. AB - We present depth-resolved grazing incidence x-ray diffraction, grazing incidence small angle scattering and x-ray reflectivity studies on the structure of mixed C(60) and diindinoperylene (DIP) films as a function of the mixing ratio. We observe enhanced out-of-plane order and smoothing of the mixed films compared to pure films upon coevaporation of DIP:C(60) thin films (in different mixing ratio) which otherwise phase separate. The mixing ratio of molecules can be tuned to alter the in-plane crystallite size as well as the interisland distances of the mixing molecules. Real-time in situ grazing incidence x-ray diffraction measurements show the kinetics and thickness dependence of phase separation, which appears to proceed only after a certain thickness. The crystallite grain size of the individual phase separated components is significantly larger at the top of the film than at the bottom with implications for the understanding of devices. PMID- 23683220 TI - Achromatic elemental mapping beyond the nanoscale in the transmission electron microscope. AB - Newly developed achromatic electron optics allows the use of wide energy windows and makes feasible energy-filtered transmission electron microscopy (EFTEM) at atomic resolution. In this Letter we present EFTEM images formed using electrons that have undergone a silicon L(2,3) core-shell energy loss, exhibiting a resolution in EFTEM of 1.35 A. This permits elemental mapping beyond the nanoscale provided that quantum mechanical calculations from first principles are done in tandem with the experiment to understand the physical information encoded in the images. PMID- 23683221 TI - Deconfined criticality flow in the Heisenberg model with ring-exchange interactions. AB - Quantum transition points in the J-Q model--the test bed of the deconfined critical point theory--and the SU(2)-symmetric discrete noncompact CP(1) representation of the deconfined critical action are directly compared by the flowgram method. We find that the flows of two systems coincide in a broad region of linear system sizes (10 < L < 50 for the J-Q model), implying that the deconfined critical point theory correctly captures the mesoscopic physics of competition between the antiferromagnetic and valence-bond orders in quantum spin systems. At larger sizes, however, we observe significant deviations between the two flows which both demonstrate strong violations of scale invariance. This reliably rules out the second-order transition scenario in at least one of the two models and suggests the most likely explanation for the nature of the transition in the J-Q model. PMID- 23683222 TI - Surface atom motion to move iron nanocrystals through constrictions in carbon nanotubes under the action of an electric current. AB - Under the application of electrical currents, metal nanocrystals inside carbon nanotubes can be bodily transported. We examine experimentally and theoretically how an iron nanocrystal can pass through a constriction in the carbon nanotube with a smaller cross-sectional area than the nanocrystal itself. Remarkably, through in situ transmission electron imaging and diffraction, we find that, while passing through a constriction, the nanocrystal remains largely solid and crystalline and the carbon nanotube is unaffected. We account for this behavior by a pattern of iron atom motion and rearrangement on the surface of the nanocrystal. The nanocrystal motion can be described with a model whose parameters are nearly independent of the nanocrystal length, area, temperature, and electromigration force magnitude. We predict that metal nanocrystals can move through complex geometries and constrictions, with implications for both nanomechanics and tunable synthesis of metal nanoparticles. PMID- 23683223 TI - Selective ultrafast probing of transient hot chemisorbed and precursor states of CO on Ru(0001). AB - We have studied the femtosecond dynamics following optical laser excitation of CO adsorbed on a Ru surface by monitoring changes in the occupied and unoccupied electronic structure using ultrafast soft x-ray absorption and emission. We recently reported [M. Dell'Angela et al. Science 339, 1302 (2013)] a phonon mediated transition into a weakly adsorbed precursor state occurring on a time scale of >2 ps prior to desorption. Here we focus on processes within the first picosecond after laser excitation and show that the metal-adsorbate coordination is initially increased due to hot-electron-driven vibrational excitations. This process is faster than, but occurs in parallel with, the transition into the precursor state. With resonant x-ray emission spectroscopy, we probe each of these states selectively and determine the respective transient populations depending on optical laser fluence. Ab initio molecular dynamics simulations of CO adsorbed on Ru(0001) were performed at 1500 and 3000 K providing insight into the desorption process. PMID- 23683224 TI - Formation of the coherent heavy fermion liquid at the hidden order transition in URu2Si2. AB - We present high-resolution angle-resolved photoemission spectra of the heavy fermion superconductor URu2Si2. Detailed measurements as a function of both photon energy and temperature allow us to disentangle a variety of spectral features, revealing the evolution of the low-energy electronic structure across the "hidden order" transition. Above the transition, our measurements reveal the existence of weakly dispersive states that exhibit a large scattering rate and do not appear to shift from above to below the Fermi level, as previously reported. Upon entering the hidden order phase, these states rapidly hybridize with light conduction band states and transform into a coherent heavy fermion liquid, coincident with a dramatic drop in the scattering rate. This evolution is in stark contrast with the gradual crossover expected in Kondo lattice systems, which we attribute to the coupling of the heavy fermion states to the hidden order parameter. PMID- 23683225 TI - Modifying the electronic orbitals of nickelate heterostructures via structural distortions. AB - We describe a general materials design approach that produces large orbital energy splittings (orbital polarization) in nickelate heterostructures, creating a two-dimensional single-band electronic surface at the Fermi energy. The resulting electronic structure mimics that of the high temperature cuprate superconductors. The two key ingredients are (i) the construction of atomic-scale distortions about the Ni site via charge transfer and internal electric fields, and (ii) the use of three-component (tricomponent) superlattices to break inversion symmetry. We use ab initio calculations to implement the approach, with experimental verification of the critical structural motif that enables the design to succeed. PMID- 23683226 TI - Optical superfluid phase transitions and trapping of polariton condensates. AB - Semiconductor microcavities are used to support freely flowing polariton quantum liquids allowing the direct observation and optical manipulation of macroscopic quantum states. Incoherent optical excitation at a point produces radially expanding condensate clouds within the planar geometry. By using arbitrary configurations of multiple pump spots, we discover a geometrically controlled phase transition, switching from the coherent phase-locking of multiple condensates to the formation of a single trapped condensate. The condensation threshold becomes strongly dependent on the programmed superfluid geometry and sensitive to cooperative interactions between condensates. We directly image persistently circulating superfluid and show how flows of light-matter quasiparticles are dominated by the quantum pressure in such configurable laser written potential landscapes. PMID- 23683227 TI - Excitation spectra of transition-metal atoms on the Ag (100) surface controlled by Hund's exchange. AB - We report photoemission experiments revealing the valence electron spectral function of Mn, Fe, Co, and Ni atoms on the Ag (100) surface. The series of spectra shows splittings of higher energy features which decrease with the filling of the 3d shell and a highly nonmonotonic evolution of spectral weight near the Fermi edge. First principles calculations demonstrate that two manifestations of Hund's exchange J are responsible for this evolution. First, there is a monotonic reduction of the effective exchange splittings with increasing filling of the 3d shell. Second, the amount of charge fluctuations and, thus, the weight of quasiparticle peaks at the Fermi level varies nonmonotonically through this 3d series due to a distinct occupancy dependence of effective charging energies U(eff). PMID- 23683228 TI - Anomalous Schottky specific heat and structural distortion in ferromagnetic PrAl2. AB - Unique from other rare earth dialuminides, PrAl(2) undergoes a cubic to tetragonal distortion below T = 30 K in a zero magnetic field, but the system recovers its cubic symmetry upon the application of an external magnetic field of 10 kOe via a lifting of the 4f crystal field splitting. The nuclear Schottky specific heat in PrAl(2) is anomalously high compared to that of pure Pr metal. First principles calculations reveal that the 4f crystal field splitting in the tetragonally distorted phase of PrAl(2) underpins the observed unusual low temperature phenomena. PMID- 23683229 TI - Topological insulating states in laterally patterned ordinary semiconductors. AB - We propose that ordinary semiconductors with large spin-orbit coupling, such as GaAs, can host stable, robust, and tunable topological states in the presence of quantum confinement and superimposed potentials with hexagonal symmetry. We show that the electronic gaps which support chiral spin edge states can be as large as the electronic bandwidth in the heterostructure miniband. The existing lithographic technology can produce a topological insulator operating at a temperature of 10-100 K. Improvement of lithographic techniques will open the way to a tunable room temperature topological insulator. PMID- 23683230 TI - Role of exciton screening in the 7/3 fractional quantum Hall effect. AB - The excitations of the 7/3 fractional Hall state, one of the most prominent states in the second Landau level, are not understood. We study the effect of screening by composite fermion excitons and find that it causes a strong renormalization at 7/3, thanks to a relatively small exciton gap and a relatively large residual interaction between composite fermions. The excitations of the 7/3 state are to be viewed as composite fermions dressed by a large exciton cloud. Their wide extent has implications for experiments as well as for analysis of finite system exact diagonalization studies. PMID- 23683231 TI - Multicomponent Skyrmion lattices and their excitations. AB - We study quantum Hall ferromagnets with a finite density of topologically charged spin textures in the presence of internal degrees of freedom such as spin, valley, or layer indices, so that the system is parametrized by a d-component spinor field. In the absence of anisotropies we find a hexagonal Skyrmion lattice that completely breaks the underlying SU(d) symmetry with the low-lying excitation spectrum separating into d(2) - 1 gapless acoustic magnetic modes and a magnetophonon. The ground state charge density modulations, which inevitably exist in these lattices, vanish exponentially in d. We discuss the role of effective mass anisotropy for SU(3)-valley Skyrmions relevant to experiments with AlAs quantum wells. Here we find a transition which breaks a sixfold rotational symmetry of the triangular lattice, followed by the formation of a square lattice at large values of anisotropy strength. PMID- 23683232 TI - Soft superconducting gap in semiconductor Majorana nanowires. AB - We theoretically consider the ubiquitous soft gap measured in the tunneling conductance of semiconductor-superconductor hybrid structures, in which recently observed signatures of elusive Majorana bound states have created much excitement. We systematically study the effects of magnetic and nonmagnetic disorder, temperature, dissipative Cooper pair breaking, and interface inhomogeneity, which could lead to a soft gap. We find that interface inhomogeneity with moderate dissipation is the only viable mechanism that is consistent with the experimental observations. Our work indicates that improving the quality of the superconductor-semiconductor interface should result in a harder induced gap. PMID- 23683233 TI - Charging Dirac states at antiphase domain boundaries in the three-dimensional topological insulator Bi2Se3. AB - Using scanning tunneling microscopy and transmission electron microscopy, we demonstrate the existence of antiphase boundaries between neighboring grains shifted by a fraction of a quintuple layer in epitaxial (0001) films of the three dimensional topological insulator Bi(2)Se(3). Scanning tunneling spectroscopy and first-principles calculations reveal that these antiphase boundaries provide electrostatic fields on the order of 10(8) V/m that locally charge the Dirac states, modulating the carrier density, and shift the Dirac point by up to 120 meV. This intrinsic electric field effect, demonstrated here near interfaces between Bi(2)Se(3) grains, provides direct experimental evidence at the atomic scale that the Dirac states are indeed robust against extended structural defects and tunable by electric field. These results also shed light on the recent observation of coexistence of Dirac states and two-dimensional electron gas on Bi(2)Se(3) (0001) after adsorption of metal atoms and gas molecules. PMID- 23683234 TI - Majorana fermions from Landau quantization in a superconductor and topological insulator hybrid structure. AB - We show that the interplay of cyclotron motion and Andreev reflection experienced by massless-Dirac-like charge carriers in topological-insulator surface states generates a Majorana-particle excitation. On the basis of an envelope-function description of the Dirac-Andreev edge states, we discuss the kinematic properties of the Majorana mode and find them to be tunable by changing the superconductor's chemical potential and/or the magnitude of the perpendicular magnetic field. Our proposal opens up new possibilities for studying Majorana fermions in a controllable setup. PMID- 23683235 TI - Quasiballistic transport of Dirac fermions in a Bi2Se3 nanowire. AB - Quantum coherent transport of surface states in a mesoscopic nanowire of the three-dimensional topological insulator Bi(2}Se(3) is studied in the weak disorder limit. At very low temperatures, many harmonics are evidenced in the Fourier transform of Aharonov-Bohm oscillations, revealing the long phase coherence length of spin-chiral Dirac fermions. Remarkably, from their exponential temperature dependence, we infer an unusual 1/T power law for the phase coherence length L(phi)(T). This decoherence is typical for quasiballistic fermions weakly coupled to their environment. PMID- 23683236 TI - Exchange-coupling-induced symmetry breaking in topological insulators. AB - An exchange gap in the Dirac surface states of a topological insulator (TI) is necessary for observing the predicted unique features such as the topological magnetoelectric effect as well as to confine Majorana fermions. We experimentally demonstrate proximity-induced ferromagnetism in a TI, combining a ferromagnetic insulator EuS layer with Bi(2)Se(3), without introducing defects. By magnetic and magnetotransport studies, including anomalous Hall effect and magnetoresistance measurements, we show the emergence of a ferromagnetic phase in TI, a step forward in unveiling their exotic properties. PMID- 23683237 TI - Momentum-dependent charge correlations in YBa2Cu3O6+delta superconductors probed by resonant X-ray scattering: evidence for three competing phases. AB - We use resonant x-ray scattering to determine the momentum-dependent charge correlations in YBa(2)Cu(3) O(6.55) samples with highly ordered chain arrays of oxygen acceptors (ortho-II structure). The results reveal nearly critical, biaxial charge density wave (CDW) correlations at in-plane wave vectors (0.315, 0) and (0, 0.325). The corresponding scattering intensity exhibits a strong uniaxial anisotropy. The CDW amplitude and correlation length are enhanced as superconductivity is weakened by an external magnetic field. Analogous experiments are carried out on a YBa(2)Cu(3)O(6.6) crystal with a dilute concentration of spinless (Zn) impurities, which had earlier been shown to nucleate incommensurate magnetic order. Compared to pristine crystals with the same doping level, the CDW amplitude and correlation length are found to be strongly reduced. These results indicate a three-phase competition between spin modulated, charge-modulated, and superconducting states in underdoped YBa(2)Cu(3)O(6+delta). PMID- 23683238 TI - Raman-scattering detection of nearly degenerate s-wave and d-wave pairing channels in iron-based Ba0.6K0.4Fe2As2 and Rb0.8Fe1.6Se2 superconductors. AB - We show that electronic Raman scattering affords a window into the essential properties of the pairing potential V(k,k') of iron-based superconductors. In Ba0.6K0.4Fe2As2 we observe band dependent energy gaps along with excitonic Bardasis-Schrieffer modes characterizing, respectively, the dominant and subdominant pairing channel. The d(x(2)-y(2)) symmetry of all excitons allows us to identify the subdominant channel to originate from the interaction between the electron bands. Consequently, the dominant channel driving superconductivity results from the interaction between the electron and hole bands and has the full lattice symmetry. The results in Rb(0.8)Fe(1.6)Se(2) along with earlier ones in Ba(Fe(0.939)Co(0.061))(2)As(2) highlight the influence of the Fermi surface topology on the pairing interactions. PMID- 23683239 TI - Field-induced quantum soliton lattice in a frustrated two-leg spin-1/2 ladder. AB - Based on high-field (31)P nuclear magnetic resonance experiments and accompanying numerical calculations, it is argued that in the frustrated S=1/2 ladder compound BiCu(2)PO(6) a field-induced soliton lattice develops above a critical field of MU(0)H(c1)=20.96(7) T. Solitons result from the fractionalization of the S=1, bosonlike triplet excitations, which in other quantum antiferromagnets are commonly known to experience Bose-Einstein condensation or to crystallize in a superstructure. Unlike in spin-Peierls systems, these field-induced quantum domain walls do not arise from a state with broken translational symmetry and are triggered exclusively by magnetic frustration. Our model predicts yet another second-order phase transition at H(c2)>H(c1), driven by soliton-soliton interactions, most likely corresponding to the one observed in recent magnetocaloric and other bulk measurements. PMID- 23683240 TI - Isolating the dynamic dipolar interaction between a pair of nanoscale ferromagnetic disks. AB - Dynamic dipolar interactions between spin wave eigenmodes of closely spaced nanomagnets determine the collective behavior of magnonic and spintronic metamaterials and devices. However, dynamic dipolar interactions are difficult to quantify since their effects must be disentangled from those of static dipolar interactions and variations in the shape, size, and magnetic properties of the nanomagnets. It is shown that when two imperfect nanoscale magnetic disks with similar but nonidentical modes are brought into close proximity, the effect of the dynamic dipolar interaction can be detected by considering the difference of the phase of precession within the two disks. Measurements show that the interaction is stronger than expected from micromagnetic simulations, highlighting both the need for characterization and control of magnetic properties at the deep nanoscale, and also the potential for improved control of collective magnetic phenomena. Our approach is equally applicable to other physical systems in which dynamic interactions are obscured by inhomogeneous broadening and static interactions. PMID- 23683241 TI - Optical field enhancement by strong plasmon interaction in graphene nanostructures. AB - The ability of plasmons to enhance the electromagnetic field intensity in the gap between metallic nanoparticles derives from their strong optical confinement relative to the light wavelength. The spatial extension of plasmons in doped graphene has recently been shown to be boldly reduced with respect to conventional plasmonic metals. Here, we show that graphene nanostructures are capable of capitalizing such strong confinement to yield unprecedented levels of field enhancement, well beyond what is found in noble metals of similar dimensions (~ tens of nanometers). We perform realistic, quantum-mechanical calculations of the optical response of graphene dimers formed by nanodisks and nanotriangles, showing a strong sensitivity of the level of enhancement to the type of carbon edges near the gap region, with armchair edges favoring stronger interactions than zigzag edges. Our quantum-mechanical description automatically incorporates nonlocal effects that are absent in classical electromagnetic theory, leading to over an order of magnitude higher enhancement in armchair structures. The classical limit is recovered for large structures. We predict giant levels of light concentration for dimers ~200 nm, leading to infrared absorption enhancement factors ~10(8). This extreme light enhancement and confinement in nanostructured graphene has great potential for optical sensing and nonlinear devices. PMID- 23683242 TI - Mechanism of enhanced optical second-harmonic generation in the conducting pyrochlore-type Pb2Ir2O7-x oxide compound. AB - The structural, electronic, and optical properties of pyrochlore-type Pb(2)Ir(2)O(6)O(0.55)('), which is a metal without spatial inversion symmetry at room temperature, were investigated. Structural analysis revealed that the structural distortion relevant to the breakdown of the inversion symmetry is dominated by the Pb-O' network but is very small in the Ir-O network. At the same time, gigantic second-harmonic generation signals were observed, which can only occur if the local environment of the Ir 5d electrons features broken inversion symmetry. First-principles electronic structure calculations reveal that the underlying mechanism for this phenomenon is the induction of the noncentrosymmetricity in the Ir 5d bands by the strong hybridization with O' 2p orbitals. Our results stimulate theoretical study of inversion-broken iridates, where exotic quantum states such as a topological insulator and Dirac semimetal are anticipated. PMID- 23683243 TI - Ferroelectric domains in multiferroic BiFeO3 films under epitaxial strains. AB - First-principles calculations are performed to investigate energetic and atomistic characteristics of ferroelectric domains walls (DWs) of BiFeO(3) (BFO) films subject to compressive strain. Significantly lower DW energies than those previously reported, and a different energetic hierarchy between the various DW types, are found for small strains. In all investigated cases (corresponding to ideal angles of 71 degrees , 109 degrees , and 180 degrees formed by the domain polarizations), the DW energy reaches its maximum value for misfit strains that are around the critical strain at which the transition between the R-like and T like phases occurs in single-domain BFO. Near these strains, several quantities depend strongly on the type of domain wall; such distinct behavior is associated with an elastic difference and a large out-of-plane polarization at the DW in the 180 degrees case. A further increase of the magnitude of the strain leads to (i) a change of hierarchy of the DW energies, (ii) large out-of-plane polarizations inside each up and down domain, and (iii) novel atomic arrangements at the domain walls. Our study can thus initiate a new research direction, namely strain engineering of domain-wall functionalities. PMID- 23683244 TI - Colloidal templating at a cholesteric-oil interface: assembly guided by an array of disclination lines. AB - We simulate colloids (radius R ~ 1 MUm) trapped at the interface between a cholesteric liquid crystal and an immiscible oil at which the helical order (pitch p) in the bulk conflicts with the orientation induced at the interface, stabilizing an ordered array of disclinations. For a weak anchoring strength W of the director field at the colloidal surface, this creates a template, favoring particle positions either on top of or midway between defect lines, depending on alpha=R/p. For small alpha, optical microscopy experiments confirm this picture, but for larger alpha no templating is seen. This may stem from the emergence at moderate W of a rugged energy landscape associated with defect reconnections. PMID- 23683245 TI - Active shape-morphing elastomeric colloids in short-pitch cholesteric liquid crystals. AB - Active elastomeric liquid crystal particles with initial cylindrical shapes are obtained by means of soft lithography and polymerization in a strong magnetic field. Gold nanocrystals infiltrated into these particles mediate energy transfer from laser light to heat, so that the inherent coupling between the temperature dependent order and shape allows for dynamic morphing of these particles and well controlled stable shapes. Continuous changes of particle shapes are followed by their spontaneous realignment and transformations of director structures in the surrounding cholesteric host, as well as locomotion in the case of a nonreciprocal shape morphing. These findings bridge the fields of liquid crystal solids and active colloids, may enable shape-controlled self-assembly of adaptive composites and light-driven micromachines, and can be understood by employing simple symmetry considerations along with electrostatic analogies. PMID- 23683246 TI - Kinetic versus energetic discrimination in biological copying. AB - We study stochastic copying schemes in which discrimination between a right and a wrong match is achieved via different kinetic barriers or different binding energies of the two matches. We demonstrate that, in single-step reactions, the two discrimination mechanisms are strictly alternative and cannot be mixed to further reduce the error fraction. Close to the lowest error limit, kinetic discrimination results in a diverging copying velocity and dissipation per copied bit. On the other hand, energetic discrimination reaches its lowest error limit in an adiabatic regime where dissipation and velocity vanish. By analyzing experimentally measured kinetic rates of two DNA polymerases, T7 and Polgamma, we argue that one of them operates in the kinetic and the other in the energetic regime. Finally, we show how the two mechanisms can be combined in copying schemes implementing error correction through a proofreading pathway. PMID- 23683247 TI - Two-step glass transition induced by attractive interactions in quasi-two dimensional suspensions of ellipsoidal particles. AB - We study experimentally the glass transition dynamics in quasi-two-dimensional suspensions of colloidal ellipsoids, aspect ratio alpha=2.1, with repulsive as well as attractive interactions. For the purely repulsive case, we find that the orientational and translational glass transitions occur at the same area fraction. Strikingly, for intermediate depletion attraction strengths, we find that the orientational glass transition precedes the translational one. By quantifying structure and dynamics, we show that quasi-long-range ordering is promoted at these attraction strengths, which subsequently results in a two-step glass transition. Most interestingly, within experimental certainty, we observe reentrant glass dynamics only in the translational degrees of freedom. PMID- 23683248 TI - Hydrodynamically driven colloidal assembly in dip coating. AB - We study the hydrodynamics of dip coating from a suspension and report a mechanism for colloidal assembly and pattern formation on smooth substrates. Below a critical withdrawal speed where the coating film is thinner than the particle diameter, capillary forces induced by deformation of the free surface prevent the convective transport of single particles through the meniscus beneath the film. Capillary-induced forces are balanced by hydrodynamic drag only after a minimum number of particles assemble within the meniscus. The particle assembly can thus enter the thin film where it moves at nearly the withdrawal speed and rapidly separates from the next assembly. The interplay between hydrodynamic and capillary forces produces periodic and regular structures below a critical ratio Ca(2/3)/sqrt[Bo] < 0.7, where Ca and Bo are the capillary and Bond numbers, respectively. An analytical model and numerical simulations are presented for the case of two-dimensional flow with circular particles in suspension. The hydrodynamically driven assembly documented here is consistent with stripe pattern formations observed experimentally in dip coating. PMID- 23683249 TI - Comment on "Quantized orbital angular momentum transfer and magnetic dichroism in the interaction of electron vortices with matter". PMID- 23683250 TI - Lloyd, Babiker, and Yuan reply. PMID- 23683251 TI - Augmented anticancer activity of a targeted, intracellularly activatable, theranostic nanomedicine based on fluorescent and radiolabeled, methotrexate folic Acid-multiwalled carbon nanotube conjugate. AB - The present study reports the design, synthesis, and biological evaluation of a novel, intravenously injectable, theranostic prodrug based on multiwalled carbon nanotubes (MWCNTs) concomitantly decorated with a fluorochrome (Alexa-fluor, AF488/647), radionucleide (Technitium-99m), tumor-targeting module (folic acid, FA), and anticancer agent (methotrexate, MTX). Specifically, MTX was conjugated to MWCNTs via a serum-stable yet intracellularly hydrolyzable ester linkage to ensure minimum drug loss in circulation. Cell uptake studies corroborated the selective internalization of AF-FA-MTX-MWCNTs (1) by folate receptor (FR) positive human lung (A549) and breast (MCF 7) cancer cells through FR mediated endocytosis. Lysosomal trafficking of 1 enabled the conjugate to exert higher anticancer activity as compared to its nontargeted counterpart that was mainly restricted to cytoplasm. Tumor-specific accumulation of 1 in Ehlrich Ascites Tumor (EAT) xenografted mice was almost 19 and 8.6 times higher than free MTX and FA-deprived MWCNTs. Subsequently, the conjugate 1 was shown to arrest tumor growth more effectively in chemically breast tumor induced rats, when compared to either free MTX or nontargeted controls. Interestingly, the anticancer activities of the ester-linked CNT-MTX conjugates (including the one deprived of FA) were significantly higher than their amide-linked counterpart, suggesting that cleavability of linkers between drug and multifunctional nanotubes critically influence their therapeutic performance. The results were also supported by in silico docking and ligand similarity analysis. Toxicity studies in mice confirmed that all CNT-MTX conjugates were devoid of any perceivable hepatotoxicity, cardiotoxicity, and nephrotoxicity. Overall, the delivery property of MWCNTs, high tumor binding avidity of FA, optical detectability of AF fluorochromes, and radio-traceability of (99m)Tc could be successfully integrated and partitioned on a single CNT-platform to augment the therapeutic efficacy of MTX against FR overexpressing cancer cells while allowing a real-time monitoring of treatment response through multimodal imaging. PMID- 23683252 TI - Formation of rigid organic nanotubes with controlled internal cavity based on frustrated aggregate internal rearrangement mechanism. AB - We introduce frustrated aggregate internal rearrangement (FAIR) mechanism for anisotropic higher-order structure formations, in which the anisotropy arose due to the structural frustration. We demonstrate the FAIR mechanism by investigating the recently observed rigid organic nanotube formations through the self-assembly of building blocks, which include rigid segments and make intermolecular H-bonds, whereas the principle of the FAIR mechanism is general and is not limited to H bonding building blocks or nanotube formations. Initially, molecules aggregate into sheetlike structures driven by nonspecific and nondirectional intermolecular interactions such as pi-pi stacking or amphiphilicity. Weak intermolecular H bonds provide additional stability to the structure. Within the aggregate, however, not all molecules have the right orientation for specific and directional H-bonds whereas collective internal rearrangement of rigid building blocks requires a large amount of energy to overcome kinetically trapped barriers. Consequently, instead of the fully H-bonded global equilibrium structure, self-assembled layers become trapped with partial and disordered H bonding schemes at various fractions leading to an anisotropic layer that undergoes spontaneous transformation into curved structures. The FAIR mechanism can readily be extended to anisotropic higher-order structures other than nanotubes and to the assembly of diverse building blocks including hybrids such as polymer nanocomposites. Also the reversible transformation from metastable nanotubes into layered sheets is potentially useful for controlling internal cavity size of nanotubes. PMID- 23683253 TI - Propafenone versus vernakalant for conversion of recent-onset atrial fibrillation. AB - INTRODUCTION: An oral loading dose of propafenone 600 mg is used in our center as in other places around the world for conversion of recent-onset atrial fibrillation (AF) in patients without structural heart disease. Vernakalant is a novel, safe, and effective drug used intravenously and has proved to be more rapid in converting recent-onset AF to sinus rhythm compared with placebo and amiodarone. There is no study that compares vernakalant with propafenone. The aim of our study is to compare the time taken for conversion of recent-onset AF in patients treated with vernakalant and propafenone. METHODS: Thirty-six hemodynamically stable patients with recent-onset AF without structural heart disease were prospectively included. A single oral dose of propafenone 600 mg was administered to 19 patients and 17 received intravenous vernakalant. Clinical and laboratory variables, conversion rate, and time to conversion were recorded. RESULTS: Baseline characteristics were similar in both groups. Time to conversion to sinus rhythm was of 166 min (120-300) in the propafenone group versus 9 min (6 18) in the vernakalant group (P = 0.0001). Conversion rate was of 78% in the propafenone group at 8 h and of 93% in the vernakalant group at 2 h; yet, this difference was not statistically significant (P = 0.4). Time to conversion had a direct impact in hospital stay, which was 43% shorter in the vernakalant group (P = 0.0001). CONCLUSION: Time to conversion of AF to sinus rhythm was significantly shorter in the vernakalant group compared with the propafenone group and was associated with shorter hospital stay. PMID- 23683254 TI - Contrast-induced acute kidney injury in frail older people: what do we learn from the dilemma? PMID- 23683255 TI - The importance of measuring impulsiveness in patients with addiction problems. PMID- 23683256 TI - Recurrent pregnancy loss and thrombophilia in women with PCOS. PMID- 23683257 TI - Update of epidermal growth factor receptor-tyrosine kinase inhibitors in non small-cell lung cancer. AB - Lung cancer is the leading cause of cancer-related death in the world. Prior to the era of targeted therapy, platinum-based doublet chemotherapy was the first line therapy of choice for patients with metastatic non-small-cell lung cancer (NSCLC). The availability of agents that target epidermal growth factor receptor (EGFR)-tyrosine kinase, as well as inhibitors against anaplastic lymphoma kinase (ALK) gene rearrangement or ROS-1 gene rearrangement product, has provided promising clinical benefits in specific subpopulations of NSCLC. At present, only first-generation EGFR-tyrosine kinase inhibitors (TKIs) (erlotinib and gefitinib) are available for clinical use. Second-generation irreversible EGFR-TKIs, such as afatinib, are still in clinical trials. In current clinical practice, EGFR-TKI is the first-line treatment of choice for metastatic NSCLC patients with tumor EGFR mutation or as salvage therapy in NSCLC patients who received systemic chemotherapy previously. Platinum-based doublet chemotherapy continues to be the standard of care for those treatment-naive patients with EGFR wild -type tumor or unknown EGFR status. Even though all investigators agree with the use of EGFR-TKI as the first-line treatment in tumor EGFR-mutated patients, only 10-30% of NSCLC patients have mutated EGFR, and there was no obvious survival difference when EGFR-TKIs were used in a second-line setting versus a first-line treatment in EGFR-mutated patients. Thus, the molecular complexity of lung cancer emphasizes the need for optimizing treatment by seeking a more personalized approach to care, including searching for driver oncogenes, managing the emergence of resistance and overcoming that resistance, and optimizing the sequence of treatment. Numerous other novel targeted agents are now in clinical development, including new agents targeting novel pathways and those that may have the potential to overcome the limitations or resistance associated with currently available EGFR-TKIs. In this report, we review the clinical data of EGFR-TKIs as molecular-targeted therapies in NSCLC. PMID- 23683258 TI - Carbon monoxide may enhance bile secretion by increasing glutathione excretion and Mrp2 expression in rats. AB - BACKGROUND: Nitric oxide (NO) donors have been reported to induce choleresis via an increased excretion of glutathione. The effects of another gas molecule, carbon monoxide (CO), on bile formation are, however, inconsistent among previous reports. We investigated the sequential changes of bile output and the biliary contents in rats with or without CO supplementation to elucidate the mechanism of CO on bile excretion. METHODS: Dichloromethane (DCM) was gastrically fed to male Sprague-Dawley rats to yield CO by liver biotransformation. The rats were divided into DCM-treated (n = 7), DCM plus L-NAME-treated (n = 6), and corn oil-treated (n = 8) groups. Bile samples were collected hourly to examine the flow rate and bile content. Serum levels of nitrite and nitrate 4 hours after DCM supplementation with or without NO synthase (NOS) inhibition were measured by capillary electrophoresis. The expression of hepatic inducible NOS was evaluated by Western blotting 6 hours after DCM administration. RESULTS: Levels of carboxyhemoglobin rose to around 10% at 4 hours after DCM supplementation and were maintained until the end of the experiments. Bile flow increased after DCM supplementation and was associated with a concomitant increase of biliary glutathione and higher hepatic multidrug resistance-associated protein 2 (Mrp2) expression. Hepatic inducible NOS expression and serum nitrate/nitrite levels were also increased. Treatment with an NOS inhibitor (L-NAME) abolished the CO induced glutathione excretion and choleresis, but not Mrp2 expression. CONCLUSION: The present study demonstrated that CO enhanced biliary output in conjunction with NO by increasing the biliary excretion of glutathione. The increment in biliary glutathione was associated with an increased expression of hepatic Mrp2. PMID- 23683259 TI - Short-term results of catheter-directed intrathrombus thrombolysis versus anticoagulation in acute proximal deep vein thrombosis. AB - BACKGROUND: Deep vein thrombosis (DVT) is a potentially progressive disease with complex clinical sequelae. The clinical practice guidelines of the American College of Chest Physicians (ACCP) recommend various treatments for all patients with objectively proven DVT. This study retrospectively compares enoxaparin with CDT on treatment efficacy and safety and the evolution of acute proximal DVT in the lower limbs. METHODS: This study comprised 53 patients with acute proximal DVT, who received either CDT followed by intravenous unfractionated heparin (UFH) or adjusted subcutaneous low-molecular-weight heparin (LMWH) (enoxaparin) for 7 14 days. Warfarin was administered to all patients for at least 6 months. The study endpoints included the evolution of DVT and treatment efficacy and safety, which were assessed with frequent duplex ultrasounds, plethysmography, and venography. The mean duration of the follow-up was 15.2 months. RESULTS: In the CDT group, patency of the iliofemoral vein segment was observed in 42.3% of the patients after 1 week (p < 0.001) and in 69.2% after 6 months. In the control group, patency was present in 15.4% of the patients after 3 months and in 38.5% after 6 months (p = 0.05). Femoral venous obstruction was found in 30.8% of CDT patients and in 61.5% of the control group (p = 0.05). Furthermore, femoral venous insufficiency was present in 46.2% of the CDT group and 53.9% of the control group after 6 months (p = 0.587). After 12 months, post-thrombotic syndrome (PTS) was found in 19.2% of the CDT patients compared to 50% of the LMWH group (p = 0.04). CONCLUSION: Duplex ultrasound analysis of thrombus progression is useful for assessing the treatment of a patient with acute proximal DVT. In this study, patients undergoing CDT experienced higher thrombus resolution and early recanalization of their veins, which may preserve venous function and further prevent development of post-thrombotic syndrome. PMID- 23683260 TI - Risk factors for acute kidney injury in the elderly undergoing contrast-enhanced computed tomography in the emergency department. AB - BACKGROUND: There have been few studies focusing on the incidence and risk factors for elderly patients undergoing computed tomography (CT) scans with intravascular contrast medium, who develop contrast-induced nephropathy (CIN) in the emergency department (ED). Our objective was to investigate the incidence of and risk factors for, CIN in elderly patients seen in the ED, who receive intravenous contrast media for CT examination. METHODS: Patients >=65 years of age who received contrast-enhanced CT were eligible for inclusion in this retrospective analysis. CIN was defined as an increase in serum creatinine (sCr) >=0.5 mg/dL 48 to 72 hours after intravenous contrast administration. Multiple logistic regression analysis for risk factors for CIN and Chi-square test were performed for trend analysis for CIN incidence and mortality of different risk scores. RESULTS: A total of 594 patients, with a mean age of 79.8 +/- 6.8 years were included. The overall incidence of CIN was 8.6%. In multivariate analyses, CIN was associated with diabetes mellitus [adjusted odds ratio (OR) = 1.93; 95% confidence interval (CI) = 1.04-3.62], precontrast sCr >1.5 mg/dL (OR = 2.72; 95% CI = 1.44-5.13), and acute hypotension (OR = 3.56; 95% CI = 1.29-9.84). CIN and mortality increased with increasing risk score (p < 0.001 and p = 0.001, respectively). The all-cause in-hospital mortality rate was 13.1%, and the mortality rates for patients with and without CIN (p < 0.001) were 47.1% and 9.9%, respectively. CONCLUSION: Our investigation confirmed diabetes mellitus, precontrast sCr >1.5 mg/dL and acute hypotension as risk factors for CIN, and also developed a simple risk score for elderly patients seen in the ED. PMID- 23683261 TI - Fistula components of brain arteriovenous malformations: angioarchitecture analysis and embolization prior to gamma-knife surgery. AB - BACKGROUND: Gamma-knife surgery (GKS) is ineffective for high-flow arteriovenous fistula (AVF). The purpose of this study was to present the angioarchitecture of the AVF of brain arteriovenous malformation (BAVM) and report our experience of endovascular embolization of AVF component prior to GKS. METHODS: In the past 10 years, a total of 523 BAVMs had been treated primarily by GKS. Among these, 10 patients with AVF components were identified and referred for embolization prior to GKS. Those patients underwent GKS within 4 weeks after embolization. We analyzed retrospectively the angioarchitecture of the AVFs of BAVMs, selection of embolic materials for embolization, and treatment outcomes. RESULTS: The location of the AVFs was anterior (n = 7) or middle (n = 3) cerebral artery. Central and peripheral types of AVFs were found in seven and three patients, respectively. Nine AVFs were totally occluded by a single session of endovascular embolization, while one failed to be embolized because it was inaccessible to a microcatheter. Detachable coils (n = 6) or combination of liquid adhesives (n = 3) were selected to embolize the AVF. No significant periprocedural neurological complication was found. BAVMs were obliterated totally by subsequent GKS in six patients and partial occlusion was achieved in one, while three still awaited the effect of GKS. Mean imaging and clinical follow-up periods were 35 and 48 months, respectively. CONCLUSION: Early detection of the central type of AVF of BAVM prior to GKS may be difficult because of its overlapping with feeder, nidus, and/or venous drains or it being overlooked. Peripheral-type AVFs were usually evident prior to GKS, particularly those with proximal dilated venous drains. Endovascular embolization is an effective modality for managing these AVFs, which may be treated by GKS ineffectively. PMID- 23683262 TI - Correlation between thrombophilia and recurrent pregnancy loss in patients with polycystic ovary syndrome: a comparative study. AB - BACKGROUND: Patients with polycystic ovary syndrome (PCOS) have an increased prevalence of thrombophilia, leading to higher rates of pregnancy loss. The aim of this study was to determine the association between thrombophilia and recurrent pregnancy loss (RPL) in patients with and without PCOS. METHODS: In this comparative case-control study, we included 60 patients with RPL (>=3 consecutive pregnancy losses at <20 weeks of gestation) and PCOS (Group 1), 60 patients with PCOS and without RPL (Group 2), 60 patients with RPL and without PCOS (Group 3), and 60 healthy individuals (Group 4). These four study groups were compared regarding serum levels of testosterone, fasting insulin, homocysteine (Hcy), plasminogen activator inhibitor activity (PAI-Fx), protein C, protein S, antithrombin III, activated protein C ratio (APCR), factor V Leiden, prothrombin G20210A, and methylene tetrahydrofolate reductase gene mutations. RESULTS: Patients in Group 1 had significantly higher levels of testosterone (p = 0.026), dehydroepiandrosterone sulfate (p = 0.035), fasting insulin (p = 0.015), Hcy (p = 0.036), and PAI-Fx (p = 0.008) compared to Group 3. They also had higher proportions of APCR (p = 0.009) and a higher prevalence of factor V Leiden mutations compared to Group 3 (p = 0.001). However, there was no significant difference in protein C (p = 0.088), protein S (p = 0.514), or antithrombin III (p = 0.627) between the four study groups. CONCLUSION: Hyperinsulinemia, hyperandrogenemia, hypofibrinolysis, and hyperhomocysteinemia as well as APCR and factor V Leiden mutations are associated with RPL in patients with PCOS. PMID- 23683263 TI - The reliability of the Chinese version of the Barratt Impulsiveness Scale version 11, in abstinent, opioid-dependent participants in Taiwan. AB - BACKGROUND: The Barratt Impulsiveness Scale (BIS) is one of the most commonly used self-report measures of trait impulsivity. However, the reliability of this measure among individuals who abuse substances has not yet been well examined. The purpose of this study was to evaluate the reliability and validity of the Chinese version of this measure in abstinent, opioid-dependent participants. METHODS: The opioid-dependent participants were all male inmates recruited from two official correction agencies located in northern Taiwan, from October 2006 to September 2007; of these participants, the retest group completed a second assessment after 1 month. The internal consistency reliability of the BIS version 11 (BIS-11) was assessed by calculating the Cronbach alpha coefficient. Test retest reliability was assessed based on intraclass correlation coefficients. Factor validity was examined using principal component analysis. Internal consistency and factor validity of the BIS-11 were investigated in a sample of 153 participants, and test-retest reliability was analyzed in 67 participants. RESULTS: A three-factor structure of BIS-11 representing psychological constructs similar to those originally identified in other translations of the BIS-11 was found. The Cronbach alpha coefficient for this instrument was 0.83, indicating high internal consistency, and the intraclass correlation coefficient was 0.66, indicating good test-retest reliability. The BIS-11 had highest reliability among participants without a criminal history. The test-retest reliability was still satisfactory among participants with a lower education level or alcohol dependence. CONCLUSION: This study suggests that the Chinese version of the BIS 11 is a reliable measure and has potential utility for investigating impulsivity in opioid-dependent individuals. PMID- 23683264 TI - Effectiveness of botulinum toxin A in treatment of refractory erythromelalgia. AB - Erythromelalgia is characterized by intense burning pain, erythema, and heat in affected areas after precipitating factors such as warm temperature or stress. It is refractory to treatment in some situations. We describe a woman with adenosquamous cell carcinoma of the lung and medically refractory erythromelalgia. The symptoms of erythromelalgia presented as refractory to any medical treatment. Due to the unresponsive nature of her condition, botulinum toxin type A (onabotulinumtoxin A) was injected over both of her cheeks, periodically for six cycles. Her symptoms responded dramatically to subcutaneous and intradermal injection of botulinum toxin type A. Repetitive injection demonstrated consistent and reproducible responses, and the efficacy was maintained for approximately 1 month. No adverse effects or complications were noted. Botulinum toxin type A might be safe and effective as an alternative treatment for refractory erythromelalgia, but further large-scale studies are required. PMID- 23683265 TI - Hepatic inflammatory pseudotumor mimicking hepatocellular carcinoma. AB - Inflammatory pseudotumor of the liver is a rare tumor. It has variable clinical presentations and image findings. It can mimic benign or malignant hepatic tumors, and may be difficult to diagnose. We present a case in which a hepatic inflammatory pseudotumor was misdiagnosed as hepatocellular carcinoma because the tumor presented a typical enhancing profile and morphology of hepatocellular carcinoma on computed tomography, and the patient had liver cirrhosis. However, a thicker tumor capsule than that of typical hepatocellular carcinoma was noted while reviewing the computed tomography images. A capsule of inflammatory pseudotumor thicker than that of hepatocellular carcinoma has never been reported in the literature before, and could be an important diagnostic clue to differentiate inflammatory pseudotumor from hepatocellular carcinoma. PMID- 23683266 TI - Omega-3 fatty acid therapy reduces triglycerides and interleukin-6 in hypertriglyeridemic HIV patients. AB - OBJECTIVES: Cardiovascular disease and osteoporosis are common in HIV-infected patients and residual systemic inflammation is thought to contribute to both of these disorders. We performed a randomized placebo-controlled trial of omega-3 acid (O3A) ethyl esters in HIV-infected patients with hypertriglyceridaemia, hypothesizing that O3A would decrease serum levels of triglycerides, markers of systemic inflammation, and markers of bone turnover. METHODS: HIV-infected patients (n = 48 recruited at three sites) with CD4 count >200 cells/MUL, suppressed viral load, and triglycerides >200 mg/dL were randomized to placebo or 3.6 g/d of O3A. Fasting lipid profiles and markers of inflammation and bone turnover were assessed at baseline and after 8 weeks of treatment. RESULTS: Baseline HIV status, lipid profile, bone metabolism and cardiovascular risk factors were similar between the groups. Inflammatory markers were similar between the treatment groups at baseline, except for interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha, which were higher in the O3A group. The concentration of triglycerides in patients receiving O3A decreased by a median (interquartile range (IQR)) of -34 (-149, 9.5) mg/dL vs. a median increase of 46.5 (-51, 123) mg/dL in the placebo group (P = 0.01). The median percentage change in IL-6 was greater in the O3A group compared with the placebo group [-39% (-63, 12%) vs. 29% (10, 177%), respectively; P = 0.006]. Similar results were observed for TNF-alpha, but not other inflammatory or bone turnover markers. CONCLUSIONS: O3A ethyl esters decreased the concentrations of triglycerides, IL-6 and TNF-alpha in patients with well-controlled HIV infection and hypertriglyceridaemia. Larger studies are required to confirm these findings and investigate their clinical significance. PMID- 23683267 TI - A combined 3D-QSAR and docking studies for the In-silico prediction of HIV protease inhibitors. AB - BACKGROUND: Tremendous research from last twenty years has been pursued to cure human life against HIV virus. A large number of HIV protease inhibitors are in clinical trials but still it is an interesting target for researchers due to the viral ability to get mutated. Mutated viral strains led the drug ineffective but still used to increase the life span of HIV patients. RESULTS: In the present work, 3D-QSAR and docking studies were performed on a series of Danuravir derivatives, the most potent HIV- protease inhibitor known so far. Combined study of 3D-QSAR was applied for Danuravir derivatives using ligand-based and receptor based protocols and generated models were compared. The results were in good agreement with the experimental results. Additionally, docking analysis of most active 32 and least active 46 compounds into wild type and mutated protein structures further verified our results. The 3D-QSAR and docking results revealed that compound 32 bind efficiently to the wild and mutated protein whereas, sufficient interactions were lost in compound 46. CONCLUSION: The combination of two computational techniques would helped to make a clear decision that compound 32 with well inhibitory activity bind more efficiently within the binding pocket even in case of mutant virus whereas compound 46 lost its interactions on mutation and marked as least active compound of the series. This is all due to the presence or absence of substituents on core structure, evaluated by 3D-QSAR studies. This set of information could be used to design highly potent drug candidates for both wild and mutated form of viruses. PMID- 23683268 TI - Improved growth behavior of atomic-layer-deposited high-k dielectrics on multilayer MoS2 by oxygen plasma pretreatment. AB - We report on the effect of oxygen plasma treatment of two-dimensional multilayer MoS2 crystals on the subsequent growth of Al2O3 and HfO2 films, which were formed by atomic layer deposition (ALD) using trimethylaluminum and tetrakis (ethylmethylamino)hafnium metal precursors, respectively, with water oxidant. Due to the formation of an ultrathin Mo-oxide layer on the MoS2 surface, the surface coverage of Al2O3 and HfO2 films was significantly improved compared to those on pristine MoS2, even at a high ALD temperature. These results indicate that the surface modification of MoS2 by oxygen plasma treatment can have a major impact on the subsequent deposition of high-k thin films, with important implications on their integration in thin film transistors. PMID- 23683269 TI - DRD2/ANKK1 Taq1A polymorphism (rs1800497) has opposing effects on D2/3 receptor binding in healthy controls and patients with major depressive disorder. AB - The A1 allele of the DRD2/ANKK1 Taq1A polymorphism (rs1800497) is associated with reduced striatal D(2/3) receptor binding in healthy individuals (Con) as well as depression and addiction. However, the effect of rs1800497 on D(2/3) receptor binding in depressed patients as well as the SNP's effect on D(2/3) binding during reward-associated dopamine release is unknown. Twelve unmedicated patients with major depressive disorder (MDD) and 24 Con completed PET scans with [(11)C]raclopride, once without receiving monetary rewards (baseline) and once while winning money. In Con, the A1 allele was associated with reduced baseline binding potential (BP(ND)) in the middle caudate and ventral striatum. However, in MDD patients the A1 allele was associated with increased baseline BP(ND) in these regions. There were no significant associations between rs1800497 and change in BP(ND) during reward-associated dopamine release. Conceivably, the A1 allele predisposes to depression and addiction via its effect on the post synaptic D(2) receptor. PMID- 23683270 TI - Oxidative stress and antioxidant enzyme activity in South Indian male smokers with chronic obstructive pulmonary disease. AB - BACKGROUND AND OBJECTIVE: Oxidative stress resulting from tobacco smoking has been suggested to play a role in the pathogenesis of chronic obstructive pulmonary disease (COPD). The aim of the present study was to evaluate the oxidant and antioxidant levels in smokers with and without COPD. METHODS: Two hundred thirty-six patients with COPD and 150 smokers with no respiratory problems were selected. COPD diagnosis and staging was done based on the Global Initiative for Chronic Obstructive Lung Disease criteria. Plasma malondialdehyde (MDA) and erythrocyte glutathione (GSH) concentrations and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione-s-transferase (GST) activities were assessed. RESULTS: COPD patients had higher levels of MDA and lower levels of antioxidants when compared with controls (P < 0.01). Analysis of variance revealed increase in MDA (P < 0.05) and decrease in CAT activity (P < 0.01) and GSH (P < 0.05) level with the progression of the disease. In patients, lung function positively correlated with CAT and SOD activities and negatively correlated with MDA levels (P < 0.01). Smoking history showed negative relation with forced expiratory volume in 1 s (FEV1 )/forced vital capacity (P < 0.05) and positive correlation with CAT activity (P < 0.01). MDA levels negatively correlated with SOD (r = -0.239; P < 0.01). In controls, MDA levels showed significant positive correlation with FEV1 and GPx (P < 0.05) and negative correlation with GSH (P < 0.01). Logistic regression showed association of higher MDA levels with increased risk and higher levels of CAT and GSH with decreased risk of progressing in the disease (odds ratio = 2.938, 2.538, 7.860). CONCLUSIONS: Our study demonstrates that there is an oxidant antioxidant imbalance in COPD patients and suggests the importance of GPx in maintaining lung function. PMID- 23683271 TI - Investigation of NADH binding, hydride transfer, and NAD(+) dissociation during NADH oxidation by mitochondrial complex I using modified nicotinamide nucleotides. AB - NADH:ubiquinone oxidoreductase (complex I) is a complicated respiratory enzyme that conserves the energy from NADH oxidation, coupled to ubiquinone reduction, as a proton motive force across the mitochondrial inner membrane. During catalysis, NADH oxidation by a flavin mononucleotide is followed by electron transfer to a chain of iron-sulfur clusters. Alternatively, the flavin may be reoxidized by hydrophilic electron acceptors, by artificial electron acceptors in kinetic studies, or by oxygen and redox-cycling molecules to produce reactive oxygen species. Here, we study two steps in the mechanism of NADH oxidation by complex I. First, molecular fragments of NAD(H), tested as flavin-site inhibitors or substrates, reveal that the adenosine moiety is crucial for binding. Nicotinamide-containing fragments that lack the adenosine do not bind, and ADP ribose binds more strongly than NAD(+), suggesting that the nicotinamide is detrimental to binding. Second, the primary kinetic isotope effects from deuterated nicotinamide nucleotides confirm that hydride transfer is from the pro S position and reveal that hydride transfer, along with NAD(+) dissociation, is partially rate-limiting. Thus, the transition state energies are balanced so that no single step in NADH oxidation is completely rate-limiting. Only at very low NADH concentrations does weak NADH binding limit NADH:ubiquinone oxidoreduction, and at the high nucleotide concentrations of the mitochondrial matrix, weak nucleotide binding constants assist product dissociation. Using fast nucleotide reactions and a balance between the nucleotide binding constants and concentrations, complex I combines fast and energy-conserving NADH oxidation with minimal superoxide production from the nucleotide-free site. PMID- 23683272 TI - Response of human dental pulp capped with biodentine and mineral trioxide aggregate. AB - INTRODUCTION: Biodentine is a new bioactive cement that is similar to the widely used mineral trioxide aggregate (MTA). It has dentin-like mechanical properties, which may be considered a suitable material for clinical indications of dentin pulp complex regeneration such as direct pulp capping. The purpose of the present study was to compare the response of the pulp-dentin complex in human teeth after direct capping with this new tricalcium silicate-based cement with that of MTA. METHODS: Pulps in 28 caries-free maxillary and mandibular permanent intact human molars scheduled for extraction for orthodontic reasons were mechanically exposed and assigned to 1 of 2 experimental groups, Biodentine or MTA, and 1 control group. Assay of periapical response and clinical examination were performed. After 6 weeks, the teeth were extracted, stained with hematoxylin-eosin, and categorized by using a histologic scoring system. RESULTS: The majority of specimens showed complete dentinal bridge formation and an absence of inflammatory pulp response. Layers of well-arranged odontoblast and odontoblast like cells were found to form tubular dentin under the osteodentin. Statistical analysis showed no significant differences between the Biodentine and MTA experimental groups during the observation period. CONCLUSIONS: Within the limitations of this study, Biodentine had a similar efficacy in the clinical setting and may be considered an interesting alternative to MTA in pulp-capping treatment during vital pulp therapy. PMID- 23683273 TI - Maxillary sinus and posterior teeth: accessing close relationship by cone-beam computed tomographic scanning in a Brazilian population. AB - INTRODUCTION: This study aimed to evaluate the close proximity established between the maxillary sinus floor and posterior teeth roots apices by using cone beam computed tomographic scanning. METHODS: The relationship of maxillary sinuses and posterior teeth roots, which were divided into 2 groups, was analyzed using i-CAT Vision software (Imaging Sciences, Hatfield, PA). Group 1 included all root apices found in close contact with the maxillary sinus floor without sinus floor elevation, whereas group 2 included all root apices that were protruded within the sinus producing an elevation of the bony cortical. RESULTS: A total of 100 maxillary sinuses and 601 roots apices were evaluated. Group 1 presented 130 of 601 (21.6%) roots and group 2 presented 86 of 601 (14.3%) roots. CONCLUSIONS: The second molar mesiobuccal root apex is frequently found in close proximity with the sinus floor, and the relation between these anatomic structures should be considered in order to prevent an iatrogenic procedure and minimize the risks from an infectious disease within the sinus. PMID- 23683274 TI - Altered coronal tissue of the human dental pulp in chronic hepatitis C virus infected patients. AB - INTRODUCTION: Hepatitis C virus (HCV) infection is characterized by a high rate of chronicity and concerns 170 million individuals worldwide. Extrahepatic manifestations are frequently observed in patients with chronic viral hepatitis. Although extrahepatic manifestations do exist with all hepatitis viruses, they are more commonly associated with chronic HCV infection. This study aimed to evaluate qualitatively and quantitatively the effect of chronic HCV infection on the coronal tissue of the human dental pulp. METHODS: Thirty sound impacted teeth were obtained from healthy individuals as healthy controls. The patient group included another 30 sound impacted teeth obtained from chronic HCV-infected patients. The coronal pulp tissues were carefully removed, fixed, and processed to be stained with hematoxylin-eosin, alcian blue (2.5)/periodic acid-Schiff, van Gieson, and fibronectin. RESULTS: The tissue sections of chronic HCV patients revealed disorganized pulp tissue, chronic inflammatory cell infiltrate, thickening, stenosis and occlusion of large-sized blood vessel arteriole, and collapsed venule and lymphatic system. The acidic, neutral, and mixed mucins were increased, whereas the amount of collagen was decreased, accompanied with marked decrease in the distribution and quantity of fibronectin glycoprotein. Application of Kruskal-Wallis test showed that there were statistically significant changes between the 2 groups (P <= .05). CONCLUSIONS: The coronal tissue of the dental pulp, like any other body tissues, is affected by chronic HCV infection, with an inappropriate cellularity, vasculature, and extracellular matrix proteins. The clinician should be alerted to these histologic changes and their subsequent implications. PMID- 23683275 TI - The critical apical diameter to obtain regeneration of the pulp tissue after tooth transplantation, replantation, or regenerative endodontic treatment. AB - INTRODUCTION: Regeneration of pulp-like tissue in the pulp chamber after tooth transplantation, replantation, or in regenerative endodontic treatment is only possible if the apical foramen is open. According to the literature, the success of regeneration decreases considerably if the foramen is smaller than 1 mm when measured on radiographs. The aim of this study was to study histologically the relation between the width of the apical foramen and regeneration of tissue in the pulp chamber after autotransplantation. METHODS: Fifteen single-rooted mature teeth of 3 adult beagle dogs were used. All experimental teeth were extracted and underwent apicoectomy. The teeth were photographed from the apical side, and the width of the foramen was calculated. The foramen width ranged from 0.24-1.09 mm. All teeth were replanted in infraocclusion. The observation period was 90 days after transplantation. RESULTS: The 10 teeth with the smallest apical diameter, ranging between 0.24 and 0.53 mm, showed vital tissue in at least one third of the pulp chamber. The 6 most successful teeth showing vital tissue in the entire pulp chamber had an apical diameter between 0.32 and 0.65 mm, and 80% of the experimental teeth with a diameter varying between 1.09 and 0.31 mm showed vital tissue in at least one third of the pulp chamber 90 days after transplantation. CONCLUSIONS: The size of the apical foramen seems not to be the all decisive factor for successful revascularization and ingrowth of new tissue after transplantation. The minimum width of the apical foramen has not been determined, but a size smaller than 1 mm does not prevent revascularization and ingrowth of vital tissue. In this animal study an apical foramen of 0.32 mm did not prevent ingrowth of new tissue in two-thirds of the pulp chamber 90 days after transplantation. PMID- 23683276 TI - Ketoprofen inhibits expression of inflammatory mediators in human dental pulp cells. AB - INTRODUCTION: Conventional root canal treatment is the treatment of choice for the irreversible pulpitis caused by bacterial infection. More recently, vital pulp therapy has been proposed as an alternative for management of inflamed dental pulp. Ketoprofen is an anti-inflammatory agent commonly used as a component of mouth rinse for oral lesions. Here, we examined the effect and mechanisms of action of ketoprofen on the expression of inflammatory mediators induced by the lipopolysaccharide (LPS) in dental pulp cells. METHODS: Human dental pulp cells were exposed to LPS or LPS + ketoprofen, and reverse transcription polymerase chain reaction was used to detect interleukin-1beta and tumor necrosis factor alpha. The effect of these treatments on mitogen-activated protein kinase pathways was assessed by Western blots for extracellular signal regulated kinase and c-Jun N-terminal kinase. RESULTS: LPS induced interleukin 1beta and tumor necrosis factor alpha in dental pulp cells. Ketoprofen effectively inhibited interleukin-1beta and tumor necrosis factor alpha production in LPS-stimulated dental pulp cells. Notably, ketoprofen inhibited phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase. CONCLUSIONS: Ketoprofen inhibited expression inflammatory mediators in dental pulp cells stimulated with LPS. The inhibitory effect of ketoprofen on inflammatory cytokines is associated with inhibition of the mitogen-activated protein kinase pathway. PMID- 23683277 TI - Adenosine monophosphate-activated protein kinase/mammalian target of rapamycin dependent autophagy protects human dental pulp cells against hypoxia. AB - INTRODUCTION: Human dental pulp cells (HDPCs) are recalcitrant to hypoxic stress. We investigated whether hypoxia-induced autophagy of HDPCs offered these cells a survival advantage and the underlying mechanism of this resistance. METHODS: The viability and apoptosis of HDPCs were examined after exposure to hypoxia by Vi CELL cell viability analyzer and flow cytometry. Autophagy was assessed by using immunofluorescence, acridine orange staining, real-time polymerase chain reaction, and Western blotting. Either 3-methyladenine or expression vectors encoding dominant negative ATG5 were used to inhibit autophagy. Rapamycin was used as an autophagic inducer. To explore the mechanisms of autophagy, adenosine monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway and hypoxia-inducible transcription factor-1 were suppressed by chemical inhibitors Compound C and YC-1, respectively. RESULTS: The exposure of HDPCs to hypoxia had no effect on viability and resulted in increasing acidic vesicular organelle-positive cells, autophagosome formation, and up-regulation of autophagy genes. Inhibition of autophagy with 3- methyladenine or expression vectors encoding dominant negative ATG5 abrogated the protective effects of HDPCs. The phosphorylation of AMPK was up-regulated, whereas the phosphorylation of mTOR was down-regulated in hypoxia-treated HDPCs, which were both attenuated by Compound C. Furthermore, treatment with Compound C rather than YC-1 reduced the autophagy. CONCLUSIONS: Our results suggested that autophagy of HDPCs might be cytoprotective against hypoxic stress via the AMPK/mTOR signaling pathway. PMID- 23683279 TI - Hypotonic-induced stretching of plasma membrane activates transient receptor potential vanilloid channels and sodium-calcium exchangers in mouse odontoblasts. AB - INTRODUCTION: A number of transient receptor potential (TRP) channels have been identified as membrane-bound sensory proteins in odontoblasts. However, the activation properties of these channels remain to be clarified. The purpose of this study was to investigate hypotonic stimulation-induced Ca(2+) entry via TRP vanilloid subfamily member (TRPV) 1, TRPV2, and TRPV4 channels, which are sensitive to osmotic and mechanical stimuli, and their functional coupling with Na(+)-Ca(2+) exchangers (NCXs) in mouse odontoblast lineage cells. METHODS: We examined TRP channel activity by measuring intracellular-free Ca(2+) concentration by using fura-2 fluorescence and ionic current recordings with whole-cell patch-clamp methods. Protein localization and messenger RNA expression were characterized using immunofluorescence and reverse-transcription polymerase chain reaction analyses. RESULTS: Extracellular hypotonic solution-induced stretching of plasma membrane resulted in the activation of Ca(2+) influx and inward currents. TRPV1, TRPV2, and TRPV4 channel antagonists inhibited the hypotonic stimulation-induced Ca(2+) entry and currents. Their respective agonists activated Ca(2+) entry. Although the increase in the intracellular free Ca(2+) concentration decayed rapidly after the applications of these TRPV channel agonists, NCX inhibitors significantly prolonged the decay time constant. The messenger RNA expression of TRPV1, TRPV2, and TRPV4 channels; NCX isoforms 2 and 3; and dentin sialophosphoprotein were up-regulated after 24 hours of exposure to the hypotonic culture medium. CONCLUSIONS: These results indicate that stretching of the odontoblast membrane activates TRPV1-, TRPV2-, and TRPV4-mediated Ca(2+) entry, and increased intracellular-free Ca(2+) concentration is extruded via NCXs. These results suggest that odontoblasts can act as sensors that detect stimuli applied to exposed dentin and drive a number of cellular functions including dentinogenesis and/or sensory transduction. PMID- 23683278 TI - Bioactivity of calcium aluminate endodontic cement. AB - INTRODUCTION: Calcium aluminate endodontic cement (CAEC) developed for use in root canal therapy has been produced with additives that improve handling properties and provide higher mechanical strength than mineral trioxide aggregate (MTA) according to prior studies. The aim of this study was to evaluate the bioactivity of CAEC containing accelerating additives (A-CAEC) in comparison with MTA, both in contact with simulated body fluid (SBF) solutions. METHODS: pH measurements were taken for set cement samples immersed in water or SBF solutions prepared according to the Kokubo and Rigo techniques. The surface of these materials kept in contact with SBF solutions were also evaluated by means of scanning electron microscopy, energy-dispersive X-ray analysis, and X-ray diffraction. RESULTS: Because of the calcium hydroxide dissociation, MTA cement is able to release more Ca(2+) ions and results in a higher pH increase compared with A-CAEC. This behavior enhances the supersaturation of Kokubo solution, resulting in the precipitation of calcium phosphate phases on the MTA surface. On the other hand, for MTA in Rigo SBF solution, the pH value attained was higher than for the Kokubo SBF solution as a result of the Mg(2+) ion precipitation, which inhibited the calcium phosphate phase formation. For A-CAEC, the optimal precipitation conditions of calcium phosphate phases are achieved in Rigo SBF solution. CONCLUSIONS: MTA and A-CAEC present bioactivity in contact with SBF solution although the composition of this solution defines the type of phase precipitated. PMID- 23683280 TI - Local injection of pulp cells enhances wound healing during the initial proliferative phase through the stimulation of host angiogenesis. AB - INTRODUCTION: The aim of this study was to examine the effect of pulp cell injection on host angiogenesis during wound healing. METHODS: Pulp cells were isolated from extracted premolars by the outgrowth method. Fluorescently labeled pulp cells or phosphate-buffered saline were locally injected into a mouse wound healing model. Wound healing was evaluated using photographs, histology, and real time reverse-transcription polymerase chain reaction. Injected cells were traced. Angiogenesis was measured by performing immunohistochemical staining of CD31, a marker of vascular endothelial cells. The level of secreted vascular endothelial growth factor in the pulp cell conditioned medium (CM) was compared with the CM of fibroblasts and keratinocytes. The paracrine effect of pulp CM on angiogenesis was evaluated by tubular network formation using endothelial cells. RESULTS: The local injection of pulp cells enhanced wound closure during the initial stage when compared to the injection of phosphate-buffered saline. The amount of extracellular matrix production and the expression of CD31+ cells were also increased in response to pulp cell injection when compared with the injection of phosphate-buffered saline. The fluorescently labeled pulp cells were engrafted into the hair follicles of the adjacent normal dermis but not into the wound site per se. A significantly higher level of vascular endothelial growth factor was secreted into the CM of pulp cells when compared with dermal fibroblast and keratinocytes. Tubular network formation of endothelial cells and the proliferation of dermal fibroblasts were significantly enhanced by the application of pulp cell CM when compared with control media. CONCLUSIONS: Our results show that local injection of pulp cells is effective in enhancing wound healing during the initial proliferative phase, especially through paracrine mechanisms regulating host angiogenesis and proliferation. PMID- 23683281 TI - Stimulation of matrix metalloproteinases by tumor necrosis factor-alpha in human pulp cell cultures. AB - INTRODUCTION: The purpose of this study was to investigate whether in vitro stimulation of pulp cells leads to increased secretion of matrix metalloproteinases (MMPs) and, if so, to identify which MMPs are affected. METHODS: Cells cultured from dental pulp were stimulated with tumor necrosis factor-alpha (TNF-alpha) (10 ng/mL) for 24 hours, and lysates were analyzed with an antibody array (Bio-Rad Laboratories, Hercules, CA). The mRNA and protein levels of MMP-3, -10, and -13 were measured by real-time polymerase chain reaction (real-time PCR), enzyme-linked immunosorbent assay (ELISA), Western blot analysis, and zymography. In addition, tumor necrosis factor receptors in the pulp cells were assayed by flow cytometry. The ELISA and real-time PCR results were analyzed by paired t tests. RESULTS: The expression of MMP-3, -10, and -13 was up-regulated in the pulp cells after 24 hours of stimulation with TNF-alpha (10 ng/mL) as seen in the antibody array, real-time PCR, and ELISA results, but MMP-10 was not detected by Western blotting or casein zymography. Flow cytometry analysis showed that the majority of the pulp cells expressed tumor necrosis factor receptor 1. CONCLUSIONS: In regions of inflammation, TNF-alpha may initiate the degradation of dental connective tissue by activating MMP-3 and MMP 13. These proteins may play an important pathologic role in the inflammation of dental pulp. PMID- 23683282 TI - Effect of nifedipine on the differentiation of human dental pulp cells cultured with mineral trioxide aggregate. AB - INTRODUCTION: Mineral trioxide aggregate (MTA) can induce differentiation of the dental pulp cells into odontoblast-like cells and generate a dentin-like mineral structure. The mechanisms underlying MTA-induced odontoblastic differentiation in human dental pulp cells (HDPCs) are not completely understood. The purpose of this study was to evaluate the effect of nifedipine as calcium channel blocker on MTA-induced odontoblastic differentiation in HDPCs. METHODS: HDPCs extracted from maxillary supernumerary incisors and third molars were directly cultured on MTA with or without nifedipine in the culture medium. Cell growth and expression of odontoblastic differentiation markers were determined by using methyl-thiazol diphenyl-tetrazolium assay and reverse transcription-polymerase chain reaction analysis, respectively. Phosphorylation of mitogen-activated protein kinase was measured by Western blotting, and calcium deposition was assessed by using alizarin red S staining. RESULTS: MTA at a concentration of 1 mg/mL significantly up-regulated the expression of dentin sialophosphoprotein and dentin matrix protein-1 and enhanced mineralized nodule formation. However, nifedipine attenuated the MTA-induced odontoblastic differentiation in HDPCs. In addition, MTA-induced mineralization was blocked by inhibition of extracellular signal regulated kinase (ERK), p38, and Jun N-terminal kinase (JNK) by using U0126, SB203580, and SP600125, respectively. Furthermore, phosphorylation of ERK and JNK in response to MTA was inhibited when the medium was supplemented with nifedipine. CONCLUSIONS: This study showed that calcium ions released from MTA play an important role in odontoblastic differentiation of HDPCs via modulation of ERK and JNK activation. PMID- 23683283 TI - Effect of statins with alpha-tricalcium phosphate on proliferation, differentiation, and mineralization of human dental pulp cells. AB - INTRODUCTION: The aim of this study was to investigate the combined effect of statin and alpha-tricalcium phosphate (alpha-TCP) on odontoblastic differentiation of human dental pulp cells and to compare them with mineral trioxide aggregate (MTA). METHODS: Experimental cements were prepared with TCP containing simvastatin and atorvastatin. Cell proliferation, cell adherence on a dentin disc, alkaline phosphatase (ALP) activity, expression of osteogenic/odontoblastic markers, and mineralization of the human dental pulp cells on experimental cement and MTA were assessed. RESULTS: The cell growth and ALP activity of TCP containing simvastatin-treated cells was greater than MTA treated cells. The mineralization and messenger RNA expression of markers (ie, dentin sialophosphoprotein, dentin matrix protein 1, bone morphogenetic protein 2, ALP, and osteonectin) of TCP containing simvastatin- and TCP containing atorvastatin-treated cells were comparable with MTA-treated cells. The enhanced cell proliferation and similar level of ALP of TCP-treated cells compared with the control indicate that alpha-TCP is an effective osteoconductive material. The differentiation effect observed in TCP containing simvastatin- and TCP containing atorvastatin-treated cells is attributed to the effect of statin. CONCLUSIONS: The results suggest that alpha-TCP can be used for local delivery of statin as a pulp capping material to accelerate reparative dentin formation. PMID- 23683284 TI - Cytotoxic effects and antibacterial efficacy of a 3-antibiotic combination: an in vitro study. AB - INTRODUCTION: A 3-antibiotic combination (3Mix) is widely used in endodontics for root canal disinfection, particularly in pulp revascularization procedures. However, the cytotoxicity of 3Mix has not been evaluated. The purpose of this study was to determine the cytotoxicity and antibacterial efficacy of 3Mix and each single antibiotic component of 3Mix. METHODS: For the cytotoxicity test, human dental pulp cells and apical papilla cells were exposed to either 3Mix or to each single antibiotic component of 3Mix using concentrations of 0.024, 0.097, 0.39, 1.56, 6.25, and 25.00 MUg/mL for 1, 3, 5, and 7 days. Cell viability was determined using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. For the antibacterial test, 25.00 MUg/mL and 0.39 MUg/mL 3Mix or single antibiotic were tested on bacteria isolated from necrotic teeth by measuring bacterial recovery on blood agar. RESULTS: The 0.024-MUg/mL concentration of all experimental groups generated the highest dental pulp cell or apical pulp cell viability at all time periods. On day 7, 0.39 MUg/mL 3Mix produced more than 90% cell viability; 25.00 MUg/mL 3Mix completely eliminated isolated bacteria, whereas 0.39 MUg/mL was unable to eradicate all bacteria. However, the overall bacterial reduction was significantly different compared with the control group (P < .01). CONCLUSIONS: All drugs except metronidazole induced cytotoxicity on cultured cells. 3Mix generated higher cytotoxicity compared with a single drug. The cytotoxicity increased in a concentration- and time-dependent manner; 0.39 MUg/mL 3Mix had less cytotoxicity and was able to significantly reduce bacteria isolated from necrotic teeth. PMID- 23683285 TI - Evaluation of root-end preparation with a new ultrasonic tip. AB - INTRODUCTION: This study was conducted to evaluate the effect of a new ultrasonic tip (Jetip) for root-end preparation. METHODS: A total of 80 single-rooted teeth were endodontically treated, and the apical 3 mm of the root apex was resected. Teeth were randomly distributed into 2 experimental groups according to the ultrasonic tips used to prepare the root-end cavity. Epoxy resin replicas of root end surfaces after root-end resection were obtained. A root-end cavity was then prepared with an ultrasonic tip, either Jetip or AS3D. Replicas of the apices were fabricated after the retropreparations, and they were processed for analysis by scanning electron microscopy (SEM) to evaluate the presence of microcracks and the quality of the root-end preparation. The morphologic characteristics of the ultrasonic tip were also assessed by SEM. The time required for root-end preparation was recorded. RESULTS: There were no statistically significant differences between the Jetip and AS3D groups in the mean time for the root-end preparation, the incidence of microcracks, or the quality of the root-end preparation (P > .05). SEM analysis showed that Jetip exhibited smoothed microprojections after the root preparations, whereas the loss of diamond particles was observed in AS3D. CONCLUSIONS: Both Jetip and AS3D provided rapid and regular root-end preparations. The cutting efficiencies of both Jetip and AS3D decreased with the number of times the tips were used. The Jetip showed smooth microprojections after root-end preparation, whereas the AS3D tip exhibited the loss of diamond particles. PMID- 23683286 TI - Success of ultrasonic technique in removing fractured rotary nickel-titanium endodontic instruments from root canals and its effect on the required force for root fracture. AB - INTRODUCTION: Fracture of rotary nickel-titanium files is a real concern among endodontists; it affects the long-term prognosis of treatment. Ultrasound is a favorable technique for removing broken files, although it may result in some complications. The aim of this study was to determine the success rate of ultrasonic technique in removing file fragments and to evaluate its influence on the force required to fracture a tooth root. METHODS: An in vitro study was carried out on 70 extracted maxillary premolars. In the experimental group a #30/.04 taper Hero file was guided into the canal to break and lodge therein. The lodged file was removed by ultrasonic vibration and use of a dental operating microscope. The canals were instrumented with Hero files by using crown-down technique and then obturated. All the teeth were prepared for mechanical testing in Testometric machine to measure the required force for root fracture. The Fisher exact test and independent two-sample t test were used to analyze data. RESULTS: Ultrasonic technique exhibited a success rate of 80% in removing broken files. Success rate in the roots with file fracture before the curve was 11.5 times more than that of file fracture cases beyond the curve. Other factors such as bypass possibility did not affect success rate. The average time required for removing file fragments was 36.3 +/- 7.15 minutes, which did not significantly differ in different file locations within the canal. According to mechanical test results, ultrasonic application did not significantly affect the required force for root fracture. The force required to fracture a root did not significantly differ in various file locations. Vertical fracture in the buccolingual direction (split tooth) was the most incident fracture pattern. Procedural errors observed in this study predominantly included transportation, perforation, and craze line. CONCLUSIONS: Ultrasonic technique was successful in removing 80% of fractured rotary files and did not significantly affect the required force for root fracture. PMID- 23683287 TI - Effect of asymmetry on the behavior of prototype rotary triple helix root canal instruments. AB - INTRODUCTION: Two factors affect the choice of instruments for root canal preparation: its ability to achieve the canal's shaping and its safety. These factors depend on the profile of the instrument and the design of its active part. In this study, we tried to assess the role of an asymmetric cross-section on the behavior of the instrument by measuring the stresses generated during the preparation of a simulated canal. METHODS: Three 25-mm-long, 0.06 taper, ISO size #30 helical nickel-titanium instruments were tested. The first HeroShaper (Micro Mega, Besancon, France) used had a symmetric triple helix section (H0). The others, based on the HeroShaper design, had a constant asymmetry of 4/100 mm (H4) or 6/100 mm (H6). Six canals were prepared using each instrument, and the experimental conditions (ie, speed and movement) were the same for each sample. A dynamometer with a sensitivity of 0.1 N recorded the stresses transmitted by the instruments. RESULTS: Torque and apical force increased proportionally with instrument penetration. At the end of the preparations, the axial stress averaged 7.39 N for the symmetric instrument and 5.92 and 5.15 N for the asymmetric instruments, which indicated a significant statistical analysis of variance (P < .001). The average torque was low (1.05-1.13 N.cm), which indicated a nonsignificant statistical analysis of variance (P = .2385). CONCLUSIONS: In this study, axial stresses decreased, but torque did not change with an asymmetric triple helix cross-section. PMID- 23683288 TI - Long-term dose- and time-dependent effects of endodontic sealers in human in vitro osteoclastogenesis. AB - INTRODUCTION: This study evaluates the concentration and time-dependent effects of endodontic sealers' extracts (AH Plus [Dentsply DeTrey, Konstanz, Germany], GuttaFlow [Roeko, Coltene/Whaledent, Germany], Tubliseal [Kerr/Sybron, Romulus, MI], Sealapex [Kerr/Sybron, Romulus, MI], and RealSeal [SybronEndo, Orange, CA]) in the differentiation and function of both unstimulated and stimulated osteoclast precursors, simulating, respectively, immature/undifferentiated precursors and cells undergoing osteoclastogenesis. METHODS: The sealers were mixed according to the manufacturers' instructions, freshly extracted with culture medium (1.3 cm(2)/mL, 24 hours, 37 degrees C, 5% CO2/air), and diluted (1:20, 1:100, 1:500, and 1:2500). Human peripheral blood mononuclear cells were used as osteoclast precursor cells. After overnight attachment, peripheral blood mononuclear cell cultures were exposed to the sealers' extracts during 21 days in the absence (unstimulated) or presence (stimulated) of recombinant macrophage colony-stimulating factor and receptor for the activation of nuclear factor kappaB ligand. Cultures performed in the absence of the extracts were used as the control. Cultures were characterized for osteoclastic differentiation and function. RESULTS: Extracts caused mostly inhibitory effects on osteoclastic cells, both in unstimulated and stimulated conditions, which were reflected by a decrease in tartrate-resistant acid phosphatase activity, the presence of actin rings, vitronectin and calcitonin receptors, the calcium phosphate resorbing ability, and the expression of osteoclastic genes. Also, the extracts induced alterations in the relative contribution of some intracellular signaling pathways involved in osteoclastogenic events. The sealers differed in the dose- and time dependent profile. An adaptive cell response was noticed for the inhibitory effects after long-term exposure. CONCLUSIONS: Endodontic sealers affect the osteoclastic differentiation and activity, which is followed by an adaptive cell response. Our results suggest that the deleterious effect in the bone periapical tissues observed with the root canal sealers might involve, at least partially, a direct effect on the osteoclastic cells. PMID- 23683289 TI - Non-Hodgkin lymphoma in the periapical region of a mandibular canine. AB - INTRODUCTION: Images and clinical characteristics of some lesions may lead to misinterpretations between diseases of endodontic and non-endodontic origin. Non Hodgkin lymphomas occur in extranodal sites and may arise primarily in the oral cavity or jaws. METHODS: A case of lymphoma associated with the roots of teeth #21-23 in a 38-year-old woman is described. The patient sought dental care because of continuous discomfort at palpation of the periapical area of teeth #21 23, which had been treated endodontically. Radiographic and clinical exams revealed no inflammatory signs. The patient reported losing 24 pounds in the last 2 months. Intraoral examination revealed an expansion of the buccal surface, a solid hard mass, and normal mucosa color. RESULTS: Conventional radiographs showed a diffuse bone radiolucent area, and cone-beam computed tomography images confirmed destruction of the buccal cortical bone, which was suggestive of malignancy. Incisional biopsy was performed, and microscopy showed a lymphoproliferative lesion of uncertain nature with pleomorphic lymphocyte-like round cells, hyperchromatic nuclei, and atypical mitoses. Immunohistochemistry was used to investigate the nature of these cells and the type of lymphoproliferative disorder, and results showed an area of diffuse large B-cell lymphoma. CONCLUSIONS: Non-Hodgkin lymphoma should be part of the differential diagnosis of other jaw lesions such as apical periodontitis. The patient was treated with chemotherapy and did not report any abnormalities after 2 years of treatment. PMID- 23683290 TI - Temporal analysis of poplar woody root response to bending stress. AB - Temperate perennial woody plants use different environmental signals to coordinate their growth and development in relation to seasonal changes. Preliminary evidences suggest that, even during dormancy, plants maintain effective metabolic activities and molecular mechanisms ensuring them an eventual recording of mechanical loads during winter times. Despite their great importance for productivity and survival, plant biology investigations have poorly characterized the root growth cycle and its response to environmental stresses. In this study, we describe the proteomic changes occurring over the time in poplar root either in the absence or in response to a bending stress; corresponding expression of cell cycle regulator and auxin transporter genes was also evaluated by reverse transcription polymerase chain reaction analysis. Our results confirm previous evidences on the effect of the bending stress on the anticipation of root growth resumption, providing additional insights on a temporal modulation of various plant metabolic processes involved in dormancy break, growth resumption and stress response in the bent root; these events seem related to the differential compression and tension force distribution occurring over the plant taproot. PMID- 23683291 TI - Trans and cis influences in hypervalent iodine(III) complexes: a DFT study. AB - Trans and cis influences of various X ligands in two isomeric structures of acyclic hypervalent compound Ph[XI(OH)] and heterocyclic lambda(3)-iodane Ph[(heterocycle)I(OH)] have been investigated on the basis of I-OH bond distance (d), electron density at I-OH bond critical point (rho), I-OH stretching frequency (nu), and molecular electrostatic potential minimum (Vmin) at the OH lone pair. d, rho, nu, and Vmin are found to be good parameters for quantifying trans and cis influences, and among them, Vmin is the most sensitive parameter. Heterocyclic lambda(3)-iodanes showed a smaller trans influence than acyclic lambda(3)-iodanes. All systems showed higher trans influence than cis influence while relative order of both is in accordance with the inductive nature of the ligands. Among the heterocyclic lambda(3)-iodanes, strong trans/cis influence is observed with N or B in the ring while P gave moderate and S gave weak trans/cis influence. Among the substituents on the cis-positioned phenyl ring in heterocyclic lambda(3)-iodanes, electron withdrawing ortho substitution significantly strengthened the hypervalent I-OH bond. The stability of a product resulting from the nucleophilic attack of Cl(-) on a lambda(3)-iodane is directly correlated with the trans/cis influence of the ligands. This relationship is helpful to make good prediction on the interaction energy of a nucleophile in trivalent hypervalent iodine complex and hence useful in designing stable acyclic and heterocyclic hypervalent complexes. PMID- 23683292 TI - Interaction between a serotonin transporter gene promoter region polymorphism and stress predicts depressive symptoms in Chinese adolescents: a multi-wave longitudinal study. AB - BACKGROUND: The serotonin transporter (5-HTT) gene may play an important role in the onset and development of mental disorders. Past studies have tested whether a functional polymorphism in the 5-HTT gene linked promoter region (5-HTTLPR) moderated the association between stress and depressive symptoms, but the results of these studies were inconsistent. Thus, the aim of the current study was to examine the interaction between 5-HTTLPR and stress that predict depressive symptoms in Chinese adolescents. METHODS: A total of 252 healthy adolescents (131 females and 121 males, aged from 14 to 18, mean = 16.00, standard deviation = 0.60) participated in this study. During the initial assessment, all participants completed the Center for Epidemiological Studies Depression Scale (CES-D) and Adolescent Life Events Questionnaire (ALEQ) and were genotyped for the 5-HTTLPR polymorphism. Participants subsequently completed CES-D and ALEQ once every three months during the subsequent 24 months. A multilevel model was used to investigate the 5-HTTLPR * stress interaction in predicting depressive symptoms. RESULTS: The results indicated no main effect of 5-HTTLPR and a significant 5 HTTLPR * stress interaction in females only. Females with at least one 5-HTTLPR S allele exhibited more depressive symptoms under stressful situations. No significant 5-HTTLPR * stress interaction was found in males. CONCLUSIONS: In Chinese adolescents, there are gender differences on the interaction between 5 HTTLPR and stress that predict depressive symptoms. The association between stress and depressive symptoms is moderated by 5-HTTLPR in Chinese female adolescents. PMID- 23683293 TI - High-throughput STR analysis for DNA database using direct PCR. AB - Since the Korean criminal DNA database was launched in 2010, we have focused on establishing an automated DNA database profiling system that analyzes short tandem repeat loci in a high-throughput and cost-effective manner. We established a DNA database profiling system without DNA purification using a direct PCR buffer system. The quality of direct PCR procedures was compared with that of conventional PCR system under their respective optimized conditions. The results revealed not only perfect concordance but also an excellent PCR success rate, good electropherogram quality, and an optimal intra/inter-loci peak height ratio. In particular, the proportion of DNA extraction required due to direct PCR failure could be minimized to <3%. In conclusion, the newly developed direct PCR system can be adopted for automated DNA database profiling systems to replace or supplement conventional PCR system in a time- and cost-saving manner. PMID- 23683295 TI - Clinical trial registration: implications for stakeholders. PMID- 23683294 TI - Exclusive rewards in mutualisms: ant proteases and plant protease inhibitors create a lock-key system to protect Acacia food bodies from exploitation. AB - Myrmecophytic Acacia species produce food bodies (FBs) to nourish ants of the Pseudomyrmex ferrugineus group, with which they live in an obligate mutualism. We investigated how the FBs are protected from exploiting nonmutualists. Two dimensional gel electrophoresis of the FB proteomes and consecutive protein sequencing indicated the presence of several Kunitz-type protease inhibitors (PIs). PIs extracted from Acacia FBs were biologically active, as they effectively reduced the trypsin-like and elastase-like proteolytic activity in the guts of seed-feeding beetles (Prostephanus truncatus and Zabrotes subfasciatus), which were used as nonadapted herbivores representing potential exploiters. By contrast, the legitimate mutualistic consumers maintained high proteolytic activity dominated by chymotrypsin 1, which was insensitive to the FB PIs. Larvae of an exploiter ant (Pseudomyrmex gracilis) taken from Acacia hosts exhibited lower overall proteolytic activity than the mutualists. The proteases of this exploiter exhibited mainly elastase-like and to a lower degree chymotrypsin 1-like activity. We conclude that the mutualist ants possess specifically those proteases that are least sensitive to the PIs in their specific food source, whereas the congeneric exploiter ant appears partly, but not completely, adapted to consume Acacia FBs. By contrast, any consumption of the FBs by nonadapted exploiters would effectively inhibit their digestive capacities. We suggest that the term 'exclusive rewards' can be used to describe situations similar to the one that has evolved in myrmecophytic Acacia species, which reward mutualists with FBs but safeguard the reward from exploitation by generalists by making the FBs difficult for the nonadapted consumer to use. PMID- 23683296 TI - Increased levels of interleukin-6 in synovial lavage fluid from patients with mandibular condyle fractures: correlation with magnetic resonance evidence of joint effusion. AB - PURPOSE: The aim of the present study was to investigate the relation between magnetic resonance (MR) evidence of joint effusion and concentrations of proinflammatory cytokines, including interleukin (IL)-1beta and IL-6, in washed out synovial fluid samples obtained from patients with mandibular condyle fractures. PATIENTS AND METHODS: Twenty-five joints in 23 patients with mandibular condyle fractures were examined. Computed tomography was used to determine the position of the fracture and MR examination was performed in all cases. Twenty-five joints underwent temporomandibular joint (TMJ) irrigation before surgical treatment for the fractures. The detection rates and concentrations of the tested cytokines were determined, and their relations to evidence of joint effusion and positions of the condylar fractures were analyzed. RESULTS: Six TMJ fractures were found in the head, 10 in the upper neck, 4 in the lower neck, and 5 in the subcondyle. MR evidence of joint effusion was observed in 17 of 25 TMJs (68.0%). The detection rate and concentration of IL-6 were significantly higher in patients with MR evidence of joint effusion and those with high condylar fractures. Moreover, there was a correlation between joint effusion grade and IL-6 concentration. CONCLUSIONS: The present findings showed a correlation between MR evidence of joint effusion and concentration of IL-6 in washed-out synovial fluid samples collected from patients with mandibular condyle fractures. These results may provide support for arthrocentesis as a reasonable treatment modality for high condylar fractures. PMID- 23683297 TI - Listening to the patient's self-reported testimony: the authentic hermeneutical witness to the compassionate nurse? AB - AIM: This paper considers whether the patient's self-reported testimony of nursing care provides an authentic basis for nursing knowledge. An international nursing and philosophical literature gives international relevance. BACKGROUND: United Kingdom reports detail patients' complaints about nursing care. Many are personal self-reported testimonies published in the media, but discounted by the nursing profession. DESIGN: Discussion paper. DATA SOURCES: Data sources 1873 2012 include policy documents, nursing studies involving grounded theory, phenomenology and narrative inquiry, nursing textbooks 1882-1971 and the interpretive paradigms of Glaser and Strauss, Heidegger, Ricoeur and Gadamer. DISCUSSION: Nursing researchers use qualitative methodologies to understand the patient's experience of nursing. Three exemplars reveal epistemological and ontological problems. Epistemologically, researchers are controlling data, their selection and interpretation. Ontologically, the researcher's present horizon dominates because no consideration is given to the historical horizon and context where the tradition of nursing developed and defined the nurse. Arguably, patients' expectations of compassionate nurses bear witness to this past horizon. IMPLICATIONS FOR NURSING: Patients' self-reported testimonies should be taken seriously as an evidence base for understanding and improving nursing care. Nursing researchers using qualitative methods should be transparent about their pre-judgements. Connections with the past horizon of nursing history should be made to cast light on the present horizon. CONCLUSION: Patients' self-reported testimonies are more congruent with methods of narrative inquiry than data solicited and filtered by the interviewer's undeclared pre-judgement. They bear witness to the horizon of the past and the meaning and purpose of nursing, its values and ethos. PMID- 23683298 TI - Postlingual adult performance in noise with HiRes 120 and ClearVoice Low, Medium, and High. AB - OBJECTIVES: The study's objectives were to evaluate speech recognition in multiple listening conditions using several noise types with HiRes 120 and ClearVoice (Low, Medium, High) and to determine which ClearVoice program was most beneficial for everyday use. METHODS: Fifteen postlingual adults attended four sessions; speech recognition was assessed at sessions 1 and 3 with HiRes 120 and at sessions 2 and 4 with all ClearVoice programs. Test measures included sentences presented in restaurant noise (R-SPACE), in speech-spectrum noise, in four- and eight-talker babble, and connected discourse presented in 12-talker babble. Participants completed a questionnaire comparing ClearVoice programs. RESULTS: Significant group differences in performance between HiRes 120 and ClearVoice were present only in the R-SPACE; performance was better with ClearVoice High than HiRes 120. Among ClearVoice programs, no significant group differences were present for any measure. Individual results revealed most participants performed better in the R-SPACE with ClearVoice than HiRes 120. For other measures, significant individual differences between HiRes 120 and ClearVoice were not prevalent. Individual results among ClearVoice programs differed and overall preferences varied. Questionnaire data indicated increased understanding with High and Medium in certain environments. DISCUSSION: R-SPACE and questionnaire results indicated an advantage for ClearVoice High and Medium. Individual test and preference data showed mixed results between ClearVoice programs making global recommendations difficult; however, results suggest providing ClearVoice High and Medium and HiRes 120 as processor options for adults willing to change settings. For adults unwilling or unable to change settings, ClearVoice Medium is a practical choice for daily listening. PMID- 23683300 TI - A model potential for acetonitrile: from small clusters to liquid. AB - A portable model potential, representing the intermolecular interaction of acetonitrile with itself and with ions, is proposed. Such model, formulated as a combination of a few effective components, given in terms of the polarizability and dipole moment values of the molecular partners, is here adopted as a building block of the force field of acetonitrile clusters in molecular dynamics simulations. Its reliability is tested by comparing the predicted features for both small ionic and neutral clusters containing acetonitrile with ab initio results and experimental information. Its application to molecular dynamics simulations of liquid acetonitrile and of the solvated Li(+), Na(+), K(+), and I( ), performed at several values of the temperature, discloses an ample and interesting phenomenology, described in an internally consistent way. Such model will be useful to assess the effect of intermolecular interactions on the dynamics of acetonitrile processes occurring in various environments of applied relevance, with emphasis on the dye-sensitized solar cell framework. PMID- 23683299 TI - Extraction and quantitation of coumarin from cinnamon and its effect on enzymatic browning in fresh apple juice: a bioinformatics approach to illuminate its antibrowning activity. AB - Enzymatic browning by polyphenoloxidase (PPO) affects food quality and taste in fruits and vegetables. Thus, the study was designed to reduce browning in apple juice by coumarin. The ethanolic extract of cinnamon was prepared and its coumarin content was quantitated by HPLC, using authentic coumarin (AC) as standard. The effect of cinnamon extract (CE) and AC on enzymatic browning, its time dependent effects, and the specific activity of PPO and peroxidase (POD) were studied in apple juice. The docking of coumarin with PPO and POD was also performed to elucidate its antibrowning mechanism. The CE (73%) and AC (82%) showed better reduction in browning, maintained its antibrowning effect at all time points, and significantly (p < 0.05) reduced the specific activity of PPO and POD when compared with controls. Coumarin showed strong interaction with binding pockets of PPO and POD, suggesting its potential use as inhibitor to enzyme mediated browning in apple juice. PMID- 23683301 TI - Water sanitation, access, use and self-reported diarrheal disease in rural Honduras. AB - INTRODUCTION: Only 79% of individuals living in rural Honduras use improved water sources. Inadequate drinking water quality is related to diarrheal illness, which in Honduras contributes to 18.6 episodes of diarrhea per child year in children under five years of age. The purpose of this study was to examine and compare access to drinking water and sanitation, as well as self-reported diarrheal disease incidence among three proximal communities in the Department of Yoro area of Honduras. METHODS: An 11-item language-specific, interviewer-administered, anonymous questionnaire was administered to 263 randomly selected adults attending a June 2011 medical brigade held in the communities of Coyoles, La Hicaca, and Lomitas. Chi-square with Fisher exact tests were utilized to compare water access, sanitation, and self-reported diarrheal incidence among these communities. RESULTS: Coyoles and La Hicaca used private faucets as their primary water sources. Coyoles had the greatest use of bottled water. Lomitas used rivers as their primary water source, and did not use bottled water. Mostly, females were responsible for acquiring water. Usage of multiple water sanitation methods was most common in Coyoles, while no sanitation method was most common in Lomitas. In Lomitas and La Hicaca, water filters were mostly provided via donation by non-governmental organizations. Lomitas had the highest reported incidence of diarrhea among self and other household members. CONCLUSIONS: Critical differences in water access, sanitation, and self-reported diarrheal incidence among three geographically distinct, yet proximal, communities highlights the need for targeted interventions even in geographically proximal rural areas. PMID- 23683302 TI - Twenty years of evidence and excellence. PMID- 23683303 TI - Defining the culture and attitude towards dietary management actions in people undergoing haemodialysis. AB - OBJECTIVES: The present study was designed to clarify the structure of culture and the three components of attitude in a desirable attitude toward dietary management actions in outpatient haemodialysis patients who are in the maintenance phase of treatment. METHODS: The participants in the study included nine patients undergoing chronic maintenance haemodialysis who have received guidance related to diet and had good test results. Ethnography, by means of participant observation and semi-structured interviews, was chosen as the research method. FINDINGS: Desirable attitude of haemodialysis patients in dietary management actions was found to have a chronological progression in one of the components of attitude: propensity of behaviour. Change in behaviour was influenced by affect and cognition. At the base of the structure of attitude lay three factors: valuing cooking with seasonal ingredients and creating special meals for seasonal occasions; family draws near, shows care and gives support; and belief in information perceived to be good for the health, which was influenced by three components of attitude: affect, cognition, and propensity of behaviour, as well as culture. CONCLUSION: Participants continue to value the food culture that they grew up with, which involves their affect towards, and cognition of, dietary management. PMID- 23683304 TI - Patient independence in chronic kidney disease and anaemia: implications of the 2012 KDIGO guideline. AB - BACKGROUND: A common complication of chronic kidney disease (CKD) is anaemia; how well this is treated may influence a patient's independence. The use and the time consuming nature of intravenous (IV) iron therapies can impose considerable challenges for patients. Time spent receiving and travelling to receive IV iron treatment can impact a patient's feelings of independence. By recommending increased prescription of IV iron and minimising erythropoiesis-stimulating agent use, the recent Kidney Disease: Improving Global Outcomes (KDIGO) Guideline on anaemia in CKD may compound this situation by increasing the number of hospital visits for therapy. METHODS: To assess the potential influence of the KDIGO Guideline on patient independence, this review explores factors that can impact the independence of a person with CKD and proposes how these potential issues may be addressed in the light of this new set of guidelines. CONCLUSIONS: Although the KDIGO Guideline has the potential to reduce patient independence, by acknowledging the needs of the individual early on and employing a multi disciplinary approach, a balance can be found between utilising the most recent guidelines and meeting the needs of the individual to ensure their on-going independence. PMID- 23683305 TI - Exploring the views of patients not on the transplant waiting list: a qualitative study. AB - BACKGROUND: Not all patients are suitable for kidney transplantation; however, little is known about the views and attitudes of patients who are not on the waiting list for transplantation. OBJECTIVE: This study aimed to determine the views and attitudes of patients who are not on the waiting list regarding the process of transplant allocation. METHODS: A grounded theory approach was used to develop theories from patient views, opinions and attitudes. Patients receiving dialysis, and not on the waiting list at a United Kingdom renal unit were identified by the renal counsellor and invited to take part. Five patients formed a focus group to enable construction of an interview schedule. Patients (n=10, different from those in the focus group) were interviewed until themes became saturated. Interview transcripts generated conceptual categories. RESULTS: Seven conceptual categories emerged regarding access to transplantation. Patients experience emotions of loss relating to transplantation exacerbated by restrictions imposed by dialysis. Patients find coping mechanisms, accept their situation and trust that clinical decisions were equitable. CONCLUSIONS: Patients trust their carers and support an efficacy argument when considering scarce resources. Communication should be improved to ensure clarity and understanding of clinical decisions. PMID- 23683307 TI - Acute embolic cerebral ischemia as an initial presentation of polycythemia vera: a case report. AB - INTRODUCTION: Patients with polycythemia vera are at high risk for vaso-occlusive events including cerebral ischemia. Although unusual, acute ischemic stroke may be an initial presentation of polycythemia vera. It had been previously assumed that cerebral ischemic events were due to increased blood viscosity and platelet activation within the central nervous system arterial vessels. However, there are now a few isolated case reports of probable micro-embolic events originating from outside of the brain. This suggests unique management issues for these patients. CASE PRESENTATION: We present the case of a 57-year-old right-handed Caucasian male in excellent health who presented to the Emergency Department with acute right-handed clumsiness. Hematologic investigations revealed a hyperviscous state and magnetic resonance imaging was consistent with cerebral emboli. Symptoms rapidly improved with phlebotomy and hydration. CONCLUSION: The etiology of stroke in polycythemic patients is likely to be multifactorial. While hemodilution has been generally discredited for general stroke management, it is potentially beneficial for patients with polycythemia vera and euvolemic hemodilution should be considered for the polycythemic patient with acute cerebral ischemia. PMID- 23683308 TI - Chronic respiratory disease, comorbid cardiovascular disease and mortality in a representative adult US cohort. AB - BACKGROUND AND OBJECTIVE: We sought to determine the relationship between chronic respiratory disease, cardiovascular disease (CVD) and mortality in a nationally representative cohort of the US population aged 40 years and older. METHODS: We analysed data from the baseline (1988-1994) and follow-up of the Third National Health and Nutrition Examination Survey (NHANES III). Subjects were classified in to one of four categories: obstructed (forced expiratory volume in 1 s/forced vital capacity <70% and forced expiratory volume in 1 s <80% predicted), restricted (forced expiratory volume in 1 s/forced vital capacity >=70% and forced vital capacity <80% predicted), symptomatic (neither obstructed nor restricted but reporting respiratory symptoms) and normal (none of the above). Subjects were classified as having overt CVD, CVD risk factors only or neither at the baseline examination. RESULTS: The analysis data set included 9054 subjects, of whom 1132 (12.0%, weighted percentage (WP)) were obstructed, 1319 (10.3%, WP) were restricted and 2457 were symptomatic (27.6%, WP). Overt CVD was present at baseline in 1284 subjects (10.4 %, WP), and CVD risk factors alone were present in 4900 (53.3%, WP). Three thousand five hundred seventy-one (28.4%, WP) subjects died during the up to 18-year follow-up period. When compared with 'normal' subjects, those in the obstructed group were more likely to have overt CVD (odds ratio 1.87, 95% confidence interval: 1.15-3.04, P < 0.001), with a similar risk seen in the restricted and symptomatic group. CONCLUSIONS: In this large US population-based cohort, the presence of obstruction, restriction or respiratory symptoms alone was associated with higher adjusted risk of overt CVD. PMID- 23683309 TI - Antidepressant, mood stabilizing and procognitive effects of very low dose sublingual ketamine in refractory unipolar and bipolar depression. AB - Intravenous ketamine (0.5 mg/kg) produces robust, rapid and long-lasting antidepressant effects, but is unpractical. Sublingual administration of ketamine renders better bioavailability (~30%) and less conversion to norketamine than oral administration. We evaluated the therapeutic effects and tolerability of very low dose sublingual (VLDS) racemic ketamine (10 mg from a 100 mg/ml solution for 5 min and swallowed), repeatedly administered every 2-3 d or weekly, in 26 out-patients with refractory unipolar or bipolar depression. According to patients' reports, VLDS ketamine produced rapid, clear and sustained effects, improving mood level and stability, cognition and sleep in 20 patients (77%), with only mild and transient light-headedness as a common side-effect (no euphoria, psychotic or dissociative symptoms). Remission remained in some patients after stopping ketamine. Thus, VLDS ketamine may have broad spectrum effects beyond its antidepressant properties, with rapid onset of action, high efficacy, good tolerability and low cost, allowing extended treatment as needed. PMID- 23683310 TI - Birth weight and ovulatory dysfunction. AB - OBJECTIVE: To explore the association between birthweight and ovulatory dysfunction in adulthood. DESIGN: Case-control study. SETTING: Northeast of Scotland University Hospital, hosting the regional fertility centre and maternity unit. POPULATION: A total of 18,846 mother-daughter record pairs from the Aberdeen Fertility Centre Data Set and the Aberdeen Maternity and Neonatal Databank (AMND). Cases were the daughters with ovulatory dysfunction attending the Aberdeen Fertility Centre between 1992 and 2007, Control group 1 included the daughters attending the fertility centre with confirmed ovulation, and Control group 2 included all women naturally fertile who gave birth in Aberdeen during the same period. METHODS: The electronic maternity records of the mothers of women in the three groups were retrieved from AMND and compared. MAIN OUTCOME MEASURES: Daughters' birthweight and standardised birthweight, characteristics of mothers and daughters at delivery and current daughters' characteristics. RESULTS: Cases, Control group 1 and Control group 2 included 466, 548 and 17,832 daughters, respectively. The mean birthweight (standard deviation) in grams was comparable between Cases 3203 (522), Control group 1, 3235 (482) P = 0.30, and Control group 2, 3226 (495) P = 0.31. The proportions of daughters born small for gestational age, large for gestational age, or preterm were comparable between the Cases group and each Control group, as was the mode of delivery and Apgar scores at 1 and 5 minutes. The age at delivery, body mass index, social class or pregnancy complications were comparable in the mothers of the Cases and each Control group. CONCLUSIONS: Ovulatory dysfunction does not appear to be related to birthweight or perinatal events. PMID- 23683311 TI - Predicting vertical phase segregation in polymer-fullerene bulk heterojunction solar cells by free energy analysis. AB - Blends of poly(3-hexylthiophene) (P3HT) and C61-butyric acid methyl ester (PCBM) are widely used as a model system for bulk heterojunction active layers developed for solution-processable, flexible solar cells. In this work, vertical concentration profiles within the P3HT:PCBM active layer are predicted based on a thermodynamic analysis of the constituent materials and typical solvents. Surface energies of the active layer components and a common transport interlayer blend, poly(3,4-ethylenedioxythiophene) poly(styrenesulfonate) (PEDOT:PSS), are first extracted using contact angle measurements coupled with the acid-base model. From this data, intra- and interspecies interaction free energies are calculated, which reveal that the thermodynamically favored arrangement consists of a uniformly blended "bulk" structure capped with a P3HT-rich air interface and a slightly PCBM-rich buried interface. Although the "bulk" composition is solely determined by P3HT:PCBM ratio, composition near the buried interface is dependent on both the blend ratio and interaction free energy difference between solvated P3HT and PCBM deposition onto PEDOT:PSS. In contrast, the P3HT-rich overlayer is independent of processing conditions, allowing kinetic formation of a PCBM-rich sublayer during film casting due to limitations in long-range species diffusion. These thermodynamic calculations are experimentally validated by angle-resolved X ray photoelectron spectroscopy (XPS) and low energy XPS depth profiling, which show that the actual composition profiles of the cast and annealed films closely match the predicted behavior. These experimentally derived profiles provide clear evidence that typical bulk heterojunction active layers are predominantly characterized by thermodynamically stable composition profiles. Furthermore, the predictive capabilities of the comprehensive free energy approach are demonstrated, which will enable investigation of structurally integrated devices and novel active layer systems including low band gap polymers, ternary systems, and small molecule blends. PMID- 23683312 TI - Differentiating sexual preference in men: using dual task rapid serial visual presentation task. AB - Cognition research suggests that allocating attention resources to evolutionarily relevant stimuli is facilitated suggesting that sexual stimuli interfere with human information processing. In a group of gay (n = 13) and straight men (n = 13) recruited in Finland, Germany and Italy, we investigated if and how sexually relevant visual stimuli affect information processing of both a target one (T1) and a subsequent target two (T2) in a dual target rapid serial visual presentation procedure. We hypothesized that: (1) due to the attentional blink (AB) phenomenon, the accuracy of reporting of T2 would decrease when following accurately identified sexually preferred T1 compared to accurately identified non sexually preferred T1; 2) due to the pop out effect, the accuracy of reporting of T1 and T2 would be relatively increased when T1 and T2 were sexually preferred by the participants compared to when they were not. Our findings did not support hypothesis 1 but supported hypothesis 2. We further found that the pop out effect had a good capacity to differentiate sexual preference between the groups of gay and straight men. We conclude that dual target rapid serial visual presentation can be used as an attention-based measurement to differentiate sexual preference in men. Limitations and the applicability in the field of measuring sexual preference were discussed. PMID- 23683313 TI - IMpACTing on adult ADHD research. PMID- 23683314 TI - Subarachnoid hemorrhage and carbon monoxide exposure: accidental association or fatal link? AB - This case study reports a fatal subarachnoid hemorrhage (SAH) with concomitant accidental carbon monoxide (CO) exposure in 32-year-old man. Autopsy results indicated an antemortem aspiration of smoke, and a massive SAH was identified as the cause of death. Intriguingly, the carboxyhemoglobin level was 30%, suggesting that CO could have played a specific role. Intracranial hemorrhages following CO exposure in brain areas and tissues such as the basal ganglia, globus pallidus, or white matter are rare, but well characterized, whereas SAH related to CO exposure has not been previously described. In this case report, the possible role of CO, either as a primary cause or as a facilitating factor, in the pathogenesis of SAH is discussed. In particular, we propose the hypothesis that the excessive vasodilating effects produced by CO on the cerebral endothelium results in consequential loss of microvascular integrity. PMID- 23683193 TI - Observation of associated near-side and away-side long-range correlations in sqrt[s(NN)]=5.02 TeV proton-lead collisions with the ATLAS detector. AB - Two-particle correlations in relative azimuthal angle (Deltao) and pseudorapidity (Deltaeta) are measured in sqrt[s(NN)] = 5.02 TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1 MUb(-1) of data as a function of transverse momentum (p(T)) and the transverse energy (SigmaE(T)(Pb)) summed over 3.1 < eta < 4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2 < |Delta eta | < 5) "near-side" (Deltao ~ 0) correlation that grows rapidly with increasing SigmaE(T)(Pb). A long-range "away-side" (Deltao ~ pi) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small SigmaE(T)(Pb), is found to match the near-side correlation in magnitude, shape (in Deltaeta and Deltao) and SigmaE(T)(Pb) dependence. The resultant Deltao correlation is approximately symmetric about pi/2, and is consistent with a dominant cos2Deltao modulation for all SigmaE(T)(Pb) ranges and particle p(T). PMID- 23683315 TI - Neonatal mortality in Ethiopia: trends and determinants. AB - BACKGROUND: The Ethiopian neonatal mortality rate constitutes 42% of under-5 deaths. We aimed to examine the trends and determinants of Ethiopian neonatal mortality. METHODS: We analyzed the birth history information of live births from the 2000, 2005 and 2011 Ethiopia Demographic and Health Surveys (DHS). We used simple linear regression analyses to examine trends in neonatal mortality rates and a multivariate Cox proportional hazards regression model using a hierarchical approach to examine the associated factors. RESULTS: The neonatal mortality rate declined by 1.9% per annum from 1995 to 2010, logarithmically. The early neonatal mortality rate declined by 0.9% per annum and was where 74% of the neonatal deaths occurred. Using multivariate analyses, increased neonatal mortality risk was associated with male sex (hazard ratio (HR) = 1.38; 95% confidence interval (CI), 1.23 - 1.55); neonates born to mothers aged < 18 years (HR = 1.41; 95% CI, 1.15 - 1.72); and those born within 2 years of the preceding birth (HR = 2.19; 95% CI, 1.89 - 2.51). Winter birth increased the risk of dying compared with spring births (HR = 1.28; 95% CI, 1.08 - 1.51). Giving two Tetanus Toxoid Injections (TTI) to the mothers before childbirth decreased neonatal mortality risk (HR = 0.44; 95% CI, 0.36 - 0.54). Neonates born to women with secondary or higher schooling vs. no education had a lower risk of dying (HR = 0.68; 95% CI, 0.49 - 0.95). Compared with neonates in Addis Ababa, neonates in Amhara (HR: 1.88; 95% CI: 1.26 - 2.83), Benishangul Gumuz (HR: 1.75; 95% CI: 1.15 - 2.67) and Tigray (HR: 1.54; 95% CI: 1.01 - 2.34) regions carried a significantly higher risk of death. CONCLUSIONS: Neonatal mortality must decline more rapidly to achieve the Millennium Development Goal (MDG) 4 target for under-5 mortality in Ethiopia. Strategies to address neonatal survival require a multifaceted approach that encompasses health-related and other measures. Addressing short birth interval and preventing early pregnancy must be considered as interventions. Programs must improve the coverage of TTI and prevention of hypothermia for winter births should be given greater emphasis. Strategies to improve neonatal survival must address inequalities in neonatal mortality by women's education and region. PMID- 23683316 TI - Patterns and processes in complex landscapes: testing alternative biogeographical hypotheses through integrated analysis of phylogeography and community ecology in Hawai'i. AB - The Island of Hawai'i is a dynamic assemblage of five volcanoes with wet forest habitat currently existing in four distinct natural regions that vary in area, age and geographical isolation. In this complex landscape, alternative assumptions of the relative importance of specific habitat characteristics on evolutionary and ecological processes predict strikingly different general patterns of local diversity and regional similarity. In this study, we compare alternative a priori hypotheses against observed patterns within two distinct biological systems and scales: community composition of wet forest vascular plant species and mitochondrial and nuclear genes of Drosophila sproati, a wet-forest restricted endemic. All observed patterns display strong and similar regional structuring, with the greatest local diversity found in Kohala and the windward side of Mauna Loa, the least in Ka'u and Kona, and a distinctive pattern of regional similarity that probably reflects the historical development of this habitat on the island. These observations largely corroborate a biogeographical model that integrates multiple lines of evidence, including climatic reconstruction, over those relying on single measures, such as current habitat configuration or substrate age. This method of testing alternative hypotheses across biological systems and scales is an innovative approach for understanding complex landscapes and should prove valuable in diverse biogeographical systems. PMID- 23683318 TI - Novel two-dimensional tetragonal monolayer: metal-TCNQ networks. AB - We present a systematic theoretical study on the structural, electronic, and magnetic properties of the novel tetragonal transition-metal-based 7,7,8,8 tetracyanoquinodimethane molecule coordination single sheets (referred to as TM@TCNQ, TM = Cr-Co). Our results unveil that, in TM@TCNQ, two valence electrons would transfer from one TM atom to TCNQ molecules, making them more stable. Among these structures, Cr@TCNQ, Mn@TCNQ, and Fe@TCNQ exhibit long-range antiferromagnetic coupling while Co@TCNQ is paramagnetic; this dictates these sheets being ideal candidates for spintronic devices. Such long-range magnetic coupling in the studied systems is related to the modulation via the TCNQ ligands. Besides, to explain the magnetic moment qualitatively, we propose a model on d splitting named "4 + 1 splitting". The possible underlying physical mechanisms are discussed in detail. In addition, TM@TCNQ may conceal promising performance for hydrogen storage according to our results. These predications strongly revive these new synthesized systems as viable candidates for spintronics and hydrogen storage. PMID- 23683317 TI - The effects of a convex rear-view mirror on ocular accommodative responses. AB - Convex mirrors are universally used as rear-view mirrors in automobiles. However, the ocular accommodative responses during the use of these mirrors have not yet been examined. This study investigated the effects of a convex mirror on the ocular accommodative systems. Seven young adults with normal visual functions were ordered to binocularly watch an object in a convex or plane mirror. The accommodative responses were measured with an infrared optometer. The average of the accommodation of all subjects while viewing the object in the convex mirror were significantly nearer than in the plane mirror, although all subjects perceived the position of the object in the convex mirror as being farther away. Moreover, the fluctuations of accommodation were significantly larger for the convex mirror. The convex mirror caused the 'false recognition of distance', which induced the large accommodative fluctuations and blurred vision. Manufactures should consider the ocular accommodative responses as a new indicator for increasing automotive safety. PMID- 23683320 TI - Single-incision laparoscopic stoma creation: experience with 31 consecutive cases. AB - INTRODUCTION: Fecal diversion may be performed using various techniques. Each technique has advantages that affect patient selection. In this report, we report our experience with 31 patients who underwent single-incision laparoscopic stoma creation using only a pre-selected stoma site as the point of port access. METHODS: A 2.5-cm skin incision was made at a previously marked stoma site, and two 5-mm trocars were placed into the abdomen through the stoma site. An optional third trocar was inserted at the stoma site only if the bowel needed to be mobilized or if adhesions needed to be divided. After full intra-abdominal exploration, a selected intestinal loop was brought up to the stoma site, and the ostomy was then matured using standard techniques. RESULTS: Between April 2009 and March 2012, 31 patients (19 men) with a mean age of 68 years (range, 46-87 years) underwent single-incision laparoscopic stoma creation. Fecal diversion included ileostomy (n = 18) and colostomy (n = 13). There were no intraoperative complications. Two patients (6.5%) required additional port placement in the midline suprapubic area. Conversion to open laparotomy was required in two patients (6.5%) because of the presence of extensive adhesions. Postoperative complications were observed in two patients and included peristomal ileus and dehydration due to high ileostomy output. CONCLUSIONS: Single-incision laparoscopic stoma creation is an effective technique that allows full intra abdominal visualization and bowel mobilization, while reducing the need for additional skin incisions beyond that of the stoma site. PMID- 23683321 TI - Renewable feedstocks in green solvents: thermodynamic study on phase diagrams of D-sorbitol and xylitol with dicyanamide based ionic liquids. AB - Experimental and theoretical studies on thermodynamic properties of three ionic liquids based on dicyanamide anion (namely, 1-butyl-3-methylimidazolium dicyanamide, 1-butyl-1-methylpyrrolidinium dicyanamide, and 1-butyl-1 methylpiperidinium dicyanamide) and their binary mixtures with sugar alcohols (D sorbitol and xylitol) were conducted in order to assess the applicability of the salts ionic liquids for dissolution of those biomass-related materials. Density and dynamic viscosity (at ambient pressure) of pure ionic liquids are reported in the temperature range from T = 293.15 to 363.15 K. Solid-liquid equilibrium phase diagrams in binary systems {sugar alcohol + ionic liquid} were measured with dynamic method up to the fusion temperature of sugar alcohol. The impact of the chemical structure of both the ionic liquid and sugar alcohol were established and discussed. For the very first time, the experimental solubility data were reproduced and analyzed in terms of equation of state rooted in statistical mechanics. For this purpose, perturbed-chain statistical associating fluid theory (PC-SAFT) was employed. In particular, new molecular schemes for the ionic liquids, D-sorbitol, and xylitol were proposed, and then the pure chemicals were parametrized by using available density and vapor pressure data. The model allowed accurate correlation of pure fluid properties for both ionic liquids and sugar alcohols, when the association term is taken into account. The results of solid-liquid equilibria modeling were also satisfactory. However, one or two adjustable binary corrections to the adopted combining rules were required to be adjusted in order to accurately capture the phase behavior. It was shown that a consistent thermodynamic description of extremely complex systems can be achieved by using relatively simple (but physically grounded) theoretical tools and molecular schemes. PMID- 23683319 TI - Presence of intervertebral discs alters observed stiffness and failure mechanisms in the vertebra. AB - Ex vivo mechanical testing is an essential tool for study of vertebral mechanics. However, the common method of testing vertebral bodies in the absence of adjacent intervertebral discs (IVDs) may limit the physiological relevance of the results. The goal of this study was to determine the influence of IVDs on vertebral mechanical properties and failure mechanisms. Rabbit thoracic vertebral bodies were tested with and without IVDs in a stepwise fashion that incorporated a micro computed tomography scan at each loading step. The image sequences were analyzed using digital volume correlation to quantify deformations throughout the vertebral body. The observed deformation patterns differed substantially between the groups. Specimens tested with IVDs exhibited a slow increase in strain in the inferior and posterior regions, followed by a sudden increase in strain in the anterior cortex right at the yield point. In contrast, the highest strains in the isolated vertebral bodies were in the posterior regions throughout the test. Specimens tested with IVDs had lower stiffness (507.49+/-184.73N/mm vs. 845.61+/ 296.09N/mm; p=0.044), higher ultimate displacement (2.00+/-0.68mm vs. 1.17+/ 0.54mm; p=0.043), and higher maximum shear strains (e.g. top 25th percentile: 0.19+/-0.11 vs. 0.06+/-0.07mm/mm; p<0.0458), and tended to have lower ultimate force (690.28+/-160.25N vs. 873.81+/-131.48N; p=0.056). Similar work to failure (648.15+/-317.86N-mm vs. 603.49+/-437.95 N-mm; p=0.844) was observed between the two groups. These results indicate that testing vertebral bodies in the absence of IVDs can elicit artifactual failure mechanisms. These artifacts may be more prominent than the effects on vertebral strength and toughness. PMID- 23683323 TI - Is there a rural gradient in the diagnosis of aortic stenosis? An analysis of a remote Scottish cohort. AB - INTRODUCTION: Calcific aortic stenosis is the most common cardiac valve lesion and is becoming increasingly prevalent as life expectancy rises. There is evidence that patients in remote and rural areas with certain diseases have worse outcomes and present to specialist services later than their urban counterparts. It is not known whether patients with aortic stenosis follow a similar pattern. The aim of this study was to investigate whether increasing rurality was associated with later presentation to healthcare services at a more advanced stage of aortic stenosis. METHODS: This was a retrospective cohort study. Using ICD-10 discharge codes and local databases, 605 patients with aortic stenosis who presented between 31 November 1999 and 1 December 2008 were identified. Aortic stenosis was defined as a pressure gradient across the aortic valve of 25 mmHg or more. Patients with prior aortic valve replacement were excluded. Clinical notes were reviewed for all patients. Gender, age and pressure gradient across the aortic valve at presentation and patient GP-practice location were recorded. Patients were then assigned a Clinical Peripherality Index score based on the postcode of their GP's practice to define rurality. Patient data were compared across the six defined levels of clinical peripherality by ANOVA. RESULTS: Mean patient age was 73 +/- 13 years, and 336 (54%) were male. The peak gradient across the valve was 41.1 +/- 26.7 mmHg. There was no association between the level of clinical peripherality and the stage of aortic stenosis at presentation, age or gender (all p >0.05). CONCLUSIONS: There was no urban-rural gradient in the severity of aortic stenosis at presentation in this remote Scottish cohort. This suggests that patients with this condition in remote areas do not present later in their disease trajectory. PMID- 23683324 TI - Coronary Microvascular function, Peripheral Endothelial Function and Carotid IMT in beta-thalassemia minor. AB - Higher prevalence of cardiovascular disease in Thalassemia patients have been known. Potential mechanisms are enhanced platelet activation, LDL oxidation, macrophage activation, and increased nitric oxide destruction. We have investigated coronary flow reserve (CFR), brachial artery flow mediated dilation (FMD) and Carotid intima-media thickness (IMT) in patients with Beta thalessemia minor (BTM). METHODS: Forty patients with BTM and 35 healthy control subjects were included. In all subjects CFR, brachial artery FMD, carotid artery IMT were measured. RESULTS: CFR measurements: Coronary baseline diastolic peak flow velocity (DPFV) of left anterior descending coronary artery (LAD) was significantly higher in the BTM group (23.8 +/- 3.9 vs. 22.1 +/- 3.0, P = 0.04). However, hyperemic DPFV was significantly lower (61.1 +/- 13.0 vs. 68.2 +/- 14.2, P = 0.02), and CFR was significantly lower (2.57 +/- 0.46 vs. 3.07 +/- 0.48, P < 0.0001) in the BTM group than that in the control group. Brachial artery FMD and carotid IMT measurements: Percent FMD measurements were significantly lower in the BTM group than that in the controls (6.22 +/- 4.29 vs. 8.10 +/- 4.00, P = 0.01). Carotid IMT measurements were significantly but slightly higher in the BTM group than that in the controls (0.57 +/- 0.07 vs. 0.54 +/- 0.04, P = 0.04). CONCLUSION: CFR reflecting coronary microvascular function and brachial artery FMD are decreased, and carotid IMT is increased in patients with BTM. PMID- 23683325 TI - The WXXW motif in the TSR1 of ADAMTS13 is important for its secretion and proteolytic activity. AB - INTRODUCTION: ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) is a metalloprotease enzyme that regulates the size and activity of the von Willebrand factor (VWF). ADAMTS13, like many other ADAMTSs, has a WXXW motif in its thrombospondin type 1 repeat domain (TSR1). However, the function of the WXXW motif in ADAMTSs is unclear. MATERIALS AND METHODS: The constructs of wild-type (WT) and WXXW mutant (W387A) ADAMTS13 was generated by PCR site-directed mutagenesis. The secretion of the protein was quantified with western blotting methods. The binding affinity of the WT or W387A mutant ADAMTS13 with Plasma-derived human VWF (pVWF) was investigated by using enzyme linked immunosorbent assay. The Cleaving activity of the WT or W387A mutant ADAMTS13 against full length pVWF was measured under denatured conditions or shear stress. The proteolytic activity was also validated with the FRETS-VWF73 assay. RESULTS: The W387A mutant was secreted less efficiently and had a reduced binding affinity for pre-denatured pVWF in comparison to WT ADAMTS13. However, both the WT and mutant ADAMTS13 interacted equally with native pVWF. The W387A mutant showed less cleaving activity against VWF under denaturing conditions, and the same result was observed when the fluorescence resonance energy transfer substrate VWF73 (FRETS-VWF73) was used as the substrate. However, under high shear stress conditions the mutant and WT ADAMTS13 were equally able to cleave VWF. CONCLUSION: The WXXW motif is important for the secretion of ADAMTS13 and that it modulates the proteolytic cleavage of VWF by ADAMTS13 under denaturing conditions. PMID- 23683326 TI - Treatment of fungal myositis with intra-lesional and intravenous itraconazole: a case report. AB - INTRODUCTION: Fungal myositis is very uncommon, even in patients who are immunocompromised. Because of its rarity and a lack of clinical experience, no consensus has been reached about the best means of treating fungal myositis. To the best of our knowledge this is the first description of the treatment of fungal myositis with simultaneous intravenous and intra-lesional itraconazole. CASE PRESENTATION: A 35-year-old Chinese woman with acute myelomonocytic leukemia developed Candida krusei fungemia and fungal myositis in the right biceps brachii after chemotherapy. A course of intravenous itraconazole and subsequently intravenous voriconazole was initiated and her blood cultures became sterile; however, our patient remained febrile and the myositis did not resolve. Intravenous itraconazole was restarted simultaneously with low-dose intra lesional itraconazole. The pyrexia settled after 48 hours and within 10 days the lesion could be seen to be resolving. After the course of intravenous and intra lesional anti-fungals was complete, oral itraconazole was administered as maintenance therapy. CONCLUSIONS: To the best of our knowledge this is the first case in which fungal myositis was successfully treated with intravenous and intra lesional itraconazole in a patient with acute myelomonocytic leukemia. The efficacy and safety of locally-administered itraconazole to treat intractable soft tissue infections requires further evaluation. PMID- 23683327 TI - Revealing the secrets of malaria parasite interaction with blood group A sugars. PMID- 23683328 TI - Saving babies' lives by antenatal malaria prevention. PMID- 23683329 TI - Primary intracranial and spinal hydatidosis: a retrospective study of 21 cases. AB - OBJECTIVE: To analyse the epidemiological characteristics, clinical symptoms, radiological aspects, treatments, and outcomes of primary central nervous system (CNS) hydatidosis and compare our results with those observed for secondary intracranial hydatidosis. PATIENTS AND METHODS: We retrospectively reviewed 21 cases of primary CNS hydatid cysts operated on at the First Affiliated Hospital of Xinjiang Medical University between 1996 and 2010. RESULTS: Of the 21 primary cases, the vast majority were intracranial hydatidosis patients (20 cases, 95.24%). Only one patient had spinal hydatidosis. Unlike previously published reports, we found that intracranial hydatid cysts were more common in adults (80.96%) than in children (19.04%), with a slight male predominance (M/F = 1.1). All symptoms, including vomiting, nausea, and focal neurological signs, resulted from the increased intracranial pressure, which was closely associated with the cyst location. For the spinal hydatidosis patient, the primary symptom of back pain was indicative of spinal cord compression syndrome. All cysts in the 21 primary cases were pathologically similar. The recurrence percentage was 28% over 12 years. Two patients with multiple intracranial hydatid cysts died due to foramen magnum herniation. CONCLUSION: Despite imaging and therapeutic advances, CNS hydatidosis remains difficult to treat, and severe complications and the high incidence of recurrence result in unsatisfactory outcomes. PMID- 23683330 TI - Factors associated with parasitic infection amongst street children in orphanages across Lima, Peru. AB - Infection caused by intestinal parasites has significant public health consequences amongst children in the developing world. Street children are an under-studied group of society subjected to increased health risks when compared to their peers. To estimate the prevalence of intestinal parasitic infection and ascertain risk factors for parasitosis amongst this population, stool samples were collected from 258 children across four orphanages in three districts of Lima, Peru. Surveys were used to determine associations between risk factors and infection status. The prevalence of parasitic infection within the study sample was 66.3%, with 30.6% testing positive for pathogenic species. Entamoeba coli was the most commonly detected parasite (41.9%) and Giardia lamblia was the most commonly detected pathogenic parasite (17.1%). Of the group 15.1% had helminth infection. When testing for association, age and BMI were risk factors for infection. A notable difference in prevalence (P < 0.00001) based on orphanage was observed, but the duration of residence in an orphanage was not a predictor for infection. A sub-analysis conducted amongst children who were given anti parasitic treatment 5 months beforehand found no significant difference in parasitosis between those who had been given treatment and those who had not (P = 0.218). It is suggested that a single dose of albendazole alone may not be effective in combating long-term infection rates. PMID- 23683331 TI - Risk factors for intestinal parasitosis, anaemia, and malnutrition among school children in Ethiopia. AB - Research on associated risk factors for intestinal parasitic infections and malnutrition in various geographic regions is needed for the development of appropriate control strategies. The aim of this study was to determine the risk factors associated with intestinal parasitic infections, anaemia, and malnutrition in school children, living in urban and rural areas of northern Ethiopia. Six hundred school children, aged 6-15 years, were randomly selected in a cross-sectional survey from 12 primary schools. Sociodemographic and anthropometric data were collected. Faecal samples were examined using direct, concentration, and the Kato-Katz methods. Urine specimens were analysed for Schistosoma haematobium ova. Haemoglobin was measured using a HemoCue spectrometer. The overall prevalence of intestinal parasitosis was 72% (95% confidence interval (CI): 66-76%). The prevalence of anaemia, stunting, and thinness were 11% (95% CI: 8-13%), 35% (95% CI: 31-38%), and 34% (95% CI: 30 38%), respectively. Poor personal hygiene habits were generally associated with anaemia and nutritional deficiency (low body mass index). Multivariate logistic regression models related Schistosoma mansoni infection with boys. Boys were also more likely to be malnourished. Hookworm infection was associated with anaemia and unhygienic finger nails. Access to clean water and latrines, with some hygiene and sanitation communication activities, could improve health of children in Ethiopia. The use of smartphone technology in demographic data collection proved to be successful. The potential advantage offered by this technology for parasitological field surveys merits further investigation. PMID- 23683332 TI - An outbreak of hepatitis E and high maternal mortality at Port Sudan, Eastern Sudan. AB - During 4 months (November 2010-March 2011) of an outbreak of hepatitis E virus (HEV), 39 pregnant women presented at Port Sudan Hospital, Sudan, with various symptoms of viral hepatitis. The diagnosis of viral hepatitis was confirmed by serology using ELISA anti-HEV IgG and IgM. The mean (SD) maternal age and gestational age were 24.0 (4.2) years and 33.6 (3.7) weeks, respectively. Eight (20.5%) women were primigravidae. There were 11 (28.2%) maternal deaths, 14 (36.0%) intrauterine fetal deaths, and eight (20.5%) cases of postpartum haemorrhage. There were nine (23.0%) cases of preterm (<37 weeks of gestation) deliveries. Fulminant hepatitis with hepatic encephalopathy was the most common cause of death among these patients. Nine of these women died before delivery and the other two died immediately following the delivery due to severe haemorrhage. There were no significant differences in clinical and biochemical data between the women who died (11) and those who survived. PMID- 23683333 TI - Evaluation of Paracheck-Pf(TM) rapid malaria diagnostic test for the diagnosis of malaria among HIV-positive patients in Ibadan, south-western Nigeria. AB - Febrile illnesses occur frequently among HIV positive patients and these are often treated presumptively as malaria in endemic areas. Parasite-based diagnosis of malaria will eliminate unnecessary treatment, reduce drug-drug interactions and the chances for the emergence of drug resistant Plasmodium. We evaluated finger prick blood samples from 387 people living with HIV (PLWHIV) and suspected of having malaria by expert microscopy and Paracheck-Pf(TM) - a histidine-rich protein-II based malaria rapid diagnostic test. The study was conducted at the PEPFAR supported AIDS Prevention Initiative in Nigeria (APIN) Clinic of the University College Hospital Ibadan, southwest Nigeria. Outcome parameters were prevalence of malaria parasitemia, sensitivity and specificity of Paracheck-Pf as well as the positive and negative predictive values for Paracheck-Pf using microscopy of Giemsa-stained blood film as gold standard. Malaria parasites were detected in 19.1% (74/387) of enrollees by microscopy and 19.3% (74/383) by Paracheck-Pf. Geometric mean parasite density was 501/MUl (range 39-749 202/MUl). Sensitivity and specificity of Paracheck-Pf at all parasite densities were 55.4% and 89.3% while corresponding figures at parasite densities >=200/MUl were 90.9% and 90.3%. Sensitivity and specificity at parasite densities >=500/MUl was 97.6% and 90.3%. Positive and negative predictive values for parasite density >=200/MUl were 55.4% and 98.7%, respectively. Paracheck-Pf was found to be a useful malaria diagnostic tool at parasite densities >=200/MUl facilitating appropriate clinical management. PMID- 23683334 TI - Serum cytokines associated with severity and complications of kala-azar. AB - OBJECTIVES: Recent clinical data suggest that severe kala-azar (or visceral leishmaniasis) is an exaggerated innate immune response mediated by inflammatory cytokines, leading to a systemic inflammatory syndrome similar to what is observed in malaria, sepsis and other diseases. We tested this hypothesis by measuring serum cytokines in individuals with kala-azar. METHODS: We compared patients with severe kala-azar (i.e. hemorrhagic manifestations, n = 38) with patients without evidence of hemorrhage (n = 96). We conducted a detailed clinical and laboratory evaluation, measuring serum IL-1beta, IL-6, IL-8, IL-10, IL-12, interferon-gamma, and TNF-alpha, and markers of disseminated intravascular coagulation (DIC). RESULTS: Infants had higher levels of inflammatory cytokines, while HIV-infected patients had lower concentrations of IL-10 and interferon gamma. Higher levels of IL-6, interferon-gamma, and IL-8 were found among deceased patients. IL-8 and interferon-gamma were independently associated with bleeding. Several cytokines were associated with different signs of severe clinical and laboratory manifestations, including DIC. IL-6 was highly positively and independently associated with IL-1beta, IL-8, IL-10, and negatively associated with TNF-alpha. IL-1beta and TNF-alpha were also highly independently associated with disease severity. CONCLUSION: In its severe form, kala-azar, a neglected tropical disease, initiates a systemic inflammatory response that leads to DIC and other manifestations. Children may have higher risk of death due to the more intense cytokine release. The data supports the notion that IL-6 is the central cytokine that is associated with lethal disease, but interferon-gamma, IL1beta, IL-8, and TNF-alpha are also involved with disease severity. Inhibition of IL-6 is a potential target of adjuvant therapy for severe or pediatric forms of this disease. PMID- 23683337 TI - Risk factors for intestinal parasitic infections in preschoolers in a low socio economic area, Diamantina, Brazil. AB - OBJECTIVE: To verify the prevalence of intestinal parasitic infections among preschoolers and to identify the associated risk factors. METHODS: The study is a cross-sectional study nested in a cohort of children who were born and resident in Diamantina, Minas Gerais, Brazil. At the time of the study, all children were aged 60 months +/- five months. They were recruited after written informed consent was obtained from parents or guardians. The study was carried out between July 2009 and July 2010. In total 214 children provided a stool sample for examination on intestinal parasitic infections. Information on potential risk factors for parasitosis was obtained from parents and guardians of the children by a questionnaire. Logistic regression was used for analysis. RESULTS: Intestinal parasitic infections were found in 27.5% (n = 59) of children. The boys' infection prevalence (26.1%, n = 36) was slightly lower than the infection prevalence of the girls (30.3%, n = 23), but not statistically different (p = 0.51). Fourteen children, (23.7%) were infected with two or more parasite species and forty-five (76.3%) with single parasites. A low per capita income of family was strongly associated with an increased risk for an infection (OR = 2.89; P = 0.003). Preschoolers whose mothers did not work outside home had a significantly lower risk for infection (OR = 0.41; p = 0.01). CONCLUSION: Intestinal parasite infection is a health problem among Diamantina preschoolers. Poverty was implicated as an important risk factor for infection, while the presence of the mother at home full-time was a protective factor. PMID- 23683335 TI - Seroprevalence of toxoplasmosis, toxocariasis and cysticercosis in a rural settlement, Sao Paulo State, Brazil. AB - BACKGROUND: The goal of this study was to estimate the seroprevalence of Toxocara spp., Toxoplasma gondii, and Taenia solium metacestode infection and determine some of the associated risk factors for people living in the Dona Carmen settlement, Pontal of Paranapanema, Sao Paulo, Brazil. METHODS: Serum samples from 194 subjects were tested and participants answered a questionnaire. An enzyme-linked immunosorbent assay (ELISA) system based on Toxocara spp. excretory secretory antigens obtained from the cultured second-stage larvae of Toxocara canis or vesicular fluid (VF) antigen from Taenia crassiceps metacestode was used to detect anti-Toxocara spp. IgG and IgE and anti-T. solium metacestode, respectively. For cysticercosis, the reactive ELISA samples were assayed by Western blotting using 18 kDa and 14 kDa proteins purified from VF. For T. gondii specific IgG and IgM antibodies, anti-SAG-1, GRA-1, and GRA-7 epitope specificity was determined by ELISA. RESULTS: Toxoplasma gondii IgG antibodies were found in 102/194 individuals (52.6%) with increased infections in females (P = 0.02) and those with <=US$300 monthly income (P = 0.01). Positive IgM antibodies were detected in 21/194 individuals (10.8%). Antibodies specific to Toxocara spp. were found in 28/194 subjects (14.4%). All the individuals with Toxocara spp. also had T. gondii-specific IgG antibodies. Taenia solium metacestode antibodies were detected in 11 subjects (5.7%), but none were reactive based on Western blotting. CONCLUSION: In spite of environmental, educational, and socioeconomic factors favoring parasite infection, the seropositivity rates of T. gondii, Toxocara spp., and T. solium metacestode-specific IgG antibodies are similar to the rates found in studies conducted in different populations in Brazil. PMID- 23683336 TI - Relevance of the eosinophil blood count in bancroftian filariasis as a screening tool for the treatment. AB - BACKGROUND: Lymphatic filariasis constitutes a major public health issue in French Polynesia. Diagnosis has been revolutionized with the availability of circulating filarial antigen (CFA) tests which are easy to perform but are costly. Filariasis is responsible for acquired eosinophilia and eosinophil blood count (EBC) is commonly used as a screening tool. METHODS: We retrospectively analysed all the results of EBCs and CFA tests performed in our laboratory over a 2-year period. We calculated the prevalence of antigenemia for nine different eosinophil cutoffs. We calculated the number of patients detected by CFA testing and the number of estimated CFA-positive patients according to their EBC. RESULTS: Over a 2-year period, we detected 7503 eosinophilic patients. For an EBC above 500/mm(3), the prevalence of positive CFA was 25.78% and the estimated number of positive CFA patients was 1934. During the same period, as CFA determination is not routinely performed, only 141 patients were detected and treated. CONCLUSION: Our current strategy against lymphatic filariasis which combines annual mass drug administration, systematic treatment of antigenemic and microfilaraemic patients, and vector control; failed to reach the target of 1% prevalence. Unfortunately, mainly for economical reasons, the antigenemia cannot be determined for all patients. In complement to existing strategy, we propose an additional action based on the treatment of eosinophilic patients in order to reduce the filariasis prevalence in our country. PMID- 23683339 TI - 'What matters to Andrew'. The problem of premissary relevance in automated health advisors. Insights from pragma-dialectics. AB - OBJECTIVE: To influence health behavior, communication has to be relevant on an individual level and, thus, fulfill the requirement of premissary relevance. This paper attempts to enrich the design of automated health advisors by, first, reviewing main solutions to the challenge of premissary relevance found in the literature and, second, highlighting the value in this field of the theory of argumentation known as pragma-dialectics. METHODS: A conceptual paper grounded in persuasion research and argumentation theory. RESULTS: Automated health advisors enable argumentative exchanges with users. But there is a need to design these systems as to make them work in an audience-centered perspective. The theory of pragma-dialectics can be used to analyze the factors that favor or hinder the agreement of users to engage in certain health behaviors, and to identify argumentation strategies targeted to behavior change. CONCLUSION: Pragma dialectics can be used to enhance the design of automated health advisors as it operationalizes the dialogical nature of the reasoning process that can influence health behavior. PRACTICE IMPLICATIONS: Premissary relevance is a challenge of communication for health promotion at large that can be promisingly addressed through synergies among persuasion research, argumentation theory and Artificial Intelligence. PMID- 23683338 TI - Effects of nitrogen conversion and environmental factors on landfill CH4 oxidation and N2O emissions in aged refuse. AB - We determined the effects of nitrification capacity and environmental factors on landfill methane oxidation potential (MOP) using an aged refuse in laboratory batch assays and compared it with two different types of soils. The nitrogen conversion in the three experimental materials after 120 h incubation yielded first-order reaction kinetics at an initial concentration of 200 mg kg(-1) NH4(+) N. The net nitrification rate for the aged refuse was 1.50 (p < 0.05) and 2.08 (p < 0.05) times that of the clay soil and the sandy soil, respectively. The net NO3(-)-N generation rate by the aged refuse was 1.93 (p < 0.05) and 2.57 (p < 0.05) times that of the clay soil and the sandy soil, respectively. When facilitated by ammonia-oxidizing bacteria during CH4 co-oxidation, the average value of the MOP in the aged refuse at a temperature range of 4-45 degrees C was 2.34 (p < 0.01) and 4.71 (p < 0.05) times greater than that of the clay soil and the sandy soil, respectively. When the moisture content ranged from 8 to 32% by mass, the average values for the MOP in the aged refuse were 2.08 (p < 0.01) and 3.15 (p < 0.01) times greater than that of the clay soil and the sandy soil, respectively. The N2O fluxes in the aged refuse at 32% moisture content were 5.33 (p < 0.05) and 12.00 (p < 0.05) times more than in the clay and the sandy soil, respectively. The increase in N2O emissions from a municipal solid waste landfill can be neglected after applying an aged refuse bio-cover because of the much higher MOP in the aged refuse. The calculated maximum MOP value in the aged refuse was 12.45 MUmol g(-1) d.w. h(-1), which was much higher than the documented data. PMID- 23683340 TI - Learning to listen: effects of using conversational transcripts to help medical students improve their use of open questions in soliciting patient problems. AB - OBJECTIVE: This study reports effects of a 'bottom-up' pedagogy using doctor patient conversation transcripts to improve medical students' use of open questions in soliciting patient problems. METHODS: We implemented an innovative approach involving students reviewing transcripts of medical interviews, skills practice using role-play and standardized patients (SPs), and reflection on these practices. We analyzed three open question categories (general, biomedical, and psychosocial) used by 27 Taiwanese medical students from two SP interviews, conducted before and after training. RESULTS: Across the full encounter, use of general and psychosocial open questions increased significantly after training (from 27 to 92 general questions and 15 to 33 psychosocial questions). The high rates of narrowly focused opening questions (52% of initial position questions, 74% of second position questions, and 85% of third position questions) prior to training were reduced to 11%, 15%, and 15% respectively after training. Students also shifted from a micro (narrow) to a macro (broad) pattern of questioning. CONCLUSION: The 'bottom-up' approach facilitated by using conversation transcripts is effective in improving communication skills. PRACTICE IMPLICATIONS: By carefully reviewing transcripts of their own performance as part of an overall communication training package, beginning medical students can become more patient-centered in soliciting patient problems. PMID- 23683341 TI - Artificial intelligence and immediacy: designing health communication to personally engage consumers and providers. AB - OBJECTIVE: We describe how ehealth communication programs can be improved by using artificial intelligence (AI) to increase immediacy. METHODS: We analyzed major deficiencies in ehealth communication programs, illustrating how programs often fail to fully engage audiences and can even have negative consequences by undermining the effective delivery of information intended to guide health decision-making and influence adoption of health-promoting behaviors. We examined the use of AI in ehealth practices to promote immediacy and provided examples from the ChronologyMD project. RESULTS: Strategic use of AI is shown to help enhance immediacy in ehealth programs by making health communication more engaging, relevant, exciting, and actionable. CONCLUSION: AI can enhance the "immediacy" of ehealth by humanizing health promotion efforts, promoting physical and emotional closeness, increasing authenticity and enthusiasm in health promotion efforts, supporting personal involvement in communication interactions, increasing exposure to relevant messages, reducing demands on healthcare staff, improving program efficiency, and minimizing costs. PRACTICE IMPLICATIONS: User centered AI approaches, such as the use of personally involving verbal and nonverbal cues, natural language translation, virtual coaches, and comfortable human-computer interfaces can promote active information processing and adoption of new ideas. Immediacy can improve information access, trust, sharing, motivation, and behavior changes. PMID- 23683342 TI - Antimicrobial resistance and prudent drug use for Streptococcus suis. AB - This paper reviews information on antimicrobial resistance patterns and prudent use of antimicrobials to reduce the impact and spread of resistant Streptococcus suis strains. S. suis is an important pathogen in swine, which can cause significant economic loss. Prudent use of antimicrobials for S. suis is essential to preserve the therapeutic efficacy of broad-spectrum antimicrobials and to minimize selection of resistant S. suis strains. Resistance of S. suis to antimicrobials commonly used in swine, including lincosamides, macrolides, sulphonamides, and tetracycline, has been documented worldwide, with resistance in up to 85% of strains. Among antimicrobials examined, resistance of S. suis has been demonstrated to be relatively low for penicillin (0-27%), ampicillin (0.6 23%), and ceftiofur (0-23%). For penicillin, this result may be due in part to the unique mechanism by which resistance is acquired through modifications in the structure of penicillin-binding proteins. Recommendations to control S. suis infection include focused and careful choice and appropriate use of antimicrobials, together with preventive measures intended to improve swine management. PMID- 23683343 TI - Ultrasound-guided transcervical forceps extraction of unruptured interstitial pregnancy. AB - This report introduces a method for ultrasound-guided transcervical forceps extraction (UTCE) of unruptured interstitial pregnancies; this method does not necessitate elective caesarean delivery for future pregnancies. This report also compares this technique with conventional methods. A retrospective review was conducted involving 16 women treated for interstitial pregnancies. Among these women, UTCE was successfully performed in six of 16 women, with only one woman requiring additional intervention; conventional treatment was performed in the other ten women. UTCE is a safe, effective and minimally invasive option for treating interstitial pregnancies and should be considered as an alternative treatment modality. PMID- 23683344 TI - Reduction of cue-induced craving through realtime neurofeedback in nicotine users: the role of region of interest selection and multiple visits. AB - This multi-visit, real-time functional magnetic resonance imaging feedback study demonstrates that treatment-seeking smokers can effectively modulate their behavioral and brain responses to smoking cues. They are more effective at decreasing activity in functionally defined regions involved in "craving" (e.g. ventral anterior cingulate cortex (vACC)) rather than increasing activity in regions involved in "resisting" (e.g. dorsal medial prefrontal cortex (dmPFC)). PMID- 23683345 TI - Do sexual health campaigns work? An outcome evaluation of a media campaign to increase chlamydia testing among young people aged 15-24 in England. AB - BACKGROUND: A national multimedia campaign was launched in January 2010, to increase the proportion of young people tested for chlamydia. This study aimed to evaluate the impact of the campaign on the coverage and positivity within the National Chlamydia Screening Programme (NSCP) in England. METHOD: An interrupted time series of anonymised NCSP testing reports for England for a 27 month period (1st April 2008 to 30th June 2010) was analysed. Reports were assigned to a pre campaign, campaign and post campaign phase according to the test date. Exclusion criteria included tests for clinical reasons, contacts of known cases, and tests returned from prisons or military services.Negative binomial and logistic regression modelling was used to provide an estimate for the change in coverage and positivity, during, and after the campaign and estimates were adjusted for secular and cyclical trends. RESULTS: Adjusting for cyclical and secular trends, there was no change in the overall testing coverage either during (RR: 0.91; 95% CI: 0.72-1.14) or after (RR: 0.88; 95%CI: 0.69-1.11) the campaign. The coverage varied amongst different socio-demographic groups, testing of men increased during the campaign phase while testing of people of black and other ethnic groups fell in this phase. The positivity rate was increased during the campaign (OR: 1.18; 95% CI 1.13-1.23) and further increased in the post-campaign phase (OR: 1.40; 95% CI 1.30-1.51). The proportion of chlamydia infections detected increased for all socio-demographic and self-reported sexual behaviour groups both during and after the campaign. CONCLUSION: The uptake of chlamydia testing rose during the campaign; however, this apparent increase was not maintained once overall trends in testing were taken into account. Nonetheless, once secular and cyclical trends were controlled for, the campaign was associated with an increased positivity linked to increased testing of high risk individuals groups in the target population who were previously less likely to come forward for testing. However, our study indicated that there may have been a disparity in the impact of the campaign on different population groups. The content and delivery of ongoing and future information campaigns aimed at increasing chlamydia screening should be carefully developed so that they are relevant to all sections of the target population. PMID- 23683347 TI - Two-in-One antibodies with dual action Fabs. AB - Mechanisms and biological roles of antibody multi-specificity are topics of high interest. Evidence of conformational flexibility in antigen-combining sites and their utility in the recognition of different antigens appeared two decades ago. In the last three years an appreciation has emerged that recognition of very much more diverse protein antigens is within the scope of multi-specificity and also that this is sometimes, but not always, associated with structural plasticity. The ability to invent non-promiscuous, high affinity antibodies which are 'specific' for more than one antigen such as the recently described dual-specific Two-in-One DAF antibodies, provides not only insights into the evolution of antibody specificity but also a promise of powerful medicines fully within the paradigm of targeted therapies. PMID- 23683346 TI - Innovation in academic chemical screening: filling the gaps in chemical biology. AB - Academic screening centers across the world have endeavored to discover small molecules that can modulate biological systems. To increase the reach of functional-genomic and chemical screening programs, universities, research institutes, and governments have followed their industrial counterparts in adopting high-throughput paradigms. As academic screening efforts have steadily grown in scope and complexity, so have the ideas of what is possible with the union of technology and biology. This review addresses the recent conceptual and technological innovation that has been propelling academic screening into its own unique niche. In particular, high-content and whole-organism screening are changing how academics search for novel bioactive compounds. Importantly, we recognize examples of successful chemical probe development that have punctuated the changing technology landscape. PMID- 23683348 TI - Engineering fatty acid biosynthesis in microalgae for sustainable biodiesel. AB - Microalgae are a promising feedstock for biodiesel and other liquid fuels due to their fast growth rate, high lipid yields, and ability to grow in a broad range of environments. However, many microalgae achieve maximal lipid yields only under stress conditions hindering growth and providing compositions not ideal for biofuel applications. Metabolic engineering of algal fatty acid biosynthesis promises to create strains capable of economically producing fungible and sustainable biofuels. The algal fatty acid biosynthetic pathway has been deduced by homology to bacterial and plant systems, and much of our understanding is gleaned from basic studies in these systems. However, successful engineering of lipid metabolism in algae will necessitate a thorough characterization of the algal fatty acid synthase (FAS) including protein-protein interactions and regulation. This review describes recent efforts to engineer fatty acid biosynthesis toward optimizing microalgae as a biodiesel feedstock. PMID- 23683349 TI - Inhibitors of BACE for treating Alzheimer's disease: a fragment-based drug discovery story. AB - Several fragment-based methods have been applied to the discovery of new lead sources for inhibitors of BACE1, an important therapeutic target for Alzheimer's disease. Among the most common fragment hits were various amidine-containing molecules in which the amidine engaged in discrete H-bond donor-acceptor interaction with the BACE1 catalytic dyad. Structure and medicinal chemistry knowledge-based optimization with emphasis on ligand efficiency resulted in identification of a key pharmacophore comprising a non-planar cyclic amidine scaffold directly attached to a phenyl group projecting into S1. This key pharmacophore is a common feature of known clinical candidates and has dominated the recent patent literature. A structural comparison of the non-planar cyclic amidine motif with other BACE1 pharmacophores highlights its uniqueness and distinct advantages. PMID- 23683350 TI - Next generation therapeutics. PMID- 23683351 TI - The RECQL4 protein, deficient in Rothmund-Thomson syndrome is active on telomeric D-loops containing DNA metabolism blocking lesions. AB - Telomeres are critical for cell survival and functional integrity. Oxidative DNA damage induces telomeric instability and cellular senescence that are associated with normal aging and segmental premature aging disorders such as Werner Syndrome and Rothmund-Thomson Syndrome, caused by mutations in WRN and RECQL4 helicases respectively. Characterizing the metabolic roles of RECQL4 and WRN in telomere maintenance is crucial in understanding the pathogenesis of their associated disorders. We have previously shown that WRN and RECQL4 display a preference in vitro to unwind telomeric DNA substrates containing the oxidative lesion 8 oxoguanine. Here, we show that RECQL4 helicase has a preferential activity in vitro on telomeric substrates containing thymine glycol, a critical lesion that blocks DNA metabolism, and can be modestly stimulated further on a D-loop structure by TRF2, a telomeric shelterin protein. Unlike that reported for telomeric D-loops containing 8-oxoguanine, RECQL4 does not cooperate with WRN to unwind telomeric D-loops with thymine glycol, suggesting RECQL4 helicase is selective for the type of oxidative lesion. RECQL4's function at the telomere is not yet understood, and our findings suggest a novel role for RECQL4 in the repair of thymine glycol lesions to promote efficient telomeric maintenance. PMID- 23683352 TI - DNA damage response in microcephaly development of MCPH1 mouse model. AB - MCPH1 encodes BRCT-containing protein MCPH1/Microcephalin/BRIT1, mutations of which in humans cause autosomal recessive disorder primary microcephaly type 1 (MCPH1), characterized by a congenital reduction of brain size particularly in the cerebral cortex. We have shown previously that a deletion of Mcph1 in mice results in microcephaly because of a premature switch from symmetric to asymmetric division of the neuroprogenitors, which is regulated by MCPH1's function in the centrosome. Because MCPH1 has been implicated in ATM and ATR mediated DNA damage response (DDR) and defective DDR is often associated with neurodevelopmental diseases, we wonder whether the DDR-related function of MCPH1 prevents microcephaly. Here, we show that a deletion of Mcph1 results in a specific reduction of the cerebral cortex at birth, which is persistent through life. Due to an effect on premature neurogenic production, Mcph1-deficient progenitors give rise to a high level of early-born neurons that form deep layers (IV-VI), while generate less late-born neurons that form a thinner outer layer (II-III) of the cortex. However, neuronal migration seems to be unaffected by Mcph1 deletion. Ionizing radiation (IR) induces a massive apoptosis in the Mcph1 null neocortex and also embryonic lethality. Finally, Mcph1 deletion compromises homologous recombination repair and increases genomic instability. Altogether, our data suggest that MCPH1 ensures proper neuroprogenitor expansion and differentiation not only through its function in the centrosome, but also in the DDR. PMID- 23683353 TI - Simple and accessible analytical methods for the determination of mercury in soil and coal samples. AB - Simple and accessible analytical methods compared to conventional methods such as US EPA Method 7471B and ASTM-D6414 for the determination of mercury (Hg) in soil and coal samples are proposed. The new methods are consisted of fewer steps without the Hg oxidizing step consequently eliminating a step necessary to reduce excess oxidant. In the proposed methods, a Hg extraction is an inexpensive and accessible step utilizing a disposable test tube and a heating block instead of an expensive autoclave vessel and a specially-designed microwave. Also, a common laboratory vacuum filtration was used for the extracts instead of centrifugation. As for the optimal conditions, first, best acids for extracting Hg from soil and coal samples was investigated using certified reference materials (CRMs). Among common laboratory acids (HCl, HNO3, H2SO4, and aqua regia), aqua regia was most effective for the soil CRM whereas HNO3 was for the coal CRM. Next, the optimal heating temperature and time for Hg extraction were evaluated. The most effective Hg extraction was obtained at 120 degrees C for 30min for soil CRM and at 70 degrees C for 90min for coal CRM. Further tests using selected CRMs showed that all the measured values were within the allowable certification range. Finally, actual soil and coal samples were analyzed using the new methods and the US EPA Method 7473. The relative standard deviation values of 1.71-6.55% for soil and 0.97-12.11% for coal samples were obtained proving that the proposed methods were not only simple and accessible but also accurate. PMID- 23683354 TI - Volatile aromatic hydrocarbons (VAHs) in residential indoor air in Brisbane, Australia. AB - Volatile aromatic hydrocarbons (VAHs: benzene, toluene, ethylbenzene, mp-xylene, o-xylene, styrene, naphthalene) in residential indoor air in Brisbane, Australia were measured in 32 houses. The total VAHs (TVAHs) levels ranged between 2 and 137MUg/m(3) and were lower than the most of the houses in the literature data. The VAHs were believed to originate from heat insulation systems, building material products as well motor vehicles but naphthalene and styrene originated from other sources. Internal garages had concentrations which are higher than the indoor air by 25-50% due to the presence of motor vehicles and may be a major source of indoor VAHs. However indoor concentrations are higher than that in the outdoor ambient air. The age of the house was found to be negatively related to VAHs concentrations in the houses with the half-life of TVAH at approximately 13years. The concentration levels of benzene, toluene, ethylbenzene and styrene are well below the guideline values set by agencies from Hong Kong, Japan, Germany and the WHO while the concentration level of naphthalene in one house exceeded the guideline value from Germany. PMID- 23683355 TI - Stability study of Iprodione in alkaline media in the presence of humic acids. AB - The influence of humic aggregates in water solution upon the chemical stability of Iprodione has been investigated under basic conditions. Taking into account that an important part of soils are colloids, the possibility of its presence implies that soil composition and its structure will play an important role in the stability of this pesticide. A kinetic model was applied to this system and the kinetic coefficients were obtained. An inhibition upon the alkaline hydrolysis of Iprodione (2-fold) was observed and it was rationalized in terms of the micellar pseudophase model. These results have been compared with the corresponding ones in the same natural colloidal aggregates in the presence of other pesticides. PMID- 23683356 TI - Shock tube measurements of the tert-butanol + OH reaction rate and the tert C4H8OH radical beta-scission branching ratio using isotopic labeling. AB - The overall rate constant for the reaction tert-butanol + OH -> products was determined experimentally behind reflected shock waves by using (18)O-substituted tert-butanol (tert-butan(18)ol) and tert-butyl hydroperoxide (TBHP) as a fast source of (16)OH. The data were acquired from 900 to 1200 K near 1.1 atm and are best fit by the Arrhenius expression 1.24 * 10(-10) exp(-2501/T [K]) cm(3) molecule(-1) s(-1). The products of the title reaction include the tert-C4H8OH radical that is known to have two major beta-scission decomposition channels, one of which produces OH radicals. Experiments with the isotopically labeled tert butan(18)ol also lead to an experimental determination of the branching ratio for the beta-scission pathways of the tert-C4H8OH radical by comparing the measured pseudo-first-order decay rate of (16)OH in the presence of excess tert butan(16)ol with the respective decay rate of (16)OH in the presence of excess tert-butan(18)ol. The two decay rates of (16)OH as a result of reactions with the two forms of tert-butanol differ by approximately a factor of 5 due to the absence of (16)OH-producing pathways in experiments with tert-butan(18)ol. This indicates that 80% of the (16)OH molecules that react with tert-butan(16)ol will reproduce another (16)OH molecule through beta-scission of the resulting tert C4H8(16)OH radical. (16)OH mole fraction time histories were measured using narrow-line-width laser absorption near 307 nm. Measurements were performed at the line center of the R22(5.5) transition in the A-X(0,0) band of (16)OH, a transition that does not overlap with any absorption features of (18)OH, hence yielding a measurement of (16)OH mole fraction that is insensitive to any production of (18)OH. PMID- 23683357 TI - A national study into the rural and remote pharmacist workforce. AB - INTRODUCTION: As for many health professionals, distance presents an enormous challenge to pharmacists working in rural and remote Australia. Previous studies have identified issues relating to the size of the rural and remote pharmacist workforce, and a number of national initiatives have been implemented to promote the recruitment and retention of pharmacists in rural and remote locations. The aim of this study was to explore and describe the current rural and remote pharmacy workforce, and to identify barriers and drivers influencing rural and remote pharmacy practice. METHODS: A mixed-methods approach was used, which comprised a qualitative national consultation and a quantitative rural and remote pharmacist workforce survey. Semi-structured interviews (n=83) and focus groups (n=15, 143 participants) were conducted throughout Australia in 2009 with stakeholders with an interest in rural and remote pharmacy, practising rural/remote pharmacists and pharmacy educators, and as well as with peak pharmacy organizations, to explore the issues associated with rural/remote practice. Based on the findings of the qualitative work a 45-item survey was developed to further explore the relevance of the issues identified in the qualitative consultation. All registered Australian pharmacists practising in non urban locations (RRMA 3-7, n=3,300) were identified and invited to participate in the study, with a response rate of 23.4%. RESULTS: The main themes identified from the qualitative consultation were the impact of national increases in the pharmacist workforce on rural/remote practice; the role of the regional pharmacy schools in contributing to the rural/remote workforce; and the perceptions of differences in pharmacist roles in rural/remote practice. The survey indicated that pharmacists practising in rural and remote locations were older than the national average (55.8 years versus 40 years). Differences in their professional role were seen in different pharmacy sectors, with hospital pharmacists spending significantly more time on the delivery of professional services and education and teaching, but less time on medication supply than community pharmacists. Rural/remote pharmacists were generally found to be satisfied with their current role. The main 'satisfiers' reported were task variety, customer appreciation, use of advanced skills, appropriate remuneration, happiness in their work location, sound relationships with other pharmacists, a happy team and relationships with other health professionals. CONCLUSION: This study described the distribution, roles and factors affecting rural and remote pharmacy practice. While the results presented provide an extensive overview of the rural/remote workforce, a comparable national study comparing rural/remote and urban pharmacists would further contribute to this discussion. Knowledge on why pharmacists chose to work in a particular geographical location, or why pharmacists chose to leave a location would further enrich our knowledge on what drives and sustains the rural/remote pharmacist workforce. PMID- 23683358 TI - Mycobacterium avium subsp. paratuberculosis sheep strains isolated from Cyprus sheep and goats. AB - Paratuberculosis, caused by Mycobacterium avium subsp. paratuberculosis (Map), is a chronic incurable infection of intestinal tract of animals. Molecular characterization of Map isolates classifies them into two major groups, 'Cattle' or Type II and 'Sheep' or Type I/III with a different phenotype, epidemiology, virulence and pathogenesis. The aim of this study was to examine 192 Map ELISA positive sheep and goats from Cyprus using faecal culture and genotype Map isolates using IS1311 PCR and restriction endonuclease analysis (IS1311 PCR-REA) with HinfI restriction enzyme. Map was isolated from only four (4.6%) faecal samples out of 88 sheep and 15 (14.4%) faecal samples out of 104 goats. Genotyping of the isolates using IS1311 PCR-REA revealed that sheep and goat populations on the island are infected primarily by 'Sheep' strains. Only three Map isolates from goats originated from one farm were characterized as 'Cattle' strains. PMID- 23683359 TI - A potential threat to malaria elimination: extensive deltamethrin and DDT resistance to Anopheles sinensis from the malaria-endemic areas in China. AB - BACKGROUND: Insecticide resistance in malaria vectors is a growing concern in many countries and requires immediate attention because of the limited chemical arsenal available for vector control. There is lack of systematic and standard monitoring data of malaria vector resistance in the endemic areas, which is essential for the ambitious goal of malaria elimination programme of China. METHODS: In 2010, eight provinces from different malaria endemic region were selected for study areas. Bioassays were performed on F1 progeny of Anopheles sinensis reared from wild-caught females using the standard WHO susceptibility test with diagnostic concentrations of 0.25% deltamethrin and 4% DDT. RESULTS: For An. sinensis, the results indicated that exposure to 0.25% deltamethrin of F1 families with mortalities ranging from 5.96% to 64.54% and less than 80% mortality to DDT at the diagnostic concentration of 4% across the study areas. CONCLUSIONS: Anopheles sinensis was completely resistant to both deltamethrin and DDT, and resistance to pyrethroid has risen strikingly compared to that recorded during 1990s. The results highlight the importance of longitudinal insecticide resistance monitoring and the urgent need for a better understanding of the status of insecticide resistance in this region. PMID- 23683360 TI - Effect of loops and G-quartets on the stability of RNA G-quadruplexes. AB - The loop length, loop composition, salt concentration, and number of G-quartets are major determinants of G-quadruplex stability. We examined the effect of each of these factors on the thermal stability and folding topology of a library of RNA quadruplexes. The thermal stability of G2 and G3 RNA quadruplexes was investigated upon varying the loop length (from 1-1-1 to 15-15-15) and salt concentration (from 1 to 100 mM KCl), while the effect of loop composition was explored using 18 naturally occurring potential RNA quadruplexes predicted in untranslated regions (UTRs). We found loop length and quadruplex stability to be inversely related for G2 RNA quadruplexes and G3 RNA quadruplexes with shorter loops. However, melting temperature saturates for G3 RNA quadruplexes with longer loops. RNA G-quadruplexes with longer loops (G3 15-15-15) displayed Tm values significantly higher than the physiological temperature. This study thus highlights the need to modify the consensus motif presently used by quadruplex prediction tools. An increase in the loop size from 7 bases to 15 bases in the consensus motif will add to its predictive value for the discovery of potential RNA quadruplexes across transcriptomes. PMID- 23683361 TI - Housefly larvae hydrolysate: orthogonal optimization of hydrolysis, antioxidant activity, amino acid composition and functional properties. AB - BACKGROUND: Antioxidant, one of the most important food additives, is widely used in food industry. At present, antioxidant is mostly produced by chemical synthesis, which would accumulate to be pathogenic. Therefore, a great interest has been developed to identify and use natural antioxidants. It was showed that there are a lot of antioxidative peptides in protein hydrolysates, possessing strong capacity of inhibiting peroxidation of macro-biomolecular and scavenging free redicals in vivo. Enzymatic hydrolysis used for preparation of antioxidative peptides is a new hot-spot in the field of natural antioxidants. It reacts under mild conditions, with accurate site-specific degradation, good repeatability and few damages to biological activity of protein. Substrates for enzymatic hydrolysis are usually plants and aqua-animals. Insects are also gaining attention because of their rich protein and resource. Antioxidative peptides are potential to be exploited as new natural antioxidant and functional food. There is a huge potential market in medical and cosmetic field as well. RESULT: Protein hydrolysate with antioxidant activity was prepared from housefly larvae, by a two step hydrolysis. Through orthogonal optimization of the hydrolysis conditions, the degree of hydrolysis was determined to be approximately 60%. Fractionated hydrolysate at 25 mg/mL, 2.5 mg/mL and 1 mg/mL exhibited approximately 50%, 60% and 50% of scavenging capacity on superoxide radicals, 1, 1-Diphenyl-2 picrylhydrazyl radicals and hydroxyl radicals, respectively. Hydrolysate did not exhibit substantial ion chelation. Using a linoneic peroxidation system, the inhibition activity of hydrolysate at 20 mg/mL was close to that of 20 MUg/mL tertiary butylhydroquinone, suggesting a potential application of hydrolysate in the oil industry as an efficient antioxidant. The lyophilized hydrolysate presented almost 100% solubility at pH 3-pH 9, and maintained nearly 100% activity at pH 5-pH 8 at 0 degrees C- 4 degrees C and room temperature during the first 6 months of storage. Essential amino acids in the hydrolysate accounted for 43% of the total amino acids. CONCLUSIONS: The results suggesting that hydrolysate could be added to food oils as an efficient antioxidant. It might be useful for food additives, diet nutrients and pharmaceutical agents. PMID- 23683362 TI - A complete molecular understanding of malaria parasite invasion of the human erythrocyte: are we there yet? PMID- 23683363 TI - Underpricing the competition in the other drug war: a novel strategy for combatting the inappropriate use of artemisinin monotherapies. PMID- 23683364 TI - Allergic diseases and helminth infections. AB - The relationships between allergic diseases and helminth infections are inconsistent. Some studies have suggested that helminth infections induce or increase the severity of atopic diseases. Other studies report that children infected with some helminths have lower prevalence and milder atopic symptoms. Expanding our knowledge on the mechanism of immunological modification as a result of helminth infection, and understanding the interaction between helminth infections and allergic diseases will be useful for developing potentially new treatments using some helminths, and for evaluating the risks and benefits of eradicating helminth infections in endemic areas. This article reviews current knowledge on the mechanisms of allergic disease, the immunological modifications that result from helminth infections, and clinical evidence of the effects of these infections on allergic diseases. PMID- 23683365 TI - Expression of Neospora caninum NcSRS2 surface protein in Pichia pastoris and its application for serodiagnosis of Neospora infection. AB - Neospora caninum is considerd a major cause of abortion in cattle worldwide. The antigenic domain of NcSRS2 in N. caninum is an important surface antigen present in the membrane of this parasite. In the present study, the Pichia pastoris expression system proved to be a useful tool for the production of recombinant protein. The truncated NcSRS2 gene (by removal of the N-terminal hydrophobic sequence), was cloned in the vector pPICZalphaB, and integrated on the genome of the methylotrophic yeast P. pastoris. Subsequently, the NcSRS2 protein was expressed, purified, and characterized using naturally infected cattle sera and Mab 6xhistag. The recombinant protein NcSRS2 was present in the supernatant of the culture, where later it was concentrated and purified using ammonium sulfate (~100 mg/ml). An indirect immunoenzymatic assay (ELISA) was performed using cattle sera from endemic N. caninum area. PMID- 23683366 TI - The pathogenesis of malaria: a new perspective. AB - With 3.3 billion people at risk of infection, malaria remains one of the world's most significant health problems. Increasing resistance of the main causative parasite to currently available drugs has created an urgent need to elucidate the pathogenesis of the disease in order to develop new treatments. A possible clue to such an understanding is that the malaria parasite Plasmodium falciparum selectively absorbs vitamin A from the host and appears to use it for its metabolism; serum vitamin A levels are also reduced in children with malaria. Although vitamin A is essential in low concentration for numerous biological functions, higher concentrations are cytotoxic and pro-oxidant, and potentially toxic quantities of the vitamin are stored in the liver. During their life cycle in the host the parasites remain in the liver for several days before invading the red blood cells (RBCs). The hypothesis proposed is that the parasites emerge from the liver packed with vitamin A and use retinoic acid (RA), the main biologically active metabolite of vitamin A, as a cell membrane destabilizer to invade the RBCs throughout the body. The characteristic hemolysis and anemia of malaria and other symptoms of the disease may thus be manifestations of an endogenous form of vitamin A intoxication associated with high concentrations of RA but low concentrations of retinol (ROL). Retinoic acid released from the parasites may also affect the fetus and cause preterm birth and fetal growth restriction (FGR) as a function of the membranolytic and growth inhibitory effects of these compounds, respectively. Subject to testing, the hypothesis suggests that parasite vitamin A metabolism could become a new target for the treatment and prevention of malaria. PMID- 23683367 TI - Detection of LipL32-specific IgM by ELISA in sera of patients with a clinical diagnosis of leptospirosis. AB - Successful treatment of leptospirosis is heavily dependent on early diagnosis and prompt initiation of antibiotic therapy. An ELISA test to detect specific IgM antibodies against LipL32 for early diagnosis of leptospirosis is described and evaluated here. One thousand one hundred and eighty sera from clinically suspected leptospirosis cases were enrolled together with 109 healthy volunteers selected from an endemic area between October 2007 and January 2010. Patients were categorized based on their clinical signs and symptoms. Sera were screened for leptospiral antibodies by the microscopic agglutination test (MAT) using a panel of locally circulating serovars followed by enzyme-linked immunosorbent assay (ELISA) based on recombinant LipL32 from Leptospira interrogans serovar Autumnalis strain N2. The sensitivity and specificity of the ELISA test were determined to establish its diagnostic efficiency. The cut-off value was determined to be 0.205. Overall sensitivity and specificity compared to the MAT were found to be 96.4 and 90.4%, respectively. The LipL32-specific IgM ELISA had good sensitivity and acceptable specificity and may be a candidate for the early serodiagnosis of human leptospirosis. PMID- 23683368 TI - Diagnosis and molecular characterization of Trichomonas vaginalis in sex workers in the Philippines. AB - Trichomonas vaginalis is a pathogenic protozoon which causes the sexually transmitted infection, trichomoniasis. The absence or non-specificity of symptoms often leads to misdiagnosis of the infection. In this study, 969 samples consisting of vaginal swabs and urine were collected and screened from social hygiene clinics across the Philippines. Of the 969 samples, 216 were used for the comparative analysis of diagnostic tools such as wet mount microscopy, culture, and PCR utilizing universal trichomonad primers, TFR1/2 and species-specific primers, TVK3/7 and TV1/2. PCR demonstrated higher sensitivity of 100% compared to 77% of the wet mount. PCR primer set TVK3/7 and culture had the same and the best expected average performance [receiver-operating characteristic (ROC): 0.98]. Prevalence of infection in the sample population was 6.8%. PMID- 23683369 TI - Social and environmental health determinants and their relationship with parasitic diseases in asymptomatic children from a shantytown in Buenos Aires, Argentina. AB - Health inequities are a common problem for all countries and are the result of not only adverse social conditions but also poor public policies. Today chronic diseases represent the most relevant threats and are a current challenge. Parasitic infections, a leading cause of child morbidity affecting low-income populations, can be transmitted because of an unhealthy environment. Notwithstanding, scarce data have been published on the epidemiological profile of intestinal parasitoses in asymptomatic children living in shantytowns. Vulnerable populations settled in slums are growing in Argentina, particularly in Buenos Aires city. Consequently, this work intended to screen healthy carriers of enteric parasites and determine the epidemiologic profile in asymptomatic children residing in one of those communities, to explore risk factors associated with the transmission of parasites, and to initiate a basic health education campaign to promote healthy behavior in the community. Fecal samples (n = 138) were analyzed by conventional parasitological methods and a survey gathered data on symptoms, family composition, and environmental and hygiene-related variables. High prevalence of feco-orally-transmitted parasitoses (83.3%) and polyparasitism were remarkable findings. The main environmental health determinants were those related to excreta disposal and water provision. Health promotion actions were performed through the diffusion of a set of posters with iconic images and brief messages for health education. Results suggest the need for an environmental sanitation policy to complement health promotion actions. It is essential to spread the results of investigations that address inequities and social determinants of health in order to integrate data with local political processes and alert on acceptable actions for developing appropriate interventions. PMID- 23683370 TI - Active detection of tuberculosis and paragonimiasis in the remote areas in North Eastern India using cough as a simple indicator. AB - One of the essential steps in targeting tuberculosis (TB) intervention is early diagnosis and treatment of patients by reducing the reservoir of infection in the community. In the North-Eastern (NE) region of India pulmonary TB and paragonimiasis are overlapping public health issues. We performed a cross sectional study in 63 remote villages from the two states Arunachal Pradesh (AP) and Assam to determine the prevalence of undiagnosed TB and paragonimiasis cases using cough as a simple indicator. In AP, 2961 individuals aged five years and above were examined and 1108 (37.4%) were found to have cough for one week or more. Of the 417 individuals who provided sputum, 11 (2.64%) were smear positive for acid-fast bacilli (AFB). All these cases were yet undiagnosed, thus the prevalence of new smear positive TB in AP was 0.37%. In Assam on the other hand 331 (23.5%) subjects out of 1410 individuals who were examined had a cough for one week or more and of the 112 individuals who provided sputum, 13 (11.6%) were smear positive for AFB. The prevalence of new smear positive TB cases was 0.78% in Assam. Sero-positivity of paragonimiasis in coughers of AP was 7.6% (n = 1091), which was significantly higher (p < 0.01) as compared to that in Assam (1.2%, n = 321). The findings of the present study suggest that TB remains a major public health concern in the NE region of India especially in the remote places and there is need to strengthen early case detection of TB. PMID- 23683371 TI - The use of steroids to prevent cutaneous reactions to benznidazole in patients with Chagas disease. AB - The treatment of Chagas disease is limited by the frequent cutaneous side effects of benznidazole. We tested the use of steroids plus escalating doses of benznidazole to prevent this complication in 17 adult patients with chronic Trypanosoma cruzi infection and found extremely good tolerance. A randomized trial is warranted. PMID- 23683372 TI - Using web-based familial risk information for diabetes prevention: a randomized controlled trial. AB - BACKGROUND: It has been suggested that family history information may be effective in motivating people to adopt health promoting behaviour. The aim was to determine if diabetic familial risk information by using a web-based tool leads to improved self-reported risk-reducing behaviour among individuals with a diabetic family history, without causing false reassurance among those without a family history. METHODS: An online sample of 1,174 healthy adults aged 35-65 years with a BMI >= 25 was randomized into two groups receiving an online diabetes risk assessment. Both arms received general tailored diabetes prevention information, whilst the intervention arm also received familial risk information after completing a detailed family history questionnaire. Separate analysis was performed for four groups (family history group: 286 control versus 288 intervention group; no family history: 269 control versus 266 intervention group). Primary outcomes were self-reported behavioural outcomes: fat intake, physical activity, and attitudes towards diabetes testing. Secondary outcomes were illness and risk perceptions. RESULTS: For individuals at familial risk there was no overall intervention effect on risk-reducing behaviour after three months, except for a decrease in self-reported saturated fat intake among low educated individuals (Beta (b) -1.01, 95% CI -2.01 to 0.00). Familial risk information resulted in a decrease of diabetes risk worries (b -0.21, -0.40 to 0.03). For individuals without family history no effect was found on risk reducing behaviour and perceived risk. A detailed family history assessment resulted in a greater percentage of individuals reporting a familial risk for diabetes compared to a simple enquiry. CONCLUSIONS: Web-based familial risk information reduced worry related to diabetes risk and decreased saturated fat intake of those at greatest need of preventative care. However, the intervention was not effective for the total study population on improving risk-reducing behaviour. The emphasis on familial risk does not seem to result in false reassurance among individuals without family history. Additionally, a detailed family history questionnaire identifies more individuals at familial risk than a simple enquiry. TRIAL REGISTRATION: NTR1938. PMID- 23683373 TI - Pulmonary manifestations of collagen diseases. AB - Collagen diseases are a large group of systemic inflammatory diseases of autoimmune etiology. The etiopathogenesis of collagen diseases is multifactorial. There is genetic susceptibility, as many connective tissue disorders show family history, and environmental factors may trigger the disease. Collagen diseases can affect almost all the organs of the body. The respiratory system is one of the most frequently affected, although the prevalence of pulmonary disease is not precisely known for the different collagen disorders. Any structure of the respiratory tract can be affected, but perhaps the most frequent is pulmonary parenchymal disease in the form of pneumonitis, which can be produced in any of the idiopathic interstitial pneumonitis patterns. The pleura, pulmonary vessels, airways and respiratory muscles may also be affected. The frequency of lung disease associated with collagen diseases is on the rise. This due in part to the better diagnostic methods that are available to us today (such as high-resolution computed tomography) and also to the appearance of new forms of pneumonitis associated with the new treatments that are currently used. The objective of this article is to offer a global vision of how collagen diseases can affect the lungs according to the latest scientific evidence. PMID- 23683374 TI - Neuromuscular electrical stimulation attenuates thigh skeletal muscles atrophy but not trunk muscles after spinal cord injury. AB - The current study examined the effects of 12weeks of surface neuromuscular electrical stimulation (NMES) and ankle weights on the cross-sectional areas (CSAs) of three thigh [Gracilis (Gra), Sartorious (Sar) and Adductor (Add)] as well as two trunk [hip flexor (HF) and back extensor (BE)] muscle groups in men with spinal cord injury (SCI). Seven individuals with chronic motor complete SCI were randomly assigned into a resistance training +diet (RT+diet; n=4) or diet control (n=3) groups. The RT+diet group underwent twice weekly training with surface NMES and ankle weights for 12weeks. Training composed of four sets of 10 repetitions of leg extension exercise while sitting in their wheelchairs. Both groups were asked to monitor their dietary intake. Magnetic resonance images were captured before and after 12weeks of interventions. Gra muscle CSA showed no change before and after interventions. A significant interaction (P=0.001) was noted between both groups as result of 9% increase and 10% decrease in the Gra muscle CSA of the RT+diet and diet groups, respectively. Sar muscle CSA increased [1.7+/-0.4-2.5+/-0.5cm(2); P=0.029] in the RT+diet group with no change [2.9+/ 1.4-2.6+/-1.3cm(2)] in the diet group; with interaction noted between both groups (P=0.002). Analysis of covariance indicated that Add muscle CSA was 38% greater in the RT+diet compared to the diet group (P=0.025) after 12weeks; a trend of interaction was also noted between both groups (P=0.06). HF and BE muscle groups showed no apparent changes in CSA in both groups. The results suggested that surface NMES can delay the process of progressive skeletal muscle atrophy after chronic SCI. However, the effects are localized to the trained thigh muscles and do not extend to the proximal trunk muscles. PMID- 23683375 TI - The first Gore-Tex femoral-popliteal bypass. PMID- 23683377 TI - Clinical significance of type II endoleaks after thoracic endovascular aortic repair. AB - BACKGROUND: To evaluate the clinical significance of type II endoleaks (ELII) after thoracic endovascular aortic repair (TEVAR). METHODS: From January 1997 to June 2012, a total of 344 patients received TEVAR in our institution. ELII was diagnosed in 30 patients (8.7%; 13 males; median age: 65 years, range: 24 to 84 years), representing the study population of this retrospective, single-center analysis. Mean follow-up was 29.5 months (range, 8 months to 9.5 years). RESULTS: Primary ELII was observed in all but two cases (28/30; 93.3%). The most common sources of ELII were the left subclavian artery (LSA; 13/30; 43.3%) and intercostal/bronchial vessels (13/30; 43.3%), followed by visceral arteries (4/30; 13.4%). Overall mortality was 33.3% (10/30). ELII-related death (secondary rupture) was observed in 20% (2/10). Reintervention (RI) procedures for ELII were performed in 9 of 30 patients (30.0%); 5 of 9 (55.6%) in cases with ELII via the LSA. Indications for RI were diameter expansion in five and extensive leakage in four cases. Treatment was successful in five patients (55.6%) but failed in four cases (44.4%). In 12 of 21 (57.1%) untreated patients, ELII sealed during follow up. In conservatively treated patients, an increase in aortic diameter has been only observed in a patient with secondary ELII. CONCLUSIONS: The results presented herein suggest that the clinical impact of ELII after TEVAR must not be underestimated. Albeit a transient finding in most cases, ELII is associated with a relevant RI rate, particularly in cases involving the LSA. RI seems indicated in patients with increasing aortic diameter and/or extensive leakage. Careful surveillance of all patients with ELII is recommended. PMID- 23683376 TI - Ten-year results of endovascular abdominal aortic aneurysm repair from a large multicenter registry. AB - OBJECTIVE: To assess outcomes after endovascular abdominal aortic aneurysm repair (EVAR) in an integrated health care system. METHODS: Between 2000 and 2010, 1736 patients underwent EVAR at 17 centers. Demographic data, comorbidities, and outcomes of interest were collected. EVAR in patients presenting with ruptured or symptomatic aneurysms was categorized as urgent; otherwise, it was considered elective. Primary outcomes were mortality and aneurysm-related mortality (ARM). Secondary outcomes were change in aneurysm sac size, endoleak status, major adverse events, and reintervention. RESULTS: Overall, the median age was 76 years (interquartile range, 70-81 years), 86% were male, and 82% were Caucasian. Most cases (93.8%) were elective, but urgent use of EVAR increased from 4% in the first 5 years to 7.3% in the last 5 years of the study period. Mean aneurysm size was 5.8 cm. Patients were followed for an average of 3 years (range, 1-11 years); 8% were lost to follow-up. Intraoperatively, 4.5% of patients required adjunctive maneuvers for endoleak, fixation, or flow-limiting issues. The 30-day mortality rate was 1.2%, and the perioperative morbidity rate was 6.6%. Intraoperative type I and II endoleaks were uncommon (2.3% and 9.3%, respectively). Life-table analysis at 5 years demonstrated excellent overall survival (66%) and freedom from ARM (97%). Postoperative endoleak was seen in 30% of patients and was associated with an increase in sac size over time. Finally, the total reintervention rate was 15%, including 91 instances (5%) of revisional EVAR. The overall major adverse event rate was 7.9% and decreased significantly from 12.3% in the first 5 years to 5.6% in the second 5 years of the study period (P < .001). Overall ARM was worse in patients with postoperative endoleak (4.1% vs 1.8%; P < .01) or in those who underwent reintervention (7.6% vs 1.6%; P < .001). CONCLUSIONS: Results from a contemporary EVAR registry in an integrated health care system demonstrate favorable perioperative outcomes and excellent clinical efficacy. However, postoperative endoleak and the need for reintervention continue to be challenging problems for patients after EVAR. PMID- 23683378 TI - Comparison of a novel real-time SonixGPS needle-tracking ultrasound technique with traditional ultrasound for vascular access in a phantom gel model. AB - OBJECTIVE: Ultrasound-guided percutaneous vascular access for endovascular procedures is well established in surgical practice. Despite this, rates of complications from venous and arterial access procedures remain a significant cause of morbidity. We hypothesized that the use of a new technique of vascular access using an ultrasound with a novel needle-guidance positioning system (GPS) would lead to improved success rates of vascular puncture for both in-plane and out-of-plane techniques compared with traditional ultrasound. METHODS: A prospective, randomized crossover study of medical students from all years of medical school was conducted using a phantom gel model. Each medical student performed three ultrasound-guided punctures with each of the four modalities (in plane no GPS, in-plane with GPS, out-of-plane no GPS, out-of-plane with GPS) for a total of 12 attempts. The success or failure was judged by the ability to aspirate a simulated blood solution from the model. The time to successful puncture was also recorded. A poststudy validated NASA Task Load Index workload questionnaire was conducted to assess the student's perceptions of the two different techniques. RESULTS: A total of 30 students completed the study. There was no significant difference seen in the mean times of vascular access for each of the modalities. Higher success rates for vascular access using the GPS for both the in-plane (94% vs 91%) and the out-of-plane (86% vs 70%) views were observed; however, this was not statistically significant. The students perceived the mental demand (median 12.0 vs 14.00; P = .035) and effort to be lower (mean 11.25 vs 14.00; P = .044) as well as the performance to be higher (mean 15.50 vs 14.00; P = .041) for the GPS vs the traditional ultrasound-guided technique. Students also perceived their ability to access vessels increased with the aid of the GPS (7.00 vs 6.50; P = .007). The majority of students expressed a preference for GPS (26/30, 87%) as opposed to the traditional counterpart. CONCLUSIONS: Use of the novel SonixGPS needle-tracking ultrasound system (UltraSonix, Richmond, BC, Canada) was not associated with a higher success rate of vascular puncture compared with the traditional ultrasound-guided technique. Assessment of mental task load significantly favored the use of the ultrasound GPS over the traditional ultrasound technique. PMID- 23683379 TI - Early management of pediatric vascular injuries through humanitarian surgical care during U.S. military operations. AB - BACKGROUND: The objective of this report is to describe our experience of pediatric vascular injuries in a U.S. military combat support hospital in Baghdad, Iraq. A retrospective study was designed using Joint Theater Trauma Registry (JTTR) records in order to evaluate the pediatric (age <18 years) population presenting with vascular trauma to a combat hospital in Baghdad, Iraq between April 2006 and August 2008. Demographic data comprised casualty, age, gender, and mechanism of injury. Physiologic data included presenting vital signs (rectal temperature, blood pressure, and heart rate), arterial pH, base deficit, hemoglobin (g/dL), and international normalized ratio. RESULTS: Twenty-five children, median age 14 years (range, 5-17 years), median weight 48 kg (range, 15 80 kg) sustained 18 (72%) blast and 7 (28%) gunshot wounds. The mean Injury Severity Score was 25 +/- 16.2. The median operative time for the vascular repairs was 189 minutes (range, 41-505 minutes). Patients were tachycardic (mean +/- standard deviation, 136 +/- 29 bpm), hypotensive (109/63 +/- 29/19 mm Hg), and acidemic (pH 7.26 +/- 0.07; BD -5.57 +/- 5.1 mEq/L) on arrival to the emergency department and were physiologically improved upon admission to the intensive care unit 3 hours later. Repair techniques were ligation (14; 39%), saphenous graft (11; 31%), lateral suture (7; 19%), end anastomosis (2; 5%), patch (1; 3%), and thrombectomy (1; 3%). Twenty-four hour mean transfusion requirements included crystalloid 102 mL/kg (range, 19-253), transfused blood 47 mL/kg (range, 0-119), fresh frozen plasma 14 mL/kg (range, 0-68), and apheresis platelets (1.2 +/- 3.68 units). Over a follow-up of 22 +/- 5.5 days, the amputation-free survival was 80%. CONCLUSIONS: This is the largest reported wartime series to demonstrate in children that damage control resuscitation despite high injury severity permits simultaneous limb salvage. PMID- 23683380 TI - Clinical presentation and outcome after failed infrainguinal endovascular and open revascularization in patients with chronic limb ischemia. AB - OBJECTIVE: Failure of prior endovascular (EV) interventions for chronic limb ischemia has been reported to negatively affect patency and limb salvage after subsequent revascularization procedures. The goal of our study was to compare the clinical presentation of patients who failed infrainguinal EV and open revascularizations (OR) and the effect of the initial intervention on final outcomes. METHODS: From June 2001 to October 2010, 216 patients (237 limbs; 66 disabling claudication [DC], 171 critical limb ischemia [CLI]) presented with failed infrainguinal OR or EV revascularization for chronic limb ischemia. Clinical presentation, reinterventions, patency and limb salvage rates, and final outcomes were analyzed. RESULTS: The EV group (n = 143) had more diabetes (44% vs 57%; P = .048) and ulcers (26% vs 38%; P = .039), whereas the OR group (n = 94) had more multilevel revascularizations (59% vs 33%; P < .001), rest pain (23% vs 9%; P = .002), and infrapopliteal interventions (58% vs 38%; P = .038). Presentation at time of failure was non-limb-threatening ischemia in 70% of DC and 16% of CLI patients (P < .001), with no difference in those initially treated with EV or OR. In CLI, 23% presented with acute limb ischemia in the OR group vs 10% in the EV group (P = .024). Early failure (<3 months) occurred in 15% of DC and in 36% of CLI patients and was more in the OR than in the EV group (30% vs 7% for DC [P = .011] and 71% vs 38% for CLI [P = .024]). Overall, 195 (82%) had attempted reinterventions (79% in DC and 85% in CLI; P = .245). In DC patients, 48% of OR had OR + EV and 26% had EV; 32% of EV had OR + EV and 47% had EV reinterventions. In CLI patients, 40% of OR had OR + EV and 42% had EV; 17% of EV had OR + EV; and 70% had EV reinterventions. A patent revascularized limb was achieved in 66% of OR and in 92% of EV patients (P < .001). Patency and limb salvage were significantly better in the EV group, mainly due to the difference in CLI patients, whereas survival was identical. CONCLUSIONS: Clinical presentation after failed infrainguinal revascularization is determined by the initial indication. CLI patients are more likely to present early with acute limb ischemia, especially after OR. EV reinterventions play a significant role in the management of patients with failed revascularization, and EV failure is associated with better outcomes than those after OR failure, likely due to OR patients having more disadvantaged anatomy and advanced disease at the time of their initial presentation. PMID- 23683382 TI - Discussion. PMID- 23683381 TI - Reduced hind limb ischemia-reperfusion injury in Toll-like receptor-4 mutant mice is associated with decreased neutrophil extracellular traps. AB - OBJECTIVE: Ischemia-reperfusion (IR) injury is a significant problem in the management of patients with acute limb ischemia. Despite rapid restoration of blood flow after technically successful open and endovascular revascularization, complications secondary to IR injury continue to occur and limit clinical success. Our aim was to create a murine model of hind limb IR injury to examine the role of Toll-like receptor-4 (TLR4) and to determine whether inactive TLR4 led to a decrease in the detection of neutrophil extracellular traps (NETs), which are known to be highly thrombogenic and may mediate microvascular injury. METHODS: A calibrated tension tourniquet was applied to unilateral hind limb of wild-type (WT) and TLR4 receptor mutant (TLR4m) mice for 1.5 hours to induce ischemia and then removed to initiate reperfusion. At the end of 48 hours of reperfusion, mice were euthanized and hind limb tissue and serum specimens were collected for analysis. Hematoxylin and eosin-stained sections of hind limb skeletal muscle tissue were examined for fiber injury. For immunohistochemistry, mouse monoclonal antihistone H2A/H2B/DNA complex antibody to detect NETs and rabbit polyclonal antimyeloperoxidase antibody were used to identify infiltrating cells containing myeloperoxidase. Muscle adenosine triphosphate levels, nuclear factor (NF)-kappaB activity, the alpha-subunit of inhibitor of NF-kappaB light polypeptide gene enhancer, poly (adenosine diphosphate-ribose) polymerase activity, and inducible nitric oxide synthase expression were measured. Systemic levels of keratinocyte-derived chemokine, monocyte chemotactic protein-1, and vascular endothelial growth factor in the serum samples were also examined. RESULTS: IR injury in the hind limb of WT mice demonstrated significant levels of muscle fiber injury, decreased energy substrates, increased NF-kappaB activation, decreased levels of alpha-subunit of inhibitor of NF-kappaB light polypeptide gene enhancer, increased inducible nitric oxide synthase expression, and increased poly (adenosine diphosphate-ribose) polymerase activity levels compared with the TLR4m samples. Additionally, there was marked decrease in the level of neutrophil and monocyte infiltration in the TLR4m mice, which corresponded to similar levels of decreased NET detection in the interstitial space and in microvascular thrombi. In situ nuclease treatment of WT tissue sections significantly diminished the level of NET immunostaining, demonstrating the specificity of the antibody to detect NETs and suggesting a potential role for nuclease treatment in IR injury. CONCLUSIONS: These results suggest a pivotal role for TLR4 in mediating hind limb IR injury and suggest that NETs may contribute to muscle fiber injury. PMID- 23683383 TI - Impaired renal function is associated with mortality and morbidity after endovascular abdominal aortic aneurysm repair. AB - BACKGROUND: Renal function may be associated with poor outcome following endovascular abdominal aortic aneurysm repair (EVAR), but this relationship has not been adequately investigated. The aim of this study is to evaluate the association of estimated glomerular filtration rate (eGFR) with cardiovascular events and all-cause mortality after EVAR. METHODS: Prospective cohort study of patients undergoing elective EVAR; eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula, and patients were divided in four groups (eGFR >= 90 mL/min/1.73 m(2), group 1; 60-89, group 2; 30-59, group 3; <30, group 4). Composite end point consisted of death, nonfatal myocardial infarction, stroke, and vascular complications. Kaplan-Meier curves were constructed, and between-group comparisons were performed adjusted for variables that differed at baseline. RESULTS: A total of 383 patients (mean age, 69 +/- 8 years; mean abdominal aortic aneurysm diameter, 6.2 +/- 1.4 cm) were included. Over a mean follow-up of 34 +/- 12 months, the following events occurred: 20 deaths (5.2%), 15 nonfatal myocardial infarctions (3.9%), 9 nonfatal strokes (2.3%), and 7 peripheral vascular complications (1.8%). Patients with an eGFR <30 had the highest mortality (35%) and incidence of complications (80%) as per the end point (P = .009 and P < .001, respectively). Adjusted Cox-regression analysis showed that a higher eGFR at baseline by 1 mL/min/1.73 m(2) was associated with a 5% lower likelihood of complications as per the end point (P < .001; hazard ratio, 0.95; 95% confidence interval, 0.94-0.97) and a 6% lower likelihood of death (P < .001; hazard ratio, 0.94; 95% confidence interval, 0.92-0.97). CONCLUSIONS: Impaired renal function is associated with an increase in cardiovascular events and mortality following elective EVAR. PMID- 23683384 TI - Prediction of postdischarge venous thromboembolism using a risk assessment model. AB - OBJECTIVE: The risk of postdischarge venous thromboembolism (VTE) (either deep vein or pulmonary embolism) is increasingly recognized yet the prescription of postdischarge thromboprophylaxis is inconsistent. There is a paucity of information to aid clinicians in identifying surgical patients who are at increased risk for postdischarge VTE. This study aimed to determine the incidence and risk factors associated with symptomatic postdischarge VTE and develop a risk score to identify patients who may benefit from extended duration thromboprophylaxis. METHODS: This was a retrospective study. All nonorthopedic cases in which the patient was discharged alive without inpatient VTE were selected from the 2005-2009 National Surgical Quality Improvement Program database. A multivariate logistic regression was used to create a risk score for postdischarge VTE prediction. The dataset was split into two-thirds for risk score development and validated in the remaining one-third. RESULTS: The overall incidence of early postdischarge VTE for 2005-2009 National Surgical Quality Improvement Program was 0.3%. The risk score stratified patients into low, moderate, and high risk for postdischarge VTE with the incidence based on the risk score ranging from 0.07% to 2.2%. The risk score had good predictive ability with c-statistic = 0.72 for model development and c-statistic = 0.71 in the validation dataset. Factors associated with postdischarge VTE on multivariate analysis included race, increasing age, steroid use, body mass index >=30, malignancy, higher American Society of Anesthesiologists class, increasing operative time, length of postsurgical stay, and major postoperative complication. CONCLUSIONS: This novel postdischarge VTE prediction score utilizes patient, operative, and early outcome factors to accurately identify patients at increased risk of a postdischarge thromboembolic event. The development of a patient- specific postdischarge VTE risk profile may help address the challenge of determining postdischarge prophylaxis requirements. PMID- 23683385 TI - [Influenza infection and pregnancy]. AB - Pregnant woman have an increased risk of respiratory complications and hospitalization related to influenza. The flu, like any systemic infection, may also be responsible for uterine contractions constituting a threat of miscarriage or premature labor according to gestational age at which it occurs. There is no specific recommendation regarding the management of influenza-like illness in pregnant women, but a nasopharyngeal sample can be performed in the presence of respiratory or general symptoms occurring during an epidemic to search influenza and establish if a specific treatment with oseltamivir (Tamiflu((r))). Surveillance in hospital or intensive care unit may be necessary. Vaccination against influenza provides a satisfactory immunity in pregnant women and reduces the risk of respiratory complications. Transplacental passage of maternal antibody protects newborns who are more likely to have severe influenza infection and because the vaccine cannot be administered before the age of 6 months. The available data show good tolerance influenza vaccination performed during pregnancy. Since 2012, vaccination against seasonal influenza is recommended for pregnant women, whatever the stage of pregnancy at the time of the vaccination campaign. PMID- 23683386 TI - A case of inguinal hernia stone alongwith diabetes and pathophysiology. PMID- 23683387 TI - Histologic evaluation and immunohistochemical localization of STRO-1 and BMP-4 in rat immature teeth: a comparison between vital and induced pulp necrosis. AB - OBJECTIVE: To assess histological features and the expression of STRO-1 and BMP-4 in dental pulp and periapical tissues in vital or necrotic rat immature teeth. DESIGN: The lower left first molars of male Wistar rats ageing four weeks (n=24) had their pulps exposed to the oral environment for 3, 6, 9 and 12 weeks (animals ageing 7, 10, 13 and 16 weeks-old, respectively; n=24). The right lower first molars served as control untouched teeth. After sample harvesting the jaws were dissected and processed for histology and immunodetection of STRO-1 and BMP-4. RESULTS: Necrotic teeth had root development arrested, while control animals showed development of dental tissues. Immunohistochemistry showed that detection of BMP-4 was restricted to vital pulps. For both groups, STRO-1 expression was evident around blood vessels walls. Neither BMP-4 nor STRO-1 was observed in the apical papilla region. CONCLUSION: STRO-1-positive precursor cells were not detected in the apical papilla. BMP-4 expression has not been detected during infection. PMID- 23683388 TI - Office-based narrow band imaging-guided flexible laryngoscopy tissue sampling: A cost-effectiveness analysis evaluating its impact on Taiwanese health insurance program. AB - BACKGROUND/PURPOSE: Narrow band imaging (NBI)-guided flexible laryngoscopy tissue sampling for laryngopharyngeal lesions is a novel technique. Patients underwent the procedure in an office-based setting without being sedated, which is different from the conventional technique performed using direct laryngoscopy. Although the feasibility and effects of this procedure were established, its financial impact on the institution and Taiwanese National Health Insurance program was not determined. METHODS: This is a retrospective case-control study. From May 2010 to April 2011, 20 consecutive patients who underwent NBI flexible laryngoscopy tissue sampling were recruited. During the same period, another 20 age-, sex-, and lesion-matched cases were enrolled in the control group. The courses for procedures and financial status were analyzed and compared between groups. RESULTS: Office-based NBI flexible laryngoscopy tissue sampling procedure took 27 minutes to be completed, while 191 minutes were required for the conventional technique. Average reimbursement for each case was New Taiwan Dollar (NT$)1264 for patients undergoing office-based NBI flexible laryngoscopy tissue sampling, while NT$10,913 for those undergoing conventional direct laryngoscopy in the operation room (p < 0.001). The institution suffered a loss of at least NT$690 when performing NBI flexible laryngoscopy tissue sampling. CONCLUSION: Office-based NBI flexible laryngoscopy tissue sampling is a cost-saving procedure for patients and the Taiwanese National Health Insurance program. It also saves the procedure time. However, the net financial loss for the institution and physician would limit its popularization unless reimbursement patterns are changed. PMID- 23683389 TI - 5-lipoxygenase activating protein reduction ameliorates cognitive deficit, synaptic dysfunction, and neuropathology in a mouse model of Alzheimer's disease. AB - BACKGROUND: 5-lipoxygenase activating protein (FLAP) is abundantly present in the central nervous system. Although its function has been extensively interrogated in the context of peripheral inflammation, novel roles for this protein are emerging in the central nervous system. The objective of our study was to investigate the functional role that FLAP plays in a mouse model of Alzheimer's disease (AD) with plaques and tangles (i.e., 3xTg mice). METHODS: By implementing a genetic knockout of FLAP and pharmacologic inhibition with a FLAP inhibitor (MK 591), we evaluated the effect on the AD-like neuropathology, cognition, and synaptic plasticity in the 3xTg mice. RESULTS: We show that reduction of FLAP leads to amelioration of cognition and memory along with the rescuing of synaptic dysfunction at an early age before the development of overt neuropathology. Genetic knockout and pharmacologic inhibition of FLAP also yielded an improvement in AD pathology through a reduction in Abeta via the gamma-secretase pathway and a decrease in tau phosphorylation through the cdk5 pathway. CONCLUSIONS: Our studies identify a novel functional role for FLAP in regulating memory and synaptic plasticity. They establish this protein at the crossroad of multiple pathways that ultimately contribute to the development of the entire AD-like phenotype, making it a viable therapeutic target with disease-modifying capacity for the treatment of this disease. PMID- 23683391 TI - Safety and efficacy of ultra-high-dose, short-term thrombolysis with rt-PA for acute lower limb ischemia. AB - OBJECTIVES: The evaluation of success and complication rates of ultra high-dose recombinant tissue plasminogen activator (rt-PA) administered over a short time frame in the treatment of acute lower limb ischemia. METHODS: This was a prospective single-center study. The outcome of treatment in 97 patients with acute limb ischemia (<14 days) with the use of catheter directed rt-PA infusion was evaluated. The mean total dose of rt-PA was 54.1 mg (50-60 mg) and was administered for a mean of 2.51 hours (2-4 hours). Thrombolytic success was defined as 95% thrombolysis of an occluded segment with return of antegrade flow. Thirty-day complication and amputation-free survival rates were calculated. RESULTS: Thrombolytic success was achieved in 83.5%. Overall clinical success was 88.7%. The 30-day amputation-free survival rate was 93.8%. Major bleeding complications occurred in 10 patients (10.3%). There were two deaths (2.1%) and four amputations (4.1%). Long-term amputation-free survival was 70%. CONCLUSIONS: Administration of ultra-high doses of rt-PA over a short time period gives promising results. Such delivery improves patient tolerance by rapid restoration of limb perfusion; however further studies are required to confirm these results. PMID- 23683392 TI - Outcomes after elective aortic aneurysm repair: a nationwide Danish cohort study 2007-2010. AB - OBJECTIVE: To assess outcomes after treatment for asymptomatic abdominal aortic aneurysm (AAA) in Denmark in a period when both open surgery (OR) and endoluminal repair (EVAR) have been routine procedures. METHODS: We performed a retrospective nationwide cohort study of patients treated for asymptomatic AAA between 2007 and 2010. Data on demographics, procedural data, perioperative complications, length of stay (LOS), 30-day reinterventions and readmissions, late aneurysm and procedure-related complications and mortality were obtained from the Danish Vascular Registry and the Danish National Patient Register. RESULTS: 525 EVAR and 1176 OR for asymptomatic AAA were identified. LOS was shorter after EVAR than OR (4 vs. 7 days, p < .001). During primary hospitalization procedure-related complications (12% vs. 6%) and general complications (21% vs. 8%) were more common after OR than EVAR (p < 0.001). The 30-day reintervention rate was higher for OR than EVAR (18% vs. 6%, p < 0.001), but there was no difference in readmissions within 30 days. During follow-up (mean 29 +/- 15 months) aneurysm related complications after EVAR were outweighed by procedure-related complications after OR. CONCLUSION: Elective AAA repair in Denmark is overall comparable with international results and both perioperative and late outcomes after EVAR of elective AAA are better than the results after OR. PMID- 23683390 TI - Meta-analysis of oxidative stress in schizophrenia. AB - BACKGROUND: Schizophrenia is associated with impaired antioxidant defense, including abnormal serum, plasma, and red blood cell (RBC) oxidative stress parameters. We performed a meta-analysis of these associations, considering the effect of clinical status and antipsychotic treatment after an acute exacerbation of psychosis. METHODS: We identified articles by searching PubMed, PsychInfo, and Institute for Scientific Information, and the reference lists of identified studies. RESULTS: Forty-four studies met the inclusion criteria. Total antioxidant status seemed to be a state marker, because levels were significantly decreased in cross-sectional studies of serum and plasma in first-episode psychosis (FEP) and significantly increased in longitudinal studies of antipsychotic treatment for acute exacerbations of psychosis (p < .01 for each). The RBC catalase and plasma nitrite seemed to be state-related markers, because levels in cross-sectional studies were significantly decreased in FEP (p < .01) and significantly increased in stable outpatients (p = .01). In contrast, RBC superoxide dismutase seemed to be a trait marker for schizophrenia, because levels in cross-sectional studies were significantly decreased in acutely relapsed inpatients, FEP, and stable outpatients (p < .01 for each). CONCLUSIONS: Oxidative stress abnormalities in FEP suggest an effect that might be independent of antipsychotic medications. Although some parameters (total antioxidant status, RBC catalase, and plasma nitrite) might be state markers for acute exacerbations of psychosis, others (RBC superoxide dismutase) might be trait markers; however, more longitudinal studies are needed. Our findings suggest that oxidative stress might serve as a potential biomarker in the etiopathophysiology and clinical course of schizophrenia. PMID- 23683393 TI - Bandages or double stockings for the initial therapy of venous oedema? A randomized, controlled pilot study. AB - OBJECTIVE/BACKGROUND: Treatment for leg oedema conventionally starts with compression bandaging followed by elastic stockings once swelling is reduced. The aim was to investigate if a kit consisting of a liner and outer stocking, each exerting 20 mmHg of pressure, would be equally effective in achieving and maintaining volume reduction compared with short-stretch bandaging (2 weeks) followed by a class II (23-33 mmHg) stocking (2 weeks). METHODS: Forty legs (28 patients) with chronic venous oedema were randomised to either short-stretch bandages applied weekly for 2 weeks, followed by an elastic stocking for 2 weeks (group A) or a light stocking ("liner") for 1 week followed by superimposing a second stocking for 3 weeks (group B). Interface pressures and leg volumes were measured weekly. RESULTS: Despite differences in the pressure (median +/- interquartile range) applied (bandage: 67 mmHg [55.7-73.0] vs. liner 24.5 mmHg [21.2-26.5]) volume reduction after 1 week was equal (12.8% [8.7-16.5] and 13.0% [10.4-20.6]). After 2 weeks (group A: 17.8% [10.6-20.0] vs. group B 16.2% [13.0 25.4]) and 4 weeks (group A: 17.3% [9.6-22.8] vs. group B: 17.0% [13.1-24.1]) volume reductions remained identical. CONCLUSIONS: The initial improvement in leg volume (1 week) was independent of the pressure applied and the reduction was maintained by superimposing a second stocking. This offers a simple alternative for managing leg oedema with reduced staffing costs. PMID- 23683394 TI - Is a high dose of vitamin d useful for peripheral arterial disease? PMID- 23683395 TI - Should the frequency of surveillance for small abdominal aortic aneurysms be reduced? AB - Different national screening programmes use a variety of surveillance intervals for patients identified with small abdominal aortic aneurysm. An individual patient meta-analysis of >15000 persons with small aneurysm has provided a strong scientific basis for safe surveillance frequency. In many screening programmes the number of surveillance visits for men could be reduced by up to half. The higher rate of aneurysm rupture in women leads to different recommendation for women. PMID- 23683396 TI - Mid-term results of endovascular aortic aneurysm repair in the young. AB - OBJECTIVES: To compare the mid-term outcome and secondary intervention rate following elective open and endovascular aortic aneurysm repair (EVAR) in patients aged 65 years and younger. METHODS: A retrospective analysis of patients aged 65 years and younger who had elective abdominal aortic aneurysm repair (AAA) between 1994 and 2012. RESULTS: One hundred and sixty-five patients under the age of 65 years (mean age: 61 years +/- 4; 8 women) had elective abdominal aneurysm repair (97 EVAR and 68 open). The overall 30-day mortality rate was 3.7% (2.1% EVAR and 5.9% open). Forty per cent of patients had died at a median follow up of 77 months (interquartile range, 36-140). Most deaths were not related to aneurysm. There was no difference in the long-term mortality between the EVAR and open groups (hazard ratio [HR] = 1.22; 95% confidence interval [CI] 0.75-1.98, p = .43), but there was a trend of better outcomes with the use of commercially made endografts over open repair (HR = 2.9; 95% CI 0.9-10.0, p = .08) and custom made endografts (HR = 3.1, 95% CI 0.9-10.3; p = .07). Eleven per cent of patients who had EVAR required a further procedure compared with 13% who had open repair. All but one of the re-interventions in the EVAR group was performed on patients who had custom-made endografts. CONCLUSIONS: Young patients with AAA have significant comorbidities and do not necessarily have long lifespans. In the less fit younger patients with AAA, the results with EVAR are comparable with fit patients who had open AAA repair. The management of fitter young patients with AAA remains controversial, but improving results with EVAR over time may increase the role of EVAR in this group. PMID- 23683397 TI - Analysis of micronomicin by liquid chromatography with pulsed electrochemical detection. AB - This paper describes the separation of the main component micronomicin from its related substances using a new established liquid chromatographic method with pulsed electrochemical detection (LC-PED). The mobile phase consists of 1 volume of acetonitrile and 99 volumes of an aqueous solution containing 1.25% (v/v) trifluoroacetic acid, 0.025% (v/v) pentafluoropropionic acid and 0.85% (v/v) of 50% sodium hydroxide. The pH of the aqueous solution is adjusted to 2.6 with 0.5 M NaOH. The influence of the different chromatographic parameters on the separation was investigated. A quadruple-potential waveform was used as detection waveform. 0.5 M NaOH was added post column at a flow rate of 0.3 mL/min to raise the pH of detection to at least 12. The LOD and LOQ of micronomicin are 0.08 MUg/mL (1.6 ng injected) and 0.25 MUg/mL (5 ng injected), respectively. The linearity of micronomicin ranges from 0.25 to 60 MUg/mL with a correlation coefficient of 0.9978. Intra-day RSD and inter-day RSD of micronomicin are 0.89% and 0.55%, respectively. This method proved to be robust and is also applicable to a wider number of C18 columns. A number of commercial samples of micronomicin sulfate were analyzed using this method and 18 peaks can be separated from the main component and from each other in one sample. Seven peaks could be identified using reference substances. The chemical structure of two unknown impurities could be characterized by LC-MS based on comparison of their fragmentation patterns with those of available reference substances. PMID- 23683398 TI - Analysis of ten abused drugs in urine by large volume sample stacking-sweeping capillary electrophoresis with an experimental design strategy. AB - A statistical tool equipped with Plackett-Burman design (PBD) and central composite design (CCD) was used for fast stacking analysis of ten frequently consumed drugs, namely codeine, morphine, methamphetamine, ketamine, alprazolam, clonazepam, diazepam, flunitrazepam, nitrazepam and oxazepam, by capillary electrophoresis (CE). This statistical design is expected to help quick analysis with few procedures, avoiding tedious work required because of the large number of variables or parameters. A large volume sample stacking (LVSS)-sweeping CE is developed for concentrating and analyzing the 10 abused drugs. First, phosphate buffer (50 mM, pH 2.3) containing methanol was filled into a capillary and then the extracted urine sample was loaded (1 psi, 200 s) to enhance sensitivity. The sweeping and separating steps were completed simultaneously by phosphate buffer (50 mM, pH 2.3) containing methanol and sodium dodecyl sulfate, within 15 min. Better resolution was obtained by the experimental design than the "one factor at a time" (OFAT) approach. During method validation, calibration plots were linear (r>0.998), over a range of 25-1500 ng/mL for the six benzodiazepines, methamphetamine and ketamine, and 50-3000 ng/mL for codeine and morphine. The RSD of precision and absolute RE of accuracy in intra-day and inter-day assays were below 14.54% and 16.61%, respectively. The minimum limits for detection (S/N=3) of analytes were in the range of 7.5-30 ng/mL. This stacking method increased sensitivity more than 200-fold and can be applied for detection of the presence of methamphetamine in an abuser's urine (3600 ng/mL), which was confirmed by GC MS. The method is considered feasible for fast screening of abused drugs in urine. PMID- 23683399 TI - Preparation of a polar monolithic coating for stir bar sorptive extraction of emerging contaminants from wastewaters. AB - A new polar monolith based on poly(poly(ethylene glycol) methacrylate-co pentaerythritol triacrylate) (poly(PEGMA-co-PETRA)) was first synthesised, after the optimisation of the polymerisation conditions, and applied as a coating for the stir bar sorptive extraction (SBSE) of a group of pharmaceuticals and personal care products (PPCPs) from environmental water samples. Several parameters affecting extraction and liquid desorption in SBSE were investigated to achieve the optimal sorption efficiencies for the studied analytes. Under the optimised experimental conditions, a rapid, simple and sensitive SBSE performance was provided by the in-house monolithic stir bar. Moreover, the in-house coating was able to extract and desorb most of the studied analytes more effectively and quickly, due to its polar behaviour and suitable mechanical and physical properties, in comparison with the recently commercialised polar stir bars (EG Silicone Twister((r)) and Acrylate Twister((r))). The analytical methodology, including SBSE followed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), was validated and successfully applied for the determination of a group of PPCPs in wastewater samples. PMID- 23683400 TI - Multi-residue analytical method for the determination of endocrine disruptors and related compounds in river and waste water using dual column liquid chromatography switching system coupled to mass spectrometry. AB - The present study describes a novel, fully automated method, based on column switching using EQuanTM columns for an integrated sample preconcentration and liquid chromatography coupled to tandem mass spectrometry (LC-LC-MS/MS). The method allows the unequivocal identification and quantification of the most relevant environmental endocrine disruptors compounds (EDCs) and compounds suspected to be EDCs, such as natural and synthetic estrogens and their conjugates, antimicrobials, parabens, bisphenol A, alkylphenolic compounds, benzotriazoles, and organophosphorus flame retardants, in surface river water and wastewater samples. Applying this technique, water samples were directly injected into the chromatographic system and the target compounds were concentrated into the loading column. Thereafter, the analytes were transferred into the analytical column for subsequent detection by MS-MS (QqQ). A comparative study employing three types of columns, with different chemical modifications, was performed in order to determine the optimal column that allowed maximum retention and subsequent elution of the analytes. Using this new optimized methodology a fast and easy online methodology for the analysis of EDCs in surface river water and wastewater with low limits of quantification (LOQ) was obtained. LOQs ranged from 0.008 to 1.54 ng/L for surface river water and from 0.178/0.364 to 12.5/25.0 ng/L (except for alkylphenol monoethoxylates) for effluent/influent waste water. Moreover, employing approximately 1h, a complete analysis was performed which was significant improvement in comparison to other methods reported previously. This method was used to track the presence and fate of target compounds in the Ebro River which is the most important river in Spain whose intensive agricultural and industrial activities concentrate mainly close to the main cities in the basin, deteriorating soil and water quality. PMID- 23683401 TI - Lactose semicarbazone as a marker for semicarbazide adulteration in milk. AB - A liquid chromatography-mass spectrometry method to detect semicarbazide and lactose semicarbazone in milk was developed as part of a programme to set up methods for detecting the economically motivated adulteration of raw milk with nitrogen-containing compounds. The detection of semicarbazide was hampered by that fact that this compound tended to give broad, poor intensity peaks in the hydrophobic interaction chromatographic method employed. When spiked into milk at levels of 20-200 ppm, semicarbazide either partially or completely reacted with the matrix, which both increased the limit of detection of the method and made the setting of a threshold by using low level spikes almost impossible. Thus using lactose semicarbazone as a marker for semicarbazide addition to milk was investigated. Lactose semicarbazone was detected in semicarbazide-spiked milk, and its identity was confirmed by fragmentation analysis and comparison with the synthesised compound. The level of lactose semicarbazone correlated with the amount of semicarbazide added to the milk, and the acidic conditions employed in the extraction method appeared to enhance the sensitivity of detection by driving the semicarbazone-forming reaction towards completion. Thus lactose semicarbazone can be used as a marker for the addition of semicarbazide to milk; however, both compounds should be monitored during surveys looking for the semicarbazide adulteration of milk. PMID- 23683402 TI - [Online hemodiafiltration: is it really more expensive?]. AB - Online hemodiafiltration has been shown to have many benefits in terms of morbi mortality and to increase middle weight molecules removal. However, this technique is supposed to have an additional cost which may be an obstacle to increase its development in hemodialysis centers. The aim of the study is to achieve an accurate pharmaco-economic evaluation for determining the real overcost of online hemodiafiltration (OL-HDF) in comparison with high flux hemodialysis (HF-HD) using standard priming. We have identified the additional costs related to the consumables and monitors and the additional costs imposed by the technique itself (water consumption and microbiological analysis). In the center, more than 28,000 sessions per year are performed with 70% in OL-HDF (90% post-dilution). The consumable overcost ranges from -2.55 to +3.35 euros per session depending on the monitor and on the HDF modality. The overcost of microbiological analysis is +1.1 euros per session. The theoretical additional water consumption is calculated from different dialysat flow rates and OL-HDF modality. Its ranges from +50.8L to +74.8L per session increasing the water overcost from +0.15 to +0.23 euros per session. This accurate evaluation shows that the cost difference of OL-HDF depends on monitor used and on the OL-HDF modality. In our center, it ranges from -1.29 to +4.58 euros per session. PMID- 23683403 TI - Discrimination against people with severe mental illness and their access to social capital: findings from the Viewpoint survey. AB - Aims. Discrimination against people with severe mental illness is an international problem. It is associated with reduced social contact and hinders recovery. This paper aims to evaluate if experienced or anticipated discrimination is associated with social capital, a known correlate of mental health. Methods. Data from the annual viewpoint cross-sectional survey of people with severe mental illness (n = 1016) were analysed. Exploratory univariate analysis was used to identify correlates of social capital in the sample, which were then evaluated in linear regression models. Additional hypotheses were tested using t tests. Results. Experienced discrimination made a modest contribution to the explained variance of social capital. Experienced discrimination from friends and immediate family was associated with reduced access to social capital from these groups, but this was not found for wider family, neighbours or mental health staff. Experience of discrimination in finding or keeping a job was also associated with reduced access to social capital. Conclusions. Further longitudinal research is needed to determine how resources within people's networks can help to build resilience, which reduces the harmful effect of discrimination on mental health. PMID- 23683404 TI - Actin is required for cellular death. AB - Actin is one of the most abundant cytoskeletal proteins, which takes part in many cellular processes. This review provides information on the history, forms and localization of actin and its role, in particular in cellular death processes. We discuss the relationships between reorganization of actin filaments and apoptosis, mitotic catastrophe and differentiation. Finally, we discuss the translocation and accumulation of actin in the nuclear area. Moreover, owing to the difficulties of F-actin localization by transmission electron microscopy (TEM), the phalloidin-based method of its detection using streptavidin-coated quantum dots is presented in this review. PMID- 23683405 TI - Type 1 metalloproteinase is selectively expressed in adult rat brain and can be rapidly up-regulated by kainate. AB - The expression of metalloproteinase MMP-1 was traced in frontal sections of the rat brain in normal conditions and 4 h after an intraperitoneal injection of kainate. In the olfactory lobe, immunoreactivity was normally detected in the lateral olfactory tract. Kainate treatment led to the appearance of additional immunoreactivity in the neuropilar tracts. In the hippocampal part of brain, immunoreactive neurons were found exclusively after the kainate treatment in several hypothalamic and amygdalar nuclei, and in the restricted cortex areas (clusters of neurons in layers 3-4 of cortex, and a stripe of cells in layer 6). In the area between the hippocampus and cerebellum, MMP-1-like immunoreactivity was normally present in the entorhinal cortex, in the lateral periaqueductal gray, and in the pontine nucleus. After kainate treatment, the immunoreactive neurons were also found in the medial entorhinal cortex and in the dorsal raphe nucleus. In the brain stem, the immunoreactive cells were normally found in six nuclei. After kainate treatment, additional immunoreactivity appeared in the inferior olive neurons and in tracts supplying the cerebellar cortex. Thus, MMP-1 is present in several brain areas in normal conditions at a detectable level, and its expression increases after kainate-induced seizures. PMID- 23683406 TI - Image-guided non-invasive ultrasound liver ablation using histotripsy: feasibility study in an in vivo porcine model. AB - Hepatocellular carcinoma (HCC), or liver cancer, is one of the fastest growing cancers in the United States. Current liver ablation methods are thermal based and share limitations resulting from the heat sink effect of blood flow through the highly vascular liver. In this study, we explore the feasibility of using histotripsy for non-invasive liver ablation in the treatment of liver cancer. Histotripsy is a non-thermal ablation method that fractionates soft tissue through the control of acoustic cavitation. Twelve histotripsy lesions ~1 cm(3) were created in the livers of six pigs through an intact abdomen and chest in vivo. Histotripsy pulses of 10 cycles, 500-Hz pulse repetition frequency (PRF), and 14- to 17-MPa estimated in situ peak negative pressure were applied to the liver using a 1-MHz therapy transducer. Treatments were performed through 4-6 cm of overlying tissue, with 30%-50% of the ultrasound pathway covered by the rib cage. Complete fractionation of liver parenchyma was observed, with sharp boundaries after 16.7-min treatments. In addition, two larger volumes of 18 and 60 cm(3) were generated within 60 min in two additional pigs. As major vessels and gallbladder have higher mechanical strength and are more resistant to histotripsy, these remained intact while the liver surrounding these structures was completely fractionated. This work shows that histotripsy is capable of non invasively fractionating liver tissue while preserving critical anatomic structures within the liver. Results suggest histotripsy has potential for the non-invasive ablation of liver tumors. PMID- 23683407 TI - Using an ultrasound elasticity microscope to map three-dimensional strain in a porcine cornea. AB - An ultrasound elasticity microscope was used to map 3-D strain volume in an ex vivo porcine cornea to illustrate its ability to measure the mechanical properties of this tissue. Mechanical properties of the cornea play an important role in its function and, therefore, also in ophthalmic diseases such as kerataconus and corneal ectasia. The ultrasound elasticity microscope combines a tightly focused high-frequency transducer with confocal scanning to produce high quality speckle over the entire volume of tissue. This system and the analysis were able to generate volume maps of compressional strain in all three directions for porcine corneal tissue, more information than any previous study has reported. Strain volume maps indicated features of the cornea and mechanical behavior as expected. These results constitute a step toward better understanding of corneal mechanics and better treatment of corneal diseases. PMID- 23683408 TI - Neck muscle stiffness quantified by sonoelastography is correlated with body mass index and chronic neck pain symptoms. AB - This study aimed to quantify neck muscle stiffness in the normal population with ultrasound elastography. We applied the acoustic radiation force impulse technique and measured shear wave velocities (SWVs) as representative values. The mean +/- standard deviation values of SWV in 20 healthy volunteers were 2.09 +/- 0.45, 1.21 +/- 0.30, 1.12 +/- 0.17 and 0.97 +/- 0.10 m/s for the trapezius, levator scapulae, scalene anterior and sternocleidomastoid muscles, respectively. The SWV values of the four muscles significantly differed (Kruskal-Wallis test, p < 0.001). The SWV values for the trapezius muscle correlated with body mass indexes (Pearson's correlation, p = 0.034). Subjects with chronic neck pain symptoms had significantly stiffer trapezius muscle (Mann-Whitney U test, p = 0.008). This study demonstrated the technique and feasibility of quantifying neck muscle stiffness using acoustic radiation force impulse elastography and shear wave velocity detection. Further study is necessary to evaluate its diagnostic power in assessing various neck muscle diseases. PMID- 23683409 TI - Influence of shell composition on the resonance frequency of microbubble contrast agents. AB - The effect of variations in microbubble shell composition on microbubble resonance frequency is revealed through experiment. These variations are achieved by altering the mole fraction and molecular weight of functionalized polyethylene glycol (PEG) in the microbubble phospholipid monolayer shell and measuring the microbubble resonance frequency. The resonance frequency is measured via a chirp pulse and identified as the frequency at which the pressure amplitude loss of the ultrasound wave is the greatest as a result of passing through a population of microbubbles. For the shell compositions used herein, we find that PEG molecular weight has little to no influence on resonance frequency at an overall PEG mole fraction (0.01) corresponding to a mushroom regime and influences the resonance frequency markedly at overall PEG mole fractions (0.050-0.100) corresponding to a brush regime. Specifically, the measured resonance frequency was found to be 8.4, 4.9, 3.3 and 1.4 MHz at PEG molecular weights of 1000, 2000, 3000 and 5000 g/mol, respectively, at an overall PEG mole fraction of 0.075. At an overall PEG mole fraction of just 0.01, on the other hand, resonance frequency exhibited no systematic variation, with values ranging from 5.7 to 4.9 MHz. Experimental results were analyzed using the Sarkar bubble dynamics model. With the dilatational viscosity held constant (10(-8) N.s/m) and the elastic modulus used as a fitting parameter, model fits to the pressure amplitude loss data resulted in elastic modulus values of 2.2, 2.4, 1.6 and 1.8 N/m for PEG molecular weights of 1000, 2000, 3000 and 5000 g/mol, respectively, at an overall PEG mole fraction of 0.010 and 4.2, 1.4, 0.5 and 0.0 N/m, respectively, at an overall PEG mole fraction of 0.075. These results are consistent with theory, which predicts that the elastic modulus is constant in the mushroom regime and decreases with PEG molecular weight to the inverse 3/5 power in the brush regime. Additionally, these results are consistent with inertial cavitation studies, which revealed that increasing PEG molecular weight has little to no effect on inethe rtial cavitation threshold in the mushroom regime, but that increasing PEG molecular weight decreases inertial cavitation markedly in the brush regime. We conclude that the design and synthesis of microbubbles with a prescribed resonance frequency is attainable by tuning PEG composition and molecular weight. PMID- 23683410 TI - Sonographic and pathologic image analysis of pure mucinous carcinoma of the breast. AB - The aims of this study were to elucidate sonographic and histologic features of pure mucinous carcinoma (P-MC) of the breast using quantitative analysis and to evaluate the relationship between quantitative analysis and visual qualitative assessment. Eleven P-MCs (nine patients) were evaluated qualitatively and quantitatively. Three experts assessed these sonographic images using the Breast Imaging Reporting and Data System (BI-RADS) lexicon. For assessment of internal echoes and posterior echoes, quantitative measures were determined using ImageJ software. Histologic thin sections were stained for classification into separate parts of the tumor (stroma, mucin and cancer cells) and were digitized. Internal echoes were isoechoic in 7 of 11 (63.6%) tumors and hypoechoic in 4 of 11 (36.4%); all P-MCs were "enhanced" in qualitative evaluation. As internal echoes increased, the proportion of stroma increased and that of mucin decreased. The high level of internal echoes is correlated with reflection and back-scattering, which are caused mainly by the interface between mucin and stroma. PMID- 23683411 TI - Sanctions against Iran and the impact on drug use and addiction treatment. PMID- 23683412 TI - [Biocompatibility of polyethylene imine (PEI)-coated magnetic Fe3O4 nanoparticles in SHI-1 cells]. AB - OBJECTIVE: To explore the feasibility of magnetic resonance cell imaging technology by using polyethylene imine (PEI)-coated magnetic nanoparticles of Fe4O4 (PEI-Fe4O4-MNPs) to track cell biology behavior. METHODS: Endocytic PEI Fe4O4-MNPs in SHI-1 cells were observed by transmission electron microscopy (TEM) . Iron contents of nano-labeled cells were analyzed by inductively coupled plasma atomic emission spectroscopy (ICP-AES) and Prussian blue staining. The proliferation ability of labeled cells was detected by cell counting kit-8 (CCK 8) assay; the differentiation and colony-forming abilities were also observed. SHI-1 cells without endocytosing PEI-Fe4O4-MNPs were used as control. RESULTS: Our data showed that PEI-Fe4O4-MNPs could label SHI-1 cells. The labeling efficiency depended on the nanoparticles' concentration and the duration of cells treating. Inhibition rates of SHI-1cells labeled by 60-100 MUg Fe/ml PEI-Fe4O4 MNPs were much higher than of 5-50 MUg Fe/ml ones following treating by 5-100 MUg Fe/ml PEI-Fe4O4-MNPs for 48 hrs. The expressions of CD11b and CD14 were (78.4+/ 18.5)% and (18.7+/-2.9)% in control vs (83.3+/-14.2)% and (20.4+/-2.1)% in cells fractions treated by 30 MUg Fe/ml PEI-Fe4O4-MNPs. Clony-forming rates of SHI-1 cells labeled by 0, 20 , 50 MUg Fe/ml PEI-Fe4O4-MNPs were (25.20+/-7.22)%, (25.93+/-13.15)%, (23.37+/-9.33)%, respectively. Differentiation and colony forming potentials of labeled cells were similar with control in the certain range of PEI-Fe4O4-MNPs concentration. CONCLUSION: SHI-1 cells were efficiently labeled by PEI-Fe4O4-MNPs with well biocompatibilities in proper range of concentration, the latter could be coupled with magnetic resonance imaging (MRI) to track cells in vivo. PMID- 23683413 TI - [Functional study of abnormal fibrinogen caused by Arg275His mutation in fibrinogen gamma chain]. AB - OBJECTIVE: To investigate the function of abnormal fibrinogen in two inherited dysfibrinogenemia pedigrees. METHODS: Routine coagulation tests were conducted in the probands and related family members. The antigen and activity levels of fibrinogen were detected by immunoturbidimetry assay and clauss assay, respectively. All the exons and exon-intron boundaries of the three fibrinogen genes and antithrombin gene(AT3)were analyzed by PCR amplification and direct sequencing. Routine thrombelastography (TEG) test and functional fibrinogen TEG test were both used to make a comprehensive evaluation of coagulation status and functional fibrinogen level in patients. The molecular weights of the three peptides from fibrinogen were measured by Western blot. The function of abnormal fibrinogen was assessed by fibrinogen dynamic polymerization and fibrinolysis velocity. RESULTS: The coagulation routine tests were normal in two probands except for prolonged thrombin time (TT) and reptilase time (RT), as well as reduced activity levels of 0.5 g/L and 0.6 g/L fibrinogen, respectively. The antigen levels of fibrinogen were 2.32 g/L and 2.66 g/L in two probands, which were in the normal reference range. The genotype analysis showed that Arg275His in fibrinogen gamma chain (gamma Arg275His) existed in both probands and patients in these two pedigrees. Meanwhile, proband B's grandfather and aunt also carried heterozygote g.5876T>C (Ser116Pro) mutation in AT3. The results of routine TEG test demonstrated that the alpha values of proband B and his father were close to and lower than the lower limit of reference range, respectively, while the MA values were normal in both of them. However, functional fibrinogen TEG test revealed obviously reduced MA value. All the probands and patients demonstrated prolonged lag-off time and reduced peak value in fibrinogen dynamic polymerization tests. Meanwhile, most of fibrin formed from the patients' plasma could not be dissolved completely by plasminogen (PLG) and urokinase typeplasminogenactivator (u-PA) at a certain time. CONCLUSION: We first reported cases of inherited dysgibrinogenemia associated with inherited AT deficiency. gammaArg275His mutation caused the abnormal fibrinogen in terms of fibrin mono polymerization and possibly in fibrinolysis. Combined use of routine TEG test and functional fibrinogen TEG test with comprehensive analyses of the parameters in both tests could better evaluate the level of functional fibrinogen and predict the risk of hemorrhage and thrombosis in patients with inherited dysfibrinogenemia. PMID- 23683415 TI - [Gene analysis in four inherited coagulation FXII deficiency pedigree]. AB - OBJECTIVE: To identify the genotype and pathogenesis in four Chinese pedigrees with Factor XII deficiency. METHODS: Activated partial thromboplastin time (APTT), FXII procoagulant activity (FXII?C), FXII antigen(FXII?Ag)and other coagulant parameters were detected. The FXII deficiency Pedigree members,all exons,boundary introns including the splice junctions of the FXII gene were amplified with Polymerase chain reaction (PCR). Expression plasmids were constructed by mutagenesis based on the wild-type and transfected into COS7 cells. FXII?C and FXII?Ag of the expression levels were tested in the supernatant and cell lysate. RESULTS: The four probands presented prolonged APTT with all the values of FXII?C and FXII?Ag were low to 2% and 1%, respectively. There were common 46C/T polymorphism in the promoter regions of FXII gene in four pedigrees. Proband A was heterozygous for two mutations, g.5741-5742delCA (His101Gln) and g.7142insertC (Lys346Gln). Proband B was a heterozygous deletion mutation g.6800 6808del9bp. The results of the transfection revealed that FXII?Ag in cell lysates and conditioned media protein FXII6800-6808del9bp were 85.6% and 51.9%. The FXII?C in the conditioned media was 56.4%. Proband C was a heterozygous mutation g.8699G>A(Gly542Ser). Proband D was a homozygous mutation 8699G>A, whose parents with consanguineous marriage. CONCLUSION: Four mutations, g.5741-5742delCA, g.7142insertC, g.6800-6808del9bp and g.8699G>A with 46C/T polymorphism in the promoter regions of FXII gene, were identified in the four Factor XII deficiency pedigrees. The two mutations g.5741-5742delCA and g.6800-6808del9bp were first found in China. FXII 6800-6808del9bp expressed in vitro suggested that almost normal proteinum synthesis but defect proteinum secretion. PMID- 23683414 TI - [FIX gene all exons sequencing technology in hemophilia B gene carriers detection and the application of prenatal gene diagnosis]. AB - OBJECTIVE: To establish a feasible protocol to provide genetic diagnosis and prenatal diagnosis in Chinese hemophilia patients and their relatives by direct exon sequencing. METHODS: In our study, genetic diagnosis was performed on 5 unrelated families with informed consent, which included 3 pregnant women who asked for prenatal diagnosis. Umbilical cord blood was obtained from 2 fetuses and amniotic fluid from another fetus. After extraction of the genomic DNA, all of the exons, exon-intron boundaries and their flanks of FIX gene were amplified by polymerase chain reaction (PCR). PCR products were detected through direct sequencing. RESULTS: Sequence analysis indicated that the patients and carriers from 5 families have the pathogenic mutations,c.1022G>A (p.R341Q), c.484 C>T (p. R162X), c.1135C>T (p.R379X), c.799C>T (p.H267Y), c.1232G>T (p.S411I), respectively. Except c.484 C>T (p. R162X), 4 of the 5 mutations were reported firstly in Chinese population. During prenatal diagnosis, one of the fetuses was found to be affected with c.484C>T; p.R162X. The remaining two fetuses were diagnosed as normal, the results of which were later verified by post-birth diagnosis, and factor FIX activities in plasma was 52.7% and 76.2%, respectively. CONCLUSION: In the quest of strict quality control, exon sequence on FIX gene was a rapid and accurate method for genetic diagnosis and prenatal diagnosis of hemophilia B. PMID- 23683416 TI - [The effect of transmission electron microscopy on diagnosis of acute myeloid leukemia]. AB - OBJECTIVE: To analyze coincidence rate of acute myeloid leukemia (AML) sub-typing between transmission electron microscopy (TEM) and clinical discharge diagnosis. METHODS: Reviewing sub-typing results of TEM, light microscopy, flow cytometric analyzing, molecular biological detection and karyotype in 793 AML cases, comparing their coincidence rates with discharge diagnosis to reveal advantages of AML sub-typing by TEM. RESULTS: General coincidence rates of TEM, light microscopy, flow cytometric analyzing, molecular biological detection and karyotype on AML sub-typing were 63%, 59%, 52%, 47%, 26% and 23% respectively, and clinical coincidence rates of TEM on M1, M2a, M4 and M5, M6, M7, t (8; 21) and t (15; 17) were 39%, 34%, 17%, 74%, 50%, 73%, 87% and 89% respectively. CONCLUSION: TEM has a higher coincidence rate in general AML sub-typing, especially strong screenings on t (15; 17), t (8; 21), M7, M5 and M6, but lower coincidence rates on M1, M2a and M4 sub-typing than other methods. PMID- 23683417 TI - [Autologous stem cell transplantation for adult patients with acute lymphoblastic leukemia and related prognostic factors]. AB - OBJECTIVE: This study was aimed to observe the efficacy of autologous stem cell transplantation (ASCT) for adult patients with acute lymphoblastic leukemia (ALL), and investigate related prognostic factors. METHODS: A total of 86 adult ALL patients underwent ASCT in Institute of Hematology and Blood Disease Hospital from November 2001 to January 2012 were followed up. Clinical characteristics and outcomes of all patients were retrospectively analyzed. Survival and univariate prognosis were analyzed by the Kaplan-Meier method and multivariate analysis by COX regression model. RESULTS: Outcomes were assessed in 81 cases, including 47 standard-risk and 34 high-risk patients. 1-, 3-, 5-, and 10-year leukemia-free survival (LFS) of standard-risk patients were (82.3+/-5.7)%, (76.9+/-6.5)%, (74.1+/-6.8)%, (67.4+/-8.9)% respectively,and relapse rates (RR) were as of (13.6+/-5.2)%, (21.6+/-6.4)%, (24.5+/-6.8)%, (31.3+/-9.0)% respectively. 1-, 3-, 5-, and 10-year LFS of high-risk patients were (55.8+/-8.9)%, (39.8+/-9.3)%, (39.8+/-9.3)%, (39.8+/-9.3)% respectively, and relapse rates (RR) were (38.8+/ 9.2)%, (56.4+/-10.0)%, (56.4+/-10.0)%, (56.4+/-10.0)% respectively. T-ALL, white blood cell count(WBC) more than 30*109/L when first visited, increased LDH, positive fusion gene of TCR and bone marrow transplantation were the adverse prognostic factors. Multivariate analysis showed bone marrow transplantation was an independent adverse prognostic factor. CONCLUSION: ASCT was a choice for adult ALL patients when suitable donors were unavailable. PMID- 23683418 TI - [Synergistic immunomodulatory effects of interferon-gamma and bone marrow mesenchymal stem cells]. AB - OBJECTIVE: To investigate mesenchymal stem cells (MSCs) immunosuppressive activity in the presence of interferon-gamma (IFN-gamma) to reveal synergistic immunomodulatory effects of IFN-gamma and MSCs. METHODS: 1 MSCs were cultured in the presence or absence of IFN-gamma(100 ng/ml), the supernatants were collected for measurements of PGE2,HGF and TGF-beta1 by ELISA kits. 2 MSCs were cultured in the presence or absence of IFN-gamma (100 ng/ml)for 48 h. The cDNA was analysed for the expression of human indoleamine 2, 3-dioxygenase(IDO)mRNA by semiquantitative RT-PCR. 3 Mononuclear cells (MNCs) were extracted from peripheral blood of healthy donors. The T cell proliferation was tested in the co culture system added with MSCs, recombinant human IFN-gamma (100 ng/ml) and anti IFN-gamma mAb (5 MUg/ml) by BrdU ELISA kit. RESULTS: 1The immunosuppressive cytokines PGE2,HGF and TGF-beta1 were detectable within 24-48 h in the supernatants. Their expressions were significantly up-regulated in the presence of IFN-gamma. Concentrations of these cytokines were as of (1715.5+/-628.6) pg/ml vs (1344.5+/-709.4) pg/ml (P=0.001);(4031.8+/-1496.8) pg/ml vs (2452.4+/-1375.3) pg/ml(P=0.011);(1753.5+/-413.8) pg/ml vs (1026.6+/-450.5) pg/ml(P<0.001),respectively. 2The expression of IDO mRNA was undetectable when MSCs were cultured alone. In contrast, The IDO mRNA expression was remarkably enhanced in the presence of IFN-gamma. 3Bone marrow-derived MSCs remarkably suppressed allogeneic T cell proliferation in vitro. Addition of exogenous IFN gamma had no significant effect on the inhibitory capacity of MSCs, the inhibitory ratios of T cell proliferation were (40.4+/-10.9)% vs(36.7+/-7.4)% (P=0.272). By contrast, the inhibitory ratio of T cell proliferation was significantly decreased in the presence of anti-IFN-gamma mAb[(40.4+/-10.9)% vs (23.9+/-7.6)%,P=0.002]. CONCLUSION: 1Human MSCs constitutively expressed immunosuppressive concentrations of PGE2, HGF and TGF-beta1, and their expressions were significantly up-regulated by IFN-gamma. 2IFN-gamma-induced expression of IDO on MSCs involved in tryptophan catabolism. 3MSCs notably suppressed allogeneic T cell proliferation in vitro. IFN-gamma promoted the immunosuppressive capacity of human MSCs, indicating the synergistic immunomodulatory effect of IFN-gamma and MSCs. PMID- 23683419 TI - [Haploidentical nonmyeloablative allogeneic peripheral blood stem cell transplantation for treatment of refractory or relapsed leukemia: long-term follow-up]. AB - OBJECTIVE: To observe the therapeutic effect and major complications of haploidentical nonmyeloablative allogeneic peripheral blood stem cell transplantation (NST) for refractory or relapsed leukemia. METHODS: The results of 30 patients, including 14 cases of acute myeloid leukemia (AML), 11 cases of acute lymphoblastic leukemia (ALL), 5 case of chronic myelogenous leukemia (CML) (accelerated and blastic phase) with refractory or relapsed leukemia (RF/RL) who underwent haploidentical NST from August 2000 to April 2009 were analyzed. The conditioning regimen consisted of fludarabine (flu), antithymocyte globulin (ATG), cyclophosphamide (CTX), total body irradiation (TBI) and cytarabine (Ara C) or myleran (Bu). Graft-versus-host disease (GVHD) prevention programmes consisted of Cyclosporine (CsA), mycophenolate mofetil (MMF), CD25 monoclonal antibody combined with mesenchymal stem cells (MSC). RESULTS: Twenty six cases of patients were full donor engraftment and 4 cases mixed chimerism into full donor chimerism. The average duration of neutrophil >0.5*108/L after NST was 11 (9-16) days, and platelet >20*108/L 17 (12-60) days. Upon follow-up of 16 to 120 months, 12-month transplant-related mortality (TRM) was 46.7%, acute II-IVgraft-versus host disease (aGVHD) incidence was 40.0%. The probability of 3-year disease relapse, EFS and overall survival (OS) rates were 16.7%, 46.2% and 50.0% respectively. CONCLUSION: Haploidentical NST could improve OS and EFS of refractory or relapsed leukemia and reducce TRM to some extent. PMID- 23683420 TI - [The relevance between quantitative and type of chromosomal abnormality and leukemia transformation in myelodysplastic syndrome]. AB - OBJECTIVE: To investigate leukemia transformation rate in myelodysplastic syndrome (MDS) and the relationship with quantitative and type of chromosomal abnormality. METHODS: This study retrospectively analyzed and rediagnosed 138 MDS patients with complete data, investigated the rate and time of leukemia transformation, and analyzed characteristics of chromosome karyotype of de novo patients. RESULTS: 29 (21.01%) of 138 patients transformed into leukemia, the rate and the median time of leukemia transformation were 21.01% and 8 (3-24) months, respectively, among which, the rate of leukemia transformation in normal karyotype, abnormal karyotype analysis of <=5 mitotic cells, and >5 mitotic cells in split phase groups were 6.2%, 23.8% and 38.5%, respectively, and median time of which were 17(13-22), 13(5-23), and 7(3-10) months, respectively. Increased trend of leukemia conversion rate along with increased quantity of chromosomal abnormality was observed (chi2=14.185, P<0.01). Leukemia transformation time negatively correlated with quantity grade of abnormal karyotype (r=-0.631, P<0.01), The leukemia transformation rates in monosomy 7/del 7q, trisomy 8, trisomy 11, complex karyotype and normal karyotype groups were 65.0%, 50.0%, 30.8% and 28.6%, being significantly different (chi2=21.555, P<0.01). Leukemia transformation rate of complex karyotype and monosomy 7/del 7 q was slightly higher than of trisomy 8 and trisomy 11, but both of them were significantly higher than of normal karyotype (chi2=8.054, P=0.005). There were no leukemia transformation cases in del 5q, del 20q, monosomy Y, and trisomy 21 group. CONCLUSION: With or without abnormal chromosome karyotype, quantity and types of abnormal karyotype had important clinical value to predict leukemia transformation in patients with MDS. PMID- 23683422 TI - [Primary bone marrow CD8 cytotoxic T-cell lymphoma coexpressed CD20: a case report and literatures review]. AB - OBJECTIVE: To report the diagnosis, differential diagnosis and treatment of a rare case of primary bone marrow CD8+ cytotoxic T-cell lymphoma coexpressed CD20. METHODS: The clinical characteristics, therapeutic course and the outcome of this patient were reviewed. Meanwhile, a series of examinations including morphology, flow cytometry, immunohistochemistry and molecular biology of bone marrow and skin samples were also performed. RESULTS: Bone marrow biopsy showed an extensive involvement by abnormal T lymphocytes. Flow cytometry and immunohistochemistry showed weakly positive CD20, CD8(+), CD2(+), CD3(+), CD5(+), TIA(+), PAX-5(-), CD4(-), CD56(-), CD57(-), CD30(-), ALK-1(-), P53(-), TdT(-), Ki-67~5%. A final diagnosis of primary bone marrow CD8+ cytotoxic T-cell lymphoma coexpressed CD20 was made. The patient initially presented a relatively indolent course was, but he was expired in the end 3 years later due to extensive involvements of skin and other organs though timely therapy was administrated. CONCLUSION: Primary bone marrow CD8 cytotoxic T-cell lymphoma coexpressed CD20 was encountered rarely in clinical practice, which might be a challenging in terms of diagnosis and differential diagnosis. Further investigation of pathogenesis and therapeutic strategies of this rare disease was warranted. PMID- 23683421 TI - [Analyses of clinical features and outcomes of 57 patients with non-gastric MALT lymphoma]. AB - OBJECTIVE: To further understand the clinical features of non-gastric mucosa associated lymphoid tissue (MALT) lymphoma and investigate its suitable treatment. METHODS: A retrospective survey of 57 non-gastric MATL lymphoma patients pathologically confirmed in our hospital from 1999 to 2011. RESULTS: The median age was 58 years (range 14-86 years). Common presenting sites of non gastric MALT lymphoma included lungs and upper respiratory tract (17 patients, 29.8%), intestinal tracts (16 patients,28.1%), orbital and ocular adnexal (7 patients, 12.3%), and salivary glands (8 patients, 14.0%). Stage I-IIdisease presented in 35 patients (61.4%), stage III-IV disease in 22 patients (38.6%). A total of 26 patients had nodal involvement and 7 patients multiple organ involvement. Regimens included surgery alone, chemotherapy alone, surgery followed by chemotherapy or chemoradiotherapy. The complete response (CR) rate was 66.0% and the overall response rate 85.7%. At a median follow-up of 52 months, the 5-year overall survival (OS) and the 5-year progression free survival (PFS) were 91.6% and 77.7%, respectively. The 5-year survival rate of surgery, chemotherapy, surgery+chemotherapy, surgery + chemotherapy + radiotherapy groups were 87.5%, 100.0%, 90.2% and 100.0%, respectively, without significant differences. The 5-year PFS of the four groups were 62.3%, 80.0%, 90.2% and 75.0% respectively. CONCLUSION: Non-gastric MALT lymphoma is characterized by disseminated onset, favorable response to treatments and good outcomes. There is no statistically significant difference in the overall survival of the various treatments. But the recurrence rate of surgery alone is relatively high (22.3%). PMID- 23683423 TI - [Improvement of detection of paternally inherited fetal mutant genes for beta globin in maternal plasma by PNA clamp]. AB - OBJECTIVE: To study improvement of detection of paternally herited fetal mutant genes for beta-globin in maternal plasma by PNA clamp to seek a noninvasive prenatal diagnostic method for beta-thalassemia. METHODS: A total of 38 maternal blood samples were collected at 7 to 20 weeks of gestation, samples in which the father carried CD41-42 mutation and mother carried normal gene or the other point mutation for beta-thalassemia were examined. The results of fetal DNA in amniotic fluid, cord blood or peripheral blood of newborns were used as the gold standard for comparison. In the study group, the total cell-free DNA was extracted from maternal plasma using QIAamp DNA Blood Mini Kit. After extraction, the total cell free DNA was separated by agarose gel (1%) electrophoresis, and the cell-free DNA with a size of 100-300 bp was retrieved from the gel slice. Then, the retrieved DNA-free cell underwent PCR amplified with a PNA clamp. The genotype was confirmed by the conventional method (reverse dot blot hybridization), and the results were compared to gold standard. Simultaneously, two control groups with different PCR procedures were set up. The PCR procedure of control group A was amplified with the extracted total cell-free DNA and PNA clamp, and the PCR procedure of control group B was amplified with the retrieved size-fractionated DNA-free cell without PNA clamp. RESULTS: Plasma samples from 38 pregnant women were detected using PCR products for hybridization, the results were compared with the gold standard. Regarding the 21 samples confirmed by gold standard with fetal genotype 41-42M/N, 19, 8, 12 cases were detected as fetal genotype 41-42M in study group, control group A and control group B respectively, the sensitivity was 90.5% (19/21), 38.1% (8/21) and 57.1% (12/21) respectively;Concerning the 17 samples confirmed by gold standard with fetal normal genotype, the amount of false positive cases were 1, 2 and 1 respectively. The respective specificity was 94.1% (16/17), 94.1% (16/17) and 88.2% (15/17) respectively. The respective accuracies were 92.1% (35/38), 63.2% (24/38) and 71.1% (27/38) respectively. The difference in sensitivity and specificity was pairwise compared by means of McNemar's test. There was significant difference between new study group and control group A or control group B (all P<0.05). CONCLUSION: The method of detection of paternally inherited fetal mutation genes for beta-thalassemia using small size of fetal DNA-free cell in maternal plasma with PNA clamp had several advantages of reliable sensitivity, specificity and accuracy, indicating its potential of clinical practicality. PMID- 23683424 TI - [p15(INK4B) methylation on prognosis and response to decitabine in patients with MDS]. AB - OBJECTIVE: To detect p15(INK4B) methylation levels and the kinetics of the methylation status before and after decitabine to explore its influences on prognosis and response to decitabine in myelodysplastic syndromes (MDS) patients. METHODS: We examined 261 MDS patients (143 male and 118 female) with the median age of 52 years (32-78). Of them, 172 cases were low-risk group (low-risk 104 cases, intermediate-1 68 cases), 89 cases high-risk group (intermediate-2 52 cases, high risk 37 cases). Collections of bone marrow mononuclear cells of MDS patients and extracted the genomic DNA, the methylation status of p15(INK4B) was detected by methylation-specific PCR (MSP) method. Survival analysis was conducted according to the level of p15(INK4B) methylation in the cohort of patients. The kinetics of the methylation levels of p15(INK4B) in 58 MDS patients before and after 2 courses of decitabine have been assessed with the method of MSP. RESULTS: The methylation level of p15(INK4B) in low-risk group patients was significantly lower than that in high-risk group (117.22 vs 157.63, P<0.05 ). The expected 2-year survival rate of p15(INK4B) methylation positive patients was lower than that of negative ones (91.8% vs 69.8%, P<0.05); the expected 2-year survival rate of p15(INK4B) methylation positive patients was shorter than that of negative ones in low-risk group(78.2% vs 92.0%, P<0.05), meanwhile there was no significant difference in terms of expected 2-year survival rate and median expected survival between p15(INK4B) methylation positive and negative patients in high-risk group [35.6% vs 38.5%, (17.0+/-9.3) month vs (18.0+/-5.7) month, P>0.05]. Multivariate analysis showed p15(INK4B) methylation degree was an independent prognostic factor for overall survival. No statistical difference of overall response (OR) rates were found between p15(INK4B) methylation positive patients and negative patients before decitabine(65.9% vs 76.5%, P>0.05), and complete remission (CR) rates between these two groups also showed no statistical difference(22.0% vs 29.4%, P>0.05). p15(INK4B) methylation levels had no obvious change before and after treatment in decitabine responders(P>0.05). CONCLUSION: The survival of newly diagnosed MDS patients with positive p15(INK4B) methylation was comparatively shorter, but p15(INK4B) methylation had no influence on response to decitabine. PMID- 23683425 TI - [The clinical study of myelodysplastic syndromes with PNH clones]. AB - OBJECTIVE: To analyze the clinical characteristics and risk factors on responses and survival of myelodysplastic syndromes (MDS) patients with paroxysmal nocturnal hemoglobinuria (PNH) clones. METHODS: The clinical data of 31 MDS cases with PNH clones from October 2004 to June 2012 were retrospectively analyzed to reveal the influence of PNH clone size on responses and survival. RESULTS: 1The chromosome karyotypes were analyzed in all patients, 23 patients with normal karyotype, 7 patients with abnormal karyotype [including 3 patients with +8, 2 Y, 1 del(7q) and 1 Xp+] and 1 patient with no mitosis. 1 patient belonged to low risk, 27 intermediate-1 risk, 2 intermediate-2 risk and 1 high-risk groups, respectively, according to IPSS. There were significantly statistical differences between responders and nonresponders in terms of infection, ANC, Reticulocyte count and IPSS (P values were 0.049, 0.006, 0.031 and 0.043, respectively). 2The overall responsive rate was 67.7%, no patients progressed to acute leukemia (AL) during median follow-up of 19 months after immunosuppressive therapy (IST). The 3 year and 5-year overall survival rates were 82.7% and 55.1%,respectively. 3According to univariate analysis,age, infection and ANC had significant influence on survival (P values were 0.050, 0.031 and 0.026, respectively). 4The PNH clone size had no significant influence on survival through univariate and COX analyses (P=0.393). CONCLUSION: MDS patients with PNH clone had less cytogenetic abnormalities, higher probability of response to IST and lower probability of progression to AL; Furthermore, the PNH clone size had no significant influence on response and survival. PMID- 23683426 TI - [The effect of the adverse events with thiopurine S-methyltransferase gene mutation on outcome of childhood acute lymphoblastic leukemia]. AB - OBJECTIVE: To investigate thiopurine S-methyltransferase (TPMT) activity and gene promoter polymorphism to probe its significance of individual chemotherapy in acute lymphoblastic leukemia (ALL) children. METHODS: HPLC method was carried out to determine TPMT activity (n=100), which activity at newly diagnosed. At the same time determination of TPMT activity in healthy children (n=180), these children come from the health care clinic. Using online primer3 software design primers, PCR products were purified. To sequence TPMT gene of the patients with clinical events(n=30). According to the method to analysis of correlation between TPMT activity and toxicity. RESULTS: The average TPMT activities were (31.72+/ 10.31) nmol.g-1Hb.h-1 and (30.70+/-9.67) nmol.g-1Hb.h-1 in ALL and healthy groups respectively, without gender differences of TPMT activities (P=0.45) in both groups. The TPMT activity with clinical events in newly diagnosed ALL patients (n=30) was (24.07+/-11.43) nmol.g-1Hb.h-1. There are significant differences of TPMT activities between severe bone marrow suppression [(20.96+/-7.24) nmol.g 1Hb.h-1] and ALL patients with clinical events groups (P<0.05). The TPMT activity of (40.46+/-8.18) nmol.g-1Hb.h-1 in recurrence children was also significantly different (P<0.05). TPMT activity in severe liver toxicity group was not significantly different (P=0. 930). Of TPMT gene sequencing in ALL patients with clinical events, only 3 children were heterozygosity mutations of TPMT*3C, while others homozygous genotype. There were significant differences of TPMT activities between heterozygosity genotype [(11.99+/-1.32) nmol.g-1Hb.h-1] and homozygous genotype groups [(24.95+/-11.32) nmol.g-1Hb.h-1] (P<0.05). There were five kinds of variations at the vicinity of the promoter region of -100 of tandem repeats (VNTR) polymorphism(*V3/*V3,*V3/*V4,*V4/*V4,*V5/*V5,*V4/*V6)without significant differences of TPMT activities among five kinds (P=0.186). CONCLUSION: TPMT activity was related to the gene polymorphism. TPMT activity determination had prognostic value and guided individualized treatment. PMID- 23683427 TI - [Molecular mechanisms of antithrombin gene mutations in 3 pedigrees with hereditary antithrombin deficiency]. PMID- 23683428 TI - [The correlation of thrombosis occurring and experimental phenotypic and genotypic in six inherited thrombophilia cases]. PMID- 23683429 TI - [Coagulation factor IX gene mutations of ten patients with hemophilia B]. PMID- 23683430 TI - [Analysis of invasive features of acute promyelocytic leukemia with central nervous system]. PMID- 23683431 TI - [Studies on expression and activity of membrane in peripheral in blood cells in patients with acute coronary syndrome]. PMID- 23683432 TI - [Clinical study of allogeneic hematopoietic stem cell transplantation for patients with leukemia failing to achieve remission with chemotherapy]. PMID- 23683433 TI - [Prevention or treatment CMV infections after allogeneic hematopoietic stem cell transplant by cytomegalovirus specific T cells]. PMID- 23683434 TI - [IDH gene mutations and acute myeloid leukemia]. PMID- 23683435 TI - [Expert consensus of diagnosis and treatment of paroxysmal nocturnal hemoglobinuria]. PMID- 23683436 TI - [G bacteria causes lethal skin and soft tissue infection in acute leukemia: two cases report]. PMID- 23683437 TI - A patient perspective. PMID- 23683438 TI - The microRNA-148/152 family: multi-faceted players. AB - MicroRNAs(miRNA) are noncoding RNAs of about 19-23 nucleotides that are crucial for many biological processes. Members of the microRNA-148/152(miR-148/152) family, which include microRNA-148a(miR-148a), microRNA-148b(miR-148b), and microRNA-152(miR-152), are expressed differently in tumor and nontumor tissues and are involved in the genesis and development of disease. Furthermore, members of the miR-148/152 family are important in the growth and development of normal tissues. Members of the miR-148/152 family regulate target genes and are regulated by methylation of CPG islands. In this review, we report recent studies on the expression of members of the miR-148/152 family, methylation of CPG islands, and their target genes in different diseases, as well as in normal tissues. PMID- 23683439 TI - Sterilising effects of pyriproxyfen on Anopheles arabiensis and its potential use in malaria control. AB - BACKGROUND: Insecticide resistance poses a major threat to current vector control campaigns. Insecticides with novel modes of action are therefore in high demand. Pyriproxyfen (PPF), a conventional mosquito pupacide, has a unique mode of action that also sterilises adult mosquitoes (unable to produce viable offspring) upon direct contact. However, the timing of PPF exposure in relation to when mosquitoes take a blood meal has an important impact on that sterilisation. This study investigated the relationship between different blood feeding and PPF exposure timings to determine the potential of PPF sterilisation in controlling Anopheles arabiensis. METHODS: Four treatment regimens were investigated: blood fed three days before PPF exposure (A), blood fed one day before PPF exposure (B), blood fed one day after PPF exposure (C) and blood fed three days after PPF exposure (D) for their impact on egg laying (fecundity) and the production of viable offspring (fertility), while the impact of PPF exposure on mosquito survival was investigated in the absence of a blood meal. All regimens and the survival study exposed mosquitoes to PPF via the bottle assay at 3 mg AI/m(2) for 30 minutes. RESULTS: Female mosquitoes that blood-fed one day prior to PPF exposure (regimen B), produced no viable offspring during that gonotrophic cycle (100% reduction in fertility). All other treatments had no significant effect. The observed reductions in fecundity and fertility were caused by the retention of eggs (97% of eggs retained, i.e. produced in the ovaries but not laid, in regimen B, p = 0.0004). Some of these retained eggs were deformed in shape. PPF exposure on mosquito survival in the absence of a blood meal was found to have no effect. CONCLUSIONS: The results presented here suggest that sterilising adult malaria vectors using PPF could form part of a malaria control strategy, taking advantage of the lack of reported resistance to PPF in mosquitoes and its unique mode of action. We propose that targeting resting mosquitoes, which are highly susceptible to PPF at low doses, is the optimal direction for developing this control tool. PMID- 23683440 TI - Selective small molecule probes for the hypoxia inducible factor (HIF) prolyl hydroxylases. AB - The hypoxia inducible factor (HIF) system is central to the signaling of low oxygen (hypoxia) in animals. The levels of HIF-alpha isoforms are regulated in an oxygen-dependent manner by the activity of the HIF prolyl-hydroxylases (PHD or EGLN enzymes), which are Fe(II) and 2-oxoglutarate (2OG) dependent oxygenases. Here, we describe biochemical, crystallographic, cellular profiling, and animal studies on PHD inhibitors including selectivity studies using a representative set of human 2OG oxygenases. We identify suitable probe compounds for use in studies on the functional effects of PHD inhibition in cells and in animals. PMID- 23683441 TI - DNA content is associated with malignancy of intracranial neoplasms. AB - OBJECTIVE: Flow cytometry has been applied to analyze the DNA-content distribution of tumors, in order to relate this to clinical and biological parameters of tumor behavior. Herewith, we investigated the value of cell cycle analysis in the characterization of intracranial lesions and its possible prognostic role. METHODS: DNA analysis was performed in tumor samples that were taken during surgery over a five year period. Diagnosed tumors were graded according to the World Health Organization 2007 classification scheme. RESULTS: Fifty-six patients were included in the study. There was a significant difference in G0/G1 phase and S-phase between low-grade and high-grade gliomas. There were 12 (57%) diploid and 9 (43%) aneuploid tumors. All aneuploid tumors were glioblastomas. Patients with G0/G1 value <= 69% and S phase value greater than 6% were associated with worse survival. As regards meningiomas, there was a significant difference in G0/G1 phase, S phase and mitoses fraction between benign and both atypical and anaplastic meningiomas. Aneuploidy was observed in the anaplastic tumors and in 2/4 atypical meningiomas. CONCLUSION: The results of the present study, showed that cell cycle analysis could differentiate low from high grade gliomas and benign from atypical/anaplastic meningiomas. Furthermore, a prognostic significance was found in glioma patients. The role of cell cycle analysis in brain tumors thus warrants further investigation. PMID- 23683442 TI - Acute fibrinous and organizing pneumonia associated with influenza A/H1N1 pneumonia after lung transplantation. AB - BACKGROUND: Immunocompromised patients, particularly after lung transplantation, are at high risk to develop atypical forms of pulmonary infections including influenza A/H1N1. Acute Fibrinous and Organizing Pneumonia (AFOP) is a special histological pattern in acute respiratory failure with high mortality. CASE PRESENTATION: We describe a 66-year-old woman with double lung transplantation in August 2009 due to end stage pulmonary fibrosis. After prolonged weaning and subsequent promising course, she developed atypical pneumonia with diffuse pulmonary infiltrates in both lungs in January 2010. Infection with influenza A/H1N1 virus was verified. The patient rapidly suffered from respiratory insufficiency and died eight days after this diagnosis. The post-mortem revealed especially in the lower parts of the lungs the classical histological pattern of pure AFOP. Molecular analyses of lung tissue were positive for influenza A/H1N1. CONCLUSION: To our knowledge we present the first case of AFOP triggered by viral infection, here proven to be influenza virus A/H1N1. Thus, also in the setting of viral infection the highly deadly differential diagnosis of AFOP must be considered. PMID- 23683443 TI - Selected papers from the 9th International Conference on Information Processing in Cells and Tissues. Editorial. PMID- 23683444 TI - Effects of esmolol, lidocaine and fentanyl on P wave dispersion, QT, QTc intervals and hemodynamic responses to endotracheal intubation during propofol induction: a comparative study. AB - BACKGROUND AND OBJECTIVES: In our study we aimed to investigate the effect of esmolol, lidocaine and fentanyl on P-wave dispersion (Pwd), QT and corrected QT (QTc) durations and hemodynamic responses to endotracheal intubation during propofol induction. METHODS: A total of eighty adult patients, American Society of Anesthesiologists (ASA) Physical Status I or II aged 18 to 60 years were included in this prospective, randomised, double-blind study. All patients had control electrocardiograms (ECGs) done before anesthesia induction. The patients were randomised into four equal groups. The control group (Group C) received saline 5mL, the esmolol group (Group E) received esmolol 0.5mg.kg(-1), the fentanyl group (Group F) received fentanyl 2MUg.kg(-1) and the lidocaine group (Group L) received lidocaine 1.5mg.kg(-1) before anesthesia induction. Anesthesia was induced with intravenous propofol. ECGs for all patients were performed during the 1(st) and 3(rd) minutes of induction, 3minutes after administration of muscle relaxant, and at 5minutes and 10minutes after intubation. Pwd and QT intervals were measured on all ECGs. QTc intervals were determined using the Bazett formula. Heart rate (HR) and mean arterial pressure (MAP) were recorded before and after induction of anesthesia, immediately after intubation, and 1, 3, 5, 7 and 10minutes after intubation. RESULTS: Compared with control, HR significantly increased in Group C, Group L and Group F after intubation. However, in Group E, there was no significant difference in HR values between control and after intubation. Compared with control, MAP significantly increased in Group C and Group L after the intubation. However, in Group E and Group F, there was no significant difference in MAP values between control and after the intubation. Compared with control, Pwd significantly increased in Group C after intubation. In Group L, Group F and Group E, there was no significant difference in Pwd values between control and after the intubation. Compared with control, QTc duration significantly increased in Group C and L after the intubation. In Group F and Group E, there was no significant difference in QTc durations between control and after the intubation. CONCLUSION: We concluded that administration of esmolol before intubation prevents tachycardia and an increase in MAP, Pwd and QTc duration caused by laryngoscopy and tracheal intubation. PMID- 23683445 TI - Identification of the lumbar interspinous spaces by palpation and verified by X rays. AB - BACKGROUND AND OBJECTIVES: Palpation has been shown to be rather inaccurate at identifying lumbar interspinous spaces in neuraxial anesthesia. The aim of this study is to assess the accuracy of the determination of the lumbar interspinous spaces by anesthesiologist's palpation using postoperative X-rays in obstetric patients. METHODS: We reviewed the anesthetic record and the post-operative abdominal X-rays of the cesarean sections. We indwelled the epidural catheter for post-operative one-shot analgesia. We included combined spinal and epidural anesthesia cases and compared the interspinous level which the anesthesiologist recorded and the epidural catheter insertion level confirmed by abdominal X-ray for each case. We also evaluated the factors (age, body weight, height, Body Mass Index, gestational age, and the type of surgery [planned / emergency]) leading to misidentification of interspinous level. RESULTS: Nine hundred and sixty seven cesarean sections were performed and a total of 835 cases were evaluated. The levels of the puncture documented by the anesthesiologists were in agreement with the actual catheter insertion levels in 563 (67%) cases. When the anesthesiologists aimed at L2-3 level, we found the catheter insertion at L1-2 in 5 cases (4.9%), none of which had any post-operative neurological deficits. No variables evaluated were significantly associated with misidentification of interspinous level by the anesthesiologists. CONCLUSIONS: There was a discrepancy between the anesthesiologists' estimation by palpation and the actual catheter insertion level shown in X-rays. It seems to be safer to choose the interspinous level L3-4 or lower in spinal anesthesia. PMID- 23683446 TI - Influence of hypnotics on cisatracurium-induced neuromuscular block. Use of acceleromyograhpy. AB - BACKGROUND AND OBJECTIVE: Different drugs, including hypnotics, may influence the pharmacodynamic effects of neuromuscular blockers (NMB). The aim of this study was to evaluate the influence of propofol and etomidate on cisatracurium-induced neuromuscular blockade. METHOD: We included 60 patients, ASA I and II, undergoing elective surgery under general anesthesia in the study and randomly allocated them into two groups, according to their hypnotic drug: GI (propofol) and GII (etomidate). Patients received intramuscular (IM) midazolam (0.1mg.kg(-1)) as premedication and we performed induction with propofol (2.5mg.kg(-1)) or etomidate (0.3mg.kg(1)), preceded by fentanyl (250mg) and followed by cisatracurium (0.1mg.kg(-1)). The patients were ventilated with 100% oxygen until obtaining a reduction of 95% or more in the adductor pollicis response amplitude, with subsequent laryngoscopy and tracheal intubation. Neuromuscular function was monitored by acceleromyograhpy. We evaluated the onset of action of cisatracurium, tracheal intubation conditions, and hemodynamic repercussions. RESULTS: The mean time and standard deviations of cisatracurium onset were: GI (86.6+/-14.3s) and GII (116.9+/-11.6s), with a significant difference (p<0, 0001). Intubation conditions were acceptable in 100% of GI and 53.3% of GII patients (p<0.0001). CONCLUSION: Induction of neuromuscular blockade with cisatracurium was faster, with better intubation conditions in patients receiving propofol compared to those receiving etomidate, without hemodynamic repercussions. PMID- 23683447 TI - Study of 0.5% lidocaine alone and combination of 0.25% lidocaine with fentanyl and vecuronium in intravenous regional anesthesia for upper limb surgeries. AB - BACKGROUND AND OBJECTIVE: Intravenous regional anesthesia (IVRA) for upper limb surgeries with traditional high dose of lidocaine can lead to life threatening side effects. In order to avoid these potential life threatening side effects, many modified techniques of IVRA have been attempted by using a low dose of lidocaine, muscle relaxant and opioid. METHOD: The present study is carried out in sixty unpremedicated ASA Class 1 and 2 patients to compare the sensory and motor characteristics, cardio-respiratory parameters and side-effects during intra-operative and post-tourniquet deflation period between the patients who received 40mL of 0.5% lidocaine alone (n=30) and those who received a combination of 40mL of 0.25% lidocaine with 0.05mg fentanyl and 0.5mg vecuronium (n=30) in IVRA for upper limb orthopedic surgeries. The results were analyzed for statistical significance using a paired student t test. RESULTS: The difference between the two groups regarding the mean time of onset and complete sensory and motor block was statistically significant. But 15 minutes after the injection of anesthetic solution, there was complete sensory and motor block in both groups. CONCLUSION: Although the short delay observed in the onset and attainment of complete sensory and motor block may theoretically delay the start of surgery for 10-15 minutes but clinically that time will be spent in the preparation of surgical field. So this combination can be used safely and effectively in intravenous regional anesthesia for upper limb orthopedic surgeries with reduced chance of local anesthetic toxicity. PMID- 23683448 TI - Effect of normal saline administration on circulation stability during general anesthesia induction with propofol in gynecological procedures - randomised controlled study. AB - BACKGROUND AND OBJECTIVE: To compare the effect of prophylactic administration of normal saline against the hypotensive effect of propofol in female patients booked for gynecological procedures. METHOD: Sixty nine ASA (I, II) patients were randomly allocated into two groups, group 1 received 5mL.kg(-1) of 0.9% normal saline 10 minutes before induction, whereas group 2 received nothing (control). Anesthesia was induced with propofol and fentanyl then maintained with propofol and remifentanil. We measured hemodynamic variables pre and post general anesthesia induction. RESULTS: Both groups had significant drops in post induction mean arterial blood pressure (P<0.001). Also both groups had significant drops in post induction heart rate ((P<0.02 in sample group and P<0.001 in control group), and 35% of patients in the control group had more than 25% drop in the pre induction mean arterial blood pressure, compared with only 17% of patients in the saline group (P<0.04). CONCLUSION: The prophylactic administration of normal saline could decrease the percentage of patients who had a significant drop in their blood pressure after propofol induction of general anesthesia. PMID- 23683449 TI - Use of simple clinical predictors on preoperative diagnosis of difficult endotracheal intubation in obese patients. AB - BACKGROUND AND OBJECTIVES: Although the incidence of difficult laryngoscopy is similar in obese and non-obese patients, there are more reports of difficult intubation in obese individuals. Alternatives for the diagnosis and prediction of difficult intubation in the preoperative period may help reduce anesthetic complications in obese patients. The aim of this study was to identify predictors for the diagnosis of difficult airway in obese patients, correlating with the clinical methods of pre-anesthetic evaluation and polysomnography. We also compared the incidence of difficult facemask ventilation and difficult laryngoscopy between obese and non-obese patients, identifying the most prevalent predictors. METHODS: Observational, prospective and comparative study, with 88 adult patients undergoing general anesthesia. In the preoperative period, we evaluated a questionnaire on the clinical predictors of the obstructive sleep apnea syndrome (OSAS) and anatomical parameters. During anesthesia, we evaluated difficult facemask ventilation and laryngoscopy. Descriptive statistics and correlation test were used for analysis. RESULTS: Patients were allocated into two groups: obese group (n=43) and non-obese group (n=45). Physical status, prevalence of snoring, hypertension, diabetes mellitus, neck circumference, and Mallampati index were higher in the obese group. Obese patients had a higher incidence of difficult facemask ventilation and laryngoscopy. There was no correlation between anatomical or clinical variable and difficult facemask ventilation in both groups. In obese patients, the diagnosis of OSAS showed strong correlation with difficult laryngoscopy. CONCLUSIONS: The clinical and polysomnographic diagnosis of OSA proved useful in the preoperative diagnosis of difficult laryngoscopy. Obese patients are more prone to difficult facemask ventilation and laryngoscopy. PMID- 23683450 TI - Combined spinal-epidural anesthesia with epidural volume extension causes a higher level of block than single-shot spinal anesthesia. AB - BACKGROUND AND OBJECTIVES: We evaluated the effects of epidural injection with levobupivacaine or serum physiologic, epidural volume extension (EVE), when using combined spinal-epidural anesthesia (CSEA) for cesarean delivery. METHODS: One hundred and thirty-eight patients with a full-term pregnancy of 37-42 weeks that were scheduled for cesarean delivery were included. Group 1 (n=48) received single-shot spinal anesthesia (SSS), group 2 (n=45) received CSEA-EVE with saline, group 3 received CSEA-EVE with levobupivacaine. The characteristics of motor and sensory block, the effects on maternal hemodynamic changes and the effects on the newborn were compared. RESULTS: Time to reach maximum sensory block was significantly shorter in groups 3 than in group 1 and 2 (p<0.05). Two segment regression time of sensory block was significantly shorter in group 1, whereas it was significantly longer in group 3 than in group 2 (p<0.05). Time to onset of motor block was significantly longer in group 1 than in groups 2 and 3 (p<0.05). Time to reach maximum motor block was significantly shorter in group 3 than in groups 1 and 2 (p<0.05). Time to recovery of motor block was significantly longer in group 3 than in groups 1 and 2 (p<0.05). The time to first analgesic was significantly longer in group 3 (p<0.05). CONCLUSIONS: Sufficient and rapid motor and sensory block was achieved in all the patients in the present study; however, motor and sensory block had faster onset, lasted longer, and was of a higher level in groups 2 and 3; these effects were more pronounced in the group 3. PMID- 23683451 TI - Application of Narcotrend(r) monitor for evaluation of depth of anesthesia in infants undergoing cardiac surgery: a prospective control study. AB - BACKGROUND AND OBJECTIVES: To investigate the clinic effectiveness, safety and feasibility of Narcotrend(r) monitor for evaluation of depth of anesthesia in congenital heart disease (CHD) infants undergoing cardiac surgery. METHODS: A total of 80 infants receiving general anesthesia in selective surgery were randomly selected. Infants were assigned into two groups (n=40 per group). In the Narcotrend group, the depth of anesthesia was monitored with the Narcotrend monitor. In the standard group, the depth of anesthesia was controlled according to the experience. The mean arterial pressure (MAP) and heart rate (HR) were determined, as well as the dose of fentanyl, muscle relaxant, recovery time and extubation time were recorded. RESULTS: In both groups, vital signs were stable during the surgery. When compared with the standard group, the MAP and HR were more stable, the total dose of fentanyl and muscle relaxant were significantly reduced and the recovery time and extubation time were markedly shortened in the Narcotrend group. CONCLUSION: The application of Narcotrend monitor was beneficial to the control of the depth of anesthesia in CHD infants receiving total intravenous anesthesia, in which small amount of narcotics can achieve optimal anesthesia. Moreover, the recovery time and extubation time are reduced and the harmful consequence such as intraoperative awareness can be avoided. PMID- 23683453 TI - Kinsbourne syndrome: case report. AB - BACKGROUND AND OBJECTIVES: Kinsbourne syndrome is a rare neurological disorder that primarily affects children previously healthy and aged between 6 and 36 months. It is characterized by opsoclonus (rapid, irregular, horizontal and vertical eye movements) and myoclonus that may affect trunk, limbs or face, and cerebellar ataxia. It may be considered a paraneoplastic syndrome by association with neuroblastomas, hepatoblastomas and, rarely, ganglioneuromas. The aim of this paper was to present the most relevant aspects of Kinsbourne syndrome, as well as the technique used for resection of mediastinal tumor in a child with this syndrome. CASE REPORT: Child, 1 year and 5 months, with a diagnosis of posterior mediastinal tumor and Kinsbourne syndrome. Premedicated with oral midazolam. Anesthesia induced with sevoflurane, nitrous oxide, fentanyl, and rocuronium. Maintenance of anesthesia with sevoflurane, nitrous oxide, fentanyl, and rocuronium. Neuromuscular block reversal with neostigmine combined with atropine. Postoperative analgesia with the use of dipyrone, morphine, and ketoprofen. Taken to the intensive care unit extubated, with stable hemodynamic and respiratory parameters. ICU discharge four days after surgery and hospital discharged on the seventh postoperative day without complications. Anatomopathological examination revealed ganglioneuroblastoma. CONCLUSIONS: Kinsbourne syndrome is a rare neurological disorder. The drugs used in our patient proved safe and allowed an uneventful anesthesia. Drugs that trigger or aggravate opsoclonus and myoclonus, such as ketamine and etomidate, should be avoided in these patients. PMID- 23683452 TI - Anesthetic management and complications of percutaneous aortic valve implantation. AB - BACKGROUND AND OBJECTIVE: Aortic stenosis is a highly prevalent and life threatening disease. In elderly patients with comorbidities, percutaneous valve implantation is an option. The aim of the study was to describe the anesthetic management and complications of general anesthesia. METHOD: Case series with 30 day and 24-month follow-ups after implantation of the CoreValve device performed at the Institute of Cardiology/University Foundation of Cardiology between December 2008 and January 2012. The patients underwent general anesthesia monitored with mean arterial pressure (PAM), electrocardiogram (ECG), pulse oximetry, capnography, transesophageal echocardiography, thermometry, and transvenous pacemaker. RESULTS: Twenty-eight patients, mean age 82.46 years, 20.98% mean EuroSCORE, functional class III/IV, successfully underwent valve implantation. Nine patients required permanent pacemaker implantation. During follow-up, two patients died: one during surgery due to LV perforation and the other on the third day of unknown causes. At 24 months, one patient diagnosed with multiple myeloma died. This anesthetic technique proved to be safe. CONCLUSION: The initial experience with percutaneous aortic valve implantation under general anesthesia has proven to be safe and effective, with no significant anesthetic complications during this procedure. PMID- 23683454 TI - Balancing the benefits and risks: lessons learned from the therapeutic interventions of a case with severe preeclampsia. AB - BACKGROUND AND OBJECTIVE: Preeclampsia is a multiple organ dysfunction syndrome (MODS) for its typical and atypical manifestations including hypertension, proteinuria, HELLP syndrome, hypertensive encephalopathy and coagulopathy. Optimal management for such patients is determined from an assessment of the balance between benefits and risks of anesthetic and obstetric therapeutic strategies. CASE REPORT: A 35-year-old pregnant woman, with one past uncomplicated pregnancy presented at 29 weeks to our medical institute as an emergency with dizziness, chest distress, palpitation, blurred vision and vaginal bleeding. After physical examination and laboratory tests, the patient was diagnosed with severe preeclampsia, HELLP syndrome, placental abruption, and MODS. The patient also presented spinal and pelvic deformity, fixation of articulus mandibularis, and tracheal displacement because of a traffic accident 11 years ago. Therefore, urgent cesarean section was performed under general anesthesia with nasal tracheal intubation using a guide wire. The patient was discharged directly home from the obstetric intensive care unit on the 7(th) postoperative day with normal blood pressure and full recovery of organic function. CONCLUSIONS: This case merits further discussion on the anesthesia considerations concerning how to make a clinical decision when treating such a patient. Neuraxial block is the first choice for preeclampsia patients undergoing cesarean section when a moderate but not progressive thrombocytopenia exists. When general anesthesia is decided, adequate sedation and analgesia is needed to better control the stress response to intubation especially in patients with neurological signs, and to prevent major cerebral complications. PMID- 23683455 TI - Fatal recrudescence of malignant hyperthermia in an infant with Moebius syndrome. AB - BACKGROUND AND OBJECTIVES: Malignant hyperthermia (MH) is a pharmacogenetic skeletal muscle disorder characterized by a hypermetabolic state after anesthesia with succinylcholine and/ or volatile anesthetics. Various neuromuscular syndromes are associated with susceptibility; however, Moebius syndrome has not been reported. Dantrolene is the drug of choice for treatment. Recurrence may occur in up to 20% of cases after the initial event treatment. CASE REPORT: Male infant, fi rst twin, 7 months old, weighing 6.5kg and presenting with Moebius syndrome was admitted for clubfoot repair. The patient had MH after exposure to sevoflurane and succinylcholine, which was readily reversed with dantrolene maintained for 24 hours. Ten hours after dantrolene discontinuation, there was recrudescence of MH that did not respond satisfactorily to treatment, and the patient died. DISCUSSION: Musculoskeletal disorders in children are associated with increased risk of developing MH, although Moebius syndrome has not yet been reported. Dantrolene is the drug of choice for treating this syndrome; prophylaxis is indicated during the fi rst 24-48 hours of the episode onset. The main risk factors for recurrence are muscular type, long latency after anesthetic exposure, and increased temperature. The child had only one risk factor. This case leads us to reflect on how we must be attentive to children with musculoskeletal disease and maintain treatment for 48 hours. PMID- 23683456 TI - The assessment of memory under total intravenous anesthesia. AB - BACKGROUND AND OBJECTIVES: In this study, we aimed to assess implicit and explicit memory in patients who had abdominal surgery under total intravenous anesthesia (TIVA) with propofol and remifentanil, in which anesthesia level was controlled by bispectral index (BIS) monitoring. METHOD: Total intravenous anesthesia was administered to 60 adult patients, to obtain BIS levels of 40-60. Patients were randomly allocated to three groups according to tapes they listened to. Patients in the category group (CT) listened to a tape containing five animal names. Patients in the word recognition group (WM) listened to a tape containing five intermediate-frequency words, adapted into Turkish. Patients in the control group (CG) listened to sea sounds until the end of surgery. Two hours after surgery, tests were administered to each patient in the recovery room to assess memory. RESULTS: There was a difference between the CT and CG groups in their Mini-Mental State Examination scores, all values were > 20. The results of the category and word recognition tests that were applied to assess implicit memory were not statistically different among the groups. There was no evidence of implicit memory in any of the patients. One patient remembered hearing 'the sound of water' as a proof of explicit memory. Eleven patients said they had dreamt. CONCLUSIONS: Although no evidence of implicit memory under adequate anesthesia with TIVA was found, one patient showed explicit memory. Although adequate depth of anesthesia provided by BIS monitoring supports our implicit memory results, it does not explain the explicit memory results. PMID- 23683457 TI - Pneumothorax after brachial plexus block guided by ultrasonography: case report. PMID- 23683458 TI - Pneumothorax after brachial plexus block guided by ultrasonography - case report. Author reply. PMID- 23683459 TI - [Post-dural puncture headache is not always trivial. Example of a chronic subdural haematoma following spinal anaesthesia for caesarean section]. PMID- 23683460 TI - [Severe toxic acute liver failure: etiology and treatment]. AB - Many substances, drugs or not, can be responsible for acute hepatitis. Nevertheless, toxic etiology, except when that is obvious like in acetaminophen overdose, is a diagnosis of elimination. Major causes, in particular viral etiologies, must be ruled out. Acetaminophen, antibiotics, antiepileptics and antituberculous drugs are the first causes of drug-induced liver injury. Severity assessment of the acute hepatitis is critical. Acute liver failure (ALF) is defined by the factor V, respectively more than 50% for the mild ALF and less than 50% for the severe ALF. Neurological examination must be extensive to the search for encephalopathy signs. According to the French classification, fulminant hepatitis is defined by the presence of an encephalopathy in the two first weeks and subfulminant between the second and 12th week after the advent of the jaundice. During acetaminophen overdose, with or without hepatitis or ALF, intravenous N-acetylcysteine must be administered as soon as possible. In the non acetaminophen related ALF, N-acetylcysteine improves transplantation-free survival. Referral and assessment in a liver transplantation unit should be discussed as soon as possible. PMID- 23683461 TI - [Ketamine, makes happy... not always in children!]. PMID- 23683462 TI - Efficient cytokine-induced IL-13 production by mast cells requires both IL-33 and IL-3. AB - BACKGROUND: IL-13 is a critical effector cytokine for allergic inflammation. It is produced by several cell types, including mast cells, basophils, and TH2 cells. In mast cells and basophils its induction can be stimulated by cross linkage of immunoglobulin receptors or cytokines. The IL-1 family members IL-33 and IL-18 have been linked to induction of IL-13 production by mast cells and basophils. In CD4 TH2 cells IL-33-mediated production of IL-13 requires simultaneous signal transducer and activator of transcription (STAT) 5 activation. OBJECTIVE: Here we have addressed whether cytokine-induced IL-13 production in mast cells and basophils follows the same logic as in TH2 cells: requirement of 2 separate signals. METHODS: By generating a bacterial artificial chromosome (BAC) transgenic IL-13 reporter mouse, we measured IL-13 production in mast cells and basophils. RESULTS: In mast cells harvested from peritoneal cavities, 2 cytokine signals are required for IL-13 production: IL-33 and IL-3. In bone marrow mast cells IL-13 production requires IL-33, but the requirement for a STAT5 inducer is difficult to evaluate because these cells require the continuous presence of IL-3 (a STAT5 activator) for survival. Poorer STAT5 inducers in culture (IL-4 or stem cell factor) result in less IL-13 production on IL-33 challenge, but the addition of exogenous IL-3 enhances IL-13 production. This implies that bone marrow-derived mast cells, like peritoneal mast cells and TH2 cells, require stimulation both by an IL-1 family member and a STAT5 inducer to secrete IL-13. Basophils follow the same rule; splenic basophils produce IL-13 in response to IL-18 or IL-33 plus IL-3. CONCLUSION: Optimal IL-13 production from mast cells and basophils requires 2 cytokine signals. PMID- 23683463 TI - Transient targeting of phosphoinositide 3-kinase acts as a roadblock in mast cells' route to allergy. AB - BACKGROUND: Tissue mast cell numbers are dynamically regulated by recruitment of progenitors from the vasculature. It is unclear whether progenitors are recruited during allergic sensitization and whether recruitment promotes allergic responses. OBJECTIVE: We sought to (1) determine the effect of mast cell recruitment on acute allergic responses and (2) to define the role of phosphoinositide 3-kinase (PI3K) isoforms in sequential steps to allergic responses. METHODS: Gene-targeted mice for PI3Kgamma or PI3Kdelta or mice treated with isoform-specific PI3K inhibitors (a novel PI3Kgamma-specific inhibitor [NVS PI3-4] and the PI3Kdelta inhibitor IC87114) were used to monitor IgE-mediated mast cell recruitment, migration, adhesion by means of intravital microscopy, degranulation, TNF-alpha release, and subsequent endothelial cell activation in vivo or in bone marrow-derived mast cells. RESULTS: Functional PI3Kgamma, but not PI3Kdelta, was crucial for mast cell accumulation in IgE-challenged skin, TNF alpha release from IgE/antigen-stimulated mast cells, and mast cell/endothelial interactions and chemotaxis. PI3Kgamma-deficient bone marrow-derived mast cells did not adhere to the endothelium in TNF-alpha-treated cremaster muscle, whereas PI3Kdelta was not required. Depletion of TNF-alpha blocked IgE-induced mast cell recruitment, which links tissue mast cell-derived cytokine release to endothelial activation and mast cell recruitment. Interference with mast cell recruitment protected against anaphylaxis and was superior to blockage of tissue mast cell degranulation. CONCLUSIONS: Interference with mast cell recruitment to exacerbated tissues provides a novel strategy to alleviate allergic reactions and surpassed attenuation of tissue mast cell degranulation. This results in prolonged drug action and allows for reduction of drug doses required to block anaphylaxis, an important feature for drugs targeting inflammatory disease in general. PMID- 23683464 TI - Diagnostic accuracy of the bronchodilator response in children. AB - BACKGROUND: The bronchodilator response (BDR) reflects the reversibility of airflow obstruction and is recommended as an adjunctive test to diagnose asthma. The validity of the commonly used definition of BDR, a 12% or greater change in FEV1 from baseline, has been questioned in childhood. OBJECTIVES: We sought to examine the diagnostic accuracy of the BDR test by using 3 large pediatric cohorts. METHODS: Cases include 1041 children with mild-to-moderate asthma from the Childhood Asthma Management Program. Control subjects (nonasthmatic and nonwheezing) were chosen from Project Viva and Home Allergens, 2 population-based pediatric cohorts. Receiver operating characteristic curves were constructed, and areas under the curve were calculated for different BDR cutoffs. RESULTS: A total of 1041 cases (59.7% male; mean age, 8.9 +/- 2.1 years) and 250 control subjects (46.8% male; mean age, 8.7 +/- 1.7 years) were analyzed, with mean BDRs of 10.7% +/- 10.2% and 2.7% +/- 8.4%, respectively. The BDR test differentiated asthmatic patients from nonasthmatic patients with a moderate accuracy (area under the curve, 73.3%). Despite good specificity, a cutoff of 12% was associated with poor sensitivity (35.6%). A cutoff of less than 8% performed significantly better than a cutoff of 12% (P = .03, 8% vs 12%). CONCLUSIONS: Our findings highlight the poor sensitivity associated with the commonly used 12% cutoff for BDR. Although our data show that a threshold of less than 8% performs better than 12%, given the variability of this test in children, we conclude that it might be not be appropriate to choose a specific BDR cutoff as a criterion for the diagnosis of asthma. PMID- 23683466 TI - Splicing defect of CD33 and inflammatory syndrome associated with occult bacterial infection. PMID- 23683465 TI - Crystal structure and immunologic characterization of the major grass pollen allergen Phl p 4. AB - BACKGROUND: Phl p 4 is a major pollen allergen but exhibits lower allergenicity than other major allergens. The natural protein is glycosylated and shows cross reactivity with related and structurally unrelated allergens. OBJECTIVE: We sought to determine the high-resolution crystal structure of Phl p 4 and to evaluate the immunologic properties of the recombinant allergen in comparison with natural Phl p 4. METHODS: Different isoallergens of Phl p 4 were expressed, and the nonglycosylated mutant was crystallized. The specific role of protein and carbohydrate epitopes for allergenicity was studied by using IgE inhibition and basophil release assays. RESULTS: The 3-dimensional structure was determined by using x-ray crystallography at a resolution of 1.9 A. The allergen is a glucose dehydrogenase with a bicovalently attached flavin adenine dinucleotide. Glycosylated and nonglycosylated recombinant Phl p 4 showed identical inhibition of IgE binding, but compared with natural Phl p 4, all recombinant isoforms displayed a reduced IgE-binding inhibition. However, the recombinant protein exhibited an approximately 10-fold higher potency in basophil release assays than the natural protein. CONCLUSION: The crystal structure reveals the compact globular nature of the protein, and the observed binding pocket implies the size of the natural substrate. Plant-derived cross-reactive carbohydrate determinants (CCDs) appear to reduce the allergenicity of the natural allergen, whereas the Pichia pastoris-derived glycosylation does not. Our results imply yet undescribed mechanism of how CCDs dampen the immune response, leading to a novel understanding of the role of CCDs. PMID- 23683467 TI - Exosome-enclosed microRNAs in exhaled breath hold potential for biomarker discovery in patients with pulmonary diseases. PMID- 23683468 TI - Body image in patients with head and neck cancer: a review of the literature. AB - OBJECTIVES: Patients with head and neck cancer have a high potential for body image disturbance due to highly visible disfigurement resulting from both the primary cancer and its treatment. The purpose of this review is to examine the conceptual framework for understanding body image in patients treated for head and neck cancer, present the current state of the science, discuss measurement issues, and identify areas for future investigation. A novel hypothetical model based on ongoing work is proposed, and it asserts that head and neck cancer therapy results in two main tumor/treatment related physical effects: (1) disfigurement and (2) dysfunction. In this model, personal, social and environmental factors moderate the effect of dysfunction and disfigurement on body image. RESULTS: A search of the empirical literature revealed a paucity of data on body image in head and neck cancers including a lack of longitudinal data as well as a lack of data on the relationship between body image disturbance and other psychosocial variables such as depression, anxiety, and social isolation over the course of treatment and throughout recovery. Additionally, the need for measurement tools specifically developed for the assessment of body image in head and neck cancer patients was identified. CONCLUSION: Prospective longitudinal studies that define the trajectory of body image issues and the mediating and moderating factors associated with body image will allow researchers to design targeted interventions to limit body image disturbance and thereby improve quality of life in patients with head and neck cancer. PMID- 23683469 TI - P53 (Pro72Arg) polymorphism associated with the risk of oral squamous cell carcinoma in gutka, niswar and manpuri addicted patients of Pakistan. AB - OBJECTIVES: The chewing habit of paan, chhaliya, and tobacco is common in the traditional culture of Pakistan. Currently, niswar, gutka and manpuri are also commercially available in the Pakistani market. Epidemiologic evidences and increased rate of oral squamous cell carcinoma (OSCC) cases may indicate a direct relationship of these chewing habits with oral carcinogenesis. The p53 gene has been known to be a tumor suppressor gene that is found mutated in common human cancers. The p53 gene contains a single nucleotide polymorphism at codon 72 of exon 4 which encodes either proline (Pro) or arginine (Arg). The aim of the present study was to investigate association of p53 gene codon 72 polymorphism with patients of oral squamous cell carcinoma consuming these carcinogenic chewable materials. MATERIALS AND METHODS: Blood and tissue samples of 260 OSCC patients were collected with informed consent from the local hospitals of Karachi. The patients were compared with controls of similar age and sex. The exon 4 of p53 gene was examined by PCR-SSCP. The tumor samples showing mobility shift were purified and sequenced. RESULTS: The C>G missense mutation at nucleotide position 215 of the coding sequence was identified which substitutes proline with arginine at codon 72 of p53 protein. When the data for CCC72CGC polymorphism was analyzed statistically, a significant difference was observed between OSCC and control samples. The Pro allelic frequencies were significantly higher in OSCC patients as compare to controls. The current study indicated the Pro form of p53 codon 72 increases the risk of developing OSCC in Pakistani population. The risk ratio for Pro allele was 1.5004 (95% confidence interval: 1.2559 to 1.7924) and odds ratio of Pro allele was 2.389 (95% confidence interval: 1.5591 to 2.8137) in comparison with the Arg and Pro alleles in the OSCC group. CONCLUSION: These evidences suggest that there may be specific genetic targets with these chewing ingredients that are responsible for causing OSCC. The p53 codon 72 polymorphism is associated with OSCC at somatic cell level but the polymorphism was not associated at inherited level. PMID- 23683470 TI - Advanced therapies for congenital heart disease: ventricular assist devices and heart transplantation. AB - Improvement in pre-, peri-, and postoperative management of congenital heart disease (CHD) has significantly increased long-term survival in children with CHD. However, there is a subset of patients with CHD who are either poor candidates for surgical palliation or in whom surgical intervention has failed and require advanced cardiac support. Heart transplant (HT) as a therapy for CHD has undergone tremendous evolution. Though transplantation remains the standard of care to improve survival and quality of life when conventional medical and surgical therapies have failed, it remains limited by the scarcity and unpredictability of donor organ availability. As such, the use of ventricular assist devices (VADs) as a bridge to transplant is gaining increasing popularity. Because of improvement in device technology, and reduced rate of VAD-related complications, the use of these devices is expanding to smaller children and more complex congenital anatomy. Challenges with VAD support and HT in the congenital heart population will be addressed in this review with focus on: (1) reasons for VAD implantation; (2) VAD support in Fontan circulation; (3) challenges with human leukocyte antigen (HLA) sensitization in HT; and (4) effect of VAD support on HT in CHD. PMID- 23683471 TI - An analysis of hiker preparedness: a survey of hiker habits in New Hampshire. AB - OBJECTIVE: Describe hiking habits in a heavily used wilderness area to better target injury prevention and reduce search-and-rescue events. METHODS: A cross sectional, convenience survey was conducted at 3 trailheads in the White Mountain National Forest of New Hampshire during summer 2011. The study group consisted of hikers who consented to a questionnaire before their trip that assessed demographics, experience, hiking gear, pretrip planning, and communication devices. RESULTS: A total of 199 hikers were surveyed. The most common age group was 20 to 29 years at 29.2% (n = 195). The most common hike was less than 12 hours at 78.5% (n = 191). All 10 items deemed essential were carried by 17.8% (n = 197) of hikers. The most common omission reason was "short trip" at 32.2% (n = 162). Defined as greater than 7 items, the 50- to 59-year-old age group was the most prepared at 56.9% (n = 51). Hiker preparedness increased with experience and fitness levels. Hikers planning trips of less than 12 hours were less prepared compared with hikers planning longer trips, at 39.3% (n = 150) and 48.8% (n = 41), respectively. GPS devices were carried by 122 of 193 hikers. Phone GPS users were less prepared than GPS-only device users at 35.8% (34 of 95) and 55.6% (15 of 27), respectively. CONCLUSIONS: One factor that may help reduce rescues is better-prepared individuals able to avoid emergency medical services activation. Most neglect of preparation results from hikers perceiving short trips as less risky. The groups most often underprepared tend to be younger, less fit, and inexperienced. Therefore, education should target younger groups and stress that all hikes, regardless of duration, carry an inherent risk. PMID- 23683472 TI - Diagnostic procedures and treatment of childhood obesity by pediatricians: 'The Dutch approach'. AB - Child Public Health professionals in the Netherlands refer obese children to a pediatrician to check for underlying causes and comorbidity. What happens to these children in terms of diagnostics and treatment when they visit a pediatrician? To get an overview of the diagnostic procedures and treatment methods a questionnaire was developed and sent to all 583 pediatricians in the Netherlands. Data was obtained of 290 pediatricians from 85% of the general hospitals and all (8) academic hospitals. To define childhood obesity Dutch pediatricians most often use the adult Body Mass Index, only 34% use the sex and age specific IOTF-BMI-criteria. 11% of the (non-obese) overweight children visiting a pediatrician have already comorbidities. All pediatricians perform at least weight and height measurements. Waist circumference is measured by only 42%, ninety-five percent measure blood pressure. To treat obese children without comorbidity thirty different intervention programs were reported. A large variation in diagnostics and interventions of childhood obesity exist. Guidelines in pediatric obesity for diagnostics and treatment are urgently needed. PMID- 23683473 TI - Developing a national medicines information strategy in Finland--a stakeholders' perspective on the strengths, challenges and opportunities in medicines information. AB - PURPOSE AND SETTING: The Finnish Medicines Agency was mandated to develop a national medicines information strategy. The objectives of this study were to assess stakeholders' views on strengths, challenges and opportunities in medicines information for the basis of the strategy. METHODS: Interviews among stakeholder representatives (n=28) from patient organizations, universities, pharmacies, and professional associations in medicine, pharmacy and nursing were conducted in 2011. Interview memos were thematically content-analysed. The draft strategy was finalized through two public hearings and a public consultation. RESULTS: Stakeholders highlighted the need to increase cooperation and coordination in medicines information. The existence of numerous quality- and evidence-based medicines information sources was identified as a strength; although the stakeholders were concerned about the fragmented and unequal access to them. The strengthening of the role of health care professionals in communicating about medicines was seen as an opportunity, but its realization requires improvements in basic and continuing education. Furthermore, the stakeholders emphasized the importance of uniform medicines information regardless of source. CONCLUSIONS: Stakeholders identified multiple strengths, challenges and opportunities in medicines information that were fundamental to developing the national medicines information strategy. An inventory of stakeholder perspectives can be recommended as a tool to support decision-making in pharmaceutical policy. PMID- 23683474 TI - A multiscale perspective on the constructal characteristics of human mobility: comment on "The emergence of design in pedestrian dynamics: locomotion, self organization, walking paths and constructal law" by Antonio F. Miguel. PMID- 23683475 TI - Predictive value of four kallikrein markers for pathologically insignificant compared with aggressive prostate cancer in radical prostatectomy specimens: results from the European Randomized Study of Screening for Prostate Cancer section Rotterdam. AB - BACKGROUND: Treatment decisions can be difficult in men with low-risk prostate cancer (PCa). OBJECTIVE: To evaluate the ability of a panel of four kallikrein markers in blood-total prostate-specific antigen (PSA), free PSA, intact PSA, and kallikrein-related peptidase 2-to distinguish between pathologically insignificant and aggressive disease on pathologic examination of radical prostatectomy (RP) specimens as well as to calculate the number of avoidable surgeries. DESIGN, SETTING, AND PARTICIPANTS: The cohort comprised 392 screened men participating in rounds 1 and 2 of the Rotterdam arm of the European Randomized Study of Screening for Prostate Cancer. Patients were diagnosed with PCa because of an elevated PSA >=3.0 ng/ml and were treated with RP between 1994 and 2004. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We calculated the accuracy (area under the curve [AUC]) of statistical models to predict pathologically aggressive PCa (pT3-T4, extracapsular extension, tumor volume >0.5cm(3), or any Gleason grade >=4) based on clinical predictors (age, stage, PSA, biopsy findings) with and without levels of four kallikrein markers in blood. RESULTS AND LIMITATIONS: A total of 261 patients (67%) had significant disease on pathologic evaluation of the RP specimen. While the clinical model had good accuracy in predicting aggressive disease, reflected in a corrected AUC of 0.81, the four kallikrein markers enhanced the base model, with an AUC of 0.84 (p < 0.0005). The model retained its ability in patients with low-risk and very-low risk disease and in comparison with the Steyerberg nomogram, a published prediction model. Clinical application of the model incorporating the kallikrein markers would reduce rates of surgery by 135 of 1000 patients overall and 110 of 334 patients with pathologically insignificant disease. A limitation of the present study is that clinicians may be hesitant to make recommendations against active treatment on the basis of a statistical model. CONCLUSIONS: Our study provided proof of principle that predictions based on levels of four kallikrein markers in blood distinguish between pathologically insignificant and aggressive disease after RP with good accuracy. In the future, clinical use of the model could potentially reduce rates of immediate unnecessary active treatment. PMID- 23683476 TI - Differences in risk factors between patterns of recurrence in patients after curative resection for advanced gastric carcinoma. AB - BACKGROUND: Recurrence patterns in patients who have undergone curative gastrectomy for advanced gastric carcinoma can be classified as peritoneal, hematogenous, or lymphatic. The aim of this study was to clarify differences in risk factors between these different types of recurrence pattern. METHODS: Postoperative courses, including sites of recurrence and periods between surgery and recurrence, of patients who had undergone curative gastrectomy for advanced gastric carcinoma (more than pT2 invasion) were surveyed in detail. Clinicopathological factors were examined as potential independent risk factors for each recurrence pattern, based on recurrence-free survival, using multivariate analysis. RESULTS: Multivariate analysis identified depth of tumor invasion (pT4 vs. pT2/3; hazard ratio (HR), 7.05; P < 0.001), number of lymph node metastases (pN2/3 vs. pN0/1; HR, 4.02; P = 0.001), and histological differentiation (G3/4 vs. G1/2; HR, 2.22; P = 0.041) as independent risk factors for peritoneal metastasis. The number of lymph node metastases (HR, 26.21; P < 0.001) and venous vessel invasion (HR, 5.09; P = 0.001) were identified as independent risk factors for hematogenous metastasis. The number of lymph node metastases (HR, 6.00; P = 0.007) and depth of tumor invasion (HR, 4.70; P = 0.023) were identified as independent risk factors for lymphatic metastasis. CONCLUSIONS: This study clarified differences in risk factors between various patterns of recurrence. Careful examination of risk factors could help prevent oversight of recurrences and improve detection of recurrences during follow-up. The number of lymph node metastases represents an independent risk factor for all three patterns of recurrence; thus, patients with multiple lymph node metastases warrant particular attention. PMID- 23683478 TI - Sixteen years of acting as editor-in-chief in Acta Dermatovenerologica Croatica. PMID- 23683480 TI - "You must not rely upon the words that very kind and beautiful girls utter, because in that regard, no offence, they all - lie":venereal diseases as a motive of Fran Gundrum's (1856-1919) work on sexual hygiene. AB - Until the works of Fran Gundrum, there was no comprehensive analysis of sexuality in Croatia. In this article, we investigate the background of Gundrum's book Sexual Health Care, the first book on sexual hygiene in Croatia. We analyzed the motivational effect venereal diseases had on writing the book, as well as the metaphoric language he used to conceptualize them. Venereal diseases are presented in his work as a consequence of irresponsible sexual behavior, and are interpreted using the analogy of natural state of English political philosopher Thomas Hobbes. All aspects of his suggestions for suppression of venereal diseases were colored by giving priority to social over individual well-being. Tradition and modernity intermix in his work, shaping him as the pioneer of sexual hygiene on our territory in the times when questions about heredity and survival of the nation started to forcefully shape public health policies. PMID- 23683477 TI - Control of arousal by the orexin neurons. AB - The orexin-producing neurons in the lateral hypothalamus play an essential role in promoting arousal and maintaining wakefulness. These neurons receive a broad variety of signals related to environmental, physiological and emotional stimuli; they project to almost every brain region involved in the regulation of wakefulness; and they fire most strongly during active wakefulness, high motor activation, and sustained attention. This review focuses on the specific neuronal pathways through which the orexin neurons promote wakefulness and maintain high level of arousal, and how recent studies using optogenetic and pharmacogenetic methods have demonstrated that the locus coeruleus, the tuberomammillary nucleus, and the basal forebrain are some of the key sites mediating the arousing actions of orexins. PMID- 23683481 TI - Endothelin-1 and its A and B receptors: are they possibly involved in vitiligo? AB - Endothelin-1 (ET-1), expressed by keratinocytes, has paracrine effects on melanocytes. The endothelin 1-axis [ET-1, endothelin A receptor (ETAR) and endothelin B receptor (ETBR)] is thought to play a role in the depigmentation process occurring in vitiligo, with no studies on the cutaneous protein expression of this axis in the disease. The aim of the present study was to compare the expression of ET-1 axis in lesional and perilesional normal epidermis of vitiligo patients with healthy controls. Ten patients with non-segmental stable vitiligo and ten healthy controls were included. Skin biopsies from all subjects were studied immunohistochemically for ET-1, ETAR and ETBR expression. No significant difference was detected in the rate of expression and the degree of staining of ET-1 axis in controls compared with each of lesional vitiligo and perilesional normal epidermis (P>0.05). There was no statistically significant difference between lesional vitiligo and perilesional normal epidermis regarding to the rates of ET-1, ETAR and ETBR expression (P=0.82, P=0.5 and P=0.99, respectively). Semi-quantitative analysis of ETAR revealed higher staining grades in lesional compared with perilesional normal epidermis, with a statistically significant difference (P=0.04). There was no statistically significant difference between the two groups regarding the staining grades of ET-1 and ETBR (P>0.05 for both markers). A highly significant positive correlation was found between ET-1 and ETAR (r =0.99, P<0.05) and between ET-1 and ETBR (r=0.87, P<0.05). The study demonstrated unaltered expression of ET-1 axis in keratinocytes in lesional vitiligo and perilesional normal epidermis. Additional studies on the differential expression of this axis in keratinocytes and melanocytes are therefore required. PMID- 23683482 TI - Frequency of onychomycoses in chronic renal failure patients undergoing hemodialysis in Porto Alegre, Brazil. AB - Onychomycosis is one of the most frequent infections affecting the fingernails or the toenails and it is caused mainly by dermatophytes. The aim of the study was to assess the frequency of onychomycoses in hemodialysis patients and to relate sex, age, duration of hemodialysis and causes of renal failure to the development of nail disorders. The study included 100 patients with chronic renal failure undergoing hemodialysis. The patients underwent detailed clinical examination of the toenails and those with any kind of clinical finding had nail scraping for mycological testing. In the study population, the frequency of onychomycosis was 39%. The most commonly isolated fungi were dermatophytes (69.23%), Candida spp. (15.38%) and nondermatophyte molds (15.38%). T. interdigitale was the most prevalent fungus followed by Candida ssp. and T. rubrum. The risk of onychomycosis increases by 1.9% for each additional year in age and diabetic patients are 88% more likely to develop onychomycosis than nondiabetic ones. The duration of hemodialysis treatment and sex were not associated with the development of onychomycosis. In conclusion, in hemodialysis patients, the frequency of onychomycosis was higher in those at advanced age and with diabetes. PMID- 23683483 TI - Biologic agents and oral diseases -- an update on clinical applications. AB - Biologic agents are targeted immune modulating agents that have been widely used in the treatment of inflammatory and neoplastic conditions with favorable results. The purpose of this review is to provide an update on the biologic agents that have been used in the treatment of diseases that affect the oral mucosa. Identification of relevant data, case reports and case series was performed using the PubMed-MEDLINE database and electronic databases of accredited organizations such as the European Medical Agency, US Food and Drug Administration, and clinicaltrials.gov (USA). According to the literature, the use of biologic agents in patients with oral diseases is limited mainly to patients suffering from refractory forms of immune-mediated diseases of the oral cavity. Biologic agents were used in all cases as off-label indications. Patient's response varied, but in general biologic agents could be considered as a therapeutic option in patients with no other alternative. A point requiring extra precaution is their safety profile because severe life threatening infections are among their side effects. Another aspect that limits their broader use is their high economic cost. We aimed to provide a practical update for the clinicians who deal with oral diseases, covering as many aspects as possible of the applications of biologic agents in oral diseases reported to date. PMID- 23683484 TI - Bullous pemphigoid with prominent milium formation. AB - Milia are very common superficial keratinous cysts, clinically seen as pearly white dome-shaped lesions with a diameter of 1-2 mm. Bullous pemphigoid (BP) is an autoimmune bullous disease characterized clinically by tense bullae on the extremities and trunk. The major target autoantigens of BP are BP180 and BP230. We report a 55-year-old Polish BP patient presenting prominent milium formation. Physical examination revealed multiple tense bullae on the erythemas scattered on the extremities and trunk. Histopathology revealed subepidermal blisters with infiltration of eosinophils in and around the blister. Direct immunofluorescence showed IgG and C3 depositions at basement membrane zone. Although indirect immunofluorescence of normal human skin sections was negative, indirect immunofluorescence of salt-split skin sections showed IgG reactivity with epidermal side. Immunoblotting showed that IgG antibodies in the serum reacted with recombinant protein of the BP180 NC16a domain. ELISA of BP180, but not BP230 and type VII collagen, showed positive results. Several months after oral prednisolone therapy, multiple large milia appeared on the healed BP lesions. Histopathology showed cysts with flaky keratinous inclusions in the mid-dermis. We diagnosed the patient as BP with milia. Since milia are occasionally found in BP, they are not a definite differential criterion from epidermolysis bullosa acquisita. PMID- 23683485 TI - Circumscribed palmar hypokeratosis -- the first case from south-east Europe. AB - Circumscribed palmar or plantar hypokeratosis (CPH) is a rare condition, usually asymptomatic, consisting of a well-demarcated erythema with central depression and hyperkeratotic border which divides it from the normal skin. We report a 77 year-old woman with a characteristic lesion of circumscribed palmar hypokeratosis on the right palm. Clinically, the lesion simulated porokeratosis of Mibelli, but histologically there was no cornoid lamella, while the characteristic depression of epidermis, with sharp stair in stratum corneum between the normal and involved skin was present. This is the first case of CPH reported in south-east Europe. After 9-year follow-up and various treatment modalities, we confirmed resistance of CPH. Since malignant transformation has been documented, careful follow-up was recommended. PMID- 23683486 TI - Human beta-defensin 4 expression in Gianotti-Crosti. AB - The Gianotti-Crosti syndrome is a relatively common children dermatosis characterized by a monomorphous erythematous papular rash limited to the face and extensor surface of the arms and legs. Although the pathogenesis is still unclear, infections are considered as the most important factor. Human beta defensins are cationic antimicrobial peptides closely related to bacterial and viral infections of many epithelia. We herein report a case of Gianotti-Crosti syndrome in a 7-year-old Caucasian girl presented with prominent eruption consisting of dome-shaped lichenoid papules on her upper and lower extremities, with spontaneous resolution. Skin biopsy revealed a dense lichenoid lymphohistiocytic infiltrate and showed strong cytoplasmic immunopositivity for human beta-defensin-4 in the stratum corneum, stratum granulosum, and stratum spinosum. Considering that beta-defensins have been described to be induced by infections, we investigated the expression of human beta-defensin-4 by immunohistochemistry in a case of Gianotti-Crosti syndrome, in order to demonstrate that it represents a cutaneous response to skin infections. PMID- 23683487 TI - Pachyonychia congenita type 2 (Jackson-Lawler syndrome) or PC-17: case report. AB - Pachyonychia congenita (PC) is a rare genodermatosis caused by mutations in any of the four genes KRT6A, KRT6B, KRT16, or KRT17, which can lead to dystrophic, thickened nails and focal palmoplantar keratoderma, among other manifestations. Although classically subdivided into two major variants, PC-1 (Jadassohn Lewandowski syndrome) and PC-2 (Jackson-Lawler syndrome), according to the localization of the mutations in the KRT6A/KRT16 or KRT6B/KRT17 genes, respectively, a classification system based on the mutant gene (PC-6a, PC-6b, PC 16 and PC-17) has been recently proposed. We report a 2-year-old female patient with a history of thickened and discolored nails, small cystic papulonodules on the central face, dry, unruly and curly hair, slight palmoplantar hyperkeratosis, and natal teeth. Both her father and paternal grandfather presented onychodystrophy, palmoplantar keratoderma, and previous excision of "sebaceous" cysts. Molecular genetic analysis of the patient revealed a missense mutation (c.1163T>C) in heterozygosity in exon 6 of the KRT17 gene, confirming the diagnosis of PC-2 (Jackson-Lawler type), or PC-17. We conclude that PC is a relatively easy and consistent clinical diagnosis, but a high index of suspicion is required if the diagnosis is to be made correctly. With this case, the authors intend to draw attention to this condition and the role of the dermatologist in the diagnosis. PMID- 23683488 TI - Serum prolactin levels in Behcet's disease. Is there a relationship between Behcet's disease and prolactin as in other autoimmune diseases? PMID- 23683489 TI - Palmar pit-like lesions as a rare presentation in epidermodysplasia verruciformis: case report. PMID- 23683490 TI - Squamous cell lung carcinoma presenting with erythema annulare centrifugum. PMID- 23683494 TI - Anticancer flavonoids are mouse-selective STING agonists. AB - The flavonoids FAA and DMXAA showed impressive activity against solid tumors in mice but failed clinical trials. They act on a previously unknown molecular target(s) to trigger cytokine release from leukocytes, which causes tumor specific vascular damage and other antitumor effects. We show that DMXAA is a competitive agonist ligand for mouse STING (stimulator of interferon genes), a receptor for the bacterial PAMP cyclic-di-GMP (c-di-GMP) and an endogenous second messenger cyclic-GMP-AMP. In our structure-activity relationship studies, STING binding affinity and pathway activation activity of four flavonoids correlated with activity in a mouse tumor model measured previously. We propose that STING agonist activity accounts for the antitumor effects of FAA and DMXAA in mice. Importantly, DMXAA does not bind to human STING, which may account for its lack of efficacy or mechanism-related toxicity in man. We propose that STING is a druggable target for a novel innate immune activation mechanism of chemotherapy. PMID- 23683495 TI - Expression of seven stem-cell-associated markers in human airway biopsy specimens obtained via fiberoptic bronchoscopy. AB - BACKGROUND: Previous reports have suggested that malignant transformations originate from adult stem cells, and may thus express the stem-cell-associated markers. The purpose of this study is to investigate the differential expression and clinical significance of seven stem-cell-associated markers (Bmi1, CD133, CD44, Sox2, Nanog, OCT4 and Msi2) in lung cancer, providing new targets for the diagnosis and treatment of lung cancer. METHODS: In this study, we evaluated the differential expression of mRNA levels seven stem-cell-associated markers by semi quantitative reverse transcription polymerase chain reaction (RT-PCR) from 112 human lung cancer and 18 non-cancer tissues obtained by bronchoscopy. We further verified the differential expression of these markers by immunohistochemistry in 50 lung cancer specimens, 30 benign inflammatory lesion tissues and 20 non-tumor adjacent lung tissues. RESULTS: With the exception of OCT4, other markers Bmi1, CD133, CD44, Sox2, Nanog and Msi2 mRNA and protein were abundantly expressed in lung cancer. Additionally, Nanog expression was highly upregulated in lung cancer tissues and rarely presented in non-cancerous lung tissues, the sensitivity and specificity of Nanog mRNA reached 63.4% and 66.7%, respectively. Nanog therefore possessed high diagnostic value, however, CD44, Bmi1 and CD133 showed poor diagnostic value in lung cancer. CONCLUSION: Nanog may serve as a promising diagnostic marker of lung cancer and potential therapeutic target in lung cancer. PMID- 23683496 TI - How does oil type determine emulsion characteristics in concentrated Na-caseinate emulsions? AB - Macroscopic properties and ensemble average diffusion of concentrated (dispersed phase 50-60 wt%) Na-caseinate-stabilised emulsions for three different oils (soybean oil, palm olein and tetradecane) were explored. On a volume fraction basis, pulsed gradient stimulated echo (PGSTE)-NMR data show that droplet dynamics for all three systems are similar within a region of the emulsion morphology diagram. The exact limits of the emulsion space depend however on which oil is considered. The reduced solubility of tetradecane in water, and Na caseinate in tetradecane, result in the stabilisation of flocs during formulation. Floc formation is not observed when soybean oil or palm olein is used under identical emulsion formulation conditions. Linear rheology experiments provide indirect evidence that the local structure and the properties of the thin film interfacial domain of tetradecane emulsions vary from those of soybean oil and palm olein emulsions. Collectively these data indicate that protein/oil interactions within a system dominate over specific oil droplet structure and size distribution, which are similar in the three systems. PMID- 23683498 TI - Association between health behaviors and cardiorespiratory fitness in adolescents: results from the cross-sectional MoMo-study. AB - PURPOSE: The aim of this study was to analyze the association between adolescent and familial health behavioral factors and cardiorespiratory fitness in German adolescent boys and girls. METHODS: This study is based on a large nationwide cross-sectional study and its substudy on physical activity and fitness of children and adolescents ("Motorik-Modul"). For 1,328 adolescents between 11 and 17 years of age, data on cardiorespiratory fitness (Physical working capacity 170, PWC(170)) and familial and adolescent health behavioral factors were collected. Health behavior was assessed using psychometric questionnaires (socioeconomic status, pubertal stage, daily physical activity, sports-club time, parental physical activity habits, etc.). A hierarchical multiple regression model was used to quantify the association between relative PWC(170) values and health behavior. RESULTS: The relationship between adolescents' health behavioral factors and cardiorespiratory fitness was stronger than the relationship between age, social status, familial health behavior and cardiorespiratory fitness. Familial health behavioral factors explained 4.1% and 2.1% of variance in cardiorespiratory fitness in girls and boys, respectively. Adolescents' health behavioral factors explained 15.2% of variance in girls and 25.7% of variance in boys. For both girls (beta = .273) and boys (beta = .400), being normal weight had the greatest effect on relative PWC(170) values. CONCLUSIONS: The difference in explained variance in cardiorespiratory fitness by familial and adolescents' health behavioral factors between girls and boys indicates that different predictors for cardiorespiratory fitness are important for girls and boys. Hence, sex specific research and interventions aimed at improving familial and adolescent health behavior may be important. PMID- 23683499 TI - Adolescents' access to their own prescription medications in the home. AB - PURPOSE: The objective of this descriptive study was to determine adolescents' access to their own medications at home, specifically prescription pain, stimulant, antianxiety, and sedative medications. METHODS: Semistructured interviews were conducted with a cohort of 501 adolescents from two southeastern Michigan school districts. Participants were asked what medications had been prescribed to them during the previous 6 months; if they had received prescription medications, they were asked in-depth questions about them, including how medications were stored and supervised at home. RESULTS: The sample was comprised of adolescents in the 8th and 9th grades, and 50.9% were male. Participants were primarily white (72.9%, n = 365) or African-American (21.6%, n = 108). Slightly less than half of the adolescents (45.9%, n = 230) reported having been prescribed medications in the previous 6 months. Of this group, 14.3% (n = 33) had been prescribed pain medications, 9.6% (n = 22) stimulants, 1.7% (n = 4) antianxiety medications, and .9% (n = 2) sedatives. In total, 57 adolescents were prescribed medications in the pain, stimulant, antianxiety, or sedative categories (including controlled medications), and the majority (73.7%, n = 42) reported that they had unsupervised access to medications with abuse potential. CONCLUSIONS: The majority of adolescents who were prescribed medications in the pain, stimulant, antianxiety, or sedative categories during the previous 6 months had unsupervised access to them at home. It is critical that clinicians educate parents and patients about the importance of proper storage and disposal of medications, particularly those with abuse potential. PMID- 23683497 TI - Activation of p53 with Nutlin-3a radiosensitizes lung cancer cells via enhancing radiation-induced premature senescence. AB - Radiotherapy is routinely used for the treatment of lung cancer. However, the mechanisms underlying ionizing radiation (IR)-induced senescence and its role in lung cancer treatment are poorly understood. Here, we show that IR suppresses the proliferation of human non-small cell lung cancer (NSCLC) cells via an apoptosis independent mechanism. Further investigations reveal that the anticancer effect of irradiation correlates well with IR-induced premature senescence, as evidenced by increased senescence-associated beta-glactosidase (SA-beta-gal) staining, decreased BrdU incorporation and elevated expression of p16(INK4a) (p16) in irradiated NSCLC cells. Mechanistic studies indicate that the induction of senescence is associated with activation of the p53-p21 pathway, and that inhibition of p53 transcriptional activity by PFT-alpha attenuates IR-induced tumor cell killing and senescence. Gain-of-function assays demonstrate that restoration of p53 expression sensitizes H1299 cells to irradiation, whereas knockdown of p53 expression by siRNA inhibits IR-induced senescence in H460 cells. Furthermore, treatment with Nutlin-3a, a small molecule inhibitor of MDM2, enhances IR-induced tumor cell killing and senescence by stabilizing the activation of the p53-p21 signaling pathway. Taken together, these findings demonstrate for the first time that pharmacological activation of p53 by Nutlin 3a can sensitize lung cancer cells to radiation therapy via promoting IR-induced premature senescence. PMID- 23683500 TI - Growth of erythroid cells from thawed unseparated cord blood in vitro without exogenous erythropoietin. AB - INTRODUCTION: Previous erythroid cell cultures have depended on added serum or erythropoietin. In this paper, the growth of erythroid cells from thawed unseparated cord blood units in vitro without serum or exogenous erythropoietin is reported. METHODS: Thawed volume-reduced cord blood was cultured in conditions designed to support the megakaryocytic lineage, with thrombopoietin and interleukins 3 and 6. Erythroid cells were detected with glycophorin A (GlyA), CD71, and benzidine (flow cytometry and immunocytochemistry). RESULTS: Nucleated and anucleated GlyA-positive, as well as benzidine-positive cells were observed from day 9. In flow cytometry, at days 0 and 9, 5.9% and 14% of all events were GlyA+, and 14% and 53% were CD71+, respectively. At days 0 and 9, 4.5% and 12% of the events were double-positive for GlyA and CD71, respectively. By day 14, the percentages of GlyA+, CD71+ and double-positive events had started to decrease (9.7%, 35%, and 5.3%, respectively). CONCLUSIONS: Erythroid cells were generated from thawed unseparated cord blood units without exogenous erythropoietin. Thawed cord blood possesses the potential for erythroid growth in vitro in a culture medium designed for other cell types. PMID- 23683501 TI - The ability of endotoxin adsorption during a longer duration of direct hemoperfusion with a polymyxin B-immobilized fiber column in patients with septic shock. AB - The patients' hemodynamic conditions of septic shock due to intra-abdominal infection were improved by the longer duration of direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX), reducing plasma endotoxins measured by the novel endotoxin detection method, named endotoxin scattering photometry (ESP) method; however, turbidimetric method could not detect endotoxins. We also observed the reduction in the endotoxin after passing through column by ESP method even after the longer duration of PMX. ESP method may more sensitively detect endotoxins than the ordinary turbidimetric method. Moreover, we demonstrated the ability of endotoxin adsorption in spite of the longer duration of PMX. PMID- 23683502 TI - Wolfgang Bargmann (1906-1978) and Heinrich von Hayek (1900-1969): careers in anatomy continuing through German National Socialism to postwar leadership. AB - None of the existing studies on the history of anatomy in National Socialism (NS) has yet explored the careers of those younger anatomists, whose professional development continued through NS times and who attained prominence in postwar German and Austrian anatomy. As they became modern anatomists' teachers and role models, the revelation that men like Wolfgang Bargmann and Heinrich von Hayek had used bodies of the executed for research in their early careers has recently led to some consternation. This study contributes to the analysis of the moral challenges inherent to a science that relies on work with "material" from human bodies and its interaction with its political environment. The results reveal that Bargmann and Hayek behaved like most other anatomists at the time, in that they used bodies of the executed for research and in that they joined the NS party or other NS political groups. As ambitious and successful young anatomists they may have felt that an early joining of NS affiliations was inevitable for the advancement of their careers. They and most of their colleagues became in some measure complicit with the NS regime. The complicated biographical realities of such luminous postwar figures as Bargmann and Hayek should lead modern anatomists to the questioning of their own ethical and political decisions in politically less demanding times. PMID- 23683504 TI - Polycystic ovary syndrome. Preface. PMID- 23683505 TI - Management of chronic hepatitis B in the Torres Strait Islands: an identified need for a comprehensive public health approach to chronic hepatitis B in remote Australian Indigenous communities. AB - We aimed to document how health service providers in the Torres Strait Island region of northern Australia respond to chronic hepatitis B, and to identify priorities for the effective clinical management of the infection. Semi structured qualitative interviews with 61 health service providers were conducted in 2011 in the Torres Strait and north Queensland region to explore issues affecting chronic hepatitis B management. Two critical issues were identified affecting the health service response to chronic hepatitis B: (i) the absence of a systems-based approach to clinically managing the infection; and (ii) variable knowledge about the infection by the health workforce. Other issues identified were competing and more urgent health priorities, the silent nature of chronic hepatitis B infection at an individual and systems level, inadequate resources and the transient health workforce. While people living in the Torres Strait region are screened, diagnosed and informed that they are infected with chronic hepatitis B, there is an ad hoc approach to its clinical management. An effective and coordinated public health response to this infection in remote and isolated Australian Indigenous communities needs to be developed and resourced. Critical elements of this response will include the development of clinical guidelines and workforce development. PMID- 23683506 TI - Cutaneous squamous cell carcinoma: defining the high-risk variant. AB - With a lifetime incidence of approximately 10% in the general population, cutaneous squamous cell carcinoma (CSCC) is the second most common type of nonmelanoma skin cancer. Most CSCCs are benign and can be completely eradicated by surgery or other dermatological procedures. There is, however, a subgroup associated with an increased likelihood of lymph node metastases and, therefore, with high morbidity and mortality. This article analyzes the various factors that define aggressive CSCC. We propose a method for defining high-risk SCC on the basis of a series of major and minor criteria. This method will allow better prognostic evaluation and enable personalized management of patients with high risk SCC, possibly leading to improved overall survival. PMID- 23683507 TI - Satisfactory response to phototherapy in pigmented purpuric dermatosis. PMID- 23683508 TI - Comparative analysis of the chloroplast proteomes of a wheat (Triticum aestivum L.) single seed descent line and its parents. AB - To understand the photosynthetic basis in a single seed descent line 10 (SSDL10) of wheat contained high ATP in leaves, the chloroplast proteome was compared to SSDL10 and its parents using a combination of 2-DE and MALDI-TOF MS and MS/MS. More than 300 protein spots could be reproducibly detected in the 2D gel. 18 spots were differentially expressed between SSDL10 and the parents, 16 of which were identified by MS with the localization in chloroplasts. These proteins are grouped into diverse functional categories, including Calvin cycle and electron transport in photosynthesis, redox homeostasis, metabolism, and regulation. In addition to Rubisco large subunit, the content of photosynthetic electron transfers such as chlorophyll a-b binding protein, ATP synthase delta subunit, ferredoxin-NADP+ oxidoreductase (FNR) was higher in SSDL10 than in its parents. Furthermore, cyclic electron transfer around photosystem I (CET) was faster in SSDL10 than in the parents. Analysis of NADPH-NBT oxidoreductase activity combined with immuno-detection further revealed that, the activity of two high molecular mass protein complexes containing FNR probably involved, the CET appeared higher in SSDL10 than in the parents. The possible mechanism for the regulative role of CET in photosynthesis in SSDL10 is discussed. PMID- 23683503 TI - Complexity of dopamine metabolism. AB - : Parkinson's disease (PD) coincides with a dramatic loss of dopaminergic neurons within the substantia nigra. A key player in the loss of dopaminergic neurons is oxidative stress. Dopamine (DA) metabolism itself is strongly linked to oxidative stress as its degradation generates reactive oxygen species (ROS) and DA oxidation can lead to endogenous neurotoxins whereas some DA derivatives show antioxidative effects. Therefore, DA metabolism is of special importance for neuronal redox-homeostasis and viability.In this review we highlight different aspects of dopamine metabolism in the context of PD and neurodegeneration. Since most reviews focus only on single aspects of the DA system, we will give a broader overview by looking at DA biosynthesis, sequestration, degradation and oxidation chemistry at the metabolic level, as well as at the transcriptional, translational and posttranslational regulation of all enzymes involved. This is followed by a short overview of cellular models currently used in PD research. Finally, we will address the topic from a medical point of view which directly aims to encounter PD. PMID- 23683510 TI - Major historical dietary changes are reflected in the dental microbiome of ancient skeletons. AB - The post-industrial lifestyle has many disadvantageous effects on our health. One of the factors is modern nutrition, which has been associated with epidemic burdens, such as obesity and cardiovascular diseases. At least two major shifts have occurred in the nutritional history of humans: the use of carbohydrate-rich diets which were adopted around 10,000 years BP due to Neolithic farming, and later the influence of industrially processed flour and white sugar after the industrial revolution in the 1850s. In a recent paper in Nature Genetics Adler et al. used a novel approach to see how these dietary changes affected the oral microbiome by analyzing the ancient microbial DNA in the calcified dental plaque from 34 early European skeletons. PMID- 23683509 TI - Down regulation of StGA3ox genes in potato results in altered GA content and affect plant and tuber growth characteristics. AB - GA biosynthesis and catabolism has been shown to play an important role in regulating tuberization in potato. Active GAs are inactivated in the stolon tips shortly after induction to tuberization. Overexpression of a GA inactivation gene results in an earlier tuberization phenotype, while reducing expression of the same gene results in delayed tuberization. In addition, overexpression of genes involved in GA biosynthesis results in delayed tuberization, while decreased expression of those genes results in earlied tuberization. The final step in GA biosynthesis is catalysed by StGA3ox1 and StGA3ox2 activity, that convert inactive forms of GA into active GA1 and GA4. In this study we cloned StGA3ox2 gene in an RNAi construct and used this construct to transform potato plants. The StGA3ox2 silenced plants were smaller and had shorter internodes. In addition, we assayed the concentrations of various GAs in the transgenic plants and showed an altered GA content. No difference was observed on the time point of tuber initiation. However, the transgenic clones had increased number of tubers with the same yield, resulting in smaller average tuber weight. In addition, we cloned the promoter of StGA3ox2 to direct expression of the GUS reporter gene to visualize the sites of GA biosynthesis in the potato plant. Finally, we discuss how changes of several GA levels can have an impact on shoot, stolon and tuber development, as well as the possible mechanisms that mediate feed-forward and feed-back regulation loops in the GA biosynthetic pathway in potato. PMID- 23683512 TI - Massively parallel sequencing reveals maternal somatic IL2RG mosaicism in an X linked severe combined immunodeficiency family. PMID- 23683511 TI - Can an airway challenge test predict respiratory diseases? A population-based international study. AB - BACKGROUND: Evidence on the longitudinal association of airway responsiveness with respiratory diseases is scarce. The best indicator of responsiveness is still undetermined. OBJECTIVE: We investigated the association of airway responsiveness with the incidence of asthma, chronic obstructive pulmonary disease (COPD), and allergic rhinitis. METHODS: We studied 3851 subjects who underwent spirometry and methacholine challenge tests both at baseline (1991 1993), when they were 20 to 44 years old, and at follow-up (1999-2002) in the European Community Respiratory Health Survey. Airway responsiveness was defined based on the methacholine dose-response slope on both occasions. Incidence rate ratios for the association of airway responsiveness with disease occurrence were computed by using Poisson regression. RESULTS: With respect to reference (slope of the fourth quintile or greater), subjects with the greatest degree of airway responsiveness (slope less than the first quintile) showed the greatest risk of developing asthma, COPD, and allergic rhinitis (incidence rate ratios of 10.82, 5.53, and 4.84, respectively; all P < .01). A low slope predicted disease occurrence, even in subjects who did not reach a 20% decrease in FEV1 at the cumulative dose of 1 mg of methacholine (PD20 >1 mg). A decrease in slope over time was an independent predictor of disease risk. CONCLUSION: Airway responsiveness predicted new-onset asthma, COPD, and allergic rhinitis. Our study supports the use of a continuous noncensored indicator of airway responsiveness, such as the slope of the methacholine dose-response curve, in clinical practice and research because it showed clear advantages over PD20. PMID- 23683513 TI - Grading local side effects of sublingual immunotherapy for respiratory allergy: speaking the same language. AB - Sublingual immunotherapy (SLIT) is increasingly used worldwide. Despite its safety being well ascertained, there is no universally accepted system to grade and classify its adverse events (AEs). According to the literature, it seems reasonable to classify and grade systemic side effects by using the previously published World Allergy Organization recommendations. On the other hand, local side effects are the most frequent with SLIT, sometimes leading to its discontinuation. Therefore grading of the severity of local side effects was perceived as necessary for the purpose of uniform reporting, classification, and quantification of this aspect. A World Allergy Organization Taskforce, after examining the available literature and the postmarketing surveillance data, proposed a clinically based grading of the severity of local AEs caused by SLIT. The use of the Medical Dictionary for Regulatory Activities nomenclature for AEs was also included in this context. The proposed grading system for SLIT-induced local reactions is expected to improve and harmonize surveillance and reporting of the safety of SLIT. PMID- 23683514 TI - Enhanced production of IL-17A in patients with severe asthma is inhibited by 1alpha,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion. AB - BACKGROUND: TH17 cells are proposed to play a role in the pathology of asthma, including steroid-resistant (SR) disease. We previously identified a steroid enhancing function of vitamin D in patients with SR asthma in restoring the impaired response to steroids for production of the anti-inflammatory cytokine IL 10. OBJECTIVE: We sought to investigate the production of the TH17-associated cytokines IL-17A and IL-22 in culture in patients with moderate-to-severe asthma defined on the basis of their clinical response to steroids and the susceptibility of this response to inhibition by steroids and the active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 (1,25[OH]2D3). METHODS: PBMCs were stimulated in culture with or without dexamethasone and 1,25(OH)2D3. A cytometric bead array, ELISA, and intracellular cytokine staining were used to assess cytokine production. The role of CD39 in inhibition of the TH17 response was studied by using quantitative real-time PCR, flow cytometry, and addition of the antagonist POM-1 to culture. RESULTS: Asthmatic patients synthesized much higher levels of IL-17A and IL-22 than nonasthmatic control subjects, with patients with SR asthma expressing the highest levels of IL-17A. Glucocorticoids did not inhibit IL-17A cytokine expression in patients and enhanced production in cultures from control subjects. Treatment with 1,25(OH)2D3 with or without dexamethasone significantly reduced both IL-17A and IL-22 levels. An antagonist of the ectonucleotidase CD39 reversed 1,25(OH)2D3-mediated inhibition of the IL 17A response. CONCLUSION: Patients with severe asthma exhibit increased levels of TH17 cytokines, which are not inhibited by steroids. 1,25(OH)2D3 inhibits TH17 cytokine production in all patients studied, irrespective of their clinical responsiveness to steroids, identifying novel steroid-enhancing properties of vitamin D in asthmatic patients. PMID- 23683515 TI - Outcomes of total hip arthroplasty in human immunodeficiency virus-positive patients. AB - Today, patients with human immunodeficiency virus (HIV) live long enough to develop chronic degenerative and HIV-associated joint disease. There is a growing population of patients infected with HIV who are candidates for total hip arthroplasty (THA). A total of 31 HIV-positive, non-hemophilic patients undergoing 41 THAs at our institution between 2000 and 2012 were identified. In hospital medical complications were reported in 5 of 41 hips, all of which resolved prior to discharge. Deep infection developed in 1 of 41 hips and revision was required in 3 of 41 hips. These results suggest that low rates of complications and revision can be achieved in the HIV-positive, non-hemophilic population. We believe that with careful patient selection, THA may improve the quality of life in the HIV-positive population. PMID- 23683516 TI - Hip osteonecrosis: does prior hip surgery alter outcomes compared to an initial primary total hip arthroplasty? AB - The purpose of this study was to assess the clinical and radiographic outcomes of total hip arthroplasty (THA) in patients who had osteonecrosis to see if prior hip preserving surgery affected outcomes. Implant survivorship, Harris hip scores, and radiographic outcomes were compared between 87 patients (92 hips) who had undergone prior hip preserving procedures and 105 patients (121 hips) who had only undergone THA. Patients were also sub-stratified into low- and high-risk groups for osteonecrosis. At a mean follow-up of 75 months, there were no significant differences in survivorship, clinical, and radiographic outcomes among the cohorts. Higher revision rates were associated with patients who were in the high-risk group. The authors believe that hip joint preserving procedures may not adversely affect the outcomes of later THA in patients with osteonecrosis. PMID- 23683517 TI - Clinical outcomes of patients with non-fatal VTE after total knee arthroplasty. AB - Venous thromboembolism (VTE) continues to be one of the most important, and highly controversial, topics in orthopaedics. While many surgeons have discussed the incidence and treatment of this potentially life-threatening complication, little has been published about the clinical outcomes of patients who receive treatment and recover from these conditions. We evaluated the clinical outcomes of patients who suffered non-fatal VTE and compared them to a matched cohort with no complications after total knee arthroplasty using our institution's joint arthroplasty registry. At two years, the patient-reported clinical outcomes were equivalent between the groups. While VTE remains an important consideration in total knee arthroplasty, it is helpful for surgeons to know that patient outcomes are not negatively affected after appropriate treatment of these complications. PMID- 23683518 TI - Comparison of mechanical stress and change in bone mineral density between two types of femoral implant using finite element analysis. AB - Stress shielding after total hip arthroplasty (THA) remains an unsolved issue. Various patterns of mechanical stress appear according to the type of femoral stem used. To compare differences in mechanical stress conditions between Zweymuller type and fit-and-fill type stems, finite element analysis (FEA) was performed. Differences in bone mineral density (BMD) changes in the femur were also compared. Maximum stress was confirmed in Gruen zone 4, whereas zone 1 had the minimum amount of stress with both types of implant. The Zweymuller stem group had less mechanical stress and lower BMD in zone 7 than the fit-and-fill stem group. In conclusion, differences in mechanical stress may be related to changes in BMD after THA. PMID- 23683519 TI - Total knee arthroplasty with an uncemented trabecular metal tibial component: a registry-based analysis. AB - Previous poor results have kept the appeal of uncemented total knee arthroplasties (TKAs) minimal. We analyzed the mid-term survivorship and reasons for failures of a contemporary uncemented porous tantalum monoblock tibial component nation-wide. During the study period (2003-2010), such tibial components were used in 1143 primary TKAs recorded in the Finnish Arthroplasty Registry. Seven-year survivorship of these TKAs was 100% (95% CI 99-100) with revision for aseptic loosening of the tibial component, and 97% (95% CI 96-98) with revision for any reason as the respective end points. The most common reasons for revisions were instability and prosthetic joint infections. In conclusion, TKAs using an uncemented porous tantalum monoblock tibial component showed excellent mid-term survivorship in a population-based setting. PMID- 23683520 TI - Structure- and sequence-analysis inspired engineering of proteins for enhanced thermostability. AB - Protein engineering strategies for increasing stability can be improved by replacing random mutagenesis and high-throughput screening by approaches that include bioinformatics and computational design. Mutations can be focused on regions in the structure that are most flexible and involved in the early steps of thermal unfolding. Sequence analysis can often predict the position and nature of stabilizing mutations, and may allow the reconstruction of thermostable ancestral sequences. Various computational tools make it possible to design stabilizing features, such as hydrophobic clusters and surface charges. Different methods for designing chimeric enzymes can also support the engineering of more stable proteins without the need of high-throughput screening. PMID- 23683521 TI - Whole-lake nitrate addition for control of methylmercury in mercury-contaminated Onondaga Lake, NY. AB - Methylmercury (MeHg) strongly bioaccumulates in aquatic food webs resulting in exposure to humans and wildlife through consumption of fish. Production of MeHg is promoted by anaerobic conditions and the supply of inorganic Hg (Hg(2+)), sulfate (SO4(2-)), and labile organic carbon. The anaerobic sediments of stratified lakes are particularly active zones for methylation of Hg(2+) and can be an important source of MeHg to the water column during summer anoxia and fall turnover. Nitrate (NO3(-)) addition has recently been proposed as a novel approach for the control of MeHg accumulation in the hypolimnia of Hg contaminated lakes. In 2011, a whole-lake NO3(-) addition pilot test was conducted in Hg-contaminated Onondaga Lake, NY with the objective of limiting release of MeHg from the pelagic sediments to the hypolimnion through maintenance of NO3(-)-N concentrations >1mgN/L. A liquid calcium-nitrate solution was added to the hypolimnion as a neutrally buoyant plume approximately three times per week during the summer stratification interval. Maximum hypolimnetic concentrations of MeHg and soluble reactive phosphorus (SRP) decreased 94% and 95% from 2009 levels, suggesting increased sorption to Fe and Mn oxyhydroxides in surficial sediments as the regulating mechanism. Increased MeHg concentrations in the upper waters during fall turnover, which had been a generally recurring pattern, did not occur in 2011, resulting in decreased exposure of aquatic organisms to MeHg. Over the 1992-2011 interval, the hypolimnetic NO3(-) supply explained 85% and 95% of the interannual variations in hypolimnetic accumulations of SRP and MeHg, respectively. PMID- 23683522 TI - Mercury in food items from the Idrija Mercury Mine area. AB - As a consequence of over 500 years of mining and smelting activities (1490-1995), and of its natural geological occurrence, the soil in the Idrija region is highly contaminated with Hg. In order to assess the present situation regarding the Hg levels in local food samples, concentrations of total mercury (THg) and monomethyl mercury (MeHg) were determined in selected vegetables, mushrooms and fish from the Idrija Hg mine area. Hg levels in the foodstuffs analysed were not very high but were elevated compared to the levels in food from non-contaminated areas. The study showed that THg accumulates in mushrooms (X=5680ng/g dry weight, Min=346ng/g dry weight, Max=17,100 dry weight) and chicory (X=1950ng/g dry weight, Min=86ng/g dry weight, Max=17,100ng/g dry weight). In addition, Se and Cd concentrations were determined by ICP-MS in those vegetable and mushroom species in which the highest Hg levels were found. The levels of Cd and Se were below the threshold levels. Based on data from previous studies, we can conclude that the levels of Hg in food have not diminished significantly during the past 15 years after closure of the Hg mine. Special attention should be given to vegetables such as chicory, representing a local seasonal vegetable eaten frequently. PMID- 23683523 TI - Mechanisms of axonal dysfunction in diabetic and uraemic neuropathies. AB - The global burden imposed by metabolic diseases and associated complications continue to escalate. Neurological complications, most commonly peripheral neuropathy, represent a significant cause of morbidity and disability in patients with diabetes and chronic kidney disease. Furthermore, health care costs are substantially increased by the presence of complications making investigation into treatment a matter of high priority. Over the last decade nerve excitability techniques have entered the clinical realm and enabled in vivo assessment of biophysical properties and function of peripheral nerves in health and disease. Studies of excitability in diabetic neuropathy have demonstrated alteration in biophysical properties, including changes in Na(+) conductances and Na(+)/K(+) pump function, which may contribute to the development of neuropathic symptoms. Interventional studies have demonstrated that these changes are responsive to pharmacological agents. Excitability studies in patients with chronic kidney disease have demonstrated prominent changes that may contribute to the development of uraemic neuropathy. In particular, these studies have demonstrated strong correlation between hyperkalaemia and the development of nerve dysfunction. These studies have provided a basis for future work assessing the benefits of potassium restriction as a therapeutic strategy in this condition. PMID- 23683524 TI - Can enoxaparin reduce thromboembolism related events after primary TKA in Asian patients? AB - The purpose of this study was to investigate the efficacy and safety of enoxaparin in preventing venous and arterial thromboembolism related events after primary total knee arthroplasty (TKA) in Asian patients. Four hundred twenty nine patients (621 TKAs) did not receive thromboprophylaxis after TKA and 907 patients (1,336 TKAs) received enoxaparin after the procedure. We assessed clinically significant venous and arterial thromboembolism related events and bleeding complications. Total thromboembolism related events occurred in 13 patients (3.03%) without thromboprophylaxis and 17 patients (1.87%) with enoxaparin (P = 0.183). Our study showed that the incidence of clinically significant thromboembolism related events after TKA was very low in Asian patients. Enoxaparin had no benefits in reducing thromboembolism related events in Asian patients. PMID- 23683525 TI - Revision of ceramic head fracture after third generation ceramic-on-ceramic total hip arthroplasty. AB - We performed 24 revisions of fractures of third generation ceramic heads. The stem was not changed in 20 revisions; a new ceramic-on-ceramic bearing was used in four and a metal-on-polyethylene bearing in 16. The stem was changed in four revisions; a new ceramic-on-ceramic bearing was used in three and a metal-on polyethylene bearing in one. During the follow-up of 57.5 months, complications occurred in five hips among the 20 stem retained revisions: a fracture of the new ceramic head in two, metallosis with pseudocyst in two, and femoral osteolysis with stem loosening in one. However, there were no complications in the four revisions where the stem was changed. Revision surgery after ceramic head fracture shows high rates of early complications. We recommend stem revision in cases of THA failure due to fracture of a modern ceramic head. PMID- 23683526 TI - Enhancement of light output power of GaN-based light-emitting diodes with photonic quasi-crystal patterned on p-GaN surface and n-side sidewall roughing. AB - In this paper, GaN-based light-emitting diodes (LEDs) with photonic quasi-crystal (PQC) structure on p-GaN surface and n-side roughing by nano-imprint lithography are fabricated and investigated. At an injection current of 20 mA, the LED with PQC structure on p-GaN surface and n-side roughing increased the light output power of the InGaN/GaN multiple quantum well LEDs by a factor of 1.42, and the wall-plug efficiency is 26% higher than the conventional GaN-based LED type. After 500-h life test (55 degrees C/50 mA), it was found that the normalized output power of GaN-based LED with PQC structure on p-GaN surface and n-side roughing only decreased by 6%. These results offer promising potential to enhance the light output powers of commercial light-emitting devices using the technique of nano-imprint lithography. PMID- 23683527 TI - Impaired odor identification in children with histories of heavy prenatal alcohol exposure. AB - Prenatal alcohol exposure can lead to behavioral and cognitive impairments across multiple domains. Many of the brain regions impacted by prenatal alcohol exposure are also linked with olfactory processing, and odor identification deficits have been documented in certain neurological disorders associated with these brain regions. As odor identification following prenatal alcohol exposure is not well studied, we compared odor identification in children with prenatal exposure to alcohol (AE) to typically developing controls (CON) (N = 16/group). It was hypothesized that children in the AE group would perform more poorly than children in the CON group on the San Diego Odor Identification Test, an identification test of 8 common household odorants. Children exposed to alcohol during prenatal development were significantly impaired in olfactory identification (M = 5.95, SE = 0.37) compared to typically developing controls (M = 7.24, SE = 0.37). These findings confirmed the hypothesis that prenatal exposure to alcohol is associated with odor identification deficits, and suggest that further research is warranted to identify the mechanisms underlying these deficits, the integrity of brain areas that are involved, and to determine whether olfactory performance might contribute to better identification of children at risk for behavioral and cognitive deficits. PMID- 23683528 TI - Effects of different exercise protocols on ethanol-induced spatial memory impairment in adult male rats. AB - Chronic ethanol consumption is often accompanied by numerous cognitive deficits and may lead to long-lasting impairments in spatial learning and memory. The aim of the present study was to evaluate the therapeutic potential of regular treadmill exercise on hippocampal-dependent memory in ethanol-treated rats. Spatial memory was tested in a Morris Water Maze task. Adult male Wistar rats were exposed to ethanol (4 g/kg, 20% v/v for 4 weeks) and effects of three exercise protocols (pre-ethanol, post-ethanol and pre-to-post-ethanol treatment) were examined. Results showed that ethanol exposure resulted in longer escape latencies during the acquisition phase of the Morris Water Maze task. Moreover, all three exercise protocols significantly decreased the latency to locate the hidden platform. During the probe trial, ethanol led to decreased time spent in the target quadrant. In contrast, performance on the probe trial was significantly better in the rats that had done the post- and pre-to-post-ethanol, but not pre-ethanol, exercises. These findings suggest that treadmill running can attenuate the adverse effects of chronic ethanol exposure on spatial memory, and may serve as a non-pharmacological alcohol abuse treatment. PMID- 23683529 TI - Cardiovascular autonomic modulation by nitric oxide synthases accounts for the augmented enalapril-evoked hypotension in ethanol-fed female rats. AB - In this study, we investigated the role of nitric oxide synthase (NOS) isoforms in the enhanced enalapril-evoked hypotension in ethanol-fed female rats by examining the effect of the selective inhibitors of eNOS [N(5)-(1-iminoethyl)-l ornithine; l-NIO], nNOS (N(omega)-propyl-l-arginine; NPLA), or iNOS (1400W) inhibition on the cardiovascular effects of enalapril in ethanol- (5% w/v) fed rats and in their pair-fed controls. In liquid diet-fed control rats, enalapril- (10 mg/kg) evoked hypotension was abolished by l-NIO (20 mg/kg), but not by NPLA (1 mg/kg) or 1400W (5 mg/kg), suggesting a preferential role for eNOS in this response. Enalapril had no effect on spectral indices of hemodynamic variability or +dP/dtmax (myocardial contractility). However, in ethanol-fed rats, the greater enalapril-evoked hypotension was associated with reductions in (i) +dP/dtmax, (ii) low-frequency/high-frequency ratio of interbeat intervals (IBILF/HF), suggesting cardiac parasympathetic dominance, and (iii) low-frequency spectral band of systolic blood pressure (BP), a marker of vasomotor sympathetic tone. While NPLA or 1400W attenuated the enalapril-evoked hemodynamic and autonomic responses in ethanol-fed rats, l-NIO virtually abolished the hypotensive response and was more efficacious in rectifying autonomic responses to enalapril. Together, these findings implicate NOS isoforms, particularly eNOS, in the altered cardiovascular autonomic control that leads to the augmented enalapril-evoked hypotension in ethanol-fed female rats. PMID- 23683532 TI - Does sow reproduction and piglet performance benefit from the addition of n-3 polyunsaturated fatty acids to the maternal diet? AB - Good sow reproductive performance and piglet survival are essential for the profitability of the pig industry. Based on basic research of fatty acid and endocrine metabolism, it has been suggested that dietary supplementation with n-3 polyunsaturated fatty acids (PUFA) could enhance reproductive outcome. However, proper requirements for these nutrients in sow diets have not been established. This review examines the literature on the effect of n-3 PUFA in the maternal diet on sow reproduction and piglet performance. Few reported studies have included biochemical analyses, e.g. eicosanoid concentrations or gene expression data, which could help elucidate any link between dietary n-3 PUFA supplementation and reproduction. Additionally, most studies used relatively low numbers of pigs, limiting the validity of the conclusions which can be drawn. In pregnant pigs, supplementing with n-3 PUFA has not been shown to increase significantly the number of embryos (in gilts) or (in most studies) the total number of piglets born (live and/or stillborn), but may prolong gestation, although the literature is not consistent. Most studies found no effect of n-3 PUFA on piglet birth weight, although positive effects on piglet vitality and pre and post-weaning growth have been reported. In contrast to the impact during pregnancy, low amounts of n-3 PUFA in the lactation diet may increase litter size in the subsequent gestation. PMID- 23683531 TI - Load-bearing properties of minimal-invasive monolithic lithium disilicate and zirconia occlusal onlays: finite element and theoretical analyses. AB - OBJECTIVE: The aim of this study was to test the hypothesis that monolithic lithium disilicate glass-ceramic occlusal onlay can exhibit a load-bearing capacity that approaches monolithic zirconia, due to a smaller elastic modulus mismatch between the lithium disilicate and its supporting tooth structure relative to zirconia. METHODS: Ceramic occlusal onlays of various thicknesses cemented to either enamel or dentin were considered. Occlusal load was applied through an enamel-like deformable indenter or a control rigid indenter. Flexural tensile stress at the ceramic intaglio (cementation) surface-a cause for bulk fracture of occlusal onlays-was rigorously analyzed using finite element analysis and classical plate-on-foundation theory. RESULTS: When bonded to enamel (supported by dentin), the load-bearing capacity of lithium disilicate can approach 75% of that of zirconia, despite the flexural strength of lithium disilicate (400MPa) being merely 40% of zirconia (1000MPa). When bonded to dentin (with the enamel completely removed), the load-bearing capacity of lithium disilicate is about 57% of zirconia, still significantly higher than the anticipated value based on its strength. Both ceramics show slightly higher load bearing capacity when loaded with a deformable indenter (enamel, glass-ceramic, or porcelain) rather than a rigid indenter. SIGNIFICANCE: When supported by enamel, the load-bearing property of minimally invasive lithium disilicate occlusal onlays (0.6-1.4mm thick) can exceed 70% of that of zirconia. Additionally, a relatively weak dependence of fracture load on restoration thickness indicates that a 1.2mm thin lithium disilicate onlay can be as fracture resistant as its 1.6mm counterpart. PMID- 23683530 TI - Adalimumab in active ulcerative colitis: a "real-life" observational study. AB - BACKGROUND AND AIMS: The effectiveness of adalimumab in the treatment of ulcerative colitis is under debate. Although controlled trials have shown that adalimumab is significantly better than placebo, the absolute clinical benefit is modest. We report data on the effectiveness of adalimumab in a cohort of ulcerative colitis patients treated in 22 Italian centres. METHODS: All patients with active disease treated with adalimumab were retrospectively reviewed. Co primary endpoints were clinical remission at weeks 4, 12, 24 and 54. Secondary endpoints were sustained clinical remission, steroid discontinuation, endoscopic remission and need for colectomy. RESULTS: Eighty-eight patients were included. Most patients had received previous infliximab treatment. Clinical remission rates were 17%, 28.4%, 36.4% and 43.2% at 4, 12, 24 and 54 weeks respectively. Twenty-two patients required colectomy. Clinical remission and low C-reactive protein at week 12 predicted clinical remission at week 54 (OR 4.17, 95% CI 2.36 19.44; OR 2.63, 95% CI 2.32-14.94, respectively). Previous immunosuppressant use was associated with a lower probability of clinical remission at week 54 (OR 0.67, 95% CI 0.08-0.66) and with a higher rate of colectomy (HR 9.7, 95% CI 1.46 9.07). CONCLUSION: In this large "real-life" experience adalimumab appears effective in patients with otherwise medically refractory ulcerative colitis. Patients achieving early remission can expect a better long-term outcome. PMID- 23683533 TI - A review of terminology for equine juvenile osteochondral conditions (JOCC) based on anatomical and functional considerations. AB - This manuscript describes a new classification of the various joint-related lesions that can be seen in the young, growing horse based on their anatomical and functional aetiopathogenesis. Juvenile osteochondral conditions (JOCC) is a term that brings together specific disorders according to their location in the joint and their biomechanical origin. When a biomechanical insult affects the process of endochondral ossification different types of osteochondrosis (OC) lesions may occur, including osteochondral fragmentation of the articular surface or of the periarticular margins, or the formation of juvenile subchondral bone cysts. In severe cases, osteochondral collapse of the articular surface or the epiphysis or even an entire small bone may occur. Tension on ligament attachments may cause avulsion fractures of epiphyseal (or metaphyseal) ossifying bone, which are classified as JOCC, but do not result from a disturbance of the process of endochondral ossification and are not therefore classified as a form of OC. The same applies to 'physitis' which can result from damage to the physeal growth plate. PMID- 23683534 TI - Compensatory load redistribution in walking and trotting dogs with hind limb lameness. AB - This study evaluated adaptations in vertical force and temporal gait parameters to hind limb lameness in walking and trotting dogs. Eight clinically normal adult Beagles were allowed to ambulate on an instrumented treadmill at their preferred speed while the ground reaction forces were recorded for all limbs before and after a moderate, reversible, hind limb lameness was induced. At both gaits, vertical force was decreased in the ipsilateral and increased in the contralateral hind limb. While peak force increased in the ipsilateral forelimb, no changes were observed for mean force and impulse when the dogs walked or trotted. In the contralateral forelimb, the peak force was unchanged, but the mean force significantly increased during walking and trotting; vertical impulse increased only during walking. Relative stance duration increased in the ipsilateral hind limb when the dogs trotted. In the contralateral fore and hind limbs, relative stance duration increased during walking and trotting, but decreased in the ipsilateral forelimb during walking. Analysis of load redistribution and temporal gait changes during hind limb lameness showed that compensatory mechanisms were similar regardless of gait. The centre of mass consistently shifted to the contralateral body side and cranio-caudally to the side opposite the affected limb. These biomechanical changes indicate substantial short- and long-term effects of hind limb lameness on the musculoskeletal system. PMID- 23683535 TI - The optimal duration of vitamin supplementation prior to the first dose of pemetrexed in patients with non-small-cell lung cancer. AB - Although folic acid and vitamin B12 supplements are recommended during pemetrexed therapy, the optimal duration for supplementation prior to the first dose of pemetrexed has not been defined. We analyzed adverse events during the first cycle of pemetrexed therapy in 350 patients with advanced non-small-cell lung cancer (NSCLC) who had received pemetrexed monotherapy. Patients were divided into two groups: group A and group B included patients who started vitamin supplements 5-14 days versus within 4 days before the first dose of pemetrexed, respectively. Groups A and B included 294 (84.0%) and 56 (16.0%) patients, respectively. The median number of cycles of pemetrexed was three in both groups. Patients in group A and B showed similar rates of leukopenia (6.1% vs. 5.4%, respectively, P = 1.00), neutropenia (5.1% vs. 3.6%, P = 1.00), thrombocytopenia (3.1% vs. 7.1%, P = 0.14), neutropenic fever (0.7% vs. 0%, P = 1.00), fatigue (20.1% vs. 19.6%, P = 0.94), and anorexia (15.0% vs. 21.4%, P = 0.23) during the first cycle of pemetrexed therapy. There were no significant differences in terms of hospitalization (4.4% vs. 5.4%, P = 0.73) or unscheduled visits due to pemetrexed-related adverse events (8.2% vs. 12.5%, P = 0.31) between groups A and B, respectively. Multivariate logistic regression analysis demonstrated that an age of >= 65 years (odds ratio, 3.49; 95% CI 1.12-10.86) and poor performance status (odds ratio, 3.96; 95% CI 1.12-14.03) were statistically significant predictive factors for grade 3 or 4 hematologic toxicity. The duration of vitamin supplementation before the first dose of pemetrexed did not affect the development of pemetrexed-related toxicities, suggesting that the initiation of pemetrexed-based chemotherapy does not have to be delayed to accommodate a vitamin supplementation schedule. PMID- 23683536 TI - Rapid increase of serum neuron specific enolase level and tachyphylaxis of EGFR tyrosine kinase inhibitor indicate small cell lung cancer transformation from EGFR positive lung adenocarcinoma? AB - We report the case of an 80-year-old male with relapsed EGFR exon 19 deletion lung adenocarcinoma treated with EGFR-tyrosine kinase inhibitor (TKI), but with poor response and rapid increase of serum neuron specific enolase (NSE). Repeat biopsy identified pathological transformation to small cell lung cancers (SCLC) retaining the same EGFR mutation. This case highlights routine serological testing of NSE may benefit for the lung adenocarcinoma patients resistant to TKIs. PMID- 23683537 TI - Coexistence of EGFR mutation and ALK translocation in NSCLC: literature review and case report of response to gefitinib. AB - The coexistence of EGFR and ALK-EML4 gene mutations represents a rare event (about 1%) in patients with non small cell lung cancer (NSCLC) and the few cases described in the literature have all been treated by different methods. We present the case of a 52-year-old woman with adenocarcinoma of the lung whose tumor had this double genetic aberration. The patient was immediately treated with gefitinib because the tumor was judged inoperable, but after two months she obtained an important clinical remission and was submitted to radical surgery. She is currently undergoing adjuvant treatment with gefitinib. A review of the literature on this double genetic aberration highlighted that further research is needed to define the best therapeutic approach. PMID- 23683538 TI - Risk factors predicting posttraumatic stress reactions in adolescents after 2011 Van earthquake. AB - OBJECTIVE: Our aims were to investigate the prevalence of PTSD, depression, anxiety-related disorders, and dissociative symptomotology, and to assess the risk factors for development of psychopathology among children and adolescents after the 2011 Van earthquake in Turkey. METHODS: The screening was conducted among 738 participants at 6months post-earthquake using the CPTSD-Reaction Index, State and Trait Anxiety Inventory for Children, Screen for Child Anxiety Related Emotional Disorders, Child Depression Inventory, Childhood Anxiety Sensitivity Index, Metacognitions Questionnaire for Children, and Adolescent Dissociative Experiences Scale. RESULTS: Less than half (40.69% of) of the participants reported severe levels of PTSD symptoms, 53.04% were at greater risk for developing an anxiety-related disorder, 37.70% met the criteria for clinical depression, and 36.73% revealed pathological levels of dissociative symptomotology. State-trait anxiety, and anxiety sensitivity were significant antecedents of psychopathology. CONCLUSION: We concluded that anxiety sensitivity is a significant risk factor in various types of psychopathology, but metacognitions seem to have a limited utility in accounting for poor psychological outcomes in young survivors of earthquake. PMID- 23683539 TI - Current practice in paediatric hypospadias surgery; a specialist survey. AB - AIM: To undertake an online survey of current hypospadias surgery practice among those specialists attending the IVth World Congress of the International Society for Hypospadias and Disorders of Sex Development (ISHID), 2011. MATERIALS AND METHODS: An online survey covering 22 separate questions relating to proximal and distal hypospadias surgery was set up, and all delegates registered for the conference were invited to complete this questionnaire anonymously. The data was analysed by three of the authors. RESULTS: A total of 162 delegates registered for the conference of whom 74% were paediatric surgeons, paediatric urologists, plastic surgeons and adult/adolescent urologists. 93 delegates completed the online survey, and most of them (57%) were from Europe. The majority of surgeons see over 20 new patients/year (90%) and perform primary hypospadias surgery in over 20 patients/year (76%). The tubularized incised plate (TIP) repair is the most frequent technique used for the management of distal hypospadias (59%); other techniques used included Mathieu, onlay and TIP with graft. A variety of techniques are used for proximal hypospadias, but nearly half of the respondents (49%) preferred a staged approach. Self reported complication rates for distal hypospadias surgery are favourable (less than 10%) for 78% of the respondents. However, proximal hypospadias complication rates are higher. CONCLUSIONS: With a majority of paediatric urologists and European delegates responding to our survey, the results suggest that there are differences in the management of proximal and distal hypospadias between surgeons, yet no differences were observed according to the region of their practice. Variations in long-term outcomes appear to be in keeping with the current literature. PMID- 23683540 TI - Acute dyskinetic reaction in a healthy toddler following methylphenidate ingestion. AB - BACKGROUND: Acute dyskinetic or dystonic reactions are a long-recognized complication of medications that alter dopamine signaling. Most reactions occur following exposure to agents that block dopamine receptors (e.g., neuroleptics). However, agents that increase dopaminergic transmission (such as methylphenidate) can also trigger acute dyskinesias. This has been previously reported only in patients also taking dopamine antagonists or, less commonly, in children with developmental abnormalities. CASE DESCRIPTION: The present report describes a previously healthy toddler who developed transient torticollis and orolingual dyskinesias following accidental exposure to methylphenidate. He had no preexisting movement disorder, central nervous system injury, or developmental abnormalities--in short, none of the previously reported risk factors for this side effect. HYPOTHESIS AND CONCLUSIONS: The unique features of this case led to the hypothesis that developmental shifts in dopamine signaling were the basis for his particular sensitivity to methylphenidate. If confirmed, this hypothesis has implications for the treatment of common childhood attentional and behavioral disorders. The article includes a literature review of dyskinetic/dystonic reactions in children and the developmental regulation of dopamine metabolism. PMID- 23683541 TI - Evaluation of the child with acute ataxia: a systematic review. AB - Evaluation of acute ataxia in a child poses a dilemma for the clinician in determining the extent and timing of initial screening tests. This article reviews the evidence concerning the diagnostic yield of commonly ordered tests in evaluating the child with acute ataxia. The literature revealed the following frequencies of laboratory screening abnormalities in children with acute ataxia: CT (~2.5%), MRI (~5%), lumbar puncture (43%), EEG (42%), and toxicology (49%). In most studies, abnormalities detected by these screening tests were nondiagnostic. There are insufficient data to assess yields of testing for autoimmune disorders or inborn errors of metabolism. A toxicology screen should be considered in all children presenting with acute ataxia. Neuroimaging should be considered in all children with new onset ataxia. Cerebrospinal fluid analysis has limited diagnostic specificity unless clinically indicated. Studies to examine neurophysiology testing did have sufficient evidence to support their use. There is insufficient evidence to establish a role for autoantibody testing or for routine screening for inborn error of metabolism in children presenting with acute ataxia. Finally, in a child presenting with ataxia and opsoclonus myoclonus, urine catecholamine testing for occult neuroblastoma is recommended. Nuclear scan may be considered, however, there is insufficient evidence for additional body imaging. PMID- 23683542 TI - THY1 is a surface marker of porcine gonocytes. AB - Gonocytes are important for the study of spermatogenesis. Identification and isolation of gonocytes has been reported in rodents but not in pigs due to a lack of molecular markers for gonocytes. The objective of this study was to identify THY1 expression in porcine testicular tissue and subsequently utilise THY1 as a marker to isolate and enrich porcine gonocytes from testes of newborn piglets. Immunohistochemical analysis showed that THY1 was expressed in gonocytes. Double immunofluorescent analysis of THY1 and ZBTB16 indicated that THY1 and ZBTB16 were partially co-localised in gonocytes. Double-immunofluorescent analysis of both THY1 and GATA4 suggested that THY1(+) cells were not Sertoli cells. Magnetic activated cell sorting of THY1(+) cells yielded a cell population with an enrichment of UCHL1(+) gonocytes 3.4-fold of that of the unsorted testicular cell population. Western blot and quantitative reverse transcription-polymerase chain reaction analyses confirmed that the selected THY1(+) fraction had a higher expression of UCHL1 than the unsorted cells. In conclusion, the study demonstrated that THY1 is a surface marker of gonocytes in testes of pre-pubertal boars and could be utilised to identify and isolate porcine gonocytes. The findings will also facilitate culture and manipulation of male germline stem cells. PMID- 23683543 TI - Difference vectors to describe dynamics of the ST segment and the ventricular gradient in acute ischemia. AB - BACKGROUND: The ECG is important in the diagnosis and triage of the acute coronary syndrome (ACS), especially in the hyperacute phase, the "golden hours," during which myocardial salvage possibilities are largest. An important triaging decision to be taken is whether or not a patient requires primary PCI, for which, as mentioned in the guidelines, the presence of an ST elevation (STE) pattern in the ECG is a major criterion. However, preexisting non-zero ST amplitudes (diagnostic, but also non-diagnostic) can obscure or even preclude this diagnosis. METHODS: In this study, we investigated the potential diagnostic possibilities of ischemia detection by means of changes in the ST vector, DeltaST, and changes in the VG (QRST integral) vector, DeltaVG. We studied the vectorcardiograms (VCGs) synthesized of the ECGs of 84 patients who underwent elective PTCA. Mean+/-SD balloon occlusion times were 260+/-76s. The ECG ischemia diagnosis (ST elevation, STE, or non-ST-elevation, NSTE), magnitudes and orientations of the ST and VG vectors, and the differences DeltaST and DeltaVG with the baseline ECG were measured after 3min of balloon occlusion. RESULTS: Planar angles between the DeltaST and DeltaVG vectors were 14.9+/-14.0 degrees . Linear regression of DeltaVG on DeltaST yielded DeltaVG=324.DeltaST (r=0.85; P<0.0001, DeltaST in mV). We adopted DeltaST>0.05mV, and the corresponding DeltaVG>16.2mV.ms as ischemia thresholds. The classical criteria characterized the ECGs of 46/84 (55%) patients after 3min of occlusion as STE ECGs. Combined application of the DeltaST and DeltaVG criteria identified 73/84 (87%) of the patients as ischemic. CONCLUSION: Differential diagnosis by DeltaST and DeltaVG (requiring an earlier made non-ischemic baseline ECG) could dramatically improve ECG guided detection of patients who urgently require catheter intervention. PMID- 23683544 TI - Is the addition of vasopressin to norepinephrine beneficial for the treatment of septic shock? PMID- 23683545 TI - Does the absence of cardiac activity on ultrasonography predict failed resuscitation in cardiac arrest? PMID- 23683546 TI - Do vasopressors improve outcomes in patients with cardiac arrest? PMID- 23683547 TI - Of stroke and biomarkers: the elusive quest for a clinical biomarker panel. PMID- 23683548 TI - Role of the laboratory in diabetes diagnosis and screening--the 2013 CDA CPGs. PMID- 23683549 TI - Site-specific cancer risk in the Baltic cohort of Chernobyl cleanup workers, 1986 2007. AB - OBJECTIVE: To assess site-specific cancer risk in the Baltic cohort of Chernobyl cleanup workers, 1986-2007. METHODS: The Baltic cohort includes 17,040 men from Estonia, Latvia and Lithuania who participated in the environmental cleanup after the accident at the Chernobyl Nuclear Power Station in 1986-1991 and who were followed up for cancer incidence until the end of 2007. Cancer cases diagnosed in the cohort and in the male population of each country were identified from the respective national cancer registers. The proportional incidence ratio (PIR) with 95% confidence interval (CI) was used to estimate the site-specific cancer risk in the cohort. For comparison and as it was possible, the site-specific standardised incidence ratio (SIR) was calculated for the Estonian sub-cohort, which was not feasible for the other countries. RESULTS: Overall, 756 cancer cases were reported during 1986-2007. A higher proportion of thyroid cancers in relation to the male population was found (PIR=2.76; 95%CI 1.63-4.36), especially among those who started their mission shortly after the accident, in April-May 1986 (PIR=6.38; 95%CI 2.34-13.89). Also, an excess of oesophageal cancers was noted (PIR=1.52; 95% CI 1.06-2.11). No increased PIRs for leukaemia or radiation related cancer sites combined were observed. PIRs and SIRs for the Estonian sub cohort demonstrated the same site-specific cancer risk pattern. CONCLUSION: Consistent evidence of an increase in radiation-related cancers in the Baltic cohort was not observed with the possible exception of thyroid cancer, where conclusions are hampered by known medical examination including thyroid screening among cleanup workers. PMID- 23683550 TI - Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma--results and treatment recommendations from the Childhood Liver Tumour Strategy Group (SIOPEL) experience. AB - PURPOSE: Fibrolamellar hepatocellular carcinoma (FL-HCC) and conventional hepatocellular carcinoma (HCC) cases in two consecutive paediatric HCC trials were analysed to compare outcome and derive treatment implications. PATIENTS AND METHODS: Data of 24 FL-HCC (24% PRETEXT IV) and 38 HCC (42% PRETEXT IV) cases from SIOPEL-2 and -3 (1995-1998, 1998-2006) were analysed. Patients were treated according to SIOPEL-2 and -3 high-risk protocol (carboplatin+doxorubicin alternating with cisplatin; seven preoperative, three postoperative cycles) or with primary surgery followed by chemotherapy as indicated. RESULTS: Thirteen of 24 FL-HCC (54%) and 32/38 HCC (84%) were initially treated with chemotherapy. Eight FL-HCC (33%) and five HCC patients (13%) had primary surgery. Partial response was observed in 31% of FL-HCC versus 53% of HCC patients (p=0.17). Complete resection was achieved in ten FL-HCC and seven HCC patients (p=0.08). Three-year event free survival (EFS) was 22% for FL-HCC versus 28% for HCC. Overall survival (OS) was not significantly different at 3 years follow up (42% for FL-HCC versus 33% for HCC, p=0.24). EFS/OS Kaplan-Meier curves did not differ significantly, with median follow up of 43 (FL-HCC) and 60 (HCC) months. No significant correlation was found between potential prognostic factors and OS. In the entire cohort nine out of 23 (39%) patients with complete resection or orthotopic liver transplantation versus 34/39 (87%) without successful surgical treatment, died. CONCLUSIONS: Long-term OS in FL-HCC and HCC is similar. With low response rates, complete resection remains the treatment of choice. PMID- 23683551 TI - Ovarian cancer: Ion channel and aquaporin expression as novel targets of clinical potential. AB - Ovarian cancer is associated with limited overall survival, due to problems in early detection and therapy. Membrane ion channels have been proposed to play a significant, concerted role in the cancer process, from initial proliferation to metastasis, and promise to be early, functional biomarkers. We review the evidence for ion channel and aquaporin expression and functioning in human ovarian cancer cells and tissues. In vitro, K(+) channels, mainly voltage-gated, including Ca(2+)-activated channels, have been found to control the cell cycle, as in other cancers. Voltage-gated, volume-regulated and intracellular Cl(-) channels have been detected in vitro and in vivo and shown to be involved in proliferation, adhesion and invasion. Evidence for 'transient receptor potential', voltage-gated sodium and calcium channels, which have been shown to contribute to pathogenesis of other carcinomas, is also emerging in ovarian cancer. Aquaporins may be involved in cell growth, migration and formation of ascites via increased water permeability of micro-vessels. It is concluded that functional expression of ion channels and their regulation by steroid hormones and growth factors are an integral part of ovarian cancer development and progression. Furthermore, ion channels may be involved in multidrug resistance, commonly associated with treatment of ovarian cancer. We propose that ion channel studies can facilitate our understanding of the pathobiology of ovarian cancer and, ultimately, can serve as viable novel targets for its clinical management. PMID- 23683552 TI - Seasonal variation in glycoconjugates of the pedal glandular system of the rayed Mediterranean limpet, Patella caerulea (Gastropoda: Patellidae). AB - Glycoconjugates secreted by the pedal system of the rayed limpet, Patella caerulea, were characterised in situ by histochemical and lectin-histochemical methods in individuals collected around the annual cycle, in November, March, and June. Stainings with periodic acid-Schiff (PAS), Alcian blue pH 2.5 (AB pH 2.5), Alcian blue pH 1.0 (AB pH 1.0), high-iron diamine-Alcian blue pH 2.5 and lectin binding assays with 9 lectins (Con A, WGA, succinylated-WGA, PNA, DBA, SBA, AAA, UEA-I, LTA) were performed. Four secreting cell types were observed in the sole, one in the peripheric region, and two in the sidewall. Glycoconjugate composition varied among cell types and also in one and the same cell type throughout the year. beta-Elimination followed by PAS and AB pH 2.5 stainings indicated that most saccharidic chains were O-linked to the protein backbone. Secretion by sole and peripheric region was acidic, carboxylated and/or sulfated, whereas that of the sidewall was neutral. Glucosaminylated and 1,4-fucosylated residuals were predominant in the cell types along the year, 1,2-fucosylated residuals being observed only in the sidewall cells in June. Mannosylated and/or glycosylated residuals were observed in all cells mostly in November. Galactosylated/galactosaminylated residuals were present mostly in the sidewall cells and in the sole subepidermal mucocytes in June. Mannosylated and/or glycosylated residuals in November are probably linked to gonad maturation or to higher locomotion and foraging activity, whereas galactosaminylation in the sole cells and 1,2-fucosylation and glucosaminylation in the sidewall cells in June are linked to a prolonged stationary state, increasing water adsorption to counteract dehydration and/or to modulate microbial interactions. PMID- 23683553 TI - Are there too many or too few physicians in Spain? Is emigration the timeless resource. AB - At the end of the last century, several Spanish doctors had to migrate overseas looking for a decent job. No decent jobs were offered by then in Spain. Last decade, the lack of doctors was a problem and a great social alarm was born. Mechanisms to attract doctors form overseas and medical training, both uncontrolled, were settled in, to get the numbers right. The result was a surplus of qualified health professionals. Today, overseas doctors who were invited to come and native doctors, both, trained for specific health situations have to leave the country. An extraordinary planning never heard of in neighbouring countries due to its "inefficiency". It was characteristic its lack of capability to take advantage of health professional's abilities - doctors and nurses-, its lack of population's health education, its waste of resources in training and its uncontrolled immigration. PMID- 23683554 TI - Attitudes of young adults from the UK towards organ donation and transplantation. AB - BACKGROUND: This study examines the attitudes of young British adults towards donating their own organs and those of their family members. METHODS: An opportunity sample of 119 participants (65 female) completed an attitude questionnaire. RESULTS: Most participants were in favour of donation though substantially fewer had signed up to the organ donation register. A minority of participants was aware of the proposed opt-out system for donation. CONCLUSIONS: The results from this study corroborate and extend previous work in that more participants were prepared to receive an organ than donate one. Knowing someone who had donated an organ was associated with a more positive attitude towards donation. Implications for policy are discussed. PMID- 23683555 TI - A meta-analysis of continuous vs intermittent infusion of loop diuretics in hospitalized patients. AB - BACKGROUND: Several studies have examined the potential benefits of continuous vs intermittent (bolus) intravenous loop diuretic administration in hospitalized patients with conflicting results. We conducted a meta-analysis to compare the efficacy of these 2 strategies in hospitalized adults and children with extracellular fluid volume expansion. METHODS: We searched MEDLINE (through October 2012) and prior meta-analyses for randomized controlled trials comparing the efficacy of continuous vs intermittent infusion of loop diuretics. Random effects model meta-analyses were performed to examine several outcomes, including net change in urine output and body weight. RESULTS: We identified 7 crossover and 11 parallel-arm randomized controlled trials (936 patients) of adults and children. In the 15 studies of adults, continuous loop diuretic infusion resulted in a nonsignificant net increase in daily urine output of 334 mL (95% confidence interval [CI], -74 to 742; P = .11) relative to the bolus infusion. In the 8 studies that used a loading dose, continuous loop diuretic infusion resulted in a significant net increase in daily urine output of 294 mL (95% CI, 31-557; P = .03) relative to the intermittent infusion. There was also a significant net decrease in body weight of 0.78 kg (95% CI, -1.54 to -0.03; P = .04) in the continuous relative to the intermittent loop diuretic infusion. In the 3 studies of children, there was no demonstrable effect on daily urine output or body weight. CONCLUSION: Continuous infusion of loop diuretics preceded by a loading dose results in greater diuresis in hospitalized adults with extracellular fluid volume expansion compared with intermittent dosing regimens. Further studies are required to examine whether these benefits translate into improved clinical outcomes. PMID- 23683556 TI - Clinical model for predicting prolonged mechanical ventilation. AB - INTRODUCTION: Mechanical ventilation (MV) predisposes patients to numerous complications, which increases with longer durations of treatment. Identifying individuals more likely to require prolonged MV (PMV) may alter ventilation strategies or potentially minimize the duration of therapy and its associated complications. Our aim was to identify clinical variables at the time of intubation that could identify individuals who will require PMV. METHODS: One hundred thirty consecutive adult patients requiring MV support in a medical intensive care unit (ICU)were retrospectively assessed. Prolonged MV was defined as MV support more than 14 days. RESULTS: Mean age was 62.3+/-21.1 years, 64.6% were men, and mean duration of MV support was 11.4+/-11.9 days. Prolonged MV was required in 31.3%. Requiring intubation after admission to the ICU, heart rate greater than 110, blood urea nitrogen more than 25 mg/dL, serum pH less than 7.25, serum creatinine more than 2.0 mg/dL, and a HCO3 less than 20 mEq/L were the only variables independently associated with PMV. Specificity for predicting PMV was 100% with 4 or more of these variables. CONCLUSION: The novel predictive model, using Intubation in the ICU, Tachycardia, Renal dysfunction, Acidemia, elevated Creatinine, and a decreased HCO3, was highly specific in identifying patients who subsequently required PMV support and performed better than Acute Physiology Age Chronic Health Evaluation III. PMID- 23683557 TI - Augmented renal clearance is a common finding with worse clinical outcome in critically ill patients receiving antimicrobial therapy. AB - INTRODUCTION: We describe incidence and patient factors associated with augmented renal clearance (ARC) in adult intensive care unit (ICU) patients. MATERIALS AND METHODS: A prospective observational study in a mixed cohort of surgical and medical ICU patients receiving antimicrobial therapy at the Ghent University Hospital, Belgium. Kidney function was assessed by the 24-hour creatinine clearance (Ccr); ARC defined as at least one Ccr of >130 mL/min per 1.73 m2. Multivariate logistic regression analysis: to assess variables associated with ARC occurrence. Therapeutic failure (TF): an impaired clinical response and need for alternate antimicrobial therapy. RESULTS: Of the 128 patients and 599 studied treatment days, ARC was present in 51.6% of the patients. Twelve percent permanently expressed ARC. ARC patients had a median Ccr of 144 mL/min per 1.73 m2 (IQR 98-196). Median serum creatinine concentration on the first day of ARC was 0.54 mg/dL (IQR 0.48-0.69). Patients with ARC were significantly younger (P<.001). Age and male gender were independently associated with ARC whereas the APACHE II score was not. ARC patients had more TF (18 (27.3%) vs. 8 (12.9%); P=.04). CONCLUSION: ARC was documented in approximately 52% of a mixed ICU patient population receiving antibiotic treatment with worse clinical outcome. Young age and male gender were independently associated with ARC presence. PMID- 23683558 TI - Effect of intraoperative dobutamine on splanchnic tissue perfusion and outcome after Whipple surgery. AB - PURPOSE: Splanchnic hypoperfusion during abdominal surgery contributes to postoperative gut sepsis and mortality. Dobutamine is an inotrope with vasodilator properties that improve hepatosplanchnic perfusion. The aim of this study was to examine the effect of intraoperative dobutamine infusion during Whipple surgery on splanchnic perfusion, hemodynamic, and overall postoperative outcome. METHODS: Sixty patients were randomly allocated to receive intraoperatively (3 MUg/kg per minute or 5 MUg/kg per minute) doses of dobutamine or saline. Baseline measurements included hemodynamic parameters, gastric tonometric parameters, and arterial and mixed venous gases. These patients had a follow-up for development for in-hospital morbidity and mortality. RESULTS: Intraoperative use of dobutamine increased oxygen-derived parameters as evidenced by increased mixed venous oxygen saturation. Tonometered gastric mucosal pH, a surrogate for splanchnic perfusion, increased in patients who received intraoperative dobutamine. Patients in the dobutamine groups demonstrated significant higher heart rates, premature ventricular contraction arrhythmias, and electrocardiographic signs of ischemia. Mean arterial blood pressure demonstrated no significant difference among groups. The overall incidence of postoperative complications was higher in control group 70 % vs 20% to 40% in dobutamine groups. CONCLUSION: Intraoperative use of dobutamine improved global oxygen delivery, splanchnic perfusion, and postoperative outcome after Whipple surgery. These findings may be of clinical importance when the therapeutic goal is to improve gut perfusion. PMID- 23683559 TI - Team coordination during cardiopulmonary resuscitation. PMID- 23683560 TI - Current oxygen management in mechanically ventilated patients: a prospective observational cohort study. AB - PURPOSE: Oxygen (O2) is the most common therapy in mechanically ventilated patients, but targets and dose are poorly understood. We aimed to describe current O2 administration and titration in such patients in an academic intensive care unit. MATERIALS AND METHODS: In consecutive ventilated (>48 hours) patients we prospectively obtained fraction of inspired O2 (FiO2), pulse oximetry O2 saturation (SpO2) and arterial O2 tension (PaO2) every 6 hours. We calculated the amount of excess O2 delivery and the intensivists' response to hyperoxemia (SpO2>98%). RESULTS: During 358 mechanical ventilation days in 51 critically ill patients, median calculated excess O2 delivery was 3472 L per patient. Patients spent most of their time with their SpO2>98% (59% [29-83]) and PaO2 between 80 and 120 mm Hg (59% [38-72]). In addition, 50% of all observations showed hyperoxemia and 4% severe hyperoxemia (PaO2>202.5 mm Hg). Moreover, 71% of the calculated total excess 263,841 L of O2 was delivered when the Fio2 was 0.3 to 0.5. When hyperoxemia occurred with an Fio2 between 0.3 and 0.4, for 88% of episodes, no Fio2 adjustments were made. CONCLUSIONS: Excess O2 delivery and liberal O2 therapy were common in mechanically ventilated patients. Current O2 therapy practice may be suboptimal and further investigations are warranted. PMID- 23683561 TI - Impact of older age and nursing home residence on clinical outcomes of US emergency department visits for severe sepsis. AB - PURPOSE: The purpose of this study is to compare the impact of older age and nursing home residence on the incidence and morbidity of severe sepsis. MATERIALS AND METHODS: This was a retrospective analysis of 19460 emergency department visits from the 2005 to 2009 National Ambulatory Medical Care Surveys with diagnosis of infection with or without severe sepsis (acute organ dysfunction). Clinical outcomes included intensive care unit (ICU) admission, hospital length of stay (LOS), and in-hospital mortality. RESULTS: Older adults (age>=65 years) were 5-fold more likely to have infections classified as severe sepsis than younger adults (6.5% vs 1.3%), and nursing home residents were 7-fold more likely to have a severe sepsis diagnosis compared with nonnursing home residents (14% vs 1.9%). Among visits for severe sepsis, older adults, compared with younger adults, had modestly higher rates of ICU admission (27% vs 21%), hospital LOS (median, 6 vs 5 days), and in-hospital mortality (24% vs 16%). Nursing home residents with severe sepsis, compared with nonnursing home residents, had significantly higher rates of ICU admission (40% vs 21%), hospital LOS (median, 7 vs 5 days), and in-hospital mortality (37% vs 15%). CONCLUSIONS: Older adults and particularly nursing home residents have a disproportionately high incidence of and morbidity from severe sepsis. PMID- 23683562 TI - Procollagen type III aminoterminal propeptide as biomarker of host response in severe sepsis. AB - PURPOSE: The purpose of this study is to test the hypothesis that procollagen type III aminoterminal propeptide (PIIINP) is early elevated in septic episodes and can indicate the acute organ dysfunction/failure characterizing severe sepsis. MATERIALS AND METHODS: This prospective study included 107 consecutive septic patients (44 with sepsis, 13 with severe sepsis, and 50 with septic shock) and 45 controls. After blood sampling (within 48 hours after onset of septic episodes), serum was assayed. Patients were followed up, and their disease severity was daily evaluated. RESULTS: Procollagen type III aminoterminal propeptide (median [range]) increased in patients with sepsis (9.4 [2.2-42.4] ng/mL) compared with controls (3.6 [1.9-4.9] ng/mL; P<.001), exhibiting further significant increase in patients with severe sepsis and septic shock (19.5 [6.0 52.4] and 20.2 [1.8-89.2] ng/mL, respectively; P<.01-.001 vs sepsis). Among biomarkers of host response severity, PIIINP was the sole that was independently associated with severe sepsis/septic shock (P=.01). The area under the receiver operating characteristic curve for PIIINP to predict which patients with sepsis would eventually develop severe sepsis/septic shock was 0.87; the cutoff of 12 ng/mL had sensitivity 82% and specificity 89%. CONCLUSIONS: Increased serum PIIINP can signify severe sepsis/septic shock and predict which patients with sepsis will eventually develop severe sepsis/septic shock, thus representing a biomarker of risk stratification of patients with sepsis. PMID- 23683563 TI - Changing sedative infusion from propofol to midazolam improves sublingual microcirculatory perfusion in patients with septic shock. AB - PURPOSE: The goal of this study was to explore possible microcirculatory alterations by changing sedative infusion from propofol to midazolam in patients with septic shock. MATERIALS AND METHODS: Patients (n=16) were sedated with propofol during the first 24 hours after intubation, then with midazolam, following a predefined algorithm. Systemic hemodynamics, perfusion parameters, and microcirculation were assessed at 2 time points: just before stopping propofol and 30 minutes after the start of midazolam infusion. Sublingual microcirculation was evaluated by sidestream dark-field imaging. RESULTS: The microvascular flow index and the proportion of perfused small vessels were greater when patients were on midazolam than when on propofol infusion (2.8 [2.4 2.9] vs 2.3 [1.9-2.6] and 96.4% [93.7%-97.6%] vs 92.7% [88.3%-94.7%], respectively; P<.005), and the flow heterogeneity index was greater with propofol than with midazolam use (0.49 [0.2-0.8] vs 0.19 [0.1-0.4], P<.05). There were no significant changes in systemic hemodynamics and perfusion parameters either during propofol use or during midazolam infusions. Data are presented as median (25th-75th percentiles). CONCLUSIONS: In this study, sublingual microcirculatory perfusion improved when the infusion was changed from propofol to midazolam in patients with septic shock. This observation could not be explained by changes in systemic hemodynamics. PMID- 23683564 TI - Assessment and management of cerebral edema and intracranial hypertension in acute liver failure. AB - Acute liver failure is uncommon but not a rare complication of liver injury. It can happen after ingestion of acetaminophen and exposure to toxins and hepatitis viruses. The defining clinical symptoms are coagulopathy and encephalopathy occurring within days or weeks of the primary insult in patients without preexisting liver injury. Acute liver failure is often complicated by multiorgan failure and sepsis. The most life-threatening complications are sepsis, multiorgan failure, and brain edema. The clinical signs of increased intracranial pressure (ICP) are nonspecific except for neurologic deficits in impending brain stem herniation. Computed tomography of the brain is not sensitive enough in gauging intracranial hypertension or ruling out brain edema. Intracranial pressure monitoring, transcranial Doppler, and jugular venous oximetry provide valuable information for monitoring ICP and guiding therapeutic measures in patients with encephalopathy grade III or IV. Osmotic therapy using hypertonic saline and mannitol, therapeutic hypothermia, and propofol sedation are shown to improve ICPs and stabilize the patient for liver transplantation. In this article, diagnosis and management of hepatic encephalopathy and cerebral edema in patients with acute liver failure are reviewed. PMID- 23683565 TI - Plethysmographic variation index predicts fluid responsiveness in ventilated patients in the early phase of septic shock in the emergency department: a pilot study. AB - PURPOSE: Feasibility study examining whether plethysmographic variability index (PVI) can predict fluid responsiveness in mechanically ventilated patients in the early phase of septic shock in the emergency department. MATERIALS AND METHODS: Monocentric, prospective, observational study that included 31 mechanically ventilated and sedated patients with septic shock in whom volume expansion was planned. The patients were equipped with a pulse oximeter that automatically calculated and displayed PVI. The intervention consisted in infusing 8 mL/kg of hydroxylethyl starch over a 20-minute period. Before and after intervention, we recorded PVI and measured the aortic velocity-time integral (VTIao) using transthoracic echocardiography. Responders were defined as patients who increased their VTIao by 15% or higher after fluid infusion. RESULTS: Sixteen patients were classified as responders, and 15 as nonresponders. Mean PVI values before intervention were significantly higher in responders vs nonresponders (30%+/-9% vs 8%+/-5%, P<.001). Plethysmographic variability index values before intervention were correlated with percent changes in VTIao induced by intervention (R2=0.67; P<.001). A PVI threshold value of 19% discriminates responders from nonresponders with a sensitivity of 94% and a specificity of 87% (area under the curve, 0.97; P<.001). CONCLUSION: Our study suggests that PVI is a feasible and interesting method to predict fluid responsiveness in early phase septic shock patients in the emergency department. PMID- 23683566 TI - Ionized hypocalcemia is an early event and is associated with organ dysfunction in children admitted to the intensive care unit. AB - PURPOSE: The purpose was to determine the frequency and risk factors of ionized hypocalcemia and to evaluate this disturbance as a predictor of mortality in a pediatric intensive care unit (ICU). MATERIALS AND METHODS: In a prospective cohort study, 337 children admitted consecutively to an ICU were monitored regarding serum ionized calcium concentrations during the first 10 days of admission. The following variables were analyzed as independent of hypocalcemia: age; malnutrition; sepsis; Pediatric Index of Mortality 2; first 3 days organ dysfunction score (Pediatric Logistic Organ Dysfunction); and use of steroids, furosemide, and anticonvulsants. Hypocalcemia was defined as a serum ionized calcium concentration less than 1.15 mmol/L. RESULTS: The rate of hypocalcemia was 77.15%. In a multivariate model, higher Pediatric Logistic Organ Dysfunction scores during the first 3 days of ICU stay were independently associated with hypocalcemia (odds ratio, 2.24; 95% confidence interval, 1.23-4.07; P=.008). Medications associated with hypocalcemia were furosemide (dose>=2 mg/[kg d]) and methylprednisolone (dose>=2 mg/[kg d]). No significant association was found between hypocalcemia and 10-day mortality. CONCLUSIONS: Ionized hypocalcemia is common during the ICU stay, particularly in the first 3 days of admission. This disturbance was not found to be a predictor of mortality, but it is independently associated with more severe organ dysfunction. PMID- 23683567 TI - Predictors of mortality in patients with stress-induced cardiomyopathy developed during critical care. AB - PURPOSE: The aims of this study were to define predictors of in-hospital mortality and to explore the implication of Acute Physiology and Chronic Health Evaluation (APACHE) II score in patients with stress-induced cardiomyopathy (SCM) developed during critical care. MATERIALS AND METHODS: All patients admitted to intensive care unit and underwent transthoracic echocardiography (TTE) were consecutively enrolled from January 2008 to May 2011. Clinical, demographic and laboratory data, APACHE II score, and transthoracic echocardiography finding were analyzed using a logistic regression model to investigate predictors of in hospital mortality. RESULTS: A total of 71 patients (60 +/- 18 years, 37% male) were included in the final analysis. In univariate and multivariate logistic regression analyses, underlying malignancies, male sex, age less than 65 years, and APACHE II score higher than 15 remained independent risk factors for in hospital mortality of SCM. The area under the receiver operating characteristic curve for APACHE II was 0.745 (95% confidence interval, 0.630-0.861; P = .001), and an APACHE II score of 15 (sensitivity 73%, specificity 68%) was the optimal cutoff value in predicting in-hospital mortality of SCM during critical care. CONCLUSION: The in-hospital mortality in patients with SCM that developed during critical care was associated with underlying malignancy, male sex, old age, and APACHE II score. PMID- 23683568 TI - Prevention of contrast-induced nephropathy by N-acetylcysteine in critically ill patients: different definitions, different results. AB - PURPOSE: The use of N-acetylcysteine (NAC) for preventing contrast induced nephropathy (CIN) is debated in the intensive care unit. NAC may alter the concentration of serum creatinine and interfere with CIN diagnosis. The effectiveness of NAC was evaluated with a special attention on its specific effect on creatinine levels compared to cystatin C. METHODS: In a first period, we prospectively enrolled patients receiving saline and low osmolality contrast media for 140 exams in 2 intensive care units with opposite policies regarding the use of NAC. Renal impairment was defined by both the classical CIN and the "sensitive" Acute Kidney Injury Network (AKIN) (taking creatinine and diuresis) definitions. In a second period, we compared the evolution of serum creatinine and cystatin C after 23 additional contrast examinations under NAC. RESULTS: Seventy exams with and without NAC were compared in the first period. Risk factors for CIN were similar in the two intensive care unit populations. No difference in CIN incidence was found with and without NAC, using the CIN (10/70 vs 15/70) or the AKIN (24/70 vs 22/70) definition. Interestingly, NAC seemed to reduce renal impairment when the creatinine criterion of the AKIN definition was considered alone [9% vs 21%, P=.033]. Overall, the incidence of renal impairment was 18%, 33% and 15% using the CIN definition, the AKIN, or using AKIN with creatinine alone. Serum creatinine significantly decreased after exams with NAC while cystatin C remained stable. CONCLUSION: The incidence of CIN does not seem to be influenced by NAC, except if small changes in creatinine only are considered. PMID- 23683569 TI - Phoxilium vs Hemosol-B0 for continuous renal replacement therapy in acute kidney injury. AB - PURPOSE: This study aimed to compare the biochemical effects of Phoxilium (containing phosphate at 1.2 mmol/L; Gambro Lundia AB, Lund, Sweden) and Hemosol B0 (Gambro Lundia AB) as dialysate and/or replacement fluid during continuous renal replacement therapy (CRRT). METHODS: We examined serum biochemistry in critically ill patients for 42 hours of Phoxilium administration for the prevention of hypophosphatemia during CRRT and compared them with corresponding results in random historical controls who received Hemosol-B0. RESULTS: We studied 15 patients in each arm (Phoxilium vs Hemosol-B0). Respective median ages were 57 (49-68) and 64 (57-67) years. Baseline patient illness severity scores, prescribed CRRT effluent rates, and cumulative phosphate intakes were comparable. After 36 to 42 hours of Phoxilium administration, serum phosphate levels increased from 0.95 (0.81-1.13) to 1.44 (1.23-1.78) mmol/L, in contrast to the decline from 1.71 (1.09-2.00) to 0.83 (0.55-1.59) mmol/L with Hemosol-B0 (P=.0001). Serum ionized calcium levels decreased from 1.27 (1.22-1.37) to 1.12 (1.06-1.21) mmol/L with Phoxilium, compared with an increase from 1.09 (0.90 1.19) to 1.20 (1.16-1.25) mmol/L with Hemosol-B0 (P<.0001). Serum bicarbonate, base excess levels, and effective strong ion difference decreased with Phoxilium and were lower than those with Hemosol-B0 at 36 to 42 hours (P<.05). CONCLUSION: Phoxilium effectively prevented hypophosphatemia during CRRT but was associated with relative metabolic acidosis and hypocalcemia compared with Hemosol-B0 use. PMID- 23683570 TI - Comparison of predictive powers of S100B and cell-free plasma DNA values in intensive care unit patients with intracranial hemorrhage. AB - PURPOSE: To investigate predictive powers of S100B and cell-free DNA (cfDNA) levels in patients in the intensive care unit (ICU) who have with intracranial hemorrhage (ICH) for prognosis. METHODS: Ninety-nine patients diagnosed with ICH were included in the study. The blood samples were drawn on the day of admittance to ICU and again on the third day. Duration of stay in the ICU and mortality were recorded. RESULTS: A positive correlation was determined between the values of S100B and cfDNA from both the analysis and the Acute Physiology and Chronic Health Evaluation II scores. For all patients, there was a positive correlation between the duration of stay in the ICU and the values of S100B and cfDNA on the third day. The levels of both S100B and cfDNA in patients who died in the ICU were significantly higher than of those who survived on the day of admittance. CONCLUSIONS: Both S100B and cfDNA values can be used as markers to predict the prognosis of ICU patients with ICH. However, S100B is more powerful for predicting the prognosis. PMID- 23683571 TI - Predictive value of elevated cystatin C in patients undergoing primary angioplasty for ST-elevation myocardial infarction. AB - OBJECTIVES: The prognostic value of cystatin C (CysC) has been documented in patients with acute coronary syndrome without ST-segment elevation. However, its value in acute ST-segment elevation myocardial infarction (STEMI) remains unclear. The aim of this study was to evaluate the prognostic value of CysC in patients with STEMI undergoing primary percutaneous coronary intervention (PCI). METHODS: We prospectively enrolled 475 consecutive STEMI patients (mean age 55.6+/-12.4 years, 380 male, 95 female) undergoing primary PCI. The study population was divided into tertiles based on admission CysC values. The high CysC group (n=159) was defined as a value in the third tertile (>1.12 mg/L), and the low CysC group (n=316) included those patients with a value in the lower two tertiles (<=1.12 mg/L). Clinical characteristics and in-hospital and one-month outcomes of primary PCI were analyzed. RESULTS: The patients of the high CysC group were older (mean age 62.8+/-13.1 vs. 52.3+/-10.5, P<.001). Higher in hospital and 1-month cardiovascular mortality rates were observed in the high CysC group (9.4% vs. 1.6%, P<.001 and 14.5% vs. 2.2%, P<.001, respectively). In Cox multivariate analysis; a high admission CysC value (>1.12 mg/L) was found to be a powerful independent predictor of one-month cardiovascular mortality (odds ratio, 5.3; 95% confidence interval, 1.25-22.38; P=.02). CONCLUSIONS: These results suggest that a high admission CysC level was associated with increased in hospital and one-month cardiovascular mortality in patients with STEMI undergoing primary PCI. PMID- 23683572 TI - Inhaled epoprostenol vs inhaled nitric oxide for refractory hypoxemia in critically ill patients. AB - PURPOSE: The purpose of this is to compare efficacy, safety, and cost outcomes in patients who have received either inhaled epoprostenol (iEPO) or inhaled nitric oxide (iNO) for hypoxic respiratory failure. MATERIALS AND METHODS: This is a retrospective, single-center analysis of adult, mechanically ventilated patients receiving iNO or iEPO for improvement in oxygenation. RESULTS: We evaluated 105 mechanically ventilated patients who received iEPO (52 patients) or iNO (53 patients) between January 2009 and October 2010. Most patients received therapy for acute respiratory distress syndrome (iNO 58.5% vs iEPO 61.5%; P=.84). There was no difference in the change in the partial pressure of arterial O2/fraction of inspired O2 ratio after 1 hour of therapy (20.58+/-91.54 vs 33.04+/-36.19 [P=.36]) in the iNO and iEPO groups, respectively. No difference was observed in duration of therapy (P=.63), mechanical ventilation (P=.07), intensive care unit (P=.67), and hospital lengths of stay (P=.26) comparing the iNO and iEPO groups. No adverse events were attributed to either therapy. Inhaled nitric oxide was 4.5 to 17 times more expensive than iEPO depending on contract pricing. CONCLUSIONS: We found no difference in efficacy and safety outcomes when comparing iNO and iEPO in hypoxic, critically ill patients. Inhaled epoprostenol is associated with less drug expenditure than iNO. PMID- 23683573 TI - Validity of the polymerase chain reaction in the diagnosis of clinically suspected cases of American visceral leishmaniasis. AB - To test the validity of the polymerase chain reaction for diagnosing American visceral leishmaniasis, 88 suspected cases were studied. Diagnosis was confirmed in 47 (53.5%) and ruled out in 41 (46.5%) patients. Samples of bone marrow and peripheral blood were processed by polymerase chain reaction to evaluate the sensitivity and specificity of the test and its agreement beyond chance with microscopy examination. The polymerase chain reaction was positive in bone marrow of 100% of the patients with amastigotes seen with microscopy examination, and in 59.5% in those where no parasite were seen. Agreement beyond chance between visualization of the parasite in bone marrow aspirates and polymerase chain reaction was considered weak (Kappa=0.41). Concordance between polymerase chain reaction of bone marrow aspirates and of peripheral blood was considered excellent (Kappa=0.88). The test turned out positive in all bone marrow aspirates of those with the disease and whereas the positivity rate was 58.5% among those without the disease, with specificity rate of 41.5%. PMID- 23683575 TI - Automated digital image analysis of islet cell mass using Nikon's inverted eclipse Ti microscope and software to improve engraftment may help to advance the therapeutic efficacy and accessibility of islet transplantation across centers. AB - Reliable assessment of islet viability, mass, and purity must be met prior to transplanting an islet preparation into patients with type 1 diabetes. The standard method for quantifying human islet preparations is by direct microscopic analysis of dithizone-stained islet samples, but this technique may be susceptible to inter-/intraobserver variability, which may induce false positive/negative islet counts. Here we describe a simple, reliable, automated digital image analysis (ADIA) technique for accurately quantifying islets into total islet number, islet equivalent number (IEQ), and islet purity before islet transplantation. Islets were isolated and purified from n = 42 human pancreata according to the automated method of Ricordi et al. For each preparation, three islet samples were stained with dithizone and expressed as IEQ number. Islets were analyzed manually by microscopy or automatically quantified using Nikon's inverted Eclipse Ti microscope with built-in NIS-Elements Advanced Research (AR) software. The AIDA method significantly enhanced the number of islet preparations eligible for engraftment compared to the standard manual method (p < 0.001). Comparisons of individual methods showed good correlations between mean values of IEQ number (r(2) = 0.91) and total islet number (r(2) = 0.88) and thus increased to r(2) = 0.93 when islet surface area was estimated comparatively with IEQ number. The ADIA method showed very high intraobserver reproducibility compared to the standard manual method (p < 0.001). However, islet purity was routinely estimated as significantly higher with the manual method versus the ADIA method (p < 0.001). The ADIA method also detected small islets between 10 and 50 um in size. Automated digital image analysis utilizing the Nikon Instruments software is an unbiased, simple, and reliable teaching tool to comprehensively assess the individual size of each islet cell preparation prior to transplantation. Implementation of this technology to improve engraftment may help to advance the therapeutic efficacy and accessibility of islet transplantation across centers. PMID- 23683576 TI - Variable performance of a human derived Sarcoptes scabiei recombinant antigen ELISA in swine mange diagnosis. AB - The performance of an indirect ELISA test based on Sarcoptes scabiei var hominis recombinant antigen Sslambda20DeltaB3 (rec-ELISA), to diagnose pig mange was investigated in 15 experimentally infected and non-infected pigs and 692 commercial pigs from 16 herds in southeast Spain. These latter animals included 6 7 month old fatteners (13 herds), 11-12 month old replacement sows (1 herd) and >=24 month old breeding sows (7 herds). All pigs were examined for mites in ear skin scrapings and the presence of S. scabiei-associated macroscopic dermatitis; moreover, fatteners were also tested for antibodies against porcine viruses including: Aujeszky disease virus (ADV), swine influenza virus (SIV), type 2 porcine circovirus (PCV2) and porcine respiratory and reproductive syndrome virus (PRRSV). S. scabiei and chronic hyperkeratotic dermatitis were detected in breeding sows from 6 herds. Mite prevalence in other pigs was 83% in replacement sows, 0% in 7 fattener's herds and 3-82% in other fattener's herds. All fattener herds had pigs with acute hypersensitivity dermatitis and the percentage of affected pigs and lesion area was significantly greater in S. scabiei infected ones. Rec-ELISA relative optical densities (RODs) were greater in older than in young pigs, as well as in infected compared to non-infected pigs. However, RODs differed significantly between infected individuals, regardless of age and origin (commercial or experimental) and the herd prevalence of S. scabiei. Low repeatability between ELISA microtiter plates, suggesting variable specific antibody binding to antigen, are likely partly responsible for ROD variation. Other potential causes of variation were examined in fatteners using random effects logistic regression analysis, after defining a seropositivity threshold value with receiver-operating characteristics (ROC) analysis. The logistic model indicated that seropositivity was associated with large dermatitis areas and with the only herd with low PCV2 seroprevalence. Pigs with more extensive dermatitis may have older infections and more rec-ELISA detectable antibodies. The possibility that PCV2, a recognized immunosupressor, depresses antibody production against S. scabiei infection merits further attention. In summary, results indicate some potential of the studied rec-ELISA as a complementary tool for herd-level swine mange diagnosis, and that work to reduce internal and external sources of assay variation is essential. PMID- 23683574 TI - Frequency of microorganisms isolated in patients with bacteremia in intensive care units in Colombia and their resistance profiles. AB - OBJECTIVE: The aim of this study was to describe the most frequently found bacterial microorganisms in bloodstream isolates taken from patients in intensive care units in Colombia and their resistance profiles. METHODS: This was a multicentre descriptive observational study that was carried out between January 2001 and June 2008 with laboratory data from 33 participating hospitals in a surveillance network. RESULTS: The most frequently found microorganisms were coagulase-negative Staphylococci 39.6%, Staphylococcus aureus 12.3%, Klebsiella pneumoniae 8.2%, Escherichia coli 5.7%, Acinetobacter baumannii, 4.0% and Pseudomonas aeruginosa 3.8%. Coagulase-negative Staphylococci registered greater than 70% oxacillin resistance rate. S. aureus presented a change in its multiresistance profile during the years of follow-up. There was a trend towards a lower resistance rate among E. coli and K. pneumoniae isolates during the study period while A. baumannii carbapenem resistance rate exceeded 50%. DISCUSSION: There has been a change in the frequency of species being isolated with a higher frequency of enterobacteriaceae compared to Gram-positive microorganisms, in general with a high resistance rate. PMID- 23683577 TI - Endothelial microvascular networks affect gene-expression profiles and osteogenic potential of tissue-engineered constructs. AB - INTRODUCTION: A major determinant of the potential size of cell/scaffold constructs in tissue engineering is vascularization. The aims of this study were twofold: first to determine the in vitro angiogenic and osteogenic gene expression profiles of endothelial cells (ECs) and mesenchymal stem cells (MSCs) cocultured in a dynamic 3D environment; and second, to assess differentiation and the potential for osteogenesis after in vivo implantation. METHODS: MSCs and ECs were grown in dynamic culture in poly(L-lactide-co-1,5-dioxepan-2-one) (poly(LLA co-DXO)) copolymer scaffolds for 1 week, to generate three-dimensional endothelial microvascular networks. The constructs were then implanted in vivo, in a murine model for ectopic bone formation. Expression of selected genes for angiogenesis and osteogenesis was studied after a 1-week culture in vitro. Human cell proliferation was assessed as expression of ki67, whereas alpha-smooth muscle actin was used to determine the perivascular differentiation of MSCs. Osteogenesis was evaluated in vivo through detection of selected markers, by using real-time RT-PCR, alkaline phosphatase (ALP), Alizarin Red, hematoxylin/eosin (HE), and Masson trichrome staining. RESULTS: The results show that endothelial microvascular networks could be generated in a poly(LLA-co-DXO) scaffold in vitro and sustained after in vivo implantation. The addition of ECs to MSCs influenced both angiogenic and osteogenic gene-expression profiles. Furthermore, human ki67 was upregulated before and after implantation. MSCs could support functional blood vessels as perivascular cells independent of implanted ECs. In addition, the expression of ALP was upregulated in the presence of endothelial microvascular networks. CONCLUSIONS: This study demonstrates that copolymer poly(LLA-co-DXO) scaffolds can be prevascularized with ECs and MSCs. Although a local osteoinductive environment is required to achieve ectopic bone formation, seeding of MSCs with or without ECs increases the osteogenic potential of tissue-engineered constructs. PMID- 23683579 TI - Cell-cell communication between malaria-infected red blood cells via exosome-like vesicles. AB - Cell-cell communication is an important mechanism for information exchange promoting cell survival for the control of features such as population density and differentiation. We determined that Plasmodium falciparum-infected red blood cells directly communicate between parasites within a population using exosome like vesicles that are capable of delivering genes. Importantly, communication via exosome-like vesicles promotes differentiation to sexual forms at a rate that suggests that signaling is involved. Furthermore, we have identified a P. falciparum protein, PfPTP2, that plays a key role in efficient communication. This study reveals a previously unidentified pathway of P. falciparum biology critical for survival in the host and transmission to mosquitoes. This identifies a pathway for the development of agents to block parasite transmission from the human host to the mosquito. PMID- 23683578 TI - Human embryonic stem cells derived by somatic cell nuclear transfer. AB - Reprogramming somatic cells into pluripotent embryonic stem cells (ESCs) by somatic cell nuclear transfer (SCNT) has been envisioned as an approach for generating patient-matched nuclear transfer (NT)-ESCs for studies of disease mechanisms and for developing specific therapies. Past attempts to produce human NT-ESCs have failed secondary to early embryonic arrest of SCNT embryos. Here, we identified premature exit from meiosis in human oocytes and suboptimal activation as key factors that are responsible for these outcomes. Optimized SCNT approaches designed to circumvent these limitations allowed derivation of human NT-ESCs. When applied to premium quality human oocytes, NT-ESC lines were derived from as few as two oocytes. NT-ESCs displayed normal diploid karyotypes and inherited their nuclear genome exclusively from parental somatic cells. Gene expression and differentiation profiles in human NT-ESCs were similar to embryo-derived ESCs, suggesting efficient reprogramming of somatic cells to a pluripotent state. PMID- 23683580 TI - Modification of 24-h ambulatory blood pressure and heart rate during contraception with the vaginal ring: a prospective study. AB - BACKGROUND: Hypertension is recognized as a major risk factor for coronary, cerebral and renal vascular disease. Hormonal methods of contraception may increase the risk for cardiovascular events. We evaluated whether the combined hormonal contraceptive vaginal ring that releases 15-mcg ethinylestradiol and 120 mcg of etonogestrel each day influences 24-h ambulatory blood pressure. STUDY DESIGN: At baseline, ambulatory blood pressure was automatically monitored every 30 min for 41 h in 18 normotensive healthy women during their follicular phase (Days 3-6). Each subject was immediately treated with the vaginal ring for six cycles. Monitoring of ambulatory blood pressure was repeated in the last days of the sixth cycle of treatment. RESULTS: During the vaginal ring, a significant increase was observed for 24-h diastolic (2.75+/-5.13 mmHg; p=.03) and mean (2.69+/-5.35 mmHg; p=.048) blood pressure and for daytime diastolic (3.04+/-6.36 mmHg; p=.05) blood pressure. No variation was found in nighttime blood pressure. Heart rate increased in the 24-h period (3.39+/-5.85 beats/min; p=.025) and in the daytime (3.38+/-6.25 beats/min; p=.034) measurements. CONCLUSIONS: In normotensive women, the vaginal ring slightly increases 24-h blood pressure and heart rate. The underlying mechanisms and the clinical impact of these slight modifications require further evaluation. PMID- 23683581 TI - The creeping Pearl: Why has the rate of contraceptive failure increased in clinical trials of combined hormonal contraceptive pills? AB - BACKGROUND: Despite several drawbacks, the Pearl Index continues to be the most widely used statistical measure of contraceptive failure. However, Pearl indices reported in studies of newer hormonal contraceptives appear to be increasing. STUDY DESIGN: We searched PubMed and Medical Intelligence Solutions databases for prospective trials evaluating oral contraceptive (OC) efficacy to examine potential factors that could contribute to increasing Pearl indices. RESULTS: Numerous potential factors were identified, including an increased rate of failures of newer OCs, deficiencies in methods of calculating contraceptive failure rates, differences in study design and changes in patient populations resulting in increased rates of contraceptive failures due to the inappropriate or inconsistent use of the method. CONCLUSIONS: The two most likely important contributors to the increase in Pearl indices are more frequent pregnancy testing with more sensitive tests and less adherent study populations. Because study populations appear to be increasingly representative of the likely actual users once the product is marketed, we can expect to see even higher failure rates in ongoing and future studies. This result poses challenges for companies and regulatory agencies. PMID- 23683582 TI - The molecular link between C-C-chemokine ligand 2-induced leukocyte recruitment and hyperalgesia. AB - The chemokine C-C-chemokine ligand 2 (CCL2) (formerly known as MCP, macrophage chemotactic protein) is one of the important genes upregulated in different types of pain both in animals and humans. CCL2 governs the recruitment of C-C chemokine receptor 2-expressing monocytes into inflamed tissue. In contrast to neutrophilic chemokines, intraplantar injection of CCL2 in Wistar rats recruited macrophages and neutrophils and simultaneously lowered nociceptive thresholds. CCL2-induced hyperalgesia was abolished by prior systemic leukocyte depletion by cyclophosphamide and was reconstituted by local adoptive transfer of donor macrophages but not of neutrophils. Antagonists against transient receptor potential vannilloid 1 inhibited thermal and against transient receptor potential ankyrin 1 blocked mechanical hyperalgesia. Peripheral but not central activation of cyclooxygenase-2 (Cox-2) were critical for CCL2-induced hyperalgesia. In vitro CCL2 did not directly stimulate Cox-2 expression or prostaglandin E2 formation but slightly enhanced the formation of reactive oxygen species in monocytes and macrophages. In vivo, increased immunoreactivity for 4-hydroxy-2-nonenal (4-HNE), a downstream product of reactive oxygen species and known inducer of Cox-2, was observed and colocalized with Cox-2 in ED1 (CD68) positive infiltrating cells. No hyperalgesia, 4-HNE, or Cox-2 immunoreactivity was seen in leukocyte-depleted rats that were reconstituted with macrophages in the absence of CCL2, supporting the important role of CCL2. PERSPECTIVE: CCL2 plays a dual role: 1) promoting monocyte/macrophage recruitment into tissue; and 2) potentially stimulating macrophages in the tissue to produce 4-HNE and subsequently Cox-2, all resulting in the induction of hyperalgesia via transient receptor potential vannilloid 1 and transient receptor potential ankyrin 1. This encourages pharmacological efforts targeting CCL2/C-C chemokine receptor 2 and macrophages for treatment of inflammatory pain. PMID- 23683583 TI - The effect of neuroticism on the recall of persistent low-back pain and perceived activity interference. AB - The assessment of persistent pain often relies on recalling and then summarizing the entire pain experience using a single rating. Newer methodologies, such as the Original Pain Recall Assessment, ask people to recall the pain they experienced over a specific period of time by tracing a single line in a graph to represent their pain levels. One advantage of this approach is that one can compare recalled levels of pain with actual daily diary pain ratings. This methodology was used to investigate the effects of neuroticism on the recall of levels and patterns of persistent pain. The study involved 70 participants who completed a measure of neuroticism, depressive symptoms, and up to 15 daily diaries that asked for ratings of pain intensity, pain unpleasantness, and activity interference due to pain. Following completion of the daily diary period, the participants were asked to recall the entire diary period using the Original Pain Recall Assessment methodology. The analyses revealed that higher levels of neuroticism were related to significantly better recall of the variability of pain unpleasantness over time. Furthermore, individuals who reported higher levels of depressive symptoms were less accurate in the recall of pain in general. PERSPECTIVE: Memory for pain is crucial in the assessment of pain, with little research devoted to the study of this topic. The current study demonstrates that people higher on neuroticism had better recall of pain unpleasantness, and people with higher levels of depressive symptoms had poorer recall of pain in general. PMID- 23683584 TI - Advanced diagnostics applied to fish liver tumours: relating pathology to underlying molecular aetiology. AB - Liver tumours in flatfish have been diagnosed using histopathology for decades in order to monitor the impacts of marine pollution in coastal and estuarine environments. This traditional method has been coupled with molecular analyses of tumours in the liver of the dab, Limanda limanda, in order to elucidate underpinning molecular level aetiology of such disease. A laser capture microdissection technique for molecular investigation of cancer has been applied in fish. The present study provides optimized steps for environmental sample utilisation: a procedure for field sample collection and handling; a method allowing reliable identification of lesions on frozen tissue sections; and, downstream molecular analyses of tumourigenesis markers (retinoblastoma gene) in laser microdissected samples. This approach facilitates the use of wild flatfish as a model of environmentally-induced tumourigenesis, and has wide applicability to any disease pathology for which the underpinning molecular aetiology is required. PMID- 23683586 TI - Plastic ingestion in marine-associated bird species from the eastern North Pacific. AB - In addition to monitoring trends in plastic pollution, multi-species surveys are needed to fully understand the pervasiveness of plastic ingestion. We examined the stomach contents of 20 bird species collected from the coastal waters of the eastern North Pacific, a region known to have high levels of plastic pollution. We observed no evidence of plastic ingestion in Rhinoceros Auklet, Marbled Murrelet, Ancient Murrelet or Pigeon Guillemot, and low levels in Common Murre (2.7% incidence rate). Small sample sizes limit our ability to draw conclusions about population level trends for the remaining fifteen species, though evidence of plastic ingestion was found in Glaucous-Winged Gull and Sooty Shearwater. Documenting levels of plastic ingestion in a wide array of species is necessary to gain a comprehensive understanding about the impacts of plastic pollution. We propose that those working with bird carcasses follow standard protocols to assess the levels of plastic ingestion whenever possible. PMID- 23683585 TI - Occurrence of contaminants of emerging concern along the California coast (2009 10) using passive sampling devices. AB - Three passive sampling devices (PSDs), polar organic chemical integrative samplers (POCIS), polyethylene devices (PEDs), and solid-phase microextraction (SPME) samplers were used to sample a diverse set of chemicals in the coastal waters of San Francisco Bay and the Southern California Bight. Seventy one chemicals (including fragrances, phosphate flame retardants, pharmaceuticals, PAHs, PCBs, PBDEs, and pesticides) were measured in at least 50% of the sites. The chemical profile from the San Francisco Bay sites was distinct from profiles from the sites in the Southern California Bight. This distinction was not due to a single compound or class, but by the relative abundances/concentrations of the chemicals. Comparing the PSDs to mussel (Mytilus spp.) tissues, a positive correlation exists for the 25 and 26 chemicals in common for the PEDs and SPME, respectively. Diphenhydramine was the only common chemical out of 40 analyzed in both POCIS and tissues detected at a common site. PMID- 23683587 TI - Cadmium interferes with maintenance of auxin homeostasis in Arabidopsis seedlings. AB - Auxin and its homeostasis play key roles in many aspects of plant growth and development. Cadmium (Cd) is a phytotoxic heavy metal and its inhibitory effects on plant growth and development have been extensively studied. However, the underlying molecular mechanism of the effects of Cd stress on auxin homeostasis is still unclear. In the present study, we found that the root elongation, shoot weight, hypocotyl length and chlorophyll content in wild-type (WT) Arabidopsis seedlings were significantly reduced after exposure to Cd stress. However, the lateral root (LR) formation was markedly promoted by Cd stress. The level and distribution of auxin were both greatly altered in primary root tips and cotyledons of Cd-treated plants. The results also showed that after Cd treatment, the IAA content was significantly decreased, which was accompanied by increases in the activity of the IAA oxidase and alteration in the expression of several putative auxin biosynthetic and catabolic genes. Application of the auxin transport inhibitor, 1-naphthylphthalamic acid (NPA) and 1-naphthoxyacetic acid (1-NOA), reversed the effects of Cd on LR formation. Additionally, there was less promotion of LR formation by Cd treatment in aux1-7 and pin2 mutants than that in the WT. Meanwhile, Cd stress also altered the expression of PINs and AUX1 in Arabidopsis roots, implying that the auxin transport pathway is required for Cd modulated LR development. Taken together, these findings suggest that Cd stress disturbs auxin homeostasis through affecting auxin level, distribution, metabolism, and transport in Arabidopsis seedling. PMID- 23683588 TI - 2,2'-Dithienyl diselenide pro-oxidant activity accounts for antibacterial and antifungal activities. AB - The aim of this study was to explore if 2,2'-dithienyl diselenide (DTDS) pro oxidant activity is related to its antibacterial and antifungal actions. The antimicrobial activity of DTDS against bacterial and fungal was investigated in the broth microdilution assay (3.02-387 MUg/ml). Additionally, the survival curve of microorganisms in the presence of DTDS (12.09-193.5 MUg/ml) was performed. The involvement of pro-oxidant activity in the DTDS antimicrobial action was investigated by supplementing the growth medium with 10 mM glutathione or ascorbic acid in the disk diffusion technique (0.64-640 MUgDTDS/discs). The levels of reactive species (RS) induced by 25 mM DTDS were also determined. The results demonstrated that DTDS was effective in preventing the Gram-positive bacteria and Candida albicans growth. The minimum inhibitory concentration, twice and half concentrations of DTDS confirmed that the activity of compound was bactericidal for some microorganisms (Enterococcus faecalis, and Staphylococcus saprophyticus), bacteriostatic for Bacillus cereus and fungistatic for C. albicans. Antibacterial and antifungal actions of DTDS are related to the increase of reactive species levels. The presence of antioxidants in the growth medium avoided the DTDS antimicrobial action. In conclusion, DTDS showed promising antibacterial and antifungal actions, possibly related to its pro oxidant activity. PMID- 23683589 TI - Synthesis of kojic acid derivatives as secondary binding site probes of D-amino acid oxidase. AB - A series of kojic acid (5-hydroxy-2-hydroxymethyl-4H-pyran-4-one) derivatives were synthesized and tested for their ability to inhibit D-amino acid oxidase (DAAO). Various substituents were incorporated into kojic acid at its 2 hydroxymethyl group. These analogs serve as useful molecular probes to explore the secondary binding site, which can be exploited in designing more potent DAAO inhibitors. PMID- 23683590 TI - Design and synthesis of 6,7-dimethoxyquinazoline analogs as multi-targeted ligands for alpha1- and AII-receptors antagonism. AB - Multiple-targeted ligands can have certain advantages for the management of hypertension which has multiple controls. Molecules with dual bioactivities are available in literature for treating metabolic disorders like diabetes, hypertension and hypercholesterolemia. After scrutinizing the SAR of prazosin type alpha1-blockers and AII-antagonists it was planned to develop dual alpha1- and AII-antagonists. Five series of quinazoline derivatives were synthesized and evaluated as dual alpha1- and AII-antagonists on rat aortic strips for the blockade of known alpha1- and AII-agonist mediated contractions. Many compounds showed balanced activity on both the receptors but compound (22) was found to be the most active derivative having higher antagonistic activity on both the receptors. In the in vivo experiments the chosen compound (22) was slightly less active than prazosin but was found to be equipotent to losartan. These findings shed a new light on the structural requirements for both alpha1- as well as AII receptor antagonists. PMID- 23683591 TI - Synthesis and evaluation of 8-amino-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one derivatives as glycogen synthase kinase-3 (GSK-3) inhibitors. AB - New potent glycogen synthase kinase-3 (GSK-3) inhibitors, 8-amino [1,2,4]triazolo[4,3-a]pyridin-3(2H)-one derivatives, were designed by modeling, synthesized and evaluated in vitro. Compound 17c showed good potency in enzyme and cell-based assays (IC50=111 nM, EC50=1.78 MUM). Moreover, it has demonstrated desirable water solubility, PK profile, and moderate brain penetration. PMID- 23683592 TI - Design, synthesis and biological evaluation of 2-mercapto-3-phenethylquinazoline bearing anilide fragments as potential antitumor agents: molecular docking study. AB - A novel series of 2-(3-phenethyl-4(3H)quinazolin-2-ylthio)-N-substituted anilide and substituted phenyl 2-(3-phenethyl-4(3H) quinazolin-2-ylthio)acetate were designed, synthesized and evaluated for their in-vitro antitumor activity. Compound 15 possessed remarkable broad-spectrum antitumor activity which almost sevenfold more active than the known drug 5-FU with GI50 values of 3.16 and 22.60 MUM, respectively. Compound 15 exhibited remarkable growth inhibitory activity pattern against renal cancer (GI50=1.77 MUM), colon cancer (GI50=2.02 MUM), non small cell lung cancer (GI50=2.04 MUM), breast cancer (GI50=2.77 MUM), ovarian cancer (GI50=2.55 MUM) and melanoma cancer (GI50=3.30 MUM). Docking study was performed for compound 15 into ATP binding site of EGFR-TK which showed similar binding mode to erlotinib. PMID- 23683593 TI - Synthesis and SAR of potent and selective tetrahydropyrazinoisoquinolinone 5 HT(2C) receptor agonists. AB - The 5-HT2C receptor has been implicated as a critical regulator of appetite. Small molecule activation of the 5-HT2C receptor has been shown to affect food intake and regulate body weight gain in rodent models and more recently in human clinical trials. Therefore, 5-HT2C is a well validated target for anti-obesity therapy. The synthesis and structure-activity relationships of a series of novel tetrahydropyrazinoisoquinolinone 5-HT2C receptor agonists are presented. Several members of this series were identified as potent 5-HT2C receptor agonists with high functional selectivity against the 5-HT2A and 5-HT2B receptors and reduced food intake in an acute rat feeding model upon oral dosing. PMID- 23683594 TI - Anthraquinone derivatives from Rumex plants and endophytic Aspergillus fumigatus and their effects on diabetic nephropathy. AB - Two new oxanthrone C-glycosides, patientosides A (14) and B (15), together with three known ones (11-13), were isolated from Rumex patientia. Their structures were identified on the basis of spectroscopic methods. The absolute configuration for 14 and 15 were deduced by analysis of their CD spectra and comparison with those of known similar compounds. Compounds 11-15, and 14 known anthraquinones (1 4, 6-10, 16-20) previously isolated from Rumex nepalensis, Rumex hastatus, and endophytic Aspergillus fumigatus, respectively, as well as a commercially available compound rhein (5) were evaluated for their inhibitory effects on IL-6 and extracellular matrix production in mesangial cells. PMID- 23683595 TI - 2-Fluoropyridine prosthetic compounds for the 18F labeling of bombesin analogues. AB - Acetylene-bearing 2-[(18)F]fluoropyridines [(18)F]FPy5yne and PEG-[(18)F]FPyKYNE were prepared via efficient nucleophilic heteroaromatic [(18)F]fluorination of their corresponding 2-trimethylammoniumpyrdinyl precursors. The prosthetic groups were conjugated to azide- and PEG3-modified bombesin(6-14) analogues via copper catalyzed azide-alkyne cycloaddition couplings to yield mono- and di-mini PEGylated ligands for PET imaging of the gastrin- releasing peptide receptor. The PEG3- and PEG2/PEG3-bearing (18)F peptides showed decreased lipophilicity relative to an analogous non-mini-PEGylated (18)F peptide. Assessment of water soluble peptide pharmacokinetics and tumour-targeting capabilities in a mouse model of prostate cancer is currently underway. PMID- 23683596 TI - Discovery of N-(4'-(indol-2-yl)phenyl)sulfonamides as novel inhibitors of HCV replication. AB - A series of novel 2-phenylindole analogs were synthesized and evaluated for activity in subgenomic HCV replicon inhibition assays. Several compounds containing small alkyl sulfonamides on the phenyl ring exhibiting submicromolar EC50 values against the genotype 1b replicon were identified. Among these, compound 25d potently inhibited the 1b replicon (EC50=0.17 MUM) with 147-fold selectivity with respect to cytotoxicity. Compound 25d was stable in the presence of human liver microsomes and had a good pharmacokinetic profile in rats with an IV half-life of 4.3h and oral bioavailability (F) of 58%. PMID- 23683597 TI - Discovery of novel HCV inhibitors: synthesis and biological activity of 6-(indol 2-yl)pyridine-3-sulfonamides targeting hepatitis C virus NS4B. AB - A novel series of 6-(indol-2-yl)pyridine-3-sulfonamides was prepared and evaluated for their ability to inhibit HCV RNA replication in the HCV replicon cell culture assay. Preliminary optimization of this series furnished compounds with low nanomolar potency against the HCV genotype 1b replicon. Among these, compound 8c has identified as a potent HCV replicon inhibitor (EC50=4 nM) with a selectivity index with respect to cellular GAPDH of more than 2500. Further, compound 8c had a good pharmacokinetic profile in rats with an IV half-life of 6h and oral bioavailability (F) of 62%. Selection of HCV replicon resistance identified an amino acid substitution in HCV NS4B that confers resistance to these compounds. These compounds hold promise as a new chemotype with anti-HCV activity mediated through an underexploited viral target. PMID- 23683598 TI - Promise, and risks, of conditional cash transfer programmes. PMID- 23683599 TI - Effect of a conditional cash transfer programme on childhood mortality: a nationwide analysis of Brazilian municipalities. AB - BACKGROUND: In the past 15 years, Brazil has undergone notable social and public health changes, including a large reduction in child mortality. The Bolsa Familia Programme (BFP) is a widespread conditional cash transfer programme, launched in 2003, which transfers cash to poor households (maximum income US$70 per person a month) when they comply with conditions related to health and education. Transfers range from $18 to $175 per month, depending on the income and composition of the family. We aimed to assess the effect of the BFP on deaths of children younger than 5 years (under-5), overall and resulting from specific causes associated with poverty: malnutrition, diarrhoea, and lower respiratory infections. METHODS: The study had a mixed ecological design. It covered the period from 2004-09 and included 2853 (of 5565) municipalities with death and livebirth statistics of adequate quality. We used government sources to calculate all-cause under-5 mortality rates and under-5 mortality rates for selected causes. BFP coverage was classified as low (0.0-17.1%), intermediate (17.2 32.0%), high (>32.0%), or consolidated (>32.0% and target population coverage >=100% for at least 4 years). We did multivariable regression analyses of panel data with fixed-effects negative binomial models, adjusted for relevant social and economic covariates, and for the effect of the largest primary health-care scheme in the country (Family Health Programme). FINDINGS: Under-5 mortality rate, overall and resulting from poverty-related causes, decreased as BFP coverage increased. The rate ratios (RR) for the effect of the BFP on overall under-5 mortality rate were 0.94 (95% CI 0.92-0.96) for intermediate coverage, 0.88 (0.85-0.91) for high coverage, and 0.83 (0.79-0.88) for consolidated coverage. The effect of consolidated BFP coverage was highest on under-5 mortality resulting from malnutrition (RR 0.35; 95% CI 0.24-0.50) and diarrhoea (0.47; 0.37-0.61). INTERPRETATION: A conditional cash transfer programme can greatly contribute to a decrease in childhood mortality overall, and in particular for deaths attributable to poverty-related causes such as malnutrition and diarrhoea, in a large middle-income country such as Brazil. FUNDING: National Institutes of Science and Technology Programme, Ministry of Science and Technology, and Council for Scientific and Technological Development Programme (CNPq), Brazil. PMID- 23683601 TI - Is it time to combine osteoporosis therapies? PMID- 23683600 TI - Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. AB - BACKGROUND: Osteoporosis medications increase bone-mineral density (BMD) and lower but do not eliminate fracture risk. The combining of anabolic agents with bisphosphonates has not improved efficacy. We compared combined teriparatide and denosumab with both agents alone. METHODS: From September, 2009, to January, 2011, we enrolled postmenopausal women with osteoporosis into this randomised, controlled trial. Patients were assigned in a 1:1:1 ratio to receive 20 MUg teriparatide daily, 60 mg denosumab every 6 months, or both. BMD was measured at 0, 3, 6, and 12 months. Women who completed at least one study visit after baseline were assessed in a modified intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT00926380. FINDINGS: 94 (94%) of 100 eligible women completed at least one study visit after baseline. At 12 months, posterior-anterior lumbar spine BMD increased more in the combination group (9.1%, [SD 3.9]) than in the teriparatide (6.2% [4.6], p=0.0139) or denosumab (5.5% [3.3], p=0.0005) groups. Femoral-neck BMD also increased more in the combination group (4.2% [3.0]) than in the teriparatide (0.8% [4.1], p=0.0007) and denosumab (2.1% [3.8], p=0.0238) groups, as did total-hip BMD (combination, 4.9% [2.9]; teriparatide, 0.7% [2.7], p<0.0001; denosumab 2.5% [2.6], p=0.0011). INTERPRETATION: Combined teriparatide and denosumab increased BMD more than either agent alone and more than has been reported with approved therapies. Combination treatment might, therefore, be useful to treat patients at high risk of fracture. FUNDING: Amgen, Eli Lilly, National Center for Research Resources. PMID- 23683602 TI - A breakthrough for the health and rights of women and girls. PMID- 23683603 TI - Efficacy and safety of platelet inhibitors. AB - Ischemic heart disease is the second leading cause of death in the world. The proportion of deaths resulting from this condition has decreased in the last two decades, mainly as a result of improved primary and secondary prevention of cardiovascular events, as well as the development of patient awareness and medical and pharmacological management. The purpose of the present review is to analyze pathophysiological events leading to platelet involvement in cardiovascular thrombosis, as well as the role of pharmacogenetics in modulating the risk of cardiovascular disorders. The present work was performed using a PubMed search with combinations of key words relevant to the subject in both English and French. In addition to the pharmacokinetic and pharmacodynamic characteristics of platelet inhibitors, this work reviews the efficacy and adverse events observed during the clinical trials with these drugs. This review further summarizes possible therapeutic drug monitoring strategies for antiplatelet drugs. The novelty of this work is the description of the lymphocyte toxicity assay as a specific method of diagnosing and predicting possible idiosyncratic adverse events attributable to antiplatelet medication. PMID- 23683604 TI - Single-walled carbon nanotubes mediated neovascularity targeted antitumor drug delivery system. AB - PURPOSE: The aim of this study was to prepare a new neovascularity targeting antitumor drug delivery system mediated by single-walled carbon nanotubes (SWNTs). METHODS: In this study, antiangiogenesis agent 2-methoxyestradiol was loaded by SWNTs via pi~pi accumulation. The SWNTs were then linked with NGR (Asn Gly-Arg) peptide, which could target tumor angiogenesis. This drug delivery system was characterized by transmission electron microscope, scanning electron microscopy, and atomic force microscope analysis. The suppression efficacy of tumor growth in cultured breast cancer cell line was evaluated by the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The in vivo antitumor activity was evaluated on the Sarcoma (S180) tumor-bearing mice model. RESULTS: The characteristics of this drug delivery system showed that the particle of complex was 190 +/- 4.3 nm in size distribution and ?23.56 +/- 2.03 mV in zeta potential. The inhibition ratio of this SWNTs drug delivery system at 24, 48, and 72 h was about 57.7%, 83.6%, and 88.2%. Compared with normal saline group, the relative tumor volumes in the 2ME, SWNTs-2ME, and NGR-SWNTs-2ME groups were decreased 1 week after administration. CONCLUSION: This novel neovascularity targeting drug delivery system containing NGR-SWNTs-2ME may be beneficial to improve treatment efficacy and minimize side effects in future cancer therapy. PMID- 23683605 TI - Compositional and material properties of rat bone after bisphosphonate and/or Strontium ranelate drug treatment. AB - PURPOSE: We investigated elemental strontium and/or bisphosphonate drug incorporation upon the compositional and biomechanical properties of vertebral bone, in a rat model of Osteoporosis secondary to ovariectomy. METHODS: Six month old female rats were ovariectomized (OVX) and divided into untreated OVX-Vehicle, OVX-RIS (Risedronate bisphosphonate [BP] treated), OVX-SrR (Strontium Ranelate [Protos(r)] treated), combination OVX-RIS+SrR, and sham-operated controls. After 16 weeks of treatment, rats were euthanized and lumbar vertebra were dissected. Micro-Computed Tomography (micro-CT), Electron Probe Micro-Analysis (EPMA), mechanical testing in compression and nano-indentation testing were then undertaken to evaluate bone morphometry, elemental composition, material properties and strength. RESULTS: Bone Volume was significantly reduced in the OVX-Vehicle (133+/-10 mm(3)) compared with OVX-RIS (169+/-22 mm(3)), OVX-SrR (145+/-2 mm(3)), and OVX-RIS+SrR (172+/-8 mm(3)). EPMA mapped elemental Sr deposition to the periosteal surface of cortical bone (50-100 um thick), endosteal trabecular surfaces (20 um thick), as well as to both vertebral growth plates. The atomic ratios of (Ca+Sr)/P were significantly reduced with SrR treatment (2.4%-6.6%), indicating Sr incorporation into bone mineral. No significant differences were measured in vertebral bone reduced modulus by nano indentation. Conversely, all BP-dosed groups had significantly increased structural bone strength. CONCLUSIONS: Thus, we conclude that BP drugs dominate the conservation of trabecular geometry and structural strength in OP rats, whereas Sr drugs likely influence bone volume and material composition locally. PMID- 23683606 TI - The single dose poloxamer 407 model of hyperlipidemia; systemic effects on lipids assessed using pharmacokinetic methods, and its effects on adipokines. AB - PURPOSE: The induction of hyperlipidemia using poloxamer 407 (P407) is gaining use for studying the effect of the condition on drug pharmacokinetics. Although a single intraperitoneal dose of P407 causes a rapid onset of hyperlipidemia, the initial lipid concentrations are much higher than seen in humans. The hyperlipidemia is also reversible in nature. Here, pharmacokinetic methods were used to assess the P407 dose response on serum lipids, adipokines and cytokines. METHODS: Single 0.5 and 1 g/kg doses of P407 were injected into rats followed by blood collection at various times for up to 12 d. Serum was assayed for lipids, selected adipokines and cytokines. RESULTS: As expected, large increases in lipid levels were seen by 36 h after dosing. Using area under the concentration vs. time curve as a measure of systemic lipid exposure, P407 increased serum baseline corrected serum lipids in a nearly dose proportional fashion. The maximum increase in lipids was observed at ~36 h, with most lipids remaining elevated for up to ~180 h, although for the 1 g/kg dose triglyceride concentrations had still not quite returned to baseline by 12 days postdose. In addition to changes in lipids, P407 significantly increased serum leptin and decreased the serum adiponectin concentrations but did not affect cytokine levels. CONCLUSION: Depending on study aims, for the use of the model it may be beneficial to perform single-dose assessments at time points later than 36 h when the lipoprotein concentrations will be more similar to those seen in patient with hyperlipidemia. PMID- 23683607 TI - Efficacy and toxicity of factor Xa inhibitors. AB - Venous thromboembolism (VTE) is a serious disease that is often neglected, and effective and safe antithrombotic treatments are a public health priority. New antithrombotics such as rivaroxaban, apixaban, betrixaban, edoxaban, darexaban, TAK-442, LY517717, eribaxaban, otamixaban are being developed to overcome current therapeutic limitations. The new oral anticoagulants and parenteral otamixaban are under evaluation in clinical trials for VTE treatment, for VTE prevention in orthopedic surgery, for stroke prevention in patients with atrial fibrillation and for cardiovascular event prevention in patients with acute coronary syndrome. These antithrombotic agents directly and selectively inhibit factor Xa, and do not require coagulation monitoring and dose adjustment. Several of these drugs have shown promising results and have the potential to either replace or act as alternatives to traditional anticoagulants (heparins, vitamin K antagonists). PMID- 23683608 TI - Population pharmacokinetic and pharmacodynamic modeling of acetazolamide in peritoneal dialysis patients and healthy volunteers. AB - PURPOSE: To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of acetazolamide (ACTZ) in peritoneal dialysis patients, ACTZ 500 mg was administered intravenously to 7 healthy subjects (HV) and 8 peritoneal dialysis patients (CAPD). METHODS: Population PK/PD modeling was performed with ACTZ serum (total and unbound), urine and dialysate concentrations, intra-ocular pressure (IOP) and covariates. A multi-compartment PK model (accounting for non-linear protein binding) and an inhibitory Emax (maximal change in IOP) PD model were selected. RESULTS: As expected, renal clearance (which almost equals total body clearance) was severely decreased in CAPD (1.2 vs 80.3 L/h) and the elimination half-life of total ACTZ was prolonged (20.6 vs 3.4 hours). The protein binding was significantly altered with a mean free fraction 4.2% in HV and 8.6% in CAPD. Moreover protein binding of ACTZ was concentration dependent in both HV and CAPD. Despite a higher free fraction of ACTZ, the Emax was lower in CAPD: 4.4+/-1.4 vs 7.4+/-2.8 mmHg. CONCLUSION: Both PK and PD are significantly altered in dialysis patients. PMID- 23683609 TI - Effect of chromium on glucose and lipid profiles in patients with type 2 diabetes; a meta-analysis review of randomized trials. AB - PURPOSE: Chromium (Cr) as an essential trace element in metabolism of carbohydrate, lipid and protein is currently prescribed to control diabetes mellitus (DM). The objective of this meta-analysis was to compare the effect of Cr versus placebo (Pl) on glucose and lipid profiles in patients with type 2 DM. METHODS: Literature searches in PubMed, Scopus, Scirus, Google Scholar and IranMedex was made by use of related terms during the period of 2000-2012. Eligible studies were randomized clinical trials (RCTs) with intake of Cr higher than 250 ug at least for three months in type 2 DM. Glycated hemoglobin (HbA1c), fasting blood sugar (FBS), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), triglyceride (TG), and body mass index (BMI) were the main outcomes. RESULTS: Seven out of 13 relevant studies met the criteria and were included in the meta-analysis. HbA1c change in diabetic patients in Cr supplement therapy comparing to Pl was -0.33 with 95%CI= -0.72 to 0.06 (P= 0.1). Change of FBG in Cr therapy vs. Pl was -0.95 with 95%CI= -1.42 to 0.49 (P< 0.0001). TC change in Cr therapy vs. Pl was 0.07 with 95%CI= -0.16 to 0.31 (P= 0.54). TG change in diabetic patients in Cr supplement therapy comparing to Pl was -0.15 with 95%CI= -0.36 to 0.07 (P= 0.18). CONCLUSIONS: Cr lowers FBS but does not affect HbA1c, lipids and BMI. PMID- 23683610 TI - Enhanced lactone stability of CZ48 in blood correlates to its lack of toxicity in mice. AB - PURPOSE: The aim of this study was to correlate the relationship between the pharmacokinetic behaviors and the toxicity of a new investigational anticancer agent CZ48, a C20-propionate ester of camptothecin (CPT) in mice. METHODS: In this study, the safety and pharmacokinetics of oral doses of CZ48 were compared with the oral doses of CPT. Mice were administered orally one of three single doses of CZ48 (50, 200 and 1000 mg/kg) and two single doses of CPT (1.5 mg/kg and 6.0 mg/kg). Blood samples were collected from all mice at the defined time points after drug administration for assessment of plasma CZ48 and CPT concentrations. RESULTS: The study showed that CZ48 was very stable in mouse blood and the majority of this agent stayed intact as the lactone form when in circulation, with only a small fraction of the CZ48 molecules metabolized into CPT. The concentration of the metabolite CPT measured in the mouse blood was only 3% of the concentration found for the maximum tolerated dose (6.0 mg/kg) of plain CPT. The stability difference between CZ48 and CPT in blood was structurally explained by the geometry of these two molecules. CONCLUSION: The lack of toxicity of CZ48 at effective doses in mice is attributed to its enhanced stability in their blood. PMID- 23683611 TI - What works in secondary schools? A systematic review of classroom-based body image programs. AB - Governments, schools, and curriculum authorities are increasingly recognizing that body image during adolescence is a public health issue that warrants attention in the school setting. After 30 years of eating disorder prevention research, and given the current interest in this area, it seems timely to review the research on interventions to improve body image in schools. We reviewed universal-selective, classroom-based programs that have been conducted since the year 2000, among adolescents, and found 16 eligible intervention programs. Seven of these programs were effective in improving body image on at least one measure, from pre to post test, though effect sizes were small (d=0.22-0.48). These effective programs were conducted among younger adolescents 12.33-13.62 years, and included activities focusing on media literacy, self esteem, and the influence of peers. Implications for school personnel and curriculum authorities are discussed, and we provide recommendations for a strategic approach to future research in this area. PMID- 23683612 TI - Women Deliver post-2015. PMID- 23683613 TI - GAVI injects new life into HPV vaccine rollout. PMID- 23683614 TI - Hepatitis C in the USA and Europe: two problems, one solution. PMID- 23683615 TI - Shared commitment to women's health abroad and at home. PMID- 23683616 TI - Maternal health in Malaysia: progress and potential. PMID- 23683617 TI - Maternal health: a missed opportunity for development. PMID- 23683618 TI - Participatory women's groups: ready for prime time? PMID- 23683619 TI - Care assessment's difficult relation with maternal mortality. PMID- 23683620 TI - Meeting the unmet need for family planning: now is the time. PMID- 23683621 TI - Maternal deaths and HIV treatment in sub-Saharan Africa. PMID- 23683622 TI - Aid for reproductive health: progress and challenges. PMID- 23683623 TI - Obstetric fistula: ending the health and human rights tragedy. PMID- 23683625 TI - Susheela Singh and Jacqueline Darroch: turning research into advocacy for reproductive health. PMID- 23683626 TI - Supplemental parenteral nutrition in critically ill patients. PMID- 23683627 TI - Supplemental parenteral nutrition in critically ill patients. PMID- 23683628 TI - Supplemental parenteral nutrition in critically ill patients. PMID- 23683629 TI - Supplemental parenteral nutrition in critically ill patients. PMID- 23683630 TI - Supplemental parenteral nutrition in critically ill patients. PMID- 23683631 TI - Supplemental parenteral nutrition in critically ill patients--authors' reply. PMID- 23683632 TI - Maternal health post-2015. PMID- 23683633 TI - Maternal health post-2015--authors' reply. PMID- 23683634 TI - Maternal health post-2015. PMID- 23683635 TI - Maternal Death Reviews. PMID- 23683636 TI - Counting the dead: properly and promptly. PMID- 23683637 TI - EU Clinical Trials Regulation. PMID- 23683638 TI - Road traffic injuries in Iraq. PMID- 23683639 TI - Effect of women's groups and volunteer peer counselling on rates of mortality, morbidity, and health behaviours in mothers and children in rural Malawi (MaiMwana): a factorial, cluster-randomised controlled trial. AB - BACKGROUND: Women's groups and health education by peer counsellors can improve the health of mothers and children. We assessed their effects on mortality and breastfeeding rates in rural Malawi. METHODS: We did a 2*2 factorial, cluster randomised trial in 185,888 people in Mchinji district. 48 equal-sized clusters were randomly allocated to four groups with a computer-generated number sequence. 24 facilitators guided groups through a community action cycle to tackle maternal and child health problems. 72 trained volunteer peer counsellors made home visits at five timepoints during pregnancy and after birth to support breastfeeding and infant care. Primary outcomes for the women's group intervention were maternal, perinatal, neonatal, and infant mortality rates (MMR, PMR, NMR, and IMR, respectively); and for the peer counselling were IMR and exclusive breastfeeding (EBF) rates. Analysis was by intention to treat. The trial is registered as ISRCTN06477126. FINDINGS: We monitored outcomes of 26,262 births between 2005 and 2009. In a factorial model adjusted only for clustering and the volunteer peer counselling intervention, in women's group areas, for years 2 and 3, we noted non significant decreases in NMR (odds ratio 0.93, 0.64-1.35) and MMR (0.54, 0.28 1.04). After adjustment for parity, socioeconomic quintile, and baseline measures, effects were larger for NMR (0.85, 0.59-1.22) and MMR (0.48, 0.26 0.91). Because of the interaction between the two interventions, a stratified analysis was done. For women's groups, in adjusted analyses, MMR fell by 74% (0.26, 0.10-0.70), and NMR by 41% (0.59, 0.40-0.86) in areas with no peer counsellors, but there was no effect in areas with counsellors (1.09, 0.40-2.98, and 1.38, 0.75-2.54). Factorial analysis for the peer counselling intervention for years 1-3 showed a fall in IMR of 18% (0.82, 0.67-1.00) and an improvement in EBF rates (2.42, 1.48-3.96). The results of the stratified, adjusted analysis showed a 36% reduction in IMR (0.64, 0.48-0.85) but no effect on EBF (1.18, 0.63 2.25) in areas without women's groups, and in areas with women's groups there was no effect on IMR (1.05, 0.82-1.36) and an increase in EBF (5.02, 2.67-9.44). The cost of women's groups was US$114 per year of life lost (YLL) averted and that of peer counsellors was $33 per YLL averted, using stratified data from single intervention comparisons. INTERPRETATION: Community mobilisation through women's groups and volunteer peer counsellor health education are methods to improve maternal and child health outcomes in poor rural populations in Africa. FUNDING: Saving Newborn Lives, UK Department for International Development, and Wellcome Trust. PMID- 23683640 TI - Women's groups practising participatory learning and action to improve maternal and newborn health in low-resource settings: a systematic review and meta analysis. AB - BACKGROUND: Maternal and neonatal mortality rates remain high in many low-income and middle-income countries. Different approaches for the improvement of birth outcomes have been used in community-based interventions, with heterogeneous effects on survival. We assessed the effects of women's groups practising participatory learning and action, compared with usual care, on birth outcomes in low-resource settings. METHODS: We did a systematic review and meta-analysis of randomised controlled trials undertaken in Bangladesh, India, Malawi, and Nepal in which the effects of women's groups practising participatory learning and action were assessed to identify population-level predictors of effect on maternal mortality, neonatal mortality, and stillbirths. We also reviewed the cost-effectiveness of the women's group intervention and estimated its potential effect at scale in Countdown countries. FINDINGS: Seven trials (119,428 births) met the inclusion criteria. Meta-analyses of all trials showed that exposure to women's groups was associated with a 37% reduction in maternal mortality (odds ratio 0.63, 95% CI 0.32-0.94), a 23% reduction in neonatal mortality (0.77, 0.65 0.90), and a 9% non-significant reduction in stillbirths (0.91, 0.79-1.03), with high heterogeneity for maternal (I(2)=58.8%, p=0.024) and neonatal results (I(2)=64.7%, p=0.009). In the meta-regression analyses, the proportion of pregnant women in groups was linearly associated with reduction in both maternal and neonatal mortality (p=0.026 and p=0.011, respectively). A subgroup analysis of the four studies in which at least 30% of pregnant women participated in groups showed a 55% reduction in maternal mortality (0.45, 0.17-0.73) and a 33% reduction in neonatal mortality (0.67, 0.59-0.74). The intervention was cost effective by WHO standards and could save an estimated 283,000 newborn infants and 41,100 mothers per year if implemented in rural areas of 74 Countdown countries. INTERPRETATION: With the participation of at least a third of pregnant women and adequate population coverage, women's groups practising participatory learning and action are a cost-effective strategy to improve maternal and neonatal survival in low-resource settings. FUNDING: Wellcome Trust, Ammalife, and National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care for Birmingham and the Black Country programme. PMID- 23683642 TI - Trends in contraceptive need and use in developing countries in 2003, 2008, and 2012: an analysis of national surveys. AB - BACKGROUND: Data for trends in contraceptive use and need are necessary to guide programme and policy decisions and to monitor progress towards Millennium Development Goal 5, which calls for universal access to contraceptive services. We therefore aimed to estimate trends in contraceptive use and unmet need in developing countries in 2003, 2008, and 2012 . METHODS: We obtained data from national surveys for married and unmarried women aged 15-49 years in regions and subregions of developing countries. We estimated trends in the numbers and proportions of women wanting to avoid pregnancy, according to whether they were using modern contraceptives, or had unmet need for modern methods (ie, using no methods or a traditional method). We used comparable data sources and methods for three reference years (2003, 2008, and 2012). National survey data were available for 81-98% of married women using and with unmet need for modern methods. FINDINGS: The number of women wanting to avoid pregnancy and therefore needing effective contraception increased substantially, from 716 million (54%) of 1321 million in 2003, to 827 million (57%) of 1448 million in 2008, to 867 million (57%) of 1520 million in 2012. Most of this increase (108 million) was attributable to population growth. Use of modern contraceptive methods also increased, and the overall proportion of women with unmet need for modern methods among those wanting to avoid pregnancy decreased from 29% (210 million) in 2003, to 26% (222 million) in 2012. However, unmet need for modern contraceptives was still very high in 2012, especially in sub-Saharan Africa (53 million [60%] of 89 million), south Asia (83 million [34%] of 246 million), and western Asia (14 million [50%] of 27 million). Moreover, a shift in the past decade away from sterilisation, the most effective method, towards injectable drugs and barrier methods, might have led to increases in unintended pregnancies in women using modern methods. INTERPRETATION: Achievement of the desired number and healthy timing of births has important benefits for women, families, and societies. To meet the unmet need for modern contraception, countries need to increase resources, improve access to contraceptive services and supplies, and provide high-quality services and large-scale public education interventions to reduce social barriers. Our findings confirm a substantial and unfinished agenda towards meeting of couples' reproductive needs. FUNDING: UK Department for International Development, the Bill & Melinda Gates Foundation, and the UN Population Fund (UNFPA). PMID- 23683641 TI - Moving beyond essential interventions for reduction of maternal mortality (the WHO Multicountry Survey on Maternal and Newborn Health): a cross-sectional study. AB - BACKGROUND: We report the main findings of the WHO Multicountry Survey on Maternal and Newborn Health (WHOMCS), which aimed to assess the burden of complications related to pregnancy, the coverage of key maternal health interventions, and use of the maternal severity index (MSI) in a global network of health facilities. METHODS: In our cross-sectional study, we included women attending health facilities in Africa, Asia, Latin America, and the Middle East that dealt with at least 1000 childbirths per year and had the capacity to provide caesarean section. We obtained data from analysis of hospital records for all women giving birth and all women who had a severe maternal outcome (SMO; ie, maternal death or maternal near miss). We regarded coverage of key maternal health interventions as the proportion of the target population who received an indicated intervention (eg, the proportion of women with eclampsia who received magnesium sulphate). We used areas under the receiver operator characteristic curves (AUROC) with 95% CI to externally validate a previously reported MSI as an indicator of severity. We assessed the overall performance of care (ie, the ability to produce a positive effect on health outcomes) through standardised mortality ratios. RESULTS: From May 1, 2010, to Dec 31, 2011, we included 314,623 women attending 357 health facilities in 29 countries (2538 had a maternal near miss and 486 maternal deaths occurred). The mean period of data collection in each health facility was 89 days (SD 21). 23,015 (7.3%) women had potentially life-threatening disorders and 3024 (1.0%) developed an SMO. 808 (26.7%) women with an SMO had post-partum haemorrhage and 784 (25.9%) had pre-eclampsia or eclampsia. Cardiovascular, respiratory, and coagulation dysfunctions were the most frequent organ dysfunctions in women who had an SMO. Reported mortality in countries with a high or very high maternal mortality ratio was two-to-three times higher than that expected for the assessed severity despite a high coverage of essential interventions. The MSI had good accuracy for maternal death prediction in women with markers of organ dysfunction (AUROC 0.826 [95% CI 0.802 0.851]). INTERPRETATION: High coverage of essential interventions did not imply reduced maternal mortality in the health-care facilities we studied. If substantial reductions in maternal mortality are to be achieved, universal coverage of life-saving interventions need to be matched with comprehensive emergency care and overall improvements in the quality of maternal health care. The MSI could be used to assess the performance of health facilities providing care to women with complications related to pregnancy. FUNDING: UNDP-UNFPA-UNICEF WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP); WHO; USAID; Ministry of Health, Labour and Welfare of Japan; Gynuity Health Projects. PMID- 23683643 TI - Effect of HIV infection on pregnancy-related mortality in sub-Saharan Africa: secondary analyses of pooled community-based data from the network for Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA). AB - BACKGROUND: Model-based estimates of the global proportions of maternal deaths that are in HIV-infected women range from 7% to 21%, and the effects of HIV on the risk of maternal death is highly uncertain. We used longitudinal data from the Analysing Longitudinal Population-based HIV/AIDS data on Africa (ALPHA) network to estimate the excess mortality associated with HIV during pregnancy and the post-partum period in sub-Saharan Africa. METHODS: The ALPHA network pooled data gathered between June, 1989 and April, 2012 in six community-based studies in eastern and southern Africa with HIV serological surveillance and verbal autopsy reporting. Deaths occurring during pregnancy and up to 42 days post partum were defined as pregnancy related. Pregnant or post-partum person-years were calculated for HIV-infected and HIV-uninfected women, and HIV-infected to HIV-uninfected mortality rate ratios and HIV-attributable rates were compared between pregnant or post-partum women and women who were not pregnant or post partum. FINDINGS: 138,074 women aged 15-49 years contributed 636,213 person-years of observation. 49,568 women had 86,963 pregnancies. 6760 of these women died, 235 of them during pregnancy or the post-partum period. Mean prevalence of HIV infection across all person-years in the pooled data was 17.2% (95% CI 17.0 17.3), but 60 of 118 (50.8%) of the women of known HIV status who died during pregnancy or post partum were HIV infected. The mortality rate ratio of HIV infected to HIV-uninfected women was 20.5 (18.9-22.4) in women who were not pregnant or post partum and 8.2 (5.7-11.8) in pregnant or post-partum women. Excess mortality attributable to HIV was 51.8 (47.8-53.8) per 1000 person-years in women who were not pregnant or post partum and 11.8 (8.4-15.3) per 1000 person years in pregnant or post-partum women. INTERPRETATION: HIV-infected pregnant or post-partum women had around eight times higher mortality than did their HIV uninfected counterparts. On the basis of this estimate, we predict that roughly 24% of deaths in pregnant or post-partum women are attributable to HIV in sub Saharan Africa, suggesting that safe motherhood programmes should pay special attention to the needs of HIV-infected pregnant or post-partum women. FUNDING: Wellcome Trust, Health Metrics Network (WHO). PMID- 23683644 TI - Reproductive health priorities: evidence from a resource tracking analysis of official development assistance in 2009 and 2010. AB - BACKGROUND: Information is scarce about the extent to which official development assistance (ODA) is spent on reproductive health to provide childbirth care; support family planning; address sexual health; and prevent, treat, and care for sexually transmitted infections, including HIV. We analysed flows of ODA to reproductive health for 2009 and 2010, assessed their distribution by donor type and purpose, and investigated the extent to which disbursements respond to need. We aimed to provide global estimates of aid to reproductive health, to assess the allocation of resources across reproductive health activities, and to encourage donor accountability in targeting aid flows to those most in need. METHODS: We applied a standard definition of reproductive health across all donors, including a portion of disease-specific activities and health systems development. We analysed disbursements to reproductive health by donor type and purpose (eg, family planning). We also reported on an indicator to monitor donor disbursements: ODA to reproductive health per woman aged 15-49 years. We analysed the extent to which funding is targeted to countries most in need, proxied by female life expectancy at birth and prevalence of HIV infection in adults. FINDINGS: Donor disbursements to reproductive health activities in all countries amounted to US$5579 million in 2009 and US$5637 million in 2010-an increase of 1.0%. ODA for such activities in the 74 Countdown priority countries increased more rapidly at 5.3%. More than half of the funding was directed towards prevention, treatment, and care of HIV infection for women of reproductive age (15-49 years of age). On average, ODA to general reproductive health activities amounted to 15.9% and ODA to family planning 7.2%. Aid to reproductive health was heavily dependent on the USA, the Global Fund, the UK, the United Nations Population Fund, and the World Bank. INTERPRETATION: Donors are prioritising reproductive health, and the slight increase in funding in 2009-10 is welcome, especially in the present economic climate. The large share of such funding for activities related to HIV infection in women of reproductive age affects the amount of ODA received by priority countries. It should thus be distinguished from resources directed to other reproductive health activities, such as family planning, which has been the focus of recent worldwide advocacy efforts. Tracking of donor aid to reproductive health should continue to allow investigation of the allocation of resources across reproductive health activities, and to encourage donor accountability in targeting aid flows to those most in need. FUNDING: Bill & Melinda Gates Foundation, World Bank, and the Governments of Australia, Canada, Norway, Sweden, and the UK. PMID- 23683645 TI - Gender and global health: evidence, policy, and inconvenient truths. PMID- 23683646 TI - Neurological presentation of schistosomiasis. PMID- 23683647 TI - Can women's groups reduce maternal and newborn deaths? PMID- 23683648 TI - Analyses confirm effect of women's groups on maternal and newborn deaths. PMID- 23683649 TI - Congenital ocular motor apraxia, the NPHP1 gene, and surveillance for nephronophthisis. AB - We present an 11-month-old girl with congenital ocular motor apraxia (COMA) and Joubert syndrome found to have a compound heterozygous mutation in the NPHP1 gene that is responsible for juvenile nephronophthisis type 1. The association of congenital ocular motor apraxia and juvenile nephronophthisis is reviewed. The patient does not currently manifest signs of renal failure, although her mutation indicates that she is at risk for the development of juvenile nephronophthisis type 1. PMID- 23683650 TI - Q&A: antibiotic resistance: what more do we know and what more can we do? PMID- 23683652 TI - World Association for the Advancement of Veterinary Parasitology (WAAVP): the 50th anniversary in 2013--history, achievements, and future perspectives. AB - In 2013 the World Association for the Advancement of Veterinary Parasitology (WAAVP) can celebrate its 50th anniversary. At this occasion in this article selected historical data are updated, and the achievements and future perspectives of the WAAVP are discussed. Although the WAAVP is a small association with only a few hundred members, it has been able to develop remarkable activities. Between 1963 and 2011 the WAAVP has organized 23 international scientific congresses, and the 24th conference will take place in Perth, Western Australia, in 2013. These conferences have achieved a high degree of international recognition as indicated by relatively large numbers of participants (up to ~800). Furthermore, the WAAVP has promoted veterinary parasitology in various ways, such as publishing international guidelines (efficacy evaluation of antiparasitic drugs, parasitological methods, standardized nomenclature of animal parasitic diseases "SNOAPAD"), stimulating international discussions on teaching and continued education ("colleges of veterinary parasitology") and by supporting the high quality journal "Veterinary Parasitology" which is the official organ of the WAAVP. In retrospect, the development of the WAAVP can be classified as very successful. New challenges associated with global changes (growth of the world population, urbanization, climate change, new developments in animal and plant production, etc.) will require new efforts in research in various fields, including veterinary parasitology. Future activities of WAAVP may include inter alia: (a) support of international parasitological networks; (b) stimulation of coordinated research aimed at the solution of defined problems; (c) increasing the exposure of WAAVP to parasitology from hitherto neglected regions of the world; (d) strengthening of official links to international organizations (FAO, WHO, etc.); (e) continuation of guideline preparation; and (d) preparation and international distribution of high quality electronic programs for self-education in veterinary parasitology. PMID- 23683651 TI - Molecular characterization of Trypanosoma (Megatrypanum) spp. infecting cattle (Bos taurus), white-tailed deer (Odocoileus virginianus), and elk (Cervus elaphus canadensis) in the United States. AB - In the United States, the generally non-pathogenic trypanosome of cattle is designated Trypanosoma (Megatrypanum) theileri and is distinguished morphologically from Trypanosoma (M.) cervi, a trypanosome originally described in mule deer and elk. Phylogenetic studies of the Megatrypanum trypanosomes using various molecular markers reveal two lineages, designated TthI and TthII, with several genotypes within each. However, to date there is very limited genetic data for T. theileri, and none for the Megatrypanum trypanosomes found in wild ungulates, in the U.S. In this study U.S. isolates from cattle (Bos taurus), white-tailed deer (Odocoileus virginianus) (WTD), and elk (Cervus elaphus canadensis) were compared by ribosomal DNA (rDNA) sequence analysis and their incidence in cattle and WTD in south Texas counties was investigated. Phylogenetic analyses showed clear separation of the bovine and cervine trypanosomes. Both lineages I and II were represented in the U.S. cattle and WTD parasites. Lineage I cattle isolates were of a previously described genotype, whereas WTD and elk isolates were of two new genotypes distinct from the cattle trypanosomes. The cattle isolate of lineage II was of a previously reported genotype and was divergent from the WTD isolate, which was of a new genotype. In La Salle, Starr, Webb, and Zapata counties in south Texas a total of 51.8% of white-tailed deer were positive for trypanosomes by 18S rDNA PCR. Of the cattle screened in Webb County, 35.4% were positive. Drought conditions prevailing in south Texas when the animals were screened suggest the possibility of a vector for Trypanosoma other than the ked (Lipoptena mazamae) and tabanid flies (Tabanus spp. and Haematopota spp.). PMID- 23683653 TI - Can we use genetic and genomic approaches to identify candidate animals for targeted selective treatment. AB - Estimated breeding values (EBV) for faecal egg count (FEC) and genetic markers for host resistance to nematodes may be used to identify resistant animals for selective breeding programmes. Similarly, targeted selective treatment (TST) requires the ability to identify the animals that will benefit most from anthelmintic treatment. A mathematical model was used to combine the concepts and evaluate the potential of using genetic-based methods to identify animals for a TST regime. EBVs obtained by genomic prediction were predicted to be the best determinant criterion for TST in terms of the impact on average empty body weight and average FEC, whereas pedigree-based EBVs for FEC were predicted to be marginally worse than using phenotypic FEC as a determinant criterion. Whilst each method has financial implications, if the identification of host resistance is incorporated into a wider genomic selection indices or selective breeding programmes, then genetic or genomic information may be plausibly included in TST regimes. PMID- 23683654 TI - The pathology and pathogenicity of a novel Haemoproteus spp. infection in wild Little Penguins (Eudyptula minor). AB - One hundred and thirty four Little Penguin (Eudyptula minor) carcases found since 2004 in south west Australia were necropsied. The livers and spleens from ten of the penguins exhibited varying degrees of multifocal, randomly scattered areas of necrosis and varying numbers of parasites were associated with these areas. Hepatomegaly and splenomegaly were noted in many of these ten cases. Necrosis and parasites were also observed in the cardiac muscle of four of the cases and in the lung tissue in one of the penguins. Using PCR, the parasites were positively identified in four of the cases as Haemoproteus spp. and morphologically identical tissue stage parasites associated with histopathological changes were observed in all ten dead penguins. This is the first study to demonstrate both the in situ presence of the Haemoproteus parasite in any member of the Sphensicidae family and mortality due to its presence. We postulate the involvement of anomalous environmental conditions in a potential increase in local vectors. PMID- 23683656 TI - Immunotherapy in Alzheimer's disease: do we have all the pieces of the puzzle? AB - Results of Phase III studies involving a large number of Alzheimer's disease (AD) patients treated by passive immunotherapy with humanized anti-amyloid beta monoclonal antibodies have recently been released. These approaches failed to show a significant clinical benefit in patients with mild to moderate AD. The most considered explanation is that the patients have been treated too late. Whereas targeting patients at asymptomatic stages of the disease is a critical step in the goal of improving the efficacy of such antibody-based strategies, several other important factors should be considered in the development and clinical evaluation of anti-amyloid beta immunotherapies, including the as yet poorly understood relationship of AD with the immune system and the importance of cerebral amyloid angiopathy. Better understanding the role of immune responses in AD and their impact on immunotherapy appears essential in the design of alternative or combinatorial immunotherapy approaches in AD, which may imply effectors other than antibodies and even additional antigenic targets. PMID- 23683655 TI - Role of prefrontal cortex glucocorticoid receptors in stress and emotion. AB - BACKGROUND: Stress-related disorders (e.g., depression) are associated with hypothalamic-pituitary-adrenocortical axis dysregulation and prefrontal cortex (PFC) dysfunction, suggesting a functional link between aberrant prefrontal corticosteroid signaling and mood regulation. METHODS: We used a virally mediated knockdown strategy (short hairpin RNA targeting the glucocorticoid receptor [GR]) to attenuate PFC GR signaling in the rat PFC. Adult male rats received bilateral microinjections of vector control or short hairpin RNA targeting the GR into the prelimbic (n = 44) or infralimbic (n = 52) cortices. Half of the animals from each injection group underwent chronic variable stress, and all were subjected to novel restraint. The first 2 days of chronic variable stress were used to assess depression- and anxiety-like behavior in the forced swim test and open field. RESULTS: The GR knockdown confined to the infralimbic PFC caused acute stress hyper-responsiveness, sensitization of stress responses after chronic variable stress, and induced depression-like behavior (increased immobility in the forced swim test). Knockdown of GR in the neighboring prelimbic PFC increased hypothalamic-pituitary-adrenocortical axis responses to acute stress and caused hyperlocomotion in the open field, but did not affect stress sensitization or helplessness behavior. CONCLUSIONS: The data indicate a marked functional heterogeneity of glucocorticoid action in the PFC and highlight a prominent role for the infralimbic GR in appropriate stress adaptation, emotional control, and mood regulation. PMID- 23683657 TI - Hyperthermia, inflammation, and perinatal brain injury. AB - Hyperthermia at the time of or following a hypoxic-ischemic insult has been associated with adverse neurodevelopmental outcome. Moreover, an elevation in temperature during labor has been associated with a variety of other adverse neurologic sequelae such as neonatal seizures, encephalopathy, stroke, and cerebral palsy. These outcomes may be secondary to a number of deleterious effects of hyperthermia including an increase in cellular metabolic rate and cerebral blood flow alteration, release of excitotoxic products such as free radicals and glutamate, and hemostatic changes. There is also an association between chorioamnionitis at the time of delivery and cerebral palsy, which is thought to be secondary to cytokine-mediated injury. We review experimental and human studies demonstrating a link between hyperthermia and perinatal brain injury. PMID- 23683658 TI - Multiple giant Virchow-Robin spaces. PMID- 23683659 TI - Unilateral aplasia of the facial nerve diagnosed by high-resolution MRI. PMID- 23683660 TI - Inhibition of Na+/H+ exchanger 1 by cariporide reduces burn-induced intestinal barrier breakdown. AB - Severe burns initiate an inflammatory cascade within the gut, which leads to intestinal mucosal injury. Although Na(+)/H(+) exchanger 1 (NHE1) is recognised as a pivotal player in several inflammatory processes, its role in burn-induced intestinal injury is relatively unknown. We hypothesised that NHE1 might be involved in the increased intestinal permeability and barrier breakdown after severe burns. Thus, we here investigate whether the inhibition of NHE1 has a protective effect on burn-induced intestinal injury. Mice were subjected to a 30% total body surface area (TBSA) full-thickness steam burn. Cariporide was used to assess the function of NHE1 in mice with burn-induced intestinal injury by fluorescence spectrophotometry, Western blotting and enzyme linked immunosorbent assay (ELISA). We found that severe burn increased intestinal permeability, associated with the up-regulation of NHE1 and raised inflammatory cytokine levels. Mice treated with the NHE1 inhibitor cariporide had significantly attenuated burn-induced intestinal permeability and a reduced inflammatory response. NHE1 inhibition also reduced nuclear factor-kappaB (NF-kappaB) activation and attenuated p38 mitogen-activated protein kinase (MAPK) phosphorylation. Our study suggests that NHE1 plays an important role in burn induced intestinal permeability through the regulation of the inflammatory response. Inhibition of NHE1 may be adopted as a potential therapeutic strategy for attenuating intestinal barrier breakdown. PMID- 23683661 TI - Epidemiology of burns undergoing hospitalization to the National Burns Unit in the Sultanate of Oman: a 25-year review. AB - AIM: The aim of this study was to describe the epidemiology of burns admitted to the National Burns Unit (NBU) in the Sultanate of Oman between 1987 and 2011. METHODS: This is a retrospective review of burn patients admitted to Oman's National Burns Unit (NBU) between 1987 and 2011. The data extracted from the national burn registry. The study describes the admission rate by gender and age groups, occupation, causes of burns, time-to-admission, length of stay and in hospital mortality of burns between 1987 and 2011. RESULTS: During a 25-year from 1987 to 2011, there were 3531 burn patients admitted to the National Burns Unit in Oman. The average admission rate to NBU is 7.02 per 100,000 persons per year. On average, males were more likely to be admitted to the NBU than females during the study period (P value < 0.04). Patients aged 1-10 years old constituted 46.6% of caseload during the study period. Flames and scalds caused 88.4% of burns. About half of all patients admitted to the NBU have burns to more than 11% of total body surface area (TBSA). The average stay in hospital was estimated to be 15.3 days per patient. The average in-hospital mortality rate was estimated to be 8.2% per year (range 1.9-22%). CONCLUSION: Burns are significant public health issue in the Sultanate of Oman. Children are disproportionately over-represented in this study. Prevention programmes are urgently needed to address this "silent and costly epidemic." PMID- 23683662 TI - Dissemination of metabolomics results: role of MetaboLights and COSMOS. AB - With ever-increasing amounts of metabolomics data produced each year, there is an even greater need to disseminate data and knowledge produced in a standard and reproducible way. To assist with this a general purpose, open source metabolomics repository, MetaboLights, was launched in 2012. To promote a community standard, initially culminated as metabolomics standards initiative (MSI), COordination of Standards in MetabOlomicS (COSMOS) was introduced. COSMOS aims to link life science e-infrastructures within the worldwide metabolomics community as well as develop and maintain open source exchange formats for raw and processed data, ensuring better flow of metabolomics information. PMID- 23683664 TI - Study of testosterone as a predictor of tumor aggressiveness in patients with prostate cancer. AB - PURPOSE: A growing body of evidence suggests that low testosterone can be an independent predictor of adverse clinicopathological features and worse prognosis in prostate cancer (PCa) patients. However, this association is still incompletely understood and the results are divisive. The aim of this study was to analyze testosterone as a predictor of aggressive disease in subjects with clinically localized PCa. MATERIALS AND METHODS: A cohort was conducted including the patients submitted to radical prostatectomy in our institution during a period of four years. The patients had clinically localized disease and their total testosterone (TT) was routinely measured preoperatively in the morning before surgery. They were stratified in groups with low (< 300 ng/dL) and normal TT (>= 300 ng/dL). Tumor aggressiveness was inferred based on preoperative PSA levels, pathological Gleason score (lower, equal or greater than 7), TNM stage and surgical margins status. RESULTS: After analyzing 164 patients we found a significant association between mean preoperative TT and extraprostatic disease (379 for pT3 vs. 421 ng/for pT2 - p < 0.001, AUC > 0.99). Conversely, men with high Gleason score had similar mean TT compared to those with lower scores. Preoperative low TT (defined as TT < 300 ng/dL) could not be statistically correlated with either preoperative PSA levels, pathological Gleason score, extraprostatic extension, positive surgical margins or seminal vesicles involvement. CONCLUSIONS: This study indicates that testosterone may be a useful predictive tool once pathological extraprostatic extension was somewhat signaled by lower TT levels preoperatively. However, it does not consolidate a clear association between aggressive tumor biology and hypogonadism. PMID- 23683663 TI - Elevated liver enzymes in individuals with undiagnosed diabetes in the U.S. AB - OBJECTIVE: We investigated the association of diabetes diagnosis and medication type with liver injury in individuals with clinical diabetes. METHODS: We analyzed 2426 patients with clinical diabetes in the National Health and Nutrition Examination Survey conducted from 1999 to 2008. Elevated alanine transaminase (ALT) and aspartate transaminase (AST) levels were used as markers of liver injury. Participants were categorized into one of three categories: 1) clinical diabetes without physician's diagnosis or diabetes medication; 2) diagnosed diabetes without diabetes medication; or 3) diagnosed diabetes with diabetes medication, further divided by classes of diabetes medications prescribed. We conducted logistic regression analysis to examine the relationship between diabetes diagnosis and medication type and elevated ALT and AST, adjusting for race/ethnicity, education, health insurance status, BMI category, alcohol consumption, physical activity, antihyperlipidemic agents, glycohemoglobin, C-reactive protein, viral hepatitis and liver disease. RESULTS: Participants with undiagnosed diabetes were more likely to have elevated ALT and AST levels (OR=1.82, 95% CI 1.47, 2.42; OR=1.99, 95% CI 1.46, 2.71, respectively). In contrast, there was no association between specific diabetes medication (i.e., sulfonylureas, biguanides/thiazolidinediones) and elevated ALT or AST levels among the treated. Our findings were confirmed in sensitivity analyses employing a lower threshold for ALT, and excluding individuals with viral hepatitis or liver disease. CONCLUSION: We found that undiagnosed diabetes is associated with liver injury, compared to diagnosed diabetes with treatment. The effect of diabetes treatment on liver injury in individuals with diabetes remains uncertain. PMID- 23683665 TI - Comparison of radiographic and pathologic sizes of renal tumors. AB - PURPOSE: The determination of the size of a renal tumor is important for staging, prognosis and selection of the appropriate surgical treatment. We investigated the difference of radiographic and pathologic size of renal tumors in a contemporary cohort of patients who underwent nephron sparing surgery and evaluated its clinical implications. MATERIALS AND METHODS: The records of 169 patients who received nephron sparing surgery for renal lesions suspicious for malignancy between January 2006 and December 2010 were reviewed retrospectively. Radiographic tumor size, defined as the largest diameter of tumor measured by CT images, and pathologic size, the largest diameter of tumor measured in the surgical specimen, were compared and analyzed. RESULTS: Among all subjects, mean radiographic and pathologic tumor size were 3.25 +/- 1.78 cm and 3.03 +/- 1.91 cm, respectively (P < 0.001), with a discrepancy of just 0.22 cm. When the patients were categorized according to radiographic tumor size in the 1 cm range, the mean radiographic tumor size was significantly greater than pathologic tumor size in the following groups: 2 to 3 cm (P < 0.001), 3 to 4 cm (P < 0.001), and 4 to 5 cm (P = 0.028). When radiographic and pathologic tumor sizes were compared according to the pathologic tumor subtype, a significant difference was observed only among those with clear cell renal carcinoma (P < 0.001). CONCLUSIONS: Renal tumor size was overestimated by radiography as compared with pathology. The difference was just 0.22 cm with little clinical significance, suggesting that CT provides an accurate method to estimate renal tumor size preoperatively. PMID- 23683666 TI - Emergency double-J stent insertion following uncomplicated Ureteroscopy: risk factor analysis and recommendations. AB - PURPOSE: Emergency double-J (DJ) stenting following "uncomplicated" ureteroscopic (UURS) stone treatment is both morbid and costly. Our study aims at identifying those patients who are more likely to require such an extra procedure. Handling of this complication will also be highlighted. MATERIALS AND METHODS: 319 cases of UURS cases were selected out of 903 patients, who were admitted for URS stone treatment at King Abdullah University Hospital during the period from May, 2003 to December, 2010. Thirty-eight of them (11.9%) had emergency post-URS DJ stenting within 24 hours of discharge. The medical records of all UURS cases were retrospectively reviewed. Comparison in demographic and stone-related variables was made using 2-paired t-test with P < 0.05. Operative findings of 38 stented patients were outlined. RESULTS: Significant risk factors for emergency stenting were noted in males with larger (> 1.5 cm) and proximal stones (38 stented vs. 281 unstented). Operative risk factors among the 38 patients were: initial procedure time > 45 minutes (42.1%), ureteral wall edema (21.1%), repeated access for stones > 1.5 cm (21.1%), impacted stone (10.5%) and ignored or missed stones/fragments (4.6%). CONCLUSIONS: The need for emergency DJ stenting following UURS stone treatment is not uncommon. The routine insertion is impractical and weakly-supported. With risk-factor stratification, selective and individualized DJ stenting policy is recommended. PMID- 23683667 TI - Effects of Serenoa repens, selenium and lycopene (Profluss(r)) on chronic inflammation associated with benign prostatic hyperplasia: results of "FLOG" (Flogosis and Profluss in Prostatic and Genital Disease), a multicentre Italian study. AB - OBJECTIVE: To evaluate the efficacy of Profluss(r) on prostatic chronic inflammation (PCI). MATERIALS AND METHODS: We prospectively enrolled 168 subjects affected by LUTS due to bladder outlet obstruction submitted to 12 cores prostatic biopsy for suspected prostate cancer + 2 cores collected for PCI valuation. First group consisted of 108 subjects, with histological diagnosis of PCI associated with BPH and high grade PIN and/or ASAP, randomly assigned to 1:1 ratio to daily Profluss(r) (group I) for 6 months or to control group (group Ic). Second group consisted of 60 subjects, with histological diagnosis of BPH, randomly assigned to 1:1 ratio to daily Profluss(r) + a-blockers treatment (group II) for 3 months or to control group (group IIc). After 6 months first group underwent 24 cores prostatic re-biopsy + 2 cores for PCI while after 3 months second group underwent two-cores prostatic for PCI. Specimens were evaluated for changes in inflammation parameters and for density of T-cells (CD3, CD8), B-cells (CD20) and macrophages (CD68). RESULTS: At follow-up there were statistical significant reductions of extension and grading of flogosis, mean values of CD20, CD3, CD68 and mean PSA value in group I compared to Ic, while extension and grading of flogosis in group II were inferior to IIc but not statistical significant. A statistically significant reduction in the density of CD20, CD3, CD68, CD8 was demonstrated in group II in respect to control IIc. CONCLUSIONS: Serenoa repens+Selenium+Lycopene may have an anti-inflammatory activity that could be of interest in the treatment of PCI in BPH and/or PIN/ASAP patients. PMID- 23683668 TI - The histology of prostate tissue following prostatic artery embolization for the treatment of benign prostatic hyperplasia. AB - OBJECTIVE: Prostatic artery embolization (PAE) for the treatment of patients with symptomatic benign prostatic hyperplasia (BPH) is believed to be a safe procedure with a low risk of adverse side effects. Artery embolization is a viable treatment option in patients who are refractory to the classic noninvasive treatments. Knowledge of the histological characteristics of prostate tissue following the procedure is still limited. In this study, we describe the microscopic aspects of the prostate following PAE for BPH. MATERIALS AND METHODS: Two patients underwent transurethral resections of the prostate (TURP) after PAE. Embolizations were performed under local anesthesia with an initial pelvic angiography to evaluate the iliac vessels and the prostate arteries using a 2.8 French microcatheter. The prostate was embolized with 300-500 um Microspheres (Embosphere (r)), using complete blood stasis as the end point. The prostate tissues were analyzed histologically to characterize the effects of the embolization. RESULTS: The embolic material within the prostate tissue was easily identified as homogeneous, bright eosin-red spheroids filling the vessel lumens. Ischemic necrosis surrounded or not by chronic inflammatory reactions containing macrophages were considered as a result of the artery embolization. Also, some aspects related to the healing process were observed being fibrotic nodules surrounded by glands with squamous metaplasia of the epithelial lining the most important. In the remaining sections, due to the precocious surgical intervention, the classic findings of BPH were still present with the glandular and stromal hyperplasia associated with nonspecific chronic prostatitis. CONCLUSIONS: This is the first description of prostate histology in BPH patients treated by PAE, a new procedure that is being used increasingly as a therapeutic intervention. The recognition of the changes caused by this new modality of treatment has become a very important differential in a chronic granulomatous reaction of the prostate tissue. PMID- 23683669 TI - Urine screening by Seldi-Tof, followed by biomarker identification, in a Brazilian cohort of patients with renal cell carcinoma (RCC). AB - PURPOSE: To screen proteins/peptides in urine of Renal Cell Carcinoma (RCC) patients by SELDI-TOF (Surface Enhanced Laser Desorption Ionization - Time of Flight) in search of possible biomarkers. MATERIAL AND METHODS: Sixty-one urines samples from Clear Cell RCC and Papillary RCC were compared to 29 samples of control urine on CM10 chip. Mass analysis was performed in a ProteinChip Reader PCS 4,000 (Ciphergen Biosystems, Fremont, CA) with the software Ciphergen Express 3.0. All chips were read at low and at high laser energy. For statistical analysis the urine samples were clustered according to the histological classification (Clear Cell and Papillary Carcinoma). For identification urine was loaded on a SDS PAGE gel and bands of most interest were excised, trypsinized and identified by MS/MS. Databank searches were performed in Swiss-Prot database using the MASCOT search algorithm and in Profound. RESULTS: Proteins that were identified from urine of controls included immunoglobulin light chains, albumin, secreted and transmembrane 1 precursor (protein K12), mannan-binding lectin associated serine protease-2 (MASP-2) and vitelline membrane outer layer 1 isoform 1. Identification of immunoglobulins and isoforms of albumin are quite common by proteomics and therefore cannot be considered as possible molecular markers. K12 and MASP-2 play important physiological roles, while vitellite membrane outer layer 1 role is unknown since it was never purified in humans. CONCLUSIONS: The down expression of Protein K-12 and MASP-2 make them good candidates for RCC urine marker and should be validated in a bigger cohort including the other less common histological RCC subtypes. PMID- 23683670 TI - Structural analysis of testicular appendices in patients with cryptorchidism. AB - OBJECTIVES: Report the incidence and structure of testicular appendices (TAs) in patients with cryptorchidism, comparing their incidence with epididymal anomalies (EA) and patency of the vaginal process (PVP) and analyzes the structure of TAs. MATERIAL AND METHODS: We studied 72 testes of patients with cryptorchidism (average of 6 years), and 8 testes from patients with hydroceles (average of 9 years). We analyzed the relations among the testis, epididymis and PVP and prevalence and histology of the TAs. The appendices of 10 patients with cryptorchidism and 8 with hydrocele were dissected and embedded in paraffin and stained with Masson trichrome; Weigert and Picro-Sirius Red with polarization and immunohistochemistry analysis of the collagen type III fibers to observe collagen. The stereological analysis was done with the software Image Pro and Image J, using a grid to determine volumetric densities (Vv). Means were statistically compared using the ANOVA and unpaired T test (p < 0.05). RESULTS: Of the 72 testes with cryptorchidism, 20 (27.77%) presented EA, 41 (56.9%) had PVP and 44 (61.1%) had TAs. Of the 44 testes with cryptorchidism and appendices, 30 (68.18%) presented PVP and 11 (25%) presented EA. There was no alteration of the epithelium in the appendices of patients in both groups. Stereological analysis documented the prevalence of ESFs (mean of 1.48%), prevalence of veins (mean of 10.11%) and decrease (p = 0.14) of SMCs in the TAs of patients with cryptorchidism (mean = 4.93%). Collagen III prevailed in the TAs of patients with cryptorchidism. CONCLUSION: The testicular appendices presented significant structural alteration in the patients with cryptorchidism, indicating that TAs present a structural remodeling. PMID- 23683671 TI - Analysis of ureteral length in adult cadavers. AB - INTRODUCTION: In some occasions, correlations between human structures can help planning surgical intra-abdominal interventions. The previous determination of ureteral length helps pre-operatory planning of surgeries, reduces costs of auxiliary exams, the correct choice of double-J catheter with low morbidity and fewer symptoms, and an adequate adhesion to treatment. OBJECTIVE: To evaluate ureteral length in adult cadavers and to analyze its correlation with anthropometric measures. MATERIALS AND METHODS: From April 2009 to January 2012 we determined ureteral length of adult cadavers submitted to necropsy and obtained the following measures: height, distance from shoulder to wrist, elbow wrist, xiphoid appendix-umbilicus, umbilicus-pubis, xiphoid appendix-pubis and between iliac spines. We analyzed the correlations between ureteral length and those anthropometric measures. RESULTS: We dissected 115 ureters from 115 adult corpses from April 2009 to January 2012. Median ureteral length didn't vary between sexes or according to height. It was observed no correlation among ureteral length and all considered anthropometric measures in all analyzed subgroups and in general population. There were no significant differences between right and left ureteral measures. CONCLUSIONS: There is no difference of ureteral length in relation to height or gender (male or female). There is no significant correlation among ureteral length and the considered anthropometric measures. PMID- 23683672 TI - Genes responsible for vaginal extracellular matrix metabolism are modulated by women's reproductive cycle and menopause. AB - OBJECTIVES: To analyze the expression of genes involved in extracellular matrix (ECM) biogenesis and remodeling in vaginal tissue of women with clinically normal pelvic floor support (defined as controls) according to the phase of menstrual cycle and postmenopausal women with and without pelvic organ prolapse (POP). MATERIALS AND METHODS: This study examined the expression of matrix metalloproteinases (MMPs), their tissue inhibitors (TIMPs), and the Lysyl oxidase (LOX) family genes in the anterior vaginal wall of Caucasian women by real-time RT-PCR. Initially, mRNA expression was assessed in premenopausal controls in the secretory (group 1, n = 10) vs. proliferative (group 2, n = 8) phase of menstrual cycle. In addition, we compared premenopausal controls in the proliferative phase (group 2) vs. postmenopausal controls (group 3, n = 5). Finally, we analyzed postmenopausal controls (group 3) vs. postmenopausal women with advanced POP (group 4, n = 13). RESULTS: According to the phase of menstrual cycle, MMP1 was significantly reduced (p = 0.003), whereas the expression of TIMP1 and LOXL4 was significantly up-regulated during proliferative phase (both p < 0.01) when compared to the secretory phase in premenopausal control women. Regarding menopausal status/ageing, all MMPs were down-regulated, while TIMP3, TIMP4 and LOXL2 were significantly up-regulated in postmenopausal control women when compared to premenopausal controls (p = 0.005, p = 0.01 and p < 0.001, correspondingly). TIMP4 and LOXL2 mRNA levels were significantly decreased in postmenopausal POP patients compared to asymptomatic postmenopausal controls (p < 0.01 for both). CONCLUSIONS: Our results indicate that ovarian cycle and age related changes influence the expression of genes encoding proteins responsible for ECM metabolism in human vagina. Moreover, POP is associated with alteration in vaginal ECM components after menopause. PMID- 23683673 TI - Effect of acute administration of sildenafil to rats with detrusor overactivity induced by chronic deficiency of nitric oxide. AB - PURPOSE: Recently, the effect of phosphodiesterase inhibitors (PDE5i) in the lower urinary tract symptoms (LUTS) associated to benign prostatic hyperplasia have been studied thoroughly. However, it remains unclear how the PDE5i improve LUTS. Therefore, the aim of the present study was to evaluate the potential of acute administration of the PDE5i sildenafil to improve detrusor overactivity (DO) induced by Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME), an nitric oxide sinthase (NOS) inhibitor, in rats. MATERIALS AND METHODS: Twenty seven MALE adult Wistar Rats were divided into the following groups: (1) control, (2) L-NAME, (3) sildenafil alone, and (4) L-NAME + sildenafil. The NOS blocker L NAME (20 mg/rat/day) was given in the drinking water. Sildenafil (100 ug/kg) was administrated intravenously (i.v.) acutely, diluted in cremophor, propylene glycol and water. All animals underwent to anesthetized cystometograms. RESULTS: The chronic and systemic administration of L-NAME markedly increased the number of non voiding contractions (2.62 (+/- 0.89)), and frequency of micturition (1.97 (+/- 0.78)), as well increased volume threshold (2.83 mL (+/- 1.64)) compared with control group, the number of non voiding contractions (1.17 (+/- 0.75)), frequency of micturition (1.08 (+/- 0.65)) and volume threshold (1.16 mL (+/- 0.38)), p < 0.001, p = 0.01, and p = 0.04, respectively. Sildenafil infusion decreased the number of micturition cycles significantly from the baseline to end point (-0.93 (+/- 0.34)) in nitric oxide (NO) deficient animals compared with sildenafil infusion alone (control) in animals with normal NO level (0.13 (+/- 0.25)), p = 0.03. CONCLUSION: Systemic reduction of nitric oxide causes detrusor overactivity and acute infusion of sildenafil reduces the number of micturition cycles in chronic NO-deficient rats. PMID- 23683674 TI - P2X7 receptor mediates activation of microglial cells in prostate of chemically irritated rats. AB - PURPOSE: Evidence shows that adenosine triphosphate (ATP) is involved in the transmission of multiple chronic pain via P2X7 receptor. This study was to investigate the P2X7 and microglial cells in the chronic prostatitis pain. MATERIALS AND METHODS: Rats were divided into control group and chronic prostatitis group (n = 24 per group). A chronic prostatitis animal model was established by injecting complete Freund's adjuvant (CFA) to the prostate of rats, and the thermal withdrawal latency (TWL) was detected on days 0, 4, 12 and 24 (n = 6 at each time point in each group). Animals were sacrificed and the pathological examination of the prostate, detection of mRNA expression of P2X7 and ionized calcium binding adaptor molecule 1 (IBA-1) and measurement of content of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in the dorsal horn of L5-S2 spinal cord were performed on days 0, 4, 12 and 24. In addition, the content of TNF-alpha and IL-1beta in the dorsal horn of L5-S2 spinal cord was measured after intrathecal injection of inhibitors of microglial cells and/or P2X7 for 5 days. RESULTS: The chronic prostatitis was confirmed by pathological examination. The expression of P2X7 and IBA-1 and the content of TNF alpha and IL-1beta in rats with chronic prostatitis were significantly higher than those in the control group. On day 4, the expressions of pro-inflammatory cytokines became to increase, reaching a maximal level on day 12 and started to reduce on day 24, but remained higher than that in the control group. Following suppression of microglial cells and P2X7 receptor, the secretion of TNF-alpha and IL-1beta was markedly reduced. CONCLUSION: In chronic prostatitis pain, the microglial cells and P2X7 receptor are activated resulting in the increased expression of TNF-alpha and IL-1beta in the L5-S2 spinal cord, which might attribute to the maintenance and intensification of pain in chronic prostatitis. PMID- 23683675 TI - Pseudoneoplastic mimics in an inactive bladder associated with ureteral strictures. PMID- 23683676 TI - Magnetic resonance imaging to detect vesico-symphyseal fistula following robotic prostatectomy. PMID- 23683677 TI - Intravesical and transperitoneal laparoscopy in the management of tumor in the residual ureter. AB - The occurrence of tumor in the residual ureter after an incomplete nephroureterectomy required by a tumor of renal collecting system is an uncommon but a well described situation. The recommended treatment in this situation is the radical excision of the remaining ureter, being the open technique the most used approach. The aim of this video is to demonstrate a new approach using intravesical and transperitoneal laparoscopy to remove the residual ureter following the oncological concepts. A 67 year-old male patient underwent an incomplete open right radical nephroureterectomy for a transitional cell carcinoma of the renal collecting system. After 16 months, the cystoscopy diagnostic revealed a recurrence of it in the residual ureter. An intravesical approach followed by a transperitoneal laparoscopy has removed the remaining ureter. Operative time was 110 minutes, blood loss 100 mL, the patient was discharged on the first postoperative day and the Foley catheter was removed on the seventh one. Pathological examination revealed low grade transitional cell carcinoma and free surgical margins, no recurrence was observed after six months. To our knowledge, this is the first treatment description of a tumor in the residual ureter with these techniques. This approach can be a minimal invasive alternative in this unusual situation. PMID- 23683678 TI - Surgical management of a locally advanced symptomatic recurrence of penile sarcoma secondary to prostate brachytherapy. AB - The surgical management of patients with symptomatic metastatic or locally advanced recurrences involving the penis remains poorly characterized. The aim of the present abstract and video is to detail our experience in the surgical management of a specific patient with a locally advanced symptomatic recurrence of penile sarcoma secondary to prostate cancer treated with primary brachytherapy. MATERIALS AND METHODS: A 70 year old male patient initially treated for localized prostate cancer with interstitial brachytherapy at an outside facility developed an unfortunate secondary malignancy consisting of a locally advanced penile sarcoma involving as well the prostate and base of the bladder. Despite our best efforts to control his pain, he developed a very symptomatic local recurrence with a secondary penile abscess and purulent periurethral drainage. At this time, it was felt a surgical resection consisting of a total penectomy, urethrectomy, cystoprostatectomy, and ileal conduit urinary diversion would be the best option for local cancer control in this particular patient. RESULTS: The patient underwent the surgical resection without any complications as illustrated in this surgical video, with a jejunal intestinal mass identified at the time of surgery which was resected with a primary bowel anastomosis performed. The patient was discharged from hospital uneventfully with his symptomatic local recurrence being successfully managed and the patient no longer requiring oral narcotics for pain control. The pathological report confirmed a locally advanced sarcoma involving the penile, prostate, and bladder which was resected with negative surgical margins and the jejunal mass was confirmed to represent a small bowel sarcoma metastatic site. CONCLUSION: As highlighted in the present video, the treatment of a symptomatic sarcoma local recurrence contiguously involving the penis can be successfully managed provided the patient is informed of the potential morbidity and psychosocial implications imparted by performing a total penectomy and adjacent organ resection. PMID- 23683679 TI - Initial experience of transurethral resection with pediatric resectoscope for incomplete anterior urethral stricture. AB - PURPOSE: Endoscopic urethrotomy is an alternative method in treatment of urethral stricture. However, it have high recurrence rate because of the remained fibrotic tissue. Removal of the fibrotic tissue can maintain the patency of the urethral lumen after the procedure. We report the therapeutic efficacy of our initial experience using pediatric resectoscope for treating anterior urethral stricture in 16 cases. MATERIALS AND METHODS: From January 2009 to April 2011, transurethral resection with pediatric resectoscope was primarily performed on 16 patients with anterior urethral stricture. Retrograde urethrography, uroflowmetry, postvoid residual volume, IPSS score and QoL score were performed preoperatively. We used 11.5Fr pediatric resectoscope (Wolf) and monopolar electrosurgical generator. The stricture was incised under vision at the 12 o'clock location or the site of maximum scar tissue or narrowing in asymmetric strictures for working space. After incision, transurethral resection with pediatric resectoscope was performed to all scar tissues. Monopolar cutting current was set on 45 watt and coagulation current was set on 30 watt, fulgurate mode. Postoperatively, drainage of the bladder was performed for 7 days using an 18F latex catheter. Patients were followed up by IPSS score, QoL score, uroflowmetry and postvoid residual volume. RESULTS: Successful results without recurrence were achieved in 11 of 16 patients. Postoperative urethral dilation had been performed average 2.4 times (0~6 times). When we classified the results by etiology, the number of successful results in strictures with a trauma, iatrogenic, or unknown cause was 5 (7/11), 3 (3/4) and 1 (1/1), respectively. In 5 patients who failed treatment, we repeated transurethral resection with pediatric resectoscope in 1 patient, and periodic urethral dilation in 4 patients. No operative complications occurred in any patients. CONCLUSIONS: Transurethral resection with pediatric resectoscope is an effective therapeutic method for anterior urethral stricture. More long-term follow-up and large scale studies are needed to confirm the efficacy of this procedure. PMID- 23683680 TI - Basic research in prostate cancer, kidney cancer, urinary incontinence, pediatric urology and erectile dysfunction. PMID- 23683681 TI - Magnetic resonance image in the diagnosis and evaluation of extra-prostatic extension and involvement of seminal vesicles of prostate cancer: a systematic review of literature and meta-analysis. AB - OBJECTIVE: Systematic review of literature and meta-analysis to evaluate the results of magnetic resonance image 1.5T with endorectal coil in the diagnosis and evaluation of extra-prostatic extension and involvement of seminal vesicles of prostate cancer, compared to the histopathological results of the radical prostatectomy specimen. MATERIALS AND METHODS: It was conducted a systematic review of literature and meta-analyses of all studies data published after 2008. In those studies, the patients with prostate cancer with indication to radical prostatectomy were submitted to magnetic resonance image (MRI) at pre-operatory period and the results were compared to those of histopathological studies after the surgery. The selected terms for research included prostate cancer, magnetic resonance, radical prostatectomy, and prostate cancer diagnosis, in the databases EMBASE, LILACS, PUBMED/MEDLINE and Cochrane Library. The data were collected using a specific qualitative instrument and the meta-analysis data were presented in the forest plot graphics, homogeneity test and sROC curves and funnel plot. RESULTS: A total of seven studies were included, with a total of 603 patients. Among these studies, six evaluated the value of MRI for the detection of prostate cancer, and the median sensitivity of meta-analysis was 0.6 and specificity 0.58, but with heterogeneity among the studies. Three studies evaluated extra-prostatic extension with a median sensitivity of 0.49, specificity 0.82 and heterogeneity only for sensitivity. Three studies evaluated invasion of seminal vesicles, with median sensitivity of 0.45 and specificity 0.96, with heterogeneity in both analysis. CONCLUSION: Magnetic resonance of 1.5T with endocoil showed low values of sensitivity and specificity for the diagnosis and staging of prostate cancer. The reviewed studies showed a significant heterogeneity among them. The best observed result was MRI specificity for invasion of seminal vesicles. More studies are necessary to evaluate new techniques and parameters before recommending the routine use of MRI in clinical practice. PMID- 23683682 TI - Radical cystectomy with W-shaped orthotopic ileal neobladder constructed with non absorbable titanium staples-long term follow-up. AB - PURPOSES: We retrospectively assessed our experience with the W-shaped orthotopic ileal pouch, which was constructed with non-absorbable titanium staples. For these purpose, we discuss the results of bladder capacity, urinary continence and early and long-term postoperative complications. MATERIALS AND METHODS: We included in the study 17 patients who underwent radical cystoprostatectomy followed by construction of an orthotopic W-shaped ileal pouch between October 2000 and November 2009. A 65-70 cm segment of ileum was isolated and prearranged into a W-configuration, leaving two 10 cm intact segments on both sides of the ileal fragment. In our technique we entirely anatomized all adjacent limbs in order to create a sphere-shaped pouch. The ureters were directly anastomized to both intact segments of the ileal division. All our patients underwent pouchscopy 6 months after operation and annually. RESULTS: Mean operative time for neobladder reconstruction and ureteral anastomoses was 87 +/- 7.67 minutes. In one patient a leak from the ileo-ileal anastomosis was confirmed on the 3rd day after operation. In 2 cases unilateral stricture of the ureteral-neobladder anastomosis was documented. Staple lines were mostly covered with ileal mucosa after 6 months. The mean functional bladder capacity was 340 +/- 27.6 mL and 375 +/- 43.4 mL at 6 and 12 months, respectively. First-year daytime and nighttime continence was good and acceptable in 90% and 78% of patients, while it increased to 95% during the 2nd year. CONCLUSIONS: The long term follow-up shows that non absorbable titanium staples can be safely used for creation of an orthotopic ileal neobladder. However, these data should be further validated in a larger series of patients. PMID- 23683683 TI - Results of preoperative electrical stimulation of pelvic floor muscles in the continence status following radical retropubic prostatectomy. AB - PURPOSE: To evaluate preoperative rectal electrical stimulation in the recovery of urinary continence in patients who undergo radical retropubic prostatectomy. MATERIALS AND METHODS: Patients were divided into 3 randomized groups: control, pelvic exercises, and electrical stimulation. A 1 hour pad-test, the ICIQ-SF, and the SF-36 were performed 1, 3, and 6 months after the surgical procedure. RESULTS: Of the 58 patients who were initially included in the study, 9 were excluded due to radiotherapy after surgical intervention, an indwelling urethral catheter for more than 30 days, high surgical risk, loss of follow-up, or incomplete participation in the study routines and spontaneous interruption. Forty-nine patients concluded the study (15 in the control group, 17 in the exercise group, and 17 in the electrical stimulation group). We did not observe any significant difference in the pad test (p > 0.05), the 8 domains of the SF 36, or ICIQ-SF score compared with control groups (control, exercise, and electrical stimulation). CONCLUSION: Preoperative rectal electrical stimulation has no impact on continence status in patients who undergo radical retropubic prostatectomy. There is no difference in the three above mentioned groups with regard to urinary leakage and quality of life. PMID- 23683684 TI - Minimally invasive pyeloplasty in horseshoe kidneys with ureteropelvic junction obstruction: a case series. AB - BACKGROUND AND PURPOSE: Horseshoe kidney is an uncommon renal anomaly often associated with ureteropelvic junction (UPJ) obstruction. Advanced minimally invasive surgical (MIS) reconstructive techniques including laparoscopic and robotic surgery are now being utilized in this population. However, fewer than 30 cases of MIS UPJ reconstruction in horseshoe kidneys have been reported. We herein report our experience with these techniques in the largest series to date. MATERIALS AND METHODS: We performed a retrospective chart review of nine patients with UPJ obstruction in horseshoe kidneys who underwent MIS repair at our institution between March 2000 and January 2012. Four underwent laparoscopic, two robotic, and one laparoendoscopic single-site (LESS) dismembered pyeloplasty. An additional two pediatric patients underwent robotic Hellstrom repair. Perioperative outcomes and treatment success were evaluated. RESULTS: Median patient age was 18 years (range 2.5-62 years). Median operative time was 136 minutes (range 109-230 min.) and there were no perioperative complications. After a median follow-up of 11 months, clinical (symptomatic) success was 100%, while radiographic success based on MAG-3 renogram was 78%. The two failures were defined by prolonged t1/2 drainage, but neither patient has required salvage therapy as they remain asymptomatic with stable differential renal function. CONCLUSIONS: MIS repair of UPJ obstruction in horseshoe kidneys is feasible and safe. Although excellent short-term clinical success is achieved, radiographic success may be lower than MIS pyeloplasty in heterotopic kidneys, possibly due to inherent differences in anatomy. Larger studies are needed to evaluate MIS pyeloplasty in this population. PMID- 23683685 TI - Occupational hazard: radiation exposure for the urologist--developing a reference standard. AB - INTRODUCTION: To date, there is a paucity of literature offering practicing urologists a reference for the amount of radiation exposure received while surgically managing urolithiasis. This study examines the cumulative radiation exposure of an urologist over 9 months. MATERIALS AND METHODS: We present a case series of fluoroscopic exposures of an experienced stone surgeon operating at an academic comprehensive stone center between April and December 2011. Radiation exposure measurements were determined by a thermoluminescent dosimeter worn on the outside of the surgeon's thyroid shield. Estimations of radiation exposure (mrem) per month were charted with fluoroscopy times, using scatter plots to estimate Spearman's rank correlation coefficients. RESULTS: The total 9-month radiation exposure was 87 mrems for deep dose equivalent (DDE), 293 mrem for lens dose equivalent (LDE), and 282 mrem for shallow dose equivalent (SDE). Total fluoroscopy time was 252.44 minutes for 64 ureteroscopies (URSs), 29 percutaneous nephrolithtomies (PNLs), 20 cystoscopies with ureteral stent placements, 9 shock wave lithotripsies (SWLs), 9 retrograde pyelograms (RPGs), 2 endoureterotomies, and 1 ureteral balloon dilation. Spearman's rank correlation coefficients examining the association between fluoroscopy time and radiation exposure were not significant for DDE (p = 0.6, Spearman's rho = 0.2), LDE (p = 0.6, Spearman's rho = 0.2), or SDE (p = 0.6, Spearman's rho = 0.2). CONCLUSIONS: Over a 9-month period, total radiation exposures were well below annual accepted limits (DDE 5000 mrem, LDE 15,000 mrem and SDE 50,000 mrem). Although fluoroscopy time did not correlate with radiation exposure, future prospective studies can account for co-variates such as patient obesity and urologist distance from radiation source. PMID- 23683687 TI - Effects of pacing, status and unbalance in time motion variables, heart rate and tactical behaviour when playing 5-a-side football small-sided games. AB - OBJECTIVES: To compare time-motion variables, heart rate and players' tactical behaviour according to game pace (slow, normal or fast), status (winning and losing) and team unbalance (superiority and inferiority) in football 5-a-side small-sided games. To identify the most discriminating variables in classifying performances according to these constraints. DESIGN: Cross-sectional field study. METHODS: The data were gathered using global positioning systems (5 Hz) in 5-a side small-sided games (7 * 5 min) played by twenty-four footballers. The tactical performance was measured using dynamical positioning variables, processed by non-linear signal processing techniques (approximate entropy). ANOVA models were used to compare between constraints and discriminant analyses to identify the variables that best discriminate between pacing and status * unbalance constraints. RESULTS: The fast paced games had the highest mean speed value, followed by normal and slow paced games (8.2 +/- 0.6 km h(-1), 7.8 +/- 0.5 km h(-1) and 6.2 +/- 0.4 km h(-1), respectively). The stronger predictor variables of pacing were the randomness in distance to team centroid and the distances covered above 13 km h(-1). The results also changed according to game status and team unbalance. The strongest predictor variables were the distance covered below 6.9 km h(-1), distance and randomness to team centroid, with higher values when winning in superiority conditions. CONCLUSIONS: Practice task design manipulating game pace, status and team unbalance significantly influenced the emergent behavioural dynamics. Collective positioning variables were more accurate in discriminating these constraints and, therefore, need to be considered when planning and monitoring performance. PMID- 23683686 TI - The pathogenesis of Epstein-Barr virus persistent infection. AB - Epstein-Barr virus (EBV) maintains a lifelong infection. According to the germinal center model (GCM), latently infected B cells transit the germinal center (GC) to become resting memory cells. Here, the virus resides quiescently, occasionally reactivating to infect new B cells, completing the cycle of infection. The GCM remains the only model that explains EBV biology and the pathogenesis of lymphoma. Recent work suggests modifications to the model notably that the virus contributes only modestly to the GC process and predictions from mathematical models that quiescence within memory B cells shapes the overall structure of viral infection but is not essential for persistence. Rather, it is the cycle of infection which allows viral persistence at the very low levels observed. PMID- 23683688 TI - Acquired factor V inhibitor associated with life-threatening bleeding and a mixing test result that indicated coagulation factor deficiency. AB - A mixing test is useful for distinguishing between coagulation factor deficiency and the presence of inhibitor as the cause of coagulopathy. However, we experienced a patient with acquired factor V (FV) inhibitor whose mixing test showed a coagulation factor deficiency pattern. A 65-year-old man with a tendency for bleeding was referred to our center. The laboratory data showed remarkable prolongation of prothrombin time and activated partial thromboplastin time (APTT). FV activity was less than 3%. A mixing test showed a coagulation factor deficiency pattern. However, neither the tendency for bleeding nor the coagulation tests were corrected by transfusion of fresh frozen plasma. A few days later, a positive test for FV inhibitor of 3 Bethesda units was obtained. Therefore, we started prednisolone and plasma exchange, and the coagulation test results normalized after 6 weeks. Although an incubation period is generally not considered necessary in a mixing test for FV inhibitor, we repeated mixing tests with various incubation periods and confirmed an incubation period-dependent prolongation of the APTT. Therefore, a mixing test with an incubation period is recommended for the detection of FV inhibitor, since a mixing test without an incubation period may show a coagulation factor deficiency pattern when the titer of FV inhibitor is low. PMID- 23683689 TI - Protective effects of antioxidants on linoleic acid-treated bovine oocytes during maturation and subsequent embryo development. AB - Linoleic acid (LA; n-6, 18:2) is the most abundant polyunsaturated fatty acid in the ovarian follicular fluid and is known to inhibit oocyte maturation and its subsequent development. In the present study, we investigated how its effects on cumulus cell expansion, oocyte nuclear maturation, and blastocyst development are altered by supplementation of the media with vitamin E (VE; 100 MUM) and glutathione peroxidase (GPx; 1 MUM) either alone or in combination, and whether it has any effect on the mRNA expression of GPx1, GPx4, or superoxide dismutase (SOD2) in the bovine cumulus oocyte complexes (COCs). LA supplementation of the culture media significantly (P <= 0.05) reduced the percentage of COCs exhibiting full cumulus cell expansion and the percentage of oocytes reaching metaphase II stage, and lowered the blastocyst rate compared with controls. And these inhibitory effects were associated with a reduction in the relative mRNA expression of GPx1 and SOD2 but not of GPx4 compared with controls. However, VE and GPx, both alone and in combination, completely abrogated the inhibitory effects of LA on nuclear maturation of oocytes and blastocyst rate but failed to do so for cumulus cell expansion. In conclusion, these data suggest that the detrimental effects of LA on oocyte developmental competence are mediated, at least in part, by a reduction in GPx1 and SOD2 mRNA expression. Moreover, VE and GPx may provide protection to most of the inhibitory effects of LA. PMID- 23683691 TI - Effect of triiodothyronine on developmental competence of bovine oocytes. AB - Developmental competence of in vitro-matured bovine oocytes is a limiting factor in production of embryos in vitro. Several studies have suggested a potential positive effect of thyroid hormones on cultured oocytes and/or their supporting cells. Therefore, the aim of the present study was to ascertain whether medium supplementation with triiodothyronine (T3) improved subsequent developmental competence of in vitro-matured bovine oocytes. For this purpose, we first documented (using reverse transcription PCR) that whereas bovine cumulus cells expressed both thyroid hormone receptor (TR)-alpha and TRbeta, immature bovine oocytes expressed TRalpha only. Thereafter, to test the effects of TH on developmental competence, abattoir-derived oocytes were matured in vitro in a medium containing 0, 25, 50, or 100 nM T3 and subjected to in vitro fertilization. Embryo quality was evaluated by assessing cleavage and blastocyst rates, morphological quality, development kinetics, and total cell number on Day 8 of culture. Notably, addition of 50 or 100 nM T3 to the in vitro maturation medium increased (P < 0.05) the rate of hatched blastocysts on the eighth day of culture, as compared with other groups (62.4 +/- 11.7, 53.1 +/- 16.3, and 32.4 +/ 5.3, respectively). Next, the relative expression levels of genes related to embryo quality POU-domain transcription factor (POU5F1) and glucose transporter-1 (GLUT 1) were compared between in vivo- and in vitro-produced blastocysts. On the basis of the previous experiments, IVP embryos originating from oocytes that were matured in vitro in the presence or absence of 50 nM T3 were evaluated. The treatment had no effect (P > 0.05) on gene expression. We concluded that supplementation of bovine oocyte in vitro maturation medium with T3 may have a beneficial effect on the kinetics of embryo development. PMID- 23683690 TI - Role of insulin-like growth factor-I and follicular fluid from ovarian follicles with different diameters on porcine oocyte maturation and fertilization in vitro. AB - The objective of this study was to determine the effects of insulin-like growth factor-I (IGF-I) (0, 60, 120, 180, and 240 ng/mL) and follicular fluid (FF) derived from 2 to 5 and 6 to 10 mm diameter follicles (SpFFs and LpFFs, respectively) added during in vitro maturation (IVM) of porcine oocytes on nuclear maturation and IVF. Cumulus-oocyte complexes (COCs) were matured in NCSU 37 medium supplemented with SpFFs or LpFFs and various IGF-I concentrations. The COCs were cultured for 44 hours, and then fertilized in vitro. Maturation and IVF results were recorded 18 hours after insemination. The IVM (%) was higher (P < 0.05) in the COCs matured in LpFFs than with SpFFs when 0 (90.0 +/- 6.9 vs. 76.3 +/- 10.7) or 60 ng/mL IGF-I (92.0 +/- 8.1 vs. 81.8 +/- 10.2) was added. In SpFFs media, there was a quadratic relationship (P < 0.01) between IGF-I concentration and IVM (peak results at IGF-I = 129 ng/mL). However, when the COCs were matured with LpFFs, there was a decreasing linear effect between IGF-I concentration and IVM. At all concentrations of IGF-I, the percentage of degenerated oocytes was higher in COCs matured in SpFFs than in LpFFs. Penetration (%) did not differ (P > 0.05) between COCs matured with SpFFs or LpFFs when 60 (66.8 +/- 9.4 vs. 72.7 +/- 11.3) or 180 ng/mL of IGF-I (75.7 +/- 10.4 vs. 73.8 +/- 13.2) were used. Monospermy (%) was similar between SpFFs and LpFFs only with addition of 120 ng/mL IGF-I. The IVF performance (%) did not differ between COCs matured with SpFFs or LpFFs when IGF-I concentrations of 120 (28.5 +/- 8.8 vs. 38.5 +/- 8.3) and 180 ng/mL (24.3 +/- 10.2 vs. 30.12 +/- 8.2) were used. There was no effect of IGF-I concentration or of FF type on the number of penetrated sperm per oocyte and on male pronuclear formation. For COCs matured with SpFFs, there was a quadratic relationship between IGF-I concentration and penetration, monospermy, and IVF performance (peak results at IGF-I = 179, 122, and 135 ng/mL, respectively). Thus, on the basis of the observed quadratic relationships, we inferred that when using SpFFs, the addition of IGF-I (122-179 ng/mL) to the IVM medium produced results similar to those obtained with LpFFs without adding IGF I. In conclusion, the addition of IGF-I to the IVM medium supplemented with SpFFs increased maturation and improved IVF results. Alternatively, IGF-I had no effect on IVM or IVF when used with LpFFs. PMID- 23683692 TI - Protracted induction of parturition enhances placental maturation, but does not influence incidence of placental retention in cows. AB - As the etiopathology of retained placenta is still not resolved in cattle, we compared the effects of protracted induction of parturition (PIP) and conventional induction of parturition (SIP) on placental maturation and the occurrence of retained placenta. PIP was induced in 13 cows by administration of 1.3 mg dexamethasone im twice daily between Days 268 and 273 of gestation and 40 mg dexamethasone im on Day 274 of gestation. For SIP, 10 cows received a single injection of 40 mg dexamethasone on Day 274 of gestation. A third group (SPON, n = 11) served as a nontreated control group. Within 2 hours after birth, two placentomes were extracted from the uterus and used for assessment of placental maturation by histology and immunohistochemistry. Incidence of retained placenta was lower (P < 0.05) in group SPON (9%) compared with groups PIP (54%) and SIP (70%). Staining with Masson's trichrome and pan-cytokeratin indicated a higher degree of atrophy and flatness of the maternal crypt epithelium in cows with physiological release of fetal membranes (REL) compared with cows with retained placentae (RET). Staining with anti-caspase-3 ratified the observations as more apoptotic cells were detected in groups SPON and PIP compared with group SIP; however, data were not statistically significant. Additionally, the expressions of the potent vasodilators endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) were evaluated. Both eNOS and iNOS were only expressed in chorionic tissue. Endothelin-1 (ET-1), a major vasoconstrictor, showed positive staining in maternal crypt epithelium and in chorionic epithelium. No differences were found for iNOS and eNOS and ET-1, neither among the experimental groups nor between RET and REL cows. These findings indicate that a PIP results in increased placental maturation, but does not influence the incidence of placental retention in cows. The expression of vasoactive substances does not seem to be related to the placental separation process. PMID- 23683693 TI - Effect of phosphodiesterase type 3 inhibitor on nuclear maturation and in vitro development of ovine oocytes. AB - The present study aims to investigate if prematuration culture (PMC) of ovine oocytes in the presence of a phosphodiesterase type 3 (PDE3) inhibitor cilostamide can improve the shortcomings of conventional in vitro maturation (IVM) system. Therefore, a two-step culture system consisting of 22 hours culture in the presence of 1, 10, and 20 MUM cilostamide (PMC medium), followed by 22 hours culture in maturation medium, was designed. The effect of cilostamide on gap junction communications and nuclear status was studied. The variables assessed were chromosome organization, spindle pattern, polar body extrusion, and embryonic development. According to the results, inhibition of PDE3 could not permanently block nuclear maturation in ovine oocytes but it delayed the process of nuclear maturation. Elevation of intra-oocyte cAMP concentration could inhibit cumulus cells expansion and maintain gap junction communications between oocyte and cumulus cells. Deletion of cilostamide and refreshing maturation medium after 22 hours culture revealed that cumulus cells were completely expanded. The inhibitory effect induced by 1 MUM cilostamide was reversible, and it increased the number of mature oocytes with aligned chromosomes and normal spindle. However, the inhibitory effects of 10 and 20 MUM cilostamide was not fully reversible and was associated with deleterious effects on chromosome organization and spindle pattern. Investigation of embryonic development via parthenogenetic activation and in vitro fertilization revealed that the blastocyst rate of oocytes that were prematured with 1 MUM cilostamide was not significantly different from oocytes that underwent conventional IVM but it was significantly reduced in oocytes that were prematured with 10 and 20 MUM cilostamide. Our results provide the evidence that reduced cAMP via PDE3 is not the only mechanism that controls the progress of nuclear maturation in sheep oocytes, and that alternative or additional mechanisms may also exist. PMID- 23683694 TI - Expression and localization of Luman RNA and protein during mouse implantation and decidualization. AB - Luman (also known as LZIP and CREB3) is a basic leucine zipper transcription factor of the cAMP response element-binding protein/activating transcription factor gene family. Although Luman had specific roles near termination of Drosophila embryogenesis, the physiological functions of Luman in female mammals have apparently not been reported. Therefore, our objective was to investigate the spatiotemporal expression and regulation of Luman in the mouse uterus during the peri-implantation period. Luman protein was clearly present in the luminal and glandular epithelium on days 1 to 4 of pregnancy (day 1, presence of a vaginal plug) and was observed in decidual cells on day 6 of pregnancy. Expression had progressively increased to day 7 when the second decidual zone was formed. On day 8, apoptosis of the decidualized cells was present, and Luman protein expression was decreased (in close association with decidualization). Luman protein was also present in decidual cells of the artificially decidualized uterus. The expression of Luman was regulated by an activated embryo (according to its expression patterns during pseudopregnancy and delayed implantation). Furthermore, expression of Luman was induced by estrogen in ovariectomized mice. We have concluded that Luman might have important roles in embryo implantation and decidualization. PMID- 23683697 TI - Effects of the presence of the curing agent sodium nitrite, used in the production of fermented sausages, on bacteriocin production by Weissella paramesenteroides DX grown in meat simulation medium. AB - Weissellin A is a listericidal bacteriocin produced by the sausage-isolated strain of Weissella paramesenteroides DX. The response of the strain to various concentrations of the added curing agent NaNO2 (0.0025, 0.005 and 0.01g/L) was evaluated in bioreactor fermentations using a meat simulation medium. The presence of nitrite suppressed bacteriocin production - the effect being more pronounced with increasing concentrations. Weissellin A was produced as a growth associated metabolite in the absence of nitrite or its presence in the low concentration of 0.005g/L under aerobic conditions. The suppressive effect of nitrite was apparent under conditions supporting increased specific production rates, e.g. 50% and 100% dissolved oxygen tension, but no effect was observed under anaerobic conditions. As the latter prevail in the microenvironment of fermented meat products, the absence of any influence of nitrite on bacteriocin production is an important finding that enlightens the role of this species of lactic acid bacteria in its common substrates. PMID- 23683695 TI - Detection of disseminated tumor cells in locally advanced breast cancer patients before primary systemic therapy. AB - AIM: To assess the prevalence and prognostic power of disseminated tumor cells (DTC) in patients with locally advanced breast cancer (LABC) before primary systemic therapy (PST). MATERIALS AND METHODS: LABC patients attending our Breast Unit were studied between 2002 and 2012, all of them being considered for PST. To determine the presence of DTC, posterior iliac crest aspirates were obtained and marrow samples were processed by gradient separation with Ficoll (Lymphoprep((r))) and immunohistochemical staining using the antiCK A45-B/B3 (EPIMET) antibody. Clinicopathologic variables were recorded before and after PST to assess response. Disease-free survival (DFS) and overall survival (OS) were determined after follow-up. The presence of DTC as a predictor of response to PST and as a prognostic tool for OS and DSF was evaluated. RESULTS: DTC were observed in 26% of 47 patients included in the study. PST consisted of chemotherapy in 94% and hormone therapy in 6%. Breast-conserving therapy was attained in 33%. Mean follow-up was 68 months. Complete clinical response (CR) after PST was seen in 26%, disease recurrence in 38%, and cancer-related death in 8%; tumor size and negative estrogen receptors were significant predictors of CR and mastectomy was associated with DFS. Persistent axillary disease after PST and previous recurrence were predictive of OS. DTC were detected more often in patients who did not achieve CR and those who presented recurrence. DTC detection was a significant prognostic factor for a worse OS (OR = 7.62; CI95%: 1.46-39.61; p = 0.009) and a decreased survival time (62 versus 82 months, p = 0.004). CONCLUSION: Presence of DTC before PST was found in a significant number of patients with LABC. DTC were found to be a significant prognostic factor for cancer-related death. DTC could be a surrogate predictor of response to PST and also of disease recurrence in LABC patients. PMID- 23683696 TI - Patient advocacy and DSM-5. AB - The revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM) provides a useful opportunity to revisit debates about the nature of psychiatric classification. An important debate concerns the involvement of mental health consumers in revisions of the classification. One perspective argues that psychiatric classification is a scientific process undertaken by scientific experts and that including consumers in the revision process is merely pandering to political correctness. A contrasting perspective is that psychiatric classification is a process driven by a range of different values and that the involvement of patients and patient advocates would enhance this process. Here we draw on our experiences with input from the public during the deliberations of the Obsessive Compulsive-Spectrum Disorders subworkgroup of DSM-5, to help make the argument that psychiatric classification does require reasoned debate on a range of different facts and values, and that it is appropriate for scientist experts to review their nosological recommendations in the light of rigorous consideration of patient experience and feedback. PMID- 23683698 TI - Sulfur-nitrogen-carbon removal of Pseudomonas sp. C27 under sulfide stress. AB - Pseudomonas sp. C27 is a facultative autotrophic bacterium that can effectively conduct mixotrophic and heterotrophic denitrification reactions using organic matters and sulfide as electron donors. There is no experimental confirmation on proteomic levels the pure C27 strain can have the capability to simultaneous removal of sulfide, nitrate and organic carbon from waters. The proteome in total C27 cell extracts was observed by two-dimensional gel electrophoresis. The 160mg/L sulfide up-regulated or specifically expressed succinate dehydrogenase, iron-sulfur protein, oxidoreductase, serine hydroxymethyltransferase, and iron superoxide dismutase for sulfide metabolism, 2-oxoglutarate dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase, NAD(+)-dependent aldehyde dehydrogenase, malate dehydrogenase and succinate dehydrogenase for carbon metabolism, and nitrous-oxide reductase and respiratory nitrate reductase for nitrogen metabolism. The study confirmed that the C27 strain has an effective enzyme system to conduct denitrifying sulfide removal reactions. Also, sulfide stress can enhance energy consumption rate and rates of nitrate reduction and sulfide oxidation by C27. Conversely, sulfide stress repressed the sulfate reducing power of C27, evidenced by down-regulation or specific un-expression of sulfate ABC transporter, periplasmic sulfate-binding protein in the (C+N+S) sample. PMID- 23683699 TI - Estimation of phosphoenolpyruvate carboxylation mediated by phosphoenolpyruvate carboxykinase (PCK) in engineered Escherichia coli having high ATP. AB - We have previously reported that phosphoenolpyruvate carboxykinase (PCK) overexpression under glycolytic conditions enables Escherichia coli to harbor a high intracellular ATP pool resulting in enhanced recombinant protein synthesis. To estimate how much PCK-mediated phosphoenolpyruvate (PEP) carboxylation is contributed to the ATP increase under engineered conditions, the kinetics of PEP carboxylation by PCK and substrate competing phosphoenolpyruvate carboxylase (PPC) were measured using recombinant enzymes. The PEP carboxylation catalytic efficiency (kcat/Km) of the recombinant PCK was 660mM(-1)min(-1), whereas that of the recombinant PPC was 1500mM(-1)min(-1). Under the presence of known allosteric effectors (fructose 1,6-bisphosphate, acetyl-CoA, ATP, malate, and aspartate) close to in vivo conditions, the catalytic efficiency of PCK-mediated PEP carboxylation (84mM(-1)min(-1)) was 28-folds lower than that of PPC (2370mM( 1)min(-1)). To verify the above results, an E. coli strain expressing native PCK and PPC under control of identical promoter was constructed by replacing PCK promoter region with that of PPC in chromosome. The native PCK activity (33nmol/mg-proteinmin) was 5-folds lower than PPC activity (160nmol/mg proteinmin) in the cell extract from the promoter-exchanged strain. Intracellular modifications of ATP concentration by PCK activity and the consequences for biotechnology are further discussed. PMID- 23683700 TI - Purification, characterisation and expression in Saccharomyces cerevisiae of LipG7 an enantioselective, cold-adapted lipase from the Antarctic filamentous fungus Geomyces sp. P7 with unusual thermostability characteristics. AB - A lipase, LipG7, has been purified from the Antarctic filamentous fungus Geomyces sp. P7 which was found to be cold-adapted and able to retain/regain its activity after heat denaturation. The LipG7 exhibits 100% residual activity following 1h incubation at 100 degrees C whilst simultaneously showing kinetic adaptations to cold temperatures. LipG7 was also found to have industrial potential as an enantioselective biocatalyst as it is able to effectively catalyse the enantioselective transesterification of a secondary alcohol. The LipG7 coding sequence has been identified and cloned using 454 pyrosequencing of the transcriptome and inverse PCR. The LipG7 protein has been heterologously expressed in Saccharomyces cerevisiae BJ5465 and shown to exhibit the same characteristics as the native protein. PMID- 23683701 TI - Two novel GH11 endo-xylanases from Myceliophthora thermophila C1 act differently toward soluble and insoluble xylans. AB - Two novel GH11 endo-xylanases from Myceliophthora thermophila C1 (C1), Xyl7 and Xyl8, were purified and the influence of solubility and molecular structure of various xylans on their efficiency was investigated. Both endo-xylanases were hindered by a high degree of substitution of a xylan. The two GH11 xylanases released different products from the xylans, in which Xyl7 displayed a degradation product composition closer to GH10 xylanases. A correlation of the degradation product composition with a specific residue at position 163 in the amino acid sequence of Xyl8 is suggested: tyrosine in Xyl8; valine in Xyl7. This is confirmed with examples of various endo-xylanases reported in literature. The C1 GH11 xylanases were more efficient on self-associated xylan compared to C1 GH10 endo-xylanases and they released more small xylooligomers from these xylans. This is contrary to the general assumption that GH10 xylanases degrade xylans to a higher degree than GH11 xylanases. PMID- 23683702 TI - Laccases from Aureobasidium pullulans. AB - Laccases are polyphenol oxidases (EC 1.10.3.2) that have numerous industrial and bioremediation applications. Laccases are well known as lignin-degrading enzymes, but these enzymes can play numerous other roles in fungi. In this study, 41 strains of the fungus Aureobasidium pullulans were examined for laccase production. Enzymes from A. pullulans were distinct from those from lignin degrading fungi and associated with pigment production. Laccases from strains in phylogenetic clade 5, which produced a dark vinaceous pigment, exhibited a temperature optimum of 50-60 degrees C and were stable for an hour at 50 degrees C, unlike enzymes from the lignin-degrading fungi Trametes versicolor and Pycnoporus cinnabarinus. Laccase purified from A. pullulans strain NRRL 50381, a representative of clade 5, was glycosylated but had a molecular weight of 60 70kDa after Endo H treatment. Laccase purified from strain NRRL Y-2568, which produced a dark olivaceous pigment, was also glycosylated, but had a molecular weight of greater than 100kDa after Endo H treatment. PMID- 23683703 TI - Aldol addition of dihydroxyacetone to N-Cbz-3-aminopropanal catalyzed by two aldolases variants in microreactors. AB - Aldol addition of dihydroxyacetone to N-Cbz-3-aminopropanal catalyzed by two d fructose-6-phosphate aldolase variants, FSA A129S and FSA A129S/A165G, overexpressed in Escherichia coli was studied in microreactors. The presence of organic solvent was necessary due to poor solubility of N-Cbz-3-aminopropanal in water. Hence, three co-solvents were evaluated: ethyl acetate, acetonitrile and dimethylformamide (DMF). The influence of these solvents and their concentration on the enzyme activity was independently tested and it was found that all solvents significantly reduce the activity of FSA depending on their concentration. The reaction was carried out in three different microreactors; two without and one with micromixers. By increasing enzyme concentration, it was possible to achieve higher substrate conversion at lower residence time. Enzyme activity measured at the outlet flow of the microreactor at different residence time revealed that enzymes are more stable at lower residence times due to shorter time of exposure to organic solvent. The reaction in the batch reactor was compared with the results in microreactor with micromixers. Volume productivity was more than three fold higher in microreactor with micromixers than in the batch reactor for both aldolases. It was found to be 0.88Md(-1) and 0.80Md(-1) for FSA A129S and FSA A129S/A165G, respectively. PMID- 23683704 TI - Crystal structure of a compact alpha-amylase from Geobacillus thermoleovorans. AB - A truncated form of an alpha-amylase, GTA, from thermophilic Geobacillus thermoleovorans CCB_US3_UF5 was biochemically and structurally characterized. The recombinant GTA, which lacked both the N- and C-terminal transmembrane regions, functioned optimally at 70 degrees C and pH 6.0. While enzyme activity was not enhanced by the addition of CaCl2, GTA's thermostability was significantly improved in the presence of CaCl2. The structure, in complex with an acarbose derived pseudo-hexasaccharide, consists of the typical three domains and binds one Ca(2+) ion. This Ca(2+) ion was strongly bound and not chelated by EDTA. A predicted second Ca(2+)-binding site, however, was disordered. With limited subsites, two novel substrate-binding residues, Y147 and Y182, may help increase substrate affinity. No distinct starch-binding domain is present, although two regions rich in aromatic residues have been observed. GTA, with a smaller domain B and several shorter loops compared to other alpha-amylases, has one of the most compact alpha-amylase folds that may contribute greatly to its tight Ca(2+) binding and thermostability. PMID- 23683705 TI - Structural and functional stabilization of phage particles in carbohydrate matrices for bacterial biosensing. AB - Infections associated with health care services are nowadays widespread and, associated to the progressive emergence of microorganisms resistant to conventional chemical antibiotics, are major causes of morbidity and mortality. One of the most representative microorganisms in this scenario is the bacterium Pseudomonas aeruginosa, which alone is responsible for ca. 13-15% of all nosocomial infections. Bacteriophages have been reported as a potentially useful tool in the diagnosis of bacterial diseases, since they specifically recognize and lyse bacterial isolates thus confirming the presence of viable cells. In the present research effort, immobilization of these biological (although metabolically inert) entities was achieved via entrapment within (optimized) porous (bio)polymeric matrices of alginate and agar, aiming at their full structural and functional stabilization. Such phage-impregnated polymeric matrices are intended for future use as chromogenic hydrogels sensitive to color changes evolving from reaction with (released) intracytoplasmatic moieties, as a detection kit for P. aeruginosa cells. PMID- 23683706 TI - Library construction and evaluation for site saturation mutagenesis. AB - We developed a method for creating and evaluating site-saturation libraries that consistently yields an average of 27.4+/-3.0 codons of the 32 possible within a pool of 95 transformants. This was verified by sequencing 95 members from 11 independent libraries within the gene encoding alkene reductase OYE 2.6 from Pichia stipitis. Correct PCR primer design as well as a variety of factors that increase transformation efficiency were critical contributors to the method's overall success. We also developed a quantitative analysis of library quality (Q values) that defines library degeneracy. Q-values can be calculated from standard fluorescence sequencing data (capillary electropherograms) and the degeneracy predicted from an early stage of library construction (pooled plasmids from the initial transformation) closely matched that observed after ca. 1000 library members were sequenced. Based on this experience, we suggest that this analysis can be a useful guide when applying our optimized protocol to new systems, allowing one to focus only on good-quality libraries and reject substandard libraries at an early stage. This advantage is particularly important when lower throughput screening techniques such as chiral-phase GC must be employed to identify protein variants with desirable properties, e.g., altered stereoselectivities or when multiple codons are targeted for simultaneous randomization. PMID- 23683708 TI - Bayesian estimation of the effective reproduction number for pandemic influenza A H1N1 in Guangdong Province, China. AB - PURPOSE: During the course of a pandemic, it is necessary to understand its transmissibility, which is often summarized by the effective reproduction number. Accurate estimation of the effective reproduction number (R) is of vital significance in real-time decision making for coping with pandemic influenza. METHODS: We used daily case notification data in Guangdong Province, China, in conjunction with Bayesian inference of two different stochastic susceptible, infectious, recovered (SIR) models to estimate the effective reproduction number. The duration of infectiousness was taken from published literature, and the proportion of imported cases was obtained from individual-level data. RESULTS: At the initial epidemic phase, 40% of the first 261 cases were not locally acquired. Explicitly accounting for imported cases and different infectious periods, the possible range of basic reproduction number was preliminarily estimated to be between 1.05 and 1.46. We showed how the daily case reports provided valuable information to estimate the effective reproduction number. We also found the potential delay in reporting had a relatively minor impact on estimating R. CONCLUSIONS: Our proposed models and findings provide a relevant contribution towards establishing a basis for monitoring the evolution of emerging infectious diseases in real time and understanding the characteristics of pandemic influenza A H1N1 in Guangdong Province. PMID- 23683710 TI - Waist-to-thigh ratio is a predictor of internal organ cancers in humans: findings from a cohort study. AB - OBJECTIVE: Studies have shown that some specific body measures are associated with the occurrence of cancers. Few studies have demonstrated the relationship with more comprehensive approaches. This study aims to explore body measures and the combinations associated with internal organ cancers. METHODS: Three dimensional anthropometric body surface scanning data collected 10,215 participants from the health examination department in a medical center of Taiwan during 2000-2010. Follow-up was conducted for an average of 8 years, and 244 internal organ cancer cases were identified. RESULTS: An increased risk of internal organ cancers was observed among the subjects with larger waist circumference/smaller thigh circumference, in which waist-to-thigh ratio (WTR) was constructed. Comparing the subjects in the fourth quartile for WTR to the subjects in the first quartile with multiple Cox regression analysis yielded a hazard ratio of 1.842 (95% confidence interval, 1.131~2.999). The association between WTR quartile and internal organ cancers was stronger among male participants, older participants, and participants with chronic conditions. CONCLUSIONS: The study has revealed that WTR is the most significant predictor for the occurrence of cancer in Asian populations. Because it is easy to measure and open to modification, WTR may be more useful in clinical and preventive medicine in the future. PMID- 23683707 TI - Molecular mechanisms of antiseizure drug activity at GABAA receptors. AB - The GABAA receptor (GABAAR) is a major target of antiseizure drugs (ASDs). A variety of agents that act at GABAARs s are used to terminate or prevent seizures. Many act at distinct receptor sites determined by the subunit composition of the holoreceptor. For the benzodiazepines, barbiturates, and loreclezole, actions at the GABAAR are the primary or only known mechanism of antiseizure action. For topiramate, felbamate, retigabine, losigamone and stiripentol, GABAAR modulation is one of several possible antiseizure mechanisms. Allopregnanolone, a progesterone metabolite that enhances GABAAR function, led to the development of ganaxolone. Other agents modulate GABAergic "tone" by regulating the synthesis, transport or breakdown of GABA. GABAAR efficacy is also affected by the transmembrane chloride gradient, which changes during development and in chronic epilepsy. This may provide an additional target for "GABAergic" ASDs. GABAAR subunit changes occur both acutely during status epilepticus and in chronic epilepsy, which alter both intrinsic GABAAR function and the response to GABAAR-acting ASDs. Manipulation of subunit expression patterns or novel ASDs targeting the altered receptors may provide a novel approach for seizure prevention. PMID- 23683709 TI - Assessing the component associations of the healthy worker survivor bias: occupational asbestos exposure and lung cancer mortality. AB - BACKGROUND: The healthy worker survivor bias is well-recognized in occupational epidemiology. Three component associations are necessary for this bias to occur: i) prior exposure and employment status; ii) employment status and subsequent exposure; and iii) employment status and mortality. Together, these associations result in time-varying confounding affected by prior exposure. We illustrate how these associations can be assessed using standard regression methods. METHODS: We use data from 2975 asbestos textile factory workers hired between January 1940 and December 1965 and followed for lung cancer mortality through December 2001. RESULTS: At entry, median age was 24 years, with 42% female and 19% non Caucasian. Over follow-up, 21% and 17% of person-years were classified as at work and exposed to any asbestos, respectively. For a 100 fiber-year/mL increase in cumulative asbestos, the covariate-adjusted hazard of leaving work decreased by 52% (95% confidence interval [CI], 46-58). The association between employment status and subsequent asbestos exposure was strong due to nonpositivity: 88.3% of person-years at work (95% CI, 87.0-89.5) were classified as exposed to any asbestos; no person-years were classified as exposed to asbestos after leaving work. Finally, leaving active employment was associated with a 48% (95% CI, 9-71) decrease in the covariate-adjusted hazard of lung cancer mortality. CONCLUSIONS: We found strong associations for the components of the healthy worker survivor bias in these data. Standard methods, which fail to properly account for time varying confounding affected by prior exposure, may provide biased estimates of the effect of asbestos on lung cancer mortality under these conditions. PMID- 23683711 TI - Risk of non-Hodgkin lymphoma in relation to tricyclic antidepressant use. AB - PURPOSE: We investigated the relationship between use of tricyclic antidepressants (TCAs) and risk of non-Hodgkin lymphoma (NHL). Previous studies provided some evidence of an association, but did not assess risk of NHL subtypes. METHODS: Cases and controls were members of Group Health, an integrated healthcare delivery system. Cases were persons diagnosed with NHL between 1980 and 2011 at age 25 years or older; eight control subjects were matched to each case on age, sex, and length of enrollment. Information on previous TCA use was ascertained from automated pharmacy data. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) for NHL, overall and for common subtypes, for various patterns of TCA use. RESULTS: We identified 2768 cases and 22,127 matched control subjects. We did not observe an appreciably increased risk of NHL among TCA ever-users compared to non-users (OR, 1.1; 95% CI, 1.0-1.2). Overall risk of NHL was associated to at most a small degree with longer-term use (OR, 1.2; 95% CI, 1.0-1.4; >=10 prescriptions), high dose use (OR, 1.1; 95% CI, 0.8-1.5; >=50 mg), or non-recent use (OR, 1.0; 95% CI, 0.9 = 1.2; >5 years previously). TCA use was not associated with NHL subtypes, except chronic lymphocytic leukemia/small lymphocytic lymphoma (OR, 1.5; 95% CI, 1.1-2.0; longer-term use). CONCLUSIONS: We found little evidence that the use of TCAs increases the risk of NHL overall or for specific common subtypes of NHL. PMID- 23683713 TI - The adoption of chronic fatigue syndrome/myalgic encephalomyelitis case definitions to assess prevalence: a systematic review. AB - PURPOSE: Prevalence estimates have been based on several case definitions of chronic fatigue syndrome (CFS). The purpose of this work is to provide a rigorous overview of their application in prevalence research. METHODS: A systematic review of primary studies reporting the prevalence of CFS since 1990 was conducted. Studies were summarized according to study design, prevalence estimates, and case definition used to ascertain cases. RESULTS: Thirty-one studies were retrieved, and eight different case definitions were found. Early estimates of CFS prevalence were based on the 1988 Centers for Disease Control and Prevention, Australian, and Oxford. The 1994 Centers for Disease Control and Prevention, however, has been adopted internationally, as a general standard. Only one study has reported prevalence according to the more recent, Canadian Consensus Criteria. Additional estimates were also found according to definitions by Ho-Yen, the 2005 Centers for Disease Control and Prevention empirical definition, and an epidemiological case definition. CONCLUSIONS: Advances in clinical case definitions during the past 10 years such as the Canadian Consensus Criteria have received little attention in prevalence research. Future assessments of prevalence should consider adopting more recent developments, such as the newly available International Consensus Criteria. This move could improve the surveillance of more specific cases found within CFS. PMID- 23683712 TI - Do the psychosocial risks associated with television viewing increase mortality? Evidence from the 2008 General Social Survey-National Death Index dataset. AB - BACKGROUND: Television viewing is associated with an increased risk of mortality, which could be caused by a sedentary lifestyle, the content of television programming (e.g., cigarette product placement or stress-inducing content), or both. METHODS: We examined the relationship between self-reported hours of television viewing and mortality risk over 30 years in a representative sample of the American adult population using the 2008 General Social Survey-National Death Index dataset. We also explored the intervening variable effect of various emotional states (e.g., happiness) and beliefs (e.g., trust in government) of the relationship between television viewing and mortality. RESULTS: We find that, for each additional hour of viewing, mortality risks increased 4%. Given the mean duration of television viewing in our sample, this amounted to about 1.2 years of life expectancy in the United States. This association was tempered by a number of potential psychosocial mediators, including self-reported measures of happiness, social capital, or confidence in institutions. Although none of these were clinically significant, the combined mediation power was statistically significant (P < .001). CONCLUSIONS: Television viewing among healthy adults is correlated with premature mortality in a nationally representative sample of U.S. adults, and this association may be partially mediated by programming content related to beliefs or affective states. However, this mediation effect is the result of many small changes in psychosocial states rather than large effects from a few factors. PMID- 23683714 TI - [CA 19.9 elevation in the absence of pancreatic tumor]. PMID- 23683715 TI - Too complicated for the field? Measuring quality of care in humanitarian aid settings. AB - While quality of care is a major concern in the western world, not many studies investigate this topic in low-income countries. Even less is known about the quality of care in humanitarian aid settings, where additional challenges from natural or manmade disasters contribute to additional challenges. This study tried to address this gap by introducing a new approach to systematically measure quality of care in a project of Medecins Sans Frontieres (MSF) in Agok area, between South Sudan and Sudan. Our objective was to obtain a valid snapshot of quality of care for a MSF project in three weeks that has the potential to serve as a baseline for quality improvement strategies. The evaluation followed a cross sectional study design to assess structural, process and outcome quality according to Donabedian's criteria of quality of care. A bundle of well established methods for collection of quantitative and qualitative data was used to assess the project by following a triangulated mixed-methods approach. Mean structural quality scored 73% of expected performance level and mean process quality 59%. The overall mortality rate for the hospital was 3.6%. On average, less complicated cases got a better level of care than patients who were seriously ill. Significant motivational issues were discovered in staff interviews potentially affecting quality of care. The tool appeared to be quick, feasible and effective in judging quality of care in the selected project. To tap the whole potential of the approach a re-evaluation should be carried out to assess the effectiveness of implemented improvement strategies in Agok. To confirm the usefulness of the approach, more studies are needed covering the variety of different humanitarian aid settings. PMID- 23683716 TI - The impact of prior percutaneous coronary intervention on long-term survival after coronary artery bypass grafting. AB - BACKGROUND: Previous studies examining the influence of prior percutaneous coronary intervention (PCI) on long-term survival after coronary artery bypass grafting (CABG) have reported conflicting results. The purpose of this study was to further examine the influence of prior PCI on long-term survival after CABG at a large tertiary referral heart institute. METHODS: Long-term survival between 1992 and 2011 was compared in non-emergent CABG cases with and without prior PCI. Hazard ratios (HR) and 95% confidence intervals (CI) were computed using a Cox regression model. RESULTS: A total of 2532 (19%) patients had prior PCI before CABG (n=13,354). The median follow-up for study participants was 8.1 years. The median survival for patients with and without prior PCI was 15 years and 14 years, respectively (p<0.0001). Long-term survival was similar between patients with and without prior PCI after adjusting for age, sex, race, hypertension, coronary artery disease severity, congestive heart failure, and prior stroke (adjusted HR=0.99, 95%CI=0.91-1.06). CONCLUSION: Findings from outcomes research are important in the planning of appropriate postoperative patient care. Our study provides additional evidence that prior PCI is not a significant predictor of long-term survival after CABG. PMID- 23683717 TI - Comparison of three risk stratification rules for predicting patients with acute coronary syndrome presenting to an Australian emergency department. AB - OBJECTIVES: To compare the predictive ability of three risk stratification tools used to assess patients presenting to the ED with potential acute coronary syndrome. DESIGN: Pre-planned analysis of an observational study. SETTING: A single tertiary referral hospital. PARTICIPANTS: 1495 patients presented with chest pain. 948 patients were screened and enrolled. Patients with at least 5 min of chest pain suggestive of ACS were eligible. INTERVENTIONS: Subjects were risk categorised using the Heart Foundation of Australia/Cardiac Society of Australia and New Zealand guidelines (HFA/CSANZ), the TIMI score and the GRACE score. Three strata of the TIMI and GRACE score were used to compare to the HFA/CSANZ risk categories. MAIN OUTCOME MEASUREMENT: 30-Day cardiac event rates including cardiac death, acute myocardial infarction and unstable angina. RESULTS: There were 152 events in 91 patients (9.6%). The discriminatory ability of the scores determined by the AUC was 0.83 (95% CI 0.79-0.87) for the GRACE score, 0.79 (95% CI 0.74-0.83) for TIMI score and 0.75 (95% CI 0.70-0.80) for HFA/CSANZ. The AUCs with three strata of the GRACE and TIMI scores were 0.76 (95% CI 0.72-0.81) and 0.68 (95% CI 0.62-0.73) respectively. CONCLUSIONS: All three scores were similar in performance in quantifying risk in ED patients with possible ACS. The GRACE score identified a sizable low risk cohort with high sensitivity and NPV but complexity of this tool may limit its utility. Improved scores are needed to allow early identification of low- and high-risk patients to support improvements in patient flow and ED overcrowding. PMID- 23683718 TI - Post-procedural inverted takotsubo cardiomyopathy. PMID- 23683719 TI - Post-mortem diagnosis: evolving a team approach. PMID- 23683720 TI - Post-mortem MRI versus conventional autopsy in fetuses and children: a prospective validation study. AB - BACKGROUND: Post-mortem MRI is a potential diagnostic alternative to conventional autopsy, but few large prospective studies have compared its accuracy with that of conventional autopsy. We assessed the accuracy of whole-body, post-mortem MRI for detection of major pathological lesions associated with death in a prospective cohort of fetuses and children. METHODS: In this prospective validation study, we did pre-autopsy, post-mortem, whole-body MRI at 1.5 T in an unselected population of fetuses (<=24 weeks' or >24 weeks' gestation) and children (aged <16 years) at two UK centres in London between March 1, 2007 and Sept 30, 2011. With conventional autopsy as the diagnostic gold standard, we assessed MRI findings alone, or in conjunction with other minimally invasive post mortem investigations (minimally invasive autopsy), for accuracy in detection of cause of death or major pathological abnormalities. A radiologist and pathologist who were masked to the autopsy findings indicated whether the minimally invasive autopsy would have been adequate. The primary outcome was concordance rate between minimally invasive and conventional autopsy. FINDINGS: We analysed 400 cases, of which 277 (69%) were fetuses and 123 (31%) were children. Cause of death or major pathological lesion detected by minimally invasive autopsy was concordant with conventional autopsy in 357 (89.3%, 95% CI 85.8-91.9) cases: 175 (94.6%, 90.3-97.0) of 185 fetuses at 24 weeks' gestation or less, 88 (95.7%, 89.3 98.3) of 92 fetuses at more than 24 weeks' gestation, 34 (81.0%, 66.7-90.0) [corrected] of 42 newborns aged 1 month or younger, 45 (84.9%, 72.9-92.1) of 53 infants aged older than 1 month to 1 year or younger, and 15 (53.6%, 35.8-70.5) of 28 children aged older than 1 year to 16 years or younger. The dedicated radiologist or pathologist review of the minimally invasive autopsy showed that in 165 (41%) cases a full autopsy might not have been needed; in these cases, concordance between autopsy and minimally invasive autopsy was 99.4% (96.6-99.9). INTERPRETATION: Minimally invasive autopsy has accuracy similar to that of conventional autopsy for detection of cause of death or major pathological abnormality after death in fetuses, newborns, and infants, but was less accurate in older children. If undertaken jointly by pathologists and radiologists, minimally invasive autopsy could be an acceptable alternative to conventional autopsy in selected cases. FUNDING: Policy research Programme, Department of Health, UK. PMID- 23683721 TI - Towards a personalized breast cancer treatment approach guided by circulating tumor cell (CTC) characteristics. AB - Circulating tumor cells (CTCs) can be found in the peripheral blood of patients with different solid tumors, including breast cancer. A CTC count is a strong established prognostic factor in various stages in several tumor types. Besides that, characterization of CTCs is expected to become an invaluable tool to predict treatment response and personalize cancer treatments. Likely, CTCs are shed by different tumor lesions and may therefore provide a comprehensive view of tumor characteristics at a certain time-point, including inter- and intratumoral heterogeneity. Obtained through a simple venipuncture, CTCs could this way serve as a "liquid biopsy". However, isolation and subsequent characterization of CTCs is technically extremely challenging, mainly due to the small number of cells amidst a large majority of leukocytes. A wide range of assays has been developed, but only the CellSearch System((r)) (Veridex, Raritan, NJ, USA) has obtained FDA approval for CTC enumeration so far. For characterization purposes, no assay has been validated at all. Nevertheless, the first studies investigating the clinical value of CTC characteristics have been performed. Here, we review these clinical studies. The various techniques used to interrogate CTCs are briefly described and an overview of the clinical relevance of CTC characterization in breast cancer is given. PMID- 23683722 TI - Selective and rapid expansion of human neural progenitor cells on substrates with terminally anchored growth factors. AB - Human neural progenitor cells (hNPCs) are a potential source for cell transplantation therapy in central nervous disorders. Neurosphere culture, the standard method for obtaining hNPCs, suffers from several limitations including the heterogeneity of cells in a neurosphere and the limitation of growth rate due to the presence of differentiated cells in the neurospheres. To overcome these limitations, we developed culture substrates that enable the selective expansion of hNPCs in adherent culture. Epidermal growth factor and basic fibroblast growth factor were fused with hexahistidine (EGF-His and bFGF-His, respectively) and were immobilized alone or in combination onto Ni ion-bound glass through coordination. When hNPCs derived from human fetal brain were cultured on these substrates, adhesion and proliferation of hNPCs took place most efficiently on the substrate with both EGF-His and bFGF-His compared to substrates with either factor alone and to a control substrate without growth factors. The rate of cell proliferation was two-fold higher in the adherent culture on the substrate immobilized with both EGF-His and bFGF-His than in the standard neurosphere culture. A cell population obtained after 5 days of culture on the substrate contained nestin-expressing progenitors (>90%). We conclude that the culture substrate with co-immobilized EGF and bFGF is effective for the selective expansion of hNPCs. PMID- 23683723 TI - The promotion of endothelial cell attachment and spreading using FNIII10 fused to VEGF-A165. AB - Synergy in the downstream signaling pathways of the vascular endothelial growth factor receptor-2 (VEGFR-2) and the integrin alphavbeta3 is critical for blood vessel formation. Thus, agents that activate both receptors could possess efficient pro-angiogenic potential. Here, we created a fibrin-binding bi functional protein (FNIII10-VEGF) consisting of the 10th type III domain of fibronectin (FNIII10) fused to a plasmin-resistant VEGF-A165 mutant (VEGF) that potentiated angiogenic processes when compared to the effect of the separate molecules. FNIII10-VEGF was able to bind both VEGFR-2 and integrin alphavbeta3. Intriguingly, cell attachment and spreading to immobilized FNIII10-VEGF was significantly enhanced compared to individual FNIII10 or VEGF proteins. Delivery of immobilized FNIII10-VEGF by covalent linkage to a fibrin matrix significantly enhanced the angiogenic response in an in vivo wound healing assay compared to soluble VEGF. Unexpectedly, the angiogenic response to fibrin-immobilized FNIII10 VEGF was reduced in comparison to the pro-angiogenic effect of fibrin-immobilized VEGF. Collectively, findings of this study corroborate a critical role for a subtle balance of the integrin-VEGF interplay in angiogenesis and provide insight in how engineered growth factors in concert with biomaterial matrices may offer a potent molecular/material approach to harness these interactions for therapeutic angiogenesis. PMID- 23683724 TI - Roles of virulence genes (PsaA and CpsA) on the invasion of Streptococcus pneumoniae into blood system. AB - BACKGROUND: Streptococcus pneumoniae (SP) is the major cause of childhood mortality worldwide, we need to understand virulence genes of SP so can better target the treatment.We investigated the expression of virulence genes PsaA and CpsA in different strains of SP interacting with monocyte cell line (THP-1) or pneumocyte cell line (A549) and the possible mechanism of SP invasion of the blood system. METHODS: A total of 23 strains of SP were collected from hospitalized patients (blood-derived and sputum-derived) in the Second Affiliated Hospital of Wenzhou Medical College. The strains and ATCC 49619 were cultured, and RNAs were extracted. THP-1 and A549 cells were stimulated by different SP and ATCC 49619 for 4 h and 8 h, respectively. Quantitative real-time PCR was used to analyze the mRNA expression of PsaA and CpsA. The data were analyzed by SPSS 17.0. RESULTS: The mRNA level of PsaA and CpsA were all significantly increased in clinical SP strains when compared to ATCC49619 after tedTHP-1 and A549 cells were stimulated. Clinical SPs showed higher virulence compared with ATCC49619. CONCLUSIONS: The expression of CpsA is the basis of the pathogenicity of SP. The expression of virulence gene PsaA may be helpful to the invasion of SP to the blood system. PMID- 23683726 TI - Reconstruction of scalp and forehead defect with local transposition split skin flap and remnant full-thickness skin graft. PMID- 23683725 TI - Botulinum toxin injection of both sides of the face to treat post-paralytic facial synkinesis. AB - OBJECTIVE: An attempt has been made to produce a new 'balance' in facial dynamics between a paralysed and a non-paralysed face with reduction of synkinesis, by concomitant injection of botulinum toxin A (BTX-A) on both sides in patients with long-lasting facial sequelae. STUDY DESIGN: Prospective clinical study. SETTING: University hospital. SUBJECTS AND METHODS: Forty-two consecutive patients who recovered partially from facial nerve paralysis were enrolled for this study. The amount injected per site of the paralysed side with synkinesis varied from 1.5 to 2.5 U, and the total dose used per patient was 10-26 U (mean 17.12+/-5.3 U). That of the non-paralysed side with muscular hypertrophy varied from 2.5 to 5 U, and the total dose used per patient was 35-72 U (mean 52.6+/-9.7 U). All patients had been evaluated by the Sunnybrook (SB) facial nerve grading systems and developed dynamic facial asymmetry ratio. RESULTS: After administration of injection of BTX A on both sides of the face, relief of facial synkinesis and enhancement of facial symmetry were observed in all patients. Before the injection, the patients showed an SB score of 38.8+/-10.68. After the injection, changes of synkinesis and symmetry score were 7.9+/-1.81 and 8.4+/-3.25, respectively, resulting in a 58.4+/-12.46 score at the last evaluation. Before the administration, the mean+/ standard deviation (SD) value of dynamic facial asymmetry was 0.83+/-0.06 and it was increased significantly to 0.90+/-0.05 1 month after administration. CONCLUSION: After BTX-A injection on both sides for synkinesis and contralateral hypertrophy, the patients showed significant suppression of the synkinesis and improvement of facial symmetry with resulting elevated quality of life, social interaction, personal appearance and food intake. PMID- 23683727 TI - Unilateral vs bilateral hip bone mineral density measurement for the diagnosis of osteoporosis. AB - It has not been established whether unilateral or bilateral hip dual-energy X-ray absorptiometry (DXA) is preferable for the diagnosis of osteoporosis. We investigated the discordance in DXA measurements in bilateral hips to determine whether unilateral DXA is valid for osteoporosis diagnosis. The subjects were 2964 Japanese patients without a previous diagnosis of primary osteoporosis. We measured bilateral femoral bone mineral density (BMD) and calculated indices, related to the unilateral results, for predicting contralateral hip osteoporosis. A likelihood ratio (LR) of a negative test (LR [-]) of less than 0.2 was considered to exclude the diagnosis. In the normal spinal BMD group, the sensitivity of unilateral DXA for women was 27-73% and LR (-) was 0.28-0.73; the sensitivity for men was 0-50% and LR (-) was 0.51-1.00; the diagnosis of contralateral osteoporosis was not excluded. Sensitivity increased and LR (-) increased with worsening spinal BMD status; however, LR (-) did not meet the cutoff for exclusion. We could exclude unilateral hip osteoporosis, in women only, by performing contralateral femoral DXA; this necessitated lowering the T score cutoff from -2.5 to -2.0. Unilateral femoral DXA is not useful for excluding the diagnosis of contralateral hip osteoporosis. PMID- 23683728 TI - Online learning in a dermatology clerkship: piloting the new American Academy of Dermatology Medical Student Core Curriculum. AB - BACKGROUND: Multiple studies have shown that both current and future primary care providers have insufficient education and training in dermatology. To address the limitations and wide variability in medical student dermatology instruction, the American Academy of Dermatology (AAD) created a standardized, online curriculum for both dermatology learners and educators. OBJECTIVE: We sought to determine the impact of the integration of the AAD online curriculum into a 2-week introductory dermatology clerkship for fourth-year medical students. METHODS: In addition to their clinical duties, we assigned 18 online modules at a rate of 1 to 3 per day. We evaluated knowledge acquisition using a 50-item, multiple-choice pretest and posttest. Postmodule and end-of-course questionnaires contained both closed and open-ended items soliciting students' perceptions about usability and satisfaction. RESULTS: All 51 participants significantly improved in their dermatology knowledge (P < .001). The majority of students found the modules easy to navigate (95%) and worth their time (93%). All respondents supported the continuation of the modules as part of the dermatology clerkship. LIMITATIONS: Without a control group who did not experience the online curriculum, we are unable to isolate the specific impact of the online modules on students' learning. CONCLUSION: This study demonstrates the successful integration of this educational resource into a 2-week, university-based dermatology clerkship. Students' perceptions regarding usability and satisfaction were overwhelmingly positive, suggesting that the online curriculum is highly acceptable to learners. Widespread use of this curriculum may be a significant advancement in standardized dermatology learning for medical students. PMID- 23683729 TI - Elastic staining versus fluorescent and polarized microscopy in the diagnosis of alopecia. AB - BACKGROUND: Recently, polarized microscopy was reported as helpful in the evaluation of alopecia biopsy specimens. OBJECTIVE: We sought to determine the usefulness of polarized microscopy relative to elastic tissue staining and fluorescent microscopy. METHODS: Histologic sections from 60 alopecia specimens were evaluated to determine the pattern of elastic tissue in elastic van Gieson stained sections. Comparable hematoxylin-eosin sections were examined under a fluorescent microscope to determine the elastic tissue pattern and examined under polarized microscopy to determine the pattern of birefringence. RESULTS: Elastic van Gieson staining demonstrated high sensitivity (1.0) and high specificity (1.0) for the identification of nonscarring alopecia. In 54 of 60 cases, fluorescent microscopy demonstrated an identical pattern of elastic tissue. High background eosin fluorescence made it impossible to interpret the elastic tissue pattern in the remaining 6 specimens. Strong birefringence in dermal collagen sparing fibrous tracts had high specificity (1.0) but lower sensitivity (0.59). Strong collagen birefringence within the dermis and broad fibrous tracts were present in all 6 cases of central centrifugal cicatricial alopecia. LIMITATIONS: Elimination of the 6 uninterpretable specimens with high background fluorescence from our calculations may be a source of bias, as these cases could potentially all have been either negative or positive. CONCLUSION: Elastic tissue staining is the most reliable means to determine the pattern of scarring in alopecia biopsy specimens. In most cases, fluorescent microscopy of hematoxylin-eosin sections shows an identical pattern. Although a pattern of collagen birefringence on polarized microscopy distinctly sparing fibrous tract is specific for nonscarring alopecia, not all cases of nonscarring alopecia demonstrate this pattern. Strong collagen birefringence within both the dermis and fibrous tracts suggests a diagnosis of central centrifugal cicatricial alopecia. PMID- 23683730 TI - Alleged isotretinoin-associated inflammatory bowel disease: disproportionate reporting by attorneys to the Food and Drug Administration Adverse Event Reporting System. AB - BACKGROUND: Some studies have purported to link isotretinoin prescribed for acne with the development of inflammatory bowel disease (IBD). OBJECTIVE: We sought to identify existence of disproportionate attorney-initiated reporting of isotretinoin-associated IBD in the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: A total of 3,338,835 cases (2003-2011) were downloaded from the FAERS. These were queried for IBD cases reported with isotretinoin for a usage indication of acne while recording reporter category. Trends were analyzed over time for reports by attorneys for all medications compared with reports of IBD with isotretinoin. Signal inflation factor was calculated to determine the distortion of pharmacovigilance signals for IBD with isotretinoin. RESULTS: There were 2214 cases of IBD resulting from isotretinoin. Attorneys reported 1944 (87.8%) cases whereas physicians reported 132 (6.0%) and consumers reported 112 (5.1%) cases (P value < .01). For the entire FAERS, only 87,905 of the total 2,451,314 (3.6%) reports for all drug reactions during the same time period were reported by attorneys (P value < .01). The signal inflation factor for IBD with isotretinoin for attorney-initiated reports was 5.82, signifying a clear distortion. LIMITATIONS: The accuracy of reports was not ascertained. CONCLUSIONS: Attorney-initiated reports inflate the pharmacovigilance signal of isotretinoin-associated IBD in the FAERS. PMID- 23683732 TI - Development and validation of an indirect Enzyme-linked immunosorbent assay for the detection of antibodies against Schmallenberg virus in blood samples from ruminants. AB - To detect Schmallenberg virus (SBV) infections in ruminants and to perform SBV epidemiological studies a cost-effective serological test is required. For these purposes an indirect whole virus Enzyme-linked Immunosorbent Assay (ELISA) for detection of SBV specific antibodies in ruminant blood samples was developed. Schmallenberg virus antigen was produced by propagation on Vero cells, partly purified and coated onto ELISA plates. The indirect ELISA procedure included the subsequent incubation of diluted samples, protein-G-HRP conjugate and TMB substrate solution. Net Optical Densities (OD) values were calculated and expressed as a sample to positive percentage (S/P%) by comparison of the average net OD with the OD of the positive control. Validation of this assay was performed using 633 samples from SBV-free sheep, goats and cattle, and 141 samples from SBV suspect ruminants. The diagnostic specificity was 98.8%. Test results of 86 ruminant serum samples using both the SBV-ELISA and an SBV virus neutralization test (VNT), designated as the gold standard serological test for SBV, showed good correlation: at an S/P cut-off of 15% only one VNT positive sample tested negative in the SBV ELISA. The diagnostic sensitivity of the ELISA, relative to the VNT, was 98.8% (95% CI: 93.3-100.0%). The ELISA showed a high repeatability (cv=6.5%) and reproducibility (100% agreement). It was concluded that this ELISA is a suitable test method for the detection of SBV antibodies in sera from cows, sheep and, possibly, goats. PMID- 23683731 TI - Comparison of allogeneic platelet lysate and fetal bovine serum for in vitro expansion of equine bone marrow-derived mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) are promising candidates for cell-based therapy and tissue engineering approaches. Fetal bovine serum (FBS) is commonly used for in vitro MSC expansion; however, the use of FBS may be associated with ethical, scientific, and safety issues. This study aimed to compare the ability of allogeneic platelet lysate (PL) and FBS to cause equine bone marrow-derived MSC expansion. MSCs were isolated from bone marrow aspirate in media supplemented with either PL or FBS, and cell proliferation properties and characteristics were examined. There were no significant differences in MSC yield, colony-forming unit fibroblast (CFU-F) assay, and population doubling time between PL and FBS cultures. In addition, both PL-MSCs and FBS-MSCs showed similar results in term of ALP staining, osteogenic differentiation, and RT-PCR, although there were subtle differences in morphology, growth pattern, and adhesive properties. These results suggest that PL is a suitable alternative to FBS for use in equine MSC expansion, without the problems related to FBS use. PMID- 23683733 TI - Rapid and inexpensive detection of common HBB gene mutations in Tunisian population by high-resolution melting analysis: implication for molecular diagnosis. AB - In Tunisia, beta-thalassemia is a common hereditary disease with a carrying rate of 2.21%. Up to now, detection of responsible mutations was made by laborious, expensive, and/or time consuming methods. The aim of this study is to develop and validate a specific assay for detection of the two most frequent mutations in Tunisian population, the IVS-I-110 (G -> A) and Cd39 (C -> T) mutations. In this study, we optimize high resolution melting analysis (HRMA) conditions for these mutations, using control DNAs. Then, we evaluate the strength of this methodology by screening a cohort of patients with beta-thalassemia. All examined reference DNA samples were unambiguously distinguished from each other. For the blinded test, the results were completely compatible with direct sequencing, performed after the HRMA. As HRMA represents a highly sensitive and high-throughput gene scanning method, it can provide timely diagnosis at low cost for effective clinical management of beta-thalassemia. PMID- 23683734 TI - Long-term outcome after drug-eluting versus bare-metal stent implantation in patients with ST-segment elevation myocardial infarction: 5 years follow-up from the randomized DEDICATION trial (Drug Elution and Distal Protection in Acute Myocardial Infarction). AB - OBJECTIVES: This study sought to compare the long-term effects of drug-eluting stent (DES) compared with bare-metal stent (BMS) implantation in patients with ST segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. BACKGROUND: The randomized DEDICATION (Drug Elution and Distal Protection in Acute Myocardial Infarction) trial evaluated the outcome after DES compared with BMS implantation in patients with STEMI undergoing primary percutaneous coronary intervention. METHODS: Patients with a high-grade stenosis/occlusion of a native coronary artery presenting with symptoms <12 h and ST-segment elevation were enrolled after giving informed consent. Patients were randomly assigned to receive a DES or a BMS in the infarct-related lesion. Patients were followed for at least 5 years, and clinical endpoints were evaluated from population registries and hospital charts. The main endpoint was the occurrence of the first major adverse cardiac event (MACE), defined as cardiac death, nonfatal recurrent myocardial infarction, and target lesion revascularization. RESULTS: Complete clinical status was available in 623 patients (99.5%) at 5 years follow-up. The combined MACE rate was insignificantly lower in the DES group (16.9% vs. 23%), mainly driven by a lower need of repeat revascularization (p = 0.07). Whereas the number of deaths from all causes tended to be higher in the DES group (16.3% vs. 12.1%, p = 0.17), cardiac mortality was significantly higher (7.7% vs. 3.2%, p = 0.02). The 5-year stent thrombosis rates were generally low and similar between the DES and the BMS groups. No cardiac deaths occurring within 1 month could be clearly ascribed to stent thrombosis, whereas stent thrombosis was involved in 78% of later-occurring deaths. CONCLUSIONS: The 5-year MACE rate was insignificantly different, but the cardiac mortality was higher after DES versus BMS implantation in patients with STEMI. Stent thrombosis was the main cause of late cardiac deaths. PMID- 23683735 TI - Transapical implantation of a second-generation transcatheter heart valve in patients with noncalcified aortic regurgitation. AB - OBJECTIVES: This study sought to report on the feasibility and early results of transcatheter aortic valve implantation employing a second-generation device in a series of patients with pure aortic regurgitation. BACKGROUND: Efficacy and safety of transcatheter aortic valve implantation in patients with calcific aortic stenosis and high surgical risk has been demonstrated. However, experience with implantation for severe noncalcified aortic regurgitation has been limited due to increased risk for valve dislocation or annular rupture. METHODS: Five patients (mean age: 66.6 +/- 7 years) underwent transapical implantation of a JenaValve (JenaValve Technology GmbH, Munich, Germany) transcatheter heart valve for moderate to severe, noncalcified aortic regurgitation. All patients were considered high risk for surgical aortic valve replacement after evaluation by an interdisciplinary heart team (logistic EuroSCORE [European System for Cardiac Operative Risk Evaluation] range 3.1% to 38.9%). Procedural and acute clinical outcomes were analyzed. RESULTS: Implantation was successful in all cases without relevant remaining aortic regurgitation or signs of stenosis in any of the patients. No major device- or procedure-related adverse events occurred and all 5 patients were alive with improved exercise tolerance at 3-month follow-up. CONCLUSIONS: Noncalcified aortic regurgitation continues to be a challenging pathology for transcatheter aortic valve implantation due to the risk for insufficient anchoring of the valve stent within the aortic annulus. This report provides first evidence that the JenaValve prosthesis may be a reasonable option in these specific patients due to its unique stent design, clipping the native aortic valve leaflets, and offering promising early results. PMID- 23683736 TI - Serial morphological and functional assessment of drug-eluting balloon for in stent restenotic lesions: mechanisms of action evaluated with angiography, optical coherence tomography, and fractional flow reserve. AB - OBJECTIVES: This study sought to elucidate the underlying mechanism through which drug-eluting balloons (DEB) restore coronary blood flow, by assessing the coronary vessel before, immediately after, and at 6-month follow-up with angiography, optical coherence tomography (OCT), and fractional flow reserve (FFR). BACKGROUND: In-stent restenosis (ISR) treatment remains challenging. Drug eluting balloons have been shown to be a valid treatment option in several studies. These studies focused on efficiency of the device, whereas the mechanisms of action of DEB in ISR treatment have not been investigated. METHODS: In this prospective, single-center observational study, patients with ISR were treated with a second-generation DEB. Serial angiographic, OCT, and FFR measurements were performed before and after the procedure, as well as at 6-month follow-up. RESULTS: Twenty-five patients were assigned to DEB treatment, with an angiographic and device success of 100% and 92%, respectively. Late luminal loss was 0.01 +/- 0.43 mm. Median percent changes [interquartile range] between pre and post-procedure, and post-procedure and follow-up were, respectively: lumen volume 75.1% increase [43.7 to 115.0], and 8% increase [-14.0 to 25.8]; stent volume 23.7% increase [15.5 to 40.0], and -1.2% decrease [-6.9 to 5.9]; and neointimal volume -14.4% decrease [-29.2 to -9.5], and -15.8% decrease [-38.1 to 28.3]. The FFR gradient along the treated stent (difference in FFR between the distal and the proximal stent edge) was 0.37 +/- 0.18 pre-procedure, 0.06 +/- 0.04 post-procedure, and 0.05 +/- 0.05 at follow-up. In all post-procedural OCT images, intrastent dissections were seen, which were sealed at follow-up OCT. CONCLUSIONS: DEB restore coronary blood flow by means of a short-term mechanical effect, causing an increase in lumen and stent volumes and compression of neointimal hyperplasia (with intra-stent dissections). Due to the local drug effect, patency persists and may even improve at follow-up, with further increase in lumen volume, decrease in neointimal volume, and complete sealing of neointimal dissections. PMID- 23683737 TI - The long-term clinical outcome of T-stenting and small protrusion technique for coronary bifurcation lesions. AB - OBJECTIVES: This study sought to report long-term clinical outcomes in patients treated with the provisional T-stenting and small protrusion (TAP) technique. BACKGROUND: Several strategies have been proposed for treating bifurcation lesions, each with its own merits and technical challenges. The TAP technique is a relatively new strategy that is technically less challenging, ensures complete coverage of the side-branch ostium, and minimizes stent overlap. Although there is reasonable amount of data for other bifurcation strategies, the long-term clinical outcomes for TAP technique are limited. METHODS: We retrospectively evaluated all patients who underwent TAP technique with drug-eluting stents between July 2005 and January 2012. The measured endpoints at follow-up were major adverse cardiac events defined as composite of cardiac death, myocardial infarction, and target vessel revascularization. RESULTS: A total of 95 patients (81.1% men) with a mean age of 64.8 years underwent TAP stenting. Procedural success was achieved in 100% of cases. True bifurcation was observed in 75 (78.9%) patients. First-generation drug-eluting stents were used in 55.8% of patients. The outcome rates at 3-year follow-up of major adverse cardiac events, cardiac death/follow-up myocardial infarction, target vessel revascularization, and target lesion revascularization were 12.9%, 3.1%, 9.7%, and 5.1%, respectively. There were no cases of follow-up myocardial infarction or stent thrombosis (definite and probable). CONCLUSIONS: These results demonstrate that TAP technique is associated with acceptable clinical outcomes with no episodes of definite and probable stent thrombosis. Further studies should compare TAP technique with other 2-stent strategies. PMID- 23683738 TI - Open-label, randomized, placebo-controlled evaluation of intracoronary adenosine or nitroprusside after thrombus aspiration during primary percutaneous coronary intervention for the prevention of microvascular obstruction in acute myocardial infarction: the REOPEN-AMI study (Intracoronary Nitroprusside Versus Adenosine in Acute Myocardial Infarction). AB - OBJECTIVES: This study sought to assess whether intracoronary adenosine or nitroprusside following thrombus aspiration (TA) is superior to TA alone for the prevention of microvascular obstruction (MVO) in ST-segment elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: MVO, due to its multifactorial pathogenesis, still occurs after TA in a sizeable portion of patients. METHODS: We performed a placebo-controlled, randomized, open-label, blind-examination, multicenter trial. A total of 240 STEMI patients with Thrombolysis In Myocardial Infarction (TIMI) flow grade 0/1 were randomly allocated 1:1:1 to receive adenosine (n = 80), nitroprusside (n = 80), or saline (n = 80) given distal to the occluded site after TA. The primary endpoint was the incidence of ST-segment resolution (STR) >70% on surface electrocardiogram at 90 min after PCI. Secondary endpoints were angiographic MVO incidence (TIMI flow grade <=2 or 3 with a myocardial blush grade <2) and major adverse cardiac event (MACE) rate at 30 days as a composite of cardiac death, myocardial infarction, target lesion revascularization, and heart failure requiring hospitalization. RESULTS: STR >70% occurred in in 71% of adenosine treated patients, in 54% of nitroprusside-treated patients, and in 51% of saline treated patients (p = 0.009 and p = 0.75, respectively, vs. saline). Angiographic MVO occurred in 18% of adenosine-treated patients, in 24% of nitroprusside treated patients, and in 30% of saline-treated patients (p = 0.06 and p = 0.37, respectively, vs. saline). MACE occurred in 10%, 14%, and 20% of patients, respectively (p = 0.08 and p = 0.29 vs. saline). CONCLUSIONS: In STEMI patients treated by PCI and TA, the additional intracoronary administration of adenosine, but not that of nitroprusside, results in a significant improvement of MVO, as assessed by STR. PMID- 23683739 TI - Transvenous, antegrade Melody valve-in-valve implantation for bioprosthetic mitral and tricuspid valve dysfunction: a case series in children and adults. AB - OBJECTIVES: The purpose of this study was to report the results of percutaneous valve-in-valve therapy using the Melody valve (Medtronic, Minneapolis, Minnesota) for patients with degenerated mitral and tricuspid bioprosthetic valves. BACKGROUND: Open surgery for replacement of degenerated bioprosthetic valves is associated with morbidity and mortality. METHODS: Nineteen patients (median age 65 years, range 10 to 88 years; 7 males) with degenerated mitral (n = 9) or tricuspid (n = 10) bioprosthetic valves underwent transvenous valve-in-valve implantation of the Melody valve. RESULTS: In the mitral patients, the mean Society of Thoracic Surgeons mortality score was 13.3 +/- 5.6%. All patients had a prosthetic valve mean diastolic inflow gradient >=5 mm Hg. Moderate or worse regurgitation was present in 7 of 9 mitral and 7 of 10 tricuspid patients. Implantation of a Melody valve was successful in all. Among the mitral patients, mean diastolic gradient decreased from 12.3 +/- 4.6 mm Hg to 5.2 +/- 2 mm Hg (p < 0.01). Residual regurgitation was trivial to mild in 6, mild to moderate in 2, and moderate in 1 patient. Among the tricuspid patients, mean diastolic gradient decreased from 10.0 +/- 4.3 mm Hg to 5.6 +/- 2.5 mm Hg (p < 0.01). Residual regurgitation was trivial to mild in 9 and mild to moderate in 1 patient. New York Heart Association functional class improved in 17 of 19 patients (p < 0.01). No periprocedural deaths, myocardial infarctions, strokes, or valve embolizations occurred. Vascular access site complications occurred in 4 patients. CONCLUSIONS: Percutaneous valve-in-valve implantation of the Melody valve in the mitral or tricuspid position for treatment of bioprosthetic valve dysfunction is feasible and can lead to significant symptomatic improvement in carefully selected high risk patients. PMID- 23683740 TI - Can lower risk patients presenting with transient ischaemic attack be safely managed as outpatients? AB - This study aimed to examine outcome in low risk transient ischaemic attack (TIA) patients presenting to emergency departments (ED) in a regional Australian setting discharged on antiplatelet therapy with expedited neurology review. All patients presenting to Gosford or Wyong Hospital ED with TIA, for whom faxed referrals to the neurology department were received between October 2008 and July 2010, were included in this prospective cohort study. Classification of low risk was based on an age, blood pressure, clinical features, duration of symptoms and diabetes (ABCD2) score <4 and the absence of high risk features, including known carotid disease, crescendo TIA, or atrial fibrillation. Patients with ABCD2 scores > or =4 or with high risk features were discussed with the neurologist on call (a decision regarding discharge or admission was then made at the neurologist's discretion). Patients were investigated with a brain CT scan and/or CT angiography, routine pathology, and an electrocardiogram. All discharged patients were commenced on antiplatelet therapy and asked to follow up with their local medical officer within 7 days. The patients were contacted by the neurology department to arrange follow-up. Our primary outcome was the number of subsequent strokes occurring within 90 days. Of 200 discharged patients for whom referrals were received, three patients had a stroke within 90 days. None of these would have been prevented through hospitalisation. In conclusion, medical assessment, expedited investigation with immediate commencement of secondary prevention and outpatient neurology review may be a reasonable alternative to admission for low risk patients presenting to the ED with TIA. PMID- 23683741 TI - Identification of microRNA-205 as a potential prognostic indicator for human glioma. AB - Altered microRNA-205 (miR-205) expression has been found in glioma tissue samples and cell lines; however, the clinical significance of this is unclear. The aim of this study was to confirm the miR-205 expression pattern in human glioma and to investigate its clinical relevance. Quantitative reverse-transcription polymerase chain reaction assays showed that miR-205 expression was significantly lower in glioma tissues than in non-neoplastic brain tissues (P<0.001). Statistical analysis revealed a significant correlation between low miR-205 expression and both high grade glioma (World Health Organization [WHO] criteria, P=0.008) and a low Karnofsky performance status score (P=0.02). Survival analysis demonstrated that the cumulative 5-year overall survival rate of patients with glioma in the high miR-205 expression group was significantly higher than that in the low miR 205 expression group (P<0.001). Multivariate Cox regression analysis further indicated that miR-205 expression (P=0.01) and WHO grade (P=0.01) were independent prognostic indicators of the overall survival of patients with glioma. Moreover, subgroup analyses revealed that the cumulative 5-year overall survival rate of patients with high grade (III-IV) glioma was significantly worse for the low miR-205 expression group than for the high miR-205 expression group (P<0.001), but no significant difference was found for patients with low grade (I II) glioma (P=0.09). In conclusion, down-regulation of miR-205 was associated with glioma progression. Our data are the first to suggest that miR-205 holds potential as a prognostic factor for glioma, especially for patients with advanced disease. PMID- 23683742 TI - Symptomatic facet cysts of the subaxial cervical spine. AB - Subaxial cervical facet cysts are uncommon. We report two patients with intraspinal, extradural, subaxial cervical spinal facet cysts, and review the literature to describe the epidemiology, clinical presentation, imaging findings, and treatment options for these lesions. Intraspinal, extradural, cervical spinal cysts should be considered as part of the differential diagnosis in patients presenting with clinical signs of cervical radiculopathy or myelopathy. PMID- 23683743 TI - Sarcoidosis associated with neuromyelitis optica. AB - Neuromyelitis optica (NMO) is an autoimmune disorder diagnosed by an elongated spinal cord lesion associated with unilateral or bilateral optic neuritis and anti-aquaporin 4 (AQP4) antibodies in the serum. It is triggered by or associated with several autoimmune diseases, but not with sarcoidosis. It responds to immunomodulators better than to steroid treatment. Sarcoidosis is an autoimmune disorder which manifests as non-caseating granulomas, usually in the lung parenchyma, but also in other tissues, including the brain. The involvement of the central nervous system in neurosarcoidosis differs considerably from that in neuromyelitis optica and the association of these two diseases concurrently in the same patient is unusual. PMID- 23683744 TI - Cardiologic predictors of sudden death in patients with myotonic dystrophy type 1. AB - The aim of this study was to analyze survival, causes of death and cardiologic predictors of sudden death in a large cohort of patients with myotonic dystrophy type 1 (DM1). The study was comprised of 171 adult DM1 patients hospitalized at the Neurology Clinic in a 20-year period. Severe electrocardiographic (ECG) abnormality included at least one of the following: rhythm other than sinus, PR interval of >=240 ms, QRS complex duration of 120 ms or more, and second-degree or third-degree atrioventricular (AV) block. Survival data were analyzed by the Kaplan-Meier test, log-rank test and Cox regression analysis. During the mean follow-up period of 9.4+/-5.4 years, a pacemaker was implanted in 5.8% of DM1 patients and 14% of patients died. The mean age at death was 55.6+/-12.5 years. The most common causes of death in our cohort were sudden death (41.7%) and respiratory failure (29.2%). The presence of palpitations (hazard ratio [HR]=4.7, p<0.05) and increased systolic blood pressure (HR=9.8, p<0.05) were significant predictors of sudden death. Among ECG parameters, severe ECG abnormality (HR=4.7, p<0.05), right bundle branch block (RBBB; HR=3.9, p<0.05) and bifascicular block (HR=5.8, p<0.05) were significant predictors of sudden death. PMID- 23683745 TI - Treating pain in newborn infants: navigating between Scylla and Charybdis. PMID- 23683746 TI - A newborn with double aortic arch. PMID- 23683747 TI - Ectopic intrathoracic kidney with right-sided congenital diaphragmatic hernia. PMID- 23683748 TI - Children's hospitals with shorter lengths of stay do not have higher readmission rates. AB - OBJECTIVE: To test the hypothesis that children's hospitals with shorter length of stay (LOS) for hospitalized patients have higher all-cause readmission rates. STUDY DESIGN: Longitudinal, retrospective cohort study of the Pediatric Health Information System of 183616 admissions within 43 US children's hospitals for appendectomy, asthma, gastroenteritis, and seizure between July 2009 and June 2011. Admissions were stratified by medical complexity, based on whether patients had a complex chronic health condition, were neurologically impaired, or were assisted with medical technology. Outcome measures include LOS; all-cause readmission rates within 3, 7, 15, and 30 days; and the association between hospital-specific mean LOS and all-cause readmission rates as determined by linear regression. RESULTS: Mean LOS was <3 days for all patients across all conditions, except for appendectomy in complex patients (mean LOS 3.7 days, 95% CI 3.47-4.01). Condition-specific 3-, 7-, 15-, and 30-day all-cause readmission rates for noncomplex patients were all <5%. Condition-specific readmission rates for complex patients ranged from <1% at 3 days for seizures to 16% at 30 days for gastroenteritis. There was no linear association between hospital-specific, condition-specific mean LOS, stratified by medical complexity, and all-cause readmission rates at any time interval within 30 days (all P values >=.10). CONCLUSION: In children's hospitals, LOS is short and readmission rates are low for asthma, appendectomy, gastroenteritis, and seizure admissions. In the conditions studied, there is no association between shorter hospital-specific LOS and higher readmission rates within the LOS observed. PMID- 23683749 TI - Treating basal-cell carcinoma in a real life setting. PMID- 23683750 TI - Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study. AB - BACKGROUND: The optimum timing of sentinel-lymph-node biopsy for breast cancer patients treated with neoadjuvant chemotherapy is uncertain. The SENTINA (SENTinel NeoAdjuvant) study was designed to evaluate a specific algorithm for timing of a standardised sentinel-lymph-node biopsy procedure in patients who undergo neoadjuvant chemotherapy. METHODS: SENTINA is a four-arm, prospective, multicentre cohort study undertaken at 103 institutions in Germany and Austria. Women with breast cancer who were scheduled for neoadjuvant chemotherapy were enrolled into the study. Patients with clinically node-negative disease (cN0) underwent sentinel-lymph-node biopsy before neoadjuvant chemotherapy (arm A). If the sentinel node was positive (pN1), a second sentinel-lymph-node biopsy procedure was done after neoadjuvant chemotherapy (arm B). Women with clinically node-positive disease (cN+) received neoadjuvant chemotherapy. Those who converted to clinically node-negative disease after chemotherapy (ycN0; arm C) were treated with sentinel-lymph-node biopsy and axillary dissection. Only patients whose clinical nodal status remained positive (ycN1) underwent axillary dissection without sentinel-lymph-node biopsy (arm D). The primary endpoint was accuracy (false-negative rate) of sentinel-lymph-node biopsy after neoadjuvant chemotherapy for patients who converted from cN1 to ycN0 disease during neoadjuvant chemotherapy (arm C). Secondary endpoints included comparison of the detection rate of sentinel-lymph-node biopsy before and after neoadjuvant chemotherapy, and also the false-negative rate and detection rate of sentinel lymph-node biopsy after removal of the sentinel lymph node. Analyses were done according to treatment received (per protocol). FINDINGS: Of 1737 patients who received treatment, 1022 women underwent sentinel-lymph-node biopsy before neoadjuvant chemotherapy (arms A and B), with a detection rate of 99.1% (95% CI 98.3-99.6; 1013 of 1022). In patients who converted after neoadjuvant chemotherapy from cN+ to ycN0 (arm C), the detection rate was 80.1% (95% CI 76.6 83.2; 474 of 592) and false-negative rate was 14.2% (95% CI 9.9-19.4; 32 of 226). The false-negative rate was 24.3% (17 of 70) for women who had one node removed and 18.5% (10 of 54) for those who had two sentinel nodes removed (arm C). In patients who had a second sentinel-lymph-node biopsy procedure after neoadjuvant chemotherapy (arm B), the detection rate was 60.8% (95% CI 55.6-65.9; 219 of 360) and the false-negative rate was 51.6% (95% CI 38.7-64.2; 33 of 64). INTERPRETATION: Sentinel-lymph-node biopsy is a reliable diagnostic method before neoadjuvant chemotherapy. After systemic treatment or early sentinel-lymph-node biopsy, the procedure has a lower detection rate and a higher false-negative rate compared with sentinel-lymph-node biopsy done before neoadjuvant chemotherapy. These limitations should be considered if biopsy is planned after neoadjuvant chemotherapy. FUNDING: Brustkrebs Deutschland, German Society for Senology, German Breast Group. PMID- 23683752 TI - Sentinel node biopsy and neoadjuvant chemotherapy. PMID- 23683751 TI - Photodynamic therapy versus topical imiquimod versus topical fluorouracil for treatment of superficial basal-cell carcinoma: a single blind, non-inferiority, randomised controlled trial. AB - BACKGROUND: Superficial basal-cell carcinoma is most commonly treated with topical non-surgical treatments, such as photodynamic therapy or topical creams. Photodynamic therapy is considered the preferable treatment, although this has not been previously tested in a randomised control trial. We assessed the effectiveness of photodynamic therapy compared with imiquimod or fluorouracil in patients with superficial basal-cell carcinoma. METHODS: In this single blind, non-inferiority, randomised controlled multicentre trial, we enrolled patients with a histologically proven superficial basal-cell carcinoma at seven hospitals in the Netherlands. Patients were randomly assigned to receive treatment with methylaminolevulinate photodynamic therapy (MAL-PDT; two sessions with an interval of 1 week), imiquimod cream (once daily, five times a week for 6 weeks), or fluorouracil cream (twice daily for 4 weeks). Follow-up was at 3 and 12 months post-treatment. Data were collected by one observer who was blinded to the assigned treatment. The primary outcome was the proportion of patients free of tumour at both 3 and 12 month follow up. A pre-specified non-inferiority margin of 10% was used and modified intention-to-treat analyses were done. This trial is registered as an International Standard Randomised controlled trial (ISRCTN 79701845). FINDINGS: 601 patients were randomised: 202 to receive MAL-PDT, 198 to receive imiquimod, and 201 to receive fluorouracil. A year after treatment, 52 of 196 patients treated with MAL-PDT, 31 of 189 treated with imiquimod, and 39 of 198 treated with fluorouracil had tumour residue or recurrence. The proportion of patients tumour-free at both 3 and 12 month follow-up was 72.8% (95% CI 66.8 79.4) for MAL-PDT, 83.4% (78.2-88.9) for imiquimod cream, and 80.1% (74.7-85.9) for fluorouracil cream. The difference between imiquimod and MAL-PDT was 10.6% (95% CI 1.5-19.5; p=0.021) and 7.3% (-1.9 to 16.5; p=0.120) between fluorouracil and MAL-PDT, and between fluorouracil and imiquimod was -3.3% (-11.6 to 5.0; p=0.435. For patients treated with MAL-PDT, moderate to severe pain and burning sensation were reported most often during the actual MAL-PDT session. For other local adverse reactions, local skin redness was most often reported as moderate or severe in all treatment groups. Patients treated with creams more often reported moderate to severe local swelling, erosion, crust formation, and itching of the skin than patients treated with MAL-PDT. In the MAL-PDT group no serious adverse events were reported. One patient treated with imiquimod and two patients treated with fluorouracil developed a local wound infection and needed additional treatment in the outpatient setting. INTERPRETATION: Topical fluorouracil was non inferior and imiquimod was superior to MAL-PDT for treatment of superficial basal cell carcinoma. On the basis of these findings, imiquimod can be considered the preferred treatment, but all aspects affecting treatment choice should be weighted to select the best treatment for patients. FUNDING: Grant of the Netherlands Organization for Scientific Research ZONMW (08-82310-98-08626). PMID- 23683753 TI - Improving epidemiologic data analyses through multivariate regression modelling. AB - : Regression modelling is one of the most widely utilized approaches in epidemiological analyses. It provides a method of identifying statistical associations, from which potential causal associations relevant to disease control may then be investigated. Multivariable regression - a single dependent variable (outcome, usually disease) with multiple independent variables (predictors) - has long been the standard model. Generalizing multivariable regression to multivariate regression - all variables potentially statistically dependent - offers a far richer modelling framework. Through a series of simple illustrative examples we compare and contrast these approaches. The technical methodology used to implement multivariate regression is well established - Bayesian network structure discovery - and while a relative newcomer to the epidemiological literature has a long history in computing science. Applications of multivariate analysis in epidemiological studies can provide a greater understanding of disease processes at the population level, leading to the design of better disease control and prevention programs. PMID- 23683754 TI - [Skin and soft-tissue infections in hospitalized patients: epidemiology, microbiological, clinical and prognostic factors]. AB - INTRODUCTION: Skin and soft-tissue infections (SSTIs) are a frequent cause of consultation in emergence services, and complicated cases require hospitalization. However there are few data in our setting about the clinical characteristics of these infections. MATERIAL AND METHODS: A retrospective review of hospital admitted patients with a diagnosis of folliculitis, cellulitis, erysipelas, abscesses, hidradenitis, furuncle, impetigo, fasciitis and Fournier's gangrene. Cases were extracted from the data base of diagnostic codes of the Archive and Clinical Documentation Department of Son Llatzer Hospital from January 2002 to November 2011. RESULTS: We studied 996 episodes in 841 hospitalized patients with any diagnosis of SSTIs. Cellulitis/erysipelas (66.7%) was the most frequently diagnosed condition, with 77% of all SSTIs being community acquired, and the majority of patients had comorbidities, mainly diabetes (33%) and heart failure (17.7%). The most frequent isolated microorganism was S.aureus (35.1%), in 19 (12.9%) cases with methicillin resistance (MRSA), 84.2% of them were nosocomial or health care acquired. Monotherapy with aminopenicillin with clavulanic acid was the empiric treatment most frequently used (35.5%). New antibiotics for Gram-positive cocci (linezolid, daptomycin, and tigecycline) were used in patients with comorbidities that presented more complications (P<.001) and more risk of mortality (P=.001). During admission 10.9% of patients died, but only in 2.7% of them mortality was related to the SSTIs. CONCLUSIONS: SSTIs attended most frequently in hospitalized patients are mainly cellulitis/erysipela, the majority community acquired. MRSA infections are mainly health care related. Use of new antibiotic for Gram positive cocci was limited. PMID- 23683755 TI - [Polycyclic lesion infiltrates in the shoulder and upper limbs]. PMID- 23683756 TI - [Vertebral osteolytic lesion in a 25 year old male]. PMID- 23683757 TI - Acceleration of autologous in vivo recellularization of decellularized aortic conduits by fibronectin surface coating. AB - Decellularization is a promising option to diminish immune and inflammatory response against donor grafts. In order to accelerate the autologous in vivo recellularization of aortic conduits for an enhanced biocompatibility, we tested fibronectin surface coating in a standardized rat implantation model. Detergent decellularized rat aortic conduits (n = 36) were surface-coated with covalently Alexa488-labeled fibronectin (50 MUg/ml, 24 h) and implanted into the systemic circulation of Wistar rats for up to 8 weeks (group FN; n = 18). Uncoated implants served as controls (group C; n = 18). Fibronectin-bound fluorescence on both surfaces of the aortic conduits was persistent for at least 8 weeks. Cellular repopulation was examined by histology and immunofluorescence (n = 24). Luminal endothelialization was significantly accelerated in group FN (p = 0.006 after 8 weeks), however, local myofibroblast hyperplasia with significantly increased ratio of intima-to-media thickness occurred (p = 0.0002 after 8 weeks). Originating from the adventitial surface, alpha-smooth muscle actin and desmin positive cell invasion into the media of fibronectin-coated conduits was significantly increased as compared to group C (p < 0.0001). In these medial areas, in situ zymography revealed enhanced matrix metalloproteinase activity. In both groups, inflammatory cell markers (CD3 and CD68) and signs of thrombosis proved negative. With regard to several markers of cell adhesion, inflammation and calcification, quantitative real-time PCR (n = 12) revealed no significant inter-group differences. Fibronectin surface coating of decellularized cardiovascular implants proved feasible and persistent for at least 8 weeks in the systemic circulation. Biofunctional protein coating accelerated the autologous in vivo endothelialization and induced a significantly increased medial recellularization. Therefore, this strategy may contribute to the improvement of current clinically applied bioprostheses. PMID- 23683758 TI - Puncture resistance of the scaled skin from striped bass: collective mechanisms and inspiration for new flexible armor designs. AB - The structure and mechanics of fish scales display unusual and attractive features which could inspire new protective materials and systems. This natural material is therefore attracting attention over the past few years, and recent work demonstrated the remarkable performance of individual fish scales. A puncture event as would occur from a predator's attack however involves more than one scale, and in this article we therefore investigate collective mechanisms occurring within the scaled skin of a fish in the event of a predator's attack. We first demonstrate that in striped bass (Morone saxatilis), the scales increase by four to five times the force required to puncture the skin. We show that individual scales from striped bass provide a remarkable barrier against sharp puncture, regardless of the stiffness of the substrate. The scalation pattern in striped bass is such that three scales overlap at any point on the surface of the fish, which we show effectively multiplies the puncture force by three. We determined that the friction between scales is negligible and therefore it does not contribute to increasing puncture force. Likewise, we found that the local arrangement of the scales had little effect on the puncture performance. Interestingly, because the scales are several orders of magnitude stiffer than the substrate, indenting a few isolated scales results in "sinking" of the scales into the substrate. The high local deflections and strain within the soft tissue may then result in blunt injury before the sharp indenter penetrates the scales. Stereo-imaging and image correlation performed around a puncture site in fish reveal that the surrounding scales collectively contribute to redistributing the puncture force over large volume, limiting local deflections and strains in the soft tissues. The structure and mechanisms of natural fish scales therefore offer an effective protection against several types of threat, and may inspire novel versatile protective systems with attractive flexural properties. PMID- 23683759 TI - The influence of cooling conditions on grain size, secondary phase precipitates and mechanical properties of biomedical alloy specimens produced by investment casting. AB - The objective of this work was to investigate and evaluate the effect of the cooling environment on the microstructure, secondary phase precipitates and mechanical properties of an as-cast cobalt alloy. The microstructure of castings has a large bearing on the mechanical properties, grain size, porosity and the morphology of carbide precipitates are thought to influence hardness, tensile strength and ductility. It is postulated that a greater understanding of microstructure and secondary phase precipitate response to casting parameters could lead to the optimisation of casting parameters and serve to reduce the requirement of thermo-mechanical treatments currently applied to refine as-cast structures and achieve adequate mechanical properties. Thermal analysis was performed to determine the critical stages of cooling. Ten millimetre diameter cylindrical specimens which could be machined into tension test specimens were cast and cooled under different conditions to impose different cooling rates. Analytical techniques such as optical microscopy (OM), scanning electron microscopy (SEM), energy dispersive x-ray spectroscopy (EDX), tensile testing and micro-hardness testing were used to study the specimens. Parameters studied include grain size, secondary dendrite arm spacing, secondary phase precipitates, porosity, hardness, ultimate tensile strength, yield strength and elongation. The microstructure of as-cast Co-28Cr-6Mo was found to consist of a dendritic matrix with secondary phases precipitated at grain boundaries and interdendritic zones. These secondary phase precipitates consist of carbides, rich in chromium and molybdenum. The size and area fraction of carbides was found to decrease significantly with increasing cooling rate while the micro-porosity was only marginally affected. The as-cast grains are illustrated for the first time showing a significant difference in size between insulated and naturally cooled specimens. The secondary dendrite arm spacing was determined to be significantly affected by the various cooling environments and the mechanical properties of hardness, ultimate tensile strength and yield strength all increased with increasing cooling rate while the ductility decreased. Correlations between microstructural features and mechanical properties are proposed. PMID- 23683760 TI - Within subject heterogeneity in tissue-level post-yield mechanical and material properties in human trabecular bone. AB - The ability to determine patient-specific mechanical properties of trabecular bone is needed for a reliable estimation of fracture risks. Tissue mechanics and material composition are important factors that contribute to trabecular bone performance, but only a few studies have investigated the post-yield behaviour of human trabecular bone, and limited knowledge for modelling is available about ultimate properties needed. Aim of this paper was to investigate absolute values and deviation of mechanical and material properties of human trabecular bone at the tissue level, in a healthy and osteoporotic donor. A combination of tensile and bending tests of single trabeculae up to failure, MUCT measurement of sample geometry and finite element analysis were incorporated to determine mechanical properties. The samples were analysed with Raman spectroscopy to evaluate the material composition. High within-subject variability was found, for both the healthy and osteoporotic donor. Nevertheless, the two donors could be separated by analysing the ultimate strain and post-yield work, as well as two of the material parameters (B-type carbonate substitution ratio and collagen cross-link ratio). It indicates that tissue level properties seem to be relevant also for macroscopic mechanical behaviour. These findings also suggest that the mechanical variability for the inelastic region at the tissue level may be associated with varying material properties, while until yielding occurs our data does not suggest any connection between the mechanical and the investigated material. Finally, a set of mechanical properties of human bone have been reported that are a relevant reference for computational studies and FE analysis. PMID- 23683762 TI - Measurement validity and statistical significance for nutritional factors in peripheral artery disease. PMID- 23683763 TI - Reply to letter to the editor. PMID- 23683764 TI - Comparing the impact of supine and leg elevation positions during coronary artery bypass graft on deep vein thrombosis occurrence: a randomized clinical trial study. AB - Deep vein thrombosis (DVT) is a common preoperative complication that occurs in patients who undergoing coronary artery bypass grafting surgery (CABG). Early ambulation, elastic stockings, intermittent pneumatic compression, and leg elevation, before and after surgery, are among preventative interventions. The goal of the study was to compare the effect of supine position with that of leg elevation on the occurrence of DVT during CABG and after, until ambulation. Between October, 2008, and May, 2011, a total of 185 eligible CABG patients admitted to the Cardiac Surgery Unit were randomly assigned to groups designated as the supine group (n = 92) or the leg-elevation group (n = 93). Of this total, 92 patients were assigned to the supine group and 93 to the leg-elevation group. Doppler ultrasonography of the superficial and deep veins in the lower extremities was performed for each patient before and after surgery. Logistic regression analysis was conducted to investigate the possible independent factors associated with DVT. DVT was detected in 25 (13.5%) patients: 17 (18.4%) patients in the supine position group and 8 (8.6%) in the leg-elevation group (P value = .065). After adjustment for confounding factors there was no effect of position on the presence of DVT (P = .126).Clots were often localized in legs ipsilateral to the saphenous vein harvest. The authors conclude that a positive, albeit not statistically significant, trend was evident toward higher incidence of silent DVT in supine position during and after CABG in comparison with leg elevation. Future studies with larger sample sizes are required to confirm this result. PMID- 23683765 TI - Wire vascular closure device: evaluation of an evidence-based protocol for post endovascular procedure patients. AB - Vascular closure devices (VCDs) can shorten the time to hemostasis, ambulation and discharge and improve patient comfort.(1) An evidence-based practice (EBP) project was initiated to assess impact of a shortened postoperative compression and bed rest protocol on patients undergoing arteriotomy using a wire vascular closure device (WVCD). Following protocol development, a post-implementation evaluation was initiated to assess selected outcomes including compression and bed rest time, complication rate and possible related variables. Following implementation of the new protocol, clinicians were able to shorten both compression and bed rest times by 50%, and Post-Anesthesia Care Unit (PACU) length of stay decreased to a maximum of 5 hours. PMID- 23683766 TI - Clinical guidelines for acute stroke management: which recommendations should remain consensus-based? AB - Although guideline recommendations should be based on the highest levels of evidence available, it may be appropriate for some recommendations to remain consensus-based. This study investigated stroke clinicians' and academics' opinions about which consensus-based recommendations from the Australian National Stroke Foundation Clinical Guidelines for Acute Stroke Management (2007) should remain as such, using a self-administered questionnaire. In the study, 43 people participated (62% response rate). Of the 50 recommendations presented, at least half the participants believed that 35 (70%) of these should remain consensus based. In an adjusted multivariable analysis, recommendations perceived to be "highly likely" or "likely" to have an impact on patient outcomes were less likely to be perceived by respondents as appropriate to remain consensus-based (OR = 0.16 [95% CI 0.13-0.19], P < .001). Further, although females were less likely to state that recommendations should remain consensus-based (OR = 0.26 for female gender, [95% CI 0.08-0.88], P = .031), those with higher level of educational qualifications (OR = 1.45 per an incremental unit increase in education level [95% CI 1.04-2.03], P = .028) and those from nursing and medicine disciplines in comparison with allied health (OR = 25.2 for medical, nursing, and "other" disciplines in comparison with allied health [95% CI 1.54-413.1], P = .024) were more likely to state that a recommendations should remain consensus based. The results indicated there was agreement that it may be appropriate that a proportion of recommendations in clinical guidelines remain consensus-based. Assessing the views of what areas require more robust research evidence according to academic and clinical experts may allow for prioritization and optimal allocation of scarce research resources. PMID- 23683767 TI - Carotid artery endarterectomy: a multidisciplinary approach to improving resource utilization and quality assurance. AB - An estimated 780,000 people in the United States have a stroke each year. Carotid endarterectomy (CEA) is the most frequently performed surgical procedure to prevent the occurrence of stroke. Over the past several years, physicians, nurses, and allied healthcare workers have been challenged to perform this operation in a cost-effective manner without compromising clinical outcomes. At Maine Medical Center (MMC), Portland, Maine, an average of 250 CEAs are performed annually. As part of a quality-assurance initiative, MMC key stakeholders redesigned the care of patients undergoing CEA surgery. A critical pathway supported by a computerized order set was implemented; standardized discharge instructions and a patient teaching brochure were developed. A patient flow algorithm allowing select patients to bypass the intermediate care unit and transfer directly from the post-anesthesia care unit to a non-telemetry surgical bed was instituted. From January 1, 2010, to December 31, 2011, 467 chart audits were completed on 100% of CEA surgeries (cases with concomitant procedures excluded) using the Vascular Study Group of New England data collection form. Data analyzed supports the practice changes that were instituted. Allowing patients to be admitted to a non-telemetry surgical unit following CEA has resulted in significant cost savings and increased the availability of intermediate care beds to higher acuity patients without negatively affecting patient outcomes. PMID- 23683768 TI - Review of an article: one-year effect of a supervised exercise programme on functional capacity and quality of life in peripheral arterial disease by Marie Guidon, MSc, PhD, Hannah McGee, PhD (Disabil Rehabil 2013;35:397-404). PMID- 23683769 TI - Pathogenesis of Morquio A syndrome: an autopsied case reveals systemic storage disorder. AB - Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is a lysosomal storage disorder caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase, which results in systemic accumulation of glycosaminoglycans (GAGs), keratan sulfate and chondroitin-6-sulfate. Accumulation of these GAGs causes characteristic features as disproportionate dwarfism associated with skeletal deformities, genu valgum, pigeon chest, joint laxity, and kyphoscoliosis. However, the pathological mechanism of systemic skeletal dysplasia and involvement of other tissues remain unanswered in the paucity of availability of an autopsied case and successive systemic analyses of multiple tissues. We report here a 20-year-old male autopsied case with MPS IVA, who developed characteristic skeletal features by the age of 1.5 years and died of acute respiratory distress syndrome five days later after occipito-C1-C2 cervical fusion. We pathohistologically analyzed postmortem tissues including trachea, lung, thyroid, humerus, aorta, heart, liver, spleen, kidney, testes, bone marrow, and lumbar vertebrae. The postmortem tissues relevant with clinical findings demonstrated 1) systemic storage materials in multiple tissues beyond cartilage, 2) severely vacuolated and ballooned chondrocytes in trachea, humerus, vertebrae, and thyroid cartilage with disorganized extracellular matrix and poor ossification, 3) appearance of foam cells and macrophages in lung, aorta, heart valves, heart muscle, trachea, visceral organs, and bone marrow, and 4) storage of chondrotin-6-sulfate in aorta. This is the first autopsied case with MPS IVA whose multiple tissues have been analyzed pathohistologically and these pathological findings should provide a new insight into pathogenesis of MPS IVA. PMID- 23683770 TI - Normal plasma pipecolic acid level in pyridoxine dependent epilepsy due to ALDH7A1 mutations. PMID- 23683771 TI - Miglustat therapy in type 1 Gaucher disease: clinical and safety outcomes in a multicenter retrospective cohort study. AB - We evaluated clinical and safety outcomes in adult patients with type 1 Gaucher disease receiving miglustat in clinical practice settings. An observational, retrospective cohort study was conducted in centers across the EU and the USA. Medical chart data were collected from consecutive patients between the 20th November 2002 and 31st December 2008. A total of 115 patients were included; 34 (30%) were enzyme replacement therapy-naive ('naive') and 81 (70%) were enzyme pretreated ('pretreated'). Median (range) miglustat exposures in these groups were 15.1 (0.6-52.9)months and 15.2 (0.3-62.1)months, respectively. Low numbers of patients were anemic (10/101) or thrombocytopenic (21/101) at initiation of miglustat therapy. The median (range) hemoglobin concentration at miglustat initiation was 12.8 (10.2-16.4)g/dl in naive patients and 13.6 (7.3-17.4)g/dl in pretreated patients; median (range) changes in hemoglobin were 0.3 (-2.5-3.6) and -0.3 (-4-4.6)g/dl, respectively. The median (range) platelet counts at miglustat initiation were 101 (37-730)*10(9)/l in naive patients and 173 (43-382)*10(9)/l in pretreated patients; median (range) changes in platelet count were 8 (-77 145)*10(9)/l and -10 (-144-434)*10(9)/l, respectively. Plasma chitotriosidase was substantially reduced in naive but not in pretreated patients. Organ volumes were not routinely monitored. Forty-nine (43%) patients discontinued miglustat; most due to gastrointestinal manifestations and some due to tremor. Overall, hemoglobin and platelet counts tended to increase in naive patients treated with miglustat, and to remain stable or decrease slightly in pretreated patients. The profile of safety and tolerability observed with miglustat in the current study is similar to previous studies. PMID- 23683772 TI - Symptoms of airway reflux predict exacerbations and quality of life in bronchiectasis. AB - AIM: We have explored the association of the upper airway symptoms related to cough with exacerbation frequency, sputum microbiology and inflammatory markers in patients with non cystic fibrosis bronchiectasis. METHODS: Patients with bronchiectasis completed the Hull Airway Reflux Questionnaire (HARQ). A score of >13 was taken to indicate the presence of reflux. Patients were followed-up with longitudinal spirometry, sputum culture and Leicester cough questionnaire (LCQ). Myeloperoxidase (MPO), free neutrophil elastase (NE) activity, Interleukin (IL)-8 and Tumour Necrosis Factor (TNF)-alpha was measured from spontaneous sputum samples. RESULTS: 163 completed the study. 59.5% were female. Mean age was 65.7 years. 73.6% reported airway reflux using HARQ. Patients with airway reflux had more severe cough symptoms as assessed by the LCQ [15.2 (3.5) vs. 19.4 (1.9)], p < 0.001. Sputum levels of MPO, NE, IL-8 and TNF-alpha were all significantly higher in the reflux positive group (p < 0.05 for all comparisons). In a multivariable logistic regression, airway reflux was independently associated with cough severity (-3.27, standard error 0.81, p = 0.0002). Airway reflux, age, FEV1 % predicted and colonization with Pseudomonas aeruginosa were independently associated with an increased risk of >=3 bronchiectasis exacerbations in one year. CONCLUSION: The symptoms of airway reflux independently predict severity and exacerbation frequency in non cystic fibrosis bronchiectasis. PMID- 23683773 TI - Emergency department computed tomography utilization in the United States and Canada. AB - STUDY OBJECTIVE: We compare secular trends in computed tomography (CT) utilization in emergency departments (EDs) in the United States and Ontario, Canada. METHODS: Using a systematic survey in the US (The National Hospital Ambulatory Medical Care Survey) and administrative databases in Ontario, we performed a retrospective study of ED visits from 2003 to 2008. We calculated utilization overall, by visit characteristics, and for 5 clinical conditions in which CT is commonly indicated: abdominal pain, complex abdominal pain (abdominal pain, age >=65 years, urgent to most urgent triage), admitted complex abdominal pain (abdominal pain, age >=65 years, urgent to most urgent triage, and admitted to hospital), headache, and chest pain/shortness of breath. US data were weighted to produce national estimates. RESULTS: On-site CT was available for 97% (95% confidence interval [CI] 95% to 99%) of visits in the United States compared with 80% (95% CI 80% to 80%) in Ontario. Visits were more frequently triaged as higher acuity in the United States than in Ontario, with 15.1% (95% CI 13.9% to 16.4%) of US visits categorized as most urgent versus 11.8% (95% CI 11.8% to 11.8%) in Ontario. The proportion of all ED visits in which CT was performed was 11.4% (95% CI 10.8% to 12.0%) in the United States versus 5.9% (95% CI 5.9% to 5.9%) in Ontario. The proportion for children was 4.7% (95% CI 4.3% to 5.1%) in the United States versus 1.4% (95% CI 1.4% to 1.4%) in Ontario. The rate of visits involving CT per year increased faster from 2003 to 2008 in the United States (odds ratio 2.00; 95% CI 1.81 to 2.21) than Ontario (odds ratio 1.69; 95% CI 1.68 to 1.70). Over time, all subgroups experienced increases in CT rate except Ontario children younger than 10 years, who experienced a significant decrease. United States Ontario differences in CT proportions were significant among patients presenting with headache, abdominal pain, chest pain/shortness of breath, and complex abdominal pain. Proportions for visits involving admitted complex abdominal pain in the two jurisdictions were indistinguishable: 45.8% in the United States (95% CI 39.9% to 51.7%) versus 44.7% (95% CI 44.4% to 45.0%) in Ontario. CONCLUSION: CT was more readily available in US EDs, and US clinicians used the technology more frequently than their colleagues in Ontario for nearly every category of patients, including children. CT utilization increased over time in both jurisdictions, but faster in the United States. Different demographic features between the two jurisdictions, including triage severity, frequency of hospitalization, and availability of CT scanners, likely account for at least some of the differences in CT utilization. Investigation of both clinical and nonclinical reasons for the differences in CT utilization between the United States and Canada would be a fruitful area for further research. PMID- 23683774 TI - Urine miRNAs: potential biomarkers for monitoring progression of early stages of diabetic nephropathy. AB - With a steep increase in the incidence of type 1 and 2 diabetes globally, diabetic nephropathy (DN) has now become the leading cause of renal failure in the world. There are no suitable biomarkers for the diagnosis of early stages of DN. In recent years, tremendous efforts are being made worldwide to delineate the role of micro RNAs in the pathogenesis of DN. Circulating miRNAs in serum, plasma, urine and other body fluids, which reflect a response to various pathophysiological stresses, are being investigated in the context of diabetic nephropathy. Delineation of the changes in miRNA levels in patients with DN may lead to a better understanding of the progression of the disease. We present here an exhaustive survey of the miRNA literature, highlighting various studies performed over the last decade. The aim is to assess if changes in various miRNAs could correlate with the progression of diabetic nephropathy. Based on the survey, we found that miRNA-377, miRNA-192, miRNA-216/217 and miRNA-144 are increased in body fluids of patients with DN, while miRNA-21 and miRNA-375 are decreased. Overall, there are a very few miRNAs that are kidney specific, and although significant differences were observed in the urinary excretion of certain miRNAs, they were not correlative to their levels in the blood or plasma. Thus, it is completely plausible that urine-specific miRNAs could serve as novel biomarkers for the diagnosis of early stages of diabetic nephropathy. PMID- 23683775 TI - An implantable neural interface with electromagnetic stimulation capabilities. AB - Invasive interfaces with the Peripheral Nervous System (PNS), which currently rely on electric means for both nerves stimulation and signals recording, are needed in a number of applications, including prosthetics and assistive technologies. Recent studies showed that the quality of the signal-to-noise ratio of the afferent channel might be negatively affected by physiological reactions, including fibrosis. In this paper we propose a novel approach to the development of implantable neural interfaces, where the PNS is excited electromagnetically and in situ, while electrical means are used only for neural signals recording. Electromagnetic (EM) waves, capable of overcoming fibrotic capsules, are generated by microfabricated coils. Stimulation coils and registration electrodes are deposited on the same flexible substrate, also provided with a bio-absorbable coating, which releases anti-fibrotic drugs and neurons-specific functionalized magnetic nanoparticles (NPs). The NPs are intended to improve the capability of local EM waves to elicit membranes depolarization, thus enhancing selectivity. This paper details the concept of the proposed technology and provides a preliminary in silico feasibility study. PMID- 23683777 TI - Does screening for breast cancer with five screening modalities in average-risk women reduce mortality from breast cancer? PMID- 23683778 TI - Laparoscopic pancreaticoduodenectomies: a word of caution. Author reply. PMID- 23683779 TI - Laparoscopic pancreaticoduodenectomies: a word of caution. PMID- 23683780 TI - Laparoscopic vs open pancreaticoduodenectomy. PMID- 23683781 TI - Laparoscopic vs open pancreaticoduodenectomy. Author reply. PMID- 23683782 TI - Surgical treatment for lymphedema: optimal timing and optimal techniques. PMID- 23683783 TI - Gallbladder wall calcification and gallbladder cancer. PMID- 23683785 TI - Transepicondylar axes for femoral component rotation might produce flexion asymmetry during total knee arthroplasty in knees with proximal tibia vara. AB - BACKGROUND: Adequate rotation of the femoral component in total knee arthroplasty is mandatory for prevention of numerous adverse sequelae. Therefore, we investigate whether there is the distal femoral deformity in knees with tibia vara. The purpose of this study was to evaluate the reliability of the transepicondylar axis as a rotational landmark in knees with tibia vara. METHODS: We retrospectively reviewed and selected 101 osteoarthritic knees with proximal tibia vara and 150 osteoarthritic knees without tibia vara for inclusion in this study. The transepicondylar axis (TEA), anteroposterior (AP) axis and posterior condylar (PC) line were measured using the axial image from magnetic resonance imaging axial images. We compared the external rotation angle of the TEA relative to the PC line between groups in order to investigate the presence of distal femoral anatomical adaptation in the tibia vara group. RESULTS: The TEA in the tibia vara group had 6.1o of external rotation relative to the PC line, which was not significantly different from the 6.0o of external rotation in the non-tibia vara group. The line perpendicular to the AP axis in the tibia vara group had 6.1o of external rotation relative to the PC line, which was not significantly different from the 5.4o of external rotation in the non-tibia vara group. Distal femoral geometry was unaffected by the tibia vara deformity. CONCLUSIONS: The use of transepicondylar axes in determining femoral rotation may produce flexion asymmetry in knees with tibia vara. LEVEL OF EVIDENCE: Level III. PMID- 23683786 TI - RNA interference-mediated silencing of NANOG leads to reduced proliferation and self-renewal, cell cycle arrest and apoptosis in T-cell acute lymphoblastic leukemia cells via the p53 signaling pathway. AB - NANOG is critical for maintaining the self-renewal and proliferative properties of embryonic stem cells. Here we found that cultured T-cell acute lymphoblastic leukemia (T-ALL) cells, as well as human primary T-ALL cells, express a functional variant of NANOG. NANOG mRNA is derived predominantly from a retrogene locus termed NANOGP8. Furthermore, we showed that RNA interference-mediated NANOG knockdown inhibited cell proliferation, reduced self-renewal, promoted apoptosis and arrested the cell cycle through a p53-mediated pathway in leukemic cells. These findings demonstrate the oncogenic potential of this pluripotent gene in human T-ALL cells. PMID- 23683788 TI - Comparison of whole-body diffusion MRI and conventional radiological assessment in the staging of myeloma. AB - PURPOSE: In multiple myeloma, skeletal radiographs are still regarded as the reference imaging examination because they help to establish the stage of the disease according to the Durie-Salmon Staging System. Whole-body MRI using T1 and STIR sequences increases the detection of myeloma lesions. MRI-measured diffusion has demonstrated high sensitivity in terms of detection in oncology. The main objective of this study is to compare conventional radiographic staging with an MRI whole-body diffusion technique (called DWIBS) in detecting bone lesion monoclonal plasma cell pathologies (multiple myeloma, plasma cell leukaemia, plasmacytoma and MGUS). MATERIALS AND METHODS: Twenty-seven patients were included (multiple myeloma: 24; plasma cell leukaemia, MGUS and plasmacytoma: 1 each). All of them had a whole-body MRI diffusion examination (using a DWIBS sequence). Diffusion MRI and conventional radiographs were compared according to the Durie-Salmon Staging System. In case of doubtful lesions, 12 months of monitoring was used as the reference method for the definitive diagnosis. RESULTS: The overall concordance rate between the two techniques was 63%. The DWIBS sequence detected a higher number of lesions leading to a higher Durie Salmon stage in 37% of the patients: one stage I to II, seven stage I to III, and two stage II to III. In 18.5% of the patients, the MRI was positive while the radiographs were normal and these discrepancies were most often located in sites poorly explored by X-ray (spine, pelvis and ribs). In one patient (4%), the MRI provided a stage lower than that of the X-rays (stage II vs. III). In this case, the X-rays were positive at the humerus and femur, unlike the DWIBS sequence. Our per site analysis confirmed the clear superiority of the DWIBS sequence when compared with X-rays in the exploration of the cervical spine (56 vs. 0%, P<0.001), dorsal spine (81vs. 31%,P<0.0002), lumbar spine (70 vs. 35%, P<0.0124), pelvis (81 vs. 33%, P<0.0005) and ribs (74 vs. 36%, P<0.0009). CONCLUSION: The DWIBS MRI leads to an increase in the final Durie-Salmon stage. Although its place in the preoperative treatment of multiple myeloma still has to be assessed, this study suggests its potential interest. PMID- 23683787 TI - The prognostic impact of c-KIT mutation in systemic mastocytosis associated with acute myeloid leukaemia patients. AB - We evaluate the haematopathologic features of systemic mastocytosis associated with acute myeloid leukaemia (SM-AML) and the prognostic role of c-KIT mutation. Total 11 patients were enrolled. Cytochemistry using toluidine blue and tryptase was positive, as was immunohistochemistry for CD117 and CD25 on clustered mast cells; however, CD2 was expressed in only nine cases. In 10 cases, RUNX1-RUNX1T1 fusion gene was detected, and one patient presented with a t(5;6)(q22;q23) translocation at diagnosis. The c-KIT mutation D816V was detected in six patients. Patients with c-KIT mutations had higher relapse and death rates than those without; 4/5 (80.0%) and 5/6 (83.3%) vs. 1/5 (20%) and 2/5 (40%), respectively. Overall survival was also significantly shorter in cases with, than those without, c-KIT mutations. To identify rare cases of SM-AML, which have a dismal prognosis, c-KIT mutation study and careful examination for the presence of clustered mast cell infiltration by immunochemistry should be performed. PMID- 23683789 TI - Molecular identification of forensically relevant Diptera inferred from short mitochondrial genetic marker. PMID- 23683790 TI - Prospective associations between brain activation to cocaine and no-go cues and cocaine relapse. AB - BACKGROUND: The ability to predict potential for relapse to substance use following treatment could be very useful in targeting aftercare strategies. Recently, a number of investigators have focused on using neural activity measured by fMRI to predict relapse propensity. The purpose of the present study was to use fMRI to investigate prospective associations between brain reactivity to cocaine and response inhibition cues and relapse to cocaine use. METHODS: Thirty cocaine-dependent participants with clean cocaine urine drug screens (UDS) completed a baseline fMRI scan, including a cocaine-cue reactivity task and a go no-go response inhibition task. After participating in a brief clinical trial of d-cycloserine for the facilitation of cocaine-cue extinction, they returned for a one-week follow-up UDS. Associations between baseline activation to cocaine and inhibition cues and relapse to cocaine use were explored. RESULTS: Positive cocaine UDS was significantly associated with cocaine-cue activation in the right putamen and insula, as well as bilateral occipital regions. Associations between positive cocaine UDS and activation to no-go cues were concentrated in the postcentral gyri, a region involved in response execution. CONCLUSIONS: Although preliminary, these results suggest that brain imaging may be a useful tool for predicting risk for relapse in cocaine-dependent individuals. Further, larger scale naturalistic studies are needed to corroborate and extend these findings. PMID- 23683791 TI - Characteristics of adults seeking medical marijuana certification. AB - BACKGROUND: Very little is known about medical marijuana users. The present study provides descriptive information on adults seeking medical marijuana and compares individuals seeking medical marijuana for the first time with those renewing their medical marijuana card on measures of substance use, pain and functioning. METHODS: Research staff approached patients (n=348) in the waiting area of a medical marijuana certification clinic. Chi-square and Wilcoxon signed rank tests were used to compare participants who reported that they were seeking medical marijuana for the first time (n=195) and those who were seeking to renew their access to medical marijuana (n=153). RESULTS: Returning medical marijuana patients reported a higher prevalence of lifetime cocaine, amphetamine, inhalant and hallucinogen use than first time patients. Rates of recent alcohol misuse and drug use were relatively similar between first time patients and returning patients with the exception of nonmedical use of prescription sedatives and marijuana use. Nonmedical prescription sedative use was more common among first time visitors compared to those seeking renewal (p<0.05). The frequency of recent marijuana use was higher in returning patients than first time patients (p<0.0001). Compared to first time patients, returning patients reported somewhat lower current pain level and slightly higher mental health and physical functioning. CONCLUSIONS: Study results indicate that differences exist between first time and returning medical marijuana patients. Longitudinal data are needed to characterize trajectories of substance use and functioning in these two groups. PMID- 23683792 TI - Postoperative risks associated with alcohol screening depend on documented drinking at the time of surgery. AB - BACKGROUND: Both AUDIT-C alcohol screening scores up to a year before surgery and clinical documentation of drinking over 2 drinks per day immediately prior to surgery ("documented drinking >2d/d") are associated with increased postoperative complications and health care utilization. The purpose of this study was to evaluate whether documented drinking >2d/d contributed additional information about postoperative risk beyond past-year AUDIT-C screening results. METHOD: Male Veterans Affairs (VA) patients who had a non-emergent, non-cardiac, major surgery assessed by the VA's Surgical Quality Improvement Program 10/2003-9/2006 and completed the AUDIT-C by mailed survey in the prior year were eligible for this study. Linear or logistic regression models compared 30-day postoperative complication(s), return to operating room (OR), hospital length of stay (LOS), and intensive care unit (ICU) days across eight groups defined by past-year AUDIT C score and clinically documented drinking >2d/d, with AUDIT-C scores 1-4 and no documented drinking >2d/d as the referent, after adjusting for important covariates. RESULTS: Overall 8811 patients met inclusion criteria. Among patients with documented drinking >2d/d immediately prior to surgery, postoperative risk varied widely depending on past-year AUDIT-C score; scores >=5 were associated with increased risk of complication(s), and scores >=9 with increased hospital LOS and ICU days. Among patients without documentation of drinking >2d/d, increasing AUDIT-C scores were not associated with these outcomes. CONCLUSIONS: Clinical documentation of drinking >2d/d immediately prior to surgery contributed additional information about postoperative risk beyond past-year AUDIT-C score. However, among patients with documented drinking >2d/d, postoperative risk varied widely depending on the AUDIT-C score. PMID- 23683793 TI - Naltrexone with or without guanfacine for preventing relapse to opiate addiction in St.-Petersburg, Russia. AB - BACKGROUND: Stress is a key precipitant to discontinuing naltrexone and relapsing to opiate abuse. Alpha-2 adrenergic agonists like guanfacine may reduce stress induced craving and have reduced opiate relapse in small clinical trials. METHODS: This randomized, double blind double dummy placebo-controlled 6-month trial tested oral naltrexone with or without guanfacine for reducing stress and preventing opiate relapse. We randomized 301 patients to: naltrexone 50 mg/day+guanfacine 1 mg/day (n=75) (N/G), naltrexone+guanfacine placebo (N/P) (n=76), naltrexone placebo+guanfacine (n=75) (P/G), and double placebo (n=75) (P/P). RESULTS: Among the 75 patients in each group the percentage still retained on naltrexone treatment at six months was: N/G 26.7%, N/P 19.7% (p=0.258 to N/G), P/G 6.7% (p<0.05 to both N groups), and P/P 10.7% (p=0.013 to N+G). Guanfacine reduced the severity of stress particularly at weeks 10 and 18. Adverse events (AE) were infrequent (4.7%) without group differences, with most common AEs: headache, poor appetite, insomnia, and dizziness. CONCLUSIONS: Adding guanfacine to naltrexone did not improve treatment retention or opiate free urines, but it reduced both stress and craving at later time points in treatment, which may be related to stress-induced craving and the animal model of incubation of reinstatement. During treatment, HIV risk, anxiety, and depression reduced among all patients in treatment, regardless of group. PMID- 23683795 TI - [Gastric retention due to a duodenal obstruction secondary to chronic pancreatitis]. PMID- 23683796 TI - Energy analysis during acoustic bubble oscillations: relationship between bubble energy and sonochemical parameters. AB - In this work, energy analysis of an oscillating isolated spherical bubble in water irradiated by an ultrasonic wave has been theoretically studied for various conditions of acoustic amplitude, ultrasound frequency, static pressure and liquid temperature in order to explain the effects of these key parameters on both sonochemistry and sonoluminescence. The Keller-Miksis equation for the temporal variation of the bubble radius in compressible and viscous medium has been employed as a dynamics model. The numerical calculations showed that the rate of energy accumulation, dE/dt, increased linearly with increasing acoustic amplitude in the range of 1.5-3.0 atm and decreased sharply with increasing frequency in the range 200-1000 kHz. There exists an optimal static pressure at which the power w is highest. This optimum shifts toward a higher value as the acoustic amplitude increases. The energy of the bubble slightly increases with the increase in liquid temperature from 10 to 60 degrees C. The results of this study should be a helpful means to explain a variety of experimental observations conducted in the field of sonochemistry and sonoluminescence concerning the effects of operational parameters. PMID- 23683794 TI - Illicit use of prescription stimulants in a college student sample: a theory guided analysis. AB - BACKGROUND: The illicit use of prescription stimulants (IUPS) has emerged as a high-risk behavior of the 21st century college student. As the study of IUPS is relatively new, we aimed to understand (1) characteristics of IUPS (i.e., initiation, administration routes, drug sources, motives, experiences), and (2) theory-guided intrapersonal, interpersonal, and environmental correlates associated with use. METHODS: Using one-stage cluster sampling, 520 students (96.3% response rate) at one Pacific Northwest University completed a paper based, in-classroom survey on IUPS behaviors and expected correlates. Aim 1 was addressed using descriptive statistics and aim 2 was addressed via three nested logistic regression analyses guided by the Theory of Triadic Influence. RESULTS: The prevalence of ever engaging in IUPS during college was 25.6%. The majority (>50.0%) of users reported initiation during college, oral use, friends as the drug source, academic motives, and experiencing desired outcomes. Intrapersonal correlates associated with use included identifying as White, lower grade point average, diagnoses of attention deficit disorder, and lower avoidance self efficacy. Interpersonal correlates of use included off-campus residence, varsity sports participation, IUPS perceptions by socializing agents, and greater behavioral norms. Exposure to prescription drug print media, greater prescription stimulant knowledge, and positive attitudes towards prescription stimulants were environmental correlates associated with use. In all models, IUPS intentions were strongly associated with use. CONCLUSIONS: IUPS was prevalent on the campus under investigation and factors from the intrapersonal, interpersonal and environmental domains were associated with the behavior. Implications for prevention and future research are discussed. PMID- 23683797 TI - Carotid atherosclerotic plaque characterisation by measurement of ultrasound sound speed in vitro at high frequency, 20 MHz. AB - This study aimed to utilise a tissue mimicking material (TMM) in order to embed in vitro carotid plaque tissue so that its acoustic properties could be assessed. Here, an International Electrotechnical Commission (IEC) agar-based TMM was adapted to a clear gel by removal of the particulates. This clear TMM was measured with sound speed at 1540 ms(-1) and an attenuation coefficient of 0.15 dB cm(-1)MHz(-1). Composite sound speed was then measured through the embedded material using a scanning acoustic microscope (SAM). Both broadband reflection and transmission techniques were performed on each plaque specimen in order to ensure the consistency of the measurement of sound speed, both at 21 degrees C and 37 degrees C. The plaque was measured at two temperatures to investigate any effect on the lipid content of the plaque. The contour maps from its associated attenuation plots were used to match the speed data to the photographic mask of the plaque outline. This physical matching was then used to derive the sound speed from the percentage composition seen in the histological data by solution of simultaneous equations. Individual speed values for five plaque components were derived; TMM, elastin, fibrous/collagen, calcification and lipid. The results for derived sound speed in the TMM were consistently close to the expected value of soft tissue, 1540 ms(-1). The fibrous tissue showed a mean value of 1584 ms(-1) at 37 degrees C. The derived sound speeds for elastic and lipid exhibited large inter-quartile ranges. The calcification had higher sound speed than the other plaque components at 1760-2000 ms(-1). The limitations here lay in the difficulties in the matching process caused by the inhomogeneity of the plaque material and shrinkage during the histological process. Future work may concentrate on more homogeneous material in order to derive sound speed data for separate components. Nevertheless, this study increases the known data ranges of the individual components within a plaque. This information may be used help to assess the mechanical properties and structural integrity and its associated vulnerability or risk of embolization in future diagnostic ultrasound techniques. PMID- 23683798 TI - Mechanism of the quasi-zero axial acoustic radiation force experienced by elastic and viscoelastic spheres in the field of a quasi-Gaussian beam and particle tweezing. AB - The present analysis investigates the (axial) acoustic radiation force induced by a quasi-Gaussian beam centered on an elastic and a viscoelastic (polymer-type) sphere in a nonviscous fluid. The quasi-Gaussian beam is an exact solution of the source free Helmholtz wave equation and is characterized by an arbitrary waist w0 and a diffraction convergence length known as the Rayleigh range z(R). Examples are found where the radiation force unexpectedly approaches closely to zero at some of the elastic sphere's resonance frequencies for kw0<=1 (where this range is of particular interest in describing strongly focused or divergent beams), which may produce particle immobilization along the axial direction. Moreover, the (quasi)vanishing behavior of the radiation force is found to be correlated with conditions giving extinction of the backscattering by the quasi-Gaussian beam. Furthermore, the mechanism for the quasi-zero force is studied theoretically by analyzing the contributions of the kinetic, potential and momentum flux energy densities and their density functions. It is found that all the components vanish simultaneously at the selected ka values for the nulls. However, for a viscoelastic sphere, acoustic absorption degrades the quasi-zero radiation force. PMID- 23683799 TI - Methodological considerations for meal-induced thermogenesis: measurement duration and reproducibility. AB - Meal-induced thermogenesis (MIT) research findings have been highly inconsistent, in part, due to the variety of durations and protocols used to measure MIT. In the present study, we aimed to determine the following: (1) the proportion of a 6 h MIT response completed at 3, 4 and 5 h; (2) the associations between the shorter durations and the 6 h measures; (3) whether shorter durations improved the reproducibility of the measurement. MIT was measured in response to a 2410 kJ mixed composition meal in ten individuals (five males and five females) on two occasions. Energy expenditure was measured continuously for 6 h post-meal using indirect calorimetry, and MIT was calculated as the increase in energy expenditure above the pre-meal RMR. On average, 76, 89 and 96 % of the 6 h MIT response was completed within 3, 4 and 5 h, respectively, and MIT at each of these time points was strongly correlated with the 6 h MIT response (range for correlations, r 0.990-0.998; P< 0.01). The between-day CV for the 6 h measurement was 33 %, but it was significantly lower after 3 h of measurement (CV 26 %; P= 0.02). Despite variability in the total MIT between days, the proportion of MIT that was completed at 3, 4 and 5 h was reproducible (mean CV: 5 %). While 6 h are typically required to measure the complete MIT response, the 3 h measures provide sufficient information about the magnitude of the MIT response and may be applicable for testing individuals on repeated occasions. PMID- 23683800 TI - Effect of zinc supplementation on serum antibody titers to heat shock protein 27 in patients with thalassemia major. AB - Objective This current study was conducted to determine the effect of zinc supplementation on antibody titers to heat shock protein 27 (anti-HSP27) in patients with beta-thalassemia major (beta-TM). Methods This was a double-blinded placebo-controlled clinical trial conducted at Dr Sheikh Hospital (Mashhad, Iran) from 2011 to 2012. Sixty-four patients (41 females and 23 males), aged between 8 and 18 years with transfusion-dependent beta-TM were randomly allocated to two age- and sex-matched groups. The zinc (case) group received 30 mg of daily zinc sulfate supplementation and the placebo (control) group received same shape and color placebo over 9 months period of the trial. Serum anti-HSP27 titers were measured at the third and ninth months of the trial, using an in-house enzyme linked immune-absorbent assay. Result There was a significant difference in anti HSP27 titers, between the groups after 9 months. The baseline value of anti-HSP27 was 0.44 +/- 0.15 in zinc group and were significantly decreased to 0.40 +/- 0.18 after 9 months on treatment, while the baseline value of anti-HSP27 were significantly increased from 0.43 +/- 0.17 to 0.44 +/- 0.18 in the placebo group (P = 0.01). Conclusion Serum anti-HSP27 titers were significantly reduced in patients with beta-TM treated with zinc supplements compared to a group treated with a placebo. It suggests that the potential antioxidant and anti-inflammatory effects of zinc supplements may account for a reduction in anti-HSP27 titers in patients with beta-TM. PMID- 23683801 TI - Relationship between heart rate variability, blood pressure and arterial wall properties during air and oxygen breathing in healthy subjects. AB - Previous studies reported that normobaric hyperoxia influences heart rate, arterial pressure, cardiac output and systemic vascular resistance, but the mechanisms underlying these changes are still not fully understood. Several factors are considered including degeneration of endothelium-derived nitric oxide by reactive oxygen species, the impact of oxygen-free radicals on tissues and alterations of autonomic nervous system function. Recently, new devices for the detailed non-invasive assessment of large and small arteries have been developed. Therefore, the aim of our study was to assess heart rate variability (HRV) as a potential indicator of autonomic balance and its relation to blood pressure and vascular properties during medical air (MAB) and 100% oxygen breathing (OXB) in healthy volunteers. In 12 healthy subjects we assessed heart rate and blood pressure variability, baroreflex sensitivity, respiratory frequency, common carotid artery diameter and its wall distensibility, as well as changes in the digital artery pulse waveform, stroke index and systemic vascular resistance during MAB and OXB. Mean and systolic blood pressure have increased significantly while digital pulse amplitude and carotid artery diameter were significantly lower during hyperoxia. Heart rate variability measures did not differ during MAB and OXB. However, the correlations between spectral HRV components and those hemodynamic parameters which have changed due to hyperoxia varied substantially during MAB (correlated significantly) and OXB (no significant correlations were noted). Our findings suggest that autonomic nervous system might not be the main mediator of the cardiovascular changes during 100% oxygen breathing in healthy subjects. It seems that the direct vascular responses are initial consequences of hyperoxia and other cardiovascular parameter alterations are secondary to them. PMID- 23683802 TI - Acoustic analysis of voice: Iranian teachers. AB - INTRODUCTION: In Iran, the total number of elementary schoolteachers is estimated to be nearly 300 000 people and this population is at risk for developing voice disorders. Acoustical characteristics of voice for schoolteachers in Iran are unknown but are relevant to the quantitative description, diagnosis, intervention, reassessment, and outcomes of their voices. MATERIALS AND METHODS: Fifteen female and 15 male Iranian primary schoolteachers in the age range of 35 40 years with 15 years teaching experience volunteered to participate in the study. The control group consisted of 30 Iranian adults aged 35-40 years (15 men and 15 women). Recordings and audio signal analyses were carried out using Praat software. Each subject was asked to sustain the vowel /a/ using habitual and constant vocal pitch, loudness, and quality for at least 5 seconds. Five tokens from each subject were obtained. RESULTS: For the male subjects, the results indicated no significant difference (at the 0.05 level) for each variable between the two groups. However, for the female subjects, t tests showed significant differences between the teachers and the nonteacher controls in all parameters at the 0.01 level. The Iranian female teachers had significantly lower F(0) (190.27 Hz) than the control group (236.32 Hz). Also, for the perturbation acoustic parameters (jitter% and shimmer%), the female teacher group had significantly higher values than their corresponding control group. Similarly, the harmonics-to noise ratio (HNR) measures for the Iranian female teacher population were significantly lower than for their corresponding control group. DISCUSSION AND CONCLUSIONS: The results indicate that female Iranian teachers appear to be more susceptible to voice stability change than the male Iranian teachers. Also, acoustic analysis of voice for teachers may significantly contribute to the objective voice examination of this group. Further investigations of factors that promote individual susceptibility to vocal stability are necessary. PMID- 23683803 TI - Laryngeal lipotransfer: review of a 14-year experience. AB - OBJECTIVE: To determine the efficacy of lipotransfer for treatment of various vocal fold (VF) pathologies. STUDY TYPE: Retrospective review. METHODS: We reviewed retrospectively the indications for and techniques of laryngeal lipotransfer and its effect on glottic closure and mucosal wave. One hundred four patients treated with lipotransfer between 1997 and 2010 were screened for inclusion in this study. Fifteen patients were excluded. Strobovideolaryngoscopic examinations for the 89 included subjects were reviewed to determine the change in glottic closure and mucosal wave. The degree of improvement, if any, was graded as mild, moderate, or substantial. The population was divided into the following four groups for analysis: (1) single lateral lipoinjection, (2) combination of lipoinjection and thyroplasty, (3) multiple lipoinjections with or without other injection medialization procedures, and (4) lipoimplantation for treatment of VF scar. RESULTS: Lipotransfer was used alone and as an adjunct procedure to treat glottic insufficiency (GI) secondary to VF motion abnormality or vibratory margin pathology. Augmentation was accomplished either by lateral injection or by medial implantation through an access tunnel. Most patients showed a statistically significant improvement in glottic closure because of lipoinjection and in mucosal wave because of lipoimplantation. Few minor and no serious complications occurred. CONCLUSION: Laryngeal lipotransfer is safe and effective for treatment of GI and VF scar. PMID- 23683804 TI - Voice Handicap Index associated with common mental disorders in elementary school teachers. AB - OBJECTIVE/HYPOTHESIS: To verify the relationship between common mental disorders (CMDs) and the Voice Handicap Index (VHI) in elementary school teachers from municipal schools. The VHI mean scores in the group of teachers with symptoms of mental disorder were significantly higher than those in the group of teachers with no symptoms in the total scores of three subscales: disability (functional domain), handicap (emotional domain), and impairment (organic domain). DESIGN: An observational cross-sectional, quantitative study was conducted in the public schools of urban and rural areas of the city of Pelotas. METHOD: A total of 575 teachers participated. Vocal handicap was measured using VHI, producing a total score and three subscales, including emotional, functional, and organic domains. The Self-Reporting Questionnaire, 20 items scale was used to measure mental disorder symptoms. A log transformation was used, followed by linear regression, to evaluate the relationship between the independent variables and the outcomes. RESULTS: Teachers with CMD symptoms and who took a sick leave from teaching because of voice problems obtained the lowest scores in VHI (P < 0.050). Emotional, functional, and organic voice handicap scores were significantly higher in teachers with CMD symptoms (P < 0.001). CONCLUSIONS: A close association between voice problems and mental disorders was identified based on the statistically significant association between high levels of voice handicap and the mental disorders. PMID- 23683805 TI - Functional hoarseness in children: short-term play therapy with family dynamic counseling as therapy of choice. AB - Children with nonorganic voice disorders (NVDs) are treated mainly using direct voice therapy techniques such as the accent method or glottal attack changes and indirect methods such as vocal hygiene and voice education. However, both approaches tackle only the symptoms and not etiological factors in the family dynamics and therefore often enjoy little success. The aim of the "Bernese Brief Dynamic Intervention" (BBDI) for children with NVD was to extend the effectiveness of pediatric voice therapies with a psychosomatic concept combining short-term play therapy with the child and family dynamic counseling of the parents. This study compares the therapeutic changes in three groups where different procedures were used, before intervention and 1 year afterward: counseling of parents (one to two consultations; n = 24), Brief Dynamic Intervention on the lines of the BBDI (three to five play therapy sessions with the child plus two to four sessions with the parents; n = 20), and traditional voice therapy (n = 22). A Voice Questionnaire for Parents developed by us with 59 questions to be answered on a four-point Likert scale was used to measure the change. According to the parents' assessment, a significant improvement in voice quality was achieved in all three methods. Counseling of parents (A) appears to have led parents to give their child more latitude, for example, they stopped nagging the child or demanding that he/she should behave strictly by the rules. After BBDI (B), the mothers were more responsive to their children's wishes and the children were more relaxed and their speech became livelier. At home, they called out to them less often at a distance, which probably improved parent-child dialog. Traditional voice therapy (C) seems to have had a positive effect on the children's social competence. BBDI seems to have the deepest, widest, and therefore probably the most enduring therapeutic effect on children with NVD. PMID- 23683806 TI - Vocal tract and glottal function during and after vocal exercising with resonance tube and straw. AB - OBJECTIVE: The present study aimed to investigate the vocal tract and glottal function during and after phonation into a tube and a stirring straw. METHODS: A male classically trained singer was assessed. Computerized tomography (CT) was performed when the subject produced [a:] at comfortable speaking pitch, phonated into the resonance tube and when repeating [a:] after the exercise. Similar procedure was performed with a narrow straw after 15 minutes silence. Anatomic distances and area measures were obtained from CT midsagittal and transversal images. Acoustic, perceptual, electroglottographic (EGG), and subglottic pressure measures were also obtained. RESULTS: During and after phonation into the tube or straw, the velum closed the nasal passage better, the larynx position lowered, and hypopharynx area widened. Moreover, the ratio between the inlet of the lower pharynx and the outlet of the epilaryngeal tube became larger during and after tube/straw phonation. Acoustic results revealed a stronger spectral prominence in the singer/speaker's formant cluster region after exercising. Listening test demonstrated better voice quality after straw/tube than before. Contact quotient derived from EGG decreased during both tube and straw and remained lower after exercising. Subglottic pressure increased during straw and remained somewhat higher after it. CONCLUSION: CT and acoustic results indicated that vocal exercises with increased vocal tract impedance lead to increased vocal efficiency and economy. One of the major changes was the more prominent singer's/speaker's formant cluster. Vocal tract and glottal modifications were more prominent during and after straw exercising compared with tube phonation. PMID- 23683807 TI - Laryngeal movements during inspiratory muscle training in healthy subjects. AB - BACKGROUND: Inspiratory muscle training (IMT) has been used to treat patients with exercise-induced vocal cord dysfunction (VCD); the theoretical basis being the close relationship between the diaphragm and the posterior cricoarytenoid muscle, which is the main abductor of the larynx. Before launching a treatment protocol in patients with VCD, we aimed to substantiate this theory by performing laryngoscopy in healthy subjects during standardized IMT programs. METHODS: Twenty healthy volunteers at mean age 24 years were examined with video-recorded continuous transnasal flexible laryngoscopy while performing standardized training programs using a resistive loading IMT device (Respifit S). All subjects were exposed to two modes of training, that is, the resistance set to generate mouth pressures >=80% of the maximal attainable inspiratory mouth pressure (PImax) and 60-80% of PImax. Laryngeal movements were scored in retrospect from the video recordings by a senior laryngologist. RESULTS: At pressure settings of >=80% of PImax, laryngeal movements could not be assessed in one subject. Abduction was observed in 10 (53%) subjects, six to a maximal extent and four to a moderate extent. At pressure settings of 60-80% of PImax, abduction was observed in 18 (90%) subjects, seven to a maximal extent and 11 to a moderate extent. CONCLUSIONS: IMT can produce laryngeal abduction in healthy subjects, and training programs may conceivably contribute positively in patients suffering from laryngeal adduction during exercise. Individual response patterns varied between subjects and individualized programs seem crucial for effect. Use of high resistances seemed to be counterproductive. PMID- 23683808 TI - Beneficial effects of histone deacetylase inhibition with severe hemorrhage and ischemia-reperfusion injury. AB - BACKGROUND: Valproic acid (VPA) is a histone deacetylase inhibitor that may decrease cellular metabolic needs following traumatic injury. We hypothesized that VPA may have beneficial effects in preventing or reducing the cellular and metabolic sequelae of ischemia-reperfusion injury. METHODS: Twenty-eight Yorkshire swine underwent 35% blood volume hemorrhage, followed by a lethal truncal ischemia-reperfusion injury and 6 h of resuscitation. Physiologic and laboratory parameters were closely measured and the pigs divided into four groups: sham, control (injury protocol), VPA dosing before cross-clamp (VPA-B), and VPA dosing after cross-clamp (VPA-A). RESULTS: All animals developed significant coagulopathy, acidosis, and anemia. Animals receiving VPA-A had decreased acidosis and coagulopathy as measured by pH (P = 0.016) and international normalized ratio (P = 0.013) over the resuscitation. VPA-A pigs had a decreased requirement for crystalloid (P = 0.007) and epinephrine (P < 0.0001) during resuscitation. Pathologic analysis demonstrated decreased liver injury with VPA administration. VPA administration increased levels of acetylated proteins in liver and lung tissues, and was associated with increased expression of heat shock protein 70 versus controls. CONCLUSIONS: Valproic acid conferred a significant cardiovascular, metabolic, and pathologic protective effect in a model of severe injury. Earlier administration (VPA-B) was significantly less effective compared with dosing after initial hemorrhage control. PMID- 23683809 TI - Non-tuberculous mycobacterial disease is common in patients with non-cystic fibrosis bronchiectasis. AB - BACKGROUND: Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms. Cystic fibrosis (CF) patients are susceptible to NTM, but data about NTM in patients with non-CF bronchiectasis are limited. METHODS: We conducted a retrospective, descriptive study at the University of Illinois Medical Center. All patients diagnosed with bronchiectasis (code 494) using the International Classification of Diseases, ninth revision (ICD-9), between 1999 and 2006, were identified. Clinical data including lung function, radiology studies, and presence of NTM in sputum were abstracted for those who met the study criteria. RESULTS: One hundred eighty-two patients were enrolled in the study. Patients were divided into two groups: bronchiectasis with NTM isolates (n = 68) and bronchiectasis without isolates (n =114), and compared for clinical characteristics and underlying diseases. Mycobacterium avium complex (MAC) was the most common isolate. Fifty-five patients (30%) met the American Thoracic Society criteria for diagnosis of NTM disease. Gram-negative rods were commonly co-isolated. The probability of NTM isolation was significantly higher in elderly female patients (p = 0.04). Moreover, the probability of NTM isolation was significantly higher in the female group with low body mass index (BMI) (p = 0.002). CONCLUSIONS: NTM infections are common in non-CF bronchiectasis. MAC is the most frequently isolated NTM in these patients. There is also great variability in age and sex characteristics for NTM in non-CF bronchiectasis patients. Female patients with a low BMI are a high risk group for NTM infection in non-CF bronchiectasis. Routine screening for NTM is strongly recommended in this patient population. PMID- 23683810 TI - Increasing phylogenetic resolution still informative for Y chromosomal studies on West-European populations. AB - Many Y-chromosomal lineages which are defined in the latest phylogenetic tree of the human Y chromosome by the Y Chromosome Consortium (YCC) in 2008 are distributed in (Western) Europe due to the fact that a large number of phylogeographic studies focus on this area. Therefore, the question arises whether newly discovered polymorphisms on the Y chromosome will still be interesting to study Western Europeans on a population genetic level. To address this question, the West-European region of Flanders (Belgium) was selected as study area since more than 1000 Y chromosomes from this area have previously been genotyped at the highest resolution of the 2008 YCC-tree and coupled to in-depth genealogical data. Based on these data the temporal changes of the population genetic pattern over the last centuries within Flanders were studied and the effects of several past gene flow events were identified. In the present study a set of recently reported novel Y-SNPs were genotyped to further characterize all those Flemish Y chromosomes that belong to haplogroups G, R-M269 and T. Based on this extended Y-SNP set the discrimination power increased drastically as previous large (sub-)haplogroups are now subdivided in several non-marginal groups. Next, the previously observed population structure within Flanders appeared to be the result of different gradients of independent sub-haplogroups. Moreover, for the first time within Flanders a significant East-West gradient was observed in the frequency of two R-M269 lineages, and this gradient is still present when considering the current residence of the DNA donors. Our results thus suggest that an update of the Y-chromosomal tree based on new polymorphisms is still useful to increase the discrimination power based on Y-SNPs and to study population genetic patterns in more detail, even in an already well-studied region such as Western Europe. PMID- 23683811 TI - Competence development as perceived by degree and non-degree graduates in Japan: a longitudinal study. AB - BACKGROUND: A degree programme is believed to prepare graduates with a higher level of competence than their diploma counterparts. However, there have been inconsistent findings reported as to whether or not degree-graduates outperformed those who take diplomas. OBJECTIVES: This study aimed to identify graduates' perceptions of competence development in their first year of employment, and to compare the competence levels of graduates with different educational backgrounds. DESIGN: This study adopted a longitudinal design. SETTINGS: This study has been performed in five hospitals in Japan. PARTICIPANTS: 122 Japanese graduates participated in this study. METHODS: The self-assessed competence of the graduates was collected in the 3rd, 6th, 9th, and 12th months of their employment using a survey method. The data were analysed using a linear mixed model. RESULTS: The results suggested that the graduates perceived their competence to be rapidly growing during the first half of the graduate year, and slowly later. The results also indicated that the graduates' perception of their competence showed a significant variation. The most striking finding of the study was that, on average, the non-degree graduates rated their competence higher than their degree counterparts. CONCLUSIONS: The current university orientation on emphasising intellectual and theoretical components of education, with less focus on practical components might have led to the development of lower competence among the BN graduates. A fine balance between theoretical and practical components needs to be established in a university curriculum. PMID- 23683812 TI - Toward a model of curriculum analysis and evaluation - Beka: a case study from Australia. AB - All curricula vary in the way that it is constructed, implemented and experienced. Regardless of the context, ongoing evaluation of learning objectives, processes and content within curriculum is critical. Based primarily on the work of Glatthorn (1987), Print (1993) and Reid (2005), this paper describes a case study of an undergraduate nursing curriculum. The analysis described in this paper forms the basis of a process incorporating four key steps: benchmarking, evidencing, knowing and applying (BEKA). By critiquing the literature, and explaining the merge of others' processes and models of curriculum analysis, it is argued that the BEKA framework of curriculum analysis forms a useful and powerful tool enabling understanding of the actual process of teaching, coverage of curriculum content and assessment, and demonstrating linkages between theory and practice. PMID- 23683813 TI - The educational needs of neonatal nurses regarding neonatal palliative care. AB - BACKGROUND: Studies have shown that education can improve the knowledge, attitudes, and beliefs of neonatal nurses regarding neonatal palliative care. However, no study has investigated the need for neonatal nurse education in neonatal palliative care in Taiwan. OBJECTIVE: The purpose of this study was to explore neonatal nurses' experiences in caring for dying neonates and their educational backgrounds regarding palliative care, as well as to assess their educational needs. METHODS: A cross-sectional survey was used for this research. A research structural questionnaire was used to investigate the research goals. RESULTS: One hundred fifteen nurses participated in this survey. Few participants indicated having received neonatal palliative care education (13%), but most responded that palliative care is necessary in neonatal nursing education (97.4%). Participants also responded that they were often or always exposed to death in NICU (62.6%), but few reported providing pain management to dying neonates (8.7%) and few had experience providing symptomatic care for dying neonates (19.1%). Fifty percent ranked "pain control" as the area in which they most required training. Another high-ranked need was in discussing with parents and families the outcomes of CPR and their neonate's progress. CONCLUSION: Research indicates that the education currently provided to neonatal nurses does not meet their distinctive needs. Neonatal nurses in Taiwan expressed an urgent desire for training in pain control and communication. Research suggests that the most important topics to trainees are pain management and end-of-life communication. Additionally, non-pharmacological pain control interventions are valuable and should be included in an educational program. PMID- 23683814 TI - 'I found the OSCE very stressful': student midwives' attitudes towards an objective structured clinical examination (OSCE). AB - BACKGROUND: The Objective Structured Clinical Examination (OSCE) has become widely accepted as a strategy for assessing clinical competence in nursing and midwifery education and training. There is a dearth of information, however, on the OSCE procedure from the perspective of midwifery students. In particular, there is an absence of an objective quantification of midwifery students' attitudes towards the OSCE. OBJECTIVES: The objective of this study is to report the conduct and findings of a survey of midwifery students' attitudes towards a Lactation and Infant Feeding OSCE and to consider these attitudes in the context of the international literature and the empirical evidence base. METHODS: A descriptive survey design using an 18-item Likert (1 to 5 point) scale was used to capture the relevant data. Potential participants were 3rd year midwifery students who had undertaken a Lactation and Infant Feeding OSCE (n=35) in one School of Nursing & Midwifery in the Republic of Ireland. Survey responses were analysed using the Statistical Package for the Social Sciences Version 18. RESULTS: Thirty-three students completed the survey providing a 94% response rate. Midwifery students' attitudes towards individual aspects of the OSCE varied. Overall, midwifery students were neutral/unsure of the OSCE as a strategy for assessing clinical competence (mean 3.3). Most agreed that the examiner made them feel at ease (mean 3.94). Contrastingly this does not appear to appease student nerves and stress as the majority agreed that the OSCE evokes nervousness (mean 4.27) and stress (mean 4.30). Midwifery students, overall, disagreed that the OSCE reflected real life clinical situations (mean 2.48). Midwifery students were neutral/unsure that the OSCE provided an opportunity to show their practical skills (mean 3.36). CONCLUSION: The findings of this study identified that midwifery students were neutral/unsure of the OSCE as a strategy for assessing clinical competence. This has relevance for OSCE development at the authors' institution. The results suggest the need to explore further why students responded in this way. This will assist to develop this OSCE further to ensure that it becomes a positive assessment process for midwifery students and for student learning as they progress through their midwifery education and training. PMID- 23683815 TI - Professing nursing or not: what's in a title? PMID- 23683816 TI - An implementation framework for using OSCEs in nursing curricula. AB - The implementation framework outlined in this paper has been developed from feedback of a trial across three different nursing and midwifery programmes and is designed to assist educators to incorporate OSCEs within their curricula. There is value in flagging the pedagogical principles embodied in the framework and alerting educators to their importance for more meaningful student learning. For each step practical advice is provided contributing to the utility of this approach. Considerations are systematic ensuring that the use of OSCEs in health care curricula assures judicious use of resources to achieve desired student outcomes. PMID- 23683817 TI - Influence of health rights discourses and community organizing on equitable access to health: the case of HIV, tuberculosis and cancer in Peru. AB - BACKGROUND: The right to health is recognized as a fundamental human right. Social participation is implied in the fulfillment of health rights since Alma Ata posited its relevance for successful health programs, although a wide range of interpretations has been observed for this term. While Peruvian law recognizes community and social participation in health, it was the GFATM requirement of mixed public-civil society participation in Country Coordination Mechanisms (CCM) for proposal submission what effectively led to formal community involvement in the national response to HIV and, to a lesser extent, tuberculosis. This has not been the case, however, for other chronic diseases in Peru. This study aims to describe and compare the role of health rights discourse and community involvement in the national response to HIV, tuberculosis and cancer. METHODS: Key health policy documents were identified and analyzed. In-depth interviews were conducted with stakeholders, representatives of civil society organizations (CSO), and leaders of organizations of people affected by HIV, cancer and tuberculosis. RESULTS AND DISCUSSION: A health rights discourse, well established in the HIV field, is expanding to general health discussions and to the tuberculosis (TB) field in particular. Both HIV and TB programs have National Multisectoral Strategic Plans and recognize participation of affected communities' organizations. Similar mechanisms are non-existent for cancer or other disease-focused programs, although other affected patients are starting some organization efforts. Interviewees agreed that reaching the achievements of HIV mobilization is difficult for other diseases, since the HIV response was modeled based on a global movement with strong networks and advocacy mechanisms, eventually succeeding in the establishment of financial sources like the GFATM. Nevertheless, organizations linked to cancer and other diseases are building a National Patient Network to defend health rights. CONCLUSIONS: There are new efforts to promote and protect health rights in Peru, probably inspired by the achievements of organizations of people living with HIV (PLHA). The public health sector must consolidate the participation of affected communities' organizations in decision-making processes and implementation of health programs. PLHA organizations have become a key political and social actor in Peruvian public health policy. PMID- 23683818 TI - Meaningful and engaging teaching techniques for student nurses: a literature review. AB - Helping undergraduate nursing students to contextualise theory learnt in the classroom to their professional practice can be challenging for nurse educators. This article provides a critical review of contemporary literature that explores strategies and techniques that nurse educators within university settings have adopted to address this challenge. This review was conducted as part of a broader research project that involved interviewing nurse educators to explore how they attempt to make their teaching meaningful and engaging for student nurses. The data was analysed using thematic analysis and the intention is to share the wealth of ideas gleaned with other nurse educators, including in the form of an evidence-based inventory of teaching approaches found to be effective in enhancing the meaningfulness and engagement of content to nursing learners. PMID- 23683819 TI - Kalphalambdaosigma kappaalphaiota Agammaalphathetaosigma: how mitochondrial beauty translates into biological virtue. AB - We are currently witnessing a stream of major discoveries describing the elementary constituents of complex mitochondrial machineries that define the shape, dynamics and intracellular distribution of the organelle. On the basis of these findings the next wave of research holds the promise of unveiling the so far hidden relationships between the fascinating ultrastructural mitochondrial anatomy and its key roles in many areas of cell biology. PMID- 23683820 TI - Journal of Pediatric and Adolescent Gynecology. Introduction. PMID- 23683821 TI - Internet addiction in Hong Kong adolescents: a three-year longitudinal study. AB - OBJECTIVE: The present study investigated the prevalence and psychosocial correlates of Internet addiction in Hong Kong adolescents using a longitudinal design. DESIGN: Three waves of data were collected over 3 years from students in 28 secondary schools in Hong Kong (Wave 1: 3,325 students, age = 12.59 +/- 0.74 y; Wave 2: 3,638 students, age = 13.64 +/- 0.75 y; Wave 3: 4,106 students, age = 14.65 +/- 0.80 y). MAIN OUTCOME MEASURES: Young's 10-item Internet Addiction Test, Chinese Positive Youth Development Scale, and Chinese Family Assessment Instrument were used. RESULTS: At Wave 3, 22.5% of the participants met the criterion of Internet addiction, which was lower than those observed at Wave 1 (26.4%) and Wave 2 (26.7%). Using different measures at Wave 1 to predict Internet addiction at Wave 3, it was found that male students showed more problematic Internet use behavior than did female students; good family functioning predicted lower probability of having Internet addiction; positive youth development indicators negatively predicted Internet addictive behaviors over time. CONCLUSIONS: The results suggest that strengthening family functioning and promoting positive youth development could be a direction for preventing Internet addiction in Hong Kong adolescents. PMID- 23683822 TI - Consumption of pornographic materials in early adolescents in Hong Kong. AB - STUDY OBJECTIVE: The purpose of this study was to examine longitudinal changes in pornography consumption and related psychosocial correlates (ie, positive youth development qualities and family function) among Hong Kong early adolescents. DESIGN AND PARTICIPANTS: In this study, adolescent consumption of pornographic materials was examined in 3 waves of longitudinal data. A total of 3,325 Secondary 1 students (Grade 7) from 28 schools participated in the study at Wave 1. The mean age of the participants was 12.6 years old (SD = .74). RESULTS: Results showed that the internet was the most common medium for consuming pornography materials. Boys consumed more pornographic materials than did girls. Findings showed that family functioning and positive youth development were negatively associated with consumption of pornographic materials over time. CONCLUSION: This study highlights the importance of developing adolescents' competencies and establishing an atmosphere that reduces the use of pornographic materials among adolescents. It sheds light on designing early prevention programs on pornography consumption for young people in Hong Kong. PMID- 23683823 TI - The Project P.A.T.H.S. in Hong Kong: development, training, implementation, and evaluation. AB - We review, a multi-year positive youth development program entitled "P.A.T.H.S. to Adulthood: A Jockey Club Youth Enhancement Scheme" (Project P.A.T.H.S.), which was initiated and funded by The Hong Kong Jockey Club Charities Trust with the involvement of 5 universities in Hong Kong, is described. The Research Team developed curricula-based positive youth development programs for junior secondary school students (20 hours per grade) and designed training programs for the potential program implementers (20 hours per grade). Roughly half of the secondary schools and more than 200,000 students in Hong Kong joined the program. Multiple evaluation strategies including objective outcome evaluation, subjective outcome evaluation, secondary data analyses, process evaluation, interim evaluation, qualitative evaluation based on focus groups, student weekly diaries, case studies, and repertory grid method were employed. Existing evaluation findings revealed that different stakeholders had positive perceptions of the program, workers, and benefits of the program. Results also showed that the program was effective in promoting holistic positive youth development and reducing risk behavior in Chinese adolescents in Hong Kong. PMID- 23683824 TI - Self-harm and suicide attempts among young Chinese adolescents in Hong Kong: prevalence, correlates, and changes. AB - OBJECTIVE: To examine the prevalence of and changes in self-harm and suicide attempts and to predict these behaviors in relation to family functioning and positive youth development. DESIGN: We used quantitative data based on a large sample of adolescent participants. Participants had joined this study in a previous year when they were in Grade 7 (Wave 1). The present study focused on Wave 2 data and the comparison with Wave 1 data. SETTING AND PARTICIPANTS: The participants consisted of 2,579 Grade 8 students from 28 secondary schools in Hong Kong. A multi-stage cluster random sampling was adopted. MAIN OUTCOME MEASURE: Self-harm behavior, suicide attempt, the Chinese Family Assessment Instrument, the Chinese Positive Youth Development Scale. RESULTS: Approximately 23.5% of Grade 8 students had engaged in self-harm behavior in the preceding 12 months. Girls showed more self-harm behavior compared with the boys. Nearly 4.0% of adolescents attempted suicide in the preceding 12 months. Perceived family functioning and positive youth development predicted self-harm and suicidal ideation. Among the 4 second-order positive youth development qualities, the construct "general positive youth development qualities" was the strongest predictor of self-harm and suicide attempts. Compared with the Wave 1 data, more suicidal symptoms were observed in Wave 2, although the prevalence of self-harm behavior was similar across time. CONCLUSIONS: The prevalence of self-harm behavior among Chinese adolescents was high, but the level of suicidal behavior was low. Perceived family functioning and positive youth development can be regarded as protective factors for adolescents against self-harm and suicidal behaviors. General positive youth development quality is most important among the 4 second-order positive youth development qualities. PMID- 23683825 TI - Sexual behavior and intention to engage in sexual behavior in junior secondary school students in Hong Kong. AB - STUDY OBJECTIVES: The present study examined the prevalence, changes, and demographic as well as psychosocial correlates of sexual behavior and intention to engage in sexual behavior in early adolescents in Hong Kong, with sexual behavior indexed by sexual intercourse. DESIGN: Three waves of longitudinal data on sexual intercourse, intention to engage in sexual intercourse, family functioning, and positive youth development were collected from 28 secondary schools in Hong Kong. RESULTS: There were significant influences of grade and gender on adolescent sexual behavior or intention to engage in sexual behavior. Significant main effects of immigration status on sexual behavior were also found. While no effect of family economic background was found, effect of family intactness existed for sexual behavior. Family functioning and positive youth development at Grade 7 were negatively associated with students' sexual behavior and intention to engage in sexual behavior at Grade 9. CONCLUSION: Grade, gender, immigration status, and family intactness were related to sexual behavior and/or intention to engage in sexual behavior in junior secondary school students. Promoting positive youth development and family functioning could serve as protective factors to reduce sexual behavior and intention to engage in sexual behavior in Chinese early adolescents in Hong Kong. PMID- 23683826 TI - Compensated dating in Hong Kong: prevalence, psychosocial correlates, and relationships with other risky behaviors. AB - STUDY OBJECTIVE: We sought to study the prevalence of the compensated dating (CD) phenomenon among early adolescents in Hong Kong and to identify psychosocial correlates of CD, particularly basic demographic factors, positive youth development (PYD) qualities, and perceived family functioning. DESIGN AND PARTICIPANTS: In 2010, during the Wave 2 data collection of a 6-year longitudinal study on PYD in Hong Kong, 3,638 Grade 8 students were surveyed. RESULTS: (a) For prevalence rate of CD, less than 3% of the respondents had ever engaged in CD; (b) Males reported a higher percentage of CD than females did; (c) Different measures of PYD and perceived family functioning were negatively related to adolescents' CD behavior; (d) Higher levels of PYD and better mutual support, love, and concern among family members were related to a lower level of CD; and (e) A mild relationship was found between CD and substance abuse. CONCLUSIONS: Although the prevalence rate of CD was not high, it was alarming. CD was related to other forms of risky behavior. Higher levels of PYD and better family functioning were negatively related to CD. PMID- 23683827 TI - Soluble amyloid precursor protein-alpha rescues age-linked decline in neural progenitor cell proliferation. AB - Neurogenesis is thought to play a role in cognitive function and hippocampal plasticity. Previous studies suggest that neurogenesis declines with aging. However, the onset and mechanism of declined neurogenesis are not fully elucidated. Here we show that the major decline in neurogenesis takes place during adulthood, before aging. Decline in neurogenesis takes place in the subgranular layer of the dentate gyrus and in the subventricular zone, and is primarily due to a reduced number of fast-proliferating neural progenitor cells. Importantly, this decline can be rescued by intraventricular injection of recombinant soluble amyloid precursor protein (sAPPalpha), which regulates neural progenitor cell proliferation in the adult brain. The counterpart, sAPPbeta, a product of the amyloidogenic cleavage pathway of amyloid precursor protein, fails to exhibit a proliferative effect in vitro and in vivo, in equimolar concentrations to sAPPalpha. These observations suggest that adulthood is an appropriate time window for an intervention that upregulates neurogenesis, such as enhancement of sAPPalpha levels, for the prevention of declining brain plasticity and cognitive function. PMID- 23683828 TI - Multidose stereotactic radiosurgery (9 Gy * 3) of the postoperative resection cavity for treatment of large brain metastases. AB - PURPOSE: To evaluate the clinical outcomes with linear accelerator-based multidose stereotactic radiosurgery (SRS) to large postoperative resection cavities in patients with large brain metastases. METHODS AND MATERIALS: Between March 2005 to May 2012, 101 patients with a single brain metastasis were treated with surgery and multidose SRS (9 Gy * 3) for large resection cavities (>3 cm). The target volume was the resection cavity with the inclusion of a 2-mm margin. The median cavity volume was 17.5 cm(3) (range, 12.6-35.7 cm(3)). The primary endpoint was local control. Secondary endpoints were survival and distant failure rates, cause of death, performance measurements, and toxicity of treatment. RESULTS: With a median follow-up of 16 months (range, 6-44 months), the 1-year and 2-year actuarial survival rates were 69% and 34%, respectively. The 1-year and 2-year local control rates were 93% and 84%, with respective incidences of new distant brain metastases of 50% and 66%. Local control was similar for radiosensitive (non-small cell lung cancer and breast cancer) and radioresistant (melanoma and renal cell cancer) brain metastases. On multivariate Cox analysis stable extracranial disease, breast cancer histology, and Karnofsky performance status >70 were associated with significant survival benefit. Brain radionecrosis occurred in 9 patients (9%), being symptomatic in 5 patients (5%). CONCLUSIONS: Adjuvant multidose SRS to resection cavity represents an effective treatment option that achieves excellent local control and defers the use of whole-brain radiation therapy in selected patients with large brain metastases. PMID- 23683831 TI - [Personalizing the reference level: gold standard to evaluate the quality of service perceived]. AB - OBJECTIVE: To know the cutoff point at which in-house Nuclear Medicine Department (MND) customers consider that the quality of service is good (personalized cutoff). MATERIAL AND METHOD: We conducted a survey of the professionals who had requested at least 5 tests to the Nuclear Medicine Department. A total of 71 doctors responded (response rate: 30%). A question was added to the questionnaire for the user to establish a cutoff point for which they would consider the quality of service as good. The quality non-conformities, areas of improvement and strong points of the six questions measuring the quality of service (Likert scale 0 to 10) were compared with two different thresholds: personalized cutoff and one proposed by the service itself a priori. Test statistics: binomial and Student's t-test for paired data. RESULTS: A cutoff value of 7 was proposed by the service as a reference while 68.1% of respondents suggested a cutoff above 7 points (mean 7.9 points). The 6 elements of perceived quality were considered strong points with the cutoff proposed by the MND, while there were 3 detected with the personalized threshold. Thirteen percent of the answers were nonconformities with the service cutoff versus 19.2% with the personalized one, the differences being statistically significant (difference 95% CI 6.44%:0,83 12.06). CONCLUSIONS: The final image of the perceived quality of an in-house customer is different when using the cutoff established by the Department versus the personalized cutoff given by the respondent. PMID- 23683829 TI - Does quality of radiation therapy predict outcomes of multicenter cooperative group trials? A literature review. AB - Central review of radiation therapy (RT) delivery within multicenter clinical trials was initiated in the early 1970s in the United States. Early quality assurance publications often focused on metrics related to process, logistics, and timing. Our objective was to review the available evidence supporting correlation of RT quality with clinical outcomes within cooperative group trials. A MEDLINE search was performed to identify multicenter studies that described central subjective assessment of RT protocol compliance (quality). Data abstracted included method of central review, definition of deviations, and clinical outcomes. Seventeen multicenter studies (1980-2012) were identified, plus one Patterns of Care Study. Disease sites were hematologic, head and neck, lung, breast, and pancreas. Between 0 and 97% of treatment plans received an overall grade of acceptable. In 7 trials, failure rates were significantly higher after inadequate versus adequate RT. Five of 9 and 2 of 5 trials reported significantly worse overall and progression-free survival after poor-quality RT, respectively. One reported a significant correlation, and 2 reported nonsignificant trends toward increased toxicity with noncompliant RT. Although more data are required, protocol-compliant RT may decrease failure rates and increase overall survival and likely contributes to the ability of collected data to answer the central trial question. PMID- 23683830 TI - Neurolymphomatosis as a late relapse of non-Hodgkin's lymphoma detected by 18F FDG PET/CT: a case report. AB - Neurolymphomatosis is a rare condition defined as an infiltration of nerves, nerve roots or nervous plexuses by haematological malignancy. Its diagnosis may sometimes be difficult with conventional imaging techniques. This paper aims to emphasize the importance of this entity and the role of (18)F-FDG PET/CT in this indication. We present the case of a 53-year-old male who complained of sharp pain in his right hip and right leg paresthesia after 2 years of complete remission from Non-Hodgkin's lymphoma. Physical examination and CT scan were negative and the lumbar MRI showed protrusion of L5-S1 disc. Physiotherapy, nonsteroid antiinflammatory drugs and steroids were inefficient. PET/CT was performed four months after the onset of the symptoms, revealing focal FDG uptake in the right S1 nerve root and linear FDG uptake along the right sacral plexus suggesting relapse. This was confirmed by histology. PMID- 23683833 TI - Employing directed evolution for the functional analysis of multi-specific proteins. AB - Multi-specific proteins located at the heart of complex protein-protein interaction (PPI) networks play essential roles in the survival and fitness of the cell. In addition, multi-specific or promiscuous enzymes exhibit activity toward a wide range of substrates so as to increase cell evolvability and robustness. However, despite their high importance, investigating the in vivo function of these proteins is difficult, due to their complex nature. Typically, deletion of these proteins leads to the abolishment of large PPI networks, highlighting the difficulty in examining the contributions of specific interactions/activities to complex biological processes and cell phenotypes. Protein engineering approaches, including directed evolution and computational protein design, allow for the generation of multi-specific proteins in which certain activities remain intact while others are abolished. The generation and examination of these mutants both in vitro and in vivo can provide high resolution analysis of biological processes and cell phenotypes and provide new insight into the evolution and molecular function of this important protein family. PMID- 23683832 TI - Mass casualty triage after an airplane crash near Amsterdam. AB - INTRODUCTION: Triage is an important aspect of the management of mass casualty incidents. This study describes the triage after the Turkish Airlines Crash near Amsterdam in 2009. The results of the triage and the injuries of P3 casualties were evaluated. In addition, the role of the trauma mechanism and its effect on spinal immobilisation during transport was analysed. METHODS: Retrospective analysis of investigational reports, ambulance forms, and medical charts of survivors of the crash. Outcomes were triage classification, type of injury, AIS, ISS, emergency interventions and the spinal immobilisation during transport. RESULTS: A minimal documentation of prehospital triage was found, and no exact numbers could be recollected. During inhospital triage 28% was triaged as P1, 10% had an ISS >= 16 and 3% met the modified Baxt criteria for emergency intervention. 40% was triaged P3, 72% had an ISS <= 8 and 63% was discharged from the Emergency Department after evaluation. In hospital over-triage was up to 89%. Critical mortality rate was 0%. Nine per cent of P3 casualties and 17% of 'walking' casualties had serious injuries. Twenty-two per cent of all casualties was transported with spinal immobilisation. Of the casualties diagnosed with spinal injury 22% was not transported with spinal immobilisation. CONCLUSION: After the Turkish Airlines Crash documentation of prehospital triage was minimal. According to the Baxt criteria the overtriage was high. Injuries sustained by plane crash survivors that seem minimally harmed must not be underestimated. Considering the high energy trauma mechanism, too little consideration was given to spinal immobilisation during transport. PMID- 23683834 TI - 20(S)-Protopanaxadiol (PPD) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs. AB - Novel 20(S)-protopanoxadiol (PPD) analogues were designed, synthesized, and evaluated for the chemosensitizing activity against a multidrug resistant (MDR) cell line (KBvcr) overexpressing P-glycoprotein (P-gp). Structure-activity relationship analysis showed that aromatic substituted aliphatic amine at the 24 positions (groups V) effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as docetaxel (DOC), vincristine (VCR), and adriamycin (ADM). PPD derivatives 12 and 18 showed 1.3-2.6 times more effective reversal ability than verapamil (VER) for DOC and VCR. Importantly, no cytotoxicity was observed by the active PPD analogues (5MUM) against both non-MDR and MDR cells, suggesting that PPD analogues serve as novel lead compounds toward a potent and safe resistance modulator. Moreover, a preliminary mechanism study demonstrated that the chemosensitizing activity of PPD analogues results from inhibition of P-glycoprotein (P-gp) overexpressed in MDR cancer cells. PMID- 23683835 TI - Synthesis of organic nitrates of luteolin as a novel class of potent aldose reductase inhibitors. AB - Aldose reductase (AR) plays an important role in the design of drugs that prevent and treat diabetic complications. Aldose reductase inhibitors (ARIs) have received significant attentions as potent therapeutic drugs. Based on combination principles, three series of luteolin derivatives were synthesised and evaluated for their AR inhibitory activity and nitric oxide (NO)-releasing capacity in vitro. Eighteen compounds were found to be potent ARIs with IC50 values ranging from (0.099+/-0.008) MUM to (2.833+/-0.102) MUM. O(7)-Nitrooxyethyl-O(3'),O(4') ethylidene luteolin (La1) showed the most potent AR inhibitory activity [IC50=(0.099+/-0.008) MUM]. All organic nitrate derivatives released low concentrations of NO in the presence of l-cysteine. Structure-activity relationship studies suggested that introduction of an NO donor, protection of the catechol structure, and the ether chain of a 2-carbon spacer as a coupling chain on the luteolin scaffold all help increase the AR inhibitory activity of the resulting compound. This class of NO-donor luteolin derivatives as efficient ARIs offer a new concept for the development and design of new drug for preventive and therapeutic drugs for diabetic complications. PMID- 23683836 TI - Synthesis and antibacterial activity of novel phosphonium salts on the basis of pyridoxine. AB - A series of 13 phosphonium salts on the basis of pyridoxine derivatives were synthesized and their antibacterial activity against clinically relevant strains was tested in vitro. All compounds were almost inactive against gram-negative bacteria and exhibited structure-dependent activity against gram-positive bacteria. A crucial role of ketal protection group in phosphonium salts for their antibacterial properties was demonstrated. Among synthesized compounds 5,6 bis[triphenylphosphonio(methyl)]-2,2,8-trimethyl-4H-[1,3]dioxino[4,5-c]pyridine dichloride (compound 20) was found to be the most effective towards Staphylococcus aureus and Staphylococcus epidermidis strains (MIC 5MUg/ml). The mechanism of antibacterial activity of this compound probably involves cell penetration and interaction with genomic and plasmid DNA. PMID- 23683837 TI - Cross-roads in the classification of papillomaviruses. AB - Acceptance of an official classification for the family Papillomaviridae based purely on DNA sequence relatedness, was achieved as late as 2003. The rate of isolation and characterization of new papillomavirus types has greatly depended on and subjected to the development of new laboratory techniques. Introduction of every new technique led to a temporarily burst in the number of new isolates. In the following, the bumpy road towards achieving a classification system combined with the controversies of implementing and accepting new techniques will be summarized. An update of the classification of the 170 human papillomavirus (HPV) types presently known is presented. Arguments towards the implementation of metagenomic sequencing for this rapidly growing family will be presented. PMID- 23683839 TI - Response to treatments in youth with disruptive behavior disorders. AB - OBJECTIVE: Predictors of poor response to treatments in youths with disruptive behavior disorders (DBDs), including conduct disorder (CD) and oppositional defiant disorder (ODD), are under-studied. Multimodal psychosocial interventions are the best option, but a significant portion of patients needs adjunctive pharmacotherapy. The concept of "psychopathy", and namely, the callous (lack of empathy and guilt) and unemotional (shallow emotions) trait, has been considered a possible specifier indicating a more severe subgroup of patients. We explored whether the callous-unemotional trait (CU) may affect the response to multimodal treatment in referred youths with DBDs. METHOD: 118 youths (102 males, age range 6-14years, mean age 11.1+/-2.5years) completed a 12-month multimodal intervention, 48 of whom (41%) needed an associated pharmacotherapy. The patients were assessed according to psychopathological profile (Child Behavior Checklist, CBCL), severity and improvement (Clinical Global Impression-Severity and Improvement scores, CGI-S and CGI-I), functional impairment (Children-Global Assessment Scale, C-GAS), and psychopathic dimension (Antisocial Process Screening Device, APSD), including CU dimension. RESULTS: 58 patients (49.2%) were non-responders. They had more frequently a diagnosis of CD than ODD, presented a comorbid mood disorder, higher CBCL scores in rule-breaking behavior, and higher APSD ("psychopathic") scores. Subjects with higher or lower CU differed only according to the rate of responders (35% vs. 60%, p<.05). The linear blockwise regression indicated that pre-treatment functional impairment (C GAS) and baseline CU trait were predictors of non-response. The logistic regression indicated that only the value of baseline APSD-CU trait was a predictor of non-response. CONCLUSIONS: A careful assessment of baseline clinical functioning and psychopathological features, namely the psychopathic traits, can identify the most problematic patients, and has specific prognostic and treatment implications. PMID- 23683838 TI - Functional analysis of the stem loop S3 and S4 structures in the coronavirus 3'UTR. AB - We designed a series of mutations to separately destabilize two helical stems (designated S3 and S4) predicted by a covariation-based model of the coronavirus 3'UTR (Zust et al., 2008). Mouse hepatitis virus genomes containing three or four nucleotide mutations that destabilize either S3 or S4 were viable, whereas genomes carrying these mutations in both S3 and S4 were not viable. A genome carrying these mutations in S3 and S4 plus compensatory mutations restoring base pairing yielded a virus with wild type phenotype. Larger mutations which completely disrupt S3 or S4 generated various phenotypes. Mutations opening up S3 were lethal. Disruptions of S4 generated both viable and lethal mutants. Genomes carrying the original mutations in S3 or S4 plus compensatory mutations restoring base pairing were viable and had robust growth phenotypes. These results support the Zust model for the coronavirus 3'UTR and suggest that the S3 stem is required for virus viability. PMID- 23683840 TI - Novel use of Coblation technology in an unusual congenital tracheal stenosis. AB - BACKGROUND: We report the case of an unusual late presentation of congenital tracheal stenosis in a 13-year-old boy. He was treated with minimally invasive Coblation resection of the stenotic segment, avoiding a major open tracheal resection and reconstruction. This case report is the first to document the use of an ultra-fine Coblation wand in the treatment of congenital tracheal stenosis. RESULTS: The case proceeded well, without any complications. The patient had a fully healed and patent trachea at 12-week post-operative review. CONCLUSION: Complex cases of congenital stenosis should be managed with a multidisciplinary approach. Different and novel treatment options should be explored to find one that suits the individual patient. Minimally invasive Coblation technology can offer less invasive treatment with quicker recovery and shorter hospitalisation. PMID- 23683842 TI - D-index dose not predict the development of pulmonary infection in acute myeloid leukemia patients undergoing consolidation chemotherapy with high-dose cytarabine. AB - The D-index is calculated as the area over the neutrophil curve during neutropenia. We investigated the impact of the D-index on pulmonary infection in 33 acute myeloid leukemia patients undergoing consolidation chemotherapy with high-dose cytarabine. There was no difference in the D-index between chemotherapies with and without pulmonary infection. The cumulative D-index (c-D index) until the development of infection exceeded 4000 in four of five patients with pulmonary infection. Although there was no difference in the total D-index throughout the overall consolidation chemotherapy, the total D-index from induction to consolidation and the D-index at induction chemotherapy were higher in patients with pulmonary infection during consolidation than in those without it (P = 0.014 and 0.019, respectively). Our results showed that the cumulative effect of neutropenia might determine the risk of pulmonary infection in consolidation chemotherapy. We are planning a clinical trial of c-D-index-guided preemptive antifungal therapy. PMID- 23683841 TI - Efficacy of a dilemma-focused intervention for unipolar depression: study protocol for a multicenter randomized controlled trial. AB - BACKGROUND: Depression is one of the more severe and serious health problems because of its morbidity, disabling effects and for its societal and economic burden. Despite the variety of existing pharmacological and psychological treatments, most of the cases evolve with only partial remission, relapse and recurrence.Cognitive models have contributed significantly to the understanding of unipolar depression and its psychological treatment. However, success is only partial and many authors affirm the need to improve those models and also the treatment programs derived from them. One of the issues that requires further elaboration is the difficulty these patients experience in responding to treatment and in maintaining therapeutic gains across time without relapse or recurrence. Our research group has been working on the notion of cognitive conflict viewed as personal dilemmas according to personal construct theory. We use a novel method for identifying those conflicts using the repertory grid technique (RGT). Preliminary results with depressive patients show that about 90% of them have one or more of those conflicts. This fact might explain the blockage and the difficult progress of these patients, especially the more severe and/or chronic. These results justify the need for specific interventions focused on the resolution of these internal conflicts. This study aims to empirically test the hypothesis that an intervention focused on the dilemma(s) specifically detected for each patient will enhance the efficacy of cognitive behavioral therapy (CBT) for depression. DESIGN: A therapy manual for a dilemma-focused intervention will be tested using a randomized clinical trial by comparing the outcome of two treatment conditions: combined group CBT (eight, 2-hour weekly sessions) plus individual dilemma-focused therapy (eight, 1-hour weekly sessions) and CBT alone (eight, 2-hour group weekly sessions plus eight, 1-hour individual weekly sessions). METHOD: Participants are patients aged over 18 years meeting diagnostic criteria for major depressive disorder or dysthymic disorder, with a score of 19 or above on the Beck depression inventory, second edition (BDI-II) and presenting at least one cognitive conflict (implicative dilemma or dilemmatic construct) as assessed using the RGT. The BDI-II is the primary outcome measure, collected at baseline, at the end of therapy, and at 3- and 12-month follow-up; other secondary measures are also used. DISCUSSION: We expect that adding a dilemma-focused intervention to CBT will increase the efficacy of one of the more prestigious therapies for depression, thus resulting in a significant contribution to the psychological treatment of depression. TRIAL REGISTRATION: ISRCTN92443999; ClinicalTrials.gov Identifier: NCT01542957. PMID- 23683843 TI - Colonoscopic surveillance of first-degree relatives of colorectal cancer patients in a faecal occult blood screening programme. AB - BACKGROUND: In some Italian areas, colonoscopic surveillance of first-degree relatives (FDRs) of colorectal cancer (CRC) patients is provided as a part of local population-based faecal occult blood test (FOBT) screening programmes. The objective of the present study was to assess the feasibility and early results of this surveillance model. METHODS: Data from district screening centres were used to evaluate the process of identification and selection of eligible FDRs (residence in the Emilia-Romagna Region, age 40-75 years, no recent colonoscopy) of screen-detected CRC patients and the detected prevalence of disease. The probability for an FDR to undergo colonoscopy and to be diagnosed with CRC and advanced adenoma was estimated using the Kaplan-Meier method. The sex- and age standardised ratio of detected prevalence to that expected based on results from a colonoscopy screening study of the Italian general population was estimated. RESULTS: Between 2005 and 2011, 9319 FDRs of 2437 screen-detected CRC patients (3.8 per patient) were identified and contacted. Their likelihood of being eligible for, and accepting, colonoscopy was 0.11 (95% confidence interval: 0.11 0.12). Among the 926 subjects undergoing colonoscopy, the prevalence of previous negative screening FOBT was 63%. Eleven CRCs (1.2%) and 100 advanced adenomas (10.8%) were detected. The standardised ratio of detected prevalence to that expected was 0.91 (95% confidence interval: 0.19-2.66) for CRC and 1.48 (1.04 2.05) for advanced adenoma. CONCLUSIONS: The procedure of selection of FDRs was extremely ineffective. Due to previous negative screening tests, the prevalence of disease was less than expected. A population-based FOBT screening programme is a highly unsuitable setting for the provision of surveillance to FDRs of CRC patients. PMID- 23683844 TI - Incidence patterns and trends of malignant gonadal and extragonadal germ cell tumors in Germany, 1998-2008. AB - BACKGROUND: Malignant gonadal (GGCT) and extragonal germ cell tumors [GCT (EGCT)] are thought to originate from primordial germ cells. In contrast to well reported population-based data of GGCTs in males, analyses of GGCTs in females and EGCTs in both sexes remain limited. METHODS: In a pooling project of nine population based cancer registries in Germany for the years 1998-2008, 16,883 malignant GCTs and their topographical sites were identified using ICD-O morphology and topography for persons aged 15 years and older. We estimated age-specific and age standardized incidence rates. RESULTS: Among males, the incidence of testicular GCTs increased over time. In contrast, there was no increase in the incidence of EGCTs. Among females, rates of ovarian GCTs were stable, while rates of EGCTs declined over time. The most frequent extragonadal sites were mediastinum among males and placenta among females. CONCLUSIONS: Our results underline different incidence trends and distinct age-specific incidence patterns of malignant GGCTs and EGCTs, as reported recently by several population-based registries. The differences suggest that GGCT and EGCT may have different etiologies. PMID- 23683845 TI - A multimethod approach for cross-cultural training in an internal medicine residency program. AB - BACKGROUND: Cultural competence training in residency is important to improve learners' confidence in cross-cultural encounters. Recognition of cultural diversity and avoidance of cultural stereotypes are essential for health care providers. METHODS: We developed a multimethod approach for cross-cultural training of Internal Medicine residents and evaluated participants' preparedness for cultural encounters. The multimethod approach included (1) a conference series, (2) a webinar with a national expert, (3) small group sessions, (4) a multicultural social gathering, (5) a Grand Rounds presentation on cross-cultural training, and (6) an interactive, online case-based program. RESULTS: The program had 35 participants, 28 of whom responded to the survey. Of those, 16 were white (62%), and residents comprised 71% of respondents (n=25). Following training, 89% of participants were more comfortable obtaining a social history. However, prior to the course only 27% were comfortable caring for patients who distrust the US system and 35% could identify religious beliefs and customs which impact care. Most (71%) believed that the training would help them give better care for patients from different cultures, and 63% felt more comfortable negotiating a treatment plan following the course. CONCLUSIONS: Multimethod training may improve learners' confidence and comfort with cross-cultural encounters, as well as lay the foundation for ongoing learning. Follow-up is needed to assess whether residents' perceived comfort will translate into improved patient outcomes. PMID- 23683846 TI - Cassandra's prophecy: medic or mother? Exploring the relevance of age-related fertility decline to women in medicine. AB - This commentary presents a response to 'Cassandra's prophecy' from the perspective of a final-year medical student, in an attempt to gauge the particular relevance of age-related fertility decline to female doctors. Women in the UK are increasingly trying to have children at an older age, with a resultant rise in the incidence of age-related fertility decline and obstetric problems. The literature suggests that the trend towards older motherhood is seen particularly among highly educated women, but that such women lack sufficient knowledge about how fertility and obstetric outcomes decline with age. Recent data indicate that female doctors have children significantly later than women in the general population, but are overall no more likely to remain childless. However, there is significant variation between different specialties; for instance, female surgeons have children significantly later and are more likely to be childless by age 35, as compared with both male surgeons and female doctors in other specialties. This commentary explores various explanations for and implications of these data, in the context of recent changes in NHS workforce gender demographics. PMID- 23683847 TI - Retrospective analysis of outcomes after IVF using an aneuploidy risk model derived from time-lapse imaging without PGS. AB - Time-lapse imaging of human preimplantation IVF embryos has enabled objective algorithms based on novel observations of development (morphokinetics) to be used for clinical selection of embryos. Embryo aneuploidy, a major cause of IVF failure, has been correlated with specific morphokinetic variables used previously to develop an aneuploidy risk classification model. The purpose of this study was to evaluate the effectiveness and potential impact of this model for unselected IVF patients without biopsy and preimplantation genetic screening (PGS). Embryo outcomes - no implantation, fetal heart beat (FHB) and live birth (LB) - of 88 transferred blastocysts were compared according to calculated aneuploidy risk classes (low, medium, high). A significant difference was seen for FHB (P<0.0001) and LB (P<0.01) rates between embryos classified as low and medium risk. Within the low-risk class, relative increases of 74% and 56%, compared with rates for all blastocysts, were observed for FHB and LB respectively. The area under the receiver operating characteristic curve was 0.75 for FHB and 0.74 for LB. This study demonstrates the clinical relevance of the aneuploidy risk classification model and introduces a novel, non-invasive method of embryo selection to yield higher implantation and live birth rates without PGS. PMID- 23683848 TI - Testing the Newcastle Ottawa Scale showed low reliability between individual reviewers. AB - OBJECTIVES: To assess inter-rater reliability and validity of the Newcastle Ottawa Scale (NOS) used for methodological quality assessment of cohort studies included in systematic reviews. STUDY DESIGN AND SETTING: Two reviewers independently applied the NOS to 131 cohort studies included in eight meta analyses. Inter-rater reliability was calculated using kappa (kappa) statistics. To assess validity, within each meta-analysis, we generated a ratio of pooled estimates for each quality domain. Using a random-effects model, the ratios of odds ratios for each meta-analysis were combined to give an overall estimate of differences in effect estimates. RESULTS: Inter-rater reliability varied from substantial for length of follow-up (kappa = 0.68, 95% confidence interval [CI] = 0.47, 0.89) to poor for selection of the nonexposed cohort and demonstration that the outcome was not present at the outset of the study (kappa = -0.03, 95% CI = 0.06, 0.00; kappa = -0.06, 95% CI = -0.20, 0.07). Reliability for overall score was fair (kappa = 0.29, 95% CI = 0.10, 0.47). In general, reviewers found the tool difficult to use and the decision rules vague even with additional information provided as part of this study. We found no association between individual items or overall score and effect estimates. CONCLUSION: Variable agreement and lack of evidence that the NOS can identify studies with biased results underscore the need for revisions and more detailed guidance for systematic reviewers using the NOS. PMID- 23683849 TI - Diffusion-weighted imaging of the liver: a comprehensive review. AB - Diffusion-weighted magnetic resonance imaging is based on the Brownian motion of water and enables quantification of the apparent diffusion coefficient throughout the body. This article discusses the principles of diffusion-weighted magnetic resonance imaging, as well as the possible applications and limitations as they apply to liver imaging. This will introduce the readers to this novel magnetic resonance imaging tool, which has a promising future. PMID- 23683851 TI - MR evaluation of rectal cancer: current concepts. AB - Magnetic resonance imaging has become more frequently utilized for staging, preoperative planning, and post-neoadjuvant evaluation of rectal cancer. It offers detailed resolution of the layers of the rectal wall, visualization of the mesorectal fascia, and identification of locoregional nodal involvement. Many advances have been made since the original protocols and include the use of phased-array coils, orthogonally obtained images and 3-dimensional sequences, the use of diffusion-weighted and perfusion protocols to better evaluate the tumor before and after neoadjuvant therapy, and the development of techniques to better evaluate metastatic nodes. Magnetic resonance imaging shows similar accuracy to endorectal ultrasound when staging and offers a less invasive technique that is not limited by patient discomfort or decreased luminal size. This article is meant to provide an update on the recent advances in rectal cancer imaging while addressing the controversial issues that exist in staging, technique, and imaging protocol. PMID- 23683850 TI - Radiographic evaluation of the patient with lung cancer: surgical implications of imaging. AB - Lung cancer is the leading cause of cancer deaths in the United States. Despite many advances in treatment, surgery remains the preferred treatment modality for patients presenting with early stage disease. Imaging is critical in the preoperative evaluation of these patients being considered for a curative resection. Advanced imaging techniques provide valuable information, including primary diagnostics, staging, and intraoperative localization for suspected lung cancer. Knowledge of surgical implications of imaging findings can aid both radiologists and surgeons in delivering safe and effective care. PMID- 23683852 TI - Hepatobiliary oncologic emergencies: imaging appearances and therapeutic options. AB - During the course of their disease, many patients with cancer may require urgent care related to hepatobiliary disease. Cross-sectional imaging of these patients is usually performed initially, and the radiologist plays a pivotal role in the initial diagnosis. In this article, we discuss the commonly seen hepatobiliary oncologic emergencies, briefly review imaging diagnosis, and discuss in detail the management options for these conditions. The radiologist's awareness and prompt diagnosis aid in formulating a management plan to decrease morbidity and mortality in these potentially lethal conditions. PMID- 23683854 TI - Risk factors associated with Lawsonia intracellularis in English pig farms. AB - Porcine proliferative enteropathy (PPE) caused by the bacterium Lawsonia intracellularis causes considerable economic loss to the pig industry. The objective of this study was to evaluate the seroprevalence of L. intracellularis exposure in different age groups of pigs (growers to finishers) within English farms and to identify potential risk factors. Samples were obtained in a cross sectional study of 147 farms between 2008 and 2009. Twelve samples (six growers and six finishers) from each farm were tested for L. intracellularis by antibody ELISA. At animal level there was a significant positive linear trend between seroprevalence and age in weeks (r(2)=2.65, P<0.001), with seroprevalence lowest (24.73%) at 11 weeks and highest (93.33%) at 24 weeks. At farm level, seroprevalence was significantly lower in growers than finishers (56.80% vs. 94.26%, P<0.001). Farms reporting minor Salmonella problems and those that brought boars onto the farm had higher odds of testing positive in growers (OR 5.69 and 4.31, respectively. On the other hand, farms where producers considered temperature as an important stress factor (OR=0.3) and which had more than two sites on which pigs are kept (OR=0.16) were less likely to test positive in growers. The current study confirmed the high prevalence of L. intracellularis in English pig farms. The potential risk factors and further information of the disease impact on the farm productivity will aid the development of appropriate control strategies through better understanding of the disease. PMID- 23683853 TI - Ultrastable pRNA hexameric ring gearing hexameric phi29 DNA-packaging motor by revolving without rotating and coiling. AB - Biomotors have previously been classified into two categories: linear and rotational motors. It has long been popularly believed that viral DNA packaging motors are rotation motors. We have recently found that the DNA-packaging motor of bacteriophage phi29 uses a third mechanism: revolution without rotation. phi29 motor consists of three-coaxial rings of hexameric RNA, a hexameric ATPase, and a dodecameric channel. The motor uses six ATP to revolve one helical turn of dsDNA around the hexameric ring of ATPase gp16. Each dodecameric segment tilts at a 30 degrees -angle and runs anti-parallel to the dsDNA helix to facilitate translation in one direction. The negatively charged phosphate backbone interacts with four positively charged lysine rings, resulting in four steps of transition. This review will discuss how the novel pRNA meets motor requirements for translocation concerning structure, stoichiometry, and thermostability; how pRNA studies have led to the generation of the concept of RNA nanotechnology; and how pRNA is fabricated into nanoparticles to deliver siRNA, miRNA, and ribozymes to cancer and virus-infected cells. PMID- 23683855 TI - Effect of temperature on the survival of porcine circovirus type 2b in fresh pork. AB - Porcine circovirus type 2b (PCV2b) causes PCV-associated disease in pigs. This study was conducted to investigate the effect of temperature on the survival of PCV2b in fresh pork. Several pieces of longissimus dorsi muscle were injected with 100 MUL of a suspension containing 10(5.2) TCID50 (50% tissue culture infective doses) of the virus. Virus-inoculated pieces of pork were stored at 25 degrees C, 4 degrees C and -20 degrees C and tested for the presence of infectious virus after different times of storage. PCV2b was found to survive in fresh pork for up to 2 days post inoculation (dpi) at room temperature, for 6 dpi at 4 degrees C and for up to 30 dpi at -20 degrees C indicating that the survival of PCV2b in fresh pork depends on temperature of storage. PMID- 23683856 TI - Monitoring and treating chronic pain in cats: bring on the challenge! PMID- 23683857 TI - Immunohistochemical study of porcine lung lesions associated with Pasteurella multocida. AB - Infectious bronchopneumonia is a widespread disease in modern commercial pig production and Pasteurella multocida is frequently associated with the lesions. To evaluate porcine lung lesions associated with P. multocida, populations of inflammatory cells were examined by immunohistochemistry in necrotic lung lesions from nine pigs and exudative lung lesions from eleven pigs. Lungs from five pigs served as controls. All cases were selected from naturally infected pigs using co infection based criteria to make them as comparable as possible. The inflammatory cells demonstrated by immunohistochemistry were T-lymphocytes (CD3(+), CD4(+) and CD8(+) subsets), B-lymphocytes, neutrophils, macrophages, and IgA(+), IgM(+) and IgG(+) cells. The results showed that (1) a significant increase in all inflammatory cells was found in lesions associated with P. multocida, (2) necrotic lesions had a larger number of CD3(+) T-lymphocytes and IgA(+) cells, and (3) cases with exudative lesions had a more CD8(+) T-lymphocytes, B lymphocytes, macrophages and neutrophils. No differences in the numbers of CD4(+) T-lymphocytes, IgG(+) and IgM(+) positive cells were found between necrotic and exudative cases. The results show that P. multocida significantly alters the inflammatory response in the lung and that lesions associated with P. multocida display diverse inflammatory responses according to their distinct morphological pattern. PMID- 23683858 TI - Postprandial human triglyceride-rich lipoproteins increase chemoattractant protein secretion in human macrophages. AB - This study tested the hypothesis that postprandial triglyceride-rich lipoproteins (ppTGRL) have inflammatory effects in primary human monocyte-derived macrophages (HMDM). ppTGRL were isolated from normolipidemic human volunteers, and the production of chemokines and of inflammatory prostaglandins and leukotrienes via the arachidonic acid cascade in HMDM was determined, and their effect on monocyte chemotaxis were assessed. In addition, the possible role of extracellular lipases in the inflammatory effects of ppTGRL was evaluated. ppTGRL were found to increase the secretion of chemoattractants, including monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1alpha and -1beta and IL 8, by HMDM and to have a stimulatory effect on monocyte chemotaxis. HMDM secretion of leukotrienes B4 (LTB4) and lipoxin A (LXA4), which are potent activators of monocyte migration, was also stimulated by ppTGRL. Inclusion of the lipoprotein lipase (LPL) inhibitor orlistat did not alter the effects of ppTGRL on chemokine production, and the expression of mRNA for LPL and other secreted lipases was unaffected by the lipoproteins. These findings support the hypothesis that ppTGRL induce the secretion of chemokines by macrophages which promote monocyte recruitment, and that extracellular lipolysis of the particles is not required for these effects and provide further evidence to indicate that the postprandial lipoproteins contribute to a pro-atherogenic pattern after a fat rich meal. PMID- 23683859 TI - A randomized controlled trial of IV immunoglobulin in patients with postpolio syndrome. AB - OBJECTIVE: To investigate in a single-center randomized control trial whether a single IVIg course improves short-term outcome in patients with postpolio syndrome (PPS). METHODS: Fifty-one patients with PPS were randomly allocated to receive 2g/kg IVIg body weight or placebo infused over 5 consecutive days. The primary endpoint was health-related quality of life (HRQoL) limited to the physical component score (PCS) in the Short-Form-36 (SF-36). Secondary endpoints included the SF-36 mental component score (MCS), 6-minute walk test, visual analog scale, 101-numeric rating, and fatigue severity scale. Muscle strength was graded according to the Medical Research Council scale and by dynamometer. Primary and secondary outcome variables were tested double-blind at baseline, 2months, and 4months. RESULTS: At two months, although SF-36 PCS scores were similar in both arms, the role physical (RP) domain improved significantly in the treatment arm (p=0.05) and so did the composite MCS (p=0.015), and role emotional (RE) subscale (p=0.02). No differences were found in the remaining outcome measures. At 4months, none of the outcome variables differed significantly between groups. CONCLUSIONS: Although the study did not reach the primary endpoint, we showed that a single IVIg course improves HRQoL related to mental activity, as measured by the SF-36 composite MCS, and role limitations including RP and RE SF-36 subscales at 2months, in patients with PPS. A single IVIg course leaves, gait, muscle strength, fatigue and bodily pain unchanged in patients with PPS. CLASSIFICATION OF EVIDENCE: Class I evidence indicates that IVIg did not change SF-36 PCS, and Class II evidence indicates that IVIg improved scores on the SF-36 MCS, RP, and RE. PMID- 23683860 TI - Low androstenedione/sex hormone binding globulin ratio increases fracture risk in postmenopausal women. The Women's Health in the Lund Area study. AB - The Women's Health in the Lund Area (WHILA) project (n=6917) is a cohort study that started in 1995 and includes a postal questionnaire, physical examination, bone density measurement and blood laboratory analyses. Fracture data have been added, and in this report fracture risk and its association with sex hormones was analysed in postmenopausal women without current hormone therapy (HT). A total of 409 women (median age 56.8 years) with 489 fractures were identified from the postmenopausal women without HT during a median follow-up time of 8.4 years. Lower serum levels of androstenedione (p<0.001), testosterone (p=0.008), androstenedione/sex hormone binding globulin (SHBG) ratio (p<0.001), testosterone/SHBG ratio (p=0.003) and higher levels of SHBG (p=0.005) were observed in women with fractures compared to no fracture. No difference in oestradiol levels was observed. Androstenedione and androstenedione/SHBG ratio were further divided into percentiles. Increased fracture risk was found in postmenopausal women with androstenedione in 5th percentile compared to 11-89th percentile HR 1.51 (95% CI 1.02-2.24). The androstenedione/SHBG ratio (11-89th percentile as reference) showed increased fracture risk in women with low ratio 5th percentile HR 1.75 (95% CI 1.20-2.54) and decreased fracture risk with high ratio 95th percentile HR 0.52 (95% CI 0.28-0.98). An increased fracture risk during follow-up was encountered in postmenopausal women with low serum androstenedione and androstenedione/SHBG ratio at baseline and a decreased fracture risk with high androstenedione/SHBG ratio. This study suggests that postmenopausal osteoporosis is influenced by lower levels of androgens. PMID- 23683861 TI - An unmatched case controlled study of clinicopathologic abnormalities in dogs with Bartonella infection. AB - We compared clinicopathologic findings in dogs with Bartonella infection to Bartonella spp. negative dogs suspected of a vector-borne disease. Cases (n=47) and controls (n=93) were selected on the basis of positive or negative enrichment culture PCR results, respectively. Signalment, clinicopathologic findings and treatments were extracted from medical records. DNA sequencing identified Bartonella henselae (n=28, 59.6%), Bartonella vinsonii subsp. berkhoffii (n=20, 42.6%), Bartonella koehlerae (n=3, 6.4%), Bartonella volans-like (n=3, 6.4%) and Bartonella bovis (n=1, 2.1%). There were no significant differences in age, breed, size, sex or neuter status between cases and controls. Dogs infected with Bartonella sp. often had a history of weight loss [OR=2.82; 95% CI: 1.08-7.56] and were hypoglobulinemic [OR=4.26; 95% CI: 1.31-14.41]. With the exception of weight loss and hypoglobulinemia, clinicopathologic abnormalities in Bartonella infected dogs in this study were similar to dogs suspected of other vector-borne infections. PMID- 23683862 TI - Role of hake as a source of omega-3 fatty acids in cardiovascular disease prevention. PMID- 23683863 TI - Congenital hand anomalies: a review of the literature, 2009-2012. AB - Research on congenital hand anomalies continues to slowly advance the field via retrospective investigations and surgical technique improvements. This manuscript reviews progress in the field over the last 4 years regarding an assortment of common congenital hand anomalies. We have also highlighted a few key manuscripts regarding upper extremity anomalies. PMID- 23683864 TI - Current pediatric nomograms are only one source of error for quantification in pediatric echocardiography: what to expect from future research. PMID- 23683865 TI - A tool for safety evaluations of road improvements. AB - Road safety impact assessments are requested in general, and the directive on road infrastructure safety management makes them compulsory for Member States of the European Union. However, there is no widely used, science-based safety evaluation tool available. We demonstrate a safety evaluation tool called TARVA. It uses EB safety predictions as the basis for selecting locations for implementing road-safety improvements and provides estimates of safety benefits of selected improvements. Comparing different road accident prediction methods, we demonstrate that the most accurate estimates are produced by EB models, followed by simple accident prediction models, the same average number of accidents for every entity and accident record only. Consequently, advanced model based estimates should be used. Furthermore, we demonstrate regional comparisons that benefit substantially from such tools. Comparisons between districts have revealed significant differences. However, comparisons like these produce useful improvement ideas only after taking into account the differences in road characteristics between areas. Estimates on crash modification factors can be transferred from other countries but their benefit is greatly limited if the number of target accidents is not properly predicted. Our experience suggests that making predictions and evaluations using the same principle and tools will remarkably improve the quality and comparability of safety estimations. PMID- 23683866 TI - [Indications of dexmedetomidine in the current sedoanalgesia tendencies in critical patients]. AB - Recently, dexmedetomidine has been marketed in Spain and other European countries. The published experience regarding its use has placed dexmedetomidine on current trends in sedo-analgesic strategies in the adult critically ill patient. Dexmedetomidine has sedative and analgesic properties, without respiratory depressant effects, inducing a degree of depth of sedation in which the patient can open its eyes to verbal stimulation, obey simple commands and cooperate in nursing care. It is therefore a very useful drug in patients who can be maintained on mechanical ventilation with these levels of sedation avoiding the deleterious effects of over or infrasedation. Because of its effects on alpha2-receptors, it's very useful for the control and prevention of tolerance and withdrawal to other sedatives and psychotropic drugs. The use of dexmedetomidine has been associated with lower incidence of delirium when compared with other sedatives. Moreover, it's a potentially useful drug for sedation of patients in non-invasive ventilation. PMID- 23683867 TI - Cloning of cytochrome P450 3A137 complementary DNA in silver carp and expression induction by ionic liquid. AB - Cytochrome P450 (CYP) enzymes, especially CYP 3A, are responsible for metabolizing of various kinds of endogenous and exogenous compounds in animals. In the present study, a full-length sequence of CYP 3A137 cDNA in silver carp was cloned and sequenced, and then a phylogenetic tree of CYP 3A was structured. Additionally, the acute toxicity of the ionic liquid 1-octyl-3-methylimidazolium bromide ([C8mim]Br) on silver carp and transcription and microsome enzyme activity of CYP 3A137 in the liver of silver fish after rifampicin or [C8mim]Br exposure were also determined in this study. The results show that the full length of CYP 3A137 cDNA is 1810 base pair (bp) long and contains an open reading frame of 1539bp encoding a protein of 513 amino acids. Sequence analysis reveals that CYP 3A137 is highly conserved in fish. Moreover, the results of quantitative real-time polymerase chain reaction reveal that CYP 3A137 in silver carp is constitutively expressed in all tissues examined and the sequence of expression rate is liver>intestine>kidney>spleen>brain>heart>muscle. Finally, the results of acute toxicity tests indicate that both rifampicin and [C8mim]Br significantly up regulate the expression of CYP 3A137 at mRNA level and increase CYP 3A137 enzyme activity in fish liver, suggesting that CYP 3A137 be involved in metabolism of [C8mim]Br in silver carp. PMID- 23683868 TI - Impact of PCB-118 and transformer oil toxicity on anaerobic digestion of sludge: anaerobic toxicity assay results. AB - In this study, possible toxicity of increasing doses of PCB-118 and transformer oil (TO) on anaerobic sludge digestion was investigated. For this purpose, five different sets of reactors were prepared in which four different PCB-118 concentration (1, 10, 20, and 30mgL(-1)) and three different TO concentration (0.38, 0.76, and 1.52gL(-1)) were applied. Throughout the study, biogas production and composition, pH, TS, VS, and COD as well as PCB concentration were monitored. Toxicity was investigated by anaerobic toxicity assay (ATA) evaluating the reduction in methane production. A notable inhibition was observed mostly in 30mgL(-1) PCB reactors. A negative influence of PCB-118 and TO was observed on COD and solids removal. A maximum of 26.5% PCB-118 removal was attained. PMID- 23683869 TI - Endocrine disrupting chemicals in fish bile: a rapid method of analysis using English sole (Parophrys vetulus) from Puget Sound, WA, USA. AB - This study describes a recently developed and rapid method to measure bisphenol A (BPA), 17beta-estradiol (E2) and 17alpha-ethynylestradiol (EE2) in bile of fish using enzymatic hydrolysis of samples followed by solid-phase extraction and ultra-performance liquid chromatography with tandem mass spectrometry. The limits of quantitation (LOQ) for BPA, EE2 and E2 were 6.3ngmL(-1), 12.5ngmL(-1) and 6.3ngmL(-1), respectively. These compounds were analyzed in bile of male English sole (Parophrys vetulus) collected from urban and non-urban sites in Puget Sound, WA, USA. The BPA and E2 concentrations (and occurrence) ranged from 0.997. Intra-day and inter-day repeatability values expressed as relative standard deviation were 1.9% and 5.9%, respectively. The quantitation limit and detection limit were 6.3 and 2.5 ng g(-1). The target analyte was detected in 5 out of 16 edible oil samples. The recovery rates in real samples ranged from 89.5 to 99.7%. PMID- 23683893 TI - Determination of adsorbable organic fluorine from aqueous environmental samples by adsorption to polystyrene-divinylbenzene based activated carbon and combustion ion chromatography. AB - A new method for the determination of trace levels of adsorbable organic fluorine (AOF) in water is presented. Even if the individual contributing target compounds are widely unknown, this surrogate parameter is suited to identify typical organofluorine contaminations, such as with polyfluorinated chemicals (PFCs), and represents a lower boundary of the organofluorine concentration in water bodies. It consists of the adsorption of organofluorine chemicals on a commercially available synthetic polystyrene-divinylbenzene based activated carbon (AC) followed by analysis of the loaded AC by hydropyrolysis combustion ion chromatography (CIC). Inorganic fluorine is displaced by excess nitrate during the extraction step and by washing the loaded activated carbon with an acidic sodium nitrate solution. Due to its high purity the synthetic AC had a very low and reproducible fluorine blank (0.3 MUg/g) compared to natural ACs (up to approximately 9 MUg/g). Using this AC, fluoride and the internal standard phosphate could be detected free of chromatographic interferences. With a sample volume of 100 mL and 2* 100 mg of AC packed into two extraction columns combined in series, a limit of quantification (LOQ), derived according to the German standard method DIN 32645, of 0.3 MUg/L was achieved. The recoveries of six model PFCs were determined from tap water and a municipal wastewater treatment plant (WWTP) effluent. Except for the extremely polar perfluoroacetic acid (recovery of approximately 10%) the model substances showed fairly good (50% for perfluorobutanoic acid (PFBA)) to very good fluorine recoveries (100+/-20% for perfluorooctanoic acid (PFOA), perfluorobutanesulfonate (PFBS), 6:2 fluorotelomersulfonate (6:2 FTS)), both from tap water and wastewater matrix. This new analytical protocol was exemplarily applied to several surface water and groundwater samples. The obtained AOF values were compared to the fluorine content of 19 target PFCs analyzed by high performance liquid chromatography electrospray tandem mass spectrometry (HPLC-(-)ESI-MS/MS). In groundwater contaminated by PFC-containing aqueous film-forming foams (AFFFs) up to 50% of the AOF could be attributed to PFC target chemicals, while in diffuse contaminated samples only <5% of the AOF could be identified by PFC analysis. PMID- 23683894 TI - A preliminary identification and determination of characteristic volatile organic compounds from cotton, polyester and terry-towel by headspace solid phase microextraction gas chromatography-mass spectrometry. AB - Analysis of fifteen volatile organic compounds previously associated with laundry malodour has been investigated using headspace solid phase microextraction gas chromatography-mass spectrometry. Limits of detection (all determined on a 25 cm(2) area of fabric) ranged from a low of 0.4 ng (for guaiacol) through to a high of 28 ng (for 3-methylindole) on cotton; values on polyester ranged from a low of 0.7 ng (for dimethyl trisulfide) through to a high of 37 ng (for 3 methylindole); and, values on terry-towel ranged from a low of 1.7 ng (for guaiacol) through to a high of 157 ng (for ethyl benzene). There was a lack of correlation between the level of malodour and the occurrence of any of the VOCs detected; it could be that other compounds not evaluated in this study are responsible for malodour or it could be a collaborative effect of the various compounds studied. PMID- 23683895 TI - Enantioseparations of amino acids by capillary array electrophoresis with 532 nm laser induced fluorescence detection. AB - Capillary array electrophoresis (CAE) is a promising technique for multiple enantiomeric separations. Carboxytetramethylrhodamine succinimidyl ester (TAMRA SE), a rhodamine-core fluorescent probe, has rarely been applied as an original precolumn derivatization reagent for chiral amino acid (AA) analysis so far. For these purposes, high-throughput enantiomeric separations of 12 TAMRA SE-AAs by a home-made 532 nm CAE-LIF scanner are presented. The effect of cyclodextrins (CDs) and a variety of organic modifiers was quickly investigated. Baseline separations were achieved in 100 mM Tris-borate buffer (pH 10.0) containing 2 mM beta-CD and 10 mM hexamethylenediamine (HDA). Multiple determination of the enantiomeric excess (ee) in non-racemic mixtures of alanine is successfully presented. PMID- 23683896 TI - Tell me more: roles of NPRs in plant immunity. AB - Plants and animals maintain evolutionarily conserved innate immune systems that give rise to durable resistances. Systemic acquired resistance (SAR) confers plant-wide immunity towards a broad spectrum of pathogens. Numerous studies have revealed that NON-EXPRESSOR OF PATHOGENESIS-RELATED GENES 1 (NPR) is a key regulator of SAR. Here, we review the mechanisms of NPR1 action in concert with its paralogues NPR3 and NPR4 and other SAR players. We provide insights into the mechanisms of salicylic acid (SA) perception. We discuss the binding of NPR3 and NPR4 with SA that modulates NPR1 coactivator capacity, leading to diverse immune outputs. Finally, we highlight the function of NPR1 as a bona fide SA receptor and propose a possible model of SA perception in planta. PMID- 23683899 TI - Biochemical and physiological responses in Caenorhabditis elegans exposed to sublethal concentrations of the organophosphorus insecticide, monocrotophos. AB - The objective of this study was to investigate the impact of sublethal concentrations of MCP on definitive markers of toxicity and oxidative balance in the nematode, Caenorhabditis elegans. Exposure of worms to 0.85, 1.7 and 3.4mM (1/40, 1/20 and 1/10 LC50; LC50=34 mM) for 4h at 20 degrees C induced significant perturbations in physiological parameters such as decreased brood size (47-73%), increased paralysis (47-85%) and inhibition of the activities of acetylcholinesterase (75-86%) and carboxylesterase (76-81%). These changes were accompanied by distinct oxidative impairments as evidenced by increased reactive oxygen species, decline in glutathione content and decrease in superoxide dismutase activity. Our results clearly demonstrate that low concentrations of MCP may alter the physiological and biochemical status in the nematode, thereby affecting the organism's fitness. Our findings on C. elegans provide an easy diagnosis for OPI contamination and may become helpful in evaluating the ecotoxicological effects of OPI in the aquatic environment near agricultural fields. PMID- 23683897 TI - Changes in CD34+ cell count in peripheral blood after whole blood donation. AB - AIM: We aimed to investigate the change in the number of stem cells and white cells in the early period following blood donation. PATIENTS AND METHOD: 22 male (71%) and 9 female (29%), 31 volunteers in total were included in the study. 450 ml of whole blood were collected from each of the volunteers for the donation. Complete blood counts were performed on the volunteers before and at 6 and 24h after the donation and CD34+ cell counts per ml of peripheral blood were measured by flow cytometry technique. RESULTS: There was a statistically significant increase in the number of CD34+ cells in the peripheral blood at 6h following blood donation (p<0.001). At 24h, however, there was a statistically significant decrease in the number of CD34+ cells, compared to 6h (p<0.001). There was a statistically significant increase in the number of leukocytes in the peripheral blood at 6h following blood donation (p<0.001). At 24h, there was a decrease in the number of leukocytes, which was statistically significant compared to 6h (p<0.001). When the difference in CD34+ cell and leukocytes counts before blood donation and at 24h after blood donation were compared, the results were not statistically significant. CONCLUSION: As the result of this study, a transient increase in the number of CD34+ cells in the peripheral blood after blood donation was demonstrated, with a decline in CD34+ cell counts back to levels prior to donation at 24h. PMID- 23683900 TI - Historical contamination and ecological risk of organochlorine pesticides in sediment core in northeastern Chinese river. AB - Twenty-eight surface sediment samples and one sediment core were analyzed for 21 organochlorine pesticides (OCPs), in order to provide extensive information of distribution, sources, pollution history and ecological risk of these OCP compounds in Daling River area, China. The results showed that hexachlorocyclohexanes (HCHs) and dichlorodiphenyltrichloroethanes (DDTs) were the most frequently detected contaminants in the surface sediment samples with concentrations (in ngg(-1) dry weight (dw)) from 1.1 to 30 and from 2.2 to 45, respectively. Analysis of variance showed significant (P<0.05) differences between HCHs and DDTs residues in surface sediment sampled from the various locations. Residues of HCHs and DDTs in sediment core (in ngg(-1)dw) ranged from 2.1 to 18 and 9.1 to 53, respectively. The temporal trends of HCHs and DDTs concentrations in the sediment core were affected by application history, emission and soil residues. Compositional analysis of HCHs and DDTs indicated that new sources were lindane and dicofol mainly due to agricultural activities. Additionally, based on the available sediment quality guidelines, slight potential health risks of DDTs may exist to benthic organisms in Daling River and Bohai Sea. PMID- 23683901 TI - Dysfunctional co-expression network analysis of familial hypercholesterolemia. AB - Familial hypercholesterolemia (FH) is an inherited disorder of blood lipid metabolism characterized by high serum low-density lipoprotein cholesterol levels and premature coronary artery disease. In this study, we used a system biology approach to identify co-expressed gene pairs that were potentially involved in the progression of FH and constructed a conserved co-expression network using these genes. A total of 4232 co-expressed relationships were identified and we verified the significance by random permutation. FH patients showed differences in lipoprotein and cholesterol metabolism in circulating monocytes and lymphocytes compared to healthy controls. We hope our study could aid in understanding of FH and could provide the basis for FH biomarker identification. PMID- 23683902 TI - Gas chromatography-mass spectrometry of JWH-018 metabolites in urine samples with direct comparison to analytical standards. AB - JWH-018 (1-pentyl-3-(1-naphthoyl)indole) is one of numerous potential aminoalkylindoles contained in products marketed as 'K2' or 'Spice'. Investigation of the urinary metabolites from consumption of these compounds is important because they are banned in the United States and many European countries. An efficient extraction procedure and gas chromatography-mass spectrometry (GC-MS) method were developed for detection of 'K2' metabolites in urine from individuals suspected of using these products. Analytical standards were used to elucidate the structure-specific mass spectral fragmentations and retention properties to confirm proposed identifications and support quantitative studies. A procedure for the synthesis of one of these metabolites (5 hydroxypentyl JWH-018) was also developed. Results are comparable to existing LC MS/MS methods, with the same primary metabolites detected. The specific metabolite hydrolysis products include 4-hydroxpentyl, 5-hydroxypentyl, and N pentanoic acid derivatives. PMID- 23683903 TI - Geographic diversity of Helicobacter pylori in cadavers: forensic estimation of geographical origin. AB - A method for determining the geographical origin of unidentified cadavers by determining the genotype of Helicobacter pylori, which is latent in one-half of the world's population, was developed. In the first stage, DNA was extracted from samplings at 5 points in the gastric mucosa of 177 individuals randomly selected from cadavers undergoing medico-legal autopsy. 16S-rDNA of H. pylori DNA was detected by polymerase chain reaction (PCR) in 101 cadavers (57.0%); by sex, 74 of 123 (60.1%) males and 28 of 54 (46.4%) females were positive. There were no significant differences in H. pylori detection rate among the 5 sampling points of the gastric mucosa, cause of death, or age. In the second stage, amplified fragments of H. pylori vacA regions s and m from 17 individuals with the following ethnic backgrounds were sequenced: Japanese, 10; Chinese, 2; South Korean, 1; Taiwanese, 1; Thai, 1; Afghan, 1; and Filipino, 1. A phylogenetic tree constructed with these and 28 previously reported H. pylori strain sequences revealed 3 major gene clusters consisting of East Asian type I (Japanese, South Korean and Chinese), Western type II, and Southeast Asia type III. The Taiwanese and Filipino samples deviated from the clusters type III to which they typically belong. The ultimate aim of the present study was to develop a more accurate method of determining of geographic origin of unidentified cadavers through the combination of the present method with other, virus-based methods H. pylori DNA was detected from over half of the cadavers tested and vacA genotypes showed specificity to geographical origin. Therefore, these results suggest that the H. pylori genome provides valuable additional information for tracing the geographical origin of unidentified cadavers. PMID- 23683904 TI - Profiling counterfeit Cialis, Viagra and analogs by UPLC-MS. AB - In this work, the chemical profile of 43 commercial samples of tablets for male erectile dysfunction (Viagra, Cialis, Lazar, Libiden, Maxfil, Plenovit, Potent 75, Rigix, Vimax, Pramil 75 and Pramil) and 65 counterfeit samples (Viagra and Cialis) were obtained from UPLC-MS data. Methanol extracts of crushed tablets were investigated by ultra performance liquid chromatography (UPLC) with diode array detection (DAD) coupled with eletrospray ionization in the positive ion mode (ESI(+)) quadrupole time-of-flight (Q-Tof) mass spectrometry (MS). A validated method was employed for the simultaneous determination of sildenafil citrate (SLD) and tadalafil (TAD). The ultra-chromatograms obtained with method provide high resolution of MS, and are a quick (less to 1.5 min) and reliable tool in the distinction between authentic and counterfeit tablets. It was observed in most cases the presence of other active pharmaceutical ingredients (APIs) than specified on the package (TAD and SLD). Additionally, high concentrations of TAD and SLD were detected in counterfeit samples when compare with observed values for a typical commercial product. Chemometric methods were employed and the samples were grouped in five groups as function of API content. PMID- 23683905 TI - Trends in counterfeits amphetamine-type stimulants after its prohibition in Brazil. AB - Brazil is one of the world's highest users of anorectic drugs, mainly diethylpropione, fenproporex and sibutramine. The present work focuses on physical and chemical characteristics of 17 counterfeited capsules containing amphetamine-type stimulants (ATS) from three seizures conducted by Brazilian Federal Police. The physical profile was useful in indicating forgery, bring complementary information, but the use of this data singly was not sufficient to distinguish between authentic and counterfeited medicines. The chemical analysis revealed that the seizures capsules labeled as Desobesi-M (fenproporex 25mg), actually contained the active pharmaceutical ingrediente (API) sibutramine. The amount of this API ranged from 1/3 to 2 times the amount of drug found in commercial product, may reach twice the recommended daily dose. Multivariate analysis with application of principal component analysis on data from spectroscopy attenuated total reflectance Fourier transform infrared classified the samples according to their similarities, indicating that two seizures had common origin. This study represents the first step in the elucidation of falsification of ATS in Brazil. Considering the forensic intelligence these information are valuable in order to develop and establish a database that enables correlate samples from different locations and/or suppliers and to map the profile and trends of trafficking. PMID- 23683906 TI - Cartridge case image matching using effective correlation area based method. AB - A firearm leaves a unique impression on fired cartridge cases. The cross correlation function plays an important role in matching the characteristic features on the cartridge case found at the crime scene with a specific firearm, for accurate firearm identification. This paper proposes that the computational forensic techniques of alignment and effective correlation area-based approaches to image matching are essential to firearm identification. Specifically, the reference and the corresponding cartridge cases are aligned according to the phase-correlation criterion on the transform domain. The informative segments of the breech face marks are identified by a cross-covariance coefficient using the coefficient value in a window located locally in the image space. The segments are then passed to the measurement of edge density for computing effective correlation areas. Experimental results on a new dataset show that the correlation system can make use of the best properties of alignment and effective correlation area-based approaches, and can attain significant improvement of image-correlation results, compared with the traditional image-matching methods for firearm identification, which employ cartridge-case samples. An analysis of image-alignment score matrices suggests that all translation and scaling parameters are estimated correctly, and contribute to the successful extraction of effective correlation areas. It was found that the proposed method has a high discriminant power, compared with the conventional correlator. This paper advocates that this method will enable forensic science to compile a large-scale image database to perform correlation of cartridge case bases, in order to identify firearms that involve pairwise alignments and comparisons. PMID- 23683907 TI - Finite element analysis of pedestrian lower limb fractures by direct force: the result of being run over or impact? AB - The elucidation and prediction of the biomechanics of lower limb fractures could serve as a useful tool in forensic practices. Finite element (FE) analysis could potentially help in the understanding of the fracture mechanisms of lower limb fractures frequently caused by car-pedestrian accidents. Our aim was (1) to develop and validate a FE model of the human lower limb, (2) to assess the biomechanics of specific injuries concerning run-over and impact loading conditions, and (3) to reconstruct one real car-pedestrian collision case using the model created in this study. We developed a novel lower limb FE model and simulated three different loading scenarios. The geometry of the model was reconstructed using Mimics 13.0 based on computed tomography (CT) scans from an actual traffic accident. The material properties were based upon a synthesis of data found in published literature. The FE model validation and injury reconstruction were conducted using the LS-DYNA code. The FE model was validated by a comparison of the simulation results of three-point bending, overall lateral impact tests and published postmortem human surrogate (PMHS) results. Simulated loading scenarios of running-over the thigh with a wheel, the impact on the upper leg, and impact on the lower thigh were conducted with velocities of 10 m/s, 20 m/s, and 40 m/s, respectively. We compared the injuries resulting from one actual case with the simulated results in order to explore the possible fracture bio mechanism. The peak fracture forces, maximum bending moments, and energy lost ratio exhibited no significant differences between the FE simulations and the literature data. Under simulated run-over conditions, the segmental fracture pattern was formed and the femur fracture patterns and mechanisms were consistent with the actual injury features of the case. Our study demonstrated that this simulation method could potentially be effective in identifying forensic cases and exploring of the injury mechanisms of lower limb fractures encountered due to inflicted lesions. This model can also help to distinguish between possible and impossible scenarios. PMID- 23683908 TI - Oral intercourse or secondary transfer? A Bayesian approach of salivary amylase and foreign DNA findings. AB - The Bayesian Approach allows forensic scientists to evaluate the significance of scientific evidence in light of two conflicting hypothesis. This aids the investigator to calculate a numerical value of the probability that the scientific findings support one hypothesis over conflicting opinions. In the case where oral intercourse is alleged, alpha-amylase, an indicator of saliva, is detected on penile swabs. The value of this finding is unknown as it may indicate the presence of saliva resulting from oral intercourse however it may also represent the presence of saliva due to innocent means such as background levels of salivary-alpha-amylase in the male population due to secondary transfer. Therefore, it is difficult to attach significance to this finding without background information and knowledge. A population study of the background levels of salivary-alpha-amylase was performed by analysing items of underwear worn under normal circumstances by 69 male volunteers. The Phadebas press test was used to screen the garments for amylase-containing stains and the positive areas were subjected to further confirmation of saliva by the RSID-Saliva kit. 44% of underwear screened had stains containing amylase. This study determined the background level of salivary-alpha-amylase and DNA on the inside front of male underwear which has potential implications on the interpretation of evidence in alleged oral intercourse. PMID- 23683909 TI - Glucocorticosteroids as markers of death from hypothermia. AB - In the course of hypothermia, biochemical changes occur that are associated with stimulation of protective thermogenic mechanisms as well as mobilization of internal energy resources mediated by the hormone system. The objective of the investigation was the assessment of validity of determinations of cortisol, cortisone and corticosterone as hypothermia markers in cases of fatal hypothermia combined with concomitant insobriety of the victims. The experimental group consisted of blood samples collected in the course of medico-legal autopsies of 23 hypothermia victims. The controls included blood samples originating from 34 victims of violent sudden deaths (deaths by hanging and traffic road accidents at the scene) and from ten individuals deceased after prolonged agony in consequence of post-traumatic subdural hematomas. In both groups, three subgroups were distinguished that included cases with ethanol levels within the following ranges: 0.0-0.99, 1.0-2.99 and >=3.00/00. The comparison of determination results showed that irrespectively of blood ethanol concentration, cortisol, cortisone and corticosterone levels seen in hypothermia victims were significantly higher as compared to the controls (P<0.001). PMID- 23683910 TI - Experimental and theoretical studies of the spreading of bloodstains on painted surfaces. AB - The spreading of bloodstains on matt, vinyl silk and gloss painted surfaces, following both perpendicular and non-perpendicular impact, has been studied with a view to understanding whether surface-specific properties affect the size and shape of the final stain. In all cases the dimensions of the stains on the rougher, matt paint are up to 5% less than on the other painted surfaces though this difference decreases with impact velocity. Both the diameter of circular stains and the width of elliptical stains have been successfully modelled as a function of the perpendicular component of impact velocity vn using a modification of the energy conservation approach through the inclusion of a single, empirical constant characteristic of the surface itself. By further development of this theory, the characteristic dynamical length parameter which governs the spreading has been modified to be dependent on angle thus enabling the length of elliptical stains to be predicted independently for the first time. For all these surfaces, experiment shows that the impact angles, calculated using the conventional trigonometric formula, are in deficit by around 1 degrees at high vn increasing to around 5 degrees at lower vn. By modelling this deficit independently using the theoretical expressions for stain width and length, this variation with vn has been successfully explained. This work has demonstrated some of the fundamental systematic sources of error in using the conventional formula for interpreting elliptical stains and established some of the basic theory on which to develop the interpretation of casework stains on surfaces, in the future. PMID- 23683912 TI - Survey on batch-to-batch variation in spray paints: a collaborative study. AB - This study represents the most extensive analysis of batch-to-batch variations in spray paint samples to date. The survey was performed as a collaborative project of the ENFSI (European Network of Forensic Science Institutes) Paint and Glass Working Group (EPG) and involved 11 laboratories. Several studies have already shown that paint samples of similar color but from different manufacturers can usually be differentiated using an appropriate analytical sequence. The discrimination of paints from the same manufacturer and color (batch-to-batch variations) is of great interest and these data are seldom found in the literature. This survey concerns the analysis of batches from different color groups (white, papaya (special shade of orange), red and black) with a wide range of analytical techniques and leads to the following conclusions. Colored batch samples are more likely to be differentiated since their pigment composition is more complex (pigment mixtures, added pigments) and therefore subject to variations. These variations may occur during the paint production but may also occur when checking the paint shade in quality control processes. For these samples, techniques aimed at color/pigment(s) characterization (optical microscopy, microspectrophotometry (MSP), Raman spectroscopy) provide better discrimination than techniques aimed at the organic (binder) or inorganic composition (fourier transform infrared spectroscopy (FTIR) or elemental analysis (SEM - scanning electron microscopy and XRF - X-ray fluorescence)). White samples contain mainly titanium dioxide as a pigment and the main differentiation is based on the binder composition (CH stretches) detected either by FTIR or Raman. The inorganic composition (elemental analysis) also provides some discrimination. Black samples contain mainly carbon black as a pigment and are problematic with most of the spectroscopic techniques. In this case, pyrolysis-GC/MS represents the best technique to detect differences. Globally, Py-GC/MS may show a high potential of discrimination on all samples but the results are highly dependent on the specific instrumental conditions used. Finally, the discrimination of samples when data was interpreted visually as compared to statistically using principal component analysis (PCA) yielded very similar results. PCA increases sensitivity and could perform better on specific samples, but one first has to ensure that all non-informative variation (baseline deviation) is eliminated by applying correct pre-treatments. Statistical treatments can be used on a large data set and, when combined with an expert's opinion, will provide more objective criteria for decision making. PMID- 23683911 TI - Evaluation of DFO/PVP and its application to latent fingermarks development on thermal paper. AB - A new method for improved development of latent fingermarks on thermal paper by 1,8-diazafluoren-9-one (DFO) treatment is described. Compared with conventional DFO solution, the mixed solution of DFO/PVP (polyvinylpyrrolidone) described here reduces black background staining without removing the thermosensitive layer and develops fingermarks by the reaction of DFO with amino acid deposited on the thermal paper's surface. An advantage of this approach is that the developed fluorescent fingermarks have high contrast and can be observed and photographed when excited in the 515 nm region and observed through an orange-red barrier long pass filter with no background coloration. In addition, the method reported here does not involve any pre- or post treatment of the substrate and exhibits high sensitivity with good stability. Experimental results showed that the method was able to develop very old fingermarks, up to 154 days old, demonstrating the feasibility of using the method to develop identifiable latent fingermarks operationally. Furthermore, we extended our experiments to various types of thermal papers. Notably, this method exhibits several very attractive features, namely time saving, simple procedures, inexpensive, convenient operation, and PVP is non-toxic and reasonably priced. Finally, in this study an attempt has been made to explain the reaction mechanism of the process and the effects of PVP. PMID- 23683913 TI - Temperature-dependent appearance of forensically useful beetles on carcasses. AB - Estimating the pre-appearance interval (PAI) of carrion insects from temperature is a new and promising improvement of entomological methods for post-mortem interval estimation. In order to use this approach in casework, a taxon should demonstrate a close relationship between PAI and temperature. In this article we test this relationship in selected species of beetles, namely Thanatophilus sinuatus Fabr., T. rugosus L., Necrodes littoralis L. (Silphidae), Necrobia rufipes De Geer, N. violacea L. (Cleridae), Dermestes frischii Kug. (Dermestidae), Creophilus maxillosus L., Philonthus politus L., Ontholestes murinus L. (Staphylinidae), Saprinus semistriatus Scriba, S. planiusculus Motch. and Margarinotus brunneus Fabr. (Histeridae). Data were collected from 30 pig carcasses decomposing under different temperature conditions in open and forest habitats of Western Poland. Beetles were sampled with pitfall traps and with manual and soil sampling. The on-site temperature of the ground level was recorded. The relationship was tested separately in adult and larval stages. All species, except for D. frischii, revealed significant relationship between PAI and temperature. In all cases PAI was found to decrease exponentially with an increase in temperature. Moreover, above some temperature it was nearly constant. The relationship was strong in the case of adult and larval N. littoralis, adult N. rufipes, adult and larval C. maxillosus, adult P. politus, S. semistriatus and S. planiusculus. The relationship of moderate strength was found for adult and larval T. sinuatus, adult N. violacea and adult M. brunneus. In the case of adult T. rugosus and O. murinus the relationship was weak. Current results demonstrate that there are solid premises for estimating PAI from temperature in T. sinuatus, N. littoralis, N. rufipes, N. violacea, C. maxillosus, P. politus, S. semistriatus, S. planiusculus and M. brunneus. Implications for forensic entomology are discussed. PMID- 23683914 TI - Abiotic environmental factors influencing blowfly colonisation patterns in the field. AB - The accuracy of minimum post-mortem interval (mPMI) estimates usually hinges upon the ability of forensic entomologists to predict the conditions under which calliphorids will colonise bodies. However, there can be delays between death and colonisation due to poorly understood abiotic and biotic factors, hence the need for a mPMI. To quantify the importance of various meteorological and light-level factors, beef liver baits were placed in the field (Victoria, Australia) on 88 randomly selected days over 3 years in all seasons and observed every 60-90 min for evidence of colonisation. Baits were exposed during daylight, and the following parameters were measured: barometric pressure, light intensity, wind speed, ambient temperature, relative humidity and rainfall. Collected data were analysed using backward LR logistic regression to produce an equation of colonisation probability. This type of analysis removes factors with the least influence on colonisation in successive steps until all remaining variables significantly increase the accuracy of predicting colonisation presence or absence. Ambient temperature was a positive predictor variable (an increase in temperature increased the probability of calliphorid colonisation). Relative humidity was a negative predictor variable (an increase in humidity decreased the probability of calliphorid colonisation). Barometric pressure, light intensity, wind speed and rainfall did not enhance the accuracy of the probability model; however, analysis of species activity patterns suggests that heavy rainfall and strong wind speeds inhibit calliphorid colonisation. PMID- 23683915 TI - Forensic profiling of sassafras oils based on comprehensive two-dimensional gas chromatography. AB - Safrole, the main compound in the essential oil of several plants of the Laurel family (Lauraceae), and its secondary product piperonylmethylketone are the predominantly used precursors for the illicit synthesis of 3,4 methylenedioxymethamphetamine (MDMA) which is, in turn, the most common active ingredient in Ecstasy tablets. Analytical methods with adequate capacity to identify links and origin of precursors, such as safrole, provide valuable information for drug-related police intelligence. Authentic sassafras oil samples from police seizures were subjected to comparative analysis based on their chemical profiles obtained by comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry (GC * GC-TOFMS). The enhanced separation power and increased sensitivity of GC * GC allowed for the detection of minor compounds present in the essential oils which were of particular interest in case of very pure samples whose impurity profiles were not very pronounced. Discrimination of such samples was still possible even in the absence of characteristic main compounds. PMID- 23683916 TI - An accurate method for microanalysis of carbon monoxide in putrid postmortem blood by head-space gas chromatography-mass spectrometry (HS/GC/MS). AB - Carbon monoxide (CO) may be the cause of more than half the fatal poisonings reported in many countries, with some of these cases under-reported or misdiagnosed by medical professionals. Therefore, an accurate and reliable analytical method to measure blood carboxyhemoglobin level (COHb%), in the 1% to lethal range, is essential for correct diagnosis. Herein a method was established, i.e. head-space gas chromatography-mass spectrometry (HS/GC/MS) that has numerous advantages over other techniques, such as UV spectrometry, for determination of COHb%. There was a linear relationship (R(2)=0. 9995) between the peak area for CO and the COHb% in blood. Using a molecular sieve-packed column, CO levels in the air down to 0.01% and COHb% levels in small blood samples down to 0.2% could be quantitated rapidly and accurately. Furthermore, this method showed good reproducibility with a relative standard deviation for COHb% of <1%. Therefore, this technique provides an accurate and reliable method for determining CO and COHb% levels and may prove useful for investigation of deaths potentially related to CO exposure. PMID- 23683917 TI - Genetic analysis of sudden unexplained death: a multidisciplinary approach. AB - Each year infants, children and young adults die suddenly and unexpectedly. In many cases the cause of death can be elucidated by medico-legal autopsy, however, a significant number of these cases remain unexplained despite a detailed postmortem investigation and are labeled as sudden unexplained death (SUD). Post mortem genetic testing, so called molecular autopsy, revealed that primary arrhythmogenic disorders including long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT) may account for a certain number of these cases. Because of the inheritance of these diseases, close relatives of the deceased may also at potential risk of carrying fatal cardiac disorders. Therefore, advanced diagnostic analyses, genetic counseling and interdisciplinary collaboration should be integral parts of clinical and forensic practice. In the present study, we performed mutation analyses of the major genes causing cardiac channelopathies in 15 SUD cases. In four cases we found putative pathogenic mutations in cardiac ion channel genes. Clinical and genetic examination of family members of SUD victims was also performed and affected family members were identified. This study demonstrates that molecular genetic screening needs to become an inherent part of the postmortem examination. This will enhance the ability of screening family members of SUD victims who may be at risk. The present data also illustrate that detection and follow up of familial cases of sudden death is challenging and requires a close multidisciplinary collaboration between different medical disciplines, with great responsibility for the forensic pathologist. PMID- 23683918 TI - Can fatty acid and mineral compositions of sturgeon eggs distinguish between farm raised versus wild white (Acipenser transmontanus) sturgeon origins in California? Preliminary report. AB - The objective was to investigate the potential of using fatty acid and mineral compositions of sturgeon eggs to distinguish their source, either farm-raised or wild fish. Trafficking of illegally obtained wild white sturgeon eggs is a major concern to the California Department of Fish and Game, but there is no forensic method to separate wild and farm-raised white sturgeon eggs. The extension of these findings in future work will be to use the fatty acid and mineral compositions as forensic indicators of caviar produced legally from farm raised sturgeon compared with illegal caviar produced from sturgeon poached from the wild. Samples (10) of sturgeon eggs were collected from a commercial aquaculture facility in the Sacramento Valley. Eggs from wild sturgeon (9) were obtained primarily from confiscations of illegally caught sturgeon by fish and game law enforcement personnel. The total lipid content of sturgeon eggs was analyzed for fatty acid composition. The most notable difference was the higher concentration (P<0.001) of C18:2n6 in farm raised eggs (6.5 mg/100g total lipid) than wild eggs (0.6 mg/100g total lipid) while other differences between fatty acids were smaller. Eicosapentaenoic acid (C20:5n3) was higher (P<0.02) in farm-raised (5.56 mg/100g) than wild (4.49 mg/100g). Docosahexaenoic acid (C22:6n3), C18:1 cis 9&10, and C20:4n6 were not different for origin of the eggs. Concentration of selenium was markedly higher (P<0.001) in eggs from wild sturgeon (10.0 mg/kg dry weight) than farm-raised sturgeon (2.7 mg/kg dry weight). Concentrations of iron, zinc, copper, phosphorus, sulfur, calcium, and potassium did not differ between farm-raised and wild eggs. Arsenic concentration in wild eggs was 3.3mg/kg dry weight whereas arsenic was not detected in the farm-raised eggs. Fatty acid and mineral compositions of eggs differed significantly between farm-raised and wild sturgeon and these should be investigated further as biological markers for forensic identification of caviar origin. PMID- 23683919 TI - Perspectives for Forensic Intelligence in anti-doping: thinking outside of the box. AB - Today's approach to anti-doping is mostly centered on the judicial process, despite pursuing a further goal in the detection, reduction, solving and/or prevention of doping. Similarly to decision-making in the area of law enforcement feeding on Forensic Intelligence, anti-doping might significantly benefit from a more extensive gathering of knowledge. Forensic Intelligence might bring a broader logical dimension to the interpretation of data on doping activities for a more future-oriented and comprehensive approach instead of the traditional case based and reactive process. Information coming from a variety of sources related to doping, whether directly or potentially, would feed an organized memory to provide real time intelligence on the size, seriousness and evolution of the phenomenon. Due to the complexity of doping, integrating analytical chemical results and longitudinal monitoring of biomarkers with physiological, epidemiological, sociological or circumstantial information might provide a logical framework enabling fit for purpose decision-making. Therefore, Anti Doping Intelligence might prove efficient at providing a more proactive response to any potential or emerging doping phenomenon or to address existing problems with innovative actions or/and policies. This approach might prove useful to detect, neutralize, disrupt and/or prevent organized doping or the trafficking of doping agents, as well as helping to refine the targeting of athletes or teams. In addition, such an intelligence-led methodology would serve to address doping offenses in the absence of adverse analytical chemical evidence. PMID- 23683920 TI - Prevalence of Oculo-auriculo-vertebral Spectrum in Dermolipoma. AB - OBJECTIVE: To describe the observed frequency of oculo-auriculo-vertebral spectrum (OAVS) in patients with dermolipoma. DESIGN: Retrospective case series. PARTICIPANTS: Patients with primary presentation of ocular dermolipoma. METHODS: All patients with ocular dermolipoma or lipodermoid were identified from the authors' clinical databases from 1990 to 2011 inclusive. Case notes were reviewed retrospectively for the gender and age of presentation, the laterality of dermolipoma, and features of OAVS. MAIN OUTCOME MEASURES: The frequency of OAVS in patients with dermolipoma, the severity of the OAVS phenotype, and other concurrent ophthalmic features observed. RESULTS: Thirty-four patients (24 females) presented with dermolipoma at ages ranging from 6 months to 57 years (mean, 20 years; median, 16 years). Twelve patients (35.5%) had features of OAVS (10 patients with dermolipoma had ipsilateral OAVS and 2 patients had contralateral features of OAVS). Ten patients with dermolipoma had hemifacial microsomia, and 2 patients had features of Goldenhar's syndrome. None of the patients had bilateral dermolipoma and OAVS. Other associated ophthalmic features were limbal dermoids (2 cases), lateral canthal coloboma (3 cases), and facial nerve palsy (1 case). CONCLUSIONS: Dermolipoma is an independent ocular association of OAVS that is more commonly observed than previously reported. It is an ocular feature in both the milder and more complex forms of the spectrum. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article. PMID- 23683921 TI - Choroidal thickness measurement in myopic eyes by enhanced depth optical coherence tomography. AB - PURPOSE: To measure choroidal thickness (CT) in myopic eyes using enhanced depth imaging (EDI). DESIGN: A cross-sectional study. PARTICIPANTS: Fifty-six consecutive patients with spherical equivalent refractive error of at least 6 diopters (D) were evaluated. METHODS: Enhanced depth imaging optical coherence tomography (OCT) images were obtained by positioning the spectral-domain OCT device close enough to the eye to acquire an enhanced signal of the choroidal layer. Choroidal depth was measured as the distance between the outer reflective retinal pigment epithelium (RPE) layer and the inner sclera border. Measurements were made in a horizontal fashion across the fovea at 500-MUm intervals of the sections. The CT was measured at the subfoveal region in a horizontal fashion, 3 mm temporal to fovea and 3 mm nasal to fovea. MAIN OUTCOME MEASURES: Correlations among CT with age, refractive error in diopters, and visual acuity in logarithm of the minimum angle of resolution (logMAR) were analyzed with linear mixed models. RESULTS: The mean age of the 56 patients was 50.4 years (+/- 2.03 years standard deviation; interquartile range [IQR], 42-62 years), and the mean refractive error was -8.7 D (IQR, -6.1 to -11 D). The mean subfoveal CT was 118 MUm (+/- 68 MUm) and correlated negatively with age (P = 0.032) and refractive error (P = 0.011). Regression analysis suggested that subfoveal CT decreased by 11.9 MUm for each decade of life and by 6.205 MUm for each diopter of myopia. The subfoveal CT was inversely correlated with the logMAR visual acuity (P = 0.008), and visual acuity improved by 0.02 (logMAR) in a 10-MUm increase in CT. CONCLUSIONS: Choroidal thickness decreases with age and severity of myopia. Visual acuity decreases in line with decreasing subfoveal CT. A reduction in CT is related to aging and the severity of myopia, whereas visual acuity depends on subfoveal CT. Our study supports the theory that choroidal abnormality may play a key role in the pathogenesis of myopic degeneration. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23683922 TI - RTEL1 tagging SNPs and haplotypes were associated with glioma development. AB - As glioma ranks as the first most prevalent solid tumors in primary central nervous system, certain single-nucleotide polymorphisms (SNPs) may be related to increased glioma risk, and have implications in carcinogenesis. The present case control study was carried out to elucidate how common variants contribute to glioma susceptibility. Ten candidate tagging SNPs (tSNPs) were selected from seven genes whose polymorphisms have been proven by classical literatures and reliable databases to be tended to relate with gliomas, and with the minor allele frequency (MAF)>5% in the HapMap Asian population. The selected tSNPs were genotyped in 629 glioma patients and 645 controls from a Han Chinese population using the multiplexed SNP MassEXTEND assay calibrated. Two significant tSNPs in RTEL1 gene were observed to be associated with glioma risk (rs6010620, P=0.0016, OR: 1.32, 95% CI: 1.11-1.56; rs2297440, P=0.001, OR: 1.33, 95% CI: 1.12-1.58) by chi2 test. It was identified the genotype "GG" of rs6010620 acted as the protective genotype for glioma (OR, 0.46; 95% CI, 0.31-0.7; P=0.0002), while the genotype "CC" of rs2297440 as the protective genotype in glioma (OR, 0.47; 95% CI, 0.31-0.71; P=0.0003). Furthermore, haplotype "GCT" in RTEL1 gene was found to be associated with risk of glioma (OR, 0.7; 95% CI, 0.57-0.86; Fisher's P=0.0005; Pearson's P=0.0005), and haplotype "ATT" was detected to be associated with risk of glioma (OR, 1.32; 95% CI, 1.12-1.57; Fisher's P=0.0013; Pearson's P=0.0013). Two single variants, the genotypes of "GG" of rs6010620 and "CC" of rs2297440 (rs6010620 and rs2297440) in the RTEL1 gene, together with two haplotypes of GCT and ATT, were identified to be associated with glioma development. And it might be used to evaluate the glioma development risks to screen the above RTEL1 tagging SNPs and haplotypes. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1993021136961998. PMID- 23683923 TI - DOG1-like genes in cereals: investigation of their function by means of ectopic expression in Arabidopsis. AB - The Arabidopsis gene DOG1 (AtDOG1) functions in seed dormancy and in sugar signaling. Little is known about the structural and functional features of plant genes homologous to AtDOG1, except for one type (clade 1) of Triticeae AtDOG1 like genes, which was previously demonstrated to be functionally orthologous to AtDOG1. Here, through phylogenetic, structural, and functional analyses of cereal AtDOG1-like genes, we characterized their features: these genes exist as a gene family that can be classified into five distinct clades (1-5). Of these, AtDOG1 like genes in clades 1-4 have a similar architecture to AtDOG1: they encode proteins with three conserved regions. In contrast, the clade 5 genes are distinct; their encoded proteins lack these conserved regions, but harbor domains that interact with DNA. Ectopic expression of the cereal AtDOG1-like genes of clades 2-4 in Arabidopsis demonstrated that like the clade 1 genes, they performed the same function as AtDOG1. The correlation between the depth of seed dormancy and the efficiency of sugar signaling in transgenic Arabidopsis conferred by genes in clades 1-4 suggests a close link in the underlying mechanisms between the seed dormancy and sugar signaling functions of AtDOG1. PMID- 23683924 TI - Transcription analyses of GmICHG, a gene coding for a beta-glucosidase that catalyzes the specific hydrolysis of isoflavone conjugates in Glycine max (L.) Merr. AB - Isoflavone conjugate-hydrolyzing beta-glucosidase (GmICHG) of soybeans [Glycine max (L.) Merr.] catalyzes the specific hydrolysis of isoflavone conjugates (beta 7-O-(malonyl)glucosides of isoflavones) to produce free isoflavones. In this study, changes in the transcription levels of GmICHG in the individual organs of soybean seedlings (cv. Enrei) in response to microbial infection and abiotic stresses were analyzed and compared with those of genes coding for 2 hydroxyisoflavanone synthase (GmIFS) and isoflavone 7-O-glucosyltransferase (GmIF7GT). GmICHG was originally expressed in abundance only in the roots and at low levels only in the other organs. The transcription of GmICHG in the roots and other organs was suppressed upon infection of the roots by Phytophthora sojae. Upon wounding of the cotyledon, a transient long-distance up-regulation of GmICHG transcription in the roots was observed; upon fungal infection in the cotyledon, however, a delayed elevation of GmICHG transcription took place in the roots with the maximum at 10 h after the infection. Such long-distance up-regulation patterns were not observed with either GmIFS or GmIF7GT. The transcription levels of GmICHG remained essentially unchanged upon treatment of the roots with Bradyrhizobium japonicum. The transcription of GmICHG in the roots was also sensitive to a variety of stresses on the roots, such as flooding, elicitation with yeast extract, drought, and treatment with plant hormones such as abscisic, salicylic, and jasmonic acids and ethylene. PMID- 23683925 TI - Genetic identification of a novel locus, ACCELERATED FLOWERING 1 that controls chromatin modification associated with histone H3 lysine 27 trimethylation in Arabidopsis thaliana. AB - Flowering on time is a critically important for successful reproduction of plants. Here we report an early-flowering mutant in Arabidopsis thaliana, accelerated flowering 1-1D (afl1-1D) that exhibited pleiotropic developmental defects including semi-dwarfism, curly leaf, and increased branching. Genetic analysis showed that afl1-1D mutant is a single, dominant mutant. Chromosomal mapping indicates that AFL1 resides at the middle of chromosome 4, around which no known flowering-related genes have been characterized. Expression analysis and double mutant studies with late flowering mutants in various floral pathways indicated that elevated FT is responsible for the early-flowering of afl1-1D mutant. Interestingly, not only flowering-related genes, but also several floral homeotic genes were ectopically overexpressed in the afl1-1D mutants in both FT dependent and -independent manner. The degree of histone H3 Lys27-trimethylation (H3K27me3) was reduced in several chromatin including FT, FLC, AG and SEP3 in the afl1-1D, suggesting that afl1-1D might be involved in chromatin modification. In support, double mutant analysis of afl1-1D and lhp1-4 revealed epistatic interaction between afl1-1D and lhp1-4 in regard to flowering control. Taken together, we propose that AFL1 regulate various aspect of development through chromatin modification, particularly associated with H3K27me3 in A. thaliana. PMID- 23683926 TI - Differential expression of acetohydroxyacid synthase genes in sunflower plantlets and its response to imazapyr herbicide. AB - Acetohydroxyacid synthase (AHAS) catalyzes the first reaction in branch chain amino acids biosynthesis. This enzyme is the target of several herbicides, including all members of the imidazolinone family. Little is known about the expression of the three acetohydroxyacid synthase genes (ahas1, ahas2 and ahas3) in sunflower. The aim of this work was to evaluate ahas gene expression and AHAS activity in different tissues of sunflower plantlets. Three genotypes differing in imidazolinone resistance were evaluated, two of which carry an herbicide resistant-endowing mutation known as Ahasl1-1 allele. In vivo and in vitro AHAS activity and transcript levels were higher in leaves than in roots. The ahas3 transcript was the less abundant in both tissues. No significant difference was observed between ahas1 and ahas2 transcript levels of the susceptible genotype but a higher ahas1 transcript level was observed in leaves of genotypes carrying Ahasl1-1 allele. Similar transcript levels were found for ahas1 and ahas2 in roots of genotypes carrying Ahasl1-1 allele whereas higher ahas2 abundance was found in the susceptible genotype. Herbicide treatment triggered tissue-specific, gene and genotype-dependent changes in ahas gene expression. AHAS activity was highly inhibited in the susceptible genotype. Differential responses were observed between in vitro and in vivo AHAS inhibition assays. These findings enhance our understanding of AHAS expression in sunflower genotypes differing for herbicide resistance and its response to herbicide treatment. PMID- 23683927 TI - Identification of genomic loci associated with crown rust resistance in perennial ryegrass (Lolium perenne L.) divergently selected populations. AB - The inheritance of crown rust resistance in perennial ryegrass is complex with both major and minor quantitative trait loci (QTL) being detected on all seven linkage groups. However, QTL mapping populations have only few segregating alleles, limiting the transferability of results to other materials. In this study, a synthetic population was developed from four crown rust resistant and susceptible parents as starting material for a divergent selection experiment of crown rust resistance to be closer to practice in plant breeding programs, and to identify genome regions relevant across a broader range of genotypes. Following three cycles of directional selection, perennial ryegrass populations were produced with a two-fold difference in average rust resistance. Divergently selected populations were genotyped at 7 resistance gene analog-derived expressed sequence tag (RGA-derived EST) as well as 15 simple sequence repeat (SSR) loci. A test for selective neutrality (Waples test), which tests the hypothesis of genetic drift versus selection, identified significant differences in allele frequencies for 7 loci (32%). The selection effect was bidirectional with the same loci showing significant response in both positively and negatively selected populations. A region under selection represented by markers LpSSR006 and EST13 on linkage group (LG) 4 was further confirmed by colocation with two separate QTL for crown rust resistance in a VrnA, a two-way pseudo-testcross mapping population. This suggests suitability of alleles identified for introgression into perennial ryegrass germplasm, where quantitative resistance to crown rust is desired. PMID- 23683928 TI - Multiple effects of chitosan on plant systems: solid science or hype. AB - Chitosan, a naturally occurring polymer, became available in the 1980s in industrial quantities enabling it to be tested as an agricultural chemical. A usual procedure for developing agricultural chemicals starts by testing a number of different chemically synthesized molecules on a targeted biological system. Alternately, chitosan has been investigated as a single natural molecule assayed with numerous biological systems. This report describes the unique properties of the molecule and its oligomers, primarily in plant defense, additionally in yield increase, induction of cell death and stomatal closing. The plant plasma membrane and nuclear chromatin have been proposed as targets, though chitosan oligomers enter most regions of the cell. Subsequent changes occur in: cell membranes, chromatin, DNA, calcium, MAP kinase, oxidative burst, reactive oxygen species (ROS), callose, pathogenesis related (PR) genes/proteins, and phytoalexins. Chitosan oligomer mode(s) of action are proposed for different plant systems. Chitosan efficacy was based on documentation from published data. Attention was given to how chitosan, either applied externally or released by fungal inoculum, is transferred into plant cells and its subsequent action upon membrane and/or chromatin components. Within is a proposed scheme describing chitosan generation, signaling routes and mechanisms of defense gene activation. Examples of beneficial chitosan applications to major crop/food plants were included. PMID- 23683929 TI - Sensorial, biochemical and molecular changes in Raboso Piave grape berries applying "Double Maturation Raisonnee" and late harvest techniques. AB - At ripening, Vitis vinifera cv Raboso Piave grapes have high acidity, which results in an astringent wine that is not easy to drink. To overcome this limitation, several researches have attempted to alter the polyphenols profile mainly by applying different harvest techniques. The aim of this work was to investigate sensorial, biochemical, and molecular changes in Raboso Piave grape berries subjected to delayed harvests as Late Harvest (LH) and "Double Maturation Raisonnee" (DMR) techniques. At the molecular level, a microarray study was conducted comparing Traditional Harvest berries (TH) to LH and DMR ones. Gene ontology enrichment analysis pointed out that LH and DMR techniques affected metabolism of acids, sugars and polyphenols. A Principal Component Analysis, performed on transcriptomic data, pointed out that malate catabolism as well as some branches of flavonoids biosynthesis are significantly affected by DMR. In DMR grape berries, the flavonol and catechin accumulations were induced and depressed, respectively. In parallel, the transcription of flavonol synthase and leucoanthocyanidin-reductase 2, the main genes responsible for flavonol and catechin biosynthesis, were similarly induced and down-regulated. These changes resulted in a brighter colored wine with lower astringency. PMID- 23683930 TI - The carotenoid biosynthetic pathway: thinking in all dimensions. AB - The carotenoid biosynthetic pathway serves manifold roles in plants related to photosynthesis, photoprotection, development, stress hormones, and various volatiles and signaling apocarotenoids. The pathway also produces compounds that impact human nutrition and metabolic products that contribute to fragrance and flavor of food and non-food crops. It is no surprise that the pathway has been a target of metabolic engineering, most prominently in the case of Golden Rice. The future success and predictability of metabolic engineering of carotenoids rests in the ability to target carotenoids for specific physiological purposes as well as to simultaneously modify carotenoids along with other desired traits. Here, we ask whether predictive metabolic engineering of the carotenoid pathway is indeed possible. Despite a long history of research on the pathway, at this point in time we can only describe the pathway as a parts list and have almost no knowledge of the location of the complete pathway, how it is assembled, and whether there exists any trafficking of the enzymes or the carotenoids themselves. We discuss the current state of knowledge regarding the "complete" pathway and make the argument that predictive metabolic engineering of the carotenoid pathway (and other pathways) will require investigation of the three dimensional state of the pathway as it may exist in plastids of different ultrastructures. Along with this message we point out the need to develop new types of visualization tools and resources that better reflect the dynamic nature of biosynthetic pathways. PMID- 23683931 TI - Transcriptional activation of flavan-3-ols biosynthesis in grape berries by UV irradiation depending on developmental stage. AB - The accumulation of flavan-3-ols in response to ultraviolet (UV) irradiation was investigated in grape berries with emphasis on the expression of three structural genes (VvANR, VvLAR1 and VvLAR2), and three regulatory genes (VvMYB5a, VvMYB5b and VvMYBPA1), and as well as the contents of flavan-3-ols. UV-A irradiation showed a promoting effect on the transcription of three structural genes at 3 week (flavan-3-ol accumulation period), 7-week (the end of flavan-3-ol accumulation) and 11-week (the beginning of anthocyanin synthesis) periods of berry development. UV-B irradiation also up-regulated all or part of the structural genes, but the activation effect of UV-C irradiation appeared only in the 7-week and 11-week grapes. The developmental stage-dependent activation by the three types of UV was also initiated for three regulatory genes, but the transcriptional up-regulation of the structural genes by UV irradiation was not entirely regulated by these transcription factors. The increase in the content of 2,3-trans-flavan-3-ols or 2,3-cis-flavan-3-ols by UV irradiation paralleled overall with the expression up-regulation of their corresponding structural genes in the 3-week and the 7-week grapes, but not in the 11-week grapes, indicating that the overexpression of structural genes by UV radiation does not translate into a higher content of flavan 3-ols at mature stage. PMID- 23683932 TI - Salicylic acid improves the salinity tolerance of Medicago sativa in symbiosis with Sinorhizobium meliloti by preventing nitrogen fixation inhibition. AB - In this work we have investigated the contribution of pretreatment with 0.1 and 0.5mM salicylic acid (SA) to the protection against salt stress in root nodules of Medicago sativa in symbiosis with Sinorhizobium meliloti. SA alleviated the inhibition induced by salinity in the plant growth and photosynthetic capacity of M. sativa-S. meliloti symbiosis. In addition, SA prevented the inhibition of the nitrogen fixation capacity under salt stress since nodule biomass was not affected by salinity in SA pretreated plants. Antioxidant enzymes peroxidase (POX), superoxide dismutase (SOD), ascorbate peroxidase (APX), dehidroascorbate reductase (DHAR) and glutathione reductase (GR), key in the main pathway that scavenges H2O2 in plants, were induced by SA pretreatments which suggest that SA may participate in the redox balance in root nodules under salt stress. Catalase activity (CAT) was inhibited around 40% by SA which could be behind the increase of H2O2 detected in nodules of plants pretreated with SA. The accumulation of polyamines (PAs) synthesized in response to salinity was prevented by SA which together with the induction of 1-aminocyclopropane-l-carboxylic acid (ACC) content suggest the prevalence of the ethylene signaling pathway induced by SA in detriment of the synthesis of PAs. In conclusion, SA alleviated the negative effect of salt stress in the M. sativa-S. meliloti symbiosis through the increased level of nodule biomass and the induction of the nodular antioxidant metabolism under salt stress. The H2O2 accumulation and the PAs inhibition induced by SA in nodules of M. sativa suggest that SA activates a hypersensitive response dependent on ethylene. PMID- 23683933 TI - Isolation and characterization of a carrot nucleolar protein with structural and sequence similarity to the vertebrate PESCADILLO protein. AB - The nuclear matrix is involved in many nuclear events, but its protein architecture in plants is still not fully understood. A cDNA clone was isolated by immunoscreening with a monoclonal antibody raised against nuclear matrix proteins of Daucus carota L. Its deduced amino acid sequence showed about 40% identity with the PESCADILLO protein of zebrafish and humans. Primary structure analysis of the protein revealed a Pescadillo N-terminus domain, a single breast cancer C-terminal domain, two nuclear localization signals, and a potential coiled-coil region as also found in animal PESCADILLO proteins. Therefore, we designated this gene DcPES1. Although DcPES1 mRNA was detected in all tissues examined, its levels were highest in tissues with proliferating cells. Immunofluorescence using specific antiserum against the recombinant protein revealed that DcPES1 localized exclusively in the nucleolus. Examination of fusion proteins with green fluorescent protein revealed that the N-terminal portion was important for localization to the nucleoli of tobacco and onion cells. Moreover, when the nuclear matrix of carrot cells was immunostained with an anti-DcPES1 serum, the signal was detected in the nucleolus. Therefore, the DcPES1 protein appears to be a component of or tightly bound to components of the nuclear matrix. PMID- 23683934 TI - The mitochondrial glutathione peroxidase GPX3 is essential for H2O2 homeostasis and root and shoot development in rice. AB - Glutathione (GSH) peroxidases (GPXs: EC 1.11.1.9 and EC1.11.1.12) are non-heme thiol peroxidases that catalyze the reduction of H2O2 or organic hydroperoxides to water, and they have been identified in almost all kingdoms of life. The rice glutathione peroxidase (OsGPX) gene family is comprised of 5 members spread throughout a range of sub cellular compartments. The OsGPX gene family is induced in response to exogenous H2O2 and cold stress. In contrast, they are down regulated in response to drought and UV-B light treatments. Transgenic rice plants have been generated that lack mitochondrial OsGPX3. These GPX3s plants showed shorter roots and shoots compared to non-transformed (NT) plants, and higher amounts of H2O2 mitochondrial release were observed in the roots of these plants cultivated under normal conditions. This accumulation of H2O2 is positively associated with shorter root length in GPX3s plants compared to NT ones. Moreover, GPX3 promoter analysis indicated that it is mainly expressed in root tissue. These results suggest that silencing the mitochondrial OsGPX3 gene impairs normal plant development and leads to a stress-induced morphogenic response via H2O2 accumulation. PMID- 23683935 TI - Morpho-anatomical and physiological responses to waterlogging of sesame (Sesamum indicum L.). AB - Waterlogging threatens severely to the sesame production in China, India and Burma, which are the top three sesame producers of the world. It was of great importance to explore the dynamics and mechanisms of action of anaerobic proteins and antioxidant enzymes together with the morph-anatomic adaptions in waterlogged sesame. The sesame accessions ZZM2541 and Ezhi-2 respond to waterlogging in considerably different performance. The stress induced wilting and leaf chlorosis in both accessions, but symptom occurred earlier in the susceptive Ezhi-2. In the more tolerant ZZM2541, adventitious roots formed above the flooding level, and plentiful of aerenchyma developed in the root and stem. However, it was discovered no apparent intercellular spaces existing in the spongy mesophyll in leaves of both accessions. The activities of ADH, PDC and LDH increased in roots of both accessions after suffering of the stress. The increase of ADH and PDC activity was more pronounced in ZZM2541, while a significantly higher LDH activity appeared in Ezhi-2. All the activities of SOD, APX and CAT were higher in the leaves of ZZM2541 than in Ezhi-2, and the leaves of Ezhi-2 showed a higher content of MDA throughout the duration of waterlogging. It was suggested that the tolerance to waterlogging of ZZM2541 appears to depend on a combination of metabolic and morpho-anatomical adaptions. PMID- 23683936 TI - The end of cheap uranium. AB - Historic data from many countries demonstrate that on average no more than 50-70% of the uranium in a deposit could be mined. An analysis of more recent data from Canada and Australia leads to a mining model with an average deposit extraction lifetime of 10+/-2 years. This simple model provides an accurate description of the extractable amount of uranium for the recent mining operations. Using this model for all larger existing and planned uranium mines up to 2030, a global uranium mining peak of at most 58+/-4 ktons around the year 2015 is obtained. Thereafter we predict that uranium mine production will decline to at most 54+/-5 ktons by 2025 and, with the decline steepening, to at most 41+/-5 ktons around 2030. This amount will not be sufficient to fuel the existing and planned nuclear power plants during the next 10-20 years. In fact, we find that it will be difficult to avoid supply shortages even under a slow 1%/year worldwide nuclear energy phase-out scenario up to 2025. We thus suggest that a worldwide nuclear energy phase-out is in order. If such a slow global phase-out is not voluntarily effected, the end of the present cheap uranium supply situation will be unavoidable. The result will be that some countries will simply be unable to afford sufficient uranium fuel at that point, which implies involuntary and perhaps chaotic nuclear phase-outs in those countries involving brownouts, blackouts, and worse. PMID- 23683937 TI - [Brachytherapy role in pediatric rhabdomyosarcomas]. AB - Brachytherapy in paediatric malignancies is rarely used, limited to expert institutions. The most frequent tumour sites treated with brachytherapy are gynaecological rhabdomyosarcomas, and prostate/bladder rhabdomyosarcomas. Ballistic advantages make brachytherapy technique the treatment of choice, with a high and selective protection of organs at risk. Techniques, brachytherapy modalities (low dose-rate, high dose-rate, pulsed dose-rate), doses and indications vary according to centres. Brachytherapy advantages are in relation with ballistic properties, allowing a very high dose to the target with normal tissue sparing. This review analyzes brachytherapy techniques, indications and results according to the two most frequent tumour sites: gynaecological and bladder/prostate tumours. This technique requires a muldisciplinary approach. PMID- 23683939 TI - Sudden bilateral sensorineural hearing loss associated with urticarial vasculitis. AB - BACKGROUND: Bilateral sensorineural hearing loss associated with recurrent urticarial skin lesions may be signs of underlying Muckle-Wells syndrome. Previous reports have described the hearing loss to be progressive in nature. METHOD: To our knowledge, this paper presents the first published case of sudden onset, bilateral sensorineural hearing loss associated with urticarial vasculitis due to underlying Muckle-Wells syndrome. RESULTS: The patient underwent a cochlear implantation with a modest outcome. CONCLUSION: Cochlear implantation may help to rehabilitate sudden hearing loss associated with this condition, but early diagnosis may allow treatment with interleukin-1beta inhibitors such as anakinra. PMID- 23683938 TI - LOX-1 ligands containing apolipoprotein B and carotid intima-media thickness in middle-aged community-dwelling US Caucasian and Japanese men. AB - OBJECTIVE: The serum level of LOX-1 ligand containing ApoB (LAB) may reflect atherogenicity better than LDL cholesterol (LDLC), total LDL particles and usual measurement of oxidized LDL. The association between LAB and intima-media thickness (IMT) of carotid artery was investigated by ultrasound in US and Japan men. METHODS: Participants were 297 US Caucasian and 310 Japanese men, aged 40-49 years without past history of cardiovascular disease. Serum LAB levels were measured by ELISAs with recombinant LOX-1 and monoclonal anti-apolipoprotein B antibody. RESULTS: Serum LAB levels [median (interquartile range), MUg/L] were 1321 (936, 1730) in US Caucasians and 940 (688, 1259) in Japanese. For Caucasian men, average IMT was higher in higher LAB quartile, which was 0.653, 0.667, 0.688, and 0.702 mm, respectively (p for trend = 0.02). Linear regression analysis showed serum LAB was significantly associated with IMT after adjustment for LDLC or total LDL particles in addition to other traditional or novel risk factors for atherosclerosis such as C-reactive protein. However, there was no significant relationship between LAB and IMT in Japanese men. CONCLUSION: Serum LAB, a new candidate biomarker for residual risk, was associated with an increased carotid IMT in US Caucasian men independently of various risk factors; however, ethnic difference should be clarified in the future. PMID- 23683940 TI - Radiation risk perception: a discrepancy between the experts and the general population. AB - Determining the differences in the perception of risks between experts who are regularly exposed to radiation, and lay people provides important insights into how potential hazards may be effectively communicated to the public. In the present study we examined lay people's (N = 1020) and experts' (N = 332) perception of five different radiological risks: nuclear waste, medical x-rays, natural radiation, an accident at a nuclear installation in general, and the Fukushima accident in particular. In order to link risk perception with risk communication, media reporting about radiation risks is analysed using quantitative and qualitative content analyses. The results showed that experts perceive radiological risks differently from the general public. Experts' perception of medical X-rays and natural radiation is significantly higher than in general population, while for nuclear waste and an accident at a nuclear installation, experts have lower risk perception than the general population. In depth research is conducted for a group of workers that received an effective dose higher than 0.5 mSv in the year before the study; for this group we identify predictors of risk perception. The results clearly show that mass media don't use the same language as technical experts in addressing radiological risks. The study demonstrates that the discrepancy in risk perception and the communication gap between the experts and the general population presents a big challenge in understanding each other. PMID- 23683941 TI - Fate determination of mature autoreactive B cells. AB - A large antibody repertoire is generated in developing B cells in the bone marrow. Before these B cells achieve immunocompetence, those expressing autospecificities must be purged. To that end, B cells within the bone marrow and just following egress from the bone marrow are subject to tolerance induction. Once B cells achieve immunocompetence, the antibody repertoire can be further diversified by somatic hypermutation of immunoglobulin genes in B cells that have been activated by antigen and cognate T cell help and have undergone a germinal center (GC) response. This process also leads to the generation of autoreactive B cells which must be again purged to protect the host. Thus, B cells within the GC and just following egress from the GC are also subject to tolerance induction. Available data suggest that B cell intrinsic processes triggered by signaling through the B cell receptor activate tolerance mechanisms at both time points. Recent data suggest that GC and post-GC B cells are also subject to B cell extrinsic tolerance mechanisms mediated through soluble and membrane-bound factors derived from various T cell subsets. PMID- 23683943 TI - Autoimmunity in rheumatoid arthritis: citrulline immunity and beyond. AB - Rheumatoid arthritis (RA) represents a disease where we have recently acquired new knowledge on etiology and molecular pathogenesis, by combining data from studies on genetic end environmental determinants of disease with molecular and cellular immunology. This combined approach has provided insights into the heterogeneous nature of the clinical syndrome we call RA, and the subdivisions into different functional disease subsets now permit a better use of molecular immunology in contexts where genotypes and environmental triggers are defined. In this chapter, we discuss a series of different autoimmunities described in RA, with an initial emphasis on immunity to autoantigens that have been posttranslationally modified by citrullination. We then discuss a series of unresolved issues and challenges related both to the citrulline immunity and to other immune events in RA. Our perspective is that current studies on genes, environment, and immunity in this disease provides us with a great outlook to investigate interesting general aspects of autoimmunity and development of human autoimmune disease--in addition to the opportunity to better understand, prevent, and ultimately treat RA. PMID- 23683944 TI - Alternate considerations for current concepts in ITP. AB - Immune thrombocytopenia (ITP) is one of the most common forms of autoimmune disease affecting both adults and children. In recent years, there have been tremendous developments in the understanding of the pathogenesis and treatment of this condition. However, certain concepts related to ITP are worth consideration in view of alternative explanations and evidence available. These include (i) ITP is a disorder where thrombocytopenia is induced by autoantibodies against platelets or megakaryocytes, (ii) the mechanism of action of corticosteroids in ITP is through suppression of these autoantibodies, (iii) splenectomy is effective in ITP since spleen is the site of platelet destruction, and (iv) splenectomized ITP patients are at a major risk of infections. PMID- 23683945 TI - Electronic health record systems in ophthalmology: impact on clinical documentation. AB - OBJECTIVE: To evaluate quantitative and qualitative differences in documentation of the ophthalmic examination between paper and electronic health record (EHR) systems. DESIGN: Comparative case series. PARTICIPANTS: One hundred fifty consecutive pairs of matched paper and EHR notes, documented by 3 attending ophthalmologist providers. METHODS: An academic ophthalmology department implemented an EHR system in 2006. Database queries were performed to identify cases in which the same problems were documented by the same provider on different dates, using paper versus EHR methods. This was done for 50 consecutive pairs of examinations in 3 different diseases: age-related macular degeneration (AMD), glaucoma, and pigmented choroidal lesions (PCLs). Quantitative measures were used to compare completeness of documenting the complete ophthalmologic examination, as well as disease-specific critical findings using paper versus an EHR system. Qualitative differences in paper versus EHR documentation were illustrated by selecting representative paired examples. MAIN OUTCOME MEASURES: (1) Documentation score, defined as the number of examination elements recorded for the slit-lamp examination, fundus examination, and complete ophthalmologic examination and for critical clinical findings for each disease. (2) Paired comparison of qualitative differences in paper versus EHR documentation. RESULTS: For all 3 diseases (AMD, glaucoma, PCL), the number of complete examination findings recorded was significantly lower with paper than the EHR system (P <= 0.004). Among the 3 individual examination sections (general, slit lamp, fundus) for the 3 diseases, 5 of the 9 possible combinations had significantly lower mean documentation scores with paper than EHR notes. For 2 of the 3 diseases, the number of critical clinical findings recorded was significantly lower using paper versus EHR notes (P <= 0.022). All (150/150) paper notes relied on graphical representations using annotated hand-drawn sketches, whereas no (0/150) EHR notes contained drawings. Instead, the EHR systems documented clinical findings using textual descriptions and interpretations. CONCLUSIONS: There were quantitative and qualitative differences in the nature of paper versus EHR documentation of ophthalmic findings in this study. The EHR notes included more complete documentation of examination elements using structured textual descriptions and interpretations, whereas paper notes used graphical representations of findings. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23683946 TI - A structural equation model of quality of life in adults with type 2 diabetes in Korea. AB - PURPOSE: The purpose of this study was to test a structural equation model in which self-efficacy and self-care activity predicts the quality of life (QOL) of individuals with type 2 diabetes in Korea. METHOD: A survey about self-care activity, self-efficacy, glucose control, and QOL was completed by 132 diabetic patients from public health centers in Korea. Data were analyzed using SPSSWIN 18.0 and AMOS 19.0. RESULTS: The mean age of the participants was 63.2 years. The proposed model was a good fit for the data based on the model fit indices. Self efficacy had a significant effect on self-care activity (95%), and this model explained 25% of the variance in QOL. CONCLUSIONS: The findings indicate that self-efficacy and self-care activity play important roles in explaining QOL in adults with type 2 diabetes. Nursing strategies to increase QOL in this population should contain self-efficacy enhancement to promote the performance of self-care activity. PMID- 23683947 TI - The effect of victim age on burnt bone fragmentation: implications for remains recovery. AB - This research investigates how victim bone age affects the fragmentation and subsequent recovery of burnt bone. It could be inferred that the lower density and higher organic content of bone from younger individuals results in more significant bone breakdown compared to bone from older individuals. Previous research has suggested that while neonate bone can be difficult to destroy in a burn environment it is more fragile post-burning. Results comparing fragmentation of calcined piglet and fattening-pig remains reveal that, while consisting of smaller fragments, the younger material is less fragmented with more complete or almost complete bone elements. These observations have significant implications for remains recovery, especially of younger remains, as it highlights the value of this material as well as the importance of utilising search and recovery strategies that minimise post-burning disturbance. Younger bone responds differently to the burn environment and, therefore; it needs to be taken into consideration when planning remains discovery and retrieval to ensure maximum benefit to the investigation and individuals involved. PMID- 23683948 TI - Induction chemotherapy for squamous cell head and neck cancer: a neverending story? AB - Induction chemotherapy prior to planned definitive local therapy for head and neck squamous cell carcinoma has been studied for at least three decades but the debate on its role is still open. Recent landmark studies, including those presented at outstanding meetings and those still ongoing on induction chemotherapy in different clinical situations, are critically reviewed. Data confirm that a docetaxel, cisplatin and 5-fluorouracil (TPF) based induction chemotherapy may be considered in clinical practice as one of the possible options when a larynx preservation strategy is attempted. On the contrary, current data do not support the use of induction chemotherapy before a planned surgical intervention for advanced oral cavity and oropharyngeal tumors. Currently, for patients with locoregionally advanced unresectable disease, concomitant chemo-radiation remains the standard of care in waiting for results of the few ongoing studies that hopefully will clarify the role of induction TPF before either concomitant chemo-radiation or bio-radiation. PMID- 23683949 TI - Predictors of left ventricular remodeling after surgical repair or replacement for pure severe mitral regurgitation caused by leaflet prolapse. AB - We sought to determine whether preoperative baseline echocardiographic analysis and the type of surgical procedure are predictive of the magnitude and timing of postoperative left ventricular (LV) remodeling in patients undergoing valve surgery for pure severe mitral regurgitation (MR) secondary to leaflet prolapse. Seventy-two consecutive patients without coronary artery disease undergoing valve repair (MVr; n = 42) or replacement (MVR; n = 30) underwent preoperative, early (1 to 2 days) and late postoperative (4.5 +/- 2.5 and 18 +/- 8.0 months) echocardiography. Patients were categorized according to their baseline LV ejection fraction (EF) (Group 1: EF >=60%, Group 2: EF = 50% to 59%, Group 3: EF <50%). Preservation of the subvalvular apparatus was achieved in most patients undergoing MV replacement (87%). Over a median follow-up period of 450 days, LVEF changed as follows: Group 1: 63% +/- 2% to 60% +/- 3% (p <0.0001); Group 2: 55% +/- 3% to 52% +/- 6% (p <0.0001); Group 3: 43% +/- 4% to 42% +/- 5% (p <0.01). Two-thirds of the observed changes in LV diameters and volumes occurred in the first 6 months. Preoperative LVEF was the best predictor of postoperative LVEF >=60% (odds ratio 1.50, 95% confidence interval, 1.25 to 1.97; p <0.0001). No significant difference was found in LV remodeling parameters between patients undergoing MVr and MVR. In conclusion, patients with pure severe MR due to valve prolapse LVEF remained normal after surgery only in patients with baseline LVEF >=60%. MVR with subvalvular preservation was associated with similar postoperative remodeling as MVr. PMID- 23683950 TI - Frequency of Takotsubo cardiomyopathy in postmenopausal women presenting with an acute coronary syndrome. AB - Takotsubo cardiomyopathy (TC) may be more common than previously reported in postmenopausal women (PMW) presenting with acute coronary syndrome (ACS). TC often masquerades as an ACS with electrocardiographic changes, elevated troponins, and/or chest discomfort. Its exact incidence in ACS is unknown but most studies suggest it is 1% to 2.2%. As most patients with TC are PMW, it was hypothesized that the incidence would be greater in this population. A prospective evaluation was carried out in all middle-aged and older women (>=45 years of age) presumed to be peri- or postmenopausal with an elevated troponin presenting to a community hospital over a 1-year period (July 2011 to July 2012). Troponin results above the upper limit of normal were screened on a daily basis through a computerized system. The patients' in-hospital charts were reviewed and determined if they fulfilled the criteria for acute myocardial infarction according to the universal definition of myocardial infarction. Prespecified criteria were used to identify all patients with TC. Of the 1,297 PMW screened for positive troponins, 323 patients (24.9%) fulfilled the criteria for acute myocardial infarction and of these, 19 (5.9%) met the prespecified criteria for TC. Three additional patients with TC had acute neurologic events. Most patients (81.8%) had the apical variant. In conclusion, TC may be more common than reported in PMW with clinical and laboratory criteria suggesting acute myocardial infarction. Heightened awareness of TC in this population appears warranted. PMID- 23683951 TI - Correlation of brain natriuretic peptide levels in patients with severe aortic stenosis undergoing operative valve replacement or percutaneous transcatheter intervention with clinical, echocardiographic, and hemodynamic factors and prognosis. AB - Brain natriuretic peptide (BNP) is a marker of systolic and diastolic dysfunction and a strong predictor of mortality in heart failure patients. The present study aimed to assess the relationship of BNP with aortic stenosis (AS) severity and prognosis. The cohort comprised 289 high-risk patients with severe AS who were referred for transcatheter aortic valve implantation. Patients were divided into tertiles based on BNP level: I (n = 96); II (n = 95), and III (n = 98). Group III patients were more symptomatic, had higher Society of Thoracic Surgeons and EuroSCORE scores, and had a greater prevalence of renal failure, atrial fibrillation, and previous myocardial infarction; lower ejection fraction and cardiac output; and higher pulmonary pressure and left ventricular end diastolic pressure. The degree of AS did not differ among the 3 groups. Stepwise forward multiple regression analysis identifies ejection fraction and pulmonary artery systolic pressure as independent correlates with plasma BNP. Mortality rates during a median follow-up of 319 days (range 110 to 655) were significantly lower in Group I compared with Groups II and III, p <0.001. After multivariable adjustment, the strongest correlates for mortality were renal failure (hazard ratio 1.44, p = 0.05) and medical/balloon aortic valvuloplasty (HR 2.2, p <0.001). Mean BNP decreased immediately after balloon aortic valvuloplasty from 1,595 +/- 1,229 to 1,252 +/- 1,076, p = 0.001 yet increased to 1,609 +/- 1,264, p = 0.9 at 1 to 12 months. After surgical aortic valve replacement, there was a nonsignificant, immediate decrease in BNP level from 928 +/- 1,221 to 896 +/- 1,217, p = 0.77, continuing up to 12 months 533 +/- 213, p = 0.08. After transcatheter aortic valve implantation, there was no significant decrease in BNP immediately after the procedure; however, at 1-year follow-up, the mean BNP level decreased significantly from 568 +/- 582 to 301 +/- 266 pg/dl, p = 0.03. In conclusion, a high BNP level in high-risk patients with severe AS is not an independent marker for higher mortality. BNP level does not appear to be significantly associated with the degree of AS severity but does reflect heart failure status. PMID- 23683952 TI - Usefulness of the D-dimer concentration as a predictor of mortality in patients with out-of-hospital cardiac arrest. AB - During cardiac arrest and after cardiopulmonary resuscitation, activation of blood coagulation occurs, with a lack of adequate endogenous fibrinolysis. The aim of the present study was to determine whether the serum D-dimer concentration on admission is an independent predictor of all-cause mortality in patients with out-of-hospital cardiac arrest. We enrolled 182 consecutive patients (122 men, mean age 64.3 +/- 15 years), who had presented to the emergency department from January 2007 to July 2012 because of out-of-hospital cardiac arrest. Information about the initial arrest rhythm, biochemical parameters, including the D-dimer concentration on admission, neurologic outcomes, and 30-day all-cause mortality were retrospectively collected. Of the 182 patients, 79 (43.4%) had died. The patients who died had had lower systolic (100 +/- 39.6 vs 120.5 +/- 26.9 mm Hg; p = 0.0004) and diastolic (58.3 +/- 24.1 vs 74 +/- 16.3 mm Hg; p <0.0001) blood pressure on admission. The deceased patients more often had had a history of myocardial infarction (32.9% vs 25.2%; p = 0.04) and less often had had an initial shockable rhythm (41.8% vs 60.2%; p = 0.02). The patients who died had had a significantly higher mean D-dimer concentration (9,113.6 +/- 5,979.2 vs 6,121.6 +/- 4,597.5 MUg/L; p = 0.005) compared with patients who stayed alive. On multivariate logistic regression analysis, an on-admission D-dimer concentration >5,205 MUg/L (odds ratio 5.7, 95% confidence interval 1.22 to 26.69) and hemoglobin concentration (odds ratio 1.66, 95% confidence interval 1.13 to 2.43) were strong and independent predictors of all-cause mortality. In conclusion, patients with a higher D-dimer concentration on admission had a poorer prognosis. The D-dimer concentration was an independent predictor of all-cause mortality. PMID- 23683954 TI - Effect of elevated pulmonary vascular resistance on outcomes after percutaneous mitral valvuloplasty. AB - Patients with mitral stenosis with severe pulmonary hypertension constitute a high-risk subset for surgical commissurotomy or valve replacement. The aim of the present study was to examine the effect of elevated pulmonary vascular resistance (PVR) on percutaneous mitral valvuloplasty (PMV) procedural success, short- and long-term clinical outcomes (i.e., mortality, mitral valve surgery, and redo PMV) in 926 patients. Of the 926 patients, 263 (28.4%) had PVR >=4 Woods units (WU) and 663 (71.6%) had PVR <4 WU. Patients with PVR >=4 WU were older and more symptomatic and had worse valve morphology for PMV. The patients with PVR >=4 WU also had lower PMV procedural success than those with PVR <4 WU (78.2% vs 85.6%, p = 0.006). However, after multivariate adjustment, PVR was no longer an independent predictor of PMV success nor an independent predictor of the combined end point at a median follow-up of 3.2 years. In conclusion, elevated PVR at PMV is not an independent predictor of procedural success or long-term outcomes. Therefore, appropriately selected patients with rheumatic mitral stenosis might benefit from PMV, even in the presence of elevated preprocedural PVR. PMID- 23683953 TI - Relation of short-term heart rate variability to incident heart failure (from the Multi-Ethnic Study of Atherosclerosis). AB - Whether autonomic dysfunction predates the development of symptomatic heart failure (HF) or is simply a consequence of severe HF is unknown. We hypothesized that reduced heart rate variability (a marker of abnormal autonomic function) at baseline is associated with incident HF in subjects free of clinically recognized cardiovascular disease. In the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based study of subclinical cardiovascular disease in adults aged 45 to 84 years, we measured the heart rate variability using a standard 30-second, 12 lead electrocardiogram to measure the standard deviation of normal-to-normal intervals (SDNN) and the root mean square of successive differences in RR intervals (RMSSD). During a median follow-up of 7.6 years, 95 participants developed HF (incidence rate 2.7/1,000 person-years). After adjusting for age, gender, and ethnicity, the hazard ratio for incident HF stratified by the RMSSD tertile was 2.4 (95% confidence interval 1.4 to 4.2) for the lowest tertile and 1.7 (95% confidence interval 1.0 to 3.2) for the middle tertile (highest tertile was the referent group; p for trend <0.001). The inverse association between the RMSSD and incident HF persisted after adjustment for additional covariates, including diabetes, systolic blood pressure, heart rate, subclinical atherosclerosis, left ventricular end-systolic volume, interim myocardial infarction, and high-sensitivity C-reactive protein (p for trend = 0.009). A similarly significant inverse association was also observed for SDNN. In conclusion, baseline autonomic dysfunction was a risk factor for the development of HF in a multiethnic cohort. These population-based findings implicate autonomic dysfunction in the pathogenesis of HF, and decreased short-term heart rate variability might be a novel form of stage B (asymptomatic) HF. PMID- 23683955 TI - Use of new synthetic talc as reinforcing nanofillers for polypropylene and polyamide 6 systems: thermal and mechanical properties. AB - New layered synthetic nanotalc prepared at a lab-scale by a conventional hydrothermal process and commercial natural fine talc were used in order to establish a comparative study in terms of their contributions on the improvement of the final properties of two different polymers: a nonpolar polyolefin matrix and a polyamide. All samples were prepared by melt extrusion in a co-rotating microcompounder. The surface properties of talc - surface energy and isoelectric point - were probed. The particles' crystalline structure and the distribution/dispersion within the polymer matrix were performed using transmission electron microscopy and X-ray diffraction. The effect of talc particles on the crystallinity, the thermal and mechanical properties was highlighted as a function of the surface properties of talc. In the case of talc filled PP systems, it seems that the incorporation of both natural and synthetic talc greatly improves the thermal stability of polypropylene matrix. The highest elastic modulus was obtained in presence of highly nucleating natural talc. Oppositely, the best ductility was observed for the synthetic talc-filled PP systems. For PA6/talc nanocomposites, a remarkable improvement in the dispersion of talc layers was shown and a significant increase in Young's modulus was determined due to the closer affinity between the hydrophilic nanotalc lamellae and the polar PA6 matrix. PMID- 23683942 TI - Epigenetic control of cytokine gene expression: regulation of the TNF/LT locus and T helper cell differentiation. AB - Epigenetics encompasses transient and heritable modifications to DNA and nucleosomes in the native chromatin context. For example, enzymatic addition of chemical moieties to the N-terminal "tails" of histones, particularly acetylation and methylation of lysine residues in the histone tails of H3 and H4, plays a key role in regulation of gene transcription. The modified histones, which are physically associated with gene regulatory regions that typically occur within conserved noncoding sequences, play a functional role in active, poised, or repressed gene transcription. The "histone code" defined by these modifications, along with the chromatin-binding acetylases, deacetylases, methylases, demethylases, and other enzymes that direct modifications resulting in specific patterns of histone modification, shows considerable evolutionary conservation from yeast to humans. Direct modifications at the DNA level, such as cytosine methylation at CpG motifs that represses promoter activity, are another highly conserved epigenetic mechanism of gene regulation. Furthermore, epigenetic modifications at the nucleosome or DNA level can also be coupled with higher order intra- or interchromosomal interactions that influence the location of regulatory elements and that can place them in an environment of specific nucleoprotein complexes associated with transcription. In the mammalian immune system, epigenetic gene regulation is a crucial mechanism for a range of physiological processes, including the innate host immune response to pathogens and T cell differentiation driven by specific patterns of cytokine gene expression. Here, we will review current findings regarding epigenetic regulation of cytokine genes important in innate and/or adaptive immune responses, with a special focus upon the tumor necrosis factor/lymphotoxin locus and cytokine driven CD4+ T cell differentiation into the Th1, Th2, and Th17 lineages. PMID- 23683956 TI - Ensemble average TIRM for imaging amperometry. AB - Colloidal particles can function as probes of local electrochemical current density if a functional relationship between the response of the particles and the electric field in the vicinity of the particles can be established. The nanometer scale movement of a single colloidal particle during cyclic voltammetry can be observed with the aid of total internal reflection microscopy. The intensity of scattered light can be related back to the current density local to that particle, and hence the method is called imaging amperometry. Data acquisition and optical constraints, however, make a single-particle method impractical for analysis of macro-scale (~1 cm(2)) surfaces covered by several hundred thousand particles. Subdivision of the electrode into small patches, each containing an ensemble of particles, solves this problem if the scattering from the ensembles can be related to the local electric field. For example, a 100*100 array of square 100 MUm patches each containing approximately two dozen particles would form a mosaic of electrochemical activity with 0.01% area resolution on a 1cm(2) electrode having location-dependent electrocatalytic properties. The focus of this contribution, therefore, is adaptation of the method from single particles to particle ensembles. The algebraic relationship between current density and scattering intensity for single particles holds for ensembles if the mean scattering intensity is corrected to its mode. Currents calculated from particle light scattering at different locations on a single ITO/gold patterned electrode agree well with currents measured on these two electrode materials, which have quite different electrocatalytic properties. PMID- 23683957 TI - Influence of the 524-VAAEIL-529 sequence of annexins A6 in their interfacial behavior and interaction with lipid monolayers. AB - Annexin A6 (AnxA6), a calcium- and membrane-binding protein, is expressed in mammalian cells in two isoforms: AnxA6-1 and AnxA6-2, the latter lacking the 524 VAAEIL-529 sequence at the start of repeat 7. The different intracellular localization of these two isoforms suggests distinct function in membrane dynamics. The aim of this work was to analyze the behavior of AnxA6 isoforms at the air/water interface alone and in the presence of membrane mimicking lipid monolayers. Using Langmuir technique showed that AnxA6-2 was less adsorbed to the neat air-water interface than AnxA6-1 at acidic pH and minor differences in their PM-IRRAS spectra were observed. Both isoforms exhibited similar behavior towards cholesterol monolayer. However, the interactions of AnxA6-2 with cholesterol ester monolayer were most favorable compared to AnxA6-1. Our experimental data are discussed in relation with the different intracellular localization of the two isoforms and with our constructed model of AnxA6-2 with the known crystal structure of AnxA6-1 showing the persistence of the 516-529 alpha-helix in AnxA6 2 despite the absence of the 524-VAAEIL-529 sequence. PMID- 23683958 TI - Graphene oxide nanoplatelet dispersions in concentrated NaCl and stabilization of oil/water emulsions. AB - Stable dispersions of graphene oxide nanoplatelets were formed in water at pH 2 10 even with 5 wt% NaCl. For these conditions, oil-in-water emulsions stabilized with graphene oxide nanoplatelets remained partially stable for 1 year. The droplet sizes were as small as ~1 MUm with a low nanoplatelet concentration of 0.2 wt%. The emulsions were stable even for nanoplatelet concentrations down to 0.001 wt%. The stabilities of the emulsions even at high salinity may be attributed to the high anion density at the graphene oxide nanoplatelet edges which protrude into the water phase. Furthermore, the graphene oxide nanoplatelets are shown to adsorb on the surfaces of the oil droplets. The conceptual picture of graphene oxide nanoplatelets adsorbed to a greater extent on the water side of the oil/water interface, along with the high density of anions on their edges, cause the oil/water interface to curve about the oil phase, resulting in oil-in-water emulsion droplets. The dispersion stability with a very small amount of graphene oxide-based stabilizer, offers an intriguing opportunity for applications including CO2 sequestration and enhanced oil recovery in deep subsurface formations, which generally contain high-salinity brines. PMID- 23683959 TI - Examination of the effect of alpha radiolysis on plutonium(V) sorption to quartz using multiple plutonium isotopes. AB - The objective of this research was to determine if radiolysis at the mineral surface was a plausible mechanism for surface-mediated reduction of plutonium. Batch sorption experiments were used to monitor the amount of plutonium sorbed to high-purity quartz as a function of time, pH, and total alpha radioactivity. Three systems were prepared using both (238)Pu and (242)Pu in order to increase the total alpha radioactivity of the mineral suspensions while maintaining a constant plutonium concentration. The fraction of sorbed plutonium increased with increasing time and pH regardless of the total alpha radioactivity of the system. Increasing the total alpha radioactivity of the solution had a negligible effect on the sorption rate. This indicated that surface-mediated reduction of Pu(V) in these systems was not due to radiolysis. Additionally, literature values for the Pu(V) disproportionation rate constant did not describe the experimental results. Therefore, Pu(V) disproportionation was also not a main driver for surface mediated reduction of plutonium. Batch desorption experiments and X-ray absorption near edge structure spectroscopy were used to show that Pu(IV) was the dominant oxidation state of sorbed plutonium. Thus, it appears that the observed surface-mediated reduction of Pu(V) in the presence of high-purity quartz was based on the thermodynamic favorability of a Pu(IV) surface complex. PMID- 23683960 TI - Controlling chain organization and photophysical properties of conjugated polymer nanoparticles prepared by reprecipitation method: the effect of initial solvent. AB - This study explores roles of initial solvent on the formation of conjugated polymer nanoparticles (CPNs) and their photophysical properties. Stable aqueous CPN dispersion of poly(2-methoxy-5-(2'-ethylhexyloxy)-1,4-phenylvinylene)(MEH PPV) and regioregular poly(3-octylthiophene)(rr-P3OT) are prepared via reprecipitation technique. This preparation method involves the injection of polymer solution in organic solvents into an excess amount of water. We demonstrate that water solubility of the initial solvent is a major factor dictating mechanism of the CPN formation. Dichloromethane (DCM) and tetrahydrofuran (THF), possessing very different water solubilities, are used as initial solvents in this work. The resultant CPNs exhibit quite different sizes and photophysical properties. The preparation of MEH-PPV nanoparticles from DCM solution provides average size of about 127 nm. Their absorption and photoluminescence (PL) spectra shift to higher energy region compared to those of the isolated chain. When the THF solution is used, opposite results are observed. Average size of the nanoparticles decreases to about 40 nm. Significant redshift of their absorption and PL spectra is also detected. Detailed data analysis indicates that the individual chain conformation and degree of segmental aggregation within the CPNs are quite different. This leads to drastic discrepancies of their photophysical properties. The use of DCM and THF as initial solvents provides the MEH-PPV nanoparticles with green (lambda max=535 nm) and red (lambda max=590 nm) photoemission, respectively. The investigation of rr-P3OT provides consistent results. Our study offers a new and simple route to control size and photophysical properties of CPNs by careful selection of the initial solvents. PMID- 23683961 TI - The GMS hypospadias score: assessment of inter-observer reliability and correlation with post-operative complications. AB - OBJECTIVE: An agreed upon method for describing the severity of hypospadias has not been established. Herein we assess the inter-observer reliability of the GMS hypospadias score and correlate it with the risk of a post-operative complication. METHODS: A 3-component method for grading the severity of hypospadias was developed (GMS). Eighty-five consecutive patients presenting for hypospadias repair were graded independently by at least 2 surgeons using the GMS criteria. Scores were compared statistically to determine agreement between the observers. The outcomes of these patients were then reviewed to determine how the GMS score correlates to the risk of a surgical complication. RESULTS: The G, M, and S scores had excellent agreement between observers. The GMS total score was exactly the same or differed by one point in 79/85 (93%) of patients. The complication rate was 5.6% for patients with a GMS score of 6 or less, but was 25.0% for patients with a GMS score greater than 6. CONCLUSIONS: The GMS score provides a concise method for describing the severity of hypospadias and appears to have high inter-observer reliability. The GMS score also appears to correlate with the risk of a surgical complication. PMID- 23683962 TI - Therapeutic update in large vessel vasculitides. AB - The term large vessel vasculitidis includes two distinct clinical entities: Takayasu's arteritis and giant cell arteritis. Takayasu's arteritis mainly affects children and women under 40 years, affecting the aorta and its major branches. Its incidence in Southern Europe is low. Giant cell arteritis is the most common vasculitis in those 60. Its incidence in the European population is greater than that of Takayasu's arteritis. It mainly affects the extracranial vessels, especially those derived from the carotid artery. Both conditions are characterized by inflammation of the vessel wall, this causing structural damage and the expression of different clinical manifestations. The treatment of choice of both conditions is based on high-dose glucocorticoids associated, in some cases, to immunosuppressants. Biologic agents have been reserved for cases refractory to conventional therapies. PMID- 23683963 TI - Hospitalizations due to severe hypoglycemia in patients with diabetes mellitus in Spain. AB - BACKGROUND AND OBJECTIVES: One of the most important therapeutic complications in patients with diabetes mellitus (DM) is hypoglycemia. This study has estimated the number of hospitalizations due to severe hypoglycemia in patients with type DM1 and DM2. PATIENTS AND METHODS: The study hospital population was defined using the National Catalogue of Hospitals (CNH) 2007 (last available data), and has included 260 general hospitals of the National Health System. The number of hospitalizations due to severe hypoglycemia was obtained from the Basic Minimum Data Set (BMDS) for the 183 hospitals. For the remaining 77 hospitals, this number was estimated based on the available information. RESULTS: In 2007, there were 26,701 (0.82%) hospitalizations with hypoglycemia. In DM2 patients, 8,242 (0.25%) episodes were reported as primary diagnosis and 16,649 (0.51%) as secondary. In DM1 patients, 1,157 (0.04%) and 653 (0.02%) episodes were reported as primary and secondary diagnosis, respectively. Overall incidence in DM2 was 1.82 episodes/10,000 inhabitants-year, this ranging between 1.10 episodes/10,000 inhabitants-year in the Islas Canarias to 3.37 in Castilla y Leon. CONCLUSIONS: Severe hypoglycemia is an important reason for hospitalization of patients with DM in Spain, there being great variability according to the Autonomous Regions. PMID- 23683965 TI - Community-based incidence rate of cardiovascular disease and mortality in 50-75 year old adults. AB - BACKGROUNDS AND OBJECTIVES: Updated information on the incidence of the principal cardiovascular diseases (CVD) and cardiovascular mortality is not available in Spain. We have studied the incidence rate of new cases of myocardial infarction, heart failure, stroke and cardiovascular mortality in the adult population in Sanlucar de Barrameda (Spain). MATERIAL AND METHODS: A community-based prospective follow-up study was conducted. The study enrolled 858 participants aged 50-75 years who were randomly selected from the population and followed-up for 5 years. Age and gender-adjusted incidence rates of cardiovascular disease and cardiovascular mortality were calculated, obtaining complete information for 855 participants. Prognostic risk factors of new cases of cardiovascular disease were obtained using Cox proportional hazard modeling. RESULTS: The community based incidence rate of heart failure was 455/100.000 persons-year. The incidence of myocardial infarction, stroke and cardiovascular mortality (506, 216 and 225/100.000 persons-year, respectively) was also very elevated. Male gender, family history of early cardiovascular disease, diabetes, hypertension and sedentary life style were independent risk factors of cardiovascular disease. CONCLUSIONS: The community-based incidence rate of heart failure in Sanlucar de Barrameda (Spain) is very high, and it is the first to be reported in Spain. The incidence of myocardial infarction is among the highest in Spain. PMID- 23683966 TI - Improved ethanol fermentation by heterologous endoinulinase and inherent invertase from inulin by Saccharomyces cerevisiae. AB - It is hypothesized that introduction of an endoinulinase gene into Saccharomyces cerevisiae will improve its inulin utilization and ethanol fermentation through collaboration between the heterologous endoinulinase and the inherent invertase SUC2. The aim of this work was to test the hypothesis by introducing the endoinulinase gene inuA from Aspergillus niger into S. cerevisiae. The results showed that heterologous inuA expressed in S. cerevisiae selectively digested long chains of inulin into short fructooligosaccharides and parts of these fructooligosaccharides could be efficiently utilized by the yeast. This study demonstrated that collaboration between heterologous endoinulinase and inherent invertase improved inulin degradation and ethanol fermentation in S. cerevisiae. PMID- 23683968 TI - [Respiratory infection by Mycobacterium mucogenicum]. PMID- 23683967 TI - [Patients' characteristics and clinical management of atrial fibrillation in primary healthcare in Spain: FIATE Study]. AB - BACKGROUND AND OBJECTIVES: The main therapeutic objective in atrial fibrillation (AF) patients is stroke prevention. This study is aimed to determine whether the anticoagulant therapy may be appropriate regarding to the Guidelines and patients' profile in primary healthcare in Spain. PATIENTS AND METHODS: A national, multicenter, cross-sectional study of AF patients attended in primary healthcare in Spain has been conducted. The study involved 185 family physicians whose patients were randomized. RESULTS: A total of 3,759 AF patients were randomized from the clinical records, and 2,070 were included in the study, at an average age of 74 (11) years old (50.7% female). Most of them (78%) had permanent AF and high comorbidity rates (hypertension 75%, obesity 30%, diabetes 27%, heart failure 20%, coronary heart disease 17%, and social risk 15%). Patients diagnosed in primary healthcare were more frequently asymptomatic than in hospital setting (36%; P<.001). The therapeutic strategy was based on the heart rate control in 4 out of 5 patients. Anticoagulation therapy was widely used (84%), more frequently in patients with permanent vs. non-permanent AF (91 vs. 60%, P<.001). Follow-up and monitoring was mainly performed in primary care (72%). The anticoagulation control was suboptimal, with a 66% of the international normalized ratio (INR) in therapeutic range, dropping to 33% when the last 3 available INR were included (P<.001). CONCLUSIONS: A high rate of patients with anticoagulant therapy in primary healthcare has been found in this research. INR control, however, remains suboptimal. Heart rate control is the most commonly used strategy. The decision about the anticoagulation should be based on the thromboembolic risk rather than in the arrhytmia type. PMID- 23683970 TI - [Cholesterol emboli-induced ischemic colitis]. PMID- 23683969 TI - [Prevalence of type 2 diabetes mellitus in overweight or obese outpatients in Spain. OBEDIA Study]. AB - BACKGROUND AND OBJECTIVE: The increase in the prevalence of type 2 diabetes mellitus (T2DM) is related to the increase of obesity. We aimed to determine the Spanish prevalence of T2DM in patients with overweight or obesity attended by either family or specialist physicians. PATIENTS AND METHOD: Cross-sectional, multicenter and simultaneous 2-phase design, performed under clinical conditions. Phase A was designed to determine T2DM prevalence: 169,023 patients were recruited. Phase B was designed to define socio-demographic, clinical and metabolic profile of T2DM according to the body mass index (BMI): 7,754 patients were included. RESULTS: T2DM prevalence in overweight or obese patients was 23.6%; 17.8% of overweight patients were diabetic and T2DM was present in 34.8% of obese people. According to sex, 20.2% of men and 16.4% of women had T2DM. Overall, the mean of risk factors related to T2DM was 4.4 (SD 0,8); out of them, 92.6% patients had dyslipidemia, 73.7% hypertension and 62.5% performed a low physical activity. 37.8% of diabetic patients had vascular involvement. Only 43.1% of patients showed a proper metabolic control of T2DM (glycosilated hemoglobin<7%). CONCLUSIONS: T2DM is related to overweight and obesity and higher the BMI is, higher the T2DM prevalence. Dyslipidemia, hypertension and a low physical activity in diabetic patients are more frequent when BMI increases. Patients with inadequate metabolic control have a higher BMI. PMID- 23683971 TI - Proceedings of the editorial board meeting of The American Journal of Cardiology on March 10, 2013. PMID- 23683972 TI - Accuracy of three-dimensional versus two-dimensional echocardiography for quantification of aortic regurgitation and validation by three-dimensional three directional velocity-encoded magnetic resonance imaging. AB - Quantitative assessment of aortic regurgitation (AR) remains challenging. The present study evaluated the accuracy of 2-dimensional (2D) and 3-dimensional (3D) transthoracic echocardiography (TTE) for AR quantification, using 3D 3 directional velocity-encoded magnetic resonance imaging (VE-MRI) as the reference method. Thirty-two AR patients were included. With color Doppler TTE, 2D effective regurgitant orifice area (EROA) was calculated using the proximal isovelocity surface area method. From the 3D TTE multiplanar reformation data, 3D EROA was calculated by planimetry of the vena contracta. Regurgitant volumes (RVol) were obtained by multiplying the 2D-EROA and 3D-EROA by the velocity-time integral of AR jet and compared with that obtained using VE-MRI. For the entire population, 3D TTE RVol demonstrated a strong correlation and good agreement with VE-MRI RVol (r = 0.94 and -13.6 to 15.6 ml/beat, respectively), whereas 2D TTE RVol showed a modest correlation and large limits of agreement with VE-MRI (r = 0.70 and -22.2 to 32.8 ml/beat, respectively). Eccentric jets were noted in 16 patients (50%). In these patients, 3D TTE demonstrated an excellent correlation (r = 0.95) with VE-MRI, a small bias (0.1 ml/beat) and narrow limits of agreement (-18.7 to 18.8 ml/beat). Finally, the kappa agreement between 3D TTE and VE-MRI for grading of AR severity was good (k = 0.96), whereas the kappa agreement between 2D TTE and VE-MRI was suboptimal (k = 0.53). In conclusion, AR RVol quantification using 3D TTE is accurate, and its advantage over 2D TTE is particularly evident in patients with eccentric jets. PMID- 23683973 TI - A cash-back rebate program for healthy food purchases in South Africa: results from scanner data. AB - BACKGROUND: Improving diet quality is a key health promotion strategy. There is much interest in the role of prices and financial incentives to encourage healthy diet, but no data from large population interventions. PURPOSE: This study examines the effect of a price reduction for healthy food items on household grocery shopping behavior among members of South Africa's largest health plan. METHODS: The HealthyFood program provides a cash-back rebate of up to 25% for healthy food purchases in over 400 designated supermarkets across all provinces in South Africa. Monthly household supermarket food purchase scanner data between 2009 and 2012 are linked to 170,000 households (60% eligible for the rebate) with Visa credit cards. Two approaches were used to control for selective participation using these panel data: a household fixed-effect model and a case control differences-in-differences model. RESULTS: Rebates of 10% and 25% for healthy foods are associated with an increase in the ratio of healthy to total food expenditure by 6.0% (95% CI=5.3, 6.8) and 9.3% (95% CI=8.5, 10.0); an increase in the ratio of fruit and vegetables to total food expenditure by 5.7% (95% CI=4.5, 6.9) and 8.5% (95% CI=7.3, 9.7); and a decrease in the ratio of less desirable to total food expenditure by 5.6% (95% CI=4.7, 6.5) and 7.2% (95% CI=6.3, 8.1). CONCLUSIONS: Participation in a rebate program for healthy foods led to increases in purchases of healthy foods and to decreases in purchases of less-desirable foods, with magnitudes similar to estimates from U.S. time-series data. PMID- 23683974 TI - School soft drink availability and consumption among U.S. secondary students. AB - BACKGROUND: Consumption of sugar-sweetened beverages (SSBs) such as soft drinks has been associated with significantly increased energy intake and body weight. One strategy used to reduce soft drink consumption among adolescents has been reducing availability in schools; however, research is limited on associations between availability of soft drinks in school and student consumption. PURPOSE: This study examines associations between regular and diet soft drink availability in schools and student consumption using data from 329 secondary schools and 9284 students. METHODS: Data were obtained from two sources: (1) nationally representative cross-sectional samples of students in Grades 8, 10, and 12 from U.S. public and private schools in 2010 and 2011 in the Monitoring the Future study and (2) administrators of the same schools in the Youth, Education, and Society study. Multilevel modeling conducted in 2012 examined associations between school availability and student consumption controlling for student sociodemographics and school characteristics. RESULTS: In the total sample of more than 9000 students, regular and diet soft drink availability in school was not related to student consumption of these beverages in multivariate models. Yet, among African-American high school students, school regular and diet soft drink availability was significantly related to higher daily consumption (both before and after controlling for student and school factors). CONCLUSIONS: Although removal of soft drinks from schools may not result in significantly lower overall student consumption, such actions may result in significant decreases in soft drink consumption for specific student groups. PMID- 23683975 TI - Vending and school store snack and beverage trends: Minnesota secondary schools, 2002-2010. AB - BACKGROUND: The Child Nutrition and WIC Reauthorization Act of 2004 (hereafter called the 2004 Reauthorization Act) was federal legislation that required school districts participating in the federally funded school meal program to develop and implement policies addressing nutrition guidelines for all foods and beverages available on school campuses by the onset of the 2006/2007 school year. PURPOSE: Vending machine and school store (VMSS) availability and low-nutrient, energy-dense snacks and beverages in VMSS were assessed in a statewide sample of Minnesota secondary schools before and after the 2004 Reauthorization Act was implemented in 2006/2007. METHODS: The CDC School Health Profiles principal survey was collected from a representative sample of middle (n=170) and high (n=392) schools biennially from 2002 to 2010. Trends were estimated using general linear models with a logit link and linear spline modeling. Analyses were conducted in 2012. RESULTS: Among high schools, VMSS (p=0.001) and sugar sweetened beverages (p=0.004), high-fat salty snacks (p=0.001), and candy (p=0.001) in VMSS decreased from 2002 to 2008. In 2008, a change in slope direction from negative to positive occurred for all food practices and an increase in VMSS (p=0.014) and sugar-sweetened beverages (p=0.033) was seen. Among middle schools, VMSS (p=0.027), sugar-sweetened beverages (p=0.001), high fat salty snacks (p=0.001), and candy (p=0.029) decreased from 2002 to 2010. CONCLUSIONS: This study supports a link between policy and sustainable decreases in some food practices but not others and a differential effect that favors middle schools over high schools. Policy-setting is a dynamic process requiring ongoing surveillance to identify shifting trends. PMID- 23683976 TI - Nutritional quality at eight U.S. fast-food chains: 14-year trends. AB - BACKGROUND: Frequent consumption of fast-food menu items that are high in fat, sugar, and sodium contribute to poor dietary quality, increasing individuals' risk for diet-related chronic diseases. PURPOSE: To assess 14-year trends in the nutritional quality of menu offerings at eight fast-food restaurant chains in the U.S. METHODS: Data on menu items and food and nutrient composition were obtained in 2011 from archival versions of the University of Minnesota Nutrition Coordinating Center Food and Nutrient Database for eight fast-food restaurant chains. In this database, ingredient and nutrition information for all foods sold by the fast-food restaurants were updated biannually between 1997/1998 and 2009/2010. Healthy Eating Index (HEI)-2005 scores were calculated for each restaurant menu as a measure of the extent to which menu offerings were consistent with Dietary Guidelines for Americans and compared over time. RESULTS: Of a possible index total of 100 (healthiest), the HEI-2005 score across all eight fast-food restaurants was 45 in 1997/1998 and 48 in 2009/2010. Individually, restaurant scores in 1997/1998 ranged from 37 to 56 and in 2009/2010 ranged from 38 to 56. The greatest improvements in nutritional quality were seen in the increase of meat/beans, decrease in saturated fat, and decrease in the proportion of calories from solid fats and added sugars. The HEI-2005 score improved in six restaurants and decreased in two. CONCLUSIONS: The nutritional quality of menu offerings at fast-food restaurant chains included in this study increased over time, but further improvements are needed. Fast-food restaurants have an opportunity to contribute to a healthy diet for Americans by improving the nutritional quality of their menus. PMID- 23683977 TI - Menu labeling regulations and calories purchased at chain restaurants. AB - BACKGROUND: The federal menu labeling law will require chain restaurants to post caloric information on menus, but the impact of labeling is uncertain. PURPOSE: The goal of the current study was to examine the effect of menu labeling on calories purchased, and secondarily, to assess self-reported awareness and use of labels. DESIGN: Single-community pre-post-post cross-sectional study. Data were collected in 2008-2010 and analyzed in 2011-2012. SETTING/PARTICIPANTS: 50 sites from 10 chain restaurants in King County, Washington, selected through stratified, two-stage cluster random sampling. A total of 7325 customers participated. Eligibility criteria were: being an English speaker, aged >= 14 years, and having an itemized receipt. The study population was 59% male, 76% white non-Hispanic, and 53% aged<40 years. INTERVENTION: A regulation requiring chain restaurants to post calorie information on menus or menu boards was implemented. MAIN OUTCOME MEASURES: Mean number of calories purchased. RESULTS: No significant changes occurred between baseline and 4-6 months postregulation. Mean calories per purchase decreased from 908.5 to 870.4 at 18 months post implementation (38 kcal, 95% CI=-76.9, 0.8, p=0.06) in food chains and from 154.3 to 132.1 (22 kcal, 95% CI=-35.8, -8.5, p=0.002) in coffee chains. Calories decreased in taco and coffee chains, but not in burger and sandwich establishments. They decreased more among women than men in coffee chains. Awareness of labels increased from 18.8% to 61.7% in food chains and from 4.4% to 30.0% in coffee chains (both p<0.001). Among customers seeing calorie information, the proportion using it (about one third) did not change substantially over time. After implementation, food chain customers using information purchased on average fewer calories compared to those seeing but not using (difference=143.2 kcal, p<0.001) and those not seeing (difference=135.5 kcal, p<0.001) such information. CONCLUSIONS: Mean calories per purchase decreased 18 months after implementation of menu labeling in some restaurant chains and among women but not men. PMID- 23683978 TI - 5-year changes in afterschool physical activity and sedentary behavior. AB - BACKGROUND: The afterschool period holds promise for the promotion of physical activity, yet little is known about the importance of this period as children age. PURPOSE: To examine changes in physical activity of children aged 5-6 years and 10-12 years and their sedentary time in the afterschool period over 3 and 5 years, and to determine the contribution of this period to daily physical activity and sedentary behavior over time. METHODS: Data from two longitudinal studies conducted in Melbourne, Australia, were used. Accelerometer data were provided for 2053 children at baseline (Children Living in Active Neighbourhoods Study [CLAN]: 2001; Health, Eating and Play Study [HEAPS]: 2002/2003); 756 at 3 year follow-up (time point 2 [T2]); and 622 at 5-year follow-up (T3). Light (LPA), moderate (MPA) and vigorous (VPA) physical activity were determined using age-adjusted cut-points. Sedentary time was defined as <= 100 counts/minute. Multilevel analyses, conducted in April 2012, assessed change in physical activity and sedentary time and the contributions of the afterschool period to overall levels. RESULTS: Afterschool MPA and VPA decreased among both cohorts, particularly in the younger cohort, who performed less than half of their baseline levels at T3 (MPA: T1=24 minutes; T3=11 minutes; VPA: T1=12 minutes; T3=4 minutes). LPA also declined in the older cohort. Afterschool sedentary time increased among the younger (T1=42 minutes; T3=64 minutes) and older cohorts (T1=57 minutes; T3=84 minutes). The contribution of the afterschool period to overall MPA and VPA increased in the older cohort from 23% to 33% over 5 years. In the younger cohort, the contribution of the afterschool period to daily MPA and VPA decreased by 3% over 5 years. CONCLUSIONS: The importance of the afterschool period for children's physical activity increases with age, particularly as children enter adolescence. PMID- 23683979 TI - Sexual orientation disparities in cardiovascular biomarkers among young adults. AB - BACKGROUND: Emerging evidence from general population studies suggests that lesbian, gay, and bisexual (LGB) adults are more likely to experience adverse cardiovascular outcomes relative to heterosexuals. No studies have examined whether sexual orientation disparities exist in biomarkers of early cardiovascular disease risk. PURPOSE: To determine whether sexual orientation disparities in biomarkers of early cardiovascular risk are present among young adults. METHODS: Data come from Wave IV (2008-2009) of the National Longitudinal Study for Adolescent Health (N=12,451), a prospective nationally representative study of U.S. adolescents followed into young adulthood (mean age=28.9 years). A total of 520 respondents identified as lesbian, gay, or bisexual. Biomarkers included C-reactive protein, glycosylated hemoglobin, systolic and diastolic blood pressure, and pulse rate. Analyses were conducted in 2012. RESULTS: In gender-stratified models adjusted for demographics (age, race/ethnicity); SES (income, education); health behaviors (smoking, regular physical activity, alcohol consumption); and BMI, gay and bisexual men had significant elevations in C-reactive protein, diastolic blood pressure, and pulse rate, compared to heterosexual men. Despite having more risk factors for cardiovascular disease, including smoking, heavy alcohol consumption, and higher BMI, lesbians and bisexual women had lower levels of C-reactive protein than heterosexual women in fully adjusted models. CONCLUSIONS: Evidence was found for sexual orientation disparities in biomarkers of cardiovascular risk among young adults, particularly in gay and bisexual men. These findings, if confirmed in other studies, suggest that disruptions in core physiologic processes that ultimately confer risk for cardiovascular disease may occur early in the life course for sexual-minority men. PMID- 23683980 TI - Problem behavior and urban, low-income youth: a randomized controlled trial of positive action in Chicago. AB - BACKGROUND: Youth problem behaviors remain a public health issue. Youth in low income, urban areas are particularly at risk for engaging in aggressive, violent, and disruptive behaviors. PURPOSE: To evaluate the effects of a school-based social-emotional learning and health promotion program on problem behaviors and related attitudes among low-income, urban youth. DESIGN: A matched-pair, cluster RCT. SETTING/PARTICIPANTS: Participants were drawn from 14 Chicago Public Schools over a 6-year period of program delivery with outcomes assessed for a cohort of youth followed from Grades 3 to 8. Data were collected from Fall 2004 to Spring 2010, and analyzed in Spring 2012. INTERVENTION: The Positive Action program includes a scoped and sequenced K-12 classroom curriculum with six components: self-concept, social and emotional positive actions for managing oneself responsibly, and positive actions directed toward physical and mental health, honesty, getting along with others, and continually improving oneself. The program also includes teacher, counselor, family, and community training as well as activities directed toward schoolwide climate development. MAIN OUTCOME MEASURES: Youth reported on their normative beliefs in support of aggression and on their bullying, disruptive, and violent behaviors; parents rated youths' bullying behaviors and conduct problems; schoolwide data on disciplinary referrals and suspensions were obtained from school records. RESULTS: Multilevel growth-curve modeling analyses conducted on completion of the trial indicated that Positive Action mitigated increases over time in (1) youth reports of normative beliefs supporting aggressive behaviors and of engaging in disruptive behavior and bullying (girls only) and (2) parent reports of youth bullying behaviors (boys only). At study end-point, students in Positive Action schools also reported a lower rate of violence-related behavior than students in control schools. Schoolwide findings indicated positive program effects on both disciplinary referrals and suspensions. Program effect sizes ranged from -0.26 to -0.68. CONCLUSIONS: These results extend evidence of the effectiveness of the Positive Action program to low-income, minority, urban school settings, and to middle school-aged youth. PMID- 23683981 TI - Cost savings associated with prohibiting smoking in U.S. subsidized housing. AB - BACKGROUND: Tobacco smoking in multiunit housing can lead to secondhand-smoke (SHS) exposure among nonsmokers, increased maintenance costs for units where smoking is permitted, and fire risks. During 2009-2010, approximately 7.1 million individuals lived in subsidized housing in the U.S., a large proportion of which were children, elderly, or disabled. PURPOSE: This study calculated the annual economic costs to society that could be averted by prohibiting smoking in all U.S. subsidized housing. METHODS: Estimated annual cost savings associated with SHS-related health care, renovation of units that permit smoking, and smoking attributable fires in U.S. subsidized housing were calculated using residency estimates from the U.S. Department of Housing and Urban Development and previously reported national and state cost estimates for these indicators. When state estimates were used, a price deflator was applied to account for differential costs of living or pricing across states. Estimates were calculated overall and by cost type for all U.S. subsidized housing, as well as for public housing only. Data were obtained and analyzed between January and March 2011. RESULTS: Prohibiting smoking in all U.S. subsidized housing would yield cost savings of approximately $521 million per year, including $341 million in SHS related healthcare expenditures, $108 million in renovation expenses, and $72 million in smoking-attributable fire losses. Prohibiting smoking in U.S. public housing alone would yield cost savings of approximately $154 million per year. CONCLUSIONS: Efforts to prohibit smoking in all U.S. subsidized housing would protect health and generate substantial cost savings to society. PMID- 23683982 TI - Interventions to prevent post-traumatic stress disorder: a systematic review. AB - CONTEXT: Traumatic events are prevalent worldwide; trauma victims seek help in numerous clinical and emergency settings. Using effective interventions to prevent post-traumatic stress disorder (PTSD) is increasingly important. This review assessed the efficacy, comparative effectiveness, and harms of psychological, pharmacologic, and emerging interventions to prevent PTSD. EVIDENCE ACQUISITION: The following sources were searched for research on interventions to be included in the review: MEDLINE; Cochrane Library; CINAHL; EMBASE; PILOTS (Published International Literature on Traumatic Stress); International Pharmaceutical Abstracts; PsycINFO; Web of Science; reference lists of published literature; and unpublished literature (January 1, 1980 to July 30, 2012). Two reviewers independently selected studies, extracted data or checked accuracy, assessed study risk of bias, and graded strength of evidence. All data synthesis occurred between January and September 2012. EVIDENCE SYNTHESIS: Nineteen studies covered various populations, traumas, and interventions. In meta analyses of three trials (from the same team) for people with acute stress disorder, brief trauma-focused cognitive behavioral therapy was more effective than supportive counseling in reducing the severity of PTSD symptoms (moderate strength); these two interventions had similar results for incidence of PTSD (low strength); depression severity (low-strength); and anxiety severity (moderate strength). PTSD symptom severity after injury decreased more with collaborative care than usual care (single study; low-strength). Debriefing did not reduce incidence or severity of PTSD or psychological symptoms in civilian traumas (low strength). Evidence about relevant outcomes was unavailable for many interventions or was insufficient owing to methodologic shortcomings. CONCLUSIONS: Evidence is very limited regarding best practices to treat trauma exposed individuals. Brief cognitive behavioral therapy may reduce PTSD symptom severity in people with acute stress disorder; collaborative care may help decrease symptom severity post-injury. PMID- 23683983 TI - Tracking physical activity and sedentary behavior in childhood: a systematic review. AB - CONTEXT: To date, no reviews have investigated the evidence of tracking of physical activity and sedentary behavior specifically during early childhood (aged 0-5.9 years) or from early childhood to middle childhood (aged 6-12 years). It is important to review the evidence of tracking of these behaviors to determine their stability during the foundational early years of life. EVIDENCE ACQUISITION: A literature search of studies was conducted in seven electronic databases (January 1980 to April 2012). Studies were compared on methodologic quality and evidence of tracking of physical activity or sedentary behavior. Tracking was defined as the stability (or relative ranking within a cohort) of behaviors, such as physical activity and sedentary behavior, over time. EVIDENCE SYNTHESIS: Eleven studies met the inclusion criteria. All studies reporting physical activity outcomes had high methodologic quality; 71% of studies reporting sedentary behavior outcomes had high methodologic quality. Of the tracking coefficients for physical activity, 4% were large, 60% were moderate, and 36% were small. Of the tracking coefficients for sedentary behavior, 33% were large, 50% were moderate, and 17% were small. Overall, there was evidence of moderate tracking of physical activity during early childhood, and from early childhood to middle childhood, and of moderate-to-large tracking of sedentary behavior during early childhood and from early childhood to middle childhood. CONCLUSIONS: This review highlights the importance of establishing recommended levels of physical activity and sedentary behavior during the early years of life. Based on this review, the following recommendations are made: (1) early childhood should be targeted as a critical time to promote healthy lifestyle behaviors through methodologically sound prevention studies; and (2) future tracking studies should assess a broad range of sedentary behaviors using objective measures. PMID- 23683984 TI - Financial incentives for healthy behavior: ethical safeguards for behavioral economics. AB - Economic incentives to promote healthy behavior are becoming increasingly common and have been suggested as an approach to decreasing healthcare costs. Ethical concerns about programs with such incentives are that they may contribute to inequities, be coercive, interfere with therapeutic relationships, undermine personal responsibility for health, and decrease social solidarity. Additionally, they may be a source of stigma or discrimination, promote dependence, and be unfair for those already engaged in targeted health behaviors or those who cannot fulfill the incentivized behaviors. Incentive programs need to incorporate appropriate safeguards to monitor these risks and support fairness in offering economic incentives to promote healthy behavior. PMID- 23683985 TI - Prevention screening and counseling: strategy for integration into medical education and practice. AB - Providing optimal preventive services across the life span is integral to improving the nation's health. However, teaching future health professionals evidence-based prevention screening and counseling has notable limitations. Applying the U.S. Preventive Services Task Force (Task Force) preventive services recommendations is necessary but not sufficient to teach comprehensive and practical preventive services delivery. Certain important health topics have not yet been investigated by the Task Force; other Task Force health topics have insufficient evidence or nonspecific recommendations. The purpose of the current paper is to provide a strategy and develop a tool to educate future healthcare professionals in recommendations for prevention screening and counseling. Age specific preventive history charts for children and adults were created using a total of 60 recommendations from the following sources (with number of recommendations shown): the Task Force (n=37); four primary care professional organizations (n=15); and a representative panel of experts (n=8). Using a systematic approach that incorporates other accredited organizations and inclusion criteria (as described) yielded a practical tool that is applicable in both educational and clinical settings. PMID- 23683986 TI - Strategies to reduce indoor tanning: current research gaps and future opportunities for prevention. AB - Exposure to ultraviolet radiation from indoor tanning device use is associated with an increased risk of skin cancer, including risk of malignant melanoma, and is an urgent public health problem. By reducing indoor tanning, future cases of skin cancer could be prevented, along with the associated morbidity, mortality, and healthcare costs. On August 20, 2012, the CDC hosted a meeting to discuss the current body of evidence on strategies to reduce indoor tanning as well as research gaps. Using the Action Model to Achieve Healthy People 2020 Overarching Goals as a framework, the current paper provides highlights on the topics that were discussed, including (1) the state of the evidence on strategies to reduce indoor tanning; (2) the tools necessary to effectively assess, monitor, and evaluate the short- and long-term impact of interventions designed to reduce indoor tanning; and (3) strategies to align efforts at the national, state, and local levels through transdisciplinary collaboration and coordination across multiple sectors. Although many challenges and barriers exist, a coordinated, multilevel, transdisciplinary approach has the potential to reduce indoor tanning and prevent future cases of skin cancer. PMID- 23683988 TI - Nutritional quality of menu offerings at eight fast-food chains in the U.S.: a commentary. PMID- 23683987 TI - Preventing skin cancer through reduction of indoor tanning: current evidence. AB - Exposure to ultraviolet radiation from indoor tanning devices (tanning beds, booths, and sun lamps) or from the sun contributes to the risk of skin cancer, including melanoma, which is the type of skin cancer responsible for most deaths. Indoor tanning is common among certain groups, especially among older adolescents and young adults, adolescent girls and young women, and non-Hispanic whites. Increased understanding of the health risks associated with indoor tanning has led to many efforts to reduce use. Most environmental and systems efforts in the U.S. (e.g., age limits or requiring parental consent/accompaniment) have occurred at the state level. At the national level, the U.S. Food and Drug Administration and the Federal Trade Commission regulate indoor tanning devices and advertising, respectively. The current paper provides a brief review of (1) the evidence on indoor tanning as a risk factor for skin cancer; (2) factors that may influence use of indoor tanning devices at the population level; and (3) various environmental and systems options available for consideration when developing strategies to reduce indoor tanning. This information provides the context and background for the companion paper in this issue of the American Journal of Preventive Medicine, which summarizes highlights from an informal expert meeting convened by the CDC in August 2012 to identify opportunities to prevent skin cancer by reducing use of indoor tanning devices. PMID- 23683989 TI - What's impeding post-traumatic stress disorder prevention? PMID- 23683990 TI - Neighborhood walkability: field validation of geographic information system measures. AB - BACKGROUND: Given the health benefits of walking, there is interest in understanding how physical environments favor walking. Although GIS-derived measures of land-use mix, street connectivity, and residential density are commonly combined into indices to assess how conducive neighborhoods are to walking, field validation of these measures is limited. PURPOSE: To assess the relationship between audit- and GIS-derived measures of overall neighborhood walkability and between objective (audit- and GIS-derived) and participant reported measures of walkability. METHODS: Walkability assessments were conducted in 2009. Street-level audits were conducted using a modified version of the Pedestrian Environmental Data Scan. GIS analyses were used to derive land-use mix, street connectivity, and residential density. Participant perceptions were assessed using a self-administered questionnaire. Audit, GIS, and participant reported indices of walkability were calculated. Spearman correlation coefficients were used to assess the relationships between measures. All analyses were conducted in 2012. RESULTS: The correlation between audit- and GIS-derived measures of overall walkability was high (R=0.7 [95% CI=0.6, 0.8]); the correlations between objective (audit and GIS-derived) and participant-reported measures were low (R=0.2 [95% CI=0.06, 0.3]; R=0.2 [95% CI=0.04, 0.3], respectively). For comparable audit and participant-reported items, correlations were higher for items that appeared more objective (e.g., sidewalk presence, R=0.4 [95% CI=0.3, 0.5], versus safety, R=0.1 [95% CI=0.003, 0.3]). CONCLUSIONS: The GIS-derived measure of walkability correlated well with the in-field audit, suggesting that it is reasonable to use GIS-derived measures in place of more labor-intensive audits. Interestingly, neither audit- nor GIS-derived measures correlated well with participants' perceptions of walkability. PMID- 23683991 TI - Equity-specific effects of 26 Dutch obesity-related lifestyle interventions. AB - CONTEXT: Reducing health inequalities is a policy priority in many developed countries. Little is known about effective strategies to reduce inequalities in obesity and its underlying behaviors. The goal of the study was to investigate differential effectiveness of interventions aimed at obesity prevention, the promotion of physical activity or a healthy diet by SES. EVIDENCE ACQUISITION: Subgroup analyses in 2010 and 2011 of 26 Dutch studies funded by The Netherlands Organization for Health Research and Development after 1990 (n=17) or identified by expert contact (n=9). Methodologic quality and differential effects were synthesized in harvest plots, subdivided by setting, age group, intensity, and time to follow-up. EVIDENCE SYNTHESIS: Seven lifestyle interventions were rated more effective and four less effective in groups with high SES; for 15 studies no differential effects could be demonstrated. One study in the healthcare setting showed comparable effects in both socioeconomic groups. The only mass media campaign provided modest evidence for higher effectiveness among those with high SES. Individually tailored and workplace interventions were either more effective in higher-SES groups (n=4) or no differential effects were demonstrated (n=9). School-based studies (n=7) showed mixed results. Two of six community studies provided evidence for better effectiveness in lower-SES groups; none were more effective in higher-SES groups. One high-intensity community-based study provided best evidence for higher effectiveness in low-SES groups. CONCLUSIONS: Although for the majority of interventions aimed at obesity prevention, the promotion of physical activity, or a healthy diet, no differential effectiveness could be demonstrated, interventions may widen as well as reduce socioeconomic inequalities in these outcomes. Equity-specific subgroup analyses contribute to needed knowledge about what may work to reduce socioeconomic inequalities in obesity and underlying health behaviors. PMID- 23683992 TI - The role of physicians in promoting healthier built environments. PMID- 23683994 TI - The impact of a depression awareness campaign on mental health literacy and mental morbidity among gay men. AB - BACKGROUND: High prevalences of depression and suicidality have been found among gay men. This paper assesses the possible impact of Blues-out, a depression awareness campaign based on the European Alliance Against Depression targeting the gay/lesbian community in Geneva, Switzerland. METHODS: In 2007 and 2011, pre- and post-intervention surveys were conducted among two distinct samples of gay men in Geneva, recruited by probability-based time-space sampling. Effect sizes and net percent changes are reported for mental health literacy and mental health outcomes in 2007 and 2011 as well as among men aware and unaware of Blues-out in 2011. RESULTS: 43% of the respondents correctly recognized depression in 2011 with no change vis-a-vis 2007. Despite small effect sizes, significant net decreases (from -18% to -28%) were seen in lifetime suicide plans, 12-month suicidal ideation, lifetime depression, and 4-week psychological distress between 2007 and 2011. These decreases were not accompanied by changes in any of the numerous items on attitudes/knowledge, found only when comparing men aware and unaware of Blues-out in 2011. More men aware of Blues-out found specialists and psychological therapies helpful than their counterparts and correctly identified depression and gay men's greater risk for depression. LIMITATIONS: Community level assessment with no control. CONCLUSIONS: Although improvement in depression recognition and decrease in suicide attempts could not be replicated unequivocally in this adapted intervention among gay men, there are indications that this evidence-based depression awareness campaign may have lessened suicidality and mental morbidity and improved mental health literacy and help seeking. PMID- 23683993 TI - Treatment response for acute depression is not associated with number of previous episodes: lack of evidence for a clinical staging model for major depressive disorder. AB - Mental illness has been observed to follow a neuroprogressive course, commencing with prodrome, then onset, recurrence and finally chronic illness. In bipolar disorder and schizophrenia responsiveness to treatment mirrors these stages of illness progression, with greater response to treatment in the earlier stages of illness and greater treatment resistance in chronic late stage illness. Using data from 5627 participants in 15 controlled trials of duloxetine, comparator arm (paroxetine, venlafaxine, escitalopram) or placebo for the treatment of an acute depressive episode, the relationship between treatment response and number of previous depressive episodes was determined. Data was dichotomised for comparisons between participants who had >3 previous episodes (n=1697) or <=3 previous episodes (n=3930), and additionally for no previous episodes (n=1381) or at least one previous episode (n=4246). Analyses were conducted by study arm for each clinical trial, and results were then pooled. There was no significant difference between treatment response and number of previous depressive episodes. This unexpected finding suggests that treatments to reduce symptoms of depression during acute illness do not lose efficacy for patients with a longer history of illness. PMID- 23683995 TI - Functional analysis of bovine Nramp1 and production of transgenic cloned embryos in vitro. AB - Natural resistance-associated macrophage protein 1 (Nramp1) plays an important role in restraining the growth of intracellular pathogens within macrophages. In this study, Nramp1 cDNA was cloned from Qinchuan cattle and its anti-bacterial activity was demonstrated as being able to significantly inhibit the growth of Salmonella abortusovis and Brucella abortus in macrophages. Calf fibroblasts stably transfected with pSP-NRAMP1-HA vector were used to reconstruct bovine embryos by somatic cell nuclear transfer (SCNT). Reconstructed embryos were maturated in vitro and the blastocyst formation rate (14.0%) was similar to that of control embryos (14.5%). Transgenic blastocysts were transplanted into 43 recipient cattle, of which 14 recipients became pregnant as evidenced by non return estrus and by rectal palpation. One fetus was aborted after 61/2 months of pregnancy and transgene integration was confirmed by semi-quantitative polymerase chain reaction. Together, this study showed that bovine Nramp1 retains biological function against the growth of intracellular bacteria and can be used to reconstruct embryos and produce Nramp1 transgenic cattle, which may benefit the animal and enhance their ability to prevent attack by intracellular pathogens. PMID- 23683996 TI - Immunohistochemical detection of S100A1 in the postmortem diagnosis of acute myocardial infarction. AB - BACKGROUND: Sudden cardiac death resulting from acute myocardial infarction (AMI) constitutes a significant percentage of the caseload for forensic and clinical pathologists. When sudden death occurs at an early stage (<6 h), pathologists experience difficulty in the postmortem diagnosis of AMI. Because of the specific tissue distribution of S100A1 and its relationship with acute ischemic heart disease, this study aimed to evaluate the performance of S100A1 in the postmortem diagnosis of AMI. METHODS: We constructed a rat model of AMI through permanent ligation of the left anterior descending coronary artery (LAD) to investigate the depletion of S100A1 from ischemic cardiomyocytes by immunohistochemistry and measuring S100A1 plasma concentrations by enzyme-linked immunosorbent assay at varying post-infarction intervals. In addition, immunohistochemical staining of S100A1 for definite infarction, suspected early infarction, and in normal human hearts, was also performed to test its practical feasibility for postmortem diagnosis of AMI at an early stage. RESULTS: As early as 15 min after ligation of the LAD, depletion of S100A1 was observed in ischemic cardiomyocytes, and S100A1 plasma concentration was also significantly higher than that of the sham-operated group (P < 0.001). With continuation of the occlusion time, the depleted areas of S100A1 further expanded and S100A1 plasma concentrations further increased. For autopsy material, all human cases of definite myocardial infarction and suspected early infarction showed well-defined areas without S100A1 staining. None of the normal human cases showed diffuse depletion of S100A1. CONCLUSION: Our results suggest that immunohistochemical detection of S100A1 is useful for the postmortem diagnosis of AMI at an early stage. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/4366650979519818. PMID- 23683997 TI - Management of anastomotic stricture after artificial urinary sphincter placement in patients who underwent salvage prostatectomy. AB - OBJECTIVE: To report on a safe endoscopic management technique for the treatment of an anastomotic stricture (AS) in patients with an artificial urinary sphincter (AUS). METHODS: Five patients with a history of salvage prostatectomy after radiation therapy that developed an AS after AUS placement were treated with a rigid ureteroscope and a Holmium YAG (Ho: YAG) laser to incise the AS. The AUS was opened and deactivated but not decoupled or removed during the procedure. The rigid ureteroscope allowed complete control of the laser fiber to incise the stricture at the 3 and 9 o' clock positions and then circumferentially. RESULTS: There were no intraoperative complications and the mean operative time was 42.6 minutes. Of the 5 patients who underwent holmium laser incision of an AS after AUS placement, none developed AUS malfunction or required device replacement. No patients reported worsening of urinary incontinence after treatment. Two patients required repeat holmium laser incision for AS recurrence. CONCLUSION: Using a rigid ureteroscope and a holmium laser to incise an AS after AUS placement seems to be a safe management option that does not damage the AUS or result in worsening incontinence. This treatment strategy provides an endoscopic alternative to using open surgical technique to uncouple or remove the AUS while treating the AS. PMID- 23683998 TI - Molecular characterization of a H5N1 highly pathogenic avian influenza virus clade 2.3.2.1b circulating in Vietnam in 2011. AB - The emergence of highly pathogenic avian influenza (HPAI) H5N1 viruses and the risk of a human pandemic have highlighted the need for advance stockpiling of vaccine. Current vaccines may be sub-optimally matched to the actual pandemic virus due to the rapid dissemination and ongoing evolution of avian H5N1 viruses. We report here the evaluation of efficacy of NIBRG-14 vaccine (clade 1 A/Vietnam/1194/2004) against the H5N1 HPAI virus strains circulating in Vietnam. The birds were either vaccinated with a single or booster dose of vaccine by subcutaneous injection; then challenged with three H5N1 HPAI viruses (clade 1, clade 2.3.2.1a and clade 2.3.2.1b) at day 21 post-vaccination (p. v.). The results showed that NIBRG-14 vaccine protected birds from clade 1 and clade 2.3.2.1a infections. Notably, we observed that NIGRG-14 vaccine did not confer protection against clade 2.3.2.1b challenge virus. To get new insights of how H5N1 clade 2.3.2.1b (A/Duck/QuangNgai/1037/11) virus can escape from the host immune response induced by the vaccine, we further analyzed the HA gene - a key virulence determinant of the virus. Amino acid sequence analysis indicated that this virus contained the sequence SPQRERRRK-R/G at the cleavage site in the HA molecule, indicating its high virulence. Additionally, we identified numerous mutations with amino acid substitutions in the hemagglutinin: M226I, I239S located at N-link glycosylation site and 2H, 45N, 53K 120D, 133A and 14N mutations at antigenic site, which can affect receptor specificity as well as viral pathogenicity. Notably, I239S and S133A mutations are unique to A/Duck/QuangNgai/1037/2011, suggesting that it may involve in the virus' ability to evade the host immune system. Taken together, phylogenetic analysis showed that continual mutations in the HA gene may have generated a novel antigenic strain and that probably changed the virulence of the virus and made the H5N1 clade 2.3.2.1b resistant to NIBRG-14 vaccine. PMID- 23683999 TI - Evaluation of the immune response elicited by vaccination with viral vectors encoding FMDV capsid proteins and boosted with inactivated virus. AB - The aim of the present study was to assess the effect of introducing a priming step with replication-defective viral vectors encoding the capsid proteins of FMDV, followed by a boost with killed virus vaccines, using a suitable BALB/c mice model. Additionally, the immune response to other combined vector immunization regimens was studied. For this purpose, we analyzed different prime boost immunizations with recombinant adenovirus (Ad), herpesvirus amplicons (Hs) and/or killed virus (KV) vaccines. The highest antibody titers were found in the group that received two doses of adjuvanted KV (P<0.002). Antibody titers were higher in those groups receiving a mixed regimen of vectors, compared to immunization with either vector alone (P<0.0001). Priming with any of the viral vectors induced a shift of the cytokine balance toward a Th1 type immune response regardless of the delivery system used for boosting. The highest IgG1 titer was induced by two doses of adjuvanted KV (P=0.0002) and the highest IgG2a titer corresponded to the group primed with Ad and boosted with KV (P=0.01). Re stimulation of all groups of mice with 0.5 MUg of inactivated virus five months later resulted in a fast increase of antibody titers in all the groups tested. After virus stimulation, antibody titers in the groups that received KV alone or Ad prime-KV boost, were indistinguishable (P=0.800). Protection from challenge was similar (75%) in the groups of animals that received Ad prime-Hs boost or Ad prime-KV boost, or two doses of oil-adjuvanted KV. The data presented in this study suggest that sequential immunization with viral vectors-based vaccines combined with protein-based vaccines have the potential to enhance the quality of the immune response against FMDV. PMID- 23684000 TI - Positive versus negative sentinel nodes in early breast cancer patients: axillary or loco-regional relapse and survival. A study spanning 2000-2012. AB - Sentinel Node Biopsy (SNB) is a minimally invasive alternative to elective axillary lymph node dissection (ALND) for nodal staging in early breast cancer. The present study was conducted to evaluate prognostic implications of a negative sentinel node (SN) versus a positive SN (followed by completion ALND) in a closely followed-up sample of early breast cancer patients. We studied 889 consecutive breast cancer patients operated for 908 primaries. Patients received adjuvant therapy with chemotherapy, hormone therapy and eventually trastuzumab. Radiation therapy was based on tangential radiation fields that usually included axillary level I. Median follow-up was 47 months. Axillary recurrence was seen in 1.2% (2/162) of positive SN patients, and 0.8% (5/625) of negative SN patients (p = n.s.). There was an overall 3.2% loco-regional failure rate (29/908). Incidence of distant recurrence was 3.3% (23/693) for negative SN patients, and 4.6% (9/196) for positive SN patients (p = n.s.). Overall mortality rate was 4% (8/198) for positive SN patients, while the corresponding specific mortality rate was 2.5% (5/198). For patients with negative SNs, overall mortality was 4.9% (34/693), and the specific mortality was 1.4% (19/693) (p = n.s.). We did not find significant differences in axillary/loco-regional relapse, distant metastases, disease-free interval or mortality between SN negative and SN positive patients, with a follow-up over 4 years. PMID- 23684001 TI - Screw-wire osteo-traction (SWOT) in the reduction and fixation of frontonasal dysjunction in Le Fort II/III upper mid-facial fractures. PMID- 23684002 TI - Pharmacokinetic analysis of doripenem in elderly patients with nosocomial pneumonia. AB - Doripenem is a parenteral carbapenem antibiotic with broad-spectrum antimicrobial activity. A pharmacokinetic (PK) analysis of a 1-h intravenous (i.v.) dose of 500 mg doripenem in ten clinically ill, elderly patients with nosocomial pneumonia (NP) was conducted. Concentrations of unchanged doripenem were measured in plasma using a validated liquid chromatography method coupled to a tandem mass spectrometry assay. Geometric means of maximum plasma concentration, area under the plasma concentration-time curve over the dosing interval at steady state, time to reach maximum plasma concentration, and terminal elimination half-life for 500 mg doripenem as a 1-h infusion were 22.40 MUg/mL, 57.02 MUgh/mL, 1.0h and 1.89h, respectively. In addition, a population PK analysis was performed to examine the influencing factors on the pharmacokinetics of doripenem and to estimate the time above minimum inhibitory concentration (T>MIC) by a post hoc Bayesian estimation. The effect of creatinine clearance was the most significant covariate on doripenem clearance. The estimated %T>MIC against a MIC of 2 MUg/mL exceeded 40% in all patients. In the treatment of NP in elderly patients, a 1-h i.v. dose of 500 mg doripenem three times daily may provide a favourable antimicrobial effect against bacteria with MICs up to 2MUg/mL and would therefore be a treatment option for NP. PMID- 23684003 TI - Antimicrobial resistance: action to combat the rising microbial challenges. AB - Antimicrobial therapy transformed medical practice from a merely diagnosis focused approach 80 years ago to a treatment-focused approach, saving millions of lives in the years to follow. Today, numerous medical advances made possible by effective antibiotics are being threatened by the relentlessly rising rates of bacteria resistant to all currently available antibiotics. This phenomenon is a consequence of antibiotic misuse, which exerts undue selective pressure on micro organisms, combined with defective infection control practices that accelerate their spread. Its impact on societies worldwide is immense, resulting in loss of human life and money. An alarming pattern of resistance involving multidrug resistant and sometimes pandrug-resistant Gram-negative bacteria is currently emerging. In response to the global public health threat posed by antimicrobial resistance (AMR), a number of national and international actions and initiatives have been developed in recent years to address this issue. Although the optimally effective and cost-effective strategy to reduce AMR is not known, a multifaceted approach is most likely to be successful. It should include actions aiming at optimising antibiotic use, strengthening surveillance and infection control, and improving healthcare worker and public education with regard to antibiotics. Research efforts to bring new effective antibiotics to patients need to be fostered in order to negate the consequences of the current lack of antimicrobial therapy options. A holistic view of AMR as well as intersectoral collaboration between human and veterinary medicine is required to best address the problem. PMID- 23684004 TI - Beyond the traditional immune response: bacterial interaction with phagocytic cells. AB - The human immune response is well equipped to sense and react to infectious agents in order to achieve efficient immune defence in most instances. A major event in the early control of infection is phagocytic killing of the pathogen. However, important human pathogens have evolved sophisticated mechanisms to modulate the immune response and thereby promote their own survival. In this review, we focus on pathogen-mediated modulation and/or exploitation of phagocytic cells. In particular, the mechanisms employed by Streptococcus pyogenes are described, with special attention given to intracellular persistence and stimulation of phagocytic cells leading to disease severity. The crucial role of these mechanisms in the pathogenesis of severe invasive streptococcal infections, such as necrotising fasciitis and streptococcal toxic shock syndrome, is described. PMID- 23684005 TI - In vitro activities of PNU-100480 and linezolid against drug-susceptible and drug resistant Mycobacterium tuberculosis isolates. PMID- 23684006 TI - Allometry and physiologic time: comment on "Physiologic time: a hypothesis" by West & West. PMID- 23684007 TI - How to establish causality in epilepsy surgery. AB - Focality in electro-clinical or neuroimaging data often motivates epileptologists to consider epilepsy surgery in patients with medically-uncontrolled seizures, while not all focal findings are causally associated with the generation of epileptic seizures. With the help of Hill's criteria, we have discussed how to establish causality in the context of the presurgical evaluation of epilepsy. The strengths of EEG include the ability to determine the temporal relationship between cerebral activities and clinical events; thus, scalp video-EEG is necessary in the evaluation of the majority of surgical candidates. The presence of associated ictal discharges can confirm the epileptic nature of a particular spell and whether an observed neuroimaging abnormality is causally associated with the epileptic seizure. Conversely, one should be aware that scalp EEG has a limited spatial resolution and sometimes exhibits propagated epileptiform discharges more predominantly than in situ discharges generated at the seizure onset zone. Intraoperative or extraoperative electrocorticography (ECoG) is utilized when noninvasive presurgical evaluation, including anatomical and functional neuroimaging, fails to determine the margin between the presumed epileptogenic zone and eloquent cortex. Retrospective as well as prospective studies have reported that complete resection of the seizure-onset zone on ECoG was associated with a better seizure outcome, but not all patients became seizure free following such resective surgery. Some retrospective studies suggested that resection of sites showing high-frequency oscillations (HFOs) at >80Hz on interictal or ictal ECoG was associated with a better seizure outcome. Others reported that functionally-important areas may generate HFOs of a physiological nature during rest as well as sensorimotor and cognitive tasks. Resection of sites showing task-related augmentation of HFOs has been reported to indeed result in functional loss following surgery. Thus, some but not all sites showing interictal HFOs are causally associated with seizure generation. Furthermore, evidence suggests that some task-related HFOs can be transiently suppressed by the prior occurrence of interictal spikes. The significance of interictal HFOs should be assessed by taking into account the eloquent cortex, seizure-onset zone, and cortical lesions. Video-EEG and ECoG generally provide useful but still limited information to establish causality in presurgical evaluation. A comprehensive assessment of data derived from multiple modalities is ultimately required for successful management. PMID- 23684009 TI - Sequence kernel association tests for the combined effect of rare and common variants. AB - Recent developments in sequencing technologies have made it possible to uncover both rare and common genetic variants. Genome-wide association studies (GWASs) can test for the effect of common variants, whereas sequence-based association studies can evaluate the cumulative effect of both rare and common variants on disease risk. Many groupwise association tests, including burden tests and variance-component tests, have been proposed for this purpose. Although such tests do not exclude common variants from their evaluation, they focus mostly on testing the effect of rare variants by upweighting rare-variant effects and downweighting common-variant effects and can therefore lose substantial power when both rare and common genetic variants in a region influence trait susceptibility. There is increasing evidence that the allelic spectrum of risk variants at a given locus might include novel, rare, low-frequency, and common genetic variants. Here, we introduce several sequence kernel association tests to evaluate the cumulative effect of rare and common variants. The proposed tests are computationally efficient and are applicable to both binary and continuous traits. Furthermore, they can readily combine GWAS and whole-exome-sequencing data on the same individuals, when available, and are also applicable to deep resequencing data of GWAS loci. We evaluate these tests on data simulated under comprehensive scenarios and show that compared with the most commonly used tests, including the burden and variance-component tests, they can achieve substantial increases in power. We next show applications to sequencing studies for Crohn disease and autism spectrum disorders. The proposed tests have been incorporated into the software package SKAT. PMID- 23684008 TI - GLP-1 promotes angiogenesis in human endothelial cells in a dose-dependent manner, through the Akt, Src and PKC pathways. AB - INTRODUCTION: Novel anti-diabetic medications that mimic or augment the physiological actions of GLP-1 improve cardiovascular risk factors in diabetics and GLP-1 has been proposed to have a beneficial role in the cardiovascular system. GLP-1 may have a direct cardioprotective role by decreasing infarct size and protecting from ischemia-reperfusion injury while prolonging survival in rodent models. The mechanisms underlying these observations remain largely unknown. In vitro studies suggest that GLP-1 may promote endothelial cell proliferation, but no study to date has evaluated a potential direct effect of GLP-1 on angiogenesis. SPECIFIC AIM: To evaluate whether GLP-1 affects angiogenesis in humans and to elucidate underlying molecular mechanisms. MATERIAL AND METHODS: We utilized a 3D culture system where spherules of human umbilical vein endothelial cells (HUVECs) embedded in a collagen scaffold were treated with escalating doses of human recombinant GLP-1 (50-2000 nmol/L) and the formation of new vessels was observed and quantified. Signaling inhibitors were utilized to identify molecular pathways through which GLP-1 promotes angiogenesis. RESULTS: We demonstrate that GLP-1 promotes angiogenesis in a dose-dependent manner. The maximum effect on angiogenesis was observed at a GLP-1 dose of 500 nmol/L, while increased angiogenesis occurred in response to doses ranging from 200 nmol/L to 1000 nmol/L. Pre-treatment of the system with Akt inhibitor IV, Bisindolylmaleimide (PKC inhibitor) and src inhibitor I resulted in a significant decrease of the GLP-1 induced angiogenesis. CONCLUSIONS: This is the first study to demonstrate that GLP-1 promotes angiogenesis in a HUVEC three dimensional in vitro model. This effect requires pharmacological doses and is mediated through the Akt, PKC and src pathways. PMID- 23684010 TI - Mutations in POFUT1, encoding protein O-fucosyltransferase 1, cause generalized Dowling-Degos disease. AB - Dowling-Degos disease (DDD), or reticular pigmented anomaly of the flexures, is a type of rare autosomal-dominant genodermatosis characterized by reticular hyperpigmentation and hypopigmentation of the flexures, such as the neck, axilla, and areas below the breasts and groin, and shows considerable heterogeneity. Loss of-function mutations of keratin 5 (KRT5) have been identified in DDD individuals. In this study, we collected DNA samples from a large Chinese family affected by generalized DDD and found no mutation of KRT5. We performed a genome wide linkage analysis of this family and mapped generalized DDD to a region between rs1293713 and rs244123 on chromosome 20 [corrected]. By exome sequencing, we identified nonsense mutation c.430G>T (p.Glu144(*)) in POFUT1, which encodes protein O-fucosyltransferase 1, in the family. Study of an additional generalized DDD individual revealed the heterozygous deletion mutation c.482delA (p.Lys161Serfs(*)42) in POFUT1. Knockdown of POFUT1 reduces the expression of NOTCH1, NOTCH2, HES1, and KRT5 in HaCaT cells. Using zebrafish, we showed that pofut1 is expressed in the skin and other organs. Morpholino knockdown of pofut1 in zebrafish produced a phenotype characteristic of hypopigmentation at 48 hr postfertilization (hpf) and abnormal melanin distribution at 72 hpf, replicating the clinical phenotype observed in our DDD individuals. At 48 and 72 hpf, tyrosinase activities decreased by 33% and 45%, respectively, and melanin protein contents decreased by 20% and 25%, respectively. Our findings demonstrate that POFUT1 mutations cause generalized DDD. These results strongly suggest that the protein product of POFUT1 plays a significant and conserved role in melanin synthesis and transport. PMID- 23684011 TI - FAM111A mutations result in hypoparathyroidism and impaired skeletal development. AB - Kenny-Caffey syndrome (KCS) and the similar but more severe osteocraniostenosis (OCS) are genetic conditions characterized by impaired skeletal development with small and dense bones, short stature, and primary hypoparathyroidism with hypocalcemia. We studied five individuals with KCS and five with OCS and found that all of them had heterozygous mutations in FAM111A. One mutation was identified in four unrelated individuals with KCS, and another one was identified in two unrelated individuals with OCS; all occurred de novo. Thus, OCS and KCS are allelic disorders of different severity. FAM111A codes for a 611 amino acid protein with homology to trypsin-like peptidases. Although FAM111A has been found to bind to the large T-antigen of SV40 and restrict viral replication, its native function is unknown. Molecular modeling of FAM111A shows that residues affected by KCS and OCS mutations do not map close to the active site but are clustered on a segment of the protein and are at, or close to, its outer surface, suggesting that the pathogenesis involves the interaction with as yet unidentified partner proteins rather than impaired catalysis. FAM111A appears to be crucial to a pathway that governs parathyroid hormone production, calcium homeostasis, and skeletal development and growth. PMID- 23684014 TI - Unusual Le Fort I fracture. PMID- 23684013 TI - Treatment of chronic recurrent dislocation of the temporomandibular joint with injection of autologous blood alone, intermaxillary fixation alone, or both together: a prospective, randomised, controlled clinical trial. AB - Our aim was to evaluate the efficacy of autologous blood injection in the treatment of chronic recurrent dislocation of the temporomandibular joint (TMJ) in a prospective randomised controlled clinical study. Forty-eight patients (11 men and 37 women) with chronic recurrent dislocation of the TMJ were randomly assigned to 1 of 3 equally sized groups. Patients in the first group were treated with injection of autologous blood (ABI) alone into the superior joint space and the pericapsular tissues. Those in the second group were treated with intramaxillary fixation (IMF) alone for 4 weeks, and those in the third group were treated with ABI and IMF for 4 weeks. Interincisal distance, digital panoramic radiograph, incidence of recurrent dislocation, and pain in the TMJ were assessed postoperatively at 2 weeks and at 1, 3, 6, and 12 months. The mean (SD) reduction in interincisal distance in the group treated with both techniques was 11.0 (1.9), which was significantly higher than in either the group treated with ABI, which was 8.5 (2.4) or IMF, which was 9.1 (2.1). The results in the ABI group and the IMF group did not differ significantly. The combined group showed the biggest decrease. The ABI alone group had the most recurrences (n=8, which were treated by repeated injections with no recurrence after the third). The IMF alone group had only 3 and there were none in the combined group. We conclude that ABI is a simple and safe technique for the treatment of dislocation of the TMJ in the outpatient clinic. Recurrence can be overcome by multiple injections. However, the best clinical results are given by a combination of ABI and IMF. PMID- 23684012 TI - Germline BAP1 mutations predispose to renal cell carcinomas. AB - The genetic cause of some familial nonsyndromic renal cell carcinomas (RCC) defined by at least two affected first-degree relatives is unknown. By combining whole-exome sequencing and tumor profiling in a family prone to cases of RCC, we identified a germline BAP1 mutation c.277A>G (p.Thr93Ala) as the probable genetic basis of RCC predisposition. This mutation segregated with all four RCC-affected relatives. Furthermore, BAP1 was found to be inactivated in RCC-affected individuals from this family. No BAP1 mutations were identified in 32 familial cases presenting with only RCC. We then screened for germline BAP1 deleterious mutations in familial aggregations of cancers within the spectrum of the recently described BAP1-associated tumor predisposition syndrome, including uveal melanoma, malignant pleural mesothelioma, and cutaneous melanoma. Among the 11 families that included individuals identified as carrying germline deleterious BAP1 mutations, 6 families presented with 9 RCC-affected individuals, demonstrating a significantly increased risk for RCC. This strongly argues that RCC belongs to the BAP1 syndrome and that BAP1 is a RCC-predisposition gene. PMID- 23684015 TI - Risk factors for clinical mastitis, ketosis, and pneumonia in dairy cattle on organic and small conventional farms in the United States. AB - The US regulations for production of organic milk include a strict prohibition against the use of antimicrobials and other synthetic substances. The effect of these regulations on dairy animal health has not been previously reported. The objective of this study was to characterize disease detection and identify risk factors for selected diseases on organic (ORG) and similarly sized conventional (CON) farms. Dairy herds (n=292) were enrolled across 3 states (New York, Oregon, Wisconsin) with CON herds matched to ORG herds based on location and herd size. During a single herd visit, information was collected about herd management practices and animal disease occurring in the previous 60 d, and paperwork was left for recording disease occurrences during 60 d after the visit. For analysis, CON herds were further divided into grazing and nongrazing. Poisson regression models were used to assess risk factors for rate of farmer-identified and recorded cases of clinical mastitis, ketosis, and pneumonia. An increased rate of farmer-identified and recorded cases of clinical mastitis was associated with use of CON management, use of forestripping, presence of contagious pathogens in the bulk tank culture, proactive detection of mastitis in postpartum cows, and stall barn housing. An increased rate of farmer-identified and recorded cases of ketosis was associated with having a more sensitive definition of ketosis, using stall barn housing, and feeding a greater amount of concentrates. An increased rate of farmer-identified and recorded cases of pneumonia was associated with a lack of grazing, small or medium herd size, and Jersey as the predominant breed. Overall, disease definitions and perceptions were similar among grazing systems and were associated with the rate of farmer-identified and recorded cases of disease. PMID- 23684016 TI - Effect of castration method on neurohormonal and electroencephalographic stress indicators in Holstein calves of different ages. AB - As public concern for food animal welfare increases, a need to validate objective pain assessment tools exists in order to formulate animal welfare policies and facilitate regulatory approval of compounds to alleviate pain in livestock in the United States. The aims of this study were (1) to compare the physiological response to pain induced by surgical and nonsurgical (band) castration in calves and (2) to elucidate age-related differences in pain response of calves subjected to different castration methods. Seventy-six Holstein bull calves were blocked by age (<=8-wk and >=6-mo-old) and randomly assigned to 1 of 4 treatment groups: control (n=20), castration by banding (n=18), cut-and-clamp surgical castration (n=20), and cut-and-pull surgical castration (n=18). Measurements included electroencephalogram, heart rate variability, infrared thermography, electrodermal activity, and concentrations of serum cortisol and plasma substance P before, during, and within 20min following castration. Electroencephalogram recordings showed desynchronization for all treatments, consistent with increased arousal; yet the magnitude of desynchronization was greatest for 6-mo-old calves castrated by cut-and-clamp. Additionally, older calves in the cut-and-pull group showed greater desynchronization than younger calves in the same group. Based on the heart rate variability analysis, 6-mo-old calves in the control or cut-and pull castration groups showed greater sympathetic tone than younger calves in the same treatment groups. Overall, younger calves showed lower electrodermal activity than older calves. Regardless of treatment, concentrations of cortisol and plasma substance P were greater in 6-mo-old calves relative to their younger counterparts, indicating a more robust response to all treatments in older calves. In summary, neurohormonal and electroencephalographic stress responses of calves to castration were age-specific. Castration by cut-and-clamp showed the most pronounced stress response in 6-mo-old calves. These findings provide evidence that support welfare policies recommending castration at an early age and the use of analgesic compounds at the time of surgical castration especially in older calves. However, the potential long-term negative consequences of early untreated pain must be considered and warrant further investigation. PMID- 23684017 TI - Use of dairies by postreproductive flocks of European starlings. AB - Knowledge of the behavior and movement patterns of European starlings (Sturnus vulgaris L.) is important to wildlife managers that seek to resolve conflicts at livestock facilities. We captured and radio tagged 10 starlings at each of 5 dairies in northeastern Ohio. From September 19 to October 31, 2007, we obtained sufficient data from 40 birds to study their behavior and movements. The birds visited the dairies where they were initially captured (home sites) on 85% of the days, spending 58% of each day at the dairies. Onsite arrival and departure times were 2.5h after sunrise and 3.1h before sunset. Daily visits by radio-tagged cohorts from the other dairies were greatest for the 2 most proximate dairies (1.3 km apart), with number of visits between this pairing >7* that of the 9 other pairings combined (4.1-6.5 km apart). Two birds used their home sites intermittently as roosts, arriving 3.8h before sunset and departing 0.2h after sunrise. In addition to using home-site roosts, these birds also used a distant roost (22km) that was used by 36 of the 40 birds. The efficacy of starling management programs, especially lethal management, depends on degree of site fidelity, use of other facilities, and roosting behavior. For example, starlings that use dairies as roosting sites may require a different management strategy than required at dairies used as daytime sites because of differences in arrival and departure behavior. Our research will help resource managers evaluate current management strategies already in place and change them, if needed, to fit the behavior profile of starlings using dairies and other types of livestock facilities. PMID- 23684018 TI - Hypophagic effects of propionic acid are not attenuated during a 3-day infusion in the early postpartum period in Holstein cows. AB - We previously showed that propionic acid was more hypophagic than acetic acid when infused intraruminally in cows in the postpartum period and that the degree of hypophagia from short-term propionic acid infusion (18 h) was related to the acetyl coenzyme A (CoA) concentration in the liver. The objective of this experiment was to evaluate adaptation over time with longer-term infusions over 3 d. Twelve multiparous cows (2-13 d postpartum) were blocked by calving date and assigned randomly to treatment sequence in a crossover design experiment. The experiment was 12 d long with covariate periods preceding each 3-d infusion period. Treatments were 1.0 M propionic acid or 1.0 M acetic acid, infused intraruminally at 0.5 mol of volatile fatty acids/h beginning 6 h before feeding and continuing for 78 h with 3 d between infusions. Propionic acid decreased dry matter intake (DMI) relative to acetic acid (15.9 vs. 17.0 kg/d). However, a period-by- treatment interaction was detected for DMI. During period 1, propionic acid decreased DMI relative to acetic acid (14.3 vs. 17.5 kg/d) because of a reduction in meal size (1.30 vs. 1.65 kg), with no effect on intermeal interval. Propionic acid decreased DMI over the first 4 h following feeding (5.86 vs. 8.23 kg) but did not affect DMI 4 to 24 h after feeding. The depression in DMI in period 1 was positively related to hepatic acetyl-CoA concentration during the covariate period. Propionic acid was increasingly more hypophagic than acetic acid as hepatic acetyl-CoA concentration was elevated. No treatment-by-day interaction for DMI was observed, suggesting little or no measurable adaptation to treatment over the 3-d infusion period. These results suggest that hypophagia from propionic acid is enhanced when hepatic acetyl-CoA concentrations are elevated, such as when cows are in a lipolytic state. PMID- 23684019 TI - Technical note: identification of suitable normalizers for microRNA expression analysis in milk somatic cells of the yak (Bos grunniens). AB - MicroRNA are approximately 18- to 22-nucleotide nonprotein coding molecules that play important roles in the regulation of gene expression at the posttranscriptional level. In the present study, we assessed the suitability of 8 noncoding small RNA as normalizers for microRNA (miR) quantitative analysis in milk somatic cells of lactating yaks, including 3 small nuclear RNA (snRNA; RNU1A, RNU5A, and RNU6B), 3 small nucleolar RNA (snoRNA; SNORA73A, Z30, and SNORA74A), 1 rRNA (5S), and 1 transfer RNA (Met-tRNA). The snRNA RNU1A, RNU5A, and SNORA73A were identified as the most stable references in milk somatic cells of lactating yaks. Also, a minimum of 3 reference RNA (RNU1A, RNU5A, and SNORA73A) were required for the normalization of microRNA expression data in milk somatic cells of the lactating yak. We further evaluated the suitability of the combination of RNU1A, RNU5A, and SNORA73A as reference RNA in milk somatic cells of lactating yaks via detecting the relative expression of miR 16b, miR 21-5p, miR 145, and miR 155 as microRNA of putative interest. In comparison to the colostrum period, on the whole, the expressions of the 4 microRNA were found to be upregulated at an early period and, thereafter, a declining pattern was exhibited from early to final periods in all microRNA investigated. Based on the results from this study, we recommend that the combination of RNU1A, RNU5A, and SNORA73A can be used as normalizers for microRNA quantitative analysis in future longitudinal studies on milk somatic cells of lactating yaks in relation to lactation. PMID- 23684020 TI - Protein composition affects variation in coagulation properties of buffalo milk. AB - The aim of this study was to investigate the effects exerted by the content of casein and whey protein fractions on variation of pH, rennet-coagulation time (RCT), curd-firming time (K20), and curd firmness of Mediterranean buffalo individual milk. Measures of milk protein composition and assessment of genotypes at CSN1S1 and CSN3 were obtained by reversed-phase HPLC analysis of 621 individual milk samples. Increased content of alphaS1-casein (CN) was associated with delayed coagulation onset and increased K20, whereas average pH, RCT, and K20 decreased when beta-CN content increased. Milk with low kappa-CN content exhibited low pH and RCT relative to milk with high content of kappa-CN. Increased content of glycosylated kappa-CN was associated with unfavorable effects on RCT. Effects of milk protein composition on curd firmness were less important than those on pH, RCT, and K20. Likely, this occurred as a consequence of the very short RCT of buffalo milk, which guaranteed a complete strengthening of the curd even in the restricted 31 min time of analysis of coagulation properties and for samples initially showing soft curds. Effects of CSN1S1-CSN3 genotypes on coagulation properties were not to be entirely ascribed to existing variation in milk protein composition associated with polymorphisms at CSN1S1 and CSN3 genes. Although the role of detailed milk protein composition in variation of cheese yield needs to be further investigated, findings of this study suggest that modification of the relative content of specific CN fractions can relevantly influence the behavior of buffalo milk during processing. PMID- 23684021 TI - Elimination kinetics of cephapirin sodium in milk after an 8-day extended therapy program of daily intramammary infusion in healthy lactating Holstein-Friesian cows. AB - The objective of this study was to determine the elimination kinetics of extended therapy with intramammary (IMM) cephapirin in lactating dairy cattle. Eight healthy Holstein-Friesian cows were administered cephapirin (200mg) into all 4 mammary glands every 24 h after milking. Cows were milked 3 times per day and concentrations of cephapirin and desacetyl cephapirin were determined in bucket milk using liquid chromatography-mass spectrometry. Milk concentration-time data after the last of the 8 IMM infusions were fitted using compartment and noncompartmental models. The maximum cephapirin concentration was 128+/-57 ug/mL (mean +/- SD), the elimination rate constant from the central compartment was 0.278+/-0.046 (h(-1)), clearance was 0.053+/-0.023 L/h, the half time for elimination was 2.55+/-0.40 h, and the mean residence time was 2.65+/-0.79 h. The cephapirin concentration was below the approved tolerance in all cows by 96 h after the last infusion, which is the labeled withholding time for the preparation used. Extended therapy for 8 d provided milk cephapirin concentrations above the minimum inhibitory concentration for common gram positive mastitis pathogens (0.1 to 1.0 ug/mL) for the duration of therapy and for an additional 16 to 32 h after the end of treatment. Our findings suggest that this IMM cephapirin sodium formulation, which is labeled for 2 doses 12 h apart, could be administered at a 24-h interval for up to 8 d in cows milked 3 times per day, with no significant effect on residue levels by 96 h after the last treatment. Longer withdrawal times would be prudent for cows with low milk production. PMID- 23684022 TI - Comparison of different methods for imputing genome-wide marker genotypes in Swedish and Finnish Red Cattle. AB - This study investigated the imputation accuracy of different methods, considering both the minor allele frequency and relatedness between individuals in the reference and test data sets. Two data sets from the combined population of Swedish and Finnish Red Cattle were used to test the influence of these factors on the accuracy of imputation. Data set 1 consisted of 2,931 reference bulls and 971 test bulls, and was used for validation of imputation from 3,000 markers (3K) to 54,000 markers (54K). Data set 2 contained 341 bulls in the reference set and 117 in the test set, and was used for validation of imputation from 54K to high density [777,000 markers (777K)]. Both test sets were divided into 4 groups according to their relationship to the reference population. Five imputation methods (Beagle, IMPUTE2, findhap, AlphaImpute, and FImpute) were used in this study. Imputation accuracy was measured as the allele correct rate and correlation between imputed and true genotypes. Results demonstrated that the accuracy was lower when imputing from 3K to 54K than from 54K to 777K. Using various imputation methods, the allele correct rates varied from 93.5 to 97.1% when imputing from 3K to 54K, and from 97.1 to 99.3% when imputing from 54K to 777K; IMPUTE2 and Beagle resulted in higher accuracies and were more robust under various conditions than the other 3 methods when imputing from 3K to 54K. The accuracy of imputation using FImpute was similar to those results from Beagle and IMPUTE2 when imputing from 54K to high density, and higher than the remaining 2 methods. The results also showed that a closer relationship between test set and reference set led to a higher accuracy for all the methods. In addition, the correct rate was higher when the minor allele frequency was lower, whereas the correlation coefficient was lower when the minor allele frequency was lower. The results indicate that Beagle and IMPUTE2 provide the most robust and accurate imputation accuracies, but considering computing time and memory usage, FImpute is another alternative method. PMID- 23684023 TI - Effects of gas composition in headspace and bicarbonate concentrations in media on gas and methane production, degradability, and rumen fermentation using in vitro gas production techniques. AB - Headspace gas composition and bicarbonate concentrations in media can affect methane production and other characteristics of rumen fermentation in in vitro gas production systems, but these 2 important factors have not been evaluated systematically. In this study, these 2 factors were investigated with respect to gas and methane production, in vitro digestibility of feed substrate, and volatile fatty acid (VFA) profile using in vitro gas production techniques. Three headspace gas compositions (N2+ CO2+ H2 in the ratio of 90:5:5, CO2, and N2) with 2 substrate types (alfalfa hay only, and alfalfa hay and a concentrate mixture in a 50:50 ratio) in a 3*2 factorial design (experiment 1) and 3 headspace compositions (N2, N2 + CO2 in a 50:50 ratio, and CO2) with 3 bicarbonate concentrations (80, 100, and 120 mM) in a 3*3 factorial design (experiment 2) were evaluated. In experiment 1, total gas production (TGP) and net gas production (NGP) was the lowest for CO2, followed by N2, and then the gas mixture. Methane concentration in headspace gas after fermentation was greater for CO2 than for N2 and the gas mixture, whereas total methane production (TMP) and net methane production (NMP) were the greatest for CO2, followed by the gas mixture, and then N2. Headspace composition did not affect in vitro digestibility or the VFA profile, except molar percentages of propionate, which were greater for CO2 and N2 than for the gas mixture. Methane concentration in headspace gas, TGP, and NGP were affected by the interaction of headspace gas composition and substrate type. In experiment 2, increasing concentrations of CO2 in the headspace decreased TGP and NGP quadratically, but increased the concentrations of methane, NMP, and in vitro fiber digestibility linearly, and TMP quadratically. Fiber digestibility, TGP, and NGP increased linearly with increasing bicarbonate concentrations in the medium. Concentrations of methane and NMP were unaffected by bicarbonate concentration, but TMP tended to increase due to increasing bicarbonate concentration. Although total VFA concentration and molar percentage of butyrate were unchanged, the molar percentage of acetate, and acetate-to-propionate ratio decreased, whereas the molar percentage of propionate increased quadratically with increasing bicarbonate concentration. This study demonstrated for the first time that headspace composition, especially CO2 content, and bicarbonate concentration in media could significantly influence gas and methane production, and rumen fermentation in gas production techniques. PMID- 23684024 TI - The amino acid composition of rumen-undegradable protein: a comparison between forages. AB - The objective of this study was to improve knowledge regarding the amino acid profile of the insoluble portion of ingested forage escaping rumen degradation. Six forage categories were analyzed. Categories varied in botanical composition and each contained 2 samples. Samples within categories were derived from the same parent material but differed in harvest, maturity, or conservation type. The rumen-undegradable protein of all forages was measured by incubation for 16h in the rumen of 3 nonlactating cows. All residues were corrected for microbial colonization. The AA profile of the residue was different to the original profile. Degradation trends of individual AA, in terms of increase or decrease relative to the original concentration, were similar between all forages. The AA profiles of forage residues, both within and between categories, were more similar to each other than to their respective original profile. This information may aid in improving the accuracy of estimating postruminal AA supply from forages while decreasing the number of samples required to be analyzed. PMID- 23684025 TI - Short communication: effects of level of rumen-degradable protein and corn distillers grains in corn silage-based diets on milk production and ruminal fermentation in lactating dairy cows. AB - Two of the potential obstacles precluding inclusion of higher levels of dry distillers grains with solubles (DDGS) in corn-based dairy cow diets are the low levels of rumen-degradable protein (RDP) and the fatty acid content and composition of DDGS. Therefore, the objective of this experiment was to evaluate the production and rumen responses to dietary alterations in the level of RDP and DDGS for dairy cows fed a high corn silage diet. The experimental design was a replicated 4*4 Latin square with 21-d periods: 14 d of adaptation and 7 d of sampling; 16 uncannulated cows and 4 ruminally cannulated cows were blocked and assigned randomly to treatment sequences. Rations were provided as total mixed rations and were formulated to be high or low in RDP, with or without DDGS replacing soybean-based concentrates: high RDP, no DDGS (HRDP0); low RDP, no DDGS (LRDP0); low RDP, 10% DDGS; and low RDP, 20% DDGS. Body weight (696kg) and dry matter intake (26.6 kg/d) were not affected by treatment. Rumen ammonia concentration was greater for HRDP0 than LRDP0, but was unaffected by level of DDGS inclusion. The mean and minimum rumen pH and time pH was <5.5 were not different between diets. Milk production tended to be lower for cows fed HRDP0 than LRDP0 and tended to be linearly reduced as DDGS inclusion increased. Milk protein yield tended to be greater for cows fed LRDP0 than HRDP0, but was unaffected by DDGS level. Milk fat production, concentration, and fat-corrected milk were linearly reduced by increasing levels of DDGS. Based on these results, feeding DDGS at 20% of diet dry matter is not recommended for diets based on high corn silage. PMID- 23684026 TI - The relationship between endometrial cytology during estrous cycle and cutoff points for the diagnosis of subclinical endometritis in grazing dairy cows. AB - The objectives of this study were to assess the effect of the stage of estrous cycle on the percentage of endometrial polymorphonuclear cells (PMN) obtained by cytobrush to determine cutoff values for the diagnosis of subclinical endometritis under pastoral conditions, to measure the prevalence of subclinical endometritis 21 to 62d in milk (DIM), and to evaluate the effect of subclinical endometritis on reproductive performance in grazing dairy cows. The first experiment was conducted on a commercial dairy farm in Buenos Aires province (Argentina), where 17 postpartum cyclic dairy cows without clinical endometritis were selected and synchronized by Ovsynch protocol. Endometrial cytology (cytobrush technique) and blood (tail vessels) samples were obtained on d0, 4, 11, and 18 of the estrous cycle (corresponding to estrus, metestrus, diestrus, and proestrus, respectively) and used for measuring percentage of PMN and P4 concentration, respectively. The percentage of PMN was determined 3times by blinded count by 2 operators. Data were analyzed with PROC MIXED, PROC GENMOD, and PROC FREQ from SAS 9.1. The percentage of PMN did not vary with the stage of the estrous cycle. In addition, PMN counts were below any of the reported thresholds in this study (4%) for most of the cows. Therefore, the risk for false positive test results as a consequence of physiological changes in the counts of PMN during estrous cycle is low. The second experiment was conducted on 4 commercial dairy farms in Buenos Aires province (Argentina), where lactating Holstein dairy cows (n=418) 21 to 62 DIM without clinical endometritis were studied. Samples of endometrial cytology were collected with the cytobrush technique. Data were analyzed with receiver operator characteristic curves with Sigmaplot 10.0, and with PROC GLIMMIX, PROC PHREG, and PROC LIFETEST from SAS 9.1. Cutoff values for the diagnosis of subclinical endometritis in grazing dairy cows are 8% PMN for 21 to 33 DIM, 6% PMN for 34 to 47 DIM, 4% PMN for 48 to 62 DIM, and overall 5% PMN for 21 to 62 DIM; the prevalence of subclinical endometritis 21 to 62 DIM was 17%. Finally, subclinical endometritis diagnosed at 21 to 62 DIM decreases the hazard for pregnancy (hazard ratio=0.668; 95% confidence interval=0.492-0.909) and increases the calving to conception interval by d30 compared with normal cows (median 95% confidence interval=133 vs. 93, respectively). PMID- 23684027 TI - Particle size alterations of feedstuffs during in situ neutral detergent fiber incubation. AB - Particle size alterations during neutral detergent fiber (NDF) determination and in situ rumen incubation were analyzed by dry sieving and image analysis to evaluate the in situ procedure for estimation of NDF degradation parameters and indigestible NDF concentration in terms of particle size. Early-cut and late-cut grass silages, corn silage, alfalfa silage, rapeseed meal, and dried distillers grains were examined. Treatments were (1) drying and grinding of forage samples and grinding of concentrates; (2) neutral detergent-soluble (NDS) extraction; (3) machine washing and NDS extraction; (4) 24-h rumen incubation, machine washing, and NDS extraction; and (5) 288-h rumen incubation, machine washing, and NDS extraction. Degradation profiles for potentially degradable NDF were determined and image analysis was used to estimate particle size profiles and thereby the risk for particle loss. Particle dimensions changed during NDF determination and in situ rumen incubation and variations depended on feedstuff and treatment. Corn silage and late-cut grass silage varied most in particle area among feedstuffs, with an increase of 139% between 0 and 24h and a decrease of 77% between 24 and 288 h for corn silage and a decrease of 74% for late-cut grass silage between 24- and 288-h in situ rumen incubation. Especially for late-cut grass silage residues after 288 h in situ rumen incubation, a high mass proportion in the critical zone for escape was found. Particle area decreased linearly with increasing incubation time. Particle loss during in situ rumen incubation cannot be excluded and is likely to vary among feedstuffs. PMID- 23684028 TI - Evaluation of inbreeding depression in Holstein cattle using whole-genome SNP markers and alternative measures of genomic inbreeding. AB - The effects of increased pedigree inbreeding in dairy cattle populations have been well documented and result in a negative impact on profitability. Recent advances in genotyping technology have allowed researchers to move beyond pedigree analysis and study inbreeding at a molecular level. In this study, 5,853 animals were genotyped for 54,001 single nucleotide polymorphisms (SNP); 2,913 cows had phenotypic records including a single lactation for milk yield (from either lactation 1, 2, 3, or 4), reproductive performance, and linear type conformation. After removing SNP with poor call rates, low minor allele frequencies, and departure from Hardy-Weinberg equilibrium, 33,025 SNP remained for analyses. Three measures of genomic inbreeding were evaluated: percent homozygosity (FPH), inbreeding calculated from runs of homozygosity (FROH), and inbreeding derived from a genomic relationship matrix (FGRM). Average FPH was 60.5+/-1.1%, average FROH was 3.8+/-2.1%, and average FGRM was 20.8+/-2.3%, where animals with larger values for each of the genomic inbreeding indices were considered more inbred. Decreases in total milk yield to 205d postpartum of 53, 20, and 47kg per 1% increase in FPH, FROH, and FGRM, respectively, were observed. Increases in days open per 1% increase in FPH (1.76 d), FROH (1.72 d), and FGRM (1.06 d) were also noted, as well as increases in maternal calving difficulty (0.09, 0.03, and 0.04 on a 5-point scale for FPH, FROH, and FGRM, respectively). Several linear type traits, such as strength (-0.40, -0.11, and -0.19), rear legs rear view (-0.35, -0.16, and -0.14), front teat placement (0.35, 0.25, 0.18), and teat length (-0.24, -0.14, and -0.13) were also affected by increases in FPH, FROH, and FGRM, respectively. Overall, increases in each measure of genomic inbreeding in this study were associated with negative effects on production and reproductive ability in dairy cows. PMID- 23684029 TI - Short communication: validation of a point-of-care glucometer for use in dairy cows. AB - The purpose of this study was to evaluate the diagnostic performance of a hand held electronic glucometer (Precision Xtra; Abbott Diabetes Care Inc., Mississauga, ON, Canada) for cow-side use in dairy cattle. This device has been validated for measuring blood concentrations of beta-hydroxybutyrate in dairy cows. This study was designed to assess the accuracy of whole-blood glucose measurements from the glucose meter relative to a reference chemical analyzer in a diagnostic laboratory. Duplicate samples were taken from the same cows at the same time, into blood tubes with either the glycolysis-inhibiting preservative sodium fluoride (NaF) or without preservative. Glucometer readings were taken on whole blood with no preservative, and laboratory measurements were conducted on serum preserved with NaF. Blood samples were collected from cows between 3 wk before and 5 wk after calving, including during a glucose tolerance test conducted 1 wk before expected calving. Passing-Bablok and Bland-Altman data analyses were used to evaluate the performance of the glucometer relative to the laboratory results. A strong correlation was observed in 709 samples from 81 cows between the hand-held meter and serum from samples preserved with NaF (R(2)=0.95). Overall, 96% of measurements with the glucometer fell within the 95% confidence limits of analysis in the laboratory, although at higher-than physiologic glucose concentrations (>5.2mmol/L) the glucometer tended to overestimate. The hand-held glucometer appears suitable for rapid measurement of glucose under field conditions in dairy cattle. PMID- 23684030 TI - Behavioral and physiological effects of a short-term feed restriction in lactating dairy cattle with different body condition scores at calving. AB - Body condition score (BCS) around calving, and the typical BCS loss for up to 100 d after parturition, is associated with both production and reproductive performance of dairy cattle. In addition, there is public concern that thin cows may have impaired welfare, particularly in early lactation where feed demand exceeds pasture growth, and a lag exists between peak milk energy requirements and intake. The aim of this experiment was to determine how BCS at calving influences behavioral and physiological responses to a short-term feed restriction at 47 DIM. Body condition score (on a 10-point scale) at calving was manipulated by modifying the diets in the previous lactation of healthy dairy cattle to generate 3 treatment groups: low BCS (3.4; n=17), medium BCS (4.6; n=18), or high BCS (5.4; n=20). Cows were tested in 4 groups for 8 consecutive days; testing consisted of different levels of feed allocation (d 1 and 2: 100%; d 3 and 4: 75%; d 5: 50%; d 6 to 8: 125%), where 100% was 15kg of DM/cow per day. All BCS groups had similar and marked behavioral and physiological responses to feed restriction. For example, they increased vocalization, time spent eating silage and grazing, aggressive behavior, and fat metabolism (as measured by concentrations of beta-hydroxybutyrate and nonesterified fatty acids), and reduced milk production. Body condition affected some of these responses. Fewer cows with low BCS engaged in aggressive interactions in a feed competition test (trough filled with silage that could be consumed in 15 min) on the first day of feed restriction (low: 32%; medium: 74%; high: 64%; standard error of difference=15.4%). High BCS cows had greater concentrations of beta hydroxybutyrate and nonesterified fatty acids throughout the experimental period, which suggests more fat mobilization; however, plasma leptin and fecal glucocorticosteroid metabolite concentrations were unaffected by BCS. Whereas cows demonstrated marked responses to feed restriction, the results suggest that a BCS of 3.4, 4.6, or 5.4 in healthy cows at calving does not overwhelmingly influence this response at 47 DIM. PMID- 23684031 TI - Technical note: a modified method to quantify prolamin proteins in dry and high moisture corn. AB - Numerous studies have evaluated laboratory methods to quantify prolamin proteins in dry corn; however, the utility of methods to quantify functional prolamins, which impede starch digestibility, in high-moisture corn (HMC) is less defined. As a result, a common rapid turbidimetric (rTM) laboratory procedure was modified (rapid Bradford method, rBM), extracting buffer-soluble proteins before prolamin solubilization in an effort to better quantify functional prolamins in HMC. Twenty samples of dry and HMC were evaluated by rTM and rBM procedures. Prolamin concentration in dry corn, as estimated by rTM or rBM methods, ranged from 6.12 to 2.20g/100 g of DM or 5.46 to 2.41g/100 g of DM, respectively. Dry corn mean prolamin concentrations, as estimated by rTM or rBM methods, were similar at 3.65 or 3.66g/100 g of DM. Prolamin concentration in HMC, as estimated by rTM, ranged from 4.99 to 3.24g/100 g of DM, with a mean prolamin concentration of 4.19g/100 g of DM, but estimation of prolamins in HMC by the rBM method resulted in lower mean (4.19 vs. 3.24g/100 g of DM) prolamin concentration. Prolamin concentration in dry and HMC measured by rTM was negatively related to peak absolute rates (PAR; mL/0.1 g of DM) of in vitro gas production. However, relationships between rTM prolamin concentration and PAR were not homogeneous and were different between dry and HMC. Prolamin proteins as determined by rBM were likewise negatively related to PAR, but corn type did not influence rBM prolamin concentration by PAR relationships. Data suggest that the rBM method defined more similar functional prolamin proteins, which impede starch degradability, in dry and HMC. PMID- 23684032 TI - Purification and identification of five novel antioxidant peptides from goat milk casein hydrolysates. AB - The present research described the preparation, purification, and identification of antioxidant peptides from goat milk casein (GMC). Goat milk casein was hydrolyzed by using a combination of neutral and alkaline proteases to obtain goat milk casein hydrolysates (GMCH) with high antioxidant activity. After desalting by nonpolar macroporous absorption resin, GMCH was isolated and purified by gel filtration chromatography and reversed-phase HPLC, respectively, and further identified by nanoliter electrospray ionization-tandem mass spectrometry. Antioxidant activities of GMC, GMCH, and pure peptides were evaluated and compared using free radical scavenging activity, metal ion chelating ability, and anti-lipid peroxidation ability. Compared with GMC, the free radical-scavenging ability and ferrous ion-chelating ability of GMCH increased significantly. The inhibition effect of lipid peroxidation of GMCH was much stronger than that of tert-butylhydroquinone and phytogermine and a little lower than that of ascorbic acid. The antioxidant activity of GMCH could be attributed to the high antioxidant activity of oligopeptides, especially 5 novel oligopeptides: Val-Tyr-Pro-Phe, Phe-Gly-Gly-Met-Ala-His, Phe-Pro-Tyr-Cys-Ala-Pro, Tyr-Val-Pro-Glu-Pro-Phe, and Tyr-Pro-Pro-Tyr-Glu-Thr-Tyr, which were first observed in GMCH. The antioxidant activity of these 5 novel oligopeptides and GMCH increased 3.59 to 380 times compared with GMC, combining anti-lipid peroxidation ability of GMCH, which indicated that GMCH and its purified fractions in different stages could be used as functional food ingredients, food additives, and pharmaceutical agents in the future. PMID- 23684033 TI - An automated walk-over weighing system as a tool for measuring liveweight change in lactating dairy cows. AB - Automated walk-over weighing systems can be used to monitor liveweights of cattle. Minimal literature exists to describe agreement between automated and static scales, and no known studies describe repeatability when used for daily measurements of dairy cows. This study establishes the repeatability of an automated walk-over cattle-weighing system, and agreement with static electronic scales, when used in a commercial dairy herd to weigh lactating cows. Forty-six lactating dairy cows from a seasonal calving, pasture-based dairy herd in southwest Victoria, Australia, were weighed once using a set of static scales and repeatedly using an automated walk-over weighing system at the exit of a rotary dairy. Substantial agreement was observed between the automated and static scales when assessed using Lin's concordance correlation coefficient. Weights measured by the automated walkover scales were within 5% of those measured by the static scales in 96% of weighings. Bland and Altman's 95% limits of agreement were -23.3 to 43.6 kg, a range of 66.9 kg. The 95% repeatability coefficient for automated weighings was 46.3 kg. Removal of a single outlier from the data set increased Lin's concordance coefficient, narrowed Bland and Altman's 95% limits of agreement to a range of 32.5 kg, and reduced the 95% repeatability coefficient to 18.7 kg. Cow misbehavior during walk-over weighing accounted for many of the larger weight discrepancies. The automated walk-over weighing system showed substantial agreement with the static scales when assessed using Lin's concordance correlation coefficient. This contrasted with limited agreement when assessed using Bland and Altman's method, largely due to poor repeatability. This suggests the automated weighing system is inadequate for detecting small liveweight differences in individual cows based on comparisons of single weights. Misbehaviors and other factors can result in the recording of spurious values on walk-over scales. Excluding outlier weights and comparing means of 7 consecutive daily weights may improve agreement sufficiently to allow meaningful assessment of small short-term changes in automated weights in individuals and groups of cows. PMID- 23684034 TI - Comparison of 2 systems of pasture allocation on milking intervals and total daily milk yield of dairy cows in a pasture-based automatic milking system. AB - Cows milked in pasture-based automatic milking systems (AMS) have greater milking intervals than cows milked in indoor AMS. Long milking intervals greater than 16h have a negative effect on milk yield and udder health. The impact of 2 systems of pasture allocation in AMS on milking interval and yield was investigated at the FutureDairy AMS research farm (Elizabeth Macarthur Agricultural Institute, New South Wales Department of Primary Industries, Camden, New South Wales, Australia) in late November to early December 2010. Two- (2WG) versus 3-way grazing (3WG) allocations per 24-h period were compared in a field study to test the hypothesis that an increase in the frequency of pasture allocation would reduce the milking interval and, therefore, increase milking frequency. The study involved the entire milking herd of 145 cows, with (mean +/- SD) DIM=121+/-90d, 7-d average milking frequency=1.52+/-0.41 milkings/cow per day, and 7-d average milk yield=21.3+/-7.6kg/cow per day. Cows were milked using 2 DeLaval VMS milking units (DeLaval International AB, Tumba, Sweden). Cows in the 3WG treatment had 31% reduced milking interval, 40% greater milking frequency, and 20% greater daily milk production compared with 2WG. Increased milking frequency and milk production for 3WG was associated with greater utililization levels of the AMS milking units throughout the day. These results support the recommendation that, wherever possible, farmers installing AMS should incorporate sufficient infrastructure to accommodate 3WG, which provides additional flexibility with managing extremely long (and short) milking intervals. PMID- 23684035 TI - Effects of lasalocid and intermittent feeding of chlortetracycline on the growth of prepubertal dairy heifers. AB - Forty Holstein heifers entered the 12-wk study at approximately 12 wk of age. At enrollment, heifers were blocked by birth date and assigned to 1 of 4 treatments: (1) carrier (30 g; control); (2) lasalocid + carrier (1 mg/kg of body weight; L); (3) chlortetracycline + carrier (22 mg/kg of body weight; CTC); (4) L + CTC + carrier (CTCL). Heifers on CTC and CTCL were provided treatment Monday through Friday and carrier only on Saturday and Sunday. These heifers were provided their respective treatment during wk 1 to 4, 6, and 10; wk 5, 7 to 9, and 11 to 12 heifers were provided the nonmedicated carrier. Heifers were individually fed a total mixed ration with treatments top-dressed at 1200 h daily. Dry matter intake was monitored for each heifer and feed provided was adjusted according to individual intakes. Skeletal measurements were taken weekly and blood samples were obtained every Monday, Wednesday, and Friday. Blood samples were analyzed for thyroxine concentration via radial immunoassay. Heifers supplemented with L had lower average daily gain , overall body weight gain, and trends for lower daily body length gain and overall girth gain compared with CTC heifers, but similar to control and CTCL heifers. Heifers fed L had lower hip height gain and overall hip height gain compared with CTCL heifers, but similar to control and CTC heifers. Heifers fed L had lower overall withers height gain compared with control heifers, but similar to CTC and CTCL heifers. No treatment effect on thyroxine concentrations was observed. These data indicate that L did not increase growth. Results from this experiment indicate that supplementing heifers with L was not beneficial and no benefits to supplementing heifers with CTC or the combination of CTC and L were evident compared with control heifers. Heifers in this study experienced minimal health problems and were regarded to be under low stress levels. Supplementing CTC and L may be beneficial to growing heifers under conditions where disease exposure and stressors are greater. PMID- 23684036 TI - Effect of early exposure to different feed presentations on feed sorting of dairy calves. AB - This study examined how early exposure to different feed presentations affects development of feed sorting in dairy calves. Twenty Holstein bull calves were exposed for the first 8 wk of life to 1 of 2 feed presentation treatments: concentrate and chopped grass hay (<2.5cm) offered ad libitum at a ratio of 7:3 as a mixture (MIX), or as separate components (COM). Calves received 8L/d of milk replacer (1.2kg of dry matter), with the amount progressively reduced after 5 wk to facilitate weaning by the end of wk 7. All calves received the MIX diet in wk 9 to 11 and, subsequently, a novel total mixed ration (TMR; containing 40.5% corn silage, 22.0% haylage, 21.5% high-moisture corn, and 16.0% protein supplement) in wk 12 to 13. Intake was recorded daily and calves were weighed twice a week. Fresh feed and orts were sampled on d 1 to 4 of wk 6, 8, 9, 11, 12, and 13 for analysis of feed sorting, which was assessed through nutrient analysis for the MIX diet and particle size analysis for the TMR. The particle separator had 3 screens (19, 8, and 1.18mm) producing long, medium, short, and fine particle fractions. Sorting of nutrients or particle fractions was calculated as the actual intake as a percentage of predicted intake; values >100% indicate sorting for, whereas values <100% indicate sorting against. Feed presentation did not affect dry matter intake or growth. Prior to weaning, all calves selected in favor of hay; MIX calves consumed more neutral detergent fiber (NDF) than predicted (103.6%) and less nonfiber carbohydrates (NFC) than predicted (92.6%), and COM calves consumed, as a percentage of dry matter intake, 40.3% hay (vs. 30% offered rate). In wk 8, calves fed COM consumed more NFC than calves fed MIX (1.0 vs. 0.95kg/d) and less NDF (0.43 vs. 0.54kg/d), indicating greater selection in favor of concentrate. However, when provided the MIX diet, calves previously fed COM did not sort, whereas calves previously fed MIX consumed more NFC intake than predicted (103.2%) and less NDF intake than predicted (97.6%). Calves previously fed MIX maintained increased sorting after transition to the novel TMR, sorting against long particles (86.5%) and for short (101.8%) and fine (101.2%) particles. These results indicate that initially providing dairy calves with solid feeds as separate components, compared with as a mixed ration, reduces the extent of feed sorting in the weeks after transition to a common ration. PMID- 23684037 TI - Microbiology of Cheddar cheese made with different fat contents using a Lactococcus lactis single-strain starter. AB - Flavor development in low-fat Cheddar cheese is typified by delayed or muted evolution of desirable flavor and aroma, and a propensity to acquire undesirable meaty-brothy or burnt-brothy off-flavor notes early in ripening. The biochemical basis for these flavor deficiencies is unclear, but flavor production in bacterial-ripened cheese is known to rely on microorganisms and enzymes present in the cheese matrix. Lipid removal fundamentally alters cheese composition, which can modify the cheese microenvironment in ways that may affect growth and enzymatic activity of starter or nonstarter lactic acid bacteria (NSLAB). Additionally, manufacture of low-fat cheeses often involves changes to processing protocols that may substantially alter cheese redox potential, salt-in-moisture content, acid content, water activity, or pH. However, the consequences of these changes on microbial ecology and metabolism remain obscure. The objective of this study was to investigate the influence of fat content on population dynamics of starter bacteria and NSLAB over 9 mo of aging. Duplicate vats of full fat, 50% reduced-fat, and low-fat (containing <6% fat) Cheddar cheeses were manufactured at 3 different locations with a single-strain Lactococcus lactis starter culture using standardized procedures. Cheeses were ripened at 8 degrees C and sampled periodically for microbiological attributes. Microbiological counts indicated that initial populations of nonstarter bacteria were much lower in full-fat compared with low-fat cheeses made at all 3 sites, and starter viability also declined at a more rapid rate during ripening in full-fat compared with 50% reduced-fat and low-fat cheeses. Denaturing gradient gel electrophoresis of cheese bacteria showed that the NSLAB fraction of all cheeses was dominated by Lactobacillus curvatus, but a few other species of bacteria were sporadically detected. Thus, changes in fat level were correlated with populations of different bacteria, but did not appear to alter the predominant types of bacteria in the cheese. PMID- 23684038 TI - Nonstarter lactic acid bacteria volatilomes produced using cheese components. AB - In long-ripened cheese, flavor formation occurs during ripening. The metabolism of lactic acid bacteria (LAB) leads to the production of different compounds that contribute to the flavor of cheese. The contribution of LAB to the formation of cheese flavor has previously been studied. However, the specific nonstarter LAB (NSLAB) metabolic reactions in ripened cheese that lead to the formation of flavor compounds remain unclear. In ripened cheese, the nutrient sources available include small peptides or amino acids, citrate, lactate, free fatty acids, and starter LAB cell lysis products. Thus, the aim of this study was to evaluate the ability of NSLAB to produce volatile flavor compounds by using an in vitro system that used only the nutrients available in ripened cheese as the energy source. Moreover, the potential contribution of the NSLAB volatilome on total cheese flavor is discussed. For this purpose, the production of volatile compounds on cheese-based medium (CBM) and on starter LAB lysed cell medium (LCM) by 2 Lactobacillus casei and 2 Lactobacillus rhamnosus strains, previously isolated from ripened Parmigiano Reggiano cheese, was investigated. The generated volatile compounds were analyzed with head-space gas chromatography mass spectrometry. Overall, ketones, aldehydes, alcohols, and acids were the most abundant compounds produced. Differences in volatilome production were found between NSLAB grown in LCM and CBM. The catabolic metabolism of amino acids and fatty acids were required for NSLAB growth on LCM. Conversely, pyruvate metabolism was the main catabolic pathway that supported growth of NSLAB in CBM. This study can be considered a first step toward a better understanding of how microbiota involved in the long ripening of cheese may contribute to the development of cheese flavor. PMID- 23684039 TI - Replacing alfalfa silage with corn silage in dairy cow diets: Effects on enteric methane production, ruminal fermentation, digestion, N balance, and milk production. AB - The objective of this study was to determine the effects of replacing alfalfa silage (AS) with corn silage (CS) in dairy cow total mixed rations (TMR) on enteric CH4 emissions, ruminal fermentation characteristics, apparent total-tract digestibility, N balance, and milk production. Nine ruminally cannulated lactating cows were used in a replicated 3*3 Latin square design (32-d period) and fed (ad libitum) a TMR [forage:concentrate ratio of 60:40; dry matter (DM) basis], with the forage portion consisting of either alfalfa silage (0% CS; 56.4% AS in the TMR), a 50:50 mixture of both silages (50% CS; 28.2% AS and 28.2% CS in the TMR), or corn silage (100% CS; 56.4% CS in the TMR). Increasing the CS proportion (i.e., at the expense of AS) in the diet was achieved by decreasing the corn grain proportion and increasing that of soybean meal. Intake of DM and milk yield increased quadratically, whereas DM digestibility increased linearly as the proportion of CS increased in the diet. Increasing the dietary CS proportion resulted in changes (i.e., lower ruminal pH and acetate:propionate ratio, reduced fiber digestibility, decreased protozoa numbers, and lower milk fat and higher milk protein contents) typical of those observed when cows are fed high-starch diets. A quadratic response in daily CH4 emissions was observed in response to increasing the proportion of CS in the diet (440, 483, and 434 g/d for 0% CS, 50% CS, and 100% CS, respectively). Methane production adjusted for intake of DM, and gross or digestible energy was unaffected in cows fed the 50% CS diet, but decreased in cows fed the 100% CS diet (i.e., quadratic effect). Increasing the CS proportion in the diet at the expense of AS improved N utilization, as reflected by the decreases in ruminal NH3 concentration and manure N excretion, suggesting low potential NH3 and N2O emissions. Results from this study, suggest that total replacement of AS with CS in dairy cow diets offers a means of decreasing CH4 output and N losses. However, the reduction in fiber degradation and the resulting increase in volatile solids content of the manure may lead to increased CH4 emissions from manure storage. PMID- 23684040 TI - Prednisolone and cefapirin act synergistically in resolving experimental Escherichia coli mastitis. AB - Mastitis in dairy cows is typically treated with intramammary antibiotics. The combination of antibiotics with corticosteroids tends to have a large market share where these products are registered. Our objective was to investigate the effect of prednisolone in combination with cefapirin on the inflammatory response of experimentally induced Escherichia coli mastitis. Six midlactating Holstein Friesian cows were challenged in 3 quarters with E. coli and treated at 4, 12, 24, and 36 h postinfection with 300 mg of cefapirin in 1 quarter and a combination of 300 mg of cefapirin and 20mg of prednisolone in another quarter. At 24h (n=3) or 48 h (n=3) postinfection cows were euthanized for tissue sampling. Clinical scores, somatic cell count, and California mastitis test scores, as well as IL-1beta, IFN-gamma, IL-4, and IL-10 levels and bacterial growth in milk, were measured every 6h. Experimental inoculation caused a moderate clinical mastitis in all cows in challenged, untreated quarters. The E. coli challenge strain was recovered from all infected quarters and confirmed by PCR-based fingerprinting. Challenged, untreated control quarters showed increased concentrations of all measured cytokines together with recruitment of polymorphonuclear neutrophilic leukocytes at 24 and 48 h postchallenge. Both treatments reduced udder swelling and sensitivity with no statistically significant difference between treatment groups. Administration of cefapirin alone or in combination with prednisolone resulted in significantly lower concentrations of IFN-gamma, IL-1beta, and IL-10 compared with challenged, untreated quarters. Treated quarters did show IL-4 production, but concentrations were significantly decreased compared with untreated, challenged quarters. Quarters treated with the combination of cefapirin and prednisolone showed a significantly lower concentration of IL-4 compared with cefapirin-only treatment. At both 24 and 48 h postinoculation, the level of polymorphonuclear neutrophilic leukocyte recruitment was lowest in challenged quarters treated with a combination of cefapirin and prednisolone, followed by cefapirin alone. Taken together, treatment with cefapirin alone inhibited bacterial growth in milk and reduced the host inflammatory responses. Addition of prednisolone to cefapirin had a synergistic effect, resulting in a lower density of leukocytes in tissue and milk and a quicker restoration of milk quality. PMID- 23684041 TI - beta-Lactoglobulin-linoleate complexes: In vitro digestion and the role of protein in fatty acid uptake. AB - The dairy protein beta-lactoglobulin (BLG) is known to bind fatty acids such as the salt of the essential longchain fatty acid linoleic acid (cis,cis-9,12 octadecadienoic acid, n-6, 18:2). The aim of the current study was to investigate how bovine BLG-linoleate complexes, of various stoichiometry, affect the enzymatic digestion of BLG and the intracellular transport of linoleate into enterocyte-like monolayers. Duodenal and gastric digestions of the complexes indicated that BLG was hydrolyzed more rapidly when complexed with linoleate. Digested as well as undigested BLG-linoleate complexes reduced intracellular linoleate transport as compared with free linoleate. To investigate whether enteroendocrine cells perceive linoleate differently when part of a complex, the ability of linoleate to increase production or secretion of the enteroendocrine satiety hormone, cholecystokinin, was measured. Cholecystokinin mRNA levels were different when linoleate was presented to the cells alone or as part of a protein complex. In conclusion, understanding interactions between linoleate and BLG could help to formulate foods with targeted fatty acid bioaccessibility and, therefore, aid in the development of food matrices with optimal bioactive efficacy. PMID- 23684042 TI - Lameness detection based on multivariate continuous sensing of milk yield, rumination, and neck activity. AB - The objective of this study was to develop and validate a mathematical model to detect clinical lameness based on existing sensor data that relate to the behavior and performance of cows in a commercial dairy farm. Identification of lame (44) and not lame (74) cows in the database was done based on the farm's daily herd health reports. All cows were equipped with a behavior sensor that measured neck activity and ruminating time. The cow's performance was measured with a milk yield meter in the milking parlor. In total, 38 model input variables were constructed from the sensor data comprising absolute values, relative values, daily standard deviations, slope coefficients, daytime and nighttime periods, variables related to individual temperament, and milk session-related variables. A lame group, cows recognized and treated for lameness, to not lame group comparison of daily data was done. Correlations between the dichotomous output variable (lame or not lame) and the model input variables were made. The highest correlation coefficient was obtained for the milk yield variable (rMY=0.45). In addition, a logistic regression model was developed based on the 7 highest correlated model input variables (the daily milk yield 4d before diagnosis; the slope coefficient of the daily milk yield 4d before diagnosis; the nighttime to daytime neck activity ratio 6d before diagnosis; the milk yield week difference ratio 4d before diagnosis; the milk yield week difference 4d before diagnosis; the neck activity level during the daytime 7d before diagnosis; the ruminating time during nighttime 6d before diagnosis). After a 10-fold cross validation, the model obtained a sensitivity of 0.89 and a specificity of 0.85, with a correct classification rate of 0.86 when based on the averaged 10-fold model coefficients. This study demonstrates that existing farm data initially used for other purposes, such as heat detection, can be exploited for the automated detection of clinically lame animals on a daily basis as well. PMID- 23684043 TI - Effects of adjustable and stationary fans with misters on core body temperature and lying behavior of lactating dairy cows in a semiarid climate. AB - Cows readily seek shade to reduce solar heat load during periods of high ambient temperature. Typically, auxiliary cooling systems are oriented to maximize cooling for shaded cows. However, when a shade structure is oriented north-south, stationary fan and mister cooling systems are unable to track shade as the sun's angle shifts throughout the day, and thus can become ineffective. The FlipFan Dairy Cooling System (Schaefer Ventilation Equipment, Sauk Rapids, MN) employs fans and misters that follow shade and compensate for wind speed by rotating on a horizontal axis. Multiparous, lactating Holstein cows (n=144) on a commercial dairy in Arizona were cooled by a fixed system comprised of stationary fans and misters acting as control or the adjustable FlipFan operated for 16.5 h/d (0830 to 0100 h). Core body temperatures (CBT) of 64 cows (4 pens/treatment; 8 cows/pen; 6d) and lying behavior of 144 cows (4 pens/treatment; 18 cows/pen; 5d) were collected by intravaginal and leg data loggers, respectively. Cows were balanced by milk production, blocked by days in milk, and randomly assigned to pen within block. Pen was the experimental unit. In a second experiment, isothermal maps were developed using a fixed system of thermal data loggers arranged in the shaded areas of the pens at different times of day and were analyzed for differences in the temperature-humidity index (THI) achieved by each cooling treatment. Ambient conditions consisted of a mean temperature of 33.0 degrees C, mean relative humidity of 40.3%, and mean THI of 80.2. Mean 24-h CBT for FlipFan was lower than control (38.9 vs. 39.1+/-0.04 degrees C). A treatment * time interaction was observed in which CBT of FlipFan was 0.4 degrees C lower than control from 0600 to 0800h and 1500 to 1600h. Cows cooled by FlipFan spent more time lying down compared with those cooled by control (9.5 vs. 8.6 h/d). Cows under FlipFan had more frequent lying bouts than did those under control (12.8 vs. 10.7 bouts/d). Lower CBT and decreased standing time are consistent with the findings of other studies when ambient heat load was reduced. In the second experiment, the FlipFan system achieved a lower THI in the morning and evening (5.9 and 1.7%, respectively), and the THI also tended to be 0.8% lower in the afternoon compared with that of control. Results indicate that FlipFan is more effective than a stationary fan and mister system at decreasing CBT, increasing lying time and bouts, and providing a more desirable microenvironment for cows throughout the day in a semiarid environment. PMID- 23684044 TI - Short communication: aquaporin-7 mRNA in adipose depots of primiparous and pluriparous dairy cows: long-term physiological and conjugated linoleic acid induced changes. AB - Aquaglyceroporins act as channel proteins and regulate water and glycerol exchange through cell membranes. The aquaglyceroporin aquaporin-7 (AQP7) is abundantly expressed in adipose tissue (AT) and regulates the release of glycerol produced by lipolysis. We aimed to investigate the expression of AQP7 mRNA during lactation in subcutaneous (s.c.) and visceral (v.c.) adipose depots of primiparous and pluriparous dairy cows. In 2 independent experiments, Holstein cows were supplemented with conjugated linoleic acids (CLA) or a control (CON) fat supplement at 100g/d. Pluriparous cows were supplemented starting with the first day in milk (DIM) up to 182 DIM and biopsies from s.c. AT were collected at d -21, 1, 21, 70, 105 182 196, 224, and 252 relative to calving (CLA=11; CON=10). Samples from 3s.c. and v.c. adipose depots were investigated in primiparous cows (n=25) receiving the supplements from 1 DIM until slaughter at 1, 42, or 105 DIM. The AQP7 mRNA abundance decreased from d -21 to 1 in s.c. AT of pluriparous cows without further increase to d 252 of lactation. In primiparous cows of the CON group, the AQP7 mRNA abundance increased from 1 to 105 DIM in s.c. AT from the tail head and in mesenteric AT. In retroperitoneal AT, the only depot for which a significant decrease in mass was observed with DIM, AQP7 mRNA abundance was greater at 42 and 105 than 1 DIM. Comparing the different fat depots, retroperitoneal AT had the highest and mesenterial AT had the lowest AQP7 mRNA abundance, but no general difference was observed between v.c. and s.c. fat depots. The values were not affected by CLA treatment with the exception of mesenteric AT, for which lower AQP7 mRNA abundance values were recorded in the CLA than in the CON group. The longitudinal characterization of the AQP7 mRNA expression profile throughout lactation revealed differences between primiparous and pluriparous cows, with an increase of AQP7 mRNA abundance up to 105 DIM only in the primiparous cows. Due to a lack of CLA effects in pluriparous cows and the limitation to just one fat depot in primiparous cows, a modulatory effect of CLA on AQP7 mRNA abundance in dairy cows is not supported by our study. PMID- 23684045 TI - Prevalence and clinical correlations of catatonia in older adults referred to a liaison psychiatry service in a general hospital. AB - AIM: To determine the frequency and clinical correlations of catatonia in older patients referred to a liaison psychiatry service in a general hospital. PATIENTS AND METHODS: All patients over 65 years referred to liaison psychiatry were screened for catatonic phenomena with the Bush-Francis Catatonia Screening Instrument (BFCSI) between January and May 2012. Their clinical characteristics and the outcome of treatment were recorded. RESULTS: One hundred and twelve patients over 65 years were referred. Ten (8.9%) met research diagnostic criteria for catatonia and 7 (6.3%) Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria for catatonia. All patients presented with the inhibited variant and 5 to 12 catatonic signs. Three patients presented concomitant delirium. The etiology of catatonia was multifactorial, and complications and death were frequent (40% and 20%, respectively). Lorazepam achieved full resolution of catatonia in 50% of patients. CONCLUSIONS: Catatonia in older adults referred to liaison psychiatry in a general hospital is not infrequent and has a multifactorial etiology. The BFCSI is a simple and reliable instrument to detect catatonia in this population. Lorazepam seems to be an effective treatment. PMID- 23684046 TI - Characteristics and associated factors in patient falls, and effectiveness of the lower height of beds for the prevention of bed falls in an acute geriatric hospital. AB - OBJECTIVES: Whereas several studies about patient falls have provided data for long-term healthcare institutions, less information is available for acute care centres. The objective was to analyze the characteristics of the patient falls and associated factors, and the effectiveness of the lower beds' height to reduce the frequency and the harms of the patient falls in an acute geriatric hospital. METHODS: A descriptive and retrospective study using a mandatory safety incident report, the IHI Global Trigger Tool, and the claims related to patient falls between 2007 and 2011 in a 200-bed university-associated geriatric hospital. RESULTS: The falls rate was 5.4 falls per 1000 patient days (1.3% of falls led to fractures) and there was exitus in 6 patients (0.6%). Nearly half of the falls ocurred during the night shift (42.4%). By wards, falls were more frequent in acute geriatric wards (42.9%). A 7.5% of patients had a fall before admission. 3 (0.2%) claims due to possible clinical negligence were found. A reduction (28.3%) of bed falls with the lower height of the bed and a 1.88 times less falls with harm (RR 0.53; CI 95% 0.83-0.34) (p=0.006) was observed. CONCLUSION: The prevention of patient falls is an important task in geriatric units with a potential reduction of harms and costs, some measures such as the lower height of the bed showed a significant reduction of the falls. PMID- 23684047 TI - [Effectiveness of lifestyle intervention program in persons with obesity treated in a day hospital]. AB - INTRODUCTION: Obesity is a chronic disease that affects approximately 25% of the Spanish population, causing high morbidity and associated healthcare costs. OBJECTIVE: To evaluate the effectiveness of an intervention program on lifestyles in obese patients treated in a day hospital scheme. METHODS: A prospective non- controlled intervention study was conducted on obese patients treated in the Endocrinology and Nutrition day hospital, Puerto Real University Hospital, and included in program of lifestyle modification to achieve a weight loss of >= 5% minimum. RESULTS: We studied 262 patients with a mean age of 44.6+/-16.0 years (71% women) with an initial weight, body mass index and waist circumference of 110.4+/-21.1kg, 41.6+/-6.6Kg/m(2) and 120.5+/-13.2cm, respectively. Patients who continued in the study lost an average of 4.8+/-4.8kg (n=165) and 7.0+/-6.2kg (n=48) at three and six months, respectively, with 51.5% (n=135) patients reaching the weight loss goal of >= 5%. There were no statistically differences in weight loss between any clinical or follow-up variables analysed. 43.5% of patients voluntarily left the study without reaching the weight loss goal. CONCLUSION: The intervention on lifestyles in obese patients treated in a day hospital achieves moderate weight loss in the medium term, with half of patients achieving a weight loss >=5%. PMID- 23684048 TI - [Evaluation by focus groups on women's expectations and perceptions during the birth process]. AB - OBJECTIVES: Delivery care giving is undergoing excessive interventionism today, not supported by scientific evidence, neglecting organisational aspects and individualisation. This study analyses the perception of mothers during their delivery, postpartum and breastfeeding periods in the Galician Health Service, in order to inform and help to improve this service. MATERIAL AND METHODS: A total of 14 focus group meetings were held (one in each Galician public hospital), consisting of women who, in 2008, delivered by vaginal delivery or those who were not scheduled for a caesarean section. RESULTS: The process of birth analysis can identify a sequence of important elements both positive and negative, for mothers, and may lead to suggestions for improvement. Their experiences and opinions, especially in aspects such as participation in decision-making, mechanisation of labour and lactation, may help to conduct an assessment of the maternity ward operating. When investigating expectations and demands from users, information from perceived quality is received, and also mothers' experience is shared. CONCLUSIONS: Mothers call for humanity, empathy, information and participation. Facing the implementation of these elements, the key processes for working harder are the dilation stage and hospital staying. PMID- 23684049 TI - [Relationship between process indicators measured using electronic records and intermediate health outcomes in patients with diabetes]. AB - OBJECTIVE: To study relationship between institutional process indicators (measured using electronic records) and intermediate outcomes of patients with diabetes. METHOD: Cross-sectional epidemiological study. Setting Primary care health district 1. Madrid. 2010. PATIENTS: all patients with diabetes; n = 16.652. Main measures variables. Independent. Institutional process indicators. Dependent. Intermediate outcomes: GHb, BP, LDL, tobacco and weight within target limits and detected complications. Confounding. Age, gender, type and years for DM, co-morbidity, drugs and professional variables. RESULTS: GHb of 55.9% (SE 0,4) of patients was within target limits. Bivariate analysis and multivariate logistic regression showed that the recording of some process indicators was associated with an increase in the probability to achieve targets in intermediate outcomes: reviewing personal and family history, lifestyle and drug therapy, creatinine, GHb, BP and weight measurement, smoking advice, EKG, ankle-arm index, and eye examination. OR were from 1,15 (CI 95%: 1.01-1.32) to 2.05 (CI 95%: 1.76 2.39). Relationship among other indicators and higher probability to achieve targets was not found: classification, reviewing care plan, glucose, BMI, LDL and microalbuminury measurement. CONCLUSIONS: In diabetes, a lot of institutional process indicators measured on electronic records was associated with increase of probability to achieve targets in intermediate outcomes. It suggests to maintain process and outcome measurement, to include other outcomes, to include other interventions, to prioritize improvements in process indicators that show low performance and high impact and to keep out or to change process indicators that relationship was not found. PMID- 23684050 TI - On health literacy and health outcomes: background, impact, and future directions. AB - This article presents an overview of an emerging area of research called health literacy. It draws attention to the undisputed relationship between literacy levels of the population, the complexity of health systems and health outcomes. Authors believe that instead of focusing on improving individual skills, health institutions and health care settings should concentrate their efforts on making their physical and social environment more accessible and easy to navigate for their users. A more balanced approach to health literacy action includes improving the quality and accessibility of information, professionals' communication skills, and eliminating structural barriers to healthful action. PMID- 23684051 TI - Sensory phenomena: clinical correlates and impact on quality of life in adult patients with Tourette syndrome. AB - Tourette syndrome (TS) is a neurodevelopmental condition characterised by multiple tics, with frequent behavioural co-morbidity. Sensory phenomena (SP) are unpleasant sensations which provide involuntary urges to tic in patients with TS. While SP have a central role in tic expression, little is known about their clinical correlates or association with health-related quality of life (HR-QOL) in TS. We conducted a cross-sectional study on 72 adult outpatients with TS, recruited at a specialist clinic. All participants completed a comprehensive battery of psychometric measures, including the Premonitory Urges for Tics Scale (PUTS) to assess SP and a disease-specific quality of life scale (GTS-QOL) to assess HR-QOL. SP were very common (97.2% of patients), with a median PUTS total score of 28/40. Bivariate analyses showed that PUTS scores were most significantly correlated with self-report measures of vocal tic severity and compulsivity. PUTS scores were also significantly correlated with GTS-QOL scores, most notably with the psychological subscale. SP are frequently reported by adults with TS, are associated with perceived tic severity and compulsivity, and can significantly affect psychological well-being. Standardised measurement of SP should be incorporated into routine assessment of patients with TS to optimise their clinical management. PMID- 23684052 TI - Serum prolactin and smoking status in chronic antipsychotic-treated male patients with schizophrenia. AB - We investigated the effects of smoking status on the serum prolactin levels in schizophrenia. The serum prolactin concentration was significantly higher in nonsmokers compared with smokers. Moreover, smoking was an independent predictor of prolactin concentration. These findings suggest that smoking has an impact on prolactin concentration in male schizophrenic patients. PMID- 23684053 TI - Religious coping among psychotic patients: relevance to suicidality and treatment outcomes. AB - Religious coping is very common among individuals with psychosis, however its relevance to symptoms and treatment outcomes remains unclear. We conducted a prospective study in a clinical sample of n=47 psychiatric patients with current/past psychosis receiving partial (day) treatment at McLean Hospital. Subjects completed measures of religious involvement, religious coping and suicidality prior to treatment, and we assessed for psychosis, depression, anxiety and psychological well-being over the course of treatment. Negative religious coping (spiritual struggle) was associated with substantially greater frequency and intensity of suicidal ideation, as well as greater depression, anxiety, and less well-being prior to treatment (accounting for 9.0-46.2% of the variance in these variables). Positive religious coping was associated with significantly greater reductions in depression and anxiety, and increases in well being over the course of treatment (accounting for 13.7-36.0% of the variance in change scores). Effects remained significant after controlling for significant covariates. Negative religious coping appears to be a risk factor for suicidality and affective symptoms among psychotic patients. Positive religious coping is an important resource to this population, and its utilization appears to be associated with better treatment outcomes. PMID- 23684054 TI - Short-term remission in schizophrenia as a combination of several outcome measures. AB - Clinical, cognitive, metabolic and functioning variables have been evaluated in patients with schizophrenia in an 8-week trial with Ziprasidone. The aim of this post-hoc analysis is to investigate how these variables interact in determining short-term remission. Baseline values or the variation from baseline to endpoint were considered predictors. 262 schizophrenic patients were recruited. Two logistic regressions were conducted to determine which variables predict remission. The first was performed on baseline values as predictors. The second used the variation from baseline to endpoint (delta) of the outcome evaluations as predictors. Using literature reported criteria for remission, we distinguished 124 subjects (47.33%) in remission, and 138 not in remission at the end of the trial. The first logistic regression does not show a good fit. The second logistic regression, with delta scores as predictors, reports instead an overall good fit (71.8% of the predicted cases assigned to the right category). The analysis reveals that general score from Positive and Negative Syndrome Scale (PANSS), cholesterol LDL, subjective well-being under neuroleptic, Simpson-Angus Scale (SAS) delta scores, drug dosage and premorbid intelligence entered in the equation. These results suggest that indexes such as cognition, metabolic status, other than symptoms, have to be taken into account in order to refine the short term remission prediction. PMID- 23684055 TI - Gender differences in reactivity to alcohol cues in binge drinkers: a preliminary assessment of event-related potentials. AB - Binge drinking is associated with functional brain abnormalities similar to those observed in alcoholics and can be viewed as a first step towards alcohol dependence. Adult men are twice as likely as women to develop alcoholism. This study investigates (1) the presence of alcohol cue reactivity in bingers, a feature that has been proposed to underlie the emergence of alcohol dependence; and (2) a possible higher alcohol cue reactivity in men binge drinkers which could explain their higher risk for alcohol use disorders in adulthood.The P3 component of the event-related potentials (ERPs) was recorded during a visual oddball task in which controls (n=27: 10 men and 17 women) and binge drinkers (n=29: 15 men and 14 women) had to detect infrequent deviant stimuli (related to alcohol or not) among frequent neutral stimuli. Results showed that binge drinkers, compared to light drinkers, displayed increased P3 reactivity to alcohol related cues with a greater effect among men. Our results suggest the phenomenon of alcohol cue reactivity to be a possible avenue by which a higher risk population, binge drinkers, and men in particular, are prone to develop problematic alcohol use. PMID- 23684056 TI - Deep abdominal muscle activity following supratentorial stroke. AB - This study assessed the level and symmetry of deep abdominal muscle activation following a supratentorial stroke during a modified hip flexion task. Movement related activation levels in the transversus abdominus (TrA) and internal oblique (IO) were investigated in people with a subacute (<3.25months) supratentorial stroke (n=11) and a matched control group (n=11). Electromyographic activity in TrA and IO were recorded using fine wires inserted under ultrasound guidance while participants performed a standardised head lift or unilateral hip flexion. During head lift there was no significant difference in the amplitude of activation ipsi- and contra-lateral to the stroke or between groups. During unilateral hip flexion the TrA and IO were activated more on both sides when moving the paretic leg. In the control group muscle activity was modulated by task with activity being higher ipsilateral to the moving leg; in contrast in the stroke group IO muscle activity tended to be higher on the non-paretic side irrespective of moving limb. Greater TrA and IO muscle activity during hip flexion of the paretic leg may represent compensatory activity that acts to facilitate activation of the paretic hip flexors and/or the presence of overflow. PMID- 23684057 TI - Molecularly targeted therapies in locally advanced non-small-cell lung cancer. AB - Approximately a third of the patients with non-small cell lung cancer (NSCLC) present with locally advanced disease not amenable to curative resection. Concurrent chemoradiation is currently the treatment of choice for these patients. Outcomes in patients with locally advanced NSCLC treated with concurrent chemoradiation are modest at best. No significant progress has been made over the past decade in this subset of patients with NSCLC. Several trials have examined the role of molecular targeted therapies in this setting. We review the results of these trials and present the outline of a proposed prospective clinical trial to evaluate targeted drugs in molecularly selected group of patients with locally advanced NSCLC. PMID- 23684058 TI - Optimal length of time of cryopreserved umbilical cord blood infusion after thawing. AB - OBJECTIVE: Dimethyl sulfoxide (DMSO) can damage hematopoietic progenitor cells (HPCs) at room temperature. To minimize the time of contact between DMSO and the thawed umbilical cord blood (UCB), there is an incentive to infuse the UCB as quickly as possible. However, the infusion of cryopreserved UCB also results in side effects. Currently, it is difficult to determine the optimal length of time for cryopreserved UCB infusion, not only to ensure the maximum effect of engraftment but also to reduce the toxicity of the cord blood infusion. METHODS: Ten units of cord blood were thawed to assess viability, apoptotic events of CD34(+) cells and CD45(+) cells, and the number of colony-forming units (CFUs) at four time points: 0, 10, 20, and 30 minutes post-thaw (PT). The infusion time, side effects, and the speed of platelet and neutrophil engraftment of the 10 patients were monitored. RESULTS: Within 30 minutes, the viability decreased (P < 0.01), the percentage of early apoptotic CD34(+) cells and CD45(+) cells was unchanged. At time point PT30, the number of CFUs was decreased compared to PT0 (P < 0.05), but it was unchanged within 20 minutes. All the 10 UCB cells engrafted well in patients. CONCLUSION: This study indicates that post-thawed UCB HPCs are preserved for less than 30 minutes at room temperature; thus, the optimal length of time of cryopreserved cord blood infusion should be no more than 20 minutes after thawing. PMID- 23684059 TI - Moon walkers and urban pollution. PMID- 23684060 TI - Statin use and risk of COPD exacerbation requiring hospitalization. AB - BACKGROUND: Despite recent studies that suggested statins' beneficial effects on chronic obstructive pulmonary disease (COPD) outcomes, the impact, if any, of statins on COPD exacerbations remains unclear. This study aimed to examine the association between statin use and risk of hospitalized COPD exacerbation, and to assess whether the association varied by statin initiation, dose, or duration of use. METHODS: A retrospective nested case-control study among patients with COPD was conducted analyzing a nationwide health insurance claims database in Taiwan. Cases were subjects hospitalized for COPD exacerbations; each case was matched to 4 randomly selected controls on age, sex, cohort entry, and number of COPD related outpatient visits by an incident-density sampling approach. Conditional logistic regressions were employed to quantify the COPD exacerbation risk associated with statin use. RESULTS: The study cohort comprised 14,316 COPD patients, from which 1584 cases with COPD exacerbations and 5950 matched controls were identified. Any use of statins was associated with a 30% decreased risk of COPD exacerbation (95% confidence interval [CI], 0.56-0.88), and current use of statins was related to a greater reduced risk (adjusted odds ratio [OR] 0.60; 95% CI, 0.44-0.81). A dose-dependent reduced risk of COPD exacerbation by statins was observed (medium average daily dose: adjusted OR 0.60; 95% CI, 0.41-0.89; high daily dose: adjusted OR 0.33; 95% CI, 0.14-0.73). The reduced risk remained significant for either short or long duration of statin use. CONCLUSIONS: Statin use was associated with a reduced risk of COPD exacerbation, with a further risk reduction for statins prescribed more recently or at high doses. PMID- 23684061 TI - Chronic Q fever causing aortitis. PMID- 23684062 TI - Catching the cheats. PMID- 23684063 TI - Does aldosterone blockade improve physical performance in older individuals? PMID- 23684064 TI - Ifosfamide-induced Fanconi syndrome and desmopressin-responsive nephrogenic diabetes insipidus. PMID- 23684065 TI - Amyotrophic lateral sclerosis and pseudo-infarct pattern on the electrocardiogram. PMID- 23684066 TI - Association of physical activity, asthma, and allergies: a cohort of farming and nonfarming children. PMID- 23684067 TI - C3a receptor promotes viral containment in mice inoculated with vaccinia virus at sites of allergic skin inflammation. PMID- 23684068 TI - T-cell receptor ligation causes Wiskott-Aldrich syndrome protein degradation and F-actin assembly downregulation. AB - BACKGROUND: Wiskott-Aldrich syndrome protein (WASP) links T-cell receptor (TCR) signaling to the actin cytoskeleton. WASP is normally protected from degradation by the Ca(++)-dependent protease calpain and by the proteasome because of its interaction with the WASP-interacting protein. OBJECTIVE: We investigated whether WASP is degraded after TCR ligation and whether its degradation downregulates F actin assembly caused by TCR ligation. METHODS: Primary T cells, Jurkat T cells, and transfected 293T cells were used in immunoprecipitation experiments. Intracellular F-actin content was measured in splenic T cells from wild-type, WASP-deficient, and c-Casitas B-lineage lymphoma (Cbl)-b-deficient mice by using flow cytometry. Calpeptin and MG-132 were used to inhibit calpain and the proteasome, respectively. RESULTS: A fraction of WASP in T cells was degraded by calpain and by the ubiquitin-proteasome pathway after TCR ligation. The Cbl-b and c-Cbl E3 ubiquitin ligases associated with WASP after TCR signaling and caused its ubiquitination. Inhibition of calpain and lack of Cbl-b resulted in a significantly more sustained increase in F-actin content after TCR ligation in wild-type T cells but not in WASP-deficient T cells. CONCLUSION: TCR ligation causes WASP to be degraded by calpain and to be ubiquitinated by Cbl family E3 ligases, which targets it for destruction by the proteasome. WASP degradation might provide a mechanism for regulating WASP-dependent TCR-driven assembly of F actin. PMID- 23684069 TI - Filaggrin gene mutation associations with peanut allergy persist despite variations in peanut allergy diagnostic criteria or asthma status. PMID- 23684071 TI - Reply: To PMID 23021878. PMID- 23684070 TI - Factors associated with degree of atopy in Latino children in a nationwide pediatric sample: the Genes-environments and Admixture in Latino Asthmatics (GALA II) study. AB - BACKGROUND: Atopy varies by ethnicity, even within Latino groups. This variation might be due to environmental, sociocultural, or genetic factors. OBJECTIVE: We sought to examine risk factors for atopy within a nationwide study of US Latino children with and without asthma. METHODS: Aeroallergen skin test responses were analyzed in 1830 US Latino subjects. Key determinants of atopy included country/region of origin, generation in the United States, acculturation, genetic ancestry, and site to which subjects migrated. Serial multivariate zero-inflated negative binomial regressions stratified by asthma status examined the association of each key determinant variable with the number of positive skin test responses. In addition, the independent effect of each key variable was determined by including all key variables in the final models. RESULTS: In baseline analyses African ancestry was associated with 3 times (95% CI, 1.62 5.57) as many positive skin test responses in asthmatic participants and 3.26 times (95% CI, 1.02-10.39) as many positive skin test responses in control participants. Generation and recruitment site were also associated with atopy in crude models. In final models adjusted for key variables, asthmatic patients of Puerto Rican (exp[beta] [95% CI], 1.31 [1.02-1.69]) and mixed (exp[beta] [95% CI], 1.27 [1.03-1.56]) ethnicity had a greater probability of positive skin test responses compared with Mexican asthmatic patients. Ancestry associations were abrogated by recruitment site but not region of origin. CONCLUSIONS: Puerto Rican ethnicity and mixed origin were associated with degree of atopy within US Latino children with asthma. African ancestry was not associated with degree of atopy after adjusting for recruitment site. Local environment variation, represented by site, was associated with degree of sensitization. PMID- 23684073 TI - Should clinicians use omalizumab for the treatment of nasal polyps? PMID- 23684074 TI - Growth factor receptor-bound protein 14: a potential new gene associated with oocyte competence. AB - The Grb14 protein is a member of the Grb7 protein family. This protein family acts by binding to tyrosine kinase receptors, promoting cell proliferation and differentiation. There is evidence of the involvement of tyrosine kinase factors in the bovine oocyte maturation process. However, Grb14 has not been studied for bovine cumulus-oocyte complexes (COCs). The aim of the present study was to characterize Grb14 mRNA expression in bovine COCs during follicular development. Furthermore, we demonstrated that the expression of Grb14 mRNA is not regulated by estradiol. mRNA expression of Grb14 was assessed in 480 COCs from follicles of different sizes (1-3, 4-6, 6-8 or >8 mm) by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Grb14 mRNA expression decreased in COCs throughout follicular growth (P < 0.05). The role of estradiol in the expression of Grb14 mRNA in COCs was studied. Grb14 mRNA abundance did not differ in COCs cultured in the presence or absence of 17beta-estradiol or fulvestrant. In conclusion, we showed that Grb14 mRNA is downregulated in COCs during antral follicle development, a finding that suggests a role for Grb14 in oocyte competence. PMID- 23684072 TI - Mechanism of Siglec-8-mediated cell death in IL-5-activated eosinophils: role for reactive oxygen species-enhanced MEK/ERK activation. AB - BACKGROUND: Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is expressed on human eosinophils, where its ligation induces cell death. Paradoxically, Siglec-8-mediated cell death is markedly enhanced by the presence of the activation and survival factor IL-5 and becomes independent of caspase activity. OBJECTIVE: In this report we investigate the mechanism of Siglec-8 mediated cell death in activated eosinophils. METHODS: Human peripheral blood eosinophils were treated with agonistic anti-Siglec-8 antibody and IL-5, and cell death was determined by using flow cytometry and morphology. Phosphorylation of mitogen-activated protein kinase (MAPK) was determined by using phosphoLuminex, flow cytometry, and Western blotting. Reactive oxygen species (ROS) accumulation was determined by using dihydrorhodamine fluorescence. RESULTS: Costimulation with anti-Siglec-8 and IL-5 significantly increased the rate and proportion of cell death by means of necrosis accompanied by granule release compared with that seen after stimulation with anti-Siglec-8 alone, in which apoptosis predominated. Together with the caspase-independent mode of cell death in costimulated cells, these findings suggest the activation of a specific and distinct biochemical pathway of cell death during anti-Siglec-8/IL-5 costimulation. Phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and MAPK-ERK kinase (MEK) 1 was significantly enhanced and sustained in costimulated cells compared with that seen in cells stimulated with IL-5 alone; anti-Siglec-8 alone did not cause ERK1/2 phosphorylation. MEK1 inhibitors blocked anti-Siglec-8/IL-5-induced cell death. ROS accumulation was induced by Siglec-8 ligation in a MEK-independent manner. In contrast, an ROS inhibitor prevented the anti-Siglec-8/IL-5-induced enhancement of ERK phosphorylation and cell death. Exogenous ROS mimicked stimulation by anti-Siglec-8 and was sufficient to induce enhanced cell death in IL-5-treated cells. Collectively, these data suggest that the enhancement of ERK phosphorylation is downstream of ROS generation. CONCLUSIONS: In activated eosinophils ligation of Siglec-8 leads to ROS-dependent enhancement of IL-5 induced ERK phosphorylation, which results in a novel mode of biochemically regulated eosinophil cell death. PMID- 23684076 TI - Mandibular implants placed during ablative tumour surgery--which patients can benefit? PMID- 23684075 TI - Novel bone adhesives: a comparison of bond strengths in vitro. AB - Fracture fixation using adhesive is a promising alternative in craniofacial surgeries, replacing the plates and screws system. The advantages include the ease of application and avoidance of drilling holes that may weaken the bone and cause fractures. In this study the bond strengths of selected adhesives were evaluated and compared with resorbable plates and screws. Four adhesives, octyl cyanoacrylate, N-butyl-cyanoacrylate, a novel methyl-methacrylate, and a novel cyanoacrylate derivative, were tested for their microtensile and shear bond strengths. The bone samples were cut into rectangular bars and bonded with selected adhesives for microtensile testing. For the shear bond test, paired bars were bonded at the overlap, while two other sets of bars were attached by a Lactosorb plate using either adhesive or screws. Data were analysed by analysis of variance (ANOVA). The microtensile bond strengths of N-butyl-cyanoacrylate, novel cyanoacrylate derivative, and novel methyl-methacrylate derivative were significantly greater than octyl-cyanoacrylate. When bone sections were fixed with resorbable plates and adhesives, shear bond strength was significantly greater for N-butyl-cyanoacrylate than plate and screws, while the bond strengths of other adhesives were comparable with the plate and screws. N-Butyl cyanoacrylate was shown to have the greatest potential for fixation of fractured bone in craniofacial surgical applications. PMID- 23684077 TI - Donor-site morbidity after fibula free flap transfer: a comparison of subjective evaluation using a visual analogue scale and point evaluation system. AB - The aims of this study were: (1) to compare the visual analogue scale (VAS) with the point evaluation system (PES) in the subjective evaluation of donor-site morbidity after fibula free flap transfer; (2) to compare the functional outcomes of fibula free flap surgery between patients with a normal body mass index (BMI) and patients with a high BMI, and between skin paddle and non-skin paddle harvesting; and (3) to determine the correlation between functional outcomes and related factors. This study included 15 patients who underwent a vascularized fibula free flap transfer for oral and maxillofacial reconstruction. Demographic data, preoperative, intraoperative, and postoperative data were collected. Subjective self-evaluation of functional outcomes was done using a VAS followed by a PES. Comparison of the VAS and PES scores was assessed with Pearson's correlation coefficient. The statistical significance was set at P<0.05. The VAS score was significantly correlated with the PES score (r=0.63, P=0.01). The tourniquet times for the skin paddle group were longer than for the non-skin paddle group (P=0.02), while the satisfaction score of the non-skin paddle group was higher than that of the skin paddle group (P=0.03). The VAS is a potential option for the subjective evaluation of donor-site morbidity after fibula free flap transfer. PMID- 23684078 TI - Reduction genioplasty enhances quality of life in female patients with prognathism and maxillary hypoplasia undergoing bimaxillary osteotomy. AB - The structure of the chin determines facial attractiveness and is directly linked to quality of life (QoL). In patients with prognathism and maxillary hypoplasia, bimaxillary osteotomy (BIMAX) with mandibular setback does not always lead to a more slender chin or improved aesthetics. The aim of the present study was to evaluate whether QoL differed between females undergoing BIMAX alone (group I; n=30) and those undergoing BIMAX combined with reduction genioplasty (group II; n=30). Presurgical and postsurgical evaluations included cephalography, photogrammetry, and the Oral Health Impact Profile with one additional domain (aesthetics). Setback of the hard tissue pogonion was significantly greater (P=0.006) in group II (7.1mm) than in group I (2.7mm). Only in group II were soft tissue pogonion changes highly significant (P<0.001), amounting to a mean of 5mm. In both groups, the QoL domains 'social disability', 'psychological discomfort', and 'dissatisfied with aesthetics' changed significantly towards lower impact scores. Changes in the latter two domains were significantly greater in group II patients than in group I patients (P=0.021; P<0.001) and were correlated with changes in the soft tissue pogonion in the horizontal (P=0.024; P=0.022) and vertical directions (P=0.037; P=0.042). Genioplasty addresses both psychological and aesthetic concerns, and therefore significantly enhances postsurgical QoL. PMID- 23684079 TI - The effect of unsteady flow due to acceleration on hydrodynamic forces acting on the hand in swimming. AB - This study describes the effect of hand acceleration on hydrodynamic forces acting on the human hand in angular and general motions with variable hand accelerations. Even if accelerations of a swimmer's hand are believed to have an important role in generating hydrodynamic forces on the hand, the effect of accelerations in angular and general motions on hydrodynamic forces on the swimmers hand has not been previously quantified. Understanding how hand acceleration influences force generation can provide useful information to enhance swimming performance. A hand-forearm model attached to a tri-axial load cell was constructed to measure hydrodynamic forces acting only on the hand when the model was rotated and accelerated in a swimming flume. The effect of acceleration on hydrodynamic forces on the hand was described by comparing the difference between accelerating and non-accelerating hands in different flow conditions. Hydrodynamic forces on the accelerating hand varied between 1.9 and 10 times greater than for the non-accelerating hand in angular motion and varied between 1.7 and 25 times greater than for the non-accelerating hand in general motion. These large increases occurred not only during positive acceleration phases but also during negative acceleration phases, and may be due to the added mass effect and a vortex formed on the dorsal side of the hand. This study provides new evidence for enhanced stroke techniques in swimming to generate increased propulsion by changing hand velocity during a stroke. PMID- 23684080 TI - Towards a viscoelastic model for the unfused midpalatal suture: development and validation using the midsagittal suture in New Zealand white rabbits. AB - Maxillary expansion treatment is a commonly used procedure by orthodontists to widen a patient's upper jaw. As this is typically performed in adolescent patients, the midpalatal suture, connective tissue adjoining the two maxilla halves, remains unfused. Studies that have investigated patient response to expansion treatment, generally through finite element analysis, have considered this suture to behave in a linear elastic manner or it was left vacant. The purpose of the study presented here was to develop a model that could represent the midpalatal suture's viscoelastic behavior. Quasilinear viscoelastic, modified superposition, Schapery's, and Burgers modeling approaches were all considered. Raw data from a previously published study using New Zealand White Rabbits was utilized for model parameter estimation and validation. In this study, Sentalloy((r)) coil springs at load levels of 0.49N (50g), 0.98N (100g), and 1.96N (200g) were used to widen the midsagittal suture of live rabbits over a period of 6 weeks. Evaluation was based on a models ability to represent experimental data well over all three load sets. Ideally, a single set of model constants could be used to represent data over all loads tested. Upon completion of the analysis it was found that the modified superposition method was able to replicate experimental data within one standard deviation of the means using a single set of constants for all loads. Future work should focus on model improvement as well as prediction of treatment outcomes. PMID- 23684081 TI - Successful treatment of a 14-year-old patient with intestinal malrotation with laparoscopic Ladd procedure: case report and literature review. AB - Midgut malrotation is an anomaly of intestinal rotation that occurs during fetal development and usually presents in the neonatal period. We present a rare case of malrotation in a 14-year-old patient who presented with cramping, generalized right abdominal pain, and vomiting for a duration of one day. A computed tomography abdominal scan and upper gastrointestinal contrast studies showed malrotation of the small bowel without volvulus. Laparoscopy revealed typical Ladd's bands and a distended flabby third and fourth duodenal portion extrinsically obstructing the misplaced duodeno-jejunal junction. The Ladd procedure, including widening of the mesenteric base and appendectomy, was performed. Symptoms completely resolved in a half-year follow up period. Patients with midgut malrotation may present with vague abdominal pain, intestinal obstruction, or intestinal ischemia. The laparoscopic Ladd procedure is feasible and safe, and it appears to be as effective as the standard open Ladd procedure in the diagnosis and treatment of teenage or adult patients with intestinal malrotation. PMID- 23684083 TI - Non-pharmacological strategies for the treatment of acute ischaemic stroke. AB - Early recanalisation and an increase in collateral blood supply are predictors of favourable outcome in acute ischaemic stroke. Since individual responses to intravenous treatment with alteplase are heterogeneous, additional intra-arterial thrombolytic and mechanical endovascular treatment is increasingly given. Despite encouraging findings from single-centre studies, data from randomised clinical trials have not proven the hypothesis that interventional recanalisation leads to a better outcome. Advanced thrombectomy devices, the effect of ultrasound enhanced thrombolysis, and imaging-guided selection of patients outside the currently approved time-window are all under investigation. Although neuroprotective agents have not shown benefit in clinical trials, non pharmacological treatment strategies-such as decompressive surgery, therapeutic hypothermia, transcranial laser treatment, or augmentation of cerebral collateral perfusion by different means (eg, partial aortic occlusion or sphenopalatine ganglion stimulation)-are topics of current research. The future of acute stroke therapy relies on evidence for individually tailored, effective, safe, and rapidly accessible treatment probably consisting of combined pharmacological and improved non-pharmacological approaches. PMID- 23684084 TI - Streamlining of prehospital stroke management: the golden hour. AB - Thrombolysis with alteplase administered within a narrow therapeutic window provides an effective therapy for acute ischaemic stroke. However, mainly because of prehospital delay, patients often arrive too late for treatment, and no more than 1-8% of patients with stroke obtain this treatment. We recommend that all links in the prehospital stroke rescue chain must be optimised so that in the future more than a small minority of patients can profit from time-sensitive acute stroke therapy. Measures for improvement include continuous public awareness campaigns, education of emergency medical service personnel, the use of standardised, validated scales for recognition of stroke symptoms and for triaging to the appropriate institution, and advance notification to the receiving hospital. In the future, use of telemedicine technologies for interaction between the emergency site and hospital, and the strategy of treatment directly at the emergency site (mobile stroke unit concept), could contribute to more efficient use of resources and reduce the time taken to instigate treatment to within 60 min--the golden hour--of the onset of the symptoms of stroke. PMID- 23684085 TI - Tau pathology and neurodegeneration. AB - The pathway leading from soluble and monomeric to hyperphosphorylated, insoluble and filamentous tau protein is at the centre of many human neurodegenerative diseases, collectively referred to as tauopathies. Dominantly inherited mutations in MAPT, the gene that encodes tau, cause forms of frontotemporal dementia and parkinsonism, proving that dysfunction of tau is sufficient to cause neurodegeneration and dementia. However, most cases of tauopathy are not inherited in a dominant manner. The first tau aggregates form in a few nerve cells in discrete brain areas. These become self propagating and spread to distant brain regions in a prion-like manner. The prevention of tau aggregation and propagation is the focus of attempts to develop mechanism-based treatments for tauopathies. PMID- 23684086 TI - Sexual function, satisfaction with life and menopausal symptoms in middle-aged women. AB - PURPOSE: To assess sexual function, satisfaction with life (SWL), and menopause related symptoms among mid-aged Spanish women. MATERIALS AND METHODS: Cross sectional study of 260 women, aged 40-59, attending the public gynecology consultations completed the 14-item Changes in Sexual Functioning Questionnaire (CSFQ-14), the SWL Scale (SWLS), the Menopause Rating Scale (MRS), and a socio demographic questionnaire. RESULTS: Median [inter quartile range] age was 47 [8.0] years, 87.7% had a stable partner, 27.0% were postmenopausal, and 53.9% had increased body mass index (BMI). The prevalence of sexual dysfunction was 46.5% (CSFQ-14 score<=41). Postmenopausal status was associated with lower CSFQ-14 scores (worse sexual function) and severe menopausal symptoms whereas there were not significant differences in SWLS scores. CSFQ-14 scores correlated with SWLS (p<0.04), and inversely correlated with menopausal symptoms (p<0.02). Multiple linear regression analysis model predicted 26.6% of the total CSFQ-14 score variance, and higher scores (better sexual function) were correlated with better SWL, and inversely correlated to female age and worse menopausal symptoms. A second model predicted 38.4% of the SWLS score variance. The SWLS score correlated with the total CSFQ-14 score and BMI, and inversely correlated with economical problems, female tobacco use, lack of healthiness, menopausal symptoms, not having a partner, and partner's lack of healthiness. CONCLUSIONS: Lower sexual function was related to low SWL, age and menopausal symptoms while low SWLS score was related with economical problems, smoking, menopausal symptoms, and partner factors. PMID- 23684087 TI - Kinetics and kinematics after the Bridle procedure for treatment of traumatic foot drop. AB - BACKGROUND: The Bridle procedure restores active ankle dorsiflexion through a tri tendon anastomosis of the tibialis posterior, transferred to the dorsum of the foot, with the peroneus longus and tibialis anterior tendon. Inter-segmental foot motion after the Bridle procedure has not been measured. The purpose of this study is to report kinetic and kinematic variables during walking and heel rise in patients after the Bridle procedure. METHODS: 18 Bridle and 10 control participants were studied. Walking and heel rise kinetic and kinematic variables were collected and compared using an ANOVA. FINDINGS: During walking the Bridle group, compared with controls, had reduced ankle power at push-off [2.3 (SD 0.7) W/kg, 3.4 (SD 0.6) W/kg, respectively, P<.01], less hallux extension during swing [-13 (SD 7) degrees , 15 (SD 6) degrees , respectively, P<.01] and slightly less ankle dorsiflexion during swing [6 (SD 4) degrees , 9 (SD 2) degrees , respectively, P=.03]. During heel rise the Bridle group had 4 (SD 6) degrees of forefoot on hindfoot dorsiflexion compared to 8 (SD 3) degrees of plantarflexion in the controls (P<.01). INTERPRETATION: This study provides evidence that the Bridle procedure restores the majority of dorsiflexion motion during swing. However, plantarflexor function during push-off and hallux extension during swing were reduced during walking in the Bridle group. Abnormal mid-tarsal joint motion, forefoot on hindfoot dorsiflexion instead of plantarflexion, was identified in the Bridle group during the more challenging heel rise task. Intervention after the Bridle procedure must maximize ankle plantarflexor function and midfoot motion should be examined during challenging tasks. PMID- 23684088 TI - The Flexible Axial Stimulation (FAST) intramedullary nail provides interfragmentary micromotion and enhanced torsional stability. AB - BACKGROUND: Recent advances in intramedullary (IM) nailing have focused on removing free play at the nail-screw interface to provide enhanced construct torsional stiffness. These changes also increase axial construct stiffness and reduce axial interfragmentary movement, which is required for optimal secondary fracture healing. This study tested whether a novel intramedullary nail, the Flexible Axial Stimulation (FAST) nail, can simultaneously provide controlled axial interfragmentary motion with enhanced torsional stiffness. METHODS: Novel tibial nails and matched controls (N=6 per group) were tested in a cadaveric osteotomy fracture model and in explanted bench testing. In cadaver and bench tests, nails were tested in axial tension/compression, torsion, bending, and shear. Overall construct stiffness values were calculated in each loading mode and axial and torsional low-load micromotion plateaus were quantified. FINDINGS: The novel nails produced 1 mm of controlled axial interfragmentary motion, which was associated with a 22% reduction in axial stiffness compared to standard controls (P=0.026, effect size 2.5). The novel constructs also allowed less low load torsional movement compared to the controls (3.8 deg vs. 7.1 deg, P=0.010, effect size 1.9), which was associated with a 14% increase in overall construct torsional stiffness (P=0.003, effect size 1.3). There were no observable differences in performance between the novel and control nails in anteroposterior/mediolateral bending or shear. INTERPRETATION: These results suggest that an IM nailing construct can provide axial interfragmentary motion while retaining high torsional stiffness, a combination which may potentially enhance healing. PMID- 23684089 TI - Adverse events associated with EUS and EUS with FNA. PMID- 23684091 TI - Serrated lesions and hyperplastic (serrated) polyposis relationship with colorectal cancer: classification and surveillance recommendations. PMID- 23684092 TI - Positive domino effect, choice of conscious sedation, and endoscopic unit efficiency. PMID- 23684093 TI - Guidewires in ERCP. PMID- 23684094 TI - What is an adequate management strategy for pharyngeal low-grade dysplasia? PMID- 23684095 TI - Response. PMID- 23684096 TI - The way to remove an over-the-scope-clip (with video). PMID- 23684097 TI - Response. PMID- 23684098 TI - Acute hemorrhagic colitis after oral administration of oseltamivir for influenza. PMID- 23684099 TI - Exploring women's perspectives of access to care during pregnancy and childbirth: a qualitative study from rural Papua New Guinea. AB - OBJECTIVES: to explore women's perceptions and experiences of pregnancy and childbirth in a rural community in PNG. DESIGN: a qualitative, descriptive study comprising focus group discussions (FGDs) and in depth interviews. SETTING: this study took place in a rural community in Eastern Highlands Province, PNG. PARTICIPANTS: 51 women participated in seven focus group discussions. In depth interviews were undertaken with 21 women, including women recruited at the antenatal clinic, women purposively selected in the community and three key informants in the community. FINDINGS: the majority of women mentioned the benefits of receiving antenatal care at the health facility and the importance of a supervised, facility birth. Women faced numerous challenges with regards to accessing these services, including geographical, financial and language barriers. Cultural and customary beliefs surrounding childbirth and lack of decision making powers also impacted on whether women had a supervised birth. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: distance, terrain and transport as well as decision making processes and customary beliefs influenced whether a woman did or did not reach a health facility to give birth. While the wider issue of availability and location of health services and health system strengthening is addressed shorter term, community based interventions could be of benefit. These interventions should include safe motherhood and birth preparedness messages disseminated to women, men and key family and community members. PMID- 23684100 TI - Stride length-cadence relationship is disrupted in below-knee prosthesis users. AB - The aim of this study was to evaluate the linearity of the relationship between stride length and cadence (STRIDELC) over three self-selected speeds (normal, slow, fast) in below-knee prosthesis users (n=14, 11 men, mean age 43+/-12 years, mean time since amputation 9.2+/-6.9 years) in comparison to controls (n=20, 11 men, mean age 43+/-17 years). The step length-cadence relationship (STEPLC) was also calculated for the prosthetic and intact legs in prosthesis users and compared to the dominant leg of controls. The goodness of linear fit (R2) and slope over 3 speeds were used as outcome measures. Prosthesis users walked significantly slower than controls (slow-fast speed means 82-131 vs. 97-169 cm/s, respectively, ANOVA p<0.0001) due to both lower cadence (42-53 vs. 47-63 strides/min, p<0.0001) and shorter stride length (116-149 vs. 123-161 cm, p<0.0001). The R2 of STRIDELC relationship in below-knee prosthesis users (0.76+/ 0.13) was significantly lower than in controls (0.91+/-0.03, p<0.001). The R2 values of STEPLC relationship between the prosthetic and intact legs in prosthesis users were correlated (r=0.85, p<0.001) and both (0.67+/-0.19, 0.58+/ 0.21, respectively) were significantly smaller than in the dominant leg of controls (0.86+/-0.04, p<0.01). The slopes of STRIDELC and STEPLC were not different. The R2 of 0.84 for STRIDELC best discriminated prosthesis users from controls with high sensitivity (71%) and specificity (95%). The results indicate that coupling between stride/step length and cadence is disturbed in prosthesis users. Upon further investigation, the goodness of linear fit may prove to be useful in assessing prosthetic design, optimizing prosthetic fit, and predicting clinical outcomes. PMID- 23684101 TI - Spatio-temporal parameters and lower-limb kinematics of turning gait in typically developing children. AB - Turning is a requirement for most locomotor tasks; however, knowledge of the biomechanical requirements of successful turning is limited. Therefore, the aims of this study were to investigate the spatio-temporal and lower-limb kinematics of 90 degrees turning. Seventeen typically developing children, fitted with full body and multi-segment foot marker sets, having performed both step (outside leg) and spin (inside leg) turning strategies at self-selected velocity, were included in the study. Three turning phases were identified: approach, turn, and depart. Stride velocity and stride length were reduced for both turning strategies for all turning phases (p<0.03 and p<0.01, respectively), while stance time and stride width were increased during only select phases (p<0.05 and p<0.01, respectively) for both turn conditions compared to straight gait. Many spatio temporal differences between turn conditions and phases were also found (p<0.03). Lower-limb kinematics revealed numerous significant differences mainly in the coronal and transverse planes for the hip, knee, ankle, midfoot, and hallux between conditions (p<0.05). The findings summarized in this study help explain how typically developing children successfully execute turns and provide greater insight into the biomechanics of turning. This knowledge may be applied to a clinical setting to help improve the management of gait disorders in pathological populations, such as children with cerebral palsy. PMID- 23684103 TI - [Health care utilisation in France: an analysis of the main drivers of health care use inequalities related to migration]. AB - In using a general health survey representative of the French population, the 2006 and 2008 French Health, health care and insurance survey, this study explores inequalities in health care utilization between immigrants and natives. Our objective is to highlight the most important factors generating health care use inequalities relating to immigration in using non-linear decomposition. Estimation results reveal that for equivalent health care needs, immigrants present a lower demand for GP and specialist care than the French population. The implementation of non-linear decompositions suggests that health care use inequalities between French and immigrant populations are for the most part attributable to differences in the distribution of observable characteristics between both populations. In particular, immigrant lower health coverage represents the first factor generating inequalities in the propensity to contact a GP while education and income are the most important drivers of inequalities in the propensity to contact a specialist. PMID- 23684102 TI - MicroRNA-9 enhances migration and invasion through KLF17 in hepatocellular carcinoma. AB - Metastasis is one of the hallmarks of cancer malignancy that usually causes more detrimental effects than a primary tumor. Many microRNAs were reported to be involved in the process of tumor metastasis. Hep11 and Hep12 cells were derived from primary and recurrence (intrahepatic metastatic) sites of hepatocellular carcinoma (HCC), respectively. Hep12 exhibited a higher invasive and migratory potential than Hep11. There was also a significantly higher expression of miR-9 in Hep12 cells than in Hep11 cells. Further studies in HCC cell lines demonstrated that miR-9 could promote tumor cell migration and invasion. In addition, miR-9 downregulated KLF17 protein expression by targeting the 3'UTR region of the KLF17 gene directly. As a transcription factor, KLF17 directly acted on the promoters of EMT-related genes (ZO-1, Vimentin and Fibronectin (FN)) in HCC cell lines. Therefore, we conclude that miR-9 may possibly promote HCC migration and invasion through regulation of KLF17. PMID- 23684104 TI - [Toulouse, an "urban figure of public health". Dealing with public local struggles against health social differences]. AB - When drawing up the portrait of "urban figures of public health", in 1998, Didier Fassin considered Toulouse to be one of the worthy "local experiments". Fifteen years after his precursory work, the recently developed local public policy against health social differences gives an opportunity to question ourselves about the effectiveness of such a quality then associated to the city. A cognitive analysis of the elaboration of the Toulousian health public policy meaning enables to notice that the process of health legitimization on a local scale takes the following forms. On the one hand, renaming health as a legitimate object of public policies sets it up as a common wealth. On the other hand, local public policy puts the emphasis on health education and tries to increase the standing of social appraisal coming from associative experiments and abilities of the inhabitants themselves. Finally, it calls for citizens' mobilization and solidarity in order to promote a "health democracy" able to struggle efficiently against health social differences. PMID- 23684105 TI - [Public health program planning through the capabilities lens]. AB - As a theory of distributive justice, Amartya Sen's theory of capabilities questions the choices and decisions associated with the development and planning of public health programs. In this paper, the authors describe Sen's approach and explore its implications for public health by applying it to the case of tobacco control programs. Based on the tobacco control objectives set by the WHO and on the MPOWER package of measures, they notice that the translation of the objectives in capabilities call for a greater attention to the conditions of living of the different population groups. It also put into doubt the measures restricting access to tobacco products that do not account for their differing impacts on adults. The authors conclude that this ethical perspective is likely to be controversial as it may rank freedom as a value that overrides health. PMID- 23684106 TI - [Social inequalities in health, early child development and biological embedding]. AB - This paper describes evidence that led to the concept of biological embedding and introduces approaches designed to elucidate its mechanisms and role. Biological embedding occurs when: experience gets under the skin and alters human biological and developmental processes; systematic differences in experience in different social environments in society lead to systematically different biological and developmental states; these differences are stable and long term; and, finally, they have the capacity to influence health, well-being, learning, or behavior over the life course. The concept of biological embedding emerged from insights in population health on the unique characteristics of socioeconomic gradients: ubiquity in poor and post-scarcity societies alike; gradient seen regardless of whether SES is measured by income, education or occupation; cutting widely across health, well-being, learning and behavior outcomes; replicating itself on new conditions entering society; and, often, showing that flatter gradients mean better overall societal outcomes. Most important, the gradient begins the life course as a gradient in developmental health, suggesting that the emergence of a multifaceted resilience/vulnerability early in life is the best place to look for evidence of biological embedding. In order to understand its character, the metaphor of the "archeology of biological embedding" has been used, wherein the surficial stratum of the "dig" is experience and behavior; the shallow stratum is organ system and cellular function; and the deep stratum is gene function. We are now ready to address the fundamental question of biological embedding: how do early childhood environments work together with genetic variation and epigenetic regulation to generate gradients in health and human development across the life course? PMID- 23684107 TI - Videodermatoscopy and scabies. PMID- 23684108 TI - Prevalence and patterns of retention in cardiac care in young adults with congenital heart disease. AB - The population with adult congenital heart disease is expanding. Cardiac care retention and follow-up patterns were assessed in 153 adults with congenital heart disease (median age, 24.5 years), previously compliant as teenagers. The majority (125; 81.7%) were retained in care, most often by a pediatric cardiologist (69%). The rate of retention was surprisingly high. PMID- 23684110 TI - Hemorrhagic pyloroduodenal duplication cyst misdiagnosed as child abuse. PMID- 23684109 TI - Cord blood endothelial colony-forming cells from newborns with congenital diaphragmatic hernia. AB - Endothelial colony-forming cells (ECFCs) are decreased in the cord blood of preterm infants with moderate-to-severe bronchopulmonary dysplasia. We quantified ECFCs from infants with congenital diaphragmatic hernia, a neonatal disorder with severe lung hypoplasia. Unlike newborns who develop bronchopulmonary dysplasia, those with congenital diaphragmatic hernia had increased and highly-proliferative cord blood ECFCs. PMID- 23684112 TI - Finally: a focus on cognition in schizophrenia. PMID- 23684111 TI - [Definitive chemoradiotherapy for esophageal cancer: 66Gy versus 50Gy, a retrospective study]. AB - PURPOSE: To compare the influence of radiation dose, high dose versus standard dose, on survival for patients with esophageal carcinomas treated with definitive radiochemotherapy. PATIENTS AND METHODS: Between 2003 and 2006, 143 consecutive patients with squamous-cell carcinoma and adenocarcinoma, clinical stage I to IVA, treated in two different institutions were retrospectively reviewed, 83 patients had received more than 50.4Gy, median dose 66Gy (50.7-72Gy) and 60 less than or equal to 50.4Gy, median dose 50Gy (38-50.4Gy). RESULTS: Median age was higher in high dose group (67.6 versus 61.7 years). Nutritional status and stage were better in high dose group with a lower weight loss (5.1 versus 7.9%), a higher body mass index (25.7 versus 22.9), more N0 patients (60.2 versus 31.7%) and less stage III (27.7 versus 63.3%). Median follow up was 20.8 months (2.8 92.4 months), and 64.9 months (4.2-92.4 months) for the 33 surviving patients. No statistically significant difference was shown for local/locoregional control, disease-free survival. Overall survival at 2-, 3- and 5-year and median survival was respectively 44.7%, 36.8%, 19.1% and 21.2 months in high dose group and 50.8%, 31.6%, 20.7% and 24.6 months in standard dose group (P=0.9). CONCLUSION: No difference was found between the two groups in terms of local/distant control and overall survival. A prospective randomised study is needed. PMID- 23684113 TI - Effect of mood states and infertility stress on patients' attitudes toward embryo transfer and multiple pregnancy. AB - OBJECTIVE: To examine whether mood state or infertility stress influences perceptions of risk, preferences for embryo transfer, or views on multiple pregnancy. DESIGN: Observational cohort study. SETTING: Hospital-based fertility clinic. PATIENT(S): One hundred seventy-six women participating in IVF treatment. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Mood scores, ratings of risk, preference for multiple embryo transfer, and attitudes toward multiple pregnancy. RESULT(S): Growing feelings of tension across the cycle corresponded with increases in the perceived riskiness of double-embryo transfer, but there was no change in strength of transfer preferences. Women experiencing negative moods, such as depression, viewed twin and triplet pregnancy as less likely, whereas increasing positive feelings across the cycle were associated with increasing desire for twin pregnancy. Overall, women perceived double- and triple-embryo transfer as less risky by cycle end than at cycle beginning and felt more certain about multiple-embryo transfer. CONCLUSION(S): The dyssynchrony observed among changes in mood, perceptions of risk, and transfer preferences challenges assumptions about the way medical risk information influences transfer preferences, and the findings suggest that mood states experienced during an IVF cycle might affect transfer preferences by influencing attitudes toward multiple pregnancy. Additional considerations beyond providing risk information are needed to facilitate effective patient decision making. PMID- 23684114 TI - The nose knows tubal function? PMID- 23684115 TI - Actinomycosis pelvic abscess after in vitro fertilization. AB - OBJECTIVE: To report a case of pelvic actinomycosis presenting as large, multiloculated abscesses after an in vitro fertilization (IVF) cycle for male factor infertility. DESIGN: A case report and literature review. SETTING: University hospital. PATIENT(S): A 31-year-old nulligravid woman presenting with urinary retention, pelvic pain, and fever 6 days after transvaginal oocyte retrieval and an embryo transfer for male factor infertility. INTERVENTION(S): Intravenous and oral antimicrobial therapy, and computed tomography (CT)-guided drainage of pelvic abscesses. MAIN OUTCOME MEASURE(S): Clinical and radiologic resolution of symptoms and infection. RESULT(S): The CT scan revealed several large, multiloculated pelvic and tuboovarian abscesses. The patient defervesced after 6 days of intravenous antibiotics, but the pelvic pain did not improve. After CT-guided drainage of the pelvic abscesses, the patient's symptoms improved. The drained material was cultured, and the patient was diagnosed with pelvic actinomycosis tuboovarian abscesses, an infrequent cause of tuboovarian abscess and a rare complication of assisted reproductive technology (ART). The patient was switched from intravenous to oral antibiotics and discharged home. CONCLUSION(S): Pelvic Actinomyces israelii presenting as pelvic abscesses may occur as a rare complication of ART. Physicians should consider a diagnosis of tuboovarian abscess in a patient reporting fever and pelvic pain after IVF and embryo transfer. PMID- 23684116 TI - Transforming growth factor-beta1 and its receptor soluble endoglin are altered in polycystic ovary syndrome during controlled ovarian stimulation. AB - OBJECTIVE: To evaluate the relationship between transforming growth factor (TGF) beta1 and its receptor, soluble endoglin (sENG), in the serum and follicular fluid of women with polycystic ovarian syndrome (PCOS) compared with that of non PCOS normal ovulating women during controlled ovarian stimulation (COS). DESIGN: Prospective case-control study. SETTING: Academic-affiliated assisted reproductive technology unit. PATIENT(S): Fourteen PCOS and 14 matched non-PCOS control women undergoing COS. INTERVENTION(S): Serum was collected on day 3 (baseline), day of hCG, and day of retrieval. Follicular fluid (FF) was collected on day of oocyte retrieval. ELISA was performed to determine TGF-beta1 and sENG protein levels. MAIN OUTCOME MEASURE(S): Serum and FF levels of TGF-beta1 and sENG. RESULT(S): Serum TGF-beta1 did not change significantly during COS but was increased in PCOS compared with non-PCOS women on day 3 and days of hCG administration and oocyte retrieval. Serum sENG increased after hCG administration only in the non-PCOS control group. In addition, serum sENG was decreased in PCOS compared with non-PCOS control women on the days of hCG and retrieval. Accordingly, the bioavailability of TGF-beta1 (TGF-beta1/sENG ratio) was increased in women with PCOS compared with non-PCOS controls at all three time points. No differences in either factor were noted in FF between groups. CONCLUSION(S): The increased TGF-beta1 bioavailability in PCOS is not only due to increased TGF-beta1 levels but also to decreased levels of its receptor, sENG. These data suggest that increased TGF-beta1 bioavailability may contribute to the pathogenesis of PCOS and its increased risk for ovarian hyperstimulation. PMID- 23684117 TI - Perceived discomfort functions based on joint moment for various joint motion directions of the upper limb. AB - The aim of the present study was to formulate the relationship between the perceived discomfort and the joint moment ratio for twelve joint motion directions of the upper limb by considering the between-subject variability, and to investigate the effect of joint motion direction. Three approximation models (i.e., linear, exponential, and logistic function models) were compared in terms of the accuracy of predicting the perceived discomfort, and the logistic function was selected because its average error was lowest. The concept of L-R fuzzy number was used to consider the individual variability of perceived discomfort, and a simplified distribution of perceived discomfort was represented. Cluster analysis showed that the twelve discomfort functions formed two clusters: one for elbow flexion and a second for the remaining joint motions. The data show that elbow flexion is more sensitive than other joint motions to increases in the joint moment ratio. PMID- 23684119 TI - Fundamentals of systems ergonomics/human factors. AB - Ergonomics/human factors is, above anything else, a systems discipline and profession, applying a systems philosophy and systems approaches. Many things are labelled as system in today's world, and this paper specifies just what attributes and notions define ergonomics/human factors in systems terms. These are obviously a systems focus, but also concern for context, acknowledgement of interactions and complexity, a holistic approach, recognition of emergence and embedding of the professional effort involved within organization system. These six notions are illustrated with examples from a large body of work on rail human factors. PMID- 23684118 TI - Postural stability when walking: effect of the frequency and magnitude of lateral oscillatory motion. AB - While walking on an instrumented treadmill, 20 subjects were perturbed by lateral sinusoidal oscillations representative of those encountered in transport: frequencies in the range 0.5-2 Hz and accelerations in the range 0.1-2.0 ms(-2) r.m.s., corresponding to velocities in the range 0.032-0.16 ms(-1) r.m.s. Postural stability was assessed from the self-reported probability of losing balance (i.e., perceived risk of falling) and the movements of the centre of pressure beneath the feet. With the same acceleration at all frequencies, the velocities and displacements of the oscillatory perturbations were greater with the lower frequency oscillations, and these caused greater postural instability. With the same velocity at all frequencies, postural instability was almost independent of the frequency of oscillation. Movements of the centre of pressure show that subjects attempted to compensate for the perturbations by increasing their step width and increasing their step rate. PMID- 23684120 TI - Customization of user interfaces to reduce errors and enhance user acceptance. AB - Customization is assumed to reduce error and increase user acceptance in the human-machine relation. Reconfiguration gives the operator the option to customize a user interface according to his or her own preferences. An experimental study with 72 computer science students using a simulated process control task was conducted. The reconfiguration group (RG) interactively reconfigured their user interfaces and used the reconfigured user interface in the subsequent test whereas the control group (CG) used a default user interface. Results showed significantly lower error rates and higher acceptance of the RG compared to the CG while there were no significant differences between the groups regarding situation awareness and mental workload. Reconfiguration seems to be promising and therefore warrants further exploration. PMID- 23684121 TI - The association between the disruption of motor imagery and the number of depressive episodes of major depression. AB - BACKGROUND: Mental rotation performance may be used as an index of mental slowing or bradyphrenia, and may reflect, in particular, speed of motor preparation. Previous studies suggest depressive patients present the correlates of impaired behavioural performance for mental rotation and psychomotor disturbance. The aim of this study is to compare the mental rotation abilities of patients with a first episode of depression, recurrent depression and healthy control subjects with regard to hand tasks. METHODS: We tested 32 first episode of depression, 38 recurrent depression and 36 healthy control subjects by evaluating the performance of depressed patients with regard to the hand mental rotation tasks. RESULTS: First, the first episode and recurrent depression subjects were significantly slower and made more errors than controls in mentally rotating hands. Second, the first depressive episode but not the recurrent depression displayed the same pattern of response times to stimuli at various orientations relative to control subjects in the hand task. Third, in particular, recurrent depression subjects were significantly slower and made more errors during the mental transformation of hands than first depressive episode relative to control subjects and the differences were significantly larger in female than male subjects in the mental rotation hand task. LIMITATIONS: Patients were on antidepressant medication. CONCLUSIONS: These results suggest that the impaired behavioural performance for mental representation processing are related to the number of previous episodes. Moreover, the recurrent major depressive episodes may contribute to the reinforcement of cognitive impairments and further the development or maintenance of mental representation dysfunctions, especially in female patients. A deficit on mental rotation in the depressive patients may be potential biomarkers for recurrence chronically. PMID- 23684123 TI - Vagal nerve activity as a moderator of brain-immune relationships. AB - We investigated whether vagal tone, as assessed by heart rate variability (HRV), moderates the neural correlates of immune and physiological responses to acute stress. Participants with low and high baseline HRV underwent a reversal learning task as an acute stressor. Natural killer cells, norepinephrine, and adrenocorticotropic hormone in peripheral blood changed with acute stress in the high HRV group only. Activity in the prefrontal cortex and striatum correlated with the immune and physiological indices in the high HRV group. High vagal tone may reflect more flexible top-down brain regulation of immune and physiological activity. PMID- 23684122 TI - First evidence on the validity and reliability of the Safety Organizing Scale Nursing Home version (SOS-NH). AB - BACKGROUND: The Safety Organizing Scale is a valid and reliable measure on safety behaviors and practices in hospitals. PURPOSE OF THE STUDY: This study aimed to explore the psychometric properties of the Safety Organizing Scale-Nursing Home version (SOS-NH). DESIGN AND METHODS: In a cross-sectional analysis of staff survey data, we examined validity and reliability of the 9-item Safety SOS-NH using American Educational Research Association guidelines. SUBJECTS AND SETTING: This substudy of a larger trial used baseline survey data collected from staff members (n = 627) in a variety of work roles in 13 nursing homes (NHs) in North Carolina and Virginia. RESULTS: Psychometric evaluation of the SOS-NH revealed good response patterns with low average of missing values across all items (3.05%). Analyses of the SOS-NH's internal structure (eg, comparative fit indices = 0.929, standardized root mean square error of approximation = 0.045) and consistency (composite reliability = 0.94) suggested its 1-dimensionality. Significant between-facility variability, intraclass correlations, within-group agreement, and design effect confirmed appropriateness of the SOS-NH for measurement at the NH level, justifying data aggregation. The SOS-NH showed discriminate validity from one related concept: communication openness. IMPLICATIONS: Initial evidence regarding validity and reliability of the SOS-NH supports its utility in measuring safety behaviors and practices among a wide range of NH staff members, including those with low literacy. Further psychometric evaluation should focus on testing concurrent and criterion validity, using resident outcome measures (eg, patient fall rates). PMID- 23684125 TI - Time interval required for return to baseline of the background rhythm on electroencephalogram after recorded electrographic seizures. AB - Our objective was to assess the time interval that is required for the return to baseline of the background rhythm in the electroencephalogram (EEG) after ictal electrographic activity. We completed a retrospective EEG review of 28 adults and 13 children admitted to the epilepsy monitoring unit at Massachusetts General Hospital. EEG background rhythm on admission was considered the baseline rhythm per patient. In children the maximum time interval that was required for background rhythm to return to its baseline was 300 min, with average time of 120 min compared to a maximum of 420 min, with average time of 84 min for adults. Background slowing was shorter for frontal lobe seizures and longer for temporal lobe seizures. This study of patients with epilepsy shows that the time required for postictal slowing to resolve is short, and on average background rhythm returns to baseline within 2 h. PMID- 23684124 TI - Rasburicase in tumor lysis syndrome of the adult: a systematic review and meta analysis. AB - BACKGROUND: The use of rasburicase has been evaluated extensively in children, but not in adults. We review the current literature to evaluate its effect on adults. STUDY DESIGN: Systematic review and meta-analysis. SETTING & POPULATION: Adults receiving rasburicase for tumor lysis syndrome (TLS). SELECTION CRITERIA FOR STUDIES: Electronic databases, regulatory documents, and websites were searched up to August 7, 2012. Reference lists of published articles were examined for additional relevant references. Any controlled trial or observational studies (controlled before and after) were included. Studies considering children only or mixing data for children and adults were excluded. INTERVENTION: Rasburicase for TLS. OUTCOMES: The primary outcome was TLS development. Secondary outcomes included percentage of patients improving, total adverse events, acute kidney failure, deaths, and serum uric acid and creatinine levels. RESULTS: 21 studies (24 publications) reported data for 1,261 adult patients, 768 receiving rasburicase for either the treatment or prophylaxis of TLS; these comprised 4 controlled trials and 17 observational studies. No statistically significant differences in clinical TLS development were observed in the controlled trials between the rasburicase and control groups. For the observational studies, 7.4% of patients developed clinical TLS after rasburicase (95% CI, 1.7%-16.7%), 93.4% of patients achieved normalized serum uric acid levels after rasburicase treatment (95% CI, 91.7%-94.6%), 4.4% developed acute kidney injury (95% CI, 3.0%-6.0%), and 2.6% died (95% CI, 0.95%-5.0%). The mean reduction in serum uric acid levels ranged from 5.3-12.8 mg/dL, and for serum creatinine levels, from 0.10-2.1 mg/dL. LIMITATIONS: Controlled trials differed in outcomes reported; meta-analysis was not performed. CONCLUSIONS: Rasburicase is effective in reducing serum uric acid levels in adults with TLS but at a significant cost, and evidence currently is lacking in adults to report whether rasburicase use improves clinical outcomes compared with other alternatives. Until new evidence is available, use of rasburicase may be limited to adult patients with a high risk of TLS. PMID- 23684126 TI - Significance of triphasic waves in patients with acute encephalopathy: a nine year cohort study. AB - OBJECTIVE: Triphasic waves (TWs) are a frequent electroencephalography (EEG) finding in encephalopathy, yet their origin and prognostic significance are not well understood. The aim of this study was to determine the clinical and EEG characteristics in encephalopathic patients with TWs. We hypothesized that specific EEG characteristics are predictive of outcome. METHODS: Consecutive adult encephalopathic patients with TWs on EEG and neuroimaging were included. EEG analysis included semiquantitative evaluation of TWs, background activity, and EEG reactivity. The study endpoint was death. RESULTS: Over a nine-year period, 105 patients with TWs were included. Common abnormalities on neuroimaging were white matter lesions (60%) and cerebral atrophy (59%). Pathologic conditions included infections (56%), renal (50%) and liver insufficiency (12%), and respiratory failure (20%). Mortality was 20%. Absent EEG background reactivity and respiratory failure were independently associated with death (OR 3.73, 95%CI 1.08-12.80, p=0.037 and OR 6.47, 95%CI 1.98-21.12, p=0.02). CONCLUSIONS: These results suggest that TWs are a marker of structural brain disease coupled with toxic-metabolic perturbations, and that etiologies or underlying pathologies were not predictive for outcome while non-reactive EEG was independently associated with death. SIGNIFICANCE: In contrast to clinical, EEG and neuroimaging findings, non-reactive EEG patterns predicted death in encephalopathic patients with TWs. PMID- 23684127 TI - A machine learning approach using EEG data to predict response to SSRI treatment for major depressive disorder. AB - OBJECTIVE: The problem of identifying, in advance, the most effective treatment agent for various psychiatric conditions remains an elusive goal. To address this challenge, we investigate the performance of the proposed machine learning (ML) methodology (based on the pre-treatment electroencephalogram (EEG)) for prediction of response to treatment with a selective serotonin reuptake inhibitor (SSRI) medication in subjects suffering from major depressive disorder (MDD). METHODS: A relatively small number of most discriminating features are selected from a large group of candidate features extracted from the subject's pre treatment EEG, using a machine learning procedure for feature selection. The selected features are fed into a classifier, which was realized as a mixture of factor analysis (MFA) model, whose output is the predicted response in the form of a likelihood value. This likelihood indicates the extent to which the subject belongs to the responder vs. non-responder classes. The overall method was evaluated using a "leave-n-out" randomized permutation cross-validation procedure. RESULTS: A list of discriminating EEG biomarkers (features) was found. The specificity of the proposed method is 80.9% while sensitivity is 94.9%, for an overall prediction accuracy of 87.9%. There is a 98.76% confidence that the estimated prediction rate is within the interval [75%, 100%]. CONCLUSIONS: These results indicate that the proposed ML method holds considerable promise in predicting the efficacy of SSRI antidepressant therapy for MDD, based on a simple and cost-effective pre-treatment EEG. SIGNIFICANCE: The proposed approach offers the potential to improve the treatment of major depression and to reduce health care costs. PMID- 23684128 TI - On the control of brain-computer interfaces by users with cerebral palsy. AB - OBJECTIVE: Brain-computer interfaces (BCIs) have been proposed as a potential assistive device for individuals with cerebral palsy (CP) to assist with their communication needs. However, it is unclear how well-suited BCIs are to individuals with CP. Therefore, this study aims to investigate to what extent these users are able to gain control of BCIs. METHODS: This study is conducted with 14 individuals with CP attempting to control two standard online BCIs (1) based upon sensorimotor rhythm modulations, and (2) based upon steady state visual evoked potentials. RESULTS: Of the 14 users, 8 are able to use one or other of the BCIs, online, with a statistically significant level of accuracy, without prior training. Classification results are driven by neurophysiological activity and not seen to correlate with occurrences of artifacts. However, many of these users' accuracies, while statistically significant, would require either more training or more advanced methods before practical BCI control would be possible. CONCLUSIONS: The results indicate that BCIs may be controlled by individuals with CP but that many issues need to be overcome before practical application use may be achieved. SIGNIFICANCE: This is the first study to assess the ability of a large group of different individuals with CP to gain control of an online BCI system. The results indicate that six users could control a sensorimotor rhythm BCI and three a steady state visual evoked potential BCI at statistically significant levels of accuracy (SMR accuracies; mean +/- STD, 0.821 +/- 0.116, SSVEP accuracies; 0.422 +/- 0.069). PMID- 23684129 TI - S-adenosylmethionine modifies cocaine-induced DNA methylation and increases locomotor sensitization in mice. AB - Several studies suggest that individual variability is a critical component underlying drug addiction as not all members of a population who use addictive substance become addicted. There is evidence that the overall epigenetic status of a cell (epigenome) can be modulated by a variety of environmental factors, such as nutrients and chemicals. Based on these data, our aim was to investigate whether environmental factors like S-adenosylmethionine (SAM) via affecting epigenome could alter cocaine-induced gene expression and locomotor sensitization in mice. Our results demonstrate that repeated SAM (10 mm/kg) pretreatment significantly potentiated cocaine-induced locomotor sensitization. Using mouse nucleus accumbens (NAc) tissue, whole-genome gene expression profiling revealed that repeated SAM treatment affected a limited number of genes, but significantly modified cocaine-induced gene expression by blunting non-specifically the cocaine response. At the gene level, we discovered that SAM modulated cocaine-induced DNA methylation by inhibiting both promoter-associated CpG-island hyper- and hypomethylation in the NAc but not in the reference tissue cerebellum. Finally, our in vitro and in vivo data show that the modulating effect of SAM is in part due to decreased methyltransferase activity via down-regulation of Dnmt3a mRNA. Taken together, our results suggest that environmental factors that affect the NAc-cell epigenome may alter the development of psychostimulant-induced addiction and this may explain, at least partly, why some individuals are more vulnerable to drug addiction. PMID- 23684130 TI - A comparison of patient and nurse expectations regarding nursing care in the emergency department. AB - INTRODUCTION: Patient satisfaction, an important measurable outcome, allows nurses to assess what can be improved in nursing practice. The purpose of this study is to compare expectations of patients and nurses using 3 nursing care attributes: 1) friendliness, courtesy, and respectfulness; 2) comfort measures; and 3) degree of information sharing. METHODS: This is an Institutional Review Board-exempt survey of paired patients' and nurses' perceptions of nursing care in a 50-bed emergency department of a level 1 trauma center. The survey consists of questions that addressed 3 performance attributes of nursing care. The respondent circled their responses in a Likert scale of 5 choices from 1: "way below expectation" to 5: "way above expectation." An open-ended comment section followed each question; the last survey item asked for recommendations on how to make nursing care extraordinary. RESULTS: Nineteen males and 30 female patients, ages 18-89 participated. Of the nurse participants, 20% had <5 years ED experience, 22% had 5-10 years, and 52% had >10 years. The patients rated the care they received consistently higher than nurses. The difference in the average patient ratings vs. the average nurse's rating was significant. (P = < 0.002, paired T test and Sign test). Patient ratings were also consistently higher when patients either knew their nurse's name or were able to identify them by sight. The higher average rating was significant in all 3 attributes (P = 0.02, Wilcoxon Rank-sum test). DISCUSSION: The unexpected highly positive patient rating did not identify specific areas for practice improvement; it did provide positive feedback for excellent care, reinforcing good nursing practice. PMID- 23684131 TI - The incidence of fever in US Critical Care Air Transport Team combat trauma patients evacuated from the theater between March 2009 and March 2010. AB - INTRODUCTION: Most critically ill injured patients are transported out of the theater by Critical Care Air Transport Teams (CCATTs). Fever after trauma is correlated with surgical complications and infection. The purposes of this study are to identify the incidence of elevated temperature in patients managed in the CCATT environment and to describe the complications reported and the treatments used in these patients. METHODS: We performed a retrospective review of available records of trauma patients from the combat theater between March 1, 2009, and March 31, 2010, who were transported by the US Air Force CCATT and had an incidence of hyperthermia. We then divided the cohort into 2 groups, patients transported with an elevation in temperature greater than 100.4 degrees F and patients with no documented elevation in temperature. We used a standardized, secure electronic data collection form to abstract the outcomes. Descriptive data collected included injury type, temperature, use of a mechanical ventilator, cooling treatment modalities, antipyretics, intravenous fluid administration, and use of blood products. We also evaluated the incidence of complications during the transport in patients who had a recorded elevation in temperature greater than 100.4 degrees F. RESULTS: A total of 248 trauma patients met the inclusion criteria, and 101 trauma patients (40%) had fever. The mean age was 28 years, and 98% of patients were men. The mechanism of injury was an explosion in 156 patients (63%), blunt injury in 11 (4%), and penetrating injury in 45 (18%), whereas other trauma-related injuries accounted for 36 patients (15%). Of the patients, 209 (84%) had battle-related injuries and 39 (16%) had non-battle related injuries. Traumatic brain injury was found in 24 patients (24%) with an incidence of elevated temperature. The mean temperature was 101.6 degrees F (range, 100.5 degrees F-103.9 degrees F). After evaluation of therapies and treatments, 80 trauma patients (51%) were intubated on a mechanical ventilator (P < .001). Of the trauma patients with documented fever, 22 (22%) received administration of blood products. Nineteen patients received antipyretics during their flight (19%), 9 received intravenous fluids (9%), and 2 received nonpharmacologic cooling interventions, such as cooling blankets or icepacks. We identified 1 trauma patient with neurologic changes (1%), 6 with hypotension (6%), 48 with tachycardia (48%), 33 with decreased urinary output (33%), and 1 with an episode of shivering or sweating (1%). We did not detect any transfusion reactions or deaths during flight. CONCLUSION: Fever occurred in 41% of critically ill combat-injured patients evacuated out of the combat theater in Iraq and Afghanistan. Fewer than 20% of patients with a documented elevated temperature received treatments to reduce the temperature. Intubation of patients with ventilators in use during the transport was the only factor significantly associated with fever. Serious complications were rare, and there were no deaths during these transports. PMID- 23684132 TI - Harvest of pulmonary artery endothelial cells from patients undergoing right heart catheterization. PMID- 23684133 TI - Propofol inhibits hypoxia/reoxygenation-induced human gastric epithelial cell injury by suppressing the Toll-like receptor 4 pathway. AB - This study aimed to investigate the role of the Toll-like receptor 4 (TLR4) pathway in normal human gastric epithelial (GES-1) cells under hypoxia/reoxygenation (H/R) in vitro, and the effect of propofol on injured GES-1 cells as well as its possible mechanism. Before H/R induction, GES-1 cells were preconditioned with fat emulsion, propofol, or epigallocatechin gallate. Then cell viability, cell apoptosis, and related molecules in the cells were analyzed under experimental conditions. We found that propofol 50 MUmol/L markedly inhibited the H/R injury under hypoxia 1.5 h/reoxygenation 2 hours by promoting GES-1 cell viability and decreasing cell apoptosis. The TLR4 signal may be involved in the protective effect of propofol against H/R injury. The malondialdehyde contents and superoxide dismutase activities were recovered under propofol preconditioning. In summary, propofol preconditioning may exert a protective effect on H/R injury in GES-1 cells and the mechanism may be via inhibition of the activated TLR4 signal under H/R conditions. PMID- 23684134 TI - The feasibility and correlation of atrial fibrillation vulnerability test to the indices of atrial substrates using atrial burst decremental pacing. AB - Pulmonary vein isolation and atrial substrate modification using catheter ablation have been developed as a standard treatment for atrial fibrillation (AF). However, the standard end-point for these procedures is still not well established. This study aimed to investigate the characteristics among positive and negative AF vulnerability patients with normal structural heart, in order to define the endpoint of the atrial substrate modification. Fifty supraventricular tachycardia patients with normal heart structure referred for electrophysiological study and catheter ablation were enrolled. After eliminating the underling arrhythmias, the basic cycle length, effective refractory period of the right atrium, and the P wave indices in 12-lead electrocardiograms were measured. The AF vulnerability test was performed by atrial burst decremental pacing with a pacing cycle length decreasing from 290 ms to 200 ms. The AF vulnerability test was considered as positive when the duration of the induced AF or atrial tachyarrhythmias (ATs) was longer than 10 seconds. The parameters of atrial substrates were compared between patients with positive and negative values of the AF vulnerability test. ATs or AF were induced in 24 (48%) patients. Among these patients, 12 (24%) induced ATs or AF were found to be sustained (duration more than 10 seconds). However, only two of these patients could reproduce the positive result after 10 minutes of the first induced protocol. Comparing the patient baseline characteristics, P wave characteristics and cardiac echo parameters, there were no significant differences between the positive and negative AF vulnerability groups. In conclusion, AF and ATs could be induced in patients with a structurally normal heart. The traditional clinical indices of atrial substrates were not significantly different between the positive and negative AF vulnerability patients. Protocols other than atrial burst decremental pacing should be investigated to evaluate the endpoint of the atrial substrate modification. PMID- 23684135 TI - Urinary neutrophil gelatinase-associated lipocalin levels predict cisplatin induced acute kidney injury better than albuminuria or urinary cystatin C levels. AB - Cisplatin-induced acute kidney injury (AKI) is a major concern among clinicians in prescribing cisplatin-based chemotherapy. This study evaluated and compared the ability of urinary biomarkers, including urinary neutrophil gelatinase associated lipocalin (NGAL), cystatin C, and the urinary albumin to creatinine ratio (ACR) to predict cisplatin-induced AKI. Thirty-three cancer patients receiving cisplatin-based chemotherapy were prospectively studied, including 10 (30%) who developed AKI (the study group). Changes of urinary biomarkers were compared at 4 hours, 8 hours, and 12 hours, and 1 day, 2 days, 3 days, and 4 days after cisplatin intravenous infusions (75mg/m(2)) versus the baseline. There was a significant increase in urinary NGAL levels from 12 hours to 4 days (p<0.05) compared to baseline after cisplatin infusion in the AKI group. The magnitude of these changes over time differed significantly by group (p<0.001). The area under the receiver operating curve describing the relationship between urinary NGAL levels and AKI within 12 hours was 0.865 (95% confidence interval=0.691-1.000). Urinary NGAL levels independently predicted AKI 12 hours after cisplatin (p=0.045) after adjustments for age, gender, body mass index, baseline serum creatinine, and urinary total protein. Urinary NGAL levels may be an early biomarker of AKI in patients receiving cisplatin-based treatment. PMID- 23684136 TI - Hepatocellular carcinoma cells cause different responses in expressions of cancer promoting genes in different cancer-associated fibroblasts. AB - Cancer-associated fibroblast (CAF) is one of the most crucial components of the tumor microenvironment to promote the invasiveness of cancer cells. The interactions between cancer cells and CAFs are bidirectional. Our recent study showed that up-regulations of chemokine (C-C motif) ligand 2 (CCL2), chemokine (C C motif) ligand 26 (CCL26), interleukin 6 (IL6), and lysyl oxidase-like 2 (LOXL2) genes in cancer cells were parts of the common effects of CAFs on hepatocellular carcinoma (HCC) cells to promote proliferation, migration and invasion of cancer cells. However, the subject of how HCC cells to influence the gene expressions of CAFs still needs to be clarified. The purpose of this study was to investigate this issue. Two human HCC (HCC24/KMUH, HCC38/KMUH) and two human CAF cell lines (F26/KMUH, F28/KMUH) were studied. Influence of HCC38/KMUH cancer cells on differential expressions of genes in F28/KMUH CAFs was detected by microarray to select target genes for further analysis. Both HCC cell lines increased proliferation (all p < 0.005) and migration (all p < 0.0001) of two CAF cell lines. HCC24/KMUH cancer cells had stronger ability to promote migration of F26/KMUH CAFs than HCC38/KMUH cancer cells did (p < 0.0001). Eleven up-regulated cancer-promoting genes, including apelin (APLN), CCL2, CCL26, fibroblast growth factor 1 (FGF1), fibroblast growth factor 2 (FGF2), IL6, mucin 1 (MUC1), LOXL2, platelet-derived growth factor alpha polypeptide (PDGFA), phosphoglycerate kinase 1 (PGK1), and vascular endothelial growth factor A (VEGFA) detected by microarray showed good correlation with results of quantitative reverse transcriptase polymerase chain reaction study. Among these genes, HCC24/KMUH cancer cells had same tendency of effects on differential expressions of genes in F28/KMUH CAFs as HCC38/KMUH cancer cells did. However, the responses of F26/KMUH CAFs to different HCC cell lines were variable. Only PGK1 gene was consistently up-regulated and PDGFA gene was consistently down-regulated caused by both HCC cell lines in F26/KMUH CAFs. Besides PGK1 gene, HCC38/KMUH cancer cells only up-regulated APLN, LOXL2, and VEGFA genes and HCC24/KMUH cancer cells only up-regulated FGF2 gene in F26/KMUH CAFs. In conclusion, HCC cells can promote proliferation and migration of CAFs. However, the impact of HCC cells on differential expressions of cancer promoting genes in CAFs is influenced by the characteristics of CAFs. This implies that blocking single or several particular cancer-promoting genes in CAFs is unable to become a common stratagem for the treatment of HCC. PMID- 23684137 TI - Early predictors of narcotics-dependent patients in the emergency department. AB - It is not unusual that narcotics-dependent patients fulfill their medical requirements in the emergency department (ED). The behavior of these patients varies, and their manifestations and predictors are still not fully studied. We performed this retrospective study by prospectively collecting data on patients with suspected drug dependence who were undiagnosed at first and then treated for some kind of reported pain at the ED. Patients who were confirmed to have narcotics dependence were compared with control patients in a ratio of 1:3 matching for age, gender, disease, and clinical diagnoses. From January 2006 to October 2009, 26 of 223 patients treated for pain were found to be drug dependent (12 males and 14 females). The average dose of narcotics used was higher than the control group [3.23 +/- 1.14 vs. 1.12 +/- 0.36, p < 0.001, confidence interval (CI): 1.648-2.583]. Numbers of patients making unscheduled returns to the ED within 24 hours were significant [24/26 vs. 8/78, p <= 0.001, odds ratio (OR) 105.00, 95% CI 20.834-529.175]. In addition, patients showing aggressive attitudes were significant (17/26 vs. 2/78, p < 0.001, OR 71.78, 95% CI 14.206 362.663). In the case group, six of them told the physician that they were allergic to medicines other than the particular one they wanted, and three of the six presented injuries that were reported to be in the same (or repeated) place for unscheduled returns, which were not found in the control group. In this study, some behaviors were commonly observed in the at-risk group. These patients were prone to manifest some types of symptoms and behaviors, such as uncontrolled pain with three doses of analgesics, aggressive attitude, returning to the ED within 24 hours with the complaint of the same severe pain, repeating the same injury, claiming allergy to other analgesics, and asking for certain analgesics. All these behaviors should alert the physician to suspect a drug-seeking problem. PMID- 23684138 TI - Are prophylactic antibiotics necessary for urodynamic study? AB - The aim of this study was to assess the efficacy of prophylactic fosfomycin tromethamine (FT) and ciprofloxacin in preventing bacteriuria caused by urodynamic studies (UDS). A total of 426 adult patients presenting for UDS were enrolled the study. A midstream urine sample was taken 72 hours before and 5 days after the procedure. All patients underwent a standard UDS. The 411 patients who had sterile urine before intervention were included in the study. Patients were randomized into three groups. Group1 received no prophylaxis (n = 133), Group 2 (n = 141) received oral ciprofloxacin (500 mg) 1 hour before the procedure, and Group 3 (n = 137) received a single dose of FT approximately 12 hours before the procedure. Bacteriuria was evaluated for each group. Bacteriuria was detected in 3 (2.3%), 6 (4.3%) and 3 patients (1.6%) in Group 1, Group 2, and Group 3, respectively. The most common identified microorganism was Escherichia coli (E coli) in 6 patients (50%). Among the E coli group, extended spectrum beta lactamase producing E coli was seen in 2 patients (33.3%). Univariate analysis demonstrated that a history of urogenital operation (p < 0.01) and female gender (p < 0.01) were significant risk factors for bacteriuria. On multiple logistic regression analysis, the past urogenital operation history was the only significant independent risk factor for significant bacteriuria after UDS (OR = 14, 95% CI = 1.82-23.8, p = 0.01). The prevalence of bacteriuria after UDS was relatively low in the current study population. Therefore, for most patients, it may be unnecessary to use preventive prophylactic antibiotics. However, our results suggest that in patients with a previous history of urologic surgery, the risk for significant bacteriuria is increased and the use of prophylaxis should be considered. PMID- 23684139 TI - Relationship between dental caries status and anemia in children with severe early childhood caries. AB - Severe early childhood caries (SECC) is a public health problem among preschool children. Malnutrition is a condition commonly prevalent in children with SECC. This study investigated the nutritional status among preschool children with SECC. Children with SECC (n = 101) aged 2-5 years from the Division of Pediatric Dentistry in an academic hospital in Southern Taiwan were recruited for our cross sectional study. The nutritional status of the children was assessed based on anthropometric measurements and clinical tests. By applying the criteria established by the World Health Organization, we found that 9% and 46% of the children with SECC were diagnosed as being anemic and iron deficient, respectively. Using national standards for the body mass index, 30% of children with SECC were classified as underweight. The relationship between the caries status of the children and anemia was examined using multivariable logistic regression analysis (p < 0.05). Our results show that SECC is strongly associated with anemia (7.25-fold), indicating that clinicians and dentists should provide treatment to improve both the oral hygiene and the nutritional status of children with SECC. PMID- 23684140 TI - Glomerulonephritis associated with tuberculosis: a case report and literature review. AB - Rapidly progressive glomerulonephritis caused mycobacterium tuberculosis is rare; however, three case have been reported to date. Crescentic glomerulonephritis is a life-threatening disease and together with the presence of tuberculous infection is associated with a poor outcome if treatment is inadequate and delayed. We describe the case of a 31-year-old female patient with nephrotic syndrome and progressive renal failure secondary to pulmonary tuberculosis. Renal biopsy showed crescent formation in 14 out of 27 glomeruli, and there was diffuse linear staining of immunoglobulin G deposits. Treatment included corticosteroids in combination with antituberculosis drugs for 2 months, and resulted in a significant improvement in renal function, the disappearance of proteinuria and pulmonary symptoms. We also present a review of the pertinent literature and discuss the pathophysiology of tuberculosis-related acute postinfectious glomerulonephritis. PMID- 23684141 TI - Hajdu-Cheney syndrome with ventricular septal defect. PMID- 23684142 TI - Bisphosphonate-related atypical femoral fracture. PMID- 23684143 TI - Prognostic factors for outcomes of allogeneic stem cell transplantation in chronic phase chronic myeloid leukemia in the era of tyrosine kinase inhibitors. AB - The aim of this study was to estimate the prognostic factors for the outcomes of chronic myeloid leukemia (CML) patients receiving allogeneic stem cell transplantation (SCT) in chronic phase (CP) in the era of tyrosine kinase inhibitors (TKIs). Ninety-seven patients who underwent allogeneic SCT in CP were analyzed. Forty-seven were TKI-naive at the time of transplant, and 50 received TKI(s) treatment before transplantation. After a median follow-up of 115.8 months, the 4-year overall survival and event-free survival were 80.4 and 58.8%, respectively. Multivariate analysis showed that there were no differences in survival outcomes based on prior TKI therapy. Older age was a prognostic factor for higher treatment-related mortality (TRM), and the type of graft source and younger age were associated with relapse, but prior TKI therapy and disease status at the time of transplant were not associated with either TRM or relapse. Additionally, a major molecular response at 1 month and an MR(4.5) at 3 months were important predictors of favorable long-term outcomes. This study demonstrates the prognostic factors for the outcomes of allogeneic SCT in CP CML and shows that survival outcomes were not affected by the administration of long term multi-TKI treatment prior to transplantation. PMID- 23684144 TI - Temporary hemodialysis catheter placement by nephrology fellows: implications for nephrology training. AB - The insertion of temporary hemodialysis catheters is considered to be a core competency of nephrology fellowship training. Little is known about the adequacy of training for this procedure and the extent to which evidence-based techniques to reduce complications have been adopted. We conducted a web-based survey of Canadian nephrology trainees regarding the insertion of temporary hemodialysis catheters. Responses were received from 45 of 68 (66%) eligible trainees. The median number of temporary hemodialysis catheters inserted during the prior 6 months of training was 5 (IQR, 2-11), with 9 (20%) trainees reporting they had inserted none. More than one-third of respondents indicated that they were not adequately trained to competently insert temporary hemodialysis catheters at both the femoral and internal jugular sites. These findings are relevant to a discussion of the current adequacy of procedural skills training during nephrology fellowship. With respect to temporary hemodialysis catheter placement, there is an opportunity for increased use of simulation-based teaching by training programs. Certain infection control techniques and use of real-time ultrasound should be more widely adopted. Consideration should be given to the establishment of minimum procedural training requirements at the level of both individual training programs and nationwide certification authorities. PMID- 23684145 TI - KDOQI US commentary on the 2012 KDIGO clinical practice guideline for management of blood pressure in CKD. AB - In response to the 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guideline for blood pressure management in patients with chronic kidney disease not on dialysis, the National Kidney Foundation organized a group of US experts in hypertension and transplant nephrology to review the recommendations and comment on their relevancy in the context of current US clinical practice and concerns. The overriding message was the dearth of clinical trial evidence to provide strong evidence-based recommendations. For patients with CKD with normal to mildly increased albuminuria, goal blood pressure has been relaxed to <=140/90 mm Hg for both diabetic and nondiabetic patients. In contrast, KDIGO continues to recommend goal blood pressure <=130/80 mm Hg for patients with chronic kidney disease with moderately or severely increased albuminuria and for all renal transplant recipients regardless of the presence of proteinuria, without supporting data. The expert panel thought the KDIGO recommendations were generally reasonable but lacking in sufficient evidence support and that additional studies are greatly needed. PMID- 23684146 TI - A solid-phase microextraction fiber with carbon nanoparticles as sorbent material prepared by a simple flame-based preparation process. AB - A novel carbon nanoparticles-coated solid-phase microextraction (SPME) fiber was prepared via a simple and low-cost flame-based preparation process, with stainless steel wire as support. Surface characteristic of the fiber was studied with scanning electron microscope. A nano-scaled brushy structure was observed. Coupled to gas chromatography (GC), the fiber was used to extract phthalate esters (PAEs) and polycyclic aromatic hydrocarbons (PAHs) in aqueous samples. Analytical performances of the proposed method were investigated under the optimum extraction conditions (extraction temperature, 40 degrees C; content of KCl, 30% (w/v); extraction time, 50min for PAEs and 40min for PAHs) and compared with other reports for the same analytes. Calibration ranges were 0.06-500MUgL( 1) for di-n-butyl phthalate (DBP), and 0.1-300MUgL(-1) for di-cyclohexyl phthalate (DCHP) and di-(2-ethyl-hexyl) phthalate (DEHP). For the eight PAHs, good linearity was obtained ranging from 0.01 to 150MUgL(-1). Limits of detection were 0.005MUgL(-1) for three PAEs and 0.001-0.003MUgL(-1) for eight PAHs. The fiber exhibited excellent stability. It can be used for 100 times with RSDs of extraction efficiency less than 22.4%. The as-established SPME-GC method was applied to determine PAEs in food-wrap and PAHs in cigarette ash and snow water, and satisfactory results were obtained. The carbon nanoparticles-coated SPME fiber was efficient for sampling of organic compounds from aqueous samples. PMID- 23684147 TI - The role of heat shock protein 70 induced by geranylgeranylacetone in carbon tetrachloride-exposed adult rat testes. AB - Carbon tetrachloride (CCl4) induces testicular damage, through formation of free radical metabolites. Molecular chaperone heat shock protein of 70kDa (HSP 70) protects cells from various stresses. This study was designed to investigate the potential role of induction of HSP70 using geranylgeranylacetone (GGA) on testicular damage caused by CCl4. Rats were divided into group I (control group), Group II (CCl4 group) received CCl4 s.c. for 4 weeks, group III received CCl4 s.c. for 4 weeks simultaneously with daily single oral dose of GGA (GGA - treated CCl4 group). Serum testosterone, testicular lactate dehydrogenase (LDH) and alkaline phosphatase (ALP), testicular malondialdehyde (MDA), total nitrite and total antioxidant capacity (T-AOC) were measured. Evaluation of histopathological changes and immunohistochemical HSP70 expression for testicular biopsies were performed. Group II showed lower values of gonado-somatic index, serum testosterone, testicular LDH, ALP, T-AOC and greater values of testicular MDA and total nitrite than in control. Testicular morphology showed widening of seminiferous lumen, less spermatogenesis, vacuolization of germinative epithelium. Group III had higher values of gonado-somatic index, serum testosterone, testicular LDH, ALP, T-AOC with less testicular MDA and total nitrite than in group II. They have less damage and restored the altered testicular morphology. Immunohistochemical HSP70 expression was increased in the testicular spermatogenic and sertoli cells in group II that was significantly accentuated in group III. These findings suggest that GGA-induced activation of HSP 70 significantly alleviate CCl4 inflicting testicular damage by HSP 70 mediated cytoprotection and antioxidant effects. PMID- 23684148 TI - A novel ingestible electronic drug delivery and monitoring device. AB - BACKGROUND: We developed an ingestible electronic drug delivery and monitoring system. This system includes an electronic capsule comprising a drug reservoir, a pH and temperature sensor, a microprocessor and wireless transceiver, a stepper motor, and batteries. The location of the capsule in the gut derived from pH data can be monitored in real time. The stepper motor can be remotely actuated to expel the contents of the drug reservoir. OBJECTIVES: First human study. DESIGN: Two consecutive observational studies. SETTING: University medical center. SUBJECTS: Twenty healthy volunteers. INTERVENTIONS: Study I: Ingestion and passage of the capsule. Study II: Ingestion and passage of the capsule, loaded with (99m)technetium-pertechnetate ((99m)Tc); remotely actuated expulsion of (99m)Tc in the gut. MAIN OUTCOME MEASUREMENTS: Study I: Safety, tolerability, and functionality (wireless pH and temperature recording). Study II: Tracing of the capsule and expulsion and distribution of (99m)Tc from the drug reservoir by scintigraphy. Correlating location pH with scintigraphy. RESULTS: Study I: Ingestion and passage of the capsule was safe and well tolerated. Transmitted pH and temperature data were received by the recorder in 96.5% +/- 3%. Study II: pH determined passage of the esophagogastric, gastroduodenal, and ileocolonic junction correlated well with scintigraphy. Expulsion of (99m)Tc from the capsule was successful in 9 of 10 subjects. LIMITATIONS: Subjects with relatively low body mass index. CONCLUSIONS: This electronic drug delivery and monitoring system may be a promising tool for targeted delivery of substances to well-defined areas of the GI tract. PMID- 23684149 TI - Laparoscopic Heller's myotomy versus pneumatic dilation in the treatment of idiopathic achalasia: a meta-analysis of randomized, controlled trials. AB - BACKGROUND: Pneumatic dilation (PD) and laparoscopic Heller's myotomy (LHM) are the mainstays of therapy in idiopathic achalasia. Equipoise exists in choosing the first-line therapy. OBJECTIVE: To assess comparative efficacies and adverse event rates of these methods. DESIGN: Intention-to-treat, fixed-model, Mantel Haenszel meta-analysis of randomized, controlled trials comparing PD with LHM. SETTING: Randomized controlled trial comparing PD versus LHM. PATIENTS: Patients with newly diagnosed idiopathic achalasia. INTERVENTION: Comprehensive electronic and manual literature search from 1966 to March 2012 independently by two reviewers. MAIN OUTCOME MEASUREMENTS: Response rate, rate of different adverse events, and quality of life after each therapy. RESULTS: Three of 161 retrieved studies between 2007 and 2011, including 346 patients, were included. At 1 year, the cumulative response rate was significantly higher with LHM (86% vs 76%, odds ratio 1.98 (confidence interval 1.14-3.45); P = .02), with no significant heterogeneity (P = .39; I(2) 0%). Rates of major mucosal tears requiring subsequent intervention with LHM were significantly lower than those of esophageal perforation with PD requiring postprocedural medical or surgical therapy (0.6% and 4.8%, respectively; P = .04). Postprocedural rates of gastroesophageal reflux, lower esophageal sphincter pressures, and quality of life scores did not differ in trials with sufficient data. Data on longer follow up were not available. LIMITATIONS: Lack of data on follow-ups over 1 year and a small number of included studies. CONCLUSION: This meta-analysis suggests that LHM may provide greater response rates as compared with graded PD in the treatment of newly diagnosed idiopathic achalasia, with lesser rates of major adverse events, in up to 1 year after treatment, although additional data are needed to confirm the validity of this conclusion in long-term follow-up. PMID- 23684150 TI - Caenorhabditis elegans reveals novel Pseudomonas aeruginosa virulence mechanism. AB - The susceptibility of Caenorhabditis elegans to different virulent phenotypes of Pseudomonas aeruginosa makes the worms an excellent model for studying host pathogen interactions. Including the recently described liquid killing, five different killing assays are now available offering superb possibilities for performing high-throughput screens for novel antibiotics using a whole-body infection system. PMID- 23684152 TI - Phenol-soluble modulins, hellhounds from the staphylococcal virulence-factor pandemonium. AB - Phenol-soluble modulins are secreted peptides with multiple functions in Staphylococcus aureus pathogenesis and spreading. Recent studies by Otto and coworkers show that these hellhounds of the staphylococcal virulence-factor pandemonium are unleashed through an essential ABC transporter, which represents an exciting new target for stopping the spread of this important pathogen. PMID- 23684151 TI - Programmed cell death in bacteria and implications for antibiotic therapy. AB - It is now well appreciated that programmed cell death (PCD) plays critical roles in the life cycle of diverse bacterial species. It is an apparently paradoxical behavior as it does not benefit the cells undergoing PCD. However, growing evidence suggests that PCD can be 'altruistic': the dead cells may directly or indirectly benefit survivors through generation of public goods. This property provides a potential explanation on how PCD can evolve as an extreme form of cooperation, although many questions remain to be addressed. From another perspective, as PCD plays a critical role in bacterial pathogenesis, it has been proposed as a potential target for new antibacterial therapy. To this end, understanding the population and evolutionary dynamics resulting from PCD and public goods production may be a key to the success of designing effective antibiotic treatment. PMID- 23684153 TI - Primary pulmonary adenocarcinoma mimicking papillary thyroid carcinoma. AB - We herein reported a primary pulmonary papillary carcinoma with colloid-like luminal content in the glandular cavity and classic nuclear features such as pseudo-inclusions, intranuclear grooves in the tumor cell nuclei and ground glass nuclei which closely mimics papillary thyroid carcinoma. Meanwhile, lymph node in the left pulmonary hilum was involved and showed similar features to the primary pulmonary papillary carcinoma. This specific histopathological presentation caused a diagnostic dilemma.The patient didn't show previous concomitant or subsequent evidence of a thyroid tumor. Immunohistochemistry further confirmed pulmonary origin and excluded a metastasis from the thyroid, as it was thyroglobulin negative, thyroid transcription factor 1 and surfactant apoprotein A positive, which was consistent with the imageology and history.Based on the above features, the diagnosis of primary pulmonary papillary carcinoma was confirmed. Understanding the existence of papillary thyroid carcinoma-like pulmonary papillary carcinoma will avoid misdiagnosis or unnecessary clinical and radiologic investigations in future. PMID- 23684154 TI - Is there a gender gap in Italian radiology? A cross-sectional study. AB - BACKGROUND: Although the number of women entering the medical profession has increased, this has not led to an even distribution in all branches of medicine. In countries where the health service is mainly private, there are still fewer female radiologists, especially at managerial level. The aim of this paper is to make a comparison of work-related stress, satisfaction and perceived organizational justice in male and female radiologists in Italy. METHODS: Italian radiologists were asked to answer an anonymous questionnaire during two successive national radiology Congresses. RESULTS: Women reported a psychophysical workload that was the same as that of their male colleagues, but claimed that they had less control over their work, made a greater effort to fulfill job requirements, were more over-committed in their work and received fewer rewards for the work performed than their male colleagues. On account of the lack of procedural, distributive and informative justice, women radiologists perceived the work environment as significantly less fair compared to their male colleagues. Moreover, they derived less satisfaction from their job. They suffered from anxiety, depression and minor psychiatric disorders to a greater extent than their male counterparts. CONCLUSION: Despite the significant number of women radiologists in Italy, the gender gap still exists and can be witnessed in horizontal and vertical segregation. Policies should be introduced to contrast gender bias. PMID- 23684155 TI - Assessment of thickness and function of masticatory and cervical muscles in adults with and without temporomandibular disorders. AB - OBJECTIVE: The aim of this study was to evaluate the maximal bite force (MBF), electromyographic (EMG) activity and thickness of the masseter, anterior part of the temporalis and sternocleidomastoid (SCM) muscles in a group of young adults with and without temporomandibular disorders (TMDs). DESIGN: Nineteen individuals comprised the TMD group (6 males/13 females, aged 25.4+/-3.8 years), classified based on the Research Diagnostic Criteria for TMD (RDC/TMD), and 19 comprised the control group (6 males/13 females, aged 24.1+/-3.6 years). The MBF was determined with a transducer placed between the dental arches at the first molars level (N). The muscles were evaluated bilaterally at rest and during maximal voluntary clenching (MVC) by assessing EMG activity and performing ultrasonography (USG). The mean values of these measures for both sides of the mouth were used. The normality of the distributions was assessed by the Shapiro-Wilks test. Variables between groups and genders were compared using two-way factorial ANOVA test and correlated using the Spearman coefficient (alpha=0.05). Unpaired t test was used to compare variables between TMD subgroups. Logistic regression analysis was used to identify the variables associated with the presence of TMD. RESULTS: MBF, EMG and USG data were similar among clinical groups and among TMD subgroups. The thickness of masseter and SCM muscles in the relaxed and clenching states were significantly higher in males than females. On the other hand, the EMG of the temporalis muscle in the rest state was significantly higher in females than males. Additionally, the MBF was positively correlated with the USG characteristics of masseter and SCM muscles, as well as with the EMG activity of masseter and temporalis muscles in the TMD group. In this group, there was also a positive correlation between the thickness of the masseter muscle and its activity. On the other hand, the thickness of the SCM muscle was negatively correlated with its activity. A lower MBF was independently associated with the presence of TMD. CONCLUSIONS: Subjects with TMD exhibited similar values of MBF, thickness and electrical activity of masticatory and cervical muscles when compared with controls; positive correlations observed between these variables may suggest a muscular alteration in TMD patients and a co-activation of masticatory and cervical muscles during mandibular movement. This fact may also be confirmed by the negative association between bite forces and presence of TMD. PMID- 23684156 TI - The no-touch saphenous vein as the preferred second conduit for coronary artery bypass grafting. AB - BACKGROUND: Injury incurred while saphenous veins are being obtained results in poor graft patency and impairs the results of coronary artery bypass grafting. A novel method of obtaining veins, the no-touch technique, has shown improved long term saphenous vein graft patency. METHODS: This randomized trial included 108 patients undergoing coronary artery bypass grafting and compared the patency of no-touch saphenous vein with that of radial artery grafts. Each patient was assigned to receive one no-touch saphenous vein and one radial artery graft to either the left or the right coronary territory to complement the left internal thoracic artery. RESULTS: Angiography was performed in 99 patients (92%) at a mean of 36 months postoperatively. Graft and grafted coronary artery patency was evaluated. The patency of grafts for no-touch saphenous vein and radial artery was 94% versus 82% (p = 0.01), respectively. The patency of coronary arteries grafted with no-touch saphenous vein and radial artery grafts was 95% versus 84% (p = 0.005), respectively. Eighty-nine of 96 (93%) left internal thoracic artery grafts were patent. CONCLUSIONS: No-touch saphenous vein grafts showed a significantly higher patency rate than the radial artery grafts and the patency was comparable to the patency for left internal thoracic artery grafts. This highlights the improvement in saphenous vein graft quality with the no-touch technique and increases the number of situations in which saphenous veins may be preferable to radial artery grafts as conduits in coronary artery bypass grafting. PMID- 23684157 TI - Patient-prosthesis mismatch and reduction in left ventricular mass after aortic valve replacement. AB - BACKGROUND: The presence of patient-prosthesis mismatch (PPM) after aortic valve replacement may influence patient survival. We examined the relationship between PPM and changes in left ventricular mass index at 3 months follow-up and also overall survival. METHODS: From patients included in the Mosaic trial, we studied data from 266 patients who underwent aortic valve replacement with the Medtronic Mosaic porcine bioprosthesis and had an echocardiography performed 3 months postoperatively. Complete echocardiographic data, to calculate left ventricular mass index, was available in 78% of the patients. The primary outcome for this substudy was prevalence and severity of PPM. Secondary outcomes were reduction in left ventricular mass index at 3 months follow-up and medium-term survival. Patients without PPM were defined as having an indexed effective orifice area greater than 0.85 cm(2)/m(2), and those with moderate and severe PPM as having an indexed effective orifice area between 0.65 cm(2)/m(2) and 0.85 cm(2)/m(2) or below 0.65 cm(2)/m(2), respectively. RESULTS: PPM was found in 217 (82%) patients. No difference in overall survival was found between patients with PPM and those without PPM. The change in left ventricular mass index was significantly different between groups (no PPM -31.4 +/- 28.0 g/m(2), moderate PPM 1.1 +/- 34.4 g/m(2), and severe PPM -5.9 +/- 29.7 g/m(2), respectively (p = 0.01). CONCLUSIONS: The presence of PPM did not influence medium-term survival. However, patients without PPM showed a marked reduction in left ventricular mass index as soon as 3 months postoperatively. PMID- 23684158 TI - Impact of induction therapy on airway complications after sleeve lobectomy for lung cancer. AB - BACKGROUND: Sleeve lobectomy is a valid alternative to pneumonectomy for the treatment of centrally located operable non-small cell lung cancer (NSCLC), but concern has been evoked regarding a potentially increased risk of bronchial anastomosis complications after induction therapy. This study examined the impact of induction therapy on airway healing after sleeve lobectomy for NSCLC. METHODS: Bronchial anastomosis complications were recorded with respect to the induction regimen applied (neoadjuvant chemotherapy vs chemoradiotherapy) in a consecutive series of patients with sleeve lobectomy for NSCLC. RESULTS: Ninety-nine patients underwent sleeve resection, 28 of them after induction therapy. Twelve patients received chemotherapy alone, and 16 patients had radiochemotherapy. There were no significant differences in postoperative 90-day mortality (3.6% vs 2.8%) and morbidity (54% vs 49%) for patients with and without induction therapy. Bronchial anastomosis complications occurred in 3 patients (10.8%) with neoadjuvant therapy and in 2 (2.8%) without (p = 0.3). In the induction therapy group, two bronchial stenoses occurred after radiochemotherapy and one bronchopleural fistula after chemotherapy alone. In patients without induction therapy, one bronchial stenosis and one bronchopleural fistula were observed. All bronchial stenoses were successfully treated by dilatation, and both bronchopleural fistulas occurring after right lower lobectomy were successfully treated by reoperation and completion sleeve bilobectomy with preservation of the upper lobe. CONCLUSIONS: Sleeve lobectomy for NSCLC can be safely performed after induction chemotherapy and radiochemotherapy with mortality and incidence of airway complications similar to that observed in nonpretreated patients. The treatment of airway complications does not differ for patients with and without induction therapy. PMID- 23684159 TI - A national study of nodal upstaging after thoracoscopic versus open lobectomy for clinical stage I lung cancer. AB - BACKGROUND: Nodal upstaging after surgical intervention for non-small cell lung cancer (NSCLC) occurs when unsuspected lymph node metastases are found during the final evaluation of surgical specimens. Recent data from The Society of Thoracic Surgery (STS) database demonstrated significantly lower nodal upstaging after thoracoscopic (VATS) lobectomy than after thoracotomy. STS data, however, may be biased from voluntary reporting, and survival was not investigated. We used a complete national registry to compare nodal upstaging and survival after lobectomy by VATS or thoracotomy. METHODS: The Danish Lung Cancer Registry was used to identify patients who underwent lobectomy for clinical stage I NSCLC from 2007 to 2011. Patient demographics, comorbidity, preoperative staging, surgical approach, number of lymph nodes harvested, final pathology, and survival were evaluated. Nodal upstaging was identified by comparing cT N M with pT N M. RESULTS: Lobectomy for clinical stage I NSCLC was performed in 1,513 patients: 717 (47%) by VATS and 796 (53%) by thoracotomy. Nodal upstaging occurred in 281 patients (18.6%) and was significantly higher after thoracotomy for N1 upstaging (13.1% vs 8.1%; p<0.001) and N2 upstaging (11.5% vs 3.8%; p<0.001). Overall unadjusted survival was significantly higher after VATS, but after adjusting for differences in sex, age, comorbidity, and pT N M by Cox regression analysis, we found no difference between VATS and thoracotomy (hazard ratio, 0.98; 95% confidence interval, 0.80 to 1.22, p=0.88). CONCLUSIONS: National data confirm that nodal upstaging was lower after VATS than after open lobectomy for clinical stage I NSCLC. Multivariate survival analysis, however, showed no difference in survival, indicating that differences in nodal upstaging result from patient selection for reasons not captured in our registry. PMID- 23684160 TI - Number of entry tears is associated with aortic growth in type B dissections. AB - BACKGROUND: Aortic growth rate in acute type B aortic dissection (ABAD) is a significant predictor for aortic complications and death. To improve the overall outcome, radiologic predictors might stratify patients who benefit from successful medical management vs those who require intervention. This study investigated whether the number of identifiable entry tears in ABAD patients is associated with aortic growth. METHODS: ABAD patients with uncomplicated clinical conditions and therefore treated with medical therapy were evaluated. Those with a computed tomography angiography (CTA) obtained at clinical presentation and a subsequent CTA obtained at least 90 days after medical treatment were included (2005 to 2010). The CTAs were investigated for the number of entry tears between the true and false lumen. Diameters of the dissected aortas were measured at five levels on the baseline and on the last available follow-up CTA, and annual aortic growth rates were calculated. The number of entry tears in these patients and the location in the aorta were compared with the aortic growth rate. RESULTS: Included were 60 patients who presented with 243 dissected segments. Mean growth rates during follow-up (median, 23.2; range, 3 to 132 months) were significantly higher in patients with 1 entry tear (5.6 +/- 8.9 mm) than in those with 2 (2.1 +/- 1.7 mm; p = 0.001) and 3 entry tears (mean 2.2 +/- 4.1; p = 0.010). The distance of the primary entry tear from the left subclavian artery did not have an effect on the aortic growth rate (median, 38; interquartile range, 24 to 137 mm; p = 0.434). CONCLUSIONS: The number of entry tears in ABAD patients detected on the first CTA after clinical presentation is a significant predictor for aortic growth. Patients with 1 entry tear at presentation show a higher growth rate than other patients and might benefit from more strict surveillance or early prophylactic intervention. PMID- 23684161 TI - Extraanatomic bypass technique for the treatment of midaortic syndrome in children. AB - BACKGROUND: This report aims to introduce the extraanatomic bypass technique to treat the midaortic syndrome and to document its long-term effectiveness and durability. METHODS: Fourteen patients (mean age, 6.7 +/- 3.76 years; range 8 months to 11 years) received diagnoses of midaortic syndrome, characterized by severe narrowing of the abdominal aorta with involvement of the renal and visceral branches. Angiography showed variable lengths of high-grade midaortic stenosis, with 7 children having visceral artery involvement and 9 having renal artery involvement. All children were hypertensive (mean blood pressure, 165 +/- 15.7 mm Hg). Three had had previous nephrectomies. Six patients had had previous percutaneous transluminal renal artery angioplasties. The midaortic obstruction was relieved by descending abdominal aorta bypass (left thoracoabdominal approach) and by an ascending abdominal aorta bypass (median sternotomy and transabdominal approach) in 12 patients. No visceral artery revascularization was done. RESULTS: There was a considerable blood pressure reduction in all patients and relief of intermittent claudication in 6 affected patients. One patient had a bilateral renal artery bypass 2 weeks postoperatively because of recurrence of renal hypertension. At a mean follow-up time of 5.8 +/- 1.36 years (range, 9 months to 15 years), there was no further reoperation nor mortality. Twelve patients had complete relief of hypertension, and 2 had mild hypertension. All patients have normal renal function and no signs or symptoms of visceral malperfusion. Growth and development have proceeded normally. Follow-up magnetic resonance tomography showed patent grafts without any strictures. CONCLUSIONS: Extraanatomic bypass provides very effective and long-term relief of hypertension and any malperfusion in midaortic syndrome. PMID- 23684162 TI - Differences in associations between cannabis and stimulant disorders in first admission psychosis. AB - BACKGROUND: Substance use in early psychosis is associated with male gender and earlier onset. Evidence about other correlates of substance use is less consistent. Stimulants (e.g. methamphetamine, cocaine) may precipitate psychosis. However the associations of stimulant disorders in early psychosis are difficult to examine because of lower prevalence and overlap with cannabis disorders. METHODS: Hospital records were used to identify 9919 persons aged 15-29 with a first hospital admission with psychosis in New South Wales (NSW), Australia. Correlates of illicit drug disorders, cannabis disorders and stimulant disorders were examined using univariate and multivariate logistic regression. RESULTS: Half of first psychosis admissions had comorbid substance diagnoses. Cannabis and stimulant disorders were increased more than ten-fold compared to the age-matched Australian population. Stimulant disorders were equally common in women and men and associated with urban location, social advantage and older age at first admission. Cannabis disorders were associated with male gender, younger age and non-metropolitan location. Diagnoses of drug-induced psychoses were more strongly associated with stimulants than with cannabis. Compared to people with cannabis diagnoses alone, those with both cannabis and stimulant disorders were older, more likely to have a diagnosis of drug-induced psychosis and more likely to have comorbid alcohol disorders. CONCLUSIONS: Cannabis is the most commonly used substance in psychosis, and the associations of illicit drug use in psychoses are largely those of cannabis disorders. There are significant differences between the personal, socio-economic and diagnostic correlates of cannabis and stimulant disorders in young people with first admission psychosis. PMID- 23684163 TI - Analysis of CpG SNPs in 34 genes: association test with suicide attempt in schizophrenia. AB - BACKGROUND: Suicide is the act of intentionally causing one's own death. The lifetime suicide risk in schizophrenia is 4.9% and 20% to 50% of patients with SCZ will attempt suicide during their life. The other risk factors for suicidal behavior in schizophrenia include prior history of suicide attempts, active psychosis, depression and substance abuse. To date, there are no robust genetic or epigenetic predictors of suicide or suicide attempt in this specific population. METHODS: We collected detailed clinical information and DNA samples from 241 schizophrenia patients and performed the genetic analyses in suicide attempters and non-attempters, among these patients. Using the structured research interview, we determined the presence of suicide attempt lifetime and then we tested 384 DNA variants in candidate genes supposed to be involved in the neurobiology of schizophrenia. We applied a novel mapping analysis using a specific bioinformatic tool that analyzed only the polymorphic CpG sites in our SNP panel. This analysis looked at the presence or absence of methylation sites affected by the SNP allele. The SNPs in the candidate genes were studied under a different perspective considering their direct contribution to the availability of methylation sites within the gene of interest. The level of potential methylation was compared using a linear model in attempters and non-attempters. RESULTS: Among the 384 SNPs selected from the Illumina Bead Chip only the rs2661319 in the RGS4 gene was significantly associated with suicide attempt (p = 0.002). There were 119 CpG SNPs in the aforementioned panel. The gene-wise potential methylation level of RGS4 was 55% in the attempters and 65% in the non attempters with a p-value of 0.005. The total level of potential metylation in the overall panel (119 SNPs combined) was not associated with suicide attempt. However, when considering the potential methylation at chromosome 1, we found that suicide attempt (p = 0.036) was associated with lower methylation. DISCUSSION: The overall results showed no strong association between CpG SNPs and suicide attempt but the information regarding the CpG SNP potential methylation could be used as covariate in future methylation analysis. PMID- 23684164 TI - Production of small nano-sized particles by complex formation between polycations and linearized plasmid DNA at a low pH. AB - We report on the technical advance of linearized pDNA (pDNA(linear)) above the circular one (pDNA(circ)) for preparation of small-sized DNA/polycation complexes (DPC) at a low pH. Also, the resistance of the DPC formed with pDNA(linear) against poly-L-asparagine indicates that effective ion-pairing occurred between the pDNA(linear) and polycations. PMID- 23684165 TI - Partition separation and characterization of the polyhydroxyalkanoates synthase produced from recombinant Escherichia coli using an aqueous two-phase system. AB - Polyhydroxyalkanoates (PHAs) are renewable and biodegradable polyesters which can be synthesized either by numerous of microorganisms in vivo or synthase in vitro. The synthesis of PHAs in vitro requires an efficient separation for high yield of purified enzyme. The recombinant Escherichia coli harboring phaC gene derived from Ralstonia eutropha H16 was cultivated in the chemically defined medium for overexpression of synthase in the present work. The purification and characteristics of PHA synthase from clarified feedstock by using aqueous two phase systems (ATPS) was investigated. The optimized concentration of ATPS for partitioning PHA synthase contained polyethylene glycol 6000 (30%, w/w) and potassium phosphate (8%, w/w) with 3.25 volume ratio in the absence of NaCl at pH 8.7 and 4 degrees C. The results showed that the partition coefficient of enzyme activity and protein content are 6.07 and 0.22, respectively. The specific activity, selectivity, purification fold and recovery of phaC(Re) achieved 1.76 U mg-1, 29.05, 16.23 and 95.32%, respectively. Several metal ions demonstrated a significant effect on activity of purified enzyme. The purified enzyme displayed maximum relative activity as operating condition at pH value of 7.5 and 37 degrees C. As compared to conventional purification processes, ATPS can be a promising technique applied for rapid recovery of PHA synthase and preparation of large quantity of PHA synthase on synthesis of P(3HB) in vitro. PMID- 23684166 TI - Tolosa-Hunt syndrome masquerading as Gradenigo syndrome in a teenager. AB - Tolosa-Hunt syndrome is an idiopathic chronic granulomatous inflammatory process commonly involving the cavernous sinus and the orbit. Symptoms include unilateral eye pain, ophthalmoplegia, headache, and facial pain in the distribution of the upper divisions of the trigeminal nerve and are highly responsive to steroid therapy. Gradenigo syndrome describes extension of a middle ear infection to the petrous apex, with trigeminal pain and ophthalmoplegia, typically responsive to antibiotics and often surgical drainage. We report a case of a 17 year-old girl with apparent Gradenigo syndrome, presenting with unilateral eye pain, abducens palsy, headache, hearing loss and serous otitis media, who was ultimately diagnosed with Tolosa-Hunt syndrome. PMID- 23684167 TI - Prognostic role of human epidermal growth factor receptor 2 status in premenopausal early breast cancer treated with adjuvant tamoxifen. AB - BACKGROUND: Hormone therapy is the most prescribed systemic therapy for patients with breast cancer (BC). Some patients fail to respond to tamoxifen; one pathway seems to involve human epidermal growth factor receptor 2 (HER2) overexpression. To better understand this matter, we reviewed our single-center experience of premenopausal patients who were chemotherapy naive and treated with 5 years of tamoxifen for early-stage BC by focusing on estrogen receptor (ER), progesterone receptor, HER2 status, and Ki-67 proliferative index. PATIENTS AND METHODS: We reviewed 425 patients treated with tamoxifen for early-stage BC. Previous solid tumors, age less than 18 years, BC recurrences or contralateral tumor, tamoxifen discontinuation, adjuvant chemotherapy, and a follow-up shorter than 6 months were considered exclusions criteria of the study. RESULTS: At a mean follow-up of 8.1 years, the mean (SD) time to local relapse was 6.7 +/- 3.6 years; range, 2.0 10.7 years), whereas the mean (SD) time to distant metastases was 4.7 +/- 2.3 years; range, 2.2-8.8 years). HER2 status did not influence local relapse-free survival (log-rank test, 0.40), distant metastases-free survival (log-rank test, 0.72), and overall survival rate (log-rank test, 0.87). CONCLUSIONS: Resistance to tamoxifen is a complex trait, and its pathway is still unclear; in patients with BC, a multidisciplinary approach is highly recommended. In our experience, we did not find a statistically significant difference in tamoxifen treatment efficacy according to HER2 status. PMID- 23684168 TI - Comparison of two radiotherapeutic hypofractionated schedules in the application of tumor bed boost. AB - AIM: Evaluation of related radiation toxicity and efficacy in terms of local control of 2 radiotherapeutic hypofractionated schedules in the application of tumor bed boost by using 2 different planning techniques. METHOD: Eighty-one patients with stage I-II disease were retrospectively selected with either concomitant (group A) or sequential (group B) boost for the tumor bed. In group A, 27 patients were treated with a total dose of 46 Gy to the whole breast and 54 Gy to the tumor bed in 20 concomitant fractions. In group B, 54 patients were treated with a total dose of 42.4 Gy in 16 fractions to the whole breast and 53 Gy to the tumor bed by 4 sequential fractions. The boost was administered with multiple photon-beam fields. The median follow-up time was 24 months. RESULTS: The statistical analysis for the 2 groups of the study showed that skin toxicity was significantly worse in group A (P < .05, Kruskal-Wallis H test). For groups A and B at the completion of radiation therapy, grade 1 skin toxicity was observed in 18/27 patients (66.6%) and 13/54 patients (24.1%), respectively, whereas grade 2/3 was observed in 9/27 patients (33.3%) vs. 5/54 patients (9.3%), respectively (P < .001). One year after irradiation, in group A and in group B, the skin toxicity was of grade 1 in 6/27 patients (22.2%) vs. 2/54 patients (3.7%), respectively (P = .008). Within 2 years, the breast returned to its original form in all patients. No patient showed local disease recurrence. CONCLUSIONS: The accelerated hypofractionated schedules in the application of the tumor bed boost by using the 2 different planning techniques appears to be effective and well tolerated. PMID- 23684169 TI - [Immigrant children have more risk for childhood obesity and metabolic syndrome]. PMID- 23684171 TI - [Mosaic trisomy 13]. PMID- 23684172 TI - [Accidental poisoning by intranasal fentanyl]. PMID- 23684173 TI - [Acute respiratory insufficiency as debut of idiopathic pulmonary hemosiderosis in an infant]. PMID- 23684170 TI - [Outcome at two years corrected age of a cohort of very low birth weight infants from hospitals within the neonatal SEN1500 network]. AB - OBJECTIVE: To describe growth and neurodevelopmental status of 4,944 children who completed a follow-up at two years of corrected age out of the 10,456 newborns with weight <=1500g born between the years 2002-2007 and discharged from hospitals within the network SEN1500. A total of 522 newborns were excluded as they had some type of malformation. The total number of children assessed represents the 49.76% of children discharged alive and without malformations. METHODS: A retrospective review was conducted using prospectively collected data in the SEN1500 database. We compared growth data at two years of corrected age according to birth weight and sex. Motor impairment, incidence of cerebral palsy, visual and hearing disabilities, and abnormal neurodevelopment for gestational age were analysed between groups. We studied the associations between cerebral palsy (CP) and perinatal factors. RESULTS: At 2 years of age 44.2% of children had a weight <2 SD for corrected age. Children with birth weight <=1000g showed worse outcomes in growth. Some type of motor impairment was observed in 6.96% of the infants, and 4.56% of them were diagnosed with CP. The incidence was higher among males with birth weight <=1000g. There was an incidence of 5.21% of visual disability, with 0.5% of children being blind in one or both eyes. Cerebral palsy was associated with retinopathy of prematurity, severe intraventricular haemorrhage, and periventricular leukomalacia, in particular cystic periventricular leukomalacia. PMID- 23684174 TI - Laryngeal cysts in infants and children--a pathologist's perspective (with review of literature). AB - OBJECTIVES: To expose the rarity of the phenomena of congenital laryngeal cysts. Additionally, a discussion is presented in support of the basic similarities between laryngeal duplication cyst and bronchogenic cyst and a proposal to use the term 'bronchogenic cyst' (appended by the location) is put forth. MATERIALS AND METHODS: Three cases of cysts of the larynx, two in the neonate and one, in a child were discovered in the pediatric age group from the archives of the Department of Pathology, Kasturba Medical College, Mangalore. OBSERVATIONS: Laryngeal duplication cyst/bronchogenic cyst in a 6-day-old male infant was lined by predominantly respiratory with focal squamous epithelium. The wall contained fibromuscular bundles within a myxoid stroma studded with seromucinous glands. The fibromuscular bundles were positive for smooth muscle actin (SMA) and negative with desmin. A 3-year-old male child diagnosed of laryngocele had the cyst lined by respiratory epithelium and the wall densely infiltrated with lymphoid cells. A 20-day-old male neonate with laryngomalacia had a small arytenoid cyst lined by squamous epithelium. CONCLUSION: On morphological grounds, a laryngeal duplication cyst may be called a bronchogenic cyst and published reports do not deny that both these entities are cognate. Hence, pathologists should enjoy the freedom to write 'bronchogenic cyst' as the final impression if the histological features should so indicate. Otolaryngologtists however might term the congenital cyst as Type 1, 2a or 2b (according to Forte's classification) taking into account the laryngoscopic, radiologic, intraoperative and pathological findings. PMID- 23684175 TI - Non-syndromic hearing impairment in a multi-ethnic population of Northeastern Brazil. AB - OBJECTIVE: There are many hearing impaired individuals in Monte Santo, a rural municipality in the state of Bahia, Brazil, including multiple familial cases strongly suggestive of a genetic aetiology. METHODS: The present study investigated 81 subjects with hearing impairment (HI) recruited from 36 families. Mutations often associated with HI, i.e. the DFNB1 mutations c.35delG in GJB2, deletions del(GJB6-D13S1830) and del(GJB6-D13S1854), and A1555G in the mitochondrial gene MTRNR1 were initially analyzed, with additional mutations in GJB2 identified by sequencing the coding region of the gene. RESULTS: Seven different mutations were present in GJB2 with mutations c.35delG and p.Arg75Gln, which are known to be pathogenic, identified in 37.0% of the subjects. Individuals homozygous for the c.35delG mutation were diagnosed in eight families, corresponding to 24.7% of unrelated individuals with nonsyndromic hearing impairment (NSHI), and an additional heterozygote for this mutation was present in a single family. Ten individuals (12.4%) in another family were heterozygous for the mutation p.Arg75Gln. CONCLUSIONS: Significant heterogeneity was observed in the alleles and patterns of NSHI inheritance among the subjects studied, probably due to the extensive inter-ethnic admixture that characterizes the peoples of Brazil, together with a high prevalence of community endogamy and consanguineous marriage. PMID- 23684176 TI - Success of supraglottoplasty for severe laryngomalacia: the experience from Northeastern Ontario, Canada. AB - OBJECTIVES: To review the outcomes of supraglottoplasty performed in children with severe laryngomalacia at a pediatric university teaching hospital and to determine if these outcomes are influenced by gender, age at time of supraglottoplasty, or medical comorbidities. METHODS: Retrospective chart review of children who underwent supraglottoplasty for severe laryngomalacia between 2001 and 2010 at the Children's Hospital of Eastern Ontario in Ottawa, Canada. Statistical significance was obtained using 2-tailed Fisher's exact test. The outcome measures were resolution of laryngomalacia symptoms or persistence of laryngomalacia symptoms with or without additional surgery. RESULTS: Among 26 post-primary supraglottoplasty patients, 46.2% had resolution and 53.8% had persistence, including 19.2% with partial improvement and 34.6% requiring revision supraglottoplasty and/or tracheostomy. Resolution was present in 35.7% of males and 58.3% of females (p = 0.43); in 33.3% of all patients <=2 months old and 52.9% of all patients >2 months old (p = 0.43); and in 50.0% of non-comorbid patients <=2 months old and 80.0% of non-comorbid patients >2 months old (p = 0.52). 71.4% of persistence cases were found in comorbid patients. 83.3% of comorbid patients had persistence, compared to 28.6% of non-comorbid patients (p=0.008). Of the 3 patients with overlapping comorbid categories, 2 required at least 2 revision supraglottoplasties and ultimately required a tracheostomy. CONCLUSIONS: Persistence of laryngomalacia symptoms post-primary supraglottoplasty was not associated with gender or age at time of surgery, and was more commonly found in children with comorbidities. Patients with coexisting medical conditions appear to require more aggressive surgical management, beyond one revision supraglottoplasty. PMID- 23684177 TI - Pediatric follicular dendritic cell sarcoma of the head and neck: a case report and review of the literature. AB - OBJECTIVE: Follicular dendritic cell sarcoma is a rare disease with a non specific and insidious presentation that is further complicated by difficult diagnostic and therapeutic assessment. METHODS: The database PubMed was searched for reports of follicular dendritic cell sarcoma between 1986 (first case published) and 2012. All of the articles presenting informations regarding one or more cases of follicular dendritic cell sarcoma of the head and neck region, in patients less than 18 years of age, were included. The reference lists for pertinent reports were also scanned to ensure that all relevant literature was included. RESULTS: We present a case of a 14 year-old girl, with a 2-month history of a right-sided level II neck mass. After a carefull radiologic evaluation the mass was resected combined with a right selective neck dissection. Histology with immunohistochemical staining was positive for follicular dendritic cell sarcoma. No recurrence was seen after 31 months follow-up. The literature search identified six more cases of pediatric follicular dendritic cell sarcoma of the head and neck. This is the first female patient with follicular dendritic cell sarcoma in the pediatric population. CONCLUSIONS: Current treatment of head and neck follicular dendritic cell sarcoma consists of wide radical resection, with associated radiotherapy or chemotherapy only for cases with aggressive disease such as extracapsular invasion, tumor size >=6 cm or after failure of the first-line surgical treatment. PMID- 23684178 TI - Incisionless otoplasty: a retrospective review and outcomes analysis. AB - OBJECTIVE: To report outcomes following incisionless otoplasty, a minimally invasive surgical technique that can be used to treat protruding ears. METHODS: Two independent review authors retrospectively reviewed the electronic charts of consecutive patients (n=19) who underwent incisionless otoplasty by a single surgeon between October 2007 and June 2011 at McMaster Children's Hospital. Main outcome measures were pre- and post-operative protrusion measurements, and complication rates. Research Ethics Board approval was granted through Hamilton Health Sciences and McMaster University. Descriptive statistics were reported. RESULTS: Nineteen children (mean age 8.8 +/- 3.7 years) underwent incisionless otoplasty with an average follow-up of 43.9 +/- 9.3 weeks (95% CI, 24.4-64.4 weeks). Pre- and post-operative measurements, respectively, for both ears combined were 24.2 mm and 15.0 mm at the level of the most superior helical point, 26.3 mm and 15.7 mm at the superior conchal attachment, 25.5 mm and 16.6 mm at the inferior conchal attachment, and 15.0 mm and 14.1 mm at the lobule. Two patients exhibited asymmetry necessitating revision surgery. Three patients extruded sutures, two of which experienced localized suture abscesses. No patients developed post-operative haematomas or perichondritis. CONCLUSIONS: Among our cohort of patients, otoplasty using an incisionless technique seems to be successful in improving ear protrusion among children and is associated with few complications. PMID- 23684179 TI - The road ahead: practice integration in gastroenterology. PMID- 23684180 TI - microRNAs as novel antidepressant targets: converging effects of ketamine and electroconvulsive shock therapy in the rat hippocampus. AB - Early-life stress is a main contributory factor to the onset of depression. Treatments remain inadequate and as such, a large unmet medical need for novel therapeutics remains. Impeding advancement is the poor understanding of the molecular pathology. microRNAs (miRNAs) are novel regulators of gene expression. A paucity of information regarding their role in depressive pathology and antidepressant action remains. This study investigated changes to hippocampal miRNA levels induced via early-life stress in Sprague-Dawley rats and whether antidepressant treatments could reverse these changes. Investigated were the selective serotonin reuptake inhibitor fluoxetine, the rapid acting N-methyl-d aspartate receptor antagonist ketamine and electroconvulsive shock therapy (ECT). Microarray analysis revealed early-life stress affected the expression of multiple hippocampal miRNAs. Antidepressant treatments reversed some of these effects including a stress-induced change to miR-451. Ketamine and ECT possessed the highest number of common targets suggesting convergence on common pathways. Interestingly all three treatments possessed miR-598-5p as a common target. This demonstrates that changes to hippocampal miRNA expression may represent an important component of stress-induced pathology and antidepressant action may reverse these. PMID- 23684181 TI - Young people, sex and relationships: miles to go and promises to keep. PMID- 23684182 TI - Termination of pregnancy as emergency obstetric care: the interpretation of Catholic health policy and the consequences for pregnant women: an analysis of the death of Savita Halappanavar in Ireland and similar cases. AB - Issues arising from the death of Savita Halappanavar in Ireland in October 2012 include the question of whether it is unethical to refuse to terminate a non viable pregnancy when the woman's life may be at risk. In Catholic maternity services, this decision intersects with health professionals' interpretation of Catholic health policy on treatment of miscarriage as well as the law on abortion. This paper explores how these issues came together around Savita's death and the consequences for pregnant women and maternity services worldwide. It discusses cases not only in Ireland but also the Americas. Many of the events presented are recent, and most of the sources are media and individual reports. However, there is a very worrying common thread across countries and continents. If further research unearths more cases like Savita's, any Catholic health professionals and/or hospitals refusing to terminate a pregnancy as emergency obstetric care should be stripped of their right to provide maternity services. In some countries these are the main or only existing maternity services. Even so, governments should refuse to fund these services, and either replace them with non-religious services or require that non-religious staff are available at all times specifically to take charge of such cases to prevent unnecessary deaths. At issue is whether a woman's life comes first or not at all. PMID- 23684183 TI - Meeting the commitments of the ICPD Programme of Action to young people. AB - Some of the commitments nations have made in international agreements, notably in the ICPD Programme of Action (1994) and the resolution of the UN Committee on Population & Development (2012), to young people include: realisation of the right to education and attainment of a secondary school education; delaying marriage beyond childhood and ensuring free and full choice in marriage-related decisions; exercise of the right to health, including access to friendly health services and counselling; access to health-promoting information, including on sexual and reproductive matters; acquisition of protective assets and agency, particularly among girls and young women, and promotion of gender equitable roles and attitudes; protection from gender-based violence; and socialisation in a supportive environment. These are crucial for a successful transition to adulthood with reference to sexual and reproductive health outcomes. This paper assesses the extent to which these commitments have been realised, drawing from available studies conducted in the 2000s in developing countries. It concludes that while some progress has been made in most of these aspects, developing countries have a long way to go before they can be said to be helping their young people achieve a successful sexual and reproductive health-related transition to adulthood. PMID- 23684184 TI - Using popular culture for social change: Soul City videos and a mobile clip for adolescents in South Africa. PMID- 23684185 TI - "It would be weird to have that on Facebook": young people's use of social media and the risk of sharing sexual health information. AB - In today's media environment, information is not simply passed from producers to consumers, but is mediated by participants of new media cultures, including information on sexual health. In focus groups held in Sydney and regional Australia in 2011, we asked young people aged 16-22 about the potential for sexual health promotion via Facebook and other social media. Our findings point to the complex ways in which young people use social media, and the unlikelihood of traditional take-home sexual health messages having traction in social media spaces. Five key aspects which emerged were: the participatory culture of social network sites; the stigma of sexual health, especially sexually transmitted infections (STIs); young people's careful presentations of self; privacy concerns; and the importance of humour in sexual health messaging. Fears of bullying and gossip (or 'drama') were also likely to prevent the dissemination of sexual health messages in this environment. However, humorous online videos were noted by participants as a significant way to avoid stigma and enable the sharing of sexual health information. The young people in our study were interested in sexual health information, but did not want to access it at the cost of their own sense of comfort and belonging in their social networks. Any sexual health promotion within these sites must be understood as a site-specific intervention. PMID- 23684186 TI - When target groups talk back: at the intersection of visual ethnography and adolescent sexual health. PMID- 23684187 TI - Advocating for safe abortion in Rwanda: how young people and the personal stories of young women in prison brought about change. AB - In June 2012, a new abortion law came into effect in Rwanda as part of a larger review of Rwanda's penal code. This was a significant step in a country where it was previously taboo even to discuss abortion. This article describes some of the crucial elements in how this success was achieved in Rwanda, which began through a project launched by Rutgers WPF on "sensitive issues in young people's sexuality" in several countries. This paper describes how the Rwandan Youth Action Movement decided to work on unsafe abortion as part of this project. They gathered data on the extent of unsafe abortion and testimonies of young Rwandan women in prison for abortions; organized debates, values clarification exercises, interviews and a survey in four universities; launched a petition for law reform; produced awareness-raising materials; worked with the media; and met with representatives from government ministries, the national women's and youth councils, and parliamentarians - all of which played a significant role in the advocacy process for amendment of the law, which was revised when the penal code came up for review in June 2012. This history shows how important the role of young people can be in producing change and exposes, through personal stories, the need for a better abortion law, not only in Rwanda but also elsewhere. PMID- 23684188 TI - CrowdOutAIDS: crowdsourcing youth perspectives for action. AB - To develop a strategy for how to better engage young people in decision-making processes on AIDS, UNAIDS launched the participatory online policy project CrowdOutAIDS in 2011. A total of 3,497 young people aged 15-29 from 79 countries signed up to nine online forums, and volunteers recruited through the online platform hosted 39 community-based offline forums with an additional 1,605 participants. This article describes the participatory approach of using social media and crowdsourcing solutions to integrate youth perspectives into strategy and policy processes. In these forums, youth consistently identified the need to change the way sex and relationships are dealt with through changing how sex is talked about, putting comprehensive sexuality education in place, and overcoming social and cultural taboos. The outcome document recommended three major priorities: dispel taboos surrounding sex and sexuality, eliminate stigma and discrimination against young people living with HIV, and remove social and legal barriers. Six strategic actions were also recommended: strengthen young people's skills for effective leadership, ensure full youth participation in the AIDS response, increase access to HIV-related information, strengthen strategic networks, increase UNAIDS's outreach to young people, and increase young people's access to financial support. Through leveraging social media and crowdsourcing, it is possible to integrate grassroots perspectives from across the globe into a new model of engagement and participation, which should be further explored for community empowerment and mobilization. PMID- 23684189 TI - The importance of a positive approach to sexuality in sexual health programmes for unmarried adolescents in Bangladesh. AB - This article explores the mismatch that exists between what unmarried adolescents in Bangladesh experience, want and need in regard to their sexuality and what they receive from their society, which negatively impacts on their understanding of sexuality and their well-being. The findings provide a picture of Bangladeshi adolescents' (12-18 years) sexual feelings, experiences, behaviours, anxieties and concerns - in particular in relation to desire, pleasure, sexual power, masturbation, virginity, romantic love and dating, and arranged marriage - and how socio-sexual norms and taboos influence these. Curiosity of boys and girls about sex was driven by a need and desire to know and understand, but also because it was exciting to read about and talk about sex. Young people are not just passive recipients of adult norms and messages around sexuality, but agents who actively construe meanings and navigate between what is expected from them and what they want, need and feel themselves. Adolescents have a need for information and support - long before they ever have sex. We call for a positive, rights-based approach to sexuality education for adolescents and a focus beyond health outcomes alone to support adolescents and young people to make sense of the multiplicity of messages they encounter and reduce unnecessary feelings of guilt and anxiety. PMID- 23684190 TI - Contextualising sexual harassment of adolescent girls in Bangladesh. AB - Violence against women is a social mechanism confirming women's subordination in many societies. Sexual violence and harassment have various negative psychological impacts on girls, including a persistent feeling of insecurity and loss of self-esteem. This article aims to contextualize a particular form of sexual harassment, namely "eve teasing", experienced by Bangladeshi adolescent girls (12-18 years) which emerged from a study of adolescent sexual behaviour carried out by young people. The study used qualitative methods and a participatory approach, including focus group discussions, key informant interviews and observation. Despite taboos, unmarried adolescents actively seek information about sex, erotic pleasure and romance. Information was easily available from videos, mobile phone clips and pornographic magazines, but reinforced gender inequality. "Eve teasing" was one outlet for boys' sexual feelings; they gained pleasure from it and could show their masculinity. The girls disliked it and were afraid of being blamed for provoking it. Thus, "eve teasing" is a result of socio-cultural norms relating to sexuality, as well as a lack of access to sexual and reproductive health information and services in Bangladesh. These findings underscore the importance of comprehensive sexuality education that goes beyond a mere health focus and addresses gender norms and helps youth to gain social-sexual interaction skills. PMID- 23684191 TI - "I have grown up controlling myself a lot." Fear and misconceptions about sex among adolescents vertically-infected with HIV in Tanzania. AB - With increased access to HIV treatment throughout Africa, a generation of HIV positive children is now transitioning to adulthood while living with a chronic condition requiring lifelong medication, which can amplify the anxieties of adolescence. This qualitative study explored how adolescents in Tanzania with HIV experience their nascent sexuality, as part of an evaluation of a home-based care programme. We interviewed 14 adolescents aged 15-19 who had acquired HIV perinatally, 10 of their parents or other primary caregivers, and 12 volunteer home-based care providers who provided support, practical advice, and referrals to clinical services. Adolescents expressed unease about their sexuality, fearing that sex and relationships were inappropriate and hazardous, given their HIV status. They worried about having to disclose their status to partners, the risks of infecting others and for their own health. Thus, many anticipated postponing or avoiding sex indefinitely. Caregivers and home-based care providers reinforced negative views of sexual activity, partly due to prevailing misconceptions about the harmful effects of sex with HIV. The adolescents had restricted access to accurate information, appropriate guidance, or comprehensive reproductive health services and were likely to experience significant unmet need as they initiated sexual relationships. Care programmes could help to reduce this gap by facilitating open communication about sexuality between adolescents and their caregivers, providers, and HIV-positive peers. PMID- 23684192 TI - Gendered norms, sexual exploitation and adolescent pregnancy in rural Tanzania. AB - Adolescent pregnancy places girls at increased risk for poor health and educational outcomes that limit livelihood options, economic independence, and empowerment in adulthood. In Tanzania, adolescent pregnancy remains a significant concern, with over half of all first births occurring before women reach the age of 20. A participatory research and action project (Vitu Newala) conducted formative research in a rural district on the dynamics of sexual risk and agency among 82 girls aged 12-17. Four major risk factors undermined girls' ability to protect their own health and well-being: poverty that pushed them into having sex to meet basic needs, sexual expectations on the part of older men and boys their age, rape and coercive sex (including sexual abuse from an early age), and unintended pregnancy. Transactional sex with older men was one of the few available sources of income that allowed adolescent girls to meet their basic needs, making this a common choice for many girls, even though it increased the risk of unintended (early) pregnancy. Yet parents and adult community members blamed the girls alone for putting themselves at risk. These findings were used to inform a pilot project aimed to engage and empower adolescent girls and boys as agents of change to influence powerful gender norms that perpetuate girls' risk. PMID- 23684193 TI - Policy commitments vs. lived realities of young pregnant women and mothers in school, Western Cape, South Africa. AB - Reproductive rights in South Africa continue to be undermined for young women who fall pregnant and become mothers while still at school. Before 1994, exclusionary practices were common and the majority of those who fell pregnant failed to resume their education. With the adoption of new policies in 2007, young pregnant women and mothers are supposed to be supported to complete school successfully. Notwithstanding these new policies, there are incongruities between policy implementation and young women's lived experience in school. This paper explores the experiences of pregnancy and parenting among a group of 15 young women who fell pregnant and became mothers while attending three high schools in Khayelitsha township, a working-class community in the Western Cape of South Africa. Qualitative, in-depth interviews, conducted between 2007 and 2008, highlighted two key areas of concern: continuing exclusionary practices on the part of schools, based on conservative interpretations of policy, and negative and moralistic responses from teachers and peers. Such practices resulted in secrecy and shame about being pregnant, affecting the young women's emotional and physical well-being and their decisions whether to remain in school during pregnancy and return after having the baby. Further attention is required to ensure appropriate implementation of policies aimed at supporting pregnant and parenting young women to complete their education successfully. PMID- 23684194 TI - Sex education in the eyes of primary school teachers in Novo Hamburgo, Rio Grande do Sul, Brazil. AB - Sex education has been included in the National Curriculum of the Brazilian Ministry of Education since 1996 as a cross-cutting theme that should be linked to the contents of each school subject in primary and high schools. This paper presents a study of the implementation of this policy in the primary schools of Novo Hamburgo, Rio Grande do Sul, Brazil, based on interviews between January 2011 and April 2012 with 82 teachers working in those schools. We found that sex education was not being taught as a cross-cutting theme in any of the schools, and that any lessons were mostly dominated by a biomedical discourse focusing primarily on the reproductive organs, fertility, pregnancy, and contraception. Sexual health and relationships and non-heterosexual sex and relationships were being neglected. Sex education was also considered a possible means of correcting or controlling sexual identities and behaviours deemed abnormal or immoral. We recommend far more discussion of how to implement the National Curriculum recommendations. We call for education courses to provide theoretical and methodological training on sex education for teachers, and recommend that the boards of educational institutions take up sex education as a priority subject. Lastly, we suggest that each school studies local sexuality-related problems and based on the findings, each teacher presents a pedagogical proposal of how to integrate sex education into the subjects they teach. PMID- 23684196 TI - When a girl's decision involves the community: the realities of adolescent Maya girls' lives in rural indigenous Guatemala. AB - Adolescent Maya girls are among the most vulnerable, marginalized sub-populations in Guatemala, a country that is largely young, indigenous and poor. Adolescent Maya girls have limited access to secondary schooling, opportunities to work or earn an income, and sexual and reproductive health information and services. This article explores the extent to which adolescent Maya girls are able to adopt what they have learned in a community-based skills-building and sex education programme in isolated rural, indigenous Guatemalan communities. This is presented through an interview between the authors, who met and worked together in the Population Council's programme Abriendo Oportunidades (Opening Opportunities) for girls aged 8-19 years. The interview discusses what can be done so that indigenous adolescents not only obtain the sexual health information they need, but develop the skills to make decisions, communicate with their peers and parents, and exercise their rights. Much culturally and linguistically sensitive work must be done, using a community-based participatory approach, so that young people who do want to use condoms for protection or contraceptive methods not only have access to the methods, but the support of their families and communities, and government-sponsored sex education programmes, to use them. PMID- 23684195 TI - The Sexuality Education Initiative: a programme involving teenagers, schools, parents and sexual health services in Los Angeles, CA, USA. AB - In response to abstinence-only programmes in the United States that promote myths and misconceptions about sexuality and sexual behaviour, the comprehensive sexuality education community has been sidetracked from improving the sexuality education available in US schools for almost two decades now. Much work is still needed to move beyond fear-based approaches and the one-way communication of information that many programmes still use. Starting in 2008 Planned Parenthood Los Angeles developed and launched a teen-centred sexuality education programme based on critical thinking, human rights, gender equality, and access to health care that is founded on a theory of change that recognises the complex relationship between the individual and broader environment of cultural norms, socio-economic inequalities, health disparities, legal and institutional factors. The Sexuality Education Initiative is comprised of a 12-session classroom sexuality education curriculum for ninth grade students; workshops for parents; a peer advocacy training programme; and access to sexual health services. This paper describes that experience and presents the rights-based framework that was used, which seeks to improve the learning experience of students, strengthen the capacity of schools, teachers and parents to help teenagers manage their sexuality effectively and understand that they have the right to health care, education, protection, dignity and privacy. PMID- 23684197 TI - Beyond the clinic walls: empowering young people through Youth Peer Provider programmes in Ecuador and Nicaragua. AB - Youth in Latin America experience high rates of teen pregnancy and sexually transmitted infections, but traditional health services are not meeting their health care needs. Youth require access to tailored health care and information to make informed, healthy decisions. To break down barriers to these vital sexual and reproductive health services, Planned Parenthood Global, a division of Planned Parenthood Federation of America, developed a Youth Peer Provider model which has been implemented in Latin America since the early 1990s. The model goes beyond peer education to train Youth Peer Providers under age 20 to provide condoms, oral contraceptive pills, emergency contraception, injectable contraceptives, and sexual and reproductive health information to their peers. Peers with needs beyond Youth Peer Providers' capacity are referred to health professionals offering youth-friendly services. Survey results reveal high levels of contraceptive use among those served by the Youth Peer Providers: 98% of sexually active survey respondents wishing to avoid pregnancy report contraceptive use at least five years after joining the programme. Results of qualitative programme evaluations highlight higher self-esteem, stronger communication and decision-making skills, close relationships with friends and family, more interest in school, understanding of responsibility in relationships, and other positive outcomes among programme participants. PMID- 23684198 TI - Integrating gender and rights into sexuality education: field reports on using It's All One. AB - International policy agreements, along with emerging evidence about factors influencing programme effectiveness, have led to calls for a shift in sexuality education toward an approach that places gender norms and human rights at its heart. Little documentation exists, however, about the degree to which this shift is actually taking place on the ground or what it entails. Field experiences in using new curriculum tools, such as It's All One, offer one lens onto these questions. To gain a sense of practitioners' experience with this tool, a two part exercise was conducted. First, responses from an on-line survey of It's All One users were synthesized. Additionally, five programmes were selected for documentation, including two school-based programmes (Nigeria, China), two reaching extremely vulnerable youth (Haiti, Guatemala), and one reaching adolescents from a polygamous Mormon community (United States). Findings suggest the shift to an empowerment approach is indeed taking place in diverse geographic and programmatic contexts, and that It's All One has strengthened the ways their programmes address gender, foster young people's critical thinking skills and use interactive teaching methods. A common challenge across many programmes is strengthening teacher capacity. Recommendations for further implementation and research are presented. PMID- 23684199 TI - Evolving capacity and decision-making in practice: adolescents' access to legal abortion services in Mexico City. AB - The rights of adolescents and young people in international law and agreements have evolved significantly from a focus on protection to a recognition of "evolving capacities" and decision-making ability. Unclear policies and regulations and variations in actual practice may leave providers with little clarity on how to support adolescent decision-making and instead create unintended barriers. This study in Mexico City in 2009 explored whether regulations and clinical attitudes and practice were supporting or hindering the access of adolescent girls aged 12-17 to information regarding abortion and to abortion services. We surveyed abortion clinic directors and staff, and adolescents arranging or just having had an abortion, and sent mystery clients to clinics to ask for information. While providers were generally positive about adolescents' ability to decide on abortion, they had different understandings about the need for adult accompaniment and who that adult should be, and mystery clients seeking information were more likely to receive complete information if accompanied by an adult. Clarification of consent and accompaniment requirements is needed, and providers need to be made aware of them; adolescents should have access to information and counselling without accompaniment; and improvements in privacy and confidentiality in public sector clinics are also needed. These all support complementary concepts of protection and autonomy in adolescent decision making on abortion. PMID- 23684200 TI - Rights-based services for adolescents living with HIV: adolescent self-efficacy and implications for health systems in Zambia. AB - A rights-based approach in HIV service delivery for adults is increasingly taking root in sub-Saharan Africa in the context of greater availability of antiretroviral therapy. Yet there has been comparatively little progress in strengthening a rights-based approach to adolescent HIV services, which we learned during a qualitative study in 2010 among 111 adolescents living with HIV, 21 parents and 38 health providers in three districts in Zambia. Adolescents in the study expressed a range of information and support needs and wanted locally relevant interventions to meet those needs. They wanted greater access to HIV, sexual and reproductive health information, information on how to protect themselves, privacy and confidentiality in service sites, skills training so as to be able to earn money, and better control over disclosure of their HIV status to others. Both health workers and parents acknowledged that information and services needed to be improved to meet those needs far better. This paper provides examples of successful programmes in Zimbabwe, Uganda, Tanzania, Botswana and South Africa and calls for adolescent services to be linked to both paediatric and adult services, peer networks to be established to increase adolescents' ability to collectively voice their concerns and support each other, interventions supporting adolescents' control over self-disclosure, and lastly that adolescent health should become a training specialty in sub-Saharan Africa. PMID- 23684201 TI - Advancing adolescent capacity to consent to transgender-related health care in Colombia and the USA. AB - Many sexual and reproductive health care services, including gender reassignment treatment, facilitate reproductive autonomy and self-determination of gender identity. Individuals who are unable to refuse or consent to these services on their own behalf, such as adolescents, are at risk of violations of their rights to privacy and self-determination. This paper explores the issue of adolescent capacity to consent to transgender-related health care in Colombia and the United States (USA), focusing on the two countries' struggles to balance the rights of adolescents to make autonomous and confidential decisions with the rights of their parents. Unfortunately, many countries, including Colombia and the USA, have been slow to develop jurisprudence and legislation that explicitly protect transgender adolescents' capacity to consent to gender assignment treatment. Courts in Colombia, however, have developed jurisprudence that restricts parents' ability to make medical decisions on behalf of their infant intersex children, which lays a strong normative foundation for advancing adolescent capacity to consent to transgender-related health care. It is a strategy that may prove effective in other countries in the Americas, even those with different frameworks for adolescent medical decision-making capacity, such as the USA. PMID- 23684202 TI - Young women's experiences of side-effects from contraceptive implants: a challenge to bodily control. AB - In the UK, long-acting reversible contraceptives have been welcomed by sexual health policy-makers and many practitioners as a particularly effective way of preventing unintended pregnancy, especially teenage conception. However, little is known about women's individual experiences of these forms of contraception beyond limited data on retention rates and reasons for discontinuation. The main aims of this research were to gain a fuller understanding of why some young women have their implants removed, and what may help them maintain this method of contraception if they wish to do so. The contraceptive choices of 20 young women (aged 16-22) who had chosen the implant, and later discontinued it, were examined. They had experienced unacceptable side effects that they attributed to the implant, and interpreted as a threat to their bodily control, which they were not prepared to tolerate. These feelings were exacerbated if they then encountered delays after requesting removal. Although they remained concerned to avoid unintended pregnancy, they generally moved to a less reliable form of contraception following implant removal and felt discouraged from trying other long-acting contraception. We suggest that principles of contraceptive choice should include facilitating the discontinuation of unsatisfactory methods; implant removal should therefore be readily available when requested, regardless of the length of time the implant has been in place. Long-acting forms of contraception do not suit all women, and will not obviate the need for other forms of reproductive control, including legal abortion. PMID- 23684203 TI - Improving quality of life with new menstrual hygiene practices among adolescent tribal girls in rural Gujarat, India. AB - The Government of India has started a new scheme aimed at offering sanitary pads at a subsidized rate to adolescent girls in rural areas. This paper addresses menstrual health and hygiene practices among adolescent girls in a rural, tribal region of South Gujarat, India, and their experiences using old cloths, a new soft cloth (falalin) and sanitary pads. Qualitative and quantitative data were collected in a community-based study over six months, with a pre-and post- design, among 164 adolescent girls from eight villages. Questions covered knowledge of menstruation, menstrual practices, quality of life, experience and satisfaction with the different cloths/pads and symptoms of reproductive tract infections. Knowledge regarding changes of puberty, source of menstrual blood and route of urine and menstrual flow was low. At baseline 90% of girls were using old cloths. At the end of the study, 68% of adolescent girls said their first choice was falalin cloths, while 32% said it was sanitary pads. None of them preferred old cloths. The introduction of falalin cloths improved quality of life significantly (p<0.000) and to a lesser extent also sanitary pads. No significant reduction was observed in self-reported symptoms of reproductive tract infections. Falalin cloths were culturally more acceptable as they were readily available, easy to use and cheaper than sanitary pads. PMID- 23684204 TI - Chemical sexualities: the use of pharmaceutical and cosmetic products by youth in South Sulawesi, Indonesia. AB - Although young people in their everyday lives consume a bewildering array of pharmaceutical, dietary and cosmetic products to self-manage their bodies, moods and sexuality, these practices are generally overlooked by sexual and reproductive health programmes. Nevertheless, this self-management can involve significant (sexual) health risks. This article draws from the initial findings of the University of Amsterdam's ChemicalYouth project. Based on interviews with 142 youths, focus group discussions and participant observation in South Sulawesi, Indonesia, we found that young people - in the domain of sexual health turn to pharmaceuticals and cosmetics to: (1) feel clean and attractive; (2) increase (sexual) stamina; (3) feel good and sexually confident; (4) counter sexual risks; and (5) for a group of transgender youths, to feminize their male bodies. How youth achieve these desires varies depending on their income and the demands of their working lives. Interestingly, the use of pharmaceuticals and cosmetics was less gendered than expected. Sexual health programmes need to widen their definitions of risk, cooperate with harm reduction programmes to provide youth with accurate information, and tailor themselves to the diverse sexual health concerns of their target groups. PMID- 23684205 TI - Moving beyond the "male perpetrator, female victim" discourse in addressing sex and relationships for HIV prevention: peer research in Eastern Zambia. AB - Despite the resources put into HIV education programmes with young people in sub Saharan Africa in the past two decades, there is little clear evidence of impact. Many programmes continue to be oriented towards individual behaviour change (and in reality, often sexual abstinence) with insufficient focus on understanding how societies constrain or enable individual agency in sexual decision-making and how this is affected by social norms. If education programmes do address gender they often reinforce a "male perpetrator, female victim" discourse, where girls and women are held responsible for boys' and men's sexuality as well as their own. This paper discusses the discourses around gender, sexuality and HIV constructed by young women and men (aged 16-29) in a rural Eastern Zambia village. Data on young women's and men's narratives were gathered using a participatory peer approach. Research uncovered numerous and sometimes conflicting discourses (cultural, moral, economic, and sexual) influencing young women's and men's thinking about sexuality and sexual behaviour, in particular the limited possibilities for safe consensual sex, and thus their vulnerability to HIV. The research suggests that the realities young people face are much more complex than HIV prevention strategies address. We recommend a more nuanced approach, tailored to the community contexts involved. PMID- 23684206 TI - Early relationships and marriage in conflict and post-conflict settings: vulnerability of youth in Uganda. AB - While there is increased attention to child marriage, defined as marriage before 18 years of age, in countries where the practice is especially prevalent, less attention has been directed at understanding the factors affecting relationships, marriage and cohabitation among adolescents affected by conflict and displacement. This article presents factors which contribute to early relationships and informal marriages in conflict and post-conflict settings, based on qualitative research undertaken among two distinct populations in Uganda: internally displaced persons in Mucwini transit camp in northern Uganda and Congolese refugees in the Nakivale refugee settlement in southwestern Uganda. Themes were examined through a social-ecological framework. Findings indicate that fundamental shifts in economies, family relationships, and communication combined with structural changes encountered in settlements resulted in changed relationships and marriage patterns. Participants reported that poverty, splintering of family, and lack of education - which they believed to be exacerbated by conflict in both settings - had profoundly affected the views, perceptions and behaviours of youth around relationships and marriage. We identify interventions applicable to humanitarian settings that would offer refugee and internally displaced adolescents greater and more meaningful opportunities for development. PMID- 23684207 TI - Delay in termination of pregnancy among unmarried adolescents and young women attending a tertiary hospital abortion clinic in Trivandrum, Kerala, India. AB - Unwed pregnancy among adolescents is a disturbing event in Indian belief-systems, and very young motherhood limits girls' social, economic and educational prospects. Girls who seek abortions are always at higher risk for delay in care seeking; this paper looks at the reasons why. It reports the experiences of 34 unmarried adolescent girls and young women, aged 10-24 years, who obtained induced abortion from a tertiary care abortion clinic over a period of seven months in 2004. Ten were below 19 years of age, the rest were 20-24 years. Only eight of the 34 pregnancies were <12 weeks. The reasons for delay were fear of disclosure, lack of any support system and scarcity of resources. In 30 cases, the decision to terminate was made jointly with family members, especially the mother. Only half knew about contraception, of whom two used condoms. Only two of the partners accompanied the girl to the abortion clinic and another two offered some financial support. Because of the conflict between wanting to have sex and feeling guilty about it, these young people experienced terrible distress in the course of unwanted pregnancy. Comparing the adolescents who attended the clinic in 2004 with those we have seen in 2012-2013, the paper shows that as regards the essentials, much has remained the same. PMID- 23684208 TI - "One Billion Rising" at Johns Hopkins Bloomberg School of Public Health: a reflection. PMID- 23684209 TI - [Cross-cultural adaptation of the World Health Organization Disability Assessment Schedule (WHODAS 2.0) into Portuguese]. AB - OBJECTIVE: The World Health Organization Disability Assessment Schedule (WHODAS 2.0) was designed to assess the functioning level in six life domains (cognition, mobility, self-care, getting along, life activities, and participation in community activities). There are different versions, from the simplest to the most complete, various presentations (either interviews or self-administered), comprehending the domains of the International Classification of Functioning, Disability and Health (ICF). This study aimed to make a cross-cultural adaptation of the complete version into Portuguese. METHODS: The proceeding was developed over six stages: translation, back-translation, semantic equivalence, evaluation of previous stages by experts, tool pretest, and final version. RESULTS: After the pretest, an adjustment to a more colloquial Portuguese was made. The versions were shown to be similar regarding general and referential meaning. CONCLUSION: WHODAS 2.0 was shown to be easily applied and understood by women in the pregnancy-postpartum cycle. PMID- 23684210 TI - Lung age in women with morbid obesity. AB - OBJECTIVE: To investigate the influence of morbid obesity on the lung age in women and to correlate with body mass, body mass index (BMI), and ventilatory variables. METHODS: This was a cross-sectional study with 72 morbidly obese women and a control group consisting of 37 normal weight women. The subjects performed a pulmonary function test to determine lung age, and the results were correlated to anthropometric variables and lung volumes. RESULTS: The morbidly obese group had significantly higher lung age (50.1+/-6.8 years) than the control group (38.8+/-11.4 years). There was no difference in chronological age between groups. There was a significant positive correlation among chronological age, body mass, BMI, and lung age (r=0.3647, 0.4182, and 0.3743, respectively). There was a negative correlation among forced vital capacity (FVC), forced expiratory volume in one second (FEV1), FEV1/FVC ratio, expiratory reserve volume (ERV), and lung age (r=-0.7565, -0.8769, --0.2723, and -0.2417, respectively). CONCLUSION: Lung age is increased in morbidly obese women and is associated with increased body mass and BMI. PMID- 23684211 TI - Association between nonalcoholic fatty liver disease and coronary artery disease. AB - OBJECTIVE: Although some investigations have shown a relationship between nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases, there are few studies analyzing the relationship between NAFLD and coronary artery disease (CAD). The aim of this article was to review the relationship between NAFLD and CAD and the methods of diagnosis used to assess such relationship. METHODS: A review was performed using search engines of indexed scientific material, including MEDLINE (by PubMed), Web of Science, IBECS, and LILACS, to identify articles published in Portuguese, English, and Spanish until August, 2012. The studies were eligible if they included the following data: place and year of publication, prevalence and methods used to diagnose NAFLD (ultrasound, computed tomography, nuclear magnetic resonance, or biopsy) and CAD (coronary angiography, or computed tomography), and the exclusion of patients due to alcohol consumption greater than 20g/day. RESULTS: Ten articles were selected, most of which were cross-sectional studies. The studies mostly observed the association between NAFLD and the presence and severity of CAD. CONCLUSION: The analysis of the review showed that evaluating the existence of NAFLD in patients with CAD from its subclinical form up to the symptomatic clinical form is important due to the higher risk of acute myocardial infarction and consequent increase of mortality. PMID- 23684212 TI - [Evaluation of the length of hospital stay in cases of coronary artery bypass graft by payer]. AB - OBJECTIVE: The length of hospital stay (LOS) allows for the evaluation of the efficiency of a given hospital facility, as well as providing a basis for measuring the number of hospital beds required to provide assistance to the population in a specific area. METHODS: A retrospective survey was conducted on a database of 3,010 patients submitted to coronary artery bypass graft (CABG) from July, 2009 to July, 2010. RESULTS: Among 2,840 patients that met the inclusion criteria, 92.1% had their surgery paid by the Brazilian Unified Health System (Sistema Unico de Saude - SUS) and 7.9% by health plans or themselves (non-SUS). 70.2% were male, the average age was 61.9 years old, and the average risk score (EuroScore) was 2.9%. The SUS and the non-SUS groups did not differ regarding the waiting time for surgery (WTS) (2.59+/- 3.10 vs. 3,02+/-3,70 days for SUS and non SUS respectively; p=0.790), but did differ with respect to the length of stay in intensive care unit (2.17+/-3.84 vs. 2.52+/-2.72 days for SUS and non-SUS respectively; p < 0.001), the postoperative period (8.34+/-10.32 vs. 9,19+/-6.97 days for SUS and non-SUS respectively; p < 0.001), and the total LOS (10.93+/ 11.08 vs. 12.21+/-8.20 days for SUS and non-SUS respectively; p < 0.001). The non SUS group had more events of non-elective surgery (p=0.002) and surgery without cardiopulmonary bypass (p=0.012). The groups did not differ regarding the associated valve procedure (p=0.057) nor other non-valve procedures (p=0.053), but they did differ with respect to associated non-cardiac procedures (p=0.017). ICU readmission (p=0.636) and postoperative complications rates were similar in both groups (p=0.055). CONCLUSION: The Non-SUS group showed longer LOS compared to the SUS group. PMID- 23684213 TI - [Child, teenager, and traffic: some important considerations]. PMID- 23684214 TI - Cardiovascular risk in individuals with depression. AB - Depression and cardiovascular diseases (CVD) are both common illnesses. Several studies demonstrated that depressed individuals have higher mortality compared to age- and gender-matched population, with an excess of cardiovascular deaths. There is a bidirectional association between depression and CVD. Several factors can interact and influence this relationship: poverty and social inequality, reduced accessibility to health care, biological alterations (as reduced heart rate variability, endothelial dysfunction, increased inflammation and platelet function, and hyperactivity of hypothalamic-pituitary-adrenal axis), side effects of psychiatric medication, lower adherence to medical treatments, and higher frequency of cardiovascular risk factors (higher tobacco use, physical inactivity, obesity, diabetes mellitus). This article aims to update the current evidence of the possible mechanisms involved in the association between depression and CVD. PMID- 23684215 TI - Distribution of eating disorders in children and adolescents using the proposed DSM-5 criteria for feeding and eating disorders. AB - PURPOSE: To determine the distribution of eating disorders (ED) in children and adolescents comparing the fourth edition of the Diagnostic and Statistical Manual (DSM) to the proposed fifth edition DSM criteria. METHODS: A total of 215 consecutive patients (15.4 +/- 3.3 years) presenting for initial ED evaluation to adolescent medicine physicians from six institutions were assigned ED diagnoses using current DSM-IV criteria as well as proposed DSM-5 criteria. RESULTS: Diagnoses of anorexia nervosa and bulimia nervosa increased using the proposed DSM-5 criteria (from 30.0% to 40.0% and from 7.3% to 11.8%, p < .001). Approximately 14% of patients received the presumptive DSM-5 diagnosis of avoidant/restrictive food intake disorder. Cases of ED not otherwise specified decreased from 62.3% to 32.6% (p < .001). CONCLUSIONS: Proposed DSM-5 criteria substantially decreased the frequency of ED not otherwise specified diagnoses and increased the number of cases of anorexia nervosa and bulimia nervosa in a population of young patients presenting for ED treatment. Avoidant/restrictive food intake disorder appears to be a significant diagnosis. PMID- 23684216 TI - Two-method measurement for adolescent obesity epidemiology: reducing the bias in self-report of height and weight. AB - BACKGROUND: Despite validation studies demonstrating substantial bias, epidemiologic studies typically use self-reported height and weight as primary measures of body mass index because of feasibility and resource limitations. PURPOSE: To demonstrate a method for calculating accurate and precise estimates that use body mass index when objectively measuring height and weight in a full sample is not feasible. METHODS: As part of a longitudinal study of adolescent health, 1,840 adolescents (ages 12-18) self-reported their height and weight during telephone surveys. Height and weight was measured for 407 of these adolescents. Sex-specific, age-adjusted obesity status was calculated from self reported and from measured height and weight. Prevalence and predictors of obesity were estimated using self-reported data, measured data, and multiple imputation (of measured data). RESULTS: Among adolescents with self-reported and measured data, the obesity prevalence was lower when using self-report compared with actual measurements (p < .001). The obesity prevalence from multiple imputation (20%) was much closer to estimates based solely on measured data (20%) compared with estimates based solely on self-reported data (12%), indicating improved accuracy. In multivariate models, estimates of predictors of obesity were more accurate and approximately as precise (similar confidence intervals) as estimates based solely on self-reported data. CONCLUSIONS: The two-method measurement design offers researchers a technique to reduce the bias typically inherent in self-reported height and weight without needing to collect measurements on the full sample. This technique enhances the ability to detect real, statistically significant differences, while minimizing the need for additional resources. PMID- 23684217 TI - Prevalence and factors associated with baseline chronic kidney disease in China: a 10-year study of 785 upper urinary tract urothelial carcinoma patients. AB - BACKGROUND/PURPOSE: There is relatively little literature on prevalence of chronic kidney disease (CKD) prior to surgery in patients with upper urinary tract urothelial carcinoma (UTUC). We evaluated the prevalence and clinical associated factors of baseline CKD in patients with UTUC. METHODS: There were 785 patients with a pathologic diagnosis of UTUC from January 2002 to December 2011 who were analyzed in this study. Estimated glomerular filtration rate (eGFR) was calculated by re-expressed Modification of Diet in Renal Disease (MDRD) formulas for the Chinese population. A multivariate logistic regression was performed to evaluate the odds ratios (ORs) for CKD stage 3 or higher in UTUCs after data differences were tested. RESULTS: The prevalence of CKD in UTUCs presenting at our hospital was 58.6% and 70.8% in the group age 70 years and older. Older age [per year increased; OR = 1.050; 95% confidence interval (CI): 1.034-1.067], lower tumor stage (T stage; per stage increased; OR = 0.666; 95% CI: 0.544 0.816), higher tumor grade (per grade increased; OR = 1.392; 95% CI: 1.004-1.930) and the main tumor locating in the pelvis (ureter as reference; OR = 0.648; 95% CI: 0.475-0.885) were independently associated with decreased kidney function in the multivariate logistic regression. The use of serum creatinine (Scr) only to evaluate the renal function would ignore a large proportion of patients suffering from CKD stage 3 in UTUCs, especially in those older than 70 years (39.3% vs. 54.1%, p = 0.022). CONCLUSION: We demonstrated a high prevalence (58.6%) of CKD in patients with UTUC, particularly in the group older than 70 years (70.8%). Older age, lower T stage, higher tumor grade, and the main tumor locating in pelvis (ureter as reference) were independently associated with CKD in UTUCs. PMID- 23684218 TI - Baicalin ameliorates neuropathic pain by suppressing HDAC1 expression in the spinal cord of spinal nerve ligation rats. AB - BACKGROUND/PURPOSE: In a recent study, we found that baicalin exhibited a potent analgesic effect on carrageenan-evoked thermal hyperalgesia. The underlining mechanisms may be associated with inhibition of inflammatory mediator overproduction, including proinflammatory cytokines, nitric oxide (NO), and prostaglandin E2 (PGE2). In the present study, we examined the effect of baicalin on the antinociceptive effect of morphine and histone deacetylase 1 (HDAC1) expression in the spinal cord dorsal horn in neuropathic pain rats. METHODS: Neuropathic pain was induced by tight ligation of the left L5 spinal nerve of the rats. An intrathecal catheter was implanted for drug administration. Nociception was assessed by using the plantar test with the Hargreaves radiant heat apparatus, and the von Frey test with the dynamic plantar anesthesiometer. Spinal cords were removed for histone acetyl-H3 and HDAC1 western blot analysis at the end of the nociceptive assessment. RESULTS: The results showed that hyperalgesia and allodynia were observed in the spinal nerve ligated (SNL) left hindlimb; it was companied by histone-H3 deacetylation and HDAC1 overexpression on the ipsilateral side of the spinal cord dorsal horn. Intrathecal injection of baicalin (10 MUg) significantly attenuated the allodynia and hyperalgesia, and enhanced the antinociceptive effect of morphine (15 MUg). Moreover, baicalin reversed the histone-H3 acetylation and suppressed HDAC1 expression on the ipsilateral side of the spinal cord dorsal horn of SNL rats. CONCLUSION: The present findings suggest that baicalin can ameliorate neuropathic pain by suppressing HDAC1 expression and preventing histone-H3 acetylation in the spinal cord dorsal horn of SNL rats. PMID- 23684219 TI - Anti-hyperglycaemic activity of swietenia macrophylla king (meliaceae) seed extracts in normoglycaemic rats undergoing glucose tolerance tests. AB - BACKGROUND: Swietenia macrophylla King (Meliaceae) is used to treat diabetes mellitus in Malaysia. This study aims to evaluate the anti-hyperglycaemic potential of petroleum ether (PE), chloroform (CE) and methanol (ME) extracts of S. macrophylla seeds, in normoglycaemic and streptozotocin (STZ)-induced diabetic rats. METHODS: Following treatment of normoglycaemic rats with S. macrophylla seed extracts, hypoglycaemic and intraperitoneal glucose tolerance tests (IPGTT) were performed, and blood glucose concentrations were measured. Similarly, glucose concentrations were measured after 1 and 14 days of extract treatment of STZ-induced diabetic rats. Glucose absorption by isolated everted intestine and glucose uptake by isolated abdominal muscle were tested after treatment with seed extracts. Gas chromatography mass spectrometry (GC-MS) analysis was performed on PE of S. macrophylla seeds to identify the compounds responsible for its activity. RESULTS: None of the extracts had a significant effect on the blood glucose levels of 60 randomly selected normoglycaemic (normal) and diabetic rats undergoing hypoglycaemic tests. PE, however, significantly reduced blood glucose levels in 30 randomly selected normoglycaemic rats undergoing IPGTT tests 30-120 minutes after glucose administration. Repeated doses of 1000 mg/kg and 500 mg/kg PE to STZ-induced diabetic rats for 14 days did not reduce blood glucose levels significantly. PE did not significantly reduced the intestinal absorption of glucose, but significantly increased glucose uptake by abdominal muscle in the absence or presence of insulin. GC-MS analysis indicated that diterpenes, triterpenoids, fatty acid methyl esters, aldehydes and phytosterols may be responsible for the glucose lowering effects of PE. CONCLUSION: PE extracts of S. macrophylla seeds showed anti-hyperglycaemic activity on IPGTTs . GC-MS analysis on the PE revealed that several compounds, including fucosterol and beta sitosterol, may be responsible for these anti-hyperglycaemic properties. PMID- 23684220 TI - Effect of surface wettability on microfluidic EDGE emulsification. AB - The effect of wettability on microfluidic EDGE emulsification was investigated at dispersed phase contact angles between 90 degrees and 160 degrees . The highest contact angle (160 degrees ) produced monodispersed emulsions with droplet size 5.0 MUm and coefficient of variation <10%; however, pressure stability was very low. This was greatly enhanced at contact angles <150 degrees ; the plateaus filled completely, and the droplet generation frequencies increased up to a factor of 2.0 and 3.5 for Tween20 and Tween60 respectively at the same pressures. The emulsion became highly polydispersed at contact angles <100 degrees due to wetting with the dispersed phase. PMID- 23684221 TI - The impact of alkyl sulfate surfactant geometry and electrolyte on the co adsorption of anionic surfactants with model perfumes at the air-solution interface. AB - The impact of surfactant geometry and electrolyte on the co-adsorption of anionic surfactants and model perfumes at the air-solution interface has been studied by neutron reflectivity. The more hydrophobic perfume linalool, competes more favourably for the surface with sodium dodecylsulfate than was previously reported for the anionic surfactant, sodium dodecyl 6-benzenesulfonate. Due to an increase in surface activity of the sodium dodecylsulfate, the addition of electrolyte results in a reduction in the linalool adsorption. Changing the alkyl chain length affects the relative adsorption of linalool and surfactant at the interface. Similar measurements for the different alkyl sulfates and with electrolyte with the more hydrophilic perfume phenyl ethanol, reveal broadly similar trends. Although the relative adsorption of phenyl ethanol with sodium dodecylsulfate is substantially enhanced compared to sodium dodecyl-6 benzenesulfonate the effects are not as significant as was observed with linalool. The variations with alkyl chain geometry show the importance of the hydrophobic interaction between the perfume and surfactant and changes in the packing constraints on the relative adsorption. The results highlight the importance of the specific interaction between the surfactant and perfume, and the surfactant and perfume geometries on the relative adsorption at the interface. PMID- 23684222 TI - Toward the understanding of the interfacial dairy fouling deposition and growth mechanisms at a stainless steel surface: a multiscale approach. AB - The microstructures of two dairy fouling deposits obtained at a stainless steel surface after different processing times in a pilot plate heat exchanger were investigated at different scales. Electron-Probe Micro Analysis, Time-of-Flight Secondary Ion Mass Spectrometry, Atomic Force Microscopy, and X-Ray Photo electron Spectroscopy techniques were used for this purpose. The two model fouling solutions were made by rehydrating whey protein in water containing calcium or not. Results on samples collected after 2h processing show that the microstructure of the fouling layers is completely different depending on calcium content: the layer is thin, smooth, and homogeneous in absence of calcium and on the contrary very thick and rough in presence of calcium. Analyses on substrates submitted to 1 min fouling reveal that fouling mechanisms are initiated by the deposit of unfolded proteins on the substrate and start immediately till the first seconds of exposure with no lag time. In presence of calcium, amorphous calcium carbonate nuclei are detected in addition to unfolded proteins at the interface, and it is shown that the protein precedes the deposit of calcium on the substrate. Moreover, it is evidenced that amorphous calcium carbonate particles are stabilized by the unfolded protein. They are thus more easily trapped in the steel roughnesses and contribute to accelerate the deposit buildup, offering due to their larger characteristic dimension more roughness and favorable conditions for the subsequent unfolded protein to depose. PMID- 23684223 TI - Dielectric and electrophoretic response of montmorillonite particles as function of ionic strength. AB - Montmorillonite is a sheet-like clay mineral. The surface charge of the faces is always negative, whereas the surface charges of the edges depend on pH. In this study, pH is around 6.5 implying that the edges are slightly positive; however, the overall charge of the particle appears to be negative as the surface of the faces is 50 times larger than the edges. In the presence of an applied electric field, montmorillonite particles and their double layer will polarize. This polarization affects the electrokinetic response of the particles. In this article, we investigated the effect of ionic strength on the electrokinetic response of montmorillonite particles using the dielectric spectroscopy and electrophoretic mobility. The experimental dipole coefficient found by dielectric spectroscopy was compared to the semi-analytical formula presented by Chassagne [C. Chassagne, J. Colloid Interface Sci. 326 (2008)]. The amplitude of the dipole coefficient of montmorillonite particles increased and the relaxation frequency shifted to lower frequencies with decreasing ionic strength. This tendency is in qualitative agreement with the theoretical prediction. A better agreement between the experimental and theoretical amplitudes of the dipole coefficient and between the high-frequency experimental and theoretical mobilities was obtained when a Stern layer conductivity is introduced. The same values for the zeta potential and Stern layer conductivities were used in both measurement sets. The relaxation frequencies were not changed by addition of a Stern layer. This discrepancy between experimental and theoretical relaxation frequencies are due to the limitation of the theory that is not valid at low kappaa, as discussed in the conclusion. PMID- 23684224 TI - Surface tension and surface Deltachi-potential of concentrated Z+:Z- electrolyte solutions. AB - Schmutzer's model for the surface of aqueous electrolyte solutions is generalized to Z+:Z- salts. The thickness of the ion-free layer is calculated from the thickness of the "hydrophobic gap" at the water surface (1.38A) and the radii of the ionic hydration shells. The overlap between the adsorption and the diffuse double layers is accounted for. The proposed model predicts the dependence of the surface tension sigma and the surface Deltachi-potential on the electrolyte concentration c(el) in agreement with the available data, without adjustable parameters. The Hofmeister effect on sigma for salts of the same valence type is explained with their ion-specific activity coefficients. The negative value (toward air) of the Deltachi-potential of most 1:1 electrolytes originates from the dipole moment of the water molecules at the surface. The negative chi potential due to water dipoles is inversely proportional to the dielectric permittivity epsilon of the solution. Since epsilon diminishes as c(el) increases, most 1:1 electrolyte solutions exhibit a more negative chi-potential than pure water (Deltachi<0). The Hofmeister series of Deltachi of 1:1 salts (Deltachi(LiCl) ~ Deltachi(NaCl)13%). RESULTS: Forty-four patients were entered and prognostic variables were similar between the subgroups. Luminal B patients achieved higher objective response rate than luminal A (69% versus 19%; P = 0.001), longer time to progression (12.2 months versus 8.6 months; P = 0.039), and longer overall survival (24.6 months versus 19.5 months; P = 0.041). The multivariate analysis confirmed the predictive value of luminal B subtype for longer time to progression. CONCLUSIONS: Identification by Ki67 labelling index of human epidermal growth factor receptor-2-negative luminal A could predict a substantial benefit from systemic chemotherapy. Endocrine therapy would be the most appropriate therapy for luminal A tumours. PMID- 23684361 TI - Extended spectrum beta-lactamase producing Klebsiella pneumoniae-related keratitis. PMID- 23684362 TI - Saliva concentration of amoxicillin, erythromycin, and ciprofloxacin in outpatients: a comparison between the young and the elderly. PMID- 23684363 TI - Propofol protects against nitrosative stress-induced apoptotic insults to cerebrovascular endothelial cells via an intrinsic mitochondrial mechanism. AB - BACKGROUND: Cerebrovascular endothelial cells (CECs), major component cells of the blood-brain barrier, can be injured by oxidative stress. Propofol can protect cells from oxidative injury. The aim of this study was to evaluate the effects of propofol on nitrosative stress-induced insults to CECs and its possible mechanisms. METHODS: Primary CECs isolated from mouse cerebral capillaries were exposed to2 nitric oxide (NO) donors: sodium nitroprusside (SNP) or S nitrosoglutathione (GSNO). Cellular NO levels, cell morphologies, and cell viabilities were analyzed. DNA fragmentation and apoptotic cells were quantified using flow cytometry. Proapoptotic Bcl2-antagonist-killer (Bak) and cytochrome c were immunodetected. Bak translocation was analyzed using confocal microscopy. Caspases-9 and -3 activities were measured fluorometrically. Permeability of the CEC monolayer was assayed by measuring the transendothelial electrical resistance. RESULTS: Exposure of CECs to SNP increased cellular NO levels and simultaneously decreased cell viability (P < .01). Meanwhile, treatment of CECs with propofol at a therapeutic concentration (50 MUM) decreased SNP-induced cell death (P < .01). SNP induced DNA fragmentation and cell apoptosis, but propofol decreased the cell injury (P < .01). Sequentially, propofol decreased SNP enhanced Bak levels and translocation from the cytoplasm to mitochondria (P < .05). Exposure of CECs to propofol attenuated GSNO-induced cell death, apoptosis, and caspase-3 activation (P < .01). Additionally, propofol protected CECs against SNP-induced disruption of the CEC monolayer (P < .05). Consequently, SNP-enhanced cascade activation of caspases-9 and -3 was decreased by propofol (P < .01). CONCLUSION: This study suggested that propofol at a therapeutic concentration can protect against nitrosative stress-induced apoptosis of CECs due to downregulation of the intrinsic Bak-mitochondrion-cytochrome c-caspase protease pathway. PMID- 23684364 TI - Normal prothrombinase activity, increased systemic thrombin activity, and lower antithrombin levels in patients with disseminated intravascular coagulation at an early phase of trauma: comparison with acute coagulopathy of trauma-shock. AB - BACKGROUND: We tested the hypotheses that an increase in systemic thrombin activity occurs in both disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype and in acute coagulopathy of trauma shock (ACoTS), and that the patients diagnosed as having ACoTS overlap or are identical with those diagnosed as having DIC. METHODS: We made a prospective study of 57 trauma patients, including 30 patients with DIC and 27 patients without DIC. Patients with ACoTS, defined as a prothrombin time ratio >1.2, were also investigated. We included 12 healthy volunteers as controls. The levels of soluble fibrin, antithrombin, prothrombinase activity, soluble thrombomodulin, and markers of fibrin(ogen)olysis were measured on days 1 and 3 after the trauma. The systemic inflammatory response syndrome and the Sequential Organ Failure Assessment were scored to evaluate the extent of inflammation and organ dysfunction. RESULTS: Patients with DIC showed more systemic inflammation and greater Sequential Organ Failure Assessment scores and were transfused with more blood products than the patients without DIC. On day 1, normal prothrombinase activity, increased soluble fibrin, lesser levels of antithrombin, and increased soluble thrombomodulin were observed in patients with DIC in comparison with controls and non-DIC patients. These changes were more prominent in patients with DIC who met the overt criteria for DIC established by the International Society on Thrombosis and Haemostasis. Multiple regression analysis showed that antithrombin is an independent predictor of high soluble fibrin in DIC patients. Greater levels of fibrin and fibrinogen degradation products, D-dimer, and the fibrin and fibrinogen degradation products/D-dimer ratio indicated increased fibrin(ogen)olysis in DIC patients. Almost all ACoTS patients overlapped with the DIC patients. The changes in the measured variables in ACoTS patients coincided with those in DIC patients. CONCLUSION: Normal prothrombinase activity and insufficient control of coagulation give rise to systemic increase in thrombin generation and its activity in patients with DIC with the fibrinolytic phenotype at an early phase of trauma. The same is true in patients with ACoTS, and shutoff of thrombin generation was not observed. PMID- 23684366 TI - Using a robot to personalise health education for children with diabetes type 1: a pilot study. AB - OBJECTIVE: Assess the effects of personalised robot behaviours on the enjoyment and motivation of children (8-12) with diabetes, and on their acquisition of health knowledge, in educational play. METHODS: Children (N=5) played diabetes quizzes against a personal or neutral robot on three occasions: once at the clinic, twice at home. The personal robot asked them about their names, sports and favourite colours, referred to these data during the interaction, and engaged in small talk. Fun, motivation and diabetes knowledge was measured. Child-robot interaction was observed. RESULTS: Children said the robot and quiz were fun, but this appreciation declined over time. With the personal robot, the children looked more at the robot and spoke more. The children mimicked the robot. Finally, an increase in knowledge about diabetes was observed. CONCLUSION: The study provides strong indication for how a personal robot can help children to improve health literacy in an enjoyable way. Children mimic the robot. When the robot is personal, they follow suit. Our results are positive and establish a good foundation for further development and testing in a larger study. PRACTICE IMPLICATIONS: Using a robot in health care could contribute to self-management in children and help them to cope with their illness. PMID- 23684367 TI - Introducing technology into medical education: two pilot studies. AB - OBJECTIVES: Educators are integrating new technology into medical curriculum. The impact of newer technology on educational outcomes remains unclear. We aimed to determine if two pilot interventions, (1) introducing iPads into problem-based learning (PBL) sessions and (2) online tutoring would improve the educational experience of our learners. METHODS: We voluntarily assigned 26 second-year medical students to iPad-based PBL sessions. Five students were assigned to Skype for exam remediation. We performed a mixed-method evaluation to determine efficacy. RESULTS: Pilot 1: Seventeen students completed a survey following their use of an iPad during the second-year PBL curriculum. Students noted the iPad allows for researching information in real time, annotating lecture notes, and viewing sharper images. Data indicate that iPads have value in medical education and are a positive addition to the curriculum. Pilot 2: Students agreed that online tutoring is at least or more effective than in-person tutoring. CONCLUSIONS: In our pilot studies, students experienced that iPads and Skype are beneficial in medical education and can be successfully employed in areas such as PBL and remediation. PRACTICE IMPLICATIONS: Educators should continue to further examine innovative opportunities for introducing technology into medical education. PMID- 23684368 TI - Cardiovascular anesthetic complications and treatment in oral surgery. AB - Perioperative hypertension is a common problem. If hypertension is left untreated in patients at risk, infarctions and stroke are possible. There are limited choices of antihypertensive agents for the office. Aggressive antihypertensive therapy is not indicated because most of the episodes seen in the office are hypertensive urgencies and not emergencies. Hypotension is usually managed by decreasing the depth of anesthesia, intravenous fluids, and then vasopressors, typically ephedrine or phenylephrine. Consider treatment of hypotension whenever the mean arterial pressure decreases less than 60 mm Hg. PMID- 23684369 TI - Screening for progranulin mutations by serum protein dosage in common neurodegenerative disorders. PMID- 23684370 TI - Mesencephalic area measured by transcranial sonography in the differential diagnosis of parkinsonism. AB - BACKGROUND: Transcranial B-mode sonography (TCS) has become an important tool in the differential diagnosis of parkinsonism given that current technology enables an adequate assessment of brain structures. In this study we aimed at evaluating the usefulness of midbrain area measured by TCS in the differential diagnosis between Parkinson's Disease (PD) and Progressive Supranuclear Palsy (PSP). METHODS: Patients with a diagnosis of PD or PSP according to current clinical criteria were recruited. PSP patients were classified as Richardson's syndrome and PSP-parkinsonism. TCS was performed and the mesencephalic area and third ventricle width were measured offline by an examiner blinded to clinical diagnosis. RESULTS: TCS was performed in 60 patients (75% PD, 25% PSP). Eight patients (13,3%) had inadequate acoustic window. Patients with PSP had a smaller mesencephalic area (3.58 cm(2) vs 5.28 cm(2), p < 0.001). A mesencephalic area >=4.27 cm(2) discriminates PD from PSP with a positive predictive value 100%. Patients with PSP also had a higher third ventricle diameter (8.84 mm vs 5.11 mm, p < 0.001). Within the PSP group patients with Richardson's syndrome had a wider third ventricle than patients with PSP-Parkinsonism phenotype (9.57 mm vs 7 mm, p = 0.01), but no differences were found in the mesencephalic area between both phenotypes. CONCLUSIONS: Measurement of the mesencephalic area and the third ventricle width by TCS is a non-invasive, easily accessible technique that is useful in the differential diagnosis between PD and PSP, at least in the late stages of the disease. PMID- 23684371 TI - Regional bone geometry of the tibia in triathletes and stress reactions--an observational study. AB - OBJECTIVES: The association between tibial morphology and tibial stress fractures or tibial stress syndrome was examined in triathletes with an unusually high incidence of these injuries. DESIGN: A cross-sectional study design examined associations between tibial geometry from MRI images and training and injury data between male and female triathletes and between stress fracture (SF) and non stress fracture (NSF) groups. METHODS: Fifteen athletes (7 females, 8 males) aged 17-23 years who were currently able to train and race were recruited from the New Zealand Triathlete Elite Development Squad. Geometric measurements were taken at 5 zones along the tibia using MRI and compared between symptomatic and asymptomatic tibiae subjects. RESULTS: SF tibiae displayed either oedema within the cancellous bone and/or stress fracture on MRI. When collapsed across levels, symptomatic tibiae had thicker medial cortices (F1,140=9.285, p=0.003), thicker lateral cortices (F1,140=10.129, p=0.002) and thinner anterior cortices (F1,140=14.517, p=0.000) than NSF tibiae. Only medial cortex thickness in SF tibia was significantly different (F4,140=3.358, p=0.012) at different levels. Follow-up analysis showed that athletes showing oedema within the cancellous bone and/or stress fracture on MRI had, within 2 years of analysis, subsequently taken time off training and racing due a tibial stress fracture. CONCLUSIONS: The thinner anterior cortex in SF tibiae is associated with a stress reaction in these triathletes. PMID- 23684372 TI - Adductor squeeze test values and hip joint range of motion in Gaelic football athletes with longstanding groin pain. AB - OBJECTIVES: The objective of the present study was to investigate whether differences exist in adductor squeeze test values and hip joint range of motion between athletes with longstanding groin pain and injury-free controls. DESIGN: Observational study with a case control design. METHODS: Eighteen Gaelic football players with current longstanding groin pain and 18 matched injury-free controls were assessed on their performance of the adductor squeeze test. Adductor squeeze test values were quantified using a sphygmomanometer. A fluid-filled inclinometer was used to assess hip joint internal and external rotation range of motion. A bent knee fall-out test was also utilised to examine hip joint range of motion. RESULTS: A significant difference in adductor squeeze test values was observed between the control group (269 +/- 25 mmHg) and longstanding groin pain group (202 +/- 36 mmHg; p<0.01). Furthermore the longstanding groin pain group had a decreased bent knee fall-out (p<0.01) bilaterally, as well as decreased hip joint internal rotation (p<0.05) and hip joint external rotation (p<0.05) range of motion bilaterally when compared to the control group. CONCLUSIONS: Gaelic football players with longstanding groin pain exhibit decreased adductor squeeze test values and hip joint range of motion when compared to non-injured players. These findings have implications for assessment and rehabilitation practices, as well as return to play criteria. PMID- 23684373 TI - Metabolic complications with the use of mTOR inhibitors for cancer therapy. AB - BACKGROUND: mTOR inhibitors are now approved by regulatory agencies for the treatment of a variety of malignancies. The risk of metabolic complications with these agents is not well characterized. METHODS: PubMed was searched for articles published from 2001 until 2011. Eligible studies included prospective randomized trials evaluating temsirolimus, everolimus, and ridaforolimus in patients with all solid tumor malignancies. Sixteen eligible phase II clinical trials and 8 randomized controlled clinical trials were included in a systematic review and meta-analysis and the number of metabolic related AEs (hyperglycemia, hypercholesterolemia, and hypertriglyceridemia) was extracted. Incidence rates and incident rate ratios were calculated. FINDINGS: Twenty-four trials, including 4261 patients, were included in the calculation of the incidence rate. The average incidence rate of all grade metabolic related events was 0.70 (95% CI, 0.47, 0.93). The average incidence rate of serious (grade 3 and 4) metabolic related adverse events was 0.11 (95% CI, 0.08, 0.15). The incidence rate ratio (IRR) of a metabolic adverse event with mTOR inhibitor therapy compared with control was 2.93 (95% CI, 2.33, 3.70) and of serious grade 3 and 4 metabolic adverse events was 4.58 (95% CI, 2.86, 7.34). The IRR of all grade hyperglycemia was 2.95 (95% CI, 2.14, 4.05) and of grade 3-4 hyperglycemia was 5.25 (95% CI, 3.07, 9.00). The IRR of all grade hypertriglyceridemia was 2.49 (95% CI, 1.76, 3.52) and of grade 3-4 hypertriglyceridemia was 2.01 (95% CI, 0.65, 6.27). The IRR of all grade hypercholesterolemia was 3.35 (95% CI, 2.17, 5.18) and of grade 3-4 hypercholesterolemia was 6.51 (95% CI, 1.48, 28.59). These findings suggest a statistically significant increase in the risk of hyperglycemia, hypercholesterolemia (all grades and grade 3 and 4), and all grade hypertriglyceridemia associated with mTOR therapy when compared with control. INTERPRETATION: The risk of all grade and grade 3-4, hyperglycemia, hypercholesterolemia, and hypertriglyceridemia, are increase in patients treated with mTOR inhibitors compared with control. PMID- 23684374 TI - [Ultrasound-guided axillary block versus ultrasound-guided infraclavicular block for upper extremity surgery]. AB - BACKGROUND: Most upper limb regional anaesthesia techniques are successful, and differences in efficacy should dictate the choice of technique. METHODS: This prospective, randomised study compares ultrasound-guided infraclavicular (IB) and ultrasound-guided axillary brachial plexus blocks (AB) for upper limb surgery. Anaesthesia time (performance time and onset time) was the primary outcome measure. The success rate (surgical anaesthesia), analgesia duration, postoperative pain scores, and the incidence of complications over the following 24h were recorded. RESULTS: A total of 82 patients were included in the study, and received either IB (n=42) or AB (n=40). No differences were observed between the 2 groups in terms of total anaesthesia-related time, performance time, success rate (90-95%), or postoperative pain scores. Compared with the infraclavicular approach, ultrasound-guided AB group required a longer onset time, 10.2min (SD+/-1.4), than IB group, 6.35min (SD+/-2). IB was also associated with a longer analgesia duration than that of AB; 20h (SD+/-1.36) versus 13.70h (SD+/-2.16), respectively. The only complications we observed were uneventful vascular punctures. CONCLUSIONS: We can conclude that compared to ultrasound guided AB, ultrasound-guided IB provides a similar efficacy, a shorter onset time and longer lasting analgesia. PMID- 23684375 TI - Multimedia based health information to parents in a pediatric acute ward: a randomized controlled trial. AB - OBJECTIVE: To determine whether multimedia based health information presented to parents of children with breathing difficulties in a pediatric acute ward, is more effective than verbal information, to reduce parental anxiety and increase satisfaction. METHODS: This randomized controlled trial was conducted in a pediatric acute ward in Norway, from January to March 2011. Parents were randomly assigned to a multimedia intervention (n=53), or verbal health information (n=48). Primary outcome measure was parental anxiety, and secondary outcome measures were parental satisfaction with nursing care and health information. RESULTS: Parental anxiety decreased from arrival to discharge within both groups. At discharge the anxiety levels in the intervention group were no lower than in the control group. There was no difference in satisfaction with nursing care between the groups, but parents in the intervention group reported higher satisfaction with the health information given in the acute ward (p=.005). CONCLUSION: Multimedia based health information did not reduce anxiety more than verbal information, among parents to children with breathing difficulties. However, after discharge the parents were more satisfied with the multimedia approach. PRACTICE IMPLICATIONS: More research is needed to recommend the use of multimedia based information as a routine to parents in pediatric emergency care. PMID- 23684376 TI - [SemFYC Self-Care Week]. PMID- 23684377 TI - [How to review the medication in patients with multiple chronic conditions?]. PMID- 23684379 TI - Chronic chorioamnionitis is the most common placental lesion in late preterm birth. AB - OBJECTIVES: The pathogenesis of late preterm birth remains elusive for the mechanisms of disease responsible. Placental examination can often provide important clues for the pathogenesis of pregnancy complications. This study was conducted to determine placental pathologic findings according to the gestational age and the clinical circumstances of preterm birth. STUDY DESIGN: Placental pathologic findings and obstetrical and neonatal outcomes were reviewed in a consecutive preterm birth cohort from a single tertiary center (N = 1206). Placentas of term births (N = 300) were used as normal controls. RESULTS: Acute chorioamnionitis (22.7% vs. 16.7%), maternal vascular underperfusion (6.4% vs. 0.5%), and chronic chorioamnionitis (20.8% vs. 10.5%) were significantly more frequent in preterm births than in term births (P < 0.05, for each). Among preterm births, chronic chorioamnionitis was the most common pathology of late preterm birth (gestational age <37 and >=34 weeks), while acute chorioamnionitis was the most common lesion of extremely preterm birth (gestational age <28 weeks). While the frequency of acute chorioamnionitis decreased with advancing gestation, that of chronic chorioamnionitis increased (P < 0.001, for each). The upward trend of the frequency of chronic chorioamnionitis was related to advancing gestation in both spontaneous and indicated preterm births (P < 0.001, for each). CONCLUSIONS: Chronic chorioamnionitis is a common pathology of late preterm birth. It is suggested that chronic chorioamnionitis, a feature of maternal anti-fetal rejection, is an important etiology of preterm birth, especially of late preterm birth. PMID- 23684378 TI - Kiss1 and Kiss1r mRNA expression in the rat placenta: changes with gestational age and regulation by glucocorticoids. AB - INTRODUCTION: Kisspeptin, the neuropeptide product of the KISS1 gene, is synthesized by neurons within the hypothalamus and is critical for fertility. Human placenta also expresses KISS1 and kisspeptin receptor (KISS1R) mRNA within the trophoblast compartment, where it is thought to act as a physiological invasion inhibitor. METHODS: We determined the expression of Kiss1 mRNA in rat placenta and examined the effect of gestational age and feto-placental growth restriction, achieved through excess maternal glucocorticoid exposure. RESULTS: Dexamethasone induced fetal growth restriction at both day 16 and day 22 of gestation, but placental growth restriction only at day 22. Real-time quantitative RT-PCR revealed an increase in Kiss1 and Kiss1r mRNA from day 16-22 in the labyrinth and junctional zones of the rat placenta. Immunolocalization confirmed kisspeptin expression in the placenta and was prominent in trophoblast tissue. Dexamethasone exposure elevated the expression of Kiss1 mRNA in the labyrinth and junctional zones of day 16 placentas. In contrast, Kiss1 mRNA in the labyrinth zone was reduced following dexamethasone-treatment at day 22. Kiss1r expression was increased in both placental zones at day 16 and 22 in response to dexamethasone-treatment. CONCLUSIONS: We confirm the presence of Kiss1 and Kiss1r mRNA in the rat placenta with expression increasing over the final third of pregnancy, suggestive of a role in restricting placental growth. Furthermore, the effects of dexamethasone on placental Kiss1/Kiss1r suggest glucocorticoid-induced placental growth retardation could be mediated, in part, via early stimulation of Kiss1 and the subsequent inhibition of trophoblast proliferation and invasion. PMID- 23684380 TI - Oxygen tension modulates AQP9 expression in human placenta. AB - Placental hypoxia has been implicated in pregnancy pathologies such as preeclampsia. We have previously reported that AQP9 is highly expressed in syncytiotrophoblast from normal placentas and shows an overexpression in preeclamptic placentas, with a lack of functionality for water transport. Up to now, the response of AQP9 to changes in the oxygen tension in trophoblast cells is still unknown. OBJECTIVE: Our aim was to establish whether alterations in oxygen levels may modulate AQP9 expression in human placenta. METHODS: A theoretical analysis of the human AQP9 gene to find conserved DNA regions that could serve as putative HIF-1 binding sites. Then, explants from normal placentas were cultured at different concentrations of oxygen or with 250 MUM CoCl2. AQP9 molecular expression and water uptake was determined. RESULTS: Fourteen consensus HIF-1 binding sites were found in the human AQP9 gene, but none of them in the promoter region. However, placental AQP9 decreased abruptly when HIF-1alpha is expressed by deprivation of oxygen or CoCl2 stabilization. In contrast, after reoxygenation, HIF-1alpha was undetectable while AQP9 increased significantly and changed its cellular distribution, showing the same pattern as that previously described in preeclamptic placentas. Accordingly with the decrease in AQP9 expression, water uptake decreased in explants exposed to hypoxia or treated with CoCl2. Conversely as we expected, after reoxygenation, water uptake decreased dramatically compared to the control and was not sensitive to HgCl2. CONCLUSION: Our findings suggest that oxygen tension may modulate AQP9 expression in human placenta. However, the role of AQP9 still remains uncertain. PMID- 23684381 TI - miR-155* mediates suppressive effect of PTEN 3'-untranslated region on AP-1/NF kappaB pathway in HTR-8/SVneo cells. AB - Among miRNAs, miR-155 is a known regulator of immune system. Accumulating studies have revealed the connections between miR-155 and activator protein 1 (AP 1)/nuclear factor (NF)-kappaB. However, miR-155*, a miR-155 paralog, has so far been less studied. Here we demonstrated that miR-155*, induced by lipopolysaccharide (LPS) in an AP-1/NF-kappaB dependent manner, played a positive feedback role in AP-1/NF-kappaB pathway via targeting interleukin-1 receptor associated kinase M (IRAKM) and NF-kappaB inhibitor interacting Ras-like 1 (NKIRAS1) in trophoblasts. Our study further proved that miR-155*-targeted PTEN 3'-untranslated region (3'UTR) increased IRAKM and NKIRAS1 expression by competing for miR-155* binding, thereby suppressing AP-1/NF-kappaB activation induced by LPS. PMID- 23684382 TI - Impaired anatomical connectivity and related executive functions: differentiating vulnerability and disease marker in bipolar disorder. AB - BACKGROUND: Bipolar 1 disorder (BD1) has been associated with impaired set shifting, increased risk taking, and impaired integrity of frontolimbic white matter. However, it remains unknown to what extent these findings are related to each other and whether these abnormalities represent risk factors or consequences of the illness. METHODS: We addressed the first question by comparing 19 patients with BD1 and 19 healthy control subjects (sample 1) with diffusion tensor imaging, the Intra-Extra Dimensional Set Shift Task, and the Cambridge Gambling Task. The second question we approached by applying the same protocol to 22 healthy first-degree relatives of patients with BD1 and 22 persons without a family history of mental disorders (sample 2). RESULTS: In comparison with their control groups, BD1 patients and healthy first-degree relatives of patients with BD1 showed significantly reduced fractional anisotropy (FA) in the right anterior limb of the internal capsule and right uncinate fasciculus. White matter integrity in corpus callosum was reduced in BD1 patients only. In addition, reduced FA in anterior limb of the internal capsule correlated significantly with an increased number of errors during set shifting and increased risk taking and reduced FA in uncinate fasciculus correlated significantly with increased risk taking. CONCLUSIONS: Similar white matter alterations in BD1 patients and healthy relatives of BD1 patients are associated with comparable behavioral abnormalities. Further, results indicate that altered frontolimbic and frontothalamic connectivity and corresponding behavioral abnormalities might be a trait and vulnerability marker of BD1, whereas interhemispheric connectivity appears to be a disease marker. PMID- 23684383 TI - Proteomic similarities between heterozygous reeler mice and schizophrenia. PMID- 23684384 TI - Altered regional homogeneity patterns in adults with attention-deficit hyperactivity disorder. AB - PURPOSE: Investigating the discriminative brain map for patients with attention deficit/hyperactivity disorder (ADHD) based on feature selection and classifier; and identifying patients with ADHD based on the discriminative model. MATERIALS AND METHODS: A dataset of resting state fMRI contains 23 patients with ADHD and 23 healthy subjects were analyzed. Regional homogeneity (ReHo) was extracted from resting state fMRI signals and used as model inputs. Raw ReHo features were ranked and selected in a loop according to their p values. Selected features were trained and tested by support vector machines (SVM) in a cross validation procedure. Cross validation was repeated in feature selection loop to produce optimized model. RESULTS: Optimized discriminative map indicated that the ADHD brains exhibit more increased activities than normal controls in bilateral occipital lobes and left front lobe. The altered brain regions included portions of basal ganglia, insula, precuneus, anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), thalamus, and cerebellum. Correlation coefficients indicated significant positive correlation of inattentive scores with bilateral cuneus and precuneus, and significant negative correlation of hyperactive/impulsive scores with bilateral insula and claustrum. Additionally, the optimized model produced total accuracy of 80% and sensitivity of 87%. CONCLUSION: ADHD brain regions were more activated than normal controls during resting state. Linear support vector classifier can provide useful discriminative information of altered ReHo patterns for ADHD; and feature selection can improve the performances of classification. PMID- 23684385 TI - Ovarian fibromas: MR imaging findings with emphasis on intratumoral cyst formation. AB - PURPOSE: The purpose of this study was to assess MR imaging findings of ovarian fibromas with emphasis on intratumoral cyst formation. MATERIALS AND METHODS: MR images with a 1.5-T unit obtained in 17 consecutive patients (age range, 18-87 years; mean age, 58 years) with 17 histologically proven ovarian fibromas were retrospectively reviewed for the size, configuration, signal intensity of solid components, and presence of cystic degeneration and edema within tumor. Size, number, and location of intratumoral cysts were also assessed. RESULTS: The maximum diameter of tumors ranged from 3.3 to 19.1cm (mean, 10.9 cm). Seven (41%) tumors were multinodular. On T2-weighted images, solid components of tumors were heterogeneously mixed hypo- and hyperintensity in 16 (94%) tumors. Nine (53%) tumors demonstrated cysts and 16 (94%) demonstrated edema within tumor. The maximum diameter of the largest cysts ranged from 1.0 to 13.2 cm (mean, 6.4 cm), and the number of cysts per tumor ranged from 1 to 60 (mean, 15.6). Of the nine tumors with cystic formation, the predominant location of the cysts was peripheral in five (56%), exophytic in two (22%), central (11%) in one, and diffuse in one (11%). CONCLUSION: Peripheral or exophytic cyst formation may be characteristic MR imaging features with ovarian fibromas. PMID- 23684386 TI - Safety and efficacy of radioactive seed localization with I-125 prior to lumpectomy and/or excisional biopsy. AB - PURPOSE: To evaluate the safety and efficacy of pre-operative I-125 radioactive seed localization (RSL) as an alternative to wire localization (WL). METHODS: A waiver was granted by the institutional review board for this HIPAA compliant study. Review of 356 consecutive single site nonpalpable mammographic and ultrasound guided I-125 RSLs done between November 2011 and April 2012 was conducted. Preoperative mammograms and specimen radiographs were reviewed for seed-target distance, lesion location, and target/seed removal. During a brief surgical training period, 35 of 356 women had both RSL and wire localization (WL) of the same lesion. Chi-square and single sample t-tests were used to compare margin status and duration of procedures. RESULTS: Of the 356 RSLs, 303 (85.1%) were performed >= 1 day before surgery. Mammographic guidance was used in 330 (93%) and ultrasound in 26 (7%). Mean seed to target distance was 1mm (range 0 20mm); all targeted lesions were retrieved. In 31 women in whom mammographic guidance was used for both RSL and WL, median procedure time was not significantly different (RSL 9.0 min; WL 7.0 min; p=0.91), and median seed migration distance was <1mm (range 0-15 mm). No difference was detected between margin status with RSL alone versus WL (p=0.40 and p=0.65 for positive and <1mm margins, respectively). Two adverse events occurred requiring an additional wire/surgery. CONCLUSION: RSL >= 1 day before surgery is a safe effective procedure for pre-operative localization, with few adverse events and surgical outcomes comparable to those achieved with wire localization. PMID- 23684387 TI - Age-independent co-expression of antimicrobial gene clusters in the blood of septic patients. AB - Recent research has unravelled the clinical potential of profiling the blood transcriptome to diagnose diseases. However, resulting molecular marker sets comprised features with varying robustness and performance, depending on the dimension of training data. Thus, we investigated patterns that are inherent in large-scale data and suitable for feature selection in application to blood samples from septic patients. By integrating >300 microarray samples in correlation and enrichment analysis, we found general response patterns including a vast majority of co-expressed genes. Differentially expressed genes significantly mapped to immune response-associated categories and revealed strongly correlating upregulated genes related to antimicrobial functions. Classifiers using >20 uncorrelated features from enriched functional categories performed with 85% correct classification on average (10-fold cross-validation), comparable with correlated features, whilst single genes achieved up to 83% correct classifications in identifying septic patients. Independent interplatform comparison, however, validated only a subset of these features, including the antimicrobial cluster (area under the receiver operating characteristic curve >0.8). Based on these results, we propose feature selection for classification incorporating correlation and enriched functional categories to obtain robust marker candidates. Results of this transcriptomic meta-analysis suggest age independent diagnostic opportunities, although further observational and animal interventional experiments are required to confirm the relevance of antimicrobial genes in sepsis. PMID- 23684388 TI - Pharmacokinetic/pharmacodynamic evaluation of the efficacy and safety of daptomycin against Staphylococcus aureus. AB - Daptomycin is a novel lipopeptide exhibiting concentration-dependent bactericidal activity against multidrug-resistant Gram-positive pathogens, including MRSA. Approval of daptomycin is granted at 4-6 mg/kg once daily, however off-label use of doses up to 12 mg/kg daily has been utilised without evidence of significant toxicity. Our aim was to optimise daptomycin regimens by assessing the probability of bacteriological efficacy (pTA) and toxicity (pTOX) at various MICs using Monte Carlo simulation (MCS) techniques. Population pharmacokinetic, pharmacodynamic and toxicodynamic models were developed based on current literature. MCS was performed for 10000 patients, who were assigned true weight and creatinine clearances, and were infected with four Staphylococcus aureus strains at each MIC. Bacteriostatic and bactericidal %pTA was calculated following administration of 6, 8, 10 and 12 mg/kg daptomycin; activity was deemed adequate at %pTA >= 90%. Considerable pharmacodynamic variability was observed in derived AUC/MIC targets between strains. Bacteriostatic targets were adequately attained against all strains at MIC <= 1 mg/L with daptomycin > 6 mg/kg. However, bactericidal target attainment was only achieved against all strains at the lowest MIC of 0.5 mg/L with daptomycin > 8 mg/kg. At MIC = 2 mg/kg, bactericidal target attainment was extremely poor even at the highest dose of 12 mg/kg. pTOX increased from 3.31% to 17.7% following exposure to 6 mg/kg to 12 mg/kg daily, respectively. Formal benefit:risk analyses favoured doses of 10 mg/kg against infections with MIC < 2 mg/L, whilst modest improvements in activity at 12 mg/kg could not justify the marked increase in pTOX. PMID- 23684389 TI - Identification and characterisation of small-molecule inhibitors of Rv3097c encoded lipase (LipY) of Mycobacterium tuberculosis that selectively inhibit growth of bacilli in hypoxia. AB - The mycobacterial Rv3097c-encoded lipase LipY is considered as a true lipase involved in the hydrolysis of triacylglycerol stored in lipid inclusion bodies for the survival of dormant mycobacteria. To date, orlistat is the only known LipY inhibitor. In view of the important emerging role of this enzyme, a search for small-molecule inhibitors of LipY was made, leading to the identification of some new compounds (8a-8d, 8f, 8h and 8i) with potent inhibitory activities against recombinant LipY, with no cytotoxicity [50% inhibitory concentration (CC(50)) >= 500 MUg/mL]. The compounds 6a, 8c and 8f potently inhibited (>90%) the growth of Mycobacterium tuberculosis H37Rv grown under hypoxia (oxygen depleted condition) but had no effect on aerobically grown bacilli, suggesting that these new small molecules are highly selective towards the growth inhibition of hypoxic cultures of M. tuberculosis and hence provide new leads for combating latent tuberculosis. PMID- 23684390 TI - [Multiresistant Gram-negative bacterial infections: Enterobacteria, Pseudomonas aeruginosa, Acinetobacter baumannii and other non-fermenting Gram-negative bacilli]. AB - Multiresistant Gram-negative bacteria represent a major health problem worldwide. This is related to the severity of the infections they cause, the difficulties for empiric (even directed) treatment, the ease of multiresistance spread, and the absence of new antimicrobial agents active against this group of pathogens. Accordingly, antimicrobial therapy should be based on the results of susceptibility testing, and may require using antimicrobial combinations. The production of extended-spectrum beta-lactamases represents the most important current problem of resistance among enterobacteria; these organisms cause nosocomial infections, but can also be cultured from non-hospitalised patients. In our country, enterobacteria producing plasmid-mediated AmpC enzymes or most carbapenemases are still uncommon, at the moment. Enterobacteria expressing these types of beta-lactamases present high rates of resistance to aminoglycosides and quinolones, because plasmids coding for beta-lactamases also contain other genes involved in additional resistances and/or the selection of additional chromosomal mutations. Among multiresistant Gram-negative non-fermenting bacteria, the most clinically relevant organism is Pseudomonas aeruginosa, an organism with intrinsic resistance to multiple agents and with ability to capture acquired resistance mechanisms. Other organisms in the latter group include Acinetobacter baumannii, with increasing rates of resistance to antimicrobial agents, and to a lesser extent Stenotrophomonas maltophilia. PMID- 23684391 TI - Characterization of a new and thermostable esterase from a metagenomic library. AB - A new gene encoding an esterase (designated as EstEP16) was identified from a metagenomic library prepared from a sediment sample collected from a deep-sea hydrothermal field in east Pacific. The open reading frame of this gene encoded 249 amino acid residues. It was cloned, overexpressed in Escherichia coli, and the recombinant protein was purified to homogeneity. The monomeric EstEP16 presented a molecular mass of 51.7 kDa. Enzyme assays using p-nitrophenyl esters with different acyl chain lengths as the substrates confirmed its esterase activity, yielding highest specific activity with p-nitrophenyl acetate. When p nitrophenyl butyrate was used as a substrate, recombinant EstEP16 exhibited highest activity at pH 8.0 and 60 degrees C. The recombinant enzyme retained about 80% residual activity after incubation at 90 degrees C for 6 h, which indicated that EstEP16 was thermostable. Homology modeling of EstEP16 was developed with the monoacylglycerol lipase from Bacillus sp. H-257 as a template. The structure showed an alpha/beta-hydrolase fold and indicated the presence of a typical catalytic triad. The activity of EstEP16 was inhibited by addition of phenylmethylsulfonyl fluoride, indicating that it contains serine residue, which plays a key role in the catalytic mechanism. PMID- 23684392 TI - Marijuana for diabetic control. PMID- 23684393 TI - The impact of marijuana use on glucose, insulin, and insulin resistance among US adults. AB - BACKGROUND: There are limited data regarding the relationship between cannabinoids and metabolic processes. Epidemiologic studies have found lower prevalence rates of obesity and diabetes mellitus in marijuana users compared with people who have never used marijuana, suggesting a relationship between cannabinoids and peripheral metabolic processes. To date, no study has investigated the relationship between marijuana use and fasting insulin, glucose, and insulin resistance. METHODS: We included 4657 adult men and women from the National Health and Nutrition Examination Survey from 2005 to 2010. Marijuana use was assessed by self-report in a private room. Fasting insulin and glucose were measured via blood samples after a 9-hour fast, and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated to evaluate insulin resistance. Associations were estimated using multiple linear regression, accounting for survey design and adjusting for potential confounders. RESULTS: Of the participants in our study sample, 579 were current marijuana users and 1975 were past users. In multivariable adjusted models, current marijuana use was associated with 16% lower fasting insulin levels (95% confidence interval [CI], 26, -6) and 17% lower HOMA-IR (95% CI, -27, -6). We found significant associations between marijuana use and smaller waist circumferences. Among current users, we found no significant dose-response. CONCLUSIONS: We found that marijuana use was associated with lower levels of fasting insulin and HOMA-IR, and smaller waist circumference. PMID- 23684394 TI - What patients' problems do nurses e-chart? Longitudinal study to evaluate the usability of an interface terminology. AB - BACKGROUND: The nurses' ability to document patient's status, problems and progress is an important issue in patients' safety. Nursing terminologies are intended to support nursing practice but as any other clinical tool, they should be evaluated to assure quality and warrant effective written communication among clinicians. OBJECTIVES: This study was aimed to evaluate the usability of the diagnosis axis of an interface terminology by assessing its completeness and the frequency of use of its concepts. DESIGN: Observational, longitudinal, multicentre study. SETTING: A total of 8 hospitals representing 162 acute medical surgical, obstetric and mental health nursing wards, step-down units and home in patient units were included. PARTICIPANTS: Overall, 246,400 electronic care plans were studied; 53.5% from male patients; 14.6% paediatrics and 33.7% from patients elder than 70 years old. Most were admitted due to cardiocirculatory, respiratory, digestive or musculoskeletal conditions (50.5%), other acute medical or surgical disorders (29.8%) and obstetrics (19.3%). METHODS: The main outcome measures were: the use of nursing diagnoses from the interface terminology evaluated and their accumulated frequency, analysed over a 3-year retrospective review of the electronic nursing care plans. The analysis of data included descriptive statistics with a confidence level of 95% for confidence intervals. RESULTS: Most of the diagnostic concepts from the interface terminology were used (92.3%) by nurses to illustrate patients' problems in the electronic care plans. Their frequency of use widely varied, from some very frequent diagnoses like Risk for haemorrhage (51.4%; CI 95%: 51.25-51.65) or Acute pain (49.6%; CI: 49.49 49.88) to others used only in exceptional cases like Faecal impaction or Extravasation. The first nursing diagnosis related to family or caregiver emerges in the 32nd place of the ranking. CONCLUSIONS: Results for outcome measures oriented that the diagnosis axis of this interface terminology meets the usability criterion of completeness when assessing for the use of its concepts in the acute care setting. PMID- 23684395 TI - Surgery in young adults with inflammatory bowel disease: a narrative account. AB - BACKGROUND: Inflammatory Bowel Disease comprises two major intestinal disorders, Crohn's Disease and Ulcerative Colitis. When medical management cannot control the disease, surgery is necessary. Having an operation is a major concern for young people with Inflammatory Bowel Disease. Some may try to avoid or defer it. Despite this, afterwards they may have a significant improvement in quality of life. OBJECTIVES: The aim of the study was to explore the experiences of young people with Inflammatory Bowel Disease who have had, or are about to have, surgery for their condition. DESIGN AND METHOD: Narrative study using semi structured interviews. PARTICIPANTS: Twenty-four young adults aged between 18 and 25 (11 male and 13 female) with Inflammatory Bowel Disease who had undergone or were awaiting surgery from one tertiary referral centre in the United Kingdom. FINDINGS: Key factors that affected young people as they approached and adjusted to an operation were elicited which provided an understanding of this change in their lives from their own perspective. The prospect of having an operation, particularly the fear of a stoma, generated anxiety and concern for many of these young people. As young adults, participants tended to want to be involved in deciding when their surgery should occur and to have their opinions considered. The data revealed the different types of support that were given to these participants, what they found helpful and the function that they served. Gender differences were identified in the nature of support required from partners and in body image concerns. Issues and concerns were identified which can be addressed in clinical nursing practice to prepare young adults for this life changing event. These helped to explain how young people viewed the prospect, impact and experience of surgery. CONCLUSION: The findings of this study revealed new information relating to the experience of surgery in young adults with Inflammatory Bowel Disease including their perceptions of the event itself, their decision making, their greatest concerns, the support they require and their ways of coping. Since there is little published work regarding how surgery affects this particular patient group, the study should be of interest to specialist nurses who are closely involved in the care of young adults with Inflammatory Bowel Disease. PMID- 23684396 TI - Philematology: the science of kissing. A message for the marital month of june. PMID- 23684397 TI - A surfeit of possibilities: nonhealing ulcers. PMID- 23684398 TI - Challenges with continuity clinic and core faculty accreditation requirements. PMID- 23684399 TI - A mysterious case of dysphagia demystified by medication reconciliation. PMID- 23684400 TI - The reply. PMID- 23684401 TI - Increased mortality in geriatric patients with hospital-acquired hypernatremia. PMID- 23684402 TI - The reply. PMID- 23684403 TI - Heart failure: predictive ability of edema for volume overload. PMID- 23684404 TI - The reply. PMID- 23684405 TI - Prescribe escitalopram instead of citalopram. PMID- 23684406 TI - The reply. PMID- 23684407 TI - Risk assessment of longevity for oldest old people by a prospective study. PMID- 23684408 TI - Endogenous IL-1alpha is a chromatin-associated protein in mouse macrophages. AB - The cytokine interleukin-1alpha (IL-1alpha) is synthesized as a 31kDa peptide that lacks a leader peptide and is not secreted by the conventional secretory pathway. A distinctive characteristic of pro-IL-1alpha is the presence of a nuclear localization sequence in its amino-terminal moiety that allows its translocation to the nucleus. However no nuclear function(s) of the endogenous pro-IL-1alpha has been reported to date. In the present study, we used murine macrophages that produce IL-1alpha in response to pro-inflammatory stimuli, to gain further insight into the biology of the endogenous IL-1alpha protein in innate immune cells. We show that endogenous IL-1alpha is essentially found as a chromatin-associated nuclear protein in LPS-stimulated macrophages. In contrast to IL-1beta, IL-1alpha was not released upon inflammasome activation unless significant cell damage occurred. IL-1beta mRNA and protein levels were specifically decreased in IL-1alpha deficient macrophages after LPS stimulation. However, overexpression of human pro-IL-1alpha did not rescue this defective IL 1beta production, suggesting that this finding might be related to the insertion of the targeting construct into the IL-1 locus, rather than to a specific nuclear function of pro-IL-1alpha. Finally, by using both genomic and proteomic approaches, we could not identify a nuclear function of IL-1alpha. Taken together, these observations suggest that in macrophages IL-1alpha primarily acts as an alarmin that is rapidly released upon cell damage to activate early mechanisms of host defense. PMID- 23684409 TI - Transcriptional profiling and pathway analysis of CSF-1 and IL-34 effects on human monocyte differentiation. AB - CSF-1 is the well-known ligand for CSF-1R, which plays a vital role in monocyte macrophage generation, survival, and function. IL-34 is a newly discovered cytokine that also signals through CSF-1R. Although there are limited data for downstream signaling and pathway activation for CSF-1, none are published, to date, for expression profiles of IL-34. The objective of this study was to characterize and compare the signaling pathways downstream of the CSF-1R receptor, based on these two ligands. This was accomplished through transcriptional profiling and pathway analysis of CD14(+) human monocytes differentiated with each ligand. Additionally, cells were treated with a CSF-1R inhibitor GW2580 to establish that observations associated with each ligand were CSF-1R mediated. Gene expression profiles were generated for each condition using Agilent 4x44K Whole Human Genome Microarrays. Overall profiles generated by each cytokine were similar (~75% of genes) with a dampened effect noted on some pathways (~25% of genes) with IL-34. One key difference observed, between the two cytokines was in the repression of CCR2 message. A similar divergence in protein level was established by FACS analysis. The differential effect on CCR2 expression has major implications for monocyte/macrophage biology including homeostasis and function. Further study of IL-34 effects on monocyte/macrophage biology will shed light on the specific role each ligand plays and the context in which these roles are important. To our knowledge, this study is the first to illustrate downstream transcriptional profiles and pathways of IL-34 in comparison with CSF-1 and identify notable differences in CCR2 expression. PMID- 23684410 TI - Zooming in on the schedule of bone-modifying drugs. PMID- 23684412 TI - Technical considerations and results of chimney grafts for the treatment of juxtarenal aneursyms. AB - OBJECTIVE: To present our initial experience and technical considerations for the use of chimney grafts in the treatment of patients that require endovascular aneurysm repair with aortic branch preservation. METHODS: All patients treated with a chimney procedure between October 2009 and June 2011 were included in our analyses. Chimney procedures were only performed in patients that were unsuitable for open repair and without opportunity to use fenestrated grafts (because of unsuitable anatomy or emergency operation). Open brachial or axillary access was used to deploy covered chimney grafts in the target vessels, and subsequently, a stent graft was deployed via femoral cut-down access. RESULTS: Thirteen patients (12 males; mean age, 77.2 +/- 6.2 years; mean maximal diameter, 71.4 +/- 10.2 mm) underwent a chimney procedure with the preservation of 22 aortic side branches. Primary technical success was 92.3% due to occlusion of one renal artery within 24 hours. Thirty-day mortality was 0%. Infrarenal mean neck length was 2.6 mm +/- 3.2 mm (range, 0-8 mm) and could be extended to 27.3 mm +/- 9.9 mm (range, 18-53 mm) by the use of chimney grafts. During follow-up (median, 10.8 months; interquartile range, 7.4-19.4), one patient died from complications from mesenteric ischemia based on a stenosis of the celiac trunk attributable to the bare stent of the stent graft, and one patient died from aneurysm rupture. Other complications included late occlusion of one renal artery and a type II endoleak, which was unsuccessfully treated with coil embolization and required laparotomy. If we disregard the ruptured patient who had an enormous increase of aneurysm diameter, mean aortic aneurysm diameter reduced from 70.7 +/- 10.3 mm (range, 54 89 mm) to 66.7 +/- 13.9 mm (range, 48-96 mm) during follow-up (P = .13). In three patients, the aneurysm diameter decreased by more than 5 mm and in two patients, the diameter increased by more than 5 mm. The aneurysm diameter remained stable in the other eight patients. CONCLUSIONS: Until off-the-shelf fenestrated or branched stent grafts become available, the chimney procedure offers a minimally invasive treatment option in patients requiring aneurysm exclusion with side branch revascularization. Although long-term follow-up has to be awaited, the initial results show that chimney grafts can help to decrease or stabilize the aneurysm diameter in most patients, but aneurysm rupture was not prevented in all patients. PMID- 23684411 TI - Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority trial. AB - BACKGROUND: Zoledronic acid reduces skeletal-related events in patients with breast cancer, but concerns have been raised about prolonged monthly administration. We assessed the efficacy and safety of a reduced dosing frequency of zoledronic acid in women treated previously with monthly zoledronic acid. METHODS: We did this non-inferiority, phase 3 trial in 62 centres in Italy. We enrolled patients with breast cancer who had one or more bone metastases and had completed 12-15 months of monthly treatment with zoledronic acid. Patients were randomly assigned with a permutated block (size four to eight) random list stratified by centre in a 1:1 ratio to zoledronic acid 4 mg once every 12 weeks or once every 4 weeks, and followed up for at least 1 year. Neither patients nor investigators were masked to treatment allocation. The primary outcome was skeletal morbidity rate (skeletal-related events per patient per year) in the intention-to-treat population. We used a non-inferiority margin of 0.19. The trial is registered with EudraCT, number 2005-004942-15. FINDINGS: We screened 430 patients and enrolled 425, of whom 209 were assigned to the 12-week group and 216 to the 4-week group. The skeletal morbidity rate was 0.26 (95% CI 0.15-0.37) in the 12-week group versus 0.22 (0.14-0.29) in the 4-week group. The between group difference was 0.04 and the upper limit of one-tailed 97.5% CI was 0.17, which is lower than the non-inferiority margin. The most common grade 3-4 adverse events were bone pain (56 [27%] patients in the 12-week group vs 65 [30%] in the 4-week group), nausea (24 [11%] vs 33 [15%]), and asthenia (18 [9%] vs 33 [15%]). Renal adverse events occurred in one patient (<1%) in the 12-week group versus two (1%) in the 4-week group. One patient (<1%) in the 4-week group had grade 1 acute renal failure. Osteonecrosis of the jaw occurred in four patients in the 12 week group versus three in the 4-week group. No treatment-related deaths were reported. Median N-terminal telopeptide concentration changed from baseline more in the 12-week group than in the 4-week group after 12 months (12.2% vs 0.0%; p=0.011). INTERPRETATION: Our results raise the possibility of decreasing administration of zoledronic acid to a 12-weekly regimen to reduce exposure during the second year, while maintaining its therapeutic effects. However, the effects on N-terminal telopeptide should be investigated further before changing current practice. FUNDING: Novartis Farma. PMID- 23684413 TI - Balloon-assisted over-the-wire technique for placement of the venous outflow component of the Hemodialysis Reliable Outflow (HeRO) device. AB - A modified technique for placement of the venous outflow component (VOC) of the Hemodialysis Reliable Outflow (HeRO) device (Hemosphere Inc, Minneapolis, Minn) is described. The purpose of the technique is to improve the system's trackability and facilitate device insertion in patients with central venous occlusion. Device preparation requires placement of a 6-mm * 4-cm angioplasty balloon within the leading end of the VOC. The leading 2 cm of the balloon are placed just distal to the radiopaque marker of the VOC. The balloon is inflated to profile and locked in this position within the leading end of the VOC. The VOC and balloon combination is advanced over the wire through the 20F peel-away sheath provided by the manufacturer. The described technique was used to successfully implant the HeRO device in 12 patients with central venous occlusion. This technique is recommended for placement of the VOC of the HeRO device in patients with central venous occlusions. PMID- 23684414 TI - Association of clinical attributes and treadmill walking performance in patients with claudication due to peripheral artery disease. AB - BACKGROUND: Patients with claudication secondary to peripheral artery disease have a substantial impairment in walking capacity. This study evaluated factors suspected to be correlated with treadmill walking performance in an effort to gain insights into the pathophysiology of the impairment. METHODS: A multivariate model was developed to define the associations between clinical and laboratory biomarkers with treadmill peak walking time (PWT) in patients enrolled in three clinical trials. The model was initially developed in a cohort of 385 patients from one trial using 23 candidate-independent variables and then tested in the combined data from the other two trials (351 patients). RESULTS: The final model was built from 14 variables that met the predefined univariate criteria of P < .15. Main effects remaining in the model were age, resting ankle-brachial index, smoking status, hypertension, statin use, country (United States vs non-United States countries), and high-sensitivity C-reactive protein. The model was highly statistically significant (P < .0001) but explained only a limited portion of the population heterogeneity (r(2) = 0.173). The main effects plus interaction terms had an r(2) = 0.2178. The main effects model was tested in an independent cohort of 351 patients from two other clinical trials in peripheral arterial disease that did not include high-sensitivity C-reactive protein. The model successfully fit the data set, based on prospectively defined root mean squared error and was statistically significant (P = .0005) but had lower overall explanatory power than in the index cohort (r(2) = 0.0687). CONCLUSIONS: As expected, age and ankle brachial index contributed to exercise limitation among patients with PAD. The association of C-reactive protein, hypertension, and smoking with PWT is consistent with a role for inflammation or oxidative stress in determining treadmill walking performance. In contrast to previous reports from smaller and more homogenous populations, clinical attributes and biomarkers explain only a small portion of PWT heterogeneity. PMID- 23684415 TI - What's in a name? Measures, indicators, and consequences in pediatric prescribing. PMID- 23684416 TI - Original research: postpartum testing rates among women with a history of gestational diabetes--systematic review. AB - AIMS: Gestational diabetes mellitus (GDM) is increasing and 30% have persistent postpartum dysglycemia. Reported compliance with recommended postpartum testing ranges 9-95% without a clear explanation for this wide variation. Small and conflicting differences in testing rates are associated with some demographics (race, use of insulin), but system factors likely play a larger role. A systematic literature review was performed to identify system based factors that could explain the broad variation in postpartum GDM testing rates. METHODS: Original articles reporting postpartum testing rates among women with GDM were identified within PubMed, OVID, EMBASE, and the Cochrane Database of systematic reviews. Articles that did not report rates for the entire GDM cohort were excluded. RESULTS: 54/307 citations met inclusion criteria. The use of proactive patient contact programs increased postpartum testing rates from an average of 33% (range 9-71%) up to 60% (range 14-95%). CONCLUSIONS: Proactively contacting patients via phone calls, education programs, or postal reminders was associated with higher postpartum testing rates. Rather than working to identifying individual demographic factors, systems based approaches were associated with a larger potential impact, and appear easily generalizable. Clinicians should think beyond individual habits and consider systematic approaches to improving testing rates. PMID- 23684418 TI - Toscana virus inhibits the interferon beta response in cell cultures. AB - Toscana virus (TOSV) is an emerging pathogen in the Mediterranean basin where it causes summertime outbreaks of aseptic meningitis and meningoencephalitis. Many aspects of TOSV biology remain unknown including the possible implication of an amplifying mammalian host besides its vector. The three experiments described here were designed to assess the relationship between TOSV and type-I interferon (IFN) response. The main findings were as follows. First, TOSV growth in Vero cells is sensitive to an antiviral state induced by low-dose addition of exogenous IFN beta (IFN-beta) (10IU/ml). Second, no IFN-beta mRNA or IFN-beta was detectable after infection of HeLa and 293T cells by TOSV. Finally, TOSV inhibits IFN-beta production induced by Sendai virus, a well known inducer of IFN-beta production. In addition to showing that TOSV can inhibit the IFN-beta response, these findings suggest that anti-IFN capability is maintained by regular contact with that of a mammalian host. PMID- 23684417 TI - Pathogenesis of Lassa fever virus infection: I. Susceptibility of mice to recombinant Lassa Gp/LCMV chimeric virus. AB - Lassa virus (LASV) is a BSL-4 restricted agent. To allow study of infection by LASV under BSL-2 conditions, we generated a recombinant virus in which the LASV glycoprotein (Gp) was placed on the backbone of lymphocytic choriomeningitis virus (LCMV) Cl13 nucleoprotein, Z and polymerase genes (rLCMV Cl13/LASV Gp). The recombinant virus displayed high tropism for dendritic cells following in vitro or in vivo infection. Inoculation of immunocompetent adults resulted in an acute infection, generation of virus-specific CD8(+) T cells and clearance of the infection. Inoculation of newborn mice with rLCMV Cl13/LASV Gp resulted in a life long persistent infection. Interestingly, adoptive transfer of rLCMV Cl13/LASV Gp immune memory cells into such persistently infected mice failed to purge virus but, in contrast, cleared virus from mice persistently infected with wt LCMV Cl13. PMID- 23684419 TI - Liver enzymes and type 2 diabetes: a complex two-way relationship. PMID- 23684420 TI - Sound localization with bilateral cochlear implants in noise: how much do head movements contribute to localization? AB - Bilateral cochlear implant (CI) users encounter difficulties in localizing sound sources in everyday environments, especially in the presence of background noise and reverberation. They tend to show large directional errors and front-back confusions compared to normal hearing (NH) subjects in the same conditions. In this study, the ability of bilateral CI users to use head movements to improve sound source localization was evaluated. Speech sentences of 0.5, 2, and 4.5 seconds were presented in noise to the listeners in conditions with and without head movements. The results show that for middle and long signal durations, the CI users could significantly reduce the number of front-back confusions. The angular accuracy, however, did not improve. Analysis of head trajectories showed that the CI users had great difficulties in moving their head towards the position of the source, whereas the NH listeners targeted the source loudspeaker correctly. PMID- 23684421 TI - High-dose bevacizumab in the treatment of patients with advanced clear cell renal carcinoma: a phase II trial of the Sarah Cannon Oncology Research Consortium. AB - BACKGROUND: The dose of bevacizumab necessary to optimally inhibit tumor angiogenesis in advanced renal cell carcinoma is unknown. In this phase II trial, we evaluated the efficacy and safety of 2 escalated doses of bevacizumab in patients with advanced clear cell renal carcinoma. PATIENTS AND METHODS: Eligible patients had metastatic or locally advanced unresectable clear cell renal carcinoma. Patients who were previously untreated or who had previously received vascular endothelial growth factor receptor (VEGFR)-targeted therapy were eligible and were considered separately in the efficacy evaluation. Two doses of bevacizumab were evaluated in sequential cohorts: 15 mg/kg every 2 weeks and 15 mg/kg weekly. The initial reevaluation was at 8 weeks; responding and stable patients continued treatment, with reevaluations every 8 weeks until tumor progression or unacceptable toxicity occurred. RESULTS: One hundred nineteen eligible patients were enrolled and received bevacizumab 15 mg/kg every 2 weeks (n = 61) or bevacizumab 15 mg/kg weekly (n = 58). Seventy patients were previously untreated with VEGFR-targeted therapy. In previously untreated patients, the overall response rate was 19%, with a median progression-free survival (PFS) of 7.8 months. Less activity was seen in patients previously treated with VEGFR-targeted agents (overall response rate, 4%; median PFS, 3.7 months). There was no suggestion of any difference in efficacy between the 2 dose levels tested. Both dose levels were tolerated well by most patients, with a spectrum of toxicity typical for bevacizumab. Grade 3/4 proteinuria was more frequent with both of these escalated doses, particularly with 15 mg/kg weekly. CONCLUSION: Although administration of escalated doses of bevacizumab was feasible in patients with advanced clear cell renal carcinoma, there was no suggestion that these doses were more efficacious than bevacizumab administered at the standard dose of 10 mg/kg every 2 weeks. PMID- 23684422 TI - Prognostic factors of survival for patients with metastatic renal cell carcinoma with brain metastases treated with targeted therapy: results from the international metastatic renal cell carcinoma database consortium. AB - BACKGROUND: The outcomes and prognosis of patients with brain metastases from advanced renal cell carcinoma (RCC) are not well characterized in the targeted therapy era. METHODS: Data from patients with metastatic RCC (mRCC) and brain metastases treated with targeted therapy were collected through the International Metastatic Renal Cell Carcinoma Database Consortium from 7 cancer centers. RESULTS: Overall, 106 (15%) of 705 patients with mRCC had brain metastases. Forty seven patients had brain metastases at the start of first-line anti-vascular endothelial growth factor therapy, and the rest developed metastases during follow-up. Of the patients with brain metastases, 12%, 42% and 29% were in the favorable, intermediate, and poor prognosis groups, respectively, per the Heng criteria. Ninety percent had cerebral metastases, 17% had cerebellar metastases, 37% had a Karnofsky performance status (KPS) <80%, and 80% had neurologic symptoms at presentation. The median largest size and number of brain metastases was 1.8 cm (range, 0.2-6.6 cm) and one (range, 1 to innumerable), respectively. The patients were treated with sunitinib (n = 77), sorafenib (n = 23), bevacizumab (n = 5), and temsirolimus (n = 1). Local disease treatment included whole brain radiotherapy (81%), stereotactic radiosurgery (25%), and neurosurgery (25%). On multivariable analysis, KPS < 80%, diagnosis to treatment with targeted therapy <1 year, and a higher number of brain metastases (>4) was associated with worse survival from the time of diagnosis with brain metastases. CONCLUSIONS: Patients with brain metastases from RCC are unlikely to be in the favorable risk group. KPS at the start of therapy, diagnosis to treatment time, and the number of brain metastases are prognostic factors for overall survival. PMID- 23684423 TI - The BAFF/APRIL system: emerging functions beyond B cell biology and autoimmunity. AB - The BAFF system plays a key role in the development of autoimmunity, especially in systemic lupus erythematosus (SLE). This often leads to the assumption that BAFF is mostly a B cell factor with a specific role in autoimmunity. Focus on BAFF and autoimmunity, driven by pharmaceutical successes with the recent approval of a novel targeted therapy Belimumab, has relegated other potential roles of BAFF to the background. Far from being SLE-specific, the BAFF system has a much broader relevance in infection, cancer and allergy. In this review, we provide the latest views on additional roles of the BAFF system in health and diseases, as well as an update on BAFF and autoimmunity, with particular focus on current clinical trials. PMID- 23684424 TI - Impact of hospital market competition on endovascular aneurysm repair adoption and outcomes. AB - OBJECTIVE: The share of total abdominal aortic aneurysm (AAA) repairs performed by endovascular aneurysm repair (EVAR) increased rapidly from 32% in 2001 to 65% in 2006 with considerable variation between states. We hypothesized that hospitals in competitive markets were early EVAR adopters and had improved AAA repair outcomes. METHODS: Nationwide Inpatient Sample and linked Hospital Market Structure (HMS) data was queried for patients who underwent repair for nonruptured AAA in 2003. In HMS, the Herfindahl Hirschman Index (HHI, range 0-1) is a validated and widely accepted economic measure of competition. Hospital markets were defined using a variable geographic radius that encompassed 90% of discharged patients. We conducted bivariate and multivariable linear and logistic regression analyses for the dependent variable of EVAR use. A propensity score adjusted multivariable logistic regression model was used to control for treatment bias in the assessment of competition on AAA repair outcomes. RESULTS: A weighted total of 21,600 patients was included in our analyses. Patients at more competitive hospitals (lower HHI) were at increased odds of undergoing EVAR vs open repair (odds ratio, 1.127 per 0.1 decrease in HHI; P < .0127) after adjusting for patient demographics, comorbidities, and hospital level factors (bed size, teaching status, AAA repair volume, and ownership). Competition was not associated with differences in in-hospital mortality or vascular, neurologic, or other minor postoperative complications. CONCLUSIONS: Greater hospital competition is significantly associated with increased EVAR adoption at a time when diffusion of this technology passed its tipping point. Hospital competition does not influence post-AAA repair outcomes. These results suggest that adoption of novel vascular technology is not solely driven by clinical indications but may also be influenced by market forces. PMID- 23684425 TI - Vascular remodeling and intimal hyperplasia in a novel murine model of arteriovenous fistula failure. AB - OBJECTIVE: The arteriovenous fistula (AVF) still suffers from a high number of failures caused by insufficient outward remodeling and intimal hyperplasia (IH) formation from which the exact mechanism is largely unknown. A suitable animal model is of vital importance in the unraveling of the underlying pathophysiology. However, current murine models of AVF failure do not incorporate the surgical configuration that is commonly used in humans. Because the hemodynamic profile is one of the key determinants that play a role in vascular remodeling in the AVF, it is preferable to use this same configuration in an animal model. Here we describe a novel murine model of AVF failure in which the configuration (end-to side) is similar to what is most frequently performed in humans. METHODS: An AVF was created in 45 C57BL/6 mice by anastomosing the end of a branch of the external jugular vein to the side of the common carotid artery with interrupted sutures. The AVFs were harvested and analyzed histologically at days 7, 14, and 28. Identical veins of unoperated-on mice served as controls. Intravenous near infrared fluorescent fluorophores were used to assess the patency of the fistula. RESULTS: The patency rates at days 7, 14, and 28 days were 88%, 90%, and 50%, respectively. The mean circumference increased up to day 14, with a maximum 1.4 fold increase at day 7 compared with the control group (1.82 +/- 0.7 vs 1.33 +/- 0.3 mm; P = .443). Between days 14 and 28, the circumference remained constant (2.36 +/- 0.2 vs 2.45 +/- 0.2 mm; P = .996). At 7 days after surgery, the intimal area consisted mainly of an acellular layer that was structurally analogous to a focal adherent thrombus. Starting at 14 days after surgery, venous IH increased significantly compared with the unoperated-on group (14 days: 115,090 +/- 22,594 MUm(2), 28 days: 234,619 +/- 47,828 MUm(2), unoperated group: 2368 +/- 1056 MUm(2); P = .001 and P < .001, respectively) and was mainly composed of cells positive for alpha-smooth muscle actin. We observed leukocytes in the adventitial side of the vein at all time points. CONCLUSIONS: Our novel murine AVF model, which incorporates a clinically relevant configuration of the anastomosis, displays similar features that are characteristic of failing human AVFs. Moreover, our findings suggest that coagulation and inflammation could both potentially play an important role in the formation of IH and subsequent AVF failure. Near-infrared fluoroscopy was a suitable alternative for conventional imaging techniques. This murine AVF-model is a valuable addition to the AVF animal model arsenal. PMID- 23684426 TI - Silver acetate coating promotes early vascularization of Dacron vascular grafts without inducing host tissue inflammation. AB - BACKGROUND: Silver acetate is frequently used as an antimicrobial coating of prosthetic vascular grafts. However, the effects of this coating on the early inflammatory and angiogenic host tissue response still remain elusive. Therefore, the aim of the present in vivo study was to analyze the biocompatibility and vascularization of silver acetate-coated and uncoated vascular grafts during the initial phase after implantation. METHODS: Two different prosthetic vascular grafts (ie, uncoated Dacron and silver acetate-coated Dacron Silver) were implanted into the dorsal skinfold chamber of C57BL/6 mice (n = 8 per group) to study angiogenesis and leukocytic inflammation at the implantation site by means of repetitive intravital fluorescence microscopy over a 14-day period. At the end of the in vivo experiments, collagen formation, apoptosis, and cell proliferation were analyzed in the newly developed granulation tissue surrounding the implants by histology and immunohistochemistry. RESULTS: During the initial 14 days after implantation, Dacron Silver exhibited an improved vascularization, as indicated by a significantly increased functional capillary density compared with Dacron. This was not associated with a stronger leukocytic inflammatory host tissue response to the implants. Moreover, silver acetate coating did not affect collagen formation, apoptosis, and cell proliferation at the implantation site. CONCLUSIONS: Silver acetate coating of prosthetic vascular grafts improves their early vascularization without inducing severe inflammatory side effects. Accordingly, this material modification crucially contributes to an improved incorporation of the implants into the host tissue, which may decrease the risk of vascular graft infection. PMID- 23684428 TI - Study of the heat transfer in solids using infrared photothermal radiometry and simulation by COMSOL Multiphysics. AB - It is reported the study of the heat transfer through a homogeneous and isotropic solid exited by square periodic light beam on its front surface. For this, we use the Infrared Photothermal Radiometry in order to obtain the evolution of the temperature difference on the rear surface of three samples, silicon, copper and wood, as a function of the exposure time. Also, we solved the heat transport equation for this problem with the boundary conditions congruent with the physical situation, by means of numerical simulation based in finite element analysis. Our results show a good agreement between the experimental and numerical simulated results, which demonstrate the utility of this methodology for the study of the thermal response of solids. PMID- 23684429 TI - Determination of neutron fluence-to-dose conversion coefficients by means of artificial neural networks. AB - An Artificial Neural Network has been designed to determinate the effective dose, the ambient dose equivalent and the personal dose equivalent fluence-to-dose conversion factors using seven count rates obtained with a Bonner Sphere Spectrometer. The data of 211 neutron spectra and their respective fluence-to dose conversion coefficients were used to train and to test ANN. The ANN was trained using the trainsec algorithm, the definitive ANN was 7:8:9:10. From the 30 set of data used to test the ANN performance the largest difference was 11% that is close to the difference obtained in neutron dosimetry. PMID- 23684427 TI - Ca2+ signaling in human induced pluripotent stem cell-derived cardiomyocytes (iPS CM) from normal and catecholaminergic polymorphic ventricular tachycardia (CPVT) afflicted subjects. AB - Derivation of cardiomyocytes from induced pluripotent stem cells (iPS-CMs) allowed us to probe the Ca(2+)-signaling parameters of human iPS-CMs from healthy and catecholaminergic polymorphic ventricular tachycardia (CPVT1)-afflicted individuals carrying a novel point mutation p.F2483I in ryanodine receptors (RyR2). iPS-CMs were dissociated on day 30-40 of differentiation and patch clamped within 3-6 days. Calcium currents (ICa) averaged ~8pA/pF in control and mutant iPS-CMs. ICa-induced Ca(2+)-transients in control and mutant cells had bell-shaped voltage-dependence similar to that of ICa, consistent with Ca(2+) induced Ca(2+)-release (CICR) mechanism. The ratio of ICa-activated to caffeine triggered Ca(2+)-transients was ~0.3 in both cell types. Caffeine-induced Ca(2+) transients generated significantly smaller Na(+)-Ca(2+) exchanger current (INCX) in mutant cells, reflecting their smaller Ca(2+)-stores. The gain of CICR was voltage-dependent as in adult cardiomyocytes. Adrenergic agonists enhanced ICa, but differentially altered the CICR gain, diastolic Ca(2+), and Ca(2+)-sparks in mutant cells. The mutant cells, when Ca(2+)-overloaded, showed longer and wandering Ca(2+)-sparks that activated adjoining release sites, had larger CICR gain at -30mV yet smaller Ca(2+)-stores. We conclude that control and mutant iPS CMs express the adult cardiomyocyte Ca(2+)-signaling phenotype. RyR2 F2483I mutant myocytes have aberrant unitary Ca(2+)-signaling, smaller Ca(2+)-stores, higher CICR gains, and sensitized adrenergic regulation, consistent with functionally altered Ca(2+)-release profile of CPVT syndrome. PMID- 23684430 TI - VEGF induces TGF-beta1 expression and myofibroblast transformation after glaucoma surgery. AB - Subconjunctival fibrosis at the surgical site determines the outcome of glaucoma surgery. Myofibroblast transformation has a significant role in fibrosis, and vascular endothelial growth factor (VEGF) is reported to trigger myofibroblast transformation by inducing transforming growth factor (TGF)-beta1. In the present study, we used IHC, Western blot analysis, enzyme-linked immunosorbent assay, and electron microscopy to determine the contribution of VEGF to myofibroblast transformation in subconjunctival fibrosis after glaucoma surgery. A rabbit trabeculectomy model was generated, and VEGF stimulation or VEGF inhibition was performed during surgery. VEGF stimulation induced TGF-beta1 expression in a dose dependent manner. Down-regulation of epithelial markers (E-cadherin and beta catenin) and up-regulation of mesenchymal marker (alpha-smooth muscle actin) were observed in the subconjunctival layers after trabeculectomy with VEGF stimulation. Up-regulations of Smad and Snail, which play a central role in myofibroblast transformation, were observed in the conjunctival and subconjunctival layers at the site of trabeculectomy. Electron microscopy revealed changes of the conjunctival epithelial cells, especially the presence of myofilaments and increased rough endoplasmic reticulum in the cytoplasm. Myofibroblast transformation was activated by VEGF stimulation and decreased by VEGF inhibition. These findings suggest that VEGF potentially affected the TGF beta1/Smad/Snail pathway, thereby triggering myofibroblast transformation. Therapeutic approaches modulating VEGF may control myofibroblast transformation and reduce subconjunctival fibrosis after glaucoma surgery. PMID- 23684431 TI - [Labour epidural analgesia for a parturient with a factor XI deficiency: an ill considered challenge or a reasonable risk?]. AB - The authors report the performance of a labour epidural analgesia in a 26-year old parturient presenting a moderate factor XI (FXI) deficiency. If haemostasis disorders usually contraindicate an epidural analgesia (with a risk of epidural haematoma), a moderate FXI deficiency is not an absolute contraindication to perform such an epidural analgesia. Desmopressin, sometimes used in surgery to reduce the bleeding, was administered to withdraw the catheter in better haemostasis conditions. No neurological signs were observed. PMID- 23684432 TI - [How do residents in anesthesiology learn their future speciality? A resident satisfaction survey in the Northwest of France]. AB - STUDY DESIGN: Opinion survey. OBJECTIVES: To know the level of satisfaction and the expectations of the residents in anesthesiology in the Northwest of France. MATERIALS AND METHODS: A standardized questionnaire assessing the theoretical and practical training was mailed to the 4th- and 5th-year anesthesiology residents (DESAR 4 and 5) in the Northwest of France over a 6-month period. Four items were studied: the profile of responders, the approval of theoretical and practical teaching, and the improvement propositions. RESULTS: The response rate was 61%. A change in speciality has never been looked for by 95% of residents. The training was considered as good or very good in 90% of cases. The elements of theoretical teaching are variably considered according to their merits. Practical training gave entire satisfaction whatever its type and place. Additional specific training in regional anesthesia, difficult intubation and echocardiography is required. Most DESAR would be interested in obtaining a post-internship job or a stage in private hospitals. DISCUSSION: Teaching generally meets the expectations of students. These regional data are similar with the results of French national surveys. They highlight the good quality of training but suggest it could be further improved. CONCLUSION: The homogeneity of teaching, based on the objectives proposed by the French College of Anesthesiologists, and the dynamism of the French Society of Anesthesiology and Critical Care Medicine ensures the quality of training for future specialists. PMID- 23684433 TI - [Ambulatory emergency surgery: still moving toward another step!]. PMID- 23684434 TI - Survivors' experiences of media coverage after traumatic injury events. AB - Survivors' experiences of media at traumatic events, is still a limited research area. The aim of this study is to explore survivors' experiences of interacting with journalists and media coverage, including their experiences of being portrayed in the media, following two Swedish train crashes. Qualitative interviews were conducted with passengers from two train crashes in Sweden. A qualitative content analysis generated meaning units, subcategories, and categories. Survivors experienced interacting with journalists mainly in three ways: harmful, inconsequential, and helpful. Media content and personal media exposure was experienced in a similar way: uncomfortable, insignificant, and useful. Journalists and media coverage have a large impact on survivors' experiences following a traumatic event. It is important that emergency responders, such as ambulance nurses, are aware of how victims are affected by journalists' presence and the media coverage that follows so that negative outcomes can be reduced and the positive can be enhanced. The present study also shows that media coverage in the long term can become important pieces of information for the victim in order to understand and process the traumatic event. PMID- 23684436 TI - Vitamin D status and resistance exercise training independently affect glucose tolerance in older adults. AB - We assessed the influence of serum 25-hydroxyvitamin D (25[OH]D) and parathyroid hormone (PTH) concentrations on oral glucose tolerance, body composition, and muscle strength in older, nondiabetic adults who performed resistance exercise training (RT) while consuming diets with either 0.9 or 1.2 g protein kg(-1) d( 1). We hypothesized that individuals with insufficient 25(OH)D and/or high PTH would have less improvement in glucose tolerance after 12 weeks of RT compared with individuals with sufficient 25(OH)D and lower PTH. Sixteen men and 19 women (aged 61 +/- 8 years; range, 50-80 years; body mass index, 26.3 +/- 3.6 kg/m(2)) performed RT 3 times/wk for 12 weeks, with oral glucose tolerance tests done at baseline and postintervention. Protein intake did not influence the responses described below. Plasma glucose area under the curve (P = .02) and 2-hour plasma glucose concentration (P = .03) were higher for vitamin D-insufficient subjects (25[OH]D <50 nmol/L, n = 7) vs vitamin D-sufficient subjects (25[OH]D >=50 nmol/L, n = 28). These differences remained significant after adjustment for age and body mass index. Resistance exercise training reduced fat mass (mean +/- SD, 6% +/- 7%; P < .001) and increased lean body mass (2% +/- 3%, P < .001) and whole body muscle strength (32% +/- 17%, P < .001) in these weight-stable subjects but did not affect 25(OH)D or PTH concentrations. Oral glucose tolerance improved after RT (-10% +/- 16% in glucose area under the curve and -21% +/- 40% in 2-hour glucose, P = .001), but baseline 25(OH)D and PTH did not influence these RT induced changes. These findings indicate that vitamin D status and RT independently affect glucose tolerance, and a training-induced improvement in glucose tolerance does not offset the negative effect of insufficient vitamin D status in older, nondiabetic adults. PMID- 23684435 TI - Pomegranate and type 2 diabetes. AB - Over the last decade, various studies have linked pomegranate (Punica granatum Linn), a fruit native to the Middle East, with type 2 diabetes prevention and treatment. This review focuses on current laboratory and clinical research related to the effects of pomegranate fractions (peels, flowers, and seeds) and some of their active components on biochemical and metabolic variables associated with the pathologic markers of type 2 diabetes. This review systematically presents findings from cell culture and animal studies as well as clinical human research. One key mechanism by which pomegranate fractions affect the type 2 diabetic condition is by reducing oxidative stress and lipid peroxidation. This reduction may occur by directly neutralizing the generated reactive oxygen species, increasing certain antioxidant enzyme activities, inducing metal chelation activity, reducing resistin formation, and inhibiting or activating certain transcriptional factors, such as nuclear factor kappaB and peroxisome proliferator-activated receptor gamma. Fasting blood glucose levels were decreased significantly by punicic acid, methanolic seed extract, and pomegranate peel extract. Known compounds in pomegranate, such as punicalagin and ellagic, gallic, oleanolic, ursolic, and uallic acids, have been identified as having anti diabetic actions. Furthermore, the juice sugar fraction was found to have unique antioxidant polyphenols (tannins and anthocyanins), which could be beneficial to control conditions in type 2 diabetes. These findings provide evidence for the anti-diabetic activity of pomegranate fruit; however, before pomegranate or any of its extracts can be medically recommended for the management of type 2 diabetes, controlled, clinical studies, are needed. PMID- 23684437 TI - Carotenoid bioavailability from raw vegetables and a moderate amount of oil in human subjects is greatest when the majority of daily vegetables are consumed at one meal. AB - While the impact of food composition and processing on carotenoid bioavailability has been the subject of several investigations, the effect of meal patterning remains unknown. The aim of this pilot study was to assess the impact of select consumption patterns on the bioavailability of carotenoids from vegetables. On three randomized testing days, subjects consumed raw salad vegetables and 8 g canola oil over a two meal period in three meal patterns. Meal patterns included consumption of 100% of vegetables and oil in the first meal and 0% in the second, 75% in the first meal and 25% in the second, and 50% in the first meal and 50% in the second. Additional protein-rich "chef's salad" ingredients were distributed equally between meals. We hypothesized that carotenoid absorption would be highest when 50% of vegetables and oil were consumed at each meal and lowest when 100% were consumed at once. Blood was collected 0 to 12 hours postprandially and triacylglycerol-rich lipoprotein fractions (TRL) were isolated by ultracentrifugation. TRL carotenoid concentrations were analyzed by high performance liquid chromatography-diode array detector. Considering all carotenoids, absorption expressed as area under the curve was greatest when >=75% of vegetables were consumed in a single meal (P < .05). Absorption of carotenes also followed this trend (P < .05 for alpha- and beta-carotene). For xanthophylls, consuming all vegetables in one meal increased absorption compared to intake of 50% at each meal (P < .05). These data suggest that carotenoid absorption may be the greatest when daily recommended vegetables are consumed in one meal compared to smaller doses over multiple meals. PMID- 23684438 TI - Daily flaxseed consumption improves glycemic control in obese men and women with pre-diabetes: a randomized study. AB - The study hypothesis was that fasting glucose, insulin, fructosamine, C-reactive protein, and interleukin-6 decrease and adiponectin increases with daily flaxseed consumption in overweight or obese individuals with pre-diabetes. In this randomized, cross-over study overweight or obese men and postmenopausal women (n = 25) with pre-diabetes consumed 0, 13, or 26 g ground flaxseed for 12 weeks. Glucose, insulin, homeostatic model assessment (HOMA-IR), and normalized percent of alpha-linolenic fatty acid (ALA) were significantly different by treatment (multiple analysis of variance, P = .036, P = .013, P = .008, P = .024 respectively). Paired t tests showed glucose decreased on the 13 g intervention compared to the 0 g period [13 g = -2.10 +/- 1.66 mg/L (mean +/- SEM), 0 g = 9.22 +/- 4.44 mg/L, P = .036]. Insulin decreased on the 13 g intervention but not the 26 g (P = .021) and 0 g (P = .013) periods (13 g = -2.12 +/- 1.00 mU/L, 26 g = 0.67 +/- 0.84 mU/L, 0 g = 1.20 +/- 1.16 mU/L). HOMA-IR decreased on the 13 g period but not on the 26 g (P = .012) and 0 g (P = .008) periods (13 g = -0.71 +/ 0.31, 26 g = 0.27 +/- 0.24, 0 g = 0.51 +/- 0.35). The alpha-linolenic fatty acid decrease for the 0 g period was different than the 13 g (P = .024) and 26 g (P = .000) periods (13 g = 0.20 +/- 0.04, 26 g = 0.35 +/- 0.07, 0 g = -0.01 +/- 0.07). Fructosamine, high sensitivity C-reactive protein, adiponectin, and high sensitivity interleukin-6 had no significant differences. Flaxseed intake decreased glucose and insulin and improved insulin sensitivity as part of a habitual diet in overweight or obese individuals with pre-diabetes. PMID- 23684439 TI - Triphasic multinutrient supplementation during acute resistance exercise improves session volume load and reduces muscle damage in strength-trained athletes. AB - We hypothesized that triphasic multinutrient supplementation during acute resistance exercise would enhance muscular performance, produce a more favorable anabolic profile, and reduce biochemical markers of muscle damage in strength trained athletes. Fifteen male strength-trained athletes completed two acute lower-body resistance exercise sessions to fatigue 7 days apart. After a 4-hour fast, participants consumed either a multinutrient supplement (Musashi 1-2-3 Step System, Notting Hill, Australia) (SUPP) or placebo (PLA) beverage preexercise (PRE), during (DUR), and immediately postexercise (IP). Session volume loads were calculated as kilograms * repetitions. Lower-body peak power was measured using unloaded repeated countermovement jumps, and blood samples were collected to assess biochemistry, serum hormones, and muscle damage markers at PRE, DUR, IP, 30 minutes postexercise (P30), and 24 hours postexercise (P24h). The SUPP demonstrated increased glucose concentrations at DUR and IP compared with at PRE (P < .01), whereas PLA demonstrated higher glucose at P30 compared with at PRE (P < .001). Session volume load was higher for SUPP compared with PLA (P < .05). Cortisol increased at DUR, IP, and P30 compared with at PRE in both treatments (P < .05); however, SUPP also displayed lower cortisol at P24h compared with at PRE and PLA (P < .01). The total testosterone response to exercise was higher for PLA compared with SUPP (P < .01); however, total creatine kinase and C-reactive protein responses to exercise were lower for SUPP compared with PLA (P < .05). These data indicate that although triphasic multinutrient supplementation did not produce a more favorable anabolic profile, it improved acute resistance exercise performance while attenuating muscle damage in strength-trained athletes. PMID- 23684440 TI - White button, portabella, and shiitake mushroom supplementation up-regulates interleukin-23 secretion in acute dextran sodium sulfate colitis C57BL/6 mice and murine macrophage J.744.1 cell line. AB - Interleukin-23 (IL-23), a cytokine produced primarily by dendritic cells, is involved in host defense against gut pathogens and promotes innate immunity and inflammatory responses through the IL-23/interleukin-17 axis. We previously reported that extracts from edible mushrooms enhanced antimicrobial alpha defensin production n HL60 cells. Because IL-23 is involved in defensin production, we hypothesized that edible mushrooms may modulate its secretion and gut inflammation. Eight-week-old C57BL/6 mice were fed the AIN76 diet or the same diet supplemented with 5% white button (WBM), portabella, or shiitake mushrooms. To assess in vivo and in vitro cytokine secretion, 7 to 8 mice per group received 3% dextran sodium sulfate (DSS) in drinking water during the last 5 days of the 6 week feeding period. To delineate the mechanisms by which mushrooms alter IL-23 secretion, J.744.1 cells were incubated with (100 MUg/mL) WBM, portabella, and shiitake extracts without and with 100 MUg/mL curdlan (a dectin-1 agonist) or 1 mg/mL laminarin (a dectin-1 antagonist). The dectin-1 receptor is a pattern recognition receptor found in phagocytes, and its activation promotes antimicrobial innate immunity and inflammatory responses. In DSS-untreated mice, mushrooms significantly increased IL-23 plasma levels but decreased those of interleukin-6 (IL-6) (P < .05). In DSS-treated mice, mushroom-supplemented diets increased IL-6 and IL-23 levels (P < .05). Mushroom extracts potentiated curdlan induced IL-23 secretion, and mushroom-induced IL-23 secretion was not blocked by laminarin in vitro, suggesting the involvement of both dectin-1-dependent and dectin-1-independent pathways. Although all mushrooms tended to increase IL-6 in the colon, only WBM and shiitake tended to increase IL-23 levels. These data suggest that edible mushrooms may enhance gut immunity through IL-23. PMID- 23684441 TI - Phycocyanin prevents hypertension and low serum adiponectin level in a rat model of metabolic syndrome. AB - Endothelial dysfunction is associated with hypertension, atherosclerosis, and metabolic syndrome. Phycocyanin is a pigment found in the blue-green algae, Spirulina, which possesses antihypertensive effect. In this study, we hypothesized that phycocyanin derived from Spirulina exerts antihypertensive actions by improving endothelial dysfunction in metabolic syndrome. Spontaneously hypertensive/NIH-corpulent (SHR/NDmcr-cp) rats were divided into 4 groups then fed a normal diet with or without phycocyanin (2500-, 5000-, or 10,000-mg/kg diet) for 25 weeks. At 34 weeks of age, although systolic blood pressure was not significantly different among groups, phycocyanin-fed groups exhibited a dose dependent decrease in blood pressure. Serum levels of adiponectin and messenger RNA levels of adiponectin and CCAAT/enhancer-binding protein alpha in the adipose tissue of rats fed diets containing phycocyanin tended to be higher than those of rats fed a normal diet, but the differences were not statistically significant. Immunohistochemistry analysis showed a significant and positive correlation between aortic endothelial nitric oxide synthase (eNOS) expression levels, a downstream target of the adiponectin receptor, and serum adiponectin levels, although there were no significant differences in eNOS expression among groups. There was also no significant correlation between eNOS expression levels and systolic blood pressure. These results suggest that long-term administration of phycocyanin may ameliorate systemic blood pressure by enhancing eNOS expression in aorta that is stimulated by adiponectin. Phycocyanin may be beneficial for preventing endothelial dysfunction-related diseases in metabolic syndrome. PMID- 23684442 TI - Aronia melanocarpa (chokeberry) polyphenol-rich extract improves antioxidant function and reduces total plasma cholesterol in apolipoprotein E knockout mice. AB - We hypothesized that a polyphenol-rich chokeberry extract (CBE) would modulate hepatic lipid metabolism and improve antioxidant function in apolipoprotein E knockout (apoE(-/-)) mice. ApoE(-/-) mice were fed diets containing 15% fat with 0.2% cholesterol alone or supplemented with 0.005% or 0.05% CBE for 4 weeks. CBE polyphenol content was determined by the total phenols, 4 dimethylaminocinnamaldehyde, and ultra high-performance liquid chromatography mass spectrometry methods. The 0.05% CBE diet provided mice with mean daily doses of 1.2 mg gallic acid equivalents of total phenols, 0.19 mg anthocyanins, 0.17 mg phenolic acids, 0.06 mg proanthocyanidins (as catechin-equivalents), and 0.02 mg flavonols. The 0.05% CBE group had 12% less plasma total cholesterol concentrations than the control. Despite the hypocholesterolemic effect of CBE, hepatic mRNA levels of low-density lipoprotein receptor, hydroxyl-3 methylglutaryl coenzyme A reductase and cholesterol 7alpha-hydroxylase in CBE-fed mice were not significantly different from controls. Dietary CBE did not alter hepatic lipid content or the hepatic expression of genes involved in lipogenesis and fatty acid beta-oxidation such as fatty acid synthase, carnitine palmitoyltransferase 1 and acyl-CoA oxidase. Plasma paraoxonase and catalase activities were significantly increased in mice fed 0.05% CBE. Both CBE diets increased hepatic glutathione peroxidase (GPx) activity but the 0.05% CBE group had 24% less proximal intestine GPx activity relative to controls. Thus, dietary CBE lowered total cholesterol and improved plasma and hepatic antioxidant function at nutritionally-relevant doses in apoE(-/-) mice. Furthermore, the CBE cholesterol-lowering mechanism in apoE(-/-) mice was independent of hepatic expression of genes involved in cholesterol metabolism. PMID- 23684443 TI - Blooming reduces the antioxidant capacity of dark chocolate in rats without lowering its capacity to improve lipid profiles. AB - Dark chocolate contains high levels of antioxidants which are linked to a reduced risk of cardiovascular disease. Chocolate blooming occurs after exposure to high temperatures. Although bloomed chocolate is safe for human consumption, it is not known whether or not the biological function of bloomed chocolate is affected. We hypothesized that bloomed chocolate would reduce the antioxidant potential and lipid-lowering properties of chocolate through altered expression of related genes. Thirty Sprague-Dawley rats were divided into 3 groups and fed either the control (CON), regular dark chocolate (RDC), or bloomed dark chocolate (BDC) diet. After 3 weeks, serum lipid levels and antioxidant capacity were measured. Hepatic expression of key genes was determined by real time polymerase chain reaction (PCR). Sensory characteristics of bloomed versus regular chocolate were assessed in 28 semi-trained panelists. Rats fed RDC exhibited greater serum antioxidant capacities compared to the CON (P < .05). Antioxidant levels of BDC were not different from RDC or CON. Both RDC and BDC lowered TG compared to CON (P < .05). The rats fed RDC had higher high-density lipoprotein levels compared to the CON (P < .05). In rats given RDC, fatty acid synthase gene expression was down-regulated and low-density lipoprotein receptor transcription was up regulated (P < .05). Sensory panelists preferred the appearance and surface smoothness of the regular chocolate compared to bloomed chocolate (P < .001). Although blooming blunted the robust antioxidant response produced by regular dark chocolate, these results suggest that bloomed dark chocolate yields similarly beneficial effects on most blood lipid parameters or biomarkers. However, regular dark chocolate may be more beneficial for the improvement of antioxidant status and modulation of gene expression involved in lipid metabolism and promoted greater sensory ratings. PMID- 23684444 TI - Eicosapentaenoic acid and docosahexaenoic acid exert anti-inflammatory and antinociceptive effects in rodents at low doses. AB - In the present study, we evaluated omega-3 polyunsaturated fatty acid (PUFA) (consisting of 20:5n-3 and 22:6n-3) properties on inflammation and nociception. Among the in vivo tests, writhing, formalin, and hot plate tests were conducted in mice, and carrageenan-induced paw edema, peritonitis, and Hargreaves tests were performed in rats. Following the carrageenan-induced edema, immunohistochemistry for tumor necrosis factor-alpha (TNF-alpha) was also carried out. We found that omega-3 PUFA treatment significantly decreased acetic acid induced abdominal contortions as well as the first and second phases of the formalin test, which were reversed by naloxone. The carrageenan-induced rat paw edema was significantly reduced, along with neutrophil migration to the peritoneal cavity in the omega-3 PUFA treatment. In addition, there was a decrease in TNF-alpha immunostained cells in the inflamed paw with the omega-3 treatment compared with no omega-3. Withdrawal threshold in response to the thermal stimulation was significantly increased by the omega-3 treatment in the Hargreaves and hot plate tests. The in vitro studies (myeloperoxidase, lactate dehydrogenase, MTT cell viability and lipid peroxidation assays) were performed in human neutrophils. These studies showed that omega-3 treatment significantly decreased myeloperoxidase release, presented no cytotoxicity, and did not alter lipid peroxidation. Our study suggests that omega-3 PUFA anti-inflammatory and antinociceptive actions may involve inhibition of cyclooxygenases and microglial activation, leading to a reduced release of proinflammatory cytokines such as TNF alpha, among other factors. The omega-3 PUFAs are potential candidates used alone or in combination with conventional nonsteroidal anti-inflammatory drugs, for the treatment of diseases where inflammation plays an important role. PMID- 23684447 TI - The 2013 EAU guidelines on chronic pelvic pain: is management of chronic pelvic pain a habit, a philosophy, or a science? 10 years of development. AB - CONTEXT: Progress in the science of pain has led pain specialists to move away from an organ-centred understanding of pain located in the pelvis to an understanding based on the mechanism of pain and integrating, as far as possible, psychological, social, and sexual dimensions of the problem. This change is reflected in all areas, from taxonomy through treatment. However, deciding what is adequate investigation to rule out treatable disease before moving to this way of engaging with the patient experiencing pain is a complex process, informed by pain expertise as much as by organ-based medical knowledge. OBJECTIVE: To summarise the evolving changes in the management of patients with chronic pelvic pain by referring to the 2012 version of the European Association of Urology (EAU) guidelines on chronic pelvic pain. EVIDENCE ACQUISITION: The working panel highlights some of the most important aspects of the management of patients with chronic pelvic pain emerging in recent years in the context of the EAU guidelines on chronic pelvic pain. The guidelines were completely updated in 2012 based on a systematic review of the literature from online databases from 1995 to 2011. According to this review, levels of evidence and grades of recommendation were added to the text. A full version of the guidelines is available at the EAU office or Web site (www.uroweb.org). EVIDENCE SYNTHESIS: The previously mentioned issues are explored in this paper, which refers throughout to dilemmas for the physician and treatment team as well as to the need to inform and engage the patient in a collaborative empirical approach to pain relief and rehabilitation. These issues are exemplified in two case histories. CONCLUSIONS: Chronic pelvic pain persisting after appropriate treatment requires a different approach focussing on pain. This approach integrates the medical, psychosocial, and sexual elements of care to engage the patient in a collaborative journey towards self management. PMID- 23684446 TI - From high doses of oral rivastigmine to transdermal rivastigmine patches: user experience and satisfaction among caregivers of patients with mild to moderate Alzheimer disease. AB - INTRODUCTION: Rivastigmine, a treatment for mild to moderate Alzheimer disease (AD), is the first cholinesterase inhibitor to be available in the transdermal format. We aim to describe user experience and satisfaction with the rivastigmine patch, as well as any clinical changes perceived in patients. METHODS: Observational, cross-sectional, multicentre study with 239 investigators and 1851 informal caregivers of patients with mild to moderate AD. Patients were treated with transdermal rivastigmine patches for >= 6 months and had previously received high doses of oral rivastigmine. RESULTS: Mean caregiver age was 59.8+/-14.4 years and 70.9% were women. They spent 10.0+/-7.1hours per day providing care and 79.8% lived with the patient. Patch instructions were described as easy to follow by 97.1% of the caregivers and 92.1% of them rated patch application as easy or very easy. The most commonly cited disadvantage was adhesion problems (26.8%). Discontinuation of treatment was due to cutaneous reactions in most cases. Overall, 76.5% of the caregivers were satisfied or very satisfied with transdermal treatment and 77.4% considered that its interference with daily activities was minimal or null. The patch was preferred to oral treatment by 94.3% of caregivers. Clinical Global Impression of Change ratings improved according to 61.3% of the caregivers and 53% of the investigators. Few caregivers reported medication forgetfulness. CONCLUSIONS: Most caregivers of patients with mild to moderate AD preferred the transdermal format of rivastigmine to the oral format. Caregivers also reported overall satisfaction, ease of use, and reduced impact on daily activities for transdermal rivastigmine format, in addition to patient improvement compared to their condition under the previous treatment. PMID- 23684445 TI - Phosphatase regulation of immunoreceptor signaling in T cells, B cells and mast cells. AB - Recent progress has begun to reveal the often complex and changing roles of phosphotyrosine and phosphoinositide phosphatases in regulation of immunoreceptor signaling. The resultant confusion has been further increased by discoveries of new players. Here we provide a review of recent progress in defining the roles of these enzymes in immunoreceptor-dependent mast cell, T cell and B cell activation. PMID- 23684448 TI - HbA1c in the diagnosis of diabetes and abnormal glucose tolerance in patients with Graves' hyperthyroidism. AB - OBJECTIVE: To assess the suitability of HbA1c as a criterion for the diagnosis of diabetes in patients with Graves' disease. METHODS: This study enrolled 310 patients with untreated newly diagnosed Graves' disease, 208 patients with euthyroid goiter and 329 age-matched (control) subjects without thyroid disease from Fuzhou, China. The performance of HbA1c against the OGTT for diagnosing diabetes was determined. The Framingham risk score was used to assess general cardiovascular disease (CVD) risk. RESULTS: The percentage of patients with abnormal glucose metabolism as classified by HbA1c levels was lower than by OGTT criteria in patients with Graves' disease-33.2% vs. 41.3% for pre-diabetes and 4.5% vs. 11.3% for diabetes, respectively. The sensitivity of HbA1c for diagnosing diabetes in patients with Graves' disease was lower than in patients with euthyroid goiter and subjects without thyroid disease (34.9%, 63.2% and 60.6% respectively), while the specificity was similar (99.3%, 98.6%, 97.4%). Approximately 7.4% of patients with Graves' disease diagnosed with diabetes according to OGTT criteria were misdiagnosed as not having the disease by HbA1c, much higher than that for the other two groups. Patients with Graves' disease with diabetes not diagnosed with the disease by HbA1c showed a high risk for CVD. CONCLUSIONS: The low sensitivity of the HbA1c criterion underestimated the percentage of diabetes in patients with Graves' disease. Patients with diabetes who were misdiagnosed as not having the disease by HbA1c were at high risk for CVD. PMID- 23684449 TI - Effect of indomethacin on cerebrovascular reactivity in patients with type 2 diabetes mellitus. AB - AIM: Impaired cerebral vasoreactivity to endothelium-dependent stimuli were described in type 2 diabetes mellitus (T2DM), but the mechanisms underlying that impairment are still unclear. The aim of this study was to investigate the role of cyclooxygenases' metabolites in response to acute hypercapnic stimulus in cerebral vessels, in patients with T2DM. METHODS: Vascular responses in the breath-holding test (BHT) were assessed in the absence/presence of a non selective, reversible-inhibitor of cyclooxygenases, indomethacin (INDO), by functional transcranial Doppler sonography of the middle cerebral artery (N of patients=50; 33 men and 17 women). The functional hemodynamic parameter mean flow velocity (MFV) was assessed at rest, before and 90min after 100mg of INDO, and during the BHT. Breath holding index (BHI) [(MFV at the end of BHT minus MFV at rest)/MFV at rest)*100/s of breath-holding] was calculated after BHT performed before and 90min after INDO. RESULTS: MFV at rest significantly decreased after INDO administration compared with a control condition before INDO (at rest before INDO from 49.36+/-15.09 to 36.72+/-8.45 after INDO, p<0.001) However, overall cerebral vessel vasoreactivity to hypercapnia, evaluated with BHI, was significantly improved after INDO administration compared with the BHI before INDO administration (from 0.68+/-0.4 to 1.27+/-0.42, p<0.001). CONCLUSIONS: The improvement in cerebral vasoreactivity in response to BHT after INDO administration suggests that the production of a vasoconstrictor metabolite of cyclooxygenase in diabetic patients was reduced by indomethacin consumption. PMID- 23684450 TI - Bronchopulmonary dysplasia in a double-hit mouse model induced by intrauterine hypoxia and postnatal hyperoxia: closer to clinical features? AB - Despite increased survival of very preterm newborns, bronchopulmonary dysplasia (BPD) remains a major threat, as it affects long-term pulmonary function and neurodevelopmental outcome. Recent research focused on mechanisms of lung repair. Animal models of BPD in term rodents use postnatal hyperoxia in order to mimic features observed in very preterm human neonates: reduced alveolarization and impaired septal architecture without profound inflammatory changes. In contrast, BPD in very preterm human neonates involves prenatal hits e.g. infections and growth restriction plus postnatal ventilation. BPD induced in rodents by postnatal hyperoxia also exhibits reduced alveolarization however without septal pathology but with marked inflammation. We therefore aimed to establish an animal model combining prenatal growth restriction (FiO2 0.1 for 4 days) with postnatal hyperoxia (FiO2 0.7 for 2 weeks). In double-hit mice the development was retarded: body weight and length, lung and brain weight were significantly reduced by day P14 compared with normoxic controls. Histomorphometric analysis revealed reduced alveolarization and increased septal thickness without pronounced inflammatory lesions. A down-regulation of SftpB and SftpC genes was observed in double-hit animals compared with controls. Thus, we established a new model of BPD using pre- and postnatal hits. PMID- 23684451 TI - Pharmacokinetics of linezolid in the mediastinum and pleural space. AB - The purpose of this study was to investigate the penetration of linezolid into the mediastinum and pleural space by comparing its concentration in the serum, mediastinum, and pleural space. The linezolid area under the concentration-versus time curve from zero to 12h (AUC)(mediastinum fluid/serum) and AUC(pleural fluid/serum) ratio were 1.32 and 1.64, respectively. The results suggest that the linezolid concentration in the mediastinum varies as in the serum, and that the concentration in the mediastinum is the same as or greater than that in the serum. PMID- 23684452 TI - Progress towards the control and elimination of neglected tropical diseases in Brazil. PMID- 23684453 TI - Impact of parental smoking on childhood asthma. AB - OBJECTIVE: To evaluate the exposure to environmental tobacco smoke (ETS) of the childhood population in this community and its relationship with asthma symptoms. METHODS: A cross-sectional study was conducted using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire on children and adolescents in this community. The symptoms "wheezing ever", "current asthma", "severe asthma", and "exercise-induced asthma" were defined by this questionnaire. Parental smoking was classified into four mutually exclusive categories: 1) no parent smokes; 2) only the mother smokes; 3) only the father smokes; and 4) both parents smoke. The odds ratio of the prevalence of asthma symptoms according to ETS exposure was calculated using logistic regression. RESULTS: A total of 10,314 children and 10,453 adolescents were included. Over 51% of the children and adolescents were exposed to ETS at home. ETS is associated with a higher prevalence of asthma symptoms, particularly if the mother or both parents smoke. CONCLUSION: The prevalence of ETS is still high in this community, although there has been a decreasing tendency in the last 15 years. ETS is associated with higher prevalence of asthma. PMID- 23684454 TI - Persistent pulmonary hypertension of the newborn: recent advances in pathophysiology and treatment. AB - OBJECTIVES: Although recognized for decades, little is known about the etiology, physiopathology, and prevention of persistent pulmonary hypertension of the newborn (PPHN), and its treatment remains a major challenge for neonatologists. In this review, the clinical features and physiopathology of the syndrome will be addressed, as well as its general and specific treatments. DATA SOURCE: A review was carried out in PubMed, Cochrane Library, and MRei consult databases, searching for articles related to the syndrome and published between 1995 and 2011. DATA SYNTHESIS: Risk factors and the physiopathological mechanisms of the syndrome are discussed. The clinical presentation depends on the different factors involved. These are related to the etiology and physiopathology of the different forms of the disease. In addition to the measures used to allow for the decrease in pulmonary vascular resistance after birth, in some instances pulmonary vasodilators will be required. Although inhaled nitric oxide has proved effective, other vasodilators have been recently used, but clinical evidence is still lacking to demonstrate their benefits in the treatment of PPHN. CONCLUSIONS: Despite recent technological advances and new physiopathological knowledge of this disease, mortality associated with PPHN remains at 10%. More clinical research and evidence-based experimental results are needed to prevent, treat, and reduce the morbidity/mortality associated with this neonatal syndrome. PMID- 23684455 TI - Determination of body size measures and blood pressure levels among children. PMID- 23684456 TI - Epidemiological assessment of neglected diseases in children: lymphatic filariasis and soil-transmitted helminthiasis. AB - OBJECTIVE: To report the prevalence of lymphatic filariasis and intestinal parasitic infections in school-aged children living in a filariasis endemic area and discuss about the therapeutic regimen adopted in Brazil for the large-scale treatment of filariasis. METHODS: A cross-sectional study including 508 students aged 5-18 years old, enrolled in public schools within the city of Olinda, Pernambuco. The presence of intestinal parasites was analyzed using the Hoffman, Pons and Janer method on 3 stool samples. The diagnosis of filarial infection was performed using the rapid immunochromatographic technique (ICT) for the antigen, and the polycarbonate membrane filtration for the presence of microfilariae. Descriptive statistics of the data was performed using EpiInfo version 7. RESULTS: The prevalence of filariasis was 13.8% by ICT and 1.2% by microfilaraemia, while intestinal parasites were detected in 64.2% of cases. Concurrent diagnosis of filariasis and intestinal parasites was 9.4%, while 31.5% of students were parasite-free. Among individuals with intestinal parasites, 55% had one parasite and 45% had more than one parasite. Geohelminths occurred in 72.5% of the parasited individuals. In the group with filarial infection the prevalence of soil-transmitted helminthiasis was 54.5%. CONCLUSIONS: The simultaneous diagnosis of filariasis and intestinal parasites as well as the high frequency of geohelminths justify the need to reevaluate the treatment strategy used in the Brazilian filariasis large-scale treatment program. PMID- 23684457 TI - Molecular characterization of rotavirus genotypes in immunosuppressed and non immunosuppressed pediatric patients. AB - OBJECTIVE: To describe the genotypic variability of group A rotavirus (RVA) found in immunosuppressed and non-immunosuppressed pediatric patients treated at the Hospital de Clinicas da Universidade Federal do Parana (HC-UFPR), Curitiba, Parana. METHODS: A cross-sectional study was conducted with 1,140 stool samples collected from April, 2001 to December, 2008 in outpatients and hospitalized patients with acute gastroenteritis referred to the hospital. RVA diagnosis was performed through the latex agglutination method and enzyme immunoassay. Reverse transcription followed by multiplex hemi-nested polymerase chain reaction (PCR) and nucleotide sequencing were used for genotype characterization. Genotype combinations, clinical, epidemiological, laboratory data, and presence of hospital-acquired infections were reported. RESULTS: A total of 80 rotavirus positive stool samples were analyzed. The most frequent associations between genotypes G and P were: G4 P[8] (38.9%), G1 P[8] (30.5%), G9 P[8] (13.9%), G2 P[4] (6.9%), and G3 P[8] (1.4%). G2 P[4] was the most prevalent genotype after the vaccine implementation in the years 2006 and 2008. A total of 62,5% of infected children were aged less than 12 months. Of these, 55.6% had severe dehydration and 26.7% needed intensive care. A frequency of 12.5% of nosocomial infections was found. No correlation was observed between genotype and severity of infection in the study patients. CONCLUSION: RVA infections can be associated with severe clinical manifestations, and the surveillance of genotypic variability of this virus is crucial to monitor the emergence of new strains and the impact of the immunization in these patients. PMID- 23684458 TI - Anthropometric measures and blood pressure in school children. AB - OBJECTIVE: To investigate the association of blood pressure and body mass index, waist circumference, waist-to-height ratio and triceps skinfold, in children and adolescents in Curitiba, state of Parana, Brazil. METHODS: Cross-sectional study with a random sample of 1,441 students from public schools, aged from 10 to 16 years (655 boys and 786 girls). The following indicators were assessed: weight, height, waist circumference, triceps skinfold, systolic and diastolic blood pressures, pubertal stage, and socioeconomic status. Pearson correlation tests and multivariate logistic regression were used, considering p<0.05. RESULTS: We found weak correlations among all the anthropometric parameters and systolic and diastolic levels, with coefficients values ranging from 0.18 to 0.28 (p<0.001). In multivariate analysis, only body mass index [odds ratio (OR)=2.9; 95% confidence interval (95%CI) 1.9-4.5] and triceps skinfold (OR=1.9; 95%CI 1.3-3.1) were found as predictors of high blood pressure, regardless of abdominal adiposity, sexual maturation and socioeconomic status. CONCLUSION: Total body adiposity seems to be a better predictor of high blood pressure risk than abdominal fat in this population. PMID- 23684460 TI - Electrochemically prepared solid-phase microextraction coatings--a review. AB - During the last decade, electrochemically prepared coatings have gained widespread acceptance for solid-phase microextraction (SPME) applications. The current review classified these coatings as electropolymerized conductive polymers (CPs), electrodeposited metal oxides, electrophoretically deposited carbon nanotubes (CNTs) and anodized metals. These electrochemical methods resulted in easily controlled and reproducible SPME coatings with inherent characteristics such as biocompatibility, thermal stability and porous structure. The objective of this review is to provide a concise overview of recent developments in the electrochemically prepared SPME coatings and their analytical applications. PMID- 23684459 TI - Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. AB - Glioblastoma multiforme (GBM) displays cellular hierarchies harboring a subpopulation of stem-like cells (GSCs). Enhancer of Zeste Homolog 2 (EZH2), the lysine methyltransferase of Polycomb repressive complex 2, mediates transcriptional repression of prodifferentiation genes in both normal and neoplastic stem cells. An oncogenic role of EZH2 as a transcriptional silencer is well established; however, additional functions of EZH2 are incompletely understood. Here, we show that EZH2 binds to and methylates STAT3, leading to enhanced STAT3 activity by increased tyrosine phosphorylation of STAT3. The EZH2 STAT3 interaction preferentially occurs in GSCs relative to non-stem bulk tumor cells, and it requires a specific phosphorylation of EZH2. Inhibition of EZH2 reverses the silencing of Polycomb target genes and diminishes STAT3 activity, suggesting therapeutic strategies. PMID- 23684461 TI - Warping methods for spectroscopic and chromatographic signal alignment: a tutorial. AB - Warping methods are an important class of methods that can correct for misalignments in (a.o.) chemical measurements. Their use in preprocessing of chromatographic, spectroscopic and spectrometric data has grown rapidly over the last decade. This tutorial review aims to give a critical introduction to the most important warping methods, the place of warping in preprocessing and current views on the related matters of reference selection, optimization, and evaluation. Some pitfalls in warping, notably for liquid chromatography-mass spectrometry (LC-MS) data and similar, will be discussed. Examples will be given of the application of a number of freely available warping methods to a nuclear magnetic resonance (NMR) spectroscopic dataset and a chromatographic dataset. As part of the Supporting Information, we provide a number of programming scripts in Matlab and R, allowing the reader to work the extended examples in detail and to reproduce the figures in this paper. PMID- 23684464 TI - Synthesis and electrocatalytic activity of haemin-functionalised iron(II, III) oxide nanoparticles. AB - Haemin-functionalised magnetic iron(II, III) oxide (Fe3O4) nanoparticles (Fe3O4/haemin) were synthesised by changing the acidity of a solution of the two compounds. The nanoparticles were characterised by transmission electron microscopy, UV-vis absorption spectroscopy, X-ray diffraction, Fourier transform infrared spectroscopy, measurement of magnetisation, and electrochemical techniques. The properties of both haemin and Fe3O4 were retained. Thus, Fe3O4/haemin nanoparticles exhibited pronounced electrocatalytic activity towards trichloroacetic acid (TCA) like haemin itself. Interestingly, electrocatalytic activity towards TCA was affected by detection temperature, which was controlled via electrically heated carbon paste electrodes. The maximal catalytic current was 5.8 times higher at 60 degrees C than at room temperature (25 degrees C). This proposed electrochemical sensor for TCA possessed a linear detection range of 5-80 MUM and a detection limit of 0.3 MUM at 60 degrees C. PMID- 23684463 TI - Direct electrochemistry with enhanced electrocatalytic activity of hemoglobin in hybrid modified electrodes composed of graphene and multi-walled carbon nanotubes. AB - A graphene (GR) and multi-walled carbon nanotubes (MWCNT) hybrid was prepared and modified on a 1-hexylpyridinium hexafluorophosphate based carbon ionic liquid electrode (CILE). Hemoglobin (Hb) was immobilized on GR-MWCNT/CILE surface with Nafion as the film forming material and the modified electrode was denoted as Nafion/Hb-GR-MWCNT/CILE. Spectroscopic results revealed that Hb molecules retained its native structure in the GR-MWCNT hybird. Electrochemical behaviors of Hb were carefully investigated by cyclic voltammetry with a pair of well defined redox peaks obtained, which indicated that direct electron transfer of Hb was realized in the hybrid modified electrode. The result could be attributed to the synergistic effects of GR-MWCNT hybrid with enlarged surface area and improved conductivity through the formation of a three-dimensional network. Electrochemical parameters of the immobilized Hb on the electrode surface were further calculated with the results of the electron transfer number (n) as 1.03, the charge transfer coefficient (a) as 0.58 and the electron-transfer rate constant (ks) as 0.97 s(-1). The Hb modified electrode showed good electrocatalytic ability toward the reduction of different substrates such as trichloroacetic acid in the concentration range from 0.05 to 38.0 mmol L(-1) with a detection limit of 0.0153 mmol L(-1) (3sigma), H2O2 in the concentration range from 0.1 to 516.0 mmol L(-1) with a detection limit of 34.9 nmol/L (3sigma) and NaNO2 in the concentration range from 0.5 to 650.0 mmol L(-1) with a detection limit of 0.282 MUmol L(-1) (3sigma). So the proposed electrode had the potential application in the third-generation electrochemical biosensors without mediator. PMID- 23684462 TI - Nuclear magnetic resonance metabonomic profiling using tO2PLS. AB - Blood plasma collected from adult fish (black bream, Sparidae) exposed to a dose of 5 mg kg(-1) 17beta-estradiol underwent metabonomic profiling using nuclear magnetic resonance (NMR). An extension of the orthogonal 2 projection to latent structure (O2PLS) analysis, tO2PLS, was proposed and utilized to classify changes between the control and experimental metabolic profiles. As a bidirectional modeling tool, O2PLS examines the (variable) commonality between two different data blocks, and extracts the joint correlations as well as the unique variations present within each data block. tO2PLS is a proposed matrix transposition of O2PLS to allow for commonality between experiments (spectral profiles) to be observed, rather than between sample variables. tO2PLS analysis highlighted two potential biomarkers, trimethylamine-N-oxide (TMAO) and choline, that distinguish between control and 17beta-estradiol exposed fish. This study presents an alternative way of examining spectroscopic (metabolite) data, providing a method for the visual assessment of similarities and differences between control and experimental spectral features in large data sets. PMID- 23684465 TI - At-line bioprocess monitoring by immunoassay with rotationally controlled serial siphoning and integrated supercritical angle fluorescence optics. AB - In this paper we report a centrifugal microfluidic "lab-on-a-disc" system for at line monitoring of human immunoglobulin G (hIgG) in a typical bioprocess environment. The novelty of this device is the combination of a heterogeneous sandwich immunoassay on a serial siphon-enabled microfluidic disc with automated sequential reagent delivery and surface-confined supercritical angle fluorescence (SAF)-based detection. The device, which is compact, easy-to-use and inexpensive, enables rapid detection of hIgG from a bioprocess sample. This was achieved with, an injection moulded SAF lens that was functionalized with aminopropyltriethoxysilane (APTES) using plasma enhanced chemical vapour deposition (PECVD) for the immobilization of protein A, and a hybrid integration with a microfluidic disc substrate. Advanced flow control, including the time sequenced release of on-board liquid reagents, was implemented by serial siphoning with ancillary capillary stops. The concentration of surfactant in each assay reagent was optimized to ensure proper functioning of the siphon-based flow control. The entire automated microfluidic assay process is completed in less than 30 min. The developed prototype system was used to accurately measure industrial bioprocess samples that contained 10 mg mL(-1) of hIgG. PMID- 23684466 TI - Simultaneous determination of 19 triazine pesticides and degradation products in processed cereal samples from Chinese total diet study by isotope dilution-high performance liquid chromatography-linear ion trap mass spectrometry. AB - A selective and sensitive isotope dilution-high performance liquid chromatography linear ion trap mass spectrometry (Isotope Dilution-HPLC-LIT-MS(3)) method was developed for the simultaneous determination of 19 triazine pesticides and their degradation products in processed cereal samples from Chinese total diet study (TDS). The method integrated the addition of isotope internal standards, liquid liquid extraction (LLE), clean-up with MCX solid-phase extraction (SPE) cartridges and HPLC-LIT-MS(3) analysis with selected reaction monitoring (SRM) mode. Matrix-matched calibration curves showed good linearity (R(2)>=0.9940) verified by applying the Mandel's fitting test (p>0.087) performed at the 95% confidence level. Decision limits (CCalphas) and detection capabilities (CCbetas) of the 19 triazine pesticides and their degradation products fell in the ranges of 0.0020-0.4200 MUg kg(-1) and 0.0024-0.4500 MUg kg(-1), respectively. Recoveries ranged from 70.1% to 112.8%, with the relative standard deviations (RSDs) ranging from 1.5% to 13.5%. Furthermore, the proposed method was applied to analyzing the proposed cereal samples from the fourth Chinese TDS. Eleven triazines were detected in six cereal samples with the concentrations ranging from 0.013 to 0.987 MUg kg(-1). This method can also be used for the further determination of the triazines in other food group composites, and ultimately served as a methodological foundation for assessing the triazines in the average Chinese diet in the general population. PMID- 23684467 TI - Sensitivity of microarray based immunoassays using surface-attached hydrogels. AB - A promising pathway to improve on the sensitivity of protein microarrays is to immobilize the capture antibodies in a three dimensional hydrogel matrix. We describe a simple method based on printing of an aqueous protein solution containing a photosensitive polymer and the capture antibody onto a plastic chip surface. During short UV-exposure photocrosslinking occurs, which leads to formation of a hydrogel, which is simultaneously bound to the substrate surface. In the same reaction the antibody becomes covalently attached to the forming hydrogel. As the capture antibodies are immobilized in the three-dimensional hydrogel microstructures, high fluorescence intensities can be obtained. The chip system is designed such, that non-specific protein adsorption is strongly prevented. Thus, the background fluorescence is strongly reduced and very high signal-to-background ratios are obtained (SBR>6 for c(BSA)=1 pM; SBR>100 for c(BSA)>100 pM). The kinetics of antigen binding to the arrayed antibodies can be used to determine the concentration of a specific protein (for example the tumor marker beta2-microglobulin) in solution for a broad range of analyte concentrations. By varying size and composition of the protein-filled hydrogel microstructures as well as adjusting the extent of labeling it is possible to easily adapt the surface concentration of the probe molecules such that the fluorescence signal intensity is tuned to the prevalence of the protein in the analyte. As a consequence, the signal tuning allows to analyze solutions, which contain both proteins with high (here: upper mg mL(-1) range) and with very low concentrations (here: lower MUg mL(-1) range). This way quantitative analysis with an exceptionally large dynamic range can be performed. PMID- 23684468 TI - On-line simultaneous and rapid separation of anions and cations from a single sample using dual-capillary sequential injection-capillary electrophoresis. AB - A novel capillary electrophoresis (CE) approach has been developed for the simultaneous rapid separation and identification of common environmental inorganic anions and cations from a single sample injection. The method utilised a sequential injection-capillary electrophoresis instrument (SI-CE) with capacitively-coupled contactless conductivity detection (C(4)D) constructed in house from commercial-off-the-shelf components. Oppositely charged analytes from a single sample plug were simultaneously injected electrokinetically onto two separate capillaries for independent separation and detection. Injection was automated and may occur from a syringe or be directly coupled to an external source in a continuous manner. Software control enabled high sample throughput (17 runs per hour for the target analyte set) and the inclusion of an isolation valve allowed the separation capillaries to be flushed, increasing throughput by removing slow migrating species as well as improving repeatability. Various environmental and industrial samples (subjected only to filtering) were analysed in the laboratory with a 3 min analysis time which allowed the separation of 23 inorganic and small organic anions and cations. Finally, the system was applied to an extended automated analysis of Hobart Southern Water tap water for a period of 48 h. The overall repeatability of the migration times of a 14 analyte standard sample was less than 0.74% under laboratory conditions. LODs ranged from 5 to 61 MUg L(-1). The combination of automation, high confidence of peak identification, and low limits of detection make this a useful system for the simultaneous identification of a range of common inorganic anions and cations for discrete or continuous monitoring applications. PMID- 23684469 TI - The piriformis muscle syndrome: an exploration of anatomical context, pathophysiological hypotheses and diagnostic criteria. AB - INTRODUCTION: The piriformis muscle syndrome (PMS) has remained an ill-defined entity. It is a form of entrapment neuropathy involving compression of the sciatic nerve by the piriformis muscle. Bearing this in mind, a medical examination is likely to be suggestive, as a classical range of symptoms corresponds to truncal sciatica with frequently fluctuating pain, initially in the muscles of the buttocks. PATHOPHYSIOLOGICAL HYPOTHESES: The piriformis muscle is biarticular, constituting a bridge in front of and below the sacroiliac joint and behind and above the coxo-femoral joint. It is essentially a lateral rotator but also a hip extensor, and assumes a secondary role as an abductor. Its action is nonetheless conditioned by the position of the homolateral coxo-femoral joint, and it can also function as a hip medial rotator, with the hip being flexed at more than 90 degrees . The main clinical manoeuvres are derived from these types of biomechanical considerations. For instance, as it is close to the hip extensors, the piriformis muscle is tested in medial rotation stretching, in resisted contraction in lateral rotation. On the other hand, when hip flexion surpasses 90 degrees , the piriformis muscle is stretched in lateral rotation, and we have consequently laid emphasis on the manoeuvre we have termed Heel Contra-Lateral Knee (HCLK), which must be prolonged several tens of seconds in order to successfully reproduce the buttocks-centred and frequently associated sciatic symptoms. CONCLUSION: A PMS diagnosis is exclusively clinical, and the only objective of paraclinical evaluation is to eliminate differential diagnoses. The entity under discussion is real, and we favour the FAIR, HCLK and Freiberg stretching manoeuvres and Beatty's resisted contraction manoeuvre. PMID- 23684470 TI - Piriformis muscle syndrome: diagnostic criteria and treatment of a monocentric series of 250 patients. AB - OBJECTIVES: Piriformis Muscle Syndrome (PMS) is caused by sciatic nerve compression in the infrapiriformis canal. However, the pathology is poorly understood and difficult to diagnose. This study aimed to devise a clinical assessment score for PMS diagnosis and to develop a treatment strategy. MATERIAL AND METHODS: Two hundred and fifty patients versus 30 control patients with disco radicular conflict, plus 30 healthy control subjects were enrolled. A range of tests was used to produce a diagnostic score for PMS and an optimum treatment strategy was proposed. RESULTS: A 12-point clinical scoring system was devised and a diagnosis of PMS was considered 'probable' when greater or equal to 8. Sensitivity and specificity of the score were 96.4% and 100%, respectively, while the positive predictive value was 100% and negative predictive value was 86.9%. Combined medication and rehabilitation treatments had a cure rate of 51.2%. Hundred and twenty-two patients (48.8%) were unresponsive to treatment and received OnabotulinumtoxinA. Visual Analogue Scale (VAS) results were 'Very good/Good' in 77%, 'Average' in 7.4% and 'Poor' in 15.6%. Fifteen of 19 patients unresponsive to treatment underwent surgery with 'Very good/Good' results in 12 cases. CONCLUSIONS: The proposed evaluation score may facilitate PMS diagnosis and treatment standardisation. Rehabilitation has a major role associated in half of the cases with botulinum toxin injections. PMID- 23684471 TI - An ultrasonic methodology for determining the mechanical and geometrical properties of a thin layer using a deconvolution technique. AB - An ultrasonic method is proposed for simultaneously determining the thickness, density, sound velocity, and attenuation of a thin layer from a reflection spectrum at normal incidence. The normal theoretical reflection spectrum of a thin layer is established as a function of three dimensionless parameters to reduce the number of independent parameters. The inverse algorithm, using the least squares method, is adopted to determine the dimensionless parameters, and the corresponding convergence zones are investigated. The measured reflection spectrum at normal incidence is obtained using Wiener filtering, and spectral extrapolations following Wiener filtering are applied to obtain the time-of flights by identifying the overlapping pulse-echoes inside the thin layer and the superposing pulse-echoes from the reference material and front surface of the specimen. The thickness of the thin layer can then be calculated and as initial estimate for the inverse algorithm. The density, sound velocity, and attenuation are then determined by the measured thin layer thickness and determined dimensionless parameters. Two 500 MUm stainless steel and aluminum plates were immersed in coupling water and a 5 MHz flat transducer was applied. The relative errors of measured thickness, density, and sound velocity were less than 6%, and the ultrasound attenuation was close to its true value. The validity of the proposed technique was verified. PMID- 23684472 TI - Annealing effect on the generation of dual mode acoustic waves in inclined ZnO films. AB - ZnO films with different inclined angles on steel substrates were sputter deposited by changing the substrate tilt angle during deposition and then used to fabricate ZnO film ultrasonic transducers. The ultrasonic performance of those devices was characterized using a standard pulse-echo method. A dual mode wave with both longitudinal and shear wave components was detected from the ZnO device at 0 degrees inclined angle. At a columnar inclined angle of 31 degrees , longitudinal wave excitation was suppressed with a nearly pure shear wave detected. Post annealing of the ZnO film improved the crystallinity and decreased the film stress. The dispersion of the received echoes was observed when the grain sizes of ZnO films were increased after annealing. The frequency components of the waveforms were analyzed and identified using a short time Fourier transform. Post-annealing of the ZnO films changed the primary frequency and enhanced the propagation of the relative high-frequency acoustic wave. PMID- 23684473 TI - FEM simulation of Rayleigh waves for CMOS compatible SAW devices based on AlN/SiO2/Si(100). AB - A simulation study of Rayleigh wave devices based on a stacked AlN/SiO2/Si(100) device was carried out. Dispersion curves with respect to acoustic phase velocity, reflectivity and electromechanical coupling efficiency for tungsten W and aluminium Al electrodes and different layer thicknesses were quantified by 2D FEM COMSOL simulations. Simulated acoustic mode shapes are presented. The impact of these parameters on the observed Rayleigh wave modes was discussed. High coupling factors of 2% and high velocities up to 5000 m/s were obtained by optimizing the AlN/SiO2 thickness ratio. PMID- 23684474 TI - Animal laboratory training improves lung ultrasound proficiency and speed. AB - BACKGROUND: Although lung ultrasound (US) is accurate in diagnosing pneumothorax (PTX), the training requirements and methods necessary to perform US examinations must be defined. OBJECTIVE: Our aim was to test whether animal laboratory training (ALT) improves the diagnostic competency and speed of PTX detection with US. METHODS: Twenty medical students without lung US experience attended a 1-day course. Didactic, practical, and experimental lectures covered the basics of US physics, US machines, and lung US, followed by hands-on training to demonstrate the signs of normal lung sliding and PTX. Each student's diagnostic skill level was tested with three subsequent examinations (at day 1, day 2, and 6-month follow-up) using experimentally induced PTX in porcine models. The outcome measures were sensitivity and specificity for US detection of PTX, self-reported diagnostic confidence, and scan time. RESULTS: The students improved their skills between the initial two examinations: sensitivity increased from 81.7% (range 69.1%-90.1%) to 100.0% (range 94.3%-100.0%) and specificity increased from 90.0% (range 82.0%-94.8%) to 98.9% (range 92.3%-100.0%); with no deterioration 6 months later. There was a significant learning curve in choosing the correct answers (p = 0.018), a 1-point increase in the self-reported diagnostic confidence (7.8-8.8 on a 10-point scale; p < 0.05), and a 1-min reduction in the mean scan time per lung (p < 0.05). CONCLUSIONS: Without previous experience and after undergoing training in an animal laboratory, medical students improved their diagnostic proficiency and speed for PTX detection with US. Lung US is a basic technique that can be used by novices to accurately diagnose PTX. PMID- 23684475 TI - Unintentional use of mistaken insulin products: a retrospective review of poison center data. AB - BACKGROUND: There are no guidelines for the management of accidental insulin administration. We hypothesized that home monitoring of asymptomatic patients (pts) was safe following unintentionally insulin administration. METHODS: Retrospective review of poison center (PCC) charts from 1/1/2000-12/31/2010 looking for accidental insulin administrations. INCLUSION CRITERIA: pt must be prescribed insulin. Information recorded from charts: pt age/gender, "intended" and "mistaken" insulin formulations/doses, use of oral diabetic agents, management site, Emergency Department (ED) referral, symptoms, blood glucose values, and treatments. Defined outcomes: symptoms (e.g., altered sensorium); hypoglycemia (<60 mg/dL); management site; health care facility (HCF) admission; and death. Multiple logistic regression was used to determine outcome predictors. RESULTS: 652 charts met inclusion criteria. Mean age was 56.4 years; most (58.5%) were women. Most (89%) calls originated from home, 10.7% from a HCF, 0.3% from Emergency Medical Services (EMS). Overall, 397 (60.9%) pts were managed at home. Two pts managed at home were later evaluated by EMS; neither required admission. Symptoms developed in 56 (8.6%) pts. There were no deaths. Only 40 (6.1%) pts were admitted to a HCF; 18 (45%) pts were hypoglycemic. The development of hypoglycemia (odds ratio [OR] 5.94; p < 0.001) and amount of insulin accidentally administered (OR 1.04; p < 0.001) predicted HCF referral. The type and dose of insulin administered did not predict symptoms. CONCLUSIONS: Based on a retrospective analysis of a single PCC's cases, home observation of asymptomatic patients after unintentional administration of a wrong insulin formulation appears safe. PMID- 23684476 TI - Cognition in schizophrenia: summary Nice Consultation Meeting 2012. PMID- 23684479 TI - Effects of mood and rumination on cortisol levels in daily life: an ambulatory assessment study in remitted depressed patients and healthy controls. AB - The influence of naturally occurring emotional and cognitive experiences on hypothalamic-pituitary-adrenal axis (HPAA) activity is still underinvestigated, particularly in clinical populations. The present study examined effects of mood and rumination on cortisol levels in daily life in remitted depressed patients with recurrent episodes or a chronic precourse (n=31) and healthy controls (n=32). Ambulatory assessment of subjective variables (valence, calmness, energetic-arousal, ruminative self-focus), daily stressors, and saliva cortisol samples was performed five times a day on two consecutive workdays, whereby cortisol was collected 20min after the subjective assessments. In addition, depressive symptoms and trait rumination (brooding, reflection) were measured retrospectively. Multilevel models revealed that remitted depressed patients showed lower cortisol activity compared to healthy controls. Depressive symptoms and trait rumination did not predict HPAA activity, whereas, by controlling for daily stressors, higher daily means of ruminative self-focus and lower daily means of valence, energetic arousal and calmness were associated with higher daily cortisol levels. Separate analyses per group revealed that mean daily ruminative self-focus predicted higher cortisol in both samples. In contrast, lower daily means of calmness, but also of valence and energetic arousal, were significantly linked to higher cortisol output only in healthy controls, but not in the patient sample. These findings indicate that naturally occurring rumination and low mood are associated with increased activation of the HPAA in daily life. Moreover, our data revealed a potentially reduced mood-cortisol coupling in remitted recurrent depression, possibly indicating that during the course of recurrent depression HPAA activation might become less responsive toward subtle emotional experiences in natural contexts. PMID- 23684480 TI - What future for neuroendocrinology in psychiatry? AB - In psychiatry, neuroendocrine techniques were initially considered a potential "window into the brain" by indirectly marking central nervous system limbic dysfunction. At present this conception has evolved, owing to significant progress over the last decades demonstrating direct involvement of neuropeptides and neurohormones in psychiatric diseases. In a synchronic perspective, neuroendocrine investigations evaluate a functional status at a given moment in the evolution of the disease, which results from both etiopathogenic processes and compensatory homeostatic mechanisms. These vital physiological changes appear to be potential targets for novel hormonally based pharmacotherapies. However, in the past few years, the interest for the study of neuroendocrine dysregulations in psychiatric patients has declined. In order to better understand this relative disinterest, this article will attempt to shed light on strengths and limitations of the neuroendocrine approaches in psychiatry. It is necessary to bear in mind that the usefulness of these techniques in the clinical, pathophysiological and therapeutic fields depends largely on the selectivity of stimuli and the appropriateness of the methodologies used. Owing to the complexity of the clinical phenomena, multifactorial approaches (combining several neuroendocrine challenge tests to imaging, immunological, neurophysiological, neurochemical and/or genetic techniques) are to be privileged in psychiatric investigations. Despite the inherent limitations of these approaches, due to their technical and ethical constraints, the neuroendocrine strategy can inform modern clinical practice and lead to new breakthroughs in future science and practice. PMID- 23684478 TI - Adult cognitive ability and socioeconomic status as mediators of the effects of childhood disadvantage on salivary cortisol in aging adults. AB - In this longitudinal study we investigate the influence of childhood disadvantage on midlife hypothalamic-pituitary-adrenal (HPA) axis regulation. Two mechanisms by which early life stress may affect later pathophysiology are through its influence on cognitive functioning or later socioeconomic (SES) disadvantage. We predicted that individual differences in young adult cognitive ability and midlife SES would mediate the influence of childhood disadvantage on midlife cortisol. On each of three nonconsecutive days, participants provided five salivary cortisol samples corresponding to their diurnal rhythm (N=727 men; mean age 55, SD=2.6). We calculated three measures of cortisol regulation (area-under the curve cortisol reflecting total daytime cortisol output; cortisol-awakening response; and wake-to-bed slope), averaging scores for each measure across multiple days. Childhood disadvantage combined four dichotomous indicators used previously by Rutter (1985): father low SES; mother education less than 12th grade; major family disruption/separation before age 18; and large family size (more than 5 siblings). The two mediators were a measure of general cognitive ability assessed at age 20 and highest achieved midlife SES. Men from more disadvantaged childhoods were significantly more likely to have dysregulated cortisol at midlife, with higher daytime cortisol levels decades after their childhood experience. Effects of childhood disadvantage were both direct and indirect. Cognitive ability and adult SES, however, only partially mediated the associations between early life stress and midlife cortisol. Specific indirect effects accounted for 33.8% of the total effect of childhood disadvantage [beta=0.12 (0.05; 0.18)] on total daytime cortisol. Associations remained significant after accounting for ethnicity, smoking status, and self-reported depressive symptoms. PMID- 23684481 TI - Bcl-2 gene silence enhances the sensitivity toward 5-Fluorouracil in gastric adenocarcinoma cells. AB - Because of increased insensitivity or resistance to chemical treatment in tumor patients, specific apoptotic gene silence may provide a rational approach for the development of novel therapeutic strategies. This study was to investigate whether downregulation of Bcl-2 expression by small interfering RNA (siRNA) against the Bcl-2 gene would enhance the apoptosis and sensitivity of gastric adenocarcinoma SGC-7901 cell to 5-Fluorouracil. Transfections of SGC-7901 cells with siRNA were performed using cationic liposomes. Sequence-specific downregulation of Bcl-2 expression was measured by RT-PCR and Western blot analysis. Cell proliferation assay was determined by MTT assay and apoptotic cell rates were determined by flow cytometry assay. Results showed that the siRNA could downregulate Bcl-2 expression, which increased apoptosis and sensitivity of SGC-7901 cell to 5-Fluorouracil (P<0.05). This study indicated that inhibition of Bcl-2 expression by siRNA would be useful a new useful protocol to increase the effect of 5-Fluorouracil on treatment of gastric adenocarcinoma, which may play an important role in developing novel therapeutic strategies in the future. PMID- 23684482 TI - Progressive burden of myelofibrosis in untreated patients: assessment of patient reported outcomes in patients randomized to placebo in the COMFORT-I study. AB - Patient-reported outcomes (PROs) and spleen size in patients not receiving therapy (N=154) in COMFORT-I, a randomized, double-blind study of the JAK1/JAK2 inhibitor ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis were evaluated. Baseline PROs indicated considerable disease burden. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 scores, modified Myelofibrosis Symptom Assessment Form v2.0 Total Symptom Score, and Patient Reported Outcome Measurement Information System Fatigue scores worsened from baseline through week 24. At weeks 4 and 24, 18.3 and 40.2% of patients evaluated their condition as having worsened from baseline on the Patient Global Impression of Change questionnaire. Spleen volume and palpable length increased in most patients. These results demonstrate the progressive and debilitating effects of myelofibrosis. The consequences of delayed intervention should be assessed in the management of patients with myelofibrosis and treatment should be considered as clinically indicated for symptomatic relief or splenomegaly control. PMID- 23684483 TI - MDR-1 and GST polymorphisms are involved in myelodysplasia progression. AB - Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal stem cell disorders characterized by abnormal hematopoietic differentiation and maturation, which progress toward acute leukemia in approximately 30% of the cases. Drug metabolism polymorphisms in Cytochrome P450 2B6 (CYP2B6), Glutathione S transferase (GST) and Dehydrogenase Quinone 1 (NQO1) enzymes and P-glycoprotein (MDR-1) could modify enzyme activity. Thus, the aim of this study was to identify the influence of CYP2B6 G15631T, GSTT1, GSTM1, NQO1 C609T and MDR-1 C3435T polymorphisms on MDS progression. We analyzed 78 MDS patients using the PCR-RFLP and multiplex method. The frequency of GST deletions and MDR-1 CC genotype was lower in progression-free patients compared to patients with progression; GST: 17% vs. 35% (P=0.018); MDR-1 gene: 19% vs. 48% (P=0.012). We also verified the influence of GST deletions and MDR-1 C3435T on patient overall survival and found no significant difference (RR=0.75; P=0.599 and RR=0.79; P=0.594 respectively). We concluded that GSTM1 deletion may contribute toward MDS progression probably due to toxic metabolite accumulation which generates cell toxicity and DNA damage. Moreover, MDR-1 C3435T may have a protective effect against MDS progression because the expected lower expression of P-glycoprotein would lead to a higher degree of cell death. To the best of our knowledge, this is the first study showing the relationship of these polymorphisms with MDS progression. PMID- 23684485 TI - Perspectives of young people and their parents in the transition of cochlear implant services: implications for improved service delivery. AB - OBJECTIVES: Youth and young adults with cochlear implants are now transitioning from pediatric to adult services in increasing numbers. Research in other areas of health care has indicated that there is a gap in the transition from pediatric services for the young adult, and that it is important to obtain their perspectives to reduce disruption and improve care. Previous research has documented issues from the perspective of cochlear implant professionals. The objectives of this study were to examine current practices from the perspective of young adults and their families and to make recommendations for future practice. METHODS: Interviews were conducted with 11 individuals, including cochlear implant recipients and their parents. All patients were within 4 years of transition between pediatric and adult hospital services: four youths were pediatric patients, and two had been discharged to adult services. Qualitative research methodology was used to identify key themes. RESULTS: All participants indicated that they had not anticipated a change to an adult hospital as part of their plan of care. Key themes from interviews were differences between pediatric and adult hospitals, challenges in establishing new relationships with professionals, specific concerns about new health care settings and procedures, and the need for youth to develop independent health-related skills in the context of parental involvement. DISCUSSION: Themes identified through interviews with young people with cochlear implants and their parents were similar to research in other areas of health care, as well as to themes identified in focus groups with professionals providing cochlear implant services. There were some differences which highlight both needs in the provision of health care and opportunities for providers and patients to collaborate to provide improved service delivery. PMID- 23684486 TI - Carpentier-Edwards pericardial valve in the aortic position: 25-years experience. AB - BACKGROUND: The Carpentier-Edwards pericardial valve was designed to minimize structural valve deterioration. Excellent durability and low incidence of valve related complications have been reported. The objective of the present study was to analyze clinical results after 25 years of experience with this valve implanted in the aortic position. The effect of patient age at the time of surgery was also evaluated. METHODS: This is a retrospective cohort study of 2,405 patients from November 1981 to March 2011. Primary outcomes of interest were survival and freedom from major adverse effects such as thromboembolic, endocarditis, and reoperation. RESULTS: Sixty percent were male, with a mean age of 71 +/- 9 years old. Actuarial survival rates including early deaths averaged 78% +/- 2%, 55% +/- 2%, and 16 % +/- 2% after 5, 10, and 20 years of follow-up, respectively. The freedom rate of valve reoperation for prosthesis dysfunction and all other causes averaged 98 % +/- 0.2%, 96% +/- 1%, and 67% +/- 4% at 5, 10, and 20 years. Patients younger than 60 years of age had a 15-year survival averaging 54% +/- 5% compared with patients aged between 60 and 70 years of age averaging 46% +/- 3% and with patients older than 70 years of age averaging 28% +/- 3% (p = 0.001). Survival at 5, 10, and 20 years for patients who had concomitant CABG [coronary artery bypass grafting] were 78% +/- 1%, 55% +/- 2%, and 9% +/- 3% compared with no concomitant CABG (84% +/- 1%, 62% +/- 2%, and 22% +/- 3% (p < 0.001)). CONCLUSIONS: Carpentier-Edwards pericardial valve implantation in the aortic position is secure and durable. The effects of age influence reoperation rate and survival as well as a concomitant coronary artery bypass procedure. PMID- 23684488 TI - Cardiovascular and kidney disease traits-pleiotropic or just polygenic? PMID- 23684487 TI - Normalized cardiopulmonary exercise function in patients with pectus excavatum three years after operation. AB - BACKGROUND: During exercise cardiac function is often limited in patients with pectus excavatum. Therefore, we hypothesized that cardiopulmonary exercise function would improve after the Nuss procedure. METHODS: Seventy-five teenagers (49 patients, 26 controls) were investigated at rest and during bicycle exercise before surgery, and 1 year and 3 years postoperatively (after pectus-bar removal). Echocardiography and lung spirometry were performed at rest. Cardiac output, heart rate, and aerobic exercise capacity were measured using a photoacoustic gas-rebreathing technique during rest and exercise. RESULTS: Forty four patients and 26 controls completed 3 years follow-up. Preoperatively, patients had lower maximum cardiac index, mean +/- SD, 6.6 +/- 1.2 l.min(-1).m( 2) compared with controls 8.1 +/- 1.0 l.min(-1).m(-2) during exercise (p = 0.0001). One year and 3 years postoperatively, patients' maximum cardiac index had increased significantly and after 3 years there was no difference between patients and controls (8.1 +/- 1.2 l.min(-1).m(-2) and 8.3 +/- 1.6 l.min(-1).m( 2), respectively [p = 0.572]). The maximum oxygen consumption was unchanged. Left ventricular dimensions increased in patients over 3 years; however, no difference was seen between the 2 groups. Preoperatively, patients had lower forced expiratory volume in the first second of expiration (FEV1; 86% +/- 13%) as compared with controls (94% +/- 10%), p = 0.009. Postoperatively, no difference was found in FEV1 between the 2 groups. CONCLUSIONS: Before operation, FEV1 and maximum cardiac index were lower in patients compared with healthy, age-matched controls. One year after, both parameters had increased, although only FEV1 had normalized. After 3 years and bar removal, cardiopulmonary function in patients during exercise had normalized. PMID- 23684489 TI - alpha-Klotho and kidney function decline: an important step forward in understanding the link between mineral metabolism and kidney disease progression. PMID- 23684490 TI - Dialysis bundling and small dialysis organizations: a call for close monitoring. PMID- 23684491 TI - Bioimpedance technology and optimal fluid management. PMID- 23684493 TI - Understanding hypernatremia. PMID- 23684492 TI - Hurricane Sandy as a kidney failure disaster. PMID- 23684494 TI - In reply to 'understanding hypernatremia' and 'thiazides for hypervolemic hypernatremia: a valid therapeutic strategy?'. PMID- 23684495 TI - Thiazides for hypervolemic hypernatremia: a valid therapeutic strategy? PMID- 23684496 TI - Relationship between retinopathy and cognitive impairment may be confounded by visual impairment. PMID- 23684497 TI - Single-side renal sympathetic denervation in a hypertensive patient with a single kidney. PMID- 23684498 TI - Quiz page June 2013: graft dysfunction after kidney transplantation in an adolescent. PMID- 23684499 TI - Selection of candidate genes for grape proanthocyanidin pathway by an integrative approach. AB - Proanthocyanidins (PA) play a major role in plant protection against biotic and abiotic stresses. Moreover these molecules are known to be beneficial for human health and are responsible for astringency of foods and beverages such as wine and thus have a great impact on the final quality of the product. Genes playing a role in the PA pathway are only partially known. The amount of available transcriptomic and genetic data to select candidate genes without a priori knowledge from orthologous function increases every day. However, the methods used so far generate so many candidate genes that it is impossible to validate all of them. In this study, we used an integrative strategy based on different screening methods to select a reduced list of candidate genes. We have crossed results from different screening methods including QTL mapping and three transcriptomic studies to select 20 candidate genes, located in QTL intervals and fulfilling at least two transcriptomic screenings. This list includes three glucosyltransferases, already suspected to have a role in the PA biosynthetic pathway. Among the 17 remaining genes, we selected three genes to perform further analysis by association genetic studies. For each of these genes, we found a polymorphism linked to PA variation. The three genes (VvMybC2-L1, VvGAT-like and VvCob-like), not previously known to play a role in PA synthesis, are promising candidates for further molecular physiology studies. PMID- 23684500 TI - Echocardiographic estimation of pulmonary arterial systolic pressure in acute heart failure. Prognostic implications. AB - BACKGROUND: Prognostic implications of echocardiographic assessment of pulmonary hypertension (PH) in non-selected patients hospitalized for acute heart failure (AHF) are not clearly defined. The aim of this study was to evaluate the association between echocardiography-derived PH in AHF and 1-year all-cause mortality. METHODS: We prospectively included 1210 consecutive patients admitted for AHF. Patients with significant heart valve disease were excluded. Pulmonary arterial systolic pressure (PASP) was estimated using transthoracic echocardiography during hospitalization (mean time after admission 96+/-24h). Patients were categorized as follows: non-measurable, normal PASP (PASP<=35mmHg), mild (PASP 36-45mmHg), moderate (PASP 46-60mmHg) and severe PH (PASP >60mmHg). The independent association between PASP and 1-year mortality was assessed with Cox regression analysis. RESULTS: At 1-year follow-up, 232 (19.2%) deaths were registered. PASP was measured in 502 (41.6%) patients with a median of 46 [38-55] mmHg. The distribution of population was: 708 (58.5%), 76 (6.3%), 147 (12.1%), 190 (15.7%) and 89 (7.4%) for non-measurable, normal PASP, mild, moderate and severe PH, respectively. One-year mortality was lower for patients with normal PASP (1.32 per 10 person-years), intermediate for patients with non-measurable, mild and moderate PH (2.48, 2.46 and 2.62 per 10 persons-year, respectively) and higher for those with severe PH (4.89 per 10 person-years). After multivariate adjustment, only patients with PASP >60mmHg displayed significant adjusted increase in the risk of 1-year all-cause mortality, compared to patients with normal PASP (HR=2.56; CI 95%: 1.05-6.22, p=0.038). CONCLUSIONS: In AHF, severe pulmonary hypertension derived by echocardiography is an independent predictor of 1-year-mortality. PMID- 23684502 TI - [The public health in historical perspective]. PMID- 23684501 TI - Inactivation of Wnt/beta-catenin signaling in human adipose-derived stem cells is necessary for chondrogenic differentiation and maintenance. AB - The Wnt/beta-catenin signaling pathway plays critical roles in self-renewal and differentiation of mesenchymal stem cells. However, very little is known about its role in the chondrogenesis of human adipose-derived stem cells (hADSCs). In this study, we analyzed protein expression of several key components of the Wnt/beta-catenin signaling pathway using a 21-day in vitro model of hADSC chondrogenesis. Wnt1, beta-catenin, and GSK3beta levels increased sharply at day 12, peaked at day 18, and then declined. Expression of TCF1, a target gene of Wnt/beta-catenin signaling, closely followed that of Wnt1. These results were consistent with changes in endonuclear beta-catenin levels. Gene expression of the chondrocyte-specific markers, collagen type II (COL II), SOX9, and aggrecan, increased during hADSC chondrogenesis, peaked at day 12, and then declined. Adding a Wnt inhibitor (days 0-21) resulted in consistently elevated levels of COL II, SOX9, and aggrecan mRNA. In contrast, adding Wnt1 (days 0-21) to cultures led to sustained Wnt/beta-catenin signaling over the 21 days and suppressed expression of chondrocyte-specific markers. Moreover, adding Wnt1 at late stages of differentiation (day 18) further diminished chondrocyte-specific marker expression. Together, these results showed that inactivation of Wnt/beta-catenin signaling is needed for the progression of chondrogenesis and the maturation and phenotype maintenance of chondroid cells. PMID- 23684503 TI - Changes of age at onset in patients with type 1 diabetes during the last two decades. PMID- 23684504 TI - Effect of treatment with atenolol on 5-year survival in cats with preclinical (asymptomatic) hypertrophic cardiomyopathy. AB - OBJECTIVES: To investigate the effect of treatment with atenolol on 5-year survival in cats with preclinical hypertrophic cardiomyopathy (HCM). ANIMALS: 63 Client-owned cats with preclinical HCM and 31 healthy control cats. METHODS: Prospective, observational, open-label, clinical cohort study. Cats with HCM were diagnosed by echocardiography, treated with atenolol (6.25-12.5 mg q12h, PO; n = 42) or untreated (n = 21), and were observed for 5 years after enrollment. The study end point was death from any cause. Cats of similar body weight, age, gender, and breed without evidence of heart disease were studied concurrently and served as controls. RESULTS: During the observational period, 27 cats with HCM died; 14 (22%) due to cardiac disease and 13 (21%) due to non-cardiac disease. Ten control cats (32%) died of non-cardiac disease. There was no significant difference (P = 0.307) in all-cause mortality between control and HCM. Cardiac mortality was higher in cats with HCM compared to control cats (P = 0.005). There was no significant difference in all-cause mortality (P = 0.729) and cardiac mortality (P = 0.897) between cats with HCM treated or untreated with atenolol. Age and left atrial size at diagnosis were the only predictors of 5-year outcome. CONCLUSIONS: Our study failed to demonstrate an effect of atenolol on 5-year survival in cats with preclinical HCM. PMID- 23684505 TI - Atrial natriuretic peptide and cardiac troponin I concentrations in healthy Warmblood horses and in Warmblood horses with mitral regurgitation at rest and after exercise. AB - OBJECTIVE: Atrial natriuretic peptide (ANP) and cardiac troponin I (cTnI) serve as biomarkers for increased cardiac pressure/volume loading and for myocardial stress or damage. The objective was to describe the time course of plasma ANP concentrations (CpANP) and plasma cTnI concentrations (CpcTnI) in horses with mitral regurgitation (MR) compared to healthy horses at rest and after exercise, and to describe the relationship of CpANP with cardiac dimensions and intracardiac pressures. ANIMALS: 15 healthy Warmblood horses and 7 Warmblood horses with MR. METHODS: Cardiac dimensions at rest were measured using echocardiography. All horses underwent standardized treadmill exercise. Biomarker concentrations and intracardiac pressures were measured at rest and after exercise. Hypotheses were tested using statistical methods. The level of significance was P < 0.05. RESULTS: Horses with MR showed increased left atrial (LA) and left ventricular (LV) dimensions but similar exercise capacity compared to healthy horses. Pulmonary capillary wedge pressures (PCWP) and CpANP increased with exercise. Horses with MR had higher PCWP and higher CpANP at rest and after exercise compared to healthy horses, with the maximum difference in CpANP reached 10 min after exercise. CpANP was significantly related to PCWP and - although inconsistently and only in healthy horses - to echocardiographic indices of LA and LV size and function. CpcTnI was low throughout the study in both groups. CONCLUSIONS: CpANP is increased in horses with MR and is related to LA pressures and to left heart dimensions. MR is not necessarily associated with exercise intolerance and exercise-induced myocardial stress or damage. PMID- 23684506 TI - The ontogeny of escape behavior, locomotor performance, and the hind limb in Sceloporus woodi. AB - Flight initiation distance describes the distance at which an animal flees during the approach of a predator. This distance presumably reflects the tradeoff between the benefits of fleeing versus the benefits of remaining stationary. Throughout ontogeny, the costs and benefits of flight may change substantially due to growth-related changes in sprint speed; thus ontogenetic variation in flight initiation distance may be substantial. If escape velocity is essential for surviving predator encounters, then juveniles should either tolerate short flight initiation distances and rely on crypsis, or should have high flight initiation distances to remain far away from their predators. We examined this hypothesis in a small, short-lived lizard (Sceloporus woodi). Flight initiation distance and escape velocity were recorded on an ontogenetic series of lizards in the field. Maximal running velocity was also quantified in a laboratory raceway to establish if escape velocities in the field compared with maximal velocities as measured in the lab. Finally a subset of individuals was used to quantify how muscle and limb size scale with body size throughout ontogeny. Flight initiation distance increased with body size; larger animals had higher flight initiation distances. Small lizards had short flight initiation distances and remained immobile longer, thus relying on crypsis for concealment. Escape velocity in the field did not vary with body size, yet maximum velocity in the lab did increase with size. Hind limb morphology scaled isometrically with body size. Isometric scaling of the hind limb elements and its musculature, coupled with similarities in sprint and escape velocity across ontogeny, demonstrate that smaller S. woodi must rely on crypsis to avoid predator encounters, whereas adults alter their behavior via larger flight initiation distance and lower (presumably less expensive) escape velocities. PMID- 23684507 TI - The effect of exergaming on vascular function in children. AB - OBJECTIVES: To assess whether exergaming can induce measurable changes in heart rate (HR), energy expenditure (EE), and flow-mediated dilation (FMD) arterial function in healthy children. STUDY DESIGN: Fifteen children (8 males, 10.1 +/- 0.7 years, body mass index 17.9 +/- 2.4 kg.m(-2)) undertook a graded exercise test and 2 * 15 minute exergaming sessions (Xbox 360-Kinect); high intensity exergaming (HiE, Kinect Sports-200 m Hurdles) and low intensity exergaming (LoE, Kinect Sports-Ten Pin Bowling). Brachial artery FMD, a measure of endothelial function and arterial health, was measured before and immediately after each exergaming intervention. Actihearts were used to measure EE and HR during game play and a physical activity enjoyment scale assessed enjoyment. RESULTS: Average HR during HiE (146 +/- 11 beats per minute) was greater than during LoE (104 +/- 11 beats per minute, P < .05), a pattern reinforced by EE data (HiE 294.6 +/- 75.2 J.min(-1).kg(-1), LoE 73.7 +/- 44.0 J.min(-1).kg(-1), P < .05). FMD decreased after HiE (P < .05), whereas no change was observed following LoE. Subjects reported no differences in enjoyment between LoE and HiE. CONCLUSION: HiE, but not LoE, induced large HR and EE responses that were associated with effects on vascular function. This study suggests that an acute bout of HiE exergaming may provide a substrate for beneficial arterial adaptations in children. PMID- 23684508 TI - Vascular microanastomosis through an endoscopic approach: feasibility study on two cadaver forearms. AB - The size of the incisions for free muscle flaps is often very large, and a source of deep adhesions and unaesthetic scars. But it is justified by performing the microsurgical step comfortably. In the hopes of shortening the size of incisions, the goal of this work was to study the feasibility of vascular microanastomoses through an endoscopic approach. The material consisted of two cadavers, a telemanipulator, and a vascular clamp. The antebrachial skin was detached then distended by gas insufflation. Four incisions, 1cm each, allowed the insertion of four trocarts connected to the telemanipulator. The artery was dissected (radial or ulnar) and the vascular clamp was introduced under the skin through one of the trocarts, and then installed on the dissected artery. The vascular anastomosis was performed with the use of a 10/0 nylon suture. The anastomosis lasted 2 hours under insufflation without any leak. The two arteries were identified then dissected without difficulty. The anastomosis was performed in good conditions. The assembling and disassembling of the clamp were time consuming. The main difficulties were caused by a long suture and a very fragile needle. Our results demonstrate the feasibility of vascular microanastomosis through an endoscopic approach. The next step is to perform the first clinical case for example on a latissimus dorsi free muscle flap. PMID- 23684509 TI - Intranodular clusters of activated cells with T follicular helper phenotype in nodular lymphocyte predominant Hodgkin lymphoma: a pilot study of 32 cases from Finland. AB - In nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), little is known about the presence of intranodular clusters of cytologically activated lymphoid cells producing a moth-eaten pattern histologically. This pilot study of 32 NLPHL cases from Finland ascertained (1) the frequency of the intranodular clusters of activated lymphoid cells, (2) the immunophenotype of the activated cells, (3) the size and immunophenotype of the rosetting cells, and (4) the clinical significance of the activated cells. Histologically, intranodular clusters of activated cells produced a moth-eaten pattern in 100% (32 cases; subtle in 62.5%, overt in 37.5%). In immunostains, activated cells in subtle clusters (20 cases) were very difficult to identify. Twelve cases had overt clusters of activated cells, which were positive with CD3, CD4, PD1, CXCL13 (T follicular helper [T(FH)] phenotype), but rarely with Ki-67 and BCL2. Most activated rosetting cells had the same immunophenotype as the nonrosetting cells, except for CXCL13. Clinical presentation for all 32 Finnish patients was distinctive: 97% men, 97% with peripheral lymphadenopathy and 35.5% with stage III/IV disease. Only 22% relapsed; 97% were in remission. There was no significant clinical difference between cases with overt and subtle clusters. Intranodular activated TFH cells in NLPHL appeared to be nonproliferating and not long-living, and they were not associated with any adverse clinical outcome. Although most activated cells were TFH cells, it seemed that they were unable to increase the number of malignant cells. The pathogenetic role of the intranodular activated TFH and the small T cells in NLPHL needs further investigation. PMID- 23684510 TI - Fibronectin expression in carcinoma cells correlates with tumor aggressiveness and poor clinical outcome in patients with invasive breast cancer. AB - Fibronectin (FN), a large heterodimeric glycoprotein, can be found in soluble form in plasma or in insoluble form as an extracellular matrix protein. Cellular FN is produced by various types of benign and malignant epithelial and mesenchymal cells and is widely distributed in malignant tumors. We evaluated FN expression in cancer cells (epithelial FN; E-FN) and intratumor stroma (stromal FN, S-FN) of 1596 invasive breast cancer samples using immunohistochemistry on tissue microarrays. Correlations of FN expression with clinicopathologic factors and patient survival were investigated. Among 1512 informative cases, E-FN expression was observed in 355 (23.5%) cases, and S-FN expression showed no/weak staining in 362 (23.9%), moderate staining in 744 (49.2%), and strong staining in 406 (26.9%) cases. E-FN expression was correlated with advanced pT (P < .001) and pN (P < .001), histologic type (P = .006), high histologic grade (P < .001), lymphovascular invasion (P < .001), hormone receptor negativity (P < .001), and human epidermal growth factor receptor-2 (HER2) positivity (P < .001). Strong S FN expression showed an association with advanced pN (P = .002), histologic type (P < .001), high histologic grade (P < .001), lymphovascular invasion (P < .001), and HER2 positivity (P < .001). Patients with E-FN expression showed worse overall survival (P < .001) and disease-free survival (P < .001) than did those with negative expression of FN. E-FN expression was an independent prognostic factor, especially in the hormone receptor-positive group. Expression of S-FN did not have a significant effect on patient survival. In conclusion, E-FN expression could be a promising prognostic marker in patients with invasive breast cancer. PMID- 23684511 TI - Obstructive sleep apnea and cardiovascular risk: meta-analysis of prospective cohort studies. AB - BACKGROUND: Previous studies suggest obstructive sleep apnea (OSA) may increase cardiovascular risk, but the results are inconclusive due to various limitations. We aimed to systematically evaluate the effect of OSA on the incidence of cardiovascular events by a meta-analysis of prospective cohort studies. METHODS: We searched multiple electronic databases for studies that examined the prospective relationship between OSA and incidence of coronary heart disease (CHD), stroke, or total cardiovascular diseases (CVD) among adults. Either fixed- or random-effects models were used to calculate the pooled risk estimates. Sensitivity analysis was conducted to examine the robustness of pooled outcomes. RESULTS: Of 17 studies included, 9 reported results on total CVD, 7 reported on fatal or non-fatal CHD, and 10 reported on fatal or non-fatal stroke. The pooled relative risks (95% confidence interval) for individuals with moderate-severe OSA compared with the reference group were 2.48 (1.98-3.10) for total CVD, 1.37 (0.95 1.98) for CHD, and 2.02 (1.40-2.90) for stroke. These results did not materially change in the sensitivity analyses according to various inclusion criteria. CONCLUSIONS: In conclusion, findings from this meta-analysis supported that moderate-severe OSA significantly increased cardiovascular risk, in particular stroke risk. PMID- 23684512 TI - Hypercholesterolemia and reduced HDL-C promote hematopoietic stem cell proliferation and monocytosis: studies in mice and FH children. AB - Previous studies have shown that mice with defects in cellular cholesterol efflux show hematopoietic stem cell (HSPC) and myeloid proliferation, contributing to atherogenesis. We hypothesized that the combination of hypercholesterolemia and defective cholesterol efflux would promote HSPC expansion and leukocytosis more prominently than either alone. We crossed Ldlr(-/-) with Apoa1(-/-) mice and found that compared to Ldlr(-/-) mice, Ldlr(-/-)/Apoa1(+/-) mice, with similar LDL-cholesterol levels but reduced HDL-cholesterol (HDL-C) levels, had expansion of HSPCs, monocytosis and neutrophilia. Ex vivo studies showed that HSPCs expressed high levels of Ldlr, Scarb1 (Srb1), and Lrp1 and were able to take up both native and oxidized LDL. Native LDL directly stimulated HSPC proliferation, while co-incubation with reconstituted HDL attenuated this effect. We also assessed the impact of HDL-C levels on monocytes in children with familial hypercholesterolemia (FH) (n = 49) and found that subjects with the lowest level of HDL-C, had increased monocyte counts compared to the mid and higher HDL-C levels. Overall, HDL-C was inversely correlated with the monocyte count. These data suggest that in mice, a balance of cholesterol uptake and efflux mechanisms may be one factor in driving HSPC proliferation and monocytosis. Higher monocyte counts in children with FH and low HDL-cholesterol suggest a similar pattern in humans. PMID- 23684513 TI - Complexities of gammaherpesvirus transcription revealed by microarrays and RNAseq. AB - Technological advances in genome-wide transcript analysis, referred to as the transcriptome, using microarrays and deep RNA sequencing methodologies are rapidly extending our understanding of the genetic content of the gammaherpesviruses (gammaHVs). These vast transcript analyses continue to uncover the complexity of coding transcripts due to alternative splicing, translation initiation and termination, as well as regulatory RNAs of the gammaHVs. A full assessment of the transcriptome requires that our analysis be extended to the virion and exosomes of infected cells since viral and host mRNAs, miRNAs, and other noncoding RNAs seem purposefully incorporated to exert function upon delivery to naive cells. Understanding the regulation, biogenesis and function of the recently discovered transcripts will extend beyond pathogenesis and oncogenic events to offer key insights for basic RNA processes of the cell. PMID- 23684514 TI - Elevated C-reactive protein and cognitive deficits in individuals with bipolar disorder. AB - BACKGROUND: Some individuals with bipolar disorder have cognitive deficits even when euthymic. In previous studies, we found an association between elevated levels of C-reactive protein (CRP), a marker of inflammation, and reduced cognitive functioning in schizophrenia. This issue has not been examined in bipolar disorder. METHODS: We measured the levels of high sensitivity CRP in serum samples from 107 individuals with bipolar disorder. Cognitive functioning was measured with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Trail Making Test Part A and WAIS Information and Letter Number Sequencing. We estimated the odds of RBANS scores <=70 for participants whose CRP levels were above the 75th and the 90th percentile of the level of non psychiatric controls. We also examined the association between cognitive scores and CRP levels. Covariates included demographic factors, mood symptom severity, cigarette smoking status, and body mass index. RESULTS: There was a significantly increased odds of low RBANS total score for individuals who had a CRP level higher than the 90th percentile (OR=4.32, p=.018) and the 75th percentile (OR=3.07, p=.04)) of the control group. There was an inverse relationship between CRP levels and performance on RBANS total (t=-2.48, p=.015); RBANS immediate memory (t=-2.16, p=.033); RBANS attention (t=-2.18, p=.032); RBANS language (t= 2.13, p=.036); Trail Making A (t=-2.39, p=.019). LIMITATIONS: Factors which we did not measure such as diet, allergen exposure, and underlying autoimmune disorders may contribute to CRP levels. CONCLUSIONS: Inflammation may play a major role in the cognitive deficits associated with bipolar disorder. PMID- 23684515 TI - Altered brain structural connectivity in post-traumatic stress disorder: a diffusion tensor imaging tractography study. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is characterized by dysfunction of several discrete brain regions such as medial prefrontal gyrus with hypoactivation and amygdala with hyperactivation. However, alterations of large scale whole brain topological organization of structural networks remain unclear. METHODS: Seventeen patients with PTSD in motor vehicle accident survivors and 15 normal controls were enrolled in our study. Large-scale structural connectivity network (SCN) was constructed using diffusion tensor tractography, followed by thresholding the mean factional anisotropy matrix of 90 brain regions. Graph theory analysis was then employed to investigate their aberrant topological properties. RESULTS: Both patient and control group showed small-world topology in their SCNs. However, patients with PTSD exhibited abnormal global properties characterized by significantly decreased characteristic shortest path length and normalized characteristic shortest path length. Furthermore, the patient group showed enhanced nodal centralities predominately in salience network including bilateral anterior cingulate and pallidum, and hippocampus/parahippocamus gyrus, and decreased nodal centralities mainly in medial orbital part of superior frontal gyrus. LIMITATIONS: The main limitation of this study is the small sample of PTSD patients, which may lead to decrease the statistic power. Consequently, this study should be considered an exploratory analysis. CONCLUSIONS: These results are consistent with the notion that PTSD can be understood by investigating the dysfunction of large-scale, spatially distributed neural networks, and also provide structural evidences for further exploration of neurocircuitry models in PTSD. PMID- 23684516 TI - Affective temperaments and hopelessness as predictors of health and social functioning in mood disorder patients: a prospective follow-up study. AB - BACKGROUND: Affective disorders are highly disabling illnesses constituting a significant burden for the patients, their family and the society. Therefore, it would be very useful to find tools which carefully subtype these conditions and have a strong and reliable predictive power concerning the course of illness and health and social functioning. To date, the role of hopelessness and affective temperaments in the prediction of health and social functioning and the course of affective disorders has not been studied. Thus, the aim of the present study was to assess whether affective temperaments and hopelessness, measured during hospitalization, can be useful in the prediction of global functioning (the severity of the illness and the presence and severity of psychosocial problems) at follow-up in inpatients with major depressive disorder and bipolar disorder (BD). METHODS: The patients were 96 consecutive patients admitted to the inpatient psychiatric clinic of Sant'Andrea Hospital between January 2009 and December 2010. All patients completed the Temperament Evaluation of Memphis, Pisa, Paris and San Diego (TEMPS-A) and the Beck Hopelessness Scale on admission. They were contacted on average 14 months after discharge and were asked to complete a telephone interview based on the Health of the Nation Outcome Scales (HoNOS). RESULTS: Two patients committed suicide before the follow-up assessment. Around 77% of the patients who completed the follow-up assessment were diagnosed as BD, and around 47% reported severe hopelessness. In the multivariate analyses, a factor derived from hopelessness and hyperthymia scores and unemployment, independently predicted severity of the illness and psychosocial functioning at the follow-up. CONCLUSIONS: Screening for the affective temperament profile and for hopelessness has importance for designing the treatment and rehabilitation plans of affective disorder patients, as these variables are involved in the course and outcome of affective disorder patients and influence their health and social functioning. PMID- 23684517 TI - Cross-sectional imaging of the metal-on-metal hip prosthesis: the London ultrasound protocol. PMID- 23684518 TI - Variants of hepatic arterial supply in a Caribbean population: a computed tomography based study. AB - AIM: To evaluate the spectrum of hepatic arterial variants in unselected patients undergoing computed tomography (CT) of the abdomen at the main regional referral centre in the northern Anglophone Caribbean. MATERIALS AND METHODS: Two radiologists independently reviewed 309 CT angiographic studies performed over 2 years between 1 July 2010 and 30 June 2012 at a regional hepatobiliary referral centre for the Northern Caribbean. The anatomical variations were described according to a conventional classification proposed by Michels et al. RESULTS: In this Caribbean population, the majority of patients had conventional Michels' type 1 vascular anatomy (63.4%). However, a statistically significantly greater incidence of Michels' type 2 variations (20.4%) were found than that reported in the international literature and a lower incidence of type 3 (5.2%), type 6 (0.6%), and type 9 (0) patterns than previously reported. One case with variations not previously described in this classification was also encountered. CONCLUSION: Although 63.4% of persons in a Caribbean population have conventional vascular anatomy, the distribution of anatomical variants is quite different to that seen in North American and European centres. Interventional radiologists and hepatobiliary surgeons practicing in the Caribbean must be cognizant of these differences in order to minimize morbidity and mortality during invasive procedures. PMID- 23684519 TI - Comparison of the reliability of two hydronephrosis grading systems: the Society for Foetal Urology grading system vs. the Onen grading system. AB - AIM: To compare the reliability of the conventional ultrasonography grading system for hydronephrosis as suggested by the Society for Fetal Urology (SFU) in 1993 and that developed by Onen in 2007. MATERIALS AND METHODS: One hundred and eighty kidneys in 90 paediatric patients were assessed by four radiologists using each of the two grading systems twice. The SFU system was graded 0-4 (0 = no hydronephrosis; 1 = visualized only renal pelvis; 2 = plus a few caliceal dilatation; 3 = all calyceal dilatation; 4 = plus parenchymal thinning). The Onen system was graded 0-4 (0 = no hydronephrosis; 1 = only renal pelvic dilatation; 2 = plus caliceal dilatation; 3 = plus <50% renal parenchymal loss; 4 = plus >50% renal parenchymal loss). Cohen's kappa statistic was used to estimate intra- and interobserver agreement. The weighted least-squares approach was used to compare the intra-observer agreement, and bootstrapping was used to compare the interobserver agreement between the two systems. RESULTS: Intra-observer agreement was substantial to almost perfect in both the SFU (kappa 0.79-0.95) and the Onen (kappa 0.66-0.97) grading system without difference. The overall interobserver agreement was substantial in both the SFU (kappa 0.61-0.68) and the Onen (kappa 0.66-0.76) grading system. However, interobserver agreement was fair to moderate for SFU grades 1 and 2 and Onen grades 2 and 3. CONCLUSION: Both the SFU and Onen grading system are reliable with good intra- and interobserver agreement. However, decreased interobserver agreement was demonstrated for SFU grades 1 and 2 and Onen grades 2 and 3. PMID- 23684520 TI - Classification of congenital anomalies of the hand and upper limb: development and assessment of a new system. AB - The Oberg, Manske, and Tonkin (OMT) classification of congenital hand and upper limb anomalies was proposed in 2010 as a replacement for the Swanson International Federation of Societies for Surgery of the Hand classification system, which has been the accepted system of classification for the international surgical community since 1976. The OMT system separates malformations from deformations and dysplasias. Malformations are subdivided according to the axis of formation and differentiation that is primarily affected and whether the anomalies involve the whole limb or the hand plate. This review outlines the development of classification systems and explores the difficulty of incorporating our current knowledge of limb embryogenesis at a molecular level into current systems. An assessment of the efficacy of the OMT classification demonstrates acceptable inter- and intraobserver reliability. A prospective review of 101 patients confirms that all diagnoses could be classified within the OMT system. Consensus expert opinion allowed classification of those conditions for which there is not a clear understanding of the mechanism of dysmorphology. A refined and expanded OMT classification is presented. PMID- 23684521 TI - Lipofibromatous hamartoma of the median nerve: a comprehensive review and systematic approach to evaluation, diagnosis, and treatment. AB - Many modalities exist for diagnosing and treating lipofibromatous hamartoma (LFH), with no clear consensus. This is the first comprehensive study to review the existing literature on LFH of the median nerve and to suggest a systematic approach to its diagnosis and treatment. An electronic and manual search was conducted on Medline, Embase, Google Scholar, Current Contents, and Science Citation Index for original and review articles in English or French, from 1946 to November 2012. After 2 levels of screening, 106 references containing case reports were retained. Data extraction included patient demographics, clinical information, diagnostic modalities, treatment, and follow-up. A total of 180 cases were reported in the literature. One third of patients had associated macrodactyly (32%). Gender distribution is equal in LFH with or without macrodactyly, with most patients (71%) presenting before age 30 years. The main presenting symptom is an enlargement (88%) over the volar forearm, wrist, or hand, with or without digital hypertrophy, followed by paresthesia (39%). A soft, mobile, nontender, nonfluctuant mass with variable degree of compressive median neuropathy is found on physical examination. Biopsy, which reveals abundant mature fat cells and fibrous connective tissue infiltrating between nerve fascicles and the space between the epineurium and the perineurium, is not necessary because the pathognomonic features of the mass on magnetic resonance imaging offer an accurate diagnosis. Treatment of nerve compression symptoms and macrodactyly should be addressed separately. Carpal tunnel release is the mainstay of treatment for neuropathy, and ray or digital amputation, wedge osteotomy, middle phalangectomy with arthroplasty, and epiphysiodesis are suggested options in the management of macrodactyly. Based on our review of the literature, we propose an algorithm for the diagnosis and treatment of LFH of the median nerve with or without macrodactyly. PMID- 23684522 TI - Update on embryology of the upper limb. AB - Current concepts in the steps of upper limb development and the way the limb is patterned along its 3 spatial axes are reviewed. Finally, the embryogenesis of various congenital hand anomalies is delineated with an emphasis on the pathogenetic basis for each anomaly. PMID- 23684523 TI - Quantification of branched-chain keto acids in tissue by ultra fast liquid chromatography-mass spectrometry. AB - Branched-chain keto acids (BCKAs) are associated with increased susceptibility to several degenerative diseases. However, BCKA concentrations in tissues or the amounts of tissue available are frequently at the limit of detection for standard plasma methods. To accurately and quickly determine tissue BCKAs, we have developed a sensitive ultra fast liquid chromatography-mass spectrometry (UFLC MS) method. BCKAs from deproteinized tissue extractions were o-phenylenediamine (OPD) derivatized, ethyl acetate extracted, lyophilized in a vacuum centrifuge, and reconstituted in 200 mM ammonium acetate. Samples were injected onto a Shimadzu UFLC system coupled to an AB-Sciex 5600 Triple TOF mass spectrometer instrument that detected masses of the OPD BCKA products using a multiple reaction monitoring method. An OPD-derivatized (13)C-labeled keto acid was used as an internal standard. Application of the method for C57BL/6J (wild-type) and PP2Cm knockout mouse tissues, including kidney, adipose tissue, liver, gastrocnemius, and hypothalamus, is shown. The lowest tissue concentration measured by this method was 20 nM, with the standard curve covering a wide range (7.8-32,000 nM). Liquid chromatography-mass spectrometry run times for this assay were less than 5 min, facilitating high throughput, and the OPD derivatives were found to be stable over several days. PMID- 23684524 TI - A whole-of-curriculum approach to improving nursing students' applied numeracy skills. AB - BACKGROUND: Nursing students often perform poorly on numeracy tests. Whilst one off interventions have been trialled with limited success, a whole-of-curriculum approach may provide a better means of improving applied numeracy skills. OBJECTIVE: The objective of the study is to assess the efficacy of a whole-of curriculum approach in improving nursing students' applied numeracy skills. DESIGN: Two cycles of assessment, implementation and evaluation of strategies were conducted following a high fail rate in the final applied numeracy examination in a Bachelor of Nursing (BN) programme. Strategies included an early diagnostic assessment followed by referral to remediation, setting the pass mark at 100% for each of six applied numeracy examinations across the programme, and employing a specialist mathematics teacher to provide consistent numeracy teaching. SETTING: The setting of the study is one Australian university. PARTICIPANTS: 1035 second and third year nursing students enrolled in four clinical nursing courses (CNC III, CNC IV, CNC V and CNC VI) were included. METHODS: Data on the percentage of students who obtained 100% in their applied numeracy examination in up to two attempts were collected from CNCs III, IV, V and VI between 2008 and 2011. A four by two chi(2) contingency table was used to determine if the differences in the proportion of students achieving 100% across two examination attempts in each CNC were significantly different between 2008 and 2011. RESULTS: The percentage of students who obtained 100% correct answers on the applied numeracy examinations was significantly higher in 2011 than in 2008 in CNC III (chi(2)=272, 3; p<0.001), IV (chi(2)=94.7, 3; p<0.001) and VI (chi(2)=76.3, 3; p<0.001). CONCLUSIONS: A whole-of-curriculum approach to developing applied numeracy skills in BN students resulted in a substantial improvement in these skills over four years. PMID- 23684525 TI - An international internship on social development led by Canadian nursing students: empowering learning. AB - BACKGROUND: A Canadian nursing student-led knowledge dissemination project on health promotion for social development was implemented with local professionals and communities in Brazil. OBJECTIVES: (a) to identify how student-interns contrasted Canadian and Brazilian cultural and social realities within a primary healthcare context from a social development perspective; (b) to examine how philosophical underpinnings, including social critical theory and notions of social justice, guided student-interns in acknowledging inequalities in primary healthcare in Brazil; and (c) to participate in the debate on the contribution of Canadian nursing students to the global movement for social development. DESIGN AND SETTING: A qualitative appraisal of short-term outcomes of an international internship in the cities of Birigui & Aracatuba (Sao Paulo-Brazil). PARTICIPANTS: Four Canadian fourth-year undergraduate nursing students enrolled in a metropolitan university program. METHODS: Recruitment was through an email invitation to the student-interns, who accepted, and signed informed consent forms. Their participation was unpaid and voluntary. One-time individual interviews were conducted at the end of their internships. Transcriptions of the audio-recorded interviews were coded using the qualitative software program ATLAS ti 6.0. The findings were analyzed using thematic analysis. RESULTS: Student interns' learning unfolded from making associations among concepts, new ideas, and their previous experiences, leading to a personal transformation through which they established new conceptual and personal connections. The two main themes revealed by the thematic analysis were dichotomizing realities, that is, acknowledging the existence of "two sides of each situation," and discovering an unexpected reciprocity between global and urban health. Furthermore, the student interns achieved personal and professional empowerment. CONCLUSIONS: The knowledge gained from the international experience helped the student-interns learn how to collaborate with Brazilian society's sectors to improve the social conditions of a "marginalized population". Student-interns became aware of their inner power to promote change by making invisible inequity visible in their own terms. PMID- 23684526 TI - Excretion profile of corticosteroids in bovine urine compared with tissue residues after therapeutic and growth-promoting administration of dexamethasone. AB - The illicit use of dexamethasone as growth-promoting agent in animal breeding is still practiced within the EU constituting a health risk for meat consumers. An experimental study was developed to assess dexamethasone urinary excretion and tissue distribution (liver, kidney, and muscle) in male calves after therapeutic and growth-promoting administration. Urine and tissue samples collected from treated and untreated bovines were also investigated for the presence of other natural and synthetic corticosteroids (prednisolone, prednisone, hydrocortisone, and cortisone), in order to study a possible correlation with dexamethasone administration and to clarify prednisolone origin. Analyses were performed by a multi-residue LC-MS/MS method developed and validated according to the Commission Decision 2002/657/EC. The results confirm the rapid rate of dexamethasone urinary excretion, irrespective of the dosage, the duration and the route of administration, and the disappearance of cortisone and hydrocortisone during the treatment. Dexamethasone was distributed to the tissues where the elimination rate proceeded relatively slower as suggested by the presence of residues one month after the withdrawal of the therapeutic treatment. An increase in the number of positive findings for prednisolone, in association with higher levels of cortisone and hydrocortisone, was observed in urine samples collected from slaughterhouse rather than those collected at the farm. Prednisone residues were found only in one urine sample that showed the highest levels of prednisolone, hydrocortisone, and cortisone. The occurrence of prednisolone residues in urine and even in tissue samples confirms the endogenous nature of this molecule. PMID- 23684527 TI - A large left ventricular diverticulum in a patient with congenital pulmonic stenosis. PMID- 23684528 TI - Parapharyngeal space benign tumours: our experience. AB - Only about 0.5% of all head and neck neoplasms occur in the parapharyngeal space (PPS) and approximately 80% of these tumours are benign lesions. Various surgical approaches some of which are associated with mandibulotomy to increase exposure have been described. This article describes our 16-years' experience in treating 60 PPS benign tumours with special focus on our surgical techniques intended to ensure adequate mass exposure and structure safety. On the basis of our experience we assert that mandibulotomy is currently not advocated in the surgical management of benign PPS tumours i.e. not even in very select cases. The transparotid approach is the treatment of choice for parotid gland lesions involving PPS and in cases of multinodular or uninodular pleomorphic adenoma relapse involving the PPS. The transcervical approach is suitable for the safe removal of even large PPS masses in most cases. PMID- 23684529 TI - Reconstruction of critical-size mandibular defects in immunoincompetent rats with human adipose-derived stromal cells. AB - In patients with bony defects, autologous bone grafts are the "gold standard" for reconstruction. In children, autologous bone harvesting is limited but tissue engineering offers an alternative. Next to bone marrow, adipose tissue is a source of mesenchymal stromal cells, and adipose-derived stromal cells (ADSC) can differentiate into osteocytes. The aim of this study was to evaluate the efficacy of bioactive implants (ADSC in fibrin glue) for repair of critical-size mandibular defects in athymic rats. Human adult ADSC embedded in fibrin glue were implanted into a critical-size defect in the rat mandible and their efficacy was compared to those of protected bone healing (pbh), autologous bone graft, and an empty defect. The newly formed bone was quantified using high-resolution flat panel volumetric CT (fpvCT) during different observation times. After eight weeks, the specimens were assessed histologically and by micro-computed tomography (MU-CT). The radiographic examination demonstrated a significantly higher level of ossified defect area in the ADSC side compared with the pbh side. The autologous bone graft side showed significantly enhanced bone formation compared to the empty defect. The histological findings in the specimens with ADSC showed bony bridging of the defect. ADSC were capable of defect reconstruction under our experimental conditions. PMID- 23684530 TI - Theoretical assessment of an intramedullary condylar component versus screw fixation for the condylar component of a hemiarthroplasty alloplastic TMJ replacement system. AB - Virtual design gives flexibility to explore constructive solutions or structures. It enables analysis that would often be impossible even if expensive real prototypes were available. Simulations using finite element models allow access to the stress and strain tensor or to the deformation tensor within an implant or a tissue which is impossible experimentally, even in vitro. This study is based on two numerical models of temporomandibular joint (TMJ) implants, comparing two bone-implant connections: an external connection performed with surgical screws (commercial model) and an internal connection carried out by penetration into the intramedullary space. The finite element models were constructed based on a cadaveric mandible and considering the five principal muscles in action. Strain distributions into the surrounding bone tissue are analysed and in both models they show significant differences at the external surface of the mandible in displacements. However, while the intramedullary fixation increases strains in the cancellous tissue, the study shows that strain distribution is mainly influenced by the number and distribution of screws in commercial solution. PMID- 23684531 TI - Effects of various electrode configurations on music perception, intonation and speaker gender identification. AB - Advances in speech coding strategies and electrode array designs for cochlear implants (CIs) predominantly aim at improving speech perception. Current efforts are also directed at transmitting appropriate cues of the fundamental frequency (F0) to the auditory nerve with respect to speech quality, prosody, and music perception. The aim of this study was to examine the effects of various electrode configurations and coding strategies on speech intonation identification, speaker gender identification, and music quality rating. In six MED-EL CI users electrodes were selectively deactivated in order to simulate different insertion depths and inter-electrode distances when using the high definition continuous interleaved sampling (HDCIS) and fine structure processing (FSP) speech coding strategies. Identification of intonation and speaker gender was determined and music quality rating was assessed. For intonation identification HDCIS was robust against the different electrode configurations, whereas fine structure processing showed significantly worse results when a short electrode depth was simulated. In contrast, speaker gender recognition was not affected by electrode configuration or speech coding strategy. Music quality rating was sensitive to electrode configuration. In conclusion, the three experiments revealed different outcomes, even though they all addressed the reception of F0 cues. Rapid changes in F0, as seen with intonation, were the most sensitive to electrode configurations and coding strategies. In contrast, electrode configurations and coding strategies did not show large effects when F0 information was available over a longer time period, as seen with speaker gender. Music quality relies on additional spectral cues other than F0, and was poorest when a shallow insertion was simulated. PMID- 23684532 TI - Revisiting the clinical and histopathological aspects of patients with chromoblastomycosis from the Brazilian Amazon region. AB - BACKGROUND AND AIMS: Chromoblastomycosis is a chronic fungal infection caused by species of the family Dematiaceae. Fonsecaea pedrosoi is the most common etiological agent. The objective of this study was to describe the epidemiological and mycological profile of patients with chromoblastomycosis from the Amazon region of Brazil and to correlate the clinical forms with the histopathological findings and severity criteria. METHODS: Sixty-five patients were submitted to mycological (direct, culture, and microculture) and histopathological (hematoxylin-eosin staining) examination. Severity of the disease was classified according to the criteria proposed by Carrion in 1950. RESULTS: Most patients were males (93.8%) and laborers (89.2%). There was a predominance of verrucous lesions (55.4%), which were mainly found on the lower limbs (81.5%). Two major types of tissue reaction were observed: a granulomatous reaction characterized by the formation of suppurative granulomas rich in fungal cells, which were almost always seen in verrucous lesions, and a reaction characterized by the formation of tuberculoid granulomas with few parasites, which were mainly found in well-delimited erythematous plaque-like and cicatricial lesions (p = 0.0001). A peculiar type of organized mycotic granuloma was observed in 20 subjects. Suppurative granulomas were more frequently detected in severe lesions (p = 0.0189) and in lesions with a duration of >10 years (p = 0.0408). CONCLUSIONS: These results suggest that verrucous lesions present a less competent inflammatory tissue response than patients who develop a well-formed tuberculoid reaction. The latter is associated with a more effective immune response as observed in the limited clinical forms of chromoblastomycosis. PMID- 23684533 TI - Evaluation of cytokines in multiple sclerosis patients treated with mesenchymal stem cells. AB - BACKGROUND AND AIMS: Mesenchymal stem cells (MSC) are currently strong candidates for stem cell therapy. Cytokines have a profound effect on the resultant immune responses. This study aims to evaluate variations in the cytokine profile of multiple sclerosis patients treated with autologous MSC. METHODS: Twenty five patients received one dose of intrathecal MSCs (mean number: 29.5 * 106). To measure the gene expression of FOXP3, IFN-gamma, TGF-beta, IL-4, IL-10, IL-6, and their serum proteins, samples were collected at five intervals: day 0 prior to injection and months 1, 3, 6, and 12 after MSC therapy. Gene expression was evaluated via real-time PCR and protein values were measured by ELISA. RESULTS: There were no statistically significant variations in gene expression and serum level of cytokines after a 1-year follow-up of MSC-treated MS patients. The only correlation found was an increase in IL-6 gene expression in patients with progressive disease. CONCLUSION: Intrathecal injection of MSCs does not affect cytokine variation in peripheral blood. Because the condition of most of our patients either improved or stabilized after stem cell therapy (SCT), we speculate that the immunomodulatory or neuroregenerative effects of MSC are exerted locally in the central nervous system. PMID- 23684534 TI - Reply: Human germline genetic modification: scientific and bioethical perspectives. PMID- 23684535 TI - ACR white paper on teleradiology practice: a report from the Task Force on Teleradiology Practice. AB - Teleradiology services are now embedded into the workflow of many radiology practices in the United States, driven largely by an expanding corporate model of services. This has brought opportunities and challenges to both providers and recipients of teleradiology services and has heightened the need to create best practice guidelines for teleradiology to ensure patient primacy. To this end, the ACR Task Force on Teleradiology Practice has created this white paper to update the prior ACR communication on teleradiology and discuss the current and possible future state of teleradiology in the United States. This white paper proposes comprehensive best-practice guidelines for the practice of teleradiology, with recommendations offered regarding future actions. PMID- 23684536 TI - Differential roles of NADPH oxidases and associated regulators in polarized growth, conidiation and hyphal fusion in the symbiotic fungus Epichloe festucae. AB - The endophytic fungus Epichloe festucae systemically colonizes the intercellular spaces of temperate grasses to establish mutualistic symbiotic associations. We have previously shown that reactive oxygen species produced by a specific NADPH oxidase isoform, NoxA, and associated regulators, NoxR and RacA, have a critical role in regulating hyphal growth in the host plant to maintain a mutualistic symbiotic interaction. We also identified BemA and Cdc24, homologues of polarity establishment proteins of yeast, as interactors of NoxR. In this study, we investigated culture developmental phenotypes of 'knockout' mutants of noxA and noxB and their associated regulators, noxR, racA and bemA. On nutrient-rich medium, all of the mutants except racA, which had undulating hyphae, hyphal swellings and increased branching, had a colony growth phenotype similar to the wild type strain. In contrast, on water agar, noxA, noxR and bemA mutants had disorganized hyphal growth and distorted instead of straight hyphae. These changes in hyphal growth characteristics indicate that NoxA and associated regulators have a crucial role in polarized growth under conditions of nutrient starvation. Conidiation in the noxA mutant was greater than wild type, and further enhanced in the noxA/noxB double mutant suggesting ROS negatively regulates asexual development. In contrast, deletion of noxR had no effect on conidiation. Hyphae of the wild type and noxB mutant of E. festucae had frequent vegetative hyphal fusions, whereas noxA, noxR and racA mutants totally lost this ability and fusions in the bemA mutant were significantly reduced. These results indicate that NoxA, NoxB and their associated regulators have distinct or overlapping functions for the regulation of different hyphal morphogenesis processes. PMID- 23684537 TI - Prevalence and correlates of heavy smoking and nicotine dependence in adolescents with bipolar and cannabis use disorders. AB - The study examined the prevalence and correlates of heavy smoking and nicotine dependence in adolescents with bipolar and cannabis use disorders. Participants were 80 adolescents between 13 and 22 years of age with co-occurring bipolar I disorder and cannabis abuse or dependence who reported ever trying a cigarette. Diagnostic and symptom severity measures were completed as part of the baseline assessments for a clinical trial. Almost half (49%) of these participants who ever tried a cigarette were current heavy smokers (>=10 cigarettes/day), and 70% met DSM-IV-TR lifetime criteria for nicotine dependence. Heavy smoking was associated with older age, heavier marijuana use and greater compulsive craving, lifetime diagnoses of attention-deficit/hyperactivity disorder, conduct disorder, illicit drug use disorders, and poorer overall functioning. Nicotine dependence was related to White race, higher current mania severity, and poorer overall functioning. These findings suggest that heavy smoking and nicotine dependence were highly prevalent among these adolescents. Although both were associated with greater physical and psychosocial problems, only heavy smoking was linked to a clear pattern of more severe substance-related and psychiatric problems. Further research to elucidate mechanisms and develop interventions to address early, entrenched patterns of co-use of tobacco and marijuana is warranted. PMID- 23684538 TI - Are variations in whole blood BDNF level associated with the BDNF Val66Met polymorphism in patients with first episode depression? AB - Brain derived neurotrophic factor (BDNF) seems to play an important role in the pathophysiology of affective disorders. The current study investigated whether blood level BDNF is correlated with the severity of depressive symptoms and recent (six months prior to onset of depression) experience of stressful life events (SLE) in a cohort of patients with a first depressive episode. 262 patients with first episode depression (females 174, males 88, age range 18-70, mean age 41) participated and control sample of 84 participants was included (females 52, males 32, age range 22-70, mean age 42). Symptomatology was rated using Hamilton Rating Scale for Depression (HAMD-17) and Becks Depression Inventory (BDI 21). No differences in whole blood BDNF was seen in relation to the BDNF Val66Met polymorphism and no significant correlations between whole blood BDNF and HAMD-17 or BDI 21 scores were found. No significant associations between the experiences of SLE before onset of depression and BDNF level were observed. Finally, peripheral BDNF differentiated between patients and healthy control persons. In the current sample of first episode depressed patients, the Val66Met polymorphism was not associated with whole blood BDNF and whole blood BNDF level was not associated with the experience of recent SLE. PMID- 23684539 TI - Chromatin effector Pygo2 mediates Wnt-notch crosstalk to suppress luminal/alveolar potential of mammary stem and basal cells. AB - Epigenetic mechanisms regulating lineage differentiation of mammary stem cells (MaSCs) remain poorly understood. Pygopus 2 (Pygo2) is a histone methylation reader and a context-dependent Wnt/beta-catenin coactivator. Here we provide evidence for Pygo2's function in suppressing luminal/alveolar differentiation of MaSC-enriched basal cells. We show that Pygo2-deficient MaSC/basal cells exhibit partial molecular resemblance to luminal cells, such as elevated Notch signaling and reduced mammary repopulating capability upon transplantation. Inhibition of Notch signaling suppresses basal-level and Pygo2-deficiency-induced luminal/alveolar differentiation of MaSC/basal cells, whereas activation of Wnt/beta-catenin signaling suppresses luminal/alveolar differentiation and Notch3 expression in a Pygo2-dependent manner. We show that Notch3 is a direct target of Pygo2 and that Pygo2 is required for beta-catenin binding and maintenance of a poised/repressed chromatin state at the Notch3 locus in MaSC/basal cells. Together, our data support a model where Pygo2-mediated chromatin regulation connects Wnt signaling and Notch signaling to restrict the luminal/alveolar differentiation competence of MaSC/basal cells. PMID- 23684540 TI - Generation of functional thymic epithelium from human embryonic stem cells that supports host T cell development. AB - Inducing immune tolerance to prevent rejection is a key step toward successful engraftment of stem-cell-derived tissue in a clinical setting. Using human pluripotent stem cells to generate thymic epithelial cells (TECs) capable of supporting T cell development represents a promising approach to reach this goal; however, progress toward generating functional TECs has been limited. Here, we describe a robust in vitro method to direct differentiation of human embryonic stem cells (hESCs) into thymic epithelial progenitors (TEPs) by precise regulation of TGFbeta, BMP4, RA, Wnt, Shh, and FGF signaling. The hESC-derived TEPs further mature into functional TECs that support T cell development upon transplantation into thymus-deficient mice. Importantly, the engrafted TEPs produce T cells capable of in vitro proliferation as well as in vivo immune responses. Thus, hESC-derived TEP grafts may have broad applications for enhancing engraftment in cell-based therapies as well as restoring age- and stress-related thymic decline. PMID- 23684541 TI - [Epignathus teratoma: diagnostic and neonatal management; a case report]. AB - Epignathus teratoma is a rare tumor whose prognosis essentially depends on its resectability and on neonatal care. When it is undiagnosed prenatally, mortality is close to 100 % at birth, because of obstruction of the upper airways. We present a case of epignathus teratoma detected during obstetrical ultrasound screening. Diagnosis enabled planning for a safe delivery in a suitable multidisciplinary unit and use of the EXIT procedure. PMID- 23684542 TI - Sprengerinin C exerts anti-tumorigenic effects in hepatocellular carcinoma via inhibition of proliferation and angiogenesis and induction of apoptosis. AB - The multi-targeted therapy for liver cancer has been considered as a novel strategy to fight hepatocellular carcinoma. In this study, we first found that sprengerinin C, a naturally derived compound strongly suppressed tumor angiogenesis in human umbilical vein endothelial cells. A mechanism study revealed that sprengerinin C blocked vascular endothelial growth factor receptor 2-dependent phosphoinositide 3-kinase/Akt/mTOR/matrix metalloproteinase and p38 MAPK/matrix metalloproteinase pathways, two major pathways for tumor angiogenesis. Moreover, sprengerinin C inhibited vascular endothelial growth factor release, a vital event for early angiogenesis response, from hypoxic HepG 2/BEL7402 cells by suppressing hypoxia-inducible factor-1alpha transcriptional activity. Furthermore, sprengerinin C induced HepG-2/BEL7402 cell apoptosis by activating NADPH oxidase/reactive oxygen species-dependent caspase apoptosis pathway and suppressed HepG-2/BEL7402 cell growth through p53-mediated G2/M-phase arrest. Sprengerinin C also showed a significant anti-tumor effect in the nude mouse xenograft model of human hepatocellular carcinoma. These results provide new insights into development of potent candidate compounds for liver cancer through affecting multiple tumor progression steps of angiogenesis, apoptosis and proliferation. PMID- 23684543 TI - Topically applied substance P enhanced healing of open excision wound in rats. AB - Significant social and financial burden due to wounds need newer drugs/formulations to speed up the healing process. Substance P (SP), a neuropeptide, is associated with release of various cytokines and growth factors from inflammatory, epithelial and endothelial cells. In the present study, temporal effects of topically applied SP (10(-7)M in normal saline) were evaluated in the modulation of various cytokines and growth factors that participate in cutaneous wound healing. Gross examination of full thickness open excision wound in rats revealed that once daily topical application of SP significantly increased the wound closure, as compared to control group. SP treatment significantly increased tumor necrosis factor-alpha (TNF-alpha) and decreased interleukin 10 (IL-10) levels on day 3. On the contrary, on day 7 level of TNF-alpha decreased and that of IL-10 increased. The mRNA and protein expressions of vascular endothelial growth factor (VEGF) and transforming growth factor-beta1 (TGF-beta1) increased on days 3 and 7, and decreased on day 14 in SP treated wounds. Histopathological evaluation of hematoxylin and eosin stained wound sections showed that SP treatment produced increased early leukocytes infiltration, fibroblast proliferation, angiogenesis, collagen deposition and re epithelialization. Results of the present study demonstrate that topical application of SP enhanced wound healing by modulating cytokines, growth factors and cells. Based on the results, it is suggested that SP could be of beneficial use in diabetic wounds where levels of VEGF, TGF-beta1 and SP decrease along with impairment of inflammatory reaction. PMID- 23684544 TI - Differential interactions of the broad spectrum drugs artemisinin, dihydroartemisinin and artesunate with serum albumin. AB - Artemisinin is a drug, widely used in malaria treatment. As the binding affinity of artemisinin and its derivatives dihydroartemisinin and artesunate to blood serum proteins might influence the effectiveness of the drug, binding of artemisinin and derivatives to serum albumin was studied under near physiological conditions. Binding kinetics indicate a simple, single-step association process for all artemisinin derivatives. The determined changes in enthalpy and entropy upon drug binding clearly indicate that hydrophobic forces are most important for artemisinin and dihydroartemisinin binding, whereas binding of artesunate is governed by both hydrophilic and hydrophobic forces. Key residues, which are most likely involved in binding of the respective compounds, were identified in subsequent protein/drug docking studies. The obtained results not only explain differences in between artemisinin and derivatives but generally illustrate how slight modifications in a drug can significantly affect principles underlying drug binding to target proteins. PMID- 23684545 TI - Ultrasonic-assisted preparation of nano eggshell powder: a novel catalyst in green and high efficient synthesis of 2-aminochromenes. AB - The nano eggshell powder (NESP) has been prepared by ultrasound irradiation and used as a novel and biodegradable catalyst with high catalytic activity and reusability in green synthesis of 2-aminochromenes via condensation of alpha- or beta-phathol, malononitrile and aromatic aldehydes at 120 degrees C under solvent-free conditions. The reaction proceeds to completion within 10-35 min in 91-98% yield. Nano eggshell catalyst was characterized by scanning electron microscopy, X-ray powder diffraction, IR spectroscopy and X-ray fluorescence, thermal gravimetric, surface area and elemental analyses. In addition, the catalytic activity and chemical structure of nano-sized eggshell were compared with pure CaCO3. PMID- 23684546 TI - Functional impairment in adults positively screened for attention-deficit hyperactivity disorder: the role of symptom presentation and executive functioning. AB - BACKGROUND: While the number of symptoms of attention-deficit hyperactivity disorder (ADHD) decreases with age, a high proportion of adults with ADHD symptoms suffer from persistent functional impairment (Fi) linked to these symptoms. Our objective was to investigate the specific roles of two potentially important predictors of this Fi: the clinical symptom presentation and the deficit in executive functions (EFs). METHODS: A total of 158 subjects from a community sample positively screened for ADHD were classified into two groups: those with and without Fi. Following a detailed diagnostic process, participants were administered a self-rating scale for ADHD symptoms as well as a neuropsychological test battery containing tests of EF and attention relevant as potential cognitive endophenotypes for ADHD. RESULTS: The overall number as well as the number of inattentive, hyperactive and impulsive symptoms, confirmed both by examiner and self-report, were significantly higher among Fi subjects. The highest odds ratio for Fi was associated with impulsive symptoms. Additionally, self-reported complaints of problems with self-concept were significantly higher among Fi subjects. No significant relationship between Fi and neuropsychological measures of EF and attention was detected. CONCLUSIONS: This study revealed that the number of symptoms, in particular that of impulsivity, had a significant impact on Fi in adults with symptoms of ADHD. Furthermore, our results underline the importance of assessing complaints and behaviors related to self-concept, which are not included in DSM-IV diagnostic criteria of ADHD but nonetheless may be associated with functional outcome of the disorder. PMID- 23684547 TI - The relevance of self-esteem and self-schemas to persecutory delusions: a systematic review. AB - BACKGROUND: Self-esteem is frequently targeted in psychological approaches to persecutory delusions (PD). However, its precise role in the formation and maintenance of PD is unclear and has been subject to a number of theories: It has been hypothesized that PD function to enhance self-esteem, that they directly reflect negative conceptualizations of the self, that self-esteem follows from the perceived deservedness of the persecution (poor-me versus bad-me-paranoia) and that the temporal instability of self-esteem is relevant to PD. In order to increase our understanding of the relevance of self-esteem to PD, this article systematically reviews the existing research on self-esteem in PD in the light of the existing theories. METHODS: We performed a literature search on studies that investigated self-esteem in PD. We included studies that either investigated self esteem a) within patients with PD or compared to controls or b) along the continuum of subclinical paranoia in the general population. We used a broad concept of self-esteem and included paradigms that assessed implicit self-esteem, specific self-schemas and dynamic aspects of self-esteem. RESULTS: The literature search identified 317 studies of which 52 met the inclusion criteria. The reviewed studies consistently found low global explicit self-esteem and negative self-schemas in persons with PD. The studies therefore do not support the theory that PD serve to enhance self-esteem but underline the theory that they directly reflect specific negative self-schemas. There is evidence that low self-esteem is associated with higher perceived deservedness of the persecution and that PD are associated with instable self-esteem. Only few studies investigated implicit self esteem and the results of these studies were inconsistent. CONCLUSIONS: We conclude by proposing an explanatory model of how self-esteem and PD interact from which we derive clinical implications. PMID- 23684548 TI - Low distress tolerance as an indirect risk factor for suicidal behavior: considering the explanatory role of non-suicidal self-injury. AB - Although some theorists conceptualize the relationship between emotion dysregulation and suicidal behavior as direct, recent research suggests that this relationship may be indirect and mediated by repeated experiences with certain behaviors (e.g., non-suicidal self-injury; NSSI) common among individuals with heightened emotion dysregulation. To date, however, this research has been limited in both scope (e.g., examining few components of emotion dysregulation) and generalizability (e.g., over-emphasis on undergraduate samples). This study sought to extend the research in this area by examining the mediating role of NSSI in the association between one relevant aspect of emotion dysregulation (i.e., low distress tolerance [DT]) and suicidal behavior with a clear intent to die among an at-risk sample of substance use disorder (SUD) patients in residential treatment. SUD patients (N=93) completed a structured interview assessing past suicidal behavior and questionnaires assessing DT and NSSI. Consistent with hypotheses, results revealed a significant indirect association between low DT and lifetime suicide attempts through NSSI frequency. These results suggest that exposure to painful and provocative events through experience with NSSI may be one pathway through which certain facets of emotion dysregulation increase the risk for suicidal behaviors (consistent with theories that individuals low in DT may be unable and/or unwilling to engage in suicidal behavior unless they have experienced sufficient levels of painful and/or provocative events capable of changing their relationship with and experience of pain and fear of death). PMID- 23684549 TI - VEGF and depression: a comprehensive assessment of clinical data. AB - Vascular Endothelial Growth Factor (VEGF), initially identified as an angiogenic mitogen, is believed to play a role in hippocampal neurogenesis and response to stress. It exerts neuroprotective effects and influences synaptic transmission. The possible role of VEGF in depression has been hypothesized in the context of the neurotrophic model of depression, which postulates that stress can lead to decreased level of neurotrophins. Since VEGF has emerged as a potential component in the pathophysiology of stress and stress-related disorders, animal and clinical studies have attempted to delineate its precise role. In this review article we provide a synopsis of basic studies that are of direct relevance to the clinical findings in depression and antidepressant drug action. We have classified the studies on the basis of higher, lower or no different levels of VEGF as compared to control subjects. It became evident that there is conflicting data regarding VEGF levels in depressed patients. The fact that no definitive trend is apparent in the published data is likely attributable to differences in study designs. However, promising leads have emerged in our effort to understand and clarify this wide variation in results. Further study could establish the potential use of VEGF as a biomarker to aid in making a correct diagnosis and a successful treatment plan. Delineating the relationship of VEGF and depression ultimately has the potential to shed light on the still elusive neural mechanisms underlying the pathophysiology of depression and the mechanisms by which antidepressants exert their effects. PMID- 23684550 TI - Dose-response effect between cannabis use and psychosis liability in a non clinical population: evidence from a snowball sample. AB - This study aimed to explore the associations between daily cannabis use and the specific profiles of subclinical symptoms in a non-clinical population obtained through snowball sampling, taking into account alcohol use, other drug use, social exclusion and age at onset of cannabis use. We included 85 daily cannabis users and 100 non-daily cannabis users. Both the case and the control populations were identified by snowball sampling. Daily cannabis use was associated with more alcohol intake and other drug use, as well as with early onset in the use of cannabis. Daily cannabis use appeared to exert a dose-response effect on first rank symptoms, mania symptoms and auditory hallucinations, even after adjusting for sex, age, other drug use, social exclusion and age at onset of cannabis use. The paranoid dimension was only associated with the heaviest consumption of cannabis. Initial age of cannabis use modified the effects of daily cannabis use on the first-rank and voices experiences. Daily cannabis use was associated with significantly more first-rank and voices experiences among those subjects who started to use cannabis before 17 years of age. Our study supports the association of psychotic experiences with cannabis use even among non-psychotic subjects. PMID- 23684551 TI - MicroRNA-21 suppresses PTEN and hSulf-1 expression and promotes hepatocellular carcinoma progression through AKT/ERK pathways. AB - MicroRNAs (miRNAs) have been believed to associate with malignant progression including cancer cell proliferation, apoptosis, differentiation, angiogenesis, invasion and metastasis. However, the functions of miRNAs are intricate, one miRNA can directly or indirectly target multiple genes and function as oncogene or tumor suppressor gene. In this study, we found that miR-21 inhibits PTEN and human sulfatase-1 (hSulf-1) expression in hepatocellular carcinoma (HCC) cells. The hSulf-1 is a heparin-degrading endosulfatase, which can inhibit the heparin binding growth factor-mediated signaling transduction into cells. Therefore, miR 21-mediated suppression of both hSulf-1 and PTEN led to activation of AKT/ERK pathways and epithelial-mesenchymal transition (EMT) in HCC cells, and finally enhance the activity of HCC cell proliferation and movement and promote HCC xenograft tumor growth in mouse models. These findings may provide candidate targets for prevention and treatment of HCC. PMID- 23684552 TI - The in vivo immunomodulatory and synergistic anti-tumor activity of thymosin alpha1-thymopentin fusion peptide and its binding to TLR2. AB - In the present study, the immunomodulatory and synergistic anti-tumor activity of thymosin alpha1-thymopentin fusion peptide (Talpha1-TP5) was investigated in vivo. In addition, the potential receptor of Talpha1-TP5 was investigated by surface plasmon resonance (SPR) binding studies. It was found that Talpha1-TP5 (305 MUg/kg) alleviated immunosuppression induced by hydrocortisone (HC). Talpha1 TP5 (305 MUg/kg) combined with cyclophosphamide (CY) had a better tumor growth inhibitory effect than CY alone. Furthermore, Talpha1-TP5 had a higher affinity (KD=6.84 MUmol/L) to toll-like receptor 2 (TLR2) than Talpha1 (K(D)=35.4 MUmol/L), but its affinity was not significantly different from that of TP5. The results of our present work indicate that Talpha1-TP5 can possibly be developed as a new immunomodulatory agent. PMID- 23684553 TI - Quantification of dry needling and posture effects on myofascial trigger points using ultrasound shear-wave elastography. AB - OBJECTIVES: To determine (1) whether the shear modulus in upper trapezius muscle myofascial trigger points (MTrPs) reduces acutely after dry needling (DN), and (2) whether a change in posture from sitting to prone affects the shear modulus. DESIGN: Ultrasound images were acquired in B mode with a linear transducer oriented in the transverse plane, followed by performance of shear-wave elastography (SWE) before and after DN and while sitting and prone. SETTING: University. PARTICIPANTS: Women (N=7; mean age +/- SD, 46+/-17y) with palpable MTrPs were recruited. INTERVENTION: All participants were dry needled in the prone position using solid filament needles that were inserted and manipulated inside the MTrPs. SWE was performed before and after DN in the sitting and prone positions. MAIN OUTCOME MEASURE: MTrPs were evaluated by shear modulus using SWE. RESULTS: Palpable reductions in stiffness were noted after DN and in the prone position. These changes were apparent in the shear modulus map obtained with ultrasound SWE. With significant main effects, the shear modulus reduced from before to after DN (P<.01) and from the sitting to the prone position (P<.05). No significant interaction effect between time and posture was observed. CONCLUSIONS: The shear modulus measured with ultrasound SWE reduced after DN and in the prone position compared with sitting, in agreement with reductions in palpable stiffness. These findings suggest that DN and posture have significant effects on the shear modulus of MTrPs, and that shear modulus measurement with ultrasound SWE may be sensitive enough to detect these effects. PMID- 23684554 TI - Optogenetic strategies to investigate neural circuitry engaged by stress. AB - Optogenetic techniques have given researchers unprecedented access to the function of discrete neural circuit elements and have been instrumental in the identification of novel brain pathways that become dysregulated in neuropsychiatric diseases. For example, stress is integrally linked to the manifestation and pathophysiology of neuropsychiatric illness, including anxiety, addiction and depression. Due to the heterogeneous populations of genetically and neurochemically distinct neurons in areas such as the bed nucleus of the stria terminalis (BNST), as well as their substantial number of projections, our understanding of how neural circuits become disturbed after stress has been limited. Using optogenetic tools, we are now able to selectively isolate distinct neural circuits that contribute to these disorders and perturb these circuits in vivo, which in turn may lead to the normalization of maladaptive behavior. This review will focus on current optogenetic strategies to identify, manipulate, and record from discrete neural circuit elements in vivo as well as highlight recent optogenetic studies that have been utilized to parcel out BNST function. PMID- 23684555 TI - Increased consumption of salmon during pregnancy partly prevents the decline of some plasma essential amino acid concentrations in pregnant women. AB - BACKGROUND & AIMS: Oily fish is a good source of n-3 long-chain polyunsaturated fatty acids. Since these fatty acids may change efficiency of amino acid (AA) absorption, we determined whether increased salmon consumption influences plasma AA concentrations in pregnant women and their newborns. METHODS: Pregnant women were randomly allocated to remain on their habitual diet (n = 61; control group) or to consume two 150 g farmed salmon portions per week from 20 weeks pregnancy until birth (n = 62; salmon group). Plasma AA concentrations were determined in women at w20, w34 and w38 of pregnancy and in umbilical cord at delivery. RESULTS: Concentrations of arginine, valine, leucine and lysine were affected by both time of pregnancy and salmon intake (p < 0.05), with a smaller gestation associated decrease in the salmon group. Total essential AA concentrations were similar in both groups at w20, but at w38 were higher in salmon group (p < 0.05). Cord plasma AA concentrations, higher than in maternal plasma (p < 0.01), were similar in the two groups (p > 0.05). CONCLUSIONS: Two portions/wk of oily fish increased plasma essential AA concentrations during pregnancy and could contribute to a maternal health benefit. Two portions/wk of salmon did not affect plasma AA concentrations in the newborn. CLINICAL TRIALS IDENTIFIER: NCT00801502. PMID- 23684556 TI - Modulation of benzo[a]pyrene induced neurotoxicity in female mice actively immunized with a B[a]P-diphtheria toxoid conjugate. AB - Benzo[a]pyrene (B[a]P) is a small molecular weight carcinogen and the prototype of polycyclic aromatic hydrocarbons (PAHs). While these compounds are primarily known for their carcinogenicity, B[a]P and its metabolites are also neurotoxic for mammalian species. To develop a prophylactic immune strategy against detrimental effects of B[a]P, female Balb/c mice immunized with a B[a]P diphtheria toxoid (B[a]P-DT) conjugate vaccine were sub-acutely exposed to 2mg/kg B[a]P and behavioral performances were monitored in tests related to learning and memory, anxiety and motor coordination. mRNA expression of the NMDA receptor (NR1, 2A and 2B subunits) involved in the above behavioral functions was measured in 5 brain regions. B[a]P induced NMDA1 expression in three (hippocampus, amygdala and cerebellum) of five brain regions investigated, and modulated NMDA2 in two of the five brain regions (frontal cortex and cerebellum). Each one of these B[a]P-effects was reversed in mice that were immunized against this PAH, with measurable consequences on behavior such as anxiety, short term learning and memory. Thus active immunization against B[a]P with a B[a]P-DT conjugate vaccine had a protective effect and attenuated the pharmacological and neurotoxic effects even of high concentrations of B[a]P. PMID- 23684557 TI - Dichlorodiphenyltrichloroethane technical mixture regulates cell cycle and apoptosis genes through the activation of CAR and ERalpha in mouse livers. AB - Dichlorodiphenyltrichloroethane (DDT) is a widely used organochlorine pesticide and a xenoestrogen that promotes rodent hepatomegaly and tumours. A recent study has shown significant correlation between DDT serum concentration and liver cancer incidence in humans, but the underlying mechanisms remain elusive. We hypothesised that a mixture of DDT isomers could exert effects on the liver through pathways instead of classical ERs. The acute effects of a DDT mixture containing the two major isomers p,p'-DDT (85%) and o,p'-DDT (15%) on CAR and ERalpha receptors and their cell cycle and apoptosis target genes were studied in mouse livers. ChIP results demonstrated increased CAR and ERalpha recruitment to their specific target gene binding sites in response to the DDT mixture. The results of real-time RT-PCR were consistent with the ChIP data and demonstrated that the DDT was able to activate both CAR and ERalpha in mouse livers, leading to target gene transcriptional increases including Cyp2b10, Gadd45beta, cMyc, Mdm2, Ccnd1, cFos and E2f1. Western blot analysis demonstrated increases in cell cycle progression proteins cMyc, Cyclin D1, CDK4 and E2f1 and anti-apoptosis proteins Mdm2 and Gadd45beta. In addition, DDT exposure led to Rb phosphorylation. Increases in cell cycle progression and anti-apoptosis proteins were accompanied by a decrease in p53 content and its transcriptional activity. However, the DDT was unable to stimulate the beta-catenin signalling pathway, which can play an important role in hepatocyte proliferation. Thus, our results indicate that DDT treatment may result in cell cycle progression and apoptosis inhibition through CAR- and ERalpha-mediated gene activation in mouse livers. These findings suggest that the proliferative and anti-apoptotic conditions induced by CAR and ERalpha activation may be important contributors to the early stages of hepatocarcinogenesis as produced by DDT in rodent livers. PMID- 23684559 TI - Cobalt triggers necrotic cell death and atrophy in skeletal C2C12 myotubes. AB - Severe poisoning has recently been diagnosed in humans having hip implants composed of cobalt-chrome alloys due to the release of particulate wear debris on polyethylene and ceramic implants which stimulates macrophagic infiltration and destroys bone and soft tissue, leading to neurological, sensorial and muscular impairments. Consistent with this premise, in this study, we focused on the mechanisms underlying the toxicity of Co(II) ions on skeletal muscle using mouse skeletal C2C12 myotubes as an in vitro model. As detected using propidium iodide incorporation, increasing CoCl2 doses (from 5 to 200MUM) affected the viability of C2C12 myotubes, mainly by cell necrosis, which was attenuated by necrostatin 1, an inhibitor of the necroptotic branch of the death domain receptor signaling pathway. On the other hand, apoptosis was hardly detectable as supported by the lack of caspase-3 and -8 activation, the latter resulting in only faint activation after exposure to higher CoCl2 doses for prolonged time points. Furthermore, CoCl2 treatment resulted in atrophy of the C2C12 myotubes which was characterized by the increased expression of HSP25 and GRP94 stress proteins and other typical 'pro-atrophic molecular hallmarks, such as early activation of the NF-kB pathway and down-regulation of AKT phosphorylation, followed by the activation of the proteasome and autophagy systems. Overall, these results suggested that cobalt may impact skeletal muscle homeostasis as an inducer of cell necrosis and myofiber atrophy. PMID- 23684558 TI - Comparative developmental toxicity of environmentally relevant oxygenated PAHs. AB - Oxygenated polycyclic aromatic hydrocarbons (OPAHs) are byproducts of combustion and photo-oxidation of parent PAHs. OPAHs are widely present in the environment and pose an unknown hazard to human health. The developing zebrafish was used to evaluate a structurally diverse set of 38 OPAHs for malformation induction, gene expression changes and mitochondrial function. Zebrafish embryos were exposed from 6 to 120h post fertilization (hpf) to a dilution series of 38 different OPAHs and evaluated for 22 developmental endpoints. AHR activation was determined via CYP1A immunohistochemistry. Phenanthrenequinone (9,10-PHEQ), 1,9-benz-10 anthrone (BEZO), xanthone (XAN), benz(a)anthracene-7,12-dione (7,12-B[a]AQ), and 9,10-anthraquinone (9,10-ANTQ) were evaluated for transcriptional responses at 48hpf, prior to the onset of malformations. qRT-PCR was conducted for a number of oxidative stress genes, including the glutathione transferase(gst), glutathione peroxidase(gpx), and superoxide dismutase(sod) families. Bioenergetics was assayed to measure in vivo oxidative stress and mitochondrial function in 26hpf embryos exposed to OPAHs. Hierarchical clustering of the structure-activity outcomes indicated that the most toxic of the OPAHs contained adjacent diones on 6-carbon moieties or terminal, para-diones on multi-ring structures. 5-carbon moieties with adjacent diones were among the least toxic OPAHs while the toxicity of multi-ring structures with more centralized para-diones varied considerably. 9,10-PHEQ, BEZO, 7,12-B[a]AQ, and XAN exposures increased expression of several oxidative stress related genes and decreased oxygen consumption rate (OCR), a measurement of mitochondrial respiration. Comprehensive in vivo characterization of 38 structurally diverse OPAHs indicated differential AHR dependency and a prominent role for oxidative stress in the toxicity mechanisms. PMID- 23684561 TI - Determination for dry layer resistance of sucrose under various primary drying conditions using a novel simulation program for designing pharmaceutical lyophilization cycle. AB - Dry layer resistance, which is the resistance of dried cake against water vapor flow generated from sublimation, is one of the important parameters to predict maximum product temperature and drying time during primary drying in lyophilization. The purpose of this study was to develop the predictive model of dry layer resistance under various primary drying conditions using the dry layer resistance obtained from a preliminary lyophilization run. When the maximum dry layer resistance was modified under the assumption that the chamber pressure is zero, the modified dry layer resistance, which is defined as specific dry layer resistance, correlated well with the sublimation rate. From this correlation, the novel predictive model including the empirical formula of sublimation rate and specific dry layer resistance is proposed. In this model, the dry layer resistance under various conditions of shelf temperature and chamber pressure was successfully predicted based on the relationship of the sublimation rate and specific dry layer resistance of the edge and center vials obtained from the product temperature in one preliminary cycle run. It is expected that this predictive model could be a practical and useful tool to predict product temperature during primary drying. PMID- 23684562 TI - Comparison of the diagnostic and prognostic values of B-type and atrial-type natriuretic peptides in acute heart failure. AB - BACKGROUND: We compared diagnostic and prognostic properties of brain natruiretic peptide (BNP), proBNP, NT-proBNP and MR-pro-atrial natriuretic peptide (ANP) in patients admitted with shortness of breath (SOB). METHODS: All 4 NPs were measured in patients admitted to the emergency unit with SOB (in 2 centers) or acute heart failure (AHF) (1 FINN-AKVA cohort) and in a control population of stable chronic HF. Follow-up was 1 (2 centers) and 5 years (1 FINN-AKVA cohort). Area under the curve (AUC) was used to assess diagnostic properties. AUC, multivariate Cox regression, net reclassification improvement (NRI), and Kaplan Meier analyses were used to assess mortality. RESULTS: We included 710 patients ("Biomarcoeurs" cohort n=336; FINN-AKVA study, n=306; stable chronic HF, n=68). Pro-BNP was almost as powerful as BNP to diagnose AHF (AUC 0.953 vs 0.973 respectively, p=0.003), NT-proBNP also performed well (0.922, p<0.001 vs BNP). MR proANP performed less well (0.901). AUC over time showed greater MR-proANP values over the first year. At 5 years, MR-proANP had the best prognostic value (AUC 0.668 vs 0.604 for BNP, p=0.042). Kaplan Meier analysis confirmed better survival with MR-proANP<=416.8 pmol/L at 5 years. NRI at 5 years was greater for MR-proANP (0.23, p<0.05) than for proBNP, BNP or NTproBNP (p=NS). CONCLUSION: Our study provides firm evidence that all NPs perform equally well for diagnostic purposes, and that MR-proANP has long term prognostic value in patients with acute heart failure. PMID- 23684563 TI - Late catch-up phenomenon after drug-eluting balloon angioplasty. PMID- 23684564 TI - Percutaneous coronary intervention in aorto-ostial lesions. Immediate and medium term results in a real world cohort. PMID- 23684566 TI - NHLH2: at the intersection of obesity and fertility. AB - Nescient helix-loop-helix 2 (NHLH2/NSCL2) is a neuronal transcription factor originally thought to be involved in neuronal development and childhood neuroblastomas. Accumulating evidence has since identified roles for NHLH2 in adult phenotypes of obesity and fertility. We summarize these findings here and attempt to link genotype with phenotype in mouse models and humans. In particular, NHLH2 (Nhlh2 in mice) is one of only two genes that are genetically linked to physical activity levels. Nhlh2 also controls obesity and fertility, with strong sexual dimorphism for both phenotypes in Nhlh2 mutant animals. We propose that Nhlh2 might function as a molecular sensor in different adult hypothalamic neurons to regulate energy balance, leading to normal body weight and reproduction. PMID- 23684567 TI - Pediatric stapedectomy: does cause of fixation affect outcomes? AB - OBJECTIVE: To compare outcomes of stapedectomy in patients with congenital stapes fixation versus juvenile otosclerosis. METHODS: A retrospective chart review was performed from January 1, 1999 until January 1, 2011 to identify patients under 18 years old who underwent a stapedectomy. Age, gender, pre- and postoperative audiograms, intraoperative findings including etiology of stapes fixation, prosthesis type, and complications were recorded. RESULTS: Twenty-two children were identified who had undergone a stapedectomy (two patients underwent sequential bilateral surgery) resulting in a total of 24 ears. The cause of fixation included juvenile otosclerosis (n=7) and congenital stapes fixation (n=17). The overall mean pre-operative air-bone gap (ABG) was 34.7 dB (SD: 13.5) compared to a postoperative mean ABG of 9.0 (SD: 9.3) (p<0.001). The mean postoperative ABG of 9.6 (SD: 10.5) in the congenital stapes fixation group was similar to the mean postoperative ABG of 7.2dB (SD: 5.4) in children with juvenile otosclerosis (p=0.6). Two patients developed delayed profound sensorineural hearing loss approximately two weeks after surgery. One patient with profound sensorineural hearing loss recovered to a profound mixed hearing loss with a speech discrimination score of 80%. CONCLUSIONS: Pediatric stapedectomy has comparable results to stapedectomy in adults regardless of the cause of stapes fixation; however, delayed sensorineural hearing loss may be higher in the pediatric population. PMID- 23684565 TI - Contribution of iNOS/sGC/PKG pathway, COX-2, CYP4A1, and gp91(phox) to the protective effect of 5,14-HEDGE, a 20-HETE mimetic, against vasodilation, hypotension, tachycardia, and inflammation in a rat model of septic shock. AB - We have previously demonstrated that a stable synthetic analog of 20 hydroxyeicosatetraenoic acid (20-HETE), N-[20-hydroxyeicosa-5(Z),14(Z) dienoyl]glycine (5,14-HEDGE), prevents vascular hyporeactivity, hypotension, tachycardia, and inflammation in rats treated with lipopolysaccharide (LPS) and mortality in endotoxemic mice. These changes were attributed to decreased production of inducible nitric oxide (NO) synthase (iNOS)-derived NO, cyclooxygenase (COX)-2-derived vasodilator prostanoids, and proinflammatory mediators associated with increased cyctochrome P450 (CYP) 4A1-derived 20-HETE and CYP2C23-dependent antiinflammatory mediator formation. The aim of this study was to determine whether decreased expression and activity of iNOS, soluble guanylyl cyclase (sGC), protein kinase G (PKG), COX-2, gp91(phox) (NOX2; a superoxide generating NOX enzyme), and peroxynitrite production associated with increased expression of COX-1 and CYP4A1 and 20-HETE formation in renal and cardiovascular tissues of rats contributes to the effect of 5,14-HEDGE to prevent vasodilation, hypotension, tachycardia, and inflammation in response to systemic administration of LPS. Mean arterial pressure fell by 28mmHg and heart rate rose by 47beats/min in LPS (10mg/kg, i.p.)-treated rats. Administration of LPS also increased mRNA and protein expression of iNOS and COX-2 associated with a decrease in COX-1 and CYP4A1 mRNA and protein expression. Increased NOS activity, iNOS-heat shock protein 90 complex formation (an index for iNOS activity), protein expression of phosphorylated vasodilator stimulated phosphoprotein (an index for PKG activity), gp91(phox), p47(phox) (NOXO2; organizer subunit of gp91(phox)), and nitrotyrosine (an index for peroxynitrite production) as well as cGMP (an index for sGC activity), 6-keto-PGF1alpha (a stable metabolite PGI2) and PGE2 levels (indexes for COX activity), and nitrotyrosine levels by LPS were also associated with decreased CYP hydroxylase activity as measured by 20-HETE formation from arachidonic acid in renal microsomes of LPS-treated rats. These effects of LPS, except iNOS mRNA and COX-1 protein expression, were prevented by 5,14-HEDGE (30mg/kg, s.c.; 1h after LPS). A competitive antagonist of vasoconstrictor effects of 20-HETE, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (30mg/kg, s.c.; 1h after LPS) reversed the effects of 5,14-HEDGE, except iNOS and COX-1 mRNA and protein expression as well as expression of CYP4A1 mRNA. These results suggest that increased CYP4A1 expression and 20-HETE formation associated with suppression of iNOS/sGC/PKG pathway, COX-2, and gp91(phox) participate in the protective effect of 5,14-HEDGE against vasodilation, hypotension, tachycardia, and inflammation in the rat model of septic shock. PMID- 23684568 TI - Impact of Schistosoma mansoni and Echinococcus granulosus experimental coinfection on interleukin 10 and interferon gamma cytokines profile. AB - The interactions between various aspects of the immune responses mediated by concomitant parasite infections may influence the resultant cytokines profiles. We tested this hypothesis by developing two Schistosoma mansoni and Echinococcus granulosus coinfection murine models. Our aim was to explore the effect of echinoccocis on the immune responses induced by schistosomiasis, either when the two infections were induced synchronously or when echinococcosis was induced during egg deposition period of S. mansoni infection. The proliferation of antigens specific stimulated splenocytes, taken from studied groups, was determined. Then, IFN-gamma, and IL-10 production from stimulated cells were measured. Significant elevation of IFN-gamma, 4weeks after synchronous coinfection, was occurred compared to S. mansoni infected group, associated with modest elevation of IL10 level. On the other hand, echinococcosis coinfection during egg deposition period of schistosomiasis resulted in significant marked reduction in IL10 level in comparison to S. mansoni infected mice. These results suggested that echinococcosis coinfection, during the switching from Th1 to Th2 cytokine stage of murine schistosomiasis, can alter the ability of S. mansoni infection to skew the cytokines response towards Th2 profile. It is clear that the timing and sequence of concomitant infections are of vital importance for the outcome of the immune response. PMID- 23684569 TI - Pomegranate (Punica granatum) peel is effective in a murine model of experimental Cryptosporidium parvum ultrastructural studies of the ileum. AB - The current treatments for cryptosporidiosis are ineffective, and there is an urgent need to search for more effective and safer alternatives. One such alternative may be treatments derived from natural resources. The pomegranate peel has been used effectively in traditional medicine to cure diarrhea and dysentery. The purpose of this study was to examine the effectiveness of a Punica granatum (pomegranate) peel suspension as a treatment for Cryptosporidium parvum infection. In this study, the effects of this treatment on the ultrastructure of both the intestinal epithelial layer of infected nursling mice and the parasite were observed with a transmission electron microscope. The histological study focused on the examination of the microvilli, columnar epithelium, goblet cells, lamina propria, and crypts of Lieberkuhn. Examination of the ileums of infected mice that received the pomegranate peel suspension demonstrated that the general structure of the ileal tissue of these mice was similar to that of the control group. In the infected mice treated with the suspension, but not the infected/untreated mice, there was an improvement in all ultrastructure aspects at 28days post-inoculation. The study of the ultrastructure of the parasite (C. parvum) in mice treated with the suspension showed that there was decomposition in the parasite to the extent that in some cases we were unable to identify the stage of the parasite due to the severe degeneration. Significant decomposition of the nutrition organ was also observed. Additionally, microgamonte and macrogamonte were not observed in the suspension-treated group, explaining the disappearance of the sexual phases of the parasite in the lumens of this group. In all, this examination demonstrated the restoration of the normal structures of villi and the disappearance of acute symptoms in the suspension-treated mice and showed that the suspension directly affected the parasite at various stages of its development and led to its decomposition and death. PMID- 23684570 TI - Portal venous gas secondary to bowel preparation for colonoscopy. PMID- 23684571 TI - Chikungunya virus: an update on antiviral development and challenges. AB - Chikungunya virus (CHIKV) has re-emerged as a significant public health threat since the 2005 chikungunya fever epidemic in La Reunion. Driven by the medical importance of this virus, as well as the lack of approved antivirals, research into the field of CHIKV antivirals has recently intensified. Potential therapeutics that have been reported to show anti-CHIKV activity in vitro range from known broad-spectrum antivirals like chloroquine to novel strategies involving RNA silencing technology. Although most of the earlier efforts focused on compounds that target host components, some recent studies have reported viral targets such as nonstructural proteins. This article examines the reported in vitro and in vivo efficacies, as well as the therapeutic potential of these antiviral compounds. PMID- 23684572 TI - FGF2 and FGFR1 signaling regulate functional recovery following cuprizone demyelination. AB - In demyelinating diseases, such as multiple sclerosis, remyelination offers the potential to recover function of viable denuded axons by restoring saltatory conduction and/or protecting from further damage. Mice with genetic reduction of fibroblast growth factor 2 (Fgf2) or Fgf receptor 1 (Fgfr1) exhibit dramatically improved remyelination following experimental demyelination with cuprizone. The current studies are the first to test neurobehavioral outcomes with these gene deletions that improved remyelination. The cuprizone protocols used did not produce overt abnormalities but did reduce bilateral sensorimotor coordination (complex wheel task) and increase sociability (two chamber apparatus with novel mouse). A significant effect of genotype was observed on the complex wheel task but not in the sociability apparatus. Specifically, complex wheel velocities for Fgf2 nulls improved significantly after removal of cuprizone from the diet. This improvement in Fgf2 null mice occurred following either acute (6 weeks) or chronic (12 weeks) demyelination. Plp/CreERT:Fgfr1(fl/fl) mice administered tamoxifen at 10 weeks of cuprizone treatment to induce Fgfr1 knockdown also showed improved recovery of running velocities on the complex wheels. Therefore, constitutive deletion of Fgf2 or Fgfr1 knockdown in oligodendrocyte lineage cells is sufficient to overcome impairment of sensorimotor coordination after cuprizone demyelination. PMID- 23684573 TI - Selective reduction of drebrin and actin in dendritic spines of hippocampal neurons by activation of 5-HT(2A) receptors. AB - Abnormal architecture of dendritic spines is associated with neurodevelopmental and neurodegenerative diseases. The 5-HT(2A) receptor is a potential therapeutic target for mental illnesses and it is functionally and genetically associated with many types of psychiatric disorders. It has been reported that 5-HT(2A) receptor activation alters spine architecture. Although actin cytoskeleton has a key role in the regulation of spine architecture, it is not clarified whether 5 HT(2A)+ receptor activation affect the actin cytoskeleton in dendritic spines. In the present study, we examined the effect of 5-HT(2A) receptor activation on the actin cytoskeleton in dendritic spines of mature hippocampal neurons in low density culture. Immunocytochemical analysis showed that 15 min exposure of 5 HT(2A) receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) significantly decreased the cluster densities of drebrin (control, 37.0+/-6.9 per 100 MUm, DOI, 12.5+/-2.9) and F-actin (control, 18.3+/-4.9; DOI, 7.7+/-2.1) at dendritic spines without any detectable changes in the cluster densities of synapsin I and PSD-95. At the same time period DOI exposure did not affect spine architecture (spine density: control, 38.3+/-5.1 per 100 MUm; DOI, 25.6+/-3.5; spine length: control, 1.99+/-0.18; DOI, 2.00+/-0.29; spine width: control, 0.72+/-0.06; DOI, 0.77+/-0.11). Thus, it is indicated that decrease of drebrin and F-actin can occur at the dendritic spines without morphological changes. Together our data suggest that 5-HT(2A) receptors activation is involved in the regulation of distribution of cytoskeleton in the dendritic spines. PMID- 23684574 TI - Midazolam provides cytoprotective effect during corticosterone-induced damages in rat astrocytes by stimulating steroidogenesis. AB - Midazolam is a benzodiazepine derivative drug that has powerful anxiolytic, amnestic, hypnotic, and sedative properties. The cytoprotective effect of midazolam on brain astrocytes is poorly understood. This study aimed to investigate the cytoprotective effect of midazolam on astrocytes exposed to corticosterone, a stress-produced glucocorticoid. We found that midazolam stimulated pregnenolone and progesterone secretion in astrocytes in a dose dependent manner. Midazolam protected astrocytes from corticosterone-induced damages in a dose-dependent manner. In addition, we demonstrated that progesterone reduced corticosterone-induced damages. Finally, we applied trilostane, an inhibitor of 3beta-hydroxysteroid dehydrogenase, to inhibit pregnenolone metabolism and found that pretreatment with trilostane significantly inhibited the cytoprotective effect of midazolam on corticosterone-induced cytotoxicity in rat astrocytes in a dose-dependent manner. Taken together, these results demonstrate that midazolam has cytoprotective effect on astrocytes. This is, at least partially, derived from midazolam-induced steroidogenesis including progesterone and downstream products in astrocytes. Our data provide new insights into the cytoprotective effect of midazolam. PMID- 23684575 TI - Gallbladder perforation related to bevacizumab. PMID- 23684576 TI - Proton-pump inhibitors can decrease gastrointestinal bleeding after percutaneous coronary intervention. AB - BACKGROUND: Current medical therapies for patients who have an acute coronary syndrome (ACS) focus on the coagulation cascade and platelet inhibition. These, coupled with early use of cardiac catheterization and revascularization, have decreased morbidity and mortality rates in patients who have acute ischemic heart disease with risk of bleeding. OBJECTIVE: The study aimed to determine the incidence of gastrointestinal bleeding after percutaneous coronary intervention (PCI). The effect of proton-pump inhibitor (PPI) treatment was also analyzed. METHODS: This case-control study evaluated gastrointestinal bleeding within a year of PCI for stable angina and acute coronary syndromes at Nanjing First Hospital between 2008 and 2011. Cases were identified and outcomes assessed using linkage analysis of data from cardiology and gastroenterology department databases. Analysis of the case and control groups for both risk and protective factors was performed using independent two-sample Student's t-test with Fisher's exact P value and logistic regression. RESULTS: The incidence of gastrointestinal bleeding following PCI was 1.3% (35/2680 patients). The risk factors for gastrointestinal bleeding were advanced age, female gender, smoking, drinking, previous peptic ulcer and previous gastrointestinal bleeding. PPI use after PCI (P=0.000) was accompanied by a lower risk of gastrointestinal bleeding, with only a few cases of gastrointestinal bleeding events reported. CONCLUSION: The incidence of gastrointestinal bleeding associated with the combination of aspirin and clopidogrel therapy was estimated to be 1.3%. Advanced age, being female, smokers, drinkers, previous peptic ulcer and previous gastrointestinal bleeding were significant independent risk factors. PPI for the prevention and treatment of gastrointestinal bleeding induced by the combination of aspirin and clopidogrel in patients after PCI was safe and effective. PMID- 23684577 TI - Gas gangrene in the abdominal wall: a physician's nightmare. PMID- 23684578 TI - DXA predictions of human femoral mechanical properties depend on the load configuration. AB - The aim of this study was to evaluate the ability of dual energy X-rays absorptiometry (DXA) areal bone mineral density (aBMD) measured in different regions of the proximal part of the human femur for predicting the mechanical properties of matched proximal femora tested in two different loading configurations. 36 pairs of fresh frozen femora were DXA scanned and tested until failure in two loading configurations: a fall on the side or a one-legged standing. The ability of the DXA output from four different regions of the proximal femur in predicting the femoral mechanical properties was measured and compared for the two loading scenarios. The femoral neck DXA BMD was best correlated to the femoral ultimate force for both configurations and predicted significantly better femoral failure load (R(2)=0.80 vs. R(2)=0.66, P<0.05) when simulating a side than when simulating a standing configuration. Conversely, the work to failure was predicted similarly for both loading configurations (R(2)=0.54 vs. R(2)=0.53, P>0.05). Therefore, neck BMD should be considered as one of the key factors for discriminating femoral fracture risk in vivo. Moreover, the better predictive ability of neck BMD for femoral strength if tested in a fall compared to a one-legged stance configuration suggests that DXA's clinical relevance may not be as high for spontaneous femoral fractures than for fractures associated to a fall. PMID- 23684579 TI - Validity and reliability of measuring activities, movement intensity and energy expenditure with the DynaPort MoveMonitor. AB - The purpose of this study was to evaluate the validity and reliability of assessing activities, movement intensity (MI) and energy expenditure (EE) measured by accelerometry. 28 Able-bodied participants performed standardized tasks while an accelerometer was worn and oxygen uptake was measured. After uploading the accelerometer data to the manufacturer's website, a report was received that gave minute-by-minute MI and EE of the performed activities. Validity was assessed by comparing reported activities and EE with the actual performed activities and calculated EE from the oxygen uptake, and by testing whether MI differed between walking velocities and cycling resistances. Reliability was assessed by performing the protocol twice. Except for standing (classified predominantly (82%) as sitting), most activities were categorized mainly correctly (93-100%). A difference in MI was detected between walking speeds but not between cycling resistances. EE was overestimated for walking (ICC=0.54) and underestimated for cycling (ICC=0.03). Reliability of MI was high (ICC=0.91) but reliability for the relative time spent in activities or the step count was weak to moderate. In conclusion, most activities were categorized correctly, MI seemed to be valid and reliable but reliability is low for relative time spent in activities and EE cannot be estimated well. PMID- 23684580 TI - TETRA mobile radios interfere with electroencephalography recording equipment. AB - We observed an anomaly in the human electroencephalogram (EEG) associated with exposure to terrestrial trunked radio (TETRA) Radiofrequency Fields (RF). Here, we characterize the time and frequency components of the anomaly and demonstrate that it is an artefact caused by TETRA RF interfering with the EEG recording equipment and not by any direct or indirect effect on the brain. PMID- 23684581 TI - Tracing Sox10-expressing cells elucidates the dynamic development of the mouse inner ear. AB - The inner ear is constituted by complicated cochlear and vestibular compartments, which are derived from the otic vesicle, an embryonic structure of ectodermal origin. Although the inner ear development has been analyzed using various techniques, the developmental events have not been fully elucidated because of the intricate structure. We previously developed a Sox10-IRES-Venus mouse designed to express green fluorescent protein under the control of the Sox10 promoter. In the present study, we showed that the Sox10-IRES-Venus mouse enabled the non-destructive visualization and understanding of the morphogenesis during the development of the inner ear. The expression of the transcription factor Sox10 was first observed in the invaginating otic placodal epithelium, and continued to be expressed in the mature inner ear epithelium except for the hair cells and mesenchymal cells. We found that Sox10 was expressed in immature hair cells in the developing inner ear, suggesting that hair cells were generated from the Sox10-expressing prosensory cells. Furthermore, we demonstrated that scattered Sox10-expressing cells existed around the developing inner ear, some of which differentiated into pigmented melanocytes in the stria vascularis, suggesting that they were neural crest cells. Further analyzing the Sox10-IRES Venus mice would provide important information to better understand the development of the inner ear. PMID- 23684582 TI - Loss of DOK2 induces carboplatin resistance in ovarian cancer via suppression of apoptosis. AB - OBJECTIVE: Ovarian cancers are highly heterogeneous and while chemotherapy is the preferred treatment many patients are intrinsically resistant or quickly develop resistance. Furthermore, all tumors that recur ultimately become resistant. Recent evidence suggests that epigenetic deregulation may be a key factor in the onset and maintenance of chemoresistance. We set out to identify epigenetically silenced genes that affect chemoresistance. METHODS: The epigenomes of a total of 45 ovarian samples were analyzed to identify epigenetically altered genes that segregate with platinum response, and further filtered with expression data to identify genes that were suppressed. A tissue culture carboplatin resistance screen was utilized to functionally validate this set of candidate platinum resistance genes. RESULTS: Our screen correctly identified 19 genes that when suppressed altered the chemoresistance of the cells in culture. Of the genes identified in the screen we further characterized one gene, docking protein 2 (DOK2), an adapter protein downstream of tyrosine kinase, to determine if we could elucidate the mechanism by which it increased resistance. The loss of DOK2 decreased the level of apoptosis in response to carboplatin. Furthermore, in cells with reduced DOK2, the level of anoikis was decreased. CONCLUSIONS: We have developed a screening methodology that analyzes the epigenome and informatically identifies candidate genes followed by in vitro culture screening of the candidate genes. To validate our screening methodology we further characterized one candidate gene, DOK2, and showed that loss of DOK2 induces chemotherapy resistance by decreasing the level of apoptosis in response to treatment. PMID- 23684583 TI - Lipid digestion, absorption and uptake in Solea senegalensis. AB - Dietary lipids are the major energy source for metabolic purposes in most fish species, and improve dietary protein utilization for growth. In a previous study we have reported a low tolerance of Senegalese sole juveniles to dietary lipid levels and suggested a maximal dietary inclusion level of 8% lipids for both optimal growth and nutrient utilization. The mechanisms behind this apparent poor utilization of the dietary lipids are still to be elucidated. The primary aim of the present study was to investigate the overall process of digestion and lipid absorption in relation to dietary lipid levels. Triplicate groups of twenty fish (mean initial mass 29g) were fed two isonitrogenous diets (54% of protein dry matter basis) with different lipid levels (L4 and L17, 4 and 17% lipids dry matter basis), for 88days. Protein and lipid apparent digestibility coefficients as well as lipase activity were similar in both groups suggesting that Solea senegalensis has the ability to digest equally well a low fat or a high fat diet. Plasma triglyceride concentrations were significantly higher 5 and 16h after feeding in fish fed the L17 compared to those fed L4, following dietary lipid supply, demonstrating effective lipid absorption. Expression of proteins related to lipid transport (microsomal triglyceride transfer protein), trafficking (Fatty acid binding protein 11) and fatty acid uptake (VLDL-r) was significantly higher in liver of fish fed the high fat diet 16h after the meal, but remained unchanged in muscle. In conclusion, it seems that high fat diets do not impair lipid digestion and absorption. PMID- 23684584 TI - The size of the metastatic lymph node is an independent prognostic factor for the patients with cervical cancer treated by definitive radiotherapy. AB - BACKGROUND AND PURPOSE: Lymph node (LN) metastasis is a well-known prognostic factor of the cervical cancer. In the current study, the size of metastatic LN was evaluated for its significance in the patients treated with definitive radiotherapy. MATERIALS AND METHODS: LN metastasis was evaluated for the 268 consecutive patients. The short-axis diameters of the largest LN were measured on magnetic resonance images for the 155 patients with LN metastasis. All the patients were classified into three groups: the negative lymphadenopathy (group N), the small (<15mm) lymphadenopathy (group SP), and the large (>=15mm) lymphadenopathy (group LP). RESULTS: Patients in the group LP showed significantly lower survival rates than the groups N and SP (5-year overall survival rates of 89%, 82%, and 58%, for groups N, SP, and LP, respectively, P<0.001; 5-year disease-free survival rates of 80%, 67%, and 50%, respectively, P<0.001). Regarding the pattern of failure, patients in the group LP showed inferior regional control rates and higher distant metastasis. CONCLUSION: The current study shows that the patients with large metastatic LNs are at increased risk of dying from early distant metastasis with substantial number of combined regional failures. Adoption of more effective systemic treatment as well as high radiotherapy dose for LNs may improve cure rates for these patients. PMID- 23684585 TI - Late toxicity and biochemical control in 554 prostate cancer patients treated with and without dose escalated image guided radiotherapy. AB - BACKGROUND AND PURPOSE: To compare rates of late gastrointestinal toxicity, late genitourinary toxicity and biochemical failure between patients treated for prostate cancer with implanted fiducial marker image guided radiotherapy (FMIGRT), and those treated without FMIGRT. METHODS AND MATERIALS: We performed a single institution retrospective study comparing all 311 patients who received 74 Gy without fiducial markers in 2006 versus all 243 patients who received our updated regimen of 78 Gy with FMIGRT in 2008. Patient records were reviewed 27 months after completing radiotherapy. Biochemical failure was defined using the Phoenix definition. Details of late gastrointestinal and genitourinary toxicities were graded according to CTCAEv4. Moderate/severe toxicity was defined as a grade 2 or higher toxicity. Cumulative incidence and prevalence curves for moderate/severe toxicity were constructed and compared using multistate modeling while biochemical failure free survival was compared using the log rank test. A Cox regression model was developed to correct for confounding factors. RESULTS: Median follow-up time for both groups was 22 months. The hazard ratio for moderate/severe late gastrointestinal toxicity in the non-FMIGRT group was 3.66 [95% CI (1.63-8.23), p=0.003] compared to patients in the FMIGRT group. There was no difference in the hazard ratio of moderate/severe late genitourinary toxicity between the two groups (0.44 [95% CI (0.19-1.00)]), but patients treated with FMIGRT did have a quicker recovery from their genitourinary toxicities HR=0.24 [95% CI (0.10-0.59)]. We were unable to detect any differences in biochemical failure free survival between the cohorts HR=0.60 [95% CI (0.30-1.20), p=0.143]. CONCLUSION: Despite dose escalation, the use of FMIGRT in radical radiotherapy for prostate cancer significantly reduces the incidence of gastrointestinal toxicity and the duration of late genitourinary toxicity when compared to conventional non-FMIGRT techniques. PMID- 23684586 TI - Prediction of rectum and bladder morbidity following radiotherapy of prostate cancer based on motion-inclusive dose distributions. AB - BACKGROUND AND PURPOSE: In radiotherapy (RT) of prostate cancer the key organs at risk (ORs) - the rectum and the bladder - display considerable motion, which may influence the dose/volume parameters predicting for morbidity. In this study we compare motion-inclusive doses to planned doses for the rectum and bladder and explore their associations with prospectively recorded morbidity. MATERIALS AND METHODS: The study included 38 prostate cancer patients treated with hypo fractionated image-guided intensity-modulated RT that had an average of nine repeat CT scans acquired during treatment. These scans were registered to the respective treatment planning CT (pCT) followed by a new dose calculation from which motion-inclusive dose distributions were derived. The pCT volumes, the treatment course averaged volumes as well as the planned and motion-inclusive doses were associated with acute and late morbidity (morbidity cut-off: >= Grade 2). RESULTS: Acute rectal morbidity (observed in 29% of cases) was significantly associated with both smaller treatment course averaged rectal volumes (population median: 75 vs. 94 cm(3)) and the motion-inclusive volume receiving doses close to the prescription dose (2 Gy-equivalent dose of 76 Gy). CONCLUSION: Variation in rectum and bladder volumes leads to deviations between planned and delivered dose/volume parameters that should be accounted for to improve the ability to predict morbidity following RT. PMID- 23684587 TI - Prediction of response to radiotherapy in the treatment of esophageal cancer using stem cell markers. AB - BACKGROUND AND PURPOSE: In this study, we investigated whether cancer stem cell marker expressing cells can be identified that predict for the response of esophageal cancer (EC) to CRT. MATERIALS AND METHODS: EC cell-lines OE-33 and OE 21 were used to assess in vitro, stem cell activity, proliferative capacity and radiation response. Xenograft tumors were generated using NOD/SCID mice to assess in vivo proliferative capacity and tumor hypoxia. Archival and fresh EC biopsy tissue was used to confirm our in vitro and in vivo results. RESULTS: We showed that the CD44+/CD24- subpopulation of EC cells exerts a higher proliferation rate and sphere forming potential and is more radioresistant in vitro, when compared to unselected or CD44+/CD24+ cells. Moreover, CD44+/CD24- cells formed xenograft tumors faster and were often located in hypoxic tumor areas. In a study of archival pre-neoadjuvant CRT biopsy material from EC adenocarcinoma patients (N=27), this population could only be identified in 50% (9/18) of reduced responders to neoadjuvant CRT, but never (0/9) in the complete responders (P=0.009). CONCLUSION: These results warrant further investigation into the possible clinical benefit of CD44+/CD24- as a predictive marker in EC patients for the response to chemoradiation. PMID- 23684588 TI - HDR brachytherapy combined with interstitial hyperthermia in locally advanced cervical cancer patients initially treated with concomitant radiochemotherapy--a phase III study. AB - BACKGROUND AND PURPOSE: The aim of this randomised trial was to investigate whether hyperthermia (HT) combined with interstitial brachytherapy (ISBT) has any influence on local control (LC), disease-free survival (DFS), or acute and late side effects in patients with advanced cervical cancer. MATERIALS AND METHODS: After radiochemotherapy, consecutive patients with cervical cancer (FIGO stage II III) were randomly assigned to two treatment groups, either ISBT alone or ISBT combined with interstitial hyperthermia (ISHT). A total of 205 patients were included in the statistical analysis. Once a week, HT, at a temperature above 42.5 degrees C, was administered for 45min before and during the HDR BT. RESULTS: The median follow-up time was 45months (range 3-72months). An effect of hyperthermia was not detected for disease-free survival (DFS) (log-rank test: p=0.178) or for local control (LC) (p=0.991). According to Cox's analysis, HT did not significantly influence failure or interactions with potential prognostic factors for LC or DFS. Statistical differences were not observed for the distribution of early and late complications between the HT and non HT groups. CONCLUSIONS: ISHT is well-tolerated and does not affect treatment-related early or late complications. Improvements in DFS and LC were not observed following the addition of ISHT to ISBT. PMID- 23684589 TI - The CD36 dynamic change after radiation therapy in lung cancer patients and its correlation with symptomatic radiation pneumonitis. AB - This study was carried out to investigate the relationship between serum CD36 levels and radiation pneumonitis in 30 patients irradiated for lung cancer. We found CD36 may become an important index for predicting the occurrence and development of radiation pneumonitis and evaluating the curative effect. PMID- 23684590 TI - Translational repression controls temporal expression of the Plasmodium berghei LCCL protein complex. AB - Plasmodium LCCL proteins comprise a family of six proteins that function as a protein complex and have essential roles in sporozoite transmission. In Plasmodium berghei, family members PbLAP1, PbLAP2 and PbLAP3 have been shown to be expressed in gametocytes and, following gametogenesis and fertilization, to be targeted to distinctive multivesicular organelles termed crystalloids that form in the ookinete. Here, we show by GFP-tagging that PbLAP4, PbLAP5 and PbLAP6, like their family members, are associated with the crystalloids. However, in contrast to their family members, protein expression of PbLAP4, PbLAP5 and PbLAP6 was not detected in gametocytes, even though transcription of the corresponding genes is most prominent in the sexual blood stage parasites. These results suggest that translational repression controls expression of the LCCL protein repertoire and, consequently, the temporal function of the protein complex during P. berghei development in the mosquito. PMID- 23684592 TI - Thrombotic microangiopathies: the past as prologue. PMID- 23684594 TI - Use of optical coherence tomography to guide treatment of an undeployed stent trapped in the right coronary artery to cover a proximal stent outflow dissection. PMID- 23684593 TI - An Integrated Model for Patient Care and Clinical Trials (IMPACT) to support clinical research visit scheduling workflow for future learning health systems. AB - We describe a clinical research visit scheduling system that can potentially coordinate clinical research visits with patient care visits and increase efficiency at clinical sites where clinical and research activities occur simultaneously. Participatory Design methods were applied to support requirements engineering and to create this software called Integrated Model for Patient Care and Clinical Trials (IMPACT). Using a multi-user constraint satisfaction and resource optimization algorithm, IMPACT automatically synthesizes temporal availability of various research resources and recommends the optimal dates and times for pending research visits. We conducted scenario-based evaluations with 10 clinical research coordinators (CRCs) from diverse clinical research settings to assess the usefulness, feasibility, and user acceptance of IMPACT. We obtained qualitative feedback using semi-structured interviews with the CRCs. Most CRCs acknowledged the usefulness of IMPACT features. Support for collaboration within research teams and interoperability with electronic health records and clinical trial management systems were highly requested features. Overall, IMPACT received satisfactory user acceptance and proves to be potentially useful for a variety of clinical research settings. Our future work includes comparing the effectiveness of IMPACT with that of existing scheduling solutions on the market and conducting field tests to formally assess user adoption. PMID- 23684595 TI - Takosubo cardiomyopathy presenting as a non-ST segment elevation myocardial infarction in the setting of cocaine use and asthma exacerbation. PMID- 23684596 TI - Hereditary patterns of bicuspid aortic valve in a hundred families. AB - BACKGROUND: To study the following characteristics of bicuspid aortic valves (BAVs): 1) the recurrence rate in our population, 2) patterns of hereditary transmission in different BAV morphologies and 3) the aortic dimensions of BAVs in first-degree relatives (FDRs). METHODS: A cross-sectional, prospective study of 100 consecutive families of BAV patients attending a university hospital. The following aortic valve morphologies were analysed and categorised: fusion of the right and left coronary cusps (BAV type A), right and noncoronary cusps (type B) and of the left and noncoronary cusps (type C). RESULTS: There were 553 subjects studied, 100 cases with a BAV (46.8+/-15 years, 66% male, type 67% A, 32% B and 1% C; 42% with aortic dilatation), 348 FDRs (44.8% male), and 105 healthy control subjects (50% male). We detected 16 BAVs among 348 FDRs. The recurrence rates were 15% for families, 4.6% for FDRs, 7.05% in men and 2.60% in women. The morphologic concordance in family members was 68.8%. The aortic dimensions in 270 adult FDRs with a tricuspid aortic valve were significantly smaller compared with BAV patients (sinus index diameter 1.60+/-0.19 cm/m(2) vs. 1.82+/-0.29 cm/m(2), p<0.001; tubular index diameter 1.51+/-0.23 cm/m(2) vs. 2.00+/-0.45 cm/m(2), p<0.001) and similar to 103 control subjects(sinus index diameter 1.60+/-0.19 cm/m(2) vs. 1.59+/-0.17 cm/m(2), p=0.600 and tubular index diameter 1.51+/-0.23 cm/m(2) vs. 1.53+/-0.18 cm/m(2), p=0.519). CONCLUSIONS: In our population, the BAV recurrence rate in FDRs was low (4.6%). The hereditary transmission of morphologic BAV types seems by chance, and the aortic dimensions in tricuspid FDRs are normal. PMID- 23684597 TI - Acute STEMI care in the 2010s: what has the STREAM trial shown in reperfusing early cases and what should the next breakthrough be? PMID- 23684598 TI - Prognostic significance of peak oxygen consumption <= 10 ml/kg/min in heart failure: context vs. criteria. AB - BACKGROUND: Both heart failure (HF) treatment and management may distort or enhance the predictive accuracy of low peak oxygen consumption (pVO2<=10 ml/kg/min), blurring the identification of specific patients in whom heart transplantation (HT) could make a clinical difference. The aim of this study was to re-evaluate the prognostic significance of pVO2<=10 ml/kg/min in systolic HF in light of changes in medical treatment and management. METHODS: Two-year outcomes were compared across the "millennium dawn" (MD) between two HF cohorts with pVO2<=10 ml/kg/min and gas exchange ratio>1.10: 116 patients were recorded between 1994 and 1999 (pre-MD: mean pVO2 8.6+/-1.1 ml/kg/min) and 90 between 2001 and 2008 (post-MD: mean pVO2 8.8+/-1.0 ml/kg/min). Cardiac-related death was considered an event and event censoring was interrupted at 24 months for surviving patients. RESULTS: Patients across the MD had the same age, NYHA class, left ventricular ejection fraction and pVO2 (pre-MD: mean pVO2 8.6+/-1.1; post MD: mean pVO2 8.8+/-1.0 ml/kg/min: NS). Seventy-one patients (34%) died: 51 (44%) in the pre-MD and 20 (22%) in the post-MD group (p<0.01). The post-MD group showed a better mean 1-year (83% vs. 68%; chi(2)=5.17, p=0.0229) and 2-year survival (77% vs. 56%; chi(2)=8.87, p=0.0029) compared to pre-MD patients. CONCLUSIONS: Two-year outcome of HF patients with pVO2<=10 ml/kg/min has significantly improved in the post-MD era, suggesting the HT indication should not rely on a single CPET parameter, rather on a multifactorial clinical approach. PMID- 23684599 TI - p-Coumaric acid attenuates apoptosis in isoproterenol-induced myocardial infarcted rats by inhibiting oxidative stress. AB - BACKGROUND: Cardiac apoptosis plays an important role in the pathology of myocardial infarction. The protective effects of p-coumaric acid on cardiac apoptosis were evaluated in isoproterenol induced myocardial infarcted rats. METHODS: Rats were pretreated with p-coumaric acid (8 mg/kg body weight) daily for a period of 7 days. After pretreatment, isoproterenol (100 mg/kg body weight) was injected subcutaneously into rats at an interval of 24 h for 2 days to induce myocardial infarction. Cardiac diagnostic markers, heart lipid peroxidation, antioxidant system, histopathological changes of the heart and apoptosis were evaluated in isoproterenol induced myocardial infarcted rats. RESULTS: Isoproterenol induced myocardial infarcted rats showed a significant increase in the levels of serum cardiac diagnostic markers, heart lipid peroxidation products and a significant decrease in the activities/levels of heart antioxidants. Histopathological findings of myocardial infarcted rats revealed marked necrosis and edema. Reverse Transcription Polymerase Chain Reaction study revealed an increase in the myocardial expression of Bax, caspase-8, caspase-9 and Fas genes and a decrease in the myocardial expression of Bcl-2 and Bcl-xL genes. p-Coumaric acid pretreatment showed protective effects on apoptosis by inhibiting oxidative stress. p-Coumaric acid pretreated isoproterenol induced myocardial infarcted heart also confirmed these findings. The possible mechanisms for the protective effects of p-coumaric acid could be attributed to antilipid peroxidative, antioxidant and antiapoptotic properties. CONCLUSION: Thus, p-coumaric acid protected the myocardial infarcted rat's heart against apoptosis by inhibiting oxidative stress. PMID- 23684600 TI - Case reports of bail-out maneuvers for implantation of a second core valve prosthesis during the same TAVI procedure. PMID- 23684601 TI - Practice patterns, feasibility and efficacy of percutaneous coronary interventions (PCI) using small French size vascular access. PMID- 23684603 TI - Neuromuscular disorders and Takotsubo syndrome. PMID- 23684602 TI - Distinctive profile of sudden cardiac arrest in middle-aged vs. older adults: a community-based study. AB - BACKGROUND: While sudden cardiac arrest (SCA) rates increase with age, middle aged adults (35-59 years) may comprise a significant proportion of SCA cases in the community (30-40%). However, there is a lack of studies evaluating SCA risk factors specifically associated with this age-group of the population. METHODS: Using prospective multiple-source surveillance methodology we identified cases of SCA >=35 years in the ongoing Oregon Sudden Unexpected Death Study (Portland, Oregon metropolitan area, population~1,000,000). Out-of-hospital SCA cases, aged 35-59 years were compared to older SCA cases (>=60 years) in a comprehensive analysis of clinical profile of SCA. RESULTS: The middle-aged (n=753) compared to older (n=1251) cases were more likely to be male, obese, have sleep apnea and seizure disorder (all p<=0.001); and were less likely to have a history of hypertension, diabetes mellitus, known coronary artery disease, congestive heart failure and syncope (all p<0.01). In multivariable analyses the middle-aged group had higher likelihood of male sex (O.R. 1.67, 95% C.I. 1.29-2.18), obesity (2.20, 1.52-3.19), sleep apnea (2.30, 1.44-3.68) and seizure disorder (2.69, 1.64-4.42); and lower rates of known coronary artery disease (0.57, 0.43-0.74) and congestive heart failure (0.35, 0.25-0.48). CONCLUSIONS: SCA in the middle-aged adult was distinguishable from older subjects by higher rates of obesity, sleep apnea and seizure disorder; and lower prevalence of traditional clinical risk markers. With the growing epidemic of obesity, these findings have implications for SCA burden; and suggest the need for a clinical and investigational focus on SCA prediction and prevention in the middle-aged adult, that is distinct from older adults. PMID- 23684591 TI - Decision making for oral anticoagulants in atrial fibrillation: the ATA-AF study. AB - BACKGROUND: Oral anticoagulants offer the best long-term protection against ischemic stroke in patients with atrial fibrillation (AF). However, vitamin K antagonists (VKA) are cumbersome to use and their prescription is far from guidelines recommendations. We report the results of a large survey on the attitudes of prescription of VKA in patients with AF. METHODS: 7148 patients were enrolled by 196 Internal Medicine (MED) and 164 Cardiology (CARD) centers, and VKA specifically analyzed. Thrombotic and hemorrhagic risks were evaluated by means of CHADS2 and CHA2DS2VASc scores, and a study-specific bleeding score (modified HAS-BLED). RESULTS: 63.9% of non-valvular patients had a CHADS2 score>=2 (MED: 75.3%-CARD: 53.1%), and 28.4% a bleeding score>=3 (41.9% MED-15.8% CARD). VKA were prescribed in 55.5% of non-valvular patients (46.3% MED and 64.2% CARD), in 81% of high-risk valvular patients and in 58.8% of the overall study population. Among patients at high risk of bleeding (score>=3), VKA were prescribed in 26.9% of subjects, while, in the subgroup at high risk of thrombosis (CHADS2 Score<2), these were prescribed in 54.4%. Age>=75, paroxysmal AF, cognitive impairment, need for assistance, CHADS2<2 and bleeding score>=3 were independent predictors of non-use of VKA. CONCLUSIONS: Oral anticoagulants are more frequently used in CARD than in MED, plausibly due to greater complexity of MED patients. Stratification of thrombotic and hemorrhagic risk significantly drives the choice for VKA. However the fraction of patients in whom prescription or non-prescription is based on other individual characteristics is not negligible. PMID- 23684604 TI - A case of lamin A/C mutation cardiomyopathy with overlap features of ARVC: a critical role of genetic testing. PMID- 23684605 TI - Fibromuscular dysplasia of the renal artery: an underdiagnosed cause of severe hypertension. PMID- 23684606 TI - A population-based study of venous thrombosis in pregnancy in Scotland 1980-2005. AB - OBJECTIVES: Data on time trends in the incidence of pregnancy-related venous thromboembolism (VTE) are sparse. This report charts the incidence of pregnancy related VTE over the period 1980-2005 in Scotland, and discusses the results in relation to potential risk factors. STUDY DESIGN: 1475301 maternity discharges from Scottish hospitals recorded on the Scottish Morbidity Record 2 (SMR2) were included. Incidences of pregnancy-related VTE, antenatal deep venous thromboembolism (DVT), postnatal DVT and pulmonary embolism (PTE) were derived relative to the number of deliveries, and risk factors were analysed using Poisson regression. RESULTS: Over the period, VTE incidence rose from 13.7 to 18.3 per 10000 deliveries, antenatal DVTs from 8.8 to 12.2 per 10000 deliveries and PTE from 1.5 to 3.0 per 10000 deliveries. Postnatal DVTs, on the other hand, declined from 4.2 to 2.7 per 10000 deliveries. Risk factors were: age over 35 years; three or more previous pregnancies; previous VTE; obstetric haemorrhage; and preeclampsia. Antenatal DVT risk was highest in the most deprived areas, where events started increasing before those in less deprived areas. Postnatal DVT risk was increased following caesarean delivery, especially when unplanned, although after 1996, events following emergency caesarean decreased. CONCLUSION: During the 26-year period, pregnancy-related VTEs increased, with the greatest rise for antenatal DVTs. Postnatal DVTs, on the other hand, declined over the period, particularly following emergency section. Thromboprophylaxis use following emergency delivery may have led to the postpartum reduction. To continue to prevent events, risk assessment and intervention are required, particularly antenatally. PMID- 23684607 TI - A genetic screen identifies TCF3/E2A and TRIAP1 as pathway-specific regulators of the cellular response to p53 activation. AB - The p53 transcription factor participates in diverse cellular responses to stress, including cell-cycle arrest, apoptosis, senescence, and autophagy. The molecular mechanisms defining the ultimate outcome of p53 activation remain poorly characterized. We performed a genome-wide genetic screen in human cells to identify pathway-specific coregulators of the p53 target gene CDKN1A (p21), an inhibitor of cell-cycle progression, versus BBC3 (PUMA), a key mediator of apoptosis. Our screen identified numerous factors whose depletion creates an imbalance in the p21:PUMA ratio upon p53 activation. The transcription factor TCF3, also known as E2A, drives p21 expression while repressing PUMA across cancer cell types of multiple origins. Accordingly, TCF3/E2A depletion impairs the cell-cycle-arrest response and promotes apoptosis upon p53 activation by chemotherapeutic agents. In contrast, TRIAP1 is a specific repressor of p21 whose depletion slows down cell-cycle progression. Our results reveal strategies for driving cells toward specific p53-dependent responses. PMID- 23684608 TI - RhoGAPs attenuate cell proliferation by direct interaction with p53 tetramerization domain. AB - Many Rho GTPase activation proteins (RhoGAPs) are deleted or downregulated in cancers, but the functional consequences are still unclear. Here, we show that the RhoGAP ArhGAP11A induces cell-cycle arrest and apoptosis by binding to the tumor suppressor p53. The RhoGAP domain of ArhGAP11A binds to the tetramerization domain of p53, but not to its family members p63 or p73. The interaction stabilizes the tetrameric conformation of p53 and enhances its DNA-binding activity, thereby inducing cell-cycle arrest and apoptosis. Upon DNA damage stress, ArhGAP11A accumulates in the nucleus and interacts with p53, whereas knockdown of ArhGAP11A partially blocks p53 transcriptional activity. These findings explain why RhoGAPs are frequently deleted in cancers and suggest that the RhoGAP family sits at the crossroads between the cell-migration and proliferation pathways. PMID- 23684609 TI - Senp1 is essential for desumoylating Sumo1-modified proteins but dispensable for Sumo2 and Sumo3 deconjugation in the mouse embryo. AB - Posttranslational modification with small ubiquitin-like modifier (Sumo) regulates numerous cellular and developmental processes. Sumoylation is dynamic with deconjugation by Sumo-specific proteases (Senps) regulating steady-state levels. Different Senps are found in distinct subcellular domains, which may limit their deconjugation activity to colocalizing Sumo-modified proteins. In vitro, Senps can discriminate between the different Sumo paralogs: Sumo1 versus the highly related Sumo2 and Sumo3 (Sumo2/3), which can form poly-Sumo chains. However, a full understanding of Senp specificity in vivo is still lacking. Here, using biochemical and genetic approaches, we establish that Senp1 has an essential, nonredundant function to desumoylate Sumo1-modified proteins during mouse embryonic development. Senp1 specificity for Sumo1 conjugates represents an intrinsic function and not simply a product of colocalization. In contrast, Senp1 has only a limited role in Sumo2/3 desumoylation, although it may regulate Sumo1 mediated termination of poly-Sumo2/3 chains. PMID- 23684610 TI - Essential regulation of lung surfactant homeostasis by the orphan G protein coupled receptor GPR116. AB - GPR116 is an orphan seven-pass transmembrane receptor whose function has been unclear. Global disruption of the Gpr116 gene in mice revealed an unexpected, critical role for this receptor in lung surfactant homeostasis, resulting in progressive accumulation of surfactant lipids and proteins in the alveolar space, labored breathing, and a reduced lifespan. GPR116 expression analysis, bone marrow transplantation studies, and characterization of conditional knockout mice revealed that GPR116 expression in ATII cells is required for maintaining normal surfactant levels. Aberrant packaging of surfactant proteins with lipids in the Gpr116 mutant mice resulted in compromised surfactant structure, function, uptake, and processing. Thus, GPR116 plays an indispensable role in lung surfactant homeostasis with important ramifications for the understanding and treatment of lung surfactant disorders. PMID- 23684611 TI - Two distinct modes of ATR activation orchestrated by Rad17 and Nbs1. AB - The ATM- and Rad3-related (ATR) kinase is a master regulator of the DNA damage response, yet how ATR is activated toward different substrates is still poorly understood. Here, we show that ATR phosphorylates Chk1 and RPA32 through distinct mechanisms at replication-associated DNA double-stranded breaks (DSBs). In contrast to the rapid phosphorylation of Chk1, RPA32 is progressively phosphorylated by ATR at Ser33 during DSB resection prior to the phosphorylation of Ser4/Ser8 by DNA-PKcs. Surprisingly, despite its reliance on ATR and TopBP1, substantial RPA32 Ser33 phosphorylation occurs in a Rad17-independent but Nbs1 dependent manner in vivo and in vitro. Importantly, the role of Nbs1 in RPA32 phosphorylation can be separated from ATM activation and DSB resection, and it is dependent upon the interaction of Nbs1 with RPA. An Nbs1 mutant that is unable to bind RPA fails to support proper recovery of collapsed replication forks, suggesting that the Nbs1-mediated mode of ATR activation is important for the repair of replication-associated DSBs. PMID- 23684612 TI - The Ets transcription factor GABP is a component of the hippo pathway essential for growth and antioxidant defense. AB - The transcriptional coactivator Yes-associated protein (YAP) plays an important role in organ-size control and tumorigenesis. However, how Yap gene expression is regulated remains unknown. This study shows that the Ets family member GABP binds to the Yap promoter and activates YAP transcription. The depletion of GABP downregulates YAP, resulting in a G1/S cell-cycle block and increased cell death, both of which are substantially rescued by reconstituting YAP. GABP can be inactivated by oxidative mechanisms, and acetaminophen-induced glutathione depletion inhibits GABP transcriptional activity and depletes YAP. In contrast, activating YAP by deleting Mst1/Mst2 strongly protects against acetaminophen induced liver injury. Similar to its effects on YAP, Hippo signaling inhibits GABP transcriptional activity through several mechanisms. In human liver cancers, enhanced YAP expression is correlated with increased nuclear expression of GABP. Therefore, we conclude that GABP is an activator of Yap gene expression and a potential therapeutic target for cancers driven by YAP. PMID- 23684613 TI - A conserved role for atlastin GTPases in regulating lipid droplet size. AB - Lipid droplets (LDs) are the major fat storage organelles in eukaryotic cells, but how their size is regulated is unknown. Using genetic screens in C. elegans for LD morphology defects in intestinal cells, we found that mutations in atlastin, a GTPase required for homotypic fusion of endoplasmic reticulum (ER) membranes, cause not only ER morphology defects, but also a reduction in LD size. Similar results were obtained after depletion of atlastin or expression of a dominant-negative mutant, whereas overexpression of atlastin had the opposite effect. Atlastin depletion in Drosophila fat bodies also reduced LD size and decreased triglycerides in whole animals, sensitizing them to starvation. In mammalian cells, co-overexpression of atlastin-1 and REEP1, a paralog of the ER tubule-shaping protein DP1/REEP5, generates large LDs. The effect of atlastin-1 on LD size correlates with its activity to promote membrane fusion in vitro. Our results indicate that atlastin-mediated fusion of ER membranes is important for LD size regulation. PMID- 23684614 TI - Planarians require an intact brain to behaviorally react to cocaine, but not to react to nicotine. AB - Planarians possess a rudimentary brain with many features in common with vertebrate brains. They also display a remarkable capacity for tissue regeneration including the complete regeneration of the nervous system. Using the induction of planarian seizure-like movements (pSLMs) as a behavioral endpoint, we demonstrate that an intact nervous system is necessary for this organism to react to cocaine exposure, but not necessary to react to nicotine administration. Decapitated planarians (Girardia tigrina) display pSLMs indistinguishable from intact worms when exposed to nicotine, but cocaine-induced pSLMs are reduced by about 95% upon decapitation. Decapitated worms recover their normal sensitivity to cocaine within 5 days after head amputation. In worms where half of the brain was removed or partially dissected, the expression of cocaine-induced pSLMs was reduced by approximately 75%. Similar amputations at the level of the tail did not show a significant decrease to cocaine exposure. To the best of our knowledge, our work is the first report that explores how regenerating planarians react to the exposure of cocaine. PMID- 23684615 TI - Selective suppression of excitatory synapses on GABAergic interneurons by norepinephrine in juvenile rat prefrontal cortical microcircuitry. AB - The noradrenergic system of the brain is thought to facilitate neuronal processes that promote behavioral activation, alertness, and attention. It is known that norepinephrine (NE) can be significantly elevated in the prefrontal cortex under normal conditions such as arousal and attention, and following the administration of psychostimulants and various other drugs prescribed for psychiatric disorders. However, how NE modulates neuronal activity and synapses in the local prefrontal circuitry remains elusive. In this study, we characterized the actions of NE on individual monosynaptic connections among layer V pyramidal neurons (P) and fast spiking (FS) GABAergic interneurons in the juvenile (postnatal days 20-23) rat prefrontal local circuitry. We found that NE selectively depresses excitatory synaptic transmission in P-FS connections but has no detectable effect on the excitatory synapses in P-P connections and the inhibitory synapses in FS-P connections. NE apparently exerts distinctly different modulatory actions on identified synapses that target GABAergic interneurons but has no effect on those in the pyramidal neurons in this specific developmental period. These results indicate that, depending on the postsynaptic targets, the effects of NE in prefrontal cortex are synapse-specific, at least in the juvenile animals. PMID- 23684616 TI - Interleukin-10 regulates the fetal hyaluronan-rich extracellular matrix via a STAT3-dependent mechanism. AB - BACKGROUND: The midgestational fetus is capable of regenerative healing. We have recently demonstrated a novel role for the anti-inflammatory cytokine interleukin 10 (IL-10) as a regulator of hyaluronan (HA) in the extracellular matrix. The signaling pathway of IL-10 has been studied in monocytes but is unknown in dermal fibroblasts. We hypothesized IL-10 signals through its primary receptor, IL-10R1, to activate STAT3, resulting in HA synthesis. METHODS: Murine midgestational (E14.5) fetal fibroblasts were evaluated in vitro. Pericellular matrix was quantified using a particle exclusion assay. STAT3 levels and cellular localization were evaluated by Western blot/band densitometry and immunocytochemistry/confocal microscopy. HA levels were quantified by enzyme linked immunosorbent assay. The effects of IL-10R1 signal blockade by a neutralizing antibody and STAT3 inhibition were evaluated. An ex vivo midgestation fetal forearm culture incisional wound model in control and transgenic IL-10-/- mice was used to evaluate the role of STAT3 on the extracellular matrix. RESULTS: Fetal fibroblasts produce a robust hyaluronan-rich pericellular matrix that is IL-10R1 and STAT3 dependent. Inhibition of IL-10R1 signaling results in decreased phosphorylated STAT3 levels and inhibition of nuclear localization. Inhibition of STAT3 results in decreased HA production. At day 3, midgestation fetal wounds have efficient re-epithelialization, which is significantly slowed in IL-10-/- wounds at the same gestation and with inhibition of STAT3. CONCLUSIONS: Our data demonstrate that IL-10 regulates HA synthesis through its primary receptor IL-10R1 and STAT3 activation. This supports a novel nonimmunoregulatory mechanism of IL-10 in its role in fetal regenerative wound healing. PMID- 23684617 TI - Augmented environments for the targeting of hepatic lesions during image-guided robotic liver surgery. AB - BACKGROUND: Stereotactic navigation technology can enhance guidance during surgery and enable the precise reproduction of planned surgical strategies. Currently, specific systems (such as the CAS-One system) are available for instrument guidance in open liver surgery. This study aims to evaluate the implementation of such a system for the targeting of hepatic tumors during robotic liver surgery. MATERIAL AND METHODS: Optical tracking references were attached to one of the robotic instruments and to the robotic endoscopic camera. After instrument and video calibration and patient-to-image registration, a virtual model of the tracked instrument and the available three-dimensional images of the liver were displayed directly within the robotic console, superimposed onto the endoscopic video image. An additional superimposed targeting viewer allowed for the visualization of the target tumor, relative to the tip of the instrument, for an assessment of the distance between the tumor and the tool for the realization of safe resection margins. RESULTS: Two cirrhotic patients underwent robotic navigated atypical hepatic resections for hepatocellular carcinoma. The augmented endoscopic view allowed for the definition of an accurate resection margin around the tumor. The overlay of reconstructed three-dimensional models was also used during parenchymal transection for the identification of vascular and biliary structures. Operative times were 240 min in the first case and 300 min in the second. There were no intraoperative complications. CONCLUSIONS: The da Vinci Surgical System provided an excellent platform for image-guided liver surgery with a stable optic and instrumentation. Robotic image guidance might improve the surgeon's orientation during the operation and increase accuracy in tumor resection. Further developments of this technological combination are needed to deal with organ deformation during surgery. PMID- 23684618 TI - A clinical trial of acupuncture about time-varying treatment and points selection in primary dysmenorrhea. AB - OBJECTIVE: To observe the clinical therapeutic effects of acupuncture at single point Shiqizhui (EX-B8) and multi-points in time-varying treatment for primary dysmenorrhea. METHODS: 600 patients with primary dysmenorrhea were randomly assigned to the single point group (n=200) including group A (treating before the menstruation, n=100) and group B (immediately treating as soon as pain occurrence, n=100), the multi-points group (n=200) including group C (treating before the menstruation, n=100) and group D (immediately treating as soon as pain occurrence, n=100), or the control group, group E (n=200, no treatment). The therapeutic effects were analyzed after treatment for three menstrual cycles and interviewed for three follow-up periods. RESULTS: Acupuncture could effectively relieve menstrual pain for primary dysmenorrhea compared with the control group (P<0.05, P<0.01). Immediate pain relief occurred following acupuncture within 5 min in group B (P<0.01) and group D (P<0.01), and the two groups obviously relieved menstrual pain for VAS scores. Both group A and group C obviously relieved menstrual pain (P<0.01), and group C was better than group A (P<0.05). Compared with group D, Group C was much better for CMSS scores in cycle 1. CONCLUSION: Treating before the menstruation is better than immediately treating as soon as pain occurrence at the improvement in symptoms of dysmenorrheal at multi-points. And single point is better than multi-points when immediately treating as soon as pain occurrence. The present trial suggest Shiqizhui (EX-B8) should be chosen as a convenient point. PMID- 23684619 TI - Efficacy of ponatinib against ABL tyrosine kinase inhibitor-resistant leukemia cells. AB - Because a substantial number of patients with chronic myeloid leukemia acquire resistance to ABL tyrosine kinase inhibitors (TKIs), their management remains a challenge. Ponatinib, also known as AP24534, is an oral multi-targeted TKI. Ponatinib is currently being investigated in a pivotal phase 2 clinical trial. In the present study, we analyzed the molecular and functional consequences of ponatinib against imatinib- or nilotinib-resistant (R) K562 and Ba/F3 cells. The proliferation of imatinib- or nilotinib-resistant K562 cells did not decrease after treatment with imatinib or nilotinib. Src family kinase Lyn was activated. Point mutation Ba/F3 cells (E334V) were also highly resistant to imatinib and nilotinib. Treatment with ponatinib for 72h inhibited the growth of imatinib- and nilotinib-resistant cells. The phosphorylation of BCR-ABL, Lyn, and Crk-L was reduced. This study demonstrates that ponatinib has an anti-leukemia effect by reducing ABL and Lyn kinase activity and this information may be of therapeutic relevance. PMID- 23684620 TI - Gas6/Axl mediates tumor cell apoptosis, migration and invasion and predicts the clinical outcome of osteosarcoma patients. AB - Dysregulation of the receptor tyrosine kinase Axl and its ligand Gas6 has been shown to promote multiple tumorigenic processes, as well as to correlate with worse prognosis in many different tumor types. However, studies of Axl expression and function in osteosarcoma have rarely been reported. In this study, we report that activated Axl is highly expressed in osteosarcoma cells, and this expression is significantly correlated with the recurrence and lung metastasis of osteosarcoma patients. High expression of activated Axl was an independent predictor for worse prognosis in osteosarcoma. Additionally, we confirmed a strong positive correlation between P-Axl and MMP-9 expression in those osteosarcoma patients. In osteosarcoma cell lines MG63 and U2OS, 200 ng/ml rhGas6 could cause obvious increase of P-Axl expression within 30 min, consistent with the expression of P-AKT. In both of the cell lines, Axl activated by rhGas6 could protect the tumor cells from apoptosis caused by serum starvation, and promote tumor cells' migration and invasion in vitro. Together with previous data, these studies suggest that activated Axl participate in the progression of osteosarcoma by resisting tumor cells apoptosis and promoting their migration and invasion, which may be linked to the expression of MMP-9. In the mechanism, AKT signaling pathway may contribute to the function of P-Axl in osteosarcoma rather than ERK pathway. PMID- 23684621 TI - Antigen presentation by small intestinal epithelial cells uniquely enhances IFN gamma secretion from CD4+ intestinal intraepithelial lymphocytes. AB - Small intestinal epithelial cells (sIECs) express major histocompatibility complex class II molecules even in a normal condition, and are known to function as antigen presenting cells (APCs) at least in vitro. These findings raised the possibility that sIECs play an important role in inducing immune responses against luminal antigens, especially those of intestinal intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs). We herein showed that antigenic stimulation with sIECs induced markedly greater secretion of interferon gamma (IFN-gamma) by CD4(+) IELs, but not interleukin (IL)-4, IL-10 and IL-17 although the proliferative response was prominently lower than that with T cell depleted splenic APCs. In contrast, no enhanced IFN-gamma secretion by CD4(+) LPLs and primed splenic CD4(+) T cells was observed when stimulated with sIECs. Taken together, these results suggest that sIECs uniquely activate CD4(+) IELs and induce remarkable IFN-gamma secretion upon antigenic stimulation in vivo. PMID- 23684622 TI - Dynamic adipocyte phosphoproteome reveals that Akt directly regulates mTORC2. AB - A major challenge of the post-genomics era is to define the connectivity of protein phosphorylation networks. Here, we quantitatively delineate the insulin signaling network in adipocytes by high-resolution mass spectrometry-based proteomics. These data reveal the complexity of intracellular protein phosphorylation. We identified 37,248 phosphorylation sites on 5,705 proteins in this single-cell type, with approximately 15% responding to insulin. We integrated these large-scale phosphoproteomics data using a machine learning approach to predict physiological substrates of several diverse insulin-regulated kinases. This led to the identification of an Akt substrate, SIN1, a core component of the mTORC2 complex. The phosphorylation of SIN1 by Akt was found to regulate mTORC2 activity in response to growth factors, revealing topological insights into the Akt/mTOR signaling network. The dynamic phosphoproteome described here contains numerous phosphorylation sites on proteins involved in diverse molecular functions and should serve as a useful functional resource for cell biologists. PMID- 23684623 TI - Pharmacology, physiology, and mechanisms of incretin hormone action. AB - Incretin peptides, principally GLP-1 and GIP, regulate islet hormone secretion, glucose concentrations, lipid metabolism, gut motility, appetite and body weight, and immune function, providing a scientific basis for utilizing incretin-based therapies in the treatment of type 2 diabetes. Activation of GLP-1 and GIP receptors also leads to nonglycemic effects in multiple tissues, through direct actions on tissues expressing incretin receptors and indirect mechanisms mediated through neuronal and endocrine pathways. Here we contrast the pharmacology and physiology of incretin hormones and review recent advances in mechanisms coupling incretin receptor signaling to pleiotropic metabolic actions in preclinical studies. We discuss whether mechanisms identified in preclinical studies have potential translational relevance for the treatment of human disease and highlight controversies and uncertainties in incretin biology that require resolution in future studies. PMID- 23684624 TI - Adiponectin regulates bone mass via opposite central and peripheral mechanisms through FoxO1. AB - The synthesis of adiponectin, an adipokine with ill-defined functions in animals fed a normal diet, is enhanced by the osteoblast-derived hormone osteocalcin. Here we show that adiponectin signals back in osteoblasts to hamper their proliferation and favor their apoptosis, altogether decreasing bone mass and circulating osteocalcin levels. Adiponectin fulfills these functions, independently of its known receptors and signaling pathways, by decreasing FoxO1 activity in a PI3-kinase-dependent manner. Over time, however, these local effects are masked because adiponectin signals in neurons of the locus coeruleus, also through FoxO1, to decrease the sympathetic tone, thereby increasing bone mass and decreasing energy expenditure. This study reveals that adiponectin has the unusual ability to regulate the same function in two opposite manners depending on where it acts and that it opposes, partially, leptin's influence on the sympathetic nervous system. It also proposes that adiponectin regulation of bone mass occurs through a PI3-kinase-FoxO1 pathway. PMID- 23684625 TI - Retrospective study of the functional recovery of men compared with that of women with long-term facial paralysis. AB - Sex is likely to play an important part in reanimation of the face after paralysis, with women being superior in terms of resistance to neural injury and regeneration. Our aim was to evaluate the influence of the sex of the patient on the recovery of facial paralysis after surgical reanimation by comparing the degree of restored movement between men and women with long-standing paralysis that was reanimated by transfer of the hypoglossal nerve or cross-face nerve grafting. Between 1999 and 2010 we operated on 174 patients with facial paralysis. Of these we studied 26 cases (19 women and 7 men) with complete long standing paralysis reanimated with either cross-face nerve grafting (n=14) or transfer of the hemihypoglossal nerve (n=12). The degree of movement restored was recorded in each case. Statistical analysis showed that in cases with long standing paralysis women had significantly more movement restored than men for both cross-face nerve grafting (p=0.02) and hypoglossal transposition (p=0.04). We conclude that, after a neural injury, women tend to maintain the viability of the facial musculature longer than men, which suggests that they are more resistant to both denervation and the development of muscular atrophy. Whether this phenomenon can be explained by neural or muscular processes, or both, warrants further studies. PMID- 23684626 TI - Complement-triggered pathways orchestrate regenerative responses throughout phylogenesis. AB - Adult tissue plasticity, cell reprogramming, and organ regeneration are major challenges in the field of modern regenerative medicine. Devising strategies to increase the regenerative capacity of tissues holds great promise for dealing with donor organ shortages and low transplantation outcomes and also provides essential impetus to tissue bioengineering approaches for organ repair and replacement. The inherent ability of cells to reprogram their fate by switching into an embryonic-like, pluripotent progenitor state is an evolutionary vestige that in mammals has been retained mostly in fetal tissues and persists only in a few organs of the adult body. Tissue regeneration reflects the capacity of terminally differentiated cells to re-enter the cell cycle and proliferate in response to acute injury or environmental stress signals. In lower vertebrates, this regenerative capacity extends to several organs and remarkably culminates in precise tissue patterning, through cellular transdifferentiation and complex morphogenetic processes that can faithfully reconstruct entire body parts. Many lessons have been learned from robust regeneration models in amphibians such as the newt and axolotl. However, the dynamic interactions between the regenerating tissue, the surrounding stroma, and the host immune response, as it adapts to the actively proliferating tissue, remain ill-defined. The regenerating zone, through a sequence of distinct molecular events, adopts phenotypic plasticity and undergoes rigorous tissue remodeling that, in turn, evokes a significant inflammatory response. Complement is a primordial sentinel of the innate immune response that engages in multiple inflammatory cascades as it becomes activated during tissue injury and remodeling. In this respect, complement proteins have been implicated in tissue and organ regeneration in both urodeles and mammals. Distinct complement-triggered pathways have been shown to modulate critical responses that promote tissue reprogramming, pattern formation, and regeneration across phylogenesis. This article will discuss the mechanistic insights underlying the crosstalk of complement with cytokine and growth factor signaling pathways that drive tissue regeneration and will provide a unified conceptual framework for considering complement modulation as a novel target for regenerative therapeutics. PMID- 23684627 TI - Role of complement in host-microbe homeostasis of the periodontium. AB - Complement plays a key role in immunity and inflammation through direct effects on immune cells or via crosstalk and regulation of other host signaling pathways. Deregulation of these finely balanced complement activities can link infection to inflammatory tissue damage. Periodontitis is a polymicrobial community-induced chronic inflammatory disease that can destroy the tooth-supporting tissues. In this review, we summarize and discuss evidence that complement is involved in the dysbiotic transformation of the periodontal microbiota and in the inflammatory process that leads to the destruction of periodontal bone. Recent insights into the mechanisms of complement involvement in periodontitis have additionally provided likely targets for therapeutic intervention against this oral disease. PMID- 23684630 TI - Analysis of the complete genome sequences of one swine and two human hepatitis E virus genotype 4 strains isolated in Beijing, China. AB - Full-length sequences were determined and analyzed for two human (MO and W3) and one swine (W2-5) hepatitis E virus (HEV) isolates from Beijing, China. The genomes of the three strains were composed of 7242, 7239, 7239 nucleotides, respectively, excluding the poly (A) tails, and were 84% identical to each other. All were classified into genotype 4. Sequence analysis shows that the 2 human isolates have up to 91-94% nucleotide identity in full length genome with swine strains isolated in China, while the swine isolate share 92% identity with the human strain T1 from Beijing. At the amino acid level, the three strains share 94%, 97% and 89-92% identity in the ORF1, ORF2 and ORF3, proteins respectively. The human strains MO and W3 have the highest identity, 97%, 98-99% and 96-98% in ORFs 1-3, respectively, to swine strains CHN-XJ-SW13 and CHN-XJ-SW33 from Xinjiang, China, while swine strain W2-5 has highest identity with the human strain HE-JA2, 96%, 99% and 91% in ORFs 1-3, respectively. Genotype specific amino acid substitutions were found at a single site in all three ORFs by sequences alignment, and genotype specific short sequences (5-10aa in length) were found in ORF1 and the C-terminus of ORF3. However, no difference was found at any amino acid position that discriminates between human and swine HEVs within genotype 4 for any of the three ORFs. These results indicated that the genotype 4 HEV strains from humans and pigs in China may evolve from the common ancestor. PMID- 23684629 TI - Genetic characterization of E2 region of Chikungunya virus circulating in Odisha, Eastern India from 2010 to 2011. AB - Chikungunya virus (CHIKV) infection has caught attention yet again as it rages around the globe affecting millions of people. The virus caused epidemic outbreaks affecting more than 15,000 people in Odisha, Eastern India since 2010. In this study, complete genetic characterization of E2 gene of CHIKV circulating in Odisha from 2010 to 2011 was performed by virus isolation, RT-PCR, molecular phylogenetics and bioinformatics methods. Phylogenetic analyses revealed the circulation of Indian Ocean Lineage (IOL) strains of ECSA genotype of CHIKV in Odisha. Several mutations were detected in the E2 gene, viz. E2-R82G, E2-L210Q, E2-I211T, E2-V229I and E2-S375T which had various adaptive roles during the evolution of CHIKV. The CHIKV E2 peptide 57KTDDSHD63 was predicted to be the most probable T-cell epitope and peptide 84FVRTSAPCT92 predicted to be the common T and B cell epitope having high antigenicity. The amino acid positions 356-379 and 365-385 were predicted to be transmembrane helical domains and indicated E2 protein anchorage in intracellular membranes for effective interaction with the host receptors. Positive selection pressure was observed in five specific sites, 210, 211, 318, 375, and 377 which were observed to be fixed advantageously in most viral isolates. Structural modeling revealed that E2 gene of CHIKV was composed of 3 domains and the major adaptive mutations were detected in domain B, which can modulate binding of CHIKV to host cells, while the transmembrane domain in domain C and the epitopes were located in domain A, which was found to be most conserved. This is the first report from Eastern India demonstrating a predictive approach to the genetic variations, epitopic regions and the transmembrane helices of the E2 region. The results of this study, combined with other published observations, will expand our knowledge about the E2 region of CHIKV which can be exploited to develop control measures against CHIKV. PMID- 23684628 TI - The role of the complement system in metabolic organs and metabolic diseases. AB - Emerging evidence points to a close crosstalk between metabolic organs and innate immunity in the course of metabolic disorders. In particular, cellular and humoral factors of innate immunity are thought to contribute to metabolic dysregulation of the adipose tissue or the liver, as well as to dysfunction of the pancreas; all these conditions are linked to the development of insulin resistance and diabetes mellitus. A central component of innate immunity is the complement system. Interestingly, the classical view of complement as a major system of host defense that copes with infections is changing to that of a multi functional player in tissue homeostasis, degeneration, and regeneration. In the present review, we will discuss the link between complement and metabolic organs, focusing on the pancreas, adipose tissue, and liver and the diverse effects of complement system on metabolic disorders. PMID- 23684631 TI - Sequence and phylogenetic analyses of human rotavirus strains: comparison of VP7 and VP8(*) antigenic epitopes between Tunisian and vaccine strains before national rotavirus vaccine introduction. AB - Group A rotaviruses (RVA) are the leading cause of severe gastroenteritis in infants and young children worldwide. Due to their epidemiological complexity, it is important to compare the genetic characteristics of vaccine strains with the RVA strains circulating before the introduction of the vaccine in the Tunisian immunization program. In the present study, the nucleotide sequences of VP7 and VP8* (n=31), the main targets for neutralizing antibodies, were determined. Comparison of antigenic epitopes of 11 G1P[8], 12 G2P[4], 4 G3P[8], 2 G4P[8], 1 G6P[9] and 1 G12P[8] RVA strains circulating in Tunisia from 2006 to 2011 with the RVA strains present in licensed vaccines showed that multiple amino acid differences existed in or near putative neutralizing domains of VP7 and VP8*. The Tunisian G3 RVA strains were found to possess a potential extra N-linked glycosylation site. The Tunisian G4 RVA were closely related to the G4 vaccine strain in RotaTeq, belonging to the same lineage, but the alignment of their VP7 amino acids revealed an insertion of an asparagine residue at position 76 which is close to a glycosylation site (aa 69-71). Despite several differences detected between Tunisian and vaccine strains, which may affect binding of neutralizing antibodies, both vaccines are known to protect against the vast majority of the circulating genotypes, providing an indication of the high vaccine efficiency that can be expected in a future rotavirus immunization program. PMID- 23684632 TI - Positive affect and processes of recovery among treatment-seeking methamphetamine users. AB - BACKGROUND: Revised Stress and Coping Theory proposes that positive affect serves adaptive functions, independent of negative affect. However, scant research has examined whether, how, and under what circumstances positive affect is associated with decreased substance use. METHODS: Eighty-eight methamphetamine-using men who have sex with men (MSM) completed the baseline assessment for substance abuse treatment outcome study which included measures of positive and negative affect, cognitive-behavioral change processes (i.e., approach-oriented coping, self efficacy for managing methamphetamine triggers, and abstinence-related action tendencies), abstinence-specific social support, and self-reported substance use. Participants also provided a urine sample for toxicology screening. RESULTS: After controlling for demographic characteristics and negative affect, higher positive affect was independently associated with greater approach-oriented coping, abstinence-related action tendencies, and abstinence-specific social support. Positive affect was also independently associated with greater self efficacy for managing methamphetamine triggers, but only at lower levels of negative affect. Through these cognitive-behavioral and social pathways, positive affect was indirectly associated with lower frequency of stimulant use in the past 30 days, lower odds of reporting stimulant use two or more days in a row, and lower odds of providing a urine sample that was reactive for stimulant metabolites. On the other hand, negative affect was not indirectly associated with any measure of stimulant use. CONCLUSIONS: Clinical research is needed to examine the pathways whereby positive affect may predict better substance abuse treatment outcomes. PMID- 23684633 TI - Unintended effects of training on clinicians' interest, confidence, and commitment in using motivational interviewing. AB - BACKGROUND: Improving clinicians' interest, confidence, and commitment in using evidence-based treatment (EBT) is often an aim of training clinicians in EBT. However, the degree to which these areas actually improve through training and what their relationship is to treatment integrity is unknown. METHOD: Using data from a multi-site study (Martino et al., 2010) comparing three methods of clinician training in motivational interviewing (MI), changes in interest, confidence, and commitment over time and their relationship to MI adherence and competence were assessed using mixed-effects regression models. Individual patterns of change were examined through cluster analysis. RESULTS: Interest, confidence, and commitment declined over time across training conditions with two distinct patterns: 76% clinicians largely maintained strong interest in MI over time with only slight decreases in confidence and commitment (the "maintainers"), while 24% began with lower initial interest, confidence, and commitment, which subsequently declined over time (the "decliners"). Interest and commitment were not associated with MI adherence and competence; confidence was associated with increased competence in the use of advanced MI strategies. However, decliners demonstrated greater use of MI-inconsistent techniques than maintainers overall (d=0.28). CONCLUSIONS: Training in MI may have an unintended consequence of diminishing clinicians' interest, confidence, or commitment in using MI in practice. While attitudinal variables in this study show mixed relationships to MI integrity, they may have some utility in identifying less enthusiastic participants, better preparing them for training, or tailoring training approaches to meet individual training needs. PMID- 23684634 TI - Reticulospinal plasticity after cervical spinal cord injury in the rat involves withdrawal of projections below the injury. AB - Restoring voluntary fine motor control of the arm and hand is one of the main goals following cervical spinal cord injury (SCI). Although the functional improvement achievable with rehabilitative training in rat models is frequently accompanied by corticospinal tract (CST) plasticity, CST rewiring alone seems insufficient to account for the observed recovery. Recent investigations in animal models of SCI have suggested that the reticulospinal tract (RtST) might contribute to mediating improved motor performance of the forelimb. Here we investigate whether the spared RtST can compensate for the loss of CST input and whether RtST projections rearrange in response to cervical SCI. Animals underwent unilateral ablation of the dorsal CST and rubrospinal tract at spinal level C4, while the ventral RtST projections were spared. At the end of the six-week recovery period, injured animals had made significant improvements in single pellet reaching. This was not accompanied by increased sprouting of the injured CST above the injury compared to uninjured control animals. Injury-induced changes in RtST fiber density within the gray matter, as well as in the number of RtST collaterals entering the gray matter or crossing the cord midline were minor above the injury. However, all analyses directly below the injured spinal level consistently point to a significant decrease of RtST projections. The mechanism and the functional relevance behind this new finding warrant further study. Our results also suggest that mechanisms other than anatomical plasticity, such as plastic changes on a cellular level, might be responsible for the observed spontaneous recovery. PMID- 23684635 TI - Cell biology of the intercalated cell in the kidney. AB - The intercalated cell of the collecting tubule of the mammalian kidney is specialized for the transport of H(+) and HCO3. They exist in two forms; one specialized for acid secretion and the other secretes HCO3 into the urine. We discovered many years ago that feeding animals an acid diet converts the HCO3 secreting form to an acid secreting type. Here I discuss the molecular basis of this transformation. The conversion of the cell types is mediated by an extracellular matrix protein hensin (also known as DMBT1). However much remains to be identified in the differentiation of these cells. PMID- 23684636 TI - Conformational dynamics in phosphoglycerate kinase, an open and shut case? AB - Domain motions are essential to many catalytic mechanisms in enzymes but they are often difficult to study. X-ray crystal structures can provide molecular details of snapshots of catalysis but many states important in the cycle remain inaccessible using this technique. Phosphoglycerate kinase (PGK) undergoes large domain movements in order to catalyse the production of ATP. PGK is the enzyme responsible for the first ATP generating step of glycolysis and has been implicated in oncogenesis and the in vivo activation of l-nucleoside pro-drugs effective against retroviruses. Its mechanism requires considerable hinge bending to bring the substrates into proximity in order for phosphoryl transfer to occur. The enzyme has been the subject of intense study for decades but new crystal structures, methods in solution scattering and modelling techniques are throwing light on the dynamics of catalysis of this archetypal kinase. Here, I argue that Brownian forces acting on the protein are the dominant factor in the catalytic cycle and that the enzyme has evolved measures to harness this force for efficient catalysis. PMID- 23684637 TI - The Mpn1 RNA exonuclease: cellular functions and implication in disease. AB - Recent studies from independent laboratories have decisively disclosed the identity of the long-sought 3-5' RNA exonuclease that trims posttranscriptionally the oligouridine tail of U6, which is the small catalytic non-coding RNA promoting premRNA splicing within the spliceosome. This exonuclease, dubbed Mpn1 or Usb1, is a highly conserved enzyme that specifically removes uridines from the 3' end of U6, and directly generates terminal 2',3' cyclic phosphate groups. Mutations in the human gene encoding hMpn1 have been reported in patients diagnosed with the rare genodermatosis Clericuzio-type poikiloderma with neutropenia (PN). Mpn1-associated functions in U6 small nuclear RNA posttranscriptional regulation suggest the existence of sophisticated cellular pathways involved in surveillance and stabilization of U6. In this light, PN pathology might turn out to be a consequence of disturbed quality control of RNAs involved in crucial biological events. PMID- 23684638 TI - Pharmacological protein targets in polyglutamine diseases: mutant polypeptides and their interactors. AB - Polyglutamine diseases are a group of pathologies affecting different parts of the brain and causing dysfunction and atrophy of certain neural cell populations. These diseases stem from mutations in various cellular genes that result in the synthesis of proteins with extended polyglutamine tracts. In particular, this concerns huntingtin, ataxins, and androgen receptor. These mutant proteins can form oligomers, aggregates, and, finally, aggresomes with distinct functions and different degrees of cytotoxicity. In this review, we analyze the effects of different forms of polyQ proteins on other proteins and their functions, which are considered as targets for therapeutic intervention. PMID- 23684640 TI - Regulation of lipid synthesis in oil crops. AB - Oil crops are in increasing demand both for food and as renewable sources of chemicals. It is therefore vital to understand how oil accumulation is regulated. Different ways of obtaining such information are discussed with an emphasis on metabolic control analysis. The usefulness of the latter has been well illustrated by its application to help raise yields in oilseed rape. PMID- 23684641 TI - The dynamics of the catalytic site in small GTPases, variations on a common motif. AB - Small GTPases control many cellular processes. Their catalytic downregulation by GTPase activating proteins (GAP) is essential. Many structural models of GTPase.GAP complexes obtained by X-ray structural analysis are available nowadays. They reveal important insights into the catalytic site and can suggest important catalytic residues. But this information is static. Time-resolved FTIR spectroscopy can resolve the dynamics of the catalytic site at atomic detail. For the investigation of GAP catalyzed GTPase reactions of small GTPases, the order of events like the action of certain catalytic amino acids, bond breakages and protein conformational changes can be elucidated. This is elaborated for many small GTPases like Ras, Rap, Ran, Rho and Rab and their cognate GAPs. Variations on a common dynamic motif of the catalytic site of small GTPase will be presented. PMID- 23684639 TI - Non-coding RNAs in DNA damage and repair. AB - Non-coding RNAs (ncRNAs) are increasingly recognized as central players in diverse biological processes. Upon DNA damage, the DNA damage response (DDR) elicits a complex signaling cascade, which includes the induction of multiple ncRNA species. Recent studies indicate that DNA-damage induced ncRNAs contribute to regulation of cell cycle, apoptosis and DNA repair, and thus play a key role in maintaining genome stability. This review summarizes the emerging role of ncRNAs in DNA damage and repair. PMID- 23684642 TI - Helicobacter pylori secretes the chaperonin GroEL (HSP60), which binds iron. AB - Helicobacter pylori is a bacterium that can use multiple iron sources. However, it is unknown whether this bacterium secretes molecules such as siderophores or haemophores to scavenge iron. Here, we report the first secreted iron-binding protein of H. pylori, which we purified by haem-affinity chromatography. Mass spectrometry analysis revealed its identity as chaperonin (HpGroEL). When we compared HpGroEL with EcGroEL from Escherichia coli, they were homologous, showing 60% similarity. Additionally, purified cytoplasmic HpGroEL could also bind iron. Perhaps H. pylori secretes HpGroEL to maintain the appropriate folding of extracellular proteins and to bind iron. PMID- 23684643 TI - Arf GTPase regulation through cascade mechanisms and positive feedback loops. AB - Arf GTPases, together with Rab GTPases, are key regulators of intracellular membrane traffic. Their specific membrane targeting and activation are tightly regulated in time and space by guanine nucleotide exchange factors (GEFs). GEFs are multidomain proteins, which are under tight regulation to ensure fully coordinated and accurate membrane traffic events. Recently, two Arf GEFs, Sec7 and Arno, have been shown to be part of Arf GEF cascades similar to the Rab GEF cascades. Both GEFs are autoinhibited in solution and require an active Arf molecule to be recruited to the membrane and to switch to an open conformation. As such, positive feedback loops, whereby the amount of Arf-GTP on a given organelle increases not linearly with time, can be established. PMID- 23684644 TI - The epigenetic landscape of B lymphocyte tolerance to self. AB - Despite frequent exposures to a variety of potential triggers, including antigens produced by pathogens or commensal microbiota, B-lymphocytes are able to mount highly protective responses to a variety of threats, while remaining tolerant to self-components. A number of cytokines, signaling pathways and transcription factors have been characterized to elucidate the mechanisms underlying B cell tolerance to self. It is, however, unclear how the signals received by B lymphocytes are converted into complex and sustained patterns of gene expression that can allow production of protective antibodies and maintain immune tolerance to self-components. Mounting evidence now suggests an important role for epigenetic mechanisms in modulating and transmitting signals for B lymphocyte tolerization to self-antigens. It is likely that a better insight into epigenetic regulation of B cell tolerance will lead to development of gene-specific therapeutic approaches that optimize host defense mechanisms to exogenous threats, while preventing development and/or progression of autoimmune inflammatory diseases. PMID- 23684645 TI - Key role of lipids in heat stress management. AB - Heat stress is a common and, therefore, an important environmental impact on cells and organisms. While much attention has been paid to severe heat stress, moderate temperature elevations are also important. Here we discuss temperature sensing and how responses to heat stress are not necessarily dependent on denatured proteins. Indeed, it is clear that membrane lipids have a pivotal function. Details of membrane lipid changes and the associated production of signalling metabolites are described and suggestions made as to how the interconnected signalling network could be modified for helpful intervention in disease. PMID- 23684646 TI - Copper chaperones. The concept of conformational control in the metabolism of copper. AB - Copper chaperones compose a specific class of proteins assuring safe handling and specific delivery of potentially harmful copper ions to a variety of essential copper proteins. Copper chaperones are structurally heterogeneous and can exist in multiple metal-loaded as well as oligomeric forms. Moreover, many copper chaperones can exist in various oxidative states and participate in redox catalysis, connected with their functioning. This review is focused on the analysis of the structural and functional properties of copper chaperones and their partners, which allowed us to define specific regulatory principles in copper metabolism connected with copper-induced conformational control of copper proteins. PMID- 23684647 TI - The amyloid precursor protein: a biochemical enigma in brain development, function and disease. AB - For 20 years the amyloid cascade hypothesis of Alzheimer disease (AD) has placed the amyloid-beta peptide (Abeta), formed from the amyloid precursor protein (APP), centre stage in the process of neurodegeneration. However, no new therapeutic agents have reached the clinic through exploitation of the hypothesis. The APP metabolites, including Abeta, generated by its proteolytic processing, have distinct physiological functions. In particular, the cleaved intracellular domain of APP (AICD) regulates expression of several genes, including APP itself, the beta-secretase BACE-1 and the Abeta-degrading enzyme, neprilysin and this transcriptional regulation involves direct promoter binding of AICD. Of the three major splice isoforms of APP (APP695, APP751, APP770), APP695 is the predominant neuronal form, from which Abeta and transcriptionally active AICD are preferentially generated by selective processing through the amyloidogenic pathway. Despite intensive research, the normal functions of the APP isoforms remain an enigma. APP plays an important role in brain development, memory and synaptic plasticity and secreted forms of APP are neuroprotective. A fuller understanding of the physiological and pathological actions of APP and its metabolic and gene regulatory network could provide new therapeutic opportunities in neurodegeneration, including AD. PMID- 23684648 TI - Human small heat shock proteins: protein interactomes of homo- and hetero oligomeric complexes: an update. AB - Small heat shock proteins (sHsps) regulate a large number of fundamental cellular processes and are involved in many pathological diseases. They share complex oligomerization and phosphorylation properties allowing them to interact and modulate the activity of many client proteins. Here, the up-to date protein interactome of the ten human sHsps is presented as an illustration of their multiple cellular functions. In addition of forming homo-oligomers, some of these proteins interact whith each other and form hetero-oligomeric complexes that could bear new protein targets recognition abilities. Here, novel informations are presented on how the formation of HspB1/HspB5 complex can stimulate the activity of the oxidoresistance promoting enzyme glucose 6-phosphate dehydrogenase through its interaction with newly formed highly phosphorylated HspB1 homo-oligomers. PMID- 23684649 TI - Molecular chaperones as enzymes that catalytically unfold misfolded polypeptides. AB - Stress-denatured or de novo synthesized and translocated unfolded polypeptides can spontaneously reach their native state without assistance of other proteins. Yet, the pathway to native folding is complex, stress-sensitive and prone to errors. Toxic misfolded and aggregated conformers may accumulate in cells and lead to degenerative diseases. Members of the canonical conserved families of molecular chaperones, Hsp100s, Hsp70/110/40s, Hsp60/CCTs, the small Hsps and probably also Hsp90s, can recognize and bind with high affinity, abnormally exposed hydrophobic surfaces on misfolded and aggregated polypeptides. Binding to Hsp100, Hsp70, Hsp110, Hsp40, Hsp60, CCTs and Trigger factor may cause partial unfolding of the misfolded polypeptide substrates, and ATP hydrolysis can induce further unfolding and release from the chaperone, leading to spontaneous refolding into native proteins with low-affinity for the chaperones. Hence, specific chaperones act as catalytic polypeptide unfolding isomerases, rerouting cytotoxic misfolded and aggregated polypeptides back onto their physiological native refolding pathway, thus averting the onset of protein conformational diseases. PMID- 23684650 TI - Functional interrogation of kinases and other nucleotide-binding proteins. AB - The largest mammalian enzyme family is the kinases. Kinases and other nucleotide binding proteins are key regulators of signal transduction pathways and the mutation or overexpression of these proteins is often the difference between health and disease. As a result, a massive research effort has focused on understanding how these proteins function and how to inhibit them for therapeutic benefit. Recent advances in chemical biological tools have enabled functional interrogation of these enzymes to provide a deeper understanding of their physiological roles. In addition, these innovative platforms have paved the way for a new generation of drugs whose properties have been guided by functional profiling. PMID- 23684652 TI - Genetic dissection of sodium and potassium transport along the aldosterone sensitive distal nephron: importance in the control of blood pressure and hypertension. AB - In this review, we discuss genetic evidence supporting Guyton's hypothesis stating that blood pressure control is critically depending on fluid handling by the kidney. The review is focused on the genetic dissection of sodium and potassium transport in the distal nephron and the collecting duct that are the most important sites for the control of sodium and potassium balance by aldosterone and angiotensin II. Thanks to the study of Mendelian forms of hypertension and their corresponding transgenic mouse models, three main classes of diuretic receptors (furosemide, thiazide, amiloride) and the main components of the aldosterone- and angiotensin-dependent signaling pathways were molecularly identified over the past 20 years. This will allow to design rational strategies for the treatment of hypertension and for the development of the next generation of diuretics. PMID- 23684653 TI - Inorganic pyrophosphatases: one substrate, three mechanisms. AB - Soluble inorganic pyrophosphatases (PPases) catalyse an essential reaction, the hydrolysis of pyrophosphate to inorganic phosphate. In addition, an evolutionarily ancient family of membrane-integral pyrophosphatases couple this hydrolysis to Na(+) and/or H(+) pumping, and so recycle some of the free energy from the pyrophosphate. The structures of the H(+)-pumping mung bean PPase and the Na(+)-pumping Thermotoga maritima PPase solved last year revealed an entirely novel membrane protein containing 16 transmembrane helices. The hydrolytic centre, well above the membrane, is linked by a charged "coupling funnel" to the ionic gate about 20A away. By comparing the active sites, fluoride inhibition data and the various models for ion transport, we conclude that membrane-integral PPases probably use binding of pyrophosphate to drive pumping. PMID- 23684654 TI - A physiological role for the supramolecular organization of rhodopsin and transducin in rod photoreceptors. AB - Vertebrate vision in rod photoreceptors begins when a photon hits the visual pigment rhodopsin (Rh) and triggers the phototransduction cascade. Although the fine biochemical and biophysical details of this paradigmatic signalling pathway have been studied for decades, phototransduction still presents unclear mechanistic aspects. Increasing lines of evidence suggest that the visual pigment rhodopsin (Rh) is natively organized in dimers on the surface of disc membranes, and may form higher order "paracrystalline" assemblies, which are not easy to reconcile with the classical collision-coupling mechanistic scenario evoked to explain the extremely fast molecular processes required in phototransduction. The questioned and criticized existence of paracrystalline Rh rafts can be fully accepted only if it can be explained in functional terms by a solid mechanistic picture. Here we discuss how recent data suggest a physiological role for supramolecular assemblies of Rh and its cognate G protein transducin (Gt), which by forming transient complexes in the dark may ensure rapid activation of the cascade even in a crowded environment that, according to the classical picture, would otherwise stop the cascade. PMID- 23684651 TI - The cell stress machinery and retinal degeneration. AB - Retinal degenerations are a group of clinically and genetically heterogeneous disorders characterised by progressive loss of vision due to neurodegeneration. The retina is a highly specialised tissue with a unique architecture and maintaining homeostasis in all the different retinal cell types is crucial for healthy vision. The retina can be exposed to a variety of environmental insults and stress, including light-induced damage, oxidative stress and inherited mutations that can lead to protein misfolding. Within retinal cells there are different mechanisms to cope with disturbances in proteostasis, such as the heat shock response, the unfolded protein response and autophagy. In this review, we discuss the multiple responses of the retina to different types of stress involved in retinal degenerations, such as retinitis pigmentosa, age-related macular degeneration and glaucoma. Understanding the mechanisms that maintain and re-establish proteostasis in the retina is important for developing new therapeutic approaches to fight blindness. PMID- 23684655 TI - [Iron and invasive fungal infection]. AB - Iron is an essential factor for both the growth and virulence of most of microorganisms. As a part of the innate (or nutritional) immune system, mammals have developed different mechanisms to store and transport this element in order to limit free iron bioavailability. To survive in this hostile environment, pathogenic fungi have specific uptake systems for host iron sources, one of the most important of which is based on the synthesis of siderophores-soluble, low molecular-mass, high-affinity iron chelators. The increase in free iron that results from iron-overload conditions is a well-established risk factor for invasive fungal infection (IFI) such as mucormycosis or aspergillosis. Therefore, iron chelation may be an appealing therapeutic option for these infections. Nevertheless, deferoxamine -the first approved iron chelator- paradoxically increases the incidence of IFI, as it serves as a xeno-siderophore to Mucorales. On the contrary, the new oral iron chelators (deferiprone and deferasirox) have shown to exert a deleterious effect on fungal growth both in vitro and in animal models. The present review focuses on the role of iron metabolism in the pathogenesis of IFI and summarises the preclinical data, as well as the limited clinical experience so far, in the use of new iron chelators as treatment for mucormycosis and invasive aspergillosis. PMID- 23684656 TI - Topical corticosteroid delivery into human skin using hydrofluoroalkane metered dose aerosol sprays. AB - Drug loaded hydrofluoroalkane (HFA) sprays can generate effective pharmaceutical formulations, but a deeper understanding of the manner in which these dynamic systems drive the process of in situ semi-solid dosage form assembly is required. The aim of this study was to investigate the effect of the matrix assembly and composition on drug localisation in human skin. Comparing the characteristics of sprays constituting HFA 134a, ethanol (EtOH), poly(vinyl pyrrolidone) K90, isopropyl myristate (IPM), and poly(ethylene glycol) (PEG) demonstrated that the addition of non-volatile solvents acted to delay EtOH evaporation, control the degree of drug saturation (DS) and enhance the corticosteroid delivery from HFA spray formulations. In a dose matched skin penetration study the HFA sprays containing only EtOH as a co-solvent delivered 2.1 MUg BMV (DS 13.5) into the tissue, adding IPM to the EtOH HFA delivered 4.03 MUg BMV (DS 11.2), whist adding PEG to the EtOH HFA delivered 6.1 MUg BMV (DS 0.3). Compared to commercial cream (delivering 0.91 MUg BMV) the EtOH/PEG HFA spray deposited over 6 times (p<0.05) more drug into the skin. Post spray deposition characterisation of the semi-solid suggested that the superior performance of the EtOH/PEG HFA spray was a consequence of retarding EtOH evaporation and presenting the drug in an EtOH rich PEG residual phase, which promoted BMV passage through the SC and into epidermis. PMID- 23684657 TI - Process development for spray drying of sticky pharmaceuticals; case study of bioadhesive nicotine microparticles for compressed medicated chewing gum. AB - Spray drying of pharmaceutical compounds with sticky properties is a challenging task and may require substantial time and resources. By including small-scale studies of single droplet drying kinetics a relatively high number of experiments with less material is allowed. This means one can construct a more robust design space according to Quality by Design (QbD) formulation development principles. In the current study we present a case study on the development of spray dried microparticles comprising nicotine bitartrate and hypromellose or alginate polymer, for incorporation into medicated chewing gum. By illustration of initial studies on single droplet drying kinetics, subsequent characterization of microparticles, and final characterization of compressed chewing gum this paper summarizes the entire development process. PMID- 23684658 TI - Brain targeting of olanzapine via intranasal delivery of core-shell difunctional block copolymer mixed nanomicellar carriers: in vitro characterization, ex vivo estimation of nasal toxicity and in vivo biodistribution studies. AB - Olanzapine (OZ) is atypical antipsychotic drug that suffers from low brain permeability due to efflux by P-glycoproteins and hepatic first-pass metabolism. The current work aimed to develop OZ-loaded micellar nanocarriers and investigate their nose-to-brain targeting potential. OZ-loaded (5mg/ml) micelles (F1-F12) were prepared, using a Pluronic((r)) mixture of L121 and P123, adopting thin-film hydration method. The micelles were evaluated for turbidity, particle size, morphology, drug-entrapment efficiency (EE%), drug-loading characteristics, in vitro drug release and ex vivo nasal toxicity in sheep. The in vivo biodistribution and pharmacokinetic studies in the brain/blood following intravenous (i.v.) and intranasal (i.n.) administrations of technetium-labeled OZ loaded micelles and OZ-solution were evaluated in rats. Spherical micelles ranging in size from 18.97 to 380.70 nm were successfully developed. (1)H NMR studies confirmed OZ incorporation into micelle core. At a drug:Pluronic((r)) L121:Pluronic((r)) P123 ratio of 1:8:32 (F11), the micelles achieved a conciliation between kinetic and thermodynamic stability, high drug-EE%, controlled drug-release characteristics and evoked minor histopathological changes in sheep nasal mucosa. The significantly (P<0.05) higher values for F11 micelles (i.n.); brain/blood ratio (0.92), drug targeting index (5.20), drug targeting efficiency (520.26%) and direct transport percentage (80.76%) confirm the development of a promising non-invasive OZ-loaded nose-to-brain delivery system. PMID- 23684659 TI - Involvement of cholesterol depletion from lipid rafts in apoptosis induced by methyl-beta-cyclodextrin. AB - Methyl-beta-cyclodextrin (M-beta-CyD), which is widely used as a lipid rafts disrupting agent, is known to induce cytotoxicity at high concentration. In the present study, we investigated the potential of M-beta-CyD as an antitumor drug. M-beta-CyD markedly caused apoptotic cell-death in KB cells, a human oral squamous carcinoma cell line, Ihara cells, a highly pigmented human melanoma cell line, and M213 cells, a human cholangiocarcinoma cell line, through cholesterol depletion in cell membranes. The DNA content and mitochondrial transmembrane potential in KB cells were significantly decreased after treatment with M-beta CyD. Additionally, M-beta-CyD elevated the caspase-3/7 activity in KB cells. Meanwhile, M-beta-CyD did not induce the formation of autophagic vacuoles in KB cells. M-beta-CyD drastically inhibited the tumor growth after intratumoral injection to Colon-26 cells-bearing mice. These results strongly suggest that M beta-CyD induced apoptosis in tumor cells and had the potential a novel antitumor agent and/or its lead compound. PMID- 23684660 TI - Preparation and evaluation of agglomerated crystals by crystallo-co agglomeration: an integrated approach of principal component analysis and Box Behnken experimental design. AB - Poor mechanical properties of crystalline drug particles require wet granulation technique for tablet production which is uneconomical, laborious, and tedious. The present investigation was aimed to improve flow and mechanical properties of racecadotril (RCD), a poorly water soluble antidiarrheal agent, by a crystallo-co agglomeration (CCA) technique. The influence of various excipients and processing conditions on formation of directly compressible agglomerates of RCD was evaluated. Principal component analysis and Box-Behnken experimental design was implemented to optimize the agglomerates with good micromeritics and mechanical properties. The overall yield of the process was 88-98% with size of agglomerates between 351 and 1214 MUm. Further, higher rotational speed reduced the size of agglomerates and disturbed sphericity. The optimized batch of agglomerates exhibited excellent flowability and crushing strength. The optimized batch of RCD agglomerates was characterized by fourier transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffractometry and gas chromatography which illustrated absence of drug-excipient interaction with minimal entrapment of residual solvent. Hence, it may be concluded that both excipients and processing conditions played a vital role to prepare spherical crystal agglomerates of RCD by CCA and it can be adopted as an excellent alternative to wet granulation. PMID- 23684661 TI - Failure analysis of alumina on alumina total hip arthroplasty with a layered acetabular component: minimum ten-year follow-up study. AB - This prospective study reports the outcome of total hip arthroplasty (THA) performed in a consecutive series of patients using an alumina ceramic on a ceramic-layered component (Alumina-Bearing-Surface system). The cohort consisted of 270 hips in 229 patients. The study evaluated the clinical and radiological results over a mean follow-up of 11.4 years. Revision THA was performed on 58 hips, including alumina alternative failure in 50 hips, loosening in 4 hips, recurrent dislocation in 2 hips, stem neck fracture in 1 hip and hematoma in 1 hip. The survival rate was 68% with revision for any reason as the end point. The risk factors of implant failure are the preoperative range of motion of the hip joint and postoperative dislocation. PMID- 23684662 TI - Influence of dairy product consumption on children's blood pressure: results from the QUALITY cohort. AB - Identifying dietary factors associated with blood pressure in children and adolescents could help guide recommendations for prevention of elevated blood pressure. Our objective was to examine the association between blood pressure and dairy product consumption during preadolescence in a cross-sectional study. Baseline data from 610 children aged 8 to 10 years from the Quebec Adipose and Lifestyle Investigation in Youth cohort was used for this analysis. Blood pressure was measured using a standard protocol. Children's average dairy intake was assessed from three nonconsecutive 24-hour dietary recalls, and was divided into tertiles. Linear regression models adjusted for age; sex; height; physical activity level; sugar-sweetened beverages, total energy, calcium, sodium, and saturated fat intake; parental history of hypertension; parental education; weight status; and intake of fruits and vegetables. In our fully adjusted model, high dairy intake (>=2 servings of dairy per day) was associated with 1.74 mm Hg lower systolic blood pressure (P<0.05) and with 0.87 mm Hg lower diastolic blood pressure (P=0.10) compared with low intake. We found no significant association of calcium, magnesium, or potassium intake on children's blood pressure, suggesting the role of other antihypertensive components in dairy products. Our results indicate that high intake of dairy (>=2 servings per day) has antihypertensive effects on blood pressure among youth. PMID- 23684664 TI - Regarding the article: "Prevalence of pneumococcal disease, serotype distribution, and antimicrobial susceptibility in Mexican children younger than 5 years of age". PMID- 23684663 TI - Diabetic neuropathic pain development in type 2 diabetic mouse model and the prophylactic and therapeutic effects of coenzyme Q10. AB - The early onset of type 2 diabetes mellitus (DM), driven by increasing obesity, is associated with peripheral neuropathy. Here, we characterize diabetic neuropathic pain in New Zealand obese diabetic mice (NZO/HILtJ) as a polygenic model of obesity with type 2 diabetes and investigate the role of coenzyme Q10 (CoQ10) in the prevention and treatment of diabetic neuropathic pain. Since the overexpression of mitogen-activated protein kinase (MAPK), nuclear factor-kappaB proteins (NF-Kb), toll-like receptor 4 (TLR4) and downstream cytokines (such as CCL2, CXCL10) are considered important factors contributing to the development of neuropathic pain, the expression of these factors and the inhibitory effects of CoQ10 were evaluated. NZO/HILtJ mice spontaneously developed type 2 DM and increased body mass with diabetic neuropathic pain. CoQ10 treatment decreased pain hypersensitivity and long-term supplementation prevented the development of diabetic neuropathic pain but did not attenuate diabetes. Spinal cord, blood serum, liver tissue, and dorsal root ganglia (DRG) from diabetic mice demonstrated increased lipid peroxidation, which was decreased by CoQ10 treatment. The percentage of positive neurons of p65 (the activated marker of NF KB) and MAPK in DRG were significantly higher in DM mice compared to controls. However, CoQ10 treatment significantly decreased p65 and MAPK positive neurons in the DRG of DM mice. RT-PCR demonstrated that elevated levels of mRNA of CCL2, CXCL10 or TLR4 in the spinal cord of DM mice decreased significantly when DM mice were treated with CoQ10. CONCLUSION: This model may be useful in understanding the mechanisms of neuropathic pain in type 2 DM induced neuropathic pain and may facilitate preclinical testing of therapies. CoQ10 may decrease oxidative stress in the central and peripheral nervous system by acting as an anti-oxidant and free-radical scavenger. These results suggest that CoQ10 might be a reasonable preventative strategy for long-term use and using CoQ10 treatment may be a safe and effective long-term approach in the treatment of diabetic neuropathy. PMID- 23684665 TI - Differences in composition of honey samples and their impact on the antimicrobial activities against drug multiresistant bacteria and pathogenic fungi. AB - BACKGROUND AN AIMS: Antibiotic multiresistant microbes represent a challenging problem. Because honey has a potent antibacterial property, the antimicrobial effects of different honey samples against multiresistant pathogens and their compositions were investigated. METHODS: Five honey samples were used: Talah, Dhahian, Sumra-1, Sidr, and Sumra-2. Samples were analyzed to determine chemical composition such as fructose, glucose, sucrose, pH, total flavonoids, total phenolics, hydrogen peroxide concentration, minerals and trace elements. Antimicrobial activities of the samples against 17 (16 were multiresistant) human pathogenic bacteria and three types of fungi were studied. Specimens of the isolates were cultured into 10 mL of 10-100% (volume/volume) honey diluted in broth. Microbial growth was assessed on a solid plate media after 24 h and 72 h incubation. RESULTS: The composition of honey samples varied considerably. Sumra 1 and 2 contained the highest level of flavonoids and phenolics and the lowest level of hydrogen peroxide, whereas Dhahian honey contained the highest level of hydrogen peroxide. Sixteen pathogens were antibiotic multiresistant. A single dose of each honey sample inhibited all the pathogens tested after 24 h and 72 h incubation. The most sensitive pathogens were Aspergillus nidulans, Salmonella typhimurum and Staphylococcus epidermidis (S. epidermidis). Although there was no statistically significant difference in the effectiveness of honey samples, the most effective honey against bacteria was Talah and against fungi were Dhahian and Sumra-2. CONCLUSIONS: Various honey samples collected from different geographical areas and plant origins showed almost similar antimicrobial activities against multiresistant pathogens despite considerable variation in their composition. Honey may represent an alternative candidate to be tested as part of management of drug multiresistant pathogens. PMID- 23684666 TI - Regarding the article: "Human germline genetic modification: scientific and bioethical perspectives". PMID- 23684667 TI - Effects of L-thyroxine therapy on circulating leptin and adiponectin levels in subclinical hypothyroidism: a prospective study. AB - Subclinical hypothyroidism (SCH) is defined by increased thyrotropin (TSH) and normal free thyroxine (fT4) levels. Controversial data are available regarding the effects of SCH on adipose tissue. Adiponectin and leptin are two major adipokines secreted from adipose tissue. We aimed to determine the levels of adiponectin and leptin in women with SCH and potential effects of L-thyroxine therapy on those levels. Forty three women with SCH and 53 age- and BMI-matched healthy euthyroid control women were included. Adiponectin and leptin levels, total cholesterol (TC), triglycerides (TG), HDL-, and LDL cholesterol, fat mass (FM) and fat-free mass (FFM) were determined in all participants. Patients received L-thyroxine treatment for 6 months after which all measurements were repeated. Patients with SCH and controls had similar baseline values for adiponectin, leptin, lipids, FM and FFM. All patients reached euthyroid status after 6 months of replacement therapy. Treatment resulted in an increase in adiponectin (p <0.01) and a decrease in leptin levels (p <0.05). Lipid levels, FM and FFM did not show a significant change. Achievement of euthyroid status by replacement therapy increases adiponectin and decreases leptin levels in women with SCH in this prospective study independent of a change in body fat mass. PMID- 23684668 TI - Hypothalamic neurogenesis in the adult brain. AB - Adult-born new neurons are continuously added to the hippocampus and the olfactory bulb to serve aspects of learning and perceptual functions. Recent evidence establishes a third neurogenic niche in the ventral hypothalamic parenchyma surrounding the third ventricle that ensures the plasticity of specific brain circuits to stabilize physiological functions such as the energy balance regulatory system. Hypothalamic lesion studies have demonstrated that regions associated with reproduction-related functions are also capable of recruiting newborn neurons to restore physiological functions and courtship behavior. Induced by lesion or other stimulation, elevated neurotrophic factors trigger neurogenic cascades that contribute to remodeling of certain neural circuits to meet specific transient functions. This insight raises the possibility that event-specific changes, such as increased GnRH, may be mediated by courtship-sensitive neurotrophic factors. We will discuss the potentially integral and ubiquitous roles of neurogenesis in physiological and biological phenomena, roles that await future experimental exploration. PMID- 23684669 TI - Farewell editorial. PMID- 23684670 TI - A novel homozygous mutation of GJC2 derived from maternal uniparental disomy in a female patient with Pelizaeus-Merzbacher-like disease. AB - Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating disorder of the central nervous system characterized by nystagmus, motor developmental delay, ataxia, and progressive spasticity. The gap junction protein gamma-2 gene (GJC2), encoding the gap junction protein connexin 47, is one of the genes responsible for this condition. In this study, a novel homozygous mutation in GJC2 (c.746C>G; p.P249R) was identified in a 21-year-old female patient with PMLD. Although her mother was a carrier of this mutation, the Mendelian inheritance pattern could not be determined because the paternal sample was unavailable. Alternatively, chromosomal microarray testing together with single nucleotide polymorphism typing (CGH+SNP) was performed to determine the gene copy number and analyze the haplotype in the 1q42.13 region in which GJC2 is located. The result showed no deletion, but the GJC2 region was involved in the loss-of-heterozygosity region. Furthermore, haplotype of chromosome 1, in which GJC2 is located, revealed that both copies of chromosome 1 were derived from the patient's mother, indicating maternal uniparental disomy of chromosome 1. This study showed the advantage of the SNP genotyping microarray for detecting the origin of the mutation. PMID- 23684672 TI - Postsynaptic density protein (PSD)-95 expression is markedly decreased in the hippocampal CA1 region after experimental ischemia-reperfusion injury. AB - Synaptic plasticity is important for functional recovery after cerebral ischemic injury. In the present study, we investigated chronological change in the immunoreactivity of PSD-95, a kind of postsynaptic density protein, in the hippocampus proper (CA1-3 regions) after 5 min of transient cerebral ischemia in gerbils. PSD-95 immunoreactivity was observed in MAP-2-immunoreactive dendrites in the CA1-3 regions of the sham group. The PSD-95 immunoreactivity was shown as beaded structure in the MAP-2-immunoreactive dendrites. However, PSD-95 immunoreactivity began to be dramatically decreased in MAP-2-immunoreactive dendrites in the CA1 region, not CA2-3 region, at early time after ischemia reperfusion. At 5 days after ischemia-reperfusion, MAP-2 immunoreactivity almost disappeared in the ischemic CA1 region, and PSD-95 immunoreactivity was much lower than that in the sham group. In brief, PSD-95 immunoreactivity in the CA1 dendrites was markedly decreased at early time after ischemia-reperfusion. We suggest that decreased PSD-95 immunoreactivity in the ischemic CA1 region may lead to a deficit of postsynaptic plasticity in the brain. PMID- 23684671 TI - Association between the C242T polymorphism of p22phox gene and ischemic stroke: a meta-analysis. AB - Recently, increasing studies have been focused on the association between the p22phox gene C242T polymorphism and ischemic stroke (IS). However, the results were controversial. As far as we know, there is no previous systematic review or meta-analysis concerning this association. Thus, we conducted this meta-analysis to evaluate this association. The strength of association was evaluated by the odds ratio (OR) with the corresponding 95% confidence intervals (CIs). Heterogeneity was assessed by Q-test and the I(2) statistic. Publication bias was tested using funnel plots and Egger's regression test. Cumulative meta-analysis was performed to assess the trend in pooled OR over time. There was no significant association of the p22phox gene C242T polymorphism with IS in the overall analysis and subgroup analysis by ethnicity and subtypes of IS. However, statistical significance was found in the dominant model (OR: 1.57, 95%CI: 1.18 2.09), codominant model (OR: 1.62, 95%CI: 1.20-2.17) and allelic model (OR: 1.44, 95%CI: 1.11-1.87) among the hospital-based studies. The cumulative meta-analysis also suggested no trend of association between this polymorphism and IS from 2007 to 2011 as more data accumulated over time. Our meta-analysis indicated that the p22phox gene C242T polymorphism is unrelated to the risk of IS in the overall analysis and subgroup analysis by ethnicity and subtypes of IS. However, statistical significance was found in the subgroup analysis by source of controls among the hospital-based studies. PMID- 23684673 TI - Biodegradable polymer biolimus-eluting stent versus durable polymer everolimus eluting stent: a randomized, controlled, noninferiority trial. AB - OBJECTIVES: NEXT (NOBORI Biolimus-Eluting Versus XIENCE/PROMUS Everolimus-Eluting Stent Trial) was designed for evaluating the noninferiority of a biolimus-eluting stent (BES) relative to an everolimus-eluting stent (EES) in terms of target lesion revascularization (TLR) at 1 year. BACKGROUND: Efficacy and safety data comparing biodegradable polymer BES with durable polymer cobalt-chromium EES are currently limited. METHODS: The NEXT trial is a prospective, multicenter, randomized, open-label, noninferiority trial comparing BES with EES. Between May and October 2011, 3,235 patients were randomly assigned to receive either BES (n = 1,617) or EES (n = 1,618). RESULTS: At 1 year, the primary efficacy endpoint of TLR occurred in 67 patients (4.2%) in the BES group, and in 66 patients (4.2%) in the EES group, demonstrating noninferiority of BES relative to EES (p for noninferiority <0.0001, and p for superiority = 0.93). Cumulative incidence of definite stent thrombosis was low and similar between the 2 groups (0.25% vs. 0.06%, p = 0.18). An angiographic substudy enrolling 528 patients (BES: n = 263, and EES: n = 265) demonstrated noninferiority of BES relative to EES regarding the primary angiographic endpoint of in-segment late loss (0.03 +/- 0.39 mm vs. 0.06 +/- 0.45 mm, p for noninferiority <0.0001, and p for superiority = 0.52) at 266 +/- 43 days after stent implantation. CONCLUSIONS: One-year clinical and angiographic outcome after BES implantation was noninferior to and not different from that after EES implantation in a mostly stable coronary artery disease population. One-year clinical outcome after both BES and EES use was excellent, with a low rate of TLR and extremely low rate of stent thrombosis. PMID- 23684674 TI - Transcatheter aortic valve replacement in Europe: adoption trends and factors influencing device utilization. AB - OBJECTIVES: The authors sought to examine the adoption of transcatheter aortic valve replacement (TAVR) in Western Europe and investigate factors that may influence the heterogeneous use of this therapy. BACKGROUND: Since its commercialization in 2007, the number of TAVR procedures has grown exponentially. METHODS: The adoption of TAVR was investigated in 11 European countries: Germany, France, Italy, United Kingdom, Spain, the Netherlands, Switzerland, Belgium, Portugal, Denmark, and Ireland. Data were collected from 2 sources: 1) lead physicians submitted nation-specific registry data; and 2) an implantation-based TAVR market tracker. Economic indexes such as healthcare expenditure per capita, sources of healthcare funding, and reimbursement strategies were correlated to TAVR use. Furthermore, we assessed the extent to which TAVR has penetrated its potential patient population. RESULTS: Between 2007 and 2011, 34,317 patients underwent TAVR. Considerable variation in TAVR use existed across nations. In 2011, the number of TAVR implants per million individuals ranged from 6.1 in Portugal to 88.7 in Germany (33 +/- 25). The annual number of TAVR implants performed per center across nations also varied widely (range 10 to 89). The weighted average TAVR penetration rate was low: 17.9%. Significant correlation was found between TAVR use and healthcare spending per capita (r = 0.80; p = 0.005). TAVR-specific reimbursement systems were associated with higher TAVR use than restricted systems (698 +/- 232 vs. 213 +/- 112 implants/million individuals >= 75 years; p = 0.002). CONCLUSIONS: The authors' findings indicate that TAVR is underutilized in high and prohibitive surgical risk patients with severe aortic stenosis. National economic indexes and reimbursement strategies are closely linked with TAVR use and help explain the inequitable adoption of this therapy. PMID- 23684675 TI - Transcatheter aortic valve adoption rates. PMID- 23684676 TI - Cardiac troponin after percutaneous coronary intervention and 1-year mortality in non-ST-segment elevation acute coronary syndrome using systematic evaluation of biomarker trends. AB - OBJECTIVES: This study sought to review cardiac troponin (cTn) trends during non ST-segment elevation acute coronary syndrome (NSTE ACS) in patients undergoing percutaneous coronary intervention (PCI) in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndromes) and SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors) studies and to study the relationship between post-PCI cTn and mortality. BACKGROUND: The prognostic value of cTn post-PCI is controversial. In patients with NSTE ACS, it is especially difficult to distinguish between cTn elevations due to PCI or index myocardial infarction (MI). METHODS: Time and cTn (indexed by upper limit of normal [ULN]) data pairs were plotted for 10,199 patients and independently reviewed by 2 physicians to identify patients in whom post-PCI cTn elevation could be distinguished from that of index MI. Post-PCI cTn peak was identified for each plot, and its relationship with 1-year mortality was evaluated using Cox modeling, correcting for 15 clinical variables from the EARLY ACS 1-year mortality model (including baseline cTn). We used an identical methodology to assess the association between creatine kinase-myocardial band and 1-year mortality. RESULTS: Patients with cTn (re )elevation post-PCI not evaluable were identified and excluded from further analysis (4,198 [41%] with cTn rising prior to PCI; 229 [2%] with missing cTn). Among the remainder (n = 5,772 [57%]), in the multivariable model, peak cTn post PCI was associated with a 7% increase in mortality (hazard ratio [HR] for 10 * ULN increase: 1.07, 95% confidence interval [CI]: 1.02 to 1.11; p = 0.0038). Peak post-PCI creatine kinase-myocardial band was significantly associated with 1-year mortality (HR for 1 * ULN increase: 1.13, 95% CI: 1.05 to 1.21; p = 0.0013). CONCLUSIONS: We used a methodology that differentiated post-PCI cTn (re )elevation from that of presenting MI in more than one-half of patients with NSTE ACS undergoing PCI. This identified a highly significant relationship between post-PCI cTn and 1-year mortality, with implications for both incorporating a cTn post-PCI MI definition and preventing PCI-related myonecrosis. PMID- 23684677 TI - A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. AB - Over the past decade, myocardial structure, cardiomyocyte function, and intramyocardial signaling were shown to be specifically altered in heart failure with preserved ejection fraction (HFPEF). A new paradigm for HFPEF development is therefore proposed, which identifies a systemic proinflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations. The new paradigm presumes the following sequence of events in HFPEF: 1) a high prevalence of comorbidities such as overweight/obesity, diabetes mellitus, chronic obstructive pulmonary disease, and salt-sensitive hypertension induce a systemic proinflammatory state; 2) a systemic proinflammatory state causes coronary microvascular endothelial inflammation; 3) coronary microvascular endothelial inflammation reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes; 4) low PKG activity favors hypertrophy development and increases resting tension because of hypophosphorylation of titin; and 5) both stiff cardiomyocytes and interstitial fibrosis contribute to high diastolic left ventricular (LV) stiffness and heart failure development. The new HFPEF paradigm shifts emphasis from LV afterload excess to coronary microvascular inflammation. This shift is supported by a favorable Laplace relationship in concentric LV hypertrophy and by all cardiac chambers showing similar remodeling and dysfunction. Myocardial remodeling in HFPEF differs from heart failure with reduced ejection fraction, in which remodeling is driven by loss of cardiomyocytes. The new HFPEF paradigm proposes comorbidities, plasma markers of inflammation, or vascular hyperemic responses to be included in diagnostic algorithms and aims at restoring myocardial PKG activity. PMID- 23684678 TI - Heart failure with preserved ejection fraction: time for a new approach? PMID- 23684679 TI - The impact of integration of a multidetector computed tomography annulus area sizing algorithm on outcomes of transcatheter aortic valve replacement: a prospective, multicenter, controlled trial. AB - OBJECTIVES: This study prospectively investigated the impact of integration of a multidetector computed tomography (MDCT) annular area sizing algorithm on transcatheter aortic valve replacement (TAVR) outcomes. BACKGROUND: Appreciation of the 3-dimensional, noncircular geometry of the aortic annulus is important for transcatheter heart valve (THV) sizing. METHODS: Patients being evaluated for TAVR in 4 centers underwent pre-procedural MDCT. Recommendations for balloon expandable THV size selection were based on an MDCT sizing algorithm with an optimal goal of modest annulus area oversizing (5% to 10%). Consecutive patients who underwent TAVR with the algorithm (MDCT group) were compared with consecutive patients without the algorithm (control group). The primary endpoint was the incidence of more than mild paravalvular regurgitation (PAR), and the secondary endpoint was the composite of in-hospital death, aortic annulus rupture, and severe PAR. RESULTS: Of 266 patients, 133 consecutive patients underwent TAVR (SAPIEN XT THV) in the MDCT group and 133 consecutive patients were in the control group. More than mild PAR was present in 5.3% (7 of 133) of the MDCT group and in 12.8% (17 of 133) in the control group (p = 0.032). The combined secondary endpoint occurred in 3.8% (5 of 133) of the MDCT group and in 11.3% (15 of 133) of the control group (p = 0.02), driven by the difference of severe PAR. CONCLUSIONS: The implementation of an MDCT annulus area sizing algorithm for TAVR reduces PAR. Three-dimensional aortic annular assessment and annular area sizing should be considered for TAVR. PMID- 23684681 TI - Preserve the brain: primary goal in the therapy of atrial fibrillation. PMID- 23684680 TI - Determinants and outcomes of acute transcatheter valve-in-valve therapy or embolization: a study of multiple valve implants in the U.S. PARTNER trial (Placement of AoRTic TraNscathetER Valve Trial Edwards SAPIEN Transcatheter Heart Valve). AB - OBJECTIVES: This study investigated the determinants and outcomes of acute insertion of a second transcatheter prosthetic valve (TV) within the first (TV-in TV) or transcatheter valve embolization (TVE) after transcatheter aortic valve replacement (TAVR). BACKGROUND: TAVR failure can occur with both TV-in-TV and TVE as a consequence of TAVR malpositioning. Only case reports and limited series pertaining to these complications have been reported to date. METHODS: Patients undergoing TAVR in the PARTNER (Placement of AoRTic TraNscathetER Valve Trial Edwards SAPIEN Transcatheter Heart Valve) randomized trial (cohorts A and B) and accompanying registries were studied. Data were dichotomized for those with and without TV-in-TV or TVE, respectively. RESULTS: From a total of 2,554 consecutive patients, 63 (2.47%) underwent TV-in-TV and 26 (1.01%) TVE. The indication for TV in-TV was significant aortic regurgitation in most patients, often due not only to malpositioning but also to leaflet dysfunction. Despite similar aortic valve function on follow-up echoes, TV-in-TV was an independent predictor of 1-year cardiovascular mortality (hazard ratio [HR]: 1.86, 95% confidence interval [CI]: 1.03 to 3.38, p = 0.041), with a nonsignificant trend toward greater all-cause mortality (HR: 1.43, 95% CI: 0.88 to 2.33, p = 0.15). Technical and anatomical reasons accounted for most cases of TVE. A multivariable analysis found TVE to be an independent predictor of 1-year mortality (HR: 2.68, 95% CI: 1.34 to 5.36, p = 0.0055) but not cardiovascular mortality (HR: 1.30, 95% CI: 0.48 to 3.52, p = 0.60). CONCLUSIONS: Acute TV-in-TV and TVE are serious sequelae of TAVR, often resulting in multiple valve implants. They carry an excess of mortality and are caused by anatomic and technical factors, which may be avoidable with judicious procedural planning. PMID- 23684682 TI - Associations between routine coronary computed tomographic angiography and reduced unnecessary hospital admissions, length of stay, recidivism rates, and invasive coronary angiography in the emergency department triage of chest pain. AB - OBJECTIVES: This study was designed to assess the effects on resource utilization of routine coronary computed tomographic angiography (CCTA) in triaging chest pain patients in the emergency department (ED). BACKGROUND: The routine use of CCTA for ED evaluation of chest pain is feasible and safe. METHODS: We conducted a retrospective multivariate analysis of data from two risk-matched cohorts of 894 ED patients presenting with chest pain to assess the impact of CCTA versus standard evaluation on admissions rate, length of stay, major adverse cardiovascular event rates, recidivism rates, and downstream resource utilization. RESULTS: The overall admission rate was lower with CCTA (14% vs. 40%; p < 0.001). Standard evaluation was associated with a 5.5-fold greater risk for admission (odds ratio [OR]: 5.53; p < 0.001). Expected ED length of stay with standard evaluation was about 1.6 times longer (OR: 1.55; p < 0.001). There were no differences in the rates of death and acute myocardial infarction within 30 days of the index visit between the two groups. The likelihood of returning to the ED within 30 days for recurrent chest pain was 5 times greater with standard evaluation (OR: 5.06; p = 0.022). Standard evaluation was associated with a 7 fold greater likelihood of invasive coronary angiography without revascularization (OR: 7.17; p < 0.001), while neither group was significantly more likely to receive revascularization (OR: 2.06; p = 0.193). The median radiation dose with CCTA was 5.88 mSv (n = 1039; confidence interval: 5.2 to 6.4). CONCLUSIONS: The routine use of CCTA in ED evaluation of chest pain reduces healthcare resource utilization. PMID- 23684683 TI - Impact of genetics on the clinical management of channelopathies. AB - There are few areas in cardiology in which the impact of genetics and genetic testing on clinical management has been as great as in cardiac channelopathies, arrhythmic disorders of genetic origin related to the ionic control of the cardiac action potential. Among the growing number of diseases identified as channelopathies, 3 are sufficiently prevalent to represent significant clinical and societal problems and to warrant adequate understanding by practicing cardiologists: long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome. This review will focus selectively on the impact of genetic discoveries on clinical management of these 3 diseases. For each disorder, we will discuss to what extent genetic knowledge and clinical genetic test results modify the way cardiologists should approach and manage affected patients. We will also address the optimal use of genetic testing, including its potential limitations and the potential medico-legal implications when such testing is not performed. We will highlight how important it is to understand the ways that genotype can affect clinical manifestations, risk stratification, and responses to the therapy. We will also illustrate the close bridge between molecular biology and clinical medicine, and will emphasize that consideration of the genetic basis for these heritable arrhythmia syndromes and the proper use and interpretation of clinical genetic testing should remain the standard of care. PMID- 23684684 TI - Modeling serum level of s100beta and bispectral index to predict outcome after cardiac arrest. AB - OBJECTIVES: This study was designed to evaluate multimodal prognostication in patients after cardiac arrest (CA). BACKGROUND: Accurate methods to predict outcome after CA are lacking. METHODS: Seventy-five patients with CA treated with therapeutic hypothermia after cardiac resuscitation were enrolled in this prospective observational study. Serum levels of neuron-specific enolase (NSE) and neuron-enriched S100 beta (S100beta) were measured 48 h after CA. Bispectral index (BIS) was continuously monitored during the first 48 h after CA. The primary endpoint was neurological outcome, as defined by the cerebral performance category (CPC) at 6-month follow-up: scores 1 or 2 indicated good outcome, and scores 3 to 5, poor outcome. The secondary endpoint was survival. RESULTS: A total of 46 (61%) patients survived at 6 months and 41 (55%) patients had CPC 1 or 2. Levels of NSE and S100beta were higher in patients with poor outcomes compared with patients with good outcomes (4-fold and 10-fold, respectively; p < 0.001). BIS was lower in patients with poor outcomes (10-fold; p < 0.001). NSE, S100beta, or BIS alone predicted neurological outcome, with areas under the receiver-operating characteristic curve (AUC) above 0.80. Combined determination of S100beta and BIS had an incremental predictive value (AUC: 0.95). S100beta improved discriminations based on BIS (p = 0.0008), and BIS improved discriminations based on S100beta (p < 10(-5)). Patients with S100beta level above 0.03 MUg/l and BIS below 5.5 had a 3.6-fold higher risk of poor neurological outcome (p < 0.0001). S100beta and BIS predicted 6-month mortality (log-rank statistic: 50.41; p < 0.001). CONCLUSIONS: Combined determination of serum level of S100beta and BIS monitoring accurately predicts outcome after CA. PMID- 23684685 TI - Brief episodes of silent atrial fibrillation predict clinical vascular brain disease in type 2 diabetic patients. AB - OBJECTIVES: This study evaluated whether subclinical episodes of atrial fibrillation (AF) were associated with an increased risk of silent cerebral infarct (SCI) and stroke in diabetic patients younger than 60 years who did not have other clinical evidence of AF and cerebrovascular disease at baseline. BACKGROUND: In type 2 diabetic patients, one-fourth of strokes are of unknown cause, and subclinical episodes of AF may be a common etiologic factor. METHODS: A total of 464 type 2 diabetic patients younger than 60 years were included in a longitudinal observational study and matched to patients without diabetes. Patients underwent 48-h electrocardiographic Holter monitoring quarterly to detect brief subclinical episodes of AF (duration of AF <48 h) and were followed up for 37 months. The outcomes were SCI, assessed by magnetic resonance imaging of the brain, and stroke events during the follow-up period. RESULTS: The prevalence of subclinical episodes of AF was significantly greater among patients with diabetes compared with matched healthy subjects (11% vs. 1.6%, p < 0.0001). During an average duration of 37 months, 43 stroke events occurred in the diabetic population and no events occurred in healthy subjects. Diabetic patients with silent episodes of AF (n = 176) had a higher baseline prevalence of SCI (61% vs. 29%; p < 0.01) and a higher number of stroke events (17.3% vs. 5.9%; p < 0.01) during the follow-up period than the other patients (n = 288). An episode of silent AF was an independent determinant of SCI (odds ratio: 4.441; p < 0.001; confidence interval: 2.42 to 8.16) and an independent predictor of the occurrence of stroke in diabetic patients (hazard ratio: 4.6; p < 0.01; confidence interval: 2.7 to 9.1). CONCLUSIONS: Subclinical episodes of AF occurred frequently in type 2 diabetic patients and were associated with a significantly increased risk of SCI and stroke. PMID- 23684686 TI - Subtle post-procedural cognitive dysfunction after atrial fibrillation ablation. AB - OBJECTIVES: This study sought to determine whether post-operative neurocognitive dysfunction (POCD) occurs after ablation for atrial fibrillation (AF). BACKGROUND: Ablation for AF is a highly effective strategy; however, the risk of transient ischemic attack and stroke is approximately 0.5% to 1%. In addition, magnetic resonance imaging studies report a 7% to 14% prevalence of silent cerebral infarction. Whether cerebral ischemia results in POCD after ablation for AF is not well established. METHODS: The study included 150 patients; 60 patients undergoing ablation for paroxysmal atrial fibrillation (PAF), 30 patients undergoing ablation for persistent atrial fibrillation (PeAF), and 30 patients undergoing ablation for supraventricular tachycardia (SVT) were compared with a matched nonoperative control group of patients with AF awaiting radiofrequency ablation (n = 30). Eight neuropsychological tests were administered at baseline and at 2 days and 90 days post-operatively. The tests were administered at the same time points to the nonoperative control group. The reliable change index was used to calculate POCD. RESULTS: The prevalences of POCD at day 2 post-procedure were 28% in patients with PAF, 27% in patients with PeAF, 13% in patients with SVT, and 0% in control patients with AF (p = 0.007). At day 90, the prevalences of POCD were 13% in patients with PAF, 20% in patients with PeAF, 3% in patients with SVT, and 0% in control patients with AF (p = 0.03). When analyzing the 3 procedural groups together, 29 of 120 patients (24%) manifested POCD at day 2 and 15 of 120 patients (13%) at day 90 post-procedure (p = 0.029). On univariate analysis, increasing left atrial access time was associated with POCD at day 2 (p = 0.04) and day 90 (p = 0.03). CONCLUSIONS: Ablation for AF is associated with a 13% to 20% prevalence of POCD in patients with AF at long-term follow-up. These results were seen in a patient population with predominant CHADS2 (Congestive heart failure, Hypertension, Age >=75 years, Diabetes mellitus, previous Stroke/transient ischemic attack) scores of 0 to 1, representing the majority of patients undergoing ablation for AF. The long-term implications of these subtle changes require further study. PMID- 23684688 TI - Provocation of an autoimmune response to cardiac voltage-gated sodium channel NaV1.5 induces cardiac conduction defects in rats. AB - OBJECTIVES: This study sought to test the hypothesis that inducing an autoimmune response against the cardiac sodium channel (NaV1.5) induces arrhythmias. BACKGROUND: Sporadic evidence supports the concept that autoantibodies may cause cardiac arrhythmias but substantial experimental investigations using in vivo models have been lacking to date. The NaV1.5 is essential for cardiac impulse propagation and its dysfunction has been linked to conduction disease. METHODS: Rats were immunized with a peptide sequence derived from the third extracellular loop of the first domain of NaV1.5. After 28 days, we evaluated in vivo both the electrical and mechanical parameters of cardiac function. Histopathology, myocardial gene and protein expression were assessed. Whole-cell patch-clamp was used to measure sodium current (INa) density in isolated cardiomyocytes. RESULTS: NaV1.5-immunized rats had high titers of autoantibodies against NaV1.5. On ECG recording, NaV1.5-immunized animals showed significantly prolonged PR-intervals. During Holter ECG-monitoring we observed repeated prolonged episodes of third degree atrioventricular and sinoatrial block in every NaV1.5-immunized animal, but not in controls. Immunization had no effect on cardiac function. In comparison to controls, myocardial NaV1.5 mRNA and protein levels were decreased in immunized rats. INa density was reduced in cardiomyocytes incubated with sera from NaV1.5-immunized rats and from patients with idiopathic atrioventricular block (AVB) in comparison to sera from respective controls. In patients with idiopathic AVB, we observed autoantibodies against NaV1.5 that were absent in sera from healthy controls. CONCLUSIONS: Provocation of an autoimmune response against NaV1.5 induces conductance defects probably caused by a reduced expression level and an inhibition of NaV1.5 by autoantibodies, resulting in decreased INa. PMID- 23684687 TI - Changes in cardiovascular risk factors by hysterectomy status with and without oophorectomy: Study of Women's Health Across the Nation. AB - OBJECTIVES: The aim of this study was to compare the changes in risk factors for cardiovascular disease (CVD) leading up to and after hysterectomy with or without bilateral oophorectomy with the changes observed up to and after natural menopause. BACKGROUND: Evidence suggests that hysterectomy status with or without bilateral oophorectomy might increase risk for CVD, but most studies retrospectively assess menopausal status. METHODS: Study of Women's Health across the Nation enrolled 3,302 pre-menopausal women not using hormone therapy between 42 and 52 years of age and followed them annually for over 11 years for sociodemographic characteristics, menopausal status, surgeries, body mass index, medication use, lifestyle factors, lipids, blood pressure, insulin resistance, and hemostatic and inflammatory factors. By 2008, 1,769 women had reached natural menopause, 77 women had a hysterectomy with ovarian conservation, and 106 women had a hysterectomy with bilateral oophorectomy. Piece-wise hierarchical growth models compared these groups on annual changes in CVD risk factors before and after final menstrual period or surgery. RESULTS: Multivariable analyses showed that annual changes in CVD risk factors did not vary by group, with few exceptions, and the significant group differences that did emerge were not in the anticipated direction. CONCLUSIONS: Hysterectomy with or without ovarian conservation is not a key determinant of CVD risk factor status either before or after elective surgery in midlife. These results should provide reassurance to women and their clinicians that hysterectomy in midlife is unlikely to accelerate the CVD risk of women. PMID- 23684689 TI - VEGF-releasing biodegradable nanospheres administered by craniotomy: a novel therapeutic approach in the APP/Ps1 mouse model of Alzheimer's disease. AB - This study attempts to develop a novel nanotechnology-based strategy to deliver vascular endothelial growth factor (VEGF) to the brain, as a possible therapeutic approach for AD. For this purpose, VEGF was encapsulated in biodegradable poly(lactic-co-glycolic acid) (PLGA) nanospheres (VEGF-NS). The nanosphere particle size was about 200 nm, with a narrow size distribution, and the zeta potential around -30 mV. The encapsulation efficiency of VEGF was 44.06+/-5.61%, showing a biphasic release profile in vitro. The biological activity and neuroprotective effect of encapsulated VEGF were investigated in neuronal cell cultures, confirming the neuronal proliferative effect and the protection against Abeta42 induced neurotoxicity. In vivo studies were carried out in amyloid precursor protein/presenilin-1 (APP/Ps1) mice administering VEGF-NS through minimally invasive craniotomy. The results obtained showed that VEGF-NS were able to improve behavioral deficits, decrease Abeta deposits and promote angiogenesis, as well as reduce neuronal loss and cerebrovascular abnormalities. Furthermore, their ability to protect neuronal cultures against neuroinflammation induced by LPS provides new insight for future therapeutic approaches in other neurodegenerative disorders. PMID- 23684690 TI - RNA silencing and its suppression: novel insights from in planta analyses. AB - Plants employ multiple layers of innate immunity to fight pathogens. For both RNA and DNA viruses, RNA silencing plays a critical role in plant resistance. To escape this antiviral silencing-based immune response, viruses have evolved various counterdefense strategies, the most widespread being production of viral suppressors of RNA silencing (VSRs) that target various stages of the silencing mechanisms. Recent findings from in planta analyses have provided new insights into the mode of action of VSRs and revealed that plants react to the perturbation of the silencing pathways brought by viral infection by deploying a battery of counter-counterdefense measures. As well as discussing which experimental approaches have been most effective in delivering clear and unambiguous results, this review provides a detailed account of the surprising variety of offensive and defensive strategies set forth by both viruses and hosts in their struggle for survival. PMID- 23684691 TI - Nicotinic acetylcholine receptors as therapeutic targets: emerging frontiers in basic research and clinical science--editorial comments. PMID- 23684692 TI - Cysteinyl leukotriene-receptor-1 antagonists interfere with PGE2 synthesis by inhibiting mPGES-1 activity. AB - Because of their favourable safety profile and beneficial anti-inflammatory properties, the CysLT1 receptor antagonists (LTRA), montelukast, zafirlukast and pranlukast are approved for the treatment of asthma and are frequently prescribed as add-on therapeutics to reduce the amount of inhaled glucocorticoids and beta2 agonists. There is evidence that some of these anti-inflammatory properties might be of a secondary nature and therefore, unrelated to the CysLT1 antagonism. Here, we show that LTRA inhibit PGE2 formation in cytokine-stimulated Hela and A549 carcinoma cells and in lipopolysaccharide (LPS)-stimulated human leukocyte preparations (IC50~20MUM). Neither expression of enzymes involved in PGE2 synthesis nor arachidonic acid release and COX activities were inhibited by the compounds. In contrast, mPGES-1 activity was suppressed at low micromolar levels (IC50 between 2 and 4MUM). This suppression was specific for PGE2 synthesis, since PGD2 and PGI2 levels in LPS-stimulated leukocyte preparations were not negatively affected. PGF2alpha levels were concomitantly inhibited, probably due to its direct synthesis from PGE2. Several major conclusions can be drawn from this study: (A) clinical trials investigating elevated doses of the compounds are helpful to confirm suppression of PGE2 synthesis in vivo; (B) studies investigating the role of CysLTs in cell culture or animal models of inflammation and cancer have to be reassessed carefully, if higher doses of LTRA were applied or serum levels in cell culture assays were low; and (C) LTRA may serve as new scaffolds for the development of potent, selective and well tolerated mPGES-1 inhibitors. PMID- 23684694 TI - Planning waste cooking oil collection systems. AB - This research has been motivated by a real-life problem of a waste cooking oil collection system characterized by the existence of multiple depots with an outsourced vehicle fleet, where the collection routes have to be plan. The routing problem addressed allows open routes between depots, i.e., all routes start at one depot but can end at the same or at a different one, depending on what minimizes the objective function considered. Such problem is referred as a Multi-Depot Vehicle Routing Problem with Mixed Closed and Open Inter-Depot Routes and is, in this paper, modeled through a mixed integer linear programming (MILP) formulation where capacity and duration constraints are taken into account. The model developed is applied to the real case study providing, as final results, the vehicle routes planning where a decrease of 13% on mileage and 11% on fleet hiring cost are achieved, when comparing with the current company solution. PMID- 23684693 TI - Decreased PCDD/F formation when co-firing a waste fuel and biomass in a CFB boiler by addition of sulphates or municipal sewage sludge. AB - Polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) are formed during waste incineration and in waste-to-energy boilers. Incomplete combustion, too short residence times at low combustion temperatures (<700 degrees C), incineration of electronic waste and plastic waste containing chlorine are all factors influencing the formation of PCDD/Fs in boilers. The impact of chlorine and catalysing metals (such as copper and iron) in the fuel on PCDD/F formation was studied in a 12 MW(th) circulating fluidised bed (CFB) boiler. The PCDD/F concentrations in the raw gas after the convection pass of the boiler and in the fly ashes were compared. The fuel types were a so-called clean biomass with low content of chlorine, biomass with enhanced content of chlorine from supply of PVC, and solid recovered fuel (SRF) which is a waste fuel containing higher concentrations of both chlorine, and catalysing metals. The PCDD/F formation increased for the biomass with enhanced chlorine content and it was significantly reduced in the raw gas as well as in the fly ashes by injection of ammonium sulphate. A link, the alkali chloride track, is demonstrated between the level of alkali chlorides in the gas phase, the chlorine content in the deposits in the convection pass and finally the PCDD/F formation. The formation of PCDD/Fs was also significantly reduced during co-combustion of SRF with municipal sewage sludge (MSS) compared to when SRF was fired without MSS as additional fuel. PMID- 23684695 TI - Adsorption characteristics of siloxanes in landfill gas by the adsorption equilibrium test. AB - Due to the increase in energy cost by constantly high oil prices and the obligation to reduce greenhouse effect gases, landfill gas is frequently used as an alternative energy source for producing heat and electricity. Most of landfill gas utility facilities, however, are experiencing problems controlling siloxanes from landfill gas as their catalytic oxidizers are becoming fouled by silicon dioxide dust. To evaluate adsorption characteristics of siloxanes, an adsorption equilibrium test was conducted and parameters in the Freundlich and Langmuir isotherms were analyzed. Coconut activated carbon (CA1), coal activated carbon (CA2), impregnated activated carbon (CA3), silicagel (NCA1), and activated alumina (NCA2) were used for the adsorption of the mixed siloxane which contained hexamethyldisiloxane (L2), octamethylcyclotetrasiloxane (D4), and decamethylcyclopentasiloxane (D5). L2 had higher removal efficiency in noncarbon adsorbents compared to carbon adsorbents. The application of Langmuir and Freundlich adsorption isotherm demonstrated that coconut based CA1 and CA3 provided higher adsorption capacity on L2. And CA2 and NCA1 provided higher adsorption capacity on D4 and D5. Based on the experimental results, L2, D4, and D5 were converted by adsorption and desorption in noncarbon adsorbents. Adsorption affinity of siloxane is considered to be affect by the pore size distribution of the adsorbents and by the molecular size of each siloxane. PMID- 23684696 TI - Antenatal stress: an Irish case study. AB - BACKGROUND: stress in pregnancy is common and impacts negatively on women, infants and families. A number of factors contribute to high levels of stress in pregnancy, including financial concerns, marital discord, low support systems and low socio-economic status. OBJECTIVES: the aim of this study was to evaluate stress anxiety levels and depressive symptoms among low risk women in an area in Ireland that was particularly impacted by the 2008 economic crisis. DESIGN: a quantitative descriptive cross-sectional design was used. Data were collected using the Edinburgh Postnatal Depression Scale (EPDS), the Perceived Stress Scale and the State Trait Anxiety Inventory (STAI). Data was collected at a single time during the second trimester. SETTING: this paper reports a case study of one maternity service in Ireland. Participants included low risk pregnant women who were attending the hospital clinic for routine antenatal care. RESULTS: of 150 questionnaires distributed, 74 completed questionnaires were returned indicating a 49.3% return rate. Findings indicated high levels of stress, anxiety and depressive symptomatology among participants. There were no significant difference in mean EPDS score for different age groups (F4,69=2.48, P=0.052), living arrangements (F4,68=0.90, P=0.5) or usual occupation (F4,69=1.45, P=0.2). A score of >= 12 was taken as indicative of probable antenatal depression and 86.5% of participants responded with a score of 12 or above. PSS scores were also high and more than three quarters of respondents scored >= 15 (75.6%) and more than a third had scores >= 20 (35.1%), out of a total score of 40. There was a significant difference in mean PSS score between the different age groups (F4,69=3.60, P=0.010) but not for living arrangements or usual occupation. A STAI score of >= 39 was taken as indicative of antenatal anxiety, and 74.3% of participants responded with a score of 39 or above. There were no significant differences in mean STAI score between the different age groups (F4,68=1.68, P=0.16), living arrangements (F4,67=2.30, P=0.068) or usual occupations (F4,68=1.25, P=0.3). KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: this study found high levels of antenatal stress, anxiety, and depressive symptoms in a low risk pregnant population, in an economically impacted region in Ireland. These findings have implications for fetal development and maternal health during pregnancy and in the post partum. Further studies are important to confirm rates and should be conducted over a longer time frame with data collected at more than one point in time, such as mid and late pregnancy. If findings are confirmed, early recognition and treatment of stress, anxiety and depressive symptoms is important to ameliorate some of the harmful effects of these conditions. PMID- 23684697 TI - Oxytocin and dystocia as risk factors for adverse birth outcomes: a cohort of low risk nulliparous women. AB - OBJECTIVES: augmented and not augmented women without dystocia were compared to investigate associations between oxytocin and adverse birth outcomes. Augmented women with and without dystocia were compared, to investigate associations between dystocia and adverse birth outcomes. DESIGN: a cohort of low-risk nulliparous women originally included in a randomised controlled trial. SETTING: the Department of Obstetrics and Gynaecology, Ostfold Hospital Trust, Norway. PARTICIPANTS: the study population consists of 747 well defined low-risk women. MEASUREMENTS: incidence of oxytocin augmentation, and associations between dystocia and augmentation, and mode of delivery, transfer of newborns to the intensive care unit, episiotomy and postpartum haemorrhage. FINDINGS: of all participants 327 (43.8%) were augmented with oxytocin of which 139 (42.5%) did not fulfil the criteria for dystocia. Analyses adjusted for possible confounders found that women without dystocia had an increased risk of instrumental vaginal birth (OR 3.73, CI 1.93-7.21) and episiotomy (OR 2.47, CI 1.38-4.39) if augmented with oxytocin. Augmented women had longer active phase if vaginally delivered and longer labours if delivered by caesarean section if having dystocia. Among women without dystocia, those augmented had higher body mass index, gave birth to heavier babies, had longer labours if vaginally delivered and had epidural analgesia more often compared to women not augmented. KEY CONCLUSION: in low-risk nulliparous without dystocia, we found an association between the use of oxytocin and an increased risk of instrumental vaginal birth and episiotomy. IMPLICATIONS FOR PRACTICE: careful attention should be paid to criteria for labour progression and guidelines for oxytocin augmentation to avoid unnecessary use. PMID- 23684699 TI - Lung involvement in connective tissue diseases: a comprehensive review and a focus on rheumatoid arthritis. AB - The lungs are frequently involved in Connective Tissue Diseases (CTDs). Interstitial lung disease (ILD) is one of the most common pleuropulmonary manifestations that affects prognosis significantly. In practice, rheumatologists and other physicians tend to underestimate the impact of CTD-ILDs and diagnose respiratory impairment when it has reached an irreversible fibrotic stage. Early investigation, through clinical evidence, imaging and - in certain cases - lung biopsy, is therefore warranted in order to detect a possible ILD at a reversible initial inflammatory stage. In this review, we focus on lung injury during CTDs, with particular attention to ILDs, and examine their prevalence, clinical manifestations and histological patterns, as well as therapeutic approaches and known complications till date. Although several therapeutic agents have been approved, the best treatment is still not certain and additional trials are required, which demand more knowledge of pulmonary involvement in CTDs. Our central aim is therefore to document the impact that lung damage has on CTDs. We will mainly focus on Rheumatoid Arthritis (RA), which - unlike other rheumatic disorders - resembles Idiopathic Pulmonary Fibrosis (IPF) in numerous aspects. PMID- 23684698 TI - Potential role of human-specific genes, human-specific microRNAs and human specific non-coding regulatory RNAs in the pathogenesis of systemic sclerosis and Sjogren's syndrome. AB - The etiology and pathogenesis of human autoimmune diseases remain unknown despite intensive investigations. Although remarkable progress has been accomplished through genome wide association studies in the identification of genetic factors that may predispose to their occurrence or modify their clinical presentation to date no specific gene abnormalities have been conclusively demonstrated to be responsible for these diseases. The completion of the human and chimpanzee genome sequencing has opened up novel opportunities to examine the possible contribution of human specific genes and other regulatory elements unique to the human genome, such as microRNAs and non-coding RNAs, towards the pathogenesis of a variety of human disorders. Thus, it is likely that these human specific genes and non coding regulatory elements may be involved in the development or the pathogenesis of various disorders that do not occur in non-human primates including certain autoimmune diseases such as Systemic Sclerosis and Primary Sjogren's Syndrome. Here, we discuss recent evidence supporting the notion that human specific genes or human specific microRNA and other non-coding RNA regulatory elements unique to the human genome may participate in the development or in the pathogenesis of Systemic Sclerosis and Primary Sjogren's Syndrome. PMID- 23684700 TI - Is there a crossroad between infections, genetics, and Henoch-Schonlein purpura? AB - Henoch-Schonlein purpura is the most common systemic vasculitis in childhood, characterized by the presence of immunoglobulin A deposits in the small vessels of skin, gastrointestinal tube, joints and kidneys. Although there have been great efforts made in elucidating its pathogenic mechanisms, Henoch-Schonlein purpura etiology remains unknown: the basic scene comes across an abnormal inflammatory process deriving from immune reactions to various antigenic stimuli, which might be bacterial, viral, or parasitic agents, in a genetically prone individual. Then, a peculiar immune complex deposition in the vascular walls and overproduction of different proinflammatory molecules elicit different clinical signs, which might be differentiated according to either a specific trigger or a specific genetic make-up. The aim of this review is to make a critical appraisal of the last 15years' medical literature concerning the relationship between infections, genetics, and Henoch-Schonlein purpura in pediatrics. PMID- 23684701 TI - Preventing congenital neonatal heart block in offspring of mothers with anti SSA/Ro and SSB/La antibodies: a review of published literature and registered clinical trials. AB - Offspring of women with anti-SSA/Ro-SSB/La antibodies are believed to be at risk for congenital heart block (CHB). Whether this risk can be reduced, and what constitutes standard of care treatment is, however, unclear. The objective of this review therefore was to determine whether currently proposed standard of care treatments to avoid CHB in offspring of mothers at risk are evidence-based. To do so, we conducted a review of the literature under appropriate keywords and phrases in Medline/PubMed and Google Scholar for the years 2000-2013. Reference lists were further reviewed, and relevant manuscripts were pulled. We also reviewed www.clinicaltrials.gov for registered studies. In the absence of randomized prospective clinical trials, a meta-analysis was not feasible. We, therefore, reviewed lower evidence level studies individually. Risk of CHB actually appears more closely associated with general autoimmunity than, specifically, with SSA/Ro-SSB/La antibodies. This and other observations raise questions whether CHB is caused by passively transferred maternal autoimmunity, as is currently widely believed. Observational studies suggest the possible effectiveness of intravenous gamma globulin (IV-Ig) and hydroxychloroquine (Plaquenil) in reducing CHB-risk. Evidence for both is, however, inconclusive, and studies are biased in favor of hydroxychloroquine and against IV-Ig. Based on the review of the literature, current evidence of effectiveness for any treatment has to be judged as insufficient. Among the available treatment options, some considerations favor IV-Ig over hydroxychloroquine or, alternatively, suggest treatment with IV-Ig periconceptionally and into early gestation, with hydroxychloroquine added or replacing IV-Ig at approximately 10weeks gestational age. Benefits for the utilization of steroid drugs are unclear. Since no treatment can be considered as established, prevention of CHB in offspring should be considered experimental, and performed under appropriate study conditions. PMID- 23684702 TI - Enhanced killing activity of regulatory T cells ameliorates inflammation and autoimmunity. AB - Regulatory T cells (Treg) are pivotal suppressor elements in immune homeostasis with potential therapeutic applications in inflammatory and autoimmune disorders. Using Treg as vehicles for targeted immunomodulation, a short-lived Fas-ligand (FasL) chimeric protein (killer Treg) was found efficient in preventing the progression of autoimmune insulitis in NOD mice, and amelioration of chronic colitis and graft versus host disease. The main mechanisms of disease suppression by killer Treg are: a) in the acute phase induction of apoptosis in effector cells at the site of inflammation decreases the pathogenic burden, and b) persistent increase in FoxP3+ Treg with variable CD25 co-expression induced by FasL sustains disease suppression over extended periods of time. Reduced sensitivity of Treg to receptor-mediated apoptosis under inflammatory conditions makes them optimal vehicles for targeted immunotherapy using apoptotic agents. PMID- 23684703 TI - Carbon monoxide-foe or friend? PMID- 23684704 TI - Sarcoidosis of the prostate. PMID- 23684706 TI - Aldosterone regulates Na(+), K(+) ATPase activity in human renal proximal tubule cells through mineralocorticoid receptor. AB - The mechanisms by which aldosterone increases Na(+), K(+) ATPase and sodium channel activity in cortical collecting duct and distal nephron have been extensively studied. Recent investigations demonstrate that aldosterone increases Na-H exchanger-3 (NHE-3) activity, bicarbonate transport, and H(+) ATPase in proximal tubules. However, the role of aldosterone in regulation of Na(+), K(+) ATPase in proximal tubules is unknown. We hypothesize that aldosterone increases Na(+), K(+) ATPase activity in proximal tubules through activation of the mineralocorticoid receptor (MR). Immunohistochemistry of kidney sections from human, rat, and mouse kidneys revealed that the MR is expressed in the cytosol of tubules staining positively for Lotus tetragonolobus agglutinin and type IIa sodium-phosphate cotransporter (NpT2a), confirming proximal tubule localization. Adrenalectomy in Sprague-Dawley rats decreased expression of MR, ENaC alpha, Na(+), K(+) ATPase alpha1, and NHE-1 in all tubules, while supplementation with aldosterone restored expression of above proteins. In human kidney proximal tubule (HKC11) cells, treatment with aldosterone resulted in translocation of MR to the nucleus and phosphorylation of SGK-1. Treatment with aldosterone also increased Na(+), K(+) ATPase-mediated (86)Rb uptake and expression of Na(+), K(+) ATPase alpha1 subunits in HKC11 cells. The effects of aldosterone on Na(+), K(+) ATPase-mediated (86)Rb uptake were prevented by spironolactone, a competitive inhibitor of aldosterone for the MR, and partially by Mifepristone, a glucocorticoid receptor (GR) inhibitor. These results suggest that aldosterone regulates Na(+), K(+) ATPase in renal proximal tubule cells through an MR dependent mechanism. PMID- 23684707 TI - Cyathostoma (Cyathostoma) phenisci Baudet, 1937 (Nematoda: Syngamidae), a parasite of respiratory tract of African penguin Spheniscus demersus: morphological and molecular characterisation with some ecological and veterinary notes. AB - Here we provide a morphological and molecular analysis of the taxonomic status of Cyathostoma (Cyathostoma) phenisci Baudet, 1937, a rare nematode parasite of African penguin Spheniscus demersus. Taxonomical evaluation is supplemented wi th ecological and epidemiological analysis of the nematode's occurrence in the African penguin's population. Tracheae and air sacs of 13 among the 94 necropsied birds (overall prevalence 13.8%) contained a total of 33 nematode specimens (20 females, 13 males). The highest prevalence was observed in juveniles (6 infected, 25%) and "blues" (6 infected, 14.3%), followed by nestlings (1 infected, 7.7%); no nematodes were found in adults. Our morphological and morphometric analysis shows that C. phenisci is closely related to another species, Cyathostoma (Cyathostoma) verrucosum (Hovorka & Macko, 1959). The doubtful status of the latter species was confirmed by molecular data: comparison of ITS2 sequence of C. phenisci with previously deposited sequences of C. verrucosum showed 96.3% similarity in this region. On this basis, we recognized Cyathostoma (Cyathostoma) verrucosum (Hovorka & Macko, 1959) as a synonym of Cyathostoma (Cyathostoma) phenisci Baudet, 1937. PMID- 23684705 TI - Modulation by Syk of Bcl-2, calcium and the calpain-calpastatin proteolytic system in human breast cancer cells. AB - Syk is a 72kDa non-receptor tyrosine kinase that is best characterized in hematopoietic cells. While Syk is pro-tumorigenic in some cancer cell types, it also has been reported as a negative regulator of metastatic cell growth in others. An examination of the RelA (p65) subunit of NF-kappaB expressed in MCF7 breast cancer cells indicated that either treatment with pervanadate or stable expression of Syk protected RelA from calpain-mediated proteolysis. Similar results were observed with the tyrosine phosphatase, PTP1B, another sensitive calpain substrate. The activity of calpain in MCF7 cell lysates was inhibited by both treatment with hydrogen peroxide and expression of Syk, the former due to oxidative inactivation of calpain and the latter to enhanced expression of calpastatin (CAST), the endogenous calpain inhibitor. The level of CAST was elevated in the cytosolic fraction of Syk-positive breast cancer cells resulting in more CAST present in complex with calpain in cell lysates. The high levels of CAST coincided with elevated basal levels of calcium-and of intracellular calpain activity-in Syk-expressing cells resulting from decreased levels of Bcl-2, an inhibitor of IP3-receptor-mediated calcium release. The inhibition of cellular calpain stimulated the Syk-mediated enhancement of NF-kappaB induced by TNF alpha, enhanced tyrosine phosphorylation resulting from integrin crosslinking, and increased the localization of Syk to the plasma membrane. PMID- 23684708 TI - Presence of Twist1-positive neoplastic cells in the stroma of chromosome-unstable colorectal tumors. AB - BACKGROUND & AIMS: Cancer cells undergo an epithelial-to-mesenchymal transition (EMT) to become invasive, allowing tumors to progress. However, there is no direct evidence that human cancer cells undergo an EMT. In mouse cancer cells, up regulation of transcription factor Twist1 was shown to promote an EMT. We searched the stroma of human colorectal tumor samples for TWIST1-positive cells with a mesenchymal phenotype and neoplastic genotype. METHODS: We measured the expression of TWIST1 in human colorectal cancer (CRC) cell lines and examined the effects of overexpression or knockdown in vitro and in mice. We used immunohistochemistry to measure levels of TWIST1 in 201 colorectal tumor samples. In 20 samples, immunostaining was combined with fluorescence in situ hybridization analyses. Levels of TWIST1 messenger RNA (mRNA) were measured in blood samples from 15 patients. RESULTS: TWIST1 was required to maintain the mesenchymal phenotype and invasiveness of the microsatellite-stable CoLo741 cells (which express endogenous TWIST1) and SW480 (expressing transgenic TWIST1). TWIST1 mRNA was not translated in CRC cells with microsatellite instability (HCT116). Syngenic TWIST1-positive colon carcinoma cells (CT26) that invaded tissues surrounding tumors acquired a mesenchymal phenotype. The presence of TWIST1-positive cells in the stroma of human colorectal tumors correlated with microsatellite stability (P = .05), stage IV cancer (P = .02), and disease-free survival time (P < .01). Trisomies of chromosome 7 and/or chromosome 20 were detected in 17 of 20 colorectal tumor samples, each of which contained TWIST1 positive cells with matching chromosomal gains in the tumor stroma (86 of 776 counted cells; 11.1%). No trisomy was observed in TWIST1-negative stromal cells (0 of 1249 cells; P < .001). Levels of TWIST1 mRNA were significantly higher in blood samples from patients with CRC than controls. CONCLUSIONS: The stroma of human colorectal tumors contains TWIST1-positive cancer cells with mesenchymal phenotypes. Patients with CRC have higher levels of TWIST1 mRNA than healthy individuals. PMID- 23684710 TI - COPD and gender differences: an update. AB - Chronic obstructive lung disease (COPD) is one of the most prevalent health conditions, and a major cause of morbidity and mortality around the globe. Once thought of primarily as a disease of men, COPD is now known to be increasingly prevalent among women. Although increasing tobacco consumption among women during the past several decades might explain some of this increase, the relationship may be more complex, including factors such as differential susceptibility to tobacco, anatomic and hormonal differences, behavioral differences, and differences in response to available therapeutic modalities. Moreover, women with COPD may present differently, may have a different pattern of comorbidities, and may have a better survival after acute exacerbations. Care providers continue to have a gender bias that may affect both diagnosis and treatment. Future work should focus on factors that lead to gender differences in COPD as well as gender specific treatment strategies. PMID- 23684709 TI - Fibrosis reduces severity of acute-on-chronic pancreatitis in humans. AB - BACKGROUND & AIMS: Acute pancreatitis (AP) and chronic pancreatitis (CP) share etiologies, but AP can be more severe and is associated with a higher rate of mortality. We investigated features of CP that protect against severe disease. The amount of intrapancreatic fat (IPF) is increased in obese patients and fibrosis is increased in patients with CP, so we studied whether fibrosis or fat regulate severity of AP attacks in patients with CP. METHODS: We reviewed records from the University of Pittsburgh Medical Center/Presbyterian Hospital Autopsy Database (1998-2008) for patients with a diagnosis of AP (n = 23), CP (n = 35), or both (AP-on-CP; n = 15). Pancreatic histology samples from these patients and 50 randomly selected controls (no pancreatic disease) were analyzed, and IPF data were correlated with computed tomography data. An adipocyte and acinar cell Transwell coculture system, with or without collagen type I, was used to study the effects of fibrosis on acinar-adipocyte interactions. We studied the effects of nonesterified fatty acids (NEFAs) and adipokines on acinar cells in culture. RESULTS: Levels of IPF were significantly higher in nonobese patients with CP than in nonobese controls. In patients with CP or AP-on-CP, areas of IPF were surrounded by significantly more fibrosis than in controls or patients with AP. Fat necrosis-associated peri-fat acinar necrosis (PFAN, indicated by NEFA spillage) contributed to most of the necrosis observed in samples from patients with AP; however, findings of peri-fat acinar necrosis and total necrosis were significantly lower in samples from patients with CP or AP-on-CP. Fibrosis appeared to wall off the fat necrosis and limit peri-fat acinar necrosis, reducing acinar necrosis. In vitro, collagen I limited the lipolytic flux between acinar cells and adipocytes and prevented increases in adipokines in the acinar compartment. This was associated with reduced acinar cell necrosis. However, NEFAs, but not adipokines, caused acinar cell necrosis. CONCLUSIONS: Based on analysis of pancreatic samples from patients with CP, AP, or AP-on-CP and in vitro studies, fibrosis reduces the severity of acute exacerbations of CP by reducing lipolytic flux between adipocytes and acinar cells. PMID- 23684711 TI - Sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with operable breast cancer and positive axillary nodes at initial diagnosis. AB - AIM: To evaluate the utility of the sentinel lymph node biopsy (SLNB) in patients with operable breast cancer and positive axillary nodes at initial diagnosis treated with neoadjuvant chemotherapy (NAC). MATERIAL AND METHODS: A prospective study was performed from January 2008 to December 2012 in 52 women, mean age 50.7 years, with infiltrating breast carcinoma T1-3, N1, M0 (1 bilateral, 7 multifocal) treated with epirubicin/cyclophosphamide, docetaxel and trastuzumab in Her2/neu-positive patients. Axillary evaluation included physical examination, axillary ultrasound, and ultrasound-guided core needle biopsy of any suspicious lymph node. The day before surgery, 74-111 MBq of (99m)Tc-albumin nanocolloid was injected periareolarly. All patients underwent breast surgery, with SLNB and complete axillary lymph node dissection (ALND). The SLNs were examined by frozen sections, hematoxylin-eosin staining, immunohistochemical analysis or one-step nucleic acid amplification assay (OSNA). RESULTS: Mean tumor size: 3.5 cm. Histologic type: 81.1% invasive ductal carcinoma. Complete response of primary tumor was clinical 43.4%, pathological 41.5%. All patients were clinically node negative after NAC. Pathological complete response of axillary node was 42.2%. SLN identification rate was 84.9%. Axilla was positive in the pathology study in 6 of 8 patients without nanocolloid migration. SLN accurately represented the axillary status in 95.5%. False negative rate was 8.3%. SLN was the only positive node in 68.2% of patients. Mean number of SLN removed was 1.9 and of nodes resected from the ALND 13.2. CONCLUSION: SLN biopsy after NAC is a feasible and accurate tool in patients with operable breast cancer T1-3, N1 and clinically node-negative after therapy. PMID- 23684712 TI - Measuring input synchrony in the Ornstein-Uhlenbeck neuronal model through input parameter estimation. AB - We present a method of estimating the input parameters and through them, the input synchrony, of a stochastic leaky integrate-and-fire neuronal model based on the Ornstein-Uhlenbeck process when it is driven by time-dependent sinusoidal input signal and noise. By driving the neuron using sinusoidal inputs, we simulate the effects of periodic synchrony on the membrane voltage and the firing of the neuron, where the peaks of the sine wave represent volleys of synchronised input spikes. Our estimation methods allow us to measure the degree of synchrony driving the neuron in terms of the input sine wave parameters, using the output spikes of the model and the membrane potential. In particular, by estimating the frequency of the synchronous input volleys and averaging the estimates of the level of input activity at corresponding intervals of the input signal, we obtain fairly accurate estimates of the baseline and peak activity of the input, which in turn define the degrees of synchrony. The same procedure is also successfully applied in estimating the baseline and peak activity of the noise. This article is part of a Special Issue entitled Neural Coding 2012. PMID- 23684713 TI - Expression and cell distribution of myeloid differentiation primary response protein 88 in the cerebral cortex following experimental subarachnoid hemorrhage in rats: a pilot study. AB - Subarachnoid hemorrhage (SAH) which is mostly caused by aneurysm rupture causes a lot of death every year. Convincing evidence can be made that inflammation contributes to the poor outcome caused by SAH. Toll like receptors (TLRs), nuclear factor-kappaB (NF-kappaB), Interleukin 1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are involved in the damaging inflammation process after SAH. Myeloid differentiation primary response protein 88 (MyD88) is essential to deliver TLRs signals down to NF-kappaB and pro-inflammatory factors. The study aims to detect the expression level of MyD88 and know more about the role of MyD88 after SAH. Sprague Dawley (SD) rats were randomly divided into sham group and SAH groups at 2h, 6h, 12h and on day 1, day 2, day 3, day 5 and day 7. SAH groups suffered experimental subarachnoid hemorrhage by injection of 0.3 ml autoblood into the prechiasmatic cistern. MyD88 expression is measured by western blot analysis, real-time polymerase chain reaction (PCR), immunohistochemistry and immunofluorescence. The levels of TNF-alpha and IL-1beta were measured by real-time PCR. Our results demonstrated MyD88 expression was increased after SAH, and peaked on day 1 and day 5, which showed a parallel time course to the up regulation of IL-1beta, there was a highly positive relationship between them. Immunohistochemistry and immunofluorescence results indicated up-regulated MyD88 was mainly located in neurons while over expressed MyD88 could also be found in astrocytes and microglia. These results might have important implications during the administration of specific MyD88 antagonists in order to prevent or reduce inflammatory response following SAH. PMID- 23684714 TI - On the precision of neural computation with interaural level differences in the lateral superior olive. AB - Interaural level difference (ILD) is one of the basic binaural clues in the spatial localization of a sound source. Due to the acoustic shadow cast by the head, a sound source out of the medial plane results in an increased sound level at the nearer ear and a decreased level at the distant ear. In the mammalian auditory brainstem, the ILD is processed by a neuronal circuit of binaural neurons in the lateral superior olive (LSO). These neurons receive major excitatory projections from the ipsilateral side and major inhibitory projections from the contralateral side. As the sound level is encoded predominantly by the neuronal discharge rate, the principal function of LSO neurons is to estimate and encode the difference between the discharge rates of the excitatory and inhibitory inputs. Two general mechanisms of this operation are biologically plausible: (1) subtraction of firing rates integrated over longer time intervals, and (2) detection of coincidence of individual spikes within shorter time intervals. However, the exact mechanism of ILD evaluation is not known. Furthermore, given the stochastic nature of neuronal activity, it is not clear how the circuit achieves the remarkable precision of ILD assessment observed experimentally. We employ a probabilistic model and complementary computer simulations to investigate whether the two general mechanisms are capable of the desired performance. Introducing the concept of an ideal observer, we determine the theoretical ILD accuracy expressed by means of the just-noticeable difference (JND) in dependence on the statistics of the interacting spike trains, the overall firing rate, detection time, the number of converging fibers, and on the neural mechanism itself. We demonstrate that the JNDs rely on the precision of spike timing; however, with an appropriate parameter setting, the lowest theoretical values are similar or better than the experimental values. Furthermore, a mechanism based on excitatory and inhibitory coincidence detection may give better results than the subtraction of firing rates. This article is part of a Special Issue entitled Neural Coding 2012. PMID- 23684715 TI - Population coding is essential for rapid information processing in the moth antennal lobe. AB - We investigated how odorant information is transmitted by neurons in the moth antennal lobe (AL). The neurons were repeatedly stimulated by three different odorants and their activity was intracellularly recorded. First, the response properties of single neurons were analyzed. The neurons exhibited highly reliable responses to the odorants and 43% of AL neurons responded to two or three odorants. The population distribution of firing rates in response to odorant stimulation was relatively broad in moth AL neurons, which is consistent across insects. Second, we attempted to decode the odorant identity from the activity of the recorded neurons using the maximum likelihood method. The decoding performance rapidly improves with increasing the number of neurons. Notably, an increase in the size of neural population results in faster transfer of information and increased the duration to retain odorant information. In conclusion, the AL neurons encode odorant information reliably and the population coding can transmit odorant information to olfactory centers. Population coding allows AL to encode and transmit olfactory information faster than the discrimination latency demonstrated in behavioral experiments. This article is part of a Special Issue entitled Neural Coding 2012. PMID- 23684716 TI - Predictors of $4 generic prescription drug discount programs use in the low income population. AB - BACKGROUND: Generic drug discount programs (GDDPs) are an option to provide affordable prescription medication to low-income individuals. However, the factors that influence the use of GDDPs in low-income population are unknown. OBJECTIVES: To evaluate factors associated with utilization of generic a drug discount program in a low-income population. METHODS: A survey was administered to adult participants at health centers and community-based organizations in Houston, Texas, USA (n = 525). Exploratory factor analysis was conducted to determine the construct validity of the survey instrument and to assess distinct factors associated with GDDP utilization. Descriptive statistics were used to summarize the distribution of patient socio-demographic characteristics and questionnaire responses. Multivariate logistic regression was used to compute adjusted odds ratios and to examine the strength of association with GDDP utilization after adjusting for participant socio-demographic features that were statistically significant at a priori level of P < 0.05. RESULTS: In this study, 72% of respondents were aware of the GDDP, and 61% had utilized the GDDP. Participants were 4 times likely to use a GDDP when their physician (AOR: 4.0, 95% CI: 2.6-6.4, P < 0.001) or pharmacist (AOR: 4.0, 95% CI: 2.6-6.3, P < 0.001) talked to them about it. Participants indicated that the most important barriers to utilization of GDDPs were lack of awareness (44%), and lack of recommendation by a physician (19%). CONCLUSIONS: Increased patient awareness and physician recommendation may increase the use of GDDPs, which may lead to improved compliance with medications, better health outcomes and reduced health care costs. PMID- 23684717 TI - Advances in microalgae engineering and synthetic biology applications for biofuel production. AB - Among the technologies being examined to produce renewable fuels, microalgae are viewed by many in the scientific community as having the greatest potential to become economically viable. Algae are capable of producing greater than 50,000 kg/acre/year of biomass [1]. Additionally, most algae naturally accumulate energy dense oils that can easily be converted into transportation fuels. To reach economic parity with fossil fuels there are still several challenges. These include identifying crop protection strategies, improving harvesting and oil extraction processes, and increasing biomass productivity and oil content. All of these challenges can be impacted by genetic, molecular, and ultimately synthetic biology techniques, and all of these technologies are being deployed to enable algal biofuels to become economically competitive with fossil fuels. PMID- 23684718 TI - Carthamus red from Carthamus tinctorius L. exerts antioxidant and hepatoprotective effect against CCl(4)-induced liver damage in rats via the Nrf2 pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Carthamus red isolated from safflower (Carthamus tinctorius L., a Chinese traditional medicine) is evaluated for antioxidant and hepatoprotective activity. MATERIALS AND METHODS: Carthamus red was isolated from a Na2CO3 extract of safflower and its analysis was carried out by HPLC/MS. Acute toxicity study was determined and the antioxidant activity was investigated using various established in vitro systems. An in vivo study against CCl4-induced liver injury was also conducted and compared with that of silymarin, a known hepatoprotective drug. RESULTS: Carthamus red did not show any toxicity and mortality up to 2000mg/kg dose, and it showed strong antioxidant ability in vitro. In the in vivo study, carthamus red treatment lowered the serum levels of ALT, AST, ALP and total protein in liver damage rat models. Meanwhile, Nrf2, GSTalpha and NQO1 expressions were up-regulated at the protein level by carthamus red intervention. Additionally, the activities of antioxidant enzymes and level of GSH were elevated by carthamus red intervention, while the content of TBARS, which is an oxidative stress marker, was lessened. HE stain analysis showed that the condition of liver damage was mitigated. CONCLUSION: This study demonstrates that carthamus red may serve as a candidate with strong a hepatoprotective effect and antioxidant activity in liver damage. PMID- 23684719 TI - The cultural-bound disease "empacho" in Argentina. A comprehensive botanico historical and ethnopharmacological review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Empacho is one of the most recognized cultural bound syndromes in Argentina. It is a digestive disorder with many causes, being excessive food intake the most frequent. It is easily diagnosed in household medicine and there are different treatments applied for releasing the obstruction of the gastrointestinal tract. Therapeutics includes the use of medicinal plants and abdominal maneuvers, as well as rituals of magical and/or religious nature. The aim of this work is to analyze the compiled literature, considering documents from the XVIIIth century up to present, related to the employed plant species for the treatment of empacho. MATERIAL AND METHODS: The bibliographic and journal collections of several Argentinean and foreign libraries and bookstores were consulted, in addition to the comprehensive review of the specific information found online. RESULTS: Ninety (90) primary sources, spanning three hundred years (from 1710 to 2010) were found; most of them included ethnobotanical studies besides others of medical botany, pharmacobotanical and anthropological origin. A total of 152 plant species used to treat empacho were found in 360 total quotations, being Dysphania ambrosioides (L.) Mosyakin and Clemants; Alternanthera pungens Kunth; Ruta chalepensis L.; Clinopodium gilliesii (Benth.) Kuntze; Aloysia polystachya (Griseb.) Moldenke; Lippia turbinata Griseb., and Pluchea sagittalis (Lam.) Cabrera, the most frequently mentioned. The main therapeutic properties of the medicinal plants cited against empacho are stomachic, purgative, antispasmodic, bitter-tonic, carminative, and cholagogue choleretic. CONCLUSIONS: The variety of regions - spanning most of the country - from which the information comes, as well as the great variety of therapeutic strategies used, diversity of plant species and knowledge related to the treatment of empacho, is directly associated with the great significance that this disorder has within the system of medical-nosologic representations of the Argentinean popular medicine. PMID- 23684720 TI - Antimicrobial activity of Schinus lentiscifolius (Anacardiaceae). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Schinus lentiscifolius Marchand (syn. Schinus weinmannifolius Engl) is a plant native to Rio Grande do Sul (Southern Brazil) and has been used in Brazilian traditional medicine as antiseptic and antimicrobial for the treatment of many different health problems as well as to treat leucorrhea and to assist in ulcer and wound healing. Although it is a plant widely used by the population, there are no studies proving this popular use. MATERIAL AND METHODS: The crude aqueous extract, the crude neutral methanol extract, fractions prepared from this extract (n-hexane, ethyl acetate, and n butanol), pure compounds isolated from these fractions, and derivatives were investigated in vitro for antimicrobial activities against five Gram positive bacteria: Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus pyogenes, three Gram negative bacteria: Escherichia coli, Pseudomonas aeruginosa, and Shigella sonnei, and four yeasts: Candida albicans, Candida tropicalis, Cryptococcus neoformans, and Saccharomyces cerevisiae. The isolated compound moronic acid, which is the most active, was tested against a range of other bacteria such as two Gram positive bacteria, namely, Bacillus cereus, Enterococcus spp, and six Gram negative bacteria, namely, Burkholderia cepacia, Providencia stuartii, Morganella morganii, Enterobacter cloacae, Enterobacter aerogenes, and Proteus mirabilis. RESULTS: The leaf aqueous extract (decoction) of Schinus lentiscifolius showed a broad spectrum of antibacterial activity, ranging from 125 to 250 MUg/ml (MIC) against the tested bacteria and fungi. The n-hexane extract, despite being very little active against bacteria, showed an excellent antifungal activity, especially against Candida albicans (MIC=25 MUg/ml), Candida tropicalis (MIC=15.5 MUg/ml), and Cryptococcus neoformans, (MIC=15.5 MUg/ml). From the acetate fraction (the most active against bacteria), compounds 1-6 were isolated: nonadecanol (1), moronic acid (2), gallic acid methyl ester (3), gallic acid (4), quercetin (5) and quercitrin (6). The minimal inhibitory concentration (MIC) of moronic acid between 1.5 and 3 MUg/ml against most of the tested bacteria shows that it is one of the metabolites responsible for the antibacterial activity of Schinus lentiscifolius. CONCLUSION: The antimicrobial activity and some constituents of Schinus lentiscifolius are reported for the first time. The results of the present study provide scientific basis for the popular use of Schinus lentiscifolius for a number of different health problems. PMID- 23684721 TI - Identifying core herbal treatments for urticaria using Taiwan's nationwide prescription database. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Urticaria is a common skin disease that has a high impact on a patient's daily life. Chinese herbal medicine (CHM) has been frequently used for treatment of skin manifestations in addition to Western medicine. The aim of this study is to analyze a nationwide prescription database to explore the most commonly used CHM for urticaria. MATERIALS AND METHODS: A nationwide CHM prescription database was used, and data from ambulatory visits of patients with a single diagnosis of urticaria (ICD-9 code: 708) were identified for the study. Association rule mining was applied to explore the core formula and popular combinations of CHM for urticaria. RESULTS: A total of 33,355 ambulatory visits made by 12,498 patients were included in this study. On average, 6.18 CHMs were used per prescription. Xiao Feng San (XFS) and Cryptotympana pustulata Fabricius were the most commonly used herbal formula (HF) and single herb (SH), found in 49.44% and 24.67% of all prescriptions, respectively. XFS with Cryptotympana pustulata Fabricius were used most frequently in a two-combination CHM (9.95%). Moreover, XFS with Kochia scoparia (L.) Schrad. plus Dictamnus dasycarpus Turcz. were the most frequent three combination CHM (3.46%). XFS was the core formula for urticaria since it was included in nearly all combinations prescribed for the treatment of urticaria. CONCLUSIONS: XFS is the most important core herbal treatment used for urticaria in Taiwan, and Cryptotympana pustulata Fabricius with XFS is the most popular combination. Further well-designed clinical trials and animal model studies for urticaria are still needed to explore the efficacy and mechanism of CHM in urticaria. PMID- 23684722 TI - Physalin A induces apoptosis via p53-Noxa-mediated ROS generation, and autophagy plays a protective role against apoptosis through p38-NF-kappaB survival pathway in A375-S2 cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Physalin A is a bioactive withanolide isolated from natural plant Physalis alkekengi L. var. franchetii (Mast.) Makino, a traditional Chinese herbal medicine named Jindenglong which has long been used for the treatment of cough, sore throat, hepatitis, eczema, dysuria and tumors in China. AIM OF THE STUDY: Based on the previous study that physalin A induced cytotoxic effect in human melanoma A375-S2 cells, this study was designed to further illustrate the molecular mechanisms underlying. MATERIALS AND METHODS: Cell viability was evaluated in A375-S2 cells by MTT assay, and the mechanisms involved in physalin A-induced A375-S2 cell death were investigated by phase contrast microscopy and fluorescence microscopy, siRNA transfection, flow cytometry and western blot analysis. RESULTS: We demonstrated that physalin A decreased the proportion of viable A375-S2 cells in a time- and dose-dependent manner, and exposure of A375-S2 cells to physalin A led to both apoptosis and autophagy. Moreover, physalin A-induced apoptosis was triggered by activation of p53-Noxa pathway and intracellular reactive oxygen species (ROS) generation. The administration of ROS scavengers NAC and GSH resulted in the complete inhibition of physalin A-induced ROS generation and apoptosis. Application of p53 inhibitor PFT-alpha or transfection with Noxa-siRNA could also lead to the same results. Autophagy, demonstrated by the punctuate distribution of monodansylcadaverine staining, as well as the change of LC3-II/LC3-I proportion and Beclin 1 activation, played a protective role against apoptosis via up-regulation of the p38-NF-kappaB survival pathway in A375-S2 cells. Additionally, inhibition of autophagy by the specific autophagic inhibitor 3MA or blocking the p38-NF-kappaB pathway with p38 inhibitor SB203580 or NF-kappaB inhibitor PDTC obviously promoted physalin A-induced apoptosis. CONCLUSIONS: Physalin A induced apoptotic cell death via p53-Noxa-mediated ROS generation, and autophagy played a protective role against apoptosis through up-regulating the p38-NF-kappaB survival pathway in A375-S2 cells. These results stated the possibility that physalin A would be a potential agent for the treatment of melanoma in the future. PMID- 23684723 TI - Conjunctival instillation of plasminogen eliminates ocular lesion in B6.129P2 Plg(tm1Jld) transgenic mice, a model of ligneous conjunctivitis. AB - Ligneous conjunctivitis is a severe and rare chronic "idiopathic membraneous" conjunctivitis, characterized by the formation of pseudomembranes mostly on the palpebral surfaces that progressively replace the normal mucosa. Evidence has been provided that ligneous conjunctivitis is caused by a severe systemic plasminogen deficiency with decreased plasminogen antigen and decreased plasminogen functional activities. Objective of the present study is to verify the hypothesis that a topical eye application of plasminogen is able to ameliorate the consequences of this disease. Here we report the results of pre clinical studies performed to investigate the therapeutic effectiveness of an eye drop plasminogen preparation in B6.129P2-Plg(tm1Jld) transgenic mice, a model of ligneous conjunctivitis. The entity of protection mediated by plasminogen was evaluated by measuring the extent of the eye lesion by means of a computerized system and dedicated software. The results of the present study clearly showed that the administration for six times a day of plasminogen eye-drop solution in the lesioned eye of animals knock-out for plasminogen gene and developing ligneous conjunctivitis caused a dose and time related reduction of the extent of the ocular lesion. These findings may pave the road for the pharmacological treatment of the ocular lesion associated to the ligneous conjunctivitis that at the present is surgically treated by removing the pseudomembranes generated on the eye. PMID- 23684724 TI - Restrictions to protein folding determined by the protein size. AB - Experimentally measured rates of spontaneous folding of single-domain globular proteins range from microseconds to hours: the difference (11 orders of magnitude!) is akin to the difference between the life span of a mosquito and the age of the Universe. We show that physical theory with biological constraints outlines the possible range of folding rates for single-domain globular proteins of various size and stability, and that the experimentally measured folding rates fall within this narrow "golden triangle" built without any adjustable parameters, filling it almost completely. This "golden triangle" also successfully predicts the maximal allowed size of the "foldable" protein domains, as well as the maximal size of protein domains that fold under solely thermodynamic (rather than kinetic) control. In conclusion, we give a phenomenological formula for dependence of the folding rate on the size, shape and stability of the protein fold. PMID- 23684725 TI - Synthesis and evaluation of degradable polyurea block copolymers as siRNA delivery agents. AB - Chain extension by diisocyanate condensation provides a versatile and convenient means for preparing block copolymers. We have utilized this chemistry to prepare reducible multiblock polycations for siRNA delivery. This approach, an alternative to oxidative coupling, was suitable for preparing multiblock polycations with defined molecular weight and architecture. The polymer, PEG-b multi-(polyhexylurea-co-oligo-L-lysine)-b-PEG, was capable of electrostatically condensing siRNA to form nano-sized polyplexes across a broad compositional range. We demonstrated that the polyplexes enter the cells via endocytosis and interact with the endosome membrane leading to destabilization and hence endosome escape. Another feature of these polymers is their multiple intra-chain disulfide linkages. This enables weakening of the polyplex via chain scission within the cytosol's reductive environment. In addition to the controlled preparation of the polymer, the polyplexes were capable of delivering siRNA in vitro to silence greater than 50% green fluorescent protein expression with negligible toxicity. PMID- 23684726 TI - Morphine dependence is associated with changes in neuropeptide S receptor expression and function in rat brain. AB - Neuropeptide S (NPS) is a newly identified ligand for the previously discovered G protein coupled receptor 154 now named NPSR. Recently, it has been found that NPSR gene expression is altered during ethanol withdrawal. In this study we tried to elucidate if NPSR gene expression is modified in response to morphine withdrawal and its protracted abstinence. To induce opioid dependence Wistar rats were treated for 7 days with morphine. Twelve hours and 7 days after the last morphine administration brains were removed and the expression of NPSR mRNA was analyzed by in situ hybridization (ISH). Successful induction of opioid dependence was confirmed by the naloxone-precipitated withdrawal test 2 h after the last morphine administration. Moreover, 7 days after the last morphine dose animals were checked for signs of anxiety and for intracerebroventricular (ICV) NPS (0.3 and 1.0 nmol) induced anxiolytic effects by elevated plus maze (EPM). Results showed that in morphine treated rats strong somatic signs of naloxone precipitated withdrawal occurred. ISH data revealed changes in NPSR gene expression in the ventral tegmental area as well as in the basolateral amygdaloid and bed nucleus of stria terminalis at 12 h and 7 days into abstinence, respectively. At 7 days into abstinence post dependent animals showed higher levels of anxiety than controls which were significantly attenuated by NPS. These results demonstrated that morphine dependence induction led to (i) changes in NPSR mRNA expression; (ii) increased anxiety; and (iii) more potent anxiolytic like effect of NPS. PMID- 23684727 TI - Identification of 11 new exoproteins in Corynebacterium pseudotuberculosis by comparative analysis of the exoproteome. AB - This study involves the comparison between the exoproteomes of two different strains of Corynebacterium pseudotuberculosis, the etiologic agent of caseous lymphadenitis in small ruminants. In a previous study, based on a gel-free system (TPP-LC/MS(E)), 70 exoproteins for the strain 1002 and 67 for the strain C231, totaling 93 different extracellular proteins for C. pseudotuberculosis, were identified. In the present work, we have used 2D gel electrophoresis to resolve the extracellular proteins of both strains, which were then digested with trypsin, analyzed by MALDI-TOF/TOF and identified with the software MASCOT((r)). A total of 45 extracellular proteins of C. pseudotuberculosis were identified by this approach. The comparative analysis between the strains 1002 and C231 identified 13 and 3 strain-specific proteins, respectively, 11 of which are novel. These newly identified proteins may play an important role in the physiology and virulence of C. pseudotuberculosis. PMID- 23684728 TI - Anti-Aspergillus activity of green coffee 5-O-caffeoyl quinic acid and its alkyl esters. AB - The antifungal activities of 5-O-caffeoyl quinic acid (5-CQA) and of methyl, butyl, octyl, and dodecyl esters or 5-CQA, were tested on five toxigenic moulds from the Aspergillus genus (Aspergillus flavus, Aspergillus nomius, Aspergillus ochraceus, Aspergillus parasiticus, Aspergillus westerdijkiae). These mycotoxin producers' moulds may contaminate many types of food crops throughout the food chain posing serious health hazard to animals and humans. The use of chemical methods to decrease mycotoxin producer moulds contamination on food crops in the field, during storage, and/or during processing, has been proved to be efficient. In this work, the antifungal effect of 5-CQA and a homologous series of 5-CQA esters (methyl, butyl, octyl, dodecyl), was investigated using the microdilution method and the minimum inhibitory concentrations (MIC50 and MIC80). All molecules presented antifungal activity, and two esters showed a MIC for all fungi: octyl (MIC50 <= 0.5-0.75 mg/mL, MIC80 = 1.0-1.5 mg/mL) and dodecyl (MIC50 = 0.75-1.25 mg/mL) chlorogenates. Dodecyl chlorogenate showed a MIC80 (1.5 mg/mL) only for A. parasiticus. The maximum percent of growth inhibition on aspergillii was observed with octyl (78.4-92.7%) and dodecyl (54.5-83.7%) chlorogenates, being octyl chlorogenate the most potent antifungal agent. It was thus concluded that lipophilization improved the antifungal properties of 5-CQA, which increased with the ester alkyl chain length, exhibiting a cut-off effect at 8 carbons. As far as we know, it is the first report demonstrating that lipophilization may improve the antifungal activity of 5-CQA on five toxigenic moulds from the Aspergillus genus. Lipophilization would be a novel way to synthesize a new kind of antifungal agents with a good therapeutic value or a potential use as preservative in food or cosmetics. PMID- 23684729 TI - Optimality in evolution: new insights from synthetic biology. AB - Whether organisms evolve to perform tasks optimally has intrigued biologists since Lamarck and Darwin. Optimality models have been used to study diverse properties such as shape, locomotion, and behavior. However, without access to the genetic underpinnings or the ability to manipulate biological functions, it has been difficult to understand an organism's intrinsic potential and limitations. Now, novel experiments are overcoming these technical obstacles and have begun to test optimality in more quantitative terms. With the use of simple model systems, genetic engineering, and mathematical modeling, one can independently quantify the prevailing selective pressures and optimal phenotypes. These studies have given an exciting view into the evolutionary potential and constraints of biological systems, and hold the promise to further test the limits of predicting future evolutionary change. PMID- 23684730 TI - RNAi and antiviral defense in Drosophila: setting up a systemic immune response. AB - RNA interference (RNAi) controls gene expression in eukaryotic cells and thus, cellular homeostasis. In addition, in plants, nematodes and arthropods it is a central antiviral effector mechanism. Antiviral RNAi has been well described as a cell autonomous response, which is triggered by double-stranded RNA (dsRNA) molecules. This dsRNA is the precursor for the silencing of viral RNA in a sequence-specific manner. In plants, systemic antiviral immunity has been demonstrated, however much less is known in animals. Recently, some evidence for a systemic antiviral response in arthropods has come to light. Cell autonomous RNAi may not be sufficient to reach an efficient antiviral response, and the organism might rely on the spread and uptake of an RNAi signal of unknown origin. In this review, we offer a perspective on how RNAi-mediated antiviral immunity could confer systemic protection in insects and we propose directions for future research to understand the mechanism of RNAi-immune signal sorting, spreading and amplification. PMID- 23684731 TI - Kinematics and muscle activities of the lumbar spine during and after working in stooped postures. AB - Existing biomechanical evidence suggests mechanisms of low back injuries and disorders associated with prolonged stooping. However, no research has tested realistic and more natural stooped work conditions with human subjects in the investigation of the biomechanical responses of the low back in prolonged stooping. The current study was aimed to explore various biomechanical responses of the low back in more realistic and work-related loading and posture conditions of prolonged stooping. Twenty two subjects performed stooped work tasks for 7min with periodic micro-breaks in upright standing, and various measures for assessing biomechanical responses of the low back were obtained before, during and immediately after the stooped work period. Study results found significant increases (p<0.05) in the range of lumbar flexion and myoelectric activation of the low back muscles after the stooped work period. During stooped work, the low back extensor muscles did not show flexion-relaxation. It could be concluded that the natural and unrestricted stooped work conditions produced similar viscoelastic responses of the low back to what more severe stooping conditions with posture restrictions did in previous research, but could be more fatigue prone due to low but consistent activation of the low back extensor muscles during stooped work activities. PMID- 23684733 TI - Application of alpha/theta neurofeedback and heart rate variability training to young contemporary dancers: state anxiety and creativity. AB - As one in a series on the impact of EEG-neurofeedback in the performing arts, we set out to replicate a previous dance study in which alpha/theta (A/T) neurofeedback and heart rate variability (HRV) biofeedback enhanced performance in competitive ballroom dancers compared with controls. First year contemporary dance conservatoire students were randomised to the same two psychophysiological interventions or a choreology instruction comparison group or a no-training control group. While there was demonstrable neurofeedback learning, there was no impact of the three interventions on dance performance as assessed by four experts. However, HRV training reduced anxiety and the reduction correlated with improved technique and artistry in performance; the anxiety scale items focussed on autonomic functions, especially cardiovascular activity. In line with the putative impact of hypnogogic training on creativity A/T training increased cognitive creativity with the test of unusual uses, but not insight problems. Methodological and theoretical implications are considered. PMID- 23684732 TI - Colon tumour secretopeptidome: insights into endogenous proteolytic cleavage events in the colon tumour microenvironment. AB - The secretopeptidome comprises endogenous peptides derived from proteins secreted into the tumour microenvironment through classical and non-classical secretion. This study characterised the low-Mr (<3kDa) component of the human colon tumour (LIM1215, LIM1863) secretopeptidome, as a first step towards gaining insights into extracellular proteolytic cleavage events in the tumour microenvironment. Based on two biological replicates, this secretopeptidome isolation strategy utilised differential centrifugal ultrafiltration in combination with analytical RP-HPLC and nanoLC-MS/MS. Secreted peptides were identified using a combination of Mascot and post-processing analyses including MSPro re-scoring, extended feature sets and Percolator, resulting in 474 protein identifications from 1228 peptides (<=1% q-value, <=5% PEP) - a 36% increase in peptide identifications when compared with conventional Mascot (homology ionscore thresholding). In both colon tumour models, 122 identified peptides were derived from 41 cell surface protein ectodomains, 23 peptides (12 proteins) from regulated intramembrane proteolysis (RIP), and 12 peptides (9 proteins) generated from intracellular domain proteolysis. Further analyses using the protease/substrate database MEROPS, (http://merops.sanger.ac.uk/), revealed 335 (71%) proteins classified as originating from classical/non-classical secretion, or the cell membrane. Of these, peptides were identified from 42 substrates in MEROPS with defined protease cleavage sites, while peptides generated from a further 205 substrates were fragmented by hitherto unknown proteases. A salient finding was the identification of peptides from 88 classical/non-classical secreted substrates in MEROPS, implicated in tumour progression and angiogenesis (FGFBP1, PLXDC2), cell cell recognition and signalling (DDR1, GPA33), and tumour invasiveness and metastasis (MACC1, SMAGP); the nature of the proteases responsible for these proteolytic events is unknown. To confirm reproducibility of peptide fragment abundance in this study, we report the identification of a specific cleaved peptide fragment in the secretopeptidome from the colon-specific GPA33 antigen in 4/14 human CRC models. This improved secretopeptidome isolation and characterisation strategy has extended our understanding of endogenous peptides generated through proteolysis of classical/non-classical secreted proteins, extracellular proteolytic processing of cell surface membrane proteins, and peptides generated through RIP. The novel peptide cleavage site information in this study provides a useful first step in detailing proteolytic cleavage associated with tumourigenesis and the extracellular environment. This article is part of a Special Issue entitled: An Updated Secretome. PMID- 23684734 TI - Autonomic correlates of physical and moral disgust. AB - Given that the hypothesis of a common origin of physical and moral disgust has received sparse empirical support, this study aimed to shed light on the subjective and autonomic signatures of these two facets of the same emotional response. Participants (20 men, 20 women) were randomly assigned to physical or moral disgust induction by the use of audio scripts while their electrocardiogram was continuously recorded. Affect ratings were obtained before and after the induction. Time and frequency domain heart rate variability (HRV) measures were obtained. After controlling for disgust sensitivity (DS-R) and obsessive compulsive (OCI-R) tendencies, both scripts elicited disgust but whereas the physical script elicited a feeling of dirtiness, the moral script evoked more indignation and contempt. The disgust-induced subjective responses were associated with opposite patterns of autonomic reactivity: enhanced activity of the parasympathetic nervous system without concurrent changes in heart rate (HR) for physical disgust and decreased vagal tone and increased HR and autonomic imbalance for moral disgust. Results suggest that immorality relies on the same biological root of physical disgust only in subjects with obsessive compulsive tendencies. Disgust appears to be a heterogeneous response that varies based on the individuals' contamination-based appraisal. PMID- 23684735 TI - Predictive value and discriminant capacity of cepstral- and spectral-based measures during continuous speech. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study was to determine the relative strength of various cepstral- and spectral-based measures for predicting dysphonia severity and differentiating voice quality types. STUDY DESIGN: Prospective, quasi-experimental research design. METHODS: Twenty-eight dysphonic speakers and 14 normal speakers were included in this study. Among the dysphonic speakers, 14 had a predominant voice quality of breathiness and 14 had a predominant voice quality of roughness. Cepstral and spectral analyses of the first and second sentences of the Rainbow passage were performed, along with perceptual ratings of overall dysphonia severity. Linear regression was performed to determine the predictive capacity of each variable for dysphonia severity, and discriminant analysis determined the combination of variables that optimally differentiated the three voice quality types. RESULTS: A four-factor model that incorporated the cepstral- and spectral-based measures produced an R value of 0.899, explaining 81% of the variance in auditory-perceptual dysphonia severity. Cepstral peak prominence (CPP) showed the greatest predictive contribution to dysphonia severity in the regression model. The discriminant analysis produced two discriminant functions that included both CPP and its standard deviation (CPP SD) as significant contributors (P < 0.001), with an overall classification accuracy for the combined functions of 79%. CONCLUSIONS: Acoustic measures reflecting the distribution of harmonic energy and low- to high-frequency energy in continuous speech, along with the variability (standard deviations) of each, were highly predictive of dysphonia severity when combined in a multivariate linear model. Cepstral-based measures showed the highest capacity to discriminate voice quality types, with better classification accuracy for normal and dysphonic breathy than for dysphonic-rough voices. PMID- 23684736 TI - The glutathione-related detoxication responses to juvenile and ecdysone hormones in Galleria mellonella. AB - The effect of 20-hydroxyecdysone (20E) and juvenile hormone (JH) on the glutathione pathway of the greater wax moth Galleria mellonella (Lepidoptera: Pyralidae) was determined by investigating glutathione peroxidase (GSH-Px), glutathione S-transferases (GST), and glutathione reductase (GR) activities as well as reduced and oxidized glutathione (GSH and GSSG) content with respect to developmental stage. The continuous decreases of GSH-Px and GST activities dependent on the growth period of G. mellonella occurred in JH and 20E groups over and under their controls, respectively. While the GR activities of G. mellonella showed increases in young pupa (YP) for both control and in old larvae (OL) for the 20E groups after the minimum at these periods, they also increased after old pupa (OP) for the JH group with a maximum in OL period. Although GR activity levels in the JH group were significantly higher compared with controls and 20E groups up to OP period, the activity levels for the control and 20E groups were higher than those of the JH group at adult (AD) and old pupa (OP) periods, respectively. In spite of increases in the GR activity of 20E and control groups of G. mellonella, decreased GSH and increased GSSG levels were observed at aging period. GSH levels in the JH group reached a maximum at prepupa (PP) and then decreased with non-significant changes from OL to AD period. According to the results, GSH and GSSG levels, as well as GSH/GSSG ratios, were below and over control levels in 20E and JH groups, respectively, during all of the investigated developmental stages. On the contrary, the LPO levels were higher than the control for 20E and lower for the JH groups during the developmental period. These results show that while ecdysone hormone has a negative effect on the glutathione-related detoxication capacity of G. mellonella, the juvenile hormone has a positive effect on this process. PMID- 23684737 TI - Reactive oxygen species and anti-oxidant defenses in tail of tadpoles, Xenopus laevis. AB - Tail regression in tadpoles is one of the most spectacular events in anuran metamorphosis. Reactive oxygen species and oxidative stress play an important role during this process. Presently, the cell- and tissue-specific localization of antioxidant enzymes such as superoxide dismutase (SOD) and catalase as well as neuronal and inducible nitric oxide synthase isoforms (nNOS and iNOS) responsible for production of nitric oxide (NO) were carried out during different stages of metamorphosis in tail of tadpole Xenopus laevis. NO also has profound effect on the mitochondrial function having its own nitric oxide NOS enzyme. Hence, in situ staining for NO and mitochondria also was investigated. The distribution of nNOS and iNOS was found to be stage specific, and the gene expression of nNOS was up regulated by thyroxin treatment. In situ staining for NO and mitochondria shows co-localization, suggesting mitochondria being one of the sources of NO. SOD and catalase showed significant co-localization during earlier stages of metamorphosis, but before the tail regression begins, there was a significant decrease in activity as well as co-localization suggesting increased ROS accumulation. These findings are discussed in terms of putative functional importance of ROS and cytoplasmic as well as mitochondrial derived NO in programmed cell death in tail tissue. PMID- 23684738 TI - DNA damage and transcriptional changes induced by tributyltin (TBT) after short in vivo exposures of Chironomus riparius (Diptera) larvae. AB - Tributyltin (TBT) is a widespread environmental contaminant in aquatic systems whose adverse effects in development and reproduction are related to its well known endocrine-disrupting activity. In this work, the early molecular effects of TBT in Chironomus riparius (Diptera) were evaluated by analyzing its DNA damaging potential and the transcriptional response of different endocrine-related genes. Twenty-four-hour in vivo exposures of the aquatic larvae, at environmentally relevant doses of TBT, revealed genotoxic activity as shown by significant increases in DNA strand breaks quantified with the comet assay. TBT was also able to induce significant increases in transcripts from the ecdysone receptor gene (EcR), the ultraspiracle gene (usp) (insect ortholog of the retinoid X receptor), the estrogen-related receptor (ERR) gene and the E74 early ecdysone-inducible gene, as measured by real-time RT-PCR. In contrast, the expression of the vitellogenin (vg) gene remained unaltered, while the hsp70 gene appeared to be down-regulated. The ability of TBT to up-regulate hormonal target genes provides the first evidence, at genomic level, of its endocrine disruptive effects and also suggests a mechanism of action that mimics ecdysteroid hormones in insects. These data reveal for the first time the early genomic effects of TBT on an insect genome. PMID- 23684739 TI - Transitions in the heartbeat pattern during pupal diapause and adult development in the flesh fly, Sarcophaga crassipalpis. AB - The heartbeat of diapausing pupae of the flesh fly Sarcophaga crassipalpis was investigated using electrocardiographic methods including gravimetry, thermography, and optocardiography. During deep diapause, characterized by minimum metabolic activity, the heart exhibited discontinuous bouts of exclusively unidirectional, anterograde pulsations (40-60 contractions/min) that lasted only a few seconds. These bouts of cardiac pulsations were separated by periods of rest lasting 5-30 min. During infradian peaks of metabolic activity (4 day cycles) that occur throughout diapause, periods of rest were shortened and frequency of the anterograde heartbeat increased more than two-fold. Throughout diapause, the heart consistently exhibited a simple, bi-phasic pattern of pulsations generated by bouts of anterograde heartbeats interspersed with periods of cardiac rest. When the fly broke diapause and initiated pharate adult development, a new tri-phasic pattern was observed: the new pattern incorporated heartbeat reversal, as noted by the appearance of retrograde pulsations that directed hemolymph in a posterior direction. These retrograde heartbeats occurred exclusively in the abdominal portion of the dorsal vessel and were not observed in the head or thorax. The transition to pharate adult development was also accompanied by the appearance of extremely strong extracardiac pulsations that served a respiratory function. Although these pulsations made it more challenging to record heartbeat patterns in pharate adults, we observed progressive shortening of the resting periods and a continual increase in the rate of both anterograde and retrograde pulsations, a trend that was further magnified in the adult fly (anterograde contractions up to 300/min and retrograde contractions approximately 125/min). These results imply that the circulatory function of the heart is homeostatically regulated and is responsive to developmental changes and the diverse metabolic rate demands of larvae, diapausing pupae, pharate adults and adult flies. PMID- 23684740 TI - The role of serine- and metalloproteases in Nasonia vitripennis venom in cell death related processes towards a Spodoptera frugiperda Sf21 cell line. AB - Proteases are predominant venom components of the ectoparasitoid Nasonia vitripennis. Two protease families, serine proteases and metalloproteases were examined for their possible cytotoxic functions in the Spodoptera frugiperda (Sf21) cell line using protease inhibitors that inactivate one or both protease families. Viability assays on adherent cells indicated that both protease families are among the main cytotoxic compounds of N. vitripennis venom. However, viability assays and flow cytometry performed on suspension cells 24h after envenomation revealed that inactivation of metalloproteases did not improve cell survival. These results indicate that both protease families may have tissue specific functions. Time course experiments indicate that serine proteases of N. vitripennis venom are responsible for inducing apoptosis in the Sf21 cell line. However, other venom compounds could also be involved in this process and different cell death pathways may take over when a specific type of cell death is inhibited. During parasitation of their natural hosts, both protease families may possibly function in immune related processes and tissue destruction, enabling venom distribution. Overall, this study provides important insights into the functions of serine and metalloproteases in the venom of N. vitripennis. PMID- 23684742 TI - Don't die of something stupid. PMID- 23684741 TI - Physiological responses to fluctuating thermal and hydration regimes in the chill susceptible insect, Thaumatotibia leucotreta. AB - Fluctuating thermal regimes (FTR), consisting of cycles between stressful low and benign temperatures, are known to improve survival and fecundity in a variety of insects. By contrast, fluctuating hydration regimes (FHR) consisting of cycles between dehydrating and benign conditions have been less comprehensively researched. Hypothetically, either repeated stress accumulates damage and reduces survival, or the recovery periods may act as a protective mechanism by allowing low temperature- or dehydration-induced damage to be repaired. Using false codling moth (Thaumatotibia leucotreta) larvae, we investigated whether FTR and FHR resulted in protection, or accumulated damage, at the cellular and whole organism levels. Time- and age-matched controls were used to verify that the effects were due to the fluctuating stressors and not age- or time-dependent responses. Results showed that larval body water-(BWC) and lipid content (BLC) remained unchanged in response to FTR. Importantly though, FTR are protective when compared to constant low temperature exposures, potentially due to an increase in heat shock protein 70 (HSP70). However, larvae may suffer long-term fitness consequences compared to constant benign exposures. Results for FHR appear equivocal when compared to constant controls, due to high survival rates for all experiments, although the physiological responses to FHR included a decrease in larval BWC and BLC, a decrease in cuticular water loss rates, and a depletion of HSP70 during the final dehydration cycle. In conclusion, it appears that fluctuating stressors are protective in T. leucotreta when compared to constant stress conditions, likely through regulation of whole-animal metabolic rate and HSP70, although other mechanisms (e.g. ion homeostasis) are also implicated. PMID- 23684744 TI - Molecular flexibility and the electrostatic moments of curcumin and its derivatives in the active site of p300: a theoretical charge density study. AB - A molecular docking analysis and quantum chemical calculation coupled with the charge density analysis have been carried out to understand the conformational change, charge density distribution and the electrostatic properties of HAT inhibitors curcumin and its derivatives (cinnamoyl compounds) in the active site of p300. The nearest neighbours, the shortest intermolecular contacts between the inhibitors and receptor p300; their binding energies were calculated from molecular docking analysis. A high level quantum chemical calculations were performed using density functional theory (DFT-B3LYP) with the basis set 6 311G(**) combined with the theory of atoms in molecules (AIM) for the inhibitors in gas phase and in the active site of p300. It is observed that, when the molecules present in the active site of p300, relatively, their geometrical, bond topological and the electrostatic properties are significantly altered. The comparative study on the geometrical and electrostatic properties of these three inhibitors in gas phase and amino acid environment gives an insight on the molecular flexibility and the exact modification of electrostatic interaction of the inhibitor in the active site of p300. These fine details at electronic level allow to understand the exact drug-receptor interaction. PMID- 23684743 TI - The activation sequence of cellular protein handling systems after proteasomal inhibition in dopaminergic cells. AB - Dysfunction of protein handling has been implicated in many neurodegenerative diseases and inhibition of the ubiquitin-proteasome system (UPS) has been linked to the formation of protein aggregates and proteinopathies in such diseases. While proteasomal inhibition could trigger an array of downstream protein handling changes including up-regulation of heat shock proteins (HSPs), induction of molecular chaperones, activation of the ER stress/unfolded protein response (UPR), autophagy and aggresome formation, little is known of the relationship of proteasomal inhibition to the sequence of activation of these diverse protein handling systems. In this study we utilized the reversible proteasome inhibitor MG132 and examined the activity of several major protein handling systems in the immortalized dopaminergic neuronal N27 cell line. In the early phase (up to 6h after proteasomal inhibition), MG132 induced time-dependent proteasomal inhibition which resulted in stimulation of the UPR, increased autophagic flux and stimulated heat shock protein response as determined by increased levels of phosphorylation of the eukaryotic translation initiation factor 2 alpha (eIF2alpha), C/EBP homologous protein (CHOP)/GADD153, turnover of autophagy related microtubule-associated protein 1 light chain 3 (LC3) and increased levels of Hsp70 respectively. After prolonged proteasomal inhibition induced by MG132, we observed the formation of vimentin-caged aggresome-like inclusion bodies. A recovery study after MG132-induced proteasomal inhibition indicated that the autophagy-lysosomal pathway participated in the clearance of aggresomes. Our data characterizes the relationship between proteasome inhibition and activation of other protein handling systems. These data also indicated that the induction of alternate protein handling systems and their temporal relationships may be important factors that determine the extent of accumulation of misfolded proteins in cells as a result of proteasome inhibition. PMID- 23684745 TI - Biological races in humans. AB - Races may exist in humans in a cultural sense, but biological concepts of race are needed to access their reality in a non-species-specific manner and to see if cultural categories correspond to biological categories within humans. Modern biological concepts of race can be implemented objectively with molecular genetic data through hypothesis-testing. Genetic data sets are used to see if biological races exist in humans and in our closest evolutionary relative, the chimpanzee. Using the two most commonly used biological concepts of race, chimpanzees are indeed subdivided into races but humans are not. Adaptive traits, such as skin color, have frequently been used to define races in humans, but such adaptive traits reflect the underlying environmental factor to which they are adaptive and not overall genetic differentiation, and different adaptive traits define discordant groups. There are no objective criteria for choosing one adaptive trait over another to define race. As a consequence, adaptive traits do not define races in humans. Much of the recent scientific literature on human evolution portrays human populations as separate branches on an evolutionary tree. A tree-like structure among humans has been falsified whenever tested, so this practice is scientifically indefensible. It is also socially irresponsible as these pictorial representations of human evolution have more impact on the general public than nuanced phrases in the text of a scientific paper. Humans have much genetic diversity, but the vast majority of this diversity reflects individual uniqueness and not race. PMID- 23684746 TI - Small RNAs derived from structural non-coding RNAs. AB - It has been shown in small RNA sequencing-based studies that some small RNA fragments are specifically processed from known structural non-coding RNAs, either through Dicer-dependent or Dicer-independent pathways. Although these small RNAs are often less abundant compared to microRNAs in normal mammalian tissues, they are always present in all sequenced libraries. In this paper, we use the ncPRO-seq pipeline, to describe different profiles of these small RNA fragments, and to discuss their potential processing pathways and functions. To assess whether more small RNA fragments can be detected in small RNA sequencing datasets, we decided to focus on small nuclear RNAs, abbreviated as snRNAs, which are associated with Sm ribonucleoproteins to form functional RNA-protein complexes. Here, we describe a group of small RNA fragments derived from snRNAs, which are typically highly enriched in regions bound by Sm proteins. Based on this, we propose the existence of a potential novel small RNA family associated with Sm proteins. PMID- 23684747 TI - Let-7b and miR-495 stimulate differentiation and prevent metaplasia of pancreatic acinar cells by repressing HNF6. AB - BACKGROUND & AIMS: Diseases of the exocrine pancreas are often associated with perturbed differentiation of acinar cells. MicroRNAs (miRNAs) regulate pancreas development, yet little is known about their contribution to acinar cell differentiation. We aimed to identify miRNAs that promote and control the maintenance of acinar differentiation. METHODS: We studied mice with pancreas- or acinar-specific inactivation of Dicer (Foxa3-Cre/Dicer(loxP/-) mice), combined (or not) with inactivation of hepatocyte nuclear factor (HNF) 6 (Foxa3 Cre/Dicer(loxP/-)/Hnf6-/- mice). The role of specific miRNAs in acinar differentiation was investigated by transfecting cultured cells with miRNA mimics or inhibitors. Pancreatitis-induced metaplasia was investigated in mice after administration of cerulein. RESULTS: Inhibition of miRNA synthesis in acini by inactivation of Dicer and pancreatitis-induced metaplasia were associated with repression of acinar differentiation and with induction of HNF6 and hepatic genes. The phenotype of Dicer-deficient acini depends on the induction of HNF6; overexpression of this factor in developing acinar cells is sufficient to repress acinar differentiation and to induce hepatic genes. Let-7b and miR-495 repress HNF6 and are expressed in developing acini. Their expression is inhibited in Dicer-deficient acini, as well as in pancreatitis-induced metaplasia. In addition, inhibiting let-7b and miR-495 in acinar cells results in similar effects to those found in Dicer-deficient acini and metaplastic cells, namely induction of HNF6 and hepatic genes and repression of acinar differentiation. CONCLUSIONS: Let-7b, miR-495, and their targets constitute a gene network that is required to establish and maintain pancreatic acinar cell differentiation. Additional studies of this network will increase our understanding of pancreatic diseases. PMID- 23684748 TI - AP-1B-mediated protein sorting regulates polarity and proliferation of intestinal epithelial cells in mice. AB - BACKGROUND & AIMS: In epithelial cells, protein sorting mechanisms regulate localization of plasma membrane proteins that generate and maintain cell polarity. The clathrin-adaptor protein (AP) complex AP-1B is expressed specifically in polarized epithelial cells, where it regulates basolateral sorting of membrane proteins. However, little is known about its physiological significance. METHODS: We analyzed the intestinal epithelia of mice deficient in Ap1m2 (Ap1m2(-/-) mice), which encodes the AP-1B MU1B subunit, and compared it with 129/B6/CD1 littermates (controls). Notch signaling was inhibited by intraperitoneal injection of dibenzazepine, and beta-catenin signaling was inhibited by injection of IWR1. Intestinal tissue samples were collected and analyzed by immunofluorescence analysis. RESULTS: Ap1m2(-/-) mice developed intestinal epithelial cell hyperplasia. The polarity of intestinal epithelial cells was disrupted, as indicated by the appearance of ectopic microvilli-like structures on the lateral plasma membrane and mislocalization of basolateral membrane proteins, including the low-density lipoprotein receptor and E-cadherin. The E-cadherin-beta-catenin complex therefore was disrupted at the adherens junction, resulting in nuclear translocation of beta-catenin. This resulted in up regulation of genes regulated by beta-catenin/transcription factor 4 (Tcf4) complex, and increased the proliferation of intestinal epithelial cells. CONCLUSIONS: AP-1B is required for protein sorting and polarization of intestinal cells in mice. Loss of AP-1B in the intestinal epithelia results in mislocalization of E-cadherin, activation of beta-catenin/Tcf4 complex, proliferation, and hyperplasia. PMID- 23684749 TI - Identification of candidate oncogenes in human colorectal cancers with microsatellite instability. AB - Microsatellite instability can be found in approximately 15% of all colorectal cancers. To detect new oncogenes we sequenced the exomes of 25 colorectal tumors and respective healthy colon tissue. Potential mutation hot spots were confirmed in 15 genes; ADAR, DCAF12L2, GLT1D1, ITGA7, MAP1B, MRGPRX4, PSRC1, RANBP2, RPS6KL1, SNCAIP, TCEAL6, TUBB6, WBP5, VEGFB, and ZBTB2; these were validated in 86 tumors with microsatellite instability. ZBTB2, RANBP2, and PSRC1 also were found to contain hot spot mutations in the validation set. The form of ZBTB2 associated with colorectal cancer increased cell proliferation. The mutation hot spots might be used to develop personalized tumor profiling and therapy. PMID- 23684750 TI - Thromboxane A2 synthase inhibitors prevent production of infectious hepatitis C virus in mice with humanized livers. AB - BACKGROUND & AIMS: A 3-dimensional (3D) culture system for immortalized human hepatocytes (HuS-E/2 cells) recently was shown to support the lifecycle of blood borne hepatitis C virus (HCV). We used this system to identify proteins that are active during the HCV lifecycle under 3D culture conditions. METHODS: We compared gene expression profiles of HuS-E/2 cells cultured under 2-dimensional and 3D conditions. We identified signaling pathways that were activated differentially in the cells, and analyzed their functions in the HCV lifecycle using a recombinant HCV-producing cell-culture system, with small interfering RNAs and chemical reagents. We investigated the effects of anti-HCV reagents that altered these signaling pathways in mice with humanized livers (carrying human hepatocytes). RESULTS: Microarray analysis showed that cells cultured under 2 dimensional vs 3D conditions expressed different levels of messenger RNAs encoding prostaglandin synthases. Small interfering RNA-mediated knockdown of thromboxane A2 synthase (TXAS) and incubation of hepatocytes with a TXAS inhibitor showed that this enzyme is required for production of infectious HCV, but does not affect replication of the HCV genome or particle release. The TXAS inhibitor and a prostaglandin I2 receptor agonist, which has effects that are opposite those of thromboxane A2, reduced serum levels of HCV and inhibited the infection of human hepatocytes by blood-borne HCV in mice. CONCLUSIONS: An inhibitor of the prostaglandin synthase TXAS inhibits production of infectious HCV particles in cultured hepatocytes and HCV infection of hepatocytes in mice with humanized livers. It therefore might be therapeutic for HCV infection. PMID- 23684752 TI - The histone LSD1 demethylase in stemness and cancer transcription programs. AB - DNA and histone chromatin modifying enzymes play a crucial role in chromatin remodeling in several biological processes. Lysine-specific demethylase 1 (LSD1), the first identified histone demethylase, is a relevant player in the regulation of a broad spectrum of biological processes including development, cellular differentiation, embryonic pluripotency and cancer. Here, we review recent insights on the role of LSD1 activity in chromatin regulatory complexes, its functional role in the epigenetic changes during embryonic development, in the establishment and maintenance of stemness and during cancer progression. PMID- 23684751 TI - Chitin-binding domains of Escherichia coli ChiA mediate interactions with intestinal epithelial cells in mice with colitis. AB - BACKGROUND & AIMS: Inducible chitinase 3-like-1 is expressed by intestinal epithelial cells (IECs) and adheres to bacteria under conditions of inflammation. We performed a structure-function analysis of the chitin-binding domains encoded by the chiA gene, which mediates the pathogenic effects of adherent invasive Escherichia coli (AIEC). METHODS: We created AIEC (strain LF82) with deletion of chiA (LF82-DeltachiA) or that expressed chiA with specific mutations. We investigated the effects of infecting different IEC lines with these bacteria compared with nonpathogenic E coli; chitinase activities were measured using the colloidal chitin-azure method. Colitis was induced in C57/Bl6 mice by administration of dextran sodium sulfate, and mice were given 10(8) bacteria for 15 consecutive days by gavage. Stool/tissue samples were collected and analyzed. RESULTS: LF82-DeltachiA had significantly less adhesion to IEC lines than LF82. Complementation of LF82-DeltachiA with the LF82 chiA gene, but not chiA from nonpathogenic (K12) E coli, increased adhesion. We identified 5 specific polymorphisms in the chitin-binding domain of LF82 chiA (at amino acids 362, 370, 378, 388, and 548) that differ from chiA of K12 and were required for LF82 to interact directly with IECs. This interaction was mediated by an N-glycosylated asparagine in chitinase 3-like-1 (amino acid 68) on IECs. Mice infected with LF82, or LF82-DeltachiA complemented with LF82 chiA, developed more severe colitis after administration of dextran sodium sulfate than mice infected with LF82-DeltachiA or LF82 that expressed mutant forms of chiA. CONCLUSIONS: AIEC adheres to an N-glycosylated chitinase 3-like-1 on IECs via the chitin-binding domain of chiA. This mechanism promotes the pathogenic effects of AIEC in mice with colitis. PMID- 23684753 TI - Cystatin-based estimated GFR versus creatinine-based and creatinine- and cystatin based estimated GFR for ESRD and mortality risk in diabetes. PMID- 23684754 TI - Effects of exenatide on kidney function, adverse events, and clinical end points of kidney disease in type 2 diabetes. PMID- 23684755 TI - Sevelamer versus calcium carbonate in incident hemodialysis patients: results of an open-label 24-month randomized clinical trial. AB - BACKGROUND: Whether the use of sevelamer rather than a calcium-containing phosphate binder improves cardiovascular (CV) survival in patients receiving dialysis remains to be elucidated. STUDY DESIGN: Open-label randomized controlled trial with parallel groups. SETTINGS & PARTICIPANTS: 466 incident hemodialysis patients recruited from 18 centers in Italy. INTERVENTION: Study participants were randomly assigned in a 1:1 fashion to receive either sevelamer or a calcium containing phosphate binder (although not required by the protocol, all patients in this group received calcium carbonate) for 24 months. OUTCOMES: All individuals were followed up until completion of 36 months of follow-up or censoring. CV death due to cardiac arrhythmias was regarded as the primary end point. MEASUREMENTS: Blind event adjudication. RESULTS: At baseline, patients allocated to sevelamer had higher serum phosphorus (mean, 5.6 +/- 1.7 [SD] vs 4.8 +/- 1.4 mg/dL) and C-reactive protein levels (mean, 8.8 +/- 13.4 vs 5.9 +/- 6.8 mg/dL) and lower coronary artery calcification scores (median, 19 [IQR, 0-30] vs 30 [IQR, 7-180]). At study completion, serum phosphate levels were lower in the sevelamer arm (median dosages, 4,800 and 2,000 mg/d for sevelamer and calcium carbonate, respectively). After a mean follow-up of 28 +/- 10 months, 128 deaths were recorded (29 and 88 due to cardiac arrhythmias and all-cause CV death). Sevelamer-treated patients experienced lower CV mortality due to cardiac arrhythmias compared with patients treated with calcium carbonate (HR, 0.06; 95% CI, 0.01-0.25; P < 0.001). Similar results were noted for all-cause CV mortality and all-cause mortality, but not for non-CV mortality. Adjustments for potential confounders did not affect results. LIMITATIONS: Open-label design, higher baseline coronary artery calcification burden in calcium carbonate-treated patients, different mineral metabolism control in sevelamer-treated patients, overall lower than expected mortality. CONCLUSIONS: These results show that sevelamer compared to a calcium-containing phosphate binder improves survival in a cohort of incident hemodialysis patients. However, the better outcomes in the sevelamer group may be due to better phosphate control rather than reduction in calcium load. PMID- 23684756 TI - Antiobesity effects of quercetin-rich onion peel extract on the differentiation of 3T3-L1 preadipocytes and the adipogenesis in high fat-fed rats. AB - The aim of the present study was to examine the effect of quercetin-rich onion peel extract (OPE) on anti-differentiation in 3T3-L1 preadipocytes and the antiobesity in high-fat fed rats. We found that lipid accumulations and TG contents in 3T3-L1 cells were markedly suppressed by OPE. The mRNA levels of activating protein (AP2) were down-regulated and those of carnitine palmitoyl transferase-1 alpha (CPT-1alpha) and fatty acid binding protein 4 (FABP4) were up regulated by 75 and 100 MUg/ml OPE. Body weight, retroperitoneal and mesenteric fat weights of SD rats were significantly lower in the 8 week high fat (HF) diet+0.72% OPE group than in the HF group. Peroxisome proliferator-activated receptor (PPAR)gamma mRNA levels were down-regulated in the epididymal fat of OPE than those of control and HF, and significant down-regulation of CCAAT/enhancer binding protein (C/EBP)alpha mRNA levels in OPE was also observed than the control. The mRNA levels of CPT-1alpha and uncoupling protein-1 (UCP-1) were up regulated by the OPE, while those of fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) were down-regulated in HF and OPE groups compared to control group. These results suggest that quercentin-enriched OPE may have antiobesity effects by suppressing preadipocyte differentiation and inhibiting adipogenesis. PMID- 23684757 TI - Pre-clinical anti-inflammatory aspects of a cuisine and medicinal millennial herb: Malva sylvestris L. AB - Malva sylvestris has been used since ancient times for its emollient, laxative and anti-inflammatory properties, being extensively used as salads, soups and teas. The preset study evaluated the topical anti-inflammatory action of M. sylvestris hydroalcoholic extract (HE) and its compounds in mice ear inflammation caused by 12-O-tetradecanoylphorbol-acetate in mice. The LC-MS analysis of the HE confirmed the presence of scopoletin, quercetin and malvidin 3-glucoside compounds in the HE of M. sylvestris. Topical application of the HE reduced ear oedema, polymorphonuclear cells influx (myeloperoxydase activity and histological analysis) and interleukin-1beta levels in the tissue. The topical application of the compound present in the HE, malvidin 3-glucoside was also able to inhibit ear oedema and leukocytes migration. The other tested compounds, scopoletin, quercetin and malvidin 3,5-glucoside were able to prevent the formation of oedema and cell infiltration, but with less effectiveness when compared to HE and malvidin 3-glucoside. Therefore, these results consistently support the notion that M. sylvestris leaves possesses topical anti-inflammatory activity, the compound malvidin 3-glucoside seems to be major responsible for this effect, with the participation of other anti-inflammatory compounds in the extract. Thus, as recommended by population, M. sylvestris can be used as a future treatment to skin disorders. PMID- 23684758 TI - Methoxychlor induced biochemical alterations and disruption of spermatogenesis in adult rats. AB - Adult male albino rats were treated orally with methoxychlor at doses of 0, 50, 100 or 200 mg/kg/day for 15 consecutive days. Testicular weight, sperm count and motility were significantly decreased. Methoxychlor at doses of 100 and 200 mg/kg significantly inhibited alpha-glucosidase activity, while plasma testosterone was significantly decrease by the three dose levels in a dose-related pattern. Testicular activities of 3beta-HSD, 17beta-HSD, SDH were significantly decreased, while ACP, ALP (except for 50 mg/kg), and LDH were significantly increased. H2O2 production and LPO were significantly increased while the enzymic (SOD, CAT and GPx) and non-enzymic antioxidants (thiol content) were significantly decreased. Caspase-3 activity was significantly increased in a dose related manner. The findings of this study indicate that methoxychlor induces oxidative stress associated with impairment of spermatogenesis, in addition to apoptosis. These data provide insight into the mode of action of methoxychlor-induced toxicity in the rat testis. PMID- 23684759 TI - Mirroring mirror neurons in an interdisciplinary debate. PMID- 23684760 TI - Biological functions of sphingomyelins. AB - Sphingomyelin (SM) is a dominant sphingolipid in membranes of mammalian cells and this lipid class is specifically enriched in the plasma membrane, the endocytic recycling compartment, and the trans Golgi network. The distribution of SM and cholesterol among cellular compartments correlate. Sphingolipids have extensive hydrogen-bonding capabilities which together with their saturated nature facilitate the formation of sphingolipid and SM-enriched lateral domains in membranes. Cholesterol prefers to interact with SMs and this interaction has many important functional consequences. In this review, the synthesis, regulation, and intracellular distribution of SMs are discussed. The many direct roles played by membrane SM in various cellular functions and processes will also be discussed. These include involvement in the regulation of endocytosis and receptor-mediated ligand uptake, in ion channel and G-protein coupled receptor function, in protein sorting, and functioning as receptor molecules for various bacterial toxins, and for non-bacterial pore-forming toxins. SM is also an important constituent of the eye lens membrane, and is believed to participate in the regulation of various nuclear functions. SM is an independent risk factor in the development of cardiovascular disease, and new studies have shed light on possible mechanism behind its role in atherogenesis. PMID- 23684761 TI - Intense physical activity is associated with better metabolic control in patients with type 1 diabetes. AB - OBJECTIVES: To analyze the association between adherence to physical activity guideline recommendations and metabolic control in patients with type 1 diabetes (DM1). METHODS: An observational, cross-sectional study was conducted in 130 adult DM1 patients from Spain with a mean age of 33.9+/-11.5 years and disease duration of 16.5+/-9.5 years. We analyzed several clinical, anthropometric and laboratory variables together with information obtained from the Minnesota Leisure Time Physical Activity Questionnaire. RESULTS: Evaluated patients reported an average of 850.6+/-493.2min of physical activity per week, being classified as light (567.4+/-425.4min/week), moderate (169.9+/-212.1min/week) and intense activities (120.6+/-184.2). Patients who dedicated more time to intense physical activity were younger, had university studies and were males more often than those who spent none or less time on intense physical activity. We observed no differences in HbA1c levels in relation to time dedicated to moderate physical activities. However, patients who dedicated more than 150min to intense physical activity per week had lower levels of HbA1c (HbA1c: 7.2+/-1.0% versus 7.8+/-1.1% versus 8.0+/-1.0% in more than 149min, between 0 and 149min or 0min of intense physical activity per week, respectively). CONCLUSION: Performing more than 150min of intense physical activity a week is associated with better metabolic control in type 1 Spanish patients. No positive impact in metabolic control was observed in relation to the time spent in moderate physical activity. PMID- 23684762 TI - Corrosion protection and improved cytocompatibility of biodegradable polymeric layer-by-layer coatings on AZ31 magnesium alloys. AB - Composite coatings of electrostatically assembled layer-by-layer anionic and cationic polymers combined with an Mg(OH)2 surface treatment serve to provide a protective coating on AZ31 magnesium alloy substrates. These ceramic conversion coating and layer-by-layer polymeric coating combinations reduced the initial and long-term corrosion progression of the AZ31 alloy. X-ray diffraction and Fourier transform infrared spectroscopy confirmed the successful application of coatings. Potentiostatic polarization tests indicate improved initial corrosion resistance. Hydrogen evolution measurements over a 2 week period and magnesium ion levels over a 1 week period indicate longer range corrosion protection and retention of the Mg(OH)2 passivation layer in comparison to the uncoated substrates. Live/dead staining and DNA quantification were used as measures of biocompatibility and proliferation while actin staining and scanning electron microscopy were used to observe the cellular morphology and integration with the coated substrates. The coatings simultaneously provided improved biocompatibility, cellular adhesion and proliferation in comparison to the uncoated alloy surface utilizing both murine pre-osteoblast MC3T3 cells and human mesenchymal stem cells. The implementation of such coatings on magnesium alloy implants could serve to improve the corrosion resistance and cellular integration of these implants with the native tissue while delivering vital drugs or biological elements to the site of implantation. PMID- 23684763 TI - Pharmacologically tunable polyethylene-glycol-based cell growth substrate. AB - Biohybrid materials combining synthetic polymers with biological components are highly suited for tissue engineering in order to emulate the behavior of natural materials such as the extracellular matrix (ECM). In order to allow for an optimal cell-material interplay, the physical and biological parameters of the artificial matrix need to be dynamically remodeled during cultivation. Current tissue engineering concepts are mainly based on passive remodeling mechanisms including the degradation of the hydrogel and the release of incorporated biomolecules and therefore do not enable external adjustment of cultivation conditions. We present a novel hydrogel material that is able to serve as a cell growth matrix, whose degradation and presentation of cell-interacting biomolecules can be externally controlled by the addition of a pharmacological substance. The hydrogel is based on branched polyethylene glycol that is covalently decorated with the aminocoumarin-antibiotic switchable gyrase B protein conferring stimulus-responsive degradation. ECM properties were conferred to the hydrogels with cell attachment motifs and a general approach for the incorporation and inducible release of therapeutic biomolecules. This smart biohybrid material has the potential to serve as a next-generation tissue engineering device which allows for dynamic external adjustment of the physical and biological parameters, resulting in optimally controlled tissue formation. PMID- 23684764 TI - Thermally induced fracture for core-veneered dental ceramic structures. AB - Effective and reliable clinical uses of dental ceramics necessitate an insightful analysis of the fracture behaviour under critical conditions. To better understand failure characteristics of porcelain veneered to zirconia core ceramic structures, thermally induced cracking during the cooling phase of fabrication is studied here by using the extended finite element method (XFEM). In this study, a transient thermal analysis of cooling is conducted first to determine the temperature distributions. The time-dependent temperature field is then imported to the XFEM model for viscoelastic thermomechanical analysis, which predicts thermally induced damage and cracking at different time steps. Temperature dependent material properties are used in both transient thermal and thermomechanical analyses. Three typical ceramic structures are considered in this paper, namely bi-layered spheres, squat cylinders and dental crowns with thickness ratios of either 1:2 or 1:1. The XFEM fracture patterns exhibit good agreement with clinical observation and the in vitro experimental results obtained from scanning electron microscopy characterization. The study reveals that fast cooling can lead to thermal fracture of these different bi-layered ceramic structures, and cooling rate (in terms of heat transfer coefficient) plays a critical role in crack initiation and propagation. By exploring different cooling rates, the heat transfer coefficient thresholds of fracture are determined for different structures, which are of clear clinical implication. PMID- 23684766 TI - Bilateral lesions of the nigrostriatal pathways are associated with chronic mechanical pain hypersensitivity in rats. AB - Some patients with Parkinson's disease (PD) suffer from pain before motor symptoms. To model this, we proposed to assess the mechanical hypersensitivity in an animal model of PD with a bilateral lesion of the nigrostriatal pathway. PD model was validated by a decrease of locomotor activity and a 76% dopamine cell loss in the substantia nigra pars compacta. PD animals displayed a decrease of mechanical thresholds, correlated with the degree of the dopamine lesion. This animal model displays nociceptive disorders as found in PD patients and could be useful to assess the effects of new antiparkinsonian drugs. PMID- 23684765 TI - MDA5 and ISG56 mediate CXCL10 expression induced by toll-like receptor 4 activation in U373MG human astrocytoma cells. AB - Toll-like receptor (TLR) 4 is a pattern recognition receptor, and recognizes not only bacterial lipopolysaccharide (LPS) but also endogenous danger-associated molecular patterns released from dying or injured cells. It has been reported that TLR4 signaling in astrocytes plays an important role in various neurological diseases. However, details of TLR4 signaling in astrocytes are not fully elucidated. In the present study, we demonstrated that TLR4 signaling, induced by LPS, increases the expression of melanoma differentiation-associated gene 5 (MDA5) and interferon (IFN)-stimulated gene 56 (ISG56) in U373MG human astrocytoma cells. We also found that nuclear factor-kappaB, p38 mitogen activated protein kinase and IFN-beta are involved in the expression of MDA5 and ISG56 induced by LPS. RNA interference experiments revealed that MDA5 and ISG56 positively regulate the LPS-induced expression of a chemokine CXCL10, but not CCL2. In addition, it was suggested that MDA5 and ISG56 constitute a positive feedback loop. These results suggest that MDA5 and ISG56 may contribute not only to physiological inflammatory reactions but also to the pathogenesis of various neurological diseases elicited by TLR4 in astrocytes, at least in part, by regulating the expression of CXCL10. PMID- 23684767 TI - Temporal and tissue specific gene expression patterns of the zebrafish kinesin-1 heavy chain family, kif5s, during development. AB - Homo- and heterodimers of Kif5 proteins form the motor domain of Kinesin-1, a major plus-end directed microtubule motor. Kif5s have been implicated in the intracellular transport of organelles, vesicles, proteins, and RNAs in many cell types. There are three mammalian KIF5s. KIF5A and KIF5C proteins are strictly neural in mouse whereas, KIF5B is ubiquitously expressed. Mouse knockouts indicate crucial roles for KIF5 in development and human mutations in KIF5A lead to the neurodegenerative disease Hereditary Spastic Paraplegia. However, the developmental functions and the extent to which individual kif5 functions overlap have not been elucidated. Zebrafish possess five kif5 genes: kif5Aa, kif5Ab, kif5Ba, kif5Bb, and kif5C. Here we report their tissue specific expression patterns in embryonic and larval stages. Specifically, we find that kif5As are strictly zygotic and exhibit neural-specific expression. In contrast, kif5Bs exhibit strong maternal contribution and are ubiquitously expressed. Lastly, kif5C exhibits weak maternal expression followed by enrichment in neural populations. In addition, kif5s show distinct expression domains in the larval retina. PMID- 23684768 TI - Establishment of crown-root domain borders in mouse incisor. AB - Teeth are composed of two domains, the enamel-covered crown and the enamel-free root. The understanding of the initiation and regulation of crown and root domain formation is important for the development of bioengineered teeth. In most teeth the crown develops before the root, and erupts to the oral cavity whereas the root anchors the tooth to the jawbone. However, in the continuously growing mouse incisor the crown and root domains form simultaneously, the crown domain forming the labial and the root domain the lingual part of the tooth. While the crown root border on the incisor distal side supports the distal enamel extent, reflecting an evolutionary diet adaptation, on the incisor mesial side the root like surface is necessary for the attachment of the interdental ligament between the two incisors. Therefore, the mouse incisor exhibits a functional distal mesial asymmetry. Here, we used the mouse incisor as a model to understand the mechanisms involved in the crown-root border formation. We analyzed the cellular origins and gene expression patterns leading to the development of the mesial and distal crown-root borders. We discovered that Barx2, En1, Wnt11, and Runx3 were exclusively expressed on the mesial crown-root border. In addition, the distal border of the crown-root domain might be established by cells from a different origin and by an early Follistatin expression, factor known to be involved in the root domain formation. The use of different mechanisms to establish domain borders gives indications of the incisor functional asymmetry. PMID- 23684769 TI - Kin selection and local competition in a heterogeneous community. AB - When should an individual be willing to pay a cost in order to help or harm another individual in its community? Kin selection suggests that relatives should help each other, while competition for limited resources may select for harming behaviour against neighbours. This study considers social interactions between two individuals. For actions influencing non-dispersing reproduction, a condition is derived for selection to favour helping or harming, as a function of the actor's relationship to the rest of its community and to the recipient. Where two individuals differ in their relatedness to the community, the individual which is less related to the community will be the more helpful. Two individuals with a given relatedness to each other will be more helpful to each other as they jointly become less related to their community. The implications of these results are explored through an example involving a community derived from two ancestral groups. The directional selective effects will depend on the extent to which social interactions are assortative rather than random, and the distribution of opportunities for helping and harming. PMID- 23684770 TI - Development of an on-line exposure system to determine freshly produced diesel engine emission-induced cellular effects. AB - Diesel engine emission particle filters are often placed at exhaust outlets to remove particles from the exhaust. The use of filters results in the exposure to a reduced number of nanometer-sized particles, which might be more harmful than the exposure to a larger number of micrometer-sized particles. An in vitro exposure system was established to expose human alveolar epithelial cells to freshly generated exhaust. Computer simulations were used to determine the optimal flow characteristics and ensure equal exposure conditions for each well of a 6-well plate. A selective particle size sampler was used to continuously deliver diesel soot particles with different particle size distributions to cells in culture. To determine, whether the system could be used for cellular assays, alterations in cytokine production and cell viability of human alveolar A549 cells were determined after 3h on-line exposure followed by a 21-h conventional incubation period. Data indicated that complete diesel engine emission slightly affected pre-stimulated cells, but naive cells were not affected. The fractions containing large or small particles never affected the cells. The experimental set-up allowed a reliable exposure of the cells to the complete exhaust fraction or to the fractions containing either large or small diesel engine emission particles. PMID- 23684771 TI - Effects of estradiol or testosterone treatment on expression of gonadotropin subunit mRNAs and proteins in the pituitary of juvenile brown hagfish, Paramyxine atami. AB - A single functional gonadotropin (GTH) comprising two subunits, alpha and beta, was recently identified in the pituitary of brown hagfish (Paramyxine atami). Little is known about the feedback mechanisms that regulate these GTH subunits by sex steroids in the hagfish. The present study was designed to examine feedback effects of estradiol and testosterone on mRNA expression and protein expression of both GTHalpha and GTHbeta subunits in the pituitary of the juvenile P. atami. Intraperitoneal administration of estradiol over the course of 27days resulted in substantial accumulation of immunoreactive (ir)-GTHalpha and ir-GTHbeta in the adenohypophysis, but testosterone treatments over 27days had no effects on ir GTHalpha or ir-GTHbeta. Estradiol treatment for 1, 2, 4 or 14days had no effect on GTHalpha mRNA levels. In contrast, after 2days of estradiol treatment, GTHbeta mRNA levels had increased significantly from baseline, while these levels were not affected after treatment over 1, 4, or 14days. After 14days of testosterone treatment, both GTHalpha and GTHbeta mRNA levels had decreased significantly from baseline levels. These results indicate that estradiol acted primarily to suppress the secretion of GTH, and hence resulted in the accumulations of ir GTHalpha and ir-GTHbeta in the pituitary. On the other hand, testosterone appeared to suppress both the synthesis and the secretion of GTH. Thus, estradiol and testosterone probably differ in their effects on the regulation of pituitary GTH synthesis and secretion in juvenile hagfish. PMID- 23684772 TI - Efficient secretory expression of the sweet-tasting protein brazzein in the yeast Kluyveromyces lactis. AB - Brazzein is an intensely sweet-tasting protein with high water solubility, heat stability, and taste properties resembling those of carbohydrate sweeteners. In the present study, we describe the expression of the synthetic gene encoding brazzein, a sweet protein in the yeast Kluyveromyces lactis. The synthetic brazzein gene was designed based on the biased codons of the yeast, so as to optimize its expression, as well as on the extracellular secretion for expression in an active, soluble form. The synthesized brazzein gene was cloned into the secretion vector pKLAC2, which contains the yeast prepropeptide signal from the Saccharomycescerevisiae alpha-mating factor. The constructed plasmid pKLAC2-des pE1M-brazzein was introduced into the yeast K. lactis GG799. The yeast transformants were cultured for high-yield secretion of the recombinant des-pE1M brazzein in YPGal medium for 96 h at 30 degrees C. The expressed recombinant des pE1M-brazzein was purified by CM-Sepharose column chromatography and approximately 104 mg/L was obtained. The purity and conformational state of the recombinant des-pE1M-brazzein were confirmed using SDS-PAGE, HPLC, and circular dichroism. The identity of the recombinant protein was also confirmed by N terminal amino acid analysis and taste testing. The purified recombinant des-pE1M brazzein had an intrinsic sweetness in its minor form, approximately 2130 times sweeter than sucrose on a weight basis. These results demonstrate that the K. lactis expression system is useful for producing the recombinant brazzein in active form at a high yield with attributes useful in the food industry. PMID- 23684773 TI - A novel polymorphism of the CYP2J2 gene is associated with coronary artery disease in Uygur population in China. AB - BACKGROUND: Cytochrome P450 (CYP) 2J2 is expressed in the vascular endothelium and metabolizes arachidonic acid to biologically active epoxyeicosatrienoic acids (EETs). The EETs are potent endogenous vasodilators and inhibitors of vascular inflammation. The aim of the present study was to assess the association between the human CYP2J2 gene polymorphism and coronary artery disease (CAD) in a Han and Uygur population of China. METHODS: We use two independent case-control studies: a Han population (206 CAD patients and 262 control subjects) and an Uygur population (336 CAD patients and 448 control subjects). All CAD patients and controls were genotyped for the same three single nucleotide polymorphisms (SNPs) (rs890293, rs11572223 and rs2280275) of CYP2J2 gene by a real-time PCR instrument. RESULTS: In the Uygur population, for total, the distribution of SNP3 (rs2280275) genotypes showed a significant difference between CAD and control participants (P=0.048). For total and men, the distribution of SNP3 (rs2280275) alleles and the dominant model (CC vs CT+TT) showed a significant difference between CAD and control participants (for allele: P=0.014 and P=0.035, respectively; for dominant model: P=0.014 and P=0.034, respectively). The significant difference in dominant model was retained after adjustment for covariates (OR: 0.279, 95% confidence interval [CI]: 0.176-0.440, P=0.001; OR: 0.240, 95% CI: 0.128-0.457, P=0.001, respectively). CONCLUSIONS: The CC genotype of rs2280275 in CYP2J2 gene could be a protective genetic marker of CAD and T allele may be a risk genetic marker of CAD in men of Uygur population in China. PMID- 23684774 TI - Defining adrenal status with salivary cortisol by gold-standard insulin hypoglycemia. AB - BACKGROUND: Insulin-induced hypoglycemia (IHT) is considered the gold standard test for evaluating the HPA axis. Serum free cortisol or its surrogate, salivary cortisol as opposed to total cortisol concentrations, offers a better reflection of the activation of HPA axis. Our study aimed to derive reference ranges for the normal salivary cortisol levels in healthy patients and patients with adrenal insufficiency. DESIGN AND METHODS: Serum cortisol concentrations, using the gold standard of IHT, and salivary cortisol were obtained. 36 patients referred to our outpatient endocrine testing unit for evaluation of adrenal function were included in the study. Most subjects had a history of suspected hypothalamic/pituitary disease causing adrenal insufficiency. RESULTS: We found a strong linear correlation between the serum and salivary cortisol concentrations in simultaneously collected samples (r=0.81, 95% CI 0.74-0.86, p<0.0001). The corresponding salivary cortisol equivalent to a serum cortisol of 500 nmol/L, using a linear-regression equation, was 16.7 nmol/L (95% CI 13.3-20.1 nmol/L, p=0.0001). A salivary cortisol of 13.3 nmol/L has a specificity of 89.3% to detect abnormal HPA function. Using the upper 95% CI result of salivary cortisol 20.1 yields a sensitivity of 87.5%. CONCLUSION: With the present assay, adrenal insufficiency may be diagnosed with reasonable confidence if a random salivary cortisol is lower than 13.3 nmol/L and excluded if a random salivary cortisol is higher than 20.1 nmol/L. Future studies should correlate these thresholds with clinical outcomes. PMID- 23684775 TI - Declining blood lead and zinc protoporphyrin levels in Ecuadorian Andean children. AB - OBJECTIVES: To investigate current lead (Pb) exposure in children living in Andean Ecuadorian communities. Blood Pb (PbB) and zinc protoporphyrin (ZPP) levels were used respectively as biomarkers of acute and chronic Pb poisoning. The current PbB-ZPP levels were compared with previous pediatric PbB-ZPP levels recorded over years in the study area. DESIGN AND METHODS: Samples of whole blood were collected from 22 Andean children of Quechua and Mestizo backgrounds and measured for PbB concentrations by graphite furnace atomic absorption spectroscopy. ZPP/heme ratio and ZPP whole blood (ZPP WB) levels were measured with a hematofluorometer. RESULTS: The mean PbB level for children in the current study group was 14.5 MUg/dL, which was significantly lower than the mean PbB level of 41.1 MUg/dL found in the same study area in the 1996-2000 test period, and lower than the 22.2 MUg/dL mean level found in the 2003-2007 period. The current mean ZPP/heme ratio was 102.1 MUmol/mol, and the mean ZPP WB level was 46.3 MUg/dL, both lower than values previously found in children in the study area. CONCLUSION: While the current pediatric PbB-ZPP levels in the study area remain elevated in some children, the overall levels indicate a decline relative to levels observed in the same Pb-contaminated area in the period between 1996 and 2007. The elevated ZPP levels suggest a history of chronic Pb exposure, and potential iron deficiency in some children. The overall reduction in PbB-ZPP levels suggests a positive outcome of a Pb-exposure education and prevention program, and the therapeutic intervention of succimer chelation therapy. PMID- 23684776 TI - One-electron oxidation and reduction of glycosaminoglycan chloramides: a kinetic study. AB - Hypochlorous acid and its acid-base counterpart, hypochlorite ions, produced under inflammatory conditions, may produce chloramides of glycosaminoglycans, these being significant components of the extracellular matrix (ECM). This may occur through the binding of myeloperoxidase directly to the glycosaminoglycans. The N-Cl group in the chloramides is a potential selective target for both reducing and oxidizing radicals, leading possibly to more efficient and damaging fragmentation of these biopolymers relative to the parent glycosaminoglycans. In this study, the fast reaction techniques of pulse radiolysis and nanosecond laser flash photolysis have been used to generate both oxidizing and reducing radicals to react with the chloramides of hyaluronan (HACl) and heparin (HepCl). The strong reducing formate radicals and hydrated electrons were found to react rapidly with both HACl and HepCl with rate constants of 1-1.7 * 10(8) and 0.7-1.2 * 10(8)M(-1)s(-1) for formate radicals and 2.2 * 10(9) and 7.2 * 10(8)M(-1)s(-1) for hydrated electrons, respectively. The spectral characteristics of the products of these reactions were identical and were consistent with initial attack at the N-Cl groups, followed by elimination of chloride ions to produce nitrogen-centered radicals, which rearrange subsequently and rapidly to produce C 2 radicals on the glucosamine moiety, supporting an earlier EPR study by M.D. Rees et al. (J. Am. Chem. Soc.125: 13719-13733; 2003). The oxidizing hydroxyl radicals also reacted rapidly with HACl and HepCl with rate constants of 2.2 * 10(8) and 1.6 * 10(8)M(-1)s(-1), with no evidence from these data for any degree of selective attack on the N-Cl group relative to the N-H groups and other sites of attack. The carbonate anion radicals were much slower with HACl and HepCl than hydroxyl radicals (1.0 * 10(5) and 8.0 * 10(4)M(-1)s(-1), respectively) but significantly faster than with the parent molecules (3.5 * 10(4) and 5.0 * 10(4)M(-1)s(-1), respectively). These findings suggest that these potential in vivo radicals may react in a site-specific manner with the N-Cl group in the glycosaminoglycan chloramides of the ECM, possibly to produce more efficient fragmentation. This is the first study therefore to conclusively demonstrate that reducing radicals react rapidly with glycosaminoglycan chloramides in a site specific attack at the N-Cl group, probably to produce a 100% efficient biopolymer fragmentation process. Although less reactive, carbonate radicals, which may be produced in vivo via reactions of peroxynitrite with serum levels of carbon dioxide, also appear to react in a highly site-specific manner at the N-Cl group. It is not yet known if such site-specific attacks by this important in vivo species lead to a more efficient fragmentation of the biopolymers than would be expected for attack by the stronger oxidizing species, the hydroxyl radical. It is clear, however, that the N-Cl group formed under inflammatory conditions in the extracellular matrix does present a more likely target for both reactive oxygen species and reducing species than the N-H groups in the parent glycosaminoglycans. PMID- 23684778 TI - Diagnosis and treatment of lymphedema after breast cancer: a population-based study. AB - OBJECTIVE: To examine factors associated with variations in diagnosis and rehabilitation treatments received by women with self-reported lymphedema resulting from breast cancer care. DESIGN: A large, population-based, prospective longitudinal telephone survey. SETTING: California, Florida, Illinois, and New York. PARTICIPANTS: Elderly (65+ years) women identified from Medicare claims as having had an incident breast cancer surgery in 2003. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Self-reported incidence of lymphedema symptoms, formal diagnosis of lymphedema, treatments for lymphedema. RESULTS: Of the 450 breast cancer survivors with lymphedema who participated in the study, 290 (64.4%) were formally diagnosed with the condition by a physician. An additional 160 (35.6%) reported symptoms consistent with lymphedema (ie, arm swelling on the side of surgery that is absent on the contralateral arm) but were not formally diagnosed. Of those who reported being diagnosed by a physician, 39 (13.4%) received complete decongestive therapy that included multiple components of treatment (ie, manual lymphatic drainage, bandaging with short stretch bandages, the use of compression sleeves, skin care, and remedial exercises); 24 (8.3%) were treated with manual lymphatic drainage only; 162 (55.9%) used bandages, compression garments, or a pneumatic pump only; 8 (2.8%) relied solely on skin care or exercise to relieve symptoms; and 65 (22.4%) received no treatment at all. Multivariate regressions revealed that race (African American), lower income, and lower levels of social support increased a woman's probability of having undiagnosed lymphedema. Even when they were formally diagnosed, African American women were more likely to receive no treatment or to be treated with bandages/compression only rather than to receive the multimodality, complete decongestive therapy. CONCLUSIONS: Lymphedema is a disabling chronic condition related to breast cancer treatment. Our results suggest that a substantial proportion of persons reporting symptoms were not formally diagnosed with the condition, thereby reducing their opportunity for treatment. The variation in rehabilitation treatments received by women who were formally diagnosed with the condition by a physician suggests that lymphedema might not have been optimally addressed in many cases despite the availability of effective interventions. PMID- 23684777 TI - Hypoxia downregulates PPARgamma via an ERK1/2-NF-kappaB-Nox4-dependent mechanism in human pulmonary artery smooth muscle cells. AB - The ligand-activated transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) regulates metabolism, cell proliferation, and inflammation. Pulmonary hypertension (PH) is associated with reduced PPARgamma expression, and hypoxia exposure regimens that cause PH reduce PPARgamma expression. This study examines mechanisms of hypoxia-induced PPARgamma downregulation in vitro and in vivo. Hypoxia reduced PPARgamma mRNA and protein levels, PPARgamma activity, and the expression of PPARgamma-regulated genes in human pulmonary artery smooth muscle cells (HPASMCs) exposed to 1% oxygen for 72 h. Similarly, exposure of mice to hypoxia (10% O2) for 3 weeks reduced PPARgamma mRNA and protein in mouse lung. Inhibiting ERK1/2 with PD98059 or treatment with siRNA directed against either NF-kappaB p65 or Nox4 attenuated hypoxic reductions in PPARgamma expression and activity. Furthermore, degradation of H2O2 using PEG catalase prevented hypoxia-induced ERK1/2 phosphorylation and Nox4 expression, suggesting sustained ERK1/2-mediated signaling and Nox4 expression in this response. Mammalian two-hybrid assays demonstrated that PPARgamma and p65 bind directly to each other in a mutually repressive fashion. We conclude from these results that hypoxic regimens that promote PH pathogenesis and HPASMC proliferation reduce PPARgamma expression and activity through ERK1/2-, p65-, and Nox4-dependent pathways. These findings provide novel insights into mechanisms by which pathophysiological stimuli such as hypoxia cause loss of PPARgamma activity and pulmonary vascular cell proliferation, pulmonary vascular remodeling, and PH. These results also indicate that restoration of PPARgamma activity with pharmacological ligands may provide a novel therapeutic approach in selected forms of PH. PMID- 23684779 TI - Evaluation of an interdisciplinary program for chronic pain after spinal cord injury. AB - OBJECTIVE: To assess efficacy of an interdisciplinary pain program adapted for persons with spinal cord injury (SCI) and chronic pain. DESIGN: Prospective cohort. SETTING: University-affiliated rehabilitation hospital. PARTICIPANTS: Twenty-two persons with traumatic or nontraumatic SCI and chronic pain of at least 6 months' duration. METHODS: Subjects participated in an interdisciplinary pain program consisting of biweekly group sessions for 10 consecutive weeks. Sessions incorporated patient education on chronic pain and associated pain mechanisms, cognitive behavioral therapy, self-management strategies (eg, energy conservation, ergonomics, goal setting, stress management, anger management, and coping skills), group discussions and activities, and either exercise or guided relaxation at the end of each session. MAIN OUTCOME MEASURES: Multidimensional Pain Inventory SCI, Coping Inventory of Stressful Situations, Pain Stages of Change Questionnaire, and Life Satisfaction Questionnaire. RESULTS: After participation in an interdisciplinary pain program, persons with SCI and chronic neuropathic pain demonstrated increased involvement in learning and maintenance of coping strategies for chronic pain. Participation also led to less pain interference in daily life and a greater sense of control over one's life. CONCLUSIONS: Participation in an interdisciplinary pain program does not reduce pain severity, but it can help persons with SCI and chronic neuropathic pain cope with pain, lessen interference of pain, and improve their sense of control. PMID- 23684780 TI - Effect of pit and fissure sealants on caries detection by a fluorescent camera system. AB - OBJECTIVE: The aim of this study was to evaluate the effect of sealant placement on the detection of caries by a fluorescent camera (FC), the Spectra caries detector. MATERIALS AND METHODS: In a laboratory study, FC images and readings were obtained from 31 extracted teeth, before and following application of clear sealants (Shofu Clear or Delton unfilled), or opaque sealants (3M Clinpro or Delton FS). Teeth were then sectioned and examined for enamel or dentine caries. Using each tooth's true caries diagnosis, the sensitivity and specificity of the FC measurements in detecting dentine caries was calculated. In the clinical study, FC readings were obtained from 41 molars in children prior to and following application of clear sealants. RESULTS: Following application of Shofu or Delton unfilled there were reductions in the mean FC readings of 10% (p=0.5) and 8.2% (p=0.009), respectively. Application of two opaque sealants, 3M or Delton FS significantly reduced mean FC readings 16.2% and 20.8% (p<0.5), respectively. Although the carious lesions could still be observed in FC images from teeth with opaque sealants there was a significant loss of sensitivity in detecting dentinal caries. Clear sealant application caused an insignificant loss of detection sensitivity. Following application of clear sealants to children's molars there was a small (4.01%) but significant (p<0.01) reduction in FC readings recorded from these teeth. CONCLUSIONS: The FC can detect caries under clear sealants with little loss of sensitivity. Although lesions can be seen through opaque sealants, loss of sensitivity precludes accurate lesion assessment. PMID- 23684784 TI - An automatic rat brain extraction method based on a deformable surface model. AB - The extraction of the brain from the skull in medical images is a necessary first step before image registration or segmentation. While pre-clinical MR imaging studies on small animals, such as rats, are increasing, fully automatic imaging processing techniques specific to small animal studies remain lacking. In this paper, we present an automatic rat brain extraction method, the Rat Brain Deformable model method (RBD), which adapts the popular human brain extraction tool (BET) through the incorporation of information on the brain geometry and MR image characteristics of the rat brain. The robustness of the method was demonstrated on T2-weighted MR images of 64 rats and compared with other brain extraction methods (BET, PCNN, PCNN-3D). The results demonstrate that RBD reliably extracts the rat brain with high accuracy (>92% volume overlap) and is robust against signal inhomogeneity in the images. PMID- 23684782 TI - Anti-CD33-antibodies labelled with the alpha-emitter Bismuth-213 kill CD33 positive acute myeloid leukaemia cells specifically by activation of caspases and break radio- and chemoresistance by inhibition of the anti-apoptotic proteins X linked inhibitor of apoptosis protein and B-cell lymphoma-extra large. AB - AIM: The emerging interest in radioimmunotherapies employing alpha-emitters for cancer treatment like high risk-leukaemia leads to the question of how these radionuclides exhibit their cytotoxicity. To clarify the molecular mechanisms of cell death induction, we investigated the molecular effects of the alpha-emitter Bismuth-213 (Bi-213) bound to a monoclonal anti-CD33-antibody ([Bi-213]anti-CD33) on the cell cycle and on apoptosis induction in sensitive as well as in beta- and gamma-radiation-resistant CD33-positive acute myeloid leukaemia (AML) cells. METHODS: The cytotoxic potential of the radioimmunoconjugate [Bi-213]anti-CD33 was analysed in the CD33-expressing human AML cell line HL-60 and in radiation- and chemoresistant HL-60-derived cell lines. Cell cycle and apoptosis induction analyses were performed via flow cytometry. Activation of apoptosis pathways was determined by immunodetection. RESULTS: [Bi-213]anti-CD33 induced apoptotic cell death in CD33-positive AML cells specifically. Molecular analyses revealed that the intrinsic mitochondrial pathway of apoptosis was activated resulting in caspase-9 activation. In the apoptotic executioner cascade caspase-3 was activated and its substrate poly (ADP-ribose) polymerase (PARP) was cleaved. Notably, [Bi-213]anti-CD33 overcame radio- and chemoresistance by reversing deficient activation of apoptosis pathways in resistant CD33-positive AML cells and by the downregulation of inhibitors of apoptosis B-cell lymphoma-extra large (Bcl-xL) and X-linked inhibitor of apoptosis protein (XIAP) involved in leukaemia resistance. CONCLUSION: [Bi-213]anti-CD33 exhibits its cytotoxic effects specifically in CD33-expressing AML cells via induction of the intrinsic, mitochondrial pathway of apoptosis. The abrogation of chemo- and radioresistances and the reactivation of apoptotic pathways seem to be promising for the treatment of patients with so far untreatable resistant AML and underline the importance of this emerging therapeutic approach of targeted alpha-therapies. PMID- 23684783 TI - Baseline prostate-specific antigen measurements and subsequent prostate cancer risk in the Danish Diet, Cancer and Health cohort. AB - AIM: Although prostate-specific antigen (PSA) screening reduces mortality from prostate cancer, substantial over-diagnosis and subsequent overtreatment are concerns. Early screening of men for PSA may serve to stratify the male population by risk of future clinical prostate cancer. METHODS AND MATERIAL: Case control study nested within the Danish 'Diet, Cancer and Health' cohort of 27,179 men aged 50-64 at enrolment. PSA measured in serum collected at cohort entry in 1993-1997 was used to evaluate prostate cancer risk diagnosed up to 14 years after. We identified 911 prostate cancer cases in the Danish Cancer Registry through 31st December 2007 1:1 age-matched with cancer-free controls. Aggressive cancer was defined as >= T3 or Gleason score >= 7 or N1 or M1. Statistical analyses were based on conditional logistic regression with age as underlying time axis. RESULTS: Total PSA and free-to-total PSA ratio at baseline were strongly associated with prostate cancer risk up to 14 years later. PSA was grouped in quintiles and free-to-total PSA ratio divided in three risk groups. The incidence rate ratio for prostate cancer was 150 (95% confidence interval, 72 310) among men with a total PSA in the highest quintile (> 5.1 ng/ml) compared to the lowest (< 0.80 ng/ml). The risk of aggressive cancer was highly elevated in men with a PSA level in the highest quintile. The results indicate that one-time measurement of PSA could be used in an individualised screening strategy, sparing a large proportion of men from further PSA-based screening. PMID- 23684781 TI - Phase II study of satraplatin and prednisone in patients with metastatic castration-resistant prostate cancer: a pharmacogenetic assessment of outcome and toxicity. AB - BACKGROUND: We assessed the effect of excision repair cross-complementing group 1 (ERCC1) and x-ray cross-complementing group 1 (XRCC1) gene polymorphisms on treatment outcomes with satraplatin and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy. PATIENTS AND METHODS: Twenty-four patients were enrolled in this single arm study. The primary objective was to determine if the presence of ERCC1 Asn118Asn (N118N, 500C>T, rs11615) and XRCC1 Arg399Gln (R399Q, 1301G>A, rs25487) genetic variants might be associated with an impact on progression-free survival (PFS); secondary objectives included overall response, survival, and toxicity. RESULTS: After population stratification by race, white patients carrying heterozygous or variant genotypes at the ERCC1 C>T locus had a >3-fold longer median PFS (5.8 vs. 1.8 months; 2P = .18, adjusted) and 5-fold longer median overall survival (OS) (15.7 vs. 3.2 months; 2P = .010, adjusted) than did patients carrying only wild-type alleles. For the XRCC1 G>A variant, without regard to race, patients carrying the wild-type GG alleles had a longer PFS (9.3 months) than those carrying GA or AA alleles (2.7 months; 2P = .02). Similarly, those carrying GG alleles did not reach median OS, whereas those carrying GA or AA alleles had a median OS of 9.6 months (2P = .12, adjusted). Multivariable analysis by using Cox proportional hazards modeling demonstrated that only XRCC1 was associated with PFS. CONCLUSIONS: To our knowledge, this is the first prospective study to date in patients with metastatic castration-resistant prostate cancer that describes predictive germline polymorphisms of ERCC1 and XRCC1 for assessing the clinical activity of satraplatin. PMID- 23684785 TI - Protocadherin 17 regulates presynaptic assembly in topographic corticobasal Ganglia circuits. AB - Highly topographic organization of neural circuits exists for the regulation of various brain functions in corticobasal ganglia circuits. Although neural circuit specific refinement during synapse development is essential for the execution of particular neural functions, the molecular and cellular mechanisms for synapse refinement are largely unknown. Here, we show that protocadherin 17 (PCDH17), one of the nonclustered delta2-protocadherin family members, is enriched along corticobasal ganglia synapses in a zone-specific manner during synaptogenesis and regulates presynaptic assembly in these synapses. PCDH17 deficiency in mice causes facilitated presynaptic vesicle accumulation and enhanced synaptic transmission efficacy in corticobasal ganglia circuits. Furthermore, PCDH17(-/-) mice exhibit antidepressant-like phenotypes that are known to be regulated by corticobasal ganglia circuits. Our findings demonstrate a critical role for PCDH17 in the synaptic development of specific corticobasal ganglia circuits and suggest the involvement of PCDH17 in such circuits in depressive behaviors. PMID- 23684787 TI - Enrichment of Leishmania donovani ATP-binding proteins using a staurosporine capture compound. AB - Trypanosomatid parasites of the genus Leishmania cause severe human diseases collectively termed leishmaniasis. Parasite ATP-binding proteins have emerged as potent targets for chemotherapeutic intervention. However, many parasite-specific ATP-binding proteins may escape current efforts in drug target identification, validation and deconvolution due to the lack of sequence conservation and functional annotation of these proteins in early branching eukaryotic trypanosomatids. Here, we selectively enriched for ATP-binding proteins from Leishmania donovani axenic promastigote and amastigote total protein extracts utilizing a Capture CompoundTM (CC) linked to the ATP-competitive inhibitor staurosporine. As judged by in-gel kinase activity assay and competitive inhibition with free staurosporine, the CC specifically enriched for parasite phosphotransferases. Comparative nanoLC-MS(n) analysis identified 70 captured proteins, including 24 conserved protein kinases, and 32 hypothetical proteins with potential ATP-binding function. We identified conserved signature sequence motifs characteristic for staurosporine-binding protein kinases, and identified the hypothetical proteins LinJ.20.0280 and LinJ.09.1630 as novel ATP-binding proteins. Thus, functional enrichment procedures such as described here, combined with bio-informatics analyses and activity assays, provide powerful tools for the discovery of parasite-specific ATP-binding proteins that escape homology-based identification, which can be subsequently targeted for pharmacological intervention. BIOLOGICAL SIGNIFICANCE: Functional enrichment using a Capture CompoundTM linked to the ATP-competitive inhibitor staurosporine provides a powerful new tool for the discovery of parasite-specific ATP-binding proteins that escape homology-based identification, which can be subsequently targeted for pharmacological intervention. PMID- 23684786 TI - Imaging of neural ensemble for the retrieval of a learned behavioral program. AB - The encoding of long-term associative memories for learned behaviors is a fundamental brain function. Yet, how behavior is stably consolidated and retrieved in the vertebrate cortex is poorly understood. We trained zebrafish in aversive reinforcement learning and measured calcium signals across their entire brain during retrieval of the learned response. A discrete area of dorsal telencephalon that was inactive immediately after training became active the next day. Analysis of the identified area indicated that it was specific and essential for long-term memory retrieval and contained electrophysiological responses entrained to the learning stimulus. When the behavioral rule changed, a rapid spatial shift in the functional map across the telencephalon was observed. These results demonstrate that the retrieval of long-term memories for learned behaviors can be studied at the whole-brain scale in behaving zebrafish in vivo. Moreover, the findings indicate that consolidated memory traces can be rapidly modified during reinforcement learning. PMID- 23684788 TI - Identification of proteins inducing short-lived antibody responses from excreted/secretory products of Schistosoma japonicum adult worms by immunoproteomic analysis. AB - The excretory/secretory antigens of Schistosoma japonicum (Sj ESAgs) play important roles in host-parasite immune interactions. In this study, the antibody response patterns to Sj ESAgs in sera of individual rabbits at the healthy stage, 2-6 weeks post-infection and 4-16 weeks after treatment were examined. Antigens inducing short-lived antibody responses were selected by comparing differences in immune recognition of proteins in sera across the different stages by Western blotting and identified by matrix-assisted laser desorption/ionization time-of flight tandem mass spectrometry (MALDI-TOF/TOF-MS). The diagnostic value of these short-lived antibody responses for schistosomiasis was investigated. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was identified as a major antigen inducing a short-lived antibody response in Sj ESAgs. The antibody response against Sj GAPDH decreased at week 4 and disappeared between weeks 8-12 after effective chemical treatment of rabbits, and this response declined to negative levels in schistosomiasis patients one year after treatment. The intensity of the antibody response against Sj GAPDH was dependent on parasite load in mice. The sensitivity and specificity of IgG antibodies against recombinant Sj GAPDH for schistosomiasis diagnosis were 82.5% and 91.3%. Our findings suggest that Sj GAPDH induces short-lived antibody responses in the host, and detecting IgG against this antigen provides the basis for developing a potential method for diagnosis and evaluating treatment effects for schistosomiasis japonicum. BIOLOGICAL SIGNIFICANCE: Schistosomiasis is one of the world's major public health problems. Developing effective diagnostic methods for detecting schistosome-specific antibodies to effectively identify active infections is part of a critical strategy for blocking transmission of the parasite and eradicating schistosomiasis. The excretory/secretory antigens of S. japonicum (Sj ESAgs) play important roles in host-parasite immune interactions. In our study, we examine the antibody response patterns to Sj ESAgs within individual rabbits at the healthy, schistosome infection and post-treatment stages by Western blotting. Proteins among the Sj ESAgs inducing short-lived antibody responses were identified by Matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry (MALDI-TOF/TOF-MS), and their potential as immune markers for diagnosis and evaluating therapeutic effects in schistosomiasis was evaluated. Our findings suggest that S. japonicum glyceraldehyde-3-phosphate dehydrogenase (GAPDH) induces short-lived antibody responses in the host, and detecting IgG against this antigen provides the basis for developing a potential method for diagnosis and evaluating treatment effects for schistosomiasis japonicum. PMID- 23684789 TI - Quantitative proteomic analysis reveals evolutionary divergence and species specific peptides in the Alexandrium tamarense complex (Dinophyceae). AB - The Alexandrium tamarense/catenella/fundyense complex is the major causative agent responsible for harmful algal blooms and paralytic shellfish poisoning around the world. However, taxonomy of the A. tamarense complex is contentious and the evolutionary relationships within the complex are unclear. This study compared protein profiles of the A. tamarense complex collected from different geographic regions using the two dimensional fluorescence difference gel electrophoresis (2-D DIGE) approach, and identified species-specific peptides using MALDI-TOF/TOF mass spectrometry. The results showed that three Alexandrium morphotypes presented significantly different protein expression patterns with about 30-40% shared proteins. However, ecotypes from different geographic regions within a species exhibited the same expression patterns, although a few proteins were altered in abundance. Several proteins, i.e. ribulose-1,5-bisphosphate carboxylase oxygenase form II, plastid protein NAP50, methionine S adenosyltransferase, and peridinin-chlorophyll a-binding protein, were identified and presented different shift patterns in isoelectric point and/or molecular weight in the 2-D DIGE gels, indicating that amino acid mutation and/or posttranslational modification of these proteins had occurred. The species specific peptide mass fingerprint and amino acid sequence of ribulose-1,5 bisphosphate carboxylase oxygenase were characterized in the A. tamarense complex, and amino acid substitution occurred among them. This study indicated that evolutionary divergence had occurred at the proteomic level in the A. tamarense complex, and that the species-specific peptides could be used as potential biomarkers to distinguish the three morphotypes. BIOLOGICAL SIGNIFICANCE: Scientific question: The Alexandrium tamarense/catenella/fundyense complex is the major causative agent responsible for harmful algal blooms and paralytic shellfish poisoning around the world. However, taxonomy of the A. tamarense complex is contentious and the evolutionary relationships within the complex are unclear, which has seriously impeded our understanding of Alexandrium causing HABs and, consequently, the monitoring, mitigation and prevention. Technical significance: This study, for the first time, compared the global protein expression patterns of eight ecotypes from the A. tamarense complex and identified species-specific peptides using a quantitative proteomic approach combining 2-D DIGE and MALDI-TOF/TOF MS. SCIENTIFIC SIGNIFICANCE: This study demonstrated that the evolutionary divergence had occurred in the A. tamarense complex at the proteomic level, and the complex should be classified into three species, i.e. A. tamarense, A. catenella, and A. fundyense. Moreover, the species specific peptide mass fingerprints could be used as potential biomarkers to distinguish the three morphotypes. PMID- 23684790 TI - Mild overexpression of Mecp2 in mice causes a higher susceptibility toward seizures. AB - An intriguing finding about the gene encoding methyl-CpG binding protein 2 (MeCP2) is that the loss-of-function mutations cause Rett syndrome and duplication (gain-of-function) of MECP2 leads to another neurological disorder termed MECP2 duplication syndrome. To ensure proper neurodevelopment, a precise regulation of MeCP2 expression is critical, and any gain or loss of MeCP2 over a narrow threshold level may lead to postnatal neurological impairment. To evaluate MeCP2 dosage effects, we generated Mecp2(WT_EGFP) transgenic (TG) mouse in which MeCP2 (endogenous plus TG) is mildly overexpressed (approximately 1.5*). The TG MeCP2(WT_EGFP) fusion protein is functionally active, as cross breeding of these mice with Mecp2 knockout mice led to alleviation of major phenotypes in the null mutant mice, including premature lethality. To characterize the Mecp2(WT_EGFP) mouse model, we performed an extensive battery of behavioral tests, which revealed that these mice manifest increased aggressiveness and higher pentylenetetrazole (PTZ)-induced seizure propensity. Evaluation of neuronal parameters revealed a reduction in the number of tertiary branching sites and increased spine density in Mecp2(WT_EGFP) transgenic (TG) neurons. Treatment of TG neurons with epileptogenic compound-PTZ led to a marked increase in amplitude and frequency of calcium spikes. Based on our ex vivo and in vivo data, we conclude that epileptic seizures are manifested as the first symptom when MeCP2 is mildly overexpressed in mice. PMID- 23684791 TI - Sustained activation of EGFR triggers renal fibrogenesis after acute kidney injury. AB - Severe acute kidney injury (AKI) is frequently accompanied by maladaptive repair and renal fibrogenesis; however, the molecular mechanisms that mediate these acute and chronic consequences of AKI remain poorly understood. In this study, we examined the role of epidermal growth factor receptor (EGFR) in these processes using waved-2 (Wa-2) mice, which have reduced EGFR activity, and their wild-type (WT) littermates after renal ischemia. Renal EGFR phosphorylation was induced within 2 days after ischemia, increased over time, and remained elevated at 28 days in WT mice, but this was diminished in Wa-2 mice. At the early stage of postischemia (2 days), Wa-2 mice developed more severe acute renal tubular damage with less reparative responses as indicated by enhanced tubular cell apoptosis, and reduced dedifferentiation and proliferation as compared to WT animals. At the late stage of postischemia (28 days), Wa-2 mice exhibited a less severe renal interstitial fibrosis as shown by reduced activation/proliferation of renal myofibroblasts and decreased deposition of extracellular matrix proteins. EGFR activation also contributed to cell cycle arrest at the G2/M phase, a cellular event associated with production of profibrogenetic factors, in the injured kidney. Collectively, these results indicate that severe AKI results in sustained activation of EGFR, which is required for reparative response of renal tubular cells initially, but eventually leads to fibrogenesis. PMID- 23684792 TI - Regular treatments of praziquantel do not impact on the genetic make-up of Schistosoma mansoni in Northern Senegal. AB - The Senegal River Basin (SRB) experienced a major epidemic of intestinal schistosomiasis in the early nineties, after the construction of a dam for irrigation purposes. Exceptionally low cure rates following praziquantel (PZQ) treatment at the onset of the epidemic raised concerns about PZQ resistant strains of Schistosoma mansoni, although they could also be attributed to the intense transmission at that time. A field study in the same region more than 15 years later found cure rates for S. mansoni still to be low, whereas Schistosomahaematobium responded well to treatment. We collected S. mansoni miracidia from children at base-line prior to treatment, six months after two PZQ treatments and two years after the start of the study when they had received a total of five PZQ treatments. In total, 434 miracidia from 12 children were successfully genotyped with at least six out of nine DNA microsatellite loci. We found no significant differences in the genetic diversity of, and genetic differentiation between parasite populations before and after repeated treatment, suggesting that PZQ treatment does not have an impact on the neutral evolution of the parasite. This is in stark contrast with a similar study in Tanzania where a significant decrease in genetic diversity was observed in S. mansoni miracidia after a single round of PZQ treatment. We argue that PZQ resistance might play a role in our study area, although rapid re-infection cannot be excluded. It is important to monitor this situation carefully and conduct larger field studies with short-term follow-up after treatment. Since PZQ is the only general schistosomicide available, the possibility of PZQ resistance is of great concern both for disease control and for curative use in clinical practice. PMID- 23684793 TI - Linkage disequilibrium of the IS629 insertion among different clades of enterohemorrhagic Escherichia coli O157:H7/H-strains. AB - The distribution of insertion sequence (IS) 629 was investigated among enterohemorrhagic Escherichia coli O157:H7/H-(O157) strains in different clades. Minimum spanning tree analysis showed that most strains in each clade clustered in a separate branch, indicating biased distribution of the IS629 insertion in different clades. The standardized index of association of the IS629 distribution data showed linkage disequilibrium in the strains in every clade, indicating that IS629 distribution data could be used for population genetic analysis. For this population genetic analysis, the Phi(PT) value, an analogue of F(ST), was calculated and indicated that clade 7 strains could be split into two clades based on their lineages. The degree of pairwise linkage disequilibrium was quite different among these two groups. The clade 7 split was in agreement with the model of O157 paraphyletic evolution and a new designation of the lineage II clades was proposed. The prevalence of strains with an IS629 insertion in certain loci was significantly different in different clades. Some of these significant differences were in loci in strains in branches of clades that were close in the O157 phylogenetic model, suggesting that IS629 insertion/deletion was not directly related to the divergence of O157 clades. PMID- 23684794 TI - Molecular dysfunctions in acute rejection after renal transplantation revealed by integrated analysis of transcription factor, microRNA and long noncoding RNA. AB - Acute rejection remains a problem in renal transplantation. To further illustrate the mechanism of rejection, we integrated protein array-based proteomics and RNA microarray-based genomics to investigate the transcription factor, microRNA and long noncoding RNA of biopsies of three patients with acute rejections and a control group. 99 transcription factors were identified in acute rejection biopsies compared to normal renal tissue. We correlated transcription factor data with microRNA and long noncoding RNA data sets and reported the expression of 5 transcription factors (AP-1, AP-4, STATx, c-Myc and p53), 12 miRNAs and 32 lncRNAs in acute rejection biopsies. Pathway analysis demonstrated that over presentation of transcription factor pathway plays a critical role in acute rejection. This is the first study to comprehensively report the acute rejection transcription factor pathway. Integrative analysis of the transcription factor, microRNA and long noncoding RNA provided an expansive view of molecular signaling pathways in acute rejection after renal transplantation. PMID- 23684795 TI - Improving maltodextrin specificity for enzymatic synthesis of 2-O-d glucopyranosyl-l-ascorbic acid by site-saturation engineering of subsite-3 in cyclodextrin glycosyltransferase from Paenibacillus macerans. AB - In this work, the subsite-3 of cyclodextrin glycosyltransferase (CGTase) from Paenibacillus macerans was engineered to improve maltodextrin specificity for 2-O d-glucopyranosyl-l-ascorbic acid (AA-2G) synthesis. Specifically, the site saturation mutagenesis of tyrosine 89, asparagine 94, aspartic acid 196, and aspartic acid 372 in subsite-3 was separately performed, and three mutants Y89F (tyrosine->phenylalanine), N94P (asparagine->proline), and D196Y (aspartic acid >tyrosine) produced higher AA-2G titer than the wild-type and the other mutants. Previously, we found the mutant K47L (lysine->leucine) also had a higher maltodextrin specificity. Therefore, the four mutants K47L, Y89F, N94P, and D196Y were further used to construct the double, triple, and quadruple mutations. Among the 11 combinational mutants, the quadruple mutant K47L/Y89F/N94P/D196Y produced the highest AA-2G titer of 2.23g/L, which was increased by 85.8% compared to that produced by the wild-type CGTase. The reaction kinetics of all the mutants were modeled, and the pH and thermal stabilities of all the mutants were analyzed. The structure modeling indicated that the enhanced maltodextrin specificity may be related with the changes of hydrogen bonding interactions between the side chain of residue at the four positions (47, 89, 94, and 196) and the substrate sugars. PMID- 23684796 TI - A nervous predisposition to unrepaired DNA double strand breaks. AB - Ataxia-telangiectasia (A-T) has for a long time stood apart from most other human neurodegenerative syndromes by the characteristic failure of cells derived from these patients to properly repair DNA damage-induced by ionizing radiation. The discovery of mutations in the ATM gene as being the underlying cause for A-T and the demonstration that the ATM protein functions as a DNA damage-responsive kinase has defined current research focusing on decoding how the cell responds to genotoxic stress. Yet, despite significant advances in delineating the cellular DNA damage response pathways coordinated by ATM, very little headway has been made toward understanding how loss of ATM leads to progressive cerebellar ataxia and whether this can be attributed to an underlying defect in DNA double strand break repair (DSBR). Since its identification, A-T has been used as the archetypal model for how a deficiency in DNA repair affects both the development and maintenance of the nervous and immune systems in humans as well as contributing to the process of tumourigenesis. However, following the growing availability and cost effectiveness of next generation sequencing technologies, the increasing recognition of novel human disorders associated with abnormal DNA repair has demonstrated that the neuropathology typified by A-T is an 'exception' rather than the 'rule'. As a consequence, this throws into doubt the longstanding hypothesis that the neurodegeneration seen in A-T is due to the progressive loss of damaged neurons that have acquired toxic levels of unrepaired DNA lesions over time. Therefore, this review aims to address the question: Is defective DNA double strand break repair an underlying cause of neurodegeneration? PMID- 23684798 TI - The role of arginine methylation in the DNA damage response. AB - Post-translational modifications are well-known modulators of DNA damage signaling and epigenetic gene expression. Protein arginine methylation is a covalent modification that results in the addition of methyl groups to the nitrogen atoms of the arginine side chains and is catalyzed by a family of protein arginine methyltransferases (PRMTs). In the past, arginine methylation was mainly observed on abundant proteins such as RNA-binding proteins and histones, but recent advances have revealed a plethora of arginine methylated proteins implicated in a variety of cellular processes including RNA metabolism, epigenetic regulation and DNA repair pathways. Herein, we discuss these recent advances, focusing on the role of PRMTs in DNA damage signaling and its importance for maintaining genomic stability. PMID- 23684797 TI - DNA damage response in peripheral nervous system: coping with cancer therapy induced DNA lesions. AB - In the absence of blood brain barrier (BBB) the DNA of peripheral nervous system (PNS) neurons is exposed to a broader spectrum of endogenous and exogenous threats compared to that of the central nervous system (CNS). Hence, while CNS and PNS neurons cope with many similar challenges inherent to their high oxygen consumption and vigorous metabolism, PNS neurons are also exposed to circulating toxins and inflammatory mediators due to relative permeability of PNS blood nerve barrier (BNB). Consequently, genomes of PNS neurons incur greater damage and the question awaiting investigation is whether specialized repair mechanisms for maintenance of DNA integrity have evolved to meet the additional needs of PNS neurons. Here, I review data showing how PNS neurons manage collateral DNA damage incurred in the course of different anti-cancer treatments designed to block DNA replication in proliferating tumor cells. Importantly, while PNS neurotoxicity and concomitant chemotherapy-induced peripheral neuropathy (CIPN) are among major dose limiting barriers in achieving therapy goals, CIPN is partially reversible during post-treatment nerve recovery. Clearly, cell recovery necessitates mobilization of the DNA damage response and underscores the need for systematic investigation of the scope of DNA repair capacities in the PNS to help predict post-treatment risks to recovering neurons. PMID- 23684799 TI - PARP-mediated repair, homologous recombination, and back-up non-homologous end joining-like repair of single-strand nicks. AB - Double-strand breaks (DSBs) in chromosomal DNA can induce both homologous recombination (HR) and non-homologous end-joining (NHEJ). Recently we showed that single-strand nicks induce HR with a significant reduction in toxicity and mutagenic effects associated with NHEJ. To further investigate the differences and similarities of DSB- and nick-induced repair, we used an integrated reporter system in human cells to measure HR and NHEJ produced by the homing endonuclease I-AniI and a designed 'nickase' variant that nicks the same target site, focusing on the PARP and HR repair pathways. PARP inhibitors, which block single-strand break repair, increased the rate of nick-induced HR up to 1.7-fold but did not affect DSB-induced HR or mutNHEJ. Additionally, expression of the PALB2 WD40 domain in trans acted as a dominant-negative inhibitor of both DSB- and nick induced HR, sensitized cells to PARP inhibition, and revealed an alternative mutagenic repair pathway for nicks. Thus, while both DSB- and nick-induced HR use a common pathway, their substrates are differentially processed by cellular factors. These results also suggest that the synthetic lethality of PARP and BRCA may be due to repair of nicks through an error prone, NHEJ-like mechanism that is active when both PARP and HR pathways are blocked. PMID- 23684801 TI - Macroscopic characteristics of the praying mantis electroretinogram. AB - We described the macroscopic characteristics of the praying mantis ERG in three species, Tenodera aridifolia sinensis, Sphodromantis lineola, and Popa spurca. In all cases, when elicited by square wave light pulses longer than 400 ms, light adapted (LA) ERGs consisted of four component waveforms: a cornea negative transient and sustained ON, a cornea negative transient OFF, and a cornea positive sustained OFF. The former two ON, and the latter OFF components were attributed to photoreceptor depolarization and repolarization, respectively. Metabolic stress via CO2 induced anoxia selectively eliminated the transient OFF (independent of its effect on the other components) suggesting the transient OFF represents activity of the lamina interneurons on which the photoreceptors synapse. Dark adapted (DA) ERGs differed from LA ERGs in that the sustained ON and OFF amplitudes were larger, and the transient ON and OFF components were absent. Increased stimulus durations increased the amplitudes and derivatives of, and decreased the latencies to the maximum amplitudes of the OFF components. Increasing stimulus intensity increased the amplitude of the sustained ON and OFF components, but not the transient OFF. These results suggest that the mantis' visual system displays increased contrast coding efficiency with increased light adaptation, and that there are differences in gain between photoreceptor and lamina interneuron responses. Finally, responses to luminance decrements as brief a 1 ms were evident in LA recordings, and were resolved at frequencies up to 60 Hz. PMID- 23684802 TI - Excess mortality attributable to hip-fracture: a relative survival analysis. AB - INTRODUCTION: Individuals with hip fracture are at substantially increased risk of mortality. The aim of this study was to estimate the excess mortality attributable to hip fracture in elderly men and women. METHODS: The Dubbo Osteoporosis Epidemiology Study was designed as a prospective epidemiologic investigation, in which more than 2000 men and women aged 60+ as of 1989 had been followed for 21 years. During the follow-up period, the incidence of atraumatic hip fractures was ascertained by X-ray reports, and mortality was ascertained by the New South Wales Birth, Death and Marriage Registry. Relative survival ratios were estimated by taking into account the age-and-sex specific expected survival in the general Australian population from 1989 to 2010. RESULTS: During the follow-up period 151 women and 55 men sustained a hip fracture. Death occurred in 86 (57%) women and 36 (66%) men. In women, the cumulative relative survival post hip-fracture at 1, 5 and 10 years was 0.83 (95% confidence interval (CI) 0.76 0.89), 0.59 (95% CI 0.48-0.68), and 0.31 (95% CI 0.20-0.43), respectively; in men, the corresponding estimates of relative survival were: 0.63 (95% CI 0.48 0.75), 0.48 (95% CI 0.32-0.63), and 0.36 (95% CI 0.18-0.56). On average post hip fracture women died 4 years earlier (median: 4.1, inter-quartile range (IQR) 1.7 7.8) and men died 5 years earlier (median = 4.8, IQR 2.4-7.0) than expected. For every six women and for every three men with hip fracture one extra death occurred above that expected in the background population. CONCLUSION: Hip fracture is associated with reduced life expectancy, with men having a greater reduction than women, even after accounting for time-related changes in background mortality in the population. These data underscore that hip fracture is an independent clinical risk factor for mortality. PMID- 23684803 TI - Mineralization kinetics in murine trabecular bone quantified by time-lapsed in vivo micro-computed tomography. AB - Trabecular bone is a highly dynamic tissue due to bone remodeling, mineralization and demineralization. The mineral content and its spatial heterogeneity are main contributors to bone quality. Using time-lapsed in vivo micro-computed tomography (micro-CT), it is now possible to resolve in three dimensions where bone gets resorbed and deposited over several weeks. In addition, the gray values in the micro-CT images contain quantitative information about the local tissue mineral density (TMD). The aim of this study was to measure how TMD increases with time after new bone formation and how this mineralization kinetics is influenced by mechanical stimulation. Our analysis of changes in TMD was based on an already reported experiment on 15-week-old female mice (C57BL/6), where in one group the sixth caudal vertebra was mechanically loaded with 8N, while in the control group no loading was applied. Comparison of two consecutive images allows the categorization of bone into newly formed, resorbed, and quiescent bone for different time points. Gray values of bone in these categories were compared layer-wise to minimize the effects of beam hardening artifacts. Quiescent bone in the control group was found to mineralize with a rate of 8 +/- 1 mgHA/cm(3) per week, which is about half as fast as observed for newly formed bone. Mechanical loading increased the rate of mineral incorporation by 63% in quiescent bone. The week before bone resorption, demineralization could be observed with a drop of TMD by 36 +/- 4 mgHA/cm(3) in the control and 34 +/- 3 mgHA/cm(3) in the loaded group. In conclusion, this study shows how time-lapsed in vivo micro-CT can be used to assess changes in TMD of bone with high spatial and temporal resolution. This will allow a quantification of how bone diseases and pharmaceutical interventions influence not only microarchitecture of trabecular bone, but also its material quality. PMID- 23684805 TI - We cannot improve that which we do not measure. PMID- 23684806 TI - Targeted temperature management after cardiac arrest: how invasive do we need to be? PMID- 23684804 TI - Dietary and genetic manipulations of folate metabolism differentially affect neocortical functions in mice. AB - Converging evidence suggests that folate-mediated one-carbon metabolism may modulate cognitive functioning throughout the lifespan, but few studies have directly tested this hypothesis. This study examined the separate and combined effects of dietary and genetic manipulations of folate metabolism on neocortical functions in mice, modeling a common genetic variant in the MTHFD1 gene in humans. Mutant (Mthfd1(gt/+)) and wildtype (WT) male mice were assigned to a folate sufficient or deficient diet at weaning and continued on these diets throughout testing on a series of visual attention tasks adapted from the 5 choice serial reaction time task. WT mice on a deficient diet exhibited impulsive responding immediately following a change in task parameters that increased demands on attention and impulse control, and on trials following an error. This pattern of findings indicates a heightened affective response to stress and/or an inability to regulate negative emotions. In contrast, Mthfd1(gt/+) mice (regardless of diet) exhibited attentional dysfunction and a blunted affective response to committing an error. The Mthfd1(gt/+) mice also showed significantly decreased expression levels for genes encoding choline dehydrogenase and the alpha 7 nicotinic cholinergic receptor. The effects of the MTHFD1 mutation were less pronounced when combined with a deficient diet, suggesting a compensatory mechanism to the combined genetic and dietary perturbation of folate metabolism. These data demonstrate that common alterations in folate metabolism can produce functionally distinct cognitive and affective changes, and highlight the importance of considering genotype when making dietary folate recommendations. PMID- 23684807 TI - A non-invasive method based on head morphology to sex mature three-spined stickleback (Gasterosteus aculeatus L.) in rearing conditions. AB - A mathematical model to distinguish mature female and male three-spined sticklebacks Gasterosteus aculeatus L. 1758 is proposed. This method is based on sexual dimorphism in the head morphology. The discrimination was established on five distances of interest on the head, adjusted by the standard length of fish. The parameters were estimated based on a training set composed of 102 fish with an equilibrium sex ratio and validated on a test set composed of 69 fish. The model estimates the relationship between the percentage of fish that can be sexed with our model and the percentage of fish correctly sexed. For instance, to reach 1% of error in the sex determination, only 53% of the fish should be considered, whereas to reach 5% of error, 90% of the fish can be used. Compared to other available methods to sex G. aculeatus, the model is non invasive, not expensive, rapid, replicable, and can be calibrated outside of the breeding period. PMID- 23684808 TI - Molecular characterization and expression analysis of complement component C9 gene in the whitespotted bambooshark, Chiloscyllium plagiosum. AB - Complement system is known as highly sophisticated immune defense mechanism for antigen recognition as well as effector functions. Activation of the terminal pathway of the complement system leads to the assembly of terminal complement complexes (C5b-9), which induces the characteristic complement-mediated cytolysis. The lytic activity of shark complement involves functional analogues of mammalian C8 and C9. In this article, a full-length cDNA of C9 (CpC9) is identified from cartilaginous species, the whitespotted bambooshark, Chiloscyllium plagiosum by RACE. The CpC9 cDNA is 2263 bp in length, encoding a protein of 603 amino acids, which shares 42% and 43% identity with human and Xenopus C9 respectively. Through sequence alignment and comparative analysis, the CpC9 protein was found well conserved, with the typical modular architecture in TCCs and nearly unanimous cysteine composition from fish to mammal. Phylogenetic analysis places it in a clade with C9 orthologs in higher vertebrate and as a sister taxa to the Xenopus. Expression analysis revealed that CpC9 is constitutively highly expressed in shark liver, with much less or even undetectable expression in other tissues; demonstrating liver is the primary tissue for C9synthesis. To sum up, the structural conservation and distinctive phylogenetics might indicate the potentially vital role of CpC9 in shark immune response, though it remains to be confirmed by further study. PMID- 23684800 TI - DNA repair mechanisms in dividing and non-dividing cells. AB - DNA damage created by endogenous or exogenous genotoxic agents can exist in multiple forms, and if allowed to persist, can promote genome instability and directly lead to various human diseases, particularly cancer, neurological abnormalities, immunodeficiency and premature aging. To avoid such deleterious outcomes, cells have evolved an array of DNA repair pathways, which carry out what is typically a multiple-step process to resolve specific DNA lesions and maintain genome integrity. To fully appreciate the biological contributions of the different DNA repair systems, one must keep in mind the cellular context within which they operate. For example, the human body is composed of non dividing and dividing cell types, including, in the brain, neurons and glial cells. We describe herein the molecular mechanisms of the different DNA repair pathways, and review their roles in non-dividing and dividing cells, with an eye toward how these pathways may regulate the development of neurological disease. PMID- 23684809 TI - Acute toxic responses of the rockfish (Sebastes schlegeli) to Iranian heavy crude oil: feeding disrupts the biotransformation and innate immune systems. AB - To clarify the toxic effects of Iranian Heavy Crude Oil (IHCO) from the "Hebei spirit" oil spill, innate immune toxic effects defending on biotransformation pathway have been investigated on fish exposed to IHCO. Juvenile rockfish were exposed to IHCO in gelatin capsules by feeding. The effects on multiple fish biotransformation enzymes (Cytochrome P4501A and glutathione-S-transferase) and the expression level of the several immune response genes, including interleukin 1beta, granulocyte colony-stimulating factor and Cathepsin L, were measured in the liver, spleen and kidney. The tissue-specific expression patterns of these genes demonstrated that the highest expression levels of Cytochrome P4501A, glutathione-S-transferase, interleukin-1beta, granulocyte colony-stimulating factor, interferon stimulated gene 15 and Cathepsin L were found in the liver and that the TNF receptor was high in spleen. The oil-fed fish had significantly higher concentrations of biliary fluorescent metabolites and Cytochrome P4501A expression during the initial stage (12 ~ 48 h after exposure) than those in the liver and kidney of the sham group. Similarly, the highest mRNA expression levels of interleukin-1beta and granulocyte colony-stimulating factor were detected in the liver at the early stages of exposure (12 h after exposure). Following exposure, the levels of interferon stimulated gene 15 and granulocyte colony stimulating factor mRNA remained high at 120 h after exposure in the liver but the levels of interleukin-1beta and Cathepsin L gradually decreased to an expression level equal to or less than the sham group. Our data suggest that the innate immune and hepatodetoxification responses in oil-fed fish were induced at the initial stage of exposure to the IHCO at the same time but several immune related genes decreased to less than that of the sham group after the initial stage of response. Therefore, immune disturbances in fish exposed to IHCO may allow the pathogens, including the infectious diseases, to more easily affect the oil exposed fish. PMID- 23684810 TI - A heat shock protein 90 beta isoform involved in immune response to bacteria challenge and heat shock from Miichthys miiuy. AB - Heat shock protein 90 (HSP90) is highly conserved molecular chaperone that plays a critical role in cellular stress response. In this study, we reported the identification and functional analysis of a heat shock protein 90 gene from miiuy croaker (designated Mimi-HSP90). Mimi-HSP90 contained five conserved HSP90 protein family signatures and shared 89.6%-99.5% similarity with other known HSP90 beta isoform. Homology analysis and structure comparison further indicated that Mimi-HSP90 should be beta isoform member of the HSP90 family. The molecular evolutionary analysis showed that HSP90 was under an overall strong purifying select pressure among fish species. Mimi-HSP90 gene was constitutively expressed in ten examined tissues, and the expression level of liver was higher than in other tissues. The expression level of Mimi-HSP90 gene under bacterial infection and heat shock were analyzed by real-time quantitative RT-PCR, resulted in significant changes in liver, spleen, and kidney tissues. The purified recombinant pET-HSP90 protein was used to produce the polyclonal antibody in mice. The specificity of the antibody was determined by Western blot analysis. All results suggested that Mimi-HSP90 was involved in thermal stress and immune response in miiuy croaker. PMID- 23684811 TI - Immune responses during the larval stages of Mytilus galloprovincialis: metamorphosis alters immunocompetence, body shape and behavior. AB - We investigated the development of the immune system during the larval stages of the mussel Mytilus galloprovincialis. The ability of trochophore and veliger larvae to phagocytose foreign particles (Escherichia coli and zymosan) was measured. Phagocytosis was detected as early as 24 h post-fertilization (hpf) using flow cytometry and fluorescence microscopy. However, although there was a high basal production of reactive oxygen and nitrogen species (ROS and NRS), the phagocytosis of zymosan did not trigger an associated increase in radical production. In addition, a panel of immune-related mussel genes (Myticin B, Myticin C, Mytilin B, Mytimycin precursor 1, Macrophage migration inhibition factor, lysozyme, C1q, membrane attack complex protein and fibrinogen-related protein) was selected for expression profile analysis throughout the different developmental stages (trochophore, veliger, metamorphosis, post-settlement and spat). The expression of these genes increased during the transition from trochophore to spat, and the level of expression was higher in oocytes than in trochophores, suggesting that gene expression during the first larval stages might be maternal in origin. Metamorphosis was identified as a crucial stage when larvae increased the expression of immune-related genes and responded to environmental signals. Whole-mount in situ hybridization studies showed the mantle edge as an important area in the development of immunocompetence in bivalve larvae. Larvae responded to both live and heat-inactivated bacteria by modulating expression of immune-related genes. Altogether, our results support that during the early stages of M. galloprovincialis development, immune mechanisms emerge to aid larvae in managing infections. PMID- 23684813 TI - Finite element analysis of stress distribution in anchor teeth in surgically assisted rapid palatal expansion. AB - The treatment of a transverse maxillary deficiency in skeletally mature individuals should include surgically assisted rapid palatal expansion. This study evaluated the distribution of stresses that affect the expander's anchor teeth using finite element analysis when the osteotomy is varied. Five virtual models were built and the surgically assisted rapid palatal expansion was simulated. Results showed tension on the lingual face of the teeth and alveolar bone, and compression on the buccal side of the alveolar bone. The subtotal Le Fort I osteotomy combined with intermaxillary suture osteotomy seemed to reduce the dissipation of tensions. Therefore, subtotal Le Fort I osteotomy without a step in the zygomaticomaxillary buttress, combined with intermaxillary suture osteotomy and pterygomaxillary disjunction may be the osteotomy of choice to reduce tensions on anchor teeth, which tend to move mesiobuccally (premolar) and distobuccally (molar). PMID- 23684812 TI - Genome-wide, whole mount in situ analysis of transcriptional regulators in zebrafish embryos. AB - Transcription is the primary step in the retrieval of genetic information. A substantial proportion of the protein repertoire of each organism consists of transcriptional regulators (TRs). It is believed that the differential expression and combinatorial action of these TRs is essential for vertebrate development and body homeostasis. We mined the zebrafish genome exhaustively for genes encoding TRs and determined their expression in the zebrafish embryo by sequencing to saturation and in situ hybridisation. At the evolutionary conserved phylotypic stage, 75% of the 3302 TR genes encoded in the genome are already expressed. The number of expressed TR genes increases only marginally in subsequent stages and is maintained during adulthood suggesting important roles of the TR genes in body homeostasis. Fewer than half of the TR genes (45%, n=1711 genes) are expressed in a tissue-restricted manner in the embryo. Transcripts of 207 genes were detected in a single tissue in the 24h embryo, potentially acting as regulators of specific processes. Other TR genes were expressed in multiple tissues. However, with the exception of certain territories in the nervous system, we did not find significant synexpression suggesting that most tissue-restricted TRs act in a freely combinatorial fashion. Our data indicate that elaboration of body pattern and function from the phylotypic stage onward relies mostly on redeployment of TRs and post-transcriptional processes. PMID- 23684814 TI - The 'double-barrel' approach to the removal of dental implants from the maxillary sinus. AB - The purpose of this article is to present a new surgical technique - the double barrel approach - employed for the extraction of dental implants from the maxillary sinus, and to compare it with the classic canine fossa puncture (CFP). The surgical steps in the performance of the double-barrel approach (DBA) are systematically described. In order to compare the two techniques (CFP versus DBA), a prospective, randomized study was carried out between 2004 and 2011, comparing the length of duration of the procedure and the incidence of adverse effects. The average duration was 6.3 +/- 5.2 min for the DBA group and 14.8 +/- 8.4 min for the CFP group (P=0.0001, Mann-Whitney test). Nevertheless, the incidence of adverse effects within the first postoperative week did not differ between the two groups. We have demonstrated that the double-barrel approach is faster, has the same incidence of adverse effects, provides excellent visualization, and permits a more accurate withdrawal of implants in comparison with the classic CFP. It is minimally invasive, requires no sutures, and minimizes the risks to local vascular and neural structures. PMID- 23684815 TI - A new method for displaying the lingual artery using high-resolution three dimensional phase-contrast magnetic resonance angiography. AB - The aim of this study was to display the lingual artery superimposed on the anatomical image and to confirm its course and relation to the adjacent structures, noninvasively. Nineteen volunteers participated in the magnetic resonance imaging (MRI) study and one was excluded for excessive movement during scanning. A three-dimensional phase-contrast sequence (3D-PC) of magnetic resonance angiography (MRA) was used for vessel images, and a 3D-T1 high resolution volume examination (THRIVE) was used for anatomical images. Colour coded vessel images from 3D-PC MRA were superimposed on the 3D volume anatomical images, and the arterial course and relation to the adjacent structures were confirmed with multiplanar reconstructed cross-sectional (MPR) images. 3D-PC MRA images visualized the lingual artery in all 18 subjects and the sublingual artery in 14 subjects. In seven of 18 cases the bilateral sublingual arteries were shown to run side by side but had no contact with the sublingual veins. They ran together with the sublingual veins in four cases. Three cases showed irregular patterns. The bilateral sublingual arteries could not be identified in four cases. 3D-PC MRA images of the lingual artery superimposed on the anatomical images may be clinically useful to confirm its course and relationship to the adjacent structures before surgery, in order to prevent haemorrhage. PMID- 23684817 TI - An unusual disseminated viral primary infection: rash, hepatitis and polyserositis. PMID- 23684816 TI - Molecular epidemiology of respiratory syncytial virus transmission in childcare. AB - BACKGROUND: Respiratory syncytial virus (RSV) is the most important cause of serious respiratory infections in young children. No prior studies using molecular techniques to examine RSV transmission in the community childcare setting have been performed. OBJECTIVES: We seek to characterize the molecular epidemiology of RSV transmission in childcare to evaluate the impact of RSV disease in a community-based population. METHODS: We sequenced RSV-positive nasopharyngeal samples from a prospective longitudinal study of respiratory illnesses among children enrolled in childcare during three winter seasons. Phylogenetic analysis was performed to identify unique viral strains. RESULTS: RSV was detected in 59 (11%) illnesses. Compared to RSV-negative illnesses, RSV positive illnesses were associated with longer symptom duration and increased frequency of health care visits. Another respiratory virus was detected in 42 (71%) RSV-positive illnesses. RSV viral load did not differ between RSV-positive illnesses with and without another respiratory virus identified (P = 0.38). In two childcare rooms, 50% of the children had RSV detected within six days of the first case. Five (38%) of 13 illness episodes from one childcare room were sequenced and shown to be the same viral strain, suggesting rapid child-to-child transmission within the room over a 16 day period. CONCLUSIONS: RSV is rapidly transmitted within childcare. Childcare facilities may serve as ideal sites for evaluation of new prevention strategies given the high burden of RSV disease in this population and the rapidity of RSV spread between children. PMID- 23684818 TI - Insulin-degrading enzyme deficiency in bone marrow cells increases atherosclerosis in LDL receptor-deficient mice. AB - BACKGROUND: Insulin-degrading enzyme (IDE), a protease implicated in several chronic diseases, associates with the cytoplasmic domain of the macrophage Type A scavenger receptor (SR-A). Our goal was to investigate the effect of IDE deficiency (Ide(-/-)) on diet-induced atherosclerosis in low density lipoprotein deficient (Ldlr(-/-)) mice and on SR-A function. METHODS: Irradiated Ldlr(-/-) or Ide(-/-)Ldlr(-/-) mice were reconstituted with wild-type or Ide(-/-) bone marrow and, 6 weeks later, were placed on a high-fat diet for 8 weeks. RESULTS: After 8 weeks on a high-fat diet, male Ldlr(-/-) recipients of Ide(-/-) bone marrow had more atherosclerosis, higher serum cholesterol and increased lesion-associated beta-amyloid, an IDE substrate, and receptor for advanced glycation end products (RAGE), a proinflammatory receptor for beta-amyloid, compared to male Ldlr(-/-) recipients of wild-type bone marrow. IDE deficiency in male Ldlr(-/-) recipient mice did not affect atherosclerosis or cholesterol levels and moderated the effects of IDE deficiency of bone marrow-derived cells. No differences were seen between Ldlr(-/-) and Ide(-/-)Ldlr(-/-) female mice reconstituted with Ide(-/-) or wild-type bone marrow. IDE deficiency in macrophages did not alter SR-A levels, cell surface SR-A, or foam cell formation. CONCLUSION: IDE deficiency in bone marrow-derived cells results in larger atherosclerotic lesions, increased lesion-associated Abeta and RAGE, and higher serum cholesterol in male, Ldlr(-/-) mice. PMID- 23684819 TI - The effects of age and latent cytomegalovirus infection on the redeployment of CD8+ T cell subsets in response to acute exercise in humans. AB - Dynamic exercise evokes a rapid redeployment of cytotoxic T cell subsets with high expression of beta2 adrenergic receptors, presumably to enhance immunosurveillance during acute stress. As this response is affected by age and infection history, this study examined latent CMV infection as a potential confounder to age-related differences in blood CD8+ T-cell responses to exercise. Healthy young (n=16) and older (n=16) humans counterbalanced by CMV IgG serostatus (positive or negative) exercised for 30-min at ~80% peak cycling power. Those with CMV redeployed ~2-times more CD8+ T-cells and ~6-times more KLRG1+/CD28- and CD45RA+/CCR7- CD8+ subsets than non-infected exercisers. Seronegative older exercisers had an impaired redeployment of total CD8+ T-cells, CD45RA+/CCR7+ and KLRG1-/CD28+ CD8+ subsets compared to young. Redeployed CD8+ T cell numbers were similar between infected young and old. CMVpp65 specific CD8+ cells in HLA/A2(*) subjects increased ~2.7-fold after exercise, a response that was driven by the KLRG1+/CD28-/CD8+ subset. Stimulating PBMCs before and after exercise with CMVpp65 and CMV IE-1 antigens and overlapping peptide pools revealed a 2.1 and 4.4-fold increases in CMVpp65 and CMV IE-1 IFN-gamma secreting cells respectively. The breadth of the T cell response was maintained after exercise with the magnitude of the response being amplified across the entire epitope repertoire. To conclude, latent CMV infection overrides age-related impairments in CD8+ T-cell redeployment with exercise. We also show for the first time that many T-cells redeployed with exercise are specific to CMVpp65 and CMV IE-1 antigens, have broad epitope specificity, and are mostly of a high differentiated effector memory phenotype. PMID- 23684820 TI - Hierarchical porous carbon microspheres derived from porous starch for use in high-rate electrochemical double-layer capacitors. AB - Porous starch was used as a precursor for hierarchical porous carbon microspheres. The preparation consisted of stabilisation, carbonisation and KOH activation, and the resultant hierarchical porous carbon microspheres had a large BET surface area of 3251 m(2)g(-1). Due to the large surface area and the hierarchical pore structure, electrodes made of the hierarchical porous carbon microsphere materials had high specific capacitances of 304 Fg(-1) at a current density of 0.05 Ag(-1) and 197 Fg(-1) at a current density of 180 Ag(-1) when used in a symmetric capacitor with 6M KOH as the electrolyte. After 10,000 cycles, the capacitor still exhibited a stable performance with a capacitance retention of 98%. These results indicate that porous starch is an excellent precursor to prepare high performance electrode materials for EDLCs. PMID- 23684821 TI - Impact of age extension to include 47-49 year old women on the workload of the surgical department of a single Breast Cancer Screening Unit--The first non randomized experience in UK. AB - INTRODUCTION: The aim of this study was to assess the impact on the surgical unit of the first year (prevalence screening) of non-randomized invitations to 47-49 year old women for breast screening, from a single breast screening unit. METHODS: All women undergoing surgery in the age group 47-49 years, referred via screening were identified and the increased workload analysed. RESULTS: 4250 (76%) women were screened of the 5624 invited. 396 women were recalled, of whom 88 (22%) underwent a core biopsy. 32 patients required surgical intervention. 20 patients (62.5%) were confirmed to have either DCIS (6 patients) or invasive malignancy (14 patients). They required 37 theatres attendances requiring 42 operations. 16 wire guided wide local excisions (14 with sentinel node biopsy), 7 mastectomies (2 with sentinel node biopsy; 1 with axillary clearance), 6 margin re-excisions, 1 tissue expander insertion and removal, 3 Latissimus Dorsi with implant and 2 TRAM reconstructions. Other cases include haematoma drainage, scar revisions and nipple reconstructions. This group generated 100 NHS surgical outpatient consultations (78 breast and 22 plastic surgery). 12 patients (37.5%) underwent surgery for a B3 vacuum result; 10 underwent wire guided and 1 ultrasound guided skin marked excision biopsy. 1 patient was treated privately. This group generated 25 NHS surgical outpatients consultations. CONCLUSIONS: This study highlights the impact of the 47-49 year age extension within the breast screening programme on the workload of the surgical department of a UK Breast Cancer Screening Unit offering non-randomized invitations. The study will inform other surgical units of expected workload when age extension is fully implemented. PMID- 23684822 TI - Multi-serotype outer membrane vesicles of Shigellae confer passive protection to the neonatal mice against shigellosis. AB - Recently, we have demonstrated, immunization of adult female mice with outer membrane vesicles (OMVs) of Shigella boydii type 4 protected their offspring passively from shigellosis. In our present study, we have advanced our research by formulating multi-serotype outer membrane vesicles (MOMVs), mixing the OMVs of Shigella dysenteriae 1 Deltastx, Shigella flexneri 2a, 3a and 6, S. boydii type 4 and Shigella sonnei to achieve a broad spectrum protection against shigellosis. Adult mice were immunized orally with 50 MUg of MOMVs, four times at weekly intervals. Immunological parameters were observed at various time points, before, during and after immunization, in adult mice. Passive protection was examined in their offspring by measuring protective efficacy and studying intestinal colonization, after challenging with various Shigella strains. Immunized dams exhibited a consistent broad spectrum antibody response. 3-4 day-old offspring of immunized dams showed significant long term passive protection against wild type S. flexneri 2a, 3a, and 6, S. boydii type 2 and S. dysenteriae 1. Their stomach extracts, essentially containing mother's milk, have also exhibited significant levels of anti-MOMVs immunoglobulins. In conclusion, MOMVs formulation represents an easy, safe immunization strategy that was found suitable to provide complete passive protection to the neonatal mice against all four serogroups of Shigellae. It could be exploited for the development of a novel non-living vaccine against human shigellosis in near future. PMID- 23684823 TI - Immunogenicity and safety of pneumococcal conjugate polysaccharide and free polysaccharide vaccines alone or combined in HIV-infected adults in Brazil. AB - BACKGROUND: Streptococcus pneumoniae is a leading cause of hospitalization in HIV infected adults therefore pneumococcal vaccine is recommended. The ideal antipneumococcal vaccine and effective vaccination regimen remain controversial and needs further evaluation. METHODS: To assess the efficacy of pneumococcal vaccines alone and combined, a randomized, blinded clinical trial was conducted in Brazil with 331 HIV-patients aged 18-60, with CD4-T cell count >= 200 cells/mm(3). Two interventions 60 days apart were done in three schedules: 23 valent pneumococcal polysaccharide vaccine (PPV23)/placebo; 7-valent pneumococcal conjugate vaccine (PCV7)/placebo; and PCV7 plus PPV23. Safety and reactogenicity were evaluated, and immunogenicity was assessed by an IgG enzyme-linked immunosorbent assay to S. pneumoniae serotypes 6B, 9V and 14, performed at baseline, 60 and 180 days after first intervention. Comparison of immunogenicity was based on geometric mean concentration (GMC), percentages of individuals with serotype-specific IgG >= 0.35MUg/mL and >= 1.0 MUg/mL and proportion of individuals with >= 4-fold increase in specific antibody concentrations for each serotype. RESULTS: Demographic and HIV conditions were similar, and both vaccines were well tolerated across vaccine groups. Significant increase in IgG-antibodies was observed to all serotypes evaluated. A greater proportion of PCV7 recipients reached and sustained IgG antibody concentrations at least four times as high as those at baseline, for serotypes 6B and 9V. A PPV23 dose after PCV7 did not enhance immunogenicity. CONCLUSIONS: In this first trial conducted with HIV infected immunologically stable adults in South America, both PPV23 and PCV7 were safe and immunogenic. Evidence suggesting PCV7 was more immunogenic than PPV23, as it elicited higher and persistent >= 4-fold increase of antibodies for 6B and 9V serotypes in a greater proportion of HIV-patients is noteworthy. Despite current recommendation of schedules combining PCV7 and PPV23, there is little evidence to support this practice and we did not observe benefits in this combination. PMID- 23684824 TI - Impact of pneumococcal conjugate vaccines on nasopharyngeal carriage and invasive disease among unvaccinated people: review of evidence on indirect effects. AB - BACKGROUND: Invasive disease due to Streptococcus pneumoniae remains an important worldwide cause of morbidity and mortality, particularly in young children and the elderly. The development and use of pneumococcal conjugate vaccines (PCVs) have had a dramatic impact on rates of vaccine-type invasive pneumococcal disease (IPD) not only in the pediatric population targeted for vaccination but in non vaccinated age-groups as well. This indirect effect is directly mediated by a reduction of vaccine-type nasopharyngeal carriage and thus transmission by vaccinated children. Current PCV licensing procedures do not take into consideration nasopharyngeal carriage impact, and thus the indirect effect. This review summarizes the evidence for the indirect effect of PCV on vaccine-type disease and its correlation with changes in carriage among unvaccinated populations, to assess the basis for inclusion of carriage in the PCV licensing process. METHODS: Randomized controlled trials, surveillance and other observational studies published between 1994 and 2013 were systematically identified from global, regional and review databases and conference abstracts. We included as primary evidence, studies in non-vaccinated groups addressing changes in both vaccine-type IPD and carriage between pre- and post-PCV introduction periods; studies missing one of these four components were included as supporting rather than primary evidence. RESULTS: We identified studies from 14 countries, nearly all developed countries. Vaccine-type IPD and carriage in non-targeted populations consistently decreased after PCV introduction, with the magnitude of decrease growing over time. Where IPD and carriage were observed in the same population, VT-decreases occurred contemporaneously. These relationships held true across age-groups and between indigenous and non-indigenous populations in the US and Australia. CONCLUSIONS: Indirect PCV impact on VT-IPD and VT carriage has been significant. Impact on carriage should be considered for inclusion in the PCV licensure process as a predictor of indirect effects. PMID- 23684825 TI - Prevalence of chronic hepatitis B virus infection after implementation of a hepatitis B vaccination program among children in three provinces in Cambodia. AB - BACKGROUND: Hepatitis B virus (HBV) is highly endemic in Cambodia with an estimated pre-vaccine hepatitis B surface antigen (HBsAg) prevalence of 9%. By 2005, a hepatitis B vaccination program was implemented to decrease infection rates in children. We conducted a serosurvey to evaluate the impact of the vaccination program in 2011. METHODS: A cross-sectional two-stage cluster survey was conducted to estimate HBsAg prevalence among children born from 2006 to 2007 in three provinces: Phnom Penh (urban), Kratie (rural), and Ratanakiri (remote). Demographic data, as well as written or oral vaccination history were collected. Children were tested for HBsAg. Factors associated with undervaccination and HBsAg positivity were modeled. RESULTS: Coverage of timely hepatitis B vaccine birth dose (administered at <= 24 h) was 55% in Phnom Penh, 36% in Kratie, and 22% in Ratanakiri. Coverage with >= 3 hepatitis B vaccine doses (HepB3) was 91% in Phnom Penh, 82% in Kratie, and 64% in Ratanakiri. When compared with children who were born in health facilities with a skilled birth attendant (SBA), children born at home without a SBA were more likely not to have received a timely BD (adjusted relative risk [aRR]=1.94; 95% CI=1.75-2.15) as were children born at home with an SBA (aRR=1.54; 95% CI=1.32-1.80). The proportion of children who tested positive for HBsAg was 0.33% in Phnom Penh, 1.41% in Kratie, and 3.45% in Ratanakiri. In all three provinces, children who received their first dose after 7 days of life and children who never received hepatitis B vaccine had the highest HBsAg prevalence. CONCLUSIONS: Progress has been made in Cambodia in decreasing the burden of chronic HBV infection among children. Improvements in vaccination coverage will further decrease the burden of disease. PMID- 23684826 TI - Epidemiology of invasive pneumococcal disease in the pre-conjugate vaccine era: South Africa, 2003-2008. AB - INTRODUCTION: Dynamics of pneumococcal disease incidence and serotype distribution prior to introduction of pneumococcal conjugate vaccines (PCV) will assist in understanding effects of the vaccine over time and will be important in choosing the optimal PCV formulation. METHODS: We conducted active, laboratory based, national surveillance for invasive pneumococcal disease (IPD) through the Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA) from 2003 through 2008. Over 130 laboratories report to this system. Pneumococci were serotyped using Quellung and isolates screened for resistance by disk diffusion; minimum inhibitory concentrations were determined on potentially resistant isolates. We used univariate and multivariable multinomial regression models to assess differences between serotypes. RESULTS: GERMS-SA identified 8674 cases among children <5 years. Overall, 58% (3849/6668), 65% (4314/6668), and 85% (5669/6668) of cases and 61% (455/751), 64% (482/751), 82% (616/751) of deaths were due to serotypes included in 7-valent PCV, 10-valent PCV and 13-valent PCV, respectively. Serotypes 6A and 19A accounted for 16% (527/3252) of penicillin non susceptible disease. In 2008, reported incidence of IPD was 6-fold higher in children <1 compared to children 1-4 years of age: 87 per 100,000 population and 14/100,000, respectively. The relative risk of IPD was 21-fold (95% CI, 19-24) and 34-fold (29-41) greater in HIV-infected compared to HIV-uninfected children in the <1 year and 1-4-year-old age groups respectively. On multivariable analysis serotypes 6B (relative risk ratio (RRR) 0.7; confidence interval (CI) 0.5-0.9), 18C (RRR 0.3; CI 0.1-0.5), 1 (RRR 0.2; CI 0.1-0.4) and 8 (RRR 0.2; CI 0.1-0.4) were significantly less common in HIV-infected individuals than serotype 14. CONCLUSIONS: All vaccine formulations have the potential to prevent most cases and deaths from IPD in children in South Africa. Vaccines with protection against 19A would be advantageous in South Africa. PMID- 23684827 TI - Trends in compliance with two-dose influenza vaccine recommendations among children aged 6 months through 8 years. AB - Children aged <9 years may require two doses of influenza vaccine to achieve an adequate immune response to protect against the disease. We analyzed data for >2 million children in each influenza season from 2007 to 2012 from eight Immunization Information System Sentinel Sites to assess trends in two-dose compliance. Compliance was calculated by influenza season, age group, and influenza vaccination history. Two-dose compliance increased from 49% to 60% among 6-23 month olds from 2007 to 2012; no increase was observed for 2-4 or 5-8 year olds. In each season, compliance was 3-12 times higher among 6-23 month olds compared to older children and was two times higher among influenza vaccine naive children compared to previously vaccinated children. Improved messaging for providers and parents about the importance of the two-dose recommendation, about which children are eligible for two doses, and provider access to complete influenza vaccination histories for all children are needed. PMID- 23684828 TI - Post-vaccination serological test results of infants at risk of perinatal transmission of hepatitis B using an intensified follow-up programme in a London centre. AB - Immunisation of infants born to hepatitis B virus (HBV) infected mothers is an important public health measure to prevent mother-to-child transmission of HBV. Post-vaccination serological tests (PVST) inform the success of the infant HBV immunisation programme and identify infected infants. Previous studies suggested that the rates of PVST in the UK programme were unsatisfactory. We introduced an intensified local follow-up programme and offered an earlier PVST 2-3 months after the third vaccination at age 4-5 months. Of 219 infants born between 2009 and 2011, 193 infants (88.1%) had at least one PVST: 145 (66.2%) early; 94 (42.9%) standard; 46 (21.0%) both and 26 (11.9%) never tested. Twenty-four infants were identified as high risk for mother-to-child transmission according to national criteria and received both hepatitis B immunoglobulin (HBIG) and hepatitis B vaccine at birth. These infants had a significantly lower hepatitis B surface antibody (anti-HBs) levels at early PVST compared to the lower risk group who received hepatitis B vaccine only (median of 59 vs. 376 mIU/ml, P=0.006). None of the infants tested were infected with hepatitis B. This study illustrates that the rate of PVST can be improved by using an intensified follow-up programme offering an early PVST. The significantly lower anti-HBs levels in the HBIG subgroup is of concern as this group of infants is already at higher risk for acquiring HBV infection. Infants with poor antibody responses can be identified by an early PVST and offered a timely extra booster dose. PMID- 23684829 TI - Novel vaccine formulations against pertussis offer earlier onset of immunity and provide protection in the presence of maternal antibodies. AB - Whooping cough is a respiratory illness most severe in infants and young children. While the introduction of whole-cell (wP) and acellular pertussis (aP) vaccines has greatly reduced the burden of the disease, pertussis remains a problem in neonates and adolescents. New vaccines are needed that can provide early life and long-lasting protection of infants. Vaccination at an early age, however, is problematic due to the interference with maternally derived antibodies (MatAbs) and the bias towards Th2-type responses following vaccination. Here we report the development of a novel vaccine formulation against pertussis that is highly protective in the presence of MatAbs. We co formulated pertussis toxoid (PTd) and filamentous hemagglutinin (FHA) with cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODN), cationic innate defense regulator (IDR) peptide and polyphosphazene (PP) into microparticle and soluble vaccine formulations and tested them in murine and porcine models in the presence and absence of passive immunity. Vaccines composed of the new adjuvant formulations induced an earlier onset of immunity, higher anti-pertussis IgG2a and IgA titers, and a balanced Th1/Th2-type responses when compared to immunization with Quadracel((r)), one of the commercially available vaccines for pertussis. Most importantly, the vaccines offered protection against challenge infection in the presence of passively transferred MatAbs. PMID- 23684830 TI - Cutaneous vaccination: antigen delivery into or onto the skin. PMID- 23684831 TI - SPI1 defective mutants of Salmonella enterica induce cross-protective immunity in chickens against challenge with serovars Typhimurium and Enteritidis. AB - In this study we were interested in the serovar cross-protection potential of Salmonella Pathogenicity Island 1 (SPI1) attenuated vaccine strains of Salmonella enterica serovars Enteritidis and Typhimurium and immune response of vaccinated and naive chickens to Salmonella infection. The immune response was characterized by real time PCR quantifying transcripts of interleukins IL1beta, IL17, IL22, interferon gamma (IFNgamma), inducible NO synthase (iNOS), immunoglobulins IgM, IgA, IgY and Ig light chain, and six genes of acute phase response including avidin, serum amyloid A, extracellular fatty acid-binding protein (Ex-FABP), immune responsive gene 1, chemokine AH221 and trappin-6. Vaccination with SPI1 mutants of both serovars protected chickens against Salmonella infection, independent of the serovar used for the challenge and the time post infection. However, expressions of all interleukins, iNOS and Ex-FABP showed that protection against homologous serovars was significantly higher than against heterologous serovars after intravenous challenge at 4 days post infection. The vaccination with a mixture of S. Enteritidis and S. Typhimurium SPI1 mutants induced an intermediate protection against challenge with both serovars, i.e. the mixed vaccine provided an additional protective effect when compared with the chickens vaccinated with a vaccine formed by only a single Salmonella serovar. PMID- 23684832 TI - Interferon-gamma production by mononuclear cells in Bacille Calmette-Guerin revaccinated healthy volunteers predicted long-term antimycobacterial responses in a randomized controlled trial. AB - The Bacille Calmette-Guerin (BCG) vaccine is the only vaccine currently available for tuberculosis, and it demonstrates variable efficacy against the disease. The assessment of new vaccine strategies is hindered by the small annual probability that an infected individual will develop tuberculosis, and the lack of simple and reliable surrogate markers of protection. The frequency of cytokine-producing T cells as well as the production of IFN-gamma have been disputed as surrogate markers of protection. We evaluated the evolution of these immune parameters in a population from a high burden city where BCG revaccination has been shown to result in mild protection. We found that individuals whose in vitro IFN-gamma responses to mycobacterial antigens had increased by more than 3.3-fold were more likely to maintain higher responses after 1 year and to show increased expansion of IFN-gamma-producing T lymphocytes than those with lower or null increase of IFN-gamma. PMID- 23684833 TI - Evaluation of virulent and live Shigella sonnei vaccine candidates in a gnotobiotic piglet model. AB - Newborn gnotobiotic (GB) piglets given virulent Shigella orally develop many of the clinical symptoms and gastrointestinal (GI) manifestations that mimic human shigellosis. Shigella sonnei virulent strain Moseley, a mutant ShET2-1,2, lacking enterotoxin SenA and its paralog SenB, and vaccine candidates WRSS1 and WRSs3 were evaluated in this model for rates of diarrhea, colonization and other GI symptoms and pathology. Moseley-infected piglets developed diarrhea from 1 to 7 days, with the highest rates seen on days 2-4 after inoculation. In contrast, WRSs3-infected piglets did not have diarrhea over the entire experimental period. Compared to the Moseley group, lower diarrheal rates were observed in the double enterotoxin mutant and significantly lower in the WRSS1 group. Moseley infection also caused marked mucosal damage in the GI tissues at PID1 to PID8, and induced predominantly proinflammatory cytokine secretion. IL-8 and to a lesser extent IL 6 and IL-1beta were observed early after inoculation and IL-12 secretion could be measured till late in infection. The ShET2-1,2 mutant, WRSS1 and WRSs3 also colonized the GI tract in a manner similar to Moseley; however, both vaccine candidates developed milder histopathological indices and cytokine responses. WRSs3-infected animals showed the least pathology. Furthermore, unlike the other strains, WRSs3 was rarely detected in organs outside the gastrointestinal tract. These results support the development of the GB piglet model as a sensitive in vivo oral model for the evaluation of virulence of different Shigella strains which could be applied to other oral vaccine candidates. PMID- 23684835 TI - Influences on parental acceptance of HPV vaccination in demonstration projects in Uganda and Vietnam. AB - This study investigates the effect of communication strategies on human papillomavirus (HPV) vaccine uptake in HPV vaccine demonstration projects in Uganda and Vietnam. Secondary analysis was conducted on data from surveys of a representative sample of parents and guardians of girls eligible for HPV vaccine, measuring three-dose coverage achieved in demonstration projects in 2008-2010. Univariate and multivariate logistic regression analysis calculated the unadjusted and adjusted odds of receiving at least one dose of HPV vaccine depending on exposure to community influencers; information, education, and communication (IEC) channels; and demographic factors. This study found that exposure to community influencers was associated with HPV vaccine uptake in a multivariate model controlling for other factors. Exposure to non-interactive IEC channels was only marginally associated with HPV vaccine uptake. These results underscore the need of HPV vaccine programs in low- and middle-income countries to involve and utilize key community influencers and stakeholders to maximize HPV vaccine uptake. PMID- 23684834 TI - The adjuvant effect of MF59 is due to the oil-in-water emulsion formulation, none of the individual components induce a comparable adjuvant effect. AB - MF59 is a safe and effective vaccine adjuvant that has been used in a licensed seasonal influenza vaccine for 15 years. The purpose of the present studies was to directly address a question that has been asked of us on many occasions: "which is the adjuvant active component of MF59?". Since we have recently gained a number of insights on how MF59 works as an adjuvant, we were able to use these approaches to evaluate if the individual components of MF59 (squalene oil, the surfactants Span 85 and Tween 80 or the citrate buffer) showed any direct immunostimulatory activity. We assessed the ability of the individual components to stimulate the innate and adaptive immune responses that we have shown to be indicative of MF59-mediated adjuvanticity. No immune stimulatory capacities could be attributed to squalene, Tween 80 or the citrate buffer alone. Instead, we found that the lipophilic surfactant Span 85 contributes to activation of the muscle transcriptome. However, despite this local activation, Span 85 alone - like the other single components of MF59 - is not sufficient to induce an adjuvant effect. Only the fully formulated MF59 emulsion induces all the established hallmarks of innate and adaptive immune activation, which includes activation of genes indicative of transendothelial cell migration, strong influx of immune cells into the injection site and their enhanced antigen uptake and transport to the lymph nodes. These observations may have important implications in the design of optimal emulsion-based vaccine adjuvants. PMID- 23684836 TI - Developing Countries Vaccine Manufacturers Network (DCVMN): engaging to step up for vaccine discovery and access. Meeting report 2012. AB - At the annual general meeting of the Developing Countries Vaccine Manufacturers Network (DCVMN) members renewed their engagement and cooperative spirit in pursuing the mission of increasing the quality and availability of affordable vaccines for all people. Thirteen years after its establishment, DCVMN moves into the Decade of Vaccines with renewed dynamism and synergy to create greater impact and shape the global and regional vaccination landscape, while supporting national growth. The DCVMN is growing: 12 new members joined in 2012, making a total of 37 members from 14 countries; 9 of these 37 manufacturers make WHO prequalified vaccines. More than one hundred and forty delegates from 23 countries attended the annual general meeting, representing 24 vaccine manufacturers and leaders of 20 major global health institutions. Over the course of two days, delegates exchanged information and ideas on how to jointly achieve the common goal of protecting people against known and emerging infectious diseases. In an increasingly complex environment of new technologies, demanding regulatory requirements, higher cost of production, and a growing number of legal and intellectual property issues, it is observed that many manufacturers and stakeholders are engaged in technology transfer initiatives. This well-attended meeting highlighted the growing impact and important contributions of developing country vaccine manufacturers in shaping the global vaccine landscape. The successful introduction of the first ever vaccine against hepatitis E and of a new vaccine against meningitis A, tailored for African meningitis belt countries, illustrate the innovative capacity of DCVMN members. An increase in the variety of collaborations, partnerships and alliances between DCVM and various institutions was observed. Interestingly, bilateral technology transfer partnerships between DCVMs themselves are on the rise. PMID- 23684837 TI - Optimal targeting of seasonal influenza vaccination toward younger ages is robust to parameter uncertainty. AB - Identification of the optimal vaccine allocation for the control of influenza requires consideration of uncertainty arising from numerous unpredictable factors, including viral evolution and diversity within the human population's immunity as well as variation in vaccine efficacy. The best policy must account for diverse potential outcomes based on these uncertainties. Here we used a mathematical model parametrized with survey-based contact data, demographic, and epidemiological data from seasonal influenza in the United States to determine the optimal vaccine allocation for five outcome measures: infections, hospitalizations, deaths, years of life loss, and contingent valuation. We incorporated uncertainty of epidemiological parameters and derive probability distributions of optimal age- and risk-specific allocation of vaccine. Our analysis demonstrated that previous recommendations of targeting schoolchildren (ages 5-17 years) and young adults (18-44 years) are generally robust in the face of uncertainty. However, when the outcome measure is to minimize deaths, years of life loss, or contingent valuation, uncertainty analysis identified scenarios under which it is optimal to target people at high risk for complications, even when vaccine are in abundance. PMID- 23684838 TI - Hepatitis B virus vaccination in children with steroid sensitive nephrotic syndrome: immunogenicity and safety? AB - We investigated the efficacy and safety of Hepatitis B vaccine (HBVac) in steroid sensitive nephrotic syndrome (SSNS) children. 41 patients with SSNS and 30 controls were vaccinated with HBVac(Engerix B((r))). Patients were divided into 3 subgroups:full dose steroid users, alternate-day steroid users and steroid non users. Seroconversion rate was lower in steroid users than non-users at the 6th(p=0.015) and 12th(p=0.036) months. Antibody to Hepatitis B surface antigen(HBsAb) titers were significantly different between subgroups and controls at the 15th month. However, HBsAb and response rates were not different between subgroups at the 12th and 15th months (p>0.05). Five patients were unresponsive to HBVac. Relapse rates after the vaccination were higher than those in the prevaccination period (p=0.002). HBVac is less effective in producing immune response in SSNS children with steroid therapy. HBVac may trigger relapse in some patients. We recommend HBVac to SSNS children with low dose steroid therapy or after steroids are discontinued. PMID- 23684839 TI - Effects of immunization of pregnant guinea pigs with guinea pig cytomegalovirus glycoprotein B on viral spread in the placenta. AB - BACKGROUND: Cytomegalovirus (CMV) is the most common cause of congenital virus infection. Infection of guinea pigs with guinea pig CMV (GPCMV) can provide a useful model for the analysis of its pathogenesis as well as for the evaluation of vaccines. Although glycoprotein B (gB) vaccines have been reported to reduce the incidence and mortality of congenital infection in human clinical trials and guinea pig animal models, the mechanisms of protection remain unclear. METHODS: To understand the gB vaccine protection mechanisms, we analyzed the spread of challenged viruses in the placentas and fetuses of guinea pig dams immunized with recombinant adenoviruses expressing GPCMV gB and beta-galactosidase, rAd-gB and rAd-LacZ, respectively. RESULTS: Mean body weight of the fetuses in the dams immunized with rAd-LacZ followed by GPCMV challenge 3 weeks after immunization was 78% of that observed for dams immunized with rAd-gB. Under conditions in which congenital infection occurred in 75% of fetuses in rAd-LacZ-immunized dams, only 13% of fetuses in rAd-gB-immunized dams were congenitally infected. The placentas were infected less frequently in the gB-immunized animals. In the placentas of the rAd-LacZ- and rAd-gB-immunized animals, CMV early antigens were detected mainly in the spongiotrophoblast layer. Focal localization of viral antigens in the spongiotrophoblast layer suggests cell-to-cell viral spread in the placenta. In spite of a similar level of antibodies against gB and avidity indices among fetuses in each gB-immunized dam, congenital infection was sometimes observed in a littermate fetus. In such infected fetuses, CMV spread to most organs. CONCLUSIONS: Our results suggest that antibodies against gB protected against infection mainly at the interface of the placenta rather than from the placenta to the fetus. The development of strategies to block cell-to cell viral spread in the placenta is, therefore, required for effective protection against congenital CMV infection. PMID- 23684840 TI - Functional evaluation of malaria Pfs25 DNA vaccine by in vivo electroporation in olive baboons. AB - Plasmodium falciparum Pfs25 antigen, expressed on the surface of zygotes and ookinetes, is one of the leading targets for the development of a malaria transmission-blocking vaccine (TBV). Our laboratory has been evaluating DNA plasmid based Pfs25 vaccine in mice and non-human primates. Previously, we established that in vivo electroporation (EP) delivery is an effective method to improve the immunogenicity of DNA vaccine encoding Pfs25 in mice. In order to optimize the in vivo EP procedure and test for its efficacy in more clinically relevant larger animal models, we employed in vivo EP to evaluate the immune response and protective efficacy of Pfs25 encoding DNA vaccine in nonhuman primates (olive baboons, Papio anubis). The results showed that at a dose of 2.5mg DNA vaccine, antibody responses were significantly enhanced with EP as compared to without EP resulting in effective transmission blocking efficiency. Similar immunogenicity enhancing effect of EP was also observed with lower doses (0.5mg and 1mg) of DNA plasmids. Further, final boosting with a single dose of recombinant Pfs25 protein resulted in dramatically enhanced antibody titers and significantly increased functional transmission blocking efficiency. Our study suggests priming with DNA vaccine via EP along with protein boost regimen as an effective method to elicit potent immunogenicity of malaria DNA vaccines in nonhuman primates and provides the basis for further evaluation in human volunteers. PMID- 23684842 TI - Gene dosage effects: nonlinearities, genetic interactions, and dosage compensation. AB - High-throughput genomic analyses have shown that many mutations, including loss of-function (LOF) mutations, are present in diseased as well as in healthy individuals. Gene dosage effects due to deletions, duplications, and LOF mutations provide avenues to explore oligo- and multigenic inheritance. Here, we focus on several mechanisms that mediate gene dosage effects and analyze biochemical interactions among multiple gene products that are sources of nonlinear relations connecting genotypes and phenotypes. We also explore potential mechanisms that compensate for gene dosage effects. Understanding these issues is critical to understanding why an individual bearing a few damaging mutations can be severely diseased, whereas others harboring tens of potentially deleterious mutations can appear quite healthy. PMID- 23684844 TI - A 96-well based analysis of replicon elimination with the HCV NS5A replication complex inhibitor daclatasvir. AB - A 96-well based replicon elimination and colony formation assay is presented for comparing the resistance barrier of the hepatitis C virus (HCV) NS5A replication complex inhibitor daclatasvir (DCV, BMS-790052) on three HCV genotypes (gts) in a proof of concept experimental protocol. The 96-well assay format provides both individual colony as well as population characterization and is readily applicable to other HCV direct-acting antiviral agents (DAAs). The assay provides an assessment of HCV replication levels over a 5log10 range by measuring a luciferase reporter resident in the HCV replicons. Individual colony status can be measured with a separate and compatible resazurin assay to assess relative host cell fitness following inhibitor treatments. The methods employed are non toxic and leave intact isolatable colonies that can be used for phenotyping and genotyping. The utility of the assay is demonstrated by the identification and isolation of resistant variants as well as in the ranking of the relative resistance barrier for the replication complex inhibitor DCV for gts 1a, 1b and 2a. The format provides a quantitative ranking based upon luciferase activity and has the ability to monitor DAA resistance development over time for large numbers of compounds. PMID- 23684845 TI - Rapid, whole blood diagnostic test for detecting anti-hantavirus antibody in rats. AB - Hantavirus is a causative agent of rodent-borne viral zoonoses, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome. Seoul virus (SEOV) is a causative agent of urban and laboratory rat-associated HFRS worldwide. Surveillance of rodents has been done mainly by serological detection of hantavirus-specific antibodies by enzyme linked immunosorbent assay (ELISA) and immunofluorescent antibody assay (IFA). An immunochromatographic (ICG) test was developed with the N-terminal 103 amino acids of nucleocapsid protein of Hantaan virus expressed by Escherichia coli as an antigen to detect IgG antibody specific to hantavirus in sera from Rattus sp. animals. Antibody-detecting sensitivity of the ICG test was the same as that of ELISA and about 100-times higher than that of IFA. Overall sensitivities and specificities of the ICG test in comparison to ELISA and IFA for sera from 192 urban rats and 123 laboratory rats were 99.3% and 100%, respectively. Diluted whole blood samples without separation could be used for the ICG test. The ICG test enabled detection of antibodies to SEOV, Hantaan, Dobrava/Belgrade, and Thailand viruses, which are causative agents of HFRS throughout Eurasia. The ICG test is a rapid, simple and safe method for diagnosis of SEOV infection in rats. PMID- 23684843 TI - Properties and rates of germline mutations in humans. AB - All genetic variation arises via new mutations; therefore, determining the rate and biases for different classes of mutation is essential for understanding the genetics of human disease and evolution. Decades of mutation rate analyses have focused on a relatively small number of loci because of technical limitations. However, advances in sequencing technology have allowed for empirical assessments of genome-wide rates of mutation. Recent studies have shown that 76% of new mutations originate in the paternal lineage and provide unequivocal evidence for an increase in mutation with paternal age. Although most analyses have focused on single nucleotide variants (SNVs), studies have begun to provide insight into the mutation rate for other classes of variation, including copy number variants (CNVs), microsatellites, and mobile element insertions (MEIs). Here, we review the genome-wide analyses for the mutation rate of several types of variants and suggest areas for future research. PMID- 23684846 TI - Numerical taxonomy of the genus Pestivirus: new software for genotyping based on the palindromic nucleotide substitutions method. AB - The genus Pestivirus from the family Flaviviridae is represented by four established species; Bovine viral diarrhea virus 1 (BVDV-1); Bovine viral diarrhea virus 2 (BVDV-2); Border disease virus (BDV); and Classical swine fever virus (CSFV); as well a tentative species from a Giraffe. The palindromic nucleotide substitutions (PNS) in the 5' untranslated region (UTR) of Pestivirus RNA has been described as a new, simple and practical method for genotyping. New software is described, also named PNS, that was prepared specifically for this PNS genotyping procedure. Pestivirus identification using PNS was evaluated on five hundred and forty-three sequences at genus, species and genotype level using this software. The software is freely available at www.pns-software.com. PMID- 23684841 TI - Sex dimorphism and depot differences in adipose tissue function. AB - Obesity, characterized by excessive adiposity, is a risk factor for many metabolic pathologies, such as type 2 diabetes mellitus (T2DM). Numerous studies have shown that adipose tissue distribution may be a greater predictor of metabolic health. Upper-body fat (visceral and subcutaneous abdominal) is commonly associated with the unfavorable complications of obesity, while lower body fat (gluteal-femoral) may be protective. Current research investigations are focused on analyzing the metabolic properties of adipose tissue, in order to better understand the mechanisms that regulate fat distribution in both men and women. This review will highlight the adipose tissue depot- and sex-dependent differences in white adipose tissue function, including adipogenesis, adipose tissue developmental patterning, the storage and release of fatty acids, and secretory function. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. PMID- 23684847 TI - Comparison of initial feasibility of host cell lines for viral vaccine production. AB - In order to reduce the time required for the development and production of viral vaccines, host cell lines should be available as expression systems for production of viral vaccines against groups of viral pathogens. A selection of cell lines was compared for their initial feasibility as expression system for the replication of polioviruses, influenza A viruses and respiratory syncytial virus (wild type strain A2). Six adherent cell lines (Vero, HEK-293, MRC-5, CHO K1, BHK-21 c13, MDCK) and six single cell suspension cell lines (CAP, AGE1.CR.HS, sCHO-K1, BHK-21 c13 2p, MDCK SFS) were studied for their ability to propagate viruses. First, maximum cell densities were determined. Second, virus receptor expression and polarization of the cell lines regarding receptor distribution of eight different viruses were monitored using flow cytometry and immunocytochemistry. Organization of the actin cytoskeleton was studied by transfection of the cells with LifeactTM, a construct coding for actin-EGFP. Finally, the ability to produce virus progeny of the viruses studied was assayed for each cell line. The results suggest that single cell suspension cell lines grown on serum free medium are the best candidates to serve as host cell lines for virus replication. PMID- 23684850 TI - The perceptual nature of audiovisual interactions for semantic knowledge in young and elderly adults. AB - Audiovisual interactions for familiar objects are at the core of perception. The nature of these interactions depends on the amodal--sensory abstracted--or modal- sensory-dependent--approach of knowledge. According to these approaches, the interactions should be respectively semantic and indirect or perceptual and direct. This issue is therefore a central question to memory and perception, yet the nature of these interactions remains unexplored in young and elderly adults. We used a cross-modal priming paradigm combined with a visual masking procedure of half of the auditory primes. The data demonstrated similar results in the young and elderly adult groups. The mask interfered with the priming effect in the semantically congruent condition, whereas the mask facilitated the processing of the visual target in the semantically incongruent condition. These findings indicate that audiovisual interactions are perceptual, and support the grounded cognition theory. PMID- 23684849 TI - Facilitation of naming in aphasia with auditory repetition: an investigation of neurocognitive mechanisms. AB - Prior phonological processing can enhance subsequent picture naming performance in individuals with aphasia, yet the neurocognitive mechanisms underlying this effect and its longevity are unknown. This study used functional magnetic resonance imaging to examine the short-term (within minutes) and long-term (within days) facilitation effects from a phonological task in both participants with aphasia and age-matched controls. Results for control participants suggested that long-term facilitation of subsequent picture naming may be driven by a strengthening of semantic-phonological connections, while semantic and object recognition mechanisms underlie more short-term effects. All participants with aphasia significantly improved in naming accuracy following both short- and long term facilitation. A descriptive comparison of the neuroimaging results identified different patterns of activation for each individual with aphasia. The exclusive engagement of a left hemisphere phonological network underlying facilitation was not revealed. The findings suggest that improved naming in aphasia with phonological tasks may be supported by changes in right hemisphere activity in some individuals and reveal the potential contribution of the cerebellum to improved naming following phonological facilitation. Conclusions must be interpreted with caution, however, due to the comparison of corrected group control results to that of individual participants with aphasia, which were not corrected for multiple comparisons. PMID- 23684851 TI - Task probability and report of feature information: what you know about what you 'see' depends on what you expect to need. AB - We investigated the influence of dimensional set on report of object feature information using an immediate memory probe task. Participants viewed displays containing up to 36 coloured geometric shapes which were presented for several hundred milliseconds before one item was abruptly occluded by a probe. A cue presented simultaneously with the probe instructed participants to report either about the colour or shape of the probe item. A dimensional set towards the colour or shape of the presented items was induced by manipulating task probability - the relative probability with which the two feature dimensions required report. This was done across two participant groups: One group was given trials where there was a higher report probability of colour, the other a higher report probability of shape. Two experiments showed that features were reported most accurately when they were of high task probability, though in both cases the effect was largely driven by the colour dimension. Importantly the task probability effect did not interact with display set size. This is interpreted as tentative evidence that this manipulation influences feature processing in a global manner and at a stage prior to visual short term memory. PMID- 23684852 TI - The effects of the concreteness of differently valenced words on affective priming. AB - This study aimed to determine whether affective priming is influenced by the concreteness of emotional words. To address this question, we conducted three experiments using lexical decision-priming task. In Experiment 1, positive abstract (PA) and positive-concrete (PC) words were used as primes to examine the effect of the concreteness of positive words on affective priming, and in Experiment 2, negative-abstract (NA) and negative-concrete (NC) words were used as primes to examine the effect of the concreteness of negative words on affective priming. Results showed that participants responded faster to affectively congruent-abstract trails than incongruent-abstract trails in PA prime conditions, but for PC or negative word (NC and NA) prime conditions, there were no differences between the response times of congruent trails and incongruent trails. To examine the reliability of the priming effects observed in Experiments 1 and 2, we set up a neutral condition as a baseline in Experiment 3, through which we confirmed the difference in the affective priming effect between positive and negative primes in a concrete-abstract dimension. PA words were found to have the tendency to possess more emotional load and facilitate affective association between the prime and the target. The study finding suggests that aside from arousal and valence, the concreteness of positive words also has an impact on affective priming effect. PMID- 23684848 TI - Use of ex vivo and in vitro cultures of the human respiratory tract to study the tropism and host responses of highly pathogenic avian influenza A (H5N1) and other influenza viruses. AB - The tropism of influenza viruses for the human respiratory tract is a key determinant of host-range, and consequently, of pathogenesis and transmission. Insights can be obtained from clinical and autopsy studies of human disease and relevant animal models. Ex vivo cultures of the human respiratory tract and in vitro cultures of primary human cells can provide complementary information provided they are physiologically comparable in relevant characteristics to human tissues in vivo, e.g. virus receptor distribution, state of differentiation. We review different experimental models for their physiological relevance and summarize available data using these cultures in relation to highly pathogenic avian influenza H5N1, in comparison where relevant, with other influenza viruses. Transformed continuous cell-lines often differ in important ways to the corresponding tissues in vivo. The state of differentiation of primary human cells (respiratory epithelium, macrophages) can markedly affect virus tropism and host responses. Ex vivo cultures of human respiratory tissues provide a close resemblance to tissues in vivo and may be used to risk assess animal viruses for pandemic threat. Physiological factors (age, inflammation) can markedly affect virus receptor expression and virus tropism. Taken together with data from clinical studies on infected humans and relevant animal models, data from ex vivo and in vitro cultures of human tissues and cells can provide insights into virus transmission and pathogenesis and may provide understanding that leads to novel therapeutic interventions. PMID- 23684853 TI - Stroke: a global killer on the rise. PMID- 23684855 TI - Evaluation of step-down therapy from an inhaled steroid to montelukast in childhood asthma. AB - BACKGROUND: Asthma guidelines allow antileukotriene medications to be used as an alternative to inhaled corticosteroids (ICSs) in second-step intensity therapy. The aim of this study was to determine whether asthma control can be maintained after reducing treatment from low-dose ICS to montelukast. METHODS: In this prospective, real-life 12-week trial, 84 young patients with asthma (7-18 years) controlled by low-dose ICS, had treatment switched to montelukast. Symptoms and PEF were monitored daily; exhaled nitric oxide (eNO) and spirometry every four weeks; sputum eosinophil (sEo) and bronchial hyperreactivity (BHR) assessed at the beginning and at the end of the study. The primary endpoint was number of patients discontinued from the study due to asthma exacerbations. RESULTS: Eleven patients (13.1%) were discontinued due to asthma exacerbations. At the beginning, patients with elevated percentage of sEo had increased risk of exacerbations (relative risk RR, 6.6; 95% CI, 1.2-35.6), as well as those with augmented BHR (RR, 4.24; 95% CI, 1.1-16.2) as compared to patients who completed the study. An intensification of symptoms and increased use of beta-adrenergics were observed during the last visit before exclusion from the study, but not changes in spirometry, PEF, and eNO. No change in clinical parameters, inflammatory markers or BHR was observed in patients remaining in the study. CONCLUSIONS: After treatment switch from low-dose ICS to montelukast, asthma control was maintained in the majority of patients during the 12-week observation period. Sputum eosinophilia or BHR before the treatment switch was exacerbation risk factor. PMID- 23684854 TI - Regulation of cardiac nitric oxide signaling by nuclear beta-adrenergic and endothelin receptors. AB - At the cell surface, betaARs and endothelin receptors can regulate nitric oxide (NO) production. beta-adrenergic receptors (betaARs) and type B endothelin receptors (ETB) are present in cardiac nuclear membranes and regulate transcription. The present study investigated the role of the NO pathway in the regulation of gene transcription by these nuclear G protein-coupled receptors. Nitric oxide production and transcription initiation were measured in nuclei isolated from the adult rat heart. The cell-permeable fluorescent dye 4,5 diaminofluorescein diacetate (DAF2 DA) was used to provide a direct assessment of nitric oxide release. Both isoproterenol and endothelin increased NO production in isolated nuclei. Furthermore, a beta3AR-selective agonist, BRL 37344, increased NO synthesis whereas the beta1AR-selective agonist xamoterol did not. Isoproterenol increased, whereas ET-1 reduced, de novo transcription. The NO synthase inhibitor l-NAME prevented isoproterenol from increasing either NO production or de novo transcription. l-NAME also blocked ET-1-induced NO production but did not alter the suppression of transcription initiation by ET-1. Inhibition of the cGMP-dependent protein kinase (PKG) using KT5823 also blocked the ability of isoproterenol to increase transcription initiation. Furthermore, immunoblotting revealed eNOS, but not nNOS, in isolated nuclei. Finally, caged, cell-permeable isoproterenol and endothelin-1 analogs were used to selectively activate intracellular beta-adrenergic and endothelin receptors in intact adult cardiomyocytes. Intracellular release of caged ET-1 or isoproterenol analogs increased NO production in intact adult cardiomyocytes. Hence, activation of the NO synthase/guanylyl cyclase/PKG pathway is necessary for nuclear beta3ARs to increase de novo transcription. Furthermore, we have demonstrated the potential utility of caged receptor ligands in selectively modulating signaling via endogenous intracellular G protein-coupled receptors. PMID- 23684856 TI - Autophagy contributes to ING4-induced glioma cell death. AB - Previous studies suggest that ING4, a novel member of ING (inhibitor of growth) family, can inhibit brain tumor growth. However, whether autophagy is involved in ING4-induced cell death still remains unknown. In this study, we found that in addition to apoptosis, autophagy also contributed to cell death induced by ING4. Autophagy levels were elevated following the exposure to Ad-ING4, including enhanced fluorescence intensity of monodansylcadervarine (MDC), a specific in vivo marker for autophagic vacuoles, and increased expression levels of the LC3 II and Beclin-1, wheras the autophagic levels were attenuated following the pretreatment of 3-MA, the inhibitor of autophagy, which significantly decreased the Ad-ING4-induced cell death compared with caspase inhibitor zVAD. Furthermore, ING4 also induced mitochondrial dysfunction, such as mitophagy, collapse of mitochondrial membrane potential and the intracellular ROS, which indicated that mitochondria might be associated with the process of autophagic cell death of glioma cells. Finally, the relationship among Bax, Bcl-2, Beclin-1 and caspase family proteins levels were analyzed in glioma cells U251MG and LN229 infected with Ad-ING4 or Ad-lacZ. It is suggested that both autophagy and apoptosis could contribute to ING4-induced glioma cell death, and mitochondria might play an important role in this process. Our findings reveal novel aspects of the autophagy in glioma cells that underlie the cytotoxic action of ING4, possibly providing new insights in the development of combinatorial therapies for gliomas. PMID- 23684857 TI - [Social inequalities in health in 4 year-old children in the Hauts-de-Seine (France)]. AB - The social effects on health described in France on newborn and 5- to 6-year-old children suggest the existence of a social gradient among the youngest children. The favoured, though unequal, social situation of the department of the Hauts-de Seine (France), makes it particularly adapted to this study. A survey, conducted in 2010 by the departmental service of maternal and infantile protection (PMI) on a representative sample of 1227 children, who received check-ups in their first or second year of nursery school, reveals a significant increase of overweight (from 4.6 to 16.5%), of language disorders (from 8.3 to 25.3%), of the orientations to specialized consultations (from 20.6 to 36.6%), according to the socioprofessional category of the father or the social affiliation of the children in the following subgroups: children speaking or understanding a foreign language (36.6% of the sample), children schooled in priority educational zones (equivalent to education achievement zones in UK, 13.6%), children with limited social health coverage (13.4%). In contrast, the BCG and hepatitis B vaccinal coverage is systematically higher in these various groups. The multivariate analysis investigates for each health problem its links with these various subgroups, and with previous child care experiences, and PMI medical consultations. This study suggests therefore further prospects for different actions according to health problems or regarding vaccinal strategy. The development of such routine indicators of disadvantage should allow territorial health services to target their actions towards the decrease of social disparities in health and to check a posteriori the efficiency of the public systems, which have been implemented. PMID- 23684859 TI - The tricks of the trait: neural implementation of personality varies with genotype-dependent serotonin levels. AB - Gray's Reinforcement Sensitivity Theory (RST) has developed into one of the most prominent personality theories of the last decades. The RST postulates a Behavioral Inhibition System (BIS) modulating the reaction to stimuli indicating aversive events. A number of psychiatric disorders including depression, anxiety disorders, and psychosomatic illnesses have been associated with extreme BIS responsiveness. In recent years, neuroimaging studies have implicated the amygdala-septo-hippocampal circuit as an important neural substrate of the BIS. However, the neurogenetic basis of the regulation of this behaviorally and clinically essential system remains unclear. Investigating the effects of two functional genetic polymorphisms (tryptophan hydroxylase-2, G-703T, and serotonin transporter, serotonin transporter gene-linked polymorphic region) in 89 human participants, we find significantly different patterns of associations between BIS scores and amygdala-hippocampus connectivity during loss anticipation for genotype groups regarding both polymorphisms. Specifically, the correlation between amygdala-hippocampus connectivity and Gray's trait anxiety scores is positive in individuals homozygous for the TPH2 G-allele, while carriers of at least one T-allele show a negative association. Likewise, individuals homozygous for the 5-HTTLPR L(A) variant display a positive association while carriers of the S/L(G) allele show a trend towards a negative association. Thus, we show converging evidence of different neural implementation of the BIS depending on genotype-dependent levels of serotonin. We provide evidence suggesting that genotype-dependent serotonin levels and thus putative changes in the efficiency of serotonergic neurotransmission might not only alter brain activation levels directly, but also more fundamentally impact the neural implementation of personality traits. We outline the direct clinical implications arising from this finding and discuss the complex interplay of neural responses, genes and personality traits in this context. PMID- 23684858 TI - Parcellation of the human substantia nigra based on anatomical connectivity to the striatum. AB - Substantia nigra/ventral tegmental area (SN/VTA) subregions, defined by dopaminergic projections to the striatum, are differentially affected by health (e.g. normal aging) and disease (e.g. Parkinson's disease). This may have an impact on reward processing which relies on dopaminergic regions and circuits. We acquired diffusion tensor imaging (DTI) with probabilistic tractography in 30 healthy older adults to determine whether subregions of the SN/VTA could be delineated based on anatomical connectivity to the striatum. We found that a dorsomedial region of the SN/VTA preferentially connected to the ventral striatum whereas a more ventrolateral region connected to the dorsal striatum. These SN/VTA subregions could be characterised by differences in quantitative structural imaging parameters, suggesting different underlying tissue properties. We also observed that these connectivity patterns differentially mapped onto reward dependence personality trait. We show that tractography can be used to parcellate the SN/VTA into anatomically plausible and behaviourally meaningful compartments, an approach that may help future studies to provide a more fine grained synopsis of pathological changes in the dopaminergic midbrain and their functional impact. PMID- 23684860 TI - Distinct encoding of risk and value in economic choice between multiple risky options. AB - Neural encoding of value-based stimuli is suggested to involve representations of summary statistics, including risk and expected value (EV). A more complex, but ecologically more common, context is when multiple risky options are evaluated together. However, it is unknown whether encoding related to option evaluation in these situations involves similar principles. Here we employed fMRI during a task that parametrically manipulated EV and risk in two simultaneously presented lotteries, both of which contained either gains or losses. We found representations of EV in medial prefrontal cortex and anterior insula, an encoding that was dependent on which option was chosen (i.e. chosen and unchosen EV) and whether the choice was over gains or losses. Parietal activity reflected whether the riskier or surer option was selected, whilst activity in a network of regions that also included parietal cortex reflected both combined risk and difference in risk for the two options. Our findings provide support for the idea that summary statistics underpin a representation of value-based stimuli, and further that these summary statistics undergo distinct forms of encoding. PMID- 23684861 TI - A novel approach to predict subjective pain perception from single-trial laser evoked potentials. AB - Pain is a subjective first-person experience, and self-report is the gold standard for pain assessment in clinical practice. However, self-report of pain is not available in some vulnerable populations (e.g., patients with disorders of consciousness), which leads to an inadequate or suboptimal treatment of pain. Therefore, the availability of a physiology-based and objective assessment of pain that complements the self-report would be of great importance in various applications. Here, we aimed to develop a novel and practice-oriented approach to predict pain perception from single-trial laser-evoked potentials (LEPs). We applied a novel single-trial analysis approach that combined common spatial pattern and multiple linear regression to automatically and reliably estimate single-trial LEP features. Further, we adopted a Naive Bayes classifier to discretely predict low and high pain and a multiple linear prediction model to continuously predict the intensity of pain perception from single-trial LEP features, at both within- and cross-individual levels. Our results showed that the proposed approach provided a binary prediction of pain (classification of low pain and high pain) with an accuracy of 86.3 +/- 8.4% (within-individual) and 80.3 +/- 8.5% (cross-individual), and a continuous prediction of pain (regression on a continuous scale from 0 to 10) with a mean absolute error of 1.031 +/- 0.136 (within-individual) and 1.821 +/- 0.202 (cross-individual). Thus, the proposed approach may help establish a fast and reliable tool for automated prediction of pain, which could be potentially adopted in various basic and clinical applications. PMID- 23684863 TI - Everyday conversation requires cognitive inference: neural bases of comprehending implicated meanings in conversations. AB - In ordinary conversations, literal meanings of an utterance are often quite different from implicated meanings and the inference about implicated meanings is essentially required for successful comprehension of the speaker's utterances. Inference of finding implicated meanings is based on the listener's assumption that the conversational partner says only relevant matters according to the maxim of relevance in Grice's theory of conversational implicature. To investigate the neural correlates of comprehending implicated meanings under the maxim of relevance, a total of 23 participants underwent an fMRI task with a series of conversational pairs, each consisting of a question and an answer. The experimental paradigm was composed of three conditions: explicit answers, moderately implicit answers, and highly implicit answers. Participants were asked to decide whether the answer to the Yes/No question meant 'Yes' or 'No'. Longer reaction time was required for the highly implicit answers than for the moderately implicit answers without affecting the accuracy. The fMRI results show that the left anterior temporal lobe, left angular gyrus, and left posterior middle temporal gyrus had stronger activation in both moderately and highly implicit conditions than in the explicit condition. Comprehension of highly implicit answers had increased activations in additional regions including the left inferior frontal gyrus, left medial prefrontal cortex, left posterior cingulate cortex and right anterior temporal lobe. The activation results indicate involvement of these regions in the inference process to build coherence between literally irrelevant but pragmatically associated utterances under the maxim of relevance. Especially, the left anterior temporal lobe showed high sensitivity to the level of implicitness and showed increased activation for highly versus moderately implicit conditions, which imply its central role in inference such as semantic integration. The right hemisphere activation, uniquely found in the anterior temporal lobe for highly implicit utterances, suggests its competence for integrating distant concepts in implied utterances under the relevance principle. PMID- 23684862 TI - Distributed effects of methylphenidate on the network structure of the resting brain: a connectomic pattern classification analysis. AB - Methylphenidate is a psychostimulant medication that produces improvements in functions associated with multiple neurocognitive systems. To investigate the potentially distributed effects of methylphenidate on the brain's intrinsic network architecture, we coupled resting state imaging with multivariate pattern classification. In a within-subject, double-blind, placebo-controlled, randomized, counterbalanced, cross-over design, 32 healthy human volunteers received either methylphenidate or placebo prior to two fMRI resting state scans separated by approximately one week. Resting state connectomes were generated by placing regions of interest at regular intervals throughout the brain, and these connectomes were submitted for support vector machine analysis. We found that methylphenidate produces a distributed, reliably detected, multivariate neural signature. Methylphenidate effects were evident across multiple resting state networks, especially visual, somatomotor, and default networks. Methylphenidate reduced coupling within visual and somatomotor networks. In addition, default network exhibited decoupling with several task positive networks, consistent with methylphenidate modulation of the competitive relationship between these networks. These results suggest that connectivity changes within and between large-scale networks are potentially involved in the mechanisms by which methylphenidate improves attention functioning. PMID- 23684864 TI - The challenge of localizing the anterior temporal face area: a possible solution. AB - Humans recognize faces exceptionally well. However, the neural correlates of face recognition are still elusive. Accumulated evidence in recent years suggests that the anterior temporal lobe (ATL), in particular face-selective region in the ATL, is a probable locus of face recognition. Unfortunately, functional MRI (fMRI) studies encounter severe signal drop-out in the ventral ATL, where that ATL face area resides. Consequently, all previous studies localized this region in no more than half of the subjects and its volume was relatively small. Thus, a systematic exploration of the properties of the ATL face area is scarce. In the current high resolution fMRI study we used coronal slice orientation, which permitted us to localize the ATL face area in all the subjects. Furthermore, the volume of the area was much larger than was reported in previous studies. Direct within subjects comparison with data collected with the commonly used axial slice orientation confirmed that the advantage of the coronal slice orientation in revealing a reliable and larger face-selective area in the ATL. Finally, by displaying the face-selective activations resultant from coronal and axial scanning together, we demonstrate an organization principle of a chain of face selective regions along the posterior-anterior axis in the ventral temporal lobe that is highly reproducible across all subjects. By using the procedure proposed here, a significant progress can be made in studying the neural correlates of face recognition. PMID- 23684865 TI - Weighted linear least squares estimation of diffusion MRI parameters: strengths, limitations, and pitfalls. AB - PURPOSE: Linear least squares estimators are widely used in diffusion MRI for the estimation of diffusion parameters. Although adding proper weights is necessary to increase the precision of these linear estimators, there is no consensus on how to practically define them. In this study, the impact of the commonly used weighting strategies on the accuracy and precision of linear diffusion parameter estimators is evaluated and compared with the nonlinear least squares estimation approach. METHODS: Simulation and real data experiments were done to study the performance of the weighted linear least squares estimators with weights defined by (a) the squares of the respective noisy diffusion-weighted signals; and (b) the squares of the predicted signals, which are reconstructed from a previous estimate of the diffusion model parameters. RESULTS: The negative effect of weighting strategy (a) on the accuracy of the estimator was surprisingly high. Multi-step weighting strategies yield better performance and, in some cases, even outperformed the nonlinear least squares estimator. CONCLUSION: If proper weighting strategies are applied, the weighted linear least squares approach shows high performance characteristics in terms of accuracy/precision and may even be preferred over nonlinear estimation methods. PMID- 23684866 TI - Real-time fMRI links subjective experience with brain activity during focused attention. AB - Recent advances in brain imaging have improved the measure of neural processes related to perceptual, cognitive and affective functions, yet the relation between brain activity and subjective experience remains poorly characterized. In part, it is a challenge to obtain reliable accounts of participant's experience in such studies. Here we addressed this limitation by utilizing experienced meditators who are expert in introspection. We tested a novel method to link objective and subjective data, using real-time fMRI (rt-fMRI) to provide participants with feedback of their own brain activity during an ongoing task. We provided real-time feedback during a focused attention task from the posterior cingulate cortex, a hub of the default mode network shown to be activated during mind-wandering and deactivated during meditation. In a first experiment, both meditators and non-meditators reported significant correspondence between the feedback graph and their subjective experience of focused attention and mind wandering. When instructed to volitionally decrease the feedback graph, meditators, but not non-meditators, showed significant deactivation of the posterior cingulate cortex. We were able to replicate these results in a separate group of meditators using a novel step-wise rt-fMRI discovery protocol in which participants were not provided with prior knowledge of the expected relationship between their experience and the feedback graph (i.e., focused attention versus mind-wandering). These findings support the feasibility of using rt-fMRI to link objective measures of brain activity with reports of ongoing subjective experience in cognitive neuroscience research, and demonstrate the generalization of expertise in introspective awareness to novel contexts. PMID- 23684867 TI - A semi-immersive virtual reality incremental swing balance task activates prefrontal cortex: a functional near-infrared spectroscopy study. AB - Previous functional near-infrared spectroscopy (fNIRS) studies indicated that the prefrontal cortex (PFC) is involved in the maintenance of the postural balance after external perturbations. So far, no studies have been conducted to investigate the PFC hemodynamic response to virtual reality (VR) tasks that could be adopted in the field of functional neurorehabilitation. The aim of this fNIRS study was to assess PFC oxygenation response during an incremental and a control swing balance task (ISBT and CSBT, respectively) in a semi-immersive VR environment driven by a depth-sensing camera. It was hypothesized that: i) the PFC would be bilaterally activated in response to the increase of the ISBT difficulty, as this cortical region is involved in the allocation of attentional resources to maintain postural control; and ii) the PFC activation would be greater in the right than in the left hemisphere considering its dominance for visual control of body balance. To verify these hypotheses, 16 healthy male subjects were requested to stand barefoot while watching a 3 dimensional virtual representation of themselves projected onto a screen. They were asked to maintain their equilibrium on a virtual blue swing board susceptible to external destabilizing perturbations (i.e., randomizing the forward-backward direction of the impressed pulse force) during a 3-min ISBT (performed at four levels of difficulty) or during a 3-min CSBT (performed constantly at the lowest level of difficulty of the ISBT). The center of mass (COM), at each frame, was calculated and projected on the floor. When the subjects were unable to maintain the COM over the board, this became red (error). After each error, the time required to bring back the COM on the board was calculated (returning time). An eight-channel continuous wave fNIRS system was employed for measuring oxygenation changes (oxygenated-hemoglobin, O2Hb; deoxygenated-hemoglobin, HHb) related to the PFC activation (Brodmann Areas 10, 11 and 46). The results have indicated that the errors increased between the first and the second level of difficulty of the ISBT, then decreased and remained constant; the returning time progressively increased during the first three levels of difficulty and then remained constant. During the CSBT, the errors and the returning time did not change. In the ISBT, the increase of the first three levels of difficulty was accompanied by a progressive increase in PFC O2Hb and a less consistent decrease in HHb. A tendency to plateau was observable for PFC O2Hb and HHb changes in the fourth level of difficulty of the ISBT, which could be partly explained by a learning effect. A right hemispheric lateralization was not found. A lower amplitude of increase in O2Hb and decrease in HHb was found in the PFC in response to the CSBT with respect to the ISBT. This study has demonstrated that the oxygenation increased over the PFC while performing an ISBT in a semi-immersive VR environment. These data reinforce the involvement of the PFC in attention demanding balance tasks. Considering the adaptability of this virtual balance task to specific neurological disorders, the absence of motion sensing devices, and the motivating/safe semi-immersive VR environment, the ISBT adopted in this study could be considered valuable for diagnostic testing and for assessing the effectiveness of functional neurorehabilitation. PMID- 23684868 TI - A review on continuous wave functional near-infrared spectroscopy and imaging instrumentation and methodology. AB - This year marks the 20th anniversary of functional near-infrared spectroscopy and imaging (fNIRS/fNIRI). As the vast majority of commercial instruments developed until now are based on continuous wave technology, the aim of this publication is to review the current state of instrumentation and methodology of continuous wave fNIRI. For this purpose we provide an overview of the commercially available instruments and address instrumental aspects such as light sources, detectors and sensor arrangements. Methodological aspects, algorithms to calculate the concentrations of oxy- and deoxyhemoglobin and approaches for data analysis are also reviewed. From the single-location measurements of the early years, instrumentation has progressed to imaging initially in two dimensions (topography) and then three (tomography). The methods of analysis have also changed tremendously, from the simple modified Beer-Lambert law to sophisticated image reconstruction and data analysis methods used today. Due to these advances, fNIRI has become a modality that is widely used in neuroscience research and several manufacturers provide commercial instrumentation. It seems likely that fNIRI will become a clinical tool in the foreseeable future, which will enable diagnosis in single subjects. PMID- 23684869 TI - Long term cortical plasticity in visual retinotopic areas in humans with silent retinal ganglion cell loss. AB - Visual cortical plasticity induced by overt retinal lesions (scotomas) has remained a controversial phenomenon. Here we studied cortical plasticity in a silent model of retinal ganglion cell loss, documented by in vivo optical biopsy using coherence tomography. The cortical impact of non-scotomatous subtle retinal ganglion cell functional and structural loss was investigated in carriers of the mitochondrial DNA 11778G>A mutation causing Leber's hereditary optic neuropathy. We used magnetic resonance imaging (MRI) to measure cortical thickness and fMRI to define retinotopic cortical visual areas V1, V2 and V3 in silent carriers and matched control groups. Repeated Measures analysis of variance revealed a surprising increase in cortical thickness in the younger carrier group (below 21 years of age). This effect dominated in extrastriate cortex, and notably V2. This form of structural plasticity suggests enhanced plastic developmental mechanisms in extrastriate retinotopic regions close to V1 and not receiving direct retinocortical input. PMID- 23684870 TI - The roles of superficial amygdala and auditory cortex in music-evoked fear and joy. AB - This study investigates neural correlates of music-evoked fear and joy with fMRI. Studies on neural correlates of music-evoked fear are scant, and there are only a few studies on neural correlates of joy in general. Eighteen individuals listened to excerpts of fear-evoking, joy-evoking, as well as neutral music and rated their own emotional state in terms of valence, arousal, fear, and joy. Results show that BOLD signal intensity increased during joy, and decreased during fear (compared to the neutral condition) in bilateral auditory cortex (AC) and bilateral superficial amygdala (SF). In the right primary somatosensory cortex (area 3b) BOLD signals increased during exposure to fear-evoking music. While emotion-specific activity in AC increased with increasing duration of each trial, SF responded phasically in the beginning of the stimulus, and then SF activity declined. Psychophysiological Interaction (PPI) analysis revealed extensive emotion-specific functional connectivity of AC with insula, cingulate cortex, as well as with visual, and parietal attentional structures. These findings show that the auditory cortex functions as a central hub of an affective-attentional network that is more extensive than previously believed. PPI analyses also showed functional connectivity of SF with AC during the joy condition, taken to reflect that SF is sensitive to social signals with positive valence. During fear music, SF showed functional connectivity with visual cortex and area 7 of the superior parietal lobule, taken to reflect increased visual alertness and an involuntary shift of attention during the perception of auditory signals of danger. PMID- 23684871 TI - Cortical changes underlying balance recovery in patients with hemiplegic stroke. AB - Balance problems are a major sequelae of stroke and are implicated in poor recovery of activities of daily living. In a cross-sectional study, using 50 channel event-related functional near-infrared spectroscopy we previously reported a significant correlation between individual balance ability after stroke and postural perturbation-related cortical activation in the supplementary motor area (SMA) and the prefrontal cortex. However, the neural mechanisms underlying balance recovery after stroke remain unclear. Herein, we examined the cortical involvement in balance recovery after stroke by determining longitudinal regional cortical activation changes in patients with hemiplegic stroke. Twenty patients with subcortical stroke admitted to our hospital for post-acute inpatient rehabilitation participated in this study. Before and after intensive inpatient physical and occupational therapy rehabilitation, we evaluated cortical activation associated with external postural perturbations induced by combined brisk forward and backward movement on a platform. Postural perturbation-related cortical activation in the SMA of the affected and unaffected hemispheres was significantly increased after intensive rehabilitation. The increment of the postural-perturbation-related oxygenated hemoglobin signals in the SMA of the unaffected hemisphere was significantly correlated with the gain in balance function measured by the Berg Balance Scale. These findings support the conclusion that the SMA plays an important role in postural balance control, and suggest that the SMA is a crucial area for balance recovery after hemiplegic stroke. PMID- 23684872 TI - Dynamic reconfiguration of human brain functional networks through neurofeedback. AB - Recent fMRI studies demonstrated that functional connectivity is altered following cognitive tasks (e.g., learning) or due to various neurological disorders. We tested whether real-time fMRI-based neurofeedback can be a tool to voluntarily reconfigure brain network interactions. To disentangle learning related from regulation-related effects, we first trained participants to voluntarily regulate activity in the auditory cortex (training phase) and subsequently asked participants to exert learned voluntary self-regulation in the absence of feedback (transfer phase without learning). Using independent component analysis (ICA), we found network reconfigurations (increases in functional network connectivity) during the neurofeedback training phase between the auditory target region and (1) the auditory pathway; (2) visual regions related to visual feedback processing; (3) insula related to introspection and self-regulation and (4) working memory and high-level visual attention areas related to cognitive effort. Interestingly, the auditory target region was identified as the hub of the reconfigured functional networks without a-priori assumptions. During the transfer phase, we again found specific functional connectivity reconfiguration between auditory and attention network confirming the specific effect of self-regulation on functional connectivity. Functional connectivity to working memory related networks was no longer altered consistent with the absent demand on working memory. We demonstrate that neurofeedback learning is mediated by widespread changes in functional connectivity. In contrast, applying learned self-regulation involves more limited and specific network changes in an auditory setup intended as a model for tinnitus. Hence, neurofeedback training might be used to promote recovery from neurological disorders that are linked to abnormal patterns of brain connectivity. PMID- 23684873 TI - Modeling functional Magnetic Resonance Imaging (fMRI) experimental variables in the Ontology of Experimental Variables and Values (OoEVV). AB - Neuroimaging data is raw material for cognitive neuroscience experiments, leading to scientific knowledge about human neurological and psychological disease, language, perception, attention and ultimately, cognition. The structure of the variables used in the experimental design defines the structure of the data gathered in the experiments; this in turn structures the interpretative assertions that may be presented as experimental conclusions. Representing these assertions and the experimental data which support them in a computable way means that they could be used in logical reasoning environments, i.e. for automated meta-analyses, or linking hypotheses and results across different levels of neuroscientific experiments. Therefore, a crucial first step in being able to represent neuroimaging results in a clear, computable way is to develop representations for the scientific variables involved in neuroimaging experiments. These representations should be expressive, computable, valid, extensible, and easy-to-use. They should also leverage existing semantic standards to interoperate easily with other systems. We present an ontology design pattern called the Ontology of Experimental Variables and Values (OoEVV). This is designed to provide a lightweight framework to capture mathematical properties of data, with appropriate 'hooks' to permit linkage to other ontology driven projects (such as the Ontology of Biomedical Investigations, OBI). We instantiate the OoEVV system with a small number of functional Magnetic Resonance Imaging datasets, to demonstrate the system's ability to describe the variables of a neuroimaging experiment. OoEVV is designed to be compatible with the XCEDE neuroimaging data standard for data collection terminology, and with the Cognitive Paradigm Ontology (CogPO) for specific reasoning elements of neuroimaging experimental designs. PMID- 23684874 TI - Diffusion imaging quality control via entropy of principal direction distribution. AB - Diffusion MR imaging has received increasing attention in the neuroimaging community, as it yields new insights into the microstructural organization of white matter that are not available with conventional MRI techniques. While the technology has enormous potential, diffusion MRI suffers from a unique and complex set of image quality problems, limiting the sensitivity of studies and reducing the accuracy of findings. Furthermore, the acquisition time for diffusion MRI is longer than conventional MRI due to the need for multiple acquisitions to obtain directionally encoded Diffusion Weighted Images (DWI). This leads to increased motion artifacts, reduced signal-to-noise ratio (SNR), and increased proneness to a wide variety of artifacts, including eddy-current and motion artifacts, "venetian blind" artifacts, as well as slice-wise and gradient-wise inconsistencies. Such artifacts mandate stringent Quality Control (QC) schemes in the processing of diffusion MRI data. Most existing QC procedures are conducted in the DWI domain and/or on a voxel level, but our own experiments show that these methods often do not fully detect and eliminate certain types of artifacts, often only visible when investigating groups of DWI's or a derived diffusion model, such as the most-employed diffusion tensor imaging (DTI). Here, we propose a novel regional QC measure in the DTI domain that employs the entropy of the regional distribution of the principal directions (PD). The PD entropy quantifies the scattering and spread of the principal diffusion directions and is invariant to the patient's position in the scanner. High entropy value indicates that the PDs are distributed relatively uniformly, while low entropy value indicates the presence of clusters in the PD distribution. The novel QC measure is intended to complement the existing set of QC procedures by detecting and correcting residual artifacts. Such residual artifacts cause directional bias in the measured PD and here called dominant direction artifacts. Experiments show that our automatic method can reliably detect and potentially correct such artifacts, especially the ones caused by the vibrations of the scanner table during the scan. The results further indicate the usefulness of this method for general quality assessment in DTI studies. PMID- 23684875 TI - Hippocampal activation during extinction learning predicts occurrence of the renewal effect in extinction recall. AB - The renewal effect describes the reoccurrence of a previously extinguished response in situations where the context of extinction differs from that of acquisition, thus illustrating the context-dependency of extinction learning. A number of studies on contextual fear extinction have implicated hippocampus and vmPFC in processing and retrieval of context both during extinction learning and recall of extinction. In this functional magnetic resonance imaging (fMRI) study we explored the neural correlates of the renewal effect in associative learning, using a predictive learning task that required participants to learn relations between cues and outcomes presented in particular contexts. During extinction in a novel context, compared to extinction in a context identical to the acquisition context, participants who exhibited the renewal effect (REN) showed increased activation in brain regions including bilateral posterior hippocampus and left parahippocampal gyrus. This activation pattern was absent in participants that did not show the renewal effect (NOREN). In direct comparisons between the groups, the REN group exhibited higher activation in bilateral hippocampus, while the NOREN group showed higher activation in left dlPFC (BA 46) and right anterior cingulate (BA 32). During extinction recall, stimuli that had been extinguished in a different context were again presented in the context of acquisition. Here both groups exhibited predominantly prefrontal activation, with the REN group's focus upon bilateral OFC (BA 47) and bilateral vmPFC (BA 10), while the NOREN group showed generally more widespread activation, predominantly in large clusters of dlPFC (BA 8,9,45). In a direct comparison, the REN group showed higher activation than the NOREN group in left vmPFC (BA 10), while NOREN participants exhibited more activation in dlPFC (BA 9, 46). Activation in left vmPFC during extinction recall correlated with the number of renewal effect responses, while the dlPFC activation showed a negative correlation with renewal effect responses. These results highlight the differential activation patterns of processes that will eventually produce or not produce a renewal effect, indicating that during extinction learning hippocampus encodes the relation between context and cue-outcome, while in extinction recall vmPFC is active to retrieve this association. PMID- 23684876 TI - Multivariate decoding of brain images using ordinal regression. AB - Neuroimaging data are increasingly being used to predict potential outcomes or groupings, such as clinical severity, drug dose response, and transitional illness states. In these examples, the variable (target) we want to predict is ordinal in nature. Conventional classification schemes assume that the targets are nominal and hence ignore their ranked nature, whereas parametric and/or non parametric regression models enforce a metric notion of distance between classes. Here, we propose a novel, alternative multivariate approach that overcomes these limitations - whole brain probabilistic ordinal regression using a Gaussian process framework. We applied this technique to two data sets of pharmacological neuroimaging data from healthy volunteers. The first study was designed to investigate the effect of ketamine on brain activity and its subsequent modulation with two compounds - lamotrigine and risperidone. The second study investigates the effect of scopolamine on cerebral blood flow and its modulation using donepezil. We compared ordinal regression to multi-class classification schemes and metric regression. Considering the modulation of ketamine with lamotrigine, we found that ordinal regression significantly outperformed multi class classification and metric regression in terms of accuracy and mean absolute error. However, for risperidone ordinal regression significantly outperformed metric regression but performed similarly to multi-class classification both in terms of accuracy and mean absolute error. For the scopolamine data set, ordinal regression was found to outperform both multi-class and metric regression techniques considering the regional cerebral blood flow in the anterior cingulate cortex. Ordinal regression was thus the only method that performed well in all cases. Our results indicate the potential of an ordinal regression approach for neuroimaging data while providing a fully probabilistic framework with elegant approaches for model selection. PMID- 23684878 TI - A new method for estimating population receptive field topography in visual cortex. AB - We introduce a new method for measuring visual population receptive fields (pRF) with functional magnetic resonance imaging (fMRI). The pRF structure is modeled as a set of weights that can be estimated by solving a linear model that predicts the Blood Oxygen Level-Dependent (BOLD) signal using the stimulus protocol and the canonical hemodynamic response function. This method does not make a priori assumptions about the specific pRF shape and is therefore a useful tool for uncovering the underlying pRF structure at different spatial locations in an unbiased way. We show that our method is more accurate than a previously described method (Dumoulin and Wandell, 2008) which directly fits a 2-dimensional isotropic Gaussian pRF model to predict the fMRI time-series. We demonstrate that direct-fit models do not fully capture the actual pRF shape, and can be prone to pRF center mislocalization when the pRF is located near the border of the stimulus space. A quantitative comparison demonstrates that our method outperforms the direct-fit methods in the pRF center modeling by achieving higher explained variance of the BOLD signal. This was true for direct-fit isotropic Gaussian, anisotropic Gaussian, and difference of isotropic Gaussians model. Importantly, our model is also capable of exploring a variety of pRF properties such as surround suppression, receptive field center elongation, orientation, location and size. Additionally, the proposed method is particularly attractive for monitoring pRF properties in the visual areas of subjects with lesions of the visual pathways, where it is difficult to anticipate what shape the reorganized pRF might take. Finally, the method proposed here is more efficient in computation time than direct-fit methods, which need to search for a set of parameters in an extremely large searching space. Instead, this method uses the pRF topography to constrain the space that needs to be searched for the subsequent modeling. PMID- 23684877 TI - Function in the human connectome: task-fMRI and individual differences in behavior. AB - The primary goal of the Human Connectome Project (HCP) is to delineate the typical patterns of structural and functional connectivity in the healthy adult human brain. However, we know that there are important individual differences in such patterns of connectivity, with evidence that this variability is associated with alterations in important cognitive and behavioral variables that affect real world function. The HCP data will be a critical stepping-off point for future studies that will examine how variation in human structural and functional connectivity play a role in adult and pediatric neurological and psychiatric disorders that account for a huge amount of public health resources. Thus, the HCP is collecting behavioral measures of a range of motor, sensory, cognitive and emotional processes that will delineate a core set of functions relevant to understanding the relationship between brain connectivity and human behavior. In addition, the HCP is using task-fMRI (tfMRI) to help delineate the relationships between individual differences in the neurobiological substrates of mental processing and both functional and structural connectivity, as well as to help characterize and validate the connectivity analyses to be conducted on the structural and functional connectivity data. This paper describes the logic and rationale behind the development of the behavioral, individual difference, and tfMRI batteries and provides preliminary data on the patterns of activation associated with each of the fMRI tasks, at both group and individual levels. PMID- 23684879 TI - Variant in OXTR gene and functional connectivity of the hypothalamus in normal subjects. AB - The oxytocin receptor gene (OXTR) rs53576A has been associated with autism spectrum disorders (ASDs). A smaller hypothalamic volume has been reported in healthy male A-allele carriers than in male GG homozygotes and in patients with ASDs than in healthy controls. These findings prompt the hypothesis that male AA homozygotes may have weaker hypothalamic functional connectivity when compared to male G-allele carriers. We calculated local functional connectivity density (FCD) using a voxel-wise data-driven approach based on resting-state functional MRI data in 270 young healthy subjects. Both the main effect of genotype and the gender-by-genotype interaction were considered. Of the whole brain, only the local FCD of the hypothalamus exhibited the main effect of genotype. Post-hoc testing revealed significantly lower local FCD in male AA homozygotes compared to male G-allele carriers although there was only a trend of significance in the gender-by-genotype interaction. We further analyzed the resting-state functional connectivity (rsFC) of the hypothalamic region that demonstrating significant genotype differences in local FCD. We found a significant gender-by-genotype interaction in rsFC between the hypothalamic region and the left dorsolateral prefrontal cortex, but no significant main effect of genotype was found. Post-hoc testing revealed that this rsFC was significantly weaker in male AA homozygotes compared to male G-allele carriers. Our findings identify gender-dependent mechanisms of OXTR rs53576 gene variation impacting the functional connectivity of the hypothalamus in healthy individuals and suggest that these mechanisms are important for understanding ASDs. PMID- 23684881 TI - Visual callosal topography in the absence of retinal input. AB - Using probabilistic diffusion tractography, we examined the retinotopic organization of splenial callosal connections within early blind, anophthalmic, and control subjects. Early blind subjects experienced prenatal retinal "waves" of spontaneous activity similar to those of sighted subjects, and only lack postnatal visual experience. In anophthalmia, the eye is either absent or arrested at an early prenatal stage, depriving these subjects of both pre- and postnatal visual input. Therefore, comparing these two groups provides a way of separating the influence of pre- and postnatal retinal input on the organization of visual connections across hemispheres. We found that retinotopic mapping within the splenium was not measurably disrupted in early blind or anophthalmic subjects compared to visually normal controls. No significant differences in splenial volume were observed across groups. No significant differences in diffusivity were found between early blind subjects and sighted controls, though some differences in diffusivity were noted between anophthalmic subjects and controls. These results suggest that neither prenatal retinal activity nor postnatal visual experience plays a role in the large-scale topographic organization of visual callosal connections within the splenium. PMID- 23684880 TI - The WU-Minn Human Connectome Project: an overview. AB - The Human Connectome Project consortium led by Washington University, University of Minnesota, and Oxford University is undertaking a systematic effort to map macroscopic human brain circuits and their relationship to behavior in a large population of healthy adults. This overview article focuses on progress made during the first half of the 5-year project in refining the methods for data acquisition and analysis. Preliminary analyses based on a finalized set of acquisition and preprocessing protocols demonstrate the exceptionally high quality of the data from each modality. The first quarterly release of imaging and behavioral data via the ConnectomeDB database demonstrates the commitment to making HCP datasets freely accessible. Altogether, the progress to date provides grounds for optimism that the HCP datasets and associated methods and software will become increasingly valuable resources for characterizing human brain connectivity and function, their relationship to behavior, and their heritability and genetic underpinnings. PMID- 23684882 TI - Differential role of the Mentalizing and the Mirror Neuron system in the imitation of communicative gestures. AB - Successful social interaction requires recognising the intention of another person's communicative gestures. At a neural level, this process may involve neural activity in different systems, such as the mentalizing system (MS) and the mirror neuron system (MNS). The aim of the present study was to explore the neural correlates of communicative gestures during observation and execution of these gestures. Twenty participants watched video clips of an actor executing social gestures (S), non-social gestures (NS) and meaningless gestures (ML). During fMRI data acquisition, participants were asked to observe (O) and subsequently to execute (E) one of two tasks: imitate the gesture presented (IMI) or perform a motor control task (CT). For the contrast IMI>CT we found activations in the core areas of the MNS [inferior parietal lobule (IPL) and inferior frontal cortex, the posterior part of pars opercularis], as well as in areas related to the MS [superior temporal sulcus (STS) and middle cingulate cortex]. For S>NS, we found activations in the left medial orbitofrontal cortex (mOFC), right superior frontal cortex and middle cingulate cortex. The interaction of stimulus condition (S vs NS) and task (IMI vs CT) revealed activation in the right IPL. For the interaction between observation vs execution (O vs E), task (IMI vs CT) and stimulus condition (S vs NS) we found activation in the right mOFC. Our data suggest that imitation is differentially processed in the MNS as well as in the MS. The activation in IPL is enhanced during the processing of social gestures most likely due to their communicative intention. The activation of IPL together with medial frontal areas may contribute to mentalizing processes. The interaction in the mOFC suggests an involvement of self-referential processes in the processing of social gesture. PMID- 23684883 TI - Heart cycle-related effects on event-related potentials, spectral power changes, and connectivity patterns in the human ECoG. AB - The perception of one's own heartbeat is a fundamental interoceptive process that involves cortical and subcortical structures. Yet, the precise spatiotemporal neuronal activity patterns underlying the cortical information processing have remained largely elusive. Although the high temporal and spatial resolution of electrocorticographic (ECoG) recordings is increasingly being exploited in functional neuroimaging, it has not been used to study heart cycle-related effects. Here, we addressed the capacity of ECoG to characterize neuronal signals within the cardiac cycle, as well as to disentangle them from heart cycle-related artifacts. Based on topographical distribution and latency, we identified a biphasic potential within the primary somatosensory cortex, which likely constitutes a heartbeat-evoked potential (HEP) of neuronal origin. We also found two different types of artifacts: i) oscillatory potential changes with a frequency identical to the heart pulse rate, which probably represent pulsatility artifacts and ii) sharp potentials synchronized to the R-peak, corresponding to the onset of ventricular contraction and the cardiac field artifact (CFA) in EEG. Finally, we show that heart cycle-related effects induce pronounced phase synchrony patterns in the ECoG and that this kind of correlation patterns, which may confound ECoG connectivity studies, can be reduced by a suitable correction algorithm. The present study is, to our knowledge, the first one to show a focally localized cortical HEP that could be clearly and consistently observed over subjects, suggesting a basic role of primary sensory cortex in processing of heart-related sensory inputs. We also conclude that taking into account and reducing heart cycle-related effects may be advantageous for many ECoG studies, and are of crucial importance, particularly for ECoG-based connectivity studies. Thus, in summary, although ECoG poses new challenges, it opens up new possibilities for the investigation of heartbeat-related viscerosensory processing in the human brain. PMID- 23684885 TI - Fifty years ago: the quest for steroid hormone receptors. AB - In 1963 Peter Karlson put forward the revolutionary "hormone-gene" hypothesis, which would change drastically the way in which steroid hormones were thought to act at the time. From a historical perspective, this review relates the acceptance of this initially controversial idea, the discovery of the steroid receptors and the key experiments that have led to the current understanding of the mechanism of steroid hormone action. It shows how, over 50years, the field has widened beyond all expectation and has contributed to major advances not only in endocrinology, but also in molecular biology, pharmacology and therapeutics. PMID- 23684884 TI - Canonical and non-canonical roles of the histone methyltransferase EZH2 in mammary development and cancer. AB - Although hormones and downstream transcription factors are considered main drivers directing mammary gland development and oncogenic transformation, an emerging body of evidence suggests these processes are modulated by dynamic histone methylation landscapes. The methyltransferase EZH2 catalyzes the formation of trimethyl groups on lysine 27 of histone 3 (H3K27me3) and loss- and gain-of-function studies have provided insight into its role in normal mammary development and oncogenic transformation. EZH2 controls the homeostasis of mouse mammary stem cells, and mammary epithelium devoid of EZH2 does not undergo functional development during pregnancy, possibly due to a paucity of stem cells. EZH2 levels are frequently elevated in breast cancer suggesting a link between H3K27me3 and cell proliferation. In addition to its role as epigenetic regulator, recent studies have placed EZH2 into the category of transcriptional co activators and thus opened the possibility of non-canonical signaling pathways. In contrast to solid tumors, loss of EZH2 from hematopoietic cells has been linked to malignancies (Fig. 1). The challenge will be to understand not only cell-specific functions of EZH2, but also the extent to which it relies on its enzymatic activity versus its ability to serve as a transcriptional co-factor. PMID- 23684886 TI - Human chorionic gonadotropin and its free beta-subunit stimulate trophoblast invasion independent of LH/hCG receptor. AB - Both paracrine and autocrine factors are involved in the regulation of trophoblast invasion. One of these factors is human chorionic gonadotropin (hCG), which stimulates trophoblast invasion. The stimulatory activity has especially been ascribed to a hyperglycosylated form of hCG (hCG-h) that is expressed in early pregnancy. We compared the stimulatory activities of different forms of hCG and its free beta-subunit (hCGbeta) on trophoblast invasion. hCG, hCG-h, hCGbeta, and its hyperglycosylated form (hCGbeta-h) stimulated the invasion of JEG-3 choriocarcinoma cells. The stimulatory effect of hCGbeta was also confirmed with primary human trophoblasts. Down-regulation of the LH/hCG receptor by RNA interference did not significantly reduce the effect of hCGbeta and hCG on cell invasion. Increased invasion was associated with increased levels of MMP-2, MMP-9 and activity of uPA. Our findings suggest that hCG, hCGbeta and their hyperglycosylated forms stimulate the invasion of trophoblast cells independent of the classical LH/hCG-receptor. PMID- 23684887 TI - Decursin inhibited proliferation and angiogenesis of endothelial cells to suppress diabetic retinopathy via VEGFR2. AB - Diabetes induces pathologic proliferation and angiogenesis in the retina that leads to catastrophic loss of vision. Decursin is a novel therapeutic that targets the vascular endothelial growth factor (VEGF) receptor (VEGFR) with putative anti-proliferative and anti-angiogenic activities. Thereby we utilized human retinal microvascular endothelial cells (HRMEC) and human umbilical vein endothelial cells (HUVEC) under conditions of excess glucose to explore dose dependent responses of decursin on markers of migration, angiogenesis, and proliferation. Decursin dose-dependently inhibited tube formation, VEGFR-2 expression, along with relative metabolic activity and 5-bromo-2'-deoxy-uridine (BrdU) activity in both cell lines. We then correlated our findings to the streptozotocin-induced rat model of diabetes. Following three months of decursin treatment VEGFR-2 expression was significantly inhibited. Our data would suggest that decursin may be a potent anti-angiogenic and anti-proliferative agent targeting the VEGFR-2 signaling pathway, which significantly inhibits diabetic retinal neovascularization. PMID- 23684889 TI - Chromatin and epigenetic determinants of estrogen receptor alpha (ESR1) signaling. AB - The oestrogen receptor alpha (ESR1) is a transcription factor that potentiates the response to diverse stimuli, including oestrogen and growth factors, in various tissue types. Its recruitment to the DNA is directly regulated by the chromatin landscape, inclusive of chromatin compaction and epigenetic modifications. In this review we discuss our current understanding of the interplay between ESR1 signaling and the chromatin landscape. We present how the chromatin landscape primes the lineage-specific response and contributes to stimuli-specific signaling. Finally, we discuss recent efforts to decipher the relationship between genetic and epigenetic as it relates to ESR1 signaling in breast cancer. PMID- 23684890 TI - Expression and functional activity of PACAP and its receptors on cumulus cells: effects on oocyte maturation. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor PAC1 R (PACAP type 1 receptor) are transiently expressed in granulosa cells (GCs) of mouse preovulatory follicles and affect several parameters associated with the ovulatory process. We investigated the expression of PACAP and its receptors in cumulus cells (CCs) after the LH surge and their role on cumulus expansion/apoptosis and oocyte maturation. PACAP and PAC1-R expression increased in CCs isolated at different times after treatment with human chorionic gonadotropin (hCG). Moreover, PACAP was able to reverse the inhibition of oocyte meiotic maturation caused by hypoxantine in cumulus cell-oocyte complexes (COCs) and efficiently promoted male pronuclear formation after fertilisation. PACAP was also able to induce cumulus expansion and prevent CC apoptosis. Our results demonstrated the induction of PACAP and its receptors in CCs by LH and EGF, suggesting that PACAP may play a significant role in the complex interactions of gonadotropin and growth factors during ovulation and fertilisation. PMID- 23684891 TI - Dural ectasia and FBN1 mutation screening of 40 patients with Marfan syndrome and related disorders: role of dural ectasia for the diagnosis. AB - Marfan syndrome is an autosomal dominant disorder of connective tissue caused by mutations in the gene encoding fibrillin-1 (FBN1), a matrix component of microfibrils. Dural ectasia, i.e. enlargement of the neural canal mainly located in the lower lumbar and sacral region, frequently occurs in Marfan patients. The aim of our study was to investigate the role of dural ectasia in raising the diagnosis of Marfan syndrome and its association with FBN1 mutations. We studied 40 unrelated patients suspected for MFS, who underwent magnetic resonance imaging searching for dural ectasia. In all of them FBN1 gene analysis was also performed. Thirty-seven patients resulted affected by Marfan syndrome according to the '96 Ghent criteria; in 30 of them the diagnosis was confirmed when revaluated by the recently revised criteria (2010). Thirty-six patients resulted positive for dural ectasia. The degree of dural ectasia was grade 1 in 19 patients, grade 2 in 11 patients, and grade 3 in 6 patients. In 7 (24%) patients, the presence of dural ectasia allowed to reach a positive score for systemic feature criterion. Twenty-four patients carried an FBN1 mutation, that were represented by 13 missense (54%), and 11 (46%) mutations generating a premature termination codon (PTC, frameshifts and stop codons). No mutation was detected in the remaining 16 (6 patients with MFS and 10 with related disorders according to revised Ghent criteria). The prevalence of severe (grade 2 and grade 3) involvement of dura mater was higher in patients harbouring premature termination codon (PTC) mutations than those carrying missense-mutations (8/11 vs 2/13, P = 0.0111). Our data emphasizes the importance of dural ectasia screening to reach the diagnosis of Marfan syndrome especially when it is uncertain and indicates an association between PTC mutations and severe dural ectasia in Marfan patients. PMID- 23684888 TI - Mitochondrial and skeletal muscle health with advancing age. AB - With increasing age there is a temporal relationship between the decline of mitochondrial and skeletal muscle volume, quality and function (i.e., health). Reduced mitochondrial mRNA expression, protein abundance, and protein synthesis rates appear to promote the decline of mitochondrial protein quality and function. Decreased mitochondrial function is suspected to impede energy demanding processes such as skeletal muscle protein turnover, which is critical for maintaining protein quality and thus skeletal muscle health with advancing age. The focus of this review was to discuss promising human physiological systems underpinning the decline of mitochondrial and skeletal muscle health with advancing age while highlighting therapeutic strategies such as aerobic exercise and caloric restriction for combating age-related functional impairments. PMID- 23684892 TI - An eye on eye development. AB - The vertebrate eye is composed of both surface ectodermal and neuroectodermal derivatives that evaginate laterally from an epithelial anlage of the forming diencephalon. The retina is composed of a limited number of neuronal and non neuronal cell types and is seen as a model for the brain with reduced complexity. The eye develops in a stereotypic manner building on evolutionarily conserved molecular networks. Eye formation is initiated at the onset of gastrulation by the determination of the eye field in the anterior neuroectoderm. Homeobox transcription factors, in particular Six3 are crucially involved in the establishment and maintenance of retinal identity. The eye field expands by proliferation as gastrulation proceeds and is initially confined to a single retinal primordium by the differential activity of specifying transcription factors. This central field is subsequently split in response to secreted factors emanating from the ventral midline. Concomitant with medio-lateral patterning at the onset of neurulation, morphogenesis sets in and laterally evaginates the optic vesicle. Strikingly during this process the neuroectoderm in the eye field transiently loses epithelial features and cells migrate individually. In a second morphogenetic event, the vesicle is transformed into the optic cup, concomitant with onset and progression of retinal differentiation. Accompanying optic cup morphogenesis, neural differentiation is initiated from a retinal signalling centre in a stereotypic and species specific manner by secreted signalling factors. Here we will give an overview of key events during vertebrate eye formation and highlight key players in the respective processes. PMID- 23684893 TI - Spongiacidin C, a pyrrole alkaloid from the marine sponge Stylissa massa, functions as a USP7 inhibitor. AB - USP7, a deubiquitylating enzyme hydrolyzing the isopeptide bond at the C-terminus of ubiquitin, is an emerging cancer target. We isolated spongiacidin C from the marine sponge Stylissa massa as the first USP7 inhibitor from a natural source. This compound inhibited USP7 most strongly with an IC50 of 3.8 MUM among several USP family members tested. PMID- 23684894 TI - Inhibition of soluble epoxide hydrolase by fulvestrant and sulfoxides. AB - The soluble epoxide hydrolase (sEH) is a key enzyme in the metabolism of epoxy fatty acids, signaling molecules involved in numerous biologies. Toward finding novel inhibitors of sEH, a library of known drugs was tested for inhibition of sEH. We found that fulvestrant, an anticancer agent, is a potent (KI=26 nM) competitive inhibitor of sEH. From this observation, we found that alkyl sulfoxides represent a new kind of pharmacophore for the inhibition of sEH. PMID- 23684895 TI - Synthesis and anticancer activity of aminodihydroquinoline analogs: identification of novel proapoptotic agents. AB - A series of 2-aminodihydroquinoline analogs were synthesized and their in vitro cytotoxicities against metastatic breast adenocarcinoma cell line MDA-MB-231 were tested. Five out of 16 compounds exhibited promising activity and structure activity relationship revealed major role of dialkylaminoethyl substituents on dihydroquinoline ring for the activity. Two compounds, 5f and 5h, presented cytotoxicity with IC50 values of about 2 MUM when the compounds were treated to the cells without serum. The cell proliferation was inhibited mildly when the cells cultured with serum. Flow cytometry analyses showed that those compounds arrested the cells at G2/M checkpoint when the cell cycle is active while they induce apoptosis when the cell growth is restricted due to the absence of growth factors. These results suggest the two novel compounds may have anticancer activity through cell cycle arrest and pro apoptosis mechanism. PMID- 23684896 TI - Prevalence of low phospholipid-associated cholelithiasis in young female patients. AB - BACKGROUND AND AIMS: We evaluated the prevalence of low phospholipid-associated cholelithiasis, a specific form of cholelithiasis associated with at least 2 of the 3 following criteria: first symptoms before the age of 40; intrahepatic comet tail artefacts, sludge or microlithiasis on ultrasound imaging; and recurrence of symptoms after cholecystectomy. METHODS: We prospectively studied the cases of 60 consecutive female patients under 30 with symptomatic cholelithiasis. RESULTS: A diagnosis of low phospholipid-associated cholelithiasis was made in 14/60 patients (23%). The molecular analysis showed ABCB4 (n=4) and ABCB11 (n=4) gene mutations. Low phospholipid-associated cholelithiasis was frequently observed in non-overweight patients [13/27 (48%)], was present in most patients whose biliary symptoms occurred before the age of 18 [7/10 (70%)] and was often associated with cholangitis or acute pancreatitis [9/14 (64%), p<0.05] while "common" cholelithiasis was mainly associated with cholecystitis [16/46 (35%), p<0.05]. CONCLUSION: Nearly one quarter of the female patients under the age of 30 admitted for symptomatic cholelithiasis had low phospholipid-associated cholelithiasis; particularly if body weight was normal, the symptoms began before the age of 18 or in the presence of severe biliary complications. PMID- 23684898 TI - Non-invasive brain stimulation and the autonomic nervous system. AB - Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are non-invasive methods of brain stimulation (NIBS) that can induce significant effects on cortical and subcortical neural networks. Both methods are relatively safe if appropriate guidelines are followed, and both can exert neuromodulatory effects that may be applied to the investigation of the autonomic nervous system (ANS). In addition, ANS measures can shed important light onto the neurobiologic mechanisms of NIBS. Here we present a systematic review on studies testing NIBS and ANS simultaneously. We structure our findings into four broad (not mutually exclusive) categories: (i) studies in which ANS function was modified by NIBS versus those in which it was not; (ii) studies in which NIBS was used to understand ANS function, (iii) studies in which ANS was used to understand NIBS mechanisms and (iv) NIBS/ANS studies conducted in healthy subjects versus those in patients with neuropsychiatric diseases. Forty-four articles were identified and no conclusive evidence of the effects of NIBS on ANS was observed, mainly because of the heterogeneity of included studies. Based on a comprehensive summary of this literature we propose how NIBS might be further developed to enhance our understanding of the cortical mechanisms of autonomic regulation and perhaps to modulate autonomic activity for therapeutic purposes. PMID- 23684897 TI - Alzheimer's disease-associated polymorphisms in human OGG1 alter catalytic activity and sensitize cells to DNA damage. AB - Brain tissues from Alzheimer's disease (AD) patients show increased levels of oxidative DNA damage and 7,8-dihydro-8-oxoguanine (8-oxoG) accumulation. In humans, the base excision repair protein 8-oxoguanine-DNA glycosylase (OGG1) is the major enzyme that recognizes and excises the mutagenic DNA base lesion 8 oxoG. Recently, two polymorphisms of OGG1, A53T and A288V, have been identified in brain tissues of AD patients, but little is known about how these polymorphisms may contribute to AD. We characterized the A53T and A288V polymorphic variants and detected a significant reduction in the catalytic activity for both proteins in vitro and in cells. Additionally, the A53T polymorphism has decreased substrate binding, whereas the A288V polymorphism has reduced AP lyase activity. Both variants have decreased binding to known OGG1 binding partners PARP-1 and XRCC1. We found that OGG1(-/-) cells expressing A53T and A288V OGG1 were significantly more sensitive to DNA damage and had significantly decreased survival. Our results provide both biochemical and cellular evidence that A53T and A288V polymorphic proteins have deficiencies in catalytic and protein-binding activities that could be related to the increase in oxidative damage to DNA found in AD brains. PMID- 23684899 TI - The most precise computations using Euler's method in standard floating-point arithmetic applied to modelling of biological systems. AB - The explicit Euler's method is known to be very easy and effective in implementation for many applications. This article extends results previously obtained for the systems of linear differential equations with constant coefficients to arbitrary systems of ordinary differential equations. Optimal (providing minimum total error) step size is calculated at each step of Euler's method. Several examples of solving stiff systems are included. PMID- 23684900 TI - Development of a daily mortality probability prediction model from Intensive Care Unit patients using a discrete-time event history analysis. AB - As studies have pointed out, severity scores are imperfect at predicting individual clinical chance of survival. The clinical condition and pathophysiological status of these patients in the Intensive Care Unit might differ from or be more complicated than most predictive models account for. In addition, as the pathophysiological status changes over time, the likelihood of survival day by day will vary. Actually, it would decrease over time and a single prediction value cannot address this truth. Clearly, alternative models and refinements are warranted. In this study, we used discrete-time-event models with the changes of clinical variables, including blood cell counts, to predict daily probability of mortality in individual patients from day 3 to day 28 post Intensive Care Unit admission. Both models we built exhibited good discrimination in the training (overall area under ROC curve: 0.80 and 0.79, respectively) and validation cohorts (overall area under ROC curve: 0.78 and 0.76, respectively) to predict daily ICU mortality. The paper describes the methodology, the development process and the content of the models, and discusses the possibility of them to serve as the foundation of a new bedside advisory or alarm system. PMID- 23684901 TI - Relationship of cravings with weight loss and hunger. Results from a 6 month worksite weight loss intervention. AB - We examined the association of food cravings with weight loss and eating behaviors in a lifestyle intervention for weight loss in worksites. This research was part of a randomized controlled trial of a 6-month weight loss intervention versus a wait-listed control in 4 Massachusetts worksites. The intervention emphasized reducing energy intake by adherence to portion-controlled menu suggestions, and assessments were obtained in 95 participants at baseline and 6 months including non-fasting body weight, food cravings (Craving Inventory and Food Craving Questionnaire for state and trait) and the eating behavior constructs restraint, disinhibition and hunger (Eating Inventory). There were statistically significant reductions in all craving variables in the intervention group compared to the controls. Within the intervention group, changes in craving trait were significantly associated with weight loss after controlling for baseline weight, age, gender and worksite. However, in a multivariate model with craving-trait and eating behaviors (restraint, disinhibition and hunger), hunger was the only significant predictor of weight change. In contrast to some previous reports of increased food cravings with weight loss in lifestyle interventions, this study observed a broad reduction in cravings associated with weight loss. In addition, greater reductions in craving-trait were associated with greater weight change, but craving-trait was not a significant independent correlate of weight change when hunger was included in statistical models. Studies are needed to examine the effectiveness of hunger suppressing versus craving-suppressing strategies in lifestyle interventions for obesity. PMID- 23684902 TI - Parental food involvement predicts parent and child intakes of fruits and vegetables. AB - In order to develop successful interventions to improve children's diets, the factors influencing food choice need to be understood. Parental food involvement the level of importance of food in a person's life - may be one of many important factors. The aim of this study was to determine whether parental food involvement is associated with parents' and children's diet quality. As part of an intervention study, 394 parents with children aged between 18 months and 5 years were recruited from children's centres in Cornwall and Islington, UK. Questionnaires were used to collect data on socio-demographic characteristics, parents' diets, and attitudes towards food including food involvement. Children's diets were assessed using the multiple pass 24 h recall method. Parents reported low intakes of fruits and vegetables and high intakes of sugary items for themselves and their young children. Parental food involvement was strongly correlated with consumption of fruits and vegetables (amount and diversity) for both parents and children. Correlations with consumption of sugary drinks and snacks/foods were not significant. These findings indicate that parental food involvement may influence consumption of fruits and vegetables, more so than sugary items. Further research is needed to investigate how parental food involvement could mediate dietary changes. PMID- 23684903 TI - Early phase viral kinetics of chronic hepatitis C patients receiving telaprevir based triple therapy: a comparison of two real-time PCR assays. AB - Monitoring hepatitis C virus (HCV) kinetics during antiviral treatment is recommended for determining the best form of treatment management. We compared the measurement of HCV RNA by two Real-time PCR assays during the first 12weeks phase of telaprevir in combination with pegylated interferon alpha2b and ribavirin treatment for chronic hepatitis C patients. The viral kinetics of 65 patients with HCV genotype 1b was assessed. HCV RNA was tested at baseline, on day 3, and every week from 1 to 12 by both the first-generation Roche COBAS(r) AmpliPrep/COBAS(r) TaqMan(r) HCV (CAP/CTM) assay and the Abbott RealTime HCV (ART) assay. A total of 910 serum samples were obtained from the 65 patients. Of these, 168 (28.5%) of the 590 samples HCV RNA negative by CAP/CTM were positive by ART. In contrast, 17 (3.9%) of the 439 samples HCV RNA negative by ART were positive by CAP/CTM. The rates of HCV RNA negativity by ART at weeks 3, 4, and 5 were significantly lower than those by CAP/CTM (21.5% vs. 50.8%, 36.9% vs. 70.8% and 44.6% vs. 81.5%; P<0.001, P<0.0001 and P<0.05, respectively). Although the ART is superior for the determination of HCV RNA negativity, the predictive value of detectable HCV RNA for non-sustained virological response (non-SVR) by CAP/CTM is higher than by ART at weeks 4, 6, and 8. We also found that 16 (24.6%) by CAP/CTM and 28 (43.1%) by ART had a reappearance of residual HCV RNA during the telaprevir treatment period. However, the reappearance of residual HCV RNA was not associated with non-SVR. In conclusion, a significant difference was found between the two real-time PCR assays for the assessment of virological response based on undetectable HCV RNA. PMID- 23684905 TI - Insulin concentrations in cerebellum and body balance in diabetic male rats: aerobic training effects. AB - Brain insulin has had widespread metabolic, neurotrophic, and neuromodulatory functions and has been involved in the central regulation of food intake and body weight, learning and memory, neuronal development, and neuronal apoptosis. PURPOSE: The present study investigated the role of swimming training on cerebral metabolism on insulin concentrations in cerebellum and the body balance performance of diabetic rats. METHODS: Forty Male Wistar rats were divided in four groups: sedentary control (SC), trained control (TC), sedentary diabetic (SD), and trained diabetic (TD). Diabetes was induced by alloxan (32mgkg b.w.), single dose injection. The mean blood glucose of diabetic groups was 367+/ 40mg/dl. Training program consisted in swimming 5days/week, 1h/day, 8weeks, supporting a workload corresponding to 90% of maximal lactate steady state (MLSS). For the body balance testing rats were trained to traverse for 5min daily for 5-7days. All dependent variables were analyzed by one-way analysis of variance (ANOVA) and a significance level of p<0.05 was used for all comparisons. RESULTS: The body balance testing scores were different between groups. Insulin concentrations in cerebellum were not different between groups. CONCLUSION: It was concluded that in diabetic rats, aerobic training does not induce alterations on cerebellum insulin but induces important metabolic, hormonal and behavioral alterations which are associated with an improvement in glucose homeostasis, serum insulin concentrations and body balance. PMID- 23684904 TI - Refining the multisystem view of the stress response: coordination among cortisol, alpha-amylase, and subjective stress in response to relationship conflict. AB - This study investigated associations among young adults' hypothalamic-pituitary adrenal axis activity, autonomic nervous system activity, and subjective stress in response to interpersonal conflict to better characterize coordination across stress systems. Seven saliva samples were collected from 199 young adult opposite sex couples before, during, and after they discussed an unresolved relationship conflict. Samples were later assayed for cortisol and alpha-amylase (sAA). Couples rated anticipatory stress prior to the conflict and perceived stress immediately following the task. Growth curve modeling was used to examine two possible levels of within-person coordination across physiological systems: alignment between cortisol and sAA responses throughout the sampling period ("matched phase coordination"), and association between overall levels of cortisol and sAA in response to conflict ("average level coordination"). Whereas both partners showed the former type of coordination, only women showed the latter type. Positive anticipation of the stressor predicted stronger cortisol sAA matched phase coordination for women. Pre-task ratings related to women's sAA, and post-task ratings related to both partners' cortisol responses. Implications for a multisystem interpretation of normal and pathological responses to daily stress are discussed. PMID- 23684906 TI - Hypothalamic-pituitary-adrenal axis responses of horses to therapeutic riding program: effects of different riders. AB - In order to determine whether therapeutic riding could result in higher levels of stress than recreational riding, hypothalamic-pituitary-adrenal (HPA) axis response was evaluated in six horses by monitoring circulating beta-endorphin, ACTH and cortisol concentrations. Horses were already accustomed to be trained both for therapy and riding school activity since 2004. Intervention consisted of 60-minute therapeutic sessions, two times per week for 6weeks with different riders: disabled and recreational riders (session A and B respectively). The therapeutic riders' group (A) consisted of six children with psychomotor disabilities; the recreational riders' group (B) consisted of six healthy children without any previous horse riding experience. Horses were asked to perform the same gaits and exercises at all sessions, both with disabled and healthy users. The statistical analysis showed that during both sessions the mean basal beta-endorphin and ACTH levels of horses did not show any significant changes, while the one way RM-ANOVA showed significant effects of sessions A on the cortisol (F=11.50; P<0.01) levels. Horses submitted to sessions A showed lower cortisol levels both at 5min (P<0.001) and at 30min (P<0.005) after therapeutic sessions than those after session B. Results suggest that in tested horses and for the variables settled, HPA axis was less responsive to disabled than healthy, recreational riders. Among the endocrine responses, cortisol was one of the indicators of HPA axis stress response. PMID- 23684907 TI - A review of mathematical models for the formation of vascular networks. AB - Two major mechanisms are involved in the formation of blood vasculature: vasculogenesis and angiogenesis. The former term describes the formation of a capillary-like network from either a dispersed or a monolayered population of endothelial cells, reproducible also in vitro by specific experimental assays. The latter term describes the sprouting of new vessels from an existing capillary or post-capillary venule. Similar mechanisms are also involved in the formation of the lymphatic system through a process generally called lymphangiogenesis. A number of mathematical approaches have been used to analyze these phenomena. In this paper, we review the different types of models, with special emphasis on their ability to reproduce different biological systems and to predict measurable quantities which describe the overall processes. Finally, we highlight the advantages specific to each of the different modelling approaches. PMID- 23684908 TI - Role of TNF in sickness behavior and allodynia during the acute phase of Chagas' disease. AB - Chagas disease, caused by the intracellular protozoan Trypanosoma cruzi, is associated with inflammation, discomfort and pain during the acute phase. The influence of TNF-alpha (tumor necrosis factor) in this disease outcome is controversial. In this way, the aim of this work was to determine the role of the TNF-alpha blocker etanercept in the pain, discomfort, and survival during the Chagas' acute phase of mice experimentally infected with a wild virulent strain of T. cruzi. The infection with this wild strain was responsible for a severe visceral inflammation and said parasite showed a tropism in peritoneal fluid cells. Etanercept was able to restore spontaneous vertical and horizontal activities during the second week after infection and to abolish mechanical allodynia during the first week after infection. Finally, etanercept delayed the mortality without any effect on the parasitemia rates. This is the first report that correlates sickness behavior and allodynia with TNF-alpha and suggests that this cytokine may play an important role in the physiopathology of the acute phase. PMID- 23684909 TI - Disruption of the blood-brain barrier in pigs naturally infected with Taenia solium, untreated and after anthelmintic treatment. AB - Neurocysticercosis is a widely prevalent disease in the tropics that causes seizures and a variety into of neurological symptoms in most of the world. Experimental models are limited and do not allow assessment of the degree of inflammation around brain cysts. The vital dye Evans Blue (EB) was injected to 11 pigs naturally infected with Taenia solium cysts to visually identify the extent of disruption of the blood-brain barrier. A total of 369 cysts were recovered from the 11 brains and classified according to the staining of their capsules as blue or unstained. The proportion of cysts with blue capsules was significantly higher in brains from pigs that had received anthelmintic treatment 48 and 120h before the EB infusion, indicating a greater compromise of the blood-brain barrier due to treatment. The model could be useful for understanding the pathology of treatment-induced inflammation in neurocysticercosis. PMID- 23684910 TI - Schistosoma japonicum scFv-IL18 fusion DNA ameliorates hepatic fibrosis in schistosomiasis-infected mice via improving local concentration of IL-18 in liver. AB - The pathogenesis of chronic schistosomiasis is caused by irritation of the schistosome eggs trapped in liver that induce delayed hypersensitive reactions from the surrounding tissues, leading to the formation of inflammatory granuloma and subsequent fibrosis. A Schistosoma japonicum (S. japonicum) single-chain fragment variable (SjscFv) which specifically binds to the S. japonicum soluble immature egg antigen (SIEA) can be used as a target to deliver specific cytokine towards the site of hepatic fibrosis. To test this hypothesis, a novel recombinant plasmid, pVAX1/SjscFv-IL18, was constructed by fusing SjscFv to IL-18 gene with a 45bp glycine-rich linker. Furthermore, experiments on mice showed that pVAX1/SjscFv-IL18 could effectively express IL-18 in the liver and in serum. Hepatic contents of IL-2 and IFN-gamma (Th1-type) in S. japonicum-infected mice vaccinated with pVAX1/SjscFv-IL18 increased significantly but those of their IL-4 and IL-10 (Th2-type) decreased as compared to the analyzed results of 4 cytokines in the liver cells of control mice vccinated with pVAX1/IL18. Consistent with the levels of Th1 and Th2 cytokines, mice vaccinated with pVAX1/SjscFv-IL18 developed much less hepatic fibrosis 20weeks after infection, which was evaluated by average volumn of granuloma and collagen contents. These data suggested that the linkage of IL-18 to the target-specific SjscFv molecule appears to be a potentially promising trial route of therapy, the hepatic fibrosis in S. japonicum-infected mice may be ameliorated through effective expression of IL18 in liver. PMID- 23684911 TI - A comprehensive analysis of bilaterian mitochondrial genomes and phylogeny. AB - About 2800 mitochondrial genomes of Metazoa are present in NCBI RefSeq today, two thirds belonging to vertebrates. Metazoan phylogeny was recently challenged by large scale EST approaches (phylogenomics), stabilizing classical nodes while simultaneously supporting new sister group hypotheses. The use of mitochondrial data in deep phylogeny analyses was often criticized because of high substitution rates on nucleotides, large differences in amino acid substitution rate between taxa, and biases in nucleotide frequencies. Nevertheless, mitochondrial genome data might still be promising as it allows for a larger taxon sampling, while presenting a smaller amount of sequence information. We present the most comprehensive analysis of bilaterian relationships based on mitochondrial genome data. The analyzed data set comprises more than 650 mitochondrial genomes that have been chosen to represent a profound sample of the phylogenetic as well as sequence diversity. The results are based on high quality amino acid alignments obtained from a complete reannotation of the mitogenomic sequences from NCBI RefSeq database. However, the results failed to give support for many otherwise undisputed high-ranking taxa, like Mollusca, Hexapoda, Arthropoda, and suffer from extreme long branches of Nematoda, Platyhelminthes, and some other taxa. In order to identify the sources of misleading phylogenetic signals, we discuss several problems associated with mitochondrial genome data sets, e.g. the nucleotide and amino acid landscapes and a strong correlation of gene rearrangements with long branches. PMID- 23684912 TI - Broad polyphyly and historical biogeography of the neotropical wasp genus Notiospathius (Braconidae: Doryctinae). AB - Morphological convergence is a frequently observed pattern that occurs in species with similar environments, trophic niches, and/or life history strategies. In particular, adaptive morphological convergence is common in small, highly diverse invertebrate taxa sharing similar life history strategies such as parasitoidism. The genus Notiospathius is a braconid parasitoid wasp group with a vast, undetermined number of species distributed throughout the Neotropics. Members of this genus possess a considerably elongated, petiolate first metasomal tergite. This structure, however, also occurs in species of other doryctine genera, both closely and distantly related, probably due to adaptation for attacking wood and bark boring coleopteran larvae. Here we investigated the phylogenetic relationships among 117 species assigned to Notiospathius, including species of its closely related genera Masonius and Tarasco, as well as members of a number of other doryctine genera in order to test its monophyly. Separate and concatenated Bayesian partitioned analyses were carried out using two mitochondrial and three nuclear gene markers. The influence of each gene on the overall topology was verified using a cross-validation analysis for each marker with a "leave-one-out" approach. Moreover, the historical biogeography of Notiospathius was assessed calculating divergence time estimates of clades with BEAST and performing ancestral area reconstruction analyses both with RASP (Bayesian and S-DIVA) and Lagrange (DEC). All analyses recovered a polyphyletic Notiospathius consisting of three separate clades that were more related to other doryctine genera than to each other. The relationships reconstructed could not be used to confidently establish the limits of Notiospathius with respect to its closely related genera Tarasco and Masonius, and thus the generic status of the latter two taxa is maintained. Our divergence time estimates and ancestral area reconstructions indicate that the most recent common ancestor of Notiospathius sensu stricto originated in the Caribbean subregion during the Oligocene-Miocene boundary, and subsequently diversified during the mid- to late Miocene, radiating throughout the Neotropics. PMID- 23684913 TI - Investigation and correlation of physical stability, dissolution behaviour and interaction parameter of amorphous solid dispersions of telmisartan: a drug development perspective. AB - The aim of this study was to investigate if amorphous solid dispersions of telmisartan, prepared in presence of different polymers, exhibit different structural and thermodynamic characteristics and whether these differences can be correlated to their physical stability (time to crystallisation) and dissolution behaviour. Amorphous samples were prepared by melt quenching. The resulting amorphous materials were characterised using X-ray diffraction, Raman spectroscopy and differential scanning calorimetry. All freshly prepared samples were completely X-ray amorphous (with a halo being the only feature in the diffractograms). The shape of the halos in the diffractograms varied suggesting structural variations in the near order of the molecules between the different amorphous solid dispersions (ASDs). Principal component analysis of the Raman spectra of the various ASD revealed that the samples clustered in the scores plot, again suggesting structural differences due to the presence of different drug-polymer interaction. The ranking of the samples with respect to physical stability and interaction parameter was: ASD of telmisartan:eudragit>ASD of telmisartan:soluplus>ASD of telmisartan:HPMC>ASD of telmisartan:PVP>amorphous telmisartan. The interaction parameter, calculated by using the Flory Huggins theory, showed a good correlation with the experimentally determined stability whereas a weak correlation was found with dissolution behaviour of different ASD. This study showed that correlation of physical stability and dissolution behaviour with calculated interaction parameter is possible for the same amorphous systems prepared by using different polymers. This could aid in selecting the most appropriate polymer for the development of optimised formulations containing amorphous drugs. It can be concluded that ASD prepared by using different polymers have different structural and thermal properties. These differences affect the physical stability and dissolution profiles of the amorphous solids. Thus, choosing the right polymer for preparing ASD is critical for producing materials with desired dissolution profiles and enhanced stability. PMID- 23684914 TI - Hyaluronan nanocapsules as a new vehicle for intracellular drug delivery. AB - Here we report the development of new drug nanocarriers - named hyaluronan nanocapsules - for the intracellular delivery of hydrophobic anticancer drugs. These nanocapsules are composed of a lipid core and a shell of hyaluronic acid (HA). Nanocapsules were produced by a modified solvent displacement technique, which allows the formation of the polymer shell around the oily core using a cationic surfactant as an interphase bridge. The resulting nanocapsules have a size of ~200 nm, a negative zeta potential and a spherical shape. The model drug docetaxel could be efficiently encapsulated within their core. The in vitro cell culture studies (NCI-H460 cancer cell line) showed that the cytotoxicity of docetaxel could be significantly enhanced due to its encapsulation within the nanocapsules. Interestingly, the nanocapsules were stable during storage and they could also be transformed into a powder by freeze-drying. These novel nanostructures hold promise as intracellular drug delivery systems. PMID- 23684915 TI - In vitro assessment of drug-free and fenofibrate-containing lipid formulations using dispersion and digestion testing gives detailed insights into the likely fate of formulations in the intestine. AB - The solubilizing properties of lipid-based formulations (LBFs) can change dramatically following dispersion and digestion of the formulation components. This study investigated the performance of self-emulsifying LBFs consisting of four different long-chain (LC)/medium-chain (MC) lipid blends formulated with the lipophilic drug fenofibrate and either a water-insoluble surfactant polysorbate 85 (Tween 85) or its more hydrophilic relative, polysorbate 80 (Tween 80). These components allowed closely related Type II and IIIA LBFs of fenofibrate to be evaluated during in vitro dispersion and in vitro digestion testing. Initial assessment of the solvent capacity of drug-free LBFs during dispersion and digestion revealed that the solubility of fenofibrate was more dependent on the surfactant type rather than lipid composition. Type II LBFs in the dispersed state were generally better at solubilizing fenofibrate than equivalent Type IIIA LBFs, regardless of lipid composition. However, even when high drug loadings were used, supersaturation/drug precipitation after dispersion of Type II or Type IIIA LBFs was only moderate. In contrast, digestion of both Type II and IIIA LBFs led to much higher levels of drug supersaturation, and this resulted in drug precipitation. After digestion the ability of each LBF to maintain drug in a solubilized state was highly dependent on lipid composition as well as the choice of surfactant. Notably, MC lipids exhibited very good solubilizing properties in the dispersed state, but resulted in a higher degree of supersaturation on digestion, leading to higher susceptibility to drug precipitation. This study showed that replacing LC lipids with MC lipids in Type II and IIIA LBF, in the proportions used here has little effect on fenofibrate solubilization during dispersion, but is likely to promote supersaturation on digestion. Without careful consideration of drug loading and choice of surfactant in Type II/IIIA MC lipid formulations, there is a high risk of precipitation of drug in the intestine. PMID- 23684916 TI - B cell activating factor-dependent expression of vascular endothelial growth factor in MH7A human synoviocytes stimulated with tumor necrosis factor-alpha. AB - Angiogenesis in rheumatoid arthritis (RA) is one of the histological hallmarks, which is mediated by expression of vascular endothelial growth factor (VEGF) in RA synovium. VEGF expression is enhanced by TNF-alpha, the main pro-inflammatory cytokine in RA. B cell activating factor (BAFF) which plays a role in maturation and maintenance of B cells is also associated with autoimmune RA. Here, we investigated whether BAFF could regulate VEGF expression in TNF-alpha-stimulated synovium using MH7A synovial cells that are established by transfection with the SV40 T antigen. Changes in hBAFF and hVEGF were measured by western blotting, RT PCR and luciferase promoter assay. When MH7A cells were treated with TNF-alpha, we observed that TNF-alpha increased the expression of hBAFF and hVEGF. TNF-alpha also increased transcriptional activity of hBAFF and hVEGF as judged by luciferase promoter assay. Inhibition of hBAFF expression with BAFF-siRNA decreased transcriptional level and activity of hVEGF. In addition, when c-fos expression was inhibited by the transfection of MH7A cells with c-fos-siRNA, data showed that transcriptional level and activity of both hBAFF and hVEGF were attenuated by the activation with TNF-alpha. Our results demonstrate for the first time that VEGF-mediated angiogenesis in RA could be controlled by TNF-alpha induced BAFF expression through c-Fos. Data suggest that TNF-alpha-induced BAFF expression and BAFF-mediated VEGF expression in synovium may cooperate to maintain the capacity of such cells to protect B cells from apoptosis and the supply of nutrients and oxygen in inflammatory microenvironments. PMID- 23684918 TI - Mosquitofish (Gambusia affinis) responds differentially to a robotic fish of varying swimming depth and aspect ratio. AB - In this study, we explore the feasibility of using bioinspired robotics to influence the behaviour of mosquitofish (Gambusia affinis), a social freshwater fish species that is extensively studied for the ecological issues associated with its diffusion in non-native environments. Specifically, in a dichotomous choice test, we investigate the behavioural response of small shoals of mosquitofish to a robotic fish inspired by mosquitofish in its colouration, shape, aspect ratio, and locomotion. Our results indicate that the swimming depth and the aspect ratio of the robotic fish are both determinants of mosquitofish preference. In particular, we find that mosquitofish are never attracted by a robotic fish whose colouration and shape are inspired by live subjects and that the degree of repulsion varies as a function of the swimming depth and the aspect ratio. PMID- 23684917 TI - Quercetin-3-O-(2"-galloyl)-alpha-l-rhamnopyranoside inhibits TNF-alpha-activated NF-kappaB-induced inflammatory mediator production by suppressing ERK activation. AB - Quercetin and its derivatives have anti-inflammatory and anti-oxidant effects. However, the effect of quercetin-3-O-(2"-galloyl)-alpha-l-rhamnopyranoside (QGR), a new quercetin derivative, on the tumor necrosis factor (TNF)-alpha-stimulated production of inflammatory mediators in keratinocytes is unclear. In addition, the effect of QGR on the ERK and NF-kappaB-mediated inflammatory process has not been studied. In human keratinocyte HaCat cells, we investigated the effect of QGR on the TNF-alpha-stimulated production of inflammatory mediators in relation to the nuclear factor (NF)-kappaB, which regulates the transcription genes involved in immune and inflammatory responses. QGR inhibited the TNF-alpha stimulated production of cytokines and chemokines in HaCaT cells. QGR, dexamethasone, cyclosporine A, Bay 11-7085 (an inhibitor of NF-kappaB activation) and cell signaling ERK inhibitor attenuated the TNF-alpha-induced formation of inflammatory mediators and activation of the NF-kappaB and ERK. Unlike other compounds, dexamethasone and cyclosporine A did not reduce formation of reactive oxygen species. The results show that QGR may attenuate TNF-alpha-stimulated inflammatory mediator production in HaCaT cells by suppressing the activation of the ERK-mediated NF-kappaB pathway that is mediated by reactive oxygen species. Additionally, QGR may exhibit a preventive effect against the proinflammatory mediator-induced skin diseases by inhibiting the activation of the ERK and NF kappaB pathways. PMID- 23684919 TI - Genomic misconception: a fresh look at the biosafety of transgenic and conventional crops. A plea for a process agnostic regulation. AB - The regulation of genetically engineered crops, in Europe and within the legislation of the Cartagena biosafety protocol is built on false premises: The claim was (and unfortunately still is) that there is a basic difference between conventional and transgenic crops, this despite the fact that this has been rejected on scientifically solid grounds since many years. This contribution collects some major arguments for a fresh look at regulation of transgenic crops, they are in their molecular processes of creation not basically different from conventional crops, which are based in their breeding methods on natural, sometimes enhanced mutation. But the fascination and euphoria of the discoveries in molecular biology and the new perspectives in plant breeding in the sixties and seventies led to the wrong focus on transgenic plants alone. In a collective framing process the initial biosafety debates focused on the novelty of the process of transgenesis. When early debates on the risk assessment merged into legislative decisions, this wrong focus on transgenesis alone seemed uncontested. The process-focused view was also fostered by a conglomerate of concerned scientists and biotechnology companies, both with a vested interest to at least tolerate the rise of the safety threshold to secure research money and to discourage competitors of all kinds. Policy minded people and opponent activists without deeper insight in the molecular science agreed to those efforts without much resistance. It is interesting to realize, that the focus on processes was uncontested by a majority of regulators, this despite of serious early warnings from important authorities in science, mainly of US origin. It is time to change the regulation of genetically modified (GM) crops toward a more science based process-agnostic legislation. Although this article concentrates on the critique of the process-oriented regulation, including some details about the history behind, there should be no misunderstanding that there are other important factors responsible for the failure of this kind of process-oriented regulation, most importantly: the predominance of politics in the decision making processes combined with the lack of serious scientific debates on regulatory matters within the European Union and also in the Cartagena system, the obscure and much too complex decision making structures within the EU, and the active, professional, negative and intimidating role of fundamental opposition against GM crops on all levels dealing with flawed science, often declared as better parallel science published by 'independent' scientists. PMID- 23684920 TI - Two malignancies or an unusual presentation of a pleural malignancy? AB - Malignant mesothelioma is primarily located in the pleura. Progression usually involves adjacent tissue invasion. Both lymphatic and haematogenous spreads are possible, but rare. Bone involvement usually means locally invasive disease and rarely bone marrow metastases. In this report we presented two patients with a mesothelioma and bone marrow metastases. PMID- 23684921 TI - Femoral bone marrow adiposity and cortical bone cross-sectional areas in men with motor complete spinal cord injury. AB - OBJECTIVES: To (1) quantify yellow and red bone marrow (BM) and cortical bone cross-sectional areas (CSAs) of the femur in persons with motor complete spinal cord injury (SCI) compared with healthy able-bodied control subjects and (2) determine the relationships between yellow and red BM, cortical CSAs, and thigh composition and measurements from dual-energy x-ray absorptiometry in men with complete SCI. DESIGN: Cross-sectional. SETTINGS: Clinical hospital and academic settings. METHODS: Eight persons with motor complete SCI and 6 age-matched healthy control subjects underwent magnetic resonance imaging of both thighs to measure BM adiposity (BMA) and cortical CSA followed by whole-body dual-energy x ray absorptiometry to measure bone mineral density and body composition for the SCI group. RESULTS: Cortical bone CSA adjusted to total subperiosteal bone CSA was 1.5-2 times lower in men with SCI compared with able-bodied control subjects across the femoral length (P =.003). Yellow BMA CSA was 2-3 times greater in men with SCI compared with able-bodied control subjects (P < .0001). Opposite relationships were found between the yellow BMA CSA and cortical bone CSAs in men with SCI (negative association) and able-bodied control subjects (positive association). Yellow BMA was negatively associated with bone mineral density and bone mineral content and with skeletal muscle CSA and fat-free mass (P <.05) in men with SCI. Finally, yellow BMA was positively related to thigh subcutaneous adipose tissue. CONCLUSIONS: After SCI, cortical bone CSA becomes thinner and is associated with greater accumulation of yellow BMA. Yellow BMA is associated with changes in bone CSA and bone mass, as well as increased fat mass, after SCI. PMID- 23684922 TI - The gene expression of the hypothalamic feeding-regulating peptides in cisplatin induced anorexic rats. AB - Cisplatin has been widely used; however, various disadvantageous side effects afflict patients. Rikkunshito (RKT), a traditional Japanese herbal medicine, has been widely prescribed in Japan to improve anorexia; but the mechanisms are unknown. Here we studied whether RKT could improve anorexia induced by cisplatin and changes in feeding-regulating peptides in the hypothalamus in rats. Adult male rats were divided into 4 groups: water+saline (WS), water+cisplatin (WC), RKT+saline (RS), and RKT+cisplatin (RC) groups. Water or RKT (1g/kg) was intragastrically administered for 4 days, from day -1 to day 2, and saline or cisplatin (6mg/kg) was intraperitoneally (i.p.) administered at day 0. After i.p. administration, cumulative food intake, water intake, urine volume and body weight were measured. The rats were then decapitated, followed by removal of the brain, and feeding-regulating peptides in the hypothalamus were measured by in situ hybridization histochemistry. In the three-day measurements, there were no significant changes in cumulative water intake and urine volume. The body weight and cumulative food intake in WC significantly decreased compared to WS, whereas these were not observed in RC. Pro-opiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART) in the arcuate nucleus (ARC) in WC significantly increased, and neuropeptide Y (NPY) in the ARC decreased compared to WS, whereas those in RS and RC were comparable to WS. These results suggest that RKT may have therapeutic potential for anorexia induced by cisplatin. PMID- 23684923 TI - OcyKTx2, a new K+-channel toxin characterized from the venom of the scorpion Opisthacanthus cayaporum. AB - Opisthacanthus cayaporum belongs to the Liochelidae family, and the scorpions from this genus occur in southern Africa, Central America and South America and, therefore, can be considered a true Gondwana heritage. In this communication, the isolation, primary structure characterization, and K+-channel blocking activity of new peptide from this scorpion venom are reported. OcyKTx2 is a 34 amino acid long peptide with four disulfide bridges and molecular mass of 3807 Da. Electrophysiological assays conducted with pure OcyKTx2 showed that this toxin reversibly blocks Shaker B K+-channels with a Kd of 82 nM, and presents an even better affinity toward hKv1.3, blocking it with a Kd of ~18 nM. OcyKTx2 shares high sequence identity with peptides belonging to subfamily 6 of alpha-KTxs that clustered very closely in the phylogenetic tree included here. Sequence comparison, chain length and number of disulfide bridges analysis classify OcyKTx2 into subfamily 6 of the alpha-KTx scorpion toxins (systematic name, alpha KTx6.17). PMID- 23684924 TI - Caught between triterpene- and steroid-metabolism: 4alpha-carboxylic pregnane derivative from the marine alga-derived fungus Phaeosphaeria spartinae. AB - Investigation of the fungus Phaeosphaeria spartinae, an endophyte of the marine red alga Ceramium sp., led to the isolation of spartopregnenolone (1), a metabolite whose structure includes features of triterpenes and steroids, i.e. a Delta(8,9) double bond as occurring in lanosterol type triterpenoids, a carboxyl group at C-4 which is characteristic for intermediates on the way from triterpenes to steroids and an acetyl side chain as typical for pregnane type steroids. The unusual structure of compound 1 was established from extensive spectroscopic investigations and is best described as a 4alpha-carboxy-8,9 pregnene derivative. PMID- 23684925 TI - Synthetic lethal interaction between PI3K/Akt/mTOR and Ras/MEK/ERK pathway inhibition in rhabdomyosarcoma. AB - Rhabdomyosarcoma (RMS) frequently exhibits concomitant activation of the PI3K/Akt/mTOR and the Ras/MEK/ERK pathways. Therefore, we investigated whether pharmacological cotargeting of these two key survival pathways suppresses RMS growth. Here, we identify a synthetic lethal interaction between PI3K/Akt/mTOR and Ras/MEK/ERK pathway inhibition in RMS. The dual PI3K/mTOR inhibitor PI103 and the MEK inhibitor UO126 synergize to trigger apoptosis in several RMS cell lines in a highly synergistic manner (combination index <0.1), whereas either agent alone induces minimal cell death. Similarly, genetic knockdown of p110alpha and MEK1/2 cooperates to induce apoptosis. Molecular studies reveal that cotreatment with PI103/UO126 cooperates to suppress PI3K/Akt/mTOR and Ras/MEK/ERK signaling, whereas either compound alone is not only less effective to inhibit signaling, but even cross-activates the other pathway. Accordingly, PI103 alone increases ERK phosphorylation, while UO126 enhances Akt phosphorylation, consistent with negative crosstalks between these two signaling pathways. Furthermore, PI103/UO126 cotreatment causes downregulation of several antiapoptotic proteins such as XIAP, Bcl-xL and Mcl-1 as well as increased expression and decreased phosphorylation of the proapoptotic protein BimEL, thus shifting the balance towards apoptosis. Consistently, PI103/UO126 cotreatment cooperates to trigger Bax activation, loss of mitochondrial membrane potential, caspase activation and caspase-dependent apoptosis. This identification of a synthetic lethal interaction between PI3K/mTOR and MEK inhibitors has important implications for the development of novel treatment strategies in RMS. PMID- 23684926 TI - Exosomes released in vitro from Epstein-Barr virus (EBV)-infected cells contain EBV-encoded latent phase mRNAs. AB - EBV is a human herpesvirus associated with a number of malignancies. Both lymphoblastoid cell lines (LCLs), and EBV-infected nasopharyngeal carcinoma (NPC) cells have been demonstrated to release exosomes containing the EBV-encoded latent membrane protein 1 (LMP1), and mature micro-RNAs (EBV-miRNAs). Here we analyze the EBV protein and nucleic acid content of exosomes from different EBV infected cells (LCL, 721 and Daudi) and we show for the first time that exosomes released from LCLs and 721 also contain EBV-encoded latent phase mRNAs. This confirms and strengthens exosomes pathogenetic potential, and might provide insights for development of novel diagnostic and therapeutic strategies. PMID- 23684927 TI - Numerical defect of circulating dendritic cell subsets and defective dendritic cell generation from monocytes of patients with advanced melanoma. AB - The behaviour of circulating dendritic cells (DCs) and DC generation from monocytes in melanoma patients during the progression of disease have not been described. We report a significant decrease in the absolute number of total DCs, which mainly affects plasmacytoid DCs in stage IV. Additionally, monocyte-DC generation is less efficient in advanced stages, resulting in DCs that exhibit increased phagocytic capacity, potentially indicating a less mature state. These findings elucidate aspects of basic tumour-mediated immunosuppression, which may have implications for immunotherapeutic approaches, suggesting that the selection of patients for immunotherapy should also be made on the basis of their immune status. PMID- 23684928 TI - Molecular interplay between cdk4 and p21 dictates G0/G1 cell cycle arrest in prostate cancer cells. AB - This study examined the effect of 3, 9-dihydroxy-2-prenylcoumestan (pso), a furanocoumarin, on PC-3 and C4-2B castration-resistant prostate cancer (CRPC) cell lines. Pso caused significant G0/G1 cell cycle arrest and inhibition of cell growth. Molecular analysis of cyclin (D1, D2, D3, and E), cyclin-dependent kinase (cdk) (cdks 2, 4, and 6), and cdk inhibitor (p21 and p27) expression suggested transcriptional regulation of the cdk inhibitors and more significant downregulation of cdk4 than of cyclins or other cdks. Overexpression of cdk4, or silencing of p21 or p27, overcame pso-induced G0/G1 arrest, suggesting that G0/G1 cell cycle arrest is a potential mechanism of growth inhibition in CRPC cells. PMID- 23684929 TI - Increased Cdc7 expression is a marker of oral squamous cell carcinoma and overexpression of Cdc7 contributes to the resistance to DNA-damaging agents. AB - Cdc7-Dbf4 kinase (Dbf4-dependent kinase, DDK) is an essential factor of DNA replication and DNA damage response (DDR), which is associated with tumorigenesis. However, Cdc7 expression has never been associated to the outcome of oral squamous cell carcinoma (OSCC) patients, and the mechanism underlying cancer cell survival mediated by Cdc7 remains unclear. The Cdc7 protein expression of 105 OSCC tumor and 30 benign tissues was examined by immunohistochemistry assay. Overall survival rates of 80 OSCC patients were measured using Kaplan-Meier estimates and the log-rank tests. Cdc7 overexpression by adenovirus system was used to scrutinize the underlying mechanism contributed to cancer cell survival upon DDR. In silico analysis showed that increased Cdc7 is a common feature of cancer. Cdc7 overexpression was found in 96 of 105 (91.4%) studied cases of OSCC patients. Patients with higher Cdc7 expression, either categorized into two groups: Cdc7 high expression (2+ to 3+) versus Cdc7 low expression (0 to 1+) [hazard ratios (HR)=2.6; 95% confidence interval (CI)=1.28 5.43; P=0.0087] or four groups (0 to 3+) [HR=1.71; 95% CI=1.20-2.44; P=0.0032], exhibited a poorer outcome. Multivariate analysis showed that Cdc7 is an independent marker for survival prediction. Overexpressed Cdc7 inhibits genotoxin induced apoptosis to increase the survival of cancer cells. In summary, Cdc7 expression, which is universally upregulated in cancer, is an independent prognostic marker of OSCC. Cdc7 inhibits genotoxin-induced apoptosis and increases survival in cancer cells upon DDR, suggesting that high expression of Cdc7 enhances the resistance to chemotherapy. PMID- 23684930 TI - Ellagic acid inhibits human pancreatic cancer growth in Balb c nude mice. AB - Ellagic acid (EA) is a polyphenol found in several plants and fruits. The objectives of this study were to examine the molecular mechanisms by which EA inhibits pancreatic cancer growth in Balb C nude mice. PANC-1 cells were injected subcutaneously into Balb c nude mice, and tumor-bearing mice were treated with EA. The expression of Akt, Shh and Notch and their target gene products were measured by the immunohistochemistry and Western blot analysis. Treatment of PANC 1 xenografted mice with EA resulted in significant inhibition in tumor growth which was associated with suppression of cell proliferation and caspase-3 activation, and induction of PARP cleavage. EA inhibited the expression of Bcl-2, cyclin D1, CDK2, and CDK6, and induced the expression of Bax in tumor tissues compared to untreated control group. EA inhibited the markers of angiogenesis (COX-2, HIF1alpha, VEGF, VEGFR, IL-6 and IL-8), and metastasis (MMP-2 and MMP-9) in tumor tissues. Furthermore, treatment of mice with EA caused a significant inhibition in phospho-Akt, Gli1, Gli2, Notch1, Notch3, and Hey1. EA also reversed epithelial to mesenchymal transition by up-regulating E-cadherin and inhibiting the expression of Snail, MMP-2 and MMP-9. These data suggest that EA can inhibit pancreatic cancer growth, angiogenesis and metastasis by suppressing Akt, Shh and Notch pathways. In view of the fact that EA could effectively inhibit human pancreatic cancer growth by suppressing Akt, Shh and Notch pathways, our findings suggest that the use of EA would be beneficial for the management of pancreatic cancer. PMID- 23684931 TI - Human breast cancer-associated fibroblasts enhance cancer cell proliferation through increased TGF-alpha cleavage by ADAM17. AB - We demonstrate here increased expression of ADAM17 protein in cancer-associated fibroblasts (CAFs) extracted from human breast carcinomas compared with donor matched normal fibroblasts, and TGF-alpha secretion positively correlates with ADAM17 expression in these cells. In SK-BR-3 cells co-cultured with CAFs, CAF secreted TGF-alpha promotes cell proliferation by activation of EGFR, Akt, and ERK, but it does not promote cell migration. Furthermore, anti-TGF-alpha neutralizing antibodies antagonize the CAF-dependent increase in proliferation and activation of EGFR, Akt and ERK. Thus, pharmacologic inhibition of ADAM17 and TGF-alpha may have therapeutic potential for the treatment of breast cancer when fibroblast-directed therapy is considered. PMID- 23684932 TI - Numerical modelling and experimental investigation of drug release from layered silicone matrix systems. AB - Medical devices and polymeric matrix systems that release drugs or other bioactive compounds are of interest for a variety of applications. The release of the drug can be dependent on a number of factors such as the solubility, diffusivity, dissolution rate and distribution of the solid drug in the matrix. Achieving the goal of an optimal release profile can be challenging when relying solely on traditional experimental work. Accurate modelling complementing experimentation is therefore desirable. Numerical modelling is increasingly becoming an integral part of research and development due to the significant advances in computer simulation technology. This work focuses on numerical modelling and investigation of multi-layered silicone matrix systems. A numerical model that can be used to model multi-layered systems was constructed and validated by comparison with experimental data. The model could account for the limited dissolution rate and effect of the drug distribution on the release profiles. Parametric study showed how different factors affect the characteristics of drug release. Multi-layered medical silicone matrices were prepared in special moulds, where the quantity of drug in each layer could be varied, and release was investigated with Franz-diffusion cell setup. Data for long-term release was fitted to the model and the full depletion of the system predicted. The numerical model constructed for this study, whose input parameters are the diffusion, effective dissolution rate and dimensional solubility coefficients, does not require any type of steady-state approximation. These results indicate that numerical model can be used as a design tool for development of controlled release systems such as drug-loaded medical devices. PMID- 23684933 TI - Polymer-free and polyvinylpirrolidone-based electrospun solid dosage forms for drug dissolution enhancement. AB - Fast-release nano- and microfibres of lipophilic spironolactone were prepared in a continuous manner by electrostatic spinning, in which the application of polyvinylpyrrolidone K90 as matrix polymer enabled formation of solid solutions. However, instead of the anticipated immediate drug release, temporary precipitation was observed. The polyvinylpyrrolidone web gelled immediately after wetting, hindering drug diffusion and aiding the crystallisation of the solvated amorphous spironolactone. These local supersaturations could be successfully avoided by using hydroxypropyl-beta-cyclodextrin. The dependence of fibre diameter and dissolution rate on the complexing agent-polymer ratio was also studied. A small addition of hydroxypropyl-beta-cyclodextrin proved enough for a dramatic release rate enhancement even in the case of high drug loaded formulations. Transmission Raman spectroscopy, differential scanning calorimetry and X-ray powder diffraction showed that the drug was totally amorphised during processing in all formulations. Polymer-free hydroxypropyl-beta-cyclodextrin fibres containing spironolactone were also electrospun from an ethanolic solution, which is a new way of dissolution improvement in the case of poorly water-soluble drugs. This novel approach ensured nearly total drug release in a minute, making the system a suitable age-appropriate orally dissolving formulation. PMID- 23684934 TI - A P-gp vesicular transport inhibition assay - optimization and validation for drug-drug interaction testing. AB - Accurate determination of potential drug-drug interaction mediated by efflux transporters (tDDI) is crucial to assess the risk of pharmacokinetic interaction and toxicity of drugs. Passive permeability and uptake transporter mediated transport are important covariates of cell-based inhibition assays that need to be taken into consideration when performing kinetic analysis of data. Vesicular uptake inhibition has been considered by regulatory agencies as a viable alternative for testing tDDI potential of low passive permeability drugs in particular. Membranes prepared from a P-gp overexpressing human cell line has superior transport properties over membranes prepared from Sf9 cells and cholesterol enriched Sf9 membranes. P-gp expressed in this membrane effluxes N methyl-quinidine (NMQ) with high affinity (K(m) is 3.65 MUM) and a high rate (V(max) is 656 pmol/mg protein/min). Digoxin, vinblastine and paclitaxel, established P-gp substrates inhibited transport of NMQ with estimated K(i) values of 250, 0.1 and 0.6 MUM, respectively. A panel of 11 drugs that have been listed by regulatory agencies as reference inhibitors were used to validate the assay to predict clinical inhibition potential. All the drugs that have been implicated in P-gp mediated DDI were found to be inhibitors in a relevant concentration range. PMID- 23684935 TI - Stereoselective excretion and first-pass metabolism of clausenamide enantiomers. AB - Stereoselective differences in pharmacokinetics between clausenamide (CLA) enantiomers have been found after intravenous and oral administration of each enantiomer to rats. The differences could be associated with excretion and first pass metabolism of two enantiomers. The data from this study demonstrated that ( )CLA was mainly excreted in feces with 13.9% of dose, whereas (+)CLA in bile with 17.2%. A large portion of CLA enantiomers could be transformed into hydroxyl metabolites. In the in vitro metabolic system using rat liver microsomes, it was found that (-)CLA was cleared more than its antipode with peak height ratios [(+)/(-)] from 1.0 to 1.8 at the corresponding substrate concentrations from 0.25 to 2mM. Further study in rabbits showed that two enantiomers underwent an intermediate degree of first-pass metabolism. (-)CLA had lower concentrations and AUC0-8h in the portal vein and heart than those of (+)CLA with rates of hepatic extraction 64.7% for (-)-isomer and 50.8% for (+)-isomer, and intrinsic metabolic clearances of (-) and (+)CLA being 186.3 and 107.2 (l/h), respectively. The first pass metabolism was involved in CYP3A enzymes in the gut and liver, and different levels of CYP3A1 expression induced by (-)CLA or (+)CLA. Immunohistochemical analyses revealed that (-)-isomer significantly increased the expression of CYP3A1, while (+)-isomer had no obvious effects on it. Taken together, the results provided new evidence that stereoselective pharmacokinetics of CLA enantiomers could be resulted from their stereoselective excretion, first-pass metabolism and induction to metabolizing enzymes, which might be important in understanding the clinic pharmacology of active eutomer, (-)CLA, for treatment of Alzheimer's disease. PMID- 23684936 TI - Nanopharmaceuticals for improved topical vaginal therapy: can they deliver? AB - Nanopharmaceuticals have the potential to revolutionise medical treatment by permitting the design of more potent, less toxic "smart" therapeutics, ultimately leading to personalised medicine. This review summarises the challenges and potential uses of nanodelivery system for the topical drug therapy of vaginal diseases. The vaginal route of drug administration remains a challenge in the development of novel drug therapies, including nanomedicines. We attempted to provide an unbiased overview of currently investigated nanodelivery systems, some of which remain to be extensively studied under laboratory conditions, and some of which are already in clinical trials. Most nanodelivery systems are aimed at improving the treatment of vaginal infections, including HIV prevention. Promising new approaches in nanopharmaceutical design are discussed in this review, as well as the controversies related to mucoadhesiveness of nanopharmaceuticals. PMID- 23684937 TI - Sleep and mortality: cause, consequence, or symptom? PMID- 23684938 TI - Assessing objective daytime sleepiness in children and adults: do we have appropriate instruments? PMID- 23684940 TI - The robotic approach does not change the current paradigms of pelvic lymph node dissection for prostate cancer. PMID- 23684939 TI - The relationships between asthma control, daytime sleepiness, and quality of life among children with asthma: a path analysis. AB - OBJECTIVES: We aimed to examine the relationships between asthma control, daytime sleepiness, and asthma-specific health-related quality of life (HRQOL) among children with asthma. Path analyses were conducted to test if daytime sleepiness can mediate the effect of asthma control status on asthma-specific HRQOL. METHODS: 160 dyads (pairs) of asthmatic children and their parents were collected for analyses. The Asthma Control and Communication Instrument (ACCI) was used to categorize adequate and poor asthma control status. The Cleveland Adolescent Sleepiness Questionnaire (CASQ) was used to measure children's daytime sleepiness, including sleep in school, awake in school, sleep in evening, and sleep during transport. The Patient-Reported Outcomes Measurement Information System (PROMIS) Asthma Impact Scale was used to measure asthma-specific HRQOL. RESULTS: Poorly controlled asthma was associated with daytime sleepiness and impaired asthma-specific HRQOL. Asthma control status was directly associated with asthma-specific HRQOL (P<.05), whereas sleep in school and sleep in evening domains of daytime sleepiness significantly mediated the relationship between poor asthma control and impaired HRQOL (P<.01). CONCLUSIONS: Asthma control status was associated with pediatric asthma-specific HRQOL, and the association was significantly mediated by daytime sleepiness. Healthcare providers need to address pediatric sleep needs related to poor asthma control to reduce the negative impact on HRQOL. PMID- 23684941 TI - Waiting for global access to urologic care. PMID- 23684943 TI - In vivo molecular imaging of Barrett's esophagus with confocal laser endomicroscopy. PMID- 23684942 TI - Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil. AB - BACKGROUND & AIMS: Almost all gastric cancers are adenocarcinomas, which have considerable heterogeneity among patients. We sought to identify subtypes of gastric adenocarcinomas with particular biological properties and responses to chemotherapy and targeted agents. METHODS: We compared gene expression patterns among 248 gastric tumors; using a robust method of unsupervised clustering, consensus hierarchical clustering with iterative feature selection, we identified 3 major subtypes. We developed a classifier for these subtypes and validated it in 70 tumors from a different population. We identified distinct genomic and epigenomic properties of the subtypes. We determined drug sensitivities of the subtypes in primary tumors using clinical survival data, and in cell lines through high-throughput drug screening. RESULTS: We identified 3 subtypes of gastric adenocarcinoma: proliferative, metabolic, and mesenchymal. Tumors of the proliferative subtype had high levels of genomic instability, TP53 mutations, and DNA hypomethylation. Cancer cells of the metabolic subtype were more sensitive to 5-fluorouracil than the other subtypes. Furthermore, in 2 independent groups of patients, those with tumors of the metabolic subtype appeared to have greater benefits with 5-fluorouracil treatment. Tumors of the mesenchymal subtype contain cells with features of cancer stem cells, and cell lines of this subtype are particularly sensitive to phosphatidylinositol 3-kinase-AKT-mTOR inhibitors in vitro. CONCLUSIONS: Based on gene expression patterns, we classified gastric cancers into 3 subtypes, and validated these in an independent set of tumors. The subgroups have differences in molecular and genetic features and response to therapy; this information might be used to select specific treatment approaches for patients with gastric cancer. PMID- 23684944 TI - Body checking and avoidance in ethnically diverse female college students. AB - Although body checking and avoidance behaviors are common in women with eating disorders, minimal research has examined the nature or correlates of these behaviors in ethnically diverse female college students without eating disorders. Self-identified European American (n=268), Asian American (n=163), Latina (n=146), and African American (n=73) women completed self-report measures of body checking and avoidance, thin-ideal internalization, eating pathology, and clinical impairment. Results indicated that European and Asian American women reported significantly more body checking and avoidance than African American and Latina women. Generally, correlates of body checking and avoidance were consistent across ethnic groups: Regression analyses indicated that type of ethnicity predicted body checking and avoidance; and ethnicity, body checking, and body avoidance predicted eating pathology and clinical impairment. These associations suggest that body checking and avoidance are not benign behaviors in diverse nonclinical women. PMID- 23684945 TI - Probability of deceased donor kidney transplantation based on % PRA. AB - Sensitization to HLA antigens creates an obstacle for the accessibility and success of kidney transplantation (KT). Highly sensitized patients have longer waiting times and some may never receive a KT. AIM: To determine the probability of patients on the deceased donor (DD) waiting list to receive a KT based on the panel reactive antibody percentage (% PRA) in our center. METHODS: The DD waiting list from our institution was analyzed from 01/05 to 08/12 documenting the clinical variables from donor and potential recipients (ABO blood group), lymphocyte cross-match [CxM (CDC-AHG)] results, highest % PRA determination, and time on the waiting list. The patients were classified into 4 groups based on the % PRA: 0%, 1-19%, 20-79% and 80-100%. The data was analyzed using odds ratio and logistic regression (significant p<0.05). RESULTS: 58 DD (F:M 34:24, ABO group O=35, A=13, B=10) and 179 potential recipients were analyzed (F:M 98:81, ABO group O=127, A=33, B=19, participating 4.2 +/- 3.8 times with different donors to receive KT). The mean PRA for the whole group was 22 +/- 32%, median [md] 0 (0 98). A total of 100 patients received KT (mean waiting time 2.2 +/- 1.7 years, 12 days-7 years) and their mean % PRA was 11.6 +/- 24, md 0 (0-94) vs. 31.4 +/- 37 md 8.5 (0-98) in those who have not received a KT. An association between the % PRA group and KT (p<0.003) was observed. The probability of receiving KT with a 0% PRA vs. >0% was higher (OR 2.12, 1.17-3.84). There was no difference between the 0% vs. 1-19% group (OR 1); differences were observed between 0% vs. 20-79% (OR 2.5, 1.18-5.3) and 0% vs. 80-100% (OR 5, 1.67-14.9). For every percent increase in the PRA above 20%, the risk of not receiving a KT increased by 5% (1 9, p<0.01). CONCLUSIONS: The probability of receiving a DD kidney transplant is inversely related to the % PRA although a higher risk for not receiving a KT becomes evident with a PRA >20%. PMID- 23684946 TI - Impaired thymic function and CD4+ T lymphopenia, but not mannose-binding lectin deficiency, are risk factors for Pneumocystis jirovecii pneumonia in kidney transplant recipients. AB - Pneumocystis jirovecii pneumonia (PCP) incidence is increasing in kidney transplant recipients (KTR), but risk factors remain poorly defined. CD4+ T lymphopenia and mannose-binding lectin (MBL) deficiency are common immunodeficiencies in KTR. Here, we investigated whether CD4+ T lymphopenia and/or MBL deficiency would be risk factors for PCP in KTR. Furthermore, the role of thymic function in CD4+ T lymphopenia and outcome was studied by assessing CD45RA+CD31+CD4+ T cell numbers (RTE, recent thymus emigrants). In 321 de novo KTR serial determinations of peripheral T lymphocyte subsets (n=281, mean 4.2 times between days 0-365) and/or MBL levels (n=112, mean 1.8 times between days 30-180) were performed. 22/321 patients developed a PCP episode on average at day 199 (107-398) post-Tx. Age correlated inversely with RTE, CD4+ and CD8+ T-cell counts until day 180 post-Tx. RTE correlated with CD4+ T-cell counts at all time points pre- and post-Tx. PCP patients had more CMV infections (p=0.045) within the first 3 months compared to controls. Importantly, PCP patients were older (p=0.008), and had lower RTE (p=0.046) pretransplant, and lower CD4+ T-cell counts pretransplant (p=0.017), at day 60 (p=0.032) and for the average of all post-Tx values (p=0.027) compared to controls. Though treatment with T-cell depleting antibodies was associated with consecutive CD4+ T lymphopenia in the whole cohort, the number of patients who received T-cell depleting antibodies was comparable between PCP and control patients (p=0.754). A multivariate stepwise logistic regression model identified only pretransplant CD4+ T-cell counts (OR 0.011, p=0.010) and acute rejection (OR 4.66, p=0.023) as predictors of PCP. In contrast, MBL levels and incidence of MBL deficiency (<500 ng/ml) at days 30, 90 and 180 post-Tx were not different between PCP patients and controls. In conclusion, PCP risk was associated with higher age and related to both thymic functional impairment and long-lasting CD4+ T-lymphopenia that started already before transplantation. Despite frequent occurrences in KTR, low levels of serum MBL were not associated with increased risk for PCP. CD4+ T-cell counts and function should be addressed in prospective studies for more individualized approaches to PCP prophylaxis. PMID- 23684947 TI - History of metaphoric signs in radiology. AB - PURPOSE: To survey the nearly 100 year history of metaphoric sign naming in radiology describing the pace of their overall accumulation in the radiology canon, their specific rates of growth by modality and subspecialty and the characteristics of the referents to which the signs are attached. MATERIALS AND METHODS: A comprehensive list of metaphoric signs was compiled from a search of articles in several major English language radiology journals, from a roster compiled in a monograph on the subject published in 1984 and from a search of several databases to find signs published in the first half of the 20th century. RESULTS: The growth of radiological metaphorical signs naming was slow for several decades after the first one was published in 1918. It then increased rapidly until the 1980s encompassing all modalities and subspecialties. Recently the practice has shown a marked and steady decline. CONCLUSION: Metaphoric sign naming was a frequently reported contribution to the radiological literature in the second half of the 20th century corresponding with Radiology's growth as a descriptive discipline. Its decline since then may be a consequence of Radiology's evolution into a more analytic, data-driven field of inquiry. PMID- 23684948 TI - The expression of TAM receptors and their ligand Gas6 is downregulated in psoriasis. PMID- 23684949 TI - Mathematical analysis of multiscale models for hepatitis C virus dynamics under therapy with direct-acting antiviral agents. AB - Chronic hepatitis C virus (HCV) infection remains a world-wide public health problem. Therapy with interferon and ribavirin leads to viral elimination in less than 50% of treated patients. New treatment options aiming at a higher cure rate are focused on direct-acting antiviral agents (DAAs), which directly interfere with different steps in the HCV life cycle. In this paper, we describe and analyze a recently developed multiscale model that predicts HCV dynamics under therapy with DAAs. The model includes both intracellular viral RNA replication and extracellular viral infection. We calculate the steady states of the model and perform a detailed stability analysis. With certain assumptions we obtain analytical approximations of the viral load decline after treatment initiation. One approximation agrees well with the prediction of the model, and can conveniently be used to fit patient data and estimate parameter values. We also discuss other possible ways to incorporate intracellular viral dynamics into the multiscale model. PMID- 23684950 TI - A stoichiometric producer-grazer model incorporating the effects of excess food nutrient content on consumer dynamics. AB - There has been important progress in understanding ecological dynamics through the development of the theory of ecological stoichiometry. For example, modeling under this framework allows food quality to affect consumer dynamics. While the effects of nutrient deficiency on consumer growth are well understood, recent discoveries in ecological stoichiometry suggest that consumer dynamics are not only affected by insufficient food nutrient content (low phosphorus (P): carbon (C) ratio) but also by excess food nutrient content (high P:C). This phenomenon is known as the stoichiometric knife edge, in which animal growth is reduced not only by food with low P content but also by food with high P content, and needs to be incorporated into mathematical models. Here we present a Lotka-Volterra type model to investigate the growth response of Daphnia to algae of varying P:C ratios capturing the mechanism of the stoichiometric knife edge. PMID- 23684951 TI - Animal models of anxiety: a comprehensive review. AB - Animal models can be used to contribute to understanding the information about molecular mechanisms involved in anxiety and for screening and developing new medications for their treatment that would be impossible in humans. The human studies have established the genetic basis of anxiety and animal studies have been used to attempt to further clarify its genetic determinants. In the field of anxiety research, animal models can be grouped into two main classes. The first involves the animal's conditioned responses to stressful and often painful events (e.g. exposure to electric foot shock) and the second includes ethologically based paradigms and involves the animal's spontaneous or natural reactions (e.g. flight, avoidance and freezing) to stress stimuli that do not explicitly involve pain or discomfort (e.g. exposure to a novel highly illuminated test chamber or to a predator). The current review enlightens the various aspects of animal model of anxiety, which may be used for research purpose. PMID- 23684952 TI - Ubiquitin-independent proteasomal degradation. AB - Most proteasome substrates are marked for degradation by ubiquitin conjugation, but some are targeted by other means. The properties of these exceptional cases provide insights into the general requirements for proteasomal degradation. Here the focus is on three ubiquitin-independent substrates that have been the subject of detailed study. These are Rpn4, a transcriptional regulator of proteasome homeostasis, thymidylate synthase, an enzyme required for production of DNA precursors and ornithine decarboxylase, the initial enzyme committed to polyamine biosynthesis. It can be inferred from these cases that proteasome association and the presence of an unstructured region are the sole prerequisites for degradation. Based on that inference, artificial substrates have been designed to test the proteasome's capacity for substrate processing and its limitations. Ubiquitin-independent substrates may in some cases be a remnant of the pre ubiquitome world, but in other cases could provide optimized regulatory solutions. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf. PMID- 23684953 TI - N-terminally truncated forms of human cathepsin F accumulate in aggresome-like inclusions. AB - The contribution of individual cysteine cathepsins as positive mediators of programmed cell death is dependent on several factors, such as the type of stimuli, intensity and duration of the stimulus, and cell type involved. Of the eleven human cysteine cathepsins, cathepsin F is the only cathepsin that exhibits an extended N-terminal proregion, which contains a cystatin-like domain. We predicted that the wild-type human cathepsin F contains three natively disordered regions within the enzyme's propeptide and various amino acid stretches with high fibrillation propensity. Wild-type human cathepsin F and its N-terminally truncated forms, Ala(20)-Asp(484) (Delta(19)CatF), Pro(126)-Asp(484) (Delta(125)CatF), and Met(147)-Asp(484) (Delta(146)CatF) were cloned into the pcDNA3 vector and overexpressed in HEK 293T cells. Wild-type human cathepsin F displayed a clear vesicular labeling and colocalized with the LAMP2 protein, a lysosomal marker. However, all three N-terminally truncated forms of human cathepsin F were recovered as insoluble proteins, suggesting that the deletion of at least the signal peptides (Delta(19)CatF), results in protein aggregation. Noteworthy, they concentrated large perinuclear-juxtanuclear aggregates that accumulated within aggresome-like inclusions. These inclusions showed p62 positive immunoreactivity and were colocalized with the autophagy marker LC3B, but not with the LAMP2 protein. In addition, an approximately 2-3 fold increase in DEVDase activity was not sufficient to induce apoptotic cell death. These results suggested the clearance of the N-terminally truncated forms of human cathepsin F via the autophagy pathway, underlying its protective and prosurvival mechanisms. PMID- 23684955 TI - Protopanaxatriol ginsenoside Rh1 inhibits the expression of matrix metalloproteinases and the in vitro invasion/migration of human astroglioma cells. AB - Malignant gliomas are the most common and fatal brain tumors in adults. In particular, the strong invasiveness of glioma cells into the normal brain tissue makes eradication of glioma very difficult. Matrix metalloproteinases (MMPs) play a pivotal role in glioma invasion, and thus controlling MMP expression has been suggested as an important therapeutic target for brain tumors. In the present study, we investigated the effect of protopanaxatriol ginsenoside Rh1 on MMP expressions in human astroglioma U87MG and U373MG cells. RT-PCR analysis showed that Rh1 inhibits the mRNA expressions of MMP-1, -3, and -9 in PMA-stimulated U87MG and U373MG cells. Rh1 also suppressed the promoter activities of MMP-1, -3 and -9. The ELISA, Western blot, and zymographic analyses revealed that Rh1 inhibits the protein expression and/or enzymatic activity of MMP-1, -3 and -9. In accordance with the strong inhibitory effects of Rh1 on MMPs, Rh1 efficiently inhibited the invasion and migration of U87MG and U373MG glioma cells as demonstrated by Matrigel invasion assay and wound healing assay. Further mechanistic studies revealed that Rh1 inhibits MAPK and PI3K/Akt signaling pathways and downstream transcription factors such as NF-kappaB and AP-1, which play an important role in MMP gene expressions. The data collectively suggest that ginsenoside Rh1 may have a therapeutic potential for malignant gliomas. PMID- 23684956 TI - Actin carbonylation: from cell dysfunction to organism disorder. AB - Protein carbonylation is an important event in the context of proteostasis because of its frequency, non-enzymatic nature and irreversible effects. The carbonylation of proteins disturbs their function and leads to protein aggregates, which may precede cellular senescence and cell death. Actin, an evolutionarily conserved cytoskeletal protein that is involved in important cellular processes, is one of the proteins most susceptible to carbonylation. Conditions resulting in oxidative stress are likely to lead to its carbonylation, loss of function and aggregate formation. In this review, we summarise actin susceptibility to carbonylation, as verified in cell free extracts, cell lines and animal models, and review its fate through the activation of cell mechanisms aimed at removing damaged proteins. Their insufficient activity may underlie age related diseases and the ageing process. This article is part of a Special Issue entitled: Posttranslational Protein modifications in biology and Medicine. PMID- 23684954 TI - Aquaporin-4 water channels and synaptic plasticity in the hippocampus. AB - Aquaporin-4 (AQP4) is the major water channel expressed in the central nervous system (CNS) and is primarily expressed in glial cells. Many studies have shown that AQP4 regulates the response of the CNS to insults or injury, but far less is known about the potential for AQP4 to influence synaptic plasticity or behavior. Recent studies have examined long-term potentiation (LTP), long-term depression (LTD), and behavior in AQP4 knockout (KO) and wild-type mice to gain more insight into its potential role. The results showed a selective effect of AQP4 deletion on LTP of the Schaffer collateral pathway in hippocampus using an LTP induction protocol that simulates pyramidal cell firing during theta oscillations (theta burst stimulation; TBS). However, LTP produced by a different induction protocol was unaffected. There was also a defect in LTD after low frequency stimulation (LFS) in AQP4 KO mice. Interestingly, some slices from AQP4 KO mice exhibited LTD after TBS instead of LTP, or LTP following LFS instead of LTD. These data suggest that AQP4 and astrocytes influence the polarity of long-term synaptic plasticity (potentiation or depression). These potentially powerful roles expand the influence of AQP4 and astrocytes beyond the original suggestions related to regulation of extracellular potassium and water balance. Remarkably, AQP4 KO mice did not show deficits in basal transmission, suggesting specificity for long-term synaptic plasticity. The mechanism appears to be related to neurotrophins and specifically brain-derived neurotrophic factor (BDNF) because pharmacological blockade of neurotrophin trk receptors or scavenging ligands such as BDNF restored plasticity. The in vitro studies predicted effects in vivo of AQP4 deletion because AQP4 KO mice performed worse using a task that requires memory for the location of objects (object placement). However, performance on other hippocampal-dependent tasks was spared. The results suggest an unanticipated and selective role of AQP4 in synaptic plasticity and spatial memory, and underscore the growing appreciation of the role of glial cells in functions typically attributed to neurons. Implications for epilepsy are discussed because of the previous evidence that AQP4 influences seizures, and the role of synaptic plasticity in epileptogenesis. PMID- 23684957 TI - Editorial rejects? Novelty, schnovelty! AB - Because many journals are currently increasing the rate of pre-peer-review editorial rejects, the editorial criteria upon which such decisions are based are very important. Here, I spotlight 'novelty' as a criterion and argue that it is a very problematic decisive factor at this stage of the editorial process. PMID- 23684958 TI - NMR spectroscopy on domain dynamics in biomacromolecules. AB - Domain dynamics in biomacromolecules is currently an area of intense research because of its importance for understanding the huge quantity of available data relating the structure and function of proteins and nucleic acids. Control of structural flexibility is essential for the proper functioning of the biomacromolecules. Biophysical discoveries as well as computational algorithms and databases have reshaped our understanding of the often spectacular domain dynamics. At the residue level, such flexibility occurs due to local relaxation of peptide bond angles whose cumulative effect results in large changes in the secondary, tertiary or quaternary structures. The flexibility, or its absence, most often depends on the nature of interdomain linkages. Both the flexible and relatively rigid linkers are found in many multidomain biomacromolecules. Large scale structural heterogeneity of multidomain biomacromolecules and their complexes is now seen as the norm rather than the exception. Absence of such motion, as in the so-called molecular rulers, also has desirable functional effects in architecture of biomacromolecules. The contemporary methods of NMR spectroscopy are capable to provide the detailed information on domain motions in biomacromolecules in the wide range of timescales related to the timescales of their functioning. We review here the current point of view on the nature of domain motions based on these last achievements in the field of NMR spectroscopy. Experimental and theoretical aspects of the collective intra- and interdomain motions are considered. PMID- 23684959 TI - Renal function and bone mineral density in community-dwelling elderly Japanese men: the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Study. AB - End-stage renal failure deteriorates bone mass and increases fracture risk. However, there are conflicting reports in the literature regarding the effects of mild to moderate renal dysfunction on bone mineral density (BMD). We investigated the association between renal function and BMD at the spine and hip and bone metabolism markers in community-dwelling elderly Japanese men. From 2174 male volunteers aged >=65 years, we examined 1477 men after excluding those with diseases or medications known to affect bone metabolism. Renal function was assessed by serum cystatin C and estimated glomerular filtration rate (eGFR) calculated using the Modification of Diet in Renal Disease Study equation. Bone metabolism was evaluated using levels of serum amino-terminal propeptide of type I procollagen (PINP) and tartrate-resistant acid phosphatase isoenzyme 5b (TRACP 5b), which represent bone metabolic status independent of renal function. eGFR was inversely associated with BMD after adjusting for potential confounders (P < 0.01). Cystatin C showed a weaker but significant association with BMD. eGFR was modestly positively associated with PINP levels (P = 0.04), although cystatin C concentrations were neither associated with PINP nor TRACP-5b levels. Since BMD integrates bone metabolism from the past to present, inverse associations between renal function and BMD may be attributed to past factors, such as obesity. Our findings suggest that low renal function does not affect bone metabolism in a population of community-dwelling elderly Japanese men. Longitudinal studies will be necessary to clarify whether low renal function affects bone loss. PMID- 23684961 TI - Automatic segmentation of cerebral white matter hyperintensities using only 3D FLAIR images. AB - Magnetic Resonance (MR) white matter hyperintensities have been shown to predict an increased risk of developing cognitive decline. However, their actual role in the conversion to dementia is still not fully understood. Automatic segmentation methods can help in the screening and monitoring of Mild Cognitive Impairment patients who take part in large population-based studies. Most existing segmentation approaches use multimodal MR images. However, multiple acquisitions represent a limitation in terms of both patient comfort and computational complexity of the algorithms. In this work, we propose an automatic lesion segmentation method that uses only three-dimensional fluid-attenuation inversion recovery (FLAIR) images. We use a modified context-sensitive Gaussian mixture model to determine voxel class probabilities, followed by correction of FLAIR artifacts. We evaluate the method against the manual segmentation performed by an experienced neuroradiologist and compare the results with other unimodal segmentation approaches. Finally, we apply our method to the segmentation of multiple sclerosis lesions by using a publicly available benchmark dataset. Results show a similar performance to other state-of-the-art multimodal methods, as well as to the human rater. PMID- 23684962 TI - Sparsity-constrained SENSE reconstruction: an efficient implementation using a fast composite splitting algorithm. AB - Parallel imaging and compressed sensing have been arguably the most successful and widely used techniques for fast magnetic resonance imaging (MRI). Recent studies have shown that the combination of these two techniques is useful for solving the inverse problem of recovering the image from highly under-sampled k space data. In sparsity-enforced sensitivity encoding (SENSE) reconstruction, the optimization problem involves data fidelity (L2-norm) constraint and a number of L1-norm regularization terms (i.e. total variation or TV, and L1 norm). This makes the optimization problem difficult to solve due to the non-smooth nature of the regularization terms. In this paper, to effectively solve the sparsity regularized SENSE reconstruction, we utilize a new optimization method, called fast composite splitting algorithm (FCSA), which was developed for compressed sensing MRI. By using a combination of variable splitting and operator splitting techniques, the FCSA algorithm decouples the large optimization problem into TV and L1 sub-problems, which are then, solved efficiently using existing fast methods. The operator splitting separates the smooth terms from the non-smooth terms, so that both terms are treated in an efficient manner. The final solution to the SENSE reconstruction is obtained by weighted solutions to the sub-problems through an iterative optimization procedure. The FCSA-based parallel MRI technique is tested on MR brain image reconstructions at various acceleration rates and with different sampling trajectories. The results indicate that, for sparsity-regularized SENSE reconstruction, the FCSA-based method is capable of achieving significant improvements in reconstruction accuracy when compared with the state-of-the-art reconstruction method. PMID- 23684960 TI - Regional variations in MR relaxation of hip joint cartilage in subjects with and without femoralacetabular impingement. AB - The objective of this study was to analyze regional variations of magnetic resonance (MR) relaxation times (T1rho and T2) in hip joint cartilage of healthy volunteers and subjects with femoral acetabular impingement (FAI). Morphological and quantitative images of the hip joints of 12 healthy volunteers and 9 FAI patients were obtained using a 3T MR scanner. Both femoral and acetabular cartilage layers in each joint were semi-automatically segmented on sagittal 3D high-resolution spoiled gradient echo (SPGR) images. These segmented regions of interest (ROIs) were automatically divided radially into twelve equal sub-regions (30(0) intervals) based on the fitted center of the femur head. The mean value of T1rho/T2 was calculated in each sub-region after superimposing the divided cartilage contours on the MR relaxation (T1rho/T2) maps to quantify the relaxation times. T1rho and T2 relaxation times of the femoral cartilage were significantly higher in FAI subjects compared to healthy controls (39.9+/-3.3 msec in FAI vs. 35.4+/-2.3msec in controls for T1rho (P=0.0020); 33.9+/-3.1 msec in FAI vs. 31.1+/-1.7 msec in controls for T2 (P=0.0160)). Sub-regional analysis showed significantly different T1rho and T2 relaxation times in the anterior superior region (R9) of the hip joint cartilage between subjects with FAI and healthy subjects, suggesting possible regional differences in cartilage matrix composition between these two groups. Receiver operating characteristic (ROC) analysis showed that sub-regional analysis in femoral cartilage was more sensitive in discriminating FAI joint cartilage from that of healthy joints than global analysis of the whole region (T1rho: area under the curve (AUC)=0.981, P=0.0001 for R9 sub-region; AUC=0.901, P=0.002 for whole region; T2: AUC=0.976, P=0.0005 for R9 sub-region; AUC=0.808, P=0.0124 for whole region). The results of this study demonstrated regional variations in hip cartilage composition using MR relaxation times (T1rho and T2) and suggested that analysis based on local regions was more sensitive than global measures in subjects with and without FAI. PMID- 23684963 TI - Evaluation of MRI issues for an access port with a radiofrequency identification (RFID) tag. AB - OBJECTIVE: A medical implant that contains metal, such as an RFID tag, must undergo proper MRI testing to ensure patient safety and to determine that the function of the RFID tag is not compromised by exposure to MRI conditions. Therefore, the objective of this investigation was to assess MRI issues for a new access port that incorporates an RFID tag. MATERIALS AND METHODS: Samples of the access port with an RFID tag (Medcomp Power Injectable Port with CertainID; Medcomp, Harleysville, PA) were evaluated using standard protocols to assess magnetic field interactions (translational attraction and torque; 3-T), MRI related heating (3-T), artifacts (3-T), and functional changes associated with different MRI conditions (nine samples, exposed to different MRI conditions at 1.5-T and 3-T). RESULTS: Magnetic field interactions were not substantial and will pose no hazards to patients. MRI-related heating was minimal (highest temperature change, 1.7 degrees C; background temperature rise, 1.6 degrees C). Artifacts were moderate in size in relation to the device. Exposures to MRI conditions at 1.5-T and 3-T did not alter or damage the functional aspects of the RFID tag. CONCLUSIONS: Based on the findings of the test, this new access port with an RFID tag is acceptable (or, MR conditional, using current MRI labeling terminology) for patients undergoing MRI examinations at 1.5-T/64-MHz and 3-T/128 MHz. PMID- 23684964 TI - Fully-automated approach to hippocampus segmentation using a graph-cuts algorithm combined with atlas-based segmentation and morphological opening. AB - The hippocampus has been known to be an important structure as a biomarker for Alzheimer's disease (AD) and other neurological and psychiatric diseases. However, it requires accurate, robust and reproducible delineation of hippocampal structures. In this study, an automated hippocampal segmentation method based on a graph-cuts algorithm combined with atlas-based segmentation and morphological opening was proposed. First of all, the atlas-based segmentation was applied to define initial hippocampal region for a priori information on graph-cuts. The definition of initial seeds was further elaborated by incorporating estimation of partial volume probabilities at each voxel. Finally, morphological opening was applied to reduce false positive of the result processed by graph-cuts. In the experiments with twenty-seven healthy normal subjects, the proposed method showed more reliable results (similarity index=0.81+/-0.03) than the conventional atlas based segmentation method (0.72+/-0.04). Also as for segmentation accuracy which is measured in terms of the ratios of false positive and false negative, the proposed method (precision=0.76+/-0.04, recall=0.86+/-0.05) produced lower ratios than the conventional methods (0.73+/-0.05, 0.72+/-0.06) demonstrating its plausibility for accurate, robust and reliable segmentation of hippocampus. PMID- 23684965 TI - Fourier ring correlation as a resolution criterion for super-resolution microscopy. AB - Optical nanoscopy techniques using localization based image reconstruction, also termed super-resolution microscopy (SRM), have become a standard tool to bypass the diffraction limit in fluorescence light microscopy. The localization precision measured for the detected fluorophores is commonly used to describe the maximal attainable resolution. However, this measure takes not all experimental factors, which impact onto the finally achieved resolution, into account. Several other methods to measure the resolution of super-resolved images were previously suggested, typically relying on intrinsic standards, such as molecular rulers, or on a priori knowledge about the specimen, e.g. its spatial frequency content. Here we show that Fourier ring correlation provides an easy-to-use, laboratory consistent standard for measuring the resolution of SRM images. We provide a freely available software tool that combines resolution measurement with image reconstruction. PMID- 23684966 TI - Expression and function of chicken bursal growth hormone (GH). AB - Growth hormone (GH) has several effects on the immune system. Our group has shown that GH is produced in the chicken bursa of Fabricius (BF) where it may act as an autocrine/paracrine modulator that participates in B-cell differentiation and maturation. The time course of GH mRNA and protein expression in the BF suggests that GH may be involved in development and involution of the BF, since GH is known to be present mainly in B lymphocytes and epithelial cells. In addition, as GH is anti-apoptotic in other tissues, we assessed the possibility that GH promotes cell survival in the BF. This work focused on determining the mechanism by which GH can inhibit apoptosis of B cells and if the PI3K/Akt pathway is activated. Bursal cell cultures were treated with a range of GH concentrations (0.1-100nM). The addition of 10nM GH significantly increased viability (16.7+/ 0.6%) compared with the control and decreased caspase-3 activity to 40.6+/-6.5% of the control. Together, these data indicate that GH is produced locally in the BF and that the presence of exogenous GH in B cell cultures has antiapoptotic effects and increases B cell survival, probably through the PI3k/Akt pathway. PMID- 23684967 TI - Transcript variants of the porcine glucocorticoid receptor gene (NR3C1). AB - Glucocorticoid receptor (GR) is a transcription factor activated by circulating glucocorticoids and mediates their effects on various biological functions in the body. The final cellular activity of GR is modulated by alternative splicing and cell-type specific expression of its encoding gene NR3C1. To enhance the current knowledge of alternative processing of NR3C1 in mammalian species and to facilitate future studies of its regulation in the pig we explored here structural diversity, and tissue-specific distribution of transcript variants of the porcine NR3C1, and the correlation between usage of alternative promoters and alternative splicing. We experimentally identified ten alternatively used untranslated first exons (1A, 1B, 1C, 1D, 1E, 1F, 1G, 1H, 1H2 and 1J) and four transcript variants encoding different GR subtypes (GR-alpha, GR-beta, GR-P and GR-gamma). Expression profiling of nine most important target tissues of glucocorticoids revealed that the promoter of exon 1C drives constitutive expression of the predominant GR-alpha subtype. We found compelling evidence that the occurrence of exon 1D influences abundance of the GR-P splice variant, while both seems to play an important role in regulating GR activity in neuroendocrine tissues. Exons 1A and 1B in turn appear to be important for the regulation of the expression of the porcine NR3C1 in liver and spleen. Our results demonstrate that tissue-specific actions of GR depend on the usage of alternative promoter regions that favour the processing of certain GR subtypes. PMID- 23684968 TI - Metoclopramide-induced hyperprolactinemia effects on the pituitary and uterine prolactin receptor expression. AB - In this work we have evaluated the gene expression profile of prolactin and prolactin receptor in the pituitary and the uterus of female mice with metoclopramide-induced hyperprolactinemia treated with estrogen and/or progesterone. For this purpose, 49 Swiss female mice were allocated to seven groups. INTERVENTIONS: 50-day treatment with metoclopramide, progesterone and estrogen. Our results showed that in the pituitary, metoclopramide-induced hyperprolactinemia increased prolactin expression. In the castrated animals, progesterone, with or without estrogen, produced an increase in prolactin. Pituitary prolactin receptor and the estrogen and progesterone treatment were responsible for the rise in PRLR-S2. In the uterus, no differences in prolactin expression were found between the different study groups. PRLR-S1 had its expression reduced in all castrated animals as against the castrated group treated with vehicle. In the noncastrated animals, PRLR-S2 rose in the metoclopramide-treated group, and, in the castrated animals, its expression diminished in all groups in relation to the vehicle-treated castrated controls. An increase in PRLR-S3 was found in the oophorectomized animals treated with a combination of estrogen and progesterone. PRLR-L rose in the oophorectomized animals treated with progesterone in isolation or in association with estrogen. These findings suggest that metoclopramide associated to progesterone or estrogen may determine an increase in pituitary prolactin and PRLR-S2 expression. The estrogen-progesterone may enhance the expression of PRLR-S3 and PRLR-L isoform of prolactin receptor. PMID- 23684969 TI - Genome-brain-behavior interdependencies as a framework to understand hormone effects on learned behavior. AB - Hormones have profound effects on the maturation and function of the zebra finch song system. Hormones often signal through receptors that directly or indirectly regulate transcription. In this way, hormones and the genome are functionally connected. Genome-brain-behavior interdependencies are often studied on evolutionary timescales but we can now apply and test these relationships on short timescales, relevant to an individual. Here, we begin to place patterns of hormone-related gene expression into the timeframe of an individual's lifespan to consider how hormones contribute to organization of neural systems necessary for learned behavior, and how they might signal during experience in ways that affect future behavior. This framework illustrates both how much investigations into genome and hormone function are intertwined, and how much we still need to learn. PMID- 23684970 TI - Prefrontal cortex and neural mechanisms of executive function. AB - Executive function is a product of the coordinated operation of multiple neural systems and an essential prerequisite for a variety of cognitive functions. The prefrontal cortex is known to be a key structure for the performance of executive functions. To accomplish the coordinated operations of multiple neural systems, the prefrontal cortex must monitor the activities in other cortical and subcortical structures and control and supervise their operations by sending command signals, which is called top-down signaling. Although neurophysiological and neuroimaging studies have provided evidence that the prefrontal cortex sends top-down signals to the posterior cortices to control information processing, the neural correlate of these top-down signals is not yet known. Through use of the paired association task, it has been demonstrated that top-down signals are used to retrieve specific information stored in long-term memory. Therefore, we used a paired association task to examine the neural correlates of top-down signals in the prefrontal cortex. The preliminary results indicate that 32% of visual neurons exhibit pair-selectivity, which is similar to the characteristics of pair coding activities in temporal neurons. The latency of visual responses in prefrontal neurons was longer than bottom-up signals but faster than top-down signals in inferior temporal neurons. These results suggest that pair-selective visual responses may be top-down signals that the prefrontal cortex provides to the temporal cortex, although further studies are needed to elucidate the neural correlates of top-down signals and their characteristics to understand the neural mechanism of executive control by the prefrontal cortex. PMID- 23684971 TI - Long-term enhancement of brain function and cognition using cognitive training and brain stimulation. AB - Noninvasive brain stimulation has shown considerable promise for enhancing cognitive functions by the long-term manipulation of neuroplasticity. However, the observation of such improvements has been focused at the behavioral level, and enhancements largely restricted to the performance of basic tasks. Here, we investigate whether transcranial random noise stimulation (TRNS) can improve learning and subsequent performance on complex arithmetic tasks. TRNS of the bilateral dorsolateral prefrontal cortex (DLPFC), a key area in arithmetic, was uniquely coupled with near-infrared spectroscopy (NIRS) to measure online hemodynamic responses within the prefrontal cortex. Five consecutive days of TRNS accompanied cognitive training enhanced the speed of both calculation- and memory recall-based arithmetic learning. These behavioral improvements were associated with defined hemodynamic responses consistent with more efficient neurovascular coupling within the left DLPFC. Testing 6 months after training revealed long lasting behavioral and physiological modifications in the stimulated group relative to sham controls for trained and nontrained calculation material. These results demonstrate that, depending on the learning regime, TRNS can induce long term enhancement of cognitive and brain functions. Such findings have significant implications for basic and translational neuroscience, highlighting TRNS as a viable approach to enhancing learning and high-level cognition by the long-term modulation of neuroplasticity. PMID- 23684972 TI - The timescale of perceptual evidence integration can be adapted to the environment. AB - A key computation underlying perceptual decisions is the temporal integration of "evidence" in favor of different states of the world. Studies from psychology and neuroscience have shown that observers integrate multiple samples of noisy perceptual evidence over time toward a decision. An influential model posits perfect evidence integration (i.e., without forgetting), enabling optimal decisions based on stationary evidence. However, in real-life environments, the perceptual evidence typically changes continuously. We used a computational model to show that, under such conditions, performance can be improved by means of leaky (forgetful) integration, if the integration timescale is adapted toward the predominant signal duration. We then tested whether human observers employ such an adaptive integration process. Observers had to detect visual luminance "signals" of variable strength, duration, and onset latency, embedded within longer streams of noise. Different sessions entailed predominantly short or long signals. The rate of performance improvement as a function of signal duration indicated that observers indeed changed their integration timescale with the predominant signal duration, in accordance with the adaptive integration account. Our findings establish that leaky integration of perceptual evidence is flexible and that cognitive control mechanisms can exploit this flexibility for optimizing the decision process. PMID- 23684973 TI - The primate cerebellum selectively encodes unexpected self-motion. AB - BACKGROUND: The ability to distinguish sensory signals that register unexpected events (exafference) from those generated by voluntary actions (reafference) during self-motion is essential for accurate perception and behavior. The cerebellum is most commonly considered in relation to its contributions to the fine tuning of motor commands and sensorimotor calibration required for motor learning. During unexpected motion, however, the sensory prediction errors that drive motor learning potentially provide a neural basis for the computation underlying the distinction between reafference and exafference. RESULTS: Recording from monkeys during voluntary and applied self-motion, we demonstrate that individual cerebellar output neurons encode an explicit and selective representation of unexpected self-motion by means of an elegant computation that cancels the reafferent sensory effects of self-generated movements. During voluntary self-motion, the sensory responses of neurons that robustly encode unexpected movement are canceled. Neurons with vestibular and proprioceptive responses to applied head and body movements are unresponsive when the same motion is self-generated. When sensory reafference and exafference are experienced simultaneously, individual neurons provide a precise estimate of the detailed time course of exafference. CONCLUSIONS: These results provide an explicit solution to the longstanding problem of understanding mechanisms by which the brain anticipates the sensory consequences of our voluntary actions. Specifically, by revealing a striking computation of a sensory prediction error signal that effectively distinguishes between the sensory consequences of self generated and externally produced actions, our findings overturn the conventional thinking that the sensory errors coded by the cerebellum principally contribute to the fine tuning of motor activity required for motor learning. PMID- 23684974 TI - Fluid shear stress on endothelial cells modulates mechanical tension across VE cadherin and PECAM-1. AB - Fluid shear stress (FSS) from blood flow acting on the endothelium critically regulates vascular morphogenesis, blood pressure, and atherosclerosis. FSS applied to endothelial cells (ECs) triggers signaling events including opening of ion channels, activation of signaling pathways, and changes in gene expression. Elucidating how ECs sense flow is important for understanding both normal vascular function and disease. EC responses to FSS are mediated in part by a junctional mechanosensory complex consisting of VE-cadherin, PECAM-1, and VEGFR2. Previous work suggested that flow increases force on PECAM-1, which initiates signaling. Deletion of PECAM-1 blocks responses to flow in vitro and flow dependent vascular remodeling in vivo. To understand this process, we developed and validated FRET-based tension sensors for VE-cadherin and PECAM-1 using our previously developed FRET tension biosensor. FRET measurements showed that in static culture, VE-cadherin in cell-cell junctions bears significant myosin dependent tension, whereas there was no detectable tension on VE-cadherin outside of junctions. Onset of shear stress triggered a rapid (<30 s) decrease in tension across VE-cadherin, which paralleled a decrease in total cell-cell junctional tension. Flow triggered a simultaneous increase in tension across junctional PECAM-1, while nonjunctional PECAM-1 was unaffected. Tension on PECAM-1 was mediated by flow-stimulated association with vimentin. These data confirm the prediction that shear increases force on PECAM-1. However, they also argue against the current model of passive transfer of force through the cytoskeleton to the junctions, showing instead that flow triggers cytoskeletal remodeling, which alters forces across the junctional receptors. PMID- 23684976 TI - Phyllotaxis and rhizotaxis in Arabidopsis are modified by three PLETHORA transcription factors. AB - BACKGROUND: The juxtaposition of newly formed primordia in the root and shoot differs greatly, but their formation in both contexts depends on local accumulation of the signaling molecule auxin. Whether the spacing of lateral roots along the main root and the arrangement of leaf primordia at the plant apex are controlled by related underlying mechanisms has remained unclear. RESULTS: Here, we show that, in Arabidopsis thaliana, three transcriptional regulators implicated in phyllotaxis, PLETHORA3 (PLT3), PLT5, and PLT7, are expressed in incipient lateral root primordia where they are required for primordium development and lateral root emergence. Furthermore, all three PLT proteins prevent the formation of primordia close to one another, because, in their absence, successive lateral root primordia are frequently grouped in close longitudinal or radial clusters. The triple plt mutant phenotype is rescued by PLT-vYFP fusion proteins, which are expressed in the shoot meristem as well as the root, but not by expression of PLT7 in the shoot alone. Expression of all three PLT genes requires auxin response factors ARF7 and ARF19, and the reintroduction of PLT activity suffices to rescue lateral root formation in arf7,arf19. CONCLUSIONS: Intriguingly PLT 3, PLT5, and PLT7 not only control the positioning of organs at the shoot meristem but also in the root; a striking observation that raises many evolutionary questions. PMID- 23684977 TI - Membrane-bound RLCKs LIP1 and LIP2 are essential male factors controlling male female attraction in Arabidopsis. AB - Successful sexual reproduction in animals and plants requires communication between male and female gametes. In flowering plants, unlike in animals, eggs and sperm cells are enclosed in multicellular embryo sacs and pollen grains, respectively; guided growth of the pollen tube into the ovule is necessary for fertilization. Pollen tube guidance requires accurate perception of ovule-emitted guidance cues by the receptors in pollen tubes. Although several ovule-secreted peptides controlling pollen tube guidance have recently been identified, i.e., maize EGG APPARATUS1 (EA1), Torenia LURE1/LURE2, and Arabidopsis CRP810_1/AtLURE1, little is known about the receptors. Here, we identified two receptor-like kinase (RLK) genes preferentially expressed in Arabidopsis pollen tubes, Lost In Pollen tube guidance 1 (LIP1) and 2 (LIP2), which are involved in guidance control of pollen tubes. LIP1 and LIP2 were anchored to the membrane in the pollen tube tip region via palmitoylation, which was essential for their guidance control. Simultaneous inactivation of LIP1 and LIP2 led to impaired pollen tube guidance into micropyle and significantly reduced attraction of pollen tubes toward AtLURE1. Our results suggest that LIP1 and LIP2 represent essential components of the pollen tube receptor complex to perceive the female signal AtLURE1 for micropylar pollen tube guidance. PMID- 23684975 TI - Condensin and the spindle midzone prevent cytokinesis failure induced by chromatin bridges in C. elegans embryos. AB - BACKGROUND: During cell division, chromosomes must clear the path of the cleavage furrow before the onset of cytokinesis. The abscission checkpoint in mammalian cells stabilizes the cleavage furrow in the presence of a chromatin obstruction. This provides time to resolve the obstruction before the cleavage furrow regresses or breaks the chromosomes, preventing aneuploidy or DNA damage. Two unanswered questions in the proposed mechanistic pathway of the abscission checkpoint concern factors involved in (1) resolving the obstructions and (2) coordinating obstruction resolution with the delay in cytokinesis. RESULTS: We found that the one-cell and two-cell C. elegans embryos suppress furrow regression following depletion of essential chromosome-segregation factors: topoisomerase II(TOP-2), CENP-A(HCP-3), cohesin, and to a lesser degree, condensin. Chromatin obstructions activated Aurora B(AIR-2) at the spindle midzone, which is needed for the abscission checkpoint in other systems. Condensin I, but not condensin II, localizes to the spindle midzone in anaphase and to the midbody during normal cytokinesis. Interestingly, condensin I is enriched on chromatin bridges and near the midzone/midbody in an AIR-2-dependent manner. Disruption of AIR-2, the spindle midzone, or condensin leads to cytokinesis failure in a chromatin-obstruction-dependent manner. Examination of the condensin-deficient embryos uncovered defects in both the resolution of the chromatin obstructions and the maintenance of the stable cleavage furrow. CONCLUSIONS: We postulate that condensin I is recruited by Aurora B(AIR-2) to aid in the resolution of chromatin obstructions and also helps generate a signal to maintain the delay in cytokinesis. PMID- 23684978 TI - Magnetic resonance imaging in patients with borderline personality disorder: a study of volumetric abnormalities. AB - Volumetric abnormalities of the hippocampus and frontal cortex are of major interest in the study of borderline personality disorder (BPD). To our knowledge, no study has examined volumetric abnormalities in the hippocampal subregions (head, body, and tail). Our aims were to investigate hippocampal volumetric abnormalities as well as abnormalities in the gray and white matter of the frontal cortex, basal ganglia, and anterior cingulate cortex in BPD in a sample of BPD patients compared to healthy controls. Using manual volumetry as well as optimized voxel based morphometry (VBM) we assessed the volumetric differences in a sample of females with BPD (n=20), compared to healthy female controls (n=21) (HC). The analyses revealed reductions in the left hippocampal head, body, and tail, and the right hippocampal tail. Hippocampal changes were confirmed also using VBM and additional volumetric reductions were found in the caudate and dorsolateral prefrontal cortex of the BPD group. Our study reaffirms the existence of hippocampal volumetric, prefrontal and caudate abnormalities in BPD and lends support to the stress-related explanation of these reductions, whilst also bringing new data to the topic in terms of the abnormalities found in the subregions. PMID- 23684979 TI - Neural response to errors in combat-exposed returning veterans with and without post-traumatic stress disorder: a preliminary event-related potential study. AB - Post-traumatic stress disorder (PTSD) is characterized by sustained anxiety, hypervigilance for potential threat, and hyperarousal. These symptoms may enhance self-perception of one's actions, particularly the detection of errors, which may threaten safety. The error-related negativity (ERN) is an electrocortical response to the commission of errors, and previous studies have shown that other anxiety disorders associated with exaggerated anxiety and enhanced action monitoring exhibit an enhanced ERN. However, little is known about how traumatic experience and PTSD would affect the ERN. To address this gap, we measured the ERN in returning Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans with combat-related PTSD (PTSD group), combat-exposed OEF/OIF veterans without PTSD [combat-exposed control (CEC) group], and non-traumatized healthy participants [healthy control (HC) group]. Event-related potential and behavioral measures were recorded while 16 PTSD patients, 18 CEC, and 16 HC participants completed an arrow version of the flanker task. No difference in the magnitude of the ERN was observed between the PTSD and HC groups; however, in comparison with the PTSD and HC groups, the CEC group displayed a blunted ERN response. These findings suggest that (1) combat trauma itself does not affect the ERN response; (2) PTSD is not associated with an abnormal ERN response; and (3) an attenuated ERN in those previously exposed to combat trauma but who have not developed PTSD may reflect resilience to the disorder, less motivation to do the task, or a decrease in the significance or meaningfulness of 'errors,' which could be related to combat experience. PMID- 23684981 TI - The effects of binge drinking behaviour on recovery and performance after a rugby match. AB - OBJECTIVES: This study compared the effects of "normal" post-game behaviour with recommended behaviour on physical performance in the days after a rugby union game. Additionally, the habitual drinking habits of rugby players were identified. DESIGN: Prospective cohort study. METHODS: After a rugby game, 26 players were split by team into a customary behaviour group (CB), who carried out their usual post-game behaviour, or recommended behaviour group (RB), whose diet and activity was controlled in the hours after the game. Counter movement jump, lower-body strength, repeated sprint ability, CK and hydration status were measured prior to and in the days after the game. Twenty-four hour behaviour recall questionnaires where completed throughout the trial period. The Alcohol Use Disorders Identification Test (AUDIT) was also administered to participants. RESULTS: Compared to baseline values, large volumes of alcohol (p<0.01) and a loss in sleep (p<0.001) was reported by the CB group in the hours after the game. Measures of performance and hydration status were unchanged over time and no difference was evident between groups (all p<0.05). Total AUDIT scores for all participants were 17.7 +/- 5. CK was elevated in the days following the game (p<0.001). CONCLUSIONS: Physical performance was not affected by participation in a game of senior club rugby, irrespective of post-game behaviour and possible muscle damage. AUDIT scores indicate that club rugby players may be at risk of serious alcohol related harm, with post-game binge drinking likely to be a major contributor. PMID- 23684982 TI - Cell type-selective expression of the zinc finger-containing gene Nolz-1/Zfp503 in the developing mouse striatum. AB - The zinc finger-containing gene Nolz-1/Zfp503 is a developmentally regulated striatum-enriched gene. In the present study, we characterized the cell type selective expression pattern of Nolz-1 protein in the developing mouse striatum. Nolz-1 immunoreactivity was present in Isl-1-positive ventral LGE (vLGE, striatal primordia), but absent in Pax6-positive dorsal LGE (dLGE, non-striatal primordia). In the vLGE, Nolz-1 immunoreactivity was detected in early differentiating TuJ1-positive neurons, but not in Ki67-positive proliferating progenitor cells. Moreover, many Nolz-1-immunoreactive cells co-expressed Foxp1 or Foxp2, markers for striatal projection neurons. To further characterize Nolz-1 expression with respect to D1R-containing striatonigral and D2R-containing striatopallidal projection neurons, we used the Drd1-EGFP and Drd2-EGFP transgenic mice. Nolz-1 and EGFP double labeled neurons were found in the developing striatum of Drd1-EGFP and Drd2-EGFP mice, indicating Nolz-1 expression in both populations of striatal projection neurons. Notably, Nolz-1 protein was not expressed in Nkx2.1-positive interneuron progenitors, Lhx8-positive cholinergic interneuron progenitors, nNOS and calretinin-positive interneurons in E18.5 striatum. In the developing nucleus accumbens and olfactory tubercles of ventral striatum, many Nolz-1-positive cells co-expressed Sox1, an important transcriptional regulator for ventral striatum, suggesting a role of Nolz-1 in regulating development of the ventral striatum. Finally, in contrast to postnatal down-regulation of Nolz-1 in the dorsal striatum, Nolz-1 protein was persistently expressed in the olfactory tubercle from E15.5 to adulthood. Taken together, our study suggests that Nolz-1 serves as a marker for early differentiating striatal projection neurons and that Nolz-1 may regulate development of striatal projection neurons. PMID- 23684980 TI - Altered functional connectivity of the insular cortex across prefrontal networks in cocaine addiction. AB - Interoception is theorized to be an important process mediating substance use disorders, and the insular cortex is recognized as a core neural region supporting interoception. The purpose of this study was to compare the integration of the insular cortex into prefrontal-related resting-state networks between individuals with cocaine dependence and healthy controls. Participants comprised 41 patients with cocaine dependence and 19 controls who underwent a resting-state 3-T functional magnetic resonance imaging scan. Individuals with cocaine dependence demonstrated altered functional connectivity of the insular cortex, predominantly the right insular cortex, with all eight prefrontal-related resting-state networks identified through Independent Component Analysis (ICA). A conjunction analysis demonstrated that the right insular cortex was the neural region with the highest number of common group differences across the networks. There was no evidence that insular cortex connectivity commonly differed between groups for non-prefrontal-related networks. Further, seed-based functional connectivity analyses extended the network analyses and indicated that cocaine dependence was associated with greater connectivity of the right insula with the dorsomedial prefrontal cortex, inferior frontal gyrus, and bilateral dorsolateral prefrontal cortex. These data support the hypothesis that cocaine dependence is related to altered functional interactions of the insular cortex with prefrontal networks. The results suggest possible neural mechanisms by which the insular cortex and interoceptive information influence cognitive control and decision making processes presumably mediated by prefrontal networks in the cocaine dependence process. PMID- 23684983 TI - Increased vitamin D receptor expression in dorsal root ganglia neurons of diabetic rats. AB - The effects of vitamin D on the nervous system have been studied extensively. In spite of accumulating data about the substantial changes in the vitamin D receptor (VDR) signaling system, during different types of neuroinflammatory diseases, its role in diabetic neuropathy has not been investigated in detail. To assess the role of VDR signaling in diabetic neuropathy, we examined expression of VDRs in dorsal root ganglia (DRG) neurons in a rat model of streptozotocin induced diabetes mellitus type 1. Diabetes mellitus (DM) type 1 was induced with streptozotocin in male Sprague-Dawley rats. After two months, expression of VDRs was analyzed immunohistochemically in the cytoplasm of L4 and L5 DRG neurons of diabetic rats. Semi-quantitative analysis for the determination of staining in nuclei and plasma-membranes of DRG neurons was performed. A significant increase in VDR expression was observed in DRG neurons of diabetic rats. Expression of VDRs was increased in the cytoplasm, nuclei and in cell membranes of neurons. An increase in VDR expression occurred in all neurons, but the greatest increase of fluorescence intensity in cytoplasm was observed in neurons of small diameter. Results of the present study indicate that the VDR signaling system could be a potential therapeutic target for diabetic neuropathy. PMID- 23684984 TI - Transcriptional regulation of germinal center B and plasma cell fates by dynamical control of IRF4. AB - The transcription factor IRF4 regulates immunoglobulin class switch recombination and plasma cell differentiation. Its differing concentrations appear to regulate mutually antagonistic programs of B and plasma cell gene expression. We show IRF4 to be also required for generation of germinal center (GC) B cells. Its transient expression in vivo induced the expression of key GC genes including Bcl6 and Aicda. In contrast, sustained and higher concentrations of IRF4 promoted the generation of plasma cells while antagonizing the GC fate. IRF4 cobound with the transcription factors PU.1 or BATF to Ets or AP-1 composite motifs, associated with genes involved in B cell activation and the GC response. At higher concentrations, IRF4 binding shifted to interferon sequence response motifs; these enriched for genes involved in plasma cell differentiation. Our results support a model of "kinetic control" in which signaling-induced dynamics of IRF4 in activated B cells control their cell-fate outcomes. PMID- 23684985 TI - Transcriptional repression of Gata3 is essential for early B cell commitment. AB - The mechanisms underlying the silencing of alternative fate potentials in very early B cell precursors remain unclear. Using gain- and loss-of-function approaches together with a synthetic Zinc-finger polypeptide (6ZFP) engineered to prevent transcription factor binding to a defined cis element, we show that the transcription factor EBF1 promotes B cell lineage commitment by directly repressing expression of the T-cell-lineage-requisite Gata3 gene. Ebf1-deficient lymphoid progenitors exhibited increased T cell lineage potential and elevated Gata3 transcript expression, whereas enforced EBF1 expression inhibited T cell differentiation and caused rapid loss of Gata3 mRNA. Notably, 6ZFP-mediated perturbation of EBF1 binding to a Gata3 regulatory region restored Gata3 expression, abrogated EBF1-driven suppression of T cell differentiation, and prevented B cell differentiation via a GATA3-dependent mechanism. Furthermore, EBF1 binding to Gata3 regulatory sites induced repressive histone modifications across this region. These data identify a transcriptional circuit critical for B cell lineage commitment. PMID- 23684986 TI - Cochlin produced by follicular dendritic cells promotes antibacterial innate immunity. AB - Cochlin, an extracellular matrix protein, shares homologies with the Factor C, a serine protease found in horseshoe crabs, which is critical for antibacterial responses. Mutations in the COCH gene are responsible for human DFNA9 syndrome, a disorder characterized by neurodegeneration of the inner ear that leads to hearing loss and vestibular impairments. The physiological function of cochlin, however, is unknown. Here, we report that cochlin is specifically expressed by follicular dendritic cells and selectively localized in the fine extracellular network of conduits in the spleen and lymph nodes. During inflammation, cochlin was cleaved by aggrecanases and secreted into blood circulation. In models of lung infection with Pseudomonas aeruginosa and Staphylococcus aureus, Coch(-/-) mice show reduced survival linked to defects in local cytokine production, recruitment of immune effector cells, and bacterial clearance. By producing cochlin, FDCs thus contribute to the innate immune response in defense against bacteria. PMID- 23684987 TI - An inherently bifunctional subset of Foxp3+ T helper cells is controlled by the transcription factor eos. AB - At sites of inflammation, certain regulatory T cells (Treg cells) can undergo rapid reprogramming into helper-like cells without loss of the transcription factor Foxp3. We show that reprogramming is controlled by downregulation of the transcription factor Eos (Ikzf4), an obligate corepressor for Foxp3. Reprogramming was restricted to a specific subset of "Eos-labile" Treg cells that was present in the thymus and identifiable by characteristic surface markers and DNA methylation. Mice made deficient in this subset became impaired in their ability to provide help for presentation of new antigens to naive T cells. Downregulation of Eos required the proinflammatory cytokine interleukin-6 (IL-6), and mice lacking IL-6 had impaired development and function of the Eos-labile subset. Conversely, the immunoregulatory enzyme IDO blocked loss of Eos and prevented the Eos-labile Treg cells from reprogramming. Thus, the Foxp3(+) lineage contains a committed subset of Treg cells capable of rapid conversion into biologically important helper cells. PMID- 23684988 TI - The C-type lectin receptors dectin-1, MR, and SIGNR3 contribute both positively and negatively to the macrophage response to Leishmania infantum. AB - Macrophages act as the primary effector cells during Leishmania infection through production of reactive oxygen species (ROS) and interleukin-1beta (IL-1beta). However, how macrophage-killing mechanisms are activated during Leishmania macrophage interactions is poorly understood. Here, we report that the macrophage response against Leishmania infantum in vivo is characterized by an M2b-like phenotype and C-type lectin receptors (CLRs) signature composed of Dectin-1, mannose receptor (MR), and the DC-SIGN homolog SIGNR3 expression. Dectin-1 and MR were crucial for the microbicidal response as indicated by the fact that they activated Syk-p47phox and arachidonic acid (AA)-NADPH oxidase signaling pathways, respectively, needed for ROS production and also triggered Syk-coupled signaling for caspase-1-induced IL-1beta secretion. In contrast, SIGNR3 has divergent functions during Leishmania infantum pathogenesis; this CLR favored parasite resilience through inhibition of the LTB4-IL-1beta axis. These pathways also operated during infection of primary human macrophages. Therefore, our study promotes CLRs as potential targets for treatment, diagnosis, and prevention of visceral leishmaniasis. PMID- 23684989 TI - The conditions that promote fear learning: prediction error and Pavlovian fear conditioning. AB - A key insight of associative learning theory is that learning depends on the actions of prediction error: a discrepancy between the actual and expected outcomes of a conditioning trial. When positive, such error causes increments in associative strength and, when negative, such error causes decrements in associative strength. Prediction error can act directly on fear learning by determining the effectiveness of the aversive unconditioned stimulus or indirectly by determining the effectiveness, or associability, of the conditioned stimulus. Evidence from a variety of experimental preparations in human and non human animals suggest that discrete neural circuits code for these actions of prediction error during fear learning. Here we review the circuits and brain regions contributing to the neural coding of prediction error during fear learning and highlight areas of research (safety learning, extinction, and reconsolidation) that may profit from this approach to understanding learning. PMID- 23684990 TI - Glutamate receptor-dependent synaptic plasticity. PMID- 23684992 TI - Routine bacterial analysis with automated flow cytometry. AB - The impact of multi-well plate automation on bacterial flow cytometric analyses was investigated. Cell concentrations in up to 96 samples can be measured accurately, as long as a reproducible staining protocol and a total measurement time of below 80 min is used. Fluorescence distribution in the samples may, however, display some variability. PMID- 23684991 TI - A mechanistic hypothesis of the factors that enhance vulnerability to nicotine use in females. AB - Women are particularly more vulnerable to tobacco use than men. This review proposes a unifying hypothesis that females experience greater rewarding effects of nicotine and more intense stress produced by withdrawal than males. We also provide a neural framework whereby estrogen promotes greater rewarding effects of nicotine in females via enhanced dopamine release in the nucleus accumbens (NAcc). During withdrawal, we suggest that corticotropin-releasing factor (CRF) stress systems are sensitized and promote a greater suppression of dopamine release in the NAcc of females versus males. Taken together, females display enhanced nicotine reward via estrogen and amplified effects of withdrawal via stress systems. Although this framework focuses on sex differences in adult rats, it is also applied to adolescent females who display enhanced rewarding effects of nicotine, but reduced effects of withdrawal from this drug. Since females experience strong rewarding effects of nicotine, a clinical implication of our hypothesis is that specific strategies to prevent smoking initiation among females are critical. Also, anxiolytic medications may be more effective in females that experience intense stress during withdrawal. Furthermore, medications that target withdrawal should not be applied in a unilateral manner across age and sex, given that nicotine withdrawal is lower during adolescence. This review highlights key factors that promote nicotine use in females, and future studies on sex-dependent interactions of stress and reward systems are needed to test our mechanistic hypotheses. Future studies in this area will have important translational value toward reducing health disparities produced by nicotine use in females. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23684993 TI - A comparison of the efficiency of five different commercial DNA extraction kits for extraction of DNA from faecal samples. AB - Differences in the composition of the gut microbiota have been associated with a range of diseases using culture-independent methods. Reliable extraction of nucleic acid is a key step in identifying the composition of the faecal microbiota. Five widely used commercial deoxyribonucleic acid (DNA) extraction kits (QIAsymphony(r) Virus/Bacteria Midi Kit (kit QS), ZR Fecal DNA MiniPrepTM (kit Z), QIAamp(r) DNA Stool Mini Kit (kit QA), Ultraclean(r) Fecal DNA Isolation Kit (kit U) and PowerSoil(r) DNA Isolation Kit (kit P)) were evaluated, using human faecal samples. Yield, purity and integrity of total genomic DNA were compared spectrophotometrically and using gel electrophoresis. Three bacteria, commonly found in human faeces were quantified using real time polymerase chain reaction (qPCR) and total bacterial diversity was studied using denaturing gradient gel electrophoresis (DGGE) as well as terminal restriction fragment length polymorphism (T-RFLP). The measurements of DNA yield and purity exhibited variations between the five kits tested in this study. Automated kit QS exhibited the best quality and highest quantity of DNA. All kits were shown to be reproducible with CV values<=0.46 for DNA extraction. qPCR results showed that all kits were uniformly efficient for extracting DNA from the selected target bacteria. DGGE and T-RFLP produced the highest diversity scores for DNA extracted using kit Z (H'=2.30 and 1.27) and kit QS (H'=2.16 and 0.94), which also extracted the highest DNA yields compared to the other kits assessed. PMID- 23684995 TI - [Clinical features and management of acute myositis in idiopathic orbital inflammation]. AB - Acute myositis is the second most common component of non-specific orbital inflammation. We will describe its clinical features and natural history. This is a retrospective study of 10 cases. The diagnosis of acute myositis was based on clinical and imaging criteria. Our study includes five men and five women. The average age was 35.8 years (17-59 years). Clinical symptoms were: pain increased on eye movement (10/10), diplopia (4/10), proptosis (6/10), visual loss (3/10), lid edema (6/10), conjunctival hyperemia (7/10), anterior scleritis (2/10), episcleritis (2/10), chemosis (4/10), upper lid retraction (1/10), limitation of eye movement (3/10), fundus abnormalities (2/10). Imaging showed thickening of one or more extraocular muscles (10/10). Recovery was complete with anti inflammatory therapy in six patients. Three patients experienced recurrence, and one patient had a clinical rebound upon tapering the treatment. Acute myositis can be defined by pain on eye movement, signs of inflammation, and extraocular muscle thickening on imaging. If the clinical presentation is typical, histopathological analysis can be deferred but remains necessary in cases of poor response to treatment, chronic duration or suspicion of tumor infiltration. The diagnosis of acute myositis may be suspected in the presence of consistent, well defined clinical signs. Contiguous inflammation is often associated. Treatment is based on steroids or non-steroidal treatment anti-inflammatory therapy, administered alone or consecutively. Recurrences are frequent but do not alter the final prognosis. PMID- 23684994 TI - [Immediately sequential bilateral cataract surgery in dogs: a retrospective analysis of 128 cases (256 eyes)]. AB - OBJECTIVE: To describe postoperative complications and visual outcomes after immediately sequential bilateral cataract surgery (ISBCS) and to assess whether additional risk is incurred by operating on the fellow eye immediately following the first. ANIMALS STUDIED: A retrospective review of 128 dogs (256 eyes) that underwent ISBCS in three veterinary ophthalmology centers between May 2007 and December 2011 was performed. PROCEDURE: Visual status at final evaluation was recorded and intra- and postoperative complications were recorded and analyzed. Data for the first operated eye (FE) and then the second eye (SE) were statistically analyzed to assess whether performing surgery on the SE immediately after the FE resulted in any negative consequences for the second eye. RESULTS: No serious intraoperative anesthetic incident occurred due to prolonged surgery. Phacoemulsification times were significantly shorter for the SE than for the FE. On final examination, 239 eyes out of 256 (93.36%) exhibited functional vision (score 2), and three dogs were completely blind due to long-term bilateral postoperative complications. The most common postoperative complications were uveitis (58 eyes, 22.66%), postoperative ocular hypertension (POH; nine eyes, 3.5%), glaucoma (nine eyes, 3.5%) and total retinal detachment (seven eyes, 2.73%). No case of endophthalmitis was reported. These results were no worse than those typically reported for unilateral phacoemulsification. In addition, the risk of blindness and other postoperative complications was not significantly increased in the SE. CONCLUSIONS: The results of this study suggest that ISBCS is not associated with an increased incidence of intra- or postoperative complications compared to classic unilateral cataract surgery and might be a viable option for selected patients. The risk of blindness or postoperative complications was not higher in SEs than in FEs. PMID- 23684996 TI - Protective role of phosphatidylcholine against cisplatin-induced renal toxicity and oxidative stress in rats. AB - Although cisplatin is widely used in the treatment of cancers, clinical use of cisplatin is limited due to its nephrotoxicity. Pathophysiological mechanism of cisplatin-induced renal toxicity is a complex process and has not been fully understand. Reactive oxygen species (ROS) and oxidative stress have been presumed to be involved in this damage process. Phosphatidylcholine (PC) has antioxidant effect and prevents oxidative stress. Therefore, the present study aimed to investigate potential protective effects of PC on cisplatin-induced renal damage in rat. We examined the protective effects of PC on cisplatin-induced renal damage by assessment of serum creatinine, BUN, lipid peroxidation, total glutathione, glutathione peroxidase activity, catalase activity, superoxide dismutase activity and histophathological changes. PC ameliorated cisplatin induced increases in serum creatinine, urea and oxidative stress. PC also decreased tubular degeneration and hypertrophy of glomeruli. PC may have a protective effect against cisplatin-induced nephrotoxicity in rats via enhancing antioxidant enzyme activity. PMID- 23684997 TI - Taiwan food scandal: the illegal use of phthalates as a clouding agent and their contribution to maternal exposure. AB - In 2011 the Taiwan Food and Drug Administration reported that plasticizers di(2 ethylhexyl) phthalate (DEHP) and di-iso-nonyl phthalate (DiNP), endocrine disruptors, were illegally added to clouding agents used in foods and beverages. 965 products were found contaminated, of which 206 were exported to 22 countries. This study's purpose was to obtain English names for 28 contaminated products for which DEHP levels were reported, calculate estimated average daily intake (mg/kg/day) for a 50 kg woman consuming one portion, and compare to U.S. and E.U. guidelines for daily intake. We found that drinking just one bottle (500 ml) of sports drinks would result in an average DEHP intake of 0.14 mg/kg bw/day (range 0.091-0.341), which exceeds by several fold government guidelines (0.02-0.06 mg/kg bw/day). One (2 g) serving from 4/14 samples of contaminated dietary supplements exceeds the guideline of 0.02 mg/kg bw/day. In conclusion, consuming even one portion of tainted drinks and some powders would lead to daily intake of DEHP that greatly exceeds established safety guidelines, raising concerns about potential adverse effects, particularly reproductive tract development in the male fetus. Global distribution of DEHP-contaminated and other adulterated products should prompt governments to become proactive in food safety regulations and chemical testing. PMID- 23684998 TI - Anticancer, antioxidant and antibiotic activities of mushroom Ramaria flava. AB - Ramaria flava is a species of edible mushroom with some bioactivity. The anticancer, antioxidant and antibiotic activities and chemical composition of R. flava ethanol extract (EE) were evaluated. The present study exhibited that the EE displayed the strongest inhibitory activity against tumor cell MDA-MB-231 with an IC50 value of 66.54 MUg/mL in three tested tumor cell lines, and the inhibition percent was 71.66% at the concentration of 200 MUg/mL (MTT assay). The total phenolic compounds varied among four fractions of the EE from 6.66 to 61.01 mg gallic acid equivalent (GAE) per g dry weight. Water fraction exhibited high DPPH and OH radical-scavenging activities with low IC50 values of 5.86 and 18.08 MUg/mL, respectively. Meanwhile, three phenolic compounds from water fraction were also identified by HPLC. The antibiotic activities of the EE were evaluated against three microorganisms and three fungi strains by means of the agar well diffusion method and the poisoned medium technique, respectively. The EE also showed moderate antibiotic activities. These results suggest that R. flava could hold a good potential source for human health. PMID- 23684999 TI - A 90-day subchronic oral toxicity study of triterpene-enriched extract from Alismatis Rhizoma in rats. AB - Alismatis Rhizoma has been used in East Asia as a traditional treatment for various illnesses and symptoms, and the presence of protostane-type triterpenes has been claimed to provide health benefits. To investigate the subchronic toxicity of triterpene-enriched extract from Alismatis Rhizoma (TEAR), a 90-day oral toxicity study was conducted in rats. Sprague-Dawley rats were randomly divided into four groups (10 rats/sex/group) and received doses of 0, 360, 720, and 1440 mg/kg/d of TEAR for 90 days. Daily clinical observations as well as weekly measurement of body weight and food consumption were conducted. Blood samples were obtained on day 91 to measure changes in hematology and biochemistry. Urine samples were collected on days 0 and 91 for urinalysis. At necropsy, selected organs were weighed and recorded, and histological examination was performed. No mortality or obvious treatment-related clinical signs, hematology, urinalysis parameters, and macroscopic or microscopic examinations were observed. Differences in weight gain, food consumption, biochemistry, and relative organ weight between the treated group and the control group were not considered treatment-related. On the basis of these findings, the no-observed adverse-effect level for TEAR was 1440 mg/kg/d in both sexes. PMID- 23685000 TI - Elevated mercury levels in pregnant woman linked to skin cream from Mexico. AB - Mercury exposure during pregnancy can have serious health effects for a developing fetus including impacting the child's neurologic and cognitive development. Through biomonitoring in a low-income Latina population in California, we identified a patient with high levels of mercury and traced the source to face creams purchased in a pharmacy in Mexico. PMID- 23685001 TI - MRI and ultrasound fusion imaging for prenatal diagnosis. AB - OBJECTIVE: A combination of magnetic resonance imaging (MRI) images with real time high-resolution ultrasound known as fusion imaging may improve prenatal examination. This study was undertaken to evaluate the feasibility of using fusion of MRI and ultrasound (US) in prenatal imaging. STUDY DESIGN: This study was conducted in a tertiary referral center. All patients referred for prenatal MRI were offered to undergo fusion of MRI and US examination. All cases underwent 1.5 Tesla MRI protocol including at least 3 T2-weighted planes. The Digital Imaging and Communications in Medicine volume dataset was then loaded into the US system for manual registration of the live US image and fusion imaging examination. RESULTS: Over the study period, 24 patients underwent fusion imaging at a median gestational age of 31 (range, 24-35) weeks. Data registration, matching and then volume navigation was feasible in all cases. Fusion imaging allowed superimposing MRI and US images therefore providing with real time imaging capabilities and high tissue contrast. It also allowed adding a real time Doppler signal on MRI images. Significant fetal movement required repeat registration in 15 (60%) cases. The average duration of the overall additional scan with fusion imaging was 10 +/- 5 minutes. CONCLUSION: The combination of fetal real time MRI and US image fusion and navigation is feasible. Multimodality fusion imaging may enable easier and more extensive prenatal diagnosis. PMID- 23685002 TI - Morphological aspects of Angiostrongylus costaricensis by light and scanning electron microscopy. AB - Angiostrongylus costaricensis is a parasitic nematode that can cause severe gastrointestinal disease, known as abdominal angiostrongiliasis, in humans. This paper presents the characterization of first- and third-stage larvae and male and female adult worms of A. costaricensis by scanning electron and light microscopy. Several novel anatomical structures were identified by scanning electron microscopy, including details of the cuticular striations of the spicules in male worms and a protective flap of the cuticle covering the vulvar aperture in female worms. Other taxonomic features revealed by light microscopy include the gubernaculum and the esophageal-intestinal valve. The use of two microscopy techniques allowed a detailed characterization of the morphology of this nematode. A number of previously identified taxonomic features, such as the striated nature of the spicules and the lateral alae were confirmed; however, the use of scanning electron microscopy resulted in a reassessment of the correct number of papillae distributed around the oral opening and behind the cloacal opening. These observations, in combination with light microscopy-based characterization of the gubernaculum and esophageal valves, have allowed a more detailed description of this nematode taxonomy. PMID- 23685003 TI - Environmentally-induced modulations of developmental rates do not affect the selection-mediated changes in pre-adult development time of fruit flies Drosophila melanogaster. AB - In a previous study we had shown that 55 generations of selection for faster egg to-adult development in fruit flies Drosophila melanogaster results in shortening of pre-adult duration by ~29-h (~12.5%) and speeding-up of circadian clock period (tau) by ~0.5-h, implying a positive correlation between development time and tau. In Drosophila, change in ambient temperature is known to alter the rate of pre-adult development but not the speed of circadian clocks whereas 12:12-h warm/cold (WC) cycles are likely to alter both pre-adult development rate and tau (via entrainment). To study the effect of overall speeding-up/slowing-down of pre adult development and circadian clocks on the selection-mediated difference in pre-adult development time, we subjected developing flies to the following conditions: (i) different ambient temperatures (18, 25 and 29 degrees C) under constant darkness (DD) to alter the rate of pre-adult development, or (ii) cyclic WC conditions (WC1-25:18 or WC2-29:25 degrees C) to alter rate of development and tau. The results revealed that the selected (FD) stocks develop faster than controls (BD) by ~52, 28 and 21-h, at 18, 25 and 29 degrees C, respectively, and by 28 and 26-h under WC1 and WC2, respectively. The tau of activity/rest rhythm decreased considerably at 18 degrees C but it did not differ between the FD and BD flies, which suggests a break-down of correlation between development time and tau, seen under their normal rearing conditions (constant darkness--DD at 25 degrees C). While the absolute difference in development time between FD and BD stocks increased or decreased under cooler or warmer conditions, the relative difference in their pre-adult development time remained largely unaltered. These results suggest that manipulations in ambient conditions independently changes development time and tau, resulting in a break-down of the genetic correlation between them. PMID- 23685004 TI - Reconstruction of the face and neck with different types of pre-expanded anterior chest flaps: a comprehensive strategy for multiple techniques. AB - BACKGROUND: For large defects or deformities of the face and neck, the anterior chest area appears to be an excellent donor site that provides well-matched skin colour and texture. Many flap techniques based on the anterior chest area have been reported; however, there are few reports that focus on a treatment strategy for these different flap techniques. METHODS: A retrospective study was performed to propose a treatment algorithm. A total of 69 cases were reviewed from May 2005 to July 2011, in which different types of anterior chest flaps were performed for face and neck reconstruction. The reconstructive procedures, the defect characteristics and the complications were collected and analysed. RESULTS: Thirty-three pedicled thoracic branch of the supraclavicular artery flaps (the pedicled TBSA flap), 11 pedicled internal mammary artery perforator flaps (the pedicled IMAP flap), 8 free internal mammary artery perforator flaps (the free IMAP flap), 4 supercharged TBSA flaps, 17 prefabricated flaps and 3 supercharged prefabricated flaps were performed. The applications of six types of pre-expanded anterior chest flaps were described in an algorithmic approach. CONCLUSIONS: A treatment strategy for face and neck reconstruction using six anterior chest flap techniques is proposed. It recommended a personalised flap planning according to the characteristics of deformities/defects and the regionally dominant vessels of the anterior chest area. PMID- 23685005 TI - Novel use of platysma for oral sphincter substitution or countering excessive pull of a free muscle. AB - BACKGROUND: The present study demonstrates our experience with a novel use of the Platysma in facial reanimation, as a balancing procedure by counteracting an overactive free muscle transfer, and improving oral continence by re-establishing the oral sphincter mechanism. MATERIAL AND METHODS: Twelve patients, nine female (75%) and three male (25%), with a mean age of thirty-eight years (range: 2-66) are presented. Of these, in seven patients (58%) who had excessive excursion of the free muscle, the contralateral pedicled platysma was transferred to counteract the excessive pull. Four patients (33%) underwent bilateral platysma transfer for oral sphincter restoration, while one (8%) had ipsilateral platysma transfer. Evaluation of aesthetic and functional results was performed by a panel of three independent observers, and the long term efficacy of the procedure was assessed through a patient questionnaire. RESULTS: All patients demonstrated significant upgrading of their oral competence associated with eating, drinking and smiling, as it was confirmed by the behavioural analysis (p<0.01). Six of the ten patients that were available, responded to the Quality of Life Questionnaire. Five out of six were satisfied with their mouth appearance when they smile and five patients have a regular diet and without drooling. CONCLUSION: A novel use of Platysma transposition is described that can substitute for a paralysed orbicularis oris muscle in restoring oral sphincter function or to counter balance an excessively active free muscle that was previously transferred for smile restoration. This novel Platysma transfer technique is intended to be used as an adjunct to other reanimation procedures. PMID- 23685006 TI - Posttraumatic stress disorder in fibromyalgia syndrome: prevalence, temporal relationship between posttraumatic stress and fibromyalgia symptoms, and impact on clinical outcome. AB - A link between fibromyalgia syndrome (FMS) and posttraumatic stress disorder (PTSD) has been suggested because both conditions share some similar symptoms. The temporal relationships between traumatic experiences and the onset of PTSD and FMS symptoms have not been studied until now. All consecutive FMS patients in 8 study centres of different specialties were assessed from February 1 to July 31, 2012. Data on duration of chronic widespread pain (CWP) were based on patients' self-reports. Potential traumatic experiences and year of most burdensome traumatic experience were assessed by the trauma list of the Munich Composite International Diagnostic Interview. PTSD was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders IV symptom criteria by the Posttraumatic Diagnostic Scale. Age- and sex-matched persons of a general population sample were selected for controls. Three hundred ninety-five of 529 patients screened for eligibility were analysed (93.9% women, mean age 52.3 years, mean duration since chronic widespread pain 12.8 years); 45.3% of FMS patients and 3.0% of population controls met the criteria for PTSD. Most burdensome traumatic experience and PTSD symptoms antedated the onset of CWP in 66.5% of patients. In 29.5% of patients, most burdensome traumatic experience and PTSD symptoms followed the onset of CWP. In 4.0% of patients' most burdensome traumatic experience, PTSD and FMS symptoms occurred in the same year. FMS and PTSD are linked in several ways: PTSD is a potential risk factor of FMS and vice versa. FMS and PTSD are comorbid conditions because they are associated with common antecedent traumatic experiences. PMID- 23685007 TI - Nerve injury-induced changes in Homer/glutamate receptor signaling contribute to the development and maintenance of neuropathic pain. AB - While group 1 metabotropic glutamate receptors (mGluRs) and ionotropic N-methyl-d aspartate (NMDA) receptors regulate nociception, the precise molecular mechanism(s) contributing to glutamate signaling in chronic pain remain unclear. Here we not only confirmed the key involvement of Homer proteins in neuropathic pain, but also distinguished between the functional roles for different Homer family members and isoforms. Chronic constriction injury (CCI) of the sciatic nerve induced long-lasting, time-dependent increases in the postsynaptic density expression of the constitutively expressed (CC) isoforms Homer1b/c and/or Homer2a/b in the spinal dorsal horn and supraspinal structures involved in nociception (prefrontal cortex, thalamus), that co-occurred with increases in their associated mGluRs, NR2 subunits of the NMDA receptor, and the activation of downstream kinases. Virus-mediated overexpression of Homer1c and Homer2b after spinal (intrathecal) virus injection exacerbated CCI-induced mechanical and cold hypersensitivity, however, Homer1 and Homer2 gene knockout (KO) mice displayed no changes in their neuropathic phenotype. In contrast, overexpression of the immediate early gene (IEG) Homer1a isoform reduced, while KO of Homer1a gene potentiated neuropathic pain hypersensitivity. Thus, nerve injury-induced increases in CC-Homers expression promote pain in pathological states, but IEG Homer induction protects against both the development and maintenance of neuropathy. Additionally, exacerbated pain hypersensitivity in transgenic mice with reduced Homer binding to mGluR5 supports also an inhibitory role for Homer interactions with mGluR5 in mediating neuropathy. Such data indicate that nerve injury-induced changes in glutamate receptor/Homer signaling contribute in dynamic but distinct ways to neuropathic pain processing, which has relevance for the etiology of chronic pain symptoms and its treatment. PMID- 23685008 TI - The scorpion toxin Amm VIII induces pain hypersensitivity through gain-of function of TTX-sensitive Na+ channels. AB - Voltage-gated Na(+) channels (Nav) are the targets of a variety of scorpion toxins. Here, we investigated the effects of Amm VIII, a toxin isolated from the venom of the scorpion Androctonus mauretanicus mauretanicus, on pain-related behaviours in mice. The effects of Amm VIII were compared with the classic scorpion alpha-toxin AaH II from Androctonus australis. Contrary to AaH II, intraplantar injection of Amm VIII at relatively high concentrations caused little nocifensive behaviours. However, Amm VIII induced rapid mechanical and thermal pain hypersensitivities. We evaluated the toxins' effects on Nav currents in nociceptive dorsal root ganglion (DRG) neurons and immortalized DRG neuron derived F11 cells. Amm VIII and AaH II enhanced tetrodotoxin-sensitive (TTX-S) Nav currents in DRG and F11 cells. Both toxins impaired fast inactivation and negatively shifted activation. AaH II was more potent than Amm VIII at modulating TTX-S Nav currents with EC50 of 5 nM and 1 MUM, respectively. AaH II and Amm VIII also impaired fast inactivation of Nav1.7, with EC50 of 6.8 nM and 1.76 MUM, respectively. Neither Nav1.8 nor Nav1.9 was affected by the toxins. AaH II and Amm VIII reduced first spike latency and lowered action potential threshold. Amm VIII was less efficient than AaH II in increasing the gain of the firing frequency-stimulation relationship. In conclusion, our data show that Amm VIII, although less potent than AaH II, acts as a gating-modifier peptide reminiscent of classic alpha-toxins, and suggest that its hyperalgesic effects can be ascribed to gain-of-function of TTX-S Na(+) channels in nociceptors. PMID- 23685009 TI - Poly I:C induces a protective antiviral immune response in the Pacific oyster (Crassostrea gigas) against subsequent challenge with Ostreid herpesvirus (OsHV-1 MUvar). AB - In-vivo studies were carried out to investigate the protective effect of a synthetic viral analogue (poly I:C) against Ostreid herpes virus (OsHV-1 MUvar). Pacific oysters (Crassostrea gigas) were immune-primed by intramuscular injection of 240 MUg of poly I:C or sterile seawater at 1 day prior to infection with OsHV 1 MUvar. Poly I:C injection induced an antiviral state in C. gigas as the percentage of viral-infected oysters at 48 h post infection was significantly lower in the poly I:C treatment (11%) compared to seawater controls (100%). In an additional experiment, we demonstrated that the protective role of poly I:C is reproducible and elicits a specific antiviral response as immune-priming with heat-killed Vibrio splendidus provided no protection against subsequent viral infection. In both experiments, genes homologous to a toll-like receptor (TLR), MyD88, interferon regulatory factor (IRF) and protein kinase R (PKR) were up regulated in oysters immune-primed with poly I:C compared to seawater controls (p < 0.05). The MyD88, IRF and PKR genes were also significantly up-regulated in response to OsHV-1 MUvar infection (p < 0.05), which is suggestive that they are implicated in the antiviral response of C. gigas. Our results demonstrate that C. gigas can recognise double-strand RNA to initiate an innate immune response that inhibits viral infection. The observed response has striking similarities to the hallmarks of the type-1 interferon response of vertebrates. PMID- 23685010 TI - Identification and characterisation of ROS modulator 1 in Lampetra japonica. AB - Reactive oxygen species (ROS) are a heterogeneous group of highly reactive molecules that oxidise targets in biological systems. ROS are also considered important immune regulators. In this study, we identified a homologue of reactive oxygen species modulator 1 (Romo1) in the Japanese lamprey (Lampetra japonica). The L japonica Romo1 (Lj-Romo1) gene shares high sequence homology with the Romo1 genes of jawed vertebrates. Real-time quantitative PCR demonstrated the wide distribution of Lj-Romo1 in lamprey tissues. Furthermore, after the lampreys were stimulated with lipopolysaccharide (LPS), the level of Lj-Romo1 mRNA was markedly up-regulated in the liver, gill, kidney, and intestine tissues. Lj-Romo1 was localised to the mitochondria and has the capacity to increase the ROS level in cells. The results obtained in the present study will help us to understand the roles of Romo1 in ROS production and innate immune responses in jawless vertebrates. PMID- 23685011 TI - Procambarin: a glycine-rich peptide found in the haemocytes of red swamp crayfish Procambarus clarkii and its response to white spot syndrome virus challenge. AB - We cloned a novel glycine-rich peptide, procambarin, from the haemocytes of unchallenged crayfish Procambarus clarkii. The mature peptide (155 residues) has a13.44 KDa molecular mass with a theoretical pI about 12.12. It is characterized by a high level of glycine (57.42%) and a threefold repeated motif GLKPNVGGGGGFGGG. Generally, it belongs to cationic glycine-rich peptide. The transcripts of this peptide were detected in many tissues. The haemocytes showed the highest expression of glycine-rich peptide mRNA, followed by the ovaries, antennal gland and intestine. The gill, hepatopancreas and heart showed little expression of this peptide and no expression was detected in the musculature. There is no intron in the ORF of it. The fluctuation of mRNA expression level of procambarin after WSSV challenge indicates that this peptide participates in the antiviral immune reaction. PMID- 23685012 TI - Validating the M. D. Anderson Symptom Inventory (MDASI) for use in patients with ovarian cancer. AB - OBJECTIVE: The M. D. Anderson Symptom Inventory (MDASI) captures the severity of common cancer symptoms from the patient's perspective. We describe the validity and sensitivity of a module of the MDASI to be used with patients having ovarian cancer (MDASI-OC). METHODS: Ovarian cancer-specific module items were developed from 14 qualitative patient interviews. 128 patients with invasive epithelial ovarian, peritoneal, or fallopian-tube cancer treated at The University of Texas MD Anderson Cancer Center were recruited. Patients completed the MDASI-OC, socio demographic questionnaires, the Functional Assessment of Cancer Therapy-Ovary (FACT-O), and a global quality-of-life (QOL) item. Reliability was assessed using Cronbach alpha, and sensitivity using a known group was assessed. Construct validity was tested using exploratory factor analysis. RESULTS: The sample was primarily white (85.2%), had a mean age of 57.5 years (+/-12.7 years), and had previously been treated with chemotherapy (75.0%) and/or surgery (93.8%). Approximately 30% of patients reported disturbed sleep, fatigue, or numbness/tingling of at least moderate severity (>=5 on a 0-10 scale). On the ovarian-cancer-specific symptoms, approximately 20% reported back pain, feeling bloated, or constipation of at least moderate severity. Factor analysis revealed six underlying constructs (pain/sleep; cognitive; disease-related and numbness; treatment-related; affective; gastrointestinal-specific). MDASI-OC symptom and interference items had Cronbach alpha values of 0.90 and 0.89, respectively. The MDASI-OC was sensitive to symptom severity by performance status (p=0.009), QOL (p=0.002), and FACT-O scores (p<0.001). CONCLUSIONS: The 27-item MDASI-OC meets common criteria for validation and reliability and is sensitive to expected changes in symptoms related to differences in disease and treatment status. PMID- 23685014 TI - The effects of smoking on steroid metabolism and fetal programming. AB - Tobacco addiction is a serious psychosocial and health problem. A pregnant woman who smokes not only influences the maternal organism, but also passes health risks on to the unborn child. A fetus exposed to maternal smoking is not only directly influenced, but is also endangered by a wide range of diseases up to his or her adult years. The components of tobacco smoke play a significant role in the development of a number of diseases for a large proportion of the smoking population, as well as among those pregnant. This article summarizes findings regarding the impacts on the production of steroid hormones - first describing the smoking-related changes in steroidogenesis in women, and then focusing on the influence of maternal smoking on the fetus's developing steroidogenesis. We assume that if during prenatal development the fetus has already been exposed to the effect of endocrine disruptors at the time fetal steroidogenesis begins fetal programming, this exposure can have serious pathophysiological effects both in the pregnancy as well as later in life. An example of such effects might be a delay in the creation of kidney adrenal androgens, which could also be evident on the level of steroid neuroactive metabolites that may influence the individual's psychological state and lead to later addictions. PMID- 23685013 TI - Bone metastases in endometrial cancer: report on 19 patients and review of the medical literature. AB - OBJECTIVE: Because few cases of bone metastases of endometrial cancer have been reported, and information is scarce on their incidence, treatment, prognosis, and outcomes, we sought to compile a series of bone metastases of endometrial cancer and to systematically review the medical literature. METHODS: We retrospectively reviewed medical records of patients who had osseous metastases of endometrial cancer treated initially at Mayo Clinic (1984-2001), and of all patients who were referred for treatment of primary bone metastases after primary treatment for endometrial cancer elsewhere. RESULTS: Of 1632 patients with endometrial cancer, 13 (0.8%) had primary bone dissemination and 6 (0.4%) were referred after initial treatment. Three (15.8%) of these 19 had bone metastases at presentation; in the rest, median time to recurrence was 19.5 months (range, 3-114). The most common sites were the spine and hip. Median survival after metastasis was 12 months (range, 2-267). Median survival after radiotherapy alone vs. multimodal treatment was 20 months (range, 12-119) vs. 33 months (range, 9-267), respectively (P > .99). Of the 87 cases we reviewed from the literature, all but 1 (98.9%) had diagnoses based on symptoms. Multiple bone involvement and extraosseous dissemination were associated with poor prognosis. Type II endometrial cancer (i.e., serous or clear-cell histology) was associated with shorter life expectancy after diagnosis of bone metastasis compared to Type I tumors. CONCLUSIONS: The incidence of primary bone metastases of endometrial cancer is < 1%. Single bone metastases without extraosseous spread indicate less aggressive disease. Optimal treatment is unclear. PMID- 23685015 TI - Chemical synthesis, characterisation and biological evaluation of lactonic estradiol derivatives as inhibitors of 17beta-hydroxysteroid dehydrogenase type 1. AB - To control estradiol (E2) formation, we are interested in synthesizing inhibitors of 17beta-hydroxyteroid dehydrogenase type 1 (17beta-HSD1). Since the results of docking experiments have shown that E2-lactone derivatives substituted in position 19 or 20 (E-ring) could generate interactions with the active site of the enzyme, we carried out their chemical synthesis. After having prepared the 16beta,17beta-gamma-lactone-E2 in four steps starting from estrone (E1), we introduced the molecular diversity by adding a hydroxymethyl, a methylcarboxylate, a carboxy or an allyl group. The allyl derivative was used as a key intermediate to generate a hydroxyethyl side chain in alpha or beta position. Two lactols were also obtained from two hydroxyalkyl lactones. Enzymatic assays revealed that lactone and lactol derivatives weakly inhibited 17beta-HSD1 in homogenized HEK-293 cells overexpressing 17beta-HSD1 (34-60% at 1 MUM) and in intact T-47D cells expressing 17beta-HSD1 (10-40% at 10 MUM). This article is part of a Special Issue entitled "Synthesis and biological testing of steroid derivatives as inhibitors". PMID- 23685016 TI - Hydrophilic interaction chromatography (HILIC) in the analysis of antibiotics. AB - This paper presents a general overview of the application of hydrophilic interaction chromatography (HILIC) in the analysis of antibiotics in different sample matrices including pharmaceutical, plasma, serum, fermentation broths, environmental water, animal origin, plant origin, etc. Specific applications of HILIC for analysis of aminoglycosides, beta-lactams, tetracyclines and other antibiotics are reviewed. HILIC can be used as a valuable alternative LC mode for separating small polar compounds. Polar samples usually show good solubility in the mobile phase containing some water used in HILIC, which overcomes the drawbacks of the poor solubility often encountered in normal phase LC. HILIC is suitable for analyzing compounds in complex systems that elute near the void in reversed-phase chromatography. Ion-pair reagents are not required in HILIC which makes it convenient to couple with MS hence its increased popularity in recent years. In this review, the retention mechanism in HILIC is briefly discussed and a list of important applications is provided including main experimental conditions and a brief summary of the results. The references provide a comprehensive overview and insight into the application of HILIC in antibiotics analysis. PMID- 23685017 TI - Effect of tea polyphenols on the dilational rheology of human whole saliva (HWS): Part 1, HWS characterization. AB - Human whole saliva (HWS) is a physiological secretion that performs a number of essential functions including protection of oral health, lubrication of mouth tissues and food pre-digestion. The complexity of the saliva proteome reflects the unique physiochemical functionality of this biofluid. In addition, saliva influences the transduction of aroma, taste and tactile (mouthfeel) perceptions through the interaction with food and beverages. This work, which is presented as two distinct contributions, reports on the extensive interfacial properties characterization (air-liquid) of saliva either alone or after exposure to tea polyphenols. This first part discusses the complex nature of the salivary film in terms of kinetic and viscoelastic (dilational surface rheology) properties. The formation of the surface film is analyzed with time and explained in terms of the progressively irreversible adsorption of protein fractions of larger molecular weight. The viscoelastic response to appropriate frequency modulation is modelled using a general mixed kinetic model, which satisfactorily reproduces the experimental data in better agreement than the traditional Lucassen diffusive model. PMID- 23685018 TI - Cellular origin of Kaposi's sarcoma and Kaposi's sarcoma-associated herpesvirus induced cell reprogramming. AB - Kaposi's sarcoma (KS) is the most common malignancy in untreated HIV patients. KS is characterised by abnormal neoangiogenesis, inflammation, and proliferation of tumour cells [KS spindle cells (SCs)]. Kaposi's sarcoma-associated herpesvirus (KSHV) is the aetiological agent of KS. KS SCs are the predominant KSHV-infected cells in KS lesions. In this review, we report advances in understanding of the cellular origin of the KS SC, a contentious topic in KSHV research. KS SCs are now known to be of endothelial cell (EC) origin, phenotypically most similar to lymphatic ECs (LECs), but poorly differentiated. We focus on recent insights into KSHV's ability to exploit the normal differentiation pathway and intrinsic plasticity of ECs, through manipulation of EC-specific transcriptional regulators [i.e., prospero homeobox 1 (PROX1) and MAF] and discuss how this may contribute to viral persistence and KS sarcomagenesis. PMID- 23685019 TI - Uncovering the true identity of naive pluripotent stem cells. AB - Embryonic stem cells (ESCs) are pluripotent stem cells derived from the inner cell mass (ICM) of blastocyst embryos. Although first characterized over 30 years ago, the ontology of these cells remains elusive. Identifying the in vivo counterpart of murine ESCs will be essential for the derivation of stable ESC lines from other species. Several hypotheses exist concerning the ontology of murine ESCs. Recent data demonstrate that ESCs emerge from a subpopulation of ICM cells that transit through a Blimp1-positive state, suggesting that perhaps a germ cell developmental program underlies ESC derivation and maintenance. Alternatively, the common dependence of ESCs and diapause embryos on the cytokine LIF (leukemia inhibitory factor) has been thought to signify that murine ESCs employ a diapause-like program for their maintenance of pluripotency. Here we review different hypotheses regarding the nature of murine ESCs and discuss their implications for human pluripotent stem cell biology. PMID- 23685020 TI - Association of the Charlson comorbidity index and hypertension with survival in men with metastatic castration-resistant prostate cancer. AB - OBJECTIVES: The independent prognostic effect of comorbidities on outcomes in men with metastatic castration-resistant prostate cancer (mCRPC) is unclear. We sought to determine whether the Charlson comorbidity index (CCI) and hypertension (HTN) are associated with overall survival (OS) independent of known clinical prognostic factors in mCRPC. PATIENTS AND METHODS: A retrospective analysis was conducted on 221 patients with mCRPC treated with docetaxel plus prednisone combined with AT-101 (bcl-2 antagonist) or placebo on a prospective randomized phase II trial. The Cox regression analysis was performed to identify whether the CCI or HTN or both (by medical history) independently predicted OS after adjusting for baseline variables known to be associated with OS. The Wilcoxon rank sum test and the Fisher exact test were used to compare data by comorbidity groups (CCI as a continuous variable, CCI = 6 vs. CCI >= 7 and HTN vs. no HTN). RESULTS: The CCI was 6 in 116 patients (52.7%), 7 in 70 (31.8%), 8 in 23 (10.5%), 9 in 4 (1.8%), and 10 in 7 patients (3.2%). HTN was present in 107 (48.6%) patients. Patients with CCI of >= 7 were older and exhibited worse performance status and anemia than patients with CCI of 6 (P<0.05). The CCI was not independently predictive of OS on univariable and multivariable analyses. HTN alone or in combination with the CCI was borderline significantly associated with OS (P ~ 0.09) on both univariable and multivariable analyses. CONCLUSIONS: The CCI did not predict OS independent of known prognostic factors in mCRPC. Age, performance status, and anemia may adequately capture comorbidities in the context of mCRPC, given their association with higher CCI. Further prospective study of comorbidities in a larger data set may be warranted. The study of HTN in a larger data set may also be warranted given its borderline-independent association with OS. PMID- 23685022 TI - Unusual variant of single coronary artery arising from right coronary sinus. PMID- 23685021 TI - Pain sensitisers exhibit grey matter changes after repetitive pain exposure: a longitudinal voxel-based morphometry study. AB - Previous research in health and disease has shown that exposure to pain changes the density of cortical grey matter (GM). Such structural changes of the brain might, however, depend crucially on how this pain experience is evaluated and processed in the brain. In the present study we aimed to detect pain-rating patterns and underlying GM changes after the application of repetitive painful stimulation using voxel-based morphometry (VBM). Healthy volunteers were investigated (n=27), receiving 8 noxious and 8 innocuous thermal stimuli on the right forearm for 11 consecutive working days. Data were compared with a control group without any intervention (n=18). Behavioural data demonstrated that a subgroup of volunteers (n=14) sensitised, whereas the others (n=13) habituated over the stimulation days. The VBM analysis revealed no increase but a significant reduction of GM density, eg, in the anterior cingulate cortex, the insular cortex and the frontal cortex, exclusively in the group of sensitisers. By contrast, pain habituaters did not show any density changes in the GM. Depending on the individual perception of pain during the time course of stimulation, the repetitive application of painful stimuli changed the GM density in pain-processing brain regions exclusively in those subjects who were characterised by the lack of habituation. Because VBM studies investigating patients experiencing chronic pain observed similar decreases in GM density and increasing pain ratings over time, the sensitisers in our study may have a higher vulnerability to developing chronic pain syndromes in later life. PMID- 23685023 TI - Association of HbA1c with emotion regulation, intolerance of uncertainty, and purpose in life in type 2 diabetes mellitus. AB - BACKGROUND: The extant literature lacks breadth on psychological variables associated with health outcome for type 2 diabetes mellitus (T2DM). This investigation extends the scope of psychological information by reporting on previously unpublished factors. OBJECTIVE: To investigate if intolerance of uncertainty, emotion regulation, or purpose in life differentiate T2DM adults with sustained high HbA(1c) (HH) vs. sustained acceptable HbA(1c) (AH). SUBJECTS AND METHODS: Cross-sectional observational study. Adult patients with diagnosed T2DM meeting inclusionary criteria for AH, HH, or a nondiabetic reference group (NDR) were randomly selected and invited to participate. Patients who consented and participated resulted in a final sample of 312 subgrouped as follows: HH (n = 108); AH (n = 98); and NDR (n = 106). Data sources included a survey, self-report questionnaires, and electronic medical record (EMR). RESULTS: HH individuals with T2DM reported lower purpose in life satisfaction (p = 0.005) compared to the NDR group. The effect size for this finding is in the small-to-medium range using Cohen's guidelines for estimating clinical relevance. The HH-AH comparison on purpose in life was nonsignificant. The emotion regulation and intolerance of uncertainty comparisons across the three groups were not significant. CONCLUSIONS: The present study determined that lower purpose in life satisfaction is associated with higher HbA(1c). In a T2DM patient with sustained high HbA(1c), the primary care clinician is encouraged to consider screening for purpose in life satisfaction by asking a single question such as "Do the things you do in your life seem important and worthwhile?" The patient's response will assist the clinician in determining if meaning or purpose in life distress may be interferring with diabetes self-care. If this is the case, the clinician can shift the conversation to the value of behavioral and emotional health counseling. PMID- 23685024 TI - Trends in cardiovascular risk factors among people with diabetes in a population based study, Health Survey for England 1994-2009. AB - AIMS: We evaluated trends in cardiovascular risk factors in a population-based sample of people with diabetes in England from 1994 to 2009. METHODS: Data were obtained from Health Survey for England for 1994, 1998, 2003, 2006, 2008 and 2009. Participants were aged >=30 years with self-reported diabetes. RESULTS: The standerdised prevalence of diabetes increased from 2.8% in 1994 to 6.4% in 2009 and the prevalence among males was higher than females throughout. The trend in prevalence was more apparent in manual workers. From 1994 to 2009, mean systolic blood pressure declined from 148 mmHg to 137 mmHg; mean diastolic pressure declined from 80 mmHg to 70 mmHg; mean total cholesterol declined from 6.1 mmol/L to 4.5 mmol/L over the 15 years with linear trends. The proportion prescribed lipid lowering drugs increased from 2.2% to 47.4%. The percentage of current smokers declined from 17.5% to 13.4%. Mean body mass index increased from 27.7 kg/m(2) to 31.6 kg/m(2) with an overall increase of 0.24 kg/m(2) per year. Risk factor trends were generally similar between genders and social classes but the decline in smoking was not significant for men or for manual workers. CONCLUSIONS: People with clinical diabetes have experienced substantial reductions in blood pressure, total cholesterol and smoking over 15 years. Increasing body mass index and persistence of smoking in lower socioeconomic groups, may compromise these improvements. PMID- 23685025 TI - Does insulin resistance in type 2 diabetes alter vitamin D status? AB - AIMS: Data on changes of vitamin D due to insulin resistance are conflicting. We assessed vitamin D concentrations and parameters of glycemia and mineral homeostasis in patients with insulin resistant type 2 diabetes and in matched normal controls. METHODS: Sixty-nine patients with type 2 diabetes and 60 matched normal control subjects were studied. After an overnight fast, blood was collected for measuring the parameters of glycemia (glucose, insulin and HbA1c), mineral profile (corrected calcium, phosphate and alkaline phosphatase), total 25(OH) vitamin D and parathyroid hormone (PTH) levels. RESULTS: Patients had significantly elevated fasting glucose (P=0.0001), insulin (P=0.0003) and HbA1c (P=0.0005) than the controls had. They had significantly raised calculated insulin resistance compared with control subjects (P=0.0001). Patients and controls had similar levels of serum corrected calcium and ALP, whereas serum phosphate was significantly lower in the patients compared with controls (P=0.001). Patients and controls had similar levels of 25(OH)D, but the levels of 25(OH)D in both were in the deficiency range. Intact PTH was similar in the patients and controls. Levels of 25(OH)D did not demonstrate any relation with fasting insulin, insulin resistance, or HbA1c, but correlated negatively with intact PTH (r=-0.4, P=0.02). CONCLUSION: This study demonstrated prevalent vitamin D deficiency in insulin resistant type 2 diabetic and normal subjects. Insulin resistance did not influence the status of vitamin D. PMID- 23685026 TI - A comprehensive immunohistochemical approach of AKT/mTOR pathway and p-STAT3 in mycosis fungoides. AB - BACKGROUND: Although the expression pattern of phosphorylated (p)-mTOR pathway components has attracted scientific interest in several neoplasms, to our knowledge, there is no published information regarding its significance in mycosis fungoides (MF). OBJECTIVE: We sought to perform a comprehensive simultaneous assessment of key members of AKT/mTOR pathway along with p extracellular signal-regulated kinase (ERK), NOTCH1, and p-STAT3 in patients with MF. METHODS: In all, 54 skin biopsy specimens (21 tumors, 30 plaques, and 3 folliculotropic MF) from 50 patients with MF were analyzed immunohistochemically for p-mTOR, its upstream p-AKT, its downstream effectors p-p70S6K and p-4E-BP1, and for p-ERK1/2, NOTCH1, and p-STAT3. RESULTS: p-mTOR was coexpressed with p p70S6K in 67.3% of lesions, but coexpression with other molecules was less common. p-p70S6K and marginally NOTCH1 displayed higher H-scores in tumors than in plaques. Significant correlations were recorded between p-ERK and p-4E-BP1, as well as between NOTCH1 and p-p70S6K or p-4E-BP1. NOTCH1, p-4E-BP1, and p-p70S6K expression were associated with advanced stage. In survival analysis simultaneous overexpression of p-AKT and p-p70S6K, along with p-4E-BP1 positivity, adversely affected cancer-specific, disease-free, and progression-free survival in advanced stage cases. LIMITATIONS: A limitation may be the small number of cases included in our investigation, precluding multivariate survival analysis. CONCLUSIONS: Activation of AKT/mTOR pathway in MF appears to be correlated with NOTCH1, p-ERK, and p-STAT3 and is implicated in the acquisition of a more aggressive phenotype. The combination of p-AKT, p-p70S6K, and p-4E-BP1 emerges as a significant potential prognostic marker in patients with advanced stage. PMID- 23685027 TI - A case-control study of clinicopathologic features, prognosis, and therapeutic responses in patients with granulomatous mycosis fungoides. AB - BACKGROUND: Granulomatous mycosis fungoides (GMF) is an uncommon variant of mycosis fungoides (MF). OBJECTIVE: We sought to analyze the relative frequency, clinicopathologic characteristics, prognosis, and therapeutic responses of GMF. METHODS: We conducted a retrospective case-control study of patients with GMF and age- and stage-matched patients with classic MF between 1981 and 2012. RESULTS: A total of 27 patients with GMF were identified, representing 6.3% of all patients with MF at our center. Skin manifestations were similar to classic MF having an atypical lichenoid CD4(+) CD8(-) lymphocytic infiltrate with interstitial histiocytes and/or perivascular granulomas with giant cells. Fewer patients with GMF achieved a partial response or complete response with topical (57% vs 83%; P = .002) or ultraviolet light (62% vs 90%; P = .006) therapy. The 5- and 10-year progression-free survival rates were significantly lower in patients with GMF (59% and 33%) compared with patients with classic MF (84% and 56%; P = .02), but overall survival was similar between groups (86% and 72% vs 85% and 85%; P = .54). LIMITATIONS: The retrospective methodology may underestimate the frequency of GMF. The median follow-up time may be too short to detect possible differences in overall survival. CONCLUSION: More frequent disease progression and poorer response to skin-directed therapies were observed in patients with GMF. Our findings may be helpful in selecting the most appropriate treatment for these patients. PMID- 23685028 TI - Interconversion of ketoprofen recognition in firefly luciferase-catalyzed enantioselective thioesterification reaction using from Pylocoeria miyako (PmL) and Hotaria parvura (HpL) just by mutating two amino acid residues. AB - We identified the critical amino acid residues for substrate recognition using two firefly luciferases from Pylocoeria miyako (PmL) and Hotaria parvura (HpL), as these two luciferase enzymes exhibit different activities toward ketoprofen. Specifically, PmL can catalyze the apparent enantioselective thioesterification reaction, while HpL cannot. By comparing the amino acid sequences around the active site, we identified two residues (I350 and M397 in PmL and F351 and S398 in HpL) that were different between the two enzymes, and the replacement of these amino acids resulted in changing the ketoprofen recognition pattern. The inactive HpL was converted to the active enzyme toward ketoprofen and vice versa for PmL. These residues also affected the enantioselectivity toward ketoprofen; however, the bioluminescent color was not affected. In addition, using molecular dynamics calculations, the replacement of these two amino acids induced changes in the state of hydrogen bonding between ketoprofen and the S349 side chain through the active site water. As S349 is not considered to influence color tuning, these changes specifically caused the differences in ketoprofen recognition in the enzyme. PMID- 23685029 TI - Evaluation of bacteriophage therapy to control Clostridium difficile and toxin production in an in vitro human colon model system. AB - Clostridium difficile is a leading cause of hospital-acquired diarrhoea and represents a major challenge for healthcare providers. Due to the decreasing efficacy and associated problems of antibiotic therapy there is a need for synergistic and alternative treatments. In this study we investigated the use of a specific bacteriophage, PhiCD27, in a human colon model of C. difficile infection. Our findings demonstrate a significant reduction in the burden of C. difficile cells and toxin production with phage treatment relative to an untreated control, with no detrimental effect on commensal bacterial populations. The results demonstrate the potential of phage therapy, and highlight the limitations of using phages that have lysogenic capacity. PMID- 23685030 TI - Replication of white spot syndrome virus (WSSV) in the polychaete Dendronereis spp. AB - This study investigated whether WSSV replicates in naturally infected Dendronereis spp., a common polychaete (Nereididae) species in shrimp ponds in Indonesia. To detect WSSV replication, (i) immunohistochemistry (IHC) using a monoclonal antibody against WSSV VP28 protein and (ii) nested RT-PCR using specific primers set for the vp28 gene to detect WSSV-specific mRNA were applied. WSSV immunoreactive-nuclei were detected in the gut epithelium of the polychaete and WSSV mRNA was detected with nested RT-PCR. This, together with the IHC results, confirmed that WSSV could replicate in Dendronereis spp. This is the first report showing that WSSV replicated in a naturally infected non-crustacean host. PMID- 23685031 TI - Granulomatous infection of the hand and wrist due to Azospirillum spp. AB - We report a case of Azospirillum infection manifestating as granulomatous tenosynovitis of the right hand, in an immunocompetent middle-aged female. We highlight the unusual source of the infection, the diagnostic workup, as well as the treatment approach. PMID- 23685032 TI - LCC-Demons: a robust and accurate symmetric diffeomorphic registration algorithm. AB - Non-linear registration is a key instrument for computational anatomy to study the morphology of organs and tissues. However, in order to be an effective instrument for the clinical practice, registration algorithms must be computationally efficient, accurate and most importantly robust to the multiple biases affecting medical images. In this work we propose a fast and robust registration framework based on the log-Demons diffeomorphic registration algorithm. The transformation is parameterized by stationary velocity fields (SVFs), and the similarity metric implements a symmetric local correlation coefficient (LCC). Moreover, we show how the SVF setting provides a stable and consistent numerical scheme for the computation of the Jacobian determinant and the flux of the deformation across the boundaries of a given region. Thus, it provides a robust evaluation of spatial changes. We tested the LCC-Demons in the inter-subject registration setting, by comparing with state-of-the-art registration algorithms on public available datasets, and in the intra-subject longitudinal registration problem, for the statistically powered measurements of the longitudinal atrophy in Alzheimer's disease. Experimental results show that LCC-Demons is a generic, flexible, efficient and robust algorithm for the accurate non-linear registration of images, which can find several applications in the field of medical imaging. Without any additional optimization, it solves equally well intra & inter-subject registration problems, and compares favorably to state-of-the-art methods. PMID- 23685033 TI - Characterisation of developmentally hypomineralised human enamel. AB - OBJECTIVES: To investigate and clarify physical and chemical properties of enamel affected by molar incisor hypomineralisation (MIH). METHODS: A series of in vitro studies were performed on extracted molars affected by MIH and sound teeth for controls. Tooth sections underwent Vickers microhardness testing before lapping and subsequent transverse microradiographic analysis and examination under polarised light microscopy. Carbonate content was determined by CO2 release from acid digestion. Unprepared and fractured surfaces were examined under scanning electron microscopy. RESULTS: MIH-affected molars demonstrated a severe degree of hypomineralisation with an average mineral content of only 58.8%vol% mineral. Vickers microhardness was significantly reduced in MIH compared with controls (1.8+/-1.1 v 4.4+/-1.0 GPa, p<0.05) and polarised light microscopy revealed the bulk of MIH lesions had a porosity of <=5% but also substantial areas of >=10% and smaller areas exceeding 25% porosity. A surface layer was frequently observed on both intact and broken-down lesions and cervical regions of MIH teeth were typically spared. Carbonate content of MIH enamel was higher than control samples (6.6+/-2.1 v 4.4+/-1.1 wt%, p<0.05). Scanning electron microscopy showed that both the enamel rod and surface ultrastructure were defective. Clinical characteristics did not consistently correlate with all properties. CONCLUSIONS: The properties of MIH-affected enamel significantly differ from those of normal enamel and were highly variable, however some common characteristics were observed. Implications for aetiology and clinical management are discussed. PMID- 23685034 TI - Investigation of Biodentine as dentine replacement material. AB - OBJECTIVE: Biodentine was compared to glass ionomer and resin modified cements in an "open sandwich" restoration. METHODS: Fuji IX, Vitrebond and Biodentine were characterised using various techniques. The effect of etching with 35% phosphoric acid was investigated by assessment of surface topography, Fourier transform infrared (FT-IR) spectroscopy, surface micro-hardness and micro-leakage using tagged carboxylated-modified fluorescent microspheres and tracing the presence of these particles with a confocal microscope. RESULTS: Acid etching resulted in erosion of the material surface with exposure of the glass particles in the glass ionomer-based materials. Biodentine exhibited a reduction in the chlorine peak and the calcium-silicon ratio. There was no difference in the micro-hardness in etched and un-etched materials. The FT-IR plots did not show any chemical changes caused by etching for all the materials investigated. Both Vitrebond and Fuji IX exhibited no leakage at the dentine to material interface while Biodentine exhibited leakage both when it was etched and also when the surface was left unprepared. The sandwich technique was effective and prevented micro-leakage with glass ionomer-based materials but micro-leakage occurred with Biodentine. CONCLUSIONS: Biodentine demonstrated both structural and chemical changes when etched with 37% phosphoric acid. Biodentine exhibited a lower calcium to silicon ratio and a reduction in the chloride peak height when etched. When used as a dentine replacement material in the sandwich technique overlayed with composite, significant leakage occurred at the dentine to material interface. On the other hand materials based on glass ionomer cement were etched successfully and no chemical and physical changes or micro-leakage were detected when the materials were used as bases under composite restorations. The micro-hardness of all the materials was unaffected by etching. PMID- 23685035 TI - Evaluation of an anatomic dual-laminate composite resin shade guide. AB - BACKGROUND: Color assessment in aesthetic dentistry is one of the most challenging steps for direct restorative treatment. Shade selection tools should be able to mimic closely the materials and layering technique used in the final restoration, hence the development of prefabricated anatomic dual-laminate shade guides. OBJECTIVE: This study aims to compare different shade selection techniques and determine the suitability of a prefabricated anatomic dual laminate shade guide and its best mode of use compared to a conventional guide and a layered custom guide. MATERIALS AND METHODS: CIELab coordinates of different shade guides were assessed: Vitapan Classical (tab A2; Vita); Miris2 prefabricated anatomic dual-laminate shade guide, enamel WR tab on top of dentine S3 tab and nothing in-between (M2air) or glycerin gel (M2gly) or water (M2w); custom shade guide using prefabricated silicon moulds, Miris2 enamel WR composite resin moulded directly on dentine S3 pre-polymerised base (M2cus). The average values were obtained to calculate DE and compare the different shade selection techniques. Additional samples and measurements were made to compare Vitapan Classical shade tabs A1, A2 and A3 and all possible combinations of Miris2 and establish the closest matching shade (DE 3.3). RESULTS: High DE values were found (6.51-9.11) when comparing M2air to Vita, M2gly M2w M2cus. Differences appeared acceptable (DE 2.09-2.99) between Vita, M2gly and M2w and M2cus. Seven combinations of M2 were found to match Vita tab A1 and A2 and three Miris2 combinations for Vita A3 (DE 3.3). CONCLUSIONS: The use of Miris2 prefabricated anatomic dual-laminate shade guide with interposition of water or glycerin between the enamel-dentine tabs demonstrated acceptable DE values when compared to Vitapan Classical and custom guides. A chart for matching Vita shades with various combinations of Miris2 enamel/dentine shades was produced to assist the clinician in obtaining acceptable restorations. CLINICAL SIGNIFICANCE: The prefabricated anatomic dual-laminate shade guide is as efficient as a custom shade guide, facilitating clinical steps and saving material when doing compositeresin restorations. PMID- 23685036 TI - Failure of incompletely excavated teeth--a systematic review. AB - OBJECTIVES: When treating deep caries, one- and two-step incomplete caries removal reduce the risk of pulpal exposure. However, it is currently unclear if incompletely excavated teeth fail due to pulpal or rather non-pulpal complications. The present study systematically analysed how incompletely excavated teeth fail, and if certain tooth- or treatment-related factors may influence risk of failure. DATA: Clinical studies investigating clinical or radiologic failure after incomplete excavation of deep caries (depth >1/2 dentine thickness) were evaluated. Weighted annual failure rates (AFRs) were used to analyse frequency and mode of failures. Sub-analyses compared risk of failure in different groups of possible influencing factors. SOURCES: Electronic databases were screened and studies cross-referenced. Language was restricted to English and German. Grey literature was not evaluated. RESULTS: 19 studies with a median (Q25/75) follow-up of 24 (12/48) months were included. AFR was 3.8 (1.4/4.4)%. Eleven studies reported pulpal complications being the major reason for failure, and only 2 studies found more non-pulpal than pulpal failures. Sub-analyses found significantly lower risk of failure for teeth after one- compared with two-step excavation (Odds ratio [95% CI]=0.21 [0.08, 0.55]) and teeth with single- compared with multi-surface cavities (0.33 [0.16, 0.67]). Risk of bias differed widely between studies, and evidence levels were graded as very low. CONCLUSIONS: After incomplete removal of deep caries, pulpal failure was more common. One- compared with two-step excavation reduces risk of failure, and factors like number of restored surfaces seem to but influence failure, but limited evidence permits drawing definitive conclusions. CLINICAL SIGNIFICANCE: Growing evidence indicates that one-step incomplete excavation seems suitable to treat deep caries lesions, and might have advantages compared to two-step incomplete or complete caries removal. However, it is too early to recommend certain clinical strategies. PMID- 23685037 TI - TMG-chitotriomycin as a probe for the prediction of substrate specificity of beta N-acetylhexosaminidases. AB - TMG-chitotriomycin (1) produced by the actinomycete Streptomyces annulatus NBRC13369 was examined as a probe for the prediction of substrate specificity of beta-N-acetylhexosaminidases (HexNAcases). According to the results of inhibition assays, 14 GH20 HexNAcases from various organisms were divided into 1-sensitive and 1-insensitive enzymes. Three representatives of each group were investigated for their substrate specificity. The 1-sensitive HexNAcases hydrolyzed N acetylchitooligosaccharides but not N-glycan-type oligosaccharides, whereas the 1 insensitive enzymes hydrolyzed N-glycan-type oligosaccharides but not N acetylchitooligosaccharides, indicating that TMG-chitotriomycin can be used as a molecular probe to distinguish between chitin-degrading HexNAcases and glycoconjugate-processing HexNAcases. PMID- 23685038 TI - Recent developments of ionic liquids in oligosaccharide synthesis: the sweet side of ionic liquids. AB - The area of ionic liquid (IL) research has seen tremendous growth over the last few decades. The development of novel ILs with new and attractive physical and chemical properties has had a direct impact on organic synthesis. In particular, ILs have had many applications in carbohydrate chemistry including their use as solvents for dissolving high molecular weight carbohydrate polymers such as cellulose and as solvents and catalysts in oligosaccharide synthesis. In this area, ILs have been involved in protecting group manipulation reactions as well as glycosidic couplings leading to new methodologies and enhanced procedures. In addition, ILs have been successfully utilized as solution-phase purification supports. This review focuses on the most recent advances in the application of ILs to oligosaccharide synthesis. This is an emerging area that offers great promise at addressing some of the obstacles that remain on the path towards the automation of oligosaccharide synthesis. PMID- 23685039 TI - Isolated paediatric neurosarcoidosis presenting as epilepsia partialis continua: a case report and review of literature. AB - Isolated paediatric neurosarcoidosis (IPN) is exceptionally rare and only seven cases have been reported so far in the literature. We report the clinical and radiological profile of a 7 year-old boy with epilepsia partialis continua (EPC) who was initially thought to have Acute Disseminated Encephalomyelitis (ADEM), but was subsequently found to have isolated neurosarcoidosis. Additionally, we performed a literature search on Medline and Embase and secondary sources of data such as reference list of articles reviewed. Whilst cranial neuropathy is the commonest presenting feature in adults with neurosarcoidosis, paediatric patients are more likely to present with seizures. Diagnosis presents a clinical challenge as a result of its protean manifestations. Due to its rarity, there remains a lack of evidence base to inform the best choice of treatment for these children. Our patient was successfully treated with a combination of various immunomodulants. PMID- 23685040 TI - A response to the commentary on the paper "A comprehensive modeling and vibration analysis of AFM microcantilevers subjected to nonlinear tip-sample interaction forces" by Sohrab Eslami and Nader Jalili". AB - Recently we received a commentary by Passian et al. [1] on our previously published paper [2] in the Ultramicroscopy. Although the commentators, who are also our co-authors in an earlier papers in similar line (see [3,5]), claimed to discuss and better explain the concept of "virtual resonance" in [3], they went on to conclude that the experimental results and findings in [3] have been misrepresented in [2]. We have theoretically considered a general semi-empirical nonlinear interaction force consisting of different terms with which the dynamic response of the system could be very dependent. Here, we highlight these types of dependencies on the amplitude at the difference frequency. Due to the nature of this communication, we would like to limit our response to matters of fact to the authors of the commentary. PMID- 23685041 TI - The cognitive processes underpinning clinical decision in triage assessment: a theoretical conundrum? AB - High quality clinical decision-making (CDM) has been highlighted as a priority across the nursing profession. Triage nurses, in the Accident and Emergency (A&E) department, work in considerable levels of uncertainty and require essential skills including: critical thinking, evaluation and decision-making. The content of this paper aims to promote awareness of how triage nurses make judgements and decisions in emergency situations. By exploring relevant literature on clinical judgement and decision-making theory, this paper demonstrates the importance of high quality decision-making skills underpinning the triage nurse's role. Having an awareness of how judgements and decisions are made is argued as essential, in a time where traditional nurse boundaries and responsibilities are never more challenged. It is hoped that the paper not only raises this awareness in general but also, in particular, engages the triage nurse to look more critically at how they make their own decisions in their everyday practice. PMID- 23685042 TI - Brain and pineal 7alpha-hydroxypregnenolone stimulating locomotor activity: identification, mode of action and regulation of biosynthesis. AB - Biologically active steroids synthesized in the central and peripheral nervous systems are termed neurosteroids. However, the biosynthetic pathways leading to the formation of neurosteroids are still incompletely elucidated. 7alpha Hydroxypregnenolone, a novel bioactive neurosteroid stimulating locomotor activity, has been recently identified in the brain of newts and quail. Subsequently, the mode of action and regulation of biosynthesis of 7alpha hydroxypregnenolone have been determined. Moreover, recent studies on birds have demonstrated that the pineal gland, an endocrine organ located close to the brain, is an important site of production of neurosteroids de novo from cholesterol. 7alpha-Hydroxypregnenolone is a major pineal neurosteroid that stimulates locomotor activity in juvenile chickens, connecting light-induced gene expression with locomotion. This review summarizes the advances in our understanding of the identification, mode of action and regulation of biosynthesis of brain and pineal 7alpha-hydroxypregnenolone, a potent stimulator of locomotor activity. PMID- 23685043 TI - WITHDRAWN: Having your cake and eating it too: A habit of comfort food may link chronic social stress exposure and acute stress-induced cortisol hyporesponsiveness. AB - This article has been withdrawn at the request of the Publisher due to a production error that led to a duplicate version being created. The full text of the accepted version of this article can be found at http://dx.doi.org/10.1016/j.physbeh.2013.02.018. The Publisher apologizes for any inconvenience this may cause to authors and readers. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 23685044 TI - The potential health benefit of polyisoprenylated benzophenones from Garcinia and related genera: ethnobotanical and therapeutic importance. AB - The diversity present in biological activities and the medicinal significance of natural products provide a renewed interest in the use of natural compounds and, more importantly, their role as a basis for drug development. Advancements in the field of natural product chemistry provide valuable information on Garcinia fruits which revealed the presence of biologically important secondary metabolites named as polyisoprenylated benzophenones (PIBs). They are mainly present in the genus Garcinia (Guttiferae) which occupies a prominent position in the history of natural products. Compared to the long history of medicinal uses and widespread research on Garcinia, the study of polyisoprenylated benzophenones was relatively limited. During recent years, these PIBs have been recognized as interesting and valuable biologically active secondary metabolites as many of the isolated polyisoprenylated benzophenones exhibited significant cytotoxic activity in in vitro and in vivo assay. During past decades, some promising advances had been achieved in understanding the chemistry and pharmacology of polyisoprenylated benzophenones. However, there has been not any systematic review on the ethnobotanical importance, chemistry, isolation techniques, structure activity relationships and the biological activities of polyisoprenylated benzophenones. In this review, the biological activity of different structures of polyisoprenylated benzophenones isolated from genus Clusia, Garcinia, Vismia, Allanblackia, Moronobea, Symphonia, Hypericum, Tovomita, Tovomiptosis and Ochrocarpus have been described. Therefore, the goal of this review article would be a valuable reference for the natural product chemists and biologists working on these PIBs. Furthermore, the review article on polyisoprenylated benzophenones would also be useful from the drug discovery point of view as cytotoxic agents in near future. This review focuses our understanding about the specific biological effects of Garcinia fruits, which may be useful for predicting other medicinal uses, potential drug or food interactions and may benefit people where the fruits are prevalent and healthcare resources are scarce. PMID- 23685045 TI - Glycosylsphingolipids from Euonymus japonicus Thunb. AB - The stem bark of Euonymus japonicus Thunb. led to the isolation of three new glycosylsphingolipids (1-3), 1-O-[-L-rhamnopyranosyl-(1->2)-beta-D glucopyranosyl]-(2S,3R,9E)-2-N-[(2R)-hydroxystearoyl]-octadecasphinga-9-ene (euojaposphingoside A, 1), 1-O-[beta-D-glucopyranosyl-(1->2)-beta-D glucopyranosyl]-(2S,3R,4R,11E)-2-N-[(2R)-hydroxydocasanoyl]-octadecasphinga-11 ene (euojaposphingoside B, 2), 1-O-[beta-D-glucopyranosyl]-2'-O-[beta-D glucopyranosyl]-(2S,3R,4R,11E)-2-N-[(2R)-hydroxytetracosanoyl]-octadecasphinga-11 ene (euojaposphingoside C, 3) along with three known glycosylsphingolipids (4-6), 1-O-[beta-D-glucopyranosyl]-(2S,3R,9E)-3-hydroxymethyl-2-N-[(2R) hydroxynonacosanoyl)-tridecasphinga-9-ene (4), 1-O-[beta-D-glucopyranosyl] (2S,3R,9E,12E)-2-N-[(2R)-hydroxytetracosanoyl] octadecasphinga-9,12-diene (5), 1 O-[beta-D-glucopyranosyl]-(2S,3R,5R,9E)-2-N-[tridecanoyl] nonacosasphinga-9-ene (6), lupeol (7), stigmasterol (8), sitosterol (beta and alpha) (9,10) and beta carotene (11). The structure of all the compounds was achieved by spectroscopic and chemical data analysis. The antiplasmodial, antileismanial and cytotoxic activity of all compounds was tested. PMID- 23685046 TI - Structure and antioxidant activity study of sulfated acetamido-polysaccharide from Radix Hedysari. AB - A new sulfated acetamido-heteropolysaccharide, HPS4-2A, was obtained by aqueous extraction followed by precipitation with ethanol and fractionation with DEAE column chromatography from Radix Hedysari. It was composed of rhamnose, arabinose, glucose, galactose and 2-acetamido-2-deoxy-d-galactose in the molar ratio of 10.09%:25.90%:25.90%:25.0%:12.30%. Elemental analysis indicated that HPS4-2A was a sulfated polysaccharide containing small amount of sulfate groups (1.87%). Partial acid hydrolysis, GC, GC-MS, 1D and 2D NMR spectroscopy analysis of the HPS4-2A revealed a predominance of glucose, galactose and 2-acetamido-2 deoxy-D-galactose linked in a highly-branched structure. The molecular weight of HPS4-2A was determined by HPSEC and HPSEC-MALLS. AFM study indicated that HPS4-2A took a highly branched conformation, which in consistent with the result studied by SEC-MALLS. Structural features of HPS4-2A were also investigated by SEM and TEM. Antioxidant assays demonstrated that HPS4-2A possessed of strong DPPH and hydroxyl radicals scavenging activities, suggesting that HPS4-2A could potentially be used as natural antioxidant. PMID- 23685047 TI - Coniochaetones E-I, new 4H-chromen-4-one derivatives from the Cordyceps colonizing fungus Fimetariella sp. AB - Five new 4H-chromen-4-one derivatives coniochaetones E-I (1-5), along with the known compounds coniochaetones B (6) and A (7) have been isolated from solid cultures of the Cordyceps-colonizing fungus Fimetariella sp. Their structures were elucidated primarily by NMR spectroscopy and the absolute configurations of compounds 1-3 were assigned using the modified Mosher's method. Compound 4 showed weak cytotoxic activity against HeLa cells with IC50 values of 72.8 MUM. The co isolated known compound 6 showed modest inhibitory effects against Aspergilus fumigates, Fusarium oxysporum and Fusarium nivale. PMID- 23685048 TI - Participation of citral in the bronchodilatory effect of ginger oil and possible mechanism of action. AB - The extract of ginger, the rhizomes of Zingiber officinale Roscoe (Zingiberaceae), has been reported to possess anti-hyperactivity and anti inflammation on airway. The present study described brochodilatory activity of ginger oil and identified its active compound. Ginger oil was extracted by hydro distillation. The compositions of ginger oil were analyzed by gas chromatography and mass spectrometer. Citral, eucalyptol and camphene were found to be the major components. Ginger oil and citral, but not camphene, suppressed rat tracheal contraction induced by carbachol (CCh). Consistent with previous report, eucalyptol showed a relaxing effect on rat airway. Since the content of eucalyptol in ginger oil was relatively low, the contribution of eucalyptol to the bronchodilatory effect of ginger oil was small. To elucidate the mechanisms responsible for the myorelaxing effect, propranolol (a beta-adrenergic receptor antagonist), indomethacin (a COX inhibitor) and L-NAME (a NOS inhibitor) were used to block the inhibitory effects of ginger oil and citral. It was found that propranolol, but not indomethacin and L-NAME, reversed bronchodilatory effects of both ginger oil and citral, suggesting that a possible mechanism involved beta adrenergic receptor. This study provides the pharmacological basis supporting the therapeutic potential of Z. officinale rhizomes as a bronchodilator. PMID- 23685049 TI - Telomere length, TERT and shelterin complex proteins in hepatocellular carcinomas expressing "stemness"-related markers. AB - BACKGROUND & AIMS: Hepatocellular carcinomas (HCCs) expressing "stemness"-related markers have been associated with aggressive biological behavior and poor prognosis. We examined the relationship between "stemness"-related protein expression and telomere length, hTERT and shelterin complex protein expression and chromosomal instability. METHODS: Quantitative fluorescent in situ hybridization for telomere length, immunohistochemistry for K19, EpCAM, CD133, c kit, HepPar1, hTERT, TRF1, TRF2, POT1, RAP1 and TPP1, and TUNEL assay were performed in 137 HCCs, and array comparative genomic hybridization was performed with 24 HCCs. RESULTS: Telomeres were significantly longer in HCCs expressing "stemness"-related proteins (K19: p < 0.001, EpCAM: p = 0.002, CD133: p = 0.002). On analyzing different tumor cells within EpCAM-expressing HCCs, EpCAM-positive tumor cells showed longer telomeres (1.329 +/- 0.246) compared to EpCAM-negative tumor cells (0.996 +/- 0.381) within the same HCCs (p = 0.031). Telomeres were significantly longer in HCCs expressing hTERT (p = 0.048) and RAP1 proteins (p = 0.031). K19-expressing HCCs expressed hTERT (p = 0.002), TRF2 (p = 0.001) and TPP1 (p = 0.013) more frequently compared to K19-negative HCCs. EpCAM-positivity was associated with more frequent hTERT (p = 0.028), TPP1 (p = 0.017), TRF2 (p = 0.027) and POT1 (p = 0.004) expression. Copy number alterations were more frequent in K19 and EpCAM-expressing HCCs compared to HCCs without these markers (K19: p = 0.038, EpCAM: p = 0.009). HCCs with longer telomeres were associated with a shorter overall (p = 0.019) and disease-free survivals (p = 0.049), and decreased disease-free survivals were seen in TRF2-positive HCCs (p = 0.018). CONCLUSIONS: HCCs expressing "stemness"-related proteins are characterized by increased telomere length, increased expression of hTERT and shelterin complex proteins, and increased chromosomal instability compared to conventional HCCs. Longer telomeres and TRF2 expression in HCCs are associated with poor patient outcomes. PMID- 23685051 TI - A transfection reporter for the prevention of false-negative results in molecular beacon experiments. AB - We previously developed a molecular beacon-type probe to detect the strand scission in cellular base excision repair and found that the phosphodiester linkages in the fluorophore/quencher linkers were cleaved. This reaction was applied to a transfection reporter, which contained the unmodified phosphodiester in the linker to another type of fluorophore. After cotransfection of cells with the probe and the reporter, the signals were used to detect the incision and to confirm the proper transfection, respectively. This method will contribute to the prevention of false-negative results in experiments using molecular beacon-type probes. PMID- 23685050 TI - Regulatory T cells inhibit Th1 cell-mediated bile duct injury in murine biliary atresia. AB - BACKGROUND & AIMS: Biliary atresia (BA) is a pediatric inflammatory disease of the biliary system which leads to cirrhosis and the need for liver transplantation. One theory regarding etiology is that bile duct injury is due to virus-induced autoreactive T cell-mediated inflammation. Regulatory T cell (Treg) abnormalities in BA could result in unchecked bystander inflammation and autoimmunity targeting bile ducts. The aim of this study was to determine if Tregs are dysfunctional in the rotavirus-induced mouse model of BA (murine BA). METHODS: Murine BA resulted from infection of BALB/c neonates with Rhesus rotavirus (RRV). RESULTS: Liver Tregs from BA mice were decreased in number, activation marker expression, and suppressive function. Adoptive transfer studies revealed that RRV-infected mice that received Tregs had significantly increased survival (84%) compared to controls (12.5%). In addition, ablation of Tregs in older mice, followed by RRV infection, resulted in increased bile duct injury. CONCLUSIONS: These studies demonstrate that dysregulation of Tregs is present in murine BA and that diminished Treg function may be implicated in the pathogenesis of human BA. PMID- 23685052 TI - Development of an AlphaScreen assay for discovery of inhibitors of low-affinity glycan-lectin interactions. AB - The development of high-throughput screening (HTS) assays with increased sensitivity for the identification of potent and selective inhibitors of galectins has been hampered by the weak binding affinities between galectins and their carbohydrate ligands. To circumvent this obstacle, we have developed an AlphaScreen assay for a 384-well plate format in a competitive binding configuration for discovery of new inhibitors of galectin-3. His-tagged galectin 3 was bound to nickel chelate acceptor beads, whereas biotinylated asialofetuin (biotin-ASF), a galectin-3 nanomolar binding partner, was bound to streptavidin coated donor beads. Inhibitors of the carbohydrate-galectin interaction lead to a reduction of the AlphaScreen signal by competing with the biotin-ASF. The obtained IC50 values for known carbohydrate ligands of galectin-3 are in good agreement with the Kd values reported and measured for galectin-3 by isothermal titration calorimetry (ITC). Thus, the developed AlphaScreen assay in a competitive binding configuration offers several advantages over the existing screening assays for inhibitors of glycan-lectin interactions. In addition, the assay format for the galectin-3/ASF pair could be easily applied in screening for glycan- and/or small molecule-based inhibitors of other members of the galectin family. PMID- 23685053 TI - WITHDRAWN: Smart polymer-coated microplate wells: Applications in protein purification, protein refolding, and sensing of analytes. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 23685054 TI - Severe antibody-mediated rejection following IVIG infusion in a kidney transplant recipient with BK-virus nephropathy. AB - Intravenous immune-globulin (IVIG) use in renal transplantation has increased, with common uses including desensitization, treatment of antibody mediated rejection and adjunctive therapy for BK virus nephropathy. Although considered generally safe, potential side effects can occur in up to 23% of patients including acute kidney injury. We present a case of an unexpected cause of acute kidney injury in a renal transplant recipient following IVIG infusion. A 48-year old nonsensitized female with end stage renal disease secondary to polycystic kidney disease received a deceased donor kidney transplant. The initial post transplant period was unremarkable however at three years post-transplant the patient develops BK virus nephropathy. Despite a reduction in immunosuppression, graft function worsened and IVIG infusion was commenced. Immediately following the IVIG infusion, the patient develops anuric acute kidney injury necessitating hemodialysis. Renal transplant biopsy performed before and after the IVIG infusion revealed the de novo development of acute antibody mediated rejection and donor specific antibodies in the serum. Anti-HLA and donor-specific antibodies were also confirmed in a diluted sample of the IVIG preparation. We argue that the anti-HLA antibodies present in the IVIG caused an acute antibody mediated rejection in this previously nonsensitized female. PMID- 23685055 TI - Emergency physicians' knowledge of the total charges of medical care. AB - STUDY OBJECTIVES: This study aimed to evaluate emergency medical physician's knowledge of the charges for the entirety of medical care provided to patients they treated and discharged from the emergency department (ED). METHODS: The study was administered in an academic ED. Patients were eligible for the study if they were discharged from the ED by the attending who first evaluated them. Following patient discharge from the ED, the attending physician and resident were asked to estimate the total billed to the patient (all charges billed to patient before adjustments for insurance provider or coverage status were applied). The median error of the physician's estimate was compared to their years of experience. RESULTS: Physicians underestimated actual total charges 93% (127/136) of the time. The median estimate was 36% (IQR 23%-54%) of the actual final ED charge, representing a median underestimation of $1268 (IQR $766-$2347). There was no correlation between degree of error and postgraduate years of the physician. CONCLUSION: This study demonstrated a significant underestimation of a patient's total charges by emergency medical physicians. There was no correlation in years of experience and ability to accurately estimate charges. While all physicians tended to underestimate charges, physicians tended to have good inter rater agreement. PMID- 23685056 TI - Cost-effectiveness of recombinant human hyaluronidase-facilitated subcutaneous versus intravenous rehydration in children with mild to moderate dehydration. AB - OBJECTIVE: To evaluate the cost-effectiveness of recombinant human hyaluronidase facilitated subcutaneous (rHFSC) fluid administration compared to intravenous (IV) fluid administration in children with mild to moderate dehydration in the emergency department (ED). METHODS: A decision analytic model was created based on the results of a controlled clinical trial that compared the administration of isotonic fluids via rHFSC or IV for rehydration. The costs were determined from the hospital's perspective. The effectiveness unit was successful rehydration in the ED without the need for hospitalization for continued hydration. Mean estimates were determined for both the cost and effectiveness of each treatment. The incremental differences in costs and effectiveness were determined between treatments. Sensitivity analysis testing was also conducted. RESULTS: The treatment success rate was 93% with rHFSC fluids and 76% for IV fluids. Across all ages, the mean cost of rHFSC fluids was $722, compared to $889 for IV fluids. The difference in effectiveness was due to the larger number of patients for whom IV access could not be established, necessitating a rescue route of administration to deliver parenteral fluids. The difference in the overall cost was primarily due to the shorter time in the ED for patients receiving rHFSC fluids versus those treated with IV fluids. The cost-effectiveness of rHFSC compared to IV was most apparent in younger patients (<3 years of age), where IV access was more difficult to obtain. CONCLUSION: Analysis of this clinical trial data revealed that rHFSC fluid administration demonstrated greater treatment effectiveness and cost-effectiveness than traditional IV fluid administration in the ED. The primary reasons for this were the ease of obtaining parenteral access via rHFSC in young patients (especially those under 3) where IV access is difficult, and a shorter ED stay with rHFSC fluid administration. PMID- 23685057 TI - Effectiveness of therapeutic plasma exchange in patients with intermediate syndrome due to organophosphate intoxication. AB - OBJECTIVE: We aimed to determine effectiveness of therapeutic plasma exchange (TPE) in patients with intermediate syndrome (IMS) due to organophosphate (OP) intoxication. METHODS: Patients diagnosed with IMS due to OP intoxication were included in this prospective study. Therapeutic plasma exchange procedure was performed with fresh frozen plasma as a replacement fluid via Fresenius-AS-TEC 204 device by Therapeutic Apheresis Unit to patients who developed IMS during follow-up. Samples were taken from patient's blood and waste plasma collected in the device before and after TPE procedure to be studied in laboratory for detection of organic phosphate and pseudocholinesterase (PChE) levels. In this study, SPSS 18.0 software package was used for statistical analysis of the data obtained. Level of statistical significance was taken as P < .05 for all tests. RESULTS: Of all 17 patients, 4 (23.5%) were female, and 13 (76.5%) were male. A statistically significant decrease was detected in organic phosphate levels in the plasma of patients after TPE procedure (P = .012). A statistically significant increase was detected in PChE levels in the plasma of patients after TPE procedure (P = .014). Of 17 patients included in the study, 13 patients showed clinical improvement and were discharged after the TPE process. CONCLUSION: In our study, it was observed that a significant decrease in the level of blood plasma OP and a significant increase in the level of PChE were achieved with TPE process in the early period of IMS due to OP poisoning. This study indicates that TPE is one of the effective treatment options for IMS due to OP intoxication. PMID- 23685058 TI - Magnitude of D-dimer matters for diagnosing pulmonary embolus. AB - OBJECTIVE: The objective of this study is to determine whether the magnitude of the D-dimer correlates with a higher likelihood of pulmonary embolus (PE). METHODS: We performed an electronic chart review at our academic, tertiary care center, annual emergency department (ED) census greater than 100000. All patients with a chest computed tomographic (CT) scan with intravenous contrast and an elevated D-dimer level obtained in the ED between January 2001 and July 2008 were identified. Specific, predetermined, predefined data elements including sex, age, D-dimer level, and final ED diagnosis were recorded by a hypothesis-blinded extractor using a preformatted data form. D-dimer level less than 0.58 MUg/mL constitutes the normal laboratory reference range for our turbidometric D-dimer assay. Data were analyzed using standard statistical methods, and a linear regression analysis was performed for correlation analysis of D-dimer and diagnosis of PE. RESULTS: We identified 544 subjects who had both a chest CT scan performed and an elevated D-dimer level obtained in the ED. Fifty-eight subjects (10.7%; mean D-dimer, 4.9 MUg/mL) were diagnosed with PE, and 486 (89.3%; mean D dimer, 2.0) did not have a PE. The percentages of PE diagnoses for D-dimers in the ranges 0.58 to 1.0, 1.0 to 2.0, 2.0 to 5.0, 5.0 to 20.0, and greater than 20.0 (n = 11) were 3.6%, 8.0%, 16.2%, 35.3%, and 45.5%, respectively. The positive predictive value of PE for D-dimer level cutoffs of greater than 0.58, greater than 1.0, greater than 2.0, greater than 5.0, and greater than 20.0 was 10.7%, 14.6%, 22.2%, 37.8%, and 45.5%, respectively. Increasing D-dimer values were strongly correlated with the presence of PE (odds ratio, 1.1685 per stratum; P < .001). CONCLUSION: Increasing magnitude of D-dimer correlates with increasing likelihood of PE diagnosed by CT angiography. PMID- 23685059 TI - Panspinal epidural abscess concomitant with meningitis. AB - Panspinal epidural abscess is an extremely rare condition that can potentially lead to major permanent neurological deficits if treatment is delayed or suboptimal. Most patients with spinal epidural abscess have a short segment of vertebrae involved and classically present with fever, low back pain, and focal neurologic deficit. In severe cases, meningitis and septic shock may occur and lead to death. Therefore, the condition requires prompt recognition and proper intervention. Herein, we report the case of a 41-year-old diabetic man who presented at our hospital with the symptoms of headache, quadriplegia with respiratory distress and low back pain. Panspinal epidural abscess and meningitis were diagnosed by carrying out detailed neurologic examinations and neuroimaging studies, which expedited the correct diagnosis and treatment. PMID- 23685060 TI - Parenteral sedation of elderly patients with acute behavioral disturbance in the ED. AB - PURPOSES: This study aimed to investigate sedation of elderly patients with acute behavioral disturbance (ABD) in the emergency department (ED), specifically the safety and effectiveness of droperidol. BASIC PROCEDURES: This was a prospective study of elderly patients (>65 years) with ABD requiring parenteral sedation and physical restraint in the ED. Patients were treated with a standardized sedation protocol that included droperidol. Drug administration, time to sedation, additional sedation, and adverse effects were recorded. Effective sedation was defined as a drop in the sedation assessment tool score by 2 or a score of zero or less. MAIN FINDINGS: There were 49 patients with median age of 81 years (range, 65-93 years); 33 were males. Thirty patients were given 10 mg droperidol, 15 were given 5 mg droperidol, 2 were given 2.5 mg, and 2 were given midazolam. Median time to sedation for patients receiving 10 mg droperidol was 30 minutes (interquartile range, 18-40 minutes), compared with 21 minutes (interquartile range, 10-55 minutes; P = .55) for patients receiving 5 mg droperidol. Three patients were not sedated within 120 minutes. Eighteen patients required additional sedation-10 of 30 (33%; 95% confidence interval, 18%-53%) given droperidol 10 mg compared with 7 of 15 (47%; 95% confidence interval, 22%-73%) given 5 mg. Fourteen patients required resedation. Adverse effects occurred in 5 patients (hypotension [2], oversedation [2], hypotension/oversedation [1])-2 of 30 given 10 mg droperidol and 3 of 19 not treated according to protocol. Midazolam was given initially or for additional sedation in 2 of 5 adverse effects. No patient had QT prolongation. PRINCIPAL CONCLUSIONS: Droperidol was effective for sedation in most elderly patients with ABD, and adverse effects were uncommon. An initial 5-mg dose appears prudent with the expectation that many will require another dose. PMID- 23685061 TI - Lipid emulsion therapy in cardiodepressive syndrome after diltiazem overdose- case report. AB - We present a case of diltiazem overdose in which the patient ingested 5.6 g in an apparent suicide attempt. She was admitted in the emergency department 2 hours postingestion with cardiodepressive syndrome. She was treated with gastric lavage, activated charcoal, intravenous fluids, calcium, and epinephrine, without improvement in vital signs. We gave her an infusion of 20% intralipid, leading to a favorable evolution. The patient was stable hemodynamically and metabolic in the following 24 hours. She was alert and oriented and was extubated in the second day. She was discharged after 4 days in a good state and without any neurologic deficits. PMID- 23685062 TI - Gene discordance in phylogenomics of recent plant radiations, an example from Hawaiian Cyrtandra (Gesneriaceae). AB - Resolving species relationships within recent radiations requires analysis at the interface of phylogenetics and population genetics, where coalescence and hybridization may confound our understanding of relationships. We developed 18 new primer pairs for nuclear loci in Cyrtandra (Gesneriaceae), one of the largest plant radiations in the Pacific Islands, and tested the concordance of 14 loci in establishing the phylogenetic relationships of a small number of Hawaiian species. Four genes yielded tree topologies conflicting with the primary concordance tree, suggesting plastid capture and horizontal transfer via hybridization. Combining all concordant genes yielded a tree with stronger support and a different topology from the total-evidence tree. We conclude that a small number of genes may be insufficient for accurate reconstruction of the phylogenetic relationships among closely related species. Further, the combination of genes for phylogenetic analysis without preliminary concordance tests can yield an erroneous tree topology. It seems that the number of genes needed for phylogenetic analysis of closely related species is significantly greater than the small numbers commonly used, which fail to isolate coalescence, introgression and hybridization. PMID- 23685063 TI - Clinical signs, seasonal occurrence and causative agents of canine babesiosis in France: results of a multiregional study. AB - Canine babesiosis (or piroplasmosis) is an emerging tick-borne disease caused by intraerythrocytic protozoa of the genera Babesia and Theileria. In dogs, infection by these parasites usually induces a haemolytic syndrome that can be fatal when complicated. Canine babesiosis prevalence is high in France, with Babesia canis thought to be the main etiological agent of the disease. This article presents the results of a multiregional prospective longitudinal survey on canine babesiosis conducted in France from October 2006 to December 2007. A total of 836 cases were reported by veterinarians using a multiple choice questionnaire and blood samples from 70 dogs were analyzed using PCR-RFLP to identify species responsible for canine babesiosis cases across the country. The main clinical signs reported were lethargy (98%), anorexia (98%) and hyperthermia >= 39 degrees C (80%) followed by pale mucous membranes (54%), modification of urine aspect (45%) and splenomegaly (33%). The dog population at risk was mainly represented by young dogs living in rural areas. Twenty-five out of the 70 blood samples (36%) tested by diagnostic PCR were found to contain Babesia/Theileria genus-specific DNA and all had profiles similar to that of Babesia canis genomic DNA after restriction fragment length polymorphism analyses. The survey results provide a reference for further molecular studies to assess the species and vectors involved in the transmission of the disease in France and across the Mediterranean basin. PMID- 23685064 TI - Thyroid function in 36 dogs with leishmaniosis due to Leishmania infantum before and during treatment with allopurinol with or without meglumine antimonate. AB - Hypothyroidism may predispose to the development of canine leishmaniosis or it may appear during the course of the latter due to infiltration and destruction of the thyroid gland by infected macrophages. The main purpose of this study was to evaluate thyroid function through measurement of serum total thyroxin (tT4), free thyroxin (fT4), and canine thyroid stimulating hormone (cTSH) concentrations in 36 dogs with leishmaniosis, before and after 2 and 4 weeks of treatment with allopurinol with or without meglumine antimonate. Before treatment 27/36 (75%) dogs had serum tT4 concentrations below the lower limit of the reference interval but only 2 of them had concurrently serum fT4 concentrations below the lower limit of the reference interval and none had increased serum cTSH concentrations. During treatment there were no significant changes in serum tT4 or fT4 concentrations, whereas a significant increase in serum cTSH was observed. Two dogs had decreased serum tT4 and fT4 but normal cTSH concentrations before treatment and two other dogs had decreased serum tT4 and increased cTSH, but normal fT4 concentrations during the treatment period. Although hypothyroidism could not be definitively excluded in these dogs it is considered unlikely based on their overall hormonal profile, clinical presentation, and response to treatment. Therefore, hypothyroidism does not appear to be an important predisposing disease or a frequent complication of canine leishmaniosis. PMID- 23685065 TI - Exact results for amplitude spectra of fitness landscapes. AB - Starting from fitness correlation functions, we calculate exact expressions for the amplitude spectra of fitness landscapes as defined by Stadler [1996. Landscapes and their correlation functions. J. Math. Chem. 20, 1] for common landscape models, including Kauffman's NK-model, rough Mount Fuji landscapes and general linear superpositions of such landscapes. We further show that correlations decaying exponentially with the Hamming distance yield exponentially decaying spectra similar to those reported recently for a model of molecular signal transduction. Finally, we compare our results for the model systems to the spectra of various experimentally measured fitness landscapes. We claim that our analytical results should be helpful when trying to interpret empirical data and guide the search for improved fitness landscape models. PMID- 23685066 TI - Predator bioenergetics and the prey size spectrum: do foraging costs determine fish production? AB - Most models of fish growth and predation dynamics assume that food ingestion rate is the major component of the energy budget affected by prey availability, while active metabolism is invariant (here called constant activity hypothesis). However, increasing empirical evidence supports an opposing view: fish tend to adjust their foraging activity to maintain reasonably constant ingestion levels in the face of varying prey density and/or quality (the constant satiation hypothesis). In this paper, we use a simple but flexible model of fish bioenergetics to show that constant satiation is likely to occur in fish that optimize both net production rate and life history. The model includes swimming speed as an explicit measure of foraging activity leading to both energy gains (through prey ingestion) and losses (through active metabolism). The fish is assumed to be a particulate feeder that has to swim between consecutive individual prey captures, and that shifts its diet ontogenetically from smaller to larger prey. The prey community is represented by a negative power-law size spectrum. From these rules, we derive the net production of fish as a function of the size spectrum, and this in turn establishes a formal link between the optimal life history (i.e. maximum body size) and prey community structure. In most cases with realistic parameter values, optimization of life history ensures that: (i) a constantly satiated fish preying on a steep size spectrum will stop growing and invest all its surplus energy in reproduction before satiation becomes too costly; (ii) conversely, a fish preying on a shallow size spectrum will grow large enough for satiation to be present throughout most of its ontogeny. These results provide a mechanistic basis for previous empirical findings, and call for the inclusion of active metabolism as a major factor limiting growth potential and the numerical response of predators in theoretical studies of food webs. PMID- 23685067 TI - Robustness of empirical food webs with varying consumer's sensitivities to loss of resources. AB - Food web responses to species loss have been mostly studied in binary food webs, thus without accounting for the amount of energy transferred in consumer-resource interactions. We introduce an energetic criterion, called extinction threshold, for which a species goes secondarily extinct when a certain fraction of its incoming energy is lost. We study the robustness to random node loss of 10 food webs based on empirically-derived weightings. We use different extinction scenarios (random removal and from most- to least-connected species), and we simulate 10(5) replicates for each extinction threshold to account for stochasticity of extinction dynamics. We quantified robustness on the basis of how many additional species (i.e. secondary extinctions) were lost after the direct removal of species (i.e. primary extinctions). For all food webs, the expected robustness linearly decreases with extinction threshold, although a large variance in robustness is observed. The sensitivity of robustness to variations in extinction threshold increases with food web species richness and quantitative unweighted link density, while we observed a nonlinear relationship when the predictor is food web connectance and no relationship with the proportion of autotrophs. PMID- 23685068 TI - The prospects and challenges of universal vaccines for influenza. AB - Vaccination is the most effective way to reduce the impact of epidemic as well as pandemic influenza. However, the licensed inactivated influenza vaccine induces strain-specific immunity and must be updated annually. When novel viruses appear, matched vaccines are not likely to be available in time for the first wave of a pandemic. Yet, the enormous diversity of influenza A viruses in nature makes it impossible to predict which subtype or strain will cause the next pandemic. Several recent scientific advances have generated renewed enthusiasm and hope for universal vaccines that will induce broad protection from a range of influenza viruses. PMID- 23685069 TI - The emerging world of the fungal microbiome. AB - The study of the fungal microbiota ('mycobiome') is a new and rapidly emerging field that lags behind our understanding of the bacterial microbiome. Every human has fungi as part of their microbiota, but the total number of fungal cells is orders of magnitude smaller than that of the bacterial microbiota. However, the impact of the mycobiome on human health is significant, especially as a reservoir for blooms of pathogenic microbes when the host is compromised and as a potential cofactor in inflammatory diseases and metabolic disorders. PMID- 23685070 TI - Mesenchymal stem cells in regenerative medicine applied to rheumatic diseases: role of secretome and exosomes. AB - Over the last decades, mesenchymal stem cells (MSCs) have been extensively studied with regard to their potential applications in regenerative medicine. In rheumatic diseases, MSC-based therapy is the subject of great expectations for patients who are refractory to proposed treatments such as rheumatoid arthritis (RA), or display degenerative injuries without possible curative treatment, such as osteoarthritis (OA). The therapeutic potential of MSCs has been demonstrated in several pre-clinical models of OA or RA and both the safety and efficacy of MSC-based therapy is being evaluated in humans. The predominant mechanism by which MSCs participate to tissue repair is through a paracrine activity. Via the production of a multitude of trophic factors with various properties, MSCs can reduce tissue injury, protect tissue from further degradation and/or enhance tissue repair. However, a thorough in vivo examination of MSC-derived secretome and strategies to modulate it are still lacking. The present review discusses the current understanding of the MSC secretome as a therapeutic for treatment of inflammatory or degenerative pathologies focusing on rheumatic diseases. We provide insights on and perspectives for future development of the MSC secretome with respect to the release of extracellular vesicles that would have certain advantages over injection of living MSCs or administration of a single therapeutic factor or a combination of factors. PMID- 23685071 TI - Feedforward regulation ensures stability and rapid reversibility of a cellular state. AB - Cellular transitions are important for all life. Such transitions, including cell fate decisions, often employ positive feedback regulation to establish and stabilize new cellular states. However, positive feedback is unlikely to underlie stable cell-cycle arrest in yeast exposed to mating pheromone because the signaling pathway is linear, rather than bistable, over a broad range of extracellular pheromone concentration. We show that the stability of the pheromone-arrested state results from coherent feedforward regulation of the cell cycle inhibitor Far1. This network motif is effectively isolated from the more complex regulatory network in which it is embedded. Fast regulation of Far1 by phosphorylation allows rapid cell-cycle arrest and reentry, whereas slow Far1 synthesis reinforces arrest. We expect coherent feedforward regulation to be frequently implemented at reversible cellular transitions because this network motif can achieve the ostensibly conflicting aims of arrest stability and rapid reversibility without loss of signaling information. PMID- 23685072 TI - A posttranslational modification cascade involving p38, Tip60, and PRAK mediates oncogene-induced senescence. AB - Oncogene-induced senescence is an important tumor-suppressing defense mechanism. However, relatively little is known about the signaling pathway mediating the senescence response. Here, we demonstrate that a multifunctional acetyltransferase, Tip60, plays an essential role in oncogenic ras-induced senescence. Further investigation reveals a cascade of posttranslational modifications involving p38, Tip60, and PRAK, three proteins that are essential for ras-induced senescence. Upon activation by ras, p38 induces the acetyltransferase activity of Tip60 through phosphorylation of Thr158; activated Tip60 in turn directly interacts with and induces the protein kinase activity of PRAK through acetylation of K364 in a manner that depends on phosphorylation of both Tip60 and PRAK by p38. These posttranslational modifications are critical for the prosenescent function of Tip60 and PRAK, respectively. These results have defined a signaling pathway that mediates oncogene-induced senescence, and identified posttranslational modifications that regulate the enzymatic activity and biological functions of Tip60 and PRAK. PMID- 23685073 TI - Mutations in the intellectual disability gene Ube2a cause neuronal dysfunction and impair parkin-dependent mitophagy. AB - The prevalence of intellectual disability is around 3%; however, the etiology of the disease remains unclear in most cases. We identified a series of patients with X-linked intellectual disability presenting mutations in the Rad6a (Ube2a) gene, which encodes for an E2 ubiquitin-conjugating enzyme. Drosophila deficient for dRad6 display defective synaptic function as a consequence of mitochondrial failure. Similarly, mouse mRad6a (Ube2a) knockout and patient-derived hRad6a (Ube2a) mutant cells show defective mitochondria. Using in vitro and in vivo ubiquitination assays, we show that RAD6A acts as an E2 ubiquitin-conjugating enzyme that, in combination with an E3 ubiquitin ligase such as Parkin, ubiquitinates mitochondrial proteins to facilitate the clearance of dysfunctional mitochondria in cells. Hence, we identify RAD6A as a regulator of Parkin dependent mitophagy and establish a critical role for RAD6A in maintaining neuronal function. PMID- 23685074 TI - A pH-regulated quality control cycle for surveillance of secretory protein assembly. AB - To warrant the quality of the secretory proteome, stringent control systems operate at the endoplasmic reticulum (ER)-Golgi interface, preventing the release of nonnative products. Incompletely assembled oligomeric proteins that are deemed correctly folded must rely on additional quality control mechanisms dedicated to proper assembly. Here we unveil how ERp44 cycles between cisGolgi and ER in a pH regulated manner, patrolling assembly of disulfide-linked oligomers such as IgM and adiponectin. At neutral, ER-equivalent pH, the ERp44 carboxy-terminal tail occludes the substrate-binding site. At the lower pH of the cisGolgi, conformational rearrangements of this peptide, likely involving protonation of ERp44's active cysteine, simultaneously unmask the substrate binding site and RDEL motif, allowing capture of orphan secretory protein subunits and ER retrieval via KDEL receptors. The ERp44 assembly control cycle couples secretion fidelity and efficiency downstream of the calnexin/calreticulin and BiP-dependent quality control cycles. PMID- 23685075 TI - Listerin-dependent nascent protein ubiquitination relies on ribosome subunit dissociation. AB - Quality control of defective mRNAs relies on their translation to detect the lesion. Aberrant proteins are therefore an obligate byproduct of mRNA surveillance and must be degraded to avoid disrupting protein homeostasis. These defective translation products are thought to be ubiquitinated at the ribosome, but the mechanism of ubiquitin ligase selectivity for these ribosomes is not clear. Here, we in vitro reconstitute ubiquitination of nascent proteins produced from aberrant mRNAs. Stalled 80S ribosome-nascent chain complexes are dissociated by the ribosome recycling factors Hbs1/Pelota/ABCE1 to a unique 60S-nascent chain tRNA complex. The ubiquitin ligase Listerin preferentially recognizes 60S-nascent chains and triggers efficient nascent chain ubiquitination. Interfering with Hbs1 function stabilizes 80S complexes, precludes efficient Listerin recruitment, and reduces nascent chain ubiquitination. Thus, ribosome recycling factors control Listerin localization, explaining how translation products of mRNA surveillance are efficiently ubiquitinated while sparing translating ribosomes. PMID- 23685076 TI - Genetic insights into the in vivo functions of prostaglandin signaling. AB - Prostaglandins (PGs) are lipid signals that are produced at their sites of action by cyclooxygenase (COX) enzymes, the targets of non-steroidal anti-inflammatory drugs (NSAIDs), and PG-type specific synthases. Active PGs serve as ligands for G protein-coupled receptors (GPCRs). The functions of PGs have largely been elucidated using pharmacologic, expression-based (synthesis and signaling components), and genetic studies. In this review, we discuss the in vivo roles of PGs in cancer, development, and reproduction that have been characterized using genetic knockout/knockdown and overexpression approaches in mice, zebrafish, and invertebrate model systems, and how pharmacologic inhibition of PG synthesis affects cardiovascular health/disease and cancer incidence and progression. PMID- 23685077 TI - Role of arachidonic acid metabolites on the control of non-differentiated intestinal epithelial cell growth. AB - Increasingly evidence indicates that enzymes, receptors and metabolites of the arachidonic acid (AA) cascade play a role in intestinal epithelial cell proliferation and colorectal tumorigenesis. However, the information available does not provide a complete picture and contains a number of discrepancies. For this reason it might be appropriate a thorough study into the impacts of the AA cascade on intestinal epithelial cell growth. Our data show that non differentiated Caco-2 cells cultured with 10% fetal bovine serum (FBS) synthesize appreciable amounts of prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and 5-, 12 and 15-hydroxyeicosatetraenoic acid (HETE) but not LTD4, 20-HETE and epoxyeicosatrienoic acids. We also found that inhibitors of PGE2, LTB4 and 5-, 12 , 15-HETE synthesis as well as receptor antagonists of PGE2 and LTB4 blocked Caco 2 cell growth and DNA synthesis induced by 10% FBS without cytotoxic or apoptotic activity. Interestingly, PGE2, LTB4 and 5-, 12- and 15-HETE at concentrations reached in 10% FBS Caco-2 cultures (1-10nM) were able to induce Caco-2 cell growth and DNA synthesis. This was due to the interaction of PGE2 with EP1 and EP4 receptors and LTB4 and HETEs with BLT1 and BLT2 receptors. Moreover, we provide evidence that PGE2 stimulates several cell signaling pathways such as ERK, P38alpha, CREB and GSKbeta/beta-catenin involved in the regulation of Caco-2 growth. Finally, we provide evidence that the mitogenic effects of LTB4 and HETEs can be dependent, at least in part, on PGE2 synthesis. PMID- 23685078 TI - Complications of therapeutic apheresis in children. AB - Since the equipment of therapeutic apheresis is prepared for adults, the use of it in children may lead to higher complication risks and there are little data in children undergoing therapeutic apheresis. METHODS: In this study the complications experienced during therapeutic apheresis in children between April 2010 and May 2012 at our center are analyzed retrospectively. There were 14 patients who had undergone a total of 50 sessions of therapeutic apheresis. The ages of patients' ages ranged from 20months to 16years. The procedures were plasma exchange and leukodepletion. RESULTS: Complications were observed in four patients. One of them was vascular access complication because of insufficient flow. Urticeria was observed in two patients. Abdominal pain and chilling were other complications. Our patients, who underwent TA, did not experience major complications. Minimal or mild allergic reactions were observed and treated by medications. For extracorporeal volume erythrocyte prime is useful. TA will be performed more successfully with correct planning and close examination of the patient with an experienced team. PMID- 23685079 TI - Impact of pregnancy on the cardiac health of women with prior surgeries for pulmonary valve anomalies. AB - OBJECTIVE: We assessed the impact of pregnancy on long-term cardiac outcomes in women with prior surgery for congenital pulmonary valve anomalies. STUDY DESIGN: Data on all reproductive age women with prior pulmonary valve repair or replacement, cared for at a tertiary institution over a 10-year period, were analyzed. Kaplan-Meier curves and proportional hazards models were estimated to assess the impact of pregnancy and multiparity on a composite long-term adverse outcome defined as death, heart failure, or unanticipated cardiac surgery. Peripartum cardiac complications were also assessed. RESULTS: Thirty-three parous and 20 nulliparous, nonpregnant controls with primary pulmonary valve replacement or repair were identified. Among the parous women, there were 95 pregnancies (median, 3.0; 1-10) resulting in 81 live births. Peripartum cardiac complications occurred in 28 (29.8%; 95% confidence interval, 20.4-39.2) of the pregnancies. A composite adverse long-term cardiac outcome occurred in 17 of 33 parous women, over 417 person-years (4 per 100 person-years) and 1 of 20 nulliparous women over 258 person-years (0.4 per 100 person-years); women with pregnancies were more likely at any point in time to have a composite long-term adverse cardiac outcome compared with nulliparous controls. Women with 2 or more pregnancies were more likely to have a composite adverse cardiac outcome than those with less than 2 pregnancies (hazard ratio, 8.8; 95% confidence interval, 1.5-50.3). CONCLUSION: Peripartum cardiac complications are common in women with prior pulmonary valve repair or replacement. Pregnancy appears to increase the risk of long-term adverse cardiac outcomes in these patients when compared with nulliparous controls. PMID- 23685080 TI - Inner thigh taping vs traction for cervical ripening with a Foley catheter: a randomized controlled trial. AB - OBJECTIVE: To assess the effectiveness of inner thigh "Taping" compared with "Traction" using a weighted bag when an intracervical Foley catheter is used for cervical ripening. STUDY DESIGN: We performed a randomized controlled trial at a tertiary hospital on women with a singleton pregnancy in cephalic presentation admitted for labor induction with a Bishop score <=6. A 30 mL intracervical Foley catheter was placed for ripening. Women were randomly allocated to inner thigh Taping or to Traction with a 500 mL weighted bag of fluid. The primary outcome was time to delivery. Secondary outcomes were time to expulsion of the catheter, maternal discomfort (visual analog scale), mode of delivery, and maternal morbidities. RESULTS: We randomized 197 women. After exclusions (4 ineligible, 2 withdrawn by provider), we analyzed 191 (96 Taping, 95 Traction) women in their assigned groups. Groups were similar regarding maternal race, age, parity, gestational age, and induction indication. Time to delivery was not significantly different (mean +/- standard deviation: 19.8 +/- 8.5 vs 18.8 +/- 8.0 hours; P = .39). Time to catheter expulsion was shorter in the Traction Group (median, 2.6; range, 0.2-10.8 vs median, 1.5; range, 0.1-6.3 hours; P < .001). Change in Bishop and pain scores, cesarean delivery rates, clinical amnionitis, and other maternal morbidities were similar between groups. Subset analyses of those with vaginal delivery and among nulliparas, and multiparas revealed similar results. CONCLUSION: Traction on the intracervical Foley catheter during cervical ripening shortens the time to spontaneous catheter expulsion without affecting the time to delivery. PMID- 23685081 TI - Cytotoxic effects of incense particles in relation to oxidative stress, the cell cycle and F-actin assembly. AB - Epidemiological studies have suggested that combustion-derived smoke, such as that produced during incense burning, is a deleterious air pollutant. It is capable of initiating oxidative stress and mutation; however, the related apoptotic processes remain unclear. In order to elucidate the biological mechanisms of reactive oxygen species (ROS)-induced respiratory toxicology, alveolar epithelial A549 cells were exposed to incense particulate matter (PM), with and without antioxidant N-acetyl-l-cysteine (NAC). The cross-linking associations between oxidative capacity, cell cycle events, actin cytoskeletal dynamics and intracellular calcium signals were investigated. An incense PM suspension caused significant oxidative stress in A549 cells, as shown by inhibition of the cell cycle at G1 and G2/M check-points, and the induction of apoptosis at Sub-G1. At the same time, alterations in the F-actin filamentous assemblies were observed. The levels of intracellular Ca(2+) were increased after incense PM exposure. Antioxidant NAC treatment revealed that oxidative stress and F-actin remodelling was significantly mitigated. This suggests that ROS accumulation could alter cell cycle regulation and anomalous remodelling of the cortical cytoskeleton that allowed impaired cells to enter into apoptosis. This study has elucidated the integral patho-physiological interactions of incense PM and the potential mechanisms for the development of ROS-driven respiratory impairment. PMID- 23685082 TI - Mechanisms of P-gp inhibition and effects on membrane fluidity of a new rifampicin derivative, 1,8-dibenzoyl-rifampicin. AB - PURPOSE: To assess P-glycoprotein (P-gp)-modulation ability and the mechanisms of P-gp inhibition mediated by a new synthetic rifampicin derivative, 1,8-dibenzoyl rifampicin (DiBenzRif), in an in vitro model of the blood-brain barrier (BBB), RBE4 cells, and in membrane mimetic models (liposomes). METHODS: P-gp expression (western blot) and activity [rhodamine 123 accumulation studies] were assessed until 72h of exposure to DiBenzRif. The effects on intracellular ATP levels and on P-gp ATPase activity were studied using luciferin-luciferase bioluminescence assay. Membrane fluidity changes were tracked by steady-state anisotropy measurements. Non-P-gp-related rhodamine 123 accumulation was evaluated using liposomes prepared with the main lipids present in RBE4 cell membranes. RESULTS: A significant increase in intracellular rhodamine 123 content was observed in DiBenzRif-treated cells at all tested time-points. This effect was associated with a significant reduction in ATP intracellular levels, the inhibition of P-gp ATPase activity and a significant increase in membrane fluidity. DiBenzRif also favoured rhodamine 123 accumulation in a liposomal model of RBE4 cells, suggesting that it may be useful in increasing intracellular levels of substances that passively diffuse into the cells. CONCLUSION: DiBenzRif-induced inhibitory effect on P-gp increases xenobiotic accumulation in BBB cells, which may contribute to the development of therapeutic adjuvants to enhance brain penetration of drugs. PMID- 23685083 TI - Tailor-made circulatory management based on the stress-velocity relationship in preterm infants. AB - Preterm infants frequently experience pulmonary hemorrhage or cerebral intraventricular hemorrhage after birth. The immature myocardium of the left ventricle faces a high afterload after the baby is separated from the placenta. However, the preterm left ventricle has limited ability to respond to such an increase in afterload. This results in depressed cardiac function and a deterioration in hemodynamics. We speculated that the perinatal deterioration in cardiac performance would be closely related to serious hemorrhages. To prove our hypothesis, we studied the interrelationship between the perinatal changes in cardiac performance and the incidences of intraventricular and pulmonary hemorrhage. We obtained the stress-velocity relationship (rate-corrected mean fiber shortening velocity and end-systolic wall stress relationship) by M-mode echocardiography and arterial blood pressure measurement. We found that the incidences of intraventricular and/or pulmonary hemorrhages were higher in infants with an excessive afterload, which resulted in a decrease in the function of the left ventricle. We suggest that careful attention to keep the afterload at an acceptable level by vasodilator therapy and sedation may reduce or prevent these serious complications. In this review, we will discuss our data along with related literature. PMID- 23685084 TI - Author response to "Increased risks of upper tract urothelial carcinoma in male and female Chinese herbalists". PMID- 23685085 TI - 3M Cavilon No-Sting Barrier Film or topical corticosteroid (mometasone furoate) for protection against radiation dermatitis: A clinical trial. AB - BACKGROUND/PURPOSE: Evidence on the prevention of radiation dermatitis is lacking. The aim of this study was to investigate the effect of 3M Cavilon No Sting Barrier Film and topical corticosteroids on irradiated skin. METHODS: Thirty-nine postoperative breast cancer patients were randomized into three groups for intraindividual comparison (skin to be irradiated was divided into 2 parts): (1) 3M No Sting Barrier Film versus no treatment; (2) corticosteroid versus no treatment; and (3) corticosteroid versus 3M No Sting Barrier Film. The primary end points monitored were the time to first occurrence of grade 1 pruritus, pain score of 3 and grade 2 radiation dermatitis. The secondary end points studied were the incidence of grade 3 radiation dermatitis and total pain scores. Data analysis was done using the SPSS software version 10. RESULTS: Skin given the 3M barrier film experienced a later occurrence of pruritus compared to both corticosteroids and untreated, although this was statistically insignificant. Corticosteroids delayed the time to occurrence of grade 2 dermatitis compared to both untreated skin and 3M barrier film, (mean day of onset = corticosteroid: 52 vs. untreated: 43, p = 0.092; corticosteroid: 53.4 vs. 3M barrier film: 44.5, p = 0.002, t test). Skin given corticosteroids had the lowest incidence of grade 3 dermatitis among all three conditions, although the differences were statistically insignificant. No statistically significant differences were noted in total pain scores. CONCLUSION: The 3M barrier film may be helpful against dermatitis associated pruritus. Corticosteroids may delay the time of onset of severe skin reactions and also reduce the incidence of severe radiation dermatitis. PMID- 23685086 TI - Hand-held dynamic visual noise reduces naturally occurring food cravings and craving-related consumption. AB - This study demonstrated the applicability of the well-established laboratory task, dynamic visual noise, as a technique for reducing naturally occurring food cravings and subsequent food intake. Dynamic visual noise was delivered on a hand held computer device. Its effects were assessed within the context of a diary study. Over a 4-week period, 48 undergraduate women recorded their food cravings and consumption. Following a 2-week baseline, half the participants watched the dynamic visual noise display whenever they experienced a food craving. Compared to a control group, these participants reported less intense cravings. They were also less likely to eat following a craving and consequently consumed fewer total calories following craving. These findings hold promise for curbing unwanted food cravings and craving-driven consumption in real-world settings. PMID- 23685088 TI - Hurgadacin: a new steroid from Sinularia polydactyla. AB - Hurgadacin (1), a 24,25-bishomo-26-methylenecholesterol was isolated from the soft coral Sinularia polydactyla, collected from the Red Sea, near Hurghada at the Egyptian coast. The new steroid 1 was isolated together with the closely related polyhydroxy steroids 24-methylenecholestane-3beta,5alpha,6beta-triol (2) and 24-methylenecholestane-1alpha,3beta,5alpha,6beta,11alpha-pentol (3), in addition to the sesquiterpene lactiflorenol (4) and the trinorcarotenolide acetate peridinin (5), The structures of the isolated compounds were confirmed by intensive studies of their 1D and 2D NMR spectra and mass data. The antimicrobial and cytotoxic activities of the soft coral extract and the corresponding constituents were evaluated against diverse pathogenic microorganisms and brine shrimps, respectively. PMID- 23685089 TI - Induction of quinone reductase (QR) by withanolides isolated from Physalis pubescens L. (Solanaceae). AB - In the present study, it was demonstrated that the dichloromethane extract of Physalis pubescens L. (DEPP) had weak potential quinone reductase (QR) inducing activity, but an UPLC-ESI-MS method with glutathione (GSH) as the substrate revealed that the DEPP had electrophiles (with an alpha,beta-unsaturated ketone moiety). These electrophiles could induce quinone reductase (QR) activity, which might be attributed to the modification of the highly reactive cysteine residues in Keap1. Herein, four withanolides, including three new compounds physapubescin B (2), physapubescin C (3), physapubescin D (4), together with one known steroidal compound physapubescin (1) were isolated. Structures of these compounds were determined by spectroscopic analysis and that of physapubescin C (3) was confirmed by a combination of molecular modeling and quantum chemical DFT-GIAO calculations. Evaluation of the QR inducing activities of all withanolides indicated potent activities of compounds 1 and 2, which had a common alpha,beta unsaturated ketone moiety. PMID- 23685087 TI - Biosynthesis and trafficking of the bile salt export pump, BSEP: therapeutic implications of BSEP mutations. AB - The bile salt export pump (BSEP, ABCB11) is the primary transporter of bile acids from the hepatocyte to the biliary system. This rate-limiting step in bile formation is essential to the formation of bile salt dependent bile flow, the enterohepatic circulation of bile acids, and the digestion of dietary fats. Mutations in BSEP are associated with cholestatic diseases such as progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2), drug-induced cholestasis, and intrahepatic cholestasis of pregnancy. Development of clinical therapies for these conditions necessitates a clear understanding of the cell biology of biosynthesis, trafficking, and transcriptional and translational regulation of BSEP. This chapter will focus on the molecular and cell biological aspects of this critical hepatic membrane transporter. PMID- 23685090 TI - Nodulisporisteriods A and B, the first 3,4-seco-4-methyl-progesteroids from Nodulisporium sp. AB - Two new 4-methyl-progesteroids, nodulisporisteriod A (1) and nodulisporisteriod B (2), were isolated from the extract of an endolichenic fungal strain Nodulisporium sp. (No. 65-17-2-1), along with two related metabolites, demethoxyviridin (3) and inoterpene B (4). Their structures were determined by detailed spectroscopic analyses, X-ray crystallographic analysis and comparison of the NMR data with those of the closely related compounds previously reported. Nodulisporisteriod A (1) and nodulisporisteriod B (2) possess new carbon skeletons, which are the first cases of fission at C-3,4 in 4-methyl progesteroids. A hypothetical biosynthetic pathway for 1 and 2 was proposed. Moreover, the Abeta42 aggregation inhibitory activities of 1-4 were evaluated using standard thioflavin T (ThT) fluorescence assay with epigallocatechin gallate (EGCG) as positive control. Demethoxyviridin (3) displayed anti-Abeta42 aggregation activity with IC50 value of 13.4MUM. PMID- 23685091 TI - Prediction of socially desirable and discreet hand hygiene behaviors. AB - To investigate hand hygiene in settings with fewer policies regulating hygiene practice, self-reported hand hygiene behavior and personal orientation data were collected from 353 college students. Hypothesizing that in this context some behaviors would show more variability, 2 dimensions of hand hygiene behavior were created. This proved useful because socially desirable practices were predicted by health promotion focus and individual identity, whereas discreet practices were predicted by health prevention focus and collective identity. PMID- 23685092 TI - The effect of portable pulsed xenon ultraviolet light after terminal cleaning on hospital-associated Clostridium difficile infection in a community hospital. AB - There is evidence that contamination of patient rooms from previous occupants is associated with hospital-associated Clostridium difficile infection (HA-CDI). During January 2011, the use of 2 portable pulsed xenon ultraviolet light devices (PPX-UV) to disinfect patient rooms was added to routine hospital discharge cleaning in a community hospital. In 2010, the HA-CDI rate was 9.46 per 10,000 patient-days; in 2011, the HA-CDI rates was 4.45 per 10,000 patient-days (53% reduction, P = .01). The number of deaths and colectomies attributable to hospital-associated C difficile infection also declined dramatically. PMID- 23685093 TI - Microfiber and steam for environmental cleaning during an outbreak. AB - We report an outbreak of norovirus gastroenteritis occurring concurrently over two wards. Environmental cleaning was managed using two different methodologies: one ward utilized the traditional 2-step method, the other using microfiber-steam technology. Environmental cleaning using the microfiber-steam technology proved to be an effective and efficient cleaning methodology, appropriate for use during an outbreak situation. PMID- 23685094 TI - CNS drug development in Europe--past progress and future challenges. AB - Despite enormous progress in defining, diagnosing and treating mental disorders, EU health systems face a mounting challenge in responding to 'unmet need'. Mental illnesses produce a societal burden that exceeds that for either cancers or cardiovascular conditions. Leveraging advances in science and medicine to make available new innovative medicines is a key component in responding to this challenge. The dominant paradigm has been, is and will continue to be, one of incremental progress. Better medicines for depression, anxiety and psychoses in the working age population would add great value to patients and improve labour productivity. But psychotropic medicines face exceptional challenges in demonstrating their added value, due to uncertainty in patient diagnosis, selecting treatments and ensuring adherence. Also, there are major difficulties in estimating costs. Advances in understanding brain processes, identifying biomarkers and neuro-imaging techniques promise far more effective 'diagnostic therapeutic' treatments and improved patient outcomes in the future. Currently there are valuable incremental innovations in late development, which may well fail to recover their R&D costs, because of very low reimbursed prices. This will send a signal to innovators not to persist with product development in this area. Recently several leading companies have withdrawn from R&D in these mental disorders. This is a worrying development since building the capabilities to succeed in any disease sector takes many years and, once dismantled, they cannot easily be re-established. Three policy interventions could improve innovation incentives: Further 'push' incentives under i) and streamlining under ii) alone will not reverse the decline in investment incentives. An EU consensus, based upon an innovation model which encompasses the Research, Development and Market phases as a single cyclical process, which addresses the weak 'market pull incentives' under iii) is needed. There is a very real risk that without such an integrated approach to policy reforms, innovation in psychotropic medicines will become a 'desert' in the same way that it did for antibiotics in the 1990's. PMID- 23685095 TI - Cartilage adaptation after anterior cruciate ligament injury and reconstruction: implications for clinical management and research? A systematic review of longitudinal MRI studies. AB - OBJECTIVE: To summarize the current evidence of magnetic resonance imaging (MRI) measured cartilage adaptations following anterior cruciate ligament (ACL) reconstruction and of the potential factors that might influence these changes, including the effect of treatment on the course of cartilage change (i.e., surgical vs non-surgical treatment). METHODS: A literature search was conducted in seven electronic databases extracting 12 full-text articles. These articles reported on in vivo MRI-related cartilage longitudinal follow-up after ACL injury and reconstruction in "young" adults. Eligibility and methodological quality was rated by two independent reviewers. A best-evidence synthesis was performed for reported factors influencing cartilage changes. RESULTS: Methodological quality was heterogenous amongst articles (i.e., score range: 31.6-78.9%). Macroscopic changes were detectable as from 2 years follow-up next to or preceded by ultra structural and functional (i.e., contact-deformation) changes, both in the lateral and medial compartment. Moderate-to-strong evidence was presented for meniscal lesion or meniscectomy, presence of bone marrow lesions (BMLs), time from injury, and persisting altered biomechanics, possibly affecting cartilage change after ACL reconstruction. First-year morphological change was more aggravated in ACL reconstruction compared to non-surgical treatment. CONCLUSION: In view of osteoarthritis (OA) prevention after ACL reconstruction, careful attention should be paid to the rehabilitation process and to the decision on when to allow return to sports. These decisions should also consider cartilage fragility and functional adaptations after surgery. In this respect, the first years following surgery are of paramount importance for prevention or treatment strategies that aim at impediment of further matrix deterioration. Considering the low number of studies and the methodological caveats, more research is needed. PMID- 23685096 TI - Basic psychometric properties of the transfer assessment instrument (version 3.0). AB - OBJECTIVES: To refine the Transfer Assessment Instrument (TAI 2.0), develop a training program for the TAI, and analyze the basic psychometric properties of the TAI 3.0, including reliability, standard error of measurement (SEM), minimal detectable change (MDC), and construct validity. DESIGN: Repeated measures. SETTING: A winter sports clinic for disabled veterans. PARTICIPANTS: Wheelchair users (N=41) who perform sitting-pivot or standing-pivot transfers. INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: TAI version 3.0, intraclass correlation coefficients, SEMs, and MDCs for reliable measurement of raters' responses. Spearman correlation coefficient, 1-way analysis of variance, and independent t tests to evaluate construct validity. RESULTS: TAI 3.0 had acceptable to high levels of reliability (range, .74-.88). The SEMs for part 1, part 2, and final scores ranged from .45 to .75. The MDC was 1.5 points on the 10-point scale for the final score. There were weak correlations (rho range, -.13 to .25; P>.11) between TAI final scores and subjects' characteristics (eg, sex, body mass index, age, type of disability, length of wheelchair use, grip and elbow strength, sitting balance). CONCLUSIONS: With comprehensive training, the refined TAI 3.0 yields high reliability among raters of different clinical backgrounds and experience. TAI 3.0 was unbiased toward certain physical characteristics that may influence transfer. TAI fills a void in the field by providing a quantitative measurement of transfers and a tool that can be used to detect problems and guide transfer training. PMID- 23685097 TI - Effects of visceral fat area and other metabolic parameters on stone composition in patients undergoing percutaneous nephrolithotomy. AB - PURPOSE: Obesity is a risk factor for metabolic syndrome and urolithiasis, particularly uric acid stones. As estimated by visceral fat area, visceral obesity is a more specific measure of the risk of metabolic syndrome than body mass index. We investigated the effects of visceral fat area and other metabolic factors on uric acid stone formation in patients treated with percutaneous nephrolithotomy. MATERIALS AND METHODS: We retrospectively reviewed the records of 269 patients who underwent percutaneous nephrolithotomy. Visceral fat area was measured in each patient on a CT axial slice at the umbilical level using the Aquarius iNtuition fat analysis tool. Analysis was performed to determine the effect of visceral fat area and other comorbidities on uric acid stone formation. RESULTS: Of the 269 patients analyzed there was no difference in baseline comorbidities between uric acid and nonuric acid stone formers. Patients with uric acid stones had a significantly higher mean visceral fat area (209.3 vs 161.9 cm2, p = 0.001), and rates of hypertension (67.4% vs 47.3%) and coronary artery disease (14.3% vs 4.6%, each p = 0.011). On logistic regression analysis hypertension (OR 2.16, 95% CI 1.05-4.45, p = 0.04) and a high visceral fat area (OR 3.64, 95% CI 1.22-10.85, p = 0.02) were independent risk factors for uric acid stones. CONCLUSIONS: As a marker of visceral obesity, visceral fat area contributes to the risk of metabolic syndrome and urolithiasis. Uric acid stone formers showed a significantly higher hypertension rate and mean visceral fat area, which were independent risk factors for uric acid urolithiasis. Evaluating these characteristics in stone formers may facilitate a tailored metabolic assessment and treatment plan. PMID- 23685098 TI - Digoxin toxicity with normal digoxin and serum potassium levels: beware of magnesium, the hidden malefactor. AB - BACKGROUND: In recent years, digoxin use has been on the decline, with decreased incidence of digoxin toxicity. Hence, digoxin toxicity, when it occurs, remains an elusive diagnosis to emergency physicians. OBJECTIVE: To present a case of digoxin toxicity with normal levels of digoxin and serum potassium, but with severe hypomagnesemia. CASE REPORT: A 66-year-old woman presented with junctional tachycardia and ectopic atrial tachycardia. She was known to have congestive cardiac failure on diuretic therapy. Her serum digoxin level was within the normal range (2.4 nmol/L [normal = 1.9-2.6]) along with a normal serum potassium level (3.9 mmol/L [normal = 3.5-5]). However, there was severe hypomagnesemia (0.39 mmol/L [normal = 0.65-1.25]) precipitating digoxin-induced dysrhythmia, which responded well to intravenous magnesium therapy. CONCLUSION: This case reiterates that digoxin toxicity can occur in patients with normal digoxin and potassium levels, and in such patients, magnesium needs to be checked and treated to prevent potentially life-threatening dysrhythmias. PMID- 23685099 TI - The efficacy of automated intermittent boluses for continuous femoral nerve block: a prospective, randomized comparison to continuous infusions. AB - STUDY OBJECTIVE: To determine whether an automated intermittent bolus technique provides enhanced analgesia compared with a continuous infusion for femoral nerve block. DESIGN: Prospective, single-blinded, randomized controlled trial (ClinicalTrials.gov Identifier: NCT01226927). SETTING: Perioperative areas and orthopedic surgical ward of a university hospital. PATIENTS: 45 ASA physical status 1, 2, and 3 patients undergoing unilateral primary total knee arthroplasty. INTERVENTIONS: All patients received single-injection sciatic and femoral nerve blocks plus femoral nerve catheter placement for postoperative analgesia. Patients were randomly assigned to an automated intermittent bolus (5 mL every 30 min with 0.1 mL/hr basal rate) or a continuous infusion (10.1 mL/hr) delivery method of 0.2% ropivacaine. MEASUREMENTS: Consumption of intravenous patient-controlled analgesia (IV-PCA) and visual analog scale (VAS) pain scores were assessed postoperatively at set intervals until the morning of postoperative day (POD) 2. MAIN RESULTS: The mean (SEM) cumulative IV-PCA dose (mg of hydromorphone) for the 36-hour postoperative interval measured was 12.9 +/- 2.32 in the continuous infusion rate group (n = 20) and 7.8 +/- 1.02 in the intermittent bolus group [n = 21, t(39) = 2.04, P = 0.048; a 39 +/- 14% difference in total usage]. Pain scores were statistically significantly lower in the intermittent bolus group in the afternoon of POD 1 (t(39) = 2.47, P = 0.018), but were otherwise similar. CONCLUSIONS: An automated intermittent bolus infusion technique for femoral nerve catheters is associated with clinically and statistically significantly less IV-PCA use (ie, an opioid-sparing effect) than a continuous infusion technique. PMID- 23685100 TI - Impact of anesthesia technique on the incidence of major complications after open aortic abdominal surgery: a cohort study. AB - STUDY OBJECTIVE: To determine the risk factors of perioperative complications and the impact of intrathecal morphine (ITM) in major vascular surgery. DESIGN: Retrospective analysis of a prospective cohort. SETTINGS: Operating room, intensive care unit, and Postanesthesia Care Unit of a university hospital. MEASUREMENTS: Data from 595 consecutive patients who underwent open abdominal aortic surgery between January 1997 and December 2011 were reviewed. Data were stratified into three groups based on the analgesia technique delivered: systemic analgesia (Goup SA), thoracic epidural analgesia (Group TEA), and intrathecal morphine (Group ITM). Preoperative patient characteristics, perioperative anesthetic and medical interventions, and major nonsurgical complications were recorded. MAIN RESULTS: Patients managed with ITM (n=248) and those given thoracic epidural analgesia (n=70) required lower doses of intravenous (IV) sufentanil intraoperatively and were extubated sooner than those who received systemic analgesia (n=270). Total inhospital mortality was 2.9%, and 24.4% of patients experienced at least one major complication during their hospital stay. Intrathecal morphine was associated with a lower risk of postoperative morbidity (OR 0.51, 95% CI 0.28 - 0.89), particularly pulmonary complications (OR 0.54, 95% CI 0.31 - 0.93) and renal dysfunction (OR 0.52, 95% CI 0.29 - 0.97). Other predictors of nonsurgical complications were ASA physical status 3 and 4 (OR 1.94, 95% CI 1.07 - 3.52), preoperative renal dysfunction (OR 1.61, 95% CI 1.01 - 2.58), prolonged surgical time (OR 1.78, 95% CI 1.16 - 2.78), and the need for blood transfusion (OR 1.77, 95% CI 1.05 - 2.99). CONCLUSIONS: This single-center study showed a decreased risk of major nonsurgical complications in patients who received neuraxial analgesia after abdominal aortic surgery. PMID- 23685101 TI - Accuracy of the CNAP monitor, a noninvasive continuous blood pressure device, in providing beat-to-beat blood pressure readings in the prone position. AB - STUDY OBJECTIVE: To assess the accuracy of a noninvasive continuous arterial pressure (CNAP) monitor in patients who are positioned prone in the operating room. DESIGN: Prospective study. SETTING: Operating room at a children's hospital. PATIENTS: 20 pediatric patients, aged 13.8 +/- 2 years, and weight 63.7 +/- 18.8 kg, scheduled for surgery in the prone position, and for which arterial catheter placement was planned. INTERVENTIONS: Measurements were recorded with an arterial line (AL) and a new noninvasive continuous blood pressure (BP) monitor. MEASUREMENTS: Systolic (SBP), diastolic (DBP), and mean arterial (MAP) pressure readings were captured from an arterial cannula and the CNAP device every minute during anesthesia. MAIN RESULTS: The study cohort consisted of analysis of 4104 pairs of SBP, DBP, and MAP values, which showed an absolute difference between the AL and CNAP device readings of 7.9 +/- 6.3 mmHg for SBP, 5.3 +/- 4.3 mmHg for DBP, and 4.6 +/- 3.9 mmHg for MAP. Bland-Altman analysis of MAP values showed a bias of 0.26 mmHg, with upper and lower limits of agreement of 12.18 mmHg and 11.67 mmHg, respectively. CNAP readings deviated from arterial values by <= 5 mmHg in 67% of MAP values, 59% of DBP values, and 43% of SBP readings. The difference was <= 10 mmHg for 94% of MAP readings, 90% of DBP values, and 73% of SBP readings. CONCLUSIONS: During prone positioning, the CNAP monitor provided clinically acceptable accuracy for MAP values, similar to those reported in adults in the supine position. PMID- 23685102 TI - Volume increase and spatial shifts of chromosome territories in nuclei of radiation-induced polyploidizing tumour cells. AB - The exposure of tumour cells to high doses of ionizing radiation can induce endopolyploidization as an escape route from cell death. This strategy generally results in mitotic catastrophe during the first few days after irradiation. However, some cells escape mitotic catastrophe, polyploidize and attempt to undergo genome reduction and de-polyploidization in order to create new, viable para-diploid tumour cell sub-clones. In search for the consequences of ionizing radiation induced endopolyploidization, genome and chromosome architecture in nuclei of polyploid tumour cells, and sub-nuclei after division of bi- or multi nucleated cells were investigated during 7 days following irradiation. Polyploidization was induced in p53-function deficient HeLa cells by exposure to 10Gy of X-irradiation. Chromosome territories #1, #4, #12 and centromeres of chromosomes #6, #10, #X were labelled by FISH and analysed for chromosome numbers, volumes and spatial distribution during 7 days post irradiation. The numbers of interphase chromosome territories or centromeres, respectively, the positions of the most peripherally and centrally located chromosome territories, and the territory volumes were compared to non-irradiated controls over this time course. Nuclei with three copies of several chromosomes (#1, #6, #10, #12, #X) were found in the irradiated as well as non-irradiated specimens. From day 2 to day 5 post irradiation, chromosome territories (#1, #4, #12) shifted towards the nuclear periphery and their volumes increased 16- to 25-fold. Consequently, chromosome territories returned towards the nuclear centre during day 6 and 7 post irradiation. In comparison to non-irradiated cells (~500MUm(3)), the nuclear volume of irradiated cells was increased 8-fold (to ~4000MUm(3)) at day 7 post irradiation. Additionally, smaller cell nuclei with an average volume of about ~255MUm(3) were detected on day 7. The data suggest a radiation-induced generation of large intra-nuclear chromosome territories and their repositioning prior to genome reduction. PMID- 23685103 TI - Effect of cardiac output changes on exhaled carbon dioxide in newborn piglets. AB - INTRODUCTION: International neonatal resuscitation guidelines recommend that correct tube placement should be confirmed by clinical assessment and exhaled CO2 detection. Absence of exhaled CO2 after intubation suggests oesophageal intubation, non-aerated lungs, low tidal volume delivery, or low cardiac output. The relationship between changes in cardiac output and exhaled CO2 in neonates is unknown. The aim of the study was to determine if changes in cardiac output affect exhaled carbon dioxide in a porcine model of neonatal resuscitation. METHOD: Term piglets (n=5) aged 3-4 days were anesthetised, intubated, instrumented and exposed to normocapnic hypoxia. Exhaled CO2 was continuously measured using a flow sensor (Respironics NM3((r))). Pulmonary artery blood flow, a surrogate for cardiac output was measured using an ultrasonic flow probe (Transonic((r))). A semi-quantitative CO2-detector (Pedi-Cap((r))) was placed between the tracheal tube and flow sensor to assess colour change at changing levels of cardiac output. RESULTS: Median (IQR) pulmonary artery blood flow significantly decreased from 177 (147-177)mL/kg/min at baseline to 4 (3 26)mL/kg/min during hypoxia (p=0.02). Exhaled CO2 remained similar throughout the experiment, 47 (41-47)mmHg at baseline vs. 40 (38-41)mmHg at the end of the hypoxia (p=1.00). Additionally, at each time point, colour change at the Pedi Cap((r)) was observed. CONCLUSION: A significant decrease in cardiac output was not associated with changes in exhaled CO2 or failure to achieve a Pedi-Cap((r)) colour change. PMID- 23685104 TI - Clinical features of brain metastasis from salivary gland tumors. AB - Salivary gland tumors comprise a group of 24 tumor subtypes with a wide range of clinical behaviors and propensities for metastasis. Several prognostic factors have been identified that help predict the development of systemic metastases, most commonly to the lung, liver, or bone. Metastases to the brain are rare. To better understand the behavior of salivary gland tumors that metastasise to the brain, we performed a retrospective cohort analysis on a series of patients to highlight features of their medical and surgical management. From 2007 to 2011, a database of 4117 elective craniotomies were queried at a single institution to identify patients surgically treated for salivary gland metastases to the brain. Three patients were identified. Histologic subtypes included salivary duct carcinoma, poorly differentiated carcinoma, and papillary mucinous adenocarcinoma. They had all undergone previous treatment for their primary malignancy. The mean time to intracranial metastasis was 48 months from initial diagnosis (range, 14-91 months). Treatment for intracranial metastases included surgical resection, whole brain radiation, stereotactic radiosurgery, and chemotherapy. Intracranial metastases from salivary gland tumors are rare, present years after diagnosis of the primary tumor, and are treatable with multimodality therapy. PMID- 23685105 TI - Relationship between left atrial volume index and cognitive decline in elderly patients with sinus rhythm. AB - Left atrial (LA) enlargement is a predictor of cardiovascular outcomes such as atrial fibrillation (AF), stroke, and death. The aim of this study was to explore the relationship between LA size and cognitive function in elderly patients without any signs of clinical dementia, AF or previous stroke. We assessed the cognitive status and LA volume (LAV) of 108 consecutive patients (27 males; mean age, 74.8 +/- 6.9 years) with sinus rhythm. Cognitive status was assessed by the Mini Mental State Examination (MMSE). Patients with a MMSE score of <=25 were considered to have cognitive impairment. LAV was measured with two-dimensional echocardiography. LAV index (LAVI) was obtained by indexing LAV to body surface area. Thirty-five patients (32.4%) had cognitive impairment. The patients with cognitive impairment had significantly larger left atria than the patients with normal cognitive function. Receiver operating characteristic analysis revealed a cut-off point of >= 34 mL/m(2) for LAVI to predict patients with cognitive impairment (sensitivity, 97.1%; specificity, 52.1%; positive predictive value, 49.3%; negative predictive value, 97.4%). LAVI >=34 mL/m(2) was significantly associated with cognitive impairment (p = 0.001, odds ratio = 36.91, 95% confidence interval = 4.8-284.2). Logistic regression analysis revealed that LAVI >= 34 mL/m(2) and age were independently associated with cognitive impairment. Increased LAVI is associated with cognitive impairment. Assessment of cognitive function may be recommended in elderly patients with enlarged left atria. PMID- 23685106 TI - Pattern of cerebrovascular atherosclerotic stenosis in older Chinese patients with stroke. AB - The clinical pattern and angiographic distribution of cerebral atherosclerosis varies among different ethnic groups. This study was designed to identify the clinical background for intracranial and extracranial atherosclerotic stenosis in older eastern Chinese patients using digital subtraction angiography. We retrospectively reviewed the data collected from the Nanjing Stroke Registry Program, from January 2004 to March 2011. The analysis focused on the intracranial or extracranial location of stenosis in the anterior and posterior circulations. In total, records of 1041 patients were included in the study. Of these patients, 19.88% had intracranial carotid stenosis, 18.73% had stenosis in the extracranial vessels, and 33.33% had concurrent stenoses. A total of 2002 stenotic sites were detected in 749 patients. Among those patients with stenosis, a single stenosis was found in 170 (16.33%) and multiple stenoses were found in 579 (55.62%). The prevalence of intracranial stenosis in the single-stenosis group was 54.12%, while in the multiple-stenosis group it was 47.87% (p=0.127). A higher incidence of severe stenosis (70-99% blockage) and occlusion was found in the intracranial vessels than in the extracranial vessels (p=0.018). Older Chinese patients with atherosclerotic stenosis tend to have more intracranial stenoses. PMID- 23685108 TI - Aspergillus arachnoiditis post intrathecal baclofen pump insertion. AB - This report describes an unusual fungal infection of an intrathecal baclofen pump which, to our knowledge, has not been reported previously. We describe a 39-year old man with severe lower limb spasticity due to secondary progressive multiple sclerosis that was managed with insertion of an intrathecal baclofen pump. He subsequently presented with distinct neurological decline secondary to an intrathecal baclofen pump infection with Aspergillus terreus. PMID- 23685107 TI - Non-contrast 3D time-of-flight magnetic resonance angiography for visualization of intracranial aneurysms in patients with absolute contraindications to CT or MRI contrast. AB - The preoperative evaluation of patients with intracranial aneurysms typically includes a contrast-enhanced vascular study, such as computed tomography angiography (CTA), magnetic resonance angiography (MRA), or digital subtraction angiography. However, there are numerous absolute and relative contraindications to the administration of imaging contrast agents, including pregnancy, severe contrast allergy, and renal insufficiency. Evaluation of patients with contrast contraindications thus presents a unique challenge. We identified three patients with absolute contrast contraindications who presented with intracranial aneurysms. One patient was pregnant, while the other two had previous severe anaphylactic reactions to iodinated contrast. Because of these contraindications to intravenous contrast, we performed non-contrast time-of-flight MRA with 3D reconstruction (TOF MRA with 3DR) with maximum intensity projections and volume renderings as part of the preoperative evaluation prior to successful open surgical clipping of the aneurysms. In the case of one paraclinoid aneurysm, a high-resolution non-contrast CT scan was also performed to assess the relationship of the aneurysm to the anterior clinoid process. TOF MRA with 3DR successfully identified the intracranial aneurysms and adequately depicted the surrounding microanatomy. Intraoperative findings were as predicted by the preoperative imaging studies. The aneurysms were successfully clip-obliterated, and the patients had uneventful post-operative courses. These cases demonstrate that non-contrast imaging is a viable modality to assess intracranial aneurysms as part of the surgical planning process in patients with contrast contraindications. TOF MRA with 3DR, in conjunction with high-resolution non contrast CT when indicated, provides adequate visualization of the microanatomy of the aneurysm and surrounding structures. PMID- 23685109 TI - Intracellularly-retained decorin lacking the C-terminal ear repeat causes ER stress: a cell-based etiological mechanism for congenital stromal corneal dystrophy. AB - Decorin, a small leucine-rich proteoglycan (SLRP), is involved in the pathophysiology of human congenital stromal corneal dystrophy (CSCD). This disease is characterized by corneal opacities and vision impairment. In reported cases, the human gene encoding decorin contains point mutations in exon 10, generating a truncated form of decorin lacking the C-terminal 33 amino acid residues. We have previously described a transgenic mouse model carrying a similar mutation in the decorin gene that leads to an ocular phenotype characterized by corneal opacities identical to CSCD in humans. We have also identified abnormal synthesis and secretion of various SLRPs in mutant mouse corneas. In the present study, we found that mutant C-terminal truncated decorin was retained in the cytoplasm of mouse keratocytes in vivo and of transfected human embryonic kidney cells. This resulted in endoplasmic reticulum stress and an unfolded protein response. Thus, we propose a novel cell-based mechanism underlying CSCD in which a truncated SLRP protein core is retained intracellularly, its accumulation triggering endoplasmic reticulum stress that results in abnormal SLRP synthesis and secretion, which ultimately affects stromal structure and corneal transparency. PMID- 23685111 TI - Mutational control of bioenergetics of bacterial reaction center probed by delayed fluorescence. AB - The free energy gap between the metastable charge separated state P(+)QA(-) and the excited bacteriochlorophyll dimer P* was measured by delayed fluorescence of the dimer in mutant reaction center proteins of the photosynthetic bacterium Rhodobacter sphaeroides. The mutations were engineered both at the donor (L131L, M160L, M197F and M202H) and acceptor (M265I and M234E) sides. While the donor side mutations changed systematically the number of H-bonds to P, the acceptor side mutations modified the energetics of QA by altering the van-der-Waals and electronic interactions (M265IT) and H-bond network to the acidic cluster around QB (M234EH, M234EL, M234EA and M234ER). All mutants decreased the free energy gap of the wild type RC (~890meV), i.e. destabilized the P(+)QA(-) charge pair by 60 110meV at pH8. Multiple modifications in the hydrogen bonding pattern to P resulted in systematic changes of the free energy gap. The destabilization showed no pH-dependence (M234 mutants) or slight increase (WT, donor-side mutants and M265IT above pH8) with average slope of 10-15meV/pH unit over the 6-10.5pH range. In wild type and donor-side mutants, the free energy change of the charge separation consisted of mainly enthalpic term but the acceptor side mutants showed increased entropic (even above that of enthalpic) contributions. This could include softening the structure of the iron ligand (M234EH) and the QA binding pocket (M265IT) and/or increase of the multiplicity of the electron transfer of charge separation in the acceptor side upon mutation. PMID- 23685112 TI - [Evolution of the diet from the paleolithic to today: progress or regress?]. AB - The changes in eating habits and decreased physical activity have been responsible for part of the high prevalence of chronic diseases such as hypertension or diabetes, currently observed in the so-called civilized societies. These diseases are less prevalent in previous civilizations and several decades of nutrition research have enabled better understanding of the eating habits of our ancestors, and have demonstrated the value of diet called "Mediterranean or Paleolithic". This review provides an update on the latest research. What dietary changes since the Paleolithic period, and finally how can we adapt our current diet? Several animal studies or human clinical demonstrate the value of historical research and nutrition. PMID- 23685113 TI - Chronic scrotal and inguinal pain after orchidopexy in a 13-year-old boy, treated by pulsed radiofrequency of the dorsal ganglia. AB - Chronic scrotal pain can be a difficult clinical entity to treat. Many different treatment options have been proposed. We describe the case of a young boy with chronic scrotal and inguinal pain on the right side, following two orchidopexies. After many therapies had failed, we treated the dorsal root ganglia of thoracic 12, lumbar 1 and lumbar 2 with pulsed radiofrequency, finally resulting in alleviation of his pain. PMID- 23685110 TI - Chitinase inhibition promotes atherosclerosis in hyperlipidemic mice. AB - Chitinase 1 (CHIT1) is secreted by activated macrophages. Chitinase activity is raised in atherosclerotic patient sera and is present in atherosclerotic plaque. However, the role of CHIT1 in atherosclerosis is unknown. Preliminary studies of atherosclerosis in cynomolgous monkeys revealed CHIT1 to be closely correlated with areas of macrophage infiltration. Thus, we investigated the effects of a chitinase inhibitor, allosamidin, on macrophage function in vitro and on atherosclerotic development in vivo. In RAW264.7 cells, allosamidin elevated monocyte chemoattractant protein 1 and tumor necrosis factor alpha expression, and increased activator protein 1 and nuclear factor-kappaB transcriptional activity. Although inducible nitric oxide synthase, IL-6, and IL-1beta expression were increased, Arg1 expression was decreased by chitinase inhibition, suggesting that suppression of CHIT1 activity polarizes macrophages into a M1 phenotype. Allosamidin decreased scavenger receptor AI, CD36, ABCA1, and ABCG1 expression which led to suppression of cholesterol uptake and apolipoprotein AI-mediated cholesterol efflux in macrophages. These effects were confirmed with CHIT1 siRNA transfection and CHIT1 plasmid transfection experiments in primary macrophages. Apolipoprotein E-deficient hyperlipidemic mice treated for 6 weeks with constant administration of allosamidin and fed an atherogenic diet showed aggravated atherosclerotic lesion formation. These data suggest that CHIT1 exerts protective effects against atherosclerosis by suppressing inflammatory responses and polarizing macrophages toward an M2 phenotype, and promoting lipid uptake and cholesterol efflux in macrophages. PMID- 23685114 TI - Reduced bacterial colonisation of the glans penis after male circumcision in children--a prospective study. AB - OBJECTIVE: The aim of this prospective study was to evaluate the effect of male circumcision on the bacterial colonisation of the glans penis in children. PATIENTS AND METHODS: 244 males were included in this study. The study group consisted of 143 boys admitted for circumcision between August 2009 and July 2010. Periurethral swabs were taken preoperatively and one week postoperatively. The control group included 101 boys without phimosis, in which only one swab was taken. Patients were subgrouped according to age below and above five years. Bacterial cultures were analysed, results were categorized by non-uropathogenic and uropathogenic bacteria, and compared within and between groups. RESULTS: Patients in both control group and study group before circumcision showed significant bacterial colonisation (>98%), involving known uropathogenic bacteria in over 86%. After circumcision, bacterial colonisation dropped from 100% to 86.3% (p < 0.005) in boys younger than five years and from 98.57% to 77.14% (p < 0.001) in those aged five or above, respectively. Moreover, the fraction of uropathogenic bacteria decreased significantly. CONCLUSION: Male circumcision significantly reduces the bacterial colonisation of the glans penis with regard to both non-uropathogenic and uropathogenic bacteria. PMID- 23685115 TI - Genetic toxicity of high-boiling petroleum substances. AB - There are several specific types of high-boiling petroleum substances (HBPS) having final boiling points >343 degrees C), in which genetic toxicity can be related to the content of polycyclic aromatic compounds (PACs), specifically crude oils, gas oils, heavy fuel oils, lubricant base oils, waxes and aromatic extracts. Evaluation of optimized Salmonella tests covering over 250 samples from 43 types of HBPS revealed that gene mutation can be determined for these substances using a protocol optimized for the detection of mutagenic PAC. The outcomes of modified Salmonella assays can be predicted using HBPS compositional information as input to a newly developed statistical model. The general outcome of the optimized Salmonella assay can be predicted for an untested substance based on its Aromatic Ring Class (ARC) profile. Review of the results from numerous cytogenetic tests showed that although a few positive study results have been reported, most HBPS do not produce chromosomal effects when tested in rodent bone marrow assays or in in vitro chromosomal aberration assays. Results of both bacterial and cytogenetic studies can be used to satisfy genetic toxicity endpoints for the HBPS category substances. PMID- 23685116 TI - Trans-resveratrol loaded chitosan nanoparticles modified with biotin and avidin to target hepatic carcinoma. AB - Conventional liver targeted system focuses on delivering drugs to liver, bringing toxicity on hepatic normal tissues. The purpose of this study is to construct a new system capable of specially targeting to hepatic carcinoma instead of the whole liver. Based on the fact that nanoparticles (NPs) bound with either biotin or avidin tend to accumulate in tumors and avidin-attached reagents were quickly eliminated from blood circulation and assembled in liver, trans-resveratrol loaded chitosan nanoparticles (CS-NPs), CS-NPs with the surface modified either by biotin (B-CS-NPs) or by both biotin and avidin (A-B-CS-NPs) were prepared and their physiochemical properties were investigated. The in vitro release profiles of the three NPs all conformed to bioexponential equation. Pharmacokinetic experiment indicated that A-B-CS-NPs rapidly assembled in liver after injection, with the highest liver targeting index of 2.70, while the modification of biotin attenuated the liver targeting ability of NPs. Inhibitory study on HepG2 cells declared that compared to trans-resveratrol solution and CS-NPs, both B-CS-NPs and A-B-CS-NPs significantly improved the anticancer activity. When incubated with HepG2 cells at high concentration for longer time, A-B-CS-NPs exhibited superior cytotoxicity than B-CS-NPs. This study exclaims that A-B-CS-NPs may be a potent drug delivery vector specially targeting to hepatic carcinoma. PMID- 23685117 TI - Effects of beauvericin, enniatin b and moniliformin on human dendritic cells and macrophages: an in vitro study. AB - The aim of this study was to assess the in vitro effects of emerging mycotoxins beauvericin, enniatin B and moniliformin on human dendritic cells and macrophages. Beauvericin and enniatin B were cytotoxic on these cells. IC50 were equal to 1.0 MUM, 2.9 MUM and 2.5 MUM beauvericin for immature dendritic cells, mature dendritic cells and macrophages, respectively. IC50 were equal to 1.6 MUM, 2.6 MUM and 2.5 MUM for immature dendritic cells, mature dendritic cells and macrophages exposed to enniatin B, respectively. Effects on the differentiation process of monocytes into macrophages or into immature dendritic cells as well as effects on dendritic cells maturation have been studied. The differentiation process of monocytes into immature dendritic cells was not disturbed in the presence of beauvericin. Dendritic cells exposed to beauvericin during the maturation process presented a decrease of CCR7 expression and an increase of IL 10 secretion. Monocytes exposed to beauvericin during the differentiation process into macrophages presented a decrease of endocytosis ability. The differentiation process of monocytes into immature dendritic cells was not disturbed in the presence of enniatin B. Dendritic cells exposed to enniatin B during the maturation process presented a decrease of expression of the maturation makers CD80, CD86 and CCR7 and an increase of IL-10 secretion. Monocytes exposed to enniatin B during the differentiation process into macrophages presented a decrease of endocytosis ability and an increase of CD71. CD1a expression and endocytosis capacity were decreased on immature dendritic cells exposed to moniliformin. Monocytes-derived macrophages exposed to moniliformin during the differentiation process presented a decrease of endocytosis ability, and a decrease of CD71 and HLA-DR expression. According to these results, immunological disorders could be observed on human after ingestion of these alimentary toxins. PMID- 23685118 TI - Institutional adaptation to drought: the case of Fars Agricultural Organization. AB - Recurrent droughts in arid and semi-arid regions are already rendering agricultural production, mainstay of subsistence livelihoods, uncertain. In order to mitigate the impact of drought, agricultural organizations must increase their capacity to adapt. Institutional adaptation refers to the creation of an effective, long-term government institution or set of institutions in charge of planning and policy, and its capacity to develop, revise, and execute drought policies. Using the Fars Agricultural Organization in Iran, as a case study, this paper explores the institutional capacities and capabilities, necessary to adapt to the drought conditions. The STAIR model was used as a conceptual tool, and the Bayesian network and Partial Least Squares (PLS) path modeling was applied to explain the mechanisms by which organizational capacities influence drought management. A survey of 309 randomly selected managers and specialists indicated serious weaknesses in the ability of the organization to apply adaptation strategies effectively. Analysis of the causal models illustrated that organizational culture and resources and infrastructure significantly influenced drought management performance. Moreover, managers and specialists perceived human resources and strategy, goals, and action plan, respectively, as the main drivers of institutional adaptation to drought conditions. Recommendations and implications for drought management policy are offered to increase organizational adaptation to drought and reduce the subsequent sufferings. PMID- 23685119 TI - Are incentive programs working? Landowner attitudes to ecological restoration of agricultural landscapes. AB - Private property accounts for much of the planet's arable land, and most of this has been cleared for agricultural production. Agricultural areas retain only fragments of their original vegetation and this has been detrimental to many native plant and animal species. Habitat restoration and revegetation may be able to reconnect and enlarge existing remnant areas in agricultural landscapes and, thereby, enhance native plant and animal communities. However, conservation initiatives will be successful only if landowners actively participate in restoration actions. This study used four hundred postal questionnaires to assess the degree to which landowners in two regions of south-eastern Australia adopt restoration activities, their opinions regarding remnant and revegetated land and their management actions in these areas. One hundred and seventy nine completed questionnaires were received. Three quarters of respondents had undertaken restoration on their property or were planning to revegetate in the future. Landcare members were most likely to have previously revegetated and future revegetation intentions were best predicted by previous restoration activities and a primary income source that was off-farm. Landowners were more likely to manage restored and remnant areas if they perceived threats such as weeds, pest animals and fire risk would be detrimental to their property, than to enhance environmental outcomes. These results indicate that landowners are interested in restoring natural areas, but without greater assistance to restore ground layers and manage perceived threats posed by fire and invasive plants and animals, restoration actions will not have their desired biodiversity benefits. PMID- 23685120 TI - Bioremediation: how to deal with removal efficiency uncertainty? An economic application. AB - Bioremediation is a remediation strategy, which has considerable strength but also certain limitations. Complex and uncertain relationships among biomass, contaminants, and nutrients lead to an uncertain level of removal efficiency. The uncertainty inherent to a bioremediation strategy should be addressed in the remediation selection process. In order to evaluate the bioremediation strategy economically, this study takes into account the reversibility of a decision. A decision tree structures the different remediation strategies, thus giving the possible courses of action open to the decision maker. The option value indicates the importance of having the possibility to reverse a previously made decision. Compared with conventional economic evaluation tools, more information to ground the selection made is revealed. PMID- 23685121 TI - Performance and prospects of payments for ecosystem services programs: evidence from China. AB - Systematic evaluation of the environmental and socioeconomic effects of Payments for Ecosystem Services (PES) programs is crucial for guiding policy design and implementation. We evaluated the performance of the Natural Forest Conservation Program (NFCP), a national PES program of China, in the Wolong Nature Reserve for giant pandas. The environmental effects of the NFCP were evaluated through a historical trend (1965-2001) analysis of forest cover to estimate a counter factual (i.e., without-PES) forest cover baseline for 2007. The socioeconomic effects of the NFCP were evaluated using data collected through household interviews carried out before and after NFCP implementation in 2001. Our results suggest that the NFCP was not only significantly associated with increases in forest cover, but also had both positive (e.g., labor reduction for fuelwood collection) and negative (e.g., economic losses due to crop raiding by wildlife) effects on local households. Results from this study emphasize the importance of integrating local conditions and understanding underlying mechanisms to enhance the performance of PES programs. Our findings are useful for the design and implementation of successful conservation policies not only in our study area but also in similar places around the world. PMID- 23685122 TI - Neuroticism and the brain: a quantitative meta-analysis of neuroimaging studies investigating emotion processing. AB - Neuroticism is a robust personality trait that constitutes a risk factor for mood disorders. Neuroimaging findings related to neuroticism have been inconsistent across studies and hardly integrated in order to construct a model of the underlying neural correlates of neuroticism. The aim of the current meta-analysis was to provide a quantitative summary of the literature, using a parametric coordinate-based meta-analysis (PCM) approach. Data were pooled for emotion processing tasks investigating the contrasts (negative>neutral) and (positive>neutral) to identify brain regions that are consistently associated with neuroticism across studies. Significant negative and positive correlations with neuroticism were found only for the contrast (negative>neutral) after multiple comparisons correction. Differences in brain activation were found to be associated with neuroticism during fear learning, anticipation of aversive stimuli and the processing and regulation of emotion. The relationship between neuroticism and these three psychological processes and their corresponding neural correlates is discussed. Furthermore, the meta-analytic findings are incorporated into a general model of emotion processing in neuroticism. PMID- 23685123 TI - Surfactins modulate the lateral organization of fluorescent membrane polar lipids: a new tool to study drug:membrane interaction and assessment of the role of cholesterol and drug acyl chain length. AB - The lipopeptide surfactin exhibits promising antimicrobial activities which are hampered by haemolytic toxicity. Rational design of new surfactin molecules, based on a better understanding of membrane:surfactin interaction, is thus crucial. We here performed bioimaging of lateral membrane lipid heterogeneity in adherent living human red blood cells (RBCs), as a new relevant bioassay, and explored its potential to better understand membrane:surfactin interactions. RBCs show (sub)micrometric membrane domains upon insertion of BODIPY analogs of glucosylceramide (GlcCer), sphingomyelin (SM) and phosphatidylcholine (PC). These domains exhibit increasing sensitivity to cholesterol depletion by methyl-beta cyclodextrin. At concentrations well below critical micellar concentration, natural cyclic surfactin increased the formation of PC and SM, but not GlcCer, domains, suggesting preferential interaction with lipid assemblies with the highest vulnerability to methyl-beta-cyclodextrin. Surfactin not only reversed disappearance of SM domains upon cholesterol depletion but further increased PC domain abundance over control RBCs, indicating that surfactin can substitute cholesterol to promote micrometric domains. Surfactin sensitized excimer formation from PC and SM domains, suggesting increased lipid recruitment and/or diffusion within domains. Comparison of surfactin congeners differing by geometry, charge and acyl chain length indicated a strong dependence on acyl chain length. Thus, bioimaging of micrometric lipid domains is a visual powerful tool, revealing that intrinsic lipid domain organization, cholesterol abundance and drug acyl chain length are key parameters for membrane:surfactin interaction. Implications for surfactin preferential location in domains or at their boundaries are discussed and may be useful for rational design of better surfactin molecules. PMID- 23685124 TI - Progressive stages of mitochondrial destruction caused by cell toxic bile salts. AB - The cell-toxic bile salt glycochenodeoxycholic acid (GCDCA) and taurochenodeoxycholic acid (TCDCA) are responsible for hepatocyte demise in cholestatic liver diseases, while tauroursodeoxycholic acid (TUDCA) is regarded hepatoprotective. We demonstrate the direct mitochondrio-toxicity of bile salts which deplete the mitochondrial membrane potential and induce the mitochondrial permeability transition (MPT). The bile salt mediated mechanistic mode of destruction significantly differs from that of calcium, the prototype MPT inducer. Cell-toxic bile salts initially bind to the mitochondrial outer membrane. Subsequently, the structure of the inner boundary membrane disintegrates. And it is only thereafter that the MPT is induced. This progressive destruction occurs in a dose- and time-dependent way. We demonstrate that GCDCA and TCDCA, but not TUDCA, preferentially permeabilize liposomes containing the mitochondrial membrane protein ANT, a process resembling the MPT induction in whole mitochondria. This suggests that ANT is one decisive target for toxic bile salts. To our knowledge this is the first report unraveling the consecutive steps leading to mitochondrial destruction by cell-toxic bile salts. PMID- 23685125 TI - Microstructural evolution and nanoscale crystallography in scleractinian coral spherulites. AB - One of the most important aspects in the research on reef-building corals is the process by which corals accrete biogenic calcium carbonate. This process leads to the formation of a mineral/organic composite and it is believed that the development of the nano- and microstructure of the mineral phase is highly sensitive to the growth conditions. Transmission electron microscopy (TEM) analysis of large-scale (10*30MUm) focused ion beam (FIB) prepared lamellae was performed on adult and juvenile scleractinian coral skeleton specimens. This allowed for the investigation of the nano and microstructure and the crystallographic orientation of the aragonite mineral. We found the following microstructural evolution in the adult Porites lobata specimens: randomly oriented nanocrystals with high porosity, partly aligned nanocrystals with high porosity and areas of dense acicular crystals of several micrometers extension, the latter two areas are aligned close to the [001] direction (Pmcn space group). To the best of our knowledge, for the first time the observed microstructure could be directly correlated with the dark/bright bands characteristic of the diurnal growth cycle. We hypothesize that this mineral structure sequence and alignment in the adult specimen is linked to the photosynthetic diurnal cycle of the zooxanthellea regulating the oxygen levels and organic molecule transport to the calcifying medium. These observations reveal a strong control of crystal morphology by the organism and the correlation of the accretion process. No indication for a self-assembly of nanocrystalline units, i.e., a mesocrystal structure, on the micrometer scale could be found. PMID- 23685126 TI - Genetic basis and evolutionary causes of colour variation in vertebrates. PMID- 23685127 TI - Symmetries and asymmetries associated with non-random segregation of sister DNA strands in Escherichia coli. AB - The successful inheritance of genetic information across generations is a complex process requiring replication of the genome and its faithful segregation into two daughter cells. At each replication cycle there is a risk that new DNA strands incorporate genetic changes caused by miscopying of parental information. By contrast the parental strands retain the original information. This raises the intriguing possibility that specific cell lineages might inherit "immortal" parental DNA strands via non-random segregation. If so, this requires an understanding of the mechanisms of non-random segregation. Here, we review several aspects of asymmetry in the very symmetrical cell, Escherichia coli, in the interest of exploring the potential basis for non-random segregation of leading- and lagging-strand replicated chromosome arms. These considerations lead us to propose a model for DNA replication that integrates chromosome segregation and genomic localisation with non-random strand segregation. PMID- 23685128 TI - Halofuginone suppresses T cell proliferation by blocking proline uptake and inducing cell apoptosis. AB - Inactivation of T cells is a widely used strategy for immunosuppression. Halofuginone (HF) is an antiprotozoal agent for treating parasites in veterinary medicine, and has been demonstrated to inhibit collagen type 1 synthesis, T helper 17 cell differentiation and cytokine production in activated T cells. The present study was designed to examine the biological effects of HF against T cell receptor and interleukin (IL)-2 stimulated T cell proliferation. T cell proliferation in cultured murine splenocytes was determined by methylthiazol tetrazolium assay. Cell apoptosis was mainly determined by fluorescence-activated cell sorting with Annexin-V and 7-aminoactinomycin D staining. Here, we showed that HF significantly suppressed T cell proliferation in naive splenocyte cultures in response to alloantigen or anti-CD3 antibody (IC50, 2-2.5 nM; P<0.0001), or in activated T cell cultures in response to IL-2 (IC50, 16 nM; P<0.0001) in a dose-dependent manner. HF did neither attenuate IL-2 production in anti-CD3 antibody activated T cells nor disrupt STAT5 signaling in IL-2 stimulated T cells, but its anti-T cell proliferation was correlated with an increase in cell apoptosis and a decrease in proline uptake in culture medium. Further experiments showed that proline supplement in cell culture medium significantly prevented HF-mediated suppression of T cell proliferation and cell apoptosis. In conclusion, these data suggest that HF interferes with proline incorporation or uptake, resulting in apoptosis via amino acid starvation response in T cells in the response to antigen/mitogen or IL-2 stimulation. PMID- 23685130 TI - Enhanced odor discrimination learning in aged Bax-KO mice. AB - Throughout life, new neurons are continuously generated from subventricular zone and added to the olfactory bulb (OB). Because a subset of mature OB neurons undergoes spontaneous cell death, adult OB neurogenesis serves for the replacement of this cell loss. Spontaneous cell turnover should alter the neuronal circuits, but the significance of cell turnover on olfactory learning is yet poorly understood. In this study, we explored the olfactory learning behaviors of model mice showing (1) absence of cell death and cell addition (aged Bax-KO mice); (2) absence of cell death but presence of cell addition (young Bax KO mice); or (3) presence cell death but absence of cell addition (surgical lesion of rostral migratory stream of neuroblasts). Interestingly, aged Bax-KO mice with no cell replacement acquired the ability to discriminate odor differences faster than WT littermates, whereas other model mice exhibited virtually normal learning ability. These results suggest that the cell replacement is necessary for the normal olfactory learning behavior, and the chronic perturbation of cell replacement may result in the imbalance of neural circuits driving unexpected enhancement of olfactory learning ability. PMID- 23685129 TI - Agonistic anti-ICAM-1 antibodies in scleroderma: activation of endothelial pro inflammatory cascades. AB - BACKGROUND: Scleroderma (SSc) is a complex autoimmune disorder that can be characterised by the presence 2of circulating autoantibodies to nuclear, cytoplasmic and cell surface antigens. In particular antibodies directed against endothelial cell antigens (anti-endothelial cell antibodies; AECA) have been detected. ICAM-1 is an adhesion molecule expressed on the surface of human endothelial cells. We have previously shown that cross-linking ICAM-1 with monoclonal antibodies leads to pro-inflammatory activation of human endothelial and vascular smooth muscle cells and that cardiac transplant recipients with transplant associated vasculopathy make antibodies directed against ICAM-1. OBJECTIVES: To determine whether SSc patients make antibodies directed against ICAM-1 and whether these antibodies induce pro-inflammatory activation of human endothelial cells in vitro. METHODS: Using recombinant ICAM-1 as capture antigen, an ELISA was developed to measure ICAM-1 antibodies in sera from SSc patients. Antibodies were purified using ICAM-1 micro-affinity columns. HUVEC were incubated with purified anti-ICAM-1 antibodies and generation of reactive oxygen species, and expression of VCAM-1 was measured. RESULTS: Significantly elevated levels of anti-ICAM-1 antibodies were detected in patients with diffuse (dSSc; 10/31 32%) or limited (lSSc; 14/36 39%) scleroderma. Cross-linking of HUVEC with purified anti-ICAM-1 antibodies caused a significant increase in ROS production (2.471+/-0.408 fold increase above untreated after 150 min p<0.001), and significant increase in VCAM-1 expression (10.6+/-1.77% vs 4.12+/-1.33%, p<0.01). CONCLUSION: AECA from SSc patients target specific endothelial antigens including ICAM-1, and cause pro-inflammatory activation of human endothelial cells, suggesting that they are not only a marker of disease but that they contribute to its progression. PMID- 23685131 TI - Ferritin light chain interacts with PEN-2 and affects gamma-secretase activity. AB - Alzheimer's disease (AD) is primarily caused by overproduction/deposition of beta amyloid (Abeta) in the brain. Dysregulation of iron in the brain also contributes to AD. Although iron affects beta-amyloid precursor protein (APP) expression and Abeta deposition, detailed role of iron in AD requires further elucidation. Abeta is produced by sequential proteolytic cleavages of APP by beta-secretase and gamma-secretase. The gamma-secretase complex comprises presenilins (PS1 or PS2), nicastrin, APH-1, and PEN-2. Herein, we find that PEN-2 can interact with ferritin light chain (FTL), an important component of the iron storage protein ferritin. In addition, we show that overexpression of FTL increases the protein levels of PEN-2 and PS1 amino-terminal fragment (NTF) and promotes gamma secretase activity for more production of Abeta and notch intracellular domain (NICD). Furthermore, iron treatments increase the levels of FTL, PEN-2 and PS1 NTF and promote gamma-secretase-mediated NICD production. Moreover, downregulation of FTL decreases the levels of PEN-2 and PS1 NTF. Together, our results suggest that iron can increase gamma-secretase activity through promoting the level of FTL that interacts with and stabilizes PEN-2, providing a new molecular link between iron, PEN-2/gamma-secretase and Abeta generation in AD. PMID- 23685132 TI - Endothelial relaxation mechanisms and nitrative stress are partly restored by Vitamin D3 therapy in a rat model of polycystic ovary syndrome. AB - AIMS: In polycystic ovary syndrome (PCOS), metabolic and cardiovascular dysfunction is related to hyperandrogenic status and insulin resistance, however, Vitamin D3 has a beneficial effect partly due to its anti-oxidant capacity. Nitrative stress is a major factor in the development of cardiovascular dysfunction and insulin resistance in various diseases. Our aim was to determine the effects of vitamin D3 in a rat model of PCOS, particularly the pathogenic role of nitrative stress. MAIN METHODS: Female Wistar rats weighing 100-140g were administered vehicle (C), dihydrotestosterone (DHT) or dihydrotestosterone plus vitamin D3 (DHT+D) (n=10 per group). On the 10th week, acetylcholine (Ach) induced relaxation ability of the isolated thoracic aorta rings was determined. In order to examine the possible role of endothelial nitric oxide synthase (eNOS) and cyclooxygenase-2 (COX-2) pathways in the impaired endothelial function, immunohistochemical labeling of aortas with anti-eNOS and anti-COX-2 antibodies was performed. Leukocyte smears, aorta and ovary tissue sections were also immunostained with anti-nitrotyrosine antibody to determine nitrative stress. KEY FINDINGS: Relaxation ability of aorta was reduced in group DHT, and vitamin D3 partly restored Ach induced relaxation. eNOS labeling was significantly lower in DHT rats compared to the other two groups, however COX-2 staining showed an increment. Nitrative stress showed a significant increase in response to dihydrotestosterone, while vitamin D3 treatment, in case of the ovaries, was able to reverse this effect. SIGNIFICANCE: Nitrative stress may play a role in the pathogenesis of PCOS and in the development of the therapeutic effect of vitamin D3. PMID- 23685133 TI - [Aspergillus ethmoiditis associated with orbital abscess]. AB - The authors report a case of Aspergillus ethmoiditis associated with an orbital abscess, diagnosed in an immunocompetent 6-year-old child, this is a rare infection and diagnosis is difficult, cause of a delayed treatment and frightening prognosis. Mycoses have emerged as important infections in clinical practice; this phenomenon is explained by the ever-growing number of immunocompromised patients and the increasing number of people traveling in areas where fungal diseases are endemic. Surgery with mycological and anatomopathologic examination can suggest a fungal infection confirmed by culture and contribute to institute adequate treatment. PMID- 23685134 TI - HIV-1 fusion protein exerts complex immunosuppressive effects. AB - One of the routes by which HIV-1 is able to escape the immune response is by immunosuppression. The gp41 fusion protein of the HIV-1 envelope mediates virus entry by membrane fusion and also functions as an inhibitor of T cell activation. Here, we review the recent studies suggesting that some of the gp41 immunosuppressive processes are initiated by novel motifs, located within the hydrophobic regions of the protein. This indicates that the immunosuppressive process mediated by gp41 is much more complex than initially thought. Additionally, we propose a model illustrating the interactions and interferences of these regions with the T cell receptor complex. PMID- 23685135 TI - Estuarine ecosystem response to three large-scale Mississippi River flood diversion events. AB - Large inflows of nitrogen (N)-rich freshwater to estuaries can lead to expressions of eutrophication including harmful algal blooms of cyanobacteria (CyanoHABs). Lake Pontchartrain is a large, oligohaline estuary that occasionally receives episodic diversions of N-rich Mississippi River water via the Bonnet Carre Spillway to alleviate flood threats to New Orleans, LA. The extreme flood stage of the Lower Mississippi River in May 2011 prompted the tenth opening of the spillway since 1937. The 2011 opening occurred later in the season than the previous two lower discharge events (1997 and 2008) and was characterized by dissolved inorganic N loads 1.7 and 2.6 times greater than the 1997 and 2008 events, respectively. Rapid depletion of riverine nitrate (21 days) occurred post spillway closure in 2011 with no associated CyanoHAB and was followed by an internal pulse of phosphorus (P) from sediments to restore N-limitation. Our analysis of recent spillway openings indicates that there is not a simple stimulus-response relationship between N loading and CyanoHAB formation. We investigate the systemic causal relationships that determine ecosystem response to these nutrient-rich freshwater inflows and highlight several important parameters including: external N loading, timing, magnitude, plume hydrodynamics, nutrient molar ratios, internal P loading, weather, and northern tributary discharge. Our results suggest that the turbulent, fluctuating environment and nutrient composition during diversions does not favor CyanoHAB formation and that the immense size and timing of the 2011 diversion may have resulted in near complete post-diversion CyanoHAB suppression by hydraulic flushing. PMID- 23685136 TI - Photocatalytic degradation of a widely used insecticide Thiamethoxam in aqueous suspension of TiO2: adsorption, kinetics, product analysis and toxicity assessment. AB - This paper deals with the study of photocatalyzed degradation of an insecticide, Thiamethoxam in aqueous suspension of TiO2. The adsorption of Thiamethoxam on TiO2 surface under dark conditions was also investigated in order to find out equilibrium adsorption constant. The degradation kinetics was studied using spectrophotometric method under various conditions such as substrate concentration, type of catalyst, catalyst dosage, pH, and in the presence of electron acceptors such as hydrogen peroxide, potassium bromate, and ammonium persulphate under continuous purging of atmospheric oxygen, and the degradation rates were found to be strongly influenced by these parameters. The results manifested that the photocatalysis of Thiamethoxam follows pseudo-first-order kinetics. The toxicity assessments of the irradiated samples were carried out using human erythrocytes as a model system under in vitro conditions. GC-MS study showed the formation of several intermediate products which were characterised based on their molecular mass and mass fragmentation pattern. A probable mechanism for the formation of various products formed during the photocatalytic process of Thiamethoxam was also proposed. PMID- 23685137 TI - Thermophilic co-digestion of pig manure and crude glycerol: process performance and digestate stability. AB - Anaerobic co-digestion has been widely used to enhance biogas production of digesters and, therefore, to improve the anaerobic plants economic feasibility. In the present study, glycerol, a by-product of the biodiesel industry, was used as a co-substrate for pig manure. The results showed that the thermophilic anaerobic co-digestion of pig manure supplemented with 3% of glycerol, on weight basis, was satisfactory. The specific biogas production of the co-digester was 180% higher than the one obtained by the reference digester, which was only fed with pig manure. The improvement was related to the double of the organic loading rate, the high biodegradability of the crude glycerol, the slight reduction of the free ammonia concentration and the optimisation of the carbon-to-nitrogen ratio. Moreover, the analysis of the organic matter (protein, lipids, carbohydrates and fibers) of the influent and the effluent of both digesters together with their biogas flow rates indicated that the microorganisms in the co digester obtained large amounts of nutrients from the glycerol, whereas the microorganisms of the reference digester mainly produced biogas from the particulate matter. However, the digestate obtained from the co-digester cannot be directly applied as soil fertiliser or conditioner due to the presence of high levels of biodegradable matter, which may exert negative impacts on the plant soil system. Thus, a longer hydraulic retention time, a reduction of the glycerol concentration and/or a post-treatment is required if the digestate is to be used as soil fertiliser or conditioner. In contrast, pig manure digestate can be directly applied on land. PMID- 23685138 TI - Rationale and design of the Japan molecular epidemiology for lung cancer study. AB - We present the rationale for the Japan Molecular Epidemiology for Lung Cancer study designed to elucidate molecular mechanisms of carcinogenesis in smokers and never-smokers with non-small-cell lung cancer. This prospective, ongoing, multicenter study is being conducted nationwide in Japan. Although there is no doubt that active smoking is the major cause of lung cancer, the contribution of other possible factors, including environmental tobacco or wood smoke, human papilloma virus, radon, occupational exposures, and genetic susceptibility, is highly likely, based on studies of never-smokers with non-small-cell lung cancer. Because of the predominance of women in the never-smoker subgroup, the role of female hormones in lung cancer development has also been considered. We hypothesize that driver mutations, which are critical for the development of lung cancer, are triggered by the environmental factors with or without the influence of the hormone. The SWOG-led intergroup molecular epidemiology study S0424 was conducted to focus on these issues by using a detailed questionnaire and specimen collection in statistically significant cohorts of smokers and never-smokers from both sexes. The Japan Molecular Epidemiology for Lung Cancer study follows and extends the S0424 molecular epidemiology concept in principle by using a similar approach that will facilitate future comparisons between the studies but with a greater focus on more recently defined driver mutations and broad genomic sequencing. PMID- 23685139 TI - Clinical drug response to thiopurines is associated to a lower interferon-gamma production by IBD patient's T lymphocytes. PMID- 23685140 TI - Impact of mesenchymal stem cell secreted PAI-1 on colon cancer cell migration and proliferation. AB - Mesenchymal Stem Cells are known to engraft and integrate into the architecture of colorectal tumours, with little known regarding their fate following engraftment. This study aimed to investigate mediators of Mesenchymal Stem Cell (MSC) and colon cancer cell (CCC) interactions. Mesenchymal Stem Cells and colon cancer cells (HT29 and HCT-116) were cultured individually or in co-culture on 3 dimensional scaffolds. Conditioned media containing all secreted factors was harvested at day 1, 3 and 7. Chemokine secretion and expression were analyzed by Chemi-array, ELISA (Macrophage migration inhibitory factor (MIF), plasminogen activator inhibitor type 1 (PAI-1)) and RQ-PCR. Colon cancer cell migration and proliferation in response to recombinant PAI-1, MSCs and MSCs+antibody to PAI-1 was analyzed using Transwell inserts and an MTS proliferation assay respectively. Chemi-array revealed secretion of a wide range of factors by each cell population, including PAI-1 and MIF. ELISA analysis revealed Mesenchymal Stem Cells to secrete the highest levels of PAI-1 (MSC mean 10.6 ng/mL, CCC mean 1.01 ng/mL), while colon cancer cells were the principal source of MIF. MSC-secreted PAI-1 stimulated significant migration of both CCC lines, with an antibody to the chemokine shown to block this effect (67-88% blocking,). A cell-line dependant effect on CCC proliferation was shown for Mesenchymal Stem Cell-secreted PAI-1 with HCT-116 cells showing decreased proliferation at all concentrations, and HT29 cells showing increased proliferation in the presence of higher PAI-1 levels. This is the first study to identify PAI-1 as an important mediator of Mesenchymal Stem Cell/colon cancer cell interactions and highlights the significant functional impact of Mesenchymal Stem Cell-secreted PAI-1 on colon cancer cells. PMID- 23685141 TI - Insulin-dependent apolipoprotein B degradation is mediated by autophagy and involves class I and class III phosphatidylinositide 3-kinases. AB - Insulin acutely stimulates the degradation of apolipoprotein B (apo B) which decreases very low density lipoprotein (VLDL) secretion by liver. Insulin dependent apo B degradation (IDAD) occurs following phosphatidylinositide 3 kinase (PI3K) activation and involves lysosomal degradation. Insulin suppression of apo B secretion is blocked by over-expression of phosphatase and tensin homologue (PTEN) in McArdle RH7777 (McA) cells suggesting the importance of Class I PI3K generated PI (3,4,5) triphosphate (PIP3) in IDAD. Classical autophagy inhibitors including 3-methyladenine, L-asparagine and bafilomycin A1 also blocked the ability of insulin to suppress apo B secretion by rat hepatocytes (RH) suggesting that IDAD occurs through an autophagy-related mechanism. IDAD is also blocked following over-expression in McA cells of a dominant negative kinase defective Vps34, a class III PI3K that generates PI 3-monophosphate required for autophagy. Vps34 inhibition of IDAD occurs without altering insulin-dependent S473 phosphorylation of Akt indicating PI3K/PIP3/Akt signaling is intact. Cellular p62/SQSTM1, an inverse indicator of autophagy, is increased with insulin treatment consistent with the known ability of insulin to inhibit autophagy, and therefore the role of insulin in utilizing components of autophagy for apo B degradation is unexpected. Thapsigargan, an inducer of endoplasmic reticulum (ER) stress, and a recently demonstrated autophagy inhibitor, blocked apo B secretion which contrasted with other autophagy inhibitors and mutant Vps34 results which were permissive with respect to apo B secretion. Pulse chase studies indicated that intact B100 and B48 proteins were retained in cells treated with thapsigargan consistent with their accumulation in autophagosomal vacuoles. Differences between IDAD and ER stress-coupled autophagy mediated by thapsgargin suggest that IDAD involves an unique form of autophagy. Insulin action resulting in hepatic apo B degradation is novel and important in understanding regulation of hepatic VLDL metabolism. PMID- 23685142 TI - Resveratrol improves learning and memory in normally aged mice through microRNA CREB pathway. AB - Resveratrol (RSV) is a natural compound found in grapes and red wine. It has been well known for its beneficial effects as a dietary supplement in prevention of cardiovascular diseases and cancer. Recently, in vitro studies have reported the neuroprotective role of RSV in neurodegenerative process in Alzheimer's disease (AD). However, in vivo effects of RSV on the decline of brain function accompanying the aging process, especially those on cognitive loss, have not been not investigated. Here we report that, after intraventricular injection of RSV for one week in 8-9 month-old mice, the long-term memory formation and the LTP induction from hippocampus CA1 were improved. The RSV enhancement effects were blocked in SIRT1 mutant mice. Additional experiments suggest that RSV effects are likely to be mediated through reduced expressions of miR-134 and miR-124, which may in turn up-regulate CREB levels to subsequently promote BDNF synthesis. These findings demonstrate a role for RSV in cognition and a microRNA-CREB-BDNF mechanism by which RSV regulates these processes, demonstrating its value as a potential therapeutic target against CNS disorders in aging. PMID- 23685143 TI - SRp20: an overview of its role in human diseases. AB - Alternative splicing in mRNA maturation has emerged as a major field of study also because of its implications in various diseases. The SR proteins play an important role in the regulation of this process. Evidence indicates that SRp20 (SFSR3), the smallest member of the SR protein family, is involved in numerous biological processes. Here we review the state-of-the-art of knowledge about the SR proteins, in particular SRp20, in terms of its function and misregulation in human diseases including cancer also in view of its potential as a therapeutic target. PMID- 23685144 TI - Transplantation of aggregates of synovial mesenchymal stem cells regenerates meniscus more effectively in a rat massive meniscal defect. AB - Transplantation of mesenchymal stem cells (MSCs) derived from synovium is a possible therapy for meniscus regeneration. We have previously reported that intraarticular injection of 5 million synovial MSCs promoted meniscal regeneration in rat meniscal defects. However, if a similar cell number per body weight were required, preparation of required human MSCs would not be practical in a clinical situation. The use of aggregates of MSCs may be one of the solutions. Here, we investigated whether the use of aggregates of synovial MSCs regenerated meniscus more effectively in a rat meniscectomized model. The total number of synovial MSCs was adjusted to 25,000 cells, and aggregates consisting of MSCs or 25,000 MSCs suspended in PBS were placed on the meniscal defects. Five million MSCs suspended in PBS were also used as another control. For the regenerated menisci, the area was larger and the histological findings were closer to that of the normal meniscus in the aggregate groups than to that in the suspension groups at 4 weeks. The effects of transplantation of aggregates were still observed at 12 weeks. Luminescence intensity remained higher at 3 weeks and thereafter in the aggregate group than in the suspension group when the same number of luciferase expressing MSCs were transplanted. We confirmed that MSCs transplanted as aggregates existed in the regenerated meniscus focally and partially. Transplantation of aggregates of synovial MSCs regenerated meniscus more effectively in a rat massive meniscal defect. PMID- 23685145 TI - Multi-directional function of the protein phosphatase 1 regulatory subunit TIMAP. AB - TIMAP is an endothelial-cell predominant member of the MYPT family of PP1c regulatory subunits. This study explored the TIMAP-PP1c interaction and substrate specificity in vitro. TIMAP associated with all three PP1c isoforms, but endogenous endothelial cell TIMAP preferentially co-immunoprecipitated with PP1cbeta. Structural modeling of the TIMAP/PP1c complex predicts that the PP1c C terminus is buried in the TIMAP ankyrin cluster, and that the PP1c active site remains accessible. Consistent with this model, C-terminal PP1c phosphorylation by cdk2-cyclinA was masked by TIMAP, and PP1c bound TIMAP when the active site was occupied by the inhibitor microcystin. TIMAP inhibited PP1c activity toward phosphorylase a in a concentration-dependent manner, with half-maximal inhibition in the 0.4-1.2 nM range, an effect modulated by the length, and by Ser333/Ser337 phosphomimic mutations of the TIMAP C-terminus. TIMAP-bound PP1cbeta effectively dephosphorylated MLC2 and TIMAP itself. By contrast, TIMAP inhibited the PP1cbeta activity toward the putative substrate LAMR1, and instead masked LAMR1 PKA- and PKC-phosphorylation sites. This is direct evidence that MLC2 is a TIMAP/PP1c substrate. The data also indicate that TIMAP can modify protein phosphorylation independent of its function as a PP1c regulatory subunit, namely by masking phosphorylation sites of binding partners like PP1c and LAMR1. PMID- 23685146 TI - Aurora A kinase negatively regulates Rho-kinase by phosphorylation in vivo. AB - Aurora-A kinase (AurA) is a key regulator of cellular processes involving microtubules. It has also been implicated in actin-dependent events, but the mechanisms that underlie the processes are not fully understood. Here we provide genetic and biochemical evidence suggesting that AurA negatively regulates Drok, the only known Rho-kinase orthologue in Drosophila. AurA directly phosphorylates Drok in vitro, and the overexpression of the nonphosphorylatable forms of Drok in vivo causes similar, but much stronger effects than that of wild-type Drok. The defects induced by the nonphosphorylatable forms of Drok are compensated by reducing the function of myosin downstream. Thus, phosphorylation of Drok by AurA normally suppresses Drok activity. We propose that AurA directly regulates actin dependent processes by phosphorylating Rho-kinase. PMID- 23685147 TI - EBV-miR-BART1 is involved in regulating metabolism-associated genes in nasopharyngeal carcinoma. AB - EBV-miR-BART1 has been found to be highly expressed in some cancers including nasopharyngeal carcinoma (NPC), but its exact roles in the pathogenesis of NPC remain unclear. Here, we did RNA deep sequencing to compare the gene expression profile between EBV-miR-BART1-expressing CNE1 cells and the control cells to determine the possible effects of EBV-miR-BART1 in NPC. Gene expression profiling analysis unexpectedly showed a significant number of up- and down-modulated metabolism-associated genes, such as G6PD, SAT1, ASS1, PAST1, FUT1, SGPL1, DHRS3, B4GALT1, PHGDH, IDH2, PISD, UGT8, LDHB and GALNT1, in EBV-miR-BART1-expressing NPC cells, which were next confirmed by RT-qPCR. Moreover, of these metabolism genes, PSAT1 and PHGDH expression levels were significantly upregulated and most of other genes were obviously up-expressed in NPC specimens compared with chronic nasopharyngitis (CNP) tissues. Collectively, we for the first time found the effects of EBV-miR-BART1 on the expression of mechanism-associated genes in NPC, suggesting a novel role of EBV-miR-BART1 in cancer metabolism, which remains to be fully elucidated. PMID- 23685148 TI - Pitch and loudness matching of unmodulated and modulated stimuli in cochlear implantees. AB - The pitch elicited by unmodulated and amplitude modulated electrical pulse trains was examined with six adult cochlear implantees. In addition, for three of those subjects who had some hearing in their contralateral ear, the pitch of unmodulated electrical pulse trains was compared to that of complex harmonic acoustic tones. In the first experiment, pulse rate discrimination and the effects of place and level differences on pitch were examined for unmodulated pulse trains. General results were consistent with previous studies showing that variations in pulse rate, while holding loudness fixed, elicit changes in pitch at low rates, but become progressively harder to discriminate as rates approach approximately 300 pulses-per-second. Variations in place or level of stimulation generally produced changes in pitch consistent with tonotopic place and spread of excitation. In the second experiment, pitch and loudness of unmodulated pulse trains were compared with those of amplitude modulated stimuli as a function of modulation depth, rate, and shape, and presentation level. The pitch elicited by an amplitude modulated pulse train was generally higher than that of an unmodulated pulse train with a pulse rate equal to the modulation rate, and generally decreased toward that of the unmodulated pulse train as modulation depth or rate increased, or as presentation level decreased. Sharper/narrower modulation produced lower pitch. In the final experiment, the pitch heights of acoustic complex harmonic tones and unmodulated pulse trains were compared. When electrical pulse rate was equal to the fundamental frequency of the acoustic tone, similar pitch heights were elicited. The results from these experiments indicate that F0 rate pitch derived from the temporal envelope in existing clinical cochlear implant strategies may often be higher than that of acoustic harmonic tones at the same F0 in normal hearing, and that pitch growth with increasing F0 may be shallower. The relationship between F0 and rate pitch is expected to be more similar to acoustic stimulation for low F0 rates when using new pitch coding strategies that code F0 information via deep (narrow) amplitude modulation of the stimulus envelope. Although that similarity reduces as F0 approaches the upper limit of rate-pitch discrimination, that limit is reached sooner for the shallow (or broad) modulators used in existing clinical strategies. PMID- 23685149 TI - The neural processing of masked speech. AB - Spoken language is rarely heard in silence, and a great deal of interest in psychoacoustics has focused on the ways that the perception of speech is affected by properties of masking noise. In this review we first briefly outline the neuroanatomy of speech perception. We then summarise the neurobiological aspects of the perception of masked speech, and investigate this as a function of masker type, masker level and task. This article is part of a Special Issue entitled "Annual Reviews 2013". PMID- 23685150 TI - Cardioprotection by modulation of mitochondrial respiration during ischemia reperfusion: role of apoptosis-inducing factor. AB - The transient, reversible blockade of electron transport (BET) during ischemia or at the onset of reperfusion protects mitochondria and decreases cardiac injury. Apoptosis inducing factor (AIF) is located within the mitochondrial intermembrane space. A release of AIF from mitochondria into cytosol and nucleus triggers caspase-independent cell death. We asked if BET prevents the loss of AIF from mitochondria as a mechanism of protection in the buffer perfused heart. BET during ischemia with amobarbital, a rapidly reversible inhibitor of mitochondrial complex I, attenuated a release of AIF from mitochondria into cytosol, in turn decreasing the formation of cleaved and activated PARP-1. These results suggest that BET-mediated protection may occur through prevention of the loss of AIF from mitochondria during ischemia-reperfusion. In order to further clarify the role of mitochondrial AIF in BET-mediated protection, Harlequin (Hq) mice, a genetic model with mitochondrial AIF deficiency, were used to test whether BET could still decrease cell injury in Hq mouse hearts during reperfusion. BET during ischemia protected Hq mouse hearts against ischemia-reperfusion injury and improved mitochondrial function in these hearts during reperfusion. Thus, cardiac injury can still be decreased in the presence of down-regulated mitochondrial AIF content. Taken together, BET during ischemia protects both hearts with normal mitochondrial AIF content and hearts with mitochondrial AIF deficiency. Although preservation of mitochondrial AIF content plays a key role in reducing cell injury during reperfusion, the protection derived from the BET is not fully dependent on AIF-driven mechanisms. PMID- 23685152 TI - Oligomerization of TopBP1 is necessary for the localization of TopBP1 to mitotic centrosomes. AB - Human TopBP1 is involved in the DNA damage checkpoint response, chromosome replication, and other functions of cell cycle control. The C-terminal region of TopBP1 (TbpCtr: amino acid residues 1222-1522) is involved in the localization of TopBP1 to the centrosomes during mitosis. Here, we showed that the amino acid residues 741-885 of TopBP1, in addition to TbpCtr, are necessary for the centrosomal localization of TopBP1. Whereas oligomeric tags fused to TbpCtr localized to mitotic centrosomes, monomeric tags fused to TbpCtr did not. Insertion of the amino acid residues 741-885 into the monomeric tag fused to TbpCtr allowed the protein to localize to the mitotic centrosome. These results suggest that the amino acid residues 741-885 are necessary for oligomerization of TopBP1 for centrosomal localization. PMID- 23685151 TI - Hydrogen peroxide inhibits transforming growth factor-beta1-induced cell cycle arrest by promoting Smad3 linker phosphorylation through activation of Akt-ERK1/2 linked signaling pathway. AB - Hydrogen peroxide (H2O2) functions as a second messenger in growth factor receptor-mediated intracellular signaling cascade and is tumorigenic by virtue of its ability to promote cell proliferation; however, the mechanisms underlying the growth stimulatory action of H2O2 are less understood. Here we report an important mechanism for antagonistic effects of H2O2 on growth inhibitory response to transforming growth factor-beta1 (TGF-beta1). In Mv1Lu and HepG2 cells, pretreatment of H2O2 (0.05-0.2 mM) completely blocked TGF-beta1-mediated induction of p15(INK4B) expression and increase of its promoter activity. Interestingly, H2O2 selectively suppressed the transcriptional activation potential of Smad3, not Smad2, in the absence of effects on TGF-beta1-induced phosphorylation of the COOH-tail SSXS motif of Smad3 and its nuclear translocation. Mechanism studies showed that H2O2 increases the phosphorylation of Smad3 at the middle linker region in a concentration- and time-dependent manner and this effect is mediated by activation of extracellular signal activated kinase 1/2 through Akt. Furthermore, expression of a mutant Smad3 in which linker phosphorylation sites were ablated significantly abrogated the inhibitory effects of H2O2 on TGF-beta1-induced increase of p15(INK4B)-Luc reporter activity and blockade of cell cycle progression from G1 to S phase. These findings for the first time define H2O2 as a signaling molecule that modulate Smad3 linker phosphorylation and its transcriptional activity, thus providing a potential mechanism whereby H2O2 antagonizes the cytostatic function of TGF-beta1. PMID- 23685153 TI - Potential roles of adenosine deaminase-2 in diabetic retinopathy. AB - The early activation of microglia that induces retinal inflammation in DR may serve as a target for therapeutic intervention of DR. Our demonstration that retinal inflammation is attenuated via adenosine receptor A(2A)AR supports the hypothesis that a mechanism to maintain extracellular concentrations of adenosine important in normal physiology is impaired in DR. Extracellular concentrations of adenosine are regulated by the interplay of equiliberative nucleoside transporter (ENT)s with enzymes of adenosine metabolism including adenosine deaminase-1 (ADA1), adenosine kinase (AK) and CD73. In the vertebrates but not rodents, a macrophage-associated ADA2 is identified. The role of ADA2 is, therefore, understudied as the sequencing probes or antibodies to mouse ADA2 are not available. We identified increased ADA2 expression and activity in human and porcine retinas with diabetes, and in Amadori glycated albumin (AGA)- or hyperglycemia-treated porcine and human microglia. In rodent as well as porcine cells, modulation of TNF-alpha release is mediated by A(2A)AR. Quantitative analysis of normal and diabetic porcine retinas reveals that while the expression levels of ADA2, A2AAR, ENT1, TNF-alpha and MMP9 are increased, the levels of AK are reduced during inflammation as an endogenous protective mechanism. To determine the role of ADA2, we found that AGA induces ADA2 expression, ADA2 activity and TNF-alpha release, and that TNF-alpha release is blocked by ADA2 neutralizing antibody or ADA2 siRNA, but not by scrambled siRNA. These results suggest that retinal inflammation in DR is mediated by ADA2, and that the anti inflammatory activity of A(2A)AR signaling is impaired in diabetes due to increased ADA2 activity. PMID- 23685154 TI - Generation of transgenic mouse line expressing Kusabira Orange throughout body, including erythrocytes, by random segregation of provirus method. AB - Fluorescent-protein transgenic mice are useful for obtaining marked somatic cells to study kinetics of development or differentiation. Fluorescence-marked hematopoietic stem cells in particular are commonly used for studying hematopoiesis. However, as far as we know, no transgenic mouse line is described in which a fluorescent protein is stably and constitutively expressed in all hematopoietic cells, including erythrocytes and platelets. Using the random segregation of provirus (RSP) method, we generated from retrovirally transduced mouse embryonic stem cells a transgenic mouse line expressing a red/orange fluorescent protein, Kusabira Orange (KuO). KuO transgenic mouse line cells carry only one proviral integration site and stably express KuO in all hematopoietic lineage elements, including erythrocytes and platelets. Moreover, bone-marrow transplantation in KuO transgenic mice demonstrated normal hematopoieisis. KuO transgenic mice likely will prove useful for study of hematopoiesis that includes erythropoiesis and megakaryopoiesis. PMID- 23685155 TI - Thrombin-sensitive expression of the store operated Ca(2+) channel Orai1 in platelets. AB - Thrombin activates pore forming channel protein Orai1 resulting in store operated Ca(2+) entry (SOCE) with subsequent Ca(2+)-dependent release of platelet granules, activation of integrin alphaIIbbeta3, adhesion, aggregation and thrombus formation. Platelets lack nuclei and are thus unable to modify protein abundance by transcriptional regulation. Nevertheless, they still contain pre mRNA and mRNA and are thus able to express protein by stimulation of rapid translation. Platelet translation is sensitive to phosphoinositide-3-kinase (PI3K) and actin polymerization. The present study explored whether platelet activation via thrombin modifies Orai1 protein abundance. According to RT-PCR platelets contain pre-mRNA and mRNA encoding Orai1. Activation with thrombin (0.1 U/ml) results in a significant decline of pre-mRNA, which is, according to Western blotting and confocal microscopy, paralleled by a marked and statistically significant increase of Orai1 protein abundance. The increase of Orai1 protein abundance is insensitive to inhibition of transcription with actinomycin (4 MUg/ml), but is significantly blunted by inhibition of translation with puromycin (100 nM) and by inhibition of PI3K with wortmannin (100 nM) or LY294002 (25 MUM). In conclusion, activation of platelets stimulates the translational expression of Orai1, thus augmenting platelet Ca(2+) signaling. PMID- 23685156 TI - Identification of plasma APE1/Ref-1 in lipopolysaccharide-induced endotoxemic rats: implication of serological biomarker for an endotoxemia. AB - Apurinic/apyrimidinic endonuclease1/Redox factor-1 (APE1/Ref-1) is a multifunctional protein involved in base excision DNA repair and in transcriptional regulation of gene expression. We investigated whether APE1/Ref-1 increased in plasma of endotoxemic rats. Lipopolysaccharide (LPS) was used to induce endotoxemia in rats. Administration of LPS (10 mg/kg, i.p.) significantly induced plasma nitrite production and tumor necrosis factor-alpha (TNF-alpha). A 37 kDa immunoreactive band was detected in cell-free plasma of LPS-treated rats using anti-APE1/Ref-1, which reached a maximum at 12 h after the LPS injection. The 37 kDa immunoreactive band was identified as rat APE1/Ref-1 by liquid chromatography/tandem mass spectrometry. Interestingly, treatment with recombinant human APE1/Ref-1 protein (2-5 MUg/ml for 18 h) inhibited TNF-alpha induced vascular cell adhesion molecule-1 expression in human umbilical vein endothelial cells. Taken together, the level of plasma APE1/Ref-1 increased in LPS-induced endotoxemic rats, suggesting that plasma APE1/Ref-1 might serve as a serological biomarker for endotoxemia. PMID- 23685157 TI - Decreased brain volumes in manganese-exposed welders. AB - BACKGROUND: A great deal of research has been devoted to identifying subclinical functional brain abnormalities in manganese (Mn)-exposed welders. However, no previous study has investigated morphological brain abnormalities, such as changes in brain volume, in welders. This study evaluates morphological changes in brain volume among welders, and investigates the relationship between structural brain abnormalities and subclinical dysfunction in this population. METHODS: We used voxel-based morphometry (VBM) to assess differences in gray and white matter brain volumes between 40 welders with chronic Mn exposure and 26 age matched control subjects. Correlation analyses were used to investigate the relationship between brain volume changes and decreased performance on neurobehavioral tests. RESULTS: Brain volumes in the globus pallidus and cerebellar regions were significantly diminished in welders with chronic Mn exposure compared to controls (FDR-corrected P<0.05). These changes in brain volume were negatively correlated with cognitive performance and grooved pegboard scores. CONCLUSION: There are measurable brain volume reductions in the globus pallidus and cerebellum of welders chronically exposed to Mn, and these volume reductions correlate with cognitive and motor neurobehavioral deficits. Our findings therefore indicate that volumetric measurement could be a useful subclinical marker among welders that show no signs of manganism. PMID- 23685158 TI - Bivalent transition metal complexes of cetirizine: spectroscopic, equilibrium studies and biological activity. AB - Metal complexes of cetirizine.2HCl (CTZ=2-[2-[4-[(4-chlorophenyl)phenyl methyl]piperazine-1-yl]-ethoxy]acetic acid, dihydrochloride have been prepared and characterized by elemental analyses, IR, solid reflectance, magnetic moment, molar conductance, and UV-Vis spectra. The analytical data of the complexes show the formation of 1:2 [M:L] ratio, where M represents Ni(II), Co(II) and Cu(II) ions, while L represents the deprotonated CTZ ligand. IR spectra show that CTZ is coordinated to the metal ions in a monodentate manner through carboxylate-O atom. Protonation equilibria of CTZ and its metal complexation by some divalent metal ions were determined in aqueous solution at constant ionic strength (0.1 M NaCl) using an automatic potentiometric technique. Thermodynamic parameters for the protonation equilibria of CTZ were calculated and discussed. The stability order of M(II)-CTZ complexes were found to obey Mn(2+)200 cpm) from 25 +/- 3% to 9 +/- 2% (p = 0.004). Thus, reduction of the mean respiratory rate by LiCl was predominantly due to reduced contribution of high-frequency breathing that is normally associated with motor activity and/or arousal. Non-linear multifractal analysis of respiratory signals revealed that post-LiCl, respiration becomes less random and more orderly. 5-HT3 antagonist ondansetron prevented respiratory changes elicited by LiCl. We conclude that the observed changes likely reflect effects of LiCl on animals' motion, and that this effect is mediated via 5-HT3 receptors. Providing that the effects observed in our study were quite robust, we suggest that simple and non-invasive respiratory monitoring may be a promising approach for studying emesis in rodents. PMID- 23685166 TI - Sleep active cortical neurons expressing neuronal nitric oxide synthase are active after both acute sleep deprivation and chronic sleep restriction. AB - Non-rapid eye movement (NREM) sleep electroencephalographic (EEG) delta power (~0.5-4 Hz), also known as slow wave activity (SWA), is typically enhanced after acute sleep deprivation (SD) but not after chronic sleep restriction (CSR). Recently, sleep-active cortical neurons expressing neuronal nitric oxide synthase (nNOS) were identified and associated with enhanced SWA after short acute bouts of SD (i.e., 6h). However, the relationship between cortical nNOS neuronal activity and SWA during CSR is unknown. We compared the activity of cortical neurons expressing nNOS (via c-Fos and nNOS immuno-reactivity, respectively) and sleep in rats in three conditions: (1) after 18-h of acute SD; (2) after five consecutive days of sleep restriction (SR) (18-h SD per day with 6h ad libitum sleep opportunity per day); (3) and time-of-day matched ad libitum sleep controls. Cortical nNOS neuronal activity was enhanced during sleep after both 18 h SD and 5 days of SR treatments compared to control treatments. SWA and NREM sleep delta energy (the product of NREM sleep duration and SWA) were positively correlated with enhanced cortical nNOS neuronal activity after 18-h SD but not 5days of SR. That neurons expressing nNOS were active after longer amounts of acute SD (18h vs. 6h reported in the literature) and were correlated with SWA further suggest that these cells might regulate SWA. However, since these neurons were active after CSR when SWA was not enhanced, these findings suggest that mechanisms downstream of their activation are altered during CSR. PMID- 23685168 TI - Identification of the sensory nerve fiber responsible for lysophosphatidic acid induced allodynia in mice. AB - Lysophosphatidic acid (LPA) has been considered one of the molecular culprits for neuropathic pain. Understanding how LPA changes the function of primary afferent fibers might be an essential step for clarifying the pathogenesis of neuropathic pain. The present study was designed to identify the primary afferent fibers (Abeta, Adelta, or C) participating in LPA-induced allodynia in ddY mice. Mechanical allodynia and thermal hyperalgesia were evaluated by the von Frey filament test and thermal paw withdrawal test, respectively. Sensory nerve fiber responsiveness was measured using a Neurometer. Daily repeated intrathecal treatment with LPA led to a decrease in the mechanical, but not thermal nociceptive threshold, and a reduction in the threshold for paw withdrawal induced by 2000-Hz (Abeta fiber) and 250-Hz (Adelta fiber), but not 5-Hz (C fiber) sine-wave electrical stimulation. When the transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor agonist resiniferatoxin (RTX) was administered subcutaneously before the start of LPA treatment, LPA induced mechanical allodynia and Abeta and Adelta fiber hypersensitivity demonstrated by neurometry were not affected, indicating that TRPV1-expressing nerve fibers (possibly C fibers) might not be essential for LPA-induced allodynia. LPA-induced allodynia was reversed by treatment with RTX at 7 days after the start of LPA treatment. Expression of TRPV1 on myelinated nerve fibers after repeated intrathecal LPA treatment was observed in the dorsal root ganglion. These results suggest that sensitization of Abeta and Adelta fibers, but not C fibers, contributes to the development of intrathecally administered LPA-induced mechanical allodynia. Moreover, increased or newly expressed TRPV1 receptors in Abeta and Adelta fibers are considered to be involved in the maintenance of LPA-induced allodynia. PMID- 23685169 TI - Post-ischemic treatment with L-kynurenine sulfate exacerbates neuronal damage after transient middle cerebral artery occlusion. AB - Since brain ischemia is one of the leading causes of adult disability and death, neuroprotection of the ischemic brain is of particular importance. Acute neuroprotective strategies usually have the aim of suppressing glutamate excitotoxicity and an excessive N-methyl-d-aspartate (NMDA) receptor function. Clinically tolerated antagonists should antagonize an excessive NMDA receptor function without compromising the normal synaptic function. Kynurenic acid (KYNA) an endogenous metabolite of the tryptophan metabolism, may be an attractive neuroprotectant in this regard. The manipulation of brain KYNA levels was earlier found to effectively enhance the histopathological outcome of experimental ischemic/hypoxic states. The present investigation of the neuroprotective capacity of L-kynurenine sulfate (L-KYNs) administered systemically after reperfusion in a novel distal middle cerebral artery occlusion (dMCAO) model of focal ischemia/reperfusion revealed that in contrast with earlier results, treatment with L-KYNs worsened the histopathological outcome of dMCAO. This contradictory result indicates that post-ischemic treatment with L-KYNs may be harmful. PMID- 23685171 TI - A pure state decomposition approach of the mixed dynamic form factor for mapping atomic orbitals. AB - We demonstrate how the mixed dynamic form factor (MDFF) can be interpreted as a quadratic form. This makes it possible to use matrix diagonalization methods to reduce the number of terms that need to be taken into account when calculating the inelastic scattering of electrons in a crystal. It also leads in a natural way to a new basis that helps elucidate the underlying physics. The new method is applied to several cases to show its versatility. In particular, predictions are made for directly imaging atomic orbitals in crystals. PMID- 23685170 TI - Automated analysis of atrial late gadolinium enhancement imaging that correlates with endocardial voltage and clinical outcomes: a 2-center study. AB - BACKGROUND: For late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) assessment of atrial scar to guide management and targeting of ablation in atrial fibrillation (AF), an objective, reproducible method of identifying atrial scar is required. OBJECTIVE: To describe an automated method for operator-independent quantification of LGE that correlates with colocated endocardial voltage and clinical outcomes. METHODS: LGE CMR imaging was performed at 2 centers, before and 3 months after pulmonary vein isolation for paroxysmal AF (n = 50). A left atrial (LA) surface scar map was constructed by using automated software, expressing intensity as multiples of standard deviation (SD) above blood pool mean. Twenty-one patients underwent endocardial voltage mapping at the time of pulmonary vein isolation (11 were redo procedures). Scar maps and voltage maps were spatially registered to the same magnetic resonance angiography (MRA) segmentation. RESULTS: The LGE levels of 3, 4, and 5SDs above blood pool mean were associated with progressively lower bipolar voltages compared to the preceding enhancement level (0.85 +/- 0.33, 0.50 +/- 0.22, and 0.38 +/- 0.28 mV; P = .002, P < .001, and P = .048, respectively). The proportion of atrial surface area classified as scar (ie, >3 SD above blood pool mean) on preablation scans was greater in patients with postablation AF recurrence than those without recurrence (6.6% +/- 6.7% vs 3.5% +/- 3.0%, P = .032). The LA volume >102 mL was associated with a significantly greater proportion of LA scar (6.4% +/- 5.9% vs 3.4% +/- 2.2%; P = .007). CONCLUSIONS: LA scar quantified automatically by a simple objective method correlates with colocated endocardial voltage. Greater preablation scar is associated with LA dilatation and AF recurrence. PMID- 23685172 TI - Accurate measurement of Atomic Force Microscope cantilever deflection excluding tip-surface contact with application to force calibration. AB - Considerable attention has been given to the calibration of AFM cantilever spring constants in the last 20 years. Techniques that do not require tip-sample contact are considered advantageous since the imaging tip is not at risk of being damaged. Far less attention has been directed toward measuring the cantilever deflection or sensitivity, despite the fact that the primary means of determining this factor relies on the AFM tip being pressed against a hard surface, such as silicon or sapphire; which has the potential to significantly damage the tip. A recent method developed by Tourek et al. in 2010 involves deflecting the AFM cantilever a known distance from the imaging tip by pressing the cantilever against a sharpened tungsten wire. In this work a similar yet more precise method is described, whereby the deflection of the cantilever is achieved using an AFM probe with a spring constant much larger than the test cantilever, essentially a rigid cantilever. The exact position of loading on the test cantilever was determined by reverse AFM imaging small spatial markers that are milled into the test cantilever using a focussed ion beam. For V shaped cantilevers it is possible to reverse image the arm intersection in order to determine the exact loading point without necessarily requiring FIB milled spatial markers, albeit at the potential cost of additional uncertainty. The technique is applied to tip less, beam shaped and V shaped cantilevers and compared to the hard surface contact technique with very good agreement (on average less than 5% difference). While the agreement with the hard surface contact technique was very good the error on the technique is dependent upon the assumptions inherent in the method, such as cantilever shape, loading point distance and ratio of test to rigid cantilever spring constants. The average error ranged between 2 to 5% for the majority of test cantilevers studied. The sensitivity derived with this technique can then be used to calibrate the cantilever spring constant using the thermal noise method, allowing complete force calibration to be accurately performed without tip-sample contact. PMID- 23685173 TI - An apparent increase in meiotic silencing strength in crosses involving inbred Neurospora crassa strains. AB - Meiotic silencing by unpaired DNA is a presumed RNAi-mediated elimination of the transcripts of any gene that is not properly paired with a homolog in meiosis. Wild-isolated strains of Neurospora crassa can be classified into three types based on the apparent strength of meiotic silencing of the bml (beta-tubulin) and mei-3 genes in crosses of the wild strains with the tester strains ::Bml(r) and ::mei-3. Crosses with "OR" and "Sad" type wild-isolates, respectively, did or did not silence both the genes, whereas crosses with the "Esm" type silenced bml, but not mei-3(+). Presumably, bml is more sensitive to silencing than mei-3, and silencing is strongest in crosses with the OR type, weakest (or non-evident) in crosses with the Sad type, and of intermediate strength in crosses with Esm type. Now, while constructing recombinant inbred lines from the Sad type wild strains Bichpuri-1 a and Spurger-3 A, we found that although crosses of Bichpuri-1 a and Spurger-3 A, and of most of their f1 progeny, with the ::Bml(r) and ::mei-3 testers were consistently and reproducibly Sad type, those of later generation strains of each line could show Sad, Esm, or a variably expressive Sad/Esm type. Since any genotype found in a later generation is, in principle, obtainable in the f1, the observed transition from an apparently stable Sad phenotype to an apparently unstable Sad/Esm phenotype appears not to be due to genotype differences between the generations. Therefore, the Sad versus Esm difference may have a genotype-independent basis. PMID- 23685174 TI - Natural product hybrid and its superacid synthesized analogues: dodoneine and its derivatives show selective inhibition of carbonic anhydrase isoforms I, III, XIII and XIV. AB - The natural product dodoneine (a dihydropyranone phenolic compound), extracted from African mistletoe Agelanthus dodoneifolius, has been investigated as inhibitor of several human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms. By using superacid chemistry, analogues of the lactone phenolic hybrid lead compound have been synthesized and tested as CA inhibitors. Small chemical modifications of the basic scaffold revealed strong changes in the selectivity profile against different CA isoforms. These new compounds selectively inhibited isoforms CA I (K(I)s in the range of 0.13-0.76 MUM), III (K(I)s in the range of 5.13-10.80 MUM), XIII (K(I)s in the range of 0.34-0.96 MUM) and XIV (K(I)s in the range of 2.44-7.24 MUM), and can be considered as new leads, probably acting as non-zinc binders, similar to other phenols/lactones investigated earlier. PMID- 23685175 TI - Synthesis and evaluation of novel orally active p53-MDM2 interaction inhibitors. AB - We have discovered and reported potent p53-MDM2 interaction inhibitors possessing dihydroimidazothiazole scaffold. Our lead showed strong activity in vitro, but did not exhibit antitumor efficacy in vivo for the low metabolic stability. In order to obtain orally active compounds, we executed further optimization of our lead by the improvement of physicochemical properties. Thus we furnished optimal compounds by introducing an alkyl group onto the pyrrolidine at the C-2 substituent to prevent the metabolism; and modifying the terminal substituent of the proline motif improved solubility. These optimal compounds exhibited good PK profiles and significant antitumor efficacy with oral administration on a xenograft model using MV4-11 cells having wild type p53. PMID- 23685176 TI - Small molecular inhibitors of miR-1 identified from photocycloadducts of acetylenes with 2-methoxy-1,4-naphthalenequinone. AB - Small molecules which can modulate endogenous microRNAs are important chemical tools to study microRNA regulational network. In this Letter we screened the [2+2] photocycloadducts of 2-methoxy-1,4-naphthalenequinone with a series of aryl acetylenes on their activity to modulate endogenous microRNAs. A potent inhibitor of the muscle-specific miR-1 which is closely related with cardiac development and disease was identified. The small molecular inhibitor was the cyclobutene type product derived from the photocycloaddition of 2-methoxy-1,4 naphthalenequinone with tert-butyl (5-(phenylethynyl)quinolin-8-yl) carbonate. Analogues of the small molecular inhibitor were then prepared using similar photocycloaddition reactions for evaluation on inhibition activity on miR-1 to provide structure-activity relationship of the miR-1 inhibitor. PMID- 23685177 TI - Potent suppression of c-di-GMP synthesis via I-site allosteric inhibition of diguanylate cyclases with 2'-F-c-di-GMP. AB - Cyclic-di-GMP (c-di-GMP) is a central regulator of bacterial behavior. Various studies have implicated c-di-GMP in biofilm formation and virulence factor production in multitudes of bacteria. Hence it is expected that the disruption of c-di-GMP signaling could provide an effective means to disrupt biofilm and/or virulence factor formation in several bacteria of clinical relevance. C-di-GMP achieves the regulation of bacterial phenotype via binding to several effector molecules including transcription factors, enzymes and riboswitches. Crystal structure analyses of c-di-GMP effector molecules, in complex with the ligand, reveal that various classes of c-di-GMP receptors recognize this dinucleotide using different sets of recognition elements. Therefore, it is plausible that different analogues of c-di-GMP could be used to selectively modulate a specific class of c-di-GMP binding receptors, and hence modulate the bacterial phenotype. Thus far only a detailed study of the differential binding of c-di-GMP analogues to riboswitches, but not proteins, has been reported. In this report, we prepared various 2'-modified analogues of c-di-GMP and studied both polymorphisms of these analogues using DOSY NMR and the binding to several effector proteins, such as PilZ-containing proteins, diguanylate cyclases (DGC) containing I-sites, and phoshphodiesterases (PDE). 2'-Modification of c-di-GMP did not adversely affect the propensity to form higher aggregates, such as octameric forms, in the presence of potassium salts. Interestingly, we find that the selective binding to different classes of c-di-GMP binding proteins could be achieved with the 2' modified analogues and that 2'-F analogue of c-di-GMP binds to the I-site of DGCs better (four times) than the native dinucleotide, c-di-GMP, whereas c-di-GMP binds to PDEs better (10 times) than 2'-F-c-di-GMP. 2'-F-c-di-GMP potently inhibits c-di-GMP synthesis by DGCs and hence raises the potential that cell permeable analogues of 2'-F-c-di-GMP could be used to disrupt c-di-GMP signaling in bacteria. PMID- 23685178 TI - Australian marine sponge alkaloids as a new class of glycine-gated chloride channel receptor modulator. AB - Chemical analysis of a specimen of the sponge Ianthella cf. flabelliformis returned two new sesquiterpene glycinyl lactams, ianthellalactams A (1) and B (2), the known sponge sesquiterpene dictyodendrillin (3) and its ethanolysis artifact ethyl dictyodendrillin (4), and five known sponge indole alkaloids, aplysinopsin (5), 8E-3'-deimino-3'-oxoaplysinopsin (6), 8Z-3'-deimino-3' oxoaplysinopsin (7), dihydroaplysinopsin (8) and tubastrindole B (9). The equilibrated mixture 6/7 exhibited glycine-gated chloride channel receptor (GlyR) antagonist activity with a bias towards alpha3 over alpha1 GlyR, while tubastrindole B (9) exhibited a bias towards alpha1 over alpha3 GlyR. At low- to sub-micromolar concentrations, 9 was also a selective potentiator of alpha1 GlyR, with no effect on alpha3 GlyR-a pharmacology that could prove useful in the treatment of movement disorders such as spasticity and hyperekplexia. Our investigations into the GlyR modulatory properties of 1-9 were further supported by the synthesis of a number of structurally related indole alkaloids. PMID- 23685179 TI - Synthesis and properties of thymidines with six-membered amide bridge. AB - Artificial thymidine monomers possessing amide or N-methylamide bridges were designed, synthesized, and introduced into oligonucleotides. UV-melting experiments showed that these oligonucleotides preferred single-stranded RNA (ssRNA) to single-stranded DNA (ssDNA) in duplex formation. Both amide- and N methylamide-modified oligonucleotides led to a significant increase in the binding affinity to ssRNA by up to +4.7 and +3.7 degrees C of the Tm value per modification, respectively, compared with natural oligonucleotide. In addition, their oligonucleotides showed high stability against 3'-exonuclease. PMID- 23685180 TI - Design, synthesis and evaluation of retinoids with novel bulky hydrophobic partial structures. AB - Many synthetic retinoids contain an aromatic structure with a bulky hydrophobic fragment. In order to obtain retinoids with therapeutic potential that do not bind to or activate retinoic acid X receptors (RXRs), we focused on the introduction of novel hydrophobic moieties, that is, metacyclophane, phenalene and benzoheptalene derivatives. The designed compounds were synthesized and their agonistic activities towards RARs and RXRs were evaluated. Most of the active compounds showed selectivity for RARalpha and RARbeta over RARgamma, and higher RARbeta transactivating activity seemed to correlate with higher cell differentiation-inducing activity towards promyelocytic leukemia cell line HL-60. These compounds showed no agonistic activity towards RXRs. PMID- 23685181 TI - Novel artemisinin derivatives with potential usefulness against liver/colon cancer and viral hepatitis. AB - Antitumor and antiviral properties of the antimalaria drug artemisinin from Artemisia annua have been reported. Novel artemisinin derivatives (AD1-AD8) have been synthesized and evaluated using in vitro models of liver/colon cancer and viral hepatitis B and C. Cell viability assays after treating human cell lines from hepatoblastoma (HepG2), hepatocarcinoma (SK-HEP-1), and colon adenocarcinoma (LS174T) with AD1-AD8 for a short (6h) and long (72h) period revealed that AD5 combined low acute toxicity together with high antiproliferative effect (IC50=1 5MUM). Since iron-mediated activation of peroxide bond is involved in artemisinin antimalarial activity, the effect of iron(II)-glycine sulfate (ferrosanol) and iron(III)-containing protoporphyrin IX (hemin) was investigated. Ferrosanol, but not hemin, enhanced antiproliferative activity of AD5 if the cells were preloaded with AD5, but not if both compouds were added together. Five derivatives (AD1>AD2>AD7>AD3>AD8) were able to inhibit the cytopathic effect of bovine viral diarrhoea virus (BVDV), a surrogate in vitro model of hepatitis C virus (HCV), used here to evaluate the anti-Flaviviridae activity. Moreover, AD1 and AD2 inhibited the release of BVDV-RNA to the culture medium. Co-treatment with hemin or ferrosanol resulted in enhanced anti-Flaviviridae activity of AD1. In HepG2 cells permanently infected with hepatitis B virus (HBV), AD1 and AD4, at non toxic concentrations for the host cells were able to reduce the release of HBV DNA to the medium. In conclusion, high pharmacological interest deserving further evaluation in animal models has been identified for novel artemisinin-related drugs potentially useful for the treatment of liver cancer and viral hepatitis B and C. PMID- 23685182 TI - Reaction of 3',5'-di-O-acetyl-2'-deoxyguansoine with hypobromous acid. AB - Hypobromous acid (HOBr) is formed by eosinophil peroxidase and myeloperoxidase in the presence of H2O2, Cl(-), and Br(-) in the host defense system of humans, protecting against invading bacteria. However, the formed HOBr may cause damage to DNA and its components in the host. When a guanine nucleoside (3',5'-di-O acetyl-2'-deoxyguansoine) was treated with HOBr at pH 7.4, spiroiminodihydantoin, guanidinohydantoin/iminoallantoin, dehydro-iminoallantoin, diimino-imidazole, amino-imidazolone, and diamino-oxazolone nucleosides were generated in addition to an 8-bromoguanine nucleoside. The major products were spiroiminodihydantoin under neutral conditions and guanidinohydantoin/iminoallantoin under mildly acidic conditions. All the products were formed in the reaction with HOCl in the presence of Br(-). These products were also produced by eosinophil peroxidase or myeloperoxidase in the presence of H2O2, Cl(-), and Br(-). The results suggest that the products other than 8-bromoguanine may also have importance for mutagenesis by the reaction of HOBr with guanine residues in nucleotides and DNA. PMID- 23685183 TI - Trigeminal nerve anatomy in neuropathic and non-neuropathic orofacial pain patients. AB - Trigeminal neuralgia, painful trigeminal neuropathy, and painful temporomandibular disorders (TMDs) are chronic orofacial pain conditions that are thought to have fundamentally different etiologies. Trigeminal neuralgia and neuropathy are thought to arise from damage to or pressure on the trigeminal nerve, whereas TMD results primarily from peripheral nociceptor activation. This study sought to assess the volume and microstructure of the trigeminal nerve in these 3 conditions. In 9 neuralgia, 18 neuropathy, 20 TMD, and 26 healthy controls, the trigeminal root entry zone was selected on high-resolution T1 weighted magnetic resonance images and the volume (mm(3)) calculated. Additionally, using diffusion-tensor images (DTIs), the mean diffusivity and fractional anisotropy values of the trigeminal nerve root were calculated. Trigeminal neuralgia patients displayed a significant (47%) decrease in nerve volume but no change in DTI values. Conversely, trigeminal neuropathy subjects displayed a significant (40%) increase in nerve volume but again no change in DTI values. In contrast, TMD subjects displayed no change in volume or DTI values. The data suggest that the changes occurring within the trigeminal nerve are not uniform in all orofacial pain conditions. These structural and volume changes may have implications in diagnosis and management of different forms of chronic orofacial pain. PERSPECTIVE: This study reveals that neuropathic orofacial pain conditions are associated with changes in trigeminal nerve volume, whereas non neuropathic orofacial pain is not associated with any change in nerve volume. PMID- 23685184 TI - Endogenous inhibition of somatic pain is impaired in girls with irritable bowel syndrome compared with healthy girls. AB - Endogenous pain inhibition is often deficient in adults with chronic pain conditions including irritable bowel syndrome (IBS). It is unclear whether deficiencies in pain inhibition are present in young children with IBS. The present study compared endogenous pain inhibition, somatic pain threshold, and psychosocial distress in young girls with IBS versus controls. Girls with IBS did not show significant endogenous pain inhibition of heat pain threshold during a cold-pressor task in contrast to controls, who had significant pain inhibition. Girls with IBS did not differ from peers on measures of somatic pain but had more symptoms of depression, somatization, and anxiety than controls. When psychological variables were included as covariates, the difference in pain inhibition was no longer significant, although poor achieved power limits interpretation of these results. Higher-order cognitive processes including psychological variables may be contributing to observed pain inhibition. In girls with IBS, pain inhibition was positively related to the number of days without a bowel movement. To our knowledge, this is the first study to demonstrate deficiencies of endogenous pain inhibition in young children with IBS. Findings have implications for better understanding of onset and maintenance of IBS and other chronic pain conditions. PERSPECTIVE: This study found that young girls with IBS have deficient endogenous pain inhibition compared to healthy girls, which is consistent with the literature on adults. This information can facilitate clinicians in identification of risk factors for onset/maintenance of IBS and other chronic pain conditions. PMID- 23685186 TI - Are psychological predictors of chronic postsurgical pain dependent on the surgical model? A comparison of total knee arthroplasty and breast surgery for cancer. AB - Anxiety, depression, and catastrophizing are generally considered to be predictive of chronic postoperative pain, but this may not be the case after all types of surgery, raising the possibility that the results depend on the surgical model. We assessed the predictive value of these factors for chronic postsurgical pain in 2 different surgical models: total knee arthroplasty for osteoarthritis (89 patients, 65% women, age = 69 +/- 9 years, baseline pain intensity = 4.7 +/- 2.1) and breast surgery for cancer (100 patients, 100% women, age = 55 +/- 12 years, no preoperative pain). Data were collected before surgery, then 2 days and 3 months after surgery. Anxiety, depression, and catastrophizing were measured with the Spielberger State-Trait Anxiety Inventory, Beck Depression Inventory, and Pain Catastrophizing Scale, respectively. Pain was assessed with the Brief Pain Inventory. Neuropathic pain was detected with the DN4 questionnaire. Multivariate logistic regression analyses for the total knee arthroplasty and breast surgery models considered together indicated that the presence of clinically meaningful chronic pain at 3 months (pain intensity >=3/10) was predicted independently by age (P = .04), pain intensity on day 2 (P = .009), and state anxiety (P = .001). Linear regression models also showed that pain magnification, one of the dimensions of catastrophizing, independently predicted chronic pain intensity (P = .04). These results were not affected by the surgical model or by the neuropathic characteristics of the pain. Thus, state anxiety and pain magnification seem to constitute psychological risk factors for chronic postsurgical pain relevant in all surgical models. PERSPECTIVE: This prospective study performed in patients with total knee arthroplasty or breast surgery for cancer shows that state anxiety, amplification of pain, and acute postoperative pain independently predict postsurgical pain at 3 months and that this does not depend on the surgical model. PMID- 23685185 TI - Structural brain anomalies and chronic pain: a quantitative meta-analysis of gray matter volume. AB - The diversity of chronic pain syndromes and the methods employed to study them make integrating experimental findings challenging. This study performed coordinate-based meta-analyses using voxel-based morphometry imaging results to examine gray matter volume (GMV) differences between chronic pain patients and healthy controls. There were 12 clusters where GMV was decreased in patients compared with controls, including many regions thought to be part of the "pain matrix" of regions involved in pain perception, but also including many other regions that are not commonly regarded as pain-processing areas. The right hippocampus and parahippocampal gyrus were the only regions noted to have increased GMV in patients. Functional characterizations were implemented using the BrainMap database to determine which behavioral domains were significantly represented in these regions. The most common behavioral domains associated with these regions were cognitive, affective, and perceptual domains. Because many of these regions are not classically connected with pain and because there was such significance in functionality outside of perception, it is proposed that many of these regions are related to the constellation of comorbidities of chronic pain, such as fatigue and cognitive and emotional impairments. Further research into the mechanisms of GMV changes could provide a perspective on these findings. PERSPECTIVE: Quantitative meta-analyses revealed structural differences between brains of individuals with chronic pain and healthy controls. These differences may be related to comorbidities of chronic pain. PMID- 23685188 TI - Diet and vitamin D as risk factors for lung impairment and COPD. AB - Epidemiologic and observational studies have shown an association between increased intakes of certain micronutrients and higher levels of lung function and health. The National Health and Nutrition Examination Surveys of the U.S. population have demonstrated repeatedly that increased intakes or serum levels of some micronutrients, including the vitamins E, D, C, and A, and carotenes are associated positively with forced expiratory volume in 1 second (FEV1). These findings are complemented by other observational studies, including the MORGEN study as well as the Seven Countries Study, both of which found micronutrient status had positive correlations with pulmonary function. In addition, epidemiologic studies have demonstrated that dietary intake patterns with increased intakes of fruit, vegetables, fish, vitamin E, and whole grains have been associated with a decreased development of chronic obstructive pulmonary disease (COPD) in smokers and nonsmokers, higher levels of FEV1, and decreased long-term COPD mortality. Diets high in refined food have been associated with accelerated longitudinal decline in FEV1 over 5 years. Taken together, these results suggest that micronutrient status may impact lung function, and that nutrition interventions could be a useful tool in a public health campaign aimed at the prevention of lung disease. Future research should focus on the effect of nutrition interventions on the natural history of lung disease. PMID- 23685187 TI - Increased axonal regeneration and swellings in intraepidermal nerve fibers characterize painful phenotypes of diabetic neuropathy. AB - We examined changes in intraepidermal nerve fibers (IENFs) to differentiate patients with diabetic neuropathy (DN) and diabetic neuropathic pain (DN-P) from those with DN without pain (DN-NOP). Punch skin biopsies were collected from the proximal thigh (PT) and distal leg (DL) of normal subjects, patients with type 2 diabetes without evidence of DN (DM), or DN-P and DN-NOP patients. Protein gene product 9.5-positive (PGP+) immunohistochemistry was used to quantify total IENF, and growth-associated protein 43 (GAP43) for regenerating IENF. Compared to normal subjects and patients with type 2 diabetes without evidence of DN, both DN P and DN-NOP have reduced PGP+ IENF densities in DL and PT. Although GAP43+ IENF densities were also reduced in DL for both DN-P and DN-NOP, the GAP43+ IENF densities in PT of DN-P remained at the control levels. Higher GAP43/PGP ratios were detected in DN-P compared to DN-NOP in the DL and PT. In parallel, increased numbers of axonal swellings per PGP+ fiber (axonal swelling/PGP) were detected in DN-P compared to normal subjects, patients with type 2 diabetes without evidence of DN, and DN-NOP in the DL. These axonal swellings were positive for tropomyosin receptor-kinase A and substance P, suggesting that they are associated with nociception. PERSPECTIVE: Among patients with DN, the ratios of GAP43/PGP and axonal swelling/PGP are likely to differentiate painful from painless phenotypes. PMID- 23685189 TI - Oral L-citrulline administration improves memory deficits following transient brain ischemia through cerebrovascular protection. AB - L-citrulline (L-Cit) is known to increase nitric oxide (NO) production via the increase of L-arginine (L-Arg) concentration in the blood and improve endothelial dysfunction in cardiovascular diseases. However, little is known about the effects of L-Cit on cerebrovascular dysfunction. Here we showed that oral L-Cit administration prevents cerebrovascular injury following cerebral ischemia using a 20-min bilateral common carotid artery occlusion (BCCAO) mouse model. After BCCAO ischemia, mice were treated with L-Cit (50, 75, or 100 mg/kg p.o.) for 10 days once a day. L-Cit administration not only prevented neuronal cell death but also prevented capillary loss in the hippocampal region following brain ischemia. The cerebrovascular protective effect of L-Cit was associated with the restoration of endothelial nitric oxide synthase (eNOS) expression in the hippocampus. In addition, we devised a novel protocol to analyze NOx(-) (NO(2-) and NO(3-)) productions following L-Arg infusion using in vivo microdialysis and revealed that decreased L-Arg-induced NOx(-) levels were improved in the hippocampus of BCCAO mice following repeated L-Cit administration. Finally, memory deficits following brain ischemia were improved by oral administration of L-Cit. In summary, L-Cit is a potential therapeutic agent that protects cerebrovascular injury and in turn prevents neuronal cell death. Thereby, oral L Cit administration improves cognitive deficits following brain ischemia. PMID- 23685191 TI - The fate of object memory traces under change detection and change blindness. AB - Observers often fail to detect substantial changes in a visual scene. This so called change blindness is often taken as evidence that visual representations are sparse and volatile. This notion rests on the assumption that the failure to detect a change implies that representations of the changing objects are lost all together. However, recent evidence suggests that under change blindness, object memory representations may be formed and stored, but not retrieved. This study investigated the fate of object memory representations when changes go unnoticed. Participants were presented with scenes consisting of real world objects, one of which changed on each trial, while recording event-related potentials (ERPs). Participants were first asked to localize where the change had occurred. In an additional recognition task, participants then discriminated old objects, either from the pre-change or the post-change scene, from entirely new objects. Neural traces of object memories were studied by comparing ERPs for old and novel objects. Participants performed poorly in the detection task and often failed to recognize objects from the scene, especially pre-change objects. However, a robust old/novel effect was observed in the ERP, even when participants were change blind and did not recognize the old object. This implicit memory trace was found both for pre-change and post-change objects. These findings suggest that object memories are stored even under change blindness. Thus, visual representations may not be as sparse and volatile as previously thought. Rather, change blindness may point to a failure to retrieve and use these representations for change detection. PMID- 23685190 TI - Long-lasting distortion of GABA signaling in MS/DB neurons after binge-like ethanol exposure during initial synaptogenesis. AB - Using a well-established model of binge-like ethanol treatment of rat pups on postnatal days (PD) 4-9, we found that maturation of GABAA receptor (GABAAR) miniature postsynaptic currents (mPSCs) was substantially blunted for medial septum/diagonal band (MS/DB) neurons in brain slices on PD 11-16. Ethanol reduced mPSC amplitude, frequency, and decay kinetics, while attenuating or exaggerating allosteric actions of zolpidem and allopregnanolone, respectively. The impact of ethanol in vivo was long lasting as most changes in MS/DB GABAAR mPSCs were still observed as late as PD 60-85. Maturing MS/DB neurons in naive brain slices PD 4 16 showed increasing mPSC frequency, decay kinetics, and zolpidem sensitivity that were nearly identical to our earlier findings in cultured septal neurons (DuBois et al., 2004, 2006). These rapidly developing mPSC parameters continued to mature through the first month of life then stabilized throughout the remainder of the lifespan. Finally, equivalent ethanol-induced alterations in GABAAR mPSC signaling were present in MS/DB neurons from both male and female animals. Previously, we showed ethanol treatment of cultured embryonic day 20 septal neurons distorts the maturation of GABAAR mPSCs predicting that early stages of GABAergic transmission in MS/DB neurons are vulnerable to intoxication injury (DuBois et al., 2004, 2006). Since the overall character, timing, and magnitude of GABAergic mPSC developmental- and ethanol-induced changes in the in vivo model so closely mirror chronologically equivalent adaptations in cultured septal neurons, this suggests that such parallel models of ethanol impairment of GABAergic synaptic development in vivo and in vitro should be useful for translational studies exploring the efficacy and mechanism of action of potential therapeutic interventions from the cellular to whole animal level. PMID- 23685192 TI - Histone deacetylase 3 implicated in the pathogenesis of children glioma by promoting glioma cell proliferation and migration. AB - BACKGROUND: Glioma is an aggressive cancer with high mortality, especially in children. It is known that histone modification plays an important role in the pathogenesis of various cancers. However, it is unknown whether histone deacetylase 3 (HDAC3) plays a role in the tumorigenesis of children gliomas. This study was aimed to explore the potential effects of HDAC3 in children gliomas. Expression of HDAC3 was measured in children glioma samples (n=70) and normal brain tissues (n=7) by real-time PCR and western blotting. Survival of the two groups was analyzed by the Kaplan-Meier method. The effects of HDAC3 in the pathogenesis of gliomas were analyzed by silencing the glioma cells U87-MG and U251. Data showed that HDAC3 was significantly elevated in children's gliomas, following the glioma grade, with almost no expression in normal brain tissues. Ectopic HDAC3 expression was correlated with poorer prognosis of children with glioma. In glioma cell lines, inhibition of HDAC3 using siRNA could suppress proliferation and sphere formation, induce G0/G1 arrest and apoptosis, and suppress the migration of glioma cells in comparison with controls. The higher level of HDAC3 expression was associated with more advanced tumor grades and shorter survival. HDAC3 participated in the pathogenesis of children gliomas by promoting glioma cell proliferation and migration. PMID- 23685193 TI - Word-stem tones cue suffixes in the brain. AB - High and low tones on Swedish word stems are associated with different classes of suffixes. We tested the electrophysiological effects of high and low stem tones as well as tonally cued and uncued suffixes. Two different tasks were used involving either choosing the suffix-dependent meaning of the words, or pressing a button when the word ended. To determine whether effects were in fact due to association of tones with lexical material, delexicalized stimuli were also used. High tones in lexical items produced an increase in the P2 component in both tasks, interpreted as showing passive anticipatory attention allocated to the associated upcoming suffix. This effect was absent for delexicalized forms, where instead an N1 increase was found for high tones, indicating that the high pitch was unexpected in the absence of lexical material, and did not lead to anticipatory attention. A P600 effect was found for uncued high-associated suffixes in the semantic task, which was also where the largest increase was found in reaction times. This suggests that the tonal cues were most important when participants were required to process the meaning of the words. PMID- 23685194 TI - Neuroprotective effect of suppression of astrocytic activation by arundic acid on brain injuries in rats with acute subdural hematomas. AB - Acute subdural hematoma (ASDH) can cause massive ischemic cerebral blood flow (CBF) underneath the hematoma, but early surgical evacuation of the mass reduces mortality. The aim of this study was to evaluate whether arundic acid improves the secondary ischemic damage induced by ASDH. Our results confirmed that arundic acid decreases the expression of S100 protein produced by activated astrocytes around ischemic lesions due to cytotoxic edema after ASDH as well as reducing infarction volumes and numbers of apoptotic cells around the ischemic lesions. In this study, we also evaluate the relationship of brain edema and the expression of Aquaporin 4 (AQP4) in an ASDH model. The expression of AQP4 was decreased in the acute phase after ASDH. Cytotoxic edema, assumed to be the main cause of ASDH, could also cause ischemic lesions around the edema area. Arundic acid decreased the infarction volume and number of apoptotic cells via suppression of S100 protein expression in ischemic lesions without changing the expression of AQP4. PMID- 23685195 TI - Effects of an aqueous extract of Crataegus pinnatifida Bge. var. major N.E.Br. fruit on experimental atherosclerosis in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Atherosclerosis (AS) can result in severe cardiovascular diseases. Early indications of AS include disorders in lipid metabolism, inflammatory responses, and endothelial dysfunction. Statins are the preferred drugs for stabilizing atherosclerotic plaques because of their lipid lowering, anti-inflammation and endothelial-protection activities. However, they can exhibit side effects and are effective in only one-third of patients. Many natural products (especially traditional Chinese medicines (TCMs)) possessing similar lipid-lowering, anti-inflammation and antioxidant activities are of interest in many studies exploring new AS drug therapy. The widely distributed hawthorn is used to prevent and cure heart disease not only in China but also in the United States and several European countries. For example, the fruit of Crataegus pinnatifida Bge. and Crataegus pinnatifida Bge. var. major N.E.Br. (a commonly used hawthorn fruit in China) is used in combination with other TCMs to treat AS. Studies have also shown that the water extracts of these two hawthorn fruits are effective against hyperlipidemia by lowering lipid levels, reducing endothelial dysfunction, and inhibiting inflammation. The aim of the study is to investigate the effect and possible mechanisms of the aqueous extract of Crataegus pinnatifida var. major on AS rats. MATERIALS AND METHODS: The fruit of Crataegus pinnatifida var. major was extracted with 70% ethanol; the ethanol extract was chromatographed on a D101 macroporous resin to obtain a sugar-free aqueous extract (AECP). Atherosclerotic rats were fed a high-fat diet and injected with vitamin D3 and ovalbumin. Rats were divided into five groups: normal, model, model plus simvastatin, model plus low-dose AECP, and model plus high-dose AECP. AECP and simvastatin were administered (via the intragastric route) to AECP groups and the simvastatin group. For normal and model groups, water was given for 4 weeks. After 12 weeks, levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-C) and high-density lipoprotein-cholesterol (HDL-C) in blood were measured by an automatic biochemistry analyzer. Serum concentrations of interleukin (IL)-1beta, IL-8, nitric oxide (NO), endothelin (ET), 6-keto-prostaglandin F1alpha (6-keto PGF1alpha) and thromboxane B2 (TXB2) were determined by radioimmunoassay (RIA). Serum concentrations of C-reactive protein (CRP) and IL-18 were measured by enzyme-linked immunosorbent assay (ELISA). Pathological changes in arteries were observed using an optical microscope and the intima-media thickness (IMT) calculated. Cholesterol deposition was evaluated by filipin staining. Chemical ingredients in AECP were analyzed by qualitative and quantitative means by high performance liquid chromatography (HPLC). RESULTS: AECP significantly reduced the levels of TC, TG and LDL-C but increased HDL-C levels. It also decreased the concentrations of CRP, IL-1beta, IL-8 and IL-18. AECP increased levels of ET and TXB2 but increased 6-keto-PGF1alpha levels. Histopathological examination showed that AECP inhibited pathological changes in the arteries of AS rats and reduced IMT. Chemical analysis suggested that the main components of AECP were chlorogenic acid, procyanidin B2, (-)-epicatechin, rutin and isoquercitrin. CONCLUSIONS: These data suggest that AECP can inhibit AS progression in high-fat diet-fed rats. Possible mechanisms of action include improvement of lipid metabolism, decrease in inflammatory cytokine responses, and protection of the endothelium. PMID- 23685197 TI - Functional plasticity in Alzheimer's disease: effect of cognitive training on language-related ERP components. AB - Starting from the observation of a reduced gray matter in the inferior temporal regions of Alzheimer's disease (AD) patients, the present study hypothesized an altered language-related functional activity in left occipito-temporal areas in AD, and the possibility of a plastic change of these regions induced by an intensive cognitive training. To this aim, eleven mild/moderate AD underwent to a 5-week cognitive training (40 h). Before and after the training, evoked potentials were recorded from 26 scalp electrodes during a lexical decision task which required word/no-word discrimination. Stimuli included high- and low frequency words and non-words, and the recognition potential (RP) together with the N400 have been analyzed and compared with those collected from a matched healthy control group. Results comparing controls and patients before training showed a normal RP in AD patients with a clear peak over left occipito-temporal sites. In addition, controls exhibited a left anterior lateralization of N400 component to words and an inverted pattern for non-words, whereas an altered N400 with bilateral distribution at both word and non-word conditions was found in AD patients. After the cognitive training, AD patients did not show changes in the N400, but revealed a significant enhanced amplitude of RP to high-frequency words. Behavioral responses to the lexical decision task and scores from neuropsychological tests did not evidence improvements nor worsening after training. These data point to an intact functionality of left posterior linguistic networks in mild/moderate AD, and the possibility to increase plastically their activity after a cognitive training. PMID- 23685198 TI - Fat taste in humans: sources of within- and between-subject variability. AB - Non-esterified fatty acids (NEFA) are reportedly detectable through taste mechanisms in the human oral cavity. However, wide variability has been observed in NEFA taste sensitivity between and within subjects as well as across research groups. Some of this variability may be due to the hydrophobic nature of the NEFA and the methods used to make stimuli emulsions. As NEFA are poorly soluble in water, emulsification is necessary for delivery of stimuli to taste receptors. However, properties of emulsions may also be detected by somatosensory cues complicating attribution of sensory findings to taste. Additionally, learning (improved test performance) has been observed when using traditional tests for measuring sensitivity to NEFA, which may contribute greatly to within-subject variability if not standardized. Factors such as sex, diet, and BMI have been proposed to affect NEFA taste sensitivity, but the degree to which these individual factors influence NEFA detection thresholds remains to be fully established. Improved knowledge of stimulus properties and individual sensory capabilities will be needed to further evaluate the posited taste component to human oral fat detection. Progress in this area should facilitate the translation of findings on how NEFA taste may contribute to or reflect food choice and chronic disease risk. PMID- 23685196 TI - Naming and gesturing spatial relations: evidence from focal brain-injured individuals. AB - Spatial language helps us to encode relations between objects and organize our thinking. Little is known about the neural instantiations of spatial language. Using voxel-lesion symptom mapping (VLSM), we tested the hypothesis that focal brain injured patients who had damage to left frontal-parietal peri-Sylvian regions would have difficulty in naming spatial relations between objects. We also investigated the relationship between impaired verbalization of spatial relations and spontaneous gesture production. Patients with left or right hemisphere damage and elderly control participants were asked to name static (e.g., an apple on a book) and dynamic (e.g., a pen moves over a box) locative relations depicted in brief video clips. The correct use of prepositions in each task and gestures that represent the spatial relations were coded. Damage to the left posterior middle frontal gyrus, the left inferior frontal gyrus, and the left anterior superior temporal gyrus were related to impairment in naming spatial relations. Production of spatial gestures negatively correlated with naming accuracy, suggesting that gestures might help or compensate for difficulty with lexical access. Additional analyses suggested that left hemisphere patients who had damage to the left posterior middle frontal gyrus and the left inferior frontal gyrus gestured less than expected, if gestures are used to compensate for impairments in retrieving prepositions. PMID- 23685200 TI - Organophosphate poisoning in the developed world - a single centre experience from here to the millennium. AB - Organophosphate (OP) poisoning is still associated with high morbidity and mortality rates, both in resource-poor settings and in well-developed countries. Despite numerous publications dealing with this particular poison, detailed clinical data on more severe overdoses with these agents are relatively sparsely reported. A retrospective study was consequently conducted on 33 patients with OP poisoning admitted to our intensive care unit (ICU) to provide additional data on clinical features. We included moderate to severe poisonings between 2000 and 2012 who required admission to ICU. Patients ingested dimethyl-OPs in 19 cases, diethyl-OPs in 8 cases and otherwise classified OPs in 6 cases. Death (5/33) occurred rather late and only one of these fatalities died during on-going cholinergic crisis. Of the survivors (28/33), 71% recovered fully while 29% showed predominantly neurological disabilities before being transferred to neurologic rehabilitation. Aspiration pneumonia predominated in 27/33 patients and one patient died in refractory acute respiratory distress syndrome (ARDS). The intermediate syndrome occurred twice and cardiopulmonary resuscitation had to be performed in 6/33 patients. Fatalities showed a higher Poison-severity-score, APACHE-II-score and SOFA-score on admission compared with survivors and they showed significantly longer QTc-time in the ECG, lower systolic blood pressure and heart rate, a lower pH and a lower base excess on admission. Patients with diethyl-OPs required intubation significantly earlier and showed lower and more sustained inhibited activity of the plasma-cholinesterase on admission compared with patients ingesting dimethyl-OPs. Treatment with atropine and obidoxime was comparable between these groups and severity of poisoning, outcome, hemodynamics on admission, duration of mechanical ventilation and length of stay in the ICU did not significantly differ between the involved group of dimethyl- and diethyl OPs. We conclude that the fatality rate in our patient cohort treated in a well staffed and equipped ICU of a developed country is quite similarly high compared with the rate observed in developing countries. Patients died rather late when severe cholinergic crisis had mostly been overcome and death was therefore related to non-poison specific complications. PMID- 23685199 TI - Advancing oleaginous microorganisms to produce lipid via metabolic engineering technology. AB - With the depletion of global petroleum and its increasing price, biodiesel has been becoming one of the most promising biofuels for global fuels market. Researchers exploit oleaginous microorganisms for biodiesel production due to their short life cycle, less labor required, less affection by venue, and easier to scale up. Many oleaginous microorganisms can accumulate lipids, especially triacylglycerols (TAGs), which are the main materials for biodiesel production. This review is covering the related researches on different oleaginous microorganisms, such as yeast, mold, bacteria and microalgae, which might become the potential oil feedstocks for biodiesel production in the future, showing that biodiesel from oleaginous microorganisms has a great prospect in the development of biomass energy. Microbial oils biosynthesis process includes fatty acid synthesis approach and TAG synthesis approach. In addition, the strategies to increase lipids accumulation via metabolic engineering technology, involving the enhancement of fatty acid synthesis approach, the enhancement of TAG synthesis approach, the regulation of related TAG biosynthesis bypass approaches, the blocking of competing pathways and the multi-gene approach, are discussed in detail. It is suggested that DGAT and ME are the most promising targets for gene transformation, and reducing PEPC activity is observed to be beneficial for lipid production. PMID- 23685201 TI - Safety pharmacology investigations in toxicology studies: an industry survey. AB - INTRODUCTION: The Safety Pharmacology (SP) Society (SPS) conducted an industry survey in 2012 in an attempt to define current industry practices as they relate to inclusion of safety pharmacology (SP) endpoints into Toxicology studies. METHODS: A total of 361 participants from Asia (9.1%), Europe (19.4%) and North America (71.4%) responded to the survey. The preponderance of respondents were toxicologists (53.2%) followed by safety pharmacologists (27.2%) and scientists involved in the conduct of both disciplines (19.6%). Most participants (58.6%) were from pharmaceutical companies employing more than 500 employees. RESULTS: A majority (68.2%) reported having experience in designing, performing or interpreting the SP component of a study when performed as part of a toxicology study. Some participants (42.0%) had submitted data to a regulatory agency where ICHS7 studies were performed as part of a toxicology study rather than as a standalone study. When comparing species that were used in studies in which SP was added to toxicology studies, canines were the most frequently reported animals used for new chemical entities (NCE) whereas non-human (NH) primates were the most frequent for the assessment of biological agents. The most frequent primary motivator for adding ICHS7 SP endpoints to regulatory toxicology studies was to generate additional data to allow for determination of an integrated risk assessment thereby testing Confidence in Safety (CIS) to better manage and/or mitigate risk. The current ability to add safety pharmacology endpoints into regulatory toxicology studies was used to address a specific concern (by 42.1% of respondents) to allow management of risk more effectively (36.8%) or to generate data that contributes to cessation of the progression of a compound (21.1%). For an NCE, SP measurements in toxicology studies were conducted in addition to standalone SP studies (by 40.6% of respondents) or in addition/instead of standalone safety pharmacology studies (by 39.8% of respondents). For biological agents, a majority (74.3%) indicated SP measurements in toxicology were conducted instead of standalone studies as outlined in the ICHS6 guideline while inclusion of SP endpoints in toxicology studies for biological agents in addition to standalone studies was reported by only 25.7% of the respondents. DISCUSSION: The survey highlights that obtaining regulatory agreement for the proposed combined SP/Tox study designs may be useful before study conduct in some cases. Respondents suggest that such discussion could occur at the pre-IND meeting before the IND/CTA enabling program. PMID- 23685202 TI - Obesity and psychiatric disorders: commonalities in dysregulated biological pathways and their implications for treatment. AB - Rates of obesity are higher than normal across a range of psychiatric disorders, including major depressive disorder, bipolar disorder, schizophrenia and anxiety disorders. While the problem of obesity is generally acknowledged in mental health research and treatment, an understanding of their bi-directional relationship is still developing. In this review the association between obesity and psychiatric disorders is summarised, with a specific emphasis on similarities in their disturbed biological pathways; namely neurotransmitter imbalances, hypothalamus-pituitary-adrenal axis disturbances, dysregulated inflammatory pathways, increased oxidative and nitrosative stress, mitochondrial disturbances, and neuroprogression. The applicability and effectiveness of weight-loss interventions in psychiatric populations are reviewed along with their potential efficacy in ameliorating disturbed biological pathways, particularly those mediating inflammation and oxidative stress. It is proposed that weight loss may not only be an effective intervention to enhance physical health but may also improve mental health outcomes and slow the rate of neuroprogressive disturbances in psychiatric disorders. Areas of future research to help expand our understanding of the relationship between obesity and psychiatric disorders are also outlined. PMID- 23685203 TI - Chlamydia positivity in New Orleans public high schools, 1996-2005: implications for clinical and public health practices. AB - OBJECTIVE: To describe the trends in chlamydia positivity among New Orleans high school students tested in a schoolwide screening between 1996 and 2005, and to determine factors associated with chlamydia positivity among students during the 10-year period. METHODS: Between school years 1995-1996 and 2004-2005, students in New Orleans public high schools were tested for chlamydia using nucleic acid amplification tests (NAAT) in urine specimens (LCx assay until 1999-2000; BD assay from 2000-2001 to 2004-2005). For each year, we calculated chlamydia positivity by dividing the number of students testing positive by the total number of students tested. Data were analyzed separately by gender. Logistic regressions were performed to determine independent predictors of chlamydia positivity during the 10-year period. RESULTS: Between 1996 and 2005, the average chlamydia positivity was 7.0% (95% confidence interval 6.6-7.4) in boys and 13.1% (95% confidence interval 12.6-13.7) in girls (P < .001). Chlamydia detection increased with the switch from LCx to BD assay. In multivariate analyses, chlamydia positivity among boys and girls was significantly associated with age, black race, and gonorrhea coinfection. Additionally, positivity was significantly different by school year among boys (P = .03) and by NAAT used among girls (P = .008). CONCLUSIONS: The trends in chlamydia positivity observed between 1996 and 2005 more likely reflected a high and stable prevalence of chlamydia in the New Orleans school-age adolescent population. Any benefit of screening on individuals tested was likely to be mitigated by participants' uninterrupted social interactions with the dynamic forces that sustain the sexual transmission of chlamydia in the population. PMID- 23685204 TI - Drosophila as a model for intestinal dysbiosis and chronic inflammatory diseases. AB - The association between deregulated intestinal microbial consortia and host diseases has been recognized since the birth of microbiology over a century ago. Intestinal dysbiosis refers to a state where living metazoans harbor harmful intestinal microflora. However, there is still an issue of whether causality arises from the host or the microbe because it is unclear whether deregulation of the gut microbiota community is the consequence or cause of the host disease. Recent studies using Drosophila and its simple microbiota have provided a valuable model system for dissecting the molecular mechanisms of intestinal dysbiosis. In this review, we examine recent exciting observations in Drosophila gut-microbiota interactions, particularly the links among the host immune genotype, the microbial community structure, and the host inflammatory phenotype. Future genetic analyses using Drosophila model system will provide a valuable outcome for understanding the evolutionarily conserved mechanisms that underlie intestinal dysbiosis and chronic inflammatory diseases. PMID- 23685205 TI - Use of a randomized multiple baseline design: rationale and design of the spirited life holistic health intervention study. AB - Clergy suffer from high rates of obesity, chronic disease, and depression, and simultaneously underestimate the toll these take on their daily functioning. Health interventions are needed for clergy and may be tailored to their occupational context and theological beliefs. Few studies have sought to improve clergy health. No prior studies have utilized a randomized design. Spirited Life is a randomized, multiple baseline study that offered enrollment to nearly all United Methodist Church clergy in North Carolina in fall 2010. A total of 1114 clergy (response rate = 64%) enrolled. Using a multiple baseline design, we randomized participants to three cohorts. Each cohort began the health intervention in one of three consecutive years. The third cohort served as a randomized waitlist control cohort, allowing comparisons between the first and third cohorts. The two-year Spirited Life intervention consists of: 1) a theological underpinning for health stewardship based on incarnation, grace, and response and delivered during workshops; 2) the stress management program Williams LifeSkills; 3) Naturally Slim, an online weight loss program; 4) phone contact with a Wellness Advocate; and 5) $500 small grants for health goals. Metabolic syndrome is the primary endpoint. Stress and depressive severity are secondary endpoints. We measured each construct before, twice during, and at the end of the two-year intervention. Study outcomes, to be published after follow-up data are gathered, will provide evidence of the effectiveness of the combined intervention components of Spirited Life. If successful, the intervention may be considered for use with other clergy and faith populations. PMID- 23685207 TI - High functional load inhibits phonological contrast loss: a corpus study. AB - For nearly a century, linguists have suggested that diachronic merger is less likely between phonemes with a high functional load--that is, phonemes that distinguish many words in the language in question. However, limitations in data and computational power have made assessing this hypothesis difficult. Here we present the first larger-scale study of the functional load hypothesis, using data from sound changes in a diverse set of languages. Our results support the functional load hypothesis: phoneme pairs undergoing merger distinguish significantly fewer minimal pairs in the lexicon than unmerged phoneme pairs. Furthermore, we show that higher phoneme probability is positively correlated with merger, but that this effect is stronger for phonemes that distinguish no minimal pairs. Finally, within our dataset we find that minimal pair count and phoneme probability better predict merger than change in system entropy at the lexical or phoneme level. PMID- 23685206 TI - D-Cycloserine improves sociability in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorders with altered Ras/Raf/ERK1/2 signaling. AB - The genetically inbred BTBR T+ Itpr3tf/J (BTBR) mouse is a proposed model of autism spectrum disorders (ASDs). Similar to several syndromic forms of ASDs, mTOR activity may be enhanced in this mouse strain as a result of increased Ras signaling. Recently, D-cycloserine, a partial glycineB site agonist that targets the NMDA receptor, was shown to improve the sociability of the Balb/c mouse strain, another proposed genetically inbred model of ASDs. NMDA receptor activation is an important regulator of mTOR signaling activity. Given the ability of D-cycloserine to improve the sociability of the Balb/c mouse strain and the regulatory role of the NMDA receptor in mTOR signaling, we wondered if D cycloserine would improve the impaired sociability of the BTBR mouse strain. D Cycloserine (320 mg/kg, ip) improved measures of sociability in a standard sociability paradigm and spontaneous grooming that emerged during social interaction with an ICR stimulus mouse in the BTBR strain; however, similar effects were observed in the Swiss Webster comparator strain, raising questions about their strain-selectivity. Importantly, the profile of D-cycloserine's effects on both measures of sociability and stereotypies is consistent with that of a desired medication for ASDs; specifically, a desired medication would not improve sociability at the expense of worsening stereotypic behaviors or vice versa. PMID- 23685208 TI - Experimental investigations of weak definite and weak indefinite noun phrases. AB - Definite noun phrases typically refer to entities that are uniquely identifiable in the speaker and addressee's common ground. Some definite noun phrases (e.g., the hospital in Mary had to go the hospital and John did too) seem to violate this uniqueness constraint. We report six experiments that were motivated by the hypothesis that these "weak definite" interpretations arise in "incorporated" constructions. Experiments 1-3 compared nouns that seem to allow for a weak definite interpretation (e.g., hospital, bank, bus, radio) with those that do not (e.g., farm, concert, car, book). Experiments 1 and 2 used an instruction following task and picture-judgment task, respectively, to demonstrate that a weak definite need not uniquely refer. In Experiment 3 participants imagined scenarios described by sentences such as The Federal Express driver had to go to the hospital/farm. Scenarios following weak definite noun phrases were more likely to include conventional activities associated with the object, whereas following regular nouns, participants were more likely to imagine scenarios that included typical activities associated with the subject; similar effects were observed with weak indefinites. Experiment 4 found that object-related activities were reduced when the same subject and object were used with a verb that does not license weak definite interpretations. In Experiment 5, a science fiction story introduced an artificial lexicon for novel concepts. Novel nouns that shared conceptual properties with English weak definite nouns were more likely to allow weak reference in a judgment task. Experiment 6 demonstrated that familiarity for definite articles and anti-familiarity for indefinite articles applies to the activity associated with the noun, consistent with predictions made by the incorporation analysis. PMID- 23685209 TI - Modeling proteins using a super-secondary structure library and NMR chemical shift information. AB - A remaining challenge in protein modeling is to predict structures for sequences with no sequence similarity to any experimentally solved structure. Based on earlier observations, the library of protein backbone supersecondary structure motifs (Smotifs) saturated about a decade ago. Therefore, it should be possible to build any structure from a combination of existing Smotifs with the help of limited experimental data that are sufficient to relate the backbone conformations of Smotifs between target proteins and known structures. Here, we present a hybrid modeling algorithm that relies on an exhaustive Smotif library and on nuclear magnetic resonance chemical shift patterns without any input of primary sequence information. In a test of 102 proteins, the algorithm delivered 90 homology-model-quality models, among them 24 high-quality ones, and a topologically correct solution for almost all cases. The current approach opens a venue to address the modeling of larger protein structures for which chemical shifts are available. PMID- 23685210 TI - Three-dimensional RNA structure of the major HIV-1 packaging signal region. AB - HIV-1 genomic RNA has a noncoding 5' region containing sequential conserved structural motifs that control many parts of the life cycle. Very limited data exist on their three-dimensional (3D) conformation and, hence, how they work structurally. To assemble a working model, we experimentally reassessed secondary structure elements of a 240-nt region and used single-molecule distances, derived from fluorescence resonance energy transfer, between defined locations in these elements as restraints to drive folding of the secondary structure into a 3D model with an estimated resolution below 10 A. The folded 3D model satisfying the data is consensual with short nuclear-magnetic-resonance-solved regions and reveals previously unpredicted motifs, offering insight into earlier functional assays. It is a 3D representation of this entire region, with implications for RNA dimerization and protein binding during regulatory steps. The structural information of this highly conserved region of the virus has the potential to reveal promising therapeutic targets. PMID- 23685211 TI - Salmonella enterica MTAN at 1.36 A resolution: a structure-based design of tailored transition state analogs. AB - Accumulation of 5'-methylthioadenosine (MTA) and S-adenosylhomocysteine (SAH) in bacteria disrupts the S-adenosylmethionine pool to alter biological methylations, synthesis of polyamines, and production of quorum-sensing molecules. Bacterial metabolism of MTA and SAH depends on MTA/SAH nucleosidase (MTAN), an enzyme not present in humans and a target for quorum sensing because MTAN activity is essential for synthesis of autoinducer-2 molecules. Crystals of Salmonella enterica MTAN with product and transition state analogs of MTA and SAH explain the structural contacts causing pM binding affinity for the inhibitor and reveal a "water-wire" channel for the catalytic nucleophile. The crystal structure shows an extension of the binding pocket filled with polyethylene glycol. We exploited this discovery by the design and synthesis of tailored modifications of the currently existing transition state analogs to fill this site. This site was not anticipated in MTAN structures. Tailored inhibitors with dissociation constants of 5 to 15 pM are characterized. PMID- 23685213 TI - The difficult-to-treat, therapy-resistant cough: why are current cough treatments not working and what can we do? AB - Cough can persist despite exhaustive diagnostic and therapeutic effort and has been termed 'idiopathic' or 'unexplained' but perhaps 'difficult to treat' cough is a more appropriate description. In this article the reasons for poor treatment response are discussed. These include a lack of physician fidelity to management guidelines, patient non-adherence and the lack of effective medicines. A number of randomized controlled trials have been undertaken including low dose opiate therapy, the use of a speech pathology intervention, oral antibiotics and antidepressants. The success or otherwise of such interventions will be discussed. A number of approaches to deal with the problem of 'difficult to treat cough' will be considered. PMID- 23685212 TI - Crystal structure of the DNA cytosine deaminase APOBEC3F: the catalytically active and HIV-1 Vif-binding domain. AB - Human APOBEC3F is an antiretroviral single-strand DNA cytosine deaminase, susceptible to degradation by the HIV-1 protein Vif. In this study the crystal structure of the HIV Vif binding, catalytically active, C-terminal domain of APOBEC3F (A3F-CTD) was determined. The A3F-CTD shares structural motifs with portions of APOBEC3G-CTD, APOBEC3C, and APOBEC2. Residues identified to be critical for Vif-dependent degradation of APOBEC3F all fit within a predominantly negatively charged contiguous region on the surface of A3F-CTD. Specific sequence motifs, previously shown to play a role in Vif susceptibility and virion encapsidation, are conserved across APOBEC3s and between APOBEC3s and HIV-1 Vif. In this structure these motifs pack against each other at intermolecular interfaces, providing potential insights both into APOBEC3 oligomerization and Vif interactions. PMID- 23685214 TI - Giant sacral schwannoma with pelvic and lumbar spine extension. PMID- 23685215 TI - Biomechanics of lateral plate and pedicle screw constructs in lumbar spines instrumented at two levels with laterally placed interbody cages. AB - BACKGROUND CONTEXT: The lateral transpsoas approach to interbody fusion is gaining popularity because of its minimally invasive nature and resultant indirect neurologic decompression. The acute biomechanical stability of the lateral approach to interbody fusion is dependent on the type of supplemental internal fixation used. The two-hole lateral plate (LP) has been approved for clinical use for added stabilization after cage instrumentation. However, little biomechanical data exist comparing LP fixation with bilateral pedicle screw and rod (PSR) fixation. PURPOSE: To biomechanically compare the acute stabilizing effects of the two-hole LP and bilateral PSR fusion constructs in lumbar spines instrumented with a lateral cage at two contiguous levels. STUDY DESIGN: Biomechanical laboratory study of human cadaveric lumbar spines. METHODS: Eighteen L1-S1 cadaveric lumbar spines were instrumented with lateral cages at L3 L4 and L4-L5 after intact kinematic analysis. Specimens (n=9 each) were allocated for supplemental instrumentation with either LP or PSR. Intact versus instrumented range of motion was evaluated for all specimens by applying pure moments (+/-7.5 Nm) in flexion/extension, lateral bending (LB) (left+right), and axial rotation (AR) (left+right). Instrumented spines were later subjected to 500 cycles of loading in all three planes, and interbody cage translations were quantified using a nonradiographic technique. RESULTS: Lateral plate fixation significantly reduced ROM (p<.05) at both lumbar levels (flexion/extension: 49.5%; LB: 67.3%; AR: 48.2%) relative to the intact condition. Pedicle screw and rod fixation afforded the greatest ROM reductions (p<.05) relative to the intact condition (flexion/extension: 85.6%; LB: 91.4%; AR: 61.1%). On average, the largest interbody cage translations were measured in both fixation groups in the anterior-posterior direction during cyclic AR. CONCLUSIONS: Based on these biomechanical findings, PSR fixation maximizes stability after lateral interbody cage placement. The nonradiographic technique served to quantify migration of implanted hardware and may be implemented as an effective laboratory tool for surgeons and engineers to better understand mechanical behavior of spinal implants. PMID- 23685216 TI - Determining the quality and effectiveness of surgical spine care: patient satisfaction is not a valid proxy. AB - BACKGROUND CONTEXT: Given the unsustainable costs of the US health-care system, health-care purchasers, payers, and hospital systems are adopting the concept of value-based purchasing by shifting care away from low-quality providers or hospitals. Legislation now allows public reporting of these quality rankings. True measures of quality, such as surgical morbidity and validated questionnaires of effectiveness, are burdensome and costly to collect. Hence, patients' satisfaction with care has emerged as a commonly used metric as a proxy for quality because of its feasibility of collection. However, patient satisfaction metrics have yet to be validated as a measure of overall quality of surgical spine care. PURPOSE: We set out to determine whether patient satisfaction is a valid measure of safety and effectiveness of care in a prospective longitudinal spine registry. STUDY DESIGN: Prospective longitudinal cohort study. PATIENT POPULATION: All patients undergoing elective spine surgery for degenerative conditions over a 6-month period at a single medical center. OUTCOME MEASURES: Patient-reported outcome instruments (numeric rating scale [NRS], Oswestry disability index [ODI], neck disability index [NDI], short-form 12-item survey [SF-12], Euro-Qol-5D [EQ-5D], Zung depression scale, and Modified Somatic Perception Questionnaire [MSPQ] anxiety scale), return to work, patient satisfaction with outcome, and patient satisfaction with provider care. METHODS: All patients undergoing elective spine surgery for degenerative conditions over a 6-month period at a single medical center were enrolled into a prospective longitudinal registry. Data collected on all patients included demographics, disease characteristics, treatment variables, readmissions/reoperations, and all 90-day surgical morbidity. Patient-reported outcome instruments (NRS, ODI, NDI, SF-12, EQ-5D, Zung depression scale, and MSPQ anxiety scale), return to work, patient satisfaction with outcome, and patient satisfaction with provider care were recorded at baseline and 3 months after treatment. Receiver-operating characteristic (ROC) curve analysis was performed to determine whether extent of improvement in quality of life (SF-12 physical component summary [PCS]) and disability (ODI/NDI) accurately predicted patient satisfaction versus dissatisfaction. Standard interpretation of area under the curve (AUC) was used: less than 0.7, poor; 0.7 to 0.8, fair; and greater than 0.8, good accuracy. Multivariate logistic regression analysis was performed to determine if surgical morbidity (quality) or improvement in disability and quality of life (effectiveness of care) were independently associated with patient satisfaction. RESULTS: Four hundred twenty-two (84%) patients completed all questionnaires 3 months after surgery during the reviewed time period (mean age 55+/-14 years). Lumbar surgery was performed in 287 (68%) and cervical surgery in 135 (32%) patients. There were 51 (12.1%) 90-day complications, including 21 (5.0%) readmissions and 12 (2.8%) return to operating room. Three hundred fifty-eight (84.8%) patients were satisfied with provider care and 288 (68.2%) with their outcome. Satisfaction with provider care: In ROC analyses, extent of improvement in quality of life (SF-12) and disability (ODI/NDI) differentiated satisfaction versus dissatisfaction with care with very poor accuracy (AUC 0.49-0.69). In regression analysis, 3-month morbidity (odds ratio [95% confidence interval]: 1.45 [0.79-2.66]), readmission (0.66 [0.24-1.80]), improvement in quality of life (SF-12 PCS), or improvement in general health (health transition index) were not associated with satisfaction with care. Satisfaction with outcome: In ROC analyses, improvement in quality of life (SF-12) and disability (ODI/NDI) failed to differentiate satisfaction with good accuracy (AUC 0.76). Neither 90-day morbidity (1.05 [0.46-2.34]) nor 90-day readmission (0.27 [0.04-2.04]) was associated with satisfaction with outcome in regression analysis. CONCLUSIONS: Patient satisfaction is not a valid measure of overall quality or effectiveness of surgical spine care. Patient satisfaction metrics likely represent the patient's subjective contentment with health-care service, a distinct aspect of care. Satisfaction metrics are important patient-centered measures of health-care service but should not be used as a proxy for overall quality, safety, or effectiveness of surgical spine care. PMID- 23685217 TI - Do not miss it: paraspinal muscle atrophy in the concave side of the curve in patients with adult degenerative scoliosis. PMID- 23685218 TI - Traction X-ray under general anesthesia helps to save motion segment in treatment of Lenke type 3C and 6C curves. AB - BACKGROUND CONTEXT: In patients with structural lumbar curves, several studies have shown the advantages of stopping fusion at L3 and saving L4. However, fusing the L4 may still be deemed necessary in a significant number of patients with structural lumbar curves (ie, Lenke types 3 and 6) when fusion levels are selected by using traditional flexibility X-ray (TXR) methods such as supine side bends and traction. PURPOSE: The aim of this retrospective study was to evaluate the effectiveness of the traction X-ray under general anesthesia (TrUGA) method in saving the L4 in patients with Lenke types 3C and 6C curves. STUDY DESIGN: This was a retrospective clinical study. PATIENT SAMPLE: Eighty-nine consecutive patients (77 females and 12 males) with adolescent idiopathic scoliosis Lenke types 3C (46 patients) and 6C (43 patients) curves and who underwent an instrumented posterior spinal fusion by a single surgeon were included. The selection of lower instrumented vertebrae (LIV) was done by using the central sacral vertical line (CSVL). LIV was defined as the uppermost vertebrae of the lumbar curve that was not intersected by CSVL on standing anteroposterior radiograph, but became parallel to the sacrum and was intersected by CSVL at the concave bending or TrUGA. The disc wedging under LIV should be parallel or near parallel and rotation of LIV should be corrected at least one to two (Nash-Moe) grades. OUTCOME MEASURES: Radiological evaluation included preoperative standing AP, lateral and TXR, and intraoperative supine TrUGA, which was taken after the induction of anesthesia and before positioning the patient. LIV was determined by using TXR and TrUGA. Preoperative, postoperative with >=2 year follow-up curve magnitudes, LIV tilt, and disc wedging below LIV and CSVL to T1 distance were all measured. A satisfactory radiographic outcome was determined to be the result if CSVL was within 2 cm of the center of T1, the LIV tilt angle was less than 10 degrees , and any increase in thoracic and lumbar curve during follow-up was less than 5 degrees . Clinical outcome was analyzed by using follow-up Scoliosis Research Society-22 (SRS-22) questionnaire and by the global outcome scores (GOS) for improvement and deterioration measured with a 15-point scale ranging from -7 (no improvement) to +7 (significant improvement). RESULTS: The average follow-up period was 5.4 (range: 2 to 8) years. Average age at surgery was 15.5 (range: 13 to 19) years. Pedicle screw constructs were used in all patients. LIV was L3 in 85 patients, and L4 in the remaining 4 patients. Using the same selection criteria, L3 was LIV according to both the TXR and TrUGA films in 39 cases (44%) and fusion was stopped at L3. In 46 (52%) cases, TXR determined L4 to be the LIV, whereas in all those patients L3 was the LIV according to TrUGA and fusion was stopped at L3 in all. LIV was L4 according to both methods in four (4%) patients and fusion was stopped at L4. All patients had successful radiographic outcomes according to the criteria of CSVL to be within 2 cm of the center of T1, L3 tilt angle of less than 10 degrees , and L3-L4 disc wedging to be less than 10 degrees at the final follow-up. Average follow-up SRS-22 score was 4.3 (range: 3.3-5) and GOS was 6.1 (range: 3-7). None of the patients required additional surgery for decompensation or adding on, and there was no significant correction loss during follow-up. CONCLUSION: TrUGA may be an alternative method for selection of fusion levels and may help to save L4 when compared with traditional radiograph methods in surgical treatment of Lenke types 3 and 6 curves. PMID- 23685219 TI - Profiling celiac disease antibody repertoire. AB - The aim of this study was to dissect the autoantibody response in celiac disease (CD) that remains largely unknown, with the goal of identifying the disease specific autoantigenic protein pattern or the so called epitome. Sera from CD patients were used to select immunoreactive antigens from a cDNA phage-display library. Candidate genes were identified, the corresponding proteins produced and their immunoreactivity validated with sera from CD patients and controls. Thirteen CD-specific antigens were identified and further validated by protein microarray. The specificity for 6 of these antigens was confirmed by ELISA. Furthermore we showed that this antibody response was not abolished on a gluten free diet and was not shared with other autoimmune diseases. These antigens appear to be CD specific and independent of gluten induction. The utility of this panel extends beyond its diagnostic value and it may drive the attention to new targets for unbiased screens in autoimmunity research. PMID- 23685220 TI - Editorial for Lindop et al. "long-term Ro60 humoral autoimmunity in primary Sjogren's syndrome is maintained by rapid clonal turnover". PMID- 23685221 TI - Human memory-like NK cells migrating to tuberculous pleural fluid via IP-10/CXCR3 and SDF-1/CXCR4 axis produce IFN-gamma in response to Bacille Calmette Guerin. AB - We have previously shown that human memory-like NK cells were persistent in tuberculous pleurisy but it was unclear how NK cells migrated into the pleural fluids. At present, we found that NK cells from TB pleural fluid cells (PFCs) expressed significantly higher levels of CXCR3 and CXCR4 than NK cells from PBMCs. Migration assay demonstrated that IP-10 and SDF-1 induced more migration of NK cells from PFCs than PBMCs. CD45RO(+) or CD45RO(-) NK cells from PFCs were co-cultured with autologous monocytes and stimulated with BCG. The results showed CD45RO(+) but not CD45RO(-) NK cells produced significantly higher levels of IFN gamma, which was IL-12-dependent since anti-IL-12Rbeta1 mAbs could significantly inhibit the IFN-gamma by NK cells. Collectively, our data demonstrated that human Mycobacterium tuberculosis-specific NK cells were migrated into the local site of TB infection mainly via IP-10/CXCR3 and SDF-1/CXCR4 axis, memory-like NK cells might display an important role against M. tuberculosis infection. PMID- 23685222 TI - Measurement of urinary TGF-beta1 in patients with diabetes mellitus and normal controls. AB - OBJECTIVE: Increasing evidence links TGF-beta1 to progression of renal fibrosis including its association with diabetic nephropathy (DN). Current ELISA assays are not sensitive enough to measure TGF-beta1 in the urine of many clinically healthy individuals, even those with established renal disease. The objective of this study was to validate a sensitive urinary assay for TGF-beta1 and compare levels between healthy controls and patients with established DN. DESIGN AND METHODS: An ELISA method (R&D Systems) was utilized together with an amplification step to assay TGF-beta1 in urine samples from 190 patients with DN and 80 healthy controls. RESULTS: Using an ELAST (Perkin Elmer, Inc) amplification step, the ELISA for urinary TGF-beta1 had a limit of quantification of 15.6 pg/mL and limit of detection of 7 pg/mL. Preliminary studies demonstrated that TGF-beta1 was stable if urine was frozen promptly at -70 degrees C without preservatives. Using this assay, 22/80 controls (27%) had detectable levels of urinary TGF-beta1 (range <7 to 40.9 pg/mL; mean+/-SD 6.4+/-11.1 pg/mL). This was significantly lower (p<0.0001) than in the DN group in whom 114/190 (60%) had detectable levels of urinary TGF-beta1 (range <7 to 526.4 pg/mL; mean+/-SD 20.4+/ 45.8 pg/mL). Urinary protein and TGF-beta1 concentrations demonstrated modest correlation in patients with DN (r=0.47, P<0.001). TGF-beta1 measurement in patients with DN did not demonstrate significant association with progression of proteinuria or increase in serum creatinine during the next 12 months of follow up. CONCLUSION: We have validated a sensitive ELISA assay for urinary TGF-beta1, and demonstrated correlations with the degree of proteinuria and higher levels in patients with DN compared to controls. Additional study will be necessary in order to determine if serial testing can predict renal prognosis independent of known prognostic factors for patients with DN. PMID- 23685223 TI - Assessment of apoB dyslipoproteinemia in Korean population. AB - OBJECTIVES: There is sparse data on apoB dyslipoproteinemia in Asian population. The purpose of this study was to assess apoB dyslipoproteinemia and to compare the LDL-C, non-HDL and apoB for risk assessment with percentile equivalent cut off in Korean population. METHODS: With 1193 Korean adult subjects, the prevalence and characteristics of different types of dyslipoproteinemias were analyzed in each age and gender group. The percentile values of direct LDL-C, calculated LDL-C, non HDL-C, HDL-C, apoAI, apoB and apoB/apoAI ratio were estimated. RESULTS: The prevalences of normoapoB-hyperTG, hyperapoB-normoTG and hyperapoB-hyperTG dyslipoproteinemia were 6.9, 8.9 and 10.9% in men and 3.7, 6.4 and 2.8% in women. The 40th percentile of direct LDL-C, calculated LDL-C, non-HDL C and apo B were 108, 104.2, 126 and 85 mg/dl, respectively. The individual above optimal cut off was significantly underestimated with LDL-C than with non-HDL and apoB, in groups with adverse risk factors. CONCLUSIONS: This study firstly shows the prevalence of various types of dyslipoproteinemias in Asian population. The percentile values of Korean population were similar to those of NHANES. Integration of lipid markers is needed for making clinical decisions and further research involving various populations and methodologies should be performed. PMID- 23685224 TI - Inflammatory stimuli differentially modulate the transcription of paracrine signaling molecules of equine bone marrow multipotent mesenchymal stromal cells. AB - OBJECTIVE: Osteoarthritis (OA) is a degenerative disease of joint tissues that causes articular cartilage erosion, osteophytosis and loss of function due to pain. Inflammation and inflammatory cytokines in synovial fluid (SF) contribute to OA progression. Intra-articular (IA) injections of multipotent mesenchymal stromal cells (MSCs) are employed to treat OA in both humans and animals. MSCs secrete paracrine pro-inflammatory and anabolic signaling molecules that promote tissue repair. The objective of this study was to investigate the effects of OASF on the gene expression of paracrine signaling molecules by MSCs. METHODS: The effects of Lipopolysaccharide (LPS) and interleukin (IL)-1beta as well as both normal (N) and osteoarthritis (OA) SF stimulations on the expression of paracrine pro-inflammatory (tumor necrosis factor (TNF)-alpha, IL-1beta, IL-8), modulatory (IL-6) and anabolic (vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-beta1 and insulin-like growth factor (IGF)-1) signaling molecules by equine bone marrow multipotent mesenchymal stromal cells (eBM-MSCs) was investigated employing reverse transcriptase-polymerase chain reaction (RT PCR). RESULTS: In contrast with NSF, OASF significantly up-regulated the expression of VEGF in eBM-MSCs. Both NSF and OASF significantly down-regulated the expression of IL-1beta. LPS and IL-1beta significantly increased the expression of pro-inflammatory cytokines (TNF-alpha, IL-8 and IL-6; and IL-1beta and IL-8 respectively). DISCUSSION: We conclude that the transcription of paracrine signaling molecules in eBM-MSCs is modulated by SF. Furthermore, OA alters the properties of SF and the response of eBM-MSCs. Finally, the effects of LPS or IL-1beta stimulation are distinct to that observed following stimulations with OASF. PMID- 23685225 TI - Occurrence of parabens in foodstuffs from China and its implications for human dietary exposure. AB - Parabens are alkyl esters of p-hydroxybenzoic acid and are used as antimicrobial preservatives in a range of consumer products, including cosmetics, pharmaceuticals, and foodstuffs. Despite their widespread use, prior to this study, paraben concentrations in foodstuffs from China and human dietary exposure to these chemicals have been unknown. In this study, concentrations of six parabens were determined in 13 categories of food samples (n=282), including cereals and cereal products, meat, fish and seafood, eggs, dairy products, bean products, fruits, vegetables, cookies, beverages, cooking oils, condiments, and others, collected from nine cities in China. Almost all (detection rate: 99%) food samples contained at least one of the parabens analyzed, and the total concentrations (SigmaParabens; sum of six parabens) ranged from below limit of quantification (LOQ) to 2530ng/g fresh weight, with an overall mean value of 39.3ng/g. Methyl paraben (MeP), ethyl paraben (EtP), and propyl paraben (PrP) were the major paraben analogs found in foodstuffs, and these compounds accounted for 59%, 24%, and 10%, respectively, of SigmaParaben concentrations. Although the mean concentrations of SigmaParabens varied among different categories of food items (from 0.839ng/g in beverages to 100ng/g in vegetables), the concentrations were not statistically significant among the 13 food categories, including canned foodstuffs. Estimated daily intake (EDI) of parabens was based on the measured concentrations in foods and the corresponding daily food ingestion rates. The mean and 95th percentile values for EDI were 1010 and 3040ng/kg body weight (bw)/day for adult men and 1060 and 3170ng/kg bw/day for adult women, respectively. PMID- 23685226 TI - Real-time automated spectral assessment of the BOLD response for neurofeedback at 3 and 7T. AB - Echo-planar imaging is the dominant functional MRI data acquisition scheme for evaluating the BOLD signal. To date, it remains the only approach providing neurofeedback from spatially localized brain activity. Real-time functional single-voxel proton spectroscopy (fSVPS) may be an alternative for spatially specific BOLD neurofeedback at 7T because it allows for a precise estimation of the local T2* signal, EPI-specific artifacts may be avoided, and the signal contrast may increase. In order to explore and optimize this alternative neurofeedback approach, we tested fully automated real-time fSVPS spectral estimation procedures to approximate T2* BOLD signal changes from the unsuppressed water peak, i.e. lorentzian non-linear complex spectral fit (LNLCSF) in frequency and frequency-time domain. The proposed approaches do not require additional spectroscopic localizers in contrast to conventional T2* approximation based on linear regression of the free induction decay (FID). For methods comparison, we evaluated quality measures for signals from the motor and the visual cortex as well as a real-time feedback condition at high (3T) and at ultra high (7T) magnetic field strengths. Using these methods, we achieved reliable and fast water peak spectral parameter estimations. At 7T, we observed an absolute increase of spectra line narrowing due to the BOLD effect, but quality measures did not improve due to artifactual line broadening. Overall, the automated fSVPS approach can be used to assess dynamic spectral changes in real-time, and to provide localized T2* neurofeedback at 3 and 7T. PMID- 23685228 TI - State anxiety and cortisol reactivity to skydiving in novice versus experienced skydivers. AB - Previous studies have suggested that skydiving, a naturalistic stressor, is associated with increases in self-reported stress, anxiety and cortisol levels. However, it has not been established whether this stress reactivity is altered as a function of repeated exposure to skydiving. This is of interest due to previous observations that cortisol reactivity becomes habituated with repeated exposure to laboratory stressors, however, few studies have investigated such habituation to naturalistic stressors. State anxiety and cortisol reactivity to skydiving were measured in 11 first-time skydivers and 13 experienced skydivers (>=30 jumps, mean jumps=397.6), who were to complete a solo skydive. The novice skydivers reported significantly greater levels of state anxiety prior to the jump; however, there were no differences in pre-jump levels of salivary cortisol. Both groups exhibited significantly elevated salivary cortisol levels immediately post-jump, relative to i) pre-jump and ii) recovery. However, the two groups were indistinguishable with regard to their cortisol reactivity to the skydive. These findings support previous research demonstrating that skydiving elicits acute cortisol activation. Further, they suggest that i) cortisol reactivity does not habituate in experienced jumpers, and ii) that there is lack of concordance between self-reported levels of anxiety and biological stress reactivity in experienced skydivers. PMID- 23685227 TI - Novel high-speed droplet-allele specific-polymerase chain reaction: application in the rapid genotyping of single nucleotide polymorphisms. AB - BACKGROUND: Single nucleotide alterations such as single nucleotide polymorphisms (SNP) and single nucleotide mutations are associated with responses to drugs and predisposition to several diseases, and they contribute to the pathogenesis of malignancies. We developed a rapid genotyping assay based on the allele-specific polymerase chain reaction (AS-PCR) with our droplet-PCR machine (droplet-AS-PCR). METHODS: Using 8 SNP loci, we evaluated the specificity and sensitivity of droplet-AS-PCR. Buccal cells were pretreated with proteinase K and subjected directly to the droplet-AS-PCR without DNA extraction. The genotypes determined using the droplet-AS-PCR were then compared with those obtained by direct sequencing. RESULTS: Specific PCR amplifications for the 8 SNP loci were detected, and the detection limit of the droplet-AS-PCR was found to be 0.1-5.0% by dilution experiments. Droplet-AS-PCR provided specific amplification when using buccal cells, and all the genotypes determined within 9 min were consistent with those obtained by direct sequencing. CONCLUSIONS: Our novel droplet-AS-PCR assay enabled high-speed amplification retaining specificity and sensitivity and provided ultra-rapid genotyping. Crude samples such as buccal cells were available for the droplet-AS-PCR assay, resulting in the reduction of the total analysis time. Droplet-AS-PCR may therefore be useful for genotyping or the detection of single nucleotide alterations. PMID- 23685229 TI - Role of nitric oxide in additive anticonvulsant effects of agmatine and morphine. AB - The anticonvulsant effects of agmatine, an endogenous polyamine and a metabolite of l-arginine, have been shown in various experimental seizure models. Agmatine also potentiates the anti-seizure activity of morphine. The present study aimed to investigate a possible involvement of nitric oxide (NO) pathway in the protection by agmatine and morphine co-administration against pentylenetetrazole (PTZ) -induced seizure in male mice. To this end, the thresholds for the clonic seizures induced by the intravenous administration of PTZ, a GABA antagonist, were assessed. Intraperitoneal administration of morphine at lower dose (1mg/kg) increased the seizure threshold. Also intraperitoneal administration of agmatine (5 and 10mg/kg) increased the seizure threshold significantly. Combination of subeffective doses of morphine and agmatine led to potent anticonvulsant effects. Non-effective doses of morphine (0.1 and 0.5mg/kg) were able to induce anticonvulsant effects in mice pretreated with agmatine (3mg/kg). Concomitant administration of either the non-selective nitric oxide synthase (NOS) inhibitor L-NAME (1, 5mg/kg, i.p.) or the selective NOS inhibitor 7-NI (15, 30mg/kg, i.p.), with an ineffective combination of morphine (0.1mg/kg) plus agmatine (1mg/kg) produced significant anticonvulsant impacts. Moreover, the NO precursor, l arginine (30, 60mg/kg, i.p.), inhibited the anticonvulsant action of agmatine (3mg/kg) plus morphine (0.5mg/kg) co-administration. Our results indicate that pretreatment of animals with agmatine enhances the anticonvulsant effects of morphine via a mechanism which may involve the NO pathway. PMID- 23685230 TI - Changes on auditory physiology in response to the inactivation of amygdala nuclei in high anxiety rats expressing learned fear. AB - The inferior colliculus (IC) is primarily involved in the processing of acoustic stimuli, including those emitted by prey and predators. The role of the central nucleus of the IC (CIC) in fear and anxiety has been suggested based on electrophysiological, behavioral and immunohistochemical studies. The reactivity of high-anxiety rats (HA) to diverse challenges is different from low-anxiety ones (LA). In humans and laboratory animals, pathological anxiety is often accompanied by heightened vigilance and alertness, hyperactivity of the amygdala (AM), and increased amplitude of the auditory evoked potentials (AEP) from the IC. This study aims to evaluate the influence of the inactivation of the central (CEA) and basolateral (BLA) nuclei of the amygdala, after local infusions of the full GABAA agonist muscimol (1nmol/0.2MUl), on the AEP elicited in the CIC of rats tested under a learned fear state. Our results showed that both BLA and CEA inactivation change the expression of conditioned fear, in a paradigm using the context as the conditioned stimulus (CS). These changes are correlated to the innate anxiety levels of the animals. It is supposed that this shortcoming is in addition to the imbalance between the regulatory role of the top-down and bottom up processes in the control of anxiety. PMID- 23685231 TI - Relations between peripheral and brain serotonin measures and behavioural responses in a novelty test in pigs. AB - Pigs differ in their behavioural responses towards environmental challenges. Individual variation in maladaptive responses such as tail biting, may partly originate from underlying biological characteristics related to (emotional) reactivity to challenges and serotonergic system functioning. Assessing relations between behavioural responses and brain and blood serotonin parameters may help in understanding susceptibility to the development of maladaptive responses. The objective of the current study was, therefore, to assess the relationship between the pigs' serotonergic parameters measured in both blood and brain, and the behaviour of pigs during a novelty test. Pigs (n=31) were subjected to a novelty test at 11weeks of age, consisting of 5-min novel environment exposure after which a novel object (a bucket) was introduced for 5min. Whole blood serotonin, platelet serotonin level, and platelet serotonin uptake were determined at 13weeks of age. Levels of serotonin, its metabolite and serotonin turnover were determined at 19weeks of age in the frontal cortex, hypothalamus and hippocampus. The behaviour of the pigs was different during exposure to a novel object compared to the novel environment only, with more fear-related behaviours exhibited during novel object exposure. Platelet serotonin level and brain serotonergic parameters in the hippocampus were interrelated. Notably, the time spent exploring the test arena was significantly correlated with both platelet serotonin level and right hippocampal serotonin activity (turnover and concentration). In conclusion, the existence of an underlying biological trait - possibly fearfulness - may be involved in the pig's behavioural responses toward environmental challenges, and this is also reflected in serotonergic parameters. PMID- 23685232 TI - An assessment of the aversive nature of an animal management procedure (clipping) using behavioral and physiological measures. AB - Animal management often involves procedures that, while unlikely to cause physical pain, still cause aversive responses. The domestic horse (Equus caballus) regularly has excessive hair clipped off to facilitate its use as a riding/driving animal and this procedure causes adverse behavioral responses in some animals. The aim of this study was to compare behavioral and physiological measures to assess the aversive effect of this procedure. Ten horses were selected on the basis of being either compliant (C: n=5) or non-compliant (NC: n=5) during this procedure. The horses were subjected to a sham clipping procedure (SC: where the blades had been removed from the clippers) for a period of ten minutes. Measures were taken pre, during and post SC (-10min to +30min) and mean values calculated for ALL horses and for C and NC separately. Behavioral activity was scored (scale 1-5) by twenty students from video footage in (phase/group-blind scoring). Heart rate (HR), salivary cortisol and eye temperature were monitored throughout the procedure. The NC horses were found to be significantly more behaviorally active/less relaxed throughout the trial than C horses (p<0.05) with the greatest difference occurring during the SC procedure (p<0.01). NC horses were more active/less relaxed during, compared with pre or post SC (p<0.05), but showed no behavioral difference pre and post SC. HR of the NC horses was higher than that of the C horses throughout the trial but only significantly so after 10min of SC (p<0.01). ALL horses showed a significant increase in HR between +5 and +10min into the procedure (p<0.05). There was a significant increase in salivary cortisol concentration in ALL horses post procedure (p<0.01) with levels peaking at 20minute post SC. No significant differences in salivary cortisol concentration between C and NC were found at any stage of the trial. Eye temperature increased significantly in ALL horses during SC, peaking at +10min into the procedure (p<0.05) and then decreased substantially when SC had ceased (p<0.01). Although no significant differences were found between C and NC per se, there was a significant interaction between group and phase of trial (p<0.05) with the NC group showing a greater decrease in eye temperature post SC. There was a significant positive correlation between changes in salivary cortisol concentration and eye temperature (p<0.01) but no correlation between any of the other measures. Although the behavioral response of C and NC to this procedure was significantly different the physiological responses indicated that ALL horses found the procedure aversive. Eye temperature could be used as an objective and immediate measure of how an animal is responding to a specific situation in order to evaluate management procedures and adapt them where appropriate to reduce the negative impact on animal health and welfare. PMID- 23685233 TI - Influence of dietary behavior on the circadian rhythm of the autonomic nervous system as assessed by heart rate variability. AB - BACKGROUND: Misalignment of circadian systems is detrimental to human health. However, only a few studies have examined the influence of late meals on the human circadian system. The purpose of this study was to investigate whether delayed meals affect circadian rhythm as assessed by heart rate variability (HRV). METHODS: Seven healthy men (aged 22.4+/-0.4years) participated in this study, which involved delaying mealtimes by 5h for two weeks. Prior to this study, the regular mealtimes of participants were at 08:00, 13:00, and 18:00 (Baseline). During the intervention, each meal was provided at 13:00, 18:00 and 23:00 (Late mealtimes). Circadian variation was assessed by HRV based on R-R intervals calculated from a pulse at the rising phase of each spike in the QRS complex in a 24-h electrocardiograph record. The ratio of low frequency (LF) to high frequency (HF) power (LF/HF) and the ratio of HF power to total power (%HF) were calculated using spectral analysis. The phase and amplitude of HRV variables in a 24-h period were mathematically obtained with double cosinor analysis. RESULTS: The acrophase and amplitude for LF power, HF power and %HF in a 24-h period were not significantly different between Baseline and Late mealtimes. On the other hand, the acrophase significantly differed between Baseline and Late mealtimes for heart rate (95%CI, 1.1-3.8h), standard deviation of R-R intervals (95%CI, 2.5-4.4h) and LF/HF (95%CI, 1.1-2.3h). CONCLUSIONS: Our findings suggest that delayed mealtimes shift the phase of circadian rhythm of the autonomic nervous system. PMID- 23685234 TI - Brown adipose tissue thermogenesis precedes food intake in genetically obese Zucker (fa/fa) rats. AB - In Sprague-Dawley rats, brown adipose tissue (BAT) thermogenesis occurs in an episodic ultradian manner (BAT on-periods) as part of the basic rest-activity cycle (BRAC). Eating occurs approximately 15min after the onset of BAT on periods. Zucker obese (fa/fa) rats eat larger less frequent meals than control rats. In chronically instrumented conscious unrestrained Zucker obese rats we examined ultradian fluctuations in BAT, body and brain temperatures, and the relation between BAT temperature and eating. The interval between BAT temperature peaks for the 12hour dark phase was 121+/-3 (mean+/-SE) min for Zucker obese rats and 91+/-3min for control lean rats (p<0.01). Corresponding values for the light phase were 148+/-6 and 118+/-4min (p<0.01). Mean BAT and body temperatures were lower in Zucker obese rats, in comparison with lean controls, during both BAT on periods and BAT off-periods. Mean brain temperatures were lower during BAT off periods. Amplitudes of the BRAC-related increases in all 3 temperatures were greater in the Zucker obese rats. Meal onset in Zucker obese rats commenced 15+/ 1min after the onset of a BAT on-period, not significantly different for the delay observed in lean control rats (18+/-1min, p>0.05). Thus periods between eating are increased in the Zucker obese rats, but the action of leptin, absent in these animals, is not crucial for the timing of eating in relation to increases in BAT and body temperature. Lack of the normal excitatory action of leptin on brain-regulated BAT sympathetic discharge could also contribute to lower BAT thermogenesis in Zucker obese rats. PMID- 23685236 TI - Testosterone inhibits facilitating effects of parenting experience on parental behavior and the oxytocin neural system in mice. AB - Parental behavior in mammals is facilitated by sensory experiences from infant, and by endocrine hormones. However, the interactions between these factors in the parental behavior of nonreproductive adults are not understood. We examined the interactive effects of gonadal hormones and the experience of repeated pup exposure on parental behavior in sexually naive mice. We also compared oxytocin (OT) expression levels in the paraventricular nucleus of the hypothalamus to behavioral outcomes. Clear sex differences were observed in retrieving tests; initial retrieving latency was shorter in females than in males, and 5-time pup exposure shortened retrieving latency in females only. Gonadectomy influenced neither initial retrieving latency nor pup sensitization in females. In contrast, gonadectomy shortened initial retrieving latency and caused pup sensitization in males. Estrogen implants given simultaneously with gonadectomy further shortened the initial retrieving latency in males, but pup sensitization was not affected and occurred in both sexes. In contrast, simultaneous testosterone implants impaired pup sensitization in both sexes. Similar to the results for responsiveness to pups, the number of OT neurons was increased by gonadectomy in males only. In comparison to gonadectomy only, OT neurons were decreased by simultaneous testosterone implants, but were not influenced by estrogen in either sex. Considering the parallel inhibitory effects of testosterone on both pup sensitization and number of OT neurons, we postulate that sex differences in parental responsiveness facilitated by repeated pup exposure were caused by an inhibitory effect of testosterone via the OT neural system in mice. PMID- 23685238 TI - Multi-walled carbon nanotubes-dispersive solid-phase extraction combined with liquid chromatography-tandem mass spectrometry for the analysis of 18 sulfonamides in pork. AB - A simple and cost-effective pre-treatment procedure was developed for 18 sulfonamides in pork using dispersive solid phase extraction (dSPE) with multi walled carbon nanotubes (MWCNTs). The sample was analysed after purification by ultra high-performance liquid chromatography-positive electrospray ionisation tandem mass spectrometry (UHPLC-ESI-MS/MS). After extraction with phosphate buffer (pH 6.0), a dSPE procedure was conducted with MWCNTs. The pH value of the extract, extraction time with MWCNTs, type and amount of MWCNTs and type of eluent were optimised to increase the sample throughput and sensitivity. The samples were quantified using sulfamethazine-(13)C6 as an internal standard. The recoveries of the target compounds from the pork samples were most efficient when 150mg of MWCNTs with an outer diameter of less than 8nm and a length of 0.5-2MUm was used. A mixture of acetonitrile/50mM ammonium acetate (95:5, v/v) was shown to be the most suitable solvent for desorbing the compounds from the MWCNTs. The proposed method was validated according to the European Commission Decision 2002/657/EC, which determines linearity, specificity, decision limit (CCalpha), detection capability (CCbeta), recovery, precision and stability. PMID- 23685237 TI - PM2.5-induced oxidative stress triggers autophagy in human lung epithelial A549 cells. AB - Exposure to higher levels of air pollution particulate matter (PM) with an aerodynamic diameter of less than 2.5 MUm (PM2.5) links with an increased risk of cardiovascular and respiratory deaths and hospital admission as well as lung cancer. Although the mechanism underlying the correlation between PM2.5 exposure and adverse effects has not fully elucidated, PM2.5-induced oxidative stress has been considered as an important molecular mechanism of PM2.5-mediated toxicity. In this work, human lung epithelial A549 cells were used to further investigate the biological effects of PM2.5 on autophagy. The cell viability showed both time and concentration-dependent decrease when exposure to PM2.5, which can be attributed to increase of the levels of extracellular lactate dehydrogenase (LDH) release and intracellular reactive oxygen species (ROS) generation in A549 cells. Moreover, PM2.5-induced oxidative damage in A549 cells was observed through the alteration of superoxide dismutase (SOD) and catalase (CAT) activities compared to the unexposed control cells. PM2.5-induced autophagy was indicated by an increase in microtubule-associated protein light chain-3 (LC3) puncta, and accumulation of LC3 in both time- and concentration-dependent manner. PM2.5 induced mRNA expression of autophagy-related protein Atg5 and Beclin1 was also observed compared with those of the unexposed control cells. These results suggest the possibility that PM2.5-induced oxidative stress probably plays a key role in autophagy in A549 cells, which may contribute to PM2.5-induced impairment of pulmonary function. PMID- 23685239 TI - Improved GC method for the determination of the active principles of Catha edulis. AB - The GC method previously reported by our research group for the analysis of the active principles of Catha edulis, i.e. cathine, cathinone and phenylpropanolamine, was considerably improved. N-methyl-N-trimethylsilyl trifluoroacetamide (MSTFA) as derivatizing agent was employed, thus allowing an accurate determination of the analytes and a suitable internal standard for quantitative analyses (nicotinamide) was introduced. Moreover the chromatographic conditions were carefully studied to improve the separation of the alkaloids and sensitivity. To this end different chromatographic capillary columns and temperature gradients were investigated. The optimized GC method was validated and resulted adequate for the application in forensic analysis. Finally on behalf of the Tribunal, C. edulis vegetable material seized by the police in northern Italy was analyzed, the quantity of cathine ranging from 0.095 to 0.29%, the quantity of PPA from 0.010 to 0.21% and the quantity of cathinone from 0.025 to 0.374% of the weight of the vegetable material. PMID- 23685240 TI - Antibodies induced by receptor-binding domain in spike protein of SARS-CoV do not cross-neutralize the novel human coronavirus hCoV-EMC. PMID- 23685235 TI - Factors influencing behavior in the forced swim test. AB - The forced swim test (FST) is a behavioral test in rodents which was developed in 1978 by Porsolt and colleagues as a model for predicting the clinical efficacy of antidepressant drugs. A modified version of the FST added the classification of active behaviors into swimming and climbing, in order to facilitate the differentiation between serotonergic and noradrenergic classes of antidepressant drugs. The FST is now widely used in basic research and the pharmaceutical screening of potential antidepressant treatments. It is also one of the most commonly used tests to assess depressive-like behavior in animal models. Despite the simplicity and sensitivity of the FST procedure, important differences even in baseline immobility rates have been reported between different groups, which complicate the comparison of results across studies. In spite of several methodological papers and reviews published on the FST, the need still exists for clarification of factors which can influence the procedure. While most recent reviews have focused on antidepressant effects observed with the FST, this one considers the methodological aspects of the procedure, aiming to summarize issues beyond antidepressant action in the FST. The previously published literature is analyzed for factors which are known to influence animal behavior in the FST. These include biological factors, such as strain, age, body weight, gender and individual differences between animals; influence of preconditioning before the FST: handling, social isolation or enriched environment, food manipulations, various kinds of stress, endocrine manipulations and surgery; schedule and routes of treatment, dosage and type of the drugs as well as experimental design and laboratory environmental effects. Consideration of these factors in planning experiments may result in more consistent FST results. PMID- 23685241 TI - miR-146a facilitates replication of dengue virus by dampening interferon induction by targeting TRAF6. AB - OBJECTIVES: To investigate the role of miR-146a in dengue virus (DENV) replication. METHODS: Expression levels of miR-146a were measured by real-time PCR and Northern blot. Role of miR-146a was tested by overexpression and inhibition assays. Real-time PCR and 50% tissue culture infective dose (TCID50) assays were used to detect RNA levels and extracellular yields of DENV respectively. Interferon (IFN) levels induced by DENV infection were measured by real-time PCR and ELISA respectively. IFN-beta neutralization and RNAi were used to test the involvement of IFN-beta in the effects of miR-146a. TNFR-associated factor 6 (TRAF6) level was measured by Western-blot. RESULTS: miR-146a expression was significantly increased in primary human monocytes and THP-1 cells upon DENV infection. Overexpression of miR-146a increased DENV2 replication, while inhibition of miR-146a decreased the viral replication. miR-146a impaired the IFN production and the DENV2 replication suppressed by miR-146a inhibition was partially restored by neutralization of IFN-beta or depletion of interferon receptor (IFNAR) 1 or 2. Furthermore, miR-146a targets TRAF6 and overexpression of TRAF6 reversed the effects of miR-146a on IFN-beta induction and viral replication. CONCLUSIONS: DENV infection significantly induced the expression of miR-146a, which facilitated viral replication by targeting TRAF6 and dampening IFN-beta production. PMID- 23685242 TI - Mitochondrial NADH:ubiquinone oxidoreductase alterations are associated with endometriosis. AB - Genetic alterations and aberrant expression of 'mitochondrial membrane complex I' (MMC-I) underlie several complex human disorders, but no reports are documented to date in endometriosis. Sequencing of mitochondrially encoded MMC-I subunits revealed 72 mutations of which 2 missense (G10398A; A13603A/G) mutations and 1 synonymous (T10400C) mutation showed higher prevalence in patients. In silico functional analysis predicted A13603A/G, a novel heteroplasmy as a 'damaging variant'. Our results indicate higher endometriosis risk for haplotype '10398A/10400C/13603AG' and haplogroup 'N'. Immunohistochemical analysis revealed elevated MMC-I expression in eutopic endometria of patients compared to controls. In conclusion, MMC-I alterations may constitute an inheritable risk factor for endometriosis. PMID- 23685243 TI - The distribution of the Phlebotomus major complex (Diptera: Psychodidae) in Turkey. AB - The taxonomic status and distribution of the morphologically similar members of the Phlebotomus major complex in Turkey are unclear. To examine the utility of traditional morphological characters and molecular markers, sand flies were sampled from 90 localities in eleven different provinces covering a wide geographical range throughout Turkey. The morphometric variability was analysed using multivariate analyses of twelve characters, while mitochondrial cytochrome b (Cyt b) and nuclear elongation factor 1alpha (EF 1-alpha) genes were used for molecular discrimination. Three distinct monophyletic lineages were identified based on the phylogenetic analysis of the combined data set of mitochondrial and nuclear gene regions, which were also supported by parsimony haplotype network analysis and AMOVA of Cyt b. The first lineage is restricted to south eastern Turkey and represents the species Phlebotomus syriacus, the second is present mostly in the westernmost and the easternmost localities and represents P. neglectus, and the third member of this complex is distributed across the mid northern and mid-southern regions. None of the studied morphological characters were found to be sufficient to discriminate between these three members of the P. major s.l. complex; however their presence sympatrically in several localities supports their status as species rather than inter-population variability. PMID- 23685244 TI - The antioxidant activity and active component of Gnaphalium affine extract. AB - The antioxidant activity of Gnaphalium affine extract (GAE) against H2O2-induced oxidative injury in Caco-2 cells was evaluated, and the main antioxidant component was isolated and identified by column chromatography, high performance liquid chromatography, time-of-flight mass spectrometer and nuclear magnetic resonance. In vitro assays, GAE showed remarkable antioxidant activity to scavenge free radicals (ABTS, DPPH, superoxide and hydroxyl radicals), inhibit lipid peroxidation and show reducing power. In food system, GAE exhibited the obvious capacity to inhibit the oxidation of peanut oil and lard, which may be attributed to its high content of phenolic compounds. Moreover, GAE could effectively protect Caco-2 cell against H2O2-induced oxidative injury. With the isolation and purification by chromatography, quercetin was identified as the main antioxidant component of GAE, which was capable of scavenging ABTS, DPPH, superoxide and hydroxyl radicals. These results suggest that G. affine is a potential source for preparing functional foods and nutraceuticals in food industry. PMID- 23685245 TI - Protection of cyanidin-3-glucoside against oxidative stress induced by acrylamide in human MDA-MB-231 cells. AB - Acrylamide (AA) occurs in many cooked starchy foods and has caused widespread concern as a possible carcinogen. In the present study, we investigate the intervention of AA toxicity in MDA-MB-231 cells pretreated with cyanidin-3 glucoside (Cy-3-glu). Compared to the cells treated with AA, Cy-3-glu significantly inhibited AA-induced cytotoxicity, reduced reactive oxygen species (ROS) generation, recovered glutathione (GSH) depletion and decreased the activities of glutathione peroxidase (GPx) and glutathione S-transferase (GST). Moreover, the expression of GPx1, GSTP1 and gamma-glutamyl cysteine synthase (gamma-GCS) were enhanced, and cytochrome P450 2E1 (CYP2E1) expression was inhibited by the pretreatment of Cy-3-glu. Cy-3-glu presents the protective role against oxidative stress induced by AA in MDA-MB-231 cells. PMID- 23685246 TI - Strengthening the influenza vaccine virus selection and development process: outcome of the 2nd WHO Informal Consultation for Improving Influenza Vaccine Virus Selection held at the Centre International de Conferences (CICG) Geneva, Switzerland, 7 to 9 December 2011. PMID- 23685247 TI - Phenylethanoid glycosides with anti-inflammatory activities from the stems of Cistanche deserticola cultured in Tarim desert. AB - Five new phenylethanoid glycosides, cistanosides J-N (1-5), together with 15 known ones (6-20) were isolated from the stems of Cistanche deserticola cultured in Tarim desert, China. Their structures were elucidated on the basis of extensive spectroscopic analysis (IR, HR-ESIMS, 1D- and 2D-NMR) and chemical degradation. All the compounds obtained were examined for their inhibitory effect on the lipopolysaccharide (LPS)-induced nitric oxide (NO) production in mouse microglial cells (BV-2 cells), and compounds 2 and 8 showed potent inhibition on the NO production with IC50 values of 14.94 MUM and 14.32 MUM, respectively. PMID- 23685248 TI - Clinical outcomes after intravascular ultrasound and fractional flow reserve assessment of intermediate coronary lesions. Propensity score matching of large cohorts from two institutions with a differential approach. AB - AIMS: Assessment of intermediate coronary lesions can be done with fractional flow reserve (FFR) and intravascular ultrasound (IVUS). There are no randomised trials and only a small registry from one centre is available but this is subject to important bias. We sought to evaluate the clinical outcomes of an FFR strategy compared with an IVUS strategy for intermediate lesion assessment. METHODS AND RESULTS: We compared the outcome of patients assessed with FFR and IVUS in two centres with a differential approach. After propensity score matching 400 pairs of patients were included. Revascularisation was done when FFR was <0.75 or minimum lumen area was <4 mm2 in vessels >3 mm, and <3.5 mm2 in vessels 2.5-3 mm, along with plaque burden >50%. After FFR and IVUS, 72% and 51.2% of lesions, respectively, were left untreated (p<0.001). At one and two years no significant differences in MACE-free survival were observed in overall groups (97.7% at one year and 93.1% at two years in the FFR group and 97.7% at one year and 95.6% at two years in the IVUS group; p=0.35) and among those with deferred intervention (97.9% at one year and 94.2% at two years in the FFR group and 96.5% at one year and 93.6% at two years in the IVUS group; p=0.7). CONCLUSIONS: IVUS and FFR may be safely used to defer revascularisation of intermediate lesions. IVUS induces a higher degree of revascularisation but much lower than previously reported and does not affect the clinical outcome. PMID- 23685249 TI - Tissue repair through cell competition and compensatory cellular hypertrophy in postmitotic epithelia. AB - In multicellular organisms, tissue integrity and organ size are maintained through removal of aberrant or damaged cells and compensatory proliferation. Little is known, however, about this homeostasis system in postmitotic tissues, where tissue-intrinsic genetic programs constrain cell division and new cells no longer arise from stem cells. Here we show that, in postmitotic Drosophila follicular epithelia, aberrant but viable cells are eliminated through cell competition, and the resulting loss of local tissue volume triggers sporadic cellular hypertrophy to repair the tissue. This "compensatory cellular hypertrophy" is implemented by acceleration of the endocycle, a variant cell cycle composed of DNA synthesis and gap phases without mitosis, dependent on activation of the insulin/IGF-like signaling pathway. These results reveal a remarkable homeostatic mechanism in postmitotic epithelia that ensures not only elimination of aberrant cells through cell competition but also proper organ-size control that involves compensatory cellular hypertrophy induced by physical parameters. PMID- 23685251 TI - Pharmacoeconomics of hematopoietic stem cell mobilization: an overview of current evidence and gaps in the literature. AB - Adequate hematopoietic stem cell (HSC) mobilization and collection is required prior to proceeding with high dose chemotherapy and autologous hematopoietic stem cell transplant. Cytokines such as G-CSF, GM-CSF, and peg-filgrastim, alone or in combination with plerixafor, and after chemotherapy have been used to mobilize HSCs. Studies have shown that the efficiency of HSC mobilization and collection may vary when different methods of mobilization are used. No studies have shown that survival is significantly affected by the method of mobilization, but some studies have suggested that cost and resource utilization may be different between different mobilization techniques. After the FDA approval of plerixafor with G-CSF to mobilize HSCs many transplant centers became concerned about the cost of HSC mobilization. A panel of experts was convened ant this paper reviews the current literature on the pharmacoeconomics of HSC mobilization. PMID- 23685250 TI - MT1-MMP-dependent control of skeletal stem cell commitment via a beta1 integrin/YAP/TAZ signaling axis. AB - In vitro, topographical and biophysical cues arising from the extracellular matrix (ECM) direct skeletal stem cell (SSC) commitment and differentiation. However, the mechanisms by which the SSC-ECM interface is regulated and the outcome of such interactions on stem cell fate in vivo remain unknown. Here we demonstrate that conditional deletion of the membrane-anchored metalloproteinase MT1-MMP (Mmp14) in mesenchymal progenitors, but not in committed osteoblasts, redirects SSC fate decisions from osteogenesis to adipo- and chondrogenesis. By effecting ECM remodeling, MT1-MMP regulates stem cell shape, thereby activating a beta1-integrin/RhoGTPase signaling cascade and triggering the nuclear localization of the transcriptional coactivators YAP and TAZ, which serve to control SSC lineage commitment. These data identify a critical MT1 MMP/integrin/YAP/TAZ axis operative in the stem cell niche that oversees SSC fate determination. PMID- 23685252 TI - Serum-free cryopreservation of human amniotic epithelial cells before and after isolation from their natural scaffold. AB - Amniotic epithelial cells are a promising source for stem cell-based therapy through their potential capacity to differentiate into the cell lineages of all three germ layers. Long-term preservation is necessary to have a ready-to-use source of stem cells, when required. Reduced differentiation capability, decrease of viability and use of fetal bovine serum (FBS) are three drawbacks of clinical application of cryopreserved stem cells. In this study, we used human amniotic fluid instead of animal serum, and evaluated viability and multipotency of amniotic epithelial cells after cryopreservation in suspension and compared with those cryopreserved on their natural scaffold (in situ cryopreservation). There was no significant difference in viability of the cells cryopreserved in amniotic fluid and FBS. Also, the same results were achieved for expression of pluripotency marker OCT-4 when FBS was replaced by amniotic fluid in the samples with the same cryoprotectant. The cells cryopreserved in presence of scaffold had a higher level of viability compared to the cells cryopreserved in suspension. Although, the number of the cells expressed OCT-4 significantly decreased within cryopreservation in suspension, no decrease in expression of OCT-4 was observed when the cells cryopreserved with their natural scaffold. Upon culturing of post thawed cells in specific lineage differentiating mediums, the markers of neuronal, hepatic, cardiomyocytic and pancreatic were found in differentiated cells. These results show that replacement of FBS by amniotic fluid and in situ cryopreservation of amniotic epithelial cells is an effective approach to overcome limitations related to long-term preservation including differentiation during cryopreservation and decrease of viability. PMID- 23685253 TI - Xenopus laevis nucleotide binding protein 1 (xNubp1) is important for convergent extension movements and controls ciliogenesis via regulation of the actin cytoskeleton. AB - Nucleotide binding protein 1 (Nubp1) is a highly conserved phosphate loop (P loop) ATPase involved in diverse processes including iron-sulfur protein assembly, centrosome duplication and lung development. Here, we report the cloning, expression and functional characterization of Xenopus laevis Nubp1. We show that xNubp1 is expressed maternally, displays elevated expression in neural tissues and is required for convergent extension movements and neural tube closure. In addition, xNubp1knockdown leads to defective ciliogenesis of the multi-ciliated cells of the epidermis as well as the monociliated cells of the gastrocoel roof plate. Specifically, xNubp1 is required for basal body migration, spacing and docking in multi-ciliated cells and basal body positioning and axoneme elongation in monociliated gastrocoel roof plate cells. Live imaging of the different pools of actin and basal body migration during the process of ciliated cell intercalation revealed that two independent pools of actin are present from the onset of cell intercalation; an internal network surrounding the basal bodies, anchoring them to the cell cortex and an apical pool of punctate actin which eventually matures into the characteristic apical actin network. We show that xNubp1 colocalizes with the apical actin network of multiciliated cells and that problems in basal body transport in xNubp1 morphants are associated with defects of the internal network of actin, while spacing and polarity issues are due to a failure of the apical and sub-apical actin pools to mature into a network. Effects of xNubp1 knockdown on the actin cytoskeleton are independent of RhoA localization and activation, suggesting that xNubp1 may have a direct role in the regulation of the actin cytoskeleton. PMID- 23685256 TI - Mast cells and macrophages exert beneficial and detrimental effects on tumor progression and angiogenesis. AB - Mast cells and macrophages are critical regulators of inflammation and immunological response in the tumor microenvironment. Increased number of mast cells and macrophages have been reported to correlate with poor prognosis in numerous solid and hematological tumors. In contrast to their pro-tumorigenic role, mast cells and macrophages have shown also anti-tumorigenic effect in certain malignancies, for example by supporting cancer rejection. Thus, mast cells and macrophages can exert both detrimental and beneficial effects on tumor progression. Mast cell- and macrophages-derived growth factors able to promote tumor development and angiogenesis include TNF-alpha, TGF-beta1, FGF-2, VEGF, PDGF, IL-8, osteopontin, and NGF. On the contrary, mast cell- and macrophages produced cytokines that may participate in anti-tumor response include IL-1, IL 2, IL-4, IL-10, and IFN-gamma. It is to note that mast cells and macrophages may also show beneficial and detrimental effects in the same cancer depending on the tumor stage. PMID- 23685254 TI - Rab3Gap1 mediates exocytosis of Claudin-1 and tight junction formation during epidermal barrier acquisition. AB - Epidermal barrier acquisition during late murine gestation is accompanied by an increase in Akt kinase activity and cJun dephosphorlyation. The latter is directed by the Ppp2r2a regulatory subunit of the Pp2a phosphatase. This was accompanied by a change of Claudin-1 localisation to the cell surface and interaction between Occludin and Claudin-1 which are thought to be required for tight junction formation. The aim of this study was to determine the nature of the barrier defect caused by the loss of AKT/Ppp2r2a function. There was a paracellular barrier defect in rat epidermal keratinocytes expressing a Ppp2r2a siRNA. In Ppp2r2a knockdown cells, Claudin-1 was located to the cytoplasm and its expression was increased. Inhibiting cJun phosphorylation restored barrier function and plasma membrane localisation of Claudin-1. Expression of the Rab3 GTPase activating protein, Rab3Gap1, was restored in Ppp2r2a siRNA cells when cJun phosphorylation was inhibited. During normal mouse epidermal development, Claudin-1 plasma membrane localisation and Rab3Gap1 cell surface expression were co-incident with Akt activation in mouse epidermis, strongly suggesting a role of Rab3Gap1 in epidermal barrier acquisition. Supporting this hypothesis, siRNA knockdown of Rab3Gap1 prevented plasma membrane Claudin-1 expression and the formation of a barrier competent epithelium. Replacing Rab3Gap1 in Ppp2r2a knockdown cells was sufficient to rescue Claudin-1 transport to the cell surface. Therefore these data suggest Rab3Gap1 mediated exocytosis of Claudin-1 is an important component of epidermal barrier acquisition during epidermal development. PMID- 23685255 TI - Frazzled/DCC facilitates cardiac cell outgrowth and attachment during Drosophila dorsal vessel formation. AB - Drosophila embryonic dorsal vessel (DV) morphogenesis is a highly stereotyped process that involves the migration and morphogenesis of 52 pairs of cardioblasts (CBs) in order to form a linear tube. This process requires spatiotemporally regulated localization of signaling and adhesive proteins in order to coordinate the formation of a central lumen while maintaining simultaneous adhesion between CBs. Previous studies have shown that the Slit/Roundabout and Netrin/Unc5 repulsive signaling pathways facilitate site-specific loss of adhesion between contralateral CBs in order to form a luminal space. However, the concomitant mechanism by which attraction initiates CB outgrowth and discrete localization of adhesive proteins remains poorly understood. Here we provide genetic evidence that Netrin signals through DCC (Deleted in Colorectal Carcinoma)/UNC-40/Frazzled (Fra) to mediate CB outgrowth and attachment and that this function occurs prior to and independently of Netrin/UNC-5 signaling. fra mRNA is expressed in the CBs prior to and during DV morphogenesis. Loss-of-fra-function results in significant defects in cell shape and alignment between contralateral CB rows. In addition, CB outgrowth and attachment is impaired in both fra loss- and gain-of-function mutants. Deletion of both Netrin genes (NetA and NetB) results in CB attachment phenotypes similar to fra mutants. Similar defects are also seen when both fra and unc5 are deleted. Finally we show that Fra accumulates at dorsal and ventral leading edges of paired CBs, and this localization is dependent upon Netrin. We propose that while repulsive guidance mechanisms contribute to lumen formation by preventing luminal domains from coming together, site-specific Netrin/Frazzled signaling mediates CB attachment. PMID- 23685257 TI - IL-4 and MTHFR gene polymorphism in rheumatoid arthritis and their effects. AB - Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease that mainly affects the joints. Polymorphic variations of the cytokine genes and MTHFR gene have received attention as potential markers of susceptibility, severity, and/or protection in RA. The aim of this study was to investigate the MTHFR C677T and IL 4 70bp VNTR variation in Turkish patients with RA and evaluate if there was an association with clinical features, especially ocular involvement, in RA patients. The study included 297 persons (147 patients with RA and 150 healthy controls). Genomic DNA was isolated and genotyped using PCR assay for the MTHFR gene C677T and IL-4 gene 70bp VNTR polymorphisms. Our results show that there was statistically significant difference between the groups with respect to IL-4 genotype (p=0.01) and allele frequencies (p<0.002). There was no statistical significant difference in the genotype frequencies MTHFR gene, but allele frequencies showed statistically significant association (p=0.01). When we examined MTHFR and IL-4 genotype frequencies according to the clinical characteristics, we found that there was a difference between MTHFR genotypes and ocular involvement but it is not to a statistical significant degree (p=0.09). In the combined genotype analysis, MTHFR/IL-4 CCP2P2 combine genotype was estimated to have protective effect against RA, CTP1P2 combine genotype was found to be risk for RA. Our findings suggest that there is an association of IL-4 gene 70bp VNTR polymorphism and MTHFR C677T polymorphism with susceptibility of a person for development of RA. PMID- 23685258 TI - The tale of a person and a peptide: Wylie W. Vale Jr. and the role of corticotropin-releasing factor in the stress response. AB - The studies reviewed in this article certainly do not constitute the entire body of research conducted by Wylie Vale's group and his collaborators, they might constitute turning points in CRF research. In addition, the studies reviewed here show that, over the course of 31 years (from 1981 to 2012), Wylie tirelessly pursued the answers to fundamental questions regarding CRF. He was a man whose drive never seemed to falter. PMID- 23685259 TI - Promoting immunity during chronic infection--the therapeutic potential of common gamma-chain cytokines. AB - The continued global burden wrought by chronic infectious disease is unrelenting. Current therapies have curbed the severity of disease for patients, but Human Immunodeficiency Virus (HIV) and Hepatitis B (HBV) infection remain incurable and Mycobacterium tuberculosis (MTB) is rapidly becoming resistant to our existing antibiotics. Much attention has been given to enhancing T cell immunity through the use of certain common gamma-chain cytokines, which have proven to be essential and necessary for T cell survival and function. This article reviews the pre-clinical and clinical literature surrounding IL-2, IL-7, IL-15 and IL-21 and we comment on the potential therapeutic promise of these cytokines as adjuvant treatments for chronic infectious diseases. PMID- 23685260 TI - Molecular characterization of woodchuck CD4 (wCD4) and production of a depletion monoclonal antibody against wCD4. AB - CD4 T cells play an important role in the immune response against hepatitis B virus (HBV) infection. Woodchucks represent an excellent animal model to study HBV infection. In this study, we characterized the cDNA sequence of woodchuck CD4 (wCD4). The deduced wCD4 protein has four extracellular immunoglobulin-like domains comparable to the other mammalian CD4 molecules. The important extracellular cysteine residues and the intracellular tyrosine protein kinase binding site of wCD4 are also conserved. The deduced wCD4 protein shows 53-63% identity with the counterparts of other mammalians. Phylogenetic analysis indicates that wCD4 is closely related with the counterparts of primates. Two polyclonal antibodies (pAbs) and four monoclonal Abs (mAbs) against wCD4 were produced. Two pAbs and one mAbs (G2) were found to effectively suppress ConA induced proliferation in vitro. Anti-wCD4 mAb G2 depleted 60% of CD4 cells from healthy woodchucks, while the remaining CD4 cells responded well to ConA stimulation. This work provides a basis for studying CD4 T cell mediated immune responses against HBV infection in the woodchuck model. PMID- 23685262 TI - Breaking the silence: addressing skin issues in obese and overweight children. AB - Skin irritation and breakdown can cause considerable physical and psychological pain, yet skin alterations and hygiene issues are often not addressed during routine healthcare visits for children who are overweight and obese. The number of children with obesity has increased significantly, yet there is limited literature to assist children with the private physical symptoms and inconveniences that accompany obesity. Healthcare professionals focus on nutritional intake and activity and treat comorbidities related to obesity, since comorbidities affect quality of life, but so can the pain and embarrassment of skin issues. This article addresses skin issues related to being overweight and obese. PMID- 23685261 TI - Complement activation is critical for placental ischemia-induced hypertension in the rat. AB - Preeclampsia is a major obstetric problem defined by new-onset hypertension and proteinuria associated with compromised placental perfusion. Although activation of the complement system is increased in preeclampsia compared to normal pregnancy, it remains unclear whether excess complement activation is a cause or consequence of placental ischemia. Therefore, we hypothesized that complement activation is critical for placental ischemia-induced hypertension. We employed the reduced utero-placental perfusion pressure (RUPP) model of placental ischemia in the rat to induce hypertension in the third trimester and evaluated the effect of inhibiting complement activation with a soluble recombinant form of an endogenous complement regulator, human complement receptor 1 (sCR1; CDX-1135). On day 14 of a 21-day gestation, rats received either RUPP or Sham surgery and 15 mg/kg/day sCR1 or saline intravenously on days 14-18. Circulating complement component 3 decreased and complement activation product C3a increased in RUPP vs. Sham (p<0.05), indicating complement activation had occurred. Mean arterial pressure (MAP) measured on day 19 increased in RUPP vs. Sham rats (109.8+/-2.8 mmHg vs. 93.6+/-1.6 mmHg). Treatment with sCR1 significantly reduced elevated MAP in RUPP rats (98.4+/-3.6 mmHg, p<0.05) and reduced C3a production. Vascular endothelial growth factor (VEGF) decreased in RUPP compared to Sham rats, and the decrease in VEGF was not affected by sCR1 treatment. Thus, these studies have identified a mechanistic link between complement activation and the pregnancy complication of hypertension apart from free plasma VEGF and have identified complement inhibition as a potential treatment strategy for placental ischemia induced hypertension in preeclampsia. PMID- 23685263 TI - The Texas Children's Hospital Pediatric Advanced Warning Score as a predictor of clinical deterioration in hospitalized infants and children: a modification of the PEWS tool. AB - The purpose of this study was to examine the psychometric properties of the Texas Children's Hospital Pediatric Advanced Warning Score (PAWS) instrument as an indicator of clinical deterioration in infants and children. DESIGN AND METHODS: A retrospective chart review of 150 infants and children was performed. RESULTS: The overall Cronbach's alpha score was 0.75. The estimate of interrater reliability was 0.740. IMPLICATIONS: The Texas Children's Hospital Pediatric Advanced Warning Score instrument was found to be reliable and valid. PMID- 23685265 TI - Technology in nursing education: YouTube as a teaching strategy. PMID- 23685264 TI - Lasting effects of an interdisciplinary home visiting program on child behavior: preliminary follow-up results of a randomized trial. AB - Child mental health is of great concern requiring effective and appropriate parenting interventions. This pilot study was the first attempt to examine the intermediate effects of an ongoing parenting home visiting program, Minding the Baby (MTB), on parental reflective functioning (RF) and child behavior. Results indicated that the women who participated in the MTB intervention described their children-when assessed post-intervention-as having significantly fewer externalizing child behaviors. However, there was no significant difference between the two groups on parental RF from the end of the intervention to follow up. The central finding that children who participated with the MTB program were reported to have significantly fewer externalizing behaviors following the intervention has important clinical and public health implications. Recommendations for the design of future follow-up studies and for further exploration of parental RF as it relates to the MTB outcomes are discussed. PMID- 23685266 TI - Symptoms, feelings, activities and medication use in adolescents with uncontrolled asthma: lessons learned from asthma diaries. AB - This study was to describe symptoms, feelings, activities and medication use reported by adolescents with uncontrolled asthma on their 24-hour asthma diaries. Adolescents with uncontrolled asthma (13-17 years, N=29) completed asthma diaries and audio-recorded symptom sounds for 24 hours. A variety of symptoms were reported, and the most frequently reported symptoms were coughing followed by wheezing. Most self-reported coughing and wheezing were verified by audio recordings. Participants reported predominantly negative feelings and low levels of activities. High discordance between self-reports and medical records in medications was noted, raising a concern of poor treatment adherence in this vulnerable group. PMID- 23685267 TI - Physiologic responses of preterm infants to the male and female voice in the NICU. AB - The aim of this study was to investigate the effects of postconceptional age and voice type (male and female) on heart rate, respiratory rate, and oxygen saturation of preterm infants in the neonatal intensive care unit (NICU). Nineteen preterm infants born 31 weeks of gestation heard male and female voices on a weekly basis and their physiologic responses were recorded while hearing each voices. Results revealed that infants responded to the male voice with decreased HR as they grew older. Male voices, including the father's voice, can be considered an auditory stimulus for young preterm infants in the NICU. PMID- 23685268 TI - Feedback control of electrode offset voltage during functional electrical stimulation. AB - Control of the electrode offset voltage is an important issue related to the processes of functional electrical stimulation because excess charge accumulation over time damages both the tissue and the electrodes. This paper proposes a new feedback control scheme to regulate the electrode offset voltage to a predetermined reference value. The electrode offset voltage was continuously monitored using a sample-and-hold (S/H) circuit during stimulation and non stimulation periods. The stimulation current was subsequently adjusted using a proportional-integral (PI) controller to minimise the error between the reference value and the electrode offset voltage. During the stimulation period, the electrode offset voltage was maintained through the S/H circuit, and the PI controller did not affect the amplitude of the stimulation current. In contrast, during the non-stimulation period, the electrode offset voltage was sampled through the S/H circuit and rapidly regulated through the PI controller. The experimental results obtained using a nerve cuff electrode showed that the electrode offset voltage was successfully controlled in terms of the performance specifications, such as the steady- and transient-state responses and the constraint of the controller output. Therefore, the proposed control scheme can potentially be used in various nerve stimulation devices and applications requiring control of the electrode offset voltage. PMID- 23685269 TI - Multimodal detection of head-movement artefacts in EEG. AB - Artefacts arising from head movements have been a considerable obstacle in the deployment of automatic event detection systems in ambulatory EEG. Recently, gyroscopes have been identified as a useful modality for providing complementary information to the head movement artefact detection task. In this work, a comprehensive data fusion analysis is conducted to investigate how EEG and gyroscope signals can be most effectively combined to provide a more accurate detection of head-movement artefacts in the EEG. To this end, several methods of combining these physiological and physical signals at the feature, decision and score fusion levels are examined. Results show that combination at the feature, score and decision levels is successful in improving classifier performance when compared to individual EEG or gyroscope classifiers, thus confirming that EEG and gyroscope signals carry complementary information regarding the detection of head movement artefacts in the EEG. Feature fusion and the score fusion using the sum rule provided the greatest improvement in artefact detection. By extending multimodal head-movement artefact detection to the score and decision fusion domains, it is possible to implement multimodal artefact detection in environments where gyroscope signals are intermittently available. PMID- 23685270 TI - The usage of rice straw as a major substrate for the production of surfactin by Bacillus amyloliquefaciens XZ-173 in solid-state fermentation. AB - Agro-industrial byproducts, especially rice straw, are potential resources. This work was aimed to utilize raw materials to produce value-added biosurfactant in solid-state fermentation (SSF). Rice straw and soybean flour were found efficient and selected as major substrates for surfactin production. The results of Plackett-Burman design indicated that glycerol, water content, inoculum size and temperature were the significant variables identified in the screen of nine total variables. The optimum values for the four significant variables were determined by the Box-Behnken design. The optimal surfactin production was obtained when the medium contained 5 g soybean flour, 4 g rice straw, 2% (w/w) maltose and 2.65% (w/w) glycerol, pH 7.0. The ideal growth conditions for surfactin production consisted of a moisture content of 62.8% (v/w) and growth supplemented with 15.96% inoculum size in 250 mL flasks at 26.9 degrees C for 48 h. Under optimal conditions, a surfactin yield of 15.03 mg/gds was attained in 1000-fold scale-up fermentation in a 50 L fermenter, thereby validating the accuracy of this approach. This study proposed an eco-friendly and economical way to convert agro industrial byproducts into biosurfactant. PMID- 23685271 TI - The role of uncertainty and subjective influences on consequence assessment by aquatic biosecurity experts. AB - Expert judgement is often used to mitigate the knowledge gaps that limit understanding of aquatic non-indigenous species (ANS) impacts (consequences) to environmental, economic, social, cultural and human health values. To understand how this uncertainty may affect expert decision making, we explored the presence and effects of uncertainty on consequence assessment for 10 ANS by scientists and managers. We hypothesized species' distribution, taxonomy and impact type will affect assessment magnitude. These hypotheses were partially supported. We also hypothesized a difference in the relationship between consequence magnitude and uncertainty, based on assessor group. This set of hypotheses was not supported, as all group assessments had a significant negative correlation between consequence and uncertainty. Both scientists and managers assigned lower consequence when faced with knowledge gaps and other forms of uncertainty. This aligns with an "innocent until proven guilty" or hindsight approach, as opposed to a "guilty until proven innocent" or precaution approach. Based on these outcomes, the experts appeared to make decisions in violation of both the maximin principle and precaution, instead using a heuristic approach. We suggest several management strategies to prevent biases against environmental protection that occur due to use of the hindsight approach. PMID- 23685272 TI - Mechanism considerations for photocatalytic oxidation, ozonation and photocatalytic ozonation of some pharmaceutical compounds in water. AB - Aqueous solutions of four pharmaceutical compounds, belonging to the group of emergent contaminants of water: atenolol (ATL), hydrochlorothiazide (HCT), ofloxacin (OFX) and trimethoprim (TMP), have been treated with different oxidation systems, mainly, photocatalytic oxidation, ozonation and photocatalytic ozonation. TiO2 has been used as semiconductor for photocatalytic reactions both in the presence of air, oxygen or ozone-oxygen gas mixtures. Black light lamps mainly emitting at 365 nm were the source of radiation. In all cases, the influence of some variables (concentrations of semiconductor, ozone gas and pharmaceuticals and pH) on the removal of pharmaceuticals, total polyphenol content (TPC) and total organic carbon (TOC) was investigated. A discussion on the possible routes of pharmaceutical and intermediates (as TPC and TOC) elimination has been developed. Thus, OFX TiO2/UVA degradation mechanism seems to develop through the participation of non-hydroxyl free radical species. Furthermore, the presence of OFX inhibits the formation of hydroxyl radicals in the photocatalytic process. The most effective processes were those involving ozone that lead to complete disappearance of parent compounds in less than 30 min for initial pharmaceutical concentrations lower than 2.5 mg L(-1). In the ozonation systems, regardless of the pH and the presence of TiO2, pharmaceuticals are degraded through their direct reaction with ozone. Photocatalytic ozonation was the most efficient process for TPC and TOC removals (>= 80% and >=60% elimination after 2 h of treatment, respectively) as well as in terms of the ozone consumption efficiency (1, 5.5 and 4 mol of ozone consumed per mol of TOC mineralized, at pH 4, 7 and 9, respectively). Weakly acid conditions (pH 4) resulted to be the most convenient ones for TPC and TOC removal by photocatalytic ozonation. This was likely due to formation of hydroxyl radicals through the ozonide generated at these conditions. PMID- 23685273 TI - Impact assessment of a high-speed railway line on species distribution: application to the European tree frog (Hyla arborea) in Franche-Comte. AB - The aim of the present work is to assess the potential long-distance effect of a high-speed railway line on the distribution of the European tree frog (Hyla arborea) in eastern France by combining graph-based analysis and species distribution models. This combination is a way to integrate patch-level connectivity metrics on different scales into a predictive model. The approach used is put in place before the construction of the infrastructure and allows areas potentially affected by isolation to be mapped. Through a diachronic analysis, comparing species distribution before and after the construction of the infrastructure, we identify changes in the probability of species presence and we determine the maximum distance of impact. The results show that the potential impact decreases with distance from the high-speed railway line and the largest disturbances occur within the first 500 m. Between 500 m and 3500 m, the infrastructure generates a moderate decrease in the probability of presence with maximum values close to -40%. Beyond 3500 m the average disturbance is less than 10%. The spatial extent of the impact is greater than the dispersal distance of the tree frog, confirming the assumption of the long-distance effect of the infrastructure. This predictive modelling approach appears to be a useful tool for environmental impact assessment and strategic environmental assessment. The results of the species distribution assessment may provide guidance for field surveys and support for conservation decisions by identifying the areas most affected. PMID- 23685274 TI - Oaths and hypothetical bias. AB - Results from experiments using an oath to eliminate hypothetical bias in stated preference valuation are presented. An oath has several potential advantages relative to other methods for reducing hypothetical bias. Our empirical results suggest that with an oath, mean hypothetical payments are not different from mean actual payments and that when controlling for experimental participants' characteristics using regression analyses, the oath eliminated hypothetical bias. PMID- 23685276 TI - Cloning, characterization and expression of a cDNA encoding a granulin-like polypeptide in Ciona savignyi. AB - Previous study in our laboratory confirmed that a novel polypeptide, CS5931 derived from Ciona savignyi possesses potent antitumor activity. In the present study, the full length cDNA of CS5931 precursor, termed Cs-pgrn-1 was cloned. The complete cDNA sequence of this gene consists of 685 bp containing an open reading frame (ORF) of 522 bp (173 amino acid residues). In silico analysis revealed that the polypeptide consists of two identical domains, similar with granulin (GRN) found in other species, and each of the domain encodes a polypeptide identical with CS5931. Phylogenetic analysis confirmed that CS5931 shares high homology with Ciona intestinalis GRN and is conserved during evolution. The polypeptide also shows high similarity with human GRN A, B, and C. Prediction of 3D protein structure revealed the 3D structure of CS5931 is very similar with human GRN A. The CS5931 was expressed using a prokaryotic expression system and the purified polypeptide inhibited the growth of several tumor cell lines in vitro via apoptotic pathway. Our study revealed that CS5931 has the potential to be developed as a novel antitumor agent. PMID- 23685278 TI - Identification of gene microarray expression profiles in patients with chronic graft-versus-host disease following allogeneic hematopoietic cell transplantation. AB - Chronic graft-versus-host disease (GVHD) results in significant morbidity and mortality, limiting the benefit of allogeneic hematopoietic cell transplantation (HCT). Peripheral blood gene expression profiling of the donor immune repertoire following HCT may provide associated genes and pathways thereby improving the pathophysiologic understanding of chronic GVHD. We profiled 70 patients and identified candidate genes that provided mechanistic insight in the biologic pathways that underlie chronic GVHD. Our data revealed that the dominant gene signature in patients with chronic GVHD represented compensatory responses that control inflammation and included the interleukin-1 decoy receptor, IL-1 receptor type II, and genes that were profibrotic and associated with the IL-4, IL-6 and IL-10 signaling pathways. In addition, we identified three genes that were important regulators of extracellular matrix. Validation of this discovery phase study will determine if the identified genes have diagnostic, prognostic or therapeutic implications. PMID- 23685275 TI - An unsolved mystery: the target-recognizing RNA species of microRNA genes. AB - MicroRNAs (miRNAs) are an abundant class of endogenous ~21-nucleotide (nt) RNAs. These small RNAs are produced from long primary miRNA transcripts - pri-miRNAs - through sequential endonucleolytic maturation steps that yield precursor miRNA (pre-miRNA) intermediates and then the mature miRNAs. The mature miRNAs are loaded into the RNA-induced silencing complexes (RISC), and guide RISC to target mRNAs for cleavage and/or translational repression. This paradigm, which represents one of major discoveries of modern molecular biology, is built on the assumption that mature miRNAs are the only species produced from miRNA genes that recognize targets. This assumption has guided the miRNA field for more than a decade and has led to our current understanding of the mechanisms of target recognition and repression by miRNAs. Although progress has been made, fundamental questions remain unanswered with regard to the principles of target recognition and mechanisms of repression. Here I raise questions about the assumption that mature miRNAs are the only target-recognizing species produced from miRNA genes and discuss the consequences of working under an incomplete or incorrect assumption. Moreover, I present evolution-based and experimental evidence that support the roles of pri-/pre-miRNAs in target recognition and repression. Finally, I propose a conceptual framework that integrates the functions of pri-/pre-miRNAs and mature miRNAs in target recognition and repression. The integrated framework opens experimental enquiry and permits interpretation of fundamental problems that have so far been precluded. PMID- 23685279 TI - Neuroendocrine tumours--challenges in the diagnosis and classification of pulmonary neuroendocrine tumours. AB - Pulmonary neuroendocrine (NE) proliferations are a diverse group of disorders which share distinct cytological, architectural and biosynthetic features. Tumours composed of NE cells are dispersed among different tumour categories in the WHO classification of tumours and as such do not conform to a singular group with regards to treatment and prognosis. This is reflected by the highly variable behaviour of NE proliferations, ranging from asymptomatic, for instance in diffuse idiopathic pulmonary NE cell hyperplasia and tumourlets, to highly malignant cancers such as small cell lung cancer and large cell NE carcinoma. In this review NE proliferations are described as distinct entities ranging from low grade lesions to high grade cancers. The differential diagnoses are considered with each of the entries. Finally, mention is made of tumours which may show some NE features. PMID- 23685277 TI - What causes relapses of autoimmune diseases? The etiological role of autoreactive T cells. AB - Most human autoimmune diseases have a relapsing-remitting or a chronic progressive course, while animal models are usually acute and monophasic. In our experimental animal model the disease can be either monophasic or remitting, depending on the autoantigen used for induction, and it appears to lie in the effector phenotype of the elicited T helper cell response. Since both, monophasic and relapsing courses of disease are induced by immunization as well as by adoptive transfer of peptide-specific, CD4(+) T cells, we were able to directly compare the transcriptomes of pathogenic T cell lines by gene array analysis and qPCR as well as protein expression. Upregulated genes were only determined in T cells inducing relapsing uveitis and belong to certain pathways of antigen presentation, activation, inflammation, migration and survival, comprising WNT, Hedgehog, MAP-kinase and JAK/STAT-pathways. These pathways are partially interacting with each other, and the central molecule upregulated in T cells causing relapsing disease was found to be IFN-gamma. Here the course of the autoimmune diseases strictly depends on the characteristics of the autoreactive T cells, which are already determined at their early stage of antigen-specific activation. Our rat models of experimental autoimmune uveitis could help elucidating the immune mechanisms behind relapsing autoimmunity in order to develop better therapeutic strategies. PMID- 23685280 TI - Remarkable similarities between the hemichordate (Saccoglossus kowalevskii) and vertebrate GPCR repertoire. AB - Saccoglossus kowalevskii (the acorn worm) is a hemichordate belonging to the superphylum of deuterostome bilateral animals. Hemichordates are sister group to echinoderms, and closely related to chordates. S. kowalevskii has chordate like morphological traits and serves as an important model organism, helping developmental biologists to understand the evolution of the central nervous system (CNS). Despite being such an important model organism, the signalling system repertoire of the largest family of integral transmembrane receptor proteins, G protein-coupled receptors (GPCRs) is largely unknown in S. kowalevskii. Here, we identified 260 unique GPCRs and classified as many as 257 of them into five main mammalian GPCR families; Glutamate (23), Rhodopsin (212), Adhesion (18), Frizzled (3) and Secretin (1). Despite having a diffuse nervous system, the acorn worm contains well conserved orthologues for human Adhesion and Glutamate family members, with a similar N-terminal domain architecture. This is particularly true for genes involved in CNS development and regulation in vertebrates. The average sequence identity between the GPCR orthologues in human and S. kowalevskii is around 47%, and this is same as observed in couple of the closest vertebrate relatives, Ciona intestinalis (41%) and Branchiostoma floridae (~47%). The Rhodopsin family has fewer members than vertebrates and lacks clear homologues for 6 of the 13 subgroups, including olfactory, chemokine, prostaglandin, purine, melanocyte concentrating hormone receptors and MAS-related receptors. However, the peptide and somatostatin binding receptors have expanded locally in the acorn worm. Overall, this study is the first large scale analysis of a major signalling gene superfamily in the hemichordate lineage. The establishment of orthologue relationships with genes involved in neurotransmission and development of the CNS in vertebrates provides a foundation for understanding the evolution of signal transduction and allows for further investigation of the hemichordate neurobiology. PMID- 23685281 TI - Localization and functional analysis of HmgB3p, a novel protein containing high mobility-group-box domain from Tetrahymena thermophila. AB - The high-mobility-group (HMG)-box domain represents a very versatile protein domain that mediates the DNA-binding of non-sequence-specific and sequence specific proteins. HMG-box proteins are involved in various nuclear functions, including modulating chromatin structure and genomic stability. In this study, we identified the gene HMGB3 in Tetrahymena thermophila. The predicted HmgB3p contained a single HMG-box, an SK-rich-repeat domain and a neutral phosphorylated C-terminal. HMGB3 was expressed in the growth and starvation stages. Furthermore, HMGB3 showed a higher expression levels during the conjugation stage. HMGB3 knockout strains showed no obvious cytological defects, although initiation of HMGB3 knockout strain mating was delayed and maximum mating was decreased. HA HmgB3p localized on the micronucleus (MIC) during the vegetative growth and starvation stages. Furthermore, HA-HmgB3p specially decorated the meiotic and mitotic functional MIC during the conjugation stage. Truncated HMGB3 lacking the HMG box domain disappeared from MICs and diffused in the cytoplasm. Overexpressed HmgB3p was abnormally maintained in newly developing macronuclei and affected the viability of progeny. Taken together, these results show that HmgB3p is a germline micronuclear-specific marker protein. It may bind to micronucleus specific DNA sequences or structures and is likely to have some function specific to micronuclei of T. thermophila. PMID- 23685282 TI - Association of genetic polymorphisms in ADH and ALDH2 with risk of coronary artery disease and myocardial infarction: a meta-analysis. AB - Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the major enzymes responsible for alcohol metabolism in humans. Emerging evidences have shown that functional polymorphisms in ADH and ALDH genes might play a critical role in increasing coronary artery disease (CAD) and myocardial infarction (MI) risks; however, individually published studies showed inconclusive results. The aim of this meta-analysis is to evaluate the associations between the genetic polymorphisms of ADH and ALDH genes with susceptibility to CAD and MI. A literature search was conducted on PubMed, Embase, Web of Science and Chinese BioMedical databases from inception through December 1st, 2012. Crude relative risks (RRs) with 95% confidence intervals (CIs) were calculated. Twelve case control studies were included with a total of 9616 subjects, including 2053 CAD patients, 1436 MI patients, and 6127 healthy controls. Meta-analysis showed that mutant genotypes (GA+AA) of the rs671 polymorphism in the ALDH2 gene were associated with increased risk of both CAD and MI (CAD: RR=1.20, 95%CI: 1.03 1.40, P=0.021; MI: RR=1.32, 95%CI: 1.11-1.57, P=0.002). However, there were no significant associations of ADH genetic polymorphisms to CAD and MI risks (CAD: RR=0.92, 95%CI: 0.73-1.15, P=0.445; MI: RR=0.93, 95%CI: 0.84-1.03, P=0.148). In conclusion, this meta-analysis provides strong evidence that ALDH2 rs671 polymorphism may be associated with increased risks of CAD and MI. However, further studies are still needed to accurately determine whether ADH genetic polymorphisms are associated with susceptibility to CAD and MI. PMID- 23685283 TI - A novel mutation in a large family causes a unique phenotype of Mucolipidosis IV. AB - Mucolipidosis type IV is a rare autosomal recessive lysosomal storage disorder reported among Ashkenazi Jews and to a lesser extent in other ethnic groups. Several mutations have been reported in MCOLN1 which is the only known gene associated with the disorder. Here we report the first Saudi patient with Mucolipidosis type IV from a consanguineous family with two branches having a total of five patients carrying a novel transition mutation, c.1307A>G (p.Y436C) in exon 11. The clinical course of the patient was nonspecific and a lysosomal storage disorder was not highly suspected due to lack of coarse facial features, organomegaly and skeletal findings of dysostosis multiplex. The detailed bioinformatics analysis on the deleterious effects of the mutation is discussed. Emphasis is made on the importance of brain magnetic resonance imaging (MRI) findings and serum gastrin level as key clues to the diagnosis of this often subtle neurodevelopmental disorder. PMID- 23685284 TI - FB-NOF is a non-autonomous transposable element, expressed in Drosophila melanogaster and present only in the melanogaster group. AB - Most foldback elements are defective due to the lack of coding sequences but some are associated with coding sequences and may represent the entire element. This is the case of the NOF sequences found in the FB of Drosophila melanogaster, formerly considered as an autonomous TE and currently proposed as part of the so called FB-NOF element, the transposon that would be complete and fully functional. NOF is always associated with FB and never seen apart from the FB inverted repeats (IR). This is the reason why the FB-NOF composite element can be considered the complete element. At least one of its ORFs encodes a protein that has always been considered its transposase, but no detailed studies have been carried out to verify this. In this work we test the hypothesis that FB-NOF is an active transposon nowadays. We search for its expression product, obtaining its cDNA, and propose the ORF and the sequence of its potential protein. We found that the NOF protein is not a transposase as it lacks any of the motifs of known transposases and also shows structural homology with hydrolases, therefore FB-NOF cannot belong to the superfamily MuDR/foldback, as up to now it has been classified, and can be considered as a non-autonomous transposable element. The alignment with the published genomes of 12 Drosophila species shows that NOF presence is restricted only to the 6 Drosophila species belonging to the melanogaster group. PMID- 23685285 TI - Local stimulus disambiguation with global motion filters predicts adaptive surround modulation. AB - Humans have no problem segmenting different motion stimuli despite the ambiguity of local motion signals. Adaptive surround modulation, i.e., the apparent switching between integrative and antagonistic modes, is assumed to play a crucial role in this process. However, so far motion processing models based on local integration have not been able to provide a unifying explanation for this phenomenon. This motivated us to investigate the problem of local stimulus disambiguation in an alternative and fundamentally distinct motion-processing model which uses global motion filters for velocity computation. Local information is reconstructed at the end of the processing stream through the constructive interference of global signals, i.e., inverse transformations. We show that in this model local stimulus disambiguation can be achieved by means of a novel filter embedded in this architecture. This gives rise to both integrative and antagonistic effects which are in agreement with those observed in psychophysical experiments with humans, providing a functional explanation for effects of motion repulsion. PMID- 23685286 TI - Quantitative detection of nitroxyl upon trapping with glutathione and labeling with a specific fluorogenic reagent. AB - Donors of nitroxyl (HNO) have shown promise for treatment of stroke, heart failure, alcoholism and cancer. However, comparing the pharmacological capacities of various donors is difficult without first quantifying the amount of HNO released from each donor. Detection and quantitation of HNO has been complicated by the rapid self-consumption of HNO through irreversible dimerization, poor selectivity of trapping agents against other nitrogen oxides, and/or low sensitivity towards HNO. Here, an assay is described for the trapping of HNO by glutathione (GSH) followed by labeling of GSH with the fluorogenic agent, naphthalene-2,3-dicarboxaldehyde (NDA), and subsequent quantitation by fluorescence difference. The newly developed assay was used to validate the pH dependence of HNO release from isopropylamine NONOate (IPA/NO), which is a dual donor of HNO and NO at physiological pH. Furthermore, varied assay conditions were utilized to suggest the ratios of the products of the reaction of GSH with HNO. At intracellular concentrations of GSH, the disulfide (GSSG) was the major product, but significant concentrations of glutathione sulfinamide (GS(O)NH2) were also detected. This suggests that GS(O)NH2, which is a selective biomarker of HNO, may be produced in concentrations that are amenable to in vivo analysis. PMID- 23685288 TI - Donor after cardiac death kidney graft under mechanical cardiac compression evolution. PMID- 23685289 TI - The great iFR vs. FFR debate: why sometimes "the wait and see approach" is the best tactic as the best pragmatic solution will always emerge and become established. PMID- 23685287 TI - Control of angiogenesis dictated by picomolar superoxide levels. AB - Control of vascular insufficiencies due to various cardiovascular pathologies is important for developing specific and effective treatments. Fluctuations in oxidative stress significantly alter the progression of angiogenesis under physiological and pathological conditions. However, the precise amount of reactive oxygen species (ROS) required to influence subsequent signaling pathways for ischemic angiogenesis remains undefined. Here, we have determined the effect of ROS-mediated molecular mechanisms on angiogenesis in a murine model of peripheral artery disease using Gclm mutant mice (a model of compromised glutathione synthesis and therefore reduced antioxidant capacity). Left femoral artery ligation and excision were performed in Gclm WT (+/+), heterozygous (+/-), and null (-/-) mice. Blood flow (laser Doppler), angiogenic index (CD31/DAPI), and proliferation index (Ki67/DAPI) were significantly increased in Gclm(+/-) mice but not in Gclm(+/+) or Gclm(-/-) mice. Measurements of reactive oxygen species suggest that the amount of superoxide required to stimulate angiogenesis after the induction of ischemia is 9.82 pmol/mg of tissue. Protein carbonyl levels increased in a manner consistent with increasing oxidative stress. Superoxide and protein carbonyl levels were reduced by the addition of the nitroxide tempol, a known superoxide dismutase mimetic. Finally, restoration of blood flow in Gclm(+/-) mice was attenuated by a VEGF164 aptamer, verifying that slightly elevated levels of ROS restore blood flow by stimulating endothelial cell proliferation through a VEGF-dependent pathway. The results of this study reveal new information on the amount of ROS necessary for angiogenic activity and provide the foundation of critical redox parameters for vascular remodeling responses. The information obtained from this study on vascular ischemia, using a model of decreased antioxidant capacity, has provided insight into the control of revascularization and is a step forward in our ability to regulate angiogenic therapies. PMID- 23685290 TI - EuroIntervention - Methodology and Statistics Review Board. PMID- 23685291 TI - Indications for and outcomes of valve replacement for asymptomatic aortic valve stenosis. PMID- 23685292 TI - Recent data on off-pump coronary artery bypass grafting: the CORONARY and GOPCABE trials. PMID- 23685293 TI - Sharing and growing together: EuroPCR 2013. PMID- 23685294 TI - First-in-human evaluation of a sirolimus-eluting coronary stent on an integrated delivery system: the DIRECT study. AB - AIMS: The DIRECT study is a first-in-human evaluation of the safety and efficacy of the Svelte sirolimus-eluting coronary stent mounted on a fixed-wire, "all-in one" integrated delivery system (IDS) in patients with de novo coronary artery lesions. The system permits easy delivery, deployment and post-dilatation of a cobalt-chromium stent eluting sirolimus from a fully bioabsorbable amino acid coating. The stent on its IDS has a very low profile, and is designed specifically to facilitate direct stenting. METHODS AND RESULTS: Patients with symptomatic ischaemic heart disease and a single de novo native coronary lesion suitable for percutaneous coronary intervention were prospectively enrolled at four New Zealand sites. The lesion length had to be <23 mm and the vessel reference diameter 2.5-3.5 mm. The primary safety and efficacy endpoints were target vessel failure (TVF) and angiographic in-stent late lumen loss (LLL) at six months, respectively. Twenty-nine of 30 enrolled patients completed six-month follow-up. TVF occurred in two patients (7%). The in-stent LLL was 0.22 +/- 0.27 mm. No patient had clinically-driven target lesion revascularisation. Intravascular ultrasound neointimal volume was 3.3 +/- 4.4 mm3 and volume obstruction was 2.7 +/- 4.5% at six months. Optical coherence tomography showed 98 +/- 4% strut coverage at a depth of 0.12 +/- 0.06 mm. No patient developed stent thrombosis. CONCLUSIONS: Percutaneous coronary intervention using the Svelte sirolimus-eluting coronary stent mounted on an IDS appears safe and effective in de novo coronary artery lesions, with minimal in-stent proliferation and excellent stent strut coverage at six months. PMID- 23685296 TI - Incidence and predictors of stent thrombosis: a single-centre study of 5,833 consecutive patients undergoing coronary artery stenting. AB - AIMS: Stent thrombosis (ST) is an infrequent but potentially fatal complication of PCI. The reported incidence of ST varies from 0-5%, due to differences in definition of ST, inclusion/exclusion criteria, and the type of stent and dual antiplatelet therapy used. We aimed to examine the incidence of ST and associated risk factors in this "real-world, all-comers" study. METHODS AND RESULTS: All patients undergoing PCI at South Yorkshire Cardiothoracic Centre (UK) between 2007 and 2010 were included, with no exclusion criteria. ST cases were divided into definite and probable ST, according to the ARC criteria. Univariate predictors were identified using Student's t-test and chi-square test, and entered into a Cox proportional hazards model to identify factors independently associated with ST. For 5,833 PCI patients followed up for two years, the incidence of definite and probable ST together was 1.9% (n=109); of these 73% were early, 11% late and 16% very late ST. Cardiogenic shock, ST-elevation myocardial infarction (STEMI), lack of dual antiplatelet treatment, diabetes mellitus, stent length and stent diameter were the independent predictors of ST. CONCLUSIONS: The incidence of definite/probable ST in this "real-world" registry is 1.9%. Cardiogenic shock, often excluded in clinical trials, is the strongest independent predictor of ST. PMID- 23685295 TI - Early or late intervention in high-risk non-ST-elevation acute coronary syndromes: results of the ELISA-3 trial. AB - AIMS: To compare an early to a delayed invasive strategy in high-risk patients with NSTE-ACS. METHODS AND RESULTS: In this prospective multicentre trial, 542 patients hospitalised with NSTE-ACS were randomised to either an immediate (angiography and revascularisation if appropriate <12 hr) or a delayed invasive strategy (>48 hr after randomisation). Patients were eligible if they had two of the following three high-risk characteristics: evidence of extensive myocardial ischaemia on ECG, elevated biomarkers for myocardial necrosis (TropT >0.10 MUg/L), and an age above 65 years. Primary endpoint of the study was the combined incidence of death, reinfarction and/or recurrent ischaemia at 30-day follow-up. Secondary endpoints were enzymatic infarct size as assessed by a single cardiac troponin T, at 72-96 hours after admission or at discharge, and the percentage of patients without a rise in CKMB during admission. Median age was 71.9 (interquartile range [IQR] 64.5-78.4) years. Median time between randomisation and start of angiography was 2.6 (IQR 1.2-6.2) hours in the immediate and 54.9 (44.2-74.5) hours in the delayed intervention group. The composite of death, reinfarction and/or recurrent ischaemia at 30 days occurred in 12% of patients and was not significantly different between the two groups (9.9% and 14.2%, respectively, p=0.135). All secondary endpoints and bleeding complications were comparable. Hospital duration was two days shorter in the immediate intervention group (4 days [IQR 2-10] vs. 6 days [IQR 4-12]). CONCLUSIONS: Although no definitive conclusion can be drawn due to a lower than expected prevalence of the primary endpoint, an immediate invasive strategy was safe and feasible but not superior to a delayed invasive strategy in terms of the combined primary endpoint of death, reinfarction and/or recurrent ischaemia at 30 days. These results are consistent with previous randomised trials which studied the effect of timing of angiography in patients with NSTE-ACS. TRIAL REGISTRATION: ISRCTN Register 9230163. PMID- 23685297 TI - Renal denervation for resistant hypertension using an irrigated radiofrequency balloon: 12-month results from the Renal Hypertension Ablation System (RHAS) trial. AB - AIMS: Renal denervation using the point-by-point application of radiofrequency energy delivered by the first-generation Symplicity system is effective in lowering office blood pressure but may be time-consuming. The OneShot Renal Denervation System with a balloon-mounted spiral electrode potentially shortens and simplifies the procedure. This study is a hypothesis-generating first-in human study to assess feasibility, and to provide preliminary efficacy and safety data. METHODS AND RESULTS: Eligible patients had a baseline office systolic blood pressure >=160 mmHg (or >=150 mmHg for diabetics) and were on two or more antihypertensive medications. Nine patients were enrolled. The primary endpoint, the insertion of the OneShot balloon into each renal artery and the delivery of radiofrequency energy, was achieved in 8/9 (89%) of patients. The one failure (the first patient) was due to generator high-impedance safety shut-off threshold set too low for humans. Adverse events were minor. No patient developed renal artery stenosis. Baseline BP was 185.67 +/- 18.7 mmHg and the reductions at 1, 3, 6 and 12 months were 30.1 +/- 13.6 (p=0.0004), 34.2 +/- 20.2 (p=0.002), 33.6 +/- 32.2 (p=0.021) and 30.6 +/- 22.0 (p=0.019). CONCLUSIONS: The OneShot renal denervation system successfully delivered radiofrequency energy to the renal arteries in a short and straightforward procedure. Australian New Zealand Clinical Trials Registry - URL: anzctr.org.au. Trial identification: ACTRN12611000987965. PMID- 23685299 TI - Impact of ad hoc percutaneous coronary intervention with drug-eluting stents in angina patients. AB - AIMS: To evaluate the impact of ad hoc percutaneous coronary intervention (PCI) which combines coronary angioplasty and PCI in the same procedure in the era of drug-eluting stents (DES). METHODS AND RESULTS: From the IRIS-DES registry, 4,738 angina patients treated using PCI with DES were enrolled. The 18-month outcomes were compared between ad hoc and non-ad hoc groups after adjustment using inverse probability-of-treatment weighting. Ad hoc PCI was performed in 3,562 (75.2%) patients. The ad hoc PCI group had less extensive coronary disease and received fewer stents. The incidence of major adverse cardiac or cerebrovascular events, consisting of death, myocardial infarction (MI), stroke, and repeat revascularisation, did not differ between the ad hoc and the non-ad hoc groups (8.3% vs. 7.6%; adjusted hazard ratio [aHR] of ad hoc PCI, 1.22; 95% confidence interval [CI]: 0.91 to 1.63; p=0.18). The individual endpoints of death (2.0% vs. 1.9%; aHR, 1.57; 95% CI: 0.86- 2.88; p=0.14), MI (0.8% vs. 1.0%; aHR, 0.62; 95% CI: 0.29 - 1.33; p=0.22), stroke (1.0% vs. 0.9%; aHR, 1.25; 95% CI: 0.58-2.69; p=0.57), and repeat revascularisation (4.4% vs. 4.0%; aHR, 1.23; 95% CI: 0.86 1.77; p=0.25) also did not differ between the groups. CONCLUSIONS: Ad hoc PCI using DES appears to be feasible for angina patients at a relatively low risk of procedure. This approach may reasonably be performed with evaluation of objective ischaemia using non-invasive or invasive tests. PMID- 23685300 TI - Clinical and angiographic outcomes following first-in-man implantation of a novel thin-strut low-profile fixed-wire stent: the Svelte Coronary Stent Integrated Delivery System first-in-man trial. AB - AIMS: The Svelte Stent Integrated Delivery System (IDS) is a novel fixed-wire thin-strut cobalt-chromium stent characterised by a very low entry profile. The aim of the present study is to evaluate the safety and the feasibility of the Svelte stent IDS implantation in humans. METHODS AND RESULTS: The present investigation is a prospective, multicentre non-randomised single-arm study. The primary endpoint was freedom from major adverse cardiac events (MACE) at 30 days post-procedure. Invasive follow-up was scheduled at six months post implantation. A total of 47 patients were enrolled and serial OCT imaging was performed in a subgroup of 18 patients. At the index procedure the lesion success rate was 97.9% (46 patients), the mean acute gain was 1.56 +/- 0.43 mm with a mean minimum lumen diameter of 2.48 +/- 0.43 mm. Post-implantation OCT imaging revealed a minimal mean prolapse area (0.10 +/- 0.06 mm2), mean incomplete stent apposition area (0.12 +/- 0.13 mm2) and mean intraluminal mass area (0.05 +/- 0.03 mm2). Edge dissections were reported in eight cases (mean dissection width 0.17 +/- 0.07 mm proximally and 0.25 +/- 0.24 mm distally). At 30-day clinical follow-up, one case of myocardial infarction was reported. At six months, the angiographic mean in stent late loss was 0.95 +/- 0.76 mm. By OCT, a high percentage of struts was covered (97.6 +/- 15.00 %) with a mean neointimal thickness of 0.31 +/- 0.14 mm, all edge dissections were clinically silent and healed. Target lesion revascularisation (TLR) occurred in 11 patients (23.4%) and clinically driven TLR in three of these patients (6.4%). No cases of death or stent thrombosis were reported during the study. CONCLUSIONS: Implantation of the Svelte stent IDS was observed to be safe, feasible and associated with a low acute vascular injury and a high percentage of strut coverage at 6-month follow-up. PMID- 23685298 TI - A randomised comparison of a novel abluminal groove-filled biodegradable polymer sirolimus-eluting stent with a durable polymer everolimus-eluting stent: clinical and angiographic follow-up of the TARGET I trial. AB - AIMS: The study sought to evaluate the safety and efficacy of FIREHAWK, a novel abluminal groove-filled biodegradable polymer sirolimus-eluting stent (SES) for treating patients with single de novo coronary lesions compared with the durable polymer everolimus-eluting stent (EES) XIENCE V. METHODS AND RESULTS: A total of 458 patients with single de novo native coronary lesions <=24 mm in length and a coronary artery >=2.25 to <=4.0 mm in diameter were enrolled in the TARGET I study, a prospective, randomised, non-inferiority trial. The primary endpoint was in-stent late lumen loss (LLL) at nine-month follow-up. The secondary endpoint, target lesion failure (TLF), was defined as the composite of cardiac death, target vessel myocardial infarction (TVMI), or ischaemia-driven target lesion revascularisation (iTLR). Patients were centrally randomised to treatment with either biodegradable polymer SES (n=227) or durable polymer EES (n=231). The nine month in-stent LLL of the biodegradable polymer SES was comparable to the EES group (0.13 +/- 0.24 mm vs. 0.13 +/- 0.18 mm, p=0.94; difference and 95% confidence interval 0.00 [-0.04, 0.04] mm; p for non-inferiority <0.0001). Cardiac death (0.4% vs. 0.0%), TVMI (1.3% vs. 1.7%), iTLR (0.4% vs. 0.4%) and TLF (2.2% vs. 2.2%) were similar between the biodegradable polymer SES and durable polymer EES groups at 12-month follow-up (all p>0.05). No definite/probable stent thrombosis was observed in both of these groups. CONCLUSIONS: In the multicentre TARGET I trial, the novel abluminal groove-filled biodegradable polymer SES FIREHAWK was non-inferior to the durable polymer EES XIENCE V with respect to the primary endpoint of in-stent LLL at nine months for treating patients with single de novo coronary lesions. The incidences of clinical endpoints were low in both of the stents at 12-month follow-up. (ClinicalTrials.gov identifier: NCT01196819). PMID- 23685301 TI - A novel non-vascular system to treat resistant hypertension. AB - AIMS: To evaluate in a preclinical model the utility of a monopolar electrode catheter delivering radiofrequency (RF) energy placed into the renal pelvis in order to treat resistant hypertension (RH). METHODS AND RESULTS: Sixteen female domestic swine weighing 60-65 kg underwent renal pelvic denervation via ureteral access. Three animals were euthanised immediately after delivery of RF energy; five animals were allowed to survive for seven days, six animals were allowed to survive for 14 days and two animals were allowed to survive for 30 days. Renal cortical norepinephrine levels were measured in all groups of animals. Histopathology of the treated zone was performed to confirm nerve damage. Renal cortical tissue was harvested for determination of tissue norepinephrine by HPLC. The kidneys were then profusion-fixed and harvested for histopathologic analysis. Mean reduction of norepinephrine levels was 60.4% compared to control. Histopathology confirmed nerve ablation in the treated zone. CONCLUSIONS: In this small, preclinical study, we introduce a new non-vascular system to treat resistant hypertension. If the current clinical experience confirms efficacy and safety, this approach may be one way to treat patients who cannot be treated with the standard percutaneous arterial devices. PMID- 23685302 TI - Ethanol-mediated perivascular renal sympathetic denervation: preclinical validation of safety and efficacy in a porcine model. AB - AIMS: We report the use of a novel endovascular approach using chemical neurolysis, via periadventitial injection of dehydrated ethanol (EtOH) to perform renal artery denervation. METHODS AND RESULTS: A novel, three-needle delivery device was introduced into the renal arteries of adult swine using fluoroscopic guidance. EtOH was injected bilaterally with one injection per artery, via the three needles into the adventitial and periadventitial space, using EtOH doses 0.15 ml/artery; n=3, 0.30 ml/artery; n=3, and 0.60 ml/artery; n=3, with saline injection as a sham control (0.4 ml/artery; n=3), and naive subjects (n=7) as a true negative control. The renal parenchymal norepinephrine (NE) concentration at two-week follow-up was the primary efficacy endpoint. The mean renal NE reduction was 54%, 78% and 88% at doses of 0.15 ml, 0.30 ml and 0.60 ml, respectively (p<0.0001 vs. controls). Histological examination revealed marked, and deep, circumferential renal nerve injury at depths of 2-8 mm from the intimal surface. There was no evidence of device-related or EtOH-induced injury to the intimal layers. In some samples at the higher EtOH doses, there was focal loss of smooth muscle cells in the outer media. Angiography at 45 days demonstrated normal appearing renal arteries with no detectable stenoses (n=8). CONCLUSIONS: Circumferential adventitial delivery of very low doses of EtOH may be a promising alternative to energy-based systems to achieve dose-dependent, and predictable renal denervation. Further study is warranted. PMID- 23685303 TI - Emerging technologies: polymer-free phospholipid encapsulated sirolimus nanocarriers for the controlled release of drug from a stent-plus-balloon or a stand-alone balloon catheter. AB - Drug-eluting stents have proven to be effective in reducing the risk of late restenosis. In order to achieve a controlled and prolonged release of the antiproliferative agent, current drug-eluting stents utilise various biodegradable as well as non-erodible polymeric blends to coat the stent surface and to serve as drug carriers. The utilisation of polymeric compounds in current drug-eluting stents may eventually limit their performance as well as their clinical applicability due to the potential induction of undesirable local reactions. The development of alternative, polymer-free drug carriers has the potential to overcome some of the limitations of current drug-eluting stent formulations. Moreover, improvements in drug carriers may also result in an expansion of the technological possibilities for other intravascular drug delivery systems, such as metal-free or even implant-free solutions. This article describes the structure and the preclinical validation profile of a novel phospholipid encapsulated sirolimus nanocarrier, used as a coating in two formulations: a coronary stent-plus-balloon system and a stand-alone balloon catheter. The nanoparticles provided a stable, even and homogenous coating to the devices in both formulations. Dose-finding studies allowed the most appropriate identification of the best nanoparticle structure associated with an extremely efficient transfer of drug to all layers of the vessel wall, achieving high tissue concentrations that persisted days after the application, with low systemic drug leaks. PMID- 23685304 TI - How should I treat a patient with typical angina, typical angiography, negative FFR? AB - BACKGROUND: A 63-year-old man was referred for cardiac catheterisation for typical angina. At angiography, high-grade stenosis of the first diagonal branch, of the proximal circumflex and of an intermediate branch was found. After treatment of the diagonal branch, fractional flow reserve of the circumflex and intermediate branch was negative, but symptoms persisted. INVESTIGATION: Physical examination, laboratory test, stress echocardiography, fractional flow reserve, coronary flow reserve. DIAGNOSIS: Complex interaction between epicardial stenosis and microvascular hyporeactivity. MANAGEMENT: Stenting. PMID- 23685305 TI - Tools & Techniques: Analysis of clustered data in interventional cardiology: current practice and methodological advice. PMID- 23685306 TI - "First-in-man" use of bioresorbable vascular scaffold in saphenous vein graft. PMID- 23685307 TI - Lesion distribution and intrinsic variability: the challenge to beat the gold standard. PMID- 23685308 TI - Commentary on "Hybrid iFR-FFR decision-making strategy..." by Petraco et al. PMID- 23685309 TI - The FIREHAWK stent: will it achieve its potential? PMID- 23685310 TI - Mediastinal teratomas in children. Case reports and review of the literature. AB - BACKGROUND: In the pediatric age, mediastinal teratomas are an infrequent observation, accounting for only 7%-11% of extragonadal teratomas. Mainly located in the anterior mediastinum arising from the thymic gland, or exceptionally, from ectopic thyroid tissue, they may rarely be observed in the posterior mediastinum, sometimes in a paravertebral position, simulating a neuroblastoma. The Authors have extrapolated, from their entire experience of teratomas, 3 cases, mostly operated as emergencies; 1 of them was treated just after birth. Aim of this paper is to report the clinical and pathologic findings, to evaluate the surgical approach and the long-term biological behaviour in these cases, in the light of survival and current insights reported in the literature. MATERIALS AND METHODS: The Authors reviewed the most significant clinical, laboratory, radiologic and pathologic findings, surgical procedures, and early and long-term results in 3 children, 2 males and 1 female, suffering from extragonadal teratomas, located in the mediastinum, treated immediately after birth. In 1 of them the lesion was prenatally diagnosed by US scanning between the 2nd and 3rd trimester of pregnancy. All the infants were born by scheduled caesarean section in a tertiary care hospital and were then immediately referred to the N.I.C.U. because of a mostly acute clinical presentation. The 3 patients were referred to the surgical unit at different ages, namely 2 days, 10 years and 12.5 years, respectively. The initial clinical presentation was consistent with the site of the mass and/or its side-effects. The first patient, a female newborn, presented a worsening condition of respiratory distress, immediately after birth, that required mechanical ventilation and stabilization of the vital signs. Likewise, the presentation of case No. 2 was acute with dyspnea associated with an upper airways infection. Instead, the initial symptoms in case No. 3 were subacute and non-specific, characterized by worsening pain at the right shoulder extending to the neck and homolateral arm. The patients underwent laboratory and radiologic investigations that confirmed the clinical diagnosis of teratoma on the basis of elevated AFP values in 2 cases only (Case No. 1 and No. 2), while calcifications were lacking at imaging in all 3 patients. Emergency surgical management was required and, in accordance with recommended practice, the procedure was complete exeresis. RESULTS: All the patients underwent close long-term clinical, laboratory and imaging surveillance at shorter intervals during the first 5 years after the exeresis and annually thereafter. At the present time they are alive, disease-free and have not suffered any recurrence and/or distant metastases, with a follow-up of 7, 30 and 3 years respectively. CONCLUSIONS: Some extragonadal teratomas of childhood may rarely arise in the mediastinum. Being congenital tumors, prenatal diagnosis by US scan is extremely important in order to organize proper perinatal care in appropriate facilities where it is possible to define the diagnosis, and equipped with appropriate tools to carry out emergency surgery at minimal risk and to prevent severe complications after birth. An emergency procedure is frequently dictated both by complications related to the mass effect, and by the need to define the histology of the whole mass rather than just small biopsy specimens. Some teratomas can hide more or less extensive islands of immaturity or signs of malignant transformation that are clinically evident. It should be noted that calcifications and high levels of AFP and/or beta-HCG, usually pathognomonic elements for diagnosis, may not always be evident during the diagnostic work-up in mediastinal lesions. The prognosis is generally benign, although the AIEOP 2004 guidelines pointed out that high levels of circulating markers, including AFP, in children affected by mature or immature teratomas would indicate the presence of micro-foci of YST, marking them out as at high risk. The UKCCSG II and the SFOP indicated AFP values exceeding 10,000 ng / ml as the threshold identifying a group of patients with a severe prognosis.The treatment indicated is early, complete exeresis, followed by a careful, extensive microscopic examination and associated, if necessary, with adjuvant chemotherapy. Finally, in accordance with recommended practice, close, long-term clinical, laboratory and imaging surveillance is necessary, at shorter intervals during the first 5 years after the exeresis. PMID- 23685311 TI - The lung microvascular endothelium as a therapeutic target in severe influenza. AB - Severe infections with influenza virus are characterized by acute respiratory distress syndrome (ARDS), a life-threatening disorder in which the alveolocapillary membrane in the lung becomes leaky. This leads to alveolar flooding, hypoxemia and respiratory failure. Recent data suggest that influenza virus can exert both direct and indirect effects on the lung endothelium, activating it and inducing microvascular leak. These findings raise the possibility that enhancing lung endothelial barrier integrity or modulating lung endothelial activation may prove therapeutically useful for severe influenza. In this paper, we review evidence that lung endothelial activation and vascular leak are a "final common pathway" in severe influenza, as has been reported in bacterial sepsis, and that enhancing endothelial barrier function may improve the outcome of illness. We describe a number of experimental therapies that have shown promise in preventing or reversing increased vascular leak in animal models of sepsis or influenza. PMID- 23685312 TI - Increased proton leak and SOD2 expression in myotubes from obese non-diabetic subjects with a family history of type 2 diabetes. AB - Muscle insulin resistance is linked to oxidative stress and decreased mitochondrial function. However, the exact cause of muscle insulin resistance is still unknown. Since offspring of patients with type 2 diabetes mellitus (T2DM) are susceptible to developing insulin resistance, they are ideal for studying the early development of insulin resistance. By using primary muscle cells derived from obese non-diabetic subjects with (FH+) or without (FH-) a family history of T2DM, we aimed to better understand the link between mitochondrial function, oxidative stress, and muscle insulin resistance. Insulin-stimulated glucose uptake and glycogen synthesis were normal in FH+ myotubes. Resting oxygen consumption rate was not different between groups. However, proton leak was higher in FH+ myotubes. This was associated with lower ATP content and decreased mitochondrial membrane potential in FH+ myotubes. Surprisingly, mtDNA content was higher in FH+ myotubes. Oxidative stress level was not different between FH+ and FH- groups. Reactive oxygen species content was lower in FH+ myotubes when differentiated in high glucose/insulin (25mM/150pM), which could be due to higher oxidative stress defenses (SOD2 expression and uncoupled respiration). The increased antioxidant defenses and mtDNA content in FH+ myotubes suggest the existence of compensatory mechanisms, which may provisionally prevent the development of insulin resistance. PMID- 23685314 TI - A novel graphene-DNA biosensor for selective detection of mercury ions. AB - A novel electrochemical biosensor for sensitive and selective detection of mercury (II) ions (Hg2+) based on a DNA grafted graphene is proposed. Graphene oxide (GO) was reduced by dopamine, and then the single-strand probe DNA modified at the 5'-end with an alkylamino modifier (NH2-ssDNA) was grafted on the reduced graphene oxide (RGO) surface via Michael addition reaction. In the presence of Hg2+, the target DNA with four thymine-thymine (T-T) mismatches would hybridize with the probe DNA on the glassy carbon electrode (GCE) through T-Hg2+-T coordination chemistry. The hybridization of the two oligonucleotides leads to the increase in the peak currents of [Ru(NH3)6]3+, which could be used for electrochemical sensing of Hg2+. The difference in the value of the peak currents of [Ru(NH3)6]3+ before and after DNA hybridization was linear with the concentration of Hg2+ in the range from 8.0*10-9 to 1.0*10-7 M with a linear coefficiency of 0.996. The detection limit was 5.0*10-9 M (S/N=3). The proposed electrochemical biosensor is rapid, convenient and low-cost for effective sensing of Hg2+. Particularly, the proposed method was applied successfully to the determination of Hg2+ in real environmental samples. PMID- 23685315 TI - Toward embedded laboratory automation for smart Lab-on-a-Chip embryo arrays. AB - Lab-on-a-Chip (LOC) biomicrofluidic technologies are rapidly emerging bioanalytical tools that can miniaturize and revolutionize in situ research on embryos of small vertebrate model organisms such as zebrafish (Danio rerio) and clawed African frog (Xenopus laevis). Despite considerable progress being made in fabrication techniques of chip-based devices, they usually still require excessive and manual actuation and data acquisition that significantly reduce throughput and introduce operator-related analytical bias. This work describes the development of a proof-of-concept embedded platform that integrates an innovative LOC zebrafish embryo array technology with an electronic interface to provide higher levels of laboratory automation for in situ biotests. The integrated platform was designed to perform automatic immobilization, culture and treatment of developing zebrafish embryos during fish embryo toxicity (FET) biotests. The system was equipped with a stepper motor driven stage, solenoid actuated pinch valves, miniaturized peristaltic pumps as well as Peltier heating module. Furthermore, a Field Programmable Gate Array (FPGA) was used to implement an embedded hardware/software solution and interface to enable real-time control over embryo loading and immobilization; accurate microfluidic flow control; temperature stabilization and also automatic time-resolved image acquisition of developing zebrafish embryos. This work presents evidence that integration of embedded electronic interfaces with microfluidic chip-based technologies can bring the Lab-on-a-Chip a step closer to fully automated analytical systems. PMID- 23685316 TI - An electrochemical acetylcholine sensor based on lichen-like nickel oxide nanostructure. AB - Lichen-like nickel oxide nanostructure was synthesized by a simple method and characterized. The nanostructure was then applied to modify a carbon paste electrode and for the fabrication of a sensor, and the electrocatalytic oxidation of acetylcholine (ACh) on the modified electrode was investigated. The electrocatalytic efficiency of the nickel oxide nanostructure was compared with nickel micro- and nanoparticles, and the lichen-like nickel oxide nanostructure showed the highest efficiency. The mechanism and kinetics of the electrooxidation process were investigated by cyclic voltammetry, steady-state polarization curve and chronoamperometry. The catalytic rate constant and the charge transfer coefficient of ACh electrooxidation by the active nickel species, and the diffusion coefficient of ACh were reported. A sensitive and time-saving hydrodynamic amperometry method was developed for the determination of ACh. ACh was determined with a sensitivity of 392.4 mA M-1 cm-2 and a limit of detection of 26.7 MUM. The sensor had the advantages of simple fabrication method without using any enzyme or reagent and immobilization step, high electrocatalytic activity, very high sensitivity, long-term stability, and antifouling surface property toward ACh and its oxidation product. PMID- 23685313 TI - Direct and indirect effects of leptin on adipocyte metabolism. AB - Leptin is hypothesized to function as a negative feedback signal in the regulation of energy balance. It is produced primarily by adipose tissue and circulating concentrations correlate with the size of body fat stores. Administration of exogenous leptin to normal weight, leptin responsive animals inhibits food intake and reduces the size of body fat stores whereas mice that are deficient in either leptin or functional leptin receptors are hyperphagic and obese, consistent with a role for leptin in the control of body weight. This review discusses the effect of leptin on adipocyte metabolism. Because adipocytes express leptin receptors there is the potential for leptin to influence adipocyte metabolism directly. Adipocytes also are insulin responsive and receive sympathetic innervation, therefore leptin can also modify adipocyte metabolism indirectly. Studies published to date suggest that direct activation of adipocyte leptin receptors has little effect on cell metabolism in vivo, but that leptin modifies adipocyte sensitivity to insulin to inhibit lipid accumulation. In vivo administration of leptin leads to a suppression of lipogenesis, an increase in triglyceride hydrolysis and an increase in fatty acid and glucose oxidation. Activation of central leptin receptors also contributes to the development of a catabolic state in adipocytes, but this may vary between different fat depots. Leptin reduces the size of white fat depots by inhibiting cell proliferation both through induction of inhibitory circulating factors and by contributing to sympathetic tone which suppresses adipocyte proliferation. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. PMID- 23685317 TI - Electrochemical magneto immunosensor for the detection of anti-TG2 antibody in celiac disease. AB - An electrochemical magneto immunosensor for the detection of anti transglutaminase antibodies (ATG2) in celiac disease was developed. The immunological reaction is performed on magnetic beads (MBs) as a solid support in which the transglutaminase enzyme (TG2) is covalently immobilized (TG2-MB) and then ATG2 were revealed by an antibody labeled with peroxidase. The electrochemical response of the enzymatic reaction with o-phenilendiamine and H2O2 as substrates by square wave voltammetry was correlated with the ATG2. Graphite-epoxi composite cylindrical electrodes and screen printed electrodes were used as transducers in the immunosensor. A total number of 29 sera from clinically confirmed cases of celiac disease and 19 negative control sera were tested by the electrochemical magneto immunosensor. The data were submitted to the receiver-operating characteristic plot (ROC) analysis which indicated that 16.95 units was the most effective cut-off value (COV) to discriminate correctly between celiac and non-celiac patients. Using this point for prediction, sensitivity was found to be 100%, while specificity was 84%. PMID- 23685318 TI - Drug effects on ventilatory control and upper airway physiology related to sleep apnea. AB - Understanding the inter-relationship between pharmacological agents, ventilatory control, upper airway physiology and their consequent effects on sleep-disordered breathing may provide new directions for targeted drug therapy. Where available, this review focuses on human studies that contain both drug effects on sleep disordered breathing and measures of ventilatory control or upper airway physiology. Many of the existing studies are limited in sample size or comprehensive methodology. At times, the presence of paradoxical findings highlights the complexity of drug therapy for OSA. The existing studies also highlight the importance of considering inter-individual pharmacokinetics and underlying causes of sleep apnea in interpreting drug effects on sleep-disordered breathing. Practical ways to assess an individual's ventilatory control and how it interacts with upper airway physiology is required for future targeted pharmacotherapy in sleep apnea. PMID- 23685320 TI - Significant divergences between the temporal structure of the behavior in Wistar and in the spontaneously more anxious DA/Han strain of rats tested in elevated plus maze. AB - The aim of present research is to study the temporal structure of the behavior in two strains of rats with different basal level of emotionality. To this purpose, the temporal profile of the behavior in Wistar rat and in the spontaneously more anxious DA/Han strain was analyzed in the Elevated Plus Maze. Both quantitative and multivariate t-pattern analyses were carried out. In comparison with Wistar, DA/Han subjects showed a significant reduction of the permanence in open arm and a significant increase of the time spent in the central platform of the maze. Mean frequencies of each behavioral element showed significant modifications both in open and in closed arm. Multivariate t-pattern analyses demonstrated a very different temporal profile of behavior in the two strains: Wistar rats presented 197 t-patterns of different composition, whereas DA/Han rats only 26; as to the mean number of t-patterns, Wistar presented a value of 698.90, whereas DA/Han only 92.80. Similar clear-cut differences were detected for the mean number of t patterns in the two arms and for the time course of such t-patterns. Present study has evidenced that the temporal organization of the bahavior in Elevated Plus Maze is differently structured in two strains of rats with different basal level of emotionality. PMID- 23685319 TI - Splitting of the cerebellar vermis in juvenile rats--effects on social behavior, vocalization and motor activity. AB - Radical resection of malignant midline tumors of the posterior fossa in childhood followed by adjuvant therapies like chemotherapy or radiotherapy often leads to longterm survival and even healing of such patients. Therefore, quality of life becomes particular important. Postoperative neurological deficits, such as cerebellar mutism and ataxia have been attributed to splitting of the cerebellar vermis to remove these tumors. Here, we tested the effect of vermian splitting in juvenile rats on social behavior, vocalization and motor activity. Juvenile male Sprague Dawley rats, aged 23 days, underwent vermian splitting under general anesthesia after medial suboccipital craniotomy (lesioned group, n=16). In sham lesioned rats, only craniotomy was performed and the dura was opened with release of cerebrospinal fluid (n=16). Naive rats served as controls (n=14). All groups were tested on day 0 (before surgery), and on days 1-4 and 7 after surgery for locomotor activity, motor coordination, social behavior, and ultrasound vocalization during social interaction. Finally, splitting of the vermis was histologically verified. Social interaction was reduced for two days after surgery in lesioned rats compared to sham-lesioned rats and controls. Vocalization was decreased for one day compared to controls. Locomotor activity was disturbed for several days after surgery in both lesioned and sham-lesioned rats as compared to controls. Deficient social behavior and vocalization after surgery are related to vermian splitting in juvenile rats. These results indicate that similar to the human context vermian splitting can reduce communicative drive in the early postsurgical phase. PMID- 23685321 TI - Long-term loss of dopamine release mediated by CRF-1 receptors in the rat lateral septum after repeated cocaine administration. AB - The lateral septum (LS) is a brain nucleus associated to stress and drug addiction. Here we show that dopamine extracellular levels in the lateral septum are under the control of corticotrophin releasing factor (CRF). Reverse dialysis of 1MUM stressin-1, a type 1 CRF receptor (CRF-R1) agonist, induced a significant increase of LS dopamine extracellular levels in saline-treated rats that was blocked by the co-perfusion of stressin-1 with CP-154526, a specific CRF-R1 antagonist. Repeated cocaine administration (15mg/kg; twice daily for 14 days) suppressed the increase in LS dopamine extracellular levels induced by CRF-R1 activation. This suppression was observed 24h, as well as 21 days after withdrawal from repeated cocaine administration. In addition, depolarization induced dopamine release in the LS was significantly higher in cocaine-compared to saline-treated rats. Thus, our results show that the activation of CRF-R1 in the LS induces a significant increase in dopamine extracellular levels. Interestingly, repeated cocaine administration induces a long-term suppression of the CRF-R1 mediated dopamine release and a transient increase in dopamine releasability in the LS. PMID- 23685322 TI - Phosphodiesterase-5 inhibitor sildenafil prevents neuroinflammation, lowers beta amyloid levels and improves cognitive performance in APP/PS1 transgenic mice. AB - Memory deficit is a marker of Alzheimer's disease (AD) that has been highly associated with the dysfunction of cyclic GMP (cGMP) signaling and an ongoing inflammatory process. Phosphodiesterase-5 (PDE5) inhibitors prevent the breakdown of cGMP and are currently studied as a possible target for cognitive enhancement. However, it is still unknown whether inhibition of PDE5 reversed beta-amyloid peptide (Abeta)-induced neuroinflammation in APP/PS1 transgenic (Tg APP/PS1) mice. The present study evaluated the cognitive behaviors, inflammatory mediators, and cGMP/PKG/pCREB signaling in 15-month-old Tg APP/PS1 mice and age matched wild-type (WT) mice that were treated with PDE5 inhibitor sildenafil and the inhibitor of cGMP-dependent protein kinase Rp-8-Br-PET-cGMPS. In comparison with WT mice, Tg APP/PS1 mice were characterized by impaired cognitive ability, neuroinflammatory response, and down-regulated cGMP signaling. Sildenafil reversed these memory deficits and cGMP/PKG/pCREB signaling dysfunction; it also reduced both the soluble Abeta1-40 and Abeta1-42 levels in the hippocampus. These effects of sildenafil were prevented by intra-hippocampal infusion of the Rp-8-Br PET-cGMPS. These results suggest that sildenafil could restore cognitive deficits in Tg APP/PS1 mice by the regulation of PKG/pCREB signaling, anti-inflammatory response and reduction of Abeta levels. PMID- 23685323 TI - Comparison of the therapeutic effects of bone marrow mononuclear cells and microglia for permanent cerebral ischemia. AB - In this study we transplanted bone marrow mononuclear cells (BM-MNCs) or microglia into rats that had undergone permanent cerebral ischemia and observed the distribution or morphology of transplanted cells in vivo. In addition, we compared the effects of BM-MNCs and microglia on infarct volume, brain water content, and functional outcome after permanent cerebral ischemia. BM-MNCs and microglia were obtained from femur and brain, respectively, of newborn rats. Adult rats were injected with vehicle or 3 million BM-MNCs or microglia via the tail vein 24h after permanent middle cerebral artery occlusion (pMCAO). The distribution or morphologic characteristics of transplanted BM-MNCs (double stained with BrdU/Cd34 or BrdU/CD45) and microglia (double stained with BrdU/Iba 1) were detected with immunofluorescent staining at 3 or 7 and 14 days after pMCAO. Functional deficits were assessed by the modified neurologic severity score at 1, 3, 7 and 14 days after pMCAO. Brain water content was assessed at 3 days, and infarct volume was determined at 14 days. We observed more BrdU/CD45 and BrdU/Iba-1 double-stained cells than BrdU/CD34 double-stained cells around the infarcted area. Some infused microglia showed the morphology of innate microglia at 7 days after pMCAO, and the number increased at 14 days. BM-MNC treated rats showed significantly reduced infarct volume and brain water content compared to vehicle- and microglia-treated rats. In addition, BM-MNC treatment reduced neurologic deficit scores compared to those in the other groups. The results provide evidence that infusion of BM-MNCs, but not microglia, is neuroprotective after permanent cerebral ischemia. PMID- 23685324 TI - Association between DRD2, 5-HTTLPR, and ALDH2 genes and specific personality traits in alcohol- and opiate-dependent patients. AB - The vulnerability of developing addictions is associated with genetic factors and personality traits. The predisposing genetic variants and personality traits may be common to all addictions or specific to a particular class of addiction. To investigate the relationship between genetic variances, personality traits, and their interactions in addiction are important. We recruited 175 opiate-dependent patients, 102 alcohol-dependent patients, and 111 healthy controls. All participants were diagnosed using DSM-IV criteria and assessed with Tridimensional Personality Questionnaire (TPQ). The dopamine D2 receptor (DRD2), 5-HTT-linked promoter region (5-HTTLPR), and aldehyde dehydrogenase 2 (ALDH2) genes were genotyped using PCR. The genotype frequency of the 5-HTTLPR and ALDH2 was significantly different between the patients and controls (P=0.013, P<0.001, respectively), and borderline significant (P=0.05) for DRD2 polymorphism. Both Novelty Seeking (NS) and Harm Avoidance (HA) scores were higher for patients (P<0.001). After stratification by candidate genes, addicts with ALDH2 *1/*1 interacting with the low-functional group of DRD2 and 5-HTTLPR genes have higher HA traits, whereas addicts with ALDH2 *1/*2 or *2/*2 and low-functional group of DRD2 and 5-HTTLPR genes have higher NS traits. We concluded that addicts, both alcohol- and opiate-dependent patients, have common genetic variants in DRD2 and 5-HTTLPR but specific for ALDH2. Higher NS and HA traits were found in both patient groups with the interaction with DRD2, 5-HTTLPR, and ALDH2 genes. The ALDH2 gene variants had different effect in the NS and HA dimension while the DRD2 and 5-HTTLPR genes did not. PMID- 23685325 TI - Effects of mindful eating training on delay and probability discounting for food and money in obese and healthy-weight individuals. AB - Obese individuals tend to behave more impulsively than healthy weight individuals across a variety of measures, but it is unclear whether this pattern can be altered. The present study examined the effects of a mindful eating behavioral strategy on impulsive and risky choice patterns for hypothetical food and money. In Experiment 1, 304 participants completed computerized delay and probability discounting tasks for food-related and monetary outcomes. High percent body fat (PBF) predicted more impulsive choice for food, but not small-value money, replicating previous work. In Experiment 2, 102 randomly selected participants from Experiment 1 were assigned to participate in a 50-min workshop on mindful eating or to watch an educational video. They then completed the discounting tasks again. Participants who completed the mindful eating session showed more self-controlled and less risk-averse discounting patterns for food compared to baseline; those in the control condition discounted similarly to baseline rates. There were no changes in discounting for money for either group, suggesting stimulus specificity for food for the mindful eating condition. PMID- 23685326 TI - Neuroprotective effect of curcumin on okadaic acid induced memory impairment in mice. AB - Okadaic acid (OKA) has been observed to cause memory impairment in human subjects having seafood contaminated with dinoflagellate (Helicondria okadai). OKA induces tau hyperphosphorylation and oxidative stress leading to memory impairment as our previous study has shown. Curcumin a natural antioxidant has demonstrated neuroprotection in various models of neurodegeneration. However, the effect of curcumin has not been explored in OKA induced memory impairment. Therefore, present study evaluated the effect of curcumin on OKA (100ng, intracerebrally) induced memory impairment in male Swiss albino mice as evaluated in Morris water maze (MWM) and passive avoidance tests (PAT). OKA administration resulted in memory impairment with a decreased cerebral blood flow (CBF) (measured by laser doppler flowmetry), ATP level and increased mitochondrial (Ca(2+))i, neuroinflammation (increased TNF-alpha, IL-1beta, COX-2 and GFAP), oxidative nitrosative stress, increased Caspase-9 and cholinergic dysfunction (decreased AChE activity/expression and alpha7 nicotinic acetylcholine receptor expression) in cerebral cortex and hippocampus of mice brain. Oral administration of curcumin (50mg/kg) for 13 days significantly improved memory function in both MWM and PAT along with brain energy metabolism, CBF and cholinergic function. It decreased mitochondrial (Ca(2+))i, and ameliorated neuroinflammation and oxidative nitrostative stress in different brain regions of OKA treated mice. Curcumin also inhibited astrocyte activation as evidenced by decreased GFAP expression. This neuroprotective effect of curcumin is due to its potent anti-oxidant action thus confirming previous studies. Therefore, use of curcumin should be encouraged in people consuming sea food (contaminated with dinoflagellates) to prevent cognitive impairment. PMID- 23685327 TI - Prospective effects of adolescent indicators of behavioral disinhibition on DSM IV alcohol, tobacco, and illicit drug dependence in young adulthood. AB - OBJECTIVE: To identify robust predictors of drug dependence. METHODS: This longitudinal study included 2361 male and female twins from an ongoing longitudinal study at the Center for Antisocial Drug Dependence (CADD) at the University of Colorado Boulder and Denver campuses. Twins were recruited for the CADD project while they were between the ages of 12 and 18. Participants in the current study were on average approximately 15years of age during the first wave of assessment and approximately 20years of age at the second wave of assessment. The average time between assessments was five years. A structured interview was administered at each assessment to determine patterns of substance use and Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; Fourth Edition) attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), and drug dependence symptoms. Cloninger's Tridimensional Personality Questionnaire was also used to assess novelty seeking tendencies (NS). At the second wave of assessment, DSM-IV dependence symptoms were reassessed using the same interview. Path analyses were used to examine direct and indirect mechanisms linking psychopathology and drug outcomes. RESULTS: Adolescent substance use, CD, and NS predicted young adult substance dependence, whereas the predictive effects of ADHD were few and inconsistent. Furthermore, CD and NS effects were partially mediated by adolescent substance use. CONCLUSIONS: Adolescent conduct problems, novelty seeking, and drug use are important indices of future drug problems. The strongest predictor was novelty seeking. PMID- 23685328 TI - Motivations to quit cannabis use in an adult non-treatment sample: are they related to relapse? AB - BACKGROUND: The majority of cannabis smokers who quit do so without formal treatment, suggesting that motivations to quit are an important part of cessation process. However, little is known about how motivations relate to successful quitting. METHOD: A convenience sample of 385 non-treatment-seeking adult cannabis smokers (58% male, age 16-64years at start of quit attempt) who made a "serious" (self-defined) quit attempt without formal treatment while not in a controlled environment were administered the 176-item Marijuana Quit Questionnaire (MJQQ) to assess their motivations to quit and outcome of the quit attempt. Exploratory factor analysis was performed to identify significant motivational factors. Subgroup comparisons used t-tests and ANOVA. Cox proportional hazard regression and the General Linear Model were performed to evaluate the influence of motivational factors, gender, and age on relapse status at time of interview and risk of relapse over time, with time between quit attempt and interview as a covariate. RESULTS: Exploratory factor analysis identified 6 motivational factors with eigenvalues >1 which accounted for 58.4% of the total variance: self-image and self-control, health concerns, interpersonal relationship concerns, legal concerns, social acceptability concerns, and self-efficacy. Women were more likely than men to be motivated by self-image/self-control, health concerns, and social acceptability concerns. Older individuals were more likely to be motivated by health concerns. At the time of interview, 339 subjects had relapsed. Self-image and self-control, health concerns, interpersonal relationship concerns, and social acceptability concerns were associated with greater likelihood of abstinence at the study interview. Legal concerns and social acceptability concerns were associated with significantly lower hazard ratios (0.88, 0.83) for relapse during the abstinent period. CONCLUSION: These findings show gender and age differences in motivations to quit cannabis smoking and that adult cannabis smokers have motivations to quite similar to those of adolescent cannabis smokers and of adults who quit alcohol and tobacco use without formal treatment. The findings suggest areas of focus to improve secondary prevention and psychosocial treatment efforts. PMID- 23685329 TI - Alcohol mixed with energy drinks: are there associated negative consequences beyond hazardous drinking in college students? AB - OBJECTIVE: The consumption of alcohol mixed with energy drinks (AmED) is prevalent among college students as is hazardous drinking, a drinking pattern that places one at risk for alcohol-related harm. The present study, therefore, examined associations between AmED use, hazardous drinking, and alcohol-related consequences in college students. METHODS: Based on a probability sample conducted in 2010, participants were 606 undergraduate students aged 18-25. AmED consumption included lifetime and past year use. Hazardous drinking and alcohol related consequences were measured during the past year. Point prevalence was used to estimate rates of AmED use, and chi-square, ANOVA, and logistic regression were used to examine associations between AmED use, hazardous drinking, and alcohol-related consequences. RESULTS: Lifetime and past year AmED use prevalence rates were 75.2% and 64.7%, respectively. Hazardous drinkers who engaged in AmED use were significantly more likely than past year hazardous drinkers who did not engage in AmED use to have had unprotected sex (OR=2.35, CI 1.27-4.32). CONCLUSIONS: AmED use appears to be highly prevalent among college students, and AmED use may confer additional risk for unprotected sex beyond hazardous drinking. Unprotected sex has implications for public health, and students who drink hazardously and consume AmED may be at greater risk. PMID- 23685331 TI - Is serving in the armed forces associated with tobacco or cannabis initiation? A study of onset sequences before and after joining the French armed forces. AB - The aim of this study was to evaluate whether joining the military could constitute a predictor of subsequent tobacco or cannabis use. Data from four cross-sectional surveys conducted between 2005 and 2009 in the French armed forces were used to constitute a retrospective cohort (n=4208). A Markov multi state model was fitted, estimating the probabilities at 1year for all possible pathways between entry into the military profession, tobacco initiation and cannabis initiation. The model was adjusted for current substance use status. Substance initiation appeared to mainly occur before entering the services than during the service period (3.0 times greater likelihood for tobacco and 2.5 times greater likelihood for cannabis). Probabilities of primo-initiation (i.e. starting with that substance) before joining the services were similar for tobacco (3.6% at one year) and cannabis (3.5%). When the study was restrained to current users, although differences were not statistically significant, probabilities of substance primo-initiation during the service period seemed to be greater than before. While the substance use itinerary in the French general population most often begins by tobacco, military seem to have a higher propensity to cannabis primo-initiation, which could traduce more sensation seeking behaviors. If certain results in our study could also evoke a propensity to substance initiation during the service period, we did not find evidence to verify the hypothesis of a military social inducing effect. Further research is needed to identify behavioral characteristics which could explain increased use during the service period. PMID- 23685330 TI - Cannabidiol reduces cigarette consumption in tobacco smokers: preliminary findings. AB - The role of the endocannabinoid system in nicotine addiction is being increasingly acknowledged. We conducted a pilot, randomised double blind placebo controlled study set out to assess the impact of the ad-hoc use of cannabidiol (CBD) in smokers who wished to stop smoking. 24 smokers were randomised to receive an inhaler of CBD (n=12) or placebo (n=12) for one week, they were instructed to use the inhaler when they felt the urge to smoke. Over the treatment week, placebo treated smokers showed no differences in number of cigarettes smoked. In contrast, those treated with CBD significantly reduced the number of cigarettes smoked by ~40% during treatment. Results also indicated some maintenance of this effect at follow-up. These preliminary data, combined with the strong preclinical rationale for use of this compound, suggest CBD to be a potential treatment for nicotine addiction that warrants further exploration. PMID- 23685332 TI - Fabrication of 3D cell-laden hydrogel microstructures through photo-mold patterning. AB - Native tissues are characterized by spatially organized three-dimensional (3D) microscaled units which functionally define cells-cells and cells-extracellular matrix interactions. The ability to engineer biomimetic constructs mimicking these 3D microarchitectures is subject to the control over cell distribution and organization. In the present study we introduce a novel protocol to generate 3D cell laden hydrogel micropatterns with defined size and shape. The method, named photo-mold patterning (PMP), combines hydrogel micromolding within polydimethylsiloxane (PDMS) stamps and photopolymerization through a recently introduced biocompatible ultraviolet (UVA) activated photoinitiator (VA-086). Exploiting PDMS micromolds as geometrical constraints for two methacrylated prepolymers (polyethylene glycol diacrylate and gelatin methacrylate), micrometrically resolved structures were obtained within a 3 min exposure to a low cost and commercially available UVA LED. The PMP was validated both on a continuous cell line (human umbilical vein endothelial cells expressing green fluorescent protein, HUVEC GFP) and on primary human bone marrow stromal cells (BMSCs). HUVEC GFP and BMSCs were exposed to 1.5% w/v VA-086 and UVA light (1 W, 385 nm, distance from sample = 5 cm). Photocrosslinking conditions applied during the PMP did not negatively affect cells viability or specific metabolic activity. Quantitative analyses demonstrated the potentiality of PMP to uniformly embed viable cells within 3D microgels, creating biocompatible and favorable environments for cell proliferation and spreading during a seven days' culture. PMP can thus be considered as a promising and cost effective tool for designing spatially accurate in vitro models and, in perspective, functional constructs. PMID- 23685333 TI - Tbx18 expression demarcates multipotent precursor populations in the developing urogenital system but is exclusively required within the ureteric mesenchymal lineage to suppress a renal stromal fate. AB - The mammalian urogenital system derives from multipotent progenitor cells of different germinal tissues. The contribution of individual sub-populations to specific components of the mature system, and the spatiotemporal restriction of the respective lineages have remained poorly characterized. Here, we use comparative expression analysis to delineate sub-regions within the developing urogenital system that express the T-box transcription factor gene Tbx18. We show that Tbx18 is transiently expressed in the epithelial lining and the subjacent mesenchyme of the urogenital ridge. At the onset of metanephric development Tbx18 expression occurs in a band of mesenchyme in between the metanephros and the Wolffian duct but is subsequently restricted to the mesenchyme surrounding the distal ureter stalk. Genetic lineage tracing reveals that former Tbx18(+) cells of the urogenital ridge and the metanephric field contribute substantially to the adrenal glands and gonads, to the kidney stroma, the ureteric and the bladder mesenchyme. Loss of Tbx18 does not affect differentiation of the adrenal gland, the gonad, the bladder and the kidney. However, ureter differentiation is severely disturbed as the mesenchymal lineage adopts a stromal rather than a ureteric smooth muscle fate. DiI labeling and tissue recombination experiments show that the restriction of Tbx18 expression to the prospective ureteric mesenchyme does not reflect an active condensation process but is due to a specific loss of Tbx18 expression in the mesenchyme out of range of signals from the ureteric epithelium. These cells either contribute to the renal stroma or undergo apoptosis aiding in severing the ureter from its surrounding tissues. We show that Tbx18-deficient cells do not respond to epithelial signals suggesting that Tbx18 is required to prepattern the ureteric mesenchyme. Our study provides new insights into the molecular diversity of urogenital progenitor cells and helps to understand the specification of the ureteric mesenchymal sub-lineage. PMID- 23685334 TI - The cytoskeletal protein Zyxin inhibits Shh signaling during the CNS patterning in Xenopus laevis through interaction with the transcription factor Gli1. AB - Zyxin is a cytoskeletal protein that controls cell movements by regulating actin filaments assembly, but it can also modulate gene expression owing to its interactions with the proteins involved in signaling cascades. Therefore, identification of proteins that interact with Zyxin in embryonic cells is a promising way to unravel mechanisms responsible for coupling of two major components of embryogenesis: morphogenetic movements and cell differentiation. Now we show that in Xenopus laevis embryos Zyxin can bind to and suppress activity of the primary effector of Sonic hedgehog (Shh) signaling cascade, the transcription factor Gli1. By using loss- and gain-of-function approaches, we demonstrate that Zyxin is essential for reduction of Shh signaling within the dorsal part of the neural tube of X. laevis embryo. Thus, our finding discloses a novel function of Zyxin in fine tuning of the central neural system patterning which is based on the ventral-to-dorsal gradient of Shh signaling. PMID- 23685335 TI - A typology of male prisoners making near-lethal suicide attempts. AB - BACKGROUND: Prisoners are at high risk of suicide. AIMS: This study aimed to develop a typology of prison suicide. METHOD: We interviewed 60 male prisoners who made near-lethal suicide attempts in prison to obtain quantitative and qualitative data regarding psychiatric, psychological, social, and criminological factors. We analyzed this information to develop a typology to classify suicidal prisoners and validated it by having a prison psychiatrist independently rate each interview transcript. RESULTS: We developed a typology of five subgroups: attempts that (1) were due to a prisoner being unable to cope in prison, (2) were motivated by psychotic symptoms, (3) had instrumental motives, (4) were "unexpected" by the prisoners themselves, and (5) were associated with withdrawal from drugs. The interrater reliability as measured by Cohen's was good to excellent at 0.81 (p < .001), 95% CI (0.69, 0.93). CONCLUSION: With further validation in other samples, this typology may assist suicide prevention initiatives in prisons as well as other forensic institutions by informing the assessment and formulation of suicide risk. PMID- 23685336 TI - Self-harm and homeless adults. AB - BACKGROUND: Homelessness is associated with an increased incidence of mental illness and risk of self-harm, including suicide. AIMS: To assess the prevalence of self-harm (including nonsuicidal self-injury and attempted suicide) among a UK sample of homeless adults and to compare demographic, clinical, and homeless related variables to determine which are linked to self-harm in this population. METHOD: A sample of 80 homeless adults were interviewed regarding history of self harm, mental health history, demographic, and homeless-related information. RESULTS: Sixty-eight percent of the sample reported past acts of self-harm. Those with histories of self-harm started using significantly more substances since becoming homeless and were younger when they first became homeless. They were also significantly more likely to have a past psychiatric admission and thoughts of self-harm in the past year. CONCLUSION: Self-harm is common among homeless adults and linked to long-term and enduring social and mental health concerns. PMID- 23685337 TI - The relationship between prior suicidal behavior and mortality among individuals in community corrections. AB - BACKGROUND: Individuals under community corrections have multiple risk factors for mortality including exposure to a criminal environment, drug use, social stress, and a lack of medical care that predispose them to accidents, homicides, medical morbidities, and suicide. The literature suggests that prior suicidal behavior may be a particularly potent risk factor for mortality among individuals in the criminal justice system. AIMS: This study looked to extend the link between history of a suicide attempt and future mortality in a community corrections population. METHOD: Using an archival dataset (N = 18,260) collected from 2002 to 2007 of individuals being monitored under community corrections supervision for an average of 217 days (SD = 268), we examined the association between past history of a suicide attempt and mortality. RESULTS: A Cox Proportional Hazard Model controlling for age, race, gender, and substance dependence indicated that past history of a suicide attempt was independently associated with time to mortality, and demonstrated the second greatest effect after gender. CONCLUSION: These data suggest the need for a greater focus on screening and preventive services, particularly for individuals with a history of suicidal behavior, so as to reduce the risk of mortality in community corrections populations. PMID- 23685338 TI - The effect of suicide-related Internet use on users' mental health. AB - BACKGROUND: Previous studies have shown that suicide-related Internet use can have both negative and positive psychological effects. AIMS: This study examined the effect of suicide-related Internet use on users' suicidal ideation, depression/anxiety tendency, and loneliness. METHOD: A two-wave panel study of 850 Internet users was conducted via the Internet. RESULTS: Suicide-related Internet use (e.g., browsing websites about suicide methods) had negative effects on suicidal ideation and depression/anxiety tendency. No forms of suicide-related Internet use, even those that would generally be considered positive, were found to decrease users' suicidal ideation. In addition, our results suggest that the greater the suicidal ideation and feelings of depression and loneliness of Internet users, the more they used the Internet. CONCLUSION: Since suicide related Internet use can adversely influence the mental health of young adults, it is necessary to take measures to reduce their exposure to such information. PMID- 23685339 TI - Clinical and socio-demographic correlates of suicidal intent among young adults: a study from South India. AB - BACKGROUND: Intent in attempted suicide is considered an indicator of subsequent suicide. Few studies in developing countries have examined correlates of suicidal intent among young adults. AIMS: This study aimed to assess the intent score among a sample of young suicide attempters from South India and to identify the factors associated with suicide intent among them. METHOD: The clinical charts of 64 consecutive subjects aged 15-24 years attending emergency services for attempted suicide were reviewed. All participants completed a semistructured proforma, the Presumptive Stressful Life Events Scale, the Beck Hopelessness Scale, the Pierce Suicide Intent Scale, and the Global Assessment of Functioning Scale. Psychiatric diagnoses were made according to the ICD-10 clinical descriptions and diagnostic guidelines. RESULTS: The intent scores were in the moderate-to-high range for most subjects. Suicide intent score significantly varied depending on the presence or absence of psychiatric morbidity. In bivariate analysis, psychiatric morbidity and hopelessness correlated positively with suicide intent, and in linear regression, hopelessness emerged as a predictor of suicide intent. CONCLUSION: A high intent of suicide in young is associated with psychiatric morbidity and presence of hopelessness. Hopelessness may be a key predictor of suicidal intent. Assessment of suicidal intent and hopelessness among young attempters is important and may help identify high-risk individuals who need intensive interventions. PMID- 23685340 TI - Age-related differences in the quality of life in end-stage renal disease in patients enrolled in hemodialysis or continuous peritoneal dialysis. AB - BACKGROUND: The aim of the present study was to compare the experience elderly and younger patients in terms of emotional status, disease perception, methods of coping with the end-stage renal disease (ESRD) stress, and health-related quality of life in 2 different settings of renal replacement therapy: hemodialysis (HD) and continuous ambulatory peritoneal dialysis programs (CAPD). Specifically, we hypothesized that younger people will more frequently use goal-oriented strategies to cope with illness-related stress and elderly patients will use more strategies related to the control of emotion. MATERIAL AND METHODS: A total of 69 HD patients, 40 CAPD patients, and 89 healthy volunteers were analyzed. The Situation and Trait Anxiety Inventory, the Profile of Mood States, the Cognitive Stress Appraisal Questionnaire, and the Nottingham Health Profile were used to assess anxiety, long-term emotional status, coping mechanisms, and health-related quality of life. Data were collected on several biochemical and demographic variables. RESULTS: Our study revealed that younger and elderly people on dialysis faced quite different problems. Younger people in both RRT groups had statistically higher assessment of ESRD as loss or challenge and they more frequently used distractive and emotional preoccupation coping strategies. Depression, confusion, and bewilderment dominate the emotional status of both patient populations, especially in the younger cohort. Both HD(young) and CAPD(young) patients complained more about lack of energy, mobility limitations, and sleep disturbances as compared to their elderly HD and CAPD counterparts. CONCLUSIONS: There are different needs and problems in younger and elderly patients on renal replacement therapy. Younger people required more ESRD-oriented support to relieve their health-related complaints to the level observed in their peers and needed extensive psychological assistance in order to cope with negative emotions related to their disease. PMID- 23685341 TI - Catechol estrogens induce proliferation and malignant transformation in prostate epithelial cells. AB - In the current study, the non-transformed prostatic epithelial cells (BPH-1) were exposed to the catechol estrogens (CE) 2-hydroxyestradiol (2-OHE2) or 4 hydroxyestradiol (4-OHE2), or the parent hormone 17-beta-estradiol (E2) at an equimolar concentration (1MUM) for a period of 6 weeks. It was found that both 2 OHE2 and 4-OHE2 have more potent proliferation-enhancing effect than E2. Exposure to 2-OHE2, 4-OHE2 or E2 resulted in a significant increase in the protein abundance of cyclin D1 and c-myc. The treated cells exhibited a shift toward the proliferative phase as indicated by FACScan. BPH-1 cells treated with 4-OHE2 showed increased abundance of estrogen receptor-alpha (ERalpha) and its downstream IGF-1R. Reduced abundance of estrogen receptor-beta (ERbeta) and its downstream tumor suppressor FOXO-1 were observed in cells exposed to E2, 2-OHE2 and, to a greater extent, 4-OHE2. Comet assay revealed that CE, especially 4 OHE2, elicited significant genotoxic effects as compared to E2. 4-OHE2 showed greater ability to neoplastically transform BPH-1 cells as indicated by increased colony forming capacity in soft agar and matrix invasion. In conclusion, in vitro exposure to CE could neoplastically transform human prostatic epithelial cells. Further, 4-OHE2 is more carcinogenic to prostate epithelial cells than the parent hormone E2. PMID- 23685342 TI - Sequencing of the beta-tubulin genes in the ascarid nematodes Parascaris equorum and Ascaridia galli. AB - Benzimidazoles (BZ) are used to control infections of the equine roundworm Parascaris equorum and the poultry roundworm Ascaridia galli. There are still no reports of anthelmintic resistance (AR) to BZ in these two nematodes, although AR to BZ is widespread in several other veterinary parasites. Several single nucleotide polymorphisms (SNP) in the beta-tubulin genes have been associated with BZ-resistance. In the present study we have sequenced beta-tubulin genes: isotype 1 and isotype 2 of P. equorum and isotype 1 of A. galli. Phylogenetic analysis of all currently known isotypes showed that the Nematoda has more diversity among the beta-tubulin genes than the Vertebrata. In addition, this diversity is arranged in a more complex pattern of isotypes. Phylogenetically, the A. galli sequence and one of the P. equorum sequences clustered with the known Ascaridoidea isotype 1 sequences, while the other P. equorum sequence did not cluster with any other beta-tubulin sequences. We therefore conclude that this is a previously unreported isotype 2. The beta-tubulin gene sequences were used to develop a PCR for genotyping SNP in codons 167, 198 and 200. No SNP was observed despite sequencing 95 and 100 individual adult worms of P. equorum and A. galli, respectively. Given the diversity of isotype patterns among nematodes, it is likely that associations of genetic data with BZ-resistance cannot be generalised from one taxonomic group to another. PMID- 23685343 TI - Identification of essential and non-essential protein kinases by a fusion PCR method for efficient production of transgenic Trypanosoma brucei. AB - Manipulation of gene expression has been used to elucidate gene function, explore fundamental biological processes and to identify potential drug targets in Trypanosoma brucei. We show in bloodstream forms that CDC2-related kinase CRK12 (Tb11.01.4130) is essential since transcriptional inactivation in conditional null mutants is lethal but 19 other protein kinases are not essential since null mutants are viable. We did so using efficient methods for the generation of null and conditional null cell lines of T. brucei by approaches that generate transfection constructs with large targeting sequences and which use reliable transfection and selection conditions. These methods, which are described in detail in the supplementary material, employ multiple oligonucleotides and PCR reactions and several transfections but are cost effective and can simultaneously generate 24 transfectants thus shifting the rate limiting experimental steps from the production of cell lines to their analysis. PMID- 23685345 TI - Laparoscopic hiatal hernia repair. Is the mesh hiatoplasty justified? AB - AIM: Laparoscopic Nissen fundoplication represents the gold standard in GERD therapy, although, a frequent failure of this primary repair is represented by the breakdown of the hiatoplasty. Aim of our work is to evaluate if ultrastructural alterations of the diaphragmatic pillars in patients with hiatal hernia, can explain the physiopathology of hernia recurrence. MATERIAL OF STUDY: The patients were divided into two groups: group A comprised 51 patients affected by hiatal hernia and group B (control) included 30 patients not affected by hiatal hernia.. Each patient underwent four biopsies, two from the phrenoesophageal membrane and two from the diaphragmatic pillars during laparoscopic procedures. Three hundred and twenty-four specimens, 204 from the group A and 120 from the group B, were processed and analyzed by transmission electron microscopy. RESULTS: No alterations were found in the phrenoesophageal membrane in both groups; samples from the diaphragmatic pillars showed no alteration in the group without hiatal hernia (group B). Instead, 90,2% of the muscular samples from the crura of group A patients presented ultrastructural alterations: in almost 75% of the cases the lesions were considered severe with extended disruption-degeneration of the muscle architecture. DISCUSSION: Patients with hiatal hernia have ultrastructural abnormalities of the muscular tissue of the diaphragmatic pillars that are absent in patients with normal gastroesophageal junction. CONCLUSIONS: The outcome of GERD surgery could depend not only on a correct technique but also on the underlying status of the diaphragmatic crura. PMID- 23685346 TI - Synthesis, chemical characterization and biological activity of new histone acetylation/deacetylation specific inhibitors: a novel and potential approach to cancer therapy. AB - Three new triorganotin(IV) complexes of valproic acid (vp1, Me3Sn-valproate; vp2, Bu3Sn-valproate; vp3, Ph3Sn-valproate) have been synthesized and investigated by spectroscopic and biological methods. An anionic, monodentate valproate ligand was observed, ester-like coordinating the tin atom on a tetra-coordinated, monomeric environment. The structures, though, can distort towards a penta coordination, as a consequence of a long range O...Sn interaction. Crystallographic and NMR findings confirm this situation both in solid state and solution. Biological finding evidenced a clear cytotoxic action of the complexes in hepatocellular carcinoma cell cultures: one of the complexes induced an 80% cell viability reduction after 24h treatment in HepG2 cells. This effect was accompanied by the appearance of biochemical signs of apoptosis. In Chang liver cells, the same compound induced only modest effects, suggesting a potential use as anti-cancer drug. Preliminary evaluations on hyperacetylation state of histone H3 in tributyltin-valproate treated HepG2 cells showed an increase in Ac-H3 (histone H3 acetylated at lys-9 and lys-14), suggesting that the compound maintains the deacetylation inhibition activity of its ligand valproate. PMID- 23685344 TI - Identification of functional modules of AKMT, a novel lysine methyltransferase regulating the motility of Toxoplasma gondii. AB - The intracellular parasite Toxoplasma gondii is a leading cause of congenital neurological defects. To cause disease, it must reiterate its lytic cycle through host cell invasion, replication, and parasite egress. This requires the parasite to sense changes in its environment and switch between the non-motile (for replication) and motile (for invasion and egress) states appropriately. Recently, we discovered a previously unknown mechanism of motility regulation in T. gondii, mediated by a lysine methyltransferase, AKMT (for Apical complex lysine (K) methyltransferase). When AKMT is absent, activation of motility is inhibited, which compromises parasite invasion and egress, and thus severely impairs the lytic cycle. Although the methyltransferase activity of AKMT has been established, the phylogenetic relationship of AKMT with other better studied lysine methyltransferases (KMTs) was not known. Also unknown was the functional relationships between different domains of AKMT. In this work we carried out phylogenetic analyses, which show that AKMT orthologs form a new subfamily of KMTs. We systematically generated truncation mutants of AKMT, and discovered that the predicted enzymatic domain alone is a very poor enzyme and cannot complement the function of AKMT in vivo. Interestingly, the N- and C-terminal domains of the AKMT have drastically different impacts on its enzyme activity, localization as well as in vivo function. Our results thus reveal that AKMT is an unusual, parasite-specific enzyme and identified regions and interactions within this novel lysine methyltransferase that can be used as drug targets. PMID- 23685347 TI - Palladium(II) and platinum(II) bis(thiosemicarbazone) complexes of the 2,6 diacetylpyridine series with high cytotoxic activity in cisplatin resistant A2780cisR tumor cells and reduced toxicity. AB - Preparation and characterization of four novel 2,6-diacetylpyridine bis((4)N tolylthiosemicarbazonato) palladium(II) and platinum(II) complexes, [PdL(1-2)] and [PtL(1-2)], are described. All compounds have been characterized by elemental analysis and by IR and NMR spectroscopy, and the crystal and molecular structures of complexes [PdL(2)] and [PtL(2)] have been determined by a single crystal X-ray diffraction. The ligands act as dianionic tetradentate donors coordinating to the metal center in a square planar geometry through the Npyridinic atom and the Niminic and the S atoms from one thiosemicarbazone arm, the fourth coordination position is occupied by the Nhydrazinic of the other arm. The new compounds synthesized have been evaluated for antiproliferative activity in vitro against NCI-H460, HepG2, MCF-7, A2780 and A2780cisR human cancer cell lines. The cytotoxicity data suggest that [PdL(1)], [PdL(2)] and [PtL(2)] may be endowed with important antitumor properties since they are capable of not only circumventing cisplatin resistance in A2780cisR cells but also exhibiting high antiproliferative activity in breast cancer MCF-7 cells. Subsequent toxicity study, in LLC-PK1 cells, has also been carried out and shows that none of these compounds are in vitro toxic in the tested concentration range. PMID- 23685348 TI - Hemoglobin is present as a canonical alpha2beta2 tetramer in dopaminergic neurons. AB - Hemoglobin is the oxygen carrier in blood erythrocytes. Oxygen coordination is mediated by alpha2beta2 tetrameric structure via binding of the ligand to the heme iron atom. This structure is essential for hemoglobin function in the blood. In the last few years, expression of hemoglobin has been found in atypical sites, including the brain. Transcripts for alpha and beta chains of hemoglobin as well as hemoglobin immunoreactivity have been shown in mesencephalic A9 dopaminergic neurons, whose selective degeneration leads to Parkinson's disease. To gain further insights into the roles of hemoglobin in the brain, we examined its quaternary structure in dopaminergic neurons in vitro and in vivo. Our results indicate that (i) in mouse dopaminergic cell line stably over-expressing alpha and beta chains, hemoglobin exists as an alpha2beta2 tetramer; (ii) similarly to the over-expressed protein, endogenous hemoglobin forms a tetramer of 64kDa; (iii) hemoglobin also forms high molecular weight insoluble aggregates; and (iv) endogenous hemoglobin retains its tetrameric structure in mouse mesencephalon in vivo. In conclusion, these results suggest that neuronal hemoglobin may be endowed with some of the biochemical activities and biological function associated to its role in erythroid cells. This article is part of a Special Issue entitled: Oxygen Binding and Sensing Proteins. PMID- 23685349 TI - A.S.P.E.N. clinical guidelines: nutrition support of neonatal patients at risk for metabolic bone disease. AB - BACKGROUND: Premature infants are at increased risk for metabolic bone disease, with resulting delayed bone growth, osteopenia, and rickets. METHOD: A systematic review of the best available evidence to answer a series of questions regarding neonatal patients at risk of metabolic bone disease receiving parenteral or enteral nutrition was undertaken and evaluated using concepts adopted from the Grading of Recommendations, Assessment, Development and Evaluation working group. A consensus process was used to develop the clinical guideline recommendations prior to external and internal review and approval by the American Society for Parenteral and Enteral Nutrition Board of Directors. QUESTIONS: (1) What maternal risk factors predispose the neonate to metabolic bone disease? (2) What is the optimal type of feeding to promote neonatal bone health? (3) When and how should vitamin D supplements be administered? (4) Does parenteral nutrition (PN) predispose a neonate to metabolic bone disease, and if so, are there PN formulation recommendations to minimize this risk? PMID- 23685352 TI - Broncho-alveolar macrophages express chemokines associated with leukocyte migration in a mouse model of asthma. AB - The migration of eosinophils and lymphocytes into airways is a hallmark of allergic asthma; however, the role of broncho-alveolar macrophages (BAMs) in this inflammatory process has not been fully elucidated. Using a murine Ova model of allergic airway disease (AAD), RNA isolated from BAMs was used to assess differential gene expression via microarray and qRT-PCR. Significant increases in WBCs, eosinophilia, mucus accumulation and goblet cell hyperplasia were observed in Ova sensitized and challenged mice, which correlated with increased expression of genes associated with alternatively activated M2 macrophages (e.g. arginase 1, YM-1, YM-2, Resistin like-alpha, and EAR-11). Other genes associated with asthma including FcgammaRIIb, MMP-14, CCL-8, CCL-17, ADAM-8, LTBR1, aquaporin-9 and IL 7R were also expressed at higher levels in Ova sensitized/challenged animals when compared to BAMs isolated from control animals. Eotaxin 2 (CCL-24), which is known to influence eosinophil migration, was highly up-regulated in BAMs, but not Eotaxin-1 (CCL-11). Conversely, lung interstitial macrophages expressed high levels of CCL-11, but not CCL-24. Taken together, this study provides additional evidence to support the notion that M2 BAMs play a role in eosinophil and potentially other leukocyte migration patterns into asthmatic airways. PMID- 23685353 TI - High-shear granulation as a manufacturing method for cocrystal granules. AB - Cocrystal formation allows the tailoring of physicochemical as well as of mechanical properties of an API. However, there is a lack of large-scale manufacturing methods of cocrystals. Therefore, the objective of this work was to examine the suitability of high-shear wet granulation as a manufacturing method for cocrystal granules on a batch scale. Furthermore, the cocrystal granules were characterized regarding their mechanical properties as well as their dissolution behavior. High-shear wet granulation was found to be a feasible manufacturing method for cocrystal granules. Cocrystal formation depended on the exposure time of the solids to the granulation liquid (water), the amount of liquid, the impeller speed of the granulator, and on the excipients (hydroxyl propylcellulose, microcrystalline cellulose, calcium hydrogenphosphate) used in the formulation. Storage stability was strongly influenced by the excipients, since in presence of calcium hydrogenphosphate, the poorly water-soluble salt calcium tartrate monohydrate was formed at high relative humidity. Interestingly, compactability was increased by cocrystal formation compared to that of the reference granules (piracetam and the respective excipients). The drug release was slightly decreased by cocrystal formation, most likely due to the lower solubility of the cocrystal. In the presence of calcium hydrogenphosphate however, no influence of cocrystal formation on either compactability or on drug release were observed, compared with the reference tablets. It was concluded that high-shear wet granulation is a valuable, however complex, manufacturing method for cocrystals. Cocrystal formation may influence compactability and drug release and thus affect drug performance and should be investigated during pre formulation. PMID- 23685354 TI - Weak antibody-cyclodextrin interactions determined by quartz crystal microbalance and dynamic/static light scattering. AB - In a quest to elucidate the mechanism by which hydroxypropyl beta-cyclodextrin (HPbetaCD) stabilizes antibodies against shaking stress, two heavily debated hypotheses exist, namely that stabilization is due to HPbetaCD's surface activity, or due to specific interactions with proteins. In a previous study by Serno et al. (Pharm. Res. 30 (2013) 117), we could refute the first hypothesis by proving that, although HPbetaCD is slightly surface active, it does not displace the antibody at the air-water interface, and accordingly, its surface activity is not the underlying stabilizing mechanism. In the present study, we investigated the possibility of interactions between HPbetaCD and monoclonal antibodies as the potential stabilization mechanism using quartz crystal microbalance (QCM) and static as well as dynamic light scattering. In the presence of HPbetaCD, the adsorption of IgG antibodies in the native state (IgG A) and the unfolded state (IgG A and IgG B) on gold-coated quartz crystals was studied by QCM. Results show that HPbetaCD causes a reduction in protein adsorption in both the folded and the unfolded states, probably due to an interaction between the protein and the cyclodextrin, leading to a reduced hydrophobicity of the protein and consequently a lower extent of adsorption. These results were supported by investigation of the interaction between the native protein and HPbetaCD using static and dynamic light scattering experiments, which provide the protein-protein interaction parameters, B22 and kD, respectively. Both B22 and kD showed an increase in magnitude with increasing HPbetaCD-concentrations, indicating a rise in net repulsive forces between the protein molecules. This is further evidence for the presence of interactions between HPbetaCD and the studied antibodies, since an association of HPbetaCD on the protein surface leads to a change in the intermolecular forces between the protein molecules. In conclusion, this study provides evidence that the previously observed stabilizing effect of HPbetaCD on IgG antibodies is probably due to direct interactions between the cyclodextrin and the protein. PMID- 23685355 TI - Overexpression of miR-10a and miR-375 and downregulation of YAP1 in medullary thyroid carcinoma. AB - MicroRNAs are a primordial mechanism of gene expression control that appear to be crucial to cellular development and may play an important role in tumor development. Much is known about the genetics of medullary thyroid carcinomas, as approximately 25% are hereditary and harbor germ line activating mutations in the RET gene. Somatic RET mutations are also seen in roughly 50% of sporadic medullary thyroid carcinomas. Few studies, however, have evaluated the role of microRNA expression in these tumors. DNA and RNA were extracted from formalin fixed paraffin-embedded tissue blocks of 15 medullary thyroid carcinomas [10 with RET mutations (3 hereditary) and 5 without RET mutations] and 5 non-tumor thyroid glands. miRNA expression of 754 targets was quantitated by real-time PCR using the ABI OpenArray miRNA assay. Three miRNAs showed significant differential expression and were validated in a larger cohort of 59 cases by real-time PCR. Expression of potential downstream targets and upstream regulators was also investigated by real-time PCR. miR-375 and miR-10a were significantly overexpressed, while miR-455 was underexpressed in medullary thyroid carcinomas. Expression of all 3 miRNAs was validated in the larger cohort of cases (miR-375, p=3.3*10(-26); miR-10a, p=5.6*10(-14); miR-455, p=2.4*10(-4)). No significant differences in miRNA expression were found between RET mutation positive and negative tumors nor between sporadic and hereditary tumors. Expression of the potential downstream targets of miR-375, YAP1 (a growth inhibitor) and SLC16a2 (a transporter of thyroid hormone), was down-regulated in the tumors suggesting that miR-375 is a negative regulator of the expression of these genes. Thus, differential expression of miR-375, miR-10a and miR-455 may be important for tumor development and/or reflect C-cell lineage of medullary thyroid carcinoma. Furthermore, the growth inhibitor YAP1 is identified as a potential important downstream target of miR-375. PMID- 23685356 TI - HOT1 is a mammalian direct telomere repeat-binding protein contributing to telomerase recruitment. AB - Telomeres are repetitive DNA structures that, together with the shelterin and the CST complex, protect the ends of chromosomes. Telomere shortening is mitigated in stem and cancer cells through the de novo addition of telomeric repeats by telomerase. Telomere elongation requires the delivery of the telomerase complex to telomeres through a not yet fully understood mechanism. Factors promoting telomerase-telomere interaction are expected to directly bind telomeres and physically interact with the telomerase complex. In search for such a factor we carried out a SILAC-based DNA-protein interaction screen and identified HMBOX1, hereafter referred to as homeobox telomere-binding protein 1 (HOT1). HOT1 directly and specifically binds double-stranded telomere repeats, with the in vivo association correlating with binding to actively processed telomeres. Depletion and overexpression experiments classify HOT1 as a positive regulator of telomere length. Furthermore, immunoprecipitation and cell fractionation analyses show that HOT1 associates with the active telomerase complex and promotes chromatin association of telomerase. Collectively, these findings suggest that HOT1 supports telomerase-dependent telomere elongation. PMID- 23685358 TI - Impact fact-or fiction? AB - The Journal Impact Factor dominates research assessment in many disciplines and in many countries. While research assessment will always have to rely to some extent on quantitative, standardized metrics, the focus on this single measure has gone so far as to hamper and distort scientific research. The Declaration on Research Assessment (DORA), signed by influential journals, funders, academic institutions and individuals across the natural sciences, aims to raise awareness and to redress the use of non-objective research assessment practices. PMID- 23685357 TI - Eps8 controls dendritic spine density and synaptic plasticity through its actin capping activity. AB - Actin-based remodelling underlies spine structural changes occurring during synaptic plasticity, the process that constantly reshapes the circuitry of the adult brain in response to external stimuli, leading to learning and memory formation. A positive correlation exists between spine shape and synaptic strength and, consistently, abnormalities in spine number and morphology have been described in a number of neurological disorders. In the present study, we demonstrate that the actin-regulating protein, Eps8, is recruited to the spine head during chemically induced long-term potentiation in culture and that inhibition of its actin-capping activity impairs spine enlargement and plasticity. Accordingly, mice lacking Eps8 display immature spines, which are unable to undergo potentiation, and are impaired in cognitive functions. Additionally, we found that reduction in the levels of Eps8 occurs in brains of patients affected by autism compared to controls. Our data reveal the key role of Eps8 actin-capping activity in spine morphogenesis and plasticity and indicate that reductions in actin-capping proteins may characterize forms of intellectual disabilities associated with spine defects. PMID- 23685360 TI - It's getting HOT at telomeres. PMID- 23685359 TI - Drosophila Polo regulates the spindle assembly checkpoint through Mps1-dependent BubR1 phosphorylation. AB - Maintenance of genomic stability during eukaryotic cell division relies on the spindle assembly checkpoint (SAC) that prevents mitotic exit until all chromosomes are properly attached to the spindle. Polo is a mitotic kinase proposed to be involved in SAC function, but its role has remained elusive. We demonstrate that Polo and Aurora B functional interdependency comprises a positive feedback loop that promotes Mps1 kinetochore localization and activity. Expression of constitutively active Polo restores normal Mps1 kinetochore levels even after Aurora B inhibition, highlighting a role for Polo in Mps1 recruitment to unattached kinetochores downstream of Aurora B. We also show that Mps1 kinetochore localization is required for BubR1 hyperphosphorylation and formation of the 3F3/2 phosphoepitope. This is essential to allow recruitment of Cdc20 to unattached kinetochores and the assembly of anaphase-promoting complex/cyclosome inhibitory complexes to levels that ensure long-term SAC activity. We propose a model in which Polo controls Mps1-dependent BubR1 phosphorylation to promote Cdc20 kinetochore recruitment and sustained SAC function. PMID- 23685361 TI - Emodin suppresses inflammatory responses and joint destruction in collagen induced arthritic mice. AB - OBJECTIVE: Emodin (3-methyl-1,6,8-trihydroxyanthraquinone) is one of the active components present in the root and rhizome of Rheum palmatum. It has been shown to contain biological activity (antitumour, antibacterial, diuretic and vasorelaxant effects). However, the mechanisms underlying the anti-arthritic effect of emodin have not been elucidated. Here we investigated whether emodin treatment would modulate the severity of the disease in an experimental arthritis model. METHODS: We evaluated the effects of emodin on CIA mice in vivo. RESULTS: The pathological processes of RA are mediated by a number of cytokines and MMPs. Expression of these proinflammatory mediators is controlled by nuclear factor kappaB (NF-kappaB). This study was performed to explore the effect of emodin on control of the NF-kappaB activation pathway and to investigate whether emodin has anti-inflammatory effects in CIA mice in vivo. Emodin inhibited the nuclear translocation and DNA binding of NF-kappaB subunits, which were correlated with its inhibitory effect on cytoplasmic IkappaBalpha degradation in CIA mice. These events further suppressed chemokine production and MMP expression. In addition, emodin inhibited the osteoclast differentiation induced by M-CSF and receptor activation of NF-kappaB ligand in bone marrow macrophages. CONCLUSION: These findings suggest that emodin exerts anti-inflammatory effects in CIA mice through inhibition of the NF-kappaB pathway and therefore may have therapeutic value for the treatment of RA. PMID- 23685362 TI - Elevated serum BAFF levels in patients with sarcoidosis: association with disease activity. AB - OBJECTIVE: The purpose of this study was to determine serum levels of B-cell activating factor (BAFF) and its clinical association in patients with sarcoidosis. METHODS; Serum levels of BAFF from 37 patients and 21 healthy subjects were examined by ELISA. Serum angiotensin-converting enzyme (ACE), lysozyme and IFN-gamma levels in sarcoidosis patients were also measured. Isolated monocytes cultured with IFN-gamma, IL-4 or IL-10 and their expression of membrane and soluble BAFF were analysed by flow cytometry or ELISA. Peripheral B cell subsets were analysed by flow cytometry. BAFF expression in the granuloma of the skin was examined by immunohistochemistry. ANAs were determined by indirect IF using HEp-2 cells as a substrate. RESULTS: Serum BAFF levels were significantly elevated in sarcoidosis patients when compared with healthy controls. The frequency of skin and eye involvement was significantly higher in patients with elevated serum BAFF than in patients with normal levels. Serum BAFF levels were correlated with serum levels of ACE, lysozyme and IFN-gamma. Immunostaining of anti-BAFF in the skin revealed BAFF expression by epithelioid cells of granuloma. In vitro, IFN-gamma induced membrane-bound BAFF expression on monocytes and secretion of soluble BAFF by isolated monocytes. In the peripheral blood, sarcoidosis patients showed increased naive B cells with a reciprocal decrease in memory B cells and plasmablasts. Seventeen of 26 (65%) sarcoidosis patients exhibited ANA positivity. CONCLUSION: Serum BAFF levels can be used as a surrogate marker of disease activity in sarcoidosis patients. Increased BAFF may be related to the pathogenesis of sarcoidosis. PMID- 23685363 TI - Continuous bioproduction of short-chain fatty acids from sludge enhanced by the combined use of surfactant and alkaline pH. AB - This work reported the enhancement of continuous SCFA production from sludge by the combined use of surfactant (sodium dodecylbenzene sulfonate (SDBS)) and pH 10 (i.e., SDBS & pH 10). The maximal SCFA production (2056 mg COD/L) was achieved under the SDBS & pH 10 condition at a sludge retention time (SRT) of 12d, which was much higher than that of the blank, sole SDBS, or pH 10. The mechanisms investigation showed that the combined strategy had greater sludge solubilization, higher protein hydrolysis, and lower activity of methanogens. Fluorescence in situ hybridization analysis revealed that the abundance of bacteria was increased, whereas that of archaea was decreased by SDBS & pH 10. The excitation emission matrix fluorescence spectroscopy assay further suggested that SBDS caused protein structure change, which benefited protein hydrolysis. PMID- 23685364 TI - Current concentrations, temporal trends and determinants of persistent organic pollutants in breast milk of New Zealand women. AB - Breast milk samples of 39 first time mothers aged 20-30 were collected in 2007 2010 from rural and urban areas of New Zealand, following the fourth World Health Organization coordinated survey protocol. Samples were individually analysed for persistent organic pollutants (POPs) including dioxins and furans (PCDD/Fs), polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and polybrominated diphenyl ethers (PBDEs). The lipid adjusted concentrations of PCDD/Fs (mean toxic equivalent (TEQ): 3.54 pg/g) and PCBs (mean TEQ 1.29 pg/g) were low in comparison to those reported for other countries, and concentrations of dieldrin (10 ng/g) and p,p'-DDE (379 ng/g) and PBDEs were in the mid-range. Breast milk concentrations of PCDD/F-TEQ, PCB-TEQ, dieldrin and p,p'-DDE were significantly higher in rural compared to urban areas (+23%, 33%, 59%, and 44% respectively), while concentrations of several PBDEs and lindane were higher in urban areas. Concentrations of PCDD/Fs, PCBs and OCPs, but not PBDEs, increased with age, and higher body mass index was associated with lower concentrations of PCBs. Despite New Zealand's low body burdens of many chlorinated POPs in comparison to other countries, breast milk concentrations continued to decrease over time, with a decrease by half over the last 10 years for PCDD/F-TEQ (-40%), PCB-TEQ (-54%) and OCPs -34 to -90%), indicating that regulatory measures continue to have beneficial effects. Continued monitoring is needed particularly for the brominated POPs for which little New Zealand specific data is available. PMID- 23685365 TI - Exposure to ambient ultrafine particles and urinary 8-hydroxyl-2-deoxyguanosine in children with and without eczema. AB - Ambient fine and ultrafine particles (UFPs) in urban air are known to contribute to inflammatory and allergic disease. It has been suggested that oxidative stress is an underlying mechanism for the detrimental health effects. The objective of this study was to investigate the short-term effect of ambient UFPs and particulate polycyclic aromatic hydrocarbons (PAHs) on urinary 8-hydroxyl-2 deoxyguanosine (8-OHdG) concentrations in children with and without eczema. Spot urine samples were collected from 84 children twice weekly for 61 days and 8-OHdG content was measured. Significant associations were found between the ambient UFPs and particle bound PAHs and increase in urinary 8-OHdG levels. An inter quartile range (IQR) increase in the UFP concentration in the 24-h (IQR, 32,300/m(3)) period preceding urine collection was significantly associated with a 5.7% (95% confidence interval [CI], 0.16-1.27%) increase in the urinary 8-OHdG level children with AD. In children without eczema, such short-term effect of previous day UFPs on urinary 8-OHdG was not observed. There were no significant positive associations between the mass fraction of PMs and urinary 8-OHdG. The results suggest that short-term exposure to ambient UFPs plays a critical role in PM induced oxidative stress in children with eczema. PMID- 23685366 TI - A life cycle assessment of non-renewable energy use and greenhouse gas emissions associated with blueberry and raspberry production in northern Italy. AB - This study examined the emissions produced during the pre-farm, farm and post farm phases of the production cycle of raspberries and giant American whortleberries (blueberries) cultivated in one of the best-adapted areas in northern Italy. The pre-farm phase included the greenhouse gas emissions from the production of plants in the nursery and the transportation of the plants to the production farms. The farm phase involved the emissions of greenhouse gases from chemical products, the water used for irrigation, the generation of waste, and the consumption of electricity and other energy. The post-farm phase comprised the transportation of the products to the distribution centre (DC) and their storage in the DC. The use phase is not included in the system, nor is transportation from the supermarket to the home of the final consumer, but the disposal of the packaging is nevertheless taken into account. Indeed, the use of traditional plastic materials during both the field phase (nursery and cultivation) and the post-harvesting phase (packaging) produced the greatest estimated impact. PMID- 23685367 TI - Mining spatial information to investigate the evolution of karst rocky desertification and its human driving forces in Changshun, China. AB - The processes of karst rocky desertification (KRD) have been found to cause the most severe environmental degradation in southwestern China. Understanding the driving forces that cause KRD is essential for managing and restoring the areas that it impacts. Studies of the human driving forces of KRD are limited to the county level, a specific administrative unit in China; census data are acquired at this scale, which can lead to scale biases. Changshun County is studied here as a representative area and anthropogenic influences in the county are accounted for by using Euclidean distances for the proximity to roads and settlements. We propose a standard coefficient of human influence (SOI) that standardizes the Euclidean distances for different KRD transformations to compare the effects of human activities in different areas. In Changshun County, the individual influences of roads and settlements share similar characteristics. The SOIs of improved KRD transformation types are almost negative, but the SOIs of deteriorated types are nearly positive except for one form of KRD turning to the extremely severe KRD. The results indicated that the distribution and evolution of the KRD areas from 2000 to 2010 in Changshun were affected positively by human activities (e.g., KRD restoration projects) and also negatively (e.g., by intense and irrational land use). Our results demonstrate that the spatial techniques and SOI used in this study can effectively incorporate information concerning human influences and internal KRD transformations. This provides a suitable approach for studying the relationships between human activities and KRD processes at fine scales. PMID- 23685368 TI - Diagnosing the traffic impact on roadside soils through a multianalytical data analysis of the concentration profiles of traffic-related elements. AB - The road traffic has become one of the most serious environmental problems in many cities and the main source of pollution of urban soils. To diagnose properly the magnitude of such impacts on roadside soils, eight urban and metropolitan soils were selected as a function of traffic density, distance to the road and years of operation, for which the concentration of 60 elements (major, minor and trace elements) were measured by semi-quantitative ICP-MS after acid digestion, as a first step in assessing the traffic impact. With this information, a comprehensive study was carried out focusing on the quantitative analysis of the concentration of 46 elements from the 8 sampling areas, analyzing the vertical and horizontal distributions of the metals in the roadside soils. The chemometric analysis showed that only the traffic-related elements accumulate in topsoil and present a high decreasing profile with depth and the distance to the road; however, this clear behavior takes places only in old roads that have undergone the traffic impact for a long time, but not in new roads or roads with low traffic density. Finally, the geoaccumulation indexes are suggested to be used instead of the local guidelines to assess the pollution state of the roadside soils, especially for the emerging trace elements like Antimony. PMID- 23685369 TI - Reduced flow impacts salmonid smolt emigration in a river with low-head weirs. AB - The impacts of large dams on the hydrology and ecology of river systems are well understood, yet the impacts of low-head structures are poorly known. While impacts of small weirs on upstream-migrating fish have long been mitigated by fish ladders, it is assumed that downstream migration of surface-oriented fishes is unaffected under natural flow regimes. To test this, the effects of low-head weirs and the influence of river flow on the migration of brown trout (Salmo trutta) smolts in the River Tweed, UK, were examined. Movements of acoustic tagged smolts were quantified in 2010 and 2011 using automatic listening stations and manual tracking throughout the migration route. In both years, smolts exhibited major losses, most likely due to predators, with escapement rates of 19% in 2010 and 45% in 2011. Loss rates were greater in 2010 when flows were frequently below Q95 (20% of study period) compared to 2011 when more typical flows predominated (0% of study period below Q95). Smolts experienced significantly longer delays at weirs during 2010 than 2011, associated with the different hydrographs during emigration as well as weir design. Flow comparisons within the study periods and historical records show that low flows experienced in 2010 were not unusual. The swimming behaviour of smolts in relation to flow conditions differed between years, with smolts in 2010 increasing their rate of movement in relation to increasing flow at a faster rate than smolts in 2011. This is the first study to demonstrate river flow impacts on the migration success of wild salmonid smolts at small weirs. Because small weirs are common in rivers and because spring-summer low-flow periods may become more frequent with climate change (based on UKCIP09 models) and altered river hydrology, further research and improved management is needed to reduce the impacts of low river flows in combination with low-head weirs on salmonid smolt migration. PMID- 23685370 TI - Domestic water uses: characterization of daily cycles in the north region of Portugal. AB - Nowadays, there is an increasing discussion among specialists about water use efficiency and the best measures to improve it. In Portugal, there have been a few attempts to expand the implementation of in situ water reuse projects. However, there is a lack of information about indoor water uses and how they are influenced by sociodemographic characteristics. There are several studies that investigate per capita global water usage, but the partitioning of this volume per domestic device and daily cycles is yet unknown. Identified as one of the key questions in sustainable building design, the water end-use is of primary importance to the design of hydraulic networks in buildings. In order to overcome this lack, a quantitative characterization of daily water uses for each domestic device was performed, based on a weekly monitoring program in fifty-two different dwellings in the northern region of Portugal (Vila Real, Valpacos and Oporto). For forty of them, each water usage of different domestic devices of each dwelling was recorded. At the same time, the remaining twelve dwellings were also monitored in order to register the volume of water consumed in each utilization of each domestic device. This paper presents the results of this complete monitoring program, using collected data to establish indoor water use patterns for each domestic device, aiming to support a more realistic approach to residential water use. The daily cycles in the different cities, where the monitoring program was performed, are also presented, in order to evaluate possible influences of sociodemographic characteristics. PMID- 23685371 TI - Characterisation and identification of enzyme-producing autochthonous bacteria from the gastrointestinal tract of two Indian air-breathing fish. AB - Characterisation and identification of autochthonous enzyme-producing bacteria isolated from the proximal intestine and distal intestine of two species of Indian air-breathing fish, murrel (Channa punctatus) and stinging catfish (Heteropneustes fossilis), were investigated using conventional culture technique. Population levels of proteolytic strains were highest in the digestive tract of stinging catfish. In both species, the viable counts of amylase producing bacteria were somewhat higher than cellulase-producing bacteria. Among the gut bacteria isolated, 8 strains (4 from murrel and 4 from stinging catfish) were selected as potent enzyme-producers on the basis of quantitative enzyme assays. All these strains were Gram-positive rods, but only four isolates (CPF4, CPH6, CPH7 and HFH4) were capable of forming endospores. The tested bacteria grew in wide range of temperatures and pH. The strains were further identified by 16S rRNA gene sequence analysis. Two strains, CPF3 (isolated from murrel) and HFH4 (isolated from stinging catfish) showed high similarity to Bacillus sp., strain HFH7 (isolated from the stinging catfish) was most closely related to Bacillus subtilis, while five strains belonged to Bacillus licheniformis. Based on the results of the present study, we suggest that incorporation of autochthonous enzyme-producing bacteria in aquafeeds merits further investigations. PMID- 23685372 TI - A novel cobiotic containing a prebiotic and an antioxidant augments the glucose control and gastrointestinal tolerability of metformin: a case report. AB - The gut microbiome plays an important role in regulation of metabolic processes, including digestion, absorption, and synthesis of bioactive molecules that signal physiological host mechanisms. Changes in the human gut microbiome are associated with type 2 diabetes and insulin resistance. Water-soluble dietary fibres like inulin and beta-glucan are fermented in the colon, and beta-glucan increases viscosity. Blueberries improve insulin sensitivity through an antioxidant effect. A cobiotic, consisting of purified inulin, sugar-free blueberry pomace extract, and an oat preparation of purified beta-glucan was developed for twice a day (bid) consumption as a smoothie drink to repair the gastrointestinal dysbiosis in type 2 diabetes. A 30-year-old man presented with new onset type 2 diabetes and a fasting glucose (FBS) of 375 mg/dl. Metformin 500 mg bid was initiated and increased to 1 g bid after 1 week. During the first 9 days of metformin treatment, he developed diarrhoea, but his FBS only dropped to 325 mg/dl. The cobiotic bid was added on the 9th day of metformin treatment, and after 2 days, his FBS dropped to 175 mg/dl. After 8 weeks on metformin and the cobiotic, his blood sugar was 100 mg/dl and he lost 5.5 kg. His stools became soft and formed on the cobiotic, reverted to diarrhoea when off of it for 2 days, and returned to normal on resuming the cobiotic formulation. Metformin is a safe, effective and inexpensive generic medication favouring weight loss, recommended as initial treatment of type 2 diabetes by the American Diabetes Association. However, a 20% incidence of diarrhoea limits its tolerability. A safe food supplement that can increase the efficacy of metformin and its tolerability, as occurred in this case report, would have significant positive public health consequences. A controlled clinical trial of the cobiotic with metformin is planned. PMID- 23685373 TI - Bifidobacterium fermented milk and galacto-oligosaccharides lead to improved skin health by decreasing phenols production by gut microbiota. AB - A questionnaire survey found that women suffering from abnormal bowel movements have many skin problems such as a high frequency of dry skin. Although there are similarities between the structure and barrier function mechanism of the gut and skin, experimental data are insufficient to show an association between the intestinal environment and skin conditions. Phenols, for example phenol and p cresol, as metabolites of aromatic amino acids produced by gut bacteria, are regarded as bioactive toxins and serum biomarkers of a disturbed gut environment. Recent studies have demonstrated that phenols disturb the differentiation of monolayer-cultured keratinocytes in vitro, and that phenols produced by gut bacteria accumulate in the skin via the circulation and disrupt keratinocyte differentiation in hairless mice. Human studies have demonstrated that restriction of probiotics elevated serum free p-cresol levels and harmed skin conditions (reduced skin hydration, disrupted keratinisation). In contrast, daily intake of the prebiotic galacto-oligosaccharides (GOS) restored serum free p cresol levels and skin conditions in adult women. Moreover, a double-blind placebo-controlled trial demonstrated that the daily intake of fermented milk containing the probiotic Bifidobacterium breve strain Yakult and prebiotic GOS reduced serum total phenol levels and prevented skin dryness and disruption of keratinisation in healthy adult women. It is concluded that phenols produced by gut bacteria are one of the causes of skin problems. Probiotics and/or prebiotics, such as B. breve strain Yakult and/or GOS, are expected to help maintain a healthy skin by decreasing phenols production by gut microbiota. These findings support the hypothesis that probiotics and prebiotics provide health benefits to the skin as well as the gut. PMID- 23685374 TI - Survival of Lactobacillus delbrueckii UFV H2b20 in fermented milk under simulated gastric and intestinal conditions. AB - The survival of Lactobacillus delbrueckii UFV H2b20 was assessed in fermented milk, both during the storage period and after exposure to simulated gastric and intestinal juices, as well the detection of the gene fbpA involved in adherence to human gastrointestinal tract. L. delbrueckii UFV H2b20 remained stable and viable for 28 days under refrigerated storage conditions. After one day of storage, that strain exhibited a one-log population reduction following exposure in tandem to simulated gastric and intestinal juices. After 14 days of storage, a two-log reduction was observed following 90 min of exposure to the simulated gastric conditions. However, the strain did not survive following exposure to the simulated intestinal juice. The observed tolerance to storage conditions and resistance to the simulated gastric and intestinal conditions confirm the potential use of L. delbrueckii UFV H2b20 as a probiotic, which is further reinforced by the detection of fbpA in this strain. PMID- 23685375 TI - What is a health benefit? An evaluation of EFSA opinions on health benefits with reference to probiotics. AB - Probiotics are microorganisms that have a beneficial effect on the health of the host. However, before these effects can be referred to as beneficial to human health, such claims need to be evaluated by regulatory institutes such as the European Food Safety Authority (EFSA). The EFSA Panel on Dietetic Products, Nutrition and allergies (NDA) has published their opinions regarding health claims including probiotics, most of which were rejected in the past years. Using the EFSA database, the NDA dossiers published between 2005 and 2013 were analysed to provide an overview on what grounds certain health effects were accepted as beneficial and others not. The NDA Panel distinguishes between claims that are definitely beneficial, possibly beneficial or non-beneficial to human health. Overall, 78% of all analysed health claims are considered by the NDA Panel as (possibly) beneficial to human health, in particular the gut health effects. Since, in many cases, the scientific substantiation of a particular health claim was deemed insufficient, most applications were turned down. For future health claim applications concerning probiotics to be successful, they should include specific statements on what exactly the microorganism affects, and the scientific substantiation of the particular health claim should be based on the targeted (general) population. PMID- 23685376 TI - Is vitamin D supplementation necessary in healthy full-term breastfed infants? A follow-up study of bone mineralization in healthy full-term infants with and without supplemental vitamin D. AB - AIM: The aim of the study is to establish whether healthy full-term breastfed infants require supplemental vitamin D for proper bone mineralization. METHODS: Bone mineralization was studied by performing ultrasound scans of 73 healthy full term subjects at the age of 3 months. The infants were divided into three groups. Group A: breastfed without supplemental vitamin D (BF); group B: breastfed with supplement of 400 IU/day of vitamin D (BFD); group C: fed with formula (with and without supplemental vitamin D 400 IU/day) (FF). The values of mcSOS (m/sec) and mcBTT (usec) were assessed in all subjects. RESULTS: A statistically significant difference has been found between group A vs group B both in mcSOS (P=0.03) and in mcBTT (P=0.01) values and also between group A vs group C both in mcSOS (P=0.012) and in mcBTT (P=0.003) values. Significant differences between group B vs group C were not found. In 75% of subjects of group A mcSOS and mcBTT values were <= the 10th percentile, while in group B they were between the 10th and 50th percentile. In FF infants given supplemental vitamin D mcSOS and mcBTT values were between the 25th and 75th percentile. CONCLUSION: Human breast milk is an appropriate source of nutrition for the growth of healthy full-term newborns, but is poor in vitamin D as demonstrated by the impaired bone mineralization in the breastfed infants without supplemental vitamin D. The results presented demonstrate that exclusively breastfed infants require at least 400 IU/day of supplemental vitamin D. PMID- 23685377 TI - [Cryptorchidism: medium- and long-term follow-up]. AB - AIM: Cryptorchidism represents the most frequent male genital anomaly in paediatric population and may potentially interfere with fertility and determine neoplastic testicular diseases. We wanted to evaluate the correlation between age at orchiopexy and follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone levels in adulthood, determining the long-term complications of surgical treatment. METHODS: Fifty-seven patients (mean age 19 years, range 18 27) surgically treated for cryptorchidism in pediatric age were included in a medium and long-term follow-up (10-19 years). We divided this population into four groups: A) monolateral cryptorchidism operated on before 36 months of age (15); B) monolateral cryptorchidism operated on over 36 months (32); C) bilateral cryptorchidism operated on before 36 months (5); and D) bilateral cryptorchidism operated on over 36 months (5). All patients underwent andrological examination, testosterone, FSH and LH dosage, measurement of testicular volume and spermiogram. RESULTS: Significant different FSH levels were found between group A and C and between A and D (P<0.01), while groups A and D presented also different mean testicular volume (P<0.01). In addition group D showed an abnormal morphology of spermiogram. The main complications found in follow-up were hydrocele (17,5%), varicocele (8,7%) and epididymal cysts (3.6%). CONCLUSION: Monolateral cryptorchidism is associated with normal fertility when treated early (group A). Subjects in Group D, on the contrary, have a rise of FSH, a reduction of testicular volume and semen abnormalities. The long-term follow-up of these patients can also detect associated. PMID- 23685378 TI - Congenital diaphragmatic hernia: experience of 14 years. AB - AIM: Over the last two decades, new therapies have emerged for the management of congenital diaphragmatic hernia (CDH). The aim of this paper was to review our experience in the management of newborns diagnosed with CDH over a 14-year period. METHODS: Review of maternal and infant medical records, 1997-2010. RESULTS: Eighty newborns with CDH; 21 (26%) were preterm and 28 (35%) of low birthweight (<2500 g), including 3 (4%) of very low birthweight (< 1500 g). Prenatal diagnosis was made in 53 (66%) cases. The location of the hernia was: left side 48 (90.5%); right 4 (7.5%); bilateral 1 (1%). Corrective surgery was performed in 58 (73%) patients. High frequency oscillatory ventilation was used in 10 (12.5%), inhaled nitric oxide in 18 (22.5%), sildenafil in 15 (18.7%) and extracorporeal membrane oxygenation in 1 (1%). The overall survival was 49% (N.=39). Since 2003, the overall survival raised to 64%. The survival rate of the appropriate for gestational age term newborns without other congenital/chromosomal anomaly or hydrops fetalis was 67% (24/36). CONCLUSION: Our survival rate for congenital diaphragmatic hernia has improved over the last 14 years, associated to the use of new therapies, such as high-frequency oscillation ventilation (HFOV), inhaled nitric oxide and sildenafil. PMID- 23685379 TI - Outcome of congenital diaphragmatic hernia: analysis of implicated factors. AB - AIM: Congenital diaphragmatic hernia remains a significant challenge for neonatologists and pediatric surgeons. Over the last years, new therapeutic approaches, as high-frequency oscillatory ventilation, inhaled nitric oxide, permissive hypercapnia, extracorporeal membrane oxygenation, have been used for the management of these newborns. We conducted a retrospective study of all infants who were managed for congenital diaphragmatic hernia in our NICU in order to identify possible clinical characteristics which were predictive for survival. METHODS: We reviewed a single institution's experience with 42 consecutive neonates with congenital diaphragmatic hernia admitted to our NICU from 1993 to 2009. RESULTS: Prenatal data and side of congenital diaphragmatic hernia were similar in survivors and no-survivors infants except for the lung-to-head ratio (LHR), which was higher and measured later in survivors than non-survivors. Multiple regression analysis showed that a gestational age >=39 weeks, Apgar score at 5 min >=7, FiO2<0.35, MAP<13 cmH2O, OI<10 and AaDO2 >282 before surgical repair, and the absence of persistent pulmonary hypoplasia were independent predictive factors of survival. CONCLUSION: Our study suggests that the outcome of newborns with congenital diaphragmatic hernia still depends on the severity of lung hypoplasia, despite the different respiratory and therapeutical approaches. PMID- 23685381 TI - Autoimmune encephalitis in children. AB - Autoimmune encephalitis is a heterogeneous group of disorders characterized by cognitive and behavioral decline due to an immune reaction against neuronal antigens. There is increasing evidence that autoimmune encephalitis represents a significant subgroup of encephalitis in children, which are defined by the presence of antibodies against important proteins involved in neurotransmission. The distinction between the different causes of autoimmune encephalitis is important for the patient, as there is a marked difference in therapeutic response; specifically, autoimmune encephalitis associated with the classical onconeuronal antibody is unresponsive to treatment, while autoimmune encephalitis in association with antibodies against surface proteins may respond to immunomodulation. Autoimmune encephalitis may be classified into forms with prevalent involvement of the grey matter (polioencephalitis), white matter (leucoencephalitis), or endothelial cells (vasculitis). The subject of this review includes polioencephalitis, which encompasses syndromes in which there is a loss and/or alteration of neuronal function and in which autoantibodies can be detected in the serum or CSF. PMID- 23685380 TI - Transanal irrigation and intestinal transit time in children with myelomeningocele. AB - AIM: Myelomeningocele (MMC), among others functions, affects colorectal motility and bowel emptying, and often leads to constipation, faecal incontinence, or a combination of both. We investigated the benefits of transanal irrigation (TI) in children with MMC through the radiological study of intestinal transit time. METHODS: Sixteen patients aged 4 to 17 years with chronic constipation secondary to MMC resistant to conventional treatment were treated with transanal irrigation. The patients took radiopaque markers on three consecutive days. Seventy-two hours after ingestion of the first markers, the patients received abdominal X-rays before and after TI. RESULTS: The abdominal X-ray carried out before and after the procedure revealed a significant improvement in the progression of the intestinal bolus. The reduction in the number of markers present in the intestinal lumen after the procedure was significant (from 30+/ 7.37 to 10.62+/-6.29, t=6.4323, P=0.0344). CONCLUSION: In patients with bowel dysfunction secondary to MMC resistant to conventional treatments, TI has proven to be safe and effective in promoting intestinal emptying showing an improvement of the progression of the intestinal bolus. PMID- 23685382 TI - Inflammatory demyelinating diseases in children: an update. AB - Inflammatory demyelinating diseases (DD) affecting the central nervous system (CNS) are increasingly recognized in children. During the past decade significant advances have been made in this field. Pediatric DD are important not just because 3-5% of MS cases are diagnosed in childhood, but also because their pathogenesis may provide unique insights into the earliest events and triggers of acquired CNS DD. The purpose of this article is to offer an update into pediatric DD for the general pediatrician and child neurologist. Current evidence on epidemiology, pathology, diagnosis, management and prognosis are reviewed for both monophasic (ADEM and CIS) and polyphasic/chronic DD (MS and NMO). We also review new research advances including novel biomarkers and treatments from the latest literature. PMID- 23685383 TI - [Cochlear implant in children: rational, indications and cost/efficacy]. AB - A cochlear implant (CI) is a partially implanted electronic device that can help to provide a sense of sound and support speech to severely to profoundly hearing impaired patients. It is constituted by an external portion, that usually sits behind the ear and an internal portion surgically placed under the skin. The external components include a microphone connected to a speech processor that selects and arranges sounds pucked up by the microphone. This is connected to a transmitter coil, worn on the side of the head, which transmits data to an internal receiver coil placed under the skin. The received data are delivered to an array of electrodes that are surgically implanted within the cochlea. The primary neural targets of the electrodes are the spiral ganglion cells which innervate fibers of the auditory nerve. When the electrodes are activated by the signal, they send a current along the auditory nerve and auditory pathways to the auditory cortex. Children and adults who are profoundly or severely hearing impaired can be fitted with cochlear implants. According to the Food and Drug Administration, approximately 188,000 people worldwide have received implants. In Italy it is extimated that there are about 6-7000 implanted patients, with an average of 700 CI surgeries per year. Cochlear implantation, followed by intensive postimplantation speech therapy, can help young children to acquire speech, language, and social skills. Early implantation provides exposure to sounds that can be helpful during the critical period when children learn speech and language skills. In 2000, the Food and Drug Administration lowered the age of eligibility to 12 months for one type of CI. With regard to the results after cochlear implantation in relation to early implantation, better linguistic results are reported in children implanted before 12 months of life, even if no sufficient data exist regarding the relation between this advantage and the duration of implant use and how long this advantage persists in the subsequent years. With regard to cochlear implantation in children older than 12 months the studies show better hearing and linguistic results in children implanted at earlier ages. A sensitive period under 24-36 months has been identified over which cochlear implantation is reported to be less effective in terms of improvement in speech and hearing results. With regard to clinical effectiveness of bilateral cochlear implantation, greater benefits from bilateral implants compared to monolateral ones when assessing hearing in quiet and in noise and in sound localization abilities are reported to be present in both case of simultaneous or sequential bilateral implantation. However, with regard to the delay between the surgeries in sequential bilateral implantation, although benefit is reported to be present even after very long delays, on average long delays between surgeries seems to negatively affect the outcome with the second implant. With regard to benefits after cochlear implantation in children with multiple disabilities, benefits in terms of speech perception and communication as well as in quality of the daily life are reported even if benefits are slower and lower in comparison to those generally attained by implanted children without additional disabilities. Regarding the costs/efficacy ratio, the CI is expensive, in particular because of the cost of the high technological device, long life support, but even if healthcare costs are high, the savings in terms of indirect costs and quality of life are important. The CI, in fact, has a positive impact in terms of quality of life. PMID- 23685384 TI - [How to interpret the results of immunological tests for the diagnosis of tuberculosis in child]. AB - New available immunologic tests for tuberculosis (TB) diagnosis are Interferon gamma release assay (IGRA). In adults these tests showed a higher specificity than tuberculin skin test (TST) but their superior sensitivity compared to TST sensitivity has not been proved yet. In children, interpretation of results remains disputed, especially in those <5 years. Hereby we report the most recent literature data for use and interpretation of IGRA is results in children. PMID- 23685385 TI - Renal abscess due to Pseudomonas aeruginosa: report of two cases. AB - We report two cases of renal abscess due to Pseudomonas aeruginosa in previously healthy children. The first patient was a nine-year old girl with a three-week history of intermittent fever and the second was a three-year old boy with a four day history of fever. Pseudomonas aeruginosa was isolated from the urine cultures of both children. In both cases ultrasound and CT/MRI scans revealed the formation of a renal abscess. The patients were successfully treated with administration of antipseudomonal drugs for seven and five weeks, respectively. In both children no surgical intervention was required and the follow-up revealed no impact on the overall renal function or arterial pressure. PMID- 23685386 TI - Ageing dynamics of ion bombardment induced self-organization processes. AB - Instabilities caused during the erosion of a surface by an ion beam can lead to the formation of self-organized patterns of nanostructures. Understanding the self-organization process requires not only the in-situ characterization of ensemble averaged properties but also probing the dynamics. This can be done with the use of coherent X-rays and analyzing the temporal correlations of the scattered intensity. Here, we show that the dynamics of a semiconductor surface nanopatterned by normal incidence ion beam sputtering are age-dependent and slow down with sputtering time. This work provides a novel insight into the erosion dynamics and opens new perspectives for the understanding of self-organization mechanisms. PMID- 23685387 TI - Time-dependent alterations in growth, photosynthetic pigments and enzymatic defense systems of submerged Ceratophyllum demersum during exposure to the cyanobacterial neurotoxin anatoxin-a. AB - Recently, aquatic macrophytes have been considered as promising tools for eco friendly water management with a low running cost. However, only little information is available thus far regarding the metabolic capacity of macrophytes for coping with cyanobacterial toxins (cyanotoxins) in the aquatic environment. Cyanotoxins have become emerging contaminants of great concern due to the high proliferation of cyanobacteria (cyanobacterial bloom) accelerated by eutrophication and climate change. Anatoxin-a, one of the common and major cyanotoxins, is suggested as a high priority water pollutant for regulatory consideration owing to its notoriously rapid mode of action as a neurotoxin. In this study, the time-course metabolic regulation of the submerged macrophyte Ceratophyllum demersum (C. demersum) was investigated during exposure to anatoxin a at an environmentally relevant concentration (15 MUg/L). Biotransformation and antioxidative systems in C. demersum responded positively to anatoxin-a through the promoted synthesis of most of the involved enzymes within 8h. Maximum enzyme activities were exhibited after 24 or 48 h of exposure to anatoxin-a. However, an apparent decline in enzyme activities was also observed at longer exposure duration (168 and 336 h) in company with high steady-state levels of cell internal H2O2, which showed its highest level after 48 h. Meanwhile, irreversible inhibitory influence on chlorophyll content (vitality) was noticed, whereas the ratio of carotenoids to total chlorophyll was increased with the increase in exposure duration. Consequently, the reduction in growth (biomass) of C. demersum was observed in sub-chronic exposure to anatoxin-a (8 weeks). Overall results clearly indicate, on the one hand, that anatoxin-a causes negative allelopathic effects on the macrophyte by inducing oxidative stress. On the other hand, the macrophyte might have interactions with anatoxin-a, based on the prompt reaction of its enzymatic defense systems to the toxin. The result obtained from the present study could contribute to the improvement of basic knowledge about the ecological impact of anatoxin-a and the environmental fate of the toxin in the aquatic environment. PMID- 23685390 TI - Pupil responses to high-level image content. AB - The link between arousal and pupil dilation is well studied, but it is less known that other cognitive processes can trigger pupil responses. Here we present evidence that pupil responses can be induced by high-level scene processing, independent of changes in low-level features or arousal. In Experiment 1, we recorded changes in pupil diameter of observers while they viewed a variety of natural scenes with or without a sun that were presented either upright or inverted. Image inversion had the strongest effect on the pupil responses. The pupil constricted more to the onset of upright images as compared to inverted images. Furthermore, the amplitudes of pupil constrictions to viewing images containing a sun were larger relative to control images. In Experiment 2, we presented cartoon versions of upright and inverted pictures that included either a sun or a moon. The image backgrounds were kept identical across conditions. Similar to Experiment 1, upright images triggered pupil constrictions with larger amplitudes than inverted images and images of the sun evoked greater pupil contraction than images of the moon. We suggest that the modulations of pupil responses were due to higher-level interpretations of image content. PMID- 23685389 TI - The use of stereolithographic surgical templates in oral implantology. AB - AIM: The aim of this report is to analyze how to obtain a truly immediate loading in complete edentulous patients, using a dedicated software that provides beforehand both the information for a guided implant placement and the creation of a temporary prosthesis. MATERIAL OF STUDY: A CT scan was taken with a complete radiopaque scan prosthesis; CT data were imported in the software to plan the exact position of the implants. Following these guidelines a mucosa-supported surgical template was developed. A flapless implant site preparation was performed. 22 implants were placed in a complete edentulous patient. The abutments were positioned and the impressions for the final restoration were taken. The patient received immediately the temporary prosthesis that was prepared prior to the surgery in the dental laboratory. RESULTS AND DISCUSSION: Due to the flapless surgery, post-operative swelling and pain are limited. The computer-aided planning and the template guided surgery allow us to place a temporary fixed prosthesis within hours and an aesthetic and functional final restoration within some days. PMID- 23685388 TI - Serum calprotectin levels correlate with biochemical and histological markers of disease activity in TNBS colitis. AB - BACKGROUND AND AIM: Serum calprotectin is elevated in patients with inflammatory bowel disease (IBD). Whether it correlates other markers of disease activity is unknown. The aim of this study was to correlate serum calprotectin with biochemical and histological measures of intestinal inflammation. MATERIALS AND METHODS: TNBS colitis was induced in wistar rats, and serial blood samples were collected at 0, 3, and 12 days. Animals were subsequently sacrificed for pathological evaluation at day 12. Serum calprotectin and cytokines were measured by ELISA. Pathologic changes were classified at the macroscopic and microscopic levels. RESULTS: TNBS colitis induced elevated serum calprotectin, TNF and IL-6 within 24 h. Levels of serum calprotectin remained elevated in parallel to persistence of loose stool and weight loss to day 12. Serum calprotectin levels correlated with serum levels of TNF-alpha and IL6 (p < 0.001), but not CRP. Animals with liquid stool had significantly higher levels of serum calprotectin than control animals. There was a correlation between macroscopic colitis scores, and levels of serum calprotectin. CONCLUSION: Serum calprotectin levels correlate with biochemical and histological markers of inflammation in TNBS colitis. This biomarker may have potential for diagnostic use in patients with IBD. PMID- 23685391 TI - Pupil constrictions to photographs of the sun. AB - The pupil constricts in response to light increments and dilates with light decrements. Here we show that a picture of the sun, introducing a small overall decrease in light level across the field of view, results in a pupillary constriction. Thus, the pictorial representation of a high-luminance object (the sun) can override the normal pupillary dilation elicited by a light decrement. In a series of experiments that control for a variety of factors known to modulate pupil size, we show that the effect (a) does not depend on the retinal position of the images and (b) is modulated by attention. It has long been known that cognitive factors can affect pupil diameter by producing pupillary dilations. Our results indicate that high-level visual analysis (beyond the simple subcortical system mediating the pupillary response to light) can also induce pupillary constriction, with an effect size of about 0.1 mm. PMID- 23685392 TI - Inhibition of saccades elicits attentional suppression. AB - Visuospatial attention has been shown to have a central role in planning and generation of saccades but what role, if any, it plays in inhibition of saccades remains unclear. In this study, we used an oculomotor delayed match- or nonmatch to-sample task in which a cued location has to be encoded and memorized for one of two very different goals-to plan a saccade to it or to avoid making a saccade to it. We measured the spatial allocation of attention during the delay and found that while marking a location as a future saccade target resulted in an attentional benefit at that location, marking it as forbidden to saccades led to an attentional cost. Additionally, saccade trajectories were found to deviate away more from the "don't look" location than from a saccade-irrelevant distractor confirming greater inhibition of an actively forbidden location in oculomotor programming. Our finding that attention is suppressed at locations forbidden to saccades confirms and complements the claim of a selective and obligatory coupling between saccades and attention-saccades at the memorized location could neither be planned nor suppressed independent of a corresponding effect on attentional performance. PMID- 23685393 TI - Looking back at the stare-in-the-crowd effect: staring eyes do not capture attention in visual search. AB - The stare-in-the crowd effect refers to the finding that a visual search for a target of staring eyes among averted-eyes distracters is more efficient than the search for an averted-eyes target among staring distracters. This finding could indicate that staring eyes are prioritized in the processing of the search array so that attention is more likely to be directed to their location than to any other. However, visual search is a complex process, which not only depends upon the properties of the target, but also the similarity between the target of the search and the distractor items and between the distractor items themselves. Across five experiments, we show that the search asymmetry diagnostic of the stare-in-the-crowd effect is more likely to be the result of a failure to control for the similarity among distracting items between the two critical search conditions rather than any special attention-grabbing property of staring gazes. Our results suggest that, contrary to results reported in the literature, staring gazes are not prioritized by attention in visual search. PMID- 23685395 TI - Steroids pretreatment in assisted reproduction cycles. AB - The objective is to present an overview of trials and appreciate the relevant data on the effect of steroids pretreatment (oral contraceptives, 17beta estradiol and estradiol valerate) in assisted reproduction cycles. The subject of the study is to evaluate the clinical characteristics during steroids pretreatment cycles focused on the prevention of ovarian cysts, the positive contraceptive effect on the onset of regular period during long gonadotropin releasing hormone agonist protocol. In gonadotropin releasing hormone antagonist protocol the review is interested in supporting ovarian stimulation in low responders, the idea of cycle scheduling and improving treatment outcomes. The method is a review from MEDLINE/Pubmed database between 1994 and July 2012. We identified 15 randomised controlled trials (n=3069 patients). One trail (n=83 patients) assessed GnRH agonist protocol with or without steroids pretreatment, 8 trials (n=1884 patients) assessed GnRH antagonist protocols with or without steroids pretreatment and 6 trials (n=1102 patients) assessed GnRH antagonist protocols versus agonist ones with steroid pretreatment. Data demonstrates that oral contraceptives offer the effective prevention of functional ovarian cysts, the predictable onset of period during desensitisation. Existing data suggest that pretreatment with oral contraceptive pills or estradiol valerate give no advantage concerning number of oocytes or pregnancy rate. Pretreatment with oral contraceptive pills aiming to avoid weekend oocytes retrievals has to be more elucidated. In low responders oral contraceptive pill pretreatment may be beneficial in improving ovarian responses by reducing the amount of gonadotropins and the number of days required for ovarian stimulation. Current research indicates that also 17beta-estradiol may be encouraging pretreatment in low responders and in cycle scheduling. This article is part of a Special Issue entitled 'Pregnancy and Steroids'. PMID- 23685394 TI - Computational identification of active enhancers in model organisms. AB - As a class of cis-regulatory elements, enhancers were first identified as the genomic regions that are able to markedly increase the transcription of genes nearly 30years ago. Enhancers can regulate gene expression in a cell-type specific and developmental stage specific manner. Although experimental technologies have been developed to identify enhancers genome-wide, the design principle of the regulatory elements and the way they rewire the transcriptional regulatory network tempo-spatially are far from clear. At present, developing predictive methods for enhancers, particularly for the cell-type specific activity of enhancers, is central to computational biology. In this review, we survey the current computational approaches for active enhancer prediction and discuss future directions. PMID- 23685396 TI - 11beta-hydroxyandrostenedione, the product of androstenedione metabolism in the adrenal, is metabolized in LNCaP cells by 5alpha-reductase yielding 11beta hydroxy-5alpha-androstanedione. AB - 11beta-Hydroxyandrostenedione (11OHA4), which is unique to the adrenal, was first isolated from human adrenal tissue in the fifties. It was later shown in the sixties that 11beta-hydroxytestosterone (11OHT) was also produced by the human adrenal. Attention has shifted back to these adrenal androgens once more, as improved analytical techniques have enabled more accurate detection of steroid hormones. In this paper, we investigated the origin of these metabolites as well as their subsequent metabolism and examined a possible physiological role for 11OHA4 in prostate cancer cells. In H295R cells treated with forskolin and trilostane, etomidate, a reported cytochrome P450 11beta-hydroxylase (CYP11B1) inhibitor, blocked the production of corticosterone, cortisol, 11OHA4 and 11OHT. The metabolism of androstenedione and testosterone by CYP11B1 and aldosterone synthase (CYP11B2) was assayed. Androstenedione was converted by CYP11B1, while the conversion by CYP11B2 was negligible. Both enzymes readily converted testosterone. The metabolism of these 11beta-hydroxylated metabolites by 11beta hydroxysteroid dehydrogenase (11betaHSD) types 1 and 2 was subsequently investigated. 11betaHSD2 catalyzed the conversion of both 11OHA4 and 11OHT to their respective keto-steroids, while 11betaHSD1 catalyzed the conversion of 11 ketoandrostenedione and 11-ketotestosterone to their respective hydroxy-steroids in Chinese hamster ovary cells. Investigating a functional role, steroid 5alpha reductase types 1 and 2 converted 11OHA4 to 11beta-hydroxy-5alpha-androstanedione (11OH-5alpha-dione), identified by accurate mass detection. UPLC-MS/MS analyses of 11OHA4 metabolism in LNCaP androgen-dependent prostate cancer cells, identified the 5alpha-reduced metabolite as well as 11-ketoandrostenedione and 11 ketotestosterone, with the latter indicating conversion by 17beta-hydroxysteroid dehydrogenase. Downstream metabolism by 11betaHSD2 and by 5alpha-reductase may therefore indicate a physiological role for 11OHA4 and/or 11OH-5alpha-dione in normal and prostate cancer cells. PMID- 23685397 TI - Development of monoclonal antibody-based assays for the detection of Vibrio tubiashii zinc-metalloprotease (VtpA). AB - Vibrio tubiashii has been linked to disease outbreaks in molluscan species, including oysters, geoducks, and clams. In particular, oyster hatcheries in the Pacific Northwest have been plagued by intermittent vibriosis since 2006. Accurate detection of vibrios, including V. tubiashii, is critical to the hatcheries in order to allow for rapid remediation efforts. The current methods for detection of Vibrio spp. are not ideal for use at the hatchery. Plating samples require time and is not sensitive to extracelluar pathogenic products, such as the secreted zinc-metalloprotease, VtpA. Other sensitive methods to detect bacteria, such as qPCR, require a high level of laboratory skills and expensive supplies that are prohibitive for use at hatchery sites. Thus, hatcheries would benefit from a sensitive, simple method to detect V. tubiashii and its secreted toxin. Here, we describe the development of two inexpensive and highly specific tests for the shellfish-toxic zinc-metalloprotease secreted by V. tubiashii: enzyme-linked immunoassays (ELISA) and a lateral flow immunoassay (dipstick assay). Both technologies rely on a set of monoclonal antibodies used in a sandwich format, with the capture antibody recognizing a different epitope than the detection antibody on the mature VtpA protein. Both assays are quantitative and give colorimetric readouts. The sandwich ELISA was sensitive when VtpA was diluted into PBS, but was markedly less sensitive in conditions that correlate with the environment of hatchery-derived samples, such as in the presence of seawater, algae, or oyster larvae. In contrast, the dipstick assay remained very sensitive in the presence of these contaminants, is less work intensive, and much more rapid, making this format the preferred assay method for detecting VtpA on site in a hatchery or environmental setting. PMID- 23685398 TI - New triphenylamine organic dyes containing dithieno[3,2-b:2',3'-d]pyrrole (DTP) units for iodine-free dye-sensitized solar cells. AB - Three dithieno[3,2-b:2',3'-d]pyrrole (DTP) units with different hexyloxyphenyl (HOP) substituents have been developed for triphenylamine organic dyes (XS54 XS56). The introduction of the 4-HOP-DTP unit has resulted in a stronger light harvesting capacity, accounting for the observed photocurrent enhancement in the case of XS54, while the 2-HOP-DTP/2,4-HOP-DTP units induce a strikingly large photovoltage improvement in the cases of XS55 and XS56 due to their higher steric hindrance. PMID- 23685399 TI - Thyroid endocrine disruption in zebrafish larvae following exposure to hexaconazole and tebuconazole. AB - The widely used triazole fungicides have the potential to disrupt endocrine system, but little is known of such effects or underlying mechanisms of hexaconazole (HEX) and tebuconazole (TEB) in fish. In the present study, zebrafish (Danio rerio) embryos were exposed to various concentrations of HEX (0.625, 1.25 and 2.5 mg/L) and TEB (1, 2 and 4 mg/L) from fertilization to 120 h post-fertilization (hpf). The whole body content of thyroid hormone and transcription of genes in the hypothalamic-pituitary-thyroid (HPT) axis were analyzed. The results showed that thyroxine (T4) levels were significantly decreased, while triiodothyronine (T3) concentrations were significantly increased after exposure to HEX and TEB, indicating thyroid endocrine disruption. Exposure to HEX significantly induced the transcription of all the measured genes (i.e., corticotrophin-releasing hormone (CRH), thyroid-stimulating hormone (TSHbeta), sodium/iodide symporter (NIS), transthyretin (TTR), uridine diphosphate glucuronosyltransferase (UGT1ab), thyronine deiodinase (Dio1 and Dio2), thyroid hormone receptors (TRalpha and TRbeta) in the HPT axis, but did not affect the transcription of thyroglobulin (TG). However, TEB exposure resulted in the upregulation of all the measured genes, excepting that TG, Dio1and TRalpha had not changed significantly. The overall results indicated that exposure to HEX and TEB could alter thyroid hormone levels as well as gene transcription in the HPT axis in zebrafish larvae. PMID- 23685400 TI - Impact of environmental oxygen, exercise, salinity, and metabolic rate on the uptake and tissue-specific distribution of 17alpha-ethynylestradiol in the euryhaline teleost Fundulus heteroclitus. AB - 17alpha-ethynylestradiol (EE2) is a synthetic estrogen that is an endocrine disruptive toxicant in aquatic environments. The aim of this study was to determine whether metabolic rate influenced EE2 uptake in male killifish (Fundulus heteroclitus), based on the hypothesis that the mechanism of EE2 uptake at the gills is similar to that of oxygen. F. heteroclitus were exposed to 100 ng/L radiolabeled [3H]EE2 for 2 h while swimming at 0, 15, and 40 cm/s. A positive linear correlation between the rates of oxygen consumption (MO2) and EE2 accumulation was seen (r2 = 0.99, p<0.01), with more EE2 taken up at higher swimming speeds, suggesting that oxygen uptake predicts EE2 uptake. EE2 tended to accumulate in the liver (where lipophilic toxicants are metabolized), the gall bladder (where metabolized toxicants enter bile), and the gut (where bile is received). In a subsequent experiment killifish were exposed to both hypoxic and hyperoxic conditions (PO2=70-80 Torr, and PO2=400-500 Torr respectively). Despite significant decreases in MO2 during hypoxia, EE2 uptake rates increased only slightly with hypoxia, but in individual fish there was still a significant correlation between MO2 and EE2 uptake. This correlation was lost during hyperoxia, and EE2 uptake rates did not change significantly in hyperoxia. Marked influences of salinity on EE2 uptake rate occurred regardless of the oxygen condition, with higher uptake rates in 50% seawater than in freshwater or 100% seawater. Tissue distribution of EE2 in these exposures may have been influenced by changes in tissue blood flow patterns and oxygen supply. These data will be useful in eventually constructing a predictive model to manage the optimal timing for discharge of EE2 from sewage treatment plants into receiving waters. PMID- 23685401 TI - Tracking single-particle dynamics via combined optical and electrical sensing. AB - While fluorescent imaging has been extensively used for single-particle tracking, temporal and spatial resolution of the wide-field microscopy technology is not satisfactory for investigating fast-moving features. Here we report a method for probing nanometer-scale motion of an individual particle through a microstructured channel at sub-MHz by combining a resistive pulse technique to the optical sensing. We demonstrate unambiguous discriminations of translocation and non-translocation events inferred from spike-like electrical signals by fluorescence images captured synchronously to ionic current measurements. We also find a trajectory-dependent translocation dynamics of voltage-driven single particles through a microchannel. This electrical/optical approach may find applications in sensor technologies based on micro- and nano-electromechanical systems. PMID- 23685402 TI - Stability of cardiopulmonary resuscitation and do-not-resuscitate orders among long-term nursing home residents. AB - BACKGROUND: High-quality care for long-term nursing home residents should include discussions and follow-up on patients' end-of-life care wishes. Yet, recent changes to the Minimum Data Set data collection exclude this information from routine assessment of patients mandated by the Centers for Medicare & Medicaid Services, making the provision of high-quality end-of-life care less likely. We examined the stability of cardiopulmonary resuscitation (CPR) and do-not resuscitate (DNR) orders to offer guidance to policy and care practice developments. METHODS: We examined changes in DNR status of a national long-term care nursing home cohort, following them for 5 years after admission. A competing risk model was estimated to identify covariates predicting changes from CPR to DNR status and vice versa. RESULTS: About half the cohort chose DNR at admission and did not change its status. Of those who entered with CPR status, 40% changed to DNR. The most important factors influencing change were hospitalizations and nursing home transfers, followed by race and ethnicity with black race (relative to white) in particular having the largest effect on change. Other individual and nursing home characteristics influenced the likelihood of changing from CPR to DNR as well. CONCLUSIONS: Long-term nursing home patients who enter with full code CPR have a high probability of changing their status to DNR during their stay. High-quality care should offer them the opportunity to revisit their choice periodically, documenting changes in end-of-life choices when they occur, thus ensuring that care will match patients' wishes. As the Minimum Data Set plays a prominent role in patients' care, Centers for Medicare & Medicaid Services should consider reinstating information about advance directive in it. PMID- 23685404 TI - Comment on "the relationship between the C-statistic of a risk-adjustment model and the accuracy of hospital report cards: a Monte Carlo study". PMID- 23685403 TI - The impact of high-deductible health plans on men and women: an analysis of emergency department care. AB - BACKGROUND: Prior studies show that men are more likely than women to defer essential care. Enrollment in high-deductible health plans (HDHPs) could exacerbate this tendency, but sex-specific responses to HDHPs have not been assessed. We measured the impact of an HDHP separately for men and women. METHODS: Controlled longitudinal difference-in-differences analysis of low, intermediate, and high severity emergency department (ED) visits and hospitalizations among 6007 men and 6530 women for 1 year before and up to 2 years after their employers mandated a switch from a traditional health maintenance organization plan to an HDHP, compared with contemporaneous controls (18,433 men and 19,178 women) who remained in an health maintenance organization plan. RESULTS: In the year following transition to an HDHP, men substantially reduced ED visits at all severity levels relative to controls (changes in low, intermediate, and high severity visits of -21.5% [-37.9 to -5.2], -21.6% [-37.4 to -5.7], and -34.4% [-62.1 to -6.7], respectively). Female HDHP members selectively reduced low severity emergency visits (-26.9% [-40.8 to -13.0]) while preserving intermediate and high severity visits. Male HDHP members also experienced a 24.2% [-45.3 to -3.1] relative decline in hospitalizations in year 1, followed by a 30.1% [2.1 to 58.1] relative increase in hospitalizations between years 1 and 2. CONCLUSIONS: Initial across-the-board reductions in ED and hospital care followed by increased hospitalizations imply that men may have foregone needed care following an HDHP transition. Clinicians caring for patients with HDHPs should be aware of sex differences in response to benefit design. PMID- 23685405 TI - In response. PMID- 23685406 TI - Group-based trajectory models: a new approach to classifying and predicting long term medication adherence. AB - BACKGROUND: Classifying medication adherence is important for efficiently targeting adherence improvement interventions. The purpose of this study was to evaluate the use of a novel method, group-based trajectory models, for classifying patients by their long-term adherence. RESEARCH DESIGN: We identified patients who initiated a statin between June 1, 2006 and May 30, 2007 in prescription claims from CVS Caremark and evaluated adherence over the subsequent 15 months. We compared several adherence summary measures, including proportion of days covered (PDC) and trajectory models with 2-6 groups, with the observed adherence pattern, defined by monthly indicators of full adherence (defined as having >=24 d covered of 30). We also compared the accuracy of adherence prediction based on patient characteristics when adherence was defined by either a trajectory model or PDC. RESULTS: In 264,789 statin initiators, the 6-group trajectory model summarized long-term adherence best (C=0.938), whereas PDC summarized less well (C=0.881). The accuracy of adherence predictions was similar whether adherence was classified by PDC or by trajectory model. CONCLUSIONS: Trajectory models summarized adherence patterns better than traditional approaches and were similarly predicted by covariates. Group-based trajectory models may facilitate targeting of interventions and may be useful to adjust for confounding by health-seeking behavior. PMID- 23685407 TI - Novel self-assembled supramolecular architectures of Mn(II) ions with a hybrid pyrazine-bipyridine ligand. AB - A new hybrid pyrazine-bipyridine ligand L (C26H20N6) and its complexes with Mn(NO3)2, Mn(ClO4)2, MnCl2 and MnBr2 have been synthesised. By the self-assembly of L and Mn(II) ions three different kinds of supramolecular complexes have been obtained: binuclear baguette complex [Mn2L(H2O)6](NO3)4.2.5H2O 1 and tetranuclear [2 * 2] grid-type complex [Mn4L4](ClO4)8.2.5(CH3CN).2CH3OH 2 and mononuclear complexes [MnL2]X2 (where X = Cl(-)3 and X = Br(-)4). Crystal structures and magnetic properties of Mn(II) complexes 1 and 2 have been also investigated. The crystal structures reveal that in both 1 and 2 complexes the Mn(II) ions have coordination number 6 and distorted octahedral coordination geometry. In 2 four metal cations and four ligands have assembled into a grid-type [2 * 2] array, with a perchlorate anion occupying the central cavity, with clearly a good fit for the center of the cavity. The perchlorate anion, in contrast to the nitrate anion, probably acts as a template in the formation of tetranuclear grid-type complexes. Magnetic susceptibility measurements indicate that the Mn(II) ions are all high spin, and in both 1 and 2 complexes there are weak antiferromagnetic interactions between Mn(II) ions. PMID- 23685408 TI - Genetic characterization of SF3B1 mutations in single chronic lymphocytic leukemia cells. PMID- 23685409 TI - Neuropilin-1 expression promotes invasiveness of melanoma cells through vascular endothelial growth factor receptor-2-dependent and -independent mechanisms. AB - The majority of human melanoma cell lines secretes vascular endothelial growth factor-A (VEGF-A) and expresses its receptors VEGFR-1, VEGFR-2 and neuropilin-1 (NRP-1), a co-receptor for VEGF-A that amplifies the signalling through VEGFR-2. Since it is known that the VEGF-A/VEGFR-2 autocrine loop promotes melanoma cell invasiveness, the aim of the present study was to investigate the involvement of NPR-1 in melanoma progression. Syngeneic human melanoma cell lines expressing either VEGFR-2 or NRP-1, both or none of them, were analyzed for their in vitro ability to migrate, invade the extracellular matrix (ECM) and secrete active metalloproteinase-2 (MMP-2). The results indicate that NRP-1 cooperates with VEGFR-2 in melanoma cell migration induced by VEGF-A. Moreover, NRP-1 expression is sufficient to promote MMP-2 secretion and melanoma cell invasiveness, as demonstrated by the ability of cells expressing solely NRP-1 to spontaneously invade the ECM. This ability is specifically downregulated by anti-NRP-1 antibodies or by interfering with NRP-1 expression using an shRNA construct. Investigation of the signal transduction pathways triggered by NRP-1 in melanoma cells, indicated that NRP-1-dependent promotion of cell invasiveness involves Akt activation through its phosphorylation on T308. Overall, the results demonstrate that NRP-1 is involved in melanoma progression through VEGFR-2-dependent and independent mechanisms and suggest NRP-1 as a target for the treatment of the metastatic disease. PMID- 23685410 TI - Corrosion of silicon integrated circuits and lifetime predictions in implantable electronic devices. AB - Corrosion is a prime concern for active implantable devices. In this paper we review the principles underlying the concepts of hermetic packages and encapsulation, used to protect implanted electronics, some of which remain widely overlooked. We discuss how technological advances have created a need to update the way we evaluate the suitability of both protection methods. We demonstrate how lifetime predictability is lost for very small hermetic packages and introduce a single parameter to compare different packages, with an equation to calculate the minimum sensitivity required from a test method to guarantee a given lifetime. In the second part of this paper, we review the literature on the corrosion of encapsulated integrated circuits (ICs) and, following a new analysis of published data, we propose an equation for the pre-corrosion lifetime of implanted ICs, and discuss the influence of the temperature, relative humidity, encapsulation and field-strength. As any new protection will be tested under accelerated conditions, we demonstrate the sensitivity of acceleration factors to some inaccurately known parameters. These results are relevant for any application of electronics working in a moist environment. Our comparison of encapsulation and hermetic packages suggests that both concepts may be suitable for future implants. PMID- 23685411 TI - Detection and quantification of cimicoxib, a novel COX-2 inhibitor, in canine plasma by HPLC with spectrofluorimetric detection: development and validation of a new methodology. AB - Cimicoxib (CX) is a selective COX-2 inhibitor recently launched on the veterinary market. No analytical method to detect CX in biological samples has been published to date. The chromatographic separation was performed with a Kinetex C18 analytical column (100 mm * 4.6 mm, 2.6 MUm particle size) at 25 degrees C. The mobile phase consisted of acetonitrile:buffer (10 mM AcONH4, pH 4.5) (35:65, v/v) at a flow rate of 1 mL/min. Excitation and emission wavelengths were 268 and 430 nm, respectively. The extraction used 500 MUL of plasma added to 100 MUL of IS (5 MUg/mL) and 100 MUL of 10% CF3COOH, extracted with 600 MUL of C2H2:Et2O (3:7, v/v). The organic phase was evaporated and reconstituted with 200 MUL of mobile phase. The CX recovery ranged from 74.5% to 82.6%. The limit of quantification was 25 ng mL(-1). The chromatographic runs were specific with no interfering peaks at the retention times of the analytes, as confirmed by HPLC mass spectrometry experiments. The other validation parameters were in agreement with the international guidelines. The method was successfully tested on two dogs treated at two dose rates. It facilitated tracking of the plasma concentration for 24h and calculation of the main pharmacokinetic parameters. In conclusion, this method (extraction, separation and applied techniques) is simple, effective and specific. This is the first time that a method for the quantification of CX in plasma has been reported. This technique may have applications for further pharmacokinetic studies. PMID- 23685412 TI - Chemical differentiation of Da-Cheng-Qi-Tang, a Chinese medicine formula, prepared by traditional and modern decoction methods using UPLC/Q-TOFMS-based metabolomics approach. AB - In order to evaluate chemical consistency between traditional and modern decoctions of Da-Cheng-Qi-Tang (DCQT), a classical Chinese medicine formula commonly used in the treatment of digestive diseases, an ultra performance liquid chromatography-electrospray ionization-quadrupole time-of-flight mass spectrometry (UPLC-ESI-Q-TOFMS) combined with multivariate statistical analysis was established to globally characterize the chemical profile and discover differentiating chemical markers. Two kinds of decoctions, namely traditional decoction (multi-step decoction of constituent herbs), and modern decoction (one step decoction of all herbs), were prepared and subjected to UPLC-MS analysis, the datasets of tR-m/z pairs, ion intensities and sample codes were processed with supervised orthogonal partial least squared discriminant analysis (OPLS-DA) to comprehensively compare the chemical difference between these two kinds of decoction samples. The global chemical difference was found between traditional and modern decoctions, and rhein, sennoside A/B, diosmetin, magnoloside B and naringin were the components contributing most to these differences. Based on the fact that traditional decoction of DCQT presents the higher concentration of rhein and sennoside A/B, mainly contributed to laxative activity of DCQT, the purgative effect of traditional decoction might be more potent, compared with modern decoction. However, the comparative study on purgative effect of traditional and modern DCQT remains to be further investigated using pharmacological approaches. Our findings also provide the early scientific evidence of traditional decoction method of DCQT. PMID- 23685413 TI - Spontaneous perforation of Meckel's diverticulum: case report and review of literature. AB - AIMS: Meckel's diverticulum is a congenital anomaly found in approximately 2% of the general population. The complications caused by Meckel's diverticulum include intussusception, volvulus in adolescents and acute bleeding in adults 3. This is an interesting and unusual case of spontaneous perforation of Meckel's diverticulum, in a Caucasian woman. METHODS: A 46-year-old Caucasian woman was admitted because of severe abdominal pain and diarrhoea. A CT (Fig. 1) scan of the abdomen and pelvis was obtained, which demonstrated free air and a moderate amount of free fluid in the pelvis tracking up the gutters. The patient was consented and taken to theatre for diagnostic laparoscopy. A normal appendix was identified during laparoscopic examination of the abdomen. An inflammatory mass was seen with turbid fluid collection in the pelvic area on laparoscopy. The inflammatory mass turned out to be a perforated Meckel's diverticulum (Fig. 2). Wedge resection of the perforated Meckel's diverticulum was performed with endoGIA stapler fired at the base of diverticulum. Histopathology showed heterotopic gastric mucosa within the diverticulum and evidence of acute inflammation with perforation. The patient was followed up for two years and is symptom-free. DISCUSSION: The total lifetime rate of complications is widely accepted at 4%, with a male-to female ratio ranging from 1.8:1 to 3:1 4,5. Hemorrhage is the most common presentation in children and is reported in over 50% of cases 10. In adults, hemorrhage occurs often but only in 11.8% is present 5. 90% of bleeding diverticula contain heterotropic mucosa, most often gastric mucosa 13. In one study, 11% of children with complicated Meckel's diverticulum (MD) were initially diagnosed with appendicitis.8 CONCLUSIONS: The diagnosis of ruptured MD was ultimately made by laparoscopy. This case demonstrates that a healthy degree of suspicion for complicated MD should be present when dealing with a questionable diagnosis of appendicitis. Laparoscopy has a definite role in patients with symptomatic Meckel's diverticulum, especially when the diagnosis is in doubt and it has proved definitive in facilitating diagnosis. PMID- 23685414 TI - Case report of a patient with schizophrenia and a mutation in the insulin receptor substrate-4 gene. AB - This report deals with a female patient with schizophrenia who was found to have a mutation in the insulin receptor substrate-4 gene that is located on chromosome Xq22.3. Since this mutation is expected to change amino acid coding from histidine to tyrosine and cause an altered insulin receptor substrate-4 protein, and the insulin receptor substrate-4 protein may be involved in neuronal growth and function in the brain, it is possible that it is this insulin receptor substrate-4 gene mutation that underlies this patient's schizophrenia development. PMID- 23685415 TI - Gonadotropin releasing hormone in the primitive vertebrate family Myxinidae: reproductive neuroanatomy and evolutionary aspects. AB - The family Myxinidae embraces all hagfish species, and occupies an evolutionary niche intermediate between ancestral vertebrates and the gnathostomes (jawed vertebrates). Gonadotropin releasing hormone (GnRH) modulates neuroendocrine activity in vertebrates and works in the context of the hypothalamic-pituitary (H P) axis. The appearance of this neuroendocrine axis marks one of the most crucial developmental achievements in vertebrate evolution, because it enabled further diversification in general growth, metabolism, osmoregulation and reproduction as jawed vertebrates evolved. GnRH studies in hagfish draw attention because such work may be considered as providing proxy data for similar investigations conducted upon long extinct species. Indeed, the fossil record reveals little anatomical difference between those hagfish living 300 million years ago and their modern descendants. Accordingly, the hagfish can offer important evolutionary lessons as they have some highly unusual characteristics not seen in any other vertebrate; they retain many representative features of an ancestral state from which all vertebrates originated. Indeed, because central control of reproduction is perhaps the most basic function of the vertebrate H-P axis, and given the importance of GnRH in this network, research on GnRH in hagfish can help elucidate the early evolution of the H-P system itself. Like all vertebrates, hagfish have a functional hypothalamic area and a pituitary gland, constituting a basic H-P axis. But what role does GnRH play in the reproductive system of this "living fossil"? How can understanding GnRH in hagfish help advance the knowledge of vertebrate neuroendocrinology? Here, information on neuroendocrine function and the role of GnRH specifically in this very basal vertebrate is reviewed. PMID- 23685416 TI - Case definitions and diagnostic criteria for Myalgic Encephalomyelitis and Chronic fatigue Syndrome: from clinical-consensus to evidence-based case definitions. AB - The symptom spectrum of Myalgic Encephalomyelitis (ME) was first detailed in 1959 and later operationalised into a diagnostic protocol (Melvin Ramsey). In 1988 the Holmes case definition coined the term chronic fatigue syndrome (CFS). Fukuda's Centers for Disease Control and Prevention criteria are very heterogeneous and comprise patients with milder symptoms than the Holmes case definition. The CDC Empirical Criteria for CFS lack sensitivity and/or specificity. Other CFS definitions, e.g. the Oxford criteria, delineate people with idiopathic fatigue. Some authors make the clinical CFS diagnosis when slightly increased self-rated fatigue scores are present. In 2011, Carruthers' International Consensus Criteria attempted to restore the focus on selecting people who suffer from ME. Cognitive bias in criteria construction, patient selection, data collection and interpretation has led to the current state of epistemological chaos with ME, CFS, CFS/ME and ME/CFS, and CF being used interchangeably. Moreover, none of the above mentioned classifications meet statistically based criteria for validation. Diagnostic criteria should be based on statistical methods rather than consensus declarations. Ongoing discussions about which case definition to employ miss the point that the criteria did not pass appropriate external validation. In 2012, Maes et al. performed pattern recognition methods and concluded that CFS patients (according to Fukuda's criteria) should be divided into those with CFS or ME, on the basis that people with ME display a worsening of their illness following increases in physical or cognitive activity. Both ME and CFS are complex disorders that share neuro-immune disturbances, which are more severe in ME than in CFS. This paper expands on that strategy and details a range of objective tests, which confirm that a person with ME or CFS has a neuro-immune disease. By means of pattern recognition methods future research should refine the Maes' case definitions for ME and CFS by including well-scaled symptoms, staging characteristics and neuro-immune biomarkers, including immune-inflammatory assays, bioenergetic markers and brain imaging. PMID- 23685417 TI - Periodontitis and stroke. AB - There are various forms of periodontitis characterised as an inflammatory disease with more or less expressed alteration of genetic immunological components and associated with local as well as psycho-social factors. Presence of chronic destructive inflammation in the mouth - a region with rich blood supply, contributes to escape of bacteria, their virulent factors and various pro inflammatory cells, cytokines and immunologically active substances into the blood stream and their subsequent penetration into different organs and tissues, where they continue in their harmful destruction. Atherosclerosis of cerebral vessels and its consequences resulting in ischaemic stroke are the most frequents cause of acute strokes. Today's knowledge and studies of etiopathogenesis of vascular atherosclerosis present the atherosclerotic process of vascular walls as metabolic, infectious and immunological process, which progressively obliterates vascular lumen and creates conditions for acute and chronic vascular events in various regions. Inflammation is a source of chronic and acute infections in often distal organs and tissues as a risk factor of a atherosclerotic vascular process. This review study deals with epidemiological and etiopathogenetic association between chronic periodontitis and a stroke. A special emphasis is put on explanation of possible relations between an oral infection and stimulation of pro-atherogenetic mechanisms. The second part of the paper deals with principles of treatment in patients after stroke. PMID- 23685418 TI - Macroprolactinemia in women with hyperprolactinemia: a 10-year follow-up. AB - OBJECTIVES: To determine the frequency of macroprolactinemia in a cohort of hyperprolactinemic women, describing 1) the association of macroprolactinemia with clinical variables and morphological changes in the pituitary gland and 2) clinical status and prolactin levels after 10 years of follow-up. DESIGN: Blood samples were obtained from 32 patients for hormonal assessment. Treatment with cabergoline or bromocriptine was interrupted 3 months before the determination of serum prolactin and macroprolactin. Macroprolactin was measured using the polyethylene glycol (PEG) precipitation method. Computed tomography was performed in all patients. RESULTS: The frequency of macroprolactinemia was 28.1%. In 19 patients prolactin remained elevated (persistent hyperprolactinemia). In 13, prolactin returned to normal (former hyperprolactinemia). Nine patients with PEG recovery between 40 and 50%, and the only two macroprolactinemic patients with previous hyperprolactinemia were excluded from the analysis of clinical outcomes. Only one of seven macroprolactinemic patients had an abnormal pituitary image (empty sella). None had galactorrhea. MAIN FINDINGS: Classic symptoms of hyperprolactinemia and abnormal imaging findings are not common in patients in whom macroprolactin is the predominant form of PRL. CONCLUSIONS: Women with hyperprolactinemia, especially if asymptomatic, should be routinely screened for macroprolactinemia. Macroprolactinemia remains stable in the long term. PMID- 23685419 TI - Serum resistin levels are elevated in schoolchildren with atopic asthma. AB - OBJECTIVES: There are limited data on the role of adipokines in atopic asthma. DESIGN AND SETTING: To determine serum levels of resistin in asthmatic children in relation to body weight, asthma severity and gender, serum resistin (RES) levels were measured using ELISA in 89 asthmatic children (61 boys and 28 girls, aged 7.0-17.0 years) and in 33 healthy children. Among examined asthmatics 59 (19 girls and 40 boys) had normal weight (ANW) and 30 (9 girls and 21 boys) were obese (AO). RESULTS: The mean serum levels of resistin were significantly (p<0.01) higher in all non-obese asthmatic children (4.11+/-0.1 ng/mL) than in healthy children (3.83+/-0.1 ng/mL). After stratifying by gender only ANW boys and AO boys had significantly higher RES levels than boys from control group. Both AO (4.4+/-0.2 ng/mL) and ANW girls (4.38+/-0.2 ng/mL) as well as girls from control (4.09+/-0.1) group showed significantly higher mean RES serum concentrations than boys from corresponding groups (3.99+/-0.1 ng/ml, 3.83+/-0.17 ng/ml and 3.44+/-0.06 ng/ml, respectively). No relationship between examined adipokine levels and asthma severity, spirometric parameters, degree of allergic sensitization, BMI, BMI-SDS was stated. CONCLUSION: Increased serum RES in children with atopic asthma suggest that this adipokine may be implicated in its pathogenesis. PMID- 23685420 TI - The comparison of general anaesthesia using the bispectral analysis (BIS) and spinal anaesthesia in terms of the one-day health care for haemorrhoid surgery using the HAL-RAR method. AB - OBJECTIVES: The gradual advancement of one-day surgery and conjoint ambulatory anaesthesia results from possibilities to execute mini-invasive surgeries. Such surgeries offer great benefits to the patient due to faster reconvalescence and less pain as well as faster return to normal life. The HAL-RAR method for haemorrhoid surgery, introduced as early as in 1995 by Dr. Morigan in Japan. DESIGN AND SETTING: The goal of our study including 137 patients was research of effects of the spinal and general anaesthesia while monitoring the Bispectral Index (BIS) during the surgery. We focused mainly on the need of postoperative analgesia and possibility to discharge patient to home care after the surgery with the above mentioned type of anaesthesia. BIS helped us to monitor the sufficiency of anaesthesia and anaesthetics dosage regulation that was reflected in earlier awakening and faster reconvalescence, as well as saving anaesthetics. RESULTS: The length of surgery was not affected by the particular type of anaesthetic procedures (25.7 minutes for the general anaesthesia and 30.2 minutes for the spinal anaesthesia). The need for postoperative analgesia was necessary for the period of 240.0 minutes after the completion of surgery for the general anaesthesia and 313.0 minutes for the spinal anaesthesia after the administration of anaesthetics intrathecally. CONCLUSIONS: BIS is a processed EEG parameter measuring the hypnotic effect of hypnotics and sedatives in brain. BIS helps to reduce the use of anaesthetics during anaesthesia. Our results are promising and we continue in the study, monitoring also other possible parameters. PMID- 23685421 TI - Significant increase of IGF-I concentration and of IGF-I/IGFBP-3 molar ratio in generation test predicts the good response to growth hormone (GH) therapy in children with short stature and normal results of GH stimulating tests. AB - BACKGROUND: Insulin-like growth factor-I (IGF-I) generation test has been introduced for the assessment of growth hormone (GH) sensitivity, however, its significance in predicting growth response to GH therapy has also been brought up. The molar ratio of IGF-I to its binding protein-3 (IGFBP-3) determines IGF-I bioavailability. AIMS: Evaluation of usefulness of IGF-I and IGFBP-3 generation test in predicting the effectiveness of rhGH therapy in children with short stature. PATIENTS AND METHODS: The analysis comprised 60 children with short stature, normal results of GH stimulating tests but decreased IGF-I secretion. In all the patients, GH insensitivity was excluded on the basis of IGF-I and IGFBP-3 generation test. Next, GH therapy was administered and height velocity (HV), together with IGF-I and IGFBP-3 secretion, was assessed every year, during 3 years. The comparative group consisted of 30 children with partial GH deficiency (pGHD). RESULTS: Both IGF-I secretion and IGF-I/IGFBP-3 molar ratio increased significantly during generation test (p<0.05) and - further - during GH therapy (however insignificantly), together with at least doubling of pretreatment HV. There was no significant difference between the studied group of patients and children with pGHD. CONCLUSIONS: Significant increase of IGF-I in generation test speaks for GH therapy effectiveness in short children, despite normal results of GH stimulating tests. PMID- 23685422 TI - Effects of intense cycling training on plasma leptin and adiponectin and its relation to insulin resistance. AB - OBJECTIVE: Adiponectin, the most abundant protein secreted by white adipose tissue, is known for its involvement in insulin resistance (HOMA-R). The purpose of this investigation was to assess the effect of intense cycling training for six months on plasma concentrations of adiponectin and leptin and HOMA-R. METHODS: Eight trained males non professional cyclists participated in this study. They completed two times maximal exercises separated by six months heavy cycling training. Blood samples were obtained before exercise, at the end and after 30 and 60 minutes of recovery. RESULTS: Before training, adiponectin concentrations were not significantly altered after maximal exercise, but plasma leptin levels decreased significantly at the end of exercise (-21.42%, p<0.01) and after 60 min of recovery (-21.18%, p<0.05). After 6 months training, subjects exhibited a decreased in control leptin concentrations (-44.91%, p<0.05) and in HOMA-R (-30.68%, p<0.05) and showed delayed increase in adiponectin concentrations (after 30 min of recovery) (14.10%, p<0.01). CONCLUSIONS: Our results showed that adiponectin is sensitive to maximal exercise when realised after intense training and that six months heavy cycling training don't affect adiponectin concentrations, but decreases the synthesis of leptin and HOMA-R and improves aerobic capacity. Furthermore, it appears that after 6 months heavy chronic exercise adiponectin is not associated with aerobic capacity and/or insulin resistance and/or body composition modifications. PMID- 23685423 TI - Serotoninergic and melatoninergic systems are expressed in mouse embryonic fibroblasts NIH3T3 cells. AB - OBJECTIVE: Melatonin not only plays an important role in regulating circadian rhythms, but is also involved in antioxidative defense and immunomodulation. Circulating melatonin levels are derived primarily from the pineal gland while other sources of melatonin have also been reported. Recently, we reported that cultured rat cortical astrocytes and glioma C6 cells synthesize melatonin. In addition, apolipoprotein E genotype influences melatonin biosynthesis by regulating NAT and MAOA expression in C6 cells. METHODS: Here, we investigated the expression of genes and enzymes that is responsible for the multistep conversion of tryptophan to serotonin and further to melatonin in mouse embryonic fibroblasts NIH3T3 cells by radioimmunoassay, Immunofluorescence staining, real time PCR and Western blotting techniques. RESULTS: Our results showed that cultured NIH3T3 cells could synthesize melatonin and serotonin. Serotonin N acetyltransferase (NAT), the key enzyme in the pathway of melatonin synthesis, was also detectable using both by western blot and PCR methods. In addition, two other key enzymes, tryptophan hydroxylase (TPH1 and TPH2) for serotonin synthesis and the metabolic enzyme monoamine oxidase A (MAOA) for 5-HT, were present in NIH3T3 cell line. CONCLUSIONS: In conclusion, we provided evidence that the NIH3T3 cells can synthesize intrinsic serotonin and melatonin and express key enzymes related biosynthetic pathways. PMID- 23685424 TI - The influence of radioiodine therapy on ocular changes and their relation to urine cotinine level in patients with Graves' Ophthalmopathy. AB - OBJECTIVES: Radioiodine therapy (RIT) is frequently used as the definitive treatment in patients with Graves' hyperthyroidism when remission is not achieved with anti-thyroid drugs (ATDs). In this observational study, we intended to examine whether the use of high doses of radioiodine (RAI) [22 mCi (814 MBq)] with prophylaxis of oral glucocorticoids (oGCS) does not exacerbate Graves ophthalmopathy (GO) in smokers and non-smokers, especially regards to the urine level cotinine and ocular changes before and after RIT. PATIENTS AND METHODS: The studied group consisted of 26 smokers, aged 28-61 years and 25 non-smoker patients, aged 21-54 years, respectively. The patients were enrolled to RAI after one-year of ineffective ATDs treatment. Criterion for inclusion in the study were patients with mild GO with hyperthyroidism at diagnosis based on the severity (NOSPECTS) and activity (CAS) scale. All the patients were subjected to RIT with oGCS prophylaxis and evaluated prospectively during a one-year follow-up. The ophthalmological examination was performed at various stages of RIT: initial pre radioiodine administration, at the time of treatment 6, and 12 months after RAI. The present study is unique, because the urine cotinine measurement was employed to detect nicotine exposure, also in regard to smoking intensity. RESULTS: In smokers, the values of serum TPO-Abs were statistically significant in the second and six month (p<0.05) and in the second and after one year (p<0.005). The TSHR Abs concentration was significantly higher in smokers (p<0.05), rising from 22.9+/-1.2 IU/L before therapy to 29.6+/-5.3 IU/L - 2 months, 32.6+/-8.6 IU/L - 6 months, and slightly decreased 28.9+/-10.6 IU/L - 12 months. These observed changes were statistically different between groups at baseline (p<0.05) and after one-year of follow-up (p<0.005). Mean urine cotinine were considerably higher in smokers comparing to non smokers in each point of observation [903.4+/ 770.0 and 5.2+/-1.7 ng/mL at baseline (p<0.001), 412.8+/-277.3 and 3.0+/-0.6 ng/mL after 2 months (p<0.001), 452.0+/-245 and 6.6+/-3.6 after 6 months (p<0.001), 379.4+/-236.8 and 1.0+/-1.2 after one year (p<0.001)]. The CAS values in the smoking group before RIT increased statistically from 2.8+/-0.2 points at baseline to 4.3+/-0.3 after 6 months, and 4.0+/-0.5 (12 months), while in the non smoking patients it was 1.4+/-0.2, 2.8+/-0.3 and 2.2+/-0.2, respectively. The level of urine cotinine correlated positively with CAS and TSHR-Ab in the smoking group (r=0.41; p<0.05) at baseline and during follow-up (2 months: r=0.46; p<0.001, 6 months: r=0.47, p<0.005; 12 months: r=0.46; p<0.005). In the NOSPECS classification, the symptoms changed from mild to moderate, mostly in smoking patients. CONCLUSIONS: 1) ablative RIT dose with prophylactic oral prednisone is a safe treatment in both smokers and non-smokers with mild GO; 2) The post hoc analysis showed that urinary level of cotinine can be very helpful in the assessment of exacerbation of ophthalmological clinical symptoms before and after RIT particularly in smokers. PMID- 23685425 TI - Ovulation stimulation protocols utilizing GnRH-antagonist/hCG, promote cytotoxic cell populations, predominant in patients with embryo implantation complications. AB - OBJECTIVE: Gonadotropin-releasing hormone (GnRH) antagonist combined with the human chorionic gonadotropin hormone (hCG) is commonly used in assisted reproduction techniques (ARTs) to induce controlled ovarian hyperstimulation (COH) and to synchronize oocyte maturation. While hCG is known to have immunomodulatory properties, we aimed to assess its effect on immunological changes, with respect to HLA-G binding receptors and embryo implantation success. DESIGN: The study involved 103 subjects, including patients undergoing COH protocols (n=66), divided on the basis of the pair's fertility disorder (FD) causes (female FD, n=29; male FD, n=37), and age matched healthy women (n=37). The relative distribution of T cell (CD3+/CD4+, CD3+/CD8+) and NK cell (CD56bright/CD16-, CD56dim/CD16+) populations was evaluated together with HLA-G ligands KIR2DL4 and LILRB1 expression by flow cytometry in the peripheral blood of all subjects, as well as in patient follicular fluids. RESULTS: Both groups of patients exhibited a significant decrease of their CD4/CD8 index, a down modulation of LILRB1-positive CD8 T cells, and increased KIR2DL4-positive NK cell distribution, when compared to the healthy donors. We attribute these changes to the COH protocol, since the only significant change between the patient groups was in the number of cytotoxic CD56dim NK cells (elevated in the female FD group). Patients with male FD causes, having an above-average CD4/CD8 index (>=3.17) and below-average KIR2DL4+/CD56bright NK cell levels(<=13.3%), exhibited higher embryo implantation rates. CONCLUSION: The GnRH antagonist/hCG protocol promotes CD3+/CD8+ and KIR2DL4+ NK cell levels, more abundant in subjects with lower implantation rates, and thus decreases the embryotransfer success in otherwise fertile women. PMID- 23685426 TI - A fully validated method for the quantification of ethyl glucuronide and ethyl sulphate in urine by UPLC-ESI-MS/MS applied in a prospective alcohol self monitoring study. AB - A method for the quantification of ethyl glucuronide (EtG) and ethyl sulphate (EtS) in human urine is developed and fully validated according to international guidelines. Protein precipitation is used as sample preparation. During the development of the method on an UPLC-ESI-MS/MS system using a CSH C18 column, special attention was paid to reduce matrix effects to improve assay sensitivity and to improve detection of the second transition for EtS for specificity purposes. The method was linear from 0.1 to 10MUg/mL for both analytes. Ion suppression less than 24% (RSD<15%) was observed for EtG and no significant matrix effect was measured for EtS. The recovery was around 80% (RSD<14%) for both compounds. This method provides good precision (RSDr and RSDt<10%) and bias (<15%) for internal and external quality control samples. The reproducibility of the method was demonstrated by the successful participation to proficiency tests (z-score<0.86). This method was finally used to analyze urine samples obtained from twenty-seven volunteers whose alcohol consumption during the 5 days before sampling was monitored. Concentrations between 0.5 and 101.9MUg/mL (mean 10.9, median 1.4) for EtG and between 0.1 and 37.9MUg/mL (mean 3.6, median 0.3) for EtS were detected in urine samples of volunteers who declared having consumed alcohol the day before the sampling. EtG and EtS concentrations in urine were highly correlated (r=0.996, p<0.001). A moderate correlation between the number of drinks the day before sampling and the concentration of EtG (r=0.448, p<0.02) or EtS (r=0.406, p<0.04) was observed. Using a cut-off value at 0.1MUg/mL for EtG and EtS, this method is able to detect social alcohol consumption approximately 24h after the intake, without showing any false positive result. PMID- 23685427 TI - Bioanalytical LC-MS/MS of protein-based biopharmaceuticals. AB - Biotechnology increasingly delivers highly promising protein-based biopharmaceutical candidates to the drug development funnel. For successful biopharmaceutical drug development, reliable bioanalytical methods enabling quantification of drugs in biological fluids (plasma, urine, tissue, etc.) are required to generate toxicokinetic (TK), pharmacokinetic (PK), and bioavailability data. A clear observable trend is that liquid chromatography coupled to (tandem) mass spectrometry (LC-MS(/MS)) is more and more replacing ligand binding assays (LBA) for the bioanalytical determination of protein-based biopharmaceuticals in biological matrices, mainly due to improved selectivity and linear dynamic ranges. Practically all MS-based quantification methods for protein-based biopharmaceuticals traditionally rely on (targeted) proteomic techniques and include "seven critical factors": (1) internal standardization, (2) protein purification, (3) enzymatic digestion, (4) selection of signature peptide(s), (5) peptide purification, (6) liquid chromatographic separation and (7) mass spectrometric detection. For this purpose, the variety of applied strategies for all "seven critical factors" in current literature on MS-based protein quantification have been critically reviewed and evaluated. Special attention is paid to the quantification of therapeutic monoclonal antibodies (mAbs) in serum and plasma since this is a very promising and rapidly expanding group of biopharmaceuticals. Additionally, the review aims to predict the impact of strategies moving away from traditional protein cleavage isotope dilution mass spectrometry (PC-IDMS) toward approaches that are more dedicated to bioanalysis. PMID- 23685428 TI - Recent developments and applications of capillary electrophoresis with laser induced fluorescence detection in biological samples. AB - Since the human genomic project, the analysis of biomolecules using biotechnology and biopharmaceuticals has become increasingly important for the investigation of molecular mechanisms of biological processes and disease, as well as for the discovery of new biomarkers and drug targets. Among a number of analytical tools and technologies, capillary electrophoresis (CE) is emerging as a useful analytical tool for analyzing various biomolecules, as well as for performing genome sequencing in biological studies because of the simple sample preparation involved in the method and the efficient resolution of compounds of various sizes. In particular, CE with laser-induced fluorescence (CE-LIF) detection is a promising and relatively rapidly developing tool with the potential to provide a highly sensitive and specific analysis of biological molecules. This paper gives a short overview of the methodological and instrumental developments and applications of microchip-based CE and CE-LIF for the analysis of DNA, RNA, proteins, and peptides in the past 3 years. PMID- 23685429 TI - Simultaneous determination of hair cortisol, cortisone and DHEAS with liquid chromatography-electrospray ionization-tandem mass spectrometry in negative mode. AB - The present study aimed to develop a novel method for simultaneous assay of cortisol, cortisone and dehydroepiandrosterone sulfate (DHEAS) in human hair. The method was based on liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-MS/MS) in negative mode. Analytes were extracted from 20-mg hair incubated in 1ml of methanol for 5 days. 100MUl non-SPE supernatant of the incubation solution was utilized in LC-MS/MS analysis. The liquid chromatography separation was performed on a reversed-phase C18 column with a mobile phase of 80:20 (v:v) methanol and deionized water containing 0.1% formic acid. The use of ESI in negative mode and the use of a small volume of the incubation solution significantly improved assay sensitivity. The linear range was 5-250pg/mg for cortisol and cortisone, and 5-500pg/mg for DHEAS. The limit of detection was 2pg/mg for the three analytes in hair. The coefficients of variation for intra day and inter-day assay were less than 10%. The method was applied to determine the three analytes mentioned above of hair samples from 103 participants. The results indicated that there was no significant effect of age and education level on the hair cortisol, cortisone and DHEAS levels. The simple treatment procedure developed in the present study may facilitate simultaneous measurement of more steroids in hair. PMID- 23685430 TI - Robust antiviral responses to enterovirus 71 infection in human intestinal epithelial cells. AB - Enterovirus 71 (EV71) is a single-stranded RNA virus that belongs to Picornaviridae family. It causes the hand-foot-and-mouth disease and fatal neurological diseases in young children and infants. The mechanism of EV71 pathogenesis remains obscure. The intestinal tract is the initial site of EV71 replication, but no or only mild gastrointestinal symptoms are observed clinically, suggesting that host immune responses of the intestinal epithelium to EV71 may be unique, which, however, remains rarely investigated. In this study, we showed that human intestinal epithelial cells HT-29 were susceptible to EV71, and the infected cells exhibited cytopathic effects (CPEs) and were prone to apoptosis. TLR-7 and TLR-8 were induced significantly post infection and may be pivotal in the induction of IFN-beta and host innate immune responses against EV71. Among proinflammatory responses in EV71-infected intestinal epithelial cells, IL-6, CCL5, and IP10 were up-regulated and may play a key role in intestinal pathogenicity. We examined extrinsic and intrinsic apoptotic pathways and found that both were activated in EV71 infection. The mitochondria-mediated intrinsic pathway may also be activated through Bid cleaved by active caspase-8. Robust induction of IFN-beta in human intestinal epithelial cells contradicts the finding that IFN induction was suppressed in other types of the cells, suggesting that mild gastrointestinal symptoms may be the result of sufficient local antiviral inductions. Our study has demonstrated a unique way of antiviral responses in human gut different from other tissue cells in response to EV71, which may account for mild symptoms in intestinal tract. This finding will broaden our understanding of host defense mechanism and the pathogenesis of EV71 infection. PMID- 23685431 TI - Synthesis, characterization and optical properties of low nuclearity liganded silver clusters: Ag31(SG)19 and Ag15(SG)11. AB - We report a simple synthesis of silver:glutathione (Ag:SG) clusters using a cyclic reduction under oxidative conditions. Two syntheses are described which lead to solutions containing well-defined Ag31(SG)19 and Ag15(SG)11 clusters that have been characterized by mass spectrometry. The optical properties of silver:glutathione (Ag:SG) cluster solutions have been investigated experimentally. In particular, the solution containing Ag15(SG)11 clusters shows a bright and photostable emission. For Ag31(SG)19 and Ag15(SG)11 clusters, the comparison of experimental findings with DFT and TDDFT calculations allowed us to reveal the structural and electronic properties of such low nuclearity liganded silver clusters. PMID- 23685432 TI - DRIMust: a web server for discovering rank imbalanced motifs using suffix trees. AB - Cellular regulation mechanisms that involve proteins and other active molecules interacting with specific targets often involve the recognition of sequence patterns. Short sequence elements on DNA, RNA and proteins play a central role in mediating such molecular recognition events. Studies that focus on measuring and investigating sequence-based recognition processes make use of statistical and computational tools that support the identification and understanding of sequence motifs. We present a new web application, named DRIMust, freely accessible through the website http://drimust.technion.ac.il for de novo motif discovery services. The DRIMust algorithm is based on the minimum hypergeometric statistical framework and uses suffix trees for an efficient enumeration of motif candidates. DRIMust takes as input ranked lists of sequences in FASTA format and returns motifs that are over-represented at the top of the list, where the determination of the threshold that defines top is data driven. The resulting motifs are presented individually with an accurate P-value indication and as a Position Specific Scoring Matrix. Comparing DRIMust with other state-of-the-art tools demonstrated significant advantage to DRIMust, both in result accuracy and in short running times. Overall, DRIMust is unique in combining efficient search on large ranked lists with rigorous P-value assessment for the detected motifs. PMID- 23685434 TI - Human TREX component Thoc5 affects alternative polyadenylation site choice by recruiting mammalian cleavage factor I. AB - The transcription-export complex (TREX) couples mRNA transcription, processing and nuclear export. We found that CFIm68, a large subunit of a heterotetrameric protein complex mammalian cleavage factor I (CFIm), which is implicated in alternative polyadenylation site choice, co-purified with Thoc5, a component of human TREX. Immunoprecipitation using antibodies against different components of TREX indicated that most likely both complexes interact via an interaction between Thoc5 and CFIm68. Microarray analysis using human HeLa cells revealed that a subset of genes was differentially expressed on Thoc5 knockdown. Notably, the depletion of Thoc5 selectively attenuated the expression of mRNAs polyadenylated at distal, but not proximal, polyadenylation sites, which phenocopied the depletion of CFIm68. Chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-Seq) indicated that CFIm68 preferentially associated with the 5' regions of genes; strikingly, the 5' peak of CFIm68 was significantly and globally reduced on Thoc5 knockdown. We suggest a model in which human Thoc5 controls polyadenylation site choice through the co transcriptional loading of CFIm68 onto target genes. PMID- 23685435 TI - JiffyNet: a web-based instant protein network modeler for newly sequenced species. AB - Revolutionary DNA sequencing technology has enabled affordable genome sequencing for numerous species. Thousands of species already have completely decoded genomes, and tens of thousands more are in progress. Naturally, parallel expansion of the functional parts list library is anticipated, yet genome-level understanding of function also requires maps of functional relationships, such as functional protein networks. Such networks have been constructed for many sequenced species including common model organisms. Nevertheless, the majority of species with sequenced genomes still have no protein network models available. Moreover, biologists might want to obtain protein networks for their species of interest on completion of the genome projects. Therefore, there is high demand for accessible means to automatically construct genome-scale protein networks based on sequence information from genome projects only. Here, we present a public web server, JiffyNet, specifically designed to instantly construct genome scale protein networks based on associalogs (functional associations transferred from a template network by orthology) for a query species with only protein sequences provided. Assessment of the networks by JiffyNet demonstrated generally high predictive ability for pathway annotations. Furthermore, JiffyNet provides network visualization and analysis pages for wide variety of molecular concepts to facilitate network-guided hypothesis generation. JiffyNet is freely accessible at http://www.jiffynet.org. PMID- 23685433 TI - Synthetic mammalian trigger-controlled bipartite transcription factors. AB - Synthetic biology has significantly advanced the design of synthetic control devices, gene circuits and networks that can reprogram mammalian cells in a trigger-inducible manner. Prokaryotic helix-turn-helix motifs have become the standard resource to design synthetic mammalian transcription factors that tune chimeric promoters in a small molecule-responsive manner. We have identified a family of Actinomycetes transcriptional repressor proteins showing a tandem TetR family signature and have used a synthetic biology-inspired approach to reveal the potential control dynamics of these bi-partite regulators. Daisy-chain assembly of well-characterized prokaryotic repressor proteins such as TetR, ScbR, TtgR or VanR and fusion to either the Herpes simplex transactivation domain VP16 or the Krueppel-associated box domain (KRAB) of the human kox-1 gene resulted in synthetic bi- and even tri-partite mammalian transcription factors that could reversibly program their individual chimeric or hybrid promoters for trigger adjustable transgene expression using tetracycline (TET), gamma-butyrolactones, phloretin and vanillic acid. Detailed characterization of the bi-partite ScbR TetR-VP16 (ST-TA) transcription factor revealed independent control of TET- and gamma-butyrolactone-responsive promoters at high and double-pole double-throw (DPDT) relay switch qualities at low intracellular concentrations. Similar to electromagnetically operated mechanical DPDT relay switches that control two electric circuits by a fully isolated low-power signal, TET programs ST-TA to progressively switch from TetR-specific promoter-driven expression of transgene one to ScbR-specific promoter-driven transcription of transgene two while ST-TA flips back to exclusive transgene 1 expression in the absence of the trigger antibiotic. We suggest that natural repressors and activators with tandem TetR family signatures may also provide independent as well as DPDT-mediated control of two sets of transgenes in bacteria, and that their synthetic transcription factor analogs may enable the design of compact therapeutic gene circuits for gene and cell-based therapies. PMID- 23685437 TI - 1,3-Dipolar cycloaddition of 4-platinumisochromenyliums with an olefin and tandem insertion into benzylic C-H bonds. AB - Isochromenylium-4-ylplatinum(II) species, generated from 1-(2-alkynylphenyl)hex-5 en-1-ones and Pt(II), reacted with a pendant olefin via [3+2] cycloaddition to form tetracyclic Pt-carbene complexes, which underwent C-H insertion with a benzyloxy group at delta or epsilon positions to give highly complex polycycles, which are otherwise hard to access. PMID- 23685436 TI - NAFlex: a web server for the study of nucleic acid flexibility. AB - We present NAFlex, a new web tool to study the flexibility of nucleic acids, either isolated or bound to other molecules. The server allows the user to incorporate structures from protein data banks, completing gaps and removing structural inconsistencies. It is also possible to define canonical (average or sequence-adapted) nucleic acid structures using a variety of predefined internal libraries, as well to create specific nucleic acid conformations from the sequence. The server offers a variety of methods to explore nucleic acid flexibility, such as a colorless wormlike-chain model, a base-pair resolution mesoscopic model and atomistic molecular dynamics simulations with a wide variety of protocols and force fields. The trajectories obtained by simulations, or imported externally, can be visualized and analyzed using a large number of tools, including standard Cartesian analysis, essential dynamics, helical analysis, local and global stiffness, energy decomposition, principal components and in silico NMR spectra. The server is accessible free of charge from the mmb.irbbarcelona.org/NAFlex webpage. PMID- 23685438 TI - The success of Peru's Neonatal Resuscitation Initiative. PMID- 23685439 TI - Molecular dissection of step 2 catalysis of yeast pre-mRNA splicing investigated in a purified system. AB - Step 2 catalysis of pre-mRNA splicing entails the excision of the intron and ligation of the 5' and 3' exons. The tasks of the splicing factors Prp16, Slu7, Prp18, and Prp22 in the formation of the step 2 active site of the spliceosome and in exon ligation, and the timing of their recruitment, remain poorly understood. Using a purified yeast in vitro splicing system, we show that only the DEAH-box ATPase Prp16 is required for formation of a functional step 2 active site and for exon ligation. Efficient docking of the 3' splice site (3'SS) to the active site requires only Slu7/Prp18 but not Prp22. Spliceosome remodeling by Prp16 appears to be subtle as only the step 1 factor Cwc25 is dissociated prior to step 2 catalysis, with its release dependent on docking of the 3'SS to the active site and Prp16 action. We show by fluorescence cross-correlation spectroscopy that Slu7/Prp18 and Prp16 bind early to distinct, low-affinity binding sites on the step-1-activated B* spliceosome, which are subsequently converted into high-affinity sites. Our results shed new light on the factor requirements for step 2 catalysis and the dynamics of step 1 and 2 factors during the catalytic steps of splicing. PMID- 23685440 TI - Effect of a prolonged endurance marathon on vascular endothelial and inflammation markers in runners with exercise-induced hypertension. AB - OBJECTIVE: The aim of this study was to observe the changes in endothelial and inflammatory markers in middle-aged male runners with exercise-induced hypertension (EIH) at baseline and at 100-km, 200-km, and 308-km checkpoints during a prolonged endurance ultramarathon. DESIGN: Among a total of 62 ultramarathon volunteers, 8 with systolic blood pressure higher than 210 mm Hg and 8 with normal systolic blood pressure were selected for this study. The subjects were designated to EIH and control (CON) groups. Blood was collected for the analysis of soluble vascular cell adhesion molecule-1, soluble E-selectin, leukocytes, creatine kinase, and high-sensitivity C-reactive protein. RESULTS: Soluble vascular cell adhesion molecule-1 showed a significantly greater increase in the EIH group than in the CON group at 100 km and 200 km. Soluble E-selectin also showed a significantly greater increase in the EIH group than in the CON group at 100 km. Leukocytes significantly increased in the EIH group than in the CON group at 308 km. Creatine kinase and high-sensitivity C-reactive protein showed no group differences. CONCLUSIONS: Leukocytes, creatine kinase, and high sensitivity C-reactive protein showed delayed-onset increases in both groups. Increased exercise intensity may stimulate greater endothelial responses independent of the inflammatory markers in EIH. The loss of a protective effect may be greater in those with EIH than in CONs. Acknowledging and prescribing proper exercise intensity may be critical in preventing possible vascular-related complications in runners with EIH. PMID- 23685441 TI - Alternative medicines: yes; alternatives to medicine: no. PMID- 23685442 TI - Re: Alternative medicines: yes; alternatives to medicine: no. PMID- 23685443 TI - What is the place of pre-exposure prophylaxis in HIV prevention? AB - New tools are needed to bring down ongoing high HIV incidence. This review aims to evaluate the place of one of these new tools (pre-exposure prophylaxis) in a comprehensive prevention strategy. Several trials have demonstrated the safety and the efficacy of pre-exposure prophylaxis in HIV prevention. Two large trials have, however, failed to show such efficacy. This was likely due to poor adherence in these trials. New forms of long-acting pre-exposure prophylaxis currently in trials may deal with these problems of low adherence. Pre-exposure prophylaxis has been demonstrated to be cost-effective within certain settings. The introduction of pre-exposure prophylaxis into prevention programs needs to be carefully thought through. For example, pre-exposure prophylaxis-induced risk compensation, at both an individual and population level, could undermine other aspects of a comprehensive HIV prevention program. In conclusion, pre-exposure prophylaxis could be a useful additional tool for the prevention of HIV in specific high-risk groups. It should be implemented in a way that deals with issues such as ensuring high adherence and ensuring that pre-exposure prophylaxis does not detract from, but complements, other more fundamental elements of HIV prevention programs. PMID- 23685444 TI - Exercise responses during functional electrical stimulation cycling in individuals with spinal cord injury. AB - PURPOSE: This study compared acute exercise responses during arm cranking, functional electrical stimulation (FES)-assisted leg cycling, and combined arm and leg ("hybrid") cycling in individuals with spinal cord injury during maximal and submaximal exercise. METHODS: Nine male subjects with long-standing neurological lesions from C7 to T12 were recruited. All subjects performed arm crank ergometry (ACE), FES leg cycle exercise (FES-LCE), combined ACE + FES-LCE, and cycling on a hybrid FES tricycle (HYBRID). They were assessed for their peak exercise responses in all four modalities. Subsequently, their submaximal heart rates (HR), cardiac outputs (Q), stroke volumes (SV), and arteriovenous oxygen extractions (Ca-Cv)O2 were measured at 40%, 60%, and 80% of mode-specific VO2peak. RESULTS: Arm exercise alone and arm + leg exercise resulted in significantly higher VO2peak and HRpeak compared with FES-LCE (P < 0.05). Submaximal VO2 during FES-LCE was significantly lower than all other modalities across the range of exercise intensities (P < 0.05). ACE elicited 70%-94% higher steady-state VO2, and HYBRID evoked 99%-148% higher VO2 compared with FES-LCE. Steady-state FES-LCE also produced significantly lower Q, HR, and (Ca-Cv)O2. ACE evoked 31%-36% higher Q and 19%-47% greater HR than did FES-LCE. HYBRID elicited 31%-49% greater Q and 23%-56% higher HR than FES-LCE. CONCLUSIONS: Combined arm and leg exercise can develop a higher oxygen uptake and greater cardiovascular demand compared with ACE or FES-LCE alone. These findings suggested that combined arm + leg FES training at submaximal exercise intensities may lead to greater gains of aerobic fitness than would arm exercise alone. These data also proffered that FES leg cycling exercise by itself may be insufficient to promote aerobic fitness in the spinal cord injury population. PMID- 23685445 TI - Accuracy of oxygen desaturation of hemoglobin in muscle by near-infrared oximeters [corrected]. PMID- 23685446 TI - Accurary of oxygen desaturation of hemoglobin in muscle by near-infrared oximeters. Author reply. PMID- 23685447 TI - Enhanced conduit artery flow-mediated dilation in elite athletes: false or reality? [corrected]. PMID- 23685448 TI - Enhanced conduit artery flow-mediated dilation in elite athletes: false or reality? Author reply. PMID- 23685449 TI - Remarkable acidity independent actinide extraction with a both-side diglycolamide functionalized calix[4]arene. AB - A novel solvent system containing a newly synthesized both-side diglycolamide functionalized calix[4]arene (L-I) in a room temperature ionic liquid showed highly efficient extraction of actinides and a remarkable acid concentration independent extraction of trivalent actinide ion, Am(3+) suggesting its possible use for high level radioactive waste remediation. The nature of the complexes was ascertained by slope analysis, luminescence spectroscopic investigations and from the thermodynamic parameters. The sustainability of the solvent system for long term applications was also investigated. PMID- 23685450 TI - Project SHINE: effects of parent-adolescent communication on sedentary behavior in African American adolescents. AB - OBJECTIVE: This study examined parenting variables (communication, monitoring) as moderators of a family-based intervention for reducing sedentary behavior (SB) in African American adolescents. As a secondary aim, a similar model was tested using adolescent weight status as the outcome. METHODS: African American adolescents (n = 73; 12.45 +/- 1.45 years; 60% girls; 63% overweight/obese) and caregivers were randomized to a 6-week interactive, parent-based intervention or general health condition. Parent-adolescent communication and monitoring of health behaviors were self-reported by parents. Adolescent SB was self-reported by youth. RESULTS: There was a significant intervention by communication interaction, such that intervention families with more positive communication showed lower adolescent SB than those with less positive communication or those in the comparison condition. No effects were found for monitoring on SB or for the model with weight status as the outcome. CONCLUSIONS: Parent-adolescent communication may be an effective component to integrate into health promotion programs for African American adolescents. PMID- 23685451 TI - Acceptance of pain: associations with depression, catastrophizing, and functional disability among children and adolescents in an interdisciplinary chronic pain rehabilitation program. AB - OBJECTIVES: The aims of this study were: (1) investigate relations between pain acceptance, depressive symptoms, catastrophizing, and functional disability in pediatric patients in an interdisciplinary chronic pain rehabilitation program, (2) examine changes in acceptance from pre- to posttreatment, and (3) test if changes in acceptance predict changes in depressive symptoms, catastrophizing, and functional disability from pre- to posttreatment. METHODS: 112 participants, ages 11-18 years, completed the Chronic Pain Acceptance Questionnaire, Adolescent Version, Center for Epidemiological Studies-Depression-Children's Scale, Pain Catastrophizing Scale for Children, and Functional Disability Inventory on admission to and completion of the program. RESULTS: Significant and strong relations between acceptance, depression, catastrophizing, and functional disability were demonstrated. Participants demonstrated significant increases in acceptance and decreases in depression, catastrophizing, and functional disability. Finally, changes in acceptance significantly predicted changes in depressive symptoms, catastrophizing, and functional disability. CONCLUSIONS: Pain acceptance is an important variable in the treatment of pediatric chronic pain. PMID- 23685452 TI - The importance of mixed selectivity in complex cognitive tasks. AB - Single-neuron activity in the prefrontal cortex (PFC) is tuned to mixtures of multiple task-related aspects. Such mixed selectivity is highly heterogeneous, seemingly disordered and therefore difficult to interpret. We analysed the neural activity recorded in monkeys during an object sequence memory task to identify a role of mixed selectivity in subserving the cognitive functions ascribed to the PFC. We show that mixed selectivity neurons encode distributed information about all task-relevant aspects. Each aspect can be decoded from the population of neurons even when single-cell selectivity to that aspect is eliminated. Moreover, mixed selectivity offers a significant computational advantage over specialized responses in terms of the repertoire of input-output functions implementable by readout neurons. This advantage originates from the highly diverse nonlinear selectivity to mixtures of task-relevant variables, a signature of high dimensional neural representations. Crucially, this dimensionality is predictive of animal behaviour as it collapses in error trials. Our findings recommend a shift of focus for future studies from neurons that have easily interpretable response tuning to the widely observed, but rarely analysed, mixed selectivity neurons. PMID- 23685453 TI - Structural basis for alternating access of a eukaryotic calcium/proton exchanger. AB - Eukaryotic Ca(2+) regulation involves sequestration into intracellular organelles, and expeditious Ca(2+) release into the cytosol is a hallmark of key signalling transduction pathways. Bulk removal of Ca(2+) after such signalling events is accomplished by members of the Ca(2+):cation (CaCA) superfamily. The CaCA superfamily includes the Na(+)/Ca(2+) (NCX) and Ca(2+)/H(+) (CAX) antiporters, and in mammals the NCX and related proteins constitute families SLC8 and SLC24, and are responsible for the re-establishment of Ca(2+) resting potential in muscle cells, neuronal signalling and Ca(2+) reabsorption in the kidney. The CAX family members maintain cytosolic Ca(2+) homeostasis in plants and fungi during steep rises in intracellular Ca(2+) due to environmental changes, or following signal transduction caused by events such as hyperosmotic shock, hormone response and response to mating pheromones. The cytosol-facing conformations within the CaCA superfamily are unknown, and the transport mechanism remains speculative. Here we determine a crystal structure of the Saccharomyces cerevisiae vacuolar Ca(2+)/H(+) exchanger (Vcx1) at 2.3 A resolution in a cytosol-facing, substrate-bound conformation. Vcx1 is the first structure, to our knowledge, within the CAX family, and it describes the key cytosol-facing conformation of the CaCA superfamily, providing the structural basis for a novel alternating access mechanism by which the CaCA superfamily performs high-throughput Ca(2+) transport across membranes. PMID- 23685454 TI - Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells. AB - Recent molecular studies have shown that, even when derived from a seemingly homogenous population, individual cells can exhibit substantial differences in gene expression, protein levels and phenotypic output, with important functional consequences. Existing studies of cellular heterogeneity, however, have typically measured only a few pre-selected RNAs or proteins simultaneously, because genomic profiling methods could not be applied to single cells until very recently. Here we use single-cell RNA sequencing to investigate heterogeneity in the response of mouse bone-marrow-derived dendritic cells (BMDCs) to lipopolysaccharide. We find extensive, and previously unobserved, bimodal variation in messenger RNA abundance and splicing patterns, which we validate by RNA-fluorescence in situ hybridization for select transcripts. In particular, hundreds of key immune genes are bimodally expressed across cells, surprisingly even for genes that are very highly expressed at the population average. Moreover, splicing patterns demonstrate previously unobserved levels of heterogeneity between cells. Some of the observed bimodality can be attributed to closely related, yet distinct, known maturity states of BMDCs; other portions reflect differences in the usage of key regulatory circuits. For example, we identify a module of 137 highly variable, yet co-regulated, antiviral response genes. Using cells from knockout mice, we show that variability in this module may be propagated through an interferon feedback circuit, involving the transcriptional regulators Stat2 and Irf7. Our study demonstrates the power and promise of single-cell genomics in uncovering functional diversity between cells and in deciphering cell states and circuits. PMID- 23685455 TI - A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene induced senescence. AB - In response to tenacious stress signals, such as the unscheduled activation of oncogenes, cells can mobilize tumour suppressor networks to avert the hazard of malignant transformation. A large body of evidence indicates that oncogene induced senescence (OIS) acts as such a break, withdrawing cells from the proliferative pool almost irreversibly, thus crafting a vital pathophysiological mechanism that protects against cancer. Despite the widespread contribution of OIS to the cessation of tumorigenic expansion in animal models and humans, we have only just begun to define the underlying mechanism and identify key players. Although deregulation of metabolism is intimately linked to the proliferative capacity of cells, and senescent cells are thought to remain metabolically active, little has been investigated in detail about the role of cellular metabolism in OIS. Here we show, by metabolic profiling and functional perturbations, that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH) is a crucial mediator of senescence induced by BRAF(V600E), an oncogene commonly mutated in melanoma and other cancers. BRAF(V600E)-induced senescence was accompanied by simultaneous suppression of the PDH-inhibitory enzyme pyruvate dehydrogenase kinase 1 (PDK1) and induction of the PDH-activating enzyme pyruvate dehydrogenase phosphatase 2 (PDP2). The resulting combined activation of PDH enhanced the use of pyruvate in the tricarboxylic acid cycle, causing increased respiration and redox stress. Abrogation of OIS, a rate-limiting step towards oncogenic transformation, coincided with reversion of these processes. Further supporting a crucial role of PDH in OIS, enforced normalization of either PDK1 or PDP2 expression levels inhibited PDH and abrogated OIS, thereby licensing BRAF(V600E)-driven melanoma development. Finally, depletion of PDK1 eradicated melanoma subpopulations resistant to targeted BRAF inhibition, and caused regression of established melanomas. These results reveal a mechanistic relationship between OIS and a key metabolic signalling axis, which may be exploited therapeutically. PMID- 23685456 TI - ROS and ERK1/2-mediated caspase-9 activation increases XAF1 expression in dexamethasone-induced apoptosis of EBV-transformed B cells. AB - Dexamethasone (Dex) inhibits the growth of diverse types of cancer cells and is utilized clinically for the therapy of hematological malignancies. In this study, we investigated the molecular mechanisms of Dex action in the apoptosis of Epstein-Barr virus (EBV)-transformed B cells. We showed that Dex inhibited the proliferation of EBV-transformed B cells and induced apoptosis by activating caspase-9, -3 and -8. While activation of caspase-9 was triggered as early as 2 h after Dex treatment, cleavage of caspase-8 was deferred and was found 8 h after the exposure. Dex-dependent activation of caspase-8 was blocked by the specific caspase-9 inhibitor, z-LEHD-fmk. Moreover, Dex significantly increased the expression of X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) and induced the translocation of XAF1 into the cytosol. Cytosolic XAF1 with Puma induced the translocation of Bax into mitochondria. Dex led to up-regulation of reactive oxygen species (ROS) generation and the phosphorylation of ERK1/2 after the exposure. We speculated that ROS generation might be the first event of Dex induced apoptosis because ROS inhibitor NAC abrogated ROS production and ERK1/2 activation, but PD98059 did not block ROS production. NAC and PD98059 also suppressed the translocation of XAF1, Puma and Bax into mitochondria. These results demonstrated that Dex-mediated activation of caspase-9 via ROS generation and ERK1/2 pathway activation resulted in the activation of caspase-8 and the increment of XAF1, thereby induced apoptosis of EBV-transformed B cells. These findings suggest that Dex constitutes a probable therapy for EBV-associated hematological malignancies. PMID- 23685458 TI - Optimizing event-related potential based brain-computer interfaces: a systematic evaluation of dynamic stopping methods. AB - OBJECTIVE: In brain-computer interface (BCI) research, systems based on event related potentials (ERP) are considered particularly successful and robust. This stems in part from the repeated stimulation which counteracts the low signal-to noise ratio in electroencephalograms. Repeated stimulation leads to an optimization problem, as more repetitions also cost more time. The optimal number of repetitions thus represents a data-dependent trade-off between the stimulation time and the obtained accuracy. Several methods for dealing with this have been proposed as 'early stopping', 'dynamic stopping' or 'adaptive stimulation'. Despite their high potential for BCI systems at the patient's bedside, those methods are typically ignored in current BCI literature. The goal of the current study is to assess the benefit of these methods. APPROACH: This study assesses for the first time the existing methods on a common benchmark of both artificially generated data and real BCI data of 83 BCI sessions, allowing for a direct comparison between these methods in the context of text entry. MAIN RESULTS: The results clearly show the beneficial effect on the online performance of a BCI system, if the trade-off between the number of stimulus repetitions and accuracy is optimized. All assessed methods work very well for data of good subjects, and worse for data of low-performing subjects. Most methods, however, are robust in the sense that they do not reduce the performance below the baseline of a simple no stopping strategy. SIGNIFICANCE: Since all methods can be realized as a module between the BCI and an application, minimal changes are needed to include these methods into existing BCI software architectures. Furthermore, the hyperparameters of most methods depend to a large extend on only a single variable-the discriminability of the training data. For the convenience of BCI practitioners, the present study proposes linear regression coefficients for directly estimating the hyperparameters from the data based on this discriminability. The data that were used in this publication are made publicly available to benchmark future methods. PMID- 23685459 TI - A phase plane analysis of neuron-astrocyte interactions. AB - Intensive experimental studies have shown that astrocytes are active partners in modulation of synaptic transmission. In the present research, we study neuron astrocyte signaling using a biologically inspired model of one neuron synapsing one astrocyte. In this model, the firing dynamics of the neuron is described by the Morris-Lecar model and the Ca(2+) dynamics of a single astrocyte explained by a functional model introduced by Postnov and colleagues. Using the coupled neuron astrocyte model and based on the results of the phase plane analyses, it is demonstrated that the astrocyte is able to activate the silent neuron or change the neuron spiking frequency through bidirectional communication. This suggests that astrocyte feedback signaling is capable of modulating spike transmission frequency by changing neuron spiking frequency. This effect is described by a saddle-node on invariant circle bifurcation in the coupled neuron-astrocyte model. In this way, our results suggest that the neuron-astrocyte crosstalk has a fundamental role in producing diverse neuronal activities and therefore enhances the information processing capabilities of the brain. PMID- 23685457 TI - Glucose regulation of a cell cycle gene module is selectively lost in mouse pancreatic islets during ageing. AB - AIMS/HYPOTHESIS: Transcriptional networks in beta cells are modulated by extracellular signals such as glucose, thereby ensuring beta cell adaptation to systemic insulin demands. Ageing is a main risk factor for type 2 diabetes and has been associated with perturbed expression of genes essential for beta cell function. We aimed to uncover glucose-dependent gene modules in mouse pancreatic islets and investigate how this regulation is affected by ageing. METHODS: Global gene expression was assessed in pancreatic islets from young and aged wild-type and Cdkn2a (Ink4a/Arf)-deficient mice exposed to different glucose concentrations. Gene modules were identified by gene ontology and gene set enrichment analysis. RESULTS: Gene expression profiling revealed that variations in glucose levels have a widespread and highly dynamic impact on the islet transcriptome. Stimulatory glucose levels induced the expression of highly beta cell-selective genes and repressed the expression of ubiquitous genes involved in stress and antiproliferative responses, and in organelle biogenesis. Interestingly, a module comprising cell cycle genes was significantly induced between non-stimulatory and stimulatory glucose concentrations. Unexpectedly, glucose regulation of gene expression was broadly maintained in islets from old mice. However, glucose induction of mitotic genes was selectively lost in aged islets and was not even restored in the absence of the cell cycle inhibitors p16(INK4a) and p19(ARF), which have been implicated in the restricted proliferative capacity of beta cells with advanced age. CONCLUSIONS/INTERPRETATION: Glucose-dependent transcriptional networks in islets are globally conserved during ageing, with the exception of the ability of stimulatory glucose levels to induce a cell cycle gene module. PMID- 23685460 TI - Nanocrystals self-assembled in superlattices directed by the solvent-organic capping interaction. AB - Close-packed arrays of ZrO2 nanocrystals (NCs) have been self-assembled from a colloidal solution in a withdrawal dip coating process. A benzyl alcohol route was used to obtain NCs of narrowly controlled size, and then the capping layer was replaced by oleate using solvothermal treatment. The oleate solubility was explored in chloroform, hexane and toluene to prepare thin films of NCs using a dip coating process. From TEM images, the final structures show that increasing the solvent polarity improved self-assembly to prepare mono- and multi-layer superlattices, during solvent evaporation in a short time. The entangled organic chain in the NC surface offsets the limitations of the faceted NCs, improving the assembly quality, allowing the NC assembly to approach the formation of a hard sphere model, resulting in a FCC close-packed structure. Furthermore, the low interaction of chloroform with the capping layer reduces the shrinkage effect during the solvent evaporation preserving the array in the final self-assembled structure. Molecular dynamics simulations with soft potentials supported the conclusion that hexane interacts with the organic capping ligand, increasing the apparent radius of each NC and stabilizing the colloidal suspension, whereas chloroform is partially removed from the capping layer during the aggregation process, forming an array of nanoparticles. PMID- 23685461 TI - Bilateral common carotid artery occlusion as an adequate preconditioning stimulus to induce early ischemic tolerance to focal cerebral ischemia. AB - There is accumulating evidence, that ischemic preconditioning - a non-damaging ischemic challenge to the brain - confers a transient protection to a subsequent damaging ischemic insult. We have established bilateral common carotid artery occlusion as a preconditioning stimulus to induce early ischemic tolerance to transient focal cerebral ischemia in C57Bl6/J mice. In this video, we will demonstrate the methodology used for this study. PMID- 23685462 TI - Alteration of photochemistry and protein degradation of photosystem II from Chlamydomonas reinhardtii under high salt grown cells. AB - In this study, we evaluated the inhibitory effect of NaCl on cell growth, photochemistry and protein profile of photosystem (PS) II in Chlamydomonas reinhardtii. To study the effect of NaCl on the photosynthetic apparatus, the C. reinhardtii cells were grown at different concentrations (0, 50, 100 and 150 mM). NaCl induced flagellar resorption due to which the cells lost their motility, formation of palmelloids, reduced cell size and slower cell division. Chlorophyll fluorescence transients at different NaCl concentrations had decreased intensities of all peaks (OJIP) indicating the apparent inactivation energies of both donor and acceptor side of PSII. Consequently, inhibition of electron transport occurred particularly at PSII. Further, low temperature emission spectra showed that the rate of damage to the PSII was more when compared to PSI. Also, we have carried out the visible circular dichroism spectra from thylakoids where the major peaks contributed to chlorophyll a and b are equally reduced in different salt grown cells, which may explain the changes at the level of inter pigment-pigment interactions. Furthermore protein profile analysis of PSII revealed that the major subunit of light harvesting complex (LHC)II is more prone to salt stress than core proteins of PSII indicating the light harvesting funnel from LHCII to PSII core is impaired. PMID- 23685463 TI - Reconstruction with cutaneous flap after resection for breast cancer's skin metastases in a chemoresistant patient. AB - We reported a case of a breast cancer's skin metastases in a patient that had sustained 3 lines of chemotherapy. At first she received surgical treatment with Madden's mastectomy with dissection of axillary limphnodes and positioning of an expander. After that she underwent to chemo- and radiotherapy. The schedules we performed were: FEC, TC,Vinorelbine and Capecitabine. Only after the FEC there was a clinical remission just for 1 year. After that she underwent to surgery for the removal of a lozenge of skin on the right hemithorax, including also the subcutaneous tissue, a strip of muscular tissue, and a residue of the breast implant. The histology showed a multiple-nodules infiltration involving the dermis, the hypodermis, and the muscle. This pattern was valuated as a G3 breast cancer recurrence with ER 70%, PgR<5%, Ki67 50% Her2neu-. During the second line chemotherapy with TC she developed an high grade LCIS with lymphovascular infiltration on the left breast; on the right hemithorax there were cutaneous metastases with dermis' infiltration. Surgery with local excision was performed, and a cutaneous flap was realized. PMID- 23685464 TI - COMBINING ATLAS AND ACTIVE CONTOUR FOR AUTOMATIC 3D MEDICAL IMAGE SEGMENTATION. AB - Atlas based methods and active contours are two families of techniques widely used for the task of 3D medical image segmentation. In this work we present a coupled framework where the two methods are combined together, in order to exploit each's advantage while avoid their respective drawbacks. Indeed, the atlas based methods lacks the flexibility in locally tuning the segmentation boundary; whereas the active contour has the drawback that the final result heavily depends on the initialization as well as the contour evolution energy functional. Therefore, in the proposed work, the atlas based segmentation provides a probability map, which not only supplies the initial contour position, but also defines the contour evolution energy in an on-line fashion. Afterward, the active contour further converges to the desired object boundary. Finally, the method is tested on various 3D medical images to demonstrate its robustness as well as accuracy. PMID- 23685465 TI - Molecular characterization of high-level gentamicin-resistant Enterococcus faecalis from chicken meat in Korea. AB - Because the intrinsically antimicrobial-resistant Enterococcus has acquired high level aminoglycoside resistance genes, treating enterococcal infections is difficult. In this study, of the 101 food-borne Enterococcus faecalis isolates collected from retail chicken meat between 2003 and 2010, 11 high-level gentamicin-resistant (HLGR) E. faecalis isolates (MICs>2,048 MUg/mL) were found. Molecular characterization was performed to determine the basis of this resistance. All HLGR E. faecalis isolates encoded aac(6')-Ie-aph(2")-Ia and harbored at least 3 virulence traits in the asa1, esp, gelE, efaA, ace, and cylA genes. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) were performed to characterize their molecular epidemiology. A total of 8 sequence types (STs), including 3 novel STs, were identified (ST35, ST82, ST116, ST202, ST300, ST403, ST407, and ST420). ST82, which is associated with amyloid arthropathy in poultry, was the most prevalent ST among HLGR E. faecalis isolates (4 out of 11 isolates, 36.4%); all other STs were identified in the isolates as well. The STs of food-borne HLGR E. faecalis in this study have been confirmed as corresponding to clinical isolates in the MLST database (DB), except for ST300 and the new STs. Three out of 11 isolates belonged to CC116, including ST116, ST407, and ST420. This study characterized HLGR E. faecalis isolates and provided evidence for the spread of HLGR E. faecalis with virulence factors to chicken sources in Korea. The emergence of food-borne HLGR E. faecalis suggests that chicken could be a potential source of transmission of antimicrobial resistance and virulence factors. PMID- 23685466 TI - Improvement of modified charcoal-cefoperazone-deoxycholate agar by addition of potassium clavulanate for detecting Campylobacter spp. in chicken carcass rinse. AB - The presence of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (E. coli) in raw poultry is one of the most common factors that interfere with the isolation of Campylobacter by cefoperazone-based selective agar. The performance of modified charcoal-cefoperazone-deoxycholate agar (mCCDA) was improved by addition of an ESBL inhibitor, potassium clavulanate (0.5 mg/L). The ability of the supplemented medium (C-mCCDA) to detect Campylobacter species from chicken carcass rinse was compared with that of normal mCCDA. The isolation rate using C-mCCDA was significantly (p<0.05) higher compared with that using mCCDA (C mCCDA, 67 out of 120; mCCDA, 38 out of 120). Furthermore, the selectivity of the C-mCCDA as assessed by comparing the number of contaminated plates (C-mCCDA, 44 out of 120; mCCDA, 110 out of 120) and growth index (C-mCCDA, 1.76; mCCDA, 2.79) of competing flora was also better (p<0.05) than that of mCCDA. PMID- 23685467 TI - Putrescine production from different amino acid precursors by lactic acid bacteria from wine and cider. AB - The aim of this work was to study the production of biogenic amines and particularly putrescine in lactic acid bacteria (LAB) related to wine and cider. We applied an analytical protocol that involves the use of PCR and TLC techniques to determine the production of putrescine from different precursors. Moreover, we also studied the ability of the Lactobacillus and Pediococcus tested to produce histamine and tyramine. The results showed that the majority of the Lactobacillus brevis analyzed harbour both AgDI and tdc genes and are tyramine and putrescine producers. Conversely, among the other LAB tested, only one Lactobacillus hilgardii and one Pediococcus pentosaceus produced putrescine. The AgDI gene was also detected in two other LAB (Lactobacillus mali and Pediococcus parvulus), but no putrescine production was observed. Finally, hdc gene and histamine production were found in strains (L. hilgardii 5211, isolated from wine, and Lactobacillus casei 18, isolated from cider) that were not putrescine producers. PMID- 23685468 TI - Molecular characterization of clinical and environmental Vibrio parahaemolyticus isolates in Taiwan. AB - Vibrio parahaemolyticus is the most prevalent foodborne pathogen in Taiwan and it is frequently recovered from seafood. In this study, V. parahaemolyticus that was isolated in recent years from aquacultural environments and clinical specimens were comparatively analyzed by NotI-restricted pulsed-field gel electrophoresis (PFGE) and polymerase chain reaction, targeting common toxin genes (tdh, trh, ureC), MTase gene, toxR regulator, markers for pandemic strains (ORF8, group specific toxRS) and representative genes of type three secretion systems T3SS1 (vcrD1, VP1680, vopD) and T3SS2alpha (vcrD2, vopD2, vopB2, vopP, vopC, vopT). Among the 48 clinical isolates and 93 environmental isolates that were analyzed by PFGE, a total of 26 and 76 pulsetypes were identified and grouped into six and nine clusters, respectively, at 80% similarity. The pandemic O3:K6 clones and other clinical and environmental isolates were further characterized according to the distribution of these examined target genes. The MTase gene and the vopB2, vopP, vopC and vopT genes of T3SS2alpha were present at a significantly higher frequency (>90%) in the pandemic clones than in other clinical isolates. The MTase gene and some other virulence-associated genes were also present in a few of the environmental isolates, and these results suggest the horizontal transfer of these genes in the clinical and environmental isolates of this species. PMID- 23685469 TI - High symmetry superoctahedron cluster [Mn(III)18O14]26+ from the use of N,N,N',N' tetrakis(2-hydroxyethyl)ethylenediamine. AB - The use of flexible N,N,N',N'-tetrakis(2-hydroxyethyl)ethylenediamine has provided one new high symmetry superoctahedron with unprecedented aesthetically pleasing Mn(III)18 clusters, which exhibits out-of-phase signals indicative of the slow magnetic relaxation. PMID- 23685470 TI - Comparative study of reaction of cobalamin and cobinamide with thiocyanate. AB - The interaction of Co(III) and Co(II) cobalamin (Cbl) and cobinamide (Cbi) with thiocyanate was examined with UV-vis and EPR spectra. S/N-linkage isomerism was explored on Co(III) and Co(II) Cbl and Cbi models using density functional theory (DFT; BP86, B3LYP). Performed calculations suggest the prevalence of isothiocyanato isomers over thiocyanato complexes on both Co(III) and Co(II) centers. The formation of Cbl(II) complex with thiocyanate was observed at high ligand concentrations which was proposed to be hexacoordinated. DFT data maintain the possibility of hexacoordinated Co(II) complexes with thiocyanate in which one of extra-ligands is weakly coordinated. It is found that high thiocyanate concentrations could retard cyanide binding to cobalamin but not to cobinamide. PMID- 23685471 TI - Long lifetime pure organic phosphorescence based on water soluble carbon dots. AB - Carbon dots show potential in lighting and displays. However, only their fluorescence has been observed so far. Here we report the observation of phosphorescence from carbon dots in a polyvinyl alcohol matrix. The phosphorescence is attributed to C=O bonds on the surface of carbon dots and has a very long lifetime (~380 ms). PMID- 23685472 TI - Molecular adaptations of Helicoverpa armigera midgut tissue under pyrethroid insecticide stress characterized by differential proteome analysis and enzyme activity assays. AB - Helicoverpa armigera is an insect that causes important economic losses in crops. To reduce this loss, pyrethroids have been commonly used against H. armigera in farming areas. However, excess and continuous usage of pyrethroids cause resistance in H. armigera. Therefore, expressions of midgut proteins of two H. armigera field populations were compared to those of a susceptible strain by 2-D PAGE and MALDI-ToF-MS. Our results indicate that H. armigera reacts to pyrethroid induced stress mainly by increasing the expression of energy metabolism-related proteins, such as ATP synthase and arginine kinase. NADPH cytochrome P450 reductase, also up-regulated, could play a role in detoxification of toxic pyrethroid metabolites, such as 3-phenoxybenzaldehyde. Interestingly, while GSTs were not found up-regulated in the comparative proteome analysis, biochemical assays showed significant increases of enzyme activities in both field populations as compared to the susceptible strain. Similarly, although esterases were not found differentially expressed, biochemical assays showed significant increases of esterase activities in both field populations. Thus, esterases are also proposed to be involved in metabolic responses towards pyrethroid insecticide-induced stress. In conclusion, we suggest increased energy metabolism in the midgut tissue of H. armigera as a general prerequisite for compensating the costs of energy-consuming detoxification processes. PMID- 23685473 TI - Hand muscle atrophy and digital ischemia as an unusual presentation of an occluded aberrant right subclavian artery: Endovascular or open approach? AB - INTRODUCTION: An aberrant right subclavian artery (ARSA) or lusorian artery is one of the most common variations of the aortic arch. Although usually without symptoms, some ARSA's occasionally become symptomatic. PRESENTATION OF CASE: A 51 year old woman presented with a painful right middle finger. Clinical examination showed thenar muscle hypotrophy and blue discoloration of the distal phalanx suggestive of embolization. Magnetic resonance angiography revealed a non aneurysmal proximally occluded ARSA. A venous common carotid artery to subclavian artery bypass was combined with ARSA ligation proximal to the right vertebral artery. DISCUSSION: Occlusive symptomatic ARSA disease without aneurysmal dilatation is uncommon. Treatment may include bypass grafting by open surgery or angioplasty with stenting. CONCLUSION: Treatment for occlusive non-aneurysmal ARSA must be tailored to the individual. Whether an endovascular or surgical approach is preferred depends on localization of the lesion in relation to the esophagus and on the general condition of the patient. PMID- 23685474 TI - Transmesenteric hernia: A rare cause of bowel ischaemia in adults. AB - INTRODUCTION: Transmesenteric herniae are a rare cause of bowel ischaemia in adults with few reported cases in published literature. PRESENTATION OF CASE: We report a rare case of a 26-year-old female with spontaneous transmesenteric hernia of jejunum and proximal ileum due to a congenital mesenteric defect resulting in bowel gangrene, presenting initially with no haemodynamic or biochemical abnormalities. The hernia was reduced, small bowel resected and primary side to side anastomosis performed, following which the patient made a good recovery and was discharged 5 days later. DISCUSSION: The insidious onset of transmesenteric herniae and lack of specific radiological or laboratory investigations reaffirms the importance of surgeons maintaining a high index of suspicion for this critical surgical emergency. CONCLUSION: Close monitoring of the patient's general condition in cases of non-specific abdominal pain is essential to identify the rare deteriorating patient for early surgical intervention and optimal outcome. PMID- 23685475 TI - Identification and production of a novel natural pigment, cordycepoid A, from Cordyceps bifusispora. AB - A novel yellow pigment, cordycepoid A, was isolated and identified from the entomogenous fungi Cordyceps bifusispora. Cordycepoid A exhibited no significant toxicity against Chinese hamster ovary (CHO) cells and mice, and showed high stability against food addictives, metal ions and heat. A liquid/solid double phase cultural process for the production of the pigment was optimized as follows: 3 days aged liquid seed, 7.5 % inoculums, incubation temperature at 25 degrees C, 10 days of solid culture, and the last 5 days exposed to 200 Lx scattered light. The liquid seed medium and the solid culture medium were also optimized. Ethanol was selected as extracting solvent for its scale-up production. The optimal extracting conditions were determined as liquid/solid ratio at 20:1, extracting temperature at 40 degrees C, ultrasonic power at 400 W, and extracting time of 40 min. PMID- 23685476 TI - Expression, purification, and immunogenic characterization of Epstein-Barr virus recombinant EBNA1 protein in Pichia pastoris. AB - Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus associated with the development of both lymphoid and epithelial tumors. EBNA1 is the only viral protein expressed in all EBV-associated malignancies and plays important roles in EBV latency. Thus, EBNA1 is thought to be a promising antigen for immunotherapy of all EBV-associated malignancies. This study was undertaken to produce recombinant EBNA1 protein in Pichia pastoris and evaluate its immunogenicity. The truncated EBNA1 (E1DeltaGA, codons 390-641) was expressed as a secretory protein with an N-terminal histidine tag in the methylotrophic yeast P. pastoris and purified by Ni-NTA affinity chromatography. The purified proteins were then used as antigens to immunize BALB/c mice for production of polyclonal antibodies. Western blot analysis showed that the polyclonal antibodies specifically recognized the EBNA1 protein in B95-8 cell lysates. The recombinant E1DeltaGA also induced strong lymphoproliferative and Th1 cytokine responses in mice. Furthermore, mice immunized with E1DeltaGA developed CD4+ and CD8+ T cell responses. These findings showed that the yeast-expressed E1DeltaGA retained good immunogenicity and might be a promising vaccine candidate against EBV-associated malignancies. PMID- 23685477 TI - Dynamics of lactic acid bacteria populations in Rioja wines by PCR-DGGE, comparison with culture-dependent methods. AB - Lactic acid bacteria populations of red wine samples from industrial fermentations, including two different vinification methods were studied. For this investigation, polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) analysis was employed to supplement previous results that were obtained by culture-dependent methods. PCR-DGGE was aimed to study two targeted genes, 16S ribosomal DNA (rDNA) and rpoB, and the results were useful to evaluate the microbial populations in wine samples. Moreover, an improvement of a detection limit determined so far for DGGE analysis was obtained with the method described in this study, what made possible to identify lactic acid bacteria populations below 10(1) colony-forming unit/mL. The species Oenococcus oeni was the most frequently detected bacterium, but identifications close to species Oenococcus kitaharae and Lactococcus lactis that are not often found in wine were firstly identified in samples of this research. PCR-DGGE allowed to detect 9 out of 11 lactic acid bacteria species identified in this study (nine by PCR-16S rDNA/DGGE and four by PCR-rpoB/DGGE), while five species were detected using the modified de Man, Rogosa and Sharpe agar. Therefore, the two methods were demonstrated to be complementary. This finding suggests that analysis of the lactic acid bacteria population structure in wine should be carried out using both culture-dependent and culture-independent techniques with more than one primer pair. PMID- 23685478 TI - Evidence for lytic transglycosylase and beta-N-acetylglucosaminidase activities located at the polyhydroxyalkanoates (PHAs) granules of Thermus thermophilus HB8. AB - The thermophilic bacterium Thermus thermophilus HB8 accumulates polyhydroxyalkanoates (PHAs) as intracellular granules used by cells as carbon and energy storage compounds. PHAs granules were isolated from cells grown in sodium gluconate (1.5 % w/v) as carbon source. Lytic activities are strongly associated and act to the PHAs granules proved with various methods. Specialized lytic trasglycosylases (LTGs) are muramidases capable of locally degrading the peptidoglycan (PG) meshwork of Gram negative bacteria. These enzymes cleave the beta-1,4-glycosidic linkages between the N-acetylmuramic acid (MurNAc) and N acetylglucosamine (GlcNAc) residues of PG. Lysozyme-like activity/-ies were detected using lysoplate assay. Chitinolytic activity/-ies, were detected as N acetyl glucosaminidases (NAG) (E.C.3.2.1.5.52) hydrolyzing the synthetic substrate p-nitrophenyl-N-acetyl-beta-D-glucosaminide (pNP-GlcNAc) releasing pNP and GlcNAc. Using zymogram analysis two abundant LTGs were revealed hydrolyzing cell wall of Micrococcus lysodeikticus or purified PG incorporated as natural substrates, in SDS-PAGE and then renaturation. These proteins corresponded in a SDS-PAGE and Coomassie-stained gel in molecular mass of 110 and 32 kDa respectively, were analyzed by MALDI-MS (Matrix-assisted laser desorption/ionization-Mass Spectrometry). The 110 kDa protein was identified as an S-layer domain-containing protein [gi|336233805], while the 32 kDa similar to the hypothetical protein VDG1235_2196 (gi/254443957). Overall, the localization of PG hydrolases in PHAs granules appears to be involved to their biogenesis from membranes, and probably promoting septal PG splitting and daughter cell separation. PMID- 23685479 TI - Ten years of measured UV Index from the Spanish UVB Radiometric Network. AB - An analysis is made of the UV Index (UVI) obtained from the ultraviolet erythemal solar radiation (UVER) data measured by the Spanish UVB Radiometric Network between the years 2000 and 2009. Previously, the daily UVI has been evaluated using two different criteria: (a) the value corresponding to solar noon; and (b) the daily maximum value. The mean percentage of agreement is 92% if we consider the cases for which the difference is zero or one UVI unit. These results are similar to those obtained in a previous work where only 2 years were analyzed. In all the stations the UVI reaches very high values (8-10) in spring-summer, and the very high and extreme (>= 11) UVI values are more dependent on the continental effect than on the latitude effect. From the UVI values it is possible to classify the stations into four groups: Coastal stations, Continental stations (more than 200 km from the coast), Southern stations (Coastal stations but with similar values of UVI as the Continental ones due to their low latitude) and Canary Islands stations (1400 km southwest from the Iberian Peninsula thus lower latitude). The monthly mean maximum of UVI is reached in July due to the annual evolution of the total ozone column. This value corresponds, for a skin phototype II, to three times the minimal erythemal dose (MED) in an hour in a Coastal station, 3.5 MEDs in an hour measured in a Continental or Southern station and up five MEDs in an hour in the Izana station (Canary Islands). The cumulative dose on a horizontal plane over an average year has been calculated for each station. More than 40% of the annual dose is received in summer, about 35% in spring, more than 11% in autumn and less than 10% in winter except for the stations in the Canary Islands where the difference between seasons is less significant. PMID- 23685480 TI - viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia. AB - New high-dimensional, single-cell technologies offer unprecedented resolution in the analysis of heterogeneous tissues. However, because these technologies can measure dozens of parameters simultaneously in individual cells, data interpretation can be challenging. Here we present viSNE, a tool that allows one to map high-dimensional cytometry data onto two dimensions, yet conserve the high dimensional structure of the data. viSNE plots individual cells in a visual similar to a scatter plot, while using all pairwise distances in high dimension to determine each cell's location in the plot. We integrated mass cytometry with viSNE to map healthy and cancerous bone marrow samples. Healthy bone marrow automatically maps into a consistent shape, whereas leukemia samples map into malformed shapes that are distinct from healthy bone marrow and from each other. We also use viSNE and mass cytometry to compare leukemia diagnosis and relapse samples, and to identify a rare leukemia population reminiscent of minimal residual disease. viSNE can be applied to any multi-dimensional single-cell technology. PMID- 23685482 TI - Wavepacket revivals in monolayer and bilayer graphene rings. AB - We have studied the existence of quantum revivals in graphene quantum rings within a simplified model. The time evolution of a Gaussian-populated wavepacket shows revivals in monolayer and bilayer graphene rings. We have also studied this behavior for quantum rings in a perpendicular magnetic field. We have found that revival time is an observable that shows different values for monolayer and bilayer graphene quantum rings. In addition, the revival time shows valley degeneracy breaking. PMID- 23685481 TI - A large synthetic peptide and phosphopeptide reference library for mass spectrometry-based proteomics. AB - We present a peptide library and data resource of >100,000 synthetic, unmodified peptides and their phosphorylated counterparts with known sequences and phosphorylation sites. Analysis of the library by mass spectrometry yielded a data set that we used to evaluate the merits of different search engines (Mascot and Andromeda) and fragmentation methods (beam-type collision-induced dissociation (HCD) and electron transfer dissociation (ETD)) for peptide identification. We also compared the sensitivities and accuracies of phosphorylation-site localization tools (Mascot Delta Score, PTM score and phosphoRS), and we characterized the chromatographic behavior of peptides in the library. We found that HCD identified more peptides and phosphopeptides than did ETD, that phosphopeptides generally eluted later from reversed-phase columns and were easier to identify than unmodified peptides and that current computational tools for proteomics can still be substantially improved. These peptides and spectra will facilitate the development, evaluation and improvement of experimental and computational proteomic strategies, such as separation techniques and the prediction of retention times and fragmentation patterns. PMID- 23685483 TI - F1FO ATPase vesicle preparation and technique for performing patch clamp recordings of submitochondrial vesicle membranes. AB - Mitochondria are involved in many important cellular functions including metabolism, survival(1), development and, calcium signaling(2). Two of the most important mitochondrial functions are related to the efficient production of ATP, the energy currency of the cell, by oxidative phosphorylation, and the mediation of signals for programmed cell death(3). The enzyme primarily responsible for the production of ATP is the F1FO-ATP synthase, also called ATP synthase(4-5). In recent years, the role of mitochondria in apoptotic and necrotic cell death has received considerable attention. In apoptotic cell death, BCL-2 family proteins such as Bax enter the mitochondrial outer membrane, oligomerize and permeabilize the outer membrane, releasing pro-apoptotic factors into the cytosol(6). In classic necrotic cell death, such as that produced by ischemia or excitotoxicity in neurons, a large, poorly regulated increase in matrix calcium contributes to the opening of an inner membrane pore, the mitochondrial permeability transition pore or mPTP. This depolarizes the inner membrane and causes osmotic shifts, contributing to outer membrane rupture, release of pro-apoptotic factors, and metabolic dysfunction. Many proteins including Bcl-xL(7) interact with F1FO ATP synthase, modulating its function. Bcl-xL interacts directly with the beta subunit of F1FO ATP synthase, and this interaction decreases a leak conductance within the F1FOATPasecomplex, increasing the net transport of H+ by F1FO during F1FO ATPase activity(8) and thereby increasing mitochondrial efficiency. To study the activity and modulation of the ATP synthase, we isolated from rodent brain submitochondrial vesicles (SMVs) containing F1FO ATPase. The SMVs retain the structural and functional integrity of the F1FO ATPase as shown in Alavian et al. Here, we describe a method that we have used successfully for the isolation of SMVs from rat brain and we delineate the patch clamp technique to analyze channel activity (ion leak conductance) of the SMVs. PMID- 23685484 TI - Soluble Tie2 fusion protein decreases peritoneal angiogenesis in uremic rats. AB - Angiogenesis is considered to be one of the most common mechanisms leading to ultrafiltration failure (UFF) in long-term peritoneal dialysis (PD) patients. The angiopoietin (Ang)/Tie system was found to play a role in the initiation of pathological neoangiogenesis and is also involved in peritoneal angiogenesis caused by peritoneal fluid. This aim of this study was to investigate the effects of the soluble Tie2 fusion protein (sTie2/Fc) on peritoneal angiogenesis in PD treated uremic rats. The rats were divided into 6 groups: normal, sham surgery, uremic rats without PD, uremic PD-treated rats, uremic rats treated with PD and sTie2/Fc (0.25 ug/100 g) and uremic rats treated with PD and sTie2/Fc (0.5 ug/100 g). PD rats were treated once a day for 28 days prior to testing. Real-time polymerase chain reaction (RT-PCR) or tissue immunohistochemical staining was used to detect Ang-2 mRNA or protein expression in the peritoneal tissues of each group. The microvessel density (MVD) of the peritoneum was detected and quantified by immunohistochemical staining using the anti-CD34 antibody. Compared with the control group, Ang-2 mRNA and protein expression was significantly upregulated in the uremic and PD groups (P<0.05). MVD in the experimental group increased compared with the control group. sTie2/Fc treatment decreased the levels of Ang-2 mRNA and protein expression (P<0.05) in a dose-dependent manner and decreased PD-induced MVD in the peritoneum. In conclusion, angiogenesis of the peritoneum induced by PD was inhibited using sTie2/Fc in a uremic rat model. PMID- 23685485 TI - Imaging in vitreoretinal diagnostics. PMID- 23685487 TI - Glue-assisted intrascleral fixation of posterior chamber intraocular lens. AB - PURPOSE: To analyze the visual outcome of patients undergoing glue-assisted intrascleral fixation of posterior chamber intraocular lens (IOL) in the absence of posterior capsular support. MATERIALS AND METHODS: This retrospective study analyzes 25 eyes which underwent IOL implantation by the glued intrascleral fixation technique. The pre and post-operative uncorrected visual acuity (UCVA), pre and post-operative best corrected visual acuity (BCVA), intraocular pressure (IOP), IOL position, anterior chamber reaction and central macular thickness were assessed and recorded. Immediate and late post-operative complications were also recorded. RESULTS: A total of 25 eyes of 22 patients were reviewed and analyzed over a period of one year. All eyes had a foldable three-piece IOL implanted. About 84% of the eyes had a gain of one or more lines, 12% had no gain, and 4% had a fall of three lines of BCVA on Snellen's visual chart, which was attributed to cystoid macular edema (CME). Postoperatively, there was a significant improvement in the UCVA (P < 0.05) and in the BCVA (P < 0.05). Postoperative complications included decentration in one case and vitritis with chronic macular edema in another case. Optical coherence tomography (OCT) demonstrated well placed IOL with no tilt. CONCLUSION: Although the results of one year follow-up of glued intrascleral fixation are promising, long term studies are recommended. PMID- 23685489 TI - Assessment of metamorphopsia in patients with central serous chorioretinopathy. AB - BACKGROUND: To evaluate the presence and extent of metamorphopsia using M-CHARTS TM (Inami Co., Tokyo, Japan) in patients with central serous chorioretinopathy (CSC). DESIGN: Retrospective consecutive medical record review in a university hospital. MATERIALS AND METHODS: We examined 33 eyes of 33 consecutive CSC patients using M-CHARTS, which yields scores reflecting the severity of metamorphopsia. The condition was considered present when an M-CHARTS score was 0.3 or over. In all patients, optical coherence tomography (OCT) was performed, best-corrected visual acuity (BCVA) was assessed, and M-CHARTS scores were calculated at the first and the 1- and 3-month follow-up visits. The correlation between M-CHARTS scores and BCVA values was determined. We also sought to define relationships between the level of metamorphopsia and specific OCT findings. RESULTS: Of 33 CSC patients, 15 showed symptoms of metamorphopsia, and all 15 had M-CHARTS scores of over 0.3. However, no correlation was evident between BCVA values and the extent of metamorphopsia as determined using M-CHARTS. In metamorphopsia patients, the incidence of focal retinal pigment epithelial detachment was notably greater than in the non-metamorphopsia group (P = 0.03). CONCLUSION: M-CHARTS is valuable for monitoring subjective symptom improvement during the clinical course of CSC. M-CHARTS serves as a useful adjunct to OCT. PMID- 23685486 TI - Indocyanine green angiography in posterior uveitis. AB - Literature review for indocyanine green angiography and evaluate the role of indocyanine green angiogram (ICGA) in patients with posterior uveitis seen at a tertiary referral eye care centre. Detailed review of the literature on ICGA was performed. Retrospective review of medical records of patients with posterior uveitis and dual fundus and ICGA was done after institutional board approval. Eighteen patients (26 eyes) had serpiginous choroiditis out of which 12 patients had active choroiditis and six patients had healed choroiditis, six patients (12 eyes) had ampiginous choroiditis, six patients (12 eyes) had acute multifocal posterior placoid pigment epitheliopathy, eight patients (10 eyes) had multifocal choroiditis, four patients (eight eyes) had presumed ocular histoplasmosis syndrome, four patients (eight eyes) had presumed tuberculous choroiditis, two patients (four eyes) had multiple evanescent white dot syndrome and two patients (four eyes) had Vogt Koyanagi Harada (VKH) syndrome. The most characteristic feature noted on ICGA was the presence of different patterns of hypofluorescent dark spots, which were present at different stages of the angiogram. ICGA provides the clinician with a powerful adjunctive tool in choroidal inflammatory disorders. It is not meant to replace already proven modalities such as the fluorescein angiography, but it can provide additional information that is useful in establishing a more definitive diagnosis in inflammatory chorioretinal diseases associated with multiple spots. It still needs to be determined if ICGA can prove to be a follow up parameter to evaluate disease progression. PMID- 23685488 TI - Spectral domain optical coherence tomography for early detection of retinal alterations in patients using hydroxychloroquine. AB - OBJECTIVE: To determine whether early toxic effects from hydroxychloroquine (HCQ) could be detected by spectral-domain optical coherence tomography (SD-OCT) before symtomatic visual loss occured. MATERIALS AND METHODS: Fifteen subjects with a history of the chronic use of hydroxychloroquine monotherapy for less than five years without fundus changes (group 1) and 15 visually normal healthy subjects (group 2) were enrolled in this study. All participants underwent systemic and ocular examination, visual field testing, and macular scan imaging using SD-OCT. RESULTS: There were no significant differences in sex and ages between the groups (P > 0.05). Mean duration of HCQ usage in group 1 was 2.5 +/- 1.34 (range:1-5) years. Visual field testing with central 10-2 threshold program was normal in all subjects. Inner retinal thickness in parafoveal and perifoveal area were found to be significantly lower in group 1 compared to group 2 (P < 0.01 for perifoveal, P < 0.05 for parafoveal retinal measurements). However, significant thinning was demonstrated only in full retinal thickness of perifoveal area in group 1 compared to group 2 (P: 0.013). Parafoveal and perifoveal inner retinal thickness measurements of inferior quadrants were significantly reduced in group 1 compared to group 2 (P < 0.01). CONCLUSION: Significant thinning of inner retinal layer especially in parafoveal and perifoveal areas in the absence of clinical fundus changes was observed in our study. We consider that SD-OCT may determine when inner retinal thinning starts in these patients and may contribute a quantitative approach to the early diagnosis and progression of retinal changes. PMID- 23685490 TI - High altitude retinopathy. AB - High altitude retinopathy is a condition often seen among mountain climbers or among persons who reach high altitudes rapidly. In this report, we describe a case of a 57 year old healthy gentleman who presented with diminution of vision in both the eyes associated with retinal hemorrhages and the spontaneous resolution of the same. PMID- 23685491 TI - A case of Churg-Strauss syndrome and central retinal artery occlusion with good visual recovery. AB - Here we report a case of Churg-Strauss syndrome (CSS) and central retinal artery occlusion (CRAO), with good visual recovery. A 58-year-old Japanese man with CSS experienced acute painless loss of vision in his right eye. CRAO was diagnosed by fundoscopic findings (retinal whitening with a cherry-red spot). Steroid pulse therapy (methylprednisolone at 1 g daily for 3 days) followed by combined treatment with prednisolone (30 mg/day) and cyclophosphamide (150 mg/day) was administered; his visual acuity recovered to 20/30 in 1 month, and no recurrence has occurred for 1 year. Steroid pulse therapy may be effective for CRAO in CSS patients. PMID- 23685492 TI - Traumatic chorioretinal folds treated with intra-vitreal triamcinolone injection. AB - A 34-year-old male visited the hospital due to decreased visual acuity in the left eye following an injury from a car accident. In the left eye, best-corrected visual acuity (BCVA) was hand motion and intraocular pressure (IOP) was 8 mmHg. Choroidal vasodilation and chorioretinal folds were observed by spectral domain optical coherence tomography (SD-OCT). Topical and systemic steroid treatments did not improve the chorioretinal folds. Twelve months after the injury, intra vitreal triamcinolone (4 mg/0.1 ml) was injected. Six months after intra-vitreal triamcinolone injection, BCVA in the left eye had improved to 20/100. Fundus examination showed improvement in retinal vascular tortuosity and SD-OCT revealed improvements in choroidal vasodilation and chorioretinal folds. Intra-vitreal triamcinolone injection (IVTI) was effective against traumatic chorioretinal folds with no recurrence based on objective observation by fundus photography and SD-OCT. PMID- 23685493 TI - Peristence of triamcinolone crystals after intra-vitreal injection: benign crystalline hyaloidopathy. AB - We report a case of unusually long persistence of triamcinolone crystals after intra-vitreal injection. Crystals were noted on fundus examination predominantly confined to the posterior pole. Optical coherence tomography localized the crystals to the posterior hyaloidal surface. Over 6 years of follow-up the patient has retained good visual acuity and no observable changes in the retina. As the condition clinically resembles both crystalline maculopathy and asteroid hyalosis, we suggest the term 'drug-induced benign crystalline hyaloidopathy'. PMID- 23685494 TI - Submacular hemorrhage from polypoidal choroidal vasculopathy after cataract surgery. PMID- 23685495 TI - Pre-operative sub-conjunctival mitomycin C 24 hours before excision of recurrent pterygium. PMID- 23685496 TI - Regarding comparison of different techniques of cataract surgery in bacterial contamination of the anterior chamber in diabetic and non-diabetic population. PMID- 23685497 TI - Assessing Framingham cardiovascular risk scores in subjects with diabetes and their correlation with diabetic retinopathy-Comment. PMID- 23685499 TI - [Congenital diseases of the pediatric foot]. PMID- 23685498 TI - [Clubfoot treatment through the ages: the Ponseti method in comparison to other conservative approaches and operative procedures]. AB - Clubfoot is one of the most common congenital deformities of the musculoskeletal system with incidence rates ranging from 0.6 to 6.8 per 1,000 live births. The treatment of clubfoot historically belongs to one of the oldest orthopedic therapies. By the end of the nineteenth century redressement with various tools, such as clamps, braces and casts was the standard treatment of clubfoot. Through further development of operational capabilities and the fact that soft tissue structures show amore resistant reaction to pressure and strain than the surrounding cartilage and bone, operative therapy was favored in the late twentieth century. Surgical correction involves the release of contracted capsular and ligamentous structures to varying degrees and the lengthening of tendons.In 1963 Ponseti published his method. He recognized that the internal rotation and plantar flexion of the calcaneus is the key deformity. However, his method first became known worldwide at the turn of the millennium as long-term results of release operations showed stiff scar healing and the risk of over correction as problems in these operations.Many comparative studies have shown the superiority of the Ponseti method regarding invasiveness, primary correction rate, functional outcome and recurrence rate in both idiopathic and non idiopathic clubfoot. In this article the current literature regarding this will be presented as well as prominent landmarks in the development of clubfoot treatment. PMID- 23685500 TI - [Vertical talus: current diagnostic and therapy options]. AB - Congenital vertical talus is a rare condition which presents as an isolated deformity or in association with neuromuscular and/or genetic disorders. Pathoanatomically the deformity shows a dislocated talonavicular and subtalar joint. The etiology and pathogenesis are still not finally determined although in some cases a genetic basis has been identified. The clinical picture is that of a flat, convex longitudinal arch with abduction and dorsiflexion of the forefoot and an elevated heel. Clinical diagnosis is confirmed by plain radiographic imaging. Congenital vertical talus should not be confused with other deformities of the foot, such as congenital oblique talus, flexible flat feet or pes calcaneus. The object of treatment of congenital vertical talus is to restore a normal anatomical relationship between the talus, navicular and calcaneus to obtain a pain-free foot. Major reconstructive surgery has been reported to be effective but is associated with substantial complications. Good early results of a modified non-operative treatment using serial manipulation, cast treatment and minimally invasive surgery may change therapeutic concepts. PMID- 23685501 TI - [Two-point discrimination for phantom pain: effect of a 4-week therapy in an upper arm amputee with phantom pain]. AB - There is evidence that phantom pain is associated with a disrupted organization of the sensory cortex and that this organization can be normalized by training with two-point discrimination (TPD). In this case study a reduction in all three phantom modalities (i.e. phantom pain, phantom feeling and painful phantom sensation) and a reduction in pain level from m= 4.13/10 visual analogue scale (VAS) to m= 0.67/10 (VAS) could be observed in a patient with an upper limb amputation during a test period of 28 days with TPD. The quality of life and performance increased significantly. This can be a promising indication for a better social and work reintegration. PMID- 23685502 TI - [Flexible flatfoot in children: variation within normal range or need for treatment?]. AB - Flexible flatfoot in childhood is a common cause for repetitive consultations and the diagnosis is verified by the clinical examination. In most cases the findings are age-dependent variants of the norm and if asymptomatic there is no need for treatment. In the first decade of life symptomatic flexible flatfoot should initially be treated with shoe inserts. Further diagnostic steps are required once conservative treatment is unsuccessful or a rigid structural deformity is found in the clinical examination. The underlying reasons may be neuropathic or structural anatomical in origin. Lateral column lengthening as described by Evans or minimally invasive arthroereisis are well established surgical options but for arthroereisis the number of long-term studies is low. In general the indications for surgical and conservative therapy have to be judged with caution although parents often see an urgent need for treatment. PMID- 23685503 TI - Prognostic value of residual fluorescent tissue in glioblastoma patients after gross total resection in 5-aminolevulinic Acid-guided surgery. AB - BACKGROUND: There is evidence in the literature supporting that fluorescent tissue signal in fluorescence-guided surgery extends farther than tissue highlighted in gadolinium in T1 sequence magnetic resonance imaging (MRI), which is the standard to quantify the extent of resection. OBJECTIVE: To study whether the presence of residual fluorescent tissue after surgery carries a different prognosis for glioblastoma (GBM) cases with complete resection confirmed by MRI. METHODS: A retrospective review in our center found 118 consecutive patients with high-grade gliomas operated on with the use of fluorescence-guided surgery with 5 aminolevulinic acid. Within that series, the 52 patients with newly diagnosed GBM and complete resection of enhancing tumor (CRET) in early MRI were selected for analysis. We studied the influence of residual fluorescence in the surgical field on overall survival and neurological complication rate. Multivariate analysis included potential relevant factors: age, Karnofsky Performance Scale, O methylguanine methyltransferase methylation promoter status, tumor eloquent location, preoperative tumor volume, and adjuvant therapy. RESULTS: The median overall survival was 27.0 months (confidence interval = 22.4-31.6) in patients with nonresidual fluorescence (n = 25) and 17.5 months (confidence interval = 12.5-22.5) for the group with residual fluorescence (n = 27) (P = .015). The influence of residual fluorescence was maintained in the multivariate analysis with all covariables, hazard ratio = 2.5 (P = .041). The neurological complication rate was 18.5% in patients with nonresidual fluorescence and 8% for the group with residual fluorescence (P = .267). CONCLUSION: GBM patients with CRET in early MRI and no fluorescent residual tissue had longer overall survival than patients with CRET and residual fluorescent tissue. PMID- 23685505 TI - Double fascicular nerve transfer for elbow flexion: is 2 better than 1? PMID- 23685504 TI - A case series of primary central nervous system posttransplantation lymphoproliferative disorder: imaging and clinical characteristics. AB - BACKGROUND: Primary central nervous system posttransplantation lymphoproliferative disorder (PCNS-PTLD) is a rare complication after solid organ transplantation (SOT). With increasing rates of SOT, PCNS-PTLD incidence is increasing. OBJECTIVE: To describe the characteristics of PCNS-PTLD patients requiring neurosurgical intervention. METHODS: From 2000 to 2011, 10 patients with prior SOT underwent biopsy for evaluation of brain lesions and were diagnosed with PCNS-PTLD. Data collected included imaging characteristics, pathology, treatments administered, and survival outcomes. RESULTS: All patients had kidney transplantation, and 3 had concurrent pancreas transplantation. Median age at diagnosis was 49 years, with a median of 4.5 years from SOT to diagnosis (range, 1.8-11.4 years). Presenting symptoms most often included focal neurological deficits (n = 6), although several patients had nonspecific symptoms of headache and altered mental status. Brain lesions were generally multiple (n = 7), supratentorial (n = 8), and lobar or periventricular in distribution with ring enhancement. Diagnosis was established by stereotactic (n = 4) and open surgical (n = 6) biopsy. Treatments most frequently administered included reduction of immunosuppression (n = 10), dexamethasone (n = 10), rituximab (n = 8), high-dose methotrexate (n = 3), and whole-brain radiotherapy (n = 6). Six patients remain alive without PCNS-PTLD relapse, including 4 patients who have sustained remissions beyond 2 years from diagnosis of PCNS-PTLD. Of 4 observed deaths, 1 was related to progressive PCNS-PTLD. CONCLUSION: PCNS-PTLD must be considered in the differential diagnosis of any patient with prior SOT presenting with an intracranial lesion. Histological diagnosis with brain biopsy is imperative, given the risk for opportunistic infections that may have similar imaging findings and presentation. Prognosis is variable, although long-term survival has been reported. PMID- 23685508 TI - Competitive kaisers: the future of american healthcare is vertically integrated accountable care organizations where patient members pay for health care instead of health insurance. PMID- 23685509 TI - Putting on the brakes: evidence for seizure inhibition and resistance in human microelectrode recordings. PMID- 23685510 TI - Blood pressure control for spontaneous intracerebral hemorrhage: does blood pressure control cause perihematoma ischemia? PMID- 23685511 TI - The intersection between genetic engineering and immunotherapy: taking a BiTE out of glioblastoma. PMID- 23685512 TI - Magnetic resonance imaging utility in following sciatica and disc herniation after treatment. PMID- 23685513 TI - Genomic analysis of non-neurofibromatosis type 2 meningiomas. PMID- 23685514 TI - Inflammation triggered by traumatic brain injury may continue to harm the brain for a lifetime. PMID- 23685515 TI - Neuroanatomy changes with repetitive mild head injury in athletes. PMID- 23685516 TI - Endovascular therapy in acute ischemic stroke. PMID- 23685517 TI - Abnormal cortical brain rhythms in Parkinson disease. PMID- 23685518 TI - The identification of a nucleus pulposus progenitor cell population: a tie to the spinal disc degenerative disease? PMID- 23685520 TI - An environmentally sensitive fluorescent purine nucleoside that changes emission wavelength upon hybridization. AB - C7-naphthylethynylated 8-aza-7-deaza-2'-deoxyguanosine (na)G was synthesized and its photophysical properties were examined. The fluorescent nucleoside exhibited solvatofluorochromic properties (Deltalambda(fl)(max) = 67 nm). An ODN probe containing (na)G forms a stable base pair only with C and discriminates structural changes such as mismatches and deletions by a distinct change in its emission wavelength. PMID- 23685523 TI - Bilateral toe necrosis resulting from norepinephrine bitartrate usage. AB - Acute limb ischemia may manifest by ischemic rest pain, ischemic ulcers, or gangrene. Acute arterial occlusion can be the result of emboli from a distant source, acute thrombosis of a previously patent artery, or direct trauma to an artery. Toe necrosis resulting from norepinephrine bitartrate (Levophed; Hospira Inc, Lake Forest, Illinois) is a rare case. PMID- 23685524 TI - Q & A: services and products that qualified healthcare professionals can provide in skilled nursing facilities. PMID- 23685526 TI - Validation of a new classification system for skin tears. AB - OBJECTIVE: The aim of this study was to validate and establish reliability of the International Skin Tear classification system. METHOD: A consensus panel of 12 internationally recognized key opinion leaders convened in 2011 to establish consensus statements on the prevention, prediction, assessment, and treatment of skin tears. Subsequently, a new skin tear classification system was proposed. The system was then tested for interrater and intrarater reliability between the experts before being tested more widely on a sample of 327 individuals from the United States, Canada, and Europe. RESULTS: The results of the study indicated a substantial level of agreement for the expert panel (Fleiss kappa = 0.619; 2 month follow-up = 0.653). Intrarater reliability was high (Cohen kappa = 0.877). Interrater reliability was moderate (Fleiss kappa = 0.555) for healthcare professionals (n = 303) and fair for non-health professionals (Fleiss kappa = 0.338; n = 24). CONCLUSIONS: This international study established the reliability and validity of a new classification system for skin tears. PMID- 23685525 TI - A comparative study of the dressings silver sulfadiazine and Aquacel Ag in the management of superficial partial-thickness burns. AB - OBJECTIVE: : The purpose of this investigation was to determine the effectiveness of silver sulfadiazine as compared with Aquacel Ag in patients with superficial partial-thickness burns. METHODS: : Twenty-four subjects who sustained superficial partial-thickness burns who were between the ages of 19 and 53 years with time of injury from 0 to 4 days were randomly assigned into a control group (silver sulfadiazine) and experimental group (Aquacel Ag; ConvaTec, Skillman, New Jersey). Wound measurements were assessed at the time of the initial examination and every 4 days afterward until the area was re-epithelialized 100%. To ensure objectivity, the burn area was measured digitally with the software program by Aspyra (Aspyra LLC; Blue Springs, Missouri) to prevent discrepancies in wound measurements. RESULTS: : Significant differences between the silver sulfadiazine and Aquacel Ag group were noted in pain (silver sulfadiazine: 4.70 +/- 2.22, Aquacel Ag: 2.92 +/- 1.12) and the number of treatments (silver sulfadiazine: 10.27 +/- 7.46, Aquacel Ag: 4.10 +/- 1.38). CONCLUSIONS: : Utilization of Aquacel Ag in superficial-partial thickness burns could lead to a decrease in the number of treatments required to re-epithelialize burns 100% with less pain as compared with silver sulfadiazine. PMID- 23685527 TI - Hepatocyte growth factor reduces hypertrophy of skin scar: in vivo study. AB - OBJECTIVE: Excessive collagen deposition causes hypertrophic scarring after dermal wound repair. It can be functionally and cosmetically debilitating to many patients. A direct approach to the control of scar tissue formation is pharmacological regulation of collagen synthesis and deposition. Some studies reported that hepatocyte growth factor (HGF) plays an important role in scar formation. Hepatocyte growth factor can improve tissue fibrosis and reverse the imbalance of collagen metabolism. However, an in vivo study has not been reported concerning the use of HGF in controlling hypertrophy of skin scar until now. METHODS: The authors tested the ability of HGF to reduce hypertrophic scar formation in a rabbit ear model. After the placement of three 5-mm dermal wounds on each ear, New Zealand white rabbits received HGF subcutaneously in the left ear at 4 time points on postwounding days 15, 30, 45, and 90. The left ear of each animal served as a control without HGF treatment. Scars were harvested at postoperative 6 months and scar hypertrophy quantified by measurement of the scar elevation index. RESULTS: The experimental data showed that treatment of scars with HGF decreased scar formation. The HGF treatment resulted in a statistically significant reduction in the scar elevation index (P < .01). CONCLUSION: The authors' results indicate the potential use of HGF to treat hypertrophic scarring, which shows important significance for antiscarring therapy. PMID- 23685529 TI - Venous etiology clinical pathways integrated with evidence-based decisions: part 3. PMID- 23685530 TI - Online social network use by health care providers in a high traffic patient care environment. AB - BACKGROUND: The majority of workers, regardless of age or occupational status, report engaging in personal Internet use in the workplace. There is little understanding of the impact that personal Internet use may have on patient care in acute clinical settings. OBJECTIVE: The objective of this study was to investigate the volume of one form of personal Internet use-online social networking (Facebook)-generated by workstations in the emergency department (ED) in contrast to measures of clinical volume and severity. METHODS: The research team analyzed anonymous network utilization records for 68 workstations located in the emergency medicine department within one academic medical center for 15 consecutive days (12/29/2009 to 1/12/2010). This data was compared to ED work index (EDWIN) data derived by the hospital information systems. RESULTS: Health care workers spent an accumulated 4349 minutes (72.5 hours) browsing Facebook, staff cumulatively visited Facebook 9369 times and spent, on average, 12.0 minutes per hour browsing Facebook. There was a statistically significant difference in the time spent on Facebook according to time of day (19.8 minutes per hour versus 4.3 minutes per hour, P<.001). There was a significant, positive correlation between EDWIN scores and time spent on Facebook (r=.266, P<.001). CONCLUSIONS: Facebook use constituted a substantive percentage of staff time during the 15-day observation period. Facebook use increased with increased patient volume and severity within the ED. PMID- 23685531 TI - Porphyrin amino acids-amide coupling, redox and photophysical properties of bis(porphyrin) amides. AB - New trans-AB2C meso-substituted porphyrin amino acid esters with meso substituents of tunable electron withdrawing power (B = mesityl, 4-C6H4F, 4 C6H4CF3, C6F5) were prepared as free amines 3a-3d, as N-acetylated derivatives Ac 3a-Ac-3d and corresponding zinc(II) complexes Zn-Ac-3a-Zn-Ac-3d. Several amide linked bis(porphyrins) with a tunable electron density at each porphyrin site were obtained from the amino porphyrin precursors by condensation reactions (4a 4d) and mono- and bis(zinc(II)) complexes Zn(2)-4d and Zn(1)Zn(2)-4d were prepared. The electronic interaction between individual porphyrin units in bis(porphyrins) 4 is probed by electrochemical experiments (CV, EPR), electronic absorption spectroscopy, steady-state and time-resolved fluorescence spectroscopy in combination with DFT/PCM calculations on diamagnetic neutral bis(porphyrins) 4 and on respective charged mixed-valent radicals 4(+/-). The interaction via the C6H4-NHCO-C6H4- bridge, the site of oxidation and reduction and the lowest excited singlet state S1, is tuned by the substituents on the individual porphyrins and the metalation state. PMID- 23685532 TI - Inverse Kinematics of Concentric Tube Steerable Needles. AB - Prior papers have introduced steerable needles composed of precurved concentric tubes. The curvature and extent of these needles can be controlled by the relative rotation and translation of the individual tubes. Under certain assumptions on the geometry and design of these needles, the forward kinematics problem can be solved in closed form by means of algebraic equations. The inverse kinematics problem, however, is not as straightforward owing to the nonlinear map between relative tube displacements and needle tip configuration as well as to the multiplicity of solutions as the number of tubes increases. This paper presents a general approach to solving the inverse kinematics problem using a pseudoinverse solution together with gradients of nullspace potential functions to enforce geometric and mechanical constraints. PMID- 23685533 TI - Non-centrosymmetric Au-SnO2 hybrid nanostructures with strong localization of plasmonic for enhanced photocatalysis application. AB - We present an innovative approach to the production of sub-100 nm hollow Au-SnO2 hybrid nanospheres, employing a low-cost, surfactant-free and environmentally friendly solution-based route. The hollow hybrid nanostructures were synthesized using a seed-mediated hydrothermal method, which can be divided into two stages: (1) formation of multicore-shell Au@SnO2 nanoparticles (NPs) and (2) thermal diffusion and ripening to form hollow Au-SnO2 hybrid NPs. The morphology, optical properties and formation mechanism were determined by a collection of joint techniques. Photocatalytic degradation of Rhodamine B (RhB) in the liquid phase served as a probe reaction to evaluate the activity of the as-prepared hollow hybrid Au-SnO2 NPs under the irradiation of both visible light and ultraviolet light. Significantly, the as-obtained Au-SnO2 hybrid nanostructures exhibited enhanced visible light or UV photocatalytic abilities, remarkably superior to commercial pure SnO2 products and P25 TiO2, mainly owing to the effective electron hole separation at the SnO2-Au interfaces and strong localization of plasmonic near-fields effects. PMID- 23685534 TI - Measurements of radon concentrations in spa waters in Amasya, Turkey. AB - Radon concentration measurements were performed in four spas used for therapy, drinking and irrigation purposes in the Amasya basin in Turkey, during a period of time between January 2009 and May 2010. The measurements were done using commercially available WG-1001 Vacuum Water Degassing System and the AB-5R Radiation Monitor manufactured by Pylon Electronics. The observed radon concentration values ranged from 0.11 to 0.71 Bq L-1. Effective doses from inhalation of radon released from spa waters have been estimated between 0.28 and 1.78 MUSv y-1 . PMID- 23685535 TI - Assessment of real exposure to GSM mobile telephones using the SYRPOM. AB - A mobile telephone user's exposure to the radio-frequency electromagnetic field depends heavily on the power their telephone radiates, which can vary widely according to requests from the base station. This study presents the design and development of a system called SYstem for Radiated POwer Measurement (SYRPOM), which measures the power radiated by a mobile telephone. This study also describes the tests carried out on the system itself and gives the results of two measuring campaigns it has been possible to perform in this way. The first such campaign consisted of assessing the mean power received by a typical mobile telephone user carrying out various activities. The second campaign was aimed at (1) comparing the mean radiated power when stationary and when moving and (2) assessing and contrasting different models of handsets in terms of the mean radiated power. The SYRPOM has proved to be a flexible, easy-to-use high performance and innovative tool for carrying out this kind of studies. PMID- 23685536 TI - Contemporary outcomes of supraventricular tachycardia ablation in congenital heart disease: a single-center experience in 116 patients. AB - BACKGROUND: Remote magnetic navigation-guided ablation with 3-dimensional (3D) image integration could provide maximum benefit in patients with complex anatomy. We reviewed supraventricular tachycardia (SVT) ablation in adult patients with congenital heart disease to assess the contribution of these technologies. METHODS AND RESULTS: One hundred fifty-four SVT ablation procedures (228 SVTs) using a 3D-electroanatomic mapping system in 116 adult patients with congenital heart disease (mean age, 41; 76 male) were classified into 3 groups: Group A, manual mapping/ablation (n=60 procedures); Group B, remote magnetic navigation guided mapping/ablation with normal femoral vein access (49); and Group C, remote magnetic navigation-guided mapping/ablation with difficult access (45). Group A included simple anomalies with less SVTs. Group B comprised predominantly Fontan patients with more SVTs. Group C included more complex defects, such as intra atrial baffle or interrupted inferior venous access, in which retrograde aortic and superior venous accesses were used exclusively with more frequent use of image integration (97.8%; P<0.001). Acute success was 91.5%, 83.7%, and 82.2%, respectively (P=0.370). In group C, fluoroscopy time was the shortest (median, 4.2 min; P<0.001) despite the longer procedure duration (median, 253 min; P<0.001). SVTs free rates were 80.4%, 82.4%, and 75.8%, respectively (P=0.787) during a mean 20-months follow-up period. CONCLUSIONS: The combination of remote magnetic navigation, 3D-image integration, and electroanatomic mapping system facilitated safe and feasible ablation with very low fluoroscopy exposure even in patients with complex anomalies. PMID- 23685537 TI - Three-dimensional architecture of scar and conducting channels based on high resolution ce-CMR: insights for ventricular tachycardia ablation. AB - BACKGROUND: Conducting channels are the target for ventricular tachycardia (VT) ablation. Conducting channels could be identified with contrast enhanced-cardiac magnetic resonance (ce-CMR) as border zone (BZ) corridors. A 3-dimensional (3D) reconstruction of the ce-CMR could allow visualization of the 3D structure of these BZ channels. METHODS AND RESULTS: We included 21 patients with healed myocardial infarction and VT. A 3D high-resolution 3T ce-CMR was performed before CARTO-guided VT ablation. The left ventricular wall was segmented and characterized using a pixel signal intensity algorithm at 5 layers (endocardium, 25%, 50%, 75%, epicardium). A 3D color-coded shell map was obtained for each layer to depict the scar core and BZ distribution. The presence/characteristics of BZ channels were registered for each layer. Scar area decreased progressively from endocardium to epicardium (scar area/left ventricular area: 34.0+/-17.4% at endocardium, 24.1+/-14.7% at 25%, 16.3+/-12.1% at 50%, 13.1+/-10.4 at 75%, 12.1+/ 9.3% at epicardium; P<0.01). Forty-five BZ channels (2.1+/-1.0 per patient, 23.7+/-12.0 mm length, mean minimum width 2.5+/-1.5 mm) were identified, 85% between the endocardium and 50% shell and 76% present in >=1 layer. The ce-CMR defined BZ channels identified 74% of the critical isthmus of clinical VTs and 50% of all the conducting channels identified in electroanatomic maps. CONCLUSIONS: Scar area in patients with healed myocardial infarction decreases from the endocardium to the epicardium. BZ channels, more commonly seen in the endocardium, display a 3D structure within the myocardial wall that can be depicted with ce-CMR. The use of ce-CMR-derived maps to guide VT ablation warrants further investigation. PMID- 23685538 TI - Impact of international normalized ratio and activated clotting time on unfractionated heparin dosing during ablation of atrial fibrillation. AB - BACKGROUND: For ablation of atrial fibrillation, it is unclear how baseline international normalized ratio (INR) affects the dosing of unfractionated heparin (UFH). METHODS AND RESULTS: A retrospective review of 170 consecutive patients undergoing atrial fibrillation ablation with baseline activated clotting time (ACT) and INR values was performed. Patients were grouped according to INR <2.0 (G<2; n=129) and INR >=2.0 (G>=2; n=41). Clinical variables, UFH doses, and ACT values were recorded. An equation was derived to calculate the first bolus of UFH required to achieve an ACT >=300 seconds, and this was subsequently assessed in 168 patients. For the initial 170 patients, the baseline INR (2.47+/-0.31 versus 1.53+/-0.31) and ACT (185+/-26 versus 153+/-30 seconds) were significantly greater in G>=2 (P<0.001). The amount of UFH to achieve the first ACT >=300 seconds was significantly higher for G<2 versus G>=2 (9701+/-2390 versus 8268+/ 2366 U; P=0.0001). Baseline INR, ACT, and weight were predictors of the UFH dosage to achieve an ACT >=300 seconds. An equation derived to achieve an ACT >=300 seconds after a single bolus of UFH met this end point in 160 of 168 patients (95%). CONCLUSIONS: Baseline INR and ACT, in addition to weight, are the only predictors of UFH dosage needed to achieve an ACT >=300 seconds. A derived equation predicted the UFH dosage to achieve an ACT >=300 seconds. PMID- 23685539 TI - Dynamic analysis of cardiac rhythms for discriminating atrial fibrillation from lethal ventricular arrhythmias. AB - BACKGROUND: Implantable cardioverter-defibrillators (ICDs), the first line of therapy for preventing sudden cardiac death in high-risk patients, deliver appropriate shocks for termination of ventricular tachycardia (VT)/ventricular fibrillation. A common shortcoming of ICDs is imperfect rhythm discrimination, resulting in the delivery of inappropriate shocks for atrial fibrillation (AF). An underexplored area for rhythm discrimination is the difference in dynamic properties between AF and VT/ventricular fibrillation. We hypothesized that the higher entropy of rapid cardiac rhythms preceding ICD shocks distinguishes AF from VT/ventricular fibrillation. METHODS AND RESULTS: In a multicenter, prospective, observational study of patients with primary prevention ICDs, 119 patients received shocks from ICDs with stored, retrievable intracardiac electrograms. Blinded adjudication revealed shocks were delivered for VT/ventricular fibrillation (62%), AF (23%), and supraventricular tachycardia (15%). Entropy estimation of only 9 ventricular intervals before ICD shocks accurately distinguished AF (receiver operating characteristic curve area, 0.98; 95% confidence intervals, 0.93-1.0) and outperformed contemporary ICD rhythm discrimination algorithms. CONCLUSIONS: This new strategy for AF discrimination based on entropy estimation expands on simpler concepts of variability, performs well at fast heart rates, and has potential for broad clinical application. PMID- 23685540 TI - Clinical impact of adenosine triphosphate injection on arrhythmogenic superior vena cava in the context of atrial fibrillation ablation. AB - BACKGROUND: Superior vena cava (SVC) is an infrequent yet an important source of atrial fibrillation. The clinical impact of ATP injection on arrhythmogenic SVC has not been evaluated. METHODS AND RESULTS: A total of 43 patients (59+/-11 years; men, 32) who underwent ATP test for arrhythmogenic SVC after the electric isolation at either initial procedure or repeat procedure were included. Pulmonary vein antrum isolation was performed at index procedure in all patients. SVC was isolated after identifying the arrhythmogenicity at index and repeat atrial fibrillation ablation procedure in 34 (79.1%) and 9 (20.9%) patients, respectively. Atrial fibrillation originated from the SVC spontaneously and under isoproterenol infusion in 30 (75.0%) patients, and immediately after ATP injection in 10 (25.0%) patients. Tachycardia persistently confined to SVC was recorded after electric isolation in 13 (30.2%) patients. SVC reconnection was provoked by ATP test in 7 of 36 (19.4%) patients at acute phase. At median 4.0 (2.25-7.5) months after SVC isolation, reconnection was observed in 12 of 15 (80.0%) patients at repeat procedure. Among 12 patients with reconnection at baseline, SVC reconnection was provoked by ATP test after reisolation in 1 (8.3%) patient. Among 3 patients without SVC reconnection at baseline, reconnection was provoked by ATP test at chronic phase in 1 patient. CONCLUSIONS: Dormant conduction between an arrhythmogenic SVC and the right atrium can be exposed by ATP administration both immediately and late after isolation, potentially facilitating detection and ablation for isolation. PMID- 23685541 TI - Extensive chromosomal reshuffling drives evolution of virulence in an asexual pathogen. AB - Sexual recombination drives genetic diversity in eukaryotic genomes and fosters adaptation to novel environmental challenges. Although strictly asexual microorganisms are often considered as evolutionary dead ends, they comprise many devastating plant pathogens. Presently, it remains unknown how such asexual pathogens generate the genetic variation that is required for quick adaptation and evolution in the arms race with their hosts. Here, we show that extensive chromosomal rearrangements in the strictly asexual plant pathogenic fungus Verticillium dahliae establish highly dynamic lineage-specific (LS) genomic regions that act as a source for genetic variation to mediate aggressiveness. We show that such LS regions are greatly enriched for in planta-expressed effector genes encoding secreted proteins that enable host colonization. The LS regions occur at the flanks of chromosomal breakpoints and are enriched for retrotransposons and other repetitive sequence elements. Our results suggest that asexual pathogens may evolve by prompting chromosomal rearrangements, enabling rapid development of novel effector genes. Likely, chromosomal reshuffling can act as a general mechanism for adaptation in asexually propagating organisms. PMID- 23685542 TI - Deletions of recessive disease genes: CNV contribution to carrier states and disease-causing alleles. AB - Over 1200 recessive disease genes have been described in humans. The prevalence, allelic architecture, and per-genome load of pathogenic alleles in these genes remain to be fully elucidated, as does the contribution of DNA copy-number variants (CNVs) to carrier status and recessive disease. We mined CNV data from 21,470 individuals obtained by array-comparative genomic hybridization in a clinical diagnostic setting to identify deletions encompassing or disrupting recessive disease genes. We identified 3212 heterozygous potential carrier deletions affecting 419 unique recessive disease genes. Deletion frequency of these genes ranged from one occurrence to 1.5%. When compared with recessive disease genes never deleted in our cohort, the 419 recessive disease genes affected by at least one carrier deletion were longer and located farther from known dominant disease genes, suggesting that the formation and/or prevalence of carrier CNVs may be affected by both local and adjacent genomic features and by selection. Some subjects had multiple carrier CNVs (307 subjects) and/or carrier deletions encompassing more than one recessive disease gene (206 deletions). Heterozygous deletions spanning multiple recessive disease genes may confer carrier status for multiple single-gene disorders, for complex syndromes resulting from the combination of two or more recessive conditions, or may potentially cause clinical phenotypes due to a multiply heterozygous state. In addition to carrier mutations, we identified homozygous and hemizygous deletions potentially causative for recessive disease. We provide further evidence that CNVs contribute to the allelic architecture of both carrier and recessive disease causing mutations. Thus, a complete recessive carrier screening method or diagnostic test should detect CNV alleles. PMID- 23685543 TI - Severe neuronopathic autosomal recessive osteopetrosis due to homozygous deletions affecting OSTM1. AB - Autosomal recessive osteopetrosis (ARO, MIM 259700) is a genetically heterogeneous rare skeletal disorder characterized by failure of osteoclast resorption leading to pathologically increased bone density, bone marrow failure, and fractures. In the neuronopathic form neurological complications are especially severe and progressive. An early identification of the underlying genetic defect is imperative for assessment of prognosis and treatment by hematopoietic stem cell transplantation. Here we describe for the first time homozygous microdeletions of different sizes affecting the OSTM1 gene in two unrelated consanguineous families with children suffering from neuronopathic infantile malignant osteopetrosis. Patients showed an exceptionally severe phenotype with variable CNS malformations, seizures, blindness, and deafness. Multi-organ failure due to sepsis led to early death between six weeks and five months of age in spite of intensive care treatment. Analysis of the breakpoints revealed different mechanisms underlying both rearrangements. Microdeletions seem to represent a considerable portion of OSTM1 mutations and should therefore be included in a sufficient diagnostic screening. PMID- 23685544 TI - Prolonged hypocalcemia following denosumab therapy in metastatic hormone refractory prostate cancer. AB - Prostate cancer is a leading cause of cancer death, frequently associated with widespread bone metastases. We report two cases of hypocalcemia following the first dose of denosumab in metastatic hormone refractory prostate cancer, the first case requiring 26 days of intravenous calcium therapy. This is the first report of prolonged hypocalcemia following denosumab in a patient with normal renal function. PMID- 23685545 TI - In vivo pharmacological characterization of TD-4208, a novel lung-selective inhaled muscarinic antagonist with sustained bronchoprotective effect in experimental animal models. AB - Tiotropium is currently the only once-daily, long-acting muscarinic antagonist (LAMA) approved in the United States and other countries for the treatment of chronic obstructive pulmonary disease (COPD). Glycopyrronium has shown promise as a LAMA and was recently approved for once-daily maintenance treatment of COPD in the European Union. Here, we describe the in vivo preclinical efficacy and lung selectivity of a novel inhaled muscarinic antagonist, TD-4208 (biphenyl-2 ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1 ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester) and compare its profile to tiotropium and glycopyrronium. In anesthetized dogs, TD-4208, along with tiotropium and glycopyrronium, produced sustained inhibition of acetylcholine induced bronchoconstriction for up to 24 hours. In anesthetized rats, inhaled TD 4208 exhibited dose-dependent 24-hour bronchoprotection against methacholine induced bronchoconstriction. The estimated 24-hour potency (expressed as concentration of dosing solution) was 45.0 ug/ml. The bronchoprotective potencies of TD-4208 and tiotropium were maintained after 7 days of once-daily dosing, whereas glycopyrronium showed a 6-fold loss in potency after repeat dosing. To assess systemic functional activity using a clinically relevant readout, the antisialagogue effect of compounds was also evaluated. The calculated lung selectivity index (i.e., ratio of antisialagogue and bronchoprotective potency) of TD-4208 was superior to glycopyrronium after both single and repeat dosing regimens and was superior to tiotropium after repeat dosing. In conclusion, the in vivo preclinical profile suggests that TD-4208 has the potential to be a long acting bronchodilator for once-daily treatment of respiratory diseases. Its greater functional selectivity for the lung in preclinical models may translate to an improved tolerability profile compared with marketed muscarinic receptor antagonists. PMID- 23685546 TI - Monoamine transporter occupancy of a novel triple reuptake inhibitor in baboons and humans using positron emission tomography. AB - The selection of a therapeutically meaningful dose of a novel pharmaceutical is a crucial step in drug development. Positron emission tomography (PET) allows the in vivo estimation of the relationship between the plasma concentration of a drug and its target occupancy, optimizing dose selection and reducing the time and cost of early development. Triple reuptake inhibitors (TRIs), also referred to as serotonin-norepinephrine-dopamine reuptake inhibitors, enhance monoaminergic neurotransmission by blocking the action of the monoamine transporters, raising extracellular concentrations of those neurotransmitters. GSK1360707 [(1R,6S)-1 (3,4-dichlorophenyl)-6-(methoxymethyl)-4-azabicyclo[4.1.0]heptane] is a novel TRI that until recently was under development for the treatment of major depressive disorder; its development was put on hold for strategic reasons. We present the results of an in vivo assessment of the relationship between plasma exposure and transporter blockade (occupancy). Studies were performed in baboons (Papio anubis) to determine the relationship between plasma concentration and occupancy of brain serotonin reuptake transporter (SERT), dopamine reuptake transporter (DAT), and norepinephrine uptake transporter (NET) using the radioligands [(11)C]DASB [(N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine], [(11)C]PE2I [N-(3-iodoprop-2E-enyl)-2beta-carbomethoxy-3beta-(4 methylphenyl)nortropane], and [(11)C]2-[(2-methoxyphenoxy)phenylmethyl]morpholine (also known as [(11)C]MRB) and in humans using [(11)C]DASB and [(11)C]PE2I. In P. anubis, plasma concentrations resulting in half-maximal occupancy at SERT, DAT, and NET were 15.16, 15.56, and 0.97 ng/ml, respectively. In humans, the corresponding values for SERT and DAT were 6.80 and 18.00 ng/ml. GSK1360707 dose dependently blocked the signal of SERT-, DAT-, and NET-selective PET ligands, confirming its penetration across the blood-brain barrier and blockade of all three monoamine transporters in vivo. PMID- 23685547 TI - Response of neurotensin basal ganglia systems during extinction of methamphetamine self-administration in rat. AB - Because of persistent social problems caused by methamphetamine (METH), new therapeutic strategies need to be developed. Thus, we investigated the response of central nervous system neurotensin (NT) systems to METH self-administration (SA) and their interaction with basal ganglia dopamine (DA) pathways. Neurotensin is a peptide associated with inhibitory feedback pathways to nigrostriatal DA projections. We observed that NT levels decreased in rats during extinction of METH SA when lever pressing resulted in intravenous infusions of saline rather than METH. Thus, 6 h after the first session of extinction, NT levels were 53, 42, and 49% of corresponding controls in the anterior dorsal striatum, posterior dorsal striatum, and globus pallidus, respectively. NT levels were also significantly reduced in corresponding yoked rats in the anterior dorsal striatum (64% of control), but not the other structures examined. The reductions in NT levels in the anterior dorsal striatum particularly correlated with the lever pressing during the first session of extinction (r =s; 0.745). These, and previously reported findings, suggest that the extinction-related reductions in NT levels were mediated by activation of D2 receptors. Finally, administration of the neurotensin receptor 1 (NTR1) agonist [PD149163 [Lys(CH2NH)Lys-Pro,Trp-tert Leu-Leu-Oet]; 0.25 or 0.5 mg/kg] diminished lever pressing during the first extinction session, whereas the NTR1 antagonist [SR48692 [2-[(1-(7-chloro-4 quinolinyl)-5-(2,6-imethoxyphenyl)pyrazol-3 yl)carbonylamino]tricyclo(3.3.1.1.(3.7))decan-2-carboxylic acid]; 0.3 mg/kg per administration] attenuated the reduction of lever pressing during the second to fourth days of extinction. In summary, these findings support the hypothesis that some of the endogenous basal ganglia NT systems contribute to the elimination of contingent behavior during the early stages of the METH SA extinction process. PMID- 23685548 TI - Compound heterozygous mutations of TYMP as underlying causes of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). AB - Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), an autosomal recessive multiorgan disease, frequently associated with mutations in the thymidine phosphorylase (TYMP) gene. TYMP encodes thymidine phosphorylase (TP), which has an essential role in the nucleotide salvage pathway for mitochondrial DNA (mtDNA) replication. This study reports an MNGIE patient with novel compound heterozygous missense mutations (Thr151Pro and Leu270Pro) in TYMP. Each mutation was inherited from one parent. Neither mutation was found in the controls and the mutation sites were well conserved between different species. Neither large deletion nor causative point mutations were found in the mtDNA. The patient presented with MNGIE symptoms, including gastrointestinal discomfort, external ophthalmoplegia, pigmentary retinopathy and demyelinating type diffuse sensory motor polyneuropathy. The patient demonstrated an early-onset but mild phenotype, with 9.6% TP activity; therefore, patients with these compound heterozygous mutations may exhibit a mild phenotype with a variable onset age according to TP activity level. PMID- 23685550 TI - Characterization of cell growth and starch production in the marine green microalga Tetraselmis subcordiformis under extracellular phosphorus-deprived and sequentially phosphorus-replete conditions. AB - Microalgal starch is a potential feedstock for biofuel production. Nutrient stress is widely used to stimulate starch accumulation in microalgae. Cell growth and starch accumulation in the marine green microalga Tetraselmis subcordiformis were evaluated under extracellular phosphorus deprivation with initial cell densities (ICD) of 1.5, 3.0, 6.0, and 9.0*106 cells mL-1. The intracellular stored phosphorus supported cell growth when extracellular phosphorus was absent. The maximum starch content of 44.1% was achieved in the lowest ICD culture, while the maximum biomass productivity of 0.71 g L-1 day-1, starch concentration of 1.6 g L-1, and starch productivity of 0.30 g L-1 day-1 were all obtained in the culture with the ICD of 3.0*106 cells mL-1. Appropriate ICD could be used to regulate the intracellular phosphorus concentration and maintain adequate photosynthetic activity to achieve the highest starch productivity, along with biomass and starch concentration. The recovery of phosphorus-deprived T. subcordiformis in medium containing 0.5, 1.0, or 6.0 mM KH2PO4 was also tested. Cell growth and starch accumulation ability could be recovered completely. A phosphorus pool in T. subcordiformis was shown to manipulate its metabolic activity under different environmental phosphorus availability. Though lower starch productivity and starch content were achieved under phosphorus deprivation compared with nitrogen- or sulfur-deprived conditions, the higher biomass and starch concentration make T. subcordiformis a good candidate for biomass and starch production under extracellular phosphorus deprivation. PMID- 23685551 TI - Controlled cervical laceration injury in mice. AB - Use of genetically modified mice enhances our understanding of molecular mechanisms underlying several neurological disorders such as a spinal cord injury (SCI). Freehand manual control used to produce a laceration model of SCI creates inconsistent injuries often associated with a crush or contusion component and, therefore, a novel technique was developed. Our model of cervical laceration SCI has resolved inherent difficulties with the freehand method by incorporating 1) cervical vertebral stabilization by vertebral facet fixation, 2) enhanced spinal cord exposure, and 3) creation of a reproducible laceration of the spinal cord using an oscillating blade with an accuracy of +/- 0.01 mm in depth without associated contusion. Compared to the standard methods of creating a SCI laceration such as freehand use of a scalpel or scissors, our method has produced a consistent lesion. This method is useful for studies on axonal regeneration of corticospinal, rubrospinal, and dorsal ascending tracts. PMID- 23685552 TI - Two isoforms of Sister-Of-Mammalian Grainyhead have opposing functions in endothelial cells and in vivo. AB - OBJECTIVE: Sister-of-Mammalian Grainyhead (SOM) is a member of the Grainyhead family of transcription factors. In humans, 3 isoforms are derived from differential first exon usage and alternative splicing and differ only in their N terminal domain. SOM2, the only variant also present in mouse, induces endothelial cell migration and protects against apoptosis. The functions of the human specific isoforms SOM1 and SOM3 have not yet been investigated. Therefore we wanted to elucidate their functions in endothelial cells. APPROACH AND RESULTS: Overexpression of SOM1 in primary human endothelial cells induced migration, phosphorylation of Akt1 and endothelial nitric oxide synthase, and protected against apoptosis, whereas SOM3 had opposite effects; isoform-specific knockdowns confirmed the disparate effects on apoptosis. After reporter assays demonstrated that both are active transcription factors, microarray analyses revealed that they induce different target genes, which could explain the different cellular effects. Overexpression of SOM3 in zebrafish embryos resulted in increased lethality and severe deformations, whereas SOM1 had no deleterious effect. CONCLUSIONS: Our data demonstrate that the splice variant-derived isoforms SOM1 and SOM3 induce opposing effects in primary human endothelial cells and in a whole animal model, most likely through the induction of different target genes. PMID- 23685553 TI - Multilocus genetic risk scores for coronary heart disease prediction. AB - OBJECTIVE: Current guidelines do not support the use of genetic profiles in risk assessment of coronary heart disease (CHD). However, new single nucleotide polymorphisms associated with CHD and intermediate cardiovascular traits have recently been discovered. We aimed to compare several multilocus genetic risk score (MGRS) in terms of association with CHD and to evaluate clinical use. APPROACH AND RESULTS: We investigated 6 Swedish prospective cohort studies with 10 612 participants free of CHD at baseline. We developed 1 overall MGRS based on 395 single nucleotide polymorphisms reported as being associated with cardiovascular traits, 1 CHD-specific MGRS, including 46 single nucleotide polymorphisms, and 6 trait-specific MGRS for each established CHD risk factors. Both the overall and the CHD-specific MGRS were significantly associated with CHD risk (781 incident events; hazard ratios for fourth versus first quartile, 1.54 and 1.52; P<0.001) and improved risk classification beyond established risk factors (net reclassification improvement, 4.2% and 4.9%; P=0.006 and 0.017). Discrimination improvement was modest (C-index improvement, 0.004). A polygene MGRS performed worse than the CHD-specific MGRS. We estimate that 1 additional CHD event for every 318 people screened at intermediate risk could be saved by measuring the CHD-specific genetic score in addition to the established risk factors. CONCLUSIONS: Our results indicate that genetic information could be of some clinical value for prediction of CHD, although further studies are needed to address aspects, such as feasibility, ethics, and cost efficiency of genetic profiling in the primary prevention setting. PMID- 23685556 TI - Mechanisms of coronary thrombosis in cigarette smoke exposure. AB - Acute rupture or erosion of a coronary atheromatous plaque and subsequent coronary artery thrombosis cause the majority of sudden cardiac deaths and myocardial infarctions. Cigarette smoking is a major risk factor for acute coronary thrombosis. Indeed, a majority of sudden cardiac deaths attributable to acute thrombosis are in cigarette smokers. Both active and passive cigarette smoke exposure seem to increase the risk of coronary thrombosis and myocardial infarctions. Cigarette smoke exposure seems to alter the hemostatic process via multiple mechanisms, which include alteration of the function of endothelial cells, platelets, fibrinogen, and coagulation factors. This creates an imbalance of antithrombotic/prothrombotic factors and profibrinolytic/antifibrinolytic factors that support the initiation and propagation of thrombosis. PMID- 23685554 TI - Interleukin-6-signal transducer and activator of transcription-3 signaling mediates aortic dissections induced by angiotensin II via the T-helper lymphocyte 17-interleukin 17 axis in C57BL/6 mice. AB - OBJECTIVE: Dysregulated angiotensin II (Ang II) signaling induces local vascular interleukin-6 (IL-6) secretion, producing leukocyte infiltration and life threatening aortic dissections. Precise mechanisms by which IL-6 signaling induces leukocyte recruitment remain unknown. T-helper 17 lymphocytes (Th17) have been implicated in vascular pathology, but their role in the development of aortic dissections is poorly understood. Here, we tested the relationship of IL-6 signal transducer and activator of transcription-3 signaling with Th17-induced inflammation in the formation of Ang II-induced dissections in C57BL/6 mice. APPROACH AND RESULTS: Ang II infusion induced aortic dissections and CD4(+) interleukin 17A (IL-17A)-expressing Th17 cell accumulation in C57BL/6 mice. A blunted local Th17 activation, macrophage recruitment, and reduced incidence of aortic dissections were seen in IL-6(-/-) mice. To determine the pathological roles of Th17 lymphocytes, we treated Ang II-infused mice with IL-17A neutralizing antibody or infused Ang II in genetically deficient IL-17A mice and found decreased aortic chemokine monocytic chemotactic protein-1 production and macrophage recruitment, leading to a reduction in aortic dissections. This effect was independent of blood pressure in IL-17A-neutralizing antibody experiment. Application of a cell-permeable signal transducer and activator of transcription 3 inhibitor to downregulate the IL-6 pathway decreased aortic dilation and Th17 cell recruitment. We also observed increased aortic Th17 infiltration and IL-17 mRNA expression in patients with thoracic aortic dissections. Finally, we found that Ang II-mediated aortic dissections occurred independent of blood pressure changes. CONCLUSIONS: Our results indicate that the IL-6-signal transducer and activator of transcription-3 signaling pathway converges on Th17 recruitment and IL-17A signaling upstream of macrophage recruitment, mediating aortic dissections. PMID- 23685555 TI - Dkk1 and MSX2-Wnt7b signaling reciprocally regulate the endothelial-mesenchymal transition in aortic endothelial cells. AB - OBJECTIVE: Endothelial cells (ECs) can undergo an endothelial-mesenchymal transition with tissue fibrosis. Wnt- and Msx2-regulated signals participate in arteriosclerotic fibrosis and calcification. We studied the impact of Wnt7, Msx2, and Dkk1, a Wnt7 antagonist, on endothelial-mesenchymal transition in primary aortic ECs. APPROACH AND RESULTS: Transduction of aortic ECs with vectors expressing Dkk1 suppressed EC differentiation and induced a mineralizing myofibroblast phenotype. Dkk1 suppressed claudin 5, PECAM, cadherin 5 (Cdh5), Tie1, and Tie2. Dkk1 converted the cuboidal cell monolayer into a spindle-shaped multilayer and inhibited EC cord formation. Myofibroblast and osteogenic markers, SM22, type I collagen, Osx, Runx2, and alkaline phosphatase, were upregulated by Dkk1 via activin-like kinase/Smad pathways. Dkk1 increased fibrotic mineralization of aortic ECs cultured under osteogenic conditions--the opposite of mesenchymal cell responses. Msx2 and Wnt7b maintained morphology and upregulated markers of differentiated ECs. Deleting EC Wnt7b with the Cdh5-Cre transgene in Wnt7b(fl/fl);LDLR(-/-) mice upregulated aortic osteogenic genes (Osx, Sox9, Runx2, and Msx2) and nuclear phospho-Smad1/5, and increased collagen and calcium accumulation. CONCLUSIONS: Dkk1 enhances endothelial-mesenchymal transition in aortic ECs, whereas Wnt7b and Msx2 signals preserve EC phenotype. EC responses to Dkk1, Wnt7b, and Msx2 are the opposite of mesenchymal responses, coupling EC phenotypic stability with osteofibrogenic predilection during arteriosclerosis. PMID- 23685558 TI - Hepatic steatosis is associated with aortic valve sclerosis in the general population: the Study of Health in Pomerania (SHIP). AB - OBJECTIVE: We aimed to analyze the association between hepatic steatosis and aortic valve sclerosis in the general population. APPROACH AND RESULTS: Cross sectional data of 2212 men and women, aged 45 to 81 years, from the baseline examination of the population-based Study of Health in Pomerania (SHIP-0) were analyzed. Hepatic steatosis was primarily defined as the presence of a hyperechogenic ultrasound pattern of the liver. Aortic valve sclerosis was determined by echocardiography. In our sample, hepatic steatosis was present in 877 (39.7%) individuals. Among participants with hepatic steatosis, aortic valve sclerosis was more common (n=323; 36.8%) compared with participants without hepatic steatosis (n=379; 28.4%; P<0.001). After adjustment for potential confounders, individuals with hepatic steatosis had 33% higher odds of aortic valve sclerosis compared with those without hepatic steatosis (95% confidence interval, 6%-66%; P=0.014). Additional adjustment for high-sensitive C-reactive protein, serum ferritin levels, and white blood cells slightly reduced the association to 32% (95% confidence interval, 4%-66%; P=0.021). CONCLUSIONS: Our findings add evidence that hepatic steatosis and aortic valve sclerosis are interrelated after adjustment for major confounders. The release of proatherogenic substances by the steatotic liver or its contribution to insulin resistance and dyslipidemia may contribute to the development of calcification and sclerosis of the aortic valve. PMID- 23685557 TI - Understanding the effects of tobacco smoke on the pathogenesis of aortic aneurysm. AB - Aneurysmal arterial disease is a vascular degenerative condition that is distinct from atherosclerotic and other occlusive arterial diseases. There is regionalization of the predisposition to aneurysm formation within the vascular tree, and the pathological process varies with location. Infrarenal abdominal aortic aneurysm (AAA) is the most common manifestation of aneurysmal disease, and smoking is the dominant risk factor. Smoking is a much greater risk factor for AAA than for atherosclerosis. In addition to playing a role in the pathogenesis of AAA, smoking also increases the rate of expansion and risk of rupture of established AAA. The mechanistic relationship between AAA and smoking is being established by the use of enhanced animal models that are dependent on smoke or smoke components. The mechanisms seem to involve durable alterations in vascular smooth muscle cell and inflammatory cell function. This review examines the clinical, epidemiological, and mechanistic evidence implicating smoking as a cause of aneurysms, focusing on AAA. PMID- 23685559 TI - Bone marrow-derived Kruppel-like factor 10 controls reendothelialization in response to arterial injury. AB - OBJECTIVE: The objective of this study was to investigate the role of Kruppel like factor (KLF) 10, a zinc-finger transcription factor, in bone marrow (BM) derived cell responses to arterial endothelial injury. Accumulating evidence indicates that BM-derived progenitors are recruited to sites of vascular injury and contribute to endothelial repair. APPROACH AND RESULTS: In response to carotid artery endothelial denudation, KLF10 mRNA expression was markedly increased in both BM and circulating lin(-) progenitor cells. To examine the specific role of KLF10 in arterial reendothelialization, we used 2 models of endothelial denudation (wire- and thermal-induced injury) of the carotid artery in wild-type (WT) and KLF10(-/-) mice. WT mice displayed higher areas of reendothelialization compared with KLF10(-/-) mice after endothelial injury using either method. BM transplant studies revealed that reconstitution of KLF10(-/-) mice with WT BM fully rescued the defect in reendothelialization and increased lin(-)CD34(+)kinase insert domain receptor(+) progenitors in the blood and injured carotid arteries. Conversely, reconstitution of WT mice with KLF10(-/-) BM recapitulated the defects in reendothelialization and peripheral cell progenitors. The media from cultured KLF10(-)/(-) BM progenitors was markedly inefficient in promoting endothelial cell growth and migration compared with the media from WT progenitors, indicative of defective paracrine trophic effects from KLF10(-)/(-) BM progenitors. Finally, BM-derived KLF10(-/-) lin(-) progenitors from reconstituted mice had reduced CXC-chemokine receptor 4 expression and impaired migratory responses. CONCLUSIONS: Collectively, these observations demonstrate a protective role for BM-derived KLF10 in paracrine and homing responses important for arterial endothelial injury and highlight KLF10 as a possible therapeutic target to promote endothelial repair in vascular disease states. PMID- 23685560 TI - Evidence of a polygenic origin of extreme high-density lipoprotein cholesterol levels. AB - OBJECTIVE: There are several known monogenic causes of high and low high-density lipoprotein cholesterol (HDL-C) levels, but traditional sequencing studies have had limited success in identifying mutations in the majority of individuals with extreme HDL-C levels. The aim of this study was to assess the power of a targeted high-throughput sequencing strategy to elucidate the genetic basis of extreme HDL C phenotypes. APPROACH AND RESULTS: We sequenced 195 genes with either established or implicated roles in lipid and lipoprotein metabolism plus 78 lipid unrelated genes in patients with HDL-C <1st (n=40) or >99th (n=40) percentile values, and the results were compared with those of 498 individuals representative of the Dutch general population and 95 subjects with normal HDL-C (between 40th and 60th percentile values). The extreme HDL cohort carried more rare nonsynonymous variants in the lipid geneset than both the general population (odds ratio, 1.39; P=0.019) and normal HDL-C (odds ratio, 1.43; P=0.040) cohorts. The prevalence of such variants in the lipid-related and lipid-unrelated genesets was similar in the control groups, indicative of equal mutation rates. In the extreme HDL cohort, however, there was enrichment of rare nonsynonymous variants in the lipid versus the control geneset (odds ratio, 2.23; P<0.0001), and 70% of the lipid-related variants altered conserved nucleotides. The lipid geneset comprised 4 nonsense, 10 splice-site, and 8 coding indel variants, whereas the control geneset contained only 1 such variant. In the lipid geneset, 87% and 28% of the patients carried >= 2 and >= 5 rare variants. CONCLUSIONS: This study suggests that most extreme HDL-C phenotypes have a polygenic origin. PMID- 23685561 TI - Dendrimer-encapsulated copper as a novel oligonucleotides label for sensitive electrochemical stripping detection of DNA hybridization. AB - This paper describes the synthesis and characterization of a novel electrochemical label for sensitive electrochemical stripping detection of DNA hybridization based on dendrimer-encapsulated copper. The generation 4.5 (G 4.5) carboxyl-terminated poly(amidoamine) dendrimer with a trimesyl core was used as a template for synthesis of Cu2+/dendrimer nanocomposites (Cu-DNCs). Ratios of Cu2+/dendrimer were optimized in order to obtain stable nanocomposites with maximal copper loading in the interior of a polymeric shell. Cu-DNCs labeled DNA probe was employed for determining a target ssDNA immobilized on multi-walled carbon nanotubes-modified glassy carbon electrode (GCE) based on a specific hybridization reaction. The hybridization events were monitored by electrochemical detection of Cu anchored on the hybrids after the release in a diluted nitric acid by anodic stripping differential pulse voltammetry (ASDPV). The results showed that only a complementary sequence could form a dsDNA with the Cu-DNCs DNA probe and give an obvious electrochemical signal. The non complementary sequence exhibited negligible signal change compared with the blank measurement (means: the electrode containing no target DNA incubating in hybridization buffer solution containing Cu-DNCs DNA probe for a certain time). The use of Cu encapsulated-dendrimer as tags and ASDPV for the detection of the released Cu ions could enhance the hybridization signal, and result in the increase of the sensitivity for the target DNA. Under the conditions employed here, the detection limit for measuring the full complementary sequence is down to pM level. PMID- 23685562 TI - Selective room temperature phosphorescence sensing of target protein using Mn doped ZnS QDs-embedded molecularly imprinted polymer. AB - The direct correlation between disease states and protein levels makes the sensitive, convenient, and precise detection of proteins the focus of scientific research. This paper demonstrates a new strategy for producing phosphorescent molecularly imprinted polymer (MIP) for specific recognition of a target protein. The technique provides surface graft imprinting in aqueous solutions using vinyl modified Mn-doped ZnS QDs as supports, methacrylic acid and acrylamide as functional monomers, and bovine hemoglobin as a template. The QDs act as antennae for recognition signal amplification and optical readout, and the MIP shell provides analyte selectivity and prevents interfering molecules from coming into contact with the QDs. The small particle sizes and the nontoxicity of the MIP-QDs composites allows for good dispersibility and stability in an aqueous solution. Under optimal conditions, good linear correlations were obtained for bovine hemoglobin over the concentration range from 1.0*10-7 to 5.0*10-6 mol L-1 and with recoveries of 96.7-103.8% and 92.6-94.2% for urine and serum samples, respectively. The long lifetime of the MIP-QDs composites phosphorescence avoids interference due to autofluorescence and scattering of the biomatrix, facilitating composites' application for detection of bovine hemoglobin in biological fluids. PMID- 23685563 TI - Low-temperature superstructures of a series of Cd6M (M = Ca, Y, Sr, Pr, Nd, Sm, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu) crystalline approximants. AB - The low-temperature (LT) superstructure and the phase transition temperature have been investigated for a series of Cd6M crystalline approximants by transmission electron microscopy as well as electrical resistivity measurements. Except for M = Lu, Cd6M is found to undergo a phase transition to a monoclinic phase at a low temperature and the transition temperature (Tc) scales well with the size of the M atom. For M = Ca, Y, Pr, Nd, Sm, Gd, Tb, Dy, Ho, Er and Tm the LT superstructure is explained by a ?2a * a * ?2a lattice with the space group C2/c, and for M = Sr and Yb a ?2a * 2a * ?2a monoclinic lattice with P2/m. On the other hand, no phase transition is observed for M = Lu, indicating that a Cd4 tetrahedron at the cluster center remains disordered down to the lowest temperature, i.e. 16 K. It is shown that the volume inside the Cd20 dodecahedron plays a crucial role in the occurrence of the phase transition, and long-term aging in particular promotes the phase transition for late rare-earth elements such as Ho, Er and Tm, suggesting that the transition is sensitive to and is even hindered by disorder such as atomic vacancies. The absence of the transition for M = Lu is attributed to the highest activation energy for the transition due to the smallest volume inside the Cd20 dodecahedron. PMID- 23685564 TI - Study of the volatile compounds and odor-active compounds of dry-cured Iberian ham extracted by SPME. AB - The volatile compounds and the most odor-active compounds of dry-cured Iberian ham were investigated by extracting them using a solid phase microextraction technique with a 2 cm Carboxen/PDMS/DVB fiber. The detection frequency method was applied to estimate the potential contribution of each compound to the odor of hams. Twenty-one volatile compounds were tentatively identified for the first time in dry-cured ham by gas chromatography-mass spectrometry, and eight in dry cured Iberian ham. Gas chromatography-olfactometry allowed the identification for the first time of six compounds not previously reported as odorants of Iberian ham, and also two odorants were newly identified in dry-cured ham. According to the detection frequency method, the most odor active compounds found were 3 methylbutanoic acid (dirty sock-like smelling), hexanal (cut grass-like odor), 3 methylbutanal (sweaty and bitter almond-like odor), 2-methyl-3-furanthiol (toasted nuts-like odor) and 1-octen-3-one (mushroom-like odor). PMID- 23685565 TI - Differential sweetness of commercial sour liquids elicited by miracle fruit in healthy young adults. AB - Miracle fruit (Synsepalum dulcificum) contains the glycoprotein miraculin which turns a sour taste into a sweet one. Chemical analyses and sensory evaluation experiments were conducted to examine the sweetening effect of miracle fruit with regard to five different commercial sour liquids which were diluted until they were subjectively equally sour. HPLC-based analyses revealed that (1) the predominating acids in two and three of the liquids were citric acid and acetic acid, respectively and (2) all five liquids contained fructose and glucose. Healthy young adults (eight males and 10 females) in the sensory evaluation experiments were asked to chew a miracle fruit and apply their saliva to the oral mucosae. They were asked to score the sweetness elicited by the five liquids relative to a sucrose standard at 0, 15, 25 and 35 min thereafter. The citric acid-based liquids were perceived as being sweeter than the acetic acid-based liquids at all timepoints. Thus, commercial sour liquids that mainly contain citric acid are more effective than acetic acid-based liquids in eliciting a perception of sweetness after the miracle fruit application, while the sugars in the liquids seemed to play a minimal role as determinants of sweetness. PMID- 23685566 TI - Effect of ante-mortem hypoxia on the physicochemical and functional properties of white shrimp (Litopenaeus vannamei) muscle stored on ice. AB - The effect of ante-mortem hypoxia on the physicochemical and functional properties of raw and cooked white shrimp was studied. Hue angle was greater (p <= 0.05) for stressed raw shrimp compared to control (greener color); whereas a lower angle was detected for cooked stressed shrimp (redder/orange coloration). In addition, hue angle increased (p <= 0.05) over the ice storage period for control and stressed shrimp (raw and/or cooked). Muscle hardness and shear force showed no differences when comparing control and stressed shrimp (raw and/or cooked). However, during ice storage, shear force increased (p <= 0.05) by 22% and 9% for control and stressed raw shrimp, respectively; in contrast, shear force and muscle hardness decreased for cooked shrimp (p <= 0.05). Control showed more (p <= 0.05) elasticity than stressed cooked shrimp. Stressed raw shrimp showed a water holding capacity 10.8% lower (p <= 0.05) than control. However, during the storage, water holding capacity increased (p <= 0.05) reaching similar values to control after day 4. Muscle protein solubility of stressed shrimp was 31% lower than control; however, no differences (p > 0.05) were observed after the second day. The thermal stability of myosin (T max) showed differences (p <= 0.05) among control and stressed shrimp, whereas no differences for DeltaH were observed. Results showed the influence of ante-mortem hypoxia on the physicochemical and functional properties of white shrimp muscle. PMID- 23685567 TI - Analgesics and road traffic crashes in senior drivers: an epidemiological review and explorative meta-analysis on opioids. AB - AIM: To assess the epidemiological evidence associating the use of analgesics with the occurrence of road traffic crashes in senior drivers including a meta analysis with specific focus on opioids. METHODS: Systematic literature review of articles published between 1991 and 2012 retrieved from major databases using relevant key words. Eligible articles were fully reviewed and the main characteristics and results summarized. The methodological quality was assessed using the Newcastle-Ottawa Scale. Heterogeneity tests and forest and funnel plots were used as part of the meta-analysis on opioids. RESULTS: From the potentially eligible articles, nine were selected (4 case-control, 1 case-crossover, and 4 cohort studies) of which four were of medium and five of high quality; seven investigated opioids and four non-steroidal anti-inflammatory drugs. Crash involvement (n=7) rather than responsibility (n=2) was investigated. Age and sex were the most common covariates adjusted for. Both opioids and non-steroidal anti inflammatory drugs showed mixed results including differences across estimates between and within studies. A marginal positive effect was observed in the pooled analyses on opioids (n=6, OR 1.20; 95% CI 1.08-1.32). CONCLUSIONS: The evidence is unconvincing in terms of number of studies, control of major confounders, and consistency of the results. The effect seen for opioids can be attributed to the lack of adjustment of key confounders such as concomitant illness or the consumption of alcohol or other psychoactive medications. There is a need for more efficient designs like larger population-based retrospective cohorts and nested case-control or case-crossover studies based on registers of high quality allowing adjustment for these factors and for the selection of unequivocal outcomes (e.g. drivers' responsibility) to produce more persuasive empirical evidence. PMID- 23685568 TI - Short-term cultivation of porcine cumulus cells influences the cyclin-dependent kinase 4 (Cdk4) and connexin 43 (Cx43) protein expression--a real-time cell proliferation approach. AB - The CC (cumulus cell) proliferation index in relation to the expression and distribution of Cdk4 and Cx43 proteins, which are crucial factors for oocyte maturation, was investigated. Cumulus-oocyte complexes (COCs) were recovered from pubertal crossbred Landrace gilts and treated with collagenase, and separated CCs were cultured in standard TCM199 medium for 44 h. At each step of in vitro cultivation (IVC) of CCs (0, 12, 24 and 44 h), a normalized proliferation index was assessed. Cdk4 and Cx43 protein expression and the CC-specific cellular distribution were analyzed by confocal microscopic observation. The normalized proliferation index (number of cells attached, measured by impedance) was increased in the first 12 h of IVC (P<0.01) and differed between 12 h and 24 h of cultivation (P<0.001). Later, between 24 h-44 h of IVC, the CC proliferation rate was stable, and no significant differences were observed. Based on the confocal microscopic observation, increased expression of both Cdk4 and Cx43 was found after 44 h of IVC compared with the expression of these proteins before IVC. Moreover, after IVC, a substantial translocation of Cdk4 and Cx43 was noted from the nucleus to the cytoplasm of CCs. In conclusion, it was demonstrated for the first time that CCs can be cultured in vitro separately without oocytes and that the proliferation index was significantly increased in the first 12 h of IVC, which may reflect the process of ordinary cumulus cell expansion. Furthermore, the expression of both Cdk4 and Cx43 in CCs suggested that these proteins may be regarded as markers not only of proper oocyte maturation but also of CC differentiation. Translocation of these proteins into the cytoplasm of CCs after 44 h of IVC may be related to the expansion process. PMID- 23685569 TI - Synthesis and antimalarial testing of neocryptolepine analogues: addition of ester function in SAR study of 2,11-disubstituted indolo[2,3-b]quinolines. AB - This report describes the synthesis, and in vitro and in vivo antimalarial evaluations of certain ester-modified neocryptolepine (5-methyl-5H-indolo[2,3 b]quinoline) derivatives. The modifications were carried out by introducing ester groups at the C2 and/or C9 position on the neocryptolepine core and the terminal amino group of the 3-aminopropylamine substituents at the C11 position with a urea/thiourea unit. The antiplasmodial activities of our derivative agents against two different strains (CQS: NF54, and CQR: K1) and the cytotoxic activity against normal L6 cells were evaluated. The test results showed that the ester modified neocryptolepine derivatives have higher antiplasmodial activities against both strains and a low cytotoxic activity against normal cells. The best results were achieved by compounds 9c and 12b against the NF54 strain with the IC50/SI value as 2.27 nM/361 and 1.81 nM/321, respectively. While against K1 strain, all the tested compounds showed higher activity than the well-known antimalarial drug chloroquine. Furthermore, the compounds were tested for beta haematin inhibition and 12 were found to be more active than chloroquine (IC50 = 18 MUM). Structure activity relationship studies exposed an interesting linear correlation between polar surface area of the molecule and beta-haematin inhibition for this series. In vivo testing of compounds 7 and 8a against NF54 strain on Plasmodium berghei female mice showed that the introduction of the ester group increased the antiplasmodial activity of the neocryptolepine core substantially. PMID- 23685571 TI - Synthesis and biological evaluation of sulforaphane derivatives as potential antitumor agents. AB - A series of sulforaphane derivatives were synthesized and evaluated in vitro for their cytotoxicity against five cancer cell lines (HepG2, A549, MCF-7, HCT-116 and SH-SY5Y). The pharmacological results showed that many of the derivatives displayed more potent cytotoxicity than sulforaphane (SFN). Furthermore, SFN and derivative 85 could induce cell cycle arrest at S or G2/M phase and cell apoptosis. SFN and 85 exhibited time- and dose-dependent activation on Nrf2 transcription factor, and 85 acted as a more potent Nrf2 inducer than SFN. PMID- 23685572 TI - Design, synthesis and evaluation of novel tacrine-coumarin hybrids as multifunctional cholinesterase inhibitors against Alzheimer's disease. AB - A series of tacrine-coumarin hybrids (8a-t) were designed, synthesized and evaluated as multifunctional cholinesterase (ChE) inhibitors against Alzheimer's disease (AD). The screening results showed that most of them exhibited a significant ability to inhibit ChE and self-induced beta-amyloid (Abeta) aggregation, and to act as metal chelators. Especially, 8f displayed the greatest ability to inhibit acetylcholinesterase (AChE, IC50 = 0.092 MUM) and Abeta aggregation (67.8%, 20 MUM). It was also a good butyrylcholinesterase inhibitor (BuChE, IC50 = 0.234 MUM) and metal chelator. Besides, kinetic and molecular modeling studies indicated that 8f was a mixed-type inhibitor, binding simultaneously to active, peripheral and mid-gorge sites of AChE. These results suggested that 8f might be an excellent multifunctional agent for AD treatment. PMID- 23685570 TI - Further studies on 2-arylacetamide pyridazin-3(2H)-ones: design, synthesis and evaluation of 4,6-disubstituted analogs as formyl peptide receptors (FPRs) agonists. AB - Formyl peptide receptors (FPRs) play an essential role in the regulation of endogenous inflammation and immunity. In the present studies, a large series of pyridazin-3(2H)-one derivatives bearing an arylacetamide chain at position 2 was synthesized and tested for FPR agonist activity. The pyridazin-3(2H)-one ring was confirmed to be an appropriate scaffold to support FPR agonist activity, and its modification at the 4 and 6 positions led to the identification of additional active agonists, which induced intracellular Ca(2+) flux in HL-60 cells transfected with either FPR1, FPR2, or FPR3. Seven formyl peptide receptor 1 (FPR1)-specific and several mixed FPR1/FPR2 dual agonists were identified with low micromolar EC50 values. Furthermore, these agonists also activated human neutrophils, inducing intracellular Ca(2+) flux and chemotaxis. Finally, molecular docking studies indicated that the most potent pyridazin-3(2H)-ones overlapped in their best docking poses with fMLF and WKYMVM peptides in the FPR1 and FPR2 ligand binding sites, respectively. Thus, pyridazinone-based compounds represent potential lead compounds for further development of selective and/or potent FPR agonists. PMID- 23685573 TI - Platinum(II) complexes containing aminophosphonate esters: Synthesis, characterization, cytotoxicity and action mechanism. AB - New platinum(II) complexes containing aminophosphonate ester were synthesized and fully characterized, which were found to possess better solubility in both organic solvents and water than cisplatin. These platinum(II) complexes exhibited considerable cytotoxicity against tumor cells MG-63, SK-OV-3, HepG2, BEL-7404 and low cytotoxicity to normal human liver cells HL-7702. Their antitumor activities were achieved through the induction of cell apoptosis and the cell cycle arrest at G1 phase. The electrophoretic mobility studies and CD spectral analysis revealed that the binding mode of complex 6 to DNA might be different from that of cisplatin. PMID- 23685574 TI - Breaking the ice: therapeutic hypothermia for in-hospital cardiac arrest*. PMID- 23685575 TI - The sooner, the better: early beta-blocker administration in patients with ST elevation myocardial infarction*. PMID- 23685576 TI - Palliative care in the ICU: lots of questions, few answers*. PMID- 23685577 TI - Central venous oxygen saturation: not easily replaced*. PMID- 23685578 TI - The venous saturation paradox: measure it early, but leave it alone afterward*. PMID- 23685579 TI - Why is lightening sedation in critically ill patients so difficult?*. PMID- 23685580 TI - Predicting mortality in patients admitted with sepsis using endotoxin activity: will it help us see through the crystal ball?*. PMID- 23685581 TI - Trends in mortality and early central line placement in septic shock: true, true, and related?*. PMID- 23685582 TI - Critical crossroads in the care of human immunodeficiency virus-infected persons*. PMID- 23685583 TI - Are advance directives useful in acute stroke?*. PMID- 23685584 TI - Rationing: it is time for the conversation*. PMID- 23685585 TI - Monitoring breathing effort: a work in progress*. PMID- 23685586 TI - Paradise by the dashboard light*. PMID- 23685587 TI - Physicians' decision-making roles for critically ill patients: what is the "right" approach?*. PMID- 23685588 TI - Moving forward with rehabilitation research in critical care*. PMID- 23685589 TI - The effect of selenium therapy on mortality in patients with sepsis syndrome: simple selenium supplementation or real (5 H2O).Na2SeO3 pharmacological effect?*. PMID- 23685590 TI - Enhanced external counter pulsation and neurologic recovery for cardiac arrest: is it ready for prime time?*. PMID- 23685591 TI - Insulin: a rescue for organ injury in acute traumatic conditions*. PMID- 23685592 TI - The authors reply. PMID- 23685593 TI - APOE-based psychopharmacogenetics and delirium. PMID- 23685594 TI - The authors reply. PMID- 23685595 TI - The true effect of the rapid response team. PMID- 23685596 TI - The authors reply. PMID- 23685597 TI - Stress hyperglycemia: an essential survival response! PMID- 23685598 TI - The author replies. PMID- 23685599 TI - The effect of etomidate on mortality in sepsis remains unclear. PMID- 23685600 TI - The authors reply. PMID- 23685601 TI - Ventilator-associated pneumonia reduced-mortality untouched. PMID- 23685602 TI - The author replies. PMID- 23685603 TI - How about the association between patient's characteristics and hospital mortality? PMID- 23685604 TI - The authors reply. PMID- 23685605 TI - Timing is crucial when considering antiplatelet therapy for trauma. PMID- 23685606 TI - Does effective chest compression after cardiopulmonary resuscitation require that rescuers perform adequate-force/depth high-impulse chest compressions and are typical rescuers able to do so? PMID- 23685607 TI - Where is the lead? PMID- 23685608 TI - Diastolic dysfunction and N-terminal pro-brain natriuretic peptide in children with meningococcal sepsis. PMID- 23685609 TI - Reporting and handling missing values in clinical studies in intensive care units. AB - INTRODUCTION: Missing values occur in nearly all clinical studies, despite the best efforts of the investigators, and cause frequently unrecognised biases. Our aims were (1) to assess the reporting and handling of missing values in the critical care literature; (2) to describe the impact of various techniques for handling missing values on the study results; (3) to provide guidance on the management of clinical study analysis in case of missing data. METHODS: We reviewed 44 published manuscripts in three critical care research journals. We used the Conflicus study database to illustrate how to handle missing values. RESULTS: Among 44 published manuscripts, 16 (36.4 %) provided no information on whether missing data occurred, 6 (13.6 %) declared having no missing data, 20 (45.5 %) reported that missing values occurred but did not handle them and only 2 (4.5 %) used sophisticated missing data handling methods. In our example using the Conflicus study database, we evaluated correlations linking job strain intensity to the type and proportion of missing values. Overall, 8 % of data were missing; however, using only complete cases would have resulted in discarding 24 % of the questionnaires. A greater number and a higher percentage of missing values for a particular variable were significantly associated with a lower job strain score (indicating greater stress). Among respondents who fully completed the job strain questionnaire, the comparison of those whose questionnaires did and did not have missing values showed significant differences in terms of age, number of children and country of birth. We provided an algorithm to manage clinical studies analysis in case of missing data. CONCLUSION: Missing data are common and generate interpretation biases. They should be reported routinely and taken into account when modelling data from clinical studies. PMID- 23685610 TI - Precautions with heated humidifier systems in particular environments. PMID- 23685611 TI - Quantitative and simultaneous translational control of distinct mammalian mRNAs. AB - The introduction of multiple genes into cells is increasingly required for understanding and engineering biological systems. Small-molecule-responsive transcriptional regulation has been widely used to control transgene expression. In contrast, methods for specific and simultaneous regulation of multiple genes with a single regulatory protein remain undeveloped. In this report, we describe a method for quantitatively tuning the expression of multiple transgenes with a translational regulatory protein. A protein that binds a specific RNA motif inserted in the 5'-untranslated region (UTR) of an mRNA modulates the translation of that message in mammalian cells. We provide two independent mechanisms by which to rationally fine-tune the output: the efficiency of translation correlates well with the distance between the inserted motif and the 5' terminus of the mRNA and is further modulated by the tandem insertion of multiple RNA motifs. The combination of these two approaches allowed us to fine-tune the translational efficiency of target mRNAs over a wide dynamic range. Moreover, we controlled the expression of two transgenes simultaneously and specifically by engineering each cis-regulatory 5'-UTR. The approach provides a useful alternative regulatory layer for controlling gene expression in biological research and engineering. PMID- 23685612 TI - The PhyloFacts FAT-CAT web server: ortholog identification and function prediction using fast approximate tree classification. AB - The PhyloFacts 'Fast Approximate Tree Classification' (FAT-CAT) web server provides a novel approach to ortholog identification using subtree hidden Markov model-based placement of protein sequences to phylogenomic orthology groups in the PhyloFacts database. Results on a data set of microbial, plant and animal proteins demonstrate FAT-CAT's high precision at separating orthologs and paralogs and robustness to promiscuous domains. We also present results documenting the precision of ortholog identification based on subtree hidden Markov model scoring. The FAT-CAT phylogenetic placement is used to derive a functional annotation for the query, including confidence scores and drill-down capabilities. PhyloFacts' broad taxonomic and functional coverage, with >7.3 M proteins from across the Tree of Life, enables FAT-CAT to predict orthologs and assign function for most sequence inputs. Four pipeline parameter presets are provided to handle different sequence types, including partial sequences and proteins containing promiscuous domains; users can also modify individual parameters. PhyloFacts trees matching the query can be viewed interactively online using the PhyloScope Javascript tree viewer and are hyperlinked to various external databases. The FAT-CAT web server is available at http://phylogenomics.berkeley.edu/phylofacts/fatcat/. PMID- 23685616 TI - A cobalt-based 3D porous framework with excellent catalytic ability for the selective oxidation of cis-cyclooctene. AB - A 3D porous framework [Co3(MU2-OH)4(I)2].2H2O (I = hypoxanthine) with two types of 1D channels possess excellent catalytic ability for the selective oxidation of cis-cyclooctene. PMID- 23685613 TI - Prediction of clustered RNA-binding protein motif sites in the mammalian genome. AB - Sequence-specific interactions of RNA-binding proteins (RBPs) with their target transcripts are essential for post-transcriptional gene expression regulation in mammals. However, accurate prediction of RBP motif sites has been difficult because many RBPs recognize short and degenerate sequences. Here we describe a hidden Markov model (HMM)-based algorithm mCarts to predict clustered functional RBP-binding sites by effectively integrating the number and spacing of individual motif sites, their accessibility in local RNA secondary structures and cross species conservation. This algorithm learns and quantifies rules of these features, taking advantage of a large number of in vivo RBP-binding sites obtained from cross-linking and immunoprecipitation data. We applied this algorithm to study two representative RBP families, Nova and Mbnl, which regulate tissue-specific alternative splicing through interacting with clustered YCAY and YGCY elements, respectively, and predicted their binding sites in the mouse transcriptome. Despite the low information content in individual motif elements, our algorithm made specific predictions for successful experimental validation. Analysis of predicted sites also revealed cases of extensive and distal RBP binding sites important for splicing regulation. This algorithm can be readily applied to other RBPs to infer their RNA-regulatory networks. The software is freely available at http://zhanglab.c2b2.columbia.edu/index.php/MCarts. PMID- 23685617 TI - Coexistence of plasmonic and magnetic properties in Au89Fe11 nanoalloys. AB - We describe an environmentally friendly, top-down approach to the synthesis of Au89Fe11 nanoparticles (NPs). The plasmonic response of the gold moiety and the magnetism of the iron moiety coexist in the Au89Fe11 nanoalloy with strong modification compared to single element NPs, revealing a non-linear surface plasmon resonance dependence on the iron fraction and a transition from paramagnetic to a spin-glass state at low temperature. These nanoalloys are accessible to conjugation with thiolated molecules and they are promising contrast agents for magnetic resonance imaging. PMID- 23685618 TI - Pyridine-based dicarbene ligand: synthesis and structure of a bis-2-pyridylidene palladium complex. AB - We herein report the synthesis of a bis-2-pyridylidene palladium(II) complex as an isoelectronic structure of the well-known 2,2'-bipyridine complexes. One-pot or stepwise C-Cl oxidative addition followed by base-mediated C-H palladation of the chlorobipyridine dication to palladium(0) yielded the bis-2-pyridylidene palladium(II) carbonate smoothly. PMID- 23685619 TI - Developing the Sense of Agency Rating Scale (SOARS): an empirical measure of agency disruption in hypnosis. AB - Two experiments report on the construction of the Sense of Agency Rating Scale (SOARS), a new measure for quantifying alterations to agency. In Experiment 1, 370 participants completed a preliminary version of the scale following hypnosis. Factor analysis revealed two underlying factors: Involuntariness and Effortlessness. In Experiment 2, this two factor structure was confirmed in a sample of 113 low, medium and high hypnotisable participants. The two factors, Involuntariness and Effortlessness, correlated significantly with hypnotisability and pass rates for ideomotor, challenge and cognitive items. Twelve week test retest correlations showed that Involuntariness was highly stable, but Effortlessness only moderately stable. Analysis of the combined datasets from Experiments 1 and 2 showed both SOARS scores were significantly related to the derived factors of Woody, Barnier, and McConkey's (2005) 4-factor model of hypnotisability. This scale clarifies conceptual confusion around agentive action and provides empirical support for a multifactorial account of sense of agency. PMID- 23685621 TI - Terminology, taxonomy, and facilitation of motor learning in clinical practice: protocol of a delphi study. AB - BACKGROUND: Facilitating motor learning in patients during clinical practice is complex, especially in people with cognitive impairments. General principles of motor learning are available for therapists to use in their practice. However, the translation of evidence from the different fields of motor learning for use in clinical practice is problematic due to lack of uniformity in definition and taxonomy of terms related to motor learning. OBJECTIVE: The objective of this paper was to describe the design of a Delphi technique to reach consensus on definitions, descriptions, and taxonomy used within motor learning and to explore experts' opinions and experiences on the application of motor learning in practice. METHODS: A heterogeneous sample of at least 30 international experts on motor learning will be recruited. Their opinions regarding several central topics on motor learning using a Delphi technique will be collected in 3 sequential rounds. The questionnaires in the 3 rounds will be developed based on the literature and answers of experts from earlier rounds. Consensus will be reached when at least 70% of the experts agree on a certain topic. Free text comments and answers from open questions on opinions and experiences will be described and clustered into themes. RESULTS: This study is currently ongoing. It is financially supported by Stichting Alliantie Innovatie (Innovation Alliance Foundation), RAAK-international (Registration number: 2011-3-33int). CONCLUSIONS: The results of this study will enable us to summarize and categorize expert knowledge and experiences in a format that should be more accessible for therapists to use in support of their clinical practice. Unresolved aspects will direct future research. PMID- 23685620 TI - Theory of Mind experience sampling in typical adults. AB - We explored the frequency with which typical adults make Theory of Mind (ToM) attributions, and under what circumstances these attributions occur. We used an experience sampling method to query 30 typical adults about their everyday thoughts. Participants carried a Personal Data Assistant (PDA) that prompted them to categorize their thoughts as Action, Mental State, or Miscellaneous at approximately 30 pseudo-random times during a continuous 10-h period. Additionally, participants noted the direction of their thought (self versus other) and degree of socializing (with people versus alone) at the time of inquiry. We were interested in the relative frequency of ToM (mental state attributions) and how prominent they were in immediate social exchanges. Analyses of multiple choice answers suggest that typical adults: (1) spend more time thinking about actions than mental states and miscellaneous things, (2) exhibit a higher degree of own- versus other-directed thought when alone, and (3) make mental state attributions more frequently when not interacting (offline) than while interacting with others (online). A significant 3-way interaction between thought type, direction of thought, and socializing emerged because action but not mental state thoughts about others occurred more frequently when participants were interacting with people versus when alone; whereas there was an increase in the frequency of both action and mental state attributions about the self when participants were alone as opposed to socializing. A secondary analysis of coded free text responses supports findings 1-3. The results of this study help to create a more naturalistic picture of ToM use in everyday life and the method shows promise for future study of typical and atypical thought processes. PMID- 23685622 TI - Ulinastatin reduces urinary sepsis-related inflammation by upregulating IL-10 and downregulating TNF-alpha levels. AB - The aim of the present study was to determine the efficacy of ulinastatin (UTI) for the treatment of sepsis and to investigate the associated molecular mechanisms. Twenty-four male rabbits were randomly divided into 4 groups, the normal, sham, sepsis model and UTI groups, each containing 6 rabbits. Serum levels of interleukin (IL)-10 and tumor necrosis factor-alpha (TNF-alpha) were measured by enzyme-linked immunosorbent assay (ELISA). Liver, kidney and lung tissues were stained with hematoxylin and eosin (H&E) 36 h after sacrifice and morphological changes were observed under an optical microscope. The expression levels of IL-10 and TNF-alpha proteins in rabbit kidney tissue in each group were determined by immunohistochemical detection and western blot analysis. ELISA results indicated that, compared with the sepsis model, IL-10 levels were significantly higher in the UTI treatment group (183.91+/-11.521 pg/ml) at 36 h (P=0.000), while serum TNF-alpha concentration decreased significantly in the UTI treatment group (31.637+/-2.770 pg/ml; P=0.000). Results of western blot analysis were consistent with the immunohistochemistry, indicating that UTI upregulates IL 10 and downregulates TNF-alpha levels. In the current study, UTI was demonstrated to effectively treat urinary sepsis and alleviate the inflammatory response in tissues. These effects were mediated by the upregulation of IL-10 and downregulation of TNF-alpha levels. PMID- 23685623 TI - Naive adult stem cells isolation from primary human fibroblast cultures. AB - Over the last decade, several adult stem cell populations have been identified in human skin (1-4). The isolation of multipotent adult dermal precursors was first reported by Miller F. D laboratory (5, 6). These early studies described a multipotent precursor cell population from adult mammalian dermis (5). These cells--termed SKPs, for skin-derived precursors-- were isolated and expanded from rodent and human skin and differentiated into both neural and mesodermal progeny, including cell types never found in skin, such as neurons (5). Immunocytochemical studies on cultured SKPs revealed that cells expressed vimentin and nestin, an intermediate filament protein expressed in neural and skeletal muscle precursors, in addition to fibronectin and multipotent stem cell markers (6). Until now, the adult stem cells population SKPs have been isolated from freshly collected mammalian skin biopsies. Recently, we have established and reported that a population of skin derived precursor cells could remain present in primary fibroblast cultures established from skin biopsies (7). The assumption that a few somatic stem cells might reside in primary fibroblast cultures at early population doublings was based upon the following observations: (1) SKPs and primary fibroblast cultures are derived from the dermis, and therefore a small number of SKP cells could remain present in primary dermal fibroblast cultures and (2) primary fibroblast cultures grown from frozen aliquots that have been subjected to unfavorable temperature during storage or transfer contained a small number of cells that remained viable (7). These rare cells were able to expand and could be passaged several times. This observation suggested that a small number of cells with high proliferation potency and resistance to stress were present in human fibroblast cultures (7). We took advantage of these findings to establish a protocol for rapid isolation of adult stem cells from primary fibroblast cultures that are readily available from tissue banks around the world (Figure 1). This method has important significance as it allows the isolation of precursor cells when skin samples are not accessible while fibroblast cultures may be available from tissue banks, thus, opening new opportunities to dissect the molecular mechanisms underlying rare genetic diseases as well as modeling diseases in a dish. PMID- 23685624 TI - Longer lived parents: protective associations with cancer incidence and overall mortality. AB - BACKGROUND: Children of centenarians have lower cardiovascular disease prevalence and live longer. We aimed to estimate associations between the full range of parental attained ages and health status in a middle-aged U.S. representative sample. METHODS: Using Health and Retirement Study data, models estimated disease incidence and mortality hazards for respondents aged 51-61 years at baseline, followed up for 18 years. Full adjustment included sex, race, smoking, wealth, education, body mass index, and childhood socioeconomic status. Mother's and father's attained age distributions were used to define short-, intermediate-, and long-lived groups, yielding a ranked parental longevity score (n = 6,055, excluding short-long discordance). Linear models (n = 8,340) tested mother's or father's attained ages, adjusted for each other. RESULTS: With increasing mother's or father's survival (>65 years), all-cause mortality declined 19% (hazard ratio [HR] = 0.81, 95% CI: 0.76-0.86, p < .001) and 14% per decade (HR = 0.87, 95% CI: 0.81-0.92, p < .001). Estimates changed only modestly when fully adjusted. Parent-in-law survival was not associated with mortality (n = 1,809, HR = 1.00, 95% CI: 0.90-1.12, p = .98). Offspring with one or two long-lived parents had lower cancer incidence (938 cases, HR per parental longevity score = 0.76, 95% CI: 0.61-0.94, p = .01) versus two intermediate parents. Similar HRs for diabetes (HR = 0.89, 95% CI: 0.84-0.96, p = .001), heart disease (HR = 0.88, 95% CI: 0.82-0.93, p < .001), and stroke (HR = 0.86, 95% CI: 0.78-0.95, p = .002) were significant, but there was no trend for arthritis. CONCLUSIONS: The results provide the first robust evidence that increasing parental attained age is associated with lower cancer incidence in offspring. Health advantages of having centenarian parents extend to a wider range of parental longevity and may provide a quantitative trait of slower aging. PMID- 23685625 TI - Chronic kidney disease and outcomes in heart failure with preserved versus reduced ejection fraction: the Cardiovascular Research Network PRESERVE Study. AB - BACKGROUND: There is scant evidence on the effect that chronic kidney disease (CKD) confers on clinically meaningful outcomes among patients with heart failure with preserved left ventricular ejection fraction (HF-PEF). METHODS AND RESULTS: We identified a community-based cohort of patients with HF. Electronic medical record data were used to divide into HF-PEF and reduced left ventricular EF on the basis of quantitative and qualitative estimates. Level of CKD was assessed by estimated glomerular filtration rate (eGFR) and by dipstick proteinuria. We followed patients for a median of 22.1 months for outcomes of death and hospitalization (HF-specific and all-cause). Multivariable Cox regression estimated the adjusted relative-risk of outcomes by level of CKD, separately for HF-PEF and HF with reduced left ventricular EF. We identified 14 579 patients with HF-PEF and 9762 with HF with reduced left ventricular EF. When compared with patients with eGFR between 60 and 89 mL/min per 1.73 m(2), lower eGFR was associated with an independent graded increased risk of death and hospitalization. For example, among patients with HF-PEF, the risk of death was nearly double for eGFR 15 to 29 mL/min per 1.73 m(2) and 7* higher for eGFR<15 mL/min per 1.73 m(2), with similar findings in those with HF with reduced left ventricular EF. CONCLUSIONS: CKD is common and an important independent predictor of death and hospitalization in adults with HF across the spectrum of left ventricular systolic function. Our study highlights the need to develop new and effective interventions for the growing number of patients with HF complicated by CKD. PMID- 23685626 TI - Polarization dependence of magnetic Bragg scattering in YMn2O5. AB - The polarization dependence of the intensity of elastic magnetic scattering from YMn2O5 single crystals has been measured at 25 K in magnetic fields between 1 and 9 T. A significant polarization dependence was observed in the intensities of magnetic satellite reflections, propagation vector tau = 1/2, 0, 1/4, measured with both the [100] and [010] axes parallel to the common polarization and applied field direction. The intensity asymmetries A observed in sets of orthorhombic equivalent reflections show systematic relationships which allow the phase relationship between different components of their magnetic interaction vectors to be determined. They fix the orientation relationships between the small y and z moments on the Mn(4+) and Mn(3+) sub-lattices and have allowed a further refinement of the magnetic structure, which determines the phases of the vector Fourier components with much higher precision. Systematic differences found between values of A(hkl) and A(h-k-l-) suggest that there is a small modulation of the nuclear structure which has the same wavevector as the magnetic modulation and gives rise to a small nuclear structure factor for the satellite reflections. The magnitudes of the differences suggest shifts in the atomic positions of the order of 0.05 A. PMID- 23685629 TI - Phytotoxicity of zinc and manganese to seedlings grown in soil contaminated by zinc smelting. AB - Historic emissions from two zinc smelters have injured the forest on Blue Mountain near Palmerton, Pennsylvania, USA. Seedlings of soybeans and five tree species were grown in a greenhouse in a series of mixtures of smelter contaminated and reference soils and then phytotoxic thresholds were calculated. As little as 10% Palmerton soil mixed with reference soil killed or greatly stunted seedlings of most species. Zinc was the principal cause of the phytotoxicity to the tree seedlings, although Mn and Cd may also have been phytotoxic in the most contaminated soil mixtures. Calcium deficiency seemed to play a role in the observed phytotoxicity. Exposed soybeans showed symptoms of Mn toxicity. A test of the effect of liming on remediation of the Zn and Mn phytotoxicity caused a striking decrease in Sr-nitrate extractable metals in soils and demonstrated that liming was critical to remediation and restoration. PMID- 23685627 TI - ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. AB - Autophagy is the primary cellular catabolic program activated in response to nutrient starvation. Initiation of autophagy, particularly by amino-acid withdrawal, requires the ULK kinases. Despite its pivotal role in autophagy initiation, little is known about the mechanisms by which ULK promotes autophagy. Here we describe a molecular mechanism linking ULK to the pro-autophagic lipid kinase VPS34. Following amino-acid starvation or mTOR inhibition, the activated ULK1 phosphorylates Beclin-1 on Ser 14, thereby enhancing the activity of the ATG14L-containing VPS34 complexes. The Beclin-1 Ser 14 phosphorylation by ULK is required for full autophagic induction in mammals and this requirement is conserved in Caenorhabditis elegans. Our study reveals a molecular link from ULK1 to activation of the autophagy-specific VPS34 complex and autophagy induction. PMID- 23685628 TI - Subtelomeric hotspots of aberrant 5-hydroxymethylcytosine-mediated epigenetic modifications during reprogramming to pluripotency. AB - Mammalian somatic cells can be directly reprogrammed into induced pluripotent stem cells (iPSCs) by introducing defined sets of transcription factors. Somatic cell reprogramming involves epigenomic reconfiguration, conferring iPSCs with characteristics similar to embryonic stem cells (ESCs). Human ESCs (hESCs) contain 5-hydroxymethylcytosine (5hmC), which is generated through the oxidation of 5-methylcytosine by the TET enzyme family. Here we show that 5hmC levels increase significantly during reprogramming to human iPSCs mainly owing to TET1 activation, and this hydroxymethylation change is critical for optimal epigenetic reprogramming, but does not compromise primed pluripotency. Compared with hESCs, we find that iPSCs tend to form large-scale (100 kb-1.3 Mb) aberrant reprogramming hotspots in subtelomeric regions, most of which exhibit incomplete hydroxymethylation on CG sites. Strikingly, these 5hmC aberrant hotspots largely coincide (~80%) with aberrant iPSC-ESC non-CG methylation regions. Our results suggest that TET1-mediated 5hmC modification could contribute to the epigenetic variation of iPSCs and iPSC-hESC differences. PMID- 23685630 TI - Application of MicroRespTM for soil ecotoxicology. AB - MicroRespTM is a miniaturised method for measuring substrate induced respiration (SIR) in soil. We modified the MicroRespTM method to develop a rapid tool for quantifying the ecotoxicological impact of contaminants. The method is based on reduction in SIR across a gradient of contaminant, allowing for determination of dose-response curves EC-values. Contaminants are mixed into soil samples at a range of concentrations; each sample is then dispensed into a column of eight wells in 96 well format (deep) plates. Moisture and glucose are added to the samples at levels to provide maximum response. Released CO2 from the soils is then measured using colorimetric gel-traps, following the standard MicroRespTM methodology. Examination revealed that this method works over a range of soil types and is insensitive to minor variations in assay length (2-7 h), alteration of moisture content (+/-20 MUL from optimum), and soil storage conditions (4 degrees C versus fresh). PMID- 23685631 TI - Nitrogen deposition alters nitrogen cycling and reduces soil carbon content in low-productivity semiarid Mediterranean ecosystems. AB - Anthropogenic N deposition poses a threat to European Mediterranean ecosystems. We combined data from an extant N deposition gradient (4.3-7.3 kg N ha-1 yr-1) from semiarid areas of Spain and a field experiment in central Spain to evaluate N deposition effects on soil fertility, function and cyanobacteria community. Soil organic N did not increase along the extant gradient. Nitrogen fixation decreased along existing and experimental N deposition gradients, a result possibly related to compositional shifts in soil cyanobacteria community. Net ammonification and nitrification (which dominated N-mineralization) were reduced and increased, respectively, by N fertilization, suggesting alterations in the N cycle. Soil organic C content, C:N ratios and the activity of beta-glucosidase decreased along the extant gradient in most locations. Our results suggest that semiarid soils in low-productivity sites are unable to store additional N inputs, and that are also unable to mitigate increasing C emissions when experiencing increased N deposition. PMID- 23685632 TI - Occurrence and risk assessment of organophosphorus and brominated flame retardants in the River Aire (UK). AB - This study presents the occurrence and risk of PBDEs, new brominated and organophosphorus flame retardants along a river affected by urban and industrial pressures (River Aire, UK). Tris(2-choroethyl) phosphate (TCEP), tris(2-chloro-1 methylethyl) phosphate (TCPP), tris[2-chloro-1-(chloromethyl)ethyl] phosphate (TDCP) and triphenyl phosphate (TPhP) were detected in all samples, with TCPP present at the highest concentrations, ranging from 113 to 26,050 ng L-1. BDE-209 was detected in most of the sampled sites, ranging from 17 to 295 ng L-1, while hexabromobenzene (HBB) and pentabromoethyl benzene (PBEB) were seldom detected. A risk quotients based on predicted no effect concentrations (PNEC) and flame retardants water concentration proved significant risk for adverse effects for algae, Daphnia and fish in sites close to industrial and urban sewage discharges. This study provides a protocol for the risk estimation of priority and new generation flame retardants based on river concentrations and toxicological values. PMID- 23685633 TI - Shape-Based Approach to Robust Image Segmentation using Kernel PCA. AB - Segmentation involves separating an object from the background. In this work, we propose a novel segmentation method combining image information with prior shape knowledge, within the level-set framework. Following the work of Leventon et al., we revisit the use of principal component analysis (PCA) to introduce prior knowledge about shapes in a more robust manner. To this end, we utilize Kernel PCA and show that this method of learning shapes outperforms linear PCA, by allowing only shapes that are close enough to the training data. In the proposed segmentation algorithm, shape knowledge and image information are encoded into two energy functionals entirely described in terms of shapes. This consistent description allows to fully take advantage of the Kernel PCA methodology and leads to promising segmentation results. In particular, our shape-driven segmentation technique allows for the simultaneous encoding of multiple types of shapes, and offers a convincing level of robustness with respect to noise, clutter, partial occlusions, or smearing. PMID- 23685635 TI - In situ chemical mapping of a lithium-ion battery using full-field hard X-ray spectroscopic imaging. AB - In situ tracking of chemical phase transformation, mapping, and composition information of a battery with CuO as the anode was performed with quantitative analysis at sub-30 nm resolution with a 40 * 40 MUm field of view using transmission X-ray microscopy combined with spectroscopy. A size-dependent and core-shell lithiation-delithiation mechanism was suggested for the electrochemical reaction. PMID- 23685634 TI - Construct validity testing of the Arthroscopic Knot Trainer (ArK). AB - PURPOSE: This study introduced a novel simulator called the Arthroscopic Knot Trainer (ArK) and reports preliminary evidence to support its construct validity. To our knowledge, the ArK is the first non-anatomical tissue reduction simulator designed to meet learning objectives specific for developing knot-tying skills. MATERIALS AND METHODS: A step-by-step instructional video was used to teach orthopaedic residents how to tie an arthroscopic SMC knot. Residents were video recorded to assess time of completion, number of knots tied in 10 min and re assessed 6 months later. Subjects were surveyed for content evidence after using the ArK. Data were analysed by paired t test and independent sample t test in order to compare the mean time to tie knots from test at baseline to retest at 6 months and the between group mean time, respectively. RESULTS: Content evidence supports the ArK trainer as appropriate for teaching and assessing arthroscopic knot-tying skills. Relation to other variables evidence supports the ArK trainer model whether stratified by year of training or by self-reported experience; time required for knot tying was inversely correlated with experience in tying arthroscopic knots. Internal structure evidence was supported with similar findings at retesting. CONCLUSIONS: There are three sources of evidence supporting the construct validity of the ArK as a simulator for arthroscopic knot tying: content, relationship to other variable and internal structure evidence. The ArK is easy to use and has the capacity to distinguish between groups with different skill levels. PMID- 23685636 TI - A highly selective and sensitive ratiometric chemodosimeter for Hg2+ ions based on an iridium(III) complex via thioacetal deprotection reaction. AB - A novel luminescent biscyclometalated iridium(III) complex [Ir(C^N)2bpy]PF6 (Ir S, bpy = 2,2'-bipyridine) containing two 2-phenylpyridine (ppy) cyclometalating ligands (C^N) functionalized with 1,3-dithiane for the detection of Hg(2+) ions has been synthesized and characterized by spectroscopic and photophysical measurements. The luminescence of Ir-S exhibits a ratiometric response upon the addition of Hg(2+) ions. The absorption, emission, (1)H NMR and ESI mass spectral changes of Ir-S in the absence and presence of Hg(2+) ions have all demonstrated the Hg(2+)-promoted thioacetal deprotection reaction of Ir-S and the generation of a complex [Ir(pba)2bpy]PF6 (Ir-CHO, Hpba = 4-(pyridin-2-yl)benzaldehyde). DFT calculation studies suggest that the dominant participation of the 1,3-dithiane group in the HOMO of Ir-S leads to different excited states and distinct excited energies of Ir-S and Ir-CHO and consequently results in their different emission properties. The titration and competition experiments significantly reveal the highly sensitive and selective properties of Ir-S as a promising indicator for Hg(2+) ions over other metal cations. PMID- 23685637 TI - Milrinone therapy for enterovirus 71-induced pulmonary edema and/or neurogenic shock in children: a randomized controlled trial. AB - OBJECTIVE: Enterovirus 71-induced brainstem encephalitis with pulmonary edema and/or neurogenic shock (stage 3B) is associated with rapid mortality in children. In a small pilot study, we found that milrinone reduced early mortality compared with historical controls. This prospective, randomized control trial was designed to provide more definitive evidence of the ability of milrinone to reduce the 1-week mortality of stage 3B enterovirus 71 infections. DESIGN: Prospective, unicenter, open-label, randomized, controlled study. SETTING: Inpatient ward of a large tertiary teaching hospital in Ho Chi Minh City, Vietnam. PATIENTS: Children (<= 18 yr old) admitted with proven enterovirus 71 induced pulmonary edema and/or neurogenic shock. INTERVENTIONS: Patients were randomly assigned to receive intravenous milrinone (0.5 MUg/kg/min) (n = 22) or conventional management (n = 19). Both groups received dopamine or dobutamine and intravenous immunoglobulin. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was 1-week mortality. The secondary endpoints included length of ventilator dependence and hospital stay and adverse events. The median age was 2 years with a predominance of boys in both groups. The 1-week mortality was significantly lower, 18.2% (4/22) in the milrinone compared with 57.9% (11/19) in the conventional management group (relative risk = 0.314 [95% CI, 0.12-0.83], p = 0.01). The median duration of ventilator-free days was longer in the milrinone treatment group (p = 0.01). There was no apparent neurologic sequela in the survivors in either group, and no drug-related adverse events were documented. CONCLUSIONS: Milrinone significantly reduced the 1-week mortality of enterovirus 71-induced pulmonary edema and/or neurogenic shock without adverse effects. Further studies are needed to determine whether milrinone might be useful to prevent progression of earlier stages of brainstem encephalitis. PMID- 23685638 TI - Body mass index is associated with hospital mortality in critically ill patients: an observational cohort study. AB - OBJECTIVE: Obesity is associated with a variety of diseases, which results in a decreased overall life expectancy. Nevertheless, some studies suggest that being overweight may reduce hospital mortality of certain patient groups, referred to as obesity paradox. Conflicting results for critically ill patients are reported. Therefore, we wished to investigate the association of body mass index and hospital mortality in critically ill patients. DESIGN: Observational cohort study in Dutch critically ill patients. SETTING: A dataset from the Dutch National Intensive Care Evaluation registry that includes patients admitted to Dutch ICUs was used. PATIENTS: One hundred fifty-four thousand three hundred and eight ICU patients of teaching and nonteaching units in urban and nonurban hospitals. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We used logistic regression analysis, correcting for case mix (Simplified Acute Physiology Score II, age, gender, admission type, neoplasm, AIDS, hematologic malignancy, immunologic insufficiency, mechanical ventilation, and calendar year), to determine the relationship between body mass index and hospital mortality. Body mass index was included in the model as a continuous nonlinear covariate in a restricted regression spline transformation. To facilitate interpretation, adjusted odds ratios were calculated for the World Health Organization-based body mass index classes. Body mass index was found to be significantly associated with hospital mortality, with risks quickly increasing for underweight patients (body mass index < 18.5 kg/m). Obese and seriously obese patients, with a body mass index of 30-39.9 kg/m, had the lowest risk of death with an adjusted odds ratio of 0.86 (0.83-0.90). CONCLUSIONS: This large observational database shows an inverse association between obesity and hospital mortality in critically ill patients that could not be explained by a variety of known confounders. PMID- 23685639 TI - PELOD-2: an update of the PEdiatric logistic organ dysfunction score. AB - OBJECTIVE: Multiple organ dysfunction syndrome is the main cause of death in adult ICUs and in PICUs. The PEdiatric Logistic Organ Dysfunction score developed in 1999 was primarily designed to describe the severity of organ dysfunction. This study was undertaken to update and improve the PEdiatric Logistic Organ Dysfunction score, using a larger and more recent dataset. DESIGN: Prospective multicenter cohort study. SETTING: Nine multidisciplinary, tertiary-care PICUs of university-affiliated hospitals in France and Belgium. PATIENTS: All consecutive children admitted to these PICUs (June 2006-October 2007). INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: We collected data on variables considered for the PEdiatric Logistic Organ Dysfunction-2 score during PICU stay up to eight time points: days 1, 2, 5, 8, 12, 16, and 18, plus PICU discharge. For each variable considered for the PEdiatric Logistic Organ Dysfunction-2 score, the most abnormal value observed during time points was collected. The outcome was vital status at PICU discharge. Identification of the best variable cutoffs was performed using bivariate analyses. The PEdiatric Logistic Organ Dysfunction-2 score was developed by multivariable logistic regressions and bootstrap process. We used areas under the receiver-operating characteristic curve to evaluate discrimination and Hosmer-Lemeshow goodness-of-fit tests to evaluate calibration. We enrolled 3,671 consecutive patients (median age, 15.5 mo; interquartile range, 2.2-70.7). Mortality rate was 6.0% (222 deaths). The PEdiatric Logistic Organ Dysfunction-2 score includes ten variables corresponding to five organ dysfunctions. Discrimination (areas under the receiver-operating characteristic curve = 0.934) and calibration (chi-square test for goodness-of-fit = 9.31, p = 0.317) of the PEdiatric Logistic Organ Dysfunction-2 score were good. CONCLUSION: We developed and validated the PEdiatric Logistic Organ Dysfunction-2 score, which allows assessment of the severity of cases of multiple organ dysfunction syndrome in the PICU with a continuous scale. The PEdiatric Logistic Organ Dysfunction-2 score now includes mean arterial pressure and lactatemia in the cardiovascular dysfunction and does not include hepatic dysfunction. The score will be in the public domain, which means that it can be freely used in clinical trials. PMID- 23685640 TI - Sodium bicarbonate infusion to reduce cardiac surgery-associated acute kidney injury: a phase II multicenter double-blind randomized controlled trial. AB - OBJECTIVES: Cardiac surgery-associated acute kidney injury occurs in up to 50% of patients and is associated with increased mortality and morbidity. This study aimed to discover if perioperative urinary alkalinization with sodium bicarbonate infusion reduces the prevalence of cardiac surgery-associated acute kidney injury. DESIGN: This study was a phase IIb multicenter double-blind randomized controlled trial. SETTING: This study was conducted in three tertiary hospitals in New Zealand and Australia. PATIENTS: A total of 427 patients scheduled to undergo elective cardiac surgery, who were at increased risk of development of cardiac surgery-associated acute kidney injury using recognized risk factors. MEASUREMENTS AND MAIN RESULTS: Patients were randomly allocated to receive either sodium bicarbonate (n = 215) or sodium chloride (n = 212) infusion, commencing at the start of anesthesia, in a dose of 0.5 mEq/kg/hr for the first hour and then 0.2 mmol/kg/hr for 23 hours. The primary outcome measure was the number of patients with development of cardiac surgery-associated acute kidney injury, defined as an increase in creatinine greater than 25% or 0.5 mg/dL (44 umol/L) from baseline to peak value within the first five postoperative days. Significant differences among the groups in both plasma and urinary biochemistry were achieved 6 hours after commencement of the infusion, and these changes persisted for more than 24 hours. A total of 100 out of 215 patients (47% [95% CI, 40% 53%]) in the sodium bicarbonate group and 93 of 212 patients (44% [95% CI, 37% 51%]) in the sodium chloride group with development of acute kidney injury within the first five postoperative days (p = 0.58). There were also no significant differences in ventilation hours, ICU or hospital length of stay, or mortality. CONCLUSIONS: Perioperative alkalinization of blood and urine using an infusion of sodium bicarbonate did not result in a decrease in the prevalence of acute kidney injury in patients following cardiac surgery. PMID- 23685641 TI - A comprehensive long-term retrospective analysis of silent corticotrophic adenomas vs hormone-negative adenomas. AB - BACKGROUND: Silent corticotrophic adenomas (SCAs) stain adrenocorticotropic hormone (ACTH)+ without causing Cushing disease. SCAs are reportedly more aggressive, but information comes from small series. OBJECTIVE: To determine whether SCAs behave more aggressively than hormone-negative adenomas (HNAs), and characterize SCA ACTH production alterations. METHODS: SCAs (n = 75) and HNAs (n = 1726) diagnosed at our institution from 1990 to 2011 were retrospectively reviewed. RT-PCR was used to compare expression of ACTH-producing factors. RESULTS: SCA patients exhibited comparable sex and age as HNA patients (P = .7 .9). SCAs exhibited comparable size as HNAs (2.2 vs 2.0 cm, P = .2), with cavernous sinus invasion in 30% of SCAs vs 18% of HNAs (P = .03). SCA patients had higher mean preoperative serum ACTH (46 vs 19 ng/L; P = .005; normal = 5-27 ng/L), but comparable serum cortisol (13 vs 12 MUg/dL; normal = 4-22 MUg/dL; P < .05) as HNA patients. SCAs were gross totally resected 59% of the time, vs 53% for HNAs (P = .8). Kaplan-Meier 3-year progression/recurrence rates were 34% for strongly ACTH-positive Type I SCAs, 10% for weakly ACTH-positive Type II SCAs, and 6% for HNAs (P < .001 SCA vs HNA; P < .001 Type I vs HNA; and P = .08 Type II vs HNA). Expression of ACTH precursor pro-opiomelanocortin was 900-fold elevated in SCAs and 1300-fold elevated in Cushing disease-causing adenomas (CDCAs) vs HNAs (P < .001). Transcription of PC1/3, which cleaves pro-opiomelanocortin into ACTH, was 30-fold higher in CDCAs than SCAs (P = .02). CONCLUSION: In the largest series to date, SCAs exhibited comparable size, but increased cavernous sinus invasion and progression/recurrence vs HNAs. SCAs exhibit deficient pro opiomelanocortin to ACTH conversion. Close follow-up is warranted for SCAs. PMID- 23685642 TI - Reflective plasmonic color filters based on lithographically patterned silver nanorod arrays. AB - We demonstrate reflection-mode plasmonic color filters based on lithographically patterned silver nanorods with ultrasmall inter-rod gaps. Fine and effective tuning of the plasmon resonance is shown by varying array periodicities. We determine the dependence of reflected intensity on diameter/periodicity ratio and then develop reflective plasmonic color filters using dense nanorod arrays. Experimental results agree well with theoretical calculations. Our approach is potentially useful for plasmon-assisted sensing, imaging and displays. PMID- 23685643 TI - Whole-body nanoparticle aerosol inhalation exposures. AB - Inhalation is the most likely exposure route for individuals working with aerosolizable engineered nano-materials (ENM). To properly perform nanoparticle inhalation toxicology studies, the aerosols in a chamber housing the experimental animals must have: 1) a steady concentration maintained at a desired level for the entire exposure period; 2) a homogenous composition free of contaminants; and 3) a stable size distribution with a geometric mean diameter < 200 nm and a geometric standard deviation sigmag < 2.5 (5). The generation of aerosols containing nanoparticles is quite challenging because nanoparticles easily agglomerate. This is largely due to very strong inter-particle forces and the formation of large fractal structures in tens or hundreds of microns in size (6), which are difficult to be broken up. Several common aerosol generators, including nebulizers, fluidized beds, Venturi aspirators and the Wright dust feed, were tested; however, none were able to produce nanoparticle aerosols which satisfy all criteria (5). A whole-body nanoparticle aerosol inhalation exposure system was fabricated, validated and utilized for nano-TiO2 inhalation toxicology studies. Critical components: 1) novel nano-TiO2 aerosol generator; 2) 0.5 m(3) whole-body inhalation exposure chamber; and 3) monitor and control system. Nano TiO2 aerosols generated from bulk dry nano-TiO2 powders (primary diameter of 21 nm, bulk density of 3.8 g/cm(3)) were delivered into the exposure chamber at a flow rate of 90 LPM (10.8 air changes/hr). Particle size distribution and mass concentration profiles were measured continuously with a scanning mobility particle sizer (SMPS), and an electric low pressure impactor (ELPI). The aerosol mass concentration (C) was verified gravimetrically (mg/m(3)). The mass (M) of the collected particles was determined as M = (Mpost-Mpre), where Mpre and Mpost are masses of the filter before and after sampling (mg). The mass concentration was calculated as C = M/(Q*t), where Q is sampling flowrate (m(3)/min), and t is the sampling time (minute). The chamber pressure, temperature, relative humidity (RH), O2 and CO2 concentrations were monitored and controlled continuously. Nano TiO2 aerosols collected on Nuclepore filters were analyzed with a scanning electron microscope (SEM) and energy dispersive X-ray (EDX) analysis. In summary, we report that the nano-particle aerosols generated and delivered to our exposure chamber have: 1) steady mass concentration; 2) homogenous composition free of contaminants; 3) stable particle size distributions with a count-median aerodynamic diameter of 157 nm during aerosol generation. This system reliably and repeatedly creates test atmospheres that simulate occupational, environmental or domestic ENM aerosol exposures. PMID- 23685644 TI - A248, a novel synthetic HDAC inhibitor, induces apoptosis through the inhibition of specificity protein 1 and its downstream proteins in human prostate cancer cells. AB - Histone deacetylase (HDAC) inhibitors are emerging as potent anticancer agents due to their ability to induce apoptosis in various cancer cells, including prostate cancer cells. In the present study, we synthesized a novel HDAC inhibitor, A248, and investigated its apoptotic activity and molecular target in the DU145 and PC3 human prostate cancer cell lines. A248 inhibited the growth of DU145 and PC3 cells and induced apoptosis, as demonstrated by nuclear fragmentation and the accumulation of cells at subG1 phase of cell cycle. The treatment of DU145 and PC3 prostate cancer cells with A248 resulted in the downregulation of specificity protein 1 (Sp1) expression. Since the expression levels of survivin and Mcl-1 depend on Sp1, we also investigated the effects of A248 on survivin and Mcl-1 expression using western blot analysis and immunocytochemistry. The results showed that A248 markedly decreased the expression of survivin and Mcl-1. These data suggest that A248 has apoptotic activity in human prostate cancer cells and that Sp1 may be the molecular target of A248 treatment for inducing apoptosis in prostate cancer cells. PMID- 23685645 TI - Effect of dimethyl sulfoxide on ionic liquid 1-ethyl-3-methylimidazolium acetate pretreatment of eucalyptus wood for enzymatic hydrolysis. AB - Ground eucalyptus wood was pretreated with 1-ethyl-3-methylimidazolium acetate ([EMIM]OAc)-dimethyl sulfoxide (DMSO) solutions with different mixing ratios under various conditions. The changes in the composition and structure of the biomass were investigated; and the enzymatic hydrolysis performance of the pretreated biomass was evaluated. [EMIM]OAc-DMSO pretreatment had a relatively mild effect on the composition of the biomass, but excessively high pretreatment temperatures led to massive loss of xylan after pretreatment. The enzymatic digestibility of the biomass was significantly improved with increased pretreatment temperature. X-ray diffraction analysis revealed that the disruption of cellulose crystal structure by [EMIM]OAc at a sufficiently high temperature was primarily responsible for the remarkable improvement in the digestibility. Appropriate addition of DMSO could help minimize the consumption of [EMIM]OAc without impairing the performance of the ionic liquid, and contribute to the improvement in pretreatment efficiency due to the viscosity reduction effect on the pretreatment liquor. PMID- 23685646 TI - Robust nanobioconjugates of Candida antarctica lipase B--multiwalled carbon nanotubes: characterization and application for multiple usages in non-aqueous biocatalysis. AB - Present work elucidates two approaches for covalent attachment of the enzyme Candida antarctica lipase B (CALB) on multiwalled carbon nanotubes (MWCNTs). One method of enzyme immobilization involved carbodiimide chemistry while in the other approach, the cross linker (3-Aminopropyl) triethoxysilane (APTES) followed by succinic acid anhydride (SAA) were employed prior to carbodiimide activation. Modified MWCNTs were characterized by transmission electron microscopy (TEM), Fourier transformation infrared spectroscopic (FTIR), Raman spectroscopy and thermal gravitometric analysis (TGA). The lipase-MWCNTs conjugates were applied for synthesis of the flavor ester 'pentyl valerate' in cyclohexane and effects of solvent, temperature and agitation on ester synthesis were studied. Upon subject to reusability studies for 50 cycles, the bionanoconjugates were found to be highly sturdy and exhibited ~ 79% activity (immobilization using carbodiimide) whereas the nanoconjugate prepared using APTES and SAA retained only up to ~ 30% activity. PMID- 23685647 TI - Fouling potential evaluation of soluble microbial products (SMP) with different membrane surfaces in a hybrid membrane bioreactor using worm reactor for sludge reduction. AB - The fouling characteristics of soluble microbial products (SMP) in the membrane bioreactor coupled with Static Sequencing Batch Worm Reactor (SSBWR-MBR) were tested with different types of membranes. It was noted that the flux decrements of S-SMP (SMP in SSBWR-MBR) with cellulose acetate (CA), polyvinylidene fluoride (PVDF) and polyether sulfones (PES) membranes were respectively 6.7%, 8.5% and 9.5% lower compared to those of C-SMP (SMP in Control-MBR) with corresponding membranes. However, for both the filtration of the C-SMP and S-SMP, the CA membrane exhibited the fastest diminishing rate of flux among the three types of membranes. The surface morphology analysis showed that the CA membrane exhibited more but smaller protuberances compared to the PVDF and PES. The second minimums surrounding each protruding asperity on CA membrane were more than those on the PVDF and PES membranes, enhancing the attachment of SMP onto the membrane surface. PMID- 23685648 TI - Enhancement effect of ethanol on lipid and fatty acid accumulation and composition of Scenedesmus sp. AB - The effects of ethanol concentration gradients along with varied cultivation times on lipid and fatty acid accumulation and composition of Scenedesmus sp. were studied. The maximum increment of algal density, lipid productivity, lipid content and fatty acid content were 6.61, 11.75, 1.34 and 3.14 times higher than the control group under 12h photoperiod. Algal light deprivation inhibited ethanol positive effects on algal growth and lipid biomass. The cumulative quantity of C16:0 and C18:0 decreased correspondingly with the increase of ethanol concentrations and cultivation times. Besides, unsaturated fatty acids appeared early in algal cells and increased 57.02% in maximum. However, only 2.27% (14)C was transferred from ethanol to fatty acids. The results indicated that adding proper amount of ethanol in algal culture medium was beneficial to biodiesel feedstock production and biodiesel properties. PMID- 23685649 TI - The stability of aerobic granular sludge under 4-chloroaniline shock in a sequential air-lift bioreactor (SABR). AB - The aerobic granular sludge technology has a great potential in treatment of municipal wastewater and industrial wastewater containing toxic non-degradable pollutants. However, the formation and structural stability of aerobic granular sludge is susceptible to toxic shock. In the study, the effect of 4-chloroaniline (4-ClA) as a common toxic pollutant on the granular structure and performance was investigated, and the mechanism was revealed to provide more information on 4-ClA degradation with aerobic granular sludge process. The results showed that a 4-ClA shock at influent 200 mg L(-1) could cause the disintegration of aerobic granular sludge and decrease of the pollutant removal performance. The analysis of extracellular polymeric substances (EPS) within the mature and disintegrated granular sludge showed that the decrease of protein content in EPS, especially the components like Amide I 3-turn helix and beta-sheet structures and aspartate, was not good for the stability of aerobic granular sludge. The microbial community results demonstrated that the disappearance of dominant bacteria like Kineosphaera limosa or appearance like Acinetobacter, might contribute to the reduction of EPS and disintegration of aerobic granular sludge. PMID- 23685651 TI - A cigarette, doctor? ... No thanks! PMID- 23685650 TI - Comparison of sludge digestion under aerobic and anaerobic conditions with a focus on the degradation of proteins at mesophilic temperature. AB - Aerobic and anaerobic digestion are popular methods for the treatment of waste activated sludge. However, the differences in degradation of sludge during aerobic and anaerobic digestion remain unclear. In this study, the sludge degradation during aerobic and anaerobic digestion was investigated at mesophilic temperature, focused on protein based on the degradation efficiency and degree of humification. The duration of aerobic and anaerobic digestion was about 90 days. The final degradation efficiency of volatile solid was 66.1 +/- 1.6% and 66.4 +/- 2.4% under aerobic and anaerobic conditions, respectively. The final degradation efficiency of protein was 67.5 +/- 1.4% and 65.1 +/- 2.6% under aerobic and anaerobic conditions, respectively. The degradation models of volatile solids were consistent with those of protein under both aerobic and anaerobic conditions. The solubility of protein under aerobic digestion was greater than that under anaerobic digestion. Moreover, the humification index of dissolved organic matter of aerobic digestion was greater than that during anaerobic digestion. PMID- 23685652 TI - Almanac 2012: cell therapy in cardiovascular disease. the national society journals present selected research that has driven recent advances in clinical cardiology. AB - The rapid translation from bench to bedside that has been seen in the application of regenerative medicine to cardiology has led to exciting new advances in our understanding of some of the fundamental mechanisms related to human biology. The first generation of cells used in phase l-ll trials (mainly bone marrow mononuclear cells) are now entering phase III clinical trials with the goal of producing a cell-based therapeutic that can change the outcome of cardiac disease. First generation cell therapy appears to have addressed safety concerns as well as showing "activity" in numerous published meta-analyses. With the knowledge gained to date, the field is moving towards the next generation of cells-the "engineered" cell-that have been developed to display a phenotype that will further enhance the myocardial repair/salvage process. This almanac review covers the latest basic research that may soon have application to humans as well as the results of the latest clinical trials. PMID- 23685654 TI - Effects of chronic anaerobic training on markers of sub-clinical atherosclerosis. AB - INTRODUCTION: Although several cardiovascular adaptations in response to different types of exercise are already known, data comparing the effects of the type of exercise training on early markers of atherosclerosis are limited. METHODS: Forty-nine tennis players, 28 weightlifters and 20 non-trained healthy volunteers were recruited for the study. Flow-mediated dilatation (FMD) and intima-media thickness (IMT) in the carotid and femoral arteries were measured in all volunteers for assessment of endothelial function and vascular remodelling, respectively. RESULTS: Systolic blood pressure (BP) differed significantly among the three study groups (p=0.002) independently of age, body mass index (BMI), frequency, duration and intensity of exercise (p=0.033). FMD was significantly lower in weightlifters than tennis players (p=0.002), while mean carotid IMT was significantly higher in weightlifters as compared to tennis players (p=0.009) and the control group (p=0.003). Although the differences found in FMD were not independent of blood pressure and shear stress, mean carotid IMT remained significantly higher in weightlifters after adjustment for age, BMI and systolic BP, as well as the frequency, duration and intensity of exercise. CONCLUSIONS: The anaerobic exercise involved in weightlifting correlated with worse endothelial function and increased IMT as compared to exercise in the form of tennis. The type of anaerobic exercise may be an important determinant of subclinical atherosclerosis, possibly explaining the elevated cardiovascular risk seen in athletes performing anaerobic training. PMID- 23685653 TI - Effects of smoking on heart rate at rest and during exercise, and on heart rate recovery, in young adults. AB - INTRODUCTION: There is an established link between smoking, abnormal heart rate (HR) values, and impaired cardiovascular health in middle-aged or older populations. The purpose of this study was to examine the effects of smoking on resting HR and on HR responses during and after exercise in young adults. METHODS: A sample of 298 young adults (159 men), aged 20-29 years old, were selected from a large population of health-science students based on health status, body mass index, physical activity, and smoking habit. All subjects underwent a maximal Bruce treadmill test and their HR was recorded during, at peak, and after termination of exercise. RESULTS: Smokers had significantly higher resting HR values than non-smokers. Both female and male smokers showed a significantly slower HR increase during exercise. Female smokers failed to reach their age-predicted maximum HR by 6.0 bpm and males by 3.6 bpm. The actual maximum HR achieved (HRmax) was significantly lower for both female smokers (191.0 bpm vs.198.0 bpm) and male smokers (193.2 bpm vs.199.3 bpm), compared to non-smokers. Heart rate reserve was also significantly lower in female (114.6 bpm vs. 128.1 bpm) and male smokers (120.4 bpm vs. 133.0 bpm). During recovery, the HR decline was significantly attenuated, but only in female smokers. Females had a higher resting HR and showed a higher HR response during sub-maximal exercise compared to males. CONCLUSIONS: Smoking was found to affect young smokers' HR, increasing HR at rest, slowing HR increase during exercise and impairing their ability to reach the age-predicted HRmax. In addition, smoking was associated with an attenuated HR decline during recovery, but only in females. PMID- 23685655 TI - Cryoablation of atrioventricular nodal reentrant tachycardia in children and adolescents: improved long-term outcomes with increasing experience. AB - BACKGROUND: Cryoablation is increasingly used for the treatment of atrioventricular nodal reentrant tachycardia (AVNRT). There are limited data regarding its efficacy and late outcomes in the pediatric population. METHODS: We reviewed the clinical records of 70 consecutive pediatric and adolescent patients (mean age: 12.2 +/- 3, range: 5-19 years) with AVNRT, with or without additional structural heart disease, who underwent catheter ablation with the intention to use cryoablation as the primary modality between September 2004 and July 2011. RESULTS: The acute success rate was 97.14%. No long-term complications occurred. Patients were followed up for an average time of 46 +/- 22.5 months (range 5-90). The recurrence rate was 16%, decreasing from 28% in the first 25 cases to 8.9% in the last 45 cases (p<0.05). Wenckebach point prolongation during cryoapplications was associated with a lower recurrence rate (p<0.05). No other risk factors for recurrence were identified, including persistence of slow pathway conduction. Patients with congenital heart disease had a similar success rate to patients with a structurally normal heart. CONCLUSIONS: When applied to pediatric patients, cryoablation has an excellent success and safety profile, which can improve with increasing experience. Transient Wenckebach point prolongation during cryo-applications may be associated with improved late outcomes. PMID- 23685656 TI - Correlation of plasma B-type natriuretic peptide with shunt volume in children with congenital heart disease involving left-to-right shunt. AB - INTRODUCTION: Concentrations of B-type natriuretic peptide (BNP) are recognised as a reliable marker of ventricular dysfunction in adults. In this study, plasma levels of BNP were determined in children with congenital heart disease (CHD) involving a left-to-right shunt, and were correlated with the shunt volume. METHODS: Seventy-six children (38 boys/38 girls, mean age 22.4 months) with CHD (Group A: 31 with atrial septal defect [ASD], 23 with ventricular septal defect [VSD], 8 with ASD and VSD, 14 with patent ductus arteriosus [PDA]) and 34 healthy children (group B) were studied. BNP was measured by chemiluminescent microparticle immunoassay in all children. The amount of shunt (the ratio of pulmonary blood flow/systemic blood flow: Qp/Qs) was measured using Doppler velocimetry and two-dimensional echocardiography. A haemodynamically significant left-to-right shunt was defined as Qp/Qs>1.5. Correlations were evaluated between all patient groups and healthy subjects and BNP was compared with echocardiographic data reflecting right and left ventricle volume overload. RESULTS: Thirty-four children of group A had Qp/Qs>1.5 (group A1) and 42 Qp/Qs<1.5 (group A2). BNP levels were higher in group A1 than group A2 (p=0.015), while there were no significant differences in BNP between group A2 and group B (p=0.79). BNP 24.4 pg/ml was determined as the cut-off point to identify patients with Qp/Qs>1.5. BNP values were similar among patients with ASD and VSD, but they were significantly higher in patients with PDA. BNP was positively correlated with Qp/Qs (r=0.59, p<0.001), and with the pulmonary artery velocity (r=0.27) and gradient (r=0.49), while there was a negative correlation with ejection fraction (r=-0.14). BNP levels were significantly higher in 10 infants with clinical signs of heart failure (p=0.025). CONCLUSION: These results, which are consistent with previous reports, suggest a possible role of BNP as an early diagnostic marker of the significance of shunt in children with CHD. PMID- 23685657 TI - Practical recommendations for the diagnosis, investigation and management of hypertension in children and adolescents: hellenic society of hypertension consensus document. PMID- 23685658 TI - The impact of bariatric surgery procedures on type 2 diabetes, hyperlipidemia and hypertension. PMID- 23685659 TI - Diastolic flow within the pulmonary trunk in children: differential diagnosis. PMID- 23685660 TI - Transcatheter closure of an atrial septal defect with single coronary artery and retro-aortic right coronary artery. AB - Isolated single coronary artery in the presence of an atrial septal defect (ASD) is a rare congenital anomaly. There are no clear guidelines regarding the management of ASD in these patients. Transcatheter closure of the ASD in the presence of a single coronary artery that has a retro-aortic course is a matter of concern because of the possible risk of coronary impingement by the left atrial disc. Here we report the first case of an ASD device closure in a patient with a retro-aortic right coronary artery. The immediate results were good; however, long-term follow up is warranted to look for late complications. PMID- 23685661 TI - Right-sided implantation of a cardiac resynchronization therapy defibrillator in a case of persistent left superior vena cava. AB - Persistent left superior vena cava represents a congenital venous anomaly that poses a particular obstacle to the implantation of cardiac rhythm management devices. In the present report we briefly describe the rightsided implantation of a biventricular defibrillator in a patient with persistent left superior vena cava. We also briefly discuss the technically challenging procedures applied in such cases. PMID- 23685662 TI - Cardiac resynchronization therapy in becker muscular dystrophy. AB - A 44-year-old male patient with known Becker muscular dystrophy and concomitant non-ischemic dilated cardiomyopathy presented to our department because of worsening heart failure and presyncope. Upon admission, the patient was in New York Heart Association functional class III despite optimal pharmacological treatment; his ECG showed sinus rhythm with left bundle branch block and a wide QRS complex. Non-sustained ventricular tachycardia was recorded during 24-hour Holter monitoring. A complete three-dimensional echocardiographic study was performed and documented the dilatation and concomitant hypertrabeculation of the left ventricle (LV), with severely depressed systolic LV performance (ejection fraction 20%), as well as mechanical dyssynchrony--mainly in terms of intraventricular delay. A biventricular cardioverter-defibrillator (CRT-D) was implanted in this patient, with the LV lead in a lateral vein and the right ventricular defibrillating lead in the apical part of the interventricular septum. Echocardiography-guided device programming was performed in order to achieve the optimal atrio-, inter-, and intraventricular resynchronization. The patient's clinical condition was substantially improved within one month after the implantation. PMID- 23685663 TI - Compliance and fixed-dose combination therapy in a sample of greek hypertensive patients. PMID- 23685664 TI - "Beware old age, for it never comes alone". PMID- 23685665 TI - Aging, genes and environment: lessons from the Ikaria study. PMID- 23685666 TI - Why culture matters in health interventions: lessons from HIV/AIDS stigma and NCDs. AB - Theories about health behavior are commonly used in public health and often frame problems as ascribed or related to individuals' actions or inaction. This framing suggests that poor health occurs because individuals are unable or unwilling to heed preventive messages or recommended treatment actions. The recent United Nations call for strategies to reduce the global disease burden of noncommunicable diseases like diabetes requires a reassessment of individual based approaches to behavior change. We argue that public health and health behavior intervention should focus more on culture than behavior to achieve meaningful and sustainable change resulting in positive health outcomes. To change negative health behaviors, one must first identify and promote positive health behaviors within the cultural logic of its contexts. To illustrate these points, we discuss stigma associated with obesity and human immunodeficiency virus and acquired immune deficiency syndrome. We conclude that focusing on positive behaviors and sustaining cultural and personal transformations requires a culturally grounded approach to public health interventions, such as that provided by the PEN-3 model. PMID- 23685667 TI - Three-dimensional radiochromic film dosimetry for volumetric modulated arc therapy using a spiral water phantom. AB - We validated 3D radiochromic film dosimetry for volumetric modulated arc therapy (VMAT) using a newly developed spiral water phantom. The phantom consists of a main body and an insert box, each of which has an acrylic wall thickness of 3 mm and is filled with water. The insert box includes a spiral film box used for dose distribution measurement, and a film holder for positioning a radiochromic film. The film holder has two parallel walls whose facing inner surfaces are equipped with spiral grooves in a mirrored configuration. The film is inserted into the spiral grooves by its side edges and runs along them to be positioned on a spiral plane. Dose calculation was performed by applying clinical VMAT plans to the spiral water phantom using a commercial Monte Carlo-based treatment-planning system, Monaco, whereas dose was measured by delivering the VMAT beams to the phantom. The calculated dose distributions were resampled on the spiral plane, and the dose distributions recorded on the film were scanned. Comparisons between the calculated and measured dose distributions yielded an average gamma-index pass rate of 87.0% (range, 91.2-84.6%) in nine prostate VMAT plans under 3 mm/3% criteria with a dose-calculation grid size of 2 mm. The pass rates were increased beyond 90% (average, 91.1%; range, 90.1-92.0%) when the dose-calculation grid size was decreased to 1 mm. We have confirmed that 3D radiochromic film dosimetry using the spiral water phantom is a simple and cost-effective approach to VMAT dose verification. PMID- 23685668 TI - Pelvic insufficiency fracture after definitive radiotherapy for uterine cervical cancer: retrospective analysis of risk factors. AB - The purpose of this study is to determine the incidence, clinical characteristics and risk factors of postradiation pelvic insufficiency fracture (PIF) in women with uterine cervical cancer. We reviewed the medical records of 126 patients who received definitive radiotherapy (RT) for uterine cervical cancer between 2003 and 2009 at our institution. Among them, 99 patients who underwent at least one computed tomography (CT) or magnetic resonance imaging of the pelvis during their follow-up at more than 6 months were included in this analysis. The relationship between the incidence of PIF and several patient- and treatment-related factors was analyzed. The median follow-up period was 21 months. Of the 126 patients, 33 (with a total of 50 lesions) were diagnosed with PIF. The 2-year cumulative incidence was 32%. Univariate analysis showed that age >=70 years (P= 0.0010), postmenopausal state (P = 0.0013), and lower CT density of bone and bone marrow (P= 0.020) significantly related to PIF. In a multivariate analysis, of the 59 patients whose CT densities were evaluable, lower CT density was the only significant factor associated with PIF (P = 0.0026). In conclusion, postradiation PIFs were detected in a considerable number of patients after definitive RT for cervical cancer. Predisposing factors were older age, postmenopausal state, and decreased density of bone and bone marrow on CT. PMID- 23685669 TI - 198Au grain implantation for early tongue cancer in patients of advanced age or poor performance status. AB - Brachytherapy using (198)Au grains is minimally invasive and the only curative treatment for early tongue cancer in patients of advanced age or poor performance status available in our institution. From March 1993 to February 2008, (198)Au grains were used to treat a group of 96 Stage I-II tongue cancer patients who could not undergo surgery or brachytherapy using (192)Ir pins because of an advanced age (>=75 years) or poor performance status (>=2). The patients were followed for 3.9 +/- 3.3 years, and the cause-specific survival and local control rates were determined. Survival analyses were performed using the Kaplan-Meier method, and univariate and multivariate analyses were performed using the Cox proportional hazard model. The results were compared with those for a group of 193 early tongue-cancer patients who underwent treatment using iridium pins. The 5-year cause-specific survival and local control rates of the (198)Au grains group were 71% and 68%, respectively, both of which were 16% lower than the corresponding rates for the (192)Ir pins group. Our study demonstrated that as the last curative treatment available, (198)Au grain implantation could be used to achieve moderate treatment results for early tongue cancer in patients of advanced age or poor performance status. PMID- 23685670 TI - The role of nitric oxide radicals in removal of hyper-radiosensitivity by priming irradiation. AB - In this study, a mechanism in which low-dose hyper-radiosensitivity (HRS) is permanently removed, induced by low-dose-rate (LDR) (0.2-0.3 Gy/h for 1 h) but not by high-dose-rate priming (0.3 Gy at 40 Gy/h) was investigated. One HRS negative cell line (NHIK 3025) and two HRS-positive cell lines (T-47D, T98G) were used. The effects of different pretreatments on HRS were investigated using the colony assay. Cell-based ELISA was used to measure nitric oxide synthase (NOS) levels, and microarray analysis to compare gene expression in primed and unprimed cells. The data show how permanent removal of HRS, previously found to be induced by LDR priming irradiation, can also be induced by addition of nitric oxide (NO) donor DEANO combined with either high-dose-rate priming or exposure to prolonged cycling hypoxia followed by reoxygenation, a treatment not involving radiation. The removal of HRS appears not to involve DNA damage induced during priming irradiation as it was also induced by LDR irradiation of cell-conditioned medium without cells present. The permanent removal of HRS in LDR-primed cells was reversed by treatment with inducible nitric oxide synthase (iNOS) inhibitor 1400W. Furthermore, 1400W could also induce HRS in an HRS-negative cell line. The data suggest that LDR irradiation for 1 h, but not 15 min, activates iNOS, and also that sustained iNOS activation is necessary for the permanent removal of HRS by LDR priming. The data indicate that nitric oxide production is involved in the regulatory processes determining cellular responses to low-dose-rate irradiation. PMID- 23685671 TI - Unexpected non-Hoogsteen-based mutagenicity mechanism of FaPy-DNA lesions. AB - 8-Oxopurines (8-oxodG and 8-oxodA) and formamidopyrimidines (FaPydG and FaPydA) are major oxidative DNA lesions involved in cancer development and aging. Their mutagenicity is believed to result from a conformational shift of the N9-C1' glycosidic bonds from anti to syn, which allows the lesions to form noncanonical Hoogsteen-type base pairs with incoming triphosphates during DNA replication. Here we present biochemical data and what are to our knowledge the first crystal structures of carbocyclic FaPydA and FaPydG containing DNA in complex with a high fidelity polymerase. Crystallographic snapshots show that the cFaPy lesions keep the anti geometry of the glycosidic bond during error-free and error-prone replication. The observed dG.dC->dT.dA transversion mutations are the result of base shifting and tautomerization. PMID- 23685673 TI - The relationship between anorexia nervosa and body dysmorphic disorder. AB - Anorexia nervosa (AN) and body dysmorphic disorder (BDD) are severe body image disorders that highly impair individuals in their daily functioning. They are discrete but overlapping nosological entities. In this review, we examine similarities between AN and BDD with regard to clinical, personality and demographic aspects, such as comorbidity, phenomenology, and treatment outcome. The review suggests that the two disorders are highly comorbid, and show similar ages of onset, illness trajectories, and comparable clinical and personality characteristics. However, important differences emerge in their responsiveness to psychosocial and psychopharmacological treatment, which are discussed. Clinical implications of these findings are summarized and directions for future research are delineated, with a focus on how current treatment components from each disorder may inform new interventions for both disorders. PMID- 23685674 TI - Ultrasound and MRI of the peroneal tendons and associated pathology. AB - Lateral ankle pain is common with overuse and sports-related injuries and may cause considerable morbidity. The differential diagnosis of lateral ankle pain is extensive. Disorders of the peroneal tendons should be an important consideration during interpretation of a routine ankle magnetic resonance imaging (MRI) or ultrasound (US). This article presents a review of the common causes of peroneal tendon pathology with particular reference to anatomy, US, and MRI features. The importance of dynamic evaluation with ultrasound is also emphasized. PMID- 23685676 TI - A platinum turnstile with a palladium lock. AB - An organometallic molecular turnstile composed of a stator based on an alpha,omega-diphosphine bearing, in a symmetric fashion, the 2,6-pyridyl diamide moiety as a central tridentate chelating unit and a rotor composed of Pt(II) equipped with two pyridyl groups in trans configuration was designed. The switching between its open and closed states using Pd(II) was investigated both in solution and in the solid state. PMID- 23685677 TI - Effects of strontium impurity on the structure and dynamics of Al88Si12 liquid. AB - The effects of strontium modification on the structure and dynamics of Al88Si12 liquid are studied by means of ab initio molecular dynamics simulations. By replacing 0.5% and 4.0% of Al with Sr, we show that the addition of Sr lowers the self-diffusion of Al and Si of the liquid and reduces the nearest-neighbor correlation between Si atoms. The simulation provides an explanation for the change in morphology of the eutectic phases observed in rapidly solidified Al-Si alloys modified with Sr. PMID- 23685672 TI - Inhibitors that stabilize a closed RAF kinase domain conformation induce dimerization. AB - RAF kinases have a prominent role in cancer. Their mode of activation is complex but critically requires dimerization of their kinase domains. Unexpectedly, several ATP-competitive RAF inhibitors were recently found to promote dimerization and transactivation of RAF kinases in a RAS-dependent manner and, as a result, undesirably stimulate RAS/ERK pathway-mediated cell growth. The mechanism by which these inhibitors induce RAF kinase domain dimerization remains unclear. Here we describe bioluminescence resonance energy transfer-based biosensors for the extended RAF family that enable the detection of RAF dimerization in living cells. Notably, we demonstrate the utility of these tools for profiling kinase inhibitors that selectively modulate RAF dimerization and for probing structural determinants of RAF dimerization in vivo. Our findings, which seem generalizable to other kinase families allosterically regulated by kinase domain dimerization, suggest a model whereby ATP-competitive inhibitors mediate RAF dimerization by stabilizing a rigid closed conformation of the kinase domain. PMID- 23685678 TI - Simple and efficient synthesis of [MCI(NHC)] (M = Au, Ag) complexes. AB - A facile and efficient synthetic route leading to catalytically relevant N heterocyclic carbene (NHC) gold complexes is described. The method consists of one pot synthesis starting from readily available imidazolium salts and [AuCl(tht)], in the presence of K2CO3. Using the same protocol NHC silver complexes have been synthesised starting from AgNO3. PMID- 23685679 TI - Renohepatic crosstalk: does acute kidney injury cause liver dysfunction? AB - The concept of hepatorenal syndrome is well recognized, although incompletely understood. The converse clinical problem of hepatic dysfunction in patients with acute kidney injury (AKI) is less well recognized yet may be a contributor to the high patient morbidity and mortality seen in this group. This review draws together the available evidence for AKI's effect on the liver from animal models, pharmacological studies and recent clinical data. It examines liver function beyond clinically used blood tests, to determine the effect of AKI on hepatic synthetic function, acute phase response and drug metabolism. Parallels are drawn with other organ crosstalk in AKI and with liver-kidney interactions in chronic kidney disease. Definition of the pathophysiology of renohepatic crosstalk may lead to improved management strategies for this vulnerable patient group. PMID- 23685680 TI - Restitutio ad integrum: a dream or a real possibility? AB - The subject of organ regeneration has attracted substantial investigative attention and has been extensively reviewed. Therefore, I shall focus on several only recently emerged issues and on those aspects of stem cell-mediated regeneration which, although are important in my opinion, have nevertheless evaded the radar of scientific pursuit. Specifically, I shall describe the recent work on the prominence of local lineage-restricted stem cells, as opposed to the bone marrow-derived or circulating ones, in regeneration. This will be followed by an attempt to re-interpret a bulk of published data on the beneficial effects of cell therapy with the focus on the secretome of stem cells. Multiple factors that conspire to cause insufficient or failed regeneration in adult mammals will be screened with emphasis placed on the mechanical forces, senescence and exhaustion, each leading to phenotypical switch and/or stem cell incompetence. Finally, I shall enumerate several potential pathways to induce or restore stem cell competence. Although a significant amount of work has been performed in the non-renal field, I would hope that some of the mechanisms and concepts discussed herein will eventually trickle into kidney regeneration. PMID- 23685681 TI - Anatomy of an evidence-based policy. PMID- 23685682 TI - Neutralizing a caustic chemical. PMID- 23685686 TI - An algorithm for care: managing type 2 diabetes. PMID- 23685687 TI - Observing electroconvulsive therapy. PMID- 23685689 TI - Put a stop to bullying new nurses. PMID- 23685691 TI - Getting a grip on stress. PMID- 23685692 TI - A gift from the heart. PMID- 23685693 TI - How is patient education linked to patient satisfaction? PMID- 23685695 TI - Dimensional analysis: calculate dosages the easy way. PMID- 23685696 TI - How effective are nerve blocks after orthopedic surgery? A quality improvement study. PMID- 23685698 TI - Teaching patients with an intellectual disability. PMID- 23685700 TI - Supramolecular alignment of gold nanorods via cucurbit[8]uril ternary complex formation. AB - We have shown, for the first time, that a three component system is capable of aligning gold nanorods (AuNRs) through supramolecular host-guest interactions leading to control over AuNR end-to-end assembly. Viologen end-functionalised AuNRs were prepared that were capable of selectively binding to a cucurbit[8]uril (CB[8]) macrocyclic host molecule. These end-functionalised AuNRs could participate in 1 : 1 : 1 ternary complexation with synthesised telechelic linker molecules bearing second guest moieties, in the presence of CB[8]. When the linker length was long and flexible aggregation and precipitation of AuNRs were readily observed, but with no control over the AuNR conformation. On the other hand, when the linker length was shortened thereby imparting a more rigid connection between neighboring gold nanorods, the end-to-end assembly of AuNRs was achieved. We also note that in the presence of a molecule capable of occupying the entirety of the CB[8] cavity, end-to-end assembly is not observed as the system's ability to form a 1 : 1 : 1 ternary complex is halted. Thus, the end-to-end assembly relies upon both having a relatively short and rigid linker as well as the specific, yet tuneable supramolecular 1 : 1 : 1 ternary complexation between the three components. PMID- 23685701 TI - Modelling of calcium leaching and its influence on radionuclide migration across the concrete engineered barrier in a NSDF. AB - A multi barrier concept of disposal is adopted for both low and intermediate level radioactive waste disposal to prevent the spread of radionuclides into the human environment. Concrete engineered barrier is a part of multi barrier system for radioactive waste disposal. As long as the concrete barrier is intact, the containment of radioactive waste within the disposal facility is assured. However, every concrete structure has a finite lifetime. Concrete barriers degrade with time with lifetime dependent on type of concrete, external and internal environmental factors. This degradation allows the free moment of the radionuclides out of the concrete barrier. Hence an attempt was made to model the Calcium (Ca) leaching from side wall of a concrete engineered barrier in a Near Surface Disposal Facility (NSDF) and its influence on radionuclide migration across the concrete barrier, limited to conditions specified in the paper. The conceptual model assumes that rain water seeps into the engineered barrier through the top cover and dissolves radionuclides from the nuclear waste matrix. The modelling was attempted with Finite Difference analysis and validated with the results available in literature. The influence of Ca leaching on radionuclide migration in concrete barrier has been discussed for eight different radionuclides (Cs-137, Sr-90, I-129, H-3, Pu-239, Am-241, Co-60 and Tc-99). PMID- 23685702 TI - Studies on soil to grass transfer factor (Fv) and grass to milk transfer coefficient (Fm) for cesium in Kaiga region. AB - Detailed studies were carried out to establish site-specific soil to grass transfer factors (Fv) and grass to cow milk transfer coefficients (Fm) for radioactive cesium ((137)Cs) and stable cesium (Cs) for Kaiga region, where a nuclear power station has been in operation for more than 10 years. The study included adopted cows, cows of local farmers, and cows from the dairy farm. A grass field was developed specifically for the study and 2 local breed cows were adopted and allowed to graze in this grass field. The soil and grass samples were collected regularly from this field and analyzed for the concentrations of (137)Cs and stable Cs to evaluate the soil to grass Fv values. The milk samples from the adopted cows were analyzed for the (137)Cs and stable Cs concentrations to evaluate Fm values. For comparison, studies were also carried out in dominant grazing areas in different villages around the nuclear power plant and the cows of local farmers which graze in these areas were identified and milk samples were collected and analyzed regularly. The geometric mean values of Fv were found to be 1.1 * 10(-1) and 1.8 * 10(-1) for (137)Cs and stable Cs, respectively. The Fm of (137)Cs had geometric mean values of 1.9 * 10(-2) d L(-1) and 4.6 * 10(-2) d L(-1), respectively, for adopted Cows 1 and 2; 1.7 * 10(-2) d L(-1) for the cows of local farmers, and 4.0 * 10(-3) d L(-1) for the dairy farm cows. The geometric mean values of Fm for stable Cs were similar to those of (137)Cs. The Fm value for the dairy farm cows was an order of magnitude lower than those for local breed cows. The Fm values observed for the local breed cows were also an order of magnitude higher when compared to the many values reported in the literature and in the IAEA publication. Possible reasons for this higher Fm values were identified. The correlation between Fv and Fm values for (137)Cs and stable Cs and their dependence on the potassium content ((40)K and stable K) in the soil and grass were also studied. In order to estimate the ingestion dose accurate data of the dietary habits of the population was necessary and this data was collected through a well planned demographic survey. The internal doses to a child due to the ingestion of (137)Cs along with the milk of the local cows and from the dairy farm were found to be 0.29 MUSv y(-1) and 0.04 MUSv y(-1),while that to an adult were 0.39 MUSv y(-1) and 0.05 MUSv y(-1), respectively. PMID- 23685704 TI - Automatic Atlas-based Three-label Cartilage Segmentation from MR Knee Images. AB - This paper proposes a method to build a bone-cartilage atlas of the knee and to use it to automatically segment femoral and tibial cartilage from T1 weighted magnetic resonance (MR) images. Anisotropic spatial regularization is incorporated into a three-label segmentation framework to improve segmentation results for the thin cartilage layers. We jointly use the atlas information and the output of a probabilistic k nearest neighbor classifier within the segmentation method. The resulting cartilage segmentation method is fully automatic. Validation results on 18 knee MR images against manual expert segmentations from a dataset acquired for osteoarthritis research show good performance for the segmentation of femoral and tibial cartilage (mean Dice similarity coefficient of 78.2% and 82.6% respectively). PMID- 23685703 TI - Direct imaging of ER calcium with targeted-esterase induced dye loading (TED). AB - Visualization of calcium dynamics is important to understand the role of calcium in cell physiology. To examine calcium dynamics, synthetic fluorescent Ca(2+) indictors have become popular. Here we demonstrate TED (= targeted-esterase induced dye loading), a method to improve the release of Ca(2+) indicator dyes in the ER lumen of different cell types. To date, TED was used in cell lines, glial cells, and neurons in vitro. TED bases on efficient, recombinant targeting of a high carboxylesterase activity to the ER lumen using vector-constructs that express Carboxylesterases (CES). The latest TED vectors contain a core element of CES2 fused to a red fluorescent protein, thus enabling simultaneous two-color imaging. The dynamics of free calcium in the ER are imaged in one color, while the corresponding ER structure appears in red. At the beginning of the procedure, cells are transduced with a lentivirus. Subsequently, the infected cells are seeded on coverslips to finally enable live cell imaging. Then, living cells are incubated with the acetoxymethyl ester (AM-ester) form of low-affinity Ca(2+) indicators, for instance Fluo5N-AM, Mag-Fluo4-AM, or Mag-Fura2-AM. The esterase activity in the ER cleaves off hydrophobic side chains from the AM form of the Ca(2+) indicator and a hydrophilic fluorescent dye/Ca(2+) complex is formed and trapped in the ER lumen. After dye loading, the cells are analyzed at an inverted confocal laser scanning microscope. Cells are continuously perfused with Ringer like solutions and the ER calcium dynamics are directly visualized by time-lapse imaging. Calcium release from the ER is identified by a decrease in fluorescence intensity in regions of interest, whereas the refilling of the ER calcium store produces an increase in fluorescence intensity. Finally, the change in fluorescent intensity over time is determined by calculation of DeltaF/F0. PMID- 23685705 TI - HMGB1 release by human liver L02 and HepG2 cells induced by lipopolysaccharide. AB - Liver cells release the high mobility group box-1 (HMGB1) protein when exposed to lipopolysaccharides (LPSs). However, the timing and levels of protein released remain unclear. The present study aimed to characterize the secretion of the late pro-inflammatory cytokine HMGB1 by liver L02 and HepG2 cells. The human mononuclear macrophage cell line U937 was used as a control. Various concentrations of LPS were added to human U937, L02 and HepG2 cells for different durations, and the cells were analyzed at different time-points following this addition. Reverse transcription polymerase chain reaction (RT-PCR) was used to measure cellular HMGB1 mRNA levels, western blotting was performed to detect HMGB1 in cellular supernatants and the translocation of HMGB1 from the nucleus to the cytosol was examined using immunofluorescence staining. L02 and HepG2 cells exhibited higher HMGB1 mRNA levels compared with the control U937 cells 20 and 24 h following continuous exposure to LPS. U937 cells exhibited higher HMGB1 mRNA levels compared with the corresponding L02 and HepG2 cells 16 h following LPS exposure. The phase of HMGB1 protein detected in the cellular supernatants of L02 and HepG2 cells (16 h) was later than that of U937 cells (8 h). For the three cell lines, HMGB1 levels demonstrated a time dependency; however, the protein level was the highest in U937 cells. In the three cell lines, translocation of HMGB1 from the nucleus to the cytosol occurred; however, the phases of HMGB1 translocation in L02 and HepG2 cells occurred later than in U937 cells. LPS induced secretion of the late pro-inflammatory cytokine HMGB1 by liver cells is characterized by a late phase of release and smaller quantity, and the process of HMGB1 secretion appears to be associated with HMGB1 translocation. PMID- 23685707 TI - Lessons from radiofrequency redo-procedure after cryoballoon pulmonary vein isolation for paroxysmal atrial fibrillation. AB - BACKGROUND: To gain further insights into mechanisms leading to atrial fibrillation (AF) recurrence after a first ablation procedure using cryoballoon technique, the data collected during redo procedure were analyzed. METHODS AND RESULTS: From a total of 112 patients who underwent cryoballoon pulmonary vein isolation (PVI) for paroxysmal AF, 44 had a second ablation procedure using radiofrequency catheter, because of recurrent atrial arrhythmia. PV reconduction was observed in 109 of the 171 initially isolated veins (64%). Conduction recovery was found, respectively, at the left inferior PV, right inferior PV, right superior PV and left superior PV in 35 patients (80%), 26 patients (67%), 23 patients (52%) and 17 patients (39%). The mean number of reconnected PVs per patient was significantly lower with the 23-mm cryoballoon as compared to the 28 mm. Conduction gaps were focal and located at inferior parts of inferior veins and at the ridge between left atrial appendage and left veins. Mean procedure and fluoroscopy time were 109 +/- 32 min and 14.7 +/- 8.3 min, respectively. A 3-D mapping system was used in only 8 patients (18%). CONCLUSIONS: Atrial arrhythmia recurrences following cryoballoon PVI were associated with focal PV reconnections, occurring at preferential anatomical sites. These gaps were readily ablated with focal radiofrequency delivery, explaining the lack of need of 3-D mapping system and short procedure time. These results do not support the use of cryoballoon to perform redo procedures. PMID- 23685706 TI - Long-term outcome of drug-eluting vs. bare-metal stents in patients with acute myocardial infarction. Subgroup analysis of the nagoya acute myocardial infarction study (NAMIS). AB - BACKGROUND: The purpose of the present study was to compare the 5-year clinical outcomes after implantation of drug-eluting stent (DES) and bare-metal stent (BMS) in Japanese patients with acute myocardial infarction (AMI). METHODS AND RESULTS: This study was a subgroup analysis of the Nagoya Acute Myocardial Infarction Study (NAMIS). It included 658 AMI patients, of which 280 were treated with a DES and 378 with a BMS. The major adverse cardiac event (MACE)-free rates during the 5-year follow-up period were similar between the 2 groups (95.7% vs. 96.8%, P=0.482). A significant difference was seen, however, in the target lesion revascularization (TLR) rates (7.9% vs. 17.7%, P<0.0001). Interestingly, there was no significant difference between the 2 groups from year 1 to 5 with regard to late TLR (2.5% vs. 2.1%, P=0.906), despite the markedly lower incidence of TLR within the first year in the DES group compared with the BMS group (5.4% vs. 15.6%, P<0.0001). CONCLUSIONS: In this long-term follow-up analysis of DES compared to BMS in Japanese patients with AMI, there was no significant difference in the incidence of MACE. Although a lower rate of TLR was observed in DES group within the first year, the superiority of DES in relation to the incidence of TLR disappeared after the first year following primary percutaneous coronary intervention. PMID- 23685708 TI - Ewing sarcoma versus osteomyelitis: differential diagnosis with magnetic resonance imaging. AB - OBJECTIVE: To find and evaluate characteristic magnetic resonance imaging (MRI) patterns for the differentiation between Ewing sarcoma and osteomyelitis. MATERIALS AND METHODS: We identified 28 consecutive patients referred to our department for MRI (1.5 T) of an unclear bone lesion with clinical symptoms suggestive of Ewing sarcoma or osteomyelitis. MRI scans were re-evaluated by two experienced radiologists, typical MR imaging features were documented and a diagnostic decision between Ewing sarcoma and osteomyelitis was made. Statistical significance of the association between MRI features and the biopsy-based diagnosis was assessed using Fisher's exact test. RESULTS: The most clear-cut pattern for determining the correct diagnosis was the presence of a sharp and defined margin of the bone lesion, which was found in all patients with Ewing sarcoma, but in none of the patients with osteomyelitis (P < 0.0001). Contrast enhancing soft tissue was present in all cases with Ewing sarcoma and absent in 4 patients with osteomyelitis (P = 0.0103). Cortical destruction was found in all patients with Ewing sarcoma, 4 patients with osteomyelitis did not present any cortical reaction (P = 0.0103). Cystic or necrotic areas were identified in 13 patients with Ewing sarcoma and in 1 patient with osteomyelitis (P = 0.004). Interobserver reliability was very good (kappa = 1) in Ewing sarcoma and moderate (kappa = 0.6) in patients with osteomyelitis. CONCLUSIONS: A sharp and defined margin, optimally visualized on T1-weighted images in comparison to short tau inversion recovery (STIR) images, is the most significant feature of Ewing sarcoma in differentiating from osteomyelitis. PMID- 23685709 TI - Imaging evaluation of inflammation in the musculoskeletal system: current concepts and perspectives. AB - Inflammation is the non-specific stereotyped reaction of the musculoskeletal system to various types of aggression, such as infection, tumor, autoimmune diseases, or trauma. Precise evaluation and, increasingly, reliable quantification of inflammation are now key factors for optimal patient management, as targeted therapies (e.g., anti-angiogenesis, anti-macrophages, anti-cytokines) are emerging as everyday drugs. In current practice, inflammation is evaluated mostly using MRI and US on the basis of its non-specific extracellular component due to the increased volume of free water. Inflamed tissue is described as areas of low T1 signal and high T2 signal on magnetic resonance imaging or as hypoechogenic areas on ultrasound imaging, and the evaluation of the increased tissue vascularity can be performed using gadolinium enhanced MRI or power Doppler US. Emerging new imaging tools, regrouped under the label "cellular and molecular imaging" and defined as the in vivo characterization and measurement of biologic processes at the cellular and molecular level, demonstrate the possible shift of medical imaging from a macroscopic and non-specific level to a microscopic and targeted scale. Cellular and molecular imaging now allows the investigation of specific pathways involved in inflammation (e.g., angiogenesis, cell proliferation, and recruitment, proteases generation, metabolism, gene expression). PET and SPECT imaging are the most commonly used "molecular" imaging modalities, but recent progress in MR, US, and optical imaging has been made. In the future, those techniques might enable a detection of inflammation at its very early stage, its quantification through the definition of biomarkers, and possibly demonstrate the response to therapy at molecular and cellular levels. PMID- 23685710 TI - Real-time sonoelastography of Achilles tendon in patients with ankylosing spondylitis. AB - OBJECTIVE: Real-time sonoelastography (SE) is a new ultrasound-based imaging technique that provides information on tissue elasticity and stiffness. We determined the efficacy of SE for assessing Achilles tendon abnormalities in patients with ankylosing spondylitis (AS). MATERIALS AND METHODS: Forty-one consecutive AS patients and 32 asymptomatic healthy subjects were enrolled. Achillodynia was scored on a 0- to 100-mm visual analog scale. A high-resolution ultrasound machine equipped with an elastography-compatible linear probe was used to perform bilateral B-mode ultrasound, Doppler ultrasound, and SE examinations of Achilles tendons. Tendons were divided into proximal, middle, and distal segments. B-mode examinations included tendon thicknesses, echotextures, and enthesopathic findings. SE using color-coded images was performed in the same areas. Normal consistent tendon structures were coded as blue or green, and moderately (yellow) or severely (red) softened areas were considered pathological. RESULTS: The distal third of the Achilles tendons was the most commonly affected part in the AS patients compared with healthy subjects (p = 0.001), whose middle third was more commonly affected. Achillodynia intensity tended to be higher in patients with pathological B-mode or SE examination findings (p = 0.09 and p = 0.07 respectively). Softening detected by SE in the distal third was associated with enthesopathy findings such as calcaneal bone erosions (Fisher's X (2), p = 0.07) and tendinous enlargement (Fisher's X (2), p = 0.001). B-mode and SE findings had moderate to good correlation in the assessment of Achilles tendon abnormalities. CONCLUSIONS: Sonoelastography may be useful for the evaluation of tendon abnormalities in patients with AS; in addition; it may be useful for the evaluation of other inflammatory rheumatic conditions. PMID- 23685711 TI - Intramuscular myxoma of the buttock mimicking low-grade fibromyxoid sarcoma: diagnostic usefulness of MUC4 expression. AB - Intramuscular myxoma (IM) is a benign intramuscular neoplasm composed of fibroblasts and abundant myxoid stroma. Some malignant soft tissue tumors can undergo myxomatous degeneration, which makes it difficult to distinguish them from IM. We describe a case of IM of the buttock region mimicking low-grade fibromyxoid sarcoma. The tumor appeared as a well-defined ovoid mass with a cystic lesion on MRI images, and mild uptake on PET images was seen. This was originally misdiagnosed as low-grade fibromyxoid sarcoma (LGFMS) after core needle biopsy. The mass was excised en bloc and sent for histology. The surgical specimen showed the features of LGFMS with the same characteristics as those mentioned in the previous biopsy report. After surgery, MUC4 expression, a highly sensitive and specific immunohistochemical marker for LGFMS, and FUS gene rearrangement by FISH was not detected upon re-examination; therefore, a conclusive diagnosis of IM was made. The patient had no local recurrence at the 3 year follow-up. Our case suggests that IM with mild FDG uptake is frequently confused with other low-grade malignant myxoid tumors. In addition, absence of MUC4 expression is the definitive key to distinguish IM from LGFMS. PMID- 23685712 TI - Nanoparticle encapsulation in red blood cells enables blood-pool magnetic particle imaging hours after injection. AB - Magnetic particle imaging (MPI) is a new medical imaging approach that is based on the nonlinear magnetization response of super-paramagnetic iron oxide nanoparticles (SPIOs) injected into the blood stream. To date, real-time MPI of the bolus passage of an approved MRI SPIO contrast agent injected into the tail vein of living mice has been demonstrated. However, nanoparticles are rapidly removed from the blood stream by the mononuclear phagocyte system. Therefore, imaging applications for long-term monitoring require the repeated administration of bolus injections, which complicates quantitative comparisons due to the temporal variations in concentration. Encapsulation of SPIOs into red blood cells (RBCs) has been suggested to increase the blood circulation time of nanoparticles. This work presents first evidence that SPIO-loaded RBCs can be imaged in the blood pool of mice several hours after injection using MPI. This finding is supported by magnetic particle spectroscopy performed to quantify the iron concentration in blood samples extracted from the mice 3 and 24 h after injection of SPIO-loaded RBCs. Based on these results, new MPI applications can be envisioned, such as permanent 3D real-time visualization of the vessel tree during interventional procedures, bleeding monitoring after stroke, or long-term monitoring and treatment control of cardiovascular diseases. PMID- 23685713 TI - Management of primary and recurrent endolymphatic sac tumors. AB - OBJECTIVE: To report the clinical presentation, management strategies, and outcomes of 14 endolymphatic sac tumors (EST). STUDY DESIGN: Retrospective case series. SETTING: Collective experience accrued from 2 tertiary referral centers. PATIENTS: All patients with ESTs. INTERVENTION: Microsurgery, stereotactic radiosurgery (SRS). MAIN OUTCOME MEASURE(S): Treatment-related morbidity, recurrence. RESULTS: Fourteen ESTs (13 patients) met inclusion criteria. Eight tumors were sporadic, and 6 were associated with von Hippel-Lindau disease (VHL). Twelve lesions were managed primarily, whereas 2 were referred for treatment of sizable recurrences after subtotal resection. Including all patients, the median age at diagnosis was 36 years, and the median duration of posttreatment follow-up was 78 months. Among primary tumors, the median delay between symptom onset and diagnosis was 36 months, and the median tumor diameter at presentation was 23 mm with most lesions demonstrating intracranial involvement. Subjects with VHL frequently presented with smaller, less extensive tumors and were more commonly female compared with patients with sporadic disease. Of the 9 ESTs presenting with normal facial nerve function, 8 maintained good (HB 1-2) posttreatment capacity. Two of 5 ears with useful preoperative hearing maintained pretreatment hearing levels after surgery. One of 12 tumors managed primarily recurred after microsurgical resection. Primary SRS was used in 1 medically infirm patient providing durable tumor control (94 mo) at last follow-up. Among recurrent tumors, 2 were managed successfully with reexcision, whereas 1 underwent salvage surgery followed by 2 sequential treatments of SRS for 2 separate intracranial recurrences; no in-field recurrence has been detected to date. CONCLUSION: ESTs are rare primary neoplasms of the temporal bone that may occur sporadically or in association with VHL. Outcomes after treatment of small less-extensive tumors are favorable compared with patients with advanced primary or recurrent disease. Furthermore, subtotal resection carries a high risk of bulky or multifocal recurrence. As such, early gross total resection remains the management strategy of choice for primary and recurrent ESTs; however, SRS should be considered in poor surgical candidates or in cases of focal intracranial recurrence when the morbidity of salvage surgery is high. PMID- 23685714 TI - Eccrine hidrocystoma in the middle ear associated with a preauricular fistula. PMID- 23685716 TI - Method for accurate measurements of nuclear-spin optical rotation for applications in correlated optical-NMR spectroscopy. AB - The nuclear-spin optical rotation (NSOR) effect recently attracted much attention due to potential applications in combined optical-NMR spectroscopy and imaging. Currently, the main problem with applications of NSOR is low SNR and accuracy of measurements. In this work we demonstrate a new method for data acquisition and analysis based on a low-power laser and an emphasis on software based processing. This method significantly reduces cost and is suitable for application in most NMR spectroscopy laboratories for exploration of the NSOR effect. Despite the use of low laser power, SNR can be substantially improved with fairly simple strategies including the use of short wavelength and a multi-pass optical cell with in-flow pre-polarization in a 7 T magnet. Under these conditions, we observed that NSOR signal can be detected in less than 1 min and discuss strategies for further improvement of signal. With higher SNR than previously reported, NSOR constants can be extracted with improved accuracy. On the example of water, we obtained measurements at a level of accuracy of 5%. We include a detailed theoretical analysis of the geometrical factors of the experiment, which is required for accurate quantification of NSOR. This discussion is particularly important for relatively short detection cells, which will be necessary to use in spectroscopy or imaging applications that impose geometrical constraints. PMID- 23685715 TI - Broadband homonuclear correlation spectroscopy driven by combined R2(n)(v) sequences under fast magic angle spinning for NMR structural analysis of organic and biological solids. AB - We recently described a family of experiments for R2n(v) Driven Spin Diffusion (RDSD) spectroscopy suitable for homonuclear correlation experiments under fast MAS conditions [G. Hou, S. Yan, S.J. Sun, Y. Han, I.J. Byeon, J. Ahn, J. Concel, A. Samoson, A.M. Gronenborn, T. Polenova, Spin diffusion drive by R-symmetry sequencs: applications to homonuclear correlation spectroscopy in MAS NMR of biological and organic solids, J. Am. Chem. Soc. 133 (2011) 3943-3953]. In these RDSD experiments, since the broadened second-order rotational resonance conditions are dominated by the radio frequency field strength and the phase shifts, as well as the size of reintroduced dipolar couplings, the different R2n(v) sequences display unique polarization transfer behaviors and different recoupling frequency bandwidths. Herein, we present a series of modified R2n(v) sequences, dubbed COmbined R2n(v)-Driven (CORD), that yield broadband homonuclear dipolar recoupling and give rise to uniform distribution of cross peak intensities across the entire correlation spectrum. We report NMR experiments and numerical simulations demonstrating that these CORD spin diffusion sequences are suitable for broadband recoupling at a wide range of magnetic fields and MAS frequencies, including fast-MAS conditions (nur=40 kHz and above). Since these CORD sequences are largely insensitive to dipolar truncation, they are well suited for the determination of long-range distance constraints, which are indispensable for the structural characterization of a broad range of systems. Using U-(13)C,(15)N-alanine and U-(13)C,(15)N-histidine, we show that under fast MAS conditions, the CORD sequences display polarization transfer efficiencies within broadband frequency regions that are generally higher than those offered by other existing spin diffusion pulse schemes. A 89-residue U-(13)C,(15)N-dynein light chain (LC8) protein has also been used to demonstrate that the CORD sequences exhibit uniformly high cross peak intensities across the entire chemical shift range. PMID- 23685717 TI - Selective molecular adsorption in sub-nanometer cages of a Cu2O surface oxide. AB - In this study the identity of diverse adsorption sites on a 5-7 Cu2O/Cu(111) surface oxide structure has been identified. The 5-7 membered rings formed by a topological defect on stoichiometric Cu2O present different electronic structures from the originating hexagonal rings, as shown by combined bias dependent scanning tunneling microscopy (STM) and density functional theory (DFT) calculations. The adsorption of CO as a probe molecule on the 5-7 structure, studied using infrared reflection-absorption spectroscopy (IRRAS), shows the existence of special adsorption sites. By combining experimental and theoretical results, it is determined that CO molecules can be selectively confined inside the 7-membered oxide rings with internal dimensions of ~0.85 nm, leading to a marked different adsorbate-substrate interaction than in either clean Cu(111) or Cu2O. The implication of these newly discovered sites on the chemistry of copper for catalytic reactions is discussed. PMID- 23685718 TI - Synaptic mechanisms of adaptation and sensitization in the retina. AB - Sensory systems continually adjust the way stimuli are processed. What are the circuit mechanisms underlying this plasticity? We investigated how synapses in the retina of zebrafish adjust to changes in the temporal contrast of a visual stimulus by imaging activity in vivo. Following an increase in contrast, bipolar cell synapses with strong initial responses depressed, whereas synapses with weak initial responses facilitated. Depression and facilitation predominated in different strata of the inner retina, where bipolar cell output was anticorrelated with the activity of amacrine cell synapses providing inhibitory feedback. Pharmacological block of GABAergic feedback converted facilitating bipolar cell synapses into depressing ones. These results indicate that depression intrinsic to bipolar cell synapses causes adaptation of the ganglion cell response to contrast, whereas depression in amacrine cell synapses causes sensitization. Distinct microcircuits segregating to different layers of the retina can cause simultaneous increases or decreases in the gain of neural responses. PMID- 23685719 TI - A functional and perceptual signature of the second visual area in primates. AB - There is no generally accepted account of the function of the second visual cortical area (V2), partly because no simple response properties robustly distinguish V2 neurons from those in primary visual cortex (V1). We constructed synthetic stimuli replicating the higher-order statistical dependencies found in natural texture images and used them to stimulate macaque V1 and V2 neurons. Most V2 cells responded more vigorously to these textures than to control stimuli lacking naturalistic structure; V1 cells did not. Functional magnetic resonance imaging (fMRI) measurements in humans revealed differences between V1 and V2 that paralleled the neuronal measurements. The ability of human observers to detect naturalistic structure in different types of texture was well predicted by the strength of neuronal and fMRI responses in V2 but not in V1. Together, these results reveal a particular functional role for V2 in the representation of natural image structure. PMID- 23685720 TI - Olfactory cortical neurons read out a relative time code in the olfactory bulb. AB - Odor stimulation evokes complex spatiotemporal activity in the olfactory bulb, suggesting that both the identity of activated neurons and the timing of their activity convey information about odors. However, whether and how downstream neurons decipher these temporal patterns remains unknown. We addressed this question by measuring the spiking activity of downstream neurons while optogenetically stimulating two foci in the olfactory bulb with varying relative timing in mice. We found that the overall spike rates of piriform cortex neurons (PCNs) were sensitive to the relative timing of activation. Posterior PCNs showed higher sensitivity to relative input times than neurons in the anterior piriform cortex. In contrast, olfactory bulb neurons rarely showed such sensitivity. Thus, the brain can transform a relative time code in the periphery into a firing rate based representation in central brain areas, providing evidence for the relevance of a relative time-based code in the olfactory bulb. PMID- 23685721 TI - Activity-dependent silencing reveals functionally distinct itch-generating sensory neurons. AB - The peripheral terminals of primary sensory neurons detect histamine and non histamine itch-provoking ligands through molecularly distinct transduction mechanisms. It remains unclear, however, whether these distinct pruritogens activate the same or different afferent fibers. Using a strategy of reversibly silencing specific subsets of murine pruritogen-sensitive sensory axons by targeted delivery of a charged sodium-channel blocker, we found that functional blockade of histamine itch did not affect the itch evoked by chloroquine or SLIGRL-NH2, and vice versa. Notably, blocking itch-generating fibers did not reduce pain-associated behavior. However, silencing TRPV1(+) or TRPA1(+) neurons allowed allyl isothiocyanate or capsaicin, respectively, to evoke itch, implying that certain peripheral afferents may normally indirectly inhibit algogens from eliciting itch. These findings support the presence of functionally distinct sets of itch-generating neurons and suggest that targeted silencing of activated sensory fibers may represent a clinically useful anti-pruritic therapeutic approach for histaminergic and non-histaminergic pruritus. PMID- 23685722 TI - Interhemispheric asymmetry of olfactory input-dependent neuronal specification in the adult brain. AB - The vertebrate brain is anatomically and functionally asymmetric. The left and right cerebral hemispheres harbor neural stem cell niches at the ventricular subventricular zone (V-SVZ) of the ventricular walls, where new neurons are continuously generated throughout life. However, any interhemispheric asymmetry of neural stem cell niches remains unclear. We performed gene-trap screens in adult zebrafish to identify genes that are differentially expressed in the two hemispheres and found that adult-born neurons expressing the neural zinc-finger protein Myt1 exist predominantly in the left V-SVZ. This lateralization could be reversed by left olfactory sensory deprivation-induced inactivation of Notch signaling. The olfactory behavioral preference for attractive amino acids was also impaired by sensory deprivation of the left olfactory system, but not of the right olfactory system. Our findings suggest that olfactory input generates interhemispheric differences in the fate of adult-born neurons in the zebrafish brain. PMID- 23685723 TI - How to determine "ballooning" of the levator hiatus on clinical examination: a retrospective observational study. AB - INTRODUCTION AND HYPOTHESIS: Dimensions of the levator hiatus determined on imaging are strong predictors of symptoms and signs of female pelvic organ prolapse (FPOP) and of FPOP recurrence. A clinical equivalence can be recorded as genital hiatus (Gh) + perineal body (Pb) using the ICS prolapse quantification system. The objective of this study was to stratify the Gh+Pb measurement to provide clinicians with clinical diagnostic criteria similar to those available on imaging. METHODS: A retrospective study of the data sets of 477 patients seen in a tertiary urogynecological clinic. RESULTS: On average, Gh was 4.2 (range, 1.5-8.5) cm, Pb 3.8 (range, 2.0-7.0) cm, Gh+Pb 7.9 cm (range, 4.2-13.0). The sum of Gh+Pb was strongly associated with symptoms (p < 0.001) and signs (p < 0.001) of FPOP. On receiver-operator characteristic statistics, the area under the curve was determined as 0.707 (0.658-0.755) in predicting symptoms of FPOP, and as 0.890 (0.854-0.925) for predicting FPOP >= stage 2, using 7 cm as the optimal cut off for Gh+Pb. Using the data sets of 309 patients with abnormal (i.e. >=7 cm) Gh+Pb measurements, we stratified abnormal hiatal distensibility, or "ballooning", into mild, moderate, marked and severe as Gh+Pb = 7.0-7.99 cm, 8.0 8.99 cm, 9.0-9.99 cm and 10 cm or more respectively, as the optimal compromise between easily remembered cut-off numbers and quartiles. CONCLUSIONS: The sum of Gh+Pb measurement may allow clinicians to determine the degree of excessive hiatal distensibility or 'ballooning' without requiring imaging assessment. PMID- 23685724 TI - Radioactivity analysis following the Fukushima Dai-ichi nuclear accident. AB - A total of 118 samples were analyzed using HPGe gamma-spectrometry. (131)I, (134)Cs, (137)Cs and (136)Cs were detected in aerosol air samples that were collected 22 days after the accident with values of 1720 uBq m(-)3, 247 uBq m( )3, 289 uBq m(-)3 and 23 uBq m(-)3, respectively. (131)I was detected in rainwater and soil samples and was also measurable in vegetables collected between April 2 and 13, 2011, with values ranging from 0.55 Bq kg(-1) to 2.68 Bq kg(-1). No (131)I was detected in milk, drinking water, seawater or marine biota samples. PMID- 23685725 TI - Variation of atmospheric Be-7 in relation to PM concentrations. AB - In the present study, the influences of particulate matter (PM) and seasonal monsoons on (7)Be concentrations in surface air (CBe) are elucidated. The (7)Be and the corresponding PM concentrations in the air were monitored simultaneously throughout a 14-year period (1998-2011) in Hsinchu, Taiwan. During the autumn and winter seasons (Oct.-Feb.), both the PM and the (7)Be concentrations increased as a result of the northeasterly monsoon. In contrast, the lowest PM and (7)Be concentrations were observed in July and August. This timing is due to the occurrence of southwest monsoons, which carry air masses with low PM concentrations and are associated with depleted (7)Be from low latitudes. The activity concentration of (7)Be in the PM (APM) was used to explain the seasonal variations of (7)Be with respect to the PM concentrations. In contrast, APM is not sensitive enough to vary with the seasons. The air masses transported by the monsoons are believed to be partially mixed with the PM locally produced in Taiwan, which explains their seasonal variations. The (7)Be concentrations in surface air can be experimentally predicted from the PM concentrations based on CBe (mBq/m(3))=0.0767 PM (MUg/m(3)) across seasons. The annual averages of the PM and (7)Be concentrations are 48.1 MUg/m(3) and 3.7 mBq/m(3), respectively. The estimated CBe was either slightly overestimated or underestimated, depending on the season. The highest deviations occurred in July and August, when CBe was underestimated by 33%. PMID- 23685726 TI - Posttraumatic reactions to an earthquake: multidimensional scaling profile analysis of adolescent survivors. AB - The current study examined the prototypical profiles of posttraumatic stress reactions among a sample of 282 adolescent survivors of the 2008 Wenchuan earthquake in China. Based on a dimensional perspective, the results of profile analysis via multidimensional scaling (PAMS) model revealed a two-dimensional solution corresponding to four profiles: intrusion, avoidance/arousal, partial avoidance, and hyperarousal. These profiles of posttraumatic stress symptoms equally manifested across gender. In addition, the Intrusion Profile was found to be associated with more elevated psychological distress symptoms. Results are discussed with respect to the typical posttraumatic stress symptoms following the earthquake. PMID- 23685728 TI - Initial adhesion of Listeria monocytogenes to fine polished stainless steel under flow conditions is determined by prior growth conditions. AB - Listeria monocytogenes is a food-borne pathogen known to persist in food production environments, where it is able to attach and form biofilms, potentially contaminating food products ready for consumption. In this study the first step in the establishment of L. monocytogenes in a food-processing environment was examined, namely the initial adhesion to stainless steel under specific dynamic flow conditions. It was found that the intrinsic ability of L. monocytogenes to adhere to solid surfaces under flow conditions is dependent on nutrient availability. The addition of L-leucine to the growth medium altered the fatty acid composition of the L. monocytogenes cells and increased adhesion. The growth conditions resulting in the highest adhesion (growth medium with added glucose) had cells with the highest electron donating and lowest electron accepting properties, whereas growth conditions resulting in lowest adhesion (growth medium with added mannose) had cells with the lowest electron donating properties and highest electron accepting properties. The highest and lowest adhesion conditions correlated with differences in expression of cell surface protein of L. monocytogenes and among these the autolysin amidase (Ami). This study implies that food composition influences the adhesion of L. monocytogenes to solid surfaces during dynamic flow conditions. PMID- 23685727 TI - Biodiversity of Enterococcus faecalis based on genomic typing. AB - Enterococcus faecalis is a common inhabitant of the gastrointestinal tracts of different animals and is also found in other environments, such as plants, soil, food and water. The diverse nature of E. faecalis, which includes pathogenic, commensal and probiotic strains, calls for the development of tools for accurate discrimination and characterization at the strain level. Here we studied the genetic relationships among 106 E. faecalis strains isolated from diverse origins and possessing different degrees of virulence. Strain typing was conducted using a set of selected simple-sequence repeat (SSR) loci combined with multilocus sequence typing (MLST) analysis, which discriminated among the strains and separated them into three main clusters. While pathogenic and commensal isolates were dispersed along the dendrogram, probiotic and cheese-originated strains were highly associated with one specific cluster (cluster 1). The strain panel was further characterized by testing the occurrence of two virulence determinants (esp gene and beta-hemolysis). The two determinants showed low abundance among probiotic and cheese-originated strains within cluster 1 when compared to non cluster 1 cheese-originated strains, indicating a possible association of cluster 1 with non-virulent strains. Our results further emphasize the importance and challenge of precise characterization of E. faecalis strains from various sources. PMID- 23685729 TI - Effects of PPAR-alpha agonist and IGF-1 on estrogen sulfotransferase in human vascular endothelial and smooth muscle cells. AB - Estrogen has a protective role in vascular functions and estrogen levels are modulated by estrogen sulfotransferase (SULT1E1). In this study, we investigated the effects of the peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist WY14643 and insulin-like growth factor-1 (IGF-1) on the expression and activity of SULT1E1 in vascular cells. Human umbilical vein endothelial cells (HUVECs) and human umbilical artery smooth muscle cells (HUASMCs) were primarily cultured from fresh umbilical cord. SULT1E1 was highly expressed in HUVECs and HUASMCs according to immunofluorescence microscopy detection. WY14643 decreased, while IGF-1 increased, SULT1E1 mRNA and SULT1E1 protein levels, as demonstrated by RT-qPCR and western blot analysis, respectively, in the HUVECs and HUASMCs. SULT1E1 activity was indicated by counting the transformed 3H-estradiol sulfate from 3H-labeled 17beta-estradiol added into the cell culture medium. The activity of SULT1E1 reduced following treatment with WY14643, whereas SULT1E1 activity was enhanced in the presence of IGF-1. The human SULT1E1 promoter-reporter plasmid was constructed. The activity of the SULT1E1 promoter increased 30-fold compared with the pGL3-basic vector. The PPAR-alpha agonist WY14643 downregulated, while IGF-1 upregulated, the luciferase activity of the SULT1E1 promoter. In conclusion, the PPAR-alpha agonist WY14643 and IGF-1 may regulate SULT1E1 expression at the transcriptional level and modulate the levels of active estrogens in endothelial cells and smooth muscle cells, thereby affecting the physiology and pathophysiology of vascular walls. PMID- 23685730 TI - Hurdles to the global antipolio campaign in Pakistan: an outline of the current status and future prospects to achieve a polio free world. AB - The Global Polio Eradication Initiative to eradicate polio completely by the year 2000 has been successful, except for three endemic and some non-endemic countries. Pakistan, one of the three endemic polio reservoirs, is posing a serious threat to the success of the initiative. Currently, the expanded programme on immunisation has been geared to win the race over polio virus in Pakistan. After the remarkable decrease in polio cases from 198 in 2011 to only 58 in 2012, Pakistan seemed to be at the verge of success. However, hurdles continue to retard the campaign. The war against terrorism, misconceptions about polio vaccine, religious misinterpretations, frustration among vaccinators, lack of awareness, social considerations, natural calamities, inaccessibility, and inefficient vaccines and so on are continually rupturing the foundations of the worldwide initiative in the country. Weak health management is found at the hub of majority of the challenges. Stricter policies, well managed and supervised plans and strategic actions, risk analysis and enhanced communication may help giving the final punch to polio virus in the country. Analysis suggested that there is some literature available on the challenges to polio elimination, yet there is not a single publication up to date that considers all the possible hurdles in a single manuscript. This paper sorts out the breaches that hamper the goal of eliminating polio from Pakistan. We have evaluated all the possible barriers and explained them with a perspective that will help develop area specific strategies against polio virus and thus eradicate polio virus from the world. PMID- 23685731 TI - Drastic shift from positive to negative estrogen effect on bone morphogenetic protein signaling in pulmonary arterial endothelial cells under hypoxia. AB - BACKGROUND: To investigate the possible role of sex hormones in the pathogenesis of pulmonary arterial hypertension (PAH), the effect of beta-estradiol (E2) on bone morphogenetic protein (BMP) signaling, a key signaling pathway involved in PAH, was studied in human pulmonary arterial endothelial cells (HPAEC). METHODS AND RESULTS: BMP signaling molecules, including BMP receptor, Smad1/5/8 and Id1, were studied in HPAEC under 1% O2 (hypoxia) and 21% O2 (normoxia) as well as the effect of hypoxia-inducible factor (HIF)-1alpha expression in the presence of E2 on BMP signaling. The effects of an estrogen receptor (ER) antagonist (ICI 182,780) and cycloheximide, and the interaction of ER with Smad or HIF-1alpha were also studied. In the presence of E2, BMP signaling was augmented under normoxia but suppressed under hypoxia. HIF-1alpha accumulation suppressed BMP signaling, whereas HIF-1alpha inhibition augmented signaling. These effects were cancelled by ICI 182,780. Moreover, binding between ER, HIF-1alpha and phosphorylated (p)-Smad1/5/8 proteins occurred only under hypoxia. On inhibition of de novo synthesis with cycloheximide, however, p-Smad1/5/8 expression was suppressed only under normoxia. CONCLUSIONS: The effects of E2 on BMP signaling in HPAEC altered depending on O2 concentration and different mechanisms may be involved. BMP and sex hormones may play an important role in PAH development. PMID- 23685732 TI - Respiratory variation of vertebral arterial flow in a patient scheduled for coronary artery bypass graft surgery: lesson from atypical subclavian steal phenomenon. PMID- 23685733 TI - Coronary artery aneurysm after kawasaki disease in a single coronary artery. PMID- 23685734 TI - Functional molecular imaging linking macrophages to reverse cholesterol transport. PMID- 23685735 TI - Lipogels: surface-adherent composite hydrogels assembled from poly(vinyl alcohol) and liposomes. AB - Drug-eluting engineered surface coatings are of paramount importance for many biomedical applications from implantable devices to tissue engineering. Herein, we present the assembly of lipogels, composite physical hydrogels assembled from poly(vinyl alcohol) and liposomes using thiol-disulfide exchange between end group modified PVA and thiocholesterol containing liposomes, and the response of adhering cells to these coatings. We demonstrate the controlled loading of liposomes into the polymer matrix and the preserved mechanical properties of the lipogels. Furthermore, the lipogels are successfully rendered cell adhesive by incorporation of poly(l-lysine) into the PVA polymer matrix or by poly(dopamine) coating of the lipogels. The successful lipid uptake from the lipogels by macrophages, hepatocytes, and myoblasts was monitored by flow cytometry. Finally, the delivery of active cargo, paclitaxel, to adherent myoblasts is shown, thus illustrating the potential of the lipogels as a drug eluting interface for biomedical applications. PMID- 23685736 TI - Manufacturing devices and instruments for easier rat liver transplantation. AB - Orthotopic rat liver transplantation is a popular model, which has been shown in a recent JoVE paper with the use of the "quick-linker" device. This technique allows for easier venous cuff-anatomoses after a reasonable learning curve. The device is composed of two handles, which are carved out from scalpel blades, one approximator, which is obtained by modifying Kocher's forceps, and cuffs designed from fine-bore polyethylene tubing. The whole process can be performed at a low cost using common laboratory material. The present report provides a step-by-step protocol for the design of the required pieces and includes stencils. PMID- 23685737 TI - 3D shape-based analysis of cell line-specific compound response in cancers. AB - The rapid increase in the volume of high-throughput anticancer chemical screening data requires a better interpretation of the relationships between diverse chemical structures and their varied effects in distinct cancer subtypes. Unexpected compound efficacy or resistance in cancer cells has been difficult to explain, in part because there has been no systematic analysis of compound response profiles in cancer cells with different genotypic backgrounds. In this study, we compared 2D chemical- and 3D shape-based similarity search methods to study the structure-activity relationships of anticancer compounds in a collection of heterogeneous cancer cell lines. The 3D shape-based metric provided better resolution than the 2D chemical topology-based method for identifying compound pairs with similar cellular response profiles. We confirmed that the 3D method exclusively identified compound pairs with different chemical scaffolds that stimulated highly similar cellular responses. The present analyses provide useful guidelines for investigating the lineage- and genotype-specific activities of diverse compounds and their mechanisms of action. PMID- 23685738 TI - aPKC iota/lambda: a potential target for the therapy of Hh-dependent and Smo inhibitor-resistant advanced BCC. PMID- 23685739 TI - Muscle activation patterns in infants with myelomeningocele stepping on a treadmill. AB - PURPOSE: To characterize how infants with myelomeningocele (MMC) activate lower limb muscles over the first year of life, without practice, while stepping on a motorized treadmill. METHODS: Twelve infants with MMC were tested longitudinally at 1, 6, and 12 months. Electromyography was used to collect data from the tibialis anterior, lateral gastrocnemius, rectus femoris, biceps femoris. RESULTS: Across the first year, infants showed no electromyographic activity for approximately 50% of the stride cycle with poor rhythmicity and timing of muscles, when activated. Single muscle activation predominated; agonist antagonist coactivation was low. Probability of individual muscle activity across the stride decreased with age. CONCLUSIONS: Infants with MMC show high variability in timing and duration of muscle activity, few complex combinations, and very little change over time. PMID- 23685740 TI - Forefoot mobility in ankle and foot orthoses: effect on gait of children with cerebral palsy. AB - BACKGROUND AND PURPOSE: Typical gait requires flexibility in the ankle and foot. During gait, it is critical that the ankle dorsiflex and the toes extend. The purpose of this report is to demonstrate that when foot orthoses block critical movement undesirable compensations that may interfere with gait can appear. CASE DESCRIPTION: Three children with spastic cerebral palsy demonstrate the effect on gait when the blocks attributable to the orthoses were removed. INTERVENTION: All children received electrical stimulation and used foot orthoses. OUTCOMES: Internal hip rotation and toe walking occurred when orthoses blocked digit extension. A block may be small and unnoticed but can still influence gait and force the child to compensate for the loss of mobility. PMID- 23685741 TI - Perceived effectiveness and barriers to physical therapy services for families and children with Friedreich ataxia. AB - PURPOSE: To describe the frequency, type, and perceived effectiveness of physical therapy interventions for children with Friedreich ataxia (FA); identify barriers to therapy; and solicit advice from parents. METHOD: Parents of 30 children with FA participated in semistructured interviews. Qualitative and quantitative methods were used to analyze the data. RESULTS: Sixty-seven percent of children received direct physical therapy service. Stretching and strengthening exercises were used most frequently, and their perceived usefulness increased as the children aged. Seventy-three percent received home exercise programs; 9% implemented these consistently. External barriers included a lack of expert providers and limited reimbursement. Internal barriers included limited time and energy, lack of awareness of services, and children's preferences not to be treated differently. Parents advised therapists to become experts, advocates, and use approaches based on family and child preferences. CONCLUSIONS: Outcomes provide a starting point for developing further research, education, and effective interventions for children with FA. PMID- 23685742 TI - Perivascular adipose tissue potentiates contraction of coronary vascular smooth muscle: influence of obesity. AB - BACKGROUND: This investigation examined the mechanisms by which coronary perivascular adipose tissue (PVAT)-derived factors influence vasomotor tone and the PVAT proteome in lean versus obese swine. METHODS AND RESULTS: Coronary arteries from Ossabaw swine were isolated for isometric tension studies. We found that coronary (P=0.03) and mesenteric (P=0.04) but not subcutaneous adipose tissue augmented coronary contractions to KCl (20 mmol/L). Inhibition of CaV1.2 channels with nifedipine (0.1 umol/L) or diltiazem (10 umol/L) abolished this effect. Coronary PVAT increased baseline tension and potentiated constriction of isolated arteries to prostaglandin F2alpha in proportion to the amount of PVAT present (0.1-1.0 g). These effects were elevated in tissues obtained from obese swine and were observed in intact and endothelium denuded arteries. Coronary PVAT also diminished H2O2-mediated vasodilation in lean and, to a lesser extent, in obese arteries. These effects were associated with alterations in the obese coronary PVAT proteome (detected 186 alterations) and elevated voltage-dependent increases in intracellular [Ca(2+)] in obese smooth muscle cells. Further studies revealed that the Rho-kinase inhibitor fasudil (1 umol/L) significantly blunted artery contractions to KCl and PVAT in lean but not obese swine. Calpastatin (10 MUmol/L) also augmented contractions to levels similar to that observed in the presence of PVAT. CONCLUSIONS: Vascular effects of PVAT vary according to anatomic location and are influenced by an obese phenotype. Augmented contractile effects of obese coronary PVAT are related to alterations in the PVAT proteome (eg, calpastatin), Rho-dependent signaling, and the functional contribution of K(+) and CaV1.2 channels to smooth muscle tone. PMID- 23685744 TI - Beryllium derivatives of a phenyl-substituted beta-diketiminate: a well-defined ring opening reaction of tetrahydrofuran. AB - The phenyl-substituted beta-diketiminate ligand precursor (Ph)LH, [(Dipp)NC(Ph)CHC(Ph)NH(Dipp)] (Dipp = 2,6-di-isopropylphenyl) and its lithium and beryllium halide derivatives [(Ph)LLi(OEt2)], [(Ph)LBeCl] and [(Ph)LBeI] have been synthesised and characterised by NMR and X-ray structural analysis. The iodoberyllium complex [(Ph)LBeI] reacts with THF in a well-defined ring-opening insertion reaction to form the 4-iodo-n-butoxide complex [(Ph)LBeO(CH2)4I]. PMID- 23685743 TI - Sex differences in the effectiveness of early coronary computed tomographic angiography compared with standard emergency department evaluation for acute chest pain: the rule-out myocardial infarction with Computer-Assisted Tomography (ROMICAT)-II Trial. AB - BACKGROUND: We evaluate sex-based differences in the effectiveness of early cardiac computed tomographic angiography (CCTA) and standard emergency department (ED) evaluation in patients with acute chest pain. METHODS AND RESULTS: In the Rule-Out Myocardial Infarction With Computer-Assisted Tomography (ROMICAT)-II multicenter, controlled trial, we randomized 1000 patients (47% women) 40 to 74 years of age with symptoms suggestive of acute coronary syndrome to an early CCTA or standard ED evaluation. In this prespecified analysis, women in the CCTA arm had a greater reduction in length of stay, lower hospital admission rates, and lesser increased cumulative radiation dose than men in a comparison of ED strategies (P for interaction <=0.02). Although women had lower acute coronary syndrome rates than men (3% versus 12%; P<0.0001), sex differences in length of stay persisted after adjustment for baseline differences, including acute coronary syndrome rate (P for interaction <0.03). Length of stay was similar between sexes with normal CCTA findings (P=0.11). There was no missed acute coronary syndrome for either sex. No difference was observed in major adverse cardiac events between sexes and ED strategies (P for interaction =0.39). Women had more normal CCTA examinations than men (58% versus 37%; P<0.0001), less obstructive coronary disease by CCTA (5% versus 17%; P=0.0001), but similar normalcy rates for functional testing (P=0.65). Men in the CCTA arm had the highest rate of invasive coronary angiography (18%), whereas women had comparable low 5% rates regardless of ED strategy. CONCLUSIONS: This trial provides data supporting an early CCTA strategy as an attractive option in women presenting to the ED with symptoms suggestive of acute coronary syndrome. The findings may be explained by lower CAD prevalence and severity in women than men. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01084239. PMID- 23685745 TI - Systematic evaluation of fluorescence correlation spectroscopy data analysis on the nanosecond time scale. AB - Signal fluctuations in a fluorescence time trace on nanosecond time scales can be induced by specific quenching interactions that report on the dynamics of biomolecules. Fluorescence correlation spectroscopy is an analysis tool to investigate dynamic processes on time scales from pico- to milliseconds or longer. Under certain conditions, e.g. in a solvent of high viscosity, a fluorescence labeled dynamic biomolecule yields multiple independent correlation decays due to rotational and translational diffusion, fluorescence quenching interactions, and fluorophore photophysics. We compared parameter estimation for FCS data with multiple correlation decays by dynamical fingerprint analysis and by the non-linear Levenberg-Marquardt fitting procedure and identified conditions for which dynamical fingerprint analysis can be of advantage. In this context we identified a previously unrecognized photophysical process in ATTO655 that introduces fluorescence intermittency on nanosecond time scales that is absent in MR121. The optimized fitting procedure is used to resolve the viscosity dependence of fluorescence quenching for photoinduced electron transfer probes. PMID- 23685746 TI - Dosimetric consequences of pencil beam width variations in scanned beam particle therapy. AB - Scanned ion beam delivery enables the highest degree of target dose conformation attainable in external beam radiotherapy. Nominal pencil beam widths (spot sizes) are recorded during treatment planning system commissioning. Due to changes in the beam-line optics, the actual spot sizes may differ from these commissioning values, leading to differences between planned and delivered dose. The purpose of this study was to analyse the dosimetric consequences of spot size variations in particle therapy treatment plans. For 12 patients with skull base tumours and 12 patients with prostate carcinoma, scanned-beam carbon ion and proton treatment plans were prepared and recomputed simulating spot size changes of (1) +/-10% to simulate the typical magnitude of fluctuations, (2) +/-25% representing the worst case scenario and (3) +/-50% as a part of a risk analysis in case of fault conditions. The primary effect of the spot size variation was a dose deterioration affecting the target edge: loss of target coverage and broadening of the lateral penumbra (increased spot size) or overdosage and contraction of the lateral penumbra (reduced spot size). For changes <=25%, the resulting planning target volume mean 95%-isodose line coverage (CI-95%) deterioration was ranging from negligible to moderate. In some cases changes in the dose to adjoining critical structures were observed. PMID- 23685747 TI - Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and pathways driving tumorigenesis. AB - Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas of Schwann cell lineage origin that occur sporadically or in association with the inherited syndrome neurofibromatosis type 1. To identify genetic drivers of MPNST development, we used the Sleeping Beauty (SB) transposon-based somatic mutagenesis system in mice with somatic loss of transformation-related protein p53 (Trp53) function and/or overexpression of human epidermal growth factor receptor (EGFR). Common insertion site (CIS) analysis of 269 neurofibromas and 106 MPNSTs identified 695 and 87 sites with a statistically significant number of recurrent transposon insertions, respectively. Comparison to human data sets identified new and known driver genes for MPNST formation at these sites. Pairwise co-occurrence analysis of CIS-associated genes identified many cooperating mutations that are enriched in Wnt/beta-catenin, PI3K-AKT-mTOR and growth factor receptor signaling pathways. Lastly, we identified several new proto-oncogenes, including Foxr2 (encoding forkhead box R2), which we functionally validated as a proto-oncogene involved in MPNST maintenance. PMID- 23685748 TI - A functional variant in the CFI gene confers a high risk of age-related macular degeneration. AB - Up to half of the heritability of age-related macular degeneration (AMD) is explained by common variants. Here, we report the identification of a rare, highly penetrant missense mutation in CFI encoding a p.Gly119Arg substitution that confers high risk of AMD (P = 3.79 * 10-6; odds ratio (OR) = 22.20, 95% confidence interval (CI) = 2.98-164.49). Plasma and sera from cases carrying the p.Gly119Arg substitution mediated the degradation of C3b, both in the fluid phase and on the cell surface, to a lesser extent than those from controls. Recombinant protein studies showed that the Gly119Arg mutant protein is both expressed and secreted at lower levels than wild-type protein. Consistent with these findings, human CFI mRNA encoding Arg119 had reduced activity compared to wild-type mRNA encoding Gly119 in regulating vessel thickness and branching in the zebrafish retina. Taken together, these findings demonstrate that rare, highly penetrant mutations contribute to the genetic burden of AMD. PMID- 23685750 TI - Increase in cardiac troponin I in a lamb with tetralogy of fallot. AB - This study describes a case of tetralogy of Fallot in a lamb showing failure to thrive and signs of respiratory distress. Physical examination, electrocardiography, thoracic radiographies, echocardiography and cardiac troponin I evaluation were performed. The value of cardiac troponin I was compared with the values of 10 healthy lambs of the same age and breed, and the affected animal demonstrated an increase in cardiac troponin I. Due to the poor prognosis, euthanasia was indicated, and necropsy confirmed the diagnosis. This is the first report of an increase in cardiac troponin I in a lamb with tetralogy of Fallot. PMID- 23685751 TI - 68Ga-DOTA0-Tyr3-octreotide positron emission tomography in head and neck squamous cell carcinoma. AB - PURPOSE: 68Ga-labelled DOTA0-Tyr3-octreotide positron emission tomography (PET)/CT (68Ga-DOTATOC PET/CT) is a routinely used imaging modality for neuroendocrine tumours expressing somatostatin receptors (SSTRs). Recent studies have shown that SSTRs are also expressed in head and neck squamous cell carcinoma (HNSCC). This is the first prospective clinical trial investigating SSTR expression in patients with HNSCC using 68Ga-DOTATOC. METHODS: Patients with previously untreated HNSCC underwent 68Ga-DOTATOC PET/CT (120 MBq, range 81-150 MBq). Tumour tracer uptake was scored, the maximum standardized uptake value (SUVmax) was measured and the tumour to background uptake ratio was calculated. For each patient, PET/CT findings were correlated with immunohistochemical SSTR expression in tumour specimens. RESULTS: Fifteen HNSCC patients were included in the study from May 2011 to May 2012. Tumour-specific 68Ga-DOTATOC uptake was detected in all patients with an median SUVmax of 4.0 (range 2.2-6.5). Uptake was weak in seven (47%), moderate in five (33%) and strong in three (20%) patients. All tumour specimens were SSTR positive on immunohistochemistry. Of the 15 patients, 14 were positive for SSTR subtype 2, characterized by the highest affinity to octreotide. CONCLUSION: SSTR expression in HNSCC can be visualized clinically using 68Ga-DOTATOC PET/CT. SSTR expression in HNSCC could provide a potential target for SSTR-based therapy in patients not amenable to standard treatment modalities, but this cannot be predicted by SSTR immunohistochemistry. PMID- 23685752 TI - 18F-FDG PET/CT in HIV-related central nervous system pathology. AB - PURPOSE: To evaluate the utility of 18F-FDG PET/CT in suspected cerebral pathology in HIV-infected individuals. METHODS: 18F-FDG PET/CT scans from 29 HIV infected individuals (29 brain scans, 22 whole-body scans) who presented with neurological symptoms and signs were retrospectively reviewed and compared with subsequent clinical investigations. RESULTS: The majority of patients (n=25) were referred to differentiate infection from malignant causes of cerebral pathology. Ten of the 11 patients with an eventual diagnosis of toxoplasmosis infection were correctly diagnosed by 18F-FDG PET/CT showing lesional uptake less than that of normal brain cortex (mean SUVmax 3.5, range 1.9 - 5.8). All five patients with a final diagnosis of primary central nervous system lymphoma (PCNSL) were correctly diagnosed by 18F-FDG PET/CT showing lesional uptake greater than that of normal brain cortex (mean SUVmax 18.8, range 12.4 - 29.9). Four of the five patients with 18F-FDG PET/CT features suggesting a vasculitic process had vasculitis confirmed as the final diagnosis. Three patients showed variable uptake in multiple cerebral lesions (including final diagnoses of tuberculosis and metastases from lung cancer in two patients) and there were four other miscellaneous diagnoses. In 12 patients biopsies were performed at sites guided by PET abnormality (7 brain, 5 lymph nodes) confirming or excluding significant disease in 11. CONCLUSION: 18F-FDG PET/CT is particularly useful for differentiating between infection and PCNSL in HIV-infected patients with a cerebral lesion on MRI or CT. 18F-FDG PET/CT was also a helpful tool in the diagnostic work-up of patients with other HIV-related cerebral pathology. Additional advantages of 18F-FDG PET/CT are the abilities to assess abnormally increased glucose metabolism in the body and to identify potential sites for biopsy. PMID- 23685749 TI - The mutational landscape of adenoid cystic carcinoma. AB - Adenoid cystic carcinomas (ACCs) are among the most enigmatic of human malignancies. These aggressive salivary gland cancers frequently recur and metastasize despite definitive treatment, with no known effective chemotherapy regimen. Here we determined the ACC mutational landscape and report the exome or whole-genome sequences of 60 ACC tumor-normal pairs. These analyses identified a low exonic somatic mutation rate (0.31 non-silent events per megabase) and wide mutational diversity. Notably, we found mutations in genes encoding chromatin state regulators, such as SMARCA2, CREBBP and KDM6A, suggesting that there is aberrant epigenetic regulation in ACC oncogenesis. Mutations in genes central to the DNA damage response and protein kinase A signaling also implicate these processes. We observed MYB-NFIB translocations and somatic mutations in MYB associated genes, solidifying the role of these aberrations as critical events in ACC. Lastly, we identified recurrent mutations in the FGF-IGF-PI3K pathway (30% of tumors) that might represent new avenues for therapy. Collectively, our observations establish a molecular foundation for understanding and exploring new treatments for ACC. PMID- 23685753 TI - Transcriptome alteration in a rice introgression line with enhanced alkali tolerance. AB - Alkali stress inhibits plant growth and development and thus limits crop productivity. To investigate the possible genetic basis of alkali tolerance in rice, we generated an introgressed rice line (K83) with significantly enhanced tolerance to alkali stress compared to its recipient parental cultivar (Jijing88). By using microarray analysis, we examined the global gene expression profiles of K83 and Jijing88, and found that more than 1200 genes were constitutively and differentially expressed in K83 in comparison to Jijing88 with 572 genes up- and 654 down-regulated. Upon alkali treatment, a total of 347 genes were found up- and 156 down-regulated in K83 compared to 591 and 187, respectively, in Jijing88. Among the up-regulated genes in both K83 and Jijing88, only 34 were constitutively up-regulated in K83, suggesting that both the constitutive differentially expressed genes in K83 and those induced by alkali treatment are most likely responsible for enhanced alkali tolerance. A gene ontology analysis based on all annotated, differentially expressed genes revealed that genes with expression alterations were enriched in pathways involved in metabolic processes, catalytic activity, and transport and transcription factor activities, suggesting that these pathways are associated with alkali stress tolerance in rice. Our results illuminated the novel genetic aspects of alkali tolerance in rice and established a repertory of potential target genes for biotechnological manipulations that can be used to generate alkali-tolerant rice cultivars. PMID- 23685754 TI - Nitrosative responses in citrus plants exposed to six abiotic stress conditions. AB - Nitrosative status has emerged as a key component in plant response to abiotic stress; however, knowledge on its regulation by different environmental conditions remains unclear. The current study focused on nitrosative responses in citrus plants exposed to various abiotic stresses, including continuous light, continuous dark, heat, cold, drought and salinity. Morphological observations and physiological analysis showed that abiotic stress treatments were sensed by citrus plants. Furthermore, it was revealed that nitrosative networks are activated by environmental stress factors in citrus leaves as evidenced by increased nitrite (NO) content along with the release of NO and superoxide anion (O2-) in the vascular tissues. The expression of genes potentially involved in NO production, such as NR, AOX, NADHox, NADHde, PAO and DAO, was affected by the abiotic stress treatments demonstrating that NO-derived nitrosative responses could be regulated by various pathways. In addition, S-nitrosoglutathione reductase (GSNOR) and nitrate reductase (NR) gene expression and enzymatic activity displayed significant changes in response to adverse environmental conditions, particularly cold stress. Peroxynitrite (ONOO-) scavenging ability of citrus plants was elicited by continuous light, dark or drought but was suppressed by salinity. In contrast, nitration levels were elevated by salinity and suppressed by continuous light or dark. Finally, S-nitrosylation patterns were enhanced by heat, cold or drought but were suppressed by dark or salinity. These results suggest that the nitrosative response of citrus plants is differentially regulated depending on the stress type and underscore the importance of nitrosative status in plant stress physiology. PMID- 23685756 TI - Novel multistep BRET-FRET energy transfer using nanoconjugates of firefly proteins, quantum dots, and red fluorescent proteins. AB - Sequential bioluminescence resonance energy transfer (BRET) and fluorescence resonance energy transfer (FRET) from firefly luciferase to red fluorescent proteins using quantum dot or rod acceptor/donor linkers is described. The effect of morphology and tuned optical properties on the efficiency of this unique BRET FRET system was evaluated. PMID- 23685755 TI - Understanding risk factors for perioperative ischemic events with carotid stenting: is patient age over 80 years or is unfavorable arch anatomy to blame? AB - OBJECTIVE: Several studies have reported increased perioperative risk after carotid artery stenting (CAS) for patients >=80 years of age; however, most have not considered unfavorable anatomic features noted more frequently in this population as a confounding variable. The purpose of this study was to show a correlation between poor aortic arch anatomy and perioperative ischemic complications after CAS. METHODS: Our prospectively maintained database was queried for all CAS procedures performed on symptomatic patients between 2009 and 2011. Retrospective analysis of consecutive CAS procedures was performed. The primary endpoint was perioperative (within 30 days) ischemic events (stroke, transient ischemic attack (TIA)). Event incidence was compared between groups dichotomized by age and anatomical features. Incidence of unfavorable arch (acute angle between aortic arch and treated common carotid artery) was compared between age groups. RESULTS: Perioperative ischemic events included four ischemic strokes and three TIAs (all events ipsilateral to the treated vessel). Event incidence was more frequent in patients with unfavorable arch anatomy (7.9%) than in those with favorable aortic arch features (0.7%) (p=0.0073). Event incidence in patients >=80 years of age (4.5%) was not statistically different than that in patients <80 years (2.3%) (p=0.428). Unfavorable aortic arch anatomy was increased in frequency in patients aged 80 years and over (<80 years, 29%; >=80 years, 52%; p<0.001). CONCLUSIONS: In the present series, the incidence of perioperative complications was increased in patients with unfavorable aortic arch anatomy but not in patients >=80 years. CAS represents a revascularization option for patients of all ages; however, patients with unfavorable aortic arch anatomy may represent a group at relatively high risk for periprocedural ischemic events. PMID- 23685757 TI - Effects of combined c-myc and Bmi-1 siRNAs on the growth and chemosensitivity of MG-63 osteosarcoma cells. AB - Osteosarcoma is the most common form of primary malignant bone tumor. Patients who are insensitive to chemotherapy treatment often have a poor prognosis. According to our previous study, recombinant adenovirus (Myc-AS) in combination with caffeine enhances the induction of apoptosis and the chemotherapeutic effects of cisplatin (CDDP) in MG-63 osteosarcoma cells. The present study aimed to investigate the combinational effects of the small interfering RNAs (siRNAs) c myc and Bmi-1 on the growth and chemosensitivity of MG-63 osteosarcoma cells. The results indicated that the cell growth inhibition rates of MG-63 cells gradually increased with increasing concentrations of CDDP (P<0.05). This observation was consistent in the single and combined siRNA groups. At a concentration of 5.0 ug/ml CDDP, the growth inhibition rates were 53.3+/-5.2, 42.7+/-6.3 and 40.9+/ 4.7% in the combined, c-myc and Bmi-1 siRNA groups, respectively. The cell growth inhibition rate in the combined siRNA group was higher than that observed in the two single siRNA groups (P<0.05). The cell apoptotic rate was 37.3+/-4.9% in the combined siRNA group, which was significantly higher than that observed in the c myc (24.8+/-5.6%) and Bmi-1 siRNA groups (22.7+/-6.1%; P<0.05). These results suggest that the chemosensitivity of MG-63 cells to CDDP may be markedly enhanced in the siRNA combination group. A decrease in cell proliferation and increased cell apoptosis were also observed in the siRNA combination group. The present study may provide novel insights to further elucidate the pathogenesis and drug resistance mechanisms involved in osteosarcoma. It may also improve our understanding of the underlying mechanisms involved in chemotherapeutic sensitivity, and thus aid the development of future therapeutic strategies for the treatment of osteosarcoma. PMID- 23685758 TI - Oral transmission of Listeria monocytogenes in mice via ingestion of contaminated food. AB - L. monocytogenes are facultative intracellular bacterial pathogens that cause food borne infections in humans. Very little is known about the gastrointestinal phase of listeriosis due to the lack of a small animal model that closely mimics human disease. This paper describes a novel mouse model for oral transmission of L. monocytogenes. Using this model, mice fed L. monocytogenes-contaminated bread have a discrete phase of gastrointestinal infection, followed by varying degrees of systemic spread in susceptible (BALB/c/By/J) or resistant (C57BL/6) mouse strains. During the later stages of the infection, dissemination to the gall bladder and brain is observed. The food borne model of listeriosis is highly reproducible, does not require specialized skills, and can be used with a wide variety of bacterial isolates and laboratory mouse strains. As such, it is the ideal model to study both virulence strategies used by L. monocytogenes to promote intestinal colonization, as well as the host response to invasive food borne bacterial infection. PMID- 23685759 TI - Deeper attentional masking by lateral objects in children with autism. AB - Autism spectrum disorder (ASD) is often associated with a detail-oriented perception and overselective attention in visual tasks, such as visual search and crowding. These results were obtained manipulating exclusively the spatial properties of the stimuli: few is known about the spatio-temporal dynamics of visual processing in ASD. In this study we employed an attentional masking (AM) paradigm comparing children with ASD and IQ-matched typically developing (TD) controls. The AM effect refers to an impaired identification of a target followed by a competitive masking object at different proximities in space and time. We found that ASD and TD groups did not differ in the AM effect provoked by the competitive object displayed in the same position of the target. In contrast, children with ASD showed a deeper and prolonged interference than the TD group when the masking object was displayed in the lateral position. These psychophysical results suggest that the inefficient attentional selection in ASD depends on the spatio-temporal interaction between competitive visual objects. These evidence are discussed in the light of the ASD altered neural connectivity hypothesis and the reentrant theory of perception. PMID- 23685761 TI - Changes in bone mineral density and body composition of children with well controlled homocystinuria caused by CBS deficiency. AB - Homocystinuria due to cystathionine beta-synthase (CBS) deficiency is an inherited disorder of the metabolism of methionine. Clinical manifestations include mental retardation, dislocation of the optic lens, vascular lesions, arterial and venous thromboembolism, skeletal abnormalities, and osteoporosis. Most homocystinuria patients diagnosed in adulthood have severe osteoporosis, and homocystinuria is frequently mentioned as a cause of osteoporosis. Good control of plasma homocysteine may prevent or delay some of these complications. However, the effectiveness of bone mineral density (BMD) gain or fracture prevention has not been addressed. Here, we describe changes in BMD and body composition in 5 CBS deficiency patients who were diagnosed at young age and were managed with good metabolic control. We found that the BMD of each region was within the normal range. BMD gain was adequate and the patients had no significant change in skeletal morphology. PMID- 23685762 TI - Post-retrieval late process contributes to persistence of reactivated fear memory. AB - Several studies have demonstrated the mechanisms involved in memory persistence after learning. However, little is known about memory persistence after retrieval. In this study, a protein synthesis inhibitor, anisomycin, was infused into the basolateral amygdala of mice 9.5 h after retrieval of contextual conditioned fear. Anisomycin attenuated fear memory after 7 d, but not after 2 d. In contrast, infusion of anisomycin 5- or 24-h post-retrieval was ineffective. These findings indicate that anisomycin attenuates the persistence of reactivated fear memory in a time-dependent manner. We propose that late protein synthesis is required for memory persistence after retrieval. PMID- 23685763 TI - Repetitive visual stimulation enhances recovery from severe amblyopia. AB - Severe amblyopia, characterized by a significant reduction in visual acuity through the affected eye, is highly resistant to reversal in adulthood. We have previously shown that synaptic plasticity can be reactivated in the adult rat visual cortex by dark exposure, and the reactivated plasticity can be harnessed to promote the recovery from severe amblyopia. Here we show that deprived-eye visually evoked responses are rapidly strengthened in dark-exposed amblyopes by passive viewing of repetitive visual stimuli. Surprisingly, passive visual stimulation rapidly enhanced visually evoked responses to novel stimuli and enhanced the recovery from severe amblyopia driven by performance of active visual discriminations. Thus a series of simple, noninvasive manipulations of visual experience can be used in combination to significantly guide the recovery of visual response strength, selectivity, and spatial acuity in adult amblyopes. PMID- 23685764 TI - Implication of dopaminergic modulation in operant reward learning and the induction of compulsive-like feeding behavior in Aplysia. AB - Feeding in Aplysia provides an amenable model system for analyzing the neuronal substrates of motivated behavior and its adaptability by associative reward learning and neuromodulation. Among such learning processes, appetitive operant conditioning that leads to a compulsive-like expression of feeding actions is known to be associated with changes in the membrane properties and electrical coupling of essential action-initiating B63 neurons in the buccal central pattern generator (CPG). Moreover, the food-reward signal for this learning is conveyed in the esophageal nerve (En), an input nerve rich in dopamine-containing fibers. Here, to investigate whether dopamine (DA) is involved in this learning-induced plasticity, we used an in vitro analog of operant conditioning in which electrical stimulation of En substituted the contingent reinforcement of biting movements in vivo. Our data indicate that contingent En stimulation does, indeed, replicate the operant learning-induced changes in CPG output and the underlying membrane and synaptic properties of B63. Significantly, moreover, this network and cellular plasticity was blocked when the input nerve was stimulated in the presence of the DA receptor antagonist cis-flupenthixol. These results therefore suggest that En-derived dopaminergic modulation of CPG circuitry contributes to the operant reward-dependent emergence of a compulsive-like expression of Aplysia's feeding behavior. PMID- 23685765 TI - An electron-rich free-standing carbon@Au core-shell nanofiber network as a highly active and recyclable catalyst for the reduction of 4-nitrophenol. AB - A three-dimensional (3D) free-standing network composed of cross-linked carbon@Au core-shell nanofibers was fabricated by combining the electrospinning technique and an in situ reduction approach. The results showed that a uniform Au layer of approximately 5 nm thickness was formed around the electrospun carbon nanofiber. What's more, it's interesting to note that the Au layer was composed of small Au nanoparticles. And, the as-prepared CNFs@Au network exhibited excellent catalytic activity for the reduction of 4-nitrophenol (4-NP) based on the electron-rich catalytic platform arising from the synergistic effect between carbon and Au. Notably, the free-standing 3D nanofibrous cross-linked network structure could improve the catalyst's performance in separation and reuse. PMID- 23685767 TI - Age-related changes in mitochondrial membrane composition of Nothobranchius rachovii. AB - Mitochondrial membrane composition may be a critical factor in the mechanisms of the aging process by influencing the propagation of reactions involved in mitochondrial function during periods of high stress. Changes affecting either lipid class or fatty acid compositions could affect phospholipid properties and alter mitochondrial function and cell viability. In the present study, mitochondrial membrane phospholipid compositions were analyzed throughout the life cycle of Nothobranchius rachovii. Mitochondrial phospholipids showed several changes with age. Proportions of cardiolipin decreased and those of sphingomyelin increased between 11- and 14-month-old fish. Fatty acid compositions of individual phospholipids in mitochondria were also significantly affected with age. These data suggest increasing damage to mitochondrial lipids during the life cycle of N. rachovii that could be one of the main factors related with and contributing to degraded mitochondrial function associated with the aging process. PMID- 23685766 TI - The MAT-sf: clinical relevance and validity. AB - BACKGROUND: The measurement of mobility is essential to both aging research and clinical practice. A newly developed self-report measure of mobility, the mobility assessment tool-short form (MAT-sf), uses video animations to improve measurement accuracy/precision. Using a large baseline data set, we recalibrated the items, evaluated the extent to which older patients' self-efficacy (i.e., confidence) for walking was related to MAT-sf scores beyond their actual 400-m walk time, and assessed the relationship of the MAT-sf with body mass index and other clinical variables. METHODS: The analyses employed baseline data from the Lifestyle Interventions and Independence for Elders Study. RESULTS: Item recalibration demonstrated that the MAT-sf scoring algorithm was robust. In an analysis with 400-m walk time and self-efficacy regressed on the MAT-sf, both variables shared unique variance with the MAT-sf (p < .001). The MAT-sf was inversely related to several comorbidities, most notably hypertension and arthritis (p < .001), and scores were lowest when body mass index >= 35 kg/m(2). Finally, MAT-sf scores were directly related to Short Physical Performance Battery scores, inversely related to difficulty with activities of daily living (p < .001) and higher for men than for women (p < .001). CONCLUSIONS: The findings extend the validity and clinical utility of this innovative tool for assessing self-reported mobility in older adults. Longitudinal data on the MAT-sf from the Lifestyle Interventions and Independence for Elders Study will enable us to evaluate the relative contributions of self-report and performance-based measures of mobility on important health outcomes. PMID- 23685768 TI - One step, two steps, three steps more ... Directional vulnerability to falls in community-dwelling older people. AB - BACKGROUND: Falls leading to disability are common occurrences with advancing age. Stepping is a natural protective option for maintaining balance and preventing falls. There are directionally dependent challenges for protective stepping associated with falls among older individuals. The aim of this study was to determine the stepping response patterns evoked by different directions of externally applied postural disturbances in younger and older adults and in relation to falls. METHODS: Seventy-five community-dwelling adults were tested: 26 younger adults and 49 older adults. Fall history of older participants was tracked prospectively for 1 year after testing. Steps were randomly evoked in 12 directions by a motorized waist-pull system. The number of recovery steps, type of stepping strategy, and first step kinematic characteristics were determined. RESULTS: Younger participants mainly used single recovery steps regardless of the perturbation direction. For the older groups, multiple steps occurred predominantly and were least for the forward-backward directions and greatest for the lateral directions. Trials with three or more recovery steps were increased laterally only for the fallers. Overall, fallers initiated stepping earliest, but other stepping characteristics were similar between the groups for forward backward perturbations. Aging differences in stepping strategies for diagonal and lateral perturbations included numerous interlimb collisions. Adaptive changes in stepping characteristics between forward and lateral perturbations were also observed in relation to age and risk of falls. CONCLUSIONS: These results indicated an age-associated reduction in balance recovery effectiveness through stepping particularly for the lateral direction among older individuals at greater risk for falls. PMID- 23685769 TI - Challenges of diagnosing dementia in the oldest old population. AB - People aged 90 and older are the fastest growing age group in most parts of the world. Since the prevalence of dementia has been shown to increase exponentially after the age of 65, there is an acceptance that the oldest old population has a high burden of dementia; however, there is a lack of consensus on how best to diagnose dementia in this population. This review summarizes the various approaches to diagnosing dementia and the prevalence and incidence rates of dementia that have been reported. We also summarize the literature on cognitive and functional performance and biomarkers for dementia and discuss the limitations to interpretation of these data. Finally, we make recommendations for both researchers and clinicians who intend to diagnose dementia in the oldest old population. PMID- 23685770 TI - Science supporting the art of medicine: improving the management of breathlessness. PMID- 23685771 TI - Art therapy among palliative care inpatients with advanced cancer. PMID- 23685772 TI - UK paramedics can legally withhold resuscitation in defined circumstances. PMID- 23685773 TI - Paramedics possibility to withhold resuscitation. PMID- 23685774 TI - Evaluating ambivalence: social-cognitive and affective brain regions associated with ambivalent decision-making. AB - Ambivalence is a state of inconsistency that is often experienced as affectively aversive. In this functional magnetic resonance imaging study, we investigated the role of cognitive and social-affective processes in the experience of ambivalence and coping with its negative consequences. We examined participants' brain activity during the dichotomous evaluation (pro vs contra) of pretested ambivalent (e.g. alcohol), positive (e.g. happiness) and negative (e.g. genocide) word stimuli. We manipulated evaluation relevance by varying the probability of evaluation consequences, under the hypothesis that ambivalence is experienced as more negative when outcomes are relevant. When making ambivalent evaluations, more activity was found in the anterior cingulate cortex, the insula, the temporal parietal junction (TPJ) and the posterior cingulate cortex (PCC)/precuneus, for both high and low evaluation relevance. After statistically conservative corrections, activity in the TPJ and PCC/precuneus was negatively correlated with experienced ambivalence after scanning, as measured by Priester and Petty's felt ambivalence scale (1996). The findings show that cognitive and social-affective brain areas are involved in the experience of ambivalence. However, these networks are differently associated with subsequent reduction of ambivalence, thus highlighting the importance of understanding both cognitive and affective processes involved in ambivalent decision-making. PMID- 23685777 TI - Disposition and excretion of 14C-AHTN (7-acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4 tetrahydronaphthalene) and 14c-hhcb (1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethyl cyclopenta-gamma-2-benzopyran) after intravenous administration to Sprague-Dawley rats and domestic pigs. AB - 7-Acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (AHTN ) and 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-gamma-2-benzopyran (HHCB) are polycyclic musks widely used as fragrance ingredients in consumer products. Because their metabolic fate following systemic exposure is not fully characterized, disposition and excretion of (14)C-AHTN- and (14)C-HHCB-derived radioactivity were studied in Sprague-Dawley rats and domestic pigs following a single intravenous dose. Rats administered with AHTN or HHCB excreted 21% or 28% of the radioactivity in urine and 67% or 61% in feces, respectively, within 7 days. In pigs administered AHTN or HHCB, 86% or 74% of the dose was excreted in the urine, and 12% or 15% in feces, respectively, during the 14-day collection period. Radioactivity in the whole blood and plasma of both species and tissues of rats declined steadily until the end of the study (28 days) for both the materials. Radioactivity in rat adipose tissue reached peak at 2 hours after dosing, decreasing steadily thereafter. Radioactivity in pig blood declined rapidly from 70 ng equivalents/g at 10 minutes to 1 ng equivalent/g or less by 28 days after administration of either AHTN or HHCB. Radioactivity in pig skin and adipose tissue decreased to below the limit of detection by 28 days for both the materials. Thin-layer chromatography showed multiple radioactive components in both species' urine after administration of either material. Components found in the urine of the 2 species were qualitatively similar but quantitatively different. Both AHTN and HHCB were completely metabolized and excreted. No unchanged parent compound was detected in rat or pig urine. PMID- 23685778 TI - A holistic approach towards defined product attributes by Maillard-type food processing. AB - A fractional factorial experimental design was used to quantify the impact of process and recipe parameters on selected product attributes of extruded products (colour, viscosity, acrylamide, and the flavour marker 4-hydroxy-2,5-dimethyl 3(2H)-furanone, HDMF). The study has shown that recipe parameters (lysine, phosphate) can be used to modulate the HDMF level without changing the specific mechanical energy (SME) and consequently the texture of the product, while processing parameters (temperature, moisture) impact both HDMF and SME in parallel. Similarly, several parameters, including phosphate level, temperature and moisture, simultaneously impact both HDMF and acrylamide formation, while pH and addition of lysine showed different trends. Therefore, the latter two options can be used to mitigate acrylamide without a negative impact on flavour. Such a holistic approach has been shown as a powerful tool to optimize various product attributes upon food processing. PMID- 23685776 TI - How emotional abilities modulate the influence of early life stress on hippocampal functioning. AB - Early life stress (ELS) is known to have considerable influence on brain development, mental health and affective functioning. Previous investigations have shown that alexithymia, a prevalent personality trait associated with difficulties experiencing and verbalizing emotions, is particularly related to ELS. The aim of the present study was to investigate how neural correlates of emotional experiences in alexithymia are altered in the presence and absence of ELS. Therefore, 50 healthy individuals with different levels of alexithymia were matched regarding ELS and investigated with respect to neural correlates of audio visually induced emotional experiences via functional magnetic resonance imaging. The main finding was that ELS modulated hippocampal responses to pleasant (>neutral) stimuli in high-alexithymic individuals, whereas there was no such modulation in low-alexithymic individuals matched for ELS. Behavioral and psychophysiological results followed a similar pattern. When considered independent of ELS, alexithymia was associated with decreased responses in insula (pleasant > neutral) and temporal pole (unpleasant > neutral). Our results show that the influence of ELS on emotional brain responses seems to be modulated by an individual's degree of alexithymia. Potentially, protective and adverse effects of emotional abilities on brain responses to emotional experiences are discussed. PMID- 23685779 TI - Tip apex shaping of gas field ion sources. AB - A procedure to control W(111) tip shape during etching to a single atom is described. It is demonstrated that the base of a single atom tip (SAT) can be shaped in order to alter the final operating voltage and emission opening angle of single atom tips for use as gas field ion sources or electron cold field emission sources. The operating voltages for single atom tips varied between 5 and 17kV during helium ion beam generation. The emission properties of SATs were evaluated by fitting SAT images and measuring the full width at half maximum (FWHM) of the helium ion images. The FWHM is related to the linear opening angle and was evaluated as a function of SAT operating voltage. The results show that a forward focussing effect is observed such that the spot size decreases faster than is expected solely from an acceleration effect, indicating an affect from the tip shape. These results have consequences in designing gas field ion sources where etching is used to prepare the emitter. PMID- 23685775 TI - From neural signatures of emotional modulation to social cognition: individual differences in healthy volunteers and psychiatric participants. AB - It is commonly assumed that early emotional signals provide relevant information for social cognition tasks. The goal of this study was to test the association between (a) cortical markers of face emotional processing and (b) social cognitive measures, and also to build a model which can predict this association (a and b) in healthy volunteers as well as in different groups of psychiatric patients. Thus, we investigated the early cortical processing of emotional stimuli (N170, using a face and word valence task) and their relationship with the social-cognitive profiles (SCPs, indexed by measures of theory of mind, fluid intelligence, speed processing and executive functions). Group comparisons and individual differences were assessed among schizophrenia (SCZ) patients and their relatives, individuals with attention deficit hyperactivity disorder (ADHD), individuals with euthymic bipolar disorder (BD) and healthy participants (educational level, handedness, age and gender matched). Our results provide evidence of emotional N170 impairments in the affected groups (SCZ and relatives, ADHD and BD) as well as subtle group differences. Importantly, cortical processing of emotional stimuli predicted the SCP, as evidenced by a structural equation model analysis. This is the first study to report an association model of brain markers of emotional processing and SCP. PMID- 23685780 TI - Methane emissions and contaminant degradation rates at sites affected by accidental releases of denatured fuel-grade ethanol. AB - The recent increase in the use of denatured fuel-grade ethanol (DFE) has enhanced the probability of its environmental release. Due to the highly labile nature of ethanol (EtOH), it is expected to rapidly biodegrade, increasing the potential for inducing methanogenic conditions in the subsurface. As environmental releases of DFE can be expected to occur at the ground surface or in the vadose zone (e.g., due to surficial spills from rail lines or tanker trucks and leaking underground storage tanks), the potential for methane (CH4) generation at DFE spill sites requires evaluation. An assessment is needed because high CH4 generation rates may lead to CH4 fluxes towards the ground surface, which is of particular concern if spills are located close to human habitation-related to concerns of soil vapor intrusion (SVI). This work demonstrates, for the first time, the measurement of surficial gas release rates at large volume DFE spill sites. Two study sites, near Cambria and Balaton, in MN are investigated. Total carbon emissions at the ground surface (summing carbon dioxide (CO2) and CH4 emissions) are used to quantify depth-integrated DFE degradation rates. Results from both sites demonstrate that substantial CO2 and CH4 emissions do occur-even years after a spill. However, large total carbon fluxes, and CH4 emissions in particular, were restricted to a localized area within the DFE source zone. At the Balaton site, estimates of total DFE carbon losses in the source zone ranged between 5 and 174 MUmol m(-2) s(-1), and CH4 effluxes ranged between non-detect and 9 MUmol m(-2) s(-1). At the Cambria site estimates of total DFE carbon losses in the source zone ranged between 8 and 500 MUmol m(-2) s(-1), and CH4 effluxes ranged between non-detect and 393 MUmol m(-2) s(-1). Substantial CH4 accumulation, coupled with oxygen (O2) depletion, measured in samples collected from custom-designed gas collection chambers at the Cambria site suggests that the development of explosion or asphyxiation hazards is possible in confined spaces above a rapidly degrading DFE release. However, the results also indicate that the development of such hazards is locally constrained, will require a high degree of soil moisture, close proximity to the source zone, a good connection between the soil and the confined space, and poorly aerated conditions. PMID- 23685781 TI - Gamma delta T cells are activated by polysaccharide K (PSK) and contribute to the anti-tumor effect of PSK. AB - Polysaccharide K (PSK) is a widely used mushroom extract that has shown anti tumor and immunomodulatory effects in both preclinical and clinical studies. Therefore, it is important to understand the mechanism of actions of PSK. We recently reported that PSK can activate toll-like receptor 2 and enhances the function of NK cells. The current study was undertaken to study the effect of PSK on gamma delta (gammadelta) T cells, another important arm of the innate immunity. In vitro experiments using mouse splenocytes showed that gammadelta T cells produce IFN-gamma after treatment with PSK and have up-regulated expression of CD25, CD69, and CD107a. To investigate whether the effect of PSK on gammadelta T cells is direct or indirect, purified gammadelta T cells were cultured either alone or together with bone marrow-derived DC in a co-culture or trans-well system and then stimulated with PSK. Results showed that direct cell-to-cell contact between gammadelta T cells and DC is required for optimal activation of gammadelta T cells. There was also reciprocal activation of DC by PSK-activated gammadelta T cells, as demonstrated by higher expression of costimulatory molecules and enhanced production of IL-12 by DC in the presence of gammadelta T cells. PSK can also co-stimulate gammadelta T cells with anti-TCR and anti-CD3 stimulation, in the absence of DC. Finally, in vivo treatment with PSK activates gammadelta T cells among the tumor infiltrating lymphocytes, and depleting gammadelta T cells during PSK treatment attenuated the anti-tumor effect of PSK. All together, these results demonstrated that gammadelta T cells are activated by PSK and contribute to the anti-tumor effect of PSK. PMID- 23685783 TI - Study of PET scanner designs using clinical metrics to optimize the scanner axial FOV and crystal thickness. AB - The aim of this study is to understand the trade-off between crystal thickness and scanner axial field-of-view FOV (AFOV) for clinical PET imaging. Clinical scanner design has evolved towards 20-25 mm thick crystals and 16-22 cm long scanner AFOV, as well as time-of-flight (TOF) imaging. While Monte Carlo studies demonstrate that longer AFOV and thicker crystals will lead to higher scanner sensitivity, cost has prohibited the building of commercial scanners with >22 cm AFOV. In this study, we performed a series of system simulations to optimize the use of a given amount of crystal material by evaluating the impact on system sensitivity and noise equivalent counts (NEC), as well as image quality in terms of lesion detectability. We evaluated two crystal types (LSO and LaBr3) and fixed the total crystal volume used for each type (8.2 L of LSO and 17.1 L of LaBr3) while varying the crystal thickness and scanner AFOV. In addition, all imaging times were normalized so that the total scan time needed to scan a 100 cm long object with multiple bed positions was kept constant. Our results show that the highest NEC cm(-1) in a 35 cm diameter *70 cm long line source cylinder is achieved for an LSO scanner with 10 mm long crystals and AFOV of 36 cm, while for LaBr3 scanners, the highest NEC cm(-1) is obtained with 20 mm long crystals and an AFOV of 38 cm. Lesion phantom simulations show that the best lesion detection performance is achieved in scanners with long AFOV (>=36 cm) and using thin crystals (<=10 mm of LSO and <=20 mm of LaBr3). This is due to a combination of improved NEC, as well as improved lesion contrast estimation due to better spatial resolution in thinner crystals. Alternatively, for lesion detection performance similar to that achieved in standard clinical scanner designs, the long AFOV scanners can be used to reduce the total scan time without increasing the amount of crystal used in the scanner. In addition, for LaBr3 based scanners, the reduced lesion contrast relative to LSO based scanners requires improved timing resolution and longer scan times in order to achieve lesion detectability similar to that achieved in an LSO scanner with similar NEC cm(-1). PMID- 23685784 TI - Comparison of the Macintosh, McCoy, Airtraq laryngoscopes and the intubating laryngeal mask airway in a difficult airway with manual in-line stabilisation: a cross-over simulation-based study. AB - CONTEXT: Patients with multisystem trauma undergoing intubation with manual in line stabilisation (MILS) have a higher incidence of difficult or failed intubations. OBJECTIVE: To compare the effectiveness of the Macintosh laryngoscope with three other intubating devices in a high fidelity simulation model. DESIGN: Cross-over, simulation-based study. SETTING: Tertiary referral and level 1 trauma centre between June and November 2011. PARTICIPANTS: Thirty-five experienced airway physicians. INTERVENTION: Each participant performed tracheal intubations on a Laerdal SimMan manikin in both a normal airway and a difficult airway scenario with MILS. The devices utilised in a randomised order were the Macintosh, McCoy, Airtraq laryngoscopes and the intubating laryngeal mask airway (iLMA). MAIN OUTCOME MEASURES: The primary outcome was time to intubation. Success rates, grade of laryngoscopy and force of intubation were also measured. RESULTS: One hundred and forty intubations were attempted by 35 participants in both the normal and MILS scenarios. In the normal airway, there was no difference in success rates and time to intubation. In the difficult airway with MILS, there was no difference in success rates. However, the Airtraq was associated with a longer time to intubation than the Macintosh, McCoy and iLMA, 39.3, 26.7, 23.3, 39.3, 22.8 s, respectively (P < 0.0001). The Airtraq delivered the best glottic view and lowest force of intubation in both scenarios (P < 0.0001), but was associated with the only failed intubation in the study. The McCoy was associated with a significant improvement in the glottic visualisation (P < 0.05) and reduction in the force of intubation (P <0.0001) compared with the Macintosh. CONCLUSION: In this manikin study, the McCoy demonstrated multiple advantages over the Macintosh. The iLMA was associated with the fastest time to intubation and minimum force of insertion. PMID- 23685782 TI - TLR8 stimulation enhances cetuximab-mediated natural killer cell lysis of head and neck cancer cells and dendritic cell cross-priming of EGFR-specific CD8+ T cells. AB - BACKGROUND: Cetuximab is an anti-epidermal growth factor receptor (EGFR) monoclonal antibody that prolongs survival in the treatment for head and neck cancer (HNC), but only in 10-20 % of patients. An immunological mechanism of action such as natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) has been suggested. We investigated the effects of activating toll-like receptor (TLR)-8 to enhance activity of cetuximab-stimulated, FcgammaR bearing cells. OBJECTIVE: To determine the capability of TLR8-stimulation to enhance the activation and function of NK cells and dendritic cells (DC) in the presence of cetuximab-coated HNC cells. METHODS: Peripheral blood mononuclear cells (PBMC), NK, DC, and CD8(+) T cells were isolated and analyzed using (51)Cr release ADCC, flow cytometry analysis, cytokine ELISA, and EGFR853-861 tetramer staining. RESULTS: TLR8 stimulation of unfractionated PBMC led to enhanced cetuximab-mediated ADCC in healthy donors (p < 0.01) and HNC patients (p < 0.001), which was dependent on NK cells. Secretion of Th1 cytokines TNFalpha (p < 0.0001), IFNgamma (p < 0.0001), and IL-12p40 (p < 0.005) was increased. TLR8 stimulation of PBMC augmented cetuximab-enhanced NK cell degranulation (p < 0.001). TLR8-stimulated NK cells enhanced DC maturation markers CD80, CD83, and CD86 in co-culture with cetuximab-treated HNC cells. TLR8 stimulation of NK-DC co cultures significantly increased DC priming of EGFR-specific CD8(+) T cells in the presence of cetuximab. DISCUSSION: VTX-2337 and cetuximab combination therapy can activate innate and adaptive anti-cancer immune responses. Further investigation in human trials will be important for determining the clinical benefit of this combination and for determining biomarkers of response. PMID- 23685785 TI - Fad7 gene identification and fatty acids phenotypic variation in an olive collection by EcoTILLING and sequencing approaches. AB - The omega-3 fatty acid desaturases (FADs) are enzymes responsible for catalyzing the conversion of linoleic acid to alpha-linolenic acid localized in the plastid or in the endoplasmic reticulum. In this research we report the genotypic and phenotypic variation of Italian Olea europaea L. germoplasm for the fatty acid composition. The phenotypic oil characterization was followed by the molecular analysis of the plastidial-type omega-3 FAD gene (fad7) (EC 1.14.19), whose full length sequence has been here identified in cultivar Leccino. The gene consisted of 2635 bp with 8 exons and 5'- and 3'-UTRs of 336 and 282 bp respectively, and showed a high level of heterozygousity (1/110 bp). The natural allelic variation was investigated both by a LiCOR EcoTILLING assay and the PCR product direct sequencing. Only three haplotypes were identified among the 96 analysed cultivars, highlighting the strong degree of conservation of this gene. PMID- 23685787 TI - Specificity control for read alignments using an artificial reference genome guided false discovery rate. AB - MOTIVATION: Accurate estimation, comparison and evaluation of read mapping error rates is a crucial step in the processing of next-generation sequencing data, as further analysis steps and interpretation assume the correctness of the mapping results. Current approaches are either focused on sensitivity estimation and thereby disregard specificity or are based on read simulations. Although continuously improving, read simulations are still prone to introduce a bias into the mapping error quantitation and cannot capture all characteristics of an individual dataset. RESULTS: We introduce ARDEN (artificial reference driven estimation of false positives in next-generation sequencing data), a novel benchmark method that estimates error rates of read mappers based on real experimental reads, using an additionally generated artificial reference genome. It allows a dataset-specific computation of error rates and the construction of a receiver operating characteristic curve. Thereby, it can be used for optimization of parameters for read mappers, selection of read mappers for a specific problem or for filtering alignments based on quality estimation. The use of ARDEN is demonstrated in a general read mapper comparison, a parameter optimization for one read mapper and an application example in single-nucleotide polymorphism discovery with a significant reduction in the number of false positive identifications. AVAILABILITY: The ARDEN source code is freely available at http://sourceforge.net/projects/arden/. PMID- 23685788 TI - In situ observations of gas phase dynamics during graphene growth using solid state carbon sources. AB - A single-layer graphene has been uniformly grown on a Cu surface at elevated temperatures by thermal processing of a poly(methyl methacrylate) (PMMA) film in a rapid thermal annealing (RTA) system under vacuum. The detailed chemistry of the transition from solid-state carbon to graphene on the catalytic Cu surface was investigated by performing in situ residual gas analysis while PMMA/Cu-foil samples were being heated, in conjunction with interrupted growth studies to reconstruct ex situ the heating process. The data clearly show that the formation of graphene occurs by vaporizing hydrocarbon molecules from PMMA, such as methane and/or methyl radicals, which act as precursors, rather than by the direct graphitization of solid-state carbon. We also found that the temperature for vaporizing hydrocarbon molecules from PMMA and the length of time the gaseous hydrocarbon atmosphere is maintained, which are dependent on both the heating temperature profile and the amount of a solid carbon feedstock, are the dominant factors that determine the crystalline quality of the resulting graphene film. Under optimal growth conditions, the PMMA-derived graphene was found to have a carrier (hole) mobility as high as ~2700 cm(2) V(-1) s(-1) at room temperature, which is superior to common graphene converted from solid carbon. PMID- 23685786 TI - T cell regulation mediated by interaction of soluble CD52 with the inhibitory receptor Siglec-10. AB - Functionally diverse T cell populations interact to maintain homeostasis of the immune system. We found that human and mouse antigen-activated T cells with high expression of the lymphocyte surface marker CD52 suppressed other T cells. CD52(hi)CD4(+) T cells were distinct from CD4(+)CD25(+)Foxp3(+) regulatory T cells. Their suppression was mediated by soluble CD52 released by phospholipase C. Soluble CD52 bound to the inhibitory receptor Siglec-10 and impaired phosphorylation of the T cell receptor-associated kinases Lck and Zap70 and T cell activation. Humans with type 1 diabetes had a lower frequency and diminished function of CD52(hi)CD4(+) T cells responsive to the autoantigen GAD65. In diabetes-prone mice of the nonobese diabetic (NOD) strain, transfer of lymphocyte populations depleted of CD52(hi) cells resulted in a substantially accelerated onset of diabetes. Our studies identify a ligand-receptor mechanism of T cell regulation that may protect humans and mice from autoimmune disease. PMID- 23685790 TI - The water-soluble argentivorous molecule: Ag(+)-pi interactions in water. AB - Ag(+)-pi interactions between Ag(+) ions and a water-soluble tetra-armed cyclen bearing aromatic side-arms (tetracesium 4,4',4'',4'''-((1,4,7,10 tetraazacyclododecane-1,4,7,10-tetrayl)tetrakis(methylene))tetrabenzoate, Cs4) are reported. The structure of the Ag(+) complex with Cs4 was examined using cold ESI-MS, and (1)H NMR and UV spectroscopies. It is found that when it forms Ag(+) complexes in water, Cs4 behaves like an insectivorous plant (Venus flytrap). PMID- 23685789 TI - Accelerated type 1 diabetes induction in mice by adoptive transfer of diabetogenic CD4+ T cells. AB - The nonobese diabetic (NOD) mouse spontaneously develops autoimmune diabetes after 12 weeks of age and is the most extensively studied animal model of human Type 1 diabetes (T1D). Cell transfer studies in irradiated recipient mice have established that T cells are pivotal in T1D pathogenesis in this model. We describe herein a simple method to rapidly induce T1D by adoptive transfer of purified, primary CD4+ T cells from pre-diabetic NOD mice transgenic for the islet-specific T cell receptor (TCR) BDC2.5 into NOD.SCID recipient mice. The major advantages of this technique are that isolation and adoptive transfer of diabetogenic T cells can be completed within the same day, irradiation of the recipients is not required, and a high incidence of T1D is elicited within 2 weeks after T cell transfer. Thus, studies of pathogenesis and therapeutic interventions in T1D can proceed at a faster rate than with methods that rely on heterogenous T cell populations or clones derived from diabetic NOD mice. PMID- 23685791 TI - Effect of soluble factors derived from oral cancer cells on the production of interferon-gamma from peripheral blood mononuclear cells following stimulation with OK-432. AB - The streptococcal antitumor agent OK-432 is commonly used as an immunopotentiator for immunotherapy in various types of malignant tumors including oral cancer. It has been demonstrated that OK-432 elicits an antitumor effect by stimulating immunocompetent cells, thereby inducing multiple cytokines including interferon (IFN)-gamma, interleukin (IL)-2 and IL-12. Serum concentrations of IFN-gamma in patients with oral cancer were examined 24 h after administration of OK-432. Serum concentrations of IFN-gamma in patients with advanced cancer were significantly lower than those in patients with early cancer. These results suggested that some soluble factors produced by cancer cells may inhibit IFN gamma production with OK-432. Thus, in the present study, an in vitro simulation model was established for the immune status of patients with oral cancer by adding conditioned medium (CM) derived from oral cancer cell lines into a culture of peripheral blood mononuclear cells (PBMCs) derived from a healthy volunteer. We investigated whether soluble factors derived from oral cancer cells affected IFN-gamma production from PBMCs following stimulation with OK-432. PBMCs stimulated with OK-432 produced a large amount of IFN-gamma; however, both IFN gamma production and cytotoxic activity from PBMCs induced by OK-432 were inhibited by the addition of CM in a dose-dependent manner. In order to examine these inhibitory effects against IFN-gamma production, the contribution of inhibitory cytokines such as IL-4, IL-6, IL-10, transforming growth factor-beta and vascular endothelial growth factor was investigated. However, neutralization of these inhibitory cytokines did not recover IFN-gamma production inhibited by CM. These results indicated that unknown molecules may inhibit IFN-gamma production from PBMCs following stimulation with OK-432. PMID- 23685794 TI - Update on 1-benzylpiperazine (BZP) party pills. AB - N-benzylpiperazine (BZP) has become popular among recreational drug users as the major active ingredient of "party pills" due to its stimulant and euphoric properties. Before BZP legal restrictions, these pills were sold as a safe and legal alternative to classical amphetamines like ecstasy. New Zealand, given the size of its legal market prior to BZP control, is the country that most contributed to the knowledge about the patterns of use, motivations and positive and adverse effects resulting from its consumption, though the interest in BZP party pills was observed all over the world. The use of these pills has been associated with hospitalizations for adverse events and continued availability over the Internet makes this intoxication a continued concern. This paper provides a review on the characteristics of BZP recreational use, specifically the target population, patterns and motivations of use, and evolution of legal status. Moreover, the in vivo and in vitro studies performed in order to understand its pharmacology, toxicology and kinetics are also discussed. Lastly, analytical methodologies for the identification of BZP in clinical and forensic settings are addressed. PMID- 23685793 TI - Safety of retained microcatheters: an evaluation of radiofrequency heating in endovascular microcatheters with nitinol, tungsten, and polyetheretherketone braiding at 1.5 T and 3 T. AB - BACKGROUND: The use of ethylene-vinyl alcohol copolymer for liquid embolization of cranial vascular lesions has resulted in microcatheter fragments entrapped in patients following endovascular procedures. Undergoing subsequent diagnostic MRI examinations poses a safety concern due to the possibility of radiofrequency heating of the metallic braid incorporated into the microcatheter. Heating of nitinol, tungsten, and polyetheretherketone (PEEK) braided microcatheters was assessed and compared using a phantom model. METHODS: Microcatheters coupled with fluoroptic temperature probes were embedded in a polyacrylamide gel within a head and torso phantom. Experiments were performed at 1.5 T and 3 T, analyzing the effects of different catheter immersion lengths, specific absorption rate (SAR) levels, short clinical scans, long clinical scans, and microcatheter fragment lengths. RESULTS: The maximal increase in temperature for the nitinol braided microcatheter during a 15 min scan was 3.06 degrees C using the T1 fast spin echo sequence at 1.5 T and 0.45 degrees C using the balanced steady state free precession sequence at 3 T. The same scans for fragment lengths of 9, 18, 36, and 72 cm produced maximal temperature rises of 0.68, 0.80, 1.70, and 1.07 degrees C at 1.5 T, respectively. The temperature changes at 3 T for these fragment lengths were 0.66, 0.83, 1.07, and 0.72 degrees C, respectively. The tungsten and PEEK braided microcatheters did not demonstrate heating. CONCLUSIONS: Substantial heating of nitinol braided microcatheters occurred and was a function of SAR level and geometric considerations. SAR and time limitations on MR scanning are proposed for patients with this microcatheter entrapped in their vasculature. In contrast, tungsten and PEEK braided microcatheters showed potential safe use in MRI. PMID- 23685795 TI - The essential comet assay: a comprehensive guide to measuring DNA damage and repair. AB - The comet assay (single cell gel electrophoresis) is the most common method for measuring DNA damage in eukaryotic cells or disaggregated tissues. The assay depends on the relaxation of supercoiled DNA in agarose-embedded nucleoids (the residual bodies remaining after lysis of cells with detergent and high salt), which allows the DNA to be drawn out towards the anode under electrophoresis, forming comet-like images as seen under fluorescence microscopy. The relative amount of DNA in the comet tail indicates DNA break frequency. The assay has been modified to detect various base alterations, by including digestion of nucleoids with a lesion-specific endonuclease. We describe here recent technical developments, theoretical aspects, limitations as well as advantages of the assay, and modifications to measure cellular antioxidant status and different types of DNA repair. We briefly describe the applications of this method in genotoxicity testing, human biomonitoring, and ecogenotoxicology. PMID- 23685796 TI - Effect of caffeic acid on Ca(2+) homeostasis and apoptosis in SCM1 human gastric cancer cells. AB - Caffeic acid is a natural phenolic compound that affects cellular Ca(2+) homeostasis and viability in different cells. This study examined the effect of caffeic acid on cytosolic free Ca(2+) concentrations ([Ca(2+)] i ) and viability in SCM1 human gastric cancer cells. The Ca(2+)-sensitive fluorescent dye fura-2 was used to measure [Ca(2+)] i . Caffeic acid-evoked [Ca(2+)] i rises concentration dependently. The response was reduced by removing extracellular Ca(2+). Caffeic acid-evoked Ca(2+) entry was inhibited by store-operated channel inhibitors (nifedipine, econazole, and SK&F96365) and protein kinase C activator (phorbol 12-myristate 13 acetate, PMA), but not by protein kinase C inhibitor (GF109203X). In Ca(2+)-free medium, treatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin or 2,5-di-tert-butylhydroquinone (BHQ) abolished caffeic acid-evoked [Ca(2+)] i rise. Conversely, treatment with caffeic acid decreased thapsigargin or BHQ-evoked [Ca(2+)] i rise. Inhibition of phospholipase C with U73122 abolished caffeic acid-evoked [Ca(2+)] i rise. At 200 800 MUM, caffeic acid inhibited cell viability, which was not changed by chelating cytosolic Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N' tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Caffeic acid between 400 and 800 MUM also induced apoptosis. Collectively, in SCM1 cells, caffeic acid-induced [Ca(2+)] i rises by evoking phospholipase C-dependent Ca(2+) release from the endoplasmic reticulum and Ca(2+) entry via store-operated Ca(2+) channels. Caffeic acid also caused Ca(2+)-independent apoptosis. PMID- 23685797 TI - Enhanced 2 MUm broad-band emission and NIR to visible frequency up-conversion from Ho3+/Yb3+ co-doped Bi2O3-GeO2-ZnO glasses. AB - In this work, a new and non-conventional oxide glass composition based on Bi2O3 GeO2-ZnO system has been formulated with an aim to realize low phonon oxide glass and elucidate its performance when co-doped with Ho(3+)/Yb(3+) for the energy transfer based NIR emission at 2 MUm from Ho(3+) ions under Yb(3+) excitation. The glass with 1.0 mol% Ho2O3 and 0.5 mol% Yb2O3 has exhibited maximum energy transfer rate (3602 s(-1)) and energy transfer efficiency (65.92%). Important radiative properties have been predicted for emission transitions of Ho(3+) ions using intensity parameters derived from measured absorption spectra using standard Judd-Ofelt theory. At lower acceptor ion concentration (0.1 mol%), an efficient NIR to visible up-conversion emission has been observed based on two photon absorption process which has found to be reduced significantly at higher Ho(3+) concentrations with simultaneous enhancement in 2 MUm emission. Hence, this newly developed glass codoped with Yb(3+)/Ho(3+) is promising glass for sensitized 2 MUm emission applications as broad band tunable lasers because of the combination of low phonon energy (707 cm(-1)), high energy transfer efficiency, moderately high emission cross-section (5.33*10(-21) cm(2)) and larger effective half-width of the emission band value of 169 nm. PMID- 23685798 TI - Effect of interaction with micelles on the excited-state optical properties of zinc porphyrins and J-aggregates formation. AB - This work reports on the photophysical properties of zinc porphyrins meso tetrakis methylpyridiniumyl (Zn(2+)TMPyP) and meso-tetrakis sulfonatophenyl (Zn(2+)TPPS) in homogeneous aqueous solutions and in the presence of sodium dodecyl sulfate (SDS) and cetyltrimethyl ammonium bromide (CTAB) micelles. The excited-state dynamic was investigated with the Z-scan technique, UV-Vis absorption, and fluorescence spectroscopy. Photophysical parameters were obtained by analyzing the experimental data with a conventional five-energy-level diagram. The interaction of the charged side porphyrin groups with oppositely charged surfactants can reduce the electrostatic repulsion between porphyrin molecules leading to aggregation, which affected the porphyrin characteristics such as absorption cross-sections, lifetimes and quantum yields. The interaction between anionic ZnTPPS with cationic CTAB micelles induced the formation of porphyrin J aggregates, while this effect was not observed in the interaction of ZnTMPyP with SDS micelles. This difference is, probably, due to the difference in electrostatic repulsion between the porphyrin molecules. The insights obtained by these results are important for the understanding of the photophysical behavior of porphyrins, regarding potential applications in pharmacokinetics as encapsulation of photosensitizer for drug delivery systems and in its interaction with cellular membrane. PMID- 23685799 TI - Detect changes in protein structure of carinata meal during rumen fermentation in relation to basic chemical profile and comparison with canola meal using ATR FT/IR molecular spectroscopy with chemometrics. AB - As far as we know, no study has been carried out on whether protein structure changes in the feed during rumen fermentation from other research team. This study was conducted to characterize protein structure spectral changes in carinata meal during ruminal fermentation using Fourier transform infrared spectroscopy (FT/IR) technique with ATR. The objectives were to find out whether (1) protein internal structure (in terms of protein amide profile and protein secondary structure profile) changed after in situ ruminal fermentation at 0, 12, 24 and 48 h in carinata meal and conventional canola meal was used as a reference; (2) there was any correlation between protein spectral parameters and basic chemical profile in in situ rumen residue samples; and (3) the protein structural chemical make-up of carinata meal differed from canola meal during 48 h rumen incubation. The results showed that protein structure features in both carinata meal and canola meal were altered as incubation time increased (P<0.0001) and linear and curvilinear relationships (P<0.05) on amide II height and area, height and area ratio of amide I and II as well as height ratio of alpha-helix and beta-sheet were observed within 48 h ruminal fermentation. And the amide I height and area as well as alpha-helix height and beta-sheet height were in the highest level of IR absorbance at 0 h and then gradually declined linearly (P<0.0001) by 30-38% after 48 h incubation. These results indicated that not only quantities decreased but also inherent structure changed in protein chemical make-up during ruminal fermentation. Meanwhile, strong correlations were found between protein spectral parameters and some basic nutrients profile such as CP (positively) and NDF (negatively). And both AHCA and PCA results showed that in situ rumen residues from carinata meal was not distinguished from those from canola meal, suggesting some relationship in structural make-up exhibited between them within protein region during 48 h rumen fermentation. Further studies are still needed to investigate detailed information on structural changes in protein of various feedstuffs in order to fully and deeply understand protein degradation during rumen fermentation on both metabolic basis and molecular biological basis. PMID- 23685800 TI - Theoretical investigation of 5-(2-acetoxyethyl)-6-methylpyrimidin-2,4-dione: conformational study, NBO and NLO analysis, molecular structure and NMR spectra. AB - Structural and conformational, natural bond orbital (NBO) and nonlinear optical (NLO) analysis was performed, and (1)H and (13)C NMR chemical shifts values of 5 (2-Acetoxyethyl)-6-methylpyrimidin-2,4-dione [C9H12N2O4] in the ground state were calculated by using Density Functional Theory (DFT-B3LYP/6-311++G(d,p)) and Hartree-Fock (HF/6-311++G(d,p)) methods. The NMR data were calculated by means of the GIAO, CSGT, and IGAIM methods. In addition, the molecular frontier orbital energies, thermodynamic parameters (in the range of 200-700 K), molecular surfaces, Mulliken charges and atomic polar tensor-based charges were investigated. Besides, the analysis of all possible conformational of the title compound, a detailed potential energy curve for tau1(C8O3C10O4), tau2 (C8O3C10C11) and tau3 (C5C7C8O3) dihedral angles were performed in steps of 10 degrees from 0 degrees to 360 degrees , and depicted to find the most stable form. Finally, the calculated HOMO and LUMO energies show that charge transfer occurs within the title compound. PMID- 23685801 TI - FT-IR, FT-Raman spectra and DFT calculations of melaminium perchlorate monohydrate. AB - Melaminium perchlorate monohydrate (MPM), an organic material has been synthesized by slow solvent evaporation method at room temperature. Powder X-ray diffraction analysis confirms that MPM crystal belongs to triclinic system with space group P-1. FTIR and FT Raman spectra are recorded at room temperature. Functional group assignment has been made for the melaminium cations and perchlorate anions. Vibrational spectra have also been discussed on the basis of quantum chemical density functional theory (DFT) calculations using Firefly (PC GAMESS) version 7.1 G. Vibrational frequencies are calculated and scaled values are compared with experimental values. The assignment of the bands has been made on the basis of the calculated PED. The Mulliken charges, HOMO-LUMO orbital energies are analyzed directly from Firefly program log files and graphically illustrated. HOMO-LUMO energy gap and other related molecular properties are also calculated. The theoretically constructed FT-IR and FT-Raman spectra of MPM coincide with the experimental one. The chemical structure of the compound has been established by (1)H and (13)C NMR spectra. No detectable signal was observed during powder test for second harmonic generation. PMID- 23685802 TI - Vibrational analysis, electronic structure and nonlinear optical properties of levofloxacin by density functional theory. AB - The Fourier transform (FT-IR) spectrum of Levofloxacin was recorded in the region 4000-400 cm(-1) and a complete vibrational assignment of fundamental vibrational modes of the molecule was carried out using density functional method. The observed fundamental modes have been compared with the harmonic vibrational frequencies computed using DFT (B3LYP) method by employing 6-31 G (d, p) basis sets. The most stable geometry of the molecule under investigation has been determined from the potential energy scan. The first-order hyperpolarizability (betao) and other related properties (MU, alphao) of Levofloxacin are calculated using density functional theory (DFT) on a finite field approach. UV-vis spectrum of the molecule was recorded and the electronic properties, such as HOMO and LUMO energies were performed by DFT using 6-31 G (d, p) basis sets. Stability of the molecule arising from hyperconjugative interactions, charge delocalization have been analyzed using natural bond orbital analysis (NBO). The calculated HOMO and LUMO energies show that, the charge transfer occurs within the molecule. The other molecular properties like molecular electrostatic potential (MESP), Mulliken population analysis and thermodynamic properties of the title molecule have been calculated. PMID- 23685803 TI - Synthesis, characterization and equilibrium studies of some potential antimicrobial and antitumor complexes of Cu(II), Ni(II), Zn(II) and Cd(II) ions involving 2-aminomethylbenzimidazole and glycine. AB - The ternary complexes of Cu(II), Zn(II), Ni(II) and Cd(II) with 2 aminomethylbenzimidazole (AMBI) and glycine as a representative example of amino acids have been isolated and characterized by elemental analyses, IR, ESR, UV vis, magnetic moment, molar conductance and (1)H NMR spectra. AMBI behaves as neutral bidentate ligands with coordination through imidazole and amino group nitrogens while the glycine amino acid behaves as a monodenate anion with coordination involving the amino group and carboxylate oxygen after deprotonation. The magnetic and spectral data indicates a square planar geometry for both Cu(2+) and Ni(2+) complexes and a tetrahedral geometry for both Zn(2+) and Cd(2+) complexes. The isolated chelates have been screened for their antifungal and antibacterial activities using the disc diffusion method. A cytotoxicity of the compounds against colon (HCT116) and larynx (HEP2) cancer cells have been studied. The stability constants of ternary M-AMBI-Gly complexes were determined potentiometrically in aqueous solution at I=0.1 mol dm(-3) NaCl. PMID- 23685804 TI - Protective effects and active ingredients of yi-qi-fu-mai sterile powder against myocardial oxidative damage in mice. AB - This study aims to evaluate the protective effects of Yi-Qi-Fu-Mai sterile powder (YQFM) on myocardial oxidative damage and tries to identify the active components responsible for its pharmacological benefits. YQFM and the n-butanol extract of YQFM (YQFM-Bu) were administered to ISO-induced myocardial injury mice. Left ventricle weight index and histopathological analyses were conducted. Serum enzymatic activities of lactate dehydrogenase (LDH), creatine kinase (CK) and superoxide dismutase (SOD), myeloperoxidase (MPO), and the levels of malondialdehyde (MDA) were also measured. Our results demonstrated that both YQFM and YQFM-Bu significantly restored the abnormal activities of CK, LDH, MPO, SOD, and the levels of MDA in ISO-induced myocardial injury mice, and these biochemical results were further supported by histopathological data. Our in vitro findings also confirmed that both YQFM and YQFM-Bu exhibit significant radical scavenging activity. Furthermore, the major active fractions of YQFM were identified by UPLC-MS/MS. Twenty-five ginsenosides and three lignans were identified from YQFM-Bu. These findings suggested YQFM-Bu is the major active fraction of YQFM with the ginsenosides and lignans as potential active components responsible for its protective effect against myocardial injury, and YQFM exerted its beneficial effects on myocardial injury mainly through inhibiting oxidative damage and maintaining the functional integrity of myocardial tissue. PMID- 23685805 TI - Rat submandibular gland perfusion method for clarifying inhibitory regulation of GABAA receptor. AB - GABA is an inhibitory transmitter found in rat salivary gland. However, the inhibitory potential of GABA on salivary secretion is unclear. Using an in vivo cannulation method, intraperitoneal administration of GABA was ineffective in the absence of gabaculine, a GABA transaminase inhibitor, on pilocarpine-induced salivary secretion, suggesting that GABA was rendered metabolically inactive before reaching the salivary gland. We hypothesized that the action of a drug on the salivary glands could be measured directly using a submandibular gland perfusion system. The submandibular gland artery, veins, and duct were cannulated in situ so that physiological functions such as innervation would not be compromised. Hank's balanced salt solution (pH 7.4) was perfused at a rate of 0.5 ml/min together with 1 MUM carbachol (CCh) over a 5-min period every 30 min. Amount of secreted saliva showed no change to the recurrent addition of CCh to the perfusate. GABA or muscimol dose-dependently inhibited CCh-induced salivary secretion. This effect was blocked by bicuculline, a GABA(A)-receptor (GABA(A)-R) antagonist, and enhanced by clonazepam, a central-type benzodiazepine-receptor agonist. These results suggest that salivary secretion is suppressed by GABA(A)-R in rat salivary gland and that the perfusion method used was effective in clarifying inhibitory regulation of GABA(A)-R. PMID- 23685807 TI - Utilitarian prioritization of radiation oncology patients based on maximization of population tumour control. AB - An objective method for establishing patient prioritization in the context of a radiotherapy waiting list is investigated. This is based on a utilitarian objective, being the greatest probability of local tumour control in the population of patients. A numerical simulation is developed and a clinical patient case-mix is used to determine the influence of the characteristics of the patient population on resulting optimal patient scheduling. With the utilitarian objective, large gains in tumour control probability (TCP) can be achieved for individuals or cohorts by prioritizing patients for that fraction of the patient population with relatively small sacrifices in TCP for a smaller fraction of the population. For a waiting list in steady state with five patients per day commencing treatment and leaving the list (and so with five patients per day entering the list), and a mean wait time of 35 days and a maximum of 90 days, optimized wait times ranged from a mean of one day for patients with tumour types with short effective doubling times to a mean of 66.9 days for prostate cancer patients. It is found that, when seeking the optimal daily order of patients on the waiting list in a constrained simulation, the relative rather than absolute value of TCP is the determinant of the resulting optimal waiting times. An increase in the mean waiting time mostly influences (increases) the optimal waiting times of patients with fast-growing tumours. The proportional representation of groups (separated by tumour type) in the patient population has an influence on the resulting distribution of optimal waiting times for patients in those groups, though has only a minor influence on the optimal mean waiting time for each group. PMID- 23685806 TI - Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice. AB - Metabolic syndrome describes a set of obesity-related disorders that increase diabetes, cardiovascular, and mortality risk. Studies of liver-specific protein tyrosine phosphatase 1b (PTP1b) deletion mice (L-PTP1b(-/-)) suggest that hepatic PTP1b inhibition would mitigate metabolic-syndrome through amelioration of hepatic insulin resistance, endoplasmic-reticulum stress, and whole-body lipid metabolism. However, the altered molecular-network states underlying these phenotypes are poorly understood. We used mass spectrometry to quantify protein phosphotyrosine network changes in L-PTP1b(-/-) mouse livers relative to control mice on normal and high-fat diets. We applied a phosphosite-set-enrichment analysis to identify known and novel pathways exhibiting PTP1b- and diet dependent phosphotyrosine regulation. Detection of a PTP1b-dependent, but functionally uncharacterized, set of phosphosites on lipid-metabolic proteins motivated global lipidomic analyses that revealed altered polyunsaturated-fatty acid (PUFA) and triglyceride metabolism in L-PTP1b(-/-) mice. To connect phosphosites and lipid measurements in a unified model, we developed a multivariate-regression framework, which accounts for measurement noise and systematically missing proteomics data. This analysis resulted in quantitative models that predict roles for phosphoproteins involved in oxidation-reduction in altered PUFA and triglyceride metabolism. PMID- 23685809 TI - Hippocampus and medial prefrontal cortex contributions to trace and contextual fear memory expression over time. AB - Previous work has shown that damage to the dorsal hippocampus (DH) occurring at recent, but not remote, timepoints following acquisition produces a deficit in trace conditioned fear memory expression. The opposite pattern has been observed with lesions to the medial prefrontal cortex (mPFC). The present studies address: (1) whether these lesion effects are observable within 30 d of training; (2) whether lesions of the ventral hippocampus (VH) produce temporally graded retrograde amnesia similar to DH lesions; and (3) whether the lesion-to-test interval critically contributes to these lesion deficits. In Experiment 1, excitotoxic lesions of the DH, VH, or mPFC were made at 1 or 30 d following trace fear conditioning. DH and VH lesioned animals showed a deficit in freezing to the tone at the recent, but not remote, timepoint. Medial PFC lesioned animals showed the opposite pattern. In Experiment 2, lesions to DH, VH, or mPFC were made 1 d following training, while testing occurred 30 d later. There were no deficits in freezing to the tone in any lesion condition compared to controls. These results suggest that systems consolidation of trace fear memory occurs within 30 d of acquisition, but does not depend on hippocampus-mPFC interactions during this period. PMID- 23685808 TI - The beneficial effects of leptin on REM sleep deprivation-induced cognitive deficits in mice. AB - Leptin, a 167 amino acid peptide, is synthesized predominantly in the adipose tissues and plays a key role in the regulation of food intake and body weight. Recent studies indicate that leptin receptor is expressed with high levels in many brain regions that may regulate synaptic plasticity. Here we show that deprivation of rapid eye movement (REMD) sleep resulted in impairment of both cue and contextual fear memory. In parallel, surface expression of GluR1 was reduced in the amygdala. Intraperitoneal injection of leptin to the REMD mice rescued memory impairment and reversed surface GluR1 reduction. Using whole-cell recording to evaluate the synaptic function of the thalamus-lateral amygdala (LA) pathway, we found a decrease in frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) concomitant with reduced AMPA/NMDA ratios in the REMD mice. By contrast, paired-pulse facilitation (PPF) was increased. The effects of REMD on mEPSCs and AMPA/NMDA ratio could be reversed by leptin treatment, whereas on PPR it could not. Phosphatase and tensin homolog (PTEN), a dual protein/lipid phosphatase, down-regulates the effect of the PI-3 kinase pathway. Fear conditioning increased whereas REMD led to a decrease in the phosphorylated states of PTEN, Akt, and glycogen synthase kinase-3beta (GSK3beta), and the effects of REMD were reversed by leptin. These results suggest that both pre- and postsynaptic functions of the thalamus-LA pathway were altered by fear conditioning and REMD in opposite directions. Leptin treatment reversed REMD-induced memory deficits primarily by a postsynaptic action by restoring surface expression of GluR1 without affecting PPR. PMID- 23685810 TI - Synthesis of all four stereoisomers of 5-formyl-4-hydroxymethyl-1,3-oxazolidin-2 ones from D-glucosamine. AB - All four stereoisomers of 5-formyl-4-hydroxymethyl-1,3-oxazolidin-2-ones (FHOs) were conveniently prepared from D-glucosamine by base-catalyzed epimerizations. 2 N,3-O-Carbonyl-D-glucosamine (7) was successively treated with NaBH4 and NaIO4 to give (4S,5R)-FHO 18, which was epimerized with DBU in DMF to give (4S,5S)-FHO 20. The glucosamine derivative 7 was epimerized to 2-N,3-O-carbonyl-D-mannosamine 23, from which (4R,5R)- and (4R,5S)-FHO derivatives (27 and 31) were prepared. The NMR measurements revealed that the 4,5-cis-4(or 5)-formyl-5(or 4)-hydroxymethyl oxazolidinone derivatives form five-membered lactol ring, whereas the 4,5-trans disubstituted derivatives form the hydrate or methanol adduct of the open-chain aldehyde, or the symmetrical dimer. PMID- 23685811 TI - N-linked glycolipids by Staudinger coupling of glycosylated alkyl diazides with fatty acids. AB - Aiming for new glycolipids with enhanced chemical stability and close structural similarity to natural cell membrane lipids for the development of a drug delivery system, we have synthesized double amide analogs of glyco-glycerolipids. The synthesis applied a Staudinger reaction based coupling of a 1,3-diazide with fatty acid chlorides. While the concept furnished the desired glucosides in reasonable yields, the corresponding lactosides formed a tetrahydropyrimidine based 1:1 coupling product instead. This unexpected coupling result likely originates from steric hindrance at the iminophosphorane intermediate and provides an interesting core structure for potentially bioactive surfactants. The assembly behavior of both glycolipid types was investigated by optical polarizing microscopy, DSC and surface tension studies. PMID- 23685812 TI - pi-Stacking effects on the EPR parameters of a prototypical DNA spin label. AB - The character and value of spin labels for probing environments like double stranded DNA depend on the degree of change in the spin Hamiltonian parameters of the spin label induced by the environment. Herein we provide a systematic theoretical investigation of this issue, based on a density functional theory method applied to a spin labeled DNA model system, focusing on the dependence of the EPR properties of the spin label on the pi stacking and hydrogen bonding that occur upon incorporating the spin label into the selected base pair inside DNA. It is found that the EPR spin Hamiltonian parameters of the spin label are only negligibly affected by its incorporation into DNA, when compared to its free form. This result gives a theoretical ground for the common empirical assumption regarding the behaviour of spin Hamiltonian parameters made in EPR based measurements of the distance between spin labels incorporated into DNA. PMID- 23685813 TI - Publishing and patenting the fruits of academic research: the key to a successful parallel track. AB - Researchers can participate in the patent process without sacrificing a robust publishing career. The key is timing, combined with a basic understanding of how the patent process works. PMID- 23685814 TI - PLA2G3 promotes mast cell maturation and function. PMID- 23685815 TI - Deconstructing development. PMID- 23685816 TI - T cell exhaustion: a means or an end? PMID- 23685817 TI - Killer T cells find meaningful encounters through iMATEs. PMID- 23685824 TI - TH2, allergy and group 2 innate lymphoid cells. AB - The initiation of type 2 immune responses by the epithelial cell-derived cytokines IL-25, IL-33 and TSLP has been an area of extensive research in the past decade. Such studies have led to the identification of a new innate lymphoid subset that produces the canonical type 2 cytokines IL-5, IL-9 and IL-13 in response to IL-25 and IL-33. These group 2 or type 2 innate lymphoid cells (ILC2 cells) represent a critical source of type 2 cytokines in vivo and serve an important role in orchestrating the type 2 response to helminths and allergens. Further characterization of ILC2 cell biology will enhance the understanding of type 2 responses and may identify new treatments for asthma, allergies and parasitic infections. Interactions between ILC2 cells and the adaptive immune system, as well as examination of potential roles for ILC2 cells in the maintenance of homeostasis, promise to be particularly fruitful areas of future research. PMID- 23685825 TI - Reductions in serum lipids with a 4-year decline in serum perfluorooctanoic acid and perfluorooctanesulfonic acid. AB - BACKGROUND: Several epidemiological cross-sectional studies have found positive associations between serum concentrations of lipids and perfluorooctanoic acid (PFOA, or C8). A longitudinal study should be less susceptible to biases from uncontrolled confounding or reverse causality. METHODS: We investigated the association between within-individual changes in serum PFOA and perfluorooctanesulfonic acid (PFOS) and changes in serum lipid levels (low density lipoprotein [LDL] cholesterol, high-density lipoprotein cholesterol, total cholesterol, and triglycerides) over a 4.4-year period. The study population consisted of 560 adults living in parts of Ohio and West Virginia where public drinking water had been contaminated with PFOA. They had participated in a cross-sectional study in 2005-2006, and were followed up in 2010, by which time exposure to PFOA had been substantially reduced. RESULTS: Overall serum concentrations of PFOA and PFOS fell by half from initial geometric means of 74.8 and 18.5 ng/mL, respectively, with little corresponding change in LDL cholesterol (mean increase 1.8%, standard deviation 26.6%). However, there was a tendency for people with greater declines in serum PFOA or PFOS to have greater LDL decrease. For a person whose serum PFOA fell by half, the predicted fall in LDL cholesterol was 3.6% (95% confidence interval = 1.5-5.7%). The association with a decline in PFOS was even stronger, with a 5% decrease in LDL (2.5-7.4%). CONCLUSIONS: Our findings from this longitudinal study support previous evidence from cross-sectional studies of positive associations between PFOA and PFOS in serum and LDL cholesterol. PMID- 23685826 TI - Water-related parasitic diseases in China. AB - Water-related parasitic diseases are directly dependent on water bodies for their spread or as a habitat for indispensable intermediate or final hosts. Along with socioeconomic development and improvement of sanitation, overall prevalence is declining in the China. However, the heterogeneity in economic development and the inequity of access to public services result in considerable burden due to parasitic diseases in certain areas and populations across the country. In this review, we demonstrated three aspects of ten major water-related parasitic diseases, i.e., the biology and pathogenicity, epidemiology and recent advances in research in China. General measures for diseases control and special control strategies are summarized. PMID- 23685827 TI - Investigating unmet health needs in primary health care services in a representative sample of the Greek population. AB - Unmet health care needs are determined as the difference between the services judged necessary and the services actually received, and stem from barriers related to accessibility, availability and acceptability. This study aims to examine the prevalence of unmet needs and to identify the socioeconomic and health status factors that are associated with unmet needs. A cross-sectional study was conducted in Greece in 2010 and involved data from 1,000 consenting subjects (>18 years old). Multiple binary logistic regression analysis was applied to investigate the predictors of unmet needs and to determine the relation between the socio-demographic characteristics and the accessibility, availability and acceptability barriers. Ninety nine participants (9.9%) reported unmet health needs during the 12 months prior to the research. The most frequently self-reported reasons were cost and lack of time. Youth, parenthood, physician consultations, and poor mental health increased the likelihood of unmet needs. Women were less likely to report accessibility and availability than acceptability barriers. Educational differences were evident and individuals with primary and secondary education were associated with significantly more accessibility and availability barriers compared with those with tertiary education. Unmet health needs pose a significant challenge to the health care system, especially given the difficult current financial situation in Greece. It is believed that unmet health needs will continue to increase, which will widen inequalities in health and health care access. PMID- 23685828 TI - Environmental and individual correlates of various types of physical activity among community-dwelling middle-aged and elderly Japanese. AB - Recent studies have suggested the importance of the neighborhood environment in determining the specific type of physical activity. However, few studies on this topic have been undertaken in Japan. This study examined the association of three types of physical activity and their associations with individual and neighborhood environmental factors among middle-aged and elderly Japanese. Participants were 2,449 adults aged 40-69 living in Fujisawa city who had undergone health checkups and responded to our survey by mail. Individual factors, the International Physical Activity Questionnaire (long form), and its environmental module acted as inputs to the study. The adjusted odds ratios (ORs) of high levels of moderate-to-vigorous intensity leisure-time physical activity (LTPA), walking for active recreation, and transportation were calculated in relation to individual and neighborhood environmental factors through multiple logistic regression models. Not working and good self-rated health were significantly associated with a higher level of each physical activity outcome. According to the adjusted ORs, higher educational attainment, higher economic status, good access to exercise facilities, and owning motor vehicles were associated with longer LTPA time. However, different sets of factors were associated with longer walking times for recreation and transportation. The results suggest that diverse individual and neighborhood environmental characteristics are associated with different physical activity outcomes. Therefore, customizing environments to become activity-friendly is necessary to increase physical activity effectively among middle-aged and elderly Japanese. PMID- 23685829 TI - Global and local reactivity indices for electrophilic/nucleophilic free radicals. AB - A set of five DFT reactivity indices, namely, the global electrophilicity omega degrees and nucleophilicity N degrees indices, the radical Parr function P, and the local electrophilicity omega and nucleophilicity N indices, for the study of free radicals (FRs) are proposed. Global indices have been tested for a series of 32 FRs having electrophilic and/or nucleophilic activations. As expected, no correlation between the proposed global electrophilicity omega degrees and global nucleophilicity N degrees has been found. Analysis of the local electrophilicity omega and nucleophilicity N indices for FRs, together with analysis of the local electrophilicity omegak and nucleophilicity Nk indices for alkenes, allows for an explanation of the regio- and chemoselectivity in radical additions of FRs to alkenes. Finally, an ELF bonding analysis for the C-C bond formation along the nucleophilic addition of 2-hydroxyprop-2-yl FR 28 to methyl acrylate 35 evidences that the new C-C bond is formed by C-to-C coupling of two radical centres, which are properly characterized through the use of the Parr functions. PMID- 23685830 TI - Blood loss reduction in cementless total hip replacement with fibrin spray or bipolar sealer: a randomised controlled trial on ninety five patients. AB - PURPOSE: Several studies have investigated effectiveness of fibrin spray or bipolar sealer to control peri-operative bleeding and reduce the need for blood transfusion, but a direct comparison between the two methods has not been previously performed. We conducted a prospective randomised trial, with standard electrocautery as a control group. METHODS: In our investigation, 95 patients were randomised to one of three parallel groups receiving (1) 10 mL of topical fibrin spray before closure, (2) haemostasis with radiofrequency energy using a bipolar sealer, and (3) standard electrocautery. All patients and staff apart from the surgeons were blinded until data analysis was complete. Peri-operative blood loss has been calculated using a formula described by Ward and Gross (considering estimated patient blood volume, pre- and post-operative haemoglobin and haematocrit levels), with mention of eventual blood re-infusion or transfusion, at given intervals from surgery (6, 24, 48, 72 hours). RESULTS: Mean blood loss was lower for both methods investigated, compared to the control group at every time interval considered, although differences were stronger for fibrin spray [Quixil]. Mean blood saving at the given intervals from surgery (6-24-48-72 hours) was respectively 96 ml, 129 ml, 296 ml, and 121 ml for bipolar sealer [Aquamantys] and 235 ml, 368 ml, 642 ml, and 490 ml for fibrin spray. These results are statistically significant (p = 0.05) for fibrin spray at every interval compared to control values, while a significance is detectable for bipolar sealer only at 48 hours after surgery. CONCLUSIONS: The fibrin spray group had the best performance in terms of blood loss, significantly reduced in comparison with the control group and bipolar sealer group. Blood loss reduction for the bipolar sealer was remarkable only at 48 hours, compared with the control group. Blood loss reduction for fibrin spray was significant at every time interval considered. Differences between the two treatments investigated and the control group narrowed slightly at 72 hours, as an expression of spontaneous homeostasis. Notable is the fact that blood volume saved with fibrin spray at 24 and 48 hours is comparable to the volume of at least one blood unit. A cost effectiveness analysis should be considered in term of expense, biological risks (related to blood transfusion or human-derived products use) and bleeding-related complications. PMID- 23685831 TI - Conversion of shoulder arthroplasty to reverse implants: clinical and radiological results using a modular system. AB - PURPOSE: Revision of a shoulder arthroplasty to a reverse arthroplasty is a highly demanding procedure. The aim of this study is to report the clinical results of hemi and total shoulder prosthesis revisions to reverse implants without removal of the humeral stem, using a modular shoulder replacement system (SMR Lima LTD). We retrospectively reviewed 26 patients who underwent an operation from 2004 to 2009. METHODS: The patients were divided into two groups: in Group I, 18 patients underwent a revision of hemiarthroplasty implanted for fracture; in Group II, eight patients underwent a revision of anatomical total prosthesis. All patients were evaluated at a mean follow-up of 32.3 (+/-12.7) months using the Constant score rating scale and by range of motion evaluation, EQ-VAS, X-ray and CT scan. RESULTS: The Constant score of each patient was 47.88 (+/-5.88) after the revision. The EQ-VAS improved from 40 (+/-20) to 70 (+/-10). All patients improved in terms of range of motion. The radiographs and CT scans obtained after revision showed good integration and no signs of loosening of the implant. The mean time of surgery was recorded as 62' (+/-8'), with a maximum blood loss of less than 300 ml in all cases. CONCLUSIONS: Our study demonstrates that using a full modular system at the time of the first implant allows avoidance of the step to remove the humeral stem and metal back in cases of shoulder prosthesis revision to a reverse prosthesis, resulting in a short operative time, few intraoperative complications and a satisfactory clinical outcome at medium-term follow-up. PMID- 23685832 TI - Fundamental immunology of skin transplantation and key strategies for tolerance induction. AB - Transplantation of allogeneic or xenogeneic skin grafts can evoke strong immune responses that lead to acute rejection of the graft tissues. In this process, donor-derived dendritic cells play crucial roles in the triggering of such immune responses. Both the innate and acquired host immune systems participate in graft rejection. At present, the rejection of skin grafts cannot be well-controlled by ordinary systemic immunosuppression therapy. Although several strategies for the long-term survival of allogeneic or xenogeneic skin grafts have been demonstrated in animal models, the induction of long-term tolerance to skin grafts is still a great challenge in clinical settings. In this article, we review the progress in the understanding of immune responses to skin grafts and discuss the possible methods that can decrease the immunogenicity of graft tissues and improve the survival of skin grafts, especially those included in preoperative pre treatments. PMID- 23685833 TI - Biosensor for detection of antibiotic resistant Staphylococcus bacteria. AB - A structurally transformed lytic bacteriophage having a broad host range of Staphylococcus aureus strains and a penicillin-binding protein (PBP 2a) antibody conjugated latex beads have been utilized to create a biosensor designed for discrimination of methicillin resistant (MRSA) and sensitive (MSSA) S. aureus species (1,2). The lytic phages have been converted into phage spheroids by contact with water-chloroform interface. Phage spheroid monolayers have been moved onto a biosensor surface by Langmuir-Blodgett (LB) technique (3). The created biosensors have been examined by a quartz crystal microbalance with dissipation tracking (QCM-D) to evaluate bacteria-phage interactions. Bacteria spheroid interactions led to reduced resonance frequency and a rise in dissipation energy for both MRSA and MSSA strains. After the bacterial binding, these sensors have been further exposed to the penicillin-binding protein antibody latex beads. Sensors analyzed with MRSA responded to PBP 2a antibody beads; although sensors inspected with MSSA gave no response. This experimental distinction determines an unambiguous discrimination between methicillin resistant and sensitive S. aureus strains. Equally bound and unbound bacteriophages suppress bacterial growth on surfaces and in water suspensions. Once lytic phages are changed into spheroids, they retain their strong lytic activity and show high bacterial capture capability. The phage and phage spheroids can be utilized for testing and sterilization of antibiotic resistant microorganisms. Other applications may include use in bacteriophage therapy and antimicrobial surfaces. PMID- 23685834 TI - Predictive impact of adiponectin for detecting dysglycemia in non-fasting Japanese employees with metabolic risk factors. AB - The screening of dysglycemia in the non-fasting state is a challenging issue in healthcare practice. We investigated whether the additional measurement of circulating adiponectin levels could improve screening performance. We used a database of 1190 Japanese employees with metabolic risk factors, who underwent a 75-g oral glucose tolerance test (OGTT), following non-fasting health check-ups. Dysglycemia was defined as fasting glucose levels >=6.1 mmol/L or 2-hr glucose levels >=7.8 mmol/L during the OGTT. Logistic regression analysis revealed that decreased adiponectin levels were associated with dysglycemia, independently of postprandial glucose (PG) and hemoglobin A1c (HbA1c) levels, as well as other health check-up data (p<0.01). The trivariate model with PG, HbA1c, and adiponectin levels (PG+A1c+ADN model) had a larger area under the receiver operating characteristic curves (AUC) than the bivariate model with only PG and HbA1c levels (0.746 vs. 0.729; p=0.01). However, the AUC of the multivariate model with PG, HbA1c, and other health check-up data, but not adiponectin levels (PG+A1c+Other model) was 0.815, much larger than that of the PG+A1c+ADN model (p<0.01). The addition of adiponectin levels to the PG+A1c+Other model had a significantly larger AUC than the A1c+PG+Other model only in the subgroup without abdominal obesity (p=0.01), but not in the overall population (p=0.06) or in the subgroup with abdominal obesity (p=0.62). In conclusion, circulating adiponectin levels were independently associated with dysglycemia in non-fasting Japanese employees with metabolic risk factors, but they improved the screening capacity only in those without abdominal obesity. PMID- 23685835 TI - Identification and analysis of in vivo VEGF downstream markers link VEGF pathway activity with efficacy of anti-VEGF therapies. AB - PURPOSE: The aim of this study was to identify conserved pharmacodynamic and potential predictive biomarkers of response to anti-VEGF therapy using gene expression profiling in preclinical tumor models and in patients. EXPERIMENTAL DESIGN: Surrogate markers of VEGF inhibition [VEGF-dependent genes or VEGF dependent vasculature (VDV)] were identified by profiling gene expression changes induced in response to VEGF blockade in preclinical tumor models and in human biopsies from patients treated with anti-VEGF monoclonal antibodies. The potential value of VDV genes as candidate predictive biomarkers was tested by correlating high or low VDV gene expression levels in pretreatment clinical samples with the subsequent clinical efficacy of bevacizumab (anti-VEGF) containing therapy. RESULTS: We show that VDV genes, including direct and more distal VEGF downstream endothelial targets, enable detection of VEGF signaling inhibition in mouse tumor models and human tumor biopsies. Retrospective analyses of clinical trial data indicate that patients with higher VDV expression in pretreatment tumor samples exhibited improved clinical outcome when treated with bevacizumab-containing therapies. CONCLUSIONS: In this work, we identified surrogate markers (VDV genes) for in vivo VEGF signaling in tumors and showed clinical data supporting a correlation between pretreatment VEGF bioactivity and the subsequent efficacy of anti-VEGF therapy. We propose that VDV genes are candidate biomarkers with the potential to aid the selection of novel indications as well as patients likely to respond to anti-VEGF therapy. The data presented here define a diagnostic biomarker hypothesis based on translational research that warrants further evaluation in additional retrospective and prospective trials. PMID- 23685837 TI - TOF PET offset calibration from clinical data. AB - In this paper, we present a timing calibration technique for time-of-flight positron emission tomography (TOF PET) that eliminates the need for a specialized data acquisition. By eliminating the acquisition, the process becomes fully automated, and can be performed with any clinical data set and whenever computing resources are available. It also can be applied retroactively to datasets for which a TOF offset calibration is missing or suboptimal. Since the method can use an arbitrary data set to perform a calibration prior to a TOF reconstruction, possibly of the same data set, one also can view this as reconstruction from uncalibrated data. We present a performance comparison with existing calibration techniques. PMID- 23685836 TI - Vaccination with dendritic cell/tumor fusions following autologous stem cell transplant induces immunologic and clinical responses in multiple myeloma patients. AB - PURPOSE: A multiple myeloma vaccine has been developed whereby patient-derived tumor cells are fused with autologous dendritic cells, creating a hybridoma that stimulates a broad antitumor response. We report on the results of a phase II trial in which patients underwent vaccination following autologous stem cell transplantation (ASCT) to target minimal residual disease. EXPERIMENTAL DESIGN: Twenty-four patients received serial vaccinations with dendritic cell/myeloma fusion cells following posttransplant hematopoietic recovery. A second cohort of 12 patients received a pretransplant vaccine followed by posttransplant vaccinations. Dendritic cells generated from adherent mononuclear cells cultured with granulocyte macrophage colony-stimulating factor, interleukin-4, and TNF alpha were fused with autologous bone marrow-derived myeloma fusion cells using polyethylene glycol. Fusion cells were quantified by determining the percentage of cells that coexpress dendritic cell and myeloma fusion antigens. RESULTS: The posttransplant period was associated with reduction in general measures of cellular immunity; however, an increase in CD4 and CD8(+) myeloma-specific T cells was observed after ASCT that was significantly expanded following posttransplant vaccination. Seventy-eight percent of patients achieved a best response of complete response (CR)+very good partial response (VGPR) and 47% achieved a CR/near CR (nCR). Remarkably, 24% of patients who achieved a partial response following transplant were converted to CR/nCR after vaccination and at more than 3 months posttransplant, consistent with a vaccine-mediated effect on residual disease. CONCLUSIONS: The posttransplant period for patients with multiple myeloma provides a unique platform for cellular immunotherapy in which vaccination with dendritic cell/myeloma fusion fusions resulted in the marked expansion of myeloma-specific T cells and cytoreduction of minimal residual disease. PMID- 23685838 TI - In silico evolution of guiding track designs for molecular shuttles powered by kinesin motors. AB - Molecular shuttles powered by kinesin motors require guiding tracks to perform specific tasks in nanoscale devices. Here, using our simulation of molecular shuttle movements, we describe an in silico evolutionary design method that makes it possible to automatically design the guiding tracks in accordance with their functions defined by designers. With this design method, we designed two types of pre-existing guiding track modules with improved performances, as well as one with a novel function. PMID- 23685839 TI - Hypothalamic glucagon signaling inhibits hepatic glucose production. AB - Glucagon activates hepatic protein kinase A (PKA) to increase glucose production, but the gluco-stimulatory effect is transient even in the presence of continuous intravenous glucagon infusion. Continuous intravenous infusion of insulin, however, inhibits glucose production through its sustained actions in both the liver and the mediobasal hypothalamus (MBH). In a pancreatic clamp setting, MBH infusion with glucagon activated MBH PKA and inhibited hepatic glucose production (HGP) in rats, as did central glucagon infusion in mice. Inhibition of glucagon receptor-PKA signaling in the MBH and hepatic vagotomy each negated the effect of MBH glucagon in rats, whereas the central effect of glucagon was diminished in glucagon receptor knockout mice. A sustained rise in plasma glucagon concentrations transiently increased HGP, and this transiency was abolished in rats with negated MBH glucagon action. In a nonclamp setting, MBH glucagon infusion improved glucose tolerance, and inhibition of glucagon receptor-PKA signaling in the MBH enhanced the ability of intravenous glucagon injection to increase plasma glucose concentrations. We also detected a similar enhancement of glucose concentrations that was associated with a disruption in MBH glucagon signaling in rats fed a high-fat diet. We show that hypothalamic glucagon signaling inhibits HGP and suggest that hypothalamic glucagon resistance contributes to hyperglycemia in diabetes and obesity. PMID- 23685840 TI - Inhibition of TGF-beta signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. AB - Osteoarthritis is a highly prevalent and debilitating joint disorder. There is no effective medical therapy for the condition because of limited understanding of its pathogenesis. We show that transforming growth factor beta1 (TGF-beta1) is activated in subchondral bone in response to altered mechanical loading in an anterior cruciate ligament transection (ACLT) mouse model of osteoarthritis. TGF beta1 concentrations are also high in subchondral bone from humans with osteoarthritis. High concentrations of TGF-beta1 induced formation of nestin positive mesenchymal stem cell (MSC) clusters, leading to formation of marrow osteoid islets accompanied by high levels of angiogenesis. We found that transgenic expression of active TGF-beta1 in osteoblastic cells induced osteoarthritis, whereas inhibition of TGF-beta activity in subchondral bone attenuated the degeneration of articular cartilage. In particular, knockout of the TGF-beta type II receptor (TbetaRII) in nestin-positive MSCs led to less development of osteoarthritis relative to wild-type mice after ACLT. Thus, high concentrations of active TGF-beta1 in subchondral bone seem to initiate the pathological changes of osteoarthritis, and inhibition of this process could be a potential therapeutic approach to treating this disease. PMID- 23685841 TI - Inflammatory Flt3l is essential to mobilize dendritic cells and for T cell responses during Plasmodium infection. AB - Innate sensing mechanisms trigger a variety of humoral and cellular events that are essential to adaptive immune responses. Here we describe an innate sensing pathway triggered by Plasmodium infection that regulates dendritic cell homeostasis and adaptive immunity through Flt3 ligand (Flt3l) release. Plasmodium induced Flt3l release in mice requires Toll-like receptor (TLR) activation and type I interferon (IFN) production. We found that type I IFN supports the upregulation of xanthine dehydrogenase, which metabolizes the xanthine accumulating in infected erythrocytes to uric acid. Uric acid crystals trigger mast cells to release soluble Flt3l from a pre-synthesized membrane-associated precursor. During infection, Flt3l preferentially stimulates expansion of the CD8 alpha(+) dendritic cell subset or its BDCA3(+) human dendritic cell equivalent and has a substantial impact on the magnitude of T cell activation, mostly in the CD8(+) compartment. Our findings highlight a new mechanism that regulates dendritic cell homeostasis and T cell responses to infection. PMID- 23685842 TI - Semaphorin 3d signaling defects are associated with anomalous pulmonary venous connections. AB - Total anomalous pulmonary venous connection (TAPVC) is a potentially lethal congenital disorder that occurs when the pulmonary veins do not connect normally to the left atrium, allowing mixing of pulmonary and systemic blood. In contrast to the extensive knowledge of arterial vascular patterning, little is known about the patterning of veins. Here we show that the secreted guidance molecule semaphorin 3d (Sema3d) is crucial for the normal patterning of pulmonary veins. Prevailing models suggest that TAPVC occurs when the midpharyngeal endothelial strand (MES), the precursor of the common pulmonary vein, does not form at the proper location on the dorsal surface of the embryonic common atrium. However, we found that TAPVC occurs in Sema3d mutant mice despite normal formation of the MES. In these embryos, the maturing pulmonary venous plexus does not anastomose uniquely with the properly formed MES. In the absence of Sema3d, endothelial tubes form in a region that is normally avascular, resulting in aberrant connections. Normally, Sema3d provides a repulsive cue to endothelial cells in this area, establishing a boundary. Sequencing of SEMA3D in individuals with anomalous pulmonary veins identified a phenylalanine-to-leucine substitution that adversely affects SEMA3D function. These results identify Sema3d as a crucial pulmonary venous patterning cue and provide experimental evidence for an alternate developmental model to explain abnormal pulmonary venous connections. PMID- 23685843 TI - Real-time in vivo analysis of T cell activation in the central nervous system using a genetically encoded calcium indicator. AB - To study T cell activation in vivo in real time, we introduced a newly developed fluorescence resonance energy transfer-based, genetically encoded calcium indicator into autoantigen-specific and non-autoantigen-specific CD4(+) T cells. Using two-photon microscopy, we explored the responses of retrovirally transduced calcium indicator-expressing T cells to antigen in the lymph nodes and the central nervous system. In lymph nodes, the administration of exogenous antigen caused an almost immediate arrest of T cells around antigen-presenting cells and an instant rise of cytosolic calcium. In contrast, encephalitogenic T cells entering the leptomeningeal space, one main portal into the central nervous system parenchyma during experimental autoimmune encephalomyelitis, showed elevated intracellular calcium concentrations while still meandering through the space. This approach enabled us to follow the migration and activation patterns of T cells in vivo during the course of the disease. PMID- 23685844 TI - A squaraine-based red emission off-on chemosensor for biothiols and its application in living cells imaging. AB - A new probe based on the squaraine skeleton with a 2,4-dinitrobenzenesulfonyl unit is reported as a fluorescent probe for biothiol. It shows turn-on properties with red emission towards biothiols in acetonitrile-PBS buffer (1 : 9, v/v) solution, and its properties of rapid response, high selectivity and high sensitivity make it a potential probe with real applications. Moreover, the in vitro assays show that the probe can be used in fluorescence imaging for the detection of intracellular biothiol levels. PMID- 23685846 TI - Serum HMGB1 as a diagnostic marker for malignant peritoneal mesothelioma. AB - BACKGROUND: Diffuse malignant peritoneal mesothelioma (DMPM) is an aggressive malignant tumor of mesothelial origin that shows a limited response to cytoreductive surgery along with intraperitoneal chemotherapy. Therefore, early diagnosis of DMPM is very important. Some researchers have previously reported that high-mobility group box 1 (HMGB1) was correlated with pulmonary fibrosis. DMPM involves the malignant transformation of mesothelial cells, which originate from mesenchymal cells, similar to lung fibroblasts. Here, we investigated serum levels of HMGB1 in patients with MPM and compared them with those of a population that had been exposed to asbestos without developing MPM. STUDY: The serum concentrations of HMGB1 were measured in 13 DMPM patients and 45 individuals with benign asbestos-related diseases. RESULT: We demonstrated that the patients with DMPM had significantly higher serum levels of HMGB1 compared with the population who had been exposed to asbestos but did not develop DMPM. CONCLUSION: Our data suggest that serum HMGB1 concentration is a useful serum marker for DMPM. PMID- 23685845 TI - Low nitric oxide bioavailability is associated with better responses to sildenafil in patients with erectile dysfunction. AB - Erectile dysfunction (ED) is a multifactorial disease associated with vascular dysfunction, low nitric oxide (NO) bioavailability, and oxidative stress. However, it is not known whether low NO bioavailability and oxidative stress affect the responsiveness of ED patients to sildenafil. We tested this hypothesis by studying 28 healthy subjects (control group), 26 patients with ED without comorbidities (ED group), and 18 patients with ED and diabetes mellitus (ED/DM group). The International Index for Erectile Function (IIEF) questionnaire was used to assess the erectile function of all participants, and their responsiveness to sildenafil was assessed as the percentage of change in the five item version of IIEF score before and after sildenafil treatment. Levels of whole blood nitrite, antioxidants markers (ferric reducing ability of plasma (FRAP) and reduced glutathione), and oxidative stress markers (thiobarbituric acid reactive substance and protein carbonyl) were determined. We found a negative correlation between whole blood nitrite levels and the responses to sildenafil in both ED groups (P<0.05). FRAP correlated negatively with the responses to sildenafil in the ED/DM group (P<0.05). No other significant associations were found. Our findings show evidence that low NO bioavailability is associated with better responses to sildenafil in patients with ED (with or without DM). PMID- 23685847 TI - Causes of bleeding and outcomes in patients hospitalized with upper gastrointestinal bleeding. AB - GOALS: To evaluate sources of upper gastrointestinal bleeding (UGIB) at an urban US hospital and compare them to sources at the same center 20 years ago, and to assess clinical outcomes related to source of UGIB. BACKGROUND: Recent studies suggest changes in causes and outcomes of UGIB. STUDY: Consecutive patients with hematemesis, melena, and/or hematochezia undergoing upper endoscopy with an identified source at LA County+USC Medical Center from January 2005 to June 2011 were identified retrospectively. RESULTS: Mean age of the 1929 patients was 52 years; 75% were male. A total of 1073 (55%) presented with hematemesis, 809 (42%) with melena alone, and 47 (2%) with hematochezia alone. The most common causes were ulcers in 654 patients (34%), varices in 633 (33%), and erosive esophagitis in 156 (8%), compared with 43%, 33%, and 2% in 1991. During hospitalization, 207 (10.7%) patients required repeat endoscopy for UGIB (10.6% for both ulcers and varices) and 129 (6.7%) died (5.2% for ulcers; 9.2% for varices). On multivariate analysis, hematemesis (OR=1.38; 95% CI, 1.04-1.88) and having insurance (OR=1.44; 95% CI, 1.07-1.94) were associated with repeat endoscopy for UGIB. Varices (OR=1.53; 95% CI, 1.05-2.22) and having insurance (OR=4.53; 95% CI, 2.84-7.24) were associated with mortality. CONCLUSION: Peptic ulcers decreased modestly over 2 decades, whereas varices continue as a common cause of UGIB at an urban hospital serving lower socioeconomic patients. Inpatient mortality, but not rebleeding requiring endoscopy, was higher with variceal than nonvariceal UGIB, indicating patients with variceal UGIB remain at risk of death from decompensation of underlying illness even after successful control of bleeding. PMID- 23685848 TI - Catalytic oxidation of CO by N2O conducted via the neutral oxide cluster couple VO2/VO3. AB - Neutral vanadium and cobalt oxide clusters are generated at the same time employing a V-Co mixed target. Experimental results indicate that the reaction VO2 + N2O -> VO3 + N2 occurs in a fast flow reactor. This interpretation is further supported for a gas mixture of CO and N2O in the flow cell: regeneration of VO2 is observed for this case via the reaction VO3 + CO -> VO2 + CO2. A full catalytic cycle for the reaction N2O + CO -> N2 + CO2 is thus complete at room temperature enabled by the VO2/VO3 cluster couple. DFT calculations demonstrate that the entire catalytic process is overall barrierless and reproduce the experimental results quite well. PMID- 23685849 TI - Feature constrained compressed sensing CT image reconstruction from incomplete data via robust principal component analysis of the database. AB - In computed tomography (CT), incomplete data problems such as limited angle projections often cause artifacts in the reconstruction results. Additional prior knowledge of the image has shown the potential for better results, such as a prior image constrained compressed sensing algorithm. While a pre-full-scan of the same patient is not always available, massive well-reconstructed images of different patients can be easily obtained from clinical multi-slice helical CTs. In this paper, a feature constrained compressed sensing (FCCS) image reconstruction algorithm was proposed to improve the image quality by using the prior knowledge extracted from the clinical database. The database consists of instances which are similar to the target image but not necessarily the same. Robust principal component analysis is employed to retrieve features of the training images to sparsify the target image. The features form a low-dimensional linear space and a constraint on the distance between the image and the space is used. A bi-criterion convex program which combines the feature constraint and total variation constraint is proposed for the reconstruction procedure and a flexible method is adopted for a good solution. Numerical simulations on both the phantom and real clinical patient images were taken to validate our algorithm. Promising results are shown for limited angle problems. PMID- 23685850 TI - Robust reagent addition and perfusion strategies for droplet-interface bilayers. AB - We have designed two novel devices which extend the applications for the droplet interface bilayer (DIB) as a model membrane system. The add-chip allows successive reagent additions to one side of the lipid bilayer during an experiment while maintaining a simple setup with much lower volumes than in planar bilayer systems. The flow-chip is capable of multiple complete solution perfusions concurrently with electrophysiology measurements. Both devices preserve all of the key advantages that DIBs have relative to planar membranes, including low volume, leaflet asymmetry and the ability to separate the monolayers prior to further analysis of a droplet's contents. As a demonstration, we use these devices to monitor and quantitate molecular transport across DIBs. PMID- 23685851 TI - Heat exposure, cardiovascular stress and work productivity in rice harvesters in India: implications for a climate change future. AB - Excessive workplace heat exposures create well-known risks of heat stroke, and it limits the workers' capacity to sustain physical activity. There is very limited evidence available on how these effects reduce work productivity, while the quantitative relationship between heat and work productivity is an essential basis for climate change impact assessments. We measured hourly heat exposure in rice fields in West Bengal and recorded perceived health problems via interviews of 124 rice harvesters. In a sub-group (n = 48) heart rate was recorded every minute in a standard work situation. Work productivity was recorded as hourly rice bundle collection output. The hourly heat levels (WBGT = Wet Bulb Globe Temperature) were 26-32 degrees C (at air temperatures of 30-38 degrees C), exceeding international standards. Most workers reported exhaustion and pain during work on hot days. Heart rate recovered quickly at low heat, but more slowly at high heat, indicating cardiovascular strain. The hourly number of rice bundles collected was significantly reduced at WBGT>26 degrees C (approximately 5% per degrees C of increased WBGT). We conclude that high heat exposure in agriculture caused heat strain and reduced work productivity. This reduction will be exacerbated by climate change and may undermine the local economy. PMID- 23685852 TI - Low self-efficacy is a risk factor for depression among male Japanese workers: a cohort study. AB - The identification of risk factors for depression is necessary for the primary prevention of depression. The aim of this study is to determine whether self efficacy (SE) is associated with onset of depression among workers. Medical expenditure records of 1,803 workers, who were clerks, system engineers, researchers, and service and sales workers in a software development company, were analyzed. Gender, age, job post, marital status, working hours, and SE were measured at baseline. Participants were divided according to quartiles of SE points. Risk ratios for undergoing a medical consultation due to depression were calculated using a multivariable Cox proportional hazards model. Of the 1,803 participants, 58 underwent medical consultation due to depression during a mean of 1.8 years of follow-up. Compared with the lowest quartile (Q1) of SE, adjusted hazard ratios (HR) were 0.65 (95%CI 0.34-1.25) for Q2, 0.49 (0.24-1.00) for Q3, and 0.40 (0.18-0.88) for Q4. In men, adjusted HRs were 0.87 (0.41-1.86) for Q2, 0.61 (0.26-1.41) for Q3, and 0.37 (0.14-0.98) for Q4. In women, no significant association was found. The present study suggests that low SE is a risk factor for onset of depression among male Japanese workers. PMID- 23685853 TI - [A rare cause of recurrent monarthritis of the knee]. AB - Isolated monarthritis caused by Tropheryma whipplei without involvement of the gastrointestinal tract is rare but is nowadays often described as an early manifestation of the disease. In a male patient with recurrent knee joint arthritis for several years, we could ultimately diagnose Whipple's disease based on PCR positive biopsies of synovial tissue and fluid. Furthermore, the patient was found to be an asymptomatic T. whipplei carrier. With adequate antibiotic therapy the patient has meanwhile fully recovered. PMID- 23685854 TI - [Bilateral chronic dacryoadenitis]. AB - Lacrimal and/or salivary gland enlargement is a common symptom leading to referral for rheumatological evaluation. Besides glandular enlargement in Sjogren's syndrome, sarcoidosis, lymphoma and other diseases, the symptom can also be found in IgG4-related disease. This is an increasingly recognized syndrome of unknown etiology comprising a collection of disorders that share specific clinical, serological and pathological features. PMID- 23685855 TI - [Value of fluorescence imaging for detection of synovitis of the hand in comparison to 3 T MRI]. PMID- 23685856 TI - [Adalimumab for early rheumatoid arthritis - Chances and risks: Initial analyses of the OPTIMA study]. PMID- 23685857 TI - TNF-alpha signalling and inflammation: interactions between old acquaintances. AB - INTRODUCTION: Inflammation is a very important part of innate immunity and is regulated in many steps. One such regulating step is the cytokine network, where tumor necrosis factor alpha (TNF-alpha) plays one of the most important roles. METHODS: A PubMed and Web of Science databases search was performed for studies providing evidences on the role of TNF-alpha in inflammation, apoptosis, and cancer. RESULTS AND CONCLUSION: This review concisely summarizes the role of this pro-inflammatory cytokine during inflammation. It is focused mainly on TNF-alpha intracellular signaling and its influence on the typical inflammatory features in the organism. Being one of the most important pro-inflammatory cytokines, TNF alpha participates in vasodilatation and edema formation, and leukocyte adhesion to epithelium through expression of adhesion molecules; it regulates blood coagulation, contributes to oxidative stress in sites of inflammation, and indirectly induces fever. The connection between TNF-alpha and cancer is mentioned as well. PMID- 23685859 TI - The role of the cholinergic system in the signal attenuation rat model of obsessive-compulsive disorder. AB - RATIONALE: In comparison to studies of the involvement of the serotonergic, dopaminergic, and glutamatergic systems in the pathophysiology of obsessive compulsive disorder (OCD), research on the involvement of the cholinergic system in this disorder has remained sparse. OBJECTIVES: The aim of this study was to test the role of the cholinergic system in compulsive behavior using the signal attenuation rat model of OCD. In this model, "compulsive" behavior is induced by attenuating a signal indicating that a lever-press response was effective in producing food. METHODS: The acetylcholinesterase inhibitor physostigmine (0.05, 0.10, and 0.15 mg/kg), the nicotinic agonist nicotine (0.03, 0.06, 0.10, 0.30, 0.60, and 1.00 mg/kg), the nicotinic antagonist mecamylamine (1, 3, 5, and 8 mg/kg), the muscarinic agonist oxotremorine (0.0075, 0.0150, and 0.0300 mg/kg), and the muscarinic antagonist scopolamine (0.15, 0.50, 1.00, and 1.50 mg/kg) were acutely administered to rats just before assessing their lever-press responding following signal attenuation (experiments 1, 3, 5, 7, and 9, respectively). Because the effects of signal attenuation are assessed under extinction conditions, drug doses that were effective in the above experiments were also tested in an extinction session of lever-press responding that was not preceded by signal attenuation (experiments 2, 4, 6, 8, and 10). RESULTS: Acute systemic administration of the cholinergic agents did not exert a selective anti- or pro compulsive effect in the signal attenuation model. CONCLUSIONS: Acetylcholine does not seem to play a role in the signal attenuation rat model of OCD. PMID- 23685860 TI - Insights into functional pharmacology of alpha1 GABA(A) receptors: how much does partial activation at the benzodiazepine site matter? AB - RATIONALE: Synthesis of ligands inactive or with low activity at alpha1 GABA(A) receptors has become the key concept for development of novel, more tolerable benzodiazepine (BZ)-like drugs. WYS8, a remarkably (105 times) alpha1-subtype selective partial positive modulator, may serve as a pharmacological tool for refining the role of alpha1 GABA(A) receptors in mediation of BZs' effects. OBJECTIVES: Here, the effects of WYS8 on GABA-induced currents and on diazepam induced potentiation of recombinant BZ-sensitive GABA(A) receptors were studied in more detail. In addition, the behavioral profile of WYS8 (0.2, 1, and 10 mg/kg i.p.), on its own and in combination with diazepam, was tested in the spontaneous locomotor activity, elevated plus maze, grip strength, rotarod, and pentylenetetrazole tests. RESULTS: WYS8, applied at an in vivo attainable concentration of 100 nM, reduced the stimulation of GABA currents by 1 MUM diazepam by 57 % at alpha1beta3gamma2, but not at alpha2beta3gamma2, alpha3beta3gamma2, or alpha5beta3gamma2 GABA(A) receptors. The administration of WYS8 alone induced negligible behavioral consequences. When combined with diazepam, WYS8 caused a reduction in sedation, muscle relaxation, and anticonvulsant activity, as compared with this BZ alone, whereas ataxia was preserved, and the anxiolytic effect of 2 mg/kg diazepam was unmasked. CONCLUSIONS: Hence, a partial instead of full activation at alpha1 GABA(A) receptors did not necessarily result in the attenuation of the effects assumed to be mediated by activation of these receptors, or in the full preservation of the effects mediated by activation of other GABA(A) receptors. Thus, the role of alpha1 GABA(A) receptors appears more complex than that proposed by genetic studies. PMID- 23685861 TI - Ferroelectric-field-effect-enhanced electroresistance in metal/ferroelectric/semiconductor tunnel junctions. AB - Ferroelectric tunnel junctions (FTJs), composed of two metal electrodes separated by an ultrathin ferroelectric barrier, have attracted much attention as promising candidates for non-volatile resistive memories. Theoretical and experimental works have revealed that the tunnelling resistance switching in FTJs originates mainly from a ferroelectric modulation on the barrier height. However, in these devices, modulation on the barrier width is very limited, although the tunnelling transmittance depends on it exponentially as well. Here we propose a novel tunnelling heterostructure by replacing one of the metal electrodes in a normal FTJ with a heavily doped semiconductor. In these metal/ferroelectric/semiconductor FTJs, not only the height but also the width of the barrier can be electrically modulated as a result of a ferroelectric field effect, leading to a greatly enhanced tunnelling electroresistance. This idea is implemented in Pt/BaTiO3/Nb:SrTiO3 heterostructures, in which an ON/OFF conductance ratio above 10(4), about one to two orders greater than those reported in normal FTJs, can be achieved at room temperature. The giant tunnelling electroresistance, reliable switching reproducibility and long data retention observed in these metal/ferroelectric/semiconductor FTJs suggest their great potential in non-destructive readout non-volatile memories. PMID- 23685862 TI - Ferroelectric tunnel junctions: Beyond the barrier. PMID- 23685858 TI - The reinstatement model of drug relapse: recent neurobiological findings, emerging research topics, and translational research. AB - BACKGROUND AND RATIONALE: Results from many clinical studies suggest that drug relapse and craving are often provoked by acute exposure to the self-administered drug or related drugs, drug-associated cues or contexts, or certain stressors. During the last two decades, this clinical scenario has been studied in laboratory animals by using the reinstatement model. In this model, reinstatement of drug seeking by drug priming, drug cues or contexts, or certain stressors is assessed following drug self-administration training and subsequent extinction of the drug-reinforced responding. OBJECTIVE: In this review, we first summarize recent (2009-present) neurobiological findings from studies using the reinstatement model. We then discuss emerging research topics, including the impact of interfering with putative reconsolidation processes on cue- and context induced reinstatement of drug seeking, and similarities and differences in mechanisms of reinstatement across drug classes. We conclude by discussing results from recent human studies that were inspired by results from rat studies using the reinstatement model. CONCLUSIONS: Main conclusions from the studies reviewed highlight: (1) the ventral subiculum and lateral hypothalamus as emerging brain areas important for reinstatement of drug seeking, (2) the existence of differences in brain mechanisms controlling reinstatement of drug seeking across drug classes, (3) the utility of the reinstatement model for assessing the effect of reconsolidation-related manipulations on cue-induced drug seeking, and (4) the encouraging pharmacological concordance between results from rat studies using the reinstatement model and human laboratory studies on cue- and stress-induced drug craving. PMID- 23685863 TI - A general approach to DNA-programmable atom equivalents. AB - Nanoparticles can be combined with nucleic acids to programme the formation of three-dimensional colloidal crystals where the particles' size, shape, composition and position can be independently controlled. However, the diversity of the types of material that can be used is limited by the lack of a general method for preparing the basic DNA-functionalized building blocks needed to bond nanoparticles of different chemical compositions into lattices in a controllable manner. Here we show that by coating nanoparticles protected with aliphatic ligands with an azide-bearing amphiphilic polymer, followed by the coupling of DNA to the polymer using strain-promoted azide-alkyne cycloaddition (also known as copper-free azide-alkyne click chemistry), nanoparticles bearing a high density shell of nucleic acids can be created regardless of nanoparticle composition. This method provides a route to a virtually endless class of programmable atom equivalents for DNA-based colloidal crystallization. PMID- 23685864 TI - Defective twin boundaries in nanotwinned metals. AB - Coherent twin boundaries (CTBs) are widely described, both theoretically and experimentally, as perfect interfaces that play a significant role in a variety of materials. Although the ability of CTBs in strengthening, maintaining the ductility and minimizing the electron scattering is well documented, most of our understanding of the origin of these properties relies on perfect-interface assumptions. Here we report experiments and simulations demonstrating that as grown CTBs in nanotwinned copper are inherently defective with kink-like steps and curvature, and that these imperfections consist of incoherent segments and partial dislocations. We further show that these defects play a crucial role in the deformation mechanisms and mechanical behaviour of nanotwinned copper. Our findings offer a view of the structure of CTBs that is largely different from that in the literature, and underscore the significance of imperfections in nanotwin-strengthened materials. PMID- 23685865 TI - Cinnamate-based DNA photolithography. AB - As demonstrated by means of DNA nanoconstructs, as well as DNA functionalization of nanoparticles and micrometre-scale colloids, complex self-assembly processes require components to associate with particular partners in a programmable fashion. In many cases the reversibility of the interactions between complementary DNA sequences is an advantage. However, permanently bonding some or all of the complementary pairs may allow for flexibility in design and construction. Here, we show that the substitution of a cinnamate group for a pair of complementary bases provides an efficient, addressable, ultraviolet light based method to bond complementary DNA covalently. To show the potential of this approach, we wrote micrometre-scale patterns on a surface using ultraviolet light and demonstrated the reversible attachment of conjugated DNA and DNA-coated colloids. Our strategy enables both functional DNA photolithography and multistep, specific binding in self-assembly processes. PMID- 23685866 TI - Segmentation editing improves efficiency while reducing inter-expert variation and maintaining accuracy for normal brain tissues in the presence of space occupying lesions. AB - Image segmentation has become a vital and often rate-limiting step in modern radiotherapy treatment planning. In recent years, the pace and scope of algorithm development, and even introduction into the clinic, have far exceeded evaluative studies. In this work we build upon our previous evaluation of a registration driven segmentation algorithm in the context of 8 expert raters and 20 patients who underwent radiotherapy for large space-occupying tumours in the brain. In this work we tested four hypotheses concerning the impact of manual segmentation editing in a randomized single-blinded study. We tested these hypotheses on the normal structures of the brainstem, optic chiasm, eyes and optic nerves using the Dice similarity coefficient, volume, and signed Euclidean distance error to evaluate the impact of editing on inter-rater variance and accuracy. Accuracy analyses relied on two simulated ground truth estimation methods: simultaneous truth and performance level estimation and a novel implementation of probability maps. The experts were presented with automatic, their own, and their peers' segmentations from our previous study to edit. We found, independent of source, editing reduced inter-rater variance while maintaining or improving accuracy and improving efficiency with at least 60% reduction in contouring time. In areas where raters performed poorly contouring from scratch, editing of the automatic segmentations reduced the prevalence of total anatomical miss from approximately 16% to 8% of the total slices contained within the ground truth estimations. These findings suggest that contour editing could be useful for consensus building such as in developing delineation standards, and that both automated methods and even perhaps less sophisticated atlases could improve efficiency, inter-rater variance, and accuracy. PMID- 23685867 TI - Synthesis and biological evaluation of new paclitaxel analogs and discovery of potent antitumor agents. AB - Reaction of 10-deacetylbaccatin III (III) and its 7-TES derivative (IV) with DAST under various conditions resulted in the formation of an array of new fluorinated and non-fluorinated 13-keto taxoid compounds (2a-4a) through a vinylogous pinacol pinacolone rearrangement. Further fluorination of some of these products (2a, 3a) with NFSi or Selectfluor gave additional derivatives. Sodium borohydride reduction of the 13-keto group of these products (2a, 2b, 3a, 3b, 4a, 8, 9, 11 14) led to a series of 9alpha-hydroxy taxoid derivatives, which were esterified using the docetaxel side chain employing the corresponding protected beta-lactam, followed by deprotection to furnish a library of docetaxel analogs and related compounds. A selected number of synthesized compounds (7, 10, 19a, 19b, 21a, 21b, 23, 27, 29, 34-36) were submitted to the National Cancer Institute (NCI) 60 cell line screening program and tested for cytotoxic properties. Taxoids 19a, 19b, 21a, 21b, 23, 27, 29, 34 and 35 were found to exhibit significant anticancer activity against various cancerous cell lines with 23, 27, and 29 being the most potent compounds, demonstrating GI50 values of <=5 nM in several assays. PMID- 23685868 TI - Ischemic preconditioning protects against spinal cord ischemia-reperfusion injury in rabbits by attenuating blood spinal cord barrier disruption. AB - Ischemic preconditioning has been reported to protect against spinal cord ischemia-reperfusion (I-R) injury, but the underlying mechanisms are not fully understood. To investigate this, Japanese white rabbits underwent I-R (30 min aortic occlusion followed by reperfusion), ischemic preconditioning (three cycles of 5 min aortic occlusion plus 5 min reperfusion) followed by I-R, or sham surgery. At 4 and 24 h following reperfusion, neurological function was assessed using Tarlov scores, blood spinal cord barrier permeability was measured by Evan's Blue extravasation, spinal cord edema was evaluated using the wet-dry method, and spinal cord expression of zonula occluden-1 (ZO-1), matrix metalloproteinase-9 (MMP-9), and tumor necrosis factor-alpha (TNF-alpha) were measured by Western blot and a real-time polymerase chain reaction. ZO-1 was also assessed using immunofluorescence. Spinal cord I-R injury reduced neurologic scores, and ischemic preconditioning treatment ameliorated this effect. Ischemic preconditioning inhibited I-R-induced increases in blood spinal cord barrier permeability and water content, increased ZO-1 mRNA and protein expression, and reduced MMP-9 and TNF-alpha mRNA and protein expression. These findings suggest that ischemic preconditioning attenuates the increase in blood spinal cord barrier permeability due to spinal cord I-R injury by preservation of tight junction protein ZO-1 and reducing MMP-9 and TNF-alpha expression. PMID- 23685869 TI - Ultraviolet (UV) and hydrogen peroxide activate ceramide-ER stress-AMPK signaling axis to promote retinal pigment epithelium (RPE) cell apoptosis. AB - Ultraviolet (UV) radiation and reactive oxygen species (ROS) impair the physiological functions of retinal pigment epithelium (RPE) cells by inducing cell apoptosis, which is the main cause of age-related macular degeneration (AMD). The mechanism by which UV/ROS induces RPE cell death is not fully addressed. Here, we observed the activation of a ceramide-endoplasmic reticulum (ER) stress-AMP activated protein kinase (AMPK) signaling axis in UV and hydrogen peroxide (H2O2)-treated RPE cells. UV and H2O2 induced an early ceramide production, profound ER stress and AMPK activation. Pharmacological inhibitors against ER stress (salubrinal), ceramide production (fumonisin B1) and AMPK activation (compound C) suppressed UV- and H2O2-induced RPE cell apoptosis. Conversely, cell permeable short-chain C6 ceramide and AMPK activator AICAR (5 amino-1-beta-D-ribofuranosyl-imidazole-4-carboxamide) mimicked UV and H2O2's effects and promoted RPE cell apoptosis. Together, these results suggest that UV/H2O2 activates the ceramide-ER stress-AMPK signaling axis to promote RPE cell apoptosis. PMID- 23685871 TI - Influence of growth conditions on magnetite nanoparticles electro-crystallized in the presence of organic molecules. AB - Magnetite nanoparticles were synthesized by electrocrystallization in the presence of thiourea or sodium butanoate as an organic stabilizer. The synthesis was performed in a thermostatic electrochemical cell containing two iron electrodes with an aqueous solution of sodium sulfate as electrolyte. The effects of organic concentration, applied potential and growth temperature on particle size, morphology, structure and magnetic properties were investigated. The magnetite nanoparticles were characterized by X-ray diffraction, electron microscopy, magnetometry and Mossbauer spectrometry. When the synthesis is performed in the presence of sodium butanoate at 60 degrees C, a paramagnetic ferric salt is obtained as a second phase; it is possible to avoid formation of this phase, increase the specific magnetization and improve the structure of the oxide particles by tuning the growth conditions. Room-temperature magnetization values range from 45 to 90 Am2kg-1, depending on the particle size, type of surfactant and synthesis conditions. Mossbauer spectra, which were recorded at 290 K for all the samples, are typical of nonstoichiometric Fe3-deltaO4, with a small excess of Fe3+, 0.05 <= delta <= 0.15. PMID- 23685870 TI - The role of peritoneal alternatively activated macrophages in the process of peritoneal fibrosis related to peritoneal dialysis. AB - It has been confirmed that alternatively activated macrophages (M2) participate in tissue remodeling and fibrosis occurrence, but the effect of M2 on peritoneal fibrosis related to peritoneal dialysis (PD) hasn't been elucidated. This study was therefore conducted to assess the association between M2 and peritoneal fibrosis related to PD. In this study, peritoneal fibrosis was induced by intraperitoneal (i.p.) injection of Lactate-4.25% dialysate (100 mL/kg) to C57BL/6J mice for 28 days, and liposome-encapsulated clodronate (LC, the specific scavenger of macrophages) was used to treat the peritoneal fibrosis mice model by i.p. injection at day 18 and day 21. All animals were sacrificed at day 29. Parietal peritonea were stained with Masson's trichrome, and the expression of type I collagen (Col-I), fibronectin, mannose receptor (CD206), transforming growth factor beta (TGF-beta), chemokine receptor 7 (CCR7), chitinase 3-like 3 (Ym-1) and arginase-1 (Arg-1) was determined by Western blotting, immunofluorescence and quantitative real-time PCR. Our results revealed that peritoneal thickness, Col-I, fibronectin, CD206, TGF-beta, Ym-1 and Arg-1 were upregulated in the peritoneal fibrosis mice model, and all of these indexes were downregulated in those treated with LC. Additionally, there was no difference in the level of CCR7 between the model and treatment group. Our study indicated that peritoneal M2 played an important role in the process of peritoneal fibrosis related to PD and might be a potential target for intervention therapy of peritoneal fibrosis. PMID- 23685872 TI - An ultrasensitive electrochemiluminescence immunoassay for carbohydrate antigen 19-9 in serum based on antibody labeled Fe3O4 nanoparticles as capture probes and graphene/CdTe quantum dot bionanoconjugates as signal amplifiers. AB - The CdTe quantum dots (QDs), graphene nanocomposite (CdTe-G) and dextran-Fe3O4 magnetic nanoparticles have been synthesized for developing an ultrasensitive electrochemiluminescence (ECL) immunoassay for Carcinoembryonic antigen 19-9 (CA 19-9) in serums. Firstly, the capture probes (CA 19-9 Ab1/Fe3O4) for enriching CA 19-9 were synthesized by immobilizing the CA 19-9's first antibody (CA 19-9 Ab1) on magnetic nanoparticles (dextran-Fe3O4). Secondly, the signal probes (CA 19-9 Ab2/CdTe-G), which can emit an ECL signal, were formed by attaching the secondary CA 19-9 antibody (CA 19-9 Ab2) to the surface of the CdTe-G. Thirdly, the above two probes were used for conjugating with a serial of CA 19-9 concentrations. Graphene can immobilize dozens of CdTe QDs on their surface, which can emit stronger ECL intensity than CdTe QDs. Based on the amplified signal, ultrasensitive antigen detection can be realized. Under the optimal conditions, the ECL signal depended linearly on the logarithm of CA 19-9 concentration from 0.005 to 100 pg/mL, and the detection limit was 0.002 pg/mL. Finally, five samples of human serum were tested, and the results were compared with a time resolved fluorescence assay (TRFA). The novel immunoassay provides a stable, specific and highly sensitive immunoassay protocol for tumor marker detection at very low levels, which can be applied in early diagnosis of tumor. PMID- 23685874 TI - LED based NMR illumination device for mechanistic studies on photochemical reactions--versatile and simple, yet surprisingly powerful. AB - An LED based illumination device for mechanistic studies on photochemical reactions by means of NMR spectroscopy is presented. The LEDs are directly switched by the NMR spectrometer with the help of a one-stage electronic circuit. This allows for continuous or alternatively pulsed operation of the LEDs. Continuous operation provides direct comparability with conditions in synthetic chemistry, in pulsed operation the short time light power can be enhanced ninefold. The LEDs are efficiently coupled to a 1000 MUm core optical fiber guiding the light into the spectrometer by simply bringing it in close contact to the fiber. The tip of the fiber is roughened by sandblasting and thus emits light in a uniform and efficient way over the full length of the receiver coil. The combination of these techniques tremendously increases the amount of light brought into the NMR sample and makes LEDs an easy, versatile and handy light source for the in situ illumination of NMR samples allowing even for single millisecond time resolved Photo-CIDNP spectroscopy. PMID- 23685875 TI - Identifying the trend of reactivity for sp2 materials: an electron delocalization model from first principles calculations. AB - The reactivity of sp(2) carbon materials is studied using the adsorption and dissociation of O2 on graphene and graphene oxide as model systems. The reactions on the basal plane, zigzag and armchair edges of graphene and graphene oxide with different oxygen-containing groups are calculated using first principles calculations. Two Bronsted-Evans-Polanyi relationships are identified and an electron delocalization model is suggested to understand the general trend of reactivity for sp(2) carbon materials. PMID- 23685873 TI - Claudins overexpression in ovarian cancer: potential targets for Clostridium Perfringens Enterotoxin (CPE) based diagnosis and therapy. AB - Claudins are a family of tight junction proteins regulating paracellular permeability and cell polarity with different patterns of expression in benign and malignant human tissues. There are approximately 27 members of the claudin family identified to date with varying cell and tissue-specific expression. Claudins-3, -4 and -7 represent the most highly differentially expressed claudins in ovarian cancer. While their exact role in ovarian tumors is still being elucidated, these proteins are thought to be critical for ovarian cancer cell invasion/dissemination and resistance to chemotherapy. Claudin-3 and claudin-4 are the natural receptors for the Clostridium perfringens enterotoxin (CPE), a potent cytolytic toxin. These surface proteins may therefore represent attractive targets for the detection and treatment of chemotherapy-resistant ovarian cancer and other aggressive solid tumors overexpressing claudin-3 and -4 using CPE-based theranostic agents. PMID- 23685876 TI - Dissolvable fluidic time delays for programming multi-step assays in instrument free paper diagnostics. AB - Lateral flow tests (LFTs) are an ingenious format for rapid and easy-to-use diagnostics, but they are fundamentally limited to assay chemistries that can be reduced to a single chemical step. In contrast, most laboratory diagnostic assays rely on multiple timed steps carried out by a human or a machine. Here, we use dissolvable sugar applied to paper to create programmable flow delays and present a paper network topology that uses these time delays to program automated multi step fluidic protocols. Solutions of sucrose at different concentrations (10-70% of saturation) were added to paper strips and dried to create fluidic time delays spanning minutes to nearly an hour. A simple folding card format employing sugar delays was shown to automate a four-step fluidic process initiated by a single user activation step (folding the card); this device was used to perform a signal amplified sandwich immunoassay for a diagnostic biomarker for malaria. The cards are capable of automating multi-step assay protocols normally used in laboratories, but in a rapid, low-cost, and easy-to-use format. PMID- 23685877 TI - Indications for and results of arthroscopy in the arthritic knee: a European survey. AB - PURPOSE: The place of arthroscopic treatment in osteoarthritis of the knee has generated much controversy. A survey was initiated to collect the opinion of experienced surgeons. METHODS: Of the 211 surgeons interviewed, 170 (80.6%) replied to the electronic questionnaire. Respondents had at least ten years of experience in arthroscopy and currently perform more than 100 arthroscopies per year. Various indications and treatment modalities for arthroscopy in osteoarthritis of the knee had to be evaluated on a scale from "excellent" to "no indication". RESULTS: The respondents generally believe that an improvement is more likely in low-grade osteoarthritis (p < 0.001) and in neutral leg axis (p < 0.001). The outcome was rated better if symptoms had persisted for less than six months (p < 0.001) and for patients that were younger than 60 years (p < 0.001). Partial meniscectomy and notchplasty in cases of extension deficit were considered as successful treatment options. Debridement was an accepted indication, with an outcome mainly rated as fair. A majority saw no indication for joint lavage, arthroscopic treatment of arthrofibrosis and removal of osteophytes. The outcome appears to be poor if a bone edema is diagnosed on magnetic resonance imaging prior to arthroscopy. Only 55.9% of respondents were comfortable with the current definition of osteoarthritis. CONCLUSIONS: Experienced arthroscopic surgeons all over Europe believe arthroscopy in osteoarthritis is appropriate, under certain conditions. The major task for surgeons is to select the right patients who are likely to benefit from this intervention. PMID- 23685878 TI - Characterisation of in vivo release of gentamicin from polymethyl methacrylate cement using a novel method. AB - PURPOSE: The purpose of this study was to investigate the in vivo elution kinetics of gentamicin from bone cement by assessing antibiotic levels in the urine. METHODS: Urinary samples of 35 patients who had undergone primary total hip arthroplasty were collected post-operatively. Gentamicin concentrations were analysed using the fluorescence polarisation immunoassay technique. RESULTS: The mean duration of urinary gentamicin release in all cases was 43 days (range 13 95). There was still detectable gentamicin at the final collection in 20% (7/35) of cases, and in these cases, the mean gentamicin release was 71 days. CONCLUSIONS: From the assessment of urinary gentamicin, we were able to demonstrate the biphasic gentamicin elution from bone cement. In addition, there were detectable concentrations of the antibiotic from the urinary samples for prolonged periods of up to two to six months. Our study indicates that the assessment of urinary antibiotics can offer a non-invasive method of monitoring the in vivo release kinetics of antibiotics from bone cement. PMID- 23685879 TI - Reply to: Comment on Langlois et al.: Charnley-Kerboull total hip arthroplasty combining zirconia on polyethylene. A minimum eight-year follow-up prospective study. PMID- 23685880 TI - A potential role for parasites in the maintenance of color polymorphism in urban birds. AB - Urbanization is a major challenge for biodiversity conservation, yet the evolutionary processes taking place in urbanized areas remain poorly known. Human activities in cities set new selective forces in motion which need to be investigated to predict the evolutionary responses of animal species living in urban areas. In this study, we investigated the role of urbanization and parasites in the maintenance of melanin-based color polymorphism in the feral pigeon Columba livia. Using a correlative approach, we tested whether differently colored genotypes displayed alternative phenotypic responses to urbanization, by comparing body condition, blood parasite prevalence and parasite load between colored morphs along an urbanization gradient. Body condition did not vary with urbanization, but paler individuals had a higher body condition than darker individuals. Moreover, paler morphs were less often parasitized than darker morphs in moderately urbanized habitats, but their parasite prevalence increased with urbanization. In contrast, darker morphs had similar parasite prevalence along the urbanization gradient. This suggests that paler morphs did better than darker morphs in moderately urbanized environments but were negatively affected by increasing urbanization, while darker morphs performed equally in all environments. Thus, differently colored individuals were distributed non-randomly across the urban habitat and suffered different parasite risk according to their location (a gene-by-environment interaction). This suggests that melanin-based coloration might reflect alternative strategies to cope with urbanization via different exposure or susceptibility to parasites. Spatial variability of parasite pressures linked with urbanization may, thus, play a central role in the maintenance of plumage color polymorphism in this urban species. PMID- 23685881 TI - Letter to the editor on obstetric acupressure and acupuncture. PMID- 23685883 TI - Air filter devices including nonwoven meshes of electrospun recombinant spider silk proteins. AB - Based on the natural sequence of Araneus diadematus Fibroin 4 (ADF4), the recombinant spider silk protein eADF4(C16) has been engineered. This highly repetitive protein has a molecular weight of 48kDa and is soluble in different solvents (hexafluoroisopropanol (HFIP), formic acid and aqueous buffers). eADF4(C16) provides a high potential for various technical applications when processed into morphologies such as films, capsules, particles, hydrogels, coatings, fibers and nonwoven meshes. Due to their chemical stability and controlled morphology, the latter can be used to improve filter materials. In this protocol, we present a procedure to enhance the efficiency of different air filter devices, by deposition of nonwoven meshes of electrospun recombinant spider silk proteins. Electrospinning of eADF4(C16) dissolved in HFIP results in smooth fibers. Variation of the protein concentration (5-25% w/v) results in different fiber diameters (80-1,100 nm) and thus pore sizes of the nonwoven mesh. Post-treatment of eADF4(C16) electrospun from HFIP is necessary since the protein displays a predominantly alpha-helical secondary structure in freshly spun fibers, and therefore the fibers are water soluble. Subsequent treatment with ethanol vapor induces formation of water resistant, stable beta-sheet structures, preserving the morphology of the silk fibers and meshes. Secondary structure analysis was performed using Fourier transform infrared spectroscopy (FTIR) and subsequent Fourier self-deconvolution (FSD). The primary goal was to improve the filter efficiency of existing filter substrates by adding silk nonwoven layers on top. To evaluate the influence of electrospinning duration and thus nonwoven layer thickness on the filter efficiency, we performed air permeability tests in combination with particle deposition measurements. The experiments were carried out according to standard protocols. PMID- 23685882 TI - N-truncated amyloid beta (Abeta) 4-42 forms stable aggregates and induces acute and long-lasting behavioral deficits. AB - N-truncated Abeta4-42 is highly abundant in Alzheimer disease (AD) brain and was the first Abeta peptide discovered in AD plaques. However, a possible role in AD aetiology has largely been neglected. In the present report, we demonstrate that Abeta4-42 rapidly forms aggregates possessing a high aggregation propensity in terms of monomer consumption and oligomer formation. Short-term treatment of primary cortical neurons indicated that Abeta4-42 is as toxic as pyroglutamate Abeta3-42 and Abeta1-42. In line with these findings, treatment of wildtype mice using intraventricular Abeta injection induced significant working memory deficits with Abeta4-42, pyroglutamate Abeta3-42 and Abeta1-42. Transgenic mice expressing Abeta4-42 (Tg4-42 transgenic line) developed a massive CA1 pyramidal neuron loss in the hippocampus. The hippocampus-specific expression of Abeta4-42 correlates well with age-dependent spatial reference memory deficits assessed by the Morris water maze test. Our findings indicate that N-truncated Abeta4-42 triggers acute and long-lasting behavioral deficits comparable to AD typical memory dysfunction. PMID- 23685884 TI - Haplotype TGTG from SNP 45T/G and 276G/T of the adiponectin gene contributes to risk of polycystic ovary syndrome. AB - BACKGROUND: Haplotypes of adiponectin gene single nucleotide polymorphisms (SNP) might be related to metabolic disorders. AIM: To assess whether the prevalence of SNP 45T/G and 276G/T of the adiponectin gene and their haplotypes differ between polycystic ovary syndrome (PCOS) and non-hirsute cycling controls and to investigate the relationship between these haplotypes and risk factors for cardiovascular disease. SUBJECTS AND METHODS: In this case-control study, 80 women with PCOS and 1500 non-hirsute controls with regular cycles underwent clinical and laboratory measurements. Genotype distribution was analyzed by conventional PCR-restriction fragment length polymorphism. RESULTS: Compared to controls, PCOS women had greater body mass index (BMI) (31.0+/-7.9 kg/m2 vs 23.4+/-4.6 kg/m2; p<0.001), waist circumference (92.2+/-18.8 cm vs 74.5+/-10.2 cm; p<0.001), and systolic and diastolic blood pressure (124.6+/-19.9 vs 111.5+/ 13.0 mmHg and 79.2+/-12.5 vs 71.8+/-10.6 mmHg; p<0.025), as well as a worse lipid profile (p<0.007), even after adjustment for age and BMI. Genotype distribution was similar in PCOS and controls (45T/G: p=0.399; 276G/T: p=0.135). Six haplotypes were inferred and their frequencies differed significantly between the groups (p=0.001). The TGTG haplotype was more frequent in PCOS than controls (41.3 vs 18.9%). In PCOS, the GG genotype for SNP 276 (p=0.031) and the TGTG haplotype (p=0.023) were associated with higher systolic blood pressure vs other genotypes and haplotypes. Body composition, glucose, insulin, and lipid profile were similar across genotypes and haplotypes in both groups. CONCLUSIONS: Haplotype TGTG from adiponectin gene variants 45T/G and 276G/T is related to susceptibility to PCOS, and might be associated with increased blood pressure in PCOS. PMID- 23685885 TI - Comparative analysis of RNA sequencing methods for degraded or low-input samples. AB - RNA-seq is an effective method for studying the transcriptome, but it can be difficult to apply to scarce or degraded RNA from fixed clinical samples, rare cell populations or cadavers. Recent studies have proposed several methods for RNA-seq of low-quality and/or low-quantity samples, but the relative merits of these methods have not been systematically analyzed. Here we compare five such methods using metrics relevant to transcriptome annotation, transcript discovery and gene expression. Using a single human RNA sample, we constructed and sequenced ten libraries with these methods and compared them against two control libraries. We found that the RNase H method performed best for chemically fragmented, low-quality RNA, and we confirmed this through analysis of actual degraded samples. RNase H can even effectively replace oligo(dT)-based methods for standard RNA-seq. SMART and NuGEN had distinct strengths for measuring low quantity RNA. Our analysis allows biologists to select the most suitable methods and provides a benchmark for future method development. PMID- 23685886 TI - Further studies on bis-charged tetraazacyclophanes as potent inhibitors of small conductance Ca(2+)-activated K+ channels. AB - Previously, quinolinium-based tetraazacyclophanes, such as UCL 1684 and UCL 1848, have been shown to be extraordinarily sensitive to changes in chemical structure (especially to the size of the cyclophane system) with respect to activity as potent non-peptidic blockers of the small conductance Ca(2+)-activated K(+) ion channels (SKCa). The present work has sought to optimize the structure of the linking chains in UCL 1848. We report the synthesis and SKCa channel-blocking activity of 29 analogues of UCL 1848 in which the central CH2 of UCL 1848 is replaced by other groups X or Y = O, S, CF2, CO, CHOH, CC, CHCH, CHMe to explore whether subtle changes in bond length or flexibility can improve potency still further. The possibility of improving potency by introducing ring substituents has also been explored by synthesizing and testing 25 analogues of UCL 1684 and UCL 1848 with substituents (NO2, NH2, CF3, F, Cl, CH3, OCH3, OCF3, OH) in the 5, 6 or 7 positions of the aminoquinolinium rings. As in our earlier work, each compound was assayed for inhibition of the afterhyperpolarization (AHP) in rat sympathetic neurons, an action mediated by the SK3 subtype of the SKCa channel. One of the new compounds (39, R(7) = Cl, UCL 2053) is twice as potent as UCL 1848 and UCL 1684: seven are comparable in activity. PMID- 23685887 TI - New insight into adenosine receptors selectivity derived from a novel series of [5-substituted-4-phenyl-1,3-thiazol-2-yl] benzamides and furamides. AB - A series of [5-substituted-4-phenyl-1,3-thiazol-2-yl] benzamide and furamide analogues were investigated in radioligand binding studies at adenosine receptor subtypes with an aim to obtain potent and selective adenosine receptor ligands. Benzamide and furamide linked to thiazole was found to be crucial for high adenosine receptor affinity. The most potent compound indentified in this study was 5d with low nanomolar affinity for all four adenosine receptor subtypes. Compounds 5a and 5g showed moderate selectivity for A2A adenosine receptors. Molecular docking versus all four human adenosine receptors combined with membrane molecular dynamics studies were performed to rationalise the peculiar selectivity profile of 5d antagonist. PMID- 23685888 TI - Efficient catalysts for asymmetric Mannich reactions. AB - Efficient chiral catalysts for direct asymmetric three-component Mannich reactions of ketones, aldehydes and an amine (p-anisidine) have been developed. The corresponding beta-amino carbonyl compounds (Mannich adducts) were obtained in good chemical yields and excellent enantio- and diastereoselectivities. The reaction conditions have been optimized by invoking ultrasonication and the influence of some structural moieties of the catalysts on the chemical yield and stereoselectivity of the Mannich products has been evaluated. PMID- 23685890 TI - Operational strategies for producing bioethanol in a continuous single-stage reactor. AB - Novel strategies to facilitate the transition from batch to continuous simultaneous saccharification and fermentation were studied in this work. Implementing these strategies in bioethanol production plants to change production to a continuous mode will avoid large modifications in the process configuration. Therefore, experiments were carried out in a single-stage reactor applying strategies that favour a priori viability of yeast and stability of the process. The effects of (a) hydraulic residence time (HRT), (b) anaerobic and microaerobic operation, (c) inoculation strategy and (d) growth inhibition due to high ethanol concentrations were evaluated. The highest ethanol concentration (6.3 % w/w) was achieved during anaerobic operation, with reinoculations every 3 4 days and an HRT of 60 h; however, the processes suffered severe instability under these conditions. The greatest productivity and stability of the process was achieved using periodic microaeration and an HRT of 36 h (0.169 % ethanol weight/h), overcoming the result obtained during batch operation (0.128 % ethanol weight/h). PMID- 23685889 TI - Meroterpenes from marine invertebrates: structures, occurrence, and ecological implications. AB - Meroterpenes are widely distributed among marine organisms; they are particularly abundant within brown algae, but other important sources include microorganisms and invertebrates. In the present review the structures and bioactivities of meroterpenes from marine invertebrates, mainly sponges and tunicates, are summarized. More than 300 molecules, often complex and with unique skeletons originating from intra- and inter-molecular cyclizations, and/or rearrangements, are illustrated. The reported syntheses are mentioned. The issue of a potential microbial link to their biosynthesis is also shortly outlined. PMID- 23685891 TI - Osteoporosis and related factors in older females with skeletal pain or numbness: a retrospective study in East China. AB - OBJECTIVE: To analyse relationships between incidence of osteoporosis, age and clinical symptoms in older female patients in East China. METHODS: Data from females aged >= 30 years, admitted to QiLu Hospital between January 1999 and December 2011 were retrospectively assessed for osteoporosis. Correlations between osteoporosis diagnosis, age and clinical symptoms were analysed. Factors associated with osteoporosis were assessed using logistic regression. RESULTS: Out of 4212 patients enrolled, 1673 were assigned to the osteoporosis group and 2539 to the nonosteoporosis group. Neck, shoulder and arm pain negatively correlated with osteoporosis diagnosis. Lumbar and back pain had no correlation with osteoporosis diagnosis. In patients with osteoporosis there was no relationship between bone density and site of clinical symptoms. Bone density decreased, as age increased, in patients aged >50 years in the osteoporosis group. CONCLUSION: The present study revealed a relationship between epidemiological distribution of osteoporosis and associated factors in adult females suffering from pain or numbness, in East China. PMID- 23685893 TI - Influence of laparoscopic carbon dioxide pneumoperitoneum on neonate circulation and respiration. AB - OBJECTIVE: This study investigated the influence of laparoscopic carbon dioxide (CO2) pneumoperitoneum on neonate circulation and respiration. METHODS: The study included neonates undergoing elective laparoscopic abdominal surgery. CO2 insufflation pressure was maintained within 8-14 mmHg for pneumoperitoneum creation. Heart rate (HR), mean arterial pressure (MAP), peripheral oxygen saturation (SpO2), partial pressure of end-tidal carbon dioxide (P ETCO2) and maximum inspiratory pressure were monitored continuously. Arterial blood samples were collected: 5 min before pneumoperitoneum creation (baseline); 5, 10, and 20 min after CO2 insufflation; 10 min after CO2 exsufflation; 10 min after surgery. pH, partial pressure of CO2 (PaCO2) and arterial oxygen saturation (SaO2) were also measured. RESULTS: Thirty-six neonates were included. HR and MAP significantly increased after pneumoperitoneum creation, then decreased to baseline after CO2 exsufflation. PaCO2 and P ETCO2 were significantly higher after pneumoperitoneum creation, whereas pH was significantly lower 20 min after pneumoperitoneum creation compared with baseline. No significant differences were observed in SpO2 and SaO2. CONCLUSION: CO2 pneumoperitoneum had a significant effect on neonatal circulation and respiration, suggesting that the pneumoperitoneal pressure should be limited within a certain range in neonates undergoing laparoscopic surgery. PMID- 23685894 TI - Immunohistochemical levels of matrix metalloproteinase-2 and CD44 variant 6 protein in the diagnosis and lateral cervical lymph node metastasis of papillary thyroid carcinoma. AB - OBJECTIVES: To investigate the ability of matrix metalloproteinase (MMP)-2 and CD44 variant 6 (CD44v6) protein levels to diagnose papillary thyroid cancer (PTC), compared with routine diagnostic methods using tissue sections; to explore the relationship between MMP-2 and CD44v6 protein levels and lymph node metastases (LNM) in PTC. METHODS: Archival PTC specimens from patients with PTC, with or without lateral cervical LNM, were included in this retrospective immunohistochemical study. MMP-2 and CD44v6 protein levels were analysed immunohistochemically using routinely prepared tissue sections. RESULTS: Specimens from 66 patients with PTC were reviewed retrospectively (35 patients with lateral cervical LNM; 31 patients without LNM). The percentages of samples with cells that demonstrated positive protein staining differed significantly between PTC specimens, benign thyroid nodules and adjacent normal follicular epithelium (MMP-2: 86.4%, 60.0%, and 25.7%, respectively; CD44v6: 80.3%, 37.1% and 22.9%, respectively). The level of CD44v6 protein staining was found to be significantly and positively correlated with the level of MMP-2 protein staining in PTC specimens. CONCLUSIONS: Both MMP-2 and CD44v6 might be useful tumour markers for predicting risk of lateral cervical LNM in patients with PTC. PMID- 23685892 TI - Efficacy and safety of a 14-day administration of tolvaptan in the treatment of patients with ascites in hepatic oedema. AB - OBJECTIVE: To investigate the efficacy and safety of 14 days' orally administered tolvaptan as adjunctive treatment for hepatic oedema in Japanese liver cirrhosis patients with insufficient response to conventional diuretics, with the option to increase dose in those who did not respond initially. METHODS: This multicentre, single-arm, phase 3 study allocated patients with liver cirrhosis and persistent ascites to 7-day treatment with 7.5 mg/day tolvaptan followed by an additional 7 days' treatment. Responders at day 7 (achieving >= 1 kg body-weight reduction) continued on 7.5 mg/day tolvaptan; nonresponders (<1 kg body-weight reduction) received 15 mg/day tolvaptan. Conventional diuretic treatment continued throughout. The primary endpoint was change in body weight from baseline, as a marker of ascites volume. RESULTS: A total of 51 patients received 7.5 mg/day tolvaptan for 7 days, which caused a significant reduction in mean body weight (55% response rate). During the second 7-day treatment period, 30 patients received 7.5 mg/day tolvaptan and 13 patients received tolvaptan 15 mg/day: response rates were 43% and 23%, respectively. Two serious adverse events were observed. Serum sodium was within normal range. CONCLUSIONS: Tolvaptan therapy for 14 days (with possible dose increase as necessary), in combination with conventional diuretics, effectively reduced body weight in patients with hepatic oedema. PMID- 23685895 TI - Expression of the NOB1 gene and its clinical significance in papillary thyroid carcinoma. AB - OBJECTIVE: The aim of this study was to explore the relationships between expression of the NIN1/RPN12 binding protein 1 homologue gene (NOB1) in papillary thyroid carcinoma tissue and clinicopathological variables. METHODS: Expression of NOB1 in papillary thyroid carcinoma, normal thyroid and benign thyroid tumour tissue was evaluated at the mRNA and protein levels by real-time fluorescence quantitative reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. Relationships between immunohistochemical scores and several clinicopathological variables were also examined. RESULTS: Expression of NOB1 mRNA and protein in papillary thyroid carcinomatissue was significantly higher than in normal thyroid tissue and benign thyroid tissue, while there was no significant difference between normal thyroid tissue and benign thyroid tumour tissue. A high level of NOB1 protein expression was associated with large tumour size and Union for International Cancer Control stage, but was not significantly correlated with sex or age. CONCLUSIONS: Compared with normal thyroid and benign thyroid tumour tissue, papillary thyroid carcinomas showed higher expression of NOB1, which indicates that the expression level of the NOB1 gene in the thyroid may play a key role in the occurrence and development of papillary thyroid carcinoma. PMID- 23685896 TI - Gene cloning and enzymatic characterization of an endoprotease Endo-Pro Aspergillus niger. AB - A novel endoprotease Endo-Pro-Aspergillus niger (endoprotease EPR) was first successfully expressed at high level in the methylotrophic yeast Pichia pastoris and the purification procedure was established. The endoprotease EPR is 95 % identity with proline specific endopeptidase from A. niger CBS513.88 (EMBL; AX458699), while sharing low identity with those from other microorganisms. The purified endoprotease EPR was a monomer of 60 kDa. Furthermore, the peptide mass fingerprinting (PMF) analysis confirmed that the purified protein was an endoprotease Endo-Pro-Aspergillus niger. A three-dimensional model revealed that the active site of the enzyme was located in Ser(179)-Asp(458)-His(491), based on template 3n2zB with sequence identity of 17.6 %. The optimum pH and temperature of the endoprotease EPR were pH 4-5 and 35 degrees C, and the stabilities were pH 3-7 and 15-60 degrees C, respectively. Furthermore, the endoprotease EPR had the ability to digest peptides with the C-terminal of proline as well as alanine, and was also capable of hydrolyzing larger peptides. The properties of the endoprotease EPR made it a highly promising candidate for future application in the field of brewing and food process. PMID- 23685897 TI - Genotyping and subtyping of mumps virus isolates from the Indian subcontinent. AB - Mumps is a vaccine-preventable disease that usually occurs as a self-limiting parotitis, but it can also lead to several life-threatening complications, including pancreatitis, meningitis, and encephalitis. The molecular epidemiology of the virus is poorly understood. The present study describes an outbreak of mumps virus infection in Punjab, India. The etiology was confirmed by serology and RNA detection to be mumps virus in 72 % of the cases and 50 % of contacts. This study, for the first time, revealed the mumps virus genotypes circulating in the Indian subcontinent as subtype G2 of genotype G. PMID- 23685898 TI - Epidemiological survey of porcine epidemic diarrhea virus in swine farms in Shanghai, China. AB - An epidemiological survey of porcine diarrheal disease prevalence between September 2011 and January 2012 revealed that porcine epidemic diarrhea virus (PEDV) contributed to outbreaks of diarrhea in pig farms in Shanghai, China. The distribution profile of 10 PEDV strains revealed three distinct genotypes coexisting in the same pig farm. Two of the ten field strains that were isolated exhibited a distinct evolution from the others. In addition to PEDV, other enteric pathogens, including porcine kobuvirus, porcine teschovirus and Lawsonia intracellularis, were identified. PMID- 23685899 TI - Dedicated breast CT: geometric design considerations to maximize posterior breast coverage. AB - An Institutional Review Board-approved protocol was used to quantify breast tissue inclusion in 52 women, under conditions simulating both craniocaudal (CC) and mediolateral oblique (MLO) views in mammography, dedicated breast CT in the upright subject position, and dedicated breast CT in the prone subject position. Using skin as a surrogate for the underlying breast tissue, the posterior aspect of the breast that is aligned with the chest-wall edge of the breast support in a screen-film mammography system was marked with the study participants positioned for CC and MLO views. The union of skin marks with the study participants positioned for CC and MLO views was considered to represent chest-wall tissue available for imaging with mammography and served as the reference standard. For breast CT, a prone stereotactic breast biopsy unit and a custom-fabricated barrier were used to simulate conditions during prone and upright breast CT, respectively. For the same breast marked on the mammography system, skin marks were made along the breast periphery that was just anterior to the apertures of the prone biopsy unit and the upright barrier. The differences in skin marks between subject positioning simulating breast CT (prone, upright) and mammography were quantified at six anatomic locations. For each location, at least one study participant had a skin mark from breast CT (prone, upright) posterior to mammography. However for all study participants, there was at least one anatomic location where the skin mark from mammography was posterior to that from breast CT (prone, upright) positioning. The maximum amount by which the skin mark from mammography was posterior to breast CT (prone and upright) over all six locations was quantified for each study participant and pair-wise comparison did not exhibit statistically significant difference between prone and upright breast CT (paired t- test, p = 0.4). Quantitatively, for 95% of the study participants the skin mark from mammography was posterior to breast CT (prone or upright) by at the most 9 mm over all six locations. Based on the study observations, geometric design considerations targeting chest-wall coverage with breast CT equivalent to mammography, wherein part of the x-ray beam images through the swale during breast CT are provided. Assuming subjects can extend their chest in to a swale, the optimal swale-depth required to achieve equivalent coverage with breast CT images as mammograms for 95% of the subjects varies in the range of ~30-50 mm for clinical prototypes and was dependent on the system geometry. PMID- 23685900 TI - Oncogenes and angiogenesis: a way to personalize anti-angiogenic therapy? AB - The acquisition of oncogenic mutations and promotion of angiogenesis are key hallmarks of cancer. These features are often thought of as separate events in tumor progression and the two fields of research have frequently been considered as independent. However, as we highlight in this review, activated oncogenes and deregulated angiogenesis are tightly associated, as mutations in cancer cells can lead to perturbation of the pro- and anti-angiogenic balance thereby causing aberrant angiogenesis. We propose that normalization of the vascular network by targeting oncogenes in the tumor cells might lead to more efficient and sustained therapeutic effects compared to therapies targeting tumor vessels. We discuss how pharmacological inhibition of oncogenes in tumor cells restores a functional vasculature by bystander anti-angiogenic effect. As genetic alterations are tumor specific, targeted therapy, which potentially blocks the angiogenic program activated by individual oncogenes may lead to personalized anti-angiogenic therapy. PMID- 23685901 TI - Stiffness, working stroke, and force of single-myosin molecules in skeletal muscle: elucidation of these mechanical properties via nonlinear elasticity evaluation. AB - In muscles, the arrays of skeletal myosin molecules interact with actin filaments and continuously generate force at various contraction speeds. Therefore, it is crucial for myosin molecules to generate force collectively and minimize the interference between individual myosin molecules. Knowledge of the elasticity of myosin molecules is crucial for understanding the molecular mechanisms of muscle contractions because elasticity directly affects the working and drag (resistance) force generation when myosin molecules are positively or negatively strained. The working stroke distance is also an important mechanical property necessary for elucidation of the thermodynamic efficiency of muscle contractions at the molecular level. In this review, we focus on these mechanical properties obtained from single-fiber and single-molecule studies and discuss recent findings associated with these mechanical properties. We also discuss the potential molecular mechanisms associated with reduction of the drag effect caused by negatively strained myosin molecules. PMID- 23685904 TI - New section: memories and retrospectives. PMID- 23685905 TI - Contribution of polymeric swelling to the overall response of capacitive gas sensors. AB - A new method for investigation of the swelling of polymers on exposure to gas or vapour has been devised and tested. It uses an optical profilometer (based on the chromatic aberration of a lens system) which is integrated into a computer controlled gas-dosing and mixing setup. Gas and/or vapour concentration-dependent measurements have been carried out for thick layers of the polymers commonly used in gravimetric and capacitive gas sensors: poly(acrylic acid) (PAA), poly(vinyl pyrrolidone) (PVP), poly(ether urethane) (PEUT), and polydimethylsiloxane (PDMS). The thickness of PAA, PVP, and PEUT films changed significantly on exposure to humidity. These data have been used to derive the sorption isotherms of the respective polymers, which were found to be Henry or Flory-Huggins isotherms. Comparison of the geometrical (swelling) responses with capacitive responses revealed a strong correlation. The correlation, which occurs because both types of response are proportional to the water content of the polymer, is also valid for polymers with nonlinear gas responses. Finally the geometrical and electrical characteristics of the capacitive samples were used to explain the dependence of the capacitive response of different polymers on the concentration of the target gas or vapour. In this way was deduced that PDMS, which does not swell on exposure to humidity, swells in the presence of 2,3-dimethylpentane, for which no profilometer evaluations are yet available. PMID- 23685902 TI - Social environmental effects on gene regulation. AB - Social environmental conditions, particularly the experience of social adversity, have long been connected with health and mortality in humans and other social mammals. Efforts to identify the physiological basis for these effects have historically focused on their neurological, endocrinological, and immunological consequences. Recently, this search has been extended to understanding the role of gene regulation in sensing, mediating, and determining susceptibility to social environmental variation. Studies in laboratory rodents, captive primates, and human populations have revealed correlations between social conditions and the regulation of a large number of genes, some of which are likely causal. Gene expression responses to the social environment are, in turn, mediated by a set of underlying regulatory mechanisms, of which epigenetic marks are the best studied to date. Importantly, a number of genes involved in the response to the social environment are also associated with susceptibility to other external stressors, as well as certain diseases. Hence, gene regulatory studies are a promising avenue for understanding, and potentially developing strategies to address, the effects of social adversity on health. PMID- 23685906 TI - Heat-transfer-based detection of L-nicotine, histamine, and serotonin using molecularly imprinted polymers as biomimetic receptors. AB - In this work, we will present a novel approach for the detection of small molecules with molecularly imprinted polymer (MIP)-type receptors. This heat transfer method (HTM) is based on the change in heat-transfer resistance imposed upon binding of target molecules to the MIP nanocavities. Simultaneously with that technique, the impedance is measured to validate the results. For proof-of principle purposes, aluminum electrodes are functionalized with MIP particles, and L-nicotine measurements are performed in phosphate-buffered saline solutions. To determine if this could be extended to other templates, histamine and serotonin samples in buffer solutions are also studied. The developed sensor platform is proven to be specific for a variety of target molecules, which is in agreement with impedance spectroscopy reference tests. In addition, detection limits in the nanomolar range could be achieved, which is well within the physiologically relevant concentration regime. These limits are comparable to impedance spectroscopy, which is considered one of the state-of-the-art techniques for the analysis of small molecules with MIPs. As a first demonstration of the applicability in biological samples, measurements are performed on saliva samples spiked with L-nicotine. In summary, the combination of MIPs with HTM as a novel readout technique enables fast and low-cost measurements in buffer solutions with the possibility of extending to biological samples. PMID- 23685903 TI - Nucleolar control of p53: a cellular Achilles' heel and a target for cancer therapy. AB - Nucleoli perform a crucial cell function, ribosome biogenesis, and of critical relevance to the subject of this review, they are also extremely sensitive to cellular stresses, which can cause loss of function and/or associated structural disruption. In recent years, we have learned that cells take advantage of this stress sensitivity of nucleoli, using them as stress sensors. One major protein regulated by this role of nucleoli is the tumor suppressor p53, which is activated in response to diverse cellular injuries in order to exert its onco protective effects. Here we discuss a model of nucleolar regulation of p53, which proposes that key steps in the promotion of p53 degradation by the ubiquitin ligase MDM2 occur in nucleoli, thus providing an explanation for the observed link between nucleolar disruption and p53 stability. We review current evidence for this compartmentalization in p53 homeostasis and highlight current limitations of the model. Interestingly, a number of current chemotherapeutic agents capable of inducing a p53 response are likely to do so by targeting nucleolar functions and these compounds may serve to inform further improved therapeutic targeting of nucleoli. PMID- 23685907 TI - Androgen-deprivation therapy in men with metastatic prostate cancer: less may not necessarily be more. PMID- 23685908 TI - Role of LM23 in cell proliferation and apoptosis and its expression during the testis development. AB - LM23, a gene expressed specifically in the testis in a stage-specific manner, has a diverse range of functions that are important in both the life and death of spermatogenic cells. The aim of this study was to further investigate the expression of LM23 in the developing rat testis and the biological function of LM23 in proliferation and antiapoptosis in vitro. Semiquantitative reverse transcription (RT)-PCR and real-time PCR were used to examine the expression of LM23 in testis at different developmental stages. The results suggested that LM23 mRNA levels in the testis increased progressively after birth. The role of LM23 in proliferation was analyzed with cell counting kit-8 (CCK8), colony-forming efficiency (CFE) and flow cytometry assays. The results indicated that ectopic expression of LM23 in 293T cells significantly promoted cell proliferation by increasing cell numbers in S phase. Several methods were used, including CCK8, annexin V and propidium iodide staining and western blotting, to determine the role of LM23 in apoptosis. The results showed that LM23 played a protective role in H2O2-induced apoptosis of 293T cells, mediated at least in part through the Akt/PI3K signal pathway. Taken together, these results provide new insights into the role of LM23 in the development of the testes and spermatogenesis. PMID- 23685909 TI - Clinical outcomes in patients with stage I non-seminomatous germ cell cancer. AB - This study assesses the long-term outcomes in Han Chinese patients with clinical stage I non-seminomatous germ cell testicular cancer (CSI NSGCT) treated with surveillance, retroperitoneal lymph node dissection (RPLND) and adjuvant chemotherapy. We retrospectively evaluated 89 patients with a mean age of 26.5 years. After orchiectomy, 37 patients were treated with surveillance, 34 underwent RPLND and 18 were managed with chemotherapy. The overall survival rate, the recurrence-free survival rate and the risk factors were evaluated. The median follow-up length was 92 months (range: 6-149 months). Thirteen of the 89 patients (14.6%) had relapses, and one died by the evaluation date. The overall survival rate was 98.9%. The cumulative 4-year recurrence-free rates were 80.2%, 92.0% and 100% for the surveillance, RPLND and chemotherapy groups, respectively. The disease-free period tended to be briefer in patients with a history of cryptorchidism and those with stage Is. Therefore, surveillance, RPLND and adjuvant chemotherapy might be reliable strategies in compliant patients with CSI NSGCT. Surveillance should be recommended for patients with the lowest recurrence rate, especially those without lymphovascular invasion. This study might aid the establishment of a standard therapy for CSI NSGCT in China. PMID- 23685911 TI - 3D structure through planting core-shell Si@TiN into an amorphous carbon slag: improved capacity of lithium-ion anodes. AB - A 3D-structured anode material, planting core-shell Si@TiN into an amorphous carbon slag (3D STC), was synthesized via a facile pyrolyzing process in assistance with the low-temperature reduction route in a liquid Na-NH3 system. The as-prepared samples were characterized by X-ray diffraction, field emission scanning electron microscopy, transmission electron microscopy, cyclic voltammetry and galvanostatic discharge-charge tests. From morphological analysis, TiN nanoparticles were homogeneously dispersed on the surface of Si to form the Si@TiN core-shell structure, subsequently plating into an amorphous C slag to form the 3D STC composite. The electrochemical capacity of the 3D STC anode was measured at a higher rate of 1 C with the cut-off voltages of 0.01 V and 1.5 V. It was found that the initial charge capacity reached up to 1604.6 mA h g(-1). In particular, the reversible charge capacity was as high as 588.7 mA h g(-1) over 100 cycles, with a small capacity loss of about 0.63% per cycle, exhibiting the excellent cycle stability of the 3D STC anode at the higher rate of 1 C. Furthermore, the reversible capacity of the 3D STC anode decreased from 2048.8 mA h g(-1) to 624.0 mA h g(-1) with increasing the current rate from 0.1 C to 2 C, while it was still maintained at 1419.7 mA h g(-1) as the current rate returned to 0.1 C. Consequentially, the 3D structure with a continuous conductive path could provide facile lithium insertion/extraction and fast electron transfer, making for the high rate capacity and good cycle stability. PMID- 23685910 TI - Penoscrotal extramammary Paget's disease: surgical techniques and follow-up experiences with thirty patients. AB - To report the surgical management, complications and prognosis of patients with penoscrotal extramammary Paget's disease (EMPD) at different clinical stages. Between 2003 and 2008, a total of 30 male patients with penoscrotal EMPD were enrolled and evaluated. All enrolled subjects received frozen biopsy-guided local wide resection and immediate reconstruction. Patients were followed every 3 months postoperatively. Among the 30 patients who accepted and underwent frozen biopsy-guided local wide resection treatment and reconstruction, two (6.7%) cases exhibited positive margins, verified by pathological examination, and underwent re-excision after surgery. The technique of primary closure or an adjacent flap was used in 10 (33.3%) cases, split-thickness skin grafts were used in 15 (50%), and an anterolateral thigh perforator flap was used in five cases (16.7%). The postoperative complications were acceptable. The mean follow-up time was 64.9 +/- 29.6 months. Of all 30 cases, 22 patients (73.3%) survived with no evidence of recurrence, four patients (13.3%) exhibited local recurrence, two patients (6.7%) exhibited both local recurrence and distant metastasis and the remaining two patients (6.7%) exhibited distant metastasis. Five patients died from metastasis or cachexia. Current surgical techniques, including primary closure, adjacent flaps, split-thickness skin flaps and anterolateral thigh perforator flaps are able to reconstruct all types of defects with acceptable complications. Some patients with negative margins went on to exhibit local recurrence, potentially due to adnexal carcinoma or internal malignancy. PMID- 23685912 TI - Peripheral anterior synechia reduce extent of angle widening after laser peripheral iridotomy in eyes with primary angle closure. AB - PURPOSE: To quantify the effect of laser peripheral iridotomy (LPI) on angle widening in primary angle closure with and without peripheral anterior synechia (PAS). PATIENTS AND METHODS: Prospective hospital-based study of 44 consecutive patients (69 eyes) with primary angle closure. Comprehensive ophthalmic examination and ultrasound biomicroscopy were performed at enrollment and 2 weeks following LPI. The following angle parameters: angle opening distance, trabecular iris angle, and angle recess area were obtained. On the basis of the presence of PAS, angle quadrants were divided into 3 groups: group A comprised quadrants in PAS-negative eyes; group B, the unaffected quadrants in PAS-positive eyes; and group C, the quadrants with PAS in PAS-positive eyes. Correlation between PAS and angle width was determined and changes in angle parameters following LPI were compared between groups. RESULTS: Sixty-six eyes of 42 patients (31 eyes with PAS) were available for analysis. Groups A, B, and C provided 140, 66, and 58 quadrants, respectively, for analysis. There was a moderate negative correlation between angle width changes (angle opening distance, trabecular-iris angle, angle recess area) after LPI and PAS extent at baseline (r=-0.46 to -0.39; P<0.01). The change in angle width was significantly different between groups A and B compared to group C (P<0.01); there was no difference between groups A and B. CONCLUSIONS: Changes in anterior chamber angle following LPI were inversely correlated with presence of PAS. Quadrants unaffected by PAS can be expected to widen as much as in eyes with only appositional closure. In quadrants with PAS the ultrasound biomicroscopy parameters did not change following LPI. PMID- 23685913 TI - Nd: YAG laser goniopuncture: indications and procedure. AB - Laser goniopuncture is a complementary adjunct to nonfiltering glaucoma surgery such as deep sclerectomy, viscocanalostomy, and canaloplasty, contributing to intraocular pressure control and the avoidance of additional incisional surgery. Goniopuncture is associated with a low complication rate and demonstrates minimal inflammation, hemorrhage, and hypotony when performed correctly. This article provides a detailed description of how to perform this procedure and methods of preventing and addressing complications. PMID- 23685914 TI - Daytime fluctuation of intraocular pressure in patients with primary angle closure glaucoma after trabeculectomy. AB - PURPOSE: To evaluate the daytime fluctuation of intraocular pressure (IOP) in patients with primary angle-closure glaucoma (PACG) after trabeculectomy. PARTICIPANTS AND METHODS: A total of 176 patients with PACG participated in a clinical trial of trabeculectomy with or without releasable sutures. Applanation IOP was measured at 5, 7, and 10 AM, and 2, 6, and 10 PM at 3 months posttrabeculectomy. We documented the mean, peak, and trough IOPs, determined the fluctuation of daytime IOP, and explored the associations of IOP fluctuation with baseline factors. RESULTS: IOP measurements were obtained in 173 patients. The mean daytime IOP was 13.2+/-3.7 mm Hg; mean peak IOP 15.1+/-4.1 mm Hg, mean trough IOP 11.3+/-3.5 mm Hg, and mean fluctuation 3.8+/-2.1 mm Hg. Fluctuation was positively correlated with peak (r=0.528, R2=0.28, P<0.001) and mean IOP (r=0.278, R2=0.08, P<0.001), but not with the trough IOP (r=0.015, P=0.843). Fluctuation was lower with extent of bleb (0.6 mm Hg/unit increase in extent; 95% CI, 0.1-1.2 mm Hg) and in blebs with microcysts (1.1 mm Hg less fluctuation; 95% CI, 0.2-1.9 mm Hg). Fluctuation was not associated with sex, age, baseline IOP, extent of peripheral anterior synechia or number of glaucoma medications before surgery, mean deviation of the visual field, vertical cup:disc ratio, or the use of releasable sutures. CONCLUSIONS: The mean fluctuation of daytime IOP after trabeculectomy for PACG was about 4 mm Hg. The fluctuation was positively associated with higher peak and mean IOP and negatively associated with extent of bleb and presence of microcysts. PMID- 23685915 TI - The future of the patient-specific Body-on-a-chip. AB - As significant advancements in technology focused on Organ-on-a-chip continue, it is feasible to consider the future of Body-on-a-chip technology. With serious work being done to realize functioning artificial livers, kidneys, hearts, and lungs on chips, the next step is not only to interconnect these organs but also to consider the integration of stem cell technology to create interconnected patient-specific organs. Such a patient-specific Body-on-a-chip requires a sophisticated set of tools for micropattering cell cultures in 3D to create interconnected tissue-like organ structures. This review discusses advanced methods of the past two years in on-Chip organs, the complex 3D patterning of cultures and state-of-the-art scaffolding, and discusses some of the most relevant advancements in human-induced pluripotent stem cell (hiPSC) research applied to these organs and scaffolds for the future of a patient-specific Body on-a-chip. We anticipate that such a technology would have a wide area of application, primarily benefiting drug development, chemical safety testing, and disease modeling. PMID- 23685916 TI - Using vacuum-assisted suspension to manage residual limb wounds in persons with transtibial amputation: a case series. AB - BACKGROUND: Persons with amputation and residual limb wounds would benefit from the ability to continue wearing a prosthesis while healing. Sockets with vacuum assisted suspension may reduce intra-socket motion and be less disruptive to wound healing. The purpose of this case series was to measure residual limb wound size over time in persons with transtibial amputation while using prostheses with vacuum-assisted suspension. CASE DESCRIPTION AND METHODS: Six subjects with residual limb wounds were fit with vacuum-assisted suspension sockets. Wound surface area was calculated using ImageJ software at the time of fit and each subsequent visit until closure. FINDINGS AND OUTCOME: Average wound surface area at initial measurement was 2.17 +/- 0.65 cm(2). All subjects were instructed to continue their normal activity level while wounds healed, with a mean of 177.6 +/ 113 days to wound closure. CONCLUSION: Results suggest that well-fitting sockets with vacuum-assisted suspension in compliant individuals did not preclude wound healing. Further research is required to substantiate these case-based observations. CLINICAL RELEVANCE: Residual limb wounds are typically treated by suspension of prosthetic use until healing occurs, increasing the risk of long term prosthesis nonuse. Our results suggest that vacuum-assisted suspension sockets may be used while healing occurs. PMID- 23685917 TI - Analysis of locomotor adaptations in young children with limb loss in an early prosthetic knee prescription protocol. AB - BACKGROUND: Traditionally, clinical protocols for the treatment of young children who require a knee prosthesis have favored stability, with the prosthetic knee locked into full extension until after the child has learned to walk. Recently, an Early Knee protocol has been investigated, in which children receive an articulating knee in their first prosthesis and use it while learning to crawl and walk. OBJECTIVES: This study investigated the presence of swing phase clearance adaptations in the walking gait of seven young children aged 18-92 months, who had been fitted according to the Early Knee protocol. STUDY DESIGN: Before-and-after experimental design. METHODS: Each subject completed walking trials with the knee freely flexing and trials with the knee locked into full extension to mimic a traditional knee protocol. RESULTS: Subjects utilized the articulating knee in walking, with an average of 70.4 degrees of peak swing phase knee flexion. Some clearance adaptations were present with the flexing knee; more were present and their magnitude was increased when the knee was locked. In particular, there was a statistically significant increase in circumduction. CONCLUSIONS: These results suggest that the Early Knee protocol can reduce the adoption of clearance adaptations while walking is developing. CLINICAL RELEVANCE: Treatment of young children who require a knee prosthesis is inconsistent. Traditionally, no knee is provided until independent walking is achieved. A newer Early Knee protocol provides an articulating knee in the first prosthesis. This study found that children use the articulating knee in walking and develop fewer clearance adaptations. PMID- 23685918 TI - A custom-made neoprene thumb carpometacarpal orthosis with thermoplastic stabilization: an orthosis that promotes function and improvement in patients with the first carpometacarpal joint osteoarthritis. AB - BACKGROUND AND AIM: Patients with mild to moderate first carpometacarpal joint osteoarthritis report pain, a reduction in pinch and grip strength and hand function. The purpose of this study was to analyze the effect of a custom-made neoprene thumb carpometacarpal orthosis with thermoplastic stabilization on pain, function, grip strength, and key pinch in these patients. TECHNIQUE: A total of 11 volunteer patients participated in this study. All the above-mentioned parameters were evaluated at baseline and also 30, 60, and 90 days after using the splint. DISCUSSION: A decrease in pain was observed after 30 days, and this continued to improve during treatment with the splint. After 90 days of using the splint, grip strength was improved. Function and pinch strength also increased significantly and was maintained during the study period compared to baseline. CLINICAL RELEVANCE: A custom-made neoprene thumb carpometacarpal orthosis with thermoplastic stabilization may be a suitable conservative approach for the treatment of first carpometacarpal joint osteoarthritis. PMID- 23685919 TI - The effect of seat shape on the risk of pressure ulcers using discomfort and interface pressure measurements. AB - BACKGROUND: It is clinically known that shape is important when selecting or designing a wheelchair support surface for the prevention of pressure ulcers (a L 2 billion annual cost to the National Health Service, UK); however, the effect of different levels of shape contouring has not been adequately studied. OBJECTIVES: To investigate the effect of seat shape on the risk of pressure ulcers using discomfort and interface pressure measurements. STUDY DESIGN: Randomised, repeated trial. METHODS: Thirty able-bodied participants sat with restricted movement for 30 min in three sessions to evaluate two cushion shapes against a flat baseline surface. Visual Analog Scaling and pressure mapping were used to measure surrogates for pressure ulcer risk, discomfort and interface pressures, respectively. RESULTS: Linear regression revealed a reduction in discomfort (p < 0.05) on the custom contoured shapes. Interface pressures measured were also lower (p < 0.05) on the custom contoured shapes, and a negative Pearson's correlation (p < 0.05) indicated an association between smaller hip widths and increased discomfort for the commercially shaped cushion. CONCLUSIONS: The results of this study confirm that custom contoured shapes were effective at reducing pressure ulcer surrogate measures in the participants of this study and therefore suggests that the contribution of a cushion's three-dimensional contours on pressure ulcer risk should be further researched. CLINICAL RELEVANCE: The measurement of seat shape, discomfort and interface pressure in surrogate participants can help inform the design of wheelchair seating for individuals who are insensate or otherwise at risk of developing pressure ulcers. This knowledge can now be implemented using modern three-dimensional shape acquisition, analysis and fabrication technologies. PMID- 23685920 TI - Is there any relationship between orthotic usage and functional activities in children with neuromuscular disorders? AB - BACKGROUND: Contractures of Achilles tendons and gastrocnemius muscle deteriorate the performance in daily living activities of patients with neuromuscular diseases. Ankle-foot orthoses help to prevent the progression of deformities and to obtain optimal position of the joints to support standing and walking. OBJECTIVE: To investigate the relationship between orthotic usage and functional activities in pediatric patients with different neuromuscular diseases. STUDY DESIGN: Retrospective study. METHODS: A total of 127 subjects' physical assessment forms were analyzed. Functional level, type of orthoses, falling frequencies, ankle joint range of motion, and timed performance tests were examined in two consecutive dates with an interval of 3 months. RESULTS: A total of 91 patients were using orthoses while 36 patients were not within assessment dates. A total of 64 of 91 (70.3%) patients were diagnosed with Duchenne muscular dystrophy. A total of 81 (89.0%) subjects were using plastic ankle-foot orthoses for positioning at nights and 10 (11%) were using different types of the orthoses (knee-ankle-foot orthoses, dynamic ankle-foot orthoses, and so on) for gait in the study group. CONCLUSIONS: Night ankle-foot orthoses were not found to be effective directly on functional performance in children with neuromuscular diseases, although they protect ankle from contractures and may help to correct gait and balance. CLINICAL RELEVANCE: This retrospective study shows that the positive effects of using an ankle-foot orthosis at night are not reflected in the functional performance of children with neuromuscular diseases. This may be due to the progressive deteriorating nature of the disease. PMID- 23685922 TI - Synchrony in affect among stressed adults: the Notre Dame Widowhood Study. AB - OBJECTIVES: This study examined 3 types of synchrony (i.e., asynchrony, synchrony, and desynchrony) between positive and negative affect in a sample of adult widows and assessed whether individual differences in synchrony type predicted adjustment over time. METHODS: Participants included 34 widows from the Notre Dame Widowhood Study, who reported on their positive and negative affect across a 98-day period following conjugal loss and responded to follow-up questionnaires every 4 months for 1 year. RESULTS: Multilevel models revealed that although the nomothetic average of the synchrony scores indicated a negative or desynchronous relationship between positive and negative affect, an ideographic view identified evidence of individual differences. Furthermore, patterns of change in the relationship between positive and negative affect suggested that, over time, desynchrony in affect generally abates for widows but individual differences were predictive of adjustment over time. Furthermore, distinct trajectories that the women follow from the time of their husband's death include patterns of resilience and delayed negative reaction, each of which predicted present levels of grief. DISCUSSION: Discussion focuses on (a) individual differences in the within-person structure in affect, (b) the dynamic processes involving negative and positive affect, and (c) the predictive power of synchrony scores. PMID- 23685921 TI - Daily emotional and physical reactivity to stressors among widowed and married older adults. AB - OBJECTIVES: Widowhood may result in declines in health and potentially stressful changes to daily routines. However, little research has examined how daily stressors contribute to physical and emotional well-being in widowhood. The objectives of the current study were to examine daily stressor exposure and reactivity in widowed versus married older adults. METHOD: Participants included all 100 widowed and 342 married adults aged 65 and older from the National Study of Daily Experiences, a daily diary study from the second wave of the Midlife in the United States. Daily stressors were measured using the Daily Inventory of Stressful Events; multilevel modeling assessed daily reactivity to stressors using daily negative affect (emotional reactivity) and daily physical symptoms (physical reactivity) as outcomes. RESULTS: Married participants reported more stressors in general, and specifically more interpersonal stressors (e.g., arguments). Both married and widowed participants were reactive to daily stressors. Married participants were physically and emotionally reactive to interpersonal stressors. Widowed participants were more physically reactive to home-related stressors. DISCUSSION: Attention to the types of daily stressors that widowed older adults experience in daily life and the potential physical effects of daily stressors during widowhood may help to alleviate some of the physical distress that widowed older adults may experience. PMID- 23685923 TI - Leisure, gender, and kinship in dementia caregiving: psychological vulnerability of caregiving daughters with feelings of guilt. AB - OBJECTIVES: The moderator role of guilt on the effect of leisure activities on dementia caregivers' depressive symptoms was analyzed, considering differences by kinship and guilt as a multidimensional construct. METHOD: Participants were 351 caregivers (58.97% daughters, 10.54% sons, 19.66% wives, and 10.83% husbands). Measures included frequency of leisure activities, depressive symptoms, and guilt (total scale and 5 factors). RESULTS: A moderator role of guilt was found only for daughters. Specifically, significant interactions between guilt and frequency of leisure activities were found for the total scale and for the Factors 1 (guilt about doing wrong by the care recipient), 2 (guilt about failing to meet the challenges of caregiving), and 3 (guilt about self-care). For those daughters who reported lower levels of leisure activities, showing higher levels of guilt was associated with higher scores in depressive symptoms, whereas those with lower levels of guilt showed lower depressive symptoms scores. DISCUSSION: Feelings of guilt may have different consequences on caregivers' distress depending on caregivers' gender and kinship. Daughters with higher levels of guilt who do not engage in leisure activities may be especially vulnerable to suffering psychological distress. PMID- 23685924 TI - Reduced activity restriction buffers the relations between chronic stress and sympathetic nervous system activation. AB - OBJECTIVES: Caregivers of dementia patients are at risk for developing cardiovascular disease (CVD), and this risk increases the longer they provide care. Greater perceptions that caregiving restricts social/recreational activities (i.e., activity restriction [AR]) has been associated with poorer health, and AR may exacerbate the relations between stress and health outcomes. The current study examined the interactive role of greater exposure to stress and increased AR on plasma catecholamine (CAT) levels: norepinephrine (NE) and epinephrine (EPI). METHOD: A total of 84 dementia caregivers completed a standard assessment battery, and a nurse collected blood, which was assayed for NE and EPI. Separate regressions for NE and EPI were used to determine whether the relations between years caregiving and CATs were greater in those with high versus low AR. RESULTS: A significant interaction was found between years caregiving and AR in predicting resting EPI (p = .032) but not resting NE (p = .103). Post hoc analyses indicated that years caregiving was significantly associated with EPI when AR was high (p = .008) but not when AR was low (p = .799). Additionally, years caregiving was not significantly associated with NE when AR was high or low. DISCUSSION: The subjective experience of AR can play an important role in determining risk for detrimental physical health outcomes, particularly CVD risk. PMID- 23685925 TI - Personality traits and chronic disease: implications for adult personality development. AB - OBJECTIVE: Personality traits have been associated with chronic disease. Less is known about the longitudinal relation between personality and disease and whether chronic disease is associated with changes in personality. Method. Participants from the Baltimore Longitudinal Study of Aging (N = 2,008) completed the Revised NEO Personality Inventory and a standard medical interview at regularly scheduled visits; the Charlson Comorbidity Index, a weighted sum of 19 serious diseases, was derived from this interview. Using data from 6,685 visits, we tested whether personality increased risk of disease and whether disease was associated with personality change. RESULTS: Measured concurrently, neuroticism and conscientiousness were associated with greater disease burden. The impulsiveness facet of neuroticism was the strongest predictor of developing disease across the follow-up period: For every standard deviation increase in impulsiveness, there was a 26% increased risk of developing disease and a 36% increased risk of getting more ill. Personality traits changed only modestly with disease: As participants developed chronic illnesses, they became more conservative (decreased openness). Discussion. This research indicates that personality traits confer risk for disease, in part, through health-risk behaviors. These traits, however, were relatively resistant to the effect of serious disease. PMID- 23685926 TI - Is self-rated health comparable between non-Hispanic whites and Hispanics? Evidence from the health and retirement study. AB - OBJECTIVES: Using subsequent all-cause mortality as a yardstick for retrospective health, this study assessed the comparability of self-rated health (SRH) between non-Hispanic whites and Hispanics. METHODS: Based on longitudinal data from 6,870 white and 886 Hispanic respondents aged between 51 and 61 in the 1992 Health and Retirement Study, we related SRH in 1992 to risk of mortality in the 1992-2008 period. Logit models were used to predict white-Hispanic differences in reporting fair or poor SRH. Survival curves and cox proportional hazard models were estimated to assess whether and the extent to which the SRH-mortality association differs between non-Hispanic whites and Hispanics. RESULTS: Hispanic respondents reported worse SRH than whites at the baseline, yet they had similar risk of mortality as whites in the 1992-2008 period. Overall, Hispanics rated their health more pessimistically than whites. This was especially the case for Hispanics who rated their health fair or poor at the baseline, whereas their presumed health conditions, as reflected by subsequent risk of mortality, should be considerably better than their white counterparts. DISCUSSION: Health disparities between whites and Hispanics aged between 51 and 61 will be overestimated if the assessment has been solely based on differences in SRH between the two groups. Findings from this study call for caution in relying on SRH to quantify and explain health disparities between non-Hispanic whites and Hispanics in the United States. PMID- 23685927 TI - Polymorphisms in MTHFR, MTHFD, and PAI-1 and recurrent miscarriage among North Indian women. AB - PURPOSE: The aim of this study was to investigate the association between MTHFR C677T, A1298C, MTHFD G1958A and plasminogen activator inhibitor type 1 (PAI-1) 4G/5G polymorphism among first trimester recurrent miscarriages. MATERIALS AND METHODS: DNA was extracted from peripheral blood samples from 200 patients and 300 controls. Polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) and sequencing were used to identify the polymorphisms. We have analyzed the frequencies, odds ratio, Hardy-Weinberg equilibrium. RESULTS: MTHFR C677T, A1298C, and MTHFD G1958A variant alleles were found to be significantly more prevalent in patients than control. However, variant genotype of MTHFR C677T (OR = 2.54; 95 % CI = 1.23-5.24; p value = 0.014), 1298C (OR = 2.23; 95 % CI = 1.09-4.52; p value = 0.028), and MTHFD-1958 showed significant association with pregnancy loss (OR = 2.36; 95 % CI = 1.39-4.02; p value = 0.002). Both MTHFR 677 and MTHFD 1958 showed susceptible effect under recessive model of inheritance. PAI-1 mutations showed no significance. CONCLUSION: We observed significant susceptible effects of MTHFR C677T, A1298C, and MTHFD G1958A among RM cases. Our data points toward the multifactorial nature of the recurrent miscarriage as relative contribution of variant genotype of MTHFR C677T is only twofold and further decreased to only onefold, and MTHFD-1958 lost its significance upon meta-analysis. PMID- 23685928 TI - Environmental survey in the Tuul and Orkhon River basins of north-central Mongolia, 2010: metals and other elements in streambed sediment and floodplain soil. AB - Streambed sediment and subsurface floodplain soil were sampled for elemental analyses from 15 locations in river basins of north-central Mongolia during August 2010. Our primary objective was to conduct a reconnaissance-level assessment of potential inputs of toxicologically important metals and metalloids to Lake Baikal, Russia, that might originate from mining and urban activities within tributaries of the Selenga River in Mongolia. Samples were collected in triplicate from all sites, then dried, and sieved to <2 mm for analysis by portable X-ray florescence spectroscopy and by inductively coupled plasma mass spectrometry after digestion with concentrated nitric and hydrochloric acids. Arsenic, copper, and mercury were greatly elevated in sediment and floodplain soil collected from tributary streams located near two major mining operations. Lead and zinc were moderately elevated in streambed sediment and in floodplain soil obtained from a small tributary in the capital city of Ulaanbaatar, but those concentrations were considerably less than probable effects benchmarks. Historical and possibly present mining activities have led to considerable metal contamination in certain tributaries of the Orkhon River in north-central Mongolia; however, metals originating from those sources did not appear to be accumulating in sediments at our downstream-most sampling sites located near the border between Mongolia and Russia. PMID- 23685929 TI - Statistical distributions of trace metal concentrations in the northwestern Mediterranean atmospheric aerosol. AB - The concentrations of 11 crustal and anthropogenic trace metals (Li, Al, V, Mn, Fe, Co, Ni, Cu, Zn, Cd, Pb) were measured from 2006 to 2008 in the atmospheric aerosol at a northwestern Mediterranean coast (station of Cap Ferrat, situated on the southeastern coast of France). Statistical models (lognormal, Weibull, and gamma) that best represented the trace metal distribution for this environment are described. The lognormal model was selected for the distributions of (in decreasing strength of the fit) Al, Co, Li, Zn, Mn, Cu, Pb, and Cd, i.e., metals that are introduced into the atmospheric aerosol by pulses inducing temporal variability in their concentrations. The gamma model was associated with Fe, i.e., metals that exhibit less inter-annual variability than the former trace metals. The third mode (Weibull) represented the distribution of the concentrations of V and Ni. The statistical approach presented in this study contributed to better define and constrain the distribution of the 11 trace metals of the atmospheric aerosol from the northwestern Mediterranean coast. In a close future, knowledge of these statistical distributions will allow using convolution models to separate their natural and anthropogenic contributions, therefore increasing our ability to study anthropogenic emissions of trace metals and their impact on the environment. PMID- 23685930 TI - Pathologic brain network activity: memory impairment in epilepsy. PMID- 23685931 TI - Hippocampal interictal epileptiform activity disrupts cognition in humans. AB - OBJECTIVE: We investigated whether interictal epileptiform discharges (IED) in the human hippocampus are related to impairment of specific memory processes, and which characteristics of hippocampal IED are most associated with memory dysfunction. METHODS: Ten patients had depth electrodes implanted into their hippocampi for preoperative seizure localization. EEG was recorded during 2,070 total trials of a short-term memory task, with memory processing categorized into encoding, maintenance, and retrieval. The influence of hippocampal IED on these processes was analyzed and adjusted to account for individual differences between patients. RESULTS: Hippocampal IED occurring in the memory retrieval period decreased the likelihood of a correct response when they were contralateral to the seizure focus (p < 0.05) or bilateral (p < 0.001). Bilateral IED during the memory maintenance period had a similar effect (p < 0.01), particularly with spike-wave complexes of longer duration (p < 0.01). IED during encoding had no effect, and reaction time was also unaffected by IED. CONCLUSIONS: Hippocampal IED in humans may disrupt memory maintenance and retrieval, but not encoding. The particular effects of bilateral IED and those contralateral to the seizure focus may relate to neural compensation in the more functional hemisphere. This study provides biological validity to animal models in the study of IED-related transient cognitive impairment. Moreover, it strengthens the argument that IED may contribute to cognitive impairment in epilepsy depending upon when and where they occur. PMID- 23685932 TI - Long-term cognitive function, neuroimaging, and quality of life in primary CNS lymphoma. AB - OBJECTIVE: To describe and correlate neurotoxicity indicators in long-term primary CNS lymphoma (PCNSL) survivors who were treated with high-dose methotrexate-based regimens with or without whole-brain radiotherapy (WBRT). METHODS: Eighty PCNSL survivors from 4 treatment groups (1 with WBRT and 3 without WBRT) who were a minimum of 2 years after diagnosis and in complete remission underwent prospective neuropsychological, quality-of-life (QOL), and brain MRI evaluation. Clinical characteristics were compared among treatments by using the chi(2) test and analysis of variance. The association among neuroimaging, neuropsychological, and QOL outcomes was assessed by using the Pearson correlation coefficient. RESULTS: The median interval from diagnosis to evaluation was 5.5 years (minimum, 2 years; maximum, 26 years). Survivors treated with WBRT had lower mean scores in attention/executive function (p = 0.0011), motor skills (p = 0.0023), and neuropsychological composite score (p = 0.0051) compared with those treated without WBRT. Verbal memory was better in survivors with longer intervals from diagnosis to evaluation (p = 0.0045). On brain imaging, mean areas of total T2 abnormalities were different among treatments (p = 0.0006). Total T2 abnormalities after WBRT were more than twice the mean of any non-WBRT group and were associated with poorer neuropsychological and QOL outcomes. CONCLUSIONS: Our results suggest that in patients treated for PCNSL achieving complete remission and surviving at least 2 years, the addition of WBRT to methotrexate-based chemotherapy increases the risk of treatment-related neurotoxicity. Verbal memory may improve over time. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in patients treated for PCNSL achieving complete remission and surviving at least 2 years, the addition of WBRT to methotrexate-based chemotherapy increases the risk of treatment-related neurotoxicity. PMID- 23685933 TI - Cognitive outcomes of patients undergoing therapeutic hypothermia after cardiac arrest. AB - OBJECTIVE: We aimed to study the long-term cognitive abilities of patients surviving out-of-hospital cardiac arrest who were treated with therapeutic hypothermia (TH). METHODS: We prospectively identified and examined consecutive survivors of out-of-hospital cardiac arrest who underwent TH at our institution from June 2006 to May 2011. The results of brain imaging, serum neuron-specific enolase (NSE) measurements, and EEGs were recorded. We assessed cognitive domains using the modified Telephone Interview for Cognitive Status. An education adjusted score of >= 32 was considered normal. RESULTS: Of 133 total patients, 77 (58%) were alive at a median follow-up of 20 months (interquartile range 14-24 months). We interviewed 56 patients (73% of those alive). Median age was 67 years (range 24-88 years). Fifty-one patients (91%) were living independently. Modified Telephone Interview for Cognitive Status scores ranged from 16 to 41. Thirty three (60%) were considered cognitively normal and 22 (40%) were cognitively impaired. The time to assessment did not differ among the cognitive outcomes (p = 0.557). The median duration of coma was 2 days, possibly indicating that patients with severe anoxic injury were not included. Eighteen patients were not working at the time of their cardiac arrest (17 were retired and 1 was unemployed). Of the 38 patients who were working up to the time of the cardiac arrest, 30 (79%) returned to work. Cognitive outcome was not associated with age, time to return of spontaneous circulation, brain atrophy, or leukoaraiosis. CONCLUSIONS: The majority of surviving patients who underwent TH after cardiac arrest in this series had preserved cognitive function and were able to return to work. PMID- 23685934 TI - Plasmablastic lymphoma after standard-dose temozolomide for newly diagnosed glioblastoma. PMID- 23685935 TI - Effects of polysaccharides from different species of Dendrobium (Shihu) on macrophage function. AB - Dendrobium spp. are precious medicinal plants, used in China for thousands of years as health foods and nutrients. Polysaccharides are the main effective ingredients in Dendrobium plants. In this study, the chemical characteristics and the effects of crude polysaccharides (CPs) from five species of Dendrobium on macrophage function were investigated and compared in vitro for the first time. Chemical characteristic studies showed that CPs from different species of Dendrobium were diverse, displaying widely varied Mw distributions and molar ratios of monosaccharides. Their effects on macrophage functions, such as promoting phagocytosis, release of NO and cytokines IL-1alpha, IL-6, IL-10 and TNF-alpha, were also different. Moreover, CPs from D. officinale, especially collected from Yunnan Province, exerted the strongest immunomodulatory activities and could be explored as a novel potential functional food. The diverse chemical characteristics of CPs from different species of Dendrobium might contribute to their varied effects on macrophage functions, which should be further investigated. PMID- 23685936 TI - Effect of leguminous lectins on the growth of Rhizobium tropici CIAT899. AB - Rhizobium tropici is a Gram-negative bacterium that induces nodules and fixed atmospheric nitrogen in symbiotic association with Phaseolus vulgaris (common bean) and some other leguminous species. Lectins are proteins that specifically bind to carbohydrates and, consequently, modulate different biological functions. In this study, the d-glucose/ d-mannose-binding lectins (from seeds of Dioclea megacarpa, D. rostrata and D. violacea) and D-galactose-binding lectins (from seeds of Bauhinia variegata, Erythina velutina and Vatairea macrocarpa) were purified using chromatographic techniques and evaluated for their effect on the growth of R. tropici CIAT899. All lectins were assayed with a satisfactory degree of purity according to SDS-PAGE analysis, and stimulated bacterial growth; in particular, the Dioclea rostrata lectin was the most active among all tested proteins. As confirmed in the present study, both d-galactose- and d-glucose/d mannose-binding lectins purified from the seeds of leguminous plants may be powerful biotechnological tools to stimulate the growth of R. tropici CIAT99, thus improving symbiotic interaction between rhizobia and common bean and, hence, the production of this field crop. PMID- 23685937 TI - Dried root of Rehmannia glutinosa prevents bone loss in ovariectomized rats. AB - Dried root of Rehmannia glutinosa is a kidney-tonifying herbal medicine with a long history of safe use in traditional folk medicine for the treatment of joint diseases. This study was conducted to investigate prevention of bone loss by a standardized dried root of R. glutinosa in an ovariectomized (OVX) rat model of osteoporosis. The OVX groups were divided into five groups treated with distilled water, 17beta-estradiol (E2 10 ug/kg, once daily, i.p) and dried root of R. glutinosa extracts (DRGE 30, 100, and 300 mg/kg, twice daily, p.o) for eight weeks. We measured the body, organs, and uterus weights, and femur and lumbar vertebrae bone mineral density (BMD), serum alkaline phosphatase (ALP), estradiol levels. The treatments with DRGE 300 mg/kg significantly inhibited BMD decrease in the femur and lumbar (17.5% and 16.4%, p < 0.05, respectively) by OVX without affecting the body, organs, and uterus weights. Also, serum ALP level in the DRGE 300 mg/kg treated group was significantly decreased, but the estradiol level did not change in serum of the DRGE 300 mg/kg treated group. These results show that DRGE is able to prevent OVX-induced bone loss without influencing hormones such as estrogen. PMID- 23685938 TI - Vasodilator compounds derived from plants and their mechanisms of action. AB - The present paper reviews vasodilator compounds isolated from plants that were reported in the past 22 years (1990 to 2012) and the different mechanisms of action involved in their vasodilator effects. The search for reports was conducted in a comprehensive manner, intending to encompass those metabolites with a vasodilator effect whose mechanism of action involved both vascular endothelium and arterial smooth muscle. The results obtained from our bibliographic search showed that over half of the isolated compounds have a mechanism of action involving the endothelium. Most of these bioactive metabolites cause vasodilation either by activating the nitric oxide/cGMP pathway or by blocking voltage-dependent calcium channels. Moreover, it was found that many compounds induced vasodilation by more than one mechanism. This review confirms that secondary metabolites, which include a significant group of compounds with extensive chemical diversity, are a valuable source of new pharmaceuticals useful for the treatment and prevention of cardiovascular diseases. PMID- 23685939 TI - Gold nanoparticle contrast agents in advanced X-ray imaging technologies. AB - Recently, there has been significant progress in the field of soft- and hard-X ray imaging for a wide range of applications, both technically and scientifically, via developments in sources, optics and imaging methodologies. While one community is pursuing extensive applications of available X-ray tools, others are investigating improvements in techniques, including new optics, higher spatial resolutions and brighter compact sources. For increased image quality and more exquisite investigation on characteristic biological phenomena, contrast agents have been employed extensively in imaging technologies. Heavy metal nanoparticles are excellent absorbers of X-rays and can offer excellent improvements in medical diagnosis and X-ray imaging. In this context, the role of gold (Au) is important for advanced X-ray imaging applications. Au has a long history in a wide range of medical applications and exhibits characteristic interactions with X-rays. Therefore, Au can offer a particular advantage as a tracer and a contrast enhancer in X-ray imaging technologies by sensing the variation in X-ray attenuation in a given sample volume. This review summarizes basic understanding on X-ray imaging from device set-up to technologies. Then this review covers recent studies in the development of X-ray imaging techniques utilizing gold nanoparticles (AuNPs) and their relevant applications, including two- and three-dimensional biological imaging, dynamical processes in a living system, single cell-based imaging and quantitative analysis of circulatory systems and so on. In addition to conventional medical applications, various novel research areas have been developed and are expected to be further developed through AuNP-based X-ray imaging technologies. PMID- 23685941 TI - Influence of 4- or 5-substituents on the pyrrolidine ring of 5-[1-(2 methoxymethylpyrrolidinyl)sulfonyl]isatin derivatives on their inhibitory activities towards caspases-3 and -7. AB - A series of new 4- or 5-substituted pyrrolidine derivatives of 5-[1-(2 methoxymethylpyrrolidinyl)sulfonyl]isatin bearing additional n-butyl or 4 fluorobutyl groups at the isatin nitrogen were prepared and their inhibitory activities have been tested against caspases-3 and -7, which are known to participate in the execution of the programmed cell death, called apoptosis. Several analogues fluorinated at the 4-position of the pyrrolidine ring were also synthesized since such inhibitors might be developed as (18)F-radiotracers for molecular imaging of activated caspases in vivo by PET. Enantiomerically pure diastereomeric 4-fluoropyrrolidinyl derivatives inhibited the enzymes in the nanomolar scale, i.e.100-1000 times more efficient than the corresponding 4 methoxy analogues. The 4,4-difluorinated compound showed the best result with IC50 = 362 nM and 178 nM for the aforementioned caspases. In contrast, the 4 methoxy and 4-trifluoromethyl analogues exhibited less inhibition potencies for the enzymes in the MUM scale, whereas all 4-OPEG4 (PEG4 = tetraethyleneglycol) and 5-methoxymethyl derivatives were inactive. PMID- 23685940 TI - Combination therapy with telaprevir for chronic hepatitis C virus genotype 1 infection in patients with HIV: a randomized trial. AB - BACKGROUND: Telaprevir (TVR) plus peginterferon-alpha2a (PEG-IFN-alpha2a) and ribavirin substantially increases treatment efficacy for genotype 1 chronic hepatitis C virus (HCV) infection versus PEG-IFN-alpha2a-ribavirin alone. Its safety and efficacy in patients with HCV and HIV-1 are unknown. OBJECTIVE: To assess the safety and efficacy of TVR plus PEG-IFN-alpha2a-ribavirin in patients with genotype 1 HCV and HIV-1 and to evaluate pharmacokinetics of TVR and antiretrovirals during coadministration. DESIGN: Phase 2a, randomized, double blind, placebo-controlled study. (ClinicalTrials.gov: NCT00983853). SETTING: 16 international multicenter sites. PATIENTS: 62 patients with HCV genotype 1 and HIV-1 who were HCV treatment-naive and receiving 0 or 1 of 2 antiretroviral regimens were randomly assigned to TVR plus PEG-IFN-alpha2a-ribavirin or placebo plus PEG-IFN-alpha2a-ribavirin for 12 weeks, plus 36 weeks of PEG-IFN-alpha2a ribavirin. MEASUREMENTS: HCV RNA concentrations. RESULTS: Pruritus, headache, nausea, rash, and dizziness were higher with TVR plus PEG-IFN-alpha2a-ribavirin during the first 12 weeks. During this period, serious adverse events occurred in 5% (2 in 38) of those receiving TVR plus PEG-IFN-alpha2a-ribavirin and 0% (0 in 22) of those receiving placebo plus PEG-IFN-alpha2a-ribavirin; the same number in both groups discontinued treatment due to adverse events. Sustained virologic response occurred in 74% (28 in 38) of patients receiving TVR plus PEG-IFN alpha2a-ribavirin and 45% (10 in 22) of patients receiving placebo plus PEG-IFN alpha2a-ribavirin. Rapid HCV suppression was seen with TVR plus PEG-IFN-alpha2a ribavirin (68% [26 in 38 patients] vs. 0% [0 in 22 patients] undetectable HCV RNA levels by week 4). Two patients had on-treatment HCV breakthrough with TVR resistant variants. Patients treated with antiretroviral drugs had no HIV breakthroughs; antiretroviral exposure was not substantially modified by TVR. LIMITATION: Small sample size and appreciable dropout rate. CONCLUSION: In patients with HCV and HIV-1, more adverse events occurred with TVR versus placebo plus PEG-IFN-alpha2a-ribavirin; these were similar in nature and severity to those in patients with HCV treated with TVR. With or without concomitant antiretrovirals, sustained virologic response rates were higher in patients treated with TVR versus placebo plus PEG-IFN-alpha2a-ribavirin. PMID- 23685942 TI - Biological activity, design, synthesis and structure activity relationship of some novel derivatives of curcumin containing sulfonamides. AB - Five series of curcumin derivatives with sulfonamides 3a-3e, 4a-4e, 5a-5e, 6a-6e and 7a-7e have been synthesized and evaluated for in vitro antibacterial activity against selected medically important gram-(+) and gram-(-) bacterial species viz. Staphylococcus aureus, Bacillus cereus, Salmonella typhi, Pseudomonas aeruginosa and Escherichia coli, and antifungal activity against few pathogenic fungal species viz. Aspergillus niger, Aspergillus flavus, Trichoderma viride and Curvularia lunata. The cytotoxicity has been determined by measuring IC50 values against human cell lines HeLa, Hep G-2, QG-56 and HCT-116. Among the compounds screened, 3a-3e showed the most potent biological activity against tested bacteria and fungi. Compounds 3a-3e displayed higher cytotoxicity than curcumin. The curcumin derivatives were also evaluated for in vivo anti-inflammatory activity. In contrast, the compounds 6a-6e and 7a-7e showed dramatically decrease in biological activity. PMID- 23685943 TI - 2-(3-Fluoro-4-methylsulfonylaminophenyl)propanamides as potent TRPV1 antagonists: structure activity relationships of the 2-oxy pyridine C-region. AB - The structure activity relationships of 2-oxy pyridine derivatives in the C region of N-(6-trifluoromethyl-pyridin-3-ylmethyl) 2-(3-fluoro-4 methylsulfonylaminophenyl)propanamides as hTRPV1 antagonists were investigated. The analysis indicated that the lipophilicity of the 2-oxy substituents was critical for potent antagonism and 4 or 5 carbons appeared to be optimal for activity. Multiple compounds proved to have comparable activity to 1, which had been reported as the most potent antagonist for capsaicin activity among the previous series of compounds. Further analysis of compounds 22 (2-isobutyloxy) and 53 (2-benzyloxy) in the formalin test in mice demonstrated strong analgesic activity with full efficacy. Docking analysis of 53S using our hTRPV1 homology model indicated that the A- and B-region 2-(3-fluoro-4 methylsulfonylaminophenyl)propanamide made important hydrophobic and hydrogen bonding interactions with Tyr511 and that the C-region 6-trifluoromethyl and 2 benzyloxy groups of pyridine occupied the two hydrophobic binding pockets, respectively. PMID- 23685944 TI - Cytotoxic activities of substituted 3-(3,4,5-trimethoxybenzylidene)-1,3 dihydroindol-2-ones and studies on their mechanisms of action. AB - The synthesis of new trimethoxybenzylidene-indolinones is reported. Their cytotoxic activity was evaluated according to Developmental Therapeutics Program, National Cancer Institute, Bethesda, MD, drug screen protocols. The study of the mechanism of action suggests that inhibition of Nox4 in B1647 cells (acute myeloid leukemia) could contribute to the antiproliferative effect of some compounds. Moreover, inhibition of tubulin assembly was observed for the most cytotoxic compound, and the structural basis for this activity was delineated by binding models. PMID- 23685945 TI - Angiotensin-converting enzyme gene insertion/deletion polymorphism with metabolic syndrome in Turkish patients. AB - BACKGROUND: The ACE gene has received substantial attention in recent years as candidate for a variety of diseases. The most common polymorphism in ACE gene is the Insertion/Deletion (I/D, rs4646994) polymorphism located on intron 16. AIM: We investigated the association between metabolic syndrome (MS) and the insertion (I) - deletion (D) polymorphisms in the angiotensin converting enzyme (ACE) gene in south-east of Turkey. SUBJECTS AND METHODS: One hundred and sixty subjects, with 101 cases of MS and 59 age- and gender-matched healthy controls were included in the study. RESULTS: The frequency of ACE I/D polymorphism was found to be 49.5% for DD, 36.6% for ID, and 13.9% for II in the MSstudy group and 44.1% for DD, 42.4% for ID and 13.5% for II in the control group. Allele frequencies were found to be 0.68% for D and 0.32% for I allele in the study group with MS and 0.65% for D, 0.35% for I allele in the control group. The I/D polymorphism of the ACE gene, DD, ID, and II genotypes occurred with similar frequencies in the study group with MS and the control group with no significant differences (p<0.05). On applying one-way analysis of variance to different ACE gene polymorphic groups in patients with MS were not significantly associated to ACE gene polymorphism and waist circumference, systolic blood pressure, diastolic blood pressure, fasting blood glucose, HDL, and LDL (p<0.05). CONCLUSIONS: Further studies of patients in larger numbers and of different ethnic backgrounds may be necessary to elucidate the association between the ACE I/D gene polymorphism and MS. PMID- 23685947 TI - Vitamin D: an intervention for cognitive impairment in hemodialysis patients that could make sense. PMID- 23685946 TI - Comparison of risk factors and outcomes in HIV immune complex kidney disease and HIV-associated nephropathy. AB - BACKGROUND AND OBJECTIVES: HIV-associated nephropathy (HIVAN) is well described, but the clinical features of a group of renal pathologies characterized by Ig or immune complex depositions referred to as HIV-associated immune complex kidney disease (HIVICK) have not been well established. The objective of this study is to assess risk factors for HIVICK compared with contemporaneous control participants. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A nested case control study of 751 HIV-infected patients followed from January 1996 to June 2010 was conducted. Groups were compared using the chi-squared test or rank-sum analysis. Conditional logistic regression was used to estimate odds ratios (ORs) for HIVICK. Incidences of overall ESRD and with/without combined antiretroviral therapy (cART) exposure were calculated. RESULTS: HIVICK patients were predominantly African American (92%). Compared with matched controls, patients with HIVICK were more likely to have HIV RNA >400 copies/ml (OR, 2.5; 95% confidence interval [95% CI], 1.2 to 5.2), diabetes (OR, 2.8; 95% CI, 1.1 to 6.8), and hypertension (OR, 2.3; 95% CI, 1.2 to 4.5). Compared with HIVAN, patients with HIVICK had more antiretroviral therapy exposure, lower HIV viral loads, and higher CD4 and estimated GFR. ESRD was less common in the HIVICK versus the HIVAN group (30% versus 82%; P<0.001), and the use of cART was not associated with ESRD in HIVICK patients (25% versus 26; P=0.39). CONCLUSIONS: HIVICK was predominantly observed in African-American patients and associated with advanced HIV disease. ESRD incidence is lower in HIVICK patients compared with those with HIVAN. Unlike HIVAN, cART use was not associated with the incidence of ESRD in HIVICK. PMID- 23685948 TI - Metabolic syndrome, CKD progression, and death: the good, the bad, and the ugly. PMID- 23685949 TI - Spatial resolution characterization of differential phase contrast CT systems via modulation transfer function (MTF) measurements. AB - By adding a Talbot-Lau interferometer to a conventional x-ray absorption computed tomography (CT) imaging system, both differential phase contrast (DPC) signal and absorption contrast signal can be simultaneously measured from the same set of CT measurements. The imaging performance of such multi-contrast x-ray CT imaging systems can be characterized with standard metrics such as noise variance, noise power spectrum, contrast-to-noise ratio, modulation transfer function (MTF), and task-based detectability index. Among these metrics, the measurement of the MTF can be challenging in DPC-CT systems due to several confounding factors such as phase wrapping and the difficulty of using fine wires as probes. To address these technical challenges, this paper discusses a viable and reliable method to experimentally measure the MTF of DPC-CT. It has been found that the spatial resolution of DPC-CT is degraded, when compared to that of the corresponding absorption CT, due to the presence of a source grating G0 in the Talbot-Lau interferometer. An effective MTF was introduced and experimentally estimated to describe the impact of the Talbot-Lau interferometer on the system MTF. PMID- 23685950 TI - Activation of muscarinic receptors inhibits glutamate-induced GSK-3beta overactivation in PC12 cells. AB - AIM: To investigate the actions of the muscarinic agonist carbachol on glutamate induced neurotoxicity in PC12 cells, and the underlying mechanisms. METHODS: PC12 cells were treated with different concentrations of glutamate for 24 or 48 h. The cell viability was measured using MTT assay, and the expression and activation of GSK-3beta were detected with Western blot. beta-Catenin translocation was detected using immunofluorescence. Luciferase reporter assay and real-time PCR were used to analyze the transcriptional activity of beta-catenin. RESULTS: Glutamate (1, 3, and 10 mmol/L) induced PC12 cell death in a dose-dependent manner. Moreover, treatment of the cells with glutamate (1 mmol/L) caused significant overactivation of GSK-3beta and prevented beta-catenin translocation to the nucleus. Pretreatment with carbachol (0.01 MUmol/L) blocked glutamate induced cell death and GSK-3beta overactivation, and markedly enhanced beta catenin transcriptional activity. CONCLUSION: Activation of muscarinic receptors exerts neuroprotection in PC12 cells by attenuating glutamate-induced GSK-3beta overactivation, suggesting potential benefits of muscarinic agonists for Alzheimer's disease. PMID- 23685951 TI - Matrine inhibits the adhesion and migration of BCG823 gastric cancer cells by affecting the structure and function of the vasodilator-stimulated phosphoprotein (VASP). AB - AIM: Vasodilator-stimulated phosphoprotein (VASP) expression is upregulated in human cancers and correlates with more invasive advanced tumor stages. The aim of this study was to elucidate the mechanisms by which matrine, an alkaloid derived from Sophora species plants, acted on the VASP protein in human gastric cancer cells in vitro. METHODS: VASP was expressed and purified. Intrinsic fluorescence spectroscopy was used to study the binding of matrine to VASP. CD spectroscopy was used to examine the changes in the VASP protein secondary structure. Human gastric carcinoma cell line BGC823 was tested. Scratch wound and cell adhesion assays were used to detect the cell migration and adhesion, respectively. Real time PCR and Western blotting assays were used to measure mRNA and protein expression of VASP. RESULTS: In the fluorescence assay, the dissociation constant for binding of matrine to VASP protein was 0.86 mmol/L, thus the direct binding between the two molecules was weak. However, matrine (50 MUg/mL) caused obvious change in the secondary structure of VASP protein shown in CD spectrum. Treatments of BGC823 cells with matrine (50 MUg/mL) significantly inhibited the cell migration and adhesion. The alkaloid changed the subcellular distribution of VASP and formation of actin stress fibers in BGC823 cells. The alkaloid caused small but statistically significant decreases in VASP protein expression and phosphorylation, but had no significant effect on VASP mRNA expression. CONCLUSION: Matrine modulates the structure, subcellular distribution, expression and phosphorylation of VASP in human gastric cancer cells, thus inhibiting the cancer cell adhesion and migration. PMID- 23685952 TI - Understanding and targeting cancer stem cells: therapeutic implications and challenges. AB - Cancer stem cells (CSCs) have been identified as rare cell populations in many cancers, including leukemia and solid tumors. Accumulating evidence has suggested that CSCs are capable of self-renewal and differentiation into various types of cancer cells. Aberrant regulation of gene expression and some signaling pathways has been observed in CSCs compared to other tumor cells. CSCs are thought to be responsible for cancer initiation, progression, metastasis, recurrence and drug resistance. The CSC hypothesis has recently attracted much attention due to the potential for discovery and development of CSC-related therapies and the identification of key molecules involved in controlling the unique properties of CSC populations. Over the past several years, a tremendous amount of effort has been invested in the development of new drugs, such as nanomedicines, that can take advantage of the "Achilles' heel" of CSCs by targeting cell-surface molecular markers or various signaling pathways. Novel compounds and therapeutic strategies that selectively target CSCs have been identified, some of which have been evaluated in preclinical and clinical studies. In this article, we review new findings related to the investigation of the CSC hypothesis, and discuss the crucial pathways involved in regulating the development of CSC populations and the advances in studies of drug resistance. In addition, we review new CSC targeted therapeutic strategies aiming to eradicate malignancies. PMID- 23685953 TI - Inside job: ligand-receptor pharmacology beneath the plasma membrane. AB - Most drugs acting on the cell surface receptors are membrane permeable and thus able to engage their target proteins in different subcellular compartments. However, these drugs' effects on cell surface receptors have historically been studied on the plasma membrane alone. Increasing evidence suggests that small molecules may also modulate their targeted receptors through membrane trafficking or organelle-localized signaling inside the cell. These additional modes of interaction have been reported for functionally diverse ligands of GPCRs, ion channels, and transporters. Such intracellular drug-target engagements affect cell surface expression. Concurrent intracellular and cell surface signaling may also increase the complexity and therapeutic opportunities of small molecule modulation. Here we discuss examples of ligand-receptor interactions that are present in both intra- and extracellular sites, and the potential therapeutic opportunities presented by this phenomenon. PMID- 23685954 TI - Enhancing the potency of lithospermate B for inhibiting Na+/K+-ATPase activity by forming transition metal ion complexes. AB - AIM: To determine whether replacing Mg(2+) in magnesium lithospermate B (Mg-LSB) isolated from danshen (Salvia miltiorrhiza) with other metal ions could affect its potency in inhibition of Na(+)/K(+)-ATPase activity. METHODS: Eight metal ions (Na(+), K(+), Mg(2+), Cr(3+), Mn(2+), Co(2+), Ni(2+), and Zn(2+)) were used to form complexes with LSB. The activity of Na(+)/K(+)-ATPase was determined by measuring the amount of inorganic phosphate (Pi) liberated from ATP. Human adrenergic neuroblastoma cell line SH-SY5Y was used to assess the intracellular Ca(2+) level fluctuation and cell viability. The metal binding site on LSB and the binding mode of the metal-LSB complexes were detected by NMR and visible spectroscopy, respectively. RESULTS: The potencies of LSB complexed with Cr(3+), Mn(2+), Co(2+), or Ni(2+) increased by approximately 5 times compared to the naturally occurring LSB and Mg-LSB. The IC50 values of Cr-LSB, Mn-LSB, Co-LSB, Ni LSB, LSB, and Mg-LSB in inhibition of Na(+)/K(+)-ATPase activity were 23, 17, 26, 25, 101, and 128 MUmol/L, respectively. After treatment of SH-SY5Y cells with the transition metal-LSB complexes (25 MUmol/L), the intracellular Ca(2+) level was substantially elevated, and the cells were viable for one day. The transition metals, as exemplified by Co(2+), appeared to be coordinated by two carboxylate groups and one carbonyl group of LSB. Titration of LSB against Co(2+) demonstrated that the Co-LSB complex was formed with a Co(2+):LSB molar ratio of 1:2 or 1:1, when [Co(2+)] was less than half of the [LSB] or higher than the [LSB], respectively. CONCLUSION: LSB complexed with Cr(3+), Mn(2+), Co(2+), or Ni(2+) are stable, non-toxic and more potent in inhibition of Na(+)/K(+)-ATPase. The transition metal-LSB complexes have the potential to be superior substitutes for cardiac glycosides in the treatment of congestive heart failure. PMID- 23685955 TI - Disease modeling and drug screening for neurological diseases using human induced pluripotent stem cells. AB - With the general decline of pharmaceutical research productivity, there are concerns that many components of the drug discovery process need to be redesigned and optimized. For example, the human immortalized cell lines or animal primary cells commonly used in traditional drug screening may not faithfully recapitulate the pathological mechanisms of human diseases, leading to biases in assays, targets, or compounds that do not effectively address disease mechanisms. Recent advances in stem cell research, especially in the development of induced pluripotent stem cell (iPSC) technology, provide a new paradigm for drug screening by permitting the use of human cells with the same genetic makeup as the patients without the typical quantity constraints associated with patient primary cells. In this article, we will review the progress made to date on cellular disease models using human stem cells, with a focus on patient-specific iPSCs for neurological diseases. We will discuss the key challenges and the factors that associated with the success of using stem cell models for drug discovery through examples from monogenic diseases, diseases with various known genetic components, and complex diseases caused by a combination of genetic, environmental and other factors. PMID- 23685956 TI - P21-activated kinase 5 plays essential roles in the proliferation and tumorigenicity of human hepatocellular carcinoma. AB - AIM: To investigate the roles of P21-activated kinase 5 (PAK5) in proliferation and tumorigenicity of human hepatocellular carcinoma (HCC). METHODS: HCC and matched paraneoplastictis tissue samples were obtained from 30 patients. Human HCC cell lines SMMC7721, HepG2, Hep3B, SK-HEP-1, Huh-7, and liver cell line HL 7702 were examined. The expression of PAK5 gene was studied using real-time qPCR and Western blotting. Cell proliferation was quantified with the MTT assay. Cell cycle was analyzed with flow cytometry. The tumorigenicity of Lv-shRNA transfected HepG2 cells was evaluated in BALB/cA nude mice. RESULTS: The mRNA level of PAK5 was significantly higher in 25 out of 30 HCC samples compared to the matched paraneoplastic tissues. The HCC cell lines showed varying expression of PAK5 protein, and the highest level was found in the HepG2 cells. PAK5 gene silencing in HepG2 cells markedly reduced the cell proliferation and colony formation, and induced cell cycle arrest in the G1 phase. Furthermore, PAK5 gene silencing suppressed the tumor formation in nude mice, and significantly decreased the expression of HCC-related genes Cyclin D1 and beta-catenin. CONCLUSION: PAK5 may play essential roles in the initiation and progression of human HCC. Thus, it may be an effective therapeutic target or perhaps serve as a clinical diagnostic or prognostic marker in human HCC. PMID- 23685958 TI - News from the IAEH. Discussion on the role of national public health agencies in the implementation of ecohealth strategies for infectious disease prevention. PMID- 23685957 TI - Curcumin inhibits AP-2gamma-induced apoptosis in the human malignant testicular germ cells in vitro. AB - AIM: To investigate the effects of curcumin on proliferation and apoptosis in testicular cancer cells in vitro and to investigate its molecular mechanisms of action. METHODS: NTera-2 human malignant testicular germ cell line and F9 mouse teratocarcinoma stem cell line were used. The anti-proliferative effect was examined using MTT and colony formation assays. Hoechst 33258 staining, TUNEL and Annexin V-FITC/PI staining assays were used to analyze cell apoptosis. Protein expression was examined with Western blot analysis and immunocytochemical staining. RESULTS: Curcumin (5, 10 and 15 MUmol/L) inhibited the viability of NTera-2 cells in dose- and time-dependent manners. Curcumin significantly inhibited the colony formation in both NTera-2 and F9 cells. Curcumin dose dependently induced apoptosis of NTera-2 cells by reducing FasL expression and Bcl-2-to-Bax ratio, and activating caspase-9, -8 and -3. Furthermore, curcumin dose-dependently reduced the expression of AP transcription factor AP-2gamma in NTera-2 cells, whereas the pretreatment with the proteasome inhibitor MG132 blocked both the curcumin-induced reduction of AP-2gamma and antiproliferative effect. Curcumin inhibited ErbB2 expression, and decreased the phosphorylation of Akt and ERK in NTera-2 cells. CONCLUSION: Curcumin induces apoptosis and inhibits proliferation in NTera-2 cells via the inhibition of AP-2gamma-mediated downstream cell survival signaling pathways. PMID- 23685960 TI - Determination of cocaine and methadone in urine samples by thin-film solid-phase microextraction and direct analysis in real time (DART) coupled with tandem mass spectrometry. AB - The use of thin-film solid-phase microextraction (SPME) as the sampling preparation step before direct analysis in real time (DART) was evaluated for the determination of two prohibited doping substances, cocaine and methadone, in urine samples. Results showed that thin-film SPME improves the detectability of these compounds: signal-to-blank ratios of 5 (cocaine) and 13 (methadone) were obtained in the analysis of 0.5 ng/ml in human urine. Thin-film SPME also provides efficient sample cleanup, avoiding contamination of the ion source by salt residues from the urine samples. Extraction time was established in 10 min, thus providing relatively short analysis time and high throughput when combined with a 96-well shaker and coupled with DART technique. PMID- 23685961 TI - A robust sensor platform for label-free detection of anti-Salmonella antibodies using undiluted animal sera. AB - We present a portable and easy-to-use biosensor platform, allowing for label-free detection of diagnostic markers in undiluted animal serum. Exemplarily, this is shown for the detection of anti-Salmonella antibodies. 1-lambda-Reflectometry was used as detection method, making the new biosensor platform portable, cheap, and robust. As recognition elements, lipopolysaccharides (LPSs) from Salmonella typhimurium bacteria were immobilized as sensitive layer on the transducer to carry out serological tests via a direct assay format. For this purpose, a new surface preparation protocol has been worked out allowing for immobilization of the LPS via hydrophobic interactions. It has been shown that results obtained by 1-lambda-Reflectometry are equivalent to those obtained by the non-portable Reflectometric Interference Spectroscopy setup. The new sensor platform was calibrated in both matrices, buffer and undiluted serum. Good sensitivity, selectivity and intra chip reproducibility have been observed. Furthermore, inter chip reproducibility was examined and recovery rates were found to be between 99 and 117% in undiluted serum. PMID- 23685962 TI - High mass accuracy and high mass resolving power FT-ICR secondary ion mass spectrometry for biological tissue imaging. AB - Biological tissue imaging by secondary ion mass spectrometry has seen rapid development with the commercial availability of polyatomic primary ion sources. Endogenous lipids and other small bio-molecules can now be routinely mapped on the sub-micrometer scale. Such experiments are typically performed on time-of flight mass spectrometers for high sensitivity and high repetition rate imaging. However, such mass analyzers lack the mass resolving power to ensure separation of isobaric ions and the mass accuracy for elemental formula assignment based on exact mass measurement. We have recently reported a secondary ion mass spectrometer with the combination of a C60 primary ion gun with a Fourier transform ion cyclotron resonance mass spectrometer (FT-ICR MS) for high mass resolving power, high mass measurement accuracy, and tandem mass spectrometry capabilities. In this work, high specificity and high sensitivity secondary ion FT-ICR MS was applied to chemical imaging of biological tissue. An entire rat brain tissue was measured with 150 MUm spatial resolution (75 MUm primary ion spot size) with mass resolving power (m/Deltam(50%)) of 67,500 (at m/z 750) and root-mean-square measurement accuracy less than two parts-per-million for intact phospholipids, small molecules and fragments. For the first time, ultra-high mass resolving power SIMS has been demonstrated, with m/Deltam(50%) > 3,000,000. Higher spatial resolution capabilities of the platform were tested at a spatial resolution of 20 MUm. The results represent order of magnitude improvements in mass resolving power and mass measurement accuracy for SIMS imaging and the promise of the platform for ultra-high mass resolving power and high spatial resolution imaging. PMID- 23685963 TI - tyrB-2 and phhC genes of Pseudomonas putida encode aromatic amino acid aminotransferase isozymes: evidence at the protein level. AB - Two Pseudomonas putida aminotransferases (ArAT I and ArAT II) that exhibit activity toward L-tryptophan were purified 104- and 395-fold using a six-stage purification procedure involving ammonium sulfate fractionation and chromatographic separation on phenyl-Sepharose, Sephadex G-100 superfine, DEAE cellulose and Protein-Pack Q8 HR columns. Mass spectrometry analysis resulted in the identification of 27 and 20 % of the total ArAT I and ArAT II amino acid sequences. In addition, N-terminal sequence fragments of ArAT I and ArAT II were determined using the Edman degradation method. Based on the analyses performed, the studied proteins were identified as products of the tyrB-2 and phhC genes, and the presence of these genes in the investigated bacterial strain was confirmed using molecular biology methods. Extensive analysis of the substrate specificities of ArAT I and ArAT II revealed that both enzymes most efficiently catalyzed reactions involving aromatic amino acids and 2-oxoacids followed by dicarboxylic compounds. The best substrates for ArAT I and ArAT II were L phenylalanine and phenylpyruvate. Based on these results, the studied proteins were classified as aromatic amino acid aminotransferase isozymes. PMID- 23685964 TI - Magnetically actuated artificial cilia for optimum mixing performance in microfluidics. AB - Contemporary lab-chip devices require efficient, high-performance mixing capability. A series of artificial cilia with embedded magnetic particles was fabricated to achieve precise flow manipulation through magnetically driven control. These fabricated structures were actuated in a homogeneous magnetic field generated by a built-in magnetic coil system for various beating cycles inside a microchannel. Three representative trajectories, namely, circular motion, back-and-forth oscillation, and a figure-of-eight pattern, of artificial cilia were designed and generated to mimic the motion of actual cilia. Homogeneous mixing of two highly viscous (>25 centipoise) dyed solutions by using the figure-of-eight trajectory achieved a mixing efficiency of approximately 86%. The underlying relationship between ciliated structures and the induced flow fields was further elucidated by performing a hydrodynamic analysis with micro particle image velocimetry. In addition, a numerical modeling method which used a fluid structure interaction module was applied to provide quantitative 3D illustrations of induced flow patterns, including vortical structures and vortex core locations. The results reveal that both the magnitude and distribution of induced vortices primarily affect the mixing performance of two viscous flow streams. By using magnetically controlled artificial cilia along with the presented analytical paradigms, a new active flow mixing strategy was suggested to efficiently transport/agitate flows for microfluidics and biomedical applications. PMID- 23685966 TI - Physical performance in relation to body composition and bone mineral density in healthy, overweight, and obese postmenopausal women. AB - BACKGROUND AND PURPOSE: Diminished physical performance can be detrimental among the older adults, causing falls and subsequent fractures, loss of independence, and increased morbidity and mortality rates. Therefore, it is important to maintain functional ability from the early onset of aging. The purpose of this study was to investigate the relationship between physical performance measures and body composition (bone, fat, and lean mass) in healthy, overweight and obese, early postmenopausal white women. METHODS: A total of 97 participants aged 56.0 (4.4) years (mean (SD)) with body mass index of 31.0 (4.6) kg/m(2) were included. Weight and height were recorded and 3 days of dietary records and physical activity were collected. Dual-energy x-ray absorptiometry measurements for body composition and bone mineral density were performed. Fasting blood samples were used for serum 25-hydroxy vitamin D (25OHD) analysis. Measures of physical performance included handgrip strength, 8-meter walking speed, one-leg-stance time, 8-foot Timed Get-Up-and-Go Test, and chair sit-to-stand test. RESULTS: Results showed that higher lean mass was related to better physical performance on items assessing body strength, including handgrip (r ranged from 0.22 to 0.25, P < .05) while higher body fat was related to the poorer physical performance in each of the assessed measures. Bone mineral density of the forearm was positively related to the handgrip strength (r = 0.207, P < .05). In regression analyses (controlled for age, weight, height, serum 25OHD status, calcium intake, physical activity, and smoking), fat mass of the lower extremities was inversely related to walking speed, one-leg-stance time, and Get-Up-and-Go measures, all crucial for mobility (r(2) = 0.13-0.23, P < .05). CONCLUSIONS: Overall, higher fat and lower lean mass was related to poorer physical performance, while forearm bone mineral density was related to the handgrip strength only. Further investigation may be beneficial for a better understanding of how body composition may prevent decline in physical performance among overweight/obese, mid-age, and older women. PMID- 23685965 TI - Neuromonitoring of the laryngeal nerves in thyroid surgery: a critical appraisal of the literature. AB - One of the most significant complication of thyroid surgery is injury of the recurrent laryngeal nerve. Injury of the external branch of the superior laryngeal nerve is a less obvious but occasionally significant problem. Recently, neuromonitoring during thyroidectomy has received considerable attention because of literature encouraging its use, but there is no consensus about its advantages and utility. A critical assessment of the literature on neuromonitoring was conducted in order to define its effectiveness, safety, cost-effectiveness and medical-legal impact. Available data does not show results superior to those obtained by traditional anatomical methods of nerve identification during thyroid surgery. Data about cost-effectiveness is scarce. The literature shows inconsistencies in methodology, patient selection and randomization in various published studies which may confound the conclusions of individual investigations. The current recommendation for use in "high risk" patients should be assessed because definition heterogeneity makes identification of these patients difficult. As routine use of neuromonitoring varies according to geography, its use should not be considered to be the standard of care. PMID- 23685967 TI - Activation of systemic, but not local, renin-angiotensin system is associated with upregulation of TNF-alpha during prolonged fasting in northern elephant seal pups. AB - Northern elephant seal pups naturally endure a 2-3 month post-weaning fast that is associated with activation of systemic renin-angiotensin system (RAS), a decrease in plasma adiponectin (Acrp30), and insulin resistance (IR)-like conditions. Angiotensin II (Ang II) and tumor necrosis factor-alpha (TNF-alpha) are potential causal factors of IR, while Acrp30 may improve insulin signaling. However, the effects of fasting-induced activation of RAS on IR-like conditions in seals are not well described. To assess the effects of prolonged food deprivation on systemic and local RAS, and their potential contribution to TNF alpha as they relate to an IR condition, the mRNA expressions of adipose and muscle RAS components and immuno-relevant molecules were measured along with plasma RAS components. Mean plasma renin activity and Ang II concentrations increased by 89 and 1658%, respectively, while plasma angiotensinogen (AGT) decreased by 49% over the fast, indicative of systemic RAS activation. Prolonged fasting was associated with decreases in adipose and muscle AGT mRNA expressions of 69 and 68%, respectively, corresponding with decreases in tissue protein content, suggesting suppression of local AGT production. Muscle TNF-alpha mRNA and protein increased by 239 and 314%, whereas those of adipose Acrp30 decreased by 32 and 98%, respectively. Collectively, this study suggests that prolonged fasting activates a systemic RAS, which contributes to an increase in muscle TNF alpha and suppression of adipose Acrp30. This targeted and tissue-specific regulation of TNF-alpha and Acrp30 is likely coordinated to synergistically contribute to the development of an IR-like condition, independent of local RAS activity. These data enhance our understanding of the adaptive mechanisms evolved by elephant seals to tolerate potentially detrimental conditions. PMID- 23685968 TI - The gait dynamics of the modern broiler chicken: a cautionary tale of selective breeding. AB - One of the most extraordinary results of selective breeding is the modern broiler chicken, whose phenotypic attributes reflect its genetic success. Unfortunately, leg health issues and poor walking ability are prevalent in the broiler population, with the exact aetiopathogenesis unknown. Here we present a biomechanical analysis of the gait dynamics of the modern broiler and its two pureline commercial broiler breeder lines (A and B) in order to clarify how changes in basic morphology are associated with the way these chickens walk. We collected force plate and kinematic data from 25 chickens (market age), over a range of walking speeds, to quantify the three-dimensional dynamics of the centre of mass (CoM) and determine how these birds modulate the force and mechanical work of locomotion. Common features of their gait include extremely slow walking speeds, a wide base of support and large lateral motions of the CoM, which primarily reflect changes to cope with their apparent instability and large body mass. These features allowed the chickens to keep their peak vertical forces low, but resulted in high mediolateral forces, which exceeded fore-aft forces. Gait differences directly related to morphological characteristics also exist. This was particularly evident in Pureline B birds, which have a more crouched limb posture. Mechanical costs of transport were still similar across all lines and were not exceptional when compared with more wild-type ground-running birds. Broiler chickens seem to have an awkward gait, but some aspects of their dynamics show rather surprising similarities to other avian bipeds. PMID- 23685970 TI - Nitric oxide and coral bleaching: is peroxynitrite generation required for symbiosis collapse? AB - The temperature-induced collapse ('bleaching') of the coral-dinoflagellate symbiosis is hypothesised to result from symbiont oxidative stress and a subsequent host innate immune-like response. This includes the production of nitric oxide (NO), which is involved in numerous microbial symbioses. Much of NO's cytotoxicity has been attributed to its conversion, in the presence of superoxide (O2(-)), to highly reactive peroxynitrite (ONOO(-)). However, ONOO(-) generation has yet to be observed in either a lower invertebrate or an intracellular mutualism. Using confocal laser scanning microscopy with the fluorescent ONOO(-) indicator aminophenyl fluorescein (APF), we observed strong evidence that ONOO(-) is generated in symbiotic Aiptasia pulchella under conditions known to induce thermal bleaching. However, a role for ONOO(-) in bleaching remains unclear as treatment with a peroxynitrite scavenger had no significant effect on thermal bleaching. Therefore, while ONOO(-) may have a potential for cytotoxicity, in vivo levels of the compound may be insufficient to affect bleaching. PMID- 23685969 TI - Limited effects of exogenous glucose during severe hypoxia and a lack of hypoxia stimulated glucose uptake in isolated rainbow trout cardiac muscle. AB - We examined whether exogenous glucose affects contractile performance of electrically paced ventricle strips from rainbow trout under conditions known to alter cardiomyocyte performance, ion regulation and energy demands. Physiological levels of d-glucose did not influence twitch force development for aerobic preparations (1) paced at 0.5 or 1.1 Hz, (2) at 15 or 23 degrees C, (3) receiving adrenergic stimulation or (4) during reoxygenation with or without adrenaline after severe hypoxia. Contractile responses to ryanodine, an inhibitor of Ca(2+) release from the sarcoplasmic reticulum, were also not affected by exogenous glucose. However, glucose did attenuate the fall in twitch force during severe hypoxia. Glucose uptake was assayed in non-contracting ventricle strips using 2 [(3)H] deoxy-d-glucose (2-DG) under aerobic and hypoxic conditions, at different incubation temperatures and with different inhibitors. Based upon a lack of saturation of 2-DG uptake and incomplete inhibition of uptake by cytochalasin B and d-glucose, 2-DG uptake was mediated by a combination of facilitated transport and simple diffusion. Hypoxia stimulated lactate efflux sixfold to sevenfold with glucose present, but did not increase 2-DG uptake or reduce lactate efflux in the presence of cytochalasin B. Increasing temperature (14 to 24 degrees C) also did not increase 2-DG uptake, but decreasing temperature (14 to 4 degrees C) reduced 2-DG uptake by 45%. In conclusion, exogenous glucose improves mechanical performance under hypoxia but not under any of the aerobic conditions applied. The extracellular concentration of glucose and cold temperature appear to determine and limit cardiomyocyte glucose uptake, respectively, and together may help define a metabolic strategy that relies predominantly on intracellular energy stores. PMID- 23685971 TI - Incline and peg spacing have interactive effects on the arboreal locomotor performance and kinematics of brown tree snakes, Boiga irregularis. AB - Many animals move using lateral undulations, but snakes are noteworthy for using this type of locomotion in an unusual diversity of environments, including trees in which both the spacing and orientation of branches vary considerably. Despite branches providing discrete locations for snakes to generate propulsive forces during lateral undulation, the consequences of branch spacing for the locomotion of snakes are poorly understood. Hence, we determined maximal speeds and kinematics of an arboreal snake (Boiga irregularis) crawling on horizontal and vertical cylinders with pegs that simulated different spacing between secondary branches. Peg spacing, perch orientation and their two-way interaction term had widespread, significant effects on both performance and kinematics. For the horizontal surfaces, maximal locomotor speed occurred with intermediate peg spacing, and it was nearly twice as fast as for both the smallest and largest peg spacings. By contrast, the locomotor speed of snakes on the vertical surfaces was unaffected by peg spacing, and was uniformly slower than that for the horizontal surfaces. For both perch orientations, the number of pegs touched by the snake decreased as peg spacing increased, and while touching only one peg the snakes crawled with apparent ease and steady speed. The snakes crawled vertically with only one peg as quickly as they did using 2-10 pegs. Pegs on a horizontal cylinder are probably important both for propulsion of snakes and prevention of long-axis rolling, whereas pegs protruding from vertical cylinders and those protruding from horizontal planar surfaces are probably used almost exclusively for propulsion. PMID- 23685972 TI - Repeatability of escape response performance in the queen scallop, Aequipecten opercularis. AB - In order for natural selection to operate, physiological and behavioural traits must exhibit both inter-individual variability and intra-individual consistency (i.e. repeatability) in performance. In this study, we describe individual variation and temporal repeatability in the escape responses of the queen scallop, Aequipecten opercularis, and determine whether individuals exhibited consistently high or low rankings in different aspects of the escape response. Five measures of individual performance were recorded on four occasions (days 0, 2, 7 and 28), providing proxies for sensory acuity (response latency), immediate and sustained swimming performance (burst and average clap rates), and swimming endurance (total number of claps and total time spent clapping). All components of the escape response exhibited significant inter-individual variability (all P<0.0001). Escape response latency, burst clap rate, total number of claps and total duration spent clapping maintained significant repeatability over 28 days (all P<0.016). Average clap rate was repeatable in the short term (2 days, P<0.0001) but repeatability declined by 28 days (P=0.097). Concordance analysis indicated that individuals maintained the same performance rankings over time for each component of the escape response (all P<0.001). In addition, some individuals ranked as consistently high or low performers across response latency, burst and average clap rate, and total number of claps. An individual's ability to evade predators through the provision of an escape response of an appropriate magnitude, subject to physiological, behavioural and organismal constraints, will have clear fitness-related consequences. PMID- 23685974 TI - Physiological and metabolic consequences of viral infection in Drosophila melanogaster. AB - An extensively used model system for investigating anti-pathogen defence and innate immunity involves Drosophila C virus (DCV) and Drosophila melanogaster. While there has been a significant effort to understand infection consequences at molecular and genetic levels, an understanding of fundamental higher-level physiology of this system is lacking. Here, we investigate the metabolic rate, locomotory activity, dry mass and water content of adult male flies injected with DCV, measured over the 4 days prior to virus-induced mortality. DCV infection resulted in multiple pathologies, notably the depression of metabolic rate beginning 2 days post-infection as a response to physiological stress. Even in this depressed metabolic state, infected flies did not decrease their activity until 1 day prior to mortality, which further suggests that cellular processes and synthesis are disrupted because of viral infection. Growth rate was also reduced, indicating that energy partitioning is altered as infection progresses. Microbial infection in insects typically results in an increase in excretion; however, water appeared to be retained in DCV-infected flies. We hypothesise that this is due to a fluid intake-output imbalance due to disrupted transport signalling and a reduced rate of metabolic processing. Furthermore, infected flies had a reduced rate of respiration as a consequence of metabolic depression, which minimised water loss, and the excess mass as a result of water retention is concurrent with impaired locomotory ability. These findings contribute to developing a mechanistic understanding of how pathologies accumulate and lead to mortality in infected flies. PMID- 23685973 TI - Nitric oxide affects short-term olfactory memory in the antennal lobe of Manduca sexta. AB - Nitric oxide (NO) is thought to play an important neuromodulatory role in olfaction. We are using the hawkmoth Manduca sexta to investigate the function of NO signaling in the antennal lobe (AL; the primary olfactory network in invertebrates). We have found previously that NO is present at baseline levels, dramatically increases in response to odor stimulation, and alters the electrophysiology of AL neurons. It is unclear, however, how these effects contribute to common features of olfactory systems such as olfactory learning and memory, odor detection and odor discrimination. In this study, we used chemical detection and a behavioral approach to further examine the function of NO in the AL. We found that basal levels of NO fluctuate with the daily light cycle, being higher during the nocturnal active period. NO also appears to be necessary for short-term olfactory memory. NO does not appear to affect odor detection, odor discrimination between dissimilar odorants, or learning acquisition. These findings suggest a modulatory role for NO in the timing of olfactory-guided behaviors. PMID- 23685975 TI - Long-term fasting in the anadromous Arctic charr is associated with downregulation of metabolic enzyme activity and upregulation of leptin A1 and SOCS expression in the liver. AB - The life strategy of the anadromous Arctic charr (Salvelinus alpinus) includes several months of voluntary fasting during overwintering in freshwater, leading to emaciation prior to seawater migration in spring. In this study we compared changes in condition, substrate utilization and liver metabolism between captive anadromous charr subjected to food deprivation during late winter and spring, and conspecifics fed in excess. In March, nine out of the 10 sampled fed fish had not eaten, indicating that they were in a voluntary anorexic state. In June, the fed fish were eating and all had higher body mass, condition factor and adiposity than in March. In fasted fish there were only small decreases in body mass, condition factor and adiposity between March and May, but all these parameters decreased markedly from May to June. The fasted fish were depleted in fat and glycogen in June, had suppressed activity of hepatic enzymes involved in lipid metabolism (G6PDH and HOAD) and seemed to rely on protein-derived glucose as a major energy source. This was associated with upregulated liver gene expression of leptin A1, leptin A2, SOCS1, SOCS2 and SOCS3, and reduced IGF-I expression. In an in vitro study with liver slices it was shown that recombinant rainbow trout leptin stimulated SOCS1 and SOCS3 expression, but not SOCS2, IGF-I or genes of enzymes involved in lipid (G6PDH) and amino acid (AspAT) metabolism. It is concluded that liver leptin interacts with SOCS in a paracrine fashion to suppress lipolytic pathways and depress metabolism when fat stores are depleted. PMID- 23685976 TI - Chemical structure of odorants and perceptual similarity in ants. AB - Animals are often immersed in a chemical world consisting of mixtures of many compounds rather than of single substances, and they constantly face the challenge of extracting relevant information out of the chemical landscape. To this purpose, the ability to discriminate among different stimuli with different valence is essential, but it is also important to be able to generalise, i.e. to treat different but similar stimuli as equivalent, as natural variation does not necessarily affect stimulus valence. Animals can thus extract regularities in their environment and make predictions, for instance about distribution of food resources. We studied perceptual similarity of different plant odours by conditioning individual carpenter ants to one odour, and subsequently testing their response to another, structurally different odour. We found that asymmetry in generalisation, where ants generalise from odour A to B, but not from B to A, is dependent on both chain length and functional group. By conditioning ants to a binary mixture, and testing their reaction to the individual components of the mixture, we show that overshadowing, where parts of a mixture are learned better than others, is rare. Additionally, generalisation is dependent not only on the structural similarity of odorants, but also on their functional value, which might play a crucial role. Our results provide insight into how ants make sense of the complex chemical world around them, for example in a foraging context, and provide a basis with which to investigate the neural mechanisms behind perceptual similarity. PMID- 23685977 TI - Metabolic energy sensors (AMPK and SIRT1), protein carbonylation and cardiac failure as biomarkers of thermal stress in an intertidal limpet: linking energetic allocation with environmental temperature during aerial emersion. AB - The effects of heat stress on organisms are manifested at the levels of organ function, metabolic activity, protein stability and gene expression. Here, we examined effects of high temperature on the intertidal limpet Cellana toreuma to determine how the temperatures at which (1) organ failure (cardiac function), (2) irreversible protein damage (carbonylation) and (3) expression of genes encoding proteins involved in molecular chaperoning (hsp70 and hsp90) and metabolic regulation (ampk and sirt1) occur compare with field temperatures, which commonly exceed 30 degrees C and can reach 46 degrees C. Heart failure, indexed by the Arrhenius break temperature, occurred at 34.3 degrees C. Protein carbonylation rose significantly at 38 degrees C. Genes for heat shock proteins HSP70 (hsp70) and HSP90 (hsp90), for two subunits of AMP-activated protein kinase (AMPK) (ampkalpha and ampkbeta) and for histone/protein deacetylase SIRT1 (sirt1) all showed increased expression at 30 degrees C. Temperatures of maximal expression differed among genes, as did temperatures at which upregulation ceased. Expression patterns for ampk and sirt1 indicate that heat stress influenced cellular energy homeostasis; above ~30 degrees C, upregulation of ATP-generating pathways is suggested by elevated expression of genes for ampk; an altered balance between reliance on carbohydrate and lipid fuels is indicated by changes in expression of sirt1. These results show that C. toreuma commonly experiences temperatures that induce expression of genes associated with the stress response (hsp70 and hsp90) and regulation of energy metabolism (ampk and sirt1). At high temperatures, there is likely to be a shift away from anabolic processes such as growth to catabolic processes, to provide energy for coping with stress-induced damage, notably to proteins. PMID- 23685978 TI - Rough eyes of the Northeast-Asian wood white, Leptidea amurensis. AB - The northeast-Asian wood white, Leptidea amurensis (Lepidoptera, Pieridae), belongs to the Dismorphiinae, a subfamily of the family Pieridae. We studied the structure of the compound eye in this species through a combination of anatomy, molecular biology and intracellular electrophysiology, with a particular focus on the evolution of butterfly eyes. We found that their eyes consist of three types of ommatidia, with a basic set of one short-, one middle- and one long-wavelength absorbing visual pigment. The spectral sensitivities of the photoreceptors are rather simple, and peak in the ultraviolet, blue and green wavelength regions. The ommatidia have neither perirhabdomal nor fluorescent pigments, which modulate photoreceptor spectral sensitivities in a number of other butterfly species. These features are primitive, but the eyes of Leptidea exhibit another unique feature: the rough appearance of the ventral two-thirds of the eye. The roughness is due to the irregular distribution of facets of two distinct sizes. As this phenomenon exists only in males, it may represent a newly evolved sex-related feature. PMID- 23685979 TI - The San Francisco declaration on research assessment. PMID- 23685980 TI - Cultural influence on crowding norms in outdoor recreation: a comparative analysis of visitors to national parks in Turkey and the United States. AB - Formulation of standards of quality in parks and outdoor recreation can be guided by normative theory and related empirical methods. We apply this approach to measure the acceptability of a range of use levels in national parks in Turkey and the United States. Using statistical methods for comparing norm curves across contexts, we find significant differences among Americans, British, and Turkish respondents. In particular, American and British respondents were substantially less tolerant of seeing other visitors and demonstrated higher norm intensity than Turkish respondents. We discuss the role of culture in explaining these findings, paying particular attention to Turkey as a traditional "contact culture" and the conventional emphasis on solitude and escape in American environmental history and policy. We conclude with a number of recommendations to stimulate more research on the relationship between culture and outdoor recreation. PMID- 23685981 TI - Monitoring the effects of chelating agents and electrical fields on active forms of Pb and Zn in contaminated soil. AB - The application of electrical fields and chelating agents is an innovative hybrid technology used for the decontamination of soil polluted by heavy metals. The effects of four center-oriented electrical fields and chelating agents on active fractions of lead and zinc were investigated in this pot experiment. Ethylenediaminetetraacetic acid (EDTA) as a synthetic chelator and cow manure extract (CME) and poultry manure extract (PME) as natural chelators were applied to the pots (2 g kg(-1)) 30 days after the first irrigation. Two weeks later, four center-oriented electrical fields were applied in each pot (in three levels of 0, 10, and 30 V) for 1 h each day for 14 days. The soil near the cathode and anodes was collected and analyzed as cathodic and anodic soil, respectively. Results indicated that the soluble-exchangeable fraction of lead and zinc were decreased in the cathodic soil, while the carbonate-bound fractions were increased. In the anodic soil, however, the opposite result was observed. EDTA enhanced the soluble-exchangeable form of the metals in both anodic and cathodic soils. Furthermore, the amounts of carbonate-bound heavy metals were increased by the application of CME in both soils. The organic-bound fraction of the metals was increased by the application of natural chelators, while electrical fields had no significant impacts on this fraction. PMID- 23685983 TI - Controlling surface properties of polyelectrolyte multilayers by assembly pH. AB - The control of surface properties such as the morphology, roughness, stiffness, and wettability of polyelectrolyte multilayers was carried out using poly(diallyldimethylammonium chloride) (PDADMAC) and poly(4-styrenesulfonic acid co-maleic acid, 1 : 1 SS : MA) sodium salt (PSSMA 1 : 1) as the building blocks via adjusting the assembly pH value. We found that the surface roughness of the multilayers increased with increasing assembly pH value, and that the morphology was quite different at various assembly pH values when PSSMA was assembled as the final layer. However, the surface roughness and morphology of the multilayers (PDADMAC as the final layer) showed no apparent change at various assembly pH values. Interestingly, the stiffness of the PSSMA/PDADMAC multilayers could be tuned. Nanoindentation measurements by SFM showed that the hardness of the multilayers was very different at various pH values when PSSMA was the outermost layer. Conversely, the hardness of the multilayers remained unchanged regardless of the pH when PDADMAC was the outermost layer. The water contact angle hysteresis (the difference between the advancing and receding contact angles) of the multilayers was largely affected by both surface roughness and surface hydrophilic groups which could also be tuned by assembly pH. PMID- 23685982 TI - Remote sensing imageries for land cover and water quality dynamics on the west coast of Korea. AB - As human activities influence land cover changes, the environment on human life such as water quality, has been impacted. In particular, huge constructions or reclamation projects are responsible for dramatic land cover changes. The Saemangeum area in South Korea has been one of the largest reclamation projects to progress nearly in two decades. In this study, Landsat-5 Thematic Mapper and Landsat-7 Enhanced Thematic Mapper Plus images were used to classify land cover types in the Saemangeum area. A change detection method was utilized to determine the impacts of the reclamation project. While wetland, grassland, and urban areas were increased, forest, water, and agricultural areas were decreased during the reclamation progress. Water quality analysis related to the land cover changes was conducted to determine the influence of reclamation construction on the environment. Chemical oxygen demand and suspended sediment variability were significantly impacted by the sea current changes after the dyke construction. On the contrary, water temperature and dissolved oxygen were affected by the seasonal influences rather than the reclamation construction. Total nitrogen and total phosphorus were influenced by the fertilizers and pesticides as a result of agricultural activity. The trends of suspended sediment from Landsat images were similar with those from the ground observation sites and also impacted by the dyke construction. PMID- 23685985 TI - A transparent electrode based on a metal nanotrough network. AB - Transparent conducting electrodes are essential components for numerous flexible optoelectronic devices, including touch screens and interactive electronics. Thin films of indium tin oxide-the prototypical transparent electrode material demonstrate excellent electronic performances, but film brittleness, low infrared transmittance and low abundance limit suitability for certain industrial applications. Alternatives to indium tin oxide have recently been reported and include conducting polymers, carbon nanotubes and graphene. However, although flexibility is greatly improved, the optoelectronic performance of these carbon based materials is limited by low conductivity. Other examples include metal nanowire-based electrodes, which can achieve sheet resistances of less than 10Omega ?(-1) at 90% transmission because of the high conductivity of the metals. To achieve these performances, however, metal nanowires must be defect-free, have conductivities close to their values in bulk, be as long as possible to minimize the number of wire-to-wire junctions, and exhibit small junction resistance. Here, we present a facile fabrication process that allows us to satisfy all these requirements and fabricate a new kind of transparent conducting electrode that exhibits both superior optoelectronic performances (sheet resistance of ~2Omega ?(-1) at 90% transmission) and remarkable mechanical flexibility under both stretching and bending stresses. The electrode is composed of a free-standing metallic nanotrough network and is produced with a process involving electrospinning and metal deposition. We demonstrate the practical suitability of our transparent conducting electrode by fabricating a flexible touch-screen device and a transparent conducting tape. PMID- 23685986 TI - Wheat IgE profiling and wheat IgE levels in bakers with allergic occupational phenotypes. AB - OBJECTIVES: To characterise occupational wheat allergic phenotypes (rhino conjunctivitis, asthma and dermatitis) and immunoglobulin (IgE) sensitisation to particular wheat allergens in bakers. METHODS: We conducted clinical and immunological evaluations of 81 consecutive bakers reporting occupational symptoms using commercial tests (skin prick test (SPT), specific IgE, ISAC microarray) and six additional dot-blotted wheat allergens (Tri a 39, Tri a Trx, Tri a GST, Tri a 32, Tri a 12, Tri a DH). RESULTS: Wheat SPT resulted positive in 29 bakers and was associated with work-related asthma (p<0.01). Wheat IgE was detected in 51 workers and was associated with work-related asthma (p<0.01) and rhino-conjunctivitis (p<0.05). ISAC Tri a 30 was positive in three workers and was associated with work-related dermatitis (p<0.05). Wheat dot-blotted allergens were positive in 22 bakers. Tri a 32 and Tri a GST were positive in 13 and three bakers, respectively, and both were associated with work-related dermatitis (p<0.05). This association increased (p<0.01) when Tri a 32, Tri a GST and Tri a 30 were analysed together (p<0.01). Wheat IgE levels were associated with work related dermatitis (p<0.01). CONCLUSIONS: Wheat IgE levels and wheat microarrayed allergens may be associated with some occupational allergic phenotypes. The extension of the panel of wheat allergens may be promising for discriminating the clinical manifestations of baker's allergy. PMID- 23685987 TI - STEMI of the anterior wall associated with Sneddon's syndrome. PMID- 23685988 TI - The J wave during ST-segment elevation myocardial infarction and its implications. PMID- 23685989 TI - The new crisis of confidence in psychiatric diagnosis. PMID- 23685990 TI - Surfactant protein A binds TGF-beta1 with high affinity and stimulates the TGF beta pathway. AB - We were able to demonstrate reversible, specific and high-affinity binding of radioactively-labelled TGF-beta1 ((125)I-TGF-beta1) to immobilized surfactant protein A (SP-A), with an apparent dissociation constant of 53 picomolar at ~21. Addition of a 200-fold molar excess of the latency associated peptide (LAP) prevented and dissociated the binding of (125)I-TGF-beta1 to SP-A, whereas latent TGF-beta1 had no effect. Using a bioassay for TGF-beta1 activity--a luciferase reporter assay--we were able to show that SP-A in the presence of TGF-beta1 stimulated the TGF-beta1 pathway, whereas SP-A alone had no effect. Studies with structural analogues of the distinct SP-A tail domain and head domain indicated that stimulatory activity of SP-A resided in the head domain. No activation of latent TGF-beta1 by SP-A was observed. In addition, we observed that SP-A inhibited TGF-beta1 inactivation by LAP. These results indicate that SP-A may have a regulatory role in the TGF-beta1-mediated processes in the lung. PMID- 23685991 TI - Glycogen synthase kinase 3 negatively regulates IFN regulatory factor 3 transactivation through phosphorylation at its linker region. AB - Upon virus infection, the host innate immune response is initiated through the activation of IFN regulatory factor 3 (IRF3) and NF-kappaB signaling pathways to induce IFN production. Previously, we demonstrated EBV BGLF4 kinase suppresses IRF3 function in a kinase activity-dependent manner. The replacement of Ser123, Ser173 and Thr180 into alanines at the proline-rich linker region of IRF3 abolishes BGLF4-mediated suppression. In this study, we show that BGLF4 phosphorylates glutathione-S-transferase (GST)-IRF3(110-202), but not GST IRF3(110-202)3A mutant (S123/S173/T180A) in vitro. Compared with activation mimicking mutant IRF3(5D), the phosphorylation-defective IRF3(5D)3A shows a higher transactivation activity in reporter assays, whereas the phosphorylation mimicking IRF3(5D)2D1E, with Ser123 and Ser173 mutated to aspartate and Thr180 to glutamate, has a much lower activity. To explore whether similar cellular regulation also exists in the absence of virus infection, candidate cellular kinases were predicted and the transactivation activity of IRF3 was examined with various kinase inhibitors. Glycogen synthase kinase 3 (GSK3) inhibitor LiCl specifically enhanced both IRF3(5D) and wild type IRF3 activity, even without stimulation. Expression of constitutive active GSK3beta(S9A) represses LiCl mediated enhancement of IRF3 transactivation activity. In vitro, both GSK3alpha and GSK3beta phosphorylate IRF3 at the linker region. Collectively, data here suggest GSK3 phosphorylates IRF3 linker region in a way similar to viral kinase BGLF4. PMID- 23685992 TI - [Topical pain therapy in oral mucositis: a systematic review]. AB - BACKGROUND: The pain provoked by mucositis is often described as the most excruciating symptom of cancer treatment. It often causes reduced ingestion, malnutrition, and sometimes postponement or withdrawal of the therapy. For health care providers, adequate pain treatment is a major challenge. The aim of this article is to present an overview of studies on the topical treatment of mucositis pain. METHODS: A systematic search was performed in PubMed with the keywords "mucositis" "pain" and "topical" or "local". In addition, reference lists and relevant websites were scanned for appropriate literature. RESULTS: A total of 47 articles were included. There is only scarce evidence for the topical treatment of mucositis pain. The most convincing studies tested opioids, corticoids and benzydamine. For the other substances, too few studies were performed, the results were contradictory, or the study quality was low. CONCLUSION: Based on the information gathered in this systematic search of the literature, topical treatment of mucositis pain today is based on empiricism and not on scientific evidence. PMID- 23685993 TI - [Psychological therapy of migraine: systematic review]. AB - This review summarizes the various forms of behavioral treatment of migraine which could demonstrate empirical efficacy. The main unimodal kinds of treatment are thermal and electromyography (EMG) biofeedback training and progressive muscle relaxation. The various relaxation techniques do not differ in their efficacy in treating migraine. On average a reduction in migraine frequency of 35 45 % is achieved. The mean effect sizes (ES) of various biofeedback techniques are between 0.4 and 0.6. Cognitive-behavioral treatment is applied as a multimodal treatment and on average achieves an improvement in migraine activity by 39 % and an ES of 0.54. All behavioral procedures can be used in combination or as an alternative to drug prophylaxis with comparable success. A combination of pharmacological and behavioral treatment can achieve additional success. There is strong evidence for the clinically significant efficacy of all forms of behavioral treatment in childhood and adolescence. There are no signs of differential indications. PMID- 23685994 TI - [Mental disorders in patients with fibromyalgia syndrome: screening in centres of different medical specialties]. AB - BACKGROUND: Systematic reviews have reported a wide range of prevalence rates for depressive, anxiety and posttraumatic stress disorders (PTSD) in patients with fibromyalgia syndrome (FMS) which have been partially explained by setting differences. No data are currently available on the prevalence of potential mental disorders depending on the medical specialty in Germany. MATERIAL AND METHODS: All consecutive FMS patients of 8 study centres (3 rheumatology/orthopaedic surgery, 3 psychosomatic/pain medicine, 2 physical/integrative medicine) were assessed from February 1 to July 31, 2012 with standardised questionnaires. Patients with FMS diagnosed by a study physician were included. Non-German speaking and mentally retarded patients were excluded. The German version of the Patient Health Questionnaire 4 was used to screen for potential depressive and anxiety disorders. Severe life events were assessed by the trauma list of the Munich Composite International Diagnostic Interview and symptom criteria of PTSD of the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) using the Posttraumatic Diagnostic Scale. RESULTS: Of 538 patients, 396 patients (93.9 % women, mean age 52.3 years, mean duration since chronic widespread pain 12.8 years, mean duration since FMS diagnosis 4.5 years) were analysed. In all, 65.7 % of patients met the criteria of a potential depressive disorder, 67.9 % of a potential anxiety disorder and 45.5 % of a potential PTSD. Potential depressive disorders were more frequent in the psychosomatic/pain medicine setting than in the rheumatology setting. CONCLUSION: Potential mental disorders were frequent in FMS patients regardless of the medical specialty. All FMS patients of all types of clinical settings should be screened for mental disorders. PMID- 23685997 TI - Immunohistochemical and molecular pathology of ocular uveal melanocytoma: evidence for somatic GNAQ mutations. AB - OBJECTIVE: Intraocular melanocytoma is a rare naevus variant that can be located at the optic disc or within the uvea, and belongs to the group of non-epithelial associated melanocytic lesions. We wanted to gain an understanding of the role of GNAQ, GNA11 and BRAF V600E in the pathogenesis of uveal melanocytoma and in cases of transformation to uveal melanoma and also to perform a differential immunohistochemical study comparing melanocytoma with uveal melanoma. METHODS AND RESULTS: Two patients were identified with melanocytoma, one of which had transformed to melanoma. In the latter case, the melanocytoma exhibited an immunophenotype that featured nuclear p27 and no HMB45 staining, with very low Cyclin D1 expression compared with the melanoma that featured little nuclear but more cytoplasmic p27 positivity, much higher Cyclin D1 expression and HMB45 positivity. The melanocytomas were negative for CD68 allowing distinction from melanophages. Both melanocytomas and the melanoma harboured mutations in GNAQ, with no mutations of GNA11 or BRAF V600E. CONCLUSIONS: GNAQ mutations are present in uveal melanocytomas and in a case of transformation to melanoma, implicating GNAQ-dependent mitogen activation signals, in the pathogenesis of uveal melanocytoma. This assists in explaining why a proportion of uveal melanocytoma can transform to uveal melanoma, known to harbour high-frequency GNAQ mutations at exon 5, codon 209. PMID- 23685996 TI - Adipocytokines during pregnancy and postpartum in women with gestational diabetes and healthy controls. AB - BACKGROUND: This study aims to explore the changes in maternal serum adipocytokines during pregnancy and post partum in normal and complicated with gestational diabetes (GDM) pregnancies and to investigate the relationship between serum adipocytokines and some of major metabolic parameters. MATERIALS AND METHODS: 236 pregnant women (127 with GDM and 109 control group) and 50 postpartum women (30 with GDM during pregnancy and 20 controls). Using ELISA and EIA kits, serum levels of adipocytokines were tested during pregnancy and post partum. Maternal adipocytokines levels were correlated with some metabolic parameters. RESULTS: Women with GDM had lower values of adiponectin and higher values of leptin during pregnancy (p<0.001; 0.0001) and post partum (p<0.002; 0.0001). Serum apelin was significantly lower in GDM group (p<0.009). However, we did not find significance for resistin (p<0.317) and apelin (p<0.218). Positive correlation for leptin and negative for adiponectin was found for pre-pregnancy and pregnancy body mass index, glycated hemoglobin and homeostasis model assessment of insulin resistance index. Using cut point of 8.2 MUg/ml for adiponectin and 28.7 ng/ml for leptin could exclude GDM with a sensitivity of 83.6%/81.2% and specificity of 56.6%/64.2% (area under the curve 0.702 and 0.827). CONCLUSION: There are constant differences in adiponectin and leptin levels between GDM and control group during pregnancy and post partum. Apelin was decreased in our GDM group and no differences were found for resistin and visfatin. Further studies are required to verify the mechanism of this alteration and whether the adipocytokines can be predictors for GDM at an early stage of pregnancy. PMID- 23685998 TI - Measuring corneal clouding in patients suffering from mucopolysaccharidosis with the Pentacam densitometry programme. AB - AIM: To identify a means to objectively measure corneal clouding in patients with mucopolysaccharidosis in a prospective controlled clinical trial. METHODS: Corneal haze was assessed by slit lamp examination and measured using the densitometry programme of the Pentacam, a rotating Scheimpflug camera in 33 mucopolysaccharidoses (MPS) patients and 32 controls. RESULTS: Pentacam measurements were available in 31 right and 31 left eyes of 32 patients and in 32 left and right eyes of 32 subjects in the control group. Slit lamp findings correlated very well with corneal density measurements (Spearman correlation right eye (OD)/left eye (OS)=0.782/0.791). MPS patients had higher density units (median OD/OS=14.1/14.7) than control subjects (median OD/OS=6.7/6.9, p<0.001). In patients, the corneal centre density values (median OD/OS=13.8/14.0) did not differ from corneal periphery values (median OD/OS=14.3/14.7). CONCLUSIONS: The densitometry programme of the Pentacam provides objective measurement of corneal haze in mucopolysaccharidosis patients. PMID- 23685995 TI - Human papillomavirus infections: warts or cancer? AB - Human papillomaviruses (HPVs) are prevalent pathogens of mucosal and cutaneous epithelia. Productive infections of squamous epithelia lead to benign hyperproliferative warts, condylomata, or papillomas. Persistent infections of the anogenital mucosa by high-risk HPV genotypes 16 and 18 and closely related types can infrequently progress to high-grade intraepithelial neoplasias, carcinomas-in-situ, and invasive cancers in women and men. HPV-16 is also associated with a fraction of head and neck cancers. We discuss the interactions of the mucosotropic HPVs with the host regulatory proteins and pathways that lead to benign coexistence and enable HPV DNA amplification or, alternatively, to cancers that no longer support viral production. PMID- 23685999 TI - Longitudinal changes in anterior chamber depth and axial length in Asian subjects after trabeculectomy surgery. AB - BACKGROUND/AIMS: To investigate longitudinal changes in anterior chamber depth (ACD) and axial length (AXL) over 5 years after trabeculectomy surgery in Asian patients with primary glaucoma, and to identify factors associated with these changes. METHODS: In this prospective cohort study, phakic subjects with primary glaucoma who underwent trabeculectomy had ACD and AXL measured over 5 years. The effect of intraocular pressure (IOP) on ACD and AXL was determined. Subjects were divided into two groups (high or low fluctuation of ACD/AXL) and factors were compared to determine if there were factors associated with greater fluctuation. RESULTS: 122 subjects were analysed. The majority of subjects were male (75.4%) and Chinese (77%). ACD and AXL were shallower/shorter compared with baseline at all postoperative visits, with a mean decrease of 0.11 mm (95% CI 0.07 to 0.15 mm, p<0.01) and 0.16 mm (95%CI 0.11 to 0.20 mm, p<0.01), respectively. Patients with primary open angle glaucoma (POAG) had higher odds of fluctuations in longitudinal measurements of ACD (OR=8.74, p<0.01) and AXL (OR=5.60, p<0.01) compared with patients with primary angle closure glaucoma. For every 1 mm Hg decrease in IOP, ACD and AXL decreased by 0.02 mm (p<0.01) and 0.01 mm (p=0.03), respectively, for POAG patients with emmetropia or mild myopia. CONCLUSIONS: Trabeculectomy resulted in a decrease in both ACD and AXL, and these changes were persistent over a period of 5 years. PMID- 23686000 TI - Comparative toxicity and proliferation testing of aflibercept, bevacizumab and ranibizumab on different ocular cells. AB - BACKGROUND/AIMS: Vascular endothelial growth factor (VEGF) is a key factor in the pathogenesis of neovascular retinal diseases including age-related macular degeneration. VEGF inhibitors including ranibizumab, pegaptanib or bevacizumab improve retinal morphology and vision in many patients. The recently approved drug aflibercept (VEGF Trap-Eye/Eyelea, Regeneron, Tarrytown, New York, USA) offers a new therapy modality. We therefore tested for toxic and anti proliferating effects of aflibercept. METHODS: The effects of aflibercept (0.125, 0.5, 2 mg), ranibizumab (0.125 mg) and bevacizumab (0.3125 mg) after 1, 24, 48 and 72 h on cell morphology via phase contrast pictures, cell viability via MTS assay, total cell amount via crystal violet staining, apoptosis induction via caspase 3/7 assay and proliferation via BrdU assay were investigated. Three ocular cell lines were chosen for toxicology testing: ARPE19 cells, RGC-5 cells and 661W cells. RESULTS: Aflibercept did not cause changes in cell morphology, induce apoptosis or cause permanent decrease in cell viability, cell density or proliferation in any cell line or concentration investigated. In general, aflibercept had fewer effects (upregulation or downregulation) compared with controls than bevacizumab or ranibizumab. CONCLUSIONS: In our experiments, aflibercept did not lead to any negative effects on retinal cell lines and might therefore be used safely in clinical applications. PMID- 23686001 TI - Contrast sensitivity evaluation in high risk proliferative diabetic retinopathy treated with panretinal photocoagulation associated or not with intravitreal bevacizumab injections: a randomised clinical trial. AB - PURPOSE: To compare the effect on contrast sensitivity (CS) measurements of panretinal photocoagulation (PRP) associated with intravitreal bevacizumab (IVB) injections versus PRP alone in high risk proliferative diabetic retinopathy (HR PDR). DESIGN: Prospective, randomised, masked, controlled trial. PARTICIPANTS: 42 patients with HR-PDR with visual acuity >=20/200. METHODS: Eyes were randomised to one of two groups: one underwent PRP and IVB injections (study group) and the other PRP alone (control group). PRP was performed three times during the study and IVB injection was administered twice. MAIN OUTCOME MEASURES: Mean change in CS threshold scores between and within groups, from baseline to 6 months. RESULTS: Seven patients presented with vitreous haemorrhage and were removed from the study. Mean results for CS threshold (at 1.5, 3, 6, 12 and 18 cycles per degree (cpd) frequencies) for patients with and without diabetic macular oedema showed no significant differences (p>0.05 for all comparisons) between the two groups. In 35 eyes in the control group, compared with baseline values, there was significant worsening (p<0.05) of CS at 1.5, 12 and 18 cpd after 1 month, at 12 cpd after 3 months, and at 6 and 12 cpd after 6 months. In the study group, there was significant improvement in CS at 3 cpd, 3 months after treatment. CONCLUSIONS: In eyes with HR-PDR, PRP treatment is associated with deterioration of CS while adjuvant use of bevacizumab prevents such deterioration. CS evaluation seems to support the adjuvant use of bevacizumab when using PRP for the treatment of HR-PDR. ClinicalTrials.gov Identifier NCT 01389505. PMID- 23686003 TI - A myeloma cell line established from a patient refractory to thalidomide therapy revealed high-risk cytogenetic abnormalities and produced vascular endothelial growth factor. PMID- 23686002 TI - Resveratrol supplementation preserves long bone mass, microstructure, and strength in hindlimb-suspended old male rats. AB - Resveratrol has gained popularity as an "anti-aging" compound due to its antioxidant and anti-inflammatory properties. Few studies have investigated the role of resveratrol supplementation in the prevention of age-related bone loss and skeletal disuse despite increased inactivity and age-related bone loss in the elderly. The objective of the study was to investigate the effect of resveratrol supplementation on disuse and age-related bone loss. Old (age 33 months) Fischer 344 * Brown Norway male rats were provided either trans-resveratrol (12.5 mg/kg bw/day) or deionized distilled water by oral gavage for 21 days. Rats were hindlimb-suspended (HLS) or kept ambulatory (AMB) for 14 days. Both femora and tibiae were collected. Bone mass was measured by dual-energy X-ray absorptiometry and bone microstructure was determined by micro-computed tomography. HLS of old male rats accelerated loss of bone mineral content, decreased trabecular bone volume per unit of total volume, and increased trabecular separation. Resveratrol supplementation ameliorated bone demineralization and loss of bone microarchitecture in HLS old male rats. The peak force measured by the three point bending test was reduced (P = 0.007) in HLS/control compared to AMB/control rats. Resveratrol supplementation ameliorated HLS-induced loss of femur strength. Plasma osteocalcin and alkaline phosphatase was higher (P < 0.04) and C-reactive protein was lower (P = 0.04) in old male rats given resveratrol. The bone protective effects of resveratrol appeared to be mediated through increased osteoblast bone formation, possibly due to reduced inflammation. Based on the results, resveratrol supplementation appeared to provide a feasible dietary therapy for preserving the skeletal system during disuse and age-related bone loss. PMID- 23686004 TI - Recent trends in the analysis of amino acids in fruits and derived foodstuffs. AB - The amino acid content of fruit and fruit-derived foods is studied intensely because of the contribution to nutritional value, aroma, taste and health promoting effects and their possible use as markers of origin and authenticity. In this review, based on 101 references, the most recent trends in the analysis of amino acids are presented: the most important techniques, the different sample treatment procedures (including derivatisation) and the most frequent applications are described and compared. Pertinent publications were retrieved from Scopus and Web of Knowledge database searches lastly performed in February 2012 with the keywords "amino acid", "analysis", "liquid chromatography", "gas chromatography", "electrophoresis", "fruit", and "vegetables"; the time limit was set from the year 2000 onwards. Although amino acids have been analysed in foods for decades, new technical possibilities and advancements have allowed ever increasing accuracy and targeting of the methods in order to overcome the challenges posed by the complex plant matrices and their high intrinsic variability. PMID- 23686005 TI - Downregulation of pro-inflammatory mediators by a water extract of Schisandra chinensis (Turcz.) Baill fruit in lipopolysaccharide-stimulated RAW 264.7 macrophage cells. AB - Schisandra chinensis has a long-standing history of medicinal use as a tonic, a sedative, an anti-tussive, and an anti-aging drug. Nevertheless, the antagonistic effects of S. chinensis against lipopolysaccharide (LPS)-stimulated responses have not yet been studied. In this study, we investigated whether water extract of S. chinensis fruit (WESC) has the ability to attenuate the expression of pro inflammatory mediators such as nitric oxide (NO), prostaglandin E2 (PGE2), and tumor necrosis factor-alpha (TNF-alpha) in LPS-stimulated RAW 264.7 macrophage cells. WESC inhibited the expression of LPS-induced pro-inflammatory mediators, namely, NO, PGE2, and TNF-alpha. Furthermore, gene expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), and TNF-alpha was inhibited both at mRNA and protein synthesis levels, without any cytotoxic effect. Moreover, WESC significantly suppressed LPS-induced DNA-binding activity of NF-kappaB by inhibiting degradation of IkappaBalpha. It was found that pyrrolidine dithiocarbamate (PDTC), a specific NF-kappaB inhibitor, downregulates the expression of these pro-inflammatory genes to be closely regulated by NF-kappaB activity. Furthermore, we found that WESC retains dephosphorylation of Akt in response to LPS, and consequently suppressed the DNA-binding activity of NF kappaB in RAW 264.7 macrophage cells. LY294002, a specific Akt inhibitor, attenuated LPS-induced pro-inflammatory gene expression via suppression of NF kappaB activity. Taken together, our results indicate that WESC downregulates the expression of pro-inflammatory genes involved in the synthesis of NO, PGE2, and TNF-alpha in LPS-stimulated RAW 264.7 macrophage cells by suppressing Akt dependent NF-kappaB activity. PMID- 23686006 TI - Transcriptional regulation of glutathione biosynthesis genes, gamma-glutamyl cysteine ligase and glutathione synthetase in response to cadmium and nonylphenol in Chironomus riparius. AB - We characterized Chironomus riparius glutathione (GSH) biosynthesis genes, gamma glutamyl-cysteine ligase catalytic subunit (cr-gcl) and glutathione synthetase (cr-gs) and studied their expression after cadmium (Cd) and nonylphenol (NP) exposure. The full length cDNA of the Cr-GCL catalytic subunit was 2185 base pair (bp) in length containing an open reading frame of 1905bp, a 13bp 5' and 267bp 3' untranslated regions. The theoretical molecular mass of the deduced amino acid sequence (633) was 72.65kDa with an estimated pI of 5.42. The partial cDNA of Cr GS was 739bp in length consisting 221 amino acids. The deduced amino acid sequence of Cr-GCL and Cr-GS cDNAs showed high conservation with homologs from other species. In phylogenetic analysis Cr-GCL and Cr-GS were grouped with equivalent genes from insects belonging to the dipteran order. The expression of cr-gcl and cr-gs was measured using quantitative real-time PCR after exposure to sub lethal concentrations of Cd (2, 10 and 20mg/L) and NP (10, 50 and 100MUg/L) for 12, 24, 48 and 72h using real-time PCR methods. The mRNA expression of Cr-GCL and Cr-GS was significantly modulated after exposure to different concentrations of Cd and NP for different time periods. Total GSH levels showed a non significant decrease after exposure to Cd for 24h. However, no change in GSH levels was observed after exposure to NP for 24h. These results suggest that Cr GS and Cr-GCL expression is modulated by Cd and NP stress and may play an important role in detoxification of xenobiotics and antioxidant defense. We conclude that Cr-GS and Cr-GCL could be used as biomarkers of Cd and NP stress in aquatic environment for the studied species. PMID- 23686007 TI - Aroclor 1254 induced oxidative stress and mitochondria mediated apoptosis in adult rat sperm in vitro. AB - Aroclor 1254, a commercial mixture of highly toxic environmental pollutant, is known to cause testicular toxicity. The present study was undertaken to delineate and elucidate the nature and the mechanism of action of Aroclor 1254 on rat sperm in vitro. Sperm of adult rat were incubated with 10(-9)M, 10(-8)M or 10(-7)M of Aroclor 1254 for 3h. Sperm motility was significantly decreased. Moreover, sperm viability, acrosome reaction and mitochondrial membrane potential (Deltapsim) were significantly decreased in a dose-related pattern. DNA integrity was significantly decreased at 10(-8)M and 10(-7)M of Aroclor 1254, while it did not show any significant change at 10(-9)M. Aroclor 1254 induced downstream events included cytochrome c release and caspase-3 activation, in a dose-related manner. ATP content was decreased while protein carbonyl content was significantly increased in a dose-related manner. The oxidative stress status was also assessed. Hydrogen peroxide (H2O2) production and lipid peroxidation (LPO) were significantly increased in a dose-related pattern. The antioxidant enzymes SOD, CAT and GPx were significantly decreased, while at a concentration of 10(-9)M of Aroclor 1254, GR activity did not show any significant change. The non-enzymatic antioxidant (GSH) was significantly decreased in a dose-dependent manner. In conclusion; our data clearly show that Aroclor 1254 induces toxicity, oxidative stress and culminating in mitochondria mediated apoptosis in rat sperm. PMID- 23686008 TI - Does thyroid disruption contribute to the developmental neurotoxicity of chlorpyrifos? AB - Although organophosphate pesticides are not usually characterized as "endocrine disruptors," recent work points to potential, long-term reductions of circulating thyroid hormones after developmental exposures to chlorpyrifos that are devoid of observable toxicity. We administered chlorpyrifos to developing rats on gestational days 17-20 or postnatal days 1-4, regimens that produce distinctly different, sex-selective effects on neurobehavioral performance. The prenatal regimen produced a small, but statistically significant reduction in brain thyroxine levels from juvenile stages through adulthood; in contrast, postnatal exposure produced a transient elevation in young adulthood. However, in neither case did we observe the sex-selectivity noted earlier for neurobehavioral outcomes of these specific treatment regimens, or as reported earlier for effects on serum T4 in developing mice. Thus, although chlorpyrifos has the potential to disrupt thyroid status sufficiently to alter brain thyroid hormone levels, the effect is small, and any potential contribution to neurobehavioral abnormalities remains to be proven. PMID- 23686009 TI - Antifibrotic activity of galangin, a novel function evaluated in animal liver fibrosis model. AB - This study aimed to investigate the effects of galangin on liver fibrosis in rats induced by subcutaneous injection of carbon tetrachloride (CCl4). The administration of CCl4 to rats for 12 weeks caused significant increase of hyaluronic acid, laminin, alanine transaminase, aspartate transaminase and decrease of total protein, albumin in serum, while the influences could be reversed by galangin. Galangin markedly reduced hepatic malondialdehyde, hydroxyproline concentration, increased activities of liver superoxide dismutase, glutathione peroxidase compared with CCl4-treated rats. Histological results indicated that galangin alleviated liver damage. In addition, treatment with galangin significantly down-regulated expressions of alpha-smooth muscle actin and transforming growth factor beta1. These results suggest galangin can inhibit liver fibrosis induced by CCl4 in rats, which was probably associated with its effect on removing oxygen free radicals, decreasing lipid peroxidation, as well as inhibiting hepatic stellate cells activation and proliferation. PMID- 23686011 TI - Structural comparison of biological networks based on dominant vertices. AB - It is a current practice to organize biological data in a network structure where vertices represent biological components and arrows represent their interactions. A great diversity of graph theoretical notions, such as clustering coefficient, network motifs, centrality, degree distribution, etc., have been developed in order to characterize the structure of these networks. However, none of the existent characterizations allow us to determine global similarity among networks of different sizes. It is the aim of the present paper to introduce a mathematical tool to compare networks not only with regard to their topological structure, but also in their dynamical capabilities. For this reason we aim to propose a pseudo-distance between networks, built around the notions of determination and dominancy, concepts recently introduced in the context of regulatory dynamics on networks. We use our proposed pseudo-distance to compare networks from the following bacteria: E. coli, B. subtilis, P. aeruginosa, M. tuberculosis, S. aureus and C. glutamicum. We also use this pseudo-distance to compare these real bacterial networks with equivalent homogeneous, scale-free and geometric three dimensional random networks. We found that even when bacterial networks are characterized with different levels of detail, have different sizes and represent different aspects of the organisms, the proposed pseudo-distance captures all these characteristics, and indicates how similar they are or not from random networks. PMID- 23686010 TI - The effect of calorie restriction on acute ethanol-induced oxidative and nitrosative liver injury in rats. AB - The aim of our study was to examine the effect of calorie restriction (CR) on oxidative and nitrosative liver injury in rats, induced by acute ethanol intoxication. Male Wistar rats were divided into groups: (1) control; (2) calorie restricted groups with intake of 60-70% (CR60-70) and 40-50% of daily energy needs (CR40-50); (3) ethanol-treated group (E); (4) calorie-restricted, ethanol treated groups (E+CR60-70 and E+CR40-50). Ethanol was administered in 5 doses of 2g/kg every 12h, and duration of CR was 5 weeks before ethanol treatment. Malondialdehyde and nitrite and nitrate level were significantly lower in E+CR60 70 and higher in E+CR40-50 vs. E group. Liver reduced glutathione content and activity of both superoxide dismutase izoenzymes were significantly higher in E+CR60-70 and lower in E+CR40-50 vs. E group. Oxidative stress may be a potential mechanism of hormetic effects of CR on acute ethanol-induced liver injury. PMID- 23686012 TI - Chemical information matters: an e-Research perspective on information and data sharing in the chemical sciences. AB - Recently, a number of organisations have called for open access to scientific information and especially to the data obtained from publicly funded research, among which the Royal Society report and the European Commission press release are particularly notable. It has long been accepted that building research on the foundations laid by other scientists is both effective and efficient. Regrettably, some disciplines, chemistry being one, have been slow to recognise the value of sharing and have thus been reluctant to curate their data and information in preparation for exchanging it. The very significant increases in both the volume and the complexity of the datasets produced has encouraged the expansion of e-Research, and stimulated the development of methodologies for managing, organising, and analysing "big data". We review the evolution of cheminformatics, the amalgam of chemistry, computer science, and information technology, and assess the wider e-Science and e-Research perspective. Chemical information does matter, as do matters of communicating data and collaborating with data. For chemistry, unique identifiers, structure representations, and property descriptors are essential to the activities of sharing and exchange. Open science entails the sharing of more than mere facts: for example, the publication of negative outcomes can facilitate better understanding of which synthetic routes to choose, an aspiration of the Dial-a-Molecule Grand Challenge. The protagonists of open notebook science go even further and exchange their thoughts and plans. We consider the concepts of preservation, curation, provenance, discovery, and access in the context of the research lifecycle, and then focus on the role of metadata, particularly the ontologies on which the emerging chemical Semantic Web will depend. Among our conclusions, we present our choice of the "grand challenges" for the preservation and sharing of chemical information. PMID- 23686016 TI - Nodal skip metastasis is not a predictor of survival in thoracic esophageal squamous cell carcinoma. AB - BACKGROUND: The presence of nodal skip metastasis (NSM) has been found to be of clinical importance in non-small cell lung cancer, but the study of this phenomenon in esophageal carcinoma is relatively rare. The purpose of this study was to identify risk factors influencing NSM and to assess its prognostic value in thoracic esophageal squamous cell carcinoma (ESCC). METHODS: A total of 207 patients with thoracic ESCC who underwent three-field lymphadenectomy and who had lymph node metastasis were reviewed. Associations of NSM occurrence with the clinicopathological characteristics of patients and primary tumors were evaluated using logistic regression analysis. The influence of NSM on the overall survival (OS) was assessed by log-rank tests and Cox regression analysis. RESULTS: NSM were present in 58 (26%) patients. No factor was significantly associated with the incidence of NSM except for the location of primary tumor. There were no NSMs in the 29 patients from our study with upper thoracic ESCC, and the rates of tumors occurrence in the middle and lower third of the esophagus were 38.9 and 14.9%, respectively. The median OS was 30 months, and no significant difference in OS was found between the patients with or without NSM (p=0.767). Only N status was found to be the independent risk factor for OS by Cox multivariate analysis. CONCLUSIONS: NSM is common in thoracic ESCC, especially in patients with tumors located in the middle and lower third of the esophagus. However, the presence of NSM did not predict prognosis. PMID- 23686014 TI - Inhibitory effects and mechanisms of luteolin on proliferation and migration of vascular smooth muscle cells. AB - Atherosclerosis (AS) is a complicated progress, involving many types of cells. Although the exact mechanisms of progression of atherosclerosis are uncertain, the balance of vascular smooth muscle cells (VSMCs) proliferation and apoptosis appears to play a pivotal role in the pathogenesis and progression of atherosclerosis, and much discussion has been undertaken to elucidate the detailed mechanisms, relevant gene expression and transduction pathways. Drug treatment has focused on ameliorating atherosclerosis. Some researchers have indicated that inhibiting VSMCs proliferation is involved in attenuating atherosclerosis. Luteolin is a kind of flavonoids naturally occurring in many plants and possesses beneficial effects on cardiovascular diseases. Luteolin can reduce VSMCs' proliferation and migration and this reduction is stimulated by several factors. The aim of this review is to summarize the existing inhibitory effects and mechanisms of luteolin on proliferation and migration of VSMCs, and consider whether luteolin may be a potential candidate for preventing and treating atherosclerosis. PMID- 23686015 TI - The role of margin status and reexcision in local recurrence following breast conservation surgery. AB - INTRODUCTION: Breast conservation surgery (BCS) results in survival equal to mastectomy for early-stage breast cancer. Ipsilateral breast tumor recurrence (IBTR) after BCS is thought to be related to margin status. At our institution, reexcision is performed only if tumor is at inked margin or with extensive disease close to multiple margins. The purpose of this study was to determine rates of reexcision and recurrences among BCS patients using this policy. METHODS: We performed an institutional review board-approved retrospective analysis of BCS patients who underwent surgery between January 2001 and June 2005. We identified patients who had a second breast excision within 8 weeks of the first, and those patients with an IBTR. Clinical and pathologic features of patients' tumors were reviewed. RESULTS: We identified 543 patients who underwent BCS, 84 patients (15.5 %) underwent reexcision for margin status. The crude IBTR rate was 3.4 %, and the 5-year local recurrence-free survival of the reexcised group was 90.6 % compared with 97.4 % in the non-reexcised group (p = 0.0097). Of the 64 reexcision patients, 6 (9.4 %) had an IBTR versus 12 (2.6 %) of the 459 non-reexcised patients (p = 0.0151). DISCUSSION: Our reexcision rate is low compared with other reports. This results from a policy that defines "no tumor on ink" as an adequate margin for BCS, and the use of selective irradiation boosts based on margins assessed by our pathologists. Our local recurrence rate compares favorably with those seen in other studies while minimizing the need for additional operations. A higher IBTR rate after reexcision likely reflects tumor biology. PMID- 23686017 TI - Gleason 5+4 has worse oncological and pathological outcomes compared with Gleason 4+5: significance of Gleason 5 pattern. AB - BACKGROUND: The purpose of this study was to evaluate the pathological and oncological significance of Gleason (G) 5 pattern in high-grade PCa after robotic assisted radical prostatectomy (RARP). MATERIALS AND METHODS: From a cohort of 1,046 men, 159 post-RARP patients by a single surgeon with pathological G8 (N=79) and G9 (N=80) met our inclusion criteria. G9 cancers were sub-stratified into G4+5 (N=58) and G5+4 (N=22). Clinical and pathological outcomes were evaluated with the t test or Mann-Whitney U test for continuous variables and the Pearson chi2 test for categorical variables. The Kaplan-Meier method was used to estimate the biochemical recurrence-free survival (BCRFS), and survival curves were compared using the log-rank test. Multivariate analysis was performed with Cox regression analysis. RESULTS: Baseline characteristics across all subgroups were similar except for number of positive cores on biopsy. There was a trend toward worse pathological and oncological outcomes in G9 cancers when compared with G8, although only tumor volume (TV), extracapsular extension (ECE) of tumor and lymph nodes involvement (LNI) achieved statistical significance. G4+5 PCa were statistically more likely to have ECE and a higher TV than G4+4 although the BCRFS were not significantly different. G5+4 cancers were associated with a significantly higher proportion of patients with LNI and had a statistically significant poorer BCRFS compared with G4+5 patients. CONCLUSIONS: Oncological and pathological outcomes of G8 were significantly better than G9 and merited distinction between them. G5+4 harbors a much poorer BCRFS compared with G4+5, and hence we suggest considerations for immediate adjuvant treatments. PMID- 23686013 TI - Iron absorption in Drosophila melanogaster. AB - The way in which Drosophila melanogaster acquires iron from the diet remains poorly understood despite iron absorption being of vital significance for larval growth. To describe the process of organismal iron absorption, consideration needs to be given to cellular iron import, storage, export and how intestinal epithelial cells sense and respond to iron availability. Here we review studies on the Divalent Metal Transporter-1 homolog Malvolio (iron import), the recent discovery that Multicopper Oxidase-1 has ferroxidase activity (iron export) and the role of ferritin in the process of iron acquisition (iron storage). We also describe what is known about iron regulation in insect cells. We then draw upon knowledge from mammalian iron homeostasis to identify candidate genes in flies. Questions arise from the lack of conservation in Drosophila for key mammalian players, such as ferroportin, hepcidin and all the components of the hemochromatosis-related pathway. Drosophila and other insects also lack erythropoiesis. Thus, systemic iron regulation is likely to be conveyed by different signaling pathways and tissue requirements. The significance of regulating intestinal iron uptake is inferred from reports linking Drosophila developmental, immune, heat-shock and behavioral responses to iron sequestration. PMID- 23686018 TI - Lymph node assessment: quality, not quantity. PMID- 23686019 TI - [Glucose control in the critically ill. Innovations and contemporary strategies]. AB - Glucose control should be part of standard therapy in intensive care units (ICU) due to the proven association of hyperglycemia with increased morbidity and mortality. Due to the results of the latest randomized controlled multicentre trials blood glucose target levels of 140-180 mg/dl are currently recommended. In critically ill patients glucose monitoring should not be performed using point of care (POC) devices because of inacceptable inaccuracies. Blood gas analyzers have been shown to be accurate and are mostly available nearly at the bedside. Currently new continuous glucose monitoring devices for critically ill patients using multiple technologies are under development. Depending on the accuracy and reliability these new devices will add to selective blood glucose measurements to close the time gap between measurements or will even replace these measurements. Continuous, intravenous insulin therapy according to an algorithm should be performed by nursing staff. Computerized algorithms followed by so-called dynamic paper algorithms yield the best results. Besides mean glucose levels, glucose variability and glucose complexity are also associated with outcome in critically ill patients and might therefore be future target parameters. Critically ill diabetic patients might benefit from different glucose target levels depending on the preadmission glucose control. Hypoglycemic events <80 mg/dl should be avoided because of the association with poor outcome. PMID- 23686021 TI - Assessment of trait and state aspects of depression in schizophrenia. AB - Depression and negative symptoms can be difficult to distinguish in schizophrenia. Assessments for negative symptoms usually account for the longitudinal nature of these symptoms, whereas instruments available to measure depression mainly assess current or recent symptoms. This construct difference may confound comparison of depressive and negative symptoms in schizophrenia because both domains may have trait-like aspects. We developed an instrument to measure both longitudinal "trait" as well as recent "state" symptoms of depression and tested this instrument (Maryland Trait and State Depression [MTSD] scale) in a sample of 98 individuals with schizophrenia or schizoaffective disorder and 115 community participants without psychotic illness. Exploratory factor analysis of the MTSD revealed 2 factors accounting for 73.4% of the variance; these 2 factors corresponded with "trait" and "state" depression inventory items. Neither MTSD-state nor MTSD-trait was correlated with negative symptoms as measured with the Brief Negative Symptom Scale (r = .07 and -.06, respectively) in schizophrenia patients. MTSD state and trait scores were significantly correlated with the Brief Psychiatric Rating Scale depression subscale (r = .58 and .53, respectively) as well as the Profile of Mood States depression subscale (r = .57 and .44). Persons with schizophrenia had significantly greater trait depressive symptoms than controls (P = .031). Individuals with schizoaffective disorder had significantly higher trait depression (P = .001), but not state depression (P = .146), compared with schizophrenia patients. Trait depressive symptoms are prominent in schizophrenia and are distinct from negative symptoms. PMID- 23686022 TI - A phylogenetic comparative study of flowering phenology along an elevational gradient in the Canadian subarctic. AB - Climate change is affecting high-altitude and high-latitude communities in significant ways. In the short growing season of subarctic habitats, it is essential that the timing and duration of phenological phases match favorable environmental conditions. We explored the time of the first appearance of flowers (first flowering day, FFD) and flowering duration across subarctic species composing different communities, from boreal forest to tundra, along an elevational gradient (600-800 m). The study was conducted on Mount Irony (856 m), North-East Canada (54 degrees 90'N, 67 degrees 16'W) during summer 2012. First, we quantified phylogenetic signal in FFD at different spatial scales. Second, we used phylogenetic comparative methods to explore the relationship between FFD, flowering duration, and elevation. We found that the phylogenetic signal for FFD was stronger at finer spatial scales and at lower elevations, indicating that closely related species tend to flower at similar times when the local environment is less harsh. The comparatively weaker phylogenetic signal at higher elevation may be indicative of convergent evolution for FFD. Flowering duration was correlated significantly with mean FFD, with later-flowering species having a longer flowering duration, but only at the lowest elevation. Our results indicate significant evolutionary conservatism in responses to phenological cues, but high phenotypic plasticity in flowering times. We suggest that phylogenetic relationships should be considered in the search for predictions and drivers of flowering time in comparative analyses, because species cannot be considered as statistically independent. Further, phenological drivers should be measured at spatial scales such that variation in flowering matches variation in environment. PMID- 23686020 TI - A meta-analysis of mentalizing impairments in adults with schizophrenia and autism spectrum disorder. AB - Mentalizing has been examined both in autism spectrum disorder (ASD) and schizophrenia (SCZ) primarily by either cognitive-linguistic (referred to as verbal) or emotion recognition from eyes (referred to as visual) mentalizing tasks. Each type of task is thought to measure different aspects of mentalizing. Differences in clinical features and developmental courses of each disorder may predict distinct patterns of mentalizing performance across dis orders on each type of task. To test this, a meta-analysis was conducted using 37 studies that assessed mentalizing either verbally or visually in adults with SCZ or ASD. We found that the estimated effect sizes of impairments in verbal and visual mentalizing tasks for both clinical groups were statistically large and at a similar level (overall Hedges' g = 0.73-1.05). For each disorder, adults with SCZ showed a trend towards larger impairments on verbal (overall Hedges' g = 0.99) than on visual mentalizing task (overall Hedges' g = 0.73; Qbet = 3.45, p =.06, df =1). Adults with ASD did not show different levels of impairment on the verbal versus visual tasks (Qbet = 0.08, p =.78, df =1). These results suggest that both clinical groups share, at least in part, some common cognitive processing deficits associated with mentalizing impairments. PMID- 23686023 TI - Chronic illness intrusion: role impairment and time out of role in racially and ethnically diverse older adults. AB - PURPOSE OF THE STUDY: Little is known about the effects of chronic illness on social role participation among racially and ethnically diverse older adults. This study was undertaken to better understand disruptions in role among African American, black Caribbean, white, Latino, and Asian older adults with arthritis, heart disease, or diabetes. DESIGN AND METHODS: This study consisted of a cross sectional secondary data analysis of the Collaborative Psychiatric Epidemiology Surveys. Role disruption was operationalized using time out of role and role impairment in the past 30 days. Data from participants aged 65 and older were used in negative binomial regression analyses. RESULTS: Overall, prevalence of role impairment occurred more often than time out of role. Race and ethnicity were not associated with time out of role, but they were for role impairment. Whites experienced more role impairment than any other racial or ethnic group. Within-group analyses identified that chronic illness, role participation, and socioeconomic factors are related in different ways depending on race or ethnicity. It appears that for some racially and ethnically diverse older adults, higher income and education are protective against role disruption. IMPLICATIONS: Race and ethnicity are factors in how the social roles of older adults are affected by chronic illness, and it appears that role disruption varies with type of illness. Interventions to support older adults with chronic illness should take into account the cultural factors related to role disruption. PMID- 23686025 TI - Oxytocin and behavior: evidence for effects in the brain. PMID- 23686026 TI - Concepts and strategies for clinical management of blast-induced traumatic brain injury and posttraumatic stress disorder. AB - After exposure of the human body to blast, kinetic energy of the blast shock waves might be transferred into hydraulic energy in the cardiovascular system to cause a rapid physical movement or displacement of blood (a volumetric blood surge). The volumetric blood surge moves through blood vessels from the high pressure body cavity to the low-pressure cranial cavity, causing damage to tiny cerebral blood vessels and the blood-brain barrier (BBB). Large-scale cerebrovascular insults and BBB damage that occur globally throughout the brain may be the main causes of non-impact, blast-induced brain injuries, including the spectrum of traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD). The volumetric blood surge may be a major contributor not only to blast induced brain injuries resulting from physical trauma, but may also be the trigger to psychiatric disorders resulting from emotional and psychological trauma. Clinical imaging technologies, which are able to detect tiny cerebrovascular insults, changes in blood flow, and cerebral edema, may help diagnose both TBI and PTSD in the victims exposed to blasts. Potentially, prompt medical treatment aiming at prevention of secondary neuronal damage may slow down or even block the cascade of events that lead to progressive neuronal damage and subsequent long-term neurological and psychiatric impairment. PMID- 23686027 TI - The forthcoming DSM-5, critical care medicine, and pediatric neuropsychiatry: which new concepts do we need? AB - Examination and comparison of the current DSM-IV-TR and the proposed revisions for the forthcoming DSM-5, with regard to neuropsychiatric aspects of critical illness, identified five important issues. These remain to be addressed in order to improve the care of critically ill patients. These are 1) sickness behavior, as part of the organic reaction types of the brain; 2) delirium in children and the "Differential Diagnosis of Mental Disorders Due to a General Medical Condition" in children; 3) catatonia; 4) regressive disorders in childhood in relation to somatic disorders (e.g., anti-NMDAR encephalitis); 5) age-related diagnostic criteria in relation to neuro-psychiatric disorders. PMID- 23686028 TI - Outcomes of sport-related concussion among college athletes. AB - The author collected and analyzed data for all student-athletes diagnosed with concussion between 1998 and 2011. Outcome measurements were post-concussion symptom duration, time interval until return-to-play, and clinical outcomes self reported by athletes and by athlete's parent/guardian 1 year post-injury. A total of 98 concussions occurred in 95 student athletes among a cohort averaging 350 athletes competing yearly. Athletes were managed according to expert-consensus guidelines. Forty-one (43%) of the athletes had experienced a previously diagnosed concussion (range: 1-3). Eight athletes (10.4%), retired from their sport for concussion-related issues. Six athletes (6.3%) with completed follow-up experienced memory and/or concentration impairment(s) lasting more than 1 year. PMID- 23686029 TI - Use of low-dose gabapentin for aggressive behavior in vascular and Mixed Vascular/Alzheimer Dementia. AB - Recent reports highlighting serious adverse effects of antipsychotic medication in behavioral and psychological symptoms of dementia (BPSD) has led to calls for research on alternative agents. The authors describe the use of low-dose gabapentin to treat seven patients with a diagnosis of ICD-10 vascular or Mixed Vascular/Alzheimer Dementia with serious aggressive behavior. All seven patients had impressive and clinically significant responses to treatment. Treatment was tolerated in each case without adverse reactions. Our findings suggest that gabapentin should be considered for treating aggressive behavior in patients with vascular or mixed dementia and that it is well tolerated in this context. PMID- 23686030 TI - Rostral anterior cingulate activity in major depressive disorder: state or trait marker of responsiveness to medication? AB - High rostral anterior cingulate cortex (rACC) activity has been shown to predict antidepressant treatment response; however, it is unclear whether this is a fixed versus variable marker of responsiveness. The authors measured rACC theta current density in 22 subjects 5 weeks before and again immediately before 5 weeks of blinded treatment with sertraline. Mixed-effects regression analysis found that the relationship between response and rACC activity depended significantly on the timing of the rACC assessment; rACC activity measured immediately before treatment was a significantly better predictor of response. rACC activity may constitute a variable "state" indicator of responsiveness to antidepressants. PMID- 23686031 TI - Changing associations between cognitive impairment and imaging in multiple sclerosis as the disease progresses. AB - The authors explored cross-sectional associations between MRI parameters (lesion metrics, brain volumes, magnetization transfer ratio histograms, and metabolite concentrations) and cognition in 61 patients who experienced clinically-isolated syndromes (CIS) 7 years earlier. IQ decline and poorer overall cognition were associated with T2 white-matter lesions, and slow information-processing with both T2 lesions and gray-matter atrophy. In a previous study of the same cohort, gray-matter atrophy measured shortly after CIS failed to predict development of cognitive impairment years later. Our findings suggest that gray-matter pathology, reflected by atrophy measurements, becomes increasingly important in determining cognition as MS progresses. PMID- 23686032 TI - The role of self-awareness and cognitive dysfunction in Parkinson's disease with and without impulse-control disorder. AB - The aim of this study was to investigate the clinical, neuropsychological, and self-awareness correlates of impulse-control disorder (ICD) in a group of 17 Parkinson's disease (PD) subjects with an active ICD and a comparison group of 17 PD subjects without ICD. Self-awareness was assessed with the Beck Cognitive Insight Scale and patient-caregiver discrepancy scores from ratings on the Dysexecutive Questionnaire and the Everyday Memory Questionnaire-Revised. Self awareness was comparable or increased in those with ICD, versus those without, and measures of neuropsychological functioning did not differ between the two groups. Those with ICD had more motor complications of PD therapy and were more likely to be on an antidepressant than those without ICD, whereas dopaminergic medication profiles were comparable between the two groups. In this group, PD patients with current ICDs were aware of their impulsivity. Although executive dysfunction may contribute to ICD behavior, it is not a necessary component. The awareness of the inability to resist these motivated behaviors may be a source of increased depression. PMID- 23686033 TI - Vitamin B12 levels and psychiatric symptomatology: a case series. AB - Cobalamin (Vitamin B12) has been implicated in the pathogenesis of various neuropsychiatric disorders. A review of 19 patients (14 vegetarians) with demonstrable vitamin B12 deficiency showed varied psychiatric symptomatology, with the majority not having significant hematological or neurological manifestations. PMID- 23686034 TI - Musical hallucinations associated with pontine lacunar lesions. AB - Three elderly patients experienced musical hallucinations (MH) in the context of hearing loss. In at least two of the cases, the onset was sudden. All three patients had pontine T2/FLAIR hyperintense foci on MR scan after the onset of the MH. PMID- 23686035 TI - The combined treatment of venlafaxine and quetiapine for treatment-resistant depression: a clinical study. AB - The authors studied the efficacy and safety of combined venlafaxine and quetiapine treatment for treatment-resistant depression (TRD) by dividing 95 TRD patients into two treatment groups: a combined venlafaxine (225 mg/day) and quetiapine (400 mg/day) group and a venlafaxine-only (225 mg/day) group for 8 weeks. Efficacy was assessed with the Hamilton Rating Scale for Depression, 17 items (Ham-D-17) and the Hamilton Rating Scale for Anxiety (Ham-A); safety was assessed with the Treatment-Emergent Symptom Scale (TESS). The two groups showed significant differences for the Ham-D-17 and Ham-A and no differences on the TESS. Combined venlafaxine and quetiapine treatment showed good efficacy and safety in TRD. PMID- 23686036 TI - Editor's note: Expression of concern. PMID- 23686040 TI - Is attention deficit hyperactivity disorder a kind of intermittent chaos? PMID- 23686039 TI - Serotonin syndrome with ziprasidone and sertraline. PMID- 23686041 TI - Pulmonary thromboembolism associated with clozapine. PMID- 23686042 TI - A kind of D-amino acid oxidase inhibitor, sodium benzoate, might relieve panic symptoms in a first-episode, drug-naive panic-disorder patient. PMID- 23686043 TI - Reversal of aripiprazole-induced tardive akathisia by addition of pregabalin. PMID- 23686044 TI - Venlafaxine-associated hyponatremia presenting with catatonia. PMID- 23686045 TI - Mirtazapine-induced galactorrhea: a case report. PMID- 23686046 TI - A five-year-old child with bilateral amygdala loss. PMID- 23686047 TI - Rapidly progressive anomic aphasia: a rare presentation of temporal lobe tumor. PMID- 23686048 TI - Progressive impairment of decision-making in behavioral-variant frontotemporal dementia. PMID- 23686049 TI - Combined therapeutic treatment for traumatic skull defect with brain abscess in a schizophrenic patient. PMID- 23686050 TI - Atrial flutter in a patient with Alzheimer dementia treated by rivastigmine. PMID- 23686051 TI - Fluctuating cognitive deficits and autonomic dysfunction: clarifying the diagnosis. PMID- 23686052 TI - Desvenlafaxine-induced worsening of hypertension. PMID- 23686053 TI - Aripiprazole treatment for choreoathetoid and psychotic symptoms of Huntington's disease. PMID- 23686054 TI - Reversible parietal hypometabolism in late-onset psychosis. PMID- 23686055 TI - Vitamin B12 deficiency masquerading as clozapine-resistant psychotic symptoms in schizophrenia. PMID- 23686056 TI - Successful use of paliperidone in a clozapine-resistant schizophrenic patient. PMID- 23686057 TI - Myoclonus associated with disulfiram. PMID- 23686058 TI - Handwriting abnormality in Tourette syndrome. PMID- 23686059 TI - Toluene dependency, psychosis, and cerebellar syndrome. PMID- 23686060 TI - Schizencephaly and borderline personality disorder. PMID- 23686061 TI - Application of the fuzzy logic concept in the multiple sclerosis functional composite for scoring the progress of multiple sclerosis. PMID- 23686062 TI - The behavior of eating glass, with radiological findings: a case of pica. PMID- 23686063 TI - Expanding Virchow-Robin spaces: transient global amnesia and obstructive hydrocephalus. PMID- 23686064 TI - Paliperidone-induced tardive dystonia: a case report. PMID- 23686065 TI - Schizophrenia symptoms relieved by CO-induced pallidal lesion: a case report. PMID- 23686066 TI - Symptoms of major depression after pseudoephedrine withdrawal: a case report. PMID- 23686067 TI - Folie a deux and anorexia nervosa: a case report. PMID- 23686068 TI - Methamphetamine-associated QTc prolongation in a dose-dependent and reversible manner. PMID- 23686069 TI - Brain morphology changes in a remitted patient with late-onset, drug-naive, non psychotic major depressive disorder after amisulpride monotherapy. PMID- 23686070 TI - Psychosis in a female patient with tuberous sclerosis. PMID- 23686071 TI - Clozapine-induced restless legs syndrome treated with aripiprazole. PMID- 23686072 TI - Does the immune system act as a self-organized system in multiple sclerosis? PMID- 23686074 TI - Seizure with an unusual clinical semiology mimicking psychosis: a case report. PMID- 23686073 TI - How does tonic dopamine level affect decision-making in dual tasks in Parkinson's disease? PMID- 23686075 TI - A case of isoniazid-induced delirium. PMID- 23686076 TI - Corticobasal syndrome presenting with partial Gerstmann's syndrome and digit agnosia. PMID- 23686077 TI - Marchiafava-Bigmani disease in relation to pure alcohol consumption. PMID- 23686078 TI - Removing cadmium by nano-pore zeolites to decrease aggressive behavior, stress, and hyperactivity. PMID- 23686079 TI - Fasting glucose level modulates cell surface expression of CD11b and CD66b in granulocytes and monocytes of patients with type 2 diabetes. AB - INTRODUCTION: Cardiovascular complications are the leading cause of mortality in type 2 diabetes (T2DM), in which onset and progression of atherosclerosis is linked to chronic inflammation. Activation status of innate immune cells (granulocytes [Gc], monocytes [Mc]), as reflected by increased CD11b, CD66b, and other surface markers, increases their endothelial and cytokines/chemokines release. Whereas this inflammatory activation seems inversely related to poor glycemic control, the effect of acute spontaneous hyperglycemia on innate immune cell activation remains unclear. METHODS: Expression of key markers (CD11b, CD14, CD16, CD62L, and CD66b) was therefore determined by flow cytometry on whole blood of healthy subjects and patients with T2DM with spontaneous fasting euglycemia or hyperglycemia both at baseline and after 30, 90, and 240 minutes of incubation at room temperature. RESULTS: Hyperglycemic patients with T2DM had significantly higher Gc and Mc CD11b and Gc CD66b surface mean fluorescence intensity compared with the euglycemic patients with T2DM whose values were similar to those of the healthy controls. CD16 expression in CD14+CD16+ Mc was elevated in all patients with T2DM, regardless of glycemic levels. CONCLUSION: Our data suggest that whereas the presence of diabetes per se may have a proinflammatory effect, hyperglycemia seems to further acutely exacerbate innate cell inflammatory status and their consequent endothelial adhesion and vascular damage potential. PMID- 23686084 TI - Undisplaced intracapsular hip fractures in the elderly: predicting fixation failure and mortality. A prospective study of 162 patients. AB - BACKGROUND: Reported revision of internal fixation for undisplaced intracapsular hip fractures is between 12 and 17% at 1 year. This risk is greater for elderly patients, for whom mortality after such a fracture is also higher. Our purpose was to identify predictors of fixation failure and mortality for elderly patients sustaining undisplaced intracapsular hip fractures, and to assess whether their socioeconomic status affected their outcome. METHODS: During a 3-year period we prospectively compiled a consecutive series of 162 elderly (>=65 years old) patients who underwent internal fixation for an undisplaced (Garden stage I or II) intracapsular hip fracture. Patient demographics, American Society of Anesthesiologists (ASA) grade, and posterior tilt (measured on the lateral radiograph) were recorded pre-operatively. All patients were followed up for a minimum of 1 year. Each patient's socioeconomic status was assigned by use of the Scottish Index of Multiple Deprivation. Patient mortality was established by use of the General Register Office for Scotland. RESULTS: There were 28 failures of fixation during the study period. In Cox regression analysis, ASA grade and the presence of posterior tilt (p < 0.0001) were significant independent predictors of fixation failure. Overall unadjusted mortality at 1 year was 19% (n = 30/162). Cox regression analysis also affirmed ASA grade to be the only significant independent predictor of 1-year mortality (p = 0.003). The standardised mortality rate for the cohort was 2.3 (p < 0.001), and was significantly greater for patients less than 80 years of age (p = 0.004). Socioeconomic status did not affect outcome, but the most deprived patients sustain their fracture at a significantly younger age (p = 0.001). CONCLUSION: We have demonstrated that ASA grade and posterior tilt of the femoral neck are independent predictors of fixation failure of undisplaced intracapsular hip fractures in elderly patients, and ASA grade was also an independent predictor of mortality. PMID- 23686083 TI - NELL-1 based demineralized bone graft promotes rat spine fusion as compared to commercially available BMP-2 product. AB - BACKGROUND: Spinal fusion is among the most commonly performed orthopaedic procedures. Unfortunately, current treatments such as autologous bone grafting or recombinant proteins (BMP-2) have numerous clinical shortcomings. Here, we directly compare the efficacy of NELL-1, a novel osteoinductive growth factor, to two currently available treatments, (1) recombinant BMP-2 and (2) iliac crest bone grafting, in a spinal fusion model. METHODS: Twenty-six skeletally mature athymic rats underwent posterolateral spine fusion of L4/L5 vertebrae. Treatment groups included NELL-1 (10 and 50 MUg) in a demineralized bone matrix (DBX), as compared to BMP-2 (90 MUg) in an absorbable collagen sponge (ACS) or morselized iliac crest bone. Scaffolds without recombinant protein were used as controls. Animals were sacrificed at 4 weeks post-operative and fusion was assessed by manual palpation, radiography [high-resolution X-ray, micro-computed tomography (microCT)], histology (hematoxylin and eosin, Masson's trichrome) and immunohistochemistry (osteocalcin). RESULTS: Results showed 100 % fusion in all NELL-1- and BMP-2-treated samples. In contrast, lower rates of fusion were observed in scaffold-only and bone graft treatment groups. MicroCT scans revealed radiographic evidence of fusion among spines treated with NELL-1. Bone bridging was also observed with BMP-2 treatment, but was accompanied by inner radiolucency, suggesting cyst-like bone formation. Histologically, NELL-1-treated grafts showed increased bone formation, endochondral ossification and vascularization. Although BMP-2 treated grafts exhibited increased bone formation and angiogenesis, numerous adipocytes were also observed. CONCLUSION: NELL-1 based bone grafts are comparable to BMP-2 + ACS in spinal fusion efficacy. Histological differences were observed however, including robust endochondral ossification with NELL-1 treatment as compared to lipid-filled bone with BMP-2 treatment. These findings suggest NELL-1 based bone grafts show promise for future efforts in skeletal tissue engineering. PMID- 23686080 TI - The SUBITO-DE study: sexual dysfunction in newly diagnosed type 2 diabetes male patients. AB - INTRODUCTION: No data on the prevalence of erectile dysfunction (ED) in subjects with newly diagnosed Type 2 diabetes mellitus (T2DM) are currently available. AIM: The aim of the present study was to estimate the prevalence of ED and its associated causes in a sample of male patients with recently diagnosed DM (<24 months) attending a diabetes care center. METHODS: The study comprised two phases: a cross-sectional analysis and a longitudinal reassessment of the data collected during the first phase. During the first phase, 1503 subjects (mean age 58.7+/-8.9 yr) from 27 centers were interviewed: 666 (43.3%) reported experiencing ED, 499 of which (mean age 58.8+/-8.8 yr) agreed to participate in the study (final enrolment rate, 33.3%). Concurrent morbidities were hypertension (55.3%), dyslipidemia (39.5%), and coronary heart disease (7.8%); chronic complications were neuropathy (8.9%), nephropathy (12.6%) and retinopathy (7.6%) in about one third of the sample at enrolment. RESULTS: Overall, about 20% of the patients reported having used ED drugs, but more than 50% had abandoned therapy because of the drug's ineffectiveness or high cost. The prevalence of hypogonadism was 46.9% (total testosterone level, 3.5 ng/ml). Some 20% of patients reported symptoms suggestive of depression. CONCLUSION: The present study provides data showing a high prevalence of ED, hypogonadism and depressive symptoms among male patients with newly diagnosed T2DM. Further analysis of the data will elucidate the specific determinants of such conditions and their longitudinal significance. PMID- 23686085 TI - The effect of tourniquet use on operative performance and early postoperative results of anatomic double-bundle anterior cruciate ligament reconstruction. AB - PURPOSE: The purpose of this study was to examine the effect of tourniquet use on operative performance and early postoperative results of anatomic double-bundle anterior cruciate ligament (ACL) reconstruction. METHODS: Fifty-one patients who underwent scheduled ACL reconstruction for unilateral ACL deficiency from June 2010 to October 2011 were included in this study. The mean age at surgery was 26.3 years (range 14-45 years). An anatomic bundle reconstructive procedure with an autogenous hamstring tendon graft was performed in all cases. These patients were randomly divided into two groups: the tourniquet group (T group) and no tourniquet group (NT group). The reconstructive procedure was performed with the use of a tourniquet for 28 patients in the T group, while a tourniquet was inflated only during the graft harvest for 23 patients in the NT group. The surgical procedure and postoperative management were identical for both groups. Inter-group comparison was conducted for intra- and peri-operative clinical parameters as well as early postoperative results (functional recovery at 3 months). RESULTS: The arthroscopic visual field during the procedure was not compromised even without the use of a tourniquet. There was no significant difference in operative time between the groups (P = 0.10). The amount of blood corrected through the intraarticular drain was significantly larger in the T group (P = 0.02), while total blood loss calculated by the postoperative reduction of the hemoglobin value was not significantly different between the groups (P = 0.74). Although the VAS value for postoperative numbness was significantly higher in the T group (P = 0.0002), the VAS value for pain was not significantly different (P = 0.30). Additionally, recovery of muscle strength at 3 months was not significantly different between the groups. CONCLUSION: This comparative study showed that arthroscopic procedures could be uneventfully performed without the use of a tourniquet. The clinical parameters when not using a tourniquet were not significantly different, but the use of a tourniquet resulted in an increase in postoperative intraarticular bleeding and VAS for numbness. LEVEL OF EVIDENCE: Prospective randomized study, Level II. PMID- 23686087 TI - Parasite biology: The stowaway traveller. PMID- 23686086 TI - Conditional pharmacology/toxicology V: ambivalent effects of thiocyanate upon the development and the inhibition of experimental arthritis in rats by aurothiomalate (Myocrysin(r)) and metallic silver. AB - This article discusses the bizarre and contrary effects of thiocyanate, the major detoxication product of hydrogen cyanide inhaled from tobacco smoke or liberated from cyanogenic foods, e.g. cassava. Thiocyanate both (1) promotes inflammatory disease in rats and (2) facilitates the anti-inflammatory action of historic metal therapies based on gold (Au) or silver (Ag) in three models of chronic polyarthritis in rats. Low doses of nanoparticulate metallic silver (NMS) preparations, i.e. zerovalent silver (Ag degrees ) administered orally, suppressed the mycobacterial ('adjuvant')-induced arthritis (MIA) in rats. Similar doses of cationic silver, Ag(I), administered orally as silver oxide or soluble silver salts were inactive. By contrast, NMS only inhibited the development of the collagen-induced arthritis (CIA) and pristane-induced arthritis (PIA) in rats when thiocyanate was also co-administered in drinking water. These (a) arthritis-selective and (b) thiocyanate-inducible effects of Ag degrees were also observed in some previous, and now extended, studies with the classic anti-arthritic drug, sodium aurothiomalate (ATM, Myocrisin((r))) and its silver analogue (STM), administered subcutaneously to rats developing the same three forms of polyarthritis. In the absence of either Ag degrees or ATM, thiocyanate considerably increased the severity of the MIA, CIA and PIA, i.e. acting as a pro-pathogen. Hitherto, thiocyanate was considered relatively harmless. This may not be true in rats/people with immuno-inflammatory stress and concomitant leukocyte activation. Collectively, these findings show how the drug action of a xenobiotic might be determined by the nature (and severity) of the experimental inflammation, as an example of conditional pharmacology. They also suggest that an incipient toxicity, even of normobiotics such as thiocyanate, might likewise be modulated beneficially by well-chosen xenobiotics (drugs, nutritional supplements, etc.), i.e. conditional toxicology (Powanda 1995). Thus, both the disease and the environment may determine (1) the therapeutic action and/or (2) adverse effect(s) of xenobiotics--and even some normobiotics. PMID- 23686088 TI - Non-invasive pressure measurement of the great saphenous vein in healthy controls and patients with venous insufficiency. AB - OBJECTIVES: Venous pressure measurement using an intravenous catheter is the sole method for the diagnosis of venous hypertension in patients with chronic venous insufficiency. A noninvasive tool to quantify increased venous pressure is essential for studying venous pathophysiology. Aim of the study was to investigate the value of controlled compression ultrasound (CCU) for noninvasive assessment of venous pressure (VP) of the great saphenous vein (GSV) in healthy persons and patients with venous insufficiency to quantify venous hypertension. METHODS: An optimal visible part of the GSV directly above the ankle was marked on the skin and compressed under ultrasound control and pressure needed for complete compression of the vein was recorded using a pressure manometer with a translucent silicone membrane. Complete insufficiency of the GSV (Hach IV) was documented by duplex ultrasound by an independent investigator before start of the study. VP measurement was performed while normal breathing, deep inspiration and expiration and during a standardized Valsalva maneuver. RESULTS: Twenty controls and 19 patients with complete insufficiency of the GSV were included. Valsalva maneuver induced a slight increase in VP in controls (20.1 +/- 4.5 vs 25.1 +/- 6.6 mbar) but a significant higher increase in patients from 26 to 37 mbar (IQR 18.5-28.0 vs 31.5-43.0; p < 0.001). CONCLUSION: Noninvasive venous pressure measurement of the great saphenous vein using CCU is feasible and documents an increased pressure during Valsalva maneuver in Hach IV patients compared to healthy controls. PMID- 23686089 TI - RDW in patients with systemic lupus erythematosus. Influence of anaemia and inflammatory markers. AB - Red blood cell distribution width (RDW) is a routine parameter that reflects size variations in erythrocytes. High RDW has been associated with cardiovascular events and inflammatory diseases. However, no studies evaluating the association of RDW with systemic lupus erythematosus (SLE) have been published. We aimed to explore the association of RDW with inflammatory markers in SLE. As SLE is often associated with anaemia, we considered this factor in order to know whether RDW is related with inflammation, anaemia or both in SLE. The study included 105 SLE patients (7 men, 98 women; aged 15-73 years) and 105 controls (9 men, 96 women; aged 18-71 years). Patients were divided according to anaemia status (26 with, 79 without). Biochemical, hematological and inflammatory parameters (C-reactive protein (CRP), fibrinogen and erythrocyte aggregation (EA1)) were analyzed. SLE patients showed increased RDW, CRP and EA1 (p < 0.001), and decreased hemoglobin levels (p < 0.001) when compared with controls. RDW was higher in SLE patients with anaemia (a-SLE) as compared with those without anaemia (na-SLE) (p < 0.01) or controls (p < 0.001). CRP in a-SLE was higher than in controls (p < 0.01) but lower than in na-SLE (p < 0.05). In na-SLE RDW correlated directly with fibrinogen and CRP (p < 0.001), but not in a-SLE. Our results indicate that SLE patients show higher RDW irrespectively of anaemia status, and that RDW is influenced by both anaemia and inflammation, but the influence of anaemia is stronger. PMID- 23686091 TI - Shear stress and flow dynamics of the femoral vein among obese patients who qualify for bariatric surgery. AB - The aim of this study was to evaluate the effects of obesity on wall shear stress and its relationship to erythrocyte aggregation. We studied 35 morbidly obese patients who were qualified for bariatric surgery. The control group consisted of 20 non-obese people. Blood rheological measurements were performed using the Laser-assisted Optical Rotational Cell Analyzer (Mechatronics, the Netherlands) and a cone-plate viscometer (Brookfield DV-II). The venous flow dynamics were assessed using a duplex ultrasound. The shear rate was estimated from the measured blood flow velocity and the diameter of the femoral vein. Venous wall shear stress was calculated from the whole blood viscosity and the shear rate. The shear rate (P < 0.005) and the venous wall shear stress (P < 0.05) were significantly lower in obese patients compared with the controls. The aggregation index (P < 0.001), syllectogram amplitude - AMP (P < 0.05) and Tslow (P < 0.001) were significantly higher in the obese patients; the aggregation half-time (P < 0.001) and Tfast (P < 0.001) were decreased compared with the control group. Multivariate regression analyses found waist circumference (beta -0.31, P < 0.05), thigh circumference (beta 0.33, P < 0.05) and Tslow (beta -0.47, P < 0.005) to be variables that independently influenced the shear rate. Nevertheless, the AMP (beta 0.34, P < 0.05) and Tslow (beta -0.47, P < 0.01) were independent predictors that influenced the wall shear stress. This study indicates that there is a relationship between wall shear stress in the femoral vein and the rheological impairment of the RBC among obese patients, but further studies are necessary to confirm this suggestion. PMID- 23686090 TI - Rheological blood behavior is not only influenced by cardiovascular risk factors but also by aging itself. Research into 927 healthy Spanish Mediterranean subjects. AB - It is not well-established whether the alterations that the hemorheological profile undergoes with aging are an effect of concomitant cardiovascular risk factors or are due to age itself. To clarify this issue, we investigated the effect of age on blood rheology in a population of 927 healthy subjects from eastern Spain aged between 16-85 years, divided into four age groups (<30, 30-44, 45-50, >=60 years) with and without cardiovascular risk factors. We determined blood viscosity, corrected blood viscosity (BVc), plasma viscosity (PV), erythrocyte aggregation (EA), erythrocyte deformability (EEI60) and fibrinogen, along with glucose and plasma lipids. We found that corrected blood viscosity (p = 0.007), plasma viscosity, erythrocyte aggregation, fibrinogen, glucose, and plasma lipids increased with age (p < 0.001). When subjects with cardiovascular risk factors were excluded, the effect of age on blood rheology persisted for all the cited parameters (p < 0.028). EEI60 increased with age (p = 0.033), and it was attributable to a concomitant increase in mean corpuscular volume (p < 0.001). In the Pearson's correlations, age was related to all the parameters analyzed (P < 0.019). The logistic regression analysis revealed that PV >=1.30 mPa.s, BVc >=4.90 mPa.s and EA1 >=8.3 were associated with age >=60 years (*p = 0.049, *p = 0.013, *p = 0.045, respectively). These results indicate that, although the presence of cardiovascular risk factors influences rheological properties, aging itself is associated with deterioration of rheological blood behavior, mostly related to inflammatory and lipidic changes. PMID- 23686092 TI - Low temperature Raman study of a liquid crystalline system 4-decyloxy benzoic acid (4DBA). AB - The Raman spectra of a liquid crystalline system, 4-Decyloxy benzoic acid (4DBA) have been recorded at different temperatures within the interval 300-78 K in order to identify the structural changes in crystalline state of a nematogen and to understand the molecular alignment therein. The earlier predicted dimer structure of 4DBA was optimized with DFT method and the theoretical Raman spectra of dimer as well as monomer have been calculated for comparison with the experimental spectra. The mode specific quartic coupling coefficient; A(i,omega) and phonon frequency; omegai have been calculated using temperature dependent anharmonic perturbation theory. The precise band shape analysis of Raman bands at ~807, ~881, ~1255, ~1282, ~1436, ~1576, ~1604, ~2881 and ~3081cm(-1) gives signature of temperature induced slow crystal modification. The structural changes leading to crystal modification have been discussed. PMID- 23686093 TI - Bio-fabrication of zinc oxide nanoparticles using leaf extract of Parthenium hysterophorus L. and its size-dependent antifungal activity against plant fungal pathogens. AB - The study reports the synthesis and characterization of zinc oxide nanoparticles from weed plant by a novel method. The aim of this work is to synthesize zinc oxide nanoparticles from Parthenium hysterophorus L. by inexpensive, ecofriendly and simple method. Highly stable, spherical and hexagonal zinc oxide nanoparticles were synthesized by using different concentrations of 50% and 25% parthenium leaf extracts. Both the concentrations of the leaf extract act as reducing and capping agent for conversion of nanoparticles. Formation of zinc oxide nanoparticles have been confirmed by UV-Vis absorption spectroscopy, X-ray diffraction (XRD), Fourier trans-form infrared spectroscopy (FT-IR), scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analysis with energy dispersive X-ray analysis (EDX). SEM, TEM and EDX analysis reveals that spherical and hexagonal zinc oxide nanoparticle sizes were 27+/-5 nm and 84+/-2 nm respectively and chemical composition of zinc oxide were present. We synthesized different sized zinc oxide nanoparticles and explored the size dependent antifungal activity against plant fungal pathogens. Highest zone of inhibition was observed in 25 MUg/ml of 27+/-5 nm size zinc oxide nanoparticles against Aspergillus flavus and Aspergillus niger. Parthenium mediated zinc oxide nanoparticles were synthesized and proved to be good antifungal agents and environment friendly. PMID- 23686094 TI - A comparative study of the infrared and Raman spectra of aniline and o-, m-, p phenylenediamine isomers. AB - The structural stabilities of o-, m- and p-phenylenediamine (PDA) isomers were investigated by DFT-B3LYP and ab initio MP2 calculations with the 6-311G(**) basis set. From the calculations the three isomers were predicted to exist predominantly in an anti (transoid) structure. In the o-isomer, the syn (cisoid) form is calculated to turn to the anti (transoid) form with the two HNCC torsional angles of about 44 and 10 degrees and the NH2 inversion barrier of 3-4 kcal/mol. The CCNH torsional angles in the m-PDA and p-PDA isomers were calculated to be about 25-26 degrees as compared to 20 degrees in aniline. A comparison of the Raman spectra of the three PDA-s with those of aniline shows the high sensitivity of the ring breathing mode to the nature of substituents in the aniline ring. The vibrational wavenumbers were computed at the DFT-B3LYP for aniline and the o-, m- and p-PDA isomers for the purpose of comparison. Complete vibrational assignments were made on the basis of normal coordinate analyses and potential energy distributions for aniline and the o-, m- and p-PDA molecules. PMID- 23686095 TI - Duration of first remission, hematopoietic cell transplantation-specific comorbidity index and patient age predict survival of patients with AML transplanted in second CR. AB - Allo-SCT is potentially curative for patients with AML. Patients transplanted in CR2 tend to experience inferior survival compared with those in CR1. We retrospectively investigated the impact of pretransplant variables on the outcome of patients transplanted with AML in CR2. Ninety-four patients with AML in CR2 received a transplant between 1999 and 2011 with myeloablative (MA, n=65) or reduced-intensity conditioning regimens (RIC, n=29). Variables investigated included cytogenetic risk at diagnosis (SWOG), hematopoietic cell transplantation specific comorbidity index (HCT-CI), CMV status, duration of CR1 and age. Median age of all patients was 47 years (range 18-70). Multivariable analysis for OS identified three prognostically significant categories: a favorable risk group included patients with duration of CR1 >=6 months, age <55 years and HCT-CI score 0-3, an intermediate risk group with duration of CR1 >=6 months, age <55 years and HCT-CI score 4-5 and a high-risk group with duration of CR1 <6 months or age >=55 years (P=0.0001) with 5-year survivals of 53%, 31% and 6%, respectively. Acute and chronic GVHD did not influence this risk stratification. The stated risk factors discriminate patients with different OS and may assist in decision making for allo-SCT. PMID- 23686096 TI - Herpesviruses and oral ulcerations in hematopoietic SCT recipients. PMID- 23686097 TI - Human parvoviruses B19, PARV4 and bocavirus in pediatric patients with allogeneic hematopoietic SCT. AB - Among the immunocompetent, infections with parvovirus B19 (B19V) and human bocavirus (HBoV) 1 range clinically from asymptomatic to severe, while following allogeneic hematopoietic SCT (HSCT) B19V can cause a persistent severe illness. The epidemiology and clinical impact of HBoV1 and the other emerging parvovirus 4 (PARV4) among immunocompromised patients have not been established. To determine the occurrence and clinical spectrum of B19V, PARV4 and HBoV1 infections, we performed a longitudinal molecular surveillance among 53 allogeneic HSCT recipients for pre- and post-HSCT DNAemias of these parvoviruses. Quantitative real-time PCR showed B19V DNA in sera of 16 (30%) patients, at mean levels of 4.6 * 10(3), 9.9 * 10(7), 1.1 * 10(10) and 1.6 * 10(2) B19V DNA copies/mL pre-HSCT (9/53), and at 1 (6/53), 2 (4/53) and 3 months (1/25) post HSCT, respectively. However, no clinical manifestation correlated with the presence of B19V viremia. All B19V sequences were of genotype 1. None of the sera investigated contained PARV4 or HBoV1 DNAs. Our data demonstrate B19V viremia to be frequent among pediatric allogeneic HSCT recipients, yet without apparent clinical correlates. PARV4 or HBoV1 viremias were not seen in these immunocompromised patients. PMID- 23686099 TI - [Lung parenchyma-preserving oncological surgery]. PMID- 23686098 TI - Escalating-dose HLA-mismatched DLI is safe for the treatment of leukaemia relapse following alemtuzumab-based myeloablative allo-SCT. AB - Although the feasibility of using HLA-mismatched unrelated donors as an alternate graft source for haematopoietic SCT (HSCT) has been shown, little is known about the safety of HLA-mismatched DLI for the treatment of relapse. We examined the outcome of 58 consecutive leukaemia patients who received escalating-dose DLI for treatment of relapse after alemtuzumab-conditioned myeloablative unrelated donor HSCT at our institution. High-resolution HLA typing on stored DNA samples revealed mismatches in 28/58 patients who were considered HLA-matched at the time of transplantation. Following DLI from HLA-matched (10/10) (n=30) or -mismatched (7-9/10) (n=28) unrelated donors, we found no significant difference in the incidence of acute GVHD (17.2% versus 23.1%, P=0.59), probability of remission at 3 years (62.1% versus 63.9%, P=0.89) or 5-year OS (89.8% versus 77.7%, P=0.22). We conclude that escalating-dose DLI can be safely given to HLA-mismatched recipients following T-depleted myeloablative HSCT. PMID- 23686100 TI - mTHPC-mediated photodynamic therapy of early stage oral squamous cell carcinoma: a comparison to surgical treatment. AB - BACKGROUND: mTHPC-mediated photodynamic therapy (PDT) is used for treatment of early head and neck squamous cell carcinoma. This study is a retrospective comparison of PDT with transoral surgery in the treatment of early primary squamous cell carcinoma of the oral cavity/oropharynx. METHODS: PDT data were retrieved from four study databases; surgical results were retrieved from our institutional database. To select similar primary tumors, infiltration depth was restricted to 5 mm for the surgery group. A total of 126 T1 and 30 T2 tumors were included in the PDT group, and 58 T1 and 33 T2 tumors were included in the surgically treated group. RESULTS: Complete response rates with PDT and surgery were 86 and 76% for T1, respectively, and for T2 63 and 78%. Lower local disease free survival for PDT compared to surgery was found. However, when comparing the need for local retreatment, no significant difference for T1 tumors was found, while for T2 tumors surgery resulted in significantly less need for local retreatment. No significant differences in overall survival between surgery and PDT were observed. CONCLUSIONS: PDT for T1 tumors results in a similar need for retreatment compared to surgery, while for T2 tumors PDT performs worse. Local disease-free survival for surgery is better than for PDT. This may be influenced by the benefit surgery has of having histology available. This allows an early decision on reintervention, while for PDT one has to follow a wait-and-see policy. Future prospective studies should compare efficacy as well as morbidity. PMID- 23686101 TI - Breast-conserving therapy achieves locoregional outcomes comparable to mastectomy in women with T1-2N0 triple-negative breast cancer. AB - BACKGROUND: Conflicting data exist regarding optimum local therapy for early stage triple-negative breast cancer (TNBC). We examined outcomes according to local treatment type in a large cohort of node-negative TNBC patients. METHODS: A total of 1,242 consecutive patients with TNBC treated at a single institution from 1999 to 2008 were identified. Of these, 646 with pathologic stage T1-2N0 TNBC underwent breast-conserving therapy (BCT) (N = 448) or total mastectomy (TM) without postmastectomy radiation (N = 198) and comprised the study population. Locoregional recurrence (LRR), distant metastasis (DM), and overall recurrence were investigated with a competing risk analysis using Gray's test and multivariable Fine and Gray competing risk regression. Overall survival was assessed using standard Kaplan-Meier methods and a Cox proportional hazards analysis. RESULTS: Median follow-up was 78.3 months (range 1-156). Eight-one percent of patients received adjuvant chemotherapy. TM patients were younger, were more likely to have lymphovascular invasion, and had larger tumors than patients undergoing BCT (all P <= 0.05). The 5-year cumulative incidence of LRR was 4.2 and 5.4 % for patients undergoing BCT and TM, respectively. There was no significant difference in LRR, DM, overall recurrence, disease free survival, or overall survival between groups on univariate analysis, or after adjusting for other variables in multivariate models. Lack of chemotherapy and high tumor stage independently predicted for decreased overall survival (both P < 0.001). CONCLUSIONS: A low, 5-year risk of LRR (4.7 %) was achieved in a large group of women with T1-2N0 TNBC treated with multimodality therapy. BCT was as equally effective as TM for local and distant control. PMID- 23686102 TI - Predictability of peripheral lymphocyte reduction of novel S1P1 agonists by in vitro GPCR signaling profile. AB - Surrogate readouts of G-protein-coupled receptor signaling pathways using highly engineered systems are often employed in the drug discovery process. However, accumulating data have demonstrated the importance of selecting relevant biological activity rather than technically facile assays to support high throughout screening and subsequent structure-activity relationship studies. Here we report a case study using sphingosine-1-phosphate receptor 1 (S1P(1)) as the model system to compare compound activity in six different in vitro assays with their ability to predict in vivo efficacy. S1P(1) has long been validated as a therapeutic target for autoimmune diseases. In this article, in vivo and in vitro studies on 19 S1P1 agonists are reported. In vitro activities of these S1P(1) agonists, together with S1P and FTY720p, on Ca(2+) mobilization, adenylyl cyclase inhibition, extracellular signal-related kinase (ERK) phosphorylation, beta arrestin recruitment, and receptor internalization, were determined. The in vitro potency of these compounds was correlated with their ability to induce peripheral lymphocyte reduction. The results revealed that inhibition of adenylyl cyclase and induction of beta-arrestin recruitment and receptor internalization are good indicators to predict in vivo efficacy, whereas induction of Ca(2+) mobilization through G(qi/5) coupling and ERK phosphorylation is irrelevant. This study demonstrated the importance of identifying an appropriate in vitro assay to predict in vivo activity based on the biological relevance in the drug discovery setting. PMID- 23686103 TI - Distinguishing on-target versus off-target activity in early antibacterial drug discovery using a macromolecular synthesis assay. AB - The macromolecular synthesis assay was optimized in both S. aureus and E. coli imp and used to define patterns of inhibition of DNA, RNA, protein, and cell wall biosynthesis of several drug classes. The concentration of drug required to elicit pathway inhibition differed among the antimicrobial agents tested, with inhibition detected at concentrations significantly below the minimum inhibitory concentration (MIC) for tedizolid; within 4-fold of the MIC for ciprofloxacin, cefepime, vancomycin, tetracycline, and chloramphenicol; and significantly above the MIC for rifampicin and kanamycin. In a DNA gyrase/topoisomerase IV structure based drug design optimization program, the assay rapidly identified undesirable off-target activity within certain chemotypes, altering the course of the program to focus on the series that maintained on-target activity. PMID- 23686104 TI - The G-M-N motif determines ion selectivity in the yeast magnesium channel Mrs2p. AB - The highly conserved G-M-N motif of the CorA-Mrs2-Alr1 family of Mg(2+) channels has been shown to be essential for Mg(2+) transport. We performed random mutagenesis of the G-M-N sequence of Saccharomyces cerevisiae Mrs2p in an unbiased genetic screen. A large number of mutants still capable of Mg(2+) influx, albeit below the wild-type level, were generated. Growth complementation assays, performed in media supplemented with Ca(2+) or Co(2+) or Mn(2+) or Zn(2+) at varying concentrations, lead to identification of mutants with reduced growth in the presence of Mn(2+) and Zn(2+). We hereby conclude that (1) at least two, but predominantly all three amino acids of the G-M-N motif must be replaced by certain combinations of other amino acids to remain functional, (2) replacement of any single amino acid within the G-M-N motif always impairs the function of Mrs2p, and (3) we show that the G-M-N motif determines ion selectivity, likely in concurrence with the negatively charged loop at the entrance of the channel thereby forming the Mrs2p selectivity filter. PMID- 23686105 TI - Intracarotid etomidate is a safe alternative to sodium amobarbital for the Wada test. AB - BACKGROUND: The Wada procedure (the intracarotid amobarbital procedure) has been used widely to evaluate the hemispheric dominance of language and memory before temporal lobe surgery in patients with medically refractory seizures. Because of repeated shortage of sodium amobarbital, attempts have been made to find a suitable alternative to sodium amobarbital. The aim of our study was to review our experience with the use of etomidate as an alternative to sodium amobarbital for Wada testing in patients with medically refractory seizures. METHODS: After the ethics approval, we retrospectively reviewed the charts of 29 consecutive patients who underwent Wada test with etomidate. Data from a total of 50 hemispheric injections were reviewed and analyzed. This included the electroencephalographic and motor effects of etomidate injection and their time course (onset and recovery), Wada test results (language laterality and memory performance), and all adverse events during the procedure. RESULTS: Intracarotid administration of etomidate produced a predictable electroencephalographic and motor effects in all patients. The desirable effect was seen with a single bolus dose of 2 mg followed by an infusion. Shivering was the most common side effect, seen in all the patients. Successful testing was possible in nearly all patients without any major side effects. The "pass rate" of valid tests was in good accord with our previous experience with the use of sodium amobarbital. CONCLUSION: From our experience, etomidate is a safe alternative to sodium amobarbital for the Wada test for determining the hemispheric dominance for speech and in predicting the memory outcome. PMID- 23686106 TI - Retrogasserian glycerol rhizolysis: first description of occurrence trigeminocardiac reflex. PMID- 23686107 TI - Paroxysmal sympathetic hyperactivity in a child with moyamoya disease. PMID- 23686108 TI - Up-regulation of Slc39A2(Zip2) mRNA in peripheral blood mononuclear cells from patients with pulmonary tuberculosis. AB - Zinc is the most common trace mineral after iron in the human body. In organisms, zinc transporters help zinc influx and efflux from cells. A previous study has reported that Zip2 was up-regulated over 27-fold in human monocytic THP-1 cells, when intracellular zinc was depleted by TPEN. Our study found Zip2 was over expressed in leukocytes of asthmatic infants, especially those in which the serum zinc level was lower than those in healthy infants. Pulmonary tuberculosis (PTB) patients have significantly low serum zinc levels. Here we investigated whether Zip2 level was changed in the patients with PTB. Zip2 mRNA and protein levels in peripheral blood mononuclear cells (PBMC) from PTB (n1=23) and healthy controls (n2=42) were detected by quantitative real-time PCR and western blot, respectively. mRNA expression levels of another four zinc transporters, Zip1, Zip6, Zip8 and ZnT1, were detected by quantitative real-time PCR. Zip2 mRNA level was significantly up-regulated in PTB patients (P=0.001), and Zip8 mRNA level was significantly down-regulated compared with control individuals (P<0.001). In contrast, there were no significant changes in mRNA levels of Zip1, Zip6 and ZnT1 in either group (P>0.05). Zip2 protein expression levels increased in PTB patients compared with control individuals. Our study found that knockdown of ZIP2 with siRNA caused a decrease in Zip2 levels in PBMC of PTB patients, while reducing the expression of INF-gamma (P<0.01) and increasing the expression of IL 6(P<0.01). These data provide evidence that increased expression of Zip2 gene is closely associated with immunity of PTB patients, suggesting that the Zip2 gene may play a key role in the initial infection control of the human body, by promoting and maintaining the immune response of adaptive T cells. PMID- 23686109 TI - Predictive models and spatial variations of vital capacity in healthy people from 6 to 84 years old in China based on geographical factors. AB - The aim of this study was to provide a scientific basic for a unified standard of the reference value of vital capacity (VC) of healthy subjects from 6 and 84 years old in China. The normal reference value of VC was correlated to seven geographical factors, including altitude (X1), annual duration of sunshine (X2), annual mean air temperature (X3), annual mean relative humidity (X4), annual precipitation amount (X5), annual air temperature range (X6) and annual mean wind speed (X7). Predictive models were established by five different linear and nonlinear methods. The best models were selected by t-test. The geographical distribution map of VC in different age groups can be interpolated by Kriging's method using ArcGIS software. It was found that the correlation of VC and geographical factors in China was quite significant, especially for both males and females aged from 6 to 45. The best models were built for different age groups. The geographical distribution map shows the spatial variations of VC in China precisely. The VC of healthy subjects can be simulated by the best model or acquired from the geographical distribution map provided the geographical factors for that city or county of China are known. PMID- 23686110 TI - Effect of ambient temperature and attachment method on surface temperature measurements. AB - Accurate measurement of skin surface temperature is essential in both thermo physiological and clinical applications. However, a literature review of the last two decades of physiological or clinical research revealed an inconsistency or a lack of information on how temperature sensors were attached to the skin surface. The purpose of this study was to systematically compare and quantify the performance of different commercially available temperature sensors and their typical attachment methods, and, secondly, to provide a time-efficient and reliable method for testing any sensor-tape combination. In conclusion, both the sensor type and the attachment method influenced the results of temperature measurements (both its absolute and relative dimensions). The sensor shape and the contact of its sensing area to the surface, as well as the conductance of the tape were the most important parameters to minimise the influence of environmental conditions on surface temperature measurement. These results suggest that temperature sensors and attachment methods for human subject and manikin trials should be selected carefully, with a systematic evaluation of the sensor-tape system under conditions of use, and emphasise the need to report these parameters in publications. PMID- 23686111 TI - Bioclimatic and vegetation mapping of a topographically complex oceanic island applying different interpolation techniques. AB - Different spatial interpolation techniques have been applied to construct objective bioclimatic maps of La Palma, Canary Islands. Interpolation of climatic data on this topographically complex island with strong elevation and climatic gradients represents a challenge. Furthermore, meteorological stations are not evenly distributed over the island, with few stations at high elevations. We carried out spatial interpolations of the compensated thermicity index (Itc) and the annual ombrothermic Index (Io), in order to obtain appropriate bioclimatic maps by using automatic interpolation procedures, and to establish their relation to potential vegetation units for constructing a climatophilous potential natural vegetation map (CPNV). For this purpose, we used five interpolation techniques implemented in a GIS: inverse distance weighting (IDW), ordinary kriging (OK), ordinary cokriging (OCK), multiple linear regression (MLR) and MLR followed by ordinary kriging of the regression residuals. Two topographic variables (elevation and aspect), derived from a high-resolution digital elevation model (DEM), were included in OCK and MLR. The accuracy of the interpolation techniques was examined by the results of the error statistics of test data derived from comparison of the predicted and measured values. Best results for both bioclimatic indices were obtained with the MLR method with interpolation of the residuals showing the highest R2 of the regression between observed and predicted values and lowest values of root mean square errors. MLR with correction of interpolated residuals is an attractive interpolation method for bioclimatic mapping on this oceanic island since it permits one to fully account for easily available geographic information but also takes into account local variation of climatic data. PMID- 23686112 TI - The helix 1-3 loop in the glucocorticoid receptor LBD is a regulatory element for FKBP cochaperones. AB - The heat-shock protein 90 (Hsp90) cochaperone FK506-binding protein 52 (FKBP52) upregulates, whereas FKBP51 inhibits, hormone binding and nuclear targeting of the glucocorticoid receptor (GR). Decreased cortisol sensitivity in the guinea pig is attributed to changes within the helix 1 to helix 3 (H1-H3) loop of the guinea pig GR (gpGR) ligand-binding domain. It has been proposed that this loop serves as a contact point for FKBP52 and/or FKBP51 with receptor. We examined the role of the H1-H3 loop in GR activation by FKBP52 using a Saccharomyces cerevisiae model. The activity of rat GR (rGR) containing the gpGR H1-H3 loop substitutions was still potentiated by FKBP52, confirming the loop is not involved in primary FKBP52 interactions. Additional assays also excluded a role for other intervening loops between ligand-binding domain helices in direct interactions with FKBP52 associated with enhanced receptor activity. Complementary studies in FKBP51-deficient mouse embryo fibroblasts and HEK293 cells demonstrated that substitution of the gpGR H1-H3 loop residues into rGR dramatically increased receptor repression by FKBP51 without enhancing receptor FKBP51 interaction and did not alter recruitment of endogenous Hsp90 and the p23 cochaperone to receptor complexes. FKBP51 suppression of the mutated rGR did not require FKBP51 peptidylprolyl cis-trans isomerase activity and was not disrupted by mutation of the FK1 proline-rich loop thought to mediate reciprocal FKBP influences on receptor activity. We conclude that the gpGR-specific mutations within the H1-H3 loop confer global changes within the GR-Hsp90 complex that favor FKBP51 repression over FKBP52 potentiation, thus identifying the loop as an important target for GR regulation by the FKBP cochaperones. PMID- 23686113 TI - Minireview: The effects of species ortholog and SNP variation on receptors for free fatty acids. AB - Although it is widely assumed that species orthologs of hormone-responsive G protein-coupled receptors will be activated by the same endogenously produced ligand(s), variation in potency, particularly in cases in which more than 1 receptor responds to the same hormone, can result in challenges in defining the contribution of individual receptors in different species. This can create considerably greater issues when using synthetic chemical ligands and, in some cases, may result in a complete lack of efficacy of such a ligand when used in animal models of pathophysiology. In man, the concept that distinct responses of individuals to medicines may reflect differences in the ability of such drugs to bind to or activate single nucleotide polymorphism variants of receptors is more established as a concept but, in many cases, clear links between such variants that are associated with disease phenotypes and substantial differences in receptor ligand pharmacology have been more difficult to obtain. Herein we consider each of these issues for the group of free fatty acid receptors, FFA1 FFA4, defined to be activated by free fatty acids of varying chain length, which, based on their production by 1 tissue or location and action in distinct locations, have been suggested to possess characteristics of hormones. PMID- 23686114 TI - Differential regulation of gene expression by LXRs in response to macrophage cholesterol loading. AB - The ability of cells to precisely control gene expression in response to intracellular and extracellular signals plays an important role in both normal physiology and in pathological settings. For instance, the accumulation of excess cholesterol by macrophages initiates a genetic response mediated by the liver X receptors (LXRs)-alpha (NR1H3) and LXRbeta (NR1H2), which facilitates the transport of cholesterol out of cells to high-density lipoprotein particles. Studies using synthetic LXR agonists have also demonstrated that macrophage LXR activation simultaneously induces a second network of genes that promotes fatty acid and triglyceride synthesis that may support the detoxification of excess free cholesterol by storage in the ester form. We now show that treatment of human THP-1 macrophages with endogenous or synthetic LXR ligands stimulates both transcriptional and posttranscriptional pathways that result in the selective recruitment of the LXRalpha subtype to LXR-regulated promoters. Interestingly, when human or mouse macrophages are loaded with cholesterol under conditions that mimic the development of atherogenic macrophage foam cells, a selective LXR response is generated that induces genes mediating cholesterol transport but does not coordinately regulate genes involved in fatty acid synthesis. The gene selective response to cholesterol loading occurs, even in the presence of LXRalpha binding to the promoter of the gene encoding the sterol regulatory element-binding protein-1c, the master transcriptional regulator of fatty acid synthesis. The ability of promoter bound LXRalpha to recruit RNA polymerase to the sterol regulatory element-binding protein-1c promoter, however, appears to be ligand selective. PMID- 23686115 TI - Current employment status, occupational category, occupational hazard exposure and job stress in relation to telomere length: the Multiethnic Study of Atherosclerosis (MESA). AB - OBJECTIVE: Telomere length has been proposed as a biomarker of cell senescence, which is associated with a wide array of adverse health outcomes. While work is a major determinant of health, few studies have investigated the association of telomere length with various dimensions of occupation. Accelerated cellular aging could be a common pathway linking occupational exposure to several health outcomes. METHODS: Leukocyte telomere length was assessed using quantitative PCR in a community-based sample of 981 individuals (age: 45-84 years). Questionnaires were used to collect information on current employment status, current or main occupation before retirement and job strain. The Occupational Resource Network (O*NET) database was linked to the questionnaire data to create five exposure measures: physical activity on the job, physical hazard exposure, interpersonal stressors, job control and job demands. Linear regression was used to estimate associations of occupational characteristics with telomere lengths after adjustment for age, sex, race, socioeconomic position and several behavioural risk factors. RESULTS: There were no mean differences in telomere lengths across current employment status, occupational category, job strain categories or levels of most O*NET exposure measures. There was also no evidence that being in lower status occupational categories or being exposed to higher levels of adverse physical or psychosocial exposures accelerated the association between age and telomere shortening. CONCLUSIONS: Cellular aging as reflected by shorter telomeres does not appear to be an important pathway linking occupation to various health outcomes. PMID- 23686116 TI - De novo AML patients with favourable-intermediate karyotype may benefit from the addition of low-dose gemtuzumab ozogamicin (GO) to fludarabine, Ara-C and idarubicin (FLAI): a contribution to the reopened "GO question". AB - We report the final results of a prospective trial testing the combination of fludarabine, Ara-C and idarubicin (FLAI) followed by low-dose gemtuzumab ozogamicin (FLAI-GO) in 85 patients aged 60 years or more with CD33+ acute myeloid leukaemia (AML). Median age was 68 years (60-82); karyotype was unfavourable in 21 patients (24%), intermediate in 63 (74%) and favourable in 1 (2%). There were five therapy-related deaths. Of the 80 evaluable patients, 47 achieved complete response (CR) (58%); CR rates were 65 and 32% in good intermediate/poor karyotype patients, respectively. Median length of CR was 7 months (3-76). The cumulative incidence of relapse was 84% with an actuarial survival of 50.3% at 1 year and 14.4% at 2 years. The study control population is an unselected consecutive historic cohort of 104 patients treated with the FLAI regimen, who were matched for age and prognostic factors. CR rates after FLAI-GO and FLAI were comparable. However, patients with de novo AML and intermediate favourable karyotype receiving GO had a significantly lower risk of relapse at 2 years as compared to patients not receiving GO (n = 77) (40 vs 80%, p = 0.01) and significantly better disease-free survival (p = 0.018) and overall survival (p = 0.022). PMID- 23686117 TI - Tuberculosis: lights and shadows in the current diagnostic landscape. AB - Despite the improvements in the global fight against tuberculosis (TB), critical points still remain and fuel the epidemic. Even today, only 30% of the estimate number of people suffering from TB worldwide are correctly diagnosed, and lower proportions of cases are diagnosed in high-TB-burden, low-resource settings. Current TB diagnostics are still suboptimal in their performance for childhood TB, smear-negative TB, extrapulmonary TB, HIV-TB and drug-resistant TB. Furthermore, there is no gold standard test for the identification of latent TB infection status. Improving diagnosis is therefore a strategic goal in TB research, and the pipeline of diagnostic tools is rapidly growing: new ways of performing "old" tests (e.g. sputum smear microscopy) and completely innovative tools (e.g. new technologies for molecular diagnosis) are under investigation or have already been endorsed by WHO. Some of the structural limits of current TB diagnostics are likely to be overcome by such new tools, but research is still needed. Finally, the roll-out of new technologies and the development of newer ones will necessarily have to take into account the diagnostic needs of each context they are directed to (point-of-need testing approach), together with the logistic, economic and technical constraints present in the majority of high-TB burden settings. PMID- 23686118 TI - Cross-sectional study of community serostatus to highlight undiagnosed HIV infections with oral fluid HIV-1/2 rapid test in non-conventional settings. AB - The submerged portion of undiagnosed HIV infection in Italy is about 30% of subjects found seropositive. This fact represents one of the most important public health problems hindering the control of infection progression. This means we need to fight unawareness and social stigma and promote easy and friendly access to HIV test. We developed a Prevention Program called "EASY test Project", offering a new rapid HIV test on oral fluid, to evaluate the acceptability of an alternative, free and anonymous test available in different settings (on board a "Motor Home" at public events, Points of Care, STDs outpatient prevention units and GP surgeries). From December 2008 to December 2012 we performed 7,865 HIV saliva tests, with 50 new infections found (0.6% of the total) out of 140,000 informed subjects. From the self-reported characteristics of respondents, the population approaching the EAST test project was represented by males (70%) aged between 20 and 50 years, 61% with a medium-high education level, 62% homosexuals (MSM), 88% reported unsafe sexual behaviours, and 48% had never undergone an HIV screening test. In five years of the Prevention Program, 100% of subjects interviewed gave a general favorable consent in approaching rapid and not invasive screening, immediate return of the result, and a timely specialized approach and treatment of HIV positive subjects. Results from our study confirm that the rapid and alternative test may contribute to HIV prevention strategies and to the control of the spread of infection and HIV disease progression by reaching a larger population, particularly when and where regular screening procedures are difficult to obtain or are not preferred. PMID- 23686119 TI - Human papillomavirus tumor-infiltrating T-regulatory lymphocytes and P53 codon 72 polymorphisms correlate with clinical staging and prognosis of oropharyngeal cancer. AB - The association between human papillomavirus (HPV) DNA positivity, p53 codon 72 polymorphisms, and the type of leukocyte infiltration in head and neck squamous cell carcinomas (HNSCC) and their combined impact upon patient survival is poorly investigated. For this reason, leukocyte infiltration profile and p53 codon 72 polymorphisms were assessed in freshly removed HNSCC specimens (N=71 patients). HPV detection was performed by nested-PCR followed by DNA sequencing. Viral loads were determined by quantitative RT-PCR. The choice to investigate fresh instead of archive paraffin-embedded specimens was privileged to avoid possible artifacts due to sample processing. HPV DNA was detected in 14% of cases. Oropharyngeal carcinomas were the most frequently associated with the presence of HPV16 DNA (41%) and were associated with p53 Pro/Pro or Pro/Arg polymorphisms. In HPV16 positive oropharyngeal carcinomas increased infiltrations of CD3+ and FoxP3+ T cells correlated with higher HPV16 copy numbers. The presence of HPV may trigger a stronger immune response and may be considered a reliable marker for clinical staging and a more favorable prognosis of oropharyngeal carcinoma. PMID- 23686120 TI - Enhancement of Th1 immune responses to recombinant influenza nucleoprotein by Ribi adjuvant. AB - A broad coverage influenza vaccine against multiple viral strains based on the viral nucleoprotein (NP) is a goal pursued by many laboratories. If the goal is to formulate the vaccine with recombinant NP it is essential to count on adjuvants capable of inducing cellular immunity. This work have studied the effect of the monophosphoryl lipid A and trehalose dimycolate, known as the Ribi Adjuvant System (RAS), in the immune response induced in mice immunized with recombinant NP. The NP was formulated with RAS and used to immunize BALB/c mice. Immunizations with NP-RAS increased the humoral and cellular immune responses compared to unadjuvanted NP. The predominant antibody isotype was IgG2a, suggesting the development of a Th1 response. Analysis of the cytokines from mice immunized with NP-RAS showed a significant increase in the production of IFN-g and a decreased production of IL-10 and IL-4 compared to controls without RAS. These results are similar to those usually obtained using Freund's adjuvant, known to induce Th1 and CTL responses when co-administered with purified proteins, and suggest that a similar approach may be possible to enhance the performance of a T-cell vaccine containing NP. PMID- 23686122 TI - Stress-induced L-forms of Mycobacterium bovis: a challenge to survivability. AB - This study addressed the ability of Mycobacterium bovis to produce unusual extreme morphologic forms (cell wall-deficient or L-forms) under stress conditions. Models using nutrient starvation and cryogenic stress treatments of Mycobacterium bovis, as well as the filtration technique followed by cultivation in semisolid medium, were used for isolation of L-form variants. Morphological transformations and developmental stages, typical for the bacterial L-cycle were observed by electron microscopy. Of special interest was the formation of giant filaments and common extremely thick membranous structures enveloping the entire L-form population. Following collapse of giant filamentous structures small viable cell elements, mainly granules and coccobacilli, were released and proved able to grow into large bodies or multiply by fission or budding. Derivation of viable filterable forms from L-form cultures and parental strain and their identification as Mycobacterium bovis based on specific IS6110 PCR was noteworthy. We suggest that formation of giant filaments and thick common membranous envelopes, observed under stress conditions, may serve a twofold purpose - protection against an unfavourable environment, and a role in reproduction of Mycobacterium bovis L-forms. The observed L-form conversion phenomenon in Mycobacterium bovis seems to be associated with an adaptive strategy of this pathogen for survival and reproduction in an unfavorable environment. PMID- 23686121 TI - Tuberculin skin test and QuantiFERON in children. AB - Until some time ago, the tuberculin skin test was the only available screening test for the diagnosis of tubercular infection. Now the new interferon-? release assay QuantiFERON-TB Gold shows promise of greater accuracy in the detection of Mycobacterium tuberculosis-infected subjects. The aim of our study was to evaluate the use of QuantiFERONTB Gold in children and to verify its agreement with the tuberculin skin test. A total of 27 children had a positive tuberculin skin test, 76 subjects were negative and the remaining 2 had a dubious Mantoux test. A positive QuantiFERONTB Gold result was obtained in 21 children while in 84 it was negative. No statistically significant difference was detected between the two assays, which showed a concordance of 90.57%. Our results demonstrated a good concordance between the tuberculin skin test and the interferon-? release assay, though the QuantiFERON-TB may have several advantages over the Mantoux test. PMID- 23686123 TI - Potential of probiotic strains to modulate the inflammatory responses of epithelial and immune cells in vitro. AB - Lactobacilli are important human commensal microbiota that are considered to be probiotic as they have been shown to reduce pathogenic infections and chronic inflammation. This study compared 4 strains of lactobacilli for their probiotic potential. These 4 strains showed varying capacities for adhesion and cytokine induction (interleukin [IL]-8 and IL-10) in different human epithelial cells, such as primary cultures of buccal cavity cells, and established cell lines derived from epithelia of the pharynx, intestine and cervix. After exposure to lactobacilli, secretion of cytokines (IL- 10, IL-12p70, interferon-?, and tumor necrosis factor-?) was induced at varying levels in different cultures of human immune cells, including dendritic cells, monocyte-depleted peripheral blood mononuclear cells, CD14+ cells, CD4+CD25- T cells, and regulatory T-cells. Growth inhibition of pathogenic strains was detectable in the presence of lactobacilli in vitro. Moreover, among the 4 strains tested, Lactobacillus salivarius sp. salicinius AP-32 was found to have the highest probiotic potential. This study highlights the complex host-pathogen-microbiota interactions and indicates that a combination of strains may have to be used to provide all the desirable probiotic benefits. PMID- 23686124 TI - Evaluation of brilliance CRE agar for the detection of carbapenem-resistant gram negative bacteria. AB - The aim of this work was to evaluate the performance of the new chromogenic medium BrillianceTM CREAgar (Thermo Fisher Scientific) for determining the limit of detection of carbapenem-resistant enterobacteria (CRE). A total of 70 clinical isolates were studied. Of these, 30 were well-characterized CRE, including Klebsiella pneumoniae strains producing KPC-, VIM-, and OXA-type enzymes, VIM positive Enterobacter cloacae and Escherichia coli, NDM-positive E. coli, and enterobacterial isolates characterized by porin loss associated with ESBL production or AmpC hyperproduction. Ten carbapenem-resistant non-fermentative isolates were also included as well as 30 carbapenem-susceptible isolates. Carbapenem-resistant strains were inoculated at three different concentrations onto Brilliance CRE Agar (from 1.5x101 CFU/ml up to 1.5x104 CFU/ml) whereas carbapenem-susceptible isolates were inoculated at a concentration of 1.5x102 CFU/ml. The medium sustained the growth of carbapenem-resistant isolates, showing detection limits from 1.5x101 CFU/ml (in 31/40 cases) to 1.5x104 CFU/ml. No growth was observed with carbapenem-sensitive control strains. Our results indicate that the Brilliance CRE Agar allows the growth of carbapenem-resistant isolates with low detection limits and could represent a useful screening medium for both enterobacteria and non-fermentative Gram-negative strains resistant to carbapenems. PMID- 23686125 TI - Prevalence of the lmo0036-0043 gene cluster encoding arginine deiminase and agmatine deiminase systems in Listeria monocytogenes. AB - Arginine deiminase and agmatine deiminase systems are involved in acid tolerance, and their encoding genes form the cluster lmo0036-0043 in Listeria monocytogenes. While lmo0042 and lmo0043 were conserved in all L. monocytogenes strains, the lmo0036-0041 region of this cluster was identified in all lineages I and II, and the majority of lineage IV (83.3%) strains, but absent in all lineage III and a small fraction of lineage IV (16.7%) strains, suggesting that the presence of the complete lmo0036-0043 cluster is dependent on lineages. lmo0036-0043-complete and -deficient lineage IV strains exhibit specific ascB-dapE profiles, which might represent two subpopulations with distinct genetic characteristics. PMID- 23686126 TI - Stroke in patients with tuberculous meningitis in a low TB endemic country: an increasing medical emergency? AB - Stroke due to brain vascular disease is a serious complication of tuberculous meningitis (TBM). This study evaluated the frequency, clinical characteristics, risk factors and outcomes of patients with TBM complicated by stroke admitted to the Infectious Disease Clinic, University of Perugia Hospital, Italy from 1971 to 2010. Over four decades, 419 patients were admitted with tuberculosis, of these 30 (7.1%) were diagnosed with TBM: 20 definite, one probable and nine possible. Twenty-six were evaluable for stroke and six (23%) had stroke. The latter six had advanced stages of meningitis, two tested HIV positive, three HIV negative and in one HIV was not performed. Of seven patients without stroke tested for HIV, only one resulted positive. No differences were found regarding CSF cell count, sugar, protein, microscopy or growth of Mycobacterium tuberculosis among patients with or without stroke. The overall survival rate at discharge was 83% in patients with stroke and 95% in those without stroke. It was found that stroke can be frequent among patients with TBM and the presence of HIV infection might be associated with a higher rate of stroke. Further research is needed on these findings, especially in low TB endemic countries. PMID- 23686127 TI - Port-related Delftia tsuruhatensis bacteremia in a patient with breast cancer. AB - Delftia tsuruhatensis is a non-glucose fermenting, oxidase positive, motile, gram negative bacillus first isolated from activated sludge collected from a domestic wastewater treatment plant in Japan. To the best of our knowledge only one case of infection with Delftia tsuruhatensis exists in the medical literature. This is the second case report of human infection having Delftia tsuruhatensis as a causative agent. PMID- 23686128 TI - Dysenteric syndrome due to Balantidium coli: a case report. AB - A 28-year-old man was hospitalized for a dysenteric syndrome that had developed during the previous days. Physical examination revealed abdominal pains, fever, vomiting and more than ten liquid stools per day. Fresh stool examination showed numerous mobile ciliated trophozoites of Balantidium coli. The patient reported having been on a hike the previous weekend during which he had drunk water through a hydration pouch bladder. Complete resolution was observed after intravenous rehydration and ten days of oral treatment with metronidazole (Flagyl(r)). Balantidium coli is the largest ciliate protozoan able to infect humans. This parasite is common in pigs and has a worldwide distribution. Human infections, a rare event in industrialised countries, are usually acquired by ingestion of food or water contaminated by mammal faeces. Human B. coli infections are easily treated but may be severe and even fatal if neglected. PMID- 23686129 TI - In defense of basic science funding: today's scientific discovery is tomorrow's medical advance. AB - In this address, I will discuss the importance of basic science in tackling our health problems. I will also describe how the funding cuts are damaging our economic competitiveness and turning our young people away from science. PMID- 23686130 TI - Improvements in negative symptoms and functional outcome after a new generation cognitive remediation program: a randomized controlled trial. AB - Cognitive remediation improves cognition in patients with schizophrenia, but its effect on other relevant factors such as negative symptoms and functional outcome has not been extensively studied. In this hospital-based study, 84 inpatients with chronic schizophrenia were recruited from Alava Hospital (Spain). All of the subjects underwent a baseline and a 3-month assessment that examined neurocognition, clinical symptoms, insight, and functional outcome according to the Global Assessment of Functioning (GAF) scale and Disability Assessment Schedule from World Health Organization (DAS-WHO). In addition to receiving standard treatment, patients were randomly assigned either to receive neuropsychological rehabilitation (REHACOP) or to a control group. REHACOP is an integrative program that taps all basic cognitive functions. The program included experts' latest suggestions about positive feedback and activities of daily living in the patients' environment. The REHACOP group showed significantly greater improvements at 3 months in the areas of neurocognition, negative symptoms, disorganization, and emotional distress compared with the control group (Cohen's effect size for these changes ranged from d = 0.47 for emotional distress to d = 0.58 for disorganization symptoms). The REHACOP group also improved significantly in both the GAF (d = 0.61) and DAS-WHO total scores (d = 0.57). Specifically, the patients showed significant improvement in vocational outcomes (d = 0.47), family contact (d = 0.50), and social competence (d = 0.56). In conclusion, neuropsychological rehabilitation may be useful for the reduction of negative symptoms and functional disability in schizophrenia. These findings support the integration of neuropsychological rehabilitation into standard treatment programs for patients with schizophrenia. PMID- 23686131 TI - Prevalence of site-specific thigh sarcopenia in Japanese men and women. AB - The purpose of this study was to compare the prevalence of severe sarcopenia detected by total skeletal muscle mass (SM) index and of site-specific thigh sarcopenia for differing age groups in men and women. Japanese nonobese men and women aged 20 to 85 (n = 1,994, 55 % women) had muscle thickness (MTH) measured by ultrasound at six sites on the anterior and posterior aspects of the body. SM was estimated from ultrasound-derived prediction equations. Site-specific thigh sarcopenia was calculated using ultrasound-measured MTH at the anterior and posterior aspects of the thigh (MTH ratio, anterior 50 %/posterior 50 % thigh MTH (A50/P50 MTH)). Sarcopenia was defined as a SM index (SM divided by height(2)) of >2 standard deviations (SD) below the mean for young adults. Site-specific thigh sarcopenia was defined as a ratio of A50/P50 MTH of >2 SD below the mean for young adults. Age was inversely correlated to SM index and A50/P50 MTH in men (r = -0.480 and r = -0.522) and women (r = -0.243 and r = -0.516). The prevalence rate of sarcopenia was less than 3 % for women under the age of 60, 7 % for ages 60-69, and 24 % for ages 70-80. In men, the prevalence rate of sarcopenia was less than 7 % under the age of 50, 18 % for ages 50-59, 33 % for ages 60-69, and 47 % for ages 70-85. Compared to the sarcopenia estimated by SM index, there was a higher prevalence of site-specific thigh sarcopenia observed in both sexes. These results suggest that site-specific thigh sarcopenia appears before it is able to be detected at the whole body level. PMID- 23686132 TI - Comparisons across depression assessment instruments in adolescence and young adulthood: an item response theory study using two linking methods. AB - Item response theory (IRT) methods allow for comparing the utility of instruments based on the range and precision of severity assessed by each instrument. As adolescents and young adults can display rapid increases in depressive symptoms, there is a crucial need to sensitively assess mild elevations of symptoms (as an index of initial risk) and moderate-severe symptoms (as an indicator of treatment disposition). We compare the information assessed by the Beck Depression Inventory (BDI) to the newly developed Patient Reported Outcome Measurement Information System - Depression measure (PROMIS-Depression), and the Center for Epidemiologic Studies - Depression (CES-D) scale. The present work is based on data from two fully independent samples of community adolescents and young adults. One sample completed the BDI and CES-D (n = 1,482) and the second sample (n = 673) completed the PROMIS-Depression measure and the CES-D. Using two different IRT-based linking methods, (1) equating based on common items and (2) concurrent calibration methods, analyses revealed that the PROMIS-Depression measure assessed information over the widest range of depressive severity with greatest measurement precision relative to the other instruments. This was true for both the 28-item and 8-item versions of the PROMIS-Depression measure. Findings suggest that the PROMIS-Depression measure assessed depression severity with greatest precision and over the widest severity range of the assessed instruments. However, future work is necessary to demonstrate that the PROMIS Depression measure has reliable associations with external criteria and is sensitive to treatment response. PMID- 23686133 TI - Influence of calcium hydroxide dressing and acid etching on the push-out bond strengths of three luting resins to root canal dentin. AB - OBJECTIVES: This study aims to investigate the effects of calcium hydroxide (Ca(OH)2) dressing in root canals and the effects of subsequent acid etching on the adhesion of luting resins to root canals. MATERIALS AND METHODS: Root specimens were prepared from extracted human permanent molars. Specimen canals were (1) filled with etch-and-rinse (Nexus(r) third generation (NX3)) and two self-adhesive (RelyX Unicem, Maxcem Elite) luting resins, respectively; (2) dressed with Ca(OH)2 before Ca(OH)2 removal and luting resin filling; (3) dressed with Ca(OH)2 before Ca(OH)2 removal and post-cementation; or (4) treated as described in item (2) except that the canals were further etched with phosphoric acid before luting resin filling. Push-out bond strengths were measured and analyzed using one-way analysis of variance, and Fisher's multiple comparison tests provided a follow-up comparison among these four canal treatments. Attenuated total reflectance-Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy (XPS), and scanning electron microscopy (SEM) were used to analyze the specimen surfaces. RESULTS: Ca(OH)2 dressing adversely affected the bond strengths to canal dentin of the three luting resins tested. Acid etching did not increase the bond strengths. Infrared analysis revealed that Ca(OH)2 dressing caused no structural changes on the dentin surface. XPS and SEM analyses revealed Ca(OH)2 remnants as the ultimate chemical cause leading to the decrease in bond strength. CONCLUSIONS: The bond strength of luting resin to dentin was affected by Ca(OH)2 dressing. Acid etching treatment could not increase the bond strength. CLINICAL RELEVANCE: Adhesion of the fiber post to the root canal wall may be compromised after Ca(OH)2 dressing. An effective method for complete removal of Ca(OH)2 dressing or increase of bond strength for luting resin needs to be developed. PMID- 23686134 TI - Survival and differentiation defects contribute to neutropenia in glucose-6 phosphatase-beta (G6PC3) deficiency in a model of mouse neutrophil granulocyte differentiation. AB - Differentiation of neutrophil granulocytes (neutrophils) occurs through several steps in the bone marrow and requires a coordinate regulation of factors determining survival and lineage-specific development. A number of genes are known whose deficiency disrupts neutrophil generation in humans and in mice. One of the proteins encoded by these genes, glucose-6-phosphatase-beta (G6PC3), is involved in glucose metabolism. G6PC3 deficiency causes neutropenia in humans and in mice, linked to enhanced apoptosis and ER stress. We used a model of conditional Hoxb8 expression to test molecular and functional differentiation as well as survival defects in neutrophils from G6PC3(-/-) mice. Progenitor lines were established and differentiated into neutrophils when Hoxb8 was turned off. G6PC3(-/-) progenitor cells underwent substantial apoptosis when differentiation was started. Transgenic expression of Bcl-XL rescued survival; however, Bcl-XL protected differentiated cells showed reduced proliferation, immaturity and functional deficiency such as altered MAP kinase signaling and reduced cytokine secretion. Impaired glucose utilization was found and was associated with ER stress and apoptosis, associated with the upregulation of Bim and Bax; downregulation of Bim protected against apoptosis during differentiation. ER stress further caused a profound loss of expression and secretion of the main neutrophil product neutrophil elastase during differentiation. Transplantation of wild-type Hoxb8-progenitor cells into irradiated mice allowed differentiation into neutrophils in the bone marrow in vivo. Transplantation of G6PC3(-/-) cells yielded few mature neutrophils in bone marrow and peripheral blood. Transgenic Bcl-XL permitted differentiation of G6PC3(-/-) cells in vivo. However, functional deficiencies and differentiation abnormalities remained. Differentiation of macrophages from Hoxb8-dependent progenitors was only slightly disturbed. A combination of defects in differentiation and survival thus underlies neutropenia in G6PC3(-/-) deficiency, both originating from a reduced ability to utilize glucose. Hoxb8-dependent cells are a model to study differentiation and survival of the neutrophil lineage. PMID- 23686135 TI - Danger signalling during cancer cell death: origins, plasticity and regulation. AB - Accumulating data indicates that following anti-cancer treatments, cancer cell death can be perceived as immunogenic or tolerogenic by the immune system. The former is made possible due to the ability of certain anti-cancer modalities to induce immunogenic cell death (ICD) that is associated with the emission of damage-associated molecular patterns (DAMPs), which assist in unlocking a sequence of events leading to the development of anti-tumour immunity. In response to ICD inducers, activation of endoplasmic reticulum (ER) stress has been identified to be indispensable to confer the immunogenic character of cancer cell death, due to its ability to coordinate the danger signalling pathways responsible for the trafficking of vital DAMPs and subsequent anti-cancer immune responses. However, in recent times, certain processes apart from ER stress have emerged (e.g., autophagy and possibly viral response-like signature), which have the ability to influence danger signalling. In this review, we discuss the molecular nature, emerging plasticity in the danger signalling mechanisms and immunological impact of known DAMPs in the context of immunogenic cancer cell death. We also discuss key effector mechanisms modulating the interface between dying cancer cells and the immune cells, which we believe are crucial for the therapeutic relevance of ICD in the context of human cancers, and also discuss the influence of experimental conditions and animal models on these. PMID- 23686136 TI - Evidence for a common progenitor of epithelial and mesenchymal components of the liver. AB - Tissues of the adult organism maintain the homeostasis and respond to injury by means of progenitor/stem cell compartments capable to give rise to appropriate progeny. In organs composed by histotypes of different embryological origins (e.g. the liver), the tissue turnover may in theory involve different stem/precursor cells able to respond coordinately to physiological or pathological stimuli. In the liver, a progenitor cell compartment, giving rise to hepatocytes and cholangiocytes, can be activated by chronic injury inhibiting hepatocyte proliferation. The precursor compartment guaranteeing turnover of hepatic stellate cells (HSCs) (perisinusoidal cells implicated with the origin of the liver fibrosis) in adult organ is yet unveiled. We show here that epithelial and mesenchymal liver cells (hepatocytes and HSCs) may arise from a common progenitor. Sca+ murine progenitor cells were found to coexpress markers of epithelial and mesenchymal lineages and to give rise, within few generations, to cells that segregate the lineage-specific markers into two distinct subpopulations. Notably, these progenitor cells, clonally derived, when transplanted in healthy livers, were found to generate epithelial and mesenchymal liver-specific derivatives (i.e. hepatocytes and HSCs) properly integrated in the liver architecture. These evidences suggest the existence of a 'bona fide' organ specific meso-endodermal precursor cell, thus profoundly modifying current models of adult progenitor commitment believed, so far, to be lineage-restricted. Heterotopic transplantations, which confirm the dual differentiation potentiality of those cells, indicates as tissue local cues are necessary to drive a full hepatic differentiation. These data provide first evidences for an adult stem/precursor cell capable to differentiate in both parenchymal and non parenchymal organ-specific components and candidate the liver as the instructive site for the reservoir compartment of HSC precursors as yet non-localized in the adult. PMID- 23686139 TI - Graphane and hydrogenated graphene. AB - Graphane, the fully hydrogenated analogue of graphene, and its partially hydrogenated counterparts are attracting increasing attention. We review here its structure and predicted material properties, as well as the current methods of preparation. Graphane and hydrogenated graphenes are far more complex materials than graphene, expected to have a tuneable band gap via the extent of hydrogenation, as well as exhibit ferromagnetism. The methods for hydrogenated graphene characterization are discussed. We show that hydrogenation methods based on low or high pressure gas hydrogenation lead to less hydrogen saturation than wet chemistry methods based on variations of Birch reduction. The special cases of patterning of hydrogenated graphene strips in a graphene lattice are discussed. PMID- 23686137 TI - Disease-relevant proteostasis regulation of cystic fibrosis transmembrane conductance regulator. AB - Mismanaged protein trafficking by the proteostasis network contributes to several conformational diseases, including cystic fibrosis, the most frequent lethal inherited disease in Caucasians. Proteostasis regulators, as cystamine, enable the beneficial action of cystic fibrosis transmembrane conductance regulator (CFTR) potentiators in DeltaF508-CFTR airways beyond drug washout. Here we tested the hypothesis that functional CFTR protein can sustain its own plasma membrane (PM) stability. Depletion or inhibition of wild-type CFTR present in bronchial epithelial cells reduced the availability of the small GTPase Rab5 by causing Rab5 sequestration within the detergent-insoluble protein fraction together with its accumulation in aggresomes. CFTR depletion decreased the recruitment of the Rab5 effector early endosome antigen 1 to endosomes, thus reducing the local generation of phosphatidylinositol-3-phosphate. This diverts recycling of surface proteins, including transferrin receptor and CFTR itself. Inhibiting CFTR function also resulted in its ubiquitination and interaction with SQSTM1/p62 at the PM, favoring its disposal. Addition of cystamine prevented the recycling defect of CFTR by enhancing BECN1 expression and reducing SQSTM1 accumulation. Our results unravel an unexpected link between CFTR protein and function, the latter regulating the levels of CFTR surface expression in a positive feed forward loop, and highlight CFTR as a pivot of proteostasis in bronchial epithelial cells. PMID- 23686138 TI - Interaction between the TP63 and SHH pathways is an important determinant of epidermal homeostasis. AB - Deregulation of the hedgehog (HH) pathway results in overexpression of the GLI target BCL2 and is an initiating event in specific tumor types including basal cell carcinoma of the skin. Regulation of the HH pathway during keratinocyte differentiation is not well understood. We measured HH pathway activity in response to differentiation stimuli in keratinocytes. An upregulation of suppressor of fused (SUFU), a negative regulator of the HH pathway, lowered HH pathway activity and was accompanied by loss of BCL2 expression associated with keratinocyte differentiation. We used in vitro and in vivo models to demonstrate that DeltaNp63alpha, a crucial regulator of epidermal development, activates SUFU transcription in keratinocytes. Increasing SUFU protein levels inhibited GLI mediated gene activation in suprabasal keratinocytes and promoted differentiation. Loss of SUFU expression caused deregulation of keratinocyte differentiation and BCL2 overexpression. Using in vivo murine models, we also provide evidence of GLI-mediated regulation of the TP63 pathway. p63 expression appears essential to establish an optimally functioning HH pathway. These observations present a regulatory mechanism by which SUFU acts as an interacting node between the HH and TP63 pathways to mediate differentiation and maintain epidermal homeostasis. Disruption of this regulatory node can be an important contributor to multistep carcinogenesis. PMID- 23686140 TI - Soft, transparent, electronic skin for distributed and multiple pressure sensing. AB - In this paper we present a new optical, flexible pressure sensor that can be applied as smart skin to a robot or to consumer electronic devices. We describe a mechano-optical transduction principle that can allow the encoding of information related to an externally applied mechanical stimulus, e.g., contact, pressure and shape of contact. The physical embodiment that we present in this work is an electronic skin consisting of eight infrared emitters and eight photo-detectors coupled together and embedded in a planar PDMS waveguide of 5.5 cm diameter. When a contact occurs on the sensing area, the optical signals reaching the peripheral detectors experience a loss because of the Frustrated Total Internal Reflection and deformation of the material. The light signal is converted to electrical signal through an electronic system and a reconstruction algorithm running on a computer reconstructs the pressure map. Pilot experiments are performed to validate the tactile sensing principle by applying external pressures up to 160 kPa. Moreover, the capabilities of the electronic skin to detect contact pressure at multiple subsequent positions, as well as its function on curved surfaces, are validated. A weight sensitivity of 0.193 gr(-1) was recorded, thus making the electronic skin suitable to detect pressures in the order of few grams. PMID- 23686142 TI - Radar tracking with an interacting multiple model and probabilistic data association filter for civil aviation applications. AB - The current trend of the civil aviation technology is to modernize the legacy air traffic control (ATC) system that is mainly supported by many ground based navigation aids to be the new air traffic management (ATM) system that is enabled by global positioning system (GPS) technology. Due to the low receiving power of GPS signal, it is a major concern to aviation authorities that the operation of the ATM system might experience service interruption when the GPS signal is jammed by either intentional or unintentional radio-frequency interference. To maintain the normal operation of the ATM system during the period of GPS outage, the use of the current radar system is proposed in this paper. However, the tracking performance of the current radar system could not meet the required performance of the ATM system, and an enhanced tracking algorithm, the interacting multiple model and probabilistic data association filter (IMMPDAF), is therefore developed to support the navigation and surveillance services of the ATM system. The conventional radar tracking algorithm, the nearest neighbor Kalman filter (NNKF), is used as the baseline to evaluate the proposed radar tracking algorithm, and the real flight data is used to validate the IMMPDAF algorithm. As shown in the results, the proposed IMMPDAF algorithm could enhance the tracking performance of the current aviation radar system and meets the required performance of the new ATM system. Thus, the current radar system with the IMMPDAF algorithm could be used as an alternative system to continue aviation navigation and surveillance services of the ATM system during GPS outage periods. PMID- 23686143 TI - Identifying time measurement tampering in the traversal time and hop count analysis (TTHCA) wormhole detection algorithm. AB - Traversal time and hop count analysis (TTHCA) is a recent wormhole detection algorithm for mobile ad hoc networks (MANET) which provides enhanced detection performance against all wormhole attack variants and network types. TTHCA involves each node measuring the processing time of routing packets during the route discovery process and then delivering the measurements to the source node. In a participation mode (PM) wormhole where malicious nodes appear in the routing tables as legitimate nodes, the time measurements can potentially be altered so preventing TTHCA from successfully detecting the wormhole. This paper analyses the prevailing conditions for time tampering attacks to succeed for PM wormholes, before introducing an extension to the TTHCA detection algorithm called ?T Vector which is designed to identify time tampering, while preserving low false positive rates. Simulation results confirm that the ?T Vector extension is able to effectively detect time tampering attacks, thereby providing an important security enhancement to the TTHCA algorithm. PMID- 23686144 TI - Fast estimation of strains for cross-beams six-axis force/torque sensors by mechanical modeling. AB - Strain distributions are crucial criteria of cross-beams six-axis force/torque sensors. The conventional method for calculating the criteria is to utilize Finite Element Analysis (FEA) to get numerical solutions. This paper aims to obtain analytical solutions of strains under the effect of external force/torque in each dimension. Genetic mechanical models for cross-beams six-axis force/torque sensors are proposed, in which deformable cross elastic beams and compliant beams are modeled as quasi-static Timoshenko beam. A detailed description of model assumptions, model idealizations, application scope and model establishment is presented. The results are validated by both numerical FEA simulations and calibration experiments, and test results are found to be compatible with each other for a wide range of geometric properties. The proposed analytical solutions are demonstrated to be an accurate estimation algorithm with higher efficiency. PMID- 23686141 TI - Evolution of electroencephalogram signal analysis techniques during anesthesia. AB - Biosignal analysis is one of the most important topics that researchers have tried to develop during the last century to understand numerous human diseases. Electroencephalograms (EEGs) are one of the techniques which provides an electrical representation of biosignals that reflect changes in the activity of the human brain. Monitoring the levels of anesthesia is a very important subject, which has been proposed to avoid both patient awareness caused by inadequate dosage of anesthetic drugs and excessive use of anesthesia during surgery. This article reviews the bases of these techniques and their development within the last decades and provides a synopsis of the relevant methodologies and algorithms that are used to analyze EEG signals. In addition, it aims to present some of the physiological background of the EEG signal, developments in EEG signal processing, and the effective methods used to remove various types of noise. This review will hopefully increase efforts to develop methods that use EEG signals for determining and classifying the depth of anesthesia with a high data rate to produce a flexible and reliable detection device. PMID- 23686145 TI - IPv6 addressing proxy: mapping native addressing from legacy technologies and devices to the Internet of Things (IPv6). AB - Sensors utilize a large number of heterogeneous technologies for a varied set of application environments. The sheer number of devices involved requires that this Internet be the Future Internet, with a core network based on IPv6 and a higher scalability in order to be able to address all the devices, sensors and things located around us. This capability to connect through IPv6 devices, sensors and things is what is defining the so-called Internet of Things (IoT). IPv6 provides addressing space to reach this ubiquitous set of sensors, but legacy technologies, such as X10, European Installation Bus (EIB), Controller Area Network (CAN) and radio frequency ID (RFID) from the industrial, home automation and logistic application areas, do not support the IPv6 protocol. For that reason, a technique must be devised to map the sensor and identification technologies to IPv6, thus allowing homogeneous access via IPv6 features in the context of the IoT. This paper proposes a mapping between the native addressing of each technology and an IPv6 address following a set of rules that are discussed and proposed in this work. Specifically, the paper presents a technology-dependent IPv6 addressing proxy, which maps each device to the different subnetworks built under the IPv6 prefix addresses provided by the internet service provider for each home, building or user. The IPv6 addressing proxy offers a common addressing environment based on IPv6 for all the devices, regardless of the device technology. Thereby, this offers a scalable and homogeneous solution to interact with devices that do not support IPv6 addressing. The IPv6 addressing proxy has been implemented in a multi-protocol Sensors 2013, 13 6688 card and evaluated successfully its performance, scalability and interoperability through a protocol built over IPv6. PMID- 23686146 TI - PRSS1 c.623G>C (p.G208A) variant is associated with pancreatitis in Japan. PMID- 23686147 TI - Controlling the luminescence emission from palladium grafted graphene oxide thin films via reduction. AB - The role of palladium (Pd) in the reduction of graphene oxide (GO) thin films was investigated using a Pd assisted grafting technique. The structural and optical characteristics of these thin films were obtained from various spectroscopic analyses, which confirmed increased C[double bond, length as m-dash]C-C aromatic ring vibration and oxidation of Pd with Ar annealing. In Pd free GO, annealing of films resulted in restoration of sp(2) clusters; however, Pd grafting with non annealed film enhanced the possibility of restoration and further annealing dramatically increased the restoration rate with enhanced blue photoluminescence (PL) emission. The blue PL emission originates from sp(2) cluster sites and the yellow-green PL from defect trapped states. As reduction of GO increased, yellow green emission decreased and blue PL became the prominent emission. These experimental findings open up a new feasible pathway for controlling the luminescence emission from graphene oxide that furthers the technological advancement of graphene based optoelectronic devices. PMID- 23686148 TI - Presumptive treatment and medical screening for parasites in refugees resettling to the United States. AB - More than 50,000 refugees are resettled to the United States annually, many from areas highly endemic for parasites. Some of these infections present little clinical consequence after migration, but others are responsible for morbidity and mortality. The Centers for Disease Control and Prevention has issued predeparture presumptive treatment and postarrival medical guidelines for the management of parasites. Although these guidelines are evidence based, there remain significant challenges to presumptive treatment programs in refugees. Gaps in the evidence continue; resettling populations are continually changing, thus altering the epidemiology; and there are logistical and cost barriers to fully implementing recommendations. This article will review the evolution and status of current guidelines, as well as identify gaps and challenges to full implementation. It is imperative for clinicians serving this population to be familiar with interventions received by refugees, since previous treatment will impact screening, diagnostic evaluation, and treatment decisions. PMID- 23686149 TI - Isolating shape from semantics in haptic-visual priming. AB - The exploration of a familiar object by hand can benefit its identification by eye. What is unclear is how much this multisensory cross-talk reflects shared shape representations versus generic semantic associations. Here, we compare several simultaneous priming conditions to isolate the potential contributions of shape and semantics in haptic-to-visual priming. Participants explored a familiar object manually (haptic prime) while trying to name a visual object that was gradually revealed in increments of spatial resolution. Shape priming was isolated in a comparison of identity priming (shared semantic category and shape) with category priming (same category, but different shapes). Semantic priming was indexed by the comparisons of category priming with unrelated haptic primes. The results showed that both factors mediated priming, but that their relative weights depended on the reliability of the visual information. Semantic priming dominated in Experiment 1, when participants were free to use high-resolution visual information, but shape priming played a stronger role in Experiment 2, when participants were forced to respond with less reliable visual information. These results support the structural description hypothesis of haptic-visual priming (Reales and Ballesteros in J Exp Psychol Learn Mem Cogn 25:644-663, 1999) and are also consistent with the optimal integration theory (Ernst and Banks in Nature 415:429-433, 2002), which proposes a close coupling between the reliability of sensory signals and their weight in decision making. PMID- 23686150 TI - Comparing kinematic changes between a finger-tapping task and unconstrained finger flexion-extension task in patients with Parkinson's disease. AB - Repetitive finger tapping is a well-established clinical test for the evaluation of parkinsonian bradykinesia, but few studies have investigated other finger movement modalities. We compared the kinematic changes (movement rate and amplitude) and response to levodopa during a conventional index finger-thumb tapping task and an unconstrained index finger flexion-extension task performed at maximal voluntary rate (MVR) for 20 s in 11 individuals with levodopa responsive Parkinson's disease (OFF and ON) and 10 healthy age-matched controls. Between-task comparisons showed that for all conditions, the initial movement rate was greater for the unconstrained flexion-extension task than the tapping task. Movement rate in the OFF state was slower than in controls for both tasks and normalized in the ON state. The movement amplitude was also reduced for both tasks in OFF and increased in the ON state but did not reach control levels. The rate and amplitude of movement declined significantly for both tasks under all conditions (OFF/ON and controls). The time course of rate decline was comparable for both tasks and was similar in OFF/ON and controls, whereas the tapping task was associated with a greater decline in MA, both in controls and ON, but not OFF. The findings indicate that both finger movement tasks show similar kinematic changes during a 20-s sustained MVR, but that movement amplitude is less well sustained during the tapping task than the unconstrained finger movement task. Both movement rate and amplitude improved with levodopa; however, movement rate was more levodopa responsive than amplitude. PMID- 23686151 TI - Contribution of visual velocity and displacement cues to human balancing of support surface tilt. AB - Vision helps humans in controlling bipedal stance, interacting mainly with vestibular and proprioceptive cues. This study investigates how postural compensation of support surface tilt is compromised by selectively reducing visual velocity cues by stroboscopic illumination of a stationary visual scene. Healthy adult subjects were presented with pseudorandom tilt sequences in the sagittal plane (tilt frequency range 0.017-2.2 Hz; velocity amplitude spectrum constant up to a frequency of 0.6 Hz, angular displacement amplitude spectrum increasing with decreasing frequencies). Center of mass (COM) sway responses were recorded for stroboscopic illuminations at 48, 32, 16, 8, and 4 Hz, as well as under continuous illumination and with eyes closed. With strobe duration (5 ms) and mean luminance (1 lx) kept constant, visual acuity and perceived brightness remained constant and the visual scene was perceived as stationary. Yet, tilt evoked COM excursions increased with decreasing strobe frequency in a graded way, with largest effects occurring at tilt frequencies where large tilt velocities coincided with small displacements. In addition, COM excursions were reduced at the lowest strobe frequency compared to eyes closed, with the largest effect occurring at tilt frequencies where tilt displacements were large. We conclude that two mechanisms exist, a velocity mechanism that deals with tilt compensation and is foremost affected by the stroboscopic illumination and a displacement mechanism. This compares favorably to previous findings that, transferred to a stance control model, suggest a velocity mechanism for tilt compensation and a position mechanism for gravity compensation. PMID- 23686152 TI - Re-focusing the gender lens: caregiving women, family roles and HIV/AIDS vulnerability in Lesotho. AB - Gender and HIV risk have been widely examined in southern Africa, generally with a focus on dynamics within sexual relationships. Yet the social construction of women's lives reflects their broader engagement with a gendered social system, which influences both individual-level risks and social and economic vulnerabilities to HIV/AIDS. Using qualitative data from Lesotho, we examine women's lived experiences of gender, family and HIV/AIDS through three domains: (1) marriage; (2) kinship and social motherhood, and (3) multigenerational dynamics. These data illustrate how women caregivers negotiate their roles as wives, mothers, and household heads, serving as the linchpins of a gendered family system that both affects, and is affected by, the HIV/AIDS epidemic. HIV/AIDS interventions are unlikely to succeed without attention to the larger context of women's lives, namely their kinship, caregiving, and family responsibilities, as it is the family and kinship system in which gender, economic vulnerability and HIV risk are embedded. PMID- 23686154 TI - Further support for five dimensions of obsessive-compulsive symptoms. AB - Attempts to explain the phenotypic heterogeneity of obsessive-compulsive disorder (OCD) have resulted in three to six OCD symptom dimensions. This study aimed to clarify the nature of these symptom dimensions using a self-report instrument (Vancouver Obsessional Compulsive Inventory [VOCI]) in addition to the clinician rated Yale-Brown Obsessive Compulsive Scale-Symptom Checklist (YBOCS-SC). Participants (N = 154) were recruited to a study designed to specifically assess OCD symptom dimensions. Symptoms assessed via the YBOCS-SC and the VOCI were subjected to principal components analysis (PCA). Linear regression was used to assess the relationship between the YBOCS-SC-derived symptom dimensions and the VOCI symptom subscales. PCA of the YBOCS-SC and the VOCI revealed five OCD symptom dimensions that explained 68% and 60% of the variance, respectively. The results also supported a distinction between the doubt/checking symptom dimension and the unacceptable/taboo thoughts dimension that includes mental rituals. The YBOCS-SC-derived symptom components were predicted by their respective VOCI symptom subscale scores. PMID- 23686155 TI - Psychotic-like symptoms as a risk factor of violent recidivism in detained male adolescents. AB - The aim of this study was to prospectively examine whether psychotic-like symptoms (PLSs) are positively associated with violent recidivism and whether this relation is stronger when PLSs co-occur with substance use disorders (SUDs). Participants were 224 detained male adolescents from all youth detention centers in Flanders. The Diagnostic Interview Schedule for Children was used to assess PLSs and the number of SUDs. Two to 4 years later, information on official recidivism was obtained. Although hallucinations were unrelated to violent recidivism, paranoid delusions (PDs) and threat/control override delusions (TCODs) were negatively related to violent recidivism. The relation between PLSs and violent recidivism did not become stronger in the presence of SUDs. Detained youths with PLSs do not have a higher risk for violent recidivism than detained youths without PLSs. In contrast, by identifying detained youths with PDs or TCODs, clinicians are likely to identify youths with a low risk for future violent crimes. PMID- 23686153 TI - High percentage of recent HIV infection leading to onward transmission in Odessa, Ukraine associated with young adults. AB - The proportion of new HIV diagnoses between May and December 2009 across Odessa recently-infected was estimated using the BED-CEIA assay. Logistic regression models were used to explore factors associated with testing as recent. Of 1,313 newly-diagnosed individuals, 321 (24 %) were classified as recent. Recent infection was less likely among older adults [odds ratio (OR) = 0.70 per 10-year increase, 95 % CI 0.60-0.82]. Compared to men residing in Odessa city, women in rural Odessa and non-resident men were more likely to be recently-infected (OR 1.85, 1.26-2.71 and 2.83, 1.15-6.97, respectively). Reason for test was not associated with recent infection. In sensitivity analysis, after excluding individuals tested due to clinical indications, the proportion recently-infected and the association with age remained virtually unchanged. Our findings suggest a high risk of onward transmission, particularly in younger age groups. These findings highlight the need for tailored prevention strategies and ongoing RITA testing to monitor and evaluate effectiveness of prevention programmes. PMID- 23686156 TI - Characteristics of child maltreatment and their relation to dissociation, posttraumatic stress symptoms, and depression in adult psychiatric patients. AB - Little is known about the influence of particular characteristics of childhood maltreatment, such as developmental stage, relationship to the perpetrator, and nature of the trauma, on adult psychopathology. The effects of childhood maltreatment were assessed in adult psychiatric patients (N = 287) using self rating scales and diagnostic checklists. Maltreatment was strongly associated with dissociation. This relationship was observed for all childhood developmental stages and was strongest when the perpetrator was outside the family. Dissociation was more strongly correlated with childhood emotional abuse and sexual harassment than with sexual or physical abuse. Childhood sexual abuse was found to be associated with symptoms of posttraumatic stress. The findings suggest that dissociation is a relatively specific consequence of childhood maltreatment that is largely independent of the familial relationship to the perpetrator or the child's developmental stage. PMID- 23686157 TI - Factors predicting hostility in outpatients with schizophrenia: 36-month results from the SOHO study. AB - This analysis explored the prevalence, incidence, and predictors of hostility in the European Schizophrenia Outpatient Health Outcomes (EU-SOHO) study. Data were collected at baseline and up to 36 months on the presence of hostility, clinical course and severity, medication compliance, side effects, substance/alcohol abuse, and being a crime survivor. Regression models were fitted to test the association between predictors and the presence of hostility. Hostility prevalence in the 6 months before baseline was 27.9%, and the incidence at 3 years was 14.0%. Variables related to hostility during follow-up were age, male sex, alcohol/substance abuse, tardive dyskinesia, extrapyramidal symptoms, cognitive impairment, noncompliance, and hospitalization. Being a crime survivor, being married, not living independently, and not being in paid employment were associated with hostility at baseline. Clinical and social variables are related to hostility in schizophrenia. Extrapyramidal symptoms and tardive dyskinesia, alcohol/substance abuse, cognitive impairment, medication noncompliance, and hospitalizations are predictors of future hostility. PMID- 23686158 TI - Social cognition and clinical insight in schizophrenia and bipolar disorder. AB - The association between clinical insight and social cognition assessed with an emotion perception task was investigated in schizophrenia (n = 29) and bipolar I disorder (n = 19). Persons with schizophrenia had reduced auditory emotion perception compared with individuals with bipolar I disorder, but levels of visual emotion perception and clinical insight were comparable. In the schizophrenia group, clinical insight was moderately associated with auditory and visual emotion perception (r = 0.36-0.44) and negative symptoms (r = -0.33). Better insight was associated with better social cognition and fewer negative symptoms. In the bipolar I disorder group, clinical insight showed small associations with social cognition (largest r = -0.28) and moderate to large associations with positive, negative, manic, and depressive symptoms. Poorer insight was associated with higher symptom load. Social cognition seems to be of importance for clinical insight in schizophrenia, whereas symptoms are important in bipolar I disorder. PMID- 23686159 TI - Mentalizing in self vs. parent representations and working models of parents as risk and protective factors from distress and eating disorders. AB - This study examined whether low developmental level of mentalization and symbolization, manifested as low ability to represent and reflect on mental states of the self and parents as well as malevolent working models of parents, may be risk factors in the genesis of eating disorders (EDs). We examined 71 female adolescent inpatients with ED and 45 controls without ED using the Object Representation Inventory and self-report measures assessing emotional distress and ED symptoms. The results indicated that the patients with ED presented with a significantly lower level of mentalization and symbolization and with more malevolent working models of their parents in comparison with the controls without ED. A more benevolent parental representation, specifically with the father, combined with better mentalization abilities, was found to indirectly predict lower ED symptoms, via the reduction of distress levels. These findings suggest that adequate mentalization and benevolent working models of parents may serve as a protective factor reducing the level of ED symptoms. PMID- 23686160 TI - Continuity of outpatient treatment after discharge of patients with major depressive disorder. AB - PURPOSE: This study aimed to identify the predictors associated with the continuity of outpatient treatment after discharge for patients with major depression. METHODS: The medical records of patients discharged with diagnosis of major depression were analyzed. The subjects were divided into two groups based on whether they regularly visited the outpatient clinic for more than 4 months after discharge. RESULTS: The 4-month follow-up group was older, had a lower employment rate, and had a lower rate of being divorced or separated. The 4-month follow-up group had a longer duration of illness, a higher rate of recurrent major depressive disorder, older age at onset, and a longer duration of index hospitalization. Longer duration of index hospitalization and combination therapy were significantly related to an increased likelihood of 4-month follow-up visits. CONCLUSIONS: Duration of hospitalization and prescription pattern of psychotropic medication appeared to have an influence on the continuity of outpatient treatment after discharge. PMID- 23686161 TI - The association between adult attachment style and delusional-like experiences in a community sample of women. AB - Community-based surveys have found that many otherwise well individuals endorse delusional-like experiences (DLEs). There is extensive literature that describes the demographic and psychosocial correlates of DLE; however, we know little about the association between DLE and attachment style. The association between DLEs (assessed by the Peters Delusional Inventory [PDI]) and interpersonal relationship style (as assessed by the Adult Attachment Questionnaire and the Dyadic Adjustment Scale) was examined in 3360 women. When adjusted for the presence of depressive and anxiety symptoms, high scores on the PDI (lowest versus highest quartiles) were associated with a) difficulties in adult attachment style particularly in the discomfort with closeness and preoccupation with relationships subscales and b) conflictual dyadic adjustment (adjusted odds ratios and 95% confidence intervals, 2.43 and 1.94-3.04, 2.50 and 1.99-3.14, and 2.90 and 1.38-6.06, respectively). The association between adult attachment style and DLE provides new clues into the causal pathway underpinning these common experiences. PMID- 23686162 TI - Leydig cell tumor in an anabolic steroid abuser. PMID- 23686163 TI - Notch inhibition restores TRAIL-mediated apoptosis via AP1-dependent upregulation of DR4 and DR5 TRAIL receptors in MDA-MB-231 breast cancer cells. AB - Notch is a family of transmembrane receptors whose activation through proteolytic cleavage by gamma-secretase targets genes which participate in cell development, differentiation and tumorigenesis. Notch signaling is constitutively activated in various cancers, including breast cancer and its upregulation is usually related with poor clinical outcomes. Therefore, targeting Notch signaling with gamma secretase inhibitors (GSIs) is considered a promising strategy for cancer treatment. We report that the gamma-secretase inhibitor-I (GSI-I) sensitizes human breast cancer cells to apoptosis mediated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The antiproliferative GSI-I/TRAIL synergism was stronger in ER-negative MDA-MB-231 breast cancer cells compared with ER positive MCF-7 cells. In MDA-MB-231 cells, GSI-I treatment induced upregulation of DR4 and DR5 TRAIL receptors. This effect seemed to be related to the activation of the transcription factor AP1 that was a consequence of Notch inhibition, as demonstrated by Notch-1 silencing experiments. Combined treatment induced loss of the mitochondrial transmembrane potential and activation of caspases. GSI-I alone and/or GSI-I/TRAIL combination also induced a significant decrease in the levels of some survival factors (survivin, c-IAP-2, Bcl-xL, BimEL and pAKT) and upregulation of pro-apoptotic factors BimL, BimS and Noxa, enhancing the cytotoxic potential of the two drugs. Taken together, these results indicate for the first time that GSI-I/TRAIL combination could represent a novel and potentially effective tool for breast cancer treatment. PMID- 23686165 TI - The molecular phylogenetic signature of Bali cattle revealed by maternal and paternal markers. AB - Bali cattle is a domestic cattle breed that can be found in Malaysia. It is a domestic cattle that was purely derived from a domestication event in Banteng (Bos javanicus) around 3,500 BC in Indonesia. This research was conducted to portray the phylogenetic relationships of the Bali cattle with other cattle species in Malaysia based on maternal and paternal lineage. We analyzed the cytochrome c oxidase I (COI) mitochondrial gene and SRY of Y chromosome obtained from five species of the Bos genus (B. javanicus, Bos gaurus, Bos indicus, Bos taurus, and Bos grunniens). The water buffalo (Bubalus bubalis) was used as an outgroup. The phylogenetic relationships were observed by employing several algorithms: Neighbor-Joining (PAUP version 4.0), Maximum parsimony (PAUP version 4.0) and Bayesian inference (MrBayes 3.1). Results from the maternal data showed that the Bali cattle formed a monophyletic clade, and together with the B. gaurus clade formed a wild cattle clade. Results were supported by high bootstrap and posterior probability values together with genetic distance data. For the paternal lineage, the sequence variation is low (with parsimony informative characters: 2/660) resulting an unresolved Neighbor-Joining tree. However, Bali cattle and other domestic cattle appear in two monophyletic clades distinct from yak, gaur and selembu. This study expresses the potential of the COI gene in portraying the phylogenetic relationships between several Bos species which is important for conservation efforts especially in decision making since cattle is highly bred and hybrid breeds are often formed. Genetic conservation for this high quality beef cattle breed is important by maintaining its genetic characters to prevent extinction or even decreased the genetic quality. PMID- 23686164 TI - Rediscovering ACE: novel insights into the many roles of the angiotensin converting enzyme. AB - Angiotensin-converting enzyme (ACE) is best known for the catalytic conversion of angiotensin I to angiotensin II. However, the use of gene-targeting techniques has led to mouse models highlighting many other biochemical properties and actions of this enzyme. This review discusses recent studies examining the functional significance of ACE tissue-specific expression and the presence in ACE of two independent catalytic sites with distinct substrates and biological effects. It is these features which explain why ACE makes important contributions to many different physiological processes including renal development, blood pressure control, inflammation, and immunity. PMID- 23686170 TI - Auditory system: Sound choices. PMID- 23686173 TI - Evaluation of human hand thermal images using wavelet transform based local spatial features - biomed 2013. AB - Transform-based spatial analyses of medical Infrared (IR) images are found to be useful to extract local information, which can be used to identify the abnormalities associated with in region of interest. In this work, human hand infrared images are analyzed by extracting local spatial features using wavelet transform method. The images for this study were acquired using uncooled micro bolometer with focal plane array technology based medical IR camera with dedicated software having high array resolution and spectral response under controlled protocol. The acquired images were decomposed into Intrinsic Mode Functions (IMFs) using bidimensional empirical mode decomposition. Extrema points were detected using eight connected neighbor window method and interpolated using thin plate spline interpolation technique to generate IMFs. The edge information were extracted from local phase of the first IMF. Edges were detected using phase congruency measure by applying Gabor function based wavelet transform. The results showed that it was possible to detect edges from only the first IMF without being influenced by other IMFs. It was further observed that the edge intermittence that arises due to noise component was reduced by treating images with local phase distributions. Hence, it appears that the edge information extraction could enhance the diagnostic relevance of thermal image analysis. PMID- 23686175 TI - Semiautomatic method of quantifying pleural effusions using computed tomography scans - biomed 2013. AB - Pleural effusion (PE) is a common and devastating manifestation of many pleural diseases. This complication can have dire effects by constricting breathing which increases the recovery time of the patient. Increased volumes of PE correspond with increased complications from the disorder. For this study, accurate PE volumes were found by segmentation of Computed Tomography (CT) scans. The retrospective study, with each scan conducted out of medical necessity for patient care or diagnosis, used a dataset of 105 CT scans and 179 individual pleural effusions. A semiautomatic method of segmentation was developed to quantify the volume of the PE. For this method, a thresholding method based on Hounsfield unit values of the tissues was used to determine six volumes (total lung, total pleural effusion, right lung, right pleural effusion, left lung and left pleural effusion). The volume of each PE was divided by the total lung volume to calculate PE as a percentage of the total lung. This normalization allows for direct comparison between each subject. The segmentations were conducted for a wide range of pleural effusion severities with a range from 0.122 to 67.798 percent of total lung volume. Most effusions were small with an average volume of 6.66 +/- 12.22 percent of total lung volume. These data will be used in a future study investigating the relationship between segmented PE volume and PE volume calculated from 2D chest images. PMID- 23686174 TI - Segmentation of ct liver images using phase based level set method - biomed 2013. AB - Segmentation of Liver from Abdominal CT images has received much importance due to its complexity, as the intensity of the liver is quite similar to those of other organs surrounding it. Hence, intensity based edge operators fail to segment the liver accurately. In this work, an attempt has been made to segment liver from abdominal CT images using phase-based level set method. CT images used in this work were acquired from open source online database MIDAS and nearby hospitals. These images were subjected to phase-based distance regularized level set segmentation. A distance regularization term proposed by Chumming Li et al. was used in the energy function of level set method, to maintain stability of the evolving contour. This energy function was minimized to obtain the final contour. The phase congruency measure proposed by Kovesi was used as an edge detector for the evolution of level set function. The segmentation results were compared with the ground truth using similarity measures. It was observed that the implemented technique resulted in better similarity index and they were close to the ideal values. Leakage of contour was avoided as phase information lead to robust convergence at edges. Edges and lines were found to be well distinguished using phase congruency information. As CT images are found to be helpful in detection and characterization of abnormalities in liver like hepatoma, cysts and tumors, the proposed study seems to be clinically relevant. PMID- 23686172 TI - Bridging the gap between theories of sensory cue integration and the physiology of multisensory neurons. AB - The richness of perceptual experience, as well as its usefulness for guiding behaviour, depends on the synthesis of information across multiple senses. Recent decades have witnessed a surge in our understanding of how the brain combines sensory cues. Much of this research has been guided by one of two distinct approaches: one is driven primarily by neurophysiological observations, and the other is guided by principles of mathematical psychology and psychophysics. Conflicting results and interpretations have contributed to a conceptual gap between psychophysical and physiological accounts of cue integration, but recent studies of visual-vestibular cue integration have narrowed this gap considerably. PMID- 23686176 TI - Changes, adaptations, and applications of a bio inspired machine vision sensor - biomed 2013. AB - The Musca domestica (common housefly) biomimetic sensor project is an ongoing endeavor at the University of Wyoming. The project has developed a sensor platform based on the rudimentary function of a fly?s compound eye, including the inherent hyperacuity (high sensitivity to motion) present in the insect?s vision. The design portion of the project is nearing completion, and application driven characterization can now begin. NASA is funding research into utilizing the sensor for efficient, fast, and inexpensive target tracking applications. This stage of the project is very preliminary, but is advancing and offers unique challenges and opportunities. his paper provides background information on the sensor design being considered, discusses the advances in the most current sensor platform, and offers an application currently being investigated. PMID- 23686171 TI - NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. AB - NMDA receptors (NMDARs) are glutamate-gated ion channels and are crucial for neuronal communication. NMDARs form tetrameric complexes that consist of several homologous subunits. The subunit composition of NMDARs is plastic, resulting in a large number of receptor subtypes. As each receptor subtype has distinct biophysical, pharmacological and signalling properties, there is great interest in determining whether individual subtypes carry out specific functions in the CNS in both normal and pathological conditions. Here, we review the effects of subunit composition on NMDAR properties, synaptic plasticity and cellular mechanisms implicated in neuropsychiatric disorders. Understanding the rules and roles of NMDAR diversity could provide new therapeutic strategies against dysfunctions of glutamatergic transmission. PMID- 23686177 TI - Continuous scaling 3d micro flow printing for improved spot morphology in protein microarrays - biomed 2013. AB - The protein microarray platform while innovative still poses a number of challenges which can only be met through creative and sophisticated system design. Pin printing while allowing for flexibility as to the type of medium printed does not offer the kind of spot reproducibility that a very sensitive application may require. The Continuous Flow Microspotter (CFM) was designed to not only allow for flexibility and reproducibility but to also achieve solution stability through flow scaling. This study uses the emerging CFM for printing protein and antibodies three dimensionally for general protein microarray applications. Consistent spot morphology, a continual and persistent problem in traditional pin printed microarrays, was compared under variable printed flow rates. The final assessment was performed using a rudimentary shear model. Force effects discussion and statistical data was used to demonstrate the versatility of the system. PMID- 23686178 TI - Increasing hand hygiene compliance by use of a novel hand held device at a university hospital - biomed 2013. AB - ISSUE: Hand hygiene (HH) is the single most effective modality to prevent the spread of infection in healthcare. HH is also one of the most difficult quality measures to monitor. In a 722 bed tertiary referral teaching hospital, collection of accurate and timely HH compliance data on 25 inpatient units was problematic. We needed a process that avoided confrontation and keep secret the identity of HH surveyors to avoid compromise of professional work relationships. Our solution was to employ a unique handheld device. PROJECT: iScrub(r), a hand-held application developed by The University of Iowa, was used to record compliance with HH. Dates of intervention were January 1st ? December 31st, 2011. HH observations were collected by trained nursing volunteers and displayed on a central intranet ?based database using SharePoint software(r). Data was then included in quality scorecards, and in the Infection Prevention (IP) monthly report. Episodes of non-compliance generated e-mail notifications with escalating consequences that might end with termination of employment. Multi-drug resistant organisms (MDROs) surveillance was performed by the infection prevention department (IPD). HH and MDROs monthly data analysis was published on SharePoint(r) for stakeholders? review. RESULTS: During the intervention we collected 26,657 observations. Average HH compliance was 95%,( average physician?s compliance was 88%, and average nurse?s compliance was 98%). Non compliance occurred at a similar frequency both before and after patient contact. Alcohol hand rub was the most frequently used method to perform HH. Physicians demonstrated the lowest compliance rates among healthcare workers. Time and date of observations had no effect on compliance. LESSONS LEARNED: Shielding the identity of HH observers eliminated confrontation, and probably increased the accuracy of collected data. Applying strict consequences for non-compliance with HH aided in increasing compliance among staff and physicians. Publishing HH data analysis aided in increasing the compliance with HH. Data analysis identified issues related to the use of the current application and led to the creation of a new HH application. PMID- 23686179 TI - Hacking medical devices a review - biomed 2013. AB - Programmable, implantable and external biomedical devices (such as pacemakers, defibrillators, insulin pumps, pain management pumps, vagus nerve stimulators and others) may be vulnerable to unauthorized access, commonly referred to as ?hacking?. This intrusion may lead to compromise of confidential patient data or loss of control of the device itself, which may be deadly. Risks to health from unauthorized access is in addition to hazards from faulty (?buggy?) software or circuitry. Historically, this aspect of medical device design has been underemphasized by both manufacturers and regulatory bodies until recently. However, an insulin pump was employed as a murder weapon in 2001 and successful hacking of an implantable defibrillator was demonstrated in 2008. To remedy these problems, professional groups have announced a variety of design standards and the governmental agencies of several countries have enacted device regulations. In turn, manufacturers have developed new software products and hardware circuits to assist biomedical engineering firms to improve their commercial offerings. In this paper the author discusses these issues, reviewing known problems and zero day threats, with potential solutions. He outlines his approach to secure software and hardware challenges using the Forth language. A plausible scenario is described in which hacking of an implantable defibrillator by terrorists results in a severe national security threat to the United States. PMID- 23686180 TI - Frequency content of standard posturographic measures - biomed 2013. AB - Although still considered experimental by some, computerized posturography is becoming more and more the standard assessment of balance and neuromuscular control mechanisms while standing. However, there is no consensus as to the data acquisition parameters to be used. Depending on which posturography school one belongs to, acquisition frequencies vary from a few Hz all the way to 1 kHz, and little attention is usually given to the post-sampling filter cut-off frequency (implemented either in the hardware or in the software used to acquire the data), often without realizing the consequences such choices will have on the results. But the sampling and the filter cut-off frequencies are particularly important when dealing with spectral analysis or when secondary measurements such as the center of pressure coordinates, sway path length, velocity or acceleration are calculated from the measured forces and moments. In this paper, frequency content of vertical ground reaction force and center of pressure path coordinates excursion were determined for 946 subjects of both genders, with various age, height, body type, health status and nationality. The results of this spectral analysis made it possible to draw some general conclusions as to what should be a proper acquisition frequency for posturographic data. PMID- 23686181 TI - Mapping of an insufflated peritoneal cavity - biomed 2013. AB - A study at the University of Nebraska-Lincoln in conjunction with the University of Nebraska Medical Center aimed to map the location of organs in an insufflated human abdominal cavity. The goal was to be able to give the location of organs and the abdominal wall in a coordinate system by specifying two angles and a depth. The surgeons assembled two sets of measurements from eight cadavers, four male and four female. One set of measurements mapped the insufflated abdominals walls, while the other set of measurements mapped important landmarks found within the abdominal cavity such as the pancreas and stomach. By using common statistical methods to analyze the end result, we were able to identify average locations of organs during insufflations. A better knowledge of the peritoneal cavity when insufflated can help us when designing miniature robots. Size will be of particular importance, since they are inserted completely into the peritoneal cavity. PMID- 23686182 TI - An electronic communication system for amyotrophic lateral sclerosis patients - biomed 2013. AB - Amyotrophic lateral sclerosis is a progressive degeneration of motor neurons. Patients with the disease lose their ability to speak and to use their hands as the disease progresses. We have developed a new electronic communication system that enables communication by blinking of the eyes. The system consists of a light emitting diode (LED), two silicone rubber electrodes, an electrooculogram (EOG) recorder, a microcontroller, a sound reproduction board, a pillow speaker and a low power mobile phone. The two silicone rubber electrodes record the EOG induced by blinking the eyes synchronized with LED flashing. The EOG is amplified by the EOG recorder. The microcontroller detects the blinking from the amplified EOG, and then their meanings are confirmed by voice. After that, the patient?s intention is transmitted to the nurse by a low power mobile phone so the care giver is kept in the loop. PMID- 23686183 TI - An ultra flexible capacitive electrode for an ecg recording system - biomed 2013. AB - We have developed an ultra-flexible skin electrode to monitor a patient?s electrocardiogram (ECG) during daily activity. This electrode consists of a 1.5 micrometer thick polyester film printed with electro-conductive paint. The electrode is attached to the outside of a polyethylene bag filled with a high viscoelastic fluid. When the electrode is placed securely on the skin, it correspondingly changes its shape, and electrode movement artifact is thereby decreased. The electrode improves long-term recording of the ECG by maintaining capacitance-coupled impedance between the electrode and the skin. PMID- 23686184 TI - An updated and more accurate drip infusion solution monitoring system - biomed 2013. AB - We have developed a drip infusion solution monitoring system for hospital and care facility use that is much more accurate than our previous reported system. The system consists of two electrodes and an acceleration sensor. The electrodes, which are wrapped around the infusion supply polyvinyl chloride (PVC) tube from the solution bag and the drip chamber, measure the growth and fall of each drop of infusion solution. The drip rate is detected from the fall of each drop. In addition, the acceleration sensor is attached to the outside of the drip chamber and detects the tilt angle of that chamber. The injected infusion solution amount is calculated by the infusion solution quantity per one drop and the drip rate. However, the quantity changes depend on the tilt angle of the drip chamber. The quantity of each drop is then corrected by the tilt angle of the drip chamber. PMID- 23686185 TI - A pilot study of the EEG patterns of subjects with corrected vision - biomed 2013. AB - A need exists to develop a better predictive tool for estimating deterioration in the visual system. This pilot study examined changes in EEG spectral power of subjects with varying visual impairments. EEG activity of five subjects was recorded while playing a driving game both with and without their corrective glasses. The spectral power at three channel locations in the occipital lobe were obtained and compared. Subjects having better vision displayed higher spectral power in both the theta and alpha band regions. An increase in average spectral power for the alpha band region, with changes in spectral power topographies in the theta band region, was observed. The results suggest that spectral power in the alpha and theta bands may depend on activation in the visual system. This focus, to better understand the interactions between the human brain and the visual system, will aid in developing improved visual prosthetic devices. PMID- 23686186 TI - The effects of sustained delivery of estrogen and demineralized bone matrix proteins on bone in ovariectomized female rats - biomed 2013. AB - Osteoporosis affects over ten million persons within the United States and is estimated to cost the healthcare system $18 billion dollars a year. Approximately 1.5 million persons will be diagnosed with an osteoporotic fracture and the epidemiological data reflects that prevalence of the osteoporotic fractures is four times more common than having a stroke. The current treatments strategies for osteoporosis are geared toward inhibiting the osteoclast cell resorption of bone, and not on the osteoblast bone formation. The use of demineralized bone matrix proteins (DBM) has been shown to be effective in healing osteoporotic bone fractures within a four week time period. Our goal was to deliver in a sustained manner DBM over an eight week period and compare bone strength and bone histology to osteoporotic untreated animals, osteoporotic animals given sustained delivery of physiological estrogen, as well as naive control (animals with ovary intact). Our results showed estrogen administered in a sustained fashion was able to reverse the decline in bone strength and re-establish the bone quality similar to ovary intact controls. DBM administered in a sustained manner showed similar bone quality and strength to osteoporotic control animals. Administration of DBM to mature bone in a sustained fashion may be ineffective in inducing osteoblast function or reversing osteoclast activity. It is possible that DBM may be more effective on immature bone cells. PMID- 23686187 TI - The effects of sustained delivery of corticosterone on the adrenal gland of male and female rats - biomed 2013. AB - Glucocorticoids have long been recognized to have beneficial effects in rheumatoid arthritis and asthma. Numerous clinical trials show the efficacy of short term low dose treatment to resolve inflammation. Despite the success of short term use, there is concern regarding chronic use of glucocorticoids because of the development of exogenous Cushing?s syndrome. Chronic variable stress models have detailed the effects of chronic stress exposure on body weight, plasma corticosteroid levels, ACTH levels, and adrenal weights, but limited studies detail the effects of the body systems induced by continuous exposure to glucocorticoids similar to that seen in exogenous Cushing?s syndrome. The present study uses a TCPL drug delivery system to administer corticosterone (CS) continuously in male and female animals for 24 days and evaluates long term chronic use effects on body weight, adrenal weight, and adrenal ultrastructure. Continuous release of CS resulted in slight decreases in body weight in both male and female rats and decreases in adrenal wet weight in the female rats. Ultrastructural changes were seen in the adrenal histology in both female and male rats. Male rat adrenal glands showed atrophy of the zona glomerulosa and hypertrophy of the adrenal medulla. Female rats showed disorganization of all zones within the adrenal gland and an increase in fat around the gland. The information is important for understanding physiological differences in males and females during stress. The continuous release of CS may provide insight into the pathology of exogenous Cushing?s syndrome. PMID- 23686189 TI - Assessing the survival of MRC5 and a549 cell lines upon exposure to pyruvic Acid, sodium citrate and sodium bicarbonate - biomed 2013. AB - Lung cancer is among the most prevalent and deadly cancers in United States. In general, cancer cells are known to exhibit higher rates of glycolysis in comparison to normal cells. In attempting to exploit this unique cancer-dependent ATP generation phenomenon, it was our hypothesis that upon exposure to organic inhibitors of glycolysis, cancer cells would not survive normally and that their growth and viability would be vastly decreased; essential glycolytic ATP production will be exhausted to the point of collapsing energy utilization. Furthermore, we hypothesize that no negative effect would be seen with exposures to organic inhibitors for normal lung cells. The human lung fibroblast MRC-5 and the human A549 alveolar epithelial cell lines were used as in vitro models of normal lung and lung cancers respectively. Using standard methods, both cell lines were maintained and exposed to pyruvic acid, sodium citrate and sodium bicarbonate reagents at concentration levels ranging from 31.3-2,000 ug/ml in 96 well plates in quadruplets and experiments repeated at least three times using MTT, and cell counting (T4 Cellometer) assays as well as phase-contrast photo imaging for parallel morphological displays of any changes in the course of their vitality and metabolic activities. Our results indicate that exposure of both cell lines to these organics resulted in concentration dependent cell destruction/cell survival depending on the cell line exposed. Pyruvic acid, sodium citrate and sodium bicarbonate showed statistically significant (p<0.05) differential negative effects on the A549 cell line in comparison to its unexposed control as well as to their effects on the MRC-5 cell line, presenting a potential promise for their use as cancer biotherapeutics. PMID- 23686188 TI - Therapeutic implications of the warburg effect assessing the survival of MRC5 and a549 cell lines upon exposure to honey and d glucose - biomed 2013. AB - Lung cancer is a one of the most prevalent and deadly cancers in United States. Experimental evidence support that cancer cells do exhibit higher glycolytic rates than normal cells. To exploit this unique cancer-dependent ATP generation phenomenon, we hypothesize that exposure of cancer cells to organic inhibitors of glycolysis would negatively impact their survival and alter their growth and viability resulting from the vast decrease in their essential glycolytic ATP production; no negative consequences will be seen on normal lung cells. The human lung fibroblast cell line MRC-5 and the human lung alveolar epithelial cancer cell line A549 were used in this study as models for normal lung and lung cancer respectively. Using standard methods, both cell lines were maintained and exposed to honey and D-glucose reagents at concentration levels ranging from 31.3-2,000 ug/ml in 96 well plates in quadruplets and experiments repeated at least three times using MTT (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide), and cell counting (T4 Cellometer; automated cell counting system) assays as well as phase-contrast photo-imaging. Our results indicate that exposure of both cell lines to these organics lead to concentration dependent cell destruction/cell survival depending on the cell line exposed. Honey and D-glucose showed statistically significant (p<0.05) differential negative effects on the A549 line in comparison to its unexposed control as well as to their effects on the MRC-5 cell line. These findings show a promising role for honey and D-glucose as biotherapeutic metabolites of interest for selective management of cancerous cells. PMID- 23686190 TI - Sensitivity of protein array deposition using continuous flow printing for fluorescent microarray applications - biomed 2013. AB - The promise of antibody and protein microarrays to revolutionize disease diagnostics has failed to live up to the hype primarily due to the problems associated with the printing of the antibodies and/or proteins onto the detection surface. The current standard in printing proteins is pin printing. An alternative to the pin printer is the continuous-flow microspotter (CFM), a protein printer that uses microfluidic flow to print down the proteins. The advantages of the CFM include consistent spot morphology, spot-to-spot uniformity and enhanced surface concentration. Further, the CFM is effective at capturing proteins and antibodies from either dilute or complex (e.g. blood or tissue) samples. In this study, the sensitivity of CFM printing Cy3 and Cy5 fluorescently labeled proteins was determined. Values were obtained at low concentrations tens of ng/mL with low coefficients of variation. Thus, the CFM can effectively print and quantify proteins and antibodies from low concentration and complex buffered samples. PMID- 23686191 TI - Assessment of thermal dissipation effects in a ventricular assist device - biomed 2013. AB - The heat generated during normal operation of an implantable Left Ventricular Assist Device (LVAD) can have a deleterious effect on the surrounding tissue as well as the blood flowing through the device. This effect is often overlooked and might also result in heart pump failure. Therefore, for a comprehensive design evaluation it is essential to accurately model the thermal dissipation in a LVAD system to ensure safety and device reliability. The LifeFlow artificial heart pump is a magnetically suspended axial flow LVAD in which the motor as well as the suspension system are the primary sources for heat generation. The objective of this study is to perform a thorough thermal analysis of the device using a combination of heat transfer equations, 3D-Finite Element analysis and 3D-CFD modeling. Particularly, the effects of heat generated on blood passing through the device due to the motor, magnetic suspension system and housing are studied. Conduction and convection effects due to the above contributors are analyzed. In addition, temperature distributions are estimated for different flow rates and pressure differentials. As a result of this study, it can be inferred if nominal operation of the LifeFlow LVAD would have any significant thermal effects on blood passing through the device. Results show that there is a 2.2 degrees C temperature increase in the magnetic suspension system during nominal operation, while the blood temperature is increasing by 1.6 degrees C. Assessment of thermal effects is crucial since high temperature exposure of blood could ultimately affect the patient whose systemic circulation is supported by the LVAD. PMID- 23686192 TI - A new model for mild blast injury utilizing Drosophila melanogaster - biomed 2013. AB - Current models for blast injury involve the use of mammalian species, which are costly and require extensive monitoring and housing, making it difficult to generate large numbers of injuries. The fruit fly, Drosophila melanogaster, has been utilized for many models of human disease including neurodegenerative disorders such as Parkinson?s and Alzheimer?s diseases. In this study, a model of blast injury was designed based on Drosophila, to provide a mechanism to investigate blast injury in large numbers and assess biochemical mechanisms of brain injury. Such studies may be used to identify specific pathways involved in blast-associated neurodegeneration, allowing more effective use of mammalian models. A custom-built blast wave simulator (ORA Inc.), comprised of a driver, test section, and wave eliminator, was used to create a blast wave. An acetate membrane was placed between the driver and the rectangular test section before compressed helium caused the membrane to rupture creating the blast wave. Membrane thickness correlates with the blast wave magnitude, which averaged 120 kPa for this experiment. Pressure sensors were inserted into the side of the tube in order to quantify the level of overpressure that the flies were exposed to. Five day old flies were held in a rectangular enclosed mesh fixture (10 flies per enclosure) which was placed in the center of the test section for blast delivery. Sham controls were exposed to same conditions with exception of blast. Lifespan and negative geotaxis, a measurement of motor function, was measured in flies after blast injury. Mild blast resulted in death of 28% of the flies. In surviving flies, motor function was initially reduced, but flies regained normal function by 8 days after injury. Although surviving flies regained normal motor function, flies subjected to mild blast died earlier than uninjured controls, with a 15.4% reduction in maximum lifespan and a 17% reduction in average lifespan, mimicking the scenario observed in humans exposed to mild blast. Although further work is needed, results suggest that utilizing Drosophila as a blast model may provide a rapid, effective means of assessing physiological and biochemical changes induced by mild blast. PMID- 23686193 TI - Thermally switchable adhesion of photopolymerizable acrylate polymer networks - biomed 2013. AB - Switchable adhesion behavior of flat and structured photopolymerizable acrylate networks was investigated as a function of temperature. The molecular weight and the weight fraction of poly(ethylene glycol) dimethacrylate crosslinker was altered to maintain a constant glass transition temperature of approximately 57 degrees C, but systematically vary the viscoelastic properties and the rubbery moduli (1.8-11.2 MPa). Dynamic mechanical analysis was performed to characterize the low-strain thermo-mechanical behavior of the materials. The flat samples tested with the spherical probe exhibited low pull-off forces at temperatures well above and well below the glass transition temperature of the material. A maximum pull-off force was observed in the vicinity of the glass transition temperature owing to the viscoelastic energy dissipative processes. The peak in pull-off force was observed to decrease with an increase in crosslinking density and modulus. The structured samples tested with spherical probe showed a decrease in adhesion with an increase in temperature up to the onset of glass transition, beyond which the adhesion was observed to increase due to the better contact formation allowed by the decrease in the material modulus. PMID- 23686194 TI - Morphological evaluations of human gingival fibroblasts exposed to novel dental adhesives in combination with glucocorticoids or dihydropridines - biomed 2013. AB - The present study evaluated the morphology of human gingival fibroblasts when exposed to dental adhesives in combination with glucocorticoids or dihydropridines in an in vitro environment. The cultured gingival fibroblasts used were obtained from the American Type Culture Collection (ATCC). The three dental adhesives used were Polymethyl methacrylate, OptiBond(r), and Prime & Bond(r). The glucocorticoid of choice was Cortisol along with the dihydropridine (Nifedipine). Fibroblasts were treated with each bonding agent, Cortisol, or Nifedipine for durations of 24, 48, and 72 hours. Morphological evaluation revealed that at 24 and 48 hour phases, there were no observable differences between the control and groups exposed to a combination of an adhesive and Cortisol. However, at 72 hours the cells exposed to combinations of OptiBond(r) with Cortisol and Prime & Bond(r) with Cortisol displayed predominantly spindle shaped cells compared to the predominantly round cells observed in the other samples. Cells exposed to a combination of adhesives with Nifedipine at 24 hour phase did not display any significant morphological alterations. In contrast, cells exposed to Prime & Bond(r) in combination with Nifedipine at the 48 hour phase revealed occasional morphological changes compared to control group. Likewise and at the end of 72 hour phase, the OptiBond(r)/Nifedipine and Prime & Bond(r)/Nifedipine groups displayed morphological differences such as clustering compared to the control. Biochemical analysis determined that there was a significant difference among the groups exposed to adhesives with Cortisol at 48 (P<0.002) and 72 hours (P <0.001). Glutathione (GSH) and Malondialdehyde levels (MDA) indicated that there were significant differences in the metabolic activities in groups exposed to combinations of dental adhesives and Cortisol at all phases. There were no differences in lactate dehydrogenase (LDH) levels among the groups exposed to combinations of adhesives and Cortisol or adhesives and Nifedipine. It is concluded that there were minor structural (morphological) alterations and major functional (biomarkers) changes observed upon exposing the gingival fibroblasts in combinations with Cortisol (stress environment) or Nifedipine. PMID- 23686195 TI - Tensile behavior of porous scaffolds made from poly(para phenylene) - biomed 2013. AB - The goal of this study was to fabricate and mechanically characterize a high strength porous polymer scaffold for potential use as an orthopedic device. Poly(para-phenylene) (PPP) is an excellent candidate due to its exceptional strength and stiffness and relative inertness, but has never been explicitly investigated for use as a biomedical device. PPP has strength values 3 to 10 times higher and an elastic modulus nearly an order of magnitude higher than traditional polymers such as poly(methyl methacrylate) (PMMA), polycaprolactone (PCL), ultra-high molecular weight polyethylene (UHMWPE), and polyurethane (PU) and is significantly stronger and stiffer than polyetheretherketone (PEEK). By utilizing PPP we can overcome the mechanical limitations of traditional porous polymeric scaffolds since the outstanding stiffness of PPP allows for a highly porous structure appropriate for osteointegration that can match the stiffness of bone (100-250 MPa), while maintaining suitable mechanical properties for soft tissue fixation. Porous samples were manufactured by powder sintering followed by particle leaching. The pore volume fraction was systematically varied from 50?80 vol% for a pore sizes from150-500 um, as indicated by previous studies for optimal osteointegration. The tensile modulus of the porous samples was compared to the rule of mixtures, and closely matches foam theory up to 70 vol%. The experimental modulus for 70 vol% porous samples matches the stiffness of bone and contains pore sizes optimal for osteointegration. PMID- 23686196 TI - Scanning electron image analysis to monitor of implant degradation and host healing following implantation of a drug-eluting bone graft void filler - biomed 2013. AB - Osteomyelitis is most commonly caused by Staphylococcus aureus and often sourced during orthopedic surgical intervention. Successful treatment or prevention of this bone penetrating infection requires antibiotics be delivered in excess of the minimal inhibitory concentration to prohibit the growth of the causative organism for sufficient duration. Unfortunately, current standard-of-care antibiotic therapies, administered via intravenous or oral delivery, suffer not only from systemic toxicity and low patient compliance but also provide insufficient local concentrations for therapy. To overcome these clinical inadequacies, a synthetic bone graft material was coated with an antibiotic (tobramycin)-releasing polymer (polycaprolactone) matrix to create a polymer controlled antibiotic- releasing combination therapy for use as a bone void filler in orthopedic surgeries. Even though this local delivery strategy allows antibiotic delivery over a clinically relevant time frame to prevent infection, complete healing requires the host bone to infiltrate and reabsorb the bone void filler, ultimately replacing the defect with healthy tissue. Unfortunately, the same polymer matrix that allows for controlled local antibiotic delivery may also discourage host bone healing. Efficient orthopedic healing requires the rate of polymer degradation to match the rate of host-bone infiltration. Current imaging techniques, such as histological staining and x-ray imaging, are insufficient to simultaneously assess polymer degradation and host bone integration. Alternative techniques relying on backscatter electron detection during scanning electron microscopy (SEM) imaging may allow a visual differentiation between host bone, synthetic bone, and polymer. Analysis of backscattered SEM images was automated using a custom MATLAB program to determine the ratio of bone to polymer based upon the contrast between the bone (white) and polymer (dark grey). By collecting images of the implant over time, a profile could be created to describe the rate of polymer degradation in conjunction with host-bone infiltration, allowing the intelligent tailoring of infectious osteomyelitis treatment/prevention and host graft integration. PMID- 23686197 TI - Response of thoracolumbar vertebral bodies to high rate compressive loading - biomed 2013. AB - Underbody blast (UBB) events created by improvised explosive devices are threats to warfighter survivability. High intensity blast waves emitted from these devices transfer large forces through vehicle structures to occupants, often resulting in injuries including debilitating spinal fractures. The vertical loading vector through the spine generates significant compressive forces at high strain rates. To better understand injury mechanisms and ultimately better protect vehicle occupants against UBB attacks, high-fidelity computational models are being developed to predict the human response to dynamic loading characteristic of these events. This effort details the results from a series of 23 high-rate compression tests on vertebral body specimen. A high-rate servo hydraulic test system applied a range of compressive loading rates (.01 mm/s to 1238 mm/s) to vertebral bodies in the thoracolumbar region (T7-L5). The force deflection curves generated indicate rate dependent sensitivity of vertebral stiffness, ultimate load and ultimate deflection. Specimen subjected to high-rate dynamic loading to failure experienced critical structural damage at 5.5% +/- 2.1% deflection. Compared to quasi-static loading, vertebral bodies had greater stiffness, greater force to failure, and lower ultimate failure deflection at high rates. Post-failure, an average loss in height of 15% was observed, along with a mean reduction in strength of 48%. The resulting data from these tests will allow for enhanced biofidelity of computational models by characterizing the vertebral stiffness response and ultimate deflection at rates representative of UBB events. PMID- 23686198 TI - Comparison of intra individual physiological sway complexity from force plate and inertial measurement unit - biomed 2013. AB - Center of Pressure (COP) is a clinical measure to investigate the effect of sensory input disturbances on postural stability in the healthy, elderly population as well in people suffering from neuromuscular disease. Increased center of pressure velocity and sway area are interpreted as decreased stability or poor balance and are associated with fall risk. Body mounted inertial sensors have shown great promise as an easily implemented clinical measure of balance. The aim of the present study is to investigate if force-plate and accelerometer measurements provide similar physiological information when approximate entropy (ApEn) are evaluated from a time series. Seven young and thirteen older individuals (two with fall history and nine without any past fall) participated in this study. There were different complexity measures in healthy young and elderly participants when both force-plate and Inertial Measurement Unit (IMU) were assessed during the same time interval. Thus different control mechanisms are underlying to control trunk sway as measured by IMU than that of COP measured by force-plate. PMID- 23686199 TI - Effect of skull flexural properties on brain response during dynamic head loading - biomed 2013. AB - The skull-brain complex is typically modeled as an integrated structure, similar to a fluid-filled shell. Under dynamic loads, the interaction of the skull and the underlying brain, cerebrospinal fluid, and other tissue produces the pressure and strain histories that are the basis for many theories meant to describe the genesis of traumatic brain injury. In addition, local bone strains are of interest for predicting skull fracture in blunt trauma. However, the role of skull flexure in the intracranial pressure response to blunt trauma is complex. Since the relative time scales for pressure and flexural wave transmission across the skull are not easily separated, it is difficult to separate out the relative roles of the mechanical components in this system. This study uses a finite element model of the head, which is validated for pressure transmission to the brain, to assess the influence of skull table flexural stiffness on pressure in the brain and on strain within the skull. In a Human Head Finite Element Model, the skull component was modified by attaching shell elements to the inner and outer surfaces of the existing solid elements that modeled the skull. The shell elements were given the properties of bone, and the existing solid elements were decreased so that the overall stiffness along the surface of the skull was unchanged, but the skull table bending stiffness increased by a factor of 2.4. Blunt impact loads were applied to the frontal bone centrally, using LS-Dyna. The intracranial pressure predictions and the strain predictions in the skull were compared for models with and without surface shell elements, showing that the pressures in the mid-anterior and mid-posterior of the brain were very similar, but the strains in the skull under the loads and adjacent to the loads were decreased 15% with stiffer flexural properties. Pressure equilibration to nearly hydrostatic distributions occurred, indicating that the important frequency components for typical impact loading are lower than frequencies based on pressure wave propagation across the skull. This indicates that skull flexure has a local effect on intracranial pressures but that the integrated effect of a dome like structure under load is a significant part of load transfer in the skull in blunt trauma. PMID- 23686200 TI - Using posturography to assess expertise among tai chi practitioners - biomed 2013. AB - Tai Chi, performed either seating or standing, is frequently recommended to improve various aspects of health, including balance, metabolic control, heart rate variability, sleep, or immune response. Many studies exploring mind-body interventions, both with self-reported or biologically-measured outcomes, report significant differences in outcomes among participants. However, neither the physiological or psychological mechanisms behind the variations are understood. The purpose of this study was to determine whether posturography is a useful method to assess physical skill level differences between experts and non-expert Tai Chi practitioners. While standing, participants performed a series of movements from the Tai Chi for Arthritis form based on Sun style (commencement, open/close, single whip and wave hands in cloud). Master trainers and senior trainers were considered experts; all others were considered non-experts. Body sway was assessed by the CAPS? Professional portable computerized force platform (Vestibular Technologies, LLC.). Center of Pressure motion measures were normalized by the subject's height. While standing, the experts displayed statistically greater displacement excursion and velocity when preforming commencement and wave hands in clouds forms. The results of this pilot study indicated that posturography may be a useful method to assess the quality of Tai Chi movements and potentially link the expertise of Tai Chi practitioners to changes in health related outcomes. PMID- 23686201 TI - Interactive remote medical curriculum through creative technology integration - biomed 2013. AB - By combining traditional classroom instruction with web-based educational technologies, distance education has been a reality for many years. However, limitations remain in established technologies that restrict the types of courses offered through this medium. This was the motivation for the Interactive Remote Course Delivery (IRCD) system at the Indiana University School of Medicine and our work aimed to overcome these limitations in order to allow a more interactive learning experience. What began as a need to deliver an interactive remote physiology course spurred several developments that may have the power to change the ways in which people learn, collaborate and communicate remotely. The result of extensive research brought stimulating discoveries leading to a new approach integrating separate technologies, including the combination of web-based collaborative software Adobe Connect with Polycom videoconferencing. By experimenting with the integration of these technologies we have enhanced the level of interactivity allowing the medical school curriculum to be delivered remotely. PMID- 23686202 TI - Exploring the use of five color flow cytometry to examine the effect of acute tai chi practice on pro inflammatory monocyte subtypes - biomed 2013. AB - OBJECTIVE: The purpose of this study was to determine whether five-color flow cytometry could be used to examine the effect of acute Tai Chi (TC) practice on pro-inflammatory monocyte subtypes within the total monocyte population in peripheral blood. DESIGN: A pilot pre- post- intervention design was our experimental model: pre-intervention measurements acted as the control for the post- intervention measurements. The research was conducted at Landsbaum Center for Health Education in a Midwestern community. Healthy subjects were asked to perform their style of TC for one hour. METHODS: Four milliliter of peripheral blood was collected in the BD Vacutainer CPT tubes immediately prior and after one hour of TC practice. Peripheral blood mononuclear cells (PBMCs) were isolated following the manufacturer?s protocol. PBMCs were then assessed for CD14, CD16, TLR2, TLR4, and HLA-DR expressions using five-color flow cytometry measurement. FlowJo and Graphpad Prism software were used to analyze the results. RESULTS: The proportion of pro-inflammatory CD14+CD16+ monocytes decreased immediately after one hour of TC practice (p<0.01). CONCLUSION: The results indicate that the five color flow cytometric process was sufficiently sensitive to be used to explore changes in peripheral blood pro-inflammatory monocytes following one hour of TC practice. PMID- 23686203 TI - Resistance reconstructed estimation of total peripheral resistance from computationally derived cardiac output - biomed 2013. AB - Efficient functioning of the peripheral vasculature is an essential component in healthy cardiovascular regulation. Alterations in this functioning have been linked to the etiology and pathophysiological course of cardiovascular disease (CVD), especially hypertension. Given its significant role in the maintenance of both healthy and pathological blood pressure, total peripheral resistance (TPR), an index of the vasoconstrictive and elastic properties of the peripheral vasculature, has received much attention in this regard. However, obtaining a reliable estimate of TPR remains a complex and costly endeavor, primarily due to the necessity for sophisticated instrumentation as well as associated limitations in deriving cardiac output (CO). We have previously described a simple estimation method for CO using only arterial blood pressure and heart rate (Hill et al, 2012). In the present study we extend this technique to the estimation of TPR using beat-to-beat blood pressure data from the same sample of 67 young (mean age = 20.04+/- 2.8), healthy men (n = 30) and women (n = 37). Estimated TPR (TPRest) was calculated from the computationally-derived estimate of CO and mean arterial pressure (MAP). Correlation between TPR obtained via the validated Model-Flow technique and TPRest was moderate (r =.73, p <. 000) and stronger in men (r =.78, p <. 000) compared to women (r =.66, p <. 001). These data further suggest that reconstructed measures of hemodynamic functioning may be validly and adequately estimated from limited data sources. PMID- 23686204 TI - Wavelet based automated postural event detection and activity classification with single imu - biomed 2013. AB - Mobility characteristics associated with activity of daily living such as sitting down, lying down, rising up, and walking are considered to be important in maintaining functional independence and healthy life style especially for the growing elderly population. Characteristics of postural transitions such as sit to-stand are widely used by clinicians as a physical indicator of health, and walking is used as an important mobility assessment tool. Many tools have been developed to assist in the assessment of functional levels and to detect a person?s activities during daily life. These include questionnaires, observation, diaries, kinetic and kinematic systems, and validated functional tests. These measures are costly and time consuming, rely on subjective patient recall and may not accurately reflect functional ability in the patient?s home. In order to provide a low-cost, objective assessment of functional ability, inertial measurement unit (IMU) using MEMS technology has been employed to ascertain ADLs. These measures facilitate long-term monitoring of activity of daily living using wearable sensors. IMU system are desirable in monitoring human postures since they respond to both frequency and the intensity of movements and measure both dc (gravitational acceleration vector) and ac (acceleration due to body movement) components at a low cost. This has enabled the development of a small, lightweight, portable system that can be worn by a free-living subject without motion impediment ? TEMPO (Technology Enabled Medical Precision Observation). Using this IMU system, we acquired indirect measures of biomechanical variables that can be used as an assessment of individual mobility characteristics with accuracy and recognition rates that are comparable to the modern motion capture systems. In this study, five subjects performed various ADLs and mobility measures such as posture transitions and gait characteristics were obtained. We developed postural event detection and classification algorithm using denoised signals from single wireless IMU placed at sternum. The algorithm was further validated and verified with motion capture system in laboratory environment. Wavelet denoising highlighted postural events and transition durations that further provided clinical information on postural control and motor coordination. The presented method can be applied in real life ambulatory monitoring approaches for assessing condition of elderly. PMID- 23686205 TI - Assessment of postural stability using inertial measurement unit on inclined surfaces in healthy adults - biomed 2013. AB - Fatal and nonfatal falls in the construction domain remain a significant issue in today?s workforce. The roofing industry in particular, annually ranks amongst the highest in all industries. Exposure to an inclined surface, such as an inclined roof surface, has been reported to have adverse effects on postural stability. The purpose of this preliminary study was to investigate the intra-individual differences in stability parameters on both inclined and level surfaces. Postural Stability (PS) and Limit of Stability (LOS) were assessed in seven healthy subjects (aged 25-35 years) on inclined and level surfaces using embedded force plates and an Inertial Measurement Unit (IMU). Four 90-second trials were collected on the inclined surface in distinctive positions: (1) Toes raised 20o above heel; (2) Heels raised 20o above toes (3); Transverse direction with dominant foot inverted at a lower height; (4) Transverse direction with non dominant foot inverted at a lower height. Limit of Stability was evaluated by the two measurement devices in all four directions and margin of safety was quantified for each individual on both surfaces. The results reveal significant differences in postural stability between the flat surface condition and the inclined surface condition when subject was positioned perpendicular to the surface slope with one foot descended below the other; specifically, a significant increase was identified when visual support was interrupted. The findings lend support to the literature and will assist in future research regarding early detection of postural imbalance and preventative measures to reduce fall risks in professions where workers are consistently exposed to inclined surfaces. PMID- 23686206 TI - Physical activity discrimination improvement using accelerometers and wireless sensor network localization - biomed 2013. AB - Automating documentation of physical activity data (e.g., duration and speed of walking or propelling a wheelchair) into the electronic medical record (EMR) offers promise for improving efficiency of documentation and understanding of best practices in the rehabilitation and home health settings. Commercially available devices which could be used to automate documentation of physical activities are either cumbersome to wear or lack the specificity required to differentiate activities. We have designed a novel system to differentiate and quantify physical activities, using inexpensive accelerometer-based biomechanical data technology and wireless sensor networks, a technology combination that has not been used in a rehabilitation setting to date. As a first step, a feasibility study was performed where 14 healthy young adults (mean age = 22.6 +/- 2.5 years, mean height = 173 +/- 10.0 cm, mean mass = 70.7 +/- 11.3 kg) carried out eight different activities while wearing a biaxial accelerometer sensor. Activities were performed at each participant?s self-selected pace during a single testing session in a controlled environment. Linear discriminant analysis was performed by extracting spectral parameters from the subjects? accelerometer patterns. It is shown that physical activity classification alone results in an average accuracy of 49.5%, but when combined with rule-based constraints using a wireless sensor network with localization capabilities in an in silico simulated room, accuracy improves to 99.3%. When fully implemented, our technology package is expected to improve goal setting, treatment interventions and patient outcomes by enhancing clinicians? understanding of patients? physical performance within a day and across the rehabilitation program. PMID- 23686207 TI - The mirror neuron system simply. An hypothesis? - biomed 2013. AB - The announcement that mirror neurons (MNs) had been found in macaques was made in 1996. The ensuing MN System theory (MNST) was based on the ?nearly simultaneous? activity of some neurons detected both when the macaque observed an investigator's action and when it performed the action (e.g. grasp to eat). Studying the seminal investigations on macaques published in the literature, we realized that poorly defined time-scales could lead to multiple interpretations. We also noticed that in the original experimental protocol the synchronization between the observed event and the neural activity hypothetically related to the event itself was not investigated. In spite of this criticism, the MNST has enjoyed an extraordinary popularity in general media as well as in the scientific community, and monkeys have, almost magically, acquired the functional ability of MNs. In this paper, we analyze some recent studies about the MNST, specifically those about direct measurements on humans by means of implanted electrodes performed by Mukamel and colleagues in 2010. We also consider some experiments performed on monkeys by Rochat et al. in 2010 and some indirect measurements on humans made by Kujala et al. in 2012. We find the conclusions of the authors of these works to be quite simplistic relative to the inherent complexity of neural networks, reinforcing our interpretation against the MNST. We suggest the reported measurements are the result of conventional neural activity related to the events considered (i.e. grasping, both observed and executed) and are not necessarily imputable to the hypothetical MNs. PMID- 23686208 TI - Effect of extracellular adenosine triphosphate on activity of osteoblast like cells - biomed 2013. AB - Platelet dense granules contain serotonin, adenosine triphosphate (ATP), and adenosine diphosphate (ADP). These molecules are present in platelet rich plasma (PRP), and may therefore have an impact on the efficacy of PRP therapy. Additionally, nucleotides are important extracellular signaling molecules in a variety of tissue types including bone. The purpose of this investigation was to evaluate the in vitro dose-dependent effects of extracellular adenosine triphosphate (ATP) exposure on activity of human osteoblast-like cells. MG-63 cells were exposed to phosphate buffered saline (control group) or ATP solution (20 uM, 100uM, 200 uM). Osteoblast viability was evaluated at 24, 48, and 72 hours using nonspecific and osteoblast-specific markers and cellular morphology. No significant differences in total protein, malonlydialdehyde (MDA), or glutathione were observed with ATP exposure at any timepoint. High dose ATP exposure resulted in a significantly higher production of nitric oxide compared to controls and other groups. With respect to alkaline phosphatase activity and osteopontin production, no significant differences were present with ATP exposure. Overall conclusion: Extracellular ATP exposure modulated osteoblast activity with no change in cell viability in vitro. PMID- 23686209 TI - The effects of serotonin on activated macrophages - biomed 2013. AB - Platelets are naturally active in the healing process. Derived from megakaryocytes, platelets are not actual cells because they have no nucleus or DNA and cannot synthesize their own proteins. When platelets are activated by stress, contact with tissues, or thrombin and calcium they release many powerful factors through a process referred to as degranulation. Degranulation describes the release of factors contained within two storage areas of the platelet, alpha and dense granules. A few of the known components released from the alpha granules of activated platelets include PDGF, VEGF, EGF, FGF and TGF-beta. These factors perform various functions that contribute to inflammation, tissue healing and tissue regeneration. The dense granules release their contents prior to alpha granule release at the site of activation. Well classified dense granule constituents are ionized calcium, adenosine di-phosphate, adenosine tri-phosphate , histamine, epinephrine and serotonin. Most applications of platelet rich plasma (PRP) center around a theory that growth factors released from the alpha granules of platelets play a critical role in tissue healing following injury. There is limited evidence in the literature regarding the role of the dense granule components role during inflammation. Our goal is to define serotonin release from the dense granule and the response of activated macrophage to serotonin. Serotonin has very little effect on macrophage cells in terms of both viability and function. Serotonin administered to macrophage cells does not result in a reduction of cell number, inflammatory cytokine production, or induction of a nitric oxide burst on its own. In the presence of lipopolysaccharide (LPS) activated macrophages serotonin reduces the initial LPS induced nitric oxide burst and suppress LPS induced cytokine (IL-1) production by 72 hours. Overall, the data suggest the possibility that the dense granule factors may contribute to the initial stages of healing. PMID- 23686210 TI - Development of an occult metric for common motor vehicle crash injuries - biomed 2013. AB - Detection of occult injuries, which are not easily recognized and are life threatening, in motor vehicle crashes (MVCs) is crucial in order to reduce fatalities. An Occult Injury Database (OID) was previously developed by the Center for Transportation Injury Research (CenTIR) using the National Automotive Sampling System Crashworthiness Data System (NASS-CDS) 1997-2001 which identified occult and non-occult head, thorax, and abdomen injuries. The objective of the current work was to develop an occult injury model based on underlying injury characteristics to derive an Occult Score for common MVC-induced injuries. A multiple logistic regression model was developed utilizing six injury parameters to generate a probability formula which assigned an Occult Score for each injury. The model was applied to a list of 240 injuries comprising the top 95 percent of injuries occurring in NASS-CDS 2000-2011. The parameters in the model included a continuous Cause MRR/year variable indicating the annual proportion of occupants sustaining a given injury whose cause of death was attributed to that injury. The categorical variables in the model were AIS 2-3 vs. 4-6, laceration, hemorrhage/hematoma, contusion, and intracranial. Results indicated that injuries with a low Cause MRR/year and AIS severity of 4-6 had an increased likelihood of being occult. In addition, the presence of a laceration, hemorrhage/hematoma, contusion, or intracranial injury also increased the likelihood of an injury being occult. The Occult Score ranges from zero to one with a threshold of 0.5 as the discriminator of an occult injury. Of the considered injuries, it was determined that 54% of head, 26% of thorax, and 23% of abdominal injuries were occult injuries. No occult injuries were identified in the face, spine, upper extremity, or lower extremity body regions. The Occult Score generated can be useful in advanced automatic crash notification research and for the detection of serious occult injuries in MVCs requiring prompt treatment at a trauma center. PMID- 23686211 TI - Development of a miniaturized position sensing system for measuring brain motion during impact - biomed 2013. AB - Since 2000, the Department of Defense has documented more than 253,000 cases of Traumatic Brain Injury (TBI). A significant portion of these injuries were attributed to explosive events, yet ninety-eight percent were non-penetrating. Understanding the response of the brain to blast events is critical, yet the mechanisms of brain injury from explosive trauma are poorly understood. This knowledge gap has led to an increased research focus on devices capable of investigating human brain response to non-penetrating, blast-induced loading. Furthermore, traumatic brain injury is a major issue for the civilian population as well with over 1.7 million cases of TBI per year in the US, primarily from falls and motor vehicle accidents. Current head surrogates and instrumentation are incapable of directly measuring critical parameters associated with TBI, such as brain motion, during dynamic loading. To this end, a novel sensor system for measuring brain motion inside of a human head surrogate was conceptualized and developed. The positioning system is comprised of a set of three fixed ?generator? coils and a plurality of mobile, miniaturized ?receiver? coil triads. Each generator coil transmits a sinusoidal electromagnetic signal at a unique frequency, and groups of three orthogonally arranged ?receiver? coils detect these signals. Because of the oscillatory nature of these signals, the magnetic flux through the coil is always changing, allowing the application of Faraday?s Law of Induction and the point dipole model of an electric field to model the strength and direction of the field vector at any given point. Thus, the strength of the signal measured by a particular receiver coil depends on its position and orientation relative to the fixed position of the generators. These predictable changes are used to determine the six degrees of freedom (6-DOF) motion of the receiver. To calibrate and validate the system, a receiver coil was moved about in a controlled manner, and its actual position recorded by optical methods. Comparing the known position to the computed position at each time instance, a set of calibration constants were developed for each receiver triad. These constants were then utilized to convert receiver signal data into actual receiver position and orientation. Comparing this test case and several others like it, mean error was determined to be almost always less than 1.0 mm, and less than 0.5 mm >85% of the time. Additionally, high rate validation was conducted to confirm operation of the system in the impact domain. A coil was accelerated to approximately 15 m/sec along a fixed axis by ballistic impact and tracked by high speed video. The computed position was within 1 mm of the actual position 93% of the time and within 0.5 mm 83% of the time. The successful development and calibration of this sensing system now enables the direct measurements of brain displacement due to mechanical insults applied to a human head surrogate. PMID- 23686212 TI - Human liver finite element model validation using compressive and tensile experimental data - biomed 2013. AB - Motor vehicle crashes commonly result in blunt abdominal trauma. Approximately 19,000 such injuries occur each year in the United States. While finite element models of the human body are becoming an important tool for injury assessment, their reliability depends on the accuracy of the material models used. Recently, Samur et al. proposed a hyperelastic and viscoelastic material model of the liver. The aim of this study was to compare the results of a computational model using this material law to uniaxial tension and compression data from biomechanical tests on liver samples by Kemper et al. In this study, the liver samples were modeled using the finite element method. Both the tension and compression test specimen geometries were created from descriptions in the literature. Each sample was meshed using four approaches: fine hexahedral, coarse hexahedral, fine tetrahedral, and coarse tetrahedral. The average element edge lengths of the coarse and fine meshes were 5 mm and 2.5 mm respectively. The samples were loaded in both tension and compression at four rates: 0.01 strain/sec, 0.1 strain/sec, 1 strain/sec, and 10 strain/sec. For each mesh type (n=4), strain rate (n=4), and loading condition (n=2), 32 simulations in total, the results were plotted against the published experimental data. The results were quantitatively evaluated for magnitude and phase agreement with the experimental data using an objective comparison software package, CORA. The model predicted the tensile response of the liver sample more accurately than the compressive response with an average CORA size error factor of 0.66 versus 0.19 for the compressive model (1 is a perfect match). The fine tetrahedral, fine hexahedral, and coarse hexahedral meshes predicted a similar response. The worst performing mesh was the coarse tetrahedral mesh, which had an average size error factor of 8.6% higher than the fine tetrahedral simulations. The peak stress in both tension and compression varied as a function of the loading rate. Peak tensile stress increased 13% from the lower to higher loading rate, and peak compressive stress increased 0.5%. These findings show evidence that the viscoelastic behavior is captured in the model, although it is under predicted in comparison to the literature. Future work will focus on other material models that better predict the experimentally observed loading observed in the literature. Validation of the liver model?s response to compressive and tensile loading conditions across multiple rates is important to ensure accurate injury predictions when used in a full body finite element model. PMID- 23686213 TI - Evaluation of the extent and distribution of diffuse axonal injury from real world motor vehicle crashes - biomed 2013. AB - Diffuse axonal injury (DAI) is a common traumatic brain injury (TBI) often seen as a result of motor vehicle crashes (MVC). Twelve (12) cases of DAI were selected from the Crash Injury Research and Engineering Network (CIREN) to determine the extent and distribution of injury with respect to the head contact location. Head computed tomography (CT) scans were collected for each subject and segmented using semi-automated methods to establish the volumes of DAI. The impacted area on the subject's head was approximated from evidence of a soft tissue scalp contusion on the CT scan. This was used in conjunction with subject images and identified internal vehicle contact locations to ascertain a label map of the contact location. A point cloud was developed from the contact location label map and the centroid of the point cloud was calculated as the subject's head impact location. The injury and contact location were evaluated in spherical coordinates and grouped into 0.2 by 0.2 radial increments of azimuth and elevation. The radial increments containing DAI were projected onto a meshed sphere to evaluate the radial distance from the impact location to primary location of DAI and approximate anatomical location. Of the 170 injuries observed, 123 were identified in the frontal lobe and 36 in the parietal lobe. The distribution of the DAI in relation to the change in azimuth from the contact loca y correlated with contact to the head superficial to this lobe. Results from this study provide further insight into the biomechanics of traumatic brain injury and can be used in future work as an aid to validate finite element models of the head. PMID- 23686214 TI - Seatbelt compliance among morbidly obese versus non obese patients suffering severe blunt trauma in Mississippi - biomed 2013. AB - We describe the preliminary findings of seatbelt compliance among severely injured blunt trauma patients involved in motor vehicle crashes in Mississippi. Stratification of the sample size of 1,405 patients included obese versus the non obese patients with sub-stratification of weight classes to include normal weight, overweight, obese and morbidly obese. An overview of the design of the study is included. The results demonstrate no significant difference between the numbers of restrained and unrestrained obese patients compared to their normal weight counterparts. Our findings suggest unrestrained patients regardless of weight class had higher ISS than restrained individuals. The data for Mississippi is similar to those reported nationally. Interestingly, we observed the injury severity scores in the restrained obese and morbidly obese patients were higher than the unrestrained motorists within the same weight cohort. This may reflect less movement within the vehicle resulting in less trauma. PMID- 23686215 TI - A novel bridge wire model of blast traumatic brain injury - biomed 2013. AB - Research into the mechanics of blast-induced traumatic brain injury requires a device capable of reproducing pressures of the same magnitude and time scale as a blast wave. A blast simulator based on the exploding bridge wire mechanism was created with these capabilities. Peak blast pressures in the range of 5 ? 29 psi were generated with a positive phase duration less than 20 us. A series of experiments using 0.008 inch diameter wires (10-20 psi) were used to demonstrate the ability of the blast simulator to injure in vitro primary brain cell cultures at 1, 24, and 48 hours following blast. Blast exposure caused a rapid loss of cells which was significant over controls. Propidium iodide uptake indicated limited injury to cellular membranes but the cytoskeletal structure showed signs of degeneration 1 hour following blast. These results indicate that the bridge wire blast simulator can serve as a suitable in vitro model of blast injury. PMID- 23686217 TI - A critical black feminist ethnography of treatment for women with co-occurring disorders in the psychiatric hospital. AB - The purpose of this study was to explore the perspectives of women diagnosed with co-occurring disorders on the treatments provided by a state psychiatric hospital so that appropriate recommendations for changes in treatment may be made. Critical ethnography was used and the data was viewed through the lens of intersectionality from the black feminist perspective. Seven women hospitalized in one psychiatric hospital in the Mid-Atlantic region participated in the study. Data was collected via semistructured interviews, Consumer Perceptions of Care survey, researcher's observations, and archival data. Three major findings emerged: (1) Dialectical Behavioral Therapy (DBT) was identified as a beneficial treatment, (2) a lack of trust in the system and people in the system, and (3) housing or homelessness was perceived as a barrier. Based on the results of this study, it is recommended clinicians, administrators, and policy makers listen closely to individuals receiving treatment to make decisions regarding treatment accordingly. PMID- 23686216 TI - Engagement in outpatient substance abuse treatment and employment outcomes. AB - This study, a collaboration between an academic research center and Washington State's health, employment, and correction departments, investigates the extent to which treatment engagement, a widely adopted performance measure, is associated with employment, an important outcome for individuals receiving treatment for substance use disorders. Two-stage Heckman probit regressions were conducted using 2008 administrative data for 7,570 adults receiving publicly funded treatment. The first stage predicted employment in the year following the first treatment visit, and three separate second-stage models predicted the number of quarters employed, wages, and hours worked. Engagement as a main effect was not significant for any of the employment outcomes. However, for clients with prior criminal justice involvement, engagement was associated with both employment and higher wages following treatment. Clients with criminal justice involvement face greater challenge regarding employment, so the identification of any actionable step which increases the likelihood of employment or wages is an important result. PMID- 23686218 TI - Treatment of ankylosing spondylitis with TNF blockers: a meta-analysis. AB - Biological agents directed against tumor necrosis factor (TNF) represent therapeutic options for patients with ankylosing spondylitis with high disease activity despite use of non-steroidal anti-inflammatory drugs. To evaluate the efficacy and safety of the anti-TNF agents infliximab, etanercept, adalimumab, golimumab, and certolizumab for the treatment of ankylosing spondylitis, we performed a systematic review of randomized clinical trials on adult patients with ankylosing spondylitis using articles culled from the EMBASE, MEDLINE, Cochrane Controlled Trials Register and LILACS databases (September/2012), manual literature search, and the gray literature. Study selections and data collection were performed by two independent reviewers, with disagreements solved by a third reviewer. The following outcomes were evaluated: ASAS 20 response, disease activity, physical function, vertebral mobility, adverse events, and withdraws. The meta-analysis was performed using the Review Manager((r)) 5.1 software by applying the random effects model. Eighteen studies were included in this review. No study of certolizumab was included. Patients treated with anti-TNF agents were more likely to display an ASAS 20 response after 12/14 weeks (RR 2.21; 95 % CI 1.91; 2.56) and 24 weeks (RR 2.68; 95 % CI 2.06; 3.48) compared with controls, which was also true for several other efficacy outcomes. Meta-analysis of safety outcomes and withdraws did not indicate statistically significant differences between treatment and control groups after 12 or 30 weeks. Adalimumab, infliximab, etanercept, and golimumab can effectively reduce the signs and symptoms of the axial component of ankylosing spondylitis. Safety outcomes deserve further study, especially with respect to long-term follow-ups. PMID- 23686219 TI - Anti-cyclic citrullinated peptide (anti-CCP) antibodies with brucellosis. AB - Anti-cyclic citrullinated peptide (anti-CCP) was positive in 11.5 % and rheumatoid factor was positive in 8.8 % of the patients with Brucella. After a comparative evaluation, we have found out that there was not a statistical significance concerning the anti-CCP levels between the patients with brucellosis and healthy control. PMID- 23686220 TI - Volume-based pollen size analysis: an advanced method to assess somatic and gametophytic ploidy in flowering plants. AB - Pollen size is often used as a biological parameter to estimate the ploidy and viability of mature pollen grains. In general, pollen size quantification is performed one- or two-dimensionally using image-based diameter measurements. As these approaches are elaborate and time consuming, alternative approaches that enable a quick, reliable analysis of pollen size are highly relevant for plant research. In this study, we present the volume-based particle size analysis technique as an alternative method to characterize mature pollen. Based on a comparative assay using different plant species (including tomato, oilseed rape, kiwifruit, clover, among others), we found that volume-based pollen size measurements are not biased by the pollen shape or position and substantially reduce non-biological variation, allowing a more accurate determination of the actual pollen size. As such, volume-based particle size techniques have a strong discriminative power in detecting pollen size differences caused by alterations in the gametophytic ploidy level and therefore allow for a quick and reliable estimation of the somatic ploidy level. Based on observations in Arabidopsis thaliana gametophytic mutants and differentially reproducing Boechera polyantha lines, we additionally found that volume-based pollen size analysis provides quantitative and qualitative data about alterations in male sporogenesis, including aneuploid and diploid gamete formation. Volume-based pollen size analysis therefore not only provides a quick and easy methodology to determine the somatic ploidy level of flowering plants, but can also be used to determine the mode of reproduction and to quantify the level of diplogamete formation. PMID- 23686222 TI - Pollen tube entry into the synergid cell of Arabidopsis is observed at a site distinct from the filiform apparatus. AB - In higher plants, the double-fertilization process begins with the successful delivery of two sperm cells to the female gametophyte. The sperms cells are carried by a pollen tube that upon arrival at the micropylar end of the female gametophyte, bursts, and discharges its content into one of two specialized cells called the synergid cells. At their micropylar ends, both synergid cells form a thickened cell wall with a unique structure called the filiform apparatus. The filiform apparatus is believed to play a major role in pollen tube guidance and reception. It has also been assumed that the pollen tube enters the receptive synergid cell through the filiform apparatus. Here, we show that in Arabidopsis ovules, the arriving pollen tube appears to grow beyond the filiform apparatus to enter the synergid cell at a more distant site, where the tube bursts to release its contents. Thus, fertilization in Arabidopsis might involve two spatially and temporally separable stages, recognition and entry, with the latter apparently not requiring the filiform apparatus. PMID- 23686221 TI - Arabidopsis RPG1 is important for primexine deposition and functions redundantly with RPG2 for plant fertility at the late reproductive stage. AB - Arabidopsis Ruptured Pollen Grain-1 (RPG1/Sweet8) is a member of the MtN3/saliva protein family that functions as a sugar transporter. The rpg1 mutant shows defective exine pattern formation. In this study, transmission electron microscopy (TEM) observations showed that much less primexine was deposited in rpg1 tetrads. Furthermore, microspore membrane undulation was abnormal, and sporopollenin accumulation was also defective. This suggests that a reduced primexine deposition in rpg1 leads to abnormal membrane undulation that affects exine pattern formation. Chemical staining revealed thinning of the callose wall of rpg1, as well as significantly reduced expression of Callose synthase-5 (CalS5) in rpg1. The fertility of the rpg1 mutant could be partly restored at late reproductive stages, potentially complemented in part by RPG2, another member of the MtN3/saliva family, which is expressed in the anther during microsporogenesis. The double mutant, rpg1rpg2, was almost sterile and was not restored during late reproduction. These results suggest that RPG1 and RPG2 are involved in primexine deposition and therefore pollen wall pattern formation. PMID- 23686223 TI - Isolation and characterization of multiple F-box genes linked to the S9- and S10 RNase in apple (Malus * domestica Borkh.). AB - Using 11 consensus primer pairs designed from S-linked F-box genes of apple and Japanese pear, 10 new F-box genes (MdFBX21 to 30) were isolated from the apple cultivar 'Spartan' (S(9)S(10)). MdFBX21 to 23 and MdFBX24 to 30 were completely linked to the S(9) -RNase and S(10-)RNase, respectively, and showed pollen specific expression and S-haplotype-specific polymorphisms. Therefore, these 10 F box genes are good candidates for the pollen determinant of self-incompatibility in apple. Phylogenetic analysis and comparison of deduced amino acid sequences of MdFBX21 to 30 with those of 25 S-linked F-box genes previously isolated from apple showed that a deduced amino acid identity of greater than 88.0 % can be used as the tentative criterion to classify F-box genes into one type. Using this criterion, 31 of 35 F-box genes of apple were classified into 11 types (SFBB1 11). All types included F-box genes derived from S(3-) and S(9-)haplotypes, and seven types included F-box genes derived from S(3-), S(9-), and S(10-)haplotypes. Moreover, comparison of nucleotide sequences of S-RNases and multiple F-box genes among S(3-), S(9-), and S(10-)haplotypes suggested that F-box genes within each type showed high nucleotide identity regardless of the identity of the S-RNase. The large number of F-box genes as candidates for the pollen determinant and the high degree of conservation within each type are consistent with the collaborative non-self-recognition model reported for Petunia. These findings support that the collaborative non-self-recognition system also exists in apple. PMID- 23686224 TI - Surgical outcomes of acellular human dermal grafts for large conjunctiva defects in orbital implant insertion. AB - PURPOSE: We report the surgical outcomes of acellular human dermal allografts for repair of large conjunctiva defects in primary or secondary orbital implant insertion. METHODS: This retrospective chart review examined 12 eyes in 12 patients who underwent primary or secondary orbital implant insertion using Medpor(r) and acellular human dermal allografts to decrease conjunctival tension. Only patients with at least 6 months follow-up were included. The procedure was successful if there was no exposure until the last eye-clinic visit and the patient could wear a prosthesis. It failed if additional surgery was needed to correct the orbital implant exposure. RESULTS: The mean follow-up was 24.5 (range 6-54) months. Seven patients had primary orbital implant insertion, and five had secondary orbital implant insertion with acellular human dermal allografts. All enrolled patients had successful outcomes without exposure of the central conjunctiva. Two underwent additional surgery to correct fornix contracture and regain a cosmetically good prosthesis. Of these, one patient received additional acellular human dermal grafts and had a fair outcome. The other patient ultimately required fornix reconstruction with an autologous graft using oral mucosa. CONCLUSION: Orbital implant insertion with acellular human dermis grafts had good surgical outcomes. The procedure could be effective for patients with insufficient conjunctival tissue to cover an orbital implant and a high probability of developing orbital implant exposure if tension was created by excessive direct conjunctival closure. PMID- 23686226 TI - A bystander cell-based GM-CSF secreting vaccine synergized with a low dose of cyclophosphamide presents therapeutic immune responses against murine hepatocellular carcinoma. AB - Granulocyte-macrophage colony-stimulating factor (GM-CSF) secreting cellular tumor vaccines contribute to the induction of potent antitumor immune responses in murine models and patients suffering from cancers. Hepatocellular carcinoma (HCC) is one of the most frequent and malignant cancers in China. We describe, for the first time, a GM-CSF releasing vaccine strategy that represents a step toward combating this type of cancer. In this study, a bystander cell-based GM CSF secreting vaccine against murine HCC, Hepa1-6/B78H1-GM-CSF, was co administered with a low dose of cyclophosphamide (CY). After challenging with tumor and vaccination, immunological assays demonstrated that the cellular antitumor immune responses were efficiently activated and that tumor development was significantly retarded, which was dependent on synergy with CY. The promising outcome of the anti-HCC vaccine in the murine model demonstrates the feasibility of a future clinical application for this treatment in HCC patients. PMID- 23686227 TI - T-bet in the spot light: roles in distinct T-cell fate determination. AB - The transcription factor T-bet was originally described to be important for the differentiation of the CD4(+) Th1 subset. More recent investigations implicate T bet in the lineage commitment of a variety of innate immune cells also. The T-bet appears to have a dual role in the immune system. Under certain conditions T-bet provides a beneficial role, whereas the exaggerated expression of T-bet in certain innate lymphoid cells can be detrimental to the host. Therefore, this transcription factor needs to be carefully regulated. The feedback control and the epigenetic mechanisms involved in the expression of T-bet remain to be fully elucidated. PMID- 23686225 TI - Evaluation of the in vitro activity of commercially available moxifloxacin and voriconazole eye-drops against clinical strains of Acanthamoeba. AB - PURPOSE: Acanthamoeba is an opportunistic pathogen which is the causal agent of a sight-threatening ulceration of the cornea known as "Acanthamoeba keratitis" (AK) and, more rarely, an infection of the central nervous system called "granulomatous amoebic encephalitis" (GAE). The symptoms of AK are non-specific, and so it can be misdiagnosed as a viral, bacterial, or fungal keratitis. Furthermore, current therapeutic measures against AK are arduous, and show limited efficacy against the cyst stage of Acanthamoeba. Moxifloxacin, a fourth generation fluoroquinolone, has been used with other drugs to treat GAE, but its efficacy as a treatment for AK is not known. Voriconazole has been used to treat AK; however, its cysticidal efficacy is not known. Both drugs are commercially available as eye-drops. The aim of this study was to evaluate the in-vitro activity of these eye-drops against Acanthamoeba compared to two reference drugs (chlorhexidine and amphotericin B) which are currently used to treat AK and GAE. METHODS: The sensitivity of two clinical and one type strain of Acanthamoeba to the commercial concentrations of the four drugs was evaluated with a colorimetric assay. Mature cysts were incubated with voriconazole to determine their sensitivity to this drug. The effects on cell proliferation and cell toxicity were determined using standard procedures with commercial kits. RESULTS: The four compounds were active against the Acanthamoeba strains in this study. Although it prevented encystation, moxifloxacin's amoebicidal activity was low. Voriconazole activity was greater than that of the other drugs, even at a concentration lower than in commercial eye drops. It was effective against cysts and decreased cell proliferation, with low cellular cytotoxicity. CONCLUSION: Voriconazole could be used against AK as a first-line treatment or in combination. Moxifloxacin is an interesting adjuvant to consider as it is effectively prevents encystation of the amoeba which often complicates infection resolution. In addition, moxifloxacin is effective in preventing secondary bacterial infections. PMID- 23686228 TI - Of mice and men: what rodent models don't tell us. PMID- 23686229 TI - Developing a structural model of reading: the role of hearing status in reading development over time. AB - The purpose of the present study was to develop a structural model of reading based on the Lexical Quality Hypothesis (Perfetti & Hart, 2002). Data from a 4 year longitudinal study of Dutch primary school children with and without hearing loss were used to conduct an exploratory analysis of how lexical components (i.e., decoding skills, lexical decision, and lexical use) relate to one another and to reading comprehension. Our structural model supports a positive role of the quality of the mental lexicon for reading comprehension. Furthermore, it was possible to apply the same conceptual model of reading development to both groups of children when incorporating hearing status as a grouping variable. However, a multigroup comparison model showed that the predictive values of the relations between the different tasks differed for the two groups. PMID- 23686231 TI - Inhibition of retroviral replication by members of the TRIM protein family. AB - The TRIM protein family is emerging as a central component of mammalian antiviral innate immunity. Beginning with the identification of TRIM5alpha as a mammalian post-entry restriction factor against retroviruses, to the repeated observation that many TRIMs ubiquitinate and regulate signaling pathways, the past decade has witnessed an intense research effort to understand how TRIM proteins influence immunity. The list of viral families targeted directly or indirectly by TRIM proteins has grown to include adenoviruses, hepadnaviruses, picornaviruses, flaviviruses, orthomyxoviruses, paramyxoviruses, herpesviruses, rhabdoviruses and arenaviruses. We have come to appreciate how, through intense bouts of positive selection, some TRIM genes have been honed into species-specific restriction factors. Similarly, in the case of TRIMCyp, we are beginning to understand how viruses too have mutated to evade restriction, suggesting that TRIM and viruses have coevolved for millions of years of primate evolution. Recently, TRIM5alpha returned to the limelight when it was shown to trigger the expression of antiviral genes upon recognition of an incoming virus, a paradigm shift that demonstrated that restriction factors make excellent pathogen sensors. However, it remains unclear how many of ~100 human TRIM genes are antiviral, despite the expression of many of these genes being upregulated by interferon and upon viral infection. TRIM proteins do not conform to one type of antiviral mechanism, reflecting the diversity of viruses they target. Moreover, the cofactors of restriction remain largely enigmatic. The control of retroviral replication remains an important medical subject and provides a useful backdrop for reviewing how TRIM proteins act to repress viral replication. PMID- 23686232 TI - The antiviral activities of tetherin. AB - Tetherin (BST2/CD317) has emerged as a key host cell defense molecule, inhibiting the release and spread of diverse enveloped virions from infected cells. In this chapter, I review the molecular and cellular basis for tetherin's antiviral activities and the function of virally encoded countermeasures that disrupt its function. I further describe recent advances in our understanding of tetherin's associated role in viral pattern recognition and the evidence for its role in limiting viral pathogenesis in vivo. PMID- 23686233 TI - Restriction of retroviral infection of macrophages. AB - Primate immunodeficiency viruses are highly specialized lentiviruses that have evolved to successfully infect and persist for the lifetime of the host. Despite encountering numerous potent antiviral factors, HIVs and SIVs are successful pathogens due to the acquisition of equally potent countermeasures in the form of accessory genes. The accessory gene Vpx encoded by HIV-2 and a subset of SIVs have a profound effect on the ability of lentiviruses to infect non-dividing cells, such as macrophages. Although most virus replication occurs in activated CD4(+) T cells, myeloid lineage cells are natural targets of infection and play a central role in virus transmission, dissemination, and persistence. However, myeloid lineage cells are poorly sensitive to lentiviral infection due partly to the high-level expression of a host protein that regulates nucleic acid metabolism named SAMHD1. Degradation of SAMHD1 is induced by Vpx to eliminate this intrinsic antiviral factor. Importantly, SAMHD1 has also been implicated as a negative regulator of the innate immune response, so the interplay between SAMHD1 and Vpx is likely to have significant consequences for virus replication, persistence, and immune control. PMID- 23686234 TI - Rapid adversarial co-evolution of viruses and cellular restriction factors. AB - Since the discovery of viruses over a century ago, virologists have recognized that host genetics plays a major role in viral tropism and the distribution of viruses in nature. Traditionally, studies of tropism have centered on identification of cellular factors required for viral replication, such as cell surface entry receptors. However, over the past 20 years, there has been a steady increase in the identification and characterization of restriction factors (RFs), here defined as dominant cellular factors that have evolved specifically to interfere with viral replication. Genetic studies suggest that restriction factors impose significant barriers to interspecies movement of viruses and are therefore critical determinants of viral tropism. Furthermore, the scope of the ever-expanding list of restriction factors, and the variety of antiviral mechanisms they represent, testifies to the extraordinary impact viruses have had on organismal evolution-an impact hitherto underappreciated by evolutionary biologists and virologists alike. Recent studies of RF-encoding genes that combine molecular evolutionary analysis with functional assays illustrate the potential for asking questions about virus-host interactions as they play out in natural populations and across evolutionary timescales. Most notably, it has become common to apply tests of positive selection to RF genes and couple these analyses with virological assays, to reveal evidence for antagonistic virus-host co-evolution. Herein, I summarize recent work on the evolutionary genetics of mammalian RFs, particularly those of humans, non-human primates, and model organisms, and how RFs can reveal the influence of virus-host interactions on organismal evolution. Because intensive investigation of RF evolution is fairly new (and because there is still much to learn), the discussion is organized around five broad, outstanding questions that will need to be answered before we can fully appreciate the evolutionary biology of restriction. PMID- 23686230 TI - The APOBEC3 family of retroelement restriction factors. AB - The ability to regulate and even target mutagenesis is an extremely valuable cellular asset. Enzyme-catalyzed DNA cytosine deamination is a molecular strategy employed by vertebrates to promote antibody diversity and defend against foreign nucleic acids. Ten years ago, a family of cellular enzymes was first described with several proving capable of deaminating DNA and inhibiting HIV-1 replication. Ensuing studies on the apolipoprotein B mRNA-editing enzyme catalytic polypeptide like 3 (APOBEC3) restriction factors have uncovered a broad-spectrum innate defense network that suppresses the replication of numerous endogenous and exogenous DNA-based parasites. Although many viruses possess equally elaborate counter-defense mechanisms, the APOBEC3 enzymes offer a tantalizing possibility of leveraging innate immunity to fend off viral infection. Here, we focus on mechanisms of retroelement restriction by the APOBEC3 family of restriction enzymes, and we consider the therapeutic benefits, as well as the possible pathological consequences, of arming cells with active DNA deaminases. PMID- 23686235 TI - RNA interference-mediated intrinsic antiviral immunity in plants. AB - RNA interference (RNAi) is an evolutionarily conserved, sequence-specific gene inactivation system that plays an essential role in many biological processes, such as genome defense against mobile DNA elements or regulation of factors involved in plant and animal development. In higher plants and invertebrates, it also functions as a powerful antiviral mechanism. To overcome antiviral RNAi, viruses have evolved suppressor proteins which counteract host RNAi-based antiviral processes and target one or more key points in the RNAi machinery. Here, we review recent progress in our understanding of the mechanism and function of antiviral RNAi in plants and on the viral responses through the expression of silencing suppressor proteins. As a counter-attack RNAi may also regulate innate immunity in plants and contribute to a novel layer of defense against pathogen attack. We also discuss emerging evidence that viruses use RNAi to manipulate host gene expression to modify the cellular environment for the benefit of invading viruses. PMID- 23686236 TI - RNA interference-mediated intrinsic antiviral immunity in invertebrates. AB - In invertebrates such as insects and nematodes, RNA interference (RNAi) provides RNA-based protection against viruses. This form of immunity restricts viral replication and dissemination from infected cells and viruses, in turn, have evolved evasion mechanisms or RNAi suppressors to counteract host defenses. Recent advances indicate that, in addition to RNAi, other related small RNA pathways contribute to antiviral functions in invertebrates. This has led to a deeper understanding of fundamental aspects of small RNA-based antiviral immunity in invertebrates and its contribution to viral spread and pathogenesis. PMID- 23686237 TI - Roles of microRNAs in the life cycles of mammalian viruses. AB - MicroRNAs (miRNAs) are a class of small noncoding RNAs expressed by plants, animals, and some viruses. miRNAs generally function as part of miRNA-induced silencing complexes to modestly repress mRNAs with imperfect sequence complementarity. Over the last years, many different roles of miRNA mediated regulation in the life cycles of mammalian viruses have been uncovered. In this chapter, I will mainly explore four different examples of how cellular miRNAs interact with viruses: the role of miR-155 in viral oncogenesis, viral strategies to eliminate cellular miR-27, the contribution of miR-122 to the replication of hepatitis C virus, and miRNAs as an experimental tool to control virus replication and vector transgene expression. In the final part of this chapter, I will give a brief overview of virally encoded microRNAs. PMID- 23686238 TI - Interplay between DNA tumor viruses and the host DNA damage response. AB - Viruses encounter many challenges within host cells in order to replicate their nucleic acid. In the case of DNA viruses, one challenge that must be overcome is recognition of viral DNA structures by the host DNA damage response (DDR) machinery. This is accomplished in elegant and unique ways by different viruses as each has specific needs and sensitivities dependent on its life cycle. In this review, we focus on three DNA tumor viruses and their interactions with the DDR. The viruses Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and human papillomavirus (HPV) account for nearly all of the virus associated human cancers worldwide. These viruses have also been excellent models for the study of oncogenic virus-mediated cell transformation. In this review, we will discuss how each of these viruses engage and subvert aspects of the host DDR. The first level of DDR engagement is a result of the genetic linkage between the oncogenic potential of these viruses and their ability to replicate. Namely, the promotion of cells from quiescence into the cell cycle to facilitate virus replication can be sensed through aberrant cellular DNA replication structures which activate the DDR and hinder cell transformation. DNA tumor viruses subvert this growth-suppressive DDR through changes in viral oncoprotein expression which ultimately facilitate virus replication. An additional level of DDR engagement is through direct detection of replicating viral DNA. These interactions parallel those observed in other DNA virus systems in that the need to subvert these intrinsic sensors of aberrant DNA structure in order to replicate must be in place. DNA tumor viruses are no exception. This review will cover the molecular features of DNA tumor virus interactions with the host DDR and the consequences for virus replication. PMID- 23686239 TI - Costs and benefits of bullying in the context of the peer group: a three wave longitudinal analysis. AB - Whereas previous research has shown that bullying in youth is predictive of a range of negative outcomes later in life, the more proximal consequences of bullying in the context of the peer group at school are not as clear. The present three-wave longitudinal study followed children (N = 394; 53 % girls; M(age) = 10.3 at Time 1) from late childhood into early adolescence. Joint trajectory analyses were used to examine the dynamic prospective relations between bullying on the one hand, and indices tapping perceived popularity, peer-reported social acceptance, self-perceived social competence, and internalizing symptoms on the other. Results show that although young bullies may be on a developmental path that in the long run becomes problematic, from the bullies' perspective in the shorter term personal advantages outweigh disadvantages. High bullying is highly positively related to high social status as indexed by perceived popularity. Although bullies are not very high in peer-rated social acceptance, most are not very low either. Moreover, bullies do not demonstrate elevated internalizing symptoms, or problems in the social domain as indexed by self-perceived social competence. As bullying yields clear personal benefits for the bullies without strong costs, the findings underscore the need for interventions targeting mechanisms that reward bullying (198 words). PMID- 23686240 TI - Differential effects of the peptides Stomagen, EPF1 and EPF2 on activation of MAP kinase MPK6 and the SPCH protein level. AB - The positioning and density of leaf stomata are regulated by three secretory peptides, EPIDERMAL PATTERNING FACTOR 1 (EPF1), EPF2 and stomagen. Several lines of published evidence have suggested a regulatory pathway as follows. EPF1 and EPF2 are perceived by receptor complexes consisting of a receptor-like protein, TOO MANY MOUTHS (TMM), and receptor kinases, ERECTA (ER), ERECTA-LIKE (ERL) 1 and ERL2. These receptors activate a mitogen-activated protein (MAP) kinase module. MAP kinases phosphorylate and destabilize the transcription factor SPEECHLESS (SPCH), resulting in a decrease in the number of stomatal lineage cells. Stomagen acts antagonistically to EPF1 and EPF2. However, there is no direct evidence that EPF1 and EPF2 activate or that stomagen inactivates the MAP kinase cascade, through which they might regulate the SPCH level. Experimental modulation of these peptides in Arabidopsis thaliana would change the number of stomatal lineage cells in developing leaves, which in turn would change the expression of SPCH, making the interpretation difficult. Here we reconstructed this signaling pathway in differentiated leaf cells of Nicotiana benthamiana to examine signaling without the confounding effect of cell type change. We show that EPF1 and EPF2 are able to activate the MAP kinase MPK6, and that both EPF1 and EPF2 are able to decrease the SPCH level, whereas stomagen is able to increase it. Our data also suggest that EPF1 can be recognized by TMM together with any ER family receptor kinase, whereas EPF2 can be recognized by TMM together with ERL1 or ERL2, but not by TMM together with ER. PMID- 23686241 TI - Twenty years of the Cochrane Collaboration. AB - The Cochrane Collaboration is 20 years old this year. Established in 1993, the Collaboration has sought to provide an up-to-date, critical evidence base for all those involved in health care decision-making at a variety of levels. This article illustrates the work of the Cochrane Oral Health Group, based at the University of Manchester, UK. PMID- 23686243 TI - Efficient fixation of atmospheric CO2 as carbonate by lanthanide-based complex via synergistic effect of zinc ion. AB - Reactions of [Zn(L)(H2O)] precursor and EuCl3 with the aid of CO3(2-) ions derived from atmospheric CO2 affording an unusual heteropolynuclear cluster [Zn4L4Eu4(CO3)6].EtOH. In the core of the cluster, four hetero-binuclear [ZnLEu] units linked by six CO3(2-) anions forms a well defined [Zn4Eu4] skeleton with good planarity, which plays an important role in stabilizing the cluster. PMID- 23686244 TI - Paper-based transparent flexible thin film supercapacitors. AB - Paper-based transparent flexible thin film supercapacitors were fabricated using CNF-[RGO]n hybrid paper as an electrode material and charge collector. Owing to the self-anti-stacking of distorted RGO nanosheets and internal electrolyte nanoscale-reservoirs, the device exhibited good electrochemical performance (about 1.73 mF cm(-2)), and a transmittance of about 56% (at 550 nm). PMID- 23686245 TI - Activating transcription factor 4 is involved in endoplasmic reticulum stress mediated apoptosis contributing to vascular calcification. AB - Our previous work reported that endoplasmic reticulum stress (ERS)-mediated apoptosis was activated during vascular calcification (VC). Activating transcription factor 4 (ATF4) is a critical transcription factor in osteoblastogenesis and ERS-induced apoptosis. However, whether ATF4 is involved in ERS-mediated apoptosis contributing to VC remains unclear. In the present study, in vivo VC was induced in rats by administering vitamin D3 plus nicotine. Vascular smooth muscle cell (VSMC) calcification in vitro was induced by incubation in calcifying media containing beta-glycerophosphate and CaCl2. ERS inhibitors taurine or 4-phenylbutyric acid attenuated ERS and VSMC apoptosis in calcified rat arteries, reduced calcification and retarded the VSMC contractile phenotype transforming into an osteoblast-like phenotype in vivo. Inhibition of ERS retarded the VSMC phenotypic transition into an osteoblast-like cell phenotype and reduced VSMC calcification and apoptosis in vitro. Interestingly, ATF4 was activated in calcified aortas and calcified VSMCs in vitro. ATF4 knockdown attenuated ERS-induced apoptosis in calcified VSMCs. ATF4 deficiency blocked VSMC calcification and negatively regulated the osteoblast phenotypic transition of VSMCs in vitro. Our results demonstrate that ATF4 was involved at least in part in the process of ERS-mediated apoptosis contributing to VC. PMID- 23686247 TI - Primary health care: starting point for health equity. PMID- 23686248 TI - Primary care forward: raising the profile of Cuba's nursing profession. PMID- 23686246 TI - Ubiquitin-like domain of IKKbeta regulates osteoclastogenesis and osteolysis. AB - The transcription factor NF-kappaB family is central for osteoclastogenesis and inflammatory osteolysis. Activation of NF-kappaB dimers is regulated by a kinase complex predominantly containing IKKalpha (IKK1), IKKbeta (IKK2), and a regulatory subunit, IKKgamma/NEMO. IKKalpha and IKKbeta catalyze the cytoplasmic liberation and nuclear translocation of various NF-kappaB subunits. The requirement of IKKalpha and IKKbeta for normal bone homeostasis has been established. Congruently, mice devoid of IKKalpha or IKKbeta exhibit in vitro and in vivo defects in osteoclastogenesis, and IKKbeta-null mice are refractory to inflammatory arthritis and osteolysis. To better understand the molecular mechanism underlying IKKbeta function in bone homeostasis and bone pathologies, we conducted structure-function analysis to determine IKKbeta functional domains in osteoclasts. IKKbeta encompasses several domains, of which the ubiquitination like domain (ULD) has been shown essential for IKKbeta activation. In this study, we examined the role of ULD in IKKbeta-mediated NF-kappaB activation in osteoclast precursors and its contribution to osteoclastogenesis and osteolysis. We generated and virally introduced IKKbeta in which the ULD domain has been deleted (IKKbeta?ULD) into osteoclast progenitors. The results show that deletion of ULD diminishes IKKbeta activity and that IKKbeta?ULD strongly inhibits osteoclastogenesis. In addition, unlike wild type (WT)-IKKbeta, IKKbeta?ULD fail to restore RANKL-induced osteoclastogenesis by IKKbeta-null precursors. Finally, we provide evidence that IKKbeta?ULD blocks inflammatory osteolysis in a model of murine calvarial osteolysis. Thus, we identified the ULD as crucial for IKKbeta activity and osteoclastogenesis and found that ULD-deficient IKKbeta is a potent inhibitor of osteoclastogenesis and osteolysis. PMID- 23686249 TI - Contextual and individual influences on diabetes and heart disease in Havana primary care catchment areas. AB - INTRODUCTION: A population health profile is a cumulative product of socioenvironmental and political factors that create the contexts in which health problems arise, as well as opportunities and barriers to addressing them. Research on context has focused on demonstrating its effects, direct or indirect, on health indicators, but has made few incursions into assessing its role as a mediator of other factors. While individual risk factors for chronic diseases are well known, the same cannot be said for the complex of contextual factors operating at various levels and over the lifespan. OBJECTIVES: Estimate relative influences by contextual versus individual factors as determinants of diabetes type 2 and heart disease. METHODS: A cross-sectional study was carried out in populations served by 12 family doctor-and-nurse practices in Havana, in 840 families selected by simple random sampling, 70 per practice. Principal components analysis was used, as well as contextual logistic regression models with a nested model strategy, whose fit was meant to estimate the relative contributions of contextual compared to individual risk factors for diabetes and heart disease. Context was described and analyzed at two levels: that of the family or household and that of the catchment area served by a family doctor-and nurse practice (geographically defined as a neighborhood). RESULTS: For diabetes, the contextual effect of neighborhood was modified when household effect was removed; that is, the effect of neighborhood was indirect and mediated by household. Individual coefficients were practically invariant; the principal effect of household changed noticeably on removal of individual effects, while age maintained its effect without variation. For heart disease, the effect of neighborhood was slightly modified when household effect was controlled for. Individual coefficients showed little change. There was an important direct effect of household on risk of heart disease. Age and high blood pressure coefficients hardly varied. CONCLUSIONS: We confirmed interactions between individual and contextual (neighborhood and household) factors, whose effects on individual health are not entirely mediated by individual factors. Research needs to pay more attention to context beyond its direct effect on individual risk factors. PMID- 23686250 TI - Diabetes risk in a Cuban primary care setting in persons with no known glucose abnormalities. AB - INTRODUCTION: With 333 million cases worldwide predicted for 2015, type 2 diabetes mellitus presents an important global health challenge. Its rising tide calls for health policies emphasizing prevention at the primary care level, including public education as well as early risk identification and intervention. OBJECTIVES: Estimate risk of developing type 2 diabetes in persons with no known glucose abnormalities, registered in a primary care setting in Pinar del Rio city, Cuba, using FINDRISK. METHODS: A descriptive, cross-sectional study applied FINDRISK to 620 persons aged >=18 years randomly selected from a universe of 1058 patients with no known glucose abnormalities, registered in family-doctor-and nurse office No. 23 in the Turcios Lima Teaching Polyclinic health area, Pinar del Rio city. RESULTS: The study population was predominantly aged <=45 years (53.5%) and 80.2% was overweight or obese. At least moderate risk of diabetes was found in 74.4% of the sample, and 10.5% was at very high risk, meaning an estimated 120 patients in the sample could be expected to develop type 2 diabetes within the next 10 years. CONCLUSIONS: Type 2 diabetes prevalence can be expected to increase substantially in this population over the next decade. We recommend design and timely implementation of intensive lifestyle change programs to eliminate or slow development of type 2 diabetes in at-risk individuals. We propose following cohorts identified by FINDRISK to assess its prognostic value in the Cuban population. PMID- 23686251 TI - Prognostic value of gated SPECT after reperfusion for acute myocardial infarction. AB - INTRODUCTION: Myocardial reperfusion during the course of an acute myocardial infarction improves patients' short- and long-term prognosis; coronary blood flow is successfully re-established while preserving a large amount of at-risk muscle. Clinical evolution, however, varies. Presence of residual ischemia or viable myocardial tissue affects a patient's prognosis. Assessment by noninvasive methods allows better prognostic stratification. Cardiac-gated SPECT provides appropriate parameters to support treatment selection and monitoring of these patients. OBJECTIVES: Assess the prognostic value--ability to predict occurrence of major cardiac events--of perfusion and cardiac function obtained by myocardial perfusion scintigraphy in myocardial infarction patients treated by any myocardial reperfusion method, whether pharmacological or surgical. METHODS: Forty patients were included, mean age 58.8 +/- 9 years, diagnosed with myocardial infarction. Participants were divided into two groups: primary percutaneous transluminal coronary angioplasty (15) or thrombolysis (25). All received myocardial perfusion scintigraphy with cardiac-gated SPECT to assess perfusion and left ventricular function, and were followed for six months with telephone interviews and review of clinical records. RESULTS: In the 11 patients who had major cardiac events within six months of followup, a nonsignificant increase in perfusion defect extent was seen post reperfusion. Six (54.5%) of those with major cardiac events had anterior perfusion defects. In functional parameters, a significant increase in end-diastolic and end-systolic volumes and decrease in left ventricular ejection fraction were observed post stress (p = 0.006) and at rest (p = 0.001). Post-stress end-diastolic volume of >=70 mL had a higher prognostic value for major cardiac events [sensitivity 100%; specificity 89%, area under ROC curve 0.835 (CI 0.702-0.969), p = 0.001]. CONCLUSIONS: Cardiac-gated SPECT is useful to identify variables (including left ventricular systolic dysfunction and dilation of left cavities, particularly left end systolic volume of >70 mL) predictive of major cardiac events in reperfused patients, independent of treatment modality. PMID- 23686252 TI - Nosocomial ventilator-associated pneumonia in Cuban intensive care units: bacterial species and antibiotic resistance. AB - INTRODUCTION: Nosocomial pneumonia associated with use of mechanical ventilators is one of the greatest challenges confronted by intensivists worldwide. The literature associates several bacteria with this type of infection; most common in intensive care units are Acinetobacter baumannii, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus and some of the Enterobacteriaceae family. OBJECTIVES: To identify the causal agents of nosocomial ventilator associated pneumonia in patients receiving mechanical ventilation in the intensive care units of Havana's Hermanos Ameijeiras Clinical-Surgical Teaching Hospital in 2011, and to characterize their antibiotic resistance. METHODS: A cross-sectional descriptive study was conducted using hospital administrative data of quantitative cultures from positive tracheal aspirates for January through December, 2011. Records were analyzed from 77 intensive care unit patients who developed nosocomial ventilator-associated pneumonia. Variables examined were age and sex, and pathogens identified from culture of tracheal aspirate and related antibiotic susceptibility. RESULTS Species most frequently isolated were: Acinetobacter baumannii in 53 patients (68.8%), Pseudomonas aeruginosa in 34 patients (44.2%), other species of Pseudomonas in 15 patients (19.5%), and Serratia marcescens, Klebsiella pneumoniae, and Escherichia coli in 12 patients each (15.6%). Some patients presented more than one pathogen in concurrent or successive infections. Antimicrobial susceptibility testing found high percentages of resistance to antibiotics in all these pathogens. Least resistance was found to colistin. CONCLUSIONS: The prevalence of antibiotic resistance in bacteria causing nosocomial ventilator-associated pneumonia is of concern. Colistin is the drug of choice among the antibiotics reviewed, but sensitivity to other antibiotics should be assessed to search for more appropriate broad-spectrum antibiotics for treating nosocomial ventilator associated pneumonia. Our results also suggest the need to strengthen infection control efforts, particularly in intensive care units, and to reassess compliance with quality control procedures. Multidisciplinary research involving microbiologists, epidemiologists, internists and intensivists is needed to fully understand the etiological and resistance patterns observed. PMID- 23686253 TI - Poliomyelitis and its elimination in Cuba: an historical overview. AB - INTRODUCTION: Polio was first detected in Cuba in the late 19th century among residents of the US community on the Isla de Pinos (Isle of Pines, now Isle of Youth), apparently introduced through migration from the USA. The first outbreak was reported in 1906 on the Isle, with the first epidemic reported in the former province of Las Villas in 1909. The epidemics subsequently intensified, by 1934 becoming periodic every four to five years, and accompanied by high morbidity, mortality and crippling sequelae, primarily among children. OBJECTIVE: To review and analyze the history of polio and its control in Cuba, from the disease's first appearance in 1898 until WHO/PAHO certification of elimination in 1994. METHODS: The historiological method was used; archival documents, medical records, and available polio morbidity and mortality statistics from the Ministry of Public Health's National Statistics Division before 1959 and from 1959 through 2000 were reviewed. Crude morbidity and mortality rates were calculated using population estimates at mid-period. Reports and scientific publications describing polio vaccination campaigns and their results were also reviewed, and key informants were interviewed. RESULTS: After initial introduction of polio in Cuba, five major epidemics occurred between 1932 and 1958: in 1934 (434 cases, 82 deaths); 1942 (494 cases, 58 deaths); 1946 (239 cases, 33 deaths), 1952 (492 cases, 15 deaths) and 1955 (267 cases, 8 deaths). Between 1957 and 1961 the disease's endemicity reached epidemic levels, with the last outbreak occurring in 1961, with 342 cases, 30% of them in children aged >4 years. In 1962, Cuba launched a nationwide polio vaccination campaign, the first of annual campaigns thereafter carried out in the framework of a coherent national program aimed at polio elimination. Using the Sabin oral vaccine and targeting the entire pediatric population in a single time period, five million doses were administered in the first campaign, reaching 87.5% of the target population aged 1 month through 14 years, constituting 109.4% of planned coverage. Since that year, no deaths from polio have been recorded (there were ten cases between 1963 and 1989) and WHO/PAHO certified polio elimination in Cuba in 1994. CONCLUSIONS: Cuba controlled polio with effective vaccination strategies and appropriate epidemiological measures, in the context of social, financial and political support. KEYWORDS History, poliomyelitis, epidemiology, disease control, vaccination, Sabin vaccine, Cuba. PMID- 23686254 TI - Baseline research for action: adolescent alcohol consumption in Los Palacios Municipality, Cuba. AB - In Cuba, alcohol is an important contributor to morbidity, mortality and social problems. The foundation of Cuba's universal primary health care coverage, family doctor-and-nurse offices play a critical role in prevention, early detection and treatment of alcohol abuse. Los Palacios Municipality of the westernmost province of Pinar del Rio, Cuba, is a socially complex, periurban area where alcohol abuse and alcoholism have been identified as important health problems. Adolescents constitute a population at high risk for alcohol abuse because of their receptivity to social influences, but the precise extent of the problem is unknown. This paper reports baseline findings from a survey and direct observation of alcohol consumption in the catchment area of a primary care center, conducted to inform planning for an educational intervention. KEYWORDS Alcohol, alcoholism, alcohol abuse, alcohol dependence, adolescence, primary health care, Cuba. PMID- 23686255 TI - Overview of evolving changes in Cuba's health services. AB - This paper describes the evolution of basic indicators of health services, human resources, and infrastructure, starting with a general account of processes under way since the mid-1990s aimed at health sector recovery and focused on improving quality of service, system efficiency and effectiveness, while maintaining equity. Using this background, a description is provided of objectives and essential elements of transformations currently under way in the national health system, based on processes of reorganization, consolidation and regionalization of services. Finally, implications of territorial redistribution for health system reform are discussed, focusing on tensions between rationalization and equity in real or perceived access. PMID- 23686256 TI - Cuban publishing on primary health care: an inexcusable absence. AB - Primary health care (PHC) constitutes the fundamental pillar of Cuba's universal public health system. The doctor-and-nurse teams next door, community polyclinics, maternity homes, mental health centers, seniors' day centers-all form part of a network of over 12,000 facilities dedicated to resolving some 80% of population health problems, compared to under 200 facilities at other levels of care.[1] The people and institutions in PHC are on the front lines of health promotion and disease prevention. Their work is critical to the impressive population health indicators Cuba has managed to achieve, even in the toughest economic times. Others worldwide, especially in developing countries, could benefit from this experience. Cuba's own health system needs the scientific power represented by PHC research publishing potential, driving solutions to the country's main health problems-whether diseases, risk factors and unhealthy lifestyles, or inefficient services. PMID- 23686257 TI - Genistein induces G2/M cell cycle arrest and apoptosis via ATM/p53-dependent pathway in human colon cancer cells. AB - Soybean isoflavones have been used as a potential preventive agent in anticancer research for many years. Genistein is one of the most active flavonoids in soybeans. Accumulating evidence suggests that genistein alters a variety of biological processes in estrogen-related malignancies, such as breast and prostate cancers. However, the molecular mechanism of genistein in the prevention of human colon cancer remains unclear. Here we attempted to elucidate the anticarcinogenic mechanism of genistein in human colon cancer cells. First we evaluated the growth inhibitory effect of genistein and two other isoflavones, daidzein and biochanin A, on HCT-116 and SW-480 human colon cancer cells. In addition, flow cyto-metry was performed to observe the morphological changes in HCT-116/SW-480 cells undergoing apoptosis or cell cycle arrest, which had been visualized using Annexin V-FITC and/or propidium iodide staining. Real-time PCR and western blot analyses were also employed to study the changes in expression of several important genes associated with cell cycle regulation. Our data showed that genistein, daidzein and biochanin A exhibited growth inhibitory effects on HCT-116/SW-480 colon cancer cells and promoted apoptosis. Genistein showed a significantly greater effect than the other two compounds, in a time- and dose dependent manner. In addition, genistein caused cell cycle arrest in the G2/M phase, which was accompanied by activation of ATM/p53, p21waf1/cip1 and GADD45alpha as well as downregulation of cdc2 and cdc25A demonstrated by q-PCR and immunoblotting assay. Interestingly, genistein induced G2/M cell cycle arrest in a p53-dependent manner. These findings exemplify that isoflavones, especially genistein, could promote colon cancer cell growth inhibition and facilitate apoptosis and cell cycle arrest in the G2/M phase. The ATM/p53-p21 cross regulatory network may play a crucial role in mediating the anticarcinogenic activities of genistein in colon cancer. PMID- 23686258 TI - Clinical application of actigraphy in psychotic disorders: a systematic review. AB - Actigraphy has become increasingly recognized as a useful method to study sleep/wake patterns and activity monitoring. It is a reliable tool for confirming a diagnosis and evaluating the effect of treatments for sleep problems in patients with primary psychiatric diagnoses such as schizophrenia. In addition, actigraphy is an objective measure that circumvents the lack of insight and often unreliable self-reporting of mental health related problems. However, the literature regarding the use of actigraphy in research and clinical applications related to severe psychiatric populations is scarce. Amalgamation of the evidence is needed to advance the use of actigraphy in psychiatry. We summarized the literature to date related to the use of actigraphy in patients with psychotic disorders, specifically schizophrenia. We conducted a systematic review of journal databases. Sixty-six studies emerged from the search of the electronic search engines, 14 were RCTs/case-control studies and 14 were review/guideline papers and others were case studies. Results of the RCT/case-control studies comparing the use of actigraphy with patients versus control were summarized. Actigraphy not only allows for the objective evaluation of sleep habits and circadian rhythm disorders, but also helps to clarify and compare sleep and activity patterns among severe psychiatric disorders such as schizophrenia. Additionally, actigraphy data can be used as an outcome measure for changes in sleep patterns either when primary psychotic disorders are treated and/or when the sleep disturbance associated with the psychotic disorder is treated. Finally, actigraphy serves as a supplementary tool to study neuropathology of movement related psychiatric disorders including schizophrenia. PMID- 23686259 TI - HIF-1alpha influences myeloid cell antigen presentation and response to subcutaneous OVA vaccination. AB - Hypoxia-inducible factor (HIF)-1 is a transcription factor known to play an important role in regulating the innate immune response to infection. Under baseline conditions, cellular HIF-1 levels in leukocytes are scarce, but levels rise rapidly in response to hypoxia or molecular signals of infection or inflammation such as microbial surface molecules and host-derived cytokines. Innate immune cells such as macrophages, neutrophils, and mast cells exhibit increased microbicidal activity when HIF-1 levels are increased, and mice lacking HIF-1 are more susceptible to invasive bacterial infection. In this study, we used genetic and pharmacologic means to determine whether HIF-1 also plays an important role in the adaptive immune response to infection. HIF-1alpha/Tie-2 Cre(+) mice harboring a >90 % knockdown of HIF-1 in myeloid cells were studied. We found antigen-presenting cells from these mice that expressed lower levels of MHC-II and the costimulatory molecules CD80 and CD86, and were less able to induce T cell proliferation. These differences were present at baseline and persisted after activation. Increasing HIF-1 levels in wild-type (WT) cells by using the prolyl hydroxylase inhibitor drug AKB-4924 had the opposite effect, increasing MHC and costimulatory molecule expression and T cell proliferation. In experimental vaccination, HIF-1alpha/Tie-2 Cre(+) mice exhibited a weaker T cell response and lower antibody levels in response to vaccination than WT mice, while WT mice treated with a drug to elevate HIF-1 responded more strongly to vaccination. Thus, HIF-1 participates in bridging the innate and adaptive immune responses and may merit further exploration as an adjuvant target. PMID- 23686260 TI - HMGA2 and high-grade serous ovarian carcinoma. AB - HMGA2, the High Mobility Group A2 gene, plays a very important role in fetal development and carcinogenesis. As an oncofetal gene, it is upregulated in tumors of both epithelial and mesenchymal tissue origin. Chromosomal translocations of HMGA2 are common in mesenchymal tumors, whereas the regulatory mechanisms of HMGA2 in malignant epithelial tumors are much more complex. As an architectural transcription factor, it is involved in multiple biological pathways by targeting different downstream genes in different cancers. HMGA2 is upregulated in both the early and late stages of high-grade serous ovarian carcinoma (HGSOC) and, according to The Cancer Genomic Atlas, is among a signature of genes overexpressed in ovarian cancer. Recent identification of miR-182 as a mediator of BRCA1 and HMGA2 deregulation in ovarian cancer cells may guide us toward a better understanding of the roles of HMGA2 in ovarian carcinogenesis. In this article, we will review recent developments and findings related to HMGA2, including its regulation, oncogenic properties, major functional pathways associated with the tumorigenesis of HGSOC, and its potential role as a biomarker for clinical application. PMID- 23686261 TI - Benz[a]anthracene biotransformation and production of ring fission products by Sphingobium sp. strain KK22. AB - A soil bacterium, designated strain KK22, was isolated from a phenanthrene enrichment culture of a bacterial consortium that grew on diesel fuel, and it was found to biotransform the persistent environmental pollutant and high-molecular weight polycyclic aromatic hydrocarbon (PAH) benz[a]anthracene. Nearly complete sequencing of the 16S rRNA gene of strain KK22 and phylogenetic analysis revealed that this organism is a new member of the genus Sphingobium. An 8-day time course study that consisted of whole-culture extractions followed by high-performance liquid chromatography (HPLC) analyses with fluorescence detection showed that 80 to 90% biodegradation of 2.5 mg liter(-1) benz[a]anthracene had occurred. Biodegradation assays where benz[a]anthracene was supplied in crystalline form (100 mg liter(-1)) confirmed biodegradation and showed that strain KK22 cells precultured on glucose were equally capable of benz[a]anthracene biotransformation when precultured on glucose plus phenanthrene. Analyses of organic extracts from benz[a]anthracene biodegradation by liquid chromatography negative electrospray ionization tandem mass spectrometry [LC/ESI(-)-MS/MS] revealed 10 products, including two o-hydroxypolyaromatic acids and two hydroxy naphthoic acids. 1-Hydroxy-2- and 2-hydroxy-3-naphthoic acids were unambiguously identified, and this indicated that oxidation of the benz[a]anthracene molecule occurred via both the linear kata and angular kata ends of the molecule. Other two- and single-aromatic-ring metabolites were also documented, including 3-(2 carboxyvinyl)naphthalene-2-carboxylic acid and salicylic acid, and the proposed pathways for benz[a]anthracene biotransformation by a bacterium were extended. PMID- 23686262 TI - Regulon studies and in planta role of the BraI/R quorum-sensing system in the plant-beneficial Burkholderia cluster. AB - The genus Burkholderia is composed of functionally diverse species, and it can be divided into several clusters. One of these, designated the plant-beneficial environmental (PBE) Burkholderia cluster, is formed by nonpathogenic species, which in most cases have been found to be associated with plants. It was previously established that members of the PBE group share an N-acyl-homoserine lactone (AHL) quorum-sensing (QS) system, designated BraI/R, that produces and responds to 3-oxo-C14-HSL (OC14-HSL). Moreover, some of them also possess a second AHL QS system, designated XenI2/R2, producing and responding to 3-hydroxy C8-HSL (OHC8-HSL). In the present study, we performed liquid chromatography electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) analysis to determine which AHL molecules are produced by each QS system of this group of bacteria. The results showed that XenI2/R2 is mainly responsible for the production of OHC8-HSL and that the BraI/R system is involved in the production of several different AHLs. This analysis also revealed that Burkholderia phymatum STM815 produces greater amounts of AHLs than the other species tested. Further studies showed that the BraR protein of B. phymatum is more promiscuous than other BraR proteins, responding equally well to several different AHL molecules, even at low concentrations. Transcriptome studies with Burkholderia xenovorans LB400 and B. phymatum STM815 revealed that the BraI/R regulon is species specific, with exopolysaccharide production being the only common phenotype regulated by this system in the PBE cluster. In addition, BraI/R was shown not to be important for plant nodulation by B. phymatum strains or for endophytic colonization and growth promotion of maize by B. phytofirmans PsJN. PMID- 23686263 TI - Physiological levels of glucose induce membrane vesicle secretion and affect the lipid and protein composition of Yersinia pestis cell surfaces. AB - Yersinia pestis grown with physiologic glucose increased cell autoaggregation and deposition of extracellular material, including membrane vesicles. Membranes were characterized, and glucose had significant effects on protein, lipid, and carbohydrate profiles. These effects were independent of temperature and the biofilm-related locus pgm and were not observed in Yersinia pseudotuberculosis. PMID- 23686264 TI - An engineered strong promoter for streptomycetes. AB - Well-characterized promoters are essential tools for metabolic engineering and synthetic biology. In Streptomyces coelicolor, the native kasOp is a temporally expressed promoter strictly controlled by two regulators, ScbR and ScbR2. In this work, first, kasOp was engineered to remove a common binding site of ScbR and ScbR2 upstream of its core region, thus generating a stronger promoter, kasOp3. Second, another ScbR binding site internal to the kasOp3 core promoter region was abolished by random mutation and screening of the mutant library to obtain the strongest promoter, kasOp* (where the asterisk is used to distinguish the engineered promoter from the native promoter). The activities of kasOp* were compared with those of two known strong promoters, ermEp* and SF14p, in three Streptomyces species. kasOp* showed the highest activity at the transcription and protein levels in all three hosts. Furthermore, relative to ermEp* and SF14p, kasOp* was shown to confer the highest actinorhodin production level when used to drive the expression of actII-ORF4 in S. coelicolor. Therefore, kasOp* is a simple and well-defined strong promoter useful for gene overexpression in streptomycetes. PMID- 23686265 TI - Contrasting results of culture-dependent and molecular analyses of Mycobacterium avium subsp. paratuberculosis from wood bison. AB - Reduced to near extinction in the late 1800s, a number of wood bison populations (Bison bison athabascae) have been re-established through reintroduction initiatives. Although an invaluable tool for conservation, translocation of animals can spread infectious agents to new areas or expose animals to pathogens in their new environment. Mycobacterium avium subsp. paratuberculosis, a bacterium that causes chronic enteritis in ruminants, is among the pathogens of potential concern for wood bison management and conservation. In order to inform translocation decisions, our objectives were to determine the M. avium subsp. paratuberculosis infection status of wood bison herds in Canada and to culture and genetically characterize the infective strain(s). We tested fecal samples from bison (n = 267) in nine herds using direct PCR for three M. avium subsp. paratuberculosis-specific genetic targets with different copy numbers within the M. avium subsp. paratuberculosis genome. Restriction enzyme analysis (REA) and sequencing of IS1311 were performed on seven samples from five different herds. We also evaluated a panel of different culture conditions for their ability to support M. avium subsp. paratuberculosis growth from feces and tissues of direct PCR-positive animals. Eighty-one fecal samples (30%) tested positive using direct IS900 PCR, with positive samples from all nine herds; of these, 75% and 21% were also positive using ISMAP02 and F57, respectively. None of the culture conditions supported the growth of M. avium subsp. paratuberculosis from PCR-positive samples. IS1311 REA and sequencing indicate that at least two different M. avium subsp. paratuberculosis strain types exist in Canadian wood bison. The presence of different M. avium subsp. paratuberculosis strains among wood bison herds should be considered in the planning of translocations. PMID- 23686266 TI - Increased lysine content is the main characteristic of the soluble form of the polyamide cyanophycin synthesized by recombinant Escherichia coli. AB - Cyanophycin, a polyamide of cyanobacterial or noncyanobacterial origin consisting of aspartate, arginine, and lysine, was synthesized in different recombinant strains of Escherichia coli expressing cphA from Synechocystis sp. strain PCC 6308 or PCC 6803, Anabaena sp. strain PCC 7120, or Acinetobacter calcoaceticus ADP1. The molar aspartate/arginine/lysine ratio of the water-soluble form isolated from a recombinant strain expressing CphA6308 was 1:0.5:0.5, with a lysine content higher than any ever described before. The water-insoluble form consisted instead of mainly aspartate and arginine residues and had a lower proportion of lysine, amounting to a maximum of only 5 mol%. It could be confirmed that the synthesis of soluble cyanobacterial granule polypeptide (CGP) is independent of the origin of cphA. Soluble CGP isolated from all recombinant strains contained a least 17 mol% lysine. The total CGP portion of cell dry matter synthesized by CphA6308 from recombinant E. coli was about 30% (wt/wt), including 23% (wt/wt) soluble CGP, by using terrific broth complex medium for cultivation at 30 degrees C for 72 h. Enhanced production of soluble CGP instead of its insoluble form is interesting for further application and makes recombinant E. coli more attractive as a suitable source for the production of polyaspartic acid or dipeptides. In addition, a new low-cost, time-saving, effective, and common isolation procedure for mainly soluble CGP, suitable for large-scale application, was established in this study. PMID- 23686268 TI - A new large-DNA-fragment delivery system based on integrase activity from an integrative and conjugative element. AB - During the past few decades, numerous plasmid vectors have been developed for cloning, gene expression analysis, and genetic engineering. Cloning procedures typically rely on PCR amplification, DNA fragment restriction digestion, recovery, and ligation, but increasingly, procedures are being developed to assemble large synthetic DNAs. In this study, we developed a new gene delivery system using the integrase activity of an integrative and conjugative element (ICE). The advantage of the integrase-based delivery is that it can stably introduce a large DNA fragment (at least 75 kb) into one or more specific sites (the gene for glycine-accepting tRNA) on a target chromosome. Integrase recombination activity in Escherichia coli is kept low by using a synthetic hybrid promoter, which, however, is unleashed in the final target host, forcing the integration of the construct. Upon integration, the system is again silenced. Two variants with different genetic features were produced, one in the form of a cloning vector in E. coli and the other as a mini-transposable element by which large DNA constructs assembled in E. coli can be tagged with the integrase gene. We confirmed that the system could successfully introduce cosmid and bacterial artificial chromosome (BAC) DNAs from E. coli into the chromosome of Pseudomonas putida in a site-specific manner. The integrase delivery system works in concert with existing vector systems and could thus be a powerful tool for synthetic constructions of new metabolic pathways in a variety of host bacteria. PMID- 23686267 TI - Differential role of Manduca sexta aminopeptidase-N and alkaline phosphatase in the mode of action of Cry1Aa, Cry1Ab, and Cry1Ac toxins from Bacillus thuringiensis. AB - Aminopeptidase-N (APN1) and alkaline phosphatase (ALP) proteins located in the midgut epithelium of Manduca sexta have been implicated as receptors for Cry1Aa, Cry1Ab, and Cry1Ac insecticidal proteins produced by Bacillus thuringiensis subsp. kurstaki. In this study, we analyzed the roles of ALP and APN1 in the toxicity of these three Cry1A proteins. Ligand blot analysis using brush border membrane vesicles of M. sexta showed that Cry1Aa and Cry1Ab bind preferentially to ALP during early instars while binding to APN was observed after the third instar of larval development. Cry1Ac binds to APN throughout all larval development, with no apparent binding to ALP. ALP was cloned from M. sexta midgut RNA and expressed in Escherichia coli. Surface plasmon resonance binding analysis showed that recombinant ALP binds to Cry1Ac with 16-fold lower affinity than to Cry1Aa or Cry1Ab. Downregulation of APN1 and ALP expression by RNA interference (RNAi) using specific double-stranded RNA correlated with a reduction of transcript and protein levels. Toxicity analysis of the three Cry1A proteins in ALP- or APN1-silenced larvae showed that Cry1Aa relies similarly on both receptor molecules for toxicity. In contrast, RNAi experiments showed that ALP is more important than APN for Cry1Ab toxicity, while Cry1Ac relied principally on APN1. These results indicated that ALP and APN1 have a differential role in the mode of action of Cry1A toxins, suggesting that B. thuringiensis subsp. kurstaki produces different Cry1A toxins that in conjunction target diverse midgut proteins to exert their insecticidal effect. PMID- 23686269 TI - Kinetic enrichment of 34S during proteobacterial thiosulfate oxidation and the conserved role of SoxB in S-S bond breaking. AB - During chemolithoautotrophic thiosulfate oxidation, the phylogenetically diverged proteobacteria Paracoccus pantotrophus, Tetrathiobacter kashmirensis, and Thiomicrospira crunogena rendered steady enrichment of (34)S in the end product sulfate, with overall fractionation ranging between -4.60/00 and +5.80/00. The fractionation kinetics of T. crunogena was essentially similar to that of P. pantotrophus, albeit the former had a slightly higher magnitude and rate of (34)S enrichment. In the case of T. kashmirensis, the only significant departure of its fractionation curve from that of P. pantotrophus was observed during the first 36 h of thiosulfate-dependent growth, in the course of which tetrathionate intermediate formation is completed and sulfate production starts. The almost identical (34)S enrichment rates observed during the peak sulfate-producing stage of all three processes indicated the potential involvement of identical S-S bond breaking enzymes. Concurrent proteomic analyses detected the hydrolase SoxB (which is known to cleave terminal sulfone groups from SoxYZ-bound cysteine S thiosulfonates, as well as cysteine S-sulfonates, in P. pantotrophus) in the actively sulfate-producing cells of all three species. The inducible expression of soxB during tetrathionate oxidation, as well as the second leg of thiosulfate oxidation, by T. kashmirensis is significant because the current Sox pathway does not accommodate tetrathionate as one of its substrates. Notably, however, no other Sox protein except SoxB could be detected upon matrix-assisted laser desorption ionization mass spectrometry analysis of all such T. kashmirensis proteins as appeared to be thiosulfate inducible in 2-dimensional gel electrophoresis. Instead, several other redox proteins were found to be at least 2-fold overexpressed during thiosulfate- or tetrathionate-dependent growth, thereby indicating that there is more to tetrathionate oxidation than SoxB alone. PMID- 23686270 TI - Mechanism of the synergistic inactivation of Escherichia coli by UV-C light at mild temperatures. AB - UV light only penetrates liquid food surfaces to a very short depth, thereby limiting its industrial application in food pasteurization. One promising alternative is the combination of UV light with mild heat (UV-H), which has been demonstrated to produce a synergistic bactericidal effect. The aim of this article is to elucidate the mechanism of synergistic cellular inactivation resulting from the simultaneous application of UV light and heat. The lethality of UV-H treatments remained constant below ~45 degrees C, while lethality increased exponentially as the temperature increased. The percentage of synergism reached a maximum (40.3%) at 55 degrees C. Neither the flow regimen nor changes in the dose delivered by UV lamps contributed to the observed synergism. UV-H inactivation curves of the parental Escherichia coli strain obtained in a caffeic acid selective recovery medium followed a similar profile to those obtained with uvrA mutant cells in a nonselective medium. Thermal fluidification of membranes and synergistic lethal effects started around 40 to 45 degrees C. Chemical membrane fluidification with benzyl alcohol decreased the UV resistance of the parental strain but not that of the uvrA mutant. These results suggest that the synergistic lethal effect of UV-H treatments is due to the inhibition of DNA excision repair resulting from the membrane fluidification caused by simultaneous heating. PMID- 23686271 TI - Engineering of Ralstonia eutropha H16 for autotrophic and heterotrophic production of methyl ketones. AB - Ralstonia eutropha is a facultatively chemolithoautotrophic bacterium able to grow with organic substrates or H2 and CO2 under aerobic conditions. Under conditions of nutrient imbalance, R. eutropha produces copious amounts of poly[(R)-3-hydroxybutyrate] (PHB). Its ability to utilize CO2 as a sole carbon source renders it an interesting new candidate host for the production of renewable liquid transportation fuels. We engineered R. eutropha for the production of fatty acid-derived, diesel-range methyl ketones. Modifications engineered in R. eutropha included overexpression of a cytoplasmic version of the TesA thioesterase, which led to a substantial (>150-fold) increase in fatty acid titer under certain conditions. In addition, deletion of two putative beta oxidation operons and heterologous expression of three genes (the acyl coenzyme A oxidase gene from Micrococcus luteus and fadB and fadM from Escherichia coli) led to the production of 50 to 65 mg/liter of diesel-range methyl ketones under heterotrophic growth conditions and 50 to 180 mg/liter under chemolithoautotrophic growth conditions (with CO2 and H2 as the sole carbon source and electron donor, respectively). Induction of the methyl ketone pathway diverted substantial carbon flux away from PHB biosynthesis and appeared to enhance carbon flux through the pathway for biosynthesis of fatty acids, which are the precursors of methyl ketones. PMID- 23686272 TI - Functional screening of metagenome and genome libraries for detection of novel flavonoid-modifying enzymes. AB - The functional detection of novel enzymes other than hydrolases from metagenomes is limited since only a very few reliable screening procedures are available that allow the rapid screening of large clone libraries. For the discovery of flavonoid-modifying enzymes in genome and metagenome clone libraries, we have developed a new screening system based on high-performance thin-layer chromatography (HPTLC). This metagenome extract thin-layer chromatography analysis (META) allows the rapid detection of glycosyltransferase (GT) and also other flavonoid-modifying activities. The developed screening method is highly sensitive, and an amount of 4 ng of modified flavonoid molecules can be detected. This novel technology was validated against a control library of 1,920 fosmid clones generated from a single Bacillus cereus isolate and then used to analyze more than 38,000 clones derived from two different metagenomic preparations. Thereby we identified two novel UDP glycosyltransferase (UGT) genes. The metagenome-derived gtfC gene encoded a 52-kDa protein, and the deduced amino acid sequence was weakly similar to sequences of putative UGTs from Fibrisoma and Dyadobacter. GtfC mediated the transfer of different hexose moieties and exhibited high activities on flavones, flavonols, flavanones, and stilbenes and also accepted isoflavones and chalcones. From the control library we identified a novel macroside glycosyltransferase (MGT) with a calculated molecular mass of 46 kDa. The deduced amino acid sequence was highly similar to sequences of MGTs from Bacillus thuringiensis. Recombinant MgtB transferred the sugar residue from UDP glucose effectively to flavones, flavonols, isoflavones, and flavanones. Moreover, MgtB exhibited high activity on larger flavonoid molecules such as tiliroside. PMID- 23686273 TI - Identification of critical genes for growth in olive brine by transposon mutagenesis of Lactobacillus pentosus C11. AB - Olive brine represents a stressful environment due to the high NaCl concentration, presence of phenolic compounds known as antimicrobials, and low availability of nutrients. Thus, only a few strains of lactic acid bacteria (LAB) are adapted to grow in and ferment table olives. To identify the mechanisms by which these few strains are able to grow in olive brine, Lactobacillus pentosus C11, a particularly resistant strain isolated from naturally fermented table olives, was mutagenized by random transposition using the P(junc)-TpaseIS1223 system (H. Licandro-Seraut, S. Brinster, M. van de Guchte, H. Scornec, E. Maguin, P. Sansonetti, J. F. Cavin, and P. Serror, Appl. Environ. Microbiol. 78:5417 5423, 2012). A library of 6,000 mutants was generated and screened for adaptation and subsequent growth in a medium, named BSM (brine screening medium), which presents the stressful conditions encountered in olive brine. Five transposition mutants impaired in growth on BSM were identified. Transposition occurred in two open reading frames and in three transcription terminators affecting stability of transcripts. Thus, several essential genes for adaptation and growth of L. pentosus C11 in olive brine were identified. PMID- 23686274 TI - Comparative persistence of subgroups of F-specific RNA phages in river water. AB - F-specific (F+) RNA phages are widely used as indicators for the presence of fecal contamination and/or enteric viruses in water, and identifying subgroups of F+ RNA phages provides an approach for microbial source tracking. Different survival characteristics of the F+ RNA phage subgroups result in a misinterpretation of their original proportion in water, thus giving misleading information when they are used for microbial source tracking. This study investigated the comparative persistence of subgroups of F+ RNA phages in river water under different conditions. Results suggested that temperature and pH are the major factors affecting the persistence of F+ RNA phages in river water, and organic substances promote phage survival. The comparative persistence patterns of subgroups of F+ RNA phages varied and may bias extrapolation of their initial proportions in surface water. Thus, the characteristics of water should be taken into consideration and the results should be carefully interpreted when F+ RNA phages are used for microbial source tracking. PMID- 23686276 TI - Routine preoperative (111)In-octreotide scintigraphy in patients with medullary thyroid cancer. AB - BACKGROUND: Surgery is the only potential cure for patients with medullary thyroid carcinoma (MTC). Preoperative ultrasound, computed tomography and magnetic resonance imaging are not sensitive enough for detection of microscopic disease. The aim of this study was to investigate if routine preoperative (111)In labelled (DTPA-D-Phe(1))-octreotide scintigraphy (SRS) could be used as a staging procedure in planning primary surgery in patients with MTC. METHODS: This study included patients with primary sporadic clinically overt MTC diagnosed between 1996 and 2009. All patients underwent conventional imaging of neck and thorax and SRS prior to standardised surgery. The findings on SRS were correlated to the findings on conventional imaging, histopathology and to postoperative biochemical results and survival. RESULTS: A total of 19 patients with sporadic MTC were enrolled. Median follow-up was 77(9-184) months. SRS visualised the primary tumour in 16 (84 %) patients. Fifteen (79 %) patients had locoregional lymph node metastases, but SRS detected metastatic lesions in only 8 (53 %) patients. In three patients with distant spread, SRS failed to detect metastatic lesions in two. At latest follow-up, six (32 %) patients had died, nine (47 %) patients were alive with elevated tumour markers, and four (21 %) patients were considered in complete biochemical remission. CONCLUSIONS: This study provided further evidence that SRS, compared to conventional imaging, is fairly sensitive for detection of primary MTC but not metastatic disease. Although preoperative SRS may be of prognostic value, there is no indication for its routine use as a staging procedure in planning primary surgery. PMID- 23686275 TI - The predominance of alternatively activated macrophages following challenge with cell wall peptide-polysaccharide after prior infection with Sporothrix schenckii. AB - Sporotrichosis is a subcutaneous mycosis that is caused by the dimorphic fungus Sporothrix schenckii. This disease generally occurs within the skin and subcutaneous tissues, causing lesions that can spread through adjacent lymphatic vessels and sometimes leading to systemic diseases in immunocompromised patients. Macrophages are crucial for proper immune responses against a variety of pathogens. Furthermore, macrophages can play different roles in response to different microorganisms and forms of activation, and they can be divided into "classic" or "alternatively" activated populations, as also known as M1 and M2 macrophages. M1 cells can lead to tissue injury and contribute to pathogenesis, whereas M2 cells promote angiogenesis, tissue remodeling, and repair. The aim of this study was to investigate the roles of M1 and M2 macrophages in a sporotrichosis model. Toward this end, we performed phenotyping of peritoneal exudate cells and evaluated the concomitant production of several immunomediators, including IL-12, IL-10, TGF-beta, nitric oxide, and arginase-I activity, which were stimulated ex vivo with cell wall peptide-polysaccharide. Our results showed the predominance of the M2 macrophage population, indicated by peaks of arginase-I activity as well as IL-10 and TGF-beta production during the 6th and 8th weeks after infection. These results were consistent with cellular phenotyping that revealed increases in CD206-positive cells over this period. This is the first report of the participation of M2 macrophages in sporotrichosis infections. PMID- 23686277 TI - Laparoscopic versus conventional ileoanal pouch procedure in patients undergoing elective restorative proctocolectomy (LapConPouch Trial)-a randomized controlled trial. AB - PURPOSE: Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the standard surgical procedure for ulcerative colitis (UC) and familial adenomatous polyposis (FAP). While minimal invasive techniques have been applied increasingly, clear evidence of superiority for laparoscopic pouch procedures is not yet available. The aim of the LapConPouch Trial was to compare the effectiveness of laparoscopic (LAP) versus conventional (CON) ileoanal pouch procedure in patients undergoing elective restorative proctocolectomy. METHODS: The trial was designed as a single-centre, pre-operatively randomized, controlled trial using a two-group parallel superiority design. Eligible for participation were patients scheduled for restorative proctocolectomy either for FAP or for UC. Patients and outcome assessors were blinded to group assignment. The primary endpoint was defined as the amount of blood loss. Statistical analyses were explorative since the trial had to be stopped prematurely. RESULTS: A total of 42 patients (21 LAP (50.0 %); 21 CON (50.0 %)) were randomized. The trial had to be stopped prematurely due to insufficient patient recruitment. There was no difference in the amount of blood loss between both groups: LAP 261.5 +/- 195.4 ml, CON 228.1 +/- 119.5 ml. Secondary endpoints differ in both groups. Laparoscopic surgery was superior regarding the length of skin incision; in contrast, the conventional approach was superior in duration of operation. There were no discrepancies in length of hospital stay, postoperative pain, bowel function, and quality of life between both approaches. The conversion rate from LAP to CON approach was 23.8 %. CONCLUSION: There was no difference with respect to blood loss between the LAP and the CON group. The LAP approach is feasible for restorative proctocolectomy, and IPAA seems at least as safe as CON surgery. The most obvious advantage of the minimal invasive technique is the improved cosmesis. PMID- 23686278 TI - Novel accurate bacterial discrimination by MALDI-time-of-flight MS based on ribosomal proteins coding in S10-spc-alpha operon at strain level S10-GERMS. AB - Matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is one of the most widely used mass-based approaches for bacterial identification and classification because of the simple sample preparation and extremely rapid analysis within a few minutes. To establish the accurate MALDI TOF MS bacterial discrimination method at strain level, the ribosomal subunit proteins coded in the S10-spc-alpha operon, which encodes half of the ribosomal subunit protein and is highly conserved in eubacterial genomes, were selected as reliable biomarkers. This method, named the S10-GERMS method, revealed that the strains of genus Pseudomonas were successfully identified and discriminated at species and strain levels, respectively; therefore, the S10-GERMS method was further applied to discriminate the pathovar of P. syringae. The eight selected biomarkers (L24, L30, S10, S12, S14, S16, S17, and S19) suggested the rapid discrimination of P. syringae at the strain (pathovar) level. The S10-GERMS method appears to be a powerful tool for rapid and reliable bacterial discrimination and successful phylogenetic characterization. In this article, an overview of the utilization of results from the S10-GERMS method is presented, highlighting the characterization of the Lactobacillus casei group and discrimination of the bacteria of genera Bacillus and Sphingopyxis despite only two and one base difference in the 16S rRNA gene sequence, respectively. PMID- 23686279 TI - Unique X-linked familial FSGS with co-segregating heart block disorder is associated with a mutation in the NXF5 gene. AB - Focal segmental glomerulosclerosis (FSGS) is the consequence of a disease process that attacks the kidney's filtering system, causing serious scarring. More than half of FSGS patients develop chronic kidney failure within 10 years, ultimately requiring dialysis or renal transplantation. There are currently several genes known to cause the hereditary forms of FSGS (ACTN4, TRPC6, CD2AP, INF2, MYO1E and NPHS2). This study involves a large, unique, multigenerational Australian pedigree in which FSGS co-segregates with progressive heart block with apparent X linked recessive inheritance. Through a classical combined approach of linkage and haplotype analysis, we identified a 21.19 cM interval implicated on the X chromosome. We then used a whole exome sequencing approach to identify two mutated genes, NXF5 and ALG13, which are located within this linkage interval. The two mutations NXF5-R113W and ALG13-T141L segregated perfectly with the disease phenotype in the pedigree and were not found in a large healthy control cohort. Analysis using bioinformatics tools predicted the R113W mutation in the NXF5 gene to be deleterious and cellular studies support a role in the stability and localization of the protein suggesting a causative role of this mutation in these co-morbid disorders. Further studies are now required to determine the functional consequence of these novel mutations to development of FSGS and heart block in this pedigree and to determine whether these mutations have implications for more common forms of these diseases in the general population. PMID- 23686281 TI - Rational synthesis of pindolol imprinted polymer by non-covalent protocol based on computational approach. AB - Pindolol (PDL) is a potent and specific adrenoreceptor blocking agent. It is widely used in the treatment of hypertension, cardiac arrhythmia and angina pectoris. Molecularly imprinted polymers (MIPs) are synthetic receptors having potential applications in drug delivery systems and devices such as diagnostic sensors. In the present work, ab initio quantum mechanical simulations and computational screening were used to identify functional monomer having best interactions with PDL. A virtual library of 16 functional monomers was built and the possible minimum energy conformation of the monomers and PDL were calculated using Hartree-Fock (HF) method for the synthesis of PDL imprinted polymer. The interaction energy between functional monomer and the template were corrected by means of basis set superposition error (BSSE) in all pre-polymerization complexes. The hydrogen bonding between PDL and functional monomer was evaluated by changes in bond lengths before and after complex formation. The virtual template-monomer complex with highest interaction energy is more stable during the polymerization and leads to high selectivity and specificity toward the template. The interaction energy of PDL was found to be the highest with itaconic acid followed by 4-vinyl pyridine and least with acrylonitrile. Taking a spectroscopic viewpoint, results obtained from analysis of the harmonic infrared spectrum were examined. Red and blue shifts related to the stretching frequencies of either donors or acceptors of protons were identified and compared experimentally. Stoichiometric mole ratio of template to functional monomer was optimized and confirmed by UV visible spectra titrations. The theoretical results were correlated by evaluation of binding parameters of MIPs. The experimental binding results were in good agreement with theoretical computations. PMID- 23686282 TI - Incomplete mixing versus clathrate-like structures: a molecular view on hydrophobicity in methanol-water mixtures. AB - The underlying molecular mechanisms of macroscopic excess properties were studied by molecular dynamics simulations for different compositions of methanol-water mixtures. Structural data (nearest neighbor relationships, clustering analysis) and dynamic data (hydrogen bond lifetimes, rotational autocorrelation, translational diffusion) were evaluated. Nearest neighbor relationships provide quantitative evidence and a pictorial description of incomplete mixing at the molecular level as a source for mixture anomalies, while a comparative study of water surrounding methyl moieties versus water in the bulk-like environment provides evidence against the hydrophobicity model of clathrate-like hydration. Furthermore, the formation or breakdown of the system-wide hydrogen bonding network at a critical threshold of approximately equimolar mixture is perceived to separate the mixture system into two hydrogen bonding regimes: hydrogen-bonded water clusters embedded in methanol for mixtures with low water content and methanol molecules within a system-wide hydrogen-bonded water network for mixtures with high water content. PMID- 23686280 TI - How to achieve high-level expression of microbial enzymes: strategies and perspectives. AB - Microbial enzymes have been used in a large number of fields, such as chemical, agricultural and biopharmaceutical industries. The enzyme production rate and yield are the main factors to consider when choosing the appropriate expression system for the production of recombinant proteins. Recombinant enzymes have been expressed in bacteria (e.g., Escherichia coli, Bacillus and lactic acid bacteria), filamentous fungi (e.g., Aspergillus) and yeasts (e.g., Pichia pastoris). The favorable and very advantageous characteristics of these species have resulted in an increasing number of biotechnological applications. Bacterial hosts (e.g., E. coli) can be used to quickly and easily overexpress recombinant enzymes; however, bacterial systems cannot express very large proteins and proteins that require post-translational modifications. The main bacterial expression hosts, with the exception of lactic acid bacteria and filamentous fungi, can produce several toxins which are not compatible with the expression of recombinant enzymes in food and drugs. However, due to the multiplicity of the physiological impacts arising from high-level expression of genes encoding the enzymes and expression hosts, the goal of overproduction can hardly be achieved, and therefore, the yield of recombinant enzymes is limited. In this review, the recent strategies used for the high-level expression of microbial enzymes in the hosts mentioned above are summarized and the prospects are also discussed. We hope this review will contribute to the development of the enzyme-related research field. PMID- 23686283 TI - Sequence and structural investigation of a novel psychrophilic alpha-amylase from Glaciozyma antarctica PI12 for cold-adaptation analysis. AB - A novel alpha-amylase was isolated successfully from Glaciozyma antarctica PI12 using DNA walking and reverse transcription-polymerase chain reaction (RT-PCR) methods. The structure of this psychrophilic alpha-amylase (AmyPI12) from G. antarctica PI12 has yet to be studied in detail. A 3D model of AmyPI12 was built using a homology modelling approach to search for a suitable template and to generate an optimum target-template alignment, followed by model building using MODELLER9.9. Analysis of the AmyPI12 model revealed the presence of binding sites for a conserved calcium ion (CaI), non-conserved calcium ions (CaII and CaIII) and a sodium ion (Na). Compared with its template-the thermostable alpha-amylase from Bacillus stearothermophilus (BSTA)-the binding of CaII, CaIII and Na ions in AmyPI12 was observed to be looser, which suggests that the low stability of AmyPI12 allows the protein to work at different temperature scales. The AmyPI12 amino acid sequence and model were compared with thermophilic alpha-amylases from Bacillus species that provided the highest structural similarities with AmyPI12. These comparative studies will enable identification of possible determinants of cold adaptation. PMID- 23686284 TI - Density functional theory investigation of cocaine water complexes. AB - Twenty cocaine-water complexes were studied using density functional theory (DFT) B3LYP/6-311++G** level to understand their geometries, energies, vibrational frequencies, charge transfer and topological parameters. Among the 20 complexes, 12 are neutral and eight are protonated in the cocaine-water complexes. Based on the interaction energy, the protonated complexes are more stable than the neutral complexes. In both complexes, the most stable structure involves the hydrogen bond with water at nitrogen atom in the tropane ring and C=O groups in methyl ester. Carbonyl groups in benzoyl and methyl ester is the most reactive site in both forms and it is responsible for the stability order. The calculated topological results show that the interactions involved in the hydrogen bond are electrostatic dominant. Natural bond orbital (NBO) analysis confirms the presence of hydrogen bond and it supports the stability order. Atoms in molecules (AIM) and NBO analysis confirms the C-H...O hydrogen bonds formed between the cocaine water complexes are blue shifted in nature. PMID- 23686285 TI - Comparative theoretical studies of energetic pyrazole-pyridine derivatives. AB - The pyrazole-pyridine derivatives were optimized to obtain their molecular geometries and electronic structures at the DFT-B3LYP/6-31G(d,p) and DFT-B3P86/6 31G(d,p) levels. Molecular mechanics (MM) calculations were performed for the title compounds. Heats of formation (HOFs) were predicted through designed isodesmic reactions. Detonation performance was evaluated by using the Kamlet Jacobs equations based on the calculated densities and heats of formation. The thermal stability of the title compounds was investigated via the bond dissociation energies (BDEs). The simulation results reveal that the compound with one pyrazole ring that is fully nitro-substituted performs similarly to the famous explosive HMX, and the compound with two pyrazole rings that are fully nitro-substituted outperforms HMX. According to the quantitative standard of energetics and stability as high energy density materials (HEDMs), the compound with two pyrazole rings that are fully nitro-substituted essentially satisfies this requirement. PMID- 23686286 TI - Effect of benzoannulation on tautomeric preferences of 4,6-di(pyridin-2 yl)cyclohexane-1,3-dione. AB - Density functional theory (DFT) calculations at the B3LYP/6-311+G(d,p) level show that 4,6-di(pyridin-2-yl)cyclohexane-1,3-dione is a labile compound. On the other hand, its dienolimine tautomer (4,6-di(pyridin-2-yl)cyclohaxa-1,3-diene-1,3-diol) seems stable enough to be present in vacuum. Alternatively the equilibriated species are (i) dienolimine and enolimine-enaminone ((6Z)-3-hydroxy-6-(pyridin 2(1H)-ylidene)-4-(pyridine-2-yl)cyclohex-3-enone) or (ii) dienolimine, enolimine enaminone and dienaminone ((4Z,6Z)-4,6-di(pyridin-2(1H)-ylidene)cyclohexane-1,3 dione). Benzoannulation of the pyridine ring at position 5,6 was found to increase the contribution of the tautomers which contain the enaminone moiety. Energies of the transition states between the stable tautomers were also calculated in order to estimate activation energy of the proton transfer. Values of the geometry based harmonic oscillator model of aromaticity (HOMA) index and Laplacian of the electron density in the hydrogen bond critical point (based on quantum theory of atom in molecules) shows that the enaminone moiety in the tautomers studied are stabilized by stronger intramolecular hydrogen bond than this present in the enolimine moiety. PMID- 23686287 TI - A conformational switch in PRP8 mediates metal ion coordination that promotes pre mRNA exon ligation. AB - Splicing of pre-mRNAs in eukaryotes is catalyzed by the spliceosome, a large RNA protein metalloenzyme. The catalytic center of the spliceosome involves a structure comprising the U2 and U6 snRNAs and includes a metal bound by U6 snRNA. The precise architecture of the splicesome active site, however, and the question of whether it includes protein components, remains unresolved. A wealth of evidence places the protein PRP8 at the heart of the spliceosome through assembly and catalysis. Here we provide evidence that the RNase H domain of PRP8 undergoes a conformational switch between the two steps of splicing, rationalizing yeast prp8 alleles that promote either the first or second step. We also show that this switch unmasks a metal-binding site involved in the second step. Together, these data establish that PRP8 is a metalloprotein that promotes exon ligation within the spliceosome. PMID- 23686288 TI - Preferential D-loop extension by a translesion DNA polymerase underlies error prone recombination. AB - Although homologous recombination is considered an accurate form of DNA repair, genetics suggest that the Escherichia coli translesion DNA polymerase IV (Pol IV, also known as DinB) promotes error-prone recombination during stress, which allows cells to overcome adverse conditions. However, how Pol IV functions and is regulated during recombination under stress is unknown. We show that Pol IV is highly proficient in error-prone recombination and is preferentially recruited to displacement loops (D loops) at stress-induced concentrations in vitro. We also found that high-fidelity Pol II switches to exonuclease mode at D loops, which is stimulated by topological stress and reduced deoxyribonucleotide pool concentration during stationary phase. The exonuclease activity of Pol II enables it to compete with Pol IV, which probably suppresses error-prone recombination. These findings indicate that preferential D-loop extension by Pol IV facilitates error-prone recombination and explain how Pol II reduces such errors in vivo. PMID- 23686289 TI - Maritime adaptations and dietary variation in prehistoric Western Alaska: stable isotope analysis of permafrost-preserved human hair. AB - The reconstruction of diet and subsistence strategies is integral in understanding early human colonizations and cultural adaptations, especially in the Arctic-one of the last areas of North America to be permanently inhabited. However, evidence for early subsistence practices in Western Alaska varies, particularly with regards to the emergence, importance, and intensity of sea mammal hunting. Here, we present stable carbon and nitrogen isotope data from permafrost-preserved human hair from two new prehistoric sites in Western Alaska, providing a direct measure of diet. The isotope evidence indicates a heavy reliance on sea mammal protein among the earlier Norton-period group (1,750 +/- 40 cal BP), confirming that the complex hunting technologies required to intensively exploit these animals were most likely already in place in this region by at least the beginning of 1st millennium AD. In contrast, analysis of the more recent Thule-period hair samples (650 +/- 40 cal BP; 570 +/- 30 cal BP) reveals a more mixed diet, including terrestrial animal protein. Sequential isotope analysis of two longer human hair locks indicates seasonal differences in diet in a single Norton-period individual but demonstrates little dietary variation in a Thule-period individual. These analyses provide direct evidence for dietary differences among Alaska's early Eskimo groups and confirm the antiquity of specialized sea mammal hunting and procurement technologies. The results of this study have implications for our understanding of human adaptation to maritime and high-latitude environments, and the geographical and temporal complexity in early Arctic subsistence. PMID- 23686290 TI - Sex differences in sexual concordance: a reply to Brody (2012). PMID- 23686291 TI - Optimal table feed in run-off CT angiography in patients with abdominal aortic aneurysms. AB - OBJECTIVES: To assess the influence of different table feeds (TFs) on vascular enhancement and image quality in patients with an abdominal aortic aneurysm (AAA) undergoing computed tomography (CT) angiography of the lower extremities (run-off CTA). METHODS: Seventy-nine patients (71 +/- 8 years) with an AAA (>30 mm) who underwent run-off CTA between January 2004 and August 2011 were included in this retrospective institutional review board-approved study. Run-off CTA was conducted using 16- and 64-row CT. The range of TFs was 30-86 mm/s and was categorised in quartiles TF1 (32.6 +/- 1.9 mm/s), TF2 (38.9 +/- 0.9 mm/s), TF3 (43.9 +/- 3.1 mm/s) and TF4 (57.4 +/- 10.5 mm/s). Image quality was rated independently by two radiologists and vessel enhancement was assessed. RESULTS: Image quality was diagnostic at all aortic, pelvic and almost all thigh levels. Below the knee, the number of diagnostic levels was highest for TF1 and decreased to TF4. Arterial enhancement between the aorta and fibular trunk was not different in all TF groups, P > 0.05. At the calf and foot strongest arterial enhancement was noted for TF1 and TF2 and decreased to TF4, P < 0.01. CONCLUSION: Results indicate that the highest image quality of run-off CTA in patients with an AAA may be obtained using table feeds measuring 30-35 mm/s. KEY POINTS: * CTA has become a key investigation for peripheral vascular disease. * Run-off CTA is more complex in patients with an abdominal aortic aneurysm. * Run-off CTA is feasible with a short bolus of intravenous contrast medium. * A constant 30-35 mm/s table feed provides the highest likelihood of diagnostic images. PMID- 23686292 TI - Metal artefact reduction from dental hardware in carotid CT angiography using iterative reconstructions. AB - PURPOSE: To determine the value of a metal artefact reduction (MAR) algorithm with iterative reconstructions for dental hardware in carotid CT angiography. METHODS: Twenty-four patients (six of which were women; mean age 70 +/- 12 years) with dental hardware undergoing carotid CT angiography were included. Datasets were reconstructed with filtered back projection (FBP) and using a MAR algorithm employing normalisation and an iterative frequency-split (IFS) approach. Three blinded, independent readers measured CT attenuation values and evaluated image quality and degrees of artefacts using axial images, multi-planar reformations (MPRs) and maximal intensity projections (MIP) of the carotid arteries. RESULTS: CT attenuation values of the internal carotid artery on images with metal artefacts were significantly higher in FBP (324 +/- 104HU) datasets compared with those reconstructed with IFS (278 +/- 114HU; P < 0.001) and with FBP on images without metal artefacts (293 +/- 106HU; P = 0.006). Quality of IFS images was rated significantly higher on axial, MPR and MIP images (P < 0.05, each), and readers found significantly less artefacts impairing the diagnostic confidence of the internal carotid artery (P < 0.05, each). CONCLUSION: The MAR algorithm with the IFS approach allowed for a significant reduction of artefacts from dental hardware in carotid CT angiography, hereby increasing image quality and improving the accuracy of CT attenuation measurements. KEY POINTS: * CT angiography of the neck has proven value for evaluating carotid disease * Neck CT angiography images are often degraded by artefacts from dental implants * A metal artefact reduction algorithm with iterative reconstruction reduces artefacts significantly * Visualisation of the internal carotid artery is improved. PMID- 23686293 TI - Low-grade (WHO II) and anaplastic (WHO III) gliomas: differences in morphology and MRI signal intensities. AB - OBJECTIVE: To evaluate the diagnostic potential of a multi-factor analysis of morphometric parameters and signal characteristics of brain tumours and peritumoural areas for distinguishing WHO-grade II and III gliomas at magnetic resonance imaging (MRI). METHODS: MR examinations of 108 patients with histologically proven World Health Organization (WHO) grade II and III gliomas were included. Morphological criteria and MR signal characteristics were evaluated. The data were subjected to a multifactorial logistic regression analysis to differentiate between grade II and grade III gliomas. The discriminatory power was assessed by receiver operating characteristic (ROC). RESULTS: Logistic regression analysis showed that WHO grade II and III can be distinguished based on contrast enhancement, cortical involvement, margin of the enhancing lesion and maximum diameter (width and length) of the peritumoural area (the so-called tumour infiltration zone). With the final model of logistic regression analysis and with the cut-off value >= 0.377, WHO grade III glioma is predicted with a sensitivity of 71.0 % and a specificity of 80.4 %. CONCLUSION: Measurement of maximum diameter of peritumoural area, contrast enhancement as well as cortical involvement and the margin of the contrast enhancing lesion can be used easily in clinical routine to adequately distinguish WHO grade II from grade III gliomas. KEY POINTS: * MRI offers new information concerning WHO-grade II and III gliomas. * The differentiation between such tumour grades is important for therapeutic decisions. * We assessed differences in enhancement, cortical involvement, margins and peritumoural appearances. * WHO grade III gliomas can be predicted with reasonable sensitivity and specificity. PMID- 23686294 TI - Variabines A and B: new beta-carboline alkaloids from the marine sponge Luffariella variabilis. AB - Two new beta-carboline alkaloids, variabines A (1) and B (2), were isolated from the Indonesian marine sponge Luffariella variabilis. Their structures were elucidated from spectral data, and 1 was found to be a sulfonated derivative of 2. Although numerous beta-carboline alkaloids have been isolated from natural sources to date, 1 is the first beta-carboline derivative containing a sulfate group. Compound 2 inhibited chymotrypsin-like activity of the proteasome and Ubc13 (E2)-Uev1A interaction with IC50 values of 4 and 5 MUg/mL, respectively, whereas 1 had little effect on the activity or interaction. PMID- 23686295 TI - Determination of erythrocyte sodium sensitivity in man. AB - Sodium buffer capacity of vascular endothelium depends on an endothelial glycocalyx rich in negatively charged heparan sulfate. It has been shown recently that after the mechanical interaction of blood with heparan sulfate-depleted endothelium, erythrocytes also lose this glycocalyx constituent. This observation led to the conclusion that the vascular sodium buffer capacity of an individual could be derived from a blood sample. A test system (salt blood test (SBT)) was developed based upon the sodium-dependent erythrocyte zeta potential. Erythrocyte sedimentation velocity was measured in isosmotic, biopolymer-supplemented electrolyte solutions of different sodium concentrations. Erythrocyte sodium sensitivity (ESS), inversely related to erythrocyte sodium buffer capacity, was expressed as the ratio of the erythrocyte sedimentation velocities of 150 mM over 125 mM Na(+) solutions (ESS = Na(+) 150/Na(+) 125). In 61 healthy individuals (mean age, 23 +/- 0.5 years), ESS ranged between 2 and 8. The mean value was 4.3 +/- 0.19. The frequency distribution shows two peaks, one at about 3 and another one at about 5. To test whether ESS reflects changes of the endothelial glycocalyx, a cultured endothelial monolayer was exposed for 3 hours to a rhythmically moving blood layer (drag force experiment). When applying this procedure, we found that ESS was reduced by about 21 % when the endothelium was pretreated for 4 days with the glycocalyx protective agent WS 1442. In conclusion, the SBT could possibly serve as an in vitro test system for the evaluation of erythrocyte/vascular salt sensitivity allowing follow-up measurements in the prevention and treatment of vascular dysfunctions. PMID- 23686297 TI - Silica-anchored organotin trichloride: a recyclable and clean organotin catalyst for transesterification reactions. AB - A new synthetic scheme towards silica-supported organotrichlorotin derivatives has been developed. It involves the synthesis of (11 triethoxysilyl)undecyltricyclohexyltin, followed by sol-gel processing and, subsequently in the formation of the resulting hybrid silica, by electrophilic substitution of the tricyclohexyltin function by the target grafted trichlorotin using tin tetrachloride. HR-MAS (119)Sn and CP-MAS (29)Si NMR combined with N2 sorption and TEM measurements evidenced the formation of a mesoporous organic inorganic hybrid silica including a functionally pure supported organotrichlorotin species. This silica-grafted organotrichlorotin displays a satisfactory catalytic activity in the transesterification of ethyl acetate by 1 octanol. The catalyst could be recycled four times without significant loss of activity. Furthermore, tin leaching below 10 ppm evidences the benefits of the proposed strategy to limit tin contamination of the final products. PMID- 23686296 TI - Functional transient receptor potential canonical type 1 channels in human atrial myocytes. AB - Transient receptor potential (TRP) channels are not well understood in human atrium, and the present study was therefore designed to investigate whether TRPC channels would mediate the nonselective cation current reported previously and are involved in the formation of store-operated Ca(2+) entry (SOCE) channels in human atrial myocytes using approaches of whole-cell patch voltage-clamp, RT-PCR, Western blotting, co-immunoprecipitation, and confocal scanning approaches, etc. We found that a nonselective cation current was recorded under K(+)-free conditions in human atrial myocytes, and the current was inhibited by the TRP channel blocker La(3+). Thapsigargin enhanced the current, and its effect was suppressed by La(3+) and prevented by pipette inclusion of anti-TRPC1 antibody. Endothlin-1 and angiotensin II enhanced the current that could be inhibited by La(3+). Gene and protein expression of TRPC1 channels were abundant in human atria. In addition, mRNA and protein of STIM1 and Orai1, components of SOCE channels, were abundantly expressed in human atria. Co-immunoprecipitation analysis demonstrated an interaction of TRPC1 with STIM1 and/or Orai1. Ca(2+) signaling mediated by SOCE channels was detected by a confocal microscopy technique. These results demonstrate the novel evidence that TRPC1 channels not only mediate the nonselective cation current, but also form SOCE channels in human atria as a component. TRPC1 channels can be activated by endothelin-1 or angiotensin II, which may be involved in the atrial electrical remodeling in patients with atrial fibrillation. PMID- 23686298 TI - O6-methylguanine-DNA methyltransferase (MGMT) immunohistochemistry as a predictor of resistance to temozolomide in primary CNS lymphoma. AB - Temozolomide, an alkylating agent, has shown promise in treating primary central nervous system lymphoma (PCNSL). The enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) repairs alkylating damage, such as that induced by temozolomide. We hypothesized that MGMT immunohistochemistry would predict resistance to temozolomide in PCNSL. A retrospective study of newly-diagnosed and recurrent PCNSL patients treated at our institution was conducted to study the predictive value of MGMT immunohistochemistry for response to temozolomide. 20 patients who were treated with temozolomide as a single agent were identified during the study time period. 6/20 patients demonstrated a response, corresponding to an objective response rate of 30 % (95 % CI 8-52). Five patients with low MGMT level (<30 %) showed a response to temozolomide. Only one of 10 patients (10 %) with high MGMT level (>=30 %) exhibited a response to temozolomide. Small sample numbers precluded formal statistical comparisons. Two patients with complete response remain alive without progressive disease 6.7 and 7.2 years after temozolomide initiation. Immunohistochemistry can be performed on small biopsies to selectively assess MGMT status in tumor versus surrounding inflammation. MGMT analysis by immunohistochemistry may predict response to temozolomide in PCNSL and should be prospectively investigated. PMID- 23686299 TI - [Current treatment concepts for muscular injuries]. AB - Muscular lesions represent the most common form of sports injury. The four large muscle groups hamstrings, adductors, gastrocnemius and knee extensor muscles are most often affected. Most injuries occur during excentric tension impact. Diagnostics begin with an exact medical history and detailed clinical investigations. Imaging with ultrasound and magnetic resonance imaging (MRI) are important to differentiate between structural lesions and functional disorders and to determine the extent of the injury. Most frequently treatment remains conservative and is oriented to the three phases of the healing process. In most cases (leisure sports) the rest, ice, compression and elevation (RICE) concept with subsequent pain-adapted load increase suffices for a return to sport activities. Infiltration therapy including platelet-rich plasma (PRP) is an additional therapy option but should not be used to accelerate the healing process. Surgical treatment only rarely becomes necessary for treatment of muscular injuries. PMID- 23686300 TI - Effects of carvedilol therapy on cardiac autonomic control, QT dispersion, and ventricular arrhythmias in children with dilated cardiomyopathy. AB - BACKGROUND: The purpose of this study was to examine the effects of carvedilol therapy on autonomic control of the heart and QT-interval dispersion (QTd) among children with idiopathic dilated cardiomyopathy (DCM) whose symptoms were not adequately controlled with standard congestive heart failure therapy. MATERIAL AND METHODS: Patients with DCM who were treated with carvedilol were enrolled in the study. All patients had undergone carvedilol therapy in addition to standard therapy for at least 6 months. Clinical, echocardiographic, and electrocardiographic parameters, and 24-h Holter records of patients were retrospectively evaluated before and after carvedilol treatment. RESULTS: A total 34 patients (mean age: 7.4 +/- 4.3 years) with DCM were analyzed in the study. The median follow-up period was 9.5 months. After the 6 months of carvedilol therapy the clinical score significantly improved, left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) significantly increased, and left ventricle end-diastolic dimensions and end-systolic dimensions significantly decreased. There were statistically significant increases in mean SDNN, SDANN, rMSSD, and pNN50 (p = 0.002, p = 0.001, p = 0.008, and p = 0.026, respectively). After the carvedilol therapy, SDNN was correlated with the clinical score, heart rate, LVEF, LVFS, and total premature ventricular contractions (PVCs). In addition, rMSSD and pNN50 were correlated with heart rate, LVEF and LVFS. A significant reduction was observed in QTc-minimum, QTc-maximum, and QTd values (434.9 +/- 40.7 vs. 416.1 +/- 36.5, 497.8 +/- 43.6 vs. 456.3 +/- 41.7, 58.6 +/- 17.1 vs. 49.3 +/- 15.6; p < 0.001, p = 0.001, and p = 0.008, respectively). QTd was significantly related to PVCs (r = 0.62, p = 0.02). CONCLUSIONS: We conclude that the addition of carvedilol to standard therapy can improve clinical symptoms and heart rate variability, and reduce in arrhythmia markers in children with DCM. PMID- 23686301 TI - Neutrophil-to-lymphocyte ratio predicts response to cardiac resynchronization therapy. AB - BACKGROUND: Neutrophil-to-lymphocyte (N/L) ratio has been associated with adverse outcomes in patients with acute coronary syndromes and increased risk for long term mortality in patients with acute decompensated heart failure. We aimed to investigate the prognostic value of neutrophil-to-lymphocyte ratio on response to cardiac resynchronization therapy (CRT). MATERIAL AND METHODS: Seventy consecutive patients (mean age 58 +/- 13 years; 40 men) undergoing CRT were included in the study. Hematological and echocardiographic parameters were measured before and 6 months after CRT. Echocardiographic response to CRT was defined as a >= 15% reduction in left ventricular end-systolic volume at 6-month follow-up. RESULTS: After 6 months of CRT, 49 (70%) patients were responders. After 6 months, left ventricular ejection fraction (LVEF) had significantly increased, from 21 +/- 7% to 34 +/- 11% in responder patients (p = 0.001). N/L ratio decreased significantly, from 2.4 +/- 1 to 2.1 +/- 0.7 in responders (p = 0.04). In multivariate analysis, significant associates of echocardiographic response to CRT was evaluated adjusting for age, etiology of cardiomyopathy, baseline LVEF, New York Heart Association functional class, C-reactive protein, and baseline N/L ratio. Baseline N/L ratio was the only predictor of response to CRT (OR 1.506, 95% CI, 1.011-2.243, p = 0.035). CONCLUSIONS: N/L ratio at baseline could help to identify patients with response to CRT. PMID- 23686302 TI - Discrimination of personally significant from nonsignificant sounds: a training study. AB - Discriminating personally significant from nonsignificant sounds is of high behavioral relevance and appears to be performed effortlessly outside of the focus of attention. Although there is no doubt that we automatically monitor our auditory environment for unexpected, and hence potentially significant, events, the characteristics of detection mechanisms based on individual memory schemata have been far less explored. The experiments in the present study were designed to measure event-related potentials (ERPs) sensitive to the discrimination of personally significant and nonsignificant nonlinguistic sounds. Participants were presented with random sequences of acoustically variable sounds, one of which was associated with personal significance for each of the participants. In Experiment 1, each participant's own mobile SMS ringtone served as his or her significant sound. In Experiment 2, a nonsignificant sound was instead trained to become personally significant to each participant over a period of one month. ERPs revealed differential processing of personally significant and nonsignificant sounds from about 200 ms after stimulus onset, even when the sounds were task irrelevant. We propose the existence of a mechanism for the detection of significant sounds that does not rely on the detection of acoustic deviation. From a comparison of the results from our active- and passive-listening conditions, this discriminative process based on individual memory schemata seems to be obligatory, whereas the impact of individual memory schemata on further stages of auditory processing may require top-down guidance. PMID- 23686303 TI - Current perspectives on ophthalmic manifestations of childhood rheumatic diseases. AB - Inflammatory eye diseases are an important manifestation of many pediatric rheumatologic conditions. Early screening and diagnosis are imperative as these illnesses can not only result in significant visual morbidity but are also an indicator of systemic inflammation. Time to presentation of ocular inflammation varies significantly and can range from many years prior to the onset of systemic symptoms to well after the diagnosis of the rheumatologic disorder. Due to this variability in presentation, careful monitoring by an ophthalmologist is vital to preventing ocular complications and preserving vision. Both local and systemic immunosuppressive medications have been effective in the management of ocular disease. In this review, we will focus on the known ophthalmologic manifestations of common pediatric rheumatologic diseases and discuss recent advances in therapeutic considerations for these conditions. PMID- 23686304 TI - A single compartment model of pacemaking in dissasociated substantia nigra neurons: stability and energy analysis. AB - Spontaneous oscillations in the mid-brain dopaminergic neurons are an important feature of motor control. The degeneration of these neurons is involved in movement disorders, particularly Parkinson's Disease. Modelling of this activity is an important part of developing an understanding of the pathogenic process. We develop a mathematical paradigm to describe this activity with a single compartment approach and a CellML version is made publicly available. The model explicitly describes the dynamics of the transmembrane potential with changes in the levels of important cations and is consistent with two major observations in the literature regarding its behaviour in the presence of channel blockers. Stability of the model behaviour is determined from the properties of its Monodromy matrix. We also discuss from the perspective of energy, a pharmacological intervention suggested in the treatment of Parkinson's Disease. PMID- 23686305 TI - Induction of epithelial-mesenchymal transition (EMT) in breast cancer cells is calcium signal dependent. AB - Signals from the tumor microenvironment trigger cancer cells to adopt an invasive phenotype through epithelial-mesenchymal transition (EMT). Relatively little is known regarding key signal transduction pathways that serve as cytosolic bridges between cell surface receptors and nuclear transcription factors to induce EMT. A better understanding of these early EMT events may identify potential targets for the control of metastasis. One rapid intracellular signaling pathway that has not yet been explored during EMT induction is calcium. Here we show that stimuli used to induce EMT produce a transient increase in cytosolic calcium levels in human breast cancer cells. Attenuation of the calcium signal by intracellular calcium chelation significantly reduced epidermal growth factor (EGF)- and hypoxia induced EMT. Intracellular calcium chelation also inhibited EGF-induced activation of signal transducer and activator of transcription 3 (STAT3), while preserving other signal transduction pathways such as Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. To identify calcium permeable channels that may regulate EMT induction in breast cancer cells, we performed a targeted siRNA-based screen. We found that transient receptor potential-melastatin-like 7 (TRPM7) channel expression regulated EGF-induced STAT3 phosphorylation and expression of the EMT marker vimentin. Although intracellular calcium chelation almost completely blocked the induction of many EMT markers, including vimentin, Twist and N-cadherin, the effect of TRPM7 silencing was specific for vimentin protein expression and STAT3 phosphorylation. These results indicate that TRPM7 is a partial regulator of EMT in breast cancer cells, and that other calcium-permeable ion channels are also involved in calcium dependent EMT induction. In summary, this work establishes an important role for the intracellular calcium signal in the induction of EMT in human breast cancer cells. Manipulation of calcium-signaling pathways controlling EMT induction in cancer cells may therefore be an important therapeutic strategy for preventing metastases. PMID- 23686306 TI - ADAM12-cleaved ephrin-A1 contributes to lung metastasis. AB - Eph receptor tyrosine kinases and their ephrin ligands have been implicated in neuronal development and neovascularization. Overexpression of ephrin-A1 has been implicated in tumor progression and poor prognosis. However, the mechanisms are not clear. Here, we report a role of the Eph/ephrin system in a cell adhesion mechanism. Clustered erythropoietin-producing hepatocellular receptor A1 (EphA1)/ephrin-A1 complexes on the plasma membrane did not undergo endocytosis, and the cell remained adherent to one another. The cell-cell contacts were maintained in an Eph tyrosine kinase activity-independent manner even in the absence of E-cadherin. EphA1 and ephrin-A1 co-localized in pulmonary endothelial cells, and regulated vascular permeability and metastasis in the lungs. We identified ADAM12 (A disintegrin and metalloproteinase 12) as an EphA1-binding partner by yeast two-hybrid screening and found that ADAM12 enhanced ephrin-A1 cleavage in response to transforming growth factor-beta1 in primary tumors. Released soluble ephrin-A1 in the serum deteriorated the EphA1/ephrin-A1-mediated cell adhesion in the lungs in an endocrine manner, causing lung hyperpermeability that facilitated tumor cell entry into the lungs. Depletion of soluble ephrin-A1 by its neutralizing antibody significantly inhibited lung metastasis. PMID- 23686307 TI - Brd4 maintains constitutively active NF-kappaB in cancer cells by binding to acetylated RelA. AB - Acetylation of the RelA subunit of NF-kappaB at lysine-310 regulates the transcriptional activation of NF-kappaB target genes and contributes to maintaining constitutively active NF-kappaB in tumors. Bromodomain-containing factor Brd4 has been shown to bind to acetylated lysine-310 (AcLys310) and to regulate the transcriptional activity of NF-kappaB, but the role of this binding in maintaining constitutively active NF-kappaB in tumors remains elusive. In this study, we demonstrate the structural basis for the binding of bromodomains (BDs) of bromodomain-containing protein 4 (Brd4) to AcLys310 and identify the BD inhibitor JQ1 as an effective small molecule to block this interaction. JQ1 suppresses TNF-alpha-mediated NF-kappaB activation and NF-kappaB-dependent target gene expression. In addition, JQ1 inhibits the proliferation and transformation potential of A549 lung cancer cells and suppresses the tumorigenicity of A549 cells in severe combined immunodeficiency mice. Furthermore, we demonstrate that depletion of Brd4 or treatment of cells with JQ1 induces the ubiquitination and degradation of the constitutively active nuclear form of RelA. Our results identify a novel function of Brd4 in maintaining the persistently active form of NF-kappaB found in tumors, and they suggest that interference with the interaction between acetylated RelA and Brd4 could be a potential therapeutic approach for the treatment of NF-kappaB-driven cancer. PMID- 23686309 TI - The pleiotrophin-ALK axis is required for tumorigenicity of glioblastoma stem cells. AB - Increasing evidence suggests that brain tumors arise from the transformation of neural stem/precursor/progenitor cells. Much current research on human brain tumors is focused on the stem-like properties of glioblastoma. Here we show that anaplastic lymphoma kinase (ALK) and its ligand pleiotrophin are required for the self-renewal and tumorigenicity of glioblastoma stem cells (GSCs). Furthermore, we demonstrate that pleiotrophin is transactivated directly by SOX2, a transcription factor essential for the maintenance of both neural stem cells and GSCs. We speculate that the pleiotrophin-ALK axis may be a promising target for the therapy of glioblastoma. PMID- 23686308 TI - Targeting Gli transcription activation by small molecule suppresses tumor growth. AB - Targeted inhibition of Hedgehog signaling at the cell membrane has been associated with anticancer activity in preclinical and early clinical studies. Hedgehog signaling involves activation of Gli transcription factors that can also be induced by alternative pathways. In this study, we identified an interaction between Gli proteins and a transcription coactivator TBP-associated factor 9 (TAF9), and validated its functional relevance in regulating Gli transactivation. We also describe a novel, synthetic small molecule, FN1-8, that efficiently interferes with Gli/TAF9 interaction and downregulate Gli/TAF9-dependent transcriptional activity. More importantly, FN1-8 suppresses cancer cell proliferation in vitro and inhibits tumor growth in vivo. Our results suggest that blocking Gli transactivation, an important control point of multiple oncogenic pathways, may be an effective anticancer strategy. PMID- 23686310 TI - Dysregulation of BMI1 and microRNA-16 collaborate to enhance an anti-apoptotic potential in the side population of refractory mantle cell lymphoma. AB - The proto-oncogene BMI1 and its product, Bmi1, is overexpressed in various types of tumors, particularly in aggressive tumors and tumors resistant to conventional chemotherapy. BMI1/Bmi1 is also crucially involved in cancer-initiating cell maintenance, and is recurrently upregulated in mantle cell lymphoma (MCL), especially aggressive variants. Recently, side population (SP) cells were shown to exhibit tumor-initiating characteristics in various types of tumors. In this study, we show that recurrent MCL cases significantly exhibit upregulation of BMI1/Bmi1. We further demonstrate that clonogenic MCL SP shows such tumor initiating characteristics as high tumorigenicity and self-renewal capability, and that BMI1 was upregulated in the SP from recurrent MCL cases and MCL cell lines. On screening for upstream regulators of BMI1, we found that expression of microRNA-16 (miR-16) was downregulated in MCL SP cells by regulating Bmi1 in the SPs, leading to reductions in tumor size following lymphoma xenografts. Moreover, to investigate downstream targets of BMI1 in MCL, we performed cross linking/chromatin immunoprecipitation assay against MCL cell lines and demonstrated that Bmi1 directly regulated pro-apoptotic genes such as BCL2L11/Bim and PMAIP1/Noxa, leading to enhance anti-apoptotic potential of MCL. Finally, we found that a proteasome inhibitor bortezomib, which has been recently used for relapsed MCL, effectively induced apoptosis among MCL cells while reducing expression of Bmi1 and increasing miR-16 in MCL SP. These results suggest that upregulation of BMI1 and downregulation of miR-16 in MCL SP has a key role in the disease's progression by reducing MCL cell apoptosis. Our results provide important new insight into the pathogenesis of MCL and strongly suggest that targeting BMI1/Bmi1 might be an effective approach to treating MCL, particularly refractory and recurrent cases. PMID- 23686311 TI - Control of gp130 expression by the mitogen-activated protein kinase ERK2. AB - Interleukin (IL)-6-type cytokines such as IL-6, oncostatin M (OSM) and leukaemia inhibitory factor (LIF) signal through receptor complexes that are critically dependent on gp130. The latter is the common signal-transducing molecule that couples these cytokines to their downstream effectors, Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). IL-6-type cytokine signalling additionally involves the recruitment and activation of extracellular signal-regulated kinase (ERK) 1 and ERK2. Both STATs and ERKs regulate responses mediated by members of the IL-6 family. Here, we show that ERK2, but not ERK1, also controls the expression and function of gp130 per se, as silencing ERK2 in human osteosarcoma U2OS cells inhibits the expression of gp130. This does not simply reflect quantitative differences between ERK1 and ERK2, and the effects are not restricted to osteosarcoma cells, as they can be extended to several other cancer cell types analysed to date (such as breast, prostate, lung and cervical cancer cells). Importantly, ERK2 binds to the GP130 promoter, where it perhaps interacts with the transcriptional machinery. Indeed, its role in the transcriptional regulation of the GP130 gene was corroborated using luciferase reporter assays and messenger RNA stability experiments. Considering the pivotal role that gp130 has in cancer and inflammation these data thus identify novel non overlapping functions for ERK1 and ERK2 that are biologically relevant. PMID- 23686312 TI - DNA methylation determines nucleosome occupancy in the 5'-CpG islands of tumor suppressor genes. AB - Promoter CpG island hypermethylation of tumor suppressor genes is an epigenetic hallmark of human cancer commonly associated with nucleosome occupancy and the transcriptional silencing of the neighboring gene. Nucleosomes can determine the underlying DNA methylation status. Herein, we show that the opposite is also true: DNA methylation can determine nucleosome positioning. Using a cancer model and digital nucleosome positioning techniques, we demonstrate that the induction of DNA hypomethylation events by genetic (DNMT1/DNMT3B deficient cells) or drug (a DNA demethylating agent) approaches is associated with the eviction of nucleosomes from previously hypermethylated CpG islands of tumor suppressor genes. Most importantly, the establishment of a stable cell line that restores DNMT1/DNMT3B deficiency shows that nucleosomes reoccupy their positions in de novo methylated CpG islands. Finally, we extend these results to the genomic level, combining a DNA methylation microarray and the nucleosome positioning technique. Using this global approach, we observe the dependency of nucleosome occupancy upon the DNA methylation status. Thus, our results suggest that there is a close association between hypermethylated CpG islands and the presence of nucleosomes, such that each of these epigenetic mechanisms can determine the recruitment of the other. PMID- 23686313 TI - PPISURV: a novel bioinformatics tool for uncovering the hidden role of specific genes in cancer survival outcome. AB - Multiple clinical studies have correlated gene expression with survival outcome in cancer on a genome-wide scale. However, in many cases, no obvious correlation between expression of well-known tumour-related genes (that is, p53, p73 and p21) and survival rates of patients has been observed. This can be mainly explained by the complex molecular mechanisms involved in cancer, which mask the clinical relevance of a gene with multiple functions if only gene expression status is considered. As we demonstrate here, in many such cases, the expression of the gene interaction partners (gene 'interactome') correlates significantly with cancer survival and is indicative of the role of that gene in cancer. On the basis of this principle, we have implemented a free online datamining tool (http://www.bioprofiling.de/PPISURV). PPISURV automatically correlates expression of an input gene interactome with survival rates on >40 publicly available clinical expression data sets covering various tumours involving about 8000 patients in total. To derive the query gene interactome, PPISURV employs several public databases including protein-protein interactions, regulatory and signalling pathways and protein post-translational modifications. PMID- 23686314 TI - Profilin-1 downregulation has contrasting effects on early vs late steps of breast cancer metastasis. AB - Profilin1 (Pfn1), a ubiquitously expressed actin-binding protein, has an indispensable role in migration and proliferation of normal cells. Seemingly contrary to its essential cellular functions, Pfn1's expression is downregulated in breast cancer, the significance of which is unclear. In this study, expression profiling of Pfn1 in human breast cancer specimens correlates lower Pfn1 expression levels with propensity to metastasize. Xenograft experiments further establish a causal relationship between loss of Pfn1 expression and increased dissemination of breast cancer cells (BCCs) from the primary mammary tumor. BCCs exhibit a hyperinvasive phenotype (marked by matrix metalloproteinase-9 upregulation, faster invasion through collagen matrix) and acquire increased proficiency to transmigrate through endothelial barrier (an obligatory step for vascular dissemination) when Pfn1 expression is suppressed. In Pfn1-deficient cells, hyperinvasiveness involves a phosphatidylinositol 3-kinase-PI(3,4)P2 signaling axis while augmented transendothelial migration occurs in a vascular endothelial growth factor-dependent manner. Contrasting these dissemination promoting activities, loss of Pfn1, however, dramatically inhibits metastatic outgrowth of disseminated BCCs, suggesting that Pfn1 has a key role in the metastatic colonization process. In summary, this study shows that Pfn1 has a dichotomous role in early vs late steps of breast cancer metastasis. PMID- 23686315 TI - ANGPTL4 is a secreted tumor suppressor that inhibits angiogenesis. AB - Tumor suppressors with extracellular function are likely to have advantages as targets for cancer therapy, but few are known. Here, we focused on angiopoietin like 4 (ANGPTL4), which is a secreted glycoprotein involved in lipoprotein metabolism and angiogenesis, is methylation-silenced in human cancers, but has unclear roles in cancer development and progression. We found a deletion mutation in its coiled-coil domain at its N-terminal in human gastric cancers, in addition to hypermethylation of the ANGPTL4 promoter CpG islands. Forced expression of wild-type ANGPTL4, but not ANGPTL4 with the deletion, at physiological levels markedly suppressed in vivo tumorigenicity and tumor angiogenesis, indicating that the latter caused the former. Tumor-derived ANGPTL4 suppressed in vitro vascular tube formation and proliferation of human umbilical vascular endothelial cells, partly due to suppression of ERK signaling. These showed that ANGPTL4 is a genetically and epigenetically inactivated secreted tumor suppressor that inhibits tumor angiogenesis. PMID- 23686316 TI - SATB1 collaborates with loss of p16 in cellular transformation. AB - Tumor progression is associated with invasiveness and metastatic potential. The special AT-rich binding protein 1 (SATB1) has been identified as a key factor in the progression of breast cancer cells to a malignant phenotype and is associated with progression of human tumors. In normal development, SATB1 coordinates gene expression of progenitor cells by functioning as a genome organizer. In contrast to progenitor and tumor cells, SATB1 expression in nontransformed cells is not compatible with proliferation. Here we show that SATB1 expression in mouse embryonic fibroblasts induces cell cycle arrest and senescence that is associated with elevated p16 protein levels. Deletion of p16 overcomes the SATB1-induced senescence. We further provide evidence for an interaction of SATB1 with the retinoblastoma (RB)/E2F pathway downstream of p16. A combined deletion of the RB proteins, RB, p107 and p130 (triple-mutant; TM), prevents SATB1-induced G1 arrest, which is restored upon the reintroduction of RB into SATB1-expressing TM fibroblasts. SATB1 interacts with the E2F/RB complex and regulates the cyclin E promoter in an E2F-dependent manner. These findings demonstrate that p16 and the RB/E2F pathway are critical for SATB1-induced cell cycle arrest. In the absence of p16, SATB1 causes anchorage-independent growth and invasive phenotype in fibroblasts. Our data illustrate that p16 mutations collaborate with the oncogenic activity of SATB1. Consistent with our finding, a literature survey shows that deletion of p16 is generally associated with SATB1 expressing human cell lines and tumors. PMID- 23686317 TI - Huaier aqueous extract suppresses human breast cancer cell proliferation through inhibition of estrogen receptor alpha signaling. AB - Estrogen receptor alpha (ERalpha) has been reported to play a critical role in promoting the growth of breast tumor cells. In the present study, we explored the effect of Huaier extract on estrogen receptor alpha signaling in breast cancer cell lines. Our data demonstrated that Huaier extract effectively inhibited the proliferation of the MCF-7, T47D and ZR-75-1 human breast cancer cell lines. For the mechanism analysis, we demonstrated that Huaier extract significantly reduced the mRNA and protein levels of ERalpha in all three ERalpha-positive cell lines. The downregulation of ERalpha protein levels was correlated with activation of the proteasomes. We demonstrated that Huaier extract markedly decreased the expression of both ERalpha and its downstream genes, inhibited the estrogen stimulated proliferation and reversed the estrogen-induced activation of the nuclear factor kappaB (NFkappaB) pathway. Our study provides evidence that Huaier extract is a novel estrogen receptor modulator and is a promising drug for the prevention and treatment of ERalpha-positive human breast cancers. PMID- 23686319 TI - In vivo assessment of the impact of efflux transporter on oral drug absorption using portal vein-cannulated rats. AB - The purpose of this study was to evaluate the impact of intestinal efflux transporters on the in vivo oral absorption process. Three model drugs fexofenadine (FEX), sulfasalazine (SASP), and topotecan (TPT)-were selected as P glycoprotein (P-gp), breast cancer resistance protein (BCRP), and P-gp and BCRP substrates, respectively. The drugs were orally administered to portal vein cannulated rats after pretreatment with zosuquidar (ZSQ), P-gp inhibitor, and/or Ko143, BCRP inhibitor. Intestinal availability (Fa.Fg) of the drugs was calculated from the difference between portal and systemic plasma concentrations. When rats were orally pretreated with ZSQ, Fa.Fg of FEX increased 4-fold and systemic clearance decreased to 75% of the control. In contrast, intravenous pretreatment with ZSQ did not affect Fa.Fg of FEX, although systemic clearance decreased significantly. These data clearly show that the method presented herein using portal vein-cannulated rats can evaluate the effects of intestinal transporters on Fa.Fg of drugs independently of variable systemic clearance. In addition, it was revealed that 71% of FEX taken up into enterocytes underwent selective efflux via P-gp to the apical surface, while 79% of SASP was effluxed by Bcrp. In the case of TPT, both transporters were involved in its oral absorption. Quantitative analysis indicated a 3.5-fold higher contribution from Bcrp than P-gp. In conclusion, the use of portal vein-cannulated rats enabled the assessment of the impact of efflux transporters on intestinal absorption of model drugs. This experimental system is useful for clarifying the cause of low bioavailability of various drugs. PMID- 23686318 TI - Small nucleolar RNA-derived microRNA hsa-miR-1291 modulates cellular drug disposition through direct targeting of ABC transporter ABCC1. AB - Multidrug resistance-associated protein 1 (MRP1/ABCC1) is an important membrane transporter that contributes to cellular disposition of many endobiotic and xenobiotic agents, and it can also confer multidrug resistance. This study aimed to investigate the role of human noncoding microRNA-1291 (hsa-miR-1291) in regulation of ABCC1 and drug disposition. Bioinformatics analyses indicated that hsa-miR-1291, localized within the small nucleolar RNA H/ACA box 34 (SNORA34), might target ABCC1 3'-untranslated region (3'UTR). Using splinted ligation small RNA detection method, we found that SNORA34 was processed into hsa-miR-1291 in human pancreatic carcinoma PANC-1 cells. Luciferase reporter assays showed that ABCC1 3'-UTR-luciferase activity was decreased by 20% in cells transfected with hsa-miR-1291 expression plasmid, and increased by 40% in cells transfected with hsa-miR-1291 antagomir. Furthermore, immunoblot study revealed that ABCC1 protein expression was sharply reduced in hsa-miR-1291-stably transfected PANC-1 cells, which was attenuated by hsa-miR-1291 antagomir. The change of ABCC1 protein expression was associated with an alternation in mRNA expression. In addition, hsa-miR-1291-directed downregulation of ABCC1 led to a greater intracellular drug accumulation and sensitized the cells to doxorubicin. Together, our results indicate that hsa-miR-1291 is derived from SNORA34 and modulates cellular drug disposition and chemosensitivity through regulation of ABCC1 expression. These findings shall improve the understanding of microRNA-controlled epigenetic regulatory mechanisms underlying multidrug resistance and interindividual variability in pharmacokinetics. PMID- 23686320 TI - Chiroptical detectors for the study of unusual phenomena in chiral chromatography. AB - Differentiation of enantiomers in chromatography requires specific detectors, based on polarimetry or circular dichroism. Their use is limited to chiral HPLC and SFC. We explain the operating principles of the different chiroptical detectors available and stress the influence of working wavelength and mobile phase on the output signal. Current and relevant applications of chiroptical detectors are absolute configuration assignment, measurement of enantiomeric excesses in complex mixtures and determination of elution order. We focus on the reversals of enantiomeric elution order, an important subject for the understanding of the chiral recognition mechanisms. We review the main parameters which can induce a reversal, show the usefulness of chiroptical detectors to easily identify reversals and emphasize the significance of the isoenantioselective temperature. The aim of this chapter is to highlight the valuable information provided by chiroptical detectors to study unusual behaviour in chiral HPLC and SFC, reversals of enantiomeric elution order and exchange phenomena as dynamic chromatography and self-disproportionation on achiral columns. PMID- 23686321 TI - Contrast echocardiography for the diagnosis of left ventricular thrombus in anterior myocardial infarction. AB - Although detecting left ventricular thrombus in anterior myocardial infarction is important for the prevention of embolic events, imaging of apical thrombus is often difficult using conventional echocardiography. We examined whether contrast echocardiography improves sensitivity and specificity in detecting thrombus in the left ventricle in comparison with conventional echocardiography alone in patients with anterior myocardial infarction. Participants in this single-center prospective study comprised 392 patients with anterior myocardial infarction admitted between 2000 and 2006. After conventional echocardiography, all patients underwent contrast echocardiography (left ventricular opacification and myocardial contrast echocardiography) during intravenous drip infusion of contrast media at rest. Left ventricular thrombus was diagnosed based on left ventriculography or multidetector-row computed tomography (MDCT). Mural left ventricular thrombus was confirmed by left ventriculography and/or MDCT in 32 of 393 patients (8 %). Sensitivity and specificity of conventional echocardiography alone were 88 % and 96 %, respectively, compared with 100 % each with contrast echocardiography. Among the 32 patients with left ventricular thrombus, 25 patients (78 %) showed no perfusion in the anterior wall on myocardial contrast echocardiography, even with a four-beat interval. In conclusion, contrast echocardiography offers a clinically feasible and useful method for noninvasively evaluating left ventricular thrombus in anterior myocardial infarction. PMID- 23686322 TI - 24-hour efficacy of the bimatoprost-timolol fixed combination versus latanoprost as first choice therapy in subjects with high-pressure exfoliation syndrome and glaucoma. AB - AIM: To compare the 24-h intraocular pressure (IOP) control obtained with the bimatoprost-timolol fixed combination (BTFC) versus latanoprost in newly diagnosed, previously untreated exfoliation syndrome (XFS) or exfoliative glaucoma (XFG) patients with baseline morning IOP greater than 29 mm Hg. METHODS: One eye of 41 XFS/XFG patients who met inclusion criteria was included in this prospective, observer-masked, crossover, comparison protocol. All subjects underwent a 24-h untreated curve and were then randomised to either evening administered BTFC or latanoprost for 3 months and then switched to the opposite therapy. At the end of each treatment period, patients underwent a treated 24-h IOP assessment. RESULTS: 37 patients completed the trial. At baseline, mean untreated 24-h IOP was 31.1 mm Hg. Mean 24-h IOP with BTFC was significantly lower than with latanoprost (18.9 vs 21.2 mm Hg; p<0.001). Furthermore, BTFC reduced IOP significantly more than latanoprost at every time point, for the mean peak and trough 24-h IOP (p<0.001). There was no difference, however, in mean 24 h IOP fluctuation between the two medications (3.8 with BTFC vs 4.2 with latanoprost; p=0.161). Both treatments were well tolerated and there was no statistically significant difference for any adverse event between them. CONCLUSIONS: As first choice therapy in high-pressure, at-risk exfoliation patients, BTFC controlled mean 24-h IOP significantly better than latanoprost monotherapy. PMID- 23686323 TI - Driving after pupil dilation and insurance claims. PMID- 23686324 TI - Dexamethasone implants in retinal vein occlusion: 12-month clinical effectiveness using repeat injections as-needed. AB - OBJECTIVE: To report the 12-month outcomes of the dexamethasone intravitreal implant in retinal vein occlusion (RVO), using an as-needed repeat injection protocol. DESIGN: Retrospective consecutive case series of 51 eyes of 49 patients with macular oedema as a result of RVO that received an intravitreal dexamethasone implant and were followed up for at least 12 months. RESULTS: 70% of patients responded to dexamethasone implant injection with an improvement in visual acuity (VA) and macular oedema within 3 months of injection, but only 30% of eyes gained >=15 letters. The mean change in VA letter score at 12 months compared with baseline for branch RVO (BRVO) and central RVO (CRVO) was 5.7+/-2.3 and 11.5+/-11.0 EDTRS letters, respectively. 56% of patients relapsed, with the median time to relapse being 17 weeks for patients with branch RVO and 18 weeks for patients with CRVO. Repeat injections achieved similar VA gains, but the duration of effect of repeat dexamethasone implants was much shorter at 10 weeks. 14 eyes (27%) developed a significant rise in intraocular pressure, and three of these required treatment with oral acetazolamide. Four eyes with CRVO developed neovascular glaucoma during the study. CONCLUSIONS: The intravitreal dexamethasone implant does not last the 6 months implied by the retreatment protocol in the GENEVA trial, and improved results can be achieved with an as needed retreatment protocol, particularly in CRVO. However, visual outcomes remain similar to those previously seen with triamcinolone in the SCORE study and neovascular complications remain a feature of CRVO. PMID- 23686325 TI - Near-infrared transillumination photography to detect anterior uveal melanomas through black IOLs. PMID- 23686326 TI - Choroidal naevi complicated by choroidal neovascular membrane and outer retinal tubulation. AB - AIMS: To present the outcomes of a series of patients with choroidal neovascular membrane (CNV) secondary to a choroidal naevus and report the presence of outer retinal tubulation. METHODS: In this retrospective series, patients underwent a complete clinical and imaging assessment (fundus photo, fluorescein angiography and optical coherence tomography) and were observed or managed with intravitreal anti-VEGF injections dependent on whether visual acuity was affected. RESULTS: Seventeen patients were included in this study. Of this, 46% (8/17) had classic or predominantly classic CNV and 53% (9/17) had occult or minimally classic CNV. Active treatment with intravitreal anti-VEGF injections was required in 35% (6/17). Visual acuity improved in three eyes by 2-4 Snellen lines, remained stable in one eye and worsened in two eyes by 2 Snellen lines. CNV partially regressed in five cases. In the observation group (65%, 11/17), visual acuity did not change during follow-up period. Outer retinal tubulation was found in 18% (3/17). CONCLUSIONS: Anti-VEGF treatment is effective in the management of vision threatening CNV secondary to a choroidal naevus. Functional or anatomical improvement was obtained in 66% of treated eyes. Outer retinal tubulation, noted in 18%, showed the clinical importance of this sign in determining continuation of anti-VEGF treatment. PMID- 23686327 TI - Papillorenal syndrome in a family with unusual complications. PMID- 23686328 TI - Evidence of lower macular pigment optical density in chronic open angle glaucoma. AB - BACKGROUND/AIMS: Macular pigment (MP) plays an important role in visual function and in the protection of the retina from oxidative damage. It is not known whether glaucoma, a progressive neurodegenerative disease of the optic nerve, is associated with alterations in MP. This study was designed to investigate the relationship, if any, between the optical density of MP optical density (MPOD) and glaucoma. METHODS: 40 subjects (23 males, 17 females) with open angle glaucoma (mean age 69 +/-11), and 54 normal controls (23 males, 31 females) without ocular disease (mean age 66 +/-11), visual acuity (VA) >6/18, were recruited, and underwent a comprehensive eye examination including biomicroscopy, fundoscopy, Goldmann tonometry and visual field assessment, using the 24-2 SITA fast algorithm on the Humphrey visual field analyser (II-i Series). MPOD, at 0.5 degrees of retinal eccentricity was determined, for all subjects, using heterochromatic flicker photometry. RESULTS: Median (IQR) MPOD for subjects with glaucoma was 0.23 (0.42) compared to 0.36 (0.44) for controls. The difference in MPOD between the glaucoma cases and controls was statistically significant (z= 2.158, p=0.031). There was no significant correlation (p>0.05) between MPOD and disease severity. CONCLUSIONS: These findings suggest that MPOD is lower in patients with glaucoma. Further investigation is needed to determine the significance of MP in glaucoma, its relationship to glare symptoms in glaucoma and to assess what role therapeutic strategies aimed at increasing MP levels could have in the management of glaucoma. PMID- 23686329 TI - A case of Schizophyllum commune sinusitis following unrelated cord blood transplantation for acute lymphoblastic leukemia. AB - Schizophyllum commune is a globally distributed basidiomycete fungus that is known as a rare cause of sinusitis, for which no prompt treatment has been established. We describe the first report of S. commune sinusitis following unrelated cord blood transplantation for acute lymphoblastic leukemia. Thirteen days after transplantation, a 23-year-old female developed maxillary and ethmoid sinusitis. The sinusitis was antimicrobial-resistant, and the sinus aspirate culture revealed white wooly mold, which was identified as S. commune by nucleotide sequencing. The patient was successfully treated with intravenous administration of liposomal amphotericin B for 2 months, followed by oral voriconazole. This report suggests the effectiveness of liposomal amphotericin B and voriconazole for S. commune infection in immunocompromised patients. Given the difficulty in distinguishing S. commune infection from aspergillosis by standard culture methods, the incidence of S. commune infection following allogeneic hematopoietic stem cell transplantation may be underestimated. Nucleotide sequencing may be useful in the diagnosis of S. commune infection. PMID- 23686330 TI - Genetic variability at COMT but not at OPRM1 and UGT2B7 loci modulates morphine analgesic response in acute postoperative pain. AB - PURPOSE: To investigate interindividual variability in response to pain treatment, we characterized postoperative patients for morphine metabolism and for COMT, OPRM1 and UGT2B7 polymorphisms. METHODS: A total of 109 patients treated with morphine were genotyped by DNA sequencing for 12 DNA polymorphisms of the COMT, OPRM1 and UGT2B7 genes. The plasma concentration of morphine and of M3G/M6G metabolites were evaluated by means of reversed phase high-performance liquid chromatography coupled with mass spectrometry. RESULTS: An association between average morphine consumption during the first 24 postoperative hours by patient-controlled analgesia (PCA) and COMT haplotypes was found. Specifically, patients with the diplotype for average pain intensity (APS/APS) required the lowest morphine doses compared to the other subjects (p = 0.011). The APS haplotype contains an adenine corresponding to methionine, instead of valine, at position 158 of the COMT protein. Met/Met homozygous patients consumed significantly lower morphine doses than other subjects (p = 0.014); accordingly, Val158Met genotyping alone might be used in the clinical setting to predict PCA morphine need. Considering both COMT Val158Met and OPRM1 A118G polymorphisms, carriers of both the Met/Met and AA genotypes required less morphine than other subjects, although the difference was not significant. The analysis of UGT2B7 revealed the occurrence of two common haplotypes (G_C_C_A_C and A_T_T_G_T) that did not prove to be related with plasma morphine and M3G/M6G concentration. CONCLUSIONS: By considering COMT, OPRM1, and UGT2B7 genotypes, as well as pharmacokinetic results, only COMT polymorphisms appear to be predictive of morphine need in postoperative pain therapy. PMID- 23686331 TI - Clinical trial registries: from an omen to a common and disclosed practice. AB - OBJECTIVE: Clinical trials registries are important for guaranteeing trustworthy scientific knowledge. Despite international initiatives promoting trial registration, however, complete and high quality disclosure of trial information in such registries is not routine. The role of registries in also increasing transparency is fundamental, and these databases could be contemplated by research organizations, even at more local levels. METHODS: A rare initiative was set up at the IRCCS-Mario Negri Institute for Pharmacological Research in Milan in order to make the institute's ongoing research accessible to anyone. RESULTS: The register currently includes 112 studies in which the institute participates. CONCLUSIONS: Work still needs to be done to improve the registry, but it is up and functional. Could, or should, such registries be routine for all scientific institutions? PMID- 23686332 TI - Expression of concern. PMID- 23686333 TI - Incidence and long-term outcome of sepsis on general wards and in an ICU at the General Hospital of Vienna: an observational cohort study. AB - Sepsis is one of the leading causes of death in intensive care units (ICUs) and has enormous relevance in health economics. There is growing evidence, however, that a significant percentage of patients with sepsis are not treated in an ICU. The aim of this study was to describe the epidemiology and short- and long-term mortality of sepsis according to patients' location on general wards or in an ICU over a period of a year. We retrospectively collected data on patients with sepsis admitted to the General Hospital of Vienna during a 12-month period. We used world health organization (WHO) ICD-10 classification as the selection criterion and analyzed demographic data, length of stay, and 28-day, hospital, and 3-year mortality on general wards and in the ICU. A total of 68,305 inpatient admission episodes between January 1 and December 31, 2007 were screened for sepsis. Using ICD-10 codes we identified 139 patients with sepsis, giving a cumulative hospital incidence of 2 cases/1,000 admissions; 32 % of these patients needed ICU treatment. The overall 28-day mortality rate was 29.5 %, increasing to 55.4 % 3 years after hospital discharge. On general wards the 28-day mortality rate was 12.6 %, increasing to 42.1 % 3 years after discharge; the respective rates for the ICU were 65.9 and 84.1 %. Sepsis is a disease of predominantly elderly patients. The majority of sepsis occurred on general wards and about 30 % in the ICU. Considerable number of patients with sepsis on general wards died after hospital discharge, thus the often used 28-day in-hospital mortality rate may fail to capture the true impact of sepsis on subsequent outcome. PMID- 23686336 TI - We can predict postpalatoplasty velopharyngeal insufficiency in cleft palate patients. AB - OBJECTIVES/HYPOTHESIS: To find an anatomical measurement of the cleft palate (or a calculated parameter) that predicts the occurrence of velopharyngeal insufficiency (VPI) after palatal cleft repair. STUDY DESIGN: Retrospective cohort study. METHODS: Charts were reviewed from cleft palate patients who underwent palatoplasty by the Von Langenbeck technique for isolated cleft palate or Bardach two-flap palatoplasty for cleft lip-palate. Seven anatomical cleft parameters were prospectively measured during the palatoplasty procedure. Three blinded speech-language pathologists retrospectively scored the clinically assessed VPI at 4 years of age. The recommendation of pharyngoplasty was also used as an indicator of VPI. RESULTS: From 1993 to 2008, 67 patients were enrolled in the study. The best predicting parameter was the ratio a/(30 - b1), in which a is defined as the posterior gap between the soft palate and the posterior pharyngeal wall and b1 is the width of the cleft at the hard palate level. An a/(30 - b1) ratio >0.7 to 0.8 is associated with a higher risk of developing VPI (relative risk = 2.2-5.1, sensitivity = 72%-81%, P < .03). CONCLUSIONS: The width of the cleft at the hard palate level and the posterior gap between the soft palate and the posterior pharyngeal wall were found to be the most significant parameters in predicting VPI. The best correlation was obtained with the ratio a/(30 - b1). LEVEL OF EVIDENCE: 4. PMID- 23686337 TI - Change of shoot architecture during juvenile-to-adult phase transition in soybean. AB - Juvenile-to-adult phase change is an indispensable event which guarantees a successful life cycle. Phase change has been studied in maize, Arabidopsis and rice, but is mostly unknown in other species. Soybean/Fabaceae plants undergo drastic changes of shoot architecture at the early vegetative stage including phyllotactic change and leaf type alteration from simple to compound. These characteristics make soybean/Fabaceae plants an interesting taxon for investigating vegetative phase change. Following the expansion of two cotyledons, two simple leaves simultaneously emerge in opposite phyllotaxy. The phyllotaxy of the third and fourth leaves is not fixed; both opposite and distichous phyllotaxis are observed within the same population. Leaves were compound from the third leaf. But the third leaf was rarely simple. Morphological and quantitative changes in early vegetative phase were recognized in leaf size, leaf shape, number of trichomes, stipule size and shape, and shoot meristem shape. Two microRNA genes, miR156 and miR172, are known to be associated with vegetative phase change. Examination of the expression level revealed that miR156 expression was high in the first two leaves and subsequently down-regulated, and that of miR172 showed the inverse expression pattern. These expression patterns coincided with the case of other species. Taken all data together, the first and second leaves represent juvenile phase, the fifth and upper leaves adult phase, and the third and fourth leaves intermediate stage. Further investigation of soybean phase change would give fruitful understandings on plant development. PMID- 23686338 TI - B cells use mechanical energy to discriminate antigen affinities. AB - The generation of high-affinity antibodies depends on the ability of B cells to extract antigens from the surfaces of antigen-presenting cells. B cells that express high-affinity B cell receptors (BCRs) acquire more antigen and obtain better T cell help. However, the mechanisms by which B cells extract antigen remain unclear. Using fluid and flexible membrane substrates to mimic antigen presenting cells, we showed that B cells acquire antigen by dynamic myosin IIa mediated contractions that pull out and invaginate the presenting membranes. The forces generated by myosin IIa contractions ruptured most individual BCR-antigen bonds and promoted internalization of only high-affinity, multivalent BCR microclusters. Thus, B cell contractility contributes to affinity discrimination by mechanically testing the strength of antigen binding. PMID- 23686339 TI - Targeting isoprenylcysteine methylation ameliorates disease in a mouse model of progeria. AB - Several progeroid disorders, including Hutchinson-Gilford progeria syndrome (HGPS) and restrictive dermopathy (ZMPSTE24 deficiency), arise when a farnesylated and methylated form of prelamin A accumulates at the nuclear envelope. Here, we found that a hypomorphic allele of isoprenylcysteine carboxyl methyltransferase (ICMT) increased body weight, normalized grip strength, and prevented bone fractures and death in Zmpste24-deficient mice. The reduced ICMT activity caused prelamin A mislocalization within the nucleus and triggered prelamin A-dependent activation of AKT-mammalian target of rapamycin (mTOR) signaling, which abolished the premature senescence of Zmpste24-deficient fibroblasts. ICMT inhibition increased AKT-mTOR signaling and proliferation and delayed senescence in human HGPS fibroblasts but did not reduce the levels of misshapen nuclei in mouse and human cells. Thus, targeting ICMT might be useful for treating prelamin A-associated progeroid disorders. PMID- 23686340 TI - Point-counterpoint. Ethics and genomic incidental findings. PMID- 23686341 TI - Point-counterpoint. Patient autonomy and incidental findings in clinical genomics. PMID- 23686342 TI - Dynamic topography change of the eastern United States since 3 million years ago. AB - Sedimentary rocks from Virginia through Florida record marine flooding during the mid-Pliocene. Several wave-cut scarps that at the time of deposition would have been horizontal are now draped over a warped surface with a maximum variation of 60 meters. We modeled dynamic topography by using mantle convection simulations that predict the amplitude and broad spatial distribution of this distortion. The results imply that dynamic topography and, to a lesser extent, glacial isostatic adjustment account for the current architecture of the coastal plain and proximal shelf. This confounds attempts to use regional stratigraphic relations as references for longer-term sea-level determinations. Inferences of Pliocene global sea-level heights or stability of Antarctic ice sheets therefore cannot be deciphered in the absence of an appropriate mantle dynamic reference frame. PMID- 23686343 TI - Massive Dirac fermions and Hofstadter butterfly in a van der Waals heterostructure. AB - van der Waals heterostructures constitute a new class of artificial materials formed by stacking atomically thin planar crystals. We demonstrated band structure engineering in a van der Waals heterostructure composed of a monolayer graphene flake coupled to a rotationally aligned hexagonal boron nitride substrate. The spatially varying interlayer atomic registry results in both a local breaking of the carbon sublattice symmetry and a long-range moire superlattice potential in the graphene. In our samples, this interplay between short- and long-wavelength effects resulted in a band structure described by isolated superlattice minibands and an unexpectedly large band gap at charge neutrality. This picture is confirmed by our observation of fractional quantum Hall states at +/- 5/3 filling and features associated with the Hofstadter butterfly at ultrahigh magnetic fields. PMID- 23686344 TI - Terahertz metamaterials for linear polarization conversion and anomalous refraction. AB - Polarization is one of the basic properties of electromagnetic waves conveying valuable information in signal transmission and sensitive measurements. Conventional methods for advanced polarization control impose demanding requirements on material properties and attain only limited performance. We demonstrated ultrathin, broadband, and highly efficient metamaterial-based terahertz polarization converters that are capable of rotating a linear polarization state into its orthogonal one. On the basis of these results, we created metamaterial structures capable of realizing near-perfect anomalous refraction. Our work opens new opportunities for creating high-performance photonic devices and enables emergent metamaterial functionalities for applications in the technologically difficult terahertz-frequency regime. PMID- 23686345 TI - Oral homeostasis disruption by medical plasticizer component bisphenol A in adult male rats. AB - OBJECTIVES/HYPOTHESIS: Bisphenol A (BPA) is a synthetic estrogen-like chemical mimetic widely used in the manufacture of polycarbonate plastics and epoxy resins found in numerous consumer products including food packaging, medical devices, and dental sealants. Because it is recovered in fluids and it can reach high levels in saliva, this study aimed to evaluate its safety on oral homeostasis by examining its effects on salivary glands, mouth epithelium, water consumption, and salt preference, each parameter being estrogen sensitive. STUDY DESIGN: Randomized controlled trial involving rats. METHODS: A dose-response study was conducted in adult Wistar rats randomized into five groups (n = 12). BPA was administered over 6 weeks via drinking water to obtain daily dose exposures of 0 MUg/kg, 5 MUg/kg, 50 MUg/kg, 5 mg/kg, and 12.5 mg/kg of body weight. To evaluate salt preference, 1% NaCl solution and pure water intakes were measured for 3 days by offering two-bottle choices. The rats were then killed; oral biopsies were done and submandibular glands were removed for histologic and morphometric analysis. RESULTS: According to the dose-response curve, BPA decreased total drinking but increased salt preference, which was inversely proportional to water consumption (Kruskal-Wallis, P < .01). It also causes oral dryness and histologic changes in the acinar structures of the submandibular glands at the lowest doses (Kruskal-Wallis, P < .01). CONCLUSIONS: This study shows that oral exposure to BPA in the rat disrupts thirst and buccal homeostasis and raises questions about the salivary gland secretions. PMID- 23686346 TI - Pyrroloquinoline quinine protects rat brain cortex against acute glutamate induced neurotoxicity. AB - To investigate possible protective effects of pyrroloquinoline quinone (PQQ) on the rat cortex with glutamate injection and to understand the mechanisms linking the in vivo neuroprotection of PQQ. Adult Sprague-Dawley rats received glutamate injection into the rat cortex. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling assay was performed to observe influences of co-treatment with PQQ (simultaneous injection with PQQ and glutamate) on neural cell apoptosis in the rat cortex. The production of reactive oxygen species (ROS) in the rat cortex was detected by flow cytometry using 2',7'-dichlorofluorescin diacetate labeling, and the activity of superoxide dismutase, glutathione and malondialdehyde was respectively determined. Real time quantitative RT-PCR and Western blot were applied to measure the mRNA and protein expressions of Nrf1, Nrf2, HO-1 and GCLC in the rat cortex. Western blot was used to detect the phosphorylation of Akt and GSK3beta in the rat cortex. Co-treatment with PQQ protected neural cells in the rat cortex from glutamate-induced apoptosis. PQQ decreased the ROS production induced by glutamate injection. PQQ increased the mRNA and protein expressions of Nrf2, HO-1 and GCLC and the phosphorylation of Akt and GSK3beta in the cortex of glutamate-injected rats. PQQ could produce neuroprotective effects on the rat cortex. The antioxidant properties of PQQ and PQQ-induced activation of Akt/GSK3beta signal pathway might be responsible for the in vivo neuroprotection of PQQ. PMID- 23686347 TI - Trichosanthes tricuspidata modulates oxidative toxicity in brain hippocampus against pilocarpine induced status epilepticus in mice. AB - Epilepsy prevails to be a neurological disorder in anticipation of safer drugs with enhanced anticonvulsant efficacy as presently available drugs fails to offer adequate control of epileptic seizures in about one-third of patients. The objective of this study was to evaluate the effect of Trichosanthes tricuspidata methanolic extract (TTME) against epilepsy mediated oxidative stress in pilocarpine induced mice. Intraperitonial administration of pilocarpine (85 mg/kg) induced seizure in mice was assessed by behavior observations, which is significantly (p < 0.05) reduced by TTME (100 and 200 mg/kg; i.p) in a dose dependant manner, similar to diazepam. Seizure was accompanied by significant increase in lipid peroxidation and the hippocampal nitrite content in pilocarpine group when compared with control. Moreover, the antioxidant enzymes superoxide dismutase, catalase and glutathione levels were decreased in pilocarpine administered groups. TTME administration attenuated oxidative damage as evident by decreased lipid oxidative damage and nitrite-nitrate content and restored the level of enzymatic antioxidant defenses in hippocampus. Involvement of free radicals during epilepsy is further confirmed by histopathological analysis which showed the loss of neuronal cells in hippocampus CA1 and CA3 pyramidal region. Our findings strongly support the hypothesis that TTME has anticonvulsant activity accompanied with the strong antioxidant potential plays a crucial role in reducing the oxidative stress produced by seizure. PMID- 23686348 TI - Microstructural analysis of negative anticipatory contrast: A reconsideration of the devaluation account. AB - An animal's appetitive behavior is not a fixed response to current stimulation but can be affected by the anticipation of future events. For example, rats regularly given access to a moderately valued solution followed by a higher value solution (e.g., 4 % sucrose -> 32 % sucrose) consume less of the initial solution than in control conditions where the initial solution is not followed by a higher value solution (e.g., 4 % sucrose -> 4 % sucrose). Previous analyses have suggested that this negative anticipatory contrast effect does not depend on the "expectation" of a valuable stimulus producing a functional devaluation of a currently available stimulus of lesser value. In a within-subjects anticipatory contrast procedure, this study revealed that both consumption and the mean size of licking clusters were smaller for a 4 % sucrose solution on days when it preceded 32 % sucrose than on days when 4 % preceded 4 %. Since lick cluster size typically bears a positive monotonic relationship with the concentration of palatable solutions, this reduction is indicative of a decrease in the palatability/hedonic value of the solution subject to contrast. As such, we provide direct evidence that negative anticipatory contrast does produce a functional devaluation of the solution, thus challenging prevailing theoretical assumptions. PMID- 23686349 TI - Transporters and drug-drug interactions: important determinants of drug disposition and effects. AB - Uptake and efflux transporters determine plasma and tissue concentrations of a broad variety of drugs. They are localized in organs such as small intestine, liver, and kidney, which are critical for drug absorption and elimination. Moreover, they can be found in important blood-tissue barriers such as the blood brain barrier. Inhibition or induction of drug transporters by coadministered drugs can alter pharmacokinetics and pharmacodynamics of the victim drugs. This review will summarize in particular clinically observed drug-drug interactions attributable to inhibition or induction of intestinal export transporters [P glycoprotein (P-gp), breast cancer resistance protein (BCRP)], to inhibition of hepatic uptake transporters [organic anion transporting polypeptides (OATPs)], or to inhibition of transporter-mediated [organic anion transporters (OATs), organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATEs), P gp] renal secretion of xenobiotics. Available data on the impact of nutrition on transport processes as well as genotype-dependent, transporter-mediated drug-drug interactions will be discussed. We will also present and discuss data on the variable extent to which information on the impact of transporters on drug disposition is included in summaries of product characteristics of selected countries (SPCs). Further work is required regarding a better understanding of the role of the drug metabolism-drug transport interplay for drug-drug interactions and on the extrapolation of in vitro findings to the in vivo (human) situation. PMID- 23686352 TI - Cultivable actinomycetes from rhizosphere of birch (Betula pendula) growing on a coal mine dump in Silets, Ukraine. AB - Five actinomycete strains were isolated from the rhizosphere of birch, one of a few native tree forms capable of thriving on the upper level of a coal mine dump near the village of Silets (Lvivska region, Ukraine). No such strains were isolated from surrounding gangue, or from nearby grass Calamagrostis epigeios. Using 16S rDNA sequencing and analysis of cell wall aminoacids, four of these strains were shown to belong to genus Streptomyces and one to be Amycolatopsis. The isolates were able to produce siderophores and antibacterial compounds. In comparison to the reference strain Streptomyces coelicolor M145, certain rhizospheric isolates displayed somewhat increased survival in the presence of copper, iron(III), or chromium(VI) salts. The Amycolatopsis isolate was also shown to accumulate significant quantities of heavy metals from waste extracts. Possible roles of the described strains in coal mine dump ecology are discussed. PMID- 23686353 TI - In vitro investigation of the effect of plasticizers on the blood compatibility of medical grade plasticized poly (vinyl chloride). AB - This paper reports the results of an in vitro investigation into the blood response of medical grade poly (vinyl chloride) (PVC), and two types of plasticized PVC in tubing or sheet form, with di-(2-ethylhexyl)phthalate (DEHP) and di(isononyl) cyclohexane-1,2-dicarboxylate (HEXAMOLL((r)) DINCH) as plasticizer, were selected for assessment of complement activation, coagulation system and platelet activation. The results of the study show that not only the plasticizers at PVC surface have an influence on complement activation, but also the incubation condition such as incubation time and the diameter of PVC tubing. Under static status, C3a, C5a and SC5b-9 concentration in the blood were higher after contacting with PVC plasticized with DEHP (PVC1) than after contacting with PVC plasticized with DINCH (PVC2). However, under dynamic circulation, the results were totally converse, which may be due to smaller diameter and higher shear rate of PVC2. In addition, there was a significant increase of activated partial thrombin time (APTT) and decrease of FIX concentration after plasma contacting with the PVC tubing, which indicated that the intrinsic pathway may be impacted when blood contacted with PVC tubing. However, there was no significant difference of APTT, FIX concentration and CD62p expression rate between the two materials. Moreover, the migration in the DINCH system was considerably lower than for DEHP, which indicates that DINCH could be a promising alterative plasticizer of DEHP. PMID- 23686354 TI - Characterisation, corrosion resistance and in vitro bioactivity of manganese doped hydroxyapatite films electrodeposited on titanium. AB - This work elucidated the corrosion resistance and in vitro bioactivity of electroplated manganese-doped hydroxyapatite (MnHAp) film on NaOH-treated titanium (Ti). The NaOH treatment process was performed on Ti surface to enhance the adhesion of the MnHAp coating on Ti. Scanning electron microscopy images showed that the MnHAp coating had needle-like apatite crystals, and the approximately 10 MUm thick layer was denser than HAp. Energy-dispersive X-ray spectroscopy analysis revealed that the MnHAp crystals were Ca-deficient and the Mn/P molar ratio was 0.048. X-ray diffraction confirmed the presence of single phase MnHAp, which was aligned vertically to the substrate. Fourier transform infrared spectroscopy indicated the presence of phosphate bands ranging from 500 to 650 and 900 to 1,100 cm(-1), and a hydroxyl band at 3,571 cm(-1), which was characteristic of HAp. Bond strength test revealed that adhesion for the MnHAp coating was more enhanced than that of the HAp coating. Potentiodynamic polarisation test showed that the MnHAp-coated surface exhibited superior corrosion resistance over the HAp single-coated surface. Bioactivity test conducted by immersing the coatings in simulated body fluid showed that MnHAp coating can rapidly induce bone-like apatite nucleation and growth. Osteoblast cellular tests revealed that the MnHAp coating was better at improving the in vitro biocompatibility of Ti than the HAp coating. PMID- 23686350 TI - International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein coupled receptor list: recommendations for new pairings with cognate ligands. AB - In 2005, the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) published a catalog of all of the human gene sequences known or predicted to encode G protein-coupled receptors (GPCRs), excluding sensory receptors. This review updates the list of orphan GPCRs and describes the criteria used by NC-IUPHAR to recommend the pairing of an orphan receptor with its cognate ligand(s). The following recommendations are made for new receptor names based on 11 pairings for class A GPCRs: hydroxycarboxylic acid receptors [HCA1 (GPR81) with lactate, HCA2 (GPR109A) with 3-hydroxybutyric acid, HCA3 (GPR109B) with 3-hydroxyoctanoic acid]; lysophosphatidic acid receptors [LPA4 (GPR23), LPA5 (GPR92), LPA6 (P2Y5)]; free fatty acid receptors [FFA4 (GPR120) with omega-3 fatty acids]; chemerin receptor (CMKLR1; ChemR23) with chemerin; CXCR7 (CMKOR1) with chemokines CXCL12 (SDF-1) and CXCL11 (ITAC); succinate receptor (SUCNR1) with succinate; and oxoglutarate receptor [OXGR1 with 2-oxoglutarate]. Pairings are highlighted for an additional 30 receptors in class A where further input is needed from the scientific community to validate these findings. Fifty-seven human class A receptors (excluding pseudogenes) are still considered orphans; information has been provided where there is a significant phenotype in genetically modified animals. In class B, six pairings have been reported by a single publication, with 28 (excluding pseudogenes) still classified as orphans. Seven orphan receptors remain in class C, with one pairing described by a single paper. The objective is to stimulate research into confirming pairings of orphan receptors where there is currently limited information and to identify cognate ligands for the remaining GPCRs. Further information can be found on the IUPHAR Database website (http://www.iuphar-db.org). PMID- 23686351 TI - Pharmacogenetics and cardiovascular disease--implications for personalized medicine. AB - The past decade has seen tremendous advances in our understanding of the genetic factors influencing response to a variety of drugs, including those targeted at treatment of cardiovascular diseases. In the case of clopidogrel, warfarin, and statins, the literature has become sufficiently strong that guidelines are now available describing the use of genetic information to guide treatment with these therapies, and some health centers are using this information in the care of their patients. There are many challenges in moving from research data to translation to practice; we discuss some of these barriers and the approaches some health systems are taking to overcome them. The body of literature that has led to the clinical implementation of CYP2C19 genotyping for clopidogrel, VKORC1, CYP2C9; and CYP4F2 for warfarin; and SLCO1B1 for statins is comprehensively described. We also provide clarity for other genes that have been extensively studied relative to these drugs, but for which the data are conflicting. Finally, we comment briefly on pharmacogenetics of other cardiovascular drugs and highlight beta-blockers as the drug class with strong data that has not yet seen clinical implementation. It is anticipated that genetic information will increasingly be available on patients, and it is important to identify those examples where the evidence is sufficiently robust and predictive to use genetic information to guide clinical decisions. The review herein provides several examples of the accumulation of evidence and eventual clinical translation in cardiovascular pharmacogenetics. PMID- 23686355 TI - Autogeneous coronoid process as free graft for reconstruction of mandibular condyle in patients with temporomandibular ankylosis. AB - OBJECTIVE: This study was conducted to determine the efficacy of using the autogeneous coronoid process as free graft for reconstruction of mandibular condyle and to achieve structural, functional, as well as esthetic rehabilitation of patients with temporomandibular joint (TMJ) ankylosis. MATERIALS AND METHODS: This article presents the clinical results of an evaluation of ten cases of TMJ ankylosis treated by using autogeneous coronoid process as free graft for reconstruction of mandibular condyle after resection of ankylotic mass. RESULTS: Satisfactory mouth opening were obtained in all ten cases. No patient showed signs of re-ankylosis at 12 months follow-up. Preoperative mouth opening ranged from 0 to 15 mm with mean being 4.8 mm. As a result of successful procedure, the immediate postoperative mouth opening increased ranging from 24 to 31 mm (mean, 26.5 mm). Follow up of patients at the first and 12th month showed good results with increase in mouth opening from a range of 24 to 31 mm (mean, 27.8 mm ) to 26 to 36 mm (mean, 33.13 mm). CONCLUSION: The results of this study suggest that the autogeneous coronoid process as free graft is a suitable graft material for reconstruction of mandibular condyle after resection of ankylotic mass. PMID- 23686356 TI - Modern management of bladder exstrophy repair. AB - The exstrophy-epispadias complex is a rare congenital malformation of the genitourinary system, abdominal wall musculature, and pelvic bones. Historically, surgical outcomes in patients with classic bladder exstrophy, the most common presentation of the exstrophy-epispadias complex, were poor. However, modern techniques have increased the success of achieving urinary continence, satisfactory cosmesis, and improved quality of life. Still, recent studies recognize complications that may occur during management of these patients. This review provides readers with an overview of the exstrophy-epispadias complex, the modern management of bladder exstrophy, and potential surgical complications. PMID- 23686357 TI - Use of buccal mucosa in hypospadias repair. AB - Hypospadias is an embryological disorder that results in an abnormal ventral positioning of the urethral meatus. Among multiple surgical techniques described to correct this anomaly, the use of buccal mucosa grafts has gained popularity among pediatric urologists, pediatric surgeons and plastic surgeons. Buccal mucosa grafts have shown favorable histological changes that result in an excellent scaffold for urethral reconstructive surgery. This review describes the evolution of the use of buccal mucosa grafts in hypospadias repair. PMID- 23686358 TI - Exact inference for adaptive group sequential designs. AB - Methods for controlling the type-1 error of an adaptive group sequential trial were developed in seminal papers by Cui, Hung, and Wang (Biometrics, 1999), Lehmacher and Wassmer (Biometrics, 1999), and Muller and Schafer (Biometrics, 2001). However, corresponding solutions for the equally important and related problem of parameter estimation at the end of the adaptive trial have not been completely satisfactory. In this paper, a method is provided for computing a two sided confidence interval having exact coverage, along with a point estimate that is median unbiased for the primary efficacy parameter in a two-arm adaptive group sequential design. The possible adaptations are not only confined to sample size alterations but also include data-dependent changes in the number and spacing of interim looks and changes in the error spending function. The procedure is based on mapping the final test statistic obtained in the modified trial into a corresponding backward image in the original trial. This is an advance on previously available methods, which either produced conservative coverage and no point estimates or provided exact coverage for one-sided intervals only. PMID- 23686359 TI - Multiple cerebral abscesses in Papillon-Lefevre syndrome. AB - Papillon-Lefevre syndrome is characterised by palmoplantar keratoderma, periodontitis and pyogenic infections. We describe the first case of brain abscess in a child with this syndrome. We highlight the importance of recognising any associated diagnosis, however rare or apparently irrelevant, in an acutely and critically ill child. PMID- 23686361 TI - Prevalence of C. perfringens in agricultural fields with different vegetation types. PMID- 23686362 TI - Signalling pathways regulating muscle mass in ageing skeletal muscle: the role of the IGF1-Akt-mTOR-FoxO pathway. AB - During ageing skeletal muscles undergo a process of structural and functional remodelling that leads to sarcopenia, a syndrome characterized by loss of muscle mass and force and a major cause of physical frailty. To determine the causes of sarcopenia and identify potential targets for interventions aimed at mitigating ageing-dependent muscle wasting, we focussed on the main signalling pathway known to control protein turnover in skeletal muscle, consisting of the insulin-like growth factor 1 (IGF1), the kinase Akt and its downstream effectors, the mammalian target of rapamycin (mTOR) and the transcription factor FoxO. Expression analyses at the transcript and protein level, carried out on well characterized cohorts of young, old sedentary and old active individuals and on mice aged 200, 500 and 800 days, revealed only modest age-related differences in this pathway. Our findings suggest that during ageing there is no downregulation of IGF1/Akt pathway and that sarcopenia is not due to FoxO activation and upregulation of the proteolytic systems. A potentially interesting result was the increased phosphorylation of the ribosomal protein S6, indicative of increased activation of mTOR complex1 (mTORC1), in aged mice. This result may provide the rationale why rapamycin treatment and caloric restriction promote longevity, since both interventions blunt activation of mTORC1; however, this change was not statistically significant in humans. Finally, genetic perturbation of these pathways in old mice aimed at promoting muscle hypertrophy via Akt overexpression or preventing muscle loss through inactivation of the ubiquitin ligase atrogin1 were found to paradoxically cause muscle pathology and reduce lifespan, suggesting that drastic activation of the IGF1-Akt pathway may be counterproductive, and that sarcopenia is accelerated, not delayed, when protein degradation pathways are impaired. PMID- 23686364 TI - Morphometry analysis of lymphatics in pulmonary adenocarcinomas with a lepidic growth pattern. AB - Lymph vessels play an important role in tumor progression. Pulmonary adenocarcinomas, accounting for half of non-small-cell lung carcinomas, compose a spectrum of histological types, exclusively or without a lepidic growth pattern (LGP) along preserved interalveolar septa. In that context, this study was designed to investigate the lymphatic vascular pattern associated with LGP and the concomitant invasive component of pulmonary adenocarcinomas. Using the D2-40 monoclonal antibody as a marker of lymphatic endothelial cells, the lymphatic vessel density (LVD) and vessel-area fraction (LVAF) were morphometrically analyzed in four adenocarcinomas in situ (AIS) and the LGP of eight invasive adenocarcinomas (LPIA), and compared with their invasive pattern (IPIA). LVD in AIS (2.1 +/- 0.7 mm(-2)) and LPIA (2.4 +/- 1 mm(-2)) were significantly lower than that in IPIA (14.9 +/- 13.6 mm(-2)) (p=0.001). Moreover, the lymphatic vascular pattern in LGP was similar to that of normal lung, with isolated small lymphatic vessels within the interalveolar septa. Our results showing the scarcity of lymphatics in LGP suggest an absence of septal lymphangiogenesis associated with the LGP pattern in lung adenocarcinomas, which could explain, at least partially, the better prognosis observed in tumors with exclusive or predominant lepidic spread compared with other subtypes. PMID- 23686363 TI - Melatonin ameliorates injury and specific responses of ischemic striatal neurons in rats. AB - Studies have confirmed that middle cerebral artery occlusion (MCAO) causes striatal injury in which oxidative stress is involved in the pathological mechanism. Increasing evidence suggests that melatonin may have a neuroprotective effect on cerebral ischemic damage. This study aimed to examine the morphological changes of different striatal neuron types and the effect of melatonin on striatal injury by MCAO. The results showed that MCAO induced striatum-related dysfunctions of locomotion, coordination, and cognition, which were remarkably relieved with melatonin treatment. MCAO induced severe striatal neuronal apoptosis and loss, which was significantly decreased with melatonin treatment. Within the outer zone of the infarct, the number of Darpp-32+ projection neurons and the densities of dopamine-receptor-1 (D1)+ and dopamine-receptor-2 (D2)+ fibers were reduced; however, both parvalbumin (Parv)+ and choline acetyltransferase (ChAT)+ interneurons were not significantly decreased in number, and neuropeptide Y (NPY)+ and calretinin (Cr)+ interneurons were even increased. With melatonin treatment, the loss of projection neurons and characteristic responses of interneurons were notably attenuated. The present study demonstrates that the projection neurons are rather vulnerable to ischemic damage, whereas the interneurons display resistance and even hyperplasia against injury. In addition, melatonin alleviates striatal dysfunction, neuronal loss, and morphological transformation of interneurons resulting from cerebral ischemia. PMID- 23686366 TI - Essential role of calcium in the infection process of broad-spectrum methicillin resistant Staphylococcus aureus bacteriophage. AB - Phage therapy presents an alternative therapeutic option in treating infections caused by methicillin-resistant Staphylococcus aureus (MRSA) strains not responding to antibiotic therapy. However, it is essential to study the role of external factors that may influence the yield and potency of phage preparations intended for use in various in vitro and in vivo studies. The present study focuses on the effects of calcium in the entire infection process of a broad spectrum lytic bacteriophage: MR-10. The presence of calcium increased the adsorption rate of the phage and also participated in the process of penetration of the phage genome into the host cytoplasm. A final concentration of 5 mM of calcium ions supplemented in soft agar during the phage titration process significantly increased the phage titer. Hence, incorporation of such divalent cations during the isolation of lytic phages active against MRSA strains and during the preparation of high-titer active phage preparations would definitely increase the isolation frequency and the final phage yield. This will contribute towards more effective phage preparations for use in treatments against MRSA infections. PMID- 23686365 TI - Diagnostic value of immunohistochemical staining of GP73, GPC3, DCP, CD34, CD31, and reticulin staining in hepatocellular carcinoma. AB - It has been reported that Golgi protein-73 (GP73), glypican-3 (GPC3), and des gamma-carboxy prothrombin (DCP) could serve as serum markers for the early detection of hepatocellular carcinoma (HCC). This study aimed to evaluate a panel of immunostaining markers (including GP73, GPC3, DCP, CD34, and CD31) as well as reticulin staining to distinguish HCC from the mimickers. Our results revealed that CD34 immunostaining and reticulin staining were highly sensitive for the diagnosis of HCC. A special immunoreaction pattern of GP73--a diffuse coarse block pattern in a perinuclear region or a concentrated cluster-like or cord-like pattern in a certain part of the cytoplasm--was observed in HCC cells, in contrast to the cytoplasmic fine-granular pattern in surrounding non-tumor cells and non-malignant nodules. This coarse-block pattern correlated significantly with less differentiated HCC. In comparison, GPC3 displayed a good advantage in diagnosing well-differentiated HCC. In our study, DCP and CD31 showed little diagnostic value for HCC as an immunostaining marker. When GP73, GPC3, and CD34 were combined, the specificity improved to 96.6%. Our findings demonstrate for the first time that the immunohistochemical panel of GP73, GPC3, and CD34 as well as reticulin staining is highly specific for the pathological diagnosis of HCC. PMID- 23686367 TI - Work environment and disability pension-- an 18-year follow-up study in a Norwegian working population. AB - AIMS: To investigate the associations between work environment indicators and health- related work disability. METHODS: A health survey of 5,749 working 40-42 year-old Norwegians from Nordland County were linked to a national register for disability pension during a follow-up of over 18 years. The risk for disability pension following various self-reported physical and psychosocial work environmental exposures (individual and cumulative) were estimated using Cox regression analysis. RESULTS: Both cumulative physical and psychosocial work environmental exposures were associated with an increased risk for disability pension, although this association was attenuated for most variables after adjusting for health and education. An increase in five poor psychosocial work environmental exposures was associated with a 22% increased risk for disability (adjusted hazard ratio, aHR, 1.22, 95% CI 1.04-1.44), whereas a similar increase in five poor physical work environmental exposures was associated with a 29% increased risk (aHR, 1.29, 95% CI 1.16-1.44). There were no indications of statistical interaction between either sex or education and work exposures. CONCLUSIONS: People who report a poor work environment are at a higher risk for subsequent work disability. This finding suggests that improving working conditions may be an area of intervention in order to reduce the number of people who leave the labour market with a disability pension. PMID- 23686368 TI - Adenosine triphosphate released from HIV-infected macrophages regulates glutamatergic tone and dendritic spine density on neurons. AB - Despite wide spread use of combination antiretroviral therapy (cART) in developed countries, approximately half of HIV-infected patients will develop impairments in cognitive function. Accumulating evidence suggests that neuronal dysfunction can be precipitated by HIV-infection of macrophages by mechanisms that involve alterations in innate and adaptive immune responses. HIV-infection of macrophages is known to increase the release of soluble neurotoxins. However, the composition of products released from infected macrophages is complex and not fully known. In this study we provide evidence that ATP and other immuno-/neuromodulatory nucleotides are exported from HIV-infected macrophages and modify neuronal structure. Supernatants collected from HIV-infected macrophages (HIV/MDM) contained large amounts of ATP, ADP, AMP and small amounts of adenosine, in addition to glutamate. Dilutions of these supernatants that were sub-threshold for glutamate receptor activation evoked rapid calcium flux in neurons that were completely inhibited by the enzymatic degradation of ATP, or by blockade of calcium permeable purinergic receptors. Applications of these highly diluted HIV/MDM onto neuronal cultures increased the amount of extracellular glutamate by mechanisms dependent on purinergic receptor activation, and downregulated spine density on neurons by mechanisms dependent on purinergic and glutamate receptor activation. We conclude from these data that ATP released from HIV-infected macrophages downregulates dendritic spine density on neurons by a mechanism that involves purinergic receptor mediated modulation of glutamatergic tone. These data suggest that neuronal function may be depressed in HIV infected individuals by mechanisms that involve macrophage release of ATP that triggers secondary effects on glutamate handling. PMID- 23686370 TI - Durable scar size reduction due to allogeneic mesenchymal stem cell therapy regulates whole-chamber remodeling. AB - BACKGROUND: Intramyocardial injection of mesenchymal stem cells (MSCs) in chronic ischemic cardiomyopathy is associated with reverse remodeling in experimental models and humans. Here, we tested the hypothesis that allogeneic MSC therapy drives ventricular remodeling by producing durable and progressive scar size reduction in ischemic cardiomyopathy. METHODS AND RESULTS: Gottingen swine (n=12) underwent left anterior descending coronary artery myocardial infarction (MI), and 3 months post-MI animals received either intramyocardial allogeneic MSC injection (200 mol/L cells; n=6) or left ventricle (LV) catheterization without injection (n=6). Swine were followed with serial cardiac magnetic resonance imaging for 9 months to assess structural and functional changes of the LV. Intramyocardial injection was performed using an integrated imaging platform combining electroanatomical mapping unipolar voltage and 3-dimensional cardiac magnetic resonance imaging angiography-derived anatomy to accurately target infarct border zone injections. MSC-treated animals had a 19.62 +/- 2.86% reduction in scar size at 3 months postinjection, which progressed to 28.09 +/- 2.31% from 3 to 6 months postinjection (P<0.0001). MSC-treated animals had unchanged end-diastolic volume (EDV; P=0.08) and end-systolic volume (ESV; P=0.28) from preinjection to 6 months postinjection, whereas controls had progressive dilatation in both EDV (P=0.0002) and ESV (P=0.0002). In addition, MSC-treated animals had improved LV sphericity index. Percentage change in infarct size correlated with percentage change in EDV (r=0.68; P=0.01) and ESV (r=0.77; P=0.001). Ejection fraction increased from 29.69 +/- 1.68% to 35.85 +/- 2.74% at 3 months post-MSC injection and progressed to 39.02 +/- 2.42% 6 months postinjection (P=0.0001), whereas controls had a persistently depressed ejection fraction during follow-up (P=0.33). CONCLUSION: Intramyocardial injection of allogeneic MSCs leads to a sustained and progressive reduction in infarct size, which in turn drives reverse remodeling and increases in ejection fraction. These findings support ongoing biological activity of cell therapy for substantial periods and suggest optimal end points for future clinical trials. PMID- 23686369 TI - Deficiency of TDAG51 protects against atherosclerosis by modulating apoptosis, cholesterol efflux, and peroxiredoxin-1 expression. AB - BACKGROUND: Apoptosis caused by endoplasmic reticulum (ER) stress contributes to atherothrombosis, the underlying cause of cardiovascular disease (CVD). T-cell death-associated gene 51 (TDAG51), a member of the pleckstrin homology-like domain gene family, is induced by ER stress, causes apoptosis when overexpressed, and is present in lesion-resident macrophages and endothelial cells. METHODS AND RESULTS: To study the role of TDAG51 in atherosclerosis, male mice deficient in TDAG51 and apolipoprotein E (TDAG51(-/-)/ApoE(-/-)) were generated and showed reduced atherosclerotic lesion growth (56 +/- 5% reduction at 40 weeks, relative to ApoE(-/-) controls, P<0.005) and necrosis (41 +/- 4% versus 63 +/- 8% lesion area in TDAG51(-/-)/ApoE(-/-) and ApoE(-/-), respectively; P<0.05) without changes in plasma levels of lipids, glucose, and inflammatory cytokines. TDAG51 deficiency caused several phenotypic changes in macrophages and endothelial cells that increase cytoprotection against oxidative and ER stress, enhance PPARgamma dependent reverse cholesterol transport, and upregulate peroxiredoxin-1 (Prdx-1), an antioxidant enzyme with antiatherogenic properties (1.8 +/- 0.1-fold increase in Prdx-1 protein expression, relative to control macrophages; P<0.005). Two independent case-control studies found that a genetic variant in the human TDAG51 gene region (rs2367446) is associated with CVD (OR, 1.15; 95% CI, 1.07 to 1.24; P=0.0003). CONCLUSIONS: These findings provide evidence that TDAG51 affects specific cellular pathways known to reduce atherogenesis, suggesting that modulation of TDAG51 expression or its activity may have therapeutic benefit for the treatment of CVD. PMID- 23686371 TI - Glucose regulation of load-induced mTOR signaling and ER stress in mammalian heart. AB - BACKGROUND: Changes in energy substrate metabolism are first responders to hemodynamic stress in the heart. We have previously shown that hexose-6-phosphate levels regulate mammalian target of rapamycin (mTOR) activation in response to insulin. We now tested the hypothesis that inotropic stimulation and increased afterload also regulate mTOR activation via glucose 6-phosphate (G6P) accumulation. METHODS AND RESULTS: We subjected the working rat heart ex vivo to a high workload in the presence of different energy-providing substrates including glucose, glucose analogues, and noncarbohydrate substrates. We observed an association between G6P accumulation, mTOR activation, endoplasmic reticulum (ER) stress, and impaired contractile function, all of which were prevented by pretreating animals with rapamycin (mTOR inhibition) or metformin (AMPK activation). The histone deacetylase inhibitor 4-phenylbutyrate, which relieves ER stress, also improved contractile function. In contrast, adding the glucose analogue 2-deoxy-d-glucose, which is phosphorylated but not further metabolized, to the perfusate resulted in mTOR activation and contractile dysfunction. Next we tested our hypothesis in vivo by transverse aortic constriction in mice. Using a micro-PET system, we observed enhanced glucose tracer analog uptake and contractile dysfunction preceding dilatation of the left ventricle. In contrast, in hearts overexpressing SERCA2a, ER stress was reduced and contractile function was preserved with hypertrophy. Finally, we examined failing human hearts and found that mechanical unloading decreased G6P levels and ER stress markers. CONCLUSIONS: We propose that glucose metabolic changes precede and regulate functional (and possibly also structural) remodeling of the heart. We implicate a critical role for G6P in load-induced mTOR activation and ER stress. PMID- 23686372 TI - Aliskiren effect on plaque progression in established atherosclerosis using high resolution 3D MRI (ALPINE): a double-blind placebo-controlled trial. AB - BACKGROUND: The renin-angiotensin system is well recognized as a mediator of pathophysiological events in atherosclerosis. The benefits of renin inhibition in atherosclerosis, especially when used in combination with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) are currently not known. We hypothesized that treatment with the renin inhibitor aliskiren in patients with established cardiovascular disease will prevent the progression of atherosclerosis as determined by high-resolution magnetic resonance imaging (MRI) measurements of arterial wall volume in the thoracic and abdominal aortas of high risk patients with preexisting cardiovascular disease. METHODS AND RESULTS: This was a single-center, randomized, double-blind, placebo-controlled trial in patients with established cardiovascular disease. After a 2-week single-blind placebo phase, patients were randomized to receive either placebo (n=37, mean +/- SD age 64.5 +/- 8.9 years, 3 women) or 150 mg of aliskiren (n=34, mean +/- SD age 63.9 +/- 11.5 years, 9 women). Treatment dose was escalated to 300 mg at 2 weeks and maintained during the remainder of the study. Patients underwent dark-blood, 3-dimensional MRI assessment of atherosclerotic plaque in the thoracic and abdominal segments at baseline and on study completion or termination (up to 36 weeks of drug or matching placebo). Aliskiren use resulted in significant progression of aortic wall volume (normalized total wall volume 5.31 +/- 6.57 vs 0.15 +/- 4.39 mm(3), P=0.03, and percentage wall volume 3.37 +/- 2.96% vs 0.97 +/ 2.02%, P=0.04) compared with placebo. In a subgroup analysis of subjects receiving ACEI/ARB therapy, atherosclerosis progression was observed only in the aliskiren group, not in the placebo group. CONCLUSIONS: MRI quantification of atheroma plaque burden demonstrated that aliskiren use in patients with preexisting cardiovascular disease resulted in an unexpected increase in aortic atherosclerosis compared with placebo. Although preliminary, these results may have implications for the use of renin inhibition as a therapeutic strategy in patients with cardiovascular disease, especially in those receiving ACEI/ARB therapy. CLINICAL TRIAL REGISTRATION: URL: http://ClinicalTrials.gov Unique identifier: NCT01417104. PMID- 23686373 TI - Improved oral bioavailability of BCS class 2 compounds by self nano-emulsifying drug delivery systems (SNEDDS): the underlying mechanisms for amiodarone and talinolol. AB - PURPOSE: Superior bioavailability of BCS Class 2 compounds incorporated into SNEDDS was previously reported. This study aims to elucidate the underlying mechanisms accountable for this phenomenon. METHODS: SNEDDS of amiodarone (AM) and talinolol were developed. Pharmacokinetic parameters were assessed in vivo. Effect on intestinal permeability, P-gp efflux and toxicity was evaluated in vitro (Caco-2) and ex vivo (Ussing). Solubilization was assessed in vitro (Dynamic Lipolysis Model). Effect on intraenterocyte metabolism was evaluated using CYP3A4 microsomes. RESULTS: Oral administration of AM-SNEDDS and talinolol SNEDDS resulted in higher and less variable AUC and Cmax. In vitro, higher talinolol-SNEDDS Papp indicated Pgp inhibition. Lipolysis of AM-SNEDDS resulted in higher AM concentration in the fraction available for absorption. Incubation of AM-SNEDDS with CYP3A4 indicated CYP inhibition. SNEDDS didn't alter mannitol Papp and TEER. SNEDDS effect was transient. CONCLUSIONS: Multiple mechanisms are accountable for improved bioavailability and reduced variability of Class-2 compounds by SNEDDS: increased solubilization, reduced intraenterocyte metabolism and reduced P-gp efflux. SNEDDS effect is reversible and doesn't cause intestinal tissue or cell damage. These comprehensive findings can be used for intelligent selection of drugs for which oral bioavailability will improve upon incorporation into SNEDDS, based on recognition of the drug's absorption barriers and the ability of SNEDDS to overcome them. PMID- 23686374 TI - Preparation, drug release, and cell growth inhibition of a gelatin: doxorubicin conjugate. AB - PURPOSE: To demonstrate the feasibility of a novel macromolecular delivery system for doxorubicin (DOX) which combines pH dependent DOX release with a high molecular weight and biodegradable gelatin carrier. METHODS: DOX was conjugated to gelatin using an acid labile hydrazone bond and a glycylglycine linker. The gelatin-doxorubicin conjugate (G-DOX) was evaluated for hydrazide and DOX content by spectrophotometry, molecular weight by HPLC-SEC, in vitro DOX release at various pH, and cell growth inhibition using EL4 mouse lymphoma and PC3 human prostate cells. RESULTS: G-DOX hydrazide and DOX content was 47% and 5-7%, respectively of theoretical gelatin carboxylic acid sites. During preparation of G-DOX, the molecular weight decreased to 22 kDa. DOX release was 48% in pH 4.8 phosphate buffer, 22% at pH 6.5, but 10% at pH 7.4. The G-DOX IC50 values in EL4 and PC3 cells were 0.26 MUM and 0.77 MUM, respectively; the latter value 3 times greater than that of free DOX. CONCLUSIONS: A 22 kDa macromolecular DOX conjugate containing 3.4-5.0% w/w DOX has been prepared. The pH dependent drug release in combination with a biodegradable gelatin carrier offer potential therapeutic advantages of enhanced tumor cell localization and reduced systemic toxicities of the drug. PMID- 23686375 TI - Co-delivery of vascular endothelial growth factor and angiopoietin-1 using injectable microsphere/hydrogel hybrid systems for therapeutic angiogenesis. AB - PURPOSE: We hypothesized that combined delivery of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) using microsphere/hydrogel hybrid systems could enhance mature vessel formation compared with administration of each factor alone. METHODS: Hybrid delivery systems composed of alginate hydrogels and poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres containing angiogenic factors were prepared. The release behavior of angiogenic factors from hybrid systems was monitored in vitro. The hybrid systems were injected into an ischemic rodent model, and blood vessel formation at the ischemic site was evaluated. RESULTS: The sustained release over 4 weeks of both VEGF and Ang-1 from hybrid systems was achieved in vitro. Co-delivery of VEGF and Ang-1 was advantageous to retain muscle tissues and significantly induced vessel enlargement at the ischemic site, compared to mice treated with either VEGF or Ang-1 alone. CONCLUSIONS: Sustained and combined delivery of VEGF and Ang-1 significantly enhances vessel enlargement at the ischemic site, compared with sustained delivery of either factor alone. Microsphere/hydrogel hybrid systems may be a promising vehicle for delivery of multiple drugs for many therapeutic applications. PMID- 23686376 TI - Bone morphogenetic protein-2 release from composite hydrogels of oligo(poly(ethylene glycol) fumarate) and gelatin. AB - PURPOSE: Hydrogel composites of oligo(poly(ethylene glycol) fumarate) (OPF) and gelatin microparticles (GMs) were investigated as carriers of bone morphogenetic protein-2 (BMP-2) for bone tissue engineering applications. METHODS: Hydrogel composites with different physical characteristics were prepared by changing the amount and type (acidic vs. basic) of gelatin incorporated in the OPF bulk phase. Composites with differing physical properties (degradation, swelling, and mechanical properties) and differing BMP-2 loading phase were investigated to determine the effect of these factors on BMP-2 release profiles over 28 days. RESULTS: Overall, higher gelatin amount increased the degradation and swelling of composites, and acidic GMs further increased the degradation and swelling and reduced the compressive modulus of the composites. The most significant factor affecting the release of BMP-2 from composites was the loading phase of the growth factor: GM loading reduced the burst release, increased BMP-2 release during the later phases of the experiment, and increased the cumulative release in faster degrading samples. CONCLUSIONS: The results indicate that the physical properties and the BMP-2 release kinetics of hydrogel composites can be controlled by adjusting multiple parameters at the time of the hydrogel composite fabrication. PMID- 23686377 TI - Effective embryoid body formation from induced pluripotent stem cells for regeneration of respiratory epithelium. AB - OBJECTIVES/HYPOTHESIS: We have previously demonstrated the potential use of induced pluripotent stem (iPS) cells for regeneration of respiratory epithelium by culturing embryoid bodies (EBs). The aim of the present study was to determine the most effective conditions for EB formation from iPS cells for regeneration of respiratory epithelium. STUDY DESIGN: Experimental study. METHODS: iPS cells cultured on a gelatin-coated dish were seeded on low-attachment plates for generating EBs. Under several conditions including the air-liquid interface (ALI) method, with varying cell numbers and suspension times, EBs were transferred to a gelatin-coated dish supplemented with growth factors. The shape, size, aggregation, and adhesion of EBs for iPS cell differentiation were evaluated, and the cultured tissue was histologically examined. RESULTS: EBs appropriate for differentiation were observed using 1,000 cells after 5 days of suspension culture. Respiratory epithelium-like tissue was histologically observed. The ciliary epithelium was confirmed immunohistologically. CONCLUSIONS: Based on the varying suspension times and cell numbers with the ALI method, this study presented effective conditions for EB formation from iPS cells for regeneration of respiratory epithelium. PMID- 23686378 TI - Brief communication: 5-HTTLPR genetic diversity and mode of subsistence in Native Americans. AB - The relationship between the "individualism-collectivism" and the serotonin transporter functional polymorphism (5-HTTLPR), suggested in the previous reports, was tested in Native South Amerindian populations. A total of 170 individuals from 21 populations were genotyped for the 5-HTTLPR alleles. For comparative purposes, these populations were classified as individualistic (recent history of hunter-gathering) or collectivistic (agriculturalists). These two groups showed an almost identical S allele frequency (75 and 76%, respectively). The analysis of molecular variance showed no structural differences between them. Behavioral typologies like those suggested by JY Chiao and KD Blizinsky (Proc R Soc B 277 () 529-537) are always a simplification of complex phenomena and should be regarded with caution. In addition, classification of a whole nation in the individualist/collectivist dichotomy is controversial. The focus on modes of subsistence in preindustrial societies, as was tested here, may be a good alternative although the postulated association between the 5-HTTLPR S allele and the collectivist societies was not confirmed. PMID- 23686379 TI - The effect of a supersaturated calcium phosphate mouth rinse on the development of oral mucositis in head and neck cancer patients treated with (chemo)radiation: a single-center, randomized, prospective study of a calcium phosphate mouth rinse + standard of care versus standard of care. AB - OBJECTIVES: Mucosal damage is an important and debilitating side effect when treating head and neck cancer patients with (chemo-)radiation. The aim of this randomized clinical trial was to investigate whether the addition of a neutral, supersaturated, calcium phosphate (CP) mouth rinse benefits the severity and duration of acute mucositis in head and neck cancer patients treated with (chemo)radiation. MATERIALS AND METHODS: A total of 60 patients with malignant neoplasms of the head and neck receiving (chemo)radiation were included in this study. Fifty-eight patients were randomized into two treatment arms: a control group receiving standard of care (n = 31) and a study group receiving standard of care + daily CP mouth rinses (n = 27) starting on the first day of (chemo )radiation. Oral mucositis and dysphagia were assessed twice a week using the National Cancer Institute common toxicity criteria scale version 3, oral pain was scored with a visual analogue scale. RESULTS: No significant difference in grade III mucositis (59 vs. 71 %; p = 0.25) and dysphagia (33 vs. 42 %, p = 0.39) was observed between the study group compared to the control group. Also no significant difference in time until development of peak mucositis (28.6 vs. 28.7 days; p = 0.48), duration of peak mucositis (22.7 vs. 24.6 days; p = 0.31), recuperation of peak dysphagia (20.5 vs 24.2 days; p = 0.13) and occurrence of severe pain (56 vs. 52 %, p = 0.5). CONCLUSION: In this randomized study, the addition of CP mouth rinse to standard of care did not improve the frequency, duration or severity of the most common acute toxicities during and early after (chemo)radiation. There is currently no evidence supporting its standard use in daily practice. PMID- 23686380 TI - Best supportive care in patients with brain metastases and adverse prognostic factors: development of improved decision aids. AB - PURPOSE: This study aimed to develop a survival prediction model that might aid decision making when choosing between best supportive care (BSC) and brain radiotherapy (RT) for patients with brain metastases and limited survival expectation. METHODS: A retrospective analysis of 124 patients treated with BSC, whole brain radiotherapy (WBRT), or radiosurgery was conducted. All patients had adverse prognostic features defined as 0-1.5 points according to the diagnosis specific graded prognostic assessment score (DS-GPA) or GPA if primary tumor type was not among those represented in DS-GPA. Kaplan-Meier survival curves were compared between patients treated with BSC or RT in different scenarios, reflecting more or less rigorous definitions of poor prognosis. If survival was indistinguishable and this result could be confirmed in multivariate analysis, BSC was considered appropriate. RESULTS: Irrespective of point sum examined, DS GPA by itself was not a satisfactory selection parameter. However, we defined a subgroup of 63 patients (51 %) with short survival irrespective of management approach (only 5 % of irradiated patients survived beyond 6 months; they had newly diagnosed, treatment-naive lung cancer), i.e., patients in whom foregoing RT was unlikely to compromise survival. These were patients with 0-1.5 points and aged >= 75 years, had Karnofsky performance status <= 50, or had uncontrolled primary tumor with extracranial metastases to at least two organs. CONCLUSIONS: BSC is a reasonable choice in patients with limited life expectancy. After successful external validation of the selection criteria developed in this analysis, identification of patients who are unlikely to benefit from WBRT might be improved. PMID- 23686381 TI - An extremophile Microbacterium strain and its protease production under alkaline conditions. AB - Extremophiles are potential resources for alkaline protease production. In order to search for alkaline protease producers, we isolated and screened alkaliphilic microorganisms from alkaline saline environments. The microorganism HSL10 was identified as a member of the genus Microbacterium by morphological observation, Gram staining and sequence analysis of the 16S rRNA gene and the 16S-23S rRNA intergenic spacer region. By colony-forming unit counting under alkali or salt stress, it was further identified as an alkaliphilic microbe with mild halotolerance. In addition, it was capable of secreting alkaline proteases, evidenced by larger hydrolyzation zones in the skim milk-containing medium at pH 9.0 than at pH 7.0. Subsequently, we demonstrated that both NaCl and yeast extract significantly promoted protease production by HSL10. Finally, we established a sensitive colorimetric method for the detection of protease production by HSL10 under neutral and alkaline conditions, by using the Bradford reagent for substrate staining to improve the contrast between the hydrolyzation zone and the substrate background on agar plates. HSL10 was the first example of an alkaliphilic protease-producing member in Microbacterium, and its isolation and characterization have both academic and commercial importance. PMID- 23686383 TI - Living arrangements and the elderly: an analysis of old-age mortality by household structure in Casalguidi, 1819-1859. AB - The elevated levels of protection, assistance, and care enjoyed by the elderly living in complex households has long been a key assumption of many family system theories. However, although this hypothesis has been demonstrated for contemporary contexts, quantitative evidence for past populations is particularly scarce, if not nonexistent. This article investigates the relationship between old-age mortality and living arrangements in a mid-nineteenth century Tuscan population, where the joint family system of sharecroppers coexisted alongside the nuclear system of day laborers. Our findings demonstrate that within complex households, the complexity of relationships, gender inequalities, and possible competition for care and resources among the most vulnerable household members namely, the elderly and the young-weakens the assumption that the elderly benefitted from lower rates of old-age mortality. PMID- 23686382 TI - Blocking of integrins inhibits HIV-1 infection of human cervical mucosa immune cells with free and complement-opsonized virions. AB - The initial interaction between HIV-1 and the host occurs at the mucosa during sexual intercourse. In cervical mucosa, HIV-1 exists both as free and opsonized virions and this might influence initial infection. We used cervical explants to study HIV-1 transmission, the effects of opsonization on infectivity, and how infection can be prevented. Complement opsonization enhanced HIV-1 infection of dendritic cells (DCs) compared with that by free HIV-1, but this increased infection was not observed with CD4(+) T cells. Blockage of the alpha4-, beta7-, and beta1-integrins significantly inhibited HIV-1 infection of both DCs and CD4(+) T cells. We found a greater impairment of HIV-1 infection in DCs for complement-opsonized virions compared with that of free virions when alphaM/beta2 and alpha4-integrins were blocked. Blocking the C-type lectin receptor macrophage mannose receptor (MMR) inhibited infection of emigrating DCs but had no effect on CD4(+) T-cell infection. We show that blocking of integrins decreases the HIV-1 infection of both mucosal DCs and CD4(+) T cells emigrating from the cervical tissues. These findings may provide the basis of novel microbicidal strategies that may help limit or prevent initial infection of the cervical mucosa, thereby reducing or averting systemic HIV-1 infection. PMID- 23686386 TI - The Effect of tumor subsite on short-term outcomes and costs of care after oral cancer surgery. AB - OBJECTIVES/HYPOTHESIS: To determine if epidemiologic differences exist between patients with oral tongue carcinoma compared to tumors arising from other oral cavity subsites, and the relationship between primary site and in-hospital mortality, postoperative complications, length of stay, and costs in patients undergoing surgery for oral cavity cancer. STUDY DESIGN: Retrospective cross sectional study. METHODS: The Nationwide Inpatient Sample was analyzed for patients who underwent an ablative procedure for a malignant oral cavity neoplasm in 2001 to 2008 using cross-tabulations and multivariate regression modeling. RESULTS: Overall, there were 45,071 patients treated surgically for oral cavity cancer, with oral tongue cancer comprising 35% of all oral cavity tumors. Patients with oral tongue cancer were significantly more likely to be female (odds ratio [OR] = 1.4) and undergo neck dissection (OR = 1.4), and significantly less likely to be black (OR = 0.4), over 40 years of age (OR = 0.4), have Medicaid payer status (OR = 0.7), advanced comorbidity (OR = 0.7), receive care at a teaching hospital (OR = 0.5), and undergo pedicled or free flap reconstruction (OR = 0.6, P < .001). Oral tongue primary site was not associated with in-hospital mortality or surgical complications, but was significantly associated with a reduced incidence of medical complications (OR = 0.8, P = .005). After controlling for all other variables, oral tongue primary site disease was associated with a significantly reduced length of hospitalization and hospital-related costs. CONCLUSIONS: Oral tongue cancer is associated with a distinct epidemiologic profile compared to other oral cavity cancer subsites, and is associated with lower postoperative morbidity, length of hospitalization, and hospital-related costs. Further investigation is warranted to determine if biologic factors underlie these observations. PMID- 23686385 TI - Fragment-based drug discovery using NMR spectroscopy. AB - Nuclear magnetic resonance (NMR) spectroscopy has evolved into a powerful tool for fragment-based drug discovery over the last two decades. While NMR has been traditionally used to elucidate the three-dimensional structures and dynamics of biomacromolecules and their interactions, it can also be a very valuable tool for the reliable identification of small molecules that bind to proteins and for hit to-lead optimization. Here, we describe the use of NMR spectroscopy as a method for fragment-based drug discovery and how to most effectively utilize this approach for discovering novel therapeutics based on our experience. PMID- 23686387 TI - Fine mechanisms of the interaction of silver nanoparticles with the cells of Salmonella typhimurium and Staphylococcus aureus. AB - Silver nanoparticles possess antibacterial effect for various bacteria; however mechanisms of the interaction between Ag-NPs and bacterial cells remain unclear. The aim of our study was to obtain direct evidence of Ag-NPs penetration into cells of Gram-negative bacterium S. typhimurium and Gram-positive bacterium S. aureus, and to study cell responses to Ag-NPs. The Ag-NPs (most 8-10 nm) were obtained by gas-jet method. S. typhimurium (7.81 * 107 CFU), or S. aureus (8.96 * 107 CFU) were treated by Ag-NPs (0.05 mg/l of silver) in orbital shaker at 190 rpm, 37 degrees C. Bacteria were sampled at 0.5, 1, 1.5, 2, 5 and 23 h of the incubation for transmission electron microscopy of ultrathin sections. The Ag-NPs adsorbed on outer membrane of S. typhimurium and cell wall of S. auereus; penetrated and accumulated in cells without aggregation and damaging of neighboring cytoplasm. In cells of S. aureus Ag-NPs bound with DNA fibers. Cell responses to Ag-NPs differed morphologically in S. typhimurium and S. aureus, and mainly were presented by damage of cell structures. The cytoplasm of S. aureus became amorphous, while S. typhimurium showed lumping and lysis of cytoplasm which led to formation of "empty" cells. Other difference was fast change of cell shape in S. typhimurium, and late deformation of S. aureus cells. The obtained results showed how different could be responses induced by the same NPs in relatively simple prokaryotic cells. Evidently, Ag-NPs directly interact with macromolecular structures of living cells and are exert an active influence on their metabolism. PMID- 23686388 TI - Giant intrasacral meningocele: a case report. AB - A peculiar case of intrasacral meningocele and spinal cord tethering is reported. Contents of the intrasacral meningocele and importance of CSF flow analyses with MRI are discussed. Demonstration of CSF flow from the thecal sac to meningocele in the CSF flow MR imaging may be helpful for determining the possibility of meningocele growth. In this report, we have presented the determination of CSF flow as a new surgical indication in this type of cases. PMID- 23686389 TI - Imaging the course of a hypoplastic cerebellum in a spina bifida newborn. AB - INTRODUCTION: We report about a spina bifida patient with myelomeningocele at the lumbar level L5, extensive Chiari malformation type II with vermal herniation reaching to C6 with downward pontine shift, and a severe hypoplastic cerebellum. Chromosomal diagnostic tests showed no abnormalities. CASE REPORT: The infant experienced severe central apneas successfully treated with oxygen therapy and caffeine medication; functional motor level was established at L5 with sparse anal sphincter function. DISCUSSION: After surgical intervention (myelomeningocele repair and ventriculoperitoneal shunt placement), these abnormalities significantly improved on radiological imaging; the preoperative hypoplastic, almost undetectable, cerebellum developed to a fair sized cerebellum. Apneas disappeared over time and the patient showed further developmental improvement. Herein, we illustrate and discuss the changes of the cerebellar volume before and after neurosurgical intervention. PMID- 23686390 TI - Rank-based principal stratum sensitivity analyses. AB - We describe rank-based approaches to assess principal stratification treatment effects in studies where the outcome of interest is only well-defined in a subgroup selected after randomization. Our methods are sensitivity analyses, in that estimands are identified by fixing a parameter and then we investigate the sensitivity of results by varying this parameter over a range of plausible values. We present three rank-based test statistics and compare their performance through simulations, and provide recommendations. We also study three different bootstrap approaches for determining levels of significance. Finally, we apply our methods to two studies: an HIV vaccine trial and a prostate cancer prevention trial. PMID- 23686391 TI - Brief communication: a midtarsal (midfoot) break in the human foot. AB - The absence of a midtarsal break has long been regarded as a derived feature of the human foot. Humans possess a rigid midfoot that acts as an efficient lever during the propulsive phase of bipedal gait. Non-human primates, in contrast, have a more mobile midfoot that is adaptive for tree climbing. Here, we report plantar pressure and video evidence that a small percentage of modern humans (n = 32/398) possess both elevated lateral midfoot pressures and even exhibit midfoot dorsiflexion characteristic of a midtarsal break. Those humans with a midtarsal break had on average a significantly flatter foot than those without. Midtarsal breakers also had significantly more medial weight transfer (pronation) during the stance phase of gait than those without this midfoot mobility. These data are in accordance with Elftman (Clin Orthop 16 (1960) 41-45) who suggested that pronation aligns the axes of the transverse tarsal joint, permitting elevated midfoot mobility. PMID- 23686392 TI - Automatic segmentation of the fetal cerebellum on ultrasound volumes, using a 3D statistical shape model. AB - Previous work has shown that the segmentation of anatomical structures on 3D ultrasound data sets provides an important tool for the assessment of the fetal health. In this work, we present an algorithm based on a 3D statistical shape model to segment the fetal cerebellum on 3D ultrasound volumes. This model is adjusted using an ad hoc objective function which is in turn optimized using the Nelder-Mead simplex algorithm. Our algorithm was tested on ultrasound volumes of the fetal brain taken from 20 pregnant women, between 18 and 24 gestational weeks. An intraclass correlation coefficient of 0.8528 and a mean Dice coefficient of 0.8 between cerebellar volumes measured using manual techniques and the volumes calculated using our algorithm were obtained. As far as we know, this is the first effort to automatically segment fetal intracranial structures on 3D ultrasound data. PMID- 23686393 TI - Ensuring PhD development of responsible conduct of research behaviors: who's responsible? AB - The importance of public confidence in scientific findings and trust in scientists cannot be overstated. Thus, it becomes critical for the scientific community to focus on enhancing the strategies used to educate future scientists on ethical research behaviors. What we are lacking is knowledge on how faculty members shape and develop ethical research standards with their students. We are presenting the results of a survey with 3,500 research faculty members. We believe this is the first report on how faculty work with and educate their PhD students on basic research standards. Specifically, we wanted to determine whether individual faculty members, who are advisors or mentors, differ in how they implemented components of responsible conduct of research (RCR) with their PhD students. Mentors were more likely than advisors or supervisors to report working with all of their PhDs, who graduated in the last 5 years, on the 17 recognized critical components of RCR training and research skill development. We also found about half of the faculty members believe RCR is an institutional responsibility versus a faculty responsibility. Less than a quarter have had opportunities to participate in faculty training to be a better mentor, advisor, or research teacher, and about one third of faculty did not or could not remember whether they had guidelines related to their responsibilities to PhD students. We discuss the implications of our findings and focus on ways that PhD research mentoring can be enhanced. PMID- 23686394 TI - Endoscopic horizon stabilization in natural orifice translumenal endoscopic surgery: a randomized controlled trial. AB - BACKGROUND: Spatial orientation in natural orifice translumenal endoscopic surgery (NOTES) has been identified as a potential barrier to clinical application. We aim to evaluate a triaxial inertial sensor and software that automatically corrects any movements on the roll axis of the flexible endoscope, allowing for stabilization of the image horizon during NOTES operations in a randomized controlled trial. METHODS: A total of 18 participants (11 surgeons/7 gastroenterologists) performed a transgastric task in the ELITE simulator, which included navigation to the appendix and gallbladder, diathermy of the appendix base and gallbladder fossa, and clipping of the cystic duct using a single channel gastroscope. Each participant performed the task twice with randomization to horizon stabilization occurring at the second attempt. The primary end point was change in overall performance (time taken and errors made) between the first and second attempt, and secondary end points were absolute performances in the second attempt and subjective evaluation. RESULTS: Without horizon stabilization, there was a median improvement of 42.4% in time taken and 38% in number of errors made from the first to the second attempt; however, with the software turned on, there was a statistically significant deterioration of 4.9% (P = .038) in time taken and an increase in errors made of 183% (P = ns). CONCLUSIONS: Although the software corrects the view to that preferred during surgery, the endoscopic control mechanism as well as the exit point of the instrument are altered in this process, leading to a deterioration of overall performance. Potential solutions include deploying intermittent horizon stabilization or using a robotic interface to achieve fully aligned perceptual-motor control. PMID- 23686395 TI - Tympanoplasty with intact canal wall mastoidectomy for cholesteatoma: long-term hearing outcomes. AB - OBJECTIVES/HYPOTHESIS: To review long-term hearing results after intact canal wall mastoidectomy with tympanoplasty for treatment of cholesteatoma and to identify factors associated with improved hearing outcomes. STUDY DESIGN: A retrospective analysis of all cases of cholesteatoma treated with intact canal wall mastoidectomy at a single institution by the senior author over a period of 9 years, for which at least 2 years of follow-up data exist. METHODS: Patient and disease information was collected retrospectively and analyzed. RESULTS: There were 148 patients with 156 affected ears treated and followed for a median of 5.3 years (interquartile range, 3.6-7.4 years). The majority of the operations (144/156, 92%) were staged. Hearing data were available for 150 ears. The overall postoperative mean air-bone gap was <= 20 dB in 64% of patients. This was maintained long term in most patients, with 59% of patients still with an air bone gap <= 20 dB at a median follow-up of 5.3 years. The presence of an intact stapes did not affect initial hearing outcomes, but the group with an intact stapes had improved long-term hearing results compared to those without an intact stapes (71% vs. 42% air-bone gap <= 20 dB, P < .001). The presence of a malleus handle also led to superior long-term hearing outcomes (72% vs. 48% air-bone gap <= 20 dB, P = .005). CONCLUSIONS: Long-term hearing results from intact canal wall mastoidectomy with tympanoplasty are excellent, with the majority of patients maintaining a small air-bone gap long term. The presence of a stapes and/or malleus handle confers improved long-term hearing outcomes. PMID- 23686396 TI - Bioequivalence for locally acting nasal spray and nasal aerosol products: standard development and generic approval. AB - Demonstrating bioequivalence (BE) for nasal spray/aerosol products for local action has been very challenging because the relationship between the drug in systemic circulation and the drug reaching the nasal site of action has not been well established. Thus, the current BE standard for these drug/device combination products is based on a weight-of-evidence approach, which contains three major elements: equivalent in vitro performance, equivalent systemic exposure, and equivalent local delivery. In addition, formulation sameness and device similarity are evidences to support BE. This paper presents a comprehensive review of the scientific rationale of the current BE standard and their development history for nasal spray/aerosol products, as well as the Food and Drug Administration's review and approval status of generic nasal sprays/aerosols with the application of these BE standard. PMID- 23686397 TI - The differential effects of acute right- vs. left-sided vestibular failure on brain metabolism. AB - The human vestibular system is represented in the brain bilaterally, but it has functional asymmetries, i.e., a dominance of ipsilateral pathways and of the right hemisphere in right-handers. To determine if acute right- or left-sided unilateral vestibular neuritis (VN) is associated with differential patterns of brain metabolism in areas representing the vestibular network and the visual vestibular interaction, patients with acute VN (right n = 9; left n = 13) underwent resting state (18)F-FDG PET once in the acute phase and once 3 months later after central vestibular compensation. The contrast acute vs. chronic phase showed signal differences in contralateral vestibular areas and the inverse contrast in visual cortex areas, both more pronounced in VN right. In VN left additional regions were found in the cerebellar hemispheres and vermis bilaterally, accentuated in severe cases. In general, signal changes appeared more pronounced in patients with more severe vestibular deficits. Acute phase PET data of patients compared to that of age-matched healthy controls disclosed similarities to these patterns, thus permitting the interpretation that the signal changes in vestibular temporo-parietal areas reflect signal increases, and in visual areas, signal decreases. These data imply that brain activity in the acute phase of right- and left-sided VN exhibits different compensatory patterns, i.e., the dominant ascending input is shifted from the ipsilateral to the contralateral pathways, presumably due to the missing ipsilateral vestibular input. The visual-vestibular interaction patterns were preserved, but were of different prominence in each hemisphere and more pronounced in patients with right-sided failure and more severe vestibular deficits. PMID- 23686398 TI - Brain structure is related to speech perception abilities in bilinguals. AB - Morphology of the human brain predicts the speed at which individuals learn to distinguish novel foreign speech sounds after laboratory training. However, little is known about the neuroanatomical basis of individual differences in speech perception when a second language (L2) has been learned in natural environments for extended periods of time. In the present study, two samples of highly proficient bilinguals were selected according to their ability to distinguish between very similar L2 sounds, either isolated (prelexical) or within words (lexical). Structural MRI was acquired and processed to estimate vertex-wise indices of cortical thickness (CT) and surface area (CSA), and the association between cortical morphology and behavioral performance was inspected. Results revealed that performance in the lexical task was negatively associated with the thickness of the left temporal cortex and angular gyrus, as well as with the surface area of the left precuneus. Our findings, consistently with previous fMRI studies, demonstrate that morphology of the reported areas is relevant for word recognition based on phonological information. Further, we discuss the possibility that increased CT and CSA in sound-to-meaning mapping regions, found for poor non-native speech sounds perceivers, would have plastically arisen after extended periods of increased functional activity during L2 exposure. PMID- 23686399 TI - Primary blood neutrophils express a functional cell surface Toll-like receptor 9. AB - Polymorphonuclear leukocytes (PMNs) represent one of the first lines of defense against pathogens. TLR9 is normally expressed in endosomes/lysosomes where it is activated by pathogen-derived DNA. Here we show that freshly isolated human and mouse primary PMNs express TLR9 at the cell surface ex vivo. Moreover, surface TLR9 expression is upregulated upon activation of PMNs with different stimuli and not only TLR9 agonists. Importantly, surface TLR9 is processed, active, and functional. TLR9 ligands, oligo-nucleotides containing unmethylated CpG motifs, indeed bind to surface TLR9 and binding was strongly observed at the cell surface of human cells expressing surface TLR9 and at the surface of WT but not TLR9 deficient mouse PMNs. Finally, CpG oligonucleotides cross-linked onto a solid phase and having no access to intracellular TLR9 are able to trigger cell surface TLR9 and induce neutrophil activation, even when endosomal acidification is inhibited. This is the first demonstration of a functional TLR9 expressed at the cell surface of human primary cells. This pathway may be triggered when pathogen derived TLR9 ligands cannot reach the endosome, offering a rescue mechanism for neutrophil activation. PMID- 23686400 TI - Antimicrobial resistance, virulence genes, and genetic lineages of Staphylococcus pseudintermedius in healthy dogs in tunisia. AB - Nasal swabs of 100 healthy dogs were obtained in 2011 in Tunisia and tested for Staphylococcus pseudintermedius recovery. Antimicrobial resistance profile and virulence gene content were determined. Multilocus-sequence-typing (MLST) and SmaI-pulsed-field gel electrophoresis (PFGE) were investigated. S. pseudintermedius was recovered in 55 of the 100 tested samples (55 %), and one isolate per sample was further studied. All 55 S. pseudintermedius isolates were susceptible to methicillin (MSSP) but showed resistance to the following antimicrobials (% resistant isolates/resistance gene): penicillin (56.4/blaZ), tetracycline (40/tetM), trimethoprim-sulfamethoxazole (23.7), fusidic acid (9), kanamycin (3.7/aph(3')-Ia), erythromycin-clindamycin (1.8/erm(B)), streptomycin (1.8/ant(6)-Ia), chloramphenicol (1.8) and ciprofloxacin (1.8). The following toxin genes were identified (% of isolates): lukS/F-I (98.2), expA (5.5), se-int (98.2), sec canine (1.8), siet (100), sea (5.5), seb (3.6), sec (10.9), sed (54.5), sei (5.5), sej (29.1), sek (3.6), ser (9.1), and hlg v (38.2). Ten different sequence-types were detected among 11 representative MSSP isolates: ST20, ST44, ST69, ST70, ST78, ST100, ST108, ST160, ST161, and ST162, the last three ones revealing novel alleles or allele combinations. Eleven different PFGE patterns were identified in these isolates. The nares of healthy dogs could be a reservoir of antimicrobial resistant and virulent MSSP, highlighting the presence of the recently described exfoliating gene expA and several enterotoxin genes. PMID- 23686401 TI - Management of adverse events in patients with hormone receptor-positive breast cancer treated with everolimus: observations from a phase III clinical trial. AB - Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved for the treatment of advanced renal cell carcinoma, pancreatic neuroendocrine tumors, subependymal giant cell astrocytoma associated with tuberous sclerosis complex, renal angiomyolipoma and tuberous sclerosis complex, and, in combination with exemestane, for hormone receptor-positive HER2-negative advanced breast cancer after failure of treatment with letrozole or anastrozole. Results from the phase III BOLERO-2 trial demonstrated that everolimus in combination with exemestane provided significant clinical benefit to patients with advanced hormone receptor positive breast cancer. Although everolimus is generally well tolerated, as with most therapies administered in an advanced cancer setting, drug-related adverse events (AEs) inevitably occur. Most common AEs observed in the everolimus studies include stomatitis, rash, infection, noninfectious pneumonitis, and hyperglycemia. Clinical awareness and early identification of such AEs by oncology nurses are essential to dosing (interruptions, reduction, and treatment discontinuation); quality of life; and, ultimately, patient outcomes. Because everolimus has already been shown to significantly improve clinical efficacy in patients with advanced breast cancer, a proactive approach to the practical management of AEs associated with this mTOR inhibitor as well as other most common AEs observed in this patient population has been reviewed and outlined here. PMID- 23686403 TI - Is paternal infant care associated with breastfeeding? A population-based study in Japan. AB - BACKGROUND: One qualitative study has reported that more paternal infant care and housework contributed to the maintenance of breastfeeding. However, few studies have quantitatively investigated these relationships. OBJECTIVE: This study aimed to examine the association of paternal involvement in infant care and housework with exclusive breastfeeding during the first 6 months of life. METHODS: Data from a population-based birth cohort study in Japan, the Longitudinal Survey of Babies in the 21st Century, were analyzed. We extracted information on infants who were singletons, term, normal birth weight, and living with both parents (n = 39 742). The associations between degree of paternal involvement in infant care and housework (high, middle, low) and breastfeeding patterns (exclusive, partial, formula only) were analyzed using ordered logistic regression adjusted for covariates. Maternal anxiety about childrearing was considered as a mediator. RESULTS: Compared with the low level of paternal infant care group, infants in the middle and high level groups were significantly less likely to have been breastfed (adjusted odds ratio: 0.90, 95% confidence interval [CI], 0.84-0.97; and 0.73, 95% CI, 0.67-0.79, respectively). In contrast, the amount of housework carried out by fathers was not associated with breastfeeding pattern. Maternal anxiety about childrearing did not attenuate the association between paternal infant care and breastfeeding. CONCLUSION: Paternal infant care was inversely associated with breastfeeding during the first 6 months of life. An additional intervention study about the importance of breastfeeding that aims to educate fathers who tend to involve themselves in infant care is needed. PMID- 23686402 TI - Docetaxel-induced skin toxicities in breast cancer patients subsequent to paclitaxel shortage: a case series and literature review. AB - PURPOSE: As the result of a recent national shortage in paclitaxel, some patients who were receiving or scheduled to receive weekly paclitaxel were converted to every 3-week (q3w) docetaxel with granulocyte colony-stimulating factor support. Our institution noted higher than expected incidence of severe skin toxicity events attributable to docetaxel during the shortage period among our breast cancer patients. In this report, we summarize the clinical course of the first five cases, review the literature surrounding docetaxel-induced skin toxicity, and offer possible prevention and treatment strategies to improve docetaxel tolerability. METHODS: The observation period for this case series was August 1 through October 21, 2011. All patients treated with docetaxel were identified from our electronic medical record. Operable stage I-III breast cancer patients who received >= 1 dose of docetaxel monotherapy at 75-100 mg/m(2) q3w were included in this study. The cases of grade 3-4 docetaxel-induced skin toxicities identified by the treating oncologists were then contacted and signed an informed consent through an Institutional Review Board-approved protocol. RESULTS: Thirty four patients met the inclusion criteria. Five patients (14.7 %) experienced grade 3 skin toxicity events attributable to docetaxel, a significantly higher rate than previously reported for docetaxel dosed at 75-100 mg/m(2). CONCLUSIONS: Docetaxel-induced dermatologic toxicity is well characterized; nonetheless, its etiology is largely unknown and evidence-based prevention and management strategies are lacking. This report shows that the use of docetaxel 75-100 mg/m(2) q3w subsequent to dose-dense doxorubicin and cyclophosphamide regimen can lead to unacceptable rate of severe skin toxicity. PMID- 23686404 TI - The association of prenatal media marketing exposure recall with breastfeeding intentions, initiation, and duration. AB - BACKGROUND: Infant formula marketing, either directly to consumers or through health care providers, may influence women's breastfeeding intentions, initiation, and duration. However, little is known about the impact of different types of media marketing on infant feeding intentions and behavior. OBJECTIVE: This study investigated whether different types of recalled prenatal media marketing exposure to formula and breastfeeding information are related to breastfeeding intentions and behavior. METHODS: Data were from the Infant Feeding Practices Study II, a longitudinal study from pregnancy through the infants' first year. Sample sizes ranged from 1384 to 2530. Negative binomial, logistic regression, and survival models were used to examine associations between recalled prenatal exposure to formula or breastfeeding information and breastfeeding intentions and behavior. RESULTS: Exposure to infant formula information from print media was associated with shorter intended duration of exclusive breastfeeding, and formula information from websites was related to lower odds of both intended and actual initiation. Exposure to breastfeeding information from websites was related to higher odds of both intended and actual initiation and longer intended duration of any breastfeeding. Breastfeeding information from print media was associated with longer duration of any breastfeeding, but information from broadcast media was associated with shorter duration of any breastfeeding. CONCLUSION: Mothers who recall exposure to formula information from print or websites are more likely to intend to use formula or to intend to use formula earlier and are less likely to initiate breastfeeding than mothers who do not recall seeing such information. PMID- 23686405 TI - Invited commentary: Persistent pain after inguinal hernia repair: what do we know and what do we need to know? PMID- 23686406 TI - Open preperitoneal mesh repair of inguinal hernias using a mesh with nitinol memory frame. AB - PURPOSE: To prospectively evaluate the use of a continuous Nitinol containing memory frame patch during a TIPP-technique in the open repair of inguinal and femoral hernias. METHODS: Over a 3-year period all consecutive adult patients that needed treatment for an inguinal or femoral hernia were treated by the TIPP repair using the Rebound Shield mesh. Intra-operatively the type and size of the hernia were evaluated according to the EHS classification, as well as the size of the mesh used. Baseline characteristics for all patients were evaluated considering age, gender, BMI and American society of Anesthesiologists score. Standard X-ray was performed to evaluate mesh position. All patients were evaluated for post-operative pain using the visual analogue scale (VAS 0-10 scale). RESULTS: In total 289 groin hernias were operated using a nitinol containing patch in 235 patients. The mean operating time was 38 min for unilateral hernias and 59 min for bilateral hernias. The median follow-up is 21.2 months (14-33 months) during which three patients died, unrelated to the groin hernia repair. At the time of re-evaluation 12 patients (5.0 %) complained of chronic pain, with a VAS score higher than 3 after 3 months (range 3-10). Two of these patients already had severe pain pre-operatively. A total of 3 recurrences (2.9 %) were noted with strong correlation with X-ray findings. CONCLUSION: A nitinol memory frame containing mesh is a valuable tool to achieve complete deployment of a large pore mesh in a TIPP repair for inguinal hernias with acceptable morbidity and a low recurrence rate. PMID- 23686407 TI - Aspergillus alliaceus, a new potential biological control of the root parasitic weed Orobanche. AB - During extensive surveys in fields heavily infested by broomrape in the Trakya Region-Turkey, a different new fungus, Aspergillus alliaceus, was isolated from the infected broomrape. It is aimed to investigate whether or not it is really a pathogen for Orobanche. The fungi was exposed to a greenhouse environment in order to assess its pathogenicity and virulence against Orobanche cernua. In addition, infection tests on Orobanche seeds were also performed under laboratory conditions. The fungus was subjected using two different methods, exposure to a liquid culture with conidial solution and a sclerotial solid culture with fungal mycelia. Cytological studies were carried out at light, TEM and SEM levels. The results show that the sclerotial solid culture with fungal mycelia quickly caused necrosis and was more effective than the other type. It also greatly diminished attachments, tubercles, and caused the emergence of shoots and an increase in the total shoot number of Orobanche. In addition, both when the fungi was exposed to both soil and used to contaminate sunflower seeds, its pathogenicity was more effective. Consequently, it was determined that A. alliaceus was an effective potential biological control of broomrape throughout its life cycle from dormant seed to mature plant. PMID- 23686408 TI - Communication between community and hospital pharmacists: impact on medication reconciliation at admission. AB - OBJECTIVE: To evaluate the non-intentional prescription discrepancies between home medication and hospital medication for in-patients, their potential clinical impact and the impact of pharmaceutical communication between community pharmacists (CP) and hospital clinical pharmacists (HCP) to prevent them. SETTING: Prospective study of 278 in-patient's files hospitalized in orthopaedic surgery + units. METHODS: After reconciliation by the HCP including patient interviews, GP prescription reviews and CP drug delivery analyses, we analysed patient files (prescription and patient chart) and we compared the administered drugs (home medication) to those that the patient should have received. We tracked the pharmaceutical intervention, the physician acceptance and the identified and avoided errors. The clinical impact of each discrepancy was evaluated by a team composed of a physician and a clinical pharmacist. MAIN OUTCOME MEASURE: Frequency of intentional and non-intentional discrepancy (NID), evaluation of NID clinical impact and rate of NID identified and corrected by the reconciliation procedure. RESULTS: 278 consecutive patients were included in the study. 1,532 prescription lines were analysed and 471 discrepancies were observed [IC95 % = (28.43; 33.00)]. Nonintentional discrepancies (NID) affected 9.2 % of prescription lines [IC95 % = (7.7; 10.6)] and 34.2 % of patients [IC95 % = (31.3; 37.1)]. Fifty-one patients (18.3 %) had at least one NID classified as potentially harmful. Sixty-nine percent of errors at admission were identified by the reconciliation procedure including data exchanges with CP. CONCLUSION: This study demonstrates the importance of drug reconciliation at patient's admission by the HCP supported by communication with the CP. PMID- 23686409 TI - Long-term tumor-free survival case of congenital embryonal tumor with various pathological components. AB - PURPOSE: Treatment strategy of malignant congenital brain tumor is controversial. We report a congenital embryonal tumor case with various pathological components. METHODS: A normally delivered male infant had an enlarged head circumference at 1 month after birth. The abnormality of the right side of the head was also noted during the routine 4-month health check. The head circumference was 45.1 cm (+2.25, SD); neurological status, however, was normal, with a pediatric GCS of 9 and body weight of 6,370 g (-0.85, SD). Magnetic resonance imaging (MRI) revealed right brain tumor whose size was 99 * 91 * 86 mm. The tumor was enhanced homogeneously with central necrosis, and the margin of the tumor was well circumscribed. RESULTS: We performed a subtotal removal of the tumor. The pathological diagnosis was meningioma (MIB-1 index was 2 %). The residual tumor gradually shrank, and we performed monthly MRI follow-up. The tumor abruptly recurred 7 months after the operation. The level of patient consciousness deteriorated, and emergency removal surgery was performed. The histological examination showed various types of embryonal components without meningioma-like parts. The pathological diagnosis was an embryonal tumor. The MIB-1 index was 48 %. One month after the second operation, dissemination of the tumor occurred at the right temporal lobe, cerebellum, and in subcutaneous tissue. Chemotherapy (vincristine, cisplatin, cyclophosphamide, and etoposide) was initiated following radiation therapy (3 Gy/day, 8*). Adjuvant therapies were effective, and no tumor recurrence was detected during 34 months follow-up. CONCLUSION: Treatment strategies for malignant indefinite diagnosed tumor need to be discussed. PMID- 23686410 TI - Accidental head trauma during care activities in the first year of life: a neurosurgical comparative study. AB - OBJECTIVES: This study aims to describe clinical-epidemiological data regarding accidental fall injuries occurring during homecare activities among children up to 1 year of age and to compare their outcomes according to the type of trauma. METHODS: We searched four different hospital databases on head injuries from 1999 to 2009. Patients recorded under the descriptors "accidental fall" and "home related" in the subtext were selected. Patients were classified into two groups: those who flipped over and fell from a changing table (n = 253) and those who fell from the bed sustaining a direct impact from the floor (n = 483). RESULTS: There was no difference between both groups with respect to age, gender, and Glasgow Coma Scale score. However, children who suffered injuries after an accidental fall from the changing table were more likely to require surgery (26/483 vs. 57/253, p < 0.0001), had a mean longer length of stay (LOS, 4 vs. 1 day), and a higher incidence of depressed skull fractures (12/483 vs. 24/253, p < 0.0001). Children with a direct impact from the floor after falling off the bed were expected to suffer from simple linear skull fractures, while those who flipped over the changing table were more likely to present facial, soft tissue, or skeletal injuries. CONCLUSIONS: Children who flipped over a changing table during their homecare activities were more likely to require surgery, showed a higher morbidity, and showed a longer LOS than those who fell down from the bed. These results probably reflect the different impact energy according to each injury mechanism. PMID- 23686411 TI - Human methicillin-sensitive Staphylococcus aureus biofilms: potential associations with antibiotic resistance persistence and surface polysaccharide antigens. AB - The development of persistent antibiotic resistance by human methicillin sensitive Staphylococcus aureus (MSSA) strains and substantial association with poly-N-acetyl glucosamine (PNAG) in biofilms is reported in this investigation. Sixteen of 31 MSSA strains under study were found to have developed resistance to one or more antibiotics, with four strains, two of which did not produce biofilms, showing resistance to cefoxitin, undetectable by mecA amplification. Antibiotic resistance displayed by 13/14 biofilm-forming S. aureus isolates remained persistent for 4 weeks prior to reverting back to the original antibiotic susceptibility, prompting a suggestion of determining antibiograms for clinical S. aureus isolates subcultured from biofilms developed in vitro as well as planktonic subcultures prepared from the site of infection. While there was correlation of antibiotic resistance with biofilm formation confirming previous reports, this is the first time that persistence of the biofilm-associated antibiotic resistance by S. aureus as planktonic cells is reported. Among the two methods used for assessment of biofilm formation, the tissue culture plate (TCP) method revealed that almost all strains were strong or moderate biofilm producers whereas only 19/31 strains were biofilm producers using the Congo Red agar (CRA) method indicating the superiority of the TCP method in detecting biofilm producers. We also observed no association between biofilm formation and major capsule types. However, substantial, although not absolute, association of biofilm formation with PNAG was observed, warranting continued identification of additional surface-associated polysaccharide and/or protein antigens associated with biofilm formation for development of an effective vaccine against S. aureus infections regardless of capsular phenotype. PMID- 23686412 TI - Development and relative validity of a new field instrument for detection of geriatric cachexia: preliminary analysis in hip fracture patients. AB - BACKGROUND: Geriatric cachexia is distinct from other age-related muscle wasting syndromes; however, detection and therefore treatment is challenging without the availability of valid instruments suitable for application in the clinical setting. This study assessed the sensitivity and specificity of a newly developed screening instrument utilising portable assessments against previously defined and commonly accepted diagnostic criteria for detection of geriatric cachexia. METHODS: Cross-sectional analyses from 71 older adults' post-surgical fixation for hip fracture were performed. The diagnostic criteria required measures of appendicular skeletal muscle index derived from dual-energy X-ray absorptiometry and anorexia assessed by <=70 % of estimated energy requirements. These assessments were replaced with mid-upper arm muscle circumference and the Simplified Nutritional Appetite Questionnaire, respectively, to create a field instrument suitable for screening geriatric cachexia. Sensitivity, specificity and positive and negative predictive values were calculated. RESULTS: The current diagnostic algorithm identified few patients as cachectic (4/71; 5.6 %). The sensitivity and specificity of the geriatric cachexia screening tool was 75 and 97 %, respectively. The screening tool had a positive predictive value of 60 % and a negative predictive value of 99 %. CONCLUSIONS: Given the unexpected prevalence of cachexia in such a vulnerable group, these results may suggest problems in operationalising of the consensus definition and diagnostic criteria. Although the application of a newly developed screening tool using portable field measures looks promising, the authors recommend additional research to identify the prevalence of geriatric cachexia, which captures all diagnostic criteria from the consensus definition. Future investigation may then be positioned to explore the predictive validity of screening tools using portable field measures, which potentially achieve higher sensitivity. PMID- 23686413 TI - Haploidentical cellular therapy in elderly patients with acute myeloid leukemia: description of its use in high risk patients. PMID- 23686415 TI - Risk factors for desaturation after tonsillectomy: analysis of 4092 consecutive pediatric cases. AB - OBJECTIVES/HYPOTHESIS: To identify clinical risk factors for oxygen desaturation in the first 24 hours post-tonsillectomy, thus permitting the identification of those patients who warrant inpatient monitoring. STUDY DESIGN: A retrospective analysis of 4092 consecutive patients undergoing tonsillectomy over a two-year period. METHODS: Detailed clinical data were recorded for all patients who desaturated in the postoperative period (n = 294) and randomly selected controls (n = 368). Univariate and multivariate analysis was performed in order to identify independent risk factors for desaturation. RESULTS: There were 294/4092 patients (7.2%) who experienced desaturations (defined as sustained saturations <90%) in the first 24 hours postoperatively (mean nadir, 78.7%). Multivariate analysis identified seven independent clinical risk factors for desaturation in the initial 24 hours post-tonsillectomy: trisomy 21, weight, coexistent cardiac disease, a coexistent syndromic diagnosis, a clinical diagnosis of obstructive sleep apnea (OSA), a coexistent neurologic diagnosis, and a prior diagnosis of pulmonary disease. A policy that admits all patients exhibiting any one of these risk factors except OSA would have identified 92% of the patients who subsequently desaturated. However, such a policy would also have required admission of 60% of the patients in our control group. CONCLUSIONS: These findings are generally consistent with the Clinical Practice Guidelines recently published by the American Academy of Otolaryngology. In a tertiary care center, it may not be possible to identify an algorithm that admits all children at risk of desaturation while permitting the discharge of a high percentage of patients. LEVEL OF EVIDENCE: 3b. PMID- 23686414 TI - Validation of the methotrexate-first strategy in patients with early, poor prognosis rheumatoid arthritis: results from a two-year randomized, double-blind trial. AB - OBJECTIVE: Methotrexate (MTX) taken as monotherapy is recommended as the initial disease-modifying antirheumatic drug for rheumatoid arthritis (RA). The purpose of this study was to examine outcomes of a blinded trial of initial MTX monotherapy with the option to step-up to combination therapy as compared to immediate combination therapy in patients with early, poor-prognosis RA. METHODS: In the Treatment of Early Rheumatoid Arthritis (TEAR) trial, 755 participants with early, poor-prognosis RA were randomized to receive MTX monotherapy or combination therapy (MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine). Participants randomized to receive MTX monotherapy stepped up to combination therapy at 24 weeks if the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) was >=3.2. RESULTS: Attrition at 24 weeks was similar in the MTX monotherapy and combination groups. Of the 370 evaluable participants in the initial MTX group, 28% achieved low levels of disease activity and did not step-up to combination therapy (MTX monotherapy group). The mean +/- SD DAS28-ESR in participants continuing to take MTX monotherapy at week 102 was 2.7 +/- 1.2, which is similar to that in participants who were randomized to immediate combination therapy (2.9 +/- 1.2). Participants who received MTX monotherapy had less radiographic progression at week 102 as compared to those who received immediate combination therapy (mean +/ SD change in modified Sharp score 0.2 +/- 1.1 versus 1.1 +/- 6.4). Participants assigned to initial MTX who required step-up to combination therapy at 24 weeks (72%) demonstrated similar DAS28-ESR values (3.5 +/- 1.3 versus 3.2 +/- 1.3 at week 48) and radiographic progression (change in modified Sharp score 1.2 +/- 4.1 versus 1.1 +/- 6.4 at week 102) as those assigned to immediate combination therapy. The results for either of the immediate combination approaches, whether triple therapy or MTX plus etanercept, were similar. CONCLUSION: These results in patients with early, poor prognosis RA validate the strategy of starting with MTX monotherapy. This study is the first to demonstrate in a blinded trial that initial MTX monotherapy with the option to step-up to combination therapy results in similar outcomes to immediate combination therapy. Approximately 30% of patients will not need combination therapy, and the 70% who will need it are clinically and radiographically indistinguishable from those who were randomized to receive immediate combination therapy. PMID- 23686417 TI - Influence of CYP2D6-genotype on tamoxifen efficacy in advanced breast cancer. AB - The influence of CYP2D6 genotype on the efficacy of tamoxifen (Tam) has been extensively analyzed in early breast cancer with conflicting results. However, there is only scarce data regarding this potential influence in advanced breast cancer (ABC). We hypothesize that Tam is more effective in patients with a functional CYP2D6 allele than in patients with impaired CYP2D6 activity. ABC patients with prior or ongoing palliative Tam treatment (20 mg/d) were eligible. Genomic DNA was extracted from blood (n = 51) and formalin-fixed, paraffin embedded tissue (n = 43). CYP2D6*2, *3, *4, *5, *6, *10, *17, *29, *41, CYP2D6 duplication and multiplication were determined in blood and CYP2D6*4 in tissue samples. Primary endpoint was progression free survival (PFS); secondary endpoints included clinical benefit (CB), and overall survival (OS). The clinical charts were retrospectively analyzed regarding survival and treatment effects. Genotyping was performed blinded and clinical data were analyzed separately. 94 patients were identified with a median age of 59 years (29-90 years). In 6 patients genotyping did not show conclusive results, therefore these patients were excluded from further analysis. Genotyping results were as follows: 1.1 % ultrarapid, 84.1 % extensive, 3.4 % intermediate, and 11.4 % poor metabolizers. Patients without any fully functional allele (IM/IM, IM/PM, PM/PM) had a significant shorter PFS and OS compared to patients with at least one functional allele (EM/EM, EM/IM, EM/PM) (PFS: p = 0.017; HR = 2.19; 95 % CI 1.15-4.18; OS: p = 0.028; HR = 2.79; 95 % CI 1.12-6.99). The CB rate was 73 % for EM-group and 38.5 % for IM + PM-group (p = 0.019). Our results show a significant influence of the CYP2D6 genotype on the efficacy of Tam in the treatment of ABC. In contrast to the adjuvant setting, the evidence in the palliative setting is congruent. CYP2D6 testing in ABC should be considered. PMID- 23686416 TI - Fulvestrant regulates epidermal growth factor (EGF) family ligands to activate EGF receptor (EGFR) signaling in breast cancer cells. AB - Estrogen receptor-alpha (ER) targeted therapies are routinely used to treat breast cancer. However, patient responses are limited by resistance to endocrine therapy. Breast cancer cells resistant to the pure steroidal ER antagonist fulvestrant (fulv) demonstrate increased activation of epidermal growth factor receptor (EGFR) family members and downstream ERK signaling. In this study, we investigated the effects of fulv on EGFR signaling and ligand regulation in several breast cancer cell lines. EGFR/HER2/HER3 phosphorylation and ERK1,2 activation were seen after 24-48 h after fulvestrant treatment in ER-positive breast cancer cell lines. 4-Hydroxy-tamoxifen and estradiol did not cause EGFR activation. Fulvestrant did not affect EGFR expression. Cycloheximide abolished the ability of fulv to activate EGFR suggesting the autocrine production of EGFR ligands might be responsible for fulvestrant induced EGFR signaling. qRT-PCR results showed fulv differentially regulated EGFR ligands; HB-EGF mRNA was increased, while amphiregulin and epiregulin mRNAs were decreased. Fulvestrant induced EGFR activation and upregulation of EGFR ligands were ER dependent since fulv treatment in C4-12, an ER-negative cell line derivative of MCF-7 cells, did not result in EGFR activation or change in ligand mRNA levels. ER downregulation by siRNA induced similar EGFR activation and regulation of EGFR ligands as fulvestrant. Neutralizing HB-EGF antibody blocked fulv-induced EGFR activation. Combination of fulv and EGFR family tyrosine kinase inhibitors (erlotinib and lapatinib) significantly decreased EGFR signaling and cell survival. In conclusion, fulvestrant-activated EGFR family members accompanied by ER dependent upregulation of HB-EGF within 48 h. EGF receptor or ligand inhibition might enhance or prolong the therapeutic effects of targeting ER by fulvestrant in breast cancer. PMID- 23686418 TI - The effect of geniglossal advancement on airway flow using a computational flow dynamics model. AB - OBJECTIVES/HYPOTHESIS: Obstructive sleep apnea (OSA) is a sleep disorder caused by partial or complete collapse of the pharyngeal airway. Genioglossal advancement (GGA) is a well-tolerated surgical procedure intended to address hypopharyngeal collapse, yet there are few studies that monitor changes in airflow dynamics at this site. Computation fluid dynamics (CFD) utilizes airflow simulation to predict changes in airflow after anatomic manipulation. STUDY DESIGN: We investigated the change in volume and airflow dynamics of the pharyngeal airway after GGA in a cadaveric model. METHODS: We performed serial GGA from 1 mm (control) to 3, 7, and 9 mm on a lightly preserved cadaver. After each intervention, we performed high-resolution computed tomography scans, reconstructed the pharyngeal airway, and quantified airspace volume and CFD analysis with both laminar and large eddy simulation models. RESULTS: Airway volume increased with linear GGA. In both CFD simulation models, velocity increased and pressure decreased after 9-mm advancement secondary to increased airway diameter and less abrupt changes in airway geometry. CONCLUSIONS: These results suggest that GGA may be effective in increasing airway volume and flow to address hypopharyngeal obstruction in OSA. PMID- 23686419 TI - Vacuolar transport of the medicinal alkaloids from Catharanthus roseus is mediated by a proton-driven antiport. AB - Catharanthus roseus is one of the most studied medicinal plants due to the interest in their dimeric terpenoid indole alkaloids (TIAs) vinblastine and vincristine, which are used in cancer chemotherapy. These TIAs are produced in very low levels in the leaves of the plant from the monomeric precursors vindoline and catharanthine and, although TIA biosynthesis is reasonably well understood, much less is known about TIA membrane transport mechanisms. However, such knowledge is extremely important to understand TIA metabolic fluxes and to develop strategies aimed at increasing TIA production. In this study, the vacuolar transport mechanism of the main TIAs accumulated in C. roseus leaves, vindoline, catharanthine, and alpha-3',4'-anhydrovinblastine, was characterized using a tonoplast vesicle system. Vindoline uptake was ATP dependent, and this transport activity was strongly inhibited by NH4(+) and carbonyl cyanide m chlorophenyl hydrazine and was insensitive to the ATP-binding cassette (ABC) transporter inhibitor vanadate. Spectrofluorimetry assays with a pH-sensitive fluorescent probe showed that vindoline and other TIAs indeed were able to dissipate an H(+) gradient preestablished across the tonoplast by either vacuolar H(+)-ATPase or vacuolar H(+)-pyrophosphatase. The initial rates of H(+) gradient dissipation followed Michaelis-Menten kinetics, suggesting the involvement of mediated transport, and this activity was species and alkaloid specific. Altogether, our results strongly support that TIAs are actively taken up by C. roseus mesophyll vacuoles through a specific H(+) antiport system and not by an ion-trap mechanism or ABC transporters. PMID- 23686420 TI - The sugar-dependent1 lipase limits triacylglycerol accumulation in vegetative tissues of Arabidopsis. AB - There has been considerable interest recently in the prospect of engineering crops to produce triacylglycerol (TAG) in their vegetative tissues as a means to achieve a step change in oil yield. Here, we show that disruption of TAG hydrolysis in the Arabidopsis (Arabidopsis thaliana) lipase mutant sugar dependent1 (sdp1) leads to a substantial accumulation of TAG in roots and stems but comparatively much lower TAG accumulation in leaves. TAG content in sdp1 roots increases with the age of the plant and can reach more than 1% of dry weight at maturity, a 50-fold increase over the wild type. TAG accumulation in sdp1 roots requires both ACYL-COENZYME A:DIACYLGLYCEROL ACYLTRANSFERASE1 (DGAT1) and PHOSPHATIDYLCHOLINE:DIACYLGLYCEROL ACYLTRANSFERASE1 and can also be strongly stimulated by the provision of exogenous sugar. In transgenic plants constitutively coexpressing WRINKLED1 and DGAT1, sdp1 also doubles the accumulation of TAG in roots, stems, and leaves, with levels ranging from 5% to 8% of dry weight. Finally, provision of 3% (w/v) exogenous Suc can further boost root TAG content in these transgenic plants to 17% of dry weight. This level of TAG is similar to seed tissues in many plant species and establishes the efficacy of an engineering strategy to produce oil in vegetative tissues that involves simultaneous manipulation of carbohydrate supply, fatty acid synthesis, TAG synthesis, and also TAG breakdown. PMID- 23686422 TI - Fostering interprofessional learning in a rehabilitation setting: development of an interprofessional clinical learning unit. AB - PURPOSE: The development and implementation of interprofessional (IP) clinical learning units as a method to enhance IP clinical education and improve patient care in a rehabilitation setting are described. METHODS: Using a community-based participatory research approach, academia and healthcare delivery agencies formed a partnership to create an IP clinical learning unit in a rehabilitation setting. Preimplementation data from surveys and focus group data identified areas for improvement to enhance IP understanding and collaboration. A working group developed and implemented initiatives to enhance IP practice. FINDINGS: Preimplementation, eight themes emerged from which the working group identified goals and implemented strategies to strengthen IP learning. Goals included Creation of an IP Learning Environment, Increased Awareness of IP Practice, Role Clarification, Enhanced IP Communication, and Reflection and Evaluation. Postimplementation data revealed six themes: Communication, Informal IP Learning, Role Awareness, Positive Learning Environment, Logistics, and Challenges. CONCLUSIONS: The development of the IP clinical learning unit was successful and rewarding, but not without its challenges. Formal IP education was necessary to enhance collaborative practice, even in a multidisciplinary environment. Commitment and support from all participants, particularly managers and administrators from the healthcare agency, were critical to success. CLINICAL RELEVANCE: The focus of this unit was on a stroke rehabilitation unit; however, the development and implementation principles identified may be applicable to any team-based clinical setting. PMID- 23686421 TI - Redox modulation of plant developmental regulators from the class I TCP transcription factor family. AB - TEOSINTE BRANCHED1-CYCLOIDEA-PROLIFERATING CELL FACTOR1 (TCP) transcription factors participate in plant developmental processes associated with cell proliferation and growth. Most members of class I, one of the two classes that compose the family, have a conserved cysteine at position 20 (Cys-20) of the TCP DNA-binding and dimerization domain. We show that Arabidopsis (Arabidopsis thaliana) class I proteins with Cys-20 are sensitive to redox conditions, since their DNA-binding activity is inhibited after incubation with the oxidants diamide, oxidized glutathione, or hydrogen peroxide or with nitric oxide producing agents. Inhibition can be reversed by treatment with the reductants dithiothreitol or reduced glutathione or by incubation with the thioredoxin/thioredoxin reductase system. Mutation of Cys-20 in the class I protein TCP15 abolished its redox sensitivity. Under oxidizing conditions, covalently linked dimers were formed, suggesting that inactivation is associated with the formation of intermolecular disulfide bonds. Inhibition of class I TCP protein activity was also observed in vivo, in yeast (Saccharomyces cerevisiae) cells expressing TCP proteins and in plants after treatment with redox agents. This inhibition was correlated with modifications in the expression of the downstream CUC1 gene in plants. Modeling studies indicated that Cys-20 is located at the dimer interface near the DNA-binding surface. This places this residue in the correct orientation for intermolecular disulfide bond formation and explains the sensitivity of DNA binding to the oxidation of Cys-20. The redox properties of Cys-20 and the observed effects of cellular redox agents both in vitro and in vivo suggest that class I TCP protein action is under redox control in plants. PMID- 23686424 TI - Editorial: molecular endocrinology articles in the spotlight for June 2013. PMID- 23686423 TI - Macrophages in T cell/histiocyte rich large B cell lymphoma strongly express metal-binding proteins and show a bi-activated phenotype. AB - Abundant macrophage infiltration in tumors often correlates with a poor prognosis. T cell/histiocyte rich large B cell lymphoma (THRLBCL) is a distinct aggressive B cell lymphoma entity showing a high macrophage content. To further elucidate the role of tumor-associated macrophages in THRLBCL, we performed gene expression profiling of microdissected histiocyte subsets of THRLBCL, nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), Piringer lymphadenitis, sarcoidosis, nonspecific lymphadenitis and monocytes from peripheral blood. In a supervised principal component analysis, histiocytes from THRLBCL were most closely related to epithelioid cells from NLPHL, with both types of cells expressing genes related to proinflammatory and regulatory macrophage activity. Moreover, histiocytes from THRLBCL strongly expressed metal-binding proteins like MT2A, by which histiocytes of THRLBCL can be distinguished from the other histiocyte subsets investigated. Interestingly, the validation at the protein level showed a strong expression of TXN, CXCL9, MT2A and SOD2 not only in macrophages of THRLBCL but also in the tumor cells of NLPHL and classical Hodgkin lymphoma (cHL). Overall, the present findings indicate that macrophages in the microenvironment of THRLBCL have acquired a distinct gene expression pattern that is characterized by a mixed M1/M2 phenotype and a strong expression of several metal binding proteins. The microenvironments in NLPHL and THRLBCL appear to have a similar influence on the macrophage phenotype. The high expression of metal binding proteins in histiocytes of THRLBCL may be diagnostically useful, but a potential pathophysiological role remains to be identified. PMID- 23686426 TI - Guest editorial: Perioperative pain management in orthopaedic surgery: editorial comment. PMID- 23686427 TI - Is there a role for knee arthrodesis with modular endoprostheses for tumor and revision of failed endoprostheses? AB - BACKGROUND: Knee arthrodeses are performed to treat infection after arthroplasty and tumors requiring extensive soft tissue resection. Many techniques have been described, but most have important disadvantages. Currently, endoprosthetic arthrodesis implants are available, but little is known about them. QUESTIONS/PURPOSES: Our objective was to analyze a series of knee arthrodeses with a modular prosthetic system to evaluate (1) survivorship of the implant, (2) complications, (3) whether survivorship differed between arthrodeses done for primary tumor resection and revision reconstructions, and (4) whether survivorship differed based on the presence of previous infection or the use of a gastrocnemius flap. METHODS: We present 32 patients with modular knee arthrodeses; arthrodeses were performed in 25 patients with tumors and in seven patients without tumors. There were 14 implants done at the time of tumor resection and 18 for revision of failed implants. Survivorship and complications were analyzed with Kaplan-Meier curves. Log-rank test was used for comparison between primary and revision implants, not infected and previously infected implants, and use or nonuse of a gastrocnemius flap. RESULTS: Survivorship of arthrodeses with modular endoprostheses was 50% and 25% at 5 and 10 years, respectively. There were nine infections (29%) and one implant fracture (3%). Amputation as final surgery was required in 8 patients (six owing to infection and two to oncologic failures). There was no significant difference in survivorship between arthrodeses done for primary tumor resection and as a salvage procedure for failed implants. No differences were found between patients with and without prior infection or with and without a gastrocnemius flap. CONCLUSIONS: Survivorship of a modular arthrodesis implant was 50% at 5 years owing to a high complication rate. Infection is the most common cause of failure of oncologic and revision implants. Implant fracture is a rare occurrence. Modular segmental arthrodesis provides a stable construct for patients in whom limb preservation is possible but a hinged device is contraindicated as a result of major muscle resection. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 23686428 TI - Is premorbid glenoid anatomy altered in patients with glenohumeral osteoarthritis? AB - BACKGROUND: Restoration of native, premorbid glenoid anatomy may be a goal in component placement during total shoulder arthroplasty. However, if patients with unilateral glenohumeral osteoarthritis are predisposed to the development of arthritis owing to abnormal native glenoid anatomy, this recommendation may be inappropriate. QUESTIONS/PURPOSES: The purpose of this study was to determine if patients with glenohumeral osteoarthritis have abnormal premorbid glenoid version or inclination, thereby predisposing them to subsequent glenoid disorders. We specifically tested whether: (1) premorbid glenoid version or inclination in the pathologic shoulder of patients with unilateral osteoarthritis, as determined by the glenoid vault model, is different from glenoid version or inclination in the contralateral nonpathologic shoulder of these patients; (2) there are differences between glenoid version or inclination in normal cadaver shoulders and the nonpathologic side of patients with unilateral osteoarthritis; and (3) there are differences between glenoid version or inclination in normal cadaver shoulders and the premorbid glenoid version and inclination in the pathologic shoulder of patients with unilateral osteoarthritis, as determined by the glenoid vault model. METHODS: Bilateral CT scans were obtained in 27 patients with unilateral glenohumeral osteoarthritis. Thirty normal cadaver control shoulders also underwent CT scans. Premorbid glenoid version and inclination in the pathologic shoulder, as measured by the glenoid vault model, were compared with the contralateral nonpathologic shoulder and the normal cadaver control shoulders. Glenoid version and inclination of the normal shoulders were compared with the nonpathologic side from patients with unilateral osteoarthritis. Measurements were made by two different methods using three-dimensional surgical simulation software: (1) a direct measurement technique and (2) measurements derived from placement of a glenoid vault model. Mean differences in these parameters were compared between shoulder groups using paired and unpaired Student's t-tests. RESULTS: Premorbid glenoid version and inclination in the pathologic shoulder as measured by the vault model averaged -7 degrees (SD, 5) and 10 degrees (SD, 6), respectively, compared with -7 degrees (SD, 5) and 12 degrees (SD, 6) as directly measured on the nonpathologic side, and -7 degrees (SD, 4) and 12 degrees (SD, 5) as directly measured in the normal cadaver control shoulders. There were no differences in glenoid version or inclination between the normal shoulders and the nonpathologic side of patients with unilateral osteoarthritis or between these shoulders and the premorbid version and inclination of the arthritic shoulder as measured by the vault model. CONCLUSIONS: Patients with glenohumeral osteoarthritis do not appear to have abnormal premorbid glenoid retroversion or inclination. The glenoid vault model can be used to determine premorbid glenoid version and inclination. CLINICAL RELEVANCE: The glenoid vault model may be a clinically useful tool to estimate patient-specific premorbid glenoid anatomy, which may help in preoperative or intraoperative surgical planning for total shoulder arthroplasty. PMID- 23686429 TI - Nuclear FAK: a new mode of gene regulation from cellular adhesions. AB - Focal adhesion kinase (FAK) is a protein tyrosine kinase (PTK) crucial in regulation of cell migration and proliferation. In addition to its canonical roles as a cytoplasmic kinase downstream of integrin and growth factor receptor signaling, recent studies revealed new aspects of FAK action in the nucleus. Nuclear FAK promotes p53 and GATA4 degradation via ubiquitination, resulting in enhanced cell proliferation and reduced inflammatory responses. FAK can also serve as a co-transcriptional regulator that alters a gene transcriptional activity. These findings established a new paradigm of FAK signaling from cellular adhesions to the nucleus. Although physiological stimuli for controlling FAK nuclear localization have not been completely characterized, FAK shuttles from focal adhesions to the nucleus to directly convey extracellular signals. Interestingly, nuclear translocation of FAK becomes prominent in kinase-inhibited conditions such as in de-adhesion and pharmacological FAK inhibition, while a small fraction of nuclear FAK is observed a normal growth condition. In this review, roles of nuclear FAK in regulating transcription factors will be discussed. Furthermore, a potential use of a pharmacological FAK inhibitor to target nuclear FAK function in diseases such as inflammation will be emphasized. PMID- 23686430 TI - Curcumin induces apoptosis in human colorectal carcinoma (HCT-15) cells by regulating expression of Prp4 and p53. AB - Curcumin (diferuloylmethane), the yellow pigment of turmeric, is one of the most commonly used and extensively studied phytochemicals due to its pleiotropic effects in several human cancers. In the current study, the therapeutic efficacy of curcumin was investigated in human colorectal carcinoma HCT-15 cells. Curcumin inhibited HCT-15 cells proliferation and induced apoptosis in a dose- and time dependent manner. Hoechst 33342 and DCFHDA staining revealed morphological and biochemical features of apoptosis as well as ROS generation in HCT-15 cells treated with 30 and 50 MUM curcumin. Over-expression of pre-mRNA processing factor 4B (Prp4B) and p53 mutations have been reported as hallmarks of cancer cells. Western blot analysis revealed that curcumin treatment activated caspase-3 and decreased expression of p53 and Prp4B in a time-dependent manner. Transfection of HCT-15 cells with Prp4B clone perturbed the growth inhibition induced by 30 MUM curcumin. Fractionation of cells revealed increased accumulation of Prp4B in the nucleus, following its translocation from the cytoplasm. To further evaluate the underlying mechanism and survival effect of Prp4B, we generated siRNA-Prp4B HCT15 clones. Knockdown of Prp4B with siRNA diminished the protective effects of Prp4B against curcumin-induced apoptosis. These results suggest a possible underlying molecular mechanism in which Prp4B over-expression and activity are closely associated with the survival and regulation of apoptotic events in human colon cancer HCT-15 cells. PMID- 23686431 TI - Wif1 hypermethylation as unfavorable prognosis of non-small cell lung cancers with EGFR mutation. AB - Lung cancer is a leading cause of cancer-related mortality across the world and tobacco smoking is the major risk factor. The Wnt signaling pathway is known to be involved in smoke-induced tumorigenesis in the lung. Promoter hypermethylation of Wnt inhibitory factor 1 (Wif1) has become a common event in a number of human tumors. Using a methylation-specific PCR, hypermethylation of the Wif1 gene promoter was evaluated in 139 primary nonsmall cell lung cancers (NSCLCs) and its correlation with clinicopathological and prognostic parameters was evaluated. Methylation of Wif1 was observed in 47.5% and 20.9% of neoplastic and adjacent normal lung tissues, respectively. Its methylation rate tended to be higher in stage I than stages II-IIIA. Results of Kaplan-Meier analysis showed no significant difference in overall survival according to Wif1 methylation status. However, Wif1 methylation showed an association with unfavorable prognosis of adenocarcinoma (AC) patients with EGFR mutation. According to our current findings, Wif1 promoter methylation is an early, frequent event as an epigenetic field manner and could be considered as a useful prognostic marker for AC patients with EGFR mutation. Further investigation into the therapeutic potential of this finding is warranted. PMID- 23686432 TI - In-house zinc SAD phasing at Cu Kalpha edge. AB - De novo zinc single-wavelength anomalous dispersion (Zn-SAD) phasing has been demonstrated with the 1.9 A resolution data of glucose isomerase and 2.6 A resolution data of Staphylococcus aureus Fur (SaFur) collected using in-house Cu Kalpha X-ray source. The successful in-house Zn-SAD phasing of glucose isomerase, based on the anomalous signals of both zinc ions introduced to crystals by soaking and native sulfur atoms, drove us to determine the structure of SaFur, a zinc-containing transcription factor, by Zn-SAD phasing using in-house X-ray source. The abundance of zinc-containing proteins in nature, the easy zinc derivatization of the protein surface, no need of synchrotron access, and the successful experimental phasing with the modest 2.6 A resolution SAD data indicate that inhouse Zn-SAD phasing can be widely applicable to structure determination. PMID- 23686433 TI - Angiopoietin-1 elicits pro-inflammatory responses in monocytes and differentiating macrophages. AB - The angiopoietin/Tie2 system is an important regulator of angiogenesis and inflammation. In addition to its functions in endothelial cells, Tie2 expression on non-endothelial cells allows for angiopoietin ligands to stimulate the cells. Although Ang1 is a strong Tie2 receptor agonist, little is known regarding the effect of Ang1 on non-endothelial cells, such as monocytes and macrophages. In this study, we found that Ang1 functionally binds to and stimulates monocytes via p38 and Erk1/2 phosphorylation. Ang1-mediated monocyte stimulation is associated with proinflammatory cytokine TNF-alpha expression. We also determined that Ang1 switched macrophage differentiation toward a pro-inflammatory phenotype, even in the presence of an anti-inflammatory mediator. These findings suggest that Ang1 plays a role in stimulating pro-inflammatory responses and could provide a new strategy by which to manage inflammatory responses. PMID- 23686435 TI - Outpatient parenteral antimicrobial therapy for the treatment of methicillin susceptible Staphylococcus aureus: a comparison of cefazolin and ceftriaxone. AB - PURPOSE: Although the antistaphylococcal penicillins remain the drugs of choice for methicillin-susceptible Staphylococcus aureus (MSSA) infections, cefazolin and ceftriaxone are often prescribed due to their less frequent dosing and reduced cost. The purpose of this study was to compare clinical outcomes and adverse events in patients receiving outpatient parenteral antimicrobial therapy (OPAT) with ceftriaxone or cefazolin for the treatment of MSSA infections. METHODS: A retrospective study was carried out of 122 patients evaluated at Ben Taub and Lyndon B. Johnson General Hospitals in Houston, Texas, between January 1, 2006, and March 31, 2012, with a documented MSSA infection who received cefazolin or ceftriaxone as OPAT. A favorable clinical outcome was determined by their primary care physician's assessment at follow-up in the clinic. RESULTS: Out of 122 patients, 78 (64 %) were treated with cefazolin and 44 (36 %) with ceftriaxone. Patients were predominantly young (median age 46 years), male (54.2 %), and Hispanic (51.2 %). Patients were similar in terms of baseline demographics, types of infections, and management of infections. Favorable clinical outcomes were similar between cefazolin and ceftriaxone (67.9 versus 79.8 %, p = 0.17), along with a similar incidence of adverse events and complications (5.1 versus 2.3 %, p = 0.65, and 26.9 versus 18.2 %, p = 0.38, respectively). CONCLUSIONS: OPAT with either cefazolin or ceftriaxone is similar in terms of favorable outcomes, adverse events, and complications when treating MSSA infections. A randomized clinical trial is needed in order to confirm these results. PMID- 23686436 TI - Subgaleal recurrence of craniopharyngioma of rapid growing pattern. AB - The purpose of the present clinical case is to remind clinicians that craniopharyngiomas, which are benign neoplasms with a high incidence of local recurrences, may also present ectopic recurrences which may at first go unsuspected. These tumors most commonly arise in the suprasellar region and despite their benign histology, they may infiltrate the surrounding neurovascular structures making total removal challenging. Ectopic recurrences of craniopharyngiomas are very rare. We describe an adult patient with ectopic recurrence of craniopharyngioma, emphasizing unique features of the case presentation and its physiopathological aspects. A 49-year-old male presented with headache and visual field defect and was diagnosed with a suprasellar tumor. He was submitted to neurosurgery and histological examination revealed an adamantinomatous craniopharyngioma. Postoperative magnetic resonance imaging (MRI) showed complete tumor resection. The patient remained asymptomatic with no imaging signs of local recurrence during follow up. Five years after surgery, the patient noticed a rapidly growing lump at the surgical incision site. He reported a mild to moderate local trauma 4 months before. A MRI showed a subgaleal cystic tumor arising in the pathway of the craniotomy. Surgical resection of that cystic lesion was performed and histological examination revealed an adamantinomatous craniopharyngioma. One year later no recurrences have been detected. The case reported has two particular features: the local trauma as a potential trigger for tumor progression and the rapidly growing pattern of the ectopic recurrent tumor. We emphasize that although ectopic recurrences of craniopharyngiomas are rare, they may occur away from the primary tumor and quite late in the follow up of the patient. PMID- 23686434 TI - The role of dimerisation and nuclear transport in the Hes1 gene regulatory network. AB - Hes1 is a member of the family of basic helix-loop-helix transcription factors and the Hes1 gene regulatory network (GRN) may be described as the canonical example of transcriptional control in eukaryotic cells, since it involves only the Hes1 protein and its own mRNA. Recently, the Hes1 protein has been established as an excellent target for an anti-cancer drug treatment, with the design of a small molecule Hes1 dimerisation inhibitor representing a promising if challenging approach to therapy. In this paper, we extend a previous spatial stochastic model of the Hes1 GRN to include nuclear transport and dimerisation of Hes1 monomers. Initially, we assume that dimerisation occurs only in the cytoplasm, with only dimers being imported into the nucleus. Stochastic simulations of this novel model using the URDME software show that oscillatory dynamics in agreement with experimental studies are retained. Furthermore, we find that our model is robust to changes in the nuclear transport and dimerisation parameters. However, since the precise dynamics of the nuclear import of Hes1 and the localisation of the dimerisation reaction are not known, we consider a second modelling scenario in which we allow for both Hes1 monomers and dimers to be imported into the nucleus, and we allow dimerisation of Hes1 to occur everywhere in the cell. Once again, computational solutions of this second model produce oscillatory dynamics in agreement with experimental studies. We also explore sensitivity of the numerical solutions to nuclear transport and dimerisation parameters. Finally, we compare and contrast the two different modelling scenarios using numerical experiments that simulate dimer disruption, and suggest a biological experiment that could distinguish which model more faithfully captures the Hes1 GRN. PMID- 23686437 TI - The spread of the J Project. AB - The J Project physician education and clinical research collaboration program was launched in 2004 in Eastern and Central Europe (ECE). In less than 10 years, it has achieved remarkable success. This project aims to increase knowledge in the field of primary immunodeficiency disorders (PID), and to improve the diagnosis and treatment of patients worldwide, particularly in countries with limited economic resources, which currently report fewer such patients than expected. In most ECE countries, gene sequencing, which can provide a definitive diagnosis of PID, still remains unavailable. By contrast, such technology is used elsewhere to detect the more than 200 PID-causing genes that have been discovered in the last three decades. Thus, PID awareness programs like the J Project remain critically important, to improve diagnostic facilities and treatment and to promote clinical research collaboration. This paper highlights the achievements of the J Project and the spread of its concepts and spirit to the countries of Western Asia. PMID- 23686438 TI - Isolation and characterization of siderophore producing antagonistic rhizobacteria against Rhizoctonia solani. AB - Plant protection through siderophore producing rhizobacteria (SPR) has emerged as a sustainable approach for crop health management. In present study, 220 bacteria isolated from tomato rhizosphere were screened for in vitro antagonistic activity against Rhizoctonia solani AG-4. Nine potent antagonistic strains viz., Alcaligenes sp. (MUN1, MB21, and MPF37), Enterobacter sp. (MPM1), Pseudomonas sp. (M10A and MB65), P. aeruginosa (MPF14 and MB123) and P. fluorescens (MPF47) were identified on the basis of physiological characters and 16S rDNA sequencing. These strains were able to produce hydrolytic enzymes, hydrogen cyanide, indole acetic acid, although, only few strains were able to solubilize phosphate. Two strains (MB123 and MPF47) showed significant disease reduction in glasshouse conditions were further evaluated under field conditions using three different application methods. Application of P. fluorescens (MPF47) in nursery as soil mix + seedling root treatments prior to transplantation resulted in significant disease reduction compared to control. Total chlorophyll and available iron were significantly higher in the MPF47 treated plants in contrast to infected control. In conclusion, siderophore producing bacteria MPF47 have strong biocontrol abilities and its application as soil mix + seedling root treatments provided strong shield to plant roots against R. solani and could be used for effective bio-management of pathogen. PMID- 23686439 TI - p16(INK4a) immunoprofiles of squamous lesions of the uterine cervix-implications for the reclassification of atypical immature squamous metaplasia. AB - p16(INK4a) immunoprofiles of non-precancerous and dysplastic squamous cervical lesions were defined and applied to the reclassification of atypical immature squamous metaplasia (AIM). The immunoexpression of cytokeratin 17 (CK 17) in AIM was also evaluated. Totally, 295 cervical cone biopsies representing squamous metaplasia, reactive changes, koilocytosis, flat condyloma, CIN I, CIN II, CIN III and AIM were subjected to p16(INK4a) immunohistochemistry. AIM cases were analyzed using CK 17 antibody. Typical p16(INK4a) immunoprofiles for the metaplastic, LSIL/HPV and HSIL phenotypes were recorded and used for the categorization of AIM into particular phenotype groups. Results were correlated with CK 17 immunoexpression. All CIN II and CIN III lesions, all but one case of CIN I and all flat condylomas overexpressed p16(INK4a). Other non-precancerous lesions, including koilocytosis, were predominantly negative. Contrary to the sporadic and focal immunostaining, diffuse positivity was associated with the dysplastic features of the lesion. CIN II and CIN III were characterized by a diffuse, strong/weak, full-thickness staining, whereas CIN I showed a heterogeneous diffuse/focal, weak/strong, lower half positivity. One third of AIM lesions may be reclassified as HSIL, one third as LSIL/HPV and one third shows metaplastic phenotype. All AIM cases with metaplastic and LSIL/HPV phenotypes expressed CK 17 diffusely, whereas focal positivity slightly prevailed in AIM with HSIL phenotype. We conclude that p16(INK4a) immunohistochemistry is a supporting method for the differential diagnosis of cervical lesions, which may be especially useful for the reclassification of AIM. The efficacy of CK 17 immunohistochemistry seems to be controversial for these purposes. PMID- 23686440 TI - The preclinical phase of rheumatoid arthritis: what is acknowledged and what needs to be assessed? PMID- 23686441 TI - Prospective cohort study on television viewing time and incidence of lung cancer: findings from the Japan Collaborative Cohort Study. AB - PURPOSE: To ascertain whether prolonged television viewing time was associated with lung cancer incidence in Japanese adults aged 40-79 years from a nationwide large-scale cohort study. METHODS: A total of 54,258 adults (23,090 men and 31,168 women) without a history of cancer at baseline (1988-1990) were enrolled and followed for a median of 15.6 years. The Cox proportional hazard model was used to calculate hazard ratios (HRs) and 95 % confidence interval (CI) for lung cancer according to television viewing time adjusted for age and other possible confounding factors. RESULTS: During the study period, 798 participants were diagnosed with lung cancer. The HR of male participants who watched television for more than 4 h daily was 1.36 (95 % CI 1.04-1.80) compared with <2 h/day. CONCLUSION: Our findings suggest that reducing the amount of time spent watching television may be beneficial for preventing lung cancer. PMID- 23686442 TI - Dietary intake of B vitamins and methionine and breast cancer risk. AB - PURPOSE: We investigated prospectively the relationship between dietary intakes of methionine and B vitamins associated with one-carbon metabolism and breast cancer risk, including modification by age, hormone receptor status and alcohol consumption. Interactions between different B vitamins and methionine were also examined. METHODS: During follow-up of 20,756 women from the Melbourne Collaborative Cohort Study for an average of 16 years, we ascertained 936 incident breast cancers. Dietary intakes were estimated using a 121-item food frequency questionnaire. Hazard ratios (HR) and 95 % confidence intervals were estimated using Cox regression. RESULTS: We found weak evidence for an inverse association between breast cancer risk and riboflavin intake (fourth versus first quartile, HR Q4 vs. Q1 = 0.84 (0.69, 1.01); p linear trend = 0.05) and a positive association for vitamin B12 (HR Q4 vs. Q1 = 1.21 (1.00, 1.46); p linear trend = 0.06). We did not find any significant interactions between alcohol consumption and any of the B vitamins or methionine intake (all p interaction > 0.17) or between methionine or folate intake and any other B vitamins (all p interaction > 0.07). No association varied by tumor hormone receptor status (all p homogeneity > 0.14). CONCLUSIONS: We found weak evidence of an inverse association between breast cancer risk and riboflavin intake and a positive association with vitamin B12. PMID- 23686443 TI - Hypertrophic pyloric stenosis in premature infants: evaluation of sonographic criteria and short-term outcomes. AB - PURPOSE: To examine the sonographic measurements of pyloric muscle and pyloric thickness in premature infants with hypertrophic pyloric stenosis (HPS) and to correlate these measurements with patients variables. We aimed also to evaluate the clinical features and short-term outcome of HPS in premature compared to term infants. METHODS: The medical notes and the pyloric ultrasounds of all premature infants (<37 weeks) admitted to the Neonatal Surgical Unit with HPS over a 20 year period (1990-2010) were retrospectively reviewed. Sonographic measurements of the pyloric length, muscle thickness and the pyloric ratio (muscle thickness divided by pyloric diameter) were correlated to weight at presentation, duration of symptoms and corrected gestational age. Multiple regression and correlation analysis was carried out. RESULTS: Seventy-five preterm infants were identified (51M:24F). Median gestational age was 34 weeks. Median weight at presentation was 2.74 kg. Forty-two had an ultrasound (US) before surgery, 37 measurements were analysed. Pyloric length, muscle thickness and pyloric ratio were not affected by weight at presentation (p = 0.67, p = 0.122, p = 0.849), corrected gestational age (CGA) (p = 0.921, p = 0.678, p = 0.076), or duration of symptoms (p = 0.827, p = 0.268, p = 0.281). Mean length of stay was 6 days and overall complication rate was 27 %, both higher than reported in term infants (p < 0.001). CONCLUSIONS: Premature infants with HPS have a higher female preponderance than expected. Ultrasound measurements in premature infants with HPS are not affected by weight, corrected gestational age or duration of symptoms. In addition, they have a longer hospital stay and increased complication rate compared to term infants. PMID- 23686444 TI - Botulism-induced unilateral submandibular sialoadenitis: a case report. PMID- 23686445 TI - Significance of expression of ITGA5 and its splice variants in acute myeloid leukemia: a report from the Children's Oncology Group. AB - Acute myeloid leukemia (AML) encompasses a heterogeneous group of diseases, and novel biomarkers for risk refinement and stratification are needed to optimize patient care. To identify novel risk factors, we performed transcriptome sequencing on 68 diagnostic AML samples and identified 2 transcript variants (-E2 and -E2/3) of the alpha-subunit (ITGA5) of the very late antigen-5 integrin. We then quantified expression of ITGA5 and these splice variants in specimens from participants of the AAML03P1 trial. We found no association between ITGA5 expression and clinical outcome. In contrast, patients with the highest relative expression (Q4) of the -E2/3 ITGA5 splice variant less likely had low-risk disease than Q1-3 patients (21% vs. 38%, P = 0.027). Q4 patients had worse response to chemotherapy with a higher proportion having persistent minimal residual disease (50% vs. 23%, P = 0.003) and inferior overall survival (at 5 years: 48% vs. 67%, P = 0.015); the latter association was limited to low-risk patients (Q4 vs. Q1-3: 56% vs. 85%, P = 0.043) and was not seen in standard-risk (51% vs. 60%, P = 0.340) or high-risk (33% vs. 38%, P = 0.952) patients. Our exploratory studies indicate that transcriptome sequencing is useful for biomarker discovery, as exemplified by the identification of ITGA5 -E2/3 splice variant as potential novel adverse prognostic marker for low-risk AML that, if confirmed, could serve to further risk-stratify this patient subset. PMID- 23686446 TI - Swallowing kinematics and airway protection after palatal local anesthesia in infant pigs. AB - OBJECTIVES/HYPOTHESIS: Abnormal kinematics during swallowing can result in aspiration, which may become life threatening. We tested the role of palatal sensation in the motor control of pharyngeal swallow in infants. STUDY DESIGN: In eight infant pigs, we reduced palatal sensation using local anesthesia (PLA) and measured the impact on swallowing kinematics and airway protection. METHODS: The pigs drank milk containing barium while we simultaneously recorded videofluoroscopy and electromyography from fine wire bipolar electrodes in several hyolaryngeal muscles. We compared these results to control feedings and feedings following palatal saline injections. RESULTS: After PLA, four pigs had extreme jaw movements and abnormal tongue movement uncharacteristic of sucking. For this reason, we evaluated differences between these group B pigs and the others that could suck normally after PLA (group A). In the four group A pigs, after PLA there was less hyoid elevation (P < .001) but normal jaw and tongue movements. In group B, in addition to greater jaw movement (P < .001) there was more anterior and superior tongue movement (P < .001) and a larger range of hyoid movement (P < .001). CONCLUSIONS: The airway was protected in all of the pigs, indicating that these changes allowed successful adaptation to the reduction in palatal sensation. However, the oral and pharyngeal phases of the swallow were functionally linked, and trigeminal sensation influenced the motor control of the pharyngeal swallow. LEVEL OF EVIDENCE: N/A. PMID- 23686447 TI - Characterization of MHC class II B polymorphism in bottlenecked New Zealand saddlebacks reveals low levels of genetic diversity. AB - The major histocompatibility complex (MHC) is integral to the vertebrate adaptive immune system. Characterizing diversity at functional MHC genes is invaluable for elucidating patterns of adaptive variation in wild populations, and is particularly interesting in species of conservation concern, which may suffer from reduced genetic diversity and compromised disease resilience. Here, we use next generation sequencing to investigate MHC class II B (MHCIIB) diversity in two sister taxa of New Zealand birds: South Island saddleback (SIS), Philesturnus carunculatus, and North Island saddleback (NIS), Philesturnus rufusater. These two species represent a passerine family outside the more extensively studied Passerida infraorder, and both have experienced historic bottlenecks. We examined exon 2 sequence data from populations that represent the majority of genetic diversity remaining in each species. A high level of locus co-amplification was detected, with from 1 to 4 and 3 to 12 putative alleles per individual for South and North Island birds, respectively. We found strong evidence for historic balancing selection in peptide-binding regions of putative alleles, and we identified a cluster combining non-classical loci and pseudogene sequences from both species, although no sequences were shared between the species. Fewer total alleles and fewer alleles per bird in SIS may be a consequence of their more severe bottleneck history; however, overall nucleotide diversity was similar between the species. Our characterization of MHCIIB diversity in two closely related species of New Zealand saddlebacks provides an important step in understanding the mechanisms shaping MHC diversity in wild, bottlenecked populations. PMID- 23686448 TI - Linking theory with qualitative research through study of stroke caregiving families. AB - PURPOSE: This theoretical article outlines the deliberate process of applying a qualitative data analysis method rooted in Friedemann's Framework of Systemic Organization through the study of a web-based education and support intervention for stroke caregiving families. METHODS: Directed by Friedemann's framework, the analytic method involved developing, refining, and using a coding rubric to explore interactive patterns between caregivers and care recipients from this 3 month feasibility study using this education and support intervention. Specifically, data were gathered from the intervention's web-based discussion component between caregivers and the nurse specialist, as well as from telephone caregiver interviews. FINDINGS AND CONCLUSIONS: A theoretical framework guided the process of developing and refining this coding rubric for the purpose of organizing data; but, more importantly, guided the investigators' thought processes, allowing them to extract rich information from the data set, as well as synthesize this information to generate a broad understanding of the caring situation. PMID- 23686449 TI - Using microRNA profiling in urine samples to develop a non-invasive test for bladder cancer. AB - Current standard methods used to detect and monitor bladder urothelial cell carcinoma (UCC) are invasive or have low sensitivity. The incorporation into clinical practice of a non-invasive tool for UCC assessment would enormously improve patients' quality of life and outcome. This study aimed to examine the microRNA (miRNA) expression profiles in urines of UCC patients in order to develop a non-invasive accurate and reliable tool to diagnose and provide information on the aggressiveness of the tumor. We performed a global miRNA expression profiling analysis of the urinary cells from 40 UCC patients and controls using TaqMan Human MicroRNA Array followed by validation of 22 selected potentially diagnostic and prognostic miRNAs in a separate cohort of 277 samples using a miRCURY LNA qPCR system. miRNA-based signatures were developed by multivariate logistic regression analysis and internally cross-validated. In the initial cohort of patients, we identified 40 and 30 aberrantly expressed miRNA in UCC compared with control urines and in high compared with low grade tumors, respectively. Quantification of 22 key miRNAs in an independent cohort resulted in the identification of a six miRNA diagnostic signature with a sensitivity of 84.8% and specificity of 86.5% (AUC = 0.92) and a two miRNA prognostic model with a sensitivity of 84.95% and a specificity of 74.14% (AUC = 0.83). Internal cross validation analysis confirmed the accuracy rates of both models, reinforcing the strength of our findings. Although the data needs to be externally validated, miRNA analysis in urine appears to be a valuable tool for the non-invasive assessment of UCC. PMID- 23686451 TI - Surgical anatomy of human soft palate. AB - OBJECTIVES/HYPOTHESIS: The soft palate is composed of several muscles. So far, these muscles have been analyzed separately and the whole structure of the soft palate has been described very vaguely. The purpose of this study was to describe the structure of soft palate collectively. STUDY DESIGN: Human cadaver dissection. METHODS: Anatomical dissection was performed on 20 Korean, formalin fixed cadavers (13 men and 7 women). The heads were randomly assigned to either dissection groups, medial-to-lateral (10 heads) or posterior-to-anterior (10 heads). RESULTS: Fibro-fatty layer was located in the oral side of the soft palate and became thick and dense along the midline. The levator veli palatini was distributed on the nasal side of the soft palate. The average vertical distance from the top of palatopharyngeal arch to the levator veli palatini was 12.3 +/- 5.2 mm. The palatopharyngeus was also spread out widely and filled the palatopharyngeal arch. The periosteum of the hard palate became the fascia of the soft palate, which was merged with the aponeurosis of the tensor veli palatini in the midline. The Passavant's ridge was located between the levator veli palatini and palatopharyngeus, inserting onto the aponeurosis. The palatoglossus was very thin and embedded in the palatoglossal arch. CONCLUSION: The muscles of the soft palate are intermingled with each other in the fibro-fatty layer. Comprehensive anatomical knowledge is needed to reduce unnecessary damage and obtain good surgical results for obstructive sleep apnea. PMID- 23686450 TI - The rice OsDIL gene plays a role in drought tolerance at vegetative and reproductive stages. AB - Drought is one of the critical factors limiting reproductive yields of rice and other crops globally. However, little is known about the molecular mechanism underlying reproductive development under drought stress in rice. To explore the potential gene function for improving rice reproductive development under drought, a drought induced gene, Oryza sativa Drought-Induced LTP (OsDIL) encoding a lipid transfer protein, was identified from our microarray data and selected for further study. OsDIL was primarily expressed in the anther and mainly responsive to abiotic stresses, including drought, cold, NaCl, and stress related plant hormone abscisic acid (ABA). Compared with wild type, the OsDIL overexpressing transgenic rice plants were more tolerant to drought stress during vegetative development and showed less severe tapetal defects and fewer defective anther sacs when treated with drought at the reproductive stage. The expression levels of the drought-responsive genes RD22, SODA1, bZIP46 and POD, as well as the ABA synthetic gene ZEP1 were up-regulated in the OsDIL-overexpression lines but the ABA degradation gene ABAOX3 was down-regulated. Moreover, overexpression of OsDIL lessened the down-regulation by drought of anther developmental genes (OsC4, CYP704B2 and OsCP1), providing a mechanism supporting pollen fertility under drought. Overexpression of OsDIL significantly enhanced drought resistance in transgenic rice during reproductive development, while showing no phenotypic changes or yield penalty under normal conditions. Therefore, OsDIL is an excellent candidate gene for genetic improvement of crop yield in adaption to unfavorable environments. PMID- 23686452 TI - Surgical airways for trauma patients in an emergency surgical setting: 11 years' experience at a teaching hospital in Japan. AB - PURPOSE: Airway management of trauma patients during emergency surgeries can be very difficult and presents a challenge for anesthesiologists. Difficult airways are associated with emergency surgical airways (ESA), but little is known about ESA in the operating room. We conducted this study to clarify the present use of ESA for trauma patients in emergency surgery settings. METHODS: We performed a retrospective review of all trauma patients requiring emergency surgery under general anesthesia at our hospital from January 2002 to December 2012, focusing on ESA. RESULTS: During the study period, 15,654 trauma patients were treated at our hospital, of whom 554 (3.5 %) required emergency surgery. Four of these patients (0.72 %) received ESA as definitive airway management. Two patients with severe facial injury and distorted upper airways and 1 patient with penetrating neck trauma received open standard tracheostomy (OST). These three patients received OST as the initial approach to intubation. A fourth OST was performed after several unsuccessful attempts at endotracheal intubation. No cases were classified as "cannot ventilate, cannot intubate" (CVCI), and there were no complications associated with ESA. All cases had good outcomes. Statistical analysis revealed that patients with severe facial trauma (Abbreviated Injury Scale >=3) received ESA at a significantly higher rate than others (p = 0.015, odds ratio 14.1). CONCLUSION: One of the most important functions of anesthesiologists is risk management. We should recognize risks that can cause CVCI situations, and make proper clinical decisions, including providing ESA, to assure patient safety. PMID- 23686453 TI - Original antigenic sin in dengue revisited. PMID- 23686455 TI - Adrenal cortical adenoma arising from an adrenohepatic union. AB - Although the observation of an adrenohepatic union is not a rare occurrence during autopsies, cases associated with this clinical entity are rarely described. We report a case with an adrenal cortical adenoma arising from adrenohepatic union tissue in a patient with a past history of a liver mass. PMID- 23686454 TI - Unbalanced estrogen metabolism in thyroid cancer. AB - Well-differentiated thyroid cancer most frequently occurs in premenopausal women. Greater exposure to estrogens may be a risk factor for thyroid cancer. To investigate the role of estrogens in thyroid cancer, a spot urine sample was obtained from 40 women with thyroid cancer and 40 age-matched controls. Thirty eight estrogen metabolites, conjugates and DNA adducts were analyzed by using ultraperformance liquid chromatography/tandem mass spectrometry and the ratio of adducts to metabolites and conjugates was calculated for each sample. The ratio of depurinating estrogen-DNA adducts to estrogen metabolites and conjugates significantly differed between cases and controls (p < 0.0001), demonstrating high specificity and sensitivity. These findings indicate that estrogen metabolism is unbalanced in thyroid cancer and suggest that formation of estrogen DNA adducts might play a role in the initiation of thyroid cancer. PMID- 23686456 TI - Content analyses of a priori qualitative phantom limb pain descriptions and emerging categories in mid-southerners with limb loss. AB - PURPOSE: The purposes of this descriptive study were (a) to identify the relative frequencies of a priori categories of phantom limb pain (PLP) quality descriptors reported by Mid-Southerners with limb loss, (b) to analyze their descriptions for emerging categories of PLP, and (c) to identify the relative frequencies of the emerging categories. DESIGN: This cross-sectional descriptive verbal survey assessed PLP descriptors. A content analyses determined relative frequencies of a priori PLP descriptors as well as emerging categories that were identified. FINDINGS: The most common a priori PLP quality descriptors reported by 52 amputees with PLP were intermittent, tingling/needles/numb, sharp, cramping, burning, and stabbing. The most common emerging categories reported were pain compared to illness/injury, electrical cyclical, and manipulated/positional. CONCLUSION: The detailed descriptions of PLP provide insight into the vivid experiences of PLP. CLINICAL RELEVANCE: Rehabilitation nurses can use this information with PLP assessment, patient teaching, and counseling. PMID- 23686457 TI - Ultrastructure of the male genital tract, spermatogenesis and spermatozoa of Hattena cometis Domrow (Acari: Gamasida: Ameroseiidae). AB - The ameroseiid mite Hattena cometis has a male genital system that consists of an unpaired, u-shaped testis and paired deferent ducts leading into an unpaired accessory genital gland and ejaculatory duct. The genital opening is located anteriorly immediately in front of the sternal shield. Spermatogenesis is simple, probably due to the haploid nature of the male. Eight stages of spermatogenesis could be roughly distinguished. Mature spermatozoa as found in the deferent duct lumen are peculiar in having a bisected nucleus and numerous peripheral flat chambers, which were formed from indentations of the plasmalemma. In inseminated females, spermatozoa were observed in the syncytial tissue of the sperm access system and in the somatic cells of the ovary. These spermatozoa have achieved a new structure, i.e., an electron-dense plate dividing the cell into two unequal halves. The dense plate has an intricate substructure. Its function is unknown. These sperm cells are considered to represent capacitated spermatozoa. The peripheral chambers are reduced in number inside the female. Similar sperm cells, containing a dense plate, were seen in vacuoles within the epithelium of the deferent duct of one male. These cells are evidently under destruction, but before being completely dissolved had undergone a development leading beyond that of the mature sperm cells found in the deferent duct. Apparently, entering the cell of the deferent duct epithelium or the syncytium tissue triggers the production of the dense plate (or the capacitation process). Our observations are compared with results obtained from other anactinotrichid Acari, mainly Gamasida, and confirm and complete the interpretation of the correlated evolution of components of gamasid reproductive systems. PMID- 23686458 TI - Incidence and antibiotic susceptibility of genital mycoplasmas in sexually active individuals in Hungary. AB - The aim of this study was to examine the incidence and antibiotic sensitivity of Ureaplasma urealyticum and Mycoplasma hominis strains cultured from the genital discharges of sexually active individuals who attended our STD outpatient service. Samples were taken with universal swab (Biolab(r), Budapest, Hungary) into the Urea-Myco DUO kit (Bio-Rad(r), Budapest, Hungary) and incubated in ambient air for 48 h at 37 degrees C. The determination of antibiotic sensitivity was performed in U9 and arginin broth using the SIR Mycoplasma kit (Bio-Rad(r), Budapest, Hungary) under the same conditions. Between 01.05.2008 and 31.12.2011, 373/4,466 (8.35 %) genito-urethral samples with U. urealyticum and 41/4,466 (0.91 %) genito-urethral samples with M. hominis infection were diagnosed in sexually active individuals in the National STD Center, Semmelweis University. U. urealyticum was isolated in 12.54 % in the cervix and 4.1 % in the male urethra, while M. hominis was isolated in 1.33 % in the cervix and 0.51 % in the male urethra. The affected age group was between 21 and 60 years old. U. urealyticum strains were sensitive to tetracycline (95.9 %), doxycycline (97.32 %), and azithromycin (85.79 %), and resistant to erythromycin (81.23 %), clindamycin (75.06 %), and ofloxacin (25.2 %). Cross-resistance occurred in 38.71 % of patients to erythromycin and clindamycin. M. hominis strains were sensitive to clindamycin, ofloxacin, and doxycycline in more than 95 %, to tetracycline in 82.92 %, and no cross-resistance was detected among the antibiotics. Our study confirms that the continuously changing antibiotic resistance of ureaplasmas and mycoplasmas should be followed at least in a few centers in every country, so as to determine the best local therapy options for sexually transmitted infection (STI) patients. PMID- 23686459 TI - Multilocus sequences confirm the close genetic relationship of four phytoplasmas of peanut witches'-broom group 16SrII-A. AB - Four witches'-broom diseases associated with Arachis hypogaea (peanut), Crotalaria pallida, Tephrosia purpurea, and Cleome viscosa were observed in Hainan Province, China during field surveys in 2004, 2005, and 2007. In previously reported studies, we identified these four phytoplasmas as members of subgroup 16SrII-A, and discovered that their 16S rRNA gene sequences were 99.9 100% identical to one another. In this study, we performed extensive phylogenetic analyses to elucidate relationships among them. We analyzed sequences of the 16S rRNA gene and rplV-rpsC, rpoB, gyrB, dnaK, dnaJ, recA, and secY combined sequence data from two strains each of the four phytoplasmas from Hainan province, as well as strains of peanut witches'-broom from Taiwan (PnWB-TW), "Candidatus Phytoplasma australiense", "Ca. Phytoplasma mali AT", aster yellows witches' broom phytoplasma AYWB, and onion yellows phytoplasma OY-M. In the 16S rRNA phylogenetic tree, the eight Hainan strains form a clade with PnWB-TW. Analysis of the seven concatenated gene regions indicated that the four phytoplasmas collected from Hainan province cluster most closely with one another, but are closely related to PnWB-TW. The results of field survey and phylogenetic analysis indicated that Cr. pallida, T. purpurea, and Cl. viscosa may be natural plant hosts of peanut witches'-broom phytoplasma. PMID- 23686460 TI - Comparison of high-resolution MRI with CT angiography and digital subtraction angiography for the evaluation of middle cerebral artery atherosclerotic steno occlusive disease. AB - Intracranial atherosclerotic disease is increasingly recognized as a major stroke subtype worldwide. Current diagnostic evaluation of atherosclerotic disease of the middle cerebral artery (MCA) relies on detection of stenoses with luminographic imaging studies that do not directly visualize plaque unlike high resolution MRI. This retrospective study seeks to evaluate the accuracy of high resolution MRI vessel wall imaging, computed tomographic angiography (CTA) and digital subtraction angiography (DSA) in measuring the degree of stenosis within the MCA. 28 recently symptomatic patients with MCA territory symptoms underwent preliminary imaging with CTA followed by high-resolution MRI at 3-Tesla and definitive imaging with DSA for detection of M1 territory steno-occlusive lesions. Measurements of MCA segments on MRI and CTA were compared with reference to DSA values. Sensitivity and specificity of high-resolution MRI vessel wall imaging, CTA using maximum intensity projection (MIP) and CTA using volume rendering (VR) for the detection of stenosis > 50 % and occlusion were 80.0 and 53.6 %, 72.2 and 72.7 %, and 77.8 and 18.2 %, respectively. MRI-derived values correlated better with DSA (Spearman R = 0.68, p < 0.01) than CTA MIP and VR (Spearman R = 0.45, 0.22; p = 0.02, 0.24, respectively). High-resolution MRI of the MCA is capable of accurately measuring the degree of stenosis and is more sensitive than CTA in a sample of high-risk, symptomatic patients. This study, combined with previous reports, supports the potential of morphological MRI to measure intracranial atherosclerotic plaque non-invasively. PMID- 23686461 TI - Pigments accumulation via light and oxygen in Rhodobacter capsulatus strain XJ-1 isolated from saline soil. AB - A Rhodobacter capsulatus strain, designated XJ-1, isolated from saline soil, accumulated almost only one kind of bacteriochlorophyll a anaerobically in the light, aerobically in the light and dark, and the relative contents of the bacteriochlorophyll a were 44.61, 74.89, and 77.53% of the total pigments, respectively. A new purple pigment appeared only in aerobic-light grown cells, exhibited absorption maxima at 355, 389, 520, 621, and 755 nm, especially distinctly unusual peak at 621 nm, whereas vanished in anaerobic-light and in aerobic-dark culture. Spheroidene and OH-spheroidene predominated in anaerobic phototrophic cultures. Spheroidenone was the sole carotenoid when exposed to both light and oxygen. The second keto-carotenoids, OH-spheroidenone, presented only in aerobic-dark culture in addition to spheroidenone. Strain XJ-1 would be a good model organism for the further illustration of the regulation of bacteriochlorophyll biosynthesis gene expression in response to unique habitat. PMID- 23686463 TI - The feasibility of a holistic wellness program for HIV/AIDS patients residing in a voluntary inpatient treatment program. AB - The purpose of this project was to examine the feasibility of an ongoing holistic wellness program in a residential facility treating persons with HIV/AIDS. The goal was to create a voluntary, four week holistic wellness intensive within the established inpatient behavioral health treatment program. Participants were given practicable holistic self care tools to effectively manage HIV related symptoms, general medical issues, addiction, depression, stress and anxiety. The program incorporated evidence-based holistic activities including yoga, therapeutic dance, meditation, Reiki, and reflective journaling. Narrative survey results and post-program evaluation support that an ongoing holistic wellness program within the existing treatment model is feasible and could have numerous potential beneficial effects. This project clearly exemplified the ideal opportunity for holistic nurses to implement innovative holistic interventions within the current healthcare delivery system. It is the author's observation that future studies with a larger participant group to further examine measurable benefits can lend valuable information and insight into the future development of holistic wellness programs for residential treatment facilities. PMID- 23686462 TI - Angiotensin receptor blockers and risk of prostate cancer among United States veterans. AB - To address concerns regarding increased risk of prostate cancer (PrCA) among angiotensin receptor blocker (ARB) users, we used national retrospective data from the Department of Veterans Affairs (VA) through the Veterans Affairs Informatics and Computing Infrastructure. We identified a total of 543,824 unique Veterans who were classified into either ARB treated or not-treated in 1:15 ratio. The two groups were balanced using inverse probability of treatment weights. A double-robust cox-proportional hazards model was used to estimate the hazard ratio for PrCA incidence. To evaluate for a potential Gleason score stage migration, we conducted weighted Cochrane-Armitage test. Post weighting, the rates of PrCA in treated and not-treated groups were 506 (1.5%) and 8,269 (1.6%), respectively; representing a hazard ratio of (0.91, p-value .049). There was no significant difference in Gleason scores between the two groups. We found a small, but statistically significant, reduction in the incidence of clinically detected PrCA among patients assigned to receive ARB with no countervailing effect on degree of differentiation (as indicated by Gleason score). Findings from this study support Food and Drug Administration's recent conclusion that ARB use does not increase risk of incident PrCA. PMID- 23686464 TI - Energy dialogue technique in healing and health: relieving side effects and thyroid dysfunction in a male with hemophilia receiving pegylated interferon and ribavirin treatment for hepatitis C virus--an anecdotal case study. AB - This article describes the use of energy dialogue technique (EDT), a healing intervention that provides awareness of imbalances in the energetic field that affect patients' health and guide the practitioner to sense and direct the frequency, vibration, intention, awareness, or consciousness to correct these imbalances. The authors document the effectiveness of this technique as it was used to treat side effects of the medical intervention for hepatitis C in a male with hemophilia. Following EDT, the client's symptoms of fatigue and pain improved by 30% to 40%; moreover, thyroid function returned to normal. The authors suggest that EDT be studied and explored for inclusion as a treatment modality. PMID- 23686465 TI - The journey of discovering compassionate listening. AB - This article presents the concept of "compassionate listening" in critical life moments to gain insight into the process of listening with compassion. This insight evolved through a process of layered reflection using a series of texts, particularly stories that captured critical moments in working with people who were facing crisis situations or who were dying. Writing and reflecting on these stories enabled me to identify how I engaged with patients and their loved ones as a palliative care nurse specialist. I was able to explore how compassionate listening could be used to ascertain their needs, particularly when they were unable or unsure of how to proceed. PMID- 23686466 TI - Long-term efficacy of adalimumab after drug withdrawal and retreatment in patients with active non-radiographically evident axial spondyloarthritis who experience a flare. PMID- 23686467 TI - Modulation of aphid alarm pheromone emission of pea aphid prey by predators. AB - Recent studies on animal alarm signaling have shown that alarm calls generally are not uniform, but may vary depending on the type and intensity of threat. While alarm call variability has been studied intensively in birds and mammals, little is known about such variation in insects. We investigated variability in alarm signaling in aphids, group-living insect herbivores. Under attack, aphids release droplets containing a volatile alarm pheromone, (E)-beta-farnesene (EBF), that induces specific escape behavior in conspecifics. We used a handheld gas chromatograph (zNoseTM), which allows real-time volatile analysis, to measure EBF emission by pea aphids, Acyrthosiphon pisum, under attack from different predators, lacewing or ladybird larvae. We demonstrate that aphid alarm signaling is affected by the predator species attacking. Ladybirds generally elicited smaller EBF emission peaks and consumed aphids more quickly, resulting in lower total EBF emission compared to lacewing attacks. In 52 % of the replicates with lacewings and 23 % with ladybirds, no EBF was detectable in the headspace, although aphids secreted cornicle droplets after attack. We, therefore, examined EBF amounts contained in these droplets and the aphid body. While all aphid bodies always contained EBF, many secreted droplets did not. Our experiments show that alarm signaling in insects can be variable, and both the attacker as well as the attacked may affect alarm signal variation. While underlying mechanisms of such variation in aphid-predator interactions need to be investigated in more detail, we argue that at least part of this variation may be adaptive for the predator and the aphid. PMID- 23686469 TI - Activated EGFR stimulates MUC1 expression in human uterine and pancreatic cancer cell lines. AB - MUC1 is a large cell surface mucin glycoprotein that plays diverse roles in both normal and tumor cell biology. These roles include mucosal hydration and protection, inhibition of embryo implantation, protection of tumor cells from the immune system and reduction of cytotoxic drug uptake. Similarly, the EGFR family of cell surface receptors drives many normal developmental processes as well as various aspects of tumor growth and gene expression. EGFR family members have been demonstrated to form complexes with MUC1 in various cellular contexts. Nonetheless, the role that EGFR activation plays in modulating MUC1 levels has not been considered. In this study, we demonstrate that activated EGFR drives high level MUC1 expression in multiple cell lines of uterine adenocarcinoma and pancreatic cancer origins. In some cells, addition of exogenous EGFR ligands (EGF or HB-EGF) elevates MUC1 levels while addition of the EGFR tyrosine kinase inhibitor, AG1478, reduces MUC1 levels. The thiazolidinedione, rosiglitazone, previously shown to reduce progesterone-stimulated MUC1 expression, also blocks EGFR ligand-driven MUC1 expression. This activity was observed at relatively high rosiglitazone concentrations (above 10 uM) and appeared to be largely PPARgamma independent indicating a novel utility of this drug to reduce mucin-expression in various tumor settings. Collectively, these data demonstrate that: (1) activation of EGFR stimulates MUC1 expression in multiple cellular contexts and (2) it may be possible to develop useful interventions to reduce MUC1 expression as a complementary strategy for tumor therapy. PMID- 23686468 TI - Chemical ecology of marine angiosperms: opportunities at the interface of marine and terrestrial systems. AB - This review examines the state of the field for chemically mediated interactions involving marine angiosperms (seagrasses, mangroves, and salt marsh angiosperms). Small-scale interactions among these plants and their herbivores, pathogens, fouling organisms, and competitors are explored, as are community-level effects of plant secondary metabolites. At larger spatial scales, secondary metabolites from marine angiosperms function as reliable cues for larval settlement, molting, or habitat selection by fish and invertebrates, and can influence community structure and ecosystem function. Several recent studies illustrate the importance of chemical defenses from these plants that deter feeding by herbivores and infection by pathogens, but the extent to which allelopathic compounds kill or inhibit the growth of competitors is less clear. While some phenolic compounds such as ferulic acid and caffeic acid act as critical defenses against herbivores and pathogens, we find that a high total concentration of phenolic compounds within bulk plant tissues is not a strong predictor of defense. Residual chemical defenses prevent shredding or degradation of plant detritus by detritivores and microbes, delaying the time before plant matter can enter the microbial loop. Mangroves, marsh plants, and seagrasses remain plentiful sources of new natural products, but ecological functions are known for only a small proportion of these compounds. As new analytical techniques are incorporated into ecological studies, opportunities are emerging for chemical ecologists to test how subtle environmental cues affect the production and release of marine angiosperm chemical defenses or signaling molecules. Throughout this review, we point to areas for future study, highlighting opportunities for new directions in chemical ecology that will advance our understanding of ecological interactions in these valuable ecosystems. PMID- 23686470 TI - Induced leaf intercellular CO2, photosynthesis, potassium and nitrate retention and strawberry early fruit formation under macronutrient limitation. AB - Relationships between induced high leaf intercellular CO2 concentrations, leaf K+ and NO3- ion movement and early fruit formation under macronutrient limitation are not well understood. We examined the effects and interactions of reduced K/N input treatments on leaf intercellular CO2, photosynthesis rate, carboxylation and water use efficiency, berry formation as well as leaf/fruit K+, NO3- and photosynthate retention of strawberry (Fragaria * ananassa Duch.) to enhance low input agriculture. The field study was conducted in Nova Scotia, eastern Canada during 2009-2010. The experimental treatments consisted of five K2O rates (0, 6, 12, 18, and 24 kg ha(-1)) and five N rates (0, 5, 10, 15, and 20 kg ha(-1)), representing respectively, 0, 25, 50, 75, and 100 % of regular macronutrient recommendations based on the soil testing. The treatments were arranged in a split-plot design with three blocks in the field. The cultivar was 'Mira', a June bearing crop. The results showed that strawberry plants treated with 25 %-reduced inputs could induce significantly higher leaf intercellular CO2 concentrations to improve plant photosynthesis, carboxylation and water use efficiency and translocation of leaf/fruit K+ and dissolved solids, which could advance berry formation by 6 days and produce significantly higher marketable yields (P < 0.05). Higher leaf intercellular CO2 inhibited leaf/fruit NO3- ion retention, but this inhibition did not occur in leaf/fruit K+ retention. Linear interactions of the K/N treatments were significant on fruit marketable yields, intercellular CO2, net photosynthesis, leaf transpiration rates, and leaf temperatures (P < 0.05). It was concluded that higher leaf CO2 could enhance plant photosynthesis, promote plant carboxylation and water use efficiency, and advance berry formation, but it could inhibit leaf NO3- retention. This inhibition did not find in leaf K+ ion and dissolved solid retention. Overlay co-limitation of leaf intercellular CO2 and translocation of leaf/fruit K(+)/NO3 (-) and total dissolved solids could constrain more fruit formation attributes under full macronutrient supply than reduced inputs. It was suggested that low input would be an optimal and sustainable option for improving small fruit crop physiological development and dealing with macronutrient deficiency challenge. PMID- 23686471 TI - Differential sensitivity of spinach and amaranthus to enhanced UV-B at varying soil nutrient levels: association with gas exchange, UV-B-absorbing compounds and membrane damage. AB - The metabolic reasons associated with differential sensitivity of C3 and C4 plant species to enhanced UV-B under varying soil nutrient levels are not well understood. In the present study, spinach (Spinacia oleracea L. var All Green), a C3 and amaranthus (Amaranthus tricolor L. var Pusa Badi Chaulai), a C4 plant were subjected to enhanced UV-B (280-315 nm; 7.2 kJ m(-2) day(-1)) over ambient under varying soil nutrient levels. The nutrient amendments were recommended Nitrogen (N), Phosphorus (P), Potassium (K), 1.5* recommended NPK, 1.5* recommended N and 1.5* recommended K. Enhanced UV-B negatively affected both the species at all nutrient levels, but the reductions varied with nutrient concentration and combinations. Reductions in photosynthetic rate, stomatal conductance and chlorophyll content were significantly more in spinach compared with amaranthus. The reduction in photosynthetic rate was maximum at 1.5* recommended K and minimum in 1.5* NPK amended plants. The oxidative damage to membranes measured in terms of malondialdehyde content was significantly higher in spinach compared with amaranthus. Enhanced UV-B reduced SOD activity in both the plants except in amaranthus at 1.5* recommended K. POX activity increased under enhanced UV-B at all nutrient levels in amaranthus, but only at 1.5* K in spinach. Amaranthus had significantly higher UV-B-absorbing compounds than spinach even under UV-B stress. Lowest reductions in yield and total biomass under enhanced UV-B compared with ambient were observed in amaranthus grown at 1.5* recommended NPK. Enhanced UV-B did not significantly change the nitrogen use efficiency in amaranthus at all NPK levels, but reduced in spinach except at 1.5* K. These findings suggest that the differential sensitivity of the test species under enhanced UV-B at varying nutrient levels is due to varying antioxidative and UV-B screening capacity, and their ability to utilize nutrients. Amaranthus tolerated enhanced UV-B stress more than spinach at all nutrient levels and 1.5* recommended NPK lowered the sensitivity maximally to enhanced UV-B with respect to photosynthesis, biomass and yield. PCA score has also confirmed the lower sensitivity of amaranthus compared with spinach with respect to the measured physiological and biochemical parameters. PMID- 23686472 TI - Expression profiling of bioactive genes from a medicinal plant Nigella sativa L. AB - Plants respond to stress in part by modulating gene expression either constitutively or in an inducible manner which ultimately leads to the restoration of cellular homeostasis, detoxification of toxins, and recovery of growth. Upon introduction to various elicitors such as pathogen-associated molecular patterns, a massive reprogramming of plant gene expression is initiated. Differential display PCR offers rapid and multiple comparisons of gene expression to various stress durations and intensities. Nigella sativa has acclaimed many medicinal properties in traditional medicine. To explore the underlying molecular mechanisms in response to stress in the plants, Fusarium solani (a fungus) stress was induced at different time intervals ranging from 0 to 48 h. RNA was subjected to complementary DNA (cDNA) synthesis followed by PCR using different sets of anchored primers and arbitrary primers. The expression was visualized after silver staining on urea-PAGE. Out of the 23 upregulated re amplified cDNA products, ten differential fragments showed significant homologies with domains related to cellular metabolism, signal transduction, and disease resistance. Such genes could be an informative source for developing genetically improved breeds under infectious stress. PMID- 23686473 TI - High levels of glucose induces a dose-dependent apoptosis in human periodontal ligament fibroblasts by activating caspase-3 signaling pathway. AB - Periodontitis is one of the main complications of diabetes mellitus and many researches have been done on the relationship between periodontitis and diabetes mellitus, but too much are still unclear, especially the mechanisms by which high glucose induces damage of periodontal ligament fibroblasts. So in this study, we investigated the effects of different concentration of high glucose on apoptosis in human periodontal ligament fibroblasts and the possible mechanisms involved. Human periodontal ligament fibroblasts were cultured and subjected to glucose of different concentration (5.5, 15, 25, and 35 mM) for 24 h. Apoptosis was studied by flow cytometry, caspase assays, fluorescent real-time PCR and Western blot. We also determined Fas/FasL expression was by Western blot. The application of different concentration of high glucose induced a concentration-dependent increase of apoptosis and the activity of caspase-3 in cultured human periodontal ligament fibroblasts. Furthermore, inhibitor of caspase-3 could prevent the high glucose-induced apoptosis in human periodontal ligament fibroblasts. Protein levels of Fas and FasL remained unchanged. These data indicate that high glucose induces a concentration- and caspase-3-dependent increase of apoptosis in cultured human periodontal ligament fibroblasts in vitro. Activation of caspase-3 caused by high glucose is independent of Fas/FasL signaling pathways system. These results suggest a novel mechanism for the regulation of human periodontal ligament fibroblasts apoptosis by high glucose. PMID- 23686474 TI - When a mother has cancer: pathways to relational growth for mothers and daughters coping with cancer. AB - BACKGROUND: Most research on daughters of women with cancer have focused on the daughters' adjustment to the cancer with little attention given to the impact of the cancer on the relationships between mothers and daughters. METHODS: Guided by the feminist relational-cultural theory, this study examines mothers' perceptions of their cancer experience on their relationships with daughters, focusing on their emotional connections, ruptures or disconnections in the relationships, and relational competencies. By using the grounded theory, 29 in-depth interviews of mothers with cancer were analyzed. RESULTS: Although most of the participants reported closer relationships with their daughters as a result of the cancer experience, emotions such as fear, anger, or guilt were frequently cited. Mothers were able to work through these emotions with their daughters through four relational competencies: (a) anticipatory empathy (sensitivity about the impact of cancer on each other); (b) authenticity (full presence without fear of abandonment); (c) mutual empathy (caring and emotional support); and (d)mutual empowerment (capacity to empower one another). CONCLUSION: The concept of post traumatic relational growth is introduced to describe how mothers transformed the stressful experience of cancer into an experience in which they grew emotionally in relationship with their daughters. PMID- 23686475 TI - Improvement of olfactory function for quality of life recovery. AB - OBJECTIVES/HYPOTHESIS: To explore quality of life (QoL) improvement after treatment of patients with chronic olfactory disorders; and to correlate QoL with olfactory rehabilitation and evaluate olfactory improvement values over which QoL outcomes are significantly recovered. STUDY DESIGN: Prospective clinical study. METHODS: Eighty-nine patients following endoscopic sinus surgery for chronic rhinosinusitis (CRS) and immunotherapy for allergic rhinitis (AR) were studied. Olfactory function was evaluated using Sniffin' Sticks test pre-and 12 months after treatment. All patients completed six validated QoL questionnaires either specific for olfaction (Questionnaire of Olfactory Deficits-QOD) and for assessing mental health (Zung Anxiety Scale, State-Trait Anxiety Inventory, Zung Depression Scale, Beck Depression Inventory), or generic one (Short Form-36). RESULTS: Significant improvement (all P < 0.001) of olfactory function by 27.4% in total cohort (AR: 10.4%, P = 0.004; CRS: 39.9%, P < 0.001), expressed by the combined Threshold-Discrimination-Identification (TDI) score-and of all QoL questionnaires scores (all P < 0.01) as well, was observed after treatment. There was a positive correlation between olfactory recovery and improvement of patients' QoL. ROC analysis revealed that an increase in the TDI score by 3.50 points in AR and 4.75 points in CRS was necessary for a clinically significant improvement in all QoL questionnaires results. CONCLUSIONS: QoL and mental health of patients suffering from chronic sinonasal diseases are totally recovered after treatment, presenting a direct positive relationship with smell improvement. An increase of olfactory function by 3.50 points for AR and 4.75 points for CRS might be considered the cutoff point for patients' QoL significant recovery. PMID- 23686476 TI - Prognostic significance of Beclin-1 expression in laryngeal squamous cell carcinoma. AB - Beclin-1 plays a critical role in the regulation of autophagy, apoptosis, differentiation and the development and progression of cancer. The aim of the present investigation was to analyze the Beclin-1 protein expression and to assess its prognostic significance in tissue of laryngeal squamous cell carcinoma (LSCC). Beclin-1 protein expression in 82 primary laryngeal squamous cell carcinoma and 40 paracarcinoma non-tumor tissue samples was analyzed by immunohistochemistry and correlated with clinicopathological parameters and patients' outcome. The expression of Beclin-1 in tumor tissues was significantly lower than that in non-tumor tissues (P = 0.035). Reduced Beclin-1 expression was significantly correlated with lymph node metastases (P = 0.021). Kaplan-Meier survival estimates showed a significant correlation between Beclin-1 expression and patient's survival rate (log-rank P < 0.05). Multivariate Cox proportional hazards model analysis confirmed that lymph node metastases (P = 0.048) and Beclin-1 expression (P = 0.029) were statistically significant, independent prognostic factors for LSCC. Our findings suggested that decreased Beclin-1 expression and lymph node metastases, as examined by immunohistochemistry, are both independent biomarker for poor prognosis of patients with LSCC. PMID- 23686477 TI - Efficacy of duloxetine versus alternative oral therapies: an indirect comparison of randomised clinical trials in chronic low back pain. AB - INTRODUCTION: The objective of this study was to obtain parameter estimates for the efficacy of duloxetine versus alternative oral therapies for the treatment of chronic low back pain. MATERIALS AND METHODS: Electronic databases were searched to identify randomised, double-blind placebo-controlled trials. Studies reporting pain intensity, with parallel-group design of oral treatments with length of treatment of more than 8 weeks were included. A Bayesian approach to indirect comparisons was applied, using standardised mean difference as a measure of relative treatment effect. RESULTS: Fifteen studies were identified comparing duloxetine with the following oral drug classes: non-scheduled opioids, cyclooxygenase-2 inhibitors, scheduled opioids, selective serotonin reuptake inhibitors, and 'other' (i.e. glucosamine). The primary analysis found scheduled opioids to be more effective than duloxetine for the fixed effects model. However, the estimate of the treatment difference reflected a less than small magnitude of effect (|standardised mean difference| <0.2), and there was no difference for the random effects model. No differences were found in sensitivity analyses involving the subset of patients not receiving concomitant non-steroidal anti-inflammatory medication. CONCLUSION: The available evidence shows that there does not seem to be any difference in efficacy between duloxetine and other oral pharmacological therapies, providing a valuable alternative for this disabling condition. PMID- 23686478 TI - The percutaneous stabilisation of the sacroiliac joint with hollow modular anchorage screws: a prospective outcome study. AB - PURPOSE: The use of percutaneous iliosacral screw fixation as a treatment of sacroiliac joint pain has been reported to be successful. This study was a prospective single surgeon series to evaluate the short-term outcomes of patients who underwent percutaneous sacroiliac joint stabilisation. METHODS: Between July 2004 and February 2011, 73 patients underwent percutaneous sacroiliac joint fusion in our unit. All patients completed a short form (SF)-36 questionnaire, visual analogue pain score and Majeed scoring questionnaire prior to treatment and at last follow-up. RESULTS: 55 patients (9 male and 46 female) completed follow-up. The average follow-up period was for 36.18 months (range 12-84). The mean preoperative SF-36 scores were 26.59 for physical health and 40.38 for mental health. The mean postoperative SF-36 scores were 42.93 for physical health and 52.77 for mental health. The mean visual analogue pain scores were 8.1 preoperative and 4.5 postoperative. The mean pelvic specific scoring were 36.9 preoperative and 64.78 postoperative. We noted that patients who had previous instrumented spinal surgery did significantly worse than those who had not. We had two nerve root-related complications. CONCLUSION: We conclude that in selected patient group who respond positively to CT-guided injection, a percutaneous SI joint stabilisation is beneficial in effecting pain relief and functional improvement. PMID- 23686479 TI - Truncated form of TGF-betaRII, but not its absence, induces memory CD8+ T cell expansion and lymphoproliferative disorder in mice. AB - Inflammatory and anti-inflammatory cytokines play an important role in the generation of effector and memory CD8(+) T cells. We used two different models, transgenic expression of truncated (dominant negative) form of TGF-betaRII (dnTGFbetaRII) and Cre-mediated deletion of the floxed TGF-betaRII to examine the role of TGF-beta signaling in the formation, function, and homeostatic proliferation of memory CD8(+) T cells. Blocking TGF-beta signaling in effector CD8(+) T cells using both of these models demonstrated a role for TGF-beta in regulating the number of short-lived effector cells but did not alter memory CD8(+) T cell formation and their function upon Listeria monocytogenes infection in mice. Interestingly, however, a massive lymphoproliferative disorder and cellular transformation were observed in Ag-experienced and homeostatically generated memory CD8(+) T cells only in cells that express the dnTGFbetaRII and not in cells with a complete deletion of TGF-betaRII. Furthermore, the development of transformed memory CD8(+) T cells expressing dnTGFbetaRII was IL-7 and IL-15-independent, and MHC class I was not required for their proliferation. We show that transgenic expression of the dnTGFbetaRII, rather than the absence of TGF-betaRII-mediated signaling, is responsible for dysregulated expansion of memory CD8(+) T cells. This study uncovers a previously unrecognized dominant function of the dnTGFbetaRII in CD8(+) T cell proliferation and cellular transformation, which is caused by a mechanism that is different from the absence of TGF-beta signaling. These results should be considered during both basic and translational studies where there is a desire to block TGF-beta signaling in CD8(+) T cells. PMID- 23686480 TI - IL-1alpha signaling initiates the inflammatory response to virulent Legionella pneumophila in vivo. AB - Legionella pneumophila is an intracellular bacterial pathogen that is the cause of a severe pneumonia in humans called Legionnaires' disease. A key feature of L. pneumophila pathogenesis is the rapid influx of neutrophils into the lungs, which occurs in response to signaling via the IL-1R. Two distinct cytokines, IL-1alpha and IL-1beta, can stimulate the type I IL-1R. IL-1beta is produced upon activation of cytosolic sensors called inflammasomes that detect L. pneumophila in vitro and in vivo. Surprisingly, we find no essential role for IL-1beta in neutrophil recruitment to the lungs in response to L. pneumophila. Instead, we show that IL-1alpha is a critical initiator of neutrophil recruitment to the lungs of L. pneumophila-infected mice. We find that neutrophil recruitment in response to virulent L. pneumophila requires the production of IL-1alpha specifically by hematopoietic cells. In contrast to IL-1beta, the innate signaling pathways that lead to the production of IL-1alpha in response to L. pneumophila remain poorly defined. In particular, although we confirm a role for inflammasomes for initiation of IL-1beta signaling in vivo, we find no essential role for inflammasomes in production of IL-1alpha. Instead, we propose that a novel host pathway, perhaps involving inhibition of host protein synthesis, is responsible for IL-1alpha production in response to virulent L. pneumophila. Our results establish IL-1alpha as a critical initiator of the inflammatory response to L. pneumophila in vivo and point to an important role for IL-1alpha in providing an alternative to inflammasome-mediated immune responses in vivo. PMID- 23686482 TI - Inhibition of glycogen synthase kinase-3 increases NKG2D ligand MICA expression and sensitivity to NK cell-mediated cytotoxicity in multiple myeloma cells: role of STAT3. AB - Engagement of NKG2D and DNAX accessory molecule-1 (DNAM-1) receptors on lymphocytes plays an important role for anticancer response and represents an interesting therapeutic target for pharmacological modulation. In this study, we investigated the effect of inhibitors targeting the glycogen synthase kinase-3 (GSK3) on the expression of NKG2D and DNAM-1 ligands in multiple myeloma (MM) cells. GSK3 is a pleiotropic serine-threonine kinase point of convergence of numerous cell-signaling pathways, able to regulate the proliferation and survival of cancer cells, including MM. We found that inhibition of GSK3 upregulates both MICA protein surface and mRNA expression in MM cells, with little or no effects on the basal expression of the MICB and DNAM-1 ligand poliovirus receptor/CD155. Moreover, exposure to GSK3 inhibitors renders myeloma cells more efficient to activate NK cell degranulation and to enhance the ability of myeloma cells to trigger NK cell-mediated cytotoxicity. We could exclude that increased expression of beta-catenin or activation of the heat shock factor-1 (transcription factors inhibited by active GSK3) is involved in the upregulation of MICA expression, by using RNA interference or viral transduction of constitutive active forms. On the contrary, inhibition of GSK3 correlated with a downregulation of STAT3 activation, a negative regulator of MICA transcription. Both Tyr(705) phosphorylation and binding of STAT3 on MICA promoter are reduced by GSK3 inhibitors; in addition, overexpression of a constitutively active form of STAT3 significantly inhibits MICA upregulation. Thus, we provide evidence that regulation of the NKG2D-ligand MICA expression may represent an additional immune mediated mechanism supporting the antimyeloma activity of GSK3 inhibitors. PMID- 23686481 TI - Allelic variation in KIR2DL3 generates a KIR2DL2-like receptor with increased binding to its HLA-C ligand. AB - Although extensive homology exists between their extracellular domains, NK cell inhibitory receptors killer Ig-like receptor (KIR) 2DL2*001 and KIR2DL3*001 have previously been shown to differ substantially in their HLA-C binding avidity. To explore the largely uncharacterized impact of allelic diversity, the most common KIR2DL2/3 allelic products in European American and African American populations were evaluated for surface expression and binding affinity to their HLA-C group 1 and 2 ligands. Although no significant differences in the degree of cell membrane localization were detected in a transfected human NKL cell line by flow cytometry, surface plasmon resonance and KIR binding to a panel of HLA allotypes demonstrated that KIR2DL3*005 differed significantly from other KIR2DL3 allelic products in its ability to bind HLA-C. The increased affinity and avidity of KIR2DL3*005 for its ligand was also demonstrated to have a larger impact on the inhibition of IFN-gamma production by the human KHYG-1 NK cell line compared with KIR2DL3*001, a low-affinity allelic product. Site-directed mutagenesis established that the combination of arginine at residue 11 and glutamic acid at residue 35 in KIR2DL3*005 were critical to the observed phenotype. Although these residues are distal to the KIR/HLA-C interface, molecular modeling suggests that alteration in the interdomain hinge angle of KIR2DL3*005 toward that found in KIR2DL2*001, another strong receptor of the KIR2DL2/3 family, may be the cause of this increased affinity. The regain of inhibitory capacity by KIR2DL3*005 suggests that the rapidly evolving KIR locus may be responding to relatively recent selective pressures placed upon certain human populations. PMID- 23686483 TI - IL-7 produced by thymic epithelial cells plays a major role in the development of thymocytes and TCRgammadelta+ intraepithelial lymphocytes. AB - IL-7 is a cytokine essential for T cell development and survival. However, the local function of IL-7 produced by thymic epithelial cells (TECs) is poorly understood. To address this question, we generated IL-7-floxed mice and crossed them with FoxN1 promoter-driven Cre (FoxN1-Cre) mice to establish knockout mice conditionally deficient for the expression of IL-7 by TECs. We found that alphabeta and gammadelta T cells were significantly reduced in the thymus of IL 7(f/f) FoxN1-Cre mice. Proportion of mature single-positive thymocytes was increased. In lymph nodes and the spleen, the numbers of T cells were partially restored in IL-7(f/f) FoxN1-Cre mice. In addition, gammadelta T cells were absent from the fetal thymus and epidermis of IL-7(f/f) FoxN1-Cre mice. Furthermore, TCRgammadelta(+) intraepithelial lymphocytes (IELs) were significantly decreased in the small intestines of IL-7(f/f) FoxN1-Cre mice. To evaluate the function of IL-7 produced in the intestine, we crossed the IL-7(f/f) mice with villin promoter-driven Cre (Vil-Cre) mice to obtain the mice deficient in IL-7 production from intestinal epithelial cells. We observed that alphabeta and gammadelta IELs of IL-7(f/f) Vil-Cre mice were comparable to control mice. Collectively, our results suggest that TEC-derived IL-7 plays a major role in proliferation, survival, and maturation of thymocytes and is indispensable for gammadelta T cell development. This study also demonstrates that IL-7 produced in the thymus is essential for the development of gammadelta IELs and indicates the thymic origin of gammadelta IELs. PMID- 23686485 TI - Host B7-H4 regulates antitumor T cell responses through inhibition of myeloid derived suppressor cells in a 4T1 tumor transplantation model. AB - B7-H4, a member of the B7 family of T cell immunomodulatory proteins, has been shown to inhibit T cell responses and neutrophil expansion during bacterial infections. However, the role of B7-H4 in the immune response during tumor growth has been unclear. In this study, we examined the host immune responses in B7-H4 deficient (knockout [KO]) or sufficient (wild-type [WT]) BALB/cJ mice upon transplantation of murine 4T1 carcinoma cells that had little B7-H4 expression. We reveal that host B7-H4 not only dampens the antitumor Th1 responses, but also inhibits the protumor function of myeloid-derived suppressor cells (MDSC). We observed increased expression of both antitumor immune effectors and protumor MDSC-associated transcripts in 4T1 tumors grown in B7-H4 KO mice compared with those grown in WT hosts. Consistently, MDSCs derived from B7-H4 KO mice suppressed T cell proliferation more potently than their WT counterparts. Although the primary growth of 4T1 tumors in B7-H4 KO hosts was similar to that in WT mice, tumors that had grown in B7-H4 KO hosts grew much slower than those from WT mice when subsequently transplanted into WT hosts. Importantly, this differential tumor growth during the secondary transplantation was abrogated when recipient mice lacked T cells, indicating that the immune environment in B7-H4 KO hosts allowed outgrowth of 4T1 tumors with reduced immune-evasive capacities against T cells. Thus, B7-H4 can inhibit both antitumor T cells and protumor MDSCs, influencing the immune-evasive character of the outgrowing tumors. These factors should be considered if B7-H4 blockade is to be used for cancer immunotherapy. PMID- 23686484 TI - Profound impairment of adaptive immune responses by alkylating chemotherapy. AB - Overall, cancer vaccines have had a record of failure as an adjuvant therapy for malignancies that are treated with alkylating chemotherapy, and the contribution of standard treatment to that failure remains unclear. Vaccines aim to harness the proliferative potential of the immune system by expanding a small number of tumor-specific lymphocytes into a large number of antitumor effectors. Clinical trials are often conducted after treatment with alkylating chemotherapy, given either as standard therapy or for immunomodulatory effect. There is mounting evidence for synergy between chemotherapy and adoptive immunotherapy or vaccination against self-Ags; however, the impact of chemotherapy on lymphocytes primed against tumor neoantigens remains poorly defined. We report that clinically relevant dosages of standard alkylating chemotherapies, such as temozolomide and cyclophosphamide, significantly inhibit the proliferative abilities of lymphocytes in mice. This proliferative impairment was long-lasting and led to quantitative and qualitative defects in B and T cell responses to neoantigen vaccines. High-affinity responder lymphocytes receiving the strongest proliferative signals from vaccines experienced the greatest DNA damage responses, skewing the response toward lower-affinity responders with inferior functional characteristics. Together, these defects lead to inferior efficacy and overall survival in murine tumor models treated by neoantigen vaccines. These results suggest that clinical protocols for cancer vaccines should be designed to avoid exposing responder lymphocytes to alkylating chemotherapy. PMID- 23686487 TI - SOCS3 regulates BAFF in human enterocytes under ribosomal stress. AB - Although the activation of B cells in the gastrointestinal tract is of great importance in the context of immunity to pathogens and mucosal inflammatory diseases, little is known about the mechanisms responsible for the local activation of B cells in the subepithelial area of the intestine. Epithelium derived BAFF is the major modulator of B cell development and Ig class switching. The present study was performed to address the molecular mechanism of BAFF expression in gut epithelial cells in the presence of proinflammatory stimuli. Inflammation-induced BAFF expression in mucosal epithelial cells might be responsible for diverse mucosa-associated diseases linked to intestinal inflammation and autoimmunity. Although BAFF was marginally expressed in unstimulated epithelial cells, BAFF mRNA was significantly upregulated by proinflammatory IFN-gamma. Furthermore, IFN-gamma triggered JAK/STAT1 signals via the cytokine receptor, which contributed to epithelial BAFF upregulation. In terms of signaling intervention, ribosomal insult attenuated IFN-gamma-activated JAK/STAT signal transduction and subsequent BAFF induction in gut epithelial cells. Ribosomal insults led to the superinduction of SOCS3 by enhancing its mRNA stability via HuR RNA-binding protein. Upregulated SOCS3 then contributed to the blocking of the JAK/STAT-linked signal, which mediated BAFF suppression by ribosomal stress. All of these findings show that ribosomal stress-induced SOCS3 plays a novel regulatory role in epithelial BAFF production, suggesting that epithelial ribosomal dysfunction in association with SOCS3 may be a promising therapeutic point in BAFF-associated human mucosal diseases. PMID- 23686486 TI - Galectin-1-mediated suppression of Pseudomonas aeruginosa-induced corneal immunopathology. AB - Corneal infection with Pseudomonas aeruginosa leads to a severe immunoinflammatory lesion, often causing vision impairment and blindness. Although past studies have indicated a critical role for CD4(+) T cells, particularly Th1 cells, in corneal immunopathology, the relative contribution of recently discovered Th17 and regulatory T cells is undefined. In this study, we demonstrate that after corneal P. aeruginosa infection, both Th1 and Th17 cells infiltrate the cornea with increased representation of Th17 cells. In addition to Th1 and Th17 cells, regulatory T cells also migrate into the cornea during early as well as late stages of corneal pathology. Moreover, using galectin-1 (Gal-1), an immunomodulatory carbohydrate-binding molecule, we investigated whether shifting the balance among various CD4(+) T cell subsets can modulate P. aeruginosa-induced corneal immunopathology. We demonstrate in this study that local recombinant Gal-1 (rGal-1) treatment by subconjunctival injections significantly diminishes P. aeruginosa-mediated corneal inflammation through multiple mechanisms. Specifically, in our study, rGal-1 treatment significantly diminished corneal infiltration of total CD45(+) T cells, neutrophils, and CD4(+) T cells. Furthermore, rGal-1 treatment significantly reduced proinflammatory Th17 cell response in the cornea as well as local draining lymph nodes. Also, rGal-1 therapy promoted anti-inflammatory Th2 and IL-10 response in secondary lymphoid organs. Collectively, our results indicate that corneal P. aeruginosa infection induces a strong Th17-mediated corneal pathology, and treatment with endogenously derived protein such as Gal-1 may be of therapeutic value for the management of bacterial keratitis, a prevalent cause of vision loss and blindness in humans worldwide. PMID- 23686489 TI - Protective role of the inflammatory CCR2/CCL2 chemokine pathway through recruitment of type 1 cytotoxic gammadelta T lymphocytes to tumor beds. AB - Tumor-infiltrating lymphocytes (TILs) are important prognostic factors in cancer progression and key players in cancer immunotherapy. Although gammadelta T lymphocytes can target a diversity of tumor cell types, their clinical manipulation is hampered by our limited knowledge of the molecular cues that determine gammadelta T cell migration toward tumors in vivo. In this study we set out to identify the chemotactic signals that orchestrate tumor infiltration by gammadelta T cells. We have used the preclinical transplantable B16 melanoma model to profile chemokines in tumor lesions and assess their impact on gammadelta TIL recruitment in vivo. We show that the inflammatory chemokine CCL2 and its receptor CCR2 are necessary for the accumulation of gammadelta TILs in B16 lesions, where they produce IFN-gamma and display potent cytotoxic functions. Moreover, CCL2 directed gammadelta T cell migration in vitro toward tumor extracts, which was abrogated by anti-CCL2 neutralizing Abs. Strikingly, the lack of gammadelta TILs in TCRdelta-deficient but also in CCR2-deficient mice enhanced tumor growth in vivo, thus revealing an unanticipated protective role for CCR2/CCL2 through the recruitment of gammadelta T cells. Importantly, we demonstrate that human Vdelta1 T cells, but not their Vdelta2 counterparts, express CCR2 and migrate to CCL2, whose expression is strongly deregulated in multiple human tumors of diverse origin, such as lung, prostate, liver, or breast cancer. This work identifies a novel protective role for CCL2/CCR2 in the tumor microenvironment, while opening new perspectives for modulation of human Vdelta1 T cells in cancer immunotherapy. PMID- 23686488 TI - Cross talk between follicular Th cells and tumor cells in human follicular lymphoma promotes immune evasion in the tumor microenvironment. AB - The microenvironment of human follicular lymphoma (FL), an incurable B cell non Hodgkin's lymphoma, is thought to play a major role in its pathogenesis and course. Microenvironmental cells of likely importance include follicular Th cells (TFH) and regulatory T cells (Tregs), and understanding their interactions with FL tumor cells is necessary to develop novel therapeutic strategies. We found that IL-4 and CD40L are expressed by intratumoral TFH and induce production of CCL17 and CCL22 by FL tumor cells. IL-4 alone induces only CCL17 but enhances stimulation by CD40L of both CCL17 and CCL22. Consistent with our in vitro results, mRNA transcripts of IL-4 correlated with CCL17, but not CCL22, in gene expression profiling studies of FL biopsies, whereas CD40L correlated with both CCL17 and CCL22. Tumor supernatants induced preferential migration of Tregs and IL-4-producing T cells rather than IFN-gamma-producing T cells, and Abs to CCR4 significantly abrogated the migration of Tregs. Our results suggest that through two distinct mechanisms, intratumoral TFH induce production of CCL17 and CCL22 by FL tumor cells and facilitate active recruitment of Tregs and IL-4-producing T cells, which, in turn, may stimulate more chemokine production in a feed-forward cycle. Thus, TFH appear to play a major role in generating an immunosuppressive tumor microenvironment that promotes immune escape and tumor survival and growth. Our results provide novel insights into the cross talk among TFH, tumor cells, and Tregs in FL, and offer potential targets for development of therapeutic strategies to overcome immune evasion. PMID- 23686490 TI - Reciprocal negative cross-talk between liver X receptors (LXRs) and STAT1: effects on IFN-gamma-induced inflammatory responses and LXR-dependent gene expression. AB - Liver X receptors (LXRs) exert key functions in lipid homeostasis and in control of inflammation. In this study we have explored the impact of LXR activation on the macrophage response to the endogenous inflammatory cytokine IFN-gamma. Transcriptional profiling studies demonstrate that ~38% of the IFN-gamma-induced transcriptional response is repressed by LXR activation in macrophages. LXRs also mediated inhibitory effects on selected IFN-gamma-induced genes in primary microglia and in a model of IFN-gamma-induced neuroinflammation in vivo. LXR activation resulted in reduced STAT1 recruitment to the promoters tested in this study without affecting STAT1 phosphorylation. A closer look into the mechanism revealed that SUMOylation of LXRs, but not the presence of nuclear receptor corepressor 1, was required for repression of the NO synthase 2 promoter. We have also analyzed whether IFN-gamma signaling exerts reciprocal effects on LXR targets. Treatment with IFN-gamma inhibited, in a STAT1-dependent manner, the LXR dependent upregulation of selective targets, including ATP-binding cassette A1 (ABCA1) and sterol response element binding protein 1c. Downregulation of ABCA1 expression correlated with decreased cholesterol efflux to apolipoprotein A1 in macrophages stimulated with IFN-gamma. The inhibitory effects of IFN-gamma on LXR signaling did not involve reduced binding of LXR/retinoid X receptor heterodimers to target gene promoters. However, overexpression of the coactivator CREB-binding protein/p300 reduced the inhibitory actions of IFN-gamma on the Abca1 promoter, suggesting that competition for CREB-binding protein may contribute to STAT1 dependent downregulation of LXR targets. The results from this study suggest an important level of bidirectional negative cross-talk between IFN-gamma/STAT1 and LXRs with implications both in the control of IFN-gamma-mediated immune responses and in the regulation of lipid metabolism. PMID- 23686491 TI - Recent thymic emigrants and mature naive T cells exhibit differential DNA methylation at key cytokine loci. AB - Recent thymic emigrants (RTEs) are the youngest T cells in the lymphoid periphery and exhibit phenotypic and functional characteristics distinct from those of their more mature counterparts in the naive peripheral T cell pool. We show in this study that the Il2 and Il4 promoter regions of naive CD4(+) RTEs are characterized by site-specific hypermethylation compared with those of both mature naive (MN) T cells and the thymocyte precursors of RTEs. Thus, RTEs do not merely occupy a midpoint between the thymus and the mature T cell pool, but represent a distinct transitional T cell population. Furthermore, RTEs and MN T cells exhibit distinct CpG DNA methylation patterns both before and after activation. Compared with MN T cells, RTEs express higher levels of several enzymes that modify DNA methylation, and inhibiting methylation during culture allows RTEs to reach MN T cell levels of cytokine production. Collectively, these data suggest that the functional differences that distinguish RTEs from MN T cells are influenced by epigenetic mechanisms and provide clues to a mechanistic basis for postthymic maturation. PMID- 23686492 TI - Helicobacter pylori infection inhibits phagocyte clearance of apoptotic gastric epithelial cells. AB - Increased apoptotic death of gastric epithelial cells is a hallmark of Helicobacter pylori infection, and altered epithelial cell turnover is an important contributor to gastric carcinogenesis. To address the fate of apoptotic gastric epithelial cells and their role in H. pylori mucosal disease, we investigated phagocyte clearance of apoptotic gastric epithelial cells in H. pylori infection. Human gastric mononuclear phagocytes were analyzed for their ability to take up apoptotic epithelial cells (AECs) in vivo using immunofluorescence analysis. We then used primary human gastric epithelial cells induced to undergo apoptosis by exposure to live H. pylori to study apoptotic cell uptake by autologous monocyte-derived macrophages. We show that HLA-DR(+) mononuclear phagocytes in human gastric mucosa contain cytokeratin-positive and TUNEL-positive AEC material, indicating that gastric phagocytes are involved in AEC clearance. We further show that H. pylori both increased apoptosis in primary gastric epithelial cells and decreased phagocytosis of the AECs by autologous monocyte-derived macrophages. Reduced macrophage clearance of apoptotic cells was mediated in part by H. pylori-induced macrophage TNF-alpha, which was expressed at higher levels in H. pylori-infected, compared with uninfected, gastric mucosa. Importantly, we show that H. pylori-infected gastric mucosa contained significantly higher numbers of AECs and higher levels of nonphagocytosed TUNEL positive apoptotic material, consistent with a defect in apoptotic cell clearance. Thus, as shown in other autoimmune and chronic inflammatory diseases, insufficient phagocyte clearance may contribute to the chronic and self perpetuating inflammation in human H. pylori infection. PMID- 23686494 TI - CD40 mediates downregulation of CD32B on specific memory B cell populations in rheumatoid arthritis. AB - Altered B cell function is important in the pathogenesis of rheumatoid arthritis (RA). In this report, we show that patients with active RA have an increased frequency of CD32B low/neg cells in the CD27(+)IgD(-) memory B cell subset and that these changes are associated with phenotypic and functional B cell activation. Studies using PBMCs from healthy donors revealed that downregulation of CD32B on B cells is mediated by CD40-CD40L interactions and is potentiated by IL-4 and inhibited by both IL-10 and IL-21. These findings appear physiologically relevant because CD4 T cell expression of CD40L correlated with the frequency of CD32B low/neg cells in the CD27(+)IgD(-) memory B subset in patients with RA. Our data support a model in which high levels of CD40L, present on circulating T cells in patients with RA, causes B cell activation and CD32B downregulation, resulting in secondary protection of memory B cells from CD32B-mediated cell death. PMID- 23686493 TI - Antigen-specific effector CD4 T lymphocytes school lamina propria dendritic cells to transfer innate tolerance. AB - Dendritic cells (DCs) have been shown to play a major role in oral tolerance, and this function has been associated with their ability to produce anti-inflammatory cytokines and to induce suppressive regulatory T cells. In this study, we demonstrate that upon oral administration of Ag, lamina propia (LP) DCs engage specific T cells and acquire a novel mechanism by which they transfer tolerance against diverse T cell specificities. Indeed, when Ig-myelin oligodendrocyte glycoprotein (MOG) carrying the MOG(35-55) epitope was orally administered into either T cell-sufficient or -deficient mice, only the T cell-sufficient hosts yielded CD8alpha(+) and CD8alpha(-) LP DCs that were able to transfer tolerance to a variety of MHC class II-restricted effector T cells. Surprisingly, these LP DCs upregulated programmed cell death ligand 1 during the initial interaction with MOG-specific T cells and used this inhibitory molecule to suppress activation of T cells regardless of Ag specificity. Furthermore, oral Ig-MOG was able to overcome experimental autoimmune encephalomyelitis induced with CNS homogenate, indicating that the DCs are able to modulate disease involving diverse T cell specificities. This previously unrecognized attribute potentiates DCs against autoimmunity. PMID- 23686495 TI - GB virus C particles inhibit T cell activation via envelope E2 protein-mediated inhibition of TCR signaling. AB - Viruses enter into complex interactions within human hosts, leading to facilitation or suppression of each other's replication. Upon coinfection, GB virus C (GBV-C) suppresses HIV-1 replication in vivo and in vitro, and GBV-C coinfection is associated with prolonged survival in HIV-infected people. GBV-C is a lymphotropic virus capable of persistent infection. GBV-C infection is associated with reduced T cell activation in HIV-infected humans, and immune activation is a critical component of HIV disease pathogenesis. We demonstrate that serum GBV-C particles inhibited activation of primary human T cells. T cell activation inhibition was mediated by the envelope glycoprotein E2, because expression of E2 inhibited TCR-mediated activation of Lck. The region on the E2 protein was characterized and revealed a highly conserved peptide motif sufficient to inhibit TCR-mediated signaling. The E2 region contained a predicted Lck substrate site, and substitution of an alanine or histidine for the tyrosine reversed TCR-signaling inhibition. GBV-C E2 protein and a synthetic peptide representing the inhibitory amino acid sequence were phosphorylated by Lck in vitro. The synthetic peptide also inhibited TCR-mediated activation of primary human CD4(+) and CD8(+) T cells. Extracellular microvesicles from GBV-C E2 expressing cells contained E2 protein and inhibited TCR signaling in bystander T cells not expressing E2. Thus, GBV-C reduced global T cell activation via competition between its envelope protein E2 and Lck following TCR engagement. This novel inhibitory mechanism of T cell activation may provide new approaches for HIV and immunoactivation therapy. PMID- 23686496 TI - Proresolving and tissue-protective actions of annexin A1-based cleavage-resistant peptides are mediated by formyl peptide receptor 2/lipoxin A4 receptor. AB - Endogenous mechanisms regulating the host response during inflammation resolution are critical in ensuring disposal of noxious stimuli and return to homeostasis. In this article, we engineered novel Annexin A1 (AnxA1)-based peptides, AnxA1(2 50), that displayed specific binding to the AnxA1 receptor (formyl peptide receptor 2/Lipoxin A4 receptor [FPR2/ALX]; IC50 ~4 nM). Intravenous administration of AnxA1(2-50) markedly reduced (>60%) leukocyte adhesion to postcapillary venules in wild type and Fpr1(-/-), but not Fpr2/Alx(-/-), mice. Generation of a metabolically stable form of this peptide (CR-AnxA1(2-50)), engineered by substituting a cleavage site shared by human proteinase 3 and neutrophil elastase, yielded an agonist that was resistant to neutrophil-mediated cleavage and displayed enhanced proresolving actions: accelerated resolution of self-limited inflammation and enhanced macrophage efferocytosis after sterile injury, when compared with AnxA1(2-50). These actions were retained with human primary leukocytes where CR-AnxA1(2-50) decreased neutrophil-endothelial interactions (~25-45%), and stimulated neutrophil apoptosis and macrophage efferocytosis (~45%). In murine cardiac ischemia/reperfusion injury, CR-AnxA1(2 50) elicited tissue-protective actions reducing infarct size (~60%) and incidence of 24-h death. These results identify AnxA1(2-50) and CR-AnxA1(2-50) as FPR2/ALX agonists that harness the proresolving actions of AnxA1, and thus may represent therapeutic tools for treatment of inflammatory conditions. PMID- 23686497 TI - MicroRNA-155 confers encephalogenic potential to Th17 cells by promoting effector gene expression. AB - Th17 cells are central to the pathogenesis of autoimmune disease, and recently specific noncoding microRNAs have been shown to regulate their development. However, it remains unclear whether microRNAs are also involved in modulating Th17 cell effector functions. Consequently, we examined the role of miR-155 in differentiated Th17 cells during their induction of experimental autoimmune encephalomyelitis. Using adoptive transfer experiments, we found that highly purified, myelin oligodendrocyte glycoprotein Ag-specific Th17 cells lacking miR 155 were defective in their capacity to cause experimental autoimmune encephalomyelitis. Gene expression profiling of purified miR-155(-/-)IL-17F(+) Th17 cells identified a subset of effector genes that are dependent on miR-155 for their proper expression through a mechanism involving repression of the transcription factor Ets1. Among the genes reduced in the absence of miR-155 was IL-23R, resulting in miR-155(-/-) Th17 cells being hyporesponsive to IL-23. Taken together, our study demonstrates a critical role for miR-155 in Th17 cells as they unleash autoimmune inflammation and finds that this occurs through a signaling network involving miR-155, Ets1, and the clinically relevant IL-23-IL 23R pathway. PMID- 23686498 TI - Programmed death-1 shapes memory phenotype CD8 T cell subsets in a cell-intrinsic manner. AB - Memory phenotype T cells, found in unimmunized mice, display phenotypic and functional traits of memory cells and provide essential protection against infections, playing a role in both innate and adaptive immune responses. Mechanisms governing homeostasis of these memory phenotype T cells remain ill defined. In this study, we reveal a crucial role of the negative costimulator programmed death-1 (PD-1) in regulating developmental fates of memory phenotype cells. Thus, in lymphoid organs and tissues of PD-1 knockout (KO) mice a marked accumulation of functional effector memory (T(EM)) phenotype CD8 T cells was observed. T(EM) phenotype cells from PD-1 KO mice exhibit decreased proliferation but increased survival potential. These cells could produce effector molecules constitutively, in response to phorbol esters or through bystander activation by innate stimuli. Similarly, in lymphopenia-induced proliferating CD8 T cells, whereby normally naive T cells acquire a memory phenotype, skewing toward a T(EM) phenotype was prominent in the absence of PD-1. Acquisition of the T(EM) phenotype was a CD8 T cell-intrinsic phenomenon as demonstrated by mixed bone marrow transfer experiments. Importantly, adoptively transferred PD-1 KO CD8 central memory T (T(CM)) cells converted into the T(EM) phenotype, indicating that PD-1 sets a major checkpoint in the T(CM) to T(EM) phenotype differentiation process. This was reflected by distinct patterns of gene expression of PD-1 KO T(CM) phenotype cells revealed by global transcriptional analysis. Additionally, adoptively transferred PD-1 KO T(EM) phenotype cells converted to a lesser degree to a T(CM) phenotype. Collectively, these data suggest that PD-1 shapes memory phenotype CD8 T cell subsets. PMID- 23686499 TI - Silencing the mannose 6-phosphate/IGF-II receptor differentially affects tumorigenic properties of normal breast epithelial cells. AB - Although loss of the mannose 6-phosphate/insulin-like growth factor-II receptor (M6P/IGF-IIR) in breast cancer is believed to play a role in tumorigenesis, it has not been demonstrated that M6P/IGF-IIR loss is sufficient to confer a malignant phenotype in an untransformed cell. We investigated the impact of M6P/IGF-IIR silencing using phenotypically normal (MCF-10A) and oncogenically transformed (MCF-10T, the c-Ha-ras transformed derivative of MCF-10A) human breast epithelial cell lines as model systems. In both cell lines, silencing of M6P/IGF-IIR increased cell proliferation and motility, with the effects being more pronounced in MCF-10A cells. Although anchorage-independent growth was increased by M6P/IGF-IIR silencing in MCF-10T cells, MCF-10A cells did not acquire the ability to grow in soft agar. Conversely, reduced M6P/IGF-IIR expression increased the invasive potential of MCF-10A cells, but did not enhance the already high rate of invasion of MCF-10T cells. M6P/IGF-IIR silencing had no effect on basal or IGF-II-stimulated IGF-I receptor (IGF-IR) or AKT phosphorylation in either cell line, but both were abrogated by IGF-IR kinase inhibition, which also reduced the stimulatory effect of M6P/IGF-IIR silencing on proliferation under basal and IGF-II-stimulated conditions in both cell lines. However, cell motility was neither stimulated by IGF-II nor reduced by IGF-IR inhibition, suggesting that potentiation of specific tumorigenic features in response to M6P/IGF-IIR silencing involves IGF-II- dependent and -independent mechanisms. Collectively, these data suggest that M6P/IGF-IIR silencing alone is insufficient to confer a tumorigenic phenotype, but can enhance tumorigenicity in an already transformed cell. PMID- 23686500 TI - The filter pads and filtration mechanisms of the devil rays: Variation at macro and microscopic scales. AB - Three lineages of cartilaginous fishes have independently evolved filter feeding (Lamniformes: Megachasma and Cetorhinus, Orectolobiformes: Rhincodon, and Mobulidae: Manta and Mobula); and the structure of the branchial filters is different in each group. The filter in Rhincodon typus has been described; species within the Lamniformes have simple filamentous filters, but the anatomy and ultrastructure of the branchial filter in the mobulid rays varies and is of functional interest. In most fishes, branchial gill rakers are elongated structures located along the anterior ceratobranchial and/or epibranchial arches; however, mobulid gill rakers are highly modified, flattened, lobe-like structures located on the anterior and posterior epibranchial elements as well as the ceratobranchials. The ultrastructure of the filter lobes can be smooth or covered by a layer of microcilia, and some are denticulated along the dorsal and ventral lobe surface. Flow through the mobulid oropharyngeal cavity differs from other filter-feeding fishes in that water must rapidly deviate from the free stream direction. There is an abrupt 90 degrees turn from the initial inflowing path to move through the laterally directed branchial filter pores, over the gill tissue, and out the ventrally located gill slits. The deviation in the flow must result in tangential shearing stress across the filter surface. This implies that mobulids can use cross-flow filtration in which this shearing force serves as a mechanism to resuspend food particles initially caught by sieving or another capture mode. These particles will be transported by the cross filter flow toward the esophagus. We propose that species with cilia on the rakers augment the shear mediated movement of particles along the filter with ciliary transport. PMID- 23686501 TI - Long-term tricuspid valve prosthesis-related complications in patients with congenital heart disease. AB - OBJECTIVES: In patients with acquired valvar disease, morbidity and mortality rates after tricuspid valve replacement (TVR) are high. However, in adult patients with congenital heart disease, though data concerning outcome after TVR are scarce, even poorer results are suggested in patients with Ebstein anomaly. To investigate the applicability of these results to a broader array of congenital heart disease patients, we report the long-term follow-up of prosthesis-related complications, including re-replacement of patients with a tricuspid valve prosthesis and congenital heart disease. METHODS: From the Dutch Congenital Corvitia (CONCOR) registry, we identified 20 patients with a biological or mechanical tricuspid valve prosthesis implanted between 1977 and 2012 (total of 31 prostheses). We analysed the tricuspid valve-related complications and mortality. RESULTS: Ten patients with a median age of 16.2 years at the time of surgery (interquartile range 13.2-28.2 years) received a bioprosthesis while 10 patients with a median age of 36.4 years (interquartile range 14.0-47.0) at the time of surgery received a mechanical prosthesis (P = 0.28). During a mean follow-up of 14 years, 50% needed a re-replacement because of valve-related complications (e.g. valve degeneration or valve thrombosis). The yearly percentage of patients with valve-related complications was 4.2% in patients with a bioprosthesis and 2.7% in those with a mechanical prosthesis. Within 20 years of implantation, the median duration of event-free survival was significantly shorter in 3 patients with a prosthesis-patient mismatch (PPM; 1.0 year; interquartile range 0.01-2.6), compared with 7 without mismatch (8.0 years; interquartile range 5.1-12.3; P = 0.02). CONCLUSIONS: Compared with previous literature on acquired valvar disease, we found a higher incidence of valve related complications in patients with congenital heart disease that was unrelated to prosthesis material. Our data suggest that PPM may have a negative effect on the event-free interval. PMID- 23686502 TI - Rare images of tuberculous pericarditis causing constrictive pericarditis. PMID- 23686503 TI - Multiple cardiac mycetomas in an immunosuppressed child. PMID- 23686504 TI - Acute type A aortic dissection: have we reached our limit? PMID- 23686505 TI - Giant syphilitic aortic aneurysm. PMID- 23686506 TI - Antimicrobial activity of prulifloxacin in comparison with other fluoroquinolones against community-acquired urinary and respiratory pathogens isolated in Greece. AB - Prulifloxacin, the prodrug of ulifloxacin, is a broad-spectrum fluoroquinolone rather recently introduced in certain European countries. We compared the antimicrobial potency of ulifloxacin with that of other fluoroquinolones against common urinary and respiratory bacterial pathogens. The microbial isolates were prospectively collected between January 2007 and May 2008 from patients with community-acquired infections in Greece. Minimum inhibitory concentrations (MICs) were determined for ciprofloxacin, levofloxacin, moxifloxacin (for respiratory isolates only), and ulifloxacin using the E-test method. The binary logarithms of the MICs [log2(MICs)] were compared by using the Wilcoxon signed-ranks test. A total of 409 isolates were studied. Ulifloxacin had the lowest geometric mean MIC for the 161 Escherichia coli, 59 Proteus mirabilis, and 22 Staphylococcus saprophyticus urinary isolates, the second lowest geometric mean MIC for the 38 Streptococcus pyogenes respiratory isolates (after moxifloxacin), and the third lowest geometric mean MIC for the 114 Haemophilus influenzae and the 15 Moraxella catarrhalis respiratory isolates (after ciprofloxacin and moxifloxacin). Compared with levofloxacin, ulifloxacin had lower log2(MICs) against E. coli (p < 0.001), P. mirabilis (p < 0.001), S. saprophyticus (p < 0.001), and S. pyogenes (p < 0.001). Compared with ciprofloxacin, ulifloxacin had lower log2(MICs) against P. mirabilis (p < 0.001), S. saprophyticus (p = 0.008), and S. pyogenes (p < 0.001), but higher log2(MICs) against H. influenzae (p < 0.001) and M. catarrhalis (p = 0.001). In comparison with other clinically relevant fluoroquinolones, ulifloxacin had the most potent antimicrobial activity against the community acquired urinary isolates studied and very good activity against the respiratory isolates. PMID- 23686507 TI - Synthesis of cinnamyl alcohol from cinnamaldehyde with Bacillus stearothermophilus alcohol dehydrogenase as the isolated enzyme and in recombinant E. coli cells. AB - The synthesis of the aroma chemical cinnamyl alcohol (CMO) by means of enzymatic reduction of cinnamaldehyde (CMA) was investigated using NADH-dependent alcohol dehydrogenase from Bacillus stearothermophilus both as an isolated enzyme, and in recombinant Escherichia coli whole cells. The influence of parameters such as reaction time and cofactor, substrate, co-substrate 2-propanol and biocatalyst concentrations on the bioreduction reaction was investigated and an efficient and sustainable one-phase system developed. The reduction of CMA (0.5 g/L, 3.8 mmol/L) by the isolated enzyme occurred in 3 h at 50 degrees C with 97% conversion, and yielded high purity CMO (>=98%) with a yield of 88% and a productivity of 50 g/genzyme. The reduction of 12.5 g/L (94 mmol/L) CMA by whole cells in 6 h, at 37 degrees C and no requirement of external cofactor occurred with 97% conversion, 82% yield of 98% pure alcohol and a productivity of 34 mg/gwet cell weight. The results demonstrate the microbial system as a practical and efficient method for larger-scale synthesis of CMO. PMID- 23686508 TI - Electronic health records and ambulatory quality. The authors' reply. PMID- 23686509 TI - PTSD women Veterans' prevalence of PTSD care. PMID- 23686510 TI - Decreasing disparities in breast cancer screening in refugee women using culturally tailored patient navigation. AB - BACKGROUND: Patient navigator (PN) programs can improve breast cancer screening in low income, ethnic/racial minorities. Refugee women have low breast cancer screening rates, but it has not been shown that PN is similarly effective. OBJECTIVE: Evaluate whether a PN program for refugee women decreases disparities in breast cancer screening. DESIGN: Retrospective program evaluation of an implemented intervention. PARTICIPANTS: Women who self-identified as speaking Somali, Arabic, or Serbo-Croatian (Bosnian) and were eligible for breast cancer screening at an urban community health center (HC). Comparison groups were English-speaking and Spanish-speaking women eligible for breast cancer screening in the same HC. INTERVENTION: Patient navigators educated women about breast cancer screening, explored barriers to screening, and tailored interventions individually to help complete screening. MAIN MEASURES: Adjusted 2-year mammography rates from logistic regression models for each calendar year accounting for clustering by primary care physician. Rates in refugee women were compared to English-speaking and Spanish-speaking women in the year before implementation of the PN program and over its first 3 years. RESULTS: There were 188 refugee (36 Somali, 48 Arabic, 104 Serbo-Croatian speaking), 2,072 English speaking, and 2,014 Spanish-speaking women eligible for breast cancer screening over the 4-year study period. In the year prior to implementation of the program, adjusted mammography rates were lower among refugee women (64.1 %, 95 % CI: 49-77 %) compared to English-speaking (76.5 %, 95 % CI: 69 %-83 %) and Spanish-speaking (85.2 %, 95 % CI: 79 %-90 %) women. By the end of 2011, screening rates increased in refugee women (81.2 %, 95 % CI: 72 %-88 %), and were similar to the rates in English-speaking (80.0 %, 95 % CI: 73 %-86 %) and Spanish-speaking (87.6 %, 95 % CI: 82 %-91 %) women. PN increased screening rates in both younger and older refugee women. CONCLUSION: Linguistically and culturally tailored PN decreased disparities over time in breast cancer screening among female refugees from Somalia, the Middle East and Bosnia. PMID- 23686512 TI - Mycotic brain aneurysm and cerebral hemorrhagic stroke: a pediatric case report. AB - Endocarditis due to Abiotrophia spp. is rare and often associated with negative blood cultures, infection relapse, and high rates of treatment failure and mortality (Lainscak et al., J Heart Valve Dis 14(1):33-36, 2005). The authors describe a case of an adolescent with cerebral hemorrhagic stroke due to mycotic brain aneurysm rupture. PMID- 23686511 TI - Dialysis in the frail elderly--a current ethical problem, an impending ethical crisis. AB - The current practice of hemodialysis for the frail elderly frequently ignores core bioethical principles. Lack of transparency and shared decision making coupled with financial incentives to treat have resulted in problems of overtreatment near the end of life. Imminent changes in reimbursement for hemodialysis will reverse the financial incentives to favor not treating high risk patients. In this article, we describe what is empirically known about the approach to hemodialysis today, and how it violates four core ethical principles. We then discuss how the new financial system turns physician and organizational incentives upside down in ways that may exacerbate the ethical dilemmas, but in the opposite direction. PMID- 23686513 TI - Isolated radial nerve palsy in newborns--case report of a bilateral manifestation and literature review. AB - Uni- or bilateral radial nerve palsy in newborn is a rare symptom. We report about a case of unusual bilateral radial nerve palsy in a term-born girl who recovered completely after 10 months and review the English-speaking literature about this condition. Review of the literature shows less than 60 reported cases of radial nerve palsy, most of them unilateral. CONCLUSION: Besides the clinical examination, in most cases, no further diagnostic investigation is necessary. An incomplete restitution is rare as recovery mostly occurs within 3-6 months. PMID- 23686514 TI - Rapid progression to pulmonary arterial hypertension crisis associated with mixed connective tissue disease in an 11-year-old girl. AB - Mixed connective tissue disease (MCTD) is rare in pediatric rheumatic diseases. Pulmonary arterial hypertension (PAH) associated with MCTD usually progresses gradually and is difficult to note at the asymptomatic phase. We report a 11-year old girl with MCTD complicated with rapidly progressive PAH. Although PAH was not detected by echocardiogram or chest CT scan at the initial examination, it became clear in 1 year and suddenly came to cardiac arrest during an invasive procedure. She was successfully treated with extracorporeal assist and both vasodilative and immunosuppressive medication. A combination of echocardiogram and plasma BNP levels could be a useful marker for the follow-up of such cases. PAH could develop early in the course of pediatric MCTD and needs attention to unexpected acute exacerbation, especially under emotional stress. PMID- 23686517 TI - Improved rodent models of human brain metastases. PMID- 23686516 TI - "There's a whole different way of working with adolescents": interviews with Australian Genetic Counselors about their experiences with adolescent clients. AB - Adolescence is a developmental period marked by unique physical, psychological and social changes. Guidelines about working with adolescents are available to health professionals in other fields, yet few resources are tailored specifically to genetic counselors. The current qualitative study explored the experiences of genetic counselors who work with adolescent clients to determine whether challenges exist and if further training and support are needed. Semi-structured interviews were conducted with 11 genetic counselors from Australia. Interview transcripts were analyzed using thematic analysis from which 7 key themes emerged: 1) Adolescents: A distinct client group? 2) Characteristics of adolescents; 3) Strategies for working with adolescents; 4) Confidentiality; 5) Parental involvement and presence in sessions; 6) Benefits of working with adolescents; and 7) The effectiveness of past training and education. The findings hold important implications for clinical practice and may inform future training programs and guidelines for genetic counselors internationally. PMID- 23686515 TI - Factors associated with stroke survivor behaviors as identified by family caregivers. AB - PURPOSE: Stroke survivor behaviors that caregivers identify as bothersome can lead to family caregiver stress, which can result in premature institutionalization of the survivor. The purpose of this study was to explore demographic and theory-based factors associated with survivor bothersome behaviors as identified by family caregivers. METHODS: A secondary analysis of a combined sample of 96 family caregivers of stroke survivors was conducted using baseline data from two existing studies. Bothersome behaviors were measured using the Revised Memory and Behavior Problems Checklist (RMBPC). Theory-based factors were measured using well-validated scales. RESULTS: Male stroke survivors exhibited more bothersome behaviors (t = 3.53, p < .01). After controlling for survivor gender, 35% of the variance in bothersome behaviors was explained by caregiver depressive symptoms, task difficulty, life changes, and threat appraisal (F[5, 88] = 10.82, p < .001). CONCLUSIONS: These results identify potential areas for nursing interventions designed to reduce bothersome behaviors as identified by family caregivers. PMID- 23686518 TI - Prenatal diagnosis of infantile myofibromatosis of the lung: a case report and review of the literature. AB - We present a case of infantile myofibromatosis of the lung detected at 32 weeks' gestation. The fetus was monitored with weekly ultrasound examinations measuring the mass size and amniotic fluid index. On day 2 after delivery, due to respiratory distress, an exploratory thoracotomy was undertaken and the mass was resected. PMID- 23686520 TI - Stress and development in Dictyostelium discoideum: the involvement of the catalytic calcineurin A subunit. AB - Calcium signaling is one of the most important signaling-pathways in all eukaryotes. One important target activated by an increased intracellular calcium concentration via calmodulin is the protein phosphatase calcineurin, which is composed of a catalytic subunit (calcineurin A) and a regulatory subunit (calcineurin B). The importance of calcium and calcineurin for the differentiation and development of the social amoeba Dictyostelium discoideum has already been shown by pharmacological approaches. However, so far only a RNAi silenced calcineurin B mutant has been investigated on a molecular level. Here, we describe the construction and phenotypic investigation of a RNAi-silenced calcineurin A mutant. Phenotypic aberrations during development resemble those produced by silencing of calcineurin B with ectopic tip formation of the fruiting bodies. Additionally, we tested the response of the mutants under various stress conditions in liquid culture as well as during development. Both, calcineurin A and B RNAi-mutants, are hypersensitive during development towards cation stress. Besides its role in development, calcineurin is thus also involved in the stress response in D. discoideum. Further, our data imply that many functions of calcineurin are conserved among the eukaryotes. PMID- 23686519 TI - Premature cell senescence and T cell receptor-independent activation of CD8+ T cells in juvenile idiopathic arthritis. AB - OBJECTIVE: CD8+ T cells lacking CD28 were originally reported to be a characteristic feature of juvenile idiopathic arthritis (JIA), but the relevance of these unusual cells to this disease remains to be elucidated. Because of recent evidence that loss of CD28 cells is typical of terminally differentiated lymphocytes, the aim of this study was to examine functional subsets of CD8+ T cells in patients with JIA. METHODS: Blood and/or waste synovial fluid samples were collected from children with a definite diagnosis of JIA (n = 98). Deidentified peripheral blood (n = 33) and cord blood (n = 13) samples from healthy donors were also collected. CD8+ and CD4+ T cells were screened for novel receptors, and where indicated, bioassays were performed to determine the functional relevance of the identified receptor. RESULTS: JIA patients had a naive T cell compartment with shortened telomeres, and their entire T cell pool had reduced proliferative capacity. They had an overabundance of CD31+CD28(null) CD8+ T cells, which was a significant feature of oligoarticular JIA (n = 62) as compared to polyarticular JIA (n = 36). CD31+ CD28(null) CD8+ T cells had limited mitotic capacity and expressed high levels of the senescence antigens histone gammaH2AX and/or p16. Ligation of CD31, which was independent of the T cell receptor (TCR), sufficiently induced tyrosine phosphorylation, vesicle exocytosis, and production of interferon-gamma and interleukin-10. CONCLUSION: These data provide the first evidence of cell senescence, as represented by CD31+CD28(null) CD8+ T cells, in the pathophysiology of JIA. Activation of these unusual cells in a TCR-independent manner suggests that they are maladaptive and could be potential targets for immunotherapy. PMID- 23686521 TI - Inhibition of cytochrome P450s enhances (+)-usnic acid cytotoxicity in primary cultured rat hepatocytes. AB - (+)-Usnic acid (UA) is consumed as a dietary supplement to promote weight loss; however, dietary supplements containing UA have been associated with clinical cases of severe liver injury. UA has been shown to be hepatotoxic in rats and is extensively metabolized by hepatic cytochrome P450s (CYPs); therefore, we examined if UA metabolism results in the formation of cytotoxic metabolites or if metabolism is a detoxification process in primary rat hepatocytes. When CYP activity was suppressed by the non-isoenzyme-selective inhibitor SKF-525A (20 MUM), or the CYP1A inhibitor alpha-naphthoflavone (10 MUM), or the CYP3A inhibitor ketoconazole (25 MUM), the cytotoxicity of UA at 3~6 MUM after 3~20 h of exposure was significantly increased as measured by lactate dehydrogenase (LDH) leakage. At 2 h after UA exposure, an earlier time point prior to LDH release, these CYP inhibitors potentiated UA-induced inhibition of cellular respiration as determined by the Clark type oxygen electrode. Cellular adenosine triphosphate (ATP) depletion by UA was also exacerbated by these CYP inhibitors. The CYP2B/2C inhibitor, ticlopidine at 20 MUM, showed no effects in parallel experiments. These data demonstrate that UA is bio-transformed to less toxic metabolites in rat primary hepatocytes, probably mainly by CYP1A and 3A, but not 2B/2C. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. PMID- 23686523 TI - Depressive symptoms after treatment in hepatocellular carcinoma survivors: prevalence, determinants, and impact on health-related quality of life. AB - OBJECTIVE: The purposes of this study were to investigate the prevalence and determinants of depressive symptoms among hepatocellular carcinoma (HCC) survivors and to evaluate the impact of depressive symptoms on health-related quality of life (HRQOL). METHODS: A cross-sectional study was conducted on 128 consecutive patients attending an outpatient clinic in Japan 1 year or more after curative treatment. To assess depressive symptoms and HRQOL, the participants were asked to complete the Center for Epidemiologic Studies Depressive Symptoms Scale, the European Organization for Research and Treatment of Cancer (EORTC) QLQ C30, and EORTC QLQ-HCC18, respectively. Multiple logistic regression models were used to identify factors associated with depressive symptoms. EORTC QLQ-C30 and EORTC QLQ-HCC18 scores were compared between participants with and without depressive symptoms. RESULTS: The prevalence of depressive symptoms among the HCC survivors was 28.3%. The multiple logistic regression analysis revealed that the determinants of depressive symptoms included poor Karnofsky performance status (odds ratio [OR] = 4.59, 95% CI = 1.03-20.55, p = 0.04), poor liver function (OR = 3.22, 95% CI = 1.11-10.0, p = 0.03), living alone (OR = 6.87, 95% CI = 2.53 18.63, p = 0.0002), and unemployment (OR = 5.18, 95% CI = 1.73-15.54, p = 0.003). Survivors with depressive symptoms had poorer HRQOL in almost all domains compared with survivors with no depressive symptoms. CONCLUSIONS: This study suggests that after treatment, many HCC survivors experience depressive symptoms that are strongly associated with poorer HRQOL. PMID- 23686522 TI - Spatial and temporal plasticity of synaptic organization in anterior cingulate cortex following peripheral inflammatory pain: multi-electrode array recordings in rats. AB - To explore whether experiencing inflammatory pain has an impact upon intracortical synaptic organization, the planar multi-electrode array (MEA) technique and 2-dimensional current source density (2D-CSD) imaging were used in slice preparations of the anterior cingulate cortex (ACC) from rats. Synaptic activity across different layers of the ACC was evoked by deep layer stimulation through one electrode. The layer-localization of both local field potentials (LFPs) and the spread of current sink calculated by 2D-CSD analysis was characterized pharmacologically. Moreover, the induction of long-term potentiation (LTP) and changes in LTP magnitude were also evaluated. We found that under naive conditions, the current sink was initially generated in layer VI, then spread to layer V and finally confined to layers II-III. This spatial pattern of current sink movement typically reflected changes in depolarized sites from deep layers (V-VI) to superficial layers (II-III) where intra- and extracortical inputs terminate. In the ACC slices from rats in an inflamed state (for 2 h) caused by intraplantar bee-venom injection, the spatial profile of intra-ACC synaptic organization was significantly changed, showing an enlarged current sink distribution and a leftward shift of the stimulus-response curves relative to the naive and saline controls. The change was more distinct in the superficial layers (II-III) than in the deep site. In terms of temporal properties, the rate of LTP induction was significantly increased in layers II III by inflammatory pain. However, the magnitude of LTP was not significantly enhanced by this treatment. Taken together, these results show that inflammatory pain results in distinct spatial and temporal plasticity of synaptic organization in the ACC, which may lead to altered synaptic transmission and modulation. PMID- 23686524 TI - Dopamine agonist withdrawal syndrome: implications for patient care. AB - Dopamine agonists are effective treatments for a variety of indications, including Parkinson's disease and restless legs syndrome, but may have serious side effects, such as orthostatic hypotension, hallucinations, and impulse control disorders (including pathological gambling, compulsive eating, compulsive shopping/buying, and hypersexuality). The most effective way to alleviate these side effects is to taper or discontinue dopamine agonist therapy. A subset of patients who taper a dopamine agonist, however, develop dopamine agonist withdrawal syndrome (DAWS), which has been defined as a severe, stereotyped cluster of physical and psychological symptoms that correlate with dopamine agonist withdrawal in a dose-dependent manner, cause clinically significant distress or social/occupational dysfunction, are refractory to levodopa and other dopaminergic medications, and cannot be accounted for by other clinical factors. The symptoms of DAWS include anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalized pain, and drug cravings. The severity and prognosis of DAWS is highly variable. While some patients have transient symptoms and make a full recovery, others have a protracted withdrawal syndrome lasting for months to years, and therefore may be unwilling or unable to discontinue DA therapy. Impulse control disorders appear to be a major risk factor for DAWS, and are present in virtually all affected patients. Thus, patients who are unable to discontinue dopamine agonist therapy may experience chronic impulse control disorders. At the current time, there are no known effective treatments for DAWS. For this reason, providers are urged to use dopamine agonists judiciously, warn patients about the risks of DAWS prior to the initiation of dopamine agonist therapy, and follow patients closely for withdrawal symptoms during dopamine agonist taper. PMID- 23686525 TI - CD34+/CD38- acute myelogenous leukemia cells aberrantly express Aurora kinase A. AB - We previously showed that Aurora kinase A (AURKA) is aberrantly expressed in acute myelogenous leukemia (AML) cells when compared to bone marrow mononuclear cells isolated from healthy volunteers. We have also shown that CD34(+) /CD38(-) AML cells, one of compartments enriched for leukemia stem cells in most leukemia subgroups, were relatively resistant to cytarabine-mediated growth inhibition when compared to their CD34(+) /CD38(+) counterparts. Our study attempted to identify therapeutic targets in CD34(+) /CD38(-) AML cells and found that CD34(+) /CD38(-) AML cells isolated from patients (n = 26) expressed larger amounts of AURKA than their CD34(+) /CD38(+) counterparts and CD34(+) normal hematopoietic stem/progenitor cells isolated from healthy volunteers (n = 6), as measured by real-time reverse-transcriptase polymerase chain reaction. Blockade of AURKA by the specific inhibitor MLN8237 or a short hairpin RNA (shRNA) against AURKA significantly inhibited proliferation, impaired self-renewal capability and induced apoptosis of CD34(+) /CD38(-) AML cells, in association with modulation of levels of Bcl-2 family member proteins. Importantly, inhibition of AURKA in CD34(+) /CD38(-) AML cells by MLN8237 or an shRNA significantly impaired engraftment of these cells in severely immunocompromised mice and appeared to prolong their survival. These results suggest that AURKA is a promising molecular target to eliminate chemotherapy-resistant CD34(+) /CD38(-) AML cells. PMID- 23686526 TI - Lead and the deafness of Ludwig van Beethoven. AB - OBJECTIVES/HYPOTHESIS: To reexamine the cause of Beethoven's hearing loss because of significant recent articles. DATA SOURCES: Medical and musical literature online, in print, and personal communication. METHODS: Relevant literature review. RESULTS: Evidence of otosclerosis is lacking because close gross examination of Beethoven's middle ears at autopsy did not find any otosclerotic foci. His slowly progressive hearing loss over a period of years differs from reported cases of autoimmune hearing loss, which are rapidly progressive over a period of months. He also lacked bloody diarrhea that is invariably present with autoimmune inflammatory bowel disease. The absence of mercury in Beethoven's hair and bone samples leads us to conclude that his deafness was not due to syphilis because in that era syphilis was treated with mercury. High levels of lead deep in the bone suggest repeated exposure over a long period of time rather than limited exposure prior to the time of death. The finding of shrunken cochlear nerves at his autopsy is consistent with axonal degeneration due to heavy metals such as lead. Chronic low-level lead exposure causes a slowly progressive hearing loss with sensory and autonomic findings, rather than the classic wrist drop due to motor neuropathy from sub-acute poisoning. Beethoven's physicians thought that he had alcohol dependence. He particularly liked wine that happened to be tainted with lead. CONCLUSIONS: Beethoven's chronic consumption of wine tainted with lead is a better explanation of his hearing loss than other causes. PMID- 23686528 TI - Prevalence of sexual violence and posttraumatic stress disorder in an urban African-American population. AB - Sexual violence is prevalent nationally and contributes to psychopathology in the general population. Despite elevated traumatic event exposure among economically disadvantaged urban-dwelling African-Americans, there is insufficient information on lifetime sexual violence exposure and associated psychopathology in this population. In 2008-2009, 1,306 African-Americans from a Detroit household probability sample reported on lifetime rape and sexual assault and past-month and lifetime posttraumatic stress disorder (PTSD). Lifetime sexual violence prevalence was 26.3 % for women and 5.1 % for men. Relative to non-victims, sexual violence victims: reported more other traumatic events; had 4 times greater unadjusted odds of past-month and lifetime PTSD; had 1.6 times greater adjusted odds of lifetime PTSD only after controlling for other traumatic events. Sexual violence was associated with increased risk for lifetime PTSD and exposure to other traumas. Findings highlight a need to screen for sexual violence and PTSD among urban African-Americans. PMID- 23686527 TI - Case reports of neuroleptic malignant syndrome in context of quetiapine use. AB - A retrospective analysis was followed on 20 case reports covering the possible correlation between the atypical antipsychotic, quetiapine, and neuroleptic malignant syndrome (NMS), determined by the study of 7 different NMS criteria guidelines. A great majority (19) of the case studies did not meet the requirements of all 7 guidelines, frequently due to unreported information. Nor was quetiapine proven to be the sole cause of the possible NMS in the two age groups investigated. Only one case was found to have no other medication or medical conditions confounding the relationship of quetiapine and NMS symptoms, and that case was in the context of a significant quetiapine overdose. The other 19 cases demonstrated the difficulty of identifying the cause of NMS when polypharmacy and other medical conditions are involved. The authors note the need for caution in deciding both the presence of NMS and the causal factors of the symptoms. PMID- 23686529 TI - Lifestyle physical activity behavior among South Asian Indian immigrants. AB - Little is known of the physical activity behavior of South Asian Indian immigrants (SAIs), though they have more than twice the risk for cardiovascular disease and diabetes than Whites. This was a cross-sectional descriptive face-to face survey design, comparing between men and women in leisure time (LTPA), household (HPA), and occupational physical activity (OPA). Participants also wore a Lifecorder EX (NL2200) accelerometer for 7 days. Just over half (51.8 %) of the participants met the recommended PA guidelines (>=150 min moderate-intensity or >=75 min vigorous-intensity) through LTPA. The average number of daily steps was 6,904.3, which is in the "low active" classification. Increasing lifestyle PA among SAIs is important; PA interventions appealing to gender and culture and with an aerobic component are needed. PMID- 23686530 TI - The effects of dietary supplementation with chromium picolinate throughout gestation on productive performance, Cr concentration, serum parameters, and colostrum composition in sows. AB - The objective of this study was to determine the effects of supplemental chromium as chromium picolinate (CrPic) on productive performance, chromium (Cr) concentration, serum parameters, and colostrum composition in sows. Thirty Yorkshire sows were bred with semen from a pool of Landrace boars. The sows were equally grouped and treated with either a diet containing 0 (control) or 400 ppb dietary Cr supplementation throughout gestation. The sows received the same basal diet based on corn-DDGS meal. Supplemental CrPic increased (P < 0.05) the sow body mass gain from the insemination to the day 110 of gestation in sows. No differences (P > 0.50) were observed in the gestation interval, sow mass, and backfat at insemination, after farrowing, at weaning and lactation loss. The number of piglets born alive, piglets per litter at weaning, and litter weaned mass were increased (P < 0.05) for those supplemented with CrPic compared with the control. However, the total number of piglets born, total born litter mass, average piglet birth body mass, born alive litter mass, and average born alive piglet mass did not differ among the treatments (P > 0.05). The placental masses of sows were similar among treatments (P > 0.05). Dietary supplementation with CrPic throughout gestation in sows showed increased (P < 0.01) concentration of Cr in the colostrum or serum at days 70 and 110. Compared with the control group, dietary supplementation with CrPic throughout gestation in sows decreased (P < 0.05) the serum insulin concentration, the glucose or serum urea nitrogen concentration at days 70 and 110. However, no differences (P > 0.05) were observed in total protein concentration among treatments. No differences (P > 0.05) were observed in total solids, protein, fat or lactose among sows fed the diets supplemented with CrPic compared with the control. This exciting finding provides evidence for an increase in mass gain and live-born piglets in sows supplemented with CrPic throughout gestation. PMID- 23686531 TI - A CT-based study investigating the relationship between pedicle screw placement and stimulation threshold of compound muscle action potentials measured by intraoperative neurophysiological monitoring. AB - PURPOSE: Neurophysiological monitoring aims to improve the safety of pedicle screw placement, but few quantitative studies assess specificity and sensitivity. In this study, screw placement within the pedicle is measured (post-op CT scan, horizontal and vertical distance from the screw edge to the surface of the pedicle) and correlated with intraoperative neurophysiological stimulation thresholds. METHODS: A single surgeon placed 68 thoracic and 136 lumbar screws in 30 consecutive patients during instrumented fusion under EMG control. The female to male ratio was 1.6 and the average age was 61.3 years (SD 17.7). Radiological measurements, blinded to stimulation threshold, were done on reformatted CT reconstructions using OsiriX software. A standard deviation of the screw position of 2.8 mm was determined from pilot measurements, and a 1 mm of screw-pedicle edge distance was considered as a difference of interest (standardised difference of 0.35) leading to a power of the study of 75 % (significance level 0.05). RESULTS: Correct placement and stimulation thresholds above 10 mA were found in 71 % of screws. Twenty-two percent of screws caused cortical breach, 80 % of these had stimulation thresholds above 10 mA (sensitivity 20 %, specificity 90 %). True prediction of correct position of the screw was more frequent for lumbar than for thoracic screws. CONCLUSION: A screw stimulation threshold of >10 mA does not indicate correct pedicle screw placement. A hypothesised gradual decrease of screw stimulation thresholds was not observed as screw placement approaches the nerve root. Aside from a robust threshold of 2 mA indicating direct contact with nervous tissue, a secondary threshold appears to depend on patients' pathology and surgical conditions. PMID- 23686532 TI - Measurement of clinically relevant functional health perceptions in patients with whiplash-associated disorders: the development of the whiplash specific activity and participation list (WAL). AB - PURPOSE: The International Classification of Human Functioning Disability and Health (ICF) provides insight into functional health status in patients with whiplash-associated disorders (WAD). In the assessment of functional limitations in patients with WAD, there are several condition-specific questionnaires available. Estimation of the true relationship between the separate constructs of the ICF is only possible if the items of the salient questionnaires measure exactly the constructs of interest, while not simultaneously measuring other constructs of the model. This study aimed to develop a condition specific and clinically relevant and usable instrument for patients with WAD that measures activity limitations and participation restrictions, as defined by the ICF framework. METHODS: Item generation consisted of (1) a semi-structured interview which was conducted among 69 WAD patients; (2) a Delphi study involving 13 health professionals experienced in the assessment of patients with WAD; (3) a literature search for items from self-assessment questionnaires for neck pain. RESULTS: A 35-item condition-specific self-assessment questionnaire for patients with WAD was developed. This new questionnaire measures purely activity limitations and participation restrictions according to the ICF and is based on patients' opinions and expert opinions. CONCLUSION: The whiplash activity and participation list tends to measure clinically relevant activity limitations and participation restrictions in WAD patients. PMID- 23686533 TI - Monogenoideans (Platyhelminthes) from the gill lamellae of the spotted sea trout, Cynoscion nebulosus (Perciformes, Sciaenidae), from the western coast of the Yucatan Peninsula, Mexico, with redescription of Diplectanum bilobatus Hargis 1955 (Diplectanidae). AB - The gill lamellae ectoparasites of the spotted sea trout, Cynoscion nebulosus (Sciaenidae), in the western coast of the Yucatan Peninsula, Mexico, revealed three species of Monogenoidea: Cynoscionicola heteracantha (Manter 1938) Price, 1962 (Microcotylidae); Choricotyle cynoscioni (MacCallum, 1917) Llewellyn, 1941 (Diclidophoridae); and Diplectanum bilobatus Hargis, 1955 (Diplectanidae). Brief comments about the current taxonomic status as well as supplemental observations of all these monogenoids originally described and/or reported from the same host fish species found in the USA are provided. New illustrations, prevalence and mean intensity of infection, as well morphological and biometric data based on new specimens are shown. C. heteracantha and C. cynoscioni collected in this study represent the second and first records of the species of these genera for the Atlantic coast of Mexico. The specimens of D. bilobatus are provisionally retained within Diplectanum until an emendation of the genus and a formal revision of all named species of this monogenoidean genus are undertaken. PMID- 23686535 TI - Sonographic joint assessment in rheumatoid arthritis: associations with clinical joint assessment during a state of remission. AB - OBJECTIVE: Sonography, as compared with clinical assessment, is a sensitive tool for evaluating synovitis in rheumatoid arthritis (RA). However, differences between these assessment tools may depend on how joint activity (i.e., an active joint) is defined. The present study was undertaken to compare clinically active joints with sonographically active joints in patients with RA, applying different sonographic definitions of an active joint. METHODS: Sonographic assessment of the finger and wrist joints (total of 11 joints) of each hand was performed in RA patients whose disease was in remission (Clinical Disease Activity Index <=2.8; n = 60). Gray-scale (GS) and power Doppler (PD) ultrasound signals for synovitis were evaluated on a 4-point scale (grade 0 = none, grade 3 = severe). The sensitivity and specificity of swollen joint counts were investigated using, as reference, increasingly stringent sonographic definitions of an active joint. Sonographic findings were also assessed for correlations with other clinical variables, including the Health Assessment Questionnaire (HAQ) disability index (DI). Followup analyses were performed after 6-12 months. RESULTS: GS ultrasound signals yielded positive findings for synovitis in 67.2% of the 1,320 joints assessed, and PD ultrasound signals indicated signs of synovitis in 20.4% of the joints assessed. Clinical identification of joint swelling was 100% specific for sonographic joint activity, independent of the stringency of the sonographic definition used; maximum sensitivity of the swollen joint counts was 25% for the most stringent definition (i.e., GS grade 3 and PD grade 3). Furthermore, patients with a higher-grade PD signal (grade 3) showed a higher HAQ DI score compared to patients with lower-grade PD signals (mean +/- SD HAQ DI 0.45 +/- 0.62 versus 0.20 +/- 0.35). A higher grade of PD signal at baseline was found in joints that were assessed as clinically swollen at the consecutive followup visit. CONCLUSION: Low-grade PD and GS ultrasound signals may not necessarily reflect the presence of active synovitis in RA joints. High-grade PD signals correlate well with the presence of clinical joint swelling and clinical disease activity, and a higher grade of PD signal is associated with higher degrees of functional impairment. PMID- 23686534 TI - Neuroimaging predictors of brain amyloidosis in mild cognitive impairment. AB - OBJECTIVE: To identify a neuroimaging signature predictive of brain amyloidosis as a screening tool to identify individuals with mild cognitive impairment (MCI) that are most likely to have high levels of brain amyloidosis or to be amyloid free. METHODS: The prediction model cohort included 62 MCI subjects screened with structural magnetic resonance imaging (MRI) and (11) C-labeled Pittsburgh compound B positron emission tomography (PET). We identified an anatomical shape variation-based neuroimaging predictor of brain amyloidosis and defined a structural MRI-based brain amyloidosis score (sMRI-BAS). Amyloid beta positivity (Abeta(+) ) predictive power of sMRI-BAS was validated on an independent cohort of 153 MCI patients with cerebrospinal fluid Abeta1-42 biomarker data but no amyloid PET scans. We compared the Abeta(+) predictive power of sMRI-BAS to those of apolipoprotein E (ApoE) genotype and hippocampal volume, the 2 most relevant candidate biomarkers for the prediction of brain amyloidosis. RESULTS: Anatomical shape variations predictive of brain amyloidosis in MCI embraced a characteristic spatial pattern known for high vulnerability to Alzheimer disease pathology, including the medial temporal lobe, temporal-parietal association cortices, posterior cingulate, precuneus, hippocampus, amygdala, caudate, and fornix/stria terminals. Abeta(+) prediction performance of sMRI-BAS and ApoE genotype jointly was significantly better than the performance of each predictor separately (area under the curve [AUC] = 0.88 vs AUC = 0.70 and AUC = 0.81, respectively) with >90% sensitivity and specificity at 20% false-positive rate and false-negative rate thresholds. Performance of hippocampal volume as an independent predictor of brain amyloidosis in MCI was only marginally better than random chance (AUC = 0.56). INTERPRETATION: As one of the first attempts to use an imaging technique that does not require amyloid-specific radioligands for identification of individuals with brain amyloidosis, our findings could lead to development of multidisciplinary/multimodality brain amyloidosis biomarkers that are reliable, minimally invasive, and widely available. PMID- 23686536 TI - Serious adverse events experienced by survivors of stroke in the first year following discharge from inpatient rehabilitation. AB - PURPOSE: To identify the incidence of adverse events (AE) that occurred in stroke survivors during the first year following discharge from inpatient rehabilitation and to determine the type and patterns of AE. METHODS: Data were collected for 12 months on events resulting in admissions to the emergency department, hospital, long-term care facility, or death. Descriptive statistics were used to depict the patterns of AE and univariate comparisons were made of the differences between survivors who did or did not experience one or more AE. RESULTS: Of the 159 participants, 50% reported a total of 163 AE. Most AE (82.2%) were unexpected and the majority occurred during the first 6 months; 12 recurrent strokes and 6 transient ischemic attacks occcurred. CONCLUSIONS: Education on prevention and treatment of common AE is important prior to discharge. Anticipatory guidance may help survivors and caregivers modify their lifestyle and prevent common AE. PMID- 23686547 TI - In vitro anticancer activity of Spondias pinnata bark on human lung and breast carcinoma. AB - Spondias pinnata, a commonly distributed tree in India, previously proven for various pharmacological properties and also reported for efficient anti-oxidant, free radical scavenging and iron chelating activity, continuing this, the present study is aimed to investigate the role of 70 % methanolic extract of S. pinnata bark (SPME) in promoting apoptosis in human lung adenocarcinoma cell line (A549) and human breast adenocarcinoma cell line (MCF-7). These two malignant cell lines and a normal cell line were treated with increasing concentrations of SPME and cell viability is calculated. SPME showed significant cytotoxicity to both A549 and MCF-7 cells with an IC50 value of 147.84 +/- 3.74 and 149.34 +/- 13.30 MUg/ml, respectively, whereas, comparatively no cytotoxicity was found in normal human lung fibroblast cell line (WI-38): IC50 932.38 +/- 84.44 MUg/ml. Flow cytometric analysis and confocal microscopic studies confirmed that SPME is able to induce apoptosis in both malignant cell lines. Furthermore, immunoblot result proposed the pathway of apoptosis induction by increasing Bax/Bcl-2 ratio in both cell types, which results in the activation of the caspase-cascade and ultimately leads to the cleavage of Poly adeno ribose polymerase. For the first time this study proved the anticancer potential of SPME against human lung and breast cancer by inducing apoptosis through the modulation of Bcl-2 family proteins. This might take S. pinnata in light to investigate it for further development as therapeutic anticancer source. PMID- 23686548 TI - Recent advances in crayfish hematopoietic stem cell culture: a model for studies of hemocyte differentiation and immunity. AB - Hematopoiesis is the process by which blood cells (hemocytes) mature and subsequently enter the circulation and we have developed a new technique to culture the hematopoietic progenitor cells in vitro. The reason for the successful culture was the isolation of a plasma protein that turned out to be a novel cytokine, astakine 1 (Ast1) containing a domain present in several vertebrates, so-called prokineticins. Now we have detected several astakines from other invertebrate species. Depending on our discovery of the cytokine Ast1 we have an opportunity to study in detail the differentiation of cells in the hematopoietic tissue of a crustacean, a tissue of evolutionary interest for studies of the connection between the vascular system and the nervous system. We have been able to isolate the entire hematopoietic tissue and for the first time detected a link between this tissue and the brain. We have further localized a proliferation center in the tissue and characterized its different parts. We have also used this system to isolate a new hematopoietic factor CHF that is important in the crossroad between apoptosis and hemocyte differentiation. Our technique for culture of crayfish hematopoietic stem cells provides a simple tool for studying the mechanism of hematopoiesis, but also enables detailed studies of immune defense reactions. Further, the culture system has been used for studies of viral defense and the system is suitable for gene silencing which allows functional characterization of different molecules involved in host defense as well as in hemocyte differentiation. PMID- 23686551 TI - The use of tetragnathid spiders as bioindicators of metal exposure at a coal ash spill site. AB - On 22 December 2008, a dike containing coal fly ash from the Tennessee Valley Authority Kingston Fossil Fuel Plant (TN, USA) failed, resulting in the largest coal ash spill in US history. The present study was designed to determine sediment metal concentrations at multiple site locations and to determine whether site-specific bioaccumulation of metals existed in tetragnathid spiders. Selenium and nickel were the only 2 metals to exceed the US Environmental Protection Agency sediment screening levels. Selenium concentrations in spiders were significantly higher at ash-affected sites than in those from reference sites. The ratio of methylmercury to total mercury in spiders was found to be similar to that in other organisms (65-75%), which highlights the potential use of tetragnathid spiders as an indicator species for tracing contaminant transfer between the aquatic and terrestrial ecosystems. PMID- 23686552 TI - Heterogeneous expression and functional relevance of the ubiquitin carboxyl terminal hydrolase L1 in melanoma. AB - The expression of ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) is deregulated in human cancer cells with tumor inhibiting or promoting functions. Due to less knowledge on the role of UCHL1 in melanoma progression, the expression pattern and function of UCHL1 as well as the deregulated signaling pathways were characterized. A large number of melanoma cell lines, tissue microarrays of melanoma lesions and control tissues were analyzed for UCHL1 expression using PCR, Western blot and/or immunohistochemistry. The analysis revealed that melanocyte cultures, 24 of 331 melanoma lesions, two of 18 short-term cultures and two of 19 melanoma cell lines tested, respectively, heterogeneously expressed UCHL1. The low frequency of UCHL1 expression in melanoma cells was due to gene silencing by promoter DNA hypermethylation. Using different transfection models an enzyme activity-dependent growth promoting function of UCHL1 via the activation of the mitogen-activated protein kinase signaling pathway was found in melanoma cells. Under oxygen stress a dose-dependent effect of UCHL1 was detected, which was mediated by a dynamic modification of the PI3K-Akt signaling. Thus, the aberrant UCHL1 expression in melanoma cells is linked to dynamic changes in growth properties and signal transduction cascades suggesting that UCHL1 provides a novel marker and/or therapeutic target at least for a subset of melanoma patients. PMID- 23686537 TI - Evolving gene targets and technology in influenza detection. AB - Influenza viruses cause recurring epidemic outbreaks every year associated with high morbidity and mortality. Despite extensive research and surveillance efforts to control influenza outbreaks, the primary mitigation treatment for influenza is the development of yearly vaccine mixes targeted for the most prevalent virus strains. Consequently, the focus of many detection technologies has evolved toward accurate identification of subtype and understanding the evolution and molecular determinants of novel and pathogenic forms of influenza. The recent availability of potential antiviral treatments are only effective if rapid and accurate diagnostic tests for influenza epidemic management are available; thus, early detection of influenza infection is still important for prevention, containment, patient management, and infection control. This review discusses the current and emerging technologies for detection and strain identification of influenza virus and their specific gene targets, as well as their implications in patient management. PMID- 23686553 TI - Tissue recombination techniques for mouse embryonic mammary glands. AB - This review gives detailed technical protocols for dissection of embryonic mammary rudiments and preparation of tissue recombinants composed of embryonic mouse mammary mesenchyme and epithelium. This experimental protocol was used in several seminal experiments that have greatly increased our understanding of embryonic mammary gland development, including the finding that mammary mesenchyme induces and specifies mammary epithelial identity. Analysis of mesenchymal-epithelial interactions has facilitated identification of molecular mediators of cell-cell interactions, in particular the tissue-specific roles of genes expressed in mesenchyme and epithelium during embryonic development. PMID- 23686554 TI - Embryonic mammary gland development; a domain of fundamental research with high relevance for breast cancer research. Preface. PMID- 23686555 TI - Access to the parapharyngeal space: an anatomical study comparing the endoscopic and open approaches. AB - OBJECTIVES/HYPOTHESIS: A subtemporal preauricular approach to the infratemporal fossa and parapharyngeal space has been the traditional path to tumors of this region. The morbidity associated with this procedure has lead to the pursuit of less invasive techniques. Endoscopic access using a minimally invasive transmaxillary/transpterygoid approach potentially may obviate the drawbacks associated with open surgery. The anatomy of the parapharyngeal space is complex and critical; therefore, a comparison of the anatomy exposed by these different approaches could aid in the decision making toward a minimally invasive surgical corridor. STUDY DESIGN: Technical Note. METHODS: The parapharyngeal space was accessed endonasally by removal of the medial and posterior walls of the maxillary sinus. To allow better visualization and increased triangulation of a bimanual dissection technique, a sublabial canine fossa antrostomy was created. The medial and lateral pterygoid plates were removed. Further lateral dissection exposed the relevant anatomy of the parapharyngeal space. A subtemporal preauricular infratemporal approach was also completed. RESULTS: The endoscopic approach provided sufficient access to the superior portion of the parapharyngeal space. The open approach also provided adequate access; however, it required a larger surgical window, causing greater injury. A significant advantage of the subtemporal approach is the improved access to the petrous portion of the internal carotid artery. Conversely, the endonasal approach provided improved access to the anterior and medial portions of the superior parapharyngeal space. CONCLUSION: Endoscopic endonasal access utilizing a transmaxillary/transpterygoid approach provides a sufficient surgical window for tumor extirpation. Utilization of this approach obviates some of the morbidity associated with an open procedure. LEVEL OF EVIDENCE: 5. PMID- 23686556 TI - The European KIDSCREEN approach to measure quality of life and well-being in children: development, current application, and future advances. AB - PURPOSE: The KIDSCREEN questionnaires were developed by a collaborative effort of European pediatric researchers for use in epidemiologic public health surveys, clinical intervention studies, and research projects. The article gives an overview of the development of the tool, summarizes its extensive applications in Europe, and describes the development of a new computerized adaptive test (KIDS CAT) based on KIDSCREEN experiences. METHODS: The KIDSCREEN versions (self-report and proxy versions with 52, 27, and 10 items) were simultaneously developed in 13 different European countries to warrant cross-cultural applicability, using methods based on classical test theory (CTT: descriptive statistics, CFA and MAP, internal consistency, retest reliability measures) and item response theory (IRT: Rasch modeling, DIF analyses, etc.). The KIDS-CAT was developed (in cooperation with the US pediatric PROMIS project) based on archival data of European KIDSCREEN health surveys using IRT more extensively (IRC). RESULTS: Research has shown that the KIDSCREEN is a reliable, valid, sensitive, and conceptually/linguistically appropriate QoL measure in 38 countries/languages by now. European and national norm data are available. New insights from KIDSCREEN studies stimulate pediatric health care. Based on KIDSCREEN, the Kids-CAT promises to facilitate a very efficient, precise, as well as reliable and valid assessment of QoL. CONCLUSIONS: The KIDSCREEN has standardized QoL measurement in Europe in children as a valid and cross-cultural comparable tool. The Kids-CAT has the potential to further advance pediatric health measurement and care via Internet application. PMID- 23686558 TI - The evaluation of spontaneous space closure after the extraction of first permanent molars. AB - AIM: In the UK, first permanent molars (FPMs) of poor prognosis are often planned for extraction so that second permanent molars (SPMs) erupt favourably to replace the FPMs. However, there is little published data to support this treatment strategy. The aim of this study was to assess the success of planned FPM extractions conducted 5 years ago at a dental hospital in London. METHODS: Two hundred and thirty-six SPMs from 63 patients were clinically assessed. The position of each SPM was recorded in relation to the second premolar, against patient Angle's classification and SPM radiographic development stage at the time of FPM extraction. STATISTICS: Results were analysed using ordered logistic regression. RESULTS: At the time of FPM extraction, only 54 % of SPMs were at the "ideal" stage of development (Demirjian's dental development stage E). Upper and lower arches yielded significantly different results with 92 % of all upper extractions resulting in complete space closure regardless of SPM development stage. Only 66 % of lower FPMs extracted at SPM stage E had complete space closure and no significant relationship was found between lower SPM development stage and its subsequent space closure. Space closure in both arches also appeared independent of patient Angle's classification. CONCLUSIONS: Although only over half the patients had FPMs extracted at the "ideal time", this did not appear to influence successful positioning of the upper or lower SPM. More research is required to investigate and confirm which predictive parameters have a significant effect on post-extraction orthodontic development, especially in the lower arch. PMID- 23686557 TI - Capturing the aversive state of cephalic pain preclinically. AB - OBJECTIVE: Preclinical evaluation of headache by behavioral assessment of reward from pain relief. METHODS: Inflammatory mediators (IMs) or control solution were applied to the rat dura mater to elicit a presumed state of cephalic pain. Hind paw incision was used in separate groups of animals to model noncephalic postsurgical pain. Drugs were given systemically or microinjected within the rostral ventromedial medulla (RVM), nucleus accumbens (NAc), or rostral anterior cingulate cortex (rACC). Peripheral nerve block was produced at the level of the popliteal fossa, and behavior was assessed using evoked sensory stimuli or conditioned place preference (CPP). Immunohistochemistry and brain microdialysis measurements were performed. RESULTS: Dural IMs produced long-lasting generalized cutaneous allodynia. RVM lidocaine produced CPP, increased NAc c-Fos, and dopamine release selectively in rats receiving dural IMs; CPP was blocked by intra-NAc alpha-flupenthixol, a dopaminergic antagonist. Intravenous alpha calcitonin gene-related peptide (alphaCGRP)(8-37) produced CPP and elicited NAc dopamine release selectively in rats treated with dural IMs. Prior lesion of the rACC or treatment with systemic sumatriptan or alphaCGRP(8-37) abolished RVM lidocaine-induced CPP in IM-treated rats. Sumatriptan treatment blocked NAc dopamine release in IM-treated rats receiving RVM lidocaine. Systemic sumatriptan did not alter pain relief-induced CPP in rats with incisional injury. INTERPRETATION: Cephalic pain was unmasked in rats by assessment of motivated behavior to seek relief. Relief of pain activates the dopaminergic reward pathway to elicit negative reinforcement of behavior. Medications clinically effective for migraine headache selectively elicit relief of ongoing cephalic, but not postsurgical, noncephalic pain. These studies provide a platform for exploring migraine pathophysiology and for the discovery of new headache therapies. PMID- 23686562 TI - Mineral elements in root of wild Saposhnikovia divaricata and its rhizosphere soil. AB - Mineral elements are important components of medicinal herbs, and their concentrations are affected by many factors. In this study, Ca, Mg, Na, K, Fe, Mn, Cu, and Zn concentrations in wild Saposhnikovia divaricata and its rhizosphere soil collected from seven locations at two different times in China were measured, and influences of rhizosphere soil on those minerals in plant were evaluated. The results showed that mean concentrations of eight minerals in plant samples decreased in the order: Ca > Mg > Na > K > Fe > Zn > Mn > Cu, and those in the soil samples followed the following order: Na > Fe > Ca > K > Mg > Mn > Zn > Cu. Mean concentrations of Ca, Na, Mg, and K in plants were higher than those in soils, while higher mean concentrations of the other four minerals were found in soils. It was found that there was a positive correlation of Mg, Na, and Cu concentrations in the plant with those in the soil respectively, but a negative correlation of Mn concentration in plant with that in the soil. Except Ca, K, and Mn, the other five minerals in plant were all directly affected by one or more chemical compositions of soil. The results also indicate that pH value and concentrations of total nitrogen, Mg, Mn, and Cu in soil had significant correlations with multimineral elements in plant. In a word, mineral elements uptake of S. divaricata can be changed by adjusting the soil fertility levels to meet the need of appropriate quality control of S. divaricata. PMID- 23686563 TI - The effect of iron-vitamin C co-supplementation on biomarkers of oxidative stress in iron-deficient female youth. AB - There is no study that assessed the effect of co-supplementation of iron and vitamin C on biomarkers of oxidative stress in non-anemic iron-deficient females. We investigated the effects of iron vs. iron + vitamin C co-supplementation on biomarkers of oxidative stress in iron-deficient girls. In a double-blind randomized controlled clinical trial, performed among 60 non-anemic iron deficient girls, participants were randomly assigned to receive either 50 mg/day elemental iron supplements or 50 mg/day elemental iron + 500 mg/day ascorbic acid for 12 weeks. Fasting blood samples were taken at baseline, weeks 6 and 12 for assessment of biomarkers of oxidative stress. Compared with the baseline levels, both iron and iron + vitamin C supplementation resulted in a significant reduction in serum malondialdehyde (MDA) levels (P time < 0.001) and remarkable elevation in serum total antioxidant capacity (TAC; P time < 0.001) and vitamin C levels (P time = 0.001); however, comparing the two groups we failed to find an additional effect of iron + vitamin C supplementation to that of iron alone on serum TAC and MDA levels (P group was not statistically significant). Iron + vitamin C supplementation influenced serum vitamin C levels much more than that by iron alone (P group < 0.01). We also found a significant interaction term between time and group about serum vitamin C levels while this interaction was not significant about serum TAC and MDA levels. In conclusion, we found that iron supplementation with/without vitamin C improve biomarkers of oxidative stress among non-anemic iron-deficient females and may strengthen the antioxidant defense system by decreasing reactive oxygen species. Co-supplementation of iron + vitamin C has no further effect on oxidative stress compared with iron alone. PMID- 23686564 TI - Electrocardiogram in apical hypertrophic cardiomyopathy with a speculation as to the mechanism of its features. AB - A variety of electrocardiogram (ECG) alterations in patients with apical hypertrophic cardiomyopathy (AHCM) have been described in the literature, but no relevant quantitative analysis has been provided; thus the objective of this communication was to review the relevant literature and using two cases of patients with AHCM, to provide such a quantitative analysis. Using PubMed to search the literature 13 studies on the ECG in patients with AHCM were identified and evaluated; also a quantitative analysis of the ECG attributes in two patients was carried out. Qualitative ECG features from the literature on patients with AHCM is discussed. Also a description of the ECG in two patients with AHCM has identified as typical features truly giant QRS complexes in the precordial leads, particularly in lead V4, with rightward superior, and posterior shift of the T wave vector, the latter being a newly described ECG correlate of AHCM. A speculation as to the possible mechanism of the observed ECG features is included. PMID- 23686565 TI - Genetic polymorphism of cytochrome P450 (CYP) 1A1, CYP1A2, and CYP2E1 genes modulate susceptibility to gastric cancer in patients with Helicobacter pylori infection. AB - BACKGROUND: Activity of cytochrome P450 (CYP), a polymorphic carcinogen activating enzyme, is exaggerated following Helicobacter pylori infection. We studied the role of CYP2E1, CYP1A2 (rs762551), and CYP1A1 (rs4646903) polymorphisms in association with H. pylori infection in gastric carcinogenesis. METHODS: Genotyping of CYP2E1 (96-bp insertion), CYP1A2 (164A to C), and CYP1A1 (3801C to T) was carried out in 88, 76, 53, and 170 patients with gastric cancer (GC), functional dyspepsia (FD), peptic ulcer (PU), and healthy controls (HC), respectively. Serum IgG antibody (all subjects), rapid urease test, and histology (GC, FD, and PU patients) were used to test for H. pylori. RESULTS: CYP2E1 gene polymorphism was more common among patients with GC than HC and PU [48/88 (54.5 %) vs. 67/170 (39.4 %); OR 1.9, 95 % CI 1.1-3.2, p = 0.016) and [PU 18/53 (34 %); OR 2.3 (1-4.7), p = 0.02]. CYP1A2 CC or CT genotypes was lower among patients with GC than HC [50/88 (56.8 %) vs. 120/170 (70.6 %); OR 0.54 (0.31-0.92), p = 0.023]. CYP1A1 polymorphism and CYP1A1-CYP1A2 haplotypes were comparable among different groups. CYP2E1 was also more common in patients with GC than HC and PU in the absence of H. pylori [33/60 (55 %) vs. 19/52 (36.5 %); OR 4 (1.5-11.4), p = 0.007 and PU 7/22 (31.8 %); OR 3.4 (1-11.6), p = 0.05]. CYP1A1 (CT + TT) was more common in patients with GC than PU in presence of H. pylori [17/26 (65.4 %) vs. 11/29 (38 %); OR 3.0 (1.03-9.3), p = 0.045]. CONCLUSIONS: The presence of CYP2E1 (96-bp insertion) is associated with increased risk of GC even in absence of H. pylori. CYP1A2 CC or CT is associated with reduced risk of GC. PMID- 23686566 TI - Development of glutaraldehyde-crosslinked chymotrypsin and an in situ immobilized enzyme microreactor with peptide mapping by capillary electrophoresis. AB - Immobilized proteolytic enzymes present several advantages over their soluble form, not the least of which is suppression of autoproteolysis peaks even at high enzyme-to-substrate ratios. We have made immobilized chymotrypsin by directly crosslinking it with glutaraldehyde to produce polymeric particles. Digestion of two model substrates using the particles was followed by CE peptide mapping with detection by UV absorbance or LIF. Results showed that autoproteolysis was highly suppressed and that different storage conditions of the particles in the short term (24 h) did not affect digestion of denatured BSA. As well, the chymotrypsin particles were indifferent to the presence of fluorescein groups on a casein substrate. Glutaraldehyde crosslinking of chymotrypsin inside a fused silica capillary column to make an immobilized enzyme reactor (IMER) was achieved in a series of reagent addition and washing steps, entirely automated using a commercial CE instrument. Digestion of myoglobin in the IMER for 30 min at 37 degrees C followed by peptide mapping by CE-MS of the collected digest allowed identification of 17 chymotryptic peptides of myoglobin, or 83% primary sequence coverage. PMID- 23686567 TI - Mitochondrial DNA content of mature spermatozoa and oocytes in the genetic model Drosophila. AB - Although crucial to the success of fertilization and embryogenesis, little is known about the mitochondrial DNA (mtDNA) content of mature spermatozoa and oocytes across taxa and across different fertilization systems. Oocytes are assumed to hold a large population of mtDNAs that populate emerging cells during early embryogenesis, whereas spermatozoa harbor only a limited pool of mtDNAs that is believed to sustain functionality but fails to contribute paternal mtDNA to the zygote. Recent work suggests that mature sperm of the genetic model Drosophila melanogaster lack mtDNA, questioning the significance of zygotic mechanisms for the selective elimination of paternal mtDNA and their necessity for fertilization success. This finding further contradicts previous observations of the inheritance of paternal mtDNA in drosophilids. Using quantitative polymerase chain reaction, we estimate the mtDNA content of several laboratory strains of D. melanogaster and D. simulans to shed light on this discrepancy and to describe the mitochondrial/mtDNA load of gametes within this system. These measurements led to an average estimate of 22.91+/-4.61 mtDNA molecules/copies per spermatozoon across both species and to 1.07E+07+/-2.71E+06 molecules/copies per oocyte for D. simulans. As a consequence, the ratio of paternal and maternal mtDNA in the zygote was estimated at 1:4.65E+05. PMID- 23686568 TI - A clinical treatment intervention for dysphoria: externalizing metaphors therapy. AB - The purpose of this article is to explore a novel, short-term treatment intervention for internalizing behaviours. This intervention is primarily based upon an externalizing process, transforming of metaphoric imagery, and shifting of underlying maladaptive emotional schemas. This article addresses the clinical population of children and youth, specifically through outlining the protocol, externalizing metaphors therapy. A selective review of significant works regarding the efficacy of short-term therapy was conducted, including the process of change within narrative therapy. It is proposed that two specific processes account for the mental health change experienced by clients who receive this new treatment intervention: (1) externalization of problems and (2) purposeful client generated metaphor manipulation, impacting upon underlying schemas. From these theoretical constructs, the present article outlines a three-session treatment protocol that manualizes these key clinical processes. A case study is presented to illustrate this intervention for anxiety and depression. Further clinical research is underway to address the testable hypotheses resulting from the current theoretical model. Clinical trials in brief psychotherapy are suggested to empirically evaluate the efficacy of this new treatment intervention for dysphoria. KEY PRACTITIONER MESSAGE: This article outlines a short-term treatment intervention for anxiety and depression (dysphoira) through a novel 3-session model, where the clinician-practitioner can obtain competency through a one-day workshop.Its relevance for the clinical researcher and the mental health community is in its versatility in addressing internalizing behavior for four clinical populations: (1) children and adolescents; (2) children and adolescents on the autism spectrum; (3) adults in general; and, (4) adults with a dual diagnosis. The treatment protocol described within is based upon the externalizing and deconstructive properties of Narrative Therapy, and the transformation of metaphoric imagery of Metaphor Therapy; both of which have little empirical support with narrative practices gaining international attention and widespread usage - through brief therapy, long-term therapy, and walk-in clinics in North America. For the first time, the theoretical constructs of the 3 session model are described and a case example illustrates the interlinking concepts. PMID- 23686569 TI - Performance of anti-cyclic citrullinated Peptide assays differs in subjects at increased risk of rheumatoid arthritis and subjects with established disease. AB - OBJECTIVE: To compare the diagnostic accuracy and agreement of commonly available assays for anti-citrullinated protein antibodies in patients with established rheumatoid arthritis (RA) and subjects at increased risk of RA. METHODS: Tests for anti-cyclic citrullinated peptide (anti-CCP) antibodies were performed using CCP2 IgG and CCP3.1 IgA/IgG enzyme-linked immunosorbent assays in the following groups: probands with established RA (n = 340) from the Studies of the Etiology of Rheumatoid Arthritis (SERA) cohort and their first-degree relatives (FDRs) without inflammatory arthritis (n = 681), Department of Defense Serum Repository (DoDSR) RA cases with pre-RA diagnosis samples (n = 83; 47 cases also had post-RA diagnosis samples), and blood donor and DoDSR control subjects (n = 283). RESULTS: In patients with established RA, the CCP2 assay was more specific (99.2% versus 93.1%; P < 0.01) but less sensitive (58.7% versus 67.4%; P = 0.01) than the CCP3.1 assay; the specificity of the CCP3.1 assay increased to 97.2% when cutoff levels >=3-fold the standard level were considered. In all subjects, CCP3.1 assay positivity (using standard cutoff levels) was more prevalent. Among DoDSR cases, the CCP2 assay was more specific than the CCP3.1 for predicting a future diagnosis of RA, and higher CCP levels trended toward increasing specificity for the development of RA within 2 years. At standard cutoff levels, assay agreement was good in patients with established RA (kappa = 0.76) but poor in FDRs without inflammatory arthritis (kappa = 0.25). CONCLUSION: Anti-CCP assays differ to an extent that may be meaningful for diagnosing RA in patients with inflammatory arthritis and evaluating the natural history of RA development in subjects at risk of RA. The mechanisms underlying these differences in test performance need further investigation. PMID- 23686570 TI - Comparing the effects of nanosilver size and coating variations on bioavailability, internalization, and elimination, using Lumbriculus variegatus. AB - As the production and applications of silver nanoparticles (AgNPs) increase, it is essential to characterize fate and effects in environmental systems. Nanosilver materials may settle from suspension; therefore, the authors' objective was to utilize environmentally relevant bioassays and study the impact, bioaccumulation, tissue distribution, uptake, and depuration of AgNPs on a sediment-dwelling invertebrate, Lumbriculus variegatus. Hydrodynamic diameters of uncoated 30-nm, 80-nm, and 1500-nm AgNP powders and a polyvinyl pyrrolidone (PVP) AgNP suspension were measured utilizing dynamic light scattering in freshwater media (0-280 uS/cm). Aggregation for 30 nm, 80 nm, and 1500 nm silver increased with conductivity but was minimal for PVP silver. Lumbriculus variegatus were exposed to AgNPs or silver nitrate (AgNO3 ) spiked into sediment (nominally 100 mg/kg) and water (PVP 30 nm and 70 nm Ag, nominally 5 mg/L). Uptake was assessed through inductively coupled plasma mass spectroscopy (ICP-MS) and hyperspectral imaging. Particle sizes were examined through field flow fractionation-ICP-MS (FFF-ICP-MS) and ICP-MS in single particle mode (SP-ICP-MS). Lumbriculus variegatus were also depurated for 6 h, 8 h, 24 h, and 48 h to determine gut clearance. Bioaccumulation factors of sediment-exposed L. variegatus were similar regardless of particle size or coatings. The FFF-ICP-MS and SP-ICP-MS detected AgNPs for up to 48 h post depuration. The present study provides information on bioaccumulation and interactions of AgNPs within biological systems. PMID- 23686571 TI - Impact of voluntary accreditation on short-stay rehabilitative measures in U.S. nursing homes. AB - PURPOSE: To examine accreditation from nursing homes accredited by the Commission on Accreditation of Rehabilitation Facilities (CARF) and whether this is associated with improved rehabilitation care. DESIGN: Cross-sectional association of CARF accreditation and quality. METHODS: Comparison of the short-stay quality measures (influenza and pneumococcal vaccination; pain; delirium; pressures sores; five-star quality and health inspection scores) between the sample of 246 CARF-accredited homes compared with the 15,393 nursing homes in the 2010 On-Line Survey Certification of Automated Records (OSCAR). FINDINGS: CARF-accredited nursing homes demonstrate better quality with regard to the short-stay quality measures. CONCLUSIONS: Approaches beyond traditional regulation and governmental inspections are necessary to improve the quality of care in nursing homes. CLINICAL RELEVANCE: During a patient's rehabilitation stay, minimizing iatrogenic complications is paramount. Given the findings of this study, it is unfortunate that very few nursing homes are CARF accredited. PMID- 23686572 TI - p14ARF induces apoptosis via an entirely caspase-3-dependent mitochondrial amplification loop. AB - The p14(ARF) tumor suppressor triggers cell death or cell cycle arrest upon oncogenic stress. In MCF-7 breast carcinoma cells, expression of the tumor suppressor gene p14(ARF) fails to trigger apoptosis but induces an arrest in the G1 and, to a lesser extent, in the G2 phase in the cell division cycle. Here, inhibition of cell cycle arrest resulted in apoptosis induction in caspase-3 proficient MCF-7 cells upon expression of p14(ARF) . This occurred in the absence of S-phase progression or mitotic entry. In contrast, syngeneic, caspase-3 deficient MCF-7 cells remained entirely resistant to p14(ARF) -induced apoptosis. Thus, cell cycle checkpoint abrogation overcomes resistance to p14(ARF) -induced cell death and promotes cell death via a caspase-3-dependent pathway. Cell death coincided with dissipation of the mitochondrial membrane potential, release of cytochrome c, and was inhibitable by pan-caspase inhibitors and the caspase-3/7 inhibitor zDEVD-fmk. Of note, mitochondrial events of apoptosis execution depended entirely on caspase-3 proficiency indicating that caspase-3 either acts "up-stream" of the mitochondria in a "non-canonical" pathway or mediates a mitochondrial feedback loop to amplify the apoptotic caspase signal in p14(ARF) induced stress signaling. PMID- 23686573 TI - Simple technique using a Lap-Protector for fenestration to manage empyema. AB - We describe the successful management of empyema in patients who need fenestration, but whose general condition is compromised by a high count of multi drug resistant bacteria, deteriorating health, or bronchial fistula. The procedure is performed at the bed side, under local anesthesia. After making an incision in the thoracic wall using electric cautery, fenestration is created by inserting a Lap-Protector so as to widen the intercostal space. Fenestration using a Lap-Protector, which does not require resection of the ribs, is comparable to that obtained using the conventional rib resection method. However, it causes significantly less pain at the incision site, and the gauze can be changed without pain because it is not in direct contact with the fenestration wound. Thus, fenestration using a Lap-Protector is a more convenient and effective technique than conventional fenestration with rib resection for poor risk patients with empyema. PMID- 23686574 TI - Myofilament lattice structure in presence of a skeletal myopathy-related tropomyosin mutation. AB - Human tropomyosin mutations deregulate skeletal muscle contraction at the cellular level. One key feature is the slowing of the kinetics of force development. The aim of the present study was to characterize the potential underlying molecular mechanisms by recording and analyzing the X-ray diffraction patterns of human membrane-permeabilized muscle cells expressing a particular beta-tropomyosin mutation (E41K). During resting conditions, the d1,0 lattice spacing, Delta1,0 and I1,1 to I1,0 ratio were not different from control values. These results suggest that, in presence of the E41K beta-tropomyosin mutation, the myofilament lattice geometry is well maintained and therefore may not have any detrimental influence on the contraction mechanisms and thus, on the rate of force generation. PMID- 23686575 TI - Are patterns of cortical hyperexcitability altered in catamenial epilepsy? AB - OBJECTIVE: We used transcranial magnetic stimulation to determine menstrual cycle related changes in cortical excitability in women with and without catamenial epilepsy and investigated whether these changes differed between ovulatory and anovulatory cohorts. METHODS: Healthy nonepilepsy women and women with generalized and focal epilepsy were investigated during ovulatory (n=11, 46, and 43, respectively) and anovulatory (n=9, 42, and 41) cycles. Patients were divided based on seizure pattern into catamenial (C1=perimenstrual, C2=periovulatory, C3=luteal seizure exacerbation), noncatamenial, and seizure free. Cortical excitability was assessed using motor threshold (MT) and paired pulse stimulation at short (2-15 milliseconds) and long (100-300 milliseconds) interstimulus intervals twice, at the (1) late follicular and (2) mid luteal phases of the menstrual cycle. RESULTS: In controls, cortical excitability was greatest in the follicular study, where intracortical facilitation was increased (p<0.05). The opposite was seen in women with epilepsy, where intracortical facilitation was greatest and intracortical inhibition was least in the luteal studies (p<0.05). There were no differences between the ovulatory and anovulatory groups in any of the cohorts. No changes were observed in MT. INTERPRETATION: Nonhormonal factors are involved in the cyclicity of cortical excitability across the menstrual cycle. Normal menstrual cycle variations in cortical excitability are altered in a similar pattern in ovulatory and anovulatory women with epilepsy regardless of seizure patterns. The underlying neural changes associated with epilepsy may alter responses to sex hormones. This may be an important underlying mechanism for catamenial seizure clustering. PMID- 23686577 TI - Level IIB lymph node metastasis in oropharyngeal squamous cell carcinoma. AB - OBJECTIVES/HYPOTHESIS: To determine the incidence of level IIB lymph node metastasis in patients with oropharyngeal squamous cell carcinoma (OPSCC) and to evaluate the necessity of level IIB dissection for elective and therapeutic neck dissections. STUDY DESIGN: Retrospective cohort study. METHODS: Patients with OPSCC (N = 348) were surgically managed at our institution from 2004 through 2010. Neck dissection specimens were reviewed by a pathologist, and level IIB metastases were analyzed with respect to clinical and pathologic data. RESULTS: Level IIB lymph node metastases were present in 2.5% and 25% of elective and therapeutic neck dissections, respectively. Level IIA metastasis, clinical tumor stage, clinical nodal stage, extracapsular spread, and primary tumor location in the tonsil were significantly associated with level IIB metastasis. CONCLUSIONS: This study uniquely demonstrated a statistically significant association between clinical tumor stage and tonsil subsite with level IIB metastasis in OPSCC. Considering the predicted incidence of nodal metastasis, we conclude that level IIB neck dissection can be omitted in early stage (T1 or T2) clinically node negative (cN0) OPSCC. In patients with a cN0 neck and advanced OPSCC (T3 or T4), primary tumor in the tonsil, or ipsilateral clinically node positive (cN(+) ) and contralateral cN0 neck, level IIB dissection should be considered. Level IIB dissection should be performed routinely in patients with cN(+) OPSCC. PMID- 23686576 TI - Human middle longitudinal fascicle: segregation and behavioral-clinical implications of two distinct fiber connections linking temporal pole and superior temporal gyrus with the angular gyrus or superior parietal lobule using multi tensor tractography. AB - The middle longitudinal fascicle (MdLF) is a major fiber connection running principally between the superior temporal gyrus and the parietal lobe, neocortical regions of great biological and clinical interest. Although one of the most prominent cerebral association fiber tracts, it has only recently been discovered in humans. In this high angular resolution diffusion imaging (HARDI) MRI study, we delineated the two major fiber connections of the human MdLF, by examining morphology, topography, cortical connections, biophysical measures, volume and length in seventy-four brains. These two fiber connections course together through the dorsal temporal pole and the superior temporal gyrus maintaining a characteristic topographic relationship in the mediolateral and ventrodorsal dimensions. As these pathways course towards the parietal lobe, they split to form separate fiber pathways, one following a ventrolateral trajectory and connecting with the angular gyrus and the other following a dorsomedial route and connecting with the superior parietal lobule. Based on the functions of their cortical affiliations, we suggest that the superior temporal-angular connection of the MdLF, i.e., STG(MdLF)AG plays a role in language and attention, whereas the superior temporal-superior parietal connection of the MdLF, i.e., STG(MdLF)SPL is involved in visuospatial and integrative audiovisual functions. Furthermore, the MdLF may have clinical implications in neurodegenerative disorders such as primary progressive aphasia, frontotemporal dementia, posterior cortical atrophy, corticobulbar degeneration and Alzheimer's disease as well as attention-deficit/hyperactivity disorder and schizophrenia. PMID- 23686578 TI - Body mass index and health-related quality of life in apparently healthy individuals. AB - PURPOSE: Obesity is known to be associated with a range of chronic medical comorbidities, but little is known about the impact of overweight and obesity on health-related quality of life (HRQoL) in persons without chronic diseases. The aim of this study was to assess HRQoL, body mass index (BMI) and health behavior patterns in a community sample of subjects who had no long-lasting medical comorbidities METHODS: We assessed HRQoL in 1,187 apparently healthy individuals (mean age 57 +/- 7 years), of whom 24 % were classified as normal weight, 49 % as overweight, 20 % as obese and 7 % as very obese. Two different instruments of HRQoL were used: the generic Short-Form Health Survey (SF-36) questionnaire and the preference-based instrument EuroQol (EQ-5D). RESULTS: All physical components of the SF-36 decreased linearly according to BMI categories in women. In men, only poorer physical functioning scale showed linearity with rising BMI. Scores on the mental components of the SF-36 did not differ by BMI categories in either gender. The EQ-5D index and EuroQol visual analogue scale scores decreased linearly with rising BMI only in women. CONCLUSIONS: In apparently healthy middle aged subjects, physical HRQoL decreases with increasing level of BMI and more so in women than in men. Mental components of HRQoL do not differ between the categories of BMI in either gender. PMID- 23686579 TI - Warm temperatures induce transgenerational epigenetic release of RNA silencing by inhibiting siRNA biogenesis in Arabidopsis. AB - Owing to their sessile nature, plants have evolved sophisticated genetic and epigenetic regulatory systems to respond quickly and reversibly to daily and seasonal temperature changes. However, our knowledge of how plants sense and respond to warming ambient temperatures is rather limited. Here we show that an increase in growth temperature from 22 degrees C to 30 degrees C effectively inhibited transgene-induced posttranscriptional gene silencing (PTGS) in Arabidopsis. Interestingly, warmth-induced PTGS release exhibited transgenerational epigenetic inheritance. We discovered that the warmth-induced PTGS release occurred during a critical step that leads to the formation of double-stranded RNA (dsRNA) for producing small interfering RNAs (siRNAs). Deep sequencing of small RNAs and RNA blot analysis indicated that the 22-30 degrees C increase resulted in a significant reduction in the abundance of many trans acting siRNAs that require dsRNA for biogenesis. We discovered that the temperature increase reduced the protein abundance of SUPPRESSOR OF GENE SILENCING 3, as a consequence, attenuating the formation of stable dsRNAs required for siRNA biogenesis. Importantly, SUPPRESSOR OF GENE SILENCING 3 overexpression released the warmth-triggered inhibition of siRNA biogenesis and reduced the transgenerational epigenetic memory. Thus, our study reveals a previously undescribed association between warming temperatures, an epigenetic system, and siRNA biogenesis. PMID- 23686580 TI - Assessment of multidrug resistance on cell coculture patterns using scanning electrochemical microscopy. AB - The emergence of resistance to multiple unrelated chemotherapeutic drugs impedes the treatment of several cancers. Although the involvement of ATP-binding cassette transporters has long been known, there is no in situ method capable of tracking this transporter-related resistance at the single-cell level without interfering with the cell's environment or metabolism. Here, we demonstrate that scanning electrochemical microscopy (SECM) can quantitatively and noninvasively track multidrug resistance-related protein 1-dependent multidrug resistance in patterned adenocarcinoma cervical cancer cells. Nonresistant human cancer cells and their multidrug resistant variants are arranged in a side-by-side format using a stencil-based patterning scheme, allowing for precise positioning of target cells underneath the SECM sensor. SECM measurements of the patterned cells, performed with ferrocenemethanol and [Ru(NH3)6](3+) serving as electrochemical indicators, are used to establish a kinetic "map" of constant height SECM scans, free of topography contributions. The concept underlying the work described herein may help evaluate the effectiveness of treatment administration strategies targeting reduced drug efflux. PMID- 23686581 TI - Ten principles for a landscape approach to reconciling agriculture, conservation, and other competing land uses. AB - "Landscape approaches" seek to provide tools and concepts for allocating and managing land to achieve social, economic, and environmental objectives in areas where agriculture, mining, and other productive land uses compete with environmental and biodiversity goals. Here we synthesize the current consensus on landscape approaches. This is based on published literature and a consensus building process to define good practice and is validated by a survey of practitioners. We find the landscape approach has been refined in response to increasing societal concerns about environment and development tradeoffs. Notably, there has been a shift from conservation-orientated perspectives toward increasing integration of poverty alleviation goals. We provide 10 summary principles to support implementation of a landscape approach as it is currently interpreted. These principles emphasize adaptive management, stakeholder involvement, and multiple objectives. Various constraints are recognized, with institutional and governance concerns identified as the most severe obstacles to implementation. We discuss how these principles differ from more traditional sectoral and project-based approaches. Although no panacea, we see few alternatives that are likely to address landscape challenges more effectively than an approach circumscribed by the principles outlined here. PMID- 23686583 TI - Broader perspective on ecosystem sustainability: consequences for decision making. AB - Although the concept of ecosystem sustainability has a long-term focus, it is often viewed from a static system perspective. Because most ecosystems are dynamic, we explore sustainability assessments from three additional perspectives: resilient systems; systems where tipping points occur; and systems subject to episodic resetting. Whereas foundations of ecosystem resilience originated in ecology, recent discussions have focused on geophysical attributes, and it is recognized that dynamic system components may not return to their former state following perturbations. Tipping points emerge when chronic changes (typically anthropogenic, but sometimes natural) push ecosystems to thresholds that cause collapse of process and function and may become permanent. Ecosystem resetting occurs when episodic natural disasters breach thresholds with little or no warning, resulting in long-term changes to environmental attributes or ecosystem function. An example of sustainability assessment of ecosystem goods and services along the Gulf Coast (USA) demonstrates the need to include both the resilient and dynamic nature of biogeomorphic components. Mountain road development in northwest Yunnan, China, makes rivers and related habitat vulnerable to tipping points. Ecosystems reset by natural disasters are also presented, emphasizing the need to understand the magnitude frequency and interrelationships among major disturbances, as shown by (i) the 2011 Great East Japan Earthquake and resulting tsunami, including how unsustainable urban development exacerbates geodisaster propagation, and (ii) repeated major earthquakes and associated geomorphic and vegetation disturbances in Papua New Guinea. Although all of these ecosystem perturbations and shifts are individually recognized, they are not embraced in contemporary sustainable decision making. PMID- 23686584 TI - Lipopolysaccharides reduce adipogenesis in 3T3-L1 adipocytes through activation of NF-kappaB pathway and downregulation of AMPK expression. AB - Lipopolysaccharides (LPS) from the outer membrane of Gram-negative bacteria serve as endotoxin to exert potent immune responses. However, the effect of LPS on adipogenesis has not been elucidated. The present study was designed to examine the effect of LPS on adipogenesis in 3T3-L1 preadipocytes and possible mechanism(s) of action involved. Our results revealed that LPS challenge significantly suppressed adipogenesis in 3T3-L1 preadipocytes mainly through downregulated expression of the late adipogenic markers PPARgamma and aP2 as well as AMP-activated protein kinase (AMPK) expression and activity. As an inflammatory factor, LPS was found to lead to an overt reduction in IkappaBalpha levels compared with the time-matched controls, consolidating its pro inflammatory property in 3T3-L1 preadipocytes. Our data also revealed that LPS retarded adipogenesis, the effect of which was partially reversed by the selective inhibitor of IKKbeta. IkappaBalpha was found to be involved in the anti adipogenic effect of LPS. In conclusion, LPS is capable of inhibiting adipogenesis in 3T3-L1 adipocytes possibly through activation of NF-kappaB and inhibition of AMPK. With the activation of NF-kappaB pathway and inhibition of AMPK, LPS suppresses C/EBP alpha DNA-binding activity and the expression of late adipogenic markers PPARgamma and aP2. PMID- 23686585 TI - Analytical tools for elucidating the biological role of melatonin in plants by LC MS/MS. AB - Melatonin (MT) presence in higher plants was recently discovered and the knowledge of its function in vivo is limited. Several studies have recently shown the occurrence of MT and related compounds in grapes and wines. The analysis of MT in plants and foods represents a highly challenging task due to its wide concentration range, the difficulty in the selection of the extraction solvents because of its amphipathic nature, and the fact that it reacts quickly with other matrix components. Thus, sample processing factors; preparation/cleanup procedures; and chromatographic/detection parameters, such as HILIC and reverse phase (C(8) and C(18)) chromatographic modes, ESI, and atmospheric pressure chemical ionization (APCI) in both negative and positive modes were evaluated. Taken together, we have demonstrated that optimal conditions were quite different for each of the matrices under study. A sonication-mediated extraction step was necessary for grape skin (100% v/v methanol) and plant tissues (50% v/v methanol), while wine and must required a SPE preconcentration step. HILIC-(+) APCI ionization was better for MT standards, while C(8) -(+) APCI was the best choice for grape skin and C(18) -(+ESI) was suitable for wine. On the other hand, C(8) -(+)ESI was the most appropriate for vegetal tissues of Arabidopsis thaliana. Proposed methods were validated and the LODs were in the low picogram levels range. The optimized approaches were applied to the determination of MT and its isomer in different vegetal/food samples; levels found within the range: 4.9-440 ng/g. PMID- 23686586 TI - Primary sclerosing cholangitis, autoimmune hepatitis, and overlap in Utah children: epidemiology and natural history. AB - The epidemiology and natural history of pediatric primary sclerosing cholangitis (PSC), autoimmune sclerosing cholangitis (ASC), and autoimmune hepatitis (AIH) are not well characterized. Using multiple, overlapping search strategies followed by a detailed records review, we identified all cases of pediatric PSC, ASC, AIH, and inflammatory bowel disease (IBD) in a geographically isolated region of the United States. We identified 607 cases of IBD, 29 cases of PSC, 12 cases of ASC, and 44 cases of AIH. The mean age at diagnosis was 13.0 years for PSC, 11.3 years for ASC, and 9.8 years for AIH. The incidence and prevalence of PSC, ASC, and AIH were 0.2 and 1.5 cases, 0.1 and 0.6 cases, and 0.4 and 3.0 cases per 100,000 children, respectively. The mean duration of follow-up was 5.9 years. The probability of developing complicated liver disease within 5 years of the diagnosis of liver disease was 37% [95% confidence interval (CI) = 21%-58%] for PSC, 25% (95% CI = 7%-70%) for ASC, and 15% (95% CI = 7%-33%) for AIH. The 5 year survival rates with the native liver were 78% (95% CI = 54%-91%) for PSC, 90% (95% CI = 47%-99%) for ASC, and 87% (95% CI = 71%-95%) for AIH. Cholangiocarcinoma developed in 2 of the 29 PSC patients (6.9%). PSC occurred in 9.9% of patients with ulcerative colitis (UC) and in 0.6% of patients with Crohn's disease (CD). ASC occurred in 2.3% of UC patients and 0.9% of CD patients. AIH occurred in 0.4% of UC patients and in 0.3% of CD patients. Liver disease occurred in 39 of 607 IBD patients (6.4%) overall. CONCLUSION: Immune mediated liver diseases are important sources of morbidity in children. Using a population-based design, this study quantifies the burden and natural history of immune-mediated liver disease in children. PMID- 23686587 TI - Rituximab in refractory and relapsed dermatomyositis and polymyositis: comment on the article by Oddis et al. PMID- 23686588 TI - Hydatid cyst embolization to the pulmonary artery: CT and MR features. AB - Hydatid cyst embolization to the pulmonary arteries is rare especially in the Western regions of the world. However, it can be mistaken for pulmonary embolism based on the similar clinical manifestations of cough, hemoptysis, and acute onset of chest pain. We report a case of a 32-year-old man presenting with these symptoms who was initially suspected of having pulmonary embolism. Subsequent imaging with CT and MR revealed hepatic hydatid cyst embolization to the pulmonary arteries. The significance of this case lies in the recognition of the unique radiologic features of pulmonary hydatid cyst embolization on CT and MR imaging to differentiate this entity from bland pulmonary thromboembolic disease. PMID- 23686589 TI - Diagnosis and management of giant choledochal cysts: complexities compared to smaller cysts. AB - BACKGROUND: This study presents our 11-year surgical experience with choledochal cysts (CDC), focusing on the complexity in the diagnosis and management of large size CDCs. METHODS: Medical records of 70 patients who underwent surgery for CDC between 2000 and 2011 were retrospectively reviewed. Of them, ten patients were found with cyst size >10 cm (group A), and we compared the differences in the clinical presentation, radiological diagnosis and surgical management with those with cysts <=10 cm in size (group B). RESULTS: Abdominal pain and lump were noted in all group A patients, but only 67 % and 14 % in group B patients, respectively. Sixty percent of group A, but only 14 % of group B patients, had a triad of abdominal pain, mass and jaundice. Cholangitis was more common in group A patients. Most of group B patients were correctly diagnosed with ultrasound alone, but misdiagnosis occurred more frequently in group A. Magnetic resonance cholangiopancreatography correctly achieved the diagnosis in all. Operative time (5 vs. 3 h) and blood loss (300-500 vs. 50-100 mL) were more in group A in comparison to group B. CONCLUSIONS: The clinical presentation and surgical management of giant choledochal cysts differ from their smaller counterparts. Diagnostic dilemma was common with giant CDC especially with ultrasound and CT. PMID- 23686590 TI - Biomagnification and tissue distribution of perfluoroalkyl substances (PFASs) in market-size rainbow trout (Oncorhynchus mykiss). AB - The present study investigated the biomagnification potential as well as the substance and tissue-specific distribution of perfluoroalkyl substances (PFASs) in market-size rainbow trout (Oncorhynchus mykiss). Rainbow trout with an average body weight of 314 +/- 21 g were exposed to perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) in the diet for 28 d. The accumulation phase was followed by a 28-d depuration phase, in which the test animals were fed with nonspiked trout feed. On days 0, 7, 14, 28, 31, 35, 42, and 56 of the present study, fish were sampled from the test basin for PFAS analysis. Biomagnification factors (BMFs) for all test compounds were determined based on a kinetic approach. Distribution factors were calculated for each test compound to illustrate the disposition of PFASs in rainbow trout after 28 d of exposure. Dietary exposure of market-size rainbow trout to PFASs did not result in biomagnification; BMF values were calculated as 0.42 for PFOS, >0.23 for PFNA, >0.18 for PFHxS, >0.04 for PFOA, and >0.02 for PFBS, which are below the biomagnification threshold of 1. Liver, blood, kidney, and skin were identified as the main target tissues for PFASs in market-size rainbow trout. Evidence was shown that despite relative low PFAS contamination, the edible parts of the fish (the fillet and skin) can significantly contribute to the whole-body burden. PMID- 23686592 TI - Prothrombin complex concentrate licensed for warfarin reversal. PMID- 23686591 TI - Functional outcomes and quality of life in patients treated with laparoscopic total colectomy for colonic inertia. AB - PURPOSE: To assess the functional outcomes and quality of life in patients with laparoscopic total colectomy for slow-transit constipation (STC). METHODS: All patients undergoing laparoscopic colectomy with ileorectal anastomosis for colonic inertia at two referral centers were analyzed. Their preoperative, intraoperative and postoperative details were recorded with a one-year follow-up. Their quality of life was assessed using the SF-36 questionnaire. RESULTS: Between 2004 and 2007, 710 patients were evaluated. Eight female patients (1.1 %) fulfilled the criteria for STC without obstructive defecation syndrome. Their mean age was 38 years +/- 15 (range from 22 to 62). The conversion rate was 12.5 %. The morbidity rate was 37.5 %, and mortality was nil. The preoperative abdominal pain was 6.6 +/- 0.3 and had decreased to 3.6 +/- 2.3 postoperatively (P = 0.008). At 1 year, the defecation frequency per week had increased from 0.84 +/- 0.24 to 6.75 +/- 3.4 (P = 0.001). Three patients developed nocturnal leakage (37.5 %). Eighty-eight percent of the patients recommend the procedure. All parameters of the SF-36 questionnaire had improved at the one-year follow-up examination. CONCLUSION: Laparoscopic colectomy for slow-transit constipation is safe and increased the number of evacuations per week. Although nocturnal leakage may occur, these patients experience improvements in their quality of life. PMID- 23686593 TI - Compounding pharmacy oversight moves ahead. PMID- 23686594 TI - Simple steps improve return of medications at discharge. PMID- 23686595 TI - Questioning the quality of pharmacy technician training. PMID- 23686596 TI - Physical compatibility of sodium citrate with alcohol and cefepime. PMID- 23686597 TI - Characterization of the pharmacy chief resident position. PMID- 23686598 TI - Effect of changing insulin injection site on glycemic variability. PMID- 23686599 TI - Pneumonia due to multidrug-resistant Leclercia adecarboxylata. PMID- 23686600 TI - Crizotinib for the treatment of non-small-cell lung cancer. AB - PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety, adverse effects, and dosage and administration of crizotinib in the management of non small-cell lung cancer (NSCLC) are reviewed. SUMMARY: Crizotinib (Xalkori, Pfizer Inc.) is a novel tyrosine kinase inhibitor approved for the treatment of patients with locally advanced or metastatic NSCLC who exhibit assay-confirmed mutations of the gene coding for anaplastic lymphoma kinase (ALK). The primary biochemical mechanism of crizotinib is to inhibit ALK expression, leading to increased cell proliferation and decreased apoptosis. Crizotinib is metabolized and excreted after O-dealkylation by cytochrome P-450 (CYP) isoenzyme 3A4/5; as crizotinib is also an inhibitor of CYP3A4/5, its use entails a high potential for drug interactions, including confirmed interactions with ketoconazole and rifampin that can alter crizotinib pharmacokinetics. A Phase I trial involving patients with ALK gene mutation-positive NSCLC demonstrated significant disease control with oral crizotinib use, including an overall eight-week response rate of 87% and an estimated six-month survival of 72%. At the standard dosage of 250 mg twice daily, crizotinib is well tolerated. In clinical trials to date, the most common grade 1 or 2 adverse events were nausea, diarrhea, vomiting, and visual disturbances; more severe toxicities included transaminase elevations (less than 7% of patients) and pneumonitis (less than 2% of patients). Hypogonadism leading to low testosterone levels appears to be universal among male patients treated with crizotinib. CONCLUSION: Crizotinib appears to be efficacious and well tolerated in patients with NSCLC and may have future potential applications in treating lymphomas and other cancers driven by ALK or c-MET gene mutations. PMID- 23686601 TI - Health literacy: a primer for pharmacists. AB - PURPOSE: The literature surrounding health literacy and its importance in everyday practice are reviewed. SUMMARY: Health literacy includes a patient's reading, writing, and numeracy skills, as well as his or her cultural experiences, understanding of health concepts and pathophysiology, and basic communication skills. Over one third of the American population lack the skills necessary to understand health information, make health care decisions, or follow medication instructions. Independent risk factors for low health literacy include poor socioeconomic status, ethnicity, older age, and limited education. Mounting evidence suggests that low health literacy leads to poor health outcomes, increased mortality, increases in health care costs, and poorly self-managed chronic diseases. Communication with a pharmacist to gain clarification of medication instructions is often the last opportunity to ensure that patients understand how to use their medications appropriately. Low health literacy is not always easily recognized, as patients use well-practiced coping mechanisms or avoidant behaviors. Clear communication strategies help patients become more involved in their care plans and increase positive interactions. Tools to assess health literacy have been developed and can be used by pharmacists to guide education and counseling. Advanced methods of written and oral communication should be used to improve patient comprehension and understanding. CONCLUSION: Tools such as simple word-recognition tests or comprehensive tests of functional health literacy can be used in daily practice to assess patients' health literacy. Being familiar with communication techniques such as the Indian Health Service, teach back, and Ask Me 3 can help facilitate individualized medication related education and maximize patient comprehension. PMID- 23686602 TI - Comparative risk of bloodstream infection in hospitalized patients receiving intravenous medication by open, point-of-care, or closed delivery systems. AB - PURPOSE: The impact of i.v. drug delivery via point-of-care (POC)-activated and closed systems versus traditional manual admixture systems on the risk of hospital-acquired bloodstream infection (BSI) is examined. METHODS: Using data from a proprietary hospital database, a retrospective observational cohort study of patients receiving one or more i.v. drug administrations via POC-activated or closed systems during a three-year period (2007-09) was conducted. Cases of hospital-acquired BSI were identified using diagnosis codes and billing charges for blood cultures and antibiotic use. The risk of BSI in patients with exposure to POC-activated systems, closed systems, or both relative to that of patients exposed to open systems was estimated by odds ratios (ORs) calculated by multivariate logistic regression analysis. RESULTS: The evaluated data indicated that of the 4,073,864 patients included in the study cohort, 0.5% (n = 20,251) experienced hospital-acquired BSI. After adjusting for selected confounding variables, the use of POC-activated systems was associated with a 16% reduction in BSI risk relative to the use of open systems (OR, 0.84; 95% confidence interval [CI], 0.76-0.93), and the use of closed systems correlated with a 12% risk reduction (OR, 0.88; 95% CI, 0.82-0.96). Patients who received i.v. drugs via both POC-activated and closed systems appeared to derive the greatest relative risk reduction benefit (OR, 0.12; 95% CI, 0.06-0.23). CONCLUSION: Use of POC-activated and closed systems for i.v. drug delivery was associated with a significantly reduced risk of hospital-acquired BSI compared with exclusive use of open systems in a large population of hospitalized patients. PMID- 23686603 TI - Formulary systems and pharmacy and therapeutics committees in the Western Pacific Region: exploring two Basel Statements. AB - PURPOSE: The use of formulary systems and pharmacy and therapeutics (P&T) committees in the Western Pacific Region (WPR) and the factors associated with their use were explored. METHODS: Minor additions were made to a previously validated survey and reviewed by a WPR advisory committee. The Basel Statements 26 and 27 survey was made available in eight languages and sent electronically to 1989 hospital pharmacy directors through respective hospital pharmacy associations in the WPR. RESULTS: A total of 797 responses (40%) from 34 nations were received. Of these responses, 87% of hospitals (691 of 797) used a formulary. Also, 93% of respondents (619 of 664) indicated that their hospital had a P&T committee. However, only 44% of respondents (274 of 626) reported that more than half of their formulary medicines were linked to standard treatment guidelines. Furthermore, only 41% of hospitals (247 of 601) had a policy for off label medication use. The pharmacy directors' perceived benefits of formularies were correlated with having more formulary medicines linked to standard treatment guidelines, basing their use on the best available evidence, and having a policy for the use of off-label medicines. CONCLUSION: A large proportion of hospitals in the WPR have implemented formularies and P&T committees. Although formularies are commonly used, their effectiveness may be limited, as formularies are often not linked to standard treatment guidelines or the best available evidence. PMID- 23686604 TI - Development and implementation of a nurse-driven, sliding-scale nomogram for bivalirudin in the management of heparin-induced thrombocytopenia. AB - PURPOSE: A simplified dosing nomogram to assist nurses in adjusting the rate of i.v. bivalirudin administration in cases of heparin-induced thrombocytopenia (HIT) is described. SUMMARY: To facilitate the availability of bivalirudin [corrected] as an alternative direct thrombin inhibitor (DTI) for patients with HIT at The Ohio State University Wexner Medical Center (OSUWMC), a team of clinical pharmacists developed a nomogram designed to simplify infusion dosage adjustments by nurses. In contrast to bivalirudin nomograms requiring patient specific, percentage-based dose adjustments, the nomogram developed at OSUWMC specifies fixed adjustments (0.005 or 0.01 mg/kg/hr) according to the current activated partial thromboplastin time (aPTT) value relative to aPTT goals. During pilot testing over three years, the nomogram was used to guide dosage adjustments in 65 adult patients receiving continuous infusions of bivalirudin for suspected or confirmed HIT in intensive care units. Overall, the use of the nomogram resulted in adequate anticoagulation, with 53.7% of all measured aPTT values in the target range; 30.5% of aPTT values were below target, and 15.8% of values were above target. The median time to steady state was 11.0 hours (range, 5.0 31.8 hours), and bleeding rates were consistent with those reported in the literature. Nurse adherence to the nomogram was 100%, and no dosing errors occurred during a total of 487 dosage changes. Based on the pilot study results, the nomogram was refined to improve initial dosing for patients with creatinine clearance values of >30 mL/min; other refinements were made to enhance the safety of bivalirudin therapy for HIT in patients with severe renal impairment. CONCLUSION: A nurse-driven, sliding-scale nomogram for bivalirudin therapy in patients with HIT provided a simple dosing protocol and resulted in a high rate of adherence by nurses. PMID- 23686605 TI - Literature review of interprofessional research on inpatient pharmacy operations. PMID- 23686606 TI - No shortcuts for research assessment. PMID- 23686607 TI - Solid-state amorphization of linaprazan by mechanical milling and evidence of polymorphism. AB - In this paper, we study the thermodynamic and structural changes of crystalline linaprazan (a proton pump inhibitor) upon high-energy ball milling at room temperature. The investigations have been performed by differential scanning calorimetry and powder X-ray diffraction. The results indicate that this drug undergoes a direct crystal-to-glass transformation upon milling. Moreover, upon heating, the amorphous material obtained by milling is shown to recrystallize toward two different polymorphs that appear to form a monotropic set. PMID- 23686608 TI - Molecular classification and molecular targeted therapy of cancer. PMID- 23686609 TI - Is there a link between open-angle glaucoma and dementia? The Three-City-Alienor cohort. AB - OBJECTIVE: Previous research has suggested an association between dementia and glaucoma through common risk factors or mechanisms. Our aim was to evaluate the longitudinal relationship between open-angle glaucoma (OAG) and incident dementia. METHODS: The Three-City-Bordeaux-Alienor study is a population-based cohort of 812 participants with a 3-year follow-up period. All participants were aged 72 years or older. An eye examination was performed on all subjects. An OAG was determined based on optic nerve damage and visual field loss. Incident dementia was actively screened for and confirmed by a neurologist. RESULTS: A total of 41 participants developed dementia over the 3-year follow-up period. Future incident dementia cases had an increased prevalence of OAG (17.5% vs 4.5% for nondemented participants, p = 0.003). After adjustment for age, gender, education, family history of glaucoma, vascular comorbidities, and apolipoprotein epsilon4, our results showed that participants with an OAG were four times more likely to develop dementia during the 3-year follow-up period (odds ratio = 3.9, 95% confidence interval = 1.5-10.4, p = 0.0054). An increased risk of dementia was also associated with 2 markers of optic nerve degeneration (vertical cup:disk ratio and minimal rim:disk ratio). However, no association was found between a high intraocular pressure and/or the use of intraocular pressure-lowering medications and incident dementia. INTERPRETATION: If the association between OAG and dementia is confirmed, direct and noninvasive quantification of the amount of retinal ganglion cell axonal loss may be a useful biomarker of cerebral axonal loss in the future. It may also offer new breakthroughs in understanding the underlying pathophysiological mechanisms of both diseases. PMID- 23686610 TI - Measuring activity in the ubiquitin-proteasome system: from large scale discoveries to single cells analysis. AB - The ubiquitin-proteasome system (UPS) is the primary pathway responsible for the recognition and degradation of misfolded, damaged, or tightly regulated proteins in addition to performing essential roles in DNA repair, cell cycle regulation, cell migration, and the immune response. While traditional biochemical techniques have proven useful in the identification of key proteins involved in this pathway, the implementation of novel reporters responsible for measuring enzymatic activity of the UPS has provided valuable insight into the effectiveness of therapeutics and role of the UPS in various human diseases such as multiple myeloma and Huntington's disease. These reporters, usually consisting of a recognition sequence fused to an analytical handle, are designed to specifically evaluate enzymatic activity of certain members of the UPS including the proteasome, E3 ubiquitin ligases, and deubiquitinating enzymes. This review highlights the more commonly used reporters employed in a variety of scenarios ranging from high-throughput screening of novel inhibitors to single cell microscopy techniques measuring E3 ligase or proteasome activity. Finally, a recent study is presented highlighting the development of a novel degron-based substrate designed to overcome the limitations of current reporting techniques in measuring E3 ligase and proteasome activity in patient samples. PMID- 23686611 TI - Inhibition of protein deubiquitination by PR-619 activates the autophagic pathway in OLN-t40 oligodendroglial cells. AB - Protein aggregate formation may be the result of an impairment of the protein quality control system, e.g., the ubiquitin proteasome system (UPS) and the lysosomal autophagic pathway. For proteasomal degradation, proteins need to be covalently modified by ubiquitin and deubiquitinated before the substrates are proteolytically degraded. Deubiquitination is performed by a large family of proteases, the deubiquitinating enzymes (DUBs). DUBs display a variety of functions and their inhibition may have pathological consequences. Using the broad specificity DUB inhibitor PR-619 we previously have shown that DUB inhibition leads to an overload of ubiquitinated proteins, to protein aggregate formation and subsequent inhibition of the UPS. This study was undertaken to investigate whether PR-619 modulates autophagic functions to possibly compensate the failure of the proteasomal system. Using the oligodendroglial cell line OLN t40 and a new oligodendroglial cell line stably expressing GFP-LC3, we show that DUB inhibition leads to the activation of autophagy and to the recruitment of LC3 and of the ubiquitin binding protein p62 to the forming aggresomes without impairing the autophagic flux. Furthermore, PR-619 induced the transport of lysosomes to the forming aggregates in a process requiring an intact microtubule network. Further stimulation of autophagy by rapamycin did not prevent PR-619 aggregate formation but rather exerted cytotoxic effects. Hence, inhibition of DUBs by PR-619 activated the autophagic pathway supporting the hypothesis that the UPS and the autophagy-lysosomal pathway are closely linked together. PMID- 23686614 TI - Population-based absolute risk estimation with survey data. AB - Absolute risk is the probability that a cause-specific event occurs in a given time interval in the presence of competing events. We present methods to estimate population-based absolute risk from a complex survey cohort that can accommodate multiple exposure-specific competing risks. The hazard function for each event type consists of an individualized relative risk multiplied by a baseline hazard function, which is modeled nonparametrically or parametrically with a piecewise exponential model. An influence method is used to derive a Taylor-linearized variance estimate for the absolute risk estimates. We introduce novel measures of the cause-specific influences that can guide modeling choices for the competing event components of the model. To illustrate our methodology, we build and validate cause-specific absolute risk models for cardiovascular and cancer deaths using data from the National Health and Nutrition Examination Survey. Our applications demonstrate the usefulness of survey-based risk prediction models for predicting health outcomes and quantifying the potential impact of disease prevention programs at the population level. PMID- 23686613 TI - Neuronal ubiquitin homeostasis. AB - Neurons have highly specialized intracellular compartments that facilitate the development and activity of the nervous system. Ubiquitination is a post translational modification that controls many aspects of neuronal function by regulating protein abundance. Disruption of this signaling pathway has been demonstrated in neurological disorders such as Parkinson's disease, Amyotrophic Lateral Sclerosis and Angleman Syndrome. Since many neurological disorders exhibit ubiquitinated protein aggregates, the loss of neuronal ubiquitin homeostasis may be an important contributor of disease. This review discusses the mechanisms utilized by neurons to control the free pool of ubiquitin necessary for normal nervous system development and function as well as new roles of protein ubiquitination in regulating the synaptic activity. PMID- 23686615 TI - Is there a role for elective neck dissection with salvage laryngectomy? A decision-analysis model. AB - OBJECTIVES/HYPOTHESIS: Elective neck dissection for the clinically negative neck is often a matter of debate. A decision-analysis model that was published in 1994 established the widely accepted principle that neck dissection is warranted when the risk for occult metastases is higher than 20%. The aim of the present study was to build a specific and up-to-date decision-analysis model to determine the need for elective neck dissection during salvage laryngectomy after chemoradiation failure and to identify the variables that effect the decision. STUDY DESIGN: Decision-analysis model. METHODS: A decision-analysis model was performed to compare the outcome of patients after salvage total laryngectomy with and without an elective neck dissection. Probabilities and expected utilities were derived from available literature to construct the model. Monte Carlo simulation and sensitivity analysis were used to calculate our models' outcomes and to identify the variables that influence the model most, respectively. RESULTS: When calculating our model results with published data, we found that elective neck dissection is not warranted during salvage total laryngectomy. Optimal decision was found to be sensitive by two variables: 1) the probability for cure with neck dissection, and 2) the probability for regional only recurrence after salvage laryngectomy without neck dissection. In multiway sensitivity analysis, only when cure rate with neck dissection exceeded 82%, adding neck dissection was the preferred decision. In practice, cure rates for patients after salvage total laryngectomy are around 50% to 65%. CONCLUSIONS: Based on our decision-analysis model, we do not recommend routine elective neck dissection during salvage total laryngectomy after failure of chemoradiation. PMID- 23686612 TI - Regulating the ubiquitin/proteasome pathway via cAMP-signaling: neuroprotective potential. AB - The cAMP-signaling pathway has been under intensive investigation for decades. It is a wonder that such a small simple molecule like cAMP can modulate a vast number of diverse processes in different types of cells. The ubiquitous involvement of cAMP-signaling in a variety of cellular events requires tight spatial and temporal control of its generation, propagation, compartmentalization, and elimination. Among the various steps of the cAMP signaling pathway, G-protein-coupled receptors, adenylate cyclases, phosphodiesterases, the two major cAMP targets, i.e., protein kinase A and exchange protein activated by cAMP, as well as the A-kinase anchoring proteins, are potential targets for drug development. Herein we review the recent progress on the regulation and manipulation of different steps of the cAMP-signaling pathway. We end by focusing on the emerging role of cAMP-signaling in modulating protein degradation via the ubiquitin/proteasome pathway. New discoveries on the regulation of the ubiquitin/proteasome pathway by cAMP-signaling support the development of new therapeutic approaches to prevent proteotoxicity in chronic neurodegenerative disorders and other human disease conditions associated with impaired protein turnover by the ubiquitin/proteasome pathway and the accumulation of ubiquitin-protein aggregates. PMID- 23686616 TI - Hes1 is required for the development of pharyngeal organs and survival of neural crest-derived mesenchymal cells in pharyngeal arches. AB - Hes genes are required to maintain diverse progenitor cell populations during embryonic development. Loss of Hes1 results in a spectrum of malformations of pharyngeal endoderm-derived organs, including the ultimobranchial body (progenitor of C cells), parathyroid, thymus and thyroid glands, together with highly penetrant C-cell aplasia (81%) and parathyroid aplasia (28%). The hypoplastic parathyroid and thymus are mostly located around the pharyngeal cavity, even at embryonic day (E) 15.5 to E18.5, indicating the failure of migration of the organs. To clarify the relationship between these phenotypes and neural crest cells, we examine fate mapping of neural crest cells colonized in pharyngeal arches in Hes1 null mutants by using the Wnt1-Cre/R26R reporter system. In null mutants, the number of neural crest cells labeled by X-gal staining is markedly decreased in the pharyngeal mesenchyme at E12.5 when the primordia of the thymus, parathyroid and ultimobranchial body migrate toward their destinations. Furthermore, phospho-Histone-H3-positive proliferating cells are reduced in number in the pharyngeal mesenchyme at this stage. Our data indicate that the development of pharyngeal organs and survival of neural-crest derived mesenchyme in pharyngeal arches are critically dependent on Hes1. We propose that the defective survival of neural-crest-derived mesenchymal cells in pharyngeal arches directly or indirectly leads to deficiencies of pharyngeal organs. PMID- 23686617 TI - The impact of intimate partner violence, substance use, and HIV on depressive symptoms among abused low-income urban women. AB - Intimate partner violence (IPV), substance use, and HIV are often co-occuring health problems affecting low-income urban women, and have been described as connected epidemics making up a "syndemic." Research suggests that each issue separately is associated with depressive symptoms, but no studies have examined the combined effect of IPV, substance use and HIV on women's depression. Interviews were conducted with 96 women recruited from community health clinics serving low-income women in an urban U.S. city. All women were over 17, not pregnant, English-speaking, without private insurance and had experienced physical IPV in the past year. Women were primarily African American (82%) and 82% were receiving income assistance. Twenty seven percent were HIV-positive, and 27% had used heroin or cocaine in the past 6 months. Based on the Centers for Epidemiological Studies Depression Scale (CES-D ), 73% were depressed. Women who experienced severe IPV in the past 6 months were compared to women who experienced no IPV or psychological IPV only in the past 6 months; those who experienced severe IPV were 5.3 times more likely to be depressed, controlling for HIV status, drug use, age, and relationship status. Women who experienced severe IPV, were HIV-positive, and used drugs (7.3% of sample) were 7.98 times as likely to be depressed as women without these characteristics. These findings confirm that severe IPV is significantly associated with depression among urban abused women. Furthermore, this research suggests that the syndemic effect of IPV, substance use, and HIV could be even more detrimental to women's mental health. Health practitioners and researchers should be aware of the combined impact of the IPV, substance use, and HIV syndemic and consider how they can address the mental health needs of urban women. PMID- 23686618 TI - Social support needs identified by mothers affected by intimate partner violence. AB - In order to offer optimal supports and services for mothers affected by intimate partner violence (IPV), an understanding of these mothers' perceptions of support needs, resources, barriers to support, and preferences for support intervention is warranted. Moreover, the growing recognition of the effects of IPV on maternal infant relationships and of the importance of these early relationships to long term child health outcomes suggests interventions are needed to support optimal maternal-infant relationships in these families. Thus, 64 mothers exposed to IPV when their infants were below 12 months of age participated in a retrospective qualitative study to identify mothers' support needs, resources, barriers to support, and preferences for specific support interventions to promote optimal mother-infant relationships. Participants identified both personal needs (including needs for leaving or staying with the violent partner), along with intertwined needs to care for, and help, their infants cope with the experience of violence. Mothers reported that integrated services that include information and practical support from professionals with emotional and affirmation support from peers would promote positive, nurturing mother-infant relationships and healthy child development. PMID- 23686619 TI - Survivor experience of a child sexual abuse prevention program: a pilot study. AB - Addressing gaps in the research, the current study assesses the impact of a community-based child sexual abuse prevention program on known survivor knowledge/skills, disclosures, and subjective experience. Methodologically, novel measures of program fidelity and implementation cost are applied. A pre- posttest wait-list control design was utilized with intervention (n = 10) and comparison groups (n = 10). Measures included a standardized knowledge/skill questionnaire, coding of disclosures, subjective experience questionnaires, in-depth interviews, video analysis of program adherence, and a measure of cost. Analysis involved nonparametric tests and thematic analysis of interview and video data. Cost was calculated for the group and per survivor. Survivors achieved significant gains in knowledge/skills, made further disclosures, and were positive about their program experience. No gains were identified in the control group. Costs were small. Future studies need to explore survivor experience of programs delivered in classrooms. PMID- 23686620 TI - Multiple mediators of the relationships among maternal childhood abuse, intimate partner violence, and offspring psychopathology. AB - The aim of the study was to examine whether maternal depression, mothers' and fathers' parenting, child physical punishment and negative life events (NLE) mediate the effect of maternal childhood abuse (CA), intimate partner violence (IPV) and cumulative violence (both CA and IPV) on Spanish children's and adolescents' psychopathology. Furthermore, multiple mediator models examine whether IPV mediates the effect of CA on the contextual and family factors mentioned above. Three hundred and eighteen Spanish outpatients aged 7 to 18 and their parents were assessed using a structured interview and other instruments for measuring the study variables. Structural equation models (SEMs) showed multiple pathways explaining psychopathological problems among offspring of mothers who suffered CA, IPV and both of these violent experiences. In particular, mothers' depression mediated the link between maternal CA, IPV, cumulative violence and children's externalizing, and total behavior problems. Child NLE was an important pathway between maternal CA and total behavior problems, as well as between cumulative violence and both externalizing and total problems. IPV contributed to explaining the link between maternal CA and contextual and family factors, such as child physical punishment and NLE, which were in turn, associated with children's behavior problems. Findings show the complex interconnections between different types of violence and their harmful effects on the mental health of women and their offspring, as well as the need to extend our knowledge on this subject. PMID- 23686621 TI - Defining and evaluating perceptions of victim blame in antigay hate crimes. AB - Victimology research often hinges on attribution of blame toward victims despite a lack of conceptual agreement on the definition and measure of the construct. Drawing on established blame attribution and intent literature, the present study evaluates psychometric properties of the Perceptions of Victim Blame Scale (PVBS) using mock jury samples in a vignette-based capital murder antigay hate crime context. Factor analyses show support for a three-factor structure with the following perceptions of victim blame subscales: Malice, Recklessness, and Unreliability. All factors displayed expected positive associations with homonegativity and authoritarianism. Likewise, all factors displayed null relations with trait aggression and social desirability. Only the Malice factor predicted sentencing decisions after controlling for crime condition and support for the death penalty. Results are reviewed with respect to blame attribution theory and practical application of a revised PVBS. PMID- 23686623 TI - Monitoring trends in violence: a delayed response to Estrada (2006). AB - Reliable and valid indicators of assault are required to effectively monitor population trends and ensure that resources are targeted effectively. Trends in assault, reported by the media, based on crime statistics, or on victim surveys, are substantively affected by extraneous factors. In 2006, Estrada offered up solutions to the difficulties posed by crime statistics and victim surveys, by proposing the development of indicators based on hospital discharge data, albeit with identified limitations. This article is a response to Estrada's proposition, and works through each of Estrada's identified limitations of hospital discharge data. Potential problems with Estrada's suggestions are highlighted in our article and solutions, based on the current evidence, are proposed. PMID- 23686622 TI - Patterns of resource utilization and mental health symptoms among women exposed to multiple types of victimization: a latent class analysis. AB - Although the value of resources aimed to support women who experience intimate partner violence (IPV) is clear, few studies have investigated how exposure to multiple types of victimization influences women's resource utilization. We applied latent class analysis (LCA) to a sample of 412 women who used IPV in their current relationships to test whether women's resource utilization is associated with different patterns of victimization, including current IPV victimization, past IPV victimization, and childhood victimization. Three classes of women were identified: the Low Cumulative IPV class (n = 121) included women with a low prevalence of past IPV victimization and low severity of current IPV victimization; The High Past/ Low Current IPV class (n = 258) included women with a high prevalence of past IPV victimization but low severity of current IPV victimization; and the High Cumulative IPV class (n = 33) included women with a high prevalence of past IPV victimization and severe current IPV victimization. Multiple types of childhood victimization were highly prevalent among women in all three classes. Women in the High Cumulative IPV class used a greater variety of resources, experienced a greater number of posttraumatic stress and depression symptoms, drug problems, and used more severe IPV aggression compared to women in other classes. These findings highlight the heterogeneity of resource utilization among women in relationships characterized by bidirectional IPV and underscore the potential clinical utility of adapting services to meet the specific needs of women with unique profiles of victimization. PMID- 23686624 TI - Intimate partner violence among stigmatized Latina workers. AB - Latinas recently immigrated to the United States who work in bars or cantinas are at risk of experiencing intimate partner violence (IPV) due to the heavy drinking and sex-related expectations associated with their work and the stigmatized nature of their occupation. We explored the influence of demographic characteristics, substance abuse, and sexual risk behaviors on IPV reported by cantineras for primary and nonprimary sexual partners. Results based on interviews conducted with 669 cantineras indicate that length of residency in the United States and current sexual practices predict IPV perpetrated by both their primary and nonprimary sexual partners. There were also partner-specific predictors of violence related to the substance use and working practices of cantineras. Our findings have implications for understanding the partner violence experienced by this subgroup of stigmatized Latina immigrants and for the ability of current IPV research to capture their experience. PMID- 23686625 TI - Giant aneurysm of the right sinus of Valsalva causing right ventricular outflow obstruction. PMID- 23686626 TI - Severe Neonatal Metabolic Decompensation in Methylmalonic Acidemia Caused by CblD Defect. AB - CblD disorder is an autosomal recessive, rare, heterogeneous disease with variable clinical presentations, depending on the nature and location of the MMADHC gene mutations. Mutations in MMADHC lead to three distinct phenotypes: cblD-MMA, cblD-HC, and cblD-MMA/HC. To date, 18 cblD patients have been reported. Six of them were affected by cblD-MMA, but only three had a known clinical history. One of these patients presented with a metabolic decompensation at 11 months; the second one, born prematurely, was diagnosed with cblD after being treated for intracranial hemorrhage, respiratory distress syndrome, necrotizing enterocolitis, and convulsions at birth; the third one was diagnosed at 5 years of age.Here we present a case of a cblD-MMA patient who had an acute neonatal onset with severe hyperammonemia requiring hemodiafiltration. To the best of our knowledge, this is the first cblD-MMA patient who presented acutely in the newborn period. He has developed well upon treatment with B12, carnitine, and hypoproteic diet. At present time, at the age of 7, he shows normal growth and cognitive development. Thus, it is likely that the aggressive treatment of this child with hemodiafiltration might have prevented him from long-term neurological sequelae. Overall, this case shows that even severe, neonatal-onset patients may display a vitamin B12-responsive MMA. Furthermore, it suggests that an early treatment with vitamins might be beneficial for patients presenting with neonatal onset hyperammonemia regardless of the suspected disease and before receiving the biochemical diagnosis. PMID- 23686627 TI - Determination of nitrogen mustard degradation products in water samples using a portable capillary electrophoresis instrument. AB - In this work, a new purpose-made portable CE instrument with a contactless conductivity detector was used for the determination of degradation products of nitrogen mustards in different water samples. The capillary was coated with poly(1-vinylpyrrolidone-co-2-dimethylaminoethyl methacrylate) to avoid analyte wall interactions. The coating procedure was studied to obtain the best repeatability of the migration time of the analytes. Four different coating procedures were compared; flushing the capillary with the copolymer at 100 psi for 2 min at 60 degrees C provided the best RSD values (<4%). The analytical method was also optimized. The use of 20 mM of MES adjusted to pH 6.0 with His as running buffer allowed a good baseline separation of the three analytes in different water samples without matrix interferences. The method permitted the detection of the three degradation products down to 5 MUM. PMID- 23686628 TI - Immunosuppressive therapy in adults with aplastic anaemia: single-institution experience from India. AB - OBJECTIVE: To determine overall survival and factors predicting survival after immunosuppressive therapy in patients with acquired aplastic anaemia. DESIGN: Retrospective. SETTING: Tertiary care hospital. PATIENTS: 120 adults diagnosed as having acquired aplastic anaemia between 1 January 1996 and 31 December 2009. INTERVENTIONS: Anti-thymocyte globulin (ATG) followed by ciclosporin was administered to all patients for 15-18 months as the initial treatment. Haematological response was assessed 6 months after ATG administration and 6 monthly thereafter. Platelets were transfused if levels were <10 * 10(3)/l and for symptomatic bleeding. Transfusions of red blood cells were given for haemoglobin levels <70 g/l or symptomatic anaemia. Febrile neutropenia was managed with antibiotics, with the addition of antifungal agents after 3-4 days of unresponsive fever. Granulocyte colony-stimulating factor was administered at a dose of 5 ug/kg/day (maximum 300 ug/day) subcutaneously for infective episodes. MAIN OUTCOME MEASURES: PRIMARY OUTCOME: overall survival. Secondary outcome: response to immunosuppressive therapy, failure-free survival, relapse and clonal evolutions. The response and relapse criteria were defined in accordance with the British Council for Standards in Haematology guidelines. RESULTS: Overall response at 6 months after initiation of treatment was 85.8% (103/120). Overall survival at 76 months was 83.4%. Overall survival correlated with presence of response (complete response or partial response) at 6 months after ATG administration (HR=0.021, 95% CI 0.006 to 0.079, p<0.001). The occurrence of infectious complications adversely affected the overall survival (HR=5.71, 95% CI 1.22 to 26.77, p=0.027). Six patients relapsed. There were no deaths or adverse events 12 months after treatment among responders. CONCLUSIONS: In our study, overall survival was 83.4% at a median follow-up of 76 months. The two variables that significantly affected overall survival were response to therapy at 6 months and occurrence of infectious complications. PMID- 23686630 TI - Primary extraosseous intradural spinal Ewing's sarcoma: report of two cases. AB - Two cases of primary extraosseous intradural spinal Ewing's sarcoma are reported with a review of the current literature. This rare neoplasm shares features with cerebral primitive neuroectodermal tumors, complicating a correct diagnosis. Gross total resection seems to be the main treatment, although adjuvant therapies could improve the prognosis. In case 1, a 56-year-old man presented with cauda equina syndrome. MRI showed an intradural tumor from L4 to S2. An emergency laminectomy was performed with gross total resection of a hemorrhagic tumor, followed by adjuvant treatment. In the second case, a 25-year-old female developed leg and lumbar pain. MRI study identified a homogeneously enhancing intradural mass at the L2-L3 level. A laminoplasty was performed, followed by tumor resection; no adjuvant treatment was administered afterwards. Immunohistochemical workup confirmed the diagnosis of Ewing's sarcoma in both cases. PMID- 23686631 TI - An S-shaped incision for the insertion of deep brain stimulators. AB - BACKGROUND: The S-shaped incision is a novel technique we have developed to minimise wound complications for the insertion of bilateral deep brain stimulators. METHODS: An S-shaped incision incorporating both burrholes allows better exposure compared to the traditional bilateral incisions. The burrholes are drilled under each limb of the S and the incision does not run across them, decreasing the risk of infection. The electrodes are subsequently tunneled down the right side and connected to the battery. CONCLUSION: The use of the S-shaped incision results in less wound and electrode complications compared to the traditional bilateral linear incisions in our experience. PMID- 23686632 TI - Resolution of trigeminal neuralgia following minimal coil embolization of a primitive trigeminal artery associated with a cerebellar arteriovenous malformation. PMID- 23686633 TI - Endoscopic distinction between capsule and pseudocapsule of pituitary adenomas. AB - BACKGROUND: Pseudocapsules were first identified in pituitary adenoma surgery in 1936. Since then, the distinction between pituitary capsules and pseudocapsules has been unclear, and the definitions of these entities have varied. In this study, pituitary capsules and extracapsular dissection were examined retrospectively, intra- and extrapseudocapsular resection was evaluated, and dissection of the pituitary adenoma and pseudocapsule was examined prospectively. METHODS: Between January 2009 and May 2012, endoscopic transsphenoidal pituitary surgery was performed on 224 patients in the Department of Neurosurgery, Kocaeli University Faculty of Medicine, Turkey. Data for 174 patients were analyzed retrospectively between January 2009 and December 2011, and 50 patients treated between December 2011 and May 2012 were included in a prospective study. RESULTS: In the retrospective phase of the study, capsules were examined in 21 of the 174 patients on whom extracapsular resection had been performed. In the 50 cases treated between December 2011 and May 2012, dissection of the pituitary capsule, adenohypophysis, and pseudocapsule was performed. In 30 patients in the prospective phase of the study, pseudocapsules were identified during intraoperative endoscopic observation. Remission was achieved in 28 of 33 functioning adenomas in the prospective study. The mean follow-up period in this group was 13 months. CONCLUSION: The endoscopic and histopathological evidence provided in this study demonstrates that the pituitary capsule and pseudocapsule are distinct structures. In addition, it is also shown that extracapsular dissection can be performed in functioning adenomas that invade the suprasellar region. Significantly higher rates of total resection and higher remission rates were observed in cases where extra- and intrapseudocapsular dissection was required. PMID- 23686634 TI - Intradural extramedullary benign spinal lesions radiosurgery. Medium- to long term results from a single institution experience. AB - BACKGROUND: Surgery represents the first-choice treatment for spinal intradural tumours. On the other hand, whether it is most appropriate in the setting of recurrences, residual or multiple lesions remains an open question. Moreover, some patients are less than ideal candidates for surgery. In this study we report about our own radiosurgery experience in the treatment of benign intradural extramedullary tumours of the spine. METHODS: In our study we analyzed the outcomes for 18 patients (21 lesions) treated for benign intradural extramedullary lesions, with a minimum follow-up period of 32 months. The lesions included 11 meningiomas, 9 schwannomas and 1 neurofibroma. RESULTS: The mean follow-up was 43 months (32-73 months). The median tumour volume was 2 cc (0.2 17.7 cc). Eleven lesions underwent single-fraction treatment (mean prescribed dose ranging from 10 to 13 Gy). The others received a multisession radiosurgery treatment (4-6 fractions) with a mean prescription dose ranging from 18.5 to 25 Gy. The maximum dose to the spinal cord ranged from 9.2 to 26 Gy. During the follow-up period, none of the lesions showed radiological evidence of progression. Neurological status was preserved or improved and no permanent sequelae were observed. Significant and durable pain relief was observed. CONCLUSIONS: Although surgical excision remains the primary treatment option for most intradural tumours, radiosurgery offers a real alternative therapeutic modality, especially in case of recurrent and residual lesions or when surgery is contraindicated. PMID- 23686635 TI - Evaluation of two- and three-dimensional visualization for endoscopic endonasal surgery using a novel stereoendoscopic system in a novice: a comparison on a dry laboratory model. AB - BACKGROUND: Three-dimensional (3-D) stereoscopic vision is theoretically superior to two-dimensional (2-D) vision in endoscopic endonasal surgery. However, only few reports have quantitatively compared endoscopic performance under the two visual conditions. We introduced a newly designed stereoendoscopic system with a "dual-lens and single camera" for endoscopic endonasal surgery and objectively compared the performances under 3-D and high-definition 2-D visualizations on a dry laboratory model. METHODS: Thirty subjects without experience performing endoscopic surgery, computer-simulated training or any 3-D video system were recruited and divided into two groups (Group A and Group B) for performing two different tasks. The novel 4.7-mm-diameter stereoendoscope provided high definition (HD) images. In Task 1, Group A started the task under the 3-D condition followed by the 2-D condition, and Group B vice versa. In Task 2, Group A started the task under the 2-D condition followed by the 3-D condition, and Group B vice versa. The performance accuracy and speed under the two visual conditions were analyzed. RESULTS: Significant improvement in performance accuracy and speed was seen under 3-D conditions in the both "3-D first" and "2-D first" subgroups during both tasks (P < .001). Regardless of order, the inaccuracy rate and performance time under 3-D conditions was significantly lower than that under 2-D conditions in each subject. CONCLUSIONS: We demonstrated the advantage of 3-D visualization over 2-D visualization for inexperienced subjects. Further quantitative clinical studies are required to confirm whether stereoendoscopy actually provides benefits in clinical settings. PMID- 23686636 TI - Neuroprotectin/protectin D1 protects against neuropathic pain in mice after nerve trauma. AB - Prevalence of neuropathic pain is high after major surgery. However, effective treatment for preventing neuropathic pain is lacking. Here we report that perisurgical treatment of neuroprotectin D1/protectin D1 (NPD1/PD1), derived from docosahexaenoic acid, prevents nerve injury-induced mechanical allodynia and ongoing pain in mice. Intrathecal post-treatment of NPD1/PD1 also effectively reduces established neuropathic pain and produces no apparent signs of analgesic tolerance. Mechanistically, NPD1/PD1 treatment blocks nerve injury-induced long term potentiation, glial reaction, and inflammatory responses, and reverses synaptic plasticity in the spinal cord. Thus, NPD1/PD1 and related mimetics might serve as a new class of analgesics for preventing and treating neuropathic pain. PMID- 23686639 TI - Effect of combined therapy of human Wharton's jelly-derived mesenchymal stem cells from umbilical cord with sitagliptin in type 2 diabetic rats. AB - Type 2 diabetes mellitus is the most common endocrine disease all over the world, while existing therapies can only ameliorate hyperglycemia or temporarily improve the response to insulin in target tissues, they cannot retard or improve the progressive beta-cell dysfunction persistently. Combined therapy of stem cells and sitagliptin might resolve this problem, we verified this hypothesis in a diabetic rat model. Except ten Wistar rats in normal control group, diabetic rats were divided into diabetic control group, WJ-MSCs group, sitagliptin group and WJ MSCs + sitagliptin group and received homologous therapy. Ten weeks after therapy, diabetic symptoms, FPG and GHbA1c in WJ-MSCs group, sitagliptin group and WJ-MSCs + sitagliptin group were significantly less than those in diabetic control group (P < 0.05), while fasting C-peptide and number of beta cells in WJ MSCs group and WJ-MSCs + sitagliptin group was significantly higher than those in diabetic control and sitagliptin group (P < 0.01). Glucagon and number of alpha cells in sitagliptin group and WJ-MSCs + sitagliptin group were significantly lower than those in WJ-MSCs group and diabetic control group (P < 0.01). No symptoms of rejection and toxic effect were observed. Combined therapy of WJ-MSCs and sitagliptin can effectively ameliorate hyperglycemia, promote regeneration of islet beta cells and suppress generation of islet alpha cells in diabetic rats, presenting a new therapy for type 2 diabetes although the exact mechanisms are unclear. PMID- 23686640 TI - New technologies aiding dietary programmes for weight control: the oral glucose spray. AB - To determine whether the administration of small amounts of glucose through an oral spray device (GSD) facilitates weight loss in overweight/obese subjects involved in a lifestyle modification programme. We randomly assigned 56 overweight/obese subjects to either the treatment group (n = 32) or the control group (n = 24). All subjects in both groups followed a structured dietary programme of 6,280.2 kJ (1,500 kcal)/day and exercised minimum 150 min a week and were followed-up for a period of 60 days. Subjects assigned to the treatment group were asked to spray, during early symptoms of neuroglycopenia, 10 puffs by GSD. GSD is a device that delivers to the buccal mucosa 50 mg of glucose per puff. A mean weight loss of 3.5 +/- 3.0 kg in GSD-treated group compared to 1.7 +/- 2.1 kg in control group (p = 0.01) was observed. Significant differences regarding reduction of BMI (-1.3 +/- 1.0 vs. -0.7 +/- 0.8 kg/m2; p = 0.01) and waist circumference (-3.5 +/- 3.2 vs. -0.9 +/- 3.5 cm; p = 0.02) were also detected. A short-term use of GSD, in association with dietary restriction and exercise, is helpful in improving weight loss and in reducing waist circumference in overweight/obese subjects. PMID- 23686641 TI - Reply: To PMID 22991257. PMID- 23686642 TI - Histone deacetylase inhibitors suppress immune activation in primary mouse microglia. AB - Neuroinflammation is required for tissue clearance and repair after infections or insults. To prevent excessive damage, it is crucial to limit the extent of neuroinflammation and thereby the activation of its principal effector cell, microglia. The two main major innate immune cell types in the CNS are astrocytes and microglia. Histone deacetylases (HDACs) have been implicated in regulating the innate inflammatory response, and here we addressed their role in pure astrocyte and microglia cultures. Endogenous HDAC expression levels were determined in microglia and astrocytes and after treatment with lipopolysaccharide (LPS) or LPS and interferon gamma (IFNgamma). The relative expression level of HDACs was reduced in LPS- or LPS/IFNgamma (with the exception of HDAC1 and -7)-stimulated astrocytes and increased in microglia after LPS treatment both in primary cultures and in microglia acutely isolated from LPS treated mice, so we focused on the inflammatory response in microglia. Primary microglia cultures were treated with LPS in the presence or absence of HDAC inhibitors (HDACi). Expression and release of inflammatory cytokines was determined by quantitative RT-PCR, flow cytometry, and ELISA. HDACi strongly suppressed LPS-induced cytokine expression and release by microglia. Furthermore, expression of M1- and M2-associated activation markers was suppressed, and the migratory behavior of microglia was attenuated. Our findings strongly suggest that HDACi suppress innate immune activation in microglia. PMID- 23686643 TI - Lemierre's syndrome: the forgotten disease. AB - Lemierre's syndrome is an often un-diagnosed disease seen in previously healthy young subjects, presenting with symptoms of pharyngitis, fever and elevated markers of inflammation. The syndrome is characterised by infectious thrombosis of the jugular vein due to infection with Fusobacteria, causing a variety of infectious complications. Rapid diagnosis and treatment is necessary to avoid severe complications or death. Close collaboration with local microbiologist is pivotal. Treatment consists of longterm treatment with penicillin and metronidazole. This is a case report of Lemierre's syndrome. PMID- 23686644 TI - Prednisone versus high-dose dexamethasone for untreated primary immune thrombocytopenia. A retrospective study of the Japan Hematology & Oncology Clinical Study Group. AB - High-dose dexamethasone (HDD) has been shown to be an effective initial treatment for immune thrombocytopenia (ITP), but it is not clear whether HDD offers any advantages over conventional-dose prednisone (PSL). We retrospectively compared the efficacy and toxicity of HDD and PSL for newly diagnosed ITP. The response was evaluated according to the International Working Group (IWG) criteria. We analyzed data from 31 and 69 patients in the HDD and PSL groups, respectively. There were no significant differences in patient characteristics between the two groups except for the incidence of the eradication of Helicobacter pylori. The response rate was better in the HDD group (42.7 vs. 28.4 %), and this difference was statistically significant when adjusted for other factors including the eradication of H. pylori. In the HDD group, a response was achieved earlier (28 vs. 152 days in median) and steroids were more frequently discontinued at 6 months (64.5 vs. 37.7 %). Among patients who achieved a response, there was no significant difference in the incidence of loss of response. There were no significant differences in the rate of adverse events, transition to chronic ITP, and splenectomy. In conclusion, HDD might enable the early cessation of steroids without a loss of response. PMID- 23686645 TI - Quantitative evaluation of vocal-fold mucosal irregularities using GLCM-based texture analysis. AB - OBJECTIVES/HYPOTHESIS: Visualization of the vocal folds is essential when reaching a primary diagnosis of laryngeal disease. However, the examination is subjective and highly dependent on the experience of the treating physician. The present study is the development of objective tools for the diagnosis of laryngeal malignancy based on laryngeal texture analysis. STUDY DESIGN: Texture analysis using gray-level co-occurrence matrix (GLCM) in vocal fold images of 198 patients. METHODS: Vocal-fold images were subjected to texture analysis using gray-level co-occurrence matrix (GLCM)-based parameters, which were computed by a novel digital image-processing program. Patients were divided into two groups: those with benign-looking lesions and those with malignant-looking lesions. Textural irregularities were compared using GLCM-based parameters. The relationship between the texture-analysis parameters and the diagnosis was then statistically evaluated. RESULTS: Texture irregularity was negatively correlated with energy and the inverse difference moment (IDM) and positively correlated with entropy, variance, contrast, dissimilarity, and mean values. All of the GLCM based parameters evaluated differed significantly according to the degree of differentiation of the benign- or malignant-looking lesion (P < 0.001). Entropy had a sensitivity of 82.9% and a specificity of 82.2% at a cutoff value of 5.94; for variance, the sensitivity was 82.9% and the specificity was 84.5% at a cutoff value of 167. CONCLUSION: GLCM-based texture analysis of vocal-fold lesions, especially in association with a differential diagnosis of benign and malignant looking diseases, contributes to achieving an objective image-based analysis of vocal-fold lesions. In addition, this approach can be used to create algorithms permitting a reproducible classification of laryngeal pathologies. PMID- 23686646 TI - Visual loss with inner retinal dysfunction, after snake bite: two case reports. AB - PURPOSE: To report two cases of visual loss following snake bite. METHOD: Retrospective review of medical records including history, examination finding, fundus details and investigation reports (visual field, electroretinogram, visual evoked potential and optical coherence tomogram) at two centers. RESULT: Two cases of snake bite presented to us with reduction of vision at 1 and 3 months after the incident. The subnormal b wave and abnormal pattern electroretinography in one case pointed at inner retinal dysfunction and neurotoxicity as the cause of visual loss in an apparently normal-looking fundus. The electronegative b wave in the other gave us a clue that the optic atrophy was consecutive (secondary to inner retinal dysfunction due to central retinal artery occlusion). CONCLUSION: When presented late, diagnosis of visual loss secondary to snake bite becomes difficult and puzzling due to the absence of classical findings. Electrophysiological tests in such cases give us important clue to reach at a definite diagnosis. PMID- 23686647 TI - Multidimensional control of cell structural robustness. AB - Ample adaptive and functional opportunities of a living cell are determined by the complexity of its structural organisation. However, such complexity gives rise to a problem of maintenance of the coherence of inner processes in macroscopic interims and in macroscopic volumes which is necessary to support the structural robustness of a cell. The solution to this problem lies in multidimensional control of the adaptive and functional changes of a cell as well as its self-renewing processes in the context of environmental conditions. Six mechanisms (principles) form the basis of this multidimensional control: regulatory circuits with feedback loops, redundant inner diversity within a cell, multilevel distributed network organisation of a cell, molecular selection within a cell, continuous informational flows and functioning with a reserve of power. In the review we provide detailed analysis of these mechanisms, discuss their specific functions and the role of the superposition of these mechanisms in the maintenance of cell structural robustness in a wide range of environmental conditions. PMID- 23686648 TI - Sex-specific effects of fetal exposure to the 1959-1961 Chinese famine on risk of adult hypertension. AB - Previous research is inconsistent about the effects of prenatal famine exposure on risk of adult hypertension. Follow-up of persons exposed to the 1959-1961 Chinese famine, the largest in human history, provides an opportunity to examine the long-term impact of prenatal famine exposure on adult cardiovascular disease (CVD). We investigated the effects of fetal-infant exposure to the famine on risk of hypertension in adulthood. We included 1,415 participants from the 2009 China Health and Nutrition Survey born September 1, 1956-December 31, 1964. Blood pressure (BP) measurements, self-reported previous diagnosis of hypertension and current anti-hypertension drug use were obtained from the survey. Differences in mean BP and risk of adult hypertension by famine exposure status were determined using linear and logistic regression analyses, after adjusting for confounders. Women with fetal-infant exposure to famine had higher mean systolic blood pressure (4.24 mmHg; 95% confidence interval (CI) 1.50-6.98) than those unexposed. They also had increased odds of a prior diagnosis of hypertension (odds ratio (OR) 2.16; 95% CI 1.16-4.02), and were more likely to be currently taking anti-hypertensive medications (OR 2.81; 95% CI 1.32-5.97) than unexposed women after adjusting for covariates. No statistically significant increases in mean BP or hypertension were seen among men. Exposure to famine during the fetal infant period or early childhood has deleterious effects on adult health, but the effects may be greater for women. Gender-specific intervention strategies for CVD may be warranted for populations exposed to under-nutrition during critical time periods of fetal development. PMID- 23686649 TI - Unraveling environmental drivers of a recent increase in Swiss fungi fruiting. AB - Disentangling biotic and abiotic drivers of wild mushroom fruiting is fraught with difficulties because mycelial growth is hidden belowground, symbiotic and saprotrophic supply strategies may interact, and myco-ecological observations are often either discontinuous or too short. Here, we compiled and analyzed 115 417 weekly fungal fruit body counts from permanent Swiss inventories between 1975 and 2006. Mushroom fruiting exhibited an average autumnal delay of 12 days after 1991 compared with before, the annual number of fruit bodies increased from 1801 to 5414 and the mean species richness doubled from 10 to 20. Intra- and interannual coherency of symbiotic and saprotrophic mushroom fruiting, together with little agreement between mycorrhizal yield and tree growth suggests direct climate controls on fruit body formation of both nutritional modes. Our results contradict a previously reported declining of mushroom harvests and propose rethinking the conceptual role of symbiotic pathways in fungi-host interaction. Moreover, this conceptual advancement may foster new cross-disciplinary research avenues, and stimulate questions about possible amplifications of the global carbon cycle, as enhanced fungal production in moist mid-latitude forests rises carbon cycling and thus increases greenhouse gas exchanges between terrestrial ecosystems and the atmosphere. PMID- 23686650 TI - Lethal and sublethal effects of three insecticides on two developmental stages of Xenopus laevis and comparison with other amphibians. AB - It has been suggested that Xenopus laevis is less sensitive than other amphibians to some chemicals, and therefore, that the Frog Embryo Teratogenesis Assay Xenopus (FETAX) may have limited use in risk assessments for other amphibians. However, comparisons are based mostly on results of FETAX, which emphasizes embryos. Larval X. laevis may be more sensitive to chemicals than embryos and may serve as a better life stage in risk assessments. The present study was conducted to determine the lethal and sublethal effects of 3 insecticides (malathion, endosulfan, and alpha-cypermethrin) on X. laevis embryos and larvae and to compare toxicity of X. laevis with that of other amphibians. All 3 insecticides have different modes of action, and they caused mortality, malformations, and growth inhibition in both developmental stages. Compared with embryos, larvae were more sensitive to endosulfan and alpha-cypermethrin but not to malathion. Xenopus laevis larvae had low sensitivity to endosulfan, median sensitivity to malathion, and high sensitivity to alpha-cypermethrin/cypermethrin relative to other larval amphibians. Our results suggest that X. laevis larvae may generate more protective toxicity estimates in risk assessments than embryos. Xenopus laevis may have limited use in evaluating risk of organochlorine insecticides to other amphibians but may provide useful toxicity thresholds for pyrethroid and perhaps organophosphorus insecticides. PMID- 23686651 TI - Hypercalcemia and miliary sarcoidosis in a 15-year-old boy. PMID- 23686652 TI - Human skin is permselective for the small, monovalent cations sodium and potassium but not for nickel and chromium. AB - The molar conductance of excised human skin (Lambda(skin)) immersed in electrolyte solutions comprising four cationic (Na(+), K(+), Ni(2+), and Cr(3+)) and five anionic (Cl(-), NO3(-), SO4(2-), CrO4(2-), and Cr2O7(2-)) species was determined as a function of concentration in Franz diffusion cells. Cation transport numbers for four of these electrolytes were measured in Franz cells by the electromotive force method. Parallel experiments were conducted in solutions alone to establish the validity of the technique. Molar conductance decreased with increasing concentration, following the Kohlrausch law, over a 4-12-fold concentration range. Molar conductance and cation transport values at infinite dilution were extrapolated from these data and used to estimate ionic conductances at infinite dilution. These values were subsequently used to calculate limiting ion mobilities and diffusivities in solution and skin. Results for skin showed the expected increase in cation permselectivity for monovalent cations and a 40-110-fold reduction in effective diffusivities with respect to those in solution. However, Ni(2+) and Cr(3+) were relatively less mobile in skin than in solution. Salt diffusivities calculated from ionic mobilities in skin provided a partial explanation for the difference in allergenic potency of NiCl2 compared with NiSO4 and Cr(3+) versus Cr(6+) salts. PMID- 23686654 TI - Noninvasive prenatal testing: the paradigm is shifting rapidly. PMID- 23686653 TI - Preoperative 4-week supplementation with omega-3 polyunsaturated fatty acids reduces liver volume and facilitates bariatric surgery in morbidly obese patients. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a very common condition among obese patients that may lead to the enlargement of the liver, that in turn impairs the access to the gastro-esophageal junction during laparoscopic bariatric surgery. Omega-3 polyunsaturated fatty acids (Omega-3 PUFAs) supplementation has been shown to reduce nutritional hepatic steatosis. The aim of this study was to assess the effects of a 4-week course of oral Omega-3 PUFAs supplementation on the volume of the liver. METHODS: 20 morbidly obese patients were administered oral Omega-3 PUFAs (1,500 mg daily) for 4 weeks before undergoing the laparoscopic Roux-en-Y gastric bypass (LRYGBP) without any dietary restriction. The volume of the left hepatic lobe was estimated by liver ultrasonography at baseline and at the end of treatment. The degree of difficulty to access the gastro-esophageal junction was appreciated subjectively by the operating surgeon. RESULTS: All patients completed the study and no side effect was reported. The mean volume of the left hepatic lobe decreased by 20% from 598 +/- 97 to 484 +/- 118 cm(3) after the treatment (p = 0.002). The access to the gastro-esophageal junction was reported as simple, with easy retraction of the left hepatic lobe by the operating surgeon in all cases. CONCLUSIONS: This study demonstrates that a 4-week course of oral Omega-3 PUFAs supplementation results in a significant reduction in liver size that facilitates the LRYGBP. PMID- 23686655 TI - Fetal aneuploidy detection by maternal plasma DNA sequencing: a technology assessment. AB - The American College of Obstetricians and Gynecologists currently recommends that all pregnant women be offered screening for chromosomal abnormalities, regardless of maternal age. Traditional screening tests have detection rates ranging from 85% to 90% and false-positive rates of 3% to 5%. A woman with an abnormal noninvasive test is offered a diagnostic test, but diagnostic tests are associated with a risk of pregnancy loss. Recently, analysis of cell-free fetal DNA (cffDNA) in maternal blood has been shown to have potential for the accurate detection of some of the common fetal autosomal aneuploidies. As part of a technology assessment for the California Technology Assessment Forum, we critically reviewed the evidence for the use of cffDNA as a prenatal screening test. We evaluated the evidence for its use as either a 'primary' or an 'advanced' screening test and for its use in screening for three different trisomies: 21, 18, and 13. We evaluated whether the use of cffDNA met established technology assessment criteria and established conclusions about evidence-based use of this new technology. PMID- 23686656 TI - Commercial landscape of noninvasive prenatal testing in the United States. AB - Cell-free fetal DNA-based noninvasive prenatal testing (NIPT) could significantly change the paradigm of prenatal testing and screening. Intellectual property (IP) and commercialization promise to be important components of the emerging debate about clinical implementation of these technologies. We have assembled information about types of testing, prices, turnaround times, and reimbursement of recently launched commercial tests in the United States from the trade press, news articles, and scientific, legal, and business publications. We also describe the patenting and licensing landscape of technologies underlying these tests and ongoing patent litigation in the United States. Finally, we discuss how IP issues may affect clinical translation of NIPT and their potential implications for stakeholders. Fetal medicine professionals (clinicians and researchers), genetic counselors, insurers, regulators, test developers, and patients may be able to use this information to make informed decisions about clinical implementation of current and emerging noninvasive prenatal tests. PMID- 23686657 TI - Does laboratory automation for the preanalytical phase improve data quality? AB - Our aim was to evaluate whether automation for the preanalytical phase improves data quality. Blood from 100 volunteers was collected into two vacuum tubes. One sample from each volunteer was respectively assigned to (G1) traditional processing, starting with centrifugation at 1200 g for 10 min, and (G2) the MODULAR PRE-ANALYTICALS EVO-MPA system. The routine clinical chemistry tests were performed in duplicate on the same instrument Cobas 6000 module. G1 samples were uncapped manually and immediately placed into the instrument. G2 samples were directly fed from the MPA system to the instrument without further staff intervention. At the end, (1) the G1 samples were stored for 6 h at 4 degrees C as prescribed in our accredited laboratory and (2) the G2 samples were stored for 6 h in the MPA output buffer. Results from G1 and G2, before and after storage, were compared. Significant increases were observed in G1 compared with G2 samples as follows: (1) before storage for alkaline phosphatase (ALP), lactate dehydrogenase (LDH), phosphate (P), magnesium (MG), iron (FE), and hemolysis index and (2) after storage for total cholesterol (COL), triglycerides (TG), total protein (TP), albumin (ALB), blood urea nitrogen (BUN), creatinine (CRE), uric acid (UA), ALP, pancreatic amylase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), g-glutamyltransferase (GGT), LDH, creatine kinase (CK), calcium (CA), FE, sodium (NA), potassium (K), and hemolysis index. Moreover, significant increases were observed in (3) G1-after versus G1-before storage samples for COL, high-density lipoprotein cholesterol, TG, TP, ALB, BUN, CRE, UA, AST, ALT, GGT, LDH, P, CA, MG, FE, NA, K, and hemolysis index and (4) G2 after versus G2-before storage only for BUN, AST, LDH, P, and CA. In conclusion, our results show that the MPA system improves the quality of laboratory testing. PMID- 23686659 TI - Selection is no more efficient in haploid than in diploid life stages of an angiosperm and a moss. AB - The masking hypothesis predicts that selection is more efficient in haploids than in diploids, because dominant alleles can mask the deleterious effects of recessive alleles in diploids. However, gene expression breadth and noise can potentially counteract the effect of masking on the rate at which genes evolve. Land plants are ideal to ask whether masking, expression breadth, or expression noise dominate in their influence on the rate of molecular evolution, because they have a biphasic life cycle in which the duration and complexity of the haploid and diploid phase varies among organisms. Here, we generate and compile genome-wide gene expression, sequence divergence, and polymorphism data for Arabidopsis thaliana and for the moss Funaria hygrometrica to show that the evolutionary rates of haploid- and diploid-specific genes contradict the masking hypothesis. Haploid-specific genes do not evolve more slowly than diploid specific genes in either organism. Our data suggest that gene expression breadth influence the evolutionary rate of phase-specific genes more strongly than masking. Our observations have implications for the role of haploid life stages in the purging of deleterious mutations, as well as for the evolution of ploidy. PMID- 23686658 TI - The effect of gene overlapping on the rate of RNA virus evolution. AB - Gene overlapping is widely employed by RNA viruses to generate genetic novelty while retaining a small genome size. However, gene overlapping also increases the deleterious effect of mutations as they affect more than one gene, thereby reducing the evolutionary rate of RNA viruses and hence their adaptive capacity. Although there is general agreement on the benefits of gene overlapping as a mechanism of genomic compression for rapidly evolving organisms, its effect on the pace of RNA virus evolution remains a source of debate. To address this issue, we collected sequence data from 117 instances of gene overlapping across 19 families, 30 genera, and 55 species of RNA viruses. On these data, we analyzed how genetic distances, selective pressures, and the distribution of RNA secondary structures and conserved protein functional domains vary between overlapping (OV) and nonoverlapping (NOV) regions. We show that gene overlapping generally results in a decrease in the rate of RNA virus evolution through a reduction in the frequency of synonymous mutations. However, this effect is less pronounced in genes with a terminal rather than an internal gene overlap, which might result from a greater proportion of protein functional conserved domains in NOV than in OV regions, in turn reducing the number of nonsynonymous mutations in the former. Overall, our analyses clarify the role of gene overlapping as a modulator of the evolutionary rates exhibited by RNA viruses and shed light on the factors that shape the genetic diversity of this important group of pathogens. PMID- 23686660 TI - Surgical techniques for the dissection of encased perforators in giant clinoidal meningiomas. AB - BACKGROUND: Surgical treatment of giant clinoidal meningiomas remains a challenging task for neurosurgeons. Here, we present details of the surgical techniques for the dissection of encased perforators. METHODS: The dissection of encased perforators is summarized as follows: (1) split the tumor above the encased arteries and perforators; (2) find the entrance and exit points of the perforators, and estimate the running course of the perforators within the tumor; (3) dissect and expose the perforators along the estimated line. CONCLUSIONS: The surgical techniques described in this article will aid in achieving maximum tumor resection while preserving encased perforators. PMID- 23686661 TI - Answer to: "sodium fluorescein-guided resection under the YELLOW 560-nm surgical microscope filter in malignant brain tumor surgery-a feasibility study" (April 2013, volume 155, issue 4, pp 693-69). PMID- 23686662 TI - Primary hepatic lymphoma. PMID- 23686663 TI - Robot-assisted minimally invasive surgery for pediatric solid tumors: a systematic review of feasibility and current status. AB - INTRODUCTION: Open surgery remains the primary technique for resection of pediatric solid tumors despite the popularity of minimally invasive surgery (MIS) for oncological indications in adults and nononcological indications in children. Robot-assisted surgery offers technical and ergonomic advantages that might make MIS more achievable in this setting, permitting benefits for both the patient and surgeon. The aim of this study is to critically appraise the current status of robot-assisted MIS for pediatric solid tumors. MATERIALS AND METHODS: A systematic search of multiple electronic literature databases was undertaken, supplemented by several relevant secondary sources. RESULTS: A total of 23 publications met eligibility criteria, reporting 40 cases overall. Indications for surgery were widely varied, with over 20 different pathologies described. One third of tumors were classified as malignant. Most procedures involved abdominal or retroperitoneal located tumors in adolescent patients (age range, 1-18 years). The collective complication and conversion rates were 10% and 12.5%, respectively. Oncological adverse events involved two isolated events of tumor spillage and residual disease. The evidence is limited to case reports and small case series only. CONCLUSIONS: For the diverse and highly selective cases in this review, robot-assisted MIS seems safe and feasible. Current status is low volume, in a relatively static state of adoption, and without any apparent index pathology or procedure. The benefits of robot assistance seem well suited but remain unsubstantiated by evidence. Higher quality studies are needed to determine true safety and efficacy. PMID- 23686664 TI - Enteric nervous system and esophageal-gastrointestinal motility in experimental congenital diaphragmatic hernia. AB - Gastroesophageal reflux and intestinal distension have been described in survivors of congenital diaphragmatic hernia (CDH). Deficient enteric innervation demonstrated in experimental models is a likely explanation for these symptoms. This study aimed at further characterizing these anomalies and examining esophageal and intestinal motility in this condition. Pregnant rats received either nitrofen or vehicle on E9.5. Sections of E15, E18, and E21 esophagus and small bowel were stained for protein gene product 9.5, nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase (NADPHd), and acetylcholinesterase (AChE). The proportion of neural tissue/muscle surface was measured and the NADPHd- and AChE-positive motor endplates (MEPs) were counted. E18 and E21 stomachs were stained for AChE, the ganglia were counted and measured. The peristalsis of the esophagus and small bowel was video recorded. The relative neural/muscle surface and the number of NADPHd- and AChE-positive MEPs were decreased on E15 and E18 in the esophagus and small bowel of embryos with CDH, but they tended to improve on E21. The number and the mean surface of stomach ganglia were smaller in E18 and E21 fetuses with CDH. Peristaltic movements were decreased in the esophagus and small bowel of animals with CDH. Deficient enteric innervation impaired gastrointestinal motility in experimental CDH. This could explain some long-term morbidity in the human condition. PMID- 23686665 TI - Rectal pouch index: a prognostic indicator for constipation after surgery for high and intermediate anorectal malformations. AB - BACKGROUND AND INTRODUCTION: Constipation following posterior sagittal anorectoplasty (PSARP) is common. We correlated the dimensions of rectal pouch before PSARP with the postoperative bowel habit. Classical PSARP was modified with tapering of rectal pouch by plication of its walls thus preserving the internal sphincter because we believe that this preserves continence and lead to better results. It was observed that a distinct relationship exists between the preoperative size of the rectal pouch and constipation. AIM: The aim of this study is to correlate the dimensions of preoperative rectal pouch with postoperative constipation. MATERIALS AND METHODS: PSARP was performed (n: 45) in anorectal malformations using an indigenous muscle stimulator. Before PSARP, a distal cologram via high sigmoid colostomy was performed. All the distal cologram were performed by a single senior radiologist and the pressure was kept constant between 15 and 20 cm of water while filling to rule out the confounding factor related to incomplete filling. Rectum index was calculated as follows: The maximum radiological diameter of the rectum within the pelvis in the sagittal plane was multiplied by the maximum diameter of the rectum in the frontal plane. The result of this calculation was divided by the product of multiplying the distance between the ischial spines and the distance between the posterior surface of the pubic symphysis and the anterior surface of the last sacral vertebrae. RESULTS: Symptomatic constipation requiring treatment developed in 25 patients (48%). None of these patients had anal stenosis or stricture. Constipation was managed by dietary measures and laxatives. Fifteen patients (60%) had grade 1 constipation and responded favorably. Eight and two patients had grades 2 and 3 constipation, respectively. Those patients who had a rectal pouch index of less than 0.8 had mild constipation grades 0 and 1, whereas those in whom the rectal pouch index was more than 0.8 had severe degrees of constipation (grades 2 and 3). CONCLUSION: Measuring the rectal pouch index can help in identifying the group which is likely to develop constipation after PSARP. These patients can be put on bowel training early on, after the colostomy closure, instead of waiting. PMID- 23686666 TI - Dexamethasone induces apoptosis of progenitor cells in the subventricular zone and dentate gyrus of developing rat brain. AB - The use of dexamethasone in premature infants to prevent and/or treat bronchopulmonary dysplasia adversely affects neurocognitive development and is associated with cerebral palsy. The underlying mechanisms of these effects are multifactorial and likely include apoptosis. The objective of this study was to confirm whether dexamethasone causes apoptosis in different regions of the developing rat brain. On postnatal day 2, pups in each litter were randomly divided into the dexamethasone-treated (n = 91) or vehicle-treated (n = 92) groups. Rat pups in the dexamethasone group received tapering doses of dexamethasone on postnatal days 3-6 (0.5, 0.25, 0.125, and 0.06 mg/kg/day, respectively). Dexamethasone treatment significantly decreased the gain of body and brain weight and increased brain caspase-3 activity, DNA fragments, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and cleaved caspse 3-positive cells at 24 hr after treatment. Dexamethasone increased cleaved caspse 3-positive cells in the cortex, thalamus, hippocampus, cerebellum, dentate gyrus, and subventricular zone. Double-immunofluorescence studies show that progenitor cells in the subventricular zone and dentate gyrus preferentially undergo apoptosis following dexamethasone exposure. These results indicate that dexamethasone-induced apoptosis in immature cells in developing brain is one of the mechanisms of its neurodegenerative effects in newborn rats. PMID- 23686667 TI - Methods for rearing Mesostoma ehrenbergii in the laboratory for cell biology experiments, including identification of factors that influence production of different egg types. AB - Mesostoma ehrenbergii spermatocytes are uniquely useful to study various aspects of cell division. Their chromosomes are large in size and few in number, with only three bivalent and four univalent chromosomes. During prometaphase, bipolar bivalents oscillate regularly to and from the poles for 1-2 hours. The univalents remain at the poles but occasionally move from one pole to the other. In addition, a precocious cleavage furrow forms during prometaphase and remains partially constricted until anaphase. Attempts to rear these animals indefinitely in laboratory conditions, however, have been mostly unsuccessful because of their reproductive strategy. M. ehrenbergii are hermaphroditic flatworms that can produce viviparous offspring (termed S eggs) and/or diapausing eggs (termed D eggs) and they follow either one of two reproductive patterns: (1) they first form S eggs and following the delivery of these eggs produce D eggs, or (2) they only produce D eggs. When only D eggs are formed, which is common under laboratory conditions, the stocks die out until the D eggs hatch, which is irregular and creates unpredictable wait times. Consequently, in order to maintain M. ehrenbergii stocks to study their spermatocytes, we examined various factors that might influence egg-type production. Feeding them daily and keeping them at 25 degrees C favours S egg production. Currently, our cultures have reached the 53rd generation. We herein describe our rearing and dissection methods, and some experiments which led to our present rearing methods. PMID- 23686668 TI - Subnuclear distribution of SSX regulates its function. AB - SSX, a family of genes clustered on the X chromosome, has been identified as a cancer-testis antigen and also forms a part of the SYT-SSX fusion gene found in synovial sarcoma, implying that it has an important role in tumorigenesis. However, knowledge of the molecular regulation of SSX is still limited. In this study, we demonstrate that SSX or its SYT fusion protein is distributed as nuclear speckles, in which it is co-localized with B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi1), which is a core factor of polycomb repressor complex 1. The C-terminal residues of SSX are indispensable for the nuclear speckle distribution, while the N-terminal domain is necessary for the recruitment of Bmi1, indicating that intact SSX must be needed for interaction with Bmi1 both spatially and functionally. In addition, the N-terminus of SSX also proved to contain an intrinsic nucleolar localization signal, which mediates the nucleolar translocation of SSX in particular kinds of cell stress such as the oxidation of hydrogen peroxide or heat shock. This stress-induced translocation is reversible and accompanied by HSP 70 or p14ARF traffic, suggesting that SSX is a stress response gene. It is of note that nucleolar translocation of SSX can result in disassociation of SSX from Bmi1, with consequent down-regulation of Bmi1 activity. These novel findings regarding distinct domains of SSX and its interaction with Bmi1 may shed light on the mechanism by which synovial sarcoma develops and on the up-regulation of SSX in cancer cells. PMID- 23686670 TI - Comment to Heng Luo et al.: Holmium laser division of the suture causing entrapment of a drainage tube after laparoscopic nephrectomy. PMID- 23686669 TI - Prognostic potential of ERG (ETS-related gene) expression in prostatic adenocarcinoma. AB - PURPOSE: Following patients after prostatectomy can be expensive and stressful, therefore, a novel and reliable approach to improve stratification is needed both at diagnosis of PCa and following its treatment. We evaluate the association of both ERG and claudin-4, claudin-5, and beta-catenin expression in tumor tissues of patients with organ-confined and advanced prostatic adenocarcinomas. METHODS: A total of 30 patients were included in the study. Nine men who underwent radical prostatectomy for organ-confined (pT2N0M0) cancer (OCC), 10 patients with clinically advanced cancer (CAC), and 11 controls with benign prostatic hypertrophy (BPH). Using immunohistochemistry applied to tissue microarrays, each group was evaluated for beta-catenin, claudin-4, claudin-5, and ERG expression. RESULTS: The expression of ERG was higher in the CAC group when compared to OCC and BPH (p = 0.7684, p = 0.0224, respectively). Among these patients, 5 from the CAC (45 %) and 5 from the OCC group (56 %) stained positively for ERG (p = 1.0). The mean staining score for those with ERG+ advanced cancer was greater than that for the ERG+ organ-confined cancer (p = 0.0209). ERG staining correlated with Gleason score (Pearson's correlation: 0.498, p = 0.0051), but not with serum PSA level (Pearson's correlation: 0.404, p = 0.1202). When analyzing outcome data, high ERG expressing tumors have shown a significantly worse overall survival (p = 0.0084). CONCLUSIONS: Our results of presence or absence of claudin-4 and claudin 5 and ERG staining intensities suggest their potential as prognostic factors for prostate cancer. PMID- 23686671 TI - Active targeted therapy for metastatic collecting duct carcinoma of the kidney: a case report and review of the literature. AB - Collecting duct carcinoma (CDC) is a rare and aggressive renal cell carcinoma (RCC) with extremely poor prognosis, which has been shown to have a poor response to several kinds of systemic therapy. Targeted agents have greatly changed the therapeutic landscape in advanced RCC. Nonetheless, patients with CDC are always excluded from the prospective trials with targeted therapies due to its rarity. We present a case of metastatic CDC that responded favorably to the multiple tyrosine kinase inhibitor, sorafenib, achieving a partial response in both lungs and retroperitoneal lymph nodes metastases. We also reviewed the limited number of reports of metastatic CDC treated with targeted agents and found that 33.33 % (4/12) of patients had favorable clinical activity. These suggest that targeted therapy should be considered for the treatment of metastatic CDC and its prospective evaluation is encouraged. PMID- 23686672 TI - The receptor TGR5 protects the liver from bile acid overload during liver regeneration in mice. AB - Many regulatory pathways are involved in liver regeneration after partial hepatectomy (PH) to initiate growth, protect liver cells, and sustain functions of the remnant liver. Bile acids (BAs), whose levels rise in the blood early after PH, stimulate both hepatocyte proliferation and protection, in part through their binding to the nuclear farnesoid X receptor (FXR). However, the effect of the BA receptor, TGR5 (G-protein-coupled BA receptor 1) after PH remains to be studied. Liver histology, hepatocyte proliferation, BA concentrations (plasma, bile, liver, urine, and feces), bile flow and composition, and cytokine production were studied in wild-type (WT) and TGR5 KO (knockout) mice before and after PH. BA composition (plasma, bile, liver, urine, and feces) was more hydrophobic in TGR5 KO than in WT mice. After PH, severe hepatocyte necrosis, prolonged cholestasis, exacerbated inflammatory response, and delayed regeneration were observed in TGR5 KO mice. Although hepatocyte adaptive response to post-PH BA overload was similar in WT and TGR5 KO mice, kidney and biliary adaptive responses were strongly impaired in TGR5 KO mice. Cholestyramine treatment, as well as Kupffer cell depletion, significantly improved the post-PH TGR5 KO mice phenotype. After bile duct ligation or upon a cholic acid-enriched diet, TGR5 KO mice exhibited more severe liver injury than WT as well as impaired BA elimination in urine. CONCLUSION: TGR5 is crucial for liver protection against BA overload after PH, primarily through the control of bile hydrophobicity and cytokine secretion. In the absence of TGR5, intrahepatic stasis of abnormally hydrophobic bile and excessive inflammation, in association with impaired bile flow adaptation and deficient urinary BA efflux, lead to BA overload-induced liver injury and delayed regeneration. PMID- 23686673 TI - Otologic assessment of blast and nonblast injury in returning Middle East deployed service members. AB - OBJECTIVES/HYPOTHESIS: To determine if tympanic membrane perforation offers any protection from inner ear damage and determine the incidence and pattern of otologic blast injury in military personnel returning from deployment. STUDY DESIGN: Retrospective analysis of US service members injured in Operation Iraqi Freedom and Operation Enduring Freedom from October 2006 to October 2007. METHODS: One-hundred ten blast-injured patients were compared to 54 nonblast injured patients returning from deployment. Data captured included audiogram results, presence of tympanic membrane perforation, demographic data, location and nature of injury, loss of consciousness, sleep disturbance, confusion, and symptoms of headache, dizziness, memory loss, and tinnitus. RESULTS: Of 110 blast injured patients, 18 patients suffered tympanic membrane perforation (16%), of which nine patients suffered bilateral tympanic membrane perforation (8%). Blast patients suffered more hearing loss than controls as measured by pure-tone averages of varying speech reception frequencies and at 6,000 Hz. Of the blast patients who recorded an audiogram, nearly 24% suffered moderate to profound hearing loss. There was no statistically significant difference in hearing outcomes between blast-injured patients with tympanic membrane perforations and those without; however, when comparing patients with unilateral perforations with their contralateral ear, there was a difference in hearing thresholds at 6,000 Hz. There was a significantly increased risk of tinnitus, memory loss, headache, and dizziness between blast-injured patients compared to controls. CONCLUSIONS: Due to its violent nature, blast exposure causes greater neuro-otological manifestations and deserves prompt otologic evaluation. PMID- 23686674 TI - Is it really fat? Ask a T1-map. PMID- 23686675 TI - Fetal brain inflammation may prime hyperexcitability and behavioral dysfunction later in life. PMID- 23686677 TI - Phenotypic characterization of a Chinese family with autosomal dominant cone-rod dystrophy related to GUCY2D. AB - BACKGROUND: This study aimed to evaluate the clinical phenotype and investigate the molecular genetic defect in a Chinese family with autosomal dominant cone-rod dystrophy (ADCRD). METHODS: Family history was collected and patients underwent regular ophthalmologic examinations. Two affected individuals underwent three year follow-ups to analyze the course of the disease. Venous blood was collected from family members and genomic DNA was extracted. A whole genome linkage analysis of 11 family members was performed using an Illumina Infinium Human Linkage-12 panel. All exons and exon-intron boundaries of guanylate cyclase 2D gene (GUCY2D) were sequenced for familial gene mutation. RESULTS: Decreased visual acuity and photophobia usually commenced in early childhood in these patients. The family demonstrated an age-dependent increase in macular abnormalities with progressive development of geographic atrophy. Electrophysiological testing revealed a marked loss of cone function. Initially, a genome-wide linkage analysis mapped the disease to chromosome 17 (1-36 cM), with a maximum LOD score of 1.505. Sequence analysis of the GUCY2D gene in the linkage interval detected a recurrent heterozygous mutation, c.2513G > C (p.R838P). This mutation appeared in all seven patients with ADCRD but did not appear in any of the four unaffected family members. CONCLUSIONS: A missense mutation in the GUCY2D gene caused ADCRD in this family. Clinical follow-up of this family with a typical CRD phenotype revealed disease progression during the time period. PMID- 23686678 TI - Preventive detention of sex offenders: the American experience versus international human rights norms. AB - Nearly two decades after the birth of American Sexually Violent Predator (SVP) laws and the tolerant review of their legitimacy by American courts, European courts and international bodies are beginning to develop a jurisprudence of their own with regard to preventive detention. Applying international human rights norms, these bodies have been significantly less tolerant of preventive detention, looking not only at their design but also at their implementation. Simultaneously, American courts are showing the beginnings of a second look at SVP laws, inspired and informed not by promises about the future implementation of newly passed SVP laws, but rather by the sorry record of two decades of implementation. This article examines an American SVP scheme as it has been implemented over 20 years, contrasts the international perspective, and offers some speculation about the path of reform for American SVP schemes. PMID- 23686679 TI - Stapled transanal longitudinal posterior proctectomy (STALPP) in total rectal prolapse: a 7-year experience. AB - BACKGROUND: Surgical management of complete rectal prolapse is challenging. We present our results with the novel technique stapled transanal longitudinal posterior proctectomy (STALPP) in patients with complete rectal prolapse. METHODS: We performed a retrospective study in two hospitals from January 2005 to December 2012. Twenty-one patients with complete rectal prolapse were included. In all patients, STALPP was performed. The study variables were operative time, intraoperative bleeding, number of cartridges used, length of rectum prolapsed through the anus, length of rectal wall resected, length of hospital stay and preoperative and postoperative Wexner continence score and manometric measurement of anal canal resting tone and squeeze pressure. RESULTS: The median length of prolapsed tissue was 13 cm; the mean Wexner score in the preoperative and postoperative period was 15.95 and 4.95, respectively (p = 0.025). The mean resting tone improved from 23.3 to 32.85 mmHg postoperatively (p = 0.03), as did maximal squeeze pressure from 31 to 62.7 mmHg (p = 0.003). Median operative time was 65 min; median intraoperative bleeding was 12 ml; there was no postoperative bleeding, and no reinterventions were required. The median number of cartridges used was 4. The median length of resected wall in the right posterolateral sector was 8 and 6 cm in the left. The median length of hospital stay was 4 days, and the mean follow-up period was 2 years. No mortality was reported. CONCLUSIONS: Stapled transanal longitudinal posterior proctectomy is a safe and feasible surgical alternative for patients with complete rectal prolapse. PMID- 23686680 TI - Laparoscopic right colectomy: a systematic review and meta-analysis of observational studies comparing two types of anastomosis. AB - Because of its technical difficulty, totally laparoscopic right colectomy with intracorporeal anastomosis is performed only by a small number of surgeons and most of them use a laparoscopic-assisted technique with extracorporeal anastomosis. This systematic review aims to evaluate differences in outcomes of patients undergoing right laparoscopic colectomy, either with intracorporeal or extracorporeal anastomosis. Electronic databases were searched for studies published between 1991 and 2012. Randomized controlled trials and case-control studies comparing intracorporeal to extracorporeal anastomosis in laparoscopic right colectomy were included in the systematic review. Meta-analytical models were used to evaluate anastomotic leak rate and short-term overall morbidity. Defined primary outcomes of interest were operating time, conversion rate, return of bowel function, anastomotic leak rate, and length of hospital stay. Randomized controlled trials were not found, confirming the paucity of the literature on this topic. Six case-control studies were identified involving 484 patients undergoing right laparoscopic colectomy, 272 with intracorporeal and 212 with extracorporeal anastomosis. Best outcomes seem to be associated with totally laparoscopic right colectomy with intracorporeal anastomosis, especially in terms of return of bowel function, length of hospital stay, and cosmetic results. However, our meta-analysis did not show a significant difference between the two techniques in terms of anastomotic leak rate (OR 0.98; 95 % CI 0.30-3.15) or for short-term overall morbidity (OR 0.68; 95 % CI 0.41-1.12). Comparative analysis of outcomes is in favor of intracorporeal anastomosis. However, the meta-analysis results do not allow us to draw definitive conclusions. Further prospective randomized trials are necessary to confirm our findings. PMID- 23686681 TI - Optimization of an automatic counting system for the quantification of Staphylococcus epidermidis cells in biofilms. AB - Biofilm formation is recognized as the main virulence factor in a variety of chronic infections. In vitro evaluation of biofilm formation is often achieved by quantification of viable or total cells. However, these methods depend on biofilm disruption, which is often achieved by vortexing or sonication. In this study, we investigated the effects of sonication on the elimination of Staphylococcus epidermidis cell clusters from biofilms grown over time, and quantification was performed by three distinct analytical techniques. Even when a higher number of sonication cycles was used, some stable cell clusters remained in the samples obtained from 48- and 72-h-old biofilms, interfering with the quantification of sessile bacteria by plate counting. On the other hand, the fluorescence microscopy automatic counting system allowed proper quantification of biofilm samples that had undergone any of the described sonication cycles, suggesting that this is a more accurate method for assessing the cell concentration in S. epidermidis biofilms, especially in mature biofilms. PMID- 23686682 TI - The master hearing aid. AB - As early as the 1930s the term Master Hearing Aid (MHA) described a device used in the fitting of hearing aids. In their original form, the MHA was a desktop system that allowed for simulated or actual adjustment of hearing aid components that resulted in a changed hearing aid response. Over the years the MHA saw many embodiments and contributed to a number of rationales for the fitting of hearing aids. During these same years, the MHA was viewed by many as an inappropriate means of demonstrating hearing aids; the audio quality of the desktop systems was often superior to the hearing aids themselves. These opinions and the evolution of the MHA have molded the modern perception of hearing aids and the techniques used in the fitting of hearing aids. This article reports on a history of the MHA and its influence on the fitting of hearing aids. PMID- 23686683 TI - Transcription factor Mohawk and the pathogenesis of human anterior cruciate ligament degradation. AB - OBJECTIVE: To investigate the expression and function of Mohawk (MKX) in human adult anterior cruciate ligament (ACL) tissue and ligament cells from normal and osteoarthritis (OA)-affected knees. METHODS: Knee joints were obtained at autopsy (within 24-48 hours postmortem) from 13 donors with normal knees (mean +/- SD age 36.9 +/- 11.0 years), 16 donors with knee OA (age 79.7 +/- 11.4 years), and 8 aging donors without knee OA (age 76.9 +/- 12.9 years). All cartilage surfaces were graded macroscopically. MKX expression was analyzed by immunohistochemistry and quantitative polymerase chain reaction. ACL-derived cells were used to study regulation of MKX expression by interleukin-1beta (IL-1beta). MKX was knocked down with small interfering RNA (siRNA) to analyze the function of MKX in extracellular matrix (ECM) production and differentiation in ACL-derived cells. RESULTS: The expression of MKX was significantly decreased in ACL-derived cells from OA knees compared with normal knees. Consistent with this finding, immunohistochemistry analysis showed that MKX-positive cells were significantly reduced in ACL tissue from OA donors, in particular in cells located in disorientated fibers. In ACL-derived cells, IL-1beta strongly suppressed MKX expression and reduced expression of the ligament ECM genes COL1A1 and TNXB. In contrast, SOX9, a chondrocyte master transcription factor, was up-regulated by IL 1beta treatment. Importantly, knockdown of MKX expression with siRNA up-regulated SOX9 expression in ACL-derived cells, whereas the expression of COL1A1 and TNXB was reduced. CONCLUSION: Reduced expression of MKX is a feature of degenerated ACL in OA-affected joints, and this may be mediated in part by IL-1beta. MKX appears necessary to maintain the tissue-specific cellular differentiation status and ECM production in adult human tendons and ligaments. PMID- 23686684 TI - Stereoselectivity in pharmacokinetics of rivoglitazone, a novel peroxisome proliferator-activated receptor gamma agonist, in rats and monkeys: model-based pharmacokinetic analysis and in vitro-in vivo extrapolation approach. AB - Stereoselectivity in pharmacokinetics of rivoglitazone, a novel peroxisome proliferator-activated receptor gamma agonist, in rats and monkeys was examined. The pharmacokinetic model involving chiral inversion explained well the plasma profiles of R-isomer and S-isomer after intravenous and oral administration of (R)-rivoglitazone or (S)-rivoglitazone to rats and monkeys. The high stereoselectivity was evaluated in chiral inversion clearance (R/S ratio: 7.92), metabolic clearance (5.78), and volume of distribution (4.04) in rats; however, these were low (1.73, 1.31, and 1.06) in monkeys. The stereoselectivity in chiral inversion was also observed in in vitro incubation studies in plasma, and the R/S ratio of chiral inversion showed high correlation with the R/S ratio of plasma unbound fraction. The metabolic clearance of the primary five metabolic pathways of rivoglitazone was evaluated from an in vitro-in vivo extrapolation approach using rat and monkey liver microsomes. The high stereoselectivity in metabolic clearance in rat was evaluated (R/S ratio: 5.78), which was assumed to be because of the stereoselectivity in plasma unbound fraction, on the contrary, that in monkeys exhibited low stereoselectivity (0.774). Thus, the stereoselectivity in plasma unbound fraction was estimated to be a major determinant of stereoselectivity in pharmacokinetics of rivoglitazone in rats and monkeys. PMID- 23686685 TI - Self-image of male nursing students in Hong Kong: multi-qualitative approaches. AB - The image of male nurses is closely related to the development of a female-driven nursing occupation. As a minority group in the nursing industry, male nursing students may have a negative self-image in their learning and clinical practicum. This may affect their psychological health and mental status. This study explored the positive and negative self-image of male nursing students. Eighteen participants were recruited from a local nurse-training institute. The participants were undergraduate bachelor's and master's students of nursing. The experience and opinions of the participants were collected by multiple methods. The participants' drawings and audio diaries representing their self-image as nurses were collected in advance of a discussion of ideas raised in the focus group interview. The findings were categorized into three themes: (a) self-roles, functions, and identities; (b) awareness of gender differences; and (c) the future of professional development. The findings of this study provide information on the nurse role, identity, gender differences, and professional development of male nursing students, which will drive the direction of the development of a positive image for male nurses in the future. PMID- 23686686 TI - Use of fecal immunochemical tests in the Iowa Research Network. AB - Although the fecal immunochemical test (FIT) has recently emerged as an effective and affordable colorectal cancer screening option, many family physician offices continue to use guaiac-based tests. The purpose of this study was to assess the use of FITs in the Iowa Research Network and to assess physicians' knowledge about FITs. A cover letter and questionnaire were faxed twice to the 291 physician members followed up by a mailing. One hundred and seven (37%) questionnaires were returned. Participants' mean age was 55 years with 78 male responders. Fifty-two (49%) of the physician's offices were in a nonmetro area. Fifty-one (49%) reported using guaiac-based tests and 39 (39%) reported using FITs. Many physicians were unsure of the answers for the FIT knowledge questions. FIT use is not widespread in Iowa Research Network physician offices, and not all physicians are aware of the type of fecal occult blood test being conducted in their office. PMID- 23686687 TI - 6p25 microdeletion: white matter abnormalities in an adult patient. AB - We report on a 41-year-old woman of normal intelligence with a complicated past medical history including unilateral profound hearing loss, unilateral Axenfeld Rieger anomaly, and leukoencephalopathy. She was referred to an adult neurology clinic because of a previous diagnosis of multiple sclerosis, which was non responsive to multiple medications. Due to her complicated past medical history, the medical genetics service was consulted. She was found to have a chromosome 6p25.3-6p25.2 deletion on SNP array. This report highlights chromosome 6p subtelomeric deletions as a possible underlying cause for periventricular white matter abnormalities in an adult. It emphasizes the importance of genetic testing in an adult with leukoencephalopathy and congenital anomalies. PMID- 23686688 TI - Mesostoma ehrenbergii spermatocytes--a unique and advantageous cell for studying meiosis. AB - Mesostoma ehrenbergii have a unique male meiosis: their spermatocytes have three large bivalents that oscillate for 1-2 h before entering into anaphase without having formed a metaphase plate, have a precocious ('pre-anaphase') cleavage furrow, and have four univalents that segregate between spindle poles without physical interaction between them, that is via 'distance segregation'. These unique and unconventional features make Mesostoma spermatocytes an ideal organism for studying the force produced by the spindle to move chromosomes, and to study cleavage furrow control and 'distance segregation'. We review the literature on meiosis in Mesostoma spermatocytes and describe our current research with Mesostoma spermatocytes, rearing the animals in the laboratory using methods that described in our companion article [Hoang et al. (2013); Cell Biol Int]. PMID- 23686689 TI - Laboratory tests during direct oral anticoagulant treatment? No. PMID- 23686690 TI - Laboratory tests during direct oral anticoagulant treatment? Yes. PMID- 23686691 TI - A novel endoscopic technique for long-term patency of cholesterol granulomas of the petrous apex. PMID- 23686692 TI - In vivo evidence of organic cation transporter-mediated tracheal accumulation of the anticholinergic agent ipratropium in mice. AB - Ipratropium bromide (IPR) is an anticholinergic used to treat chronic obstructive pulmonary disease (COPD), and is a substrate of organic cation transporters. The present study aimed to assess the contribution of organic cation transporters to tracheobronchial absorption of IPR in vivo by directly injecting [(3) H]IPR into the tracheal lumen of mice and measuring its accumulation in tracheal tissue. RT PCR and immunohistochemical analysis showed that Octn1, Octn2, and Oct2 were localized at epithelial cells in the respiratory tract. Electron-microscopic immunohistochemistry indicated that Octn1 and Octn2 were localized at the apical portions of ciliated epithelial cells of trachea. In vitro uptake studies in HEK293 cells expressing these transporters demonstrated that IPR is a preferred substrate of Octn2. Inhibition of mouse tracheal accumulation of [(3) H]IPR by carnitine was concentration-dependent, reaching a maximum of 42% at 1 mM, whereas inhibition by 0.1 mM MPP(+) amounted to 62%. Tracheal accumulation of [(3) H]IPR was unchanged when mice were simultaneously injected with Octn1 substrate ergothioneine and organic anion transporter substrate estrone sulfate. These results suggest that Octn2 is involved in membrane permeation of IPR in the respiratory tract in vivo. Targeting organic cation transporters may be an effective strategy for delivery of cationic anti-COPD drugs to patients. PMID- 23686694 TI - Clarifying Bunyamwera virus riddles of the past. AB - Pyrosequencing data and phylogenetic analysis for the full genome of Ilesha virus, Ngari virus and Calovo virus are described clarifying their much discussed relationship within the species Bunyamwera virus of the genus Orthobunyavirus of the Bunyaviridae. PMID- 23686695 TI - Deletion of the D domain of the human parainfluenza virus type 3 (HPIV3) PD protein results in decreased viral RNA synthesis and beta interferon (IFN-beta) expression. AB - The human parainfluenza virus type 3 (HPIV3) phosphoprotein (P) gene is unusual as it contains an editing site where nontemplated ribonucleotide residues can be inserted. This RNA editing can lead to the expression of the viral P, PD, putative W, and theoretical V protein from a single gene. Although the HPIV3 PD protein has been detected, its function and those of the W and V proteins are poorly understood. Therefore, we first used reverse genetics techniques to construct and rescue a recombinant (r)HPIV3 clone with a polyhistidine sequence at the 5' end of the P gene for tagged protein detection. Western blot analysis demonstrated the presence of the P, PD, and W proteins, but no V protein was detected. Then, we functionally studied the D domain of the PD protein by constructing two rHPIV3 knockout clones that are deficient in the expression of the D domain. Results from growth kinetic studies with infected MA-104 and A596 cells showed that viral replication of the two knockout viruses (rHPIV3-DeltaES and rHPIV3-DeltaD) was comparable to that of the parental virus in both cell lines. However, viral mRNA transcription and genomic replication was significantly reduced. Furthermore, cytokine/chemokine profiles of A549 cells infected with either knockout virus were unchanged or showed lower levels compared to those from cells infected with the parental virus. These data suggest that the D domain of the PD protein may play a luxury role in HPIV3 RNA synthesis and may also be involved in disrupting the expression of beta interferon. PMID- 23686696 TI - Acceptorless dehydrogenation of nitrogen heterocycles with a versatile iridium catalyst. PMID- 23686697 TI - Mild cognitive impairment due to Alzheimer disease in the community. AB - OBJECTIVE: The newly proposed National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) due to Alzheimer disease (AD) suggest a combination of clinical features and biomarker measures, but their performance in the community is not known. METHODS: The Mayo Clinic Study of Aging (MCSA) is a population-based longitudinal study of nondemented subjects in Olmsted County, Minnesota. A sample of 154 MCI subjects from the MCSA was compared to a sample of 58 amnestic MCI subjects from the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI-1) to assess the applicability of the criteria in both settings and to assess their outcomes. RESULTS: Fourteen percent of MCSA and 16% of ADNI-1 of subjects were biomarker negative. In addition, 14% of MCSA and 12% of ADNI-1 subjects had evidence for amyloid deposition only, whereas 43% of MCSA and 55% of ADNI-1 subjects had evidence for amyloid deposition plus neurodegeneration (magnetic resonance imaging atrophy, fluorodeoxyglucose positron emission tomography hypometabolism, or both). However, a considerable number of subjects had biomarkers inconsistent with the proposed AD model; for example, 29% of MCSA subjects and 17% of ADNI-1 subjects had evidence for neurodegeneration without amyloid deposition. These subjects may not be on an AD pathway. Neurodegeneration appears to be a key factor in predicting progression relative to amyloid deposition alone. INTERPRETATION: The NIA-AA criteria apply to most MCI subjects in both the community and clinical trials settings; however, a sizeable proportion of subjects had conflicting biomarkers, which may be very important and need to be explored. PMID- 23686699 TI - UGT1A1 6/28 polymorphisms could predict irinotecan-induced severe neutropenia not diarrhea in Chinese colorectal cancer patients. AB - The aim of this study was to investigate the associations between UDP glucuronosyltransferase (UGT) 1A1 polymorphisms and irinotecan-induced toxicities in Chinese advanced colorectal cancer patients. The genotypes of UGT1A1 6 and UGT1A1 28 were analyzed by PCR amplification and Sanger sequencing in 276 advanced colorectal cancer patients receiving irinotecan-containing chemotherapy. The influences of UGT1A1 6/28 polymorphisms on severe diarrhea and neutropenia were analyzed. The overall incidence of UGT1A1 6 and UGT1A1 28 variants was 35.5 % (GA: 28.6 %; AA: 6.9 %) and 21.0 % (TA6/TA7: 19.9 %; TA7/TA7: 1.1 %) in our cohort, respectively. A total of 16 patients (5.8 %, 16/276) had severe diarrhea and 56 patients (20.3 %, 56/276) had severe neutropenia. Neither UGT1A1 6 nor UGT1A1 28 variants were associated with severe diarrhea; however, either UGT1A1 6 (P = 0.001) or UGT1A1 28 (P = 0.029) variants were significantly associated with severe neutropenia. No differences were found between severe toxicities and clinical response in this study. Compared to western countries, Chinese patients had a distinct frequency of UGT1A1 6 or UGT1A1 28 genotypes. Both UGT1A1 6 and UGT1A1 28 variants were closely associated with irinotecan-induced severe neutropenia, but not diarrhea. PMID- 23686700 TI - High expression of transient potential receptor C6 correlated with poor prognosis in patients with esophageal squamous cell carcinoma. AB - TRPC6 plays a crucial role in the tumor progression of various cancers. The relation between the expression of TRPC6 and clinical prognosis has not been studied yet. Our study was to elucidate the role of TRPC6 in predicting outcomes of patients with esophageal squamous cell carcinoma (ESCC). Fresh frozen samples were collected immediately from 172 patients with ESCC after surgical resection from 2003 to 2008 at Sun Yat-sen University Cancer Center, including 45 pairs of tumor tissues and nontumor tissues. TRPC6 expression was measured by quantitative real-time PCR and Western blotting analyses. TRPC6 mRNA and protein were up regulated in ESCC tissues when compared with the paired nontumor tissues. High expression of TRPC6 mRNA was associated with the higher pT status (P = 0.016) and pathological staging (P = 0.040). The 5-year disease-specific survival in the high expression of TRPC6 mRNA group (>188.98, n = 81) is poorer than that in low level expression group (<=188.98, n = 91) (42.1 vs. 62.7 %, P = 0.004). Stratified analysis according to the pathological stage revealed its discernibility on DSS was only pronounced in patients with pStage III (P = 0.015). Cox multivariate analysis revealed that pN category (P < 0.001; Relative risk, 2.897, 95 % CI 1.830-4.585) and the expression of TRPC6 mRNA (P = 0.006; Relative risk, 1.863, 95 % CI 1.196-2.902) were independent prognostic factors. TRPC6 mRNA overexpression correlated with poor prognosis in patients with ESCC and might serve as a novel prognostic biomarker for resected ESCC patients in advanced stage. PMID- 23686702 TI - Failure of replantation of middle forearm amputation exposed to hot environment. PMID- 23686698 TI - Clinical and histological determinants of nonalcoholic steatohepatitis and advanced fibrosis in elderly patients. AB - The characteristics of nonalcoholic fatty liver disease (NAFLD) in elderly patients are unknown. Therefore, we aimed to examine the differences between elderly and nonelderly patients with NAFLD and to identify determinants of nonalcoholic steatohepatitis (NASH) and advanced fibrosis (bridging fibrosis or cirrhosis) in elderly patients. This is a cross-sectional analysis of adult participants who were prospectively enrolled in the NASH Clinical Research Network studies. Participants were included based on availability of the centrally reviewed liver histology data within 1 year of enrollment, resulting in 61 elderly (age >=65 years) and 735 nonelderly (18-64 years) participants. The main outcomes were the presence of NASH and advanced fibrosis. Compared to nonelderly patients with NAFLD, elderly patients had a higher prevalence of NASH (56% versus 72%, P = 0.02), and advanced fibrosis (25% versus 44%, P = 0.002). Compared to nonelderly patients with NASH, elderly patients with NASH had higher rates of advanced fibrosis (35% versus 52%, P = 0.03), as well as other features of severe liver disease including the presence of ballooning degeneration, acidophil bodies, megamitochondria, and Mallory-Denk bodies (P <= 0.05 for each). In multiple logistic regression analyses, independent determinants of NASH in elderly patients included higher aspartate aminotransferase (AST) (odds ratio [OR] = 1.12, P = 0.007) and lower platelets (OR = 0.98, P = 0.02); and independent determinants of advanced fibrosis included higher AST (OR = 1.08, P = 0.007), lower alanine aminotransferase value (OR = 0.91, P = 0.002), and an increased odds of having low high-density lipoprotein (OR = 8.35, P = 0.02). CONCLUSION: Elderly patients are more likely to have NASH and advanced fibrosis than nonelderly patients with NAFLD. Liver biopsy may be considered in elderly patients and treatment should be initiated in those with NASH and advanced fibrosis. PMID- 23686701 TI - Synergistic relationship between dipeptidyl peptidase IV and neutral endopeptidase expression and the combined prognostic significance in osteosarcoma patients. AB - Neutral endopeptidase (NEP/CD10) and dipeptidyl peptidase IV (DPP IV/CD26) are both ubiquitous glycopeptidases which play important roles in tumor pathogenesis and development. The aim of this study was to investigate the expression patterns and the prognostic significance of CD10 and CD26 in osteosarcoma patients. CD10 and CD26 expression in 116 pairs of primary osteosarcoma and corresponding noncancerous bone tissue samples from the same specimens were detected by immunohistochemistry. The Spearman's correlation was calculated between the expression levels of CD10 and CD26 in osteosarcoma tissues. The associations of CD10 and CD26 expression with the clinicopathologic features and with the prognosis of osteosarcoma were subsequently assessed. Both CD10 expression and CD26 expression in osteosarcoma tissues were significantly higher than those in corresponding noncancerous bone tissue samples (both P < 0.001). Overexpression of CD10 and CD26 were respectively observed in 68.10 % (79/116) and 70.69 % (82/116) of osteosarcoma tissues. A significant correlation was found between CD10 expression and CD26 expression in osteosarcoma tissues (r = 0.83, P < 0.001). In addition, combined overexpression of CD10 and CD26 was observed in 52.59 % (61/116) of osteosarcoma tissues. CD10-high/CD26-high expression was significantly correlated with advanced clinical stage (P = 0.001), positive metastatic status (P = 0.001), shorter overall (P < 0.001) and disease-free (P < 0.001) survival in patients with osteosarcomas. Furthermore, multivariate survival analysis showed that clinical stage, metastatic status, CD10 expression, CD26 expression and combined expression of CD10/CD26 were all independent prognostic factors for predicting both overall and disease-free survival of osteosarcoma patients. Interestingly, combined expression of CD10/CD26 had a better prognostic value than other features. This retrospective study offer the convincing evidence for the first time that the overexpression of CD10 or CD26 may be an important feature of human osteosarcomas, and the combined expression of CD10/CD26 may be an efficient prognostic indicator for this disease. PMID- 23686703 TI - Riding the wave of ependymal cilia: genetic susceptibility to hydrocephalus in primary ciliary dyskinesia. AB - Congenital hydrocephalus is a relatively common and debilitating birth defect with several known physiological causes. Dysfunction of motile cilia on the ependymal cells that line the ventricular surface of the brain can result in hydrocephalus by hindering the proper flow of cerebrospinal fluid. As a result, hydrocephalus can be associated with primary ciliary dyskinesia, a rare pediatric syndrome resulting from defects in ciliary and flagellar motility. Although the prevalence of hydrocephalus in primary ciliary dyskinesia patients is low, it is a common hallmark of the disease in mouse models, suggesting that distinct genetic mechanisms underlie the differences in the development and physiology of human and mouse brains. Mouse models of primary ciliary dyskinesia reveal strain specific differences in the appearance and severity of hydrocephalus, indicating the presence of genetic modifiers segregating in inbred strains. These models may provide valuable insight into the genetic mechanisms that regulate susceptibility to hydrocephalus under the conditions of ependymal ciliary dysfunction. PMID- 23686704 TI - Analysis of a polygalacturonase gene of Ustilago maydis and characterization of the encoded enzyme. AB - Ustilago maydis is a pathogenic fungus that produces the corn smut. It is a biotrophic parasite that depends on living plant tissues for its proliferation and development. Polygalacturonases are secreted by pathogens to solubilize the plant cell-wall and are required for pathogen virulence. In this paper, we report the isolation of a U. maydis polygalacturonase gene (Pgu1) and the functional and structural characterization of the encoded enzyme. The U. maydis Pgu1 gene is expressed when the fungus is grown in liquid culture media containing different carbon sources. In plant tissue, the expression increased as a function of incubation time. Pgu1 gene expression was detected during plant infection around 10 days post-infection with U. maydis FB-D12 strain in combination with teliospore formation. Synthesis and secretion of active recombinant PGU1 were achieved using Pichia pastoris, the purified enzyme had a optimum temperature of 34 degrees C, optimum pH of 4.5, a Km of 57.84 g/L for polygalacturonic acid, and a Vmax of 28.9 ug/min mg. Structural models of PGU1 based on homologous enzymes yielded a typical right-handed beta-helix fold of pectinolytic enzymes classified in the glycosyl hydrolases family 28, and the U. maydis PGU1 is related with endo rather than exo polygalacturonases. PMID- 23686705 TI - RNA interference mediated pten knock-down inhibit the formation of polycystic ovary. AB - Pten (phosphatase and tensin homolog deleted on chromosome 10), a kind of tumor suppressor gene, plays important roles in female reproductive system. But its expression and roles in the formation of polycystic ovaries are yet to be known. In this study, we constructed a rat model of PCOS using norethindrone and HCG injections and found the expressions of pten mRNA and PTEN protein increased significantly in the polycystic ovary tissue by immunohistochemistry, RT-PCR, and western blot. Furthermore, the results showed that in vivo ovaries could be effectively transfected by lentiviral vectors through the ovarian microinjection method and indicated that pten shRNA may inhibit the formation of polycystic ovaries by pten down-regulation. Our study provides new information regarding the role of PTEN in female reproductive disorders, such as polycystic ovary syndrome. PMID- 23686706 TI - Supplementation with vitamin D does not increase serum testosterone levels in healthy males. AB - Cross-sectional studies indicate a positive relation between serum 25 hydroxyvitamin D [25(OH)D] and testosterone. It is not known if this relation is causal, which in theory could be in both directions. A cross-sectional population based study was designed with pooled data from 3 vitamin D randomized clinical trials (RCTs) performed in Tromso with weight reduction, insulin sensitivity, and depression scores as endpoints, and one testosterone RCT in subjects with low serum testosterone (<11.0 nmol/l) and with body composition as endpoint. Serum 25(OH)D and androgens were measured in 893 males in the cross-sectional part, at baseline and after 6-12 months of supplementation with vitamin D 20 000 IU-40 000 IU per week vs. placebo in the vitamin D RCTs (n=282), and at baseline and after one year treatment with testosterone undecanoate 1 000 mg or placebo injections (at baseline and after 6, 16, 28, and 40 weeks) in the testosterone RCT (n=37). In the cross-sectional study, serum 25(OH)D was found to be a significant and positive predictor of serum testosterone. In the vitamin D RCTs, no significant effect on serum total or free testosterone levels was seen, and in the testosterone RCT no significant effect on serum 25(OH)D was seen. This was unchanged in sub-analyses in subjects with low serum 25(OH)D (or testosterone) levels. In conclusion, in subjects without significant vitamin D deficiency, there is no increase in serum testosterone after high dose vitamin D supplementation. Similarly, in subjects with moderately low serum testosterone levels, substitution with testosterone does not increase serum 25(OH)D. PMID- 23686707 TI - Targeted inhibition of Hsp90 by ganetespib is effective across a broad spectrum of breast cancer subtypes. AB - Heat shock protein 90 (Hsp90) is a molecular chaperone essential for the stability and function of multiple cellular client proteins, a number of which have been implicated in the pathogenesis of breast cancer. Here we undertook a comprehensive evaluation of the activity of ganetespib, a selective Hsp90 inhibitor, in this malignancy. With low nanomolar potency, ganetespib reduced cell viability in a panel of hormone receptor-positive, HER2-overexpressing, triple-negative and inflammatory breast cancer cell lines in vitro. Ganetespib treatment induced a rapid and sustained destabilization of multiple client proteins and oncogenic signaling pathways and even brief exposure was sufficient to induce and maintain suppression of HER2 levels in cells driven by this receptor. Indeed, HER2-overexpressing BT-474 cells were comparatively more sensitive to ganetespib than the dual HER2/EGFR tyrosine kinase inhibitor lapatinib in three-dimensional culture. Ganetespib exposure caused pleiotropic effects in the inflammatory breast cancer line SUM149, including receptor tyrosine kinases, MAPK, AKT and mTOR signaling, transcription factors and proteins involved in cell cycle, stress and apoptotic regulation, as well as providing combinatorial benefit with lapatinib in these cells. This multimodal activity translated to potent antitumor efficacy in vivo, suppressing tumor growth in MCF-7 and MDA-MB-231 xenografts and inducing tumor regression in the BT 474 model. Thus, ganetespib potently inhibits Hsp90 leading to the degradation of multiple clinically-validated oncogenic client proteins in breast cancer cells, encompassing the broad spectrum of molecularly-defined subtypes. This preclinical activity profile suggests that ganetespib may offer considerable promise as a new therapeutic candidate for patients with advanced breast cancers. PMID- 23686708 TI - RASEF is a novel diagnostic biomarker and a therapeutic target for lung cancer. AB - Genome-wide gene expression profiling revealed that the Ras and EF-hand domain containing (RASEF) transcript was significantly transactivated in the majority of lung cancers. Using lung cancer cells, transient expression of RASEF promoted cell growth, whereas RASEF knockdown not only reduced its expression but resulted in growth suppression of the cancer cells. Immunohistochemical staining using tumor tissue microarrays consisting of 341 archived non-small cell lung cancers (NSCLC) revealed the association of strong RASEF positivity with poor prognosis (P = 0.0034 by multivariate analysis). Mechanistically, RASEF interacted with extracellular signal-regulated kinase (ERK) 1/2 and enhanced ERK1/2 signaling. Importantly, inhibiting the interaction between RASEF and ERK1/2 using a cell permeable peptide that corresponded to the ERK1/2-interacting site of RASEF, suppressed growth of lung cancer cells. This study demonstrates that elevated RASEF promoted cell growth via enhanced ERK signaling and is associated with poor prognosis of NSCLC. IMPLICATIONS: RASEF may play an important role in lung carcinogenesis and could serve as a vaiable prognostic biomarker and target for the development of new molecular therapies. PMID- 23686709 TI - Objectively measured physical activity among US cancer survivors: considerations by weight status. AB - PURPOSE: We have a limited understanding of the objectively determined physical activity levels of cancer survivors at the population level. Further, we have even less of an understanding of this behavior by weight status (i.e., normal weight, overweight, and obese). Therefore, the purpose of this study was to describe accelerometer-assessed physical activity levels among US cancer survivors and to do so across weight status. METHODS: Data from the 2003-2006 NHANES was used. One hundred twenty-six adult cancer survivors wore an accelerometer for >=4 days, with weight status determined from measured body mass index. RESULTS: Approximately 13 % of cancer survivors were sufficiently active (i.e., met current physical activity guidelines). Results were not significant for light-intensity physical activity; however, results showed that obese cancer survivors engaged in 47 % less MVPA than normal weight cancer survivors (rate ratio = 0.53; 95 % CI, 0.29-0.93). CONCLUSION: Most adult cancer survivors are insufficiently active and obese cancer survivors engage in less MVPA than their counterparts. IMPLICATIONS FOR CANCER SURVIVORS: Health care professionals are encouraged to increase cancer survivors' awareness of the minimum levels of MVPA needed for optimal health, particularly among obese cancer survivors. Additionally, cancer survivors should also be informed of the positive health outcomes associated with light-intensity physical activity. PMID- 23686710 TI - Exercise training normalizes the blunted central component of the baroreflex in rats with heart failure: role of the PVN. AB - Exercise training (ExT) normalizes the increased sympathetic outflow in chronic heart failure (HF). The underlying mechanisms are not clearly understood. We hypothesized that ExT normalized the blunted central component of the baroreflex control of renal sympathetic nerve activity (RSNA) in HF. Four groups of rats [sham operated (sham)-sedentary (Sed), sham-ExT, HF-Sed, and HF-ExT] were used. HF was induced by left coronary artery ligation, and ExT consisted of 3 wk of treadmill running. In anesthetized rats, the decrease in RSNA in response to aortic depressor nerve stimulation (5-40 Hz) in the HF-Sed group was significantly lower than that in the sham-Sed group (-37 +/- 7% vs. -63 +/- 8% at 40 Hz, P < 0.05). In the HF-ExT group, responses in RSNA, mean arterial pressure (MAP), and heart rate (HR) were not significantly different from those in the sham-Sed or sham-ExT groups. ExT normalized blunted RSNA, MAP, and HR responses to bicuculline microinjections into the paraventricular nucleus (PVN) in rats with HF. Activation of the PVN by blockade of GABA receptors with bicuculline in normal control rats blunted the centrally component of the baroreflex arc. GABAA alpha1 and -beta1 receptor protein expression were significantly lower (by 48% and 30%) in the HF-Sed group, but ExT normalized this difference between the HF and sham groups. These data suggest that one mechanism by which ExT alleviates elevated sympathetic outflow in HF may be through normalization of central integrative mechanisms, perhaps via improving the inhibitory GABAergic mechanism within the PVN, on the baroreflex arc. PMID- 23686711 TI - Mechanisms of cardiovascular actions of urocortins in the hypothalamic arcuate nucleus of the rat. AB - The presence of urocortins (UCNs) and corticotropin-releasing factor (CRF) receptors has been reported in the hypothalamic arcuate nucleus (ARCN). We have previously reported that UCNs are involved in central cardiovascular regulation. Based on this information, we hypothesized that the ARCN may be one of the sites where UCNs exert their central cardiovascular actions. Experiments were done in artificially ventilated, adult male Wistar rats anesthetized with urethane. Unilateral microinjections (30 nl) of UCN1 (0.12-2 mM) elicited decreases in mean arterial pressure (MAP) and heart rate (HR). Maximum cardiovascular responses were elicited by a 1 mM concentration of UCN1. Microinjections of UCN2 and UCN3 (1 mM each) into the ARCN elicited similar decreases in MAP and HR. UCN1 was used as a prototype for the other experiments described below. HR responses elicited by UCN1 were significantly attenuated by bilateral vagotomy. Prior microinjections of NBI-27914 (CRF-1 receptor antagonist) and astressin (CRF-1 receptor and CRF-2 receptor antagonist) (1 mM each) into the ARCN significantly attenuated the cardiovascular responses elicited by UCN1 microinjections at the same site. Microinjections of UCN1 into the ARCN decreased efferent renal sympathetic nerve activity. It was concluded that microinjections of UCN1, UCN2, and UCN3 into the ARCN elicited decreases in MAP and HR. Decreases in MAP, HR, and renal sympathetic nerve activity elicited by UCN1 microinjections into the ARCN were mediated via CRF receptors. Bradycardic responses to UCN1 were mediated via the activation of vagus nerves, and decreases in MAP may be mediated via decreases in sympathetic nerve activity. PMID- 23686712 TI - Decreased time constant of the pulmonary circulation in chronic thromboembolic pulmonary hypertension. AB - This study analyzed the relationship between pulmonary vascular resistance (PVR) and pulmonary arterial compliance (Ca) in patients with idiopathic pulmonary arterial hypertension (IPAH) and proximal chronic thromboembolic pulmonary hypertension (CTEPH). It has recently been shown that the time constant of the pulmonary circulation (RC time constant), or PVR * Ca, remains unaltered in various forms and severities of pulmonary hypertension, with the exception of left heart failure. We reasoned that increased wave reflection in proximal CTEPH would be another cause of the decreased RC time constant. We conducted a retrospective analysis of invasive pulmonary hemodynamic measurements in IPAH (n = 78), proximal CTEPH (n = 91) before (pre) and after (post) pulmonary endarterectomy (PEA), and distal CTEPH (n = 53). Proximal CTEPH was defined by a postoperative mean pulmonary artery pressure (PAP) of <=25 mmHg. Outcome measures were the RC time constant, PVR, Ca, and relationship between systolic and mean PAPs. The RC time constant for pre-PEA CTEPH was 0.49 +/- 0.11 s compared with post-PEA-CTEPH (0.37 +/- 0.11 s, P < 0.0001), IPAH (0.63 +/- 0.14 s, P < 0.001), and distal CTEPH (0.55 +/- 0.12 s, P < 0.05). A shorter RC time constant was associated with a disproportionate decrease in systolic PAP with respect to mean PAP. We concluded that the pulmonary RC time constant is decreased in proximal CTEPH compared with IPAH, pre- and post-PEA, which may be explained by increased wave reflection but also, importantly, by persistent structural changes after the removal of proximal obstructions. A reduced RC time constant in CTEPH is in accord with a wider pulse pressure and hence greater right ventricular work for a given mean PAP. PMID- 23686714 TI - Civil, sensible, and constructive peer review in APS journals. PMID- 23686713 TI - Oxidative stress augments pulmonary hypertension in chronically hypoxic mice overexpressing the oxidized LDL receptor. AB - Chronic hypoxia is one of the main causes of pulmonary hypertension (PH) associated with ROS production. Lectin-like oxidized low-density lipoprotein receptor (LOX)-1 is known to be an endothelial receptor of oxidized low-density lipoprotein, which is assumed to play a role in the initiation of ROS generation. We investigated the role of LOX-1 and ROS generation in PH and vascular remodeling in LOX-1 transgenic (TG) mice. We maintained 8- to 10-wk-old male LOX 1 TG mice and wild-type (WT) mice in normoxia (room air) or hypoxia (10% O2 chambers) for 3 wk. Right ventricular (RV) systolic pressure (RVSP) was comparable between the two groups under normoxic conditions; however, chronic hypoxia significantly increased RVSP and RV hypertrophy in LOX-1 TG mice compared with WT mice. Medial wall thickness of the pulmonary arteries was significantly greater in LOX-1 TG mice than in WT mice. Furthermore, hypoxia enhanced ROS production and nitrotyrosine expression in LOX-1 TG mice, supporting the observed pathological changes. Administration of the NADPH oxidase inhibitor apocynin caused a significant reduction in PH and vascular remodeling in LOX-1 TG mice. Our results suggest that LOX-1-ROS generation induces the development and progression of PH. PMID- 23686715 TI - Quantification of the glucosamine content in the filamentous fungus Monascus ruber cultured on solid surfaces. AB - We evaluated whether the glucosamine content in the filamentous fungus Monascus ruber NBRC 32318, cultured on a solid surface (agar) containing different carbon and nitrogen sources, could be used as a measure of biomass. The relationship between the amounts of glucosamine and biomass was independent of the cultivation period, but was dependent on the carbon source (D-glucose, D-fructose, maltose, sucrose, or rice starch) and the nitrogen source (ammonium chloride, sodium nitrate, monosodium glutamate, or yeast extract) in the agar; it was also dependent on the culture method (solid-surface culture or submerged culture). We concluded that the amount of glucosamine extracted from M. ruber is a useful index for the fungal biomass when the relationship between M. ruber biomass and glucosamine content has previously been calibrated for the carbon and nitrogen sources used. Examination of microphotographs of M. ruber hyphae in conjunction with quantification of the glucosamine and biomass contents indicated that the variation in the glucosamine content per unit biomass affects the hyphal morphology of the fungus, and especially the hyphal diameter. PMID- 23686716 TI - Diagnosis of laryngotracheal stenosis from routine pulmonary physiology using the expiratory disproportion index. AB - OBJECTIVE/HYPOTHESIS: The study's objective was to determine the utility of expiratory disproportion index (EDI), the ratio of forced expiratory volume in 1 second (FEV1) to peak expiratory flow rate (PEFR) (EDI = FEV1[L] /PEFR[L/s] * 100), in differentiating between laryngotracheal stenosis (LTS) and other respiratory diagnoses. LTS is an uncommon complication of mechanical ventilation or vasculitis or a manifestation of airway compression or malignancy. It frequently masquerades as asthma and evades timely diagnosis, causing prolonged morbidity and airway-related mortality. STUDY DESIGN: Observational study. METHODS: We compared spirometry results of 9,357 healthy subjects and nonstenosis pulmonary patients with 217 cases of LTS. Bootstrap analysis, receiver-operating characteristic (ROC) statistics, and Pearson correlation were used to assess the diagnostic utility of the EDI and its correlation with stenosis severity. RESULTS: Mean EDI values were 36 +/- 7 in nonstenosis cases, 76 +/- 17 in benign stenoses, and 69 +/- 23 in tracheal cancer (P < .0001). A significant correlation existed between anatomic stenosis severity and EDI (P < .0001; R = 0.61). Area under the ROC curve was 0.98, and at a threshold of >50, EDI had a sensitivity of 95.9% and a specificity of 94.2% in differentiating between stenosis and nonstenosis cases. CONCLUSIONS: EDI can reliably diagnose LTS using routine lung function data. Its simplicity and clinical utility, first recognized by Duncan Empey, are underpinned by a unique physiology whereby PEFR, being determined by total tracheobronchial tree resistance, falls disproportionately compared with FEV1 , which is determined within small intrathoracic airways. EDI provides valuable information about the presence and extent of LTS particularly in nonspecialist clinical settings and its routine inclusion within standard lung function reports could prevent the prolonged morbidity and mortality that currently result from missed and delayed diagnoses. PMID- 23686717 TI - Overexpression of CD147 in ovarian cancer is initiated by the hypoxic microenvironment. AB - Ovarian cancer is a lethal malignant tumour characterised by activated invasion, distant metastasis, anti-cancer drug resistance, angiogenesis and metabolism. CD147, an extracellular matrix metalloproteinase inducer, is overexpressed in most ovarian tumours and plays an important role in the progression of ovarian cancer and other malignant tumours. However, the factor(s) initiating this overexpression is unknown. Because of rapid reproduction and their hypoxic microenvironment, malignant tumours use glycolysis for energy, and lactic acid produced is harmful to the cells. For survival, excessive lactate needs to be transported by monocarboxylate transporters (MCTs). Functioning of MCT1 and MCT4 require the ancillary of CD147. The gene for CD147 possesses two hypoxia inducible factors binding sites in its 3'-flank. It is logical to postulate that the hypoxic microenvironment is a major initiator of the overexpression of CD147, thus conferring on ovarian cancers their malignant properties. A model that can represent spontaneous ovarian cancer is necessary to verify this hypothesis. PMID- 23686718 TI - Mosaic isochromosome 15q and maternal uniparental isodisomy for chromosome 15 in a patient with morbid obesity and variant PWS-like phenotype. AB - Angelman and Prader-Willi syndromes are reciprocal imprinting disorders caused by loss of maternally or paternally expressed genes, respectively, within 15q11.2 q13. Angelman syndrome (AS; OMIM 105830) is a neurodevelopmental disorder and is due to the loss of maternally expressed UBE3A gene. Prader-Willi syndrome (PWS; OMIM 176270) is a clinically distinct disorder caused by the loss of paternally expressed genes in the human chromosome region 15q11.2-q13. Recently published data strongly suggest a role for the paternally expressed small nucleolar RNA (snoRNA) cluster, SNORD116, in PWS etiology. Uniparental disomy (UPD) 15 is one of the important causes of PWS and AS. Interestingly, balanced and unbalanced chromosomal aberrations in the form of Robertsonian translocation, isochromosomes, supernumerary marker chromosomes and copy number variations have been strongly linked with the occurrence of UPD. Here we report on a very unique case with a mosaic isochromosome for the entire long arm of 15, that is, i(15)(q10), resulting in mosaic uniparental isodisomy for 15q and with no copy number alterations. This is the first report of UPD15 constituted by a mosaic, but copy number neutral chromosomal rearrangement in a patient with a variant PWS like phenotype. PMID- 23686719 TI - Crystallographic analysis and structure-guided engineering of NADPH-dependent Ralstonia sp. alcohol dehydrogenase toward NADH cosubstrate specificity. AB - The NADP+-dependent alcohol dehydrogenase from Ralstonia sp. (RasADH) belongs to the protein superfamily of short-chain dehydrogenases/reductases (SDRs). As an enzyme that accepts different types of substrates--including bulky-bulky as well as small-bulky secondary alcohols or ketones--with high stereoselectivity, it offers potential as a biocatalyst for industrial biotechnology. To understand substrate and cosubstrate specificities of RasADH we determined the crystal structure of the apo-enzyme as well as its NADP+-bound state with resolutions down to 2.8 A. RasADH displays a homotetrameric quaternary structure that can be described as a dimer of homodimers while in each subunit a seven-stranded parallel beta-sheet, flanked by three alpha-helices on each side, forms a Rossmann fold-type dinucleotide binding domain. Docking of the well-known substrate (S)-1-phenylethanol clearly revealed the structural determinants of stereospecificity. To favor practical RasADH application in the context of established cofactor recycling systems, for example, those involving an NADH dependent amino acid dehydrogenase, we attempted to rationally change its cosubstrate specificity from NADP+ to NAD+ utilizing the structural information that NADP+ specificity is largely governed by the residues Asn15, Gly37, Arg38, and Arg39. Furthermore, an extensive sequence alignment with homologous dehydrogenases that have different cosubstrate specificities revealed a modified general SDR motif ASNG (instead of NNAG) at positions 86-89 of RasADH. Consequently, we constructed mutant enzymes with one (G37D), four (N15G/G37D/R38V/R39S), and six (N15G/G37D/R38V/R39S/A86N/S88A) amino acid exchanges. RasADH (N15G/G37D/R38V/R39S) was better able to accept NAD+ while showing much reduced catalytic efficiency with NADP+, leading to a change in NADH/NADPH specificity by a factor of ~3.6 million. PMID- 23686720 TI - Human pathogenic fungus Trichophyton schoenleinii activates the NLRP3 inflammasome. AB - The fungus Trichophyton schoenleinii (T. schoenleinii) is the causative agent of Trichophytosis and Tinea favosa of the scalp in certain regions of Eurasia and Africa. Human innate immune system plays an important role in combating with various pathogens including fungi. The inflammasome is one of the most critical arms of host innate immunity, which is a protein complex controlling maturation of IL-1beta. To clarify whether T. schoenleinii is able to activate the inflammasome, we analyzed human monocytic cell line THP-1 for IL-1beta production upon infection with T. schoenleinii strain isolated from Tinea favosa patients, and rapid IL-1beta secretion from THP-1 cells was observed. Moreover, applying competitive inhibitors and gene specific silencing with shRNA, we found that T. schoenleinii induced IL-1beta secretion, ASC pyroptosome formation as well as caspase-1 activation were all dependent on NLRP3. Cathepsin B activity, ROS production and K+ efflux were required for the inflammasome activation by T. schoenleinii. Our data thus reveal that the NLRP3 inflammasome plays an important role in host defense against T. schoenleinii, and suggest that manipulating NLRP3 signaling can be a novel approach for control of diseases caused by T. schoenleinii infection. PMID- 23686722 TI - Functional and structural brain changes in anti-N-methyl-D-aspartate receptor encephalitis. AB - OBJECTIVE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune encephalitis with a characteristic neuropsychiatric syndrome and severe and prolonged clinical courses. In contrast, standard clinical magnetic resonance imaging (MRI) remains normal in the majority of patients. Here, we investigated structural and functional brain changes in a cohort of patients with anti-NMDAR encephalitis. METHODS: Twenty-four patients with established diagnosis of anti-NMDAR encephalitis and age- and gender-matched controls underwent neuropsychological testing and multimodal MRI, including T1w/T2w structural imaging, analysis of resting state functional connectivity, analysis of white matter using diffusion tensor imaging, and analysis of gray matter using voxel based morphometry. RESULTS: Patients showed significantly reduced functional connectivity of the left and right hippocampus with the anterior default mode network. Connectivity of both hippocampi predicted memory performance in patients. Diffusion tensor imaging revealed extensive white matter changes, which were most prominent in the cingulum and which correlated with disease severity. In contrast, no differences in T1w/T2w structural imaging and gray matter morphology were observed between patients and controls. INTERPRETATION: Anti NMDAR encephalitis is associated with characteristic alterations of functional connectivity and widespread changes of white matter integrity despite normal findings in routine clinical MRI. These results may help to explain the clinicoradiological paradox in anti-NMDAR encephalitis and advance the pathophysiological understanding of the disease. Correlation of imaging abnormalities with disease symptoms and severity suggests that these changes play an important role in the symptomatology of anti-NMDAR encephalitis. PMID- 23686721 TI - The role of gut microbiota in the gut-brain axis: current challenges and perspectives. AB - Brain and the gastrointestinal (GI) tract are intimately connected to form a bidirectional neurohumoral communication system. The communication between gut and brain, knows as the gut-brain axis, is so well established that the functional status of gut is always related to the condition of brain. The researches on the gut-brain axis were traditionally focused on the psychological status affecting the function of the GI tract. However, recent evidences showed that gut microbiota communicates with the brain via the gut-brain axis to modulate brain development and behavioral phenotypes. These recent findings on the new role of gut microbiota in the gut-brain axis implicate that gut microbiota could associate with brain functions as well as neurological diseases via the gut-brain axis. To elucidate the role of gut microbiota in the gut-brain axis, precise identification of the composition of microbes constituting gut microbiota is an essential step. However, identification of microbes constituting gut microbiota has been the main technological challenge currently due to massive amount of intestinal microbes and the difficulties in culture of gut microbes. Current methods for identification of microbes constituting gut microbiota are dependent on omics analysis methods by using advanced high tech equipment. Here, we review the association of gut microbiota with the gut-brain axis, including the pros and cons of the current high throughput methods for identification of microbes constituting gut microbiota to elucidate the role of gut microbiota in the gut-brain axis. PMID- 23686723 TI - Platinum(IV) prodrugs with haloacetato ligands in the axial positions can undergo hydrolysis under biologically relevant conditions. AB - Losing ligands rapidly: Pt(IV) complexes with haloacetato ligands can hydrolyze rapidly under biological conditions (pH 7 and 37 degrees C, see scheme) and the rate increases with increasing pH value. Possible mechanisms for this hydrolysis are examined using H2(18)O and ESI-MS analysis. PMID- 23686724 TI - Current therapy and future directions in biliary tract malignancies. AB - OPINION STATEMENT: Cancers of the biliary tree represent a rare group of diseases with a devastating impact on patients. Gallbladder cancer often is associated with cholelithiasis. Cholangiocarcinoma may arise in the setting of biliary inflammation, such as primary sclerosing cholangitis, but most commonly occurs in patients without a particular risk factor. Surgical removal of biliary cancer is essential for cure, but it is associated with a very high rate of recurrence and for many patients is not possible at the time of diagnosis. Although risk factors differ for each anatomic site, systemic treatment is generally similar. Various adjunctive therapies, such as radiation and embolization, have been investigated for biliary tract cancers with modest success and efforts are ongoing to understand how to optimize these tools. Retrospective series and pooled analysis suggest a benefit for adjuvant treatment following resection, but prospective data are limited. Ongoing and planned phase 3 trials should help to clarify the role of adjuvant chemotherapy and radiation. For advanced disease, chemotherapy improves quality of life and survival, and gemcitabine with cisplatin represents the standard of care. However, all patients ultimately progress on this therapy, so clinical trials of new and better agents are essential to expand the existing treatment options for patients. PMID- 23686725 TI - Adjuvant and neoadjuvant therapy for gastric cancer. AB - OPINION STATEMENT: To improve outcome of resectable gastric cancer, several treatment strategies have been evaluated. These include adjuvant chemotherapy, adjuvant chemoradiotherapy, and perioperative chemotherapy. The US Intergroup 0116 trial reported the benefit of postoperative chemoradiotherapy using 5 FU/leucovorin in a U.S. population. In this study, only 10 % of patients received D2 resection. For Korean patients after D2 resection, the ARTIST trial failed to show any benefit from adding radiotherapy to adjuvant chemotherapy in terms of 3 year disease-free survival. The MAGIC trial compared perioperative chemotherapy with surgery alone and reported a prolonged 5-year overall survival in the perioperative chemotherapy arm. In resectable gastric cancer, the benefit of adjuvant chemotherapy compared with surgery alone has been clearly demonstrated. After D2 dissection, S-1 adjuvant chemotherapy improved the overall survival (ACTS-GC trial) and capecitabine/oxaliplatin combination chemotherapy improved 3 year disease-free survival (CLASSIC trial). To date, for resectable gastric cancer, the use of chemotherapy in addition to surgery is beneficial for the reduction of recurrence and to improve overall survival. The optimal sequence of chemotherapy and surgery, as well as optimal chemotherapeutic agents, should be further studied. In D2-resected gastric cancer, the addition of radiotherapy to chemotherapy does not appear to provide any additional benefit.]. PMID- 23686726 TI - Anti-hypoxia effect of adenovirus-mediated expression of heat shock protein 70 (HSP70) on primary cultured neurons. AB - Heat shock protein 70 (HSP70) has attracted great attention recently in hypoxia injury because of its close link to the recovery after hypoxic-ischemic damage in organs. However, the cellular mechanism underlying its protective roles remains unclear. In this study, we developed a recombinant adenovirus containing HSP70 GFP (vAd-HSP70-GFP) and studied the effect of virus-mediated expression of exogenous HSP70 gene on neurons in response to hypoxia-reoxygenation injury. Virus-mediated expression of HSP70 was detected as early as 24 hr and lasted until 10 days after infection. Neurons with 48 hr vAd-HSP70-GFP infection were exposed to 0, 0.5, 1, 2, 3, or 4 hr hypoxia followed by 1 hr reoxygenation. The mRNA and protein levels of HSP70 in neurons exposed to different lengths of hypoxia were compared by using RT-PCR and Western blotting (WB). The 1-hr hypoxia exposure showed the most significant increases in the HSP70 mRNA and protein level compared with other exposure durations. MTT assay showed that HSP70 overexpression significantly increased the neuronal viability, accompanied by decreased lactate dehydrogenase (LDH) activity in the culture medium after hypoxia-reoxygenation. Neurons with vAd-HSP70-GFP exhibited increased levels of mitochondrial cytochrome C (Cyt-C) and decreased levels of cytoplasmic Cyt-C compared with vAd-GFP-infected cells. These results suggest a neuroprotective role of exogenous HSP70 against hypoxia-reoxygenation injury, possibly via preventing initiation of mitochondrial apoptosis. PMID- 23686727 TI - Differential antibacterial properties of the MurA inhibitors terreic acid and fosfomycin. AB - Terreic acid is a metabolite with antibiotic properties produced by the fungus Aspergillus terreus, but its cellular target remains unknown. We recently reported that terreic acid inactivates the bacterial cell wall biosynthetic enzyme MurA in vitro by covalent reaction with residue Cys115 in a similar manner as the MurA-specific antibiotic fosfomycin. To address if terreic acid also targets MurA in vivo, we conducted antibacterial studies using selected E. coli strains in parallel with fosfomycin. While overexpression of MurA conferred resistance to fosfomycin, it did not protect cells treated with terreic acid. Furthermore, flow cytometry revealed that the antibiotic action of terreic acid appears to be primarily bacteriostatic, as opposed to the bactericidal action observed for fosfomycin. Combined, the data suggest that MurA is not the molecular target of terreic acid and that the antibiotic activity of terreic acid proceeds through a different mechanism of action. The methodology applied here provides a reliable and convenient tool to rapidly assess the potential of newly discovered in vitro inhibitors to target residue Cys115 of MurA in the cell. PMID- 23686728 TI - Lifespan extension and the doctrine of double effect. AB - Recent developments in biogerontology--the study of the biology of ageing- suggest that it may eventually be possible to intervene in the human ageing process. This, in turn, offers the prospect of significantly postponing the onset of age-related diseases. The biogerontological project, however, has met with strong resistance, especially by deontologists. They consider the act of intervening in the ageing process impermissible on the grounds that it would (most probably) bring about an extended maximum lifespan--a state of affairs that they deem intrinsically bad. In a bid to convince their deontological opponents of the permissibility of this act, proponents of biogerontology invoke an argument which is grounded in the doctrine of double effect. Surprisingly, their argument, which we refer to as the 'double effect argument', has gone unnoticed. This article exposes and critically evaluates this 'double effect argument'. To this end, we first review a series of excerpts from the ethical debate on biogerontology in order to substantiate the presence of double effect reasoning. Next, we attempt to determine the role that the 'double effect argument' is meant to fulfil within this debate. Finally, we assess whether the act of intervening in ageing actually can be justified using double effect reasoning. PMID- 23686729 TI - The perils of protection: vulnerability and women in clinical research. AB - Subpart B of 45 Code of Federal Regulations Part 46 (CFR) identifies the criteria according to which research involving pregnant women, human fetuses, and neonates can be conducted ethically in the United States. As such, pregnant women and fetuses fall into a category requiring "additional protections," often referred to as "vulnerable populations." The CFR does not define vulnerability, but merely gives examples of vulnerable groups by pointing to different categories of potential research subjects needing additional protections. In this paper, I assess critically the role of this categorization of pregnant women involved in research as "vulnerable," both as separate entities and in combination with the fetuses they carry. In particular, I do three things: (1) demonstrate that pregnant women qua pregnancy are either not "vulnerable" according to any meaningful definition of that term or that such vulnerability is irrelevant to her status as a research participant; (2) argue that while a fetus may be vulnerable in terms of dependency, this categorization does not equate to the vulnerability of the pregnant woman; and (3) suggest that any vulnerability that appends to women is precisely the result of federal regulations and dubious public perceptions about pregnant women. I conclude by demonstrating how this erroneous characterization of pregnant women as "vulnerable" and its associated protections have not only impeded vital research for pregnant women and their fetuses, but have also negatively affected the inclusion of all women in clinical research. PMID- 23686731 TI - Systemic antibiotics after incision and drainage of simple abscesses: a meta analysis. AB - BACKGROUND: Over the last decade, there has been a significant increase in the number of cutaneous abscesses. While there is general agreement that abscesses should be treated with incision and drainage, it is unclear whether systemic antibiotics should be routinely prescribed. OBJECTIVE: To evaluate whether systemic antibiotics, when compared with a placebo, improve cure rates in patients with simple abscesses after incision and drainage. METHODS DESIGN: Systematic review and meta-analysis using RevMan5. PATIENTS AND SETTINGS: Children and adults with simple abscesses treated in outpatient clinics or emergency departments. DATA SOURCES: Cochrane Central, Medline, Embase and bibliographies. OUTCOME MEASURES: Percentage of patients with complete resolution of abscess without the need for recurrent incision and drainage, additional antibiotics, or hospital admission within 7-10 days of treatment. RESULTS: We included four trials, consisting of 589 patients in total (428 adults and 161 children). Patients were randomised to one of three antibiotics (cephridine (27), cephalexin (82), or trimethoprim sulfamethoxazole (161)) or to placebo (285), with 34 lost to follow-up or having incomplete data. When given in addition to incision and drainage, systemic antibiotics did not significantly improve the percentage of patients with complete resolution of their abscesses 7-10 days after treatment (88.1% vs 86.0%; OR 1.17 (95% CI 0.70 to 1.95)). CONCLUSIONS: When given in addition to incision and drainage, systemic antibiotics do not significantly improve the percentage of patients with complete resolution of their abscesses. PMID- 23686730 TI - A double-blind, randomised, placebo-controlled trial of oral midazolam plus oral ketamine for sedation of children during laceration repair. AB - OBJECTIVES: To compare the efficacy of oral midazolam alone with a combination of oral midazolam and ketamine in children requiring laceration repair. DESIGN: A randomised, double-blind, placebo-controlled study. SETTING: Paediatric emergency department. PARTICIPANTS: Children 1-10 years of age with lacerations requiring sedation. INTERVENTIONS: Using a computer-generated sequence, children were randomly assigned in blocks of four to one of two groups: oral midazolam (0.5 mg/kg) plus oral placebo and oral midazolam (0.5 mg/kg) plus oral ketamine (5 mg/kg). The allocation sequence was kept by the pharmacy staff, and the investigators were blinded to randomisation until statistical analysis of the study was completed. MAIN OUTCOME MEASURES: Visual Analogue Scale (VAS) assessment by a parent and Sedation Score assessment by an investigator. RESULTS: 60 children were recruited; 29 were assigned for treatment with midazolam and 31 for the combination of midazolam and ketamine. There were no differences in basic demographics and wound characteristics between the groups. VAS assessment by a parent was 4.5+/-3.3 mm in the midazolam+ketamine group versus 4.4+/-2.7 mm in the midazolam alone group (mean difference 0.1, CI -1.9 to 1.71). Sedation Score during procedure was lower in the midazolam+ketamine group (mean difference 1.14, 95% CI 0.67 to 1.6). Intravenous sedation was required in two (6%) of the children in the midazolam+ketamine group, and in eight (27%) in the midazolam alone group. p=0.039. No clinically significant adverse effects were documented in either group. CONCLUSIONS: No difference was found in pain assessment during local anaesthetic injection between the group treated with midazolam and ketamine, and the group treated with midazolam alone. The combination of oral midazolam and ketamine led to deeper sedation than midazolam alone, with less children requiring intravenous sedation. CLINICAL TRIAL REGISTRATION: The trial was registered in www.clinicaltrials.gov as NCT01470157. PMID- 23686732 TI - Parental anxiety and affecting factors in acute paediatric blunt head injury. AB - OBJECTIVE: This study is designed to investigate the factors affecting parental anxiety regarding their children with head injury in the emergency department (ED). MATERIALS AND METHODS: This prospective observational study enrolled all consecutive paediatric patients admitted to the university-based ED with the presenting chief complaint of paediatric blunt head injury (PBHI). The parents were asked to respond to the 10-item questionnaire during both presentation and discharge. Anxiety and persuasion scores of the parents were calculated and magnitudes of the decreases in anxiety and persuasion scores were analysed with respect to sociodemographic and clinical variables. RESULTS: The study sample included 341 patients admitted to the ED. The anxiety and persuasion scores of mothers and fathers were not significantly different from each other on presentation while the extent of decrease in anxiety scores of mothers were significantly smaller than that of the fathers (p=0.003). The parents' education levels had significant impact on anxiety and persuasion scores recorded on presentation. The anxiety and persuasion scores were inversely related to education levels of the parents on presentation (p=0.002 and p=0.000, respectively). In addition, lower education levels were found to be associated with a greater decrease in anxiety and persuasion scores. Neurosurgical consultation also affected the magnitude of the decrease in anxiety and persuasion scores of the parents. The changes in the scores were affected negatively by the parents' age. CONCLUSIONS: Radiological investigations had no significant impact on the decrease in anxiety and persuasion scores of the parents by themselves, while neurosurgical consultation had significant impact on them. Emergency physicians should tailor their strategy to institute effective communication with the parents of children to cut down unnecessary investigations in PBHI. PMID- 23686734 TI - De novo trisomy 12p in twin girls with different levels of mosaicism. AB - We report on a pair of twins with trisomy 12p diagnosed postnatally. The girls were referred for dysmorphism and global developmental delay and have been followed from 10 months of age. They have different levels of mosaicism for both buccal cells and lymphocytes. Although their phenotypic features were similar, there were different degrees of severity which correlate with the different levels of mosaicism. PMID- 23686733 TI - The activity of atorvastatin and rosiglitazone on CD38, ZAP70 and apoptosis in lymphocytes of B-cell chronic lymphocytic leukemia in vitro. AB - There are a number of studies about the effects of statins and thiazolidinediones on lymphocytes. However, there is no study about possible effects of atorvastatin and rosiglitazone on lymphocytes in patients with chronic lymphocytic leukemia (CLL). We aimed to investigate the effects of atorvastatin and rosiglitazone on CD38, ZAP-70, Annexin V and bcl-2 in lymphocytes of CLL in vitro. Seven (4 males and 3 females) patients with CLL with average age of 56 +/- 8 years were enrolled to the study. The mean values of laboratory tests were as follows: hemoglobin: 12 +/- 1.8 g/dl; hematocrit: %35 +/- 6; platelet count: 156,000 +/- 68,000/mm(3); leukocyte count: 50,500 +/- 38,700/mm(3); and lymphocyte count: 45,700 +/- 38,100/mm(3). The study was performed in three cell cultures groups. Mononuclear cells of blood samples from peripheral veins were separated by Ficoll method. On culture plate with 24 wells, it was suspended with 2 ml RPMI 1640. Then, the plates were incubated in %5 CO2 at 37 degrees C for 24 h. 5 MUM atorvastatin calcium was given to first group, 2 MUM rosiglitazone maleate was given to second group, and the third group was included in the study as control group. After 24 h, the expressions of CD5, CD38, ZAP-70 and Annexin V by using flow cytometry with EPICS XL-MCL and the levels of bcl-2 by using ELISA method were re evaluated. Two-paired Student's t test was used for comparison of the results, and p < 0.05 was accepted as a significance level. While atorvastatin and rosiglitazone did not affect the expression of CD38 and the level of bcl-2, these drugs significantly increased the level of Annexin V when compared with control group (p < 0.001). Both drugs significantly decreased the expressions of CD5 (p = 0.03) and ZAP-70 (p < 0.05) compared with control group. Atorvastatin and rosiglitazone increased apoptosis in lymphocytes of CLL in vitro. Moreover, these drugs decreased the expressions of CD5 and ZAP-70. These drugs must be studied in more detail in the pathogenesis and treatment for CLL. PMID- 23686736 TI - Cytosolic Ca(2+) as a multifunctional modulator is required for spermiogenesis in Ascaris suum. AB - The dynamic polar polymers actin filaments and microtubules are usually employed to provide the structural basis for establishing cell polarity in most eukaryotic cells. Radially round and immotile spermatids from nematodes contain almost no actin or tubulin, but still have the ability to break symmetry to extend a pseudopod and initiate the acquisition of motility powered by the dynamics of cytoskeleton composed of major sperm protein (MSP) during spermiogenesis (sperm activation). However, the signal transduction mechanism of nematode sperm activation and motility acquisition remains poorly understood. Here we show that Ca(2+) oscillations induced by the Ca(2+) release from intracellular Ca(2+) store through inositol (1,4,5)-trisphosphate receptor are required for Ascaris suum sperm activation. The chelation of cytosolic Ca(2+) suppresses the generation of a functional pseudopod, and this suppression can be relieved by introducing exogenous Ca(2+) into sperm cells. Ca(2+) promotes MSP-based sperm motility by increasing mitochondrial membrane potential and thus the energy supply required for MSP cytoskeleton assembly. On the other hand, Ca(2+) promotes MSP disassembly by activating Ca(2+)/calmodulin-dependent serine/threonine protein phosphatase calcineurin. In addition, Ca(2+)/camodulin activity is required for the fusion of sperm-specifi c membranous organelle with the plasma membrane, a regulated exocytosis required for sperm motility. Thus, Ca(2+) plays multifunctional roles during sperm activation in Ascaris suum. PMID- 23686737 TI - Ging-Hsi Wong and Chinese physiopsychology. PMID- 23686735 TI - Induced pluripotency and direct reprogramming: a new window for treatment of neurodegenerative diseases. AB - Human embryonic stem cells (hESCs) are pluripotent cells that have the ability of unlimited self-renewal and can be differentiated into different cell lineages, including neural stem (NS) cells. Diverse regulatory signaling pathways of neural stem cells differentiation have been discovered, and this will be of great benefit to uncover the mechanisms of neuronal differentiation in vivo and in vitro. However, the limitations of hESCs resource along with the religious and ethical concerns impede the progress of ESCs application. Therefore, the induced pluripotent stem cells (iPSCs) via somatic cell reprogramming have opened up another new territory for regenerative medicine. iPSCs now can be derived from a number of lineages of cells, and are able to differentiate into certain cell types, including neurons. Patient-specifi c iPSCs are being used in human neurodegenerative disease modeling and drug screening. Furthermore, with the development of somatic direct reprogramming or lineage reprogramming technique, a more effective approach for regenerative medicine could become a complement for iPSCs. PMID- 23686738 TI - Randomized trial comparing monthly ibandronate and weekly alendronate for osteoporosis in patients with primary biliary cirrhosis. AB - Osteoporosis resulting in bone fractures is a complication in patients with primary biliary cirrhosis (PBC). Once-weekly alendronate improves bone mass and is well tolerated in these patients, but there is a concern because of poor compliance. Therefore, the efficacy, adherence, and safety of monthly ibandronate (150 mg) with weekly alendronate (70 mg) were compared in a randomized, 2-year study in 42 postmenopausal women with PBC and osteoporosis. Bone mineral density (BMD) of the lumbar spine and proximal femur (by DXA), liver function, and bone markers were measured at entry and every 6 months over 2 years. Adherence to therapy was assessed by the Morisky-Green score. At enrollment, the two groups were similar with respect to age, BMD, severity of cholestasis, previous fractures, and bone markers. Thirty-three patients, 14 in the ibandronate group and 19 in the alendronate group, completed the trial. At 2 years both treatments resulted in a significant increase in BMD at the lumbar spine (from 0.875 +/- 0.025 to 0.913 +/- 0.026 g/cm(2), P < 0.001 with alendronate, and from 0.898 +/- 0.024 to 0.949 +/- 0.027 g/cm(2), P < 0.001 with ibandronate). The mean percentage change was 4.5% and 5.7%, respectively (P = not significant). BMD increased at the total hip by 2.0% and 1.2%, respectively. Changes in bone markers were similar in both groups and one patient with alendronate developed a new vertebral fracture. Adherence to therapy was higher with ibandronate (P = 0.009). Neither treatment impaired liver function or cholestasis. CONCLUSION: Both regimens, weekly alendronate and monthly ibandronate, improve bone mass and are comparable in safety for osteoporosis therapy in patients with PBC, although adherence is higher with the monthly regimen. Further larger studies are needed to assess fracture prevention. PMID- 23686739 TI - Could contaminant induced mutations lead to a genetic diversity overestimation? AB - Contaminant driven genetic erosion reported through the inspection of selectable traits can be underestimated using neutral markers. This divergence was previously reported in the aquatic system of an abandoned pyrite mine. The most sensitive genotypes of the microcrustacean cladoceran Daphnia longispina were found to be lacking in the impacted reservoir near the entrance of the metal rich acid mine drainage (AMD). Since that divergence could be, at least partially, accounted for by mutagenicity and genotoxicity of the AMD, the present study aimed at providing such a characterization. The Allium cepa chromosomal aberration assay, using root meristematic cells, was carried out, by exposing seeds to 100, 10, 1, and 0.1 % of the local AMD. Chromosomal aberrations, cell division phases and cell death were quantified after the AMD exposure and after 24 and 48 h recovery periods. The AMD revealed to be mutagenic and genotoxic, even after diluting it to 1 and 0.1 %. Dilutions within this range were previously found to be below the lethality threshold and to elicit sublethal effects on reproduction of locally collected D. longispina clonal lineages Significant mutagenic effects (micronuclei and chromosomal breaks) were also found at 0.1 % AMD, supporting that exposure may induce permanent genetic alterations. Recovery tests showed that AMD genotoxic effects persisted after the exposure. PMID- 23686740 TI - The role of plasma Epstein-Barr virus DNA in the management of recurrent nasopharyngeal carcinoma. AB - OBJECTIVES/HYPOTHESIS: To study the role of plasma Epstein-Barr virus (EBV) DNA in patients with recurrent nasopharyngeal carcinoma (NPC) after previous chemoradiation. STUDY DESIGN: Prospective. METHODS: Sixty patients with recurrent NPC were recruited, and their plasma EBV DNA was checked preoperatively, 1 week postoperatively, and 6 months thereafter. In a pilot group of 30 patients, further testing was performed at 60 minutes after tumor resection. The plasma EBV DNA level was correlated with tumor T classification, resection margin status, and subsequent relapse. RESULTS: The mean preoperative plasma EBV DNA reflected the tumor load (T1: 48 copies/mL, T2: 316 copies/mL, T3: 890 copies/mL, P = .03). It was significantly higher in patients with positive margins at the time of surgery (722 vs. 126 copies/mL, P = .02) and in those with subsequent systemic metastasis (668 vs. 92 copies/mL, P = .01). However, it failed to predict local recurrence after surgery. Postoperative plasma EBV DNA was undetectable in all patients with positive resection margins. Serial measurements were able to identify 87.5% of local recurrences and 100% of distance metastases. CONCLUSIONS: In patients with recurrent NPC requiring salvage nasopharyngectomy, preoperative plasma EBV DNA identifies patients at high-risk of subsequent distant failure after surgery. Serial measurements of plasma EBV DNA after surgery, especially for those with high preoperative levels, is crucial to allow early detection of local of distant failure. PMID- 23686741 TI - Digital microfabrication of user-defined 3D microstructures in cell-laden hydrogels. AB - Complex 3D interfacial arrangements of cells are found in several in vivo biosystems such as blood vasculature, renal glomeruli, and intestinal villi. Current tissue engineering techniques fail to develop suitable 3D microenvironments to evaluate the concurrent effects of complex topography and cell encapsulation. There is a need to develop new fabrication approaches that control cell density and distribution within complex 3D features. In this work, we present a dynamic projection printing process that allows rapid construction of complex 3D structures using custom-defined computer-aided-design (CAD) files. Gelatin-methacrylate (GelMA) constructs featuring user-defined spiral, pyramid, flower, and dome micro-geometries were fabricated with and without encapsulated cells. Encapsulated cells demonstrate good cell viability across all geometries both on the scaffold surface and internal to the structures. Cells respond to geometric cues individually as well as collectively throughout the larger-scale patterns. Time-lapse observations also reveal the dynamic nature of mechanical interactions between cells and micro-geometry. When compared to conventional cell seeding, cell encapsulation within complex 3D patterned scaffolds provides long term control over proliferation, cell morphology, and geometric guidance. Overall, this biofabrication technique offers a flexible platform to evaluate cell interactions with complex 3D micro-features, with the ability to scale-up towards high-throughput screening platforms. PMID- 23686742 TI - Evaluation of monooleine aqueous dispersions as tools for topical administration of curcumin: characterization, in vitro and ex-vivo studies. AB - Curcumin (CUR) is a well-known natural compound showing antioxidant, anti inflammatory, and antitumor abilities but characterized by poor bioavailability and chemical instability, which drastically reduce its application in the treatment of chronic diseases such as osteoarthritis. The aim of the present study is the design and evaluation of monooleine aqueous dispersion (MAD) as novel carriers for the topical administration of CUR. CUR-loaded MAD was formulated using two different emulsifier systems, namely poloxamer 407 (MAD-A) and sodium cholate-sodium caseinate (MAD-B). These vehicles were characterized, and their influence on in vitro percutaneous absorption of CUR was also evaluated. Furthermore, an oxygen radical absorbance capacity assay was used to determine their antioxidant activity, and a Western blot analysis was performed to evaluate the inhibitory effect of the formulations on inducible nitric oxide synthase and cyclooxygenase 2 expressions. From the obtained results, CUR encapsulation efficiency was higher than 98% for MAD-A and 82% for MAD-B. Shelf life studies showed that MAD-A maintains CUR stability better than MAD-B, and both vehicles demonstrated, in vitro, control of drug diffusion through the skin. Finally, MAD-A and MAD-B were able to extend the antioxidant/anti-inflammatory effects of CUR, also confirming the protective effect toward CUR chemical stability. PMID- 23686743 TI - Corilagin inhibits hepatocellular carcinoma cell proliferation by inducing G2/M phase arrest. AB - Hepatocellular carcinoma (HCC) is one of most common types of malignant tumours. Therefore, it is very important to identify powerful drugs and their antitumour mechanisms. Corilagin has a significant antitumour potential and lower toxicity in normal cells in vitro. The IC50 values of corilagin for normal Chang-liver cells and the HCC cell lines Bel7402 and SMMC7721 were 131.4, 24.5 and 23.4 uM, respectively, in the methyl thiazolyl tetrazolium (MTT) assay. MHCC97-H xenografts in Balb/c mice intraperitoneally injected with 30 mg/kg corilagin for 5 weeks showed a 47.3% inhibition of tumour growth in vivo. Furthermore, data from flow cytometry and Western blot analyses of cell cycle and cell cycle related proteins suggest that corilagin arrests SMMC7721 cells at the G2/M phase by downregulating p-Akt and cyclin B1/cdc2 and upregulating p-p53 and p21(Cip1) . In conclusion, corilagin is a potential antitumour drug that is effective in retarding the growth of HCC, which is correlated with the activation of p-p53 p21(Cip1) -cdc2/cyclin B1. PMID- 23686744 TI - Identification of aldolase and ferredoxin reductase within the dbt operon of Burkholderia fungorum DBT1. AB - Burkholderia fungorum DBT1, first isolated from settling particulate matter of an oil refinery wastewater, is a bacterial strain which has been shown capable of utilizing several polycyclic aromatic hydrocarbons (PAHs) including dibenzothiophene (DBT). In particular, this microbe is able to efficiently degrade DBT through the Kodama pathway. Previous investigations have lead to the identification of six genes, on a total of eight, required for DBT degradation. In the present study, a combined experimental/computational approach was adopted to identify and in silico characterize the two missing genes, namely a ferredoxin reductase and a hydratase-aldolase. Thus, the finding of all enzymatic components of the Kodama pathway in B. fungorum DBT1 makes this bacterial strain amenable for possible exploitation in soil bioremediation protocols. PMID- 23686745 TI - Phenotypes of hypofrontality in older female fragile X premutation carriers. AB - OBJECTIVE: To investigate the nature of cognitive impairments and underlying brain mechanisms in older female fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome (FXTAS). METHODS: Extensive neuropsychological testing and cognitive event-related brain potentials (ERPs; particularly, the auditory P300) were examined in 84 female participants: 33 fragile X premutation carriers with FXTAS (mean age = 62.8 years), 25 premutation carriers without FXTAS (mean age = 55.4 years), and 26 normal healthy controls (mean age = 59.3 years). RESULTS: Both premutation groups exhibited executive dysfunction on the Behavioral Dyscontrol Scale, with subtle impairments in inhibition and performance monitoring in female carriers without FXTAS, and more substantial deficits in FXTAS women. However, the female carrier group without FXTAS showed more pronounced deficiencies in working memory. Abnormal ERPs were recorded over the frontal lobes, where FXTAS patients showed both P300 amplitude reduction and latency prolongation, whereas only decreased frontal P300 amplitudes were found in carriers without FXTAS. These frontal P300 measures correlated with executive function and information processing speed. INTERPRETATION: The neuropsychological testing and ERP results of the present study provide support for the hypothesis that executive dysfunction is the primary cognitive impairment among older female premutation carriers both with and without FXTAS, although these deficits are relatively mild compared to those in FXTAS males. These findings are consistent with a synergistic effect of the premutation and aging on cognitive impairment among older female fragile X premutation carriers, even in those without FXTAS symptoms. PMID- 23686746 TI - Adjuvant gemcitabine therapy improves survival in a locally induced, R0 resectable model of metastatic intrahepatic cholangiocarcinoma. AB - Complete surgical tumor resection (R0) for treatment of intrahepatic cholangiocarcinoma (ICC) is potentially curative, but the prognosis remains dismal due to frequent tumor recurrence and metastasis after surgery. Adjuvant therapies may improve the outcome, but clinical studies for an adjuvant approach are difficult and time-consuming for rare tumor entities. Therefore, animal models reflecting the clinical situation are urgently needed to investigate novel adjuvant therapies. To establish a mouse model of resectable cholangiocarcinoma including the most frequent genetic alterations of human ICC, we electroporated Sleeping Beauty-based oncogenic transposon plasmids into the left liver lobe of mice. KRas-activation in combination with p53-knockout in hepatocytes resulted in formation of a single ICC nodule within 3-5 weeks. Lineage tracing analyses confirmed the development of ICC by transdifferentiation of hepatocytes. Histologic examination demonstrated that no extrahepatic metastases were detectable during primary tumor progression. However, formation of tumor satellites close to the primary tumor and vascular invasion were observed, indicating early invasion into normal tissue adjacent to the tumor. After R0 resection of the primary tumor, we were able to prolong median survival, thereby observing tumor stage-dependent local recurrence, peritoneal carcinomatosis, and lung metastasis. Adjuvant gemcitabine chemotherapy after R0-resection significantly improved median survival of treated animals. CONCLUSION: We have developed a murine model of single, R0-resectable ICC with favorable characteristics for the study of recurrence patterns and mechanisms of metastasis after resection. This model holds great promise for preclinical evaluation of novel multimodal or adjuvant therapies to prevent recurrence and metastasis after R0-resection. PMID- 23686749 TI - Magnetic resonance imaging of solid urethral and peri-urethral lesions. AB - Solid urethral and peri-urethral lesions are rare and encompass benign and malignant aetiologies. A diagnosis without imaging is often challenging secondary to non-specific clinical symptoms and overlapping findings at the time of physical examination. Magnetic resonance (MR) imaging may be helpful in confirming a diagnosis while providing anatomical detail and delineating disease extent. This article reviews the normal MR anatomy of the male and female urethra, the MR appearance of solid primary and secondary urethral lesions, and the MR appearance of solid urethral lesion mimics. Teaching points * MRI is an important imaging technique in the evaluation of the spectrum of solid urethral lesions.* With excellent soft tissue resolution, MR is accurate in staging primary urethral carcinoma.* Disruption of the zonal anatomy of the female urethral wall indicates peri-urethral extension.* Be aware of benign urethral lesions, particularly those that may mimic solid urethral masses. PMID- 23686748 TI - Radiographic features of osteogenesis imperfecta. AB - BACKGROUND: Osteogenesis imperfecta (OI), commonly called "brittle bone disease", is a genetic disorder characterised by increased bone fragility and decreased bone density due to quantitative and/or qualitative abnormalities of type I collagen. Different types of OI exist, from mild to severe; they may lead to death, multiple bone fractures, skeletal deformity and short stature. METHODS: Severe cases are usually diagnosed before birth and may incite the parents to choose therapeutic abortion, whereas milder cases are much more difficult to diagnose and may be sometimes confused with non-accidental injury (NAI) ("child abuse") in young children. Whatever the degree of severity, conventional radiography still remains the mainstay in diagnosing OI. RESULTS: The prognosis of this disorder has changed in the last few years thanks to biphosphonate therapy. CONCLUSION: The aim of this pictorial review is to illustrate the radiographic manifestations of OI, including in children receiving biphosphonates, and to outline specific patterns that help differentiate OI from NAI when necessary. KEY POINTS: * The main radiographic features of OI are osteopenia, bone fractures and bone deformities. * Some radiographic features depend on the type of OI or may be encountered with biphosphonates. PMID- 23686747 TI - Microglia express distinct M1 and M2 phenotypic markers in the postnatal and adult central nervous system in male and female mice. AB - Although microglial activation is associated with all CNS disorders, many of which are sexually dimorphic or age-dependent, little is known about whether microglial basal gene expression is altered with age in the healthy CNS or whether it is sex dependent. Analysis of microglia from the brains of 3-day (P3)- to 12-month-old male and female C57Bl/6 mice revealed distinct gene expression profiles during postnatal development that differ significantly from those in adulthood. Microglia at P3 are characterized by relatively high iNOS, TNFalpha and arginase-I mRNA levels, whereas P21 microglia have increased expression of CD11b, TLR4, and FcRgammaI. Adult microglia (2-4 months) are characterized by low proinflammatory cytokine expression, which increases by 12 months of age. Age dependent differences in gene expression suggest that microglia likely undergo phenotypic changes during ontogenesis, although in the healthy brain they did not express exclusively either M1 or M2 phenotypic markers at any time. Interestingly, microglia were sexually dimorphic only at P3, when females had higher expression of inflammatory cytokines than males, although there were no sex differences in estrogen receptor expression at this or any other time evaluated here. Compared with microglia in vivo, primary microglia prepared from P3 mice had considerably altered gene expression, with higher levels of TNFalpha, CD11b, arginase-I, and VEGF, suggesting that culturing may significantly alter microglial properties. In conclusion, age- and sex-specific variances in basal gene expression may allow differential microglial responses to the same stimulus at different ages, perhaps contributing to altered CNS vulnerabilities and/or disease courses. PMID- 23686750 TI - Model studies of the kinetics of ester hydrolysis under stretching force. PMID- 23686751 TI - Compensation phenomena found in Acidithiobacillus ferrooxidans after starvation stress. AB - Acidithiobacillus ferrooxidans showed the compensate growth and oxidation after re-feeding with sufficient ferrous materials after starvation. Compensatory phenomena were first detected in chemoautotrophic organisms. Starvation stress of Acidithiobacillus ferrooxidans was achieved via culturing in low concentrations of iron. During compensation, growth and ferrous oxidation took place faster than in controls. In addition, some genes related to ferrous oxidation (such as rus) and carbon assimilation (cbbR, csoS3) were expressed in different patterns in the low energy environments. Their expression patterns can account for this increased growth and oxidation. Other groups of genes (cspAB, feoAB, fur) were suppressed in response to starvation stress. The presence of pyrite and joint cold stress can render compensation nearly undetectable. This may be why the compensation phenomena observed under these conditions was not the same as that observed under single starvation stress conditions. Gene expression reflected a possible mechanism of tolerance to starvation in Acidithiobacillus ferrooxidans, which would allow the organism to adapt and survive in ferrous-limited environments. PMID- 23686752 TI - Patients who require non-cardiac surgery in acute coronary syndrome. AB - The coexistence of an acute coronary syndrome (ACS) and non-cardiac surgery (NCS) in an individual patient can be summarized in two challenging clinical scenarios for the treating physician: 1) Post-operative patients who develop ACS and 2) Patients with ACS who subsequently require NCS. Both settings are characterized by a struggle on the part of treating physicians attempting to optimize antithrombotic therapies for ACS while minimizing post-surgical bleeding risk. In this review we address specific clinical issues related to patients with coexistent NCS and ACS, discussing possible management strategies balancing ischemic and bleeding risk in these complex patient scenarios. PMID- 23686755 TI - Does weight loss affect the apnea/hypopnea index? PMID- 23686753 TI - Three-dimensional echocardiography of the mitral valve: lessons learned. AB - Three-dimensional echocardiography has markedly improved our understanding of normal and pathologic mitral valve (MV) mechanics. Qualitative and quantitative analysis of three-dimensional (3D) data on the mitral valve could have a clinical impact on diagnosis, patient referral, surgical strategies, annuloplasty ring design and evaluation of the immediate and long-term surgical outcome. This review covers the contribution of 3D echocardiography in the diagnosis of MV disease, its role in selecting and monitoring surgical procedures, and in the assessment of surgical outcomes. Moreover, advantages of this technique versus the standard 2D modality, as well as future applications of advanced analysis techniques, will be reviewed. PMID- 23686756 TI - Heritability of eleven metabolic phenotypes in Danish and Chinese twins: a cross population comparison. AB - OBJECTIVES: A twin-based comparative study on the genetic influences in metabolic endophenotypes in two populations of substantial ethnic, environmental, and cultural differences was performed. DESIGN AND METHODS: Data on 11 metabolic phenotypes including anthropometric measures, blood glucose, and lipids levels as well as blood pressure were available from 756 pairs of Danish twins (309 monozygotic and 447 dizygotic twin pairs) with a mean age of 38 years (range: 18 67) and from 325 pairs of Chinese twins (183 monozygotic and 142 dizygotic twin pairs) with a mean age of 40.5 years (range: 18-69). Twin modeling was performed on full and nested models with the best fitting models selected. RESULTS: Heritability estimates were compared between Danish and Chinese samples to identify differential genetic influences on each of the phenotypes. Except for hip circumference, all other body measures exhibited similar heritability patterns in the two samples with body weight showing only a slight difference. Higher genetic influences were estimated for fasting blood glucose level in Chinese twins, whereas the Danish twins showed more genetic regulation over most lipids phenotypes. Systolic blood pressure was more genetically controlled in Danish than in Chinese twins. CONCLUSIONS: Metabolic endophenotypes show disparity in their genetic determinants in populations under distinct environmental conditions. PMID- 23686758 TI - Aquatic plant debris improve phosphorus sorption into sediment under anoxic condition. AB - The effects of plant debris on phosphorus sorption by anoxic sediment were investigated. Addition of plant debris significantly enhanced the decrease of soluble relative phosphorus (SRP) in overlying water at both 10 and 30 degrees C during the 30-day investigation. Both cellulose and glucose, two typical plant components, also clearly enhanced the SRP decrease in anoxic overlying water. The measurement of phosphorus (P) fractions in sediment revealed that the levels of unstable P forms were decreased by plant debris addition, whereas the opposites were true for stable P forms. However, under sterilized condition, plant debris/glucose addition has no effect on the SRP decrease in overlying water. Overall, our results suggested that plant debris improve P sorption into sediment under anoxic condition through a microorganism-mediated mechanism. PMID- 23686757 TI - Modulation of cell viability, oxidative stress, calcium homeostasis, and voltage- and ligand-gated ion channels as common mechanisms of action of (mixtures of) non dioxin-like polychlorinated biphenyls and polybrominated diphenyl ethers. AB - Non-dioxin-like polychlorinated biphenyls (NDL-PCBs) and polybrominated diphenyl ethers (PBDEs) are environmental pollutants that exert neurodevelopmental and neurobehavioral effects in vivo in humans and animals. Acute in vitro neurotoxic effects include changes in cell viability, oxidative stress, and basal intracellular calcium levels. Though these acute cellular effects could partly explain the observed in vivo effects, other mechanisms, such as effects on calcium influx and neurotransmitter receptor function, likely contribute to the disturbance in neurotransmission. This concise review combines in vitro data on cell viability, oxidative stress and basal calcium levels with recent data that clearly demonstrate that (hydroxylated) PCBs and (hydroxylated) PBDEs can exert acute effects on voltage-gated Ca(2+) channels as well as on excitatory and inhibitory neurotransmitter receptors in vitro. These novel mechanisms of action are shared by NDL-PCBs, OH-PBDEs, and some other persistent organic pollutants, such as tetrabromobisphenol-A, and could have profound effects on neurodevelopment, neurotransmission, and neurobehavior in vivo. PMID- 23686759 TI - Trace metals in Ganges soft-shell turtle (Aspideretes gangeticus) from two barrage: Baloki and Rasul, Pakistan. AB - The concentration of nine metals was measured in liver, kidney, heart, muscle, plastron, and carapace of Aspideretes gangeticus from Rasul and Baloki barrages, Pakistan. The results indicated that metal concentration were significant different among tissues of Ganges soft-shell turtles. However, higher concentrations of Co (5.12 MUg/g) and Ni (1.67 MUg/g) in liver, Cd (0.41 MUg/g) in heart, Fe (267.45 MUg/g), Cd (2.12 MUg/g) and Mn (2.47 MUg/g) in kidney, Cd (0.23 MUg/g), Cu (2.57 MUg/g), Fe (370.25 MUg/g), Mn (5.56 MUg/g), and Pb (8.23 MUg/g) in muscle of A. gangeticus were recorded at Baloki barrage than Rasul barrage. Whereas mean concentrations of Pb (3.33 MUg/g) in liver, Co (1.63 MUg/g), Cu (11.32 MUg/g), Pb (4.8 MUg/g) and Zn (144.69 MUg/g) in heart, Co (4.12 MUg/g) in muscle, Ni (1.31 MUg/g), Pb (2.18 MUg/g), and Zn (9.78 MUg/g) in carapace were recorded higher at Rasul barrage than Baloki barrage. The metals followed the trend Fe>Zn>Ni>Cu>Mn>Pb>Cr>Co>Cd. Metals of toxicological concern such as Cr, Pb, and Cd were at that level which can cause harmful effects to turtles. The results provide baseline data of heavy metals on freshwater turtle species of Pakistan. PMID- 23686760 TI - [Chances and risks of a new residency program for orthopedics and trauma surgery]. AB - BACKGROUND: The residency program for a specialist in orthopedics and trauma surgery is facing fundamental changes based on an initiative originating from the working group "medical training" of the German Medical Association (GMA). A survey indicated that 50 % of all trainees are dissatisfied with their current situation. It appears important to integrate the ideas and wishes of current orthopedic residents in a novel training concept. To assess this a survey was performed by the Young Forum of the German Society for Orthopedics und Trauma Surgery. MATERIAL AND METHODS: The internet-based short survey was conducted in January 2013 among members of the professional societies (DGU, DGOU and DGOOC). 408 physicians participated. RESULTS: The majority of the participating physicians is interested in a career in orthopedics and trauma surgery with primarily operative contents. Accordingly the majority (62 %, n = 253) voted against a reduction of numbers of surgical interventions with 86 % (n = 351) confirming the necessity that these operations must be carried out by the trainee himself. CONCLUSION: The upcoming changes in residency program for orthopedics and trauma surgery offer the opportunity for a well structured and practical oriented residency program. It could be a further step in increasing satisfaction in this profession. PMID- 23686761 TI - Progressive extreme heterotopic calcification. AB - The formation of ectopic calcifications in soft tissues can occur either sporadically or as a genetically determined condition, and is seen only infrequently. We report on a girl in whom widespread, rapidly progressive ectopic calcifications were detected shortly after birth. Calcifications became present around all joints, tendons and ligaments, but did not involve internal organs and skin, and eventually caused almost complete immobility of the child at 2 years. There were no other health problems and cognitive development was normal. We compare the manifestations in the child to the characteristics of known entities causing ectopic calcifications and conclude the child differs to each. Laboratory evaluation failed to identify autoimmune phenomena as well as calcium metabolism or other biochemical abnormalities; molecular studies did not identify occurrence of mutations in disease genes known to be involved in ectopic calcifications. We conclude the manifestations in the child represent an unreported entity of hitherto unknown etiology. PMID- 23686762 TI - Corticotropin releasing hormone activates CD14+ cells to induce endothelial barrier dysfunction. AB - Endothelial barrier dysfunction is associated with the pathogenesis of a number of disorders in the body, but the aetiology is unclear. We have investigated the mechanism of the psychological stress mediator, corticotropin releasing hormone (CRH), on compromising the endothelial barrier function. Human endothelial cell line, Hmvec cells, was cultured in monolayers as a model of endothelial barrier. Human peripheral CD14+ cells were collected to be used as effector immune cells. The transepithelial resistance (TER) and permeability of horseradish peroxidase (HRP) were used as indicators of endothelial barrier function. Apoptosis in Hmvec cells were analysed by flow cytometry. Human CD14+ cells expressed both receptors (R) of CRH, the CRH-R1 and CRH-R2. Exposure to CRH induced CD14+ cells to release tumour necrosis factor (TNF)-alpha. CRH-activated CD14+ cells decreased TER and increased the permeability to HRP in co-cultured Hmvec monolayers. Co-culture with CRH-activated CD14+ cells increased the apoptosis in Hmvec cells. We conclude that CRH can activate CD14+ cells to produce TNF-alpha and compromise endothelial barrier function by inducing apoptosis of the endothelial cells. PMID- 23686763 TI - Mycolytic enzymes produced by Streptomyces violaceusniger and their role in antagonism towards wood-rotting fungi. AB - Extracellular mycolytic enzymes produced under submerged fermentation by the fungal antagonist Streptomyces violaceusniger MTCC 3959 were characterized. This streptomycete produced higher amounts of extracellular chitinase and protease during late exponential phase, whereas beta-1,3-glucanase production was at peak in mid-stationary phase. Cell-free culture filtrate (CCF) exhibited a broad range of antifungal activity against both white rot and brown rot fungi. The inhibitory activity was completely lost after treatment with proteinase K and heat, indicating that extracellular antifungal metabolites are heat labile and proteinaceous in nature. Optimum pH and temperature for enzyme activity were: 9.0 and 60 degrees C for chitinase; 6.0 and 60 degrees C for beta-1,3-glucanase; and 9.0 and 70 degrees C for protease. Mycolytic enzymes were moderately thermostable, and had a wide pH stability range extending from pH 5.0 to 10.0. The zymogram analysis of CCF revealed five chitinase isoenzymes with an apparent molecular weight of 20.8, 33.3, 45.6, 67.4, and 114.8 kDa, one beta-1,3-glucanase appeared as a single band of ~131.8 kDa and four protease isoenzymes with approximate molecular weights of 22.8, 62.52, 74.64, and 120.5 kDa. S. violaceusniger MTCC 3959 produced mycolytic enzymes that can be effectively used for suppression of phytopathogenic basidiomycetes. It has the potential to be an effective biofungicide. PMID- 23686765 TI - Retrieval study at 623 human mesh explants made of polypropylene - impact of mesh class and indication for mesh removal on tissue reaction. AB - Textile meshes frequently are implanted in the abdominal wall to reinforce a hernia repair. However, revisions for mesh associated complications confirm that these devices are not completely free of risk. Explanted devices offer an opportunity to define the impact of mesh structure on tissue response. This retrieval study analyses the tissue reaction to 623 polypropylene mesh samples (170 class 1 with large pores, and 453 class 2 with small pores) explanted for pain, infection, or recurrence. Histopathological assessment included morphometry of inflammatory infiltrate (IF) and connective tissue (CT), and of collagen 1/3 ratio. Half of the meshes were removed after more than 23 month. Despite large inter-individual differences removal for infection showed more IF than for pain or recurrence with significant correlation of IF with CT. Class 1 meshes with large pores showed less IF, CT, fistula formation, calcification, and bridging than class 2 meshes with small pores. Meshes removed for recurrence showed a lowered collagen 1/3 ratio in 70%. Large pore class 1 meshes showed an improved tissue response and may be considered as favorable to prevent inflammatory side effects. The presence of lowered collagen 1/3 ratio in most of the samples with recurrences stresses the relevance of an intact healing process. Late manifestation of complications demands long-lasting follow-up. (c) 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2013. PMID- 23686764 TI - Application of permeability-limited physiologically-based pharmacokinetic models: part II - prediction of P-glycoprotein mediated drug-drug interactions with digoxin. AB - Digoxin is the recommended substrate for assessment of P-glycoprotein (P-gp) mediated drug-drug interactions (DDIs) in vivo. The overall aim of our study was to investigate the inhibitory potential of both verapamil and norverapamil on the P-gp-mediated efflux of digoxin in both gut and liver. Therefore, a physiologically-based pharmacokinetic (PBPK) model for verapamil and its primary metabolite was developed and validated through the recovery of observed clinical plasma concentration data for both moieties and the reported interaction with midazolam, albeit a cytochrome P450 3A4-mediated DDI. The validated inhibitor model was then used in conjunction with the model developed previously for digoxin. The range of values obtained for the 10 trials indicated that increases in area under the plasma concentration-time curve (AUC) profiles and maximum plasma concentration observed (Cmax ) values of digoxin following administration of verapamil were more comparable with in vivo observations, when P-gp inhibition by the metabolite, norverapamil, was considered as well. The predicted decrease in AUC and Cmax values of digoxin following administration of rifampicin because of P-gp induction was 1.57- (range: 1.42-1.77) and 1.62-fold (range: 1.53-1.70), which were reasonably consistent with observed values of 1.4- and 2.2-fold, respectively. This study demonstrates the application of permeability-limited models of absorption and distribution within a PBPK framework together with relevant in vitro data on transporters to assess the clinical impact of modulated P-gp-mediated efflux by drugs in development. PMID- 23686766 TI - Forensic pathology of companion animal abuse and neglect. AB - Submission of cases of suspected animal abuse and neglect (AAN) to veterinary pathologists is increasingly frequent. These cases require modification of postmortem procedures and written reports, as the questions asked by courts typically differ from those asked in routine diagnostic cases. Here we review the practice of veterinary forensic pathology as it applies to cases of companion AAN, as well as the fundamental principles of forensic pathology, the components of a forensic necropsy, and the goals of the necropsy in cases of blunt-force trauma, projectile wounds, and starvation. Future directions and endeavors in veterinary forensic pathology are broached. PMID- 23686767 TI - Distribution of eastern equine encephalomyelitis viral protein and nucleic acid within central nervous tissue lesions in white-tailed deer (Odocoileus virginianus). AB - An outbreak of eastern equine encephalomyelitis (EEE) occurred in Michigan free ranging white-tailed deer (Odocoileus virginianus) during late summer and fall of 2005. Brain tissue from 7 deer with EEE, as confirmed by reverse transcriptase polymerase chain reaction, was studied. Detailed microscopic examination, indirect immunohistochemistry (IHC), and in situ hybridization (ISH) were used to characterize the lesions and distribution of the EEE virus within the brain. The main lesion in all 7 deer was a polioencephalomyelitis with leptomeningitis, which was more prominent within the cerebral cortex, thalamus, hypothalamus, and brainstem. In 3 deer, multifocal microhemorrhages surrounded smaller vessels with or without perivascular cuffing, although vasculitis was not observed. Neuronal necrosis, associated with perineuronal satellitosis and neutrophilic neuronophagia, was most prominent in the thalamus and the brainstem. Positive IHC labeling was mainly observed in the perikaryon, axons, and dendrites of necrotic and intact neurons and, to a much lesser degree, in glial cells, a few neutrophils in the thalamus and the brainstem, and occasionally the cerebral cortex of the 7 deer. There was minimal IHC-based labeling in the cerebellum and hippocampus. ISH labeling was exclusively observed in the cytoplasm of neurons, with a distribution similar to IHC-positive neurons. Neurons positive by IHC and ISH were most prominent in the thalamus and brainstem. The neuropathology of EEE in deer is compared with other species. Based on our findings, EEE has to be considered a differential diagnosis for neurologic disease and meningoencephalitis in white-tailed deer. PMID- 23686768 TI - Pathology and diagnostic criteria of Clostridium difficile enteric infection in horses. AB - Clostridium difficile is commonly associated with diarrhea and colitis in humans and other mammals, including horses. To this date, the epidemiologic, microbiologic, clinical, and diagnostic aspects of C. difficile-associated disease (CDAD) in horses have been thoroughly described. However, reports describing the enteric pathology of this disease in horses are limited. This study presents a comprehensive description of the pathologic characteristics of CDAD in 21 horses and discusses the criteria for the diagnosis of the disease. Case selection was based on C. difficile A/B toxins detection (enzyme-linked immunosorbent assay) in intestinal content samples accompanied by compatible gross and microscopic enteric lesions. Grossly, multifocal, segmental, or diffuse hemorrhage; congestion; and/or marked gelatinous edema of the intestinal wall with abundant bloody or green watery contents were observed. Histologically, the most common lesion was severe necrotizing or necrohemorrhagic enteritis, colitis, or typhlocolitis, with mucosal and/or submucosal thrombosis and marked submucosal edema. The pathology of CDAD in horses is similar to that caused by other equine enteric pathogens; therefore, a definitive diagnosis requires detection of C. difficile A/B toxins in the intestinal contents. PMID- 23686769 TI - Comparing histone deacetylase inhibitor responses in genetically engineered mouse lung cancer models and a window of opportunity trial in patients with lung cancer. AB - Histone deacetylase inhibitor (HDACi; vorinostat) responses were studied in murine and human lung cancer cell lines and genetically engineered mouse lung cancer models. Findings were compared with a window of opportunity trial in aerodigestive tract cancers. In human (HOP62, H522, and H23) and murine transgenic (ED-1, ED-2, LKR-13, and 393P, driven, respectively, by cyclin E, degradation-resistant cyclin E, KRAS, or KRAS/p53) lung cancer cell lines, vorinostat reduced growth, cyclin D1, and cyclin E levels, but induced p27, histone acetylation, and apoptosis. Other biomarkers also changed. Findings from transgenic murine lung cancer models were integrated with those from a window of opportunity trial that measured vorinostat pharmacodynamic responses in pre- versus posttreatment tumor biopsies. Vorinostat repressed cyclin D1 and cyclin E expression in murine transgenic lung cancers and significantly reduced lung cancers in syngeneic mice. Vorinostat also reduced cyclin D1 and cyclin E expression, but increased p27 levels in post- versus pretreatment human lung cancer biopsies. Notably, necrotic and inflammatory responses appeared in posttreatment biopsies. These depended on intratumoral HDACi levels. Therefore, HDACi treatments of murine genetically engineered lung cancer models exert similar responses (growth inhibition and changes in gene expression) as observed in lung cancer cell lines. Moreover, enhanced pharmacodynamic responses occurred in the window of opportunity trial, providing additional markers of response that can be evaluated in subsequent HDACi trials. Thus, combining murine and human HDACi trials is a strategy to translate preclinical HDACi treatment outcomes into the clinic. This study uncovered clinically tractable mechanisms to engage in future HDACi trials. PMID- 23686770 TI - Mechanism of differentiation-enhanced photodynamic therapy for cancer: upregulation of coproporphyrinogen oxidase by C/EBP transcription factors. AB - The efficacy of photodynamic therapy (PDT) for epithelial cancers is increased when PDT is combined with calcitriol (Vit D), a form of differentiation therapy (DT). Here, we describe an underlying mechanism for this effect. Differentiation promoting agents are known to upregulate CCAAT/enhancer-binding proteins (C/EBP), powerful regulators of cellular differentiation. In subcutaneous A431 tumors in mice, pretreatment with Vit D induced the expression of C/EBPbeta isoforms, and of coproporphyrinogen oxidase (CPO), a heme pathway enzyme responsible for the conversion of 5-aminolevulinic acid (ALA) into protoporphyrin IX (PpIX), the principal light-absorbing molecule during PDT. To further investigate this apparent link between C/EBPs and CPO, two cell lines (MEL and LNCaP) were exposed to differentiating agents, and levels of PpIX, C/EBPs, and CPO were measured. Differentiating agents, or transfection of C/EBP expression vectors, increased C/EBP and CPO levels in parallel. Focusing on approximately 1,300 bp of upstream CPO gene promoter, we tested the ability of recombinant C/EBPalpha, C/EBPbeta, C/EBPdelta, and C/EBPzeta to bind to CPO gene sequences [electrophoretic mobility shift assay (EMSA) assays] and to affect transcriptional activity (luciferase assays). Multiple C/EBP consensus binding sites were identified (15 for mouse, 18 for human). Individual probes representing each site bound to C/EBPs with characteristic affinities (strong, moderate, or weak), but when sites were inactivated in the context of the native promoter, transcriptional activity was reduced nearly equally for strong or weak sites. Cooperative interactions between regularly spaced C/EBP sites seem critical for CPO transcriptional regulation by differentiation therapy. These results provide a mechanistic rationale for DT/PDT combination therapy for cancer. PMID- 23686771 TI - Mutations in TNK2 in severe autosomal recessive infantile onset epilepsy. AB - We identified a small family with autosomal recessive, infantile onset epilepsy and intellectual disability. Exome sequencing identified a homozygous missense variant in the gene TNK2, encoding a brain-expressed tyrosine kinase. Sequencing of the coding region of TNK2 in 110 patients with a similar phenotype failed to detect further homozygote or compound heterozygote mutations. Pathogenicity of the variant is supported by the results of our functional studies, which demonstrated that the variant abolishes NEDD4 binding to TNK2, preventing its degradation after epidermal growth factor stimulation. Definitive proof of pathogenicity will require confirmation in unrelated patients. PMID- 23686773 TI - Functional nanofiber mat of polyvinyl alcohol/gelatin containing nanoparticles of biphasic calcium phosphate for bone regeneration in rat calvaria defects. AB - New biodegradable mats was successfully obtained by functional polyvinyl alcohol (PVA)/Gelatin (GE) blend fiber mats containing different BCP amounts (20, 40, and 50 w/v%) of biphasic calcium phosphate (BCP) nanoparticles for bone regeneration. BCP nanoparticles were loaded and dispersed successfully in the PVA/GE fibrous matrix. The addition of BCP was found to have increased fiber diameter, tensile strength, osteoblast cell adhesion, proliferation, and protein expression. Compared to the others, the 50% BCP-loaded electrospun PVA/GE fibers had the most favorable mechanical properties, cell attachment and growth, and protein expression. In vivo bone formation was examined using rat models, and increased bone formation was observed for the 50% BCP-loaded electrospun PVA/GE blends within 2 and 4 weeks. This result suggests that the 50% BCP-PVA/GE composite nanofiber mat has high potential for use in the field of bone regeneration and tissue engineering. PMID- 23686772 TI - The NLRP3 inflammasome in Alzheimer's disease. AB - Innate immunity and inflammatory response plays an important role in the pathogenesis of Alzheimer's disease (AD). As the major resident immune cells in the brain, microglial cells constantly survey the microenvironment and are activated by and recruited to senile plaques. Subsequently, they can phagocytose amyloid-beta (Abeta) and secrete pro-inflammatory cytokines that influence the surrounding brain tissue. Recently, a wealth of information linking the microglia specific activation of NLRP3 inflammasome to AD pathogenesis has emerged. We review here the activation mechanisms of NLRP3 inflammasome in microglia and several downstream effects in the brain, demonstrating that toxic Abeta peptide can light a fire in NLRP3 inflammasome and eventually induce AD pathology and tissue damage. More importantly, it has been demonstrated that inhibition of NLRP3 could largely protect from memory loss and decrease Abeta deposition in AD transgenic mouse model. So, we further discuss the recent advances and challenges in targeting NLRP3 inflammasome for AD therapy. PMID- 23686774 TI - tcdA As a diagnostic target in a loop-mediated amplification assay for detecting toxigenic Clostridium difficile. AB - BACKGROUND: The illumigene(r) (Meridian Bioscience, Inc., Cincinnati, OH) and GeneOhm(r) (BD Diagnostics, La Jolla, CA) Clostridium difficile assays target the tcdA gene and tcdB gene, respectively. We assessed the use of tcdA as the molecular target in the illumigene(r) C. difficile loop-mediated amplification assay in detecting a wide variety of C. difficile strains including those with tcdA deletions. METHODS: We tested 38 C. difficile strains and 108 patient stool specimens using the illumigene(r) assay. The GeneOhm(r) real-time polymerase chain reaction (PCR) assay served as the reference method. Discordant results were resolved by repeat testing, anaerobic culture, and a laboratory-developed real-time PCR targeting tcdA and tcdB. RESULTS: Both illumigene(r) and GeneOhm(r) assays detected all 37 C. difficile toxin B(+) strains representing seven toxinotypes and including four toxin A(-) B(+) isolates. No cross-reactivity with 20 other Clostridium species or toxin-negative C. difficile was observed in either assay. Among patient stool specimens, agreement was 94.4% (102/108). After discordant result resolution, agreement was 96.3% (104/108). Specimens with initially discordant results had target concentrations approaching the limit of detection for the two commercial assays. Discordance appeared unrelated to whether tcdA or tcdB was the amplification target. CONCLUSION: The tcdA 5' region used by the illumigene(r) assay is a practical target for toxigenic C. difficile detection. PMID- 23686775 TI - Moderate-intensity single exercise session does not induce renal damage. AB - BACKGROUND: The aim of this study was to determine whether a single moderate intensity exercise session induces renal injury based on various parameters that reflect kidney dysfunction, including urinary L-type fatty acid-binding protein (L-FABP). METHODS: Adult outpatients (n = 31) with chronic kidney disease (CKD) not receiving renal replacement therapy participated in this study. Urine was collected before and after a single 20-min moderate-intensity exercise session. Urinary levels of L-FABP, albumin, N-acetyl-beta-d-glucosaminidase (NAG), and alpha1-microglobrin (alpha1MG) were measured. In addition, 12 patients with estimated glomerular filtration fraction less than 30 ml/min/1.73 ml(2) were selected from all patients and evaluated using the same analysis. RESULTS: Urinary values of L-FABP, albumin, NAG, and alpha1MG did not increase significantly after exercise compared with before exercise (urinary L-FABP, from 8.3 to 9.4 MUg/g of creatinine; urinary albumin, from 293.1 to 333.7 mg/g of creatinine; urinary NAG, from 9.2 to 8.2 U/g of creatinine; urinary alpha1MG, from 11.4 to 9.8 mg/g of creatinine, not significant). Similar findings were seen in all patients, regardless of degree of renal dysfunction. CONCLUSIONS: A single session of moderate-intensity exercise was not associated with an increase in renal parameters used to assess renal damage. PMID- 23686776 TI - Incidence of pulmonary aspergillosis and correlation of conventional diagnostic methods with nested PCR and real-time PCR assay using BAL fluid in intensive care unit patients. AB - BACKGROUND: Although the incidence of invasive aspergillosis in the intensive care unit (ICU) is scarce, it has emerged as major problems in critically ill patients. In this study, the incidence of pulmonary aspergillosis (PA) in ICU patients has evaluated and direct microscopy and culture has compared with nested polymerase chain reaction (PCR) and real-time PCR for detection of Aspergillus fumigatus and A. flavus in bronchoalveolar lavage (BAL) samples of the patients. METHODS: Thirty BAL samples obtained from ICU patients during a 16-month period were subjected to direct examinations on 20% potassium hydroxide (KOH) and culture on two culture media. Nested PCR targeting internal transcribed spacer ribosomal DNA and TaqMan real-time PCR assay targeting beta-tubulin gene were used for the detection of A. fumigatus and A. flavus. RESULTS: Of 30 patients, 60% were men and 40% were women. The diagnosis of invasive PA was probable in 1 (3%), possible in 11 (37%), and not IPA in 18 (60%). Nine samples were positive in nested PCR including seven samples by A. flavus and two by A. fumigatus specific primers. The lowest amount of DNA that TaqMan real-time PCR could detect was >=40 copy numbers. Only one of the samples had a positive result of A. flavus real-time PCR with Ct value of 37.5. CONCLUSIONS: Although a significant number of specimens were positive in nested PCR, results of this study showed that establishment of a correlation between the conventional methods with nested PCR and real-time PCR needs more data confirmed by a prospective study with a larger sample group. PMID- 23686777 TI - Present status of the standardization of HDL-C, LDL-C, and TG measurement values available in Japan. AB - BACKGROUND: Control sera used as evaluation samples in external quality control of HDL-C and LDL-C sometimes show disparities in results between direct methods differing in reaction principles. As a result, the present standardization status is unclear. In 2008, we investigated the present status of standardization of HDL C, LDL-C, and TG measurement values available in Japan. SUBJECTS AND METHODS: To evaluate accuracy, refrigerated fresh human serum pools used as samples were analyzed irrespective of the manufacturer's method. To evaluate precision, a questionnaire survey regarding the internal quality control status at each institution was carried out. As evaluation criteria, the permissible limits of error of BA and CVA based on JSCC proposals, and the accuracy and imprecision criterion NCEP proposals were used. RESULTS: There were 70 participating institutions for HDL-C, 65 for LDL-C, and 71 for TG. TG values from the institutions showed 83.1-91.5% for both the JSCC BA range and the NCEP criterion range. HDL-C values within the JSCC BA range were 81.4-82.6% and within the NCEP criterion range the value was 98.6%. Similarly, LDL-C values within the JSCC BA range were 89.2% and within the NCEP criterion range the value were 81.5-83.1%, respectively. Concerning precision, a questionnaire regarding internal quality control of each institution was completed. More than 90% of the institutions showed values within the CVA range proposed by the JSCC for all of HDL-C, LDL-C, and TG. CONCLUSION: Standardization of lipid assays used for metabolic syndrome based health checkups has been mostly achieved. PMID- 23686778 TI - Assessment and modeling of routinely used biochemical laboratory data of healthy individuals and end-stage renal failure (ESRF) patients by three different chemometric methods. AB - BACKGROUND: In recent years, the use of biochemical markers has received increasing attention for purposes of risk assessment and clinical management in renal failure patients. Chemometric methods are often used in medical studies and there are already indications for their specific role as a tool of the medical statistics. METHODS: Three chemometric methods, discriminant analysis (DA), binary logistic regression analysis (BLRA), and cluster analysis (CA), were used for assessment and modeling of routinely used biochemical laboratory data of 18 parameters that were determined from 185 healthy individuals (HIs) and 173 end stage renal failure (ESRF) patients. RESULTS: The above-mentioned chemometric methods were performed using the data set of 14 parameters since the rest 4 parameters did not present significant difference between healthy and patients. DA created a model using only ALB (Albumin), K (Potassium), TG (Triglyceride), and ALP (Alkaline phosphatase); BLRA model also used the above four parameters; CA classified all the cases into two clusters using the same four parameters and one more parameter, AST (aspartate aminotransferase). CONCLUSIONS: This study provides models for assessment and modeling of routinely used biochemical laboratory data, finding groups of similarity among clinical tests usually determined on HIs and ESRF patients, contributing in data mining and reducing costs. PMID- 23686779 TI - Serum thymidine kinase 1 activity in solid tumor (breast and colorectal cancer) patients treated with adjuvant chemotherapy. AB - BACKGROUND: The aim of this study was to evaluate the changing of TK1 (where TK is thymidine kinase) activity before and after adjuvant chemotherapy in patients with breast and colorectal cancer. METHODS: The study included 16 breast cancer, 25 colorectal cancer, and 38 healthy volunteers as the control group. Blood samples were taken twice from each patient; first at the beginning of the chemotherapy and second after six cycles of chemotherapy. TK1 activity was measured enzyme immunoassay method. RESULTS: The mean TK1 activity in the breast and colorectal cancer was significantly higher than the controls. TK1 activity in the colorectal cancer was higher than the breast cancer but this difference was not significant. TK1 activity after six doses of chemotherapy was lower than baseline TK1 activity before the start of chemotherapy in breast and colorectal cancer. TK1 activity was positively correlated with CA15-3, before and after chemotherapy in patients with breast cancer. TK1 activity in the colorectal cancer was also positively correlated with CA19-9, before and after chemotherapy. The values for the cutoff point, sensitivity, specificity, and the area under curve were determined for TK1 as >44.36 Du/L, 68.29%, 100% and 0.819, respectively in all subjects. CONCLUSION: Our results showed that serum TK1 activity in patients with breast and colorectal cancer was significantly higher than that of the healthy controls. Moreover, after the completion of chemotherapy the values were lower than baseline. Pretreatment TK1 activity should be considered as a useful marker for assessment tumor cell proliferation in breast and colorectal cancer. Further work is needed to understand TK1 activity better in large populations of patients with solid tumor. PMID- 23686780 TI - Molecular detection of trisomy 21 by bicolor competitive fluorescent PCR. AB - OBJECTIVE: To develop a reliable and specific method for rapid prenatal diagnosis of Trisomy 21 (Down syndrome). METHODS: We established a dual color competitive fluorescent Polymerase Chain Reaction (PCR) to measure the gene dosage of Down syndrome critical region (DSCR), a single copy sequence in chromosome 21. Another unique single copy sequence located on chromosome 2 (USC2) but not glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was chose as reference gene. RESULTS: The DSCR3/USC2 ratio of peripheral blood in trisomy 21 syndrome patients to normal subjects was 1.41~1.74 to 0.93~1.15, respectively (p < 0.01). Dual color competitive fluorescent PCR technique effectively differentiates the normal subjects from the Down syndrome patients. Next, according to the dual color competitive fluorescence quantitative PCR, among the 46 pregnant women, 3 cases were Down syndrome and 43 cases were normal, and these were confirmed by cytogenetic karyotype analysis. CONCLUSION: This indicated that the new technique may be a reliable and specific method for the rapid prenatal diagnosis of Trisomy 21. PMID- 23686781 TI - The use of factorial design, image analysis, and an efficiency calculation for multiplex PCR optimization. AB - BACKGROUND: The quality of multiplex polymerase chain reaction (PCR) assays depends on several factors. Therefore, it is important to establish the optimal conditions to achieve efficient amplification. The objective of this study was to implement a 5 * 4 factorial design combined with image analysis using agarose gels and an efficiency calculation to optimize a multiplex PCR assays for the detection of Salmonella enterica serovar typhimurium. METHODS: We used 12 ng of Salmonella DNA obtained from pure cultures and applied different annealing temperatures (65 degrees C, 64.5 degrees C, 63.3 degrees C, 61.4 degrees C, or 59 degrees C) and different MgCl2 concentrations (1 mM, 1.5 mM, 2 mM, or 2.5 mM) to amplify regions of the fliC, rfbJ, and fljB genes. The 5 * 4 factorial design was performed using Statgraphics Plus software version 5.1, and the images were analyzed using Image Lab(TM) software. RESULTS: Superior amplification was obtained using an annealing temperature of 65 degrees C and 2 mM MgCl2 . This finding was confirmed by calculating the efficiency of multiplex PCR assays (6.1%) at these conditions. CONCLUSION: We propose the application of factorial design and image analysis to determine the most suitable conditions for multiplex PCR optimization. PMID- 23686782 TI - Therapeutic advantage of anti-VAP-1 over anti-alpha4 integrin antibody in concanavalin a-induced hepatitis. AB - Hepatitis induced by concanavalin A (Con A) in mice is well known to be a T lymphocyte-mediated injury. It has been reported that T helper (Th)1 and Th2 lymphocytes use alpha4 integrin and vascular adhesion protein (VAP)-1, respectively, to adhere within the hepatic sinusoids. Therefore, we investigated whether inhibition of these molecules ameliorates or worsens the Con A-induced hepatic injury in vivo. Vehicle or antibody to alpha4 integrin or VAP-1 was intravenously administered 30 minutes before Con A administration. In control mice Con A markedly increased the serum alanine aminotransferase (ALT) level in a dose-dependent manner, and induced a massive infiltration of CD3, particularly interleukin (IL)-4 producing CD4 T cells and liver injury. Both parameters were reduced by anti-VAP-1 antibody despite antibody only blocking the adhesion, not the amine oxidase activity of VAP-1. Both activities of VAP-1 were eliminated in VAP-1-deficient mice and both Con A-induced liver injury and CD4 T-cell infiltration were eradicated. In contrast to anti-VAP-1, anti-alpha4 integrin antibody reduced interferon-gamma (IFN-gamma)-producing CD3 T cells but this worsened Con A hepatitis, suggesting inhibition of a suppressor cell. Con A induced the recruitment of CD49d(+) monocytic myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) into the liver. Anti-alpha4 integrin dramatically blocked the influx of MDSCs but not Tregs. CONCLUSION: Our findings show that VAP-1 and alpha4 integrin have opposing effects in Con A-induced hepatic injury, which is associated with blocking the recruitment of CD4 lymphocytes and monocytic MDSCs, respectively. Moreover, these data provide the rationale for a potential therapeutic approach to target adhesion molecules in autoimmune hepatitis. PMID- 23686783 TI - Control of selectivity in palladium-catalyzed oxidative carbocyclization/borylation of allenynes. PMID- 23686784 TI - Genetic evaluation of dilated cardiomyopathy. AB - Recent advances have expanded our ability to conduct a comprehensive genetic evaluation for dilated cardiomyopathy (DCM). By evaluating recent literature, this review aims to bring the reader up-to-date on the genetic evaluation of DCM. Updated guidelines have been published. Mutations in BAG3, including a large deletion, were identified in 2 % of DCM. Truncating mutations in TTN were reported in 25 % of DCM. Two new genes have been reported with autosomal recessive DCM. These studies illustrate the role of improved technologies while raising the possibility of a complex genetic model for DCM. The inclusion of TTN has led to an increased genetic testing detection rate of 40 %. While our ability to identify disease-causing variants has increased, so has the identification of variants of unknown significance. A genetic evaluation for DCM must therefore address this complexity. PMID- 23686785 TI - Anticancer activity of tolfenamic acid in medulloblastoma: a preclinical study. AB - Medulloblastoma (MB) is the most common malignancy in children arising in the brain. Morbidities associated with intensive therapy are serious concerns in treating MB. Our aim was to identify novel targets and agents with less toxicity for treating MB. Specificity protein 1 (Sp1) transcription factor regulates several genes involved in cell proliferation and cell survival including survivin, an inhibitor of apoptosis protein. We previously showed that tolfenamic acid (TA), a nonsteroidal anti-inflammatory drug, inhibits neuroblastoma cell growth by targeting Sp1. We investigated the anticancer activity of TA using human MB cell lines and a mouse xenograft model. DAOY and D283 cells were treated with vehicle (dimethyl sulfoxide) or TA (5-50 MUg/ml), and cell viability was measured at 1-3 days posttreatment. TA inhibited MB cell growth in a time- and dose-dependent manner. MB cells were treated with vehicle or TA (10 MUg/ml), and the effect on cell apoptosis was measured. Apoptosis was analyzed by flow cytometry (annexin V staining), and caspase 3/7 activity was determined using Caspase-Glo kit. The expression of Sp1, cleaved poly(ADP-ribose) polymerase (c PARP), and survivin was determined by Western blot analysis. TA inhibited the expression of Sp1 and survivin and upregulated c-PARP. Athymic nude mice were subcutaneously injected with D283 cells and treated with TA (50 mg/kg, three times per week) for 4 weeks. TA caused a decrease of ~40 % in tumor weight and volume. The tumor growth inhibition was accompanied by a decrease in Sp1 and survivin expression in tumor tissue. These preclinical data demonstrate that TA acts as an anticancer agent in MB potentially targeting Sp1 and survivin. PMID- 23686786 TI - The effect of leptin, caffeine/ephedrine, and their combination upon visceral fat mass and weight loss. AB - OBJECTIVE: To evaluate the effects of combination caffeine/ephedrine and leptin A 200 on visceral fat mass and weight loss over 24 weeks. DESIGN AND METHODS: In this randomized, double-blind, parallel-arm trial, 90 obese subjects received one of the three treatments for 24 weeks: 200 mg caffeine/20 mg ephedrine t.i.d. (CE), leptin A-200 (recombinant methionyl human Fc-leptin, 20 mg q.d.) (L), or combination leptin A-200 and caffeine/ephedrine (LCE). Outcomes included change in weight, visceral fat mass by computed tomography, lean mass and fat mass by dual energy X-ray absorptiometry. RESULTS: Groups treated with CE and LCE lost significant amounts of weight (-5.9 +/- 1.2% and -6.5 +/- 1.1%, P < 0.05) and whole body fat mass (-9.6 +/- 2.4% and -12.4 +/- 2.3%, P < 0.05) compared to leptin only group. Only treatment with LCE significantly reduced visceral fat mass (-11.0 +/- 3.3%, P < 0.05). There were no differences in lean mass between treatment groups. CONCLUSIONS: Our study provides evidence that CE is a modestly effective weight loss agent and produces significant reductions in fat mass. Leptin A-200 was not effective in producing weight loss and did not have any significant additive or synergistic actions when combined with CE. PMID- 23686787 TI - Intraoperative monitoring: normative range associated with normal postoperative glottic function. AB - OBJECTIVES/HYPOTHESIS: Despite increasing use of intraoperative nerve monitoring (IONM), there is limited information on normative electrophysiologic electromyographic (EMG) parameters. The objective of this study was to define normative parameters of recurrent laryngeal nerve (RLN) intraoperative neuromonitoring during thyroid surgery associated with normal postoperative vocal cord function. STUDY DESIGN: Prospective data collection in a tertiary care center. METHODS: Quantitative analysis of evoked waveform amplitude and threshold was performed on 125 patients with 167 nerves at risk. Values were displayed as a mean with 5th percentile and 95th percentiles (5th-95th). Postoperative vocal cord function in all patients was documented. RESULTS: All patients had normal postoperative laryngeal function (group I-normal) except for two patients who had postoperative transient vocal cord paralysis (group II-abnormal/outlier). The final amplitude between 247 and 3607 MUV at the end of dissection/end of surgery was associated in all group I patients with a normal postoperative neural function. Final intraoperative amplitude measures for group II averaged just 97.5 MUV, significantly different than our normative ranges obtained for group I, and fell outside of the group I 5% to 95% percentile range (P = .016). Final amplitude adequately predicted postoperative RLN impaired function immediately after surgery. CONCLUSIONS: We propose IONM EMG data criteria that predict normal postoperative vocal cord function monitoring and provide information about nerve functioning at the end of the operation, thereby allowing adaptation of the surgical strategy when a bilateral procedure is indicated to avoid bilateral nerve paralysis. PMID- 23686788 TI - Biosorption of heavy metals from aqueous solution by UV-mutant Bacillus subtilis. AB - To develop an efficient bio-immobilization approach for the remediation of heavy metal pollution in soil, a mutant species of Bacillus subtilis (B38) was obtained by ultraviolet irradiation and selection under high concentration of cadmium (Cd) in a previous study. In the present study, to check the applicability of this mutated species to the sorption and immobilization of other metals, the sorption of four heavy metals, Cd, chromium (Cr), mercury (Hg), and lead (Pb), on living and nonliving B38 in single- and multiple-component systems under different conditions was investigated using batch experiments. Rapid metal binding occurred on both living and nonliving B38 during the beginning of the biosorption. The sorption kinetics followed the exponential equation for living biomass and the pseudo-first-order Lagergren model for nonliving biomass, with r (2) values in the range of 0.9004-0.9933. The maximum adsorptive quantity of the heavy metals on B38 changed with the solution pH, temperature, biomass dose, and ionic strength. The nonliving biomass generally showed greater or similar adsorptive capacities as compared with the living biomass and was not likely to be affected by the solution parameters. The bacterium had a stronger affinity to the cationic heavy metals than to the anionic one, and the equilibrium sorption amounts were 210.6, 332.3, and 420.9 mg/g for Cd(II), Hg(II), and Pb(II), respectively. The results of binary and ternary sorption experiments indicated that the metals with the higher sorption capacity in the single-component systems showed greater inhibitory effects on the biosorption of other metal ions in the multiple component systems, but the sorption sites of Hg and Cd or Pb are likely to be different. The results of this study illustrated that the mutant species is a promising biosorbent for the remediation of multiple heavy metals. PMID- 23686789 TI - Perfluorinated alkylated substances in vegetables collected in four European countries; occurrence and human exposure estimations. AB - The human diet is recognised as one possible major exposure route to the overall perfluorinated alkylated substances (PFAS) burden of the human population, resulting directly from contamination of dietary food items, as well as migration of PFAS from food packaging or cookware. Most European countries carry out national monitoring programs (food basket studies) to monitor contamination with pollutants. Usually, for PFASs, non-coordinated approaches are used in Europe, since food basket studies are mainly carried out by national authorities following national requirements and questions, making comparisons between different countries difficult. A harmonised sampling campaign collecting similar food items in a uniform procedure enabling direct comparison between different regions in Europe was designed. We selected four countries (Belgium, Czech Republic, Italy and Norway), representing the four regions of Europe: West, East, South and North. In spring 2010 and 2011, 20 different types of vegetables were sampled in Belgium, Czech Republic, Italy and Norway. Perfluorinated carboxylic acids (PFCAs) were the main group of detected PFASs, with perfluorinated octanoic acid (PFOA) as the most abundant PFCA (with exception of samples from Czech Republic), followed by perfluorinated hexanoic acid and perfluorinated nonanoic acid. Dietary intake estimates for PFOA show only low human exposure due to vegetable consumption for adults and children, mostly governed by high intake of potatoes. PMID- 23686790 TI - Effect of silicate supplementation on the alleviation of arsenite toxicity in 93 11 (Oryza sativa L. indica). AB - Chronic exposure to arsenic (As) in rice has raised many health and environmental problems. As reported, great variation exists among different rice genotypes in As uptake, translocation, and accumulation. Under hydroponic culture, we find that the Chinese wild rice (Oryza rufipogon; acc. 104624) takes up the most arsenic among tested genotypes. Of the cultivated rice, the indica cv. 93-11 has the lowest arsenic translocation factor value but accumulates the maximum concentration of arsenic followed by Nipponbare, Minghui 86, and Zhonghua 11. Higher level of arsenite concentration (50 MUM) can induce extensive photosynthesis and root growth inhibition, and cause severe oxidative stress. Interestingly, external silicate (Si) supplementation has significantly increased the net photosynthetic rate, and promoted root elongation, as well as strongly ameliorated the oxidative stress by increasing the activities of antioxidant enzymes superoxide dismutase, ascorbate peroxidase, and peroxidase in roots and/or leaves of 93-11 seedlings. Notably, 1.873 mM concentration of Si considerably decreases the total As uptake and As content in roots, but significantly increases the As translocation from roots to shoots. In contrast, Si supplementation with 1.0 mM concentration significantly increases the total As uptake and As concentrations in roots and shoots of 93-11 seedlings after 50 MUM arsenite treatment for 6 days. PMID- 23686793 TI - Peptide profiling of the route from Mahoney to Sabin, and return. AB - In order to define poliovirus (PV) neurovirulence at the molecular level, we comparatively analyze the primary amino acid sequence of Mahoney, a neurovirulent PV strain, versus (i) Sabin, an attenuated PV strain, and (ii) IS1, a PV isolate obtained in temporal association to a paralysis event from a polio vaccinated subject. We identify and describe 12 pentapeptides that, originally present in the Mahoney sequence, are changed in the non-neurovirulent Sabin strain, and, successively, restored in IS1 strain. PMID- 23686791 TI - Baicalein reduces beta-amyloid and promotes nonamyloidogenic amyloid precursor protein processing in an Alzheimer's disease transgenic mouse model. AB - Baicalein, a flavonoid isolated from the roots of Scutellaria baicalensis, is known to modulate gamma-aminobutyric acid (GABA) type A receptors. Given prior reports demonstrating benefits of GABAA modulation for Alzheimer's disease (AD) treatment, we wished to determine whether this agent might be beneficial for AD. CHO cells engineered to overexpress wild-type amyloid precursor protein (APP), primary culture neuronal cells from AD mice (Tg2576) and AD mice were treated with baicalein. In the cell cultures, baicalein significantly reduced the production of beta-amyloid (Abeta) by increasing APP alpha-processing. These effects were blocked by the GABAA antagonist bicuculline. Likewise, AD mice treated daily with i.p. baicalein for 8 weeks showed enhanced APP alpha-secretase processing, reduced Abeta production, and reduced AD-like pathology together with improved cognitive performance. Our findings suggest that baicalein promotes nonamyloidogenic processing of APP, thereby reducing Abeta production and improving cognitive performance, by activating GABAA receptors. PMID- 23686792 TI - Cytotoxicity, cytocompatibility, cell-labeling efficiency, and in vitro cellular magnetic resonance imaging of gadolinium-catalyzed single-walled carbon nanotubes. AB - Cell tracking by magnetic resonance imaging (MRI) is an emerging technique that typically requires the use of MRI contrast agents (CAs). A MRI CA for cellular imaging should label cells efficiently at potentially safe concentrations, have high relaxivity, and not affect the cellular machinery. In this article, we report the cytotoxicity, cytocompatibility, and cell labeling efficiency in NIH/3T3 fibroblasts of novel, single-walled carbon nanotubes synthesized using gadolinium nanoparticles as catalysts (Gd-SWCNTs). Cells incubated with the Gd SWCNT showed a dose- (50-100 ug/mL nanotube concentration) and time- (12-48 h) dependent decrease in viability. 30% cell death was observed for cells incubated with Gd-SWCNTs at the maximum dose of 100 ug/mL for 48 h. Cells incubated with the Gd-SWCNTs at concentrations between 1-10 MUg/mL for 48 h showed no change in viability or proliferation compared to untreated controls. Additionally, at these potentially safe concentrations, up to 48 h, the cells showed no phosphatidyl serine externalization (pre-apoptotic condition), caspase-3 activity (point of no return for apoptosis), genetic damage, or changes in their division cycle. Localization of Gd-SWCNTs within the cells was confirmed by transmission electron microscopy (TEM) and Raman microscopy, and these results show 100% cell labeling efficiency. Elemental analysis also indicates significant uptake of Gd-SWCNTs by the cells (10(8) -10(9) Gd(3+) ions per cell). Finally, T1 -weighted MRI at 3 T of Gd-SWCNT-labelled cells show up to a four-fold increase in MR signal intensities as compared to untreated cells. These results indicate that Gd-SWCNTs label cells efficiently at potentially safe concentrations, and enhance MRI contrast without any structural damage to the cells. PMID- 23686794 TI - XY sex reversal, pontocerebellar hypoplasia and intellectual disability: confirmation of a new syndrome. AB - We report on a 46,XY female with pontocerebellar hypoplasia and intellectual disability. To our knowledge, this is the fourth reported patient with this constellation and further confirms a rare new syndrome. The condition is probably a single gene disorder with a currently unknown mode of inheritance. The causative gene is likely involved in the normal gonadal sex determination as well as the cerebral and cerebellar formation and function. PMID- 23686795 TI - Establishment of novel prediction system of intestinal absorption in humans using human intestinal tissues. AB - The objective of this study was to establish a novel prediction system of drug absorption in humans by utilizing human intestinal tissues. Based on the transport index (TI), a newly defined parameter, calculated by taking account of the change in drug concentrations because of precipitation on the apical side and the amounts accumulated in the tissue and transported to the basal side, the absorbability of drugs in rank order as well as the fraction of dose absorbed (Fa) in humans were estimated. Human intestinal tissues taken from ulcerative colitis or Crohn's disease patients were mounted in a mini-Ussing chamber and transport studies were performed to evaluate the permeation of drugs, including FD-4, a very low permeable marker, atenolol, a low permeable marker, and metoprolol, a high permeable marker. Although apparent permeability coefficients calculated by the conventional equation did not reflect human Fa values for FD-4, atenolol, and metoprolol, TI values were well correlated with Fa values, which are described by 100 . [1 - e (- f . (TI - alpha)) ]. Based on this equation, Fa values in humans for other test drugs were predicted successfully, indicating that our new system utilizing human intestinal tissues would be valuable for predicting oral drug absorption in humans. PMID- 23686796 TI - Isolation and molecular characterization of polyvinyl chloride (PVC) plastic degrading fungal isolates. AB - The recalcitrant nature of polyvinyl chloride creates serious environmental concerns during manufacturing and waste disposal. The present study was aimed to isolate and screen different soil fungi having potential to biodegrade PVC films. After 10 months of soil burial experiment, it was observed that a number of fungal strains were flourishing on PVC films. On morphological as well as on 18rRNA gene sequence and phylogenetic basis they were identified as Phanerochaete chrysosporium PV1, Lentinus tigrinus PV2, Aspergillus niger PV3, and Aspergillus sydowii PV4. The biodegradation ability of these fungal isolates was further checked in shake flask experiments by taking thin films of PVC (C source) in mineral salt medium. A significant change in color and surface deterioration of PVC films was confirmed through visual observation and Scanning electron microscopy. During shake flask experiments, P. chrysosporium PV1 produced maximum biomass of about 2.57 mg ml(-1) followed by A. niger PV3. P. chrysosporium PV1 showed significant reduction (178,292 Da(-1)) in Molecular weight of the PVC film than control (200,000 Da(-1)) by gel permeation chromatography. Furthermore more Fourier transform infrared spectroscopy and nuclear magnetic resonance also revealed structural changes in the PVC. It was concluded that isolated fungal strains have significant potential for biodegradation of PVC plastics. PMID- 23686797 TI - Impact of early intervention on children with autism spectrum disorders as measured by inclusion and retention in mainstream schools. AB - OBJECTIVES: To follow up the school/educational status of children with a primary diagnosis of Autism Spectrum Disorders (ASD), who had been enrolled in an Early Intervention (EI) program for 1-3 y, before the age of 6. METHODS: Data was collected through a questionnaire covering three specific areas-the families' success in following the recommendation given on completion of the EI program, issues in schooling and feedback on the EI program. The contact modes included email, post, telephonic interviews and face-to-face interviews. RESULTS: One hundred and two of the 296 children responded to the questionnaire. The responses were analyzed to identify, the number of families who had completed the program and were able to follow through with the recommendation given on completion of the EI program, difficulties faced if any, family feedback on the program and the additional help that they would have liked to receive. The reasons for failure to comply with the recommendations were analyzed. Of the 102 children who responded seven had dropped out midway through the program and 10 had discontinued after one year. Of the remaining 85 who completed the program, 71 were advised mainstreaming (83.5 %) and 14 were advised special school (16.5 %). Sixty-five of the 71 children, who were advised to enroll their child in the mainstream, were in regular school. 76.5 % of the children who completed the EI program were integrated in regular schools, 2 to 7 y after having completed the program. CONCLUSIONS: EI helps in enrolment and retention of substantial numbers of children with ASD in mainstream schools. PMID- 23686798 TI - McCarus Cosmetic HysterectomyTM - a patient-centric approach. AB - As patients are diagnosed with a health condition that requires a hysterectomy, surgical recommendations are generally discussed. Surgical options for a variety of procedures have expanded greatly in the past decade because of the development of innovations including, but not limited to, robots, advanced bipolar energy systems, HD cameras, single-site access systems, minilaparoscopic instruments, and novel uterine manipulators. These advances allow the surgeon to consider an expanded variety of procedures that may not only improve patient outcomes but also accommodate patient preferences. However, inherent bias directly related to the surgeon's specific view may influence decisions limiting hysterectomy options offered to patients. As general gynecological surgeons, we are not only empowered but also obligated to provide patients with expanded hysterectomy options that fit the indications and clinical needs of our patients. - Cosmetic minimally invasive surgery improved cosmesis compared with standard trocars. - Cosmetic minimally invasive surgery needs no skin or fascial closure. - McCarus Cosmetic HysterectomyTM affords benefits of minimally invasive surgery. - Cosmetic minimally invasive surgery represents the next evolution in minimally invasive surgery. - Cosmetic minimally invasive surgery allows expansion of hysterectomy options for benign disease. PMID- 23686799 TI - The use of PermacolTM mesh in contaminated complex abdominal wall defects. AB - The repair of complex abdominal wall defects in contaminated fields often presents a dilemma for general surgeons. Synthetic mesh, although strong, may lead to chronic infection or even visceral erosion. Leaving the abdomen open presents challenges for ward management and delays definitive care, as well as allowing the musculature to retract over time. Numerous biological mesh alternatives have arisen over the previous decade, which may make primary closure in this setting a practical alternative, although durability may prove the downside. Here we present our local experience with PermacolTM mesh (Porcine Acellular Dermal Matrix - PADM; Covidien, Mansfield, MA) in four challenging cases and discuss the role this relatively new mesh may have for these and other applications. PMID- 23686800 TI - Recurrent lumbar disc herniation treated with interspinous fusion and instrumentation: a case series. AB - OBJECTIVE: This case series assesses the pre- and postoperative disability outcomes and complications after repeat micro lumbar discectomy (MLD) combined with an interspinous process fusion in patients with recurrent lumbar disc herniation. METHODS: Four consecutive patients with recurrent lumbar disc herniation subsequent to their primary discectomy, who failed conservative nonoperative management, underwent repeat MLD and posterior instrumented fusion with an interspinous process plate. Before surgery and at follow-up, patients completed the Oswestry Disability Index (ODI). Demographic information, length of stay, estimated blood loss, and intraoperative and postoperative complications were recorded. RESULTS: The mean patient age was 45 years. Patients experienced minimal blood loss during surgery. There were no intraoperative or postoperative complications. Mean operating time was 136 minutes. Mean hospital stay was 1 day. Mean ODI score was reduced from 83.5 preoperatively to 37.0 postoperatively at a mean follow-up time of 12.9 months. As of last follow-up (mean 387 days), no patient has had symptomatic recurrence of herniation or evidence of subsequent instability. PMID- 23686801 TI - Modern dual-mobility cup implanted with an uncemented stem: about 100 cases with 12-year follow-up. AB - We report the results of a 12-year follow-up retrospective series of 100 total hip arthroplasties using cementless, press-fit, dual-mobility acetabular cups. The aim of our study was to evaluate the clinical and radiographic results of this acetabular cup at last follow-up. This continuous and homogeneous series included 100 primary total hip arthroplasties performed during the year 2000. The THA combined a Corail(r) stem (Corail(r), Depuy, Warsaw, IN) with a stainless steel Novae Sunfit(r) (Serf, Decines, France) acetabular cup. Fifteen patients died and 2 were lost to follow-up. Two cases of early dislocation were observed, and 3 cases of aseptic loosening of the acetabular component were reported. The mean stem subsidence was 0.71 mm, the mean craniopodal acetabular migration was 1.37 mm, and the mean medio-lateral acetabular migration was 1.52 mm. The 12-year survivorship is comparable to the data from the literature. The low dislocation rate at 12 years confirms the long-term, high stability of dual mobility, which should be recommended in primary THA for patients at risk for postoperative instability. The absence of true intraprosthetic dislocation events at 12-year follow-up provides evidence of the good quality of the latest generation of polyethylene liners and the necessity of combining thin-mirror, polished femoral necks with dual-mobility cups. PMID- 23686803 TI - Target expression of Staphylococcus enterotoxin A from an oncolytic adenovirus suppresses mouse bladder tumor growth and recruits CD3+ T cell. AB - We recently engineered an oncolytic adenovirus (PPE3-SEA) that expresses the superantigen, Staphylococcus enterotoxin A (SEA), and that has enhanced tumor specificity because the telomerase reverse transcriptase and hypoxia-inducible factor promoters regulate expression of E1A and E1B genes, respectively. Here, we evaluated the PPE3-SEA adenovirus anti-tumor activity against MB49 mouse bladder cancer cell proliferation in vitro and in vivo. PPE3-SEA infection of murine MB49 cells in vitro induced cytopathic effects, and significant expression of SEA mRNA and protein, as measured by RT-PCR and western blot, respectively. Subcutaneous MB29 bladder tumors were established in syngeneic C57BL/6 mice. After 10 days, tumors were injected with either oncolytic virus or PBS. Tumor dimensions were measured on days 1, 3, 5, 7, 9, and 11 post-treatment and tumor volumes were calculated. One of eight PPE3-SEA-treated mice had no tumor by day 9. PPE3-SEA treated group had significantly lower mean tumor volume beginning on day 5 post treatment (p < 0.01), more fibrous tissue in the tumor, and increased presence of infiltrating CD3+ T cells than those of the control group. Gross appearance and histologic sections from the livers and kidneys of the PPE3-SEA-treated group were similar to those of the control group. In conclusion, oncolytic adenoviruses can provide a novel delivery vehicle for SEA to tumor sites, and PPE3-SEA warrants further study as a potential anti-tumor agent for bladder cancer. PMID- 23686802 TI - Crosstalk between breast cancer stem cells and metastatic niche: emerging molecular metastasis pathway? AB - Metastatic colonization represents the final step of metastasis, and is the major cause of cancer mortality. Metastasis as an "inefficient" process requires the right population of tumor cells in a suitable microenvironment to form secondary tumors. Cancer stem cells are the only capable population of tumor cells to progress to overt metastasis. On the other hand, the occurrence of appropriate microenvironmental conditions within the target tissue would be critical for metastasis formation. Metastatic niche seems to be the specialized microenvironment to support tumor initiating cells at the distant organ. Master regulators not only determine cancer stem cell state, but also may have regulatory roles in metastatic niche elements. Meanwhile, both cancer stem cell and metastatic niche may function like two sides of the metastatic coin. Hypoxia inducible factors have multiple roles in regulation of both sides of this coin. TGF-beta superfamily, also, have been considered as master regulators of epithelial to mesenchymal transition and metastasis and may play crucial roles in regulation of metastatic niche as well. In this regard, we hypothesize the presence of a possible emerging molecular pathway in the biological process of breast cancer metastasis. In this process, non-Smad TGF-beta-induced metastasis connects cancer stem cell and metastatic niche formation through a central path, "Metastasis Pathway". PMID- 23686804 TI - Expression of PTEN and mTOR in pancreatic neuroendocrine tumors. AB - The purposes of this study were to clarify the expression patterns of phosphorylated mammalian target of rapamycin (p-mTOR), mTOR, and phosphatase and tensin homolog (PTEN) in primary pancreatic neuroendocrine tumors (pNETs) and their significance in predicting clinical behaviors and postoperative outcomes. The expressions of p-mTOR, mTOR, and PTEN were assessed in 20 normal pancreatic islets and in 90 resectable pNETs using immunohistochemistry. The associations of the biomarker expressions with clinicopathologic variables and survival duration were analyzed. The percentages of G1, G2, and G3 tumors were 54.4, 43.3, and 2.2 %, respectively. A strongly positive staining was observed for both mTOR and PTEN in normal pancreatic islets, whereas negative staining was observed for p-mTOR. In primary pNETs, the mTOR and p-mTOR positive rates were 70.8 % (63/89) and 44.4 % (40/90), respectively. p-mTOR expressions strongly correlate with mTOR expressions. No significant correlation between p-mTOR and clinicopathological features was found. The high expression rate of PTEN was 56.7 % (51/90), whereas the low expression rate was 43.4 % (39/90). PTEN loss (low expression) was significantly more frequent in patients with advanced WHO grades (p = 0.004) and in patients with higher Ki-67 index (p = 0.002). In our immunohistochemical classification system, the Ki-67 index was significantly higher in the PTEN low expression/p-mTOR-positive subgroup (2.7 +/- 2.5) than in the PTEN high expression/p-mTOR-negative subgroup (1.0 +/- 1.7, p = 0.006). Patients in the PTEN low expression/p-mTOR-positive subgroup presented a significantly lower 5 year overall survival (OS) than those in the PTEN high expression/p-mTOR-negative subgroup (p = 0.049; 5-year OS = 79 vs. 100 %, HR = 7.0). ENETS TNM staging and major vascular invasion were independently associated factors for predicting the overall survival rate of patients (p = 0.019 and 0.011, respectively). In conclusion, positive p-mTOR expression and PTEN loss may have a synergic effect on tumorigenesis and proliferation; targeted therapy based on mTOR/PTEN signal pathway and its associated molecular mechanism may play a role in the treatment of pancreatic neuroendocrine tumors. PMID- 23686805 TI - Expression of CK19 and KIT in resectable pancreatic neuroendocrine tumors. AB - The objectives of this study were to validate the immunohistochemical expression patterns of CK19 and KIT in primary pancreatic neuroendocrine tumors (pNETs) and to verify the potential biomarkers that can be used to predict the clinical behaviors and postoperative outcomes. The immunohistochemical expressions of CK19 and KIT were determined in normal pancreatic islets and resectable pNETs. Associations of the immunohistochemical features with the clinicopathologic features and prognosis were evaluated. All 20 samples from the normal control group were negative for both KIT and CK19 in normal pancreatic islets. Positive rates for KIT and CK19 in pNETs were 49.5 % (45/91) and 70.0 % (70/100), respectively. The percentages of G1, G2, and G3 tumors were 54.9, 42.9, and 2.2 %, respectively. Ki-67 index was significantly higher in the KIT-positive subgroup than in the KIT-negative subgroup (p < 0.05); however, no statistically significant difference of the Ki-67 index was found between the CK19-positive and the CK19-negative subgroups (p = 0.656). The positive CK19 expression was significantly associated with non-functioning tumors, regional lymph nodes metastases, and advanced tumor node metastasis (TNM) stage (p < 0.05). Meanwhile, the positive KIT expression was significantly associated with advanced TNM grade (p < 0.05). In univariate analysis, the overall survival in patients with positive CK19 expression was significantly lower than that in patients with CK19 negative expression (p < 0.05). Also, patients with negative KIT expression showed a tendency of longer survival duration compared with those with positive KIT expression (p = 0.188). The high-risk subgroup (2.1 +/- 2.9) might have a higher Ki-67 index than the low-risk subgroup (1.0 +/- 1.7, p = 0.208). There was a significant difference in functioning status among the three risk levels (p < 0.05). Pairwise comparison prompted that patients at high risk were more prone to have regional lymph nodes metastases, distant metastases, and/or recurrences. In conclusion, the expressions of CK19 and KIT are associated with aggressive clinical behaviors in patients with resectable pNETs. CK19 and KIT may play a role in tumor progression and metastases. PMID- 23686806 TI - Overexpression of CRKL correlates with malignant cell proliferation in breast cancer. AB - Crk-like (CRKL) is an adapter protein that has crucial roles in multiple biological processes, including cell proliferation, adhesion, and migration. However, the expression pattern of CRKL protein and its clinical significance in human breast cancers have not been well characterized. In this study, expression of CRKL was evaluated in 108 human invasive ductal carcinoma (IDC) tissues by immunohistochemistry. CRKL protein was upregulated in the cancer tissues compared with adjacent normal mammary glands. Overexpression of CRKL was found in 40 of 108 (37.03 %) breast cancer samples and correlated with advanced p-tumor-node metastasis stage (p = 0.002), nodal metastasis (p = 0.0323), and tumor size (p = 0.0075). In addition, overexpression of CRKL in the MDA-MB-435 cell line promoted cell proliferation, and small interfering RNA knockdown of CRKL in the MDA-MB-453 cell line inhibited proliferation. Further analysis of cell cycle-related molecules showed that CRKL induced cyclin D1 and phosphorylated extracellular signal-regulated kinase expression. In conclusion, this study demonstrated that overexpression of CRKL correlated with progression and malignant proliferation of human breast cancers. PMID- 23686807 TI - Circulating tumor cell detection during chemotherapy in patients with breast cancer is not associated with plasma homocysteine levels. AB - Breast cancer remains the second most frequent type of cancer in the world and the first among women, and systemic chemotherapy is an adjuvant therapeutic modality that improves survival in a great part of patients. Women with breast cancer, however, frequently show a higher risk of thromboembolism, an event associated to hyperhomocysteinemia and the presence of circulating tumor cells (CTC). Our aim is to correlate the presence of CTCs, detected by the analysis of CK19 and c-erbB2 gene expressions, and the homocysteine plasma levels in the peripheral blood in patients with breast cancer undergoing chemotherapy. Epithelial marker expression (CK19 and c-erbB2) and homocysteine levels were analyzed in a mononuclear fraction of the peripheral blood and plasma, respectively, obtained from 35 patients diagnosed with breast cancer at diagnosis and throughout chemotherapy treatment. No significant relation between the CK19 and c-erbB2 expressions and hyperhomocysteinemia was observed at any moment of the evaluation throughout the chemotherapy treatment (3 and 6 months after the onset). Among clinical data, only menopausal status showed a statistically significant correlation with homocysteine concentration. Although differences in the expressions of the analyzed epithelial markers were detected at 3 and 6 months of chemotherapy treatment, no relation between plasma homocysteine variations and the CK19 and c-erbB2 gene expressions was found in patients under chemotherapy treatment at any moment of the evaluation, suggesting that chemotherapy affects the expressions of the studied genes independently. PMID- 23686808 TI - Fabrication of regular ZnO/TiO2 heterojunctions with enhanced photocatalytic properties. AB - Facet-selective growth: Regular ZnO/TiO2 heterojunctions have been successfully synthesized using a facile hydrothermal technique (see figure). Due to the interfacial lattice matching, wurtzite ZnO can only grow on the eight {101} facets of the anatase TiO2 single crystals, while the other two {001} facets are untouched. The as-prepared regular ZnO/TiO2 heterojunctions exhibited enhanced photocatalytic generation of (.)OH radicals and enhanced photodegradation of methyl orange when irradiated with UV light. PMID- 23686810 TI - Automated analysis of diabetic retinopathy images: principles, recent developments, and emerging trends. AB - Diabetic retinopathy (DR) is a vision-threatening complication of diabetes. Timely diagnosis and intervention are essential for treatment that reduces the risk of vision loss. A good color retinal (fundus) photograph can be used as a surrogate for face-to-face evaluation of DR. The use of computers to assist or fully automate DR evaluation from retinal images has been studied for many years. Early work showed promising results for algorithms in detecting and classifying DR pathology. Newer techniques include those that adapt machine learning technology to DR image analysis. Challenges remain, however, that must be overcome before fully automatic DR detection and analysis systems become practical clinical tools. PMID- 23686813 TI - Adipose tissue-derived stem cells as a regenerative therapy for a mouse steatohepatitis-induced cirrhosis model. AB - Cirrhosis is a chronic liver disease that impairs hepatic function and causes advanced fibrosis. Mesenchymal stem cells have gained recent popularity as a regenerative therapy since they possess immunomodulatory functions. We found that injected adipose tissue-derived stem cells (ADSCs) reside in the liver. Injection of ADSCs also restores albumin expression in hepatic parenchymal cells and ameliorates fibrosis in a nonalcoholic steatohepatitis model of cirrhosis in mice. Gene expression analysis of the liver identifies up- and down-regulation of genes, indicating regeneration/repair and anti-inflammatory processes following ADSC injection. ADSC treatment also decreases the number of intrahepatic infiltrating CD11b(+) and Gr-1(+) cells and reduces the ratio of CD8(+) /CD4(+) cells in hepatic inflammatory cells. This is consistent with down-regulation of genes in hepatic inflammatory cells related to antigen presentation and helper T cell activation. CONCLUSION: These results suggest that ADSC therapy is beneficial in cirrhosis, as it can repair and restore the function of the impaired liver. PMID- 23686809 TI - Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. AB - OBJECTIVE: To see whether the distribution patterns of phosphorylated 43kDa TAR DNA-binding protein (pTDP-43) intraneuronal inclusions in amyotrophic lateral sclerosis (ALS) permit recognition of neuropathological stages. METHODS: pTDP-43 immunohistochemistry was performed on 70 MUm sections from ALS autopsy cases (N = 76) classified by clinical phenotype and genetic background. RESULTS: ALS cases with the lowest burden of pTDP-43 pathology were characterized by lesions in the agranular motor cortex, brainstem motor nuclei of cranial nerves V, VII, and X XII, and spinal cord alpha-motoneurons (stage 1). Increasing burdens of pathology showed involvement of the prefrontal neocortex (middle frontal gyrus), brainstem reticular formation, precerebellar nuclei, and the red nucleus (stage 2). In stage 3, pTDP-43 pathology involved the prefrontal (gyrus rectus and orbital gyri) and then postcentral neocortex and striatum. Cases with the greatest burden of pTDP-43 lesions showed pTDP-43 inclusions in anteromedial portions of the temporal lobe, including the hippocampus (stage 4). At all stages, these lesions were accompanied by pTDP-43 oligodendroglial aggregates. Ten cases with C9orf72 repeat expansion displayed the same sequential spreading pattern as nonexpansion cases but a greater regional burden of lesions, indicating a more fulminant dissemination of pTDP-43 pathology. INTERPRETATION: pTDP-43 pathology in ALS possibly disseminates in a sequential pattern that permits recognition of 4 neuropathological stages consistent with the hypothesis that pTDP-43 pathology is propagated along axonal pathways. Moreover, the finding that pTDP-43 pathology develops in the prefrontal cortex as part of an ongoing disease process could account for the development of executive cognitive deficits in ALS. PMID- 23686812 TI - Enantioselective construction of alpha-quaternary cyclobutanones by catalytic asymmetric allylic alkylation. PMID- 23686814 TI - Ephrin-As, Eph receptors and integrin alpha3 interact and colocalise at membrane protrusions of U251MG glioblastoma cells. AB - Glioblastoma is the most common brain cancer. Ephrins and their Eph receptors play important roles in the development of central nervous system and the regulation of cancer cell migration and invasion. In a search for the Eph receptor complexes, we used tandem affinity purification based interaction screening with tagged ephrins A1, A3 and A4 combined with protein identification by mass-spectrometry in U251MG glioblastoma cells. Ephrins bound to Eph receptors, mainly to EphA2 in these cells. Integrin alpha3 was identified in protein complexes with ephrin-As. Soluble ephrin-A1 colocalised with integrin alpha3 at the cell surface, and was rapidly endocytosed by the cells. However, integrin alpha3 did not colocalise with internalised ephrin-A1, whereas EphA2 receptor did. In U251MG cells, integrin alpha3 colocalised with EphA2 receptor at the cell edges and protrusions. Sites of EphA2-integrin alpha3 colocalisation were positive for vinculin, focal adhesion kinase and phosphotyrosine, that is, markers for cell adhesion and active signalling. The interaction between ephrin As, Eph receptors and integrin alpha3 is plausibly important for the crosstalk between Eph and integrin signalling pathways at the membrane protrusions and in the migration of brain cancer cells. PMID- 23686815 TI - Long-term results of endoscopic sinus surgery-oriented treatment for chronic rhinosinusitis with asthma. AB - OBJECTIVES/HYPOTHESIS: The aims of this study were to evaluate the efficacy of functional endoscopic sinus surgery (FESS)-oriented multimodality treatment in chronic rhinosinusitis (CRS) patients with asthma and its impact on asthma. STUDY DESIGN: Prospective, nonrandomized cohort. METHODS: Twenty-seven CRS patients with asthma who underwent FESS with postoperative topical corticosteroid spray were evaluated preoperatively; 25 of them were evaluated 1 year and 3 years postoperatively. CRS was evaluated by visual analogue scale, clinical control of CRS, and objective measurement endoscopy Lund-Kennedy scores. Asthma was assessed by subjective asthma control test and asthma control level, also by objective antiasthma medication use and pulmonary function tests. RESULTS: VAS scores of general symptoms (8.09 +/- 0.87 preoperatively) were significantly improved at 1 year (2.94 +/- 2.21) and 3 years (3.77 +/- 2.16) postoperation (P = .000). No difference in these items was found between 1 year and 3 years (P = .463). Endoscopy Lund-Kennedy scores at 1 year (4.34 +/- 3.09) and 3 years (5.80 +/- 3.38) postoperatively were significantly better (9.33 +/- 2.03 preoperatively, P = .000), and there was no difference between 1 year and 3 years of follow-up (P > .05). Significantly, asthma control level improved postoperatively (P = .025). However, antiasthma drug and pulmonary function showed no significant change postoperatively (P > .05). CONCLUSIONS: FESS-oriented multimodality treatment improves CRS with asthma significantly and persistently. Asthma control level improved. Antiasthma medication use and pulmonary function remained stable. PMID- 23686816 TI - Public science of the savage mind: contesting cultural anthropology in the Cold War classroom. AB - "What is human about human beings? How did they get that way? How can they be made more so?" These three questions formed the basis of a fifth-grade social studies curriculum project developed in the 1960s called Man: A Course of Study, or MACOS. In the years between the curriculum's development in the 1960s and its controversial implementation in the 1970s, two separate sets of concerns served to problematize the use of anthropological materials in public school classrooms. On the one hand, MACOS designers were wary of the possibly racist interpretations of exploring so-called "primitive" cultures in the classroom. On the other, conservative textbook reformers objected to claims that all cultural solutions to biological problems were morally equivalent. Once MACOS earned a place in national news, it came to embody both hopes for the redemption of American democratic society and fears about the violent nature of humans, depending on one's political perspective. These mixed messages eventually undermined the long term success of the program as public science. PMID- 23686817 TI - Deletions of 16p11.2 and 19p13.2 in a family with intellectual disability and generalized epilepsy. AB - Rare copy number variants (CNVs) have been established as an important cause of various neurodevelopmental disorders, including intellectual disability (ID) and epilepsy. In some cases, a second CNV may contribute to a more severe clinical presentation. Here we present two siblings and their mother who have mild ID, short stature, obesity and seizures. Array CGH studies show that each affected individual has two large, rare CNVs. The first is a deletion of chromosome 16p11.2, which has been previously associated with ID and autism. The second is a 0.9 Mb deletion of 19p13.2, which results in the deletion of a cluster of zinc finger genes. We suggest that, while the 16p11.2 deletion is likely the primary cause of the obesity and ID in this family, the 19p13.2 deletion may act as a modifier of the epilepsy phenotype, which is not a core feature of the 16p11.2 deletion syndrome. We investigate the potential role of ZNF44, a gene within the deleted region, in a cohort of patients with generalized epilepsy. PMID- 23686818 TI - Dendritic development of hippocampal CA1 pyramidal cells in a neonatal hypoxia ischemia injury model. AB - It is believed that neonatal hypoxia-ischemia (HI) brain injury causes neuron loss and brain functional defects. However, the effect of HI brain injury on dendritic development of the remaining pyramidal cells of the hippocampus and the reaction of contralateral hippocampal neurons require further studies. The Morris water maze and Golgi-Cox staining were used to evaluate the learning and memory and dendritic morphology of pyramidal cells. The results of Golgi-Cox staining showed CA1 pyramidal neurons of HI injury models with fewer bifurcations and shorter dendrite length than the naive control group. The density of dendritic spines of hippocampal CA1 pyramidal neurons was significantly lower in the HI brain injury group than in controls. With respect to hippocampal function, the HI brain injury group presented cognitive deficits in the reference memory task and probe trail. In the HI group, the pyramidal cells of left hippocampus that did not experienced ischemia but did experience hypoxia had more complex dendrites and higher density of spine than the HI injury side and control. The functional implementation of injured hippocampus might depend mainly on the hypertrophy of contralateral hippocampus after HI brain injury. Corticosterone can partially prevent the hippocampal pyramidal cells from HI injury and reduce the difference of the bilateral hippocampus pyramidal cells, but there was no improvement in learning and memory. PMID- 23686819 TI - Manure fertilization alters the population of ammonia-oxidizing bacteria rather than ammonia-oxidizing archaea in a paddy soil. AB - Manure fertilizers are widely used in agriculture and highly impacted the soil microbial communities such as ammonia oxidizers. However, the knowledge on the communities of archaeal versus bacterial ammonia oxidizers in paddy soil affected by manure fertilization remains largely unknown, especially for a long-term influence. In present work, the impact of manure fertilization on the population of ammonia oxidizers, related potential nitrification rates (PNRs) and the key factors manipulating the impact were investigated through studying two composite soil cores (long-term fed with manure fertilization versus undisturbed). Moreover, soil incubated with NH(4)(+) for 5 weeks was designed to verify the field research. The results showed that the copy numbers of bacterial amoA gene in the manure fed soil were significant higher than those in the unfed soil (p < 0.05), suggesting a clear stimulating effect of long-term manure fertilization on the population of ammonia-oxidizing bacteria (AOB). The detected PNRs in the manure fed soil core (14-218 nmol L(-1) N g(-1) h(-1)) were significant higher than those in the unfed soil core (5-72 nmol L(-1) N g(-1) h(-1) ; p < 0.05). Highly correlations between the PNRs and the bacterial amoA gene copies rather than archaeal amoA gene were observed, indicating strong nitrification capacity related to bacterial ammonia oxidizers. The NH(4)(+) -N significantly correlated to the abundance of AOB (p < 0.01) and explained 96.1% of the environmental variation, showing the NH(4)(+) -N was the main factor impacting the population of AOB. The incubation experiment demonstrated a clear increase of the bacterial amoA gene abundance (2.0 * 10(6) to 8.4 * 10(6) g(-1) d.w.s. and 1.6 * 10(4) to 4.8 * 10(5) g(-1) d.w.s.) in both soil but not for the archaeal amoA gene, in agreement with the field observation. Overall, our results suggested that manure fertilization promoted the population size of bacterial ammonia oxidizers rather than their archaeal counterparts whether in long-term or short-term usage and the NH(4)(+) -N was the key impact factor. PMID- 23686820 TI - Finite element analysis and cellular studies on advanced, controlled porous structures with subsurface continuity in bio-implantable titanium alloys. AB - Highly-porous metallic implant onlay materials (specifically those containing surface pores that intersect beneath the onlay surface) have been investigated recently for their potential to reduce bone resorption and to improve the overall stability of the implant. In the current study, sub-surface interconnectivity of high-aspect-ratio pores was created directly in the substrate of an implant material using wire electrical discharge machining (EDM). This technique was used to produce intersecting pores with diameters of 180-250 MUm on a clinically relevant implant material-commercially pure (CP) Grade 4 Ti-with a very high degree of control over pore morphology. These pores resulted in no significant microstructural modification to the surrounding Ti, and the inner pore surfaces could be thermally oxidized to produce a microrough, bioactive TiO2 layer. Finite element analysis of Ti models containing these EDM-attainable intersecting pore geometries suggested they produce higher bone/implant interface strengths and lower susceptibility to stress shielding of the surrounding bone as compared with models containing simpler surface geometries. In vitro experiments using mesenchymal stem cells (MSCs) demonstrated mineralized tissue ingrowth of ~ 300 MUm into EDM-produced pores. This amount of ingrowth is expected to allow for full interlocking of mineralized tissue and implant given the proper pore structure design. PMID- 23686821 TI - Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. AB - OBJECTIVE: To assess the efficacy and safety of glatiramer acetate (GA) 40mg administered 3* weekly (tiw) compared with placebo in patients with relapsing remitting multiple sclerosis (RRMS). METHODS: This randomized, double-blind study was conducted in 142 sites in 17 countries. Patients with RRMS with at least 1 documented relapse in the 12 months before screening, or at least 2 documented relapses in the 24 months before screening, and an Expanded Disability Status Scale score <= 5.5, were randomized 2:1 to receive either subcutaneous (sc) GA 40mg tiw (1ml) or placebo for 12 months. RESULTS: Of 1,524 patients screened, 1,404 were randomized to receive GA 40mg sc tiw (n = 943) or placebo (n = 461). Ninety-three percent and 91% of patients in the placebo and GA groups, respectively, completed the 12-month study. GA 40mg tiw was associated with a 34.0% reduction in risk of confirmed relapses compared with placebo (mean annualized relapse rate = 0.331 vs 0.505; p < 0.0001). Patients who received GA 40mg tiw experienced highly significant reduction (p < 0.0001) in the cumulative number of gadolinium-enhancing T1 (44.8%) and new or newly enlarging T2 lesions (34.7%) at months 6 and 12. GA 40mg tiw was safe and well tolerated. The most common adverse events in the GA group were injection site reactions (35.5% with GA vs 5.0% with placebo). INTERPRETATION: GA 40mg sc tiw is a safe and effective regimen for the treatment of RRMS, providing the convenience of fewer sc injections per week. PMID- 23686822 TI - 1H, 13C, 15N backbone and side chain NMR resonance assignments of the N-terminal NEAr iron transporter domain 1 (NEAT 1) of the hemoglobin receptor IsdB of Staphylococcus aureus. AB - Staphylococcus aureus is an opportunistic pathogen that causes skin and severe infections in mammals. Critical to S. aureus growth is its ability to scavenge iron from host cells. To this effect, S. aureus has evolved a sophisticated pathway to acquire heme from hemoglobin (Hb) as a preferred iron source. The pathway is comprised of nine iron-regulated surface determinant (Isd) proteins involved in heme capture, transport, and degradation. A key protein of the heme acquisition pathway is the surface-anchored hemoglobin receptor protein IsdB, which is comprised of two NEAr transporter (NEAT) domains that act in concert to bind Hb and extract heme for subsequent transfer to downstream acquisition pathway proteins. Despite significant advances in the structural knowledge of other Isd proteins, the structural mechanisms and molecular basis of the IsdB mediated heme acquisition process are not well understood. In order to provide more insights into the mode of function of IsdB, we have initiated NMR structural studies of the first NEAT domain of IsdB (IsdB(N1)). Herein, we report the near complete (1)H, (13)C and (15)N resonance assignments of backbone and side chain atoms, and the secondary structural topology of the 148-residue IsdB NEAT 1 domain. The NMR results are consistent with the presence of eight beta-strands and one alpha-helix characteristic of an immunoglobulin-like fold observed in other NEAT domain family proteins. This work provides a solid framework to obtain atomic-level insights toward understanding how IsdB mediates IsdB-Hb protein protein interactions critical for heme capture and transfer. PMID- 23686823 TI - Antisense oligonucleotides: treating neurodegeneration at the level of RNA. AB - Adequate therapies are lacking for Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and other neurodegenerative diseases. The ability to use antisense oligonucleotides (ASOs) to target disease associated genes by means of RNA may offer a potent approach for the treatment of these, and other, neurodegenerative disorders. In modifying the basic backbone chemistry, chemical groups, and target sequence, ASOs can act through numerous mechanisms to decrease or increase total protein levels, preferentially shift splicing patterns, and inhibit microRNAs, all at the level of the RNA molecule. Here, we discuss many of the more commonly used ASO chemistries, as well as the different mechanisms of action that can result from these specific chemical modifications. When applied to multiple neurodegenerative mouse models, ASOs that specifically target the detrimental transgenes have been shown to rescue disease associated phenotypes in vivo. These supporting mouse model data have moved the ASOs from the bench to the clinic, with two neuro-focused human clinical trials now underway and several more being proposed. Although still early in development, translating ASOs into human patients for neurodegeneration appears promising. PMID- 23686824 TI - Aldosterone mediates cardiac fibrosis in the setting of hypertension. AB - Cardiac remodeling is a deleterious consequence of arterial hypertension. This remodeling results from cardiac transcriptomic changes induced by mechanical and hormonal factors. Angiotensin II and aldosterone often collaborate in pathological situations to induce hypertrophy of cardiomyocytes, vascular inflammation, perivascular and interstitial fibrosis, and microvascular rarefaction. Experimental models of transgenic mice overexpressing renin in liver, leading to increased plasma angiotensin II and severe hypertension, and mice overexpressing aldosterone-synthase in cardiomyocytes, leading to a doubling of intracardiac aldosterone concentration have shown that cardiac fibrosis in the heart depends on a balance between pro-fibrotic (TGF-beta, galectin-3) and anti fibrotic (BNP, ANP) factors. Recent studies using cell-specific deletion of the mineralocorticoid receptor indicate that its activation in macrophages is a key step in the development of cardiac fibrosis in the setting of hemodynamic or hormonal challenges. This review focuses on the impact of inappropriate stimulation of aldosterone in the development of cardiac fibrosis. PMID- 23686825 TI - Gene transfer to the CNS using recombinant adeno-associated virus. AB - Recombinant adeno-associated virus (rAAV) vectors are great tools for gene transfer due to their ability to mediate long-term gene expression. rAAVs have been used successfully as gene transfer vehicles in multiple animal models of CNS disorders, and several clinical trials are currently underway. rAAV vectors have been used at various stages of development with no apparent toxicity. There are multiple ways of delivering AAV vectors to the mouse CNS, depending on the stage of development. In neonates, intravascular injections into the facial vein are often used. In adults, direct injections into target regions of the brain are achieved with great spatiotemporal control through stereotaxic surgeries. Recently, discoveries of new AAV vectors with the ability to cross the blood brain barrier have made it possible to target the adult CNS by intravascular injections. PMID- 23686826 TI - Gene transfer in the liver using recombinant adeno-associated virus. AB - Liver-directed gene transfer and gene therapy are rapidly gaining attention primarily because the liver is centrally involved in a variety of metabolic functions that are affected in various inherited disorders. Recombinant adeno associated virus (rAAV) is a popular gene delivery vehicle for gene therapy, and intravenous delivery of some rAAV serotypes results in very efficient transduction in the liver. rAAV-mediated gene transfer to the liver can be used to create somatic transgenic animals or disease models for studying the function of various genes and miRNAs. The liver is the target tissue for gene therapy of many inborn metabolic diseases and may also be exploited as a "biofactory" for production of coagulation factors, insulin, growth hormones, and other non hepatic proteins. Hence, efficient delivery of transgenes and small RNAs to the liver by rAAV vectors has been of long-standing interest to research scientists and clinicians alike. This unit describes methods for delivery of rAAV vectors by several injection routes, followed by a range of analytical methods for assessing the expression, activity, and effects of the transgene and its product. PMID- 23686827 TI - Influenza: propagation, quantification, and storage. AB - Influenza viruses are negative-sense, single-stranded, enveloped RNA viruses belonging to the family Orthomyxoviridae. Three types exist, influenza A, B, and C. All infect humans, but only A and B are major human pathogens. Influenza type A viruses are divided into subtypes based on genetic and antigenic differences in the two surface spike proteins, hemagglutinin (HA) and neuraminidase (NA). The appropriate cell lines to be used for isolation of influenza A or B viruses depend on the clinical information and the host of origin. MDCK cells are the preferred cell line for isolation of human influenza viruses from clinical specimens. PMID- 23686828 TI - Insertion of a GFP reporter gene in influenza virus. AB - The incorporation of a fluorescent reporter gene into a replication-competent influenza A virus (IAV) has made it possible to trace IAV infection in vivo. This protocol describes the process of inserting a green fluorescent protein (GFP) reporter into the IAV genome using the established reverse genetics system. The strategy begins with the reorganization of segment eight of the IAV genome, during which the open reading frames of nonstructural protein 1 (NS1) and the nuclear export protein (NEP) are separated to allow for GFP fusion to the NS1 protein. The NS1, GFP, and NEP open reading frames (ORF) are then cloned into the IAV rescue system backbone. Upon construction of the GFP-encoding segment eight rescue plasmid, recombinant NS1-GFP influenza virus can be rescued via co transfection with the remaining seven rescue plasmids. The generated NS1-GFP IAV can subsequently be used to visualize infected cells, both in vitro and in vivo. PMID- 23686829 TI - Poliovirus: generation and characterization of mutants. AB - Poliovirus (PV) is the prototypical picornavirus. It is a non-enveloped RNA virus with a small (~7.5-kb) genome of positive polarity. cDNA clones of several strains are available, and infectious virus can be produced by the transfection of in vitro-transcribed viral genomes into an appropriate host cell. The ease of genetic studies in poliovirus is a primary reason that it has long served as a model to study RNA virus biology, pathogenesis, and evolution. Protocols for the generation and characterization of PV mutants are presented. PMID- 23686830 TI - Poliovirus: generation, quantification, propagation, purification, and storage. AB - Poliovirus (PV) is the prototypical picornavirus. It is a non-enveloped RNA virus with a small (~7.5-kb) genome of positive polarity. It has long served as a model to study RNA virus biology, pathogenesis, and evolution. cDNA clones of several strains are available, and infectious virus can be produced by the transfection of in vitro transcribed viral genomes into an appropriate host cell. PV infects many human and non-human primate cell lines including HeLa and HeLa S3 cells, and can grow to high titer in culture. Protocols for the production, propagation, quantification, and purification of PV are presented. PMID- 23686831 TI - Susceptibility of species within the Sporothrix schenckii complex to a panel of killer yeasts. AB - The Sporothrix schenckii complex is the etiologic agent of sporotrichosis, a subacute or chronic mycosis which can affect humans and animals. Killer yeasts have been used in the medical field for development of novel antimycotics and biotyping of pathogenic fungi. The action of 18 killer yeasts on the growth of 88 characterized S. schenckii, Sporothrix globosa, Sporothrix brasiliensis, and Sporothrix mexicana clinical and environmental isolates was evaluated. Killer studies were performed on Petri dishes containing cheese black starch agar. The yeasts Candida catenulata (QU26, QU31, QU127, LV102); Trichosporon faecale (QU100); Trichosporon japonicum (QU139); Kluyveromyces lactis (QU30, QU99, QU73); Kazachstania unispora (QU49), Trichosporon insectorum (QU89), and Kluyveromyces marxianus (QU103) showed activity against all strains of the S. schenckii complex tested. Observation by optical microscopy of S. brasiliensis 61 within the inhibition haloes around the colonies of the killer yeasts QU100, QU139, and LV102 showed that there was no conidiation, but there was hyphal proliferation. The toxins were fungistatic against S. brasiliensis 61. There was no difference in susceptibility to the toxins among the S. schenckii species complex. Further investigations are necessary to clearly establish the mechanism of action of the toxins. PMID- 23686832 TI - A supramolecular peptide synthesizer. PMID- 23686833 TI - TaMe3Cl2-catalyzed intermolecular hydroaminoalkylation: a simple complex for enhanced reactivity and expanded substrate scope. PMID- 23686834 TI - International Forum of Allergy & Rhinology. Editorial. PMID- 23686835 TI - Polo-like kinase inhibitor Ro5203280 has potent antitumor activity in nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma is a cancer with its highest prevalence among the southern Chinese and is rare elsewhere in the world. The main treatment modalities include chemotherapy and radiotherapy. However, tumor chemoresistance often limits the efficacy of nasopharyngeal carcinoma treatment and reduces survival rates. Thus, identifying new selective chemotherapeutic drugs for nasopharyngeal carcinoma treatment is needed. In this current study, the antitumor efficacy of a polo-like kinase inhibitor, Ro5203280, was investigated. Ro5203280 induces tumor suppression both in vitro and in vivo. An inhibitory effect was observed with the highly proliferating cancer cell lines tested, but not with the nontumorigenic cell line. Real-time cell proliferation and fluorescence-activated cell sorting (FACS) analysis, together with immunohistochemical (IHC), immunofluorescence, and Annexin V staining assays, were used to evaluate the impact of drug treatment on cell cycle and apoptosis. Ro5203280 induces G2-M cell-cycle arrest and apoptosis. Western blotting shows it inhibits PLK1 phosphorylation and downregulates the downstream signaling molecule, Cdc25c, and upregulates two important mitosis regulators, Wee1 and Securin, as well as the DNA damage-related factor Chk2 in vitro and in vivo. In vivo tumorigenicity assays with Ro5203280 intravenous injection showed its potent ability to inhibit tumor growth in mice, with no observable signs of toxicity. These findings suggest the potential usefulness of Ro5203280 as a chemotherapeutic targeting drug for nasopharyngeal carcinoma treatment. PMID- 23686836 TI - CXCR4-targeted therapy inhibits VEGF expression and chondrosarcoma angiogenesis and metastasis. AB - Chondrosarcoma is notable for its lack of response to conventional cytotoxic chemotherapy, propensity for developing lung metastases, and poor survival. Therefore, a better understanding of angiogenic and metastatic pathways is needed. Multiple pathways regulate angiogenesis and metastasis, including chemokines and their receptors. In this study, we investigated chemokine (C-X-C motif) receptor 4 (CXCR4) signaling in chondrosarcoma and tested the hypotheses that CXCR4 inhibition suppresses tumor angiogenesis and metastasis. CXCR4 expression, analyzed by real-time PCR and Western blot, was increased in human chondrosarcoma cell line JJ compared with normal chondrocytes and was further increased in JJ by hypoxia (2% O2), vascular endothelial growth factor A (VEGFA; 10 ng/mL), and in xenograft tumors in nude mice. The CXCR4 ligand CXCL12 (10 ng/mL) doubled secreted VEGFA, measured with ELISA, under hypoxic conditions and this conditioned media increased human umbilical vein endothelial cell tube formation. These effects were inhibited by CXCR4 siRNA or AMD3100 (5 MUg/mL). In a xenograft mouse model, four weeks of AMD3100 treatment (1.25 mg/kg, intraperitoneally twice daily) inhibited tumor angiogenesis, tumor growth, and metastasis. VEGFA content in tumor extracts was decreased (7.19 +/- 0.52 ng/mL control vs. 3.96 +/- 0.66 treatment) and bioimaging of angiogenesis was decreased by 56%. Tumor volumes averaged 4.44 +/- 0.68 cm(3) in control compared with 2.48 +/- 0.61 cm(3) in the treatment group. The number of lung metastatic nodules was 23 +/- 9 in control compared with 10 +/- 6 in the treatment group (N = 8/group). Therefore, CXCR4-targeted therapy may be a treatment strategy for chondrosarcoma. PMID- 23686837 TI - Src mediates cigarette smoke-induced resistance to tyrosine kinase inhibitors in NSCLC cells. AB - The EGF receptor (EGFR) is a proto-oncogene commonly dysregulated in several cancers including non-small cell lung carcinoma (NSCLC) and, thus, is targeted for treatment using tyrosine kinase inhibitors (TKI) such as erlotinib. However, despite the efficacy observed in patients with NSCLC harboring oncogenic variants of the EGFR, general ineffectiveness of TKIs in patients with NSCLC who are current and former smokers necessitates identification of novel mechanisms to overcome this phenomenon. Previously, we showed that NSCLC cells harboring either wild-type (WT) EGFR or oncogenic mutant (MT) L858R EGFR become resistant to the effects of TKIs when exposed to cigarette smoke, evidenced by their autophosphorylation and prolonged downstream signaling. Here, we present Src as a target mediating cigarette smoke-induced resistance to TKIs in both WT EGFR- and L858R MT EGFR-expressing NSCLC cells. First, we show that cigarette smoke exposure of A549 cells leads to time-dependent activation of Src, which then abnormally binds to the WT EGFR causing TKI resistance, contrasting previous observations of constitutive binding between inactive Src and TKI-sensitive L858R MT EGFR. Next, we show that Src inhibition restores TKI sensitivity in cigarette smoke-exposed NSCLC cells, preventing EGFR autophosphorylation in the presence of erlotinib. Furthermore, we show that overexpression of a dominant-negative Src (Y527F/K295R) restores TKI sensitivity to A549 exposed to cigarette smoke. Importantly, the TKI resistance that emerges even in cigarette smoke-exposed L858R EGFR-expressing NSCLC cells could be eliminated with Src inhibition. Together, these findings offer new rationale for using Src inhibitors for treating TKI-resistant NSCLC commonly observed in smokers. PMID- 23686839 TI - Recurrence of urorectal septum malformation sequence spectrum anomalies in siblings: time to explore the genetics. AB - Urorectal septum malformation sequence (URSM) is a pattern of malformation which encompasses abnormalities of the perineal orifices, external genitalia, genitourinary system, and anorectum. The spectrum ranges from a complete form with absence of perineal openings and persistent cloaca to milder/partial forms usually with one perineal opening and internal abnormalities of anorectum, urethra, and Mullerian structures. URSM is felt to arise due to abnormalities of the caudal mesoderm, which constitutes the urorectal septum. Here, we report two male siblings, affected with a spectrum of anomalies simulating URSM. This is the first report of recurrence of URSM in sibs. It suggests the existence of hitherto unknown genetic mechanisms for this pattern of malformation. PMID- 23686840 TI - Effect of astaxanthin on vocal fold wound healing. AB - OBJECTIVES/HYPOTHESIS: Our previous study demonstrated that a large amount of reactive oxygen species (ROS) is produced during the early phase of vocal fold wound healing. In the current study, we investigated the effect of astaxanthin, which is a strong antioxidant, on the regulation of oxidative stress and scarring during vocal fold wound healing. STUDY DESIGN: Prospective animal experiment with control. METHODS: Sprague-Dawley rats were dosed with astaxanthin (Ast-treated group, 100 mg/kg/day) or olive oil (sham-treated group) by oral gavage daily from preinjury day 1 to postinjury day 4. After vocal folds were injured under the endoscope, larynges were harvested for histological and immunohistochemical examinations on postinjury days 1, 3, 5, and 56, and quantitative real time polymerase chain reaction (PCR) on postinjury days 1 and 3. RESULTS: The expression of 4-hydroxy-2-nonenal, which is an oxidative stress marker, was reduced significantly in the lamina propria of the Ast-treated group as compared to the sham-treated group. Histological examination showed significantly less tissue contraction with favorable deposition of hyaluronic acid in the lamina propria of the Ast-treated group compared to the sham-treated group. Real time PCR revealed significantly upregulated mRNA expression of basic fibroblast growth factor on postinjury day 1 and procollagen type I in the Ast-treated group compared to the sham-treated group. CONCLUSIONS: These findings suggest that astaxanthin has the potential to prevent vocal fold scarring by regulating oxidative stress during the early phase of vocal fold wound healing. PMID- 23686838 TI - Invariant NKT cell activation induces neutrophil accumulation and hepatitis: opposite regulation by IL-4 and IFN-gamma. AB - Alpha-Galactosylceramide (alpha-Galcer), a specific agonist for invariant natural killer T (iNKT) cells, is being evaluated in clinical trials for the treatment of viral hepatitis and liver cancer. However, the results from alpha-Galcer treatment are mixed, partially because of the variety of cytokines produced by activated iNKT cells that have an unknown synergistic effect on the progression of liver disease. It is well documented that injection of alpha-Galcer induces mild hepatitis with a rapid elevation in the levels of interleukin (IL)-4 and a delayed elevation in the levels of interferon-gamma (IFN-gamma), and both of these cytokines are thought to mediate many functions of iNKT cells. Surprisingly, genetic deletion of both IL-4 and IFN-gamma aggravated, rather than abolished, alpha-Galcer-induced iNKT hepatitis. Moreover, genetic ablation of IL 4, the IL-4 receptor, or its downstream signaling molecule signal transducer and activator of transcription (STAT)6 ameliorated alpha-Galcer-induced neutrophil infiltration, liver injury, and hepatitis. In contrast, genetic deletion of IFN gamma, the IFN-gamma receptor, or its downstream signaling molecule STAT1 enhanced liver neutrophil accumulation, thereby exacerbating liver injury and hepatitis. Moreover, depletion of neutrophils eradicated alpha-Galcer-induced liver injury in wild-type, STAT1 knockout, and IFN-gamma knockout mice. CONCLUSION: Our results propose a model in which activated iNKT cells rapidly release IL-4, which promotes neutrophil survival and hepatitis but also sequentially produce IFN-gamma, which acts in a negative feedback loop to ameliorate iNKT hepatitis by inducing neutrophil apoptosis. Thus, modification of iNKT production of IL-4 and IFN-gamma may have the potential to improve the efficacy of alpha-Galcer in the treatment of liver disease. PMID- 23686842 TI - Microbial community in packed bed bioreactor involved in nitrate remediation from low level radioactive waste. AB - Nitrate is the second largest contaminant of agriculture soil after pesticides. It also is a major pollutant from nuclear and metallurgical operations. Conventional methods for nitrate removal suffers from high cost and complexity leaving bioremediation as a viable alternative strategy. A pilot plant of 2.5 m(3)/day capacity has been functioning since 2005 based on microbial consortia treating actual effluent from nuclear power plant having pH of 7-8.5 (optimum) with N:C ratio of 1:1.7. The maximum biodegradable nitrate concentration of 3000 ppm could be reduced to below permissible limit (44.2 ppm) within 24 h in presence of sodium acetate as carbon source. Culture independent analysis (16S rDNA based) revealed clones having closest identity with uncultured bacterium, Pseudomonas stutzeri and Azoarcus sp. The existence of dissimilatory pathway of nitrate reduction in the community DNA is indicated by presence of nirS and nirK gene. Though the microbial mass was developed using municipal sewage, absence of Mycobacterium sp was confirmed using PCR. The understanding of the molecular identification of the consortium would help in developing the preservation strategy of the microbial mass for replication and perpetuation of the system. PMID- 23686841 TI - Validation of midbrain positron emission tomography measures for nigrostriatal neurons in macaques. AB - OBJECTIVE: Development of an effective therapy to slow the inexorable progression of Parkinson disease requires a reliable, objective measurement of disease severity. In the present study, we compare presynaptic positron emission tomography (PET) tracer uptake in the substantia nigra (SN) to cell loss and motor impairment in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primates. METHODS: Presynaptic PET tracers 6-[(18)F]-fluorodopa (FD), [(11)C]-2beta-methoxy-3beta-4-fluorophenyltropane (CFT), and [(11)C] dihydrotetrabenazine (DTBZ) were used to measure specific uptake in the SN and striatum before and after a variable dose of MPTP in nonhuman primates. These in vivo PET-based measures were compared with motor impairment, as well as postmortem tyrosine hydroxylase-positive cell counts and striatal dopamine concentration. RESULTS: We found the specific uptake of both CFT and DTBZ in the SN had a strong, significant correlation with dopaminergic cell counts in the SN (R(2) = 0.77, 0.53, respectively, p < 0.001), but uptake of FD did not. Additionally, both CFT and DTBZ specific uptake in the SN had a linear relationship with motor impairment (rs = -0.77, -0.71, respectively, p < 0.001), but FD uptake did not. INTERPRETATION: Our findings demonstrate that PET-measured binding potentials for CFT and DTBZ for a midbrain volume of interest targeted at the SN provide faithful correlates of nigral neuronal counts across a full range of lesion severity. Because these measures correlate with both nigral cell counts and parkinsonian ratings, we suggest that these SN PET measures are relevant biomarkers of nigrostriatal function. PMID- 23686843 TI - Use of antiplatelet drugs in stroke prevention: time for a rethink? PMID- 23686844 TI - Republished: non-invasive urine based tests for the detection of bladder cancer. AB - Bladder cancer is the fourth most frequently diagnosed malignant neoplasm and cause of cancer-related deaths in men and eighth in women. Patients with bladder cancer undergo repeated cystoscopic examinations of the bladder to monitor for tumour recurrence which is invasive, costly and lacks accuracy. Therefore, the development of non-invasive urine based tests for the early detection of bladder cancer would be of tremendous benefit to both patients and healthcare systems. A number of urine based markers are available for the early diagnosis of bladder cancer. The diagnosis of bladder cancer relies on identifying malignant cells in the urine. All urinary markers have a higher sensitivity as compared with cytology but they score lower in specificity. Many soluble and cell based markers have been developed. Only two of the soluble and cell based markers have obtained the Food and Drug Administration approval. In the current review, the most recent literature of urinary markers is summarised. This article reports some of the more prominent urine markers and new technologies used nowadays. PMID- 23686845 TI - Republished: paediatric early warning scores: Holy Grail and Achilles' heel. AB - Early Warning Scores (EWS) have become increasingly used by hospitals throughout the world to prevent unexpected admission to intensive care or even death in their inpatient population. It is well known that signs of deterioration are present well before collapse and by a combination of systems, EWS enable healthcare professionals to intervene at an appropriate time. A number of national bodies and regulators in the UK have required the use of Early Warning Scores in locations where children are inpatients. This article attempts to describe the background to their development, identify common problems and provide information for units interested in introducing an EWS into their department. PMID- 23686846 TI - Meet your microbiome. PMID- 23686847 TI - Nuclear structures in Tribolium castaneum oocytes. AB - The first ultrastructural and immunomorphological characteristics of the karyosphere (karyosome) and extrachromosomal nuclear bodies in the red flour beetle, Tribolium castaneum, are presented. The karyosphere forms early in the diplotene stage of meiotic prophase by the gathering of all oocyte chromosomes in a limited nuclear volume. Using the BrUTP assay, T. castaneum oocyte chromosomes united in the karyosphere maintain their transcriptional activity until the end of oocyte growth. Hyperphosphorylated RNA polymerase II and basal transcription factors (TFIID and TFIIH) were detected in the perichromatin region of the karyosphere. The T. castaneum karyosphere has an extrachromosomal capsule that separates chromosomes from the rest of the nucleoplasm. Certain structural proteins (F-actin, lamin B) were found in the capsule. Unexpectedly, the karyosphere capsule in T. castaneum oocytes was found to be enriched in TMG capped snRNAs, which suggests that the capsule is not only a structural support for the karyosphere, but may be involved in biogenesis of snRNPs. We also identified the counterparts of 'universal' extrachromosomal nuclear domains, Cajal bodies (CBs) and interchromatin granule clusters (IGCs). Nuclear bodies containing IGC marker protein SC35 display some features unusual for typical IGCs. SC35 domains in T. castaneum oocytes are predominantly fibrillar complex bodies that do not contain trimethyl guanosine (TMG)-capped small nuclear (sn) RNAs. Microinjections of 2'-O-methyl (U)22 probes into the oocytes allowed revealing poly(A)+ RNAs in these nuclear domains. Several proteins related to mRNA export (heterogeneous ribonucleoprotein core protein A1, export adapters Y14 and Aly and export receptor NXF1) were also detected there. We believe that unusual SC35 nuclear domains of T. castaneum oocytes are possibly involved in mRNP but not snRNP biogenesis. PMID- 23686848 TI - Disruption of the dynamics of microtubules and selective inhibition of glioblastoma cells by nanofibers of small hydrophobic molecules. PMID- 23686849 TI - The role of mastoidectomy in outcomes following tympanic membrane repair: a review. AB - OBJECTIVES/HYPOTHESIS: The role of mastoidectomy performed with tympanoplasty for tympanic membrane perforations in the absence of cholesteatoma remains controversial. Some authorities suggest that outcomes are improved by the pressure buffering contributed by a well-aerated mastoid. It is unclear, however, whether or not clinical evidence demonstrates a benefit by the addition of a mastoidectomy. STUDY DESIGN: Review of peer-reviewed publications. METHODS: The literature on tympanoplasty and mastoidectomy was reviewed, examining the success of tympanic membrane repair, control of drainage, and hearing improvement. RESULTS: Twenty-six articles were reviewed examining surgical outcomes for patients with perforations resulting from chronic suppurative otitis media without cholesteatoma. Most of the literature consisted of retrospective cohort studies and case series with only a few small prospective randomized trials. Retrospective studies were commonly biased by performing mastoidectomy in ears with worse disease, and methodological differences made comparisons between studies difficult to interpret. There was no evidence of improved outcomes following mastoidectomy compared to tympanoplasty alone. Subgroup analysis, including actively discharging ears, extensive mucosal inflammation, large or repeat perforations, or sclerotic mastoids had overall worse outcomes. These patients showed a nonsignificant trend toward slightly improved results with mastoidectomy. CONCLUSIONS: The available literature shows no additional benefit to performing mastoidectomy with tympanoplasty for uncomplicated tympanic membrane perforations. Patients with more complicated disease may benefit from the addition of a mastoidectomy, but there is insufficient evidence to make a recommendation for this population. Further prospective controlled studies are needed. PMID- 23686850 TI - Composite hydrogel scaffolds with controlled pore opening via biodegradable hydrogel porogen degradation. AB - Poly(beta-amino ester) (PBAE) biodegradable hydrogel systems have garnered much attention in recent years due to their appealing properties for biomedical applications. These hydrogel systems exhibit properties similar to natural soft tissue, degrade in aqueous environments, and have easily tunable properties that have been well studied and understood. In most cases, tissue engineering scaffolds must possess a three-dimensional interconnected porous network for tissue ingrowth and construct vascularization. Here, PBAE properties were explored and systems were selected to serve as both the pore-forming agent and the outer matrix of a scaffold that exhibits controlled pore opening upon degradation. To our knowledge, this is the first demonstration of a biodegradable hydrogel porogen system entrapped in a degradable hydrogel outer matrix. Scaffolds were prepared, and the degradation, compressive moduli, and porosity were analyzed. An added advantage of a degradable porogen is the potential for controlled drug release, and a model protein was released from the porogen particles to demonstrate this application. Finally, pluripotent cells seeded onto predegraded scaffolds were viable during the first 24 h of exposure, and furthermore, cell tracking confirmed the presence of cells within the pores of the scaffold. Overall, these present studies demonstrate the possibility of using these biodegradable hydrogel porogen-matrix systems as tissue engineering scaffolding materials. PMID- 23686851 TI - Pectinolytic yeasts from viticultural and enological environments: novel finding of Filobasidium capsuligenum producing pectinases. AB - In this study indigenous yeasts associated with wineries, grapes and Malbec fermented must from San Rafael viticulture region (Argentina) were isolated to select pectinolytic strains for their potential use in enology. Pectinolytic yeasts were identified by physiological and molecular methods. Among 78 isolates, only nine were able to produce extracellular pectinases. Six isolated from berry surface were identified as Aureobasidium pullulans and the remaining isolates, recovered from wineries, belonged to Saccharomyces cerevisiae and Filobasidium capsuligenum species. Pectinase production was evaluated under vinification related conditions: pH 3.5, 12 and 28 degrees C. A. pullulans U-12 produced the highest pectinolytic activity at low temperature (1.16 U ml(-1) ), while F. capsuligenum strains showed good activity at 12 and 28 degrees C (0.77 and 1.15 U ml(-1) , respectively) being this study the first report on the capacity of this species to produce pectinases. The pectinolytic activity of F. capsuligenum B-13 showed an optimum at pH 4.5 and two peaks at 20 and 50 degrees C. The enzyme half-life was 2 h at 40 degrees C and retained 65% of its activity at 40 degrees C after 1 h of incubation. This pectinolytic system displayed remarkable activity at pH and temperatures found in vinification, suggesting a potential candidate for applying to wine-making. PMID- 23686852 TI - Induction of nitric oxide synthase expression by lipopolysaccharide is mediated by calcium-dependent PKCalpha-beta1 in alveolar epithelial cells. AB - Nitric oxide (NO) plays an important role in innate host defense and inflammation. In response to infection, NO is generated by inducible nitric oxide synthase (iNOS), a gene product whose expression is highly modulated by different stimuli, including lipopolysaccharide (LPS) from gram-negative bacteria. We reported recently that LPS from Pseudomonas aeruginosa altered Na+ transport in alveolar epithelial cells via a suramin-dependent process, indicating that LPS activated a purinergic response in these cells. To further study this question, in the present work, we tested whether iNOS mRNA and protein expression were modulated in response to LPS in alveolar epithelial cells. We found that LPS induced a 12-fold increase in iNOS mRNA expression via a transcription-dependent process in these cells. iNOS protein, NO, and nitrotyrosine were also significantly elevated in LPS-treated cells. Ca2+ chelation and protein kinase C (PKCalpha-beta1) inhibition suppressed iNOS mRNA induction by LPS, implicating Ca2+-dependent PKC signaling in this process. LPS evoked a significant increase of extracellular ATP. Because PKC activation is one of the signaling pathways known to mediate purinergic signaling, we evaluated the hypothesis that iNOS induction was ATP dependent. Although high suramin concentration inhibited iNOS mRNA induction, the process was not ATP dependent, since specific purinergic receptor antagonists could not inhibit the process. Altogether, these findings demonstrate that iNOS expression is highly modulated in alveolar epithelial cells by LPS via a Ca2+/PKCalpha-beta1 pathway independent of ATP signaling. PMID- 23686853 TI - Civil, sensible, and constructive peer review in APS journals. PMID- 23686854 TI - Bicarbonate disruption of the pulmonary endothelial barrier via activation of endogenous soluble adenylyl cyclase, isoform 10. AB - It is becoming increasingly apparent that cAMP signals within the pulmonary endothelium are highly compartmentalized, and this compartmentalization is critical to maintaining endothelial barrier integrity. Studies demonstrate that the exogenous soluble bacterial toxin, ExoY, and heterologous expression of the forskolin-stimulated soluble mammalian adenylyl cyclase (AC) chimera, sACI/II, elevate cytosolic cAMP and disrupt the pulmonary microvascular endothelial barrier. The barrier-disruptive effects of cytosolic cAMP generated by exogenous soluble ACs are in contrast to the barrier-protective effects of subplasma membrane cAMP generated by transmembrane AC, which strengthens endothelial barrier integrity. Endogenous soluble AC isoform 10 (AC10 or commonly known as sAC) lacks transmembrane domains and localizes within the cytosolic compartment. AC10 is uniquely activated by bicarbonate to generate cytosolic cAMP, yet its role in regulation of endothelial barrier integrity has not been addressed. Here we demonstrate that, within the pulmonary circulation, AC10 is expressed in pulmonary microvascular endothelial cells (PMVECs) and pulmonary artery endothelial cells (PAECs), yet expression in PAECs is lower. Furthermore, pulmonary endothelial cells selectively express bicarbonate cotransporters. While extracellular bicarbonate generates a phosphodiesterase 4-sensitive cAMP pool in PMVECs, no such cAMP response is detected in PAECs. Finally, addition of extracellular bicarbonate decreases resistance across the PMVEC monolayer and increases the filtration coefficient in the isolated perfused lung above osmolality controls. Collectively, these findings suggest that PMVECs have a bicarbonate-sensitive cytosolic cAMP pool that disrupts endothelial barrier integrity. These studies could provide an alternative mechanism for the controversial effects of bicarbonate correction of acidosis of acute respiratory distress syndrome patients. PMID- 23686855 TI - Rac1 pathway mediates stretch response in pulmonary alveolar epithelial cells. AB - Alveolar epithelial cells (AECs) maintain the pulmonary blood-gas barrier integrity with gasketlike intercellular tight junctions (TJ) that are anchored internally to the actin cytoskeleton. We have previously shown that AEC monolayers stretched cyclically and equibiaxially undergo rapid magnitude- and frequency-dependent actin cytoskeletal remodeling to form perijunctional actin rings (PJARs). In this work, we show that even 10 min of stretch induced increases in the phosphorylation of Akt and LIM kinase (LIMK) and decreases in cofilin phosphorylation, suggesting that the Rac1/Akt pathway is involved in these stretch-mediated changes. We confirmed that Rac1 inhibitors wortmannin or EHT-1864 decrease stretch-stimulated Akt and LIMK phosphorylation and that Rac1 agonists PIP3 or PDGF increase phosphorylation of these proteins in unstretched cells. We also confirmed that Rac1 pathway inhibition during stretch modulated stretch-induced changes in occludin content and monolayer permeability, actin remodeling and PJAR formation, and cell death. As further validation, overexpression of Rac GTPase-activating protein beta2-chimerin also preserved monolayer barrier properties in stretched monolayers. In summary, our data suggest that constitutive activity of Rac1, which is necessary for stretch induced activation of the Rac1 downstream proteins, mediates stretch-induced increases in permeability and PJAR formation. PMID- 23686856 TI - Chronic hypoxia selectively enhances L- and T-type voltage-dependent Ca2+ channel activity in pulmonary artery by upregulating Cav1.2 and Cav3.2. AB - Hypoxia-induced pulmonary hypertension (HPH) is characterized by sustained pulmonary vasoconstriction and vascular remodeling, both of which are mediated by pulmonary artery smooth muscle cell (PASMC) contraction and proliferation, respectively. An increase in cytosolic Ca2+ concentration ([Ca2+]cyt) is a major trigger for pulmonary vasoconstriction and an important stimulus for cell proliferation in PASMCs. Ca2+ influx through voltage-dependent Ca2+ channels (VDCC) is an important pathway for the regulation of [Ca2+]cyt. The potential role for L- and T-type VDCC in the development of HPH is still unclear. Using a hypoxic-induced pulmonary hypertension mouse model, we undertook this study to identify if VDCC in pulmonary artery (PA) are functionally upregulated and determine which type of VDCC are altered in HPH. Mice subjected to chronic hypoxia developed pulmonary hypertension within 4 wk, and high-K+- and U-46619 induced contraction of PA was greater in chronic hypoxic mice than that in normoxic control mice. Additionally, we demonstrate that high-K+- and U-46619 induced Ca2+ influx in PASMC is significantly increased in the hypoxic group. The VDCC activator, Bay K8864, induced greater contraction of the PA of hypoxic mice than in that of normoxic mice in isometric force measurements. L-type and T-type VDCC blockers significantly attenuated absolute contraction of the PA in hypoxic mice. Chronic hypoxia did not increase high-K+- and U-46619-induced contraction of mesenteric artery (MA). Compared with MA, PA displayed higher expression of calcium channel voltage-dependent L-type alpha1C-subunit (Cav1.2) and T-type alpha1H-subunit (Cav3.2) upon exposure to chronic hypoxia. In conclusion, both L type and T-type VDCC were functionally upregulated in PA, but not MA, in HPH mice, which could result from selectively increased expression of Cav1.2 and Cav3.2. PMID- 23686857 TI - Proprotein convertases play an important role in regulating PKGI endoproteolytic cleavage and nuclear transport. AB - Nitric oxide and cGMP modulate vascular smooth muscle cell (SMC) phenotype by regulating cell differentiation and proliferation. Recent studies suggest that cGMP-dependent protein kinase I (PKGI) cleavage and the nuclear translocation of a constitutively active kinase fragment, PKGIgamma, are required for nuclear cGMP signaling in SMC. However, the mechanisms that control PKGI proteolysis are unknown. Inspection of the amino acid sequence of a PKGI cleavage site that yields PKGIgamma and a protease database revealed a putative minimum consensus sequence for proprotein convertases (PCs). Therefore we investigated the role of PCs in regulating PKGI proteolysis. We observed that overexpression of PCs, furin and PC5, but not PC7, which are all expressed in SMC, increase PKGI cleavage in a dose-dependent manner in human embryonic kidney (HEK) 293 cells. Moreover, furin induced proteolysis of mutant PKGI, in which alanines were substituted into the putative PC consensus sequence, was decreased in these cells. In addition, overexpression of furin increased PKGI proteolysis in LoVo cells, which is an adenocarcinoma cell line expressing defective furin without PC activity. Also, expression of alpha1-PDX, an engineered serpin-like PC inhibitor, reduced PC activity and decreased PKGI proteolysis in HEK293 cells. Last, treatment of low passage rat aortic SMC with membrane-permeable PC inhibitor peptides decreased cGMP-stimulated nuclear PKGIgamma translocation. These data indicate for the first time that PCs have a role in regulating PKGI proteolysis and the nuclear localization of its active cleavage product, which are important for cGMP mediated SMC phenotype. PMID- 23686858 TI - Neu-164 and Neu-107, two novel antioxidant and anti-myeloperoxidase compounds, inhibit acute cigarette smoke-induced lung inflammation. AB - Cigarette smoke is a profound proinflammatory stimulus that causes acute lung inflammation and chronic lung disease, including chronic obstructive pulmonary disease (COPD, emphysema, and chronic bronchitis), via a variety of mechanisms, including oxidative stress. Cigarette smoke contains high levels of free radicals, whereas inflammatory cells, including macrophages and neutrophils, express enzymes, including NADPH oxidase, nitric oxide synthase, and myeloperoxidase, that generate reactive oxygen species in situ and contribute to inflammation and tissue damage. Neu-164 and Neu-107 are small-molecule inhibitors of myeloperoxidase, as well as potent antioxidants. We hypothesized that Neu-164 and Neu-107 would inhibit acute cigarette smoke-induced inflammation. Adult C57BL/6J mice were exposed to mainstream cigarette smoke for 3 days to induce acute inflammation and were treated daily by inhalation with Neu-164, Neu-107, or dexamethasone as a control. Inflammatory cells and cytokines were assessed by bronchoalveolar lavage and histology. mRNA levels of endogenous antioxidant genes heme oxygenase-1 and glutamate-cysteine ligase modifier subunit were determined by qPCR. Cigarette smoke exposure induced acute lung inflammation with accumulation of neutrophils and upregulation of proinflammatory cytokines, including IL-6, macrophage inflammatory protein-2, and keratinocyte-derived cytokine. Both Neu-164 and Neu-107 significantly reduced the accumulation of inflammatory cells and the expression of inflammatory cytokines as effectively as dexamethasone. Upregulation of endogenous antioxidant genes was dampened. Neu-164 and Neu-107 inhibit acute cigarette smoke-induced inflammation by scavenging reactive oxygen species in cigarette smoke and by inhibiting further oxidative stress caused by inflammatory cells. These compounds may have promise in preventing or treating lung disease associated with chronic smoke exposure, including COPD. PMID- 23686860 TI - Metalated nitriles: S(N)i and S(N)i' installation of contiguous quaternary tertiary and quaternary-quaternary centers. PMID- 23686859 TI - Lipoxin A4-mediated KATP potassium channel activation results in cystic fibrosis airway epithelial repair. AB - The main cause of morbidity and mortality in cystic fibrosis (CF) is progressive lung destruction as a result of persistent bacterial infection and inflammation, coupled with reduced capacity for epithelial repair. Levels of the anti inflammatory mediator lipoxin A4 (LXA4) have been reported to be reduced in bronchoalveolar lavages of patients with CF. We investigated the ability of LXA4 to trigger epithelial repair through the initiation of proliferation and migration in non-CF (NuLi-1) and CF (CuFi-1) airway epithelia. Spontaneous repair and cell migration were significantly slower in CF epithelial cultures (CuFi-1) compared with controls (NuLi-1). LXA4 triggered an increase in migration, proliferation, and wound repair of non-CF and CF airway epithelia. These responses to LXA4 were completely abolished by the ALX/FPR2 receptor antagonist, Boc2 and ALX/FPR2 siRNA. The KATP channel opener pinacidil mimicked the LXA4 effect on migration, proliferation, and epithelial repair, whereas the KATP channel inhibitor, glibenclamide, blocked the responses to LXA4. LXA4 did not affect potassium channel expression but significantly upregulated glibenclamide sensitive (KATP) currents through the basolateral membrane of NuLi-1 and CuFi-1 cells. MAP kinase (ERK1/2) inhibitor, PD98059, also inhibited the LXA4-induced proliferation of NuLi-1 and CuFi-1 cells. Finally, both LXA4 and pinacidil stimulated ERK-MAP kinase phosphorylation, whereas the effect of LXA4 on ERK phosphorylation was inhibited by glibenclamide. Taken together, our results provided evidence for a role of LXA4 in triggering epithelial repair through stimulation of the ALX/FPR2 receptor, KATP potassium channel activation, and ERK phosphorylation. This work suggests exogenous delivery of LXA4, restoring levels in patients with CF, perhaps as a potential therapeutic strategy. PMID- 23686861 TI - Severe obstructive sleep apnea in Loeys-Dietz syndrome successfully treated using continuous positive airway pressure. AB - Loeys-Dietz syndrome is a recently recognized connective tissue disorder characterized by severe craniofacial and skeletal abnormalities as well as arterial tortuosity with aggressive aneurysm formation. Marfan syndrome, a classic connective tissue disorder, is known to be associated with a risk of obstructive sleep apnea, but sleep-related breathing disorders have not been previously documented in Loeys-Dietz syndrome. The propositus had the prototypic features of Loeys-Dietz syndrome with a de novo mutation in TGFBR2. He developed severe obstructive sleep apnea during his infancy. Continuous positive airway pressure was introduced at age 7 years and provided significant improvement in his nocturnal apnea and sleep apnea-related symptoms, such as enuresis. Marfan syndrome is known to be associated with a high risk of sleep apnea because of its characteristic craniofacial and connective tissue abnormalities. Similarly, the severe craniofacial abnormalities in Loeys-Dietz syndrome may predispose patients to severe obstructive sleep apnea, even at a very young age. Despite the severity of obstructive sleep apnea in the propositus, the administration of continuous positive airway pressure was highly effective in alleviating his symptoms. In summary, severe obstructive sleep apnea was successfully treated using continuous positive airway pressure in a patient with Loeys-Dietz syndrome. Careful evaluation and aggressive intervention for the alleviation of obstructive sleep apnea is warranted in Loeys-Dietz syndrome. PMID- 23686862 TI - Nrf2 defense pathway: Experimental evidence for its protective role in epilepsy. AB - OBJECTIVE: Epigenetic mechanisms involved in transcriptional regulation of multiple molecular pathways are potentially attractive therapeutic interventions for epilepsy, because single target therapies are unlikely to provide both anticonvulsant and disease-modifying effects. METHODS: A selection of epilepsy related gene expression data sets were retrieved using NextBio software and imported to Ingenuity Pathway Analysis for transcription factor enrichment analysis. Nuclear factor erythroid 2-related factor 2 (Nrf2)-a transcription factor that promotes the expression of numerous antioxidant, anti-inflammatory, and neuroprotective proteins-was identified as a candidate for confirmation of mRNA expression in hippocampal tissue from patients with temporal lobe epilepsy and in mice following pilocarpine-induced status epilepticus (SE). Human Nrf2 was overexpressed via an adeno-associated virus (AAV) vector after the onset of spontaneous recurrent seizures (SRS) in the animals. At the end of a 5-week continuous monitoring period for SRS, quantitative immunohistochemistry using neuronal (neuronal-specific nuclear protein), astrocytic (glial fibrillary acidic protein), and microglial (ionized calcium binding adaptor molecule 1) markers was performed. RESULTS: A significant increase in Nrf2 mRNA expression was observed in human epileptic hippocampal tissue. Nrf2 expression levels increased progressively in mice, reaching a peak at 72 hours after SE, and then declined. Similar expression patterns were observed for 3 Nrf2-regulated genes: HO-1, NQO1, and mGST. Remarkably, mice injected with AAV Nrf2 displayed significantly fewer generalized seizures, with profound reduction in microglia activation. Hippocampal neurons were preserved, whereas the number of astrocytes was unchanged. INTERPRETATION: These findings extend the potential of Nrf2-based therapies to epilepsy and add to the rapidly accumulating evidence from other neurodegenerative and inflammatory disease models. PMID- 23686863 TI - Effects of testosterone treatment on bone mineral density in men with testosterone deficiency syndrome. AB - The decline in testosterone levels found in men with testosterone deficiency syndrome (TDS) is associated with a decrease in bone mineral density (BMD). To study the safety profile and efficacy of testosterone treatment on BMD in patients with TDS. In this 2-year prospective open-label study, patients were administered 50 mg of testosterone gel daily (adjustable after 3 months up to 75 100 mg or down to 25 mg) for 12 months, followed by treatment with 1000 mg of testosterone undecanoate every 2-3 months from months 12-24. Outcome measures were as follows: (i) Changes in clinical chemistry safety parameters and total testosterone, sex hormone binding globulin and calculated free testosterone (cFT) levels; (ii) Changes in Aging Males' Symptoms Scale (AMS) and International Prostate Symptom Score scores; and (iii) Changes in lumbar spine and hip BMD. A total of 50 men aged 50-65 years with TDS (AMS >26 and cFT <0.250 nmol/mL) took part in the study. There was no significant impact of testosterone on safety. Prostate-specific antigen and haematopoietic parameters increased significantly, although the changes were not clinically significant. Total and cFT increased significantly after 3 months (p < 0.001) and there were significant improvements after 3 months in AMS scores (p < 0.001). BMD improved significantly in L2-L4 (2.90 and 4.5%), total femur (0.74 and 3%) and trochanter (1.09 and 3.2%) at 12 and 24 months respectively. Testosterone treatment in men with TDS has a good safety profile, leads to significant improvement in lumbar spine and hip BMD, and improves symptoms, as assessed by the AMS questionnaire. PMID- 23686864 TI - Structural and functional plasticity of the luteinizing hormone/choriogonadotrophin receptor. AB - BACKGROUND In recent years it became evident that several types of the luteinizing hormone/choriogonadotrophin receptor (LHCGR) exist. In addition to the classical receptor type known in rodents, an LHCGR type containing an additional exon is present in primates and humans. This specific exon 6A introduces a hitherto unknown regulatory pathway of the LHCGR at the transcriptional level which can lead to the expression of an alternative protein covering the extracellular part only. Furthermore, an LHCGR type lacking exon 10 at the mRNA and protein levels has been described in the New World primate lineage, giving rise to an additional receptor type in which amino acids of the extracellular hinge region connecting the leucine-rich repeat domain and transmembrane domain are missing. METHODS Topic-related information was retrieved by systematic searches using Medline/PubMed. Structural homology models were retrieved from a glycoprotein hormone receptors web application and from recent publications. RESULTS In a novel approach, we combine functional aspects with three-dimensional properties of the LHCGR and the different receptor types to deduce causative relationships between these two parameters. On this basis, the physiological impact and patho-physiological consequences of the different LHCGR types are inferred. CONCLUSIONS The complex system of different LHCGR types and two corresponding hormones (LH and CG) represents a major challenge for future studies on selective hormone binding, signal transduction and receptor regulation. The presence of these naturally occurring LHCGR types requires re examining of our present view on receptor function, experimental set-ups and data interpretation, but also offers new clinical approaches to interfere with LH/CG action in humans. PMID- 23686865 TI - Bevacizumab: finding its niche in the treatment of heart failure secondary to liver vascular malformations in hereditary hemorrhagic telangiectasia. PMID- 23686866 TI - Level IIB lymph node metastasis in laryngeal and hypopharyngeal squamous cell carcinoma: single-institution case series and review of the literature. AB - OBJECTIVES/HYPOTHESIS: To determine the incidence of level IIB lymph node metastasis in patients with laryngeal or hypopharyngeal squamous cell carcinoma and to evaluate the need for elective and therapeutic neck dissection of level IIB. STUDY DESIGN: Retrospective cohort study and review of the literature. METHODS: Patients with laryngeal or hypopharyngeal squamous cell carcinoma (N = 65) were primarily treated with surgery at Mayo Clinic (Rochester, Minnesota) from 2004 through 2010. Neck dissection specimens were analyzed by a pathologist, and metastases to level IIB were reported. In addition, 18 previously published studies, totaling 1,114 neck dissections, were reviewed. RESULTS: Level IIB lymph node metastases were present in 4% and 17% of elective and therapeutic neck dissections, respectively. Ipsilateral IIB metastasis was more common than contralateral IIB metastasis in elective and therapeutic neck dissection specimens. Level IIB lymph node metastasis was not significantly associated with level IIA nodal metastasis, level III nodal metastasis, clinical primary tumor stage, clinical nodal stage, or pathologic confirmation of extracapsular spread in either laryngeal or hypopharyngeal squamous cell carcinoma. CONCLUSIONS: The rate of occult IIB metastasis in laryngeal and hypopharyngeal squamous cell carcinoma is exceedingly low. In a clinically node-negative case, the ipsilateral and contralateral level IIB nodal packet should not be dissected. For clinically node-positive cases, ipsilateral level IIB dissection should be performed; contralateral IIB dissection should be performed only when indicated. PMID- 23686867 TI - Development of genus-specific primers for better understanding the diversity and population structure of Sphingomonas in soils. AB - Genus Sphingomonas has received increasing attentions due to its somewhat unique metabolic versatilities in the contaminated environment. However, due to the lack of genus-specific primers, the ecological significance of Sphingomonas in polluted soils has been rarely documented by 16S rDNA finger-printing methods. In this study, three genus-specific primer sets targeted at the 16S rRNA gene of Sphingomonas were developed and their specificities were tested with four contaminated soils from Shenfu petroleum-wastewater irrigation zone by constructing clone libraries, amplified ribosomal DNA restriction analysis (ARDRA) and sequencing the represented ARDRA patterns. Meanwhile, the newly designed primer sets and a previously reported primer set were compared, and the results showed that the newly developed primer set SA/429f-933r could detect a larger spectrum (90%) of Sphingomonas strains with higher specificity. Despite the superiority of primer set SA/429f-933r in specifically detecting Sphingomonas from contaminated soils, we cannot blink the fact that different primer sets preferentially amplified different dominant species. Therefore, two or more primer sets are recommended for evaluating the diversity and population structure of genus Sphingomonas. Additionally, a proportion (9.7%) of the cloned sequences discovered in this study were different from known Sphingomonas sequences, suggesting that new Sphingomonas sequences might present in soils from Shenfu irrigation zone. PMID- 23686868 TI - Evaluation of revised IPSS cytogenetic risk stratification and prognostic impact of monosomal karyotype in 783 patients with primary myelodysplastic syndromes. AB - Cytogenetic classification by the revised international prognostic scoring system (IPSS-R) and the prognostic value of monosomal karyotype (MK) were assessed in 783 patients with primary myelodysplastic syndromes (MDS). At 22 months median follow-up, 562 (72%) deaths were recorded. Percentages of patients with IPSS-R "very good," "good," "intermediate," "poor," and "very poor" cytogenetic categories was 5, 63, 18, 4, and 10%, respectively. The corresponding median survivals were 21, 40, 24, 18, and 6.5 months and the inter-group differences (good vs. very good/intermediate/poor vs. very poor; P < 0.01) or similarities (very good vs. intermediate vs. poor; P = 0.79) were not significantly modified in multivariable analysis. Results were similar when analysis was restricted to 602 patients managed by supportive care. MK adversely affected survival in both poor and very poor karyotype groups (P < 0.01). In conclusion, we were unable to confirm the prognostic superiority of IPSS-R-very good karyotype or prognostically distinguish between very good, intermediate and poor karyotypes. Furthermore, we show additional prognostic information from MK in poor/very poor karyotype. PMID- 23686869 TI - C3G overexpression promotes the survival of rat-derived H9C2 cardiomyocytes by p ERK1/2. AB - Integrin beta1 subunit and its downstream molecules, such as integrin-linked kinase and focal adhesion kinase, are imperative for promotion of cell proliferation, survival and anti-apoptosis in cardiomyocytes by activation of their downstream pro-survival signalling molecules, such as the phosphorylated extracellular signal-regulated kinase1/2 (p-ERK1/2). As a component of the integrin pathway, C3G (Crk-SH3 domain guanine nucleotide exchange factor) protein may be involved in the promotion of cell proliferation and survival and anti apoptosis in the H9C2 cardiomyocytes. Rat-derived H9C2 cardiomyocytes were transfected with pCXN2-flag-hC3G, a human C3G overexpression eukaryotic recombinant plasmid. Apoptosis, cell proliferation and survival were analysed in the H9C2 cardiomyocytes either treated with hypoxia/reoxygenation (H/R). Human C3G mRNA overexpression significantly elevated C3G protein expression in H9C2 cardiomyocytes whether treated with H/R or not. C3G overexpression promoted proliferation and survival and anti-apoptosis, and attenuated the proliferative and survival inhibition, and apoptosis induced by H/R by activation of its downstream pro-survival signalling molecule, p-ERK1/2. The results suggest that C3G acts as a pro-survival molecule in H9C2 cardiomyocytes by activation of p ERK1/2. PMID- 23686870 TI - Outcomes in head and neck reconstruction by surgical site and donor site. AB - OBJECTIVES/HYPOTHESIS: Define surgical outcomes of specific donor sites for free tissue transfer in head and neck reconstruction. STUDY DESIGN: Retrospective cohort review at an academic tertiary care center. METHODS: A review was made of free tissue transfer procedures performed at a university-based tertiary care facility from October 2004 to April 2011. A total of 1,051 patients underwent six types of free flaps: fasciocutaneous radial forearm (53%), osteocutaneous radial forearm (16%), rectus abdominis (11%), fibula (10%), anterior lateral thigh (7%), and latissimus dorsi (2%). Demographic data were collected, and outcomes measured were: length of hospital stay, flap viability, and major complications (infection, fistula, and hematoma). RESULTS: Of the 1,051 flaps performed, the most common operative site was oral cavity (40%, n = 414) followed by hypopharynx/larynx (22%, n = 234), cutaneous (20%, n = 206), oropharynx (9%, n = 98), midface (7%, n = 76), and skull base (2%, n = 23). The median hospital stay was 7.9 days (range, 1-76), and the overall failure rate was 2.8%. Cutaneous defects required the shortest length of hospitalization (5.8 days, P < .0001), a low free flap failure rate (1.5%, n = 3), and limited major complications (6%, n = 12). Conversely, oropharynx defects were associated with the longest hospitalization (8.9 days). Midface defects had a high incidence of complications (15%, n = 11, P = .10). Defects above the angle of the mandible had higher overall complications when compared to below. Similarly, reconstruction for primary or recurrent cancer had a total failure rate of 2.5%, whereas secondary reconstruction and radionecrosis had a failure rate of 4.0% (P = .29). Additionally, there was no statistical difference between outcomes based on donor site. CONCLUSIONS: This review demonstrates that certain subsets of patients are at higher risk for complications after free tissue transfer. Patients undergoing free flap reconstruction for cutaneous defects have substantially shorter hospital stays and are at lower risk of flap complications, whereas reconstruction for radionecrosis and secondary reconstruction tend to have higher overall flap failure rates. PMID- 23686872 TI - 23Na NMR relaxation studies of the Na-DNA/drug interaction. AB - This Minireview covers the methodological approaches of (23)Na NMR spectroscopy to the study of the structure and dynamics of the DNA molecule, in particular the application of the (23)Na NMR quadrupolar relaxation to investigate the perturbations on the polyion surface due to exogenous agents. A brief description of the (23)Na NMR quadrupolar relaxation and of the models used to describe the distribution of counterions around DNA, and the results of the application of the (23)Na NMR relaxation to the study of the cation-DNA interaction are also shown. Following sections present results of the investigation on ligand-DNA interaction and on ordered DNA systems. PMID- 23686873 TI - Energy landscapes of ligand-receptor couples probed by dynamic force spectroscopy. AB - Playing a dominant role in many biochemical processes are the dynamic properties of molecular linkages; examples include cell adhesion, enzyme-catalyzed reactions, and molecular recognition by antibodies. Dynamic force spectroscopy, namely separating molecular bonds under external force ramps has rapidly become a powerful tool to study the rugged energy landscape of noncovalent ligand-receptor bonds. The picture shows a surface and tip-bound pair being pulled apart and the derived potential energy diagram. PMID- 23686874 TI - Motion of liquids on surfaces. AB - The macroscopic manipulation of liquids is a core component to the development of microfluidic devices. Although the Marangoni effect has been described for well over a century, actively tuning such surface tension effects is a more recent achievement. This Highlight compares recently reported electro- and photochemical methods in which this liquid manipulation has occurred. One such method, electrocapillarity as utilised by Prins et al., is shown in the picture. PMID- 23686875 TI - On the potential catalytic role of electron capture in gas-phase condensation reactions: a theoretical exploratory study of the CH2O2 and CH3ON systems. AB - The potential activation by electron capture of H2+CO2 or CO+H2O reactions, leading to HCOOH (formic acid), and of CO+NH3, HCN+H2O and HNC+H2O reactions, leading to HC(O)NH2 (formamide), have been studied theoretically. Ab initio calculations at the DFT, CCSD, CCSD(T) and QCISD(T) levels have been performed with the 6-311G(3df,2p) and 6-311+G(3df,2p) basis sets, whose performances are compared in the evaluation of the negative electron affinities of HCN and HNC. A routine method, CCSD/6-311+G(3df,2p)//B3LYP/6-311G(3df,2p), was then used for a survey of the potential energy surfaces of the above reactions. It has been shown that a promising reaction pathway was found in the catalytic anionic activation of HNC+H2O condensation, at an energy <=2 eV for the incident electron. PMID- 23686876 TI - Do perchlorate and triflate anions bind to the uranyl cation in an acidic aqueous medium? A combined EXAFS and quantum mechanical investigation. AB - Structural properties of uranyl cations in acidic aqueous perchlorate and triflate solutions were investigated using uranium LIII -edge extended X-ray absorption fine-structure spectroscopy (EXAFS) in conjunction with quantum mechanical calculations of gas-phase model complexes. EXAFS spectra were measured in aqueous solutions of up to 10 M triflic and 11.5 M perchloric acid, as well as mixtures of perchloric acid and sodium perchlorate. In no case is the perchlorate anion coordinated to UO2(2+). The number of equatorial water molecules bound to UO2(2+) is always about five. In the case of the 10 M CF3SO3H solution, an inner sphere complexation of the triflate is observed with a U-S radial distance of 3.62 A. These results are in qualitative agreement with quantum mechanical calculations of model uranyl complexes, according to which the interaction energies of anions follow the order perchlorate 0.05) compared with the placebo group at the endpoint. Whortleberry reduced total cholesterol, triglyceride and LDL-C 27.6%, 19.2% and 26.3%, respectively, but increased HDL-C 37.5% compared with baseline. No adverse effects were reported. Short-term treatment with whortleberry fruit appears safe and improves lipid profile in hyperlipidemic patients. PMID- 23686895 TI - Risk factors for hospital admissions associated with adverse drug events. AB - STUDY OBJECTIVE: To identify predictors of hospital admissions associated with adverse drug events (ADEs) and to determine the preventability of ADEs in patients admitted to two hospitals. DESIGN: Prospective observational study. SETTING: Medical admission units at two British National Health Service hospitals in the United Kingdom. PATIENTS: 3904 adults age 16 years or older who were admitted to the two hospitals between June 2006 and November 2007. MEASUREMENTS AND MAIN RESULTS: Clinical pharmacists identified hospital admissions associated with drug-related problems by using medical record review, supplemented by patient interview for those identified as having an ADE. The contribution of ADEs to hospital admission and the causality, severity, and preventability of the events were independently assessed by a multidisciplinary clinical team. Multivariate logistic regression was used to identify predictors of hospital admissions associated with ADEs, and a maximum-likelihood multinomial model was used to examine predictors of the preventability of ADEs. Of the 3904 patients included in the analysis, 439 (11.2%) were judged by the review panel to have experienced ADEs. Of these, 209 patients (47.6%) experienced preventable ADEs. Four independent variables were found to have significant relationships with ADE admissions and preventability of ADEs: patient age, length of time since starting new drug, total number of prescription drugs, and hospital site. Drug classes most commonly associated with preventable ADEs were antiplatelet drugs, anticoagulants, diuretics (loop and thiazide diuretics), angiotensin-converting enzyme inhibitors, and antiepileptic drugs. CONCLUSION: Adverse drug events are an important cause of hospital admission. Better systems for health care practitioners to identify patients at high risk of preventable hospital admissions associated with ADEs (e.g., age > 65 years old, receiving more than five drugs, and starting new high-risk drugs) should be implemented in order to minimize the risks to patients and the burden on the health care system. PMID- 23686896 TI - Cardiovascular risk and bone loss in men undergoing androgen deprivation therapy for non-metastatic prostate cancer: implementation of standardized management guidelines. AB - Our objective was to evaluate the effectiveness of implementing standardized guidelines to mitigate metabolic and bone side effects of androgen deprivation therapy (ADT) in men with non-metastatic prostate cancer. We conducted a 2-year prospective cohort study at a tertiary referral teaching hospital. Overall, 236 men (mean age 69.8 +/- 7.1) commencing ADT for non-metastatic prostate cancer attended a baseline clinic visit between 2007 and 2011, and 153 men were eligible for follow-up after 2 years of continuous ADT. Of these, 113 men had data available for analysis at 2 years. At baseline, 87% of the men were overweight or obese, 61% had hypertension, 56% had hypercholesterolaemia, 27% prior cardiovascular disease, 11% osteoporosis and 40% osteopaenia. After 2 years of ADT, there was an increase in waist circumference (+2.8 +/- 6.3 cm, p = 0.002), and, in men without diabetes, in HbA1c (+0.13 +/- 0.34%, p = 0.019). Despite this, due to treatment, there were significant reductions in total cholesterol ( 0.35 +/- 1.00 mmol/L, p < 0.001), and blood pressure (systolic -7.6 +/- 19.3 mmHg; diastolic -4.7 +/- 11.6 mmHg, p < 0.001). After 2 years, men not receiving anti-resorptive therapy experienced a significant decline in lumbar spine (-0.042 +/- 0.134 g/cm(2) , p = 0.012) and total hip bone mineral density (BMD) (-0.026 +/- 0.036 g/cm(2) , p < 0.001), whereas bisphosphonate treatment maintained stable BMD. Prevalence of anaemia increased from 13.8 to 32.5%. Older age independently predicted a greater drop in haemoglobin (p = 0.005). We conclude that a structured approach to assess and treat men undergoing ADT effectively improves cardiovascular risk factors and prevents bone decay. Larger studies are needed to determine effects on cardiovascular outcomes, fracture prevention and survival. PMID- 23686898 TI - Patterning of hyperbranched polymer films. AB - This Review describes new methods for patterning functional hyperbranched poly(acrylic acid) thin polymer films. "Hyperbranched polymer" is a generic term used to describe a wide variety of polymeric materials that contain a high percentage of functional groups, that are highly branched, and that are irregular in structure. Hyperbranched polymer films (HPFs) are prepared by an iterative three-step process: activation of an acid functionalized surface, surface grafting of amine-terminated poly(tert-butyl acrylate), and hydrolysis to regenerate the acid surface. The resulting materials have a high density of acid groups, which can be functionalized with moieties that introduce interesting optical, electrochemical, biological, and mechanical properties to the films. HPFs can be patterned with micron-scale resolution using either a template-based approach or photolithography. Templates consist of self-assembled monolayers prepared by microcontact printing, whereas photolithographic patterning relies on selective hydrolysis using photoacids. Biocompatibility can be introduced by grafting a conformal layer of poly(ethylene glycol) atop the HPFs. Such patterns serve as templates for spatially segregating viable mammalian and bacterial cells. In addition to the PAA HPFs, another family of patternable HPFs consisting of dendrimers and an active anhydride copolymer is described. PMID- 23686899 TI - A new strategy for the design of molecular probes for investigating endogenous nitric oxide using an EPR or fluorescent technique. AB - A development of a new probe for NO, a molecule of profound biophysiological importance, based on the concept of "spin exchange" is described. This probe, based on the detection of a released TEMPOL radical, offers detection by EPR to 10 nm. PMID- 23686900 TI - Fluorescence confocal polarizing microscopy: imaging liquid crystal director fields in three dimensions. AB - Conventional polarizing microscopy allows only information from two dimensions, on account of optical integration along the path of light propagation. Real three dimensional imaging of orientational order has now become possible with fluorescence confocal polarizing microscopy. This technique provides a useful tool in the visualization of director fields in liquid crystal cells, as schematically shown in the picture, and will be of great potential in the study of director distributions in defect structures of anisotropic fluids. PMID- 23686901 TI - Conformational flexibility of phycocyanobilin: an AM1 semiempirical study. AB - Semiempirical AM1 studies on phycocyanobilin, the most abundant chromophore in the light-harvesting phycobiliproteins and a suitable model of the phytochrome chromophore, have been carried out. For the all-Z isomer, the structures and energies of all possible conformers, which arise from rotation about the single bonds of the exocyclic methine bridges, were calculated. In addition, the rotational barriers between the different conformers were deduced from the computed energy hypersurfaces. The cyclic helical SSS conformation is the most stable structure. Other minimum-energy structures with well-separated local minima on the energy hypersurface are the partially extended ASS and SAS conformations, although the conformational situation is characterized by a high degree of kinetic flexibility. The energy of the different conformers is mainly governed by intramolecular hydrogen bonding and steric repulsion of the substituents at the tetrapyrrolic backbone. It is very likely that the energetically most favorable conformers, SSS, ASS, and SAS, correspond with the three ground-state conformers of phycocyanobilin detected in previous time resolved absorption studies. PMID- 23686902 TI - Energetic and conformational aspects of A:T base-pair opening within the DNA double helix. AB - Free energy profiles of opening of a centrally placed A:T pair within a DNA oligomer exhibits two regimes: Elastic deformation due to hydrogen bond rupture and a roughly linear region due to loss of stacking and solvation. Thymine opens equally easily into the minor and major grooves, while adenine favors the major groove direction. No significant variations from canonical backbone conformations were observed; however base opening induces considerable changes in surrounding solvent distribution, leading finally to a water channel which passes through the double helix. PMID- 23686903 TI - Electron-induced chemistry of 5-chlorouracil. AB - Dissociative electron attachment to 5-chlorouracil cannot proceed directly , since the dissociative sigma* state is too short-lived and autodetachment occurs rapidly. Effcient fragmentation of the chlorouracil anion radical is only possible if a nondissociative pi* state is formed initially that undergoes an intersection with the sigma* state at an elongated C-Cl distance. PMID- 23686904 TI - Probing the magnetic anisotropy of lanthanide-containing metallomesogens by luminescence spectroscopy. AB - The alignment of liquid crystals through magnetism demands a high value of the magnetic anisotropy. The magnitude of the anisotropy for a series of isostructural lanthanide-containing metallomesogens can be estimated on basis of the crystal-field splitting of the (7)F1 multiplet in the corresponding europium(III) compounds. A method to rapidly measure this splitting value is accessible through photoluminescence measurements. PMID- 23686905 TI - Observation of magnetic coupling between distant metal centers in K3(MnO4)2 by muon spin relaxation measurements. AB - The site of a probe muon in the double salt K3(MnO4)2, which exhibits an antiferromagnetic phase at low temperature, and the Neel temperature of the salt were determined by zero-field muon spin relaxation. The picture shows the relaxation of the polarization asymmetry after muon insertion and a part of the crystal lattice. PMID- 23686906 TI - Localized electrodeposition by patterned redox-active monolayers. AB - Microfabrication of surface-confined metal structures by the controlled patterning of electrode surfaces with polyoxometalate (POM) monolayers can be achieved by contact printing. The obtained patterns are used to locally catalyze the electrocrystallization of metals. PMID- 23686907 TI - Durable micropatterns obtained from dissipative structures in liquid crystals. AB - A diffraction grating or more complex optical phase object can be formed and preserved from a crosslinked liquid crystalline film. The gratings are formed from electrically conductive liquid crystals, which show a rich variety of dissipative structures depending on the applied AC field strength and frequency. Addition of a crosslinking agent and irradiation with UV light thereby "freezes" the structures. PMID- 23686908 TI - The catalytic cracking of hydrocarbons: paraffins in the HZSM-5 zeolite. AB - An elementary reaction during cracking of a hydrocarbon in a nanoporous silicalite catalyst includes ejection of a hydrid ion as shown in the picture. The reaction was simulated by means of quantum molecular dynamics. PMID- 23686910 TI - Characterization of a virulent bacteriophage LK1 specific for Citrobacter freundii isolated from sewage water. AB - Citrobacter freundii is a worldwide emerging nosocomial pathogen with escalating incidence of multidrug resistance. Citrobacter freundii exists in natural environment, especially in health care settings and is difficult to eradicate. Phage therapy is considered as an alternative way of controlling bacterial infections and contaminations. In this study, we have described isolation and characterization of a virulent bacteriophage LK1 capable of specifically infecting Citrobacter freundii. A virulent bacteriophage LK1, specific for Citrobacter freundii was isolated from sewage water sample. TEM showed that phage Lk1 has an icosahedral head 70 nm in diameter and short tail of 17 nm, and can be classified as a member of the Podoviridae family. Restriction analysis indicated that phage LK1 was a dsDNA virus with an approximate genome size of 20-23 kb. Proteomic pattern generated by SDS PAGE using purified LK1 phage particles, revealed three major and six minor protein bands with molecular weight ranging from 25 to 80 kDa. Adsorption rate of LK1 relative to the host bacterium was also determined which showed significant improvement in adsorption with the addition of CaCl2 . In a single step growth experiment, LK1 exhibited a latent period of 24 min and burst size of 801 particle/cell. Moreover, pH and thermal stability of phage LK1 demonstrated a pH range of 5.0-6.0 and phage viability decreased to 0% at 65 degrees C. When LK1 was used to infect six other clinically isolated pathogenic strains, it showed relatively narrow host range. LK1 was capable of eliciting efficient lysis of Citrobacter freundii, revealing its potential as a non-toxic sanitizer for controlling Citrobacter freundii infection and contamination in both hospital and other public environments. PMID- 23686911 TI - Descriptive epidemiology of idiopathic clubfoot. AB - Clubfoot is a common structural malformation, occurring in approximately 1/1,000 live births. Previous studies of sociodemographic and pregnancy-related risk factors have been inconsistent, with the exception of the strong male preponderance and association with primiparity. Hypotheses for clubfoot pathogenesis include fetal constraint, Mendelian-inheritance, and vascular disruption, but its etiology remains elusive. We conducted a population-based case-control study of clubfoot in North Carolina, Massachusetts, and New York from 2007 to 2011. Mothers of 677 clubfoot cases and 2,037 non-malformed controls were interviewed within 1 year of delivery about socio-demographic and reproductive factors. Cases and controls were compared for child's sex, maternal age, education, cohabitation status, race/ethnicity, state, gravidity, parity, body mass index (BMI), and these pregnancy-related conditions: oligohydramnios, breech delivery, bicornuate uterus, plural birth, early amniocentesis (<16 weeks), chorionic villous sampling (CVS), and plural gestation with fetal loss. Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for state. Cases were more likely to be male (OR: 2.7; 2.2-3.3) and born to primiparous mothers (1.4; 1.2-1.7) and mothers with BMI >=30 kg/m(2) (1.4; 1.1-1.8). These associations were greatest in isolated and bilateral cases. ORs for the pregnancy related conditions ranged from 1.3 (breech delivery) to 5.6 (early amniocentesis). Positive associations with high BMI were confined to cases with a marker of fetal constraint (oligohydramnios, breech delivery, bicornuate uterus, plural birth), inheritance (family history in 1st degree relative), or vascular disruption (early amniocentesis, CVS, plural gestation with fetal loss). Pathogenetic factors associated with obesity may be in the causal pathway for clubfoot. PMID- 23686912 TI - The SUMOylation of zinc-fingers and homeoboxes 1 (ZHX1) by Ubc9 regulates its stability and transcriptional repression activity. AB - Zinc-fingers and homeoboxes protein 1 (ZHX1) belongs to the ZF (zinc-fingers) class of homeodomain transcription factors, and its function remains largely unknown. ZHX1 has been previously found to interact with the activation domain of the nuclear factor Y subunit A (NFYA) and to have a transcriptional repression activity. Here, we report that the SUMO-E2 conjugating enzyme Ubc9 was identified to interact with ZHX1 by an interaction screen using a yeast two-hybrid system. This interaction was confirmed by co-immunoprecipitation and co-localization assays. Further study showed that ZHX1 is SUMOylated by Ubc9 with SUMO1 at the sites K159, K454, and K626. Furthermore, we demonstrated that the SUMOylation of ZHX1 regulated the stability, ubiquitination and transcriptional activity of ZHX1. PMID- 23686913 TI - Skin involvement with Hodgkin disease: a rare condition late in the course of Hodgkin lymphoma. PMID- 23686914 TI - C domain-selective inhibition of angiotensin-converting enzyme. PMID- 23686916 TI - Changes in the mobile phase composition on a stepwise counter-current chromatography elution for the isolation of flavonoids from Siparuna glycycarpa. AB - This paper describes the isolation of flavonoids and other aromatic compounds from an ethyl acetate extract of leaves of Siparuna glycycarpa using stepwise elution counter-current chromatography (CCC). The elution profile yielded the following compounds: diglycosylated flavonoids, quercetin 3-O-rutinoside and quercetin 7-O-rutinoside, followed by monoglycosylated flavonoids, kaempferol-3-O beta-glucopyranoside, kaempferol-3-O-beta-rhamnopiranoside, kaempferol-3-O-beta 6''(p-coumaroyl) glucopyranoside, and quercetin-3-O-beta-glucopyranoside, and then free phenolics, protocatechuic acid, and 2',6'-dihydroxy-4, 4' dimethoxydihydrochalcone, which shows that this type of elution covers a broader range of polarity than the traditional isocratic mode. This makes it more suitable to perform separations of mixtures containing large differences in hydrophobicity. A GC analysis of a blank CCC run was performed to determine if changes in the mobile phase composition affect the chromatographic process. Results showed a gradual variation of the composition of the mobile phase emerging after the step gradient, favoring the selectivity of the solvent system. PMID- 23686915 TI - Pharmacotherapy challenges of Fontan-associated plastic bronchitis: a rare pediatric disease. AB - Pediatric pharmacotherapy is often challenging due to the paucity of available clinical data on the safety and efficacy of drugs that are commonly used in children. This quandary is even more prevalent in children with rare diseases. Although extrapolations for dosing and administration are often made from available adult data with similar disease states, this translation becomes even more problematic in rare pediatric diseases. Understanding of rare disease pathophysiology is typically poor, and few, if any, effective therapies have been studied and identified. One condition that illustrates these issues is plastic bronchitis, a rare, most often pediatric disease that is characterized by the production of obstructive bronchial airway casts. This illness primarily occurs in children with congenital heart disease, often after palliative surgery. Plastic bronchitis is a highly clinically relevant and therapeutically challenging problem with a high mortality rate, and, a generally accepted effective pharmacotherapy regimen has yet to be identified. Furthermore, the disease is ill defined, which makes timely identification and treatment of children with plastic bronchitis difficult. The pharmacotherapies currently used to manage this disease are largely anecdotal and vary between the use of macrolide antibiotics, mucolytics, bronchodilators, and inhaled fibrinolytics in a myriad of combinations. The purpose of this review is 2-fold: first, to highlight the dilemma of treating plastic bronchitis, and second, to bring attention to the continuing need for studies of drug therapies used in children so safe and effective drug regimens can be established, particularly for rare diseases. PMID- 23686917 TI - Analysis of legumain and cystatin 6 expression at the maternal-fetal interface in pigs. AB - Cathepsins (CTSs), a family of lysosomal cysteine proteases, and their inhibitors, cystatins (CSTs), play a critical role in endometrial and placental tissue remodeling during the establishment and maintenance of pregnancy in many species including rodents, sheep, cow, and pigs. In this study, we determined expression of legumain (LGMN), a cathepsinmember, and its inhibitor, CST6, at the maternal-fetal interface in pigs. Expression of both LGMN and CST6 mRNAs increased during mid- to late pregnancy in the uterine endometrium. LGMN and CST6 mRNAs localized to luminal epithelial cells (LE) and glandular epithelial cells (GE) and to the chorionic membrane (CM), with a strong intensity in GE and the CM for LGMN and in the CM for CST6 during pregnancy. LGMN protein was detected at molecular weights (MW) of approximately 50,000 and 37,000, and the abundance of the37,000-MW LGMN protein increased during mid- to latepregnancy. CST6 protein was also highly expressed in the uterine endometrium in mid- to latepregnancy. LGMN protein localized to LE, GE, and the CM during pregnancy. LGMN and CST6 were aberrantly expressed in the uterine endometrium from gilts with somatic cell nuclear transfer-derived conceptuses at term compared to those of gilts carrying conceptuses derived from natural mating. These results demonstrated that LGMN and CST6 were expressed in the uterine endometrium in a cell-type and stage-specific manner, suggesting that the LGMN and CST6 system at the maternal-fetal interface may play an important role in the establishment and maintenance of pregnancy in pigs. PMID- 23686918 TI - Isolation and characterization of indigenous Streptomyces and Lentzea strains from soils containing boron compounds in Argentina. AB - The Salta Province - in the northwest of Argentina - is the main worldwide producer of hydroboracite and leads in exports of boron mineral and its derivatives in Latin America. In addition to the natural presence of boron compounds in the soils, there are others contaminated due to the boron mining industry. Although some bacteria are known to require boron for their growth or to be capable of storing boron, no studies have been published about Streptomyces or Lentzea genera's capacity to tolerate high boron concentrations, or about their metabolic capacities in boron contaminated environments. The results of this research show the isolation and molecular characterization of eight strains belonging to the actinobacteria phylum collected from different soils contaminated with high boron concentration in Salta state. The boron tolerance assays, which show that three of the strains were able to tolerate up 60-80 mM boron, demonstrate the potential capability of this group of bacteria to grow and maybe to remove boron from the environment. They appear to be promising, considering that these microorganisms are infrequent pathogens, are metabolically versatile and many Streptomyces can synthesize boron containing metabolites. PMID- 23686919 TI - Retracted: Impact of polymorphisms in the oestrogen receptors alpha and beta (ESR1, ESR2) genes on risk of vasculogenic erectile dysfunction. AB - The above article from Andrology, 'Impact of polymorphisms in the oestrogen receptors alpha and beta (ESR1, ESR2) genes on risk of vasculogenic erectile dysfunction' by M. R. Safarinejad, A. Taghva, N. Shafiei and S. Safarinejad published online on 20 May 2013 in Wiley Online Library has been retracted by agreement between the journal Editors-in-Chief, Douglas Carrell and Ewa Rajpert De Meyts and John Wiley and Sons Ltd. The retraction has been decided due to failure by the lead author to verify the data contained in the study, and to provide evidence of the role of co-authors and their institutional affiliations. PMID- 23686922 TI - EPR monitoring of redox processes in transition metal oxide catalysts. AB - Transition metal oxides (TMO) are widely used as catalysts of a number of catalytic reactions, mainly of redox nature. This is due to the unique ability of transition metal ions to change easily their oxidation state, coordination, and/or arrangement of the coordination polyhedra. At present, the only abundant, direct information available about paramagnetic centers formed during interaction of the reagents with the TMO surface stems from EPR studies. This technique is very sensitive and allows detection of very small concentration of paramagnetic sites. Moreover, analysis of the EPR spectrum offers a direct approach to the determination of symmetry and electronic structure of the centers concerned. Such information is of particular value for understanding the operating reduction/reoxidation mechanisms, with immediate implications for solid-state structural studies, catalysis and so forth. The present work shows two aspects of the use of EPR for monitoring of redox processes with the participation of TMO: a) investigation of the reaction kinetics and b) description of the individual active sites involved in the catalytically important redox processes. The presented examples include: a) kinetic descriptions (including mathematical models) of reduction and oxidation processes in the vanadia-molybdena catalysts occurring upon interaction with propene and oxygen, b) identification of paramagnetic centers formed in the reduced molybdena, c) analysis of the butene interaction with a nickel catalyst, and d) description of the radical oxygen species on the surface of manganese-containing catalysts. PMID- 23686920 TI - Genetic heterogeneity in type III familial cutaneous syndactyly and linkage to chromosome 7q36. AB - The ZRS (zone of polarizing activity regulatory sequence) is a long-range limb specific Sonic Hedgehog (SHH) enhancer. In humans, the ZRS is located in chromosome 7q36 within intron 5 of LMBR1; approximately 1 Mb telomeric of SHH. Point mutations and duplications of the ZRS lead to a variable phenotype of preaxial polydactyly/triphalangeal thumb, tibial hypoplasia, radial ray deficiency, and type IV familial syndactyly (syndactyly of all digits with polydactyly). The ZRS is conserved among mammals and fish and regulates the expression of SHH. In mice, the conserved ZRS within the Lmbr1 gene is found in chromosome 5. The Hammertoe (Hm) mouse mutants have a mutation in the Lmbr1 locus and show syndactyly of digits 2-5 without polydactyly. No previous reports have described isolated syndactyly without polydactyly to be related to the LMBR1 locus in humans. In this report, we describe a family with simple cutaneous syndactyly involving digits 2-5, without polydactyly which is consistent with the phenotype of type III syndactyly. The locus we identified on ch7q36.3 is syntenic to the Hm locus; and affected members of the family had a phenotype analogous to Hm. Hence, the type of syndactyly described in the current report may be equivalent to Hm mice. PMID- 23686923 TI - Filamentous carbon growth on nickel/silica: potassium and bromine as catalyst promotors. AB - In a previous Communication, we reported the catalytic growth of highly ordered carbon filaments during the hydrodechlorination of chlorobenzene over nickel/silica at the remarkably low temperature of 553 K. This low temperature growth was attributed to the presence of bromine and potassium on the catalyst surface, which facilitated a restructuring of the active sites leading to a destructive chemisorption of the reactant that preceded the dissolution and precipitation of carbon in an ordered fashion. In this paper, we examine the effect of bromine and potassium built into (by impregnation with KOH, HBr and KBr) a Ni/SiO2 parent sample on filamentous carbon production through ethylene decomposition. The parent catalyst delivered a low yield of carbon (0.2 g(C)g(cat)(-1)) and promoted the competing hydrogenation (to ethane) step to the same degree; hydrogenolysis to methane represented the only other significant reaction. The nature of the carbon deposition has been characterised by high resolution transmission electron microscopy (HRTEM) and temperature-programmed oxidation (TPO). Impregnation with KOH resulted in little change in carbon yield but the hydrogenolysis step was completely suppressed. A combination of CO chemisorption/temperature programmed desorption has been employed to probe the electronic structure of the nickel sites where the presence of potassium limited CO uptake in contrast to surface bromine which served, through electron withdrawal, to strengthen the CO-Ni interaction. Incorporation of bromine into the catalyst resulted in a marked increase in nickel particle size and a dramatic enhancement of carbon yield; the sample treated with KBr delivered the appreciably higher carbon yield of 7.6 g(C)g(cat)(-1)). While the presence of bromine on the surface served to enhance carbon deposition, the additional incorporation of potassium raised the degree of order in the carbon growth. PMID- 23686924 TI - Tunable surface-enhanced Raman scattering from large gold nanoparticle arrays. AB - Raman signal enhancements in excess of 10(7) can be achieved at near-infrared wavelengths when mid-nanometer sized gold particles self-organize into close packed planar arrays. These substrates generate stable surface-enhanced Raman scattering which changes dramatically as a function of periodic structure and excitation wavelength. PMID- 23686925 TI - Surface enhanced resonance Raman scattering (SERRS)--a first example of its use in multiplex genotyping. AB - Accurate multiplex genotyping of the mutational status of the cystic fibrosis gene with the sensitive and selective SERRS technique is reported. This new assay does not require separation of the various alleles and shows that SERRS is a realistic alternative detection technique for use in modern DNA assays. PMID- 23686926 TI - Thermal detrapping rates of atomic hydrogen and atomic deuterium trapped in double four-ring Si8O12 cages measured simultaneously using EPR. AB - Does atomic hydrogen or atomic deuterium escape faster from the D4R cage of Q8M8 in thermal detrapping? An isotope effect was clearly observed by a simultaneous measurement using EPR. Arrhenius parameters were obtained and allowed the application of the absolute rate theory to explain the process. PMID- 23686927 TI - Molecular superlattices induced by alkyl substitutions in self-assembled triphenylene monolayers. AB - The configuration of the superlattices, formed from liquid-crystalline molecules on a graphite surface, are controllable through their alkyl substituents. This control may be attributed to the interplay of molecular steric interaction and the 2 D crystallization of alkyl chains. Two such lattices, as observed by STM, are shown in the accompanying graphic (C12- and (inset) C14-substituted molecules). PMID- 23686928 TI - Evidence for a transition between singlet and triplet states in the electrochemical reduction of 2,2'-4,4'-tetranitrobiphenyl. AB - Two different dianionic species, close in energy, result from the electroreduction of 2,2'-4,4'-tetranitrobiphenyl, 1. The first-formed species has biradical characteristics, such as a triplet EPR spectrum, but it slowly evolves to another EPR-silent species, essentially described as a quinoid form. DFT calculations also support the existence of two dianionic states of the dianion, singlet and triplet, differing by less than 10 kcal mol(-1) (in the gas phase); the quinoid singlet state is more stable. PMID- 23686929 TI - Kinetics of one- and two-directional charge hopping in one-dimensional systems: application to DNA. AB - A kinetic hopping model for one- (1D) and two-directional (2D) charge migration in a one-dimensional system has been developed and applied to the migration of a positive charge along guanine G sites in DNA strands. The charge lifetimes before trapping at a guanine cluster GGG allow an evaluation of the contribution of the superexchange mechanism in the charge transfer. For a 1D system with a small number of hopping sites and unbiased hopping, the explicit kinetic expression differs from a previously introduced equation but confirms the reported weak distance dependence. PMID- 23686930 TI - Absolute configuration assignment of D3-symmetric lanthanide complexes based on circular dichroism induced by interaction with a chiral probe. AB - Chiroptical properties and absolute configuration have been correlated for a series of [Ln(oda)3](3-) complexes in aqueous solution (Ln=Pr, Nd, Sm, Eu, Tb, Dy, Ho, Er, or Tm; oda=2,2'-oxydiacetic acid). Addition of the chiral probe L proline (L-Pro) to a series of the racemic complexes resulted in an excess of the Lambda-enantiomer. PMID- 23686931 TI - A dendritic antenna for near-infrared emission of Nd3+ ions. AB - An interior of 18 amide groups and a periphery functionalized with 24 dansyl groups forms a light-harvesting dendrimer which features intense absorption bands in the near-UV spectral region and a strong fluorescence band in the visible region. Upon encapsulation of Nd(3+) ions, the fluorescence of the dansyl groups is quenched and an intense sensitized near-infrared emission of Nd(3+) is observed. The associated energy transfer is shown in the cartoon. PMID- 23686933 TI - Looking for familial nodular lymphocyte-predominant Hodgkin lymphoma. PMID- 23686934 TI - Epilepsy and seizure ontology: towards an epilepsy informatics infrastructure for clinical research and patient care. AB - OBJECTIVE: Epilepsy encompasses an extensive array of clinical and research subdomains, many of which emphasize multi-modal physiological measurements such as electroencephalography and neuroimaging. The integration of structured, unstructured, and signal data into a coherent structure for patient care as well as clinical research requires an effective informatics infrastructure that is underpinned by a formal domain ontology. METHODS: We have developed an epilepsy and seizure ontology (EpSO) using a four-dimensional epilepsy classification system that integrates the latest International League Against Epilepsy terminology recommendations and National Institute of Neurological Disorders and Stroke (NINDS) common data elements. It imports concepts from existing ontologies, including the Neural ElectroMagnetic Ontologies, and uses formal concept analysis to create a taxonomy of epilepsy syndromes based on their seizure semiology and anatomical location. RESULTS: EpSO is used in a suite of informatics tools for (a) patient data entry, (b) epilepsy focused clinical free text processing, and (c) patient cohort identification as part of the multi center NINDS-funded study on sudden unexpected death in epilepsy. EpSO is available for download at http://prism.case.edu/prism/index.php/EpilepsyOntology. DISCUSSION: An epilepsy ontology consortium is being created for community-driven extension, review, and adoption of EpSO. We are in the process of submitting EpSO to the BioPortal repository. CONCLUSIONS: EpSO plays a critical role in informatics tools for epilepsy patient care and multi-center clinical research. PMID- 23686935 TI - Toward creation of a cancer drug toxicity knowledge base: automatically extracting cancer drug-side effect relationships from the literature. AB - OBJECTIVE: A comprehensive and machine-understandable cancer drug-side effect (drug-SE) relationship knowledge base is important for in silico cancer drug target discovery, drug repurposing, and toxicity predication, and for personalized risk-benefit decisions by cancer patients. While US Food and Drug Administration (FDA) drug labels capture well-known cancer drug SE information, much cancer drug SE knowledge remains buried the published biomedical literature. We present a relationship extraction approach to extract cancer drug-SE pairs from the literature. DATA AND METHODS: We used 21,354,075 MEDLINE records as the text corpus. We extracted drug-SE co-occurrence pairs using a cancer drug lexicon and a clean SE lexicon that we created. We then developed two filtering approaches to remove drug-disease treatment pairs and subsequently a ranking scheme to further prioritize filtered pairs. Finally, we analyzed relationships among SEs, gene targets, and indications. RESULTS: We extracted 56,602 cancer drug-SE pairs. The filtering algorithms improved the precision of extracted pairs from 0.252 at baseline to 0.426, representing a 69% improvement in precision with no decrease in recall. The ranking algorithm further prioritized filtered pairs and achieved a precision of 0.778 for top-ranked pairs. We showed that cancer drugs that share SEs tend to have overlapping gene targets and overlapping indications. CONCLUSIONS: The relationship extraction approach is effective in extracting many cancer drug-SE pairs from the literature. This unique knowledge base, when combined with existing cancer drug SE knowledge, can facilitate drug target discovery, drug repurposing, and toxicity prediction. PMID- 23686936 TI - A flexible framework for recognizing events, temporal expressions, and temporal relations in clinical text. AB - OBJECTIVE: To provide a natural language processing method for the automatic recognition of events, temporal expressions, and temporal relations in clinical records. MATERIALS AND METHODS: A combination of supervised, unsupervised, and rule-based methods were used. Supervised methods include conditional random fields and support vector machines. A flexible automated feature selection technique was used to select the best subset of features for each supervised task. Unsupervised methods include Brown clustering on several corpora, which result in our method being considered semisupervised. RESULTS: On the 2012 Informatics for Integrating Biology and the Bedside (i2b2) shared task data, we achieved an overall event F1-measure of 0.8045, an overall temporal expression F1 measure of 0.6154, an overall temporal link detection F1-measure of 0.5594, and an end-to-end temporal link detection F1-measure of 0.5258. The most competitive system was our event recognition method, which ranked third out of the 14 participants in the event task. DISCUSSION: Analysis reveals the event recognition method has difficulty determining which modifiers to include/exclude in the event span. The temporal expression recognition method requires significantly more normalization rules, although many of these rules apply only to a small number of cases. Finally, the temporal relation recognition method requires more advanced medical knowledge and could be improved by separating the single discourse relation classifier into multiple, more targeted component classifiers. CONCLUSIONS: Recognizing events and temporal expressions can be achieved accurately by combining supervised and unsupervised methods, even when only minimal medical knowledge is available. Temporal normalization and temporal relation recognition, however, are far more dependent on the modeling of medical knowledge. PMID- 23686937 TI - Increased CO2 stimulates reproduction in a coral reef fish. AB - Ocean acidification is predicted to negatively impact the reproduction of many marine species, either by reducing fertilization success or diverting energy from reproductive effort. While recent studies have demonstrated how ocean acidification will affect larval and juvenile fishes, little is known about how increasing partial pressure of carbon dioxide (pCO(2)) and decreasing pH might affect reproduction in adult fishes. We investigated the effects of near-future levels of pCO(2) on the reproductive performance of the cinnamon anemonefish, Amphiprion melanopus, from the Great Barrier Reef, Australia. Breeding pairs were held under three CO(2) treatments [Current-day Control (430 MUatm), Moderate (584 MUatm) and High (1032 MUatm)] for a 9-month period that included the summer breeding season. Unexpectedly, increased CO(2) dramatically stimulated breeding activity in this species of fish. Over twice as many pairs bred in the Moderate (67% of pairs) and High (55%) compared to the Control (27%) CO(2) treatment. Pairs in the High CO(2) group produced double the number of clutches per pair and 67% more eggs per clutch compared to the Moderate and Control groups. As a result, reproductive output in the High group was 82% higher than that in the Control group and 50% higher than that in the Moderate group. Despite the increase in reproductive activity, there was no difference in adult body condition among the three treatment groups. There was no significant difference in hatchling length between the treatment groups, but larvae from the High CO(2) group had smaller yolks than Controls. This study provides the first evidence of the potential effects of ocean acidification on key reproductive attributes of marine fishes and, contrary to expectations, demonstrates an initially stimulatory (hormetic) effect in response to increased pCO(2). However, any long term consequences of increased reproductive effort on individuals or populations remain to be determined. PMID- 23686938 TI - An essential primer for understanding the role of topical hemostats, surgical sealants, and adhesives for maintaining hemostasis. AB - A wide variety of topical hemostats are approved as adjunctive therapies in the maintenance of hemostasis during surgical procedures in which conventional methods are insufficient or not practical. A multidisciplinary approach to the selection and application of these agents requires input from all members of the surgical team including surgeons, perioperative nurses, blood bank specialists, and pharmacists. However, pharmacist knowledge regarding topical hemostats may be limited based on lack of formal education within college of pharmacy curricula as well as their use being predominantly in the operating room setting. Furthermore, some of these agents might be procured through central supply rather than the hospital pharmacy. Topical hemostats include agents that act as a mechanical barrier to bleeding and provide a physical matrix for clotting, biologically active agents that catalyze coagulation, combination therapies, and synthetic sealants and adhesives. Although many of the topical hemostats were approved for use before the requirement for clinical trials, this review provides an overview of the available clinical evidence regarding the appropriate uses and safety considerations associated with these agents. Proper use of these agents is vital to achieving the best clinical outcomes. Specifically, knowledge of the contraindications and potential adverse events associated with topical hemostats can help prevent unwanted outcomes. Therefore, an understanding of the benefits and potential risks associated with these agents will allow hospital pharmacists to assist in the development and implementation of institutional policies regarding the safe and effective use of hemostatic agents commonly used in the surgical suite. PMID- 23686939 TI - Evaluation of ultrasound synthetic aperture imaging using bidirectional pixel based focusing: preliminary phantom and in vivo breast study. AB - In medical ultrasound imaging, lateral resolution is limited when using a fixed transmit focusing. Various synthetic aperture (SA) techniques, in which two-way dynamic focusing is enabled by utilizing prebeamformed radio-frequency (RF) data have been proposed for improving the spatial resolution. However, SA methods were not extensively evaluated in terms of their clinical performance. In this paper, a phantom and an in vivo evaluation of the SA method with bidirectional pixel based focusing (BiPBF) is presented in comparison with the conventional beamforming. The performance of the proposed SA-BiPBF was assessed with a blind study and the established breast imaging-reporting and data system (BI-RADS), in addition to measuring contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR). Prebeamformed RF data were acquired from a tissue mimicking phantom (Model 040, CIRS Inc., Norfolk, VA, USA) and from patients with breast lesions by using a commercial ultrasound scanning system with a linear array transducer equipped with a research package and parallel data acquisition system (SonixTouch, SonixDAQ, and L14-5/38, Ultrasonix Corp., Canada). In phantom and in vivo experiments, a default setting of a breast preset was applied (e.g., the center frequency of 10 MHz and acoustic output of MI = 0.66). In phantom experiment, the SA-BiPBF method showed higher CNR and SNR values compared to the conventional method (3.4 and 23.9 dB versus 3.1 and 15.8 dB, respectively). In addition, the lateral resolution and penetration depth were increased by 95.4% and 40.3%, respectively. Consistent with the phantom experiment, in the in vivo experiment with ten patients, the CNR value for the SA method was 3.3 +/- 0.5 compared to 2.8 +/- 0.8 for the conventional method. Similarly, the SNR values with the SA BiPBF and conventional methods were 34.0 +/- 3.6 and 27.2 +/- 3.4 dB, respectively. From the experiments, it was shown in side-by-side comparisons that the image quality of the SA-BiPBF method was considerably improved in both phantom and in vivo breast images. However, the SA-BiPBF image showed different features compared to the conventional one in the in vivo experiments. These features are resulting from the increased image quality of the SA-BiPBF method but are not always perceived as improvements by the radiologists. PMID- 23686940 TI - Insights from theory and experiments on slip flow in chromatography. AB - Slip flow has become a topic of interest in reversed-phase liquid chromatography because it gives a flow enhancement that facilitates the use of submicrometer particles, providing a large improvement in separation efficiency. Moreover, slip flow provides an additional improvement in efficiency by reducing the velocity distribution in the mobile phase. The phenomenon of slip flow in open tubes is described in chromatographically relative terms. A recent paper in this journal is discussed, as it provides the first theoretical study of slip flow in packed beds, in this case for face-centered cubic geometry. The theory paper reveals that the presence of the packed bed introduces a heterogeneity in fluid velocities that is absent in open tubes, reducing the additional improvement in efficiency from slip flow. The recent paper also suggests that there is yet another factor improving efficiency, which is size-exclusion of proteins from regions of stagnant flow. The latter is supported by recently published data on restricted protein diffusion in face-centered cubic silica colloidal crystals. Extremely low plate heights are enabled by use of submicrometer particles, and further improvement appears to be possible when the analyte size is on the order of 1% of the particle diameter or larger. PMID- 23686941 TI - Feasibility of using actigraphy and motivational-based interviewing to improve sleep among school-age children and their parents. AB - Inadequate sleep occurs in 25% of our nation's children; poor sleep is associated with physical, cognitive, and social consequences. Developing good sleep hygiene in middle childhood is important, because habits typically extend to adolescence and adulthood; yet, there has been little research on sleep interventions for school-age children. The purpose of this study was to determine the feasibility of a developmentally tailored, motivation-based intervention (MBI) focused on improving sleep behaviors in school-age children aged 8-11. Nine parent-child dyads participated in an 8-week protocol utilizing MBI and comparisons of objective (actigraphy) and subjective (sleep diaries) data. Results suggest that parent and children are able to identify a target behavior to change and complete the protocol. Further, preliminary evidence indicates that sleep patterns change using MBI. Future research will be directed toward comparative effectiveness testing and exploring ways in which it can be adapted and incorporated into school nursing practice. PMID- 23686943 TI - Structure propagation for image registration. AB - Mosaicing is a commonly used technique in many medical imaging applications where subimages are stitched together in order to obtain a larger field of view. However, stitching, which involves alignment or registration in overlapping regions, is often challenging when the information shared by subimages is absent or small. While it is not possible to perform an alignment without overlap using existing techniques, imaging artifacts such as distortions towards image boundaries present further complications during registration by decreasing the reliability of available information. Without taking these into consideration, a registration approach might violate the continuity and the smoothness of structures across subimages. In this paper, we propose a novel registration approach for the stitching of subimages in such challenging scenarios. By using a perceptual grouping approach, we extend subimages beyond their boundaries by propagating available structures in order to obtain structural maps in the extended regions. These maps are then used to establish correspondences between subimages when the shared information is absent, small or unreliable. Using our approach ensures the continuity and the smoothness of structures across subimage boundaries. Furthermore, since only structures are used, the proposed method can also be used for the stitching of multi-modal images. Our approach is unique in that it also enables contactless stitching. We demonstrate the effectiveness of the proposed method by performing several experiments on synthetic and medical images. Moreover, we show how stitching is possible in the presence of a physical gap between subimages. PMID- 23686942 TI - Imaging transverse isotropic properties of muscle by monitoring acoustic radiation force induced shear waves using a 2-D matrix ultrasound array. AB - A 2-D matrix ultrasound array is used to monitor acoustic radiation force impulse (ARFI) induced shear wave propagation in 3-D in excised canine muscle. From a single acquisition, both the shear wave phase and group velocity can be calculated to estimate the shear wave speed (SWS) along and across the fibers, as well as the fiber orientation in 3-D. The true fiber orientation found using the 3-D radon transform on B-mode volumes of the muscle was used to verify the fiber direction estimated from shear wave data. For the simplified imaging case when the ARFI push can be oriented perpendicular to the fibers, the error in estimating the fiber orientation using phase and group velocity measurements was 3.5 +/- 2.6 degrees and 3.4 +/- 1.4 degrees (mean +/- standard deviation), respectively, over six acquisitions in different muscle samples. For the more general case when the push is oblique to the fibers, the angle between the push and the fibers is found using the dominant orientation of the shear wave displacement magnitude. In 30 acquisitions on six different muscle samples with oblique push angles up to 40 degrees , the error in the estimated fiber orientation using phase and group velocity measurements was 5.4 +/- 2.9 degrees and 5.3 +/- 3.2 degrees , respectively, after estimating and accounting for the additional unknown push angle. Either the phase or group velocity measurements can be used to estimate fiber orientation and SWS along and across the fibers. Although it is possible to perform these measurements when the push is not perpendicular to the fibers, highly oblique push angles induce lower shear wave amplitudes which can cause inaccurate SWS measurements. PMID- 23686944 TI - Externally navigated bronchoscopy using 2-D motion sensors: dynamic phantom validation. AB - The paper presents a new endoscope motion tracking method that is based on a novel external endoscope tracking device and our modified stochastic optimization method for boosting endoscopy navigation. We designed a novel tracking prototype where a 2-D motion sensor was introduced to directly measure the insertion retreat linear motion and also the rotation of the endoscope. With our developed stochastic optimization method, which embeds traceable particle swarm optimization in the Condensation algorithm, a full six degrees-of-freedom endoscope pose (position and orientation) can be recovered from 2-D motion sensor measurements. Experiments were performed on a dynamic bronchial phantom with maximal simulated respiratory motion around 24.0 mm. The experimental results demonstrate that our proposed method provides a promising endoscope motion tracking approach with more effective and robust performance than several current available tracking techniques. The average tracking accuracy of the position improved from 6.5 to 3.3 mm, which further approaches the clinical requirement of 2.0 mm in practice. PMID- 23686946 TI - Mariner-based transposon mutagenesis for Bacteroides species. AB - Bacteroides is one of the most predominant groups of human gut microbiota. Recent metagenomic analyses and studies on gnotobiotic mice demonstrated the tight association of Bacteroides with epithelial function, the gut immune system and systemic metabolism in the host. The mariner family transposon shows relatively low target site specificity and has hosts ranging from prokaryotes to eukaryotes. Thereby, random mutagenesis using the mariner family transposon is expected to identify key molecules for human-Bacteroides symbiosis. In this study, we constructed the plasmid pMI07 to deliver the gene cassette (ermF/ITR), which harbors the erythromycin resistant marker (ermF) and the inverted repeat sequences (ITRs) recognized by Himar1 transposase, to Bacteroides via electrotransformation. pMI07 successfully delivered ermF/ITR to the Bacteroides genomes and generated thousands of insertion mutants/MUg of pMI07 in B. thetaiotaomicron, B. fragilis, B. ovatus, and also, although to a lesser extent, B. vulgatus. Analyses of the ermF/ITR insertion sites in B. thetaiotaomicron and B. vulgatus revealed that the cassette targeted the dinucleotide TA and integrated into the genomes in an unbiased manner. The data reported here will provide useful information for transposon mutagenesis in Bacteroides species, which will enable identification of the genes responsible for their unique phenotypes. PMID- 23686947 TI - Pollen germination activates the apical membrane-located RAC/ROP GTPase switch. PMID- 23686945 TI - Retention of exogenous mRNAs selectively in the germ cells of the sea urchin requires only a 5'-cap and a 3'-UTR. AB - The abundance of an mRNA in a cell depends on its overall rates of synthesis and decay. RNA stability is an important element in the regulation of gene expression, and is achieved by a variety of processes including specific recruitment of nucleases and RNAi-associated mechanisms. These mechanisms are particularly important in stem cells, which, in many cases, have attenuated transcription. Here we report that exogenous mRNA injected into fertilized eggs of the sea urchin is selectively retained in the small micromeres, which contribute to the germ line in this organism, beginning in blastulae, when compared to adjacent somatic cells. We show that modification of this exogenous RNA using cap analogs and poly-adenosine tail deletions do not affect its selective retention in the small micromeres, but removal of the cap or of the 3' untranslated region eliminates any selective mRNA retention in the presumptive germ line. Our results illuminate a likely ancient mechanism used by stem cells to prolong the lifespan of RNAs-either through RNA protection or by the absence of basic RNA degradation mechanisms, which are employed by most other cells of an organism. PMID- 23686948 TI - Phosphatidic acid (PA) binds PP2AA1 to regulate PP2A activity and PIN1 polar localization. AB - Phospholipase D (PLD) exerts broad biological functions in eukaryotes through regulating downstream effectors by its product, phosphatidic acid (PA). Protein kinases and phosphatases, such as mammalian target of rapamycin (mTOR), Protein Phosphatase 1 (PP1) and Protein Phosphatase 2C (PP2C), are PA-binding proteins that execute crucial regulatory functions in both animals and plants. PA participates in many signaling pathways by modulating the enzymatic activity and/or subcellular localization of bound proteins. In this study, we demonstrated that PLD-derived PA interacts with the scaffolding A1 subunit of Protein Phosphatase 2A (PP2A) and regulates PP2A-mediated PIN1 dephosphorylation in Arabidopsis. Genetic and pharmacological studies showed that both PA and PP2A participate in the regulation of auxin distribution. In addition, both the phosphorylation status and polar localization of PIN1 protein were affected by PLD inhibitors. Exogenous PA triggered the membrane accumulation of PP2AA1 and enhanced the PP2A activity at membrane, while PLD inhibition resulted in the reduced endosomal localization and perinuclear aggregation of PP2AA1. These results demonstrate the important role of PLD-derived PA in normal PP2A-mediated PIN dephosphorylation and reveal a novel mechanism, in which PA recruits PP2AA1 to the membrane system and regulates PP2A function on membrane-targeted proteins. As PA and PP2A are conserved among eukaryotes, other organisms might use similar mechanisms to mediate multiple biological processes. PMID- 23686949 TI - Transport logistics in pollen tubes. AB - Cellular organelles move within the cellular volume and the effect of the resulting drag forces on the liquid causes bulk movement in the cytosol. The movement of both organelles and cytosol leads to an overall motion pattern called cytoplasmic streaming or cyclosis. This streaming enables the active and passive transport of molecules and organelles between cellular compartments. Furthermore, the fusion and budding of vesicles with and from the plasma membrane (exo/endocytosis) allow for transport of material between the inside and the outside of the cell. In the pollen tube, cytoplasmic streaming and exo/endocytosis are very active and fulfill several different functions. In this review, we focus on the logistics of intracellular motion and transport processes as well as their biophysical underpinnings. We discuss various modeling attempts that have been performed to understand both long-distance shuttling and short distance targeting of organelles. We show how the combination of mechanical and mathematical modeling with cell biological approaches has contributed to our understanding of intracellular transport logistics. PMID- 23686950 TI - A new energy framework with distribution descriptors for image segmentation. AB - Segmentation of the target object(s) from images that have multiple complicated regions, mixture intensity distributions or are corrupted by noise poses a challenge for the level set models. In addition, the conventional piecewise smooth level set models normally require prior knowledge about the number of image segments. To address these problems, we propose a novel segmentation energy function with two distribution descriptors to model the background and the target. The single background descriptor models the heterogeneous background with multiple regions. Then, the target descriptor takes into account the intensity distribution and incorporates local spatial constraint. Our descriptors, which have more complete distribution information, construct the unique energy function to differentiate the target from the background and are more tolerant of image noise. We compare our approach to three other level set models: 1) the Chan-Vese; 2) the multiphase level set; and 3) the geodesic level set. This comparison using 260 synthetic images with varying levels and types of image noise and medical images with more complicated backgrounds showed that our method outperforms these models for accuracy and immunity to noise. On an additional set of 300 synthetic images, our model is also less sensitive to the contour initialization as well as to different types and levels of noise. PMID- 23686951 TI - Monocular human motion tracking by using DE-MC particle filter. AB - Tracking human motion from monocular video sequences has attracted significantly increased interests in recent years. A key to accomplishing this task is to efficiently explore a high-dimensional state space. However, the traditional particle filter method and many of its variants have not been able to meet expectations as they lack a strategy to do efficiently sampling or stochastic search. We present a novel approach, namely differential evolution-Markov chain (DE-MC) particle filtering. By taking the advantage of the DE-MC algorithm's ability to approximate complicated distributions, substantial improvement can be made to the traditional structure of the particle filter. As a result, an efficient stochastic search can be performed to locate the modes of likelihoods. Furthermore, we apply the proposed algorithm to solve the 3D articulated model based human motion tracking problem. A reliable image likelihood function is built for visual tracker design. Based on the proposed DE-MC particle filter and the image likelihood function, we perform a variety of monocular human motion tracking experiments. Experimental results, including the comparison with the performance of other particle filtering methods demonstrate the reliable tracking performance of the proposed approach. PMID- 23686952 TI - Video texture synthesis with multi-frame LBP-TOP and diffeomorphic growth model. AB - Video texture synthesis is the process of providing a continuous and infinitely varying stream of frames, which plays an important role in computer vision and graphics. However, it still remains a challenging problem to generate high quality synthesis results. Considering the two key factors that affect the synthesis performance, frame representation and blending artifacts, we improve the synthesis performance from two aspects: 1) Effective frame representation is designed to capture both the image appearance information in spatial domain and the longitudinal information in temporal domain. 2) Artifacts that degrade the synthesis quality are significantly suppressed on the basis of a diffeomorphic growth model. The proposed video texture synthesis approach has two major stages: video stitching stage and transition smoothing stage. In the first stage, a video texture synthesis model is proposed to generate an infinite video flow. To find similar frames for stitching video clips, we present a new spatial-temporal descriptor to provide an effective representation for different types of dynamic textures. In the second stage, a smoothing method is proposed to improve synthesis quality, especially in the aspect of temporal continuity. It aims to establish a diffeomorphic growth model to emulate local dynamics around stitched frames. The proposed approach is thoroughly tested on public databases and videos from the Internet, and is evaluated in both qualitative and quantitative ways. PMID- 23686953 TI - Motion estimation using the correlation transform. AB - The zero-mean normalized cross-correlation is shown to improve the accuracy of optical flow, but its analytical form is quite complicated for the variational framework. This paper addresses this issue and presents a new direct approach to this matching measure. Our approach uses the correlation transform to define very discriminative descriptors that are precomputed and that have to be matched in the target frame. It is equivalent to the computation of the optical flow for the correlation transforms of the images. The smoothness energy is non-local and uses a robust penalty in order to preserve motion discontinuities. The model is associated with a fast and parallelizable minimization procedure based on the projected-proximal point algorithm. The experiments confirm the strength of this model and implicitly demonstrate the correctness of our solution. The results demonstrate that the involved data term is very robust with respect to changes in illumination, especially where large illumination exists. PMID- 23686954 TI - A modified model of the just noticeable depth difference and its application to depth sensation enhancement. AB - The just noticeable depth difference (JNDD) describes the threshold of human perception of the difference in the depth. In flat-panel-based three-dimensional (3-D) displays, the JNDD is typically measured by changing the depth difference between displayed image objects until the difference is perceivable. However, not only the depth, but also the perceived size changes when the depth difference increases. In this paper, we present a modified JNDD measurement method that adjusts the physical size of the object such that the perceived size of the object is maintained. We then apply the proposed JNDD measurement method to depth sensation enhancement. When the depth value difference between the objects is increased to enable the viewer to perceive the depth difference, the size of the objects is adjusted to maintain the perceived size of the objects. In addition, since the size change of the objects can produce a whole region, a depth-adaptive hole-inpainting technique is proposed to compensate for the hole region with high accuracy. The experimental results demonstrate the effectiveness of the proposed method. PMID- 23686955 TI - Optical spins and nano-antenna array for magnetic therapy. AB - Magnetic therapy is an alternative medicine practice involving the use of magnetic fields subjected to certain parts of the body and stimulates healing from a range of health problems. In this paper, an embedded nano-antenna system using the optical spins generated from a particular configuration of microrings (PANDA) is proposed. The orthogonal solitons pairs corresponding to the left-hand and right-hand optical solitons (photons) produced from dark-bright soliton conversion can be simultaneously detected within the system at the output ports. Two possible spin states which are assigned as angular momentum of either +h or h will be absorbed by an object whenever this set of orthogonal solitons is imparted to the object. Magnetic moments could indeed arise from the intrinsic property of spins. By controlling some important parameters of the system such as soliton input power, coupling coefficients and sizes of rings, output signals from microring resonator system can be tuned and optimized to be used as magnetic therapy array. PMID- 23686956 TI - Optical probing of single fluorescent molecules and proteins. AB - Single-molecule detection and analysis of organic fluorescent molecules and proteins are presented, with emphasis on the underlying principles, methodology and the application of single-molecule analysis at room temperature. This Minireview is mainly focused on the application of confocal and near-field optical microscopy to investigate the photodynamics of individual molecules embedded in ultrathin polymer layers. We discuss rotational mobility of individual probe molecules in polystyrene and poly(methylmethacrylate) thin films, fluorescence lifetime trajectories and their spatial distribution, and real-time singlet-triplet dynamics. As a whole, the single-molecule photodynamics observed is due to the dynamic nature of both polymers at room temperature, where local polymer conformational dynamics modulates the oxygen concentration and diffusion on a molecular scale, influencing the fluorescence lifetime and intersystem crossing parameters. We also discuss the photodynamics of individual autofluorescent proteins, in particular the on/off blinking and the apparent stability of the protein against bleaching. These studies illustrate the unique information obtainable with the single-molecule approach, information that is otherwise hidden in ensemble-averaged measurements. PMID- 23686957 TI - Inducing single-molecule chemical reactions with a UHV-STM: a new dimension for nano-science and technology. AB - Atomic and molecular manipulations with the scanning tunnelling microscope (STM) lead to many fascinating advances during the last decade. Recent achievements in inducing all of the basic steps of a chemical reaction with the STM at a single molecule level open up entirely new opportunities in chemistry on the nanoscale. In this article, we review various STM-based molecular manipulation techniques and their application in inducing all elementary chemical reaction steps on surfaces. Prospects for future opportunities of single-molecule chemical engineering and their possible implications to nanoscale science and technology are discussed. PMID- 23686958 TI - Selective adhesion, lipid exchange and membrane-fusion processes between vesicles of various sizes bearing complementary molecular recognition groups. AB - Equimolar mixtures of large unilamellar vesicles (LUVs) obtained from mixtures of egg lecithin and lipids containing complementary hydrogen bonding head groups (barbituric acid (BAR) and 2,4,6-triaminopyrimidine (TAP)) were shown to aggregate and fuse. These events have been studied in detail using electron microscopy and dynamic light scattering, and by fluorimetry using membrane or water-soluble fluorescence probes. It was shown that aggregation was followed by two competitive processes: a) lipid mixing leading to redispersion of the vesicles; b) fusion events generating much larger vesicles. In order to better understand the nature of the interaction, the effects of ionic strength and surface concentration of recognition lipids on the aggregation process were investigated by dynamic light scattering. Additionally, it was possible to inhibit the aggregation kinetics through addition of a soluble barbituric acid competitor. The study was extended to giant unilamellar vesicles (GUVs) to investigate the size effect and visualise the phenomena in situ. The interactions between complementary LUVs and GUVs or GUVs and GUVs were studied by optical microscopy using dual fluorescent labelling of both vesicle populations. A selective adhesion of LUVs onto GUVs was observed by electron and optical microscopies, whereas no aggregation took place in case of a GUV/GUV mixture. Furthermore, a fusion assay of GUV and LUV using the difference of size between GUV and LUV and calceine self-quenching showed that no mixing between the aqueous pools occured. PMID- 23686959 TI - Gauche, ortho, transoid and anti conformations of the tetrasilanes SiMe3SiX2SiX2SiMe3 (X=H, F, Cl, Br, I): a computational and vibrational spectroscopic study. AB - The energy profile for rotation around the central Si-Si bonds of the tetrasilanes SiMe3SiX2SiX2SiMe3 (X=H, F, Cl, Br and I) were examined by ab initio calculations and temperature-dependent Raman spectroscopy. Ethanelike intrinsic barriers to rotation were found for X=H, Cl, Br and I. MP2 calculations predict for SiMe3SiF2SiF2SiMe3 the existence of a gauche minimum with backbone dihedral angle omega~64 degrees and a twisted minimum with omega~115 degrees , as shown in the picture (solid line=HF, dashed line=MP2). The curious 115 degrees local minium can be accounted for by a unique intrinsic barrier to rotation superimposed by electrostatic interactions involving strongly polar SiF bonds. PMID- 23686960 TI - High-quality mapping of DNA-protein complexes by dynamic scanning force microscopy. AB - Biomolecular complexes, nanocircles and aggregates of DNA and streptavidin (STV) are studied by dynamic scanning force microscopy. More structural details are observed with an improved dynamic mode assisted with a special feedback circuit (Q-control), as shown in the picture. Under otherwise identical conditions, these improvements indicate that the well cited models relating enlarged lateral size to the finite geometry of the SFM tip have to be modified for soft samples susceptible to tip-sample interactions. PMID- 23686961 TI - Influence of nitrogen on the growth mechanism of decorated C:N nanotubes. AB - Nanotubes like feather boas were synthesised by the decomposition of methane in a nitrogen atmosphere using a bias-enhanced hot-filament chemical vapour deposition technique. This new type of slightly nitrogenated carbon (C:N) nanotubes exhibits a vermicular shape. Graphitic thin foils growing perpendicular to the tube axis typically cover the surface of each C:N tube. High-resolution transmission electron microscopy reveals the graphitic structure to be characterised by strong disorder at different length scales. The role of small amounts of nitrogen, which affects the structural formation of the growing C:N tubes, is discussed. PMID- 23686962 TI - Single-molecule microscopy of the green fluorescent protein using simultaneous two-color excitation. AB - In vivo microscopy of the Green Fluorescent Protein (GFP), the most important label in cell biology, with single-molecule sensitivity is hampered by an insufficient signal-to-noise ratio. A significant improvement is obtained with a novel two-color excitation technique. The picture clearly shows the increased brightness of GFP in in vitro single-molecule assays and in live-cell microscopy under two-color illumination (upper cell) as compared to normal illumination (lower cell). PMID- 23686963 TI - On the structure of Ge/GeO2 glasses. AB - Germanium-Germanium bonds or atomic germanium are unlikely to be present in germanium dioxide glasses containing excess germanium. PMID- 23686964 TI - Direct measurement of active thiol metabolite levels of clopidogrel in human plasma using tris(2-carboxyethyl)phosphine as a reducing agent by LC-MS/MS. AB - A simple, robust, and rapid LC-MS/MS method has been developed and validated for the simultaneous quantitation of clopidogrel and its active metabolite (AM) in human plasma. Tris(2-carboxyethyl)phosphine (TCEP) was used as a reducing agent to detect the AM as a disulfide-bonded complex with plasma proteins. Mixtures of TCEP and human plasma were deproteinized with acetonitrile containing 10 ng/mL of clopidogrel-d4 as an internal standard (IS). The mixtures were separated on a C18 RP column with an isocratic mobile phase consisting of 0.1% formic acid in acetonitrile and water (90:10, v/v) at a flow rate of 0.3 mL/min. Detection and quantification were performed using ESI-MS. The detector was operated in selected reaction-monitoring mode at m/z 322.0->211.9 for clopidogrel, m/z 356.1->155.2 for the AM, and m/z 326.0->216.0 for the IS. The linear dynamic range for clopidogrel and its AM were 0.05-20 and 0.5-200 ng/mL, respectively, with correlation coefficients (r) greater than 0.9976. Precision, both intra- and interday, was less than 8.26% with an accuracy of 87.6-106%. The validated method was successfully applied to simultaneously analyze clinical samples for clopidogrel and its AM. PMID- 23686965 TI - Reciprocal translocations in myelodysplastic syndromes and chronic myelomonocytic leukemias: review of 5,654 patients with an evaluable karyotype. AB - The infrequency of translocations in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemias (CMML) makes their identification and reporting interesting for the recognition of the recurrent ones and the genes involved in these neoplasias. The aims of this study were to identify new translocations associated with MDS and CMML and to establish their frequency in a cohort of 8,016 patients from the Spanish Group of MDS database. The karyotype was evaluable in 5,654 (70%) patients. Among those, 2,014 (36%) had chromosomal abnormalities, including 213 (10%) translocations identified in 195 patients. The translocations were balanced in 183 (86%) cases and unbalanced in 30 (14%) cases. All chromosomes were found to be involved in translocations, with the single exception of the Y chromosome. The chromosomes most frequently involved were in decreasing frequency: 3, 1, 7, 2, 11, 5, 12, 6, and 17. Translocations were found in karyotypes as the unique chromosomal abnormality (33%), associated with another chromosomal abnormality (11%), as a part of a complex karyotype (17%), and as a part of a monosomal karyotype (38%). There were 155 translocations not previously described in MDS or CMML and nine of them appeared to be recurrent. PMID- 23686966 TI - Antifungal attributes of siderophore produced by the Pseudomonas aeruginosa JAS 25. AB - Siderophores produced by Pseudomonas sp. play a vital role in controlling several plant diseases. Public concern about chemical pesticides has fostered an interest to seek alternative control strategies. Production of siderophore by Pseudomonas aeruginosa JAS-25 in King B medium was estimated at 400 nm and was partially purified by gel filtration chromatography using Sephadex G 25. Antifungal activity and inhibition of spore germination was studied against the phytopathogens like Fusarium oxysporum f. sp. ciceri, Fusarium udum, and Aspergillus niger by well plate assay and microphotographic method. Zone of inhibition of 3.0 cm was observed for F. udum and A. niger, proving it as potential biocontrol agent against phytopathogens. Partial 16S rRNA sequence analysis showed that the isolate JAS-25 exhibited 99% homology with P. aeruginosa and could be of novel species and the sequence of the strain was deposited in Genbank with the accession number JX104229. PMID- 23686967 TI - Renal-hepatic-pancreatic dysplasia: a sibship with skeletal and central nervous system anomalies and NPHP3 mutation. AB - We report on five consecutive sibs three with fatal renal-hepatic-pancreatic dysplastic (RHPD) syndrome and two pregnancies ending in early abortion. Three of the fetuses reached term and two survived for 15 and 58 days. They had diffusely cystic kidneys with absence of the distal collecting tubules, hepatic fibrosis, bile duct paucity, and pancreatic fibrosis with irregularly dilated ducts. These findings correspond to many of those reported by Ivemark et al. [Ivemark et al. (1959); Acta Paediat Scand 48: 1-11] as part of the RHPD syndrome. There are several notable differences in this family: one patient had hypocalvaria and a choroid plexus cyst at the right foramen of Luschka, multiple bone abnormalities including widened growth plates and abnormal development of the trabeculae of the ribs, "handle-bar" clavicles, wedge defects of the inferior margin of several thoracic vertebrae; the second patient had hypocalvaria and abnormally developed brain with bilateral exposure of the insulae; and a third patient had anencephaly. Mutational analysis of the two who survived beyond post-delivery demonstrated compound heterozygous novel frameshift mutations in the nephronophthisis type 3 gene (NPHP3). PMID- 23686968 TI - Pea aphid promotes amino acid metabolism both in Medicago truncatula and bacteriocytes to favor aphid population growth under elevated CO2. AB - Rising atmospheric CO(2) levels can dilute the nitrogen (N) resource in plant tissue, which is disadvantageous to many herbivorous insects. Aphids appear to be an exception that warrants further study. The effects of elevated CO(2) (750 ppm vs. 390 ppm) were evaluated on N assimilation and transamination by two Medicago truncatula genotypes, a N-fixing-deficient mutant (dnf1) and its wild-type control (Jemalong), with and without pea aphid (Acyrthosiphon pisum) infestation. Elevated CO(2) increased population abundance and feeding efficiency of aphids fed on Jemalong, but reduced those on dnf1. Without aphid infestation, elevated CO(2) increased photosynthetic rate, chlorophyll content, nodule number, biomass, and pod number for Jemalong, but only increased pod number and chlorophyll content for dnf1. Furthermore, aphid infested Jemalong plants had enhanced activities of N assimilation-related enzymes (glutamine synthetase, Glutamate synthase) and transamination-related enzymes (glutamate oxalate transaminase, glutamine phenylpyruvate transaminase), which presumably increased amino acid concentration in leaves and phloem sap under elevated CO(2). In contrast, aphid infested dnf1 plants had decreased activities of N assimilation-related enzymes and transmination-related enzymes and amino acid concentrations under elevated CO(2). Furthermore, elevated CO(2) up-regulated expression of genes relevant to amino acid metabolism in bacteriocytes of aphids associated with Jemalong, but down-regulated those associated with dnf1. Our results suggest that pea aphids actively elicit host responses that promote amino acid metabolism in both the host plant and in its bacteriocytes to favor the population growth of the aphid under elevated CO(2). PMID- 23686969 TI - Utility of the PedsQL rheumatology module as an outcome measure in juvenile fibromyalgia. AB - OBJECTIVE: The PedsQL rheumatology module is currently the only available measure of disease-specific quality of life for children and adolescents with juvenile fibromyalgia (FM), but limited information has been published about the psychometric properties of the instrument, specifically in juvenile FM. The objective of this study was to assess there liability, validity, and sensitivity to change of the 5 scales (pain and hurt, daily activities, treatment, worry, and communication) of the patient and parent proxy versions of the PedsQL rheumatology module in the context of a randomized controlled trial in juvenile FM. METHODS: The entire PedsQL rheumatology module was administered as a supplementary outcome measure at baseline,posttreatment, and 6-month followup assessments of 114 children and adolescents with juvenile FM enrolled in a trial testing the efficacy of cognitive-behavioral therapy. RESULTS: Internal consistency reliabilities for the scales were adequate to strong (Cronbach's alpha = 0.68-0.86). Parent proxy and child reports on most scales (except for daily activities and communication) showed moderate correlations (Spearman's r = 0.33-0.45). Support for construct validity was found by comparing child and parent reports with other related measures of pain and functioning (visual analog scale pain ratings and the Functional Disability Inventory). Finally, sensitivity to change was demonstrated by significant changes in 4 of the 5 scales (excluding the daily activities scale) after treatment. CONCLUSION: The PedsQL rheumatology module generally appears to have good utility for use in juvenile FM patients, but there are some caveats to the interpretation of specific scales in this population. PMID- 23686970 TI - Response to evidence-basis for anticoagulants for cerebral sinus venous thrombosis? PMID- 23686971 TI - The effect of lacunar infarcts on white matter tract integrity. AB - BACKGROUND AND PURPOSE: Lacunar infarcts may cause disturbances of the white matter (WM) structure remote from the primary lesion. Here, we used diffusion MRI and tractography to (1) spatially characterize microstructural abnormalities along WM tracts containing a lacunar infarct and (2) relate abnormalities in remote parts of the affected WM tract to cognitive outcome. METHODS: In 17 participants with a lacunar infarct, we reconstructed the affected WM tract using fiber tractography. The corresponding nonlesioned tract in the contralateral hemisphere served as a control tract. Diffusion parameters (fractional anisotropy and mean diffusivity) were plotted along the tract and related to measures of memory, executive functioning and information processing speed. RESULTS: Diffusion abnormalities remote from the lacune were present in the affected tract compared with the control tract up to 2 cm from the lacune (9% to 17% decrease in fractional anisotropy, 11% to 27% increase in mean diffusivity; P<0.05). The severity of these abnormalities attenuated with increasing distance to the primary lesion. Furthermore, the degree of remote WM disturbances was related to worse cognitive functioning on all 3 domains, independent of the size of the lacune (r=0.6-0.8; P<0.05). CONCLUSIONS: Lacunar infarcts are associated with abnormalities in the affected WM tract that extend centimeters beyond the lesion visible on conventional MRI. These secondary WM abnormalities may contribute to the cognitive deficits observed in patients with subcortical infarcts. PMID- 23686972 TI - Nonrelevant cerebral atherosclerosis is a strong prognostic factor in acute cerebral infarction. AB - BACKGROUND AND PURPOSE: We investigated whether the presence of nonrelevant cerebral atherosclerosis (NRCA) had prognostic value in patients with acute stroke. METHODS: We compared prognosis in 780 consecutive patients with first ever acute cerebral infarction who underwent cerebral angiography and diffusion weighted MRI. RESULTS: NRCA was present in 267 patients (34.2%). Multivariate analysis demonstrated that the presence of NRCA was independently associated with less improvement in National Institute of Health Stroke Scale score during the first 7 days (P=0.004), and a poor functional outcome (modified Rankin Scale score >2) after 3 months (odds ratio, 2.51; 95% confidence interval, 1.55-4.07). An increase in burden count of NRCA was also associated with poor outcomes. CONCLUSIONS: The presence and burden count of NRCA were associated with poor neurological outcomes in patients with acute cerebral infarction. PMID- 23686973 TI - New generation of Flow Diverter (surpass) for unruptured intracranial aneurysms: a prospective single-center study in 37 patients. AB - BACKGROUND AND PURPOSE: In patients harboring intracranial aneurysms, the major goal in treatment is to prevent bleeding. A new generation of an endoluminal device (Surpass Flow Diverter [Surpass]) was developed to reconstruct parent artery and occlude the aneurysm. We present our clinical and angiographic single center experience. METHODS: Patients with a wide range of complex unruptured aneurysms were treated with the Surpass placed in the parent artery and bridging the aneurysm. Clinical and angiographic follow-up were performed at 6 months. Data were prospectively collected. RESULTS: Thirty seven patients (mean age, 56 years; range, 32-79), harboring 49 unruptured aneurysms were treated at our center. All except 1 patient were treated with a single device. Successful delivery of the device was achieved in all patients. All 35 nonbifurcation aneurysm necks were covered completely, whereas 14 bifurcation aneurysms were only partially covered. There was no major periprocedural morbidity or mortality. During follow-up, 4 patients (10.4%) experienced transient neurological deficit. One patient (3%) developed a minor stroke at 4-month follow-up with persistent neurological deficit. Twelve patients had neurological symptoms related to their aneurysm and 7 showed improvement of these symptoms during follow-up. At 6-month follow-up, 29 of 31 aneurysms studied that had complete neck coverage showed a complete occlusion (94%) including 1 case with a 95% to 100% occlusion, whereas 5 of the 10 bifurcation aneurysms were occluded. CONCLUSIONS: Our study shows high safety and efficacy profile of a new generation endoluminal device in treatment of complex intracranial aneurysms. Long-term studies of treated bifurcation aneurysms are needed. PMID- 23686974 TI - Baseline cognitive function, recurrent stroke, and risk of dementia in patients with stroke. AB - BACKGROUND AND PURPOSE: To determine the interrelationships between baseline Mini Mental State Examination (MMSE) score and risk of overall dementia, post recurrent stroke dementia, and dementia without recurrent stroke among patients with a history of stroke. METHODS: Prospective cohort study among participants enrolled in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) for whom baseline MMSE score was available. Baseline MMSE score was divided into 4 categories: 30, 29-27, 26-24, and <24. Participants were followed for incident dementia and recurrent stroke. Logistic regression models were used to examine the association between MMSE score and dementia. RESULTS: Of the 6080 participants included in this analysis, 2493 had an MMSE score of 30, 1768 had a score of 29-28, 1369 had a score of 26-24, and 450 had a score of <24. Average follow-up time was 3.8 years. There were 407 cases of dementia, 106 of which were preceded by a recurrent stroke. The risk of overall dementia increased with decreasing MMSE score. However, the impact of MMSE score on the risk of dementia without recurrent stroke was much stronger than the impact of MMSE score on the risk of post-recurrent stroke dementia. For those with MMSE score <24, the risk of dementia without recurrent stroke was 47.89 (95% confidence interval, 28.57 80.26), whereas the risk of post-recurrent stroke dementia was only 7.17 (95% confidence interval, 3.70-13.89). Higher MMSE scores were even less strongly associated with the risk of post-recurrent stroke dementia. CONCLUSIONS: Patients with stroke with low MMSE scores are at high risk of dementia over time, even in the absence of a recurrent stroke, and should therefore be followed closely for further cognitive decline. PMID- 23686975 TI - Influence of chronic ethanol consumption on the neurological severity in patients with acute cerebral ischemia. AB - BACKGROUND AND PURPOSE: We tested the hypothesis that excessive chronic ethanol consumption is associated with more severe ischemic strokes. METHODS: We recruited patients with supratentorial cerebral ischemia within 48 hours of symptom onset. We defined heavy drinkers by a weekly consumption of ethanol of >=300 g and severe strokes by a National Institutes of Health Stroke Scale score>=6. RESULTS: Of 436 patients, 60 were heavy drinkers. Being a heavy drinker was independently associated with baseline National Institutes of Health Stroke Scale scores>=6 (odds ratio, 2.35; 95% confidence interval, 1.12-5.26; P=0.023) at the logistic regression analysis. This result was not modified with the propensity analysis. CONCLUSION: An excessive chronic ethanol consumption is associated with higher baseline stroke severity. PMID- 23686976 TI - Depression and risk of stroke in midaged women: a prospective longitudinal study. AB - BACKGROUND AND PURPOSE: Depression is known to increase stroke risk. Although limited, there is some evidence for age differences, with a suggestion for a stronger association in younger groups. We investigated the effect of depression on stroke incidence in a large cohort of midaged women. METHODS: We included 10 547 women without a history of stroke aged 47 to 52 years from the Australian Longitudinal Study on Women's Health, surveyed every 3 years from 1998 to 2010. Depression was defined at each survey using the Center for Epidemiological Studies Depression Scale (shortened version) and antidepressant use in the past month. Stroke was ascertained through self-report and mortality data. We determined the association between depression and stroke at the subsequent survey, using generalized estimating equation analysis, adjusting for time varying covariates. RESULTS: At each survey, ~24% were defined as having depression. During follow-up, 177 strokes occurred. Depression was associated with a >2-fold increased odds of stroke (odds ratio, 2.41; 95% confidence interval, 1.78-3.27), which attenuated after adjusting for age, socioeconomic status, lifestyle, and physiological factors (odds ratio, 1.94; 95% confidence interval, 1.37-2.74). Findings were robust to sensitivity analyses addressing methodological issues, including definition of depression, antidepressant use, and missing covariate data. CONCLUSIONS: Depression is a strong risk factor for stroke in midaged women, with the association partially explained by lifestyle and physiological factors. Further studies of midaged and older women from the same population are needed to confirm whether depression is particularly important in younger women and to inform targeted intervention approaches. PMID- 23686977 TI - Endovascular treatment of intracranial aneurysms in elderly patients: a systematic review and meta-analysis. AB - BACKGROUND AND PURPOSE: Use of endovascular coiling for treatment of ruptured and unruptured intracranial aneurysms (IAs) in the elderly is increasing. We performed a meta-analysis of the literature examining clinical and angiographic outcomes for treatment of IAs in the elderly. METHODS: We performed a comprehensive review of the literature from 1995 to 2012, reporting series of patients >=65 years of age with ruptured or unruptured IAs treated with endovascular approach. Event rates were pooled across studies using random effects meta-analysis. RESULTS: A total of 21 studies reporting on 1511 patients were included. Long-term aneurysm occlusion rates were 79% (95% confidence interval [CI], 70%-85%). Perioperative stroke occurred in 4% (95% CI, 3%-6%), with similar rates between patients with ruptured (5%; 95% CI, 3%-7%) and unruptured aneurysms (4%; 95% CI, 1%-14%; P=0.68). Intraprocedural rupture occurred in 1% (95% CI, 0%-3%) and 4% (95% CI, 2-6%; P=0.04) of patients with unruptured and ruptured aneurysms, respectively. Perioperative mortality rate for patients with ruptured aneurysms was 23% (95% CI, 17%-30%) and 1% (95% CI, 0%-6%) for patients with unruptured aneurysms (P<0.01). Rates of good clinical outcome at 1 year were 93% (95% CI, 88%-96%) and 66% (95% CI, 59%-72%) in patients with unruptured and ruptured aneurysms, respectively. CONCLUSIONS: This study suggests that endovascular treatment of IAs in the elderly is associated with high long term occlusion rates. Given the morbidity and mortality associated with endovascular treatment of IAs in the elderly, careful patient selection, especially in the case of patients with unruptured aneurysm, is recommended. PMID- 23686978 TI - What the SWIFT and TREVO II trials tell us about the role of endovascular therapy for acute stroke. PMID- 23686979 TI - Poststroke outcomes vary by pathogenic stroke subtype in the Atherosclerosis Risk in Communities Study. AB - BACKGROUND AND PURPOSE: Early risk of recurrence and mortality after stroke differs by subtype, but less is known about long-term recurrence and hospital readmissions. These differences have economic implications and will affect long term disability and stroke survivor quality of life. We examined recurrent stroke, all-cause hospital readmission, and mortality by index pathogenic subtype. METHODS: We identified 987 Atherosclerosis Risk in Communities Study cohort participants with first-ever stroke and followed them for a median 5.3 years after first stroke. Outcomes were compared across index subtypes (infarction: thrombotic, cardioembolic, and lacunar; hemorrhagic: subarachnoid and intracerebral) using Kaplan-Meier analysis and Cox proportional hazards regression, adjusting for age, sex, and race. RESULTS: There were 183 recurrent strokes among 147 participants, 3234 hospitalizations among 746 participants, and 529 deaths; only 14% of participants were event-free over follow-up. The majority of recurrent events were of the same subtype, except for lacunar infarcts, which were followed ~3 quarters of the time by nonlacunar events. Adjusted mortality was higher for intracerebral hemorrhage (hazard ratio, 2.3; 95% confidence interval, 1.7-3.0) compared with thrombotic stroke and lower for lacunar infarcts. Lacunar infarcts had somewhat higher recurrence compared with thrombotic infarcts (hazard ratio, 1.3; 95% confidence interval, 0.9-1.9), but lower all-cause readmission (hazard ratio, 0.8; 95% confidence interval, 0.7 1.0). Readmission was 40% higher for cardioembolic stroke relative to thrombotic stroke (hazard ratio, 1.4; 95% confidence interval, 1.1-1.7). CONCLUSIONS: Although the highest mortality was observed for intracerebral hemorrhage, there was significant burden of recurrent stroke and hospital readmissions for lacunar and cardioembolic strokes, respectively. There may be opportunities to reduce the relatively high rate of poststroke readmissions. PMID- 23686980 TI - Neuroprotection of ischemic postconditioning by downregulating the postsynaptic signaling mediated by kainate receptors. AB - BACKGROUND AND PURPOSE: Ischemic postconditioning, a brief episode of ischemia after a prolonged ischemic insult, has been found to reduce the delayed neuronal loss after stroke. However, the mechanisms underlying such endogenous neuroprotective strategy remain obscure. In this study, we try to explore the excitatory postsynaptic signal events associated with neuroprotective effect of ischemic postconditioning. METHODS: Global cerebral ischemia was induced for 15 minutes by the 4-vessel occlusion method in male Sprague-Dawley rats. Ischemic postconditioning was conducted 10 minutes later by a single reocclusion for 3 minutes. RESULTS: A severe global cerebral ischemia after 5 days of reperfusion destroyed almost all hippocampal CA1 pyramidal neurons. A brief ischemic postconditioning robustly reduced the neuronal loss after ischemia. Preadministration of phosphoinositide 3-kinase inhibitor LY294002 blocked the neuroprotection of postconditioning, whereas mitogen-activated protein kinase kinase 1 inhibitor PD98059 had no effect. Ischemic postconditioning significantly increased the Akt phosphorylation (Ser473). In addition, postconditioning not only perturbed the binding of postsynaptic density protein-95 with glutamatergic kainate receptor subunit 2 and mixed lineage kinase 3 but also suppressed the downstream activation of mixed lineage kinase 3, mitogen-activated protein kinase kinase 7, and c-Jun N-terminal kinase 3. LY294002, but not PD98059, abolished the postconditioning-induced decreases in the assembly of glutamatergic kainate receptor subunit 2-postsynaptic density protein-95-mixed lineage kinase 3 complex and in the mixed lineage kinase 3-c-Jun N-terminal kinase 3 signaling. Akt inhibitor IV, a specific Akt inhibitor, showed the same effects as LY294002. CONCLUSIONS: Ischemic postconditioning protects neurons against stroke by attenuating the postsynaptic glutamatergic kainate receptor subunit 2 postsynaptic density protein-95-mixed lineage kinase 3-c-Jun N-terminal kinase 3 signal cascade via phosphoinositide 3-kinase-Akt pathway. PMID- 23686982 TI - Framingham stroke risk score and cognitive impairment for predicting first-time stroke in the oldest old. AB - BACKGROUND AND PURPOSE: Predictive value of the conventional risk factors for stroke attenuates with age. Cognitive impairment has been implicated as a potential predictor for stroke in older subjects. Our aim was to compare the Framingham stroke risk score with cognitive functioning for predicting first-time stroke in a cohort of the oldest old individuals. METHODS: We included 480 subjects, aged 85 years, from the Leiden 85-plus Study. At baseline, data on the Framingham stroke risk score and the Mini-Mental State Examination (MMSE) score were obtained. Risk of first-time stroke was estimated in tertiles of Framingham and MMSE scores. Receiver operating characteristic curves with corresponding areas under the curves (AUCs) and 95% confidence intervals (CIs) were constructed for both Framingham and MMSE scores. RESULTS: Subjects with high Framingham risk score compared with those with low Framingham risk score did not have a higher risk of stroke (hazard ratio, 0.77; 95% CI, 0.39-1.54). Conversely, subjects with high levels of cognitive impairment compared with those with low levels of cognitive impairment had a higher risk of stroke (hazard ratio, 2.85; 95% CI, 1.48-5.51). In contrast to the Framingham risk score (AUCs, 0.48; 95% CI, 0.40 0.56), MMSE score had discriminative power to predict stroke (AUCs, 0.65; 95% CI, 0.57-0.72). There was a significant difference between AUCs for Framingham risk score and MMSE score (P=0.006). CONCLUSIONS: In the oldest old, the Framingham stroke risk score is not predictive for first-time stroke. In contrast, cognitive impairment, as assessed by MMSE score, identifies subjects at higher risk for stroke. PMID- 23686981 TI - Accuracy and clinical usefulness of intracerebral hemorrhage grading scores: a direct comparison in a UK population. AB - BACKGROUND AND PURPOSE: Various grading scores to predict survival after intracerebral hemorrhage (ICH) have been described. We aimed to test the accuracy and clinical usefulness of 3 well-known scores (original ICH score, modified ICH score, and ICH grading scale) in a large unselected cohort of typical ICH patients. METHODS: A total of 1364 ICH cases were referred to our center from January 1, 2008, to October 17, 2010. Clinical details were prospectively recorded, and the first computed tomography brain scan was retrospectively reviewed to determine ICH volume and location and to identify intraventricular hemorrhage. The original ICH, ICH grading scale, and modified ICH score were calculated. Receiver operating characteristic and decision curves for 30-day mortality were generated. RESULTS: A total of 1175 patients were included in the final analysis. All 3 scores and the Glasgow Coma Scale (GCS) divided cases into groups with highly significant differences in mortality. The area under the receiver operating characteristic curve was very similar for original ICH (0.861), ICH grading scale (0.874), and GCS (0.872), but was less for modified ICH score (0.824). Age was much less predictive (0.565). Combining GCS with age, log ICH volume, and intraventricular hemorrhage to derive a multifactorial risk of death at 30 days significantly increased the area under the receiver operating characteristic curve (0.897). All scores and GCS demonstrated a similar net benefit for threshold probabilities of 10% to 95%. Above 95%, the net benefit of GCS became inferior to the prognostic scores. CONCLUSIONS: Although existing grading scores are highly predictive of 30-day mortality, GCS alone was as predictive in our cohort, but age was not. PMID- 23686983 TI - Editorial. Turning potential into realities. PMID- 23686985 TI - Turning potential into realities: the invention of the integrated circuit (Nobel lecture). AB - The integrated circuit, "the chip", led to microelectronics growing to become the basis of all modern technology, from powerful computers and processors, spaceprobes and medical diagnostic equipment through to washing machines and cars. The chip has also led to our environment being flooded with small electronic devices, such as electronic watches and TV games. Here, the background and first steps in its development are described by its Nobel prize winning inventor. PMID- 23686986 TI - Quasi-electric fields and band offsets: teaching electrons new tricks (Nobel lecture). AB - The invention and development of fast opto- and microelectronic components based on layered semiconductor structures, termed semiconductor heterostructures, is described herein. Such fast transistors are used in radio link satellites and the base stations of mobile telephones, for examples. Laser diodes built with the same technology drive the flow of information along fiber-optic cables, and may be found also in CD players, bar-code readers, and laser pointers. The double heterostructure principle is also increasingly used in incoherent light-emitting diodes, for example in traffic lights and other light sources requiring colored visible light. PMID- 23686987 TI - The double heterostructure: the concept and its applications in physics, electronics, and technology (Nobel lecture). AB - The art and science of heterostructure design has not remained still since its founding: While the theoretical principles initially advanced rapidly, experimental realization initially lagged until the ideal AlGaAs solid solutions were found. From this point, development into application proceeded apace. In this Review, these intial steps and the current position of heterostructure applications are surveyed. New developments, such as the inclusion of quantum dots into heterostructures-with its concomitant world-record threshold current for laser activity-and future challenges are also elucidated. PMID- 23686988 TI - True single photons at room temperature. PMID- 23686989 TI - Classical and quantum magnetism in giant Keplerate magnetic molecules. AB - Complementary theoretical modeling methods are presented for the classical and quantum Heisenberg model to explain the magnetic properties of nanometer-sized magnetic molecules. Excellent quantitative agreement is achieved between our experimental data down to 0.1 K and for fields up to 60 Tesla and our theoretical results for the giant Keplerate species {Mo72Fe30}, by far the largest paramagnetic molecule synthesized to date. PMID- 23686990 TI - Tuning the magnetic properties of the high-spin molecular cluster Fe8. AB - The synthesis, crystal structure, and magnetic characterization of a high-spin cluster comprising eight iron ions are presented in this contribution. The cluster has formula [(tacn)6Fe8O2(OH)12Br4.3(ClO4)3.7].6H2O (Fe8pcl), where tacn is the organic ligand 1,4,7-triazacyclononane. It can be considered a derivative of Fe8 Br8 , a cluster whose low-temperature magnetization dynamics has been extensively investigated, in which four of the bromide ions have been replaced by perchlorate anions. The structure of the central core of the two molecules, [Fe8O(OH)12(tacn)6](8+), is essentially the same, but Fe8pcl has a higher symmetry (the bromide derivative crystallizes in the acentric P1 space group while Fe8pcl crystallizes in the monoclinic P2(1)/c space group). The magnetic properties of Fe8pcl suggest it is very similar to Fe8Br8 having a S=10 ground state as well. The zero-field splitting parameters were accurately determined by high field-high frequency EPR (HF-EPR) measurements. The two clusters have similar axial anisotropy D but Fe8pcl has a larger transverse anisotropy E: The value of E/D is 0.21 for the perchlorate derivative but 0.19 for Fe8Br8. AC susceptibility measurements revealed the cluster behaves like a superparamagnetic particle. However, due to the occurrence of large terms in the transverse anisotropy, the temperature dependence of the relaxation time cannot be reproduced by a simple Arrhenius law model. As observed in the bromide derivative, below 350 mK the relaxation time becomes temperature independent and indicating that a pure tunneling regime is attained. The comparison of the tunneling rate in the two clusters shows that in the perchlorate derivative the relaxation process is 35 times faster. The observed ratio of the tunneling rates is in reasonable agreement with that calculated from the tunneling splitting, namely the energy difference between the two almost-degenerate lowest levels Ms =+/-10, in the two clusters. PMID- 23686991 TI - Phase transition between single crystals of two thermotropic cubic phases from a mixture of 3,5-didodecyloxybenzoic acid and C18-ANBC. AB - A reversible phase transition between two different thermotropic cubic phases is observed in a mixture of two carboxylic acids. Such a transition was characterised by single-crystal X-ray diffraction and direct optical microscopy; an image of a facetted droplet just at the transition between the two phases is shown in the picture. PMID- 23686992 TI - Correlation between sonoluminescence, sonochemistry and cavitation noise spectra. AB - The acoustic signal from the sonochemical production of H2O2 in water, as measured by the intensity and the width of the second harmonic, show a sensitive and correlated dependence to the presence of small amounts (millimolar range) of an anionic surfactant (SDS) in water. The graphic shows the link from the ultrasonic reaction to the measurable quantities. New possibilities to reliably control such processes is therefore opened. PMID- 23686993 TI - Anisotropy of rotational diffusion, dipole-dipole cross-correlated NMR relaxation and angles between bond vectors in proteins. AB - Cross correlations between the fluctuations of dipolar (13)C(alpha)-(1)H(alpha) interactions yield information about the relative orientation of successive (13)C(alpha)-(1)H(alpha) bond vectors in proteins, in turn providing a direct handle on their structure and dynamics in solution. However, overall anisotropic reorientation must be taken into account in the interpretation of cross correlation rates. The protein shown, human ubiquitin, has amino acid residues in white where the cross-correlation rates deviate from those predicted for a rigid structure. PMID- 23686994 TI - Elucidating changes in interfacial water structure upon protein adsorption. AB - A coat to fit the body: Although protein adsorption onto surfaces is a complicated process, sum-frequency generation (SFG) spectroscopy probes the interfacial water structure around a silica surface as a model protein (bovine serum albumin, BSA) adsorbs onto it from solution. At pH 8.0, the attenuated SFG intensity after BSA adsorption indicates that interfacial water molecules are less ordered due to a reduction in surface xi-potential. The SFG spectrum shows the C-O stretching vibrations subject to stronger ([symbol: see text]~3200 cm( 1)) and weaker (3200 cm(-1)) hydrogen bonds. PMID- 23686995 TI - The diode behavior of asymmetrically ordered Au55 clusters. AB - Future nanoelectronic devices may well be based on an assembled monolayer of ligand-stabilized metal clusters, Au55 in this case: Irradiation of the monolayer with an electon beam generates diodic behavior. While the clusters themselves resist decomposition, the system exhibits interesting time-dependant electrical characteristics, as shown by the current-voltage curve. PMID- 23686996 TI - Conversion of protonated magadiite to a crystalline microporous silica phase via a new layered silicate. AB - Organic structure-directing agents are necessary to the formation of defined zeolitic structures; doing without the organic component can simplfy the reaction immensely. Such a transformation, of protonated magadiite to a new layered silicate, is reported herein. The picture shows the XRD patterns of as-prepared protonated magadiite and the product after simple hydrothermal treatment at two different temparatures. After calcination (500 degrees C) the final material has a surface area of 457 m(2) g(-1). PMID- 23686997 TI - Strong acceleration of chemical reactions occurring through the effects of rotational excitation on collision geometry. AB - Accelerating chemical reactions by rotational excitation increases both the energy available for barrier crossing and also changes the distribution of collisions with the barrier, as demonstrated herein on the gas-phase reactions O+HCl(DCl)->OH(OD)+Cl. In the picture, the dependence of the barrier energy Eb on the Jacobi angle gamma is given, together with the distribution of collisions with the barrier at j=0 (?) and 16 (?). Such a mechanism should arise from large amplitude oscillatory motions of molecules or reacting atomic groups. It should thus occur also in condensed phases and it should lead to nonenergetic (nonthermal) acceleration of chemical reactions by microwaves. PMID- 23686998 TI - Orthographic learning and the role of text-to-speech software in Dutch disabled readers. AB - In this study, we examined whether orthographic learning can be demonstrated in disabled readers learning to read in a transparent orthography (Dutch). In addition, we tested the effect of the use of text-to-speech software, a new form of direct instruction, on orthographic learning. Both research goals were investigated by replicating Share's self-teaching paradigm. A total of 65 disabled Dutch readers were asked to read eight stories containing embedded homophonic pseudoword targets (e.g., Blot/Blod), with or without the support of text-to-speech software. The amount of orthographic learning was assessed 3 or 7 days later by three measures of orthographic learning. First, the results supported the presence of orthographic learning during independent silent reading by demonstrating that target spellings were correctly identified more often, named more quickly, and spelled more accurately than their homophone foils. Our results support the hypothesis that all readers, even poor readers of transparent orthographies, are capable of developing word-specific knowledge. Second, a negative effect of text-to-speech software on orthographic learning was demonstrated in this study. This negative effect was interpreted as the consequence of passively listening to the auditory presentation of the text. We clarify how these results can be interpreted within current theoretical accounts of orthographic learning and briefly discuss implications for remedial interventions. PMID- 23686999 TI - Teaching mathematical word problem solving: the quality of evidence for strategy instruction priming the problem structure. AB - This study examined the quality of the research base related to strategy instruction priming the underlying mathematical problem structure for students with learning disabilities and those at risk for mathematics difficulties. We evaluated the quality of methodological rigor of 18 group research studies using the criteria proposed by Gersten et al. and 10 single case design (SCD) research studies using criteria suggested by Horner et al. and the What Works Clearinghouse. Results indicated that 14 group design studies met the criteria for high-quality or acceptable research, whereas SCD studies did not meet the standards for an evidence-based practice. Based on these findings, strategy instruction priming the mathematics problem structure is considered an evidence based practice using only group design methodological criteria. Implications for future research and for practice are discussed. PMID- 23687002 TI - Site-selective functionalization of periodic mesoporous organosilica (PMO) with macrocyclic host for specific and reversible recognition of heavy metal. AB - A novel kind of macrocyclic-host-functionalized periodic mesoporous organosilica (PMO) with excellent and reversible recognition of Pb(II) was developed. The macrocyclic host molecule cis-dicyclohexano[18]crown-6, with strong affinity to Pb(II), was carefully modified as a bridged precursor to build the PMO material. To break down the limit of the functionalization degree for PMOs incorporated with large-sized moieties, a site-selective post-functionalization method was proposed to further decorate the external surface of the PMO material. The selective recognition ability of the upgraded PMO material towards Pb(II) was remarkably enhanced without destroying the mesoporous ordering. Solid-state (13)C and (29)Si NMR spectroscopy, X-ray photoelectron spectroscopy (XPS), XRD, TEM, and nitrogen adsorption-desorption isotherm measurements were utilized for a full characterization of the structure, micromorphology, and surface properties. Reversible binding of Pb(II) was realized in the binding-elution cycle experiments. The mechanism of the supramolecular interaction between the macrocyclic host and metal ion was discussed. The synthetic strategy can be considered a general way to optimize the properties of PMOs as binding materials for practical use while preserving the mesostructure. PMID- 23687001 TI - Kinetics of heavy metal inhibition of 1,2-dichloroethane biodegradation in co contaminated water. AB - Sites co-contaminated with heavy metals and 1,2-DCA may pose a greater challenge for bioremediation, as the heavy metals could inhibit the activities of microbes involved in biodegradation. Therefore, this study was undertaken to quantitatively assess the effects of heavy metals (arsenic, cadmium, mercury, and lead) on 1,2-DCA biodegradation in co-contaminated water. The minimum inhibitory concentrations (MICs) and concentrations of the heavy metals that caused half life doubling (HLDs) of 1,2-DCA as well as the degradation rate coefficient (k(1)) and half-life (t(1/2)) of 1,2-DCA were measured and used to predict the toxicity of the heavy metals in the water microcosms. An increase in heavy metal concentration resulted in a progressive increase in the t(1/2) and relative t(1/2) and a decrease in k(1). The MICs and HLDs of the heavy metals were found to vary, depending on the heavy metals type. In addition, the presence of heavy metals was shown to inhibit 1,2-DCA biodegradation in a dose-dependent manner, with the following order of decreasing inhibitory effect: Hg(2+) > As(3+) > Cd(2+) > Pb(2+). Findings from this study have significant implications for the development of bioremediation strategies for effective degradation of 1,2-DCA and other related compounds in wastewater co-contaminated with heavy metals. PMID- 23687000 TI - Characterization of X-linked hypohidrotic ectodermal dysplasia (XL-HED) hair and sweat gland phenotypes using phototrichogram analysis and live confocal imaging. AB - Hypohidrotic ectodermal dysplasia (HED) is the most common type of ectodermal dysplasia (ED), which encompasses a large group of syndromes that share several phenotypic features such as missing or malformed ectodermal structures, including skin, hair, sweat glands, and teeth. X-linked hypohidrotic ectodermal dysplasia (XL-HED) is associated with mutations in ectodysplasin (EDA1). Hypohidrosis due to hypoplastic sweat glands and thin, sparse hair are phenotypic features that significantly affect the daily lives of XL-HED individuals and therefore require systematic analysis. We sought to determine the quality of life of individuals with XL-HED and to quantify sweat duct and hair phenotypes using confocal imaging, pilocarpine iontophoresis, and phototrichogram analysis. Using these highly sensitive and non-invasive techniques, we demonstrated that 11/12 XL-HED individuals presented with a complete absence of sweat ducts and that none produced sweat. We determined that the thin hair phenotype observed in XL-HED was due to multiple factors, such as fewer terminal hairs with decreased thickness and slower growth rate, as well as fewer follicular units and fewer hairs per unit. The precise characterization of XL-HED phenotypes using sensitive and non invasive techniques presented in our study will improve upon larger genotype phenotype studies and the assessment of future therapies in XL-HED. PMID- 23687003 TI - Which is the most useful patient-reported outcome in femoroacetabular impingement? Test-retest reliability of six questionnaires. AB - BACKGROUND/AIMS: The most reliable patient-reported outcomes (PROs) for people with femoroacetabular impingement (FAI) is unknown because there have been no direct comparisons of questionnaires. Thus, the aim was to evaluate the test retest reliability of six existing PROs in a single cohort of young active people with hip/groin pain consistent with a clinical diagnosis of FAI. METHODS: Young adults with clinical FAI completed six PRO questionnaires on two occasions, 1-2 weeks apart. The PROs were modified Harris Hip Score, Hip dysfunction and Osteoarthritis Score, Hip Outcome Score, Non-Arthritic Hip Score, International Hip Outcome Tool, Copenhagen Hip and Groin Outcome Score. RESULTS: 30 young adults (mean age 24 years, SD 4 years, range 18-30 years; 15 men) with stable symptoms participated. Intraclass correlation coefficient(3,1) values ranged from 0.73 to 0.93 (95% CI 0.38 to 0.98) indicating that most questionnaires reached minimal reliability benchmarks. Measurement error at the individual level was quite large for most questionnaires (minimal detectable change (MDC95) 12.4-35.6, 95% CI 8.7 to 54.0). In contrast, measurement error at the group level was quite small for most questionnaires (MDC95 2.2-7.3, 95% CI 1.6 to 11). CONCLUSIONS: The majority of the questionnaires were reliable and precise enough for use at the group level. Samples of only 23-30 individuals were required to achieve acceptable measurement variation at the group level. Further direct comparisons of these questionnaires are required to assess other measurement properties such as validity, responsiveness and meaningful change in young people with FAI. PMID- 23687004 TI - Urinary incontinence in physically active women and female athletes. AB - A literature review was performed on the topic of urinary incontinence during physical activity and sports. This paper reviews the prevalence, risk factors, pathophysiology and treatment modalities of urinary incontinence in physically active women and female athletes. Urinary incontinence affects women of all ages, including top female athletes, but is often under-reported. The highest prevalence of urinary incontinence is reported in those participating in high impact sports. Pelvic floor muscle training is considered the first-line treatment, although more research is needed to determine optimal treatment protocols for exercising women and athletes. Trainers, coaches and other athletes' caregivers should be educated and made aware of the need for proper urogynaecological assessment. PMID- 23687005 TI - Advancing the understanding of physical activity and cardiovascular risk factors in children: the European Youth Heart Study (EYHS). PMID- 23687006 TI - Rehabilitation of scapular dyskinesis: from the office worker to the elite overhead athlete. AB - The scapula functions as a bridge between the shoulder complex and the cervical spine and plays a very important role in providing both mobility and stability of the neck/shoulder region. The association between abnormal scapular positions and motions and glenohumeral joint pathology has been well established in the literature, whereas studies investigating the relationship between neck pain and scapular dysfunction have only recently begun to emerge. Although several authors have emphasised the relevance of restoring normal scapular kinematics through exercise and manual therapy techniques, overall scapular rehabilitation guidelines decent for both patients with shoulder pain as well as patients with neck problems are lacking. The purpose of this paper is to provide a science based clinical reasoning algorithm with practical guidelines for the rehabilitation of scapular dyskinesis in patients with chronic complaints in the upper quadrant. PMID- 23687007 TI - Surviving 30 years on the road as a team physician. PMID- 23687009 TI - Developing a diagnostic model for estimating terrestrial vegetation gross primary productivity using the photosynthetic quantum yield and Earth Observation data. AB - This article develops a new carbon exchange diagnostic model [i.e. Southampton CARbon Flux (SCARF) model] for estimating daily gross primary productivity (GPP). The model exploits the maximum quantum yields of two key photosynthetic pathways (i.e. C3 and C4 ) to estimate the conversion of absorbed photosynthetically active radiation into GPP. Furthermore, this is the first model to use only the fraction of photosynthetically active radiation absorbed by photosynthetic elements of the canopy (i.e. FAPARps ) rather than total canopy, to predict GPP. The GPP predicted by the SCARF model was comparable to in situ GPP measurements (R(2) > 0.7) in most of the evaluated biomes. Overall, the SCARF model predicted high GPP in regions dominated by forests and croplands, and low GPP in shrublands and dry-grasslands across USA and Europe. The spatial distribution of GPP from the SCARF model over Europe and conterminous USA was comparable to those from the MOD17 GPP product except in regions dominated by croplands. The SCARF model GPP predictions were positively correlated (R(2) > 0.5) to climatic and biophysical input variables indicating its sensitivity to factors controlling vegetation productivity. The new model has three advantages, first, it prescribes only two quantum yield terms rather than species specific light use efficiency terms; second, it uses only the fraction of PAR absorbed by photosynthetic elements of the canopy (FAPARps ) hence capturing the actual PAR used in photosynthesis; and third, it does not need a detailed land cover map that is a major source of uncertainty in most remote sensing based GPP models. The Sentinel satellites planned for launch in 2014 by the European Space Agency have adequate spectral channels to derive FAPARps at relatively high spatial resolution (20 m). This provides a unique opportunity to produce global GPP operationally using the Southampton CARbon Flux (SCARF) model at high spatial resolution. PMID- 23687010 TI - Direct observation of the electroadsorptive effect on ultrathin films for microsensor and catalytic-surface control. AB - Microchemical sensors and catalytic reactors make use of gases during adsorption in specific ways on selected materials. Fine-tuning is normally achieved by morphological control and material doping. The latter relates surface properties to the electronic structure of the bulk, and this suggests the possibility of electronic control. Although unusual for catalytic surfaces, such phenomena are sometimes reported for microsensors, but with little understanding of the underlying mechanisms. Herein, direct observation of the electroadsorptive effect by a combination of X-ray photoelectron spectroscopy and conductivity analysis on nanometre-thick semiconductor films on buried control electrodes is reported. For the SnO2/NO2 model system, NO3 surface species, which normally decay at the latest within minutes, can be kept stable for 1.5 h with a high coverage of 15% under appropriate electric fields. This includes uncharged states, too, and implies that nanoelectronic structures provide control over the predominant adsorbate conformation on exterior surfaces and thus opens the field for chemically reactive interfaces with in situ tunability. PMID- 23687011 TI - Readability and suitability assessment of patient education materials in rheumatic diseases. AB - OBJECTIVE: Web-based patient education materials and printed pamphlets are frequently used by providers to inform patients about their rheumatic disease. Little attention has been given to the readability and appropriateness of patient materials. The objective of this study was to examine the readability and suitability of commonly used patient education materials for osteoarthritis (OA), rheumatoid arthritis, systemic lupus erythematosus, and vasculitis. METHODS: Five or 6 popular patient resources for each disease were chosen for evaluation. Readability was measured using the Flesch-Kincaid reading grade level and suitability was determined by the Suitability Assessment of Materials (SAM), a score that considers characteristics such as content, graphics, layout/topography, and cultural appropriateness. Three different reviewers rated the SAM score and means were used in the analysis. RESULTS: Twenty-three resources written on the 4 diseases were evaluated. The education material for all 4 diseases studied had readability above the eighth-grade level and readability did not differ among the diseases. Only 5 of the 23 resources received superior suitability scores, and 3 of these 5 resources were written for OA. All 4 diseases received adequate suitability scores, with OA having the highest mean suitability score. CONCLUSION: Most patient education materials for rheumatic diseases are written at readability levels above the recommended sixth grade reading level and have only adequate suitability. Developing more appropriate educational resources for patients with rheumatic diseases may improve patient comprehension. PMID- 23687012 TI - Impact factor distortions. PMID- 23687008 TI - Associations between fine and coarse particles and mortality in Mediterranean cities: results from the MED-PARTICLES project. AB - BACKGROUND: Few studies have investigated the independent health effects of different size fractions of particulate matter (PM) in multiple locations, especially in Europe. OBJECTIVES: We estimated the short-term effects of PM with aerodynamic diameter <= 10 MUm (PM10), <= 2.5 MUm (PM2.5), and between 2.5 and 10 MUm (PM2.5-10) on all-cause, cardiovascular, and respiratory mortality in 10 European Mediterranean metropolitan areas within the MED-PARTICLES project. METHODS: We analyzed data from each city using Poisson regression models, and combined city-specific estimates to derive overall effect estimates. We evaluated the sensitivity of our estimates to co-pollutant exposures and city-specific model choice, and investigated effect modification by age, sex, and season. We applied distributed lag and threshold models to investigate temporal patterns of associations. RESULTS: A 10-MUg/m3 increase in PM2.5 was associated with a 0.55% (95% CI: 0.27, 0.84%) increase in all-cause mortality (0-1 day cumulative lag), and a 1.91% increase (95% CI: 0.71, 3.12%) in respiratory mortality (0-5 day lag). In general, associations were stronger for cardiovascular and respiratory mortality than all-cause mortality, during warm versus cold months, and among those >= 75 versus < 75 years of age. Associations with PM2.5-10 were positive but not statistically significant in most analyses, whereas associations with PM10 seemed to be driven by PM2.5. CONCLUSIONS: We found evidence of adverse effects of PM2.5 on mortality outcomes in the European Mediterranean region. Associations with PM2.5-10 were positive but smaller in magnitude. Associations were stronger for respiratory mortality when cumulative exposures were lagged over 0-5 days, and were modified by season and age. PMID- 23687017 TI - Biomedicine. Human stem cells from cloning, finally. PMID- 23687018 TI - Influenza. Synthetic vaccine strain may speed up pandemic response. PMID- 23687019 TI - Glaciology. Melting glaciers, not just ice sheets, stoking sea-level rise. PMID- 23687020 TI - Human evolution. More genomes from Denisova Cave show mixing of early human groups. PMID- 23687021 TI - U.S. science policy. Lawmakers await NSF's response to query about grants. PMID- 23687022 TI - Troubled waters for ancient shipwrecks. PMID- 23687023 TI - From quarry to temple. PMID- 23687024 TI - Food science. Following the flavor. PMID- 23687025 TI - A floating lab explores the fringes of science and gastronomy. PMID- 23687026 TI - China's "Love Canal" moment? PMID- 23687027 TI - The true challenge of giant marine reserves. PMID- 23687028 TI - The true challenge of giant marine reserves--response. PMID- 23687029 TI - Comment on "Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice". AB - Giovanoli et al. (Reports, 1 March 2013, p. 1095) applied an immune challenge to pregnant females, and therefore to all offspring, and subsequently applied stress to offspring on a per cage basis. The data, however, were analyzed as a completely randomized design, which is inappropriate given these restrictions on randomization. This will increase both false positives and false negatives. PMID- 23687030 TI - Response to comment on "Stress in puberty unmasks latent neuropathological consequences of prenatal immune activation in mice". AB - Lazic criticizes the statistical analyses used to support the conclusions in our mouse model. His theory-biased criticism is disproportionate in view of the robustness of our findings (even if different statistical methods are applied) and falls short in explaining the postpubertal onset of effects. PMID- 23687031 TI - Computational science. Troubling trends in scientific software use. PMID- 23687032 TI - Ecology. Immunity and invasive success. PMID- 23687033 TI - Cell biology. Insulin finds its niche. PMID- 23687034 TI - Materials science. Quartz on silicon. PMID- 23687035 TI - Virology. Our viral inheritance. PMID- 23687036 TI - Applied physics. Ghost imaging in three dimensions. PMID- 23687037 TI - Materials science. Complexity from simplicity. PMID- 23687038 TI - Medicine. (Poly)combing the pediatric cancer genome for answers. PMID- 23687039 TI - Retrospective. Robert G. Edwards (1925-2013). PMID- 23687040 TI - Soft-chemistry-based routes to epitaxial alpha-quartz thin films with tunable textures. AB - Piezoelectric nanostructured quartz films of high resonance frequencies are needed for microelectronic devices; however, synthesis methods have been frustrated by the inhomogeneous crystal growth, crystal twinning, and loss of nanofeatures upon crystallization. We report the epitaxial growth of nanostructured polycrystalline quartz films on silicon [Si(100)] substrates via the solution deposition and gelation of amorphous silica thin films, followed by thermal treatment. Key to the process is the combined use of either a strontium (Sr(2+)) or barium (Ba(2+)) catalyst with an amphiphilic molecular template. The silica nanostructure constructed by cooperative self-assembly permits homogeneous distribution of the cations, which are responsible for the crystallization of quartz. The low mismatch between the silicon and alpha-quartz cell parameters selects this particular polymorph, inducing epitaxial growth. PMID- 23687041 TI - Rationally designed complex, hierarchical microarchitectures. AB - The emergence of complex nano- and microstructures is of fundamental interest, and the ability to program their form has practical ramifications in fields such as optics, catalysis, and electronics. We developed carbonate-silica microstructures in a dynamic reaction-diffusion system that allow us to rationally devise schemes for precisely sculpting a great variety of elementary shapes by diffusion of carbon dioxide (CO2) in a solution of barium chloride and sodium metasilicate. We identify two distinct growth modes and show how continuous and discrete modulations in CO2 concentration, pH, and temperature can be used to deterministically switch between different regimes and create a bouquet of hierarchically assembled multiscale microstructures with unprecedented levels of complexity and precision. These results outline a nanotechnology strategy for "collaborating" with self-assembly processes in real time to build arbitrary tectonic architectures. PMID- 23687043 TI - Phase diagram of the topological superfluid 3He confined in a nanoscale slab geometry. AB - The superfluid phases of helium-3 ((3)He) are predicted to be strongly influenced by mesoscopic confinement. However, mapping out the phase diagram in a confined geometry has been experimentally challenging. We confined a sample of (3)He within a nanofluidic cavity of precisely defined geometry, cooled it, and fingerprinted the order parameter using a sensitive nuclear magnetic resonance spectrometer. The measured suppression of the p-wave order parameter arising from surface scattering was consistent with the predictions of quasi-classical theory. Controlled confinement of nanofluidic samples provides a new laboratory for the study of topological superfluids and their surface- and edge-bound excitations. PMID- 23687042 TI - Dual molecular signals mediate the bacterial response to outer-membrane stress. AB - In Gram-negative bacteria, outer-membrane integrity is essential for survival and is monitored by the sigma(E) stress-response system, which initiates damage repair pathways. One activating signal is unassembled outer-membrane proteins. Using biochemical and genetic experiments in Escherichia coli, we found that off pathway intermediates in lipopolysaccharide transport and assembly provided an additional required signal. These distinct signals, arising from disruptions in the transport and assembly of the major outer-membrane components, jointly determined the rate of proteolytic destruction of a negative regulator of the sigma(E) transcription factor, thereby modulating the expression of stress response genes. This dual-signal system permits a rapid response to dysfunction in outer-membrane biogenesis, while buffering responses to transient fluctuations in individual components, and may represent a broad strategy for bacteria to monitor their interface with the environment. PMID- 23687044 TI - 3D computational imaging with single-pixel detectors. AB - Computational imaging enables retrieval of the spatial information of an object with the use of single-pixel detectors. By projecting a series of known random patterns and measuring the backscattered intensity, it is possible to reconstruct a two-dimensional (2D) image. We used several single-pixel detectors in different locations to capture the 3D form of an object. From each detector we derived a 2D image that appeared to be illuminated from a different direction, even though only a single digital projector was used for illumination. From the shading of the images, the surface gradients could be derived and the 3D object reconstructed. We compare our result to that obtained from a stereophotogrammetric system using multiple cameras. Our simplified approach to 3D imaging can readily be extended to nonvisible wavebands. PMID- 23687045 TI - A reconciled estimate of glacier contributions to sea level rise: 2003 to 2009. AB - Glaciers distinct from the Greenland and Antarctic Ice Sheets are losing large amounts of water to the world's oceans. However, estimates of their contribution to sea level rise disagree. We provide a consensus estimate by standardizing existing, and creating new, mass-budget estimates from satellite gravimetry and altimetry and from local glaciological records. In many regions, local measurements are more negative than satellite-based estimates. All regions lost mass during 2003-2009, with the largest losses from Arctic Canada, Alaska, coastal Greenland, the southern Andes, and high-mountain Asia, but there was little loss from glaciers in Antarctica. Over this period, the global mass budget was -259 +/- 28 gigatons per year, equivalent to the combined loss from both ice sheets and accounting for 29 +/- 13% of the observed sea level rise. PMID- 23687046 TI - Invasive harlequin ladybird carries biological weapons against native competitors. AB - Invasive species that proliferate after colonizing new habitats have a negative environmental and economic impact. The reason why some species become successful invaders, whereas others, even closely related species, remain noninvasive is often unclear. The harlequin ladybird Harmonia axyridis, introduced for biological pest control, has become an invader that is outcompeting indigenous ladybird species in many countries. Here, we show that Harmonia carries abundant spores of obligate parasitic microsporidia closely related to Nosema thompsoni. These microsporidia, while not harming the carrier Harmonia, are lethal pathogens for the native ladybird Coccinella septempunctata. We propose that intraguild predation, representing a major selective force among competing ladybird species, causes the infection and ultimate death of native ladybirds when they feed on microsporidia-contaminated Harmonia eggs or larvae. PMID- 23687047 TI - ATAXIN-2 activates PERIOD translation to sustain circadian rhythms in Drosophila. AB - Evidence for transcriptional feedback in circadian timekeeping is abundant, yet little is known about the mechanisms underlying translational control. We found that ATAXIN-2 (ATX2), an RNA-associated protein involved in neurodegenerative disease, is a translational activator of the rate-limiting clock component PERIOD (PER) in Drosophila. ATX2 specifically interacted with TWENTY-FOUR (TYF), an activator of PER translation. RNA interference-mediated depletion of Atx2 or the expression of a mutant ATX2 protein that does not associate with polyadenylate binding protein (PABP) suppressed behavioral rhythms and decreased abundance of PER. Although ATX2 can repress translation, depletion of Atx2 from Drosophila S2 cells inhibited translational activation by RNA-tethered TYF and disrupted the association between TYF and PABP. Thus, ATX2 coordinates an active translation complex important for PER expression and circadian rhythms. PMID- 23687049 TI - Impact of shale gas development on regional water quality. AB - Unconventional natural gas resources offer an opportunity to access a relatively clean fossil fuel that could potentially lead to energy independence for some countries. Horizontal drilling and hydraulic fracturing make the extraction of tightly bound natural gas from shale formations economically feasible. These technologies are not free from environmental risks, however, especially those related to regional water quality, such as gas migration, contaminant transport through induced and natural fractures, wastewater discharge, and accidental spills. We review the current understanding of environmental issues associated with unconventional gas extraction. Improved understanding of the fate and transport of contaminants of concern and increased long-term monitoring and data dissemination will help manage these water-quality risks today and in the future. PMID- 23687048 TI - A role for Drosophila ATX2 in activation of PER translation and circadian behavior. AB - A negative transcriptional feedback loop generates circadian rhythms in Drosophila. PERIOD (PER) is a critical state-variable in this mechanism, and its abundance is tightly regulated. We found that the Drosophila homolog of ATAXIN-2 (ATX2)--an RNA-binding protein implicated in human neurodegenerative diseases- was required for circadian locomotor behavior. ATX2 was necessary for PER accumulation in circadian pacemaker neurons and thus determined period length of circadian behavior. ATX2 was required for the function of TWENTY-FOUR (TYF), a crucial activator of PER translation. ATX2 formed a complex with TYF and promoted its interaction with polyadenylate-binding protein (PABP). Our work uncovers a role for ATX2 in circadian timing and reveals that this protein functions as an activator of PER translation in circadian neurons. PMID- 23687051 TI - Application of nanosheets as an anti-adhesion barrier in partial hepatectomy. AB - Postoperative adhesion often causes serious adverse effects such as bowl obstruction, chronic abdominal pain, pelvic pain, and infertility. We previously reported that a poly-L-lactic acid (PLLA) nanosheet can efficiently seal a surgical incision without scarring. In this report, we examined whether the PLLA nanosheet can form an effective anti-adhesion barrier in partial hepatectomy accompanied by severe hemorrhaging in rats. To evaluate the anti-adhesive property of the nanosheet, the liver wound surface was covered with TachoComb((r)) , a well-known hemostat material used in clinical procedures, and then with the PLLA nanosheet. Dressing the wound surface with TachoComb((r)) alone caused severe adhesion with omentum and/or residual parts of the liver. By contrast, combinational usage of TachoComb((r)) and the PLLA nanosheet significantly reduced such adhesion, presumably by inhibiting the permeation of oozing blood cells and the infiltration of fibroblastic cells. Moreover, the nanosheet displayed low permeability against serum proteins as well as cells in vitro, supporting the notion that the PLLA nanosheet has anti-adhesive properties in vivo. These results strongly suggested that the PLLA nanosheet is a promising material for reducing unwanted postoperative adhesion. PMID- 23687050 TI - Early mortality after surgical resection for lung cancer: an analysis of the English National Lung cancer audit. AB - INTRODUCTION: For appropriately staged non-small cell lung cancer (NSCLC) surgical resection can dramatically improve survival, but some may not be offered this treatment because of concerns about perioperative mortality. METHODS: We used data from the National Lung Cancer Audit (NLCA) to determine the proportions of English patients who died within 30 and 90 days after surgery for NSCLC. We quantified the predictors of early postoperative death and using these results devised a score to predict risk of death within 90 days of surgery. RESULTS: We analysed data on 10 991 patients operated on between 2004 and 2010. Three per cent (334) of patients died within 30 days of their procedure and 5.9% (647) within 90 days. Age was strongly associated with early postoperative death (adjusted OR within 90 days for 80-84 years vs 70-74 years: 1.46, 95% CI 1.07 to 1.98); significant associations were also observed with performance status (PS) (adjusted OR within 90 days for PS 2 vs PS 0: 2.40, 95% CI 1.68 to 3.41), as well as lung function, stage and procedure type. CONCLUSIONS: Our results show that age is the most important predictor of death within both of these early postoperative periods. We used the data in the NLCA to develop a predictive score, based on an English population and specific to lung cancer surgery, which estimates risk of death within 90 days; this score should be tested in future cohorts. PMID- 23687053 TI - Asymmetric transfer hydrogenation of 3-nitroquinolines: facile access to cyclic nitro compounds with two contiguous stereocenters. AB - Hi, neighbor! The first organocatalyzed asymmetric transfer hydrogenation of aromatic nitro compounds was successfully developed with up to 99 % ee. The new methodology provides a direct and facile access to enantiopure cyclic nitro compounds with two contiguous stereocenters. PMID- 23687052 TI - Rhamnolipid biosurfactant against Fusarium sacchari--the causal organism of pokkah boeng disease of sugarcane. AB - Pokkah boeng disease on sugarcane caused by the fungus Fusarium sacchari results considerable damage to the crop leading to top rot, the most serious and advanced stage of pokkah boeng, where the growing point is killed and the entire top of the plant dies. In the present study, the effect of rhamnolipid biosurfactant as an antifungal agent against F. sacchari to control pokkah boeng disease was investigated. On the basis of surface tension reduction, 12 bacterial isolates were selected as potent biosurfactant producers and eight of them showed antagonistic effect against F. sacchari. Among the eight, the isolate DS9 was found as the effective inhibitor of the fungus in vitro which was further evaluated using its biosurfactant present in whole culture, cell-free culture supernatant and crude biosurfactant at various concentrations. Reductions of fungal growths were found more with crude biosurfactant. By sequencing 16S rRNA, DS9 was identified as P. aeruginosa and the produced biosurfactant was characterized as rhamnolipid by Liquid Chromatography-Mass Spectrometry (LC-MS) analysis. The rhamnolipid biosurfactant inhibits phytopathogenic fungi F. sacchari and therefore seems to be a good biocontrol agent to control pokkah boeng disease of sugarcane. PMID- 23687054 TI - Rhizobium paknamense sp. nov., isolated from lesser duckweeds (Lemna aequinoctialis). AB - A Gram-stain-negative, rod-shaped bacterium was isolated and designated strain L6 8(T) during a study of endophytic bacterial communities in lesser duckweed (Lemna aequinoctialis). Cells of strain L6-8(T) were motile with peritrichous flagella. The analysis of the nearly complete 16S rRNA gene sequence indicated that strain L6-8(T) was phylogenetically related to species of the genus Rhizobium. Its closest relatives were Rhizobium borbori DN316(T) (97.6 %), Rhizobium oryzae Alt 505(T) (97.3 %) and Rhizobium pseudoryzae J3-A127(T) (97.0 %). The sequence similarity analysis of housekeeping genes recA, glnII, atpD and gyrB showed low levels of sequence similarity (<91.5 %) between strain L6-8(T) and other species of the genus Rhizobium with validly published names. The pH range for growth was 4.0-9.0 (optimum 6.0-7.0), and the temperature range for growth was 20-45 degrees C (optimum 30 degrees C). Strain L6-8(T) tolerated NaCl up to 2 % (w/v) (optimum 1 % NaCl). The predominant components of cellular fatty acids were C19 : 0 cyclo omega8c (31.32 %), summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c; 25.39 %) and C16 : 0 (12.03 %). The DNA G+C content of strain L6-8(T) was 60.4 mol% (Tm). nodC and nifH were not amplified in strain L6-8(T). DNA-DNA relatedness between strain L6-8(T) and R. borbori DN316(T), R. oryzae Alt505(T) and R. pseudoryzae J3-A127(T) was between 11.2 and 18.3 %. Based on the sequence similarity analyses, phenotypic, biochemical and physiological characteristics and DNA-DNA hybridization, strain L6-8(T) could be readily distinguished from its closest relatives and represents a novel species of the genus Rhizobium, for which the name Rhizobium paknamense sp. nov. is proposed. The type strain is L6 8(T) ( = NBRC 109338(T) = BCC 55142(T)). PMID- 23687055 TI - Asticcacaulis solisilvae sp. nov., isolated from forest soil. AB - An obligately aerobic, chemoheterotrophic, mesophilic prosthecate bacterium, designated strain CGM1-3EN(T), was isolated from the enrichment cultures of forest soil from Cheonggyesan Mountain, Republic of Korea. Cells were Gram reaction-negative, motile rods (1.3-2.4 um long by 0.30-0.75 um wide) with single flagella. The strain grew at 10-37 degrees C (optimum 25-30 degrees C) and at pH 4.5-9.5 (optimum 5.0-7.0). The major cellular fatty acids were C16 : 0, C18 : 1omega7c 11-methyl, C12 : 1 3-OH and summed feature 8 (comprising C18 : 1omega7c/C18 : 1omega6c). The genomic DNA G+C content of strain CGM1-3EN(T) was 63.7 mol%. The closest phylogenetic neighbour to strain CGM1-3EN(T) was identified as Asticcacaulis biprosthecium DSM 4723(T) (97.2 % 16S rRNA gene sequence similarity) and the DNA-DNA hybridization value between strain CGM1 3EN(T) and A. biprosthecium DSM 4723(T) was less than 24.5 %. Strain CGM1-3EN(T) used d-glucose, d-fructose, sucrose, maltose, trehalose, d-mannose, d-mannitol, d sorbitol, d-galactose, cellobiose, lactose, raffinose, fumarate, pyruvate, dl alanine and glycerol as carbon sources. Based on data from the present polyphasic study, the forest soil isolate CGM1-3EN(T) is considered to represent a novel species of the genus Asticcacaulis, for which the name Asticcacaulis solisilvae sp. nov. is proposed. The type strain is CGM1-3EN(T) ( = AIM0088(T) = KCTC 32102(T) = JCM 18544(T)). PMID- 23687056 TI - Roseovarius lutimaris sp. nov., isolated from a marine tidal flat. AB - A novel Gram-staining-negative, moderately halophilic and strictly aerobic bacterium, designated strain 112(T), was isolated from a tidal flat at Taean, Korea. Cells were catalase- and oxidase-positive ovoids to rods and did not produce bacteriochlorophyll a. Optimum growth of strain 112(T) was observed at 30 degrees C, at pH 6.5-7.5 and in the presence of 2-4 % (w/v) NaCl. The major cellular fatty acids were summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c) and C16 : 0 and Q-10 was detected as the predominant ubiquinone. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, an unidentified aminolipid and three unidentified lipids. The genomic DNA G+C content of strain 112(T) was 58.2 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain 112(T) formed a phyletic lineage within the genus Roseovarius of the class Alphaproteobacteria. Strain 112(T) was most closely related to Roseovarius mucosus DFL-24(T), with 96.52 % similarity. On the basis of phenotypic, chemotaxonomic and molecular properties, strain 112(T) represents a novel species of the genus Roseovarius, for which the name Roseovarius lutimaris sp. nov. is proposed. The type strain is 112(T) ( = KACC 16185(T) = JCM 17743(T)). PMID- 23687057 TI - Falsochrobactrum ovis gen. nov., sp. nov., isolated from a sheep. AB - A Gram-stain-negative, rod-shaped, oxidase-positive, non-spore-forming, non motile bacterium (B1315(T)) was isolated from the placenta of a sheep with abortion. On the basis of 16S rRNA gene sequence analyses the strain was assigned to the Brucella-Ochrobactrum-Paenochrobactrum-Pseudochrobactrum group with 94.5 94.8 %, 94.3-96.1 %, 95.0-95.1 %, and 95.9-96.1 % sequence similarities to type strains of species of the four genera, respectively. Phylogenetic trees indicated a close relationship to the type strains of Ochrobactrum gallinifaecis and Ochrobactrum oryzae (95.9 and 96.1 % sequence similarity, respectively). Chemotaxonomic data confirmed the allocation of strain B1315(T) to the family Brucellaceae (quinone system: ubiquinone Q-10 and major fatty acids: C18 : 1omega7c and C19 : 0 cyclo omega8c). The polar lipid profile contained the major lipids diphosphatidylglycerol, phosphatidylmonomethylethanolamine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine and the unidentified but unique phospholipid PL7. The polyamine pattern of strain B1315(T) contained the major polyamines spermidine and putrescine. On the basis of the 16S rRNA gene and recA sequence phylogeny and chemotaxonomic data strain B1315(T) was clearly different from the genera Brucella, Ochrobactrum, Paenochrobactrum and Pseudochrobactrum. On the basis of these data we propose the novel genus Falsochrobactrum gen. nov. with the type species Falsochrobactrum ovis sp. nov. with the type strain B1315(T) ( = CCM 8460(T) = LMG 27356(T.)) The taxonomic allocation of O. gallinifaecis, which grouped inconsistently together with strain B1315(T) on the basis of 16S rRNA gene sequence data, but shows the chemotaxonomic features of the genus Ochrobactrum, remains to be clarified. PMID- 23687058 TI - Sphingomonas kyungheensis sp. nov., a bacterium with ginsenoside-converting activity isolated from soil of a ginseng field. AB - A bacterial strain THG-B283(T), which has beta-glucosidase activity, was isolated from soil of a ginseng field. Cells were Gram-reaction-negative, oxidase- and catalase-positive, aerobic, motile with one polar flagellum and rod-shaped. The strain was subjected to a polyphasic taxonomic study. Strain THG-B283(T) grew optimally at around pH 7.0, at 25-28 degrees C and in the absence of NaCl on R2A agar. 16S rRNA gene sequence analysis revealed that strain THG-B283(T) belongs to the family Sphingomonadaceae and is closely related to Sphingomonas melonis DAPP PG 224(T) (98.2 %), S. aquatilis JSS7(T) (98.1 %), S. insulae DS-28(T) (97.6 %), S. mali IFO 15500(T) (97.1 %) and S. pruni IFO 15498(T) (97.0 %). Strain THG B283(T) contained Q-10 as the predominant ubiquinone. The major fatty acids included summed feature 3 (comprising C16 : 1omega7c and/or C16 : 1omega6c), C18 : 1omega7c, C14 : 0 2-OH and C16 : 0. The DNA G+C content was 72.2 mol%. The major component in the polyamine pattern was sym-homospermidine. The major polar lipids were phosphatidylglycerol, phosphatidylethanolamine, phosphatidyldimethylethanolamine, phosphatidylcholine, sphingoglycolipid, diphosphatidylglycerol, an unidentified glycolipid, unidentified aminolipids, an unidentified phospholipid and unidentified lipids. Genomic and chemotaxonomic data supported the affiliation of strain THG-B283(T) to the genus Sphingomonas. DNA-DNA relatedness between strain THG-B283(T) and its closest phylogenetic neighbours was below 23 %. On the basis of phenotypic, phylogenetic and genetic data, strain THG-B283(T) represents a novel species of genus Sphingomonas, for which the name Sphingomonas kyungheensis sp. nov. is proposed. The type strain is THG-B283(T) ( = KACC 16224(T) = LMG 26582(T)). PMID- 23687059 TI - Description of Lactobacillus iwatensis sp. nov., isolated from orchardgrass (Dactylis glomerata L.) silage, and Lactobacillus backii sp. nov. AB - Two bacterial strains, designated IWT246(T) and IWT248, were isolated from orchardgrass (Dactylis glomerata L.) silage from Iwate prefecture, Japan, and examined for a taxonomic study. Both organisms were rod-shaped, Gram-stain positive, catalase-negative, facultatively anaerobic and homofermentative. The cell wall did not contain meso-diaminopimelic acid and the major fatty acids were C18 : 1omega9c and C19 cyclo 9,10/:1. Comparative analyses of 16S rRNA, pheS and rpoA gene sequences revealed that these strains were novel and belonged to the genus Lactobacillus. Based on 16S rRNA gene sequence similarity, the isolates were most closely related to the type strains of the following members of the genus Lactobacillus: Lactobacillus coryniformis subsp. coryniformis (96.7 % similarity), L. coryniformis subsp. torquens (96.6 %), L. bifermentans (95.5 %) and L. rennini (94.1 %). However, the 16S rRNA gene sequences of both IWT246(T) and IWT248 were 99.7 % similar to that of 'Lactobacillus backi' JCM 18665; this name has not been validly published. Genotypic, phenotypic and chemotaxonomic analyses confirmed that these novel strains occupy a unique taxonomic position. DNA-DNA hybridization experiments demonstrated genotypic separation of the novel isolates from related Lactobacillus species. The name Lactobacillus iwatensis sp. nov. is proposed for the novel isolates, with strain IWT246(T) ( = JCM 18838(T) = DSM 26942(T)) as the type strain. Our results also suggest that 'L. backi' does represent a novel Lactobacillus species. The cells did not contain meso diaminopimelic acid in their cell-wall peptidoglycan and the major fatty acids were C16 : 0, C19 cyclo 9,10/:1 and summed feature 10 (one or more of C18 : 1omega11c, C18 : 1omega9t, C18 : 1omega6t and unknown ECL 17.834). We therefore propose the corrected name Lactobacillus backii sp. nov., with the type strain JCM 18665(T) ( = LMG 23555(T) = DSM 18080(T) = L1062(T)). PMID- 23687060 TI - Fluviimonas pallidilutea gen. nov., sp. nov., a new member of the family Cytophagaceae isolated from a freshwater river. AB - A bacterial strain designated TQQ6(T) was isolated from a freshwater river in Taiwan and characterized using a polyphasic taxonomy approach. Cells of strain TQQ6(T) were strictly aerobic, Gram-staining-negative, poly-beta-hydroxybutyrate containing, non-motile, non-spore-forming, long rods surrounded by a thick capsule and forming pale orange colonies. Growth occurred at 20-40 degrees C (optimum, 25 degrees C), at pH 7.0-9.0 (optimum, pH 8.0) and with 0-0.5 % NaCl (optimum, 0 %). The predominant fatty acids were iso-C15 : 0, summed feature 3 (comprising C16 : 1omega6c and/or C16 : 1omega7c), iso-C17 : 0 3-OH, C16 : 1omega5c and C16 : 0. The major isoprenoid quinone was MK-7 and the DNA G+C content was 42.2 mol%. The polar lipid profile consisted of a mixture of phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylcholine, two uncharacterized aminophospholipids and three uncharacterized phospholipids. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain TQQ6(T) represents a distinct phyletic line that reflects a novel generic status within the family Cytophagaceae with relatively low sequence similarities (less than 90 %) to members of other genera with validly published names. On the basis of the genotypic and phenotypic data, strain TQQ6(T) represents a new genus and novel species of the family Cytophagaceae, for which the name Fluviimonas pallidilutea gen. nov., sp. nov. is proposed. The type strain is TQQ6(T) ( = BCRC 80447(T) = LMG 27056(T) = KCTC 32035(T)). PMID- 23687061 TI - Amorphus suaedae sp. nov., isolated from the root of a tidal flat plant, Suaeda maritima. AB - A novel bacterial strain, YC6899(T), was isolated from the root of Suaedae maritima growing on a tidal flat of Namhae Island, Korea. Cells were Gram reaction-negative, rod-shaped, non-motile, slightly halophilic and heterotrophic. Strain YC6899(T) grew optimally at a salinity of 2-4 %, at 25-37 degrees C and at pH 6.5-8.0. Phylogenetic analysis of 16S rRNA gene sequences demonstrated that strain YC6899(T) was closely related to Amorphus orientalis YIM D10(T) (96.1 % similarity) and Amorphus coralli RS.Sph.026(T) (95.9 %). The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, unknown aminolipids, an unknown aminophospholipid, an unknown aminoglycolipid, unknown glycolipids and unknown lipids. The major fatty acids of strain YC6899(T) were C19 : 0 cyclo omega8c and C18 : 1omega7c. The G+C content of the genomic DNA was 61.3 mol%. Strain YC6899(T) contained ubiquinone-10 (Q-10) as the major respiratory quinone system. On the basis of phenotypic, chemotaxonomic and phylogenetic data, strain YC6899(T) represents a novel species within the genus Amorphus, for which the name Amorphus suaedae sp. nov. is proposed. The type strain is YC6899(T) ( = KACC 14912(T) = NBRC 107845(T)). PMID- 23687062 TI - Thermal controls of Yellowstone cutthroat trout and invasive fishes under climate change. AB - We combine large observed data sets and dynamically downscaled climate data to explore historic and future (2050-2069) stream temperature changes over the topographically diverse Greater Yellowstone Ecosystem (elevation range = 824-4017 m). We link future stream temperatures with fish growth models to investigate how changing thermal regimes could influence the future distribution and persistence of native Yellowstone cutthroat trout (YCT) and competing invasive species. We find that stream temperatures during the recent decade (2000-2009) surpass the anomalously warm period of the 1930s. Climate simulations indicate air temperatures will warm by 1 degrees C to >3 degrees C over the Greater Yellowstone by mid-21st century, resulting in concomitant increases in 2050-2069 peak stream temperatures and protracted periods of warming from May to September (MJJAS). Projected changes in thermal regimes during the MJJAS growing season modify the trajectories of daily growth rates at all elevations with pronounced growth during early and late summer. For high-elevation populations, we find considerable increases in fish body mass attributable both to warming of cold water temperatures and to extended growing seasons. During peak July to August warming, mid-21st century temperatures will cause periods of increased thermal stress, rendering some low-elevation streams less suitable for YCT. The majority (80%) of sites currently inhabited by YCT, however, display minimal loss (<10%) or positive changes in total body mass by midcentury; we attribute this response to the fact that many low-elevation populations of YCT have already been extirpated by historical changes in land use and invasions of non-native species. Our results further suggest that benefits to YCT populations due to warmer stream temperatures at currently cold sites could be offset by the interspecific effects of corresponding growth of sympatric, non-native species, underscoring the importance of developing climate adaptation strategies that reduce limiting factors such as non-native species and habitat degradation. PMID- 23687064 TI - Photoinduced biphasic hydrogen evolution: decamethylosmocene as a light-driven electron donor. AB - Excitation of the weak electron donor decamethylosmocene on illumination with white light produces an excited-state species capable of reducing organically solubilized protons under biphasic conditions. Insight into the mechanism and kinetics of light-driven biphasic hydrogen evolution are obtained by analysis with gas chromatography, cyclic voltammetry, and UV/Vis and (1)H NMR spectroscopy. Formation of decamethylosmocenium hydride, which occurs prior to hydrogen evolution, is a rapid step relative to hydrogen release and takes place independently of light activation. Remarkably, hydride formation occurs with greater efficiency (ca. 90% conversion) under biphasic conditions than when the reaction is carried out in an acidified single organic phase (ca. 20% conversion). Cyclic voltammetry studies reveal that decamethylosmocene has a higher proton affinity than either decamethylferrocene or osmocene. PMID- 23687063 TI - Recruitment of normal stem cells to an oncogenic phenotype by noncontiguous carcinogen-transformed epithelia depends on the transforming carcinogen. AB - BACKGROUND: Cancer stem cells (CSCs) drive tumor initiation, progression, and metastasis. The microenvironment is critical to the fate of CSCs. We have found that a normal stem cell (NSC) line from human prostate (WPE-stem) is recruited into CSC-like cells by nearby, but noncontiguous, arsenic-transformed isogenic malignant epithelial cells (MECs). OBJECTIVE: It is unknown whether this recruitment of NSCs into CSCs by noncontact co-culture is specific to arsenic transformed MECs. Thus, we used co-culture to examine the effects of neighboring noncontiguous cadmium-transformed MECs (Cd-MECs) and N-methyl-N-nitrosourea transformed MECs (MNU-MECs) on NSCs. RESULTS: After 2 weeks of noncontact Cd-MEC co-culture, NSCs showed elevated metalloproteinase-9 (MMP-9) and MMP-2 secretion, increased invasiveness, increased colony formation, decreased PTEN expression, and formation of aggressive, highly branched duct-like structures from single cells in Matrigel, all characteristics typical of cancer cells. These oncogenic characteristics did not occur in NSCs co-cultured with MNU-MECs. The NSCs co cultured with Cd-MECs retained self-renewal capacity, as evidenced by multiple passages (> 3) of structures formed in Matrigel. Cd-MEC-co-cultured NSCs also showed molecular (increased VIM, SNAIL1, and TWIST1 expression; decreased E-CAD expression) and morphologic evidence of epithelial-to-mesenchymal transition typical for conversion to CSCs. Dysregulated expression of SC-renewal genes, including ABCG2, OCT-4, and WNT-3, also occurred in NSCs during oncogenic transformation induced by noncontact co-culture with Cd-MECs. CONCLUSIONS: These data indicate that Cd-MECs can recruit nearby NSCs into a CSC-like phenotype, but MNU-MECs do not. Thus, the recruitment of NSCs into CSCs by nearby MECs is dependent on the carcinogen originally used to malignantly transform the MECs. PMID- 23687065 TI - Clinical and immunological features of 888 Brazilian systemic lupus patients from a monocentric cohort: comparison with other populations. AB - Epidemiological studies with systemic lupus erythematosus (SLE) patients have been reported worldwide but, until now, a large evaluation had not been performed in Brazil. Therefore, we determined the clinical and immunological features of 888 SLE patients followed at our service from 2008 to 2012. The mean age at SLE onset and the mean disease duration were 29.9 +/- 9.5 years old and 14.5 +/- 8.4 years, respectively. A predominance of female gender (91.9%) and Caucasian ethnicity (69.9%) were observed. Cumulative mucocutaneous manifestations (90.7%) were most commonly identified (malar rash (83.2%), photosensitivity (76.9%)) followed by articular (87.4%), hematological (44.0%) and renal (36.9%) involvements. Antinuclear antibody was detected in all patients, followed by anti dsDNA (35.1%), anti-Sm (21.8%) and anti-ribosomal P protein antibodies (19.8%). Additional comparison of clinical and laboratory features between genders revealed that malar rash was observed more in female SLE patients (84.5% vs. 69.4%, p = 0.001). Male lupus patients presented a higher frequency of anti-dsDNA (45.8% vs. 34.2%, p = 0.047) and a trend of more nephritis (47.2% vs. 36.0%, p = 0.059). In conclusion, we identified a high prevalence of mucocutaneous manifestations in this Brazilian SLE cohort compared to other countries, mainly malar rash that was most commonly observed in female patients. Anti-dsDNA and other specific SLE autoantibodies were also identified in a higher frequency, predominantly in the male gender. PMID- 23687066 TI - Are there additional options for the treatment of refractory obstetric antiphospholipid syndrome? PMID- 23687067 TI - Clinical features and outcomes of posterior reversible encephalopathy syndrome in patients with systemic lupus erythematosus. AB - OBJECTIVE: To analyze the clinical features and outcomes of patients with posterior reversible encephalopathy syndrome(PRES), the risk factors of PRES related intracranial hemorrhage (ICH), and all-cause mortality in patients with systemic lupus erythematosus (SLE). METHODS: Twenty-six episodes of PRES were identified in 23 SLE patients, using an electronic medical records database of 3,746 SLE patients. RESULTS: The prevalence of PRES was 0.69% among SLE patients. The scores of the SLE Disease Activity Index without neurologic descriptors (SLEDAI-N) were significantly elevated from baseline for a mean of 3.3 during PRES (P = 0.009). Rapidly deteriorating renal function, pulmonary hemorrhage, thrombotic microangiopathy, macrophage activation syndrome, or multiple organ dysfunction syndrome appeared during 65.4% of episodes. In 16 episodes, patients completely recovered from PRES-related symptoms within a median of 7 days. Visual impairment was reversed within 2 days in 8 of 15 patients, but impairment in other patients was protracted for up to 4 months, especially when ICH was present. Hypoalbuminemia (<20 gm/liter; odds ratio [OR] 30, 95% confidence interval [95% CI] 2.04-441.84) and thrombocytopenia (<30,000/mm(3); OR 21, 95% CI 1.27-346.93) were risk factors for PRES-related ICH. Patients with SLEDAI-N scores >18 during a PRES attack had significantly higher mortality rates than did patients with SLEDAI-N scores <=18 (P = 0.009 by log rank test). CONCLUSION: PRES frequently occurs during active SLE with multiple complications. Hypoalbuminemia and thrombocytopenia may contribute to PRES-related ICH. The extra neurologic disease activity of lupus during PRES may influence the mortality rate of SLE patients. PMID- 23687068 TI - Familial trisomy 6p in mother and daughter. AB - Several patients with partial trisomy 6p resulting from parental balanced translocations or from a de novo duplication or insertion have already been described. Here, we report on the first case of familial pure trisomy 6p as a result of interstitial tandem duplication. The patient, an 11-year-old female, presented with mild dysmorphic features, moderate intellectual disability with behavioral disturbances, immunodeficiency, and epilepsy. Conventional cytogenetic analysis showed a duplication of the 6p region in the patient and in her mother presenting with a partially overlapping phenotype. The rearrangement was confirmed and defined by molecular cytogenetic analysis, including FISH and array CGH analysis showing a gain of ~13.8 Mb from 6p12.3 to 6p21.31. The phenotype of a pure partial trisomy 6p is extremely heterogeneous depending on the gene contents of the duplicated region. The clinical features of our patients have been compared with overlapping cases from the literature. PMID- 23687069 TI - Improved neural progenitor cell proliferation and differentiation on poly(lactide co-glycolide) scaffolds coated with elastin-like polypeptide. AB - Poly(lactide-co-glycolide) (PLGA) and elastin-like polypeptide (ELP) have been widely used as a biodegradable scaffold and thermoresponsive matrix, respectively. However, little attention has focused on the combinatorial use of these biomaterials for tissue engineering applications. An ELP matrix TGPG[VGRGD(VGVPG)6]20WPC (referred to as REP) contains multiple Arg-Gly-Asp motifs. This study fabricated porous PLGA scaffolds coated with various concentration of matrix via thermally induced phase transition to improve adhesion-mediated proliferation and differentiation of neural progenitor cells. Matrix-coated scaffolds were characterized by FTIR, SEM, and hematoxylin and eosin staining with respect to coating efficiency, porosity, and pore size and shape. On the matrix-coated scaffolds, cells grew as a single cell or associated each other to form a multicellular layer or cluster. In biological evaluations, cell adhesion and proliferation were significantly promoted in a matrix concentration-dependent manner. More importantly, in combination with retinoic acid, the differentiation of progenitor cells into neuronal and astroglial lineages was highly stimulated in the cells cultured on matrix-coated scaffolds than on untreated controls. Taken together, our results indicated that the REP matrix-functionalized PLGA scaffolds are suitable for improving neuronal cell functions, and thus applicable for neural tissue engineering. PMID- 23687070 TI - Targeted glycoprotein enrichment and identification in stromal cell secretomes using azido sugar metabolic labeling. AB - PURPOSE: Effectively identifying the proteins present in the cellular secretome is complicated due to the presence of cellular protein leakage and serum protein supplements in culture media. A metabolic labeling and click chemistry capture method is described that facilitates the detection of lower abundance glycoproteins in the secretome, even in the presence of serum. EXPERIMENTAL DESIGN: Two stromal cell lines were incubated with tetraacetylated sugar-azide analogs for 48 h in serum-free and low-serum conditions. Sugar-azide labeled glycoproteins were covalently linked to alkyne-beads, followed by on-bead trypsin digestion and MS/MS. The resulting glycoproteins were compared between media conditions, cell lines, and azide-sugar labels. RESULTS: Alkyne-bead capture of sugar-azide modified glycoproteins in stromal cell culture media significantly improved the detection of lower abundance secreted glycoproteins compared to standard serum-free secretome preparations. Over 100 secreted glycoproteins were detected in each stromal cell line and significantly enriched relative to a standard secretome preparation. CONCLUSION AND CLINICAL RELEVANCE: Sugar-azide metabolic labeling is an effective way to enrich for secreted glycoproteins present in cell line secretomes, even in culture media supplemented with serum. The method has utility for identifying secreted stromal proteins associated with cancer progression and the epithelial-to-mesenchymal transition. PMID- 23687071 TI - A versatile approach towards the compaction, decompaction, and immobilization of DNA at interfaces by using cyclodextrins. AB - We investigate the temperature dependence of interactions of beta-cyclodextrin (CD)/hexadecyltrimethylammonium bromide (CTAB) self-assemblies with DNA during the decompaction of DNA/CTAB complexes. By combining direct imaging techniques with density and sound-velocity measurements, we can explain the decompaction process and suggest a suitable model. The DNA-decompaction process by using CDs is accompanied by interactions with surfaces, such as glass or mica. The mechanism of beta-CD/CTAB self-assembly is elucidated and the immobilization of DNA onto negatively charged surfaces is explained. Differences between the fractal dimensions of DNA that is adsorbed onto the surfaces are related to strong and weak binding, which permit the partial relaxation of DNA on the surfaces. The beta-CD/CTAB self-assembled monolayers are demonstrated to be a facile and efficient route for surface functionalization, which allows for the immobilization of biomacromolecules in close proximity without any intermediate binding or deprotection steps. Moreover, this route is expected to show several advantages that might contribute to improving the performance of future biosensors as gentle immobilization-limiting alteration of the protein structure, oriented immobilization, thereby allowing homogeneous accessibility, reversible immobilization, thereby allowing reutilizations, and high compatibility with various types of biomacromolecules. PMID- 23687073 TI - Keeping 'a chest' of the literature. PMID- 23687072 TI - Morphological and histological changes of rabbit vocal fold after steroid injection. AB - OBJECTIVES/HYPOTHESIS: The purpose of this study was to investigate the morphological and histological change of vocal folds (VFs) after steroid injection in a rabbit model. STUDY DESIGN: Prospective animal study. SETTING: Tertiary academic medical center. SUBJECTS AND METHODS: Twenty-four New Zealand white rabbits were used in this study. We randomly classified rabbits into the 3 groups and triamcinolone acetonide suspension was injected to the right VF with different concentrations. Left VF was injected with the same volume of phosphate buffered saline as control. Endoscopic evaluation was performed to measure morphological changes. The larynges were collected for histological analysis, and the VFs were stained with hematoxylin-eosin for assessing inflammatory response, glandular atrophy, and muscular atrophy and with Masson's trichrome for assessing collagen deposition. RESULTS: In morphological assessment, there were no differences in VF mass reduction, mucosal atrophy, and granulation formation between both VFs. Histological assessments showed no significant difference in inflammatory response, glandular atrophy, and collagen deposition between both VFs. However, there was a difference in muscular atrophy and epithelial layer thinning in steroid injected right VFs. Muscular atrophy had been completely recovered over time, but mild epithelial thinning was continued until 12 weeks. The longer exposure time and larger dose did not increase the intensity of muscular atrophy or epithelial thinning. CONCLUSION: We demonstrated that the VF steroid injection resulted in no significant changes in morphology and histology of rabbit VF. However, steroid injection may induce several VF histological changes and these results are needed to be considered when treating humans. PMID- 23687074 TI - Cavitating pulmonary nodules growing in a favourable medium. PMID- 23687075 TI - Orbital wall repair in canines with beta-tricalcium phosphate and induced bone marrow stromal cells. AB - Bone tissue engineering is a new approach for the repair of orbital defects. The aim of the present study was to evaluate prefabricated beta-tricalcium phosphate (beta-TCP) combined with autologous bone marrow stromal cells (BMSCs) to repair orbital wall defect in canine models. Defects measuring 10 mm in diameter were created in the orbital medial walls of 12 dogs. The orbits were randomly divided into five groups: group 1, repaired with osteogenesis-induced BMSCs/TCP constructs; group 2, repaired with noninduced BMSCs/TCP constructs; group 3, repaired with beta-TCP scaffolds only; group 4, normal group; group 5, negative control (bone defect without treatment). Computed tomography (CT) scanning, gross observation, bone density measurements, micro-CT, and histological observations were performed. In group 1, new bone was observed with only a small amount of residual material, and bony union was achieved 3 months after surgery. In contrast, the constructs showed slow degradation with minimal bone formation in groups 2 and 3. Furthermore, the appearance and bone density of the constructs in group 1 were similar to that of normal bone: the constructs were covered with complete mucosa, and new alveolate plate grew into the ethmoidal sinuses. A large bone defect remained in group 5. This study demonstrated that biologic scaffolds composed of beta-TCP and osteogenesis-induced BMSCs have been successfully used to restore bone functionality in animal models, which may provide a potential clinical approach for orbital wall repair and bone regeneration in humans. PMID- 23687076 TI - Mortality of congenital osteochondrodysplasias: a nationwide registry-based study. AB - Osteochondrodysplasias are a heterogeneous group of more than 200 entities, characterized by abnormalities of cartilage, bone growth, and skeletal development. The aim of this study was to assess temporal and spatial changes in overall mortality due to these disorders in Spain, using data from a nationwide registry. Annual deaths showing osteochondrodysplasias as the underlying cause of death were selected using the International Classification of Diseases-9th revision (ICD-9) codes for the period 1981 through 1998, and ICD-10 codes for the period 1999 through 2008. Age-adjusted mortality rates were calculated by sex, and geographic analysis was performed by municipality. A total of 679 deaths were recorded (53% men). Age-adjusted mortality rates went from 0.09 (0.06, 0.12) per 100,000 population in 1981 to 0.05 (0.03, 0.08) per 100,000 population in 2008. A changing trend in the age-standardized mortality rate was in evidence, with an annual increase of 2.4% (-0.4, 5.2) from 1981 to 1994, and an annual decrease of 7.3% (-10.9, -3.5) from 1995 onwards. Geographic analysis showed some places situated in the west and south of Spain with greater risk of mortality. There is a need to identify risk factors and to increase overall knowledge about the life expectancy and epidemiology of osteochondrodysplasias. PMID- 23687077 TI - Subtyping of nonsmall cell lung cancer on cytology specimens: reproducibility of cytopathologic diagnoses on sparse material. AB - Cytologic examination of fine-needle aspiration (material is increasingly used in diagnosing lung cancer. High interobserver agreement in distinguishing small-cell lung cancer from nonsmall-cell lung cancer (NSCLC) on cytologic material has been demonstrated. Because of new treatment-modalities, subclassification of NSCLC into squamous cell carcinoma (SQC) and non-SQC has clinical impact. Subclassification based on morphology alone may be difficult, but applying immunohistochemistry (IHC) to clot-material has proved helpful. When insufficient material is available to make a clot from the aspirate, cytoscrape (CS) can convert cytologic material into tissue fragments useful for IHC. The purpose of this study was to test the reproducibility of pulmonary malignant diagnoses, in particular distinction between subgroups of NSCLC, based on smeared material and IHC on CS. A consecutive series of May-Grunwald-Giemsa (MGG) stained smears and CS with IHC on material from 79 patients suspected of having lung cancer was included. The material was circulated twice to four pathologists. The diagnoses were categorized in five groups: SQC, adenocarcinoma of the lung, non-SQC, benign lesion and other forms of malignancy, including metastases. Reproducibility was analyzed using Kappa statistics. Interobserver reproducibility of the diagnoses in round 1 was good to very good (kappa 0.57-0.71) and very good in round 2 (0.63 0.80). Reproducibility of subclassification of NSCLC based on MGG stained smear and IHC on CS, was very good among experienced pathologists. With only sparse material available, CS should be used to achieve reproducible diagnoses, including subtyping of NSCLC. PMID- 23687078 TI - Comparative proteomics and correlated signaling network of kidney in ApoE deficient mouse. AB - PURPOSE: Apolipoprotein E knockout (apoE-/- ) mouse is one of the most popular models for cardiovascular research, especially in the study of atherosclerosis. Naturally, large amount of studies try to uncover the role of apoE in atherosclerosis, and indeed apoE plays an important role in this pathogenesis. Kidney is an organ that contains lots of capillaries and also largely expresses apoE. Moreover, a protective role of apoE in kidney as an autocrine regulator has been demonstrated previously, however, the underlying mechanism is largely unknown. EXPERIMENTAL DESIGN: In this study, comparative proteomics is for the first time used to identify the differential proteins in kidneys of apoE-/- and wild type (WT) mice, respectively, and we try to reveal the signaling network of apoE in mice kidney using bioinformatics analysis. RESULTS: Our findings show that approximately 80 proteins are significantly differentially expressed in kidneys of apoE-/- and WT mice, and the signaling network correlated to apoE is successfully established by employing bioinformatics assay. CONCLUSIONS AND CLINICAL RELEVANCE: Taken together, we originally identify the proteins with differential expression and propose an apoE correlated molecular network in mice kidney. These findings further provide evidence of the role of apoE in mice kidney and a brand new perspective in the protection and treatment of kidney disease. PMID- 23687079 TI - Preparation of electrospun fiber mats using siloxane-containing vaterite and biodegradable polymer hybrids for bone regeneration. AB - An electrospun fiber mat using a new composite consisting of siloxane-containing vaterite (SiV) and poly(lactic-co-glycolic acid) (PLGA) (denoted by SiPLGVH) was prepared with the aim of applying it as a membrane for use in a guided bone regeneration (GBR) system. Another electrospun fiber mat using a previously described composite consisting of SiV and poly(L-lactic acid) (denoted by SiPVH) was also prepared as a comparative sample. SiPLG VH fiber mats showed superior results in terms of mechanical tensile properties and cellular behavior. Their elongation before failure was about eight times higher than that of SiPVH. The numbers of osteoblast-like cells that proliferated on the SiPLGVH fiber mats, regardless of the hydroxyapatite coating, were comparable to that of SiPVH. The cells spread more, two dimensionally, on the SiPLGVH fiber mats, since the pores between fibers were narrowed down because of swelling of the PLGA matrix during cell culture. This two-dimensional cellular proliferation quality on the SiPLGVH fiber mats is expected to be suitable for materials used in GBR, leading to control of infiltration of the soft tissue and great tissue integration with the surrounding tissue. PMID- 23687080 TI - 6p21.3 microdeletion involving the SYNGAP1 gene in a patient with intellectual disability, seizures, and severe speech impairment. AB - The chromosome 6p21.3 microdeletion phenotype was recently identified through array comparative genomic hybridization. The main features are developmental delay with severe speech impairment, seizures, and behavioral abnormalities. Three patients have been reported with deletion sizes ranging from 100 to 800 kb. We report on a 9-year-old boy with an apparently de novo, 50 kb deletion, and global developmental delay, severe speech impairment, and generalized epilepsy well-controlled by medication. There were four genes identified in this deletion, of which SYNGAP1 is considered to be responsible for speech impairment and epilepsy. We compared the clinical features of this patient with previously reported patients with 6p21.3 and patients with SYNGAP1 mutations. (c) 2013 Wiley Periodicals, Inc. PMID- 23687081 TI - Vegetable cells in urinary samples of patients with bricker ileal conduit. AB - During routine cytopathological evaluation of urines for malignant cells we have occasionally noticed vegetable cells that were only present in patients with Bricker ileal conduit. We wanted to identify the means and sources of contamination of urinary samples from these patients. During the period between May and November 2010, 637 urinary samples were routinely evaluated for malignant cells. Among them were 13 urinary samples from Bricker ileal conduit which we rescreened. We prepared all urinary samples by membrane filtration and stained them according to Papanicolaou. Subsequently, we prepared samples from ostomy adhesives made by Coloplast and by ConvaTec which are used to secure the ostomy bag onto urostomy. We also took samples from different constituents (hydrocolloids) of ostomy adhesives. On the cytopathological review, we found vegetable cells along with intestinal mucosa cells in urinary samples of seven patients with Bricker ileal conduit. With the light microscopic examination of the samples prepared from different ostomy adhesives, we found vegetable cells only in Coloplast adhesives. In preparations of hydrocolloids, we found vegetable cells only in guar gum. They were morphologically identical to those found in urine samples of patients with Bricker ileal conduit and in Sensura and Sensura Xpro (Coloplast) ostomy adhesives. We determined that the origin of vegetable cells in urines from Bricker ileal conduit is the ostomy adhesive. The vegetable cells differ from human intestinal epithelial cells regarding size, shape, and color so it is difficult to misinterpret them as dysplastic cells. PMID- 23687082 TI - Controlled hydrophobic functionalization of natural fibers through self-assembly of amphiphilic diblock copolymer micelles. AB - The functionalization of natural fibers is an important task that has recently received considerable attention. We investigated the formation of a hydrophobic layer from amphiphilic diblock copolymer micelles [polystyrene-block-poly(N methyl-4-vinyl pyridinium iodide)] on natural fibers and on a model surface (mica). A series of micelles were prepared. The micelles were characterized by using cryoscopic TEM and light scattering, and their hydrophobization capability was studied through contact angle measurements, water adsorption, and Raman imaging. Mild heat treatment (130 degrees C) was used to increase the hydrophobization capability of the micelles. The results showed that the micelles could not hydrophobize a model surface, but could render the natural fibers water repellent both with and without heat treatment. This effect was systematically studied by varying the composition of the constituent blocks. The results showed that the micelle size (and the molecular weight of the constituent diblock copolymers) was the most important parameter, whereas the cationic (hydrophilic) part played only a minor role. We hypothesized that the hydrophobization effect could be attributed to a combination of the micelle size and the shrinkage of the natural fibers upon drying. The shrinking caused the roughness to increase on the fiber surface, which resulted in a rearrangement of the self- assembled layer in the wet state. Consequently, the fibers became hydrophobic through the roughness effects at multiple length scales. Mild heat treatment melted the micelle core and decreased the minimum size necessary for hydrophobization. PMID- 23687083 TI - Multilayer scaffold of electrospun PLA-PCL-collagen nanofibers as a dural substitute. AB - Dural closure after the neurosurgery can prevent postoperative complications. Although many types of dural substitute have been developed, most of them lack functional and structural characteristics compared with the natural dura mater. In this study, we used electrospinning method to fabricate a multilayer scaffold to promote dural repair. The inner layer of the scaffold that faces the brain tissue is composed of poly-lactic acid (PLA) to reduce tissue adhesion. The middle layer of the scaffold is composed of poly-E-caprolactone and PLA, which provides a watertight seal. The outer layer of the scaffold contains a large amount of collagen to promote cell attachment and proliferation. The results from in vitro study and an animal model have shown that this multilayer fibrous scaffold has sufficient mechanic strength and biochemical properties to enhance dural repair. Therefore, fabrication of scaffold with multiple functional and structural layers may provide a novel approach for tissue engineering. PMID- 23687085 TI - A novel RASA1 mutation causing capillary malformation-arteriovenous malformation (CM-AVM) presenting during pregnancy. AB - Capillary malformation-arteriovenous malformation (CM-AVM) is a newly recognized clinical entity caused by mutation of the RASA1 gene, which encodes p120-RasGAP. Here we describe, for the first time, a patient with CM-AVM presenting during the late stages of pregnancy with pulmonary "capillary level" microvascular shunt, worsening cutaneous capillary malformations, and gross fluid overload. Sequencing revealed a novel mutation of the RASA1 gene involving a frameshift mutation in the RASGAP domain of RASA1. This report extends our current genetic and clinical understanding of CM-AVM. PMID- 23687084 TI - Multiple-flow exhaled nitric oxide, allergy, and asthma in a population of older children. AB - "Extended" (multiple-flow) measurements of exhaled nitric oxide (FeNO) potentially can distinguish proximal and distal airway inflammation, but have not been evaluated previously in large populations. We performed extended NO testing within a longitudinal study of a school-based population, to relate bronchial flux (J'awNO) and peripheral NO concentration (CalvNO) estimates with respiratory health status determined from questionnaires. We measured FeNO at 30, 50, 100, and 300 ml/sec in 1,640 subjects aged 12-15 from eight communities, then estimated J'awNO and CalvNO from linear and nonlinear regressions of NO output versus flow. J'awNO, as well as FeNO at all flows, showed influences of asthma, allergy, Asian or African ancestry, age, and height (positive), and of weight (negative), generally corroborating past findings. By contrast, CalvNO results were inconsistent across different extended NO regression models, and appeared more sensitive to small measurement artifacts. CONCLUSIONS: Extended NO testing is feasible in field surveys of young populations. In interpreting results, size, age, and ethnicity require attention, as well as instrumental and environmental artifacts. J'awNO and conventional FeNO provide similar information, probably reflecting proximal airway inflammation. CalvNO may give additional information relevant to peripheral airway, alveolar, or systemic pathology. However, it needs additional research, including testing of populations with independently verifiable peripheral or systemic pathology, to optimize measurement technique and interpretation. PMID- 23687086 TI - High levels of biological activity of Cry1Ac protein expressed on MON 87701 * MON 89788 soybean against Heliothis virescens (Lepidoptera:Noctuidae). AB - BACKGROUND: Genetically modified MON 87701 * MON 89788 soybean (Glycine max) that expresses the Cry1Ac and EPSP-synthase proteins is a new Integrated Pest Management (IPM) tool for controlling Heliothis virescens in Brazil. To Support Insect Resistance Management (IRM) programs and understand the value of this event for IPM, we conducted laboratory and field studies to assess the biological activity of Cry1Ac protein expressed on Bt soybean against this insect pest. RESULTS: Heliothis virescens was highly susceptible to purified Cry1Ac protein [LC50 (FL 95%) = 0.026 (0.021-0.033) ug Cry1Ac mL(-1) diet]. In bioassays with freeze-dried MON 87701 * MON 89788 soybean tissue diluted 25 times in an artificial diet, there was 100% mortality of H. virescens. In bioassays with leaf disc, young trifoliate, flower buds, pods and high artificial infestation under greenhouse condition, MON 87701 * MON 89788 soybean showed a high level of control against H. virescens. Moreover, larvae from first through fifth instar were highly susceptible to MON 87701 * MON 89788 soybean. CONCLUSIONS: The MON 87701 * MON 89788 soybean provides an effective alternative in controlling Heliothis virescens and complies with the concept of high-dose for IRM programs. PMID- 23687087 TI - Nras(G12D/+) promotes leukemogenesis by aberrantly regulating hematopoietic stem cell functions. AB - Oncogenic NRAS mutations are frequently identified in human myeloid leukemias. In mice, expression of endogenous oncogenic Nras (Nras(G12D/+)) in hematopoietic cells leads to expansion of myeloid progenitors, increased long-term reconstitution of bone marrow cells, and a chronic myeloproliferative neoplasm (MPN). However, acute expression of Nras(G12D/+) in a pure C57BL/6 background does not induce hyperactivated granulocyte macrophage colony-stimulating factor signaling or increased proliferation in myeloid progenitors. It is thus unclear how Nras(G12D/+) signaling promotes leukemogenesis. Here, we show that hematopoietic stem cells (HSCs) expressing Nras(G12D/+) serve as MPN-initiating cells. They undergo moderate hyperproliferation with increased self-renewal. The aberrant Nras(G12D/+) HSC function is associated with hyperactivation of ERK1/2 in HSCs. Conversely, downregulation of MEK/ERK by pharmacologic and genetic approaches attenuates the cycling of Nras(G12D/+) HSCs and prevents the expansion of Nras(G12D/+) HSCs and myeloid progenitors. Our data delineate critical mechanisms of oncogenic Nras signaling in HSC function and leukemogenesis. PMID- 23687088 TI - Induction of B7-H6, a ligand for the natural killer cell-activating receptor NKp30, in inflammatory conditions. AB - B7-H6, a member of the B7 family of immunoreceptors, is as a cell-surface ligand for the NKp30-activating receptor expressed on natural killer cells. B7-H6 is not detected in normal human tissues at steady state but is expressed on tumor cells. However, whether B7-H6 can be expressed in other conditions remains unknown. We analyzed here the pathways that lead to the expression of B7-H6 in nontransformed cells. In vitro, B7-H6 was induced at the surface of CD14(+)CD16(+) proinflammatory monocytes and neutrophils upon stimulation by ligands of Toll like receptors or proinflammatory cytokines such as interleukin-1beta and tumor necrosis factor alpha. In these conditions, a soluble form of B7-H6 (sB7-H6) was also produced by activated monocytes and neutrophils. In vivo, B7-H6 was expressed on circulating proinflammatory CD14(+)CD16(+) monocytes in a group of patients in sepsis conditions, and was linked to an increased mortality. sB7-H6 was selectively detected in the sera of patients with gram-negative sepsis and was associated with membrane vesicles that co-sedimented with the exosomal fraction. These findings reveal that B7-H6 is not only implicated in tumor immunosurveillance but also participates in the inflammatory response in infectious conditions. PMID- 23687090 TI - Defects in neutrophil granule mobilization and bactericidal activity in familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) syndrome caused by STXBP2/Munc18-2 mutations. AB - Familial hemophagocytic lymphohistiocytosis (FHL) is caused by genetic defects in cytotoxic granule components or their fusion machinery, leading to impaired natural killer cell and/or T lymphocyte degranulation and/or cytotoxicity. This may accumulate into a life-threatening condition known as macrophage activation syndrome. STXBP2, also known as MUNC18-2, has recently been identified as the disease-causing gene in FHL type 5 (FHL-5). A role for STXBP2 in neutrophils, and for neutrophils in FHL in general, has not been documented thus far. Here, we report that FHL-5 neutrophils have a profound defect in granule mobilization, resulting in inadequate bacterial killing, in particular, of gram-negative Escherichia coli, but not of Staphylococcus aureus, which rather depends on intact reduced NAD phosphate oxidase activity. This impairment of bacterial killing may contribute to the apparent susceptibility to gastrointestinal tract inflammation in patients with FHL-5. PMID- 23687089 TI - Prognostic relevance of integrated genetic profiling in adult T-cell acute lymphoblastic leukemia. AB - Adult T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic tumor associated with poor outcome. In this study, we analyzed the prognostic relevance of genetic alterations, immunophenotypic markers, and microarray gene expression signatures in a panel of 53 adult T-ALL patients treated in the Eastern Cooperative Oncology Group E2993 clinical trial. An early immature gene expression signature, the absence of bi-allelic TCRG deletion, CD13 surface expression, heterozygous deletions of the short arm of chromosome 17, and mutations in IDH1/IDH2 and DNMT3A genes are associated with poor prognosis in this series. In contrast, expression of CD8 or CD62L, homozygous deletion of CDKN2A/CDKN2B, NOTCH1 and/or FBXW7 mutations, and mutations or deletions in the BCL11B tumor suppressor gene were associated with improved overall survival. Importantly, the prognostic relevance of CD13 expression and homozygous CDKN2A/CDKN2B deletions was restricted to cortical and mature T-ALLs. Conversely, mutations in IDH1/IDH2 and DNMT3A were specifically associated with poor outcome in early immature adult T-ALLs. This trial was registered at www.clinicaltrials.gov as #NCT00002514. PMID- 23687091 TI - FLT3 inhibitor-induced neutrophilic dermatosis. AB - The FLT3-ITD mutation is associated with poor outcomes in acute myeloid leukemia. Multiple FMS-like tyrosine kinase 3 (FLT3)-inhibitors have been studied in clinical trials. Recently, potent FLT3 inhibition was shown to induce terminal differentiation of FLT3-mutant myeloblasts. In 3 patients who developed characteristic skin nodules on initiation of FLT3-inhibition, we conducted dermatopathologic evaluation of skin samples, as well as FLT3 and NPM1 mutational analysis and fluorescence in situ hybridization. All 3 patients demonstrated characteristically deep dermal and subcutaneous neutrophilic infiltrates without evidence of myeloblasts. Discovery of FLT3-ITD and NPM1 mutations in 2 of the samples, as well as the presence of FLT3-ITD and deletion of 7q in the other, confirmed the ancestry of the differentiated neutrophils as that of the original FLT3-mutant myeloblasts. FLT3 inhibition can lead to clinically distinct dermatoses, which suggests the effect of FLT3 inhibition on myeloid differentiation and a manifestation of a broader "syndrome" associated with this therapy. PMID- 23687094 TI - Lung function indices of children exposed to wood smoke in a fishing port in South-South Nigeria. AB - Children in the warm rain forest are at risk of having their lung function compromised by a variety of factors, including smoke from wood fires. A total of 358 children from a fishing port and 400 children living in a farm settlement were tested to determine their peak expiratory flow rate (PEFR), forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), forced expiratory volume in 1 s per cent and forced expiratory flow between 25 and 75%. The values for the PEFR, FVC, FEV1, forced expiratory volume in 1 s per cent and forced expiratory flow between 25 and 75% of the subjects were significantly lower than those of the controls (P value for males = <0.001, 0.01, 0.002, 0.01 and <0.001, respectively, whereas for their female counterparts = <0.001, 0.003, 0.001, 0.04 and <0.001, respectively). These deficits were observed to be more with increasing duration of exposure to wood smoke for PEFR, FVC and FEV1. Chronic exposure to fish drying using firewood can impair lung function in children. There is a need for alternative methods of fish preservation for those engaged in fish drying. PMID- 23687092 TI - Human iPS cell-derived hematopoietic progenitor cells induce T-cell anergy in in vitro-generated alloreactive CD8(+) T cells. AB - Human induced pluripotent stem cells (iPSCs) have emerged as an alternative source of pluripotent stem cells that can be used for tissue regeneration in place of the controversial human embryonic stem cells. However, immunologic knowledge about iPSC derivatives remains enigmatic. Here, we characterized human iPS-derived CD34(+) hematopoietic progenitor cells (HPCs). These HPCs poorly express major histocompatibility complex (MHC) I antigens and are MHC-II negative. Interestingly, they moderately express nonclassical HLA-G and HLA-E molecules. Consequently, alloreactive HLA-A2-specific cytotoxic T cells failed to recognize HLA-A2-expressing HPCs but became anergic. Subsequent upregulation of MHC-I using interferon-gamma stimulation and provision of CD28 cosignaling led to T-cell activation, confirming that poor delivery of signals 1 and 2 by the HPCs mediated T-cell anergy. These data indicate for the first time that HPCs induce T cell anergy, a unique characteristic of iPSC-derived cells that confers immunologic advantage for allogenic transplantation. Although iPSCs are ideal for patient-tailored treatments with the anticipation that no immunosuppression will be required, in cases of gene defects, their derivatives could be used to treat diseases in nonhistocompatible recipients. PMID- 23687095 TI - Differential relative efficacy between drug-eluting stents in patients with bare metal and drug-eluting stent restenosis; evidence in support of drug resistance: insights from the ISAR-DESIRE and ISAR-DESIRE 2 trials. AB - AIMS: In drug-eluting stent (DES) restenosis, the contribution of drug hyporesponsiveness is poorly defined. We sought to evaluate if, in the setting of treatment for in-stent restenosis, the relative efficacy of sirolimus-eluting stents (SES) and of paclitaxel-eluting stents (PES) depends on the underlying substrate in which the stents are implanted, i.e., on whether the restenosis occurs within bare metal stents or within SES. METHODS AND RESULTS: We pooled data from the ISAR-DESIRE and ISAR-DESIRE 2 randomised trials and analysed outcomes in SES-treated and PES-treated patients. In all, 650 patients were included. Angiographic follow-up was available for 87% of patients. In SES treated patients, both late loss (LL) and percentage diameter stenosis (%DS) were lower in patients treated for bare metal stent restenosis compared with SES restenosis (0.21+/-0.59 mm versus 0.41+/-0.66 mm, p=0.007; 27.6+/-19.4% versus 34.0+/-20.9%, p=0.015, respectively). In PES-treated patients, LL and %DS were similar in patients treated for bare metal stent restenosis compared with SES restenosis (0.48+/-0.59 mm versus 0.39+/-0.71, p=0.47; 33.5+/-22.2% versus 32.7+/ 18.6%, p=0.75, respectively). Similarly, in terms of overall clinical efficacy, in SES-treated patients clinical outcomes were better in patients with bare metal stent restenosis compared with SES restenosis while in PES-treated patients outcomes were similar in both groups. At multivariate analyses the use of SES to treat restenosis within SES was predictive of both higher LL and %DS. CONCLUSIONS: The efficacy of sirolimus-eluting but not paclitaxel-eluting stents is significantly reduced when used for treatment of SES restenosis as compared to bare metal stent restenosis. The lower antirestenotic efficacy following SES implantation in patients with SES restenosis may support a role for drug resistance in restenosis within these stents. PMID- 23687096 TI - The need for stent-lesion matching to optimize outcomes of intracoronary stent implantation. AB - Intracoronary stents have markedly improved the outcomes of catheter-based coronary interventions. Intracoronary stent implantation rates of over 90% during coronary angioplasty are common. Stent implantations are associated with a small but statistically significant number of adverse outcomes including restenosis, thrombosis, strut malapposition, incomplete strut endothelialization, and various types of stenting failure. Better matching of biomechanical properties of stents and lesions could further improve the clinical outcome of intracoronary stenting. Thus, in this article, we assess the need for advanced intracoronary stent-lesion matching. We reviewed the data on biomechanics of coronary stents and lesions to develop knowledge-based rationale for optimum intracoronary stent selection. The available technical information on marketed intracoronary stents and the current understanding of the biomechanical properties of coronary lesions at rest and under stress are limited, preventing the development of knowledge-based rationale for optimum intracoronary stent selection at present. Development of knowledge based selection of intracoronary stents requires standardization of mechanical stent testing, communication of the nonproprietary technical data on stents by the industry and dedicated research into procedural stent-lesion interactions. PMID- 23687097 TI - Daytime somnolence in an adult with Smith-Magenis syndrome. PMID- 23687098 TI - Opioids for back pain are linked to increased risk of erectile dysfunction. PMID- 23687100 TI - Acculturation and overweight-related attitudes and behavior among obese Hispanic adults in the United States. AB - OBJECTIVE: US Hispanics bear a disproportionate burden of excess body weight and associated morbidity, making obesity prevention and control in this population a public health priority. Development of culturally appropriate weight loss interventions requires understanding the influence of acculturation on attitudes and behavior related to obesity and weight loss. DESIGN AND METHODS: Using data from the National Health and Nutrition Examination Survey (2001-2004), we analyzed the associations of country of birth and language usage with weight perception, weight dissatisfaction, intention to lose weight, and intended weight loss of clinical significance among obese Hispanic adults (>20 years of age; unweighted n = 675) in multivariable logistic regression analyses. RESULTS: US birth was significantly associated with correct weight perception (odds ratio [OR], 4.45; 95% confidence interval [CI], 2.16-9.17) and weight dissatisfaction (OR = 2.95; 95% CI = 1.63-5.35). Compared with Spanish-speaking only, obese Hispanics, bilingual, obese Hispanics were more likely to attempt weight loss (OR = 2.78; 95% CI = 1.43-5.40) and achieve clinically significant weight loss (OR = 3.94; 95% CI = 1.51-10.3). CONCLUSIONS: The findings suggest that lack of acculturation as measured by foreign birth and limited English proficiency may contribute to within-ethnicity health inequality among obese Hispanics, even after controlling for a variety of sociodemographic characteristics, including education and income, differential healthcare access and use, and health status. Further studies should examine the underlying mechanisms, thereby informing culturally competent intervention strategies targeted at obese US Hispanics. PMID- 23687101 TI - Everolimus-eluting bioresorbable vascular scaffold (BVS) implantation in patients with ST-segment elevation myocardial infarction (STEMI). AB - AIMS: Recent studies have demonstrated favourable clinical outcomes for the everolimus-eluting bioresorbable vascular scaffold (BVS) ABSORBTM in patients with stable coronary artery disease. There are currently no data on its use in patients with ST-segment elevation myocardial infarction (STEMI). We assessed the safety and impact of BVS in the setting of primary percutaneous coronary intervention (PCI) in patients presenting with STEMI to our institution. METHODS AND RESULTS: A total of 11 patients who underwent primary PCI with intent for BVS implantation between October 2012 and April 2013 at our institution were included. Median follow-up period was 53.0 +/- 45.9 days. One patient presented to the hospital with cardiogenic shock and subsequently died. The other 10 patients did not have any major adverse cardiac events (MACE). There were no acute or subacute stent thromboses at short-term follow-up. CONCLUSIONS: These are the first real-world data using BVS in patients with STEMI. The ABSORBTM BVS may be safely used in patients with STEMI undergoing primary PCI with favourable short-term outcome. PMID- 23687099 TI - Associations of visceral and abdominal subcutaneous adipose tissue with markers of cardiac and metabolic risk in obese adults. AB - OBJECTIVE: Visceral (VAT) and abdominal subcutaneous (SAT) adipose tissues contribute to obesity but may have different metabolic and atherosclerosis risk profiles. We sought to determine the associations of abdominal VAT and SAT mass with markers of cardiac and metabolic risk in a large, multiethnic, population based cohort of obese adults. DESIGN AND METHODS: Among obese participants in the Dallas Heart Study, we examined the cross-sectional associations of abdominal VAT and SAT mass, assessed by magnetic resonance imaging (MRI) and indexed to body surface area (BSA), with circulating biomarkers of insulin resistance, dyslipidemia, and inflammation (n = 942); and with aortic plaque and liver fat by MRI and coronary calcium by computed tomography (n = 1200). Associations of VAT/BSA and SAT/BSA were examined after adjustment for age, sex, race, menopause, and body mass index. RESULTS: In multivariable models, VAT significantly associated with the homeostasis model assessment of insulin resistance (HOMA-IR), lower adiponectin, smaller LDL and HDL particle size, larger VLDL size, and increased LDL and VLDL particle number (p < 0.001 for each). VAT also associated with prevalent diabetes, metabolic syndrome, hepatic steatosis, and aortic plaque (p < 0.001 for each). VAT independently associated with C-reactive protein but not with any other inflammatory biomarkers tested. In contrast, SAT associated with leptin and inflammatory biomarkers, but not with dyslipidemia or atherosclerosis. Associations between SAT and HOMA-IR were significant in univariable analyses but attenuated after multivariable adjustment. CONCLUSION: VAT associated with an adverse metabolic, dyslipidemic, and atherogenic obesity phenotype. In contrast, SAT demonstrated a more benign phenotype, characterized by modest associations with inflammatory biomarkers and leptin, but no independent association with dyslipidemia, insulin resistance, or atherosclerosis in obese individuals. These findings suggest that abdominal fat distribution defines distinct obesity sub-phenotypes with heterogeneous metabolic and atherosclerosis risk. PMID- 23687102 TI - Misreporting of suicide after the L'Aquila earthquake. PMID- 23687105 TI - Integrated care scheme for older people and people with diabetes has not reduced emergency admissions in its first year. PMID- 23687104 TI - Aerobic exercise + weight loss decreases skeletal muscle myostatin expression and improves insulin sensitivity in older adults. AB - OBJECTIVE: To determine whether aerobic exercise training + weight loss (AEX + WL) would affect the expression of myostatin and its relationship with insulin sensitivity in a longitudinal, clinical intervention study. DESIGN AND METHODS: Thirty-three obese sedentary postmenopausal women and men (n = 17 and 16, age: 61 +/- 1 years, body mass index: 31 +/- 1 kg/m(2) , VO2 max: 21.9 +/- 1.0 mL/kg/min, X +/- Standard error of the mean (SEM)) completed 6 months of 3 days/week AEX + WL. During an 80 mU m(-2) min(-1) hyperinsulinemic-euglycemic clamp, we measured glucose utilization (M), myostatin, myogenin, and MyoD gene expression by real time RT-PCR in vastus lateralis muscle at baseline and 2 h. RESULTS: Body weight (-8%) and fat mass (-17%) decreased after AEX + WL (P < 0.001). Fat-free mass (FFM) and mid-thigh muscle area by computed tomography did not change but muscle attenuation increased (P < 0.05). VO2 max increased 14% (P < 0.001). AEX + WL increased M by 18% (P < 0.01). Myostatin gene expression decreased 19% after AEX + WL (P < 0.05). Basal mRNA myostatin levels were negatively associated with M before the intervention (r = -0.43, P < 0.05). Insulin infusion increased myoD and myogenin expression before and after AEX + WL (both P < 0.001) but basal levels did not change. The insulin effect on myostatin expression was associated with the change in M after AEX + WL (r = 0.56, P < 0.005). CONCLUSIONS: Exercise and weight loss results in a downregulation of myostatin mRNA and an improvement in insulin sensitivity in obese older men and women. PMID- 23687106 TI - Laboratory evaluation of a rapid diagnostic test for Neisseria meningitidis serogroup A. AB - BACKGROUND: Epidemics of meningococcal meningitis occur periodically in the African 'meningitis belt' and are mainly, but not only, due to serogroup A. METHODS: We tested a dipstick as a rapid detection test (RDT) to detect serogroup A using 401 cerebrospinal fluid (CSF) samples. RESULTS: The detection limits were 10(5) CFU/ml with sensitivity and specificity for detecting serogroup A in CSF samples of 88% and 99%, respectively. CONCLUSIONS: The new RDT can be used in field surveillance of meningococcal meningitis to help characterize meningitis cases particularly after introduction of the conjugate vaccine against serogroup A. PMID- 23687107 TI - Emergence of new foci of filariasis in Madhya Pradesh, India. AB - BACKGROUND: Lymphatic filariasis is a major vector-borne disease and India bears 81% of the filariasis burden in South East Asia. Screening and mass drug administration is carried out in 11 known endemic districts of Madhya Pradesh. However, regular monitoring is not carried out in non-endemic areas. METHODS: Cross sectional surveys were carried out to examine blood samples for filariasis. Entomological surveys were conducted for infective mosquitoes. RESULTS: Altogether, 24 of 252 samples were positive for filariasis with a mean microfilaria count of 0.8. The entomological investigations showed 7.4% infection and 1.4 % infectivity rates in vectors. CONCLUSION: This study reveals the emergence of new foci of lymphatic filariasis in Madhya Pradesh. We conclude that filariasis surveys should be carried out in non-endemic areas of India to achieve the goal of elimination. PMID- 23687103 TI - Low cerebral blood flow is associated with lower memory function in metabolic syndrome. AB - BACKGROUND: Metabolic syndrome (MetS)--a cluster of cardiovascular risk factors- is linked with cognitive decline and dementia. However, the brain changes underlying this link are presently unknown. In this study, we tested the relationship between MetS, cerebral blood flow (CBF), white matter hyperintensity burden, and gray matter (GM) volume in cognitively healthy late middle-aged adults. Additionally, the extent to which MetS was associated with cognitive performance was assessed. DESIGN AND METHODS: Late middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention (N = 69, mean age = 60.4 years) underwent a fasting blood draw, arterial spin labeling perfusion MRI, T1-weighted MRI, T2FLAIR MRI, and neuropsychological testing. MetS was defined as abnormalities on three or more factors, including abdominal obesity, triglycerides, HDL-cholesterol, blood pressure, and fasting glucose. RESULTS: Mean GM CBF was 15% lower in MetS compared to controls. Voxel-wise image analysis indicated that the MetS group had lower CBF across a large portion of the cortical surface, with the exception of medial and inferior parts of the occipital and temporal lobes. The MetS group also had lower immediate memory function; a mediation analysis indicated this relationship was partially mediated by CBF. Among the MetS factors, abdominal obesity and elevated triglycerides were most strongly associated with lower CBF. CONCLUSIONS: The results underscore the importance of reducing the number of cardiovascular risk factors for maintaining CBF and cognition in an aging population. PMID- 23687108 TI - Evidence of goats acting as domestic reservoirs of bovine tuberculosis. PMID- 23687109 TI - Eradication of BVDV in cattle: the Norwegian project. AB - The intention of this collaborative project was eradication of pestivirus from the Norwegian cattle population of about 30,000 dairy and beef herds, primarily by identification and culling of persistently infected (PI) animals. Testing was performed in four tiers, with examination for pestivirus antibodies by indirect ELISA in (1) bulk milk, (2) pooled milk from primiparous dairy cows and (3) pooled blood from young stock. The herds positive in the third tier were examined for pestivirus antigen in blood from all antibody-negative individuals by antigen-capture ELISA, and these animal composed tier (4). Following culling of the PI animals, a herd was considered free from pestivirus when pooled blood from young stock was antibody-negative on two sampling occasions three months apart. Number of herds with PI animals peaked at about 3000 (10 per cent) in the 2nd project year, then decreased steadily; only three herds (0.01 per cent) contained PI animals 10 years later. Solid, continuous information flow to all relevant partners was crucial to project success. The project saved losses of between 50 million and 200 million Norwegian crowns (NOK) annually (approximately 4.5 million to 18 million GBP). Project running costs for 10 years were 52.4 million NOK. Following project completion, surveillance of the Norwegian cattle population for pestivirus has continued. PMID- 23687110 TI - Deepening on breast cancer metastasis: the ERalpha-mediated modulation of KISS/KISS1R system. PMID- 23687111 TI - Bisphenol a: a model endocrine disrupting chemical with a new potential mechanism of action. PMID- 23687112 TI - Gene therapy to prolong reproductive life. PMID- 23687113 TI - GRTH: a key to understanding androgen-mediated germ cell signaling. PMID- 23687114 TI - Txnip, tanycytes, and torpor. PMID- 23687117 TI - The role of research in addressing the public health problem of gun violence. PMID- 23687115 TI - A SAS-6-like protein suggests that the Toxoplasma conoid complex evolved from flagellar components. AB - SAS-6 is required for centriole biogenesis in diverse eukaryotes. Here, we describe a novel family of SAS-6-like (SAS6L) proteins that share an N-terminal domain with SAS-6 but lack coiled-coil tails. SAS6L proteins are found in a subset of eukaryotes that contain SAS-6, including diverse protozoa and green algae. In the apicomplexan parasite Toxoplasma gondii, SAS-6 localizes to the centriole but SAS6L is found above the conoid, an enigmatic tubulin-containing structure found at the apex of a subset of alveolate organisms. Loss of SAS6L causes reduced fitness in Toxoplasma. The Trypanosoma brucei homolog of SAS6L localizes to the basal-plate region, the site in the axoneme where the central pair microtubules are nucleated. When endogenous SAS6L is overexpressed in Toxoplasma tachyzoites or Trypanosoma trypomastigotes, it forms prominent filaments that extend through the cell cytoplasm, indicating that it retains a capacity to form higher-order structures despite lacking a coiled-coil domain. We conclude that although SAS6L proteins share a conserved domain with SAS-6, they are a functionally distinct family that predates the last common ancestor of eukaryotes. Moreover, the distinct localization of the SAS6L protein in Trypanosoma and Toxoplasma adds weight to the hypothesis that the conoid complex evolved from flagellar components. PMID- 23687116 TI - Neurospora crassa NKIN2, a kinesin-3 motor, transports early endosomes and is required for polarized growth. AB - Biological motors are molecular nanomachines, which convert chemical energy into mechanical forces. The combination of mechanoenzymes with structural components, such as the cytoskeleton, enables eukaryotic cells to overcome entropy, generate molecular gradients, and establish polarity. Hyphae of filamentous fungi are among the most polarized cells, and polarity defects are most obvious. Here, we studied the role of the kinesin-3 motor, NKIN2, in Neurospora crassa. We found that NKIN2 localizes as fast-moving spots in the cytoplasm of mature hyphae. To test whether the spots represented early endosomes, the Rab5 GTPase YPT52 was used as an endosomal marker. NKIN2 colocalized with YPT52. Deletion of nkin2 caused strongly reduced endosomal movement. Combined, these results confirm the involvement of NKIN2 in early endosome transport. Introduction of a rigor mutation into NKIN2 labeled with green fluorescent protein (GFP) resulted in decoration of microtubules. Interestingly, NKIN2(rigor) was associated with a subpopulation of microtubules, as had been shown earlier for the Aspergillus nidulans orthologue UncA. Other kinesins did not show this specificity. PMID- 23687119 TI - Extracellular matrix metalloproteinase inducer shows active perivascular cuffs in multiple sclerosis. AB - Inflammatory perivascular cuffs are comprised of leucocytes that accumulate in the perivascular space around post-capillary venules before their infiltration into the parenchyma of the central nervous system. Inflammatory perivascular cuffs are commonly found in the central nervous system of patients with multiple sclerosis and in the animal model experimental autoimmune encephalomyelitis. Leucocytes that accumulate in the perivascular space secrete matrix metalloproteinases that aid their transmigration into the neural parenchyma. We described previously that the upstream inducer of matrix metalloproteinase expression, extracellular matrix metalloproteinase inducer (CD147), was elevated in experimental autoimmune encephalomyelitis, and that its inhibition reduced leucocyte entry into the central nervous system. Here we investigated whether the expression of extracellular matrix metalloproteinase inducer varies with the temporal evolution of lesions in murine experimental autoimmune encephalomyelitis, whether it was uniformly upregulated across multiple sclerosis specimens, and whether it was a feature of inflammatory perivascular cuffs in multiple sclerosis lesions. In experimental autoimmune encephalomyelitis, elevation of extracellular matrix metalloproteinase inducer was correlated with the appearance and persistence of clinical signs of disease. In both murine and human samples, extracellular matrix metalloproteinase inducer was detected on endothelium in healthy and disease states but was dramatically increased in and around inflammatory perivascular cuffs on leucocytes, associated with matrix metalloproteinase expression, and on resident cells including microglia. Leucocyte populations that express extracellular matrix metalloproteinase inducer in multiple sclerosis lesions included CD4+ and CD8+ T lymphocytes, B lymphocytes and monocyte/macrophages. The extra-endothelial expression of extracellular matrix metalloproteinase inducer was a marker of the activity of lesions in multiple sclerosis, being present on leucocyte-containing perivascular cuffs but not in inactive lesions. By using a function-blocking antibody, we implicate extracellular matrix metalloproteinase inducer in the adhesion of leucocytes to endothelial cells and determined that its activity was more crucial on leucocytes than on endothelium in leucocyte-endothelial cell engagement in vitro. Extracellular matrix metalloproteinase inducer activity regulated the level of alpha 4 integrin on leucocytes through a mechanism associated with nuclear factor kappaB signalling. Blocking extracellular matrix metalloproteinase inducer attenuated the transmigration of monocytes and B lymphocytes across a model of the blood-brain barrier in culture. In summary, we describe the prominence of extracellular matrix metalloproteinase inducer in central nervous system inflammatory perivascular cuffs, emphasize its dual role in matrix metalloproteinase induction and leucocyte adhesion, and highlight the elevation of extracellular matrix metalloproteinase inducer as an orchestrator of the infiltration of leucocytes into the central nervous system parenchyma. PMID- 23687118 TI - Weighing brain activity with the balance: Angelo Mosso's original manuscripts come to light. AB - Neuroimaging techniques, such as positron emission tomography and functional magnetic resonance imaging are essential tools for the analysis of organized neural systems in working and resting states, both in physiological and pathological conditions. They provide evidence of coupled metabolic and cerebral local blood flow changes that strictly depend upon cellular activity. In 1890, Charles Smart Roy and Charles Scott Sherrington suggested a link between brain circulation and metabolism. In the same year William James, in his introduction of the concept of brain blood flow variations during mental activities, briefly reported the studies of the Italian physiologist Angelo Mosso, a multifaceted researcher interested in the human circulatory system. James focused on Mosso's recordings of brain pulsations in patients with skull breaches, and in the process only briefly referred to another invention of Mosso's, the 'human circulation balance', which could non-invasively measure the redistribution of blood during emotional and intellectual activity. However, the details and precise workings of this instrument and the experiments Mosso performed with it have remained largely unknown. Having found Mosso's original manuscripts in the archives, we remind the scientific community of his experiments with the 'human circulation balance' and of his establishment of the conceptual basis of non invasive functional neuroimaging techniques. Mosso unearthed and investigated several critical variables that are still relevant in modern neuroimaging such as the 'signal-to-noise ratio', the appropriate choice of the experimental paradigm and the need for the simultaneous recording of differing physiological parameters. PMID- 23687120 TI - Flesh in the age of reason: the modern foundations of body and soul, and a dialogue by Jeremy Collier (1695). PMID- 23687122 TI - Disease-specific molecular events in cortical multiple sclerosis lesions. AB - Cortical lesions constitute an important part of multiple sclerosis pathology. Although inflammation appears to play a role in their formation, the mechanisms leading to demyelination and neurodegeneration are poorly understood. We aimed to identify some of these mechanisms by combining gene expression studies with neuropathological analysis. In our study, we showed that the combination of inflammation, plaque-like primary demyelination and neurodegeneration in the cortex is specific for multiple sclerosis and is not seen in other chronic inflammatory diseases mediated by CD8-positive T cells (Rasmussen's encephalitis), B cells (B cell lymphoma) or complex chronic inflammation (tuberculous meningitis, luetic meningitis or chronic purulent meningitis). In addition, we performed genome-wide microarray analysis comparing micro-dissected active cortical multiple sclerosis lesions with those of tuberculous meningitis (inflammatory control), Alzheimer's disease (neurodegenerative control) and with cortices of age-matched controls. More than 80% of the identified multiple sclerosis-specific genes were related to T cell-mediated inflammation, microglia activation, oxidative injury, DNA damage and repair, remyelination and regenerative processes. Finally, we confirmed by immunohistochemistry that oxidative damage in cortical multiple sclerosis lesions is associated with oligodendrocyte and neuronal injury, the latter also affecting axons and dendrites. Our study provides new insights into the complex mechanisms of neurodegeneration and regeneration in the cortex of patients with multiple sclerosis. PMID- 23687121 TI - Is SOD1 loss of function involved in amyotrophic lateral sclerosis? AB - Mutations in the gene superoxide dismutase 1 (SOD1) are causative for familial forms of the neurodegenerative disease amyotrophic lateral sclerosis. When the first SOD1 mutations were identified they were postulated to give rise to amyotrophic lateral sclerosis through a loss of function mechanism, but experimental data soon showed that the disease arises from a--still unknown- toxic gain of function, and the possibility that loss of function plays a role in amyotrophic lateral sclerosis pathogenesis was abandoned. Although loss of function is not causative for amyotrophic lateral sclerosis, here we re-examine two decades of evidence regarding whether loss of function may play a modifying role in SOD1-amyotrophic lateral sclerosis. From analysing published data from patients with SOD1-amyotrophic lateral sclerosis, we find a marked loss of SOD1 enzyme activity arising from almost all mutations. We continue to examine functional data from all Sod1 knockout mice and we find obvious detrimental effects within the nervous system with, interestingly, some specificity for the motor system. Here, we bring together historical and recent experimental findings to conclude that there is a possibility that SOD1 loss of function may play a modifying role in amyotrophic lateral sclerosis. This likelihood has implications for some current therapies aimed at knocking down the level of mutant protein in patients with SOD1-amyotrophic lateral sclerosis. Finally, the wide-ranging phenotypes that result from loss of function indicate that SOD1 gene sequences should be screened in diseases other than amyotrophic lateral sclerosis. PMID- 23687125 TI - The sections of Alternaria: formalizing species-group concepts. AB - The systematics of Alternaria and allied genera traditionally has been based on the characteristics of conidia and the sporulation apparatus. This emphasis on morphology in the reconstruction of organismal relationships has resulted in taxonomic uncertainty and flux for a number of taxa in Alternaria and the related genera Stemphylium, Embellisia, Nimbya and Ulocladium. The present study used a molecular phylogenetic approach for systematic resolution and incorporated extensive taxon sampling (n = 176 species) representing 10 genera and analyses of 10 protein-coding loci. Phylogenetic analyses based on five of these genes revealed eight distinct asexual lineages of Alternaria that cluster as the sister group to the asexual paraphyletic genus Ulocladium, while taxa with known teleomorphs currently circumscribed as Alternaria (the infectoria species-group) cluster among genera that also have representatives with known teleomorphs. This work proposes to elevate the eight well supported asexual lineages of Alternaria to the taxonomic rank of section. Evolutionary relationships among Alternaria and closely related genera are discussed. PMID- 23687124 TI - Arrhythmic complications after electrical cardioversion of acute atrial fibrillation: the FinCV study. AB - AIMS: To determine the incidence and risk factors of arrhythmic complications after electrical cardioversion of acute atrial fibrillation (AF). METHODS AND RESULTS: Our retrospective multicentre study collected data from 7660 cardioversions of acute (<48 h) AF in 3143 consecutive patients. Immediate arrhythmic complications were evaluated after 6906 (90.2%) electrical cardioversions performed in 2868 patients. We also assessed the predictors of arrhythmic complications and whether post-cardioversion bradycardia or asystole led to later a permanent pacemaker implantation. Altogether, 63 (0.9%) electrical cardioversions resulted in bradyarrhythmia in 54 patients. Asystole (>5 s) occurred immediately after 51 cardioversions leading to a short resuscitation in seven cases and two patients needed extrinsic pacing after the cardioversion. In nine cases, asystole was followed by bradycardia. Bradycardic ventricular rate (<40 b.p.m.) alone was seen after 12 procedures. No ventricular arrhythmias needing intervention were detected. Old age [odds ratio (OR) 1.1; 95% confidence interval (CI) 1.05-1.10, P < 0.0001], female sex (OR 2.5; 95% CI 1.4-4.8, P = 0.004), and unsuccessful cardioversion (OR 2.2; 95% CI 1.1-4.6, P = 0.03) were the independent predictors of bradycardic complications. Slow ventricular rate, use of digoxin, beta blocker, or antiarrhythmic medication did not increase the risk of bradycardic complications. Pacemaker was implanted in 24 (44.4%) patients after a median delay of 66 days. CONCLUSION: Bradycardic complications are rare and usually benign after cardioversion of acute AF. They seem to reflect sinus node dysfunction and often result in later implantation of a permanent pacemaker. PMID- 23687123 TI - beta-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation. AB - Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a 'halo' of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features. PMID- 23687126 TI - Cohort profile: The Japan diabetes complications study: a long-term follow-up of a randomised lifestyle intervention study of type 2 diabetes. AB - The Japan Diabetes Complications Study, a randomised lifestyle intervention study of type 2 diabetes conducted at 59 institutes throughout Japan that enrolled 2033 eligible patients from January 1995 to March 1996, was directed at: (i) determining the incidence and progression rates of complications of diabetes; (ii) exploring clinical risk factors for complications of diabetes; and (iii) determining the association between lifestyle factors, including diet and physical activity, and complications of diabetes, in addition to comparing, in a randomised manner, the effects on type 2 diabetes of an extensive lifestyle intervention and conventional treatment. The protocol for the study originally specified four study populations according to primary outcomes, consisting of: (1) a macroangiopathy group (N = 1771); (ii) a nephropathy group (N = 1607); (iii) a retinopathy-incident group (N = 1221); and (iv) a retinopathy-progression group (N = 410). The primary outcomes were: (i) development of retinopathy; (ii) progression of retinopathy; (iii) development of overt nephropathy; and (iv) occurrence of macroangiopathic events including proven coronary heart disease and stroke. The study was originally planned to follow patients for 8 years, and an extended follow-up is ongoing. Information about primary outcomes, laboratory tests, and other clinical variables for each patient was collected at a central data centre through an annual report from each investigator. Additionally, extensive lifestyle surveys were conducted at baseline and 5 years after the beginning of the study intervention in both the intervention and conventional treatment groups. A description of the occurrence of complications of diabetes and of all-cause mortality, provided in this paper, demonstrated a clear gender based difference in cardiovascular disease and all-cause mortality. PMID- 23687127 TI - Criminalising contagion: ethical, legal and clinical challenges of prosecuting the spread of disease and sexually transmitted infections. PMID- 23687128 TI - Female sex workers incarcerated in New York City jails: prevalence of sexually transmitted infections and associated risk behaviors. AB - OBJECTIVES: Sexually transmitted infections (STIs) are an important cause of morbidity among incarcerated women and female sex workers (FSW). Little is known about FSW incarcerated in New York City (NYC) jails. We reviewed jail health records to identify the STI and HIV prevalence among newly incarcerated FSW in NYC jails. We also examined the relationship of demographics and self-reported clinical and risk behaviour history with FSW status and compared FSW with non-FSW incarcerated women to identify FSW predictors and, guide NYC jail programme planning and policy. METHODS: We retrospectively reviewed routinely collected jail health record data to identify the prevalence of chlamydia (Ct), gonorrhoea (Ng) and HIV infection among women newly incarcerated in NYC jails in 2009-2010 (study period) and studied the relationship of STIs, demographics and self reported clinical and risk behaviour history with FSW status. RESULTS: During the study period, 10 828 women were newly incarcerated in NYC jails. Of these, 10 115 (93%) women were tested for Ct and Ng; positivity was 6.2% (95% CI 5.7% to 6.7%) and 1.7% (95% CI 1.4% to 1.9%), respectively. Nine percent had HIV infection. Seven hundred (6.5%) were defined as FSW. FSW were more likely to have Ct (adjusted OR (AOR): 1.55; 95% CI 1.17 to 2.05; p<0.0001) but not Ng or HIV. FSW were more likely to report age 20-24 years, reside in boroughs other than Manhattan, >=6 prior incarcerations, >=2 incarcerations during the study period, condom use with current sex partners, multiple sex partners and current drug use. CONCLUSIONS: Women incarcerated in NYC jails had high rates of Ct, Ng, and HIV infection. FSW were at higher risk for Ct than non-FSW incarcerated women. These findings are being used to design targeted interventions to identify FSW, provide clinical and preventive services in jail and coordinate care with community partners. PMID- 23687129 TI - 'The intention may not be cruel... but the impact may be': understanding legislators' motives and wider public attitudes to a draft HIV Bill in Malawi. AB - OBJECTIVES: The law in relation to HIV has prominence in the formation and regulation of moral norms-in regard to human rights, and in regard to criminalisation, the policing of sexuality and intimate behaviours, and the production of stigma. The research focuses on the potential and impotence of the law to govern for, and enable, the human right to health in the context of HIV in Malawi. METHODS: This one-country qualitative case study (Malawi) action research involved data collection during a 6-month period (October 2010-March 2011). Datasets include interviews with law commissioners (n=10), opinion leaders (n=22), life story participants who were people living with and closely affected by HIV (n=20), reflections of the action research team (n=6), and a review of the proposed HIV and AIDS (Prevention and Management) Bill, legal and policy documents. RESULTS: The analysis of the perspectives of the law commissioners, who formed the Special Law Commission and drafted the Bill, revealed that stigma was consciously invoked to delineate social norms and guide governance of notions of personal responsibility. The analysis of the perspectives of the life story participants, whose lives would be most directly impacted if these provisions came into force, reveals the extent to which the stigma associating criminality and HIV is falling on fertile ground through its engagement and generation of internalised stigma; unearthing an uneasy link between stigma and the law in response to HIV in Malawi. DISCUSSION: The results indicated that the proposed HIV Bill in Malawi manifests a tension between intention and impact. By incorporating criminal sanctions as part of the proposed HIV Bill, the lawmakers actively seek to use stigma to shape social attitudes and attempt to guide normative behaviour. PMID- 23687130 TI - Criminal prosecution of a male partner for sexual transmission of infectious diseases: the views of educated people living in Togo. AB - OBJECTIVE: To examine the views of educated people in Togo on the acceptability of criminal prosecution of a male partner for sexual transmission of infectious diseases (STIDs) to his female partner. METHODS: 199 adults living in Kara, Togo judged acceptability of criminal prosecution for STID in 45 scenarios composed of combinations of five factors: (a) severity of disease; (b) awareness and communication of one's serological status; (c) partners' marital status; (d) number of sexual partners the female partner has and (e) male partner's subsequent attitude (supportive or not). RESULTS: Acceptability was lower (a) when the male partner decided to take care of his female partner he had infected than when he decided to leave, (b) when both partners were informed but decided not to take precautions than when none of them was informed or when only the male partner was informed and (c) when the female partner has had several male sexual partners than when she has had only one. Two qualitatively different views were identified. For 66% of participants, when the male partner accepts to take care of his partner, he should not be sued, except when he did not disclose his serological status. For 34%, when both partners were informed, the male partner should not be sued, irrespective of other circumstances. CONCLUSIONS: Regarding criminal prosecution for STID, most people in the sample endorsed the position of the Joint United Nations Programme on HIV/AIDS that urges governments not to apply criminal law to cases where sexual partners disclosed their status or were not informed of it. PMID- 23687131 TI - Ethics gone awry: the US Public Health Service studies in Guatemala; 1946-1948. PMID- 23687132 TI - Will the STI studies in Guatemala be remembered, and for what? PMID- 23687133 TI - Principles, progress and harm in the Guatemala Syphilis Study. PMID- 23687134 TI - Ethics is not just medical ethics. PMID- 23687135 TI - Influence of anaerobic conditions on vaginal microbiota recovery from bacterial vaginosis patients. PMID- 23687136 TI - No condoms for prisoners: accumulating risks of HIV, STI but also hepatitis transmission. PMID- 23687137 TI - Nest use is influenced by the positions of nests and drinkers in aviaries. AB - The influence of the nest location and the placement of nipple drinkers on nest use by laying hens in a commercial aviary was assessed. Twenty pens in a laying hen house were equipped with the same commercial aviary system, but the pens differed in the nest location and the placement of nipple drinkers. Nests were placed along the walls in 10 pens, and nipple drinkers were installed in front of the nests in 5 of these pens. The other 10 pens were equipped with nests placed on a tier within the aviary (integrated nests). Nipple drinkers were installed in front of the nests in 5 of these pens. A total of 225 Lohmann Selected Leghorns were housed per pen. The hens were offered 4 nests per pen: 2 facing the service corridor of the laying hen house and 2 facing the outdoor area. The numbers of nest eggs and mislaid eggs were counted daily per pen. At 25, 36, and 43 wk of age, the nest platforms were videotaped and the behavior of laying hens in front of the nests was analyzed. The nest location affected the stationary and locomotive behaviors in front of the nests. Hens in front of the integrated nests and the nests with drinkers displayed more stationary behaviors than hens in front of wall-placed nests or nests without drinkers. No difference in the number of nest eggs could be detected, but the integration of the nests inside the aviary led to a more even distribution of hens while nest searching. In the pens with wall-placed nests, significantly more hens laid eggs in the nests at the wall near the service corridor than at the wall near the outdoor area. Due to this imbalance, crowding in front of the preferred nests occurred and pushing and agonistic interactions on the nest platforms were significantly more frequent. Placement of nipple drinkers in front of nests had no effect on the number of eggs laid in those nests. PMID- 23687138 TI - Changes of blood parameters associated with bone remodeling following experimentally induced fatty liver disorder in laying hens. AB - Studies have demonstrated that obesity and osteoporosis are linked disorders in humans. This study examined the hypothesis that excessive lipid consumption affects bone metabolism in laying hens. A total of one hundred 63-wk-old laying hens were randomly divided into 2 treatments and fed either a regular layer diet (control) or a high energy and low protein diet (HE-LP; experimental treatment) for 80 d. Egg production, feed intake, and BW were recorded at various days during the treatment. At d 80, ten randomly chosen birds per treatment group were killed. Abdominal fat weight, liver weight, and liver fat content were determined. Serum levels of total calcium, inorganic phosphate, and alkaline phosphatase were measured using a biochemical analyzer. Serum concentrations of osteocalcin, leptin-like protein, and estrogen were measured by enzyme-linked immunosorbent assay. Tibia length and width were measured using a vernier caliper; density of the right tibias was determined using an x-ray scanner; and mechanical properties of the left tibias were analyzed using a material testing machine. The expression of osteocalcin and osteoprotegerin mRNA in the keel bone was analyzed by real-time PCR. The concentration of osteocalcin protein in the keels was measured using western blot. Compared with control hens, hens fed the HE-LP diet had lower egg production, lower feed intake, greater liver fat content, and greater abdominal fat pad mass (P < 0.05). Feeding the HE-LP diet increased serum alkaline phosphatase activity, osteocalcin, leptin-like protein, and estrogen concentrations (P < 0.05), and decreased the keel osteocalcin concentrations (P < 0.05). There were significant positive correlations between the serum concentrations of leptin-like protein, estrogen, and osteocalcin regardless of treatment (P < 0.05). The results indicated that HE-LP diet induced a fatty liver disorder in laying hens with an upregulation in bone turnover and exacerbated skeletal damage. The data supported a role for lipid metabolism in skeletal heath of laying hens. PMID- 23687139 TI - The influence of loose-mix feeding on behavior, feed intake, and body weight of growing geese. AB - The aim of this trial was to study the influence of loose-mix feeding on behavior, feed intake, and BW of growing geese. In total, 252 one-day-old geese (Anser anser) were divided into 2 groups differing in the form of diet they received between 42 and 98 d of age (AMEn 11.55 MJ/kg, CP 16%): a complete pelleted diet containing 500 g of sorghum/kg (control group) or a mixture containing 500 g of protein-rich pellets and 500 g of sorghum whole seeds/kg (mixed group). Feed intake was measured daily from 42 to 48 d and every 3 d from 49 to 98 d. Individual BW was measured weekly from 42 to 98 d. Goose behavior was monitored by the scan sampling method throughout the experiment, which was divided into 5 periods according to the timing of access to feed: period 1 from 42 to 55 d (ad libitum feeding access), period 2 from 56 to 62 d (2 + 2 h feeding access), period 3 from 63 to 70 d (2 h feeding access), period 4 from 71 to 94 d (1 h feeding access), and period 5 from 95 to 97 d (3 h feeding access). Over the whole period, the feed intake (13,968 and 14,480 g) and the feed conversion ratio (8.53 and 8.15) were similar in both groups (P = 0.112 and P = 0.168; respectively). Body weight was similar in both groups from 42 to 91 d of age, but at 98 d of age, BW was 3.7% lower in the control than in the mixed group (P = 0.006). Goose behavior was influenced by period, because the percentage of birds feeding increased when the daily access time to the feed decreased (P < 0.001), but not by group (P > 0.05). The results suggest that a loose-mix feeding could be recommended in feeding of growing geese because it weakly influences their feed behavior but slightly increases their weight at the end of the growing period. PMID- 23687140 TI - Growth performance and hematological traits of broiler chickens reared under assorted monochromatic light sources. AB - A study was conducted to investigate the effect of different monochromatic lights on growth performance and hematological response of growing broiler chickens. A total of 360 one-day-old broiler chicks were randomly divided into 6 lighting treatments, which were replicated 6 times with 10 chicks in each replicate. Six light treatments include incandescent bulbs (as a control) and light-emitting diode white light, blue light, red light, green light, and yellow light (YL). The birds were provided with similar nutritional specifications and environmental management facilities, except for the lights throughout the experimental period. Growth performance was evaluated in terms of BW, BW gain, feed intake, and feed conversion ratio at weekly intervals. At the end of 5 wk, 2 birds from each replicate were randomly selected for blood collection to determine hematological response. The BW and feed intake was numerically higher in YL at 5 wk of age. But interestingly, this did not result in improved feed conversion ratio in YL; nevertheless, numerical values were lower in YL at 5 wk (P > 0.05). Red blood cells, blood platelet count, and percent hematocrit were numerically higher under YL, whereas white blood cell counts and percent hemoglobin remained unaffected due to light treatments. It was concluded that monochromatic light is a potential light source that might provide a beneficial effect on growth performance but is inconclusive for hematological measures of broilers. PMID- 23687141 TI - Review of the social and environmental factors affecting the behavior and welfare of turkeys (Meleagris gallopavo). AB - In modern rearing systems, turkey producers often face economic losses due to increased aggression, feather pecking, cannibalism, leg disorders, or injuries among birds, which are also significant welfare issues. The main underlying causes appear to relate to rapid growth, flock size, density, poor environmental complexity, or lighting, which may be deficient in providing the birds with an adequate physical or social environment. To date, there is little information regarding the effect of these factors on turkey welfare. This knowledge is, however, essential to ensure the welfare of turkeys and to improve their quality of life, but may also be beneficial to industry, allowing better bird performance, improved carcass quality, and reduced mortality and condemnations. This paper reviews the available scientific literature related to the behavior of turkeys as influenced by the physical and social environment that may be relevant to advances toward turkey production systems that take welfare into consideration. We addressed the effects that factors such as density, group size, space availability, maturation, lightning, feeding, and transport may have over parameters that may be relevant to ensure welfare of turkeys. Available scientific studies were based in experimental environments and identified individual factors corresponding to particular welfare problems. Most of the studies aimed at finding optimal levels of rearing conditions that allow avoiding or decreasing most severe welfare issues. This paper discusses the importance of these factors for development of production environments that would be better suited from a welfare and economic point of view. PMID- 23687142 TI - Performance comparison of laying hens segregating for the frizzle gene under thermoneutral and high ambient temperatures. AB - The effect on thermotolerance of the incompletely dominant frizzle (F) gene, which causes feather curling and feather mass reduction, was investigated in 281 laying hens that were homozygous for the frizzle mutation (FF), heterozygous (FN), or normally feathered (NN). One-half of the birds were kept under standard conditions (22 degrees C) and half were exposed to high ambient temperatures (32 degrees C) between 24 and 46 wk of age. Egg production, egg quality, feed efficiency, and dissection traits were recorded and compared. At standard conditions, egg production and quality traits did not differ among the 3 genotypes, whereas feed efficiency was lower for the homozygous birds. Under heat stress conditions, the superiority of the FF hens was evident for all egg quantity and quality traits. No significant difference was measured between heterozygous carriers and normally feathered hens, indicating that the incomplete dominant frizzle mutation behaved as a recessive mutation regarding heat tolerance. From this study, we deduced that the F mutation in its homozygous state has a beneficial effect in decreasing heat stress in poultry production, and it could be particularly advantageous in tropical countries where average temperatures are never too low to negatively affect feed efficiency. PMID- 23687143 TI - Analysis of egg production in layer chickens using a random regression model with genomic relationships. AB - Random regression models allow for analysis of longitudinal data, which together with the use of genomic information are expected to increase accuracy of selection, when compared with analyzing average or total production with pedigree information. The objective of this study was to estimate variance components for egg production over time in a commercial brown egg layer population using genomic relationship information. A random regression reduced animal model with a marker based relationship matrix was used to estimate genomic breeding values of 3,908 genotyped animals from 6 generations. The first 5 generations were used for training, and predictions were validated in generation 6. Daily egg production up to 46 wk in lay was accumulated into 85,462 biweekly (every 2 wk) records for training, of which 17,570 were recorded on genotyped hens and the remaining on their nongenotyped progeny. The effect of adding additional egg production data of 2,167 nongenotyped sibs of selection candidates [16,037 biweekly (every 2 wk) records] to the training data was also investigated. The model included a 5th order Legendre polynomial nested within hatch-week as fixed effects and random terms for coefficients of quadratic polynomials for genetic and permanent environmental components. Residual variance was assumed heterogeneous among 2-wk periods. Models using pedigree and genomic relationships were compared. Estimates of residual variance were very similar under both models, but the model with genomic relationships resulted in a larger estimate of genetic variance. Heritability estimates increased with age up to mid production and decreased afterward, resulting in an average heritability of 0.20 and 0.33 for pedigree and genomic models. Prediction of total egg number was more accurate with the genomic than with the pedigree-based random regression model (correlation in validation 0.26 vs. 0.16). The genomic model outperformed the pedigree model in most of the 2-wk periods. Thus, results of this study show that random regression reduced animal models can be used in breeding programs using genomic information and can result in substantial improvements in the accuracy of selection for trajectory traits. PMID- 23687144 TI - Imidapril inhibits right ventricular remodeling induced by low ambient temperature in broiler chickens. AB - This study explored the effect of imidapril on the right ventricular remodeling induced by low ambient temperature in broiler chickens. Twenty-four broiler chickens were randomly divided into 3 groups (n = 8), including the control group, low temperature group, and imidapril group. Chickens in the control group were raised at normal temperature, whereas chickens in the low temperature group and imidapril group were exposed to low ambient temperature (12 to 18 degrees C) from 14 d of age until 45 d of age. At the same time, chickens in the imidapril group were gavaged with imidapril at 3 mg/kg once daily for 30 d. The thickness of the right ventricular wall was observed with echocardiography. The BW and wet lung weight as well as weight of right and left ventricles and ventricular septum were measured. Both wet lung weight index and right ventricular hypertrophy index were calculated. Pulmonary arterial systolic pressure was assessed according to echocardiography. The expression of ACE and ACE2 mRNA in the right ventricular myocardial tissue was quantified by real-time PCR. Proliferating cell nuclear antigen-positive cells were detected by immunohistostaining. The concentration of angiotensin (Ang) II and Ang (1-7) in the right ventricular myocardial tissue was measured with ELISA. The results showed that right ventricular hypertrophy index, wet lung weight index, pulmonary arterial systolic pressure, expression of ACE mRNA in the right ventricular tissue, Ang II concentration, and the thickness of the right ventricular wall in the low temperature group increased significantly compared with those in the control group and imidapril group. The ACE2 mRNA expression increased 36%, whereas Ang (1-7) concentration decreased significantly in the low temperature group compared with that in the control group and imidapril group. In conclusion, imidapril inhibits right ventricular remodeling induced by low ambient temperature in broiler chickens. PMID- 23687145 TI - Comparison of 3 agar media in Fung double tubes and Petri plates to detect and enumerate Clostridium spp. in broiler chicken intestines. AB - Clostridium perfringens is an anaerobic, spore-forming bacterium that may lead to necrotic enteritis, resulting in poor feed efficiency and increased mortality in chickens. It is estimated that C. perfringens infects almost 1 million people in the United States every year. The objective of this research was to compare the Fung double tube (FDT) and conventional Petri plates using 3 different media to detect and enumerate Clostridium spp. in chicken intestines. Nine Cobb 500 broilers were randomly selected and euthanized at 21 and 42 d of age for a total of 18 samples. The jejunum and ileum from each broiler were harvested and studied in 2 methods and 3 media combinations, utilizing a 2 * 3 factorial totaling 6 treatments. The 2 methods were FDT and conventional Petri plates, and the 3 media were Shahidi-Ferguson Perfringens (SFP) with egg yolk supplement, polymyxin B, and kanamycin (E); SFP with polymyxin B and kanamycin (P); and SFP with d cycloserine (C). Enumerations were performed after 24 h of incubation at 37 degrees C. At 21 d, counts using medium C with FDT (4.51 log10 cfu/g) and plates (2.38 log10 cfu/g) were higher (P < 0.05) than using media E or P. On d 42, there were no differences among plate treatments and medium E had the highest counts (0.98 log10 cfu/g). Of all the FDT, medium C (5.35 log10 cfu/g) had the highest counts (P < 0.05), followed by medium P (3.54 log10 cfu/g). This study illustrates that the FDT method is able to enumerate Clostridium spp. at higher levels (P < 0.001) than the conventional Petri plate method; therefore, the FDT should be implemented and further explored. PMID- 23687146 TI - Comparison of 3 culture methods and PCR assays for Salmonella gallinarum and Salmonella pullorum detection in poultry feed. AB - To detect Salmonella gallinarum or Salmonella pullorum in artificially contaminated poultry feed, 9 culture combinations were compared, including 3 preenrichment/enrichment methods (tryptic soy broth plus ferrous sulfate/tetrathionate Hajna, tryptic soy broth plus ferrous sulfate/selenite cystine broth, and Salmosyst) in combination with 3 selective agars (xylose lysine desoxicholate agar added with tergitol 4, EF-18, and Onoz), respectively. Additionally, a single PCR technique was applied combined with 2 different preenrichment media (tryptic soy broth plus ferrous sulfate and Salmosyst). The specificity and positive predictive value were 1 for all methods. There were some differences among Salmonella strains for sensitivity and accuracy in the culture and Salmosyst-PCR methods. The sensitivity and accuracy values were less than 0.60 and 0.64, respectively, whereas the negative predictive values were between 0.12 and 0.23. Two PCR methods did not show any difference in the parameters of performance evaluated. Kappa coefficients showed good agreement between both methods. None of the culture combinations was able to detect S. gallinarum or S. pullorum when the inoculum was less than 3 * 102 cfu/25 g, except the Salmosyst broth method, which could recover S. gallinarum from 3 * 101 cfu/25 g onward. Overall, there were differences in the detection limits among the strains and methods used. In general, the 3 selective plating media did not show any significant difference in the parameters of performance studied for each strain. On the other hand, the agreements were slight to fair when culture methods were compared among them and with both PCR methods. The differences in the detection levels that were obtained using these methods and the difficulty in detecting S. gallinarum or S. pullorum in feed represent a potential problem when a poultry feed sample is considered to be negative. It is highly recommended to use at least 2 methods to increase the chances of detecting S. gallinarum or S. pullorum in poultry feed. PMID- 23687147 TI - Pharmacokinetics of gamithromycin after intravenous and subcutaneous administration in broiler chickens. AB - Gamithromycin is a new macrolide antibiotic that is only registered for use in cattle to treat respiratory disorders such as bovine respiratory disease. The aim of this study was to determine the pharmacokinetics of gamithromycin in broiler chickens. Gamithromycin (6 mg/kg of BW) was injected intravenously (IV) or subcutaneously (SC) to six 4-wk-old chickens in a parallel study design, and blood was collected at different time points postadministration. Quantification of gamithromycin in plasma was performed using an in-house validated liquid chromatography-tandem mass spectrometry method and the pharmacokinetics analyzed according to a 2-compartmental model. Following IV administration, the mean area under the plasma concentration-time curve (AUC0->infinity), and alpha and beta half-life of elimination (t1/2el alpha and t1/2el beta) were 3,998 h*ng/mL, 0.90 h, and 14.12 h, respectively. Similar values were obtained after a SC bolus injection, i.e., 4,095 h*ng/mL, 0.34 h, and 11.63 h, for AUC0->infinity, t1/2el alpha, and t1/2el beta, respectively. The mean maximum plasma concentration (889.46 ng/mL) appeared at 0.13 h. Gamithromycin showed a large volume of distribution after IV as well as SC administration, 27.08 and 20.89 L/kg, respectively, and a total body clearance of 1.61 and 1.77 L/h*kg, respectively. The absolute bioavailability was 102.4%, showing that there is a complete absorption of gamithromycin after a SC bolus injection of 6 mg/kg of BW. PMID- 23687148 TI - Expression profiles for genes in the turkey major histocompatibility complex B locus. AB - The major histocompatibility complex (MHC) is a highly polymorphic region of the genome essential to immune responses and animal health. In galliforms, the MHC is divided into 2 genetically unlinked regions (MHC-B and MHC-Y). Many MHC-B genes are involved in adaptive or innate immunity, yet others have nonimmune or unknown functions. The sequenced MHC-B region of the turkey (Meleagris gallopavo) contains 40 genes, the majority of which are predicted transcripts based on comparison with the chicken or quail, without direct evidence for expression. This study was designed to test for the presence of MHC-B gene transcripts in a panel of immune and nonimmune system tissues from domestic turkeys. This analysis provides the first locus-wide examination of MHC-B gene expression in any avian species. Most MHC-B genes were broadly expressed across tissues. Expression of all predicted genes was verified by reverse-transcription PCR, including B butyrophilin 2 (BTN2), a predicted gene with no previous evidence for expression in any species. Previously undescribed splice variants were also detected and sequenced from 3 genes. Characterization of MHC-B expression patterns helps elucidate unknown gene functions and potential gene coregulation. Determining turkey MHC-B expression profiles increases our overall understanding of the avian MHC and provides a necessary resource for future research on the immunological response of these genes. PMID- 23687149 TI - Influences of F-strain Mycoplasma gallisepticum vaccine on productive and reproductive performance of commercial parent broiler chicken breeders on a multi age farm. AB - The influences of F-strain Mycoplasma gallisepticum (FMG) vaccine inoculation during the pullet period on the subsequent productive and reproductive performance of parent broiler chicken breeders on a multi-age farm were evaluated. Three thousand breeders were randomly divided into 2 treatment groups that were either vaccinated with FMG (FMG-vaccinated group) or not vaccinated with FMG (FMG-free group). Body weight and egg production were determined through approximately 50 wk of age. Egg weight and feed conversion was determined at 26, 32, 35, 38, and 43 wk of age. Egg quality parameters, including eggshell strength, egg-specific gravity, egg shape index, blood-meat spots, Haugh unit score, eggshell thickness, yolk:albumen ratio, percentage yolk, albumen and eggshell weights, and percentage fertility, hatchability, and second-quality chicks were determined at 26, 32, and 43 wk of age. Air sacs were examined and lesions were scored at 20, 32, and 50 wk of age. The number of mature ovarian follicles, histologies of ovary, and lengths, and histologies of the infundibulum, magnum, isthmus, uterus, and vagina were determined. In the present study, an increase in egg production of broiler breeder hens in the FMG vaccinated group during peak of lay was compared with the FMG-free group. Feed conversion of hens in the FMG-vaccinated group was significantly less at 32, 35, 38, and 43 wk of age. Eggs from hens in the FMG-vaccinated group had a significantly higher Haugh units score at 26 wk of age and had a significantly higher eggshell thickness and lower incidence of blood-meat spots at 32 wk. Hatching eggs from hens in the FMG-vaccinated group had a significantly higher hatchability. The mean lesion score of air-sac lesion of birds in the FMG vaccinated group was significantly less than FMG-vaccinated group. Uteruses of hens in the FMG-vaccinated group had a significantly longer length compared with the FMG-free group at 32 wk of age. The results indicate that inoculation of commercial parent broiler chicken breeders with the FMG vaccine before laying may prevent infection by field M. gallisepticum, and facilitate productive and reproductive performance. PMID- 23687150 TI - A novel combined adjuvant strongly enhances mucosal and systemic immunity to low pathogenic avian influenza after oral immunization in ducks. AB - As natural reservoirs of avian influenza viruses, waterfowl play an important role in the generation, spread, and enzootic transmission of avian influenza. To prevent avian influenza in waterfowl through a simple, noninvasive, and needle free route, ducks were immunized orally with an inactivated avian influenza virus (H9N2, IAIV) combined with CpG DNA and high-dose glucose, and then the local and systemic immune responses of these ducks were investigated. In addition, the immune protection was assayed after viral challenge. After the oral administration of IAIV combined with CpG DNA and glucose, the expression levels of interleukin-2 and interleukin-6 in the small intestine tissues increased significantly in the early period after booster immunization relative to the levels after immunization with IAIV and a single adjuvant. Significant increases were also observed in the IgA and IgG antibody levels in the local intestinal tract tissues and serum at wk 3, 5, and 7 after the first immunization. Furthermore, enhanced hemagglutination inhibition titers were also detected in serum samples taken between the third and seventh weeks after immunization with IAIV and both adjuvants. In the viral challenge and transmission study, the prior administration of IAIV combined with both CpG DNA and glucose reduced the viral titers observed for the cloaca swabs and colon tissues of challenged ducks and prevented virus transmission between ducks. Our study suggests that the combination of CpG DNA and high-dose glucose can improve immunization with inactivated H9N2 virus by enhancing the local and systemic immune responses and reducing viral shedding. PMID- 23687151 TI - Quantitative real-time PCR study of the expression and regulation of the tetracycline resistance gene in Riemerella anatipestifer. AB - Riemerella anatipestifer (RA) is one of the most important pathogens of 1- to 8 wk-old ducklings that severely affects the development of the duck industry in China. Every year, antibiotic medicines including tetracycline and doxycycline are used in the duck industry. Few reports compare the expression of multidrug resistant genes in RA before and after addition of chemical drugs. With this in mind, the direct effects of gradient concentration of tetracyclines on the expression of tetracycline resistance genes (TETr) in RA at the cDNA level were studied by using a quantitative real-time PCR method. The expression of TETr, tetA, tetC, and tetM was investigated in ATCC11845 and in 30 RA isolated from different samples. Using a range of doxycycline concentrations up to 50% of the minimum inhibitory concentration (MIC), the optimal induction concentration of 0.0625 MUg/mL was selected. Under the optimal inducible expression, concentrations of TETr, tetC, and tetM cDNA were detected in all isolates, and the highest mRNA expression level of TETr genes was shown. Additionally, the expression levels of 3 TETr genes in RA14 (tetA and tetC) and RA17 (tetM and tetC) were compared. Both tetC and tetA found in isolate RA14 was found to express both tetC and tetA, and tetC cDNA was detected in isolate RA17 at all doxycycline concentrations tested, whereas tetM cDNA was not detected at any concentration. We can conclude that resistance pump is the main mechanism of tetracycline antibiotic resistance, and under the action of drug resistance pump tetC, the expression of tetM was not activated in RA17. These data suggest that the mRNA expression level of TETr genes was correlated with the MIC values, indicating that the degree of drug resistance is determined by the expression levels of TETr genes. Also, the induction of TETr is the major tetracycline resistance mechanism in RA, especially the resistance pump. However, lower concentrations of doxycycline induced higher TETr expression, and higher concentrations inhibited TETr expression. Maybe that is the reason for selection mutation to make tolerated bacteria survive. PMID- 23687152 TI - Effect of immersion and inoculation in ovo of Lactobacillus spp. in embryonated chicken eggs in the prevention of Salmonella Enteritidis after hatch. AB - The protection level against Salmonella Enteritidis was evaluated in chickens after in ovo treatment with different species of Lactobacillus spp. inoculated into the air cell or by immersion in broth culture. Two hundred forty embryonated eggs were distributed into 8 groups, corresponding to treatments with Lactobacillus acidophilus, Lactobacillus fermentum, Lactobacillus salivarius, and control. On d 18 of incubation, 4 groups were inoculated with 0.1 mL of inoculum in the air cell and 4 groups were immersed for 3 min in culture of each treatment. Two days after hatching, 0.5 mL of Salmonella Enteritidis culture was inoculated by the intraesophageal route. On d 5 of life, the chicks were euthanized and the ceca were processed to obtain Salmonella Enteritidis counts. There was no decrease in Salmonella Enteritidis colonization of chick ceca, regardless of treatment or route of administration. Lactobacillus spp. samples used in the treatment showed no probiotic potential in chicks when inoculated in ovo, in relation to Salmonella Enteritidis inhibition in poultry ceca. PMID- 23687153 TI - Effects of corn replacement by sorghum in broiler diets on performance and intestinal mucosa integrity. AB - The effect of replacing corn with low-tannin sorghum on broiler performance, carcass yield, integrity of mucosa of small intestine segments, and activity of membrane enzymes of the jejunum is investigated. A total of 594 male Cobb-500 broiler chicks were randomly assigned to 3 dietary treatments: 100% corn (control), 50% corn replacement with low-tannin sorghum (low sorghum), and 100% corn replacement with low-tannin sorghum (high sorghum). Body weight gain, feed consumption, feed conversion, and carcass yield were determined at 7, 21, and 42 d, and segments of the small intestine were collected. Feed conversion and weight gain were impaired at d 42 in broilers fed the high-sorghum diet, but no differences were observed for carcass yield among the treatments (P > 0.05). Crypt cell mitotic index of the jejunum and ileum at d 21 and 42 was lower in broilers fed the control diet than in those fed low- and high-sorghum diets (P < 0.05). Aminopeptidase activity was higher in broilers fed the control diet than in those fed low- and high-sorghum diets irrespective of age (P < 0.05). Conversely, intestinal alkaline phosphatase activity in the small intestine did not differ among the dietary treatments (P > 0.05). Our results indicate that 50% corn replacement with low-tannin sorghum is suitable for broiler diets, whereas 100% corn replacement with low-tannin sorghum had negative effects on the intestinal mucosa and performance of broilers at 42 d. PMID- 23687154 TI - Phosphorus digestibility response of broiler chickens to dietary calcium-to phosphorus ratios. AB - This study was conducted to evaluate the true digestibility of P in soybean meal (SBM) for broiler chickens fed diets with different dietary calcium-to-phosphorus ratios (Ca:P) using the regression method. The experiment used a 4 * 3 factorial arrangement with 12 diets formulated to contain combinations of 4 levels of dietary Ca:P: 0.8, 1.2, 1.6, or 2.0 and 3 levels of SBM: 31.0, 44.0, or 57.0%. A total of 576 male Ross 708 broilers were allocated to 12 dietary treatments with 8 cages (6 birds per cage) per treatment from d 15 to 22 posthatching, and the BW between groups were similar. Chromic dioxide was used as an indigestible marker to calculate P digestibility and retention. The results showed that BW gain and feed efficiency were increased (linear, P < 0.01), and prececal DM digestibility and DM retention were decreased (linear, P < 0.01) with graded SBM in diets for each Ca:P. Decreasing linear (P < 0.01) relationships were observed for apparent prececal P digestibility and total tract P retention with increased dietary SBM levels. The prececal and excreta P output increased (linear, P < 0.01; quadratic, P < 0.05) as increasing levels of SBM were added to the experimental diets. True prececal P digestibility in SBM was greater (P < 0.05) for birds fed a diet with Ca:P of 0.8 compared with those fed higher Ca:P, but there was no difference among the Ca:P ratios between 1.2 and 2.0. However, the total tract retention of P from SBM was not affected by Ca:P between 0.8 and 2.0. In conclusion, results of the present experiment demonstrated that prececal digestibility of P in SBM was not affected by Ca:P ratio between 1.2 and 2.0; and there was no difference in total tract retention of P from SBM among the Ca:P ratios between 0.8 and 2.0 in broiler chickens. PMID- 23687155 TI - Evaluation of high dietary inclusion of distillers dried grains with solubles and supplementation of protease and xylanase in the diets of broiler chickens under necrotic enteritis challenge. AB - A 2 * 2 * 2 factorial experiment was conducted to investigate the effect of a high level of sorghum distillers dried grains with solubles (DDGS; 20%), with or without a combination of protease and xylanase in broiler chickens, under a necrotic enteritis disease challenge. A total of 576 male broiler chicks were randomly assigned to 8 experimental treatments, each replicated 6 times, with 12 birds per replicate for 35 d. Oral inoculation of the challenged group with Eimeria spp. occurred on d 9, followed by 3 consecutive inoculations of Clostridium perfringens from d 14 through 16. The disease challenge and DDGS inclusion significantly (P < 0.01) interacted, depressing BW gain and feed conversion ratio only in wk 3. Disease challenge adversely influenced (P < 0.01) BW gain and feed conversion ratio of the birds in the third week and across the 35-d study. Over the last 2 wk and across the 35-d trial, the interaction between DDGS and enzyme supplementation showed a tendency (P = 0.09) to gain more BW in birds regardless of the disease challenge. Inclusion of 20% DDGS markedly (P < 0.01) interacted with disease challenge, accelerating the proliferation of C. perfringens in the ceca at d 17. Inoculation of birds with C. perfringens resulted in higher (P < 0.01) counts of C. perfringens in both ileal and cecal contents. The necrotic enteritis-related lesions (d 17) were more severe (P < 0.05) in the intestine of infected birds fed DDGS diets than in birds fed the control diet. Incorporation of DDGS to the diets improved (P < 0.01) the IgA and IgG titer at d 13 but interacted with the disease challenge, reducing the concentration of IgA at d 21 and IgM at d 35 in the infected birds. In conclusion, incorporating a high level of DDGS in the diet of broiler chickens may increase susceptibility to necrotic enteritis. Supplementation of enzymes did not reveal significant mitigation effect in infected birds but helped the birds fed DDGS to maintain feed intake and BW gain. PMID- 23687156 TI - True phosphorus digestibility of black-eyed pea and peanut flour without or with phytase supplementation in broiler chickens. AB - Two studies were conducted to determine the true P digestibility (TPD) of black eyed pea (BEP) and peanut flour (PNF) and the TPD response to phytase supplementation using the regression method. Sequential diets containing 115, 230, or 345 g of BEP/kg (experiment 1) and 115, 230, or 345 g of PNF/kg (experiment 2) without or with 1,000 units of phytase/kg were formulated. Chromic oxide was added to the diets at the rate of 5 g/kg as an indigestible marker. At 20 d posthatch in each study, 384 male broiler chickens (Ross 708) were weighed and allotted to the diets with 8 replicates of 8 birds each in a randomized complete block design. The birds had free access to the experimental diets until d 26 posthatch. In both studies, dietary P increase and phytase supplementation improved (P < 0.001) growth performance of the broiler chickens. There were linear increases (P < 0. 001) in ileal and excreta P output but a linear decrease (P < 0.001) in apparent P digestibility with an increase in dietary P levels. Phytase supplementation reduced (P < 0.001) ileal P and excreta P output and increased (P < 0.001) apparent P digestibility and retention. Apparent Ca digestibility was affected (P < 0.01) by P level and phytase addition in BEP and by P level (P < 0.05) in PNF. Apparent Ca retention in BEP increased (P < 0.05) with phytase addition. The TPD in the BEP increased (P < 0.01) from 29 without phytase to 83% with the addition of 1,000 units of phytase/kg. There was an increase (P < 0.01) in TPD of PNF from 67 without phytase to 75% with phytase supplementation. There was a corresponding increase (P < 0.01) in true P retention from 10% without phytase to 61% with phytase in birds on BEP diets and an equivalent increase (P < 0.01) in true P retention from 74% without phytase to 84% with phytase in birds that received the PNF diets. PMID- 23687157 TI - Establishment of an immortal chicken embryo liver-derived cell line. AB - A continuously growing immortal cell substrate can be used for virus propagation, diagnostic purposes, and vaccine production. The aim of this study was to develop an immortal chicken cell line for efficient propagation of avian infectious viruses. From the various chicken embryo cells that were tested for life span extension, an immortalized chicken embryo liver (CEL) cell line, named CEL-im, was derived spontaneously without either oncogenic viruses or carcinogenic chemical treatment. Currently, CEL-im cells are growing 0.8 to 1.1 population doublings per day and have reached 120 passages. The CEL-im cell line is permissive for poultry infectious viruses, including avian metapneumovirus (AMPV), Marek's disease virus serotype 1 (MDV-1), and infectious laryngotracheitis virus. The CEL-im cells produced high AMPV titer (>10(5) pfu/mL), whereas very low titers (~10 pfu/mL) for MDV-1 and infectious laryngotracheitis virus were produced. To identify genetic alterations in the immortal CEL-im cell line, telomerase activity and mRNA expression for major cell cycle regulatory genes were determined during the immortalizing process. The CEL im cell line has negative telomerase activity, and when compared with the primary passage 2 CEL cell counterpart, mRNA expression of tumor suppressor protein p53, mouse double minute 2 (Mdm2), cyclin dependent kinase (CDK) inhibitor p21 (p21(WAF)), and CDK inhibitor p16 (p16(INK4)) were downregulated in the CEL-im cell line, whereas retinoblastoma (Rb), transcription factor E2F, member 1 (E2F 1), and alternative reading frame of p16(INK4) (ARF) were upregulated. These results are similar to genetic alterations found previously in immortal chicken embryo fibroblast (CEF) cell lines that showed efficient propagation of MDV-1. Therefore, this newly established CEL-im cell line can serve as an alternative cell substrate for the propagation of poultry viruses, such as AMPV. PMID- 23687158 TI - Influence of osteoprotegerin on differentiation, activation, and apoptosis of Gaoyou duck embryo osteoclasts in vitro. AB - ABSTRACT The aim of this study was to determine the influence of osteoprotegerin (OPG) on the differentiation, activation, and apoptosis of Gaoyou duck embryo osteoclasts cultured in vitro. Bone marrow cells were harvested from 23-d-old Gaoyou duck embryos and cultured in the presence of different concentrations of OPG (group A: no added factors, group B: 30 ng/mL of OPG, and group C: 100 ng/mL of OPG). Tartrate-resistant acid phosphatase (TRAP) staining, pit formation assay, and co-staining with tetramethylrhodamine isothiocyanate (TRITC) conjugated phalloidin and Hoechst 33258 were all performed to determine the number of TRAP-positive cells, bone resorption activity, and the level of apoptosis, respectively. The number of TRAP-positive cells and the net expansion of pit formations area peaked on d 7 of culture in all 3 groups. The number of osteoclasts and the total volume of pit formations in OPG-treated groups were significantly lower compared with group A (P < 0.05). At each time point, the net expansion of pit formations area correlated with the number of TRAP-positive cells. The OPG inhibited the de novo formation of filamentous (F)-actin rings and promoted the disruption of existing F-actin rings in mature osteoclasts. In addition, OPG induced apoptosis in mature osteoclasts, as demonstrated by morphological changes in the nuclei. In osteoclast precursors, OPG inhibited differentiation and downregulated the formation of F-actin rings. In mature osteoclasts, OPG suppressed activation and enhanced the development of apoptosis, observed as a decrease in the number of TRAP-positive cells, the disruption of F actin rings and morphological changes of the nuclei. PMID- 23687159 TI - Differential gene expression between normal and pale, soft, and exudative turkey meat. AB - In response to high consumer demand, turkeys have been intensively selected for rapid growth rate and breast muscle mass and conformation. The success in breeding selection has coincided with an increasing incidence of pale, soft, and exudative (PSE) meat defect, especially in response to heat stress. We hypothesized that the underlying mechanism responsible for the development of PSE meat arises from differences in expression of several critical genes. The objective of this study was to determine differential gene expression between normal and PSE turkey meat using a 6K turkey skeletal muscle long oligonucleotide microarray. Breast meat samples were collected from Randombred Control Line 2 turkeys at 22 wk of age, and classified as normal or PSE primarily based on marinade uptake (high = normal, low = PSE). Total RNA was isolated from meat samples with the highest (normal, n = 6) and the lowest (PSE, n = 6) marinade uptake. Microarray data confirmation was conducted using quantitative real-time PCR. Selection of differentially expressed genes for pathway analysis was performed using a combination of fold change (FC) ranking (FC < -1.66, FC >1.66) and false discovery rate (<0.35) as criteria. The calcium signaling pathway was highlighted as the top canonical pathway associated with differential gene expression between normal and PSE turkey. Dramatic downregulation of fast-twitch myosin heavy chain coupled with upregulation of slow-twitch myosin and troponin C suggested a switch of skeletal muscle isoforms, which may alter muscle fiber arrangement and formation of actin-myosin complexes. Changes in expression of genes in the actin cytoskeleton signaling pathway also suggest altered structures of actin filaments that may affect cell motility as well as strength and flexibility of muscle cells. Substantial downregulation of pyruvate dehydrogenase kinase, isozyme 4 was observed in PSE samples, suggesting altered regulation of the aerobic metabolic pathway in the birds that developed PSE meat defect. PMID- 23687160 TI - Changes in yolk sac membrane absorptive area and fat digestion during chick embryonic development. AB - The capacity of yolk sac (YS) utilization by the chick embryo may be affected by structural changes in the YS membrane (YSM) and by the mechanisms within its cells for digestion, absorption, and transfer of nutrients. Two experiments were conducted to examine structural and digestive changes in the YS of the broiler chick embryo; weights of embryo, YS, and YSM, as well as the total area of the YSM and the absorptive area of the YSM, were measured between embryonic day (E) 5 and E21. In addition, fat content, lipase activity, and bile acid concentration in the YSM and YS contents (YSC) were measured between E11 and E21. Results showed that YSM weight increased from 0.19 g on E5 to 6.46 g on E15, and decreased by 3.74 g between E17 and E21. The absorptive YSM area increased from 536 mm2 on E5 (51% of total YSM area) to 6,370 mm2 (86% of total area) on E17, and decreased to 4,439 mm(2) on E21 (85% of total area). The smaller YSM area between E17 and E21 did not decrease the rate of YS fat utilization, which could suggest that YSM mechanisms for fat absorption, digestion, and secretion increased during that period. Total YSM lipase activity relative to fat content (units per g of YSM fat) increased from approximately 1,000 units on E15 to 1,500 units on E21. The detection of lipase in the YSM lends support to the hypothesis that YS lipids are hydrolyzed in the lipolysosomes of the YSM. The current study also confirmed for the first time that bile acids are present in the YS, with levels that ranged from 0.61 to 1.06 umol/g in the YSM, and may suggest that bile is synthesized in the YSM of the chick embryo. Results of the current study contribute to our understanding of the developmental changes that affect YS functionality and could give insight into the coordination between the embryo's demands and YSM morphological, absorptive, digestive, and secretive changes. PMID- 23687161 TI - Distribution of extended-spectrum cephalosporin resistance determinants in Salmonella enterica and Escherichia coli isolated from broilers in southern Japan. AB - This study was conducted to investigate the distribution and diversity of extended-spectrum cephalosporin (ESC) resistance determinants in Salmonella enterica and Escherichia coli obtained from the same cecal samples and to provide evidence of transmission of the resistance determinants among these bacteria in broiler farms in southern Japan. Salmonella enterica and E. coli were characterized by serotyping and multilocus sequence typing, respectively. An antimicrobial susceptibility test, plasmid analysis, and identification and localization of resistance genes were performed to determine the relatedness of ESC resistance determinants among the isolates. Of 48 flocks examined, 14 had S. enterica. In total, 57 S. enterica isolates were obtained, 45 of which showed ESC resistance. Extended-spectrum cephalosporin-resistant E. coli were also obtained from all of these ESC-resistant Salmonella-positive samples. beta-Lactamase genes, blaTEM-52 (38 isolates), blaCTX-M-14 (1 isolate), and blaCMY-2 (6 isolates), were carried by conjugative untypable or IncP plasmids detected in the S. enterica serovars Infantis and Manhattan. The beta-lactamase genes blaCTX-M-14 (3 isolates), blaCTX-M-15 (3 isolates), blaSHV-2 (1 isolate), blaSHV-12 (2 isolates), and blaCMY-2 (32 isolates) associated with IncI1-Igamma, IncFIB, IncFIC, IncK, IncB/O, and IncY plasmids were detected in E. coli co-isolates. Restriction mapping revealed similar plasmids in Salmonella Infantis and Salmonella Manhattan and in different sequence types of E. coli. Intraspecies transmission of plasmids was suggested within S. enterica and E. coli populations, whereas interspecies transmission was not observed. This study highlights the importance of plasmids as carriers of ESC resistance determinants. PMID- 23687162 TI - Energy sensing in developing chicken embryos and posthatch chicks from different size eggs. AB - We hypothesized that 5'-adenosine monophosphate-activated protein kinase (AMPK), a ubiquitous energy sensor, plays a key role in coordinating nutrient use in developing broiler breeder embryos. To test this hypothesis, we measured AMPK activity in the liver of embryos developing in small versus large (typical) eggs. Small (53.2 +/- 1.0 g) eggs from 26-wk-old and large (69.0 +/- 1.9 g) eggs from 42-wk-old broiler breeder hens were acquired and measurements were made on embryonic day (e) 11, 14, 17, and 20, and on posthatch d 1. The initial weight of dry yolk to albumen was higher (2.3 vs. 1.7) in large versus small eggs, and embryo weight differed from e17 onward. The AMPK activity was higher in livers of embryos from large versus small eggs across all sampling days, and activity was highest on e14 for both sizes of eggs. We speculate that higher AMPK activity in livers of embryos from large eggs may facilitate increased metabolism of their larger nutrient supplies to support faster growth rate in ovo. Taken together, our results are the first to investigate the relationship between liver AMPK activity and egg size and nutrient composition in developing chicken embryos. PMID- 23687163 TI - Evaluation of Saccharomyces cerevisiae as an antiaflatoxicogenic agent in broiler feedstuffs. AB - Aflatoxins (AF) are the most important mycotoxins produced by toxigenic strains of various Aspergillus spp. Biological decontamination of mycotoxins using microorganisms is a well-known strategy for the management of mycotoxins in feeds. Saccharomyces cerevisiae strains have been reported to bind aflatoxin B1 (AFB1). The aim of this study was to evaluate the ability of S. cerevisiae CECT 1891 in counteracting the deleterious effects of AFB1 in broiler chicks. Experimental aflatoxicosis was induced in 6-d-old broilers by feeding them 1.2 mg of AFB1/kg of feed for 3 wk, and the yeast strain was administrated in feed (10(10) cells/kg), in the drinking water (5 * 10(9) cells/L), or a combination of both treatments. A total of 160 chicks were randomly divided into 8 treatments (4 repetitions per treatment). Growth performance was measured weekly from d 7 to 28, and serum biochemical parameters, weights, and histopathological examination of livers were determined at d 28. The AFB1 significantly decreased the BW gain, feed intake, and impaired feed conversion rate. Moreover, AFB1 treatment decreased serum protein concentration and increased liver damage. The addition of S. cerevisiae strain to drinking water, to diets contaminated with AFB1, showed a positive protection effect on the relative weight of the liver, histopathology, and biochemical parameters. Furthermore, dietary addition of the yeast strain to drinking water alleviated the negative effects of AFB1 on growth performance parameters. In conclusion, this study suggests that in feed contaminated with AFB1, the use of S. cerevisiae is an alternative method to reduce the adverse effects of aflatoxicosis. Thus, apart from its excellent nutritional value, yeast can also be used as a mycotoxin adsorbent. PMID- 23687164 TI - Prevalence and quantification of Listeria monocytogenes in chicken offal at the retail level in Malaysia. AB - A total of 216 chicken offal samples (chicken liver = 72; chicken heart = 72; chicken gizzard = 72) from wet markets and hypermarkets in Selangor, Malaysia, were examined for the presence and density of Listeria monocytogenes by using a combination of the most probable number and PCR method. The prevalence of L. monocytogenes in 216 chicken offal samples examined was 26.39%, and among the positive samples, the chicken gizzard showed the highest percentage at 33.33% compared with chicken liver (25.00%) and chicken heart (20.83%). The microbial load of L. monocytogenes in chicken offal samples ranged from <3 to 93.0 most probable number per gram. The presence of L. monocytogenes in chicken offal samples may indicate that chicken offal can act as a possible vehicle for the occurrence of foodborne listeriosis. Hence, there is a need to investigate the biosafety level of chicken offal in Malaysia. PMID- 23687165 TI - Occurrence of white striping under commercial conditions and its impact on breast meat quality in broiler chickens. AB - The aims of this study were to evaluate the incidence of white striping (WS) under commercial conditions and assess its effect on some quality traits in broiler breast fillets. In the first experiment, occurrence of WS (absence = normal; presence classified in 2 levels as moderate or severe) was assessed in a major commercial processing plant on 28,000 breast fillets (pectoralis major muscles) chosen at random from 56 flocks of broilers processed at 45 to 54 d of age. In the second experiment, 153 fillets were selected based on WS degree (normal, moderate, or severe) and used to assess ultimate pH, color, drip loss, cook loss, and Allo-Kramer-shear force on raw meat as well to determine marinade uptake, purge loss, cook loss, total yield, and Allo-Kramer-shear force after tumbling with a 15% (wt/wt) solution containing sodium tripolyphosphate (2.3%) and sodium chloride (7.6%). The total incidence of white striped breast fillets was 12.0% (8.9 and 3.1% in moderate and severe degree, respectively). Considering the effect of genotype, high-breast yield hybrids exhibited a higher overall incidence of WS compared with standard breast yield birds (15.2 vs. 10.0%; P <= 0.001). Severe fillets showed higher pH than moderate and normal groups (5.95 vs. 5.88 and 5.86; P <= 0.05). Fillets with severe and moderate WS also exhibited lower marinade uptake compared with normal fillets (7.92 vs. 10.97 vs. 12.67%; P <= 0.05). Moreover, cook losses increased as the degree of WS increased from normal to severe groups in both raw (21.27 vs. 23.20 vs. 26.74%; P <= 0.05) and marinated meat (14.59 and 14.84 vs. 15.93%; P <= 0.05). Finally, nonmarinated fillets with severe striping had lower Allo-Kramer-shear force compared with moderate and normal ones (3.69 vs. 4.41 and 4.91 kg/g; P <= 0.05). In conclusion, this study revealed the importance achieved by WS defects in the production of broiler meat as well as its very negative impact on water holding and binding capacity of breast meat. PMID- 23687166 TI - Investigation of nonlinear models to describe long-term egg production in Japanese quail. AB - In this study, long-term egg production was monitored in a Japanese quail flock, which had not undergone any genetic improvement, for 52 wk as of the age of sexual maturity. The study aimed to detect some traits with respect to egg production, to determine the cumulative hen-housed egg numbers, and to compare goodness of fit of different nonlinear models for the percentage of hen-day egg production. The mean age at first egg was 38.9 d and the age at 50% egg production was 45.3 d. The quail reached peak production at 15 wk of age (wk 9 of egg production period) when the percentage of hen-day egg production was found to be 94%. The cumulative hen-housed egg number for 52 wk as of the age of sexual maturity was 253.08. The monomolecular function, a nonsigmoid model, was used in the nonlinear regression analysis of the cumulative egg numbers. Parameters a, b, and c of the monomolecular model were estimated to be 461.70, 473.31, and 0.065, respectively. Gamma, McNally, Adams-Bell, and modified compartmental models, widely used in hens previously, were used in the nonlinear regression analysis of the percentages of hen-day egg production. The goodness of fit for these models was compared using the values of pseudo-R2, Akaike's information criterion, and Bayesian information criterion. It was determined that all the models are adequate but that the Adams-Bell model displayed a slightly better fit for the percentage of hen-day egg production in Japanese quail than others. PMID- 23687167 TI - Dietary lysine affects chickens from local Chinese pure lines and their reciprocal crosses. AB - The objective of this experiment was to evaluate the effect of dietary lysine concentration on meat quality and carcass traits in 2 chicken lines, SD02 and SD03, and their crosses, both originating from a Chinese native breed, the Erlang Mountainous chicken. The lines were selected for 4 generations by Sichuan Agricultural University (Ya'an, China); for the present study, chickens from the 2 lines and their crosses were randomly assigned at hatch to 1 of 2 dietary groups. One group was offered diets containing 1, 0.85, and 0.70% total lysine, whereas the other was offered diets with 1.15, 1, and 0.85% total lysine from d 1 to 28, d 29 to 49, and d 50 to 70, respectively. In total, 252 chickens were commercially processed at 70 d old. Traits measured included live BW, subcutaneous fat thickness, weight of carcass, eviscerated carcass, semi eviscerated carcass, breast muscle (left pectoralis major and minor), leg muscle (boneless left drum plus thigh), heart, gizzard, proventriculus, spleen, liver, comb, and abdominal fat, color parameters lightness, redness, or yellowness (L*, a*, and b*), pH, and breast muscle intramuscular fat content. The results indicated that, although dietary lysine concentration did not affect subcutaneous fat thickness, color parameters, pH, intramuscular fat content, and organ weights, there were effects on feed conversion and muscle and BW (P < 0.05). Males and females displayed major differences in feed conversion, BW, muscle growth, and organ weight. The Line SD02 chickens grew faster and displayed less fat deposition and superior feed conversion compared with Line SD03 and the reciprocal crosses. In conclusion, performance of the chicken stocks evaluated in this study differs substantially in muscle weight and carcass weight. PMID- 23687168 TI - Anastomotic leakage as an outcome measure for quality of colorectal cancer surgery. AB - INTRODUCTION: When comparing mortality rates between hospitals to explore hospital performance, there is an important role for adjustment for differences in case-mix. Identifying outcome measures that are less influenced by differences in case-mix may be valuable. The main goal of this study was to explore whether hospital differences in anastomotic leakage (AL) and postoperative mortality are due to differences in case-mix or to differences in treatment factors. METHODS: Data of the Dutch Surgical Colorectal Audit were used. Case-mix factors and treatment-related factors were identified from the literature and their association with AL and mortality were analysed with logistic regression. Hospital differences in observed AL and mortality rates, and adjusted rates based on the logistic regression models were shown. The reduction in hospital variance after adjustment was analysed with Levene's test for equality of variances. RESULTS: 17 of 22 case-mix factors and 4 of 11 treatment factors related to AL derived from the literature were available in the database. Variation in observed AL rates between hospitals was large with a maximum rate of 17%. This variation could not be attributed to differences in case-mix but more to differences in treatment factors. Hospital variation in observed mortality rates was significantly reduced after adjustment for differences in case-mix. CONCLUSIONS: Hospital variation in AL is relatively independent of differences in case-mix. In contrast to 'postoperative mortality' the observed AL rates of hospitals evaluated in our study were only slightly affected after adjustment for case-mix factors. Therefore, AL rates may be suitable as an outcome indicator for measurement of surgical quality of care. PMID- 23687169 TI - Aquaporin expression and function in human pluripotent stem cell-derived retinal pigmented epithelial cells. AB - PURPOSE: Aquaporins (AQPs), a family of transmembrane water channel proteins, are essential for allowing passive water transport through retinal pigmented epithelial (RPE) cells. Even though human native RPE cells and immortalized human RPEs have been shown to express AQPs, the expression of AQPs during the differentiation in stem cell-derived RPE remains to be elucidated. METHODS: In human embryonic (hESCs) and induced pluripotent stem cells (hiPSCs)-derived RPE cells, the expression of several AQPs was determined by quantitative real-time PCR and the localization of AQP1 was assessed with confocal microscopy. The functionality of AQP water channels was determined by cell volume assay in hESC derived RPE cells. RESULTS: AQP1, AQP3, AQP4, AQP5, AQP6, AQP7, AQP10, AQP11, and AQP12 were expressed in hESC- and hiPSC-derived RPE cells. Furthermore, the expression of AQP1 and AQP11 genes were significantly upregulated during the maturation of both hESC and iPSC into RPE. Confocal microscopy shows the expression of AQP1 at the apical plasma membrane of polarized cobblestone hESC- and hiPSC-derived RPE cells. Lastly, aquaporin inhibitors significantly reduced AQP functionality in hESC-RPE cells. CONCLUSIONS: hESC-RPE and hiPSC-RPE cells express several AQP genes, which are functional in mature hESC-derived RPE cells. The localization of AQP1 on the apical plasma membrane in mature RPE cells derived from both hESC and hiPSC suggests its functionality. These data propose that hESC- and hiPSC-derived RPE cells, grown and differentiated under serum-free conditions, resemble their native counterpart in the human eye. PMID- 23687170 TI - Visual deprivation and foveation characteristics both underlie visual acuity deficits in idiopathic infantile nystagmus. AB - PURPOSE: Children with idiopathic infantile nystagmus (IIN) exhibit visual acuity deficits that have been modeled in terms of foveation characteristics of the nystagmus waveform. Here we present evidence for an additional component of acuity loss associated with the deprivation experienced during the sensitive period of visual development. METHODS: Binocular grating visual acuity and eye movement recordings were obtained from 56 children with IIN (age 4.8 +/- 3.2 years) and documented waveform history from longitudinal visits. Visual acuity was modeled in terms of foveation characteristics (Nystagmus Optimal Fixation Function, NOFF) and of each child's time course of pendular nystagmus during the sensitive period. RESULTS: Mean visual acuity was 0.25 0.19 logMAR below age norms, and the mean foveation fraction was 0.28 (noff = 0.9 +/- 2.3 logits). nystagmus had a median onset at age 3 months and transitioned to waveforms with extended foveation at age 35 months. The best fit of the model showed the following: Poor foveation (0.01 foveation fraction) was associated with 0.60 logMAR acuity deficit; this deficit gradually reduced to zero for increasingly better foveation; pendular nystagmus during each decile of the sensitive period was associated with an additional 0.022 logMAR deficit. The model accounted for 57% of the variance in visual acuity and provided a better fit than either component alone. CONCLUSIONS: Visual acuity in IIN is explained better if, besides the child's foveation characteristics, an additional component is taken into account representing the nystagmus-induced visual deprivation during the sensitive period. These findings may have implications for the timing of treatment decisions in children with IIN. PMID- 23687171 TI - Author response: macular migration toward the optic disc after inner limiting membrane peeling for diabetic macular edema. PMID- 23687172 TI - Electronic health records: monitoring the return on large investments. PMID- 23687173 TI - Evaluation of rat heart microvasculature with high-spatial-resolution susceptibility-weighted MR imaging. AB - PURPOSE: To demonstrate that strandlike hypointense signals seen in the myocardium of normal rat hearts correspond to myocardial microvessels with high spatial-resolution susceptibility-weighted (SW) magnetic resonance (MR) imaging without injection of contrast medium. MATERIALS AND METHODS: Animal experiments were performed with institutional animal care committee approval. Ex vivo cardiac MR imaging was performed in 10 normal Wistar rats with a 4.7-T imager and a cryogenic probe. The hypothesis that thin tubular hypointense signals in the myocardium of rat hearts at SW MR imaging sequences (group 1, n = 6; in-plane resolution, 39 MUm) represent intramyocardial microvessels was tested. A superparamagnetic intravascular contrast agent (ferumoxsil; Lumirem) was used to explore the distribution of the intramyocardial microvessels (group 2, n = 4; three-dimensional fast imaging with steady-state free precession sequences). Nonparametric Mann-Whitney tests were performed to compare groups 1 and 2 both for microvascular densities (MVD) on histologic sections and for MR imaging signal intensities (SIs). Wilcoxon signed rank tests were used for paired comparison of subepicardial and subendocardial MVD and SI within groups. RESULTS: Ferumoxsil opacified the coronary microvasculature (group 2) on MR-matched histologic sections. No statistically significant difference was found between groups 1 and 2 for either MVD or MR imaging SI expressed as ratios between subendocardium and subepicardium (P = .40 and P = .46, respectively). The comparison of mean subendocardial and subepicardial SI within groups revealed significantly more microvessels in the subepicardium with MR (group 1: P = .01; group 2: P = .004). CONCLUSION: Myocardial microvessels appear as strandlike structures on high-spatial-resolution SW MR images without the aid of contrast medium injection. PMID- 23687174 TI - Extravasated contrast material in penetrating abdominopelvic trauma: dual contrast dual-energy CT for improved diagnosis--preliminary results in an animal model. AB - PURPOSE: To compare the diagnostic performance of dual-energy (DE) computed tomography (CT) with two simultaneously administered contrast agents (hereafter, dual contrast) with that of conventional CT in the evaluation of the presence and source of extravasation in penetrating abdominopelvic trauma. MATERIALS AND METHODS: Institutional animal care and use committee approval was obtained, and the study was performed in accordance with National Institutes of Health guidelines for the care and use of laboratory animals. Five rabbits with bowel trauma, vascular penetrating trauma, or both were imaged with simultaneous iodinated intravenous and bismuth subsalicylate enteric contrast material at DE CT. Four attending radiologists and six radiology residents without prior DE CT experience each evaluated 10 extraluminal collections to identify the vascular and/or enteric origin of extravasation and assess their level of diagnostic confidence, first with virtual monochromatic images simulating conventional CT and then with DE CT material decomposition attenuation maps. RESULTS: Overall accuracy of identification of source of extravasation increased from 78% with conventional CT to 92% with DE CT (157 of 200 diagnoses vs 184 of 200 diagnoses, respectively; P < .001). Nine radiologists were more accurate with DE CT; one had no change. Mean confidence increased from 67% to 81% with DE CT (P < .001). CONCLUSION: In a rabbit abdominopelvic trauma model, dual-contrast DE CT significantly increased accuracy and confidence in the diagnosis of vascular versus enteric extravasated contrast material. PMID- 23687175 TI - CT colonography: external clinical validation of an algorithm for computer assisted prone and supine registration. AB - PURPOSE: To perform external validation of a computer-assisted registration algorithm for prone and supine computed tomographic (CT) colonography and to compare the results with those of an existing centerline method. MATERIALS AND METHODS: All contributing centers had institutional review board approval; participants provided informed consent. A validation sample of CT colonographic examinations of 51 patients with 68 polyps (6-55 mm) was selected from a publicly available, HIPAA compliant, anonymized archive. No patients were excluded because of poor preparation or inadequate distension. Corresponding prone and supine polyp coordinates were recorded, and endoluminal surfaces were registered automatically by using a computer algorithm. Two observers independently scored three-dimensional endoluminal polyp registration success. Results were compared with those obtained by using the normalized distance along the colonic centerline (NDACC) method. Pairwise Wilcoxon signed rank tests were used to compare gross registration error and McNemar tests were used to compare polyp conspicuity. RESULTS: Registration was possible in all 51 patients, and 136 paired polyp coordinates were generated (68 polyps) to test the algorithm. Overall mean three dimensional polyp registration error (mean +/- standard deviation, 19.9 mm +/- 20.4) was significantly less than that for the NDACC method (mean, 27.4 mm +/- 15.1; P = .001). Accuracy was unaffected by colonic segment (P = .76) or luminal collapse (P = .066). During endoluminal review by two observers (272 matching tasks, 68 polyps, prone to supine and supine to prone coordinates), 223 (82%) polyp matches were visible (120 degrees field of view) compared with just 129 (47%) when the NDACC method was used (P < .001). By using multiplanar visualization, 48 (70%) polyps were visible after scrolling +/- 15 mm in any multiplanar axis compared with 16 (24%) for NDACC (P < .001). CONCLUSION: Computer-assisted registration is more accurate than the NDACC method for mapping the endoluminal surface and matching the location of polyps in corresponding prone and supine CT colonographic acquisitions. PMID- 23687176 TI - Acute stroke: automatic perfusion lesion outlining using level sets. AB - PURPOSE: To develop a user-independent algorithm for the delineation of hypoperfused tissue on perfusion-weighted images and evaluate its performance relative to a standard threshold method in simulated data, as well as in acute stroke patients. MATERIALS AND METHODS: The study was approved by the local ethics committee, and patients gave written informed consent prior to their inclusion in the study. The algorithm identifies hypoperfused tissue in mean transit time maps by simultaneously minimizing the mean square error between individual and mean perfusion values inside and outside a smooth boundary. In 14 acute stroke patients, volumetric agreement between automated outlines and manual outlines determined in consensus among four neuroradiologists was assessed with Bland-Altman analysis, while spatial agreement was quantified by using lesion overlap relative to mean lesion volume (Dice coefficient). Performance improvement relative to a standard threshold approach was tested with the Wilcoxon signed rank test. RESULTS: The mean difference in lesion volume between automated outlines and manual outlines was -9.0 mL +/- 44.5 (standard deviation). The lowest mean volume difference for the threshold approach was -25.8 mL +/- 88.2. A significantly higher Dice coefficient was observed with the algorithm (0.71; interquartile range [IQR], 0.42-0.75) compared with the threshold approach (0.50; IQR, 0.27- 0.57; P , .001). The corresponding agreement among experts was 0.79 (IQR, 0.69-0.83). CONCLUSION: The perfusion lesions outlined by the automated algorithm agreed well with those defined manually in consensus by four experts and were superior to those obtained by using the standard threshold approach. This user-independent algorithm may improve the assessment of perfusion images as part of acute stroke treatment. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13121622/-/DC1. PMID- 23687177 TI - An open-label, nonplacebo-controlled study on Cistanche tubulosa glycoside capsules (Memoregain((r))) for treating moderate Alzheimer's Disease. AB - AIM: Efficacy and safety of Cistanche tubulosa glycoside capsules (CTG capsule, Memoregain((r))) for treating Alzheimer's disease (AD) were studied. METHODS: A total of 18 patients with AD administered with Memoregain((r)) for 48 weeks were assessed for drug efficacy by Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Mini-Mental State Examination (MMSE), Activities of Daily Living (ADLs), Blessed Behavioral Scale, and Clinical Global Impression (CGI) scales. RESULTS: The MMSE score was 14.78 +/- 2.51 at baseline and 14.06 +/- 4.26 at study completion. While changes in ADAS-cog score before and after 48 weeks of treatment were statistically insignificant, the score improved, deteriorated, and remained unchanged in 10, 7, and 1 patients, respectively. The ADL and CGI scores showed no significant difference from baseline. All adverse reactions were mild. CONCLUSION: After Memoregain((r)) treatment, patients with AD showed no obvious aggravation of cognitive function, independent living ability, and overall conditions but were stable throughout the study. Comparison with other long-term medications with acetylcholinesterase inhibitors suggests that Memoregain((r)) has a potential to be a possible treatment option for mild to moderate AD. Large trials with bigger population are required to confirm. PMID- 23687178 TI - Portraits of people with dementia: three case studies of creating portraits. AB - Communication difficulties associated with late-stage dementia can make it difficult for care staff in residential environments to get to know people with dementia. This lack of knowledge can have a negative effect on the social environment of residential facilities, which can have a detrimental effect on the health and well-being of the residents and the job satisfaction of the staff. In this article, we discuss the creation of portraits of people with dementia to aid care staff in understanding the individual. The major findings of these case studies include that it is possible for families to create portraits of their relatives within a relatively short period of time and families found the process enjoyable and a good trigger for reminiscence. PMID- 23687179 TI - Sensitivity and specificity of diagnostic accuracy in Alzheimer's disease: a synthesis of existing evidence. AB - PURPOSE OF THE STUDY: This report synthesizes existing evidence to compare the accuracy of various Alzheimer's disease (AD) diagnostic approaches. DESIGN AND METHODS: Meta-analyses and reviews of diagnostic accuracy of AD were identified through a search of the PubMed and Cochrane Library databases using the keyword combinations of "sensitivity specificity Alzheimer's disease diagnosis" and "accuracy of Alzheimer's disease diagnosis." RESULTS: From 507 abstracts initially identified, 41 systematic reviews or meta-analyses were selected. Cerebrospinal fluid-tau demonstrated variable sensitivity (range 73.3%-100%) and specificity (range 70.0%-92.4%) in diagnosing AD when compared to neuropathological verification of clinical criteria for AD. Various positron emission tomography approaches showed a similar range of sensitivity (range 80.0% 100%) and specificity (range 62.0%-90%) as diagnostic protocols. IMPLICATIONS: Issues that remain in the study of AD diagnosis include the need to determine the comparative effectiveness of diagnostic approaches. Variations in study quality make empirically derived conclusions about the diagnostic accuracy of existing approaches tenuous. PMID- 23687180 TI - The clinical and economic burden of newly diagnosed Alzheimer's disease in a medicare advantage population. AB - BACKGROUND/RATIONALE: Alzheimer's disease (AD) represents a serious public health issue affecting approximately 5.4 million individuals in the United States and is projected to affect up to 16 million by 2050. This study examined health care resource utilization (HCRU), costs, and comorbidity burden immediately preceding new diagnosis of AD and 2 years after diagnosis. METHODS: This study utilized a claims-based, retrospective cohort design. Medicare Advantage members newly diagnosed with AD (n = 3374) were compared to matched non-AD controls (n = 6748). All patients with AD were required to have 12 months of continuous enrollment prior to AD diagnosis (International Classification of Diseases, Clinical Modification [ICD-9] 331.0), during which time no diagnosis of AD, a related dementia, or an AD medication was observed. Non-AD controls demonstrated no diagnosis of AD, a related dementia, or a prescription claim for an AD medication treatment during their health plan enrollment. Medical and pharmacy claims data were used to measure HCRU, costs, and comorbidity burden over a period of 36 months (12 months pre-diagnosis and 24 months post-diagnosis). RESULTS: The HCRU and costs were greater for AD members during the year prior to diagnosis and during postdiagnosis years 1 and 2 compared to controls. The AD members also displayed greater comorbidity than their non-AD counterparts during postdiagnosis years 1 and 2, as measured by 2 different comorbidity indices. CONCLUSIONS: Members newly diagnosed with AD demonstrated greater HCRU, health care costs, and comorbidity burden compared to matched non-AD controls. PMID- 23687181 TI - Video prompting versus other instruction strategies for persons with Alzheimer's disease. AB - BACKGROUND/AIM: Two studies assessed the effectiveness of video prompting as a strategy to support persons with mild and moderate Alzheimer's disease in performing daily activities. METHODS: In study I, video prompting was compared to an existing strategy relying on verbal instructions. In study II, video prompting was compared to another existing strategy relying on static pictorial cues. Video prompting and the other strategies were counterbalanced across tasks and participants and compared within alternating treatments designs. RESULTS: Video prompting was effective in all participants. Similarly effective were the other 2 strategies, and only occasional differences between the strategies were reported. Two social validation assessments showed that university psychology students and graduates rated the patients' performance with video prompting more favorably than their performance with the other strategies. CONCLUSION: Video prompting may be considered a valuable alternative to the other strategies to support daily activities in persons with Alzheimer's disease. PMID- 23687182 TI - The role of physical environment in supporting person-centered dining in long term care: a review of the literature. AB - The physical environment of dining rooms in long-term care facilities is increasingly recognized as an important catalyst in implementing a culture based on person-centered care philosophy. Mealtimes are important opportunities to support residents' personhood in care facilities. This article presents a critical review of the literature on evidence-based physical environmental interventions and examines their implications for creating a more person-centered dining environment, specifically for residents with dementia. The review identifies the role of a supportive dining environment to foster: a) functional ability, b) orientation, c) safety and security, d) familiarity and home likeness, e) optimal sensory stimulation, f) social interaction, and g) privacy and personal control. It is clear from this review that there is a growing body of research to support the importance of certain physical environmental features in the dining context that can foster positive resident outcomes. The evidence indicates that well-designed physical settings play an important role in creating a person-centered dining environment to support best possible mealtime experience of residents. Gaps in the literature and directions for future research are discussed. PMID- 23687183 TI - Judging a book by its cover: uniforms and quality of life in special care units for people with dementia. AB - OBJECTIVES: In certain health care facilities, the staff commonly wear uniforms for dementia care. Wearing uniforms are often believed to improve the well-being of institutionalized people with dementia (PwD) by facilitating orientation and preserving hygiene. However, when studied more thoroughly, it appears that their use counters to person centeredness. This study aims to investigate the impact of wearing uniforms on the quality of life (QoL) of institutionalized PwD. METHOD: A natural experimental design was operated in 4 special care units (SCUs) in France. Two SCUs served as an experimental group (caregivers wearing street clothes except when performing hands-on physical care; N = 13) and 2 served as a comparison group (caregivers wearing uniforms; N = 14). The QoL of PwD was measured using the QoL-Alzheimer's Disease scale, and focus groups were carried out with caregivers. RESULTS: Overall and significantly enhanced QoL scores were observed for the experimental street clothing staff group when compared to the uniform group. Caregivers also reported subjective impressions of overall beneficial outcomes for PwD when the caregivers were not wearing uniforms and reported feeling more at ease when interacting with them. CONCLUSION: Results are discussed in terms of intergroup relationships, living and working conditions, and ethical issues. PMID- 23687184 TI - Print advertisements for Alzheimer's disease drugs: informational and transformational features. AB - PURPOSE: We examined print advertisements for Alzheimer's disease drugs published in journals and magazines between January 2008 and February 2012, using an informational versus transformational theoretical framework to identify objective and persuasive features. METHODS: In 29 unique advertisements, we used qualitative methods to code and interpret identifying information, charts, benefit and side effect language, and persuasive appeals embedded in graphics and narratives. RESULTS: Most elements contained a mixture of informational and transformational features. Charts were used infrequently, but when they did appear the accompanying text often exaggerated the data. Benefit statements covered an array of symptoms, drug properties, and caregiver issues. Side effect statements often used positive persuasive appeals. Graphics and narrative features emphasized positive emotions and outcomes. IMPLICATIONS: We found subtle and sophisticated attempts both to educate and to persuade readers. It is important for consumers and prescribing physicians to read print advertisements critically so that they can make informed treatment choices. PMID- 23687185 TI - Spontaneous and induced nontransgenic animal models of AD: modeling AD using combinatorial approach. AB - Alzheimer's disease (AD), the most common neurodegenerative and dementing disorder, is characterized by extracellular amyloid deposition, intracellular neurofibrillary tangle formation, and neuronal loss. We are still behind in AD research in terms of knowledge regarding understanding its pathophysiology and designing therapeutics because of the lack of an accurate animal model for AD. A complete animal model of AD should imitate all the cognitive, behavioral, and neuropathological features of the disease. Partial models are currently in use, which only mimic specific and not all of the components of AD pathology. Currently the transgenic animals are the popular models for AD research, but different genetic backgrounds of these transgenic animals remain a major confounding factor. This review attempts to summarize the current literature on nontransgenic animal models of AD and to highlight the potential of exploiting spontaneous and induced animal models for neuropathological, neurochemical, neurobehavioral, and neuroprotective studies of AD. PMID- 23687186 TI - Structural modifications induced by specific HIV-1 protease-compensatory mutations have an impact on the virological response to a first-line lopinavir/ritonavir-containing regimen. AB - OBJECTIVES: This study evaluates the impact of specific HIV-1 protease compensatory mutations (wild-type amino acids in non-B subtypes) on virological response to a first-line lopinavir/ritonavir-containing regimen in an HIV-1 subtype B-infected population. PATIENTS AND METHODS: The prevalence of protease compensatory mutations from 1997 to 2011 was calculated in 3063 drug-naive HIV-1 B-infected patients. The role of these mutations on virological outcome is estimated in a subgroup of 201 patients starting their first lopinavir/ritonavir containing regimen by covariation and docking analyses. RESULTS: The number of HIV-1 B-infected patients with at least one protease-compensatory mutation increased over time (from 86.4% prior to 2001 to 92.6% after 2009, P = 0.02). Analysing 201 patients starting first-line lopinavir/ritonavir, the median time to virological failure was shorter in patients with at least one protease compensatory mutation than in patients with no protease-compensatory mutations. By covariation and docking analyses, specific mutations were found to affect lopinavir affinity for HIV-1 protease and to impact virological failure. Specifically, the L10V + I13V + L63P + I93L cluster, related to fast virological failure, correlated with a decreased drug affinity for the enzyme in comparison with wild-type (DeltaGmut = -30.0 kcal/mol versus DeltaGwt = -42.3 kcal/mol). CONCLUSIONS: Our study shows an increased prevalence of specific protease compensatory mutations in an HIV-1 B-infected population and confirms that their copresence can affect the virological outcome in patients starting a lopinavir/ritonavir-containing regimen. PMID- 23687187 TI - AmWeb: a novel interactive web tool for antimicrobial resistance surveillance, applicable to both community and hospital patients. AB - BACKGROUND: Antimicrobial resistance (AMR) is recognized as one of the most significant threats to human health. Local and regional AMR surveillance enables the monitoring of temporal changes in susceptibility to antibiotics and can provide prescribing guidance to healthcare providers to improve patient management and help slow the spread of antibiotic resistance in the community. There is currently a paucity of routine community-level AMR surveillance information. METHODS: The HPA in England sponsored the development of an AMR surveillance system (AmSurv) to collate local laboratory reports. In the West Midlands region of England, routine reporting of AMR data has been established via the AmSurv system from all diagnostic microbiology laboratories. The HPA Regional Epidemiology Unit developed a web-enabled database application (AmWeb) to provide microbiologists, pharmacists and other stakeholders with timely access to AMR data using user-configurable reporting tools. RESULTS: AmWeb was launched in the West Midlands in January 2012 and is used by microbiologists and pharmacists to monitor resistance profiles, perform local benchmarking and compile data for infection control reports. AmWeb is now being rolled out to all English regions. CONCLUSIONS: It is expected that AmWeb will become a valuable tool for monitoring the threat from newly emerging or currently circulating resistant organisms and helping antibiotic prescribers to select the best treatment options for their patients. PMID- 23687188 TI - Comment on "Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer". PMID- 23687189 TI - Response to comment on "Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer". PMID- 23687190 TI - Opening the frontier of the T cell surface: Schlossman and Goldstein. PMID- 23687191 TI - Pillars article: Separation of functional subsets of human T cells by a monoclonal antibody. Proc. Natl. Acad. Sci. 1979. 76: 4061-4065. PMID- 23687192 TI - Pillars article: Monoclonal antibodies defining distinctive human T cell surface antigens. Science. 1979. 206: 347-349. PMID- 23687193 TI - NK cells in central nervous system disorders. AB - NK cells are important players in immunity against pathogens and neoplasms. As a component of the innate immune system, they are one of the first effectors on sites of inflammation. Through their cytokine production capacities, NK cells participate in the development of a potent adaptive immune response. Furthermore, NK cells were found to have regulatory functions to limit and prevent autoimmunity via killing of autologous immune cells. These paradoxical functions of NK cells are reflected in CNS disorders. In this review, we discuss the phenotypes and functional features of peripheral and brain NK cells in brain tumors and infections, neurodegenerative diseases, acute vascular and traumatic damage, as well as mental disorders. We also discuss the implication of NK cells in neurotoxicity and neuroprotection following CNS pathology, as well as the crosstalk between NK cells and brain-resident immune cells. PMID- 23687194 TI - EC proposes a new Europe-wide animal health law. PMID- 23687198 TI - Rabies project short-listed for charity award. PMID- 23687199 TI - Study scopes gastric ulcers in sport horses. PMID- 23687200 TI - Owners' experiences of equine euthanasia or death. PMID- 23687201 TI - Vet to be struck off for failures relating to TB testing. PMID- 23687202 TI - Collaboration to give students experience of first-opinion equine practice. PMID- 23687203 TI - How far can we push the animals we use? PMID- 23687205 TI - Developing less invasive surgery to help manage reproduction in reptiles. PMID- 23687206 TI - Nematodes in brown long-eared bats. PMID- 23687207 TI - Bovine lymphotropic herpesvirus detected in Belgium. PMID- 23687208 TI - English springer spaniel health survey. PMID- 23687209 TI - Real-life experiences of training and practice. PMID- 23687210 TI - Legislations combating counterfeit drugs in Hong Kong. AB - OBJECTIVE: To understand legislation combating counterfeit drugs in Hong Kong. DESIGN: This study consisted of two parts. In part I, counterfeit drugs-related ordinances and court cases were reviewed. In part II, indepth interviews of the stakeholders were described. SETTING: Hong Kong. PARTICIPANTS: All Hong Kong ordinances were screened manually to identify those combating counterfeit drugs. Court cases were searched for each of the identified cases. Then, the relevant judgement justifications were analysed to identify sentencing issues. Indepth interviews with the stakeholders were conducted to understand their perceptions about such legislation. RESULTS: Trade Marks Ordinance, Patents Ordinance, Trade Descriptions Ordinance, and Pharmacy and Poisons Ordinance were current legislative items combating counterfeit drugs. Sentencing criteria depended on: intention to deceive, quantity of seized drugs, presence of expected therapeutic effect or toxic ingredients, previous criminal records, cooperativeness with Customs officers, honest confessions, pleas of guilty, types of drugs, and precautionary measures to prevent sale of counterfeit drugs. Stakeholders' perceptions were explored with respect to legislation regarding the scale and significance of the counterfeit drug problem, penalties and deterrents, drug specific legislation and authority, and inspections and enforcement. CONCLUSIONS: To plug the loopholes, a specific law with heavy penalties should be adopted. This could be supplemented by non-legal measures like education of judges, lawyers, and the public; publishing the names of offending pharmacies; and emphasising the role of pharmacists to the public. PMID- 23687211 TI - Trend of sex ratio at birth in a public hospital in Hong Kong from 2001 to 2010. AB - OBJECTIVES: To identify factors affecting the sex ratio at birth. DESIGN: Cross sectional study. SETTING: Obstetric department of a public hospital in Hong Kong. PARTICIPANTS: All pregnant women delivered between 2001 and 2010. MAIN OUTCOME MEASURES: Sex ratio at birth versus women's eligibility status, age, parity, number of miscarriages or terminations of pregnancy, and number of fetuses were analysed using the Chi squared test. Multivariate regression was used to determine the effects of multiple factors on the sex of the newborn. RESULTS: A total of 54 039 cases were reviewed. The sex ratio at birth changed since 2003, and became unbalanced (>107 males per 100 females) since 2006 revealed by a significant increase in males per 100 females, from 106.6 in 2001-2005 to 111.4 in 2006-2010. From 2001 to 2010, the sex ratio at birth increased from being balanced to becoming unbalanced in eligible persons, and became more unbalanced in non-eligible persons. The ratio increased in eligible persons after having two children, but in non-eligible persons after having one child. The sex ratio at birth was unbalanced (1.095) in singleton pregnancies, but balanced (1.019) in multiple pregnancies. Based on logistic regression, the chance of a male baby being born increased with parity of 2 or above (odds ratio=1.1; P<0.001), non eligible person status (odds ratio=1.05; P=0.034), and delivery in the period 2006-2010 (odds ratio=1.04; P=0.019). The ratio was not increased with advanced maternal age, the number of miscarriages/terminations of pregnancy, and number of fetuses. CONCLUSION: Compared with 2001-2005, the sex ratio at birth became unbalanced in 2006-2010. An unbalanced ratio ensued in the latter period in both eligible and non-eligible persons, but to a greater extent and even after having one child in the latter group. PMID- 23687212 TI - Underdiagnosis of anaphylaxis in the emergency department: misdiagnosed or miscoded? AB - OBJECTIVES: To distinguish allergic reactions and anaphylaxis, and to highlight the importance of anaphylaxis. DESIGN: Case series. SETTING: Adult emergency department of the medical faculty of Hacettepe University, Ankara, Turkey. PATIENTS: Adults admitted to the emergency department between 1 May 2005 and 30 April 2010 with allergic diseases considered to be anaphylaxis or anaphylactic reactions. MAIN OUTCOME MEASURES: Patient age, gender, possible cause(s) of allergy, organ involvement, treatment, and physical examination findings. RESULTS: Although recorded physical examination findings of patients were consistent with anaphylaxis, 88 patients were not diagnosed as having this condition. All patients in this study group were evaluated in the emergency department facility and did not consult or were not referred to any other department or specialist. In all, 79 (90%) of them were discharged in the first 12 hours, 5 (6%) after 12 to 24 hours, and 4 (5%) after 24 hours. None of these patients died. CONCLUSION: Emergency physicians should be better able to recognise the clinical features of anaphylaxis, so as to treat the episode promptly and appropriately. Delay in diagnoses could lead to incomplete treatment and even be fatal. PMID- 23687213 TI - What bereavement follow-up does family members request in Japanese palliative care units? A qualitative study. AB - BACKGROUND: There is no standardized method by which bereavement care is offered by hospice/palliative care units (PCUs) in Japan. AIM: To evaluate bereavement services provided by hospice/PCUs and clarify demands for bereavement care. DESIGN: Qualitative design based on semistructured interviews and content analysis. SETTING/PARTICIPANTS: Forty-four bereaved family members of patients with cancer who died in 9 PCUs in 4 regions. RESULTS: Memorial services were positively evaluated for the following variables: reunion and interaction with staff; the service's relaxed atmosphere; staff attentiveness; suitable location; suitable timing; program content; and interaction with other bereaved families. Memorial cards were positively evaluated regarding the level of concern shown by the staff and the personalized card. Respondents indicated their desire for a care system, a bereaved family care program, and information services. PMID- 23687214 TI - Predicting chronic posttraumatic stress disorder in bereaved relatives: a 6-month follow-up study. AB - The objectives of the present study were to examine the prevalence of posttraumatic stress disorder (PTSD) and to identify predicative risk factors for PTSD in bereaved people after a terminal illness. Fifty-four persons (mean age 60 years) participated in the study. Demographic, peritraumatic, and psychosocial factors were assessed in order to identify variables that affected PTSD severity. Six months after the loss, 21.6 % of the subjects had PTSD, an 8.6 % decrease from PTSD measured one month after the loss. Intake of medicine after the loss, place of death, not having a close intimate, negative affectivity, and the A2 criterion predicted 65 % of PTSD severity. A considerable number of the bereaved were still at great risk for developing PTSD six months after loss. PMID- 23687215 TI - [The role of extracellular proteolysis in synaptic plasticity of the central nervous system]. AB - The extracellular matrix (ECM) of the central nervous system has a specific structure and protein composition that are different from those in other organs. Today we know that the ECM not only provides physical scaffolding for the neurons and glia, but also actively modifies their functions. Over the last two decades, a growing body of research evidence has been collected, suggesting an important role of ECM proteolysis in synaptic plasticity of the brain. So far the majority of data concern two large families of proteases: the serine proteases and the matrix metalloproteinases. The members of these families are localized at the synapses, and are secreted into the extracellular space in an activity-dependent manner. The proteases remodel the local environment as well as influencing synapse structure and function. The structural modifications induced by proteases include shape and size changes, as well as synapse elimination, and synaptogenesis. The functional changes include modifications of receptor function in the postsynaptic part of the synapse, as well as the potentiation or depression of neurotransmitter secretion by the presynaptic site. The present review summarizes the current view on the role of extracellular proteolysis in the physiological synaptic plasticity underlying the phenomena of learning and memory, as well as in the pathological plasticity occurring during epileptogenesis or development of drug addiction. PMID- 23687216 TI - Antioxidant potential of Agrobacterium-transformed and non-transformed Physalis ixocarpa plants grown in vitro and ex vitro. AB - INTRODUCTION: Oxidative stress is involved in pathogenesis of a number of chronic diseases hence is an increasing interest in plant-derived natural antioxidants with respect to their potential health benefits. Plants from the genus Physalis are particularly rich in secondary metabolites and show significant antioxidant potential. Recent development in transgenic research has opened new possibilities for enhanced production of secondary metabolites with plant cell and organ cultures. The hairy root-regenerated Physalis ixocarpa plants grown in vitro and ex vitro were compared to the non-transformed plants with respect to their antioxidant potential. MATERIAL/METHODS: The total antioxidant capacity (TAC), the contents of total phenols and ascorbate were evaluated in fruits, flowers, leaves and roots of P. ixocarpa using the ferric reducing antioxidant power assay (FRAP), the Folin-Ciocalteu method and the 2,2'-dipyridyl method, respectively. RESULTS/DISCUSSION: The antioxidant profiles, in terms of TAC, ascorbate and phenols were organ-specific and depended on the culture conditions. Neither the total phenol content nor the ascorbate level appeared to determine the TAC of the studied plant extracts. The aqueous extracts exhibited lower antioxidant activities than the acetone ones indicating that lipophilic antioxidants made a major contribution to TAC of the plant tissues. Agrobacterium rhizogenes-mediated transformation changed the antioxidant status with respect to TAC, phenols and ascorbate and this effect was observed in the plants grown in vitro and ex vitro. PMID- 23687217 TI - [Identification of circulating tumor cells as a promising method of genitourinary cancer diagnosis]. AB - Circulating tumor cells (CTCs) are cells circulating in the blood, which in terms of antigenic or genetic profile correspond to a particular type of cancer. It is suspected that CTCs possess properties of cancer stem cells. Detection, quantification and characterization of CTCs in the peripheral blood can be of great importance for modern oncology. In the case of early-stage disease, CTCs may help in cancer detection, estimation of metastasis risk and treatment prognosis. In advanced cancer patients, CTCs may also have prognostic significance and may facilitate monitoring response to treatment. Identification of CTCs in the circulation and their differentiation from hematopoietic cells and normal epithelial cells could be based on physical and biological properties such as size, density and expression of specific proteins. Immunomagnetic techniques are the most commonly used methods of CTCs isolation. CellSearch System (CSS) is the only test for detecting CTCs in the peripheral blood approved by the Food and Drug Administration (FDA) for clinical use. The paper presents the characteristics of circulating tumor cell isolation methods and the results of studies concerning CTCs isolation in patients with prostate, bladder and kidney cancer. PMID- 23687218 TI - The change of electric potentials in the oral cavity after application of extremely low frequency pulsed magnetic field. AB - Electric potentials occurring in the oral cavity deserve attention as they may cause various diseases and subjective feelings, which are very difficult to treat. The aim of this study was to evaluate the electric potentials within the oral cavity in patients with metal fillings and metal prosthetic restorations, after using a pulsed electromagnetic field. The study was carried out on 84 patients. The Viofor JPS Classic device was used in the treatment. It generates a pulsed electromagnetic field with low induction of the extremely low frequency (ELF) range. Average values of electric potentials in the preliminary test were about the same in both groups; they were 148.8 mV and 145.5 mV. After another appliance of ELF fields there was found a steady decline in the average value of electric potentials in the study group. This decrease was statistically highly significant, while mean values of electric potentials in the control group were characterized by a slightly upward tendency. The obtained statistically significant reduction of electric potentials in the oral cavity of patients having metal fillings and metal prosthetic restorations, after application of the Viofor JPS Classic device, implies a huge impact of ELF pulsed electromagnetic field on inhibition of electrochemical processes, as well as on inhibition of dental alloy corrosion. PMID- 23687219 TI - [Cotinine--metabolism, application as a biomarker and the effects on the organism]. AB - This review presents the current state of knowledge on cotinine, the major metabolite of nicotine. Special attention is paid to the formation of this compound in the organism, its metabolism, application in diagnostic procedures and evaluation of its in vitro and in vivo activities. For many years, cotinine has been used as a biomarker of exposure to tobacco smoke. Currently, this compound is applied in many other studies including the use of cotinine in the treatment of various diseases. Several years ago, Scott et al. patented therapeutic applications of cotinine in chronic and acute inflammation. Cotinine is an interesting compound with a well-known metabolism; therefore there are suggestions for its application in the diagnosis and treatment of certain diseases. PMID- 23687220 TI - Analysis of the influence of hormone replacement therapy on TNF-alpha serum levels in menopausal women. AB - OBJECTIVE: The aim of the study was to investigate and compare levels of TNF alpha in serum of menopausal women treated and not treated with hormone replacement therapy (HRT). DESIGN: The study was designed to verify whether there is a correlation between the concentrations of this cytokine and bone mineral density (BMD). MATERIAL/METHODS: The study was carried out on a group of 60 women during menopause - 30 untreated (control group) and 30 treated with HRT (study group). Half of the patients were after natural menopause and the other half were after ovariectomy. Blood samples were collected. Densitometry was conducted on the vertebral column. To evaluate the results of densitometric examination the T score index was calculated. RESULTS: The T-score index of the control group reached values below -2. T-score results for the study group were significantly higher than in the control group. Hormone replacement therapy used by women from the study group caused a decrease in the TNF content in serum, compared with the control group. CONCLUSIONS: Beneficial effects of HRT on bone tissue may be exerted through decreased concentration of TNF-alpha in serum. The use of HRT allows constant bone mineral density to be maintained, which leads to prevention of osteoporotic changes. PMID- 23687221 TI - Development of a method to measure and compare hospital waste: the Premier hospital waste index. AB - The authors developed 15 measures and a comparative index to assist acute care facilities in identifying and monitoring clinical and administrative functions for health care waste reduction. Primary clinical and administrative data were collected from 261 acute care facilities contained within a database maintained by Premier Inc, spanning October 1, 2010, to September 30, 2011. The measures and 4 index models were tested using the Cronbach alpha coefficient and item-to-total and Spearman rank correlations. The final index model was validated using 52 facilities that had complete data. Analysis of the waste measures showed good internal reliability (alpha = .85) with some overlap. Index modeling found that data transformation using the standard deviation and adjusting for the proportional contribution of each measure normalized the distribution and produced a Spearman rank correlation of 0.95. The waste measures and index methodology provide a simple and reliable means to identify and reduce waste and compare and monitor facility performance. PMID- 23687223 TI - Plasma viral microRNA profiles reveal potential biomarkers for chronic active Epstein-Barr virus infection. AB - BACKGROUND: Chronic active Epstein-Barr virus (CAEBV) infection has high mortality and morbidity, and biomarkers for disease severity and prognosis are required. MicroRNAs (miRNAs) are small noncoding RNAs, and EBV encodes multiple miRNAs. Because plasma contains sufficiently stable miRNAs, circulating EBV associated miRNA profiles were investigated as novel biomarkers in CAEBV infection. METHODS: Plasma miRNA expression was assessed for 12 miRNAs encoded within 2 EBV open reading frames (BART and BHRF). Expression levels were investigated in 19 patients with CAEBV infection, 14 patients with infectious mononucleosis, and 11 healthy controls. Relative expression levels of plasma miRNAs were determined by TaqMan probe-based quantitative assay. RESULTS: Plasma miR-BART1-5p, 2-5p, 5, and 22 levels in patients with CAEBV infection were significantly greater than those in patients with infectious mononucleosis and in controls. Plasma miR-BART2-5p, 4, 7, 13, 15, and 22 levels were significantly elevated in patients with CAEBV infection with systemic symptoms, compared with levels in patients with no systemic symptoms. The levels of miR-BART2-5p, 13, and 15 showed clinical cutoff values associated with specific clinical conditions, in contrast to plasma EBV loads. CONCLUSIONS: Levels of specific plasma EBV miRNAs were elevated differentially in patients with CAEBV infection. Several EBV miRNAs, particularly miR-BART2-5p, 13, and 15, are potentially biomarkers of disease severity or prognosis. PMID- 23687222 TI - Clinical and genetic determinants of plasma nevirapine exposure following an intrapartum dose to prevent mother-to-child HIV transmission. AB - OBJECTIVE: Nevirapine is metabolized by cytochrome P450 (CYP) 2B6 and CYP3A4. We characterized relationships between clinical parameters, human genetics, pharmacokinetics, and human immunodeficiency virus type 1 (HIV-1) drug resistance mutations in pregnant women following single-dose intrapartum nevirapine. METHODS: In AIDS Clinical Trials Group study A5207, women received nevirapine at onset of labor and were randomly assigned to receive lamivudine/zidovudine, emtricitabine/tenofovir, or lopinavir/ritonavir for 7 or 21 days. Plasma nevirapine level was quantified on postpartum day 1 and on weeks 1, 3, and 5. We assayed 214 polymorphisms in CYP2B6 and other genes and evaluated associations with pharmacokinetic parameters, including elimination constant, time to protein adjusted 50% inhibitory concentration (IC50), and week 5 nevirapine level below the quantification limit. RESULTS: Among 301 women with evaluable pharmacokinetic and genotype data, lower body mass index and random assignment to receive lopinavir/ritonavir were associated with more rapid nevirapine elimination. Among those of African ancestry, longer time to IC50 was associated with CYP2B6 983T -> C (P = .004) but not with CYP2B6 516G -> T (P = .8). Among Indians, slower nevirapine elimination was associated with CYP2B6 516G -> T (P = .04). Emergent resistance was infrequent and not associated with pharmacokinetics or CYP2B6 genotype. CONCLUSIONS: The effects on plasma drug exposure following single-dose nevirapine may be greater for CYP2B6 983T -> C than for 516G -> T and are less pronounced than at steady state. PMID- 23687225 TI - Population-level antibody estimates to novel influenza A/H7N9. AB - There are no contemporary data available describing human immunity to novel influenza A/H7N9. Using 1723 prospectively collected serum samples in southern Vietnam, we tested for antibodies to 5 avian influenza virus antigens, using a protein microarray. General-population antibody titers against subtype H7 virus are higher than antibody titers against subtype H5 and lower than titers against H9. The highest titers were observed for human influenza virus subtypes. Titers to avian influenza virus antigens increased with age and with geometric mean antibody titer to human influenza virus antigens. There were no titer differences between the urban and the rural location in our study. PMID- 23687224 TI - Microbial translocation and liver disease progression in women coinfected with HIV and hepatitis C virus. AB - BACKGROUND: Microbial translocation has been implicated in the pathogenesis of liver fibrosis and cirrhosis. We sought to determine whether markers of microbial translocation are associated with liver disease progression during coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). METHODS: We measured serial plasma lipopolysaccharide (LPS), endotoxin core antibody, intestinal fatty acid-binding protein (I-FABP), soluble CD14 (sCD14), interleukin 6 (IL-6), interleukin 10, and tumor necrosis factor alpha (TNF-alpha) levels over a 5-year period in 44 HIV/HCV-coinfected women, 21 of whom experienced liver disease progression and 23 were nonprogressors. RESULTS: While LPS levels did not differ significantly over time between progressors and nonprogressors (P = .60), progressors had significantly higher plasma levels of sCD14, a marker of monocyte activation by LPS, at the first time point measured (P = .03) and throughout the study period (P = .001); progressors also had higher IL-6 and I-FABP levels over the 5-year study period (P = .02 and .03, respectively). The associations between progression and sCD14, I-FABP, and IL-6 levels were unchanged in models controlling for HIV RNA and CD4(+) T-cell count. CONCLUSIONS: Although LPS levels did not differ between liver disease progressors and nonprogressors, the association of sCD14, I-FABP, and IL-6 levels with liver disease progression suggests that impairment of gut epithelial integrity and consequent microbial translocation may play a role in the complex interaction of HIV and HCV pathogenesis. PMID- 23687227 TI - A comparative trial of the GlideScope(R) video laryngoscope to direct laryngoscope in children with difficult direct laryngoscopy and an evaluation of the effect of blade size. AB - BACKGROUND: GlideScope(r) video laryngoscope (GVL) has been proposed to be useful for airway management, but its efficacy for difficult airways has not been confirmed in pediatric patients. In this study, we evaluated the usefulness of the GVL for improving the laryngoscopic view in patients whose Cormack and Lehane grade (C&L grade) was >=3 under direct laryngoscopy. We also assessed the effect of GVL blade size on the laryngoscopic view. METHODS: This randomized open trial was conducted in a tertiary pediatric center. Patients whose previous C&L grade was >=3, or who were anticipated to have a difficult airway, were enrolled. The initial modified C&L grade was scored using a direct laryngoscope (DL). If the patient's C&L grade was >=3, the laryngoscopic view was scored again using GVLw (selected based on weight) and GVLs (1 size smaller than GVLw) in random order by a single experienced anesthesiologist. All laryngoscopic views were graded both with and without the backward, upward, and right lateral displacement of the thyroid cartilage (BURP) maneuver. The primary outcome was the difference in the C&L grade between DL and GVLw, and the secondary outcome was that between GVLw and GVLs. For statistical analysis, the modified C&L grade was converted to an ordinal scale. RESULTS: Data from 23 pediatric patients were analyzed. When compared with DL, improvement of laryngoscopic view with the GVLw wa not obvious (98.3% confidence interval [CI] for differences of ordinal scale, 0-1 without BURP, P = 0.15 and 0-1 with BURP, P = 0.11). However, GVLs improved the laryngoscopic view in comparison with both DL (98.3% CI for differences, 3.5-5.0 without BURP, P = 0.00007 and 3.5-4.5 with BURP, P = 0.0001) and GVLw (98.3% CI for differences, 3.0-4.5 without BURP, P = 0.00007 and 2.5-4.0 with BURP, P = 0.0001). There was no adverse outcome during this study. CONCLUSIONS: In patients with C&L grade >=3 under direct laryngoscopy, GVLs significantly improved the laryngoscopic view when compared with DL or GVLw. The GVLs is recommended for improving the laryngoscopic view in patients with a difficult airway. PMID- 23687226 TI - Role of intestinal mucosal integrity in HIV transmission to infants through breast-feeding: the BAN study. AB - BACKGROUND: Increased intestinal permeability may be one of the mechanisms of transmission of human immunodeficiency virus (HIV) to infants through breast feeding. Intestinal permeability correlates with microbial translocation, which can be measured through quantification of bacterial lipopolysaccharide (LPS). METHODS: We evaluated levels of plasma LPS (by the Limulus amebocyte lysate assay) and immune activation markers in serial specimens from infants exposed to but uninfected with HIV and infants infected with HIV from the Breastfeeding, Antiretrovirals, and Nutrition (BAN) study. RESULTS: Plasma LPS levels increased after infants in the BAN study were weaned from the breast, at 24 weeks of age. Cotrimoxazole prophylaxis was associated with higher plasma LPS levels (P = .004). Infants with HIV infection had higher LPS levels, compared with uninfected infants (P = .004). Higher preinfection plasma LPS levels were a significant predictor of infant HIV infection through breast-feeding (hazard ratio = 1.60 for every unit increase in plasma LPS level; P = .01) and of lower infant length-for age z scores (P = .02). CONCLUSIONS: These findings suggest that disruption in intestinal integrity is a mechanism of HIV transmission to infants through breast feeding. Weaning from breast milk and use of antibiotic prophylaxis was associated with increased levels of microbial translocation, which could facilitate HIV entry through the intestine. Complementary approaches to enhance intestinal mucosal integrity in the infant may further reduce breast-feeding transmission of HIV. PMID- 23687228 TI - The impact of video laryngoscopy use during urgent endotracheal intubation in the critically ill. AB - BACKGROUND: The video laryngoscope (VL) has been shown to improve laryngoscopic views and first-attempt success rates in elective operating room and simulated tracheal intubations compared with the direct laryngoscope (DL). However, there are limited data on the effectiveness of the VL compared with the DL in urgent endotracheal intubations (UEIs) in the critically ill. We assessed the effectiveness of using a VL as the primary intubating device during UEI in critically ill patients when performed by less experienced operators. METHODS: We compared success rates of UEIs performed by Pulmonary and Critical Care Medicine (PCCM) fellows in the medical intensive care unit and medical or surgical wards. A cohort of PCCM fellows using GlideScope VL as the primary intubating device was compared with a historical cohort of PCCM fellows using a traditional Macintosh or Miller blade DL. The primary measured outcome was first-attempt intubation success rate. Secondary outcomes included total number of attempts required for successful tracheal intubation, rate of esophageal intubation, need for supervising attending intervention, duration of intubation sequence, and incidence of hypoxemia and hypotension. RESULTS: There were 138 UEIs, with 78 using a VL and 50 using a DL as the primary intubating device. The rate of first attempt success was superior with the VL as compared with the DL (91% vs 68%, P < 0.01). The rate of intubations requiring >=3 attempts (4% vs 20%, P < 0.01), unintended esophageal intubations (0% vs 14%, P < 0.01), and the average number of attempts required for successful tracheal intubation (1.2 +/- 0.56 vs 1.7 +/- 1.1, P < 0.01) all improved significantly with use of the VL compared with the DL. CONCLUSIONS: UEI using a VL as the primary device improved intubation success and decreased complications compared with a DL when PCCM fellows were the primary operators. These data suggest that the VL should be used as the primary device when urgent intubations are performed by less experienced operators. PMID- 23687229 TI - The relationship between fibrinogen levels after cardiopulmonary bypass and large volume red cell transfusion in cardiac surgery: an observational study. AB - BACKGROUND: Coagulopathy leading to excessive blood loss and large volume red cell transfusion is a frequent complication of cardiac surgery with cardiopulmonary bypass (CPB) that may be caused by low perioperative fibrinogen levels. We explored the relationship between post-CPB fibrinogen levels and large volume red cell transfusion. METHODS: Patients who underwent cardiac surgery with CPB from 2005 to 2011 at a single institution and had a fibrinogen level measured after CPB were included in this retrospective observational study. The relationship between post-CPB fibrinogen levels and large volume red cell transfusion (defined as >=5 units transfused on the day of or the day after surgery) was assessed by cubic spline function and receiver operating characteristic analyses. The independent relationship between fibrinogen levels and large volume transfusion was assessed by multivariable logistic regression and propensity score analyses. RESULTS: In the 4606 patients included, the probability of large volume transfusion increased when fibrinogen levels decreased below approximately 2.0 g/L. Using <2.0 g/L as the threshold for low fibrinogen, 1918 (42%) were categorized into the low fibrinogen group, of whom 363 (18.9%) had large volume transfusion compared with 164 (13.5%) of the 2688 patients whose fibrinogen level was >=2.0 g/L (P < 0.0001). In the low fibrinogen group, the unadjusted odds ratio (95% confidence interval) for large volume transfusion was 1.5 (1.3-1.7). The risk-adjusted odds ratio obtained by logistic regression was 1.8 (1.4-2.2) and by propensity score methods was 1.5 (1.2-2.0). CONCLUSIONS: While this study was not equipped to detect the critical fibrinogen level in bleeding patients, its results suggest that current recommendations that fibrinogen replacement not be initiated in bleeding patients unless fibrinogen levels decrease below 0.8 to 1.0 g/L may be too conservative. Randomized trials are needed to determine whether maintaining higher fibrinogen levels in bleeding patients can reduce blood loss and transfusions and by that means improve clinical outcomes in cardiac surgery. PMID- 23687230 TI - Case report: profound hypotension after anesthetic induction with propofol in patients treated with rifampin. AB - Rifampin is commonly used for the treatment of tuberculosis and staphylococcal infections, as well as for prevention of infection in cardiac valve and bone surgeries. We report a case of profound hypotension after anesthesia induction with propofol in a patient who was treated with two 600 mg doses of rifampin for prophylaxis of infection before surgery. In a retrospective case-control study of 75 patients, we confirmed this potentially serious drug-drug interaction. After rifampin, there was a significant and prolonged arterial blood pressure reduction when patients received propofol, but not thiopental. PMID- 23687231 TI - The relationship of intravenous dextrose administration during emergence from anesthesia to postoperative nausea and vomiting: a randomized controlled trial. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) may occur despite antiemetic prophylaxis and is associated with unanticipated hospital admission, financial impact, and patient dissatisfaction. Previous studies have shown variable impact of IV dextrose on PONV. We sought to determine the relationship of IV dextrose administered during emergence from anesthesia to PONV. METHODS: This was a prospective, double-blind randomized placebo-controlled trial. Adult female ASA physical status I and II nondiabetic patients scheduled for outpatient gynecologic, urologic, or breast surgery were randomly assigned to infusion of 250 mL lactated Ringer's solution (group P; n = 75) or dextrose 5% in lactated Ringer's solution (group D; n = 87) over 2 hours beginning with surgical closing. Blood glucose was determined using a point-of-care device before transfer to the operating room, in the operating room immediately before study fluid infusion, and in the recovery room after study fluid infusion. No antiemetics were given before arrival in the recovery room. PONV scores were recorded at 0, 30, 60, and 120 minutes and 24 hours after arrival in the recovery room. Medication administration was recorded. RESULTS: Data from 162 patients with normal baseline blood glucose were analyzed. There were no significant intergroup differences in demographics, history of PONV, or tobacco use. There was no significant intergroup difference in PONV during the first 2 hours after anesthesia (group D 52.9% vs group P 46.7%; difference, 6.2%; 95% confidence interval [CI], -9.2% to 21.6%; P = 0.43). Patients in groups D or P who developed PONV within 2 hours of anesthesia had similar number of severity scores >=1 during recovery stay (1.5 vs 1.0; difference, 0; 95% CI, 0%-0%; P = 0.93); and similar proportions of: PONV onset within 30 minutes of recovery room arrival (65.2% vs 57.1%; difference, 8.1%; 95% CI, -13.1% to 28.8%; P = 0.46); more than 1 dose of antiemetic medication (56.5% vs 62.9%; difference, 6.3%; 95% CI, -26.9% to 15.1%; P= 0.65); or more than 1 class of antiemetic medication (50.0% vs 54.3%; difference, 4.3%; 95% CI, -25.5% to 17.4%; P = 0.82). CONCLUSIONS: The administration of dextrose during emergence from anesthesia was not associated with a difference in the incidence of PONV exceeding 20% or in the severity of PONV in the first 2 hours after anesthesia. The relationship between PONV and the optimal dose and timing of IV dextrose administration remains unclear and may warrant further study. PMID- 23687232 TI - The prevalence of burnout and depression and their association with adherence to safety and practice standards: a survey of United States anesthesiology trainees. AB - BACKGROUND: The prevalence of burnout and depression in anesthesiology residents has not been determined. It is also unknown whether anesthesiology resident burnout/depression may affect patient care and safety. The primary objective of this study was to determine the prevalence of burnout and depression in anesthesiology residents in the United States. We hypothesized that residents at high risk of burnout and/or depression would report more medical errors as well as a lower rate of following principles identified as the best practice of anesthesiology. METHODS: A cross-sectional survey was sent to 2773 anesthesiology residents in the United States. The questionnaire was divided into 5 parts examining trainees' demographic factors, burnout (Maslach Burnout Inventory), depression (Harvard depression scale), 10 questions designed to evaluate best practice of anesthesiology, and 7 questions evaluating self-reported errors. Best practices and self-reported error rates were compared among subjects with a high risk of burnout only, high risk of depression only, high risk of burnout and depression, and low risk of burnout and depression. Pairwise comparisons were considered significant at P < 0.004 and confidence intervals (CIs) reported at 99.6%. RESULTS: There were 1508 (54%) resident responds. High burnout risk was found in 41% (575 of 1417) of respondents. Working >70 hours per week, having >5 drinks per week, and female gender were associated with increased burnout risk. Twenty-two percent (298 of 1384) screened positive for depression. Working >70 hours of work per week, smoking, female gender, and having >5 drinks per week were associated with increased depression risk. Two hundred forty (17%) respondents scored at high risk of burnout and depression, 321 (23%) at high risk of burnout, 58 (4%) at high risk of depression only, and 764 (56%) at low risk of burnout or depression. Median best practice scores (maximum = 30) for residents at high risk of burnout (difference -2; 99.6% CI, -1 to -2; P < 0.001) or high risk of burnout and depression (difference -4; 99.6% CI, -3 to -6; P < 0.001) were lower than scores of residents at low risk for burnout or depression. Thirty three percent of respondents with high burnout and depression risk reported multiple medication errors in the last year compared with 0.7% of the lower-risk responders (P < 0.001). CONCLUSION: Burnout, depression, and suicidal ideation are very prevalent in anesthesiology residents. In addition to effects on the health of anesthesiology trainees, burnout and depression may also affect patient care and safety. PMID- 23687233 TI - Incidence of intraoperative hypoxemia in children in relation to age. AB - BACKGROUND: Although respiratory problems are by far the most frequent complications of pediatric anesthesia, there are currently no reliable data on the incidence of perioperative hypoxemia in children. Most studies investigating the incidence of pediatric respiratory complications were based on self-report. METHODS: We studied the incidence of intraoperative hypoxemia as well as that of pulse oximeter artifacts prospectively in 575 pediatric noncardiac surgery patients aged between 0 and 16 years operated in a tertiary pediatric university hospital. Subsequently, the incidence of intraoperative hypoxemia was determined retrospectively in 8277 patients registered in an anesthesia information management system (AIMS) of the same hospital. RESULTS: In the prospective cohort, at least 1 episode of oxygen saturation (Spo2) <= 90% for at least 1 minute occurred in 69 of 575 cases (12%; 95% confidence interval [CI], 9%-15%). Furthermore, in 35 of 575 (6%; 95% CI, 4%-8%) cases at least 1 true hypoxemic event was observed. In total, 117 episodes of Spo2 <= 90% were observed in the prospective study, of which 3 of 117 could not be specified and 67 of 114 (54%; 95% CI, 42%-65%) episodes were classified as true hypoxemia. False-positive low Spo2 values were mainly caused by dislodgment of the pulse oximeter. In the retrospective analysis, Spo2 <= 90% and Spo2 <= 80% for at least 1 minute were documented in the AIMS in 18% (95% CI, 17%-19%) and 7.5% (95% CI, 7%-8%) of the cases, respectively; 31 and 10 episodes per 100 cases, respectively. The incidence of hypoxemia increased in younger age groups: Spo2 <= 90% for at least 1 minute occurred in 56% (95% CI, 49%-63%) of neonates (170 episodes per 100 cases). CONCLUSIONS: The incidence of intraoperative hypoxemia increased with younger age, with the highest incidence in neonates. Because of the high artifact rate, unvalidated pulse oximeter data in AIMS should be interpreted with caution because only up to 65% of all hypoxemic episodes recorded during pediatric anesthesia were caused by true hypoxia. PMID- 23687234 TI - A retrospective identification of gastroesophageal reflux disease as a new risk factor for surgical site infection in cerebral palsy patients after spine surgery. AB - BACKGROUND: Neuromuscular scoliosis is a known risk factor for surgical site infection (SSI) after spinal fusion, with reported infection rates as high as 11.2%. Although risk factors such as antibiotic timing have been previously addressed, our objective was to identify intrinsic risk factors for SSI in cerebral palsy (CP) patients with neuromuscular scoliosis. We hypothesized that CP patients who develop SSI after spine fusion would have a risk profile similar to those who develop nosocomial infection. METHODS: We retrospectively analyzed records from patients with CP who developed infections after spinal fusion from January 1998 until July 2008, who were identified by our Infection Control Officer using National Nosocomial Infection Surveillance System criteria (N = 34). Demographically and procedurally matched controls without infection were identified from our spine database (N = 37). We compared these groups for gastroesophageal reflux disease (GERD), use of gastric acid inhibitors, presence of preoperative decubitus ulcer, previous infection, and postoperative ventilation. Multivariable logistic regression was then performed to assess the relative contributions of the predictors to "deep infection" and "any infection." RESULTS: Of 30 evaluable infected patients, 70% had incisional SSI. Although many of the infections were polymicrobial, the most common pathogens identified were Gram-negative bacilli. Many significant predictors were identified by univariable logistic regression for any infection and deep infection. Multivariable logistic regression found a significant effect only for GERD (odds ratio, 6.4; 95% confidence interval, 1.9-21.3; P = 0.002) for any infection, whereas the effect of therapy with gastric acid inhibitors did not reach statistical significance (odds ratio, 6.1 [95% confidence interval, 0.84-44.6]; P = 0.07). No significant interaction between the 2 factors was detected. Among our controls and infected patients altogether, 46.3% had GERD. CONCLUSIONS: We show that GERD increases the risk for infection in CP patients after spine fusion. Prospective multicenter studies are necessary to further validate the predictive value of this risk factor. PMID- 23687235 TI - The accuracy and responsiveness of continuous noninvasive arterial pressure during rapid ventricular pacing for transcatheter aortic valve replacement. AB - BACKGROUND: The accuracy of measurement of the continuous noninvasive arterial blood pressure (CNAP) technique is unknown during sudden cardiocirculatory arrest. METHODS: In 33 patients undergoing elective transfemoral aortic valve implantation procedures under analgesic sedation, invasive arterial blood pressure (IAP) was compared with a CNAP device during episodes of severe hypotension (functional cardiocirculatory arrests by rapid pacing) and the remaining time without severe hypotension. Systolic, diastolic, and mean pairs of blood pressure measurements were extracted for both groups and were analyzed by Bland-Altman plots. The responsiveness of the CNAP technique was assessed in the various phases of severe hypotension concerning time and amplitude of changes. RESULTS: Overall CNAP accuracy (bias), calculated by subtracting IAP from CNAP, was -6.3 +/- 18.9, 7.4 +/- 10.5, and 4.0 +/- 11.3 mm Hg (mean +/- SD, systolic, diastolic, and mean). Bias increased during episodes of severe hypotension to 11.8 +/- 14.5, 13.8 +/- 12.4, and 12.9 +/- 12.4 mm Hg. The percentage of agreements (95% confidence interval) between the blood pressure pairs with a difference <=15 mm Hg was 58.5% (57.9-58.6), 75.8% (75.5-76.0), 82.2% (81.9-82.4; systolic, diastolic, mean) for all data and 56.4% (54.2-58.9; P = 0.71), 53.2%* (51.1-56.0), and 57.4%* (56.3-59.1; *P < 0.001) during rapid pacing. The responsiveness of mean CNAP and mean IAP did not differ significantly during the various phases of rapid pacing. CONCLUSIONS: The stand-alone CNAP monitor (model 500at, software V3.5) accurately and rapidly measures the changes of blood pressure that occur during sudden development of cardiocirculatory arrest and recovery to baseline blood pressures. CNAP monitors the duration of the arrest. PMID- 23687236 TI - Echo rounds: intraoperative diagnosis of transient pseudo-severe aortic stenosis. PMID- 23687237 TI - Application of Facebook "likes" as an indicator of quality in health care in public hospitals: barriers and opportunities in Peru. PMID- 23687238 TI - An integrated health care system's approach to development of a process to collect patient functional outcomes on total joint replacement procedures. AB - Health care organizations are challenged to find ways to measure not only process of care but also outcomes of care. Gundersen Health System's Orthopaedic Surgery Department in the La Crosse, Wisconsin area developed a process to collect outcomes of care for patients having hip or knee arthroplasty procedures and planned to use these data to determine impact on patients' lives. The Hip Osteoarthritis Outcomes Score and Knee Osteoarthritis Outcomes Score, adapted from the widely used Western Ontario and McMaster Universities Osteoarthritis Index, were collected preoperatively and at 1 year postoperatively. From these data, the health system determined that patients were experiencing significant improvement in 4 of 5 scales. Further recommendations include evaluating the impact of patients' age, sex, and preoperative body mass index on outcomes, as well as evaluating the impact of more patient involvement in goal setting on recovery time and functional outcomes. PMID- 23687239 TI - Postdischarge focus groups to improve the hospital experience. PMID- 23687240 TI - Emergency department utilization as a measure of physician performance. AB - Visits to the emergency department (ED) are costly, and because some of them are potentially avoidable, some types of ED visits also may be indicative of poor care management, inadequate access to care, or poor choices on the part of beneficiaries. Billings and colleagues developed an algorithm to analyze ED visits and assign probabilities that each visit falls into several categories of appropriateness. The algorithm has been used previously to assess the appropriateness of ED visits at the community or facility level. In this analysis, the authors explain how the Billings algorithm works and how it can be applied to individual physician practices. The authors then present illustrative data from 2 years of Medicare claims data from 5 states. About one third of ED visits are deemed appropriate, and about half could have been treated in a primary care outpatient setting. Another 15% were deemed preventable or avoidable. PMID- 23687241 TI - CT-detected intracranial hemorrhage among patients with head injury in Lagos, Nigeria. AB - PURPOSE: To evaluate the computed tomography (CT) findings of intracranial hemorrhage among patients with head trauma in Lagos, Nigeria. METHODS: In this retrospective, cross-sectional study, a convenience sample of 500 patients with head trauma who had diagnostic cranial CT scans was selected. All the radiological reports and CT scans of patients with head trauma were retrieved in the hospitals selected as study sites. The reports were sorted into 2 groups - normal findings and intracranial bleeding. The reports of intracranial bleeding were sorted again into different classes of intracranial bleeding as identified by the radiologist who reported it. All data were analyzed using the Epi Info public domain software package. The chi-square test was used to measure the statistical significance of study results at P < .05. RESULTS: Most of the study subjects (68%) were men. Traffic accidents accounted for 44% of all the head traumas found in the study, and 58% of the head traumas resulted in intracranial bleeding. Among the hemorrhages found, 37% were intracerebral, 25% were subdural, 16% were intraventricular, 15% were subarachnoid, and 7% were epidural. DISCUSSION: Intracranial hemorrhage was a common consequence of acute head trauma sustained from traffic accidents in the population studied, with intracerebral hemorrhage being the most prevalent type. CONCLUSION: Traffic accidents are the main cause of acute head trauma in Lagos, Nigeria. The use of CT for early diagnosis of intracranial hemorrhage appears justifiable. PMID- 23687242 TI - Understanding HPV and the future implications of contracting the virus. AB - PURPOSE: To determine the level of knowledge university freshmen have of the human papillomavirus (HPV), including awareness of the virus, the associated risks, and prevention. METHODS: A multiple-choice questionnaire was sent electronically to all freshman-level students registered at Texas State University. One-way ANOVA and Spearman correlation coefficients were run to identify significant differences in knowledge levels between sex, age, and ethnicity. RESULTS: Statistical analyses identified no strong differentiation of knowledge about HPV among students. This indicated that increased education on the subject of HPV was needed by all of the students without regard to sex, ethnicity, age, or self-identified history of HPV education. DISCUSSION: Knowledge level of HPV risks, prevention, transmission, and progression seemed high in some areas and low in others. Most students understand that cervical cancer is a risk associated with HPV; however, many students were unaware that head and neck, anal, and penile cancer also are associated with infection. Knowledge levels seem to be consistent among students of both genders and various ethnicities. CONCLUSION: Student knowledge of HPV has increased since the introduction of the HPV vaccine and related media coverage, although knowledge on the subject is still low and often inaccurate. Because college-aged students are at a higher risk of contracting the virus, educational measures must be taken to ensure all students are aware of the risks and are better prepared to protect themselves. PMID- 23687243 TI - Occupational radiation safety. AB - Radiation has the power to both save and harm lives. Radiologic technologists use radiation to provide quality medical imaging, but they must be aware of potential exposure to radiation's detrimental effects. When proper time, distance, and shielding techniques are used, dangerous exposure levels can be avoided. Protection techniques are even more important for a pregnant radiologic technologist, who must safeguard her fetus from exposure. With an employer's cooperation and appropriate protection in place, a pregnant technologist should be able to work in a radiology setting without harming her fetus. PMID- 23687244 TI - Cystic fibrosis. AB - Cystic fibrosis is an autosomal recessive genetic disorder that affects ion transport in exocrine glands. Inadequate ion transport causes dehydration and the production of thick secretions in organs such as the lungs, sinuses, pancreas, intestines, hepatobiliary tree, and vas deferens. Although cystic fibrosis usually is diagnosed through a sweat chloride test, medical imaging is used to monitor pathologic changes caused by the disease. This article discusses the respiratory and nonrespiratory manifestations of cystic fibrosis and describes the diagnosis and treatment of the disease. Because patients with cystic fibrosis tend to be young children, the article also covers ways to minimize radiation exposure from repeated imaging examinations. PMID- 23687245 TI - Image quality and the changing culture in medical imaging. PMID- 23687246 TI - A curious place to store a CD. PMID- 23687248 TI - A Look at Superman's X-ray Vision. PMID- 23687249 TI - The technologist's role in patient safety and quality in medical imaging. PMID- 23687250 TI - Institutional vs programmatic accreditation. PMID- 23687251 TI - Brain teaser. PMID- 23687252 TI - Breast implants: history, safety, and imaging. AB - Breast implants are classified as medical devices because they are used to correct the size or shape of a woman's natural breast or to create a new breast after mastectomy. Breast augmentation is the most popular cosmetic surgery performed in the United States today. Over the decades, breast implants have been constructed using different types of materials, including sponges, silicone, and saline. Each type of implant has advantages and disadvantages, and all pose a challenge in breast imaging. Breast implant rupture is common and has hidden characteristics that pose challenges for radiologic technologists and physicians. This article provides detailed information on breast reconstruction, implant safety, imaging techniques, and the latest implant materials. PMID- 23687253 TI - Computed tomography colonography. AB - Colorectal cancer is a leading cause of cancer morbidity and mortality in the United States. CT colonography, frequently referred to as "virtual colonoscopy," plays an increasingly important role in the screening and characterization of colorectal cancer, as well as the surveillance of suspicious polyps and post treatment monitoring. This article describes the epidemiology, pathobiology, diagnosis, and treatment of colorectal cancer, and the roles of CT colonography and other imaging modalities in screening, surveillance, staging, and post treatment monitoring. CT colonography techniques, including patient preparation, fecal tagging, colon insufflation (inflation), and the emerging technology of computer-aided detection also are covered. PMID- 23687256 TI - Obesity explains gender differences in the association between education level and metabolic syndrome in South Korea: the results from the Korean National Health and Nutrition Examination Survey 2010. AB - This study aimed to examine the association of educational level with metabolic syndrome (MS) and its risk factors by gender in South Korea. A total of 6178 participants aged 20 years or older from The Fifth Korean National Health and Nutrition Examination Survey were included in this study. A generalized linear model and adjusted proportion were used to identify educational disparities in MS, its components, and its risk factors (smoking, high-risk alcohol consumption, obesity, and stress). In women, a clearly inverse association between education level and MS were observed with significant trend, and the decreasing trends of all risk factors across education quartiles were in line with the inverse association. However, the association between education level and MS was not observed with a significant trend among men. An opposite trend of risk factors across education levels was shown in men, with an increasing trend for obesity and decreasing trends for smoking and high-risk alcohol consumption. These findings demonstrate that obesity can explain gender differences in the association between education level and MS in South Korea. PMID- 23687257 TI - Prevalence and demographic distribution of adult survivors of child abuse in Japan. AB - A cross-sectional study was conducted with a national epidemiological survey to investigate the prevalence and demographic distribution of adult survivors of child abuse in Japan. A self-administered questionnaire was used to measure the history of child abuse and the demographic characteristics. The participants reported the following 4 types of child abuse: physical abuse (3%), sexual abuse (0.6%), neglect (0.8%), and psychological abuse (4%). Significant unequal distribution of child abuse was found to be associated with sex, living region, marital status, job status, and educational status. We determined the prevalence of adult survivors of child abuse in Japan and found that their demographic characteristics were unequally distributed. Policy makers and public health providers should take these demographic disparities into account in considering effective public health interventions for survivors of child abuse. PMID- 23687258 TI - Symptoms of posttraumatic stress disorder, depression, and anxiety among junior high school students in worst-hit areas 3 years after the Wenchuan earthquake in China. AB - The aim of this study was to examine symptoms of posttraumatic stress disorder (PTSD), depression, and anxiety among junior high school students in worst-hit areas 3 years after the Wenchuan earthquake. Analyses were carried out on 373 of the 377 students enrolled. In addition to obtaining demographic characteristics, the Impact of Event Scale-Revised, the Zung Self-rating Depression Scale, the Zung Self-rating Anxiety Scale, and an Earthquake exposure screening scale were administered. It was found that 29.6%, 44.8%, and 37.6% of participants reported clinical symptoms of PTSD, depression, and anxiety, respectively. PTSD, depression, and anxiety were highly comorbid. Having witnessed someone being killed, family members being killed, close friends seriously injured or being killed, and felt scared remained as significant predictors for PTSD. Having witnessed someone seriously injured and felt scared remained as significant predictors for depression. Having witnessed someone seriously injured, witnessed someone being killed, and felt scared remained as significant predictors for anxiety. PMID- 23687259 TI - A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. AB - OBJECTIVES: To compare the pharmacokinetics (PK), safety and efficacy of innovator infliximab (INX) and CT-P13, a biosimilar to INX, in patients with active ankylosing spondylitis (AS). METHODS: Phase 1 randomised, double-blind, multicentre, multinational, parallel-group study. Patients were randomised to receive 5 mg/kg of CT-P13 (n=125) or INX (n=125). Primary endpoints were area under the concentration-time curve (AUC) at steady state and observed maximum steady state serum concentration (Cmax,ss) between weeks 22 and 30. Additional PK, efficacy endpoints, including 20% and 40% improvement response according to Assessment in Ankylosing Spondylitis International Working Group criteria (ASAS20 and ASAS40), and safety outcomes were also assessed. RESULTS: Geometric mean AUC was 32 765.8 MUgh/ml for CT-P13 and 31 359.3 MUgh/ml for INX. Geometric mean Cmax,ss was 147.0 MUg/ml for CT-P13 and 144.8 MUg/ml for INX. The ratio of geometric means was 104.5% (90% CI 94% to 116%) for AUC and 101.5% (90% CI 95% to 109%) for Cmax,ss. ASAS20 and ASAS40 responses at week 30 were 70.5% and 51.8% for CT-P13 and 72.4% and 47.4% for INX, respectively. In the CT-P13 and INX groups more than one adverse event occurred in 64.8% and 63.9% of patients, infusion reactions occurred in 3.9% and 4.9%, active tuberculosis occurred in 1.6% and 0.8%, and 27.4% and 22.5% of patients tested positive for anti-drug antibodies, respectively. CONCLUSIONS: The PK profiles of CT-P13 and INX were equivalent in patients with active AS. CT-P13 was well tolerated, with an efficacy and safety profile comparable to that of INX up to week 30. PMID- 23687260 TI - A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. AB - OBJECTIVES: To compare the efficacy and safety of innovator infliximab (INX) and CT-P13, an INX biosimilar, in active rheumatoid arthritis patients with inadequate response to methotrexate (MTX) treatment. METHODS: Phase III randomised, double-blind, multicentre, multinational, parallel-group study. Patients with active disease despite MTX (12.5-25 mg/week) were randomised to receive 3 mg/kg of CT-P13 (n=302) or INX (n=304) with MTX and folic acid. The primary endpoint was the American College of Rheumatology 20% (ACR20) response at week 30. Therapeutic equivalence of clinical response according to ACR20 criteria was concluded if the 95% CI for the treatment difference was within +/-15%. Secondary endpoints included ACR response criteria, European League Against Rheumatism (EULAR) response criteria, change in Disease Activity Score 28 (DAS28), Medical Outcomes Study Short-Form Health Survey (SF-36), Simplified Disease Activity Index, Clinical Disease Activity Index, as well as pharmacokinetic (PK) and pharmacodynamic (PD) parameters, safety and immunogenicity. RESULTS: At week 30, ACR20 responses were 60.9% for CT-P13 and 58.6% for INX (95% CI -6% to 10%) in the intention-to-treat population. The proportions in CT-P13 and INX groups achieving good or moderate EULAR responses (C reactive protein (CRP)) at week 30 were 85.8% and 87.1%, respectively. Low disease activity or remission according to DAS28-CRP, ACR-EULAR remission rates, ACR50/ACR70 responses and all other PK and PD endpoints were highly similar at week 30. Incidence of drug-related adverse events (35.2% vs 35.9%) and detection of antidrug antibodies (48.4% vs 48.2%) were highly similar for CT-P13 and INX, respectively. CONCLUSIONS: CT-P13 demonstrated equivalent efficacy to INX at week 30, with a comparable PK profile and immunogenicity. CT-P13 was well tolerated, with a safety profile comparable with that of INX. CLINICALTRIALS.GOV IDENTIFIER: NCT01217086. PMID- 23687261 TI - Primary Sjogren's syndrome and malignancy risk: a systematic review and meta analysis. AB - OBJECTIVE: To investigate the association between primary Sjogren's syndrome (pSS) and the risks of malignancy including overall malignancy and site-specific malignancies through a systematic review and meta-analysis. METHODS: We searched Pubmed before January 2013, with a restriction to English language publications. Studies were included if they met the following criteria: (1) a cohort or observational study; (2) pSS as one of the exposure interests; (3) cancer as an outcome of interest; (4) relative risk (RR) or standardised incidence rate (SIR) with 95% CIs. We used a random or fixed effects model to calculate the pooled RR according to the heterogeneity test. RESULTS: Fourteen studies involving more than 14 523 patients with pSS were included. Compared with the general population, patients with pSS had significantly increased risks of overall cancer (pooled RR 1.53; 95% CI 1.17 to 1.88), non-Hodgkin lymphoma (NHL) (pooled RR 13.76; 95% CI 8.53 to 18.99) and thyroid cancer (pooled RR 2.58; 95% CI 1.14 to 4.03). A significant association was found in various subgroup meta-analyses for NHL but, for overall malignancy, a significant association was only found in some groups. Additionally, the number of studies exploring the association of pSS with the risk of solid malignancies was so small that we could not carry out subgroup meta-analyses. CONCLUSIONS: This meta-analysis indicates that pSS is significantly associated with increased risks of overall malignancy, NHL and thyroid cancer. However, it is not yet known whether the apparent increased risk of overall malignancy in patients with pSS is due to the relatively high prevalence of NHL in that group. PMID- 23687263 TI - Autoantibodies against CD74 in spondyloarthritis. AB - BACKGROUND: Spondyloarthritis (SpA) is a common debilitating inflammatory disorder. Establishing the diagnosis is often difficult, since abnormalities in conventional X-ray develop with a latency of several years and only HLA-B27 is used as a laboratory marker. The goal of our study was to identify new autoantibodies as diagnostic markers of SpA. METHODS: Protein array technology was used to screen for new autoantigens in ankylosing spondylitis. Then, the results were confirmed by ELISA using Class II-associated invariant chain peptide domain of CD74 as antigen. Sera for the ELISA were obtained from 216 patients with axial (n=156) and peripheral (n=60) SpA. Sera of patients with psoriatic arthritis without axial involvement as another subtype of peripheral SpA, rheumatoid arthritis, systemic lupus erythematosus, HIV infection and blood donors served as controls. All donors provided informed consent for the study which was approved by the local ethics committee (project number 4928). RESULTS: Using protein arrays, we detected IgG antibodies against CD74 in SpA sera. Using ELISA technology on sera that had previously been frozen for several years, IgG autoantibodies against CD74 were found in 67% of the SpA patients and were even more frequent in patients with a short disease duration. In the controls, the prevalence of the new autoantibodies was 18/40 (45%) in psoriatic arthritis without axial involvement, 9/80 (11%) in rheumatoid arthritis, 6/40 (15%) in systemic lupus erythematosus, 1/40 (2.5%) in HIV and 1/125 (0.8%) in blood donors. CONCLUSIONS: Antibodies against CD74 could provide an important additional tool for diagnosis of SpA. PMID- 23687264 TI - Production of the cannibalism toxin SDP is a multistep process that requires SdpA and SdpB. AB - During the early stages of sporulation, a subpopulation of Bacillus subtilis cells secrete toxins that kill their genetically identical siblings in a process termed cannibalism. One of these toxins is encoded by the sdpC gene of the sdpABC operon. The active form of the SDP toxin is a 42-amino-acid peptide with a disulfide bond which is processed from an internal fragment of pro-SdpC. The factors required for the processing of pro-SdpC into mature SDP are not known. We provide evidence that pro-SdpC is secreted via the general secretory pathway and that signal peptide cleavage is a required step in the production of SDP. We also demonstrate that SdpAB are essential to produce mature SDP, which has toxin activity. Our data indicate that SdpAB are not required for secretion, translation, or stability of SdpC. Thus, SdpAB may participate in a posttranslation step in the production of SDP. The mature form of the SDP toxin contains a disulfide bond. Our data indicate that while the disulfide bond does increase activity of SDP, it is not essential for SDP activity. We demonstrate that the disulfide bond is formed independently of SdpAB. Taken together, our data suggest that SDP production is a multistep process and that SdpAB are required for SDP production likely by controlling, directly or indirectly, cleavage of SDP from the pro-SdpC precursor. PMID- 23687262 TI - Evidence of NLRP3-inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3-inflammasome complex in relation to susceptibility to RA and response to anti-TNF treatment. AB - BACKGROUND: The NLRP3-inflammasome, implicated in the pathogenesis of several inflammatory disorders, has been analysed in rheumatoid arthritis (RA). METHODS: Relative gene expression of NLRP3-inflammasome components was characterised in PBMCs of 29 patients receiving infliximab. A total of 1278 Caucasian patients with RA from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) cohort receiving tumour necrosis factor (TNF) antagonists (infliximab, adalimumab and etanercept) were genotyped for 34 single nucleotide polymorphisms (SNPs), spanning the genes NLRP3, MEFV and CARD8. Regression analyses were performed to test for association between genotype and susceptibility and treatment response (disease activity score across 28 joints (DAS28) and EULAR improvement criteria) at 6 months, with secondary expression quantitative trait loci (eQTL) analyses. RESULTS: At baseline, gene expression of ASC, MEFV, NLRP3-FL, NLRP3-SL and CASP1 were significantly higher compared with controls whereas CARD8 was lower in the patients. Caspase-1 and interleukin-18 levels were significantly raised in patients with RA. SNPs in NLRP3 showed association with RA susceptibility and EULAR response to anti-TNF in the BRAGGSS cohort, and in monocytes but not B cells, in eQTL analysis of 283 healthy controls. CARD8 SNPs were associated with RA susceptibility and DAS28 improvement in response to anti-TNF and eQTL effects in monocytes and B cells. CONCLUSIONS: This study found evidence of modulation of the NLRP3-inflammasome in patients with RA prior to receiving infliximab and some evidence of association for SNPs at NLRP3 and CARD8 loci with RA susceptibility and response to anti-TNF. The SNPs associated with susceptibility/response are not the main eQTL variants for either locus, and the associations with treatment response require replication in an independent cohort. PMID- 23687265 TI - Temporal expression program of quorum sensing-based transcription regulation in Sinorhizobium meliloti. AB - The Sin quorum sensing (QS) system of S. meliloti activates exopolysaccharide and represses flagellum production. The system consists of an N-acyl-homoserine lactone (AHL) synthase, SinI, and at least two LuxR-type regulators, SinR and ExpR. SinR appears to be independent of AHLs for its control of sinI expression, while ExpR is almost completely dependent upon AHLs. In this study, we confirmed 7 previously detected ExpR-DNA binding sites and used the consensus sequence to identify another 26 sites, some of which regulate genes previously not known to be members of the ExpR/AHL regulon. The activities of promoters dependent upon ExpR/AHL were titrated against AHL levels, with varied outcomes in AHL sensitivity. The data suggest a type of temporal expression program whereby the activity of each promoter is subject to a specific range of AHL concentrations. For example, genes responsible for exopolysaccharide production are activated at lower concentrations of AHLs than those required for the repression of genes controlling flagellum production. Several features of ExpR-regulated promoters appear to determine their response to AHLs. The location of the ExpR-binding site with respect to the relevant transcription start within each promoter region determines whether ExpR/AHL activates or represses promoter activity. Furthermore, the strength of the response is dependent upon the concentration of AHLs. We propose that this differential sensitivity to AHLs provides a bacterial colony with a transcription control program that is dynamic and precise. PMID- 23687266 TI - Regulation of the swarming inhibitor disA in Proteus mirabilis. AB - The disA gene encodes a putative amino acid decarboxylase that inhibits swarming in Proteus mirabilis. 5' rapid amplification of cDNA ends (RACE) and deletion analysis were used to identify the disA promoter. The use of a disA-lacZ fusion indicated that FlhD(4)C(2), the class I flagellar master regulator, did not have a role in disA regulation. The putative product of DisA, phenethylamine, was able to inhibit disA expression, indicating that a negative regulatory feedback loop was present. Transposon mutagenesis was used to identify regulators of disA and revealed that umoB (igaA) was a negative regulator of disA. Our data demonstrate that the regulation of disA by UmoB is mediated through the Rcs phosphorelay. PMID- 23687267 TI - Dual orientation of the outer membrane lipoprotein P6 of nontypeable haemophilus influenzae. AB - The majority of outer membrane (OM) lipoproteins in Gram-negative bacteria are tethered to the membrane via an attached lipid moiety and oriented facing in toward the periplasmic space; a few lipoproteins have been shown to be surface exposed. The outer membrane lipoprotein P6 from the Gram-negative pathogenic bacterium nontypeable Haemophilus influenzae (NTHi) is surface exposed and a leading vaccine candidate for prevention of NTHi infections. However, we recently found that P6 is not a transmembrane protein as previously thought (L. V. Michel, B. Kalmeta, M. McCreary, J. Snyder, P. Craig, M. E. Pichichero, Vaccine 29:1624 1627, 2011). Here we pursued studies to show that P6 has a dual orientation, existing infrequently as surface exposed and predominantly as internally oriented toward the periplasmic space. Flow cytometry using three monoclonal antibodies with specificity for P6 showed surface staining of whole NTHi cells. Confocal microscopy imaging confirmed that antibodies targeted surface-exposed P6 of intact NTHi cells and not internal P6 in membrane-compromised or dead cells. Western blots of two wild-type NTHi strains and a mutant NTHi strain that does not express P6 showed that P6 antibodies do not detect a promiscuous epitope on NTHi. Depletion of targets to nonlipidated P6 significantly decreased bactericidal activity of human serum. Protease digestion of surface-exposed P6 demonstrated that P6 is predominantly internally localized in a manner similar to its homologue Pal in Escherichia coli. We conclude that P6 of NTHi is likely inserted into the OM in two distinct orientations, with the predominant orientation facing in toward the periplasm. PMID- 23687268 TI - A differential fluorescence-based genetic screen identifies Listeria monocytogenes determinants required for intracellular replication. AB - Listeria monocytogenes is a Gram-positive, facultative intracellular pathogen capable of causing severe invasive disease with high mortality rates in humans. While previous studies have largely elucidated the bacterial and host cell mechanisms necessary for invasion, vacuolar escape, and subsequent cell-to-cell spread, the L. monocytogenes factors required for rapid replication within the restrictive environment of the host cell cytosol are poorly understood. In this report, we describe a differential fluorescence-based genetic screen utilizing fluorescence-activated cell sorting (FACS) and high-throughput microscopy to identify L. monocytogenes mutants defective in optimal intracellular replication. Bacteria harboring deletions within the identified gene menD or pepP were defective for growth in primary murine macrophages and plaque formation in monolayers of L2 fibroblasts, thus validating the ability of the screening method to identify intracellular replication-defective mutants. Genetic complementation of the menD and pepP deletion strains rescued the in vitro intracellular infection defects. Furthermore, the menD deletion strain displayed a general extracellular replication defect that could be complemented by growth under anaerobic conditions, while the intracellular growth defect of this strain could be complemented by the addition of exogenous menaquinone. As prior studies have indicated the importance of aerobic metabolism for L. monocytogenes infection, these findings provide further evidence for the importance of menaquinone and aerobic metabolism for L. monocytogenes pathogenesis. Lastly, both the menD and pepP deletion strains were attenuated during in vivo infection of mice. These findings demonstrate that the differential fluorescence-based screening approach provides a powerful tool for the identification of intracellular replication determinants in multiple bacterial systems. PMID- 23687269 TI - Refining the plasmid-encoded type IV secretion system substrate repertoire of Coxiella burnetii. AB - The intracellular bacterial agent of Q fever, Coxiella burnetii, translocates effector proteins into its host cell cytosol via a Dot/Icm type IV secretion system (T4SS). The T4SS is essential for parasitophorous vacuole formation, intracellular replication, and inhibition of host cell death, but the effectors mediating these events remain largely undefined. Six Dot/Icm substrate-encoding genes were recently discovered on the C. burnetii cryptic QpH1 plasmid, three of which are conserved among all C. burnetii isolates, suggesting that they are critical for conserved pathogen functions. However, the remaining hypothetical proteins encoded by plasmid genes have not been assessed for their potential as T4SS substrates. In the current study, we further defined the T4SS effector repertoire encoded by the C. burnetii QpH1, QpRS, and QpDG plasmids that were originally isolated from acute-disease, chronic-disease, and severely attenuated isolates, respectively. Hypothetical proteins, including those specific to QpRS or QpDG, were screened for translocation using the well-established Legionella pneumophila T4SS secretion model. In total, six novel plasmid-encoded proteins were translocated into macrophage-like cells by the Dot/Icm T4SS. Four newly identified effectors are encoded by genes present only on the QpDG plasmid from severely attenuated Dugway isolates, suggesting that the presence of specific effectors correlates with decreased virulence. These results further support the idea of a critical role for extrachromosomal elements in C. burnetii pathogenesis. PMID- 23687270 TI - Structural basis for biofilm formation via the Vibrio cholerae matrix protein RbmA. AB - During the transition from a free-swimming, single-cell lifestyle to a sessile, multicellular state called a biofilm, bacteria produce and secrete an extracellular matrix comprised of nucleic acids, exopolysaccharides, and adhesion proteins. The Vibrio cholerae biofilm matrix contains three major protein components, RbmA, Bap1, and RbmC, which are unique to Vibrio cholerae and appear to support biofilm formation at particular steps in the process. Here, we focus on RbmA, a structural protein with an unknown fold. RbmA participates in the early cell-cell adhesion events and is found throughout the biofilm where it localizes to cell-cell contact sites. We determined crystal structures of RbmA and revealed that the protein folds into tandem fibronectin type III (FnIII) folds. The protein is dimeric in solution and in crystals, with the dimer interface displaying a surface groove that is lined with several positively charged residues. Structure-guided mutagenesis studies establish a crucial role for this surface patch for RbmA function. On the basis of the structure, we hypothesize that RbmA serves as a tether by maintaining flexible linkages between cells and the extracellular matrix. PMID- 23687271 TI - Gene expression and physiological role of Pseudomonas aeruginosa methionine sulfoxide reductases during oxidative stress. AB - Pseudomonas aeruginosa PAO1 has two differentially expressed methionine sulfoxide reductase genes: msrA (PA5018) and msrB (PA2827). The msrA gene is expressed constitutively at a high level throughout all growth phases, whereas msrB expression is highly induced by oxidative stress, such as sodium hypochlorite (NaOCl) treatment. Inactivation of either msrA or msrB or both genes (msrA msrB mutant) rendered the mutants less resistant than the parental PAO1 strain to oxidants such as NaOCl and H2O2. Unexpectedly, msr mutants have disparate resistance patterns when exposed to paraquat, a superoxide generator. The msrA mutant had a higher paraquat resistance level than the msrB mutant, which had a lower paraquat resistance level than the PAO1 strain. The expression levels of msrA showed an inverse correlation with the paraquat resistance level, and this atypical paraquat resistance pattern was not observed with msrB. Virulence testing using a Drosophila melanogaster model revealed that the msrA, msrB, and, to a greater extent, msrA msrB double mutants had an attenuated virulence phenotype. The data indicate that msrA and msrB are essential genes for oxidative stress protection and bacterial virulence. The pattern of expression and mutant phenotypes of P. aeruginosa msrA and msrB differ from previously characterized msr genes from other bacteria. Thus, as highly conserved genes, the msrA and msrB have diverse expression patterns and physiological roles that depend on the environmental niche where the bacteria thrive. PMID- 23687272 TI - Identification of regions important for resistance and signalling within the antimicrobial peptide transporter BceAB of Bacillus subtilis. AB - In the low-G+C-content Gram-positive bacteria, resistance to antimicrobial peptides is often mediated by so-called resistance modules. These consist of a two-component system and an ATP-binding cassette transporter and are characterized by an unusual mode of signal transduction where the transporter acts as a sensor of antimicrobial peptides, because the histidine kinase alone cannot detect the substrates directly. Thus, the transporters fulfill a dual function as sensors and detoxification systems to confer resistance, but the mechanistic details of these processes are unknown. The paradigm and best understood example for this is the BceRS-BceAB module of Bacillus subtilis, which mediates resistance to bacitracin, mersacidin, and actagardine. Using a random mutagenesis approach, we here show that mutations that affect specific functions of the transporter BceAB are primarily found in the C-terminal region of the permease, BceB, particularly in the eighth transmembrane helix. Further, we show that while signaling and resistance are functionally interconnected, several mutations could be identified that strongly affected one activity of the transporter but had only minor effects on the other. Thus, a partial genetic separation of the two properties could be achieved by single amino acid replacements, providing first insights into the signaling mechanism of these unusual modules. PMID- 23687273 TI - The activity of sigmaV, an extracytoplasmic function sigma factor of Bacillus subtilis, is controlled by regulated proteolysis of the anti-sigma factor RsiV. AB - During growth in the environment, bacteria encounter stresses which can delay or inhibit their growth. To defend against these stresses, bacteria induce both resistance and repair mechanisms. Many bacteria regulate these resistance mechanisms using a group of alternative sigma factors called extracytoplasmic function (ECF) sigma factors. ECF sigma factors represent the largest and most diverse family of sigma factors. Here, we demonstrate that the activation of a member of the ECF30 subfamily of ECF sigma factors, sigma(V) in Bacillus subtilis, is controlled by the proteolytic destruction of the anti-sigma factor RsiV. We will demonstrate that the degradation of RsiV and, thus, the activation of sigma(V) requires multiple proteolytic steps. Upon exposure to the inducer lysozyme, the extracellular domain of RsiV is removed by an unknown protease, which cleaves at site 1. This cleavage is independent of PrsW, the B. subtilis site 1 protease, which cleaves the anti-sigma factor RsiW. Following cleavage by the unknown protease, the N-terminal portion of RsiV requires further processing, which requires the site 2 intramembrane protease RasP. Our data indicate that the N-terminal portion of RsiV from amino acid 1 to 60, which lacks the extracellular domain, is constitutively degraded unless RasP is absent, indicating that RasP cleavage is constitutive. This suggests that the regulatory step in RsiV degradation and, thus, sigma(V) activation are controlled at the level of the site 1 cleavage. Finally, we provide evidence that increased resistance to lysozyme decreases sigma(V) activation. Collectively, these data provide evidence that the mechanism for sigma(V) activation in B. subtilis is controlled by regulated intramembrane proteolysis (RIP) and requires the site 2 protease RasP. PMID- 23687274 TI - BB0172, a Borrelia burgdorferi outer membrane protein that binds integrin alpha3beta1. AB - Lyme disease is a multisystemic disorder caused by Borrelia burgdorferi infection. Upon infection, some B. burgdorferi genes are upregulated, including members of the microbial surface components recognizing adhesive matrix molecule (MSCRAMM) protein family, which facilitate B. burgdorferi adherence to extracellular matrix components of the host. Comparative genome analysis has revealed a new family of B. burgdorferi proteins containing the von Willebrand factor A (vWFA) domain. In the present study, we characterized the expression and membrane association of the vWFA domain-containing protein BB0172 by using in vitro transcription/translation systems in the presence of microsomal membranes and with detergent phase separation assays. Our results showed evidence of BB0172 localization in the outer membrane, the orientation of the vWFA domain to the extracellular environment, and its function as a metal ion-dependent integrin binding protein. This is the first report of a borrelial adhesin with a metal ion dependent adhesion site (MIDAS) motif that is similar to those observed in eukaryotic integrins and has a similar function. PMID- 23687275 TI - Fe(II) oxidation is an innate capability of nitrate-reducing bacteria that involves abiotic and biotic reactions. AB - Phylogenetically diverse species of bacteria can catalyze the oxidation of ferrous iron [Fe(II)] coupled to nitrate (NO(3)(-)) reduction, often referred to as nitrate-dependent iron oxidation (NDFO). Very little is known about the biochemistry of NDFO, and though growth benefits have been observed, mineral encrustations and nitrite accumulation likely limit growth. Acidovorax ebreus, like other species in the Acidovorax genus, is proficient at catalyzing NDFO. Our results suggest that the induction of specific Fe(II) oxidoreductase proteins is not required for NDFO. No upregulated periplasmic or outer membrane redox-active proteins, like those involved in Fe(II) oxidation by acidophilic iron oxidizers or anaerobic photoferrotrophs, were observed in proteomic experiments. We demonstrate that while "abiotic" extracellular reactions between Fe(II) and biogenic NO(2)(-)/NO can be involved in NDFO, intracellular reactions between Fe(II) and periplasmic components are essential to initiate extensive NDFO. We present evidence that an organic cosubstrate inhibits NDFO, likely by keeping periplasmic enzymes in their reduced state, stimulating metal efflux pumping, or both, and that growth during NDFO relies on the capacity of a nitrate-reducing bacterium to overcome the toxicity of Fe(II) and reactive nitrogen species. On the basis of our data and evidence in the literature, we postulate that all respiratory nitrate-reducing bacteria are innately capable of catalyzing NDFO. Our findings have implications for a mechanistic understanding of NDFO, the biogeochemical controls on anaerobic Fe(II) oxidation, and the production of NO(2)(-), NO, and N(2)O in the environment. PMID- 23687277 TI - Mutational analysis of the multiple-antibiotic resistance regulator MarR reveals a ligand binding pocket at the interface between the dimerization and DNA binding domains. AB - The Escherichia coli regulator MarR represses the multiple-antibiotic resistance operon marRAB and responds to phenolic compounds, including sodium salicylate, which inhibit its activity. Crystals obtained in the presence of a high concentration of salicylate indicated two possible salicylate sites, SAL-A and SAL-B. However, it was unclear whether these sites were physiologically significant or were simply a result of the crystallization conditions. A study carried out on MarR homologue MTH313 suggested the presence of a salicylate binding site buried at the interface between the dimerization and the DNA-binding domains. Interestingly, the authors of the study indicated a similar pocket conserved in the MarR structure. Since no mutagenesis analysis had been performed to test which amino acids were essential in salicylate binding, we examined the role of residues that could potentially interact with salicylate. We demonstrated that mutations in residues shown as interacting with salicylate at SAL-A and SAL B in the MarR-salicylate structure had no effect on salicylate binding, indicating that these sites were not the physiological regulatory sites. However, some of these residues (P57, R86, M74, and R77) were important for DNA binding. Furthermore, mutations in residues R16, D26, and K44 significantly reduced binding to both salicylate and 2,4-dinitrophenol, while a mutation in residue H19 impaired the binding to 2,4-dinitrophenol only. These findings indicate, as for MTH313, the presence of a ligand binding pocket located between the dimerization and DNA binding domains. PMID- 23687276 TI - The MerR-like regulator BrlR confers biofilm tolerance by activating multidrug efflux pumps in Pseudomonas aeruginosa biofilms. AB - A defining characteristic of biofilms is antibiotic tolerance that can be up to 1,000-fold greater than that of planktonic cells. In Pseudomonas aeruginosa, biofilm tolerance to antimicrobial agents requires the biofilm-specific MerR-type transcriptional regulator BrlR. However, the mechanism by which BrlR mediates biofilm tolerance has not been elucidated. Genome-wide transcriptional profiling indicated that brlR was required for maximal expression of genes associated with antibiotic resistance, in particular those encoding the multidrug efflux pumps MexAB-OprM and MexEF-OprN. Chromatin immunoprecipitation (ChIP) analysis revealed a direct regulation of these genes by BrlR, with DNA binding assays confirming BrlR binding to the promoter regions of the mexAB-oprM and mexEF-oprN operons. Quantitative reverse transcriptase PCR (qRT-PCR) analysis further indicated BrlR to be an activator of mexAB-oprM and mexEF-oprN gene expression. Moreover, immunoblot analysis confirmed increased MexA abundance in cells overexpressing brlR. Inactivation of both efflux pumps rendered biofilms significantly more susceptible to five different classes of antibiotics by affecting MIC but not the recalcitrance of biofilms to killing by bactericidal agents. Overexpression of either efflux pump in a DeltabrlR strain partly restored tolerance of DeltabrlR biofilms to antibiotics. Expression of brlR in mutant biofilms lacking both efflux pumps partly restored antimicrobial tolerance of biofilms to wild-type levels. Our results indicate that BrlR acts as an activator of multidrug efflux pumps to confer tolerance to P. aeruginosa biofilms and to resist the action of antimicrobial agents. PMID- 23687278 TI - Role of polyphosphate in thermophilic Synechococcus sp. from microbial mats. AB - Synechococcus OS-B', a thermophilic unicellular cyanobacterium, recently isolated from the microbial mats in Octopus Spring (Yellowstone National Park), induces a suite of genes, including phosphatases and transporters, in response to phosphorus (P) starvation. Here we describe two different approaches to examine the ability of Synechococcus OS-B' to synthesize and break down polyphosphate (poly P), a key storage compound in many prokaryotes. First, we developed a transformation protocol to create mutants in the polyphosphate kinase (ppk), the major enzyme responsible for the synthesis of poly P. The ppk mutant exhibited a pleiotropic phenotype with defects in poly P accumulation, aberrant levels of Pho regulon transcripts, growth defects, and changes in cell size and exopolysaccharide levels, among others. Second, we measured transcripts of ppk and ppx (encoding the polyphosphatase) directly from mat samples and found that the levels varied dramatically over a diel cycle. We also used Western blot analysis to quantify levels of PPK and PPX and found that these enzymes differentially accumulated during the diel cycle. Levels of polyphosphate kinase peaked at night, while polyphosphatase levels were highest during the early morning hours. We hypothesize that the opposing activities of these two enzymes allow cells to store and utilize poly P to optimize growth over a diel cycle. PMID- 23687279 TI - Neurostimulation in cluster headache: a review of current progress. AB - PURPOSE OF REVIEW: Neurostimulation has emerged as a viable treatment for intractable chronic cluster headache. Several therapeutic strategies are being investigated including stimulation of the hypothalamus, occipital nerves and sphenopalatine ganglion. The aim of this review is to provide an overview of the rationale, methods and progress for each of these. LATEST FINDINGS: Results from a randomized, controlled trial investigating sphenopalatine ganglion stimulation have just been published. Reportedly the surgery is relatively simple and it is apparently the only therapy that provides relief acutely. SUMMARY: The rationale behind these therapies is based on growing evidence from clinical, hormonal and neuroimaging studies. The overall results are encouraging, but unfortunately not all patients have benefited. All the mentioned therapies require weeks to months of stimulation for a prophylactic effect to occur, suggesting brain plasticity as a possible mechanism, and only stimulation of the sphenopalatine ganglion has demonstrated an acute, abortive effect. Predictors of effect for all modes of neurostimulation still need to be identified and in the future, the least invasive and most effective strategy must be preferred as first-line therapy for intractable chronic cluster headache. PMID- 23687280 TI - Prokineticin receptor variants (PKR1-I379V and PKR2-V331M) are protective genotypes in human early pregnancy. AB - Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) and its receptor genes (PROKR1 (PKR1) and PROKR2 (PKR2)) play an important role in human early pregnancy. We have previously shown that PROKR1 and PROKR2 are associated with recurrent miscarriage (RM) using the tag-SNP method. In this study, we aimed to identify PROKR1 and PROKR2 variants in idiopathic RM patients by genotyping of the entire coding regions. Peripheral blood DNA samples of 100 RM women and 100 controls were subjected to sequence the entire exons of PROKR1 and PROKR2. Significant non-synonymous variant genotypes present in the original 200 samples were further confirmed in the extended samples of 144 RM patients and 153 controls. Genetic variants that were over- or under-represented in the patients were ectopically expressed in HEK293 and JAR cells to investigate their effects on intracellular calcium influx, cell proliferation, cell invasion, cell-cell adhesion, and tube organization. We found that the allele and genotype frequencies of PROKR1 (I379V) and PROKR2 (V331M) were significantly increased in the normal control groups compared with idiopathic RM women (P<0.05). PROKR1 (I379V) and PROKR2 (V331M) decreased intracellular calcium influx but increased cell invasiveness (P<0.05), whereas cell proliferation, cell-cell adhesion, and tube organization were not significantly affected. In conclusion, PROKR1 (I379V) and PROKR2 (V331M) variants conferred lower risk for RM and may play protective roles in early pregnancy by altering calcium signaling and facilitating cell invasiveness. PMID- 23687281 TI - The APC/C in female mammalian meiosis I. AB - The anaphase-promoting complex or cyclosome (APC/C) orchestrates a meticulously controlled sequence of proteolytic events critical for proper cell cycle progression, the details of which have been most extensively elucidated during mitosis. It has become apparent, however, that the APC/C, particularly when acting in concert with its Cdh1 co-activator (APC/C(Cdh1)), executes a staggeringly diverse repertoire of functions that extend its remit well outside the bounds of mitosis. Findings over the past decade have not only earmarked mammalian oocyte maturation as one such case in point but have also begun to reveal a complex pattern of APC/C regulation that underpins many of the oocyte's unique developmental attributes. This review will encompass the latest findings pertinent to the APC/C, especially APC/C(Cdh1), in mammalian oocytes and how its activity and substrates shape the stop-start tempo of female mammalian first meiotic division and the challenging requirement for assembling spindles in the absence of centrosomes. PMID- 23687282 TI - Associations of CTX-II with biochemical markers of bone turnover raise questions about its tissue origin: data from CHECK, a cohort study of early osteoarthritis. PMID- 23687283 TI - Evidence-based detection of pulmonary arterial hypertension in systemic sclerosis: the DETECT study. AB - OBJECTIVE: Earlier detection of pulmonary arterial hypertension (PAH), a leading cause of death in systemic sclerosis (SSc), facilitates earlier treatment. The objective of this study was to develop the first evidence-based detection algorithm for PAH in SSc. METHODS: In this cross-sectional, international study conducted in 62 experienced centres from North America, Europe and Asia, adults with SSc at increased risk of PAH (SSc for >3 years and predicted pulmonary diffusing capacity for carbon monoxide <60%) underwent a broad panel of non invasive assessments followed by diagnostic right heart catheterisation (RHC). Univariable and multivariable analyses selected the best discriminatory variables for identifying PAH. After assessment for clinical plausibility and feasibility, these were incorporated into a two-step, internally validated detection algorithm. Nomograms for clinical practice use were developed. RESULTS: Of 466 SSc patients at increased risk of PAH, 87 (19%) had RHC-confirmed PAH. PAH was mild (64% in WHO functional class I/II). Six simple assessments in Step 1 of the algorithm determined referral to echocardiography. In Step 2, the Step 1 prediction score and two echocardiographic variables determined referral to RHC. The DETECT algorithm recommended RHC in 62% of patients (referral rate) and missed 4% of PAH patients (false negatives). By comparison, applying European Society of Cardiology/European Respiratory Society guidelines to these patients, 29% of diagnoses were missed while requiring an RHC referral rate of 40%. CONCLUSIONS: The novel, evidence-based DETECT algorithm for PAH detection in SSc is a sensitive, non-invasive tool which minimises missed diagnoses, identifies milder disease and addresses resource usage. PMID- 23687287 TI - Oral antiretroviral drugs as public health tools for HIV prevention: global implications for adherence, drug resistance, and the success of HIV treatment programs. AB - Recent data from studies on treatment as prevention (TasP) and preexposure prophylaxis (PrEP) show that antiretroviral drugs can be used in prevention, as well as in treatment. The movement from first-generation antiretroviral therapy (ART) coformulations based on thymidine analogues to second-generation ART coformulations based on tenofovir may coincide with future prevention strategies that also use tenofovir/emtricitabine, raising concerns regarding drug resistance. In published studies, failure of prophylaxis was associated with poor adherence and low plasma drug levels. Although rates of drug resistance in cases of failed prevention was low, regular human immunodeficiency virus (HIV) testing was undertaken in these clinical trials. Although legitimate concerns exist about ART adherence and drug resistance associated with PrEP and TasP in real-world settings, efforts to curb the continuing HIV epidemic through use of these novel prevention strategies should move forward because the development and approval of newer drugs reserved for prevention might take many more years. Efforts must be made to monitor ART adherence and to intervene through counseling and other means in order to optimize adherence and retention in care, whenever necessary. Finally, further research involving the generalized epidemic is needed to determine when suboptimal drug use may occur and when regular testing and monitoring of the long-term consequences of ART use may not be routine. PMID- 23687288 TI - The Impact of HIV Drug Resistance on the Selection of First- and Second-Line ART in Resource-Limited Settings. PMID- 23687289 TI - Emergence of HIV drug resistance during first- and second-line antiretroviral therapy in resource-limited settings. AB - INTRODUCTION: Antiretroviral therapy (ART) in resource-limited settings has expanded in the last decade, reaching >8 million individuals and reducing AIDS mortality and morbidity. Continued success of ART programs will require understanding the emergence of HIV drug resistance patterns among individuals in whom treatment has failed and managing ART from both an individual and public health perspective. We review data on the emergence of HIV drug resistance among individuals in whom first-line therapy has failed and clinical and resistance outcomes of those receiving second-line therapy in resource-limited settings. RESULTS: Resistance surveys among patients initiating first-line nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based therapy suggest that 76%-90% of living patients achieve HIV RNA suppression by 12 months after ART initiation. Among patients with detectable HIV RNA at 12 months, HIV drug resistance, primarily due to M184V and NNRTI mutations, has been identified in 60%-72%, although the antiretroviral activity of proposed second-line regimens has been preserved. Complex mutation patterns, including thymidine-analog mutations, K65R, and multinucleoside mutations, are prevalent among cases of treatment failure identified by clinical or immunologic methods. Approximately 22% of patients receiving second-line therapy do not achieve HIV RNA suppression by 6 months, with poor adherence, rather than HIV drug resistance, driving most failures. Major protease inhibitor resistance at the time of second-line failure ranges from 0% to 50%, but studies are limited. CONCLUSIONS: Resistance of HIV to first line therapy is predictable at 12 months when evaluated by means of HIV RNA monitoring and, when detected, largely preserves second-line therapy options. Optimizing adherence, performing resistance surveillance, and improving treatment monitoring are critical for long-term prevention of drug resistance. PMID- 23687290 TI - Transmission of drug resistant HIV and its potential impact on mortality and treatment outcomes in resource-limited settings. AB - Scale-up of antiretroviral therapy in low- and middle-income countries has been achieved by using a public health approach that involved national standard regimens and clinical monitoring in settings where laboratory infrastructure was not available. This strategy potentially allows for long periods of unrecognized viral failure, during which drug-resistant virus can be transmitted and this could compromise the long-term effectiveness of currently available first-line regimens. In response to this concern, the World Health Organization recommends population-based surveys to detect whether the prevalence of resistance in ART naive people is reaching alerting levels. Whereas adherence counseling has to be an integral component of any treatment program, it is still unclear which threshold of transmitted drug resistance (TDR) should trigger additional targeted public health actions and which action is the most cost-effective. Mathematical models can contribute to answer these questions. In order to estimate the potential long-term impact of TDR on mortality in people on ART we used the Synthesis transmission model. TDR is predicted to have potentially significant impact on future HIV mortality. It is critical to remain vigilant over transmission of drug-resistant HIV. PMID- 23687291 TI - Antiretroviral treatment sequencing strategies to overcome HIV type 1 drug resistance in adolescents and adults in low-middle-income countries. AB - Antiretroviral treatment (ART) is expanding to human immunodeficiency virus type 1 (HIV-1)-infected persons in low-middle income countries, thanks to a public health approach. With 3 available drug classes, 2 ART sequencing lines are programmatically foreseen. The emergence and transmission of viral drug resistance represents a challenge to the efficacy of ART. Knowledge of HIV-1 drug resistance selection associated with specific drugs and regimens and the consequent activity of residual drug options are essential in programming ART sequencing options aimed at preserving ART efficacy for as long as possible. This article determines optimal ART sequencing options for overcoming HIV-1 drug resistance in resource-limited settings, using currently available drugs and treatment monitoring opportunities. From the perspective of drug resistance and on the basis of limited virologic monitoring data, optimal sequencing seems to involve use of a tenofovir-containing nonnucleoside reverse-transcriptase inhibitor-based first-line regimen, followed by a zidovudine-containing, protease inhibitor (PI)-based second-line regimen. Other options and their consequences are explored by considering within-class and between-class sequencing opportunities, including boosted PI monotherapies and future options with integrase inhibitors. Nucleoside reverse-transcriptase inhibitor resistance pathways in HIV-1 subtype C suggest an additional reason for accelerating stavudine phase out. Viral load monitoring avoids the accumulation of resistance mutations that significantly reduce the activity of next-line options. Rational use of resources, including broader access to viral load monitoring, will help ensure 3 lines of fully active treatment options, thereby increasing the duration of ART success. PMID- 23687293 TI - Resistance at virological failure using boosted protease inhibitors versus nonnucleoside reverse transcriptase inhibitors as first-line antiretroviral therapy--implications for sustained efficacy of ART in resource-limited settings. AB - BACKGROUND: Increases in the prevalence of resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs) have been observed among previously untreated individuals in all areas of sub-Saharan Africa. We aimed to examine whether first line use of 2 NRTIs plus a boosted protease inhibitor (bPI) could protect against emergence of NRTI resistance mutations, compared to the use of 2 NRTIs plus 1 NNRTI. METHODS: We carried out a weighted meta-analysis of randomized clinical trials comparing bPI- with NNRTI-based first-line antiretroviral therapy regimens using random effects modeling. RESULTS: In intention to treat analyses, there was no difference in the risk of viral failure at week 48 between NNRTI and bPI (P = .19). At week 48, the overall difference between NNRTI- and PI-based regimens in selection of any major NRTI resistance mutation (crude unweighted prevalence 3.3% vs 1.6%) was 1.7% (95% confidence interval [CI], .4-3.0; P = .00927). There was a statistically significant difference in prevalence of K65R when comparing NNRTI (1.3%) with PI (0.67%); absolute weighted difference 1.0% (95% CI, .3-1.7; P = .00447). There was also a significant difference in prevalence of M184V/I between NNRTI and PI (crude unweighted prevalence 3.2% vs 1.4%); difference 1.6% (95% CI 0.1-3.1; P = .0368). CONCLUSIONS: Despite the equivalent efficacy and more favorable resistance implications of PI- versus NNRTI-based first line therapy, widespread use of PI-based first-line therapy is not warranted at this time, due to resource limitations and predicted increased risk of resistance-related failure of NNRTI/NRTI second-line regimens. PI-based first-line therapy could be reconsidered when antiretroviral agents from other classes become available for second-line regimens in resource-limited settings. PMID- 23687292 TI - Nucleoside reverse transcriptase inhibitor resistance mutations associated with first-line stavudine-containing antiretroviral therapy: programmatic implications for countries phasing out stavudine. AB - BACKGROUND: The World Health Organization Antiretroviral Treatment Guidelines recommend phasing-out stavudine because of its risk of long-term toxicity. There are two mutational pathways of stavudine resistance with different implications for zidovudine and tenofovir cross-resistance, the primary candidates for replacing stavudine. However, because resistance testing is rarely available in resource-limited settings, it is critical to identify the cross-resistance patterns associated with first-line stavudine failure. METHODS: We analyzed HIV-1 resistance mutations following first-line stavudine failure from 35 publications comprising 1,825 individuals. We also assessed the influence of concomitant nevirapine vs. efavirenz, therapy duration, and HIV-1 subtype on the proportions of mutations associated with zidovudine vs. tenofovir cross-resistance. RESULTS: Mutations with preferential zidovudine activity, K65R or K70E, occurred in 5.3% of individuals. Mutations with preferential tenofovir activity, >= two thymidine analog mutations (TAMs) or Q151M, occurred in 22% of individuals. Nevirapine increased the risk of TAMs, K65R, and Q151M. Longer therapy increased the risk of TAMs and Q151M but not K65R. Subtype C and CRF01_AE increased the risk of K65R, but only CRF01_AE increased the risk of K65R without Q151M. CONCLUSIONS: Regardless of concomitant nevirapine vs. efavirenz, therapy duration, or subtype, tenofovir was more likely than zidovudine to retain antiviral activity following first-line d4T therapy. PMID- 23687294 TI - Development of antiretroviral resistance in children with HIV in low- and middle income countries. AB - With antiretroviral therapy (ART) recommended by the World Health Organization (WHO) for children aged <2 years with human immunodeficiency virus (HIV) and continuing global ART roll-out, ART coverage in children is rising. However ART coverage in children lags considerably behind that in adults (28% vs 58%). Long duration of therapy needed for HIV-infected children requires maximal efficacy, minimal toxicity, and prevention of development of drug resistance. This requires consideration of ways to improve sequencing of regimens during childhood to minimize development of resistance and treatment failure. We consider aspects of virological failure and development of resistance in vertically HIV-infected children in resource-limited settings. We review evidence guiding choices of first- and second-line ART, the impact of drugs given to prevent mother-to-child transmission, adherence issues and, availability of appropriate drug formulations. Recommendations made during the Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN)/WHO meeting (October 2012) are summarized. PMID- 23687295 TI - Impact of antiretroviral drugs in pregnant women and their children in Africa: HIV resistance and treatment outcomes. AB - The global community has committed itself to eliminating new pediatric HIV infections by 2015 and improving maternal, newborn, and child health and survival in the context of HIV. Such objectives require regimens to prevent mother-to child transmission (pMTCT) which, while being highly efficacious, protect the efficacy of future first-line antiretroviral therapy (ART). Major obstacles to eliminating vertical transmissions globally include low rates of adherence to ART and non-completion of the 'pMTCT cascade' due to programmatic and structural challenges faced by healthcare systems in low-income countries. Providing all pregnant women with lifelong ART regardless of CD4 count/disease stage (Option B+) could be the most effective option to prevent both HIV transmission and resistance, assuming adherence is successfully maintained. This strategy is more likely to achieve sustained undetectable HIV viremia, does not involve ART interruptions, is simpler to implement, and is cost-effective. Where Option B+ is not available, options A (short course zidovudine with single-dose nevirapine and an ARV "tail") and B (combination ART during pregnancy and breastfeeding, with ART cessation after weaning in women not qualifying for ART for their own health) are also efficacious, highly cost-effective and associated with infrequent resistance selection if taken properly. PMID- 23687296 TI - Unique thermal behavior of sphingomyelin species with nonhydroxy and 2-hydroxy very-long-chain (C28-C32) PUFAs. AB - In rat germ cells and spermatozoa, sphingomyelin (SM) contains molecular species with nonhydroxy (n) and 2-hydroxy (h) very-long-chain polyunsaturated fatty acids (V), the most abundant being SMs with (n- and h-) 28:4n-6, 30:5n-6, and 32:5n-6 as acyl chains. The aim of this study was to gain information about their thermotropic behavior and interactions with other lipids. After isolation from rat testis, multilamellar and giant unilamellar vesicles from these SMs were examined using fluorescent probes. Only n-32:5 SM and h-32:5 SM displayed a gel liquid transition temperature (Tt ~ 21-22 degrees C), the rest remaining in the liquid state in the 5 degrees C-45 degrees C range. The degree of order was larger in bilayers of any of the h-V SMs than in those of their chain-matched n-V SMs. Both, but n-V SM relatively more than h-V SM, decreased the Tt of dimyristoylphosphatidylcholine as their proportion increased in binary phosphatidylcholine:SM liposomes. In contrast to the established ability of 16:0 SM to form lateral cholesterol/SM-rich ordered domains in ternary dioleoylphosphatidylcholine:cholesterol:SM bilayers, neither n-V SM nor h-V SM showed a tendency to do so. Thus, these SMs are in the fluid state and are not involved in this type of domains in spermatozoa at physiological temperatures. However, this state could be altered at the very low temperatures at which these gametes are usually preserved. PMID- 23687297 TI - Chronic conditions: lessons from the frontlines. PMID- 23687298 TI - Differential androgen deprivation therapies with anti-androgens casodex/bicalutamide or MDV3100/Enzalutamide versus anti-androgen receptor ASC J9(R) Lead to promotion versus suppression of prostate cancer metastasis. AB - Despite the fact that androgen deprivation therapy (ADT) can effectively reduce prostate cancer (PCa) size, its effect on PCa metastasis remains unclear. We examined the existing data on PCa patients treated with ADT plus anti-androgens to analyze ADT effects on primary tumor size, prostate-specific antigen (PSA) values, and metastatic incidence. We found that the current ADT with anti androgens might lead to primary tumor reduction, with PSA decreased yet metastases increased in some PCa patients. Using in vitro and in vivo metastasis models with four human PCa cell lines, we evaluated the effects of the currently used anti-androgens, Casodex/bicalutamide and MDV3100/enzalutamide, and the newly developed anti-AR compounds, ASC-J9(r) and cryptotanshinone, on PCa cell growth and invasion. In vitro results showed that 10 MUm Casodex or MDV3100 treatments suppressed PCa cell growth and reduced PSA level yet significantly enhanced PCa cell invasion. In vivo mice studies using an orthotopic xenograft mouse model also confirmed these results. In contrast, ASC-J9(r) led to suppressed PCa cell growth and cell invasion in in vitro and in vivo models. Mechanism dissection indicated these Casodex/MDV3100 treatments enhanced the TGF-beta1/Smad3/MMP9 pathway, but ASC-J9(r) and cryptotanshinone showed promising anti-invasion effects via down-regulation of MMP9 expression. These findings suggest the potential risks of using anti-androgens and provide a potential new therapy using ASC-J9(r) to battle PCa metastasis at the castration-resistant stage. PMID- 23687299 TI - Structural insights into Abeta42 oligomers using site-directed spin labeling. AB - Oligomerization of the 42-residue peptide Abeta42 plays a key role in the pathogenesis of Alzheimer disease. Despite great academic and medical interest, the structures of these oligomers have not been well characterized. Site-directed spin labeling combined with electron paramagnetic resonance spectroscopy is a powerful approach for studying structurally ill-defined systems, but its application in amyloid oligomer structure study has not been systematically explored. Here we report a comprehensive structural study on a toxic Abeta42 oligomer, called globulomer, using site-directed spin labeling complemented by other techniques. Transmission electron microscopy shows that these oligomers are globular structures with diameters of ~7-8 nm. Circular dichroism shows primarily beta-structures. X-ray powder diffraction suggests a highly ordered intrasheet hydrogen-bonding network and a heterogeneous intersheet packing. Residue-level mobility analysis on spin labels introduced at 14 different positions shows a structured state and a disordered state at all labeling sites. Side chain mobility analysis suggests that structural order increases from N- to C-terminal regions. Intermolecular distance measurements at 14 residue positions suggest that C-terminal residues Gly-29-Val-40 form a tightly packed core with intermolecular distances in a narrow range of 11.5-12.5 A. These intermolecular distances rule out the existence of fibril-like parallel in-register beta structures and strongly suggest an antiparallel beta-sheet arrangement in Abeta42 globulomers. PMID- 23687300 TI - 15-hydroxyprostaglandin dehydrogenase-derived 15-keto-prostaglandin E2 inhibits cholangiocarcinoma cell growth through interaction with peroxisome proliferator activated receptor-gamma, SMAD2/3, and TAP63 proteins. AB - Prostaglandin E2 (PGE2) is a potent lipid mediator that plays a key role in inflammation and carcinogenesis. NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes the oxidation of the 15(S)-hydroxyl group of PGE2, which leads to PGE2 biotransformation. In this study, we showed that the 15 PGDH-derived 15-keto-PGE2 is an endogenous peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand that causes PPAR-gamma dissociation from Smad2/3, allowing Smad2/3 association with the TGF-beta receptor I and Smad anchor for receptor activation and subsequent Smad2/3 phosphorylation and transcription activation in human cholangiocarcinoma cells. The 15-PGDH/15-keto PGE2-induced Smad2/3 phosphorylation resulted in the formation of the pSmad2/3 TAP63-p53 ternary complex and their binding to the TAP63 promoter, inducing TAP63 autotranscription. The role of TAP63 in 15-PGDH/15-keto-PGE2-induced inhibition of tumor growth was further supported by the observation that knockdown of TAP63 prevented 15-PGDH-induced inhibition of tumor cell proliferation, colony formation, and migration. These findings disclose a novel 15-PGDH-mediated 15 keto-PGE2 signaling cascade that interacts with PPAR-gamma, Smad2/3, and TAP63. PMID- 23687302 TI - Dynamin isoforms decode action potential firing for synaptic vesicle recycling. AB - Presynaptic nerve terminals must maintain stable neurotransmission via synaptic vesicle membrane recycling despite encountering wide fluctuations in the number and frequency of incoming action potentials (APs). However, the molecular mechanism linking variation in neuronal activity to vesicle trafficking is unknown. Here, we combined genetic knockdown and direct physiological measurements of synaptic transmission from paired neurons to show that three isoforms of dynamin, an essential endocytic protein, work individually to match vesicle reuse pathways, having distinct rate and time constants with physiological AP frequencies. Dynamin 3 resupplied the readily releasable pool with slow kinetics independently of the AP frequency but acted quickly, within 20 ms of the incoming AP. Under high-frequency firing, dynamin 1 regulated recycling to the readily releasable pool with fast kinetics in a slower time window of greater than 50 ms. Dynamin 2 displayed a hybrid response between the other isoforms. Collectively, our findings show how dynamin isoforms select appropriate vesicle reuse pathways associated with specific neuronal firing patterns. PMID- 23687301 TI - In silico screening for palmitoyl substrates reveals a role for DHHC1/3/10 (zDHHC1/3/11)-mediated neurochondrin palmitoylation in its targeting to Rab5 positive endosomes. AB - Protein palmitoylation, a common post-translational lipid modification, plays an important role in protein trafficking and functions. Recently developed palmitoyl proteomic methods identified many novel substrates. However, the whole picture of palmitoyl substrates has not been clarified. Here, we performed global in silico screening using the CSS-Palm 2.0 program, free software for prediction of palmitoylation sites, and selected 17 candidates as novel palmitoyl substrates. Of the 17 candidates, 10 proteins, including 6 synaptic proteins (Syd-1, transmembrane AMPA receptor regulatory protein (TARP) gamma-2, TARP gamma-8, cornichon-2, Ca(2+)/calmodulin-dependent protein kinase IIalpha, and neurochondrin (Ncdn)/norbin), one focal adhesion protein (zyxin), two ion channels (TRPM8 and TRPC1), and one G-protein-coupled receptor (orexin 2 receptor), were palmitoylated. Using the DHHC palmitoylating enzyme library, we found that all tested substrates were palmitoylated by the Golgi-localized DHHC3/7 subfamily. Ncdn, a regulator for neurite outgrowth and synaptic plasticity, was robustly palmitoylated by the DHHC1/10 (zDHHC1/11; z1/11) subfamily, whose substrate has not yet been reported. As predicted by CSS-Palm 2.0, Cys-3 and Cys-4 are the palmitoylation sites for Ncdn. Ncdn was specifically localized in somato-dendritic regions, not in the axon of rat cultured neurons. Stimulated emission depletion microscopy revealed that Ncdn was localized to Rab5 positive early endosomes in a palmitoylation-dependent manner, where DHHC1/10 (z1/11) were also distributed. Knockdown of DHHC1, -3, or -10 (z11) resulted in the loss of Ncdn from Rab5-positive endosomes. Thus, through in silico screening, we demonstrate that Ncdn and the DHHC1/10 (z1/11) and DHHC3/7 subfamilies are novel palmitoyl substrate-enzyme pairs and that Ncdn palmitoylation plays an essential role in its specific endosomal targeting. PMID- 23687303 TI - Enhanced phosphatidylinositol 3-kinase (PI3K)/Akt signaling has pleiotropic targets in hippocampal neurons exposed to iron-induced oxidative stress. AB - The PI3K/Akt pathway is a key component in synaptic plasticity and neuronal survival. The aim of this work was to investigate the participation of the PI3K/Akt pathway and its outcome on different molecular targets such as glycogen synthase kinase 3beta (GSK3beta) and Forkhead box-O (FoxO) transcription factors during mild oxidative stress triggered by iron overload. The exposure of mouse hippocampal neurons (HT22) to different concentrations of Fe(2+) (25-200 MUm) for 24 h led us to define a mild oxidative injury status (50 MUm Fe(2+)) in which cell morphology showed changes typical of neuronal damage with increased lipid peroxidation and cellular oxidant levels but no alteration of cellular viability. There was a simultaneous increase in both Akt and GSK3beta phosphorylation. Levels of phospho-FoxO3a (inactive form) increased in the cytosolic fraction of cells treated with iron in a PI3K-dependent manner. Moreover, PI3K and Akt translocated to the nucleus in response to oxidative stress. Iron-overloaded cells harboring a constitutively active form of Akt showed decreased oxidants levels. Indeed, GSH synthesis under oxidative stress conditions was regulated by activated Akt. Our results show that activation of the PI3K/Akt pathway during iron-induced neurotoxicity regulates multiple targets such as GSK3beta, FoxO transcriptional activity, and glutathione metabolism, thus modulating the neuronal response to oxidative stress. PMID- 23687304 TI - Molecular basis for the recognition of long-chain substrates by plant alpha glucosidases. AB - Sugar beet alpha-glucosidase (SBG), a member of glycoside hydrolase family 31, shows exceptional long-chain specificity, exhibiting higher kcat/Km values for longer malto-oligosaccharides. However, its amino acid sequence is similar to those of other short chain-specific alpha-glucosidases. To gain structural insights into the long-chain substrate recognition of SBG, a crystal structure complex with the pseudotetrasaccharide acarbose was determined at 1.7 A resolution. The active site pocket of SBG is formed by a (beta/alpha)8 barrel domain and a long loop (N-loop) bulging from the N-terminal domain similar to other related enzymes. Two residues (Phe-236 and Asn-237) in the N-loop are important for the long-chain specificity. Kinetic analysis of an Asn-237 mutant enzyme and a previous study of a Phe-236 mutant enzyme demonstrated that these residues create subsites +2 and +3. The structure also indicates that Phe-236 and Asn-237 guide the reducing end of long substrates to subdomain b2, which is an additional element inserted into the (beta/alpha)8 barrel domain. Subdomain b2 of SBG includes Ser-497, which was identified as the residue at subsite +4 by site directed mutagenesis. PMID- 23687305 TI - T cell receptor (TCR) and transforming growth factor beta (TGF-beta) signaling converge on DNA (cytosine-5)-methyltransferase to control forkhead box protein 3 (foxp3) locus methylation and inducible regulatory T cell differentiation. AB - Naive T cells can be induced to differentiate into Foxp3(+) regulatory T cells (iTregs) upon suboptimal T cell receptor (TCR) stimulus or TCR stimulus in conjunction with TGF-beta signaling; however, we do not fully understand how these signals coordinately control foxp3 expression. Here, we show that strong TCR activation, in terms of both duration and ligand affinity, causes the accumulation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) and DNMT3b and their specific enrichment at the foxp3 locus, which leads to increased CpG methylation and inhibits foxp3 transcription. During this process the augmentation of DNMT1 is regulated through at least two post-transcriptional mechanisms; that is, strong TCR signal inactivates GSK3beta to rescue DNMT1 protein from proteasomal degradation, and strong TCR signal suppresses miR-148a to derepress DNMT1 mRNA translation. Meanwhile, TGF-beta signaling antagonizes DNMT1 accumulation via activation of p38 MAP kinase. Thus, independent of transcription factor activation, TCR and TGF-beta signals converge on DNMT1 to modulate the expression of foxp3 epigenetically, which marks mother cell iTreg lineage choice within the genome of differentiating daughter cells. PMID- 23687306 TI - Dexamethasone-induced selenoprotein S degradation is required for adipogenesis. AB - Although adipogenesis is associated with induction of endoplasmic reticulum (ER) stress, the role of selenoprotein S (SEPS1), an ER resident selenoprotein known to regulate ER stress and ER-associated protein degradation, is unknown. We found an inverse relationship between SEPS1 level in adipose tissue and adiposity in mice. While SEPS1 expression was increased during adipogenesis, a markedly reduced SEPS1 protein level was found in the early phase of adipogenesis due to dexamethasone (DEX)-induced proteosomal degradation of SEPS1. Overexpression of SEPS1 in the early phase of cell differentiation resulted in impairment of adipogenesis with reduced levels of CCAAT/enhancer binding protein alpha and other adipocyte marker genes during the course of adipogenesis. Conversely, knockdown of SEPS1 resulted in the promotion of adipogenesis. Additionally, altered SEPS1 expression was associated with changes in expression of ER stress marker genes in the early phase of adipogenesis, and ubiquitin-proteasome system (UPS)-related ubiquitination and proteasome function. Our study reveals that SEPS1 is a novel anti-adipogenic selenoprotein that modulates ER stress- and UPS dependent adipogenesis. Our results also identifies a novel function of DEX in the regulation of adipogenesis through induction of SEPS1 degradation. Taken together, DEX-dependent degradation of SEPS1 in the early phase of adipogenesis is necessary for initiating ER stress- and UPS-dependent maturation of adipocytes. PMID- 23687309 TI - I. The Irish are coming. PMID- 23687308 TI - Zinc-L-carnosine binds to molecular chaperone HSP70 and inhibits the chaperone activity of the protein. AB - In this study, we have investigated the specific binding proteins of Zinc-L carnosine (Polaprezinc) using Polaprezinc-affinity column chromatography in vitro. A protein having a 70-kDa molecular mass was eluted by the linear gradient of 0-1.0 mM Polaprezinc from the affinity column and the protein was identified as the molecular chaperone HSP70 by immunoblotting. The chaperone activity of HSP70 was completely suppressed by Polaprezinc. The ATPase activity of HSP70 was affected to some extent by the reagent. In the circular dichroism (CD) spectrum, the secondary structure of HSP70 was changed in the presence of Polaprezinc, i.e. it decreased in the alpha-helix. We have determined the Polaprezinc-binding domain of HSP70 by using recombinant HSP70N- and C-domains. Although Polaprezinc could bind to both the N-terminal and the C-terminal of HSP70, the HSP70N-domain has a high affinity to the drug. Regarding the peptide cleavage of the HSP70N- and C-domains with proteinase K, the intact HSP70N still remained in the presence of Polaprezinc. On the other hand, the quantity of the intact C-domain slightly decreased under the same conditions along with the newly digested small peptides appeared. It has been suggested that Polaprezinc binds to HSP70 especially in the N-domains, suppresses the chaperone activity and delays an ATPase activities of HSP70. PMID- 23687307 TI - Regulation of signal transduction by HDL. AB - High density lipoprotein (HDL) cholesterol has direct effects on numerous cell types that influence cardiovascular and metabolic health. These include endothelial cells, vascular smooth-muscle cells, leukocytes, platelets, adipocytes, skeletal muscle myocytes, and pancreatic beta cells. The effects of HDL or apoA-I, its major apolipoprotein, occur through the modulation of intracellular calcium, oxygen-derived free-radical production, numerous kinases, and enzymes, including endothelial nitric-oxide synthase (eNOS). ApoA-I and HDL also influence gene expression, particularly genes encoding mediators of inflammation in vascular cells. In many paradigms, the change in intracellular signaling occurs as a result of cholesterol efflux, with the cholesterol acceptor methyl-beta-cyclodextrin often invoking responses identical to HDL or apoA-I. The ABC transporters ABCA1 and ABCG1 and scavenger receptor class B, type I (SR-BI) frequently participate in the cellular responses. Structure-function relationships are emerging for signal initiation by ABCA1 and SR-BI, with plasma membrane cholesterol binding by the C-terminal transmembrane domain of SR-BI uniquely enabling it to serve as a sensor of changes in membrane cholesterol. Further investigation of the processes underlying HDL and apoA-I modulation of intracellular signaling will potentially reveal new prophylactic and therapeutic strategies to optimize both cardiovascular and metabolic health. PMID- 23687310 TI - II. Difficult peripheral veins: turn on the lights. PMID- 23687311 TI - III. Tidal volume measurement: OK for science, but too difficult for a workstation standard? PMID- 23687312 TI - Anesthesia awareness campaign persists. PMID- 23687313 TI - Reply from the authors. PMID- 23687314 TI - Platelet margination in postpartum haemorrhage. PMID- 23687315 TI - Erythrocytes, haemostasis, and coagulation monitoring in postpartum haemorrhage (PPH). PMID- 23687316 TI - Observational studies are not reliable enough when making decisions about individual patient care. PMID- 23687317 TI - Safety of antifibrinolytic therapy during cardiac surgery and randomized controlled trials. PMID- 23687318 TI - Colour-coded syringe labels: a modification to enhance patient safety. PMID- 23687319 TI - Takotsubo cardiomyopathy: issues for the intensivist. PMID- 23687320 TI - Use of recombinant human deoxyribonuclease for the treatment of acute asthma. PMID- 23687321 TI - Use of magnesium in moderating tachycardia in acute severe asthma in pregnancy. PMID- 23687322 TI - Allergic reaction to mepivacaine in a child. PMID- 23687323 TI - Reducing system errors in the preoperative assessment process. PMID- 23687324 TI - Anaesthetic management of a patient with Charcot-Marie-Tooth disease for staged diaphragmatic plication. PMID- 23687325 TI - Utilizing sampled gas to decrease fresh gas flow. PMID- 23687326 TI - Does the site of anterior tracheal puncture affect the success rate of retrograde intubation? PMID- 23687333 TI - Introductory paragraph - Volume 27, Issue 6. PMID- 23687334 TI - Primary synovial chondromatosis of the subtalar joint presenting as ankle instability. PMID- 23687335 TI - Results of proximal medial gastrocnemius release for Achilles tendinopathy. AB - BACKGROUND: Most patients with Achilles tendinopathy (AT) are treated successfully with physiotherapy involving eccentric calf training. In some patients, gastrocnemius contracture persists and there are reports of improvement following gastrocnemius release. We present the first series of patients to have proximal medial gastrocnemius release (PMGR) for AT. METHOD: 16 PMGRs (12 patients) were performed at our institution over a 2-year period. Nine patients (10 PMGRs) were available for follow-up. The mean age of patients was 45 years (range, 25-63 years), with 5 female and 4 male subjects. The average follow-up period was 2.5 years (range, 1.7-3.3 years). The sample was divided into noninsertional and insertional tendinopathy, with 5 PMGRs per group. Outcome measures were visual analog scale (VAS) scores, Victorian Institute of Sport Assessment-Achilles (VISA-A) scores, American Orthopaedic Foot & Ankle Society (AOFAS) ankle-hindfoot score, and overall satisfaction. Complications and further procedures were also recorded. RESULTS: At an average of 2.5 years of follow-up, 6 out of 9 patients were highly satisfied. The noninsertional tendinopathy group enjoyed better results than the insertional group: mean VISA-A scores improved by 59% (noninsertional) versus 22% (insertional); mean AOFAS scores improved by 29% (noninsertional) versus 15% (insertional). The improvement in the noninsertional group was statistically significant (P < .05) for all 3 outcome measures. CONCLUSION: PMGR was an outpatient procedure that was well tolerated without wound healing concerns due to the proximally based incision. Patients with noninsertional tendinopathy who have failed conservative treatment can expect notable improvement, with VISA-A scores possibly normalizing after the procedure. We recommend PMGR for patients suffering recalcitrant noninsertional AT in whom gastrocnemius contracture persists despite an eccentric stretching program. LEVEL OF EVIDENCE: Level IV, case series. PMID- 23687336 TI - Connective tissue growth factor activates pluripotency genes and mesenchymal epithelial transition in head and neck cancer cells. AB - The epithelial-mesenchymal transition (EMT) is a key mechanism in both embryonic development and cancer metastasis. The EMT introduces stem-like properties to cancer cells. However, during somatic cell reprogramming, mesenchymal-epithelial transition (MET), the reverse process of EMT, is a crucial step toward pluripotency. Connective tissue growth factor (CTGF) is a multifunctional secreted protein that acts as either an oncoprotein or a tumor suppressor among different cancers. Here, we show that in head and neck squamous cell carcinoma (HNSCC), CTGF promotes the MET and reduces invasiveness. Moreover, we found that CTGF enhances the stem-like properties of HNSCC cells and increases the expression of multiple pluripotency genes. Mechanistic studies showed that CTGF induces c-Jun expression through alphavbeta3 integrin and that c-Jun directly activates the transcription of the pluripotency genes NANOG, SOX2, and POU5F1. Knockdown of CTGF in TW2.6 cells was shown to reduce tumor formation and attenuate E-cadherin expression in xenotransplanted tumors. In HNSCC patient samples, CTGF expression was positively correlated with the levels of CDH1, NANOG, SOX2, and POU5F1. Coexpression of CTGF and the pluripotency genes was found to be associated with a worse prognosis. These findings are valuable in elucidating the interplay between epithelial plasticity and stem-like properties during cancer progression and provide useful information for developing a novel classification system and therapeutic strategies for HNSCC. PMID- 23687337 TI - ETS transcription factor ESE1/ELF3 orchestrates a positive feedback loop that constitutively activates NF-kappaB and drives prostate cancer progression. AB - Chromosomal translocations leading to deregulated expression of ETS transcription factors are frequent in prostate tumors. Here, we report a novel mechanism leading to oncogenic activation of the ETS factor ESE1/ELF3 in prostate tumors. ESE1/ELF3 was overexpressed in human primary and metastatic tumors. It mediated transforming phenotypes in vitro and in vivo and induced an inflammatory transcriptome with changes in relevant oncogenic pathways. ESE1/ELF3 was induced by interleukin (IL)-1beta through NF-kappaB and was a crucial mediator of the phenotypic and transcriptional changes induced by IL-1beta in prostate cancer cells. This linkage was mediated by interaction of ESE1/ELF3 with the NF-kappaB subunits p65 and p50, acting by enhancing their nuclear translocation and transcriptional activity and by inducing p50 transcription. Supporting these findings, gene expression profiling revealed an enrichment of NF-kappaB effector functions in prostate cancer cells or tumors expressing high levels of ESE1/ELF3. We observed concordant upregulation of ESE1/ELF3 and NF-kappaB in human prostate tumors that was associated with adverse prognosis. Collectively, our results define an important new mechanistic link between inflammatory signaling and the progression of prostate cancer. PMID- 23687338 TI - Tumor MMP-1 activates endothelial PAR1 to facilitate vascular intravasation and metastatic dissemination. AB - Intravasation, the active entry of primary tumor cells into the vasculature, remains the least studied step in the metastatic cascade. Protease-mediated escape and stromal invasion of tumor cells represent widely accepted processes leading up to the intravasation step. However, molecular factors that contribute directly to tumor cell vascular penetration have not been identified. In this study, the in vivo role of the collagenolytic protease, MMP-1, in cancer cell intravasation and metastasis was analyzed by using a highly disseminating variant of human HEp3 epidermoid carcinoma, HEp3-hi/diss. Although naturally acquired or experimentally induced MMP-1 deficiency substantially suppressed HEp3-hi/diss intravasation, supplementation of recombinant MMP-1 to MMP-1-silenced primary tumors restored their impaired vascular dissemination. Surprisingly, abrogation of MMP-1 production and activity did not significantly affect HEp3-hi/diss migration or matrix invasion, suggesting noncollagenolytic mechanisms underlying MMP-1-dependent cell intravasation. In support of such noncollagenolytic mechanisms, MMP-1 silencing in HEp3-hi/diss cells modulated the microarchitecture and integrity of the angiogenic vasculature in a novel microtumor model. Concomitantly, MMP-1 deficiency led to decreased levels of intratumoral vascular permeability, tumor cell intravasation, and metastatic dissemination. Taking advantage of PAR1 deficiency of HEp3-hi/diss cells, we further show that endothelial PAR1 is a putative nontumor-cell/nonmatrix target, activation of which by carcinoma-produced MMP-1 regulates endothelial permeability and transendothelial migration. The inhibitory effects of specific PAR1 antagonists in live animals have also indicated that the mechanisms of MMP-1-dependent vascular permeability in tumors involve endothelial PAR1 activation. Together, our findings mechanistically underscore the contribution of a tumor MMP 1/endothelial PAR1 axis to actual intravasation events manifested by aggressive carcinoma cells. PMID- 23687339 TI - Rb1 haploinsufficiency promotes telomere attrition and radiation-induced genomic instability. AB - Germline mutations of the retinoblastoma gene (RB1) predispose to both sporadic and radiation-induced osteosarcoma, tumors characterized by high levels of genomic instability, and activation of alternative lengthening of telomeres. Mice with haploinsufficiency of the Rb1 gene in the osteoblastic lineage reiterate the radiation susceptibility to osteosarcoma seen in patients with germline RB1 mutations. We show that the susceptibility is accompanied by an increase in genomic instability, resulting from Rb1-dependent telomere erosion. Radiation exposure did not accelerate the rate of telomere loss but amplified the genomic instability resulting from the dysfunctional telomeres. These findings suggest that telomere maintenance is a noncanonical caretaker function of the retinoblastoma protein, such that its deficiency in cancer may potentiate DNA damage-induced carcinogenesis by promoting formation of chromosomal aberrations, rather than simply by affecting cell-cycle control. PMID- 23687341 TI - Impact of body mass index on the risk of colorectal adenoma in a metabolically healthy population. AB - Metabolically healthy obese (MHO) states exist that seem to be protected from cardiovascular risks. Although obesity is a risk factor for colorectal adenoma (CRA), there has yet to be any study of the risks of CRA in MHO individuals. In this study, we compared CRA prevalence in MHO individuals versus metabolically healthy individuals who were normal in weight. This cross-sectional study involved 18,085 Korean adults (39.1 +/- 6.7 years) who had a health checkup including a colonoscopy. High-risk CRA was defined as any adenoma over 1 cm, 3 or more adenomas, adenoma with a villous component, or high-grade dysplasia. Multinomial logistic regression models were used to measure the associations between body mass index (BMI) and the risk of low-risk and high-risk CRA. Low risk and high-risk CRA were present in 9.3% and 1.4% of the study population, respectively. After adjusting for age, sex, smoking, drinking, exercise, family history of colorectal cancer, education, and use of analgesic and aspirin, compared with normal healthy individuals, the prevalence of low-risk and high risk CRA was increased in MHO individuals [OR = 1.44; 95% confidence interval (CI), 1.23-1.69 and OR = 1.62; 95% CI, 1.09-2.41, respectively]. In fully adjusted models, the prevalence of low-risk and high-risk CRA was associated with increasing categories of BMI in a dose-response manner (P for trend < 0.001 and 0.01, respectively). Thus, excess body weight, even in the absence of a metabolic unhealthy state, was found to be positively associated with increased presence of CRAs. PMID- 23687342 TI - Atypical presentation of verrucous carcinoma: a case study and review of the literature. AB - Verrucous carcinoma is a slow-growing lesion that is most often found on the weight-bearing surface of the foot and should be considered in the differential diagnosis for chronic nonhealing wounds in the diabetic neuropathic population. Accurate diagnosis may be difficult initially and often requires repeat histopathologic evaluation by an experienced pathologist. Verrucous carcinoma can invade deeper tissues; however, extension to bone is a rare occurrence. The authors present a case report of an atypical verrucous carcinoma on the dorsal aspect of the foot and a review of the literature. Studies suggest that multiple therapies exist and recurrence does occur; however, this is less likely with wide excision and more so with Mohs' surgery. With a high clinical suspicion and thorough histopathologic exam, bone involvement and amputation may be avoided. LEVELS OF EVIDENCE: Therapeutic, Level IV. PMID- 23687340 TI - G-CSF receptor positive neuroblastoma subpopulations are enriched in chemotherapy resistant or relapsed tumors and are highly tumorigenic. AB - Neuroblastoma is a neural crest-derived embryonal malignancy, which accounts for 13% of all pediatric cancer mortality, primarily due to tumor recurrence. Therapy resistant cancer stem cells are implicated in tumor relapse, but definitive phenotypic evidence of the existence of these cells has been lacking. In this study, we define a highly tumorigenic subpopulation in neuroblastoma with stem cell characteristics, based on the expression of CSF3R, which encodes the receptor for granulocyte colony-stimulating factor (G-CSF). G-CSF receptor positive (aka G-CSFr(+) or CD114(+)) cells isolated from a primary tumor and the NGP cell line by flow cytometry were highly tumorigenic and capable of both self renewal and differentiation to progeny cells. CD114(+) cells closely resembled embryonic and induced pluripotent stem cells with respect to their profiles of cell cycle, miRNA, and gene expression. In addition, they reflect a primitive undifferentiated neuroectodermal/neural crest phenotype revealing a developmental hierarchy within neuroblastoma tumors. We detected this dedifferentiated neural crest subpopulation in all established neuroblastoma cell lines, xenograft tumors, and primary tumor specimens analyzed. Ligand activation of CD114 by the addition of exogenous G-CSF to CD114(+) cells confirmed intact STAT3 upregulation, characteristic of G-CSF receptor signaling. Together, our data describe a novel distinct subpopulation within neuroblastoma with enhanced tumorigenicity and a stem cell-like phenotype, further elucidating the complex heterogeneity of solid tumors such as neuroblastoma. We propose that this subpopulation may represent an additional target for novel therapeutic approaches to this aggressive pediatric malignancy. PMID- 23687343 TI - Body mass index and achilles tendonitis: a 10-year retrospective analysis. AB - INTRODUCTION: High body mass index (BMI) has been implicated as an etiologic agent in Achilles tendonitis (AT) and may contribute to poorer treatment outcomes. The purpose of this study was to better elucidate the role of BMI in both the development and treatment of AT. METHODS: A matched case-control (1:1) study design was used. Matching criteria were age, gender, and year of presentation. Consecutive patients who presented with a diagnosis of AT between 2002 and 2011 at a single foot and ankle specialty clinic were identified. Patients who presented with other foot pain at the same clinic served as controls (CG). The AT group was further stratified into treatment responders and nonresponders. The main effect measure for both analyses was an adjusted odds ratio. RESULTS: A total of 944 patients (472 AT; 472 CG) were included. AT patients had higher BMI than those in the CG (30.2 +/- 6.5 vs 25.9 +/- 5.3, P < .001). Overweight and obese patients were 2.6 to 6.6 times more likely than those with a normal BMI to present with Achilles tendonitis (P < .001). There was also elevated risk of presenting with AT at higher BMI categories (Mantel-Haenszel chi (2) = 8.074, P = .004). However, only age, not BMI, correlated with having failed conservative treatment among the AT group, with patients older than 65 years at the greatest risk (odds ratio = 2.4, 95% confidence interval = 1.5 to 4.1, P < .001). CONCLUSION: BMI plays a role in the development of AT but does not appear to influence patient response to conservative treatment. LEVELS OF EVIDENCE: Prognostic, Level II. PMID- 23687344 TI - The correlation of Achilles tendinopathy and body mass index. AB - With this study we intend to determine if there is a correlation between body mass index (BMI) and Achilles tendon pathology. A retrospective chart review of 197 patients was performed with CPT codes of Achilles tendinosis/tendonitis. These 197 patients were then compared with 100 random new patient encounters excluding Achilles pathology, plantar fasciitis, and surgical consults. Statistical analysis was then performed to identify correlation of BMI to incidence of Achilles tendinosis compared with patients without Achilles pathology. A total of 197 Achilles tendon pathology patients (113 male, 84 female) were analyzed and had a mean age of 52.77 +/- 11.8 years (21-82) with a BMI of 34.69 +/- 7.54 (17.9-75.9). The control group had a mean age of 42.74 +/- 12.1 years (21-78) and mean BMI of 30.56 +/- 7.55 (19.7-61.5). A significant difference was found in mean BMI between the Achilles tendinopathy group versus the control group (P < .001). There was a very significant difference in age noted between the 2 cohorts (52.77 years vs 42.74 years, P < .001), perhaps reenforcing the involvement of age-related degenerative changes. In this study, patients with Achilles pathology exhibited a significantly higher BMI than non Achilles patients (P < .001) even after accounting for age. LEVELS OF EVIDENCE: Prognostic Level II. PMID- 23687345 TI - Absence of the fourth tendon of the flexor digitorum brevis muscle: a cadaveric study. AB - This study was undertaken to help confirm the percentages concerning the presence or absence of the flexor digitorum brevis muscle tendon to the fifth toe. We also hope to be able to determine the presence based on gender and nationality. It is known to be absent occasionally; however, there is no definitive study dedicated to its prevalence. Using a pool of 60 cadavers, 97 total feet were included in our analysis. Of these feet, 47 (48%) lacked a flexor digitorum brevis tendon to the fifth toe at all. Furthermore, 25 (26%) had notably small tendons to the fifth toe. The final 25 (26%) had what the researchers deemed present tendons. This information could be helpful in surgical planning, including tendon transfer techniques, and biomechanical evaluations. Further research would need to be conducted as this was a cadaveric study. LEVELS OF EVIDENCE: Cadaver/anatomy research, Level V. PMID- 23687347 TI - Exploiting tumor vulnerabilities: epigenetics, cancer metabolism and the mTOR pathway in the era of personalized medicine. AB - Patient stratification according to drug responses, together with the discovery of novel antitumor targets, is leading to a new era of personalized cancer treatments. With the aim of identifying emerging pathways and the challenges faced by clinicians during clinical trials, the IDIBELL Cancer Conference on Personalized Cancer Medicine took place in Barcelona on December 3-4, 2012. This conference brought together speakers working in different areas of cancer research (epigenetics, metabolism and the mTOR pathway, cell death and the immune system, clinical oncology) to discuss the latest developments in personalized cancer medicine. PMID- 23687346 TI - Metformin decreases glucose oxidation and increases the dependency of prostate cancer cells on reductive glutamine metabolism. AB - Metformin inhibits cancer cell proliferation, and epidemiology studies suggest an association with increased survival in patients with cancer taking metformin; however, the mechanism by which metformin improves cancer outcomes remains controversial. To explore how metformin might directly affect cancer cells, we analyzed how metformin altered the metabolism of prostate cancer cells and tumors. We found that metformin decreased glucose oxidation and increased dependency on reductive glutamine metabolism in both cancer cell lines and in a mouse model of prostate cancer. Inhibition of glutamine anaplerosis in the presence of metformin further attenuated proliferation, whereas increasing glutamine metabolism rescued the proliferative defect induced by metformin. These data suggest that interfering with glutamine may synergize with metformin to improve outcomes in patients with prostate cancer. PMID- 23687349 TI - Next generation diagnostics of cystic fibrosis and CFTR-related disorders by targeted multiplex high-coverage resequencing of CFTR. AB - BACKGROUND: Here we have developed a novel and much more efficient strategy for the complete molecular characterisation of the cystic fibrosis (CF) transmembrane regulator (CFTR) gene, based on multiplexed targeted resequencing. We have tested this approach in a cohort of 92 samples with previously characterised CFTR mutations and polymorphisms. METHODS: After enrichment of the pooled barcoded DNA libraries with a custom NimbleGen SeqCap EZ Choice array (Roche) and sequencing with a HiSeq2000 (Illumina) sequencer, we applied several bioinformatics tools to call mutations and polymorphisms in CFTR. RESULTS: The combination of several bioinformatics tools allowed us to detect all known pathogenic variants (point mutations, short insertions/deletions, and large genomic rearrangements) and polymorphisms (including the poly-T and poly-thymidine-guanine polymorphic tracts) in the 92 samples. In addition, we report the precise characterisation of the breakpoints of seven genomic rearrangements in CFTR, including those of a novel deletion of exon 22 and a complex 85 kb inversion which includes two large deletions affecting exons 4-8 and 12-21, respectively. CONCLUSIONS: This work is a proof-of-principle that targeted resequencing is an accurate and cost-effective approach for the genetic testing of CF and CFTR-related disorders (ie, male infertility) amenable to the routine clinical practice, and ready to substitute classical molecular methods in medical genetics. PMID- 23687348 TI - Loss of function of the E3 ubiquitin-protein ligase UBE3B causes Kaufman oculocerebrofacial syndrome. AB - BACKGROUND: Kaufman oculocerebrofacial syndrome (KOS) is a developmental disorder characterised by reduced growth, microcephaly, ocular anomalies (microcornea, strabismus, myopia, and pale optic disk), distinctive facial features (narrow palpebral fissures, telecanthus, sparse and laterally broad eyebrows, preauricular tags, and micrognathia), mental retardation, and generalised hypotonia. KOS is a rare, possibly underestimated condition, with fewer than 10 cases reported to date. Here we investigate the molecular cause underlying KOS. METHODS: An exome sequencing approach was used on a single affected individual of an Italian consanguineous family coupled with mutation scanning using Sanger sequencing on a second unrelated subject with clinical features fitting the disorder. RESULTS: Exome sequencing was able to identify homozygosity for a novel truncating mutation (c.556C>T, p.Arg186stop) in UBE3B, which encodes a widely expressed HECT (homologous to the E6-AP carboxyl terminus) domain E3 ubiquitin protein ligase. Homozygosity for a different nonsense lesion affecting the gene (c.1166G>A, p.Trp389stop) was documented in the second affected subject, supporting the recessive mode of inheritance of the disorder. Mutation scanning of the entire UBE3B coding sequence on a selected cohort of subjects with features overlapping, in part, those recurring in KOS did not reveal disease causing mutations, suggesting phenotypic homogeneity of UBE3B lesions. DISCUSSION: Our data provide evidence that KOS is caused by UBE3B loss of function, and further demonstrate the impact of misregulation of protein ubiquitination on development and growth. The available clinical records, including those referring to four UBE3B mutation-positive subjects recently described as belonging to a previously unreported entity, which fits KOS, document the clinical homogeneity of this disorder. PMID- 23687350 TI - Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly. AB - BACKGROUND: Mutations in TSC1 or TSC2 cause the tuberous sclerosis complex (TSC), a disorder characterised by the development of hamartomas or benign tumours in various organs as well as the variable presence of epilepsy, intellectual disability (ID) and autism. TSC1, TSC2 and the recently described protein TBC1D7 form a complex that inhibits mTORC1 signalling and limits cell growth. Although it has been proposed that mutations in TBC1D7 might also cause TSC, loss of its function has not yet been documented in humans. METHODS AND RESULTS: We used homozygosity mapping and exome sequencing to study a consanguineous family with ID and megalencephaly but without any specific features of TSC. We identified only one rare coding variant, c.538delT:p.Y180fsX1 in TBC1D7, in the regions of homozygosity shared by the affected siblings. We show that this mutation abolishes TBC1D7 expression and is associated with increased mTORC1 signalling in cells of the affected individuals. CONCLUSIONS: Our study suggests that disruption of TBC1D7 causes ID but without the other typical features found in TSC. Although megalencephaly is not commonly observed in TSC, it has been associated with mTORC1 activation. Our observation thus reinforces the relationship between this pathway and the development of megalencephaly. PMID- 23687351 TI - A novel desmin mutation leading to autosomal recessive limb-girdle muscular dystrophy: distinct histopathological outcomes compared with desminopathies. AB - BACKGROUND: Autosomal recessive limb girdle muscular dystrophy (LGMD2) is a heterogeneous group of myopathies characterised by progressive muscle weakness involving proximal muscles of the shoulder and pelvic girdles including at least 17 different genetic entities. Additional loci have yet to be identified as there are families which are unlinked to any of the known loci. Here we have investigated a consanguineous family with LGMD2 with two affected individuals in order to identify the causative gene defect. METHODS AND RESULTS: We performed genome wide homozygosity mapping and mapped the LGMD2 phenotype to chromosome 2q35-q36.3. DNA sequence analysis of the highly relevant candidate gene DES revealed a homozygous splice site mutation c.1289-2A>G in the two affected family members. Immunofluorescent staining and western blot analysis showed that the expression and the cytoskeletal network formation of mutant desmin were well preserved in skeletal muscle fibres. Unlike autosomal dominant desminopathies, ultrastructural alterations such as disruption of myofibrillar organisation, formation of myofibrillar degradation products and dislocation/aggregation of membranous organelles were not present. This novel splice site mutation results in addition of 16 amino acids within the tail domain of desmin, which has been suggested to interact with lamin B protein. We also detected a specific disruption of desmin-lamin B interaction in the skeletal muscle of the patient by confocal laser scanning microscopy. CONCLUSIONS: Our study reveals that autosomal recessive mutations in DES cause LGMD2 phenotype without features of myofibrillar myopathy. PMID- 23687352 TI - Biomechanical factors and macrophages in plaque stability. AB - Thin-cap fibroatheromas (TCFAs) or vulnerable atherosclerotic plaques are considered a high-risk phenotype for acute cardiovascular events. TCFAs are identified by a thin rupture-prone fibrous cap, a large necrotic core, and a high content of leucocytes. Atherogenesis is dependent upon complex patterns of blood flow. Slow-flowing blood imposing low shear stress on the arterial wall up regulates inflammatory signalling in endothelial cells and leucocytes, and modulates microRNAs to promote inflammation and monocyte recruitment. Hence, low shear stress is believed to promote conditions conducive to vulnerable plaque development. In this review, we explore how biomechanical factors modulate macrophage phenotype and plaque stability. PMID- 23687353 TI - Characterization of second-phase plates in a Gd5Ge3 intermetallic compound. AB - Rare-earth compounds based on the stoichiometry R5(Si(x)Ge(1-x))4 (R = rare-earth elements) exhibit many unusual features, including possessing R5(Si(x)Ge(1-x))3 thin plates which always precipitate from the matrix despite efforts to suppress their formation. In an effort to better understand the unique relationship between these two intermetallic alloy systems, the bulk microstructure of the compound Gd5Ge3 was examined using scanning (SEM) and transmission electron microscopy (TEM) and optical microscopy. Surprisingly, SEM examination revealed a series of thin plates present in the Gd5Ge3 matrix similar to what is seen in Gd5Ge4. TEM observation revealed that a role reversal had occurred, with the thin plates possessing the orthorhombic structure and composition of Gd5Ge4. The orientation relationship between Gd5Ge4 thin plates and the Gd5Ge3 matrix was determined to be [1 0 1 0 ](1 2 1 1)(m)||[0 1 0](1 0 2)(p), the same relationship reported for Gd5Ge3 plates precipitating from a Gd5Ge4 matrix. However, by exchanging the respective roles of the phases as regards matrix vs. precipitate, the total number of precipitation variants seen can be increased from two to six. The persistence with which these two intermetallic systems co-exist is truly unique. However, understanding exactly the kinetic and thermodynamic conditions that lead to their unique relationship is hampered by the high formation temperatures at which the observed reaction occurs. PMID- 23687354 TI - The mutation, a key determinant of phenotype in ADPKD. PMID- 23687355 TI - Working out nephronophthisis genetics one family at a time. PMID- 23687356 TI - A combined epidemiologic and metabolomic approach improves CKD prediction. AB - Metabolomic approaches have begun to catalog the metabolic disturbances that accompany CKD, but whether metabolite alterations can predict future CKD is unknown. We performed liquid chromatography/mass spectrometry-based metabolite profiling on plasma from 1434 participants in the Framingham Heart Study (FHS) who did not have CKD at baseline. During the following 8 years, 123 individuals developed CKD, defined by an estimated GFR of <60 ml/min per 1.73 m(2). Numerous metabolites were associated with incident CKD, including 16 that achieved the Bonferroni-adjusted significance threshold of P<=0.00023. To explore how the human kidney modulates these metabolites, we profiled arterial and renal venous plasma from nine individuals. Nine metabolites that predicted CKD in the FHS cohort decreased more than creatinine across the renal circulation, suggesting that they may reflect non-GFR-dependent functions, such as renal metabolism and secretion. Urine isotope dilution studies identified citrulline and choline as markers of renal metabolism and kynurenic acid as a marker of renal secretion. In turn, these analytes remained associated with incident CKD in the FHS cohort, even after adjustment for eGFR, age, sex, diabetes, hypertension, and proteinuria at baseline. Addition of a multimarker metabolite panel to clinical variables significantly increased the c-statistic (0.77-0.83, P<0.0001); net reclassification improvement was 0.78 (95% confidence interval, 0.60 to 0.95; P<0.0001). Thus, the addition of metabolite profiling to clinical data may significantly improve the ability to predict whether an individual will develop CKD by identifying predictors of renal risk that are independent of estimated GFR. PMID- 23687357 TI - The Kielin/chordin-like protein checkpoint constitutes a system of checks and balances in CKD. PMID- 23687358 TI - A piece of the puzzle in the cardiorenal conundrum. PMID- 23687359 TI - Association between LDL-C and risk of myocardial infarction in CKD. AB - LDL cholesterol (LDL-C) is an important marker of coronary risk in the general population, but its utility in people with CKD is unclear. We studied 836,060 adults from the Alberta Kidney Disease Network with at least one measurement of fasting LDL-C, estimated GFR (eGFR), and proteinuria between 2002 and 2009. All participants were free of stage 5 CKD at cohort entry. We followed participants from first eGFR measurement to March 31, 2009; we used validated algorithms applied to administrative data to ascertain primary outcome (hospitalization for myocardial infarction) and Cox regression to calculate adjusted hazard ratios (HRs) for myocardial infarction by LDL-C categories within eGFR strata. During median follow-up of 48 months, 7762 patients were hospitalized for myocardial infarction, with incidence highest among participants with the lowest eGFR. Compared with 2.6-3.39 mmol/L (referent), the risk associated with having LDL-C above 4.9 mmol/L seemed greatest for GFR>=90 ml/min per 1.73 m(2) and least for eGFR=15-59.9 ml/min per 1.73 m(2). Specifically, the adjusted HRs (95% confidence intervals) of myocardial infarction associated with LDL-C of >=4.9 compared with 2.6-3.39 mmol/L in participants with eGFR=15-59.9, 60-89.9, and >=90 ml/min per 1.73 m(2) were 2.06 (1.59, 2.67), 2.30 (2.00, 2.65), and 3.01 (2.46, 3.69). In conclusion, the association between higher LDL-C and risk of myocardial infarction is weaker for people with lower baseline eGFR, despite higher absolute risk of myocardial infarction. Increased LDL-C may be less useful as a marker of coronary risk among people with CKD than the general population. PMID- 23687360 TI - Renal lesions predict progression of diabetic nephropathy in type 1 diabetes. AB - Whether early glomerular, tubulointerstitial, vascular, and global glomerulosclerotic lesions can predict progression of diabetic nephropathy is not well defined. Here, we sought to determine whether renal structural parameters predict the development of proteinuria or ESRD after long-term follow-up. We measured several renal structures in kidney biopsies from 94 normoalbuminuric patients with longstanding type 1 diabetes using unbiased morphometric methods. Greater width of the glomerular basement membrane and higher levels of glycated hemoglobin were independent predictors of progression to diabetic nephropathy in this normoalbuminuric cohort. Moreover, none of these patients with type 1 diabetes who had glomerular basement membrane widths within the normal range developed proteinuria and/or ESRD. In conclusion, careful quantitative assessment of kidney biopsies in normoalbuminuric patients with type 1 diabetes adds substantially to the prediction of progression to clinical diabetic nephropathy. PMID- 23687361 TI - LMX1B mutations cause hereditary FSGS without extrarenal involvement. AB - LMX1B encodes a homeodomain-containing transcription factor that is essential during development. Mutations in LMX1B cause nail-patella syndrome, characterized by dysplasia of the patellae, nails, and elbows and FSGS with specific ultrastructural lesions of the glomerular basement membrane (GBM). By linkage analysis and exome sequencing, we unexpectedly identified an LMX1B mutation segregating with disease in a pedigree of five patients with autosomal dominant FSGS but without either extrarenal features or ultrastructural abnormalities of the GBM suggestive of nail-patella-like renal disease. Subsequently, we screened 73 additional unrelated families with FSGS and found mutations involving the same amino acid (R246) in 2 families. An LMX1B in silico homology model suggested that the mutated residue plays an important role in strengthening the interaction between the LMX1B homeodomain and DNA; both identified mutations would be expected to diminish such interactions. In summary, these results suggest that isolated FSGS could result from mutations in genes that are also involved in syndromic forms of FSGS. This highlights the need to include these genes in all diagnostic approaches to FSGS that involve next-generation sequencing. PMID- 23687362 TI - Long-term efficacy and safety of incobotulinumtoxinA injections in patients with cervical dystonia. AB - INTRODUCTION: Previously, controlled trials have demonstrated the efficacy and tolerability of fixed doses of incobotulinumtoxinA (Xeomin, NT 201, botulinum toxin type A free from complexing proteins) to treat cervical dystonia (CD). To explore the clinical relevance of these findings, this study evaluated long-term use of flexible dosing regimens of incobotulinumtoxinA in a setting close to real life clinical practice. METHODS: Patients with CD received five injection sessions of incobotulinumtoxinA using flexible intervals (10-24 weeks) and dosing (<=300 Units) based on patients' needs. Outcome measures included Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), the Dystonia Discomfort Scale (DDS), Investigator Global Assessment of Efficacy (IGAE) and Patient Evaluation of Global Response (PEGR). RESULTS: Of 76 patients enrolled (men: 34%; naive to botulinum toxin: 25%), 64 completed the study, receiving treatment over a duration of 49.3-114.1 weeks (total maximum duration: 121 weeks). Mean TWSTRS Total and DDS scores significantly improved from study baseline to 4 weeks after each injection session (ranges of improvement: TWSTRS-Total: -11.7 to -14.3; DDS: -20.2 to -23.0). Up to 81.6% of investigators rated the efficacy as 'good' or 'very good' (IGAE) and up to 78.9% of patients rated the treatment response as 'improved' (PEGR). The most common adverse events were dysphagia, nasopharyngitis and headache. CONCLUSIONS: In this long-term study, incobotulinumtoxinA was administered using more flexible dosing regimens than those permitted in previous controlled trials. Repeated injections of highly purified incobotulinumtoxinA are effective and well tolerated for the treatment of CD in a setting close to real life clinical practice. PMID- 23687363 TI - The neuroimaging signature of frontotemporal lobar degeneration associated with Granulin mutations: an effective connectivity study. AB - It has been suggested that monogenic frontotemporal lobar degeneration (FTLD) due to Granulin (GRN) mutations might present a specific pattern of atrophy, as compared with FTLD GRN-negative disease. Recent literature has suggested that the study of functional neural networks, rather than regional structural damage, might better elucidate the pathogenic mechanisms, showing complex relationships among structural alterations observed with conventional neuroimaging. The aim of this study was to evaluate effective brain connectivity in FTLD patients carrying GRN mutations (GRN+), compared with FTLD patients without pathogenetic GRN mutations (GRN-) and healthy controls (HCs). METHODS: Twenty-six FTLD patients (13 GRN+ and 13 GRN- matched for age, sex, and phenotype) and 13 age- and sex matched HCs underwent brain perfusion SPECT. Brain regions involved in FTLD (dorsolateral, anterior cingulate, orbitofrontal, posterior temporal, temporal pole, and parietal) were used as regions of interest to identify functionally interconnected areas. An effective connectivity (path) analysis was defined with a PC algorithm (named after its inventors Peter Spirtes and Clark Glymour) search procedure and structural equation fitting. Statistically significant differences among the 3 groups were determined. RESULTS: The best-fitting model was obtained by the data-driven approach, and brain connectivity pathways resembling state-of the-art anatomic knowledge were obtained. When GRN+ and GRN- groups were considered, the former presented a selective bilateral parietotemporal disconnection, compared with GRN- patients. Furthermore, in FTLD GRN+ patients an increased compensative connectivity of the temporal regions (temporal pole and posterior temporal cortices) was observed. CONCLUSION: The present work suggests that impairment of effective functional connectivity of the parietotemporal regions is the hallmark of GRN-related FTLD. However, compensative mechanisms- which should be further investigated-may occur. PMID- 23687364 TI - Al18F: a new standard for radiofluorination. PMID- 23687365 TI - Extrapulmonary disseminated tuberculosis with tuberculous adrenalitis: a stitch in time saves nine. AB - A 40-year-old manual labourer presented with easy fatiguability, recurrent vomiting and loss of weight of 3 months, duration. Upon examination, there was significant axillary and cervical lymphadenopathy. No pallor, icterus or clubbing was evident. There was generalised hyperpigmentation and multiple oral ulcers. The blood pressure 90/60 mm Hg in the right upper limb in the supine position. Investigations showed a low serum cortisol. Mantoux test was strongly positive (20 mm).A fine needle aspiration biopsy of the cervical lymph node revealed reactive changes. Bone marrow aspiration and biopsy were normal. Cervical lymph node biopsy showed caseating granulomas suggestive of tuberculous lymphadenitis. A CT scan of the abdomen showed bilaterally enlarged adrenal glands with hypodense areas suggestive of necrosis. He was diagnosed with extrapulmonary disseminated tuberculosis with tuberculous adrenalitis. He was started on directly observed therapy (DOTS) for disseminated tuberculosis and 40 mg of prednisolone. He is improving with treatment. PMID- 23687366 TI - Parathyroidectomy in the presence of central venous stenosis. AB - Hyperparathyroidism is common in the end-stage renal failure and may require surgical intervention. In addition, following multiple vascular access attempts central venous stenosis may occur. The results in high-volume venous blood flow through neck collaterals. Here, we describe a case of severe secondary hyperparathyroidism, high flow arteriovenous fistula and central venous occlusion unresponsive to radiological intervention. A four-gland exploration was undertaken and global parathyroidectomy was performed. Despite meticulous attention to haemostasis, blood loss was considerable from the skin edges although thyroid veins were easily controlled with a drop of 2.1 g/dl in haemoglobin. Postoperative hypocalcaemia requiring intravenous calcium occurred as expected from the severity of his bone disease (preoperative parathyroid hormone (PTH) 26 times the upper normal range). The patient recovered well, despite a small subcutaneous haematoma and remains asymptomatic. PMID- 23687367 TI - Pitfalls and bugs of nuclear and CT cardiac scans in an extremely obese patient: reasons for using conventional coronary angiography as first-line test. PMID- 23687368 TI - Role of fine needle aspiration cytology in diagnosing filarial arm cysts. AB - Filariasis is prevalent in tropical and subtropical areas and is endemic in regions of India. Lymphatic filariasis in India is caused mainly by two species of nematodes: Wuchereria bancrofti and Brugia malayi, which invade the human lymphatic system. We report two cases of superficial cystic lesions of the upper limb revealed on fine needle aspiration (FNA) to be clinically unsuspected filariasis. Despite similar aetiologies, both cases revealed variations in aspirate nature, smear morphology and peripheral blood findings. FNA provides definitive diagnosis and is an important tool for diagnosing soft tissue swellings owing to filariasis. PMID- 23687369 TI - Retropharyngeal cellulitis in adolescence. AB - A healthy 10-year-old boy presented with fever and progressively worsening sore throat and dysphagia. Physical examination showed pharyngeal erythema with tender left cervical lymphadenopathy. Radiography revealed 9 mm deep prevertebral soft tissues at the C2 level, and contrast-enhanced CT showed fluid collection with no major ring enhancement in the retropharyngeal space. He was diagnosed with retropharyngeal cellulitis and treated with intravenous antibiotics. Retropharyngeal cellulitis or abscess is a relatively rare infection in adolescents but is more frequent in 2-4-year-old children. Retropharyngeal cellulitis may rapidly extend caudally, with fatal consequences. For adolescents, physicians need to be aware of this clinical entity and carefully evaluate imaging findings even when only the mild pharyngeal physical findings are noted. PMID- 23687370 TI - Advanced adenocarcinoma in a colonic interposition segment. AB - Although rarely reported in the literature, adenomatous polyp and adenocarcinoma can occur as a late complication in an interposed colonic segment. We describe a case of a late stage adenocarcinoma in a colonic interposition performed for benign oesophageal stricture. PMID- 23687371 TI - The San Francisco declaration on research assessment. PMID- 23687372 TI - New roles of the fission yeast eIF2alpha kinases Hri1 and Gcn2 in response to nutritional stress. AB - In fission yeast, three distinct eukaryotic initiation factor 2alpha (eIF2alpha) kinases (Hri1, Hri2 and Gcn2), regulate protein synthesis in response to various environmental stresses. Thus, Gcn2 is activated early after exposure to hydrogen peroxide (H2O2) and methyl methanesulfonate (MMS), whereas Hri2 is the primary activated eIF2alpha kinase in response to heat shock. The function of Hri1 is still not completely understood. It is also known that the mitogen-activated protein kinase Sty1 negatively regulates Gcn2 and Hri2 activities under oxidative stress. In this study, we demonstrate that Hri1 is mainly activated, and its expression upregulated, during transition from exponential growth to the stationary phase in response to nutritional limitation. Accordingly, both Hri1 and Gcn2, but not Hri2, are activated upon nitrogen source deprivation. In contrast, Hri2 is stimulated early during glucose starvation. We also found that Gcn2 is implicated in nitrogen starvation-induced growth arrest in the cell cycle G1 phase as well as in the non-selective protein degradation process caused upon this particular cellular stress. Moreover, Gcn2, but not Hri1 or Hri2, is essential for survival of cells growing in minimal medium, upon oxidative stress or glucose limitation. We further show that eIF2alpha phosphorylation at serine 52 by the eIF2alpha kinases is necessary for efficient cell cycle arrest in the G1 phase, for the consequent protein degradation and for sexual differentiation, under nitrogen starvation. Therefore, the eIF2alpha kinase signalling pathway modulates G1 phase cell cycle arrest, cell survival and mating under nutritional stress in the fission yeast Schizosaccharomyces pombe. PMID- 23687373 TI - A ligand-specific kinetic switch regulates glucocorticoid receptor trafficking and function. AB - The ubiquitously expressed glucocorticoid receptor (GR) is a major drug target for inflammatory disease, but issues of specificity and target tissue sensitivity remain. We now identify high potency, non-steroidal GR ligands, GSK47867A and GSK47869A, which induce a novel conformation of the GR ligand-binding domain (LBD) and augment the efficacy of cellular action. Despite their high potency, GSK47867A and GSK47869A both induce surprisingly slow GR nuclear translocation, followed by prolonged nuclear GR retention, and transcriptional activity following washout. We reveal that GSK47867A and GSK47869A specifically alter the GR LBD structure at the HSP90-binding site. The alteration in the HSP90-binding site was accompanied by resistance to HSP90 antagonism, with persisting transactivation seen after geldanamycin treatment. Taken together, our studies reveal a new mechanism governing GR intracellular trafficking regulated by ligand binding that relies on a specific surface charge patch within the LBD. This conformational change permits extended GR action, probably because of altered GR HSP90 interaction. This chemical series may offer anti-inflammatory drugs with prolonged duration of action due to altered pharmacodynamics rather than altered pharmacokinetics. PMID- 23687374 TI - Preferential invasion of mitotic cells by Salmonella reveals that cell surface cholesterol is maximal during metaphase. AB - Cell surface-exposed cholesterol is crucial for cell attachment and invasion of many viruses and bacteria, including the bacterium Salmonella, which causes typhoid fever and gastroenteritis. Using flow cytometry and 3D confocal fluorescence microscopy, we found that mitotic cells, although representing only 1-4% of an exponentially growing population, were much more efficiently targeted for invasion by Salmonella. This targeting was not dependent on the spherical shape of mitotic cells, but was instead SipB and cholesterol dependent. Thus, we measured the levels of plasma membrane and cell surface cholesterol throughout the cell cycle using, respectively, brief staining with filipin and a fluorescent ester of polyethylene glycol-cholesterol that cannot flip through the plasma membrane, and found that both were maximal during mitosis. This increase was due not only to the rise in global cell cholesterol levels along the cell cycle but also to a transient loss in cholesterol asymmetry at the plasma membrane during mitosis. We measured that cholesterol, but not phosphatidylserine, changed from a ~2080 outerinner leaflet repartition during interphase to ~5050 during metaphase, suggesting this was specific to cholesterol and not due to a broad change of lipid asymmetry during metaphase. This explains the increase in outer surface levels that make dividing cells more susceptible to Salmonella invasion and perhaps to other viruses and bacteria entering cells in a cholesterol-dependent manner. The change in cholesterol partitioning also favoured the recruitment of activated ERM (Ezrin, Radixin, Moesin) proteins at the plasma membrane and thus supported mitotic cell rounding. PMID- 23687375 TI - Poly(lactide-co-glycolide)-rifampicin nanoparticles efficiently clear Mycobacterium bovis BCG infection in macrophages and remain membrane-bound in phago-lysosomes. AB - Nanoparticles (NPs) are increasingly used as biodegradable vehicles to selectively deliver therapeutic agents such as drugs or antigens to cells. The most widely used vehicle for this purpose is based on copolymers of lactic acid and glycolic acid (PLGA) and has been extensively used in experiments aimed at delivering antibiotics against Mycobacterium tuberculosis in animal models of tuberculosis. Here, we describe fabrication of PLGA NPs containing either a high concentration of rifampicin or detectable levels of the green fluorescent dye, coumarin-6. Our goal here was twofold: first to resolve the controversial issue of whether, after phagocytic uptake, PLGA NPs remain membrane-bound or whether they escape into the cytoplasm, as has been widely claimed. Second, we sought to make NPs that enclosed sufficient rifampicin to efficiently clear macrophages of infection with Mycobacterium bovis BCG. Using fluorescence microscopy and immuno electron microscopy, in combination with markers for lysosomes, we show that BCG bacteria, as expected, localized to early phagosomes, but that at least 90% of PLGA particles were targeted to, and remained in, low pH, hydrolase-rich phago lysosomes. Our data collectively argue that PLGA NPs remain membrane-enclosed in macrophages for at least 13 days and degrade slowly. Importantly, provided that the NPs are fabricated with sufficient antibiotic, one dose given after infection is sufficient to efficiently clear the BCG infection after 9-12 days of treatment, as shown by estimates of the number of bacterial colonies in vitro. PMID- 23687376 TI - Phosphorylation of STIM1 at ERK1/2 target sites regulates interaction with the microtubule plus-end binding protein EB1. AB - STIM1 (stromal interaction molecule 1) is a key regulator of store-operated calcium entry (SOCE). Upon depletion of Ca(2+) concentration within the endoplasmic reticulum (ER), STIM1 relocalizes at ER-plasma membrane junctions, activating store-operated calcium channels (SOCs). Although the molecular details for STIM1-SOC binding is known, the regulation of SOCE remains largely unknown. A detailed list of phosphorylated residues within the STIM1 sequence has been reported. However, the molecular pathways controlling this phosphorylation and its function are still under study. Using phosphospecific antibodies, we demonstrate that ERK1/2 mediates STIM1 phosphorylation at Ser575, Ser608 and Ser621 during Ca(2+) store depletion, and that Ca(2+) entry and store refilling restore phosphorylation to basal levels. This phosphorylation occurs in parallel to the dissociation from end-binding protein 1 (EB1), a regulator of growing microtubule ends. Although Ser to Ala mutation of residues 575, 608 and 621 showed a constitutive binding to EB1 even after Ca(2+) store depletion, Ser to Glu mutation of these residues (to mimic the phosphorylation profile attained after store depletion) triggered full dissociation from EB1. Given that wild-type STIM1 and STIM1(S575E/S608E/S621E) activate SOCE similarly, a model is proposed to explain how ERK1/2-mediated phosphorylation of STIM1 regulates SOCE. This regulation is based on the phosphorylation of STIM1 to trigger dissociation from EB1 during Ca(2+) store depletion, an event that is fully reversed by Ca(2+) entry and store refilling. PMID- 23687377 TI - A mechanism of gap junction docking revealed by functional rescue of a human disease-linked connexin mutant. AB - Gap junctions are unique intercellular channels formed by the proper docking of two hemichannels from adjacent cells. Each hemichannel is a hexamer of connexins (Cxs) - the gap junction subunits, which are encoded by 21 homologous genes in the human genome. The docking of two hemichannels to form a functional gap junction channel is only possible between compatible Cxs, but the underlying molecular mechanism is unclear. On the basis of the crystal structure of the Cx26 gap junction, we developed homology models for homotypic and heterotypic channels from Cx32 and/or Cx26; these models predict six hydrogen bonds at the docking interface of each pair of the second extracellular domain (E2). A Cx32 mutation N175H and a human-disease-linked mutant N175D were predicted to lose the majority of the hydrogen bonds at the E2 docking-interface; experimentally both mutations failed to form morphological and functional gap junctions. To restore the lost hydrogen bonds, two complementary Cx26 mutants - K168V and K168A were designed to pair with the Cx32 mutants. When docked with Cx26K168V or K168A, the Cx32N175H mutant was successfully rescued morphologically and functionally in forming gap junction channels, but not Cx32 mutant N175Y. By testing more homotypic and heterotypic Cx32 and/or Cx26 mutant combinations, it is revealed that a minimum of four hydrogen bonds at each E2-docking interface are required for proper docking and functional channel formation between Cx26 and Cx32 hemichannels. Interestingly, the disease-linked Cx32N175D could be rescued by Cx26D179N, which restored five hydrogen bonds at the E2-docking interface. Our findings not only provide a mechanism for gap junction docking for Cx26 and Cx32 hemichannels, but also a potential therapeutic strategy for gap junction channelopathies. PMID- 23687378 TI - Drosophila TRP and TRPL are assembled as homomultimeric channels in vivo. AB - Family members of the cationic transient receptor potential (TRP) channels serve as sensors and transducers of environmental stimuli. The ability of different TRP channel isoforms of specific subfamilies to form heteromultimers and the structural requirements for channel assembly are still unresolved. Although heteromultimerization of different mammalian TRP channels within single subfamilies has been described, even within a subfamily (such as TRPC) not all members co-assemble with each other. In Drosophila photoreceptors two TRPC channels, TRP and TRP-like protein (TRPL) are expressed together in photoreceptors where they generate the light-induced current. The formation of functional TRP-TRPL heteromultimers in cell culture and in vitro has been reported. However, functional in vivo assays have shown that each channel functions independently of the other. Therefore, the issue of whether TRP and TRPL form heteromultimers in vivo is still unclear. In the present study we investigated the ability of TRP and TRPL to form heteromultimers, and the structural requirements for channel assembly, by studying assembly of GFP-tagged TRP and TRPL channels and chimeric TRP and TRPL channels, in vivo. Interaction studies of tagged and native channels as well as native and chimeric TRP-TRPL channels using co-immunoprecipitation, immunocytochemistry and electrophysiology, critically tested the ability of TRP and TRPL to interact. We found that TRP and TRPL assemble exclusively as homomultimeric channels in their native environment. The above analyses revealed that the transmembrane regions of TRP and TRPL do not determine assemble specificity of these channels. However, the C-terminal regions of both TRP and TRPL predominantly specify the assembly of homomeric TRP and TRPL channels. PMID- 23687379 TI - Depletion of RAD17 sensitizes pancreatic cancer cells to gemcitabine. AB - Chemotherapy of advanced pancreatic cancer has mainly been gemcitabine-based for the past 15 years, with only limited effect. Recently, combination therapy that also targets checkpoint kinase 1 (CHK1) has become an attractive option. The central role of CHK1 in many DNA-damage response pathways, however, may result in undesired cytotoxicity in normal cells, causing side effects. We were searching for other target molecules of similar function that may be more specific and thus better suited for combination therapy. To this end a negative selection RNAi screen was performed in cell lines with small hairpin RNA molecules targeting over 10,000 genes. Genes that were found to be synthetically lethal with gemcitabine and whose proteins act upstream of CHK1 were characterised in more detail. In particular, the inhibition of RAD17 potentiated gemcitabine cytotoxicity in the pancreatic cancer cell lines BxPC-3 and MiaPaca-2 and in the primary cell line JoPaca-1 that closely resembles primary tumour tissue. Further analysis showed that the synergistic effect of RAD17 knockdown and gemcitabine leads to forced mitotic entry of cells arrested in S phase by gemcitabine treatment, resulting in asymmetric DNA distribution during anaphase followed by DNA fragmentation and finally cell death by mitotic catastrophe. Our data suggest RAD17 as a novel target protein for gemcitabine combination therapy supplementing or complementing inhibition of CHK1. In contrast to CHK1, RAD17 knockdown by itself does not lead to abnormal DNA segregation, suggesting a more specific action. PMID- 23687380 TI - Vinculin tension distributions of individual stress fibers within cell-matrix adhesions. AB - Actomyosin stress fibers (SFs) enable cells to exert traction on planar extracellular matrices (ECMs) by tensing focal adhesions (FAs) at the cell-ECM interface. Although it is widely appreciated that the spatial and temporal distribution of these tensile forces play key roles in polarity, motility, fate choice, and other defining cell behaviors, virtually nothing is known about how an individual SF quantitatively contributes to tensile loads borne by specific molecules within associated FAs. We address this key open question by using femtosecond laser ablation to sever single SFs in cells while tracking tension across vinculin using a molecular optical sensor. We show that disruption of a single SF reduces tension across vinculin in FAs located throughout the cell, with enriched vinculin tension reduction in FAs oriented parallel to the targeted SF. Remarkably, however, some subpopulations of FAs exhibit enhanced vinculin tension upon SF irradiation and undergo dramatic, unexpected transitions between tension-enhanced and tension-reduced states. These changes depend strongly on the location of the severed SF, consistent with our earlier finding that different SF pools are regulated by distinct myosin activators. We critically discuss the extent to which these measurements can be interpreted in terms of whole-FA tension and traction and propose a model that relates SF tension to adhesive loads and cell shape stability. These studies represent the most direct and high resolution intracellular measurements of SF contributions to tension on specific FA proteins to date and offer a new paradigm for investigating regulation of adhesive complexes by cytoskeletal force. PMID- 23687381 TI - Plakoglobin interacts with the transcription factor p53 and regulates the expression of 14-3-3sigma. AB - Plakoglobin (gamma-catenin), a constituent of the adherens junction and desmosomes, has signaling capabilities typically associated with tumor/metastasis suppression through mechanisms that remain undefined. To determine the role of plakoglobin during tumorigenesis and metastasis, we expressed plakoglobin in human tongue squamous cell carcinoma (SCC9) cells and compared the mRNA profiles of parental SCC9 cells and their plakoglobin-expressing transfectants (SCC9-PG). We detected several p53-target genes whose levels were altered upon plakoglobin expression. In this study, we identified the p53 regulated tumor suppressor 14-3 3sigma as a direct plakoglobin-p53 target gene. Coimmunoprecipitation experiments revealed that plakoglobin and p53 interact, and chromatin immunoprecipitation and electrophoretic mobility shift assays revealed that plakoglobin and p53 associate with the 14-3-3sigma promoter. Furthermore, luciferase reporter assays showed that p53 transcriptional activity is increased in the presence of plakoglobin. Finally, knockdown of plakoglobin in MCF-7 cells followed by luciferase assays confirmed that p53 transcriptional activity is enhanced in the presence of plakoglobin. Our data suggest that plakoglobin regulates gene expression in conjunction with p53 and that plakoglobin may regulate p53 transcriptional activity, which may account, in part, for the tumor/metastasis suppressor activity of plakoglobin. PMID- 23687382 TI - Evidence for a radial SNARE super-complex mediating neurotransmitter release at the Drosophila neuromuscular junction. AB - The SNARE proteins VAMP/synaptobrevin, SNAP-25 and syntaxin are core components of the apparatus that mediates neurotransmitter release. They form a heterotrimeric complex, and an undetermined number of SNARE complexes assemble to form a super-complex. Here, we present a radial model of this nanomachine. Experiments performed with botulinum neurotoxins led to the identification of one arginine residue in SNAP-25 and one aspartate residue in syntaxin (R206 and D253 in Drosophila melanogaster). These residues are highly conserved and predicted to play a major role in the protein-protein interactions between SNARE complexes by forming an ionic couple. Accordingly, we generated transgenic Drosophila lines expressing SNAREs mutated in these residues and performed an electrophysiological analysis of their neuromuscular junctions. Our results indicate that SNAP-25-R206 and syntaxin-D253 play a major role in neuroexocytosis and support a radial assembly of several SNARE complexes interacting via the ionic couple formed by these two residues. PMID- 23687383 TI - PfSec13 is an unusual chromatin-associated nucleoporin of Plasmodium falciparum that is essential for parasite proliferation in human erythrocytes. AB - In Plasmodium falciparum, the deadliest form of human malaria, the nuclear periphery has drawn much attention due to its role as a sub-nuclear compartment involved in virulence gene expression. Recent data have implicated components of the nuclear envelope in regulating gene expression in several eukaryotes. Special attention has been given to nucleoporins that compose the nuclear pore complex (NPC). However, very little is known about components of the nuclear envelope in Plasmodium parasites. Here we characterize PfSec13, an unusual nucleoporin of P. falciparum, which shows unique structural similarities suggesting that it is a fusion between Sec13 and Nup145C of yeast. Using super resolution fluorescence microscopy (3D-SIM) and in vivo imaging, we show that the dynamic localization of PfSec13 during parasites' intra-erythrocytic development corresponds with that of the NPCs and that these dynamics are associated with microtubules rather than with F-actin. In addition, PfSec13 does not co-localize with the heterochormatin markers HP1 and H3K9me3, suggesting euchromatic location of the NPCs. The proteins associated with PfSec13 indicate that this unusual Nup is involved in several cellular processes. Indeed, ultrastructural and chromatin immunoprecipitation analyses revealed that, in addition to the NPCs, PfSec13 is found in the nucleoplasm where it is associated with chromatin. Finally, we used peptide nucleic acids (PNA) to downregulate PfSec13 and show that it is essential for parasite proliferation in human erythrocytes. PMID- 23687384 TI - Shear wave induced resonance elastography of spherical masses with polarized torsional waves. AB - Shear Wave Induced Resonance (SWIR) is a technique for dynamic ultrasound elastography of confined mechanical inclusions. It was developed for breast tumor imaging and tissue characterization. This method relies on the polarization of torsional shear waves modeled with the Helmholtz equation in spherical coordinates. To validate modeling, an in vitro set-up was used to measure and image the first three eigenfrequencies and eigenmodes of a soft sphere. A preliminary in vivo SWIR measurement on a breast fibroadenoma is also reported. Results revealed the potential of SWIR elastography to detect and mechanically characterize breast lesions for early cancer detection. PMID- 23687385 TI - After All I Have Done For You: Self-silencing Accommodations Fuel Women's Post Rejection Hostility. AB - An experimental study tests if people's hostility after experiencing rejection is partly explained by the degree to which they had initially suppressed their own feelings and beliefs to please the source of rejection. This hypothesis emerges from the literatures on women's self-silencing and that on rejection-sensitivity, which has documented that rejection-sensitive women show strong responses to rejection, but are also likely to self-silence to please their partners. An online dating paradigm examined if this self-silencing drives post-rejection hostility among women. Participants were given the opportunity to read about a potential dating partner before meeting that person, and were randomly assigned to one of 3 experimental conditions that resulted in rejection from the potential date or from another dater. Self-silencing was captured as the suppression of tastes and opinions that clashed with those of the prospective partner. Self silencing moderated the effect of rejection on hostility: Self-silencing to the prospective partner was associated with greater post-rejection hostility among women, but not men. Self-silencing to someone other than the rejecter was not predictive of hostility. Women's dispositional rejection-sensitivity predicted greater hostility after rejection, and self-silencing mediated this association. Efforts to secure acceptance through accommodation may help explain the paradoxical tendency of some people to show strong rejection-induced hostility toward those whose acceptance they have sought. PMID- 23687386 TI - The Continuation of Intimate Partner Violence from Adolescence to Young Adulthood. AB - Little attention has been paid to whether violence in adolescent romantic relationships is associated with relationship violence later in young adulthood. This study examined the continuation of intimate partner violence (IPV) from adolescence to young adulthood. Using data from the National Longitudinal Study of Adolescent Health, results from negative binomial models and propensity score models showed that being victimized by relationship partners in adolescence was significantly associated with both perpetration and victimization in romantic relationships in young adulthood. Women reported higher levels of perpetration and lower levels of victimization than men did. Those who were living together (married or cohabiting) reported higher levels of victimization and perpetration than those who were dating. Further, such associations existed beyond the effects of parent-child violence and general aggression tendencies, suggesting the continuation of relationship-specific violence. Finally, these patterns persisted after controlling for participants' age, race and ethnicity, parental education, and family structure. PMID- 23687387 TI - Some Effects of Perceptual Load on Spoken Text Comprehension. AB - Investigations of spoken language comprehension often employ subsidiary task paradigms, such as word- and phoneme-monitoring procedures. In the present experiment we investigated what kinds of effects such secondary tasks might have on the course of simultaneous comprehension processing. Subjects listened to texts either without any secondary task demands (i.e., unconstrained comprehension), under word-monitoring instructions, or under phoneme-monitoring instructions. Comprehension was evaluated immediately after the presentation of each text with verification statements probing both the representation of surface structure and, also, the representation of high-level propositions, low-level propositions, and macropropositions from the text's meaning structure. Relative to unconstrained comprehension, we found an overall facilitation of comprehension due to word monitoring, and no effects as a result of phoneme monitoring. Moreover, the pattern of results across propositional levels was consistent with predictions derived from W. Kintsch and T. A. van Dijk's (Psychological Review, 1978, 85, 363-394) theory of text comprehension. This facilitation of simultaneous comprehension processing is inconsistent with the notion of a "fixed capacity decision mechanism," to which differences in monitoring effects are typically attributed. We argue that subsidiary task paradigms can be used for investigations of spoken text comprehension, but only when accompanied with probes for the well-established characteristics of text representation. PMID- 23687388 TI - Acetone sensor based on solvothermally prepared ZnO doped with Co3O4 nanorods. AB - This paper describes a reliable and sensitive method for sensing dissolved acetone using doped nanomaterials. Large-scale synthesis of ZnO nanorods (NRs) doped with Co3O4 was accomplished by a solvothermal method at low temperature. The doped NRs were characterized in terms of their morphological, structural, and optical properties by using field-emission scanning electron microscopy coupled with energy-dispersive system, UV-Vis., Fourier transform IR, X-ray diffraction, and Xray photoelectron spectroscopy. The calcinated (at 400 degrees C) doped NRs are shown to be an attractive semiconductor nanomaterial for detecting acetone in aqueous solution using silver electrodes. The sensor exhibits excellent sensitivity, stability and reproducibility. The calibration plot is linear over a large concentration range (66.8 MUM to 0.133 mM), displays high sensitivity (~3.58 MUA cm-2 mM-1) and a low detection limit (~14.7 +/- 0.2 MUM; at SNR of 3). FigureThe present study describes a simple, reliable, accurate, sensitive, and cost effective method for the detection of acetone using solvothermally prepared semiconductor co-doped nanomaterials. PMID- 23687389 TI - Why New Hybrid Organizations are Formed: Historical Perspectives on Epistemic and Academic Drift. AB - By comparing three types of hybrid organizations-18th-century scientific academies, 19th-century institutions of higher vocational education, and 20th century industrial research institutes-it is the purpose here to answer the question of why new hybrid organizations are continuously formed. Traditionally, and often implicitly, it is often assumed that emerging groups of potential knowledge users have their own organizational preferences and demands influencing the setup of new hybrid organizations. By applying the concepts epistemic and academic drift, it will be argued here, however, that internal organizational dynamics are just as important as changing historical conjunctures in the uses of science when understanding why new hybrid organizations are formed. Only seldom have older hybrid organizations sought to make themselves relevant to new categories of knowledge users as the original ones have been marginalized. Instead, they have tended to accede to ideals supported by traditional academic organizations with higher status in terms of knowledge management, primarily universities. Through this process, demand has been generated for the founding of new hybrid organizations rather than the transformation of existing ones. Although this study focuses on Swedish cases, it is argued that since Sweden strove consistently to implement existing international policy trends during the periods in question, the observations may be generalized to apply to other national and transnational contexts. PMID- 23687391 TI - The Effect of Surface Tension on the Gravity-driven Thin Film Flow of Newtonian and Power-law Fluids. AB - Gravity-driven thin film flow is of importance in many fields, as well as for the design of polymeric drug delivery vehicles, such as anti-HIV topical microbicides. There have been many prior works on gravity-driven thin films. However, the incorporation of surface tension effect has not been well studied for non-Newtonian fluids. After surface tension effect was incorporated into our 2D (i.e. 1D spreading) power-law model, we found that surface tension effect not only impacted the spreading speed of the microbicide gel, but also had an influence on the shape of the 2D spreading profile. We observed a capillary ridge at the front of the fluid bolus. Previous literature shows that the emergence of a capillary ridge is strongly related to the contact line fingering instability. Fingering instabilities during epithelial coating may change the microbicide gel distribution and therefore impact how well it can protect the epithelium. In this study, we focused on the capillary ridge in 2D flow and performed a series of simulations and showed how the capillary ridge height varies with other parameters, such as surface tension coefficient, inclination angle, initial thickness, and power-law parameters. As shown in our results, we found that capillary ridge height increased with higher surface tension, steeper inclination angle, bigger initial thickness, and more Newtonian fluids. This study provides the initial insights of how to optimize the flow and prevent the appearance of a capillary ridge and fingering instability. PMID- 23687392 TI - Adjusting for High-dimensional Covariates in Sparse Precision Matrix Estimation by l1-Penalization. AB - Motivated by the analysis of genetical genomic data, we consider the problem of estimating high-dimensional sparse precision matrix adjusting for possibly a large number of covariates, where the covariates can affect the mean value of the random vector. We develop a two-stage estimation procedure to first identify the relevant covariates that affect the means by a joint l1 penalization. The estimated regression coefficients are then used to estimate the mean values in a multivariate sub-Gaussian model in order to estimate the sparse precision matrix through a l1-penalized log-determinant Bregman divergence. Under the multivariate normal assumption, the precision matrix has the interpretation of a conditional Gaussian graphical model. We show that under some regularity conditions, the estimates of the regression coefficients are consistent in element-wise linfinity norm, Frobenius norm and also spectral norm even when p ? n and q ? n. We also show that with probability converging to one, the estimate of the precision matrix correctly specifies the zero pattern of the true precision matrix. We illustrate our theoretical results via simulations and demonstrate that the method can lead to improved estimate of the precision matrix. We apply the method to an analysis of a yeast genetical genomic data. PMID- 23687393 TI - NONIDEAL BEHAVIOR DURING COMPLETE DISSOLUTION OF ORGANIC IMMISCIBLE LIQUID: 1. IDEAL POROUS MEDIA. AB - Column experiments were conducted using ideal natural sands and stainless-steel beads to examine the complete dissolution behavior of an organic immiscible liquid. Trichloroethene (TCE) was used as the representative organic liquid. The elution curves exhibited multi-step behavior, with multiple extended periods of relatively constant contaminant flux. These secondary steady-state stages occurred at concentrations several orders-of-magnitude below aqueous solubility for the well-sorted sands. In contrast, the secondary steady-state stages occurred within one log of aqueous solubility for the poorly-sorted sand. The nonideal behavior is hypothesized to result from constraints to hydraulic accessibility of the organic liquid to flowing water, which may be expected to be mediated by the pore-scale configuration of the flow field and the fluid phases. PMID- 23687390 TI - Sleep and circadian dysfunction in neurodegenerative disorders: insights from a mouse model of Huntington's disease. AB - Sleep disorders are common in patients with neurogenerative diseases and manifest early in the disease process. Among a number of possible mechanisms underlying the sleep disturbances, there is evidence that dysfunction in the circadian system is a contributing factor. Focusing on a mouse model of Huntington's disease has enabled us to determine that at the onset of symptoms, spontaneous electrical activity of neurons within the central clock is disrupted even though the molecular clockwork is still functional. These findings suggest that the fundamental deficit contributing to disordered sleep is reduced SCN output. The mechanism underlying this deficit is not yet known, but mitochondrial dysfunction and oxidative stress are likely involved. Disruption of circadian output from the SCN would be expected to have wide ranging impact on the body including SCN regulated brain regions and the heart. In fact, there is a great deal of overlap in the non-motor symptoms experienced by HD patients and the consequences of circadian disruption. This raises the possibility that the disordered sleep and circadian function experienced by HD patients may be an integral part of the disease. Furthermore, we speculate that circadian dysfunction may accelerate the pathology underlying HD. If these hypotheses are correct, we should focus on treating circadian misalignment and sleep disruptions early in disease progression. PMID- 23687394 TI - Effectiveness of Dyes Removal by Mixed Fungal Cultures and Toxicity of Their Metabolites. AB - Decolorization of brilliant green (0.06 g/L), Evans blue (0.15 g/L), and their mixture (total concentration 0.08 g/L, proportion 1:1 w/w) by fungi was studied. Fungal strains [Pleurotus ostreatus (BWPH), Gloeophyllum odoratum (DCa), and Fusarium oxysporum (G1)] were used separately and as a mixture of them. Zootoxicity (Daphnia magna) and phytotoxicity (Lemna minor) changes were estimated after the end of experiment. Mixtures of fungal strains were less effective in decolorization process than the same strains used separately (as a single strains). After 96 h of experiment, living biomass of strain BWPH removed up to 95.5 %; DCa, up to 84.6 %; G1, up to 79.2 % where mixtures BWPH + DCa removed up to 74.3 %; and BWPH + G1, only up to 32.2 % of used dyes. High effectiveness of dyes removal not always corresponded with decrease of toxicity. The highest decrease of zootoxicity and phytotoxicity (from V to III toxicity class or to even nontoxic) was noticed for single strains, while no changes or slight toxicity decrease was noticed in samples with strains mixtures. PMID- 23687395 TI - Mercury and Chlorinated Pesticides on the Highest Level of the Food Web as Exemplified by Herring from the Southern Baltic and African Penguins from the Zoo. AB - Aquatic birds are often used as a health indicator of the marine ecosystem. African penguins living in the zoo make good research material as they form a link between the marine and the terrestrial ecosystem in terms of xenobiotic circulation. Tests were performed on whole herring-the food of the penguins-as well as on bird muscle, liver, brain, eggs, feathers and guano in order to determine total mercury, aldrin, dieldrin, endrin, isodrin, endosulfan isomers, endosulfan sulfate, methoxychlor, dichlorodiphenyltrichloroethane (DDT) and its metabolites. In herring and penguin, the tests did not show the presence of beta endosulfan, endosulfan sulfate, aldrin and isodrin. It was shown that penguins absorb about 36.8 MUg of organochlorine pesticides and 4.6 MUg of mercury with their food on a daily basis. Xenobiotics accumulate mostly in the liver, from where they are transported to the muscles and the brain, where the highest bioaccumulation factor is reached by endrin and pp'-DDT. Conceivably, the older the penguin, the higher is the concentration level of pesticides in its liver and brain. Molting was found to be the most effective way of eliminating mercury, dieldrin and methoxychlor from the system. Insecticides, such as DDT and its metabolites, were removed most effectively by females through laying of eggs. The standard four eggs laid within a year may have contained up to 20 % of the total amount of pesticides which had been absorbed with food, but no more than 5 % of mercury. PMID- 23687396 TI - Transgressive Hybrids as Hopeful Monsters. AB - The origin of novelty is a critical subject for evolutionary biologists. Early geneticists speculated about the sudden appearance of new species via special macromutations, epitomized by Goldschmidt's infamous "hopeful monster". Although these ideas were easily dismissed by the insights of the Modern Synthesis, a lingering fascination with the possibility of sudden, dramatic change has persisted. Recent work on hybridization and gene exchange suggests an underappreciated mechanism for the sudden appearance of evolutionary novelty that is entirely consistent with the principles of modern population genetics. Genetic recombination in hybrids can produce transgressive phenotypes, "monstrous" phenotypes beyond the range of parental populations. Transgressive phenotypes can be products of epistatic interactions or additive effects of multiple recombined loci. We compare several epistatic and additive models of transgressive segregation in hybrids and find that they are special cases of a general, classic quantitative genetic model. The Dobzhansky-Muller model predicts "hopeless" monsters, sterile and inviable transgressive phenotypes. The Bateson model predicts "hopeful" monsters with fitness greater than either parental population. The complementation model predicts both. Transgressive segregation after hybridization can rapidly produce novel phenotypes by recombining multiple loci simultaneously. Admixed populations will also produce many similar recombinant phenotypes at the same time, increasing the probability that recombinant "hopeful monsters" will establish true-breeding evolutionary lineages. Recombination is not the only (or even most common) process generating evolutionary novelty, but might be the most credible mechanism for sudden appearance of new forms. PMID- 23687397 TI - Using regression mixture models with non-normal data: Examining an ordered polytomous approach. AB - Mild to moderate skew in errors can substantially impact regression mixture model results; one approach for overcoming this includes transforming the outcome into an ordered categorical variable and using a polytomous regression mixture model. This is effective for retaining differential effects in the population; however, bias in parameter estimates and model fit warrant further examination of this approach at higher levels of skew. The current study used Monte Carlo simulations; three thousand observations were drawn from each of two subpopulations differing in the effect of X on Y. Five hundred simulations were performed in each of the ten scenarios varying in levels of skew in one or both classes. Model comparison criteria supported the accurate two class model, preserving the differential effects, while parameter estimates were notably biased. The appropriate number of effects can be captured with this approach but we suggest caution when interpreting the magnitude of the effects. PMID- 23687398 TI - Egocentric Perceptions of the Environment in Primary, but not Secondary, Psychopathy. AB - Several theories of psychopathy link it to an egocentric mode of perceiving the world. This explanatory perspective is quite plausible given that psychopaths are viewed as callous, uncaring, and narcissistic. This explanatory perspective, though, has been an insufficient focus of research, particularly in basic cognitive tasks. Building on the work of Wapner and Werner (1957), an implicit measure of cognitive egocentrism was developed. Continuous variations in primary and secondary psychopathy were assessed in a sample of college undergraduates (N = 80). Individuals high in primary psychopathy exhibited cognitive egocentrism, whereas individuals low in primary psychopathy did not. On the other hand, variations in secondary psychopathy were non-predictive of performance in the task. Results are discussed in terms of theories of psychopathy, distinctions between its primary and secondary components, and the utility of modeling egocentrism in basic cognitive terms. PMID- 23687399 TI - An Ecological Systems Comparison Between Homeless Sexual Minority Youths and Homeless Heterosexual Youths. AB - This study examined risk and protective outcomes by comparing homeless sexual minority youths to heterosexual homeless youths regarding family, peer behaviors, school, mental health (suicide risk and depression), stigma, discrimination, substance use, and sexual risk behaviors. Structured interviews (N = 147) were conducted with individuals ages 16-24 at three drop-in programs serving homeless youths in Toronto. Bivariate analyses indicated statistically significant differences between homeless sexual minorities (n=66) and their heterosexual counterparts (n=81) regarding all variables: family, peer behaviors, stigma, discrimination, mental health, substance use and sexual risk behaviors with the exception of school belonging. Specifically, homeless sexual minority youths fared more poorly (e.g. lower satisfaction with family communication, experienced more stigma, used more drugs and alcohol) than their heterosexual counterparts. Improving family communication may be a worthwhile intervention if the youths are still in contact with their families. Future research should focus on victimization in the context of multiple systems. PMID- 23687400 TI - Synthesis, characterization, and mercury adsorption properties of hybrid mesoporous aluminosilicate sieve prepared with fly ash. AB - A novel hybrid mesoporous aluminosilicate sieve (HMAS) was prepared with fly ash and impregnated with zeolite A precursors. This improved the mercury adsorption of HMAS compared to original MCM-41. The HMAS was characterized by X-ray diffraction (XRD), nitrogen adsorption-desorption, Fourier transform infrared (FTIR) analysis, transmission electron microscopy (TEM) images and 29Si and 27Al magic angle spinning nuclear magnetic resonance (MAS NMR) spectra. These showed that the HMAS structure was still retained after impregnated with zeolite A. But the surface area and pore diameter of HMAS decreased due to pore blockage. Adsorption of mercury from aqueous solution was studied on untreated MCM-41and HMAS. The mercury adsorption rate of HMAS was higher than that of origin MCM-41. The adsorption of mercury was investigated on HMAS regarding the pH of mercury solution, initial mercury concentration, and the reaction temperature. The experimental data fit well to Langmuir and Freundlich isotherm models. The Dublin Radushkevich isotherm and the characterization show that the mercury adsorption on HMAS involved the ion-exchange mechanisms. In addition, the thermodynamic parameters suggest that the adsorption process was endothermic in nature. The adsorption of mercury on HMAS followed the first order kinetics. PMID- 23687401 TI - Comparative oxidation state specific analysis of arsenic species by high performance liquid chromatography-inductively coupled plasma-mass spectrometry and hydride generation-cryotrapping-atomic absorption spectrometry. AB - The formation of methylarsonous acid (MAsIII) and dimethylarsinous acid (DMAsIII) in the course of inorganic arsenic (iAs) metabolism plays an important role in the adverse effects of chronic exposure to iAs. High-performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS) and hydride generation-cryotrapping-atomic absorption spectrometry (HG-CT-AAS) have been frequently used for the analysis of MAsIII and DMAsIII in biological samples. While HG-CT-AAS has consistently detected MAsIII and DMAsIII, HPLC-ICP MS analyses have provided inconsistent and contradictory results. This study compares the capacities of both methods to detect and quantify MAsIII and DMAsIII in an in vitro methylation system consisting of recombinant human arsenic (+3 oxidation state) methyltransferase (AS3MT), S-adenosylmethionine as a methyl donor, a non-thiol reductant tris(2-carboxyethyl)phosphine, and arsenite (iAsIII) or MAsIII as substrate. The results show that reversed-phase HPLC-ICP-MS can identify and quantify MAsIII and DMAsIII in aqueous mixtures of biologically relevant arsenical standards. However, HPLC separation of the in vitro methylation mixture resulted in significant losses of MAsIII, and particularly DMAsIII with total arsenic recoveries below 25%. Further analyses showed that MAsIII and DMAsIII bind to AS3MT or interact with other components of the methylation mixture, forming complexes that do not elute from the column. Oxidation of the mixture with H2O2 which converted trivalent arsenicals to their pentavalent analogs prior to HPLC separation increased total arsenic recoveries to ~95%. In contrast, HG-CT-AAS analysis found large quantities of methylated trivalent arsenicals in mixtures incubated with either iAsIII or MAsIII and provided high (>72%) arsenic recoveries. These data suggest that an HPLC-based analysis of biological samples can underestimate MAsIII and DMAsIII concentrations and that controlling for arsenic species recovery is essential to avoid artifacts. PMID- 23687402 TI - Social and emotional information processing in preschoolers: Indicator of early school success? AB - To better connect emotional development and social cognition literatures, the intersection of preschoolers' emotion and behaviour response choices to hypothetical peer conflicts was examined among 305 4 1/2-year-olds in private childcare and Head Start. Latent class analyses identified five subgroups of children with connections between their emotion and behaviour response choices (Happy/Passive, Sad/Socially Competent, Angry/Passive, Angry/Aggressive, Sad/Passive). Subgroup membership differed across gender and economic risk status, and was also a predictor of early school success (i.e., social competence, classroom adjustment, and academic readiness). Overall, even after accounting for the associations between known predictors of young children's behaviour and school success (i.e., gender and SES), membership in the subgroups at preschool was uniquely predictive of both concurrent and later social competence, classroom adjustment, and academic readiness. Further, preschool social competence partially mediated contributions of subgroup membership on kindergarten classroom adjustment. These findings are discussed in relation to existing social information processing and emotional development literatures, including potential implications for understanding young children's early school success. PMID- 23687403 TI - Gender, Ethnicity, Religiosity, and Same-sex Sexual Attraction and the Acceptance of Same-sex Sexuality and Gender Non-conformity. AB - This study explored the role of gender, ethnicity, religiosity, and sexual attraction in adolescents' acceptance of same-sex sexuality and gender non conformity. Using an intersectionality perspective, we also tested whether the effects of gender, ethnicity, and religiosity on adolescents' attitudes would function differently in adolescents with and without same-sex attractions. Data for this study were collected by means of a paper questionnaire completed by 1,518 secondary school students (mean age = 14.56 years, SD = 1.05) in Amsterdam, the Netherlands. The sample was 48.1% female and 51.9% male. Approximately one third of adolescents in the sample were of a non-Western ethnic background (32.3%, n = 491) and 7.5% of the participants (n = 114) reported experiencing same-sex attractions. Results of our analyses showed that adolescents in our sample who were male, of non-Western ethnicity, and who were more religious (as indicated by frequency of religious service attendance), were less accepting of same-sex sexuality and gender non-conformity in comparison to female, Western and less religious peers. We also found a significant interaction effect between religiosity and sexual attractions, but only in relation to evaluation of same sex attracted, gender nonconforming females. The negative effect of religiosity on acceptance of same-sex attracted, gender non-conforming females was stronger among those adolescents who reported same-sex attractions. PMID- 23687404 TI - Efficient Computing Budget Allocation for Finding Simplest Good Designs. AB - In many applications some designs are easier to implement, require less training data and shorter training time, and consume less storage than the others. Such designs are called simple designs, and are usually preferred over complex ones when they all have good performance. Despite the abundant existing studies on how to find good designs in simulation-based optimization (SBO), there exist few studies on finding simplest good designs. We consider this important problem in this paper, and make the following contributions. First, we provide lower bounds for the probabilities of correctly selecting the m simplest designs with top performance, and selecting the best m such simplest good designs, respectively. Second, we develop two efficient computing budget allocation methods to find m simplest good designs and to find the best m such designs, respectively; and show their asymptotic optimalities. Third, we compare the performance of the two methods with equal allocations over 6 academic examples and a smoke detection problem in wireless sensor networks. We hope that this work brings insight to finding the simplest good designs in general. PMID- 23687405 TI - The Child and Adult Care Food Program and the Nutrition of Preschoolers. AB - Children spend a considerable amount of time in preschools and child care centers. As a result, these settings may have an influence on their diet, weight, and food security, and are potentially important contexts for interventions to address nutritional health. The Child and Adult Care Food Program (CACFP) is one such intervention. No national study has compared nutrition-related outcomes of children in CACFP-participating centers to those of similar children in non participating centers. We use a sample of four-year old children drawn from the Early Childhood Longitudinal Study, Birth Cohort to obtain estimates of associations between CACFP program participation and consumption of milk, fruits, vegetables, fast food, and sweets, and indicators of overweight, underweight status and food insecurity. We find that, among low-income children, CACFP participation moderately increases consumption of milk and vegetables, and may also reduce the prevalence of overweight and underweight. Effects on other outcomes are generally small and not statistically significant. PMID- 23687406 TI - Reading Expressively and Understanding Thoroughly: An Examination of Prosody in Adults with Low Literacy Skills. AB - The purpose of the current study was to explore the relationship between prosody, which is the expressive quality of reading out loud, and reading comprehension in adults with low literacy skills compared to skilled readers. All participants read a passage orally, and we extracted prosodic measures from the recordings. We examined pitch changes and how long readers paused at various points while reading. Finally, for the adults with low literacy skills, we collected information on decoding, word recognition, and reading comprehension. We found several interesting results. First, adults with low literacy skills paused longer than skilled readers and paused at a substantially greater number of punctuation marks. Second, while adults with low literacy skills do mark the end of declarative sentences with a pitch declination similar to skilled readers, their readings of questions lack a change in pitch. Third, decoding and word recognition skills were related to pauses while reading; readers with lower skills made longer and more frequent and inappropriate pauses. Finally, pausing measures explained a significant amount of variance in reading comprehension among the adults with low literacy skills. PMID- 23687407 TI - Optimization of pulsed DEER measurements for Gd-based labels: choice of operational frequencies, pulse durations and positions, and temperature. AB - In this work, the experimental conditions and parameters necessary to optimize the long-distance (>= 60 A) Double Electron-Electron Resonance (DEER) measurements of biomacromolecules labeled with Gd(III) tags are analyzed. The specific parameters discussed are the temperature, microwave band, the separation between the pumping and observation frequencies, pulse train repetition rate, pulse durations and pulse positioning in the electron paramagnetic resonance spectrum. It was found that: (i) in optimized DEER measurements, the observation pulses have to be applied at the maximum of the EPR spectrum; (ii) the optimal temperature range for Ka-band measurements is 14-17 K, while in W-band the optimal temperatures are between 6-9 K; (iii) W-band is preferable to Ka-band for DEER measurements. Recent achievements and the conditions necessary for short distance measurements (<15 A) are also briefly discussed. PMID- 23687408 TI - Form follows function: pragmatic controlled trials (PCTs) have to answer different questions and require different designs than randomized controlled trials (RCTs). AB - AIM: Rising concern for demonstrated real world comparative effectiveness has heightened interest in "pragmatic trials" design. Pragmatic trials investigate whether the efficacy, presumed or found in explanatory trials under ideal conditions, can also be detected under real world conditions, i.e. effectiveness. It is also recognized that 'real world' effects which are usually addressed in public health research gain growing interest in confirming the 'road capability' of results obtained under ideal study conditions. This paper demonstrates that studies under ideal or real world conditions use different methods, generate different information and cannot replace each other. SUBJECTS AND METHODS: The PCT design meets four requirements of public health and of effectiveness research. It includes all individuals who presented with the selected condition. It classifies the included individuals according to baseline risks. It enables plausibility controls. Finally, it compares the outcomes resulting from specified and not-specified interventions or treatments. PROPOSAL: We propose a pragmatic controlled trial (PCT) design in which patient preference and other co-factors crucial in determining the actual effectiveness of interventional options will not be neutralized by concealed randomization and blinding. This design is applicable to record the selected interventions and generated outcomes in day-to day health care and is capable of incorporating preference and other participative factors into assessment of effectiveness. CONCLUSIONS: The PCT design is useful for public health research, e.g. the effectiveness of interventions to change smoking habits or to prevent death from breast cancer, as well as for comparative effectiveness research where it will supplement the traditional randomized controlled trial (RCT). PMID- 23687409 TI - Cathelicidin a potential therapeutic peptide for gastrointestinal inflammation and cancer. AB - Cathelicidins, are host defense peptides synthesized and stored in circulating leukocytes and numerous types of epithelial tissues in particular the gastrointestinal (GI) tract and skin. They have been known for their antimicrobial activities against a variety of microbes. Recently it was discovered that they have other significant biological functions and produce appealing pharmacological actions against inflammation and cancer in the GI tract through defined mechanisms. Experimental evidence shows that these actions could be tissue and disease specific and concentration dependent. This article reviews some of the physiological functions of cathelicidins and also their therapeutic potential in the treatment of inflammation and cancer and also the delivery system for this peptide as targeted therapy for various disorders in the GI tract both in animals and humans. PMID- 23687410 TI - Relationships of CDXs and apical sodium-dependent bile acid transporter in Barrett's esophagus. AB - Barrett's esophagus (BE) is characterized by intestinal metaplasia with the differentiated epithelium replaced by another type of epithelium morphologically similar to normal intestinal epithelium. The metaplasia is preceded by bile and acid reflux into the esophagus. BE is a premalignant condition associated with increased risk of esophageal cancer, especially esophageal adenocarcinoma. The Caudal-related homeodomain transcription factors Caudal-related homeodomain transcription factor CDX1 and CDX2 are expressed exclusively in the small and large intestine, playing important roles in proliferation and differentiation of intestinal epithelial cells. Ectopic expression of CDX1 and CDX2 occurs in BE. The apical sodium-dependent bile acid transporter (ASBT) is expressed primarily in terminal ileum where it is a key factor for intestinal reabsorption of bile salts. In addition to upregulation of CDX1 and CDX2, ASBT expression is up regulated in BE. Furthermore, both CDX1/CDX2 and ASBT expressions are down regulated in high-grade esophageal dysplasia. The alteration of the above mentioned factors calls for attention: what is the relationship between CDXs and ASBT aberrant expression in BE? In this commentary, we discuss this issue on basis of the recent study done by Ma et al. PMID- 23687412 TI - Efficacy and safety of over-the-scope clip: including complications after endoscopic submucosal dissection. AB - AIM: To retrospectively review the results of over-the-scope clip (OTSC) use in our hospital and to examine the feasibility of using the OTSC to treat perforations after endoscopic submucosal dissection (ESD). METHODS: We enrolled 23 patients who presented with gastrointestinal (GI) bleeding, fistulae and perforations and were treated with OTSCs (Ovesco Endoscopy GmbH, Tuebingen, Germany) between November 2011 and September 2012. Maximum lesion size was defined as lesion diameter. The number of OTSCs to be used per patient was not decided until the lesion was completely closed. We used a twin grasper (Ovesco Endoscopy GmbH, Tuebingen, Germany) as a grasping device for all the patients. A 9 mm OTSC was chosen for use in the esophagus and colon, and a 10 mm device was used for the stomach, duodenum and rectum. The overall success rate and complications were evaluated, with a particular emphasis on patients who had undergone ESD due to adenocarcinoma. In technical successful cases we included not only complete closing by using OTSCs, but also partial closing where complete closure with OTSCs is almost difficult. In overall clinical successful cases we included only complete closing by using only OTSCs perfectly. All the OTSCs were placed by 2 experienced endoscopists. The sites closed after ESD included not only the perforation site but also all defective ulcers sites. RESULTS: A total of 23 patients [mean age 77 years (range 64-98 years)] underwent OTSC placement during the study period. The indications for OTSC placement were GI bleeding (n = 9), perforation (n = 10), fistula (n = 4) and the prevention of post-ESD duodenal artificial ulcer perforation (n = 1). One patient had a perforation caused by a glycerin enema, after which a fistula formed. Lesion closure using the OTSC alone was successful in 19 out of 23 patients, and overall success rate was 82.6%. A large lesion size (greater than 20 mm) and a delayed diagnosis (more than 1 wk) were the major contributing factors for the overall unsuccessful clinical cases. The location of the unsuccessful lesion was in the stomach. The median operation time in the successful cases was 18 min, and the average observation time was 67 d. During the observation period, none of the patients experienced any complications associated with OTSC placement. In addition, we successfully used the OTSC to close the perforation site after ESD in 6 patients. This was a single center, retrospective study with a small sample size. CONCLUSION: The OTSC is effective for treating GI bleeding, fistulae as well as perforations, and the OTSC technique proofed effective treatment for perforation after ESD. PMID- 23687411 TI - Persistent hypertransaminasemia in asymptomatic children: a stepwise approach. AB - We aimed to examine the major causes of isolated chronic hypertransaminasemia in asymptomatic children and develop a comprehensive diagnostic flow diagram. A MEDLINE search inclusive of publications throughout August 2012 was performed. We found only a small number of publications that had comprehensively investigated this topic. Consequently, it was difficult to construct a diagnostic flowchart similar to those already available for adults. In children, a "retesting panel" prescription, including gamma-glutamyl transpeptidase and creatine kinase in addition to aminotransferases, is considered a reasonable approach for proficiently confirming the persistence of the abnormality, ruling out cholestatic hepatopathies and myopathies, and guiding the subsequent diagnostic steps. If re-evaluation of physical and historical findings suggests specific etiologies, then these should be evaluated in the initial enzyme retesting panel. A simple multi-step diagnostic algorithm incorporating a large number of possible pediatric scenarios, in addition to the few common to adults, is available. Accurately classifying a child with asymptomatic persistent hypertransaminasemia may be a difficult task, but the results are critical for preventing the progression of an underlying, possibly occult, condition later in childhood or during transition. Given the high benefit/cost ratio of preventing hepatic deterioration, no effort should be spared in diagnosing and properly treating each case of persistent hypertransaminasemia in pediatric patients. PMID- 23687413 TI - Lipoic acid suppresses portal endotoxemia-induced steatohepatitis and pancreatic inflammation in rats. AB - AIM: To examine the effect of alpha-lipoic acid (LA) on mild portal endotoxemia induced steatohepatitis and associated pancreatic abnormalities in fructose-fed rats. METHODS: Rats were randomly assigned into two groups with a regular or 60% fructose-enriched diet for 8 wk. After fructose feeding for 4 wk, rats were further divided into four subgroups: with intraportal saline (FPV), with intraportal saline plus administration of LA (FPV + LA), with lipopolysaccharide (LPS) infusion (FPLPS), and with LPS infusion plus administration of LA (FPLPS + LA). Rats were treated with LPS using intraportal infusion while LA was administered orally. Metabolite levels, superoxide levels, inflammatory markers, malondialdehyde content, glutathione content and toll-like receptor 4 (TLR4) gene expression were all measured using standard biochemical techniques. Pancreatic insulin secretion was evaluated by a hyperglycemic clamp technique. Histology of liver and pancreas tissues were evaluated using hematoxylin and eosin staining and immunohistochemistry. RESULTS: Fructose-induced elevation in plasma C reactive protein, amylase, superoxide, white blood cell count as well as in hepatic and pancreatic contents of malondialdehyde, tumor necrosis factor alpha and interleukin-6 were increased in animals treated with LPS and reversed with LA administration. The augmented hepatic gene expression of TLR4 in fructose-fed rats was further increased in those with intraportal LPS infusion, which was partially reversed by LA administration. Pathological examination showed inflammatory changes and leukocyte infiltration in hepatic and pancreatic islets of animals treated with LPS but were rarely observed in those with LA treatment. In addition to affects on the liver, impaired pancreatic insulin secretion seen in fructose-fed rats was deteriorated in with LPS treatment and partially reversed with LA administration. CONCLUSION: These data suggest LA could significantly suppress mild portal-endotoxemia but not fructose-induced liver and pancreatic abnormalities in a rodent model for metabolic syndrome. PMID- 23687414 TI - Oncogene GAEC1 regulates CAPN10 expression which predicts survival in esophageal squamous cell carcinoma. AB - AIM: To identify the downstream regulated genes of GAEC1 oncogene in esophageal squamous cell carcinoma and their clinicopathological significance. METHODS: The anti-proliferative effect of knocking down the expression of GAEC1 oncogene was studied by using the RNA interference (RNAi) approach through transfecting the GAEC1-overexpressed esophageal carcinoma cell line KYSE150 with the pSilencer vector cloned with a GAEC1-targeted sequence, followed by MTS cell proliferation assay and cell cycle analysis using flow cytometry. RNA was then extracted from the parental, pSilencer-GAEC1-targeted sequence transfected and pSilencer negative control vector transfected KYSE150 cells for further analysis of different patterns in gene expression. Genes differentially expressed with suppressed GAEC1 expression were then determined using Human Genome U133 Plus 2.0 cDNA microarray analysis by comparing with the parental cells and normalized with the pSilencer negative control vector transfected cells. The most prominently regulated genes were then studied by immunohistochemical staining using tissue microarrays to determine their clinicopathological correlations in esophageal squamous cell carcinoma by statistical analyses. RESULTS: The RNAi approach of knocking down gene expression showed the effective suppression of GAEC1 expression in esophageal squamous cell carcinoma cell line KYSE150 that resulted in the inhibition of cell proliferation and increase of apoptotic population. cDNA microarray analysis for identifying differentially expressed genes detected the greatest levels of downregulation of calpain 10 (CAPN10) and upregulation of trinucleotide repeat containing 6C (TNRC6C) transcripts when GAEC1 expression was suppressed. At the tissue level, the high level expression of calpain 10 protein was significantly associated with longer patient survival (month) of esophageal squamous cell carcinoma compared to the patients with low level of calpain 10 expression (37.73 +/- 16.33 vs 12.62 +/- 12.44, P = 0.032). No significant correction was observed among the TNRC6C protein expression level and the clinocopathologcial features of esophageal squamous cell carcinoma. CONCLUSION: GAEC1 regulates the expression of CAPN10 and TNRC6C downstream. Calpain 10 expression is a potential prognostic marker in patients with esophageal squamous cell carcinoma. PMID- 23687415 TI - MAWBP and MAWD inhibit proliferation and invasion in gastric cancer. AB - AIM: To investigate role of putative mitogen-activated protein kinase activator with WD40 repeats (MAWD)/MAWD binding protein (MAWBP) in gastric cancer (GC). METHODS: MAWBP and MAWD mRNA expression level was examined by real-time reverse transcriptase-polymerase chain reaction and semi-quantitative polymerase chain reaction in six GC cell lines. Western blotting was used to examine the protein expression levels. We developed GC cells that stably overexpressed MAWBP and MAWD, and downregulated expression by RNA interference assay. Proliferation and migration of these GC cells were analyzed by 3-(4,5-dimethyl-2-thiazolyl)-2,5 diphenyl tetrazolium bromide (MTT), soft agar, tumorigenicity, migration and transwell assays. The effect of expression of MAWBP and MAWD on transforming growth factor (TGF)-beta1-induced epithelial-mesenchymal transition (EMT) was examined by transfection of MAWBP and MAWD into GC cells. We detected the levels of EMT markers E-cadherin, N-cadherin and Snail in GC cells overexpressing MAWBP and MAWD by Western blotting. The effect of MAWBP and MAWD on TGF-beta signal was detected by analysis of phosphorylation level and nuclear translocation of Smad3 using Western blotting and immunofluorescence. RESULTS: Among the GC cell lines, expression of endogenous MAWBP and MAWD was lowest in SGC7901 cells and highest in BGC823 cells. MAWBP and MAWD were stably overexpressed in SGC7901 cells and knocked down in BGC823 cells. MAWBP and MAWD inhibited GC cell proliferation in vitro and in vivo. MTT assay showed that overexpression of MAWBP and MAWD suppressed growth of SGC7901 cells (P < 0.001), while knockdown of these genes promoted growth of BGC823 cells (P < 0.001). Soft agar colony formation experiments showed that overexpression of MAWBP and MAWD alone or together reduced colony formation compared with vector group in SGC7901 (86.25 +/- 8.43, 12.75 +/- 4.49, 30 +/- 6.41 vs 336.75 +/- 22.55, P < 0.001), and knocked-down MAWBP and MAWD demonstrated opposite effects (131.25 +/- 16.54, 88.75 +/- 11.12, 341.75 +/- 22.23 vs 30.25 +/- 8.07, P < 0.001). Tumorigenicity experiments revealed that overexpressed MAWBP and MAWD inhibited GC cell proliferation in vivo (P < 0.001). MAWBP and MAWD also inhibited GC cell invasion. Transwell assay showed that the number of traverse cells of MAWBP, MAWD and coexpression group were more than that in vector group (84 +/- 16.57, 98.33 +/- 9.8, 29 +/- 16.39 vs 298 +/- 11.86, P < 0.001). Coexpression of MAWBP and MAWD significantly decreased the cells traversing the matrix membrane. Conversely, knocked-down MAWBP and MAWD correspondingly promoted invasion of GC cells (100.67 +/- 14.57, 72.66 +/- 8.51, 330.67 +/- 20.55 vs 27 +/- 11.53, P < 0.001). More importantly, coexpression of MAWBP and MAWD promoted EMT. Cells that coexpressed MAWBP and MAWD displayed a pebble-like shape and tight cell-cell adhesion, while vector cells showed a classical mesenchymal phenotype. Western blotting showed that expression of E cadherin was increased, and expression of N-cadherin and Snail was decreased when cells coexpressed MAWBP and MAWD and were treated with TGF-beta1. Nuclear translocation of p-Smad3 was reduced by attenuating its phosphorylation. CONCLUSION: Coexpression of MAWBP and MAWD inhibited EMT, and EMT-aided malignant cell progression was suppressed. PMID- 23687416 TI - Sustained virological response: a milestone in the treatment of chronic hepatitis C. AB - AIM: To evaluate the long-term eradication of hepatitis C virus (HCV) infection and liver-related complications in chronically infected patients that have achieved sustained virological response. METHODS: One hundred and fifty subjects with chronic hepatitis C (CHC) or cirrhosis and sustained virological response (SVR) between the years of 1989 and 2008 were enrolled in a long-term clinical follow-up study at the Gastrointestinal and Liver Unit of the University Hospital of Naples "Federico II". At the beginning of the study, the diagnosis of HCV infection was made on the basis of serum positivity for antibodies to HCV and detection of HCV RNA transcripts, while a diagnosis of chronic hepatitis was formulated using imaging techniques and/or a liver biopsy. SVR was achieved by interferon-based therapy, both conventional and pegylated, with and without ribavirin treatment. The patients were evaluated for follow-up at a median length of 8.6 years, but ranged from 2-19.9 years. Among them, 137 patients had pre treatment CHC and 13 had cirrhosis. The patients were followed with clinical, biochemical, virological, and ultrasound assessments on a given schedule. Finally, a group of 27 patients underwent a liver biopsy at the beginning of the study and transient elastography at their final visit to evaluate changes in liver fibrosis. RESULTS: The median follow-up was 8.6 years (range 2-19.9 years). HCV RNA remained undetectable in all patients, even in patients who eventually developed liver-related complications, indicating no risk of HCV recurrence. Three liver-related complications were observed: two cases of hepatocellular carcinoma and one case of bleeding from esophageal varices resulting in an incidence rate of 0.23%/person per year. Further, all three complications took place in patients diagnosed with cirrhosis before treatment began. Only one death due to liver-related causes occurred, resulting in a mortality rate of 0.077% person per year. This amounts to a 99.33% survival rate in our cohort of patients after therapy for HCV infection. Finally, of the 27 patients who underwent a liver biopsy at the beginning of the study, a reduction in liver fibrosis was observed in 70.3% of the cases; only three cases registering values of liver stiffness indicative of significant fibrosis. CONCLUSION: Patients with CHC and SVR show an excellent prognosis with no risk of recurrence and a very low rate of mortality. Our data indicate that virus-eradication following interferon treatment can last up to 20 years. PMID- 23687417 TI - Long-term efficacy of endoscopic coagulation for different types of gastric vascular ectasia. AB - AIM: To examine the long-term therapeutic efficacies of endoscopic cauterization for gastric vascular ectasia, according to the type of lesion. METHODS: Thirty eight patients with hemorrhagic gastric vascular ectasia (VE) were treated by endoscopic cauterization: 13 by heater probe coagulationand 25 by argon plasma coagulation. Depending on the number of lesions, 14 and 24 patients were classified into localized VE (<= 10; LVE) and extensive VE (> 10; EVE), respectively. The patients were followed-up by repeated endoscopic examinations after the therapy, and the incidences of VE recurrence and re-bleeding from the lesions were evaluated. RESULTS: Although the VE lesions disappeared initially in all the patients after the therapy, the recurrence of VE developed in 25 patients (66%) over a mid-term observation period of 32 mo, and re-bleeding occurred in 15 patients (39%). The recurrence of VE was found in all patients with EVE, with re bleeding occurring in 14 patients (58%). In contrast, only 1 patient (7%) with LVE showed recurrence of the lesions and complicating hemorrhage. Both the cumulative recurrence-free rates and cumulative re-bleeding-free rates were significantly lower in the EVE group than in the LVE group (P < 0.001 and P < 0.001, respectively). Moreover, the cumulative re-bleeding-free rate in the EVE group was 47.6% at 1 year and 25.4% at 2 years in patients with chronic renal failure, which were significantly lower than the rates in the patients without chronic renal failure (83.3% and 74.1%, respectively) (P < 0.05). CONCLUSION: The recurrence of VE and re-bleeding from the lesions was more frequent in the patients with EVE, especially in those with complicating renal failure. PMID- 23687418 TI - Extremely high prevalence of Helicobacter pylori infection in Bhutan. AB - AIM: To revealed the prevalence of Helicobacter pylori (H. pylori) infection in the Bhutanese population. METHODS: We recruited a total of 372 volunteers (214 females and 158 males; mean age of 39.6 +/- 14.9 years) from three Bhutanese cities (Thimphu, Punaka, and Wangdue). The status of H. pylori infection was determined based on five different tests: the rapid urease test (CLO test), culture, histology, immunohistochemistry (IHC), and serum anti H. pylori antibody. RESULTS: The serological test showed a significantly higher positive rate compared with the CLO test, culture, histology and IHC (P < 0.001, P < 0.001, P = 0.01, and P = 0.01, respectively). When the subjects were considered to be H. pylori positive in the case of at least one test showing a positive result, the overall prevalence of H. pylori infection in Bhutan was 73.4%. The prevalence of H. pylori infection significantly decreased with age (P < 0.01). The prevalence of H. pylori infection was lower in Thimphu than in Punakha and Wangdue (P = 0.001 and 0.06, respectively). The prevalence of H. pylori infection was significantly higher in patients with peptic ulcers than in those with gastritis (91.4% vs 71.3%, P = 0.003). CONCLUSION: The high incidence of gastric cancer in Bhutan may be attributed to the high prevalence of H. pylori infection. PMID- 23687419 TI - Prognostic value of preoperative mean corpuscular volume in esophageal squamous cell carcinoma. AB - AIM: To evaluate whether preoperative mean corpuscular volume (MCV) is a prognostic indicator in patients with resectable esophageal squamous cell carcinoma (ESCC). METHODS: A total of 298 consecutive, prospectively enrolled patients with histologically diagnosed ESCC who underwent surgery with curative intent from 2001 to 2011 were retrospectively evaluated. Patients were excluded if they had previous malignant disease, distant metastasis at the time of primary treatment, a history of neoadjuvant treatment, had undergone non-radical resection, or had died of a non-tumor-associated cause. Survival status was verified in September 2011. Pathological staging was performed based on the 2010 American Joint Committee on Cancer criteria. Preoperative MCV was obtained from blood counts performed routinely within 7 d prior to surgery. Receiver operating characteristic (ROC) curve analysis was used to determine a cutoff for preoperative MCV. RESULTS: The 298 patients consisted of 230 males and 68 females, with a median follow-up of 30.1 mo. ROC analysis showed an optimal cutoff for preoperative MCV of 95.6 fl. Fifty-nine patients (19.8%) had high (> 95.6 fl) and 239 (80.2%) had low (<= 95.6 fl) preoperative MCV. Preoperative MCV was significantly associated with gender (P = 0.003), body mass index (P = 0.017), and preoperative red blood cell count (P < 0.001). The predicted 1-, 3- and 5-year overall survival (OS) rates were 72%, 60% and 52%, respectively. Median OS was significantly longer in patients with low than with high preoperative MCV (27.5 mo vs 19.4 mo, P < 0.001). Multivariate analysis showed that advanced pT (P = 0.018) and pN (P < 0.001) stages, upper thoracic location (P = 0.010), lower preoperative albumin concentration (P = 0.002), and high preoperative MCV (P = 0.001) were negative prognostic factors in patients with ESCC. Preoperative MCV also stratified OS in patients with T3, N1-N3, G2-G3 and stage III tumors. CONCLUSION: Preoperative MCV is a prognostic factor in patients with ESCC. PMID- 23687421 TI - Massive hepatic necrosis with toxic liver syndrome following portal vein ligation. AB - Right portal vein ligation (PVL) is a safe and widespread procedure to induce controlateral liver hypertrophy for the treatment of bilobar colorectal liver metastases. We report a case of a 60-year-old man treated by both right PVL and ligation of the glissonian branches of segment 4 for colorectal liver metastases surrounding the right and median hepatic veins. After surgery, the patient developed massive hepatic necrosis with secondary pulmonary and renal insufficiency requiring transfer to the intensive care unit. This so-called toxic liver syndrome finally regressed after hemofiltration and positive oxygen therapy. Diagnosis of acute congestion of the ligated lobe was suspected. The mechanism suspected was an increase in arterial inflow secondary to portal vein ligation concomitant with a decrease in venous outflow due to liver metastases encircling the right and median hepatic vein. This is the first documented case of toxic liver syndrome in a non-cirrhotic patient with favorable issue, and a rare complication of PVL. PMID- 23687420 TI - Increased CD163 expression is associated with acute-on-chronic hepatitis B liver failure. AB - AIM: To assess CD163 expression in plasma and peripheral blood and analyze its association with disease in acute-on-chronic hepatitis B liver failure (ACHBLF) patients. METHODS: A retrospective study was conducted from January 1, 2011 to January 1, 2012. Forty patients with ACHBLF (mean age 44.48 +/- 12.28 years, range 18-69 years), 40 patients with chronic hepatitis B (CHB) (mean age 39.45 +/ 12.22 years, range 21-57 years) and 20 age- and sex-matched healthy controls (mean age 38.35 +/- 11.97 years, range 28-60 years) were included in this study. Flow cytometry was used to analyze the frequency of CD163+ peripheral blood mononuclear cells (PBMCs) and surface protein expression of CD163. Real-time transcription-polymerase chain reaction was performed to assess relative CD163 mRNA levels in PBMCs. Plasma soluble CD163 (sCD163) levels were measured by enzyme-linked immunosorbent assay. Clinical variables were also recorded. Comparisons between groups were analyzed by Kruskal-Wallis H test and Mann Whitney U test. Statistical analyses were performed using SPSS 15.0 software and a P value < 0.05 was considered statistically significant. RESULTS: Flow cytometry showed that the population of CD163+ PBMCs was significantly greater in ACHBLF patients than in CHB patients and healthy controls (47.9645% +/- 17.1542%, 32.0975% +/- 11.0215% vs 17.9460% +/- 6.3618%, P < 0.0001). However, there were no significant differences in mean fluorescence intensity of CD163+ PBMCs within the three groups (27.4975 +/- 11.3731, 25.8140 +/- 10.0649 vs 20.5050 +/- 6.2437, P = 0.0514). CD163 mRNA expression in ACHBLF patients was significantly increased compared with CHB patients and healthy controls (1.41 * 10-2 +/- 2.18 * 10-2, 5.10 * 10-3 +/- 3.61 * 10-3 vs 37.0 * 10-4 +/- 3.55 * 10-4, P = 0.02). Plasma sCD163 levels in patients with ACHBLF were significantly increased compared with CHB patients and healthy controls (4706.2175 +/- 1681.1096 ng/mL, 1089.7160 +/- 736.8395 ng/mL vs 435.9562 +/- 440.8329 ng/mL, P < 0.0001). In ACHBLF patients, plasma sCD163 levels were significantly positively associated with model for end stage liver disease scores (r = 0.5075, P = 0.008), hepatitis B virus-DNA (r = 0.6827, P < 0.0001), and negatively associated with prothrombin activity (r = 0.3348, P = 0.0347), but had no correlation with total bilirubin (r = 0.2551, P = 0.1122). Furthermore, sCD163 was obviously elevated in non-surviving patients compared with surviving patients with ACHBLF (5344.9080 +/- 1589.5199 ng/mL vs 3641.7333 +/- 1264.5228 ng/mL, P = 0.0321). CONCLUSION: CD163 and sCD163 may be related to disease severity and prognosis in ACHBLF patients. PMID- 23687422 TI - Polyarteritis nodosa diagnosed by surgically resected jejunal necrosis following acute abdomen. AB - The differential diagnosis of acute abdomen is typically extremely broad in range, with vasculitis posing a rare but potentially life-threatening cause of acute abdomen. Here, we report a case of acute abdomen with bowel wall thickening limited to jejunum, accompanied by unexplained renal dysfunction. Later, the patient was diagnosed as having polyarteritis nodosa based on surgically resected jejunal necrosis. Despite aggressive treatment, including the use of steroid pulse therapy and continuous hemodiafiltration, the patient died. Although polyarteritis nodosa is extremely rare in patients with acute abdomen, acute abdomen is relatively common manifestation of that. And it is reported that involvement of small intestine suggests poorer prognosis. Our case highlights the importance of vasculitis as a differential diagnosis of patients with atypical acute abdomen. In this report, we not only review possible clues that might have led to an earlier diagnosis in this case, but also attempt to draw some lessons for treating similar cases in the future. PMID- 23687423 TI - Two case reports of gastroendoscopy-associated Acinetobacter baumannii bacteremia. AB - Two cases of gastroendoscopy-associated Acinetobacter baumannii (A. baumannii) bacteremia were discovered at the study hospital. The first case was a 66-year old woman who underwent endoscopic retrograde cholangiopancreatography and endoscopic retrograde papillotomy, and then A. baumannii bacteremia occurred. The second case was a 70-year-old female who underwent endoscopic retrograde biliary drainage due to obstruction of intra-hepatic ducts, and bacteremia occurred due to polymicrobes (Escherichia coli, viridans streptococcus, and A. baumannii). After a literature review, we suggest that correct gastroendoscopy technique and skill in drainage procedures, as well as antibiotic prophylaxis, are of paramount importance in minimizing the risk of gastroendoscopy-associated bacteremia. PMID- 23687424 TI - Morse-Smale Regression. AB - This paper introduces a novel partition-based regression approach that incorporates topological information. Partition-based regression typically introduce a quality-of-fit-driven decomposition of the domain. The emphasis in this work is on a topologically meaningful segmentation. Thus, the proposed regression approach is based on a segmentation induced by a discrete approximation of the Morse-Smale complex. This yields a segmentation with partitions corresponding to regions of the function with a single minimum and maximum that are often well approximated by a linear model. This approach yields regression models that are amenable to interpretation and have good predictive capacity. Typically, regression estimates are quantified by their geometrical accuracy. For the proposed regression, an important aspect is the quality of the segmentation itself. Thus, this paper introduces a new criterion that measures the topological accuracy of the estimate. The topological accuracy provides a complementary measure to the classical geometrical error measures and is very sensitive to over-fitting. The Morse-Smale regression is compared to state-of-the art approaches in terms of geometry and topology and yields comparable or improved fits in many cases. Finally, a detailed study on climate-simulation data demonstrates the application of the Morse-Smale regression. Supplementary materials are available online and contain an implementation of the proposed approach in the R package msr, an analysis and simulations on the stability of the Morse-Smale complex approximation and additional tables for the climate simulation study. PMID- 23687425 TI - Executive Function in Children with Cochlear Implants: The Role of Organizational Integrative Processes. PMID- 23687426 TI - Adalimumab (tumor necrosis factor-blocker) reduces the expression of glial fibrillary acidic protein immunoreactivity increased by exogenous tumor necrosis factor alpha in an organotypic culture of porcine neuroretina. AB - PURPOSE: To determine if exogenous addition of tumor necrosis factor alpha (TNFalpha) exacerbates retinal reactive gliosis in an organotypic culture of porcine neuroretina and to evaluate if concomitant adalimumab, a TNF-blocker, diminishes it. METHODS: Porcine retinal explants from 20 eyeballs were cultured. Cultures with 100 pg/ml TNFalpha, 10 ug/ml adalimumab, 100 pg/ml TNFalpha plus 10 ug/ml adalimumab, or controls without additives were maintained for 9 days. Freshly detached retinas were processed in parallel. TNFalpha levels in control culture supernatants were quantified with enzyme-linked immunosorbent assay. Cryostat sections were doubly immunostained for glial fibrillary acidic protein (GFAP), a marker for reactive gliosis, and cellular retinaldehyde-binding protein (CRALBP), a marker for Muller cells. Sections were also labeled with the isolectin IB4, a label for microglia/macrophages. RESULTS: TNFalpha in control culture supernatants was detected only at day 1. Compared to the fresh neuroretinal samples, upregulation of GFAP and downregulation of CRALBP occurred during the 9 days of culture. Exogenous TNFalpha stimulated glial cells to upregulate GFAP and downregulate CRALBP immunoreactivity. TNFalpha-treated cultures also initiated the growth of gliotic membranes and underwent retinal disorganization. Adalimumab inhibited the spontaneous increases in GFAP and maintained CRALBP. In combination with TNFalpha, adalimumab reduced GFAP expression and conserved CRALBP, with only slight retinal disorganization. No appreciable changes in IB4 labeling were observed under the different culture conditions. CONCLUSIONS: In cultured porcine neuroretina, spontaneous reactive gliosis and retinal disorganization were exacerbated by exogenous TNFalpha. Adalimumab reduced spontaneous changes and those induced by TNFalpha. Therefore, inhibiting TNFalpha may represent a novel approach to controlling retinal fibrosis observed in some human diseases. PMID- 23687427 TI - Phenotypic map of porcine retinal ganglion cells. AB - PURPOSE: Porcine retina is an excellent model for studying diverse retinal processes and diseases. The morphologies of porcine retinal ganglion cells (RGCs) have, however, not yet been described comprehensively. The aim of the present study was to create a classification of the RGCs using the 1, 1'-dioctadecyl 3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) tracing method. METHODS: About 170 RGCs were retrogradely labeled by injecting DiI into the optic nerve of postmortem eyes and statistically analyzed by two different clustering methods: Ward's algorithm and the K-means clustering. Major axis length of the soma, soma area size, and dendritic field area size were selected as main parameters for cluster classification. RESULTS: RGC distribution in clusters was achieved according to their morphological parameters. It was feasible to combine both statistical methods, thereby obtaining a robust clustering distribution. Morphological analysis resulted in a classification of RGCs in three groups according to the soma size and dendritic field: A (large somas and large dendritic fields), B (medium to large somas and medium to large dendritic fields), C (medium to small somas and medium to small dendritic fields). Within groups, fine clustering defined several subgroups according to dendritic arborization and level of stratification. Additionally, cells stratifying in two different levels of the inner plexiform layer were observed within the clusters. CONCLUSIONS: This comprehensive study of RGC morphologies in the porcine retina provides fundamental knowledge about RGC cell types and provides a basis for functional studies toward selective RGC cell degeneration in retinal disorders. PMID- 23687428 TI - The ribbon-associated protein C-terminal-binding protein 1 is not essential for the structure and function of retinal ribbon synapses. AB - PURPOSE: Synaptic ribbons are organelles found at presynaptic active zones of sensory neurons that generate sustained graded electrical signals in response to stimuli, including retinal photoreceptor cells and bipolar neurons. RIBEYE is the major and specific protein constituent of ribbons; however, over the past decade an increasing number of other proteins have been identified at ribbon active zones, including C-terminal-binding protein 1 (CtBP1; a regulator of transcription and membrane trafficking that might bind to the B domain of RIBEYE). The appearance of CtBP1 together with RIBEYE suggests that it may contribute to ribbon function, but the possible role of CtBP1 at ribbon synapses has not yet been examined. Using CtBP1-knockout mice, we tested for functional effects of absence of CtBP1 protein. METHODS: Confocal microscopy, electrophysiology, and electron microscopy were used to examine the structure and function of ribbon synapses in the retina and in isolated bipolar neurons from CtBP1 null mice compared with their wild-type littermates. RESULTS: Expression of ribbons appeared to be normal in CtBP1 null mouse retina as revealed by immunofluorescence with an antibody to the B domain of RIBEYE and by binding studies using a fluorescent peptide that binds to RIBEYE in ribbons of living bipolar cells. Electron microscopy also showed grossly normal pre- and postsynaptic organization of ribbon synapses in both photoreceptors and bipolar cells. Synaptic vesicles were normal in size, but the overall density of reserve vesicles was reduced by ~20% in the cytoplasm of CtBP1 null ribbon synaptic terminals. However, the reduced vesicle density did not detectably alter synaptic function of bipolar neurons as revealed by activity-dependent loading of synaptic vesicles with FM4-64, presynaptic calcium current, capacitance measurements of synaptic exocytosis, and destaining of FM dye upon stimulation. CONCLUSIONS: Overall the results suggest that CtBP1 protein is not essential for the formation of functional ribbon synapses in the retina. PMID- 23687429 TI - The protective effect of antioxidants on orbital fibroblasts from patients with Graves' ophthalmopathy in response to oxidative stress. AB - PURPOSE: To investigate the biphasic effects of hydrogen peroxide (H2O2) on the orbital fibroblasts of patients with Graves' ophthalmopathy (GO) and the relation to antioxidants and proinflammatory cytokines. METHODS: Proliferation of cultured orbital fibroblasts from patients with GO and normal controls was evaluated in response to various concentrations of H2O2. The effect of low concentrations of H2O2 (6.25 MUM) on the cellular proliferation and induction of intracellular proinflammatory cytokines, and reactive oxygen species of orbital fibroblasts were assessed. Protective effects of N-acetylcysteine and vitamin C on GO fibroblasts in response to 6.25 MUM H2O2 stimulation were also investigated. RESULTS: When the GO fibroblasts were exposed to H2O2 at a concentration of 50 MUM or above, significant cytotoxicity was observed. In contrast, lower concentrations of H2O2 (3.125-25 MUM) increased the survival of GO fibroblasts with the peak cellular proliferation at 6.25 MUM H2O2. However, this biphasic effect of H2O2 on the viability of orbital fibroblasts was not found in normal controls. In addition, 6.25 MUM H2O2 led to significant elevation of the levels of transforming growth factor, beta 1, interleukin-1beta, and superoxide anion in GO fibroblasts, but no significant change in the normal controls. Pretreatment with N-acetylcysteine or vitamin C reversed the enhanced proliferation capacity and the induction of transforming growth factor, beta 1, interleukin-1beta and superoxide anion of GO fibroblasts in response to 6.25 MUM H2O2. CONCLUSIONS: These findings revealed the biphasic effect of H2O2 on cellular proliferation of GO orbital fibroblasts. Importantly, a low level of H2O2 can stimulate proliferation of GO orbital fibroblasts and induce the production of proinflammatory cytokines, which can be inhibited by pretreatment with antioxidants. This provides a theoretical basis for the rational use of antioxidant in treating GO at an early stage. PMID- 23687430 TI - A novel forkhead box C1 gene mutation in a Korean family with Axenfeld-Rieger syndrome. AB - PURPOSE: To report a case series of patients with novel forkhead box CI (FOXC1) mutations in a Korean family with Axenfeld-Rieger syndrome (ARS). METHODS: Four members of the same family underwent complete ophthalmologic and systemic examinations and genetic analysis. Genomic DNA was isolated from peripheral blood leukocytes, and all coding exons with flanking intronic regions of the FOXC1 and pituitary homeobox 2 genes were amplified using PCR, and sequenced. RESULTS: The patients were 40, 12, 11, and 10 years old (father, son, and two sisters, respectively). All four had uncontrolled intraocular pressure, glaucomatous visual field defect, retinal nerve fiber layer defect, iridocorneal adhesion on gonioscopy, hypoplasia and marked atrophy of the iris, flattening of the midface, and broad flat noses. A diagnosis of ARS was made based on characteristic ocular and systemic traits. A novel FOXC mutation, c.317delA, was identified in all affected members of the family with ARS. CONCLUSIONS: We found a novel c.317delA mutation in FOXC1 in a Korean family with ARS. We suggest that this FOXC1 mutation causes typical ARS, and that our results may be useful for better understanding of the spectrum of FOXC1 mutations and the role of FOXC1 in the development and progression of ARS. PMID- 23687431 TI - No association of age-related maculopathy susceptibility protein 2/HtrA serine peptidase 1 or complement factor H polymorphisms with early age-related maculopathy in a Chinese cohort. AB - PURPOSE: Single nucleotide polymorphisms (SNPs) of age-related maculopathy susceptibility protein 2/HtrA serine peptidase 1 (ARMS2/HTRA1) and complement factor H (CFH) have been reported to be associated with age-related macular degeneration (AMD). The purpose of this study was to investigate the association of ARMS2/HTRA1 and CFH SNPs with early age-related maculopathy (ARM) in a Han Chinese cohort. METHODS: The cohort consisted of 315 unrelated subjects, including 158 patients with early ARM and 157 recruited controls. Early ARM was diagnosed and graded according to the Age-Related Eye Disease Study criteria. Four SNPs in ARMS2/HTRA1 and six SNPs in CFH previously reported to be associated with AMD were genotyped using TaqMan genotyping assays. Logistic regression implemented with the R statistical language was used for association analysis. RESULTS: None of the ARMS2/HTRA1 and CFH SNPs showed any significant association with early ARM (all p>0.453), with the odds ratios ranging from 0.88 to 1.17. None of the SNPs were associated with unilateral or bilateral early ARM or any grade of early ARM (all p>0.249). CONCLUSIONS: The association of ARMS2/HTRA1 and CFH SNPs in early ARM was not detected in our cohort. The findings in the current study indicated that the effects of ARMS2/HTRA1 and CFH in early ARM could be much lower compared to those in AMD. PMID- 23687432 TI - Changes in gene expression associated with retinal degeneration in the rd3 mouse. AB - PURPOSE: To identify and characterize changes in gene expression associated with photoreceptor degeneration in the rd3 mouse model of Leber congenital amaurosis (LCA) type 12. METHODS: Global genome expression profiling using microarray technology was performed on total RNA extracts from rd3 and wild-type control mouse retinas at postnatal day 21. Quantitative PCR analysis of selected transcripts was performed to validate the microarray results. RESULTS: Functional annotation of differentially regulated genes in the rd3 mouse defined key canonical pathways, including phototransduction, glycerophospholipid metabolism, tumor necrosis factor receptor 1 signaling, and endothelin signaling. Overall, 1,140 of approximately 55,800 transcripts were differentially represented. In particular, a large percentage of the upregulated transcripts encode proteins involved in the immune response; whereas the downregulated transcripts encode proteins involved in phototransduction and lipid metabolism. CONCLUSIONS: This analysis has elucidated several candidate genes and pathways, thus providing insight into the pathogenic mechanisms underlying the photoreceptor degeneration in the rd3 mouse retina and indicating directions for future studies. PMID- 23687433 TI - Quantification of MUCIN 1, cell surface associated and MUCIN16, cell surface associated proteins in tears and conjunctival epithelial cells collected from postmenopausal women. AB - PURPOSE: To quantify the expression of mucin 1, cell surface associated (MUC1) and mucin 16, cell surface associated (MUC16) proteins and messenger ribonucleic acid (mRNA) in a cohort of postmenopausal women (PMW), to explore the relationship between mucin expression, dry eye symptomology, and tear stability. METHODS: Thirty-nine healthy PMW (>50 years of age) were enrolled in this study. No specific inclusion criteria were used to define dry eye; instead, a range of subjects were recruited based on responses to the Allergan Ocular Surface Disease Index (OSDI) questionnaire and tear stability measurements as assessed by non invasive tear breakup time (NITBUT). Tears were collected from the inferior tear meniscus using a disposable glass capillary tube, and total RNA and total protein were isolated from conjunctival epithelial cells collected via impression cytology. Expression of membrane-bound and soluble MUC1 and MUC16 were quantified with western blotting, and expression of MUC1 and MUC16 mRNA was assessed with real-time PCR. RESULTS: OSDI responses ranged from 0 to 60, and NITBUT ranged from 18.5 to 2.9 s. Only two statistically significant correlations were found: soluble MUC16 protein concentration and MUC16 mRNA expression with OSDI vision related (-0.47; p=0.01) and ocular symptom (0.39; p=0.02) subscores, respectively. Post hoc exploratory analysis on absolute expression values was performed on two subsets of subjects defined as asymptomatic (OSDI<=6, n=12) and moderate to severe symptomatic (OSDI>=20, n=12). The only significant difference between the two subgroups was a significant reduction in MUC16 mRNA expression found in the symptomatic dry eye group (1.52+/-1.19 versus 0.57+/-0.44; p=0.03). CONCLUSIONS: A broad exploration of mucin expression compared to either a sign (NITBUT) or symptoms of dry eye failed to reveal compelling evidence supporting a significant relationship, other than a potential association between MUC16 with specific symptoms. Furthermore, comparison of mucin protein and expression levels between the asymptomatic and moderate to severe symptomatic subgroups revealed only one significant difference, a reduction in MUC16 mRNA expression in the symptomatic subgroup. PMID- 23687434 TI - Evaluation of autosomal dominant retinal dystrophy genes in an unaffected cohort suggests rare or private missense variants may often be benign. AB - BACKGROUND: Many genes have been reported as harboring autosomal dominant mutations causing retinal dystrophy. As newly available gene panel sequencing and whole exome sequencing will open these genes up to greater scrutiny, we assess the rate of rare coding variation in these genes among unaffected individuals to provide context for variants that will be discovered when clinical subjects are sequenced. METHODS: Publicly available data from the Exome Variant Project were analyzed, focusing on 36 genes known to harbor mutations causing autosomal dominant macular dystrophy. RESULTS: Rates of rare (minor allele frequency <=0.1%) and private missense variants within autosomal dominant retinal dystrophy genes were found to occur at a high frequency in unaffected individuals, while nonsense variants were not. CONCLUSIONS: We conclude that rare missense variations in most of these genes identified in individuals with retinal dystrophy cannot be confidently classified as disease-causing in the absence of additional information such as linkage or functional validation. PMID- 23687435 TI - Diversified clinical presentations associated with a novel sal-like 4 gene mutation in a Chinese pedigree with Duane retraction syndrome. AB - PURPOSE: To determine the underlying genetic cause of Duane retraction syndrome (DRS) in a non-consanguineous Chinese Han family. METHODS: Detailed ophthalmic and physical examinations were performed on all members from a pedigree with DRS. All exons and their adjacent splicing junctions of the sal-like 4 (SALL4) gene were amplified with polymerase chain reaction and analyzed with direct sequencing in all the recruited family members and 200 unrelated control subjects. RESULTS: Clinical examination revealed a broad spectrum of phenotypes in the DRS family. Mutation analysis of SALL4 identified a novel heterozygous duplication mutation, c.1919dupT, which was completely cosegregated with the disease in the family and absent in controls. This mutation was predicted to cause a frameshift, introducing a premature stop codon, when translated, resulting in a truncated SALL4 protein, i.e., p.Met640IlefsX25. Bioinformatics analysis showed that the affected region of SALL4 shared a highly conserved sequence across different species. Diversified clinical manifestations were observed in the c.1919dupT carriers of the family. CONCLUSIONS: We identified a novel truncating mutation in the SALL4 gene that leads to diversified clinical features of DRS in a Chinese family. This mutation is predicted to result in a truncated SALL4 protein affecting two functional domains and cause disease development due to haploinsufficiency through nonsense-mediated mRNA decay. PMID- 23687436 TI - Subretinal electrical stimulation preserves inner retinal function in RCS rat retina. AB - PURPOSE: Previously, studies showed that subretinal electrical stimulation (SES) from a microphotodiode array (MPA) preserves electroretinography (ERG) b-wave amplitude and regional retinal structure in the Royal College of Surgeons (RCS) rat and simultaneously upregulates Fgf2 expression. This preservation appears to be associated with the increased current produced when the MPA is exposed to ERG test flashes, as weekly ERG testing produces greater neuroprotection than biweekly or no testing. Using an infrared source to stimulate the MPA while avoiding potential confounding effects from exposing the RCS retina to high luminance white light, this study examined whether neuroprotective effects from SES increased with subretinal current in a dose-dependent manner. METHODS: RCS rats (n=49) underwent subretinal implantation surgery at P21 with MPA devices in one randomly selected eye, and the other eye served as the control. Naive RCS rats (n=25) were also studied. To increase SES current levels, implanted eyes were exposed to 15 min per session of flashing infrared light (IR) of defined intensity, frequency, and duty cycle. Rats were divided into four SES groups that received ERG testing only (MPA only), about 450 uA/cm2 once per week (Low 1X), about 450 uA/cm2 three times per week (Low 3X), and about 1350 uA/cm2 once per week (High 1X). One eye of the control animals was randomly chosen for IR exposure. All animals were followed for 4 weeks with weekly binocular ERGs. A subset of the eyes was used to measure retina Fgf2 expression with real-time reverse-transcription PCR. RESULTS: Eyes receiving SES showed significant preservation of b-wave amplitude, a- and b-wave implicit times, oscillatory potential amplitudes, and post-receptoral parameters (Vmax and log sigma) compared to untreated eyes. All SES-treated eyes had similar preservation, regardless of increased SES from IR light exposure. SES-treated eyes tended to have greater retinal Fgf2 expression than untreated eyes, but Fgf2 expression did not increase with IR light. CONCLUSIONS: The larger post-receptoral responses (Vmax), greater post-receptoral sensitivity (logsigma), and larger oscillatory potentials suggest SES-treated eyes maintained better inner retinal function than the opposite, untreated eyes. This suggests that in addition to preserving photoreceptors in RCS rats, SES may also promote more robust signal transmission through the retinal network compared to the control eyes. These studies suggest that the protective effects of SES on RCS retinal function cannot be improved with additional subretinal current induction from the MPA, or the charge injection provided by ERG Ganzfeld flashes was not adequately mimicked by the flashing IR light used in this study. PMID- 23687437 TI - Development of novel LOXL1 genotyping method and evaluation of LOXL1, APOE and MTHFR polymorphisms in exfoliation syndrome/glaucoma in a Greek population. AB - PURPOSE: In the Greek population of Epirus, exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) occur at a high prevalence. In this study, we validate a novel lysyl oxidase-like 1 (LOXL1) genotyping method, investigate the previously reported association of LOXL1 with XFS/XFG, and evaluate apolipoprotein E (APOE) and methylenetetrahydrofolate reductase (MTHFR) polymorphisms as genetic risk factors for both conditions in our population. METHODS: Blood samples were collected from 82 patients with XFG, 69 patients with XFS, 52 patients with primary open-angle glaucoma (POAG), and 107 controls. APOE and MTHFR 677C>T genotyping was performed from extracted genomic DNA with established methods. A novel methodology of real-time PCR and melting curve analysis was developed and validated to accurately genotype the LOXL1 G153D and R141L polymorphisms by using two different fluorescent channels of the LightCycler instrument (Roche) examining each SNP separately. RESULTS: No significant differences were observed for the APOE and MTHFR polymorphisms between the patients with XFS, the patients with XFG, and the control subjects. The APOE epsilon2 allele appears to be associated with elevated risk of POAG in our population. Our novel LOXL1 genotyping method was easy to perform, fast, and accurate. A statistically significant association was found for the LOXL1 gene with XFS/XFG in this Greek population. The association of XFS and XFG with G153D appeared to be less powerful in this population (XFS: odds ratio [OR]=2.162, p=0.039, XFG: OR=2.794, p=0.002) compared to other populations, and for R141L, the association was proven only with XFG (OR=3.592, p<0.001). Neither of the two LOXL1 SNPs was significantly associated with POAG. CONCLUSIONS: We confirmed the association between LOXL1 and XFS/XFG, but the APOE and MTHFR polymorphisms are not significant risk factors for the development of XFS/XFG in our population of patients from Epirus (Greece). PMID- 23687438 TI - Nuclear translocation of myocardin-related transcription factor-A during transforming growth factor beta-induced epithelial to mesenchymal transition of lens epithelial cells. AB - PURPOSE: Transforming growth factor beta (TGFbeta) is a known inducer of epithelial to mesenchymal transition (EMT), and studies in other systems have shown that nuclear localization of the myocardin-related transcription factor (MRTF) is downstream of TGFbeta. In the following study, we investigated whether nuclear translocation of MRTF-A or MRTF-B is involved in TGFbeta-induced EMT of lens epithelial cells (LECs). We further investigated the relationship between matrix metalloproteinase-2 and -9 (MMP-2/9) and MRTF in the EMT of LECs. METHODS: Rat lens explant cultures were used as the model system. Explants were treated with TGFbeta, an MMP-2/9 inhibitor, or actin binding drugs and immunostained for alpha smooth muscle actin (alphaSMA), MRTF-A, and MRTF-B. Cytoplasmic and nuclear intensities of cells were measured using ImageJ. Production of alphaSMA was measured using western blot analysis and ImageJ. RESULTS: Untreated explant cells exhibited little alphaSMA expression, and MRTF-A and B were found to reside primarily in the cytosol. However, when stimulated with TGFbeta, a significantly greater number of cells exhibited nuclear expression of MRTF-A, accompanied by an increase in alphaSMA expression. However, MRTF-B remained in the cytoplasm following TGFbeta treatment. Cotreatment with an MMP-2/9 inhibitor and TGFbeta resulted in reduced MRTF-A nuclear localization and alphaSMA expression compared to cells treated with TGFbeta alone. CONCLUSIONS: Our results are the first to demonstrate the expression of MRTF-A in LECs and that its nuclear translocation can be stimulated by TGFbeta. Our data further suggest that MMP-2 and -9 are involved in the translocation of MRTF-A in LECs during TGFbeta-induced EMT. PMID- 23687439 TI - Novel epithelial cell adhesion molecule antibody conjugated polyethyleneimine capped gold nanoparticles for enhanced and targeted small interfering RNA delivery to retinoblastoma cells. AB - BACKGROUND: Several nanoconjugates have been designed to deliver nucleic acids such as small interfering RNA (siRNA) and DNA to cells to study silencing and expression efficacies. In the present study, we prepared novel epithelial cell adhesion molecule (EpCAM) monoclonal antibody conjugated polyethyleneimine (PEI) capped gold nanoparticles (AuNPs) loaded with EpCAM-specific siRNA molecules to knock-down the EpCAM gene in retinoblastoma (RB) cells. We chose EpCAM as a target moiety to deliver siRNA because this molecule is highly expressed in various epithelial cancers and is an ideal target as it is highly expressed in the apical surface of tumor cells while showing basolateral expression in normal cells. METHODS: The EpCAM antibody was conjugated to AuNP-PEI loaded with siRNA molecules to specifically deliver siRNA to EpCAM-expressing RB cells. Conjugation efficiencies were confirmed with ultraviolet-visible spectrophotometry, Fourier transform infrared spectroscopy, and agarose and SDS-polyacrylamide gel electrophoresis. The size and zeta potential were measured using a Zeta sizer analyzer. Nanoparticle internalization and uptake were studied using fluorescent microscopy and flow cytometry. Gene silencing efficacy was monitored with western blot analysis and real-time quantitative PCR. RESULTS: Optimal size and neutral zeta potential properties of the AuNP-PEI- EpCAM antibody (EpAb) antibody were achieved for the transfection studies. The AuNP-PEI nanoparticles did not show any cytotoxicity to the cells, which means these nanomaterials are suitable for intracellular delivery of siRNA for therapeutic interventions. With EpCAM antibody conjugation, PEI-capped AuNPs loaded with EpCAM siRNA were significantly internalized in the Y79 cells as observed with fluorescence microscopy and flow cytometry and induced a highly significant reduction in the cell viability of the Y79 cells. Through increased binding of EpCAM antibody-conjugated AuNP-PEI nanoparticles, significant downregulation of EpCAM gene was observed in the Y79 cells when compared to the cells treated with the antibody-unconjugated AuNP-PEI nanoparticles. CONCLUSIONS: Thus, a novel antibody conjugated nanocarrier designed to deliver siRNA holds promise as an effective gene therapy strategy for retinoblastoma in the near future. In addition to serving as an siRNA delivery tool for therapy, gold nanoparticles can also serve as imaging modality in diagnosis. PMID- 23687440 TI - How Do Social Interactions with a Significant Other Affect PTSD Symptoms? An Empirical Investigation with a Clinical Sample. AB - Social support and coping are both related to posttraumatic stress disorder (PTSD) symptoms, but the mechanisms underlying their relationships remain unclear. This study explores these relationships by examining the perceived frequency of supportive and countersupportive interactions with a significant other in PTSD patients. Ninety-six participants with PTSD were recruited and completed questionnaires assessing social interactions, ways of coping, and PTSD symptoms. Associations of social interactions (r2 = 4.1%-7.9%, p < .05) and coping (r2 = 15.9%-16.5%, p < .001) with symptoms were independent, and suggested a direct association between social interactions and PTSD. Countersupportive interactions were more associated to symptoms than supportive interactions. Our findings suggest the development of psychotherapies that integrate social support interventions. PMID- 23687441 TI - Relative Efficacy of Cognitive-Behavioral Therapy Administered by Videoconference for Posttraumatic Stress Disorder: A Six-Month Follow-Up. AB - Until recently, only one study was published on cognitive-behavioral therapy (CBT) of posttraumatic stress disorder (PTSD) in individual therapy via videoconference (Germain, Marchand, Bouchard, Drouin, & Guay, 2009); however, it only assessed the posttreatment effect. This study presents the follow-up of Germain et al.'s (2009) study. The main goal was to compare the effectiveness after six months of CBT for PTSD either face-to-face (n = 24) or by videoconference (n = 12). Each participant received CBT for 16 to 25 weeks and completed various questionnaires before and after treatment and at a six-month follow-up. The two treatments had equivalent levels of symptom reduction (Modified PTSD Symptom Scale: eta2 < 0.01, p > .05) and proportion of patients with a clinically significant change in symptoms (42% for face-to-face vs. 38% for videoconferencing, p > .05). Thus, CBT for PTSD via videoconference seems to be a viable alternative when adequate face-to-face treatments are less available. PMID- 23687442 TI - Safety, efficacy, and patient acceptability of single-dose fosaprepitant regimen for the prevention of chemotherapy-induced nausea and vomiting. AB - Control of chemotherapy-induced nausea and vomiting (CINV) is a crucial factor in ensuring that patients undergoing cancer chemotherapy can get the full benefit of therapy. Current antiemetic guidelines recommend that the neurokinin-1 receptor (NK-1R) antagonist aprepitant should be used as part of a combination regimen with dexamethasone and a serotonin receptor antagonist for the prevention of CINV in patients receiving highly emetogenic chemotherapy (HEC). Fosaprepitant is a water-soluble N-phosphoryl derivative of aprepitant that, when infused, is rapidly metabolized back to an active aprepitant. The existing literature in PubMed about fosaprepitant was screened and selected in order to address the emerging data from two randomized clinical trials evaluating the efficacy and safety of a single-dose fosaprepitant regimen. These phase III trials demonstrated that fosaprepitant given as a single intravenous dose of 150 mg was either noninferior to the conventional 3-day aprepitant or significantly superior to placebo for the prevention of acute and delayed CINV in patients receiving high-dose cisplatin. In both trials, fosaprepitant was well tolerated although more frequent infusion-site adverse events were observed with fosaprepitant. The new dosage regimen of fosaprepitant, therefore, would be an option for CINV control in patients receiving cisplatin-based chemotherapy. The clinical efficacy is consistent with the findings from a time-on-target, positron-emission tomography study evaluating the NK-1R occupancy in the central nervous system (CNS) over 5 days after a single-dose infusion of 150 mg fosaprepitant in healthy participants. The single-dose regimen is capable of blocking more than 90% of the NK-1Rs in the CNS for at least 48 hours after infusion, which is sufficient to control delayed CINV for 2 to 5 days after HEC. The new dosage regimen of fosaprepitant can provide a simplified treatment option that maintains high protection while ensuring adherence to scheduled antiemetic medication throughout most of the 5-day period encompassing the major risk for CINV. PMID- 23687443 TI - Prospective, open-label trial measuring satisfaction and convenience of two formulations of lamotrigine in subjects with mood disorders. AB - BACKGROUND: Lamotrigine is an anticonvulsant drug indicated for the maintenance treatment of bipolar I disorder and for various types of epilepsy. An orally disintegrating tablet (ODT) of lamotrigine was developed to provide a formulation option that might increase patient convenience and satisfaction. METHODS: Subjects with mood disorders who reported difficulty swallowing currently prescribed lamotrigine immediate-release medication (baseline) were enrolled and treated with lamotrigine ODT for three weeks (end of treatment). Subject satisfaction and convenience were measured using the Treatment Satisfaction Questionnaire for Medication (TSQM). Also measured were global psychopathology using the Clinical Global Impression severity index (CGI-S) and depressive symptoms using the Beck Depression Inventory (BDI-II). RESULTS: Lamotrigine ODT was found to be significantly more convenient to use than lamotrigine immediate release (change in baseline TSQM convenience score: 23.3, n = 97, P < 0.001). The mean TSQM global satisfaction score was similar at baseline (76.3) and after treatment with lamotrigine ODT (76.0). There were no significant changes on CGI-S and BDI-II. CONCLUSION: Subjects reported that lamotrigine ODT was significantly more convenient than lamotrigine immediate-release, while both formulations were associated with good satisfaction. Lamotrigine ODT may be a treatment option for patients who have difficulty swallowing medication. PMID- 23687444 TI - Symptom variability in COPD: a narrative review. AB - Chronic obstructive pulmonary disease (COPD) has traditionally been considered an inexorably progressive disease, associated with a constant increase of symptoms that occur as the forced expiratory volume in 1 second (FEV1) worsens, only intermittently interrupted by exacerbations. However, this paradigm has been challenged in recent decades by the available evidence. Recent studies have pointed out that COPD-related symptoms are not consistently perceived by patients in the same way, showing not only seasonal variation, but also changes in symptom perception during a week or even within a single day. According to the available data, patients experience the biggest increase in respiratory symptoms during the first hours of the early morning, followed by the nighttime. This variation over time is of considerable importance, since it impacts on daily life activities and health-related quality of life, as measured by a recently developed ad hoc questionnaire. Additionally, recent clinical trials have suggested that the use of rapid-onset long-acting bronchodilators may have an impact on morning symptoms, despite their current use as maintenance treatment for a determined period. Although this hypothesis is to be validated in future long-term clinical trials comparing fast-onset versus slow-onset inhaled drugs in COPD, it may bring forward a new concept of long-term bronchodilator therapy. At the present time, the two available long-acting, fast-onset bronchodilators used in the treatment of COPD are formoterol and the recently marketed indacaterol. Newer drugs have also been shown to have a rapid onset of action in preclinical studies. Health care professionals caring for COPD patients should consider this variation in the perception of symptoms during their clinical interview as a potential new target in the long-term treatment plan. PMID- 23687445 TI - Green synthesis of graphene and its cytotoxic effects in human breast cancer cells. AB - BACKGROUND: This paper describes an environmentally friendly ("green") approach for the synthesis of soluble graphene using Bacillus marisflavi biomass as a reducing and stabilizing agent under mild conditions in aqueous solution. In addition, the study reported here investigated the cytotoxicity effects of graphene oxide (GO) and bacterially reduced graphene oxide (B-rGO) on the inhibition of cell viability, reactive oxygen species (ROS) generation, and membrane integrity in human breast cancer cells. METHODS: The reduction of GO was characterized by ultraviolet-visible spectroscopy. Size distribution was analyzed by dynamic light scattering. Further, X-ray diffraction and high-resolution scanning electron microscopy were used to investigate the crystallinity of graphene and the morphologies of prepared graphene, respectively. The formation of defects further supports the bio-functionalization of graphene, as indicated in the Raman spectrum of B-rGO. Surface morphology and the thickness of the GO and B-rGO were analyzed using atomic force microscopy, while the biocompatibility of GO and B-rGO were investigated using WST-8 assays on MCF-7 cells. Finally, cellular toxicity was evaluated by ROS generation and membrane integrity assays. RESULTS: In this study, we demonstrated an environmentally friendly, cost effective, and simple method for the preparation of water-soluble graphene using bacterial biomass. This reduction method avoids the use of toxic reagents such as hydrazine and hydrazine hydrate. The synthesized soluble graphene was confirmed using various analytical techniques. Our results suggest that both GO and B-rGO exhibit toxicity to MCF-7 cells in a dose-dependent manner, with a dose > 60 MUg/mL exhibiting obvious cytotoxicity effects, such as decreasing cell viability, increasing ROS generation, and releasing of lactate dehydrogenase. CONCLUSION: We developed a green and a simple approach to produce graphene using bacterial biomass as a reducing and stabilizing agent. The proposed approach confers B-rGO with great potential for various biological and biomedical applications. PMID- 23687446 TI - Anchoring of self-assembled plasmid DNA/anti-DNA antibody/cationic lipid micelles on bisphosphonate-modified stent for cardiovascular gene delivery. AB - PURPOSE: To investigate the anchoring of plasmid DNA/anti-DNA antibody/cationic lipid tri-complex (DAC micelles) onto bisphosphonate-modified 316 L coronary stents for cardiovascular site-specific gene delivery. METHODS: Stents were first modified with polyallylamine bisphosphonate (PAA-BP), thereby enabling the retention of a PAA-BP molecular monolayer that permits the anchoring (via vector binding molecules) of DAC micelles. DAC micelles were then chemically linked onto the PAA-BP-modified stents by using N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP) as a crosslinker. Rhodamine-labeled DNA was used to assess the anchoring of DAC micelles, and radioactive-labeled antibody was used to evaluate binding capacity and stability. DAC micelles (encoding green fluorescent protein) were tethered onto the PAA-BP-modified stents, which were assessed in cell culture. The presence of a PAA-BP molecular monolayer on the steel surface was confirmed by X-ray photoelectron spectroscopy and atomic force microscope analysis. RESULTS: The anchoring of DAC micelles was generally uniform and devoid of large-scale patches of defects. Isotopic quantification confirmed that the amount of antibody chemically linked on the stents was 17-fold higher than that of the physical adsorbed control stents and its retention time was also significantly longer. In cell culture, numerous green fluorescent protein positive cells were found on the PAA-BP modified stents, which demonstrated high localization and efficiency of gene delivery. CONCLUSION: The DAC micelle immobilized PAA-BP-modified stents were successful as a gene delivery system. Gene delivery using DAC micelle-tethered stent-based PAA-BP functionalization should be suitable for a wide array of single or multiple therapeutic gene strategies, and could be used on cardiovascular metallic implants for achieving efficient gene therapy. PMID- 23687447 TI - Green synthesis of silver nanoparticles by Chrysanthemum morifolium Ramat. extract and their application in clinical ultrasound gel. AB - Eco-friendly green synthesis with plant extracts plays a very important role in nanotechnology, without any harmful chemicals. In this report, the synthesis of water-soluble silver nanoparticles was developed by treating silver ions with Chrysanthemum morifolium Ramat. extract at room temperature. The effect of the extract on the formation of silver nanoparticles was characterized by ultraviolet and visible absorption spectroscopy, X-ray diffraction, transmission electron microscopy, and Fourier transform infrared spectroscopy. The ultraviolet and visible absorption spectroscopy results show a strong resonance centered on the surface of silver nanoparticles (AgNP) at 430 nm. The Fourier transform infrared spectroscopy spectral study demonstrates Chrysanthemum morifolium Ramat. extract acted as the reducing and stabilizing agent during the synthesis. The X-ray diffraction analysis confirmed that the synthesized AgNP are single crystallines, corresponding with the result of transmission electron microscopy. Water-soluble AgNP, with an approximate size of 20 nm-50 nm were also observed in the transmission electron microscopy image. The bactericidal properties of the synthesized AgNP were investigated using the agar-dilution method and the growth inhibition test. The results show the AgNP had potent bactericidal activity on Staphylococcus aureus and Escherichia coli, as well as a strong antibacterial activity against gram-negative bacteria, as compared to gram-positive bacteria with a dose-dependent effect, thus providing a clinical ultrasound gel with bactericidal property for prevention of cross infections. PMID- 23687448 TI - Efficacy and safety of a hyaluronic acid filler in subjects treated for correction of midface volume deficiency: a 24 month study. AB - BACKGROUND: Hyaluronic acid (HA) fillers are an established intervention for correcting facial volume deficiency. Few studies have evaluated treatment outcomes for longer than 6 months. The purpose of this study was to determine the durability of an HA filler in the correction of midface volume deficiency over 24 months, as independently evaluated by physician investigators and subjects. METHODS: Subjects received treatment with Juvederm(TM) Voluma(TM) to the malar area, based on the investigators' determination of baseline severity and aesthetic goals. The treatment was administered in one or two sessions over an initial 4-week period. Supplementary treatment was permissible at week 78, based on protocol-defined criteria. A clinically meaningful response was predefined as at least a one-point improvement on the MidFace Volume Deficit Scale (MFVDS) and on the Global Aesthetic Improvement Scale (GAIS). RESULTS: Of the 103 subjects enrolled, 84% had moderate or significant volume deficiency at baseline. At the first post-treatment evaluation (week 8), 96% were documented to be MFVDS responders, with 98% and 100% graded as GAIS responders when assessed by the subjects and investigators, respectively. At week 78, 81.7% of subjects were still MFVDS responders, with 73.2% and 78.1% being GAIS responders, respectively. Seventy-two subjects completed the 24-month study, of whom 45 did not receive supplementary Voluma(TM) at week 78. Forty-three of the 45 (95.6%) subjects were MFVDS responders, with 82.2% and 91.1% being GAIS responders, respectively. At end of the study, 66/72 subjects were either satisfied or very satisfied with Voluma(TM), with 70/72 indicating that they would recommend the product to others. Adverse events were transient and infrequent, with injection site bruising and swelling being the most commonly reported. CONCLUSION: Voluma(TM) is safe and effective in the correction of mild to severe facial volume deficiency, achieving long-term clinically meaningful results. There was a high degree of satisfaction with the treatment outcome over the 24 months of the study. PMID- 23687450 TI - Population-based Aarhus Sarcoma Registry: validity, completeness of registration, and incidence of bone and soft tissue sarcomas in western Denmark. AB - BACKGROUND: The aim of the present study was to validate the data in the Aarhus Sarcoma Registry (ASR), to determine if this registry is population-based for western Denmark, and to examine the incidence of sarcomas using validated, population-based registry data. METHODS: This study was based on patients with bone and soft tissue sarcoma treated at the Sarcoma Centre of Aarhus University Hospital between January 1, 1979 and December 31, 2008. The validation process included a review of all medical files by two researchers using a standardized form. The Danish Cancer Registry was used as a reference to assess the completeness of registration of patients in the ASR. Crude and World Health Organization age-standardized incidence, as well as age-, gender-, and year specific incidences were estimated. RESULTS: The validation process added 385 to the 1442 patients who were registered in the ASR. Before validation, on average, 70.5% of the data for the variables was correct. Validation improved the average completeness of the registered variables from 83.7% to 99.3%. The 1827 patients in the ASR after validation include 85.3% of the patients registered in the Danish Cancer Registry. The overall World Health Organization age-standardized incidence of sarcoma in the trunk or extremities in western Denmark in the period 1979-2008 was 2.2 per 100,000, being 0.8 for bone sarcomas and 1.4 for soft tissue sarcomas. CONCLUSION: The validation process significantly improved the completeness of the variables and the quality of the ASR data. ASR is now a valuable population-based tool for epidemiological research and quality improvement in the treatment of sarcoma. It is our recommendation that documented validation of registries should be a prerequisite for publishing studies derived from them. PMID- 23687449 TI - Novel oral anticoagulants for stroke prevention in atrial fibrillation: a focus on the older patient. AB - Atrial fibrillation (AF) is a common arrhythmia that is associated with an increased risk of stroke, particularly in the elderly. Traditionally, a vitamin K antagonist such as warfarin is prescribed for stroke prevention. Warfarin is effective at lowering stroke risk but has several limitations due to food restrictions, drug interactions, and a narrow therapeutic window. Various novel oral anticoagulants (NOACs) are available or under development to provide alternative treatment options. This article reviews the efficacy and safety of three NOACs (dabigatran etexilate, rivaroxaban, and apixaban) in addition to warfarin and aspirin, for prevention of stroke in patients with AF, focusing on the elderly population. Results of clinical trials demonstrate that the efficacy of NOACs for stroke prevention in patients with AF is as good as or better than that of warfarin. The NOACs are also associated with an equivalent or lower risk of bleeding. Regardless of the medication chosen, older patients with AF must be treated cautiously due to an increased risk of stroke and bleeding, as well as potential challenges related to drug interactions and monitoring requirements. NOACs may be suitable alternatives to warfarin for stroke prevention in older patients due to several advantages, including a faster onset of action, few drug or food interactions, and no requirement for regular monitoring. However, dose adjustments may be required for certain patients, such as those with severe renal impairment or in the setting of drug interactions. PMID- 23687451 TI - Outcomes in hypertensive disorders of pregnancy in the North Indian population. AB - INTRODUCTION: Hypertensive disorders complicating pregnancy seriously endanger the safety of the mother and fetus during pregnancy. Very few studies have explored hypertensive disorders of pregnancy in India, even though this disease has been associated with adverse maternal and perinatal outcomes. This study aimed to analyze the disease pattern and risk factors associated with the disorder and assess the maternal and fetal outcomes in cases of hypertensive disorders of pregnancy. SUBJECTS AND METHODS: This case-control study was carried out over 1 year from 2011 to 2012 at the Department of Obstetrics and Gynecology, King George's Medical University, Lucknow, Uttar Pradesh, India. A total of 149 patients were enrolled in the study. As seven were lost to follow-up, analysis was carried out on 142 cases. Patients were further classified according to the National High Blood Pressure Education Program Working Group (2000) as having mild preeclampsia (65 cases), severe preeclampsia (32 cases), or eclampsia (45 cases). Thirty-one healthy pregnant non-hypertensive women were enrolled into the study as controls. RESULTS: The most common manifestation was edema, seen in 90% of cases. Proteinuria was also relatively common, 26.76% of patients with proteinuria of >=300 mg/24 hours, 47.88% with proteinuria of >=2 g/24 hours, and 25.35% with a urinary protein excretion of 3-5 g/24 hours. Central nervous system involvement was observed in 42.2% of cases, elevated bilirubin levels in 47.0%, visual symptoms in 6.4%, vaginal bleeding in 11.3%, and HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome was reported in 2.80%. Maternal deaths occurred in 2.8% of cases, all of which were from the eclampsia group. Stillbirths occurred in 16.9% of cases, and overall neonatal death observed in 4.23% of cases. CONCLUSION: Women with hypertensive disorders of pregnancy were more prone to adverse maternal and fetal outcomes than normotensive pregnant women, but we observed a decreasing trend in the present study compared with that reported in other studies, which might be due to the increased number of hospital deliveries that occurred in our study. PMID- 23687452 TI - Attitude and practices of obstetricians and gynecologists towards involvement of physiotherapists in management of obstetric and gynecologic conditions. AB - BACKGROUND: The role of physiotherapists in obstetrics and gynecology is pivotal. However, utilization of their capabilities depends on the cooperation of other health professionals in discharging their services to patients, who are the focus of the team. This study was designed to assess the attitude of obstetricians and gynecologists in south-western Nigeria towards involving physiotherapists in the management of patients with obstetric and gynecologic conditions. METHODS: This was a descriptive survey of obstetricians and gynecologists from seven hospitals in south-western Nigeria. Sixty-seven participants, including 41 senior registrars and 26 consultants, participated in the study. More consultants (73.1%) than senior registrars (46.3%) had a good knowledge of the role of physiotherapists in obstetric and gynecological practice. All participants had general knowledge of the role of physiotherapists in obstetrics and gynecology, but a limited knowledge of specific conditions amenable to treatment by physiotherapists. More senior registrars had a better attitude (73.2%) than consultants (53.8%) towards involvement of physiotherapists in their practice, and 94.0% of the obstetricians and gynecologists utilized the services of physiotherapists, with referral of patients (56.7%) mainly to physiotherapists working in general/state hospitals. CONCLUSION: There is a need for better interaction and communication between physiotherapists and obstetricians and gynecologists, which could be achieved through clinical meetings, seminars, and workshops. PMID- 23687453 TI - Noninvasive screening tools for Down syndrome: a review. AB - Down syndrome is the leading cause of prenatal chromosome abnormalities, accounting for 53% of all reported chromosome conditions. Testing strategies, guidelines, and screening options have expanded from their conception in the 1970s, and now include such options as anatomical ultrasound, maternal serum screening, and noninvasive prenatal testing. This review summarizes all currently available noninvasive diagnostic techniques for the detection of Down syndrome. By understanding fully each technology and the possible alternatives, the physician will be able to provide their patients with all the information necessary to make an informed decision regarding their medical management. PMID- 23687455 TI - Non-destructively shattered mesoporous silica for protein drug delivery. AB - Mesoporous silicas have been extensively used for entrapping small chemical molecules and biomacromolecules for drug delivery. We hypothesize that the loading density of biomacromlecules such as proteins in mesoporous silicas could be limited due to disordering in the pore structure and long diffusion time in the pore channels. We shattered mesoporous silicas non-destructively resulting in improved intramesoporous structures and reduced particle sizes in aqueous solutions by a powerful sonication, where the mesoporous structures were still well maintained. The sonication-shattered mesoporous silica can increase the protein loading density to nearly 2.7 times as high as that of the non-shattered one, demonstrating that significantly more mesopore space of the silica could be accessible by the protein molecules, which may result in more sustained protein drug delivery. PMID- 23687454 TI - Biomarkers for the differentiation of anemia and their clinical usefulness. AB - The World Health Organization defines anemia as the point at which the amount of hemoglobin in the circulation falls below World Health Organization cutoffs for specific age and sex groups. Anemia is a worldwide problem of complex etiology and is associated with many factors. The purpose of this review was to describe the biomarkers used to identify the nature of anemia in patients and in the community. The important biomarkers are the automated red cell counts, tests for nutritional deficiencies, hemoglobinopathies, and inflammation. Diseases are important potential initiators of anemia, but biomarkers of specific diseases are not included in this review, only the underlying feature common to all disease - namely, inflammation. PMID- 23687456 TI - Towards the Total Synthesis of Pl-3: Preparation of the Eastern Fragment through a Diastereoselective SmI2-Mediated Reformatsky Reaction. AB - The jatrophane diterpene Pl-3, isolated in 2003 from Euphorbia platyphyllos, is a structurally complex natural product with highly promising biological properties that include pronounced antiproliferative activity and the inhibition of the efflux-pump activity of multidrug resistance p-glycoprotein. Herein, the synthesis of the eastern fragment of Pl-3 is outlined. The target compound is synthesized in nine synthetic operations in good overall yield, starting from readily available d-ribose. The key step in the preparation of the eastern part of Pl-3 is a diastereoselective SmI2-mediated Reformatsky reaction. The proposed route is highly flexible and could also be applied to the synthesis of structurally related jatrophane diterpenes. PMID- 23687457 TI - Serum procalcitonine levels as an early diagnostic indicator of sepsis. AB - INTRODUCTION: Prompt and accurate diagnosis of sepsis is of high importance for clinicians. Procalcitonine (PCT) and C-reactive protein (CRP) have been proposed as markers for this purpose. Our aim was to evaluate the levels of PCT and CRP in early sepsis and its correlation with severity of sepsis. METHODS: Levels of PCT and CRP were taken from 60 patients with sepsis criteria and 39 patients with SIRS symptoms from the University Hospital Center "Mother Teresa" in Tirana, Albania during 2010-2012. Sensitivity, specificity and predictive values for PCT and CRP were calculated. RESULTS: PCT and CRP levels increased in parallel with the severity of the clinical conditions of the patients. The mean PCT level in patients with sepsis was 11.28 ng/ml versus 0.272 ng/ml in patients with SIRS symptoms, with a sensitivity of 97.4% and a specificity of 96.6% for PCT >0.5ng/ml. The mean CRP level in septic patients was 146.58 mg/l vs. 34.4 mg/l in patients with SIRS, with a sensitivity of 98.6% for sepsis and a specificity of 75 % for CRP >11mg/l. CONCLUSION: PCT and CRP values are useful markers to determine early diagnosis and severity of an infection. In the present study, PCT was found to be a more accurate diagnostic parameter for differentiating SIRS from sepsis and may be helpful in the follow-up of critically ill patients. PMID- 23687458 TI - Facial burns - our experience. AB - Facial burns are generally considered severe. This is due to the possibility of respiratory complications. First responders check the nostrils for singed hairs. In severe cases there may be soot around the nose and mouth and coughing may produce phlegm that includes ash. Facial and inhalational burns compromise airways. They pose difficulties in pre-hospital resuscitation and are challenge to clinicians managing surviving burn victims in the intensive care setting. Management problems - resuscitation, airway maintenance and clinical treatment of facial injuries are compounded if the victim is child. Inhalational burns reduce survivability, certainly in adult victim. In our retrospective study we found that facial burns dominated in male gender, liquids and scalds are the most common causes of facial burns in children whereas the flame and electricity were the most common causes of facial burns in adults. We came to the conclusion in our study that surgical treatment minimizes complications and duration of recovery. PMID- 23687459 TI - Relationship between information literacy and creativity: a study of students at the isfahan university of medical sciences. AB - INTRODUCTION: In an era of huge volume of publications and information products, information literacy has become a very important survival tool. Information literacy is an instrument for individual empowerment that leads one to search for the truth and the desired information for decision making with independence. While creativity is the foundation of sciences and innovation, one of the main functions of universities is expanding the frontiers of knowledge and productions of scientific information. Therefore creativity is more vital and necessary for these kinds of institutions than other organizations. In this regard, this paper investigates the relationship between information literacy and creativity of students at the Isfahan University of Medical Sciences. METHOD: This is a correlation-descriptive study. Statistical population was third year students of Isfahan University of Medical Sciences (1054 individuals) in 2011. Sample size was 250 individuals selected by stratified random Sampling. The instruments for data collection were two questionnaires, an investigator made questionnaire for information literacy and a creativity questionnaire. For questionnaires validity used content validity and for their reliability used Cronbach Alpha Coefficient (r1= 0.95, r2=0.85). SPSS 18 statistical software and descriptive and inferential statistics tests (Frequency distribution tab, Pearson Correlation, T test, Tukey test and ANOVA) were used to analyze data. RESULTS: The results indicate that mean of information literacy was higher than average and mean of creativity was lower than average. There is a significant multiple correlation between 5 dimensions of information literacy (Ability to determine extent and nature of information, effective and efficient access, critical assessment, ability of purposeful application, ability of understanding legal and economic issues) and creativity in level of (p<= 0.05). Also mean difference of ability of purposeful application based on gender was significant in level of (p<= 0.05). It means the ability of purposeful application in male students was more than female students. CONCLUSION: We are living in the information age and one of the variables that are associated with creativity is information literacy. The results indicated that the students who are more creative are more information literate and can reach higher goals. Therefore we can contemplate that increasing information literacy in the universities and other scientific education centers plays an important role in teaching and training a creative workforce. PMID- 23687460 TI - Assessment of safety culture in isfahan hospitals (2010). AB - INTRODUCTION: Many internal and external risk factors in health care organizations make safety important and it has caused the management to consider safety in their mission statement. One of the most important tools is to establish the appropriate organizational structure and safety culture. THE GOAL: The goal of this research is to inform managers and staff about current safety culture status in hospitals in order to improve the efficiency and effectiveness of health services. METHODS: This is a descriptive-survey research. The research population was selected hospitals of Isfahan, Iran. Research tool was a questionnaire (Cronbach alpha 0.75). The questionnaire including 93 questions (Likert scale) classified in 12 categories: Demographic questions, Individual attitude, management attitude, Safety Training, Induced stress, pressure and emotional conditions during work, Consultation and participation, Communications, Monitoring and control, work environment, Reporting, safety Rules, procedures and work instructions that distributed among 45 technicians, 208 Nurses and 62 Physicians. All data collected from the serve was analysis with statistical package of social science (SPSS). In this survey Friedman test, Spearman correlation, analysis of variance (ANOVA) and factor analysis have been used for data analyzing. RESULTS: The score of safety culture dimensions was 2.90 for Individual attitude, 3.12 for management attitude, 3.32 for Safety Training, 3.14 for Induced stress, pressure and emotional conditions during work, 3.31 for Consultation and participation, 2.93 for Communications, 3.28 for Monitoring and control, 3.19 for work environment, 3.36 for Reporting, 3.59 safety Rules, procedures and work instructions that Communication and individual attitude were in bad condition. Safety culture among different hospitals: governmental and educational, governmental and non-educational and non-governmental and different functional groups (physicians, nurses, diagnostic) of studied hospitals showed no significant differences. There was no relationship between safety culture and demographic data. CONCLUSION: It was concluded that is no different among governmental and educational, governmental and non-educational and non governmental in level of safety culture, all of them were on intermediate level so it is essential to attention to the safety culture in hospitals and planning to improve it. PMID- 23687461 TI - Applying theory of planned behavior in predicting of patient safety behaviors of nurses. AB - BACKGROUND: Patient safety has become a major concern throughout the world. It is the absence of preventable harm to a patient during the process of health care, ensuring safer care is an enormous challenge, psychosocial variables influences behaviors of human. The theory of planned behavior (TPB) is a well-validated behavioral decision-making model that has been used to predict social and health behaviors. This study is aimed to investigate predictors of nurse's patient safety intentions and behavior, using a TPB framework. METHODS: Stratified sampling technique was used to choose 124 nurses who worked at the selected hospitals of Isfahan in 2011. Study tool was a questionnaire, designed by researchers team including 3 nurses a physician and a psychologist based on guideline of TPB model. Questionnaire Validity was confirmed by experts and its reliability was assessed by Cronbach's alpha as 0.87. Binary logistic regression analysis was performed to evaluate how well each TPB variables predicted the variance in patient safety behavior. Analyzing was done by SPSS18. RESULTS: Finding revealed that "normative beliefs" had the greatest influence on nurses intention to implement patient safety behaviors. Analyzing data by hospital types and workplace wards showed that both in public and private hospitals normative beliefs has affected safety behaviors of nurses more than other variables. Also in surgical wards, nurses behaviors have been affected by "control beliefs" and in medical wards by normative beliefs. CONCLUSION: Normative beliefs, and subjective norms were the most influential factor of safety behavior of nurses in this study. Considering the role of cultural context in these issues, it seemseducation of managers and top individuals about patient safety and its importance is a priority also control believes were another important predicting factor of behavior in surgical wards and intensive care units. Regarding the complexity of work in these spaces, applying medical guidelines and effective supervision must be seriously followed. PMID- 23687462 TI - Social Class Status and Suicide Characteristics: A Survey among Patients Who Attempted Suicide in Isfahan. AB - INTRODUCTION: Suicide is one of the most prominent problems in health care system in current Iran. It could be impacted by various factors such as social, economic, individual and so on. Researchers show that socio-economic factors and suicide has significantly related. The people in low social class may more engage with social problems than higher social class. They may confront to problems such as crime, violence, unemployment, financial hardship, population density, disorder personality, etc. However, these difficulties could be resulted from relationship of inequality socio-economic and mental or physical health. This research attempted to examine social class status and its relationship with parts of suicide characteristics. METHODS: This study applied a descriptive approach. In the cross-sectional research 179 patients who attempted suicide and admitted to the toxicology ward of Nour hospital and to the burning ward of Imam Mousa Kazem hospital, in Isfahan, during a period of 6 months in 2010 were recruited. The randomize sampling for patients admitted to toxicology ward and census for burning ward are applied. Data collected through a questionnaire which Chronbagh coefficient's alpha was calculated (r= 0/72). Data was analyzed in SPSS software. FINDINGS: The data showed that the majority of patients who attempted suicide were young married women who had diploma and under diploma of level education. They were housewife, engaged in education and unemployment. Finding showed that there are no significant relationships between sex, age, marital status, frequency of attempted suicide and their social class. But there is significant relationship between methods of suicide and social class. Similarly, there are significant relationship between social factors (i.e. family friction, betrothal, unemployment, financial problems and so on) effected on suicide and their social classes. Parts of findings were supported by previous studies. PMID- 23687463 TI - Personality profile of women affected with borderline personality disorder. AB - INTRODUCTION: The main objective of the present study is to review the psychological profile of female patients with borderline personality disorder in the women referring to the Centers of Counseling and Psychological Services at Isfahan city based on MMPI-2 test and comparing them with ordinary women. METHOD: The present study is of the type of cause-comparative and the selection of examinees was done in form of random sampling with 50 women with the BPD and 50 ordinary women and through confirmation of test recognition of MCMI-III and clinical interviews. In addition, 370 questions of MMPI-2 have also been implemented. RESULTS: The results of this research showed a significant difference in validity of scales and the clinical scales of MMPI-2 test among women with BPD and regular women. The results of MANOVA test with the power of valuable test confirmed the existing differences. CONCLUSION: The obtained results shows that female patients with BPD has a specific and different psychological profile as compared with ordinary (regular) women and the obtained profile can be used in recognition and forecasting any disorder. PMID- 23687464 TI - Job security at isfahan university of medical sciences: implications on employees and types of contracts. AB - INTRODUCTION: Medical universities are of those organizations that serve many individuals. As a result, the employees who work at medical universities should have adequate job qualifications and requisite conditions for work. Job security is one of these needed conditions. The current study aims to determine the main components of job security among the employees of Isfahan University of Medical Sciences (IUMS). METHOD AND MATERIALS: The study had a cross-sectional design. The sample included 300 employees which were selected from the faculties of IUMS. The sample was recruited using quota sampling. First, demographic and Job security questionnaires were completed by each employee. Then, data was analyzed by descriptive methods and ANOVA in SPSS16. RESULTS: The study results showed that there was no significant difference among five subscales of Job security questionnaire and as a result, job security among the employees of IUMS but there was a significant difference in job security among male and female employees and a significant difference in job security based on type of job contract. DISCUSSION: Lower rate of job security among female employees with temporary job contracts has professional and psychological implication for both females and IUMS which should be considered in designing professional programs of IUMS. PMID- 23687465 TI - Having a suitable reference place. AB - The purpose of this study is to understand reference libraries of Isfahan University of Medical Sciences. The reference part of libraries was examined from 2008 to 2011. We found that the number of reference librarians should be increased. We found graduate students are the main patrons. We understand interaction with patrons is very important. This study will be helpful for specialist, librarian, and administrators. PMID- 23687466 TI - Medicinal behavior in Persian literature by emphasis on Ibn-Sina popular literature. AB - Content of Persian literature comes from innocents, has special effect on social and individual people life. We understand worth of medical science, physician and sick people relationship in society and impact of religion behavior in treatment. Persian literature contains some recommendation that improve belief, trust, and secretary in medical society. In this article we chose some Persian literature about medicinal behavior and discuss trough: physician relationship with GOD and its impact on treatment, and sick people with others. We hope by studying this article physician can work better and sick people obey their orders more. PMID- 23687467 TI - Young Children's Memory for the Times of Personal Past Events. AB - Remembering the temporal information associated with personal past events is critical for autobiographical memory, yet we know relatively little about the development of this capacity. In the present research, we investigated temporal memory for naturally occurring personal events in 4-, 6-, and 8-year-old children. Parents recorded unique events in which their children participated during a 4-month period. At test, children made relative recency judgments and estimated the time of each event using conventional time-scales (time of day, day of week, month of year, and season). Children also were asked to provide justifications for their time-scale judgments. Six- and 8-year-olds, but not 4 year-olds, accurately judged the order of two distinct events. There were age related improvements in children's estimation of the time of events using conventional time-scales. Older children provided more justifications for their time-scale judgments compared to younger children. Relations between correct responding on the time-scale judgments and provision of meaningful justifications suggest that children may use that information to reconstruct the times associated with past events. The findings can be used to chart a developmental trajectory of performance in temporal memory for personal past events, and have implications for our understanding of autobiographical memory development. PMID- 23687468 TI - Correlates of Adherence among Rural Indian Women Living with HIV/AIDS. AB - In this prospective, randomized clinical trial, correlates of adherence to antiretroviral therapy (ART) were assessed using a baseline questionnaire among 68 rural women living with AIDS (WLA) in India. Unadjusted analyses revealed positive relationships of ART adherence with Hindu religion, and support from spouses and parents, whereas negative associations were found with depression, poor quality of life, and having ten or more HIV symptoms. Multiple linear regression analysis also revealed that WLA who were Hindu, not depressed, had ART support from spouses and parents, and perceived some benefit from ART were more adherent to ART than their respective counterparts. This study reveals the unique challenges which rural WLA experience and the need to mitigate these challenges early in ART treatment. Further, the findings enable the refinement of an intervention program which will focus on strengthening ART adherence among rural WLA. PMID- 23687469 TI - Dual Diagnosis Capability in Mental Health and Substance Use Disorder Treatment Programs. AB - OBJECTIVE: Improved understanding of the relative strengths and weaknesses of treatment organizations' dual diagnosis capability is critical in order to guide efforts to improve services. This study assesses programs' capacity to meet the needs of clients with dual diagnosis, identifies areas where they are well equipped to serve these clients, and determines where programmatic improvement is needed. The study also undertakes an initial exploration of the potential impact that funding sources have on dual diagnosis capability. METHODS: We administered Dual Diagnosis Capability in Addiction Treatment (DDCAT) and Dual Diagnosis Capability in Mental Health Treatment (DDCMHT) assessments at 30 treatment programs in two California counties. Seven of the programs received funding to provide both mental health and substance use disorder services, 13 received funding to provide mental health services, and 10 received funding to provide substance use disorder services. RESULTS: The mean DDCAT/DDCMHT score of programs in the sample was 2.83, and just over 43% of the sample met or exceeded DDCAT/DDCMHT criteria for dual diagnosis capability. Programs scored highest and had the highest rates of dual diagnosis capability in domains related to assessment, training, and staffing, whereas scores were weakest and rates of dual diagnosis capability were lowest in the program structure, treatment, and continuity of care domains. Programs that received funding to provide both mental health and substance use disorder services consistently scored higher than the other programs in the sample, and mental health programs scored higher than substance use disorder treatment programs both on the overall assessments and in most domains. CONCLUSIONS: Findings suggest that programs in the sample are functioning at a nearly dual diagnosis capable level. However, structural barriers continue to limit providers' capacity to serve clients with co-occurring mental health and substance use disorders, and many organizations have not yet translated their potential to deliver dual diagnosis capable services into practice. By enhancing their program structure, treatment services, and continuity of care services, these treatment organizations should be able to deliver fully dual diagnosis capable services. Observed differences in dual diagnosis capability based on funding source indicate a need for further research to better understand the impact that funding streams have on dual diagnosis capability. PMID- 23687470 TI - Divergent Drinking Patterns of Restaurant Workers: The Influence of Social Networks and Job Position. AB - Restaurant workers have higher rates of problem drinking than most occupational groups. However, little is known about the environmental risks and work characteristics that may lead to these behaviors. An exploration of restaurant workers' drinking networks may provide important insights into their alcohol consumption patterns, thus guiding workplace prevention efforts. Drawing from social capital theory, this paper examines the unique characteristics of drinking networks within and between various job categories. Our research suggests that these multiple, complex networks have unique risk characteristics, and that self selection is based on factors such as job position and college attendance, among other factors. PMID- 23687471 TI - Impact of the HEALTHY Study on Vending Machine Offerings in Middle Schools. AB - PURPOSEOBJECTIVES: The purpose of this study is to report the impact of the three year middle school-based HEALTHY study on intervention school vending machine offerings. There were two goals for the vending machines: serve only dessert/snack foods with 200 kilocalories or less per single serving package, and eliminate 100% fruit juice and beverages with added sugar. METHODS: Six schools in each of seven cities (Houston, TX, San Antonio, TX, Irvine, CA, Portland, OR, Pittsburg, PA, Philadelphia, PA, and Chapel Hill, NC) were randomized into intervention (n=21 schools) or control (n=21 schools) groups, with three intervention and three control schools per city. All items in vending machine slots were tallied twice in the fall of 2006 for baseline data and twice at the end of the study, in 2009. The percentage of total slots for each food/beverage category was calculated and compared between intervention and control schools at the end of study, using the Pearson chi-square test statistic. RESULTS: At baseline, 15 intervention and 15 control schools had beverage and/or snack vending machines, compared with 11 intervention and 11 control schools at the end of the study. At the end of study, all of the intervention schools with beverage vending machines, but only one out of the nine control schools, met the beverage goal. The snack goal was met by all of the intervention schools and only one of the four control schools with snack vending machines. APPLICATIONS TO CHILD NUTRITION PROFESSIONALS: The HEALTHY study's vending machine beverage and snack goals were successfully achieved in intervention schools, reducing access to less healthy food items outside the school meals program. Although the effect of these changes on student diet, energy balance and growth is unknown, these results suggest that healthier options for snacks can successfully be offered in school vending machines. PMID- 23687472 TI - Effect on Prediction when Modeling Covariates in Bayesian Nonparametric Models. AB - In biomedical research, it is often of interest to characterize biologic processes giving rise to observations and to make predictions of future observations. Bayesian nonparametric methods provide a means for carrying out Bayesian inference making as few assumptions about restrictive parametric models as possible. There are several proposals in the literature for extending Bayesian nonparametric models to include dependence on covariates. Limited attention, however, has been directed to the following two aspects. In this article, we examine the effect on fitting and predictive performance of incorporating covariates in a class of Bayesian nonparametric models by one of two primary ways: either in the weights or in the locations of a discrete random probability measure. We show that different strategies for incorporating continuous covariates in Bayesian nonparametric models can result in big differences when used for prediction, even though they lead to otherwise similar posterior inferences. When one needs the predictive density, as in optimal design, and this density is a mixture, it is better to make the weights depend on the covariates. We demonstrate these points via a simulated data example and in an application in which one wants to determine the optimal dose of an anticancer drug used in pediatric oncology. PMID- 23687473 TI - Multidisciplinary group performance-measuring integration intensity in the context of the North West London Integrated Care Pilot. AB - INTRODUCTION: Multidisciplinary Group meetings (MDGs) are seen as key facilitators of integration, moving from individual to multi-disciplinary decision-making, and from a focus on individual patients to a focus on patient groups. We have developed a method for coding MDG transcripts to identify whether they are or are not vehicles for delivering the anticipated efficiency improvements across various providers and apply it to a test case in the North West London Integrated Care Pilot. METHODS: We defined 'integrating' as the process within the MDG meeting that enables or promotes an improved collaboration, improved understanding, and improved awareness of self and others within the local healthcare economy such that efficiency improvements could be identified and action taken. Utterances within the MDGs are coded according to three distinct domains grounded in concepts from communication, group decision making, and integrated care literatures-the Valence, the Focus, and the Level. Standardized weighted integrative intensity scores are calculated across ten time deciles in the Case Discussion providing a graphical representation of its integrative intensity. RESULTS: Intra- and Inter-rater reliability of the coding scheme was very good as measured by the Prevalence and Bias-adjusted Kappa Score. Standardized Weighted Integrative Intensity graph mirrored closely the verbatim transcript and is a convenient representation of complex communication dynamics. Trend in integrative intensity can be calculated and the characteristics of the MDG can be pragmatically described. CONCLUSION: This is a novel and potentially useful method for researchers, managers and practitioners to better understand MDG dynamics and to identify whether participants are integrating. The degree to which participants use MDG meetings to develop an integrated way of working is likely to require management, leadership and shared values. PMID- 23687474 TI - Mergers and integrated care: the Quebec experience. AB - As a researcher, I have studied the efforts to increase the integration of health and social services in Quebec, as well as the mergers in the Quebec healthcare system. These mergers have often been presented as a necessary transition to break down the silos that compartmentalize the services dispensed by various organisations. A review of the studies about mergers and integrated care projects in the Quebec healthcare system, since its inception, show that mergers cannot facilitate integrated care unless they are desired and represent for all of the actors involved an appropriate way to deal with service organisation problems. Otherwise, mergers impede integrated care by creating increased bureaucratisation and standardisation and by triggering conflicts and mistrust among the staff of the merged organisations. It is then preferable to let local actors select the most appropriate organisational integration model for their specific context and offer them resources and incentives to cooperate. PMID- 23687475 TI - Successfully integrating aged care services: a review of the evidence and tools emerging from a long-term care program. AB - BACKGROUND: Providing efficient and effective aged care services is one of the greatest public policy concerns currently facing governments. Increasing the integration of care services has the potential to provide many benefits including increased access, promoting greater efficiency, and improving care outcomes. There is little research, however, investigating how integrated aged care can be successfully achieved. The PRISMA (Program of Research to Integrate Services for the Maintenance of Autonomy) project, from Quebec, Canada, is one of the most systematic and sustained bodies of research investigating the translation and outcomes of an integrated care policy into practice. The PRISMA research program has run since 1988, yet there has been no independent systematic review of this work to draw out the lessons learnt. METHODS: Narrative review of all literature emanating from the PRISMA project between 1988 and 2012. Researchers accessed an online list of all published papers from the program website. The reference lists of papers were hand searched to identify additional literature. Finally, Medline, Pubmed, EMBASE and Google Scholar indexing databases were searched using key terms and author names. Results were extracted into specially designed spread sheets for analysis. RESULTS: Forty-five journal articles and two books authored or co-authored by the PRISMA team were identified. Research was primarily concerned with: the design, development and validation of screening and assessment tools; and results generated from their application. Both quasi experimental and cross sectional analytic designs were used extensively. Contextually appropriate expert opinion was obtained using variations on the Delphi Method. Literature analysis revealed the structures, processes and outcomes which underpinned the implementation. PRISMA provides evidence that integrating care for older persons is beneficial to individuals through reducing incidence of functional decline and handicap levels, and improving feelings of empowerment and satisfaction with care provided. The research also demonstrated benefits to the health system, including a more appropriate use of emergency rooms, and decreased consultations with medical specialists. DISCUSSION: Reviewing the body of research reveals the importance of both designing programs with an eye to local context, and building in flexibility allowing the program to be adapted to changing circumstances. Creating partnerships between policy designers, project implementers, and academic teams is an important element in achieving these goals. Partnerships are also valuable for achieving effective monitoring and evaluation, and support to 'evidence-based' policy-making processes. Despite a shared electronic health record being a key component of the service model, there was an under-investigation of the impact this technology on facilitating and enabling integration and the outcomes achieved. CONCLUSIONS: PRISMA provides evidence of the benefits that can arise from integrating care for older persons, particularly in terms of increased feelings of personal empowerment, and improved client satisfaction with the care provided. Taken alongside other integrated care experiments, PRISMA provides further evidentiary support to policy-makers pursuing integrated care programs. The scale and scope of the research body highlights the long-term and complex nature of program evaluations, but underscores the benefits of evaluation, review and subsequent adaptation of programs. The role of information technology in supporting integration of services is likely to substantially expand in the future and the potential this technology offers should be investigated and harnessed. PMID- 23687476 TI - Patient perceptions of integrated care: confused by the term, clear on the concept. AB - PURPOSE: Health care reform in the US has introduced terms such as 'the patient centered medical home' and 'integrated care' that are often unclear and unfamiliar to patients. This study explored patient experiences with the functional domains of integrated care. THEORY AND METHODS: Patients first wrote their definitions of integrated care and then participated in focus group discussions about their experiences with the health care system. Transcripts were analyzed for thematic content. RESULTS: Forty-four patients participated in one of seven focus groups in San Francisco, CA in English and Spanish. Many patients were not clear about the meaning of the term integrated care. However, patients described experiences largely reflected in an existing conceptual model of integrated care and the importance of coordination within and across teams and with community resources, continuity and sharing of information, and patient engagement. Patients with high medical needs described the ubiquitous challenges they faced in experiencing coordinated care. CONCLUSIONS: Patients may not understand the term integrated care but are relatively clear on what the concept of integrated care entails and support its successful implementation. Patients and their families are at the center of integrated care, and health systems need to support and empower them to successfully navigate the medical neighborhood. PMID- 23687477 TI - Nurses' information exchange during older patient transfer: prevalence and associations with patient and transfer characteristics. AB - INTRODUCTION: To ensure continuity of care, it is important to effectively communicate the health status of older patients who are transferred between health care organizations. The objectives of this study were to: (1) evaluate the prevalence of nursing transfer documents, and (2) identify patient and transfer characteristics associated with the presence of nursing transfer documents for older patients transferred from home care to hospital and back to home care again after hospitalization. METHODS: Nursing documents were reviewed from a total of 102 records of older inpatients admitted from home care to medical wards at a local hospital in central Norway and later discharged home. Frequencies were used to describe patient and transfer characteristics, and the prevalence of transfer documents. Pearson's chi(2) test and logistic regression were used to identify possible associations between patient and transfer characteristics and the presence of nursing transfer documents. RESULTS: While nursing admission notes were present in 1% of the patient transfers from home care to the hospital, 69% of patient discharges from the hospital to home care were accompanied by nursing discharge notes. Patient and transfer characteristics associated with the presence of a nursing discharge note were age, gender, medical department facility, and length of hospital stay. CONCLUSIONS: The low prevalence of nursing transfer documents constitutes a challenge to the continuity of care for hospitalized home care patients. Patient and transfer characteristics may impact the nurses' propensity to exchange patient information. These findings emphasize the need for nurses and managers to improve the exchange of written information. While nurses must strive to transfer accurate patient information at the right place and at the right time, the managers must facilitate this by providing appropriate guidelines and standards, as well as adequate personnel and resources. PMID- 23687478 TI - Evaluation of complex integrated care programmes: the approach in North West London. AB - BACKGROUND: Several local attempts to introduce integrated care in the English National Health Service have been tried, with limited success. The Northwest London Integrated Care Pilot attempts to improve the quality of care of the elderly and people with diabetes by providing a novel integration process across primary, secondary and social care organisations. It involves predictive risk modelling, care planning, multidisciplinary management of complex cases and an information technology tool to support information sharing. This paper sets out the evaluation approach adopted to measure its effect. STUDY DESIGN: We present a mixed methods evaluation methodology. It includes a quantitative approach measuring changes in service utilization, costs, clinical outcomes and quality of care using routine primary and secondary data sources. It also contains a qualitative component, involving observations, interviews and focus groups with patients and professionals, to understand participant experiences and to understand the pilot within the national policy context. THEORY AND DISCUSSION: This study considers the complexity of evaluating a large, multi-organisational intervention in a changing healthcare economy. We locate the evaluation within the theory of evaluation of complex interventions. We present the specific challenges faced by evaluating an intervention of this sort, and the responses made to mitigate against them. CONCLUSIONS: We hope this broad, dynamic and responsive evaluation will allow us to clarify the contribution of the pilot, and provide a potential model for evaluation of other similar interventions. Because of the priority given to the integrated agenda by governments internationally, the need to develop and improve strong evaluation methodologies remains strikingly important. PMID- 23687479 TI - Talking about the institutional complexity of the integrated rehabilitation system-the importance of coordination. AB - Rehabilitation in Finland is a good example of functions divided among several welfare sectors, such as health services and social services. The rehabilitation system in Finland is a complex one and there have been many efforts to create a coordinated entity. The purpose of this study is to open up a complex welfare system at the upper policy level and to understand the meaning of coordination at the level of service delivery. We shed light in particular on the national rehabilitation policy in Finland and how the policy has tried to overcome the negative effects of institutional complexity. In this study we used qualitative content analysis and frame analysis. As a result we identified four different welfare state frames with distinct features of policy problems, policy alternatives and institutional failure. The rehabilitation policy in Finland seems to be divided into different components which may cause problems at the level of service delivery and thus in the integration of services. Bringing these components together could at policy level enable a shared view of the rights of different population groups, effective management of integration at the level of service delivery and also an opportunity for change throughout the rehabilitation system. PMID- 23687480 TI - A collaborative chain out of phase. AB - INTRODUCTION: The aim of this study is to explore the obstacles to collaborations between nurses in hospital and municipal care in the discharge of hospital patients who need continuing care. METHODS: First, we conducted in-depth interviews of nurses in hospitals and nurses in municipal care. Second, we developed questionnaires and distributed them to a representative sample of Norwegian municipalities to study the representativeness of the most important findings from the interviews. RESULTS: Municipal care nurses reported that the information they receive from hospital departments usually is insufficient for a complete understanding of a patient's needs. Formal discharge reports from hospital serve as a post factum formalization and authorization of information collected by municipal nurses in an ad hoc fashion and via oral communication. Typically, formal information routines are out of phase with the information needed by municipal care professionals. CONCLUSIONS: Hospital information provided at discharge is neither sufficient nor timely with respect to the information needs of nurses in municipal care. Organizational efforts and the use of information technology might ease some obstacles, but several problems will remain because of differences in professional orientation and the contexts of care delivery. PMID- 23687481 TI - Strategic collaboration councils in the mental health services: what are they working with? AB - INTRODUCTION: In recent years collaboration has become an important part of the delivery of welfare services. One response to these collaborative efforts has been the introduction of strategic collaboration between different welfare agencies. Strategic collaboration is arguably the most open-ended form of service integration, as both purpose and membership are open to negotiation. This article will examine the work in strategic collaboration councils in the mental health services. METHOD: The study is based on observations in eight strategic collaboration councils in Sweden. The councils were observed over 12 months, and every meeting that was held during that time was observed and tape-recorded. RESULTS: FOUR BASIC ACTIVITIES WERE IDENTIFIED: the exchange of information, the identification of problems, organizing events and activities, and organizing the councils. Even though these activities were identified, the main focus was to exchange information. The councils' work also varied in terms of how they make decisions and agreements, and whether their focus is more on internal or external issues. CONCLUSION: FROM THE IDENTIFIED ACTIVITIES, THE COUNCILS CAN BE CLASSIFIED INTO FOUR IDEAL TYPES: the information council, the problem identification council, the decision-making council, and the self-organizing council. PMID- 23687482 TI - Understanding integrated care: a comprehensive conceptual framework based on the integrative functions of primary care. AB - INTRODUCTION: Primary care has a central role in integrating care within a health system. However, conceptual ambiguity regarding integrated care hampers a systematic understanding. This paper proposes a conceptual framework that combines the concepts of primary care and integrated care, in order to understand the complexity of integrated care. METHODS: The search method involved a combination of electronic database searches, hand searches of reference lists (snowball method) and contacting researchers in the field. The process of synthesizing the literature was iterative, to relate the concepts of primary care and integrated care. First, we identified the general principles of primary care and integrated care. Second, we connected the dimensions of integrated care and the principles of primary care. Finally, to improve content validity we held several meetings with researchers in the field to develop and refine our conceptual framework. RESULTS: The conceptual framework combines the functions of primary care with the dimensions of integrated care. Person-focused and population-based care serve as guiding principles for achieving integration across the care continuum. Integration plays complementary roles on the micro (clinical integration), meso (professional and organisational integration) and macro (system integration) level. Functional and normative integration ensure connectivity between the levels. DISCUSSION: The presented conceptual framework is a first step to achieve a better understanding of the inter-relationships among the dimensions of integrated care from a primary care perspective. PMID- 23687483 TI - Understanding integrated care: a complex process, a fundamental principle. PMID- 23687484 TI - The role of an intermediate unit in a clinical pathway. AB - INTRODUCTION: Different care models have been established to achieve more coordinated clinical pathways for older patients in the transition between hospital and home. This study explores an intermediate unit's role in a clinical pathway for older patients with somatic diseases. THEORY AND METHODS: Qualitative data were collected via interviews, observations, and a questionnaire. Participants included patients and healthcare providers within both specialist and primary healthcare. Transcripts of interviews and field notes were analyzed using a method of systematic text condensation. RESULTS: Healthcare providers in the hospital, the intermediate unit, and the municipalities have different opinions about who is a 'suitable' patient for the unit and what is the proper time for hospital discharge. This results in time-consuming negotiations between the hospital and the unit. Incompatible computer systems increase the healthcare provider's workload. Several informants are doubtful as to whether a stay in the unit is useful to the patients, while the patients are mostly pleased with their stay and the transferral. CONCLUSION AND DISCUSSION: This study describes challenges that may occur when a new unit is established in an existing healthcare system in order to achieve an appropriate clinical pathway from hospital to home. PMID- 23687485 TI - Transfer of inoculum of Metarhizium anisopliae between adult Glossina morsitans morsitans and effects of fungal infection on blood feeding and mating behaviors. AB - The transfer of conidia of Metarhizium anisopliae between tsetse flies Glossina morsitans and the effects of fungal inoculation on mating and blood meal feeding behaviors were investigated in the laboratory. Male or female flies were inoculated with fungal conidia ("donors") and allowed to pair with fungus-free mate of opposite sex ("recipients") at 1-day-interval up to three mates. Fungus treated male or female "donor" flies as well as their mates "recipients" died from fungal infection. However, mortality in male "recipient" flies declined with successive mating, from 82.5 to 32.5 %. Fungus-treated males readily located female flies and mating was successful in most cases comparable to the controls. There were no significant differences (P > 0.05) in mean duration of mating, number of jerking movements between fungus-treated and fungus-free males for all the mating lines, except in the number of jerking movements when male flies mated with the 3rd line female flies. Fungus-treated and fungus-free female flies previously mated with treated and non-treated males showed refractoriness during subsequent pairings. The number of fertile female flies was higher (P < 0.05) in fungus-free than in fungus-treated treatments, thus producing more pupae. High concentration of fungus (3.0 * 106 conidia ml-1) significantly (P < 0.05) reduced blood meal intake of flies. This study has shown that fungal infection does not affect the mating behavior of tsetse flies and fly-to-fly contamination does occur during matings. These are important attributes if entomopathogenic fungi have to be used in auto-dissemination strategy and be integrated into sterile insect technique. PMID- 23687486 TI - Calcium intake in health maintenance - a systematic review. AB - BACKGROUND: Calcium (Ca) is an essential nutrient for the human body. Despite lively research, there is uncertainty about Ca requirements in terms of desirable health outcomes including an upper intake level above which the potential for harm increases. OBJECTIVES: The aim was to conduct a review to update requirements and desirable or harmful health effects of Ca on the current scientific evidence. METHODS: We searched Medline and Swemed from January 2000 to December 2011 and included all systematic reviews that reported Ca supplementation or usual Ca intake on health outcomes. Meta-analyses, randomized clinical trials and cohort studies were included in the second search between May 2009 and March 2011 and an additional search covering studies till the end of 2011. This review concentrated on studies reporting independent effects of Ca, although a few recent trials report sole effects of Ca on health outcomes, most trials use Ca in combination with vitamin D vs. placebo. RESULTS: In total, we reviewed 38 studies addressing the effects of Ca on bone, pregnancy-related outcomes, cancers, cardiovascular outcomes, obesity, and mortality. There was a lot of heterogeneity in the study protocols, which made it difficult to draw any strong conclusions. According to the literature, high Ca intake seems to have a small positive effect on bone mineral content (BMC) or bone mineral density (BMD) in children and postmenopausal women. We did not find any consistent evidence on the effects of Ca on bone health in premenopausal women or men. Also, the evidence that Ca supplementation reduces fracture incidence is scarce and inconsistent. Maternal diet may influence the peak bone mass of offspring but more studies are required. There was no overall effect of Ca intake on cancers. Ca was associated with a decreased risk of breast cancer and a slightly increased risk of prostate cancer in two of the three studies. No associations were found with other cancers. We found no consistent association between cardiovascular outcomes and Ca intake except for blood pressure. A small decrease of 2-4 mmHg in systolic blood pressure was found in pregnant and in hypertensive subjects with Ca supplementation. Reviewed studies did not show consistent evidence relating Ca intake to either mortality or obesity. CONCLUSION: Based on this evidence, there is no need to change the Nordic recommendations for Ca intake. However, due to heterogeneity in the studies it is difficult to interpret the results and provide single summary statement. PMID- 23687487 TI - Killian-jamieson diverticula presenting synchronously with thyroid adenoma. AB - Killian-Jamieson diverticulum is a rare hypopharyngeal diverticulum, less commonly encountered compared with Zenker's diverticulum. These hypopharyngeal diverticula that cause dysphagia often mimic a thyroid tumor incidentally detected on neck ultrasonography. However, to our knowledge, Killian-Jamieson diverticula complicated by a thyroid tumor have not been previously described. We experienced a rare case of bilateral Killian-Jamieson diverticula synchronously complicated by a thyroid adenoma in a 74-year-old woman who became aware of dysphagia and a tumor in the left side of her neck. Pharyngoesophagography revealed bilateral diverticula protruding from the lateral wall of the esophagopharyngeal junction, but the appearance of the cricopharyngeal bar representing the cricopharyngeus muscle above the diverticula had become unclear because the thyroid tumor was pressing on the diverticula and the cervical esophagus. However, the diverticula were diagnosed as Killian-Jamieson diverticula because cervical computed tomography showed bilateral diverticula arising from the cervical esophagus just below the level of the cricoid cartilage, and operative finding showed that the diverticula were located above the upper esophageal longitudinal muscle. Radiographic imaging is useful for diagnosis as cause of dysphagia and cervical tumor. PMID- 23687488 TI - A case of primary biliary cirrhosis that progressed rapidly after treatment involving rituximab. AB - Primary biliary cirrhosis (PBC) is a progressive liver disease for which limited therapies are recommended. Rituximab, an anti-CD20 monoclonal antibody, is expected to be a useful therapeutic regimen for PBC. Previous studies indicated biochemical and immunological improvement in PBC after rituximab treatment. Although rituximab shows therapeutic potential for PBC, few cases have been reported and histological improvement and long-term outcome remain uncertain. Here, we report a case of PBC in a 66-year-old Japanese female patient who presented with a gastric lymphoma and who had been treated with a regimen containing rituximab for incidental malignant lymphoma. She showed biochemical and immunological improvements, and liver histology before and after rituximab treatment confirmed a decrease in liver inflammation. However, she developed liver cirrhosis a short time after rituximab treatment without biochemical or immunological worsening. Rituximab treatment for PBC might be considered and careful observation is required after treatment. PMID- 23687489 TI - Rituximab therapy for severe cutaneous leukocytoclastic angiitis refractory to corticosteroids, cellcept and cyclophosphamide. AB - We report our clinical experience with rituximab in the treatment of 2 patients with idiopathic cutaneous angiitis who relapsed after treatment with high-dose corticosteroids and cyclophosphamide. A 39-year-old woman and a 51-year-old man presented with ulcerating maculopapular rash in both lower limbs which relapsed 6 months after treatment with a combination of high-dose corticosteroids and cyclophosphamide. After treatment with 2 g of rituximab, the first patient has still been in clinical remission for 32 months while the second has finished 28 months. Interestingly, CD19 which had dropped to <0.1 one week following the start of retuximab had increased to >0.5% 8 months later in both patients. Despite that, our patients are still in clinical remission. No significant side effects were noted during infusions and up to the period of follow-up. In conclusion, rituximab is a useful and safe agent in the treatment of idiopathic cutaneous angiitis refractory to conventional therapy. Clinical remission persists years after improvement of B-cell suppression. PMID- 23687490 TI - Torus palatinus osteonecrosis related to bisphosphonate: a case report. AB - INTRODUCTION: Osteonecrosis of the palate is a rare condition which is even rarer when occurring on a torus palatinus and associated with bisphosphonate (BP). CASE PRESENTATION: We report an uncommon case of osteonecrosis of a torus palatinus. Our patient was a 67-year-old white female who presented with a painful intraoral ulcer associated with necrotic bone tissue of her torus palatinus, due to the chronic use of alendronate. CONCLUSION: We point out the possible causative relationship of BPs and osteonecrosis on torus growth. It is very important to know that torus palatinus and the use of BPs are risk factors for osteonecrosis of the maxilla. PMID- 23687491 TI - Reduction of Skin pH during Treatment for Palmoplantar Hyperhidrosis: A Conjecture on the Role of pH-Regulated Water Channel, i.e. Aquaporin. AB - Primary palmoplantar hyperhidrosis (PPH) is a disorder that involves excessive sweating on the palms and soles. Although the pathophysiology of PPH remains unknown, some treatments, including topical aluminum chloride (AC) and tap water iontophoresis (TWI), are effective at suppressing the perspiration. Herein, we report the kinetics of the skin pH of two cases of PPH treated with AC and TWI. We found that the skin pH decreased in accordance with the reduction in sweating. This finding indicates that the reduction in sweating may be attributed to the reduction of skin pH in AC and TWI. Whether or not the pH-regulated function of aquaporin can explain this finding remains unknown. PMID- 23687492 TI - In vivo Reflectance Confocal Microscopy: A Useful Tool to Select the Location of a Punch Biopsy in a Large, Clinically Indistinctive Lesion. AB - Reflectance confocal microscopy (RCM) is a noninvasive technique for in vivo imaging of the skin that allows evaluation of the total lesion area. This case report about a 66-year-old patient with a clinically indistinctive, previously treated erythematous lesion on the frontal part of the face demonstrates the use of RCM to select the proper biopsy location. PMID- 23687493 TI - Primary osteosarcoma of the heart: experience of an unusual case. AB - Primary cardiac osteosarcomas are uncommon tumors. They have an aggressive biology and hence poor prognosis. This report describes a 23-year-old male patient who was referred to our hospital with chest pain. Echocardiography showed a left atrial mass, and tumor excision revealed a cardiac osteosarcoma. Adjuvant cisplatin plus ifosfamide combination chemotherapy provided a disease-free survival of 9 months; unfortunately the patient died of metastatic disease thereafter. PMID- 23687494 TI - Mixed response to ipilimumab in a melanoma patient with brain metastases: case report and review of the literature. AB - Management of patients suffering from metastatic malignant melanoma and brain metastasis remains challenging in routine clinical practice. The inhibitory anti CTLA-4 antibody ipilimumab has recently been approved as second-line therapeutic option for melanoma patients. Increasing evidence suggests distinct therapeutic activity on central nervous system metastases, although this continues to be actively debated. Here, we present the case of a patient suffering from metastatic melanoma, including symptomatic brain metastasis, who showed a partial response to ipilimumab in extracranial tumor manifestations, while the disease was progressing intracranially. Subsequently, intracranial disease progression could be managed by local irradiation. An overview of currently available literature on the efficacy of ipilimumab in melanoma patients with central nervous system metastases is provided. PMID- 23687495 TI - Secondary malignant peritoneal mesothelioma of the greater omentum after therapy for primary pleural mesothelioma. AB - Mesothelioma is the most common malignant primary tumor of the pleura and usually associated with inhalation of asbestos fibers. In contrast, peritoneal mesothelioma is a rare entity whose pathomechanism is not yet fully understood. The coexistence of pleural mesothelioma with secondary involvement of the abdominal cavity has not been addressed in the literature. In this case report, we describe secondary malignant mesothelioma of the greater omentum. A 69-year old man with histologically proven pleural mesothelioma on the right side and no past medical history of asbestos exposure received palliative treatment consisting of a talc pleurodesis. After a 6-month interval of stable disease, a local progressive tumor of the right pleura was seen on a CT scan. Eleven months later, during follow-up, the patient presented at our emergency department with a sudden onset of diffuse abdominal pain. Abdominal ultrasound revealed a mass within the greater omentum and the coexistence of free fluid. Subsequent abdominal CT scans demonstrated tumor infiltration from the right pleura by a transdiaphragmatic route into the abdomen, where diffuse infiltration of the greater omentum was observed. Aspiration of the ascites and the biopsy of the greater omentum confirmed the diagnosis of secondary malignant mesothelioma of the peritoneum. In conclusion, we present the extremely rare diagnosis of secondary malignant mesothelioma of the abdomen, which arose as a result of local progression from the right pleura into the abdomen. PMID- 23687496 TI - Varicella zoster virus myelitis in two elderly patients: diagnostic value of nested polymerase chain reaction assay and antibody index for cerebrospinal fluid specimens. AB - BACKGROUND: Myelitis is one of the rarest neurological complications of the varicella zoster virus (VZV) infection. Focal muscle weakness with or without sensory disturbance occurs in approximately 5% of the cases after acute VZV infection, with complete recovery in 50-70%. CASE PRESENTATION: This report describes two rare cases of elderly patients with VZV myelitis secondary to dermatomal zoster rash. Patient 1 was a 79-year-old woman who developed paraplegia, numbness and decreased sensation in the left arm and below thoracic (Th)-10 after sacral zoster. Spinal cord MRI showed a high-signal-intensity lesion at the cervical spinal nerve 2 on a T2-weighted image. Patient 2 was a 73 year-old man who developed right flaccid leg weakness and urinary retention after right dorsal Th 5-8 zoster. Spinal cord MRI showed a high-signal-intensity lesion at Th 3-4 on a T2-weighted image. In both cases, although the conventional single polymerase chain reaction (PCR) assays all showed negative results, the original nested PCR assay detected VZV DNA in the cerebrospinal fluid (CSF) specimen collected on admission. In addition, the anti-VZV IgG antibody by enzyme immunoassay and antibody index were elevated in the CSF specimens during the clinical courses of both patients. On the basis of these findings, both patients were diagnosed with VZV myelitis and were treated with high-dose acyclovir and corticosteroid. This combined treatment was appropriate and effective for the improvement of their functional outcomes. CONCLUSION: The detection of VZV DNA in CSF by nested PCR assay and the evaluation of the antibody index to VZV had significant diagnostic value. PMID- 23687497 TI - Radiation-induced cavernoma after total body irradiation and haematopoietic stem cell transplantation in an adult patient suffering from acute myeloid leukaemia. AB - Cerebral cavernomas are thin-walled vascular lesions composed of dilated capillary spaces. De novo formation of cavernomas after cerebral radiotherapy has been suspected since 1994. They are mostly seen in children after irradiation of brain tumours. Radiation dose and the developing juvenile brain are predisposing factors causing cavernomas. However, the underlying mechanisms are still far from being understood. In adults, radiation-induced cavernomas (RICs) usually occur 10 years after a high cumulative radiation dosage of >30 Gy. Here, we report a 45 year-old man with new-onset focal epileptic seizures caused by a haemorrhagic lesion noted on cerebral computed tomography scan. Brain MRI showed the typical appearance of a ruptured cavernoma. Of note, a cerebral MRI scan 5 years earlier showed no corresponding lesion. The patient had been treated with haematopoietic stem cell transplantation for acute myeloid leukaemia (AML) 16 years before. As part of this procedure, total body irradiation (TBI) consisting of 12 Gy was administered. According to the data from the literature, the typical delay from irradiation and a former normal brain MRI scan, we assume that our patient suffers from a RIC. To our knowledge, this is the first documented adult AML patient with a RIC treated with TBI. We aim to increase awareness among neurologists for the association of cranial irradiation or TBI and de novo cavernomas in patients suffering from malignant diseases. PMID- 23687498 TI - The achromatic 'philosophical zombie', a syndrome of cerebral achromatopsia with color anopsognosia. AB - We describe a patient with persistent cerebral achromatopsia occurring after bilateral occipital strokes. Blinded color recognition was assessed with a computerized experimental paradigm and the patient reported the degree of confidence in the response exactness on a visual percent scale. Color recognition was accurate and above chance (Fisher's exact test, p < 0.002). The degree of confidence in the answers showed a significant correlation with recognition scores (Spearman rank order correlation, p < 0.0001). These findings constitute the exceptional condition of what we called color anopsognosia (not knowing of seeing colors) and recall the theoretic figure of the 'philosophical zombie'. However, the cognitive mechanisms of the dissociation between a subjective colorless vision and good performance for color naming still remain poorly understood. PMID- 23687499 TI - Neovascular glaucoma induced by peripheral retinal ischemia in neurofibromatosis type 1: management and imaging features. AB - PURPOSE: To report the case of a young patient affected by neurofibromatosis 1 (NF-1) with peripheral retinal ischemia-induced neovascular glaucoma and the peculiar spectral-domain optical coherence tomography (SD-OCT) features. MATERIAL AND METHODS: A 13-year-old boy affected by NF-1, as diagnosed according to established criteria, was referred with a diagnosis of hypertensive uveitis in his left eye. He underwent a complete ophthalmic examination and comprehensive blood work with viral and immunological tests. The case was documented with fluorescein angiography (FA) and SD-OCT. When the intraocular pressure (IOP) of the left eye decreased and the cornea cleared, FA revealed retinal ischemia and leakage from pathologic retinal vessels. SD-OCT revealed foveal hypoplasia secondary to the complete absence of the retinal nerve fiber layer. RESULTS: Peripheral retinal ischemia-induced neovascular glaucoma was diagnosed. The patient underwent Ahmed valve implantation to control his IOP, and subsequent retinal photocoagulation by argon laser and intravitreal bevacizumab injection were performed to control neovascularization. DISCUSSION: Retinal ischemia in NF 1 might lead to neovascular glaucoma: lowering of the IOP with surgical implantation of an Ahmed valve, regression of neovascularization by argon laser panretinal photocoagulation and intravitreal injection of bevacizumab can be a helpful way to control such a complication. PMID- 23687500 TI - Anterior segment optical coherence tomography: assisted topographic corneal epithelial thickness distribution imaging of a keratoconus patient. AB - PURPOSE: To evaluate safety, efficacy and ease of measurement of epithelial thickness in a keratoconic patient based on anterior segment optical coherence tomography (AS-OCT). METHODS: A 25-year-old male patient, previously diagnosed with keratoconus, with highly asymmetric manifestation among the two eyes, was subjected to AS-OCT corneal epithelial imaging. We investigated epithelial thickness and epithelial topographic thickness distribution. RESULTS: Mean epithelial thickness was 51.97 +/- 0.70 for the less affected right eye (OD), and 55.65 +/- 1.22 for the more affected left eye (OS). Topographic epithelial thickness variability for the OD was 1.53 +/- 0.21 MUm, while for the OS it was 9.80 +/- 0.41 MUm. CONCLUSIONS: This case further supports our previous findings with high-frequency ultrasound measurements of the increase in overall epithelial thickness in keratoconic eyes in comparison with normal eyes. AS-OCT further offers ease of use and possibly higher predictability of measurement. This case report, based on AS-OCT imaging, verifies increased overall epithelial thickness in keratoconic eyes, as introduced by a previous study [Kanellopoulos et al.: Clin Ophthalmol 2012;6:789-800], based on high-frequency scanning ultrasound biomicroscopy imaging. PMID- 23687501 TI - Rhegmatogenous Retinal Detachment with a High Risk of Proliferative Vitreoretinopathy Treated with Episcleral Surgery and an Intravitreal Dexamethasone 0.7-mg Implant. AB - PURPOSE: To report a case of rhegmatogenous retinal detachment with a high risk of proliferative vitreoretinopathy (PVR) effectively treated with episcleral surgery and an intravitreal dexamethasone 0.7-mg implant. METHODS: A 35-year-old Caucasian man with a macula-off rhegmatogenous subtotal retinal detachment that had persisted for 1 month in his myopic left eye presented several risk factors that could have led to the development of PVR after retinal detachment surgery. His best corrected visual acuity was hand motion. He received an intravitreal dexamethasone 0.7-mg implant (Ozurdex((r))) after episcleral surgery to prevent this complication. RESULTS: At least 9 months after surgery, no sign of PVR or pucker has developed in the treated eye. Visual acuity improved to 0.2, the retina was attached and no complications were observed. CONCLUSION: Intravitreal dexamethasone 0.7-mg implant (Ozurdex) could be considered as off-label treatment following episcleral surgery to prevent PVR. PMID- 23687502 TI - Anterior segment imaging and treatment of a case with syndrome of ectopia lentis, spontaneous filtering blebs, and craniofacial dysmorphism. AB - PURPOSE: To report the ultrasound biomicroscopy (UBM) and surgical findings in a subject with a syndrome of ectopia lentis, spontaneous filtering blebs, and craniofacial dysmorphism (Traboulsi syndrome). METHODS: Case report, using a 40 MHz UBM wide-field anterior segment scan and anterior segment optical coherence tomography (OCT). RESULTS: A 16-year-old orphan girl presented with visual loss to the level of 6/60 (20/200) bilaterally. She had a central corneal opacification with retrocorneal fibrosis. The anterior chamber was flat with a very poorly dilating pupil. The lens was central in location. Perilimbal conjunctival blebs were bilateral with an intraocular pressure of 8 mm Hg. UBM and anterior segment OCT revealed chronic apposition of the iris to the cornea with angle closure, delineation of the bleb tract and rarefaction of the zonules. The girl had abnormal facial features (a beaked nose and long face) with normal chromosomal studies, negative fluorescent in situ hybridization study for velocardiofacial syndrome and an absence of signs suggesting Marfan syndrome. Under general anesthesia, attempts at deepening the anterior chamber with sodium hyaluronate 3% led to a spontaneous dislocation of the lens into the anterior chamber, facilitating its aspiration. Deepening of the angle was found after lens removal. Retrocorneal fibrosis persisted after surgery, but the bleb height decreased. Best corrected visual acuity did not improve from the preoperative level beyond 6/60 (20/200) because of central retrocorneal fibrosis. CONCLUSIONS: Early surgical removal of the lens is necessary in this syndrome to avoid irreversible corneal and trabecular meshwork damage in chronic apposition of the iris to the cornea. UBM can help in the delineation of the bleb tract and document resolution of angle closure after surgery. PMID- 23687503 TI - Isolated hand paresis: a case series. AB - BACKGROUND: Hand knob infarction is a well-known stroke entity. Based on very limited data, embolic stroke mechanism has been considered the most frequent cause; however, prognosis is considered good. We wanted to shed more light on this phenomenon by assessing a cohort of patients referred to a general hospital stroke unit. METHODS: Every subject admitted to our stroke unit with an acute isolated hand paresis in the period from 2007 to 2012 was identified prospectively. Patients who had suffered from a stroke in the hand motor cortex or an adjacent area explaining the acute loss of hand function were included in the study. The Trial of Org 10172 in Acute Stroke Treatment criteria were used to classify subtypes of stroke according to etiology. The patients were followed up during autumn 2012. RESULTS: Seventeen subjects were admitted, but in 2 of them symptoms were transitory and magnetic resonance imaging was negative. Two patients were excluded due to persisting sensory deficits. The remaining 13 (11 males and 2 females) patients with an average age of 62.9 (+/- 13.4) years were included, representing 1.5% of all ischemic strokes diagnosed at the stroke unit in the given period. All patients were right-handed, and the dominant hand was affected only in 4 (31%). The average Medical Research Council's scale score was 3.1 (+/- 1.4) on admission, and classified as bad. On follow-up, which occurred on average 29.8 (+/- 19.8) months after the stroke, the score was 4.6 (+/- 0.4) and was classified as fair to good. No patient experienced a new stroke. The outcome was good to excellent in 10 patients (77%). Two patients died (15%), 1 of probable cardiac arrest and 1 of unknown cause. One patient did not participate in the follow-up. The majority of patients had evidence of both small artery (77%) and large artery (85%) disease. On average, there were 1.6 (+/- 0.4) new ischemic lesions per patient. Six patients had a solitary lesion (46%). In 5 of them, small artery occlusion was considered the probable stroke mechanism. In 4 cases, the stroke was of undetermined etiology. Three patients had atrial fibrillation, and in 2 of them cardioembolism was the probable stroke mechanism. Two patients with definite large artery atherosclerosis underwent carotid endarterectomy, and 1 of them had comorbid atrial fibrillation. CONCLUSION: Strokes causing isolated hand paresis seem to have a heterogeneous etiology. Prognosis regarding hand function is good, but long-term outcome depends on stroke etiology and secondary prophylaxis. PMID- 23687504 TI - Variation in clinical practice of intravenous thrombolysis in stroke in the Netherlands. AB - In the Netherlands in 2010, 11% of patients with ischemic stroke received intravenous thrombolysis (IVT), varying from 4 to 26% between hospitals. The aim of this study was to investigate variation in clinical practice and organization of IVT in relationship to performance and outcome. In all 84 Dutch hospitals performing IVT, a stroke neurologist was approached using a web-based survey. The response rate was 82%. The study showed considerable variation. For example, door to-needle time ranged from 25 to 80 min. High blood pressure was actively lowered before performing IVT by 57% of neurologists, while 35% chose to wait. 28% started IVT without knowledge of laboratory results. Better follow-up data are needed to see whether this variation results in differences in outcome. PMID- 23687505 TI - Increase in the Size of an Intracardiac Thrombus during Dabigatran Therapy (110 mg b.i.d.) in an Acute Cardioembolic Stroke Patient. AB - We report a case of atrial fibrillation in a patient in whom a mobile thrombus in the left atrial appendage increased in size after low-dose dabigatran therapy. A 74-year-old man was admitted to our hospital because of sudden onset of right hemiplasia and dysarthria. On admission, his National Institutes of Health Stroke Scale score was three. Axial diffusion-weighted magnetic resonance images and magnetic resonance angiography images showed hyperintense signals in the left front-parietal cerebral cortex without any intracranial stenotic lesions, and acute cardioembolic stroke associated with nonvalvular atrial fibrillation was diagnosed. Transesophageal echocardiography revealed a mobile thrombosis (1.0 * 2.2 cm) in the left atrial appendage, and dabigatran therapy (110 mg b.i.d.) was initiated to prevent stroke recurrence. Transesophageal echocardiography performed 6 days later revealed that the size of the thrombus had increased to 1.5 * 3.0 cm. Medication was changed to warfarin, and the thrombosis subsequently decreased in size. The patient did not have a recurrent stroke and was discharged with a National Institutes of Health Stroke Scale score of zero. This case demonstrates that low-dose dabigatran may not be effective in reducing the size of a thrombus. PMID- 23687506 TI - Tau pathology and parietal white matter lesions have independent but synergistic effects on early development of Alzheimer's disease. AB - BACKGROUND: White matter lesions (WMLs) are a common finding in patients with dementia. This study investigates the relationship between WMLs, hyperphosphorylated tau (P-tau) in cerebrospinal fluid (CSF) and apolipoprotein E (APOE) epsilon4 genotype in prodromal Alzheimer's disease (AD). METHODS: Baseline levels of tau, P-tau and beta-amyloid 1-42 in CSF, the presence of WMLs in the brain, and the APOE genotype were ascertained in 159 patients with mild cognitive impairment (MCI) and 38 cognitively healthy controls. RESULTS: After 5.7 years, 58 patients had developed AD. In this group, patients with normal levels of CSF P tau had higher levels of WMLs in the parietal regions than those with pathological P-tau levels (p < 0.05). Also, patients without APOE epsilon4 alleles had more WMLs in the parietal lobes than those with at least one allele (p < 0.05). MCI patients with pathological P-tau levels and parietal WMLs showed a greater risk of developing AD than those with just one of the two pathological parameters. CONCLUSIONS: We suggest that WMLs in parietal lobes and tau pathology likely have independent but synergistic effects on the reduction of the cognitive reserve capacity of the brain. In patients with a more low-grade AD pathology, WMLs in the parietal lobes might increase the risk of developing dementia. PMID- 23687507 TI - Neuropsychiatric symptoms in elderly inpatients: a multicenter cross-sectional study. AB - BACKGROUND/AIMS: We determined the prevalence of neuropsychiatric symptoms in geriatric rehabilitation patients to compare neuropsychiatric symptoms between patients with and without dementia, and to evaluate associations linking severity of cognitive impairment and neuropsychiatric symptoms. METHODS: In February 2009, we studied patients aged 75 years or older who had been admitted to four geriatric rehabilitation units in the Paris area. The twelve Neuropsychiatric Inventory items and four neuropsychiatric subsyndromes defined by the European Alzheimer's Disease Consortium were evaluated. RESULTS: Of the 194 patients, 149 (76.8%) had dementia, and 154 (79.4%) had exhibited at least one neuropsychiatric symptom during the past week. Agitation was the most common neuropsychiatric symptom in the group with dementia (36.9%) and depression in the group without dementia (35.6%). The dementia group had significantly higher prevalences of hyperactivity (p < 0.001) and delusions (p = 0.01) than the non-dementia group. In the dementia group, severity of cognitive impairment was associated with hyperactivity (p = 0.01) and psychosis (p = 0.02). CONCLUSION: The prevalence of neuropsychiatric symptoms among geriatric rehabilitation patients was high but not higher than in elderly outpatients. PMID- 23687508 TI - Symptoms of Early Dementia-11 Questionnaire (SED-11Q): A Brief Informant-Operated Screening for Dementia. AB - The aim of this study was to develop a brief informant-based questionnaire, namely the Symptoms of Early Dementia-11 Questionnaire (SED-11Q), for the screening of early dementia. 459 elderly individuals participated, including 39 with mild cognitive impairment in the Clinical Dementia Rating scale (CDR) 0.5, 233 with mild dementia in CDR 1, 106 with moderate dementia in CDR 2, and 81 normal controls in CDR 0. Informants were required to fill out a 13-item questionnaire. Two items were excluded after analyzing sensitivities and specificities. The final version of the SED-11Q assesses memory, daily functioning, social communication, and personality changes. Receiver operator characteristic curves assessed the utility to discriminate between CDR 0 (no dementia) and CDR 1 (mild dementia). The statistically optimal cutoff value of 2/3, which indicated a sensitivity of 0.84 and a specificity of 0.90, can be applied in the clinical setting. In the community setting, a cutoff value of 3/4, which indicated a sensitivity of 0.76 and a specificity of 0.96, is recommended to avoid false positives. The SED-11Q reliably differentiated nondemented from demented individuals when completed by an informant, and thus is practical as a rapid screening tool in general practice, as well as in the community setting, to decide whether to seek further diagnostic confirmation. PMID- 23687509 TI - The Effect of Solifenacin on Cognitive Function following Stroke. AB - BACKGROUND/AIMS: Our aim was to investigate the effect of solifenacin (an anticholinergic) on cognitive function after stroke. METHODS: We retrospectively reviewed 66 stroke cases who were prescribed solifenacin for more than 2 months. A control group was generated matching the patients both for sex and age. The interval changes in the Mini-Mental State Examination (MMSE) score and Clinical Dementia Rating Sum of Boxes (CDR-SB) score after solifenacin administration were compared to those of the control group. RESULTS: The baseline MMSE score of the control group was 15.9 +/- 9.2 and that of the solifenacin group was 14.3 +/- 7.8. After using solifenacin for an average of 76.9 days, there was a change in the MMSE score of 1.9 +/- 5.2. During similar periods, there was a change in the MMSE score of 2.9 +/- 3.7 in the control group (not using solifenacin). However, there was no significant difference between the two groups. Similarly, there was no significant difference in the CDR-SB score between the two groups. CONCLUSION: Solifenacin treatment did not affect the short-term cognitive performance in stroke patients. This information might be useful when prescribing anticholinergics to stroke patients. PMID- 23687510 TI - Hyponatremia - a rare but serious complication of amiodarone: a case report and review of the literature. AB - INTRODUCTION: Hyponatremia secondary to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) during amiodarone therapy is a rare but potentially lethal adverse effect. We report a case of severe hyponatremia associated with amiodarone, and discuss its clinical implications. CASE REPORT: An 84-year-old Caucasian man with a past medical history of hypertension and diabetes was admitted to the hospital with a non-ST elevation myocardial infarction. He underwent coronary artery bypass graft and developed atrial fibrillation on postoperative day 2. A loading dose of amiodarone followed by a maintenance dose was started. The serum sodium level was 136 mmol/l at discharge and subsequently decreased to 105 mmol/l 11 days later, at which time the patient represented with altered mental status. The diagnosis of SIADH was made based on euvolemic hypoosmotic hyponatremia, lack of any other medication known to cause SIADH and urine that was less than maximally dilute. The serum sodium increased gradually to 123 mmol/l after 36 h of treatment with hypertonic saline, demeclocycline and fluid restriction. CONCLUSION: SIADH-induced hyponatremia associated with amiodarone occurs rarely. Since severe hyponatremia is associated with significant neurological damage and mortality, clinicians should carefully monitor serum sodium during amiodarone therapy. PMID- 23687511 TI - Renoprotection and the Bardoxolone Methyl Story - Is This the Right Way Forward? A Novel View of Renoprotection in CKD Trials: A New Classification Scheme for Renoprotective Agents. AB - In the June 2011 issue of the New England Journal of Medicine, the BEAM (Bardoxolone Methyl Treatment: Renal Function in CKD/Type 2 Diabetes) trial investigators rekindled new interest and also some controversy regarding the concept of renoprotection and the role of renoprotective agents, when they reported significant increases in the mean estimated glomerular filtration rate (eGFR) in diabetic chronic kidney disease (CKD) patients with an eGFR of 20-45 ml/min/1.73 m(2) of body surface area at enrollment who received the trial drug bardoxolone methyl versus placebo. Unfortunately, subsequent phase IIIb trials failed to show that the drug is a safe alternative renoprotective agent. Current renoprotection paradigms depend wholly and entirely on angiotensin blockade; however, these agents [angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)] have proved to be imperfect renoprotective agents. In this review, we examine the mechanistic limitations of the various previous randomized controlled trials on CKD renoprotection, including the paucity of veritable, elaborate and systematic assessment methods for the documentation and reporting of individual patient-level, drug-related adverse events. We review the evidence base for the presence of putative, multiple independent and unrelated pathogenetic mechanisms that drive (diabetic and non diabetic) CKD progression. Furthermore, we examine the validity, or lack thereof, of the hyped notion that the blockade of a single molecule (angiotensin II), which can only antagonize the angiotensin cascade, would veritably successfully, consistently and unfailingly deliver adequate and qualitative renoprotection results in (diabetic and non-diabetic) CKD patients. We clearly posit that there is this overarching impetus to arrive at the inference that multiple, disparately diverse and independent pathways, including any veritable combination of the mechanisms that we examine in this review, and many more others yet to be identified, do concurrently and asymmetrically contribute to CKD initiation and propagation to end-stage renal disease (ESRD) in our CKD patients. We conclude that current knowledge of CKD initiation and progression to ESRD, the natural history of CKD and the impacts of acute kidney injury on this continuum remain in their infancy and call for more research. Finally, we suggest a new classification scheme for renoprotective agents: (1) the single-pathway blockers that block a single putative pathogenetic pathway involved in CKD progression, as typified by ACE inhibitors and/or ARBs, and (2) the multiple-pathway blockers that are able to block or antagonize the effects of multiple pathogenetic pathways through their ability to simultaneously block, downstream, the effects of several pathways or mechanisms of CKD to ESRD progression and could therefore concurrently interfere with several unrelated upstream pathways or mechanisms. We surmise that maybe the ideal and truly renoprotective agent, clearly a multiple pathway blocker, is on the horizon. This calls for more research efforts from all. PMID- 23687513 TI - A Novel Aerosol Method for the Production of Hydrogel Particles. AB - A novel method of generating hydrogel particles for various applications including drug delivery purposes was developed. This method is based on the production of hydrogel particles from sprayed polymeric nano/microdroplets obtained by a nebulization process that is immediately followed by gelation in a crosslinking fluid. In this study, particle synthesis parameters such as type of nebulizer, type of crosslinker, air pressure, and polymer concentration were investigated for their impact on the mean particle size, swelling behavior, and morphology of the developed particles. Spherical alginate-based hydrogel particles with a mean particle size in the range from 842 to 886 nm were obtained. Using statistical analysis of the factorial design of experiment it was found that the main factors influencing the size and swelling values of the particles are the alginate concentration and the air pressure. Thus, it was demonstrated that the method described in the current study is promising for the generation of hydrogel particles and it constitutes a relatively simple and low cost system. PMID- 23687512 TI - DNA methylation program during development. AB - DNA methylation is a key epigenetic mark when occurring in the promoter and enhancer regions regulates the accessibility of the binding protein and gene transcription. DNA methylation is inheritable and can be de novo-synthesized, erased and reinstated, making it arguably one of the most dynamic upstream regulators for gene expression and the most influential pacer for development. Recent progress has demonstrated that two forms of cytosine methylation and two pathways for demethylation constitute ample complexity for an instructional program for orchestrated gene expression and development. The forum of the current discussion and review are whether there is such a program, if so what the DNA methylation program entails, and what environment can change the DNA methylation program. The translational implication of the DNA methylation program is also proposed. PMID- 23687515 TI - Little Liars: Development of Verbal Deception in Children. AB - Lying is common among adults and a more complex issue in children. In this article, I review two decades of empirical evidence about lying in children from the perspective of speech act theory. Children begin to tell lies in the preschool years for anti- and prosocial purposes, and their tendency to lie changes as a function of age and the type of lies being told. In addition, children's ability to tell convincing lies improves with age. In the article, I highlight the central roles that children's understanding of mental states and social conventions play in the development of lying. I also identify areas for research to be done to develop a more comprehensive picture of the typical and atypical developmental courses of verbal deception in children. PMID- 23687516 TI - Opinion: Sex, Gender and the Diagnosis of Autism - A Biosocial View of the Male Preponderance. PMID- 23687517 TI - Harnessing advances in structural MRI to enhance research on Parkinson's disease. PMID- 23687518 TI - Ethnic differences in pain and pain management. AB - Considerable evidence demonstrates substantial ethnic disparities in the prevalence, treatment, progression and outcomes of pain-related conditions. Elucidating the mechanisms underlying these group differences is of crucial importance in reducing and eliminating disparities in the pain experience. Over recent years, accumulating evidence has identified a variety of processes, from neurophysiological factors to structural elements of the healthcare system, that may contribute to shaping individual differences in pain. For example, the experience of pain differentially activates stress-related physiological responses across various ethnic groups, members of different ethnic groups appear to use differing coping strategies in managing pain complaints, providers' treatment decisions vary as a function of patient ethnicity and pharmacies in predominantly minority neighborhoods are far less likely to stock potent analgesics. These diverse factors, and others may all play a role in facilitating elevated levels of pain-related suffering among individuals from ethnic minority backgrounds. Here, we present a brief, nonexhaustive review of the recent literature and potential physiological and sociocultural mechanisms underlying these ethnic group disparities in pain outcomes. PMID- 23687520 TI - IN VITRO QUANTIFICATION OF THE SIZE DISTRIBUTION OF INTRASACCULAR VOIDS LEFT AFTER ENDOVASCULAR COILING OF CEREBRAL ANEURYSMS. AB - PURPOSE: Endovascular coiling of cerebral aneurysms remains limited by coil compaction and associated recanalization. Recent coil designs which effect higher packing densities may be far from optimal because hemodynamic forces causing compaction are not well understood since detailed data regarding the location and distribution of coil masses are unavailable. We present an in vitro methodology to characterize coil masses deployed within aneurysms by quantifying intra aneurysmal void spaces. METHODS: Eight identical aneurysms were packed with coils by both balloon- and stent-assist techniques. The samples were embedded, sequentially sectioned and imaged. Empty spaces between the coils were numerically filled with circles (2D) in the planar images and with spheres (3D) in the three-dimensional composite images. The 2D and 3D void size histograms were analyzed for local variations and by fitting theoretical probability distribution functions. RESULTS: Balloon-assist packing densities (31+/-2%) were lower (p=0.04) than the stent-assist group (40+/-7%). The maximum and average 2D and 3D void sizes were higher (p=0.03 to 0.05) in the balloon-assist group as compared to the stent-assist group. None of the void size histograms were normally distributed; theoretical probability distribution fits suggest that the histograms are most probably exponentially distributed with decay constants of 6 10 mm. Significant (p<=0.001 to p=0.03) spatial trends were noted with the void sizes but correlation coefficients were generally low (absolute r<=0.35). CONCLUSION: The methodology we present can provide valuable input data for numerical calculations of hemodynamic forces impinging on intra-aneurysmal coil masses and be used to compare and optimize coil configurations as well as coiling techniques. PMID- 23687519 TI - Drug-like property profiling of novel neuroprotective compounds to treat acute ischemic stroke: guidelines to develop pleiotropic molecules. AB - The development of novel neuroprotective compounds to treat acute ischemic stroke (AIS) has been problematic and quite complicated, since many candidates that have been tested clinically lacked significant pleiotropic activity, were unable to effectively cross the blood brain barrier (BBB), had poor bioavailability or were toxic. Moreover, the compounds did not confer significant neuroprotection or clinical efficacy measured using standard behavioral endpoints, when studied in clinical trials in a heterogeneous population of stroke patients. To circumvent some of the drug development problems describe above, we have used a rational funnel approach to identify and develop promising candidates. Using a step-wise approach, we have identified a series of compounds based upon two different neuroprotection assays. We have then taken the candidates and determined their "drug-like" properties. This guidelines article details in vitro screening assays used to show pleiotropic activity of a series of novel compounds; including enhanced neuroprotective activity compared to the parent compound fisetin. Moreover, for preliminary drug de-risking or risk reduction during development, we used compound assessment in the CeeTox assay, ADME toxicity using the AMES test for genotoxicity and interaction with Cytochrome P450 using CYP450 inhibition analysis against a spectrum of CYP450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) as a measure of drug interaction. Moreover, the compounds have been studied using a transfected Madin Darby canine kidney (MDCK) cell assay to assess blood brain barrier penetration (BBB). Using this series of assays, we have identified 4 novel molecules to be developed as an AIS treatment. PMID- 23687521 TI - Work, Retirement, and Depression. PMID- 23687522 TI - Application of Immunohistochemistry and Molecular Diagnostics to Clinically Relevant Problems in Endometrial Cancer Bojana Djordjevic, Shannon Westin, Russell R. Broaddus. AB - A number of different clinical scenarios are presented in which lab-based analyses beyond the usual diagnosis based on light microscopic examination of H&E stained slides - immunohistochemistry and PCR-based assays such as sequencing, mutation testing, microsatellite instability analysis, and determination of MLH1 methylation - are most helpful for guiding diagnosis and treatment of endometrial cancer. The central goal of this information is to provide a practical guide of key current and emerging issues in diagnostic endometrial cancer pathology that require the use of ancillary laboratory techniques, such as immunohistochemistry and molecular testing. The authors present the common diagnostic problems in endometrial carcinoma pathology, types of endometrial carcinoma, description of tissue testing and markers, pathological features, and targeted therapy. PMID- 23687523 TI - Social benefit payments and acute injury among low-income mothers. AB - BACKGROUND: Human error due to risky behaviour is a common and important contributor to acute injury related to poverty. We studied whether social benefit payments mitigate or exacerbate risky behaviours that lead to emergency visits for acute injury among low-income mothers with dependent children. METHODS: We analyzed total emergency department visits throughout Ontario to identify women between 15 and 55 years of age who were mothers of children younger than 18 years, who were living in the lowest socio-economic quintile and who presented with acute injury. We used universal health care databases to evaluate emergency department visits during specific days on which social benefit payments were made (child benefit distribution) relative to visits on control days over a 7-year interval (1 April 2003 to 31 March 2010). RESULTS: A total of 153 377 emergency department visits met the inclusion criteria. We observed fewer emergencies per day on child benefit payment days than on control days (56.4 v. 60.1, p = 0.008). The difference was primarily explained by lower values among mothers age 35 years or younger (relative reduction 7.29%, 95% confidence interval [CI] 1.69% to 12.88%), those living in urban areas (relative reduction 7.07%, 95% CI 3.05% to 11.10%) and those treated at community hospitals (relative reduction 6.83%, 95% CI 2.46% to 11.19%). No significant differences were observed for the 7 days immediately before or the 7 days immediately after the child benefit payment. INTERPRETATION: Contrary to political commentary, we found that small reductions in relative poverty mitigated, rather than exacerbated, risky behaviours that contribute to acute injury among low-income mothers with dependent children. PMID- 23687524 TI - Histamine H2 receptor antagonists for decreasing gastrointestinal harms in adults using acetylsalicylic acid: systematic review and meta-analysis. AB - BACKGROUND: It is unclear if histamine H2 receptor antagonists (H2 blockers) prevent a variety of gastrointestinal harms among patients taking acetylsalicylic acid (ASA) over long periods. METHODS: Electronic databases (e.g., MEDLINE, Embase and Cochrane Central Register of Controlled Trials; from inception to November 2010) and reference lists of retrieved articles were searched. Randomized placebo-controlled trials (RCTs) assessing the efficacy of H2 blockers in reducing gastrointestinal harms (bleeding, ulcers) among adults taking ASA for 2 weeks or longer were included. Two reviewers independently abstracted study and patient characteristics and appraised study quality using the Cochrane risk-of bias tool. Peto odds ratio (OR) meta-analysis was performed, 95% confidence intervals (CIs) were calculated, and statistical heterogeneity was assessed using the I (2) and chi(2) statistics. RESULTS: Six RCTs (4 major publications and 2 companion reports) with a total of 498 participants (healthy volunteers or patients with arthritis, cardiovascular or cerebrovascular disease, or diabetes mellitus) were included. One trial adequately reported allocation concealment and sequence generation, with the other 3 trials being judged as unclear for both aspects. In one RCT, no statistically significant differences for gastrointestinal hemorrhage requiring admission to hospital (p = 0.14) or blood transfusion (p = 0.29) were observed between the group receiving concomitant famotidine and ASA and the group receiving concomitant placebo and ASA. After a median of 8 weeks' follow-up, H2 blockers were more effective than placebo in reducing gastrointestinal hemorrhage (2 RCTs, total of 447 patients, OR 0.07, 95% CI 0.02-0.23) and peptic ulcers (3 RCTs, total of 465 patients, OR 0.21, 95% CI 0.12-0.36) among patients taking ASA for 2 weeks or longer. Despite substantial clinical heterogeneity across the studies, including types of H2 blockers, dosing of ASA and underlying conditions, no statistical heterogeneity was observed. INTERPRETATION: H2 blockers reduced gastrointestinal harm among patients taking ASA for 2 weeks or longer. These results should be interpreted with caution, because of the small number of studies identified for inclusion. PMID- 23687525 TI - Derivation and validation of a diagnostic score based on case-mix groups to predict 30-day death or urgent readmission. AB - BACKGROUND: Between 5% and 10% of patients die or are urgently readmitted within 30 days of discharge from hospital. Readmission risk indexes have either excluded acute diagnoses or modelled them as multiple distinct variables. In this study, we derived and validated a score summarizing the influence of acute hospital diagnoses and procedures on death or urgent readmission within 30 days. METHODS: From population-based hospital abstracts in Ontario, we randomly sampled 200 000 discharges between April 2003 and March 2009 and determined who had been readmitted urgently or died within 30 days of discharge. We used generalized estimating equation modelling, with a sample of 100 000 patients, to measure the adjusted association of various case-mix groups (CMGs-homogenous groups of acute care inpatients with similar clinical and resource-utilization characteristics) with 30-day death or urgent readmission. This final model was transformed into a scoring system that was validated in the remaining 100 000 patients. RESULTS: Patients in the derivation set belonged to 1 of 506 CMGs and had a 6.8% risk of 30-day death or urgent readmission. Forty-seven CMG codes (more than half of which were directly related to chronic diseases) were independently associated with this outcome, which led to a CMG score that ranged from -6 to 7 points. The CMG score was significantly associated with 30-day death or urgent readmission (unadjusted odds ratio for a 1-point increase in CMG score 1.52, 95% confidence interval [CI] 1.49-1.56). Alone, the CMG score was only moderately discriminative (C statistic 0.650, 95% CI 0.644-0.656). However, when the CMG score was added to a validated risk index for death or readmission, the C statistic increased to 0.759 (95% CI 0.753-0.765). The CMG score was well calibrated for 30-day death or readmission. INTERPRETATION: In this study, we developed a scoring system for acute hospital diagnoses and procedures that could be used as part of a risk adjustment methodology for analyses of postdischarge outcomes. PMID- 23687526 TI - Influence of employment and job security on physical and mental health in adults living with HIV: cross-sectional analysis. AB - BACKGROUND: In the general population, job insecurity may be as harmful to health as unemployment. Some evidence suggests that employment is associated with better health outcomes among people with HIV, but it is not known whether job security offers additional quality-of-life benefits beyond the benefits of employment alone. METHODS: We used baseline data for 1660 men and 270 women who participated in the Ontario HIV Treatment Network Cohort Study, an ongoing observational cohort study that collects clinical and socio-behavioural data from people with HIV in the province of Ontario, Canada. We performed multivariable regression analyses to determine the contribution of employment and job security to health related quality of life after controlling for potential confounders. RESULTS: Employed men with secure jobs reported significantly higher mental health-related quality of life than those who were non-employed (beta = 5.27, 95% confidence interval [CI] 4.07 to 6.48), but insecure employment was not associated with higher mental health scores relative to non-employment (beta = 0.18, 95% CI -1.53 to 1.90). Thus, job security was associated with a 5.09-point increase on a 100 point mental health quality-of-life score (95% CI 3.32 to 6.86). Among women, being employed was significantly associated with both physical and mental health quality of life, but job security was not associated with additional health benefits. INTERPRETATION: Participation in employment was associated with better quality of life for both men and women with HIV. Among men, job security was associated with better mental health, which suggests that employment may offer a mental health benefit only if the job is perceived to be secure. Employment policies that promote job security may offer not only income stability but also mental health benefits, although this additional benefit was observed only for men. PMID- 23687527 TI - Challenges and scientific considerations in hypertension management reflected in the 2012 recommendations of the Canadian Hypertension Education Program. AB - This article provides the scientific rationale and background information for the Canadian Hypertension Education Program's 2012 recommendations for the management of hypertension. It also summarizes the key new recommendations and the theme for 2012, which is the prevention of hypertension. The full recommendations are available at www.hypertension.ca. PMID- 23687528 TI - CNODES: the Canadian Network for Observational Drug Effect Studies. AB - Although administrative health care databases have long been used to evaluate adverse drug effects, responses to drug safety signals have been slow and uncoordinated. We describe the establishment of the Canadian Network for Observational Drug Effect Studies (CNODES), a collaborating centre of the Drug Safety and Effectiveness Network (DSEN). CNODES is a distributed network of investigators and linked databases in British Columbia, Alberta, Saskatchewan, Manitoba, Ontario, Quebec and Nova Scotia. Principles of operation are as follows: (1) research questions are prioritized by the coordinating office of DSEN; (2) the linked data stay within the provinces; (3) for each question, a study team formulates a detailed protocol enabling consistent analyses in each province; (4) analyses are "blind" to results obtained elsewhere; (5) protocol deviations are permitted for technical reasons only; (6) analyses using multivariable methods are lodged centrally with a methods team, which is responsible for combining the results to provide a summary estimate of effect. These procedures are designed to achieve high internal validity of risk estimates and to eliminate the possibility of selective reporting of analyses or outcomes. The value of a coordinated multi-provincial approach is illustrated by projects studying acute renal injury with high-potency statins, community-acquired pneumonia with proton pump inhibitors, and hyperglycemic emergencies with antipsychotic drugs. CNODES is an academically based distributed network of Canadian researchers and data centres with a commitment to rapid and sophisticated analysis of emerging drug safety signals in study populations totalling over 40 million. PMID- 23687529 TI - Reformulation of controlled-release oxycodone and pharmacy dispensing patterns near the US-Canada border. AB - BACKGROUND: In August 2010, a tamper-resistant formulation of controlled-release oxycodone (OxyContin-OP) was introduced in the United States but not in Canada. Our objective was to determine whether introduction of OxyContin-OP in the United States influenced prescription volumes for the original controlled-release oxycodone formulation (OxyContin) at Canadian pharmacies near the international border. METHODS: We conducted a population-based, serial, cross-sectional study of prescriptions dispensed from pharmacies in the 3 cities with the highest volume of US-Canada border crossings in Ontario: Niagara Falls, Windsor and Sarnia. We analyzed data on all outpatient prescriptions for OxyContin dispensed by Canadian pharmacies near each border crossing between 2010 Apr. 1 and 2012 Feb. 29. We calculated and compared monthly prescription rates, adjusted per 1000 population and stratified by tablet strength. RESULTS: The number of tablets dispensed near 4 border crossings in the 3 Canadian cities remained stable over the study period. However, the rate of dispensing at pharmacies near the Detroit Windsor Tunnel increased roughly 4-fold between August 2010 and February 2011, from 505 to 1969 tablets per 1000 population. By April 2011, following warnings to prescribers and pharmacies regarding drug-seeking behaviour, the dispensing rate declined to 1683 tablets per 1000 population in this area. By November 2011, the rate had returned to levels observed in early 2010. Our analyses suggest that 242 075 excess OxyContin tablets were dispensed near the Detroit-Windsor Tunnel between August 2010 and October 2011. CONCLUSIONS: Prescribing of the original formulation of controlled-release oxycodone rose substantially near a major international border crossing following the introduction of a tamper-resistant formulation in the United States. It is possible that the restriction of this finding to the area surrounding the Detroit-Windsor Tunnel reflects specific characteristics of this border crossing, including its high traffic volume, direct access to the downtown core and drug-trafficking patterns in the Detroit area. Our findings highlight the potential impact of cross-border differences in medication availability on drug-seeking behaviour. PMID- 23687530 TI - Socio-economic- and sex-related disparities in rates of hospital admission among patients with HIV infection in Ontario: a population-based study. AB - BACKGROUND: Among people living with HIV infection in the era of combination antiretroviral therapy (cART), admission to hospital may indicate inadequate community-based care. As such, population-based assessments of the utilization of inpatient services represent a necessary component of evaluating the quality of HIV-related care. METHODS: We used a validated algorithm to search Ontario's administrative health care databases for all persons living with HIV infection aged 18 years or older between 1992/93 and 2008/09. We then conducted a population-based study using time-series and longitudinal analyses to first quantify the immediate effect of cART on hospital admission rates and then analyze recent trends (for 2002/03 to 2008/09) in rates of total and HIV-related admissions. RESULTS: The introduction of cART in 1996/97 was associated with more pronounced reductions in the rate of hospital admissions among men than among women (for total admissions, -89.9 v. -60.5 per 1000 persons living with HIV infection, p = 0.003; for HIV-related admissions, -56.9 v. -36.3 per 1000 persons living with HIV infection, p < 0.001). Between 2002/03 and 2008/09, higher rates of total hospital admissions were associated with female sex (adjusted relative rate [RR] 1.15, 95% confidence interval [CI] 1.05-1.27) and low socio-economic status (adjusted RR 1.21, 95% CI 1.14-1.29). Higher rates of HIV-related hospital admission were associated with low socio-economic status (adjusted RR 1.30, 95% CI 1.17-1.45). Recent immigrants had lower rates of both total admissions (adjusted RR 0.70, 95% CI 0.61-0.80) and HIV-related admissions (adjusted RR 0.77, 95% CI 0.61-0.96). INTERPRETATION: We observed important socio-economic- and sex-related disparities in rates of hospital admission among people with HIV living in Ontario, Canada. PMID- 23687531 TI - Association of enrolment in primary care networks with diabetes care and outcomes among First Nations and low-income Albertans. AB - BACKGROUND: The prevalence of diabetes mellitus and its complications is higher among First Nations people and people with low socio-economic status (SES). Previous studies in Alberta have shown that provision of care through Primary Care Networks (PCNs) is associated with better quality of care and better outcomes for people with diabetes, possibly because of greater utilization of chronic disease management programs. However, it is unknown whether First Nations individuals and those in lower SES groups experience these benefits. METHODS: We used administrative and laboratory data for a population-based cohort analysis of Alberta residents under 65 years of age with diabetes. The primary outcome, assessed over a 1-year period, was admission to hospital or emergency department visit for a diabetes-specific ambulatory care sensitive condition (ACSC). Secondary outcomes were 2 quality-of-care indicators (likelihood of measurement of glycated hemoglobin [HbA1c] and or retinal screening) and 2 measures of health care utilization (visits to specialist and primary care physicians). We used negative binomial regression to determine the association between care within a PCN and hospital admission or emergency department visit for diabetes-specific ACSCs. We also assessed outcomes in 3 populations of interest (individuals receiving a health care subsidy [household income less than $39 250 and not eligible for Income Support], those receiving Income Support, and First Nations individuals) relative to the remainder of the population, controlling for whether care was provided in a PCN and adjusting for several baseline characteristics. RESULTS: We identified a total of 106 653 patients with diabetes eligible for our study, of whom 43 327 (41%) received care in a PCN. Receiving care through a PCN was associated with lower rates of ACSC-related hospital admission or emergency department visits for all groups of interest, which suggests that PCNs had similar effects across each group. However, regardless of where care was provided, First Nations and low-SES patients had more than twice the adjusted rates of hospital admission or emergency department visits for diabetes-specific ACSCs than the general population and were less likely to receive guideline recommended care, including measurement of HbA1c and retinal screening. INTERPRETATION: Care in a PCN was associated with lower risks of hospital admission or emergency department visits for diabetes-specific ACSCs, even within vulnerable groups such as First Nations people and those of low SES. However, differences in outcomes and quality-of-care indicators persisted for First Nations individuals and those of low SES, relative to the general population, irrespective of where care was provided. PMID- 23687532 TI - The effect of for-profit laboratories on the accountability, integration, and cost of Canadian health care services. AB - Canadian public health care systems pay for-profit corporations to provide essential medical laboratory services. This practice is a useful window on the effects of using for-profit corporations to provide publicly funded services. Because private corporations are substantially protected by law from the public disclosure of "confidential business information," increased for-profit delivery has led to decreased transparency, thus impeding informed debate on how laboratory services are delivered. Using for-profit laboratories increases the cost of diagnostic testing and hinders the integration of health care services more generally. Two useful steps toward ending the for-profit provision of laboratory services would be to stop fee-for-service funding and to integrate all laboratory work within public administrative structures. PMID- 23687533 TI - Building access to specialist care through e-consultation. AB - BACKGROUND: Limited access to specialist care remains a major barrier to health care in Canada, affecting patients and primary care providers alike, in terms of both long wait times and inequitable availability. We developed an electronic consultation system, based on a secure web-based tool, as an alternative to face to-face consultations, and ran a pilot study to evaluate its effectiveness and acceptability to practitioners. METHODS: In a pilot program conducted over 15 months starting in January 2010, the e-consultation system was tested with primary care providers and specialists in a large health region in Eastern Ontario, Canada. We collected utilization data from the electronic system itself (including quantitative data from satisfaction surveys) and qualitative information from focus groups and interviews with providers. RESULTS: Of 18 primary care providers in the pilot program, 13 participated in focus groups and 9 were interviewed; in addition, 10 of the 11 specialists in the program were interviewed. Results of our evaluation showed good uptake, high levels of satisfaction, improvement in the integration of referrals and consultations, and avoidance of unnecessary specialist visits. A total of 77 e-consultation requests were processed from 1 Jan. 2010 to 1 Apr. 2011. Less than 10% of the referrals required face-to-face follow-up. The most frequently noted benefits for patients (as perceived by providers) included improved access to specialist care and reduced wait times. Primary care providers valued the ability to assist with patient assessment and management by having access to a rapid response to clinical questions, clarifying the need for diagnostic tests or treatments, and confirming the need for a formal consultation. Specialists enjoyed the improved interaction with primary care providers, as well as having some control in the decision on which patients should be referred. INTERPRETATION: This low-cost referral system has potential for broader implementation, once payment models for physicians are adapted to cover e-consultation. PMID- 23687534 TI - Association between perceived unmet health care needs and risk of adverse health outcomes among patients with chronic medical conditions. AB - BACKGROUND: Adults with chronic medical conditions are more likely to report unmet health care needs. Whether unmet health care needs are associated with an increased risk of adverse health outcomes is unclear. METHODS: Adults with at least one self-reported chronic condition (arthritis, chronic obstructive pulmonary disease, diabetes mellitus, heart disease, hypertension, mood disorder, stroke) from the 2001 and 2003 cycles of the Canadian Community Health Survey were linked to national hospitalization data. Participants were followed from the date of their survey until March 31, 2005, for the primary outcomes of all-cause and cause-specific admission to hospital. Secondary outcomes included length of stay, 30-day and 1-year all-cause readmission to hospital, and in-hospital death. Negative binomial regression models were used to estimate the association between unmet health care needs, admission to hospital, and length of stay, with adjustment for socio-demographic variables, health behaviours, and health status. Logistic regression was used to estimate the association between unmet needs, readmission, and in-hospital death. Further analyses were conducted by type of unmet need. RESULTS: Of the 51 932 adults with self-reported chronic disease, 15.5% reported an unmet health care need. Participants with unmet health care needs had a risk of all-cause admission to hospital similar to that of patients with no unmet needs (adjusted rate ratio [RR] 1.04, 95% confidence interval [CI] 0.94-1.15). When stratified by type of need, participants who reported issues of limited resource availability had a slightly higher risk of hospital admission (RR 1.18, 95% CI 1.09-1.28). There was no association between unmet needs and length of stay, readmission, or in-hospital death. INTERPRETATION: Overall, unmet health care needs were not associated with an increased risk of admission to hospital among those with chronic conditions. However, certain types of unmet needs may be associated with higher or lower risk. Whether unmet needs are associated with other measures of resource use remains to be determined. PMID- 23687535 TI - Inclusion of persons with mental illness in patient-centred medical homes: cross sectional findings from Ontario, Canada. AB - BACKGROUND: In Ontario, Canada, the patient-centred medical home is a model of primary care delivery that includes 3 model types of interest for this study: enhanced fee-for-service, blended capitation, and team-based blended capitation. All 3 models involve rostering of patients and have similar practice requirements but differ in method of physician reimbursement, with the blended capitation models incorporating adjustments for age and sex, but not case mix, of rostered patients. We evaluated the extent to which persons with mental illness were included in physicians' total practices (as rostered and non-rostered patients) and were included on physicians' rosters across types of medical homes in Ontario. METHODS: Using population-based administrative data, we considered 3 groups of patients: those with psychotic or bipolar diagnoses, those with other mental health diagnoses, and those with no mental health diagnoses. We modelled the prevalence of mental health diagnoses and the proportion of patients with such diagnoses who were rostered across the 3 medical home model types, controlling for demographic characteristics and case mix. RESULTS: Compared with enhanced fee-for-service practices, and relative to patients without mental illness, the proportions of patients with psychosis or bipolar disorders were not different in blended capitation and team-based blended capitation practices (rate ratio [RR] 0.91, 95% confidence interval [CI] 0.82-1.01; RR 1.06, 95% CI 0.96 1.17, respectively). However, there were fewer patients with other mental illnesses (RR 0.94, 95% CI 0.90-0.99; RR 0.89, 95% CI 0.85-0.94, respectively). Compared with expected proportions, practices based on both capitation models were significantly less likely than enhanced fee-for-service practices to roster patients with psychosis or bipolar disorders (for blended capitation, RR 0.92, 95% CI 0.90-0.93; for team-based capitation, RR 0.92, 95% CI 0.88-0.93) and also patients with other mental illnesses (for blended capitation, RR 0.94, 95% CI 0.92-0.95; for team-based capitation, RR 0.93, 95% CI 0.92-0.94). INTERPRETATION: Persons with mental illness were under-represented in the rosters of Ontario's capitation-based medical homes. These findings suggest a need to direct attention to the incentive structure for including patients with mental illness. PMID- 23687536 TI - A PERFECT MATCH CONDITION FOR POINT-SET MATCHING PROBLEMS USING THE OPTIMAL MASS TRANSPORT APPROACH. AB - We study the performance of optimal mass transport-based methods applied to point set matching problems. The present study, which is based on the L2 mass transport cost, states that perfect matches always occur when the product of the point-set cardinality and the norm of the curl of the non-rigid deformation field does not exceed some constant. This analytic result is justified by a numerical study of matching two sets of pulmonary vascular tree branch points whose displacement is caused by the lung volume changes in the same human subject. The nearly perfect match performance verifies the effectiveness of this mass transport-based approach. PMID- 23687537 TI - Necessity of lumbar puncture in patients presenting with new onset complex febrile seizures. AB - INTRODUCTION: This study aims to characterize the population of patients presenting to a pediatric emergency department (ED) for a first complex febrile seizure, and subsequently assess the rate of acute bacterial meningitis (ABM) occurrence in this population. Furthermore, this study seeks to identify whether a specific subset of patients may be at lesser risk for ABM or other serious neurological disease. METHODS: This retrospective cohort study reviewed the charts of patients between the ages of 6 months to 5 years of age admitted to an ED between 2005 and 2010 for a first complex febrile seizure (CFS). The health information department generated a patient list based on admission and discharge diagnoses, which was screened for patient eligibility. Exclusion criteria included history of a complex febrile seizure, history of an afebrile seizure, trauma, or severe underlying neurological disorder. Data extracted included age, gender, relevant medical history, descriptions of seizure, treatment received, and follow-up data. Patients presenting with two short febrile seizures within 24 hours were then analyzed separately to assess health outcomes in this population. RESULTS: There were 193 patients were eligible. Lumbar puncture was performed on 136 subjects; it was significantly more likely to be performed on patients that presented with seizure focality, status epilepticus, or a need for intubation. Fourteen patients were found to have pleocytosis following white blood cell count correction, and 1 was diagnosed with ABM (0.5% [95% confidence interval: 0.0-1.5, n=193]). Forty-three patients had 2 brief febrile seizures within 24 hours. Of the 43, 17 received lumbar puncture while in the ED. None of these patients were found to have ABM or other serious neurological disease. CONCLUSION: ABM is rare in patients presenting with a first complex febrile seizure. Patients presenting only with 2 short febrile seizures within 24 hours may be less likely to have ABM, and may not require lumbar puncture without other clinical symptoms of neurological disease. PMID- 23687538 TI - Abnormal arterial blood gas and serum lactate levels do not alter disposition in adult blunt trauma patients after early computed tomography. AB - INTRODUCTION: Arterial blood gas and serum lactate (ABG / SL) values have been shown to be markers for occult shock and poor outcome following blunt trauma. However, the utility of ABG / SL in blunt trauma patients who also receive computed tomographies (CT) of the chest, abdomen, and pelvis (CT C&A) remains unknown. METHODS: A chart review was performed of all adult blunt trauma patients who received both CT C&A and ABG / SL upon presentation to our emergency department (ED) between January 1, 2007 and December 31, 2007. These patients (n=360) were identified from our institutional trauma registry database. Patients were divided into subgroups based upon whether they had a positive or negative ED evaluation for traumatic injury requiring hospitalization or immediate operative management. The expected course for patients with negative ED evaluations regardless of ABG / SL was discharge home. The primary outcome measure was the proportion of patients with a negative ED evaluation and an abnormal ABG or SL that were admitted to the hospital. RESULTS: 2.9% of patients with a negative ED evaluation and abnormal ABG or SL were admitted. Of these, none were found to have any post-traumatic sequalae. CONCLUSION: We found that abnormal ABG / SL results do not change management or discharge disposition in patients without clinical or radiographic evidence of traumatic injury on CT C&A. Among patients who receive CT C&A, the routine measurement of arterial blood gas and lactate may be an unnecessary source of additional cost, patient discomfort, and delay in care. PMID- 23687539 TI - Oral and Intravenous Acetylcysteine for Treatment of Acetaminophen Toxicity: A Systematic Review and Meta-analysis. AB - INTRODUCTION: There are few reports summarizing the effectiveness of oral and intravenous (IV) acetylcysteine. We determined the proportion of acetaminophen poisoned patients who develop hepatotoxicity (serum transaminase > 1000 IU/L) when treated with oral and IV acetylcysteine. METHODS: Studies were double abstracted by trained researchers. We determined the proportions of patients who developed hepatotoxicity for each route using a random effects model. Studies were further stratified by early and late treatment. RESULTS: We screened 4,416 abstracts; 16 articles, including 5,164 patients, were included in the meta analysis. The overall rate of hepatotoxicity for the oral and IV routes were 12.6% and 13.2%, respectively. Treatment delays are associated with a higher rate of hepatotoxicity. CONCLUSION: Studies report similar rates of hepatotoxicity for oral and IV acetylcysteine, but direct comparisons are lacking. While it is difficult to disentangle the effects of dose and duration from route, our findings suggest that the rates of hepatotoxicity are similar for oral and IV administration. PMID- 23687540 TI - Financial implications for physicians accepting higher level of care transfers. AB - INTRODUCTION: Higher-level-of-care (HLOC) transfers to tertiary care hospitals are common. While this has been shown profitable for hospitals, the impact on physicians has not been described. Community medical center call panels continue to erode, in part due to the perception that patients needing transfer are underinsured. Surveys show that the problematic specialties to maintain call panels in community hospitals are neurosurgery, otolaryngology, plastic surgery, orthopedics and ophthalmology. This places greater stress on tertiary care hospitals' physicians. The objective of this study is to describe the financial consequences to physicians who care for HLOC transfers across specialties and compare these with all patients from each specialty and specialty-specific national reimbursement benchmarks. METHODS: Financial data were obtained for all HLOC transfers to a single tertiary care center from January 2007 through March 2008. Work relative value unit (RVU) and reimbursement were taken from a centralized professional fee billing office. National benchmarks for reimbursement per RVU were calculated from the 2006 Medical Group Management Association (MGMA) Compensation and Production Survey. RESULTS: In this period 570 patients were transferred, 319 (55.9%) through the emergency department (ED). Reimbursement per RVU varied from a high of $74.93 for neurosurgery to $25.91 for family medicine. Reimbursement to emergency medicine (EM) for HLOC patients was 16% above the average reimbursement per RVU for all ED patients ($50.5 vs. $43.7). Similarly, neurosurgery reimbursement per RVU was 22% above the reimbursement per RVU for all patients ($74.93 vs. $61.27). The remainder of specialties was reimbursed less ($25.91 vs $69.60) per RVU for HLOC patients than for all of their patients at this center. All specialties at this site were reimbursed less for each HLOC patient than national average reimbursement for all patients in each specialty. CONCLUSION: Average professional fee reimbursement for HLOC patients was higher for EM and neurosurgery than for all other patients in these specialties at this site, but lower for the rest of the specialties. Compared to the national benchmarks, this site had an overall lower reimbursement per RVU for all specialties, reflecting a poorer patient mix. At this site HLOC transfers patients are financially advantageous for EM and neurosurgery. PMID- 23687541 TI - Pneumothorax in liberia: complications of tuberculosis. AB - Tuberculosis (TB) is a known cause of secondary pneumothorax. In areas with endemic TB, complications from the disease, including pneumothorax, are increasing in prevalence. We present the cases of 3 patients (ages 32 years, 17 years, and 3 months) seen in the emergency department at John F. Kennedy Medical Center in Monrovia, Liberia, West Africa. Each presented with shortness of breath and cough, and with some degree of respiratory distress. Airway compromise was present with tracheal or mediastinal deviation. Each patient underwent tube thoracostomy with improvement in pneumothorax and respiratory status. PMID- 23687542 TI - Computer simulation as a tool for assessing decision-making in pandemic influenza response training. AB - INTRODUCTION: We sought to develop and test a computer-based, interactive simulation of a hypothetical pandemic influenza outbreak. Fidelity was enhanced with integrated video and branching decision trees, built upon the 2007 federal planning assumptions. We conducted a before-and-after study of the simulation effectiveness to assess the simulations' ability to assess participants' beliefs regarding their own hospitals' mass casualty incident preparedness. METHODS: DEVELOPMENT: Using a Delphi process, we finalized a simulation that serves up a minimum of over 50 key decisions to 6 role-players on networked laptops in a conference area. The simulation played out an 8-week scenario, beginning with pre incident decisions. TESTING: Role-players and trainees (N=155) were facilitated to make decisions during the pandemic. Because decision responses vary, the simulation plays out differently, and a casualty counter quantifies hypothetical losses. The facilitator reviews and critiques key factors for casualty control, including effective communications, working with external organizations, development of internal policies and procedures, maintaining supplies and services, technical infrastructure support, public relations and training. Pre- and post-survey data were compared on trainees. RESULTS: Post-simulation trainees indicated a greater likelihood of needing to improve their organization in terms of communications, mass casualty incident planning, public information and training. Participants also recognized which key factors required immediate attention at their own home facilities. CONCLUSION: The use of a computer simulation was effective in providing a facilitated environment for determining the perception of preparedness, evaluating general preparedness concepts and introduced participants to critical decisions involved in handling a regional pandemic influenza surge. PMID- 23687543 TI - Ten years of frequent users in an urban emergency department. AB - INTRODUCTION: The purpose of this study was to determine if differences could be detected in the presentation patterns and admission rates among frequent emergency department users (FEDU) of an urban emergency department over a 10-year period. METHODS: This was an institutional review board approved, retrospective review of all patients who presented to the ED 5 or more times for 3 distinct time periods: "year 0" 11/98-10/99, "year 5" 11/03- 10/04, and "year 10" 11/08 10/9. FEDU were grouped into those with 5-9, 10-14, 15-19, and >= 20 visits per year. Variables analyzed included number of visits, disposition, and insurance status. We performed comparisons using Kolmogorov-Smirnov and chi-square tests. A p<0.05 was considered significant. RESULTS: We found a a 66% increase in FEDU patients over the decade studied, with a significant increase in both the number of FEDU in each visit frequency category over the 3 time periods (p<0.001), as well as the total number of visits by each group of FEDU (p<0.001). The proportion of FEDU visits for the 5-9 group resulting in admission increased from 25.9% to 29% from year 0 to year 10 (p<0.001), but not for the other visit groups. In comparing admission rates between FEDU groups, the admission rate for the 5-9 group was significantly higher than the >= 20 group for the year 5 time period (p<0.001) and the year 10 time period (p<0.001) and showed a similar trend, but not significant, at year 0 (p=0.052). The overall hospital admission rate for emergency patients over the same time span remained stable at 22-24%. The overall proportion of uninsured FEDU was stable over the decade studied, while the uninsured rate for the overall ED population for the same time periods increased. CONCLUSION: The results demonstrate the FEDU population is not a homogeneous group of patients. Increased attention to differences among FEDU groups is necessary in order to plan more effective interventions. PMID- 23687544 TI - Prescription history of emergency department patients prescribed opioids. AB - INTRODUCTION: To use Colorado's prescription drug monitoring program (PDMP) to describe the recent opioid prescription history of patients discharged from our emergency department (ED) with a prescription for opioid pain medications. METHODS: Retrospective cohort study of 300 adult ED patients who received an opioid prescription. We abstracted prescription histories for the six months prior to the ED visit from the PDMP, and abstracted clinical and demographic variables from the chart. RESULTS: There were 5,379 ED visits during the study month, 3,732 of which were discharged. Providers wrote 1,165 prescriptions for opioid analgesics to 1,124/3,732 (30%) of the patients. Median age was 36 years. Thirty-nine percent were male. Patients were 46% Caucasian, 26% African American, 22% Hispanic, 2% Asian and 4% other. These were similar to our overall ED population. There was substantial variability in the number of prescriptions, prescribers and total number of pills. A majority (205/296) of patients had zero or one prescription. The 90th percentile for number of prescriptions was seven, while the 10th percentile was zero. Patients in the highest decile tended to be older, with a higher proportion of Caucasians and females. Patients in the lowest decile resembled the general ED population. The most common diagnoses associated with opioid prescriptions were abdominal pain (11.5%), cold/flu symptoms (9.5%), back pain (5.4%), flank pain (5.0%) and motor vehicle crash (4.7%). CONCLUSION: Substantial variability exists in the opioid prescription histories of ED patients, but a majority received zero or one prescription in the preceding six months. The top decile of patients averaged more than two prescriptions per month over the six months prior to ED visit, written by more than 6 different prescribers. There was a trend toward these patients being older, Caucasian and female. PMID- 23687545 TI - Hunger and Food Insecurity among Patients in an Urban Emergency Department. AB - INTRODUCTION: To determine the prevalence of hunger and food insecurity among patients presenting to the emergency department (ED) over 3 consecutive years. METHODS: This was a cross-sectional study of patients presenting to the ED at Hennepin County Medical Center, and urban, Level I trauma center. We prospectively screened adult (age >18) patients presenting to the ED during randomized daily 8-hour periods between June 1 and August 31, 2007 and 2008, and randomized every-other-day periods between June 1 and August 31, 2009. We excluded patients with high acuity complaints, altered mental status, prisoners, those who did not speak Spanish or English, or those considered to be vulnerable. Consenting participants completed a brief demographic survey. The main outcome measures included age, gender, ethnicity, employment, housing status, insurance, access to food, and having to make choices between buying food and buying medicine. All responses were self reported. RESULTS: 26,211 patients presented during the study; 15,732 (60%) were eligible, 8,044 (51%) were enrolled, and 7,852 (98%) were included in the analysis. The rate of patients reporting hunger significantly increased over the 3-year period [20.3% in 2007, 27.8% in 2008, and 38.3% in 2009 (p<0.001)]. The rate of patients reporting ever having to choose between food and medicine also increased [20.0% in 2007, 18.5% in 2008, and 22.6% in 2009 (p=0.006)]. CONCLUSION: A significant proportion of our ED patients experience food insecurity and hunger. Hunger and food insecurity have become more prevalent among patients seen in this urban county ED over the past 3 years. Emergency physicians should be aware of the increasing number of patients who must choose between obtaining food and their prescribed medications, and should consider the contribution of hunger and food insecurity to the development of health conditions for which ED treatment is sought. PMID- 23687546 TI - Evaluation of California's Alcohol and Drug Screening and Brief Intervention Project for Emergency Department Patients. AB - INTRODUCTION: Visits to settings such as emergency departments (EDs) may present a "teachable moment" in that a patient may be more open to feedback and suggestions regarding their risky alcohol and illicit drug-use behaviors. Screening, Brief Intervention, and Referral to Treatment (SBIRT) is an 'opportunistic' public health approach that targets low-risk users, in addition to those already dependent on alcohol and/or drugs. SBIRT programs provide patients with comprehensive screening and assessments, and deliver interventions of appropriate intensity to reduce risks related to alcohol and drug use. METHODS: This study used a single group pre-post test design to assess the effect of the California SBIRT service program (i.e., CASBIRT) on 6 substance-use outcomes (past-month prevalence and number of days of binge drinking, illegal drug use, and marijuana use). Trained bilingual/bicultural Health Educators attempted to screen all adult patients in 12 EDs/trauma centers (regardless of the reason for the patient's visit) using a short instrument, and then delivered a brief motivational intervention matched to the patient's risk level. A total of 2,436 randomly selected patients who screened positive for alcohol and/or drug use consented to be in a 6-month telephone follow-up interview. Because of the high loss to follow-up rate, we used an intention-to-treat approach for the data analysis. RESULTS: RESULTS of generalized linear mixed models showed modest reductions in all 6 drug-and alcohol-use outcomes. Men (versus women), those at relatively higher risk status (versus lower risk), and those with only one substance of misuse (versus both alcohol and illicit drug misuse) tended to show more positive change. CONCLUSION: These results suggest that SBIRT services provided in acute care settings are associated with modest changes in self reported recent alcohol and illicit drug use. PMID- 23687547 TI - Vital signs: fatalities and binge drinking among high school students: a critical issue to emergency departments and trauma centers. AB - The Centers for Disease Control and Prevention (CDC) has published significant data and trends related to drinking and driving among United States (U.S.) high school students. National data from 1991-2011 shows an overall 54% relative decrease (from 22% to 10.3%) in drinking and driving among U.S. high school students aged >= 16 years. In 2011, this still represents approximately 950,000 high school students ages 16-19 years. The decrease in drinking and driving among teens is not fully understood, but is believed to be due to policy developments, enforcement of laws, graduated licenses, and economic impacts. Most significant to emergency physicians is that even with these restrictions, in 2010 approximately 2,700 teens (ages 16-19) were killed in the U.S. and about 282,000 were treated and released from emergency departments for injuries suffered in motor-vehicle accidents. In the same year, 1 in 5 drivers between the ages of 16 19 who were involved in fatal crashes had positive (>0.00%) blood alcohol concentration (BAC). We present findings from the CDC's Morbidity and Mortality Weekly Report with commentary on current recommendations and policies for reducing drinking and driving among adolescents. PMID- 23687548 TI - Are Simulation Stethoscopes a Useful Adjunct for Emergency Residents' Training on High-fidelity Mannequins? AB - INTRODUCTION: Emergency medicine residents use simulation training for many reasons, such as gaining experience with critically ill patients and becoming familiar with disease processes. Residents frequently criticize simulation training using current high-fidelity mannequins due to the poor quality of physical exam findings present, such as auscultatory findings, as it may lead them down an alternate diagnostic or therapeutic pathway. Recently wireless remote programmed stethoscopes (simulation stethoscopes) have been developed that allow wireless transmission of any sound to a stethoscope receiver, which improves the fidelity of a physical examination and the simulation case. METHODS: Following institutional review committee approval, 14 PGY1-3 emergency medicine residents were assessed during 2 simulation-based cases using pre-defined scoring anchors on multiple actions, such as communication skills and treatment decisions (Appendix 1). Each case involved a patient presenting with dyspnea requiring management based off physical examination findings. One case was a patient with exacerbation of heart failure, while the other was a patient with a tension pneumothorax. Each resident was randomized into a case associated with the simulation stethoscope. Following the cases residents were asked to fill out an evaluation questionnaire. RESULTS: Residents perceived the most realistic physical exam findings on those associated with the case using the simulation stethoscope (13/14, 93%). Residents also preferred the simulation stethoscope as an adjunct to the case (13/14, 93%), and they rated the simulation stethoscope case to have significantly more realistic auscultatory findings (4.4/5 vs. 3.0/5 difference of means 1.4, p=0.0007). Average scores of residents were significantly better in the simulation stethoscope-associated case (2.5/3 vs. 2.3/3 difference of means 0.2, p=0.04). There was no considerable difference in the total time taken per case. CONCLUSION: A simulation stethoscope may be a useful adjunct to current emergency medicine simulation-based training. Residents both preferred the use of the simulation stethoscope and perceived physical exam findings to be more realistic, leading to improved fidelity. Potential sources of bias include the small population, narrow scoring range, and the lack of blinding. Further research, focusing on use for resident assessment and clinical significance with a larger population and blinding of graders, is needed. PMID- 23687549 TI - Rapid (13)C Urea Breath Test to Identify Helicobacter pylori Infection in Emergency Department Patients with Upper Abdominal Pain. AB - INTRODUCTION: In emergency department (ED) patients with upper abdominal pain, management includes ruling out serious diseases and providing symptomatic relief. One of the major causes of upper abdominal pain is an ulcer caused by Helicobacter pylori (H. pylori), which can be treated and cured with antibiotics. We sought to estimate the prevalence of H. pylori infection in symptomatic patients using a convenience sample at a single urban academic ED and demonstrate the feasibility of ED-based testing. METHODS: We prospectively enrolled patients with a chief complaint of pain or discomfort in the upper abdomen for 1 year from February 2011 until February 2012 at a single academic urban ED. Enrolled subjects were tested for H. pylori using a rapid point of care (13)C Urea Breath Test (UBT) [Exalenz Bioscience]. We compared patient characteristics between those who tested positive versus negative for the disease. RESULTS: A total of 205 patients with upper abdominal pain were tested over 12 months, and 24% (95% confidence interval: 19% to 30%) tested positive for H. pylori. Black subjects were more likely to test positive than white subjects (28% v. 6%, P < 0.001). Other factors, such as age and sex, were not different between the 2 groups. CONCLUSION: In our ED, H. pylori infection was present in 1 in 4 patients with epigastric pain, and testing with a UBT was feasible. Further study is needed to determine the risk factors associated with infection, the prevalence of H. pylori in other EDs, the effect of the test on ED length of stay and the costeffectiveness of an ED-based test-and-treat strategy. PMID- 23687550 TI - Evaluation of a new nonnvasive device in determining hemoglobin levels in emergency department patients. AB - INTRODUCTION: The Masimo Radical-7 Pulse CO-Oximeter is a medical device recently approved by the US Food and Drug Administration that performs noninvasive oximetry and estimated venous or arterial hemoglobin measurements. A portable, noninvasive device that rapidly measures hemoglobin concentration could be useful in both austere and modern hospital settings. The objective of this study is to determine the degree of variation between the device's estimated hemoglobin measurement and the actual venous hemoglobin concentration in undifferentiated emergency department (ED) patients. METHODS: We conducted a prospective, observational, cross-sectional study of adult patients presenting to the ED. The subjects consisted of a convenience sample of adult ED patients who required a complete blood count as part of their care in the ED. A simultaneous probe hemoglobin was obtained and recorded. RESULTS: Bias between probe and laboratory hemoglobin measurements was -0.5 (95% confidence interval, - 0.8 to -0.1) but this was not statistically significant from 0 (t 0.05,124 = 0.20, P > 0.5). The limits of agreement were -4.7 and 3.8, beyond the clinically relevant standard of equivalency of +/- 1 g/dL. CONCLUSION: These data suggest that noninvasive hemoglobin determination is not sufficiently accurate for emergency department use. PMID- 23687551 TI - Safety and efficacy of prehospital diltiazem. AB - INTRODUCTION: Very few studies exist on the use of diltiazem in the prehospital setting. Some practitioners believe this medication is prone to causing hypotension in this setting. Our goals were to determine whether the prehospital administration of diltiazem induced hypotension and to evaluate the efficacy of the drug. METHODS: Our two-tiered system is located in a suburban region of New Jersey with advanced life support (ALS) care provided by fly-car units. The ALS units do not transport patients, and all of them are hospital based. The ALS providers are employed by the hospital system. In New Jersey, all ALS care requires online medical control, including the administration of diltiazem. We retrospectively reviewed patient care records for those who were believed to be in rapid atrial fibrillation and were given diltiazem in a suburban emergeny medical services system over a 22-month period. We examined the differences between heart rate (HR) and blood pressure (BP) on the initial evaluation and on arrival to the emergency department (ED). A hypotensive response was defined as a final systolic BP (SBP) less than 90 mmHg and a drop in SBP of at least 10 mmHg. Diltiazem was considered effective if the ED HR was <100 beats per minute (bpm) or if it decreased >=20%. RESULTS: During the study period, 26,979 patients were transported. Of these patients, 2,488 had a documented rhythm of atrial fibrillation or atrial flutter. Of the 320 patients who received diltiazem, 42 patient encounters were excluded for incomplete data, yielding 278 patients for analysis. The average initial SBP was 139 mmHg and the average diastolic BP was 84 mmHg. The average diltiazem dosage was 16.7 mg. Two patients became hypotensive. The average initial HR was 154 bpm. On arrival to the ED, 33% of the patients had an HR < 100 bpm and 69% had a drop in HR >= 20%. The overall efficacy of prehospital diltiazem was 73%. CONCLUSION: In the prehospital setting, diltiazem is associated with a very low rate of hypotension and appears to be effective in decreasing HR adequately. Prospective studies are needed to confirm these findings. PMID- 23687552 TI - Prenatal screening for fragile x: carriers, controversies, and counseling. AB - In addition to causing developmental disability in future offspring, fragile X carrier status has important reproductive and mental health implications for the individual being tested. Accordingly, prenatal carrier screening and diagnosis using DNA-based molecular methods has become crucial in early detection, intervention, and family planning. Although the list of known genetic disorders is growing daily, controversy remains over who should be tested for fragile X. FMR1 gene mutations can result in inherited intellectual disability, infertility, and neurodegeneration syndromes that are encountered by clinicians in a variety of settings. Patients and clinicians are still largely unfamiliar with this disorder, its complicated inheritance, and its heterogeneous phenotype. Debate continues over who should be offered prenatal carrier screening. As more disease screening is offered, pretest counseling will become only more complex and clinicians will further struggle to balance the needs of the individual and allocation of public health resources. PMID- 23687553 TI - Fetal and neonatal alloimmune thrombocytopenia. AB - Fetomaternal alloimmune thrombocytopenia (FMAIT) is a relatively uncommon disease, but is the leading cause of severe thrombocytopenia in the newborn. It can cause severe complications and long-term disabilities. The main objective of screening is to reduce both the morbidity and mortality associated with FMAIT, primarily by preventing intracranial hemorrhage. However, controversy surrounds both pre- and antenatal management. This article discusses pathogenesis, screening, diagnosis, and both pre- and neonatal management of FMAIT. PMID- 23687554 TI - Sex trafficking of women and girls. AB - Sex trafficking involves some form of forced or coerced sexual exploitation that is not limited to prostitution, and has become a significant and growing problem in both the United States and the larger global community. The costs to society include the degradation of human and women's rights, poor public health, disrupted communities, and diminished social development. Victims of sex trafficking acquire adverse physical and psychological health conditions and social disadvantages. Thus, sex trafficking is a critical health issue with broader social implications that requires both medical and legal attention. Healthcare professionals can work to improve the screening, identification, and assistance of victims of sex trafficking in a clinical setting and help these women and girls access legal and social services. PMID- 23687555 TI - Application of robotics in adnexal surgery. AB - This review discusses in detail robotic tubal reanastomosis as one of the classic reproductive surgery procedures. Other applications of robotics in adnexal surgery are also reviewed, including adult and pediatric adnexectomy, resection of endometriosis, benign ovarian mass resection, early ovarian cancer resection and staging, ovarian transposition, and treatment of ovarian remnant syndrome and ovarian vein syndrome. PMID- 23687556 TI - Safety considerations for office-based obstetric and gynecologic procedures. AB - The migration of gynecologic procedures to office-based settings provides numerous advantages for patients and providers alike, including reduced patient expenses, improved scheduling convenience, favorable provider reimbursement, and enhanced continuity of care and patient satisfaction. With rising health care costs-a major concern in health care-procedures will continue to shift to practice environments that optimize care, quality, value, and efficiency. It is imperative that gynecologic offices ensure that performance and quality variations are minimized across different sites of care; physicians should strive to provide care to patients that optimizes safety and is at least equivalent to that delivered at traditional sites. The gynecologic community should nonetheless heed the Institute of Medicine's recommendations and embrace continuous quality improvement. By exercising leadership, office-based gynecologists can forge a culture of competency, teamwork, communication, and performance measurement. PMID- 23687558 TI - Discovery of TUG-770: A Highly Potent Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonist for Treatment of Type 2 Diabetes. AB - Free fatty acid receptor 1 (FFA1 or GPR40) enhances glucose-stimulated insulin secretion from pancreatic beta-cells and currently attracts high interest as a new target for the treatment of type 2 diabetes. We here report the discovery of a highly potent FFA1 agonist with favorable physicochemical and pharmacokinetic properties. The compound efficiently normalizes glucose tolerance in diet-induced obese mice, an effect that is fully sustained after 29 days of chronic dosing. PMID- 23687557 TI - Nanocrystal Core Lipoprotein Biomimetics for Imaging of Lipoproteins and Associated Diseases. AB - Lipoproteins are natural nanoparticles composed of phospholipids and apolipoproteins that transport lipids throughout the body. As key effectors of lipid homeostasis, the functions of lipoproteins have been demonstrated to be crucial during the development of cardiovascular diseases. Therefore various strategies have been used to study their biology and detect them in vivo. A recent approach has been the production of lipoprotein biomimetic particles loaded with diagnostically active nanocrystals in their core. These include, but are not limited to: quantum dots, iron oxide or gold nanocrystals. Inclusion of these nanocrystals enables the utilization of lipoproteins as probes for a variety of imaging modalities (computed tomography, magnetic resonance imaging, fluorescence) while preserving their biological activity. Furthermore as some lipoproteins naturally accumulate in atherosclerotic plaque or specific tumor tissues, nanocrystal core lipoprotein biomimetics have been developed as contrast agents for early diagnosis of these diseases. PMID- 23687559 TI - The 2'-Trifluoromethyl Analogue of Indomethacin Is a Potent and Selective COX-2 Inhibitor. AB - Indomethacin is a potent, time-dependent, nonselective inhibitor of the cyclooxygenase enzymes (COX-1 and COX-2). Deletion of the 2'-methyl group of indomethacin produces a weak, reversible COX inhibitor, leading us to explore functionality at that position. Here, we report that substitution of the 2' methyl group of indomethacin with trifluoromethyl produces CF3-indomethacin, a tight-binding inhibitor with kinetic properties similar to those of indomethacin and unexpected COX-2 selectivity (IC50 mCOX-2 = 267 nM; IC50 oCOX-1 > 100 MUM). Studies with site-directed mutants reveal that COX-2 selectivity results from insertion of the CF3 group into a small hydrophobic pocket formed by Ala-527, Val 349, Ser-530, and Leu-531 and projection of the methoxy group toward a side pocket bordered by Val-523. CF3-indomethacin inhibited COX-2 activity in human head and neck squamous cell carcinoma cells and exhibited in vivo anti inflammatory activity in the carrageenan-induced rat paw edema model with similar potency to that of indomethacin. PMID- 23687561 TI - Off-Resonant Two-Photon Absorption Cross-Section Enhancement of an Organic Chromophore on Gold Nanorods. AB - Surface-plasmon-initiated interference effects of polyelectrolyte-coated gold nanorods on the two-photon absorption of an organic chromophore were investigated. With polyelectrolyte bearing gold nanorods of 2,4,6 and 8 layers, the role of the plasmonic fields as function of distance on such effects was examined. An unusual distance dependence was found: enhancements in the two photon cross-section were at a minimum at an intermediate distance, then rose again at a further distance. The observed values of enhancement were compared to theoretical predictions using finite element analysis and showed good agreementdue to constructive and destructive interference effects. PMID- 23687560 TI - Autotransporters: The Cellular Environment Reshapes a Folding Mechanism to Promote Protein Transport. AB - We know very little about how the cellular environment affects protein folding mechanisms. Here, we focus on one unique aspect of that environment that is difficult to recapitulate in the test tube: the effect of a folding vector. When protein folding is initiated at one end of the polypeptide chain, folding starts from a much smaller ensemble of conformations than during refolding of a full length polypeptide chain. But to what extent can vectorial folding affect protein folding kinetics and the conformations of folding intermediates? We focus on recent studies of autotransporter proteins, the largest class of virulence proteins from pathogenic Gram-negative bacteria. Autotransporter proteins are secreted across the bacterial inner membrane from N->C-terminus, which, like refolding in vitro, retards folding. But in contrast, upon C->N-terminal secretion across the outer membrane autotransporter folding proceeds orders of magnitude faster. The potential impact of vectorial folding on the folding mechanisms of other proteins is also discussed. PMID- 23687562 TI - STEM Electron Diffraction and High Resolution Images Used in the Determination of the Crystal Structure of Au144(SR)60 Cluster. AB - Determination of the total structure of molecular nanocrystals is an outstanding experimental challenge that has been met, in only a few cases, by single-crystal X-ray diffraction. Described here is an alternative approach that is of most general applicability and does not require the fabrication of a single crystal. The method is based on rapid, time-resolved nanobeam electron diffraction (NBD) combined with high-angle annular dark field scanning/transmission electron microscopy (HAADF-STEM) images in a probe corrected STEM microscope, operated at reduced voltages. The results are compared with theoretical simulations of images and diffraction patterns obtained from atomistic structural models derived through first-principles density functional theory (DFT) calculations. The method is demonstrated by application to determination of the structure of the Au144(SCH2CH2Ph)60 cluster. PMID- 23687563 TI - Evidence for proposed ICD-11 PTSD and complex PTSD: a latent profile analysis. AB - BACKGROUND: The WHO International Classification of Diseases, 11th version (ICD 11), has proposed two related diagnoses, posttraumatic stress disorder (PTSD) and complex PTSD within the spectrum of trauma and stress-related disorders. OBJECTIVE: To use latent profile analysis (LPA) to determine whether there are classes of individuals that are distinguishable according to the PTSD and complex PTSD symptom profiles and to identify potential differences in the type of stressor and severity of impairment associated with each profile. METHOD: An LPA and related analyses were conducted on 302 individuals who had sought treatment for interpersonal traumas ranging from chronic trauma (e.g., childhood abuse) to single-incident events (e.g., exposure to 9/11 attacks). RESULTS: THE LPA REVEALED THREE CLASSES OF INDIVIDUALS: (1) a complex PTSD class defined by elevated PTSD symptoms as well as disturbances in three domains of self organization: affective dysregulation, negative self-concept, and interpersonal problems; (2) a PTSD class defined by elevated PTSD symptoms but low scores on the three self-organization symptom domains; and (3) a low symptom class defined by low scores on all symptoms and problems. Chronic trauma was more strongly predictive of complex PTSD than PTSD and, conversely, single-event trauma was more strongly predictive of PTSD. In addition, complex PTSD was associated with greater impairment than PTSD. The LPA analysis was completed both with and without individuals with borderline personality disorder (BPD) yielding identical results, suggesting the stability of these classes regardless of BPD comorbidity. CONCLUSION: Preliminary data support the proposed ICD-11 distinction between PTSD and complex PTSD and support the value of testing the clinical utility of this distinction in field trials. Replication of results is necessary. PMID- 23687565 TI - The effect of the N-mesityl group in NHC-catalyzed reactions. AB - The majority of N-heterocyclic carbene catalyzed reactions of alpha functionalized aldehydes, including annulations, oxidations, and redox reactions, occur more rapidly with N-mesityl substituted NHCs. In many cases, no reaction occurs with NHCs lacking ortho-substituted aromatics. By careful competition studies, catalyst analogue synthesis, mechanistic investigations, and consideration of the elementary steps in NHC-catalyzed reactions of enals, we have determined that the effect of the N-mesityl group is to render the initial addition of the NHC to the aldehyde irreversible, thereby accelerating the formation of the Breslow intermediate. These studies rationalize the experimentally observed catalyst preference for all classes of NHC-catalyzed reactions of aldehydes and provide a roadmap for catalyst selection and design. PMID- 23687566 TI - A Computational Study of the Origin of Stereoinduction in NHC-Catalyzed Annulation Reactions of alpha,beta-Unsaturated Acyl Azoliums. AB - The origin of stereoselectivity of NHC-catalyzed annulation reactions of ynals and stable enols was studied with Density Functional Theory. The data suggest that the C-C bond formation is the stereo-determining step. Only the deprotonated pathway (containing an oxy anion and overall neutral species) was found to give rise to discrimination of the competing stereoisomers. This is due predominantly to electrostatic repulsion of the beta-stabilizing enolate functionality with the pi-cloud of the aryl group in the NHC-catalyst. PMID- 23687567 TI - Total Synthesis of Ageliferin via Acyl N-amidinyliminium Ion Rearrangement. AB - Ageliferin is a marine natural product having antiviral and antimicrobial activities. These functions remain to be characterized at a molecular level. Ageliferin is also thought a biosynthetic intermediary linking oroidin type alkaloids to more complex polycyclic derivatives. This scenario has the amino tetrahydrobenzimidazole motif in ageliferin serving as a reduced progenitor of oxidized, ring-contracted spirocycles. Here we describe the reverse. Namely, a concise synthesis of ageliferin which features ring expansion of a spirocyclic precursor - itself derived from reduction. The pathway also provides access to unique isosteres of the axinellamine ring system, allowing new synthetic additions to the growing family of pyrrole / imidazole alkaloids. PMID- 23687564 TI - Computational models and emergent properties of respiratory neural networks. AB - Computational models of the neural control system for breathing in mammals provide a theoretical and computational framework bringing together experimental data obtained from different animal preparations under various experimental conditions. Many of these models were developed in parallel and iteratively with experimental studies and provided predictions guiding new experiments. This data driven modeling approach has advanced our understanding of respiratory network architecture and neural mechanisms underlying generation of the respiratory rhythm and pattern, including their functional reorganization under different physiological conditions. Models reviewed here vary in neurobiological details and computational complexity and span multiple spatiotemporal scales of respiratory control mechanisms. Recent models describe interacting populations of respiratory neurons spatially distributed within the Botzinger and pre-Botzinger complexes and rostral ventrolateral medulla that contain core circuits of the respiratory central pattern generator (CPG). Network interactions within these circuits along with intrinsic rhythmogenic properties of neurons form a hierarchy of multiple rhythm generation mechanisms. The functional expression of these mechanisms is controlled by input drives from other brainstem components,including the retrotrapezoid nucleus and pons, which regulate the dynamic behavior of the core circuitry. The emerging view is that the brainstem respiratory network has rhythmogenic capabilities at multiple levels of circuit organization. This allows flexible, state-dependent expression of different neural pattern-generation mechanisms under various physiological conditions,enabling a wide repertoire of respiratory behaviors. Some models consider control of the respiratory CPG by pulmonary feedback and network reconfiguration during defensive behaviors such as cough. Future directions in modeling of the respiratory CPG are considered. PMID- 23687569 TI - Predictors of Staphylococcus aureus Rectovaginal Colonization in Pregnant Women and Risk for Maternal and Neonatal Infections. AB - BACKGROUND: Staphylococcus aureus infections are increasing among pregnant and postpartum women and neonates, but risk factors for S. aureus colonization in pregnancy and the association between maternal colonization and infant infections are not well defined. We sought to identify risk factors for maternal S. aureus rectovaginal colonization and assess colonization as a risk factor for infections among mothers and infants. METHODS: We conducted a retrospective cohort study of pregnant women and their infants. Demographic and clinical data, including S. aureus infections that occurred in mothers from 3 months before to 3 months after delivery and in infants during the first 3 months of life, were extracted from electronic medical records. Predictors for maternal S. aureus rectovaginal colonization were assessed through multivariable logistic regression analysis. RESULTS: The cohort included 2702 women and 2789 infants. The prevalence of maternal rectovaginal colonization with methicillin-susceptible S. aureus and methicillin-resistant S. aureus (MRSA) was 13% and 0.7%. Independent predictors of colonization included multigravidity, human immunodeficiency virus seropositivity, and group B Streptococcus colonization. S. aureus colonization was associated with an increased risk of infection in mothers (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.4-8.8) but not in their infants (OR, 1.9; 95% CI, .6-5.6). The frequency of S. aureus infections was 0.8% in mothers and 0.7% in infants. CONCLUSIONS: S. aureus rectovaginal colonization was associated with an increased risk of infections in women but not in their infants. The frequency of MRSA infections was low. These data suggest that routine MRSA screening of pregnant women may not be indicated. PMID- 23687568 TI - Combinatorial strategies for oncolytic herpes simplex virus therapy of brain tumors. AB - Oncolytic viruses, such as the oncolytic herpes simplex virus (oHSV), are an exciting new therapeutic strategy for cancer as they are replication competent in tumor cells but not normal cells. In order to engender herpes simplex virus with oncolytic activity and make it safe for clinical application, mutations are engineered into the virus. Glioblastoma multiforme (GBM) is the most common and deadly primary brain tumor in adults. Despite many advances in therapy, overall survival has not been substantially improved over the last several decades. A number of different oHSVs have been tested as monotherapy in early-phase clinical trials for GBM and have demonstrated safety and anecdotal evidence of efficacy. However, strategies to improve efficacy are likely to be necessary to successfully treat GBM. Cancer treatment usually involves multimodal approaches, so the standard of care for GBM includes surgery, radiotherapy and chemotherapy. In preclinical GBM models, combinations of oHSV with other types of therapy have exhibited markedly improved activity over individual treatments alone. In this review, we will discuss the various combination strategies that have been employed with oHSV, including chemotherapy, small-molecule inhibitors, antiangiogenic agents, radiotherapy and expression of therapeutic transgenes. Effective combinations, especially synergistic ones, are clinically important not just for improved efficacy but also to permit lower and less-toxic doses and potentially overcome resistance. PMID- 23687570 TI - Evidence of Endothelial Activation in Asymptomatic Plasmodium falciparum Parasitemia and Effect of Blood Group on Levels of von Willebrand Factor in Malaria. AB - BACKGROUND: Endothelial activation may contribute to development of severe disease from Plasmodium falciparum infection, but optimal markers of endothelial activation in severe malaria, the extent of endothelial activation in asymptomatic infection, and the effect of blood group O on endothelial activation have not been defined. METHODS: Serum levels of 3 markers of endothelial activation-von Willebrand factor (VWF), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1)-were assessed in Ugandan children with cerebral malaria (CM) (n = 86), children with uncomplicated malaria (UM) (n = 81), and community children (CC) (n = 90). RESULTS: Serum VWF, sICAM-1, and sVCAM-1 levels were all elevated in asymptomatic community children with microscopy-confirmed parasitemia when compared with children without parasitemia by microscopy or polymerase chain reaction (all, P <= .05). Levels of VWF, sICAM-1, and sVCAM-1 were higher in children with UM than in CC (all, P < 0.001), but only VWF levels effectively distinguished CM from UM (P < 0.001), a finding confirmed by receiver operating characteristic analyses (area under the curve = 0.67; 95% confidence interval, .58-.75). Von Willebrand factor levels were lower in children with blood group O versus non-O blood groups across the disease spectrum, but VWF levels remained higher in CM versus UM, even after controlling for blood group. CONCLUSIONS: Endothelial activation, as assessed by serum levels of VWF, sICAM-1, and sVCAM-1, occurs even in subclinical P. falciparum parasitemia. Von Willebrand factor levels increase with greater malaria disease severity. Blood group O is associated with lower VWF levels, but presence of blood group O alone does not explain the higher VWF levels seen in children with CM. PMID- 23687571 TI - Healthcare-Associated Infections at a Children's Cancer Hospital, 1983-2008. AB - BACKGROUND: Little is known about the incidence and etiology of healthcare associated infections in immunosuppressed children. METHODS: Data collected prospectively between 1983 and 2008 were used to analyze changes in the rate, types of infection, and infecting organisms over time in patients treated at a children's cancer hospital. Neutropenia was evaluated as a risk factor. RESULTS: Over the 26-year study period, 1986 healthcare-associated infections were identified during 1653 hospitalizations. The infection rate decreased significantly from 5.6 to 2.0 infections per 100 discharges (P < .01) and from 9.0 to 3.7 infections per 1000 patient-days (P < .01). Bloodstream infections were the most common type of infection (32.7% of all infections). Staphylococci (46.4% of Gram-positive bacteria), Escherichia coli (36.7% of Gram-negative bacteria), and Candida spp. (68.7% of fungi) were the most common pathogens isolated. An absolute neutrophil count (ANC) nadir <100 per mm(3) was significantly associated (P < .0001) with an increased rate of infections compared with higher ANC nadirs. CONCLUSIONS: Despite a steady expansion in hospital capacity and patient encounters over the last 3 decades, rates of healthcare-associated infections decreased significantly at our hospital. These data suggest that sustained decreases in the rate of healthcare-associated infections in immunosuppressed children are possible. An ANC <100 per mm(3) is a risk factor for healthcare-associated infections in this population. PMID- 23687572 TI - Immunogenicity and Safety of 2 Dose Levels of a Thimerosal-Free Trivalent Seasonal Influenza Vaccine in Children Aged 6-35 Months: A Randomized, Controlled Trial. AB - BACKGROUND: Improved influenza vaccine strategies for infants and preschool children are a high priority. METHODS: The immunological response and safety of a thimerosal-free trivalent inactivated influenza vaccine at 2 different doses (0.50 mL vs 0.25 mL) was evaluated in children aged 6-35 months. The study was randomized, observer blind, multicenter, and stratified by age (6-23 months and 24-35 months), and it accounted for prior influenza immunization status. RESULTS: Three hundred seventy-four children were in the total vaccinated cohort (study vaccine 0.25-mL dose, n = 164; 0.50-mL dose, n = 167; comparator 0.25 mL, n = 43). Regulatory criteria for immunogenicity of influenza vaccines in adults were met for all virus strains and doses for both age strata. A modest but not statistically significant improvement in immune responses was observed with the higher dose and reactogenicity, and safety of the 2 doses was not significantly different. CONCLUSIONS: The 0.5-mL dose of the study vaccine, when administered to children aged 6-35 months, resulted in a modest but not statistically significant improvement in immunogenicity with clinically similar safety and reactogenicity compared with the 0.25-mL dose. Further studies comparing full- and half-dose influenza vaccine in young children are needed. CLINICAL TRIALS REGISTRATION: NCT00778895. PMID- 23687573 TI - The Burden of Infant Meningococcal Disease in the United States. PMID- 23687574 TI - Laboratory Abnormalities Among HIV-Exposed, Uninfected Infants: IMPAACT Protocol P1025. AB - BACKGROUND: Infant laboratory abnormalities have been associated with exposure to antiretrovirals and to trimethoprim/sulfamethoxazole (TMP/SMX). METHODS: We analyzed data from International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) Protocol P1025, a prospective cohort study of human immunodeficiency virus type 1 (HIV)-infected women and their infants. Live-born, singleton, HIV-uninfected infants with at least 6 months of follow-up who represented the first pregnancy on study of HIV-infected mothers with at least 1 prenatal visit, CD4 count, and viral load during pregnancy and who used at least 1 antiretroviral during pregnancy were eligible for inclusion in this analysis. RESULTS: The study population comprised 1524 infants. During the first 6 months of life, 7.4% of laboratory serious adverse events (SAEs) were related to glucose, 7.2% were related to hemoglobin, 8.7% were related to absolute neutrophil count, and 4.0% were related to total lymphocyte count. The likelihood of laboratory SAEs decreased with increasing age for hemoglobin, absolute neutrophil count, and glucose. Infant preterm birth and current receipt of antiretroviral(s) were the factors with the strongest associations with laboratory SAEs. CONCLUSIONS: The overall frequency of laboratory SAEs was low and decreased with age. Preterm infants are at higher risk of hemoglobin- and total lymphocyte count-related SAEs. PMID- 23687575 TI - Galactomannan Antigen Testing for Diagnosis of Invasive Aspergillosis in Pediatric Hematology Patients. AB - OBJECTIVE: Invasive aspergillosis (IA) can cause significant morbidity and mortality in immunocompromised children. The galactomannan (GM) enzyme immunoassay (EIA) has been shown in adult studies to be a useful adjunct in diagnosing IA. Data on this assay in children are limited by small sample sizes and conflicting results; false-positive assays were a concern in historical studies. We sought to evaluate the GM EIA in a large cohort of children who received intensive chemotherapy and/or hematopoietic stem cell transplant. A focus was placed on evaluating the assay specificity, and the potential of measuring GM antigen in urine. METHODS: A multicenter prospective observational study in children with anticipated prolonged neutropenia was performed. Serum specimens were collected twice weekly, and urine was collected once weekly during neutropenic periods. Operating characteristics were calculated using the GM EIA optical density index cutoffs of 0.5 and 1.0 for both serum and urine specimens. RESULTS: At least one serum or urine specimen was tested from 198 patients. Ten patients had one or more repeatedly positive serum specimens, while 37 patients had one or more repeatedly positive urine specimens. The specificity of serum and urine testing was 95% and 80%, respectively. Although the urine test resulted in a higher false positivity rate, it successfully identified the only case of probable IA. CONCLUSIONS: Data suggest that the serum GM EIA does not provide frequent false-positive results as previously reported. Screening for galactomannan, or a related antigen in urine, needs to be further evaluated as it may be amenable to development of surveillance strategies. PMID- 23687576 TI - Longitudinal Characterization of Herpes Simplex Virus (HSV) Isolates Acquired From Different Sites in an Immune-Compromised Child: A New HSV Thymidine Kinase Mutation Associated With Resistance. AB - BACKGROUND: Herpes simplex virus resistance to acyclovir is well described in immune-compromised patients. Management of prolonged infection and recurrences in such patients may be problematic. METHODS: A patient with neuroblastoma developed likely primary herpes gingivostomatitis shortly after starting a course of chemotherapy, with spread to the eye during treatment with acyclovir. Viral isolates were serially obtained from separate sites after treatment was begun and tested for susceptibility to acyclovir and foscarnet by plaque reduction and plating efficiency assays. The thymidine kinase and DNA polymerase genes from each isolate were sequenced. RESULTS: Initial isolates from a throat swab, an oral lesion, and conjunctiva were resistant to acyclovir within 13 days of treatment. Subsequent isolates while on foscarnet were initially acyclovir susceptible, but reactivation of an acyclovir-resistant isolate was subsequently documented while on acyclovir suppression. Genotypic analysis identified a previously unreported UL23 mutation in some resistant isolates. None of the amino acid changes identified in UL30 were associated with resistance. CONCLUSIONS: Phenotypic and genotypic antiviral resistance of herpes simplex isolates may vary from different compartments and over time in individual immune-compromised hosts, highlighting the importance of obtaining cultures from all sites. Phenotypic resistance testing should be considered for isolates obtained from at-risk patients not responding to first-line therapy. Empiric combination treatment with multiple antivirals could be considered in some situations. PMID- 23687577 TI - Epidemiologic Similarities in Pediatric Community-Associated Methicillin Resistant and Methicillin-Sensitive Staphylococcus aureus in the San Francisco Bay Area. AB - BACKGROUND: Risk factors differentiating methicillin-resistant Staphylococcus aureus (MRSA) from methicillin-sensitive S aureus (MSSA) infections in the pediatric community have been unclear. METHODS: We performed a prospective case comparison investigation of clinical, epidemiological, and molecular factors in pediatric community-associated (CA) MRSA and MSSA cases in the San Francisco Bay Area. Chart reviews were conducted in 270 CA-MRSA and 313 CA-MSSA cases. Fifty eight CA-MRSA (21.4%) and 95 CA-MSSA (30.4%) cases were interviewed. Molecular typing was performed on 111 isolates. RESULTS: MSSA represented 53.7% of CA cases and was more likely to cause invasive disease (6.2% vs 1.1%, P = .004). Few potential epidemiologic risk factors distinguished CA-MRSA from CA-MSSA. No differences were found in factors related to crowding, cleanliness, or prior antibiotic use. Compromised skin integrity due to eczema (24.3% vs 13.5%, P = .001) was associated with CA-MSSA. Many exposures to potentially infected or colonized contacts or contaminated objects were assessed; only three were associated with CA-MSSA: having a household contact who had surgery in the past year (18.9% vs 6.0%, P = .02), and regular visits to a public shower (9.1% vs 2.0%, P = .01) or gym (12.6% vs 3.3%, P = .04). Molecular typing identified clonal complex 8 as the predominant genetic lineage among CA-MRSA (96.4%) and CA MSSA (39.3%) isolates. CONCLUSIONS: In the context of recent heightened focus on CA-MRSA, the burden of serious disease caused by CA-MSSA among children should not be overlooked. MRSA and MSSA may be growing epidemiologically similar; thus, research, clinical, and public health efforts should focus on S aureus as a single entity. PMID- 23687579 TI - Nevirapine-Resistant HIV-1 DNA in Breast Milk After Single-Dose Nevirapine With or Without Zidovudine for Prevention of Mother-to-Child Transmission. AB - Among 30 human immunodeficiency virus type 1 (HIV-1)-infected women who received single-dose nevirapine (NVP), 17 (57%) had NVP-resistant HIV-1 detected in breast milk. NVP resistance in breast milk persisted for at least 8 months postpartum and was apparently transmitted to at least 1 infant. NVP resistance was detected less often in women who also received zidovudine. PMID- 23687578 TI - Clostridium difficile Infection in Children: Current State and Unanswered Questions. AB - The incidence of Clostridium difficile infection (CDI) in children has increased over the past decade. In recent years, new and intriguing data on pediatric CDI have emerged. Community-onset infections are increasingly recognized, even in children who have not previously received antibiotics. A hypervirulent strain is responsible for up to 20% of pediatric CDI cases. Unique risk factors for CDI in children have been identified. Advances in diagnostic testing strategies, including the use of nucleic acid amplification tests, have raised new questions about the optimal approach to diagnosing CDI in children. Novel therapeutic options are available for adult patients with CDI, raising questions about the use of these agents in children. Updated recommendations about infection prevention and control measures are now available. We summarize these recent developments in pediatric CDI in this review and also highlight remaining knowledge gaps that should be addressed in future research efforts. PMID- 23687580 TI - Laboratory-Confirmed Rotavirus Disease in Utah Children: Clinical and Economic Impact of Rotavirus Vaccination. AB - BACKGROUND: Rotavirus is the most common cause of infectious diarrhea in children worldwide. Recent studies have described changes in the burden of all-cause gastroenteritis; however, there are limited data on the clinical and economic impact of rotavirus vaccine on cases of laboratory-confirmed rotavirus disease. METHODS: We performed a retrospective study of laboratory-confirmed rotavirus disease from July 2003 through June 2010 at a children's hospital and a community hospital in Utah. Demographics and hospital costs for children <5 years with rotavirus symptoms and a positive rotavirus enzyme immunoassay test on a stool specimen were abstracted from electronic medical records. We compared the prevaccine period (2003-2007) with the postvaccine period (2008-2010). RESULTS: The overall incidence of rotavirus gastroenteritis declined in the postvaccine period, from 26.6 to 5.2 cases per 10 000 person-years for Salt Lake County residents. The largest decrease in the incidence of rotavirus gastroenteritis was among children <12 months (-87%; 95% confidence interval [CI], 79-93). Older children (12-23 months) also experienced significant decreases (-81%; 95% CI, 72 88), as did those 24-59 months (-61%; 95% CI, 51-71). In 2009, 3 years after rotavirus vaccine introduction, there was a 79% decrease in emergency department visits and a 78% decrease in hospitalizations across both hospitals. The cost of emergency department visits and hospitalizations for rotavirus gastroenteritis decreased by 79% and 72%, respectively, resulting in annual savings of $790 000 at a children's hospital and $140 000 at a community hospital. CONCLUSION: Rotavirus vaccination in infants has dramatically decreased the clinical burden and direct medical costs of rotavirus gastroenteritis in both infants and young children. PMID- 23687581 TI - Variation in Antibiotic Use for Children Hospitalized With Inflammatory Bowel Disease Exacerbation: A Multicenter Validation Study. AB - BACKGROUND: Antibiotics are often given for inflammatory bowel disease (IBD) exacerbations, but their use among pediatric inpatients has not been assessed. We aimed to validate administrative data for identifying hospitalizations for IBD exacerbation and to characterize antibiotic use for IBD exacerbations across children's hospitals. METHODS: To validate administrative data for identifying IBD exacerbation, we reviewed charts of 409 patients with IBD at 3 US tertiary care children's hospitals. Using the case definition with optimal test characteristics, we identified 3450 children with 5063 hospitalizations for IBD exacerbation at 36 children's hospitals between January 1, 2007 and December 31, 2009, excluding those with diagnosis codes for specific bacterial infections. We estimated predicted and expected hospital-specific antibiotic utilization rates using mixed-effects logistic regression, adjusting for patient- and hospital level factors. RESULTS: Administrative codes for receipt of intravenous steroids or endoscopy provided 79% positive predictive value and 71% sensitivity for identifying hospitalizations for IBD exacerbation. Antibiotics were administered for >=2 of the first 3 hospital days during 40.7% of IBD exacerbations in US children's hospitals; however, the proportion of patients receiving antibiotics varied significantly across hospitals from 27% to 71% (P < .001), despite adjustment for several patient- and hospital-level variables. Among those given antibiotics, the 3 most common regimens were metronidazole alone (26.9%), metronidazole with ciprofloxacin (10.3%), and ampicillin with gentamicin and metronidazole (7.0%). CONCLUSIONS: Significant variability exists in antibiotic use for children hospitalized with IBD exacerbation, which is unexplained by disease severity or hospital volume. Further study should determine the optimal antibiotic therapy for this condition. PMID- 23687582 TI - Clinical Value of an Ambulatory-Based Antibiogram for Uropathogens in Children. AB - Unnecessarily broad-spectrum antibiotic prescribing for ambulatory pediatric urinary tract infection may result from clinicians not having antibiograms specific to this population. Comparing an existing hospital-based with a proposed ambulatory uropathogen antibiogram for children in Utah, Escherichia coli accounted for a larger percentage and was more susceptible to narrower-spectrum antibiotics, demonstrating the potential need for ambulatory pediatric antibiograms. PMID- 23687585 TI - Introduction to the volume 2, second issue. PMID- 23687583 TI - Seroprevalence and Risk Factors for Cytomegalovirus Infections in Adolescent Females. AB - BACKGROUND: Congenital cytomegalovirus (CMV) is a leading cause of disability, including sensorineural hearing loss, developmental delay, and mental retardation. Understanding risk factors for acquisition of CMV infection in adolescent females will help determine vaccine strategies. METHODS: Females (12 17 years) were recruited from primary care settings in Cincinnati, Galveston, Houston, and Nashville from June 2006 to July 2010 for a seroepidemiologic study, from which seronegative participants were recruited for a CMV vaccine trial. Participants (n = 1585) responded to questions regarding potential exposures. For those with young children in the home (n = 859), additional questions were asked about feeding and changing diapers, and for those > 14 years of age (n = 1162), questions regarding sexual activity were asked. Serum was evaluated for CMV antibody using a commercial immunoglobulin G assay. RESULTS: Cytomegalovirus antibody was detected in 49% of participants. In the univariate analyses, CMV seroprevalence was significantly higher among African Americans, those with children < 3 years of age in the home, and those with a history of oral, anal, or vaginal intercourse. Among those with young children in the home, feeding children and changing diapers further increased the association with CMV infection. However, in the final multivariate analysis, only African Americans and household contact with young children were associated with CMV infection. CONCLUSIONS: By age 12, evidence of CMV infection was common. Multiple factors regarding race and personal behaviors likely contribute to seroconversion earlier in life. PMID- 23687584 TI - Noroviruses: The Most Common Pediatric Viral Enteric Pathogen at a Large University Hospital After Introduction of Rotavirus Vaccination. AB - We conducted an 8.5-year study examining enteric viruses at Texas Children's Hospital (TCH) before and after rotavirus vaccine introduction. Norovirus prevalence was 10.9%. Rotavirus prevalence decreased 64% after vaccine licensure. Noroviruses are the most common TCH enteropathogen and will likely eclipse rotaviruses as the most important US pediatric gastroenteritis pathogen. PMID- 23687586 TI - String capsule endoscopy for screening and surveillance of esophageal varices in patients with cirrhosis. AB - BACKGROUND: EGD is the gold standard for the screening and surveillance of esophageal varices. A less invasive, safer and sedationless alternative procedure is needed. OBJECTIVE: To assess the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) as well as the beyond the chance agreement (kappa index), of string capsule endoscopy (SCE) in the diagnosis of esophageal varices. METHODS: Cirrhotic patients underwent string capsule endoscopy (SCE) and EGD for screening and surveillance purposes. Varices were graded at EGD and SCE as small, medium and large. Descriptors at SCE were added as follows: PLUS, for the presence of red wale signs or, MINUS for their absence, irrespective of the estimated variceal size. Clinically significant varices were defined by their size (medium/large at either EGD or SCE) and/or, the PLUS descriptor irrespective of the estimated size at SCE. Sensitivity, specificity, PPV, NPV, accuracy and kappa index were calculated. Procedure time, procedure related discomfort and patient's preference were documented. RESULTS: 100 patients (33 for screening and 67 for surveillance) were enrolled. The sensitivity and specificity of SCE for clinically significant varices when using the PLUS/MINUS descriptors were 82% and 90%, respectively with a PPV of 84% and NPV of 89% and a kappa of 0.73. CONCLUSION: String capsule endoscopy had an acceptable sensitivity and specificity for the diagnosis of clinically significant esophageal varices but the lack of air insufflation still hampers its correlation with the grading used with EGD. PMID- 23687587 TI - Confocal endomicroscopy (CEM) improves efficiency of Barrett surveillance. AB - BACKGROUND: Endoscopists with extensive experience with confocal endomicroscopy (CEM) have demonstrated that this technology is useful for Barrett's esophagus (BE) surveillance. However, data on endoscopists with minimal experience with this technique are limited. HYPOTHESIS: For BE surveillance, an endoscopist with minimal experience in CEM-guided biopsy would achieve a similar diagnostic yield with fewer biopsies when compared to the random 4-quadrant biopsy protocol. OBJECTIVE: To compare the diagnostic yields of CEM-guided biopsy technique with the random 4-quadrant biopsy protocol. DESIGN: Randomized controlled trial. SETTING: Tertiary care center. PATIENTS: Patients with BE. METHODS: Out of 18 patients who underwent routine BE surveillance, 11 and 7 were randomly assigned to group A (CEM-guided) and to group B (random 4-quadrant biopsy), respectively. The pathologists were blinded to all clinical information. RESULTS: Mean length of endoscopic Barrett was similar in both groups, (5.1 vs. 6.3 cm, p=0.51). The diagnostic yields for detecting SIM (63.6% vs. 59.5%, p=0.5), low grade dysplasia (11. 6% vs. 11.2%, p=NS), high grade dysplasia (10.1% vs. 11.5%, p=0.88). Although the total number of individual mucosal biopsy performed were 52% lower in the CEM group (129 vs. 269), the overall diagnostic yield (85.3% vs. 82.2%, p=0.53) was similar in both groups. LIMITATIONS: Small sample size. CONCLUSIONS: For BE surveillance, limited data suggested that endoscopists with minimal experience in CEM can effective use this technology for "smart" biopsy to decrease the need for intense tissue sampling but without lowering the diagnostic yield in detecting dysplasia. PMID- 23687588 TI - Making ERCP training safe: A protocol-based strategy to minimize complications during selective biliary cannulation. AB - BACKGROUND AND AIMS: Endoscopic retrograde cholangiopancreatography (ERCP) is an advanced procedure with significant complication rate of 5 to 10%. Scant data is available on quality indicators for trainee-involved ERCP. In our study, we evaluated the outcome of trainee-involved ERCPs in which a protocol-based strategy to minimize complications during selective biliary cannulation was adopted. PATIENTS AND METHODS: Hands-on training was excluded if patients had ASA grade > 3. The trainee's attempts at selective biliary cannulation were stopped and the procedure taken over by the supervising expert endoscopist if the following factors were encountered: (1) failed cannulation after 5 attempts; (2) unsuccessful cannulation after 10 minutes; (3) edematous papilla; (4) pancreatic duct cannulation >= 2 times. After successful ductal cannulation, the trainee was allowed to continue additional hands on training in other aspects such as stone extraction and stenting. RESULTS: During the study period, 331 patients underwent ERCP. Trainee group (TG) consisted of 85 patients; mean age 70 (range 27-99). Expert group (EG) consisted of 246 patients; mean age 65 (range 19-98). The overall technical success rate was 97.9% and there was no significant difference between TG (98.8%) and EG (97.6%). The overall complication rate was 3.9% and there was no difference between TG (3.5%) and EG (4%). In TG, although inadvertent pancreatic duct cannulation occurred in 12/85 (14.1%), acute pancreatitis developed only in 3/85 (3.5%). CONCLUSION: The high success and low complication rates in trainee-involved and expert-only ERCP procedures were similar. While using a protocol-based strategy, good clinical outcome during the provision of hands-on training for ERCP was observed. PMID- 23687589 TI - Colonic diverticulosis is associated with an increased adenoma detection rate in patients undergoing first-time screening colonoscopy. AB - BACKGROUND: Diverticulosis is a common finding in patients undergoing colonoscopy. The effect of colonic diverticulosis on the colorectal adenoma detection rate (ADR) and other colonoscopy quality indicators remains unclear. OBJECTIVES: To determine if colonic diverticulosis is associated with differences in (1) colorectal ADR and (2) other quality indicators and operating characteristics in patients undergoing first-time screening colonoscopy. METHODS: Retrospective cohort study conducted at an outpatient surgical center affiliated with an academic medical center. RESULTS: 300 consecutive patients (190 women) with a median age of 57 years (range: 23-70 years) who underwent colonoscopy for various indications were included. 108 (36%) of these 300 patients had diverticulosis found on colonoscopy. 142 (47.3%) of these patients (88 women, median age of 52 years) underwent their first screening colonoscopy. In this population, the frequency of colonic diverticula was 39.2%, and the ADR was 47.5% for patients with diverticulosis and 27.4% for patients without diverticulosis. Multivariate analysis revealed that the presence of diverticulosis had an associated odds ratio of 2.3 (p=0.04) in favor of finding at least one adenoma. No statistically significant differences were found among the rates of total colonoscopy, median scope insertion and withdrawal times, and the amounts of midazolam and fentanyl required for sedation when patients with diverticulosis were compared to those without diverticulosis. CONCLUSION: Colonic diverticulosis was associated with an increased ADR in patients undergoing first-time screening colonoscopy. The presence of colonic diverticulosis did not adversely affect the cecal intubation rate, scope insertion or withdrawal times, or sedation requirements. PMID- 23687590 TI - Quality matters: A protocol-based strategy in ERCP training. PMID- 23687591 TI - Endoscopic retrograde cholangiopancreatography in patients with roux-en-Y anatomy. PMID- 23687592 TI - Endoscopic management of biliary leak following gunshot wound to the liver. PMID- 23687593 TI - Endoscopic removal of foreign body from hepatic duct using wire guided forceps and basket. PMID- 23687594 TI - Synchronous EUS-guided choledochoduodenostomy with metallic biliary and duodenal stents placement in a patient with malignant papillary tumor. PMID- 23687595 TI - Symptomatic gastric inlet patches in children treated with argon plasma coagulation: a case series. AB - The pathologic potential of gastric inlet patches is now being recognized. A recent adult study has shown the effectiveness of argon plasma coagulation in ablating the patch and the associated symptoms. There are no reports of ablation in children. We report a case series of successful argon plasma coagulation of gastric inlet patches and their symptoms in 5 children. PMID- 23687596 TI - A novel technique on EUS-guided access to dorsal pancreatic duct in a patient with pancreas divisum. PMID- 23687597 TI - Successful management of recurrent biliary colic caused by pancreatic stent migration after Whipple procedure. PMID- 23687599 TI - Introduction to volume 2, fourth issue. PMID- 23687598 TI - Is the use of prophylactic hemoclips in the endoscopic resection of large pedunculated polyps useful? A prospective and randomized study. AB - BACKGROUND: The methods for preventing post-polypectomy bleeding (PPB) are not standardised and there are groups that use hemoclips for this purpose. OBJECTIVE: To study whether the use of hemoclips reduces PPB complications. MATERIALS AND METHODS: Prospective, randomised study of patients with pedunculated polyps larger than 10 mm. The patients were included in two groups (hemoclip before polypectomy -HC- and standard polypectomy -SP-). This study has been registered with the trial registration number NCT01565993. RESULTS: 105 polypectomies were performed (98 patients), 66 (62.9%) in the HC group. The total rate of complications was 10,6% in the HC group (4.5% early bleeding, 1.5% severe delayed bleeding, 4,5% mucosal burns, 1.5% perforation). In the SP group, the rate of total complications was 7,7%, (7,7% early bleeding, no significant differences). In view of the unexpected increase in the morbidity of the hemoclip group, the study was suspended without reaching the sample size. In an ad hoc analysis, which includes the standard polypectomy patients who refused to participate in the study (35 polyps), the total morbidity was 5,7% (no perforations and 2 patients with premature bleeding).When we compared the morbidity of the HC group to the morbidity of SP group plus R group (74 polyps), we also failed to detect any significant differences in terms of PPB, but did in terms of perforation. CONCLUSION: The prophylactic use of hemoclips in polypectomies of large pedunculated polyps leads to a further risk of mucosal burns and perforation that is not acceptable, and does not reduce the risk of PPB. PMID- 23687600 TI - Gastroduodenal stents are associated with more durable patency as compared to percutaneous endoscopic gastrojejunostomy in the palliation of malignant gastric outlet obstruction. AB - BACKGROUND: Gastroduodenal outlet obstruction (GOO) is a critical complication of cancers localized within and adjacent to the upper gastrointestinal tract. Approaches to the relief of GOO include surgical bypass with gastrojejunostomy (GJ), endoluminal placement of a self-expandable metallic stent (SEMS), and percutaneous endoscopic gastrostomy with jejunal extension (PEG-J). To date no studies have compared the outcome of utilizing PEG-J with other modalities of therapy. OBJECTIVES: To determine if there is a difference in complications or effectiveness when survival and/or device patency of PEG-J is compared to that of gastroduodenal SEMS in patients with malignant GOO. METHODS: Patients who underwent placement of either PEG-J or gastroduodenal SEMS for unresectable malignant GOO were included in a retrospective cohort study. RESULTS: 24 patients (12 men) with a median age of 68.5 years underwent either PEG-J (n=12) or gastroduodenal SEMS (n=12) placement. Patients undergoing SEMS placement experienced longer overall device patency and/or survival as compared to those undergoing PEG-J (median 70 versus 35 days). Complications, including the need for re-intervention, were similar among both groups. Patients who underwent PEG-J as compared to those that had SEMS placement had a hazard ratio of 3.85 (CI 1.28 11.11) for decreased overall survival. CONCLUSION: In patients with malignant GOO, placement of a palliative SEMS for gastric decompression and nutrition was associated with longer aggregate device patency and survival as compared to PEG J. Both modalities were similar with respect to complications and the need for re intervention. PMID- 23687601 TI - Feasibility and safety of magnetic-controlled capsule endoscopy system in examination of human stomach: a pilot study in healthy volunteers. AB - OBJECTIVE: To assess the feasibility and safety of magnetic-controlled capsule endoscopy (MCE) system for examination of human stomach. METHODS: This pilot study enrolled 34 healthy volunteers. All subjects swallowed the MCE and gas producing powder for gastric distention. An external robot was used to generate magnetic field to manipulate MCE inside the stomach. The primary measurements included safety, gastric preparation, maneuverability and visualization of gastric mucosa. RESULTS: Gastric preparation and examination was well accepted by subjects and there were no adverse events. The examination in the stomach takes 43.8+/-10.0min (27-60). The cleanliness was evaluated as good in the 30 (88.2%) subjects and as moderate in 4 (11.8%) subjects. The distention of gastric cavity was evaluated as good in the 29 (85.3%) subjects and moderate in 5 (14.7%) subjects. Maneuverability of the MCE to movements of the guidance magnet robot was graded as good in 29 (85.3%) subjects and moderate in 5 (14.7%) subjects. More than 75% gastric mucosa was visualized in 27 (79.4%) subjects and 50% to 75% in 7 (20.6%) subjects. Visualization of the gastric cardia, fundus, body, angulus, antrum and pylorus was subjectively assessed as complete in 82.4%, 85.3%, 100.0%, 100.0%, 100.0% and 100.0%, respectively. Polyp and erosive lesions were found in 7 subjects. CONCLUSION: Magnetic-controlled capsule endoscopy used for examination of the human stomach is feasible and safe. PMID- 23687602 TI - Does the urgency of endoscopic retrograde cholangiopancreatography (ercp)/percutaneous biliary drainage (pbd) impact mortality and disease related complications in ascending cholangitis? (deim-i study). AB - BACKGROUND: The Tokyo Guidelines have greatly impacted the management of ascending cholangitis. Though ERCP is the favored modality for biliary decompression, no evidence exists for the timing of ERCP. The DEIM-I study set out to determine if the time from patient presentation to biliary decompression impacted in hospital all cause mortality in ascending cholangitis. METHOD: DEIM-I cohort study was a single-blinded and consisted of 250 subjects with moderate to severe ascending cholangitis who underwent ERCP/PBD. Subjects were randomized into quartiles based upon time from presentation until ERCP/PBD. The primary outcome utilized logistic regression to estimate relative risk (RR) of all cause, in hospital mortality with time to procedure as the predictive covariate. Secondary outcomes were analyzed using multivariate logistic regression and included; multiple organ failure (MOF), sepsis, systemic inflammatory response syndrome (SIRS), surgical incidence, hospital readmission and length of stay (LOS). RESULTS: The risk for hospital mortality was significantly less when biliary drainage was performed within 11 h, compared to >42 h (RR 0.34, 95%CI 0.12 to 0.99, p=0.049). Hospital readmission was lower in subjects who underwent biliary decompression less than 11 h, when compared to those greater than 22 h. Subjects who underwent biliary decompression within 21 h had significant higher risk for surgery compared to those 22-42 h. CONCLUSION: The relative risk of all cause in hospital mortality was lower in subjects who underwent biliary decompression in under 11 h compared to greater than 42 h. PMID- 23687603 TI - Which patients with dilated common bile and/or pancreatic ducts have positive findings on EUS? AB - BACKGROUND: Patients with dilated common bile duct (CBD) (>7mm) and/or pancreatic duct (PD) on abdominal imaging are often referred for endoscopic ultrasound (EUS). In many cases, the EUS shows no obvious etiology for the dilated ducts. OBJECTIVE: Find clinical factors that may predict which patients are more likely to have positive findings on EUS to explain the etiologies for the dilated ducts. DESIGN: Retrospective database analysis. SETTING: Tertiary-care university hospital. PATIENTS: Patients referred for EUS for dilated CBD and/or PD from January 2004 to February 2010 were included in this study. Only patients without an obvious etiology for the dilated ducts on abdominal imaging were included. INTERVENTIONS: An EUS was performed by using either a radial echoendoscope or a linear endoscope to evaluate the common bile duct and/or the pancreatic duct. When appropriate fine needle aspiration of the mass or cyst was performed. MAIN OUTCOME MEASUREMENTS: The characteristics of patients who had positive findings on EUS to explain the etiology of their dilated PD and/or CBD. RESULTS: A total of 140 patients were included in the study with a mean age of 64 years, 51 (36%) male and 115 (82%) white. The majority of our patients had a presenting symptom of abdominal pain 105 (75%). 49 (36%) had elevated AST or ALT, 25 (8%) had an elevated bilirubin and 13 (23%) had an elevated lipase. EUS findings explained the dilated ducts in 54 (39%) of our patients, most common diagnoses included: CBD stone in 11 (8%), non-calcific chronic pancreatitis in 9 (6%), pancreatic mass in 8 (6%), IPMN in 7 (5%). On bivarate analysis patients who were older (p = 0.006), male (p = 0.001), had elevated LFTs (p = <0.001), had elevated lipase (p = 0.021) or had dilated CBD and PD (p = 0.007) were more likely to have an etiology for their dilated duct(s) discovered on EUS. LIMITATIONS: A retrospective study with a small number of patients. CONCLUSION: Older patients, males and those patients presenting with concurrent elevations in the AST/ALT and/or lipase were more likely to have an underlying etiology discovered on EUS. Furthermore, EUS may detect an undiagnosed pancreatic malignancy in patients presenting with unexplained duct dilation. PMID- 23687604 TI - The role of endoscopic ultrasound-guided fine needle aspiration (eus-fna) for the diagnosis of intra-abdominal lymphadenopathy of unknown origin. AB - BACKGROUND AND AIMS: The diagnosis of intra-abdominal lymphadenopathy of is difficult, especially when no primary lesion has been identified. We aimed to evaluate the diagnostic yield of EUS-FNA cytology in patients with enlarged intra abdominal lymph nodes of unknown etiology. PATIENT AND METHODS: 147 patients with abdominal lymphadenopathy on imaging in whom EUS-FNA was performed with a 22 gauge needle. Performance characteristics of EUS-FNA including the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were compared between the 2 groups. RESULTS: AThe location of the enlarged lymph nodes was the celiac axis (8.2%), peri-gastric (34%), peri pancreatic (25.2%), peri-portal (27.9%), and other intra-abdominal locations (4.8%). The median number of EUS-FNA passes was 5. The final diagnosis were lymphoma in (n=27), metastatic adenocarcinoma (n=44) patients, other miscellaneous malignancies (n=22) and benign disease (n=54). The sensitivity, specificity, and accuracy of EUS-FNA were 89.7, 98.3, and 93.5% respectively. A false positive FNA result was present in only 1 case (0.7%); false negative FNA results were present in eight cases (5.8%). Lymph node morphologic features of roundness, echogenicity, and homogeneity on EUS were not a predictor of lymph node malignancy. CONCLUSION: In a retrospective cohort trial, EUS-FNA was found to be highly accurate and safe in diagnosing patients with intra-abdominal lymphadenopathy of unknown etiology. PMID- 23687605 TI - Effectiveness of a simplified "patient friendly" split dose polyethylene glycol colonoscopy prep in Veterans Health Administration patients. AB - BACKGROUND AND OBJECTIVES: Adequate colon cleansing is an important factor in performing quality colonoscopy. Split dose Polyethylene Glycol (PEG) solutions have been shown to improve colon cleansing, but the effectiveness in a large clinical practice of elderly co-morbid patients has not been demonstrated. The aim of this study was to assess the efficacy of a simplified split PEG bowel prep in Veterans Health Administration (VHA) patients. METHODS: Prospective pre-post study design of VHA patients undergoing routine colonoscopy. Bowel prep quality was assessed using a standardized semi-quantitative 5-point scale. "Standard" 4L PEG prep was consumed once the evening before the procedure. "Split" prep was consumed half in the early evening and half in the late evening or early morning depending on procedure time. RESULTS: Right colon preps were Excellent/Good in 81.4% of split preps (n=199) vs. 63% of standard preps (n=447, p<0.001). Left colon preps were Excellent/Good in 85.9% of split preps vs. 71.6% of standard preps (p<0.001). Diabetics (n=133) had significantly more right colon preps rated fair or worse compared to non-diabetics irrespective of prep (39.9% vs. 29.0%, p=0.02). Split prep in diabetics resulted in fewer right colon preps rated fair or worse compared to diabetics using standard prep (28.3% vs. 45.9%, p=0.049). Average adenomas detected per colonoscopy were 1.04 for split prep vs. 0.85 for standard prep (p=NS). Patient satisfaction was higher for split preps. CONCLUSION: System-wide implementation of a split PEG prep resulted in significantly improved bowel cleansing in VHA patients, particularly in the right colon. Improved bowel cleansing with split preps was associated with higher patient satisfaction. PMID- 23687606 TI - Is the use of prophylactic hemoclips in the endoscopic resection of large pedunculated polyps useful? A prospective and randomized study. AB - BACKGROUND: The methods for preventing post-polypectomy bleeding (PPB) are not standardised and there are groups that use hemoclips for this purpose. OBJECTIVE: To study whether the use of hemoclips reduces PPB complications. MATERIALS AND METHODS: Prospective, randomised study of patients with pedunculated polyps larger than 10 mm. The patients were included in two groups (hemoclip before polypectomy -HC- and standard polypectomy -SP-). This study has been registered with the trial registration number NCT01565993. RESULTS: 105 polypectomies were performed (98 patients), 66 (62.9%) in the HC group. The total rate of complications was 10,6% in the HC group (4.5% early bleeding, 1.5% severe delayed bleeding, 4,5% mucosal burns, 1.5% perforation). In the SP group, the rate of total complications was 7,7%, (7,7% early bleeding, no significant differences). In view of the unexpected increase in the morbidity of the hemoclip group, the study was suspended without reaching the sample size. In an ad hoc analysis, which includes the standard polypectomy patients who refused to participate in the study (35 polyps), the total morbidity was 5,7% (no perforations and 2 patients with premature bleeding).When we compared the morbidity of the HC group to the morbidity of SP group plus R group (74 polyps), we also failed to detect any significant differences in terms of PPB, but did in terms of perforation. CONCLUSION: The prophylactic use of hemoclips in polypectomies of large pedunculated polyps leads to a further risk of mucosal burns and perforation that is not acceptable, and does not reduce the risk of PPB. PMID- 23687607 TI - Sacral nerve stimulation in the treatment of fecal incontinence - the experience of a pelvic floor center : short term results. AB - OBJECTIVES: The aim of this paper is to present the data pertinent to the experiences of our Pelvic Floor Center on the utilisation of SNS in the treatment of fecal incontinence and compare these data to the data of current literature. METHODS: All patients who had had SNS treatment for fecal incontinence between the dates of 1st April 2008 and 1st April 2011 were enrolled in the study. We considered a 50% reduction of fecal incontinence episodes as a success of the test phase. The score used for assessment was the Cleveland Clinic Florida-Fecal Incontinence score (CCF-FI). RESULTS: The 21 patients treated for fecal incontinence (19 ? and 2 ?, average age 59.7 [ 26-73] years) were sub-divided on the basis of the presence or absence of sphincter damage (group A1 had damage while group A2 did not). A patient (group A1) was excluded from the study as the result of the external connector breaking during the test phase. Of the 20 remaining patients (9 from group A1 and 11 from A2), 14 (70%) felt benefit and subsequently underwent definitive stimulator implantation. The variation between the pre-operative CCF-FI and the value at 6 months was statistically significant both in group A1 (p=0.009) and in group A2 (p=0.003). The only complication reported was one case (7.1%) of infection of the definitive stimulator. CONCLUSION: SNS represents an effective treatment for patients with fecal incontinence. The results have been encouraging, and in line with current literature. PMID- 23687608 TI - A combination of snare polypectomy and apc therapy for prolapsing common bile duct adenoma. PMID- 23687609 TI - Endoscopic therapy for significant gastric outlet obstruction caused by a small pancreatic pseudocyst with a unique shape and location. AB - Large perigastric or periduodenal pseudocysts are a potential cause of gastric outlet obstruction, usually requiring interventional drainage of the pseudocysts. In contrary most of the small pseudocysts are asymptomatic and require no therapy. However, certain small pseudocysts can produce clinically significant problem depending on their location. Here we report a case of small pseudocyst (12.0 mm in width) with a unique shape and location causing significant Gastric outlet obstruction treated successfully with endoscopy. PMID- 23687610 TI - A case of mesenteric ischemia secondary to Fibromuscular Dysplasia (FMD) with a positive outcome after intervention. AB - Fibromuscular dysplasia (FMD) is a non-inflammatory, non-atherosclerotic angiopathy, which commonly affects the renal and internal carotid arteries. Although rare, FMD has the potential of involving the mesenteric vasculature. Due its low incidence and relatively little knowledge concerning its risk factors and etiology, actual diagnosis of FMD involving the mesenteric vessels requires a very high degree of suspicion. Upon review of the few reported cases of FMD causing mesenteric ischemia, it is clear that therapeutic interventions are rarely discussed and that positive outcomes are even more uncommon. Herein, we present the case of a 47 year-old female with mesenteric ischemia secondary to FMD, which was diagnosed and treated originally with angioplasty, then repeat angioplasty with stent placement, and finally with a bypass graft. Ultimately, the patient had a positive outcome, including eight month follow-up. PMID- 23687611 TI - Successful endoscopic treatment of iatrogenic biloma as a complication of endosonography-guided hepaticogastrostomy: The first case report. AB - Endosonography (EUS)-guided biliary drainage is a novel therapeutic option for patients with biliary obstruction after failed endoscopic retrograde cholangiopancreatography (ERCP). Many case reports and series worldwide have shown satisfactory clinical outcomes in terms of technical and clinical success rates, which approach 80%-100%. However, these procedures need to be performed by experts to minimize the possible complications, which have been reported in as many as 14-35% of patients. The most common complications encountered in these procedures are bile leakage, pneumoperitoneum, peritonitis, and stent related complications such as stent migration. Here, we report the case of a female patient who had cholangiocarcinoma and underwent EUS-guided hepaticogastrostomy after failed ERCP; stent malposition occurred during the procedure, leading to biloma formation that was successfully treated with EUS-guided biloma drainage. PMID- 23687612 TI - Successful management of recurrent biliary colic caused by pancreatic stent migration after Whipple procedure. PMID- 23687613 TI - Induction of spermatogenic synchrony by retinoic acid in neonatal mice. AB - Retinoic acid (RA) is required for the successful differentiation and meiotic entry of germ cells in the murine testis. The availability of RA to undifferentiated germ cells begins in a variable, uneven pattern during the first few days after birth and establishes the asynchronous pattern of germ cell differentiation in adulthood. It has been shown that synchronous spermatogenesis can be induced in 2 d postpartum mice, but not in adult mice, by treating vitamin A sufficient males with RA. In this study, neonatal males were treated at different ages with a single dose of RA and spermatogenesis was examined after recovery to adulthood. The failure of exogenous RA to alter asynchrony correlates with the appearance of meiotic preleptotene spermatocytes within the seminiferous epithelium. PMID- 23687614 TI - Physiopathological aspects of the Wnt/beta-catenin signaling pathway in the male reproductive system. AB - The Wnt/beta-catenin signaling pathway controls several biological processes throughout development and adult life. Dysregulation of Wnt/beta-catenin signaling underlies a wide range of pathologies in animals and humans, including cancer in different tissues. In this review, we provide an update of the Wnt/beta catenin signaling pathway and the possible roles of the Wnt/beta-catenin signaling in the biology of testis, epididymis and prostate. Data from our laboratory suggest the involvement of 17beta-estradiol and estrogen receptors (ERs) on the regulation of beta-catenin expression in rat Sertoli cells. We also provide emerging evidences of the involvement of Wnt/beta-catenin pathway in testis and prostate cancer. Our understanding of the role of Wnt/beta-Catenin signaling in male reproductive tissues is still evolving, and several questions are open to be addressed in the future. PMID- 23687615 TI - Actin cross-linking protein palladin and spermatogenesis. AB - In the seminiferous epithelium of the mammalian testis, the most distinctive ultrastructure is the extensive bundles of actin filaments that lie near the Sertoli-spermatid interface and the Sertoli-Sertoli cell interface known as the apical ectoplasmic specialization (apical ES) and the basal ES, respectively. These actin filament bundles not only confer strong adhesion at these sites, they are uniquely found in the testis. Recent studies have shown that ES also confers spermatid and Sertoli cell polarity in the seminiferous epithelium during the epithelial cycle. While these junctions were first described in the 1970s, there are few functional studies in the literature to examine the regulation of these actin filament bundles. It is conceivable that these actin filament bundles at the ES undergo extensive re-organization to accommodate changes in location of developing spermatids during spermiogenesis as spermatids are transported across the seminiferous epithelium. Additionally, these actin filaments are rapidly reorganized during BTB restructuring to accommodate the transit of preleptotene spermatocytes across the barrier at stage VIII of the epithelial cycle. Thus, actin binding and regulatory proteins are likely involved in these events to confer changes in F-actin organization at these sites. Interestingly, there are no reports in the field to study these regulatory proteins until recently. Herein, we summarize some of the latest findings in the field regarding a novel actin cross-linker and actin-bundling protein called palladin. We also discuss in this opinion article the likely role of palladin in regulating actin filament bundles at the ES during spermatogenesis, highlighting the significant of palladin and how this protein is plausibly working in concert with other actin binding/regulatory proteins and components of polarity proteins to regulate the cyclic events of actin organization and re-organization during the epithelial cycle of spermatogenesis. We also propose a hypothetic model by which palladin regulates ES restructuring during the epithelial cycle of spermatogenesis. PMID- 23687618 TI - Letter from the Editor. PMID- 23687619 TI - t-Bu3P-Coordinated 2-Phenylaniline-Based Palladacycle Complex as a Precatalyst for the Suzuki Cross-coupling Polymerization of Aryl Dibromides with Aryldiboronic Acids. AB - t -Bu3P-Coordinated 2-phenylaniline-based palladacycle complex, [2'-(amino kN)[1,1'-biphenyl]-2-yl-kC]chloro(tri-t-butylphosphine)palladium, as a general, highly efficient precatalyst for the Suzuki cross-coupling polymerization of aryl dibromides with aryldiboronic acids is described. Such t-Bu3P-coordinated 2 aminobiphenyl-based palladacycle complex-catalyzed Suzuki cross-coupling polymerization afforded polymers within an hour, with the yields and the molecular weights comparable to or higher than that of polymers obtained by using other palladium catalysts with much longer polymerization time. Our study provided a highly efficient catalyst system for the Suzuki cross-coupling polymerization of aryl dihalides with aryldiboronic acids. Our study also paved the road for us to investigate other monodentate ligand-coordinated palladacycle complexes including N-heterocyclic carbine-coordinated ones for cross-coupling polymerizations. PMID- 23687617 TI - A survey of Sertoli cell differentiation in men after gonadotropin suppression and in testicular cancer. AB - It is widely held that the somatic cell population that is responsible for sperm development and output (Sertoli cells) is terminally differentiated and unmodifiable in adults. It is postulated, with little evidence, that Sertoli cells are not terminally differentiated in some phenotypes of infertility and testicular cancer. This study sought to compare markers of Sertoli cell differentiation in normospermic men, oligospermic men (undergoing gonadotropin suppression) and testicular carcinoma in situ (CIS) and seminoma samples. Confocal microscopy was used to assess the expression of markers of proliferation (PCNA and Ki67) and functional differentiation (androgen receptor). As additional markers of differentiation, the organization of Sertoli cell tight junction and associated proteins were assessed in specimens with carcinoma in situ. In normal men, Sertoli cells exhibited a differentiated phenotype (i.e., PCNA and Ki67 negative, androgen 40 receptor positive). However, after long-term gonadotropin suppression, 1.7 +/- 0.6% of Sertoli cells exhibited PCNA reactivity associated with a diminished immunoreactivity in androgen receptor, suggesting an undifferentiated phenotype. Ki67-positive Sertoli cells were also observed. PCNA positive Sertoli cells were never observed in tubules with carcinoma in situ, and only rarely observed adjacent to seminoma. Tight junction protein localization (claudin 11, JAM-A and ZO-1) was altered in CIS, with a reduction in JAM-A reactivity in Sertoli cells from tubules with CIS and the emergence of strong JAM A reactivity in seminoma. These findings indicate that adult human Sertoli cells exhibit characteristics of an undifferentiated state in oligospermic men and patients with CIS and seminoma in the presence of germ cell neoplasia. PMID- 23687616 TI - Dual role of immune cells in the testis: Protective or pathogenic for germ cells? AB - The purpose of this review is to describe how the immune cells present in the testis interact with the germinal epithelium contributing to survival or apoptosis of germ cells (GCs). Physiologically, the immunosuppressor testicular microenvironment protects GCs from immune attack, whereas in inflammatory conditions, tolerance is disrupted and immune cells and their mediators respond to GC self antigens, inducing damage of the germinal epithelium. Considering that experimental models of autoimmune orchitis have clarified the local immune mechanisms by which protection of the testis is compromised, we described the following topics in the testis of normal and orchitic rats: (1) cell adhesion molecule expression of seminiferous tubule specialized junctions and modulation of blood-testis barrier permeability by cytokines (2) phenotypic and functional characteristics of testicular dendritic cells, macrophages, effector and regulatory T cells and mast cells and (3) effects of pro-inflammatory cytokines (TNF-alpha, IL-6 and FasL) and the nitric oxide-nitric oxide synthase system on GC apoptosis. PMID- 23687620 TI - TGFbeta1 microenvironment determines dendritic cell development. AB - We have recently described two types of Langerhans cells (LCs), which develop via separate pathways in steady-state conditions and during inflammation. Here, we propose that these two types of LCs differ in their requirement for transforming growth factor beta1 (TGFbeta1), and we discuss how TGFbeta1 impacts on the development of other dendritic cell subtypes. PMID- 23687621 TI - Trial watch: Chemotherapy with immunogenic cell death inducers. AB - It is now clear that the immune system plays a critical role not only during oncogenesis and tumor progression, but also as established neoplastic lesions respond to therapy. Selected cytotoxic chemicals can indeed elicit immunogenic cell death, a functionally peculiar type of apoptosis that stimulates tumor specific cognate immune responses. Such immunogenic chemotherapeutics include cyclophosphamide, doxorubicin and oxaliplatin (which are approved by FDA for the treatment of various hematological and solid malignancies), mitoxantrone (which is currently employed both as an anticancer agent and against multiple sclerosis) and patupilone (a microtubular poison in clinical development). One year ago, in the second issue of OncoImmunology, we discussed the scientific rationale behind immunogenic chemotherapy and reviewed the status of recent clinical trials investigating the off-label use of cyclophosphamide, doxorubicin, oxaliplatin and mitoxantrone in cancer patients. Here, we summarize the latest developments in this area of clinical research, covering both high-impact studies that have been published during the last 13 months and clinical trials that have been initiated in the same period to assess the antineoplastic profile of immunogenic chemotherapeutics. PMID- 23687622 TI - Tumor-associated macrophages subvert T-cell function and correlate with reduced survival in clear cell renal cell carcinoma. AB - Although malignant cells can be recognized and controlled by the immune system, in patients with clinically apparent cancer immunosurveillance has failed. To better understand local immunoregulatory processes that impact on cancer progression, we correlated intratumoral immunological profiles with the survival of patients affected by primary clear cell renal cell carcinoma (ccRCC). A retrospective analysis of 54 primary ccRCC samples for 31 different immune response-related transcripts, revealed a negative correlation of CD68 (a marker of tumor-associated macrophages, TAMs) and FOXP3 (a marker of regulatory T cells, Tregs) with survival. The subsequent analysis of 12 TAM-related transcripts revealed an association between the genes coding for CD163, interferon regulatory factor 4 (IRF4) and fibronectin 1 (FN1), all of which have been linked to the M2 TAM phenotype, with reduced survival and increased tumor stage, whereas the opposite was the case for the M1-associated gene coding for inducible nitric oxide synthetase (iNOS). The M2 signature of (CD68+) TAMs was found to correlate with CD163 expression, as determined in prospectively collected fresh ccRCC tissue samples. Upon co-culture with autologous tumor cells, CD11b+ cells isolated from paired blood samples expressed CD163 and other M2-associated proteins, suggesting that the malignant cells promote the accumulation of M2 TAMs. Furthermore, the tumor-associated milieu as well as isolated TAMs induced the skewing of autologous, blood-derived CD4+ T cells toward a more immunosuppressive phenotype, as shown by decreased production of effector cytokines, increased production of interleukin-10 (IL-10) and enhanced expression of the co-inhibitory molecules programmed death 1 (PD-1) and T-cell immunoglobulin mucin 3 (TIM-3). Taken together, our data suggest that ccRCC progressively attracts macrophages and induces their skewing into M2 TAMs, in turn subverting tumor-infiltrating T cells such that immunoregulatory functions are increased at the expense of effector functions. PMID- 23687624 TI - Non-invasive Prenatal Testing: Technologies, Clinical Assays and Implementation Strategies for Women's Healthcare Practitioners. AB - The field of prenatal genetic testing has exploded with new non-invasive technologies and test options in the past several years. It is challenging for women's healthcare providers to keep up with the multitude of publications and provide patients with the most accurate and up-to-date information possible regarding prenatal testing. In this article, we examine the sequencing technologies that provide the framework for non-invasive prenatal testing (NIPT) and review the major North American NIPT clinical validation studies published in 2011 and 2012. This paper also compares and contrasts the commercially available non-invasive prenatal tests in the United States, discusses clinical implementation recommendations from professional societies and highlights considerations for genetic counseling. PMID- 23687623 TI - Helicobacter, Inflammation, and Gastric Cancer. AB - Helicobacter pylori infection leads to long-lasting chronic inflammation and represents the most common risk factor underlying gastric cancer. Recently, new insights into the mechanisms through which H. pylori and mucosal inflammation lead to cancer development have emerged. H. pylori virulence factors, in particular specific CagA genotypes, represent main factors in gastric cancer, inducing altered intracellular signaling in epithelial cells. The chronic nature of H. pylori infection appears to relate to the VacA virulence factor and Th17/Treg mechanisms. A role of H. pylori infection in epigenetic and microRNA deregulation has been shown. Mutation of the epithelial cell genome, a hallmark of cancer, was demonstrated to accumulate in H. pylori infected stomach partly due to inadequate DNA repair. Gastric stem cells were shown to be targets of oxidative injury in the Helicobacter-inflammatory milieu. Recent advances emphasizing the contribution of bacterial factors, inflammatory mediators, and the host epithelial response in gastric carcinogenesis are reviewed. PMID- 23687626 TI - The hybrid block iterative algorithm for solving the system of equilibrium problems and variational inequality problems. AB - ABSTRACT: In this paper, we construct the hybrid block iterative algorithm for finding a common element of the set of common fixed points of an infinite family of closed and uniformly quasi - phi- asymptotically nonexpansive mappings, the set of the solutions of the variational inequality for an alpha-inverse-strongly monotone operator, and the set of solutions of a system of equilibrium problems. Moreover, we obtain a strong convergence theorem for the sequence generated by this process in the framework Banach spaces. The results presented in this paper improve and generalize some well-known results in the literature. PMID- 23687625 TI - Anticoagulants: A Review of the Pharmacology, Dosing, and Complications. AB - Anticoagulants remain the primary strategy for the prevention and treatment of thrombosis. Unfractionated heparin, low molecular weight heparin, fondaparinux, and warfarin have been studied and employed extensively with direct thrombin inhibitors typically reserved for patients with complications or those requiring intervention. Novel oral anticoagulants have emerged from clinical development and are expected to replace older agents with their ease of use and more favorable pharmacodynamic profiles. Hemorrhage is the main concerning adverse event with all anticoagulants. With their ubiquitous use, it becomes important for clinicians to have a sound understanding of anticoagulant pharmacology, dosing, and toxicity. PMID- 23687627 TI - The intuition of neutrality and consequentialist thinking: potential antinatalist implications. AB - Many people seem to share some version of what has been called the "intuition of neutrality" about creating new people, which, roughly, says that there exists a certain range of levels of well-being such that creating people within this range is, in itself, morally neutral, but creating people with a level of well-being outside this range is not morally neutral. In this paper, I will discuss different interpretations of this intuition, and specifically distinguish between what I will call counterfactual interpretations and Do-interpretations of the intuition. I will argue that it is hard to interpret the intuition in a way that does not give rise to antinatalist moral reasons, i.e. reasons favoring an empty future population, when it comes to choices of social policy. In particular, this holds if we assume a conception of relevant outcomes of actions reflecting consequentialist moral intuitions. In the end, I will formulate a normative principle of welfare promotion which I argue respects the most plausible counterfactual version of the neutrality intuition. PMID- 23687628 TI - Characterization of x-type high-molecular-weight glutenin promoters (x-HGP) from different genomes in Triticeae. AB - The sequences of x-type high-molecular-weight glutenin promoter (x-HGP) from 21 diploid Triticeae species were cloned and sequenced. The lengths of x-HGP varied from 897 to 955 bp, and there are 329 variable sites including 105 singleton sites and 224 polymorphic sites. Genetic distances of pairwise X-HGP sequences ranged from 0.30 to 16.40% within 21 species and four outgroup species of Hordeum. All five recognized regulatory elements emerged and showed higher conservation in the x-HGP of 21 Triticeae species. Most variations were distributed in the regions among or between regulatory elements. A 22 bp and 50 bp insertions which were the copy of adjacent region with minor change, were found in the x-HGP of Ae. speltoides and Ps. Huashanica, and could be regarded as genome specific indels. The phylogeny of media-joining network and neighbour joining tree both supported the topology were composed of three sperate clusters. Especially, the cluster I comprising the x-HGP sequences of Aegilops, Triticum, Henrardia, Agropyron and Taeniatherum was highly supporting by both network and NJ tree. As conferring to higher level and temporal and spatial expression, x-HGP can used as the source of promoter for constructing transgenic plants which allow endosperm-specific expression of exogenous gene on higher level. In addition, the x-HGP has enough conservation and variation; so it should be valuable in phylogenetic analyses of Triticeae family members. PMID- 23687629 TI - CFD simulation of the effect of particle size on the nanofluids convective heat transfer in the developed region in a circular tube. AB - The CFD simulation of heat transfer characteristics of a nanofluid in a circular tube under constant heat flux was considered using Fluent software (version 6.3.26) in the laminar flow. Al2O3 nanoparticles in water with concentrations of 0.5%, 1.0%, 1.5%, 2% and 2.5% were used in this simulation. All of the thermo physical properties of nanofluids were assumed to be temperature independent. Two particle sizes with average size of 20 and 50 nm were used in this research. It was concluded that heat transfer coefficient increased by increasing the Reynolds number and the concentration of nanoparticles. The maximum convective heat transfer coefficient was observed at the highest concentration of nano-particles in water (2.5%). Furthermore, the two nanofluids showed higher heat transfer than the base fluid (water) although the nanofluid with particles size of 20 nm had the highest heat transfer coefficient. PMID- 23687630 TI - Study the seasonal steroid hormones of common carp in Caspian Sea, Iran. AB - In this investigation, serum steroid hormones such as testosterone (T), 17beta estradiol (E2) and progesterone (P) in 12 female of the migratory population of Common carp (Cyprinus carpio) in southeast of Caspian Sea during a year from May 2011 to May 2012 were studied. The results of present study revealed that changes in levels of steroid hormones, (E2) and (T) were closely correlated to ovarian development. There was significant difference in level of 17 beta- estradiol between autumn and winter seasons that the highest of 17-beta estradiol level was observed in autumn season. In the case of progesterone hormone, higher levels was recorded in summer season and there was significant difference between summer and spring seasons and lower level of testosterone was observed in spring season. PMID- 23687631 TI - A bibliometric analysis of global forest ecology research during 2002-2011. AB - Bibliometric is increasingly used for the analysis of discipline dynamics and management related decision-making. This study analyzes 937,923 keywords from 78,986 articles concerning forest ecology and conducts a serial analysis of these articles' characteristics. The articles' records, published between 2002 and 2011, were downloaded from the Web of Science, and their keywords were exported by Java processing programs. The result shows that forest ecology studies focused on forest diversity, conservation, dynamics and vegetation in the last decade. Developed countries, such as the USA, Canada, and Germany, were the most productive countries in the field of forest ecology research. From 2002 to 2011, the number of articles published annually related to forest ecology grew at a stable rate, as indicated by the fit produced by a high determination coefficient (R(2) = 0.9955). The findings of this study may be applicable for planning and managing forest ecology research and partners involved in such research may use this study as a reference. PMID- 23687632 TI - Model-based iterative reconstruction for reduction of radiation dose in abdominopelvic CT: comparison to adaptive statistical iterative reconstruction. AB - PURPOSE: To evaluate dose reduction and image quality of abdominopelvic computed tomography (CT) reconstructed with model-based iterative reconstruction (MBIR) compared to adaptive statistical iterative reconstruction (ASIR). MATERIALS AND METHODS: In this prospective study, 85 patients underwent referential-, low-, and ultralow-dose unenhanced abdominopelvic CT. Images were reconstructed with ASIR for low-dose (L-ASIR) and ultralow-dose CT (UL-ASIR), and with MBIR for ultralow dose CT (UL-MBIR). Image noise was measured in the abdominal aorta and iliopsoas muscle. Subjective image analyses and a lesion detection study (adrenal nodules) were conducted by two blinded radiologists. A reference standard was established by a consensus panel of two different radiologists using referential-dose CT reconstructed with filtered back projection. RESULTS: Compared to low-dose CT, there was a 63% decrease in dose-length product with ultralow-dose CT. UL-MBIR had significantly lower image noise than L-ASIR and UL-ASIR (all p<0.01). UL-MBIR was significantly better for subjective image noise and streak artifacts than L ASIR and UL-ASIR (all p<0.01). There were no significant differences between UL MBIR and L-ASIR in diagnostic acceptability (p>0.65), or diagnostic performance for adrenal nodules (p>0.87). CONCLUSION: MBIR significantly improves image noise and streak artifacts compared to ASIR, and can achieve radiation dose reduction without severely compromising image quality. PMID- 23687633 TI - Prodrug design, synthesis and pharmacokinetic evaluation of (3' R, 4' R)-3 hydroxymethyl-4-methyl-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone. AB - 3-Hydroxymethyl-4-methyl-DCK (3, HMDCK) was discovered previously as a potent HIV non-nucleoside reverse transcriptase inhibitor (NNRTIs) (EC50: 0.004 MUM, TI: 6225) with a novel mechanism of action. It exerts anti-HIV activity by inhibiting the production of HIV-1 double-stranded viral DNA from a single-stranded DNA intermediate, rather than blocking the generation of single-stranded DNA from a RNA template, which is the mechanism of action of current HIV-1 RT inhibitors. However, the insufficient metabolic stability of 3 limits its further clinical development. In the current study, a series of ester prodrugs of 3 was designed and synthesized to explore the new drug candidates as NNRTIs. The l-alanine ester prodrug 10 exhibited desirable pharmacokinetic properties in vitro and in vivo and showed improved oral bioavailability of 26% in rat, and would be a potential clinical candidate as a new anti-AIDS drug. PMID- 23687634 TI - Waiting to inhale: An exploratory review of conditions that may predispose to pulmonary hypertension and right heart failure in persons exposed to household air pollution in low- and middle-income countries. AB - The health effects of exposure to household air pollution are gaining international attention. While the bulk of the known mortality estimates due to these exposures are derived from respiratory conditions, there is growing evidence of adverse cardiovascular health effects. Pulmonary hypertension and right heart failure are common conditions in low- and middle-income countries whose etiology may be related to common exposures in these regions such as schistosomiasis, human immunodeficiency virus, tuberculosis infections and other causes. While little is known of the interplay between exposure to household air pollution, right heart function and such conditions, the large burden of pulmonary hypertension and right heart failure in regions where there is significant exposure to household air pollution raises the possibility of a linkage. This review is presented in three parts. First, we explore what is known about pulmonary hypertension and right heart failure in low- and middle-income countries by focusing on eight common causes thereof. We then review what is known of the impact of household air pollution on pulmonary hypertension and posit that when individuals with one of these eight common comorbidities are exposed to household air pollution they may be predisposed to develop pulmonary hypertension or right heart failure. Lastly, we posit that there may be a direct link between exposure to household air pollution and right heart failure independent of pre-existing conditions which merits further investigation. Our overall aim is to highlight the multifactorial nature of these complex relationships and offer avenues for research in this expanding field of study. PMID- 23687635 TI - Climate change and our environment: the effect on respiratory and allergic disease. AB - Climate change is a constant and ongoing process. It is postulated that human activities have reached a point at which we are producing global climate change. It provides suggestions to help the allergist/environmental physician integrate recommendations about improvements in outdoor and indoor air quality and the likely response to predicted alterations in the earth's environment into his or her patient's treatment plan. It incorporates references retrieved from Pub Med searches for topics, including:climate change, global warming, global climate change, greenhouse gasses, air pollution, particulates, black carbon, soot and sea level, as well as references contributed by the individual authors. Many changes that affect respiratory disease are anticipated.Examples of responses to climate change include energy reduction retrofits in homes that could potentially affect exposure to allergens and irritants, more hot sunny days that increase ozone-related difficulties, and rises in sea level or altered rainfall patterns that increase exposure to damp indoor environments.Climate changes can also affect ecosystems, manifested as the appearance of stinging and biting arthropods in new areas.Higher ambient carbon dioxide concentrations, warmer temperatures, and changes in floristic zones could potentially increase exposure to ragweed and other outdoor allergens,whereas green practices such as composting can increase allergen and irritant exposure. Finally, increased energy costs may resultin urban crowding and human source pollution, leading to changes in patterns of infectious respiratory illnesses. Improved governmental controls on airborne pollutants could lead to cleaner air and reduced respiratory diseases but will meet strong opposition because of their effect on business productivity. The allergy community must therefore adapt, as physician and research scientists always have, by anticipating the needs of patients and by adopting practices and research methods to meet changing environmental conditions. PMID- 23687637 TI - Hepatitis B and C viruses and survival from hepatocellular carcinoma in the Arkhangelsk region: a Russian registry-based study. AB - INTRODUCTION: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. The prevalence of hepatitis B (HBV) and C (HCV) in Russia was 7.6 and 5.4 per 100,000, respectively. The aim of this study was to assess the proportion of HCV and HBV infection among HCC patients, to evaluate associations between HCV, HBV and stage of HCC and to compare survival of HCC patients by their HBV/HCV status in the Arkhangelsk region of northwest Russia. MATERIALS AND METHODS: A retrospective cohort study was conducted using data on all histologically confirmed HCC cases. Proportions of infected and non-infected HCC cases were calculated by Wilson's method. The associations between HBV, HCV and severity of HCC were assessed by Pearson's Chi-squared test. Survival data were presented using Kaplan-Meier curves and median survival. Survival time between the groups was compared using log-rank tests. Adjustment for potential confounders (sex, age groups, stage of HCC and cirrhosis stage by Child-Paquet scale) was performed using Cox regression. RESULTS: There were 583 histologically confirmed HCC cases. The viral status was registered in 311 of patients with pre mortem diagnosis, where 124 or 39.9% (95% confidence interval (CI), 34.4-45.4) had HBV, 54 or 17.4% (95% CI, 13.5-21.9) had HCV and 16 or 5.1% (95% CI, 3.2-8.2) were infected with both HBV and HCV. The median survival rates of patients were 3 months (95% CI, 2.3-3.8), 3 months (95% CI, 2.0-3.9) and 1 month (95% CI, 0.0 0.6) for patients with HBV, HCV and HBV and HCV, respectively. For virus-free patients, it was 5 months (95% CI, 3.5-6.5), log-rank test=10.74, df=3, p=0.013. Crude Cox regression showed increased risk of death for HBV and HBV and HCV groups in comparison with virus-free patients, and not reaching the level of statistical significance for HCV. After adjustment, the hazard ratios (HRs) decreased to non-significant levels or even reversed, with only exception for the group of patients infected with both hepatitis viruses. CONCLUSIONS: We found that more than half of HCC patients were infected with HBV or HCV. The study did not reveal an association between viral status of HCC patients and stage of HCC. The viral hepatitis may have an impact on survival of HCC patients. PMID- 23687636 TI - Motifs within the CA-repeat-rich region of Surfactant Protein B (SFTPB) intron 4 differentially affect mRNA splicing. AB - The first half of the surfactant protein B (SP-B) gene intron 4 is a CA-repeat rich region that contains 11 motifs. To study the role of this region on SP-B mRNA splicing, minigenes were generated by systematic removal of motifs from either the 5' or 3' end. These were transfected in CHO cells to study their splicing efficiency. The latter was determined as the ratio of completely to incompletely spliced SP-B RNA. Our results indicate that SP-B intron 4 motifs differentially affect splicing. Motifs 8 and 9 significantly enhanced and reduced splicing of intron 4, respectively. RNA mobility shift assays performed with a Motif 8 sequence that contains a CAUC cis-element and cell extracts resulted in a RNA:protein shift that was lost upon mutation of the element. Furthermore, in silico analysis of mRNA secondary structure stability for minigenes with and without motif 8 indicated a correlation between mRNA stability and splicing ratio. We conclude that differential loss of specific intron 4 motifs results in one or more of the following: a) altered splicing, b) differences in RNA stability and c) changes in secondary structure. These, in turn, may affect SP-B content in lung health or disease. PMID- 23687638 TI - Induced abortion on demand and birth rate in Sami-speaking municipalities and a control group in Finnmark, Norway. AB - OBJECTIVES: The objective of this study was to analyze the birth and induced abortion on demand (IAD) rate among women in Sami-speaking communities and a control group in Finnmark County, Norway. METHODS: The 6 northern municipalities included in the administration area of the Sami language law (study group) were matched with a control group of 9 municipalities. Population data (numbers, sex and age) were accessed from Statistics Norway. Data on birth rate and IAD during the time period 1999-2009 were derived from the Medical Birth Registry (MBR) of Norway. Data on number of women in fertile age (15-44 years) were obtained from Statistics Norway. Between 2001 and 2008, this age group was reduced by 12% (Sami) and 23% (controls), respectively. RESULTS: Finnmark County has a high IAD rate and 1 in 4 pregnancies (spontaneous abortions excluded) ended in IAD in the study and control groups. The total fertility rate per woman was 1.94 and 1.87 births, respectively. There was no difference between groups with regard to the IAD/birth ratio (P=0.94) or general fertility rate GFR (P=0.82). CONCLUSIONS: Women in the Sami-majority area and a control group in Finnmark County experienced a similar frequency of IAD and fertility rate. PMID- 23687639 TI - Conceptualizing and contextualizing food insecurity among Greenlandic children. AB - OBJECTIVE: To review the context of food insecurity in Greenlandic children, to review and compare the outcomes related to food insecurity in Greenlandic children, in other Arctic child populations and in other western societies, and to explore the measure used by the Health Behaviour in School-aged Children (HBSC) study. DESIGN: The study includes literature reviews, focus group interviews with children and analyses of data from the HBSC study. HBSC is an international cross-national school-based survey on child and adolescent health and health behaviour in the age groups 11, 13 and 15 years and performed in more than 40 countries. The item on food insecurity is "Some young people go to school or to bed hungry because there is not enough food in the home. How often does this happen to you?" (with the response options: "Always", "Often", "Sometimes", or "Never"). RESULTS: The context to food security among Inuit in Arctic regions was found to be very similar and connected to a westernization of the diet and contamination of the traditional diet. The major challenges are contamination, economic access to healthy food and socio-demographic differences in having a healthy diet. The literature on outcomes related to food insecurity in children in Western societies was reviewed and grouped based on 8 domains. Using data from the Greenlandic HBSC data from 2010, the item on food security showed negative associations on central items in all these domains. Focus group interviews with children revealed face and content validity of the HBSC item. CONCLUSION: Triangulation of the above-mentioned findings indicates that the HBSC measure of food shortage is a reliable indicator of food insecurity in Greenlandic schoolchildren. However, more research is needed, especially on explanatory and mediating factors. PMID- 23687640 TI - Application of the R0-R3 formulas using the ECToolbox software to calculate left ventricular ejection fraction in myocardial perfusion SPET and comparison with equilibrium radionuclide ventriculography. Normal cutoff values for a Chinese population. AB - The aim of this study was to compare the correlation and consistency of left ventricular ejection fraction (LVEF) obtained by ECG-gated myocardial perfusion SPET (GMPS) using the four formulas (R0-R3) in ECToolbox software and by equilibrium radionuclide ventriculography (ERNV), and determine the optimal diagnostic thresholds of the four formulas in a Chinese population. A hundred and three candidate donors (59 male and 44 female), including 38 patients with a history of myocardial infarction and 65 patients with suspected coronary heart disease, underwent both (99m)Tc-MIBI rest GMPS and technetium-99m red blood cells ((99m)Tc-RBC) ERNV within a week. The LVEF values calculated by ECToolbox R0, R1, R2 and R3 were compared with those obtained by ERNV. Using LVEF>=50% obtained by ERNV as the gold standard, the optimal diagnostic thresholds of the four formulas (R0-R3) were assessed by receiver operating characteristic (ROC) curves. Results showed that the mean LVEF value of ERNV was 54.6+/-17.5%, and the mean LVEF value of the four formulas was 64.1+/-15.7%, 56.3+/-15.1%, 69.9+/-17.9% and 56.3+/ 13.6%, respectively, showing a significantly strong correlation between the results obtained by the two methods (r>0.85, P<0.001). All mean LVEF values obtained by the four formulas were higher than the mean LVEF value obtained by ERNV, and there was very significant difference between R0 and R2 results and the ERNV result (t=12.511 and 18.652, P<0.001). Furthermore, there was significant difference between R1 and R3 results and the ERNV result (t=2.169 and 2.570, P<0.05). Using ERNV LVEF>=50% as the normal diagnostic value, the optimal diagnostic threshold of R0~R3 was 56.5%, 51.5%, 64.5% and 52.5%, respectively. There was a strong correlation between the LVEF values obtained by the four formulas in ECToolbox software and ERNV, but the numerical values of LVEF differed between the four formulas. In conclusion, A strong correlation was observed among R0, R1, R2 and R3 in the ECToolbox software when compared with ERNV and also between them for the assessment of LVEF. However, there were some differences in the numerical values of LVEF generated by the individual formulas, which must be taken into account in comparing clinical studies. PMID- 23687641 TI - A study of the time of hospital discharge of differentiated thyroid cancer patients after receiving iodine-131 for thyroid remnant ablation treatment. AB - The aim of this study was to measure the radiation exposure rate from differentiated thyroid carcinoma (DTC) patients who had received iodine-131 ((131)I) treatment, and to evaluate hospital discharge planning in relation to three different sets of regulations. We studied 100 patients, 78 females and 22 males, aged 13 to 79 years (mean 44.40+/-15.83 years) with DTC, in three Groups who were treated with 3.7, 5.5 or 7.4GBq of (131)I, respectively. The external whole-body dose rates following oral administration of (131)I were measured after each one of the first three hospitalization days. A multivariant linear analysis was performed, considering exposure rates as dependent variables to the administered dose for treatment, age, gender, regional and/or distant metastases, thyroglobulin (Tg), antibodies to Tg and thyroid remnant in the three dose groups. We found that the exposure rates after each of the three first days of hospitalization were 30, 50 and 70MUSvh-1 at 1m. All our DTC patients had an acceptable dose rate on days 2 and 3 that allowed their hospital discharge. After only 1 day of hospitalization, just 3/11 cases showed not permissible exposure rates above 70MUSvh-1. In conclusion, it is the opinion of the authors that after measuring the exposure rates, most treated, DTC patients could be discharged after only one day of hospitalization, even some of those treated with high doses of (131)I (7.4GBq). Patients, who received the higher doses of (131)I, should not be released before their individual exposure rate is measured. PMID- 23687642 TI - Towards the optimization of nuclear medicine procedures for better spatial resolution, sensitivity, scan image quality and quantitation measurements by using a new Monte Carlo model featuring PET imaging. AB - The aim of this study was to develop a Monte-Carlo model that can be used for the optimization of positron emission tomography (PET) procedures and image quality metrics. This model was developed using the Monte Carlo package of Geant4 application for tomographic emission (GATE) and the software for tomographic image reconstruction (STIR) with cluster computing to obtain reconstructed images. The PET scanner used in this study was the General Electric Discovery-ST (US). The GATE model was validated by comparing results obtained in accordance with the National Electrical Manufacturers Association NEMA-NU-2-2001 protocol [Mawlawi et al (2004) and Bettinardi et al (2004)]. All images were reconstructed with the commonly used 2D filtered back projection and the 3D reprojection algorithms. We found that the simulated spatial resolution in terms of full width at half maximum (FWHM) agreed within less than 3.29% in 2D and less than 2.51% in 3D with published data of others, respectively. The 2D values for the sensitivity, scatter fraction and count-rate were found to agree within less than 0.46%, 4.59% and 7.86%, respectively with these published values. Accordingly, our study showed that the corresponding 3D values were found to agree to less than 1.62%, 2.85% and 9.13%, respectively with Mawlawi et al (2004) published values. Sensitivity, which was also estimated without the presence of attenuation material by simulating an ideal source, showed differences between the extrapolated and the ideal source values (with and without attenuation) ranging in 2D from 0.04% to 0.82% (radial location R=0cm) and 0.52% to 0.67% in 3D mode (radial locations R=10cm). The simulated noise equivalent count rate was found to be 94.31kcps in 2D and 66.9kcps in 3D at 70 and 15kBq/mL respectively, compared to 94.08kcps in 2D and 70.88kcps in 3D at 54.6kBq/mL and 14kBq/mL respectively, from the published by others values. The simulated image quality was found in excellent agreement with these published values. In conclusion, our study showed that our Monte Carlo model can be used to assess, optimize, simplify and reduce the simulation time for the quality control procedure of PET scanners. By using this model, sensitivity can be obtained in a more simplified procedure. Reconstructed images by STIR can be also used to obtain radiopharmaceutical distribution of images and direct dose maps, quite useful to nuclear medicine practitioners. PMID- 23687643 TI - Radionuclide parathyroid imaging: a concise, updated review. AB - The hypercalcemia of hyperparathyroidism (HPT) can cause devastating effects to the patient and only surgical removal of the hyperfunctioning parathyroid tissue can definitely cure the disease. Radionuclide parathyroid imaging has no role in the diagnosis of hyperparathyroidism or in the selection of the type of treatment. However, once surgery is decided (99m)Tc-sestamibi scanning can localize abnormal parathyroid glands preoperatively. In primary HPT radionuclide assessment may occasionally be helpful before bilateral neck exploration, it can identify patients suitable for focused surgery and is a prerequisite of the minimally invasive radioguided parathyroidectomy. In secondary and tertiary HPT the clinical value of parathyroid scintigraphy remains debatable, but in persistent or recurrent disease this modality is a first line examination before reoperation. In conclusion, (99m)Tc-sestamibi assessment has a well defined clinical role in the surgical management of patients with primary hyperparathyroidism and in recurrent disease, but its usefulness in cases of secondary hyperparathyroidism is not clearly established. PMID- 23687644 TI - Hyperaccumulation of (18)F-FDG in order to differentiate solid pseudopapillary tumors from adenocarcinomas and from neuroendocrine pancreatic tumors and review of the literature. AB - Solid pseudopapillary tumors (SPT) are rare, unique pancreatic tumors with benign entity and low malignant potential. Limited information is available in the literature reporting their accumulation of fluorine-18 fluoro deoxyglucose ((18)F FDG) using positron emission tomography/computed tomography (PET/CT). The aim of this retrospective study was to define t he uptake-accumulation of (18)F-FDG PET/CT in a comparatively large cohort of SPT, and to compare their uptake with the uptake of (18)F-FDG in pancreatic ductal adenocarcinomas (PAC) and neuroendocrine tumors (PNET). Between June 2007 and January 2013, 18 pathologically proven SPT were identified from the total of patients studied by PET/CT in our Center, including 13 women and 5 men, aging from 23 to 56 years old (mean age, 38.5 years). Malignant SPT was histologically classified using the WHO criteria. Eighty-six PAC patients and 28 PNET patients were also identified and included in this study for comparison. Positron emission tomography results were considered as positive if focal accumulation of (18)F-FDG exceeded the surrounding normal pancreatic tissue. Regions of interest were drawn on the pancreatic lesions, and the maximal standardized uptake values (SUVmax values) were calculated. The mean values of SUVmax were compared with independent-samples t test or with the nonparametric Mann-Whitney U method. Correlation of SUVmax values and tumor size were analyzed in cases of SPT. Receiver operating characteristics (ROC curve) were used to study the efficiency of SUV values for the differential diagnosis between SPT versus (vs) PAC and SPT vs PNET. A value of P<0.05 was considered statistically significant. All SPT cases were (18)F-FDG PET positive, with SUVmax values ranging from 3.5-18.3. The SUVmax values of SPT had poor correlation with tumor size, and no significant difference by gender and age. Areas under the curve ROC were 0.619 and 0.526, respectively for the differentiation of SPT from PNET and PAC tumors. Five SPT tumors were malignant, and exhibited relatively low (18)F-FDG uptake (SUVmax range, 3.0-4.5) except a tumor after recurrence (SUVmax 17.7). Images of CT were of low dose and thus were not evaluated. In conclusion, our results suggest that SPT benign or malignant are consistently hyperaccumulating (18)F-FDG above SUVmax 3. Differentiation from PAC and PNET if only based on the higher SUVmax values was not possible but if based on lower SUVmax, of <=2.6 (in 14%) and <=2.5 (in 21,4%) of PAC and PNET, respectively, these pancreatic tumors could be differentiated from SPT. PMID- 23687645 TI - A rare non-small cell lung cancer (18)F-FDG PET/CT study in a young patient with genetic anomaly living in a highly polluted area. Metastatic lesions not shown by CT. PMID- 23687646 TI - Thymoma and immunodeficiency: (18)F-FDG-PET/CT imaging of Good syndrome. PMID- 23687648 TI - Real time in situ chemical characterization of sub-micron organic aerosols using Direct Analysis in Real Time mass spectrometry (DART-MS): the effect of aerosol size and volatility. AB - Direct Analysis in Real Time (DART) mass spectrometry is an atmospheric pressure ionization technique suitable for in situ chemical analysis of organic aerosols. Here, mass spectra are obtained by introducing a stream of nanometer-sized aerosols into the ionization region, which is an open space between the ion source and the atmospheric inlet of mass spectrometer. Model single component aerosols are used to show how the aerosol size and volatility influence the measured ion signals at different DART gas temperatures. The results show that for equivalent aerosol mass concentrations, the ion signal scales with particle surface area, with smaller diameter oleic acid aerosols yielding higher ion signals relative to larger diameter aerosols. For the aerosols of the same size, but different vapor pressures, the ion signal is larger for more volatile succinic acid aerosols than less volatile adipic and suberic acid particles. From the measured changes in aerosol size, produced by the DART source, the radial probing depth for these model aerosols range from 1 to 10 nm, the magnitude of which depends upon the physiochemical properties of the aerosols and DART gas temperature. An aerosol evaporation model reveals that the ion signal is correlated with changes in aerosol size and depends upon the total quantity of evaporated aerosol mass, consistent with a mechanism in which gas-phase molecules are first desorbed from the aerosol surface prior to ionization. The results of this work serve as a basis for future investigations of the mass spectra, ionization pathways, and probing depth of the aerosols using DART. PMID- 23687647 TI - Compositional sorting dynamics in coexisting lipid bilayer phases with variations in underlying e-beam formed curvature pattern. AB - Nanometer-scale curvature patterns of an underlying substrate are imposed on lipid multibilayers with each pattern imparting distinctly different sorting dynamics to a metastable pixelation pattern of coexisting liquid ordered (Lo) liquid disordered (Ld) lipid phases. Therefore, this work provides pathways toward mechanical energy-based separations for analysis of biomembrane-associate species. The central design concept of the patterned sections of the silica substrate is a square lattice pattern of 100 nm projected radius poly(methyl methacrylate) (PMMA) hemispherical features formed by electron beam lithography which pixelates the coexisting phases in order to balance membrane bending and line energy. In one variation, we surround this pattern with three PMMA walls/fences 100 nm in height which substantially slows the loss of the high line energy pixelated Lo phase by altering the balance of two competing mechanism (Ostwald ripening vs. vesiculation). In another walled variation, we form a gradient of the spacing of the 100 nm features which forces partitioning of the Lo phase toward the end of the gradient with the most open (400 nm spacing) lattice pattern where a single vesicle could grow from the Lo phase. We show that two other variations distinctly impact the dynamics, demonstrating locally slowed loss of the high line energy pixelated Lo phase and spontaneous switching of the pixel location on the unit cell, respectively. Moreover, we show that the pixelation patterns can be regenerated and sharpened by a heating and cooling cycle. We argue that localized variations in the underlying curvature pattern have rather complex consequences because of the coupling and/or competition of dynamic processes to optimize mechanical energy such as lipid diffusion, vesiculation and growth, and phase/compositional partitioning. PMID- 23687649 TI - Improving the classification accuracy for IR spectroscopic diagnosis of stomach and colon malignancy using non-linear spectral feature extraction methods. AB - Non-linear feature extraction methods, neighborhood preserving embedding (NPE) and supervised NPE (SNPE), were employed to effectively represent the IR spectral features of stomach and colon biopsy tissues for classification, and improve the classification accuracy for diagnosis of malignancy. The motivation was to utilize the NPE and SNPE's capability of capturing non-linear spectral behaviors by simultaneously preserving local relationships in order that minute spectral differences among classes would be effectively recognized. NPE and SNPE derive an optimal embedding feature such that the local neighborhood structure can be preserved in reduced spaces (variables). The IR spectra collected from stomach and colon tissues were represented by several new variables through NPE and SNPE, and also by using the principal component analysis (PCA). Then, the feature extracted variables were subsequently classified into normal, adenoma and cancer tissues by using both k-nearest neighbor (k-NN) and support vector machine (SVM), and the resulting accuracies were compared with each other. In both cases, the combination of SNPE-SVM provided the best classification performance, and the accuracy was substantially improved compared to when PCA-SVM was used. Overall results demonstrate that NPE and SNPE could be potential feature-representation strategies useful in biomedical diagnosis based on vibrational spectroscopy where effective recognition of minute spectral differences is critical. PMID- 23687650 TI - Sensitive and high resolution subcutaneous fluorescence in vivo imaging using upconversion nanoparticles and microarrays. AB - A sensitive and high resolution small animal in vivo imaging system using upconversion nanoparticles (UNPs) and microarrays was developed. The fluorescence tomography using UNPs could achieve higher precision than that using ordinary fluorophores, which was theoretically explained by the finite element method (FEM). Given the autofluorescence-insensitive property of UNPs, a high subcutaneous detection sensitivity of 0.93 * 10(-4) wt% could be achieved with a UNP volume of ~10 MUL in tissue phantoms. Furthermore, UNP fluorophore microarrays (25, 50 and 100 MUm arrays) embedded under mouse skin were prepared for subcutaneous in vivo detection. An optical clearing method was applied to enhance the skin transparency and improve the spatial resolution. The results demonstrated that the optimized system could achieve a spatial resolution of 50 MUm for in vivo detection of subcutaneous UNP microarrays. Taken together, we conclude that the proposed system and UNP microarrays could achieve sensitive, high resolution subcutaneous in vivo detection, and have great potential for high throughput detection of tumors and other diseases. PMID- 23687651 TI - Preparation of copper oxide anchored on surfactant-functionalized macroporous carbon composite and its electrochemical applications. AB - Copper oxide nanoparticles were anchored on sodium dodecyl sulphate (SDS) functionalized macroporous carbon by utilizing the supramolecular self-assembly of SDS acting as a soft template. The as-prepared composite provides new features of electrocatalytic activities and may hold great promise for the design of environmental sensors. PMID- 23687652 TI - Retention modeling in combined pH/organic solvent gradient reversed-phase HPLC. AB - An approach for retention modeling of double pH/organic solvent gradient data easily generated by automatically mixing two mobile phases with different pH and organic content according to a linear pump program is proposed. This approach is based on retention models arising from the evaluation of the retention data of a set of 17 OPA derivatives of amino acids obtained in 27 combined pH/organic solvent gradient runs performed between fixed initial pH/organic modifier values but different final ones and for different gradient duration. The derived general model is a ninth parameter equation easily manageable through a linear least squares fitting but it requires eighteen initial pH/organic modifier gradient experiments for a satisfactory retention prediction in various double gradients of the same kind with those used in the fitting procedure. Two simplified versions of the general model, which were parameterized based on six only initial pH/organic modifier gradients, were also proposed, when one of the final double gradient conditions, pH or organic content was kept constant. The full and the simplified models allowed us to predict the experimental retention data in simultaneous pH/organic solvent double gradient mode very satisfactorily without the solution of the fundamental equation of gradient elution. PMID- 23687653 TI - Grid-double-helicate interconversion. AB - An interconversion between a binuclear Cu(I) double helicate and a tetranuclear Cu(II) grid is reported. The passage from the Cu(I) double helicate to the Cu(II) grid occurs through oxidation of Cu(I) into Cu(II) or through displacement of Cu(I) by Cu(II). The conversion of the Cu(II) grid into the Cu(I) double helicate occurs through treatment of the grid with triflic acid, reduction of Cu(II) with ascorbic acid, and neutralization with triethylamine. During the studies, in order to ascertain the structure of Cu(I) complexes, a heteroleptic binuclear Cu(I) double helicate was generated. PMID- 23687654 TI - Two novel innovanoside dimers from Daphne aurantiaca and a concise total synthesis of diinnovanoside A. AB - Chemical examination of the methanolic extract from the stem bark of Daphne aurantiaca led to the isolation of two innovanoside dimers (1 and 2) with an unusual four-membered cyclobutane ring, together with the isoinnovanoside 3. Their chemical structures and configurations were elucidated by extensive spectral analysis and synthesis. PMID- 23687655 TI - A rare example of a porous Ca-MOF for the controlled release of biologically active NO. AB - A 1D-microporous 3D calcium tetracarboxylate MOF has been solvothermally prepared and its structure solved from single crystal data. It exhibits coordinatively unsaturated Ca(2+) Lewis acid sites able to trap and deliver nitric oxide at a biological level. PMID- 23687656 TI - Thioflavin-T excimer formation upon interaction with amyloid fibers. AB - The molecular mechanism of the Thioflavin-T (Th-T) binding to amyloids remains unknown. By combining experimental analysis of Th-T excitation and emission spectra with theoretical calculations we suggest that Th-T fluorescence changes upon interaction with amyloids may arise from the formation of an excimer with an oblique angle of ~120 degrees. PMID- 23687658 TI - Rape in South Africa - a call to action. PMID- 23687659 TI - A labour of love: 'no schools for medical editors'. PMID- 23687657 TI - NanoSIMS multi-element imaging reveals internalisation and nucleolar targeting for a highly-charged polynuclear platinum compound. AB - Simultaneous multi-element imaging using NanoSIMS (nano-scale secondary ion mass spectrometry), exploiting the novel combination of (195)Pt and (15)N in platinum am(m)ine antitumour drugs, provides information on the internalisation and subcellular localisation of both metal and ligands, and allows identification of ligand exchange. PMID- 23687660 TI - Western Cape academic hospitals. PMID- 23687662 TI - Improving causal inference. PMID- 23687661 TI - Commentary. PMID- 23687663 TI - Letter from Dr. Latta to the Secretary of the Central Board of Health, London, affording a view of the rationale and results of his practice in the treatment of cholera by aqueous and saline injections. 1832. PMID- 23687665 TI - What is an epidemiologist? PMID- 23687664 TI - Expression of concern from journal editor. PMID- 23687667 TI - Bridging the data gap. Reporting of health IT events is improving--gradually. PMID- 23687666 TI - [Diseases caused by human papillomavirus -- the possibilities and the public health advantages of prevention]. PMID- 23687668 TI - Feeding time. A buying guide for replacing Abbott enteral feeding pumps. PMID- 23687669 TI - Forced-air warming and surgical site infections. Our review finds insufficient evidence to support changes in current practice. PMID- 23687670 TI - Getting the message. Results of our survey on cell phone/smartphone policies. PMID- 23687672 TI - Most smartphone apps for melanoma detection are inaccurate. PMID- 23687671 TI - Safety risks of electronic health records. PMID- 23687673 TI - On pens and needles--delivering insulin safety. PMID- 23687674 TI - High-intensity focused ultrasound effective on submucosal fibroids. PMID- 23687675 TI - Balancing radiation dose and contrast dose may reduce age-specific risk in abdominal CT. PMID- 23687676 TI - Bunnell Life Pulse high-frequency ventilator heated wire breathing circuit may overheat and melt. PMID- 23687677 TI - Philips M4841a telemetry transmitters may experience short circuit and overheat if battery compartment tab breaks. PMID- 23687678 TI - The growing problem of ultrasound equipment interference. PMID- 23687679 TI - Reprogramming infusion time remaining on pumps during use may lead to medication errors. PMID- 23687680 TI - Newer study shows smoking cessation aid is safe. PMID- 23687681 TI - [Analysis of the sentence by the Supreme Court of Argentina decriminalizing abortion]. PMID- 23687682 TI - [Not Available]. PMID- 23687683 TI - [Not Available]. PMID- 23687684 TI - [The pediatrician facing childhood nowadays]. PMID- 23687685 TI - [Management of indwelling catheters in patients on home parenteral nutrition]. PMID- 23687686 TI - [Careful with "natural" therapy--the liver may suffer]. PMID- 23687687 TI - Final priority; National Institute on Disability and Rehabilitation Research- Disability and Rehabilitation Research Projects and Centers Program- Rehabilitation Research Training Centers. Final priority. AB - The Assistant Secretary for Special Education and Rehabilitative Services announces a priority for a Rehabilitation Research Training Center (RRTC) on Disability Statistics and Demographics under the Disability and Rehabilitation Research Projects and Centers program administered by the National Institute on Disability and Rehabilitation Research (NIDRR). The Assistant Secretary may use this priority for a competition in fiscal year (FY) 2013 and later years. We take this action to focus research attention on areas of national need. We intend to use this priority to improve outcomes for individuals with disabilities. PMID- 23687688 TI - Final Priority; National Institute on Disability and Rehabilitation Research- Rehabilitation Research and Training Centers. Final priority. AB - The Assistant Secretary for Special Education and Rehabilitative Services announces a priority for the Disability and Rehabilitation Research Projects and Centers Program administered by the National Institute on Disability and Rehabilitation Research (NIDRR). Specifically, we announce a priority for a Rehabilitation Research and Training Center (RRTC) on Community Living and Participation for Individuals with Psychiatric Disabilities. The Assistant Secretary may use this priority for competitions in fiscal year (FY) 2013 and later years. We take this action to focus research attention on areas of national need. We intend this priority to improve outcomes among individuals with disabilities. PMID- 23687689 TI - Final priority; technical assistance to improve state data capacity--National Technical Assistance Center to improve state capacity to accurately collect and report IDEA data. Final priority. AB - The Assistant Secretary for Special Education and Rehabilitative Services announces a priority under the Technical Assistance to Improve State Data Capacity program. The Assistant Secretary may use this priority for competitions in fiscal year (FY) 2013 and later years. We take this action to focus attention on an identified national need to provide technical assistance (TA) to States to improve their capacity to meet the data collection and reporting requirements of the Individuals with Disabilities Education Act (IDEA). We intend this priority to establish a TA center to improve State capacity to accurately collect and report IDEA data (Data Center). PMID- 23687690 TI - Phenolic constituents from Alchemilla vulgaris L. and Alchemilla mollis (Buser) Rothm. at different dates of harvest. AB - Acetone/water extracts from the leaves, including stalks, of Alchemilla vulgaris L. and A. mollis (Buser) Rothm. were investigated for their phenolic composition by liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 24 and 27 compounds were detected for A. vulgaris and A. mollis, respectively. Pedunculagin and agrimoniin, as described in earlier reports for A. vulgaris, as well as other monomeric and oligomeric ellagitannins such as sanguiin H-10, castalagin/vescalagin, and galloyl-bis-hexahydroxydiphenoyl (HHDP) hexose constituted the major phenolic fraction of both plant species. Also, gallic and chlorogenic acids were found in both extracts. Interestingly, catechin and a procyanidin trimer were detected only in A. mollis. The flavonoid fraction comprised quercetin glucuronide as major compound in addition to several other quercetin glycosides. Most interestingly, a tentatively identified kaempferol glucuronide and a methylated quercetin glucuronide were exclusively found in A. mollis. Finally, the overall phenolic fingerprints of both Alchemilla species, harvested in May and August, i.e. at the beginning and the end of the flowering period, were compared. A general accumulation of phenolic constituents was observed later in the year, especially with regard to the ellagitannins. PMID- 23687691 TI - Steps must be double checked. PMID- 23687692 TI - The author responds. PMID- 23687693 TI - Preterm birth risk diagnostic test to be given boost by partnership between Agilent Technologies and Sera Prognostics. PMID- 23687694 TI - Gold nanoparticle-based diagnostic test for rapid diagnosis of leading infectious diseases. PMID- 23687695 TI - The potential of next-generation genome sequencing in analyzing tuberculosis outbreaks. PMID- 23687698 TI - [How to carry out the translational medicine research effectively in gastrointestinal tumors]. AB - As a new concept, the definition of translational medicine remains obscure. The translational medicine connects the bench to bedside, and its importance would be more remarkable. The development of gastrointestinal surgery reflects the idea of translational medicine. To carry out the translational study, the gastrointestinal surgeon must learn how to find subjects from clinical problems, how to collect complete information and tissues, how to collect complete information and tissues, how to collaborate with others from different fields and how to utilize all kinds of resources. By translational studies, gastrointestinal surgeons may further improve the survival of patients with gastrointestinal tumor. PMID- 23687699 TI - [24-hour blood pressure monitoring]. PMID- 23687700 TI - [Is there any benefit in natriuretic peptide levels determination in patients without apparent heart failure?]. PMID- 23687701 TI - [Invasive aspergillosis: time for optimism?]. PMID- 23687702 TI - [Is dyslipidemia a risk factor in patients treated with antiretroviral drugs?]. PMID- 23687703 TI - [Blood vessel reconstruction infections]. PMID- 23687704 TI - [Monitoring of anti-tumour cell-mediated response in patients with renal cell carcinoma, disturbance of T cell proliferation]. AB - INTRODUCTION: When checking tumour growth, a number of observations indicate that the immune system plays a significant role in patients with renal cell carcinoma (,,RCC"). Infiltration by lymphocytes (tumour infiltrating lymphocytes, "TILs") is more prevalent in RCC than any other tumours. T lymphocytes are the dominant population of TIL cells. Views concerning the role ofT lymphocytic subpopulations, B lymphocytes and NK cells in an anti-tumour response are not established. AIM: The aim is to determine the phenotype and activation of lymphocytic cells and to compare their representation in tumour stroma (TIL), peripheral blood (PBL) and renal vein blood in patients with RCC. PATIENTS AND METHODS: The samples of peripheral blood taken from the cubital and renal veins and tumour stroma cells were obtained from 60 patients in the course of their surgeries carried out due to primary RCC. TILs were isolated from mechanically disintegrated tumour tissue. Immunophenotype multiparametric analysis of PBL and TILs was carried out. Their surface and activation characteristics were determined by means of flow cytometer. RESULTS: CD3+ T lymphocytes (70.4%) were the main population of TILs. The number of CD3+/CD8+ T lymphocytes was significantly higher in TILs, 39.7% (p < 0.01), while CD4+ T lymphocytes were the majority population in peripheral blood, 41.35% (p < 0.001). The representation of CD3+/69+ T lymphocytes was significantly higher in TILs, 32.05%, compared to PBL (p < 0.001). On the contrary, the numbers of CD3+/CD25+, CD8+/57+ and CD4+/RA+ (naive CD4+ T lymphocytes) were higher in PBL (p < 0.001). The differences in representation of (CD3+/16+ 56+) NK cells and CD3+/DR+ T cells in TILs and PBL were not significant. CONCLUSION: The above-mentioned results prove that the characteristics and intensity of anti-tumour responses are different in compared compartments (tumour/PBL). CD3+/CD8+ T lymphocytes are the dominant lymphocytic population of TILs. The knowledge of phenotype and functions ofeffector cells, which are responsible for anti-tumour response, are the basic precondition for understanding the anti-tumour immune response and the cause of its failure. PMID- 23687705 TI - [Definition of 24 hour ambulatory blood pressure values corresponding to office blood pressure values of 130/80 mm Hg]. AB - BACKGROUND: Ambulatory blood pressure monitoring (ABPM) provides a profile of blood pressure (BP) away from the medical environment and has been shown to be a stronger predictor of cardiovascular morbidity and mortality than office BP measurement. There are known the normal BP values for ABPM in general population with office BP value 140/90 mm Hg, but don't are known normal values for ABPM of patients with high risk hypertension which needs to have office BP below 130/80 mm Hg. AIM OF STUDY: Definition of normal BP value of ABPM in patients with office BP130 and/or 80 mm Hg. METHODS: BP measurement in 241 healthy subjects by ABPM and mercury sphygmomanometer according to European Hypertension Society criteria. Subject selection with following criteria: mean office systolic blood pressure 128-132 mm Hg or diastolic blood pressure 78-82 mm Hg. Exclusion ABPM curves with white-coat hypertension and masked hypertension. All office and ABPM inclusion criteria fulfill 37 subjects for systolic blood pressure, mean age 44 years and 48 subjects for diastolic blood pressure, mean age 45 years. RESULTS: Mean office systolic BP 129.9 +/- 1.6 mm Hg, diastolic BP 80.2 +/- 1.5 mm Hg. Mean 24hour systolic BP 119.1 +/- 12.3 (95% CI, 119.0-119.3) mm Hg, diastolic BP 71.4 +/- 10.2 (95% CI, 71.3-71.5) mm Hg, day time systolic BP 123.7 +/- 9.0 (95% CI, 123.6-123.8) mm Hg, diastolic BP 75.4 +/- 7.0 (95% CI, 75.3-75.5) mm Hg, night time systolic BP 105.8 +/- 10.4 (95% CI, 105.7-105.9) mm Hg and diastolic BP 59.8 +/- 9.0 (95% CI, 59.7-59.8) mm Hg. CONCLUSION: The normal BP value ofABPM in patients with office BP 130/80 mm Hg is for 24hour BP 119/71 mm Hg, day time BP 124/75 mm Hg and night time BP 106/60 mm Hg. PMID- 23687706 TI - [Factors related to NT-proBNP values in haemodynamically stable patients with normal systolic function of the left ventricle]. AB - INTRODUCTION: Increased values ofnatriuretic peptides are considered prognostically significant in normal population with respect to mortality and the incidence of cardiovascular events, regardless of the left ventricular function. The objective of the study is to point out the factors related to NT-proBNP values in patients without the heart failure syndrome and with normal left ventricular systolic function. METHODS: The group consisted of 290 elective patients aged between 50 and 82, with the mean age of 62 years, of whom 47% were women. The enrolled patients were heamodynamically stable, without a history of MI, with a normal left ventricular systolic function and with the serum creatinine level < 150 micromol/l. On the same day, the following procedures were performed: left heart catheterisation, NT-proBNP sampling and echocardiographic examination. Diabetes mellitus, hypertension, coronary heart disease, body mass index, age, sex, left ventricular end-diastolic pressure and aortic pulse pressure were chosen as factors with possible impact on the level of NT-proBNP. We used echo parametres to assess the size of the left ventricle, the left ventricular mass index and the presence of left ventricular diastolic function. RESULTS: The median of NT-proBNP was 110 pg/ml (min. 11; max. 1,943 pg/ml), and higher values were recorded for 116 (i.e. 40%) of the total number of patients. Based on the above-referred factors, a significant relation was demonstrated between NT-proBNP and age (p < 0.01), sex (p < .01), BMI (p = 0.03), left ventricular size (p = 0.02), left ventricular mass index (p = 0.01), and aortic pulse pressure (p < 0.01). CONCLUSION: The study has shown that the level of NT proBNP in patients does not solely depend on the haemodynamic status and left ventricular function, but is related to many other risk factors of cardiovascular mortality and morbidity. PMID- 23687707 TI - [Invasive aspergillosis in hematooncological patients: advantages and disadvantages of various diagnostic methods, treatment options and financial costs of therapy]. AB - BACKGROUND: Invasive aspergillosis (IA) is a leading invasive fungal infection in hematooncological patients. The aim of this study was to analyse the incidence, diagnostic procedures and treatment of IA in hematooncological department in large hospital in the Czech Republic. PATIENTS AND METHODS: A retrospective analysis of medical and laboratory records from patients hospitalised in our department with proven/probable IA between January 2000 and December 2006 was performed. RESULTS: 52 cases of IA in 51 patients were identified (17.3% proven IA/82.7% probable IA). Number of IA cases notably increased during study period (1 case of IA in 2000 vs 21 cases of IA in 2006) and majority of them was of nosocomial origin (61.5%). Pulmonary aspergillosis was diagnosed in 46 cases (88.5%). Patients treated for acute leukemia or undergoing allogeneic stem cell transplantation represent the group at the highest risk of IA (in total 52% of cases). Fever and signs of pulmonary involvement were the most common clinical signs of infection (presented in 92.3% and 69.2 cases respectively). Conventional diagnostic methods including autopsy were able to diagnose only 15 cases of IA (28.8%). In all other cases (71.2%) the diagnosis was done by detection of galactomannan (GM) in serum. Introduction of GM monitoring enabled erlier initiation of antifungal treatment by 4 days. Initial therapy of IA led to the treatment response (partial and complete) in 18 (34.6%) of infections--the highest percentage of response has been seen in voriconazole monotherapy group (42%) and when combination of voriconazole and caspofungin has been used (83%). Salvage therapy was initiated due to the failure of initial treatment in 21 (40.3%) of cases. Patients were treated mostly with combination ofvoriconazole and caspofungin and/or monotherapy with voriconazole has been used with treatment response 55% and 50% respectively. Introduction of new antifungal drugs together with increased number of patients with IA led to the marked increase of total costs spent on treatment of IA per year--from 11,5 thousands CZK in 2000 to 6,2 millions CZK in 2006. CONCLUSIONS: IA is the most frequent cause of infection related mortality in patients with haematological malignancies. Routine use of non-culture base methods in diagnosis of IA together with treatment using new, effective antifungals can improve prognosis of patients with this life threatening infection. PMID- 23687708 TI - [Dyslipidaemia inducted by antiretroviral agents]. AB - The clinical course of HIV/AIDS has been substantially modified by up-to date therapy in the recent years. The progress of the disorder has changed--today it is a chronic disease of many years course. Already in 1997 and 1998 it turned out that adverse metabolic changes which significantly affect the subsequent progress of the disease were produced by long-term HAART (highly active antiretroviral therapy). Gradually, more and more anthropometric, metabolic and coagulation changes are detected, closely resembling the changes seen in the metabolic syndrome, well known from cardiology and internal medicine--dyslipoproteinaemia, insulin resistance, abdominal obesity and so on. A combination of these disorders is clinically significant due to their role in the development of atherosclerosis and their, by no means negligible, involvement in the onset of ischaemic heart disease. In view of the much lower average age of HIV-positive individuals the earlier mentioned complications should be expected in much lower age categories than with HIV-negative individuals. Plasma lipid fractions (total cholesterol, triglycerides, LDL-cholesterol, HDL-cholesterol, apoA-I, apoB, LDL/HDL, apoA I/apoB) have been investigated in 69 HIV infected subjects and the changes of these parameteres in the course of progression of HIV/AIDS due to cumulative time of exposure to HAART were explored. Significant increase of the level of proatherogenic plasma lipid fractions with tendency to develop at time course was found. These disturbances are observed in the course of very good immunological stabilization and viral suppression. No unambiguous data and results of long term studies are available, that would confirm the increase of cardiovascular risk in HIV infected subjects. Nevertheless, this increase is required and anticipated. PMID- 23687709 TI - [Blood vessel reconstruction infections: a practical view]. AB - Infection represents a serious complication in vascular surgery. The average of 2 3% of reconstructions are involved. The article offers a review of current diagnosis and treatment of infection after vascular reconstruction. Emphasis is put on early diagnosis and its impact on prognosis of patients. We summarize the practical potential of surgical treatment. The situation is illustrated by our results from the years 2004-2006. During the last 3 years 19 patients were operated on for infection of the arterial reconstruction (15 ways aorto-femoral and 4 ways femoro-popliteal bypass). The main agent was Staphylococcus aureus (9 patients, i.e. 47.4%). In most cases explantation of the whole infected reconstruction was performed (13 patients). The early mortality rate is 26.3%. Amputation was necessary in 6 patients (i.e. 31.5%). Our results are fully comparable to those from other centres of vascular surgery. PMID- 23687710 TI - [Current use of magnetic resonance imaging in cardiology]. AB - Magnetic resonance imaging is a modern imaging technique that is characterized by high resolution and variable tomographic slices. The development of magnetic resonance technology in last decade led to the expansion of this method in many fields of medicine. In cardiology, the imaging is focused on the heart, aorta, pulmonary, coronary and renal arteries. Dynamic imaging is used for the evaluation of the kinetics and the function of the ventricles. Static imaging serves for the assessment of the myocardial wall in patients with cardiomyopathies and coronary artery disease. The quality of static imaging can improve paramagnetic contrast agent that increasingly accumulates in areas of acute necrosis, fibrosis or infiltration of the myocardium. Magnetic resonance imaging can also diagnose intracardiac tumors and thrombi, valvular heart disease and pericardial disorders. Despite of wide spectrum of diagnostic applications, the clinical use of magnetic resonance imaging is reduced by limited availability and high cost of the examination. PMID- 23687711 TI - [Importance of the endocannabinoid system in the regulation of energy homeostasis]. AB - The endocannabinoid system is an endogenous signaling system that plays a role in the regulation of energy homeostasis and lipid and glucose metabolism-all of which can influence cardiometabolic risk. The endocannabinoid system appears to be a promising novel mechanistic pathway that modulates important aspects afcardiovascular and metabolic function. The endocannabinoid system is normally a silent physiologic system that becomes transiently activated, that is, only when needed. Evidence suggests that the endocannabinoid system is tonically overactive in human obesity and in animal models of genetic and diet-induced obesity. However, there is evidence in studies that the ECS is tonically overactivated in obesity, although it remains unclear whether overactivation of the ECS precedes or is consequent to expression of the obese phenotype. Rimonabant, a selective cannabinoid-1 receptor (CB1) blocker, has been shown to reduce smoking, body weight and improve and improves the profile of several metabolic risk factors in high-risk patients. PMID- 23687712 TI - [Peripheral arterial disease of extremities--guidelines for diagnostic and treatment]. AB - Diagnostic and therapeutic guidelines of peripheral arterial disease of extremities recommanded by five scientific societies of Slovak Medical Association (Slovak Angiological Society, Slovak Society for Vascular Surgery, Slovak Cardiologic Society, Slovak Internal Society and Slovak Radiologic Society) are discussed in this article. Peripheral arterial disease (PAO) of extremities is an important manifestation of systemic atherosclerosis The lower the ankle-brachial pressure index, the greater the risk of serious cardiovascular events (e.g. myocardial infarction, stroke). Nevertheless, patients with PAO are undertreated with regard to use of antiplatelet drugs or lipid-lowering drugs, as compared with patients with coronary artery disease. PMID- 23687713 TI - [At least 60 deaths could be avoided in this country every day!]. AB - The number of people who die every day from cardiovascular and oncological diseases in this country is by at least 60 deaths higher than in neighbouring Austria or Germany. Data from most industrialized countries clearly show that the incidence of and morbidity related to the above diseases can be reduced by timely diagnosis and modern treatment, and especially by healthy life style. This can be achieved by health education and, first of all, by creating favourable conditions facilitating healthy behaviour. It is necessary to persuade politicians and to win social support and endorsement with their assistance. PMID- 23687715 TI - The battle for the exam room... PMID- 23687714 TI - [The scintigraphic 99mTc-MAA imaging quantification of the right-to-left shunt in a patients with multiple pulmonary arteriovenous malformation and familial teleangiectasis]. AB - AIM: To present a case report about 57-years-old woman with hypoxemia, multiple pulmonary arteriovenous (AV) malformations and lips teleangiectasis where the right-to-left shunt quantification was assessed by means of whole body scintigraphy with 9mTc-labelled human macro-aggregated albumin (MAA). MATERIAL AND METHOD: A 57-years-old woman underwent X-ray and bolus enhanced lung CT for dyspnoea, hypoxemia and cyanosis. A multiple intrapulmonary arteriovenous malformations were detected. The whole-body 99mTc-MAA scintigraphy for the right to-left shunt quantification was performed. The whole-body scintigraphy in anterior and posterior view was started after intravenous application of 185 MBq 99mTc-MAA. The double-head gamma camera Infinia (General Electric Medical Systems -GE MS) with infrared body countouring and the large field of view was used. The Gamma camera was fitted with low-energy, high resolution, parallel-hole collimator. Images were evaluated by processing system Xeleris (GE MS). RESULTS: The whole-body 99mTc-MAA scintigraphy revealed significant R-L shunt and uptake of radiotracer in extrapulmonary organs (brain, kidney, spleen). The right-to left shunt ratio was 36%. The woman underwent successful percutaneous transcatheter microembolization treatment. After treatment the woman underwent the next 99mTc-MAA whole-body scintigraphy and the R-L shunt ratio decreased to 17%. CONCLUSION: The 99mTc-MAA whole-body scintigraphy assessed the right-to-left shunt ratio and improved the management of patients with multiple intrapulmonary A-V malformations. The next 99mTc-MAA scintigraphy after the percutaneous transcatheter microembolization of multiple intrapulmonary A-V malformations confirmed success of treatment. PMID- 23687716 TI - Tobacco, government, health, and money. PMID- 23687717 TI - Are soft in-soles or orthotics better than no insoles to prevent stress fractures of the lower extremity in adults? PMID- 23687718 TI - An innovative Oklahoma program to coordinate interdisciplinary and interagency services for children with special healthcare needs at a county level. AB - Children and youth with special health care needs (CYSHCN) and their families often require multiple services from multiple providers in order to meet their needs. The Sooner SUCCESS (State Unified Children's Comprehensive Exemplary Services for Special Needs), was developed based on a complex adaptive systems approach allowing local coalitions to address their unique needs. Sooner SUCCESS provides support to families and service providers at the community level including a broad range of supports from simply helping a family identify and access a service that already exists to innovatively marshaling generic resources to meet a unique need. The program uses these family support activities coupled with the Community Needs Assessment to identify local service needs encouraging community capacity building by coordinating the efforts of the health, mental health, social and education systems to identify service gaps and develop community-based strategies to fill those gaps. PMID- 23687719 TI - Good morning Professor Columbam. PMID- 23687720 TI - Five things physicians and patients should question. PMID- 23687721 TI - The role of physicians in healthcare communications reform. PMID- 23687722 TI - The key to better health care may already be in your pocket... and it's not your wallet. PMID- 23687723 TI - Dr. Brian Yeaman. PMID- 23687724 TI - Tropospheric aerosols: size-differentiated chemistry and large-scale spatial distributions. AB - Worldwide interest in atmospheric aerosols has emerged since the late 20th century as a part of concerns for air pollution and radiative forcing of the earth's climate. The use of aircraft and balloons for sampling and the use of remote sensing have dramatically expanded knowledge about tropospheric aerosols. Our survey gives an overview of contemporary tropospheric aerosol chemistry based mainly on in situ measurements. It focuses on fine particles less than 1-2.5 microm in diameter. The physical properties of particles by region and altitude are exemplified by particle size distributions, total number and volume concentration, and optical parameters such as extinction coefficient and aerosol optical depth. Particle chemical characterization is size dependent, differentiated by ubiquitous sulfate, and carbon, partially from anthropogenic activity. Large-scale particle distributions extend to intra- and intercontinental proportions involving plumes from population centers to natural disturbances such as dust storms and vegetation fires. In the marine environment, sea salt adds an important component to aerosols. Generally, aerosol components, most of whose sources are at the earth's surface, tend to dilute and decrease in concentration with height, but often show different (layered) profiles depending on meteorological conditions. Key microscopic processes include new particle formation aloft and cloud interactions, both cloud initiation and cloud evaporation. Measurement campaigns aloft are short term, giving snapshots of inherently transient phenomena in the troposphere. Nevertheless, these data, combined with long-term data at the surface and optical depth and transmission observations, yield a unique picture of global tropospheric particle chemistry. PMID- 23687725 TI - An evaluation of the robustness of the visual air quality "preference study" method. AB - In 2012, the U.S. Environmental Protection Agency (EPA) considered setting a secondary National Ambient Air Quality Standard (NAAQS) for particulate matter (PM) to maintain urban visual air quality (VAQ) above the level that EPA believes results in adverse effects on public welfare. EPA is relying on a type of survey it calls a "VAQ preference study" to determine this level. Individuals are shown photographs of the same vista under a range of different visibility conditions and asked to state whether the VAQ in each photograph is "acceptable" or "unacceptable." EPA considers the effect on public welfare to be adverse at the VAQ level that at least 50% ofrespondents deem unacceptable (the "VAQ cutpoint"). Given its central role in setting a NAAQS, the scientific validity of this method is an important question. This study tests the robustness of the VAQ preference study method by replicating the survey instrument from a prior VAQ preference study, and by applying two variants in which the only change was use of a different range of VAQ levels. Tested on split samples, these three variants produced statistically significantly different VAQ cutpoint estimates. In contrast, all three variants produced comparable results for a calibration task at the start of each survey in which respondents were asked to rate the VAQ in each photograph on a scale of 1-7 (without any opinion on the acceptability of each level). The significantly diferent estimates of VAQ cutpoints across survey variants cannot be attributed to inability on the part of respondents to discern whether they were being shown the entire range of actual visibility conditions. This suggests that VAQ preference surveys do not actually estimate individuals' enduring preferences regarding VAQ, because absolute preferences would not be influenced by the particular levels of VAQ over which their preferences are elicited. IMPLICATIONS: In setting its particulate matter secondary National Ambient Air Quality Standard for urban visibility, the U.S. Environmental Protection Agency is relying on a survey method that has people rate a range of urban visibility levels as "acceptable" or "unacceptable." A test of that survey method using split samples finds its results are not robust to variations in the range of visibility it shows to respondents. This implies that the visibility preference survey method needs more scientific evaluation before it can be assumed to be measuring individual preferences for visibility in a valid manner. PMID- 23687726 TI - A novel process utilizing mechanochemical sulfidization to remove lead from cathode ray tube funnel glass. AB - A novelprocess ofmechanochemical sulfidization for the treatment of cathode ray tube (CRT)funnel glass has been investigated by co-grinding with the element sulfur The ground samples were characterized by means of a set of analytical methods, including scanning electron microscopy (SEM), x-ray diffraction (XRD), x ray photoelectron spectroscopy (XPS), Raman spectroscopy, and thermogravimetric analysis (TG). The analytical results showed that during the co-grinding of the CRTfunnel glass with sulfur, the Si-O-Pb bond in glass and S-S bond broke and recombined into lead sulfide (PbS). The sulfidizing reaction proceeded with an increase in grinding time and the amount of the added sulfur. The sulfidizing rate increased rapidly from 16.6%for the JO-min ground sample to 96.7% for the 120-min ground sample. Using this process, current mineralprocessing technology, such as flotation separation, might be used to recover PbS. The proposed technology could also be used to treat other leaded glass and even other lead containing wastes. IMPLICATIONS: In this research, a mechanochemical sulfidization method was proposed to recover lead from waste cathode ray tube (CRT) funnel glass. CRT funnel glass was co-ground with sulfur in N2 atmosphere by mechanical milling. After milling, lead in CRT funnel glass was transferred into lead sulfide (PbS). Using this process, current nfiineral processing technology, such as flotation separation, might be used to recover PbS from the ground sample. The process can be applied to treat other leaded glass or lead containing wastes. PMID- 23687727 TI - Analysis of BTEX groundwater concentrations from surface spills associated with hydraulic fracturing operations. AB - Concerns have arisen among the public regarding the potentialfor drinking-water contamination from the migration of methane gas and hazardous chemicals associated with hydraulic fracturing and horizontal drilling. However, little attention has been paid to the potentialfor groundwater contamination resulting from surface spills from storage and production facilities at active well sites. We performed a search for publically available data regarding groundwater contamination from spills at ULS. drilling sites. The Colorado Oil and Gas Conservation Commission (COGCC) database was selected for further analysis because it was the most detailed. The majority ofspills were in Weld County, Colorado, which has the highest density of wells that used hydraulic fracturing for completion, many producing both methane gas and crude oil. We analyzed publically available data reported by operators to the COGCC regarding surface spills that impacted groundwater From July 2010 to July 2011, we noted 77 reported surface spills impacting the groundwater in Weld County, which resulted in surface spills associated with less than 0.5% of the active wells. The reported data included groundwater samples that were analyzed for benzene, toluene, ethylbenzene, andxylene (BTEX) components of crude oil. For groundwater samples taken both within the spill excavation area and on the first reported date of sampling, the BTEX measurements exceeded National Drinking Water maximum contaminant levels (MCLs) in 90, 30, 12, and 8% of the samples, respectively. However, actions taken to remediate the spills were effective at reducing BJTEX levels, with at least 84% of the spills reportedly achieving remediation as of May 2012. Our analysis demonstrates that surface spills are an important route of potential groundwater contamination from hydraulic fracturing activities and should be a focus of programs to protect groundwater IMPLICATIONS: While benzene can occur naturally in groundwater sources, spills and migration of chemicals used for hydraulic fracturing activities have recently been thought to be a main source of benzene contamination in groundwater. However, there is little scientific literature to support that claim. Therefore, we accessed a publically available database and tracked the number of reported surface spills with potential groundwater impact over a 1-year period. Although the number of surface spills was minimal, our analysis provides scientific evidence that benzene can contaminate groundwater sources following surface spills at active well sites. PMID- 23687728 TI - Analysis of the major factors affecting the visibility degradation in two stations. AB - There are four types of PM10 (particulate matter with an aerodynamic diameter <10 microm) episodes that occur frequently in central Taiwan: long-range transport with dust storms (DS), long-range transport with frontal pollution (FP), river dust (RD), and stagnant weather (SW). During the periods of the four episodes, poor visibility usually results. Multiple linear regression was applied to visibility using eight potential influential variables (temperature, relative humidity, wind speed, PM2.5, PM2.5-10, SO2, NO2, and NO) as independent variables. Of the eight variables, PM2.5 showed the greatest explainable percentage of about 48.6% and 58.1% for Taichung and Wuchi stations, respectively. This suggested that PM2.5 was the most important contributor to reduced visibility. Compared with other type of episodes, the aerosols tended to be offine size during the SWepisodes. This is the main reason that the poorest visibility occurred during the SWepisodes. Good correlation between visibility and secondary inorganic salts (NH4+, NO3, and SO4(2-)) were found at Taichung station (r = 0.71) and Wuchi station (r = 0.81), suggesting that secondary inorganic salts did contribute significantly to the degradation ofvisibility. The visibility degradation due to the effects ofNO3- was much higher than that due to SO4(2-) and NH4+ in the urban area, whereas the visibility degradation due to the effects of NO3 , SO42-, and NH4+ did not show significant diference in the rural area. IMPLICATIONS: Of the eight potential influential variables, PM2.5 showed the greatest effects on reduced visibility. Compared with other type of episodes, the aerosols tend to be fine size during the episodes of stagnant weather. This is the main reason why the poorest visibility occurred during the SW episodes. Good correlations between visibility and secondary inorganic salts (NH4+, NO3-, and SO4(2-)) suggested that secondary inorganic salts did contribute significantly to the degradation of visibility. Among the three inorganic salts, nitrates played a leading role for visibility degradation in urban areas in central Taiwan. PMID- 23687729 TI - Assessment of frequent litter amendment application on ammonia emission from broilers operations. AB - Litter amendments have been used to control the ammonia (NH3) emission from the broiler litter during the brooding period. One of the commercially available litter amendments, sodium bisulfate, was frequently applied on the litter with two different rates on weekly basis in a laboratory setup and with a single rate on biweekly basis under field conditions. Repeated application ofsodium bisulfate led to significant reduction in NH3 emissions from broilers. The magnitude of NH3 emission reduction increases with the application rate of sodium bisulfate. The reduction rates of cumulative emissions with 366 g/wk-m2 (75 lb/wk-1000 ft) rate (from 14% to 64.5%) were higher than the reduction rate of 183 g/wk-m2 (37.5 lb/wk-1000 ft2) rate (from 0% to 55%) from 28 to 61 days of age. The cumulative NH3 emission was reduced by 51.7% with 244 g/2 wk-m2 (50 lb/2 wk-1000 ft2) rate over a three-flockperiod (8-wk average grow-out per flock) under field production conditions. Sodium bisulfate application showed no significant difference on body weight and feed conversion efficiency. However, footpad quality was significantly improved by sodium bisulfate application. Litter pH and ammonia nitrogen level of the litter were decreased by sodium bisulfate application with both rates. Organic and total nitrogen contents in the litter were higher, whereas less nitrogen was emitted as NH3. The laboratory-scale findings of emission reduction by the additives should be considered to be preliminary if the additives are to be applied under commercial production settings. IMPLICATIONS: This work demonstrated that frequent litter amendment application can be used to reduce NH3 emissions from broiler houses, with no adverse effect on the animal production performances. The NH3 reduction rates could vary with different application frequencies and rates. Using litter amendment during broiler grow-out to lower NH3 emissions should be applicable to boiler production systems. The results of this study also contribute to the baseline data for improving the national air emissions inventory for livestock and poultry production facilities. PMID- 23687730 TI - Assessment of penetration through vacuum cleaners and recommendation of wet cyclone technology. AB - In many commercial vacuum cleaners, the captured aerosol particles contained in the dust collector may accidentally release from the exhaust filtration owing to leakage or penetration. Vacuum cleaners may cause dust to become airborne by exhausting air that is not completely filtered. This may cause the operator to inhale dust, in turn causing health problems. This study aimed to investigate the dust penetration rates from three commercial vacuum cleaners and suggest the best technique for completely filtering exhaust air using a combination of cyclonic separation and water filtration. The commercial vacuum cleaners were tested inside a custom-built hood, and the exhausted particles were monitored using a sampling probe in conjunction with an aerosol particle sizer Quartzose mineral dusts were added to each vacuum cleaner through the dust transport line. A 2400 L/min wet cyclone was employed as the proposed vacuum cleaner It was designed using Stokes scaling, and its collection characteristics were evaluated using polystyrene latex beads. Surprisingly, the conventional vacuum cleaners failed to capture an overall average of approximately 14% of the particles in the given size range. However, only approximately 3.8% of the collected particles escaped from the vacuum cleaner that used the wet cyclone technology. Thus, the proposed vacuum cleaner should potentially be an effective method for vacuuming household dust. IMPLICATIONS: The successful investigation of conventional vacuum cleaners is useful for both manufacturers and users. As an effective vacuum cleaning mechanism, household dust is able to migrate along the thin water, film that forms on the inner walls of the cyclone vacuum cleaner. It collects dust in a small water inflow (3 mL/min), which allows it to capture a higher percentage of contaminants than most of the currently available vacuum cleaners. The significantly low accidental exposure rates achieved by this new vacuum cleaner enable healthy conditions in various environments, including indoors. PMID- 23687731 TI - Startup and long-term performance of biotrickling filters packed with polyurethane foam and poplar wood chips treating a mixture of ethylmercaptan, H2S, and NH3. AB - Treatment of a mixture of NH3, H2S, and ethylmercaptan (EM) was investigated for more than 15 months in two biotrickling filters packed with poplar wood chips and polyurethane foam. Inlet loads ranging from 5 to 10 g N-NH3 m-3 hr-1, from 5 to 16 g S-H2S m-3 hr-1, and from 0 to 5 g EM m-3 hr-1 were applied. During startup, the biotrickling filter packed with polyurethane foam was re-inoculated due to reduced biomass retention as well as a stronger effect of nitrogen compounds inhibition compared with the biotrickling filter packed with poplar wood. Accurate pH control between 7 and 7.5 favored pollutants abatement. In the long run, complete NH3 removal in the gas phase was achieved in both reactors, while H2S removal efficiencies exceeded 90%. EM abatement was significantly different in both reactors. A systematically lower elimination capacity was found in the polyurethane foam bioreactor. N fractions in the liquid phase proved that high nitrification rates were reached throughout steady-state operation in both bioreactors. CO2 production showed the extent of the organic packing material degradation, which allowed estimating its service lifetime in around 2 years. In the long run, the bioreactor packed with the organic packing material had a lower stability. However, an economic analysis indicated that poplar wood chips are a competitive alternative to inorganic packing materials in biotrickling filters. IMPLICATIONS: We provide new insights in the use of organic packing materials in biotrickling filters for the treatment of H2S, NH3, and mercaptans and compare them with polyurethane foam, a packing commonly used in biotrickling filters. We found interesting features related with the startup of the reactors and parameterized both the performance under steady-state conditions and the influence of the gas contact time. We provide relevant conclusions in the profitability of organic packing materials under a biotrickling filter configuration, which is infrequent but proven reliable from our research results. The report is useful to designers and users of this technology. PMID- 23687732 TI - Adaptation of urine source separation in tropical cities: Process optimization and odor mitigation. AB - Source-separating urine from other domestic wastewaters promotes a more sustainable municipal wastewater treatment system. This study investigated the feasibility and potential issues of applying a urine source-separation system in tropical urban settings. The results showed that source-separated urine underwent rapid urea-hydrolysis (ureolysis) at temperatures between 34-40 degrees C, stale/fresh urine ratios greater than 40%, and/or with slight fecal cross contamination. Undiluted (or low-diluted) urine favored ureolysis; this can be monitored by measuring conductivity as a reliable and efficient indicator The optimized parameters demonstrated that an effective urine source-separation system is achievable in tropical urban areas. On the other hand, the initial release of CO2 and NH3 led to an elevated pressure in the headspace of the collection reservoir, which then dropped to a negative value, primarily due to oxygen depletion by the microbial activity in the gradually alkalized urine. Another potential odor source during the ureolysis process was derived from the high production of volatile fatty acids (VFA), which were mainly acetic, propanoic, and butyric acids. Health concerns related to odor issues might limit the application of source separation systems in urban areas; it is therefore vital to systematically monitor and control the odor emissions from a source separation system. As such, an enhanced ureolysis process can attenuate the odor emissions. IMPLICATIONS: Urine source separation is promising to improve the management of domestic wastewater in a more sustainable way. The work demonstrates the achievability of an effective urine source-separation system in tropical urban areas. The installation of urine-stabilization tanks beneath high rise buildings lowers the risk of pipe clogging. Conductivity measurement can be utilized as a reliable process indicator for an automated system. However, urine hydrolysis raises a strong potential of odor emission (both inorganic and organic), which might limit the application of source separation systems in urban areas. An enhanced ureolysis process could shorten and attenuate the odor emissions. PMID- 23687733 TI - Investigation of roadside fine particulate matter concentration surrounding major arterials in five Southern Californian cities. AB - The built environment surrounding arterials affects the dispersion of vehicular emissions in urban areas, modifying the potential risks to public health. In order to study the influence of urban morphometry on flow and dispersion of vehicular fine particulate matter emissions, in the summer of 2008 field measurements were performed in major arterials located in five Southern Californian cities with different building geometries. In each city, local mean wind, turbulence, virtual temperature, roadside DustTrak Fine Particles (DTFP) concentration, and traffic flow data were collected in 2-hr measurement periods during morning and evening rush hours and lighter midday traffic, over a period of 3 days. The calculated Monin-Obukhov length, L, suggests that near-neutral and slightly unstable conditions were present at both street and roof levels. The nondimensional forms of turbulent wind and temperature fluctuations show,that the data at street level within the urban canopy can be represented using the Monin Obukhov similarity theory. Generalized additive models were applied to analyze the impact of meteorological and traffic-related variables on fine particle concentrations at street level Compared to other variables, urban-scale background concentrations were the most important variables in all five models. The results confirmed that turbulent mixing in urban areas dominated the variation of roadside particle concentrations regardless of urban geometry. The distance from the local sites to the nearby monitoring stations affected model performance when urban-scale concentrations were used to predict middle-scale concentrations by generalized additive models (GAMs). A radius ofinfluence for background concentrations was 6-10 km. There were also relationships between concentration and other variables affecting the local components of the concentrations, such as wind direction, sensible heat flux, and vertical wind fluctuation, although the influences were much weaker Implications: The built environment surrounding major arterials affects the dispersion of vehicular emissions in urban areas, modifying the potential risks to public health. Dispersion of pollutants within the urban canopy is governed by flow and turbulence characteristics caused by building morphometry. Current dispersion models used for regulatory purposes have difficulties simulating the flow and dispersion for complex building cases, especially when fine resolution is needed. Urban planning strategies, such as limitation of building height, pedestrian friendly community design, or zoning of building structures, modify concentrations of vehicular emissions in built environments surrounding major arterials, which may modify health risks for adjacent communities. PMID- 23687734 TI - EMR use in the ED: scant data connect EMRs with positive outcomes, but experts advise managers, providers to consider long-term benefits. AB - A Minnesota study looking into the impact of EMRs on the care of heart failure patients presenting to the ED found mixed results, with two of the sites studied showing small but statistically significant positive benefits, and one site showing little difference between the outcomes of patients who had EMR data vs. patients who presented for care with no EMR data. However, experts predict EMR functionality and usability will gradually improve, and they advise providers to take steps to ensure that EMRs don't interfere with patient-provider communications. In the study looking at the care of HF patients in the ED, data from two of the sites showed that patients with EMRs were less likely to die if hospitalized, they underwent fewer laboratory tests, and they were prescribed fewer medicines during their ED visit than HF patients without EMRs. In a third study site, patients with EMRs were associated with longer LOS in the ED. Experts acknowledge that when used inappropriately, EMRs can be distracting, and they can inhibit patient-provider communications. They advise ED providers and managers to take steps to ensure that EMRs enhance rather than diminish human interactions. The need for EDs to have effective health information exchange is underscored by a new Indiana study showing that people tend to seek emergency care at multiple sites over time. PMID- 23687735 TI - A better prediction model for patient surges from influenza? New Internet-based tool shows promise, say researchers. AB - In a study focused on Baltimore, MD, researchers have found that data culled from Google Flu Trends, a free Internet-based influenza surveillance system, shows strong correlation with hikes in ED visits from patients with flu-like symptoms. While the approach has yet to be validated in other cities or regions, experts recommend that ED administrators and providers familiarize themselves with the new surveillance tool and stay abreast of developments regarding similar surveillance mechanisms. Google Flu Trends (www.google.org/flutrends/) is a free Internet-based tool that monitors Internet-based searches for flu information. Users can customize their search by location (city, state, country). Researchers say the advantage of this approach over traditional surveillance methods is that it provides real-time data about flu-related activity in a city or region. Traditional approaches, which rely on case reports from the Centers for Disease Control and Prevention, are delayed. Researchers hope to eventually leverage this tool, and perhaps other surveillance data, into a powerful early-warning mechanism that EDs can use to better plan for patient surges due to influenza. PMID- 23687736 TI - Telemedicine helps rural EDs access critical neurology expertise for stroke patients. AB - Some rural hospitals that lack access to neurologists on site are obtaining this expertise through telemedicine hookups. The approach is particularly helpful in the case of patients exhibiting symptoms of stroke because time-to-treatment is critical in many of these patients, and yet determining which patients should receive clot-busting therapy can be tricky because the treatment comes with serious risks. Experts say a telemedicine program can offer dividends, but that effective implementation requires ongoing education. Since Sierra Vista Regional Health Center in Sierra Vista, AZ, began working with the TeleStroke Program at Carondelet Neurological Institute in Tucson, AZ, the time-to-treatment for stroke patients has remained under the 60-minute target urged by specialists. To gear up for such a program, ED staff need to be trained in program protocols, and technical issues need to be addressed so that neurologists at the specialty center can access CT results, as well as carry out video consultations with hospital providers and patients. Experts advise hospitals to see first-hand how other hospitals are utilizing telemedicine consultations for stroke patients before establishing a program themselves. PMID- 23687737 TI - Strengthened standards on flu vaccinations to pressure hospitals for progress. AB - Although, it is well-known that high flu vaccination rates among health care workers reduce the risk of hospital-related influenza cases, health care workers continue to resist getting vaccinated each year. Consequently, the Joint Commission has strengthened its standards on this issue for accredited hospitals, putting provisions in place that are designed to get health care worker vaccination rates up to 90% by 2020. Some hospitals are already achieving this standard by making the vaccinations free and highly accessible to employees, and by establishing firm flu vaccination policies. The Centers for Disease Control in Atlanta estimates that only 63.5% of health care workers received the flu vaccination last year, only a slight increase over the 2009-2010 flu season. In provisions set to go into effect in July, the Joint Commission expects accredited hospitals to monitor vaccination rates and regularly implement enhancements designed to reach the 90% threshold by 2020. The Emergency Nurses Association believes the focus should be on encouraging vaccinations, providing vaccinations, and education, but it opposes flu vaccination mandates. PMID- 23687738 TI - Sentinel alert sounds the alarm on worker fatigue; hospitals urged to mitigate risks. AB - Noting that there is a documented link between worker fatigue and adverse events, the Joint Commission has issued a Sentinel Alert, urging health care organizations to focus on the issue and make sure that policies and procedures are in place to mitigate risks. Experts advise hospital leaders to monitor worker shifts and make sure that people are able to leave work as scheduled when their shifts have concluded. Limit health care workers to no more than three consecutive days of 12-hour shifts, especially if these shifts are at night. Scrutinize handoff procedures so that worker fatigue does not lead to errors during this potentially hazardous time. Make sure that distractions are at a minimum during these transitions, and that patient information is conveyed in both verbal and in written form. PMID- 23687739 TI - Documentation traps in the world of EMRs. PMID- 23687740 TI - Mortality differentials by lifetime earnings decile: implications for evaluations of proposed Social Security law changes. AB - To evaluate the distributional effects of some proposed Social Security law changes, such as an increase in Social Security's early entitlement age, retirement policy analysts typically tabulate the number of workers who fall below a predetermined threshold of hardship. Analysts using this technique often implicitly assume that the insured population falls neatly into a low-earnings poor health group and a remaining good health group. If the hardship threshold assumption is correct, there should be no difference in mortality risk between lifetime earnings deciles above a hardship threshold. This study finds that the hardship threshold model is overwhelmingly rejected in US Social Security data, a result consistent with similar studies conducted in Canada, Germany, and England. The bottom 80-95 percent of the male lifetime earnings distribution exhibits an inverse correlation with regard to mortality risk (the higher the earnings, the lower the mortality risk) at ages 63-71. PMID- 23687741 TI - Modeling behavioral responses to eliminating the retirement earnings test. AB - The retirement earnings test (RET) is an often-misunderstood aspect of the Social Security program. Proposed RET reforms meant to encourage working at older ages could also cause earlier benefit claiming. We use Modeling Income in the Near Term data to analyze the complete repeal of the earnings test for beneficiaries aged 60 or older, first assuming no behavioral responses to repeal and secondly assuming changes to benefit claiming and workforce participation behaviors. We find that beneficiaries affected by RET repeal would generally receive significantly higher benefits when they are younger than the full retirement age (FRA), and somewhat lower benefits after reaching FRA. RET repeal would not significantly change individuals' lifetime benefits and we find no significant changes in the overall poverty rate under either scenario. We find that assumed behavioral responses-particularly the benefit claiming change--have a bigger effect on lifetime benefits than the RET policy change itself. PMID- 23687742 TI - Linking youth transition support services: results from two demonstration projects. AB - Many youths with disabilities, especially those receiving or potentially eligible for Social Security benefits, need assistance as they transition into adulthood. Upon completing secondary school, they face an abrupt end to provider-initiated public entitlement services. They often lack the knowledge and support to access and link fragmented adult support services. This article presents an overview of two projects in the Social Security Administration's Youth Transition Demonstration: California's Bridges to Youth Self-Sufficiency and Mississippi's Model Youth Transition Innovation. We report key outcomes and highlight the experience of one youth in each project who successfully completed the program. PMID- 23687743 TI - Psychosocial factors and financial literacy. AB - This study uses data from the Health and Retirement Study (HRS) to analyze the psychological and social variables associated with financial literacy. The HRS is a nationally representative longitudinal survey of individuals older than age 50 and their spouses. An ordinary least squares linear regression analysis explores the relationship between financial literacy and several economic and psychosocial variables. After controlling for earnings, level of education, and other socioeconomic variables in this exploratory study, I find that financial satisfaction and religiosity are correlated with financial literacy. PMID- 23687745 TI - [Organ donation and transplantation: a fragile organization]. PMID- 23687746 TI - [Gliptines: a new fashion?]. PMID- 23687744 TI - Effects of employer-sponsored health insurance costs on Social Security taxable wages. AB - The increasing cost of employer contributions for employee health insurance reduces the share of compensation subject to the Social Security payroll tax. Rising insurance contributions can also have a more subtle effect on the Social Security tax base because they influence the distribution of money wages above and below the taxable maximum amount. This article uses the Medical Expenditure Panel Survey to analyze trends in employer health insurance contributions and the distribution of those costs up and down the wage distribution. Our analysis shows that employer health insurance contributions increased faster than overall compensation during 1996-2008, but such contributions grew only slightly faster among workers earning less than the taxable maximum than they did among those earning more. Because employer health insurance contributions represent a much higher percentage of compensation below the taxable maximum, health insurance cost trends exerted a disproportionate downward pressure on money wages below the taxable maximum. PMID- 23687747 TI - [Fabry disease]. PMID- 23687748 TI - [Which procreation in prison?]. PMID- 23687749 TI - [Soft tissue sarcomas: clinical application of molecular biology]. AB - Soft tissue sarcomas are rare and heterogeneous tumours. Histological diagnosis is often difficult because of the numerous types and subtypes reported and morphological similarities with benign lesions in certain cases. Molecular analyses performed in an appropriate clinical and histological context improve the patients' management in the case of sarcomas with simple genomic profile: the identification of a specific and objective molecular abnormality can confirm a diagnosis, rule out another one, provide prognostic information, and guide the selection of targeted therapy About 15% of sarcomas bear a specific translocation that can be identified by FISH or RT-PCR. The search for a MDM2 amplification, reflecting the presence of an amplicon in the 12q region, is a sensitive and specific tool for the diagnosis of atypical lipomatous tumors/well-differentiated liposarcomas and dedifferentiated iposarcomas. The presence and the type of KITor PDGFRA activating mutation guide the diagnosis and treatment of GIST. Certain molecular abnormalities are found in several tumour types, emphasizing the importance of integrating the results of any molecular study within the morphological and immunohistochemical context: In France, sarcoma diagnosis is structured around a reference network (RRePS) that provides every pathologist an access to these molecular analysis tools. PMID- 23687750 TI - [How to preserve female fertility before cancer treatments?]. AB - Over the past decades, major advances in diagnosis and treatment have markedly improved the rates of cure for many young adults and children cancers. As a result, the field of fertility preservation (FP) has developed to overcome the adverse effects of cancer treatments on gonadal function. The strategy of FP will depend on patient's age, the puberty status, and the time frame before the initiation of gonadotoxic treatments. Embryo or oocyte cryopreservation after controlled ovarian hyperstimulation is currently the most established technique of FP, but ovarian tissue freezing may also be offered despite it is still considered experimental. More recently, in vitro maturation (IVM) of oocyte has been proposed in the strategy of FP since it does not require ovarian stimulation and can be performed at any time of the menstrual cycle. Therefore, IVM represents an attractive approach for urgent FP or/and in patients suffering from estrogen-sensitive cancers. In addition, GnRH agonists administration during chemotherapy has also been considered as a technique of FP, with controversial results. PMID- 23687751 TI - [Schizophrenia: still an enigma, but significant progress in the management]. PMID- 23687752 TI - [Clinical schizophrenia phenotypes: categories vs dimensions]. AB - Diagnosing schizophrenia has been problematic since the earliest clinical descriptions of the disorder In absence of available biological markers for diagnosing schizophrenia, descriptive psychopathology continues to be the basis for diagnosis and treatment. However, the existence of disagreements in the concept of schizophrenia is reflected by the large number of competing diagnostic systems that have been proposed. Two main putative factors could explain variability among schizophrenia definitions: the existence of different disorders within the schizophrenia construct, and the dimensional nature of the construct that hardly can be operationalized in terms of categorical definitions. In this report, we analyse different clinical models of schizophrenia ranging from historical to present ones. It is concluded that empirical data fit better with a dimensional view of schizophrenia than with a categorical one, and given the continuous distribution of the schizophrenia-related variables, it may be arbitrary where cutpoints are made between schizophrenic and non-schizophrenic psychoses. However, categorical and dimensional representations of schizophrenia are not antagonistic but rather complementary and combining the two approaches seems to be a useful method for analyzing the heterogeneity of the disease. PMID- 23687753 TI - [Suicidality and schizophrenia]. PMID- 23687754 TI - [Epidemiology of schizophrenic disorders, genetic and environmental risk factors]. AB - Schizophrenia is a relatively common pathology with onset at adolescence or early adulthood, more frequent in men than women. By describing distribution of cases in different populations and the factors that influence this distribution, epidemiology contributes to our understanding of the disease. Several risk factors for schizophrenia have been uncovered both genetic and environmental. The environmental factors can act at individual level (obstetric complications, season of birth, urbanicity, childhood trauma, cannabis, migration) or at population/area levels (socio-economic level, social fragmentation and social capital, ethnic density, etc.). An integrative and dynamic model based on the "vulnerability-persistence-impairment" paradigm is useful in integrating the findings about the risk factors and their complex relationships. PMID- 23687755 TI - [Cannabis and schizophrenia: what risks?]. PMID- 23687756 TI - [Early detection and early intervention in first episode psychosis]. AB - The onset of schizophrenic disorders generally occurs in late adolescence/early adulthood. However, in 75% of the cases, the onset is preceded by a prodromal stage. Subjects concerned by these prodromal symptoms are defined at "high risk" for psychosis (30% of conversion to psychosis in the next year). Early detection programs aim at improving the recognition of the prodromal symptoms in order to develop appropriate early interventions that will delay or prevent conversion to psychosis or reduce the duration of untreated psychosis (DUP). Atypical antipsychotics are not recommended when psychotic symptoms are only attenuated, while they must be rapidly prescribed when a franc psychotic episode is present. Early identification of patients with schizophrenia is a general practitioners' task provided that they can rely on a supportive specialized psychiatric team. Early intervention should be based on a comprehensive assessment of the subject, in order to propose personalized care that include cognitive therapy, psycho education, and treatment of associated disorders (depression, substance abuse). The reduction of duration of untreated psychosis will also require sensibilization campaigns in the community with the hope to improve access to care and service delivery. PMID- 23687757 TI - [Expert centers schizophrenia: an innovative tool available to patients and practitioners]. PMID- 23687758 TI - [Factors associated with risk of relapse and outcome of persons with schizophrenia]. AB - Schizophrenia is characterized by heterogeneous clinical outcome. Most often, this disease has a major negative impact on the social outcome. When a symptomatic remission is obtained, the antipsychotic should be maintained at medium or long-term to prevent the occurrence of a new episode. Medication adherence is often of poor quality. It may be improved by simplifying the drug treatment and by reducing its side-effects. The implementation of educational programs for the patient and his/her family should be encouraged. Comorbity of substance use, in particular of cannabis use, is frequent and is a strong risk factor for relapse. Request for disability benefit should be rapidly considered in order to reduce the social consequences of the disease due to lack of resources. PMID- 23687759 TI - [Somatic comorbidity of schizophrenia]. PMID- 23687760 TI - [Pharmacological treatment of schizophrenia]. AB - Decades of practice in psychiatriy and hundreds of clinical trials have demonstrated the efficacy of antipsychotics on symptoms of schizophrenia. Recently, the knowledge acquired from non-interventional studies have supplemented the information needed in daily practice by raising the issue of efficiency by incorporating not only the effectiveness and safety of treatment but also its acceptability by the patient. Adherence to antipsychotic treatment has become the key issue of the prognosis. The pharmacological management of patients with an acute episode of schizophrenia requires rapid therapeutic decisions to treat a patient who is likely to be sometimes unhelpful and agitated. The choice of treatment will have a significant impact on the prevention of psychotic relapses, on the overall prognosis and on the quality of life of the patient. In many countries of the recommendations and treatment algorithms for the management of acute psychosis were distributed, considering factors specific to the patient and his environment, his mental characteristics and local care setting. PMID- 23687761 TI - [Aids and facilities available in the management of schizophrenia]. PMID- 23687762 TI - [Psychological interventions in the treatment of schizophrenia]. AB - It is clear that the solid foundation of care in schizophrenia (trust and antipsychotic medication) should be reinforced by a set of sequences of psychological care which are presented (objectives, principles and their effectiveness). Some are needed to enhance adherence to care, reduce noncompliance and offer support to relatives (psychoeducation), others aim to improve symptoms such as residual positive symptoms (CBT) or communication difficulties (social skills). The latest target cognitive deficits (neurocognition and social cognition) and improve daily and social functioning. All of these treatments can be done effectively only in a very integrated manner and in partnership with rehabilitation professionals. PMID- 23687763 TI - [Schizophrenia: research perspectives]. AB - Current data and perspectives for schizophrenia research were reviewed in this paper. Increased incidence of schizophrenia is correlated to perinatal environmental factors, recent immigration, urban life and cannabis. Determining endophenotypes seems to be a promising strategy in the field of molecular genetics. Side effects and efficacy of treatments for schizophrenia could, now, be better predicted by the use of pharmacogenetic studies. Functional neuroimaging studies have described hypoactivations of certain brain areas supporting the hypothesis of a dysfunction of inner speech during auditory and verbal hallucinations. Dopaminergic and glutamatergic systems are disturbed in schizophrenia. These data contribute to a better understanding of the disease and may help to decrease the stigma that surrounds schizophrenia. PMID- 23687764 TI - [What congenital heart diseases may cause problems in adulthood?]. AB - The number of patients with congenital heart disease exceeds now the number of children born with these defects. This is related to the "success story" of cardiac surgery and interventional catheterism. The prevalence of this new population is about 3-4 patients/1000 adults in the general population. Some of these patients have native disease, with a relatively good tolerance up until adulthood. Nevertheless, these patients are rarely completely cured, and they face problems such as threatening atrial or ventricular arrhythmias, heart failure (more often right heart failure) endocarditis or pulmonary hypertension. Patients with complex diseases are more at risk of complications. Situations "at risk" are described in this review, one of them being the loss of follow up particularly during the transition between paediatric care and adulthood. PMID- 23687765 TI - [Role of the general practitioner or primary care physician in the management of adult congenital heart disease]. AB - Congenital heart diseases are the most common inborn defect, occurring approximately 0.8% according to the last European Union count. This rate is stable for decades. Nowadays, up to 90% of children born with congenital heart diseases underwent surgical correction and reach adulthood, gratefully to the surgery and interventional cardiology advances, in conjunction to the post surgery and following cares improvement. Both of this facts results to a growing population of adults with congenital heart diseases, actually exceeding the infant population. This arising population will lead general practitioners and primary care physicians to face more often this kind of patient. The needed cares are specifics, regarding the typical evolutions of this pathologies, as well as because congenital heart diseases wil impact other pathologies or usual cares. The need of an extended knowledge of the adult patients with congenital heart diseases is clearly emerging, and should lead the whole medical corps to work in close network. PMID- 23687766 TI - [Living with congenital heart disease in adulthood]. PMID- 23687767 TI - [Atrial septal defect in the adult]. PMID- 23687768 TI - [Contraception and congenital heart disease]. AB - Contraception counselling should be an integral part of any adolescent or adult congenital heart disease program. Both the cardiovascular safety and contraceptive efficacy of each contraceptive method should be considered for each cardiac condition. The method recommended should combine acceptability to the woman with the highest efficacy and safety profile. Agent with low dose estrogen combined with varying amounts of progestin referred to as combined oral contraceptives is one of the most effective contraception and is the most used in France. But the thrombogenicity of the estrogen component of combined hormonal contraceptives makes this method unsuitable for many women with severe congenital heart disease. Progestogin only methods offer a good alternative when estrogen is contraindicated, but efficiency differs according contraceptive preparation. PMID- 23687769 TI - [Psychological aspects in adult congenital heart disease patients]. AB - Patients with congenital heart disease mostly owe their survival to a saving chirurgical intervention which confers them a survivor's identity. The relationships between parents and children are strongly influenced by these early events. The effort made by parents to allow a good quality of life to their child is often successful. However, difficulties to anticipate late complications are frequently observed in adolescents and young adult patients. In adulthood, these patients seem to discover suddenly their disease, its consequences and the necessity of long term follow-up. The coexistence of several changes, i.e adolescence, change of medical team, transfer of parental decision to the young adult own decision make this period a vulnerable way. An adapted multidisciplinary support aimed to a real transition may limit the risks of breaking off and better organize long term follow-up. PMID- 23687770 TI - [Tetralogy of Fallot in adults]. PMID- 23687771 TI - [Social networks in 10 lessons: no. 3 entrust your presentations]. PMID- 23687772 TI - [A new program]. PMID- 23687773 TI - [Evolution in aortic insufficiency epidemiology]. PMID- 23687774 TI - [Aortic insufficiency]. PMID- 23687775 TI - [Naso-sinusoidal infections in children and adults]. PMID- 23687776 TI - [Atrial fibrillation]. PMID- 23687777 TI - [Tumours of the buccal cavity and the upper respiratory-digestive tracts]. PMID- 23687778 TI - [Fractures in children: epidemiological, diagnostic and therapeutic features]. PMID- 23687779 TI - [How teratology and embryology merged together during the 19th century]. PMID- 23687780 TI - Tailored interventions to improve hypertension management after stroke or TIA- phase II (TIMS II). AB - BACKGROUND: Reduction of blood pressure (BP) after stroke or TIA decreases stroke recurrence and is a major goal ofsecondary Stroke Prevention Clinics (SPCs). Health care providers need effective screening processes to identify those clients at highest risk of not achieving BP targets and those clients at highest risk ofnon-adherence to medication. METHODS: This multicentred, randomized controlled study used a screening process to identify SPC patients with psychosocial/cognitive deficits (e.g., lack of confidence in the utility of medications, poor memory, mild cognitive impairment) who were experiencing difficulty managing their BP to target values and evaluated whether a model of nurse-led case management program (monthly telephone calls, motivational interviewingfor lifestyle change, plus home BP monitoring and use ofdosettes for medication administration) would improve BP measures and adherence to medications. RESULTS: Both intervention (n=29) and usual care groups (n=27) showed a trend-for'reduced BP at six months (Median ql-q3, Systolic BR p=0.46; Diastolic BR p=0.37). Diabetic patients, irrespective of the group to which they were randomized, were less likely to meet Best Practice Guideline targets than those without diabetes (Chi Square test, p=0.0001). CONCLUSION: Stroke and TIA patients with diabetes may require additional resources and support in order to reach BP target values. PMID- 23687781 TI - Fifteen years of anti-HER2 therapy. PMID- 23687782 TI - FDA approves regorafenib (Stivarga) for GIST. PMID- 23687783 TI - New skin cancer target could delay drug resistance. PMID- 23687784 TI - HER2-directed therapy for metastatic breast cancer. AB - Human epidermal growth factor receptor 2 (HER2) overexpression drives the biology of 20% of breast cancers, and predicts a poor prognosis for patients. HER2 targeted therapies significantly improve outcomes for HER2-positive patients with both early and metastatic breast cancer. Currently three HER2-targeted agents, trastuzumab (Herceptin), lapatinib (Tykerb), and pertuzumab (Perjeta), are available for the treatment of HER2-positive metastatic breast cancer (MBC). Numerous studies have attempted to optimize their use by combining them with each other, or with endocrine and cytotoxic therapies. Most recently, the FDA approved the combination of trastuzumab, pertuzumab, and docetaxel as first-line treatment for MBC, and in late February 2013 approved a fourth HER2-targeted agent, trastuzumab emtansine (T-DM1, Kadcyla), for accelerated approval. These advances create a number of clinical dilemmas, including identification of the optimal sequence of HER2-targeted agents and the best drug combinations to use, as well as the recognition of primary and acquired drug resistance. In this article, we review clinical data informing the effective management of HER2-positive MBC. PMID- 23687785 TI - HER2-directed treatment of metastatic breast cancer: unanswered questions. PMID- 23687786 TI - How can we optimize treatment of HER2-positive metastatic breast cancer? PMID- 23687787 TI - Supportive care of the patient with advanced pancreatic cancer. AB - Despite advances in therapy, the average survival rate at 5 years for any patient diagnosed with pancreatic cancer remains only 6%. Throughout the course of cancer, most patients suffer a significant symptom burden and will need numerous interventions targeting these concerns. This paper highlights the most significant problems faced when caring for patients with advanced pancreatic cancer and provides an evidence-based approach to management. In addition, this review summarizes data on the health-related quality of life associated with current antineoplastic strategies, as well as critical issues facing patients and families along the disease trajectory.To provide optimal, appropriate care for patients with advanced-stage pancreatic cancer, ongoing assessment of their quality of life and of their preferences for treatment towards the end of life is crucial. PMID- 23687788 TI - The challenge of palliating pancreatic cancer. PMID- 23687789 TI - Keys to supportive care in pancreatic cancer: early palliative care, improved communication. PMID- 23687790 TI - Genomic subtypes in choosing adjuvant therapy for breast cancer. AB - The use of gene expression profiling has impacted our understanding of breast cancer biology and increasingly has played a role in guiding clinical decisions. We have used hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status for years to guide selection of therapy. More recently, gene expression analysis has facilitated the identification of at least five intrinsic subtypes of breast cancer. Potential therapeutic targets have also been identified using genomic profiling. Several tests, such as the 21-gene recurrence score assay (Oncotype DX) and the 70-gene prognosis signature (MammaPrint), have been well validated as prognostic tools for early-stage breast cancer, and have aided in adjuvant therapy decisions for early-stage, HR-positive breast cancer patients. Genomic profiling has the potential to provide additional insight into drug discovery and clinical trial design by identifying appropriate targeted therapies for subtypes of breast cancer. PMID- 23687791 TI - The evolving role of multi-gene tests in breast cancer management. PMID- 23687792 TI - Omics as useful tools in clinical practice: are we there yet? PMID- 23687793 TI - Targeted therapy in advanced urothelial carcinoma. AB - Urothelial carcinoma (UC) is a common and deadly cancer in the United States. While molecularly targeted therapies have been integrated into the standard-of care management of other solid tumors in recent years, the use of targeted therapy in UC has lagged behind. Accordingly, the management of advanced disease, along with outcomes, has remained largely unchanged for the past 2 decades. Despite the lack of new agents in the clinic, preclinical and early clinical studies have demonstrated that numerous potentially"targetable" molecular pathways exist, including the epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), human epidermal growth factor receptor 2 (HER2/neu), and insulin-like growth factor 1 receptor (IGF1R) pathways. This review focuses on targeted therapies related to these pathways of interest for the treatment of advanced UC, describing the evidence to support further investigation of these approaches. Notably, the identification and validation of new agents will only occur through accrual to urothelial cancer trials designed to answer these questions, which will require the support of the entire urologic community. PMID- 23687794 TI - "Missing the target" in urothelial cancer. PMID- 23687795 TI - Advanced urothelial carcinoma: moving the field forward. PMID- 23687796 TI - The value of adaptive regret management in retirement. AB - This 3-year longitudinal study examined the associations between regret management, everyday activities, and retirement satisfaction among recent retirees. We hypothesized that the regulation of a severe life regret can facilitate activity engagement and retirement satisfaction, but only if retirees manage their regrets adaptively by either increasing effort and commitment when possessing favorable opportunities or disengaging when opportunity is unfavorable. Cross-sectional analyses demonstrated that the highest baseline levels of activity (e.g., volunteering, traveling) and retirement satisfaction were observed among participants who perceived favorable opportunities for addressing their life regrets and had high levels of engagement. Longitudinal analyses showed that this pattern was also associated with increases in activity engagement. In contrast, disengagement protected individuals with unfavorable opportunity from 3-year declines in retirement satisfaction. These findings indicate that adaptive regulation of regrets can both contribute to gains and prevent losses in the early stages of retirement, which may have lasting consequences on retirees' quality of life. PMID- 23687797 TI - Marital satisfaction among older couples: the role of satisfaction with social networks and psychological well-being. AB - Marital satisfaction is important for health and well-being, although determinants of satisfaction among older couples are unclear. Much of the marital literature has focused on the role of the spouse, in isolation from satisfaction with broader social relationships. We conducted separate semi-structured interviews with both members of n = 40 couples (mean age 76 years) to measure satisfaction with particular types of social networks (confidant, friend, children, other relatives) as well as levels of physical and psychological well being. In order to account for the likely interdependence among observations within married couples, a series of multi-level models, culminating in a full actor-partner interdependence model, were fitted. Results indicate that an individual's own depressive symptoms were related to their levels of marital satisfaction, whereby higher scores on the depression scale predicted lower marital satisfaction scores for the individual. None of the individual's other variables (physical well-being, sociodemographic, or social network satisfaction), nor any of the spouse variables, were related to individual levels of marital satisfaction. These findings reinforce the importance of psychological well-being as influencing the quality of older couple relationships. PMID- 23687798 TI - Dementia and friendship: the quality and nature of the relationships that remain. AB - Friendships are an integral part of the human experience. Yet, dementia often takes a toll on social relationships, and many friends withdraw. This research, however, focuses on friendships that remain, despite a diagnosis of dementia. It examines the quality of the friendships of people with dementia and long-term friendships. Data were collected through focus group interviews with people with early stage dementia and their care partners, and through interviews with designated friends. The findings show that people with dementia do have friends that remain and they have a wide variety of friendships, from those based on one shared activity to those of multifaceted deep relationships. The long-term friendships, which last across the various stages of dementia, appear to fall into two types: one, where the person with dementia has become more like a family member than a friend (suffusion); and the other where the diagnosis of dementia was the impetus for the relationship to become closer (progressive friendship). PMID- 23687799 TI - Depressive symptoms negate the beneficial effects of physical activity on mortality risk. AB - The aim of this study is to: (1) compare the association between various levels of physical activity (PA) and mortality; and (2) examine the potential modifying effect of depressive symptoms on the PA-mortality associations. Previous large scale randomized studies rarely assess the association in conjunction with modifying effects of depressive symptoms. In this study, participants consisted of 624 (mean age = 77.35 years) non-institutionalized elderly from the Americans' Changing Lives Longitudinal Study. Depression was measured using the Center for Epidemiological Studies' Depression Scale. Participants in gardening, walking, and sports were first classified into four PA frequency levels, "never," "rarely," "sometimes," and "often." Those who self-reported "often" engaged in activities of gardening and walking and had reduced odds of mortality of 77% and 83%, adjusted odds ratio (ORadj) = .23 and .17, 95% confidence interval (CI) = .09-.59 and.07-.41 when compared to those who reported "never." However, mortality risk was not linked to sports activity. The modifying effects of depressive symptoms on PA (depressive symptoms x PA) were then tested, PA was not associated with increased risk for mortality for gardening (parameter estimates, PE = -.03 +/- .62, p = .958), and for walking (PE = .04 +/- .57, p = .948). Elderly people who engaged in gardening and walking might have protection effects on later risk of mortality. Depressive symptoms showed negative modifying effects that prevent PA predicting later mortality. PMID- 23687800 TI - Research priorities for the environment, agriculture and infectious diseases of poverty. AB - This report reviews the connections between environmental change, modern agricultural practices and the occurrence of infectious diseases - especially those of poverty; proposes a multi-criteria decision analysis approach to determining the key research priorities; and explores the benefits and limitations of a more systems-based approach to conceptualizing and investigating the problem. The report is the output of the Thematic Reference Group on Environment, Agriculture and Infectious Diseases of Poverty (TRG 4), part of an independent think tank of international experts, established and funded by the Special Programme for Research and Training in Tropical Diseases (TDR) to identify key research priorities through review of research evidence and input from stakeholder consultations. The report concludes that mitigating the outcomes on human health will require far-reaching strategies - spanning the environment, climate, agriculture, social-ecological, microbial and public-health sectors; as well as inter-disciplinary research and intersectoral action. People will also need to modify their way of thinking and engage beyond their own specialities, since the challenges are systemic and are amplified by the increasing inter connectedness of human populations. This is one of a series of disease and thematic reference group reports that have come out of the TDR Think Tank, all of which have contributed to the development of the Global Report for Research on Infectious Diseases of Poverty, available at www.who.int/tdr/capacity/global_report. PMID- 23687801 TI - [Role of the new version of the Control and Elimination Criteria for Schistosomiasis in acceleration of the schistosomiasis elimination program in China]. AB - Based on the historical background for revision of the Control and Elimination Criteria for Schistosomiasis for 6 times, and the role of the criteria in promotion of national schistosomiasis control program of China at various stages, the present study demonstrated the necessity of further revision of the control criteria in the current schistosomiasis elimination program. In addition, the background for revision of the novel version of the Control and Elimination Criteria for Schistosomiasis was illustrated based on literature review, retrospective survey, expert argumentation and index improvement. PMID- 23687802 TI - [Study on assessing system for endemicity of schistosomiasis]. AB - OBJECTIVE: To establish a scientific, objective and operational assessing system for schistosomiasis endemicity, so as to provide a scientific evidence for revising the current Criteria for Control and Elimination of Schistosomiasis in China (GB 15976-2006). METHODS: A questionnaire was designed based on reference review and 20 scientists working in the field of schistosomiasis control, research or management were investigated by using the Delphi method. The importance of each index reflecting the endemicity of schistosomiasis was scored by each scientist. The assessing system for endemicity of schistosomiasis was established and the normalized weight and combined weight were calculated. RESULTS: The assessing system included three indices in the first grade and seven indices in the second grade. Among the indices in the first grade, the normalized weights of infection status of human beings, infection status of livestock, and Oncomelania snail's status were 0.360 2, 0.335 2, and 0.304 6, respectively. Among the indices in the second grade, the prevalence of livestock showed the highest combined weight of 0.335 2 while the infection rate of snails showed the lowest score of 0.093 3. CONCLUSIONS: The indexes of the assessing system for the endemicity of schistosomiasis established are reasonable, comprehensive, and authoritative, which provide the scientific evidence for revising the currently available Criteria for Control and Elimination of Schistosomiasis in China. PMID- 23687803 TI - [Assessment of effect and quality control for parasitological tests in national schistosomiasis surveillance sites]. AB - OBJECTIVE: To understand the ability of pathogenic diagnosis for schistosomiasis japonica in the national surveillance sites and evaluate the effect of stool hatching method in the field, so as to provide the evidence for establishing a quality control system of pathogenic diagnosis of schistosomiasis in the surveillance sites. METHODS: The data pertaining to the parasitological diagnosis of the residents with positive serological tests were collected in 81 national surveillance sites of 12 provinces in 2011, and the effects of the Kato-Katz technique and stool hatching method were evaluated and compared. The incubation quality control samples made by the national schistosomiasis diagnosis reference laboratory were detected by both Kato-Katz technique and stool hatching method using the single-blind method, and the results were analyzed and compared for the coincidence rate, misdiagnosis rate and missing diagnosis rate in all the county laboratories in 2012. RESULTS: A total of 3 780 sero-positive residents were tested by using the Kato-Katz technique and stool hatching method in the 81 national surveillance sites in 2011, 127 persons were double egg-positive, 3 513 persons were double egg-negative, and the total coincidence rate was 96.30%. Totally 173 infected people were diagnosed by using the Kato-Katz technique and the positive detection rate was 4.58%; 221 infected people were diagnosed by using the stool hatching method and the positive detection rate was 5.85%. A total of 267 positive people were diagnosed by the Kato-Katz technique or the stool hatching method or both and the total positive detection rate was 7.06%, which was higher by 54.15% than that by using the single Kato-Katz technique (chi2 = 21.32, P < 0.01). In 2012, of 240 standard incubation quality control samples (160 positives, 80 negatives) detected by the technicians from the 80 surveillance sites, 105 samples were positive and 67 samples were negative, with a total coincidence rate of 71.67% (172/240) and a total missing diagnosis rate of 34.38% (55/160). Among them, the missing rate of the strong positive samples was 32.50% (26/80), the missing rate of the weakly positive samples was 36.25% (29/80), and the misdiagnosis rate of the negative samples was 16.25% (13/80). The detection rates of the incubation quality control samples were 61.11%, 80.00%, 77.08%, 90.48%, 58.33% and 59.26% in the surveillance sites of six provinces, including Anhui, Hubei, Hunan, Jiangsu, Jiangxi and Sichuan provinces, respectively, and a significant difference was found (chi2 = 14.27, P < 0.05). CONCLUSIONS: The detection efficiency of the stool hatching method is superior to that of the Kato-Katz technique in the field. However, the levels of the technical personnel for the stool hatching method are relatively low in most of the surveillance sites. Therefore, the technical training should be strengthened. PMID- 23687804 TI - [Development and evaluation of colloidal gold immunochromatography assay (GICA) for detection of antibody against Schistosoma japonica in smaller serum]. AB - OBJECTIVE: To develop a rapid colloidal gold immunochromatography assay (GICA) for detection of the antibody to schistosome in 5 microl sera. METHODS: A soluble egg antigen (SEA) from Schistosomajaponica was separated with sephacryl S-300 column to retain the active antigen fractions to the antibody of schistosome. The optional reaction system and detection kit with 5 microl sera were established by improving conjugated concentration and formulas of sample buffer and labeled solution. RESULTS: The sensitivity of detecting schistosomiasis patients whose stool examinations for schistosome eggs were positive was 93.7%, the specificity to health population 97.1%, the cross reaction rate to patients with paragonimiasis 5.6%. The Youden' s index value was 0.91. There was 96.1% crude coincidence of GICA and ELISA in detecting 507 cases of floating population and the Kappa value was 0.81. CONCLUSION: GICA kit is practical for detection of schistosomiasis in the field because of its advantages such as smaller serum needed, the high sensitivity, lower cross reaction rate and spread application for human and animals. PMID- 23687805 TI - [Role of socio-economy and management in sustainable transmission control of schistosomiasis in Taoyuan County, Hunan Province, China]. AB - OBJECTIVE: To clarify the role of socio-economy and management in the sustainable schistosomiasis-control in Taoyuan County, an endemic area in hilly region, Hunan Province, China. METHODS: From 1996 to 2011, the data of socio-economy, the management of schistosomiasis control organizations, environment, and the changes in schistosomiasis prevalence were collected in Taoyuan County where schistosomiasis transmission had been controlled since 2008. A sampling survey of schistosomiasis prevalence of human and bovine was performed in 2011 to verify the current status of schistosomiasis transmission. All the data were analyzed statistically to evaluate the role of socio-economy and management in the sustainable schistosomiasis control. RESULTS: During the period from 1998 to 2012, the socio-economy including the residents' productive mode and daily life in Taoyuan County improved dramatically, but the recurrence risk of schistosomiasis endemic still existed due to the retuning of out-going workers and the migrating population. Moreover, the introduction of exotic species of plants and animals may increase the risk. The low running cost of schistosomiasis control organization as well as the efficient and adequate resource allocation in the county was in line with the national requirement to strengthen the rural grass-roots public health system. CONCLUSION: The harmonious development of socio economy and the scientific and efficient health system in Taoyuan County are the key factors for the sustainable transmission control of schistosomiasis. PMID- 23687806 TI - [Effect of Pulsatilla chinensis (Bunge) Regel saponins on eggs, miracidia and cercariae of Schistosoma japonicum]. AB - OBJECTIVE: To investigate the effect of Pulsatilla chinensis (Bunge) Regel saponins (PRS) against the eggs, miracidia, cercariae of Schistosoma japonicum in vitro and compare its efficacy with praziquantel. METHODS: ICR mice were infected with the cercariae of S. japonicum by the patching abdominal method. The livers of the mice were grinded, screened, and then the eggs of S. japonicum were obtained 42 days post-infection. The miracidia were hatched by using the eggs, and the cercariae were obtained by using the infected Oncomelania snails on the light. The eggs, miracidia and cercariae of S. japonicum were incubated with 0, 1, 2, 3, 4, 5, 6, 7, 8 microg/ml PRS for different time, and praziquantel (PZQ) was used as the control. RESULTS: PRS suppressed the hatching rates of eggs for 24 h slightly superior to that of the control drug PZQ at different concentrations, especially in the 4 microg/ml concentration. After the miracidia were incubated with 1, 2, 3, 4, 5, 6, 7, 8 microg/ml PRS for 30 min, the dead rates of miracidia were 13.47, 26.05, 60.99, 90.84, 100, 100, 100, 100%, respectively. After the cercariae were incubated with 1, 2, 3, 4, 5, 6, 7, 8 microg/ml PRS for 30 min, the dead rates of cercariae were 5.32, 18.81, 44.7, 76.87, 98.28, 100, 100, 100%, respectively. PRS showed time- and dose-dependent mortality effects on the miracidia and cercariae of S. japonicum. CONCLUSION: PRS has the effects against eggs, miracidia, cercariae of S. japonicum in vitro, and it may become a new anti-schistosome agent. PMID- 23687807 TI - [Preliminary study on establishing an animal model of neuroschistosomiasis by direct injection of Schistosoma japonicum eggs through skull]. AB - OBJECTIVE: To establish an experimental model of neuroschistosomiasis and investigate the model establishment factors. METHODS: Rabbits were used for the animal model and Schistosoma japonicum eggs (1 mg/ml) were directly injected into the brain by two ways of a bone drill or needle. The symptoms were observed and in the first and second week and later, the rabbits' brains were removed for pathological examinations. RESULTS: One to two weeks after the injection of schistosome eggs, the rabbits had various neurological symptoms such as loss of appetite, hemiparesis, seizure, etc. The pathological analysis showed the schistosome egg granuloma inflammatory reaction among 90% rabbits. CONCLUSION: This new method of direct injection of S. japonicum eggs through skull into the brain provides a good and easy animal model of neuroschistosomiasis. PMID- 23687808 TI - [Epidemiological analysis of malaria prevalence in Jiangsu Province in 2011]. AB - OBJECTIVE: To analyze the malaria prevalence and epidemic characteristics in Jiangsu Province in 2011 so as to provide a basis for drawing up and adjusting effective malaria elimination strategies and measures. METHODS: The reported malaria cases from the Internet reporting system and epidemiological data of malaria were collected and analyzed statistically in Jiangsu Province. RESULTS: A total of 374 malaria cases were reported in Jiangsu Province in 2011 with the incidence of 0.05/10 000 which was similar to the number of cases in 2010. There were 13 cases of local vivax malaria which decreased by 87.00% compared with 100 cases in 2010. There were 361 imported cases including 309 imported falciparum malaria cases which increased by 49.00% compared with 207 cases in 2010. The imported falciparum cases mainly distributed in Yangzhou, Nantong, Huai' an and Taizhou cities which are located in central Jiangsu and coastal areas of northern Jiangsu. The number of imported falciparum malaria cases of these four cities accounted for 66.02% among the total cases in Jiangsu Province. There were 7 imported quartan malaria cases that were first reported and 14 imported ovale malaria cases. CONCLUSIONS: The local vivax malaria infections in Jiangsu Province decrease significantly and the endemic areas reduce significantly. However the imported falciparum malaria cases are increasing significantly year by year and the infected plasmodium parasites show diversities. Therefore, to achieve the target of malaria elimination in Jiangsu on schedule, it needs to continue to strengthen the personnel training of primary health care facilities and the disease control agencies, and strengthen the health education for export staffs and the monitoring and surveillance of the returnee. PMID- 23687809 TI - [Status of malaria epidemic and feasibility of malaria elimination in Guangxi Zhuang Autonomous Region]. AB - OBJECTIVE: To analyze the status of malaria epidemic and discuss the feasibility of malaria elimination in Guangxi Zhuang Autonomous Region. METHODS: The data of blood smear examinations of febrile patients among local residents, focus residents and mobile population in Guangxi Zhuang Autonomous Region were collected, described and analyzed statistically from 2001 to 2011. RESULTS: A total of 4 916 343 blood smear slides of local residents who had fever, 195 967 slides of focus residents, 282 461 slides of returned emigrants, and 228 341 slides of immigrants were examined, and the average positive rates of blood examinations were 0.004 8%, 0.007 7%, 0.480% and 0.127%, respectively. The indigenous malaria cases reduced from 51 in 2001 to 1 in 2009. There were no indigenous malaria cases during the period of 2010-2011. The malaria incidence has been under 1/100 000 for 11 years. The imported malaria cases were dominated in the whole region. CONCLUSIONS: Malaria situation in this region has entranced the consolidating phase of elimination according to the WHO criteria of malaria elimination. The goal of malaria elimination in Guangxi would be achieved in 2018 as long as the government and other departments pay enough attention to the imported malaria control, and the technical measures are further strengthened. PMID- 23687810 TI - [Epidemiological analysis of malaria epidemic situation in Guangdong Province, 2011]. AB - OBJECTIVE: To analyze the features of malaria epidemic in Guangdong Province in 2011 so as to provide the evidence for the elimination of malaria in Guangdong Province. METHODS: The data from the Disease Reporting Information System of Chinese Center for Disease Control and Prevention were analyzed with the descriptive epidemiological method for the epidemiological characteristics of malaria in Guangdong Province in 2011. RESULTS: A total of 96 malaria cases were reported in Guangdong Province in 2011, with an annual mean incidence of 0.092 per 100 thousand. There were 40 cases of Plasmodium vivax infection, 36 cases of Plasmodium falciparum infection and 20 cases of undivided malaria. There were 2 death cases. There were cases reported in 34 counties/cities/districts of 17 prefecture-level cities in the whole province. The cases distributed mainly in Guangzhou and Shenzhen, where there were 57 cases, reaching 59.38% of the cases of the whole province. There were cases reported every month in the whole year. From May to November, 73 cases were reported, accounting for 76.04% of the cases of the whole year. The ratio of male to female cases was 5.86: 1. The age distribution concentrated mainly on 20-50 years old. The youngest patient was 1 years old and the eldest was 65 years old. The occupation distribution concentrated mainly on the worker, commercial service, peasant, housekeeper and unemployed people (68 cases, 70.83%). In addition to the aforementioned 96 cases of local census register population, there were 32 cases of nonlocal census register population found in Guangdong, 2011. Of the total 128 cases, the main original areas of the imported cases were Africa (77, 60.16%) and Asia (30, 23.44%). The country with the most cases was Nigeria in Africa (36 cases), the second was Angola in Africa (19 cases), and the third was Myanmar in Asia (11 cases). CONCLUSION: The malaria epidemic situation in Guangdong Province is relatively stable in 2011, but the imported cases of Plasmodium falciparum infection increase. Therefore, the surveillance, prevention and control for imported cases of P. falciparum infection should be strengthened. PMID- 23687811 TI - [Analysis of overseas imported malaria situation and implication for control in Jiangsu Province, PR China]. AB - OBJECTIVE: To analyze the epidemiological characteristics of overseas imported malaria in Jiangsu Province and explore the strategies and priorities in prevention and control, so as to provide the evidence for improving the diagnosis, treatment and management of imported malaria. METHODS: The data of overseas imported malaria as well as the case epidemiological investigation in Jiangsu Province from July 18, 2011 to June 30, 2012 were collected and analyzed descriptively for the species composition, original countries, population distribution, regional distribution, onset time, diagnosis and treatment, channels to go abroad, and counterparts returned together with the patients. RESULTS: A total of 233 overseas imported malaria cases were reported, and 226 cases (97.0%) were imported from African countries. A total of 208 cases (89.3%) were falciparum malaria, and 224 cases (96.1%) were laboratory-confirmed. The imported malaria cases were young adults who were mainly migrant farmer and skilled male workers. There was no significant seasonal variation for onset time. Totally 145 cases (62.2%) got malaria onset in 20 days after returning home. The median time from onset to seeing doctor was two days and the median time from seeing doctor to being diagnosed was one day. The first visit health facilities by the patients were relatively scattered and the diagnostic health facilities were mainly medical institutions and CDC at the county level and above (220 cases, accounting for 94.4%). The ratio of standard treatment after malaria diagnosis was 100%. A total of 205 cases (88.0%) were workers dispatched to abroad as labor export by the company, and 142 cases (60.9%) cases had counterparts returned together. CONCLUSIONS: The situation of overseas imported malaria in Jiangsu Province is severe. It is necessary to further strengthen the professional training and multi-sectoral cooperation, establish the collaborative investigation mechanism for high-risk groups, and take effective prevention and control measures to reduce the risk of overseas imported malaria. PMID- 23687812 TI - [Surveillance of malaria in Global Fund Malaria Project counties of Guangxi Zhuang Autonomous Region in 2011]. AB - OBJECTIVE: To analyze the monitoring results and epidemic trend of malaria in the Global Fund Malaria Project counties of Guangxi Zhuang Autonomous Region in 2011, so as to provide the evidence for improving the preventive measures. METHODS: The data about malaria surveillance were collected and statistically analyzed in 7 Global Fund Malaria Project counties of Guangxi in 2011. RESULTS: A total of 8 cases of malaria were reported in the Global Fund Malaria Project counties of Guangxi in 2011, the average annual incidence rate was 0.04 per 10000 which increased by 100% compared with that in 2010, accounting for 7.14% (8/112) of the total number of cases in Guangxi. Totally 42 064 residents with fever were examined with blood tests and no case was found; 3 867 floating people were examined with blood tests and 8 cases of malaria were found (0.21%), including 5 cases of vivax malaria and 3 cases of falciparum malaria. The 8 malaria cases distributed in Longlin, Tiane, Nandan, Youjiang counties (district), and they all had ever worked in Africa or Southeast Asia. There were no input secondary cases or deaths throughout the year. CONCLUSIONS: The preventive measures of malaria are effective in the Global Fund Malaria Project counties of Guangxi, and the malaria epidemic situation is stable. It is the key to strengthen the malaria surveillance of the floating population who returned from Africa or Southeast Asia for consolidating the achievement of malaria prevention and control. PMID- 23687813 TI - [Characterization of Bacillus thuringrensis var. israelesis larvicide granules to larvae of mosquitoes]. AB - OBJECTIVE: To develop a new formulation of Bacillus thuringrensis var. israelesis (Bti) granules and assess its effect on mosquito control. METHODS: The Bti granule formulation was produced by coating Bti liquid on the surface of the carrier. and imitation tests, persistence tests and field tests were carried to assess its mosquito larvicidal effect, extended period and stability. RESULTS: A strain of Bti isolated from field had high toxicity to mosquito larvae and its LC50 values for larvae of Culex pipiens pallens and Aedes aegypti were 0.461 0 microl/L and 1.713 3 microl/L respectively. The developed 216 ITU/mg Bti granules had a control effect of 83.3%-100% to larvae of C. pipiens pallens at the dosage of 1-3 g/m2, and 72.7%-100% to A. aegypti at the dosage of 3-5 g/m2. When the 3rd instar larvae of C. pipiens pallens were put in the water that was treated with the granules at the dosage of 0.5 g/m2 13 days before, the larval mortality still reached to 55.3%. The field tests showed that with the treatment of 2-4 g/m2 Bti granules, the control effects on the larvae were high from 92.4% to 100% within the first 3 days and about 51.6%-75.7% after 20 days. CONCLUSION: The developed new formulation of Bti granules with the isolated strain has a preferable control effect on mosquito larvae and reveals a longer persistence and better stability than liquid formulation in the field tests. PMID- 23687814 TI - [Survey of Toxoplasma gondii infection among pregnant women in Jiangsu Province, China]. AB - OBJECTIVE: To understand the situation of Toxoplasma gondii infection among pregnant women in Jiangsu Province. METHODS: The pregnant women from 7 cities in Jiangsu Province were involved in this survey and the information was recorded according to the request of unified admission information of the case questionnaire of toxoplasmosis in Jiangsu Province. The specific antibodies IgM and IgG to Toxoplasma gondii in sera of these pregnant women were tested by ELISA. RESULTS: The specific antibody IgM to Toxoplasma gondii of all the respondents was negative. The positive rate of IgG was 3.98% (43/1 081), which was little different from the control group's 2.27% (4/176), and every city shared a similar positive rate. The positive rate of IgG of early pregnant women was 3.78%, which was also not obviously different from the 4.17% appearing in mid and late pregnant women. The respondents who previously had pathological abortions did not show positive IgG. Only 1.84% (8/435) of pregnant women had had the examinations related to Toxoplasma gondii before this survey. CONCLUSIONS: The rate of Toxoplasma gondii infection is low among pregnant women in Jiangsu Province. The situations in different areas are not far from each other. We should enhance the peri-conception tests of Toxoplasma gondii and take prevention and treatment countermeasures based on corresponding objects, and also further strengthen the healthy education. PMID- 23687815 TI - [Oncomelania snail habitat characteristics and orientation analysis in hilly areas of Jurong City]. AB - OBJECTIVE: To master the breeding and distribution of Oncomelania snails in hilly regions of Jurong City so as to provide the evidence for establishing the program of snail elimination. METHODS: The historical snail habitat environments and existing snail habitat environments in hilly areas of Jurong City were investigated according to the river systems. The geographic coordinate data of the acquisition historical and existing snail habitat environments were collected by GPS tools in the field, and the characteristics and distribution of snail habitats were analyzed by Google Earth position technology. RESULTS: A total of 399 historical snail habitat environments were investigated, and the total area was 2904.39 hm2, including 33 Class I environments with the area of 415.04 hm2, 33 Class II environments with the area of 323.19 hm2, 11 Class III environments with the area of 96.40 hm2, and 318 Class IV environments with the area of 1989.46 hm2. The environmental reformation rate was 14.29%. The Google Earth marked maps showed the aggregation relation between the distribution of existing and historical snail habitats and the water systems. CONCLUSION: The investigation has established the data-base of historical snail habitat environments and the space is marked on the Google Earth map, which could help the snail monitoring and to establish the program of snail elimination better. PMID- 23687816 TI - [Molluscicidal effect of WPN and MNSC on Lymnaea]. AB - OBJECTIVE: To evaluate the molluscicidal effect of wettable powder of 50% niclosamide ethanolamide salt (WPN) and suspension concentrate of 26% metaldehyde and niclosamide (MNSC) on Lymnaea. METHODS: WPN and MNSC were prepared as a series of solutions containing the active ingredient concentrations of 0.06, 0.13, 0.25, 0.50, 1.00, 2.00 mg/L and 4.00 mg/L, and the adult Lymnaea snails were soaked in the above mentioned series of solutions in the laboratory, and the LC50 values were calculated. The doses of active ingredient concentrations of 0.03, 0.06, 0.13, 0.25, 0.50, 1.00 g/m2 and 2.00 g/m2 of WPN and MNSC were adopted to spray on Lymnaea snails in the laboratory, and the LC50 values were calculated. A series of solutions containing the active ingredient concentrations of 1.00 mg/L, 0.50 mg/L, 0.25 mg/L, and 0.13 mg/L of WPN and MNSC were prepared, and the adult Lymnaea snails were put into the bowls with each concentration solution above mentioned and the climbing situation of the snails was observed at different time. RESULTS: By the immersion method, LC50 values of WPN at 48 h and 72 h were 0.93 mg/L and 0.64 mg/L respectively; LC50 values of MNSC at 48 h and 72 h were 0.74 mg/L and 0.51 mg/L respectively; by the spray method, when active ingredient concentrations of WPN and MNSC were 1.00 g/m2 or more, the death rates were both 100% after 3 days. In the climbing test, the Lymnaea snails did not climb in the solutions containing the active ingredient concentration of 1.00 mg/L of WPN and MNSC, however, a few snails climbed in the low concentrations. CONCLUSIONS: WPN and MNSC both have the effect of killing Lymnaea snails and inhibiting their climbing. By using the immersion method in the field, the active ingredient concentration of 2.00 mg/L of WPN and MNSC for 48 h is appropriate; by using the spray method, the active ingredient content of 1.00 g/m2 of WPN and MNSC for 3 days is appropriate. PMID- 23687817 TI - [Investigation on epidemic factors after schistosomiasis transmission controlled in Lushan County]. AB - OBJECTIVE: To explore schistosomiasis endemic factors in large mountainous areas where schistosomiasis transmission has been controlled. METHODS: Qingjiang Village, Lushan County, Sichuan Province, a alpine "Pingba" type of large mountain area, Wuxing Village, a alpine hilly type of large mountainous area, and Huoju Village, a alpine canyon type of large mountainous area were selected as study areas, and the agricultural structure, health facilities, and human behavior were investi-gated. The Oncomelania snail status was surveyed by using the system sampling method combined with the environmental sampling method. The schistosome infections of population were investigated with the serum immunology method and stool hatching method, and the schistosome infections of cattle and dogs were investigated with the plastic cup top tube hatching method. RESULTS: There was a traditional agricultural structure in these villages, and the coverage rates of harmless toilets were 23.20%, 41.17%, and 41.64% in Qingjiang Village, Wuxing Village, and Huoju Village, respectively; the safe drinking water rates were 100%, 100% and 99.16% in the aforementioned villages, respectively; the rates of using ditch water for life were 22.99%, 0 and 0.85% in the aforementioned villages, respectively. The snails, wild feces, and the infection of cattle were not found. The schistosome infection rates of residents were 0.18%, 0.15%, and 6.26% in the aforementioned villages, respectively; the schistosome infection rates of dogs were 0, 0 and 2.41% in the aforementioned villages respectively. The infection rates of field rodents were all zero in the aforementioned villages. CONCLUSIONS: We should strengthen the schistosomiasis monitoring of people and cattle, strengthening the monitoring of other infectious sources, and develop a targeted snail control method in Lushan County. PMID- 23687818 TI - [Multi-disciplinary treatment for advanced schistosomiasis]. AB - OBJECTIVE: To assess the efficiency of multi-disciplinary treatment (MDT) for advanced schistosomiasis. METHODS: A total of 173 advanced schistosomiasis patients who received MDT were selected from January 2010 to December 2011. These patients included 75 splenomegaly cases and 98 ascites cases. Other 193 advanced schistosomiasis patients who received single-discipline treatment (SDT) from January 2007 to December 2009 were also selected, and of them 84 cases were splenomegaly and 109 were ascites. The clinical efficiencies of the two different treatments were analyzed and assessed. RESULTS: Compared to the SDT group, the splenomegaly cases treated by MDT showed a shorter pre-operative preparation time and less days in hospitalization (both P < 0.01), less operation duration, decreased post-operative complications, lower hospitalization costs (all P < 0.05), and less patient complaints (P > 0.05). The ascites cases treated by MDT, compared to the SDT group, had less pre-treatment time, shorter ascites disappearing time (both P <0.01), and less hospitalization duration, decreased post-treatment complications, lower hospitalization costs and less patient complaints (all P < 0.05). Conclusion MDT has a better efficiency in the treatment of advanced schistosomiasis, and it reduces the operation complications and improves the life quality of the patients. PMID- 23687819 TI - [Malaria epidemiologic characteristics in Wuhe County of Anhui Province from 2009 to 2011]. AB - OBJECTIVE: To understand the malaria epidemiologic characteristics in Wuhe County, Anhui Province from 2009 to 2011, so as to provide the evidence for formulating effective malaria control and prevention interventions. METHODS: The data of malaria cases from the reporting system and malaria epidemiological investigations were collected and analyzed statistically in Wuhe County from 2009 to 2011. RESULTS: The total number of malaria cases was 349 in Wuhe County from 2009 to 2011, and the incidence showed a downtrend. The sex ratio of patients was 1.42: 1 (205 males vs. 144 females). The ranks of patient age groups were 11-20 years old at the first and 31-40 at the second, and the youngest was 1 year old, and the oldest was 100 years old. The seasonal factor was observed clearly, malaria cases were rare during the period of January to March, the case numbers increased in April and reached the peak during the period of June to September, and the cases from November to December accounted for only 2.01% of the total cases. Among the 349 patients, there were only 2 patients (0.57%) living in urban areas and the rest 347 patients (99.43%) all living in rural areas. The incidence of the urban population was 0.08/10 000, and it was significantly lower than that of the rural population (1.78/10,000, P < 0.05). The highest incidences occurred in hill townships, Zhuding Town and Xiaoxi Town, the annual incidences were 5.53/10,000 and 4.78/10,000, respectively. The cases in hill townships accounted for 36.10% of the total cases. The most patients in these areas lived in brick or cement buildings without mosquito-proof doors or windows. They preferred sleeping outside during summer, and were generally lack of the malaria prevention knowledge. CONCLUSION: In Wuhe County, the malaria incidence is decreasing year by year, and the epidemiologic factors are related to the living conditions, mosquito-proof facility using, sleeping habit, and malaria awareness of the residents. PMID- 23687821 TI - [Control strategy and practice of soil-transmitted parasitic diseases in Shandong Province]. AB - OBJECTIVE: To explore the sustainable development control strategies on soil transmitted parasitic diseases appropriate to current epidemic characteristics so as to effectively reduce the epidemic level and harm to people in Shandong Province. METHODS: This project was led by the Shandong Medical Department, governed and instructed by the Shandong Institute of Parasitic Diseases, concretely implemented by the centers for disease control and prevention in counties or cities. All the work was carried out according to the Control Programming of National Key Parasitic Diseases, and with the combination of routine and key control strategies according to the actual situation. RESULTS: The average infection rate of soil-transmitted parasitic diseases in Shandong Province was 18.26% in 2003. During the 2007 to 2009 period, 3,115,194 people from 74 counties in 9 cities received anthelmintic medicine. The numbers receiving health education were 39 866 923 in county, 34,730,663 in city, 3,2000 in province, respectively. The coverage rate of non-hazardous sanitary latrines was 58.05%. In 2009, 6,581 people were surveyed from 7 counties or cities and the infection rate of soil-transmitted parasitic diseases was 7.61%. During three years, 30 provincial training classes were held and 2,130 people attended, 52 municipal classes were held and 3110 people attended, and 403 county classes were held and 12,789 people attended. In the whole province, the infection rate of soil-transmitted parasitic diseases reduced to 7.10% in 2009, with the reduction rate of 61.12%, reaching the national objective. CONCLUSIONS: The comprehensive control model for soil-transmitted parasitic diseases is very successful in Shandong Province. PMID- 23687820 TI - [Investigation of infections of soil-transmitted nematodes in Fusheng Village of Poyang Lake area in Jiangxi Province]. AB - OBJECTIVE: To understand the status of soil-transmitted nematode infections in Poyang Lake area in Jiangxi Province. METHODS: The parasitic eggs of stools of residents aged 6-65 years were detected with the Kato-Katz technique in Fusheng Village of Poyang Lake area in Jiangxi Province in 2008. RESULTS: In 2008, the total average infection rate of soil-transmitted nematodes was 37.97%, and the infection rates of Ascarid lumbricoid, Trichuris trichiura and hookworm were 20.39%, 6.67% and 18.45%, respectively. The total infection rate of soil transmitted nematodes and the rate ofA. lumbricoid were higher in the female than in the male with a statistically significant difference (P < 0.01). The infection rates of T. trichiura and hookworm in the female were higher than those in the male, but there was no significant difference between them (P > 0.05). The total infection rate of soil-transmitted nematodes and the rate of hookworm in different age groups had a similar change pattern which had an increasing trend with the age growing. The infection rate ofA. lumbricoid was the lowest in the age group of 10-19 years and was the highest in the age group of 20-29 years, and then the rate showed a gradually declining trend with the age increasing. The infection rate of T. trichiura had a decreasing trend as the age grew with 2 peaks in the age groups of 10-19 and 40-49, respectively. CONCLUSIONS: The infection rates of soil-transmitted nematodes in population of Fusheng Village in Jiangxi Province are still high. The effective control measures include health education, regular anthelminthic treatment, innoxiously processing of stool and environment reform, and the interruption of the transmitting chain is the fundamental strategy. PMID- 23687822 TI - [Basic reproduction rate and its application in schistosomiasis]. AB - A key parameter in the transmission dynamics of schistosomiasis, namely basic reproduction rate (R0) is introduced in this paper, as well as its epidemiological significance, formulas in mathematical models of schistosomiasis transmission dynamics, and its application in the evaluation of schistosomiasis control measures. It suggests that the studies on transmission thresholds such as R0 are of important theoretical guiding significance to the establishment of a schistosomiasis elimination standard in China. PMID- 23687823 TI - [Role of Oncomelania hupensis in transmission of schistosomiasis japonica]. AB - Oncomelania hupensis is the only intermediate host of Schistosomajaponicum, and its ecological characteristics and compatibility with Schistosoma which have a great significance to the schistosomiasis control, play a very important role in the transmission of schistosomiasis. This paper reviews the researches on the ecological factors which effect the survive of Oncomelania snails such as temperature, humidity, vegetation, and soil, as well as the snail density, the development and breeding of snails in the foreign habitats, and its compatibility with Schistosoma. PMID- 23687824 TI - [Research progress on transmission capacity of reservoir host of Schistosoma japonicum]. AB - This paper reviews the researches related to the reservoir hosts of Schistosoma japonicum, including bovine, sheep, dog, cat and wild mouse. Combined with the implementation of the comprehensive control strategy with an emphasis on infection source control in current, it puts forward several future research directions under the condition that the effects of people and bovine as infection sources weakened gradually, such as revaluation on the actual transmission capacity of non-bovine livestock, for example, sheep, dog, pig and wild mouse, as well as discussion on some transmission threshold values in the infection link of Oncomelania snails. PMID- 23687825 TI - [Progress of research on diagnosis of schistosomiasis japonica with recombinant antigen]. AB - With the development of molecular biology technology and immunological technique, recombinant antigens for diagnosis of schistosomiasis have become a hot topic. This paper reviews the researches on recombinant antigens for diagnosis of schistosomiasis japonica in ten years. PMID- 23687826 TI - [Discussion on water conservancy projects and schistosomiasis control in Poyang Lake area]. AB - According to the schistosomiasis endemic situation in the Poyang Lake area, this paper analyzes the relationship between the water conservancy projects and schistosomiasis control, and reviews and discusses the effects of the Water Level Control Project of Poyang Lake, the Lake Dike Slope Hardening Project, and the Lifting Delta and Descending Beach Project on Oncomelania snail control. PMID- 23687827 TI - [Imported malaria and control strategies in Quanzhou City]. AB - OBJECTIVE: To understand the epidemic situation of imported malaria in Quanzhou City, and put forward control strategies, so as to provide the evidence for the elimination of malaria on time in 2014. METHODS: The data of epidemic situation, the annual sheets, and case investigation tables of malaria were collected and analyzed statistically in Quanzhou City from 2007 to 2011. RESULTS: The total imported malaria cases were 15 in Quanzhou City from 2007 to 2011, all the cases were male, and 46.67% of them focused on 40-49 years old. These cases were found through the year and mainly distributed in Quangang, Jinjiang, Shishi and Huian (City or District). The parasite rate in "three-fever" patients was 0. CONCLUSIONS: After the comprehensive measures with an emphasis on infection source management and vector control were implemented, the imported malaria endemic situation is stable in Quanzhou City. We should strengthen the health education and management of the entry-exit personnel as well as improve the control and management of imported malaria. PMID- 23687828 TI - [Evaluation on effect of schistosomiasis control after attainment of criteria for infection control in Jinxian County]. AB - OBJECTIVE: To understand the schistosomiasis epidemic situation after the attainment of criteria for infection control, and evaluate the effect of control measures in Jinxian County, Jiangxi Province. METHODS: The data of schistosomiasis epidemic situation including the infection rates of residents and Oncomelania snails were collected and analyzed statistically in the infection controlled, transmission-controlled, and transmission-interrupted areas in Jingxian County from 2008 to 2011. RESULTS: The antibody positive rates of population were decreasing year by year from 2008 to 2011 with the rate in the infection-controlled area being higher than the rates in the transmission controlled and the transmission-interrupted areas. In the infection-controlled area, the stool examination positive cases decreased from 29 cases in 2008 to 1 in 2011. In 2008, the spots with infected snails in the infection-controlled area and the transmission-controlled area were 63 and 5 spots, respectively. The spots with infected snails in the infection-controlled and transmission-controlled areas in 2011 decreased by 95.23% and 80.00%, respectively compared with that in 2008. CONCLUSION: The schistosomiasis control measures are effective after the attainment of criteria for infection control, and the epidemic situation is stable in Jinxian County. PMID- 23687829 TI - [Epidemiological investigation of imported falciparum malaria in Longlin County, Guangxi Zhuang Autonomous Region]. AB - Among 41 people returned from Equatorial Guinea, 16 persons were infected with Plasmodium falciparum (39.02%) in Longlin County, Guangxi Zhuang Autonomous Region from October 2011 to February 2012. Among the 16 cases, Plasmodiumfalciparum was found in their blood smears of 15 cases, and 1 patient was diagnosed clinically as falciparum malaria. All the 41 people were once suffered from malaria and they received antimalarial drugs when they were in Equatorial Guinea. These imported malaria cases received the standard treatment and the foci were sprayed with insecticides. No secondary malaria cases were found. In conclusion, the measures of imported malaria control are effective. The persons returned from Equatorial Guinea have a high risk of malaria; therefore, it is necessary to strengthen the monitoring of malaria for the floating population from high malaria prevalent areas. PMID- 23687830 TI - [Status of Clonorchis sinensis infection and its influencing factors among migrant workers in Baoan District, Shenzhen City]. AB - OBJECTIVE: To understand the status of Clonorchis sinensis infection and its risk factors among migrant workers in Baoan District of Shenzhen City, so as to provide the evidence for the development of control strategies. METHODS: A total of 642 migrant workers were chosen as the investigation samples by the stratified cluster sampling method. Their sera were collected and tested for Clonorchis sinensis infection with ELISA, and a questionnaires survey was performed to collect the information of clonorchiasis sinensis related to knowledge and behaviors. The influencing factors were summarized with the case-control study method. RESULTS: A total of 642 subjects were investigated, in which 530 subjects received the serological examinations and the positive rate was 6.6% (35/530). The significant differences were not found between genders (Chi2 = 1.19, P = 0.28) or among the age groups (Chi2 = 0.45, P = 0.80). The awareness rates of knowing infection route, health hazard and prevention knowledge were 50.16%, 33.64% and 27.41%, respectively. The rates of healthy behaviors such as not eating semi-cooked fish, not feeding pets with raw fish or shrimps, and differentiating between the raw and cooked food when using cutting boards were 80.67%, 78.41% and 45.95%, respectively. The awareness rate of prevention knowledge was positively related to the infection (OR = 0.16, P < 0.01). CONCLUSION: The prevention and control of Clonorchis sinensis infection among migrant workers could not be neglected, and the health education should be strengthened. PMID- 23687831 TI - [Epidemic situation of schistosomiasis in a provincial surveillance site of Shengzhou City, 2008-2011]. AB - According to "The Scheme of Schistosomiasis Surveillance in Zhejiang Province", the status of Oncomelania snails, and the schistosome infection of permanent residents, floating population, and livestock were surveyed in a provincial surveillance site of Shengzhou City, from 2008 to 2011. In 4 years, the area with residual snails was 3,060 m2, and no infected snails were found among 595 living snails. The positive rate of sero-tests for schistosomiasis of the permanent residents was 0.77%, and that of the floating population was 1.09%. No schistosomiasis cases were found. In conclusion, the area with residual snails is small and its distribution is scattered, and we still should strengthen the surveillance of snail status and imported schistosomiasis cases. PMID- 23687832 TI - [Correlation between schistosomiasis endemic situation and Oncomelania snail status in Yizheng City, Jiangsu province from 2002 to 2011]. AB - OBJECTIVE: To understand the correlation between schistosomiasis endemic situation and Oncomelania snail status, and discuss the control strategy and measures. METHODS: With a retrospective research method, the data were collected and analyzed including the snail area, infected snail area, snail density, density of infected snails, the infection rate of snails, the positive rates of blood tests and stool examinations for schistosomiasis in residents and domestic animals, and the incidence of acute schistosome infection in Yizheng City from 2002 to 2011. The correlation between the infected snails and schistosomiasis was analyzed. RESULTS: There were decline trends in snail area, infected snail area, and schistosomiasis situation. There were positive correlations between the infected snail area and snail area (r = 0.732, P < 0.05), the occurrence of acute schistosomiasis patients and infected snail area (r = 0.678, P < 0.05), and the snail area and schistosome infection rate of residents (r = 0.774, P < 0.05). CONCLUSION: In order to control schistosomiasis, we need to control infected snails, reduce snail areas, and implement comprehensive control measures. PMID- 23687833 TI - [Splenic embolization combined with double-mirror method in treatment of cirrhosis with hypersplenism of advanced schistosomiasis patients: a report of 38 cases]. AB - A total of 38 patients with schistosomiasis cirrhosis complicated with hypersplenism were cured by endoscopic variceal ligation (EVL), partial splenic embolization (PSE) and laparoscopic splenectomy (LS). After the surgery, the hemogram and liver function of all the patients recovered within two weeks. The average hospitalization time was shorter, the average hospitalization expense was less, and the complications were also less compared with those of the patients who received the routine therapy. In conclusion, the combination therapy of EVL and PSE combined with LS is effective and safe in the treatment of schistosomiasis cirrhosis complicated with hypersplenism. PMID- 23687834 TI - [Investigation on current status of infections of soil-borne nematodes in Yunxiao County]. AB - OBJECTIVE: To understand the endemic situation of soil-borne nematodes and their distribution characteristics, so as to provide the evidence for formulating prevention strategy. METHODS: According to The Survey Program of Important Human Parasitic Diseases in Fujian Province, the survey spots were determined by the stratified cluster randomly sampling method. The eggs of Ascaris lurmbricoides, hookworm and Trichuris trichiura in feces were detected by Kato-Katz technique; the eggs of Enterobius vermnicularis were checked by rectal swabs using transparent adhesive tape. A questionnaire survey was performed for recording the gender, age, education levels and related epidemiological factors. RESULTS: Altogether 2002 residents in 21 villages of 4 towns were investigated. There were 169 residents infected with soil-borne nematodes (8.44%). The infection rates of hookworm, Trichuris trichiura and Ascaris lumbricoides were 4.35%, 1.70% and 0.15% respectively. The infection rate of Enterobius vermicularis was 13.48% (43/319) in children. The infection rates of soil-borne nematodes were higher in children aged below 7 years and residents aged above 45 years, and the infection rate was higher in the women than in the men. The infection rates 'vere negative correlated with the education levels. CONCLUSION: The prevalence of soil-borne nematodes has a reduction trend in Yunxiao County. However, the infection rate of hookworm is still high in areas of mainly planting economic crops. The infection rate of Enterobius vermicularis is still high in children, and we should pay more attention to it. PMID- 23687835 TI - [Endoscopic ligation in treatment of advanced schistosomiasis patients with esophageal variceal bleeding: a report of 68 cases]. AB - OBJECTIVE: To evaluate the therapeutic effect of endoscopic ligation in the treatment of advanced schistosomiasis patients with esophageal variceal bleeding. METHODS: A total of 130 advanced schistosomiasis patients with esophageal varices rupture and bleeding were divided into a ligation group (68 cases) and a control group (64 cases), and the patients of ligation group were treated with the emergency endoscopic ligation, and the patients of control group received the routine therapy. The rebleeding rate, hemostatic success rate, and varicose veins red color sign were observed. RESULTS: In the ligation group, the rebleeding rate was 10.3% and the positive rate of varicose veins red color sign was 8.8%, which were better than those in the control group (both P values <0.01). CONCLUSION: Endoscopic ligation is an effective therapy for esophageal variceal bleeding. PMID- 23687836 TI - [Difference of Toxoplasma gondii infection status between urban and rural childbearing age women visiting to hospitals in southwest region of Shandong Province]. AB - A total of 1,839 obstetrics and gynecology clinical childbearing age women in southwest region of Shandong Province were tested for Toxoplasma gondii IgM antibody by ELISA. The results showed that the total Toxoplasma gondii infection rate was 3.10%, the infection rate was 1.66% in urban women and that was 4.49% in rural women, and there was a significant difference (P < 0.05), The infection rates were related to pet rising and the occupations that were closely contacted with animal slaughter, processing and sales (P < 0.05 for all). These results suggested that the corresponding prevention and control measures of toxoplasmosis should be formulated on the basis of different areas and occupations. PMID- 23687837 TI - [Relationship between advanced schistosomiasis and HBV infection]. AB - OBJECTIVE: To discuss the relationship between advanced schistosomiasis and HBV infection. METHODS: A total of 250 advanced schistosomiasis patients were examined with ultrasound, and their serum samples were detected for liver function, HBsAg, etc. The correlations between HBV infection and advanced types, abnormal liver function, liver cancer and mortality were analyzed, respectively. RESULTS: The positive rate of HBsAg was 58.4% (146/250). The rates of abnormal liver function (46.6%), jaundice (23.3%), cancer (17.8%) and mortality (23.3%) were significantly higher in the advanced schistosomiasis patients with HBsAg than in the advanced schistosomiasis patients without HBsAg (P values < 0.05 or 0.01). CONCLUSION: Advanced schistosomiasis combined with HBV infection aggravates the liver damage. PMID- 23687838 TI - [Surveillance of schistosomiasis in a national surveillance site, Nanzhong Village, Nanjing City, 2010-2011]. AB - OBJECTIVE: To understand the dynamic of schistosomiasis epidemic situation in a national surveillance site, Nanzhong Village, Qixia District, Nanjing City, 2010 2011, so as to provide the evidence for evaluating the control effect and formulating prevention countermeasures. METHODS: According to the National Schistosomiasis Monitoring Program, the Oncomelania snail status and the situation of endemic schistosomiasis were surveyed and the data were analyzed statistically. RESULTS: The emergence rate of frames with living Oncomelania snails decreased by 11.67% and the average density of living snails decreased by 95.49% in 2011 compared to those in 2010. No infected snail was found during the past 2 years. The infection rate of schistosome in the permernant residents decreased from 9.93% (95/957) in 2010 to 1.35% (7/519) in 2011, and no acute schistosomiasis case was found. All the stool tests of schistosome infection in domestic animals were negative. CONCLUSIONS: The schistosomiasis epidemic situation shows a decline trend year by year which demonstrates the routine comprehensive control measures are effective. However, the snail habitat area has not decreased significantly. Therefore, we should strengthen the snail control and continue the surveillance of snail status and infectious sources of schistosomiasis. PMID- 23687839 TI - [Oncomelania snail recurrence after schistosomiasis transmission interrupted in Chuxiong City]. AB - OBJECTIVE: To analyze the status of Oncomelania snail recurrence after schistosomiasis transmission interrupted in Chuxiong City, Yunnan Province, so as to provide the evidence for establishing the control strategy. METHODS: The data of snail surveillance since 1994 were collected and analyzed. RESULTS: The schistosomiasis endemic situation was stable, but the area with snails increased again seriously. In the years when the snail area was most (27.8 hm2 in 2004 and 28.0 hm2 in 2005) , it reached 12.9 times of the standard level. CONCLUSION: The Oncomelania snail recurrence is obvious, therefore, the snail severance still need to be strengthened. PMID- 23687840 TI - [Treatment of one advanced schistosomiasis patient with hepatitis B cirrhosis by lamivudine and adefovir dipivoxil]. AB - One advanced schistosomiasis patient with hepatitis B cirrhosis was treated with lamivudine and adefovir dipivoxil and the curative effect was satisfied. PMID- 23687841 TI - Make the most of mentoring. PMID- 23687842 TI - Enhancing observational data in qualitative research. PMID- 23687843 TI - The obser-view: a method of generating data and learning. AB - AIM: To introduce the 'obser-view' qualitative research method and to show how obser-view can be used in research. BACKGROUND: The author developed the obser view during a qualitative research project about nursing students' learning processes, because participants wanted to talk with the author after being observed. Conducting a non-scripted interview immediately post-observation became the obser-view. DATA SOURCES: Eleven nursing students on clinical placement in psychiatric hospital wards participated in the project. Nine participated in obser-views. REVIEW METHODS: A review o f literature resulted in two sources in which 'obserview' (not 'obser-view') was used to gain explanations of participants' actions, whereas the author sought a greater understanding of participants' actions. DISCUSSION: Whether to include a dialogue with the nursing students in the research design was a dilemma. An argument for so doing was that the method should support efforts to make the research transparent, as the obser view would give the author an inside, an outside and an inter-subject perspective of the data and increase the internal validity of the research. CONCLUSION: During the obser-view dialogue, the researcher, as a catalyst for reflection, has the opportunity to obtain participants' views of the observed situation, and for the researcher and participants to reflect on the situation both have been part of. The obser-view offers the researcher a deeper understanding of empirical data than can be gained from observation and qualitative semi-structured interviews alone, and offers participants deeper understanding of their actions. IMPLICATIONS FOR PRACTICE/RESEARCH: There is potential to use the obser-view in research involving students or patients, including families and cares of patients, whether in psychiatric or physical nursing. Further use over time will show in what other fields the obser-view method can be used to generate data and as a learning space for research and participant. PMID- 23687844 TI - Capturing clinician-client interaction: development of the 4D&4R observational tool. AB - AIM: To report on the development of an observation tool that can help a single researcher to collect field data about clinician and client interactions. BACKGROUND: Qualitative studies from a range of disciplines investigate the dynamics of interactions between clinicians and clients. These studies share and report findings but rarely provide details on the practical challenges and methods involved in managing such interactions when collecting rich ethnographic data. REVIEW METHODS: Development of the observational tool was informed by the study's requirements and context, previous research, and the authors cross disciplinary knowledge and experience. DISCUSSION: In relation to how clinicians interact with clients and how clients respond, four domains have been identified and integrated into the observational tool. These domains act as prompts during observations of interactions between clients and nurses. Use of the tool has indicated its effectiveness in assisting with observations and the recording of field notes. CONCLUSION: The article shows how to develop a tool for qualitative field-data collection. The method can be adapted to studies that require observations of interactions and its components can be modified to suit their fields of study. IMPLICATIONS FOR PRACTICE OR RESEARCH: The 4D&4R tool discussed in this article provides indicators of clinician-client interactions and is transferable to other research and practice contexts PMID- 23687845 TI - Nurse-led trials of medical devices: general principles and good practice. AB - AIM: To provide an overview of governance issues relating to medical-device trials and practical advice for nurses wishing to initiate or lead them. BACKGROUND: Medical-device trials, which are formal research studies that examine the benefits and risks of therapeutic medical devices, have traditionally been the domain of physicians and scientists. The role of nurses in these trials has historically been as data collectors or co-ordinators rather than as principal investigators. However, nurses have more recently played an increasing role in initiating and leading medical device trials. REVIEW METHODS: A review article of nurse-led trials of medical devices. DISCUSION: Central to the quality and safety of all clinical trials is adherence to the International Conference on Harmonisation Guidelines for Good Clinical Practice, which is the interationally agreed standard for the ethically and scientifically sound design, conduct and monitoring of a medical-device trial, as well as the analysis, reporting and verification of the data derived from that trial. Considerations include the class of the medical device, type of trial, regulatory status of the device, implementation of standard operating procedures, obligations of the trial sponsor, indemnity of relevant parties, scrutiny of the trial conduct, trial registration, and reporting and publication of the results. CONCLUSION: Nurse-led trials of medical devices are demanding but rewarding research enterprises. As nursing practice and research increasingly embrace technical interventions, it is vital that nurse researchers contemplating such trials understand and implement the principles of good clinical practice to protect study participants and the research team. PMID- 23687846 TI - Preparing and conducting interviews to collect data. AB - AIM: To describe three styles of interviews and discuss issues regarding planning and conducting interviews. BACKGROUND: Interviews are probably the approach most used to collect data in studies. They are particularly useful in uncovering the story behind a participant's experiences. Researchers can follow a line of questions to gain information about a topic, or further explore responses or findings. But the researcher needs to plan and decide the format of the interview before collecting data. REVIEW METHODS: The authors included papers on structured, unstructured and semi-structured interviews published in a peer reviewed joumrnal and in English. DISCUSSION: Interviews are one of the most common metods of data collection in qualitative research. However they require the researcher to have a sound understanding of their use and appropriateness. The ability to conduct interviews is one that develops over time and to aid the researcher in developing their interview skills they should consult with other researchers, seeking comments and advice and, critically, to appraise audio recordings. CONCLUSION: This article aims to support students who are undertaking research modules as part of their academic studies, writing a research proposal or novice researchers who are about to use interviews as a means of data collection. IMPLICATIONS FOR RESEARCH/PRACTICE: To conduct a successful interview, researchers need to develop their interview technique, choose the right method and carefully plan for all aspects of the process. PMID- 23687847 TI - The internet as a medium for health services research. Part 2. AB - AIM: To enable readers to make an informed decision about whether online research methods (ORMs) are appropriate for their studies. BACKGROUND: Using an ORM is an innovative way of collecting data and many research designs, such as surveys, interviews, focus groups and ethnography, can be conducted online. There are many potential benefits that can be conferred on traditional research procedures when implemented via the internet, for example economy and convenience, as there are no travel or postal requirements. Depending on the data sample, participant access can also be increased by using an intemet method, as it is possible to reach a large geographical span. The Internet can also offer full anonymity, if appropriate, and for some marginalised groups, such as those with mobility or communication difficulties, the intemet is an inclusive method for their participation. The first paper in this series, Walker (2013), introduced ORMs in general and outlined what needs to be considered when ascertaining whether an ORM is appropriate for the specific reearch needed, including ethical, validity and sampling issues. It also discussed some of the ORMs that omy be used. DISCUSSION: This second paper outlines the considerations researchers need to make when designing an online interview or focus group to ensure their method is valid. The different tools that can be used for collecting data are also discussed. Analysis includes online qualitative data capture, such as collecting data from blogs, social networking sites, chat rooms or discussion lists. This paper also contains resources and references for further reading. CONCLUSION: ORMs can provide efficient and innovative methods for collecting data, although there are certain considerations needed to ensure that they are valid for given research questions. IMPLICATIONS FOR RESEARCH/PRACTICE: As more ORMs are validated and as more people using the internet, there will be an emergence of online-only research. Careful consideration should be taken to determine whether using an ORM is an appropriate tool for the population and questions under study. PMID- 23687848 TI - Randomised controlled trials: an introduction for nurse researchers. AB - AIM: To present an overview of the main components of randomised controlled trials and identify issues for consideration during their design and management. BACKGROUND: Randomised controlled trials (RCTs) are considered to be the gold standard for determining causality and can provide high quality evidence to inform nursing practice. DATA SOURCES: A search of online databases and websites was undertaken to identify relevant contemporary literature to inform the discussion. DISCUSSION/CONCLUSION: Conducting a robust randomised controlled trial can present researchers with numerous challenges and practical considerations. The importance of taking account of the Consort guidelines during their design, conduct and reporting is emphasised. IMPLICATIONS FOR RESEARCH/PRACTICE: Evidence from well conducted RCTs contributes to the development of effective nursing interventions. To avoid bias and ensure valid results, the design, conduct and reporting of RCTs should follow the Consort guidelines. Service users should be involved in the design and management of RCTs. PMID- 23687849 TI - Publishing can inspire research. Interview by Leslie Gelling. PMID- 23687850 TI - Gene flow pattern among Aedes aegypti populations in Mexico. AB - Patterns of gene flow vary greatly among Aedes aegypti populations throughout Mexico. The populations are panmictic along the Pacific coast, isolated by distance in northeast Mexico, and exhibit moderate gene flow across the Yucatan peninsula. Nine Ae. aegypti collections from 6 cities in Oaxaca, Mexico, were taken to examine the local patterns of gene flow. Genetic variation was examined in a 387-bp region of the nicotinamide adenine dinucleotide dehydrogenase subunit 4 mitochondrial gene (ND4) using single-strand conformation polymorphism analysis, and 3 haplotypes were detected. Cluster analysis on the linearized FST genetic distances failed to group collections in geographic proximity. Regression analysis of linear or road distances on linearized F(ST) indicated that proximal collections were as diverse as distant collections across an approximately 800-km range. The geographical distribution of the Mexican mosquito haplotype frequencies was determined for the ND4 sequences from 524 individuals from Oaxaca (this study) and 2,043 individuals from our previous studies. Herein, we report on yet another pattern dominated by genetic drift among 9 Ae. aegypti collections from 6 cities in Oaxaca, Mexico, and compare it to those reported in other regions of Mexico. Molecular analysis of variance showed that there was as much genetic variation among collections 4 km apart as there was among all collections. The numbers of haplotypes and the amount of genetic diversity among the collections from Oaxaca were much lower than detected in previous studies in other regions of Mexico and may reflect the effects of control efforts or adaptations to the altitudinal limits (1,500 m) of the species in Mexico. The geographical distribution of mosquito haplotypes in Mexico is also reported. Furthermore, based on the distribution of the mosquito haplotypes in America, we suggest that mosquito dispersion is very efficient, most likely due to commercial transportation. PMID- 23687851 TI - Outbreak of Culex inatomii in disaster areas of the Great East Japan earthquake and tsunami in 2011, with ecological notes on their larval habitats, biting behavior, and reproduction. AB - Outbreaks of Culex inatomii occurred widely in disaster areas of the tsunami caused by the Great East Japan earthquake in March 2011. Mosquitoes were collected in southern Miyagi Prefecture and northern Fukushima Prefecture in August and September 2011, respectively. In southern Miyagi Prefecture, the average number of adult Cx. inatomii collected by a suction trap baited with 1 kg of dry ice ranged between 69.3 and 132.8 per day in locations within 2.6 km from the coast in tsunami areas, while no Cx. inatomii individuals were collected 8.3 km from the coast, where seawater did not reach, and which therefore escaped the tsunami disaster. There were many ground pools of brackish water of various sizes, and larvae of Cx. inatomii were collected in 48% and 36% of the pools examined in Miyagi Prefecture and Fukushima Prefecture, respectively. Ecological notes on the larval habitats, biting behavior, seasonal prevalence, and reproduction of Cx. inatomii are presented for reference based on ecological studies conducted in Sakata Wetland, Niigata Prefecture, central Japan, in June and August 2011. Ecological factors relating to the current outbreak and the potential medical importance of Cx. inatomii are discussed. PMID- 23687852 TI - Immature mosquitoes associated with urban parklands: implications for water and mosquito management. AB - The aim of the present study was to compare 2 urban habitat types: pools artificially filled with water from damaged or leaking water pipes (AF) and pools naturally filled by rainwater (NF), with regard to their favorability as breeding sites for mosquitoes. Two study areas were analyzed, 1 for 5 months and the other for 9 months, covering the whole period when AF pools contained water. The AF pools held water during the entire study, and showed lower fluctuations in surface area than NF pools. The AF pools showed higher levels of total mosquitoes and of stagnant-water mosquitoes. The floodwater mosquitoes were numerically (but not significantly) more abundant in NF pools. Nine mosquito species were identified. Habitat type, temperature, and season were significant in explaining the variability in species composition according to the canonical correspondence analysis. The most abundant species were Ochlerotatus albifasciatus (= Aedes albifasciatus, predominantly in NF pools), Culex dolosus, and Cx. pipiens (mainly in AF pools). The latter 2 species differed in their temporal dynamics, with Cx. dolosus associated with lower temperatures and Cx. pipiens with higher temperatures. Overall, the results indicate that although both habitat types harbored immature mosquitoes, the AF pools were more favorable than co-occurring rain pools. Easy-to-implement management actions such as the design of adequate drainage systems and the fast repair of broken pipes will be helpful to reduce the risk of human illness associated with mosquitoes in urban green areas. PMID- 23687853 TI - Temporal and spatial distribution of dengue vector mosquitoes and their habitat patterns in Penang Island, Malaysia. AB - We studied the diversity of Aedes breeding sites in various urban, suburban, and rural areas over time between February 2009 and February 2010 in the dengue endemic areas of Penang Island, Malaysia. We categorized the breeding sites and efficiency, and identified the key breeding containers. Among the 3 areas, the rural areas produced the highest container index (55), followed by suburban (42) and urban (32) areas. The numbers of key premises and containers were significantly higher (P < 0.000) in rural areas. The class 1 containers were identified as the key containers with higher productivity and efficiency, although class 2 and class 4 are the highest in numbers. Aedes aegypti immatures were found mostly in drums, water reservoirs, and polyethylene sheets, while mixed breeding was more common in buckets and empty paint cans in urban and suburban areas. Aedes albopictus was found mainly in miscellaneous containers such as drums, empty paint cans, and covers in all areas. The main potential containers indoors were drums, water reservoirs, and empty paint cans, and containers outdoors included empty paint cans, drums, and polyethylene sheets. PMID- 23687854 TI - Larvicidal activity of essential extract of Rosmarinus officinalis against Culex quinquefasciatus. AB - Constituents in rosemary (Rosmarinus officinalis) have been shown to have larvicidal activity against invertebrates. In order to explore the properties of crude extract of rosemary further, we studied the chemical composition and its activity against dichlorodiphenyltrichloroethane (DDT)-susceptible, DDT resistant, and field strains of Culex quinquefasciatus larvae. The major components of R. officinalis were found to be eucalyptol and camphor, with relative percentages of 10.93% and 5.51%, respectively. Minor constituents included limonene, (+)-4-carene, isoborneol, 1-methyl-4-(1-methylethylidene) cyclohexene, and pinene. The median lethal concentration (LC50) values of the essential oil of R. officinalis against DDT-susceptible, DDT-resistant, and field strains of larvae of Cx. quinquefasciatus were 30.6, 26.4, and 38.3 mg/liter, respectively. The single median lethal dose (LD50) in Kunming mice was 4752 mg/kg. Essential oils from R. officinalis may, therefore, provide an effective natural plant product for use in mosquito prevention and control. PMID- 23687855 TI - Evaluation of a new formulation of permethrin applied by water-based thermal fogger against Aedes albopictus in residential communities in St. Augustine, Florida. AB - The efficacy of a new water-based formulation containing 30% permethrin and 30% piperonyl butoxide against laboratory and field populations of Aedes albopictus was evaluated in the laboratory, in semifield experiments, and in residential communities in St. Augustine, FL. In laboratory bottle bioassay, 3 doses (3.18 g/ml, 2.26 g/ml, and 1.59 g/ml) of the permethrin product resulted in 100% mortality of adult mosquitoes in 1 h. In semifield experiments, the insecticide sprayed by the water-based thermal fogger at 381.5 ml/min application rate caused 99% mortality of caged mosquitoes. At 24 h posttreatment in the residential communities, there was 79% and 83% reduction of the natural population (numbers) of adult Ae. albopictus and all adult mosquito species collected in BioGent (BG) sentinel traps baited with a BG lure in the 3 test sites, respectively. There was also a 79% reduction in the number of Ae. albopictus eggs collected in ovitrap used in the treated sites. The reductions were significant for adult Ae. albopictus and all mosquito species at 1 wk posttreatment, but no significant reduction was observed at 2-3 wk posttreatment. These findings demonstrate the effectiveness of the new water-based permethrin product against Ae. albopictus populations in residential communities. PMID- 23687856 TI - Anomalies in the sand fly Lutzomyia longipalpis (Diptera: Psychodidae) in Brazil. AB - Lutzomyia longipalpis is the main species involved in the epidemiological cycle of visceral leishmaniasis in Brazil. This species shows a wide geographic distribution and belongs to a group that has 2 setae in the paramere with the curved tips towards the apex of this structure among other characteristics. Morphological characters in the genitalia of phlebotomines are essential for correct identification of species. The aim of this study was to report the finding of unilateral and bilateral anomalies in the paramere of L. longipalpis males collected in Varzea da Palma municipality, Minas Gerais State, Brazil. Twelve collections were made during the period April 2009 to March 2010, using Centers for Disease Control and Prevention light traps, HP model. Of the 8,832 male L. longipalpis collected, we found 6 types of unilateral anomalies and 2 types of bilateral anomalies in 0.5% of the insects collected. The anomalies were described according to number, position, and size of the setae of paramere. This information will be useful in the validation of new species. PMID- 23687857 TI - First record of the disease vector Anopheles hyrcanus in Austria. AB - Anopheles (Anopheles) hyrcanus was detected for the first time in Austria, in a floodplain forest in the city of Vienna. From May to September 2012, we found 135 females of this species within the scope of a mosquito monitoring program. Anopheles hyrcanus transmits Sindbis and Tahyna viruses and was reported to be a potential vector for human malaria and dirofilariasis. An updated distribution map depicts that An. hyrcanus has extended its range northwards across the European Alps. PMID- 23687858 TI - Description of two gynandromorphs of Culex theileri from Extremadura, Spain. AB - Two gynandromorphs of Culex theileri are described. The individuals were caught in the Centers for Disease Control and Prevention miniature light traps in the municipality of Alcollarin, Caceres, Spain, in 2011. One of the specimens presented polar gynandromorphism, whereas the other showed a combination of polar and transverse gynandromorphic features. Details are given of the main characteristics of both mosquitoes, with particular emphasis that this gynandromorphic finding is only the second reported for this mosquito species worldwide. PMID- 23687859 TI - Scanning electron microscopy of eggs of Sabethes cyaneus. AB - Mosquitoes of the Neotropical genus Sabethes, some species of which are yellow fever vectors, most often develop through the immature stages in tree holes. Sabethes eggs have not been previously characterized using scanning electron microscopy. Eggs of Sabethes cyaneus (length: 349.6 +/- 2.7 microm; width: 172.6 +/- 1.14 microm; n = 10) are almost biconical when examined from the top. From a lateral perspective 2 surfaces can be seen. One surface is smooth and more convex, whereas the other is less convex and partially covered by a network from which many fungiform tubercles arise. The micropyle is situated on the smooth surface of the pointed anterior tip and is surrounded by an irregular row of tubercles, some of which are leaf shaped. No structures possibly involved in adhesion to surfaces are visible. When hatching, the egg splits dorsoventrally approximately two-thirds of the length from the anterior end. The tubercles appear to be water repellent, and the more convex/smoother surface is downturned, and this position on water was confirmed by direct observation. The eggs float free on the water surface. PMID- 23687860 TI - Distribution of Culex species in vegetation bands of a constructed wetland undergoing integrated mosquito management. AB - The distribution and abundance of emerging Culex spp. were assessed within narrow (width: 3 m) and wide (width: 20 m) bands of California bulrush (Schoenoplectus californicus) and in the open water adjacent to emergent vegetation in 2 marshes of an ammonia-dominated wastewater treatment wetland in southern California. Emerging mosquitoes were collected along transects perpendicular to the path of water flow at 3 distances (1.5, 5, and 10 m) from the vegetation-open water interface in the wide bands of emergent vegetation, at the center of narrow bands of emergent vegetation, and at 1.5 m from the edge of emergent vegetation in the open water. The width of vegetation bands (3 vs. 20 m) influenced the effectiveness of integrated mosquito management practices, especially the application of mosquito control agents. Mosquito production from the 2 marshes also differed up to 14-fold, suggesting that the distance between the shorelines (62 vs. 74 m) of each marsh also influenced the efficacy of mosquito control agents applied from the shore and boats. Hot spots of mosquito production (75424 female Culex/m2/day) were found within the wide bands of bulrush. During summer, the relative abundance of Culex stigmatosoma among emerging mosquitoes increased from the periphery to the center of wide bands of emergent vegetation. Culex erythrothorax emergence rates were comparatively similar among the transects in the wide bands of emergent vegetation. Culex tarsalis adults increased in number from the periphery to the center of wide bands of bulrush and, in May, were > 95% of emerged mosquitoes. PMID- 23687861 TI - Diel activity patterns of male Aedes albopictus in the laboratory. AB - This study was conducted to investigate the flight and dispersal behavior of male Aedes albopictus under laboratory conditions. Two different methods, the Observer and Ethovision software devices, were used to determine the total duration, the mean and maximum flight speed, and the distance covered by these mosquitoes. During 24 h, mosquitoes were more active from 0800 to 1200 h and from 1700 to 2100 h than during the rest of the day. Male Ae. albopictus displayed different activities at different times. The flight activity was 47 min and 57 sec over 24 h. During this period, sugar-fed males flew an average distance of 236.20 m at an average speed of 8.5 cm/sec. The unfed males flew significantly faster than recently fed males, with maximum flight speeds of 44.9 cm/sec and 33.6 cm/sec, respectively. The time used for resting (22 h 2 min +/- 13 min) was significantly higher (P < 0.0001) than walking and flying times (68 min +/- 10 sec and 49 min +/- 5 min, respectively). Overall, both methods allowed observations on flight activity, and the camera recordings allowed these activities to be quantified. PMID- 23687862 TI - Child outdoor physical activity is reduced by prevalence of the Asian tiger mosquito, Aedes albopictus. AB - We tested the hypothesis that day-biting mosquitoes contribute to child obesity by reducing opportunities for summer outdoor play. The influence of Asian tiger mosquito (Aedes albopictus) prevalence on child outdoor physical activity was compared in 2 matched urban communities, one treated for mosquito abatement and one untreated. More time was spent outdoors by children where abatement took place. PMID- 23687863 TI - A new challenge for hospitals in southeast France: monitoring local populations of Aedes albopictus to prevent nosocomial transmission of dengue or chikungunya. AB - Aedes albopictus was first identified in southern France in 2004, inducing an emerging risk for autochthonous transmission around imported cases of dengue or chikungunya, and also for mosquito-borne nosocomial transmission in hospitals. Aedes albopictus has been present in Marseille since September 2009 and in Aix-en Provence since August 2010. Because of the possible admission of viremic patients with dengue or chikungunya in the hospitals of these cities, a mosquito survey was conducted in 2011 in 2 of the hospitals, with the use of mosquito traps. Aedes albopictus was detected with Eisenhans II traps and egg traps in both hospitals during the warm season. PMID- 23687864 TI - High-throughput mosquito and fly bioassay system for natural and artificial substrates treated with residual insecticides. AB - A high-throughput bioassay system to evaluate the efficacy of residual pesticides against mosquitoes and muscid flies with minimal insect handling was developed. The system consisted of 4 components made of readily available materials: 1) a CO2 anaesthetizing chamber, 2) a specialized aspirator, 3) a cylindrical flat bottomed glass bioassay chamber assembly, and 4) a customized rack. PMID- 23687865 TI - Midwives and mothers walking hand in hand. AB - From government to professional bodies to pregnant women there appears to be a consensus that maternity care has gone in a direction that satisfies nobody, yet retaining the status quo is simply unsustainable (Royal collegeof obstetricians and gynaecologists (RCOG) 2011). Too many pregnant women are receiving care in an acute setting. Not only is this costing the taxpayer money but it is costing many women physical and mental trauma as a result of unnecessary medical interventions. The Place of birth study (Hollowell et al 2011) demonstrated unequivocally that, for low risk women, birth outside of a consultant led unit (CLU) in either a midwife led unit (MLU) or home setting is safe and results in less medical intervention. PMID- 23687866 TI - Mandatory professional indemnity insurance ends independent midwifery, say campaigners. PMID- 23687867 TI - Errors in rhesus disease testing put mothers and babies at risk. PMID- 23687868 TI - Babies' lives could be saved if mothers breastfed in the hour after birth. PMID- 23687869 TI - New agenda for change deal will preserve national pay system. PMID- 23687870 TI - Changes in the NHS. AB - The NHS is no stranger to restructure and change. Further restructure is currently taking place with the introduction of clinical commissioning. Moving to clinical commissioning will transfer responsibility for commissioning maternity services from primary care trusts (PCTs) working in collaboration with local maternity service providers and acute trusts to clinical commissioning groups (CCGs) working in partnership with health and wellbeing boards and the NHS commissioning board (NHSCB). This restructure aims to increase consultation with clinical service providers and to move service planning nearer to the service user. Maternity care provision is complex and challenging. Despite these challenges, restructures must enable services to reduce morbidity, increase efficiency and improve safety and women's experiences of maternity services. PMID- 23687871 TI - Continuity of care: the elusive key to improved maternity outcomes. AB - When a vital lost key turns up in a place that you have looked a dozen times, you may begin to think the timing is fate. If maternity care is really going to improve for every woman we need to make a change in the system that will enable her to have her own midwife whom she can know and trust. Evidence shows this improves outcomes and saves money. The key is to reinvest some of those savings into paying the midwife appropriately for the commitment this level of care requires of her. PMID- 23687872 TI - Newly qualified commuter. AB - The job situation in Scotland for newly qualified midwives continues to be a challenging one. Many midwives have to search for their first job away from the comforts of home and family. This can broaden perspectives and give challenging and rewarding opportunities. It is a dilemma more and more students have to face. Will leaving family and familiar surroundings be worth it? One newly qualified midwife tells her story and encourages others to broaden their horizons and see the positives in this time of upheaval. PMID- 23687873 TI - Systemic lupus erythmatosus. AB - Systemic lupus erythmatosus (SLE) presents many challenges in pregnancy for the midwife who is increasingly being relied upon to act as coordinator of care, guiding women with complex and high risk medical conditions through maternity pathways, as part of an integrated team. The disease and its pharmacological management are implicated in a range of complications. Primary care provision involves using skilful clinical observation of abnormal signs and symptoms and referring appropriately. The midwife plays a vital role in facilitating primary care provision and all the appropriate support, whilst ensuring that evidence based information is readily available. This enables the woman and her family to achieve the most desirable outcome. PMID- 23687874 TI - NHS Tayside: implementing the Scottish antenatal parent education pack. AB - In 2011, the Scottish antenatal parent education pack was launched. The pack consisted of a national core syllabus, a parent education resources manual and accompanying toolkit and a training course. This article looks at how NHS Tayside has taken the core syllabus and resource manual as guidance and, using many of the teaching aids contained in the toolkit, has developed workbooks for key topics. This will support our aim to provide a quality parent education programme for women and their families across Tayside. PMID- 23687875 TI - Fighting fire - with teamwork. AB - Team work is a process of working collaboratively and an important aspect of inter professional team success. This article is a reflective account, following eight midwifery students who participated in group dynamics training with a team of airport fire officers. It highlights howyou can borrow teamwork and communication strategies from other high profile industries and adapt it to midwifery practice. The experience demonstrated how a team approach brought together a cluster of skills, experience and understanding, something that cannot exist in one individual. It also demonstrated that when team work is successful the results are amazing. PMID- 23687877 TI - Information for pregnant women about caesarean birth. AB - The aim of this bi-monthly column is to highlight Cochrane Systematic Reviews of relevance to pregnancy and childbirth and to stimulate discussion on the relevance and implications of the review for practice. The Cochrane Collaboration is an international organisation that prepares and maintains high quality systematic reviews to help people make well informed decisions about healthcare and health policy. A systematic review tries to search for, appraise and bring together existing research to answer a specific research question. The Cochrane Database of Systematic Reviews (CDSR) is published monthly online. Residents in countries with a national license to The Cochrane Library, including the UK and Ireland, can access the Cochrane Library online for free through www.thecochranelibrary.com PMID- 23687876 TI - An English midwife in Arkansas part 2 - the birth experience. AB - In the second of this three part series detailing my experiences as an English pregnant midwife receiving maternity care in America, this article describes my birth experience as well as the differences in intrapartum and immediate postnatal care when compared to the UK. PMID- 23687878 TI - Managing common maternal related breastfeeding challenges. PMID- 23687879 TI - The lullaby trust. PMID- 23687880 TI - A spatial mark--resight model augmented with telemetry data. AB - Abundance and population density are fundamental pieces of information for population ecology and species conservation, but they are difficult to estimate for rare and elusive species. Mark--resight models are popular for estimating population abundance because they are less invasive and expensive than traditional mark-recapture. However, density estimation using mark-resight is difficult because the area sampled must be explicitly defined, historically using ad hoc approaches. We developed a spatial mark--resight model for estimating population density that combines spatial resighting data and telemetry data. Incorporating telemetry data allows us to inform model parameters related to movement and individual location. Our model also allows <100% individual identification of marked individuals. We implemented the model in a Bayesian framework, using a custom-made Metropolis-within-Gibbs Markov chain Monte Carlo algorithm. As an example, we applied this model to a mark--resight study of raccoons (Procyon lotor) on South Core Banks, a barrier island in Cape Lookout National Seashore, North Carolina, USA. We estimated a population of 186.71 +/- 14.81 individuals, which translated to a density of 8.29 +/- 0.66 individuals/km2 (mean +/- SD). The model presented here will have widespread utility in future applications, especially for species that are not naturally marked. PMID- 23687881 TI - The AIC model selection method applied to path analytic models compared using a d separation test. AB - Classical path analysis is a statistical technique used to test causal hypotheses involving multiple variables without latent variables, assuming linearity, multivariate normality, and a sufficient sample size. The d-separation (d-sep) test is a generalization of path analysis that relaxes these assumptions. Although model selection using Akaike's information criterion (AIC) is well established for classical path analysis, this model selection technique has not yet been developed for d-sep tests. In this paper, I explain how to use the AIC statistic for d-sep tests, give a worked example, and include instructions (supplemental material) to implement the analysis in the R computing language. PMID- 23687882 TI - Physiological effects of diet mixing on consumer fitness: a meta-analysis. AB - The degree of dietary generalism among consumers has important consequences for population, community, and ecosystem processes, yet the effects on consumer fitness of mixing food types have not been examined comprehensively. We conducted a meta-analysis of 161 peer-reviewed studies reporting 493 experimental manipulations of prey diversity to test whether diet mixing enhances consumer fitness based on the intrinsic nutritional quality of foods and consumer physiology. Averaged across studies, mixed diets conferred significantly higher fitness than the average of single-species diets, but not the best single prey species. More than half of individual experiments, however, showed maximal growth and reproduction on mixed diets, consistent with the predicted benefits of a balanced diet. Mixed diets including chemically defended prey were no better than the average prey type, opposing the prediction that a diverse diet dilutes toxins. Finally, mixed-model analysis showed that the effect of diet mixing was stronger for herbivores than for higher trophic levels. The generally weak evidence for the nutritional benefits of diet mixing in these primarily laboratory experiments suggests that diet generalism is not strongly favored by the inherent physiological benefits of mixing food types, but is more likely driven by ecological and environmental influences on consumer foraging. PMID- 23687883 TI - The cost of safety: refuges increase the impact of predation risk in aquatic systems. AB - Although use of refuge habitats by prey can reduce their risk of predation, refuge use may also involve costs such as increased within-refuge competition for resources. Despite the ubiquity of refuge use by prey, it is unknown whether predator-induced use of refuges has widespread, negative nonconsumptive effects on prey growth, survival, and fecundity. We performed a meta-analysis of 204 studies of aquatic taxa containing data on 271 distinct predator--prey pairs and found strong evidence that the negative effect of predation risk on prey activity, growth, and fecundity increases when prey have access to refuge habitats. Moreover, the effect of refuge habitats on growth and activity depends upon whether the refuge provides partial or total protection from predators. These results suggest that prey choosing whether to use refuges face a trade-off between lowering the immediate risk of being consumed and increased nonconsumptive costs of refuge use. Our results suggest that changes in nonconsumptive effects in the presence of refuge habitats may alter prey population dynamics, coexistence, and metapopulation dynamics. Moreover, our results reveal key pragmatic considerations: the magnitude and direction of nonconsumptive effects may depend on the presence of refuge habitat and whether the refuge provides partial or total protection from predators. PMID- 23687884 TI - Decreasing litter size of marmots over time: a life history response to climate change? AB - The way that plants and animals respond to climate change varies widely among species, but the biological features underlying their actual response remains largely unknown. Here, from a 20-year monitoring study, we document a continuous decrease in litter size of the Alpine marmot (Marmota marmota) since 1990. To cope with harsh winters, Alpine marmots hibernate in burrows and their reproductive output should depend more on spring conditions compared to animals that are active year-round. However, we show that litter size decreased over time because of the general thinning of winter snow cover that has been repeatedly reported to occur in the Alps over the same period, despite a positive effect of an earlier snowmelt in spring. Our results contrast markedly with a recent study on North American yellow-bellied marmots, suggesting that between-species differences in life histories can lead to opposite responses to climate change, even between closely related species. Our case study therefore demonstrates the idiosyncratic nature of the response to climate change and emphasizes, even for related species with similar ecological niches, that it may be hazardous to extrapolate life history responses to climate change from one species to another. PMID- 23687885 TI - Social structure mediates environmental effects on group size in an obligate cooperative breeder, Suricata suricatta. AB - Population dynamics in group-living species can be strongly affected both by features of sociality per se and by resultant population structure. To develop a mechanistic understanding of population dynamics in highly social species we need to investigate how processes within groups, processes linking groups, and external drivers act and interact to produce observed patterns. We model social group dynamics in cooperatively breeding meerkats, Suricata suricatta, paying attention to local demographic as well as dispersal processes. We use generalized additive models to describe the influence of group size, population density, and environmental conditions on demographic rates for each sex and stage, and we combine these models into predictive and individual-based simulation models of group dynamics. Short-term predictions of expected group size and simulated group trajectories over the longer term agree well with observations. Group dynamics are characterized by slow increases during the breeding season and relatively sharp declines during the pre-breeding season, particularly after dry years. We examine the demographic mechanisms responsible for environmental dependence. While individuals appear more prone to emigrate after dry years, seasons of low rainfall also cause reductions in reproductive output that produce adult-biased age distributions in the following dispersal season. Adult subordinates are much more likely to disperse or be evicted than immature individuals, and demographic structure thus contributes to crashes in group size. Our results demonstrate the role of social structure in characterizing a population's response to environmental variation. We discuss the implications of our findings for the population dynamics of cooperative breeders and population dynamics generally. PMID- 23687886 TI - Cryptic loss of montane avian richness and high community turnover over 100 years. AB - Although there are numerous examples of individual species moving up in elevation and poleward in latitude in response to 20th century climate change, how communities have responded is less well understood and requires fully accounting for changes in species-specific detectability over time, which has been neglected in past studies. We use a hierarchical Bayesian occupancy model to examine bird species richness change and turnover along three elevation gradients surveyed 80 100 years apart in the Sierra Nevada of California, USA. Richness declined over the 20th century across all elevations. Turnover was greatest at the highest and the lowest elevations. These findings were only apparent, however, after species' detectability was incorporated into measures of species richness. Further partitioning of species richness changes by elevational life zone showed that numbers of low- and high-elevation species declined, without a concurrent expansion by mid-elevation species. Our results provide empirical evidence for biodiversity loss in protected montane areas during the 20th century and highlight the importance of accounting for detectability in comparisons of species richness over time. PMID- 23687887 TI - Relaxing the closure assumption in occupancy models: staggered arrival and departure times. AB - Occupancy statistical models that account for imperfect detection have proved very useful in several areas of ecology, including species distribution and spatial dynamics, disease ecology, and ecological responses to climate change. These models are based on the collection of multiple samples at each of a number of sites within a given season, during which it is assumed the species is either absent or present and available for detection while each sample is taken. However, for some species, individuals are only present or available for detection seasonally. We present a statistical model that relaxes the closure assumption within a season by permitting staggered entry and exit times for the species of interest at each site. Based on simulation, our open model eliminates bias in occupancy estimators and in some cases increases precision. The power to detect the violation of closure is high if detection probability is reasonably high. In addition to providing more robust estimation of occupancy, this model permits comparison of phenology across sites, species, or years, by modeling variation in arrival or departure probabilities. In a comparison of four species of amphibians in Maryland we found that two toad species arrived at breeding sites later in the season than a salamander and frog species, and departed from sites earlier. PMID- 23687888 TI - Early maternal experience shapes offspring performance in the wild. AB - Both the environments experienced by a mother as a juvenile and an adult can affect her investment in offspring. However, the implications of these maternal legacies, both juvenile and adult, for offspring fitness in natural populations are unclear. We investigated whether the juvenile growth rate and adult reproductive traits (length, body condition, and reproductive investment at spawning) of female wild Atlantic salmon (Salmo salar) were related to the growth and survival of their offspring. Adult salmon captured on their upstream migration were used to create experimental full-sib clutches of eggs, which were mixed and then placed in artificial nests in a natural stream that lacked salmon due to a migration barrier. Four months later we resampled the stream to obtain family-level estimates of offspring size and survival. Mothers that had grown slowly as juveniles (as determined by scalimetry) but had invested heavily in reproduction (egg production for a given body length) and were in relatively poor body condition (somatic mass for a given body length) at spawning produced the largest eggs. Larger eggs resulted in larger juveniles and higher juvenile survival. However, after controlling for egg size, offspring growth was positively related to maternal juvenile growth rate and reproductive investment. The predictors of offspring survival (i.e., reproductive success) varied with the juvenile growth rate of the mother: If females grew slowly as juveniles, their reproductive success was negatively related to their own body condition. In contrast, the reproductive success of females that grew quickly as juveniles was instead related positively to their own body condition. Our results show that maternal influences on offspring in the wild can be complex, with reproductive success related to the early life performance of the mother, as well as her state at the time of breeding. PMID- 23687889 TI - A community of metacommunities: exploring patterns in species distributions across large geographical areas. AB - Ecological communities show extremely complex patterns of variation in space, and quantifying the relative importance of spatial and environmental factors underpinning patterns of species distributions is one of the main goals of community ecology. Although we have accumulated good knowledge about the processes driving species distributions within metacommunities, we have few insights about whether (and how) environmental and spatial features can actually generate consistent species distributional patterns across multiple metacommunities. In this paper we applied the elements of metacommunity structure (EMS) framework to identify and classify metacommunities according to multiple but discrete patterns of species distributions. Given that each pattern has unique underlying structuring mechanisms, exploring and comparing such patterns across multiple metacommunities spanning large geographical areas provides a way to test the existence of general principles underlying species distributions within metacommunities. In this study, we applied the EMS framework into a data set containing about 9000 lakes distributed across 85 fish metacommunities across Ontario, Canada, and estimated the relative importance of local and spatial factors in explaining their distributional patterns. Nested and Clementsian gradients were the patterns that fitted most metacommunities; nested metacommunities were distributed throughout the province, while Clementsian gradient metacommunities were concentrated in the southeastern region. Sixty-five percent of nested metacommunities were located in low-energy watersheds (i.e., colder climate and shorter growing season), whereas metacommunities representing Clementsian gradients were present in high-energy watersheds (i.e., relatively warmer climate and longer growing season). Taken together, our results reveal that the environmental and spatial properties in which metacommunities are embedded are at least partially responsible for their species distributional patterns. PMID- 23687890 TI - Experimental evaluation of predation as a facilitator of invasion success in a stream fish. AB - Predator-prey relationships in poikilotherms are often size dependent, such as when adults of two interacting species are capable of eating juveniles of the other species. Such bi-directional predation can be important during the establishment and spread of an invading species, but its role remains poorly understood. Using a combination of laboratory and mesocosm experiments and field introductions, we demonstrate that guppies, Poecilia reticulata, prey on juvenile killifish, Rivulus hartii, and thereby facilitate their establishment in the habitat of a potential predator. Laboratory studies found that mature guppies can consume larval Rivulus, and experimental stream studies showed that guppies reduced the number of Rivulus surviving from eggs. Growth trials found that interspecific competition, while significant, cannot account for the declines in the survival of juvenile Rivulus seen in field surveys. Finally, a field experiment, in which guppies were introduced into previously guppy-free stream reaches, resulted in a marked reduction in the abundance of juvenile Rivulus relative to guppy-free controls. Together, these results indicate that reducing the native Rivulus population represents an important.mechanism promoting guppy invasion success. PMID- 23687891 TI - Synthesizing larval competence dynamics and reef-scale retention reveals a high potential for self-recruitment in corals. AB - Many organisms have a complex life-cycle in which dispersal occurs at the propagule stage. For marine environments, there is growing evidence that high levels of recruitment back to the natal population (self-recruitment) are common in many marine organisms. For fish, swimming behavior is frequently invoked as a key mechanism allowing high self-recruitment. For organisms with weak-swimming larvae, such as many marine invertebrates, the mechanisms behind self-recruitment are less clear. Here, we assessed whether the combination of passive retention of larvae due to re-circulation processes near reefs, and the dynamics of settlement competence, can produce the high levels of self-recruitment previously estimated by population genetic studies for reef-building corals. Additionally, we investigated whether time to motility, which is more readily measurable than competence parameters, can explain the between-species variation in self recruitment. We measured the larval competence dynamics of broadcast-spawning and brooding corals and incorporated these in a model of larval retention around reefs to estimate the potential for self-recruitment and assess its variation among species and reefs. Our results suggest that the larvae of many corals, even those with an obligate planktonic phase, develop with sufficient rapidity to allow high levels of self-recruitment, particularly for reefs with long water retention times. Time to motility explained 77-86% of the between-species variation in potential self-recruitment in scenarios with a realistic range of retention times. Among broadcast spawners, time to motility was strongly and positively correlated with egg size, i.e., broadcast spawner species with small eggs developed more rapidly and exhibited greater potential for self-recruitment. These findings suggest that, along with water retention estimates, easy-to measure species traits, such as egg size and time to motility, may be good predictors of potential self-recruitment, and therefore may be used to characterize the spectrum of self-recruitment in corals. PMID- 23687892 TI - Stochastic species distributions are driven by organism size. AB - The strengths of environmental drivers and biotic interactions are expected to show large variability across organism groups. We tested two ideas related to the degree of ecological determinism vs. stochasticity using a large data set comprising bacterio-, phyto-, and zooplankton. We expected that (1) there are predictable, size-driven differences in the degree to which planktonic taxa respond to different drivers such as water chemistry, biotic interactions, and climatic variables; and (2) species distribution models show lowest predictive performance for the smallest taxa due to the stochastic distributions of microbes. Generalized linear models (GLMs), generalized additive models (GAMs), and generalized boosted methods (GBMs) were constructed for 84 species to model their occurrence as a function of eight predictors. Predictive performance was measured as the area under the curve (AUC) of the receiver-operating characteristic plot and true skill statistic (TSS) using independent model evaluation data. We found that the model performances were typically remarkably low for all planktonic groups. The proportion of satisfactory models (AUC > 0.7) was lowest for bacteria (11.1% of the models), followed by phyto- (24.2%) and zooplankton (38.1%). The occurrences of taxa within all planktonic groups were related to climatic variables to a certain degree, but bacteria showed the strongest associations with the climatic variables. Moreover, zooplankton occurrences were more related to biotic variables than the occurrences of smaller taxa, while phytoplankton occurrences were more related to water chemistry. We conclude that the occurrences of planktonic taxa are highly unpredictable and that stochasticity in occurrences is negatively related to the organism size perhaps due to efficient dispersal and fast population dynamics among the smallest taxa. PMID- 23687893 TI - Horizontal, but not vertical, biotic interactions affect fine-scale plant distribution patterns in a low-energy system. AB - Studies of species range determinants have traditionally focused on abiotic variables (typically climatic conditions), and therefore the recent explicit consideration of biotic interactions represents an important advance in the field. While these studies clearly support the role of biotic interactions in shaping species distributions, most examine only the influence of a single species and/or a single interaction, failing to account for species being subject to multiple concurrent interactions. By fitting species distribution models (SDMs), we examine the influence of multiple vertical (i.e., grazing, trampling, and manuring by mammalian herbivores) and horizontal (i.e., competition and facilitation; estimated from the cover of dominant plant species) interspecific interactions on the occurrence and cover of 41 alpine tundra plant species. Adding plant-plant interactions to baseline SDMs (using five field-quantified abiotic variables) significantly improved models' predictive power for independent data, while herbivore-related variables had only a weak influence. Overall, abiotic variables had the strongest individual contributions to the distribution of alpine tundra plants, with the importance of horizontal interaction variables exceeding that of vertical interaction variables. These results were consistent across three modeling techniques, for both species occurrence and cover, demonstrating the pattern to be robust. Thus, the explicit consideration of multiple biotic interactions reveals that plant-plant interactions exert control over the fine-scale distribution of vascular species that is comparable to abiotic drivers and considerably stronger than herbivores in this low-energy system. PMID- 23687894 TI - Enough is enough: the effects of symbiotic ant abundance on herbivory, growth, and reproduction in an African acacia. AB - Understanding how cooperative interactions evolve and persist remains a central challenge in biology. Many mutualisms are thought to be maintained by "partner fidelity feedback," in which each partner bases their investment on the benefits they receive. Yet, we know little about how benefits change as mutualists vary their investment, which is critical to understanding the balance between mutualism and antagonism in any given partnership. Using an obligate ant-plant mutualism, we manipulated the density of symbiotic acacia ants (Crematogaster mimosae) and examined how the costs and benefits to Acacia drepanolobium trees scaled with ant abundance. Benefits of ants to plants saturated with increasing ant abundance for protection from branch browsing by elephants and attack by branch galling midges, while varying linearly for protection from cerambycid beetles. In addition, the risk of catastrophic whole-tree herbivory by elephants was highest for trees with very low ant abundance. However, there was no relationship between ant abundance and herbivory by leaf-feeding invertebrates, nor by vertebrate browsers such as giraffe, steinbuck, and Grant's gazelle. Ant abundance did not significantly influence rates of branch growth on acacias, but there was a significant negative relationship between ant abundance and the number of fruits produced by host plants, suggesting that maintaining high density ant colonies is costly. Because benefits to plants largely saturated with increasing colony size, while costs to plant reproduction increased, we suggest that ant colonies may achieve abundances that are higher than optimal for host plants. Our results highlight the conflicts of interest inherent in many mutualisms, and demonstrate the value of examining the shape of curves relating costs and benefits within these globally important interactions. PMID- 23687895 TI - The roles of productivity and ecosystem size in determining food chain length in tropical terrestrial ecosystems. AB - Many different drivers, including productivity, ecosystem size, and disturbance, have been considered to explain natural variation in the length of food chains. Much remains unknown about the role of these various drivers in determining food chain length, and particularly about the mechanisms by which they may operate in terrestrial ecosystems, which have quite different ecological constraints than aquatic environments, where most food chain length studies have been thus far conducted. In this study, we tested the relative importance of ecosystem size and productivity in influencing food chain length in a terrestrial setting. We determined that (1) there is no effect of ecosystem size or productive space on food chain length; (2) rather, food chain length increases strongly and linearly with productivity; and (3) the observed changes in food chain length are likely achieved through a combination of changes in predator size, predator behavior, and consumer diversity along gradients in productivity. These results lend new insight into the mechanisms by which productivity can drive changes in food chain length, point to potential for systematic differences in the drivers of food web structure between terrestrial and aquatic systems, and challenge us to consider how ecological context may control the drivers that shape food chain length. PMID- 23687896 TI - Phenotypic plasticity of plant response to herbivore eggs: effects on resistance to caterpillars and plant development. AB - Herbivory induces direct resistance responses in plants that negatively affect subsequently colonizing herbivores. Moreover, eggs of herbivorous insects can also activate plant resistance, which in some cases prevents hatching larvae from feeding. Until now, plant-mediated effects of eggs on subsequent herbivory, and the specificity of such responses, have remained poorly understood. We studied the specificity and effects of plant resistance induced by herbivore egg deposition against lepidopteran larvae of species with different dietary breadths, feeding on a wild annual plant, the crucifer Brassica nigra. We examined whether this plant-mediated response affects the growth of caterpillars of a specialist (Pieris brassicae) that feeds on B. nigra leaves and flowers, and a generalist (Mamestra brassicae) that rarely attacks this wild crucifer. We measured growth rates of neonate larvae to the end of their second instar after the larvae had hatched on plants exposed to eggs vs. plants without eggs, under laboratory and semi-field conditions. Moreover, we studied the effects of egg deposition by the two herbivore species on plant height and flowering rate before and after larval hatching. Larvae of both herbivore species that developed on plants previously infested with eggs of the specialist butterfly P. brassicae gained less mass compared with larvae that developed on egg-free plants. Plants exposed to butterfly eggs showed accelerated plant growth and flowering compared to egg-free plants. Egg deposition by the generalist moth M. brassicae, in contrast, had no effect on subsequent performance by either herbivore species, or on plant development. Our results demonstrate that B. nigra plants respond differently to eggs of two herbivore species in terms of plant development and induced resistance to caterpillar attack. For this annual crucifer, the retardation of caterpillar growth in response to deposition of eggs by P. brassicae in combination with enhanced growth and flowering likely result in reproductive assurance, after being exposed to eggs from an herbivore whose larvae rapidly reduce the plant's reproductive potential through florivory. PMID- 23687897 TI - Microbial abundance and composition influence litter decomposition response to environmental change. AB - Rates of ecosystem processes such as decomposition are likely to change as a result of human impacts on the environment. In southern California, climate change and nitrogen (N) deposition in particular may alter biological communities and ecosystem processes. These drivers may affect decomposition directly, through changes in abiotic conditions, and indirectly through changes in plant and decomposer communities. To assess indirect effects on litter decomposition, we reciprocally transplanted microbial communities and plant litter among control and treatment plots (either drought or N addition) in a grassland ecosystem. We hypothesized that drought would reduce decomposition rates through moisture limitation of decomposers and reductions in plant litter quality before and during decomposition. In contrast, we predicted that N deposition would stimulate decomposition by relieving N limitation of decomposers and improving plant litter quality. We also hypothesized that adaptive mechanisms would allow microbes to decompose litter more effectively in their native plot and litter environments. Consistent with our first hypothesis, we found that drought treatment reduced litter mass loss from 20.9% to 15.3% after six months. There was a similar decline in mass loss of litter inoculated with microbes transplanted from the drought treatment, suggesting a legacy effect of drought driven by declines in microbial abundance and possible changes in microbial community composition. Bacterial cell densities were up to 86% lower in drought plots and at least 50% lower on litter derived from the drought treatment, whereas fungal hyphal lengths increased by 13-14% in the drought treatment. Nitrogen effects on decomposition rates and microbial abundances were weaker than drought effects, although N addition significantly altered initial plant litter chemistry and litter chemistry during decomposition. However, we did find support for microbial adaptation to N addition with N-derived microbes facilitating greater mass loss in N plots than in control plots. Our results show that environmental changes can affect rates of ecosystem processes directly through abiotic changes and indirectly through microbial abundances and communities. Therefore models of ecosystem response to global change may need to represent microbial biomass and community composition to make accurate predictions. PMID- 23687898 TI - Responses of ecosystem carbon cycle to experimental warming: a meta-analysis. AB - Global warming potentially alters the terrestrial carbon (C) cycle, likely feeding back to further climate warming. However, how the ecosystem C cycle responds and feeds back to warming remains unclear. Here we used a meta-analysis approach to quantify the response ratios of 18 variables of the ecosystem C cycle to experimental warming and evaluated ecosystem C-cycle feedback to climate warming. Our results showed that warming stimulated gross ecosystem photosynthesis (GEP) by 15.7%, net primary production (NPP) by 4.4%, and plant C pools from above- and belowground parts by 6.8% and 7.0%, respectively. Experimental warming accelerated litter mass loss by 6.8%, soil respiration by 9.0%, and dissolved organic C leaching by 12.1%. In addition, the responses of some of those variables to experimental warming differed among the ecosystem types. Our results demonstrated that the stimulation of plant-derived C influx basically offset the increase in warming-induced efflux and resulted in insignificant changes in litter and soil C content, indicating that climate warming may not trigger strong positive C-climate feedback from terrestrial ecosystems. Moreover, the increase in plant C storage together with the slight but not statistically significant decrease of net ecosystem exchange (NEE) across ecosystems suggests that terrestrial ecosystems might be a weak C sink rather than a C source under global climate warming. Our results are also potentially useful for parameterizing and benchmarking land surface models in terms of C cycle responses to climate warming. PMID- 23687899 TI - Regional constraints to biological nitrogen fixation in post-fire forest communities. AB - Biological nitrogen fixation (BNF) is a key ecological process that can restore nitrogen (N) lost in wildfire and shape the pace and pattern of post-fire forest recovery. To date, there is limited information on how climate and soil fertility interact to influence different pathways of BNF in early forest succession. We studied asymbiotic (forest floor and soil) and symbiotic (the shrub Ceanothus integerrimus) BNF rates across six sites in the Klamath National Forest, California, USA. We used combined gradient and experimental phosphorus (P) fertilization studies to explore cross-site variation in BNF rates and then related these rates to abiotic and biotic variables. We estimate that our measured BNF rates 22 years after wildfire (6.1-12.1 kg N x ha(-1) x yr(-1)) are unlikely to fully replace wildfire N losses. We found that asymbiotic BNF is P limited, although this is not the case for symbiotic BNF in Ceanothus. In contrast, Ceanothus BNF is largely driven by competition from other vegetation: in high-productivity sites with high potential evapotranspiration (Et), shrub biomass is suppressed as tree biomass increases. Because shrub biomass governed cross-site variation in Ceanothus BNF, this competitive interaction led to lower BNF in sites with high productivity and Et. Overall, these results suggest that the effects of nutrients play a larger role in driving asymbiotic than symbiotic fixation across our post-fire sites. However, because symbiotic BNF is 8-90x greater than asymbiotic BNF, it is interspecific plant competition that governs overall BNF inputs in these forests. PMID- 23687900 TI - Loss of native herbaceous species due to woody plant encroachment facilitates the establishment of an invasive grass. AB - Although negative relationships between diversity (frequently measured as species richness) and invasibility at neighborhood or community scales have often been reported, realistic natural diversity gradients have rarely been studied at this scale. We recreated a naturally occurring gradient in species richness to test the effects of species richness on community invasibility. In central Texas savannas, as the proportion of woody plants increases (a process known as woody plant encroachment), herbaceous habitat is both lost and fragmented, and native herbaceous species richness declines. We examined the effects of these species losses on invasibility in situ by removing species that occur less frequently in herbaceous patches as woody plant encroachment advances. This realistic species removal was accompanied by a parallel and equivalent removal of biomass with no changes in species richness. Over two springs, the nonnative bunchgrass Bothriochloa ischaemum germinated significantly more often in the biomass-removal treatment than in unmanipulated control plots, suggesting an effect of native plant density independent of diversity. Additionally, significantly more germination occurred in the species-removal treatment than in the biomass-removal treatment. Changes in species richness had a stronger effect on B. ischaemum germination than changes in plant density, demonstrating that niche-related processes contributed more to biotic resistance in this system than did species neutral competitive interactions. Similar treatment effects were found on transplant growth. Thus we show that woody plant encroachment indirectly facilitates the establishment of an invasive grass by reducing native diversity. Although we found a negative relationship between species richness and invasibility at the scale of plots with similar composition and environmental conditions, we found a positive relationship between species richness and invasibility at larger scales. This apparent paradox is consistent with reports from other systems and may be the result of variation in environmental factors at larger scales similarly influencing both invasibility and richness. The habitat loss and fragmentation associated with woody plant encroachment are two of many processes that commonly threaten biodiversity, including climate change. Many of these processes are similarly likely to increase invasibility via their negative effects on native diversity. PMID- 23687901 TI - Species-area relationships always overestimate extinction rates from habitat loss: comment. PMID- 23687902 TI - Portable diagnosis method of hyperkalemia using potassium-recognizable poly(N isopropylacrylamide-co-benzo-15-crown-5-acrylamide) copolymers. AB - A novel, simple, portable, and low-cost method for diagnosis of hyperkalemia by using K(+)-recognizable poly(N-isopropylacrylamide-co-benzo-15-crown-5 acrylamide) [poly(NIPAM-co-B15C5Am)] linear copolymer as indicator is presented in this work. The pendent 15-crown-5 units in the linear copolymers can selectively and specifically recognize K(+) to form stable 2:1 "sandwich" host guest complexes, which cause the copolymer chains to change from the hydrophilic state to the hydrophobic state isothermally, whereas other tested metal ions (e.g., Li(+), Na(+), Cs(+), Mg(2+), Ca(2+), Sr(2+), Ba(2+), Cu(2+), Fe(3+), Pb(2+), Cd(2+), Cr(3+)) cannot be recognized. With increasing the 15-crown-5 content or the K(+) concentration, the poly(NIPAM-co-B15C5Am) linear copolymers exhibit higher sensitivity to K(+). The hyperkalemia can be simply diagnosed by observing the K(+)-induced optical transmittance change of human blood samples with poly(NIPAM-co-B15C5Am) linear copolymer as an indicator. Normal blood samples with low potassium level containing the poly(NIPAM-co-B15C5Am) linear copolymer are almost transparent since the copolymer is hydrophilic and soluble at the operating temperature. However, severe hyperkalemia samples with high potassium level become completely cloudy since the copolymer is hydrophobic and insoluble at this temperature. The presented diagnosis method with poly(NIPAM-co B15C5Am) linear copolymer as indicator is quite simple and low-cost, and it would bring a new candidate material to design simple and portable tools for diagnosis of hyperkalemia in the general population. Moreover, the results in this work provide valuable guidance for building novel poly(NIPAM-co-B15C5Am)-based artificial K(+)-recognizable "smart" or "intelligent" systems in various application fields. PMID- 23687903 TI - Conjugated block copolymer photovoltaics with near 3% efficiency through microphase separation. AB - Organic electronic materials have the potential to impact almost every aspect of modern life including how we access information, light our homes, and power personal electronics. Nevertheless, weak intermolecular interactions and disorder at junctions of different organic materials limit the performance and stability of organic interfaces and hence the applicability of organic semiconductors to electronic devices. Here, we demonstrate control of donor-acceptor heterojunctions through microphase-separated conjugated block copolymers. When utilized as the active layer of photovoltaic cells, block copolymer-based devices demonstrate efficient photoconversion well beyond devices composed of homopolymer blends. The 3% block copolymer device efficiencies are achieved without the use of a fullerene acceptor. X-ray scattering results reveal that the remarkable performance of block copolymer solar cells is due to self-assembly into mesoscale lamellar morphologies with primarily face-on crystallite orientations. Conjugated block copolymers thus provide a pathway to enhance performance in excitonic solar cells through control of donor-acceptor interfaces. PMID- 23687904 TI - "Flex-activated" mechanophores: using polymer mechanochemistry to direct bond bending activation. AB - We describe studies in mechanochemical transduction that probe the activation of bonds orthogonal to an elongated polymer main chain. Compression of mechanophore cross-linked materials resulted in the release of small molecules via cleavage of covalent bonds that were not integral components of the elongated polymer segments. The reactivity is proposed to arise from the distribution of force through the cross-linking units of the polymer network and subsequent bond bending motions that are consistent with the geometric changes in the overall reaction. This departure from contemporary polymer mechanochemistry, in which activation is achieved primarily by force-induced bond elongation, is a first step toward mechanophores capable of releasing side-chain functionalities without inherently compromising the overall macromolecular architecture. PMID- 23687905 TI - Exogenous galanin attenuates spatial memory impairment and decreases hippocampal beta-amyloid levels in rat model of Alzheimer's disease. AB - One of the major pathological characteristics of Alzheimer's disease (AD) is the presence of enhanced deposits of beta-amyloid peptide (Abeta). The neuropeptide galanin (GAL) and its receptors are overexpressed in degenerating brain regions in AD. The functional consequences of galaninergic systems plasticity in AD are unclear. The objective of the present study was to investigate whether exogenous galanin could attenuate spatial memory impairment and hippocampal Abeta aggregation in rat model of AD. The effects of Abeta, galanin, galanin receptor 1 agonist M617 and galanin receptor 2 agonist AR-M1896 on spatial memory were tested by Morris water maze. The effects of Abeta, galanin, M617 and AR-M1896 on hippocampal Abeta protein expression were evaluated by western blot assay. The expression of galanin, galanin receptors 1 and 2 in rats' hippocampus were detected by real time PCR and western blot assay. The results showed that (1) Galanin administration was effective in improving the spatial memory and decreasing hippocampal Abeta levels after intracerebroventricular injection of Abeta; (2) AR-M1896 rather than M617 could imitate these effects of galanin; (3) GAL and GALR2 mRNA and protein levels increased significantly in hippocampus after Abeta administration, while GALR1 mRNA and protein levels did not change; (4) GAL, AR-M1896 and M617 administration did not show significant effect on GAL, GalR1 and GalR2 mRNA and protein levels in hippocampus after Abeta administration. These results implied that galanin receptor 2, but not receptor 1 was involved in the protective effects against spatial memory impairment and hippocampal Abeta aggregation. PMID- 23687906 TI - Headache associated with cough: a review. AB - Headache only triggered by coughing is a rather uncommon condition. The aim of the present review is to present an overview of the diagnosis, clinical characteristics, pathophysiology and treatment of both primary and symptomatic cough headache and discuss other relevant headache disorders affected by coughing. The diagnosis of primary cough headache is made when headache is brought on and occurs only in association with coughing, straining or a Valsalva manoeuvre and in the absence of any abnormalities on neuro-imaging. In case an underlying pathology is identified as a cause of the headache, the diagnosis of symptomatic cough headache is made. The vast majority of these patients present with a Chiari malformation type I. Other frequently reported causes include miscellaneous posterior fossa pathology, carotid or vertebrobasilar disease and cerebral aneurysms. Consequently, diagnostic neuroimaging is key in the diagnosis of cough-related headache and guides treatment. Besides primary and symptomatic cough headache, several other both primary and secondary headache disorders exist where coughing acts as a trigger or aggravator of headache symptomatology. PMID- 23687907 TI - Development of a ReaxFF reactive force field for titanium dioxide/water systems. AB - A new ReaxFF reactive force field has been developed to describe reactions in the Ti-O-H system. The ReaxFF force field parameters have been fitted to a quantum mechanical (QM) training set containing structures and energies related to bond dissociation energies, angle and dihedral distortions, and reactions between water and titanium dioxide, as well as experimental crystal structures, heats of formation, and bulk modulus data. Model configurations for the training set were based on DFT calculations on molecular clusters and periodic systems (both bulk crystals and surfaces). ReaxFF reproduces accurately the QM training set for structures and energetics of small clusters. ReaxFF also describes the relative energetics for rutile, brookite, and anatase. The results of ReaxFF match reasonably well with those of QM for water binding energies, surface energies, and H2O dissociation energy barriers. To validate this ReaxFF description, we have compared its performance against DFT/MD simulations for 1 and 3 monolayers of water interacting with a rutile (110) surface. We found agreement within a 10% error between the DFT/MD and ReaxFF water dissociation levels for both coverages. PMID- 23687908 TI - Ocular inflammatory disease and ocular tuberculosis in a cohort of patients co infected with HIV and multidrug-resistant tuberculosis in Mumbai, India: a cross sectional study. AB - BACKGROUND: The prevalence and the patterns of ocular inflammatory disease and ocular tuberculosis (TB) are largely undocumented among Multidrug Resistant TB (MDR-TB) patients co-infected with Human Immunodeficiency Virus (HIV) and on antituberculosis and antiretroviral therapy (ART). METHODS: Lilavati Hospital and Research Center and Medecins Sans Frontieres (MSF) organized a cross-sectional ophthalmological evaluation of HIV/MDR-TB co-infected patients followed in an MSF run HIV-clinic in Mumbai, India, which included measuring visual acuity, and slit lamp and dilated fundus examinations. RESULTS: Between February and April 2012, 47 HIV/MDR-TB co-infected patients (including three patients with extensively drug-resistant TB) were evaluated. Sixty-four per cent were male, mean age was 39 years (standard deviation: 8.7) and their median (IQR) CD4 count at the time of evaluation was 264 cells/MUL (158-361). Thirteen patients (27%) had detectable levels of HIV viremia (>20 copies/ml). Overall, examination of the anterior segments was normal in 45/47 patients (96%). A dilated fundus examination revealed active ocular inflammatory disease in seven eyes of seven patients (15.5%, 95% Confidence Intervals (CI); 5.1-25.8%). 'These included five eyes of five patients (10%) with choroidal tubercles, one eye of one patient (2%) with presumed tubercular chorioretinitis and one eye of one patient (2%) with evidence of presumed active CMV retinitis. Presumed ocular tuberculosis was thus seen in a total of six patients (12.7%, 95% CI; 3.2-22.2%). Two patients who had completed anti-TB treatment had active ocular inflammatory disease, in the form of choroidal tubercles (two eyes of two patients). Inactive scars were seen in three eyes of three patients (6%). Patients with extrapulmonary TB and patients<39 years old were at significantly higher risk of having ocular TB [Risk Ratio: 13.65 (95% CI: 2.4-78.5) and 6.38 (95% CI: 1.05-38.8) respectively]. CONCLUSIONS: Ocular inflammatory disease, mainly ocular tuberculosis, was common in a cohort of HIV/MDR-TB co-infected patients in Mumbai, India. Ophthalmological examination should be routinely considered in HIV patients diagnosed with or suspected to have MDR-TB, especially in those with extrapulmonary TB. PMID- 23687909 TI - Botryoid Wilms' tumor: a case report and review of the literature. AB - Here, we report a new case of botryoid Wilms' tumor, a 4-year-old boy, who was referred to us with a chief complaint of dysuria and gross hematuria. The computed tomography and radical nephroureterectomy showed that a botryoid sarcoma like appearance occupied the right renal pelvis and extended into the bladder. Histologic examination further confirmed this case was a mixed type of Wilms' tumor. In a word, we demonstrated a rare case of botryoid Wilms' tumor, which extended from the renal pelvis into the ureter and bladder, then some degenerative and necrotic tissue with calcification discharged from urethra. Postoperative adjuvant chemotherapy was executed. At 24-month follow-up, there was no evidence of recurrence. PMID- 23687910 TI - Medicines and the media: news reports of medicines recommended for government reimbursement in Australia. AB - BACKGROUND: Previous analyses of the listings of trastuzumab on the Australian Pharmaceutical Benefits Scheme (PBS) and HPV vaccine on the National Immunisation Program (NIP) suggest a media influence on policy makers. We examined the timing and content of Australian newspaper reports of medicines in relation to Pharmaceutical Benefits Advisory Committee (PBAC) decisions. METHODS: We identified newspaper reports (2005-2008) of medicines recommended for PBS listing in 2006-2007, analysing the content for mentions of the medicine, PBS and medicine costs to the patient and the government and counting the numbers of articles published in the six months before, the month of, and the six months after the relevant PBAC meeting. Case studies examined reporting for infliximab for Crohn's Disease, pemetrexed for mesothelioma, and ADHD (Attention Deficit Hyperactivity Disorder) medicines atomoxetine and methylphenidate. RESULTS: Of 79 eligible medicines, 62 had news reports. Most often reported were HPV vaccine (1230 stories), trastuzumab (410), pemetrexed (83), botulinum toxin (71), lapatinib (65), methylphenidate (57), atomoxetine (54), infliximab (49), rotavirus vaccine (45). Eighteen medicines had >=20 news reports (total 2350 stories); nine of these cost more than AU$10,000 per course or year of treatment. For these 18 medicines, 31% of stories appeared in the six months prior to the PBAC meeting, 14% in the meeting month and 33% in the six months post-meeting. 38% of the stories had >=3 medicine mentions, 37% referred to the PBS, 24% to cost to the patient, and 9% cost to Government.There was active patient lobby group campaigning in support of listing of infliximab and pemetrexed; the stories for ADHD were often more negative, referring to the dangers of the medicines and sometimes questioning the appropriateness of treatment and public subsidy. There was little discussion of the PBAC's evidence-based decision-making processes. CONCLUSIONS: While there was no general trend to increased news reporting associated with PBAC meetings, some drugs did attract media attention. With more new and expensive drugs, decisions on public funding will become increasingly difficult. The media have an important role in enhancing public understanding of the issues around resource allocation. Specialist journalists, guidelines and checklists may help reporting. PMID- 23687911 TI - Development of new measurement system of thoracic excursion with biofeedback: reliability and validity. AB - BACKGROUND: Respiratory rehabilitation reduces breathlessness from patient with respiratory dysfunction. Chest expansion score, which represents the circumference magnitude of the thoracic cage, is used for a target when treating patients with respiratory disease. However, it is often difficult for patients to understand the changes in the respiratory status and be motivated for therapy continuously. We developed a new measurement system with biofeedback named BREATH which shows chest expansion scores in real time. The purpose of this study was to determine the reliability and validity of the novel system in advance of clinical application. METHODS: Three evaluators measured chest expansion in 33 healthy individuals using tape measure, which is used for the measurement traditionally, and BREATH. The wire for BREATH system was threaded over the thoracic continuously and the data was recorded automatically; whereas the tape was winded and measured each maximal expiration and inspiration timing by evaluator. All participants were performed both measurement simultaneously for three times during deep breath. In this study, we studied chest expansion score without using biofeedback data of BREATH to check the validity of the result. To confirm intra- and inter-evaluator reliability, we computed intra-class correlations (ICCs). We used Pearson's correlation coefficient to evaluate the validity of measurement result by BREATH with reference to the tape measure results. RESULTS: The average (standard deviation) chest expansion scores for all, men and women by the tape measure were 5.53 (1.88), 6.40 (1.69) and 5.22 (1.39) cm, respectively, and those by BREATH were 3.89 (2.04), 4.36 (1.83) and 2.89 (1.66) cm, respectively. ICC within and among the three evaluators for BREATH and the tape measure were 0.90 0.94 and 0.85-0.94 and 0.85 and 0.82, respectively. The correlation coefficient between the two methods was 0.76-0.87. CONCLUSION: The novel measurement system, BREATH, has high intra- and inter-evaluator reliabilities and validity; therefore it can lead us more effective respiratory exercise. Using its biofeedback data, this system may help patients with respiratory disease to do exercises more efficiently and clinicians to assess the respiratory exercise more accurately. PMID- 23687912 TI - Mechanisms of photoisomerization and water-oxidation catalysis of mononuclear ruthenium(II) monoaquo complexes. AB - A ligation of Ru(tpy)Cl3 (tpy = 2,2':6',2"-terpyridine) with 2-(2-pyridyl)-1,8 naphthyridine) (pynp) in the presence of LiCl gave distal-[Ru(tpy)(pynp)Cl](+) (d 1Cl) selectively, whereas the ligation gave proximal-[Ru(tpy)(pynp)OH2](2+) (p 1H2O) selectively in the absence of halide ions. (The proximal/distal isomers were defined by the structural configuration between the 1,8-naphthyridine moiety and the aquo or chloro ligand.) An aquation reaction of d-1Cl quantitatively afforded distal-[Ru(tpy)(pynp)OH2](2+) (d-1H2O) in water, and d-1H2O is quantitatively photoisomerized to p-1H2O. The mechanism of the photoisomerization was investigated by transient absorption spectroscopy and quantum chemical calculations. The temperature dependence of the transient absorption spectral change suggests existence of the thermally activated process from the (3)MLCT state with the activation energy (DeltaE = 49 kJ mol(-1)), which is close to that (41.7 kJ mol(-1)) of the overall photoisomerization reaction. However, quantum chemical calculations suggest another activation process involving the conformational change of the pentacoordinated distal structure to the proximal structure. Quantum chemical calculations provide redox potentials and pK(a) values for proton-coupled electron transfer reactions from Ru(II)-OH2 to Ru(IV)?O in good agreement with experiments and provide an explanation for mechanistic differences between d-1H2O and p-1H2O with respect to water oxidation. The calculations show that water nucleophilic attack (WNA) on d-[Ru(V)-O](3+) (the ruthenyl oxo species derived from d-1H2O, calculated DeltaG(?) of 87.9 kJ/mol) is favored over p-[Ru(V)-O](3+) (calculated DeltaG(?) of 104.6 kJ/mol) for O-O bond formation. Examination of the lowest unoccupied molecular orbitals in d- and p [Ru(V)-O](3+) indicates that more orbital amplitude is concentrated on the [Ru-O] unit in the case of d-[Ru(V)-O](3+) than in the case of p-[Ru(V)-O](3+), where some of the amplitude is instead delocalized over the pynp ligand, making this isomer less electrophilic. PMID- 23687913 TI - Mobilization with movement, thoracic spine manipulation, and dry needling for the management of temporomandibular disorder: a prospective case series. AB - The purpose of this case series was to describe the outcomes of patients with temporomandibular disorder (TMD) treated with mobilization with movement (MWM) directed at the temporomandibular joint (TMJ) and the cervical spine, thoracic manipulation, and trigger point (TrP) dry needling. Fifteen patients with TMD completed the Steigerwald/Maher TMD disability questionnaire, the Visual Analog Scale (VAS), and maximal mouth opening (MMO) at baseline. The VAS and MMO were also collected at 15 days posttreatment and at a 2-month follow-up, and the Steigerwald/Maher TMD disability questionnaire was completed at the 2-month follow-up. Repeated measure ANOVAs were used to determine the effects of the intervention on each outcome. Within-group effect sizes were calculated in order to assess clinical effectiveness. Fifteen patients participated in this case series. The ANOVA revealed significant decreases (all, p < 0.01) VAS mean, VAS Worst, and VAS Best between baseline and final visit of 25.7 (95% CI; 17.7, 33.8); 33.2 (95% CI; 23.4, 43.0); 18.4 (12.1, 24.7); and 28.3 (95% CI; 18.8, 37.9); 36.1 (95% CI; 25.0, 47.3); 19.7 (95% CI; 12.8, 26.7) between baseline and the 2-month follow-up periods, respectively. Additionally, the ANOVA revealed significant increases (all, p < 0.01) in MMO and disability following the physical therapy management strategy between baseline and final visit with a mean of 11.4 (95% CI, 6.9, 15.9) and 10.2 (95% CI, 5.2, 15.2) between baseline and the 2-month follow-up. Within-group effect sizes were large (d > 1.0) for all outcomes at both follow-up periods. Patients with TMD treated with a multimodal treatment exhibited significant and clinical improvements in pain intensity, disability, and MMO. PMID- 23687914 TI - Patient acceptance of non-invasive testing for fetal aneuploidy via cell-free fetal DNA. AB - OBJECTIVE: To evaluate factors associated with patient acceptance of noninvasive prenatal testing for trisomy 21, 18 and 13 via cell-free fetal DNA. METHODS: This was a retrospective study of all patients who were offered noninvasive prenatal testing at a single institution from 1 March 2012 to 2 July 2012. Patients were identified through our perinatal ultrasound database; demographic information, testing indication and insurance coverage were compared between patients who accepted the test and those who declined. Parametric and nonparametric tests were used as appropriate. Significant variables were assessed using multivariate logistic regression. The value p < 0.05 was considered significant. RESULTS: Two hundred thirty-five patients were offered noninvasive prenatal testing. Ninety three patients (40%) accepted testing and 142 (60%) declined. Women who accepted noninvasive prenatal testing were more commonly white, had private insurance and had more than one testing indication. There was no statistical difference in the number or the type of testing indications. Multivariable logistic regression analysis was then used to assess individual variables. After controlling for race, patients with public insurance were 83% less likely to accept noninvasive prenatal testing than those with private insurance (3% vs. 97%, adjusted RR 0.17, 95% CI 0.05-0.62). CONCLUSION: In our population, having public insurance was the factor most strongly associated with declining noninvasive prenatal testing. PMID- 23687915 TI - PA-824 , moxifloxacin and pyrazinamide combination therapy for tuberculosis. AB - INTRODUCTION: New treatment regimens are urgently required for tuberculosis (TB). The existing four-drug regimen for TB is > 20 years old, with multidrug resistant (MDR) and extensively drug-resistant (XDR) TB on the increase. AREAS COVERED: Recently, the first novel potential combination TB treatment regimen for both drug-sensitive and MDR TB incorporating a new nitroimidazole compound, PA-824 , was investigated in a Phase II proof-of-concept clinical trial. This article reviews the rationale for this novel study, discusses the development strategy for PA-824 and highlights the study findings and its implications for future development of this regimen. EXPERT OPINION: Expert opinion will be offered on the utility of this new multicomponent treatment regimen. We will highlight how this study informs the development pathway for future novel TB regimens and explore the PA-824, moxifloxacin (MOX) and pyrazinamide combination as a first step towards developing a single treatment regimen for both drug-sensitive and drug-resistant diseases. PMID- 23687916 TI - Probing the structure and dynamics of confined water in AOT reverse micelles. AB - Reverse micelles are attractive nanoscale systems used for the confinement of molecules in studies of structure and chemical reactions, including protein folding, and aggregation. The simulation of reverse micelles, in which a water "pool" is separated from a nonpolar bulk phase by a surfactant layer, poses significant challenges to empirical force fields due to the diversity of interactions between nonpolar, polar, and charged groups. We have explored the dependence of system density, reverse micelle structure, and water configurational relaxation times as a function of reverse micelle composition, including water:surfactant ratio, absolute number of water molecules, and force field using molecular dynamics simulations. The resulting structures and dynamics are found to depend more on the force field used than on varying interpretations of the water:surfactant ratio in terms of absolute size of the reverse micelle. Substantial deviations from spherical reverse micelle geometries are observed in all unrestrained simulations. Rotational anisotropy decay times and water residence times show a strong dependence on force field and water model used, but power-law relaxation in time is observed independent of the force field. Our results suggest the need for further experimental study of reverse micelles that can provide insight into the distribution and dynamics of shape fluctuations in these complex systems. PMID- 23687917 TI - Is making a risky choice based on a weighting and adding process? An eye-tracking investigation. AB - The debate about whether making a risky choice is based on a weighting and adding process has a long history and is still unresolved. To address this long-standing controversy, we developed a comparative paradigm. Participants' eye movements in 2 risky choice tasks that required participants to choose between risky options in single-play and multiple-play conditions were separately compared with those in a baseline task in which participants naturally performed a deliberate calculation following a weighting and adding process. The results showed that, when participants performed the multiple-play risky choice task, their eye movements were similar to those in the baseline task, suggesting that participants may use a weighting and adding process to make risky choices in multiple-play conditions. In contrast, participants' eye movements were different in the single-play risky choice task versus the baseline task, suggesting that participants were not likely to use a weighting and adding process to make risky choices in single-play conditions and were more likely to use a heuristic process. We concluded that an expectation-based index for predicting risk preferences is applicable in multiple-play conditions but not in single-play conditions, implying the need to improve current theories that postulate the use of a heuristic process. PMID- 23687918 TI - Retrieval-induced forgetting in recall: competitor interference revisited. AB - Participants studied category-exemplar pairs (FRUIT Cherry, FRUIT Grape) and then practiced some of the items (Cherry). In Experiment 1, practice that involved retrieving the item from memory suppressed recall of related items (Grape), a finding known as the retrieval-induced forgetting (RIF) effect. In Experiment 2, practice that involved studying the item without retrieval produced no RIF effect. Both retrieval and nonretrieval practice facilitated the subsequent recall of practiced items (Cherry). The dissociation between "strengthening" of practiced items and forgetting of related items is thought to be evidence that RIF is the result of inhibition during earlier retrieval attempts rather than interference from competing memories at retrieval. However, simulations of the SAM-REM model show that competitor interference can account for this dissociation. Experiments 3-6 supported the predictions of the model by demonstrating that nonretrieval practice can produce the RIF effect under conditions that emphasize context encoding or increase the number of competitors. PMID- 23687919 TI - Spatial working memory is necessary for actions to guide thought. AB - Directed actions can play a causal role in cognition, shaping thought processes. What drives this cross-talk between action and thought? I investigated the hypothesis that representations in spatial working memory mediate interactions between directed actions and problem solving. Participants attempted to solve an insight problem while occasionally either moving their eyes in a pattern embodying the problem's solution or maintaining fixation. They simultaneously held either a spatial or verbal stimulus in working memory. Participants who moved their eyes in a pattern that embodied the solution were more likely to solve the problem, but only while also performing a verbal working memory task. Embodied guidance of insight was eliminated when participants were instead engaged in a spatial working memory task while moving their eyes, implying that loading spatial working memory prevented movement representations from influencing problem solving. These results point to spatial working memory as a mechanism driving embodied guidance of insight, suggesting that actions do not automatically influence problem solving. Instead, cross-talk between action and higher order cognition requires representations in spatial working memory. PMID- 23687921 TI - Novel Gold(I) and Silver(I) Complexes of Phosphorus-1,1,-dithiolates and Molecular Structure of [O,O'-(Bornyl)2PS2]H3NC(CH3)3. AB - BACKGROUND: The novel chiral phosphorus-1,1-dithiolates [4-CH3OC6H4P(S)(OR)S] [H3NC(CH3)3]+ were synthesized by the reaction of [RPS2)]2 (R = 4-MeOC6H4) or P2S5 and the respective alcohol ROH (R = myrtanyl, 2-naphthylethyl, myrtenyl, borneol) in toluene. The reaction of phosphorus-1,1-dithiolates 1-4 and Au(tht)Cl, AuClPPh3 or AgNO3 and PPh3 gave rise to gold(I)- and silver(I) complexes in THF. All compounds have been characterised by elemental analyses, IR, NMR (1H-, 13C- and 31P-) spectroscopy as well as MS measurements. Optical rotation values confirmed the chirality of the compounds. The Compound 4 has been characterized structurally by X-ray crystallography. RESULTS: Phosphorus-1,1, dithiolate compounds were formed as liquids and were treated with suitable amine in order to convert them to their salts 1-4 . They have been successfully characterized spectroscopically (IR, 1H, 13C, 31P NMR) as well as mass spectra. The compound 4 has been also structurally by X-ray crystallography. The compound 4 crystallizes in the orthorhombic space group P2(1)2(1)2(1) with Z = 4. Compounds containing phosphorus and sulfur donor atoms are excellent ligands due to offering many metal complexes especially group 11-12 metals. The synthesis of gold(I) and silver(I) complexes with chiral phosphorus-1,1,-dithiolate and triphenylphosphine have been described and investigated. CONCLUSIONS: In the present work, we report the synthesis, charactreization of the chiral phosphorus 1,1-dithiolate ligands and preparing the gold(I) and silver(I) phosphorus-1,1 dithiolate or S-donor with phosphine complexes. The molecular structure of the Compound 4 was determined by X-ray diffraction. Due to an easy synthesis method of phosphorus-1,1-dithiolate compounds and a good complexion reagent, it is possible the improvement of the collecting metallic gold or silver from the minerals. When the more ionic salt of phosphorus-1,1-dithiolate compounds were prepared in this way, the water can be used as a cheap solvent. As a result, it can be an alternatively method for the collecting metallic gold or silver from the minerals in future. PMID- 23687920 TI - Cross-age comparisons reveal multiple strategies for lexical ambiguity resolution during natural reading. AB - Eye tracking was used to investigate how younger and older (60 or more years) adults use syntactic and semantic information to disambiguate noun/verb (NV) homographs (e.g., park). In event-related potential (ERP) work using the same materials, Lee and Federmeier (2009, 2011) found that young adults elicited a sustained frontal negativity to NV homographs when only syntactic cues were available (i.e., in syntactic prose); this effect was eliminated by semantic constraints. The negativity was only present in older adults with high verbal fluency. The current study shows parallel findings: Young adults exhibit inflated first fixation durations to NV homographs in syntactic prose, but not semantically congruent sentences. This effect is absent in older adults as a group. Verbal fluency modulates the effect in both age groups: High fluency is associated with larger first fixation effects in syntactic prose. Older, but not younger, adults also show significantly increased rereading of the NV homographs in syntactic prose. Verbal fluency modulates this effect as well: High fluency is associated with a reduced tendency to reread, regardless of age. This relationship suggests a trade-off between initial and downstream processing costs for ambiguity during natural reading. Together the eye-tracking and ERP data suggest that effortful meaning selection recruits mechanisms important for suppressing contextually inappropriate meanings, which also slow eye movements. Efficacy of frontotemporal circuitry, as captured by verbal fluency, predicts the success of engaging these mechanisms in both young and older adults. Failure to recruit these processes requires compensatory rereading or leads to comprehension failures (Lee & Federmeier, 2012). PMID- 23687922 TI - Clinal distribution of human genomic diversity across the Netherlands despite archaeological evidence for genetic discontinuities in Dutch population history. AB - BACKGROUND: The presence of a southeast to northwest gradient across Europe in human genetic diversity is a well-established observation and has recently been confirmed by genome-wide single nucleotide polymorphism (SNP) data. This pattern is traditionally explained by major prehistoric human migration events in Palaeolithic and Neolithic times. Here, we investigate whether (similar) spatial patterns in human genomic diversity also occur on a micro-geographic scale within Europe, such as in the Netherlands, and if so, whether these patterns could also be explained by more recent demographic events, such as those that occurred in Dutch population history. METHODS: We newly collected data on a total of 999 Dutch individuals sampled at 54 sites across the country at 443,816 autosomal SNPs using the Genome-Wide Human SNP Array 5.0 (Affymetrix). We studied the individual genetic relationships by means of classical multidimensional scaling (MDS) using different genetic distance matrices, spatial ancestry analysis (SPA), and ADMIXTURE software. We further performed dedicated analyses to search for spatial patterns in the genomic variation and conducted simulations (SPLATCHE2) to provide a historical interpretation of the observed spatial patterns. RESULTS: We detected a subtle but clearly noticeable genomic population substructure in the Dutch population, allowing differentiation of a north-eastern, central western, central-northern and a southern group. Furthermore, we observed a statistically significant southeast to northwest cline in the distribution of genomic diversity across the Netherlands, similar to earlier findings from across Europe. Simulation analyses indicate that this genomic gradient could similarly be caused by ancient as well as by the more recent events in Dutch history. CONCLUSIONS: Considering the strong archaeological evidence for genetic discontinuity in the Netherlands, we interpret the observed clinal pattern of genomic diversity as being caused by recent rather than ancient events in Dutch population history. We therefore suggest that future human population genetic studies pay more attention to recent demographic history in interpreting genetic clines. Furthermore, our study demonstrates that genetic population substructure is detectable on a small geographic scale in Europe despite recent demographic events, a finding we consider potentially relevant for future epidemiological and forensic studies. PMID- 23687923 TI - Targeting hypoxia for sensitization of tumors to radio- and chemotherapy. AB - The heterogeneous distribution of hypoxic regions within solid tumors renders them refractive to chemo- and radio-therapies and contributes positively to tumor invasion and metastasis. Moreover, hypoxia favors the enrichment of cancer stem cells by interacting with differentiation signals via the maintenance of stem cell properties of undifferentiated cells or via the induction of cellular dedifferentiation. The discovery of the hypoxia inducible factor 1alpha (HIF 1alpha) has led to the current extensive interest in the signal molecules related to tumor hypoxia and the major regulatory pathways that control the family of hypoxia-inducible factors as potential molecular targets for cancer therapeutics. Multiple approaches have been developed to circumvent hypoxia-induced resistance, such as oxygenating tumors, using radiosensitizers and more recently using bio reductively activated pro-drugs. Recent evidence suggests that radio sensitization has undergone a paradigm shift from compounds that enhance the effect of radiation via mimicking oxygen, to compounds that target HIF-mediated signaling pathways eventually reducing radio-resistance. In this paper, we give an overview of our recent understandings in hypoxia research, discuss the mechanisms of resistance of hypoxic tumors and of hypoxia-induced cancer stem cells and highlight the latest advances in cancer treatments that target tumor hypoxia and the resistant populations of cancer stem cells. Classical and novel radio-sensitization methods, mainly the molecular inhibition of HIFs and downstream targets and the use of hypoxia-activated drugs are compared and contrasted. Such multi-faceted targeted therapies ultimately enhance treatment outcomes and reduce normal tissue toxicity by the selective targeting of solid tumors. PMID- 23687924 TI - Therapeutic proteins and nanotechnology: immune response and stealth bioengineered constructs. AB - With unique potentials for organ drug delivery and targeting, intravenous administration of drugs has represented a key tool in biomedicine. A major concern of this route is the rapid capture and destruction of foreign substances by circulating immune cells. Knowledge about the inter-relationships between drugs and blood cells is essential for a better control in drug stability and bioavailability. In this review, both classical pathways and novel insights into the immune mechanisms leading to drug clearance after systemic delivery are described. Drug surface chemistry and size have been identified as critical factors for the activation of host immune responses, and their modification has been extensively explored in order to evade immune surveillance. Common strategies to camouflage drug surfaces through polymer-grafting are presented, with special emphasis on Poly(Ethylene Glycol) (PEG) linkages, one of the most diverse strategies for modifying biomolecular surfaces. Finally, the use of "smart shields", such as PEG attachments shed at particular intracellular conditions, is briefly overviewed as an interesting approach for balancing circulation half lives VS bioavailability in polymer-grafted formulations. PMID- 23687925 TI - Nanocarriers for anticancer drugs--new trends in nanomedicine. AB - This review provides a brief overview of the variety of carriers employed for targeted drug delivery used in cancer therapy and summarizes advantages and disadvantages of each approach. Particularly, the attention was paid to polymeric nanocarriers, liposomes, micelles, polyethylene glycol, poly(lactic-co-glycolic acid), dendrimers, gold and magnetic nanoparticles, quantum dots, silica nanoparticles, and carbon nanotubes. Further, this paper briefly focuses on several anticancer agents (paclitaxel, docetaxel, camptothecin, doxorubicin, daunorubicin, cisplatin, curcumin, and geldanamycin) and on the influence of their combination with nanoparticulate transporters to their properties such as cytotoxicity, short life time and/or solubility. PMID- 23687927 TI - Aptamers as targeting delivery devices or anti-cancer drugs for fighting tumors. AB - Aptamer researches applied to the treatment of human cancers have increased since their discovery in 1990. This is due to different factors including: 1) the technical possibility to select, by SELEX-based procedures, specific aptamers targeting virtually any given molecule, 2) the aptamer favorable bio-activity in vivo, 3) the low production costs and 4) the ease synthesis and storage for the marketing. In the field of cancer treatments, aptamers have been studied as tumor specific agents driving drugs into cancer cells; additionally they have been used as anti-neoplastic agents, able to inhibit tumor cell growth and dissemination when administered alone or in combination with conventional anti-neoplastic drugs. Aptamers are gaining an increased interest for pharmaceutical companies and some of them are under clinical evaluation trials. In this review we update the findings about the use of aptamers as "escort" molecules able to drive drugs into the cells and as antineoplastic drugs. Current anti-neoplastic treatments suffer from the intrinsic toxicity related to the un-specific targeting of both normal and tumorigenic proliferating cells. The aptamers could be useful to improve: 1) the selective targeting of molecules essential for the viability and expansion of tumor cells and/or the selective driving of chemotherapies into tumor cells, thus resulting in higher effectiveness and lower systemic side effects compared to conventional anti-neoplastic drugs alone and 2) to improve the therapeutic index of currently used chemotherapies. Even if some problems related to the in vivo stability and pharmacokinetic/dynamics of aptamers remain to be improved, their potential use in the treatment of different human cancers is getting closer and closer to a practical therapeutic use. PMID- 23687926 TI - Multifunctional anti-cancer nano-platforms are moving to clinical trials. AB - Cancer management needs rapid, non-invasive diagnosis and tumour-specific therapeutics which is unfortunately lacking for most cancer types. Novel approaches for cancer management aim at providing customized therapy according to individual diagnoses, determined by gene expression profiling, in particular, targeting highly selective monoclonal antibodies (mAbs) to single cancer cell antigens, in combination with highly cytotoxic drugs, thereby avoiding the unwanted side effects of conventional chemotherapy. Multifunctional nano-vectors that combine new and more powerful drugs and/or probes for diagnostic imaging with tumour surface-specific ligands/antibodies have been developed. These nano vectors have displayed superior selective anti-tumour activity compared to antibodies or standard anti-cancer drugs/agents alone both in-vitro, and in preclinical and clinical models. Anti-cancer nano-platforms can significantly improve early cancer detection and ameliorate therapeutic strategies. In the immediate future nano-technology may enable the simultaneous early detection and selective inactivation of cancer cells before they develop into full blown tumours. PMID- 23687928 TI - Semisynthetic hybrid biopolymers for non-pharmacological intervention of the microcirculation. AB - The microcirculation presents functional organic structures in the range of 1-100 micrometers, commensurate with the upper end of nanotechnology constructs. When devices are designed and deployed to deliver treatment via the circulation they ultimately contend with the smallest dimensions of both healthy and impaired microvessels, particularly the capillary system whose ability to sustain the tissue is assessed by measuring "functional capillary density" (FCD). FCD is directly determined by hydrostatic and osmotic pressures and indirectly by the effect of cardiovascular regulators, particularly the bioavailability of nitric oxide (NO) resulting from fluid mechanical effects and transport in the submicroscopic cell free plasma layer (CFL) located between blood and microvascular wall. Macromolecules using colloids as templates that are surface decorated with polyethylene glycol (PEG) become immuno-invisible and can be introduced into the circulation to manipulate the NO environment in blood and the endothelium. PEG-albumin is a class of molecules with novel plasma expansion properties that directly interacts with the microcirculation via CFL related effects. The principal application of this technology is in transfusion medicine and the plasma expanders used to treat blood losses and concomitant effects on microvascular function due to related acute inflammatory conditions and ischemia. PMID- 23687929 TI - Human therapeutics: a nanotechnology approach. PMID- 23687932 TI - Trimethylamine N-oxide (TMAO) and tert-butyl alcohol (TBA) at hydrophobic interfaces: insights from molecular dynamics simulations. AB - TMAO, a potent osmolyte, and TBA, a denaturant, have similar molecular architecture but somewhat different chemistry. We employ extensive molecular dynamics simulations to quantify their behavior at vapor-water and octane-water interfaces. We show that interfacial structure-density and orientation-and their dependence on solution concentration are markedly different for the two molecules. TMAO molecules are moderately surface active and adopt orientations with their N-O vector approximately parallel to the aqueous interface. That is, not all methyl groups of TMAO at the interface point away from the water phase. In contrast, TBA molecules act as molecular amphiphiles, are highly surface active, and, at low concentrations, adopt orientations with their methyl groups pointing away and the C-O vector pointing directly into water. The behavior of TMAO at aqueous interfaces is only weakly dependent on its solution concentration, whereas that of TBA depends strongly on concentration. We show that this concentration dependence arises from their different hydrogen bonding capabilities-TMAO can only accept hydrogen bonds from water, whereas TBA can accept (donate) hydrogen bonds from (to) water or other TBA molecules. The ability to self-associate, particularly visible in TBA molecules in the interfacial layer, allows them to sample a broad range of orientations at higher concentrations. In light of the role of TMAO and TBA in biomolecular stability, our results provide a reference with which to compare their behavior near biological interfaces. Also, given the ubiquity of aqueous interfaces in biology, chemistry, and technology, our results may be useful in the design of interfacially active small molecules with the aim to control their orientations and interactions. PMID- 23687933 TI - Evaluation of elite table tennis players' technique effectiveness. AB - This study constructed a technique effectiveness evaluation formula for table tennis players based on the relationship between the scoring rate and usage rate of techniques and established the evaluation criteria through the examination of 224 matches of the world's top 35 players. It also built a competition performance formula with the score difference theory for the exploration of the correlation between player technique effectiveness and competition performance. The results showed the three indices--the technique effectiveness of the first and third strokes (TE1,3), the second and fourth strokes (TE2,4) and the after fourth strokes (TE(>4))--could help better evaluate the technique effectiveness of elite players. The comparative analysis of Chinese elite table tennis players and players from other countries and regions revealed that Chinese players as a whole were "excellent" in all the examined techniques except in the male's "first and third strokes"; while players from other countries and regions were overall "general". The case analysis of two world top players further indicated that correlation analysis of technique effectiveness and competition performance could help identify the technique indices highly correlated with player competition performance. PMID- 23687931 TI - Emerging drugs for the treatment of diabetic ulcers. AB - INTRODUCTION: Diabetic ulcers are chronic nonhealing ulcerations that despite the available medical tools still result in high amputation rates. Growing evidence suggests that alteration of the biochemical milieu of the chronic wound plays a significant role in impaired diabetic wound healing. AREAS COVERED: The basic pathophysiology and the conventional treatment strategy of diabetic foot ulcers have been reviewed in the first section. In the second part, the most up-to-date bench and translational research in the field are described. The third section focuses on the drugs currently under development and the ongoing clinical trials evaluating their safety and efficacy. Finally, the major drug development issues and the possible scientific approaches to overcome them are analyzed. EXPERT OPINION: Significant strides in understanding the chronic wound development have led to the development of topical therapies to address aberrant expression of growth factors and overexpression of inflammatory cytokines. Current research in the laboratory suggests that while decreased growth factor expression occurs at the local wound level, increased systemic serum levels of growth factors suggest growth factor resistance. PMID- 23687934 TI - Quaternizing diboranes(4): highly divergent outcomes and an inorganic Wagner Meerwein rearrangement. AB - Apart from a few compounds under heavy use in organic chemistry, diboranes are relatively exotic and poorly understood. Recently, interest in these molecules has intensified with the advent of so-called "sp(2)-sp(3)" diboranes which exhibit useful reactivity toward organic substrates. In our hands, addition of Lewis bases to dihalodiorganyl diboranes(4) has previously shown some very surprising reactivity, including a substituent exchange between the boron atoms, and diboranes in which halide atoms bridge the B-B bond. Herein we have expanded the range of diborane(4) and Lewis base reaction partners, in the process uncovering three new reactivity patterns as well as some cases where mixtures are obtained. Trends are established for the preferential formation of certain products which rationalize the results based on electronic and steric effects. The substituent exchange, clearly based on an inorganic version of the well-known Wagner-Meerwein rearrangement, was also found to be an equilibrium reaction with the halide-bridged Lewis adducts on the other side. PMID- 23687935 TI - Gold(III)-catalyzed three-component coupling reaction (TCC) selective toward furans. AB - An efficient three-component coupling reaction toward a variety of furan derivatives has been developed. This cascade transformation proceeds via the gold catalyzed coupling reaction of phenylglyoxal derivatives, secondary amines, and terminal alkynes, under the reaction conditions, that undergoes cyclization into the furan core. PMID- 23687936 TI - Simple boric acid-based fluorescent focusing for sensing of glucose and glycoprotein via multipath moving supramolecular boundary electrophoresis chip. AB - Boric acid-based fluorescent complex probe of BBV-HPTS (boronic acid-based benzyl viologen (BBV) and hydroxypyrene trisulfonic acid trisodium salt (HPTS)) was rarely used for sensitive sensing of saccharide (especially glycoprotein) via electrophoresis. We proposed a novel model of moving supramolecular boundary (MSB) formed with monosaccharide or glycoprotein in microcolumn and the complex probe of BBV-HPTS in the cathodic injection tube, developed a method of MSB fluorescent focusing for sensitive recognition of monosaccharide and glycoprotein, and designed a special multipath capillary electrophoresis (CE) chip for relative experiments. As a proof of concept, glucose and hemoglobin A1c (HbA1c) were respectively used as the mode saccharide and glycoprotein for the relevant demonstration. The experiments revealed that (i) the complex of BBV-HPTS could interact with free glucose or bound one in glycoprotein; (ii) the fluorescent signal was a function of glucose or glycoprotein content approximately; and (iii) interestingly the fluorescent band motion was dependent on glucose content. The developed method had the following merits: (i) low cost; (ii) low limit of detection (down to 1.39 pg/mL for glucose and 2.0 pg per capillary HbA1c); and (iii) high throughput (up to 12 runs or more per patch) and speed (less than 5 min). The developed method has potential use for sensitive monitoring of monosaccharide and glycoprotein in biomedical samples. PMID- 23687930 TI - Plasma concentrations of angiogenic/anti-angiogenic factors have prognostic value in women presenting with suspected preeclampsia to the obstetrical triage area: a prospective study. AB - OBJECTIVE: To prospectively determine the prognostic value of maternal plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng) and soluble vascular endothelial growth factor receptors-1 and -2 (sVEGFR-1 and -2) in identifying patients with suspected preeclampsia (PE), who require preterm delivery (PTD) or develop adverse outcomes. STUDY DESIGN: This prospective cohort study included 85 consecutive patients who presented to the obstetrical triage area at 20-36 weeks with a diagnosis of "rule out PE." Patients were classified as: 1) those who remained stable until term (n = 37); and 2) those who developed severe PE and required PTD (n = 48). Plasma concentrations of PlGF, sEng and sVEGFR-1 and -2 were determined by ELISA. RESULTS: Patients with PlGF/sVEGFR-1 <=0.05 multiples of the median (MoM) or PlGF/sEng <=0.07 MoM were more likely to deliver preterm due to PE [adjusted odd ratio (aOR) 7.4 and 8.8], and to develop maternal (aOR 3.7 and 2.4) or neonatal complications (aOR 10.0 and 10.1). Among patients who presented <34 weeks of gestation, PlGF/sVEGFR-1 <= 0.035 MoM or PlGF/sEng <=0.05 MoM had a sensitivity of 89% (16/18), specificity of 96% (24/25) and likelihood ratio for a positive test of 22 to identify patients who delivered within 2 weeks. The addition of the PlGF/sVEGFR-1 ratio to standard clinical tests improved the sensitivity at a fixed false-positive rate of 3% (p = 0.004) for the identification of patients who were delivered due to PE within 2 weeks. Among patients who had a plasma concentration of PlGF/sVEGFR-1 ratio <=0.035 MoM, 0.036-0.34 MoM and >=0.35 MoM, the rates of PTD <34 weeks were 94%, 27% and 7%, respectively. CONCLUSIONS: The determination of angiogenic/anti-angiogenic factors has prognostic value in patients presenting to the obstetrical triage area with suspected PE for the identification of those requiring preterm delivery and at risk for adverse maternal/neonatal outcomes. PMID- 23687937 TI - The durability of examination gloves used on intensive care units. AB - BACKGROUND: The use of examination gloves is part of the standard precautions to prevent medical staff from transmission of infectious agents between patients. Gloves also protect the staff from infectious agents originating from patients. Adequate protection, however, depends on intact gloves. The risk of perforation of examination gloves is thought to correlate with duration of wearing, yet, only very few prospective studies have been performed on this issue. METHODS: A total number of 1500 consecutively used pairs of examination gloves of two different brands and materials (latex and nitrile) were collected over a period of two months on two ICU's. Used gloves were examined for micro perforations using the "water-proof-test" according to EN 455-1. Cox-regression for both glove types was used to estimate optimal changing intervals. RESULTS: Only 26% of gloves were worn longer than 15 min. The total perforation rate was 10.3% with significant differences and deterioration of integrity of gloves between brands (p<0.001). Apart from the brand, "change of wound dressing" (p = 0.049) and "washing patients" (p = 0.001) were also significantly associated with an increased risk of perforation. CONCLUSION: Medical gloves show marked differences in their durability that cannot be predicted based on the technical data routinely provided by the manufacturer. Based on the increase of micro perforations over time and the wearing behavior, recommendations for maximum wearing time of gloves should be given. Changing of gloves after 15 min could be a good compromise between feasibility and safety. HCWs should be aware of the benefits and limitations of medical gloves. To improve personal hygiene hand disinfection should be further encouraged. PMID- 23687938 TI - Serum brain biomarker level, neurocognitive performance, and self-reported symptom changes in soldiers repeatedly exposed to low-level blast: a breacher pilot study. AB - "Breachers" are a unique military and law enforcement population because they are routinely exposed to low-level blast (LLB) during training and operations. This repeated exposure has been associated with symptoms similar to that of sports concussion. This study examined effects of repeated exposure to LLB during an explosive entry course. Twenty-one members of the New Zealand Defence Force volunteered for this study. Serum samples, neurocognitive performance, and self reported symptoms were periodically measured before, during, and after a 2-week course. Serum concentrations of three biomarkers, ubiquitin C-terminal hydrolase L1, alphaII-spectrin breakdown product, and glial fibrillary acidic protein, were determined with sandwich enzyme-linked immunosorbent assays, and rank scores were derived using the area under the curve (relative to baseline) for each subject. Neurocognitive performance was measured with a computer-based test battery, and symptoms were assessed by paper-based inventory. There was a significant relationship (p<0.05) between composite biomarker and neurocognitive performance and between neurocognitive performance and symptoms. The individuals with the five highest (Top 5) and lowest (Bottom 5) composite biomarker scores were identified and compared using Wilcoxon's rank-sum test. The Top 5 had significantly longer reaction times and lower percent correct on neurocognitive performance and an increase in symptom reporting. The difference between individuals expressing the highest biomarker load during breacher training (Top 5) and those with the lowest biomarker load (Bottom 5) is reflected in neurocognitive performance deficits and self-reported symptoms. This suggests a measureable degree of brain perturbation linked to LLB exposure. Follow-up studies are underway to expand upon these results. PMID- 23687939 TI - Prognostic value of the seventh AJCC/UICC TNM classification of non-cardia gastric cancer. AB - BACKGROUND: The TNM staging criteria for gastric carcinoma have seen numerous revisions, the most recent of which are reflected in the seventh edition AJCC TNM cancer staging manual. METHODS: A retrospective evaluation of the sixth and seventh TNM classification of gastric cancer on a prospective database, regarding patients operated on for primary gastric cancer, was conducted. The end point of the study was prognosis evaluation in terms of overall survival.Patients operated on for primary gastric cancer between September 2003 and March 2012 at our Department of Emergency and General Surgery, were consecutively retrieved in this study; a total of 114 patients were considered. Cardia gastric cancers, gastric lymphomas and gastrointestinal stromal tumors (GIST) were excluded. Median and mean follow-up periods were 22.5 and 27.7 months (range 15 days to 5 years). Both TNM6 and TNM7 were used to evaluate our patients. Overall survival and survival rates at different stages were analyzed using the Kaplan-Meier method and differences were determined using a log-rank test. Cox's proportional hazard model was used to identify significant factors related to prognosis in a multivariate analysis. RESULTS: Overall survival between the sixth and seventh TNM classification was not significantly different. Both the Kaplan-Meier analysis and the multivariate analysis showed that the major negative prognostic factor was lymphovascular invasion (P<0.001 in the univariate analysis and P=0.035 to 0.048 in the multivariate analysis). Stage distribution and stage related survival changed from the sixth to the seventh edition, especially in T3 stage where median survival for the sixth edition was 720 days versus 1,200 days for the seventh edition. Moreover, differences were shown in the survival rate of N1 versus N2 stages within the seventh TNM. CONCLUSIONS: Even though further studies are needed in order to increase the number of patients studied, the seventh edition seems to provide a more accurate prognosis, especially regarding N1 and N2 tumors, showing that the most important prognostic factor is lymphovascular invasion. PMID- 23687941 TI - Early changes in muscle atrophy and muscle fiber type conversion after spinal cord transection and peripheral nerve transection in rats. AB - BACKGROUND: Spinal cord transection and peripheral nerve transection cause muscle atrophy and muscle fiber type conversion. It is still unknown how spinal cord transection and peripheral nerve transection each affect the differentiation of muscle fiber type conversion mechanism and muscle atrophy. The aim of our study was to evaluate the difference of muscle weight change, muscle fiber type conversion, and Peroxisome proliferator-activated receptor-gamma coactivatior 1alpha (PGC-1alpha) expression brought about by spinal cord transection and by peripheral nerve transection. METHODS: Twenty-four Wistar rats underwent surgery, the control rats underwent a laminectomy; the spinal cord injury group underwent a spinal cord transection; the denervation group underwent a sciatic nerve transection. The rats were harvested of the soleus muscle and the TA muscle at 0 week, 1 week and 2 weeks after surgery. Histological examination was assessed using hematoxylin and eosin (H&E) staining and immunofluorescent staing. Western blot was performed with 3 groups. RESULTS: Both sciatic nerve transection and spinal cord transection caused muscle atrophy with the effect being more severe after sciatic nerve transection. Spinal cord transection caused a reduction in the expression of both sMHC protein and PGC-1alpha protein in the soleus muscle. On the other hand, sciatic nerve transection produced an increase in expression of sMHC protein and PGC-1alpha protein in the soleus muscle. The results of the expression of PGC-1alpha were expected in other words muscle atrophy after sciatic nerve transection is less than after spinal cord transection, however muscle atrophy after sciatic nerve transection was more severe than after spinal cord transection. CONCLUSION: In the conclusion, spinal cord transection diminished the expression of sMHC protein and PGC-1alpha protein in the soleus muscle. On the other hand, sciatic nerve transection enhanced the expression of sMHC protein and PGC-1alpha protein in the soleus muscle. PMID- 23687940 TI - Zoonoses in pet birds: review and perspectives. AB - Pet birds are a not-so-well known veterinarian's clientship fraction. Bought individually or in couples, as families often do (which is a lucrative business for pet shops or local breeders) or traded (sometimes illegally) for their very high genetic or exotic value, these birds, commonly canaries, parakeets or parrots, are regularly sold at high prices. These animals, however, are potential carriers and/or transmitters of zoonotic diseases. Some of them could have an important impact on human health, like chlamydophilosis, salmonellosis or even highly pathogenic avian influenza A H5N1. This review paper, although non exhaustive, aims at enlightening, by the description of several cases of bird human transmission, the risks encountered by bird owners, including children. Public health consequences will be discussed and emphasis will be made on some vector-borne diseases, known to be emergent or which are underestimated, like those transmitted by the red mite Dermanyssus gallinae. Finally, biosecurity and hygiene, as well as prevention guidelines will be developed and perspectives proposed. PMID- 23687942 TI - Curcumin in reverse micelle: an example to control excited-state intramolecular proton transfer (ESIPT) in confined media. AB - In this Article, we focused on the modulation of the photophysical properties of curcumin, an anti-cancer drug, in aqueous and nonaqueous reverse micelles of AOT in n-heptane using steady-state and time-resolved fluorescence spectroscopy. The instability of curcumin is a common problem which restricts its numerous applications like Alzheimer disease, HIV infections, cystic fibrosis, etc. Our study reveals that curcumin shows comparatively higher stability after encapsulation into the interfacial region of the reverse micelle. To get a vivid description of the microenvironment, we added hydrogen-bond-donor (HBD) as well as non-hydrogen-bond-donor (NBD) core solvents. For experimental purposes, we used water, ethylene glycol (EG), glycerol (GY) as HBD solvents and N,N-dimethyl formamide (DMF) as a NBD solvent. With increasing amount of core solvents, irrespective of HBD or NBD, the fluorescence intensity and lifetime of curcumin increase with remarkable red-shift inside the reverse micelle. This is attributed to the modulation of the nonradiative rates associated with the excited-state intermolecular hydrogen bonding between the pigment and the polar solvents. We obtained a high partition constant at W0 = 0 (W0 = [core solvent]/[AOT]) which is certainly due to the hydrogen bonding between the negatively charged sulfonate group of AOT and hydroxyl groups of curcumin. Steady-state anisotropy and time resolved results give an idea about the microenvironment sensed by the curcumin molecules. The red-shift of emission spectra, increase in the value of ET(30), as well as the increase in the fluorescence lifetime were interpreted as being caused by the partition of the probe between the micellar interface and the polar core solvent. Indeed, we show here that it is possible to control the excited state intramolecular proton transfer (ESIPT) process of curcumin by simply changing the properties of the AOT reverse micelle interfaces by choosing the appropriate polar solvents to make the reverse micelle media. PMID- 23687944 TI - Ambient heat capacities and entropies of ionic solids: a unique view using the Debye equation. AB - Entropies of solids are obtained experimentally as integrals of measured heat capacities over the temperature range from zero to ambient. Correspondingly, the Debye phonon distribution equation for solids provides a theoretical connection between these two chemical thermodynamic measures. We examine how the widely applicable Debye equation illuminates the relation between the corresponding experimental measures using more than 250 ionic solids. Estimation of heat capacities for simple ionic solids by the Dulong-Petit heat capacity limit, by the Neumann-Kopp elemental sum, and by the ion sum method is examined in relation to the Debye equation. We note that, and explain why, the ambient temperature heat capacities and entropies of ionic solids are found to be approximately equal, and how deviations from equality may be related to the Debye temperature, ThetaD, which characterizes the Debye equation. It is also demonstrated that Debye temperatures may be readily estimated from the experimental ratio of ambient heat capacity to entropy, C(p)/S(p), rather than requiring resort to elaborate theoretical or experimental procedures for their determination. Correspondingly, ambient mineral entropies and heat capacities are linearly correlated and may thus be readily estimated from one another. PMID- 23687943 TI - Body mass index and musculoskeletal pain: is there a connection? AB - BACKGROUND: Back pain is one of the most common complaints that patients report to physicians and two-thirds of the population has an elevated body mass index (BMI), indicating they are either overweight or obese. It was once assumed that extra body weight would stress the low back and lead to pain, however, researchers have reported inconsistencies association between body weight and back pain. In contrast, more recent studies do indicate that an elevated BMI is associated with back pain and other musculoskeletal pain syndromes due to the presence of a chronic systemic inflammatory state, suggesting that the relationship between BMI and musculoskeletal pains be considered in more detail. OBJECTIVE: To describe how an elevated BMI can be associated with chronic systemic inflammation and pain expression. To outline measurable risk factors for chronic inflammation that can be used in clinical practice and discuss basic treatment considerations. DISCUSSION: Adiposopathy, or "sick fat" syndrome, is a term that refers to an elevated BMI that is associated with a chronic systemic inflammatory state most commonly referred to as the metabolic syndrome. The best available evidence suggests that the presence of adiposopathy determines if an elevated BMI will contribute to musculoskeletal pain expression. It is not uncommon for physicians to fail to identify the presence of adiposopathy/metabolic syndrome. CONCLUSION: Patients with an elevated BMI should be further examined to identify inflammatory factors associated with adiposopathy, such as the metabolic syndrome, which may be promoting back pain and other musculoskeletal pain syndromes. PMID- 23687945 TI - Broad host range vectors for expression of proteins with (Twin-) Strep-tag, His tag and engineered, export optimized yellow fluorescent protein. AB - BACKGROUND: In current protein research, a limitation still is the production of active recombinant proteins or native protein associations to assess their function. Especially the localization and analysis of protein-complexes or the identification of modifications and small molecule interaction partners by co purification experiments requires a controllable expression of affinity- and/or fluorescence tagged variants of a protein of interest in its native cellular background. Advantages of periplasmic and/or homologous expressions can frequently not be realized due to a lack of suitable tools. Instead, experiments are often limited to the heterologous production in one of the few well established expression strains. RESULTS: Here, we introduce a series of new RK2 based broad host range expression plasmids for inducible production of affinity- and fluorescence tagged proteins in the cytoplasm and periplasm of a wide range of Gram negative hosts which are designed to match the recently suggested modular Standard European Vector Architecture and database. The vectors are equipped with a yellow fluorescent protein variant which is engineered to fold and brightly fluoresce in the bacterial periplasm following Sec-mediated export, as shown from fractionation and imaging studies. Expression of Strep-tag(r)II and Twin-Strep tag(r) fusion proteins in Pseudomonas putida KT2440 is demonstrated for various ORFs. CONCLUSION: The broad host range constructs we have produced enable good and controlled expression of affinity tagged protein variants for single-step purification and qualify for complex co-purification experiments. Periplasmic export variants enable production of affinity tagged proteins and generation of fusion proteins with a novel engineered Aequorea-based yellow fluorescent reporter protein variant with activity in the periplasm of the tested Gram negative model bacteria Pseudomonas putida KT2440 and Escherichia coli K12 for production, localization or co-localization studies. In addition, the new tools facilitate metabolic engineering and yield assessment for cytoplasmic or periplasmic protein production in a number of different expression hosts when yields in one initially selected are insufficient. PMID- 23687946 TI - Evidence of improving antiretroviral therapy treatment delays: an analysis of eight years of programmatic outcomes in Blantyre, Malawi. AB - BACKGROUND: Impressive achievements have been made towards achieving universal coverage of antiretroviral therapy (ART) in sub-Saharan Africa. However, the effects of rapid ART scale-up on delays between HIV diagnosis and treatment initiation have not been well described. METHODS: A retrospective cohort study covering eight years of ART initiators (2004-2011) was conducted at Queen Elizabeth Central Hospital (QECH) in Blantyre, Malawi. The time between most recent positive HIV test and ART initiation was calculated and temporal trends in delay to initiation were described. Factors associated with time to initiation were investigated using multivariate regression analysis. RESULTS: From 2004 2011, there were 15,949 ART initiations at QECH (56% female; 8% children [0-10 years] and 5% adolescents [10-20 years]). Male initiators were likely to have more advanced HIV infection at initiation than female initiators (70% vs. 64% in WHO stage 3 or 4). Over the eight years studied, there were declines in treatment delay, with 2011 having the shortest delay at 36.5 days. On multivariate analysis CD4 count <50 cells/MUl (adjusted geometric mean ratio [aGMR]: aGMR: 0.53, bias corrected accelerated [BCA] 95% CI: 0.42-0.68) was associated with shorter ART treatment delay. Women (aGMR: 1.12, BCA 95% CI: 1.03-1.22) and patients diagnosed with HIV at another facility outside QECH (aGMR: 1.61, BCA 95% CI: 1.47-1.77) had significantly longer treatment delay. CONCLUSIONS: Continued improvements in treatment delays provide evidence that universal access to ART can be achieved using the public health approach adopted by Malawi However, the longer delays for women and patients diagnosed at outlying sites emphasises the need for targeted interventions to support equitable access for these groups. PMID- 23687947 TI - The development and use of an ELISA-based method to follow the distribution of cellulase monocomponents during the hydrolysis of pretreated corn stover. AB - BACKGROUND: It is widely recognised that fast, effective hydrolysis of pretreated lignocellulosic substrates requires the synergistic action of multiple types of hydrolytic and some non-hydrolytic proteins. However, due to the complexity of the enzyme mixture, the enzymes interaction with and interference from the substrate and a lack of specific methods to follow the distribution of individual enzymes during hydrolysis, most of enzyme-substrate interaction studies have used purified enzymes and pure cellulose model substrates. As the enzymes present in a typical "cellulase mixture" need to work cooperatively to achieve effective hydrolysis, the action of one enzyme is likely to influence the behaviour of others. The action of the enzymes will be further influenced by the nature of the lignocellulosic substrate. Therefore, it would be beneficial if a method could be developed that allowed us to follow some of the individual enzymes present in a cellulase mixture during hydrolysis of more commercially realistic biomass substrates. RESULTS: A high throughput immunoassay that could quantitatively and specifically follow individual cellulase enzymes during hydrolysis was developed. Using monoclonal and polyclonal antibodies (MAb and PAb, respectively), a double antibody sandwich enzyme-linked immunosorbent assay (ELISA) was developed to specifically quantify cellulase enzymes from Trichoderma reesei: cellobiohydrolase I (Cel7A), cellobiohydrolase II (Cel6A), and endoglucanase I (Cel7B). The interference from substrate materials present in lignocellulosic supernatants could be minimized by dilution. CONCLUSION: A double-antibody sandwich ELISA was able to detect and quantify individual enzymes when present in cellulase mixtures. The assay was sensitive over a range of relatively low enzyme concentration (0 - 1 MUg/ml), provided the enzymes were first pH adjusted and heat treated to increase their antigenicity. The immunoassay was employed to quantitatively monitor the adsorption of cellulase monocomponents, Cel7A, Cel6A, and Cel7B, that were present in both Celluclast and Accellerase 1000, during the hydrolysis of steam-pretreated corn stover (SPCS). All three enzymes exhibited different individual adsorption profiles. The specific and quantitative adsorption profiles observed with the ELISA method were in agreement with earlier work where more labour intensive enzyme assay techniques were used. PMID- 23687948 TI - Poor pregnancy outcome in women with type 1 diabetes is predicted by elevated HbA1c and spikes of high glucose values in the third trimester. AB - OBJECTIVE: To analyse data from a randomised, controlled study of prandial insulin aspart versus human insulin, both with NPH insulin, in pregnant women with type 1 diabetes for potential factors predicting poor pregnancy outcomes. RESEARCH DESIGN/METHOD: Post hoc analysis including 91 subjects randomised prior to pregnancy with known outcome in early pregnancy and 259 subjects randomised prior to pregnancy/during pregnancy of <10 weeks' gestation with known late pregnancy outcomes. Poor early-pregnancy outcomes included fetal loss <22 gestational weeks and/or congenital malformation (n=18). Poor late-pregnancy outcomes included: composite endpoint including pre-eclampsia, preterm delivery and perinatal death (n=78); preterm delivery (n=63); and excessive fetal growth (n=88). RESULTS: 18 patients experienced a malformed/lost fetus in early pregnancy - none preceded by severe hypoglycaemia. Albuminuria in early pregnancy was a significant predictor of poor late-pregnancy outcome (composite endpoint; p=0.012). In the third trimester, elevated HbA1c, >= 1 plasma glucose (PG) measurement >11 mmol/L (198 mg/dL) and %PG values outside 3.9-7.0 mmol/L (70-126 mg/dL) were significant predictors of poor late-pregnancy outcomes (all p<0.05). CONCLUSIONS: Elevated HbA1c, high glucose spikes and out-of-range %PG in the third trimester, and albuminuria in early pregnancy, are associated with poor late-pregnancy outcomes. PMID- 23687949 TI - High-throughput screen of essential gene modules in Mycobacterium tuberculosis: a bibliometric approach. AB - BACKGROUND: Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (M. tuberculosis). The annotation of functional genome and signaling network in M. tuberculosis are still not systematic. Essential gene modules are a collection of functionally related essential genes in the same signaling or metabolic pathway. The determination of essential genes and essential gene modules at genomic level may be important for better understanding of the physiology and pathology of M. tuberculosis, and also helpful for the development of drugs against this pathogen. The establishment of genomic operon database (DOOR) and the annotation of gene pathways have felicitated the genomic analysis of the essential gene modules of M. tuberculosis. METHOD: Bibliometric approach has been used to perform a High-throughput screen for essential genes of M. tuberculosis strain H37Rv. Ant colony algorithm were used to identify the essential genes in other M. tuberculosis reference strains. Essential gene modules were analyzed by operon database DOOR. The pathways of essential genes were assessed by Biocarta, KEGG, NCI-PID, HumanCyc and Reactome. The function prediction of essential genes was analyzed by Pfam. RESULTS: A total approximately 700 essential genes were identified in M. tuberculosis genome. 40% of operons are consisted of two or more essential genes. The essential genes were distributed in 92 pathways in M. tuberculosis. In function prediction, 61.79% of essential genes were categorized into virulence, intermediary metabolism/respiration, cell wall related and lipid metabolism, which are fundamental functions that exist in most bacteria species. CONCLUSION: We have identified the essential genes of M. tuberculosis using bibliometric approach at genomic level. The essential gene modules were further identified and analyzed. PMID- 23687950 TI - Advances in the development and use of human tissue-based techniques for drug toxicity testing. AB - INTRODUCTION: Unacceptable failure rates in clinical trials are largely responsible for the high costs of bringing successful drugs to market - costs that are passed on to patients, insurers or healthcare providers. Furthermore, failures in clinical trials deny patients much-needed new drugs and potentially expose them to unnecessary risk. With so many medicines reaching their patent expiry date, pressure is on the pharmaceutical industry to not only increase its output of effective medicines but also improve its ability to minimise safety issues. AREAS COVERED: This review focuses on the availability and use of human tissues and their derivatives to explore potential toxicity problems of new drugs. The growth in the number and quality of human material-based assays and enabling technologies is reviewed, followed by a discussion of the application of such assays to identify specific toxicities, using specific examples. EXPERT OPINION: Although human tissues are now beginning to be seen as playing an important role in evaluating the potential for toxicity of new drugs in the clinic, their importance deserves to be more widely recognised and their use in the identification of toxicity issues as early as possible in the drug development life cycle should be significantly increased. PMID- 23687952 TI - Comperative study of catalase immobilization on chitosan, magnetic chitosan and chitosan-clay composite beads. AB - Catalase was immobilized on chitosan and modified chitosan. Studies were carried out on free-immobilized catalase concerning the determination of optimum temperature, pH, thermal, storage stability, reusability, and kinetic parameters. Optimum temperature and pH for free catalase and catalase immobilized were found as 35 degrees C and 7.0, respectively. After 100 times of repeated tests, the immobilized catalases on chitosan-clay and magnetic chitosan maintain over 50% and 60% of the original activity, respectively. The ease of catalase immobilization on low-cost matrices and good stability upon immobilization in the present study make it a suitable product for further use in the food industry. PMID- 23687951 TI - Schiff bases attached L-glutamine and L-asparagine: first investigation on antimutagenic and antimicrobial analyses. AB - This study was conducted to evaluate the antimutagenic and antimicrobial activities of Schiff bases attached L-glutamine and L-asparagine. Antibacterial activities of the compounds against S. aureus, Sh. dys. typ 7, L. monocytogenes 4b, E. coli, S. typhi H, S. epidermis, Br. abortus, M. luteus, B. cereus, P. putida, and antifungal activity against Candida albicans were studied. These compounds were investigated for antimutagenic properties against Aflatoxin Bi (AFBi) using micronuclei (MN) assay in human lymphocyte cell culture in vitro. The protective role of these compounds against AFBi-induced MN is probably related to its doses. PMID- 23687954 TI - Dynamics of players' relative positioning during baseline rallies in tennis. AB - This study analysed how the relative positioning of players on court influenced patterns of interpersonal coordination in baseline rallies in tennis. We developed a model (PA index) that assigns a weight to the position of each player on court and determines a positional advantage, based on the relative proportionality between the lateral and longitudinal displacement values during rallies. To test the model, data from 27 randomly-selected baseline rallies from three ATP World Tour matches (professional tennis players' tournaments organized by Association of Tennis Professionals) on clay were analysed. Results revealed that the PA index of players on court described their interpersonal coordination dynamics during baseline rallies. It also identified the emergence of rally breaks in the interpersonal coordination patterns of competing dyads that led to a point being scored. Data suggest that positional advantage data may assist coaches in the design of training tasks to enhance players' court coverage and performance during competitive interactions, acting as a valuable tool for performance analysis in tennis. PMID- 23687956 TI - Calculation of normal contact forces between silica nanospheres. AB - In this work, interaction forces between two silica nanospheres after contact, including the van der Waals (vdW) attraction, Born repulsion, and mechanical contact forces are studied by molecular dynamics (MD) simulations. The effects of interaction path (approach or departure), initial relative velocity, and relative orientations of two nanospheres are first examined. The results show that the interparticle forces are, to a large degree, independent of these variables. Then, emphasis is given to other important variables. At a small contact deformation, the size dependence of the vdW attraction and Born repulsion qualitatively agrees with the prediction based on the conventional theories, but this becomes vague upon further deformation due to the gradually flattened shape of deformed particles. An alternative approach is provided to calculate the interparticle vdW attraction and Born repulsion forces. Moreover, the MD simulations show that the Hertz model still holds to describe the mechanical contact force at low compression, which is obtained by subtracting the vdW attraction and Born repulsion forces from the total normal force. Comparisons with the Johnson-Kendall-Roberts (JKR) and Derjaguin-Muller-Toporov (DMT) models, in terms of force-displacement relationships and contact radius, show that the two models can be used to provide the first approximation, but there is some deviation from the MD simulated results. The origins of the quantitative difference are analyzed. New equations are formulated to estimate the interaction forces between silica nanospheres, which should be useful in the dynamic simulation of silica nanoparticle systems. PMID- 23687953 TI - Electrochemical investigations into kinase-catalyzed transformations of tau protein. AB - The formation of neurofibrillary tangles by hyperphosphorylated tau is a well recognized hallmark of Alzheimer's disease. Resulting from malfunctioning protein kinases, hyperphosphorylated tau is unable to bind microtubules properly, causing it to self-associate and aggregate. The effects of tau phosphorylation on tau conformation and aggregation are still largely unexplored. The conformational analysis of tau and its hyperphosphorylated forms is usually performed by a variety of spectroscopic techniques, all of which require ample sample concentrations and/or volumes. Here we report on the use of surface based electrochemical techniques that allow for detection of conformational changes and orientation of tau protein as a function of tau phosphorylation by tyrosine and serine/threonine kinases. The electrochemical methods utilize 5'-gamma-ferrocenyl adenosine triphosphate (Fc-ATP) derivative as a cosubstrate and tau immobilized on gold surface to probe the role of the following protein kinases: Sarcoma related kinase (Src), Abelson tyrosine kinase (Abl), tau-tubulin kinase (TTBK), proto-oncogene tyrosine protein kinase Fyn (Fyn), and glycogen synthase kinase 3 beta (Gsk-3beta). The single kinase and sequential kinase-catalyzed Fc phosphorylations modulate the electrochemical signal, pointing to the dramatic changes around the Fc group in the Fc-phosphorylated tau films. The location and orientation of the Fc-group in Fc-tau film was investigated by the surface plasmon resonance based on antiferrocene antibodies. Additional surface characterization of the Fc-tau films by time-of-flight secondary ion-mass spectrometry and X-ray photoelectron spectroscopy revealed that Fc phosphorylations influence the tau orientation and conformation on surfaces. When Fc-phosphorylations were performed in solution, the subsequently immobilized Fc tau exhibited similar trends. This study illustrates the validity and the utility of the labeled electrochemical approach for probing the changes in protein film properties, conformation, and orientation as a function of the enzymatically catalyzed modifications. PMID- 23687955 TI - Dispersive microextraction based on "magnetic water" coupled to gas chromatography/mass spectrometry for the fast determination of organophosphorus pesticides in cold-pressed vegetable oils. AB - This article presents a novel application of dispersive microextraction based on "magnetic water" (m-water) for the purification of organophosphorus pesticides (methamidophos, omethoate, monocrotophos) from cold-pressed vegetable oils. In the present study, a trace amount of water (extractant) was adsorbed on bare Fe3O4 by hydrophilic interaction to form m-water. Rapid extraction can be achieved while the m-water is dispersed in the sample solution with the aid of a vigorous vortex. After extraction, the analyte-adsorbed m-water can be readily isolated from the sample solution by a magnet, which could greatly simplify the operation and reduce the whole pretreatment time. Several parameters affecting the extraction efficiency were investigated, and under the optimized conditions, a simple and effective method for pesticide analysis was established by coupling with gas chromatography/mass spectrometry (GC/MS). The linearity range of the proposed method was 2-100 ng/g with satisfactory correlation coefficients (R) of 0.9997-0.9998, and the limits of quantification (LOQ) for the target compounds were in the range of 0.70-1.27 ng/g. In addition, the reproducibility was obtained by evaluating the intra- and interday precisions with relative standard deviations (RSDs) less than 7.2% and 6.5%, respectively. Finally, the established "magnetic water" microextraction method was successfully applied for the determination of pesticide residues in several kinds of cold-pressed vegetable oils. PMID- 23687957 TI - Clinical implication of the BRAFV600E mutation in papillary thyroid carcinoma. AB - BACKGROUND: The BRAFV600E mutation is the most common genetic alteration in papillary thyroid carcinoma (PTC). In recent studies, the BRAFV600E mutation has been associated with poor clinicopathological characteristics, such as lymph node metastasis, extrathyroidal extension, and advanced stage. However, other studies have failed to establish an association between the BRAFV600E mutation and clinicopathological features. Therefore, we investigated the relationship between the BRAFV600E mutation and its clinicopathological factors at a single institution. METHODS: A total of 327 consecutive patients with PTC were enrolled in this study and underwent thyroid surgery at Yeouido St. Mary's Hospital between February 2010 and December 2011.BRAFV600E mutation analysis was performed using polymerase chain reaction (PCR)-based amplification of DNA extracted from paraffin-embedded tumour specimens. RESULTS: The BRAFV600E mutation was detected in the tumours of 241 (73.7%) patients. Lymph node metastasis, TNM stage, and multifocality were not significantly associated with the BRAFV600E mutation. However, larger tumour size, extrathyroidal extension, histologic type (classic type), and concurrent Hashimoto's thyroiditis were associated with the BRAFV600E mutation in the univariate analysis, although no clinicopathological features were associated with the BRAFV600E mutation in the multivariate analysis. CONCLUSION: There was no idependent prognostic factor associated with BRAFV600E mutation status in this study. The BRAFV600E mutation is unlikely to serve as a prognostic factor for PTC. PMID- 23687958 TI - Catalytic decarboxylative fluorination for the synthesis of tri- and difluoromethyl arenes. AB - Treatment of readily available alpha,alpha-difluoro- and alpha-fluoroarylacetic acids with Selectfluor under Ag(I) catalysis led to decarboxylative fluorination. This operationally simple reaction gave access to tri- and difluoromethylarenes applying a late-stage fluorination strategy. Translation to [(18)F]labeling is demonstrated using [(18)F]Selectfluor bis(triflate), a reagent affording [(18)F]tri- and [(18)F]difluoromethylarenes not within reach with [(18)F]F2. PMID- 23687959 TI - Were reactions of triplet silylenes observed? AB - The observation that (iPr3Si)(tBu3Si)Si: (1) yields an intramolecular C-H bond insertion product at room temperature, together with earlier computational predictions that triplet 1 is slightly more stable (or isoenergetic) than singlet 1 and additional considerations, led previous investigators to conclude that 1 is the first silylene to exhibit triplet electronic state reactivity. In this paper we test, using DFT and ab initio methods, whether the occurrence of intramolecular C-H bond insertion indeed indicates the presence of a triplet state silylene. DFT calculations at the B3LYP/6-31+G(d,p)//B3LYP/6-31+G(d,p) level show that singlet (iPr3Si)(tBuMe2Si)Si: (9), a close model of singlet 1, inserts intramolecularly into a C-H bond of the tBu group with a barrier of 22.7 kcal/mol (22.2 kcal/mol at SCS-MP2/cc-PVTZ). However, for triplet9 the barrier of this insertion reaction is significantly higher, 34.6 kcal/mol (41.9 kcal/mol at SCS-MP2/cc-PVTZ). This implies that at room temperature the intramolecular insertion reaction of the singlet is 10(9)-10(12) faster than that of the triplet. We conclude, in contrast to previous conclusions, that the observed intramolecular C-H bond insertion reactions of 1 as well as of (tBu3Si)2Si: (2) occur from the singlet state. Furthermore, the occurrence of an intramolecular C H bond insertion cannot serve as evidence for the presence of a triplet silylene, either in cases where the singlet and triplet states are nearly isoenergetic (e.g., 1 and 9) or even for silylenes where the triplet state is the ground state (e.g., 2), because the corresponding singlet silylenes insert intramolecularly much faster. The search for a genuine reaction of a triplet silylene has to continue. PMID- 23687961 TI - A 3D printed fluidic device that enables integrated features. AB - Fluidic devices fabricated using conventional soft lithography are well suited as prototyping methods. Three-dimensional (3D) printing, commonly used for producing design prototypes in industry, allows for one step production of devices. 3D printers build a device layer by layer based on 3D computer models. Here, a reusable, high throughput, 3D printed fluidic device was created that enables flow and incorporates a membrane above a channel in order to study drug transport and affect cells. The device contains 8 parallel channels, 3 mm wide by 1.5 mm deep, connected to a syringe pump through standard, threaded fittings. The device was also printed to allow integration with commercially available membrane inserts whose bottoms are constructed of a porous polycarbonate membrane; this insert enables molecular transport to occur from the channel to above the well. When concentrations of various antibiotics (levofloxacin and linezolid) are pumped through the channels, approximately 18-21% of the drug migrates through the porous membrane, providing evidence that this device will be useful for studies where drug effects on cells are investigated. Finally, we show that mammalian cells cultured on this membrane can be affected by reagents flowing through the channels. Specifically, saponin was used to compromise cell membranes, and a fluorescent label was used to monitor the extent, resulting in a 4-fold increase in fluorescence for saponin treated cells. PMID- 23687960 TI - Iron overload and glucose metabolism in subjects with beta-thalassaemia major: an overview. AB - Thalassaemia is one of the most common genetic disorders caused by a reduction of the globin chains leading to chronic haemolytic anaemia from birth. The mainstay of treatment is blood transfusion to maintain adequate levels of the haemoglobin. Iron overload in beta-thalassaemia major patients is secondary to multiple blood transfusions and increased iron absorption. Excess iron potentially catalyzes free-radicals generation and impairment in cellular function and integrity. Extensive iron-induced injury develops in the heart, liver, pancreas and endocrine system. Pancreatic iron loading in thalassaemia major patients begins at early childhood, and the prevalence of diabetes mellitus (DM) ranges from 6.4% to 14.1% in cross-sectional studies. Both insulin resistance and decreased insulin secretion contribute to DM in thalassaemia major patients. This has been shown by oral glucose tolerance test, euglycemic insulin clamp, homeostatic model assessment, intravenous glucose tolerance test and continuous glucose monitoring system. The prevalence of DM in thalassaemia has been shown to correlate with serum ferritin concentration, hepatitis C infection, and pancreatic and cardiac iron measured by imaging techniques. Therefore the incidence of disturbed glucose homeostasis depends on adherence to chelation treatment, the adequacy of the dosage, the chemical properties of the chelating agent and the prevention of liver infections. PMID- 23687962 TI - Probing structure and dynamics of bulk and confined crude oils by multiscale NMR spectroscopy, diffusometry, and relaxometry. AB - We propose using a set of noninvasive multiscale NMR techniques for probing the structure and dynamics of bulk and confined crude oils with and without asphaltene. High-field 1D (1)H and (13)C NMR spectroscopies evidence the proton species and the amount of asphaltene and give an average chain length for the hydrocarbon aliphatic chains. Two-dimensional (1)H diffusion-ordered NMR spectroscopy (DOSY) spectra allow us to identify two populations of hydrocarbons characterized by two distributions of translational diffusion coefficients in the presence of asphaltene and a single one without asphaltene. A detailed analysis of the distributions of longitudinal, T1, relaxation times measured at different magnetic fields is proposed in terms of highly skewed bimodal (or monomodal) log normal distributions, confirming the two environments in the presence of asphaltene and a single one without asphaltene. We show that these distributions are similar to the gas and gel permeation chromatography distributions, thus showing a connection of the hydrocarbon dynamics with their chain lengths. The remarkable observed features of the nuclear magnetic relaxation dispersion (NMRD) profiles of <1/T1> for bulk and confined crude oils with and without asphaltene are interpreted with an original relaxation model of intermittent surface dynamics of proton species at the proximity of asphaltene nanoaggregates and bulk dynamics in between clusters of these nanoaggregates. This allows us to probe the 2D translational diffusion correlation time and the time of residence of hydrocarbons in the proximity of the asphaltene nanoaggregates. Provided that the diffusion of the hydrocarbons close to the asphaltene nanoaggregates is three times smaller than the bulk diffusion, as the DOSY experiments show, this time of residence gives an average radius of exploration for the 2D hydrocarbon diffusion, r2D ~ 3.9 nm, of the same order of magnitude as the aggregate sizes found by J. Eyssautier with SAXS and SANS in asphaltene solutions and by O. C. Mullins with the observation of gravitational gradients of asphaltenes in oilfield reservoirs. PMID- 23687963 TI - Accumulation of inorganic polyphosphate enables stress endurance and catalytic vigour in Pseudomonas putida KT2440. AB - BACKGROUND: Accumulation of inorganic polyphosphate (polyP), a persistent trait throughout the whole Tree of Life, is claimed to play a fundamental role in enduring environmental insults in a large variety of microorganisms. The share of polyP in the tolerance of the soil bacterium Pseudomonas putida KT2440 to a suite of physicochemical stresses has been studied on the background of its capacity as a host of oxidative biotransformations. RESULTS: Cells lacking polyphosphate kinase (Ppk), which expectedly presented a low intracellular polyP level, were more sensitive to a number of harsh external conditions such as ultraviolet irradiation, addition of beta-lactam antibiotics and heavy metals (Cd(2+) and Cu(2+)). Other phenotypes related to a high-energy phosphate load (e.g., swimming) were substantially weakened as well. Furthermore, the ppk mutant was consistently less tolerant to solvents and its survival in stationary phase was significantly affected. In contrast, the major metabolic routes were not significantly influenced by the loss of Ppk as diagnosed from respiration patterns of the mutant in phenotypic microarrays. However, the catalytic vigour of the mutant decreased to about 50% of that in the wild-type strain as estimated from the specific growth rate of cells carrying the catabolic TOL plasmid pWW0 for m-xylene biodegradation. The catalytic phenotype of the mutant was restored by over-expressing ppk in trans. Some of these deficits could be explained by the effect of the ppk mutation on the expression profile of the rpoS gene, the stationary phase sigma factor, which was revealed by the analysis of a PrpoS -> rpoS'-'lacZ translational fusion. Still, every stress-related effect of lacking Ppk in P. putida was relatively moderate as compared to some of the conspicuous phenotypes reported for other bacteria. CONCLUSIONS: While polyP can be involved in a myriad of cellular functions, the polymer seems to play a relatively secondary role in the genetic and biochemical networks that ultimately enable P. putida to endure environmental stresses. Instead, the main value of polyP could be ensuring a reservoire of energy during prolonged starvation. This is perhaps one of the reasons for polyP persistence in live systems despite its apparent lack of essentiality. PMID- 23687964 TI - Isolation and analysis of a very virulent Marek's disease virus strain in China. AB - BACKGROUND: A severe MD was broken out at a farm in Shandong, China, despite FC126 vaccination of the chickens at 1-day-old. The mortality of the flocks reached up to 38.3%. The infected chickens were found to have MD pathological changes, including enlargement of spleens, livers and kidneys, and tumors occured on organs later. Samples were collected from the chickens for diagnosis. METHODS: The collected samples were inoculated into primary duck embryo fibroblast (DEF) cells, and the MDV strain named SD2012-1 was isolated. In order to identify the isolate, amplification by PCR and sequencing of oncogenic Meq and vIL-8 gene were processed, the obtained sequences were compared with the sequences of reference strains, and SD2012-1 was used to challenge immunized SPF chickens. RESULTS: A very virulent MDV isolate strain, SD2012-1, was isolated from a chicken flock in Shandong Province, China, the isolate had the characteristics of very virulent MDV-1, nucleotide and deduced amino acid sequence comparisons of Meq and vIL-8 gene of SD2012-1 with those of reference strains showed SD2012-1 had high homology with MDV strains isolated from China, SD2012-1 could break through the protection provided by HVT vaccine and HVT + SB-1 vaccine immunization and caused the mortality of SPF chickens over 60%. The immune failure occured at the farm could be due to the improper selection of vaccines. SD2012-1 produced death later and the gross postmortem lesions of chickens died early and later were different. CONCLUSIONS: MDV strain SD2012-1 isolated from Shandong Province, China was found to have the characteristics of very virulent MDV-1, which could break through the protection provided by HVT vaccine and HVT + SB-1 vaccine, the virus seemed to have a long latent period, and cause different gross postmortem lesions of chickens between chickens died early and later. A better immunization way should be chosen to prevent infection of this MDV strain in field. PMID- 23687965 TI - Systematic review and stratified meta-analysis of the efficacy of RhoA and Rho kinase inhibitors in animal models of ischaemic stroke. AB - BACKGROUND: There is currently only one clinically approved drug, tissue plasminogen activator (tPA), for the treatment of acute ischaemic stroke. The RhoA pathway, including RhoA and its downstream effector Rho kinase (ROCK), has been identified as a possible therapeutic target. Our aim was to assess the impact of study design characteristics and study quality on reported measures of efficacy and to assess for the presence and impact of publication bias. METHODS: We conducted a systematic review and meta-analysis on publications describing the efficacy of RhoA and ROCK inhibitors in animal models of focal cerebral ischaemia where outcome was assessed as a change in lesion size or neurobehavioural score, or both. RESULTS: We identified 25 published papers which met our inclusion criteria. RhoA and ROCK inhibitors reduced lesion size by 37.3% in models of focal cerebral ischaemia (95% CI, 28.6% to 46.0%, 41 comparisons), and reduced neurobehavioural data by 40.5% (33.4% to 47.7%, 30 comparisons). Overall study quality was low (median=4, interquartile range 3-5) and measures to reduce bias were seldom reported. Publication bias was prevalent and associated with a substantial overstatement of efficacy for lesion size. CONCLUSIONS: RhoA and ROCK inhibitors appear to be effective in animal models of stroke. However the low quality score, publication bias and limited number of studies are areas which need attention prior to conducting clinical trials. PMID- 23687966 TI - Burden experienced by community health volunteers in Taiwan: a survey. AB - BACKGROUND: Volunteers in Taiwan complement the delivery of health services by paid health professionals. However, in doing so, community health volunteers experience burdens associated with their activities. The reasons for these burdens and degree to which they are experienced are explored in this paper. Our study adds to international research regarding the burden experienced by volunteers. This project is the first to assess how community health volunteers in Taiwan experience burden. METHODS: The 20 item Burden on Community Health Volunteer (BCHV) instrument, specifically designed for this project, was administered to 435 volunteers attached to Community Health Promotion Development Centres in northern Taiwan. RESULTS: The overall burden experienced by volunteers is relatively low. However, a multivariate adjusted regression analysis revealed significant differences in volunteer burden depending on the number of people each volunteer served on average per week, as well as the volunteer's marital status and their perceptions about personal health. Volunteers who served many people and who perceived their own health as poor experienced a higher level of burden. Those who were a widow or a widower felt less burdened than others. CONCLUSIONS: The results of the study identify areas where burden is high and where strategies can be developed to reduce the level of burden experienced by community health volunteers in Taiwan. Community health volunteers in Taiwan complement the role of nurses and other health care providers so their retention is important to ongoing service delivery. PMID- 23687967 TI - Hydroxamate anchors for improved photoconversion in dye-sensitized solar cells. AB - We present the first analysis of performance of hydroxamate linkers as compared to carboxylate and phosphonate groups when anchoring ruthenium-polypyridyl dyes to TiO2 surfaces in dye-sensitized solar cells (DSSCs). The study provides fundamental insight into structure/function relationships that are critical for cell performance. Our DSSCs have been produced by using newly synthesized dye molecules and characterized by combining measurements and simulations of experimental current density-voltage (J-V) characteristic curves. We show that the choice of anchoring group has a direct effect on the overall sunlight-to electricity conversion efficiency (eta), with hydroxamate anchors showing the best performance. Solar cells based on the pyridyl-hydroxamate complex exhibit higher efficiency since they suppress electron transfer from the photoanode to the electrolyte and have superior photoinjection characteristics. These findings suggest that hydroxamate anchoring groups should be particularly valuable in DSSCs and photocatalytic applications based on molecular adsorbates covalently bound to semiconductor surfaces. In contrast, analogous acetylacetonate anchors might undergo decomposition under similar conditions suggesting limited potential in future applications. PMID- 23687968 TI - Chicken innate immune response to oral infection with Salmonella enterica serovar Enteritidis. AB - The characterization of the immune response of chickens to Salmonella infection is usually limited to the quantification of expression of genes coding for cytokines, chemokines or antimicrobial peptides. However, processes occurring in the cecum of infected chickens are likely to be much more diverse. In this study we have therefore characterized the transcriptome and proteome in the chicken cecum after infection with Salmonella Enteritidis. Using a combination of 454 pyrosequencing, protein mass spectrometry and quantitative real-time PCR, we identified 48 down- and 56 up-regulated chicken genes after Salmonella Enteritidis infection. The most inducible gene was that coding for MMP7, exhibiting a 5952 fold induction 9 days post-infection. An induction of greater than 100 fold was observed for IgG, IRG1, SAA, ExFABP, IL-22, TRAP6, MRP126, IFNgamma, iNOS, ES1, IL-1beta, LYG2, IFIT5, IL-17, AVD, AH221 and SERPIN B. Since prostaglandin D2 synthase was upregulated and degrading hydroxyprostaglandin dehydrogenase was downregulated after the infection, prostaglandin must accumulate in the cecum of chickens infected with Salmonella Enteritidis. Finally, above mentioned signaling was dependent on the presence of a SPI1 encoded type III secretion system in Salmonella Enteritidis. The inflammation lasted for 2 weeks after which time the expression of the "inflammatory" genes returned back to basal levels and, instead, the expression of IgA and IgG increased. This points to an important role for immunoglobulins in the restoration of homeostasis in the cecum after infection. PMID- 23687969 TI - Differences in the gingival crevicular fluid composition between adults and adolescents undergoing orthodontic treatment. AB - OBJECTIVES: To investigate differences in the gingival crevicular fluid (GCF) composition between adolescent and adult patients undergoing orthodontic treatment with fixed appliances. MATERIALS AND METHODS: Ten adolescents (14.4 +/- 1.43) and 10 adults (28.5 +/- 7.83) with Class I malocclusions and minor upper incisor crowding were allocated to two different age groups. Brackets were bonded only in the upper arch over the 20-week period of the experiment. Samples of GCF were collected from the labial sides of the upper incisors (experimental sites) and lower incisors (control sites) of each subject at five time points. Aliquots from diluted GCF were screened for the presence of receptor activator of nuclear factor kappa B ligand (RANKL), osteoprotegerin (OPG), interleukin-1 (IL-1), interleukin-1 receptor antagonist (IL-1RA), and metalloproteinase-9 (MMP-9) using a microarray technique. The values were statistically analyzed. RESULTS: In adults, the ratio of IL-1 to IL-1RA decreased significantly (P = .033) in experimental sites 3 weeks after appliance placement and first archwire activation. In adolescents, the ratio of RANKL to OPG peaked 6 weeks after the insertion of the first rectangular archwire. This ratio peak found in adolescents was a consequence of a decrease in the mean concentration of OPG. No significant changes over time were observed in the concentration of MMP-9. CONCLUSION: This study demonstrates age trends in the GCF levels of IL-1, IL-1RA, RANKL, and OPG that may be used to track differences in tissue response between adults and adolescents undergoing orthodontic treatment. PMID- 23687970 TI - Water-soluble mmp-9 inhibitor prodrug generates active metabolites that cross the blood-brain barrier. AB - MMP-9 plays a detrimental role in the pathology of several neurological diseases and, thus, represents an important target for intervention. The water-soluble prodrug ND-478 is hydrolyzed to the active MMP-9 inhibitor ND-322, which in turn is N-acetylated to the even more potent metabolite ND-364. We used a sensitive bioanalytical method based on ultraperformance liquid chromatography with multiple-reaction monitoring detection to measure levels of ND-478, ND-322, and ND-364 in plasma and brain after administration of ND-478 and the metabolites. ND 478 did not cross the blood-brain barrier, as was expected; however the active metabolites ND-322 and ND-364 distributed to the brain. The active compound after administration of either ND-478 or ND-322 is likely ND-364. ND-322 is N acetylated in both brain and liver, but it is so metabolized preferentially in liver. Since N-acetyltransferases involved in the metabolism of ND-322 to ND-364 are polymorphic, direct administration of the N-acetylated ND-364 would achieve the requisite therapeutic levels in the brain. PMID- 23687971 TI - Hormone-related pharmacokinetic variations associated with anti-breast cancer drugs. AB - INTRODUCTION: Breast cancer is the most common female cancer, with more than one million new patients diagnosed annually worldwide. Generally speaking, there are three types of drugs used in management of breast cancer namely: hormonal treatment, chemotherapeutic agents and target-based agents. There is increasing evidence that hormones play an important role in development of both hormone dependent and hormone-independent breast cancers. AREAS COVERED: This review summarizes the pharmacokinetics of various types of drugs used to treat breast cancer. Furthermore, the authors discuss hormone-related variations including: the menstrual status, gender and exogenous hormones influencing drug absorption, distribution, metabolism or excretion (ADME). The authors also describe the physiological factors such as body weight and age that affect the pharmacokinetics of several drugs. EXPERT OPINION: The factors affecting the pharmacokinetics of anti-breast cancer drugs are multifaceted. Hormones appear to be a key factor determining the pharmacokinetics (and efficacy) of hormonal therapy due to their role in cancer progression. In chemotherapy, the effects of hormones on the drug pharmacokinetics are possibly mediated through P glycoprotein (P-gp) efflux and/or cytochrome P450 metabolism. In many cases, dosing regimen should be adjusted for drugs used in treatment of breast cancers based on the hormone levels in the body. PMID- 23687972 TI - Sub-10 nm Fe3O4@Cu(2-x)S core-shell nanoparticles for dual-modal imaging and photothermal therapy. AB - Photothermal nanomaterials have recently attracted significant research interest due to their potential applications in biological imaging and therapeutics. However, the development of small-sized photothermal nanomaterials with high thermal stability remains a formidable challenge. Here, we report the rational design and synthesis of ultrasmall (<10 nm) Fe3O4@Cu2-xS core-shell nanoparticles, which offer both high photothermal stability and superparamagnetic properties. Specifically, these core-shell nanoparticles have proven effective as probes for T2-weighted magnetic resonance imaging and infrared thermal imaging because of their strong absorption at the near-infrared region centered around 960 nm. Importantly, the photothermal effect of the nanoparticles can be precisely controlled by varying the Cu content in the core-shell structure. Furthermore, we demonstrate in vitro and in vivo photothermal ablation of cancer cells using these multifunctional nanoparticles. The results should provide improved understanding of synergistic effect resulting from the integration of magnetism with photothermal phenomenon, important for developing multimode nanoparticle probes for biomedical applications. PMID- 23687973 TI - Clinical accuracy of estimated fetal weight in term pregnancies in a teaching hospital. AB - OBJECTIVE: To evaluate whether clinical characteristics alter the accuracy of clinical estimation of fetal weight (EFW) in term pregnancies in a teaching hospital. METHODS: Secondary analysis of a retrospective cohort study of patients presenting for labor at term. Clinical EFW was performed using Leopold maneuvers. A Spearman's rank correlation coefficient (r) was used to evaluate the linear relationship between clinical EFW and actual birth weight (BW). Body mass index (BMI), gestational age, fetal station, and admission diagnosis were evaluated with respect to their impact on clinical EFW. The primary outcome was an absolute error between clinical EFW and actual BW >500 g. RESULTS: Of 3797 patients, 941 (24.8%) had an absolute error in clinical EFW exceeding 500 g. The overall correlation between clinical EFW and actual BW was weak (r = 0.4). There was a significant trend of improved accuracy of clinical EFW with increasing gestational age; however, BMI, fetal station, and admission diagnosis did not have significant effects. Of 221 cases of macrosomia (>4000 g), 181 (81.9%) were undetected by clinical EFW. CONCLUSION: The correlation between clinical EFW and actual BW is overall weak, particularly in patients with macrosomic fetuses; however, BMI, admission diagnosis, and fetal station do not have a significant impact. PMID- 23687974 TI - Pseudoaneurysm of the superior lateral genicular artery: case report of a rare complication after total knee arthroplasty. AB - BACKGROUND: Pseudoaneurysm of superior lateral genicular artery following total knee arthroplasty is a rare complication and has been reported following lateral release performed for eversion of patella in a knee with tight lateral structures. CASE PRESENTATION: This report describes a case of pseudo aneurysm of superior lateral geniculate artery that developed after primary Total knee arthroplasty for a stiff knee in a 68 year old patient. Patient presented with pain and rapidly increasing swelling in early post operative period. Diagnosis was made on duplex ultrasound and confirmed by angiography. Angiographic coil embolisation of the pseudoaneurysm was performed. Since no lateral release was performed in this case, the probable mechanism was shear injury to the vessel. CONCLUSION: Pseudoaneurysm of superior lateral genicular artery can occur in absence of lateral release by shear injury to an atherosclerotic vessel. Angiographic coil embolisation appears to be the best method for treating such post arthroplasty pseudoaneurysm because of less chance of infection, non interference with rehabilitation and diagnosis and treatment during same procedure. PMID- 23687975 TI - Synthesis, insecticidal activities, and SAR studies of novel pyridylpyrazole acid derivatives based on amide bridge modification of anthranilic diamide insecticides. AB - Anthranilic diamides are one of the most important classes of modern agricultural insecticides. To discover new structure-modified compounds with high activity, series of novel carbonyl thioureas, carbonyl ureas, oxadiazoles, carbonyl thiophosphorylureas, oxadiazole-containing amides, and thiazoline-containing amides were designed through the modification of the amide bridge based on the structure of chlorantraniliprole and were synthesized, and bioassays were carried out. The compounds were characterized and confirmed by melting point, IR, (1)H NMR, and elemental analyses or HRMS. Preliminary bioassays indicated that some compounds exhibited significant insecticidal activities against oriental armyworm, diamondback moth, beet armyworm, corn borer, and mosquito. Among them, trifluoroethoxyl-containing carbonyl thiourea 20a showed best larvicidal activity against oriental armyworm, with LC50 and LC95 values of 0.1812 and 0.7767 mg/L, respectively. Meanwhile, 20c and 20e showed 86 and 57% death rates against diamondback moth at 0.005 mg/L, and the LC50 values of the two compounds were 0.0017 and 0.0023 mg/L, respectively, which were lower than that of the control chlorantraniliprole. The relationship between structure and insecticidal activity was discussed, and the HF calculation results indicated that the carbonyl thiourea moiety plays an important role in the insecticidal activity. The present work demonstrated that the trifluoroethoxyl-containing carbonyl thioureas can be used as lead compounds for further development of novel insecticides. PMID- 23687976 TI - Significant sequelae after bacterial meningitis in Niger: a cohort study. AB - BACKGROUND: Beside high mortality, acute bacterial meningitis may lead to a high frequency of neuropsychological sequelae. The Sahelian countries belonging to the meningitis belt experience approximately 50% of the meningitis cases occurring in the world. Studies in Africa have shown that N. meningitidis could cause hearing loss in up to 30% of the cases, exceeding sometimes measles. The situation is similar in Niger which experiences yearly meningitis epidemics and where rehabilitation wards are rare and hearing aids remain unaffordable. The aim of this study was to estimate the frequency of neuropsychological sequelae after acute bacterial meningitis in four of the eight regions of Niger. METHODS: Subjects exposed to acute bacterial meningitis were enrolled into a cohort with non exposed subjects matched on age and gender. Consenting subjects were interviewed during inclusion and at a control visit two months later. If clinical symptoms or psychological troubles persisted at both visits among the exposed subjects with a frequency significantly greater than that observed among the non exposed subjects, a sequelae was retained. The comparison of the frequency of sequelae between non exposed and exposed subjects to bacterial meningitis was also calculated using the Fisher exact test. RESULTS: Three persisting functional symptoms were registered: headaches, asthenia, and vertigo among 31.3, 36.9, and 22.4% respectively of the exposed subjects. A significant motor impairment was retrieved among 12.3% of the exposed versus 1.6% of the non exposed subjects. Hearing loss significantly disabled 31.3% of the exposed subjects and 10.4% exhibited a serious deafness. CONCLUSIONS: This study carried out in Niger confirms two serious neurological sequelae occurring at high frequencies after bacterial meningitis: severe and profound hearing loss and motor impairment. Cochlear implantation and hearing aids are too expensive for populations living in developing countries. Neurological sequelae occurring after meningitis should sensitize African public health authorities on the development of rehabilitation centers. All these challenges can be met through existing strategies and guidelines. PMID- 23687977 TI - Expressions of candidate molecules in the human fallopian tube and chorionic villi of tubal pregnancy exposed to levonorgestrel emergency contraception. AB - BACKGROUND: Cases of ectopic pregnancy (EP) following levonorgestrel (LNG) emergency contraception (EC) failure were reported, however, the effects of LNG on tubal microenvironment or chorionic villi in EP have not yet been documented. METHODS: Fifty-five women with tubal pregnancy were divided into two groups according to whether LNG-EC was administrated during the cycle of conception. The serum concentrations of beta-hCG, E2 and P were measured. The mRNA and protein expressions of estrogen and progesterone receptors, leukemia inhibitory factor, vascular endothelial growth factor, inducible nitric oxide synthase, and endocannabinoid receptor - CB1 in the ectopic implantation site and chorionic villi were examined. RESULTS: Compared to those unexposed to LNG-EC, women with tubal pregnancy exposed to LNG-EC during the cycle of conception had no statistically significances in the serum concentrations of beta-hCG, E2 P, nor in the pathological types of tubal pregnancy or the expressions of ER-alpha, PR, LIF, VEGF, iNOS and CB1. CONCLUSIONS: The expressions of candidate molecules in the fallopian tube and chorionic villi were not altered by exposure to LNG-EC. A routine therapy with no additional intervention might thus be applied to tubal pregnancy exposed to LNG-EC. PMID- 23687978 TI - Leg mass characteristics of accurate and inaccurate kickers--an Australian football perspective. AB - Athletic profiling provides valuable information to sport scientists, assisting in the optimal design of strength and conditioning programmes. Understanding the influence these physical characteristics may have on the generation of kicking accuracy is advantageous. The aim of this study was to profile and compare the lower limb mass characteristics of accurate and inaccurate Australian footballers. Thirty-one players were recruited from the Western Australian Football League to perform ten drop punt kicks over 20 metres to a player target. Players were separated into accurate (n = 15) and inaccurate (n = 16) groups, with leg mass characteristics assessed using whole body dual energy x-ray absorptiometry (DXA) scans. Accurate kickers demonstrated significantly greater relative lean mass (P <= 0.004) and significantly lower relative fat mass (P <= 0.024) across all segments of the kicking and support limbs, while also exhibiting significantly higher intra-limb lean-to-fat mass ratios for all segments across both limbs (P <= 0.009). Inaccurate kickers also produced significantly larger asymmetries between limbs than accurate kickers (P <= 0.028), showing considerably lower lean mass in their support leg. These results illustrate a difference in leg mass characteristics between accurate and inaccurate kickers, highlighting the potential influence these may have on technical proficiency of the drop punt. PMID- 23687979 TI - Clinical significance and evaluation of polysensitisation using skin sensitisation profiling in atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic allergic inflammatory disease characterised by late eczematous lesions and allergenic sensitisation that occur. Skin prick testing has been used for the causative investigation of individual allergens. However, there exists no proper tool to evaluate polysensitisation status. In this study, skin sensitisation indices were suggested, and the clinical significance of polysensitisation was evaluated. METHODS: A total of 188 AD patients were involved in this study. Blood tests including blood eosinophil % and serum total IgE were conducted. Skin prick tests for 50 important allergens were performed. The skin sensitisation index (SSI) was compared with the blood eosinophil % and the serum total IgE. RESULTS: The degree of sensitisation may be related to the serum total IgE rather than the number of allergens to which a patient is sensitised. The skin sensitisation profile was associated with IgE related laboratory results but not with clinical activity or blood eosinophil %. CONCLUSIONS: For the evaluation of polysensitisation, skin sensitisation profiles may be needed and the skin sensitisation profile was useful for the description of polysensitisation. Polysensitisation seems to be one mechanism for the elevation of serum total IgE. Further studies may be needed to ascertain the clinical significance of skin polysensitisation and the application of the skin sensitisation profile in clinical use. PMID- 23687980 TI - Ultrafiltration membranes with a thin poly(styrene)-b-poly(isoprene) selective layer. AB - Ultrafiltration membranes with an 80 nm thick block polymer derived selective layer containing 20 nm cylindrical pores were prepared by removing poly(lactide) (PLA) from a poly(styrene)-b-poly(isoprene)-b-poly(lactide) (PS-PI-PLA) film onto a microporous polymer support. The block polymer film adopted a core(PLA) shell(PI) cylindrical morphology in which vertically-oriented PLA cylinders were degraded to leave PI-lined channels in a PS matrix. Thanks to the combination of PS and PI in the nanoporous matrix, chemical cross-linking was not needed to provide mechanical stability in the thin film. The membranes showed a hydraulic flux of 165 L m(-2) h(-1) bar(-1) and were able to size-discriminate poly(ethylene oxide) (PEO) solutes in agreement with theoretical predictions. PMID- 23687981 TI - A theoretical analysis of colloid attachment and straining in chemically heterogeneous porous media. AB - A balance of applied hydrodynamic (T(H)) and resisting adhesive (T(A)) torques was conducted over a chemically heterogeneous porous medium that contained random roughness of height h(r) to determine the fraction of the solid surface area that contributes to colloid immobilization (S(f)*) under unfavorable attachment conditions. This model considers resistance due to deformation and the horizontal component of the adhesive force (F(AT)), spatial variations in the pore scale velocity distribution, and the influence of hr on lever arms for T(H) and T(A). Values of S(f)* were calculated for a wide range of physicochemical properties to gain insight into mechanisms and factors influencing colloid immobilization. Colloid attachment processes were demonstrated to depend on solution ionic strength (IS), the colloid radius (r(c)), the Young's modulus (K), the amount of chemical heterogeneity (P+), and the Darcy velocity (q). Colloid immobilization was also demonstrated to occur on a rough surface in the absence of attachment. In this case, S(f)* depended on IS, r(c), the roughness fraction (f0), h(r), and q. Roughness tended to enhance T(A) and diminish T(H). Consequently, the effect of IS on S(f)* was enhanced by h(r) relative to attachment. In contrast, the effects of r(c) and q on S(f)* were diminished by hr in comparison to attachment. Colloid immobilization adjacent to macroscopic roughness locations shares many similarities to grain-grain contact points and may be viewed as a type of straining process. In general, attachment was more important for higher IS and variance in the secondary minimum, and for smaller r(c), q, and K, but diffusion decreased these values. Conversely, straining was dominant for the opposite conditions. Discrepancies in the literature on mechanisms of colloid retention are likely due to a lack of consideration of all of these factors. PMID- 23687982 TI - Corticosteroids effect on caspase 3 expression in an in-vitro model of hypoxic brain cells. AB - OBJECTIVE: Effects of corticosteroids (CS) in the brain of growth-restricted fetus remain largely unstudied. We investigated if dexamethasone (DXM) exposure contributes to neuronal injury in an in-vitro model of neuronal cells under hypoxic conditions (surrogate for fetal growth restriction). STUDY DESIGN: U87 glioblastoma cells exposed to hypoxic or normoxic conditions for 10 h were incubated in the absence or presence of DXM for 48 h. Apoptosis as possible indicator of neurotoxicity was determined using a caspase-3-specific activity assay and western blotting. Caspase-3 was calculated as percentage of mean caspase-3 cleavage. Each experiment was performed in triplicate (n = 48). Caspase 3 activity in cell culture media was also measured by ELISA. RESULTS: Pro-caspase 3 (32 kDa) was expressed in culture, but activated 17 Kd caspase 3 was not expressed in cell lysate. There was no difference in ratio of caspase 3 activation when U87 cells were exposed to 10 v of hypoxia as compared to normoxia (0.46 +/- 0.44 versus 0.37 +/- 0.37). The pro-apoptotic effects of DXM were not increased by pre-exposure to hypoxia: (0.37 +/- 0.37 versus 0.47 +/- 0.40). CONCLUSION: The addition of DXM to hypoxic U87 cells had no additive or synergistic effects on the activation of caspase 3. Therefore, we speculate that the administration of CS in the setting of fetal growth restriction would not lead to increased apoptosis with potential neuronal injury. PMID- 23687983 TI - Bis(toluene)chromium(I) [1,2,5]thiadiazolo[3,4-c][1,2,5]thiadiazolidyl and [1,2,5]thiadiazolo[3,4-b]pyrazinidyl: new heterospin (S1 = S2 = 1/2) radical-ion salts. AB - Bis(toluene)chromium(0), Cr(0)(eta(6)-C7H8)2 (3), readily reduced [1,2,5]thiadiazolo[3,4-c][1,2,5]thiadiazole (1) and [1,2,5]thiadiazolo[3,4 b]pyrazine (2) in a tetrahydrofuran solvent with the formation of heterospin, S1 = S2 = 1/2, radical-ion salts [3](+)[1](-) (4) and [3](+)[2](-) (5) isolated in high yields. The salts 4 and 5 were characterized by single-crystal X-ray diffraction (XRD), solution and solid-state electron paramagnetic resonance, and magnetic susceptibility measurements in the temperature range 2-300 K. Despite the formal similarity of the salts, their crystal structures were very different and, in contrast to 4, in 5 anions were disordered. For the XRD structures of the salts, parameters of the Heisenberg spin Hamiltonian were calculated using the CASSCF/NEVPT2 and broken-symmetry density functional theory approaches, and the complex magnetic motifs featuring the dominance of antiferromagnetic (AF) interactions were revealed. The experimental chiT temperature dependences of the salts were simulated using the Van Vleck formula and a diagonalization of the matrix of the Heisenberg spin Hamiltonian for the clusters of 12 paramagnetic species with periodic boundary conditions. According to the calculations and chiT temperature dependence simulation, a simplified magnetic model can be suggested for the salt 4 with AF interactions between the anions ([1](-)...[1](-), J1 = 5.77 cm(-1)) and anions and cations ([1](-)...[3](+), J2 = -0.84 cm(-1)). The magnetic structure of the salt 5 is much more complex and can be characterized by AF interactions between the anions, [2](-)...[2](-), and by both AF and ferromagnetic (FM) interactions between the anions and cations, [2](-)...[3](+). The contribution from FM interactions to the magnetic properties of the salt 5 is in qualitative agreement with the positive value of the Weiss constant Theta (0.4 K), whereas for salt 4, the constant is negative (-7.1 K). PMID- 23687984 TI - Predictors of suicidal behaviour in 36,304 individuals sickness absent due to stress-related mental disorders -- a Swedish register linkage cohort study. AB - BACKGROUND: Stress-related mental disorders (SRMD), which correspond to the diagnostic code F43 in the International Classification of Diseases, version 10, rank among the leading causes of sickness absence in several European countries. Despite the size of this health problem, research on risk factors for severe medical outcomes, like suicidal behavior, is lacking to date. The aim of this study was to investigate predictors of suicide attempt and suicide among sickness absentees with SRMD. METHODS: A cohort of 36,304 non-retired individuals, aged 16 64 years on 31.12.2004, with at least one sickness absence spell due to SRMD, initiated in 2005, was followed up with regard to suicide attempt (2006-2009) and suicide (2006-2008). Univariate and multivariate hazard ratios (HR) with 95% confidence intervals (CI) were estimated for a number of predictors. RESULTS: During the follow-up period, 266 individuals attempted suicide and 34 committed suicide. In the multivariate analyses, the following factors increased the risk of suicide attempt: =< 25 years of age, low educational level, lone parenthood, > 1 sickness absence spell, long duration of the first spell of sickness absence due to SRMD (> 180 days), > 4 and > 8 days of inpatient care due to somatic or mental diagnoses (2000-2005), and > 4 and > 1 outpatient visits due to somatic or mental diagnoses (2001-2005), respectively. Hazard ratios ranged from 1.4 to 4.2. Health care due to mental diagnoses and > 1 spell of sickness absence regardless of diagnosis were predictive of suicide. CONCLUSIONS: Several predictors related to socio-demographics, sickness absence and health-care consumption were identified as risk factors for suicidal behavior. Consideration of these risk factors is of both clinical and public health importance. PMID- 23687985 TI - The association between polymorphisms in the MDR1 gene and risk of cancer: a systematic review and pooled analysis of 52 case-control studies. AB - BACKGROUND: The multidrug resistance (MDR) 1 gene encodes a 170-kDa membrane transporter called P-glycoprotein, which plays an important role in protecting cells against lipophilic xenobiotics by the way of an ATP-dependent cellular efflux mechanism. Three polymorphisms of MDR1, 3435C > T located in exon 26, 1236C > T in exon 12 and 2677G > T/A in exon 21 were the most extensively studied and were identified functionally important and ethnically diverse mapping to the gene region. Considering the potential influence of altering MDR1 activity, it is plausible that MDR1 polymorphisms might play a role in the development of cancer. Although the effects of MDR1 polymorphisms on susceptibility to human cancer have been investigated in many studies, the results still remain conflicting. METHODS: To resolve these conflicts, we performed a quantitative synthesis of the association between these three polymorphisms and cancer risk, including 52 studies (15789 cases and 20274 controls) for 3435C > T polymorphism, 10 studies (2101 cases and 2842 controls) for 1236C > T polymorphism and 18 studies (3585 cases and 4351 controls) for 2677G > T/A polymorphism. RESULTS: The stratified analyses for 3435C > T polymorphism, individuals with T-allele in 3435C > T had significantly higher ALL risks (TT versus CC: OR =1.286, 95% CI =1.123-1.474); significantly elevated risks were observed among Caucasian populations (TT versus CC: OR =1.276, 95% CI =1.112-1.464). When restricting the analysis to the source of controls, we found that HB (hospital-based) genetic models had higher risks (TT versus CC: OR =1.307, 95% CI =1.046-1.632), as well as in PB (population based) genetic models (TT versus CC: OR =1.294, 95% CI =1.079-1.55).The T/A allele frequency of 2677G > T/A polymorphism was associated with higher risk of cancer (TT + TA + AA vs. GG: OR =1.348, 95% CI =1.031-1.762), significantly elevated risks were observed among Asian populations (TT + TA + AA vs. GG: OR =1.642, 95% CI =1.340-2.012), and elevated risks could be associated with PB models (TT + TA + AA vs. GG: OR =1.641, 95% CI =1.018-2.646). CONCLUSIONS: Our meta-analysis suggested that 3435C > T polymorphism and 2677G > T/A polymorphism were associated with cancer risk when all studies were pooled together, while 1236C > T polymorphism not. PMID- 23687986 TI - Isotope effects and mechanism of the asymmetric BOROX Bronsted acid catalyzed aziridination reaction. AB - The mechanism of the chiral VANOL-BOROX Bronsted acid catalyzed aziridination reaction of imines and ethyldiazoacetate has been studied using a combination of experimental kinetic isotope effects and theoretical calculations. A stepwise mechanism where reversible formation of a diazonium ion intermediate precedes rate-limiting ring closure to form the cis-aziridine is implicated. A revised model for the origin of enantio- and diastereoselectivity is proposed based on relative energies of the ring-closing transition structures. PMID- 23687987 TI - Repetitive transcranial magnetic stimulation (rTMS) for treating major depression and schizophrenia: a systematic review of recent meta-analyses. AB - BACKGROUND: In recent years, repetitive transcranial magnetic stimulation (rTMS) has been developed for the treatment of major depression (MD) and schizophrenia. Although rTMS has shown some promising findings, the lack of standardization in the methodology employed has resulted in discordant findings. OBJECTIVES: The objective of this systematic review was to summarize several meta-analytical studies exploring the efficacy of rTMS in either MD or schizophrenia in order to examine the methodologies that increase the efficacy of rTMS and to provide some recommendations for future studies. METHODS: We searched the MEDLINE database for potentially relevant meta-analytic studies on the use of rTMS for treating major depression and schizophrenia published from January 2000 to October 2011. RESULTS: Fifteen rTMS meta-analytical studies were reviewed (11 on MD and 5 on schizophrenia). Several variables were reviewed including outcome measures, side effects of rTMS, site of stimulation, frequency and intensity of stimulation, and number of treatment sessions. CONCLUSIONS: Overall, rTMS appears to be an effective and promising therapeutic for both MD and schizophrenia. PMID- 23687988 TI - 2D IR spectroscopy using four-wave mixing, pulse shaping, and IR upconversion: a quantitative comparison. AB - Recent technological advances have led to major changes in the apparatuses used to collect 2D IR spectra. Pulse shaping offers several advantages including rapid data collection, inherent phase stability, and phase-cycling capabilities. Visible array detection via upconversion allows the use of visible detectors that are cheaper, faster, more sensitive, and less noisy than IR detectors. However, despite these advantages, many researchers are reluctant to implement these technologies. Here we present a quantitative study of the S/N of 2D IR spectra collected with a traditional four-wave mixing (FWM) apparatus, with a pulse shaping apparatus, and with visible detection via upconversion to address the question of whether weak chromophores at low concentrations are still accessible with such an apparatus. We find that the enhanced averaging capability of the pulse shaping apparatus enables the detection of small signals that would be challenging to measure even with the traditional FWM apparatus, and we demonstrate this ability on a sample of cyanylated dihydrofolate reductase. PMID- 23687989 TI - Self-assembling properties of porphyrinic photosensitizers and their effect on membrane interactions probed by NMR spectroscopy. AB - Aggregation and membrane penetration of porphyrinic photosensitizers play crucial roles for their efficacy in photodynamic therapy. The current study was aimed at comparing the aggregation behavior of selected photosensitizers and correlating it with membrane affinity. Self-assembling properties of 15 amphiphilic free-base chlorin and porphyrin derivatives bearing carboxylate substituents were studied in phosphate buffered saline (PBS) by (1)H NMR spectroscopy, making use of ring current induced aggregation shifts. All compounds exhibited aggregation in PBS to a different degree with dimers or oligomers showing slow aggregate growth over time. Aggregate structures were proposed on the basis of temperature dependent chemical shift changes. All chlorin compounds revealed similar aggregation maps with their hydrophobic sides overlapping and their carboxylate groups protruding toward the exterior. In contrast, for the porphyrin compounds, the carboxylate groups were located in overlapping regions. Membrane interactions were probed using 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayer vesicles and 1,2 dihexanoyl-sn-glycero-3-phosphocholine (DHPC) micelles as models. The chlorin derivatives had higher membrane affinity and were all monomerized by DHPC micelles as opposed to the porphyrin compounds. The observed differences were attributed to the different aggregate structures proposed for the chlorin and porphyrin derivatives. Free accessibility of the carboxylate groups seemed to promote initial surface interaction with phospholipid bilayers and micelles. PMID- 23687990 TI - Experimental models for predicting drug absorption and metabolism. AB - INTRODUCTION: For orally administered drugs, their intestinal absorption and hepatic metabolism are key players for determining a drug's systemic bioavailability and thus therapeutic effect. Drug absorption and metabolism are both complicated processes, with many physicochemical and physiological factors involved. Understanding the contribution of each of these processes is essential in regulating a drug's level in the bloodstream and in maintaining its optimum therapeutic outcome and safety. Several animal models have been established for studying the intestine and liver as barriers to drug delivery and systemic bioavailability. AREAS COVERED: This review provides an overview of available animal and cell-based models that have been used to characterize and predict drug intestinal absorption and hepatic clearance in humans. Among the most commonly used models to study drug intestinal absorption are in-vitro Caco-2 cells, in situ rat intestinal perfusion and the in vivo animal models. On the other hand, hepatic clearance is mostly studied using in vitro techniques. The authors also review in silico approaches which play significant role during early pharmaceutical research. EXPERT OPINION: The current models developed have greatly contributed to our knowledge of drug interactions with physiological factors, while also useful in the prediction of drug intestinal absorption and metabolism. However, much work remains in this area for the successful extrapolation of in vitro-in vivo data and in furthering the development of reliable and accurate models. PMID- 23687992 TI - Generation of arynes via ate complexes of arylboronic esters with an ortho leaving group. AB - An efficient method of generating aryne has been achieved by treating ortho (trifluoromethanesulfonyloxy)arylboronic acid pinacol ester with tert- or sec butyllithium. Monitoring the reaction by (11)B NMR has indicated that a boron-ate complex formed in situ is the eventual precursor that converts into aryne near room temperature. The prior formation of the ate complex at a low temperature has enabled us to use various arynophiles, including those bearing base-sensitive groups. The ready availability of the aryne precursors and mutual orthogonality in aryne generation with widely used ortho-silylaryl triflate have enhanced the utility of the method. PMID- 23687991 TI - H-rev107 regulates prostaglandin D2 synthase-mediated suppression of cellular invasion in testicular cancer cells. AB - BACKGROUND: H-rev107 is a member of the HREV107 type II tumor suppressor gene family which includes H-REV107, RIG1, and HRASLS. H-REV107 has been shown to express at high levels in differentiated tissues of post-meiotic testicular germ cells. Prostaglandin D2 (PGD2) is conjectured to induce SRY-related high-mobility group box 9 (SOX9) expression and subsequent Sertoli cell differentiation. To date, the function of H-rev107 in differentiated testicular cells has not been well defined. RESULTS: In the study, we found that H-rev107 was co-localized with prostaglandin D2 synthase (PTGDS) and enhanced the activity of PTGDS, resulting in increase of PGD2 production in testis cells. Furthermore, when H-rev107 was expressed in human NT2/D1 testicular cancer cells, cell migration and invasion were inhibited. Also, silencing of PTGDS would reduce H-rev107-mediated increase in PGD2, cAMP, and SOX9. Silencing of PTGDS or SOX9 also alleviated H-rev107 mediated suppression of cell migration and invasion. CONCLUSIONS: These results revealed that H-rev107, through PTGDS, suppressed cell migration and invasion. Our data suggest that the PGD2-cAMP-SOX9 signal pathway might play an important role in H-rev107-mediated cancer cell invasion in testes. PMID- 23687993 TI - Overcoming product inhibition in catalysis of the intramolecular Schmidt reaction. AB - A method for carrying out the intramolecular Schmidt reaction of alkyl azides and ketones using a substoichiometric amount of catalyst is reported. Following extensive screening, the use of the strong hydrogen-bond-donating solvent hexafluoro-2-propanol was found to be consistent with low catalyst loadings, which ranged from 2.5 mol % for favorable substrates to 25 mol % for more difficult cases. Reaction optimization, broad substrate scope, and preliminary mechanistic studies of this improved version of the reaction are described. PMID- 23687995 TI - Comparative pathogenesis of type 1 (European genotype) and type 2 (North American genotype) porcine reproductive and respiratory syndrome virus in infected boar. AB - BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) now has two main genotypes, genotype 1 (European) and genotype 2 (North American). There is a lack of data on the comparison of pathogenicity of the two genotypes in boars. The objectives of the present study were to evaluate the amount of PRRSV present in semen over time and compare the viral distribution and microscopic lesions of type 1 and type 2 PRRSV-infected boars. METHODS: Twenty-four 8-month old PRRSV-naive Duroc boars were randomly allocated to 3 treatment groups. The boars in groups 1 (n = 9) and 2 (n = 9) were intranasally inoculated with type 1 or type 2 PRRSV, respectively. The boars in groups 1 (n = 6) served as negative controls. Semen and blood samples were collected up to 35 days post-inoculation (dpi), and necropsies were performed on 14, 21, and 35 dpi. RESULTS: There were no significant differences in the genomic copy number of PRRSV, microscopic testicular lesion score, number of PRRSV-positive germ cells, or number of apoptotic cells between the type 1 and type 2 PRRSV-infected boars throughout the experiment. Histopathological changes were manifested by the desquamation of spermatocytes and the presence of multinucleated giant cells in seminiferous tubules of both type 1 and type 2 PRRSV-infected boars. The distribution of PRRSV positive cells was focal; the virus was found in single germ cells or small clusters of germ cells, localized to the spermatogonia, spermatocytes, spermatids, and non-sperm cells in type 1 and type 2 PRRSV-infected boars. CONCLUSIONS: The results of this study demonstrated that two genotypes of PRRSV do not have significantly different virulence toward the male reproductive system of pigs. PMID- 23687997 TI - A patient who experienced thyroid storm complicated by rhabdomyolysis, deep vein thrombosis, and a silent pulmonary embolism: a case report. AB - BACKGROUND: Thyroid storm is a serious condition of thyrotoxicosis. Hyperthyroidism often presents with thrombotic events, especially at cerebral sites; however, the possible association between a lower extremity deep vein thrombosis (LEDVT) and thyroid storm has not been previously reported. We encountered a patient who developed thyroid storm, associated with rhabdomyolysis, followed by LEDVT and a small silent pulmonary embolism (PE). The case is discussed with references to the pertinent literature. CASE PRESENTATION: A 50-year-old woman with no past medical history was referred to our hospital because of severe diarrhea, muscle weakness in her lower limbs (manual muscle testing: MMT 3), and disturbances of consciousness. She was diagnosed as having Graves' disease based on the presence of struma, exophthalmos, and hyperthyroidism with TSH receptor antibody positivity; we further determined that the patient was experiencing thyroid storm based on the results of the Burch Wartofsky scoring system and a Japanese diagnostic criteria. Treatment with steroids, iodine potassium, methimazole, and propranolol was initiated. Severe watery diarrhea continued, and the laboratory data revealed hypokalemia (2.0 meq/L). On day 14, a blood analysis showed a sudden elevation in her creatinine kinase (CK) level, leading to a diagnosis of rhabdomyolysis. Thereafter, the muscle weakness in her lower limbs advanced to a degree of MMT 1. Seven days after the diagnosis of rhabdomyolysis, pitting edema began to appear in bilateral lower extremities. Contrast-enhanced CT scans revealed a LEDVT involving the left common iliac vein, bilateral femoral veins, and left popliteal vein. Furthermore, a small PE was identified. Hyperthyroidism often presents with thrombotic events, especially at cerebral sites, but few reports of PE or LEDVT have been made. CONCLUSION: This case suggests that the occurrence of thyroid storm may be associated with a risk of LEDVT and/or PE. We suggest that DVT preventive measures are undertaken, and that a lower limb venous echo or contrast-enhanced CT examination would be considered if LEDVT is suspected. PMID- 23687996 TI - Autoantibodies to tumor-associated antigens as biomarkers in human hepatocellular carcinoma (HCC). AB - Tumor-associated antigens (TAAs) recognized by cellular and/or humoral effectors of the immune system are attractive targets for diagnostic and therapeutic approaches to human cancer. Different approaches can be used to comprehensively characterize and validate the identified TAA/anti-TAA systems, which are potential biomarkers in cancer immunodiagnosis. Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. The high fatality rate of HCC within one year after its detection might be partly attributed to a lack of diagnostic methods that enable the early detection. Our previous studies have shown that novel autoantibodies can appear which are not detected prior to pre-malignant conditions during transition from chronic liver disease to HCC. The hypothesis we advance is the transition to malignancy can be associated with autoantibody response to certain cellular proteins that might have some role in tumorigenesis. We propose that the information that the cancer patient's immune system is conveying in the form of autoantibodies to tumor-associated antigens (TAAs) should be utilized to a greater extent in identifying early signs of tumorigenesis. In this review, we will focus on the important features of TAA and the possibility that autoantibodies to TAAs can be used as biomarkers in immunodiagnosis and prognosis of HCC. PMID- 23687998 TI - Influence of apple and citrus pectins, processed mango peels, a phenolic mango peel extract, and gallic Acid as potential feed supplements on in vitro total gas production and rumen methanogenesis. AB - Several food processing byproducts were assessed as potential feed and feed supplements. Since their chemical composition revealed a high nutritional potential for ruminants, the Hohenheim in vitro gas test was used to investigate total gas, methane, and volatile fatty acid production as well as protozoal numbers after ruminal digestion of different substrate levels. Processing byproducts used were low- and high-esterified citrus and apple pectins, integral mango peels, and depectinized mango peels. In addition, the effect of a phenolic mango peel extract and pure gallic acid was investigated. The highest decrease in methane production (19%) was achieved by supplementing high levels of low esterified citrus pectin to the hay-based diet. Interestingly, total gas production was not affected at the same time. Showing valuable nutritional potential, all byproducts exhibited, e.g., high metabolizable energy (11.9-12.8 MJ/kg DM). In conclusion, all byproducts, particularly low-esterified citrus pectin, revealed promising potential as feed and feed supplements. PMID- 23687999 TI - Impact of 13-valent pneumococcal conjugate vaccine (PCV13) in a pandemic similar to the 2009 H1N1 in the United States. AB - BACKGROUND: High rates of bacterial coinfection in autopsy data from the 2009 H1N1 influenza ("flu") pandemic suggest synergies between flu and pneumococcal disease (PD) during pandemic conditions, and highlight the importance of interventions like the 13-valent pneumococcal conjugate vaccine (PCV13) that may mitigate the impact of a pandemic. METHODS: We used a decision-analytic model, estimated from published sources, to assess the impact of pediatric vaccination with PCV13 versus the 7-valent vaccine (PCV7) on PD incidence and mortality in a normal flu season (10% flu incidence) and in a pandemic similar to 2009-2010 H1N1 (20% flu incidence, mild virulence, high impact in children). Both direct and indirect (herd) effects against PD were considered. Effectiveness of PCV13 was extrapolated from observed PCV7 data, using assumptions of serotype prevalence and PCV13 protection against the 6 serotypes not in PCV7. To simulate 2009-2010 H1N1, autopsy data were used to estimate the overall proportion of flu deaths with bacterial coinfections. By assuming that increased risk of death during the pandemic occurred among those with comorbidity (using obesity as proxy) and bacterial coinfections primarily due to S. pneumoniae or S. aureus, we estimated the proportion co-infected among all (fatal and non-fatal) flu cases (7.6% co infected with any organism; 2.2% with S. pneumoniae). PD incidence, mortality, and total healthcare costs were evaluated over a 1-year horizon. RESULTS: In a normal flu season, compared to PCV7, PCV13 is expected to prevent an additional 13,400 invasive PD (IPD) cases, 399,000 pneumonia cases, and 2,900 deaths, leading to cost savings of $472 M. In a pandemic similar to 2009-2010 H1N1, PCV13 would prevent 22,800 IPD cases, 872,000 pneumonia cases, and 3,700 deaths, resulting in cost savings of $1.0 B compared to PCV7. CONCLUSIONS: In a flu pandemic similar to the 2009-2010 H1N1, protection against the 6 additional serotypes in PCV13 would likely be effective in preventing pandemic-related PD cases, mortality, and associated costs. PMID- 23688000 TI - Epidemiology of polycystic ovary syndrome: a cross sectional study of university students at An-Najah national university-Palestine. AB - BACKGROUND: Polycystic Ovary Syndrome (PCOS) is the most common gynecological endocrinopathy in women of reproductive age. Despite its heavy burden on female reproduction and general health, there is no study regarding PCOS prevalence in Palestine. This study aims to establish prevalence of PCOS among female university students at An-Najah National University-Palestine and to explore its possible risk factors. METHODS: A cross sectional study was conducted on 137 female students using convenience sampling method for age group (18-24) years. PCOS cases were identified according to the National Institute of health (NIH) criteria through clinical interview and assessment for participants at the University clinics. Menstrual irregularities regarding cycle and flow were identified and clinical hyperandrogenism was assessed as the self-reported degree of hirsutism using the modified Ferriman Gallwey (mF-G) scoring method of more than 8 score. Biochemical hyperandrogenism for girls with menstrual irregularities was assessed by measuring free testosterone level. Data were analyzed using SPSS version 17 applying descriptive methods; different risk factor relationships were estimated using bivariate analysis and multivariate logistic regression. RESULTS: The estimated prevalence of PCOS was 7.3%, acne was the only studied risk factor among others to be statistically significantly related to PCOS patients (OR=8.430, P-value=0.015). Clinical Hirsutism was found in 27% of participants, 70% of whom had idiopathic hirsutism. CONCLUSIONS: Prevalence of PCOS in Palestine seems to be relatively high but similar to other Mediterranean statistics. We recommend further studies using wider age group and larger sample for all parts of Palestine in order to generalize results. PMID- 23688001 TI - Electrochemically controlled stiffness of multilayers for manipulation of cell adhesion. AB - Stimuli-responsive thin films attract considerable attention in different fields. Herein, an electrochemical redox multilayers with tunable stiffness is constructed through the layer-by-layer self-assembly method. The redox ferrocene modified poly(ethylenimine) play an essential role to induce multilayers' swelling/shrinking under an electrochemical stimulus, resulting reversible change of elastic modulus of the multilayers. The adhesion of fibroblast cells can be thus controlled from well spreading to round shape. Such soft multilayers with electrochemically controlled stiffness could have potentials for cell-based applications. PMID- 23688002 TI - "It is not superstition that worries me, Herr Doctor, but genes and chromosomes" Inspector Kemp, from the movie Young Frankenstein, 1974. PMID- 23688003 TI - Efficacy of temsirolimus in metastatic chromophobe renal cell carcinoma. AB - BACKGROUND: Renal cell carcinoma (RCC) is a histopathologically and molecularly heterogeneous disease with the chromophobe subtype (chRCC) accounting for approximately 5% of all cases. The median overall survival of advanced RCC has improved significantly since the advent of tyrosine kinase inhibitors and mammalian target of rapamycin (mTOR) inhibitors. However, high-quality evidence for the use of new generation tyrosine kinase inhibitors in patients with advanced chRCC is lacking. Few published case reports have highlighted the use of temsirolimus in chRCC. CASE PRESENTATION: Here, we report the case of a 36-year old Caucasian woman with metastatic chRCC with predominantly skeletal metastases who was refractory to sunitinib who demonstrated a durable clinical response to temsirolimus lasting 20 months. We review the available evidence pertaining to the use of new generation molecularly targeted agents, in particular mTOR inhibitors in chRCC and discuss their emerging role in the management of this disease which would aid the oncologists faced with the challenge of treating this rare type of RCC. CONCLUSION: Conducting randomised clinical trials in this rarer sub-group of patients would be challenging and our case report and the evidence reviewed would guide the physicians to make informed decision regarding the management of these patients. PMID- 23688004 TI - Viscoelasticity moduli of aqueous C14EO8 solutions as studied by drop and bubble profile methods. AB - The drop and bubble profile methods are used to study the viscoelasticity modulus of C14EO8 aqueous solutions within a wide concentration range. To determine the equilibrium concentration of the surfactant in the drop bulk, the correction is introduced for the surfactant losses caused by its adsorption on the drop surface. It is shown that with this correction the frequency dependencies of the viscoelasticity modulus measured by either of the two experimental techniques are almost the same. The theoretical model is used, which describes the surfactant dilational rheology assuming the diffusion-governed adsorption. The experimental data for C14EO8 solutions is described by the reorientation model that assumes the two states of surfactant molecules with different molar areas in the surface layer and the intrinsic compressibility of the molecules. PMID- 23688005 TI - Acculturation in elite sport: a thematic analysis of immigrant athletes and coaches. AB - To identify key issues concerning the acculturation of immigrant athletes in sport psychology, a thematic analysis (Braun & Clarke, 2006) was conducted on focus group interview data from immigrant elite athletes relocated to Canada (n = 13) and coaches working with such athletes (n = 10). Two central themes were identified: (a) navigating two world views which referred to acculturation as a fluid process where athletes navigated between cultural norms of the home community and the host community, and (b) acculturation loads, which referred to whether immigrants and those in the host country shared acculturation (i.e., acculturation as a two-way process) or managed the load with or without support from others (i.e., acculturation as one-directional). Each of these central themes comprised sub-themes, which provided further insight into the experiences of acculturation for immigrant elite athletes. From the project, the authors recommend further research utilising case studies to provide a holistic description of the acculturation process from the vantage of various people within the sport context. PMID- 23688006 TI - Palladium-catalyzed chelation-assisted aromatic C-H nitration: regiospecific synthesis of nitroarenes free from the effect of the orientation rules. AB - A palladium-catalyzed chelation-assisted ortho-nitration of aryl C-H bond is described. A range of azaarenes such as 2-arylquinoxalines, pyridines, quinoline, and pyrazoles were nitrated with excellent chemo- and regioselectivity. Using the O-methyl oximyl group as a removable directing group, the regiospecific synthesis of a variety of o-nitro aryl ketones was achieved starting from aryl ketones via a three-step process involving the Pd-catalyzed ipso-nitration of C-H bond as a key step. Mechanistic investigations support a silver-mediated radical mechanism involving Pd((II/III) and/or Pd(II/IV) catalytic cycles under oxidizing conditions. PMID- 23688007 TI - Increased risk of cardiovascular complications in chronic kidney disease: a possible role of leptin. AB - Leptin is a small peptide hormone (16 kDa), a product of the obesity gene (Ob), and is mainly synthesized and secreted by adipocytes. It is removed from the blood by the kidneys. The kidney is not only a site of leptin clearance, but also a target organ for its action in different pathophysiological states. Several studies have documented a strong relationship between chronic kidney disease (CKD) and accelerated cardiovascular disease (CVD) defined as a cardiorenal syndrome. Patients with stage 3 and 4 CKD develop cardiovascular complications and are at increased risk of death from CVD. Renal dysfunction promotes several mechanisms responsible for exacerbation of cardiovascular disease. These include activation of the renin-angiotensin system, oxidative stress, elevated asymmetric dimethylarginine (ADMA), low-grade inflammation with increased circulating cytokines, and dyslipidemia. Recently, it has been observed that plasma leptin level is elevated in patients with cardiorenal syndrome. In obesity, hyperleptinemia combined with selective leptin resistance appear to have a critical role in the development and progression of kidney disease, CVD and metabolic syndrome. This has clinical implications for the treatment of obesity related hypertension and kidney disease. In this paper the role of leptin in chronic kidney disease and accelerated cardiovascular disease is out lined. The link between hyperleptinemia and development and progression of morphologic changes that effect kidney in obese patients is also discussed. PMID- 23688008 TI - Novel superactive leptin antagonists and their potential therapeutic applications. AB - Random mutagenesis of mouse leptin antagonist (L39A/D40A/F41) followed by selection of high-affinity mutants by yeastsurface display indicated that replacing residue D23 with a non-negatively charged amino acid (most specifically with Leu) leads to dramatically enhanced affinity of leptin toward LEPR leading to development of superactive mouse, human, ovine and rat leptin antagonists (D23L/L39A/D40A/F41A). Superactive leptin antagonist mutants of mouse, human, rat or ovine leptins were developed in our laboratory, expressed in E. coli, refolded and purified to homogeneity as monomeric proteins. Pegylation of leptin antagonists resulted in potent and effective long-acting reagents suitable for in vivo studies or therapies. In the present review we explain the mechanism of leptin inhibition and summarize the possible use of leptin antagonists as possible leptin blockers in various human pathologies such as antiinflammatory and anti-autoimmune diseases, uremic cachexia, and cancer. We also suggest the use of leptin antagonists as research reagents for creation of a novel, fast and reversible model of T2DM in mice. PMID- 23688009 TI - Leptin in thrombosis and atherosclerosis. AB - A world-wide obesity epidemic is threatening to have a major impact on the prevalence of chronic and acute vascular diseases. In addition to weight loss interventions, which have met with modest success to date, it will be important to understand mechanisms by which obesity promotes vascular disease processes. Studies of leptin, a hormone produced by the adipocyte, have supported the concept that adipocyte-specific products may be mediating some of the vascular risk associated with obesity. This mini-review provides an overview of some of the preclinical studies demonstrating causal relationships between leptin and vascular endpoints. Therapeutic strategies designed to block leptin-mediated signaling events in cells contributing to vascular disease may prove beneficial in obese subjects at risk for vascular complications. PMID- 23688011 TI - Leptin-induced endothelial dysfunction: a target for therapeutic interventions. AB - Leptin has received much attention since its cloning in 1994. Initially, leptin research centered on satiety, energy balance and sympathetic activation. However, hyperleptinemia has since been identified as an independent risk factor for various cardiovascular pathologies including atherosclerotic coronary artery disease. Over the last decade, multiple studies have implicated leptin as an important mediator in endothelial dysfunction and neointimal hyperplasia, both key steps in the evolution of atherosclerotic vascular changes. Additionally, more recent evidence indicates that paracrine leptin release from perivascular adipose tissue (PVAT) has deleterious effects on the underlying endothelium and vascular smooth muscle cells (SMC), including the coronary circulation. This report reviews pertinent literature on leptin-mediated endothelial dysfunction, SMC proliferation and the role of PVAT-derived leptin with an emphasis on the coronary circulation and discussions of currently proposed molecular mechanisms of PVAT-mediated coronary endothelial dysfunction and neointimal hyperplasia. PMID- 23688010 TI - Role of C reactive protein (CRP) in leptin resistance. AB - Increased plasma levels of both leptin and C reactive protein (CRP) have been reported in a number of conditions, including obesity, and have been linked to cardiovascular pathophysiological processes and increased cardiovascular risk; interestingly these two biomarkers appear to be able to reciprocally regulate their bioavailability, through complex mechanisms that have not been completely clarified yet. Here we first review clinical evidence suggesting not only that the circulatory levels of CRP and leptin show an independent correlation, but also that assessing them in tandem may result in an increased ability to predict cardiovascular disease. We summarize also molecular studies showing that leptin is able to promote CRP production from hepatocytes and endothelial cells in vitro and discuss the studies addressing the possibility that in vivo leptin administration may be able to modulate plasma CRP levels. Furthermore, we describe two studies demonstrating that CRP directly binds leptin in extra cellular settings, thus impairing its biological actions. Finally we report genetic evidence that common variations at the leptin receptor locus are associated with CRP blood levels. Overall, the data reviewed here show that the chronic elevation of CRP observed in obese subjects may worsen leptin resistance, contributing to the pathogenesis of cardiovascular disease, and highlight a potential link between conditions, such as leptin resistance and endothelial dysfunction, that may be amenable of pharmacological treatment targeted to the disruption of leptin-CRP interaction. PMID- 23688012 TI - Transactivation of ErbB receptors by leptin in the cardiovascular system: mechanisms, consequences and target for therapy. AB - Many experimental and clinical studies have demonstrated that elevated leptin concentration in patients with obesity/metabolic syndrome contributes to the pathogenesis of cardiovascular disorders including arterial hypertension, atherosclerosis, restenosis after coronary angioplasty and myocardial hypertrophy. Receptor tyrosine kinases belonging to the ErbB family, especially ErbB1 (epidermal growth factor receptor) and ErbB2 are abundantly expressed in the blood vessels and the heart. EGFR is activated not only by its multiple peptide ligands but also by many other factors including angiotensin II, endothelin-1, norepinephrine, thrombin and prorenin; the phenomenon referred to as "transactivation". Augmented EGFR signaling contributes to abnormalities of vascular tone and renal sodium handling as well as vascular remodeling and myocardial hypertrophy through various intracellular mechanisms, in particular extracellular signal-regulated kinases (ERK) and phosphoinositide 3-kinase (PI3K). Recent experimental studies indicate that chronically elevated leptin transactivates the EGFR through the mechanisms requiring reactive oxygen species and cytosolic tyrosine kinase, c-Src. In addition, hyperleptinemia increases ErbB2 activity in the arterial wall. Stimulation of EGFR and ErbB2 downstream signaling pathways such as ERK and PI3K in the vascular wall and the kidney may contribute to the increase in vascular tone, enhanced tubular sodium reabsorption as well as vascular and renal lesions in hyperleptinemic obese subjects. PMID- 23688013 TI - Autophagy inhibition rescues against leptin-induced cardiac contractile dysfunction. AB - Leptin hormone plays a vital role in the pathophysiological changes in heart geometry and function. Nonetheless, the precise mechanism(s) triggering leptin induced cardiomyocyte contractile dysfunction is not well understood. The present study was designed to examine if autophagy plays a role in leptin-induced cardiac contractile anomalies. Cardiomyocyte contractile function was evaluated using an IonOptix edge detection system in cardiomyocytes following treatment with leptin in the presence or absence of the autophagy inhibiting chemical 3-methyladenine (3-MA). Immunoblotting was employed to evaluate expression of AMPK, Beclin1, Atg 5, p62 and LC3-II. GFP-LC3 puncta was used to assess autophagosome formation. Leptin suppressed cardiac contractile function as evidenced by decreased peak shortening, maximal velocity of shortening and relengthening, increased time-to 90% relengthening, all the observed effects were reduced or obliterated by autophagy inhibition. Leptin promoted superoxide generation, AMPK activation and overt autophagy induction. Leptin promoted autophagy as evidenced by enhanced LC3 II, Beclin, Atg 5 and decreased p62 levels. Pharmacological inhibition of reactive oxygen species (ROS) using tempol significantly attenuated leptin induced autophagosome formation and cardiac contractile anomalies. In addition, genetic deletion of AMPKalpha2 or pharmacological inhibition of AMPK using compound C abrogated leptin or superoxide induced cardiac contractile dysfunction and autophagosome formation. In summary, our data revealed that leptin impairs cardiac contractile function through a superoxide generation-AMPK activation-and autophagy dependent mechanism. PMID- 23688014 TI - What fans the fire: insights into mechanisms of leptin in metabolic syndrome associated heart diseases. AB - Obesity and metabolic syndrome are one of the most devastating risk factors for cardiovascular diseases. The obesity gene product leptin plays a central role in the regulation of food intake and energy expenditure. The physiological and pathophysiological roles of leptin in cardiovascular system have been investigated extensively since its discovery in 1994. In addition to its well established metabolic effects, more recent evidence have depicted a rather pivotal role of leptin in inflammation, oxidative stress, endoplasmic reticulum stress, apoptosis and tissue remodeling en route to the pathogenesis of type 2 diabetes mellitus, hypertension, atherosclerosis, and insulin resistance. Under physiological condition, leptin is known to reduce appetite, promote energy expenditure, increase sympathetic activity, facilitate glucose utilization and improve insulin sensitivity. In addition, leptin may regulate cardiac and vascular function through a nitric oxide-dependent mechanism. However, hyperleptinemia usually occurs with progressively increased body weight and metabolic syndrome development, leading to a state of global or selective leptin resistance. Both central and peripheral leptin resistance may be present under pathophysiological conditions such as inflammation, insulin resistance, hyperlipidemia and a cadre of other cardiovascular diseases including hypertension, atherosclerosis, obesity, ischemic heart disease and heart failure. In this review, we will discuss cardiovascular actions of leptin related to various components of metabolic syndrome. Particular emphasis will be given to insights derived from therapeutic interventions with lifestyle modification, cardiovascular drugs, anti-diabetic and anti-obesity drugs. PMID- 23688015 TI - Mechanisms linking leptin to arterial and venous thrombosis: potential pharmacological targets. AB - Epidemiological evidence strongly links excess body weight with an increased risk to develop atherothrombotic complications. Obesity is frequently associated with systemic and local inflammation as well as elevated circulating leptin levels, and clinical studies found hyperleptinemia to correlate not only with measures of adiposity, but also with circulating biomarkers of an increased metabolic and cardiovascular risk or surrogate markers of subclinical atherosclerosis. Moreover, experimental studies in mice with systemic disruption of the leptin leptin receptor system as well as after administration or neutralization of the adipokine demonstrated that leptin promotes both arterial and venous thrombosis. In addition to directly binding to and activating platelets and thus potentiating their aggregation in response to agonist stimulation, leptin enhances the expression of prothrombotic and anti-fibrinolytic proteins in vascular and inflammatory cells. On the other hand, its ability to mobilize and recruit vascular progenitor cells from the bone marrow to sites of vascular injury was found to be impaired in hyperleptinemic, obese humans and rodents. Thus, leptin promotes thrombus formation and resolution by several different mechanisms involving primary hemostasis, the coagulation cascade as well as the integrity of the vessel wall. Dissection of the molecular mechanisms underlying each of its actions may pave the road for novel therapeutic options in targeting the increased risk of thrombosis associated with obesity, keeping in mind unresolved issues of a cell-specific leptin resistance as well as individual differences in the responsiveness to leptin. PMID- 23688016 TI - Leptin and vascular smooth muscle cells. AB - This review concerns the influence of leptin on vascular smooth muscle cells (VSMC). VSMC express different isoforms of the leptin receptor (Ob-R) able to activate a wide range of intracellular signalling pathways, mediating many relevant biological actions. In particular, leptin promotes processes deeply involved in atherogenesis, such as VSMC migration, hypertrophy, proliferation, osteogenic differentiation and metalloproteinase expression. The intracellular signalling molecules involved are JAK/STAT, PI3K/Akt, ERK 1/2, p38 MAPK, mTOR, and RhoA/ROCK. Some of these leptin actions are particularly evident in stretching conditions; others are mediated by the NAD(P)H-induced increase of Reactive Oxygen Species. A leptin-induced activation of angiotensin and endothelin systems, with up-regulation of the synthesis of the two hormones and of their receptors, has also been demonstrated. Other studies, however, showed that leptin increases in VSMC the nitric oxide production by activating the inducible nitric oxide synthase, and, via nitric oxide, exerts a vasodilating effect and impairs the proliferative and vasoconstricting actions of angiotensin II. Both the potentially harmful and the potentially beneficial effects exerted by leptin in VSMC are lost in VSMC from animal models of genetically determined leptinresistance. Cultured VSMC from leptin-resistant animals are also resistant to insulin and to nitric oxide. It is not known, however, whether in human obesity, a condition characterized by hypothalamic leptin resistance and by compensatory hyperleptinemia, VSMC are sensitive or resistant to leptin: only in the first case the predictive role of circulating leptin on cardiovascular events could support a pathogenetic influence of the hormone on atherosclerosis. PMID- 23688017 TI - Leptin as a cardiac pro-hypertrophic factor and its potential role in the development of heart failure. AB - The identification of the adipocyte as a source of production of biologically active peptides has materialized into an active area of research related to the role of these peptides in physiology and pathophysiology. Moreover, this research has resulted in the identification of the adipocyte as an endocrine organ producing potent bioactive compounds. An increasing number of these adipokines are being identified, the first of which was leptin, a product of the obesity gene whose primary function is to act as a satiety factor but which is now known to exert a myriad of effects. It is now recognized that virtually all adipokines produce effects on numerous organ systems including the heart and many of these, including leptin, are produced by cardiac tissue. Here we focus primarily on the diverse effects of leptin on the heart especially as it pertains to hypertrophy and discuss the potential cell signaling mechanisms underlying their actions. Current evidence suggests that leptin is a cardiac hypertrophic factor and from clinical studies there is evidence that hyperleptinemia is associated with cardiovascular risk especially as it pertains to heart failure. While more substantial research needs to be carried out, leptin may represent a potential link between obesity, which is associated with hyperleptinemia, and increased cardiovascular risk. PMID- 23688018 TI - Leptin and the cardiovascular system - a target for therapeutic interventions. PMID- 23688019 TI - Monometallic osmium(II) complexes with bis(N-methylbenzimidazolyl)benzene or pyridine: a comparison study with ruthenium(II) analogues. AB - Seven bis-tridentate osmium complexes with Mebib or Mebip (Mebib is the 2 deprotonated form of 1,3-bis(N-methylbenzimidazolyl)benzene and Mebip is bis(N methylbenzimidazolyl)pyridine) have been prepared, and their electrochemical and spectroscopic properties are compared with ruthenium structural analogues. Among them, four complexes have the [Os(NCN)(NNN)]-type coordination, including [Os(Mebib)(Mebip)](PF6)2 (1(PF6)2), [Os(dpb)(Mebip)](PF6) (2(PF6), dpb is the 2 deprotonated form of 1,3-di(pyrid-2-yl)benzene), [Os(Mebib)(ttpy)](PF6) (3(PF6), ttpy = 4'-tolyl-2,2':6',2"-terpyridine), and [Os(dpb)(ttpy)](PF6) (4(PF6)). The other three complexes are [Os(Mebip)2](PF6)2 (5(PF6)2), [Os(Mebip)(tpy)](PF6)2 (6(PF6)2, tpy = 2,2':6',2"-terpyridine), and [Os(ttpy)2](PF6)2 (7(PF6)2) with the [Os(NNN)(NNN)]-type coordination. Single crystals of 2(PF6) and 6(PF6)2 have been obtained, and their structures are studied by X-ray crystallographic analysis. The Os(II/III) redox potentials of 1(PF6)2 to 7(PF6)2 progressively increase from +0.04, +0.23, +0.24, +0.36, +0.56, +0.79 to +0.94 V vs Ag/AgCl, which are 200-300 mV less positive relative to the Ru(II/III) potentials of their ruthenium counterparts. The highest occupied molecular orbital energy levels of 1(+)-7(2+) are calculated to vary in a descending order. The ruthenium and osmium complexes have singlet metal-to-ligand charge-transfer (MLCT) transitions of similar energies and band shapes, while the osmium complexes display additional (3)MLCT transitions in the lower-energy region. Complexes 6(PF6)2 and 7(PF6)2 emit weakly at 780 and 740 nm, respectively. Complex 1(PF6)2 was synthesized as the oxidized Os(III) salt because of the low Os(II/III) potential. The transformation of 1(2+) to 1(+) by chemical reduction or electrolysis led to the emergence of the (1)MLCT transitions in the visible region. PMID- 23688021 TI - Highly selective bis(imino)pyridine iron-catalyzed alkene hydroboration. AB - Bis(imino)pyridine iron dinitrogen complexes have been shown to promote the anti Markovnikov catalytic hydroboration of terminal, internal, and geminal alkenes with high activity and selectivity. The isolated iron dinitrogen compounds offer distinct advantages in substrate scope and overall performance over known precious metal catalysts and previously reported in situ generated iron species. PMID- 23688020 TI - Functionalization of nanostructured ZnO films by copper-free click reaction. AB - The copper-free click reaction was explored as a surface functionalization methodology for ZnO nanorod films grown by metal organic chemical vapor deposition (MOCVD). 11-Azidodecanoic acid was bound to ZnO nanorod films through the carboxylic acid moiety, leaving the azide group available for Cu-free click reaction with alkynes. The azide-functionalized layer was reacted with 1 ethynylpyrene, a fluorescent probe, and with alkynated biotin, a small biomolecule. The immobilization of pyrene on the surface was probed by fluorescence spectroscopy, and the immobilization of biotin was confirmed by binding with streptavidin-fluorescein isothiocyanate (streptavidin-FITC). The functionalized ZnO films were characterized by Fourier transform infrared attenuated total reflectance (FTIR-ATR), steady-state fluorescence emission, fluorescence microscopy, and field emission scanning electron microscopy (FESEM). PMID- 23688023 TI - Nonlinear dynamical behavior in the photodecomposition of N-bromo-1,4 benzoquinone-4-imine. AB - Photodecomposition of N-bromo-1,4-benzoquinone-4-imine in water with and without the presence of oxidants was investigated, exhibiting nonlinear kinetic features such as autocatalytic excursion. An acidic environment was found to be essential for the observed photodecomposition. Mechanistic studies through NMR and mass spectrometry show the conversion of N-bromo-1,4-benzoquinone-4-imine into 1,4 benzoquinone. When bromate was introduced to the studied system, transient spontaneous oscillations were uncovered, forming a new photocontrolled chemical oscillator. The system's sensitivity to the intensity of the illumination is great as decreases halt the oscillations from occurring. Phase diagrams show that as the concentration of N-bromo-1,4-benzoquinone-4-imine is increased, broader concentration ranges of both bromate and sulfuric acid allow the system to exhibit spontaneous oscillations. Electrospray-TOF mass spectroscopy and (13)C NMR spectra suggest that 3,4,4-tribromo-2-hydroxycyclohexa-2,5-dienone is a major product in the bromate system. PMID- 23688022 TI - X-ray irradiation promotes apoptosis of hippocampal neurons through up-regulation of Cdk5 and p25. AB - BACKGROUND: Cranial radiation therapy has been used for the treatment of primary and metastatic brain tumors. A prominent feature of brain injury induced by the radiation therapy is hippocampal dysfunction, characterized by a decline in memory. Cdk5 plays an important role in memory formation. Abnormal Cdk5 activity is associated with neuronal apoptosis induced by neurotoxic stimuli. However, the roles of Cdk5 in hippocampal apoptosis in response to X-ray irradiation have not been explored. METHODS: The expression of Cdk5 activators, p35 and p25, in hippocampal neurons was tested in both in vivo animal and in vitro couture after X-ray irradiation. RESULTS: After X-ray irradiation at 20 Gy and 30 Gy in rats, the number of hippocampal neuronal pyknosis was increased, but the number of hippocampal neuron was decreased, in the hippocampal CA1 region of rats. In these animals undergone with X-ray irradiation, the expression of p35 was significantly down-regulated, but it was up-regulated in p25. These opposite expressions were also shown in the primary cultured hippocampal neurons with 30 Gy irradiation. The apoptosis induced by X-ray irradiation were significantly prevented by the pretreatment of Cdk5 inhibitor, roscovitine, in both in vivo and in vitro settings. CONCLUSIONS: X-ray irradiation resulted in a hippocampal neuronal apoptosis through up-regulation of p25, the Cdk5 activator. Hyperactivity of Cdk5 was involved in the pathogenesis of X-ray irradiation-induced hippocampal neuronal apoptosis. Blockade of Cdk5 signal pathway effectively protected neurons from the irradiation-induced brain injury. PMID- 23688024 TI - Characterization of a novel swollenin from Penicillium oxalicum in facilitating enzymatic saccharification of cellulose. AB - BACKGROUND: Plant expansins and fungal swollenin that can disrupt crystalline cellulose have great potential for applications in conversion of biomass. Recent studies have been mainly focused on Trichoderma reesei swollenin that show relatively low activity in the promotion of cellulosic hydrolysis. Our aim was to isolate a novel swollenin with greater disruptive activity, to establish an efficient way of producing recombinant swollenin, and to optimize the procedure using swollenin in facilitation of cellulosic hydrolysis. RESULTS: A novel gene encoding a swollenin-like protein, POSWOI, was isolated from the filamentous fungus Penicillium oxalicum by Thermal Asymmetric Interlaced PCR (TAIL-PCR). It consisted of a family 1 carbohydrate-binding module (CBM1) followed by a linker connected to a family 45 endoglucanase-like domain. Using the cellobiohydrolase I promoter, recombinant POSWOI was efficiently produced in T. reesei with a yield of 105 mg/L, and showed significant disruptive activity on crystalline cellulose. Simultaneous reaction with both POSWOI and cellulases enhanced the hydrolysis of crystalline cellulose Avicel by approximately 50%. Using a POSWOI-pretreatment procedure, cellulases can produce nearly twice as many reducing sugars as without pretreatment. The mechanism by which POSWOI facilitates the saccharification of cellulose was also studied using a cellulase binding assay. CONCLUSION: We present a novel fungal swollenin with considerable disruptive activity on crystalline cellulose, and develop a better procedure for using swollenin in facilitating cellulosic hydrolysis. We thus provide a new approach for the effective bioconversion of cellulosic biomass. PMID- 23688025 TI - Combinatorial atmospheric pressure chemical vapor deposition of graded TiO2-VO2 mixed-phase composites and their dual functional property as self-cleaning and photochromic window coatings. AB - A combinatorial film with a phase gradient from V:TiO2 (V: Ti >= 0.08), through a range of TiO2-VO2 composites, to a vanadium-rich composite (V: Ti = 1.81) was grown by combinatorial atmospheric pressure chemical vapor deposition (cAPCVD). The film was grown from the reaction of TiCl4, VCl4, ethyl acetate (EtAc), and H2O at 550 degrees C on glass. The gradient in gas mixtures across the reactor induced compositional film growth, producing a single film with numerous phases and compositions at different positions. Seventeen unique positions distributed evenly along a central horizontal strip were investigated. The physical properties were characterized by wavelength dispersive X-ray (WDX) analysis, X ray diffraction (XRD), Raman spectroscopy, scanning electron microscopy (SEM), and UV-visible spectroscopy. The functional properties examined included the degree of photoinduced hydrophilicity (PIH), UVC-photocatalysis, and thermochromism. Superhydrophilic contact angles could be achieved at all positions, even within a highly VO2-rich composite (V: Ti = 1.81). A maximum level of UVC photocatalysis was observed at a position bordering the solubility limit of V:TiO2 (V: Ti ~ 0.21) and fragmentation into a mixed-phase composite. Within the mixed-phase TiO2: VO2 composition region (V: Ti = 1.09 to 1.81) a decrease in the semiconductor-to-metal transition temperature of VO2 from 68 to 51 degrees C was observed. PMID- 23688026 TI - Safety and feasibility of laparoscopic radical cystectomy for the treatment of bladder cancer. AB - BACKGROUND AND PURPOSE: Radical cystectomy is the mainstay of the management of muscle invasive bladder cancer. Numerous centers have adopted a minimally invasive approach to replace the standard open procedure. The objective of the study was to review published literature comparing laparoscopic radical cystectomy (LRC) and open radical cystectomy (ORC). MATERIALS AND METHODS: A systematic review of the literature according to Cochrane guidelines was conducted (1993 to 2012) for studies comparing LRC and ORC. All studies comparing the two procedures were included. The outcome measures were the patient demographics, operative time, blood loss, transfusion rates, time to oral intake, length of hospital stay, and complications. A meta-analysis was conducted. For continuous data, a Mantel-Haenszel chi-square test was used, and for dichotomous data, an inverse variance was used, each expressed as risk ratio with 95% confidence interval. P<0.05 was considered significant. RESULTS: Four hundred twenty-seven patients were included-211 patients in the laparoscopic group and 216 patients in the open group (eight studies). There was no significant difference between the two groups in any of the demographic parameters except for age (age: P<0.0001; sex: P=0.1; body mass index: P=0.05). The laparoscopic group had significantly longer operative times (P<0.0001), but less blood loss (P<0.00001), less transfusion rates (P<0.0001), less time to oral intake (P<0.0001), less analgesic requirement (P=0.0009), and shorter length of hospital stay (P<0.0001). Significantly more minor complications developed in the ORC group than in the LRC group (P=0.02). There was no difference between the two groups regarding lymph node dissection yields, major complications, positive margins, pathologic results, local recurrence, or distant metastases (all P>0.05). There were significantly more positive nodes in the ORC group, however. CONCLUSION: In experienced hands, LRC is a feasible and safe alternative to ORC with less blood loss, transfusion and analgesic requirement, shorter lengths of hospital stay, and less complications. LRC does, however, have longer operative times. PMID- 23688028 TI - Electrospun Zn(1-x)Mn(x)Fe2O4 nanofibers as anodes for lithium-ion batteries and the impact of mixed transition metallic oxides on battery performance. AB - The structural and electrochemical properties of the mixed transition metallic oxides Zn1-xMnxFe2O4 nanofibers, which crystallize in a cubic spinel AFe2O4 structure, are investigated systematically with a gradual substitution of Zn by Mn. The crystal structural information studied by X-ray diffraction (XRD) depicts the formation of single phase spinel structure, while electron-dispersive X-ray spectroscopy (EDS) reveals the stoichiometric ratio between Zn and Mn. ZnFe2O4 exhibits a good capacity of ~532 mAh g(-1) at 50th cycle through the interbeneficial conversion reaction and alloy-dealloy mechanism, with a first discharge working voltage of ~0.83 V. Subsequently, the characteristic redox potential of each spinel is gradually reduced with the replacement of Mn. Furthermore, Zn0.3Mn0.7Fe2O4 demonstrates the highest capacity of ~612 mA h g(-1) at 50th cycle among the solid solution series. Ex situ characterization by high resolution transmission electron microscope (TEM) and electron energy loss spectroscopy (EELS) is conducted to study the participation of Mn in the battery performance. This report represents an example of how the electrochemical performance could be flexibly adjusted by tuning the ratio of transition metals within the spinel. PMID- 23688027 TI - Voluntary movements as a possible non-reflexive pain assay. AB - BACKGROUND: The quantification of pain intensity in vivo is essential for identifying the mechanisms of various types of pain or for evaluating the effects of different analgesics. A variety of behavioral tests for pain measurement have been devised, but many are limited because animals are physically restricted, which affects pain sensation. In this study, pain assessment was attempted with minimal physical restriction, and voluntary movements of unrestrained animals were used to evaluate the intensities of various types of pain. RESULTS: The number of times animals reared or total distances traveled was measured using a motion-tracking device and found to be markedly reduced in carrageenan-induced inflammatory, acetic acid-induced visceral, and streptozotocin-induced neuropathic pain tests. These two voluntary movement parameters were found to be highly correlated with paw withdrawal latency from irradiating heat. In addition, these parameters were markedly reversed by morphine and by non-steroidal anti inflammatory drugs in inflammatory pain models. These parameters were also useful to detect hypoalgesia in TRPV1-/- mice. CONCLUSIONS: These results suggest that parameters of voluntary movement, such as, number of rearing and total distance moved, are effective indicators of pain intensity for many types of pain and that they can be used to evaluate degree of pain perception. PMID- 23688029 TI - Comparison of normal fasting and one-hour glucose levels as predictors of future diabetes during a 34-year follow-up. AB - INTRODUCTION: Early identification of those at risk of developing type 2 diabetes (T2DM) is essential. We examined how normoglycemic levels of fasting blood glucose (FBG) and 1-hour glucose predict the development of diabetes among men initially at low risk. METHODS: In the Helsinki Businessmen Study (men born in 1919- 1934), 1,145 men had normal FBG (< 5.0 mmol/L) in 1974, and 1-hour glucose values available. Multivariate, adjusted models were used to investigate how fasting and 1-hour glucose at baseline related to new-onset diabetes during a follow-up of 34 years. RESULTS: The median FBG and 1-hour glucose values at baseline were 4.4 and 6.6 mmol/L, respectively. During follow-up, 108 men developed diabetes. The risk of incident diabetes was doubled for the highest quintile of FBG (fully adjusted relative risk (RR) 2.22, 95% confidence interval (CI) 1.10-4.50), and quadrupled for that of 1-hour glucose (RR 4.23, 95% CI 2.49 7.17). FBG could not separate the risk for those with higher levels of glucose in the range < 5.0 mmol/L, whereas 1-hour glucose discriminated the risk better at higher values. CONCLUSIONS: Higher values in the normoglycemic range for both fasting and 1-hour glucose predicted long-term incidence of diabetes in healthy middle-aged men. PMID- 23688030 TI - Interactions of ionic liquids and acetone: thermodynamic properties, quantum chemical calculations, and NMR analysis. AB - The interactions between ionic liquids (ILs) and acetone have been studied to obtain a further understanding of the behavior of their mixtures, which generally give place to an exothermic process, mutual miscibility, and negative deviation of Raoult's law. COSMO-RS was used as a suitable computational method to systematically analyze the excess enthalpy of IL-acetone systems (>300), in terms of the intermolecular interactions contributing to the mixture behavior. Spectroscopic and COSMO-RS results indicated that acetone, as a polar compound with strong hydrogen bond acceptor character, in most cases, establishes favorable hydrogen bonding with ILs. This interaction is strengthened by the presence of an acidic cation and an anion with dispersed charge and non-HB acceptor character in the IL. COSMO-RS predictions indicated that gas-liquid and vapor-liquid equilibrium data for IL-acetone systems can be finely tuned by the IL selection, that is, acting on the intermolecular interactions between the molecular and ionic species in the liquid phase. NMR measurements for IL-acetone mixtures at different concentrations were also carried out. Quantum-chemical calculations by using molecular clusters of acetone and IL species were finally performed. These results provided additional evidence of the main role played by hydrogen bonding in the behavior of systems containing ILs and HB acceptor compounds, such as acetone. PMID- 23688031 TI - Catalytic activation of carbohydrates as formaldehyde equivalents for Stetter reaction with enones. AB - We disclose the first catalytic activation of carbohydrates as formaldehyde equivalents to generate acyl anions as one-carbon nucleophilic units for a Stetter reaction. The activation involves N-heterocyclic carbene (NHC)-catalyzed C-C bond cleavage of carbohydrates via a retro-benzoin-type process to generate the acyl anion intermediates. This Stetter reaction constitutes the first success in generating formal formaldehyde-derived acyl anions as one-carbon nucleophiles for non-self-benzoin processes. The renewable nature of carbohydrates, accessible from biomass, further highlights the practical potential of this fundamentally interesting catalytic activation. PMID- 23688032 TI - Establishing reference intervals for electrolytes in newborns and infants using direct ISE analyzer. AB - BACKGROUND: To generate clinically applicable reference intervals (RIs) for commonly requested electrolytes in Ethiopian newborns and infants that can help in early detection, close monitoring and correction of electrolyte abnormalities. Cord blood (from newborns, n = 60) and venous blood samples (from infants, n = 57) were collected and analyzed using direct ISE analyzer, AVL (9181). MedCalc(r) software was applied to determine the robust upper and lower end points covering 95% of the reference values of each electrolyte with respective 90% CIs. FINDINGS: This is an extension report of our recent study; and hence is resulted from the same data source. The level of Na+ and K+ showed difference in newborns and infants even though combined RIs were suggested by the Haris and Boyd rule as 126-143 mmol/l and 4.0-7.9 mmol/l respectively. However, Cl- values failed to show such a difference and thus a combined RI was determined to be 100-111 mmol/l. Almost all maternal, neonatal and infantile factors were not able to affect the values of the electrolytes. CONCLUSION: Combined RIs are suggested for the interpretation of electrolyte values in newborns and infants without taking the effect of maternal, neonatal and infantile factors into account. Since the RIs were different from previously reported values, it will be appropriate to apply such RIs for the interpretation of electrolyte values in Ethiopian pediatric population. PMID- 23688033 TI - Comparative analysis of sequentiality using SDIS-GSEQ and THEME: a concrete example in soccer. AB - Within an observational design aimed at studying what type of soccer is better adapted to the possibilities of the 11-12 year-old child, a comparison was made of the results obtained using two fully consolidated analysis techniques in observational methods, and which form the basis in the development of two respective software programs: SDIS-GSEQ and THEME, which allow one to detect the existence of sequential patterns hidden in a data set. This work is intended to shed light on the comparison of results obtained using these two analysis techniques. In particular, the data used for the analysis are multicode event data (using the lexicon of the sequential analysis), and do not incorporate the duration parameter. Accordingly, for the detection of regular structures using the THEME program (T-patterns), a constant duration has conventionally been assigned to each occurrence. Using THEME, among the greatest number of sequential structures detected, diachronic and synchronic correspondence was observed (T patterns reflecting identical multi-events) with each and every one of the sequential patterns obtained using the lag technique, by the SDIS-GSEQ software. This coincidence strengthens the link between the algorithms that support SDIS GSEQ and THEME. The results indicate that 7-a-side soccer and 9-a-side soccer types facilitate the spatial mastery of the game by the child, compared with the adult form, 11-a-side soccer. PMID- 23688034 TI - Risk interaction of obesity, insulin resistance and hormone-sensitive lipase promoter polymorphisms (LIPE-60 C > G) in the development of fatty liver. AB - BACKGROUND: Hormone sensitive lipase (HSL) promoter (LIPE-60 C > G) polymorphism has been found to be involved in hepatic steatosis, obesity, diabetes and dyslipidemia. The precise interactions between these risk factors and genetic susceptibility that may affect non-alcoholic fatty liver disease (NAFLD) are still not fully determined. METHODS: A cross-sectional study was conducted in 1056 men. To avoid the confounding effect of plasma glucose, the study population was classified into normal glucose tolerance (NGT, n = 729) and glucose intolerance (GI, n = 299) groups. NAFLD was diagnosed by abdominal ultrasound after ruling out any history of alcohol abuse. A multivariate regression model was used to estimate the impact of these factors on NAFLD. RESULTS: In the NGT group, subjects with NAFLD often have complicated metabolic abnormalities. The coexistence of NAFLD and GI has been demonstrated to have a synergistic effect raising BMI, serum insulin and HOMA-insulin resistance (HOMA-IR). BMI and adipose insulin resistance (Adipo-IR), but not HOMA-IR, significantly contributed to a greater risk of developing NAFLD. Serum triglyceride was significantly up regulated in men with the (CG + GG) genotype of HSL promoter polymorphism, NAFLD and Adiopo-IR in sequence. CONCLUSION: Adipo-IR, rather than HOMA-IR, appears to be a consistent insulin resistance index in the study of NAFLD. G allele of the HSL promoter polymorphism may contribute the greatest impact raising serum triglyceride in a state of glucose intolerance. PMID- 23688035 TI - MicroRNA-488 regulates zinc transporter SLC39A8/ZIP8 during pathogenesis of osteoarthritis. AB - BACKGROUND: Even though osteoarthritis (OA) is the most common musculoskeletal dysfunction, there are no effective pharmacological treatments to treat OA due to lack of understanding in OA pathology. To better understand the mechanism in OA pathogenesis and investigate its effective target, we analyzed miRNA profiles during OA pathogenesis and verify the role and its functional targets of miR-488. RESULTS: Human articular chondrocytes were obtained from cartilage of OA patients undergoing knee replacement surgery and biopsy samples of normal cartilage and the expression profile of miRNA was analyzed. From expression profile, most potent miR was selected and its target and functional role in OA pathogenesis were investigated using target validation system and OA animal model system. Among miRNAs tested, miR-488 was significantly decreased in OA chondrocytes Furthermore, we found that exposure of IL-1beta was also suppressed whereas exposure of TGF-beta3 induced the induction of miR-488 in human articular chondrocytes isolated from biopsy samples of normal cartilages. Target validation study showed that miR-488 targets ZIP8 and suppression of ZIP8 in OA animal model showed the reduced cartilage degradation. Target validation study showed that miR 488 targets ZIP8 and suppression of ZIP8 in OA animal model showed the reduced cartilage degradation. CONCLUSIONS: miR-488 acts as a positive role for chondrocyte differentiation/cartilage development by inhibiting MMP-13 activity through targeting ZIP-8. PMID- 23688036 TI - Proteomic analysis of human spermatozoa proteins with oxidative stress. AB - BACKGROUND: Oxidative stress plays a key role in the etiology of male infertility. Significant alterations in the sperm proteome are associated with poor semen quality. The aim of the present study was to examine if elevated levels of reactive oxygen species cause an alteration in the proteomic profile of spermatozoa. METHODS: This prospective study consisted of 52 subjects: 32 infertile men and 20 normal donors. Seminal ejaculates were classified as ROS+ or ROS- and evaluated for their proteomic profile. Samples were pooled and subjected to LC-MS/MS analysis through in-solution digestion of proteins for peptide characterization. The expression profile of proteins present in human spermatozoa was examined using proteomic and bioinformatic analysis to elucidate the regulatory pathways of oxidative stress. RESULTS: Of the 74 proteins identified, 10 proteins with a 2-fold difference were overexpressed and 5 were underexpressed in the ROS+ group; energy metabolism and regulation, carbohydrate metabolic processes such as gluconeogenesis and glycolysis, protein modifications and oxidative stress regulation were some of the metabolic processes affected in ROS+ group. CONCLUSIONS: We have identified proteins involved in a variety of functions associated with response and management of oxidative stress. In the present study we focused on proteins that showed a high degree of differential expression and thus, have a greater impact on the fertilizing potential of the spermatozoa. While proteomic analyses identified the potential biomarkers, further studies through Western Blot are necessary to validate the biomarker status of the proteins in pathological conditions. PMID- 23688037 TI - Tailoring fungal morphology of Aspergillus niger MYA 135 by altering the hyphal morphology and the conidia adhesion capacity: biotechnological applications. AB - Current problems of filamentous fungi fermentations and their further successful developments as microbial cell factories are dependent on control fungal morphology. In this connection, this work explored new experimental procedures in order to quantitatively check the potential of some culture conditions to induce a determined fungal morphology by altering both hyphal morphology and conidia adhesion capacity. The capacity of environmental conditions to modify hyphal morphology was evaluated by examining the influence of some culture conditions on the cell wall lytic potential of Aspergillus niger MYA 135. The relative value of the cell wall lytic potential was determined by measuring a cell wall lytic enzyme activity such as the mycelium-bound beta-N-acetyl-D-glucosaminidase (Mb NAGase). On the other hand, the quantitative value of conidia adhesion was considered as an index of its aggregation capacity. Concerning microscopic morphology, a highly negative correlation between the hyphal growth unit length (lHGU) and the specific Mb-NAGase activity was found (r = -0.915, P < 0.001). In fact, the environment was able to induce highly branched mycelia only under those culture conditions compatible with specific Mb-NAGase values equal to or higher than 190 U gdry.wt-1. Concerning macroscopic morphology, a low conidia adhesion capacity was followed by a dispersed mycelial growth. In fact, this study showed that conidia adhesion units per ml equal to or higher than 0.50 were necessary to afford pellets formation. In addition, it was also observed that once the pellet was formed the lHGU had an important influence on its final diameter. Finally, the biotechnological significance of such results was discussed as well. PMID- 23688038 TI - A method for synthesis of homoallylic bromide. AB - Cyclopropyl Grignard reagents react with carbonyl compounds in the presence of diethyl phosphite to give homoallylic bromides. The reaction is effectively carried out under mild conditions in a one-pot fashion with moderate to good yields. PMID- 23688039 TI - Design of affordable and ruggedized biomedical devices using virtual instrumentation. AB - Abstract This paper presents the designs of four low-cost and ruggedized biomedical devices, including a blood pressure monitor, thermometer, weighing scale and spirometer, designed for the East African context. The design constraints included a mass-production price point of $10, accuracy and precision comparable to commercial devices and ruggedness to function effectively in the harsh environment of East Africa. The blood pressure device, thermometer and weighing scale were field-tested in Kenya and each recorded data within 6% error of the measurements from commercial devices and withstood the adverse climate and rough handling. The spirometer functioned according to specifications, but a re design is needed to improve operability and usability by patients. This article demonstrates the feasibility of designing and commercializing virtual instrumentation-based biomedical devices in resource-constrained environments through context-driven design. The next steps for the devices include designing them such that they can be more easily manufactured, use standardized materials, are easily calibrated in the field and have more user-friendly software programs that can be updated remotely. PMID- 23688040 TI - Unexpected and unusual triboelectrification behavior of polymer films containing carboxyl group. AB - The triboelectrification behavior of polymer films when in contact with iron carrier beads was investigated using a homemade special instrument which can control relative humidity under a nitrogen atmosphere. The films showed a large humidity-dependent charging behavior; the charge amount increases with the ambient humidity in the range of a few percent RH to ca. 60% RH. This dependence is explained in terms of the model based on the water charging during the friction and the penetration of the positively charged water into the film. However, it was found that the humidity dependence is significantly depressed by the doping of carboxylic acids into the film or by the introduction of a carboxyl group in the polymer backbone. This depression is again explained by the above charged-water penetration model in which carboxylate ions trap the positively charged water on the film surface. PMID- 23688041 TI - Visible-light photoredox in homolytic aromatic substitution: direct arylation of arenes with aryl halides. AB - Direct arylation of unactivated arenes or heteroarenes with aryl halides could be carried out in the presence of potassium tert-butoxide and dimethyl sulfoxide under visible-light irradiation. Ir(ppy)3 was found to be an effective photoredox catalyst for this reaction. The reactions of aryl iodides occurred at room temperature. Elevated temperature was required for aryl bromides. Homolytic aromatic substitution was proposed to be the operative reaction pathway. PMID- 23688042 TI - Characterizing PvARP, a novel Plasmodium vivax antigen. AB - BACKGROUND: Plasmodium vivax continues to be the most widely distributed malarial parasite species in tropical and sub-tropical areas, causing high morbidity indices around the world. Better understanding of the proteins used by the parasite during the invasion of red blood cells is required to obtain an effective vaccine against this disease. This study describes characterizing the P. vivax asparagine-rich protein (PvARP) and examines its antigenicity in natural infection. METHODS: The target gene in the study was selected according to a previous in silico analysis using profile hidden Markov models which identified P. vivax proteins that play a possible role in invasion. Transcription of the arp gene in the P. vivax VCG-1 strain was here evaluated by RT-PCR. Specific human antibodies against PvARP were used to confirm protein expression by Western blot as well as its subcellular localization by immunofluorescence. Recognition of recombinant PvARP by sera from P. vivax-infected individuals was evaluated by ELISA. RESULTS: VCG-1 strain PvARP is a 281-residue-long molecule, which is encoded by a single exon and has an N-terminal secretion signal, as well as a tandem repeat region. This protein is expressed in mature schizonts and is located on the surface of merozoites, having an apparent accumulation towards their apical pole. Sera from P. vivax-infected patients recognized the recombinant, thereby suggesting that this protein is targeted by the immune response during infection. CONCLUSIONS: This study showed the characterization of PvARP and its antigenicity. Further assays orientated towards evaluating this antigen's functional importance during parasite invasion are being carried out. PMID- 23688043 TI - Perioperative management of intracranial aneurysm and subarachnoid hemorrhage. AB - Stroke is the third leading cause of death and the leading cause of disability in contemporary society. Aneurysmal subarachnoid hemorrhage (aSAH) is a hemorrhagic stroke which accounts for 7% of all stroke cases and 22 to 25% of cerebrovascular deaths. Aneurysmal subarachnoid hemorrhage is a very complex disease and many controversies on its pathophysiology and management have not yet been settled. The aim of this review is to present the most recent evidence-based advances in the pathophysiology and perioperative management of aSAH. PMID- 23688044 TI - Global analytical potential energy surface for the electronic ground state of NH3 from high level ab initio calculations. AB - The analytical, full-dimensional, and global representation of the potential energy surface of NH(3) in the lowest adiabatic electronic state developed previously (Marquardt, R.; et al. J. Phys. Chem. B 2005, 109, 8439-8451) is improved by adjustment of parameters to an enlarged set of electronic energies from ab initio calculations using the coupled cluster method with single and double substitutions and a perturbative treatment of connected triple excitations (CCSD(T)) and the method of multireference configuration interaction (MRCI). CCSD(T) data were obtained from an extrapolation of aug-cc-pVXZ results to the basis set limit (CBS), as described in a previous work (Yurchenko, S.N.; et al. J. Chem. Phys 2005, 123, 134308); they cover the region around the NH3 equilibrium structures up to 20,000 hc cm(-1). MRCI energies were computed using the aug-cc-pVQZ basis to describe both low lying singlet dissociation channels. Adjustment was performed simultaneously to energies obtained from the different ab initio methods using a merging strategy that includes 10,000 geometries at the CCSD(T) level and 500 geometries at the MRCI level. Characteristic features of this improved representation are NH3 equilibrium geometry r(eq)(NH(3)) ~ 101.28 pm, alpha(eq)(NH(3)) ~ 107.03 degrees , the inversion barrier at r(inv)(NH(3)) ~ 99.88 pm and 1774 hc cm(-1) above the NH(3) minimum, and dissociation channel energies 41,051 hc cm(-1) (for NH(3) -> ((2)B(2))NH(2) + ((2)S(1/2))H) and 38,450 hc cm(-1) (for NH(3) -> ((3)Sigma(-))NH +((1)Sigma(g)(+))H(2)); the average agreement between calculated and experimental vibrational line positions is 11 cm(-1) for (14)N(1)H(3) in the spectral region up to 5000 cm(-1). A survey of our current knowledge on the vibrational spectroscopy of ammonia and its isotopomers is also given. PMID- 23688047 TI - Vosaroxin: a new valuable tool with the potential to replace anthracyclines in the treatment of AML? AB - INTRODUCTION: Despite significant advances in diagnosis and supportive care, the majority of patients diagnosed with acute myeloid leukemia (AML) ultimately die of their disease. Standard intensive induction treatment continues to comprise cytarabine and a topoisomerase II (topo II) poison, usually an anthracycline. Vosaroxin , a novel first-in-class quinolone derivative has been developed for use in the treatment of AML as a new-generation topo II inhibitor. It has shown promising activity as a monotherapy and also in combination with intermediate dose cytarabine (IDAC) in relapsed and refractory patient cohorts with minimal toxicity and good tolerability. AREAS COVERED: The authors discuss the mechanism of action of vosaroxin, the pharmacokinetics, safety and tolerability, preclinical and clinical trial results available as well as areas of ongoing research. EXPERT OPINION: Vosaroxin has shown efficacy as a novel cytotoxic agent, and despite a similar mechanism of action has significant advantages over anthracyclines. It evades common resistance pathways of p53 and P-glycoprotein (P gp) and does not appear to generate significant reactive oxygen species (ROS) associated with these agents. Should future investigation confirm its efficacy and advantageous safety profile, vosaroxin could potentially replace older generation topoisomerase poisons in the treatment of AML and other malignant conditions. PMID- 23688045 TI - Factors influencing the efficiency of generating genetically engineered pigs by nuclear transfer: multi-factorial analysis of a large data set. AB - BACKGROUND: Somatic cell nuclear transfer (SCNT) using genetically engineered donor cells is currently the most widely used strategy to generate tailored pig models for biomedical research. Although this approach facilitates a similar spectrum of genetic modifications as in rodent models, the outcome in terms of live cloned piglets is quite variable. In this study, we aimed at a comprehensive analysis of environmental and experimental factors that are substantially influencing the efficiency of generating genetically engineered pigs. Based on a considerably large data set from 274 SCNT experiments (in total 18,649 reconstructed embryos transferred into 193 recipients), performed over a period of three years, we assessed the relative contribution of season, type of genetic modification, donor cell source, number of cloning rounds, and pre-selection of cloned embryos for early development to the cloning efficiency. RESULTS: 109 (56%) recipients became pregnant and 85 (78%) of them gave birth to offspring. Out of 318 cloned piglets, 243 (76%) were alive, but only 97 (40%) were clinically healthy and showed normal development. The proportion of stillborn piglets was 24% (75/318), and another 31% (100/318) of the cloned piglets died soon after birth. The overall cloning efficiency, defined as the number of offspring born per SCNT embryos transferred, including only recipients that delivered, was 3.95%. SCNT experiments performed during winter using fetal fibroblasts or kidney cells after additive gene transfer resulted in the highest number of live and healthy offspring, while two or more rounds of cloning and nuclear transfer experiments performed during summer decreased the number of healthy offspring. CONCLUSION: Although the effects of individual factors may be different between various laboratories, our results and analysis strategy will help to identify and optimize the factors, which are most critical to cloning success in programs aiming at the generation of genetically engineered pig models. PMID- 23688046 TI - The role of family background on adolescent khat chewing behavior in Jazan Region. AB - BACKGROUND: Khat is a well-known natural stimulant from the Catha edulis plant and is widely used in certain Red Sea countries, including Yemen and the province of Jazan in Saudi Arabia. Jazan is located in the southwestern part of the Kingdom of Saudi Arabia adjacent to Yemen, where the practice of khat chewing is deeply rooted throughout the entire population. The main objective of this paper was to assess the association between family background, i.e., parent and sibling khat use, and adolescents' khat chewing behavior in Jazan. Other variables were also tested for association, including parents' education levels, family income, and peer influence. MATERIAL AND METHODS: A cross-sectional study was conducted with a representative sample (n = 4,100) of intermediate and upper secondary school students of Jazan. The participants were selected using a three-stage cluster random sampling. A structured self-administered questionnaire was used for data collection. Descriptive statistics, a chi-squared test, and logistic regression were performed to examine the associations and predictors of khat chewing. RESULTS: A total of 3,923 students of both genders from 72 intermediate and upper secondary schools in Jazan were involved in this study. Of these participants, 42.8% (1,678) were from intermediate schools and 43.8% (1,717) were females. The prevalence of current khat chewing among the students was 20.5% (95% confidence interval (CI) 19.27-21.79) and was significantly higher for males at 33.1% (95% CI 31.16-35.08) than for females, of whom 4.3% (95% CI 3.39-5.31) (P < 0.001) chew khat. The multivariate logistic regression analysis suggests that the most important independent predictors of student khat chewing included the students' smoking status (odds ratio (OR) = 14.03, P < 0.001), a friend using khat (OR = 5.65, P < 0.001), a sister using khat (OR = 2.04, P < 0.05), a father using khat (OR = 1.45, P < 0.001), and a brother using khat (OR = 1.56, P < 0.05). CONCLUSION: The results highlight the significant impact of peer and familial khat abuse in adolescent khat chewing behavior. The findings suggest that khat control programs need to focus on peers and family members to reduce the prevalence of the habit along with its unfavorable consequences. PMID- 23688048 TI - Band gap engineering of zinc selenide thin films through alloying with cadmium telluride. AB - This work investigates band gap engineering of zinc selenide (ZnSe) thin films. This was achieved by mixing ZnSe with cadmium telluride (CdTe). The mass ratio (x) of CdTe in the starting material was varied in the range x = 0-0.333. The films were prepared using thermal evaporation. The chemical composition of the films was investigated through energy dispersive spectroscopy and Rutherford backscattering spectrometry. Structural analysis was carried out using X-ray diffraction and atomic force microscopy. Normal incidence transmittance and reflectance were measured over the wavelength range 300-1300 nm. The absorption coefficients and band gaps were determined from these spectrophotometric measurements. The band gap monotonically decreased from 2.58 eV (for x = 0) to 1.75 eV (for x = 0.333). Photocurrent measurements indicated that the maximum current density was obtained for films with x = 0.286. A figure of merit, based on crystallinity, band gap, and photocurrent, was defined. The optimum characteristics were obtained for the films with x = 0.231, for which the band gap was 2.14 eV. PMID- 23688049 TI - Strongyloides stercoralis is a cause of abdominal pain, diarrhea and urticaria in rural Cambodia. AB - BACKGROUND: We document clinical manifestations of 21 patients heavily infected with S. stercoralis (more than 250 larvae in a single Baermann test) from a community in rural Cambodia, both before and three weeks after ivermectin (200 MUg/kg BW, single oral dose) treatment. FINDINGS: Out of 21 patients, 20 (95.2%), 18 (85.7%) and 14 (66.7%) reported frequent abdominal pain, diarrhea and periods of sensation of itching, respectively, during the previous six months; epigastric (11, 55.0%) and peri-umbilical (13, 65.0%) pains were most frequent. Five patients (23.8%) reported having experienced urticaria the week preceding the examination. One patient suffered from extended urticaria. Three weeks after treatment, most symptoms had been almost entirely resolved. CONCLUSIONS: In rural communities of Cambodia, strongyloidiasis with high parasite load is endemic. It is associated with substantial symptoms and clinical signs, particularly abdominal pain, diarrhea and urticaria. Access to adequate diagnosis and treatment is a pressing issue that needs attention. PMID- 23688051 TI - Cell polarity-driven instability generates self-organized, fractal patterning of cell layers. AB - As a model system to study physical interactions in multicellular systems, we used layers of Escherichia coli cells, which exhibit little or no intrinsic coordination of growth. This system effectively isolates the effects of cell shape, growth, and division on spatial self-organization. Tracking the development of fluorescence-labeled cellular domains, we observed the emergence of striking fractal patterns with jagged, self-similar shapes. We then used a large-scale, cellular biophysical model to show that local instabilities due to polar cell-shape, repeatedly propagated by uniaxial growth and division, are responsible for generating this fractal geometry. Confirming this result, a mutant of E. coli with spherical shape forms smooth, nonfractal cellular domains. These results demonstrate that even populations of relatively simple bacterial cells can possess emergent properties due to purely physical interactions. Therefore, accurate physico-genetic models of cell growth will be essential for the design and understanding of genetically programmed multicellular systems. PMID- 23688050 TI - Nanoplasmonic quantitative detection of intact viruses from unprocessed whole blood. AB - Infectious diseases such as HIV and hepatitis B pose an omnipresent threat to global health. Reliable, fast, accurate, and sensitive platforms that can be deployed at the point-of-care (POC) in multiple settings, such as airports and offices, for detection of infectious pathogens are essential for the management of epidemics and possible biological attacks. To the best of our knowledge, no viral load technology adaptable to the POC settings exists today due to critical technical and biological challenges. Here, we present for the first time a broadly applicable technology for quantitative, nanoplasmonic-based intact virus detection at clinically relevant concentrations. The sensing platform is based on unique nanoplasmonic properties of nanoparticles utilizing immobilized antibodies to selectively capture rapidly evolving viral subtypes. We demonstrate the capture, detection, and quantification of multiple HIV subtypes (A, B, C, D, E, G, and subtype panel) with high repeatability, sensitivity, and specificity down to 98 +/- 39 copies/mL (i.e., HIV subtype D) using spiked whole blood samples and clinical discarded HIV-infected patient whole blood samples validated by the gold standard, i.e., RT-qPCR. This platform technology offers an assay time of 1 h and 10 min (1 h for capture, 10 min for detection and data analysis). The presented platform is also able to capture intact viruses at high efficiency using immuno surface chemistry approaches directly from whole blood samples without any sample preprocessing steps such as spin-down or sorting. Evidence is presented showing the system to be accurate, repeatable, and reliable. Additionally, the presented platform technology can be broadly adapted to detect other pathogens having reasonably well-described biomarkers by adapting the surface chemistry. Thus, this broadly applicable detection platform holds great promise to be implemented at POC settings, hospitals, and primary care settings. PMID- 23688052 TI - Reflex anuria following acute cardiac event. AB - BACKGROUND: Reflex anuria is an uncommon cause for acute renal failure, which occurs almost always after manipulation or irritation to kidneys, ureter, bladder or other pelvic organs. CASE PRESENTATION: Here we describe a case of acute renal failure due to reflex anuria following acute cardiac event. This patient had background history of urolithiasis. In the absence of other pre renal, renal or post- renal causes for acute kidney injury, we believe reflex anuria is the causative entity for acute renal failure in our patient. CONCLUSION: Acute renal failure due to reflex anuria is related to a reflex mechanism involving arteriolar vasoconstriction and urethral spasm. Patients with reflex anuria can be successfully managed with medical or surgical interventions. Our case suggests that reflex anuria should be considered as one of the differential diagnosis of acute renal failure following acute cardiac event, especially in patients with background urological problem. PMID- 23688053 TI - Conductivity, spectroscopic, and computational investigation of H3O+ solvation in ionic liquid BMIBF4. AB - The hydrogen ion is one of the most important species in aqueous solutions, as well as in protic ionic liquids (PILs). PILs are important potential alternatives to H2O for swelling the proton exchange membranes (PEMs) and improving the high temperature performance of fuel cells. The hydrogen ion (H(+)) or hydronium (H3O(+)) solvation mechanism is not only a fundamental principle of acid/base chemistry in ionic liquids but also key to understanding the charge- and proton transport properties of the PIL solutions. In this paper, a PIL system was prepared by mixing 1-butyl-3-methyl-imidazolium tetrafluoroborate (BMIBF4) IL with an aqueous solution of a strong acid, HBF4. Water can be partially evaporated from the solution under a vacuum at room temperature. Conductivity and vibrational spectroscopy (IR and Raman) measurements were used in combination with density functional theory (DFT) calculations to characterize the molecular level solvation of H(+) and H2O in the IL solution. When water is present at high molar fraction, the cations (BMI(+) and H(+)) and anions (BF4(-)) are both solvated by water and the solutions have high conductivity. After water evaporation, the PIL solution has excess H(+) and reduced conductivity, which is still significantly higher than that of pure BMIBF4. Vibrational spectroscopy suggests that the BMI(+) and BF4(-) ions are desolvated from water during the water evaporation. DFT calculations assist the interpretation of the vibrational spectroscopy and show that the remaining water is in the form of H3O(+) solvated by the IL molecular ions. Hence, the species remaining after evaporation is a ternary PIL consisting of BMI(+) cation, BF4(-) anion, and H3O(+) cation. The H3O(+) may be the principle charge carrier in the PIL solution and responsible for the high solution conductivity. PMID- 23688054 TI - Prognostic values of VEGF and IL-8 in malignant pleural effusion in patients with lung cancer. AB - OBJECTIVE: The aim of this study was to evaluate the prognostic value of VEGF and IL-8 in pleural effusion in patients with lung cancer. MATERIALS AND METHOD: Commercially available ELISA was used to determine VEGF and IL-8 levels. RESULTS: The level of VEGF showed significant correlations with lymph node metastasis and distant metastasis. But, IL-8 was only correlated with lymph node metastasis. Univariate and multivariate analysis revealed elevated VEGF level was an independent predictor of shorter OS and DFS. CONCLUSION: VEGF could be an important component that contributes to pleural effusion formation, and an important prognostic factor for lung cancer. PMID- 23688055 TI - Backstroke start kinematic and kinetic changes due to different feet positioning. AB - The backstroke swimming start international rules changed in 2005. This study compared two backstroke start variants, both with feet parallel to each other but in complete immersion and emersion. Six elite swimmers performed two sets of 4 maximal 15 m bouts, each set using one of the variants. The starts were videotaped in the sagittal plane with two cameras, providing bi-dimensional dual media kinematic evaluation, and an underwater force plate and a handgrip instrumented with a load cell collected kinetic data. Backstroke start with feet immerged displayed greater centre-of-mass horizontal starting position, centre-of mass horizontal velocity at hands-off and take-off angle. Backstroke start with feet emerged showed greater wall contact time, centre-of-mass horizontal and downward vertical velocity at take-off, lower limbs horizontal impulse, and centre-of-mass downward vertical velocity during flight phase. Backstroke start with feet immerged and emerged displayed similar centre-of-mass horizontal water reach, back arc angle and 5 m starting time. Irrespective of the swimmer's feet positioning, coaches should emphasise each variant's mechanical advantages during the wall contact phases. Furthermore, the maintenance of those advantages throughout the flight should be stressed for better backstroke start performance. PMID- 23688056 TI - Photoswitching of enzyme activity by laser-induced pH-jump. AB - Controlled initiation of biochemical events and in particular of protein activity is a powerful tool in biochemical research. Specifically, optical trigger signals are an attractive approach for remote control of enzyme activity. We present a method for generating optical control of enzyme activity applicable to a widespread range of enzymes. The approach is based on short laser pulses as optical "switches" introducing an instantaneous change of the pH-value for activation of protein function. The pH-jump is induced by proton release from 2 nitrobenzaldehyde. Reaction conditions were chosen to yield a pH-jump of almost 3 units on switching from inactive to active conditions for the enzyme. In this experimental setup, irradiation can be realized without any loss of enzyme activity. Following this change in pH-value, a controlled activation of hydrolytic activity of acid phosphatase is successfully demonstrated. This application provides a general method for photocontrol of enzymatic function for proteins having a significant pH-profile. The kinetic data for the substrate 6 chloro-8-fluoro-4-methylumbelliferone phosphate are determined. PMID- 23688057 TI - The relationship between respiratory variation in the pulmonary arterial pressure tracing and intra-thoracic pressure changes: a pilot study. AB - Respiratory variation in the systemic arterial blood pressure tracing is predictive of the change in cardiac output following volume administration. However, significant inter-individual variability exists. Animal data suggest that systemic arterial respiratory variation loses its predictive ability in the setting of right ventricular failure. Human studies suggest that patients with elevated pulmonary artery pressures are relatively unresponsive to volume administration. The current respiratory variation paradigm neglects the haemodynamic contribution of the right ventricular system. The goal of this study was to determine whether respiratory variation in the pulmonary arterial system could be attributed to intra-thoracic pressure changes. Systemic (radial) and pulmonary arterial pressure waveforms as well as all ventilatory variables were extracted from a haemodynamic database. Using a fast Fourier transformation, the ratio of respiratory (0.15-0.5 Hz) to cardiac (0.67-3 Hz) power was calculated every minute for both arterial waveforms, yielding two 'spectral power ratios' (SPoR). SPoR was compared to all available ventilatory parameters using a linear regression technique. From 19 patients 3422 min of data was analysed. There were statistically significant (p < 0.05) but clinically insignificant correlations between SPoR(radial) and mean airway pressure (r = -0.0462) and minute ventilation (r = -0.130). All tested correlations between SPoR(pulmonary) and ventilatory parameters were statistically significant, with correlations ranging from 0.112-0.224 (median 0.194). The correlation between SPoR(pulmonary) and SPoR(radial) was stronger than the correlation between either measure of respiratory variation and any of the ventilatory parameters (r = 0.342, p < 0.001). Respiratory variation in the pulmonary arterial tracing does not appear to be closely related to ventilatory parameters and is more closely related to systemic arterial respiratory variation, a well-validated estimate of volume status. The observed respiratory variation in the pulmonary arterial pressure tracing may be related to cyclical changes in pre-load or after-load that occur with mechanical ventilation and may affect the predictive power of systemic arterial respiratory variation. PMID- 23688058 TI - A study of exocyclic radical reductions of polysubstituted tetrahydropyrans. AB - Exocyclic radical reductions were thoroughly investigated in the context of the synthesis of polysubstituted tetrahydropyrans, which are found in numerous macrolides. The radical precursors studied herein were generated by tandem cycloetherification and iodoetherification reactions or, alternatively, by semicyclic acetals substitutions. DFT calculations (BHandHLYP/TZVP) performed at the transition-state level for the hydrogen radical delivery are in good accordance with the experimental data and enabled the identification of important conformational factors that govern the selectivities obtained. This study demonstrates that both the preferred reactive conformation of the radical and steric interactions with the incoming hydride have to be considered in order to fully rationalize the levels of diastereoselection generated in acyclic free radical processes. PMID- 23688059 TI - Cost-effectiveness analyses of training: a manager's guide. AB - The evidence on the cost and cost-effectiveness of global training programs is sparse. This manager's guide to cost-effectiveness analysis (CEA) is for professionals who want to recognize and support high quality CEA. It focuses on CEA of training in the context of program implementation or rapid program expansion. Cost analysis provides cost per output and CEA provides cost per outcome. The distinction between these two analyses is essential for making good decisions about value. A hypothetical example of a cost analysis compares the cost per trainee of a computer-based anti-retroviral therapy (ART) training to a more intensive ART training. In a CEA of the same example, cost per trainee who met ART clinical performance standards is compared. The cost analysis is misleading when the effectiveness differs across trainings. Two additional hypothetical examples progress from simple to more complex costs and from a narrow to a broader scope: 1) CEA of the cost per ART patient with 95% adherence that compares the performance of doctors to counselors who attend additional training, and 2) CEA of the cost per infant HIV infection averted for a Prevention of Mother to Child Transmission program that compares the current program to one with additional training. To create an evidence base on CEA of training, more well-designed analyses and data on the cost of training are needed. Analysts should understand more about how capacity is built, how quality is improved within a health facility, and the costs associated with them. Considering the life of an investment in training, evaluations are needed on how many trainees apply the skills taught, how long trainees continue to apply them, and how long the content of the training conforms to national or international guidelines. Better data on effectiveness of training is also needed. It is feasible to measure effectiveness by clinical performance standards, or intermediate outcomes and coverage. Intermediate outcomes and coverage can also be combined with published estimates on health outcomes. PMID- 23688061 TI - Total synthesis of (-)-hippodamine by stereocontrolled construction of azaphenalene skeleton based on extended one-pot asymmetric azaelectrocyclization. AB - The first asymmetric total synthesis of (-)-hippodamine has been accomplished via the concise construction of its azaphenalene core, which is featured by the 2,4,6 chiral piperidine synthesis based on one-pot asymmetric azaelectrocyclization in the partially activated substituent system and the subsequent intramolecular Mannich reaction. PMID- 23688060 TI - Rate of progression of CT-quantified emphysema in male current and ex-smokers: a follow-up study. AB - BACKGROUND: Little is known about the factors associated with CT-quantified emphysema progression in heavy smokers. The objective of this study was to investigate the effect of length of smoking cessation and clinical / demographical factors on the rate of emphysema progression and FEV1-decline in male heavy smokers. METHODS: 3,670 male smokers with mean (SD) 40.8 (17.9) packyears underwent chest CT scans and pulmonary function tests at baseline and after 1 and 3 years follow-up. Smoking status (quitted >=5, >=1-<5, <1 years or current smoker) was noted. Rate of progression of emphysema and FEV1-decline after follow-up were assessed by analysis of variance adjusting for age, height, baseline pulmonary function and emphysema severity, packyears, years in study and respiratory symptoms. The quitted >=5 group was used as reference. RESULTS: Median (Q1-Q3) emphysema severity,<-950 HU, was 8.8 (5.1 - 14.1) and mean (SD) FEV1 was 3.4 (0.73) L or 98.5 (18.5) % of predicted. The group quitted '>5 years' showed significantly lower rates of progression of emphysema compared to current smokers, 1.07% and 1.12% per year, respectively (p<0.001). Current smokers had a yearly FEV1-decline of 69 ml, while subjects quit smoking >5 years had a yearly decline of 57.5 ml (p<0.001). CONCLUSION: Quit smoking >5 years significantly slows the rate of emphysema progression and lung function decline. TRIAL REGISTRATION: Registered at http://www.trialregister.nl with trial number ISRCTN63545820. PMID- 23688062 TI - Polymorphism of the parasite lactate dehydrogenase gene from Plasmodium vivax Korean isolates. AB - BACKGROUND: Assaying for the parasitic lactate dehydrogenase (pLDH) is widely used as a rapid diagnostic test (RDT), but the efficacy of its serological effectiveness in diagnosis, that is antibody detection ability, is not known. The genetic variation of Korean isolates was analysed, and recombinant protein pLDH was evaluated as a serodiagnostic antigen for the detection of Plasmodium vivax malaria. METHODS: Genomic DNA was purified, and the pLDH gene of P. vivax was amplified from blood samples from 20 patients. The samples came from five epidemic areas: Bucheon-si, Gimpo-si, and Paju-si of Gyeonggi Province, Gangwha gun of Incheon metropolitan city, and Cheorwon-gun of Gangwon Province, South Korea, from 2010 to 2011. The antigenicity of the recombinant protein pLDH was tested by western blot and enzyme-linked immunosorbent assay (ELISA). RESULTS: Sequence analysis of 20 Korean isolates of P. vivax showed that the open reading frame (ORF) of 951 nucleotides encoded a deduced protein of 316 amino acids (aa). This ORF showed 100% identity with the P. vivax Belem strain (DQ060151) and P. vivax Hainan strain (FJ527750), 89.6% homology with Plasmodium falciparum FCC1_HN (DQ825436), 90.2% homology with Plasmodium berghei (AY437808), 96.8% homology with Plasmodium knowlesi (JF958130), and 90.2% homology with Plasmodium reichenowi (AB122147). A single-nucleotide polymorphism (SNP) at nucleotide 456 (T to C) was also observed in the isolate from Bucheon, but it did not change in the amino acid sequence. The expressed recombinant protein had a molecular weight of approximately 32 kDa, as analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis. Of the 40 P. vivax patients, 34 (85.0%) were positive by ELISA. CONCLUSIONS: The pLDH genes of 19 isolates of P. vivax were identical, except one for SNP at nucleotide 456. This observation indicates that this gene is relatively stable. Based on these results, the relationship between antibody production against pLDH and the pattern of disease onset should be investigated further before using pLDH for serodiagnosis. PMID- 23688063 TI - No difference in striatal dopamine transporter availability between active smokers, ex-smokers and non-smokers using [123I]FP-CIT (DaTSCAN) and SPECT. AB - BACKGROUND: Mesolimbic and nigrostriatal dopaminergic pathways play important roles in both the rewarding and conditioning effects of drugs. The dopamine transporter (DAT) is of central importance in regulating dopaminergic neurotransmission and in particular in activating the striatal D2-like receptors. Molecular imaging studies of the relationship between DAT availability/dopamine synthesis capacity and active cigarette smoking have shown conflicting results. Through the collaboration between 13 SPECT centres located in 10 different European countries, a database of FP-CIT-binding in healthy controls was established. We used the database to test the hypothesis that striatal DAT availability is changed in active smokers compared to non-smokers and ex-smokers. METHODS: A total of 129 healthy volunteers were included. Subjects were divided into three categories according to past and present tobacco smoking: (1) non smokers (n = 64), (2) ex-smokers (n = 39) and (3) active smokers (n = 26). For imaging of the DAT availability, we used [123I]FP-CIT (DaTSCAN) and single photon emission computed tomography (SPECT). Data were collected in collaboration between 13 SPECT centres located in 10 different European countries. The striatal measure of DAT availability was analyzed in a multiple regression model with age, SPECT centre and smoking as predictor. RESULTS: There was no statistically significant difference in DAT availability between the groups of active smokers, ex-smokers and non-smokers (p = 0.34). Further, we could not demonstrate a significant association between striatal DAT and the number of cigarettes per day or total lifetime cigarette packages in smokers and ex-smokers. CONCLUSION: Our results do not support the hypothesis that large differences in striatal DAT availability are present in smokers compared to ex-smokers and healthy volunteers with no history of smoking. PMID- 23688065 TI - VEGF, M-CSF and CA 15-3 as a new tumor marker panel in breast malignancies: a multivariate analysis with ROC curve. AB - The plasma levels of Vascular endothelial growth factor, macrophage-colony stimulating factor (M-CSF) and CA15-3 in breast cancer patients (BC) were investigated and compared with control groups: benign breast tumor patients and the healthy subjects. Cytokine levels were determined by the use of enzyme-linked immunosorbent assay, CA 15-3 - by chemiluminescent microparticle immunoassay method. Our results have demonstrated significant differences in the concentration of cytokines and CA 15-3 between the groups of BC patients and two control groups. Cytokines have demonstrated equal to CA 15-3 or even higher values of the diagnostic sensitivity (SE), the predictive values of positive and negative test results (PV-PR, PV-NR), and the area under the ROC curve (AUC) in the studied groups. The combined use of tested parameters resulted in the increase of the SE, PV-PR and AUC. These findings suggest the usefulness of both cytokines in the diagnosis of BC, but only M-CSF in discrimination between cancer and non-carcinoma lesions, especially in combination with CA 15-3. PMID- 23688064 TI - In situ magnetic separation of antibody fragments from Escherichia coli in complex media. AB - BACKGROUND: In situ magnetic separation (ISMS) has emerged as a powerful tool to overcome process constraints such as product degradation or inhibition of target production. In the present work, an integrated ISMS process was established for the production of his-tagged single chain fragment variable (scFv) D1.3 antibodies ("D1.3") produced by E. coli in complex media. This study investigates the impact of ISMS on the overall product yield as well as its biocompatibility with the bioprocess when metal-chelate and triazine-functionalized magnetic beads were used. RESULTS: Both particle systems are well suited for separation of D1.3 during cultivation. While the triazine beads did not negatively impact the bioprocess, the application of metal-chelate particles caused leakage of divalent copper ions in the medium. After the ISMS step, elevated copper concentrations above 120 mg/L in the medium negatively influenced D1.3 production. Due to the stable nature of the model protein scFv D1.3 in the biosuspension, the application of ISMS could not increase the overall D1.3 yield as was shown by simulation and experiments. CONCLUSIONS: We could demonstrate that triazine functionalized beads are a suitable low-cost alternative to selectively adsorb D1.3 fragments, and measured maximum loads of 0.08 g D1.3 per g of beads. Although copper-loaded metal-chelate beads did adsorb his-tagged D1.3 well during cultivation, this particle system must be optimized by minimizing metal leakage from the beads in order to avoid negative inhibitory effects on growth of the microorganisms and target production. Hereby, other types of metal chelate complexes should be tested to demonstrate biocompatibility. Such optimized particle systems can be regarded as ISMS platform technology, especially for the production of antibodies and their fragments with low stability in the medium. The proposed model can be applied to design future ISMS experiments in order to maximize the overall product yield while the amount of particles being used is minimized as well as the number of required ISMS steps. PMID- 23688066 TI - Biotechnological production and applications of microbial phenylalanine ammonia lyase: a recent review. AB - Phenylalanine ammonia lyase (PAL) catalyzes the nonoxidative deamination of l phenylalanine to form trans-cinnamic acid and a free ammonium ion. It plays a major role in the catabolism of l-phenylalanine. The presence of PAL has been reported in diverse plants, some fungi, Streptomyces and few Cyanobacteria. In the past two decades, PAL has gained considerable significance in several clinical, industrial and biotechnological applications. Since its discovery, much knowledge has been gathered with reference to the enzyme's importance in phenyl propanoid pathway of plants. In contrast, there is little knowledge about microbial PAL. Furthermore, the commercial source of the enzyme has been mainly obtained from the fungi. This study focuses on the recent advances on the physiological role of microbial PAL and the improvements of PAL biotechnological production both from our laboratory and many others as well as the latest advances on the new applications of microbial PAL. PMID- 23688067 TI - Aqueous two-phase systems strategies to establish novel bioprocesses for stem cells recovery. AB - During the past decade, stem cell transplantation has emerged as a novel therapeutic alternative for several diseases. Nevertheless, numerous challenges regarding the recovery and purification steps must be addressed to supply the number of cells required and in the degree of purity needed for clinical treatments. Currently, there is a wide range of methodologies available for stem cells isolation. Nevertheless, there is not a golden standard method that accomplishes all requirements. A desirable recovery method for stem cells has to guarantee high purity and should be sensitive, rapid, quantitative, scalable, non or minimally invasive to preserve viability and differentiation capacity of the purified cells. In this context, aqueous two-phase systems (ATPS) represent a promising alternative to fulfill the mentioned requirements, promoting the use of stem cell-based therapies for incurable diseases. This practical review focuses on presenting the bases for the development of a novel and scalable bioprocess for the purification of stem cells, with a case scenario of CD133(+) cells. The bioengineering strategies include the application of immunoaffinity ATPS in its multiple variants, including antibody-polymer conjugation, antibody addition and antibody immobilization. Conclusions are drawn in the light of the potential generic implementation of these strategies as an initial step in the establishment of bioprocesses for the purification of stem cells. PMID- 23688068 TI - Six pairs of things to celebrate on International Clinical Trials Day. AB - The Editor has invited me to mark the occasion with a few words "on the development and/or impact of randomised trials over the last decade, or perhaps some thoughts about the future." I do so here by citing some recent developments that give me cause for both pride about the present state of randomised controlled trials (RCTs) and optimism about their future. Respecting the sample size of James Lind's trial and the space allotted me by the Editor, they appear in six pairs. PMID- 23688071 TI - Intramolecular excimer formation between 3,6-di(thiophen-2-yl)pyrrolo[3,4 c]pyrrole-1,4(2H,5H)-dione chromophoric groups linked by a flexible alkyl spacer. AB - Bichromophoric molecules containing two 3,6-di(thiophen-2-yl)pyrrolo[3,4 c]pyrrole-1,4(2H,5H)-dione (DPP) moieties linked via aliphatic spacers of different length are synthesized. Optical absorption spectroscopy indicates that the molecules adopt an extended conformation in solution. Fluorescence spectroscopy shows that photons are emitted from the locally excited singlet state in an extended conformation. In sufficiently polar solvents, quenching of fluorescence occurs and fluorescence quantum yield (PhiF) and fluorescence lifetime (tauF) measurements indicate formation of an intramolecular excimer as the quenching mechanism. The redox potentials of the molecules and the solvent polarity dependence of the quenching are consistent with significant charge transfer character of the excimer state. Photoinduced absorption measurements show enhanced intersystem crossing to the triplet state in polar solvents. Results indicate that in donor-acceptor pi-conjugated materials involving the DPP moiety, excimer-like interchain polaron pair excited states could play an important role in the photophysics because of their close proximity in energy to the lowest singlet excited state. PMID- 23688070 TI - Chronic mild stress facilitates melanoma tumor growth in mouse lines selected for high and low stress-induced analgesia. AB - Both chronic stress conditions and hyperergic reaction to environmental stress are known to enhance cancer susceptibility. We described two mouse lines that displayed high (HA) and low (LA) swim stress-induced analgesia (SSIA) to investigate the relationship between inherited differences in sensitivity to stress and proneness to an increased growth rate of subcutaneously inoculated melanoma. These lines display several genetic and physiological differences, among which distinct sensitivity to mutagens and susceptibility to cancer are especially noticeable. High analgesic mice display high proneness both to stress and a rapid local spread of B16F0 melanoma. However, stress-resistant LA mice do not develop melanoma tumors after inoculation, or if so, tumors regress spontaneously. We found that the chronic mild stress (CMS) procedure leads to enhanced interlinear differences in melanoma susceptibility. Tumors developed faster in stress conditions in both lines. However, LA mice still displayed a tendency for spontaneous regression, and 50% of LA mice did not develop a tumor, even under stressed conditions. Moreover, we showed that chronic stress, but not tumor progression, induces depressive behavior, which may be an important clue in cancer therapy. Our results clearly indicate how the interaction between genetic susceptibility to stress and environmental stress determine the risk and progression of melanoma. To our knowledge, HA/LA mouse lines are the first animal models of distinct melanoma progression mediated by inherited differences in stress reactivity. PMID- 23688069 TI - Chronic kidney disease is associated with adverse outcomes among elderly patients taking clopidogrel after hospitalization for acute coronary syndrome. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with worse outcomes among patients with acute coronary syndrome (ACS). Less is known about the impact of CKD on longitudinal outcomes among clopidogrel treated patients following ACS. METHODS: Using a retrospective cohort design, we identified patients hospitalized with ACS between 10/1/2005 and 1/10/10 at Department of Veterans Affairs (VA) facilities and who were discharged on clopidogrel. Using outpatient serum creatinine values, estimated glomerular filtration rate [eGFR (1.73 ml/min/m2)] was calculated using the CKD-EPI equation. The association between eGFR and mortality, hospitalization for acute myocardial infarction (AMI), and major bleeding were examined using Cox proportional hazards models. RESULTS: Among 7413 patients hospitalized with ACS and discharged taking clopidogrel, 34.5% had eGFR 30-60 and 11.6% had eGFR < 30. During 1-year follow-up after hospital discharge, 10% of the cohort died, 18% were hospitalized for AMI, and 4% had a major bleeding event. Compared to those with eGFR > =60, individuals with eGFR 30-60 (HR 1.45; 95% CI: 1.18-1.76) and < 30 (HR 2.48; 95% CI: 1.97-3.13) had a significantly higher risk of death. A progressive increased risk of AMI hospitalization was associated with declining eGFR: HR 1.20; 95% CI: 1.04-1.37 for eGFR 30-60 and HR 1.47; 95% CI: 1.22-1.78 for eGFR < 30. eGFR < 30 was independently associated with over a 2-fold increased risk in major bleeding (HR 2.09; 95% CI: 1.40-3.12) compared with eGFR > = 60. CONCLUSION: Lower levels of kidney function were associated with higher rates of death, AMI hospitalization, and major bleeding among patients taking clopidogrel after hospitalization for ACS. PMID- 23688072 TI - Probing cell-free gene expression noise in femtoliter volumes. AB - Cell-free systems offer a simplified and flexible context that enables important biological reactions while removing complicating factors such as fitness, division, and mutation that are associated with living cells. However, cell-free expression in unconfined spaces is missing important elements of expression in living cells. In particular, the small volume of living cells can give rise to significant stochastic effects, which are negligible in bulk cell-free reactions. Here, we confine cell-free gene expression reactions to cell-relevant 20 fL volumes (between the volumes of Escherichia coli and Saccharomyces cerevisiae ), in polydimethylsiloxane (PDMS) containers. We demonstrate that expression efficiency varies widely among different containers, likely due to non-Poisson distribution of expression machinery at the observed scale. Previously, this phenomenon has been observed only in liposomes. In addition, we analyze gene expression noise. This analysis is facilitated by our use of cell-free systems, which allow the mapping of the measured noise properties to intrinsic noise models. In contrast, previous live cell noise analysis efforts have been complicated by multiple noise sources. Noise analysis reveals signatures of translational bursting, while noise dynamics suggest that overall cell-free expression is limited by a diminishing translation rate. In addition to offering a unique approach to understanding noise in gene circuits, our work contributes to a deeper understanding of the biophysical properties of cell-free expression systems, thus aiding efforts to harness cell-free systems for synthetic biology applications. PMID- 23688073 TI - Binding and aggregation mechanism of amyloid beta-peptides onto the GM1 ganglioside-containing lipid membrane. AB - Accumulation and fibril formation of amyloid beta (Abeta) peptides onto a ganglioside-rich lipid membrane is a cause of neuro-disturbance diseases. To find out a measure for suppressing the nucleation of a seed for amyloid fibrils, the mechanism of the initial binding of Abeta to the membrane should be clarified. Molecular dynamics simulations were carried out to investigate the adhesion process of Abeta peptides onto a GM1-ganglioside-containing membrane. Multiple computational trials were executed to analyze the probability of occurrence of Abeta binding by using calculation models containing a mixed lipid membrane, water layer, and one, two, or three Abetas. The simulations demonstrated that Abeta peptides approached the membrane after fluctuation in the water layer and occasionally made steady contact with the membrane. Once the steady contact had been established, Abeta was unlikely to be detached from the membrane and developed into a more stably bound form. In the stably bound form, neuraminic acids on the GM1 cluster strongly held the side chain of Lys28 of Abeta, which caused deformation of the C-terminal region of the Abeta. Since the C-terminal region of the Abeta peptide contains many hydrophobic residues, its deformation on the membrane enhances the hydrophobic interaction with other Abeta peptides. The contact region of two Abetas evolved into a parallel beta-sheet form, and the third Abeta was observed to be bound to the complex of two Abetas to make a bundle of Abeta peptides. Some key structures involved in the Abeta aggregation on the GM1-containing membrane were deduced from the multiple simulations. PMID- 23688074 TI - An in situ ionic-liquid-assisted synthetic approach to iron fluoride/graphene hybrid nanostructures as superior cathode materials for lithium ion batteries. AB - A tactful ionic-liquid (IL)-assisted approach to in situ synthesis of iron fluoride/graphene nanosheet (GNS) hybrid nanostructures is developed. To ensure uniform dispersion and tight anchoring of the iron fluoride on graphene, we employ an IL which serves not only as a green fluoride source for the crystallization of iron fluoride nanoparticles but also as a dispersant of GNSs. Owing to the electron transfer highways created between the nanoparticles and the GNSs, the iron fluoride/GNS hybrid cathodes exhibit a remarkable improvement in both capacity and rate performance (230 mAh g(-1) at 0.1 C and 74 mAh g(-1) at 40 C). The stable adhesion of iron fluoride nanoparticles on GNSs also introduces a significant improvement in long-term cyclic performance (115 mAh g(-1) after 250 cycles even at 10 C). The superior electrochemical performance of these iron fluoride/GNS hybrids as lithium ion battery cathodes is ascribed to the robust structure of the hybrid and the synergies between iron fluoride nanoparticles and graphene. PMID- 23688075 TI - Stepwise ligand exchange for the preparation of a family of mesoporous MOFs. AB - A stepwise ligand exchange strategy is utilized to prepare a series of isoreticular bio-MOF-100 analogues. Specifically, in situ ligand exchange with progressively longer dicarboxylate linkers is performed on single crystalline starting materials to synthesize products with progressively larger mesoporous cavities. The new members of this series of materials, bio-MOFs 101-103, each exhibit permanent mesoporosity and pore sizes ranging from ~2.1-2.9 nm and surface areas ranging from 2704 to 4410 m(2)/g. The pore volume for bio-MOF 101 is 2.83 cc/g. Bio-MOF-102 and 103 have pore volumes of 4.36 and 4.13 cc/g, respectively. Collectively, these data establish this unique family of MOFs as one of the most porous reported to date. PMID- 23688077 TI - Structure-based drug design to overcome drug resistance: challenges and opportunities. AB - Drug resistance is a common concern for the development of novel antiviral, antimicrobial and anticancer therapies. To overcome this problem, several strategies have been developed, many of which involving the theme of this review, the use of structure-based drug design (SBDD) approaches. These include the successful design of new compounds that target resistant mutant proteins, as well as the development of drugs that target multiple proteins involved in specific biochemical pathways. Finally, drug resistance can also be considered in the early stages of drug discovery, through the use of strategies to delay the development of resistance. The purpose of this brief review is to underline the usefulness of SBDD approaches based on case studies, highlighting present challenges and opportunities in drug design. PMID- 23688076 TI - PCR on yeast colonies: an improved method for glyco-engineered Saccharomyces cerevisiae. AB - BACKGROUND: Saccharomyces cerevisiae is extensively used in bio-industries. However, its genetic engineering to introduce new metabolism pathways can cause unexpected phenotypic alterations. For example, humanisation of the glycosylation pathways is a high priority pharmaceutical industry goal for production of therapeutic glycoproteins in yeast. Genomic modifications can lead to several described physiological changes: biomass yields decrease, temperature sensitivity or cell wall structure modifications. We have observed that deletion of several N mannosyltransferases in Saccharomyces cerevisiae, results in strains that can no longer be analyzed by classical PCR on yeast colonies. FINDINGS: In order to validate our glyco-engineered Saccharomyces cerevisiae strains, we developed a new protocol to carry out PCR directly on genetically modified yeast colonies. A liquid culture phase, combined with the use of a Hot Start DNA polymerase, allows a 3-fold improvement of PCR efficiency. The results obtained are repeatable and independent of the targeted sequence; as such the protocol is well adapted for intensive screening applications. CONCLUSIONS: The developed protocol enables by passing of many of the difficulties associated with PCR caused by phenotypic modifications brought about by humanisation of the glycosylation in yeast and allows rapid validation of glyco-engineered Saccharomyces cerevisiae cells. It has the potential to be extended to other yeast strains presenting cell wall structure modifications. PMID- 23688078 TI - ABC transporters in multidrug resistance and pharmacokinetics, and strategies for drug development. AB - Multidrug resistance (MDR) is a serious problem that hampers the success of cancer pharmacotherapy. A common mechanism is the overexpression of ATP-binding cassette (ABC) efflux transporters in cancer cells such as P-glycoprotein (P gp/ABCB1), multidrug resistance-associated protein 1 (MRP1/ABCC1) and breast cancer resistance protein (BCRP/ABCG2) that limit the exposure to anticancer drugs. One way to overcome MDR is to develop ABC efflux transporter inhibitors to sensitize cancer cells to chemotherapeutic drugs. The complete clinical trials thus far have showen that those tested chemosensitizers only add limited or no benefits to cancer patients. Some MDR modulators are merely toxic, and others induce unwanted drug-drug interactions. Actually, many ABC transporters are also expressed abundantly in the gastrointestinal tract, liver, kidney, brain and other normal tissues, and they largely determine drug absorption, distribution and excretion, and affect the overall pharmacokinetic properties of drugs in humans. In addition, ABC transporters such as P-gp, MRP1 and BCRP co-expressed in tumors show a broad and overlapped specificity for substrates and MDR modulators. Thus reliable preclinical assays and models are required for the assessment of transporter-mediated flux and potential effects on pharmacokinetics in drug development. In this review, we provide an overview of the role of ABC efflux transporters in MDR and pharmacokinetics. Preclinical assays for the assessment of drug transport and development of MDR modulators are also discussed. PMID- 23688080 TI - Structure-based design of conformationally flexible reverse transcriptase inhibitors to combat resistant HIV. AB - Reverse transcriptase (RT) is one of the most important targets for HIV drug discovery. However, the emergence of resistant mutants has become one of the biggest challenges in HIV-1 RT drug discovery/development and attracted great research interests worldwide. It is particularly important to develop novel anti HIV-1 RT agents that have improved potency and efficacy against the wild-type (WT) RT, but also target resistant RT forms. Previous crystal complex structures of HIV-1 RT revealed the interaction mechanism between the enzyme and inhibitors, which promoted the exploitation of inhibitor that had sufficient conformational flexibility to combat resistance. Hence, the potential flexibility of a drug should be part of the strategy considered in the early stages of designing drugs that are intended to be broadly effective against mutated targets associated with drug resistance. This review provides an overview of the state of the art in this field, including design strategies and challenges for medicinal chemists. PMID- 23688081 TI - Resistance mutations against HCV protease inhibitors and antiviral drug design. AB - The treatment for hepatitis C virus (HCV) infection has been significantly improved with the approval of the first two HCV NS3/4A protease inhibitors, telaprevir (Incivek) and boceprevir (Victrelis). These two direct acting antivirals (DAAs) are used clinically in combination with pegylated interferon alpha (PEG-IFNalpha) and ribavirin (RBV). The sustained virologic response (SVR) rates are increased to ~70% and the duration of the treatment is ~50% shorter among treatment-naive patients with genotype 1 HCV. Variants (quasi species) are almost constantly introduced during HCV replication due to its rapid replication rate and the low fidelity of its polymerase. Drug resistant variants carrying mutations that affect the binding of DAAs have the growth advantage over wild type virus and could become the dominant viral quasi species during treatment with DAAs. Mutations at a number of key positions of the NS3/4A protease have been reported to be associated with drug resistance. This review summarizes the mutations that are responsible for resistance against the two approved protease inhibitors and several compounds in advanced clinical trials. The impacts of the resistance mutations on the binding of the inhibitors as well as the design of next-generation protease inhibitors are discussed from the perspective of medicinal chemistry. PMID- 23688079 TI - Structural basis of resistance to anti-cytochrome bc1 complex inhibitors: implication for drug improvement. AB - The emergence of drug resistance has devastating economic and social consequences, a testimonial of which is the rise and fall of inhibitors against the respiratory component cytochrome bc1 complex, a time tested and highly effective target for disease control. Unfortunately, the mechanism of resistance is a multivariate problem, including primarily mutations in the gene of the cytochrome b subunit but also activation of alternative pathways of ubiquinol oxidation and pharmacokinetic effects. There is a considerable interest in designing new bc1 inhibitors with novel modes of binding and lower propensity to induce the development of resistance. The accumulation of crystallographic data of bc1 complexes with and without inhibitors bound provides the structural basis for rational drug design. In particular, the cytochrome b subunit offers two distinct active sites that can be targeted for inhibition - the quinol oxidation site and the quinone reduction site. This review brings together available structural information of inhibited bc1 by various quinol oxidation- and reductionsite inhibitors, the inhibitor binding modes, conformational changes upon inhibitor binding of side chains in the active site and large scale domain movements of the iron-sulfur protein subunit. Structural data analysis provides a clear understanding of where and why existing inhibitors fail and points towards promising alternatives. PMID- 23688082 TI - Acetohydroxyacid synthase: a target for antimicrobial drug discovery. AB - Acetohydroxyacid synthase (AHAS) (EC 2.2.1.6) (also known as acetolactate synthase) is the first common enzyme in the branched chain amino acid (BCAA) biosynthesis pathway. This pathway is present in microorganisms and in plants but not in animals, making it an attractive target for both drug and herbicide discovery. The function of AHAS is to catalyze the conversion of two molecules of pyruvate to 2-acetolactate or to convert one molecule of pyruvate and a molecule of 2-ketobutyrate into 2-aceto-2-hydroxybutyrate. Three cofactors are required for the activity of AHAS: thiamine diphosphate (ThDP), Mg2+ and flavin-adenine dinucleotide (FAD). AHAS is the target for several classes of commercial herbicides that include the sulfonylurea and imidazolinone families. These herbicides are potent and selective inhibitors of AHAS with Ki values that can be in the low nM range. Such compounds also exhibit low application rates as herbicides (typically ~3 g ha-1) and have low mammalian toxicity (LD50 values typically >4g/kg), thereby highlighting their utility and effectiveness as biocidal agents. However, somewhat surprisingly given the central importance of AHAS in the metabolism of microorganisms, no inhibitors of this enzyme have been commercialized into antimicrobial agents. Here we provide an overview of the biochemical characterization of AHASs from bacterial and fungal sources, analyse the structural features of these enzymes that are criticial to catalysis andprovide the current data on AHAS inhibitors that have potential to be developed into antimicrobial therapeutics. PMID- 23688083 TI - Structural insights into chitinolytic enzymes and inhibition mechanisms of selective inhibitors. AB - Chitin biodegradation is linked to fungi cell differentiation, nematode egg hatching, arthropods morphogenesis and human defense against malaria and other pathogens infection as well. Two classes of enzymes for chitin degradation include glycosyl hydrolase (GH) family 18 chitinases and family 20 beta-N-acetyl D-hexosaminidases. However, more and more research papers have revealed that either GH 18 family chitinases or GH 20 family beta-N-acetyl-D-hexosaminidases are a family composed of a number of isoforms, each of which plays an exclusive role in different life processes. The development of novel and specific inhibitors towards chitinolytic enzymes is of great importance in the investigation of or interference with chitin biodegradation. This review focuses on identified enzymes that are specifically involved in chitin degradation. And the latest progresses on crystal structures and specific inhibitors are summarized within the realm of this field. PMID- 23688084 TI - Therapeutic peptides: new arsenal against drug resistant pathogens. AB - Our incessant tug-of-war with multidrug resistant pathogenic bacteria has prompted researchers to explore novel methods of designing therapeutics in order to defend ourselves against infectious diseases. Combined advances in whole genome analysis, bioinformatics algorithms, and biochemical techniques have led to the discovery and subsequent characterization of an abundant array of functional small peptides in microorganisms and multicellular organisms. Typically classified as having 10 to 100 amino acids, many of these peptides have been found to have dual activities, executing important defensive and regulatory functions in their hosts. In higher organisms, such as mammals, plants, and fungi, host defense peptides have been shown to have immunomodulatory and antimicrobial properties. In microbes, certain growth-inhibiting peptides have been linked to the regulation of diverse cellular processes. Examples of these processes include quorum sensing, stress response, cell differentiation, biofilm formation, pathogenesis, and multidrug tolerance. In this review, we will present a comprehensive overview of the discovery, characteristics, and functions of host and bacteria-derived peptides with antimicrobial activities. The advantages and possible shortcomings of using these peptides as antimicrobial agents and targets will also be discussed. We will further examine current efforts in engineering synthetic peptides to be used as therapeutics and/or drug delivery vehicles. PMID- 23688085 TI - Structure-based drug design: strategies and challenges. PMID- 23688086 TI - Endostatin, an angiogenesis inhibitor, ameliorates bleomycin-induced pulmonary fibrosis in rats. AB - BACKGROUND: Recent evidence has demonstrated the role of angiogenesis in the pathogenesis of pulmonary fibrosis. Endostatin, a proteolytic fragment of collagen XVIII, is a potent inhibitor of angiogenesis. The aim of our study was to assess whether endostatin has beneficial effects on bleomycin (BLM)-induced pulmonary fibrosis in rats. METHODS: The rats were randomly divided into five experimental groups: (A) saline only, (B) BLM only, (C) BLM plus early endostatin treatment, (D) BLM plus late endostatin treatment, and (F) BLM plus whole-course endostatin treatment. We investigated the microvascular density (MVD), inflammatory response and alveolar epithelial cell apoptosis in rat lungs in each group at different phases of disease development. RESULTS: Early endostatin administration attenuated fibrotic changes in BLM-induced pulmonary fibrosis in rats. Endostatin treatment decreased MVD by inhibiting the expression of VEGF/VEGFR-2 (Flk-1) and the activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2). Endostatin treatment also decreased the number of inflammatory cells infiltrating the bronchoalveolar lavage fluid during the early inflammatory phase of BLM-induced pulmonary fibrosis. In addition, the levels of tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor beta1 (TGF-beta1) were reduced by endostatin treatment. Furthermore, endostatin decreased alveolar type II cell apoptosis and had an epithelium-protective effect. These might be the mechanism underlying the preventive effect of endostatin on pulmonary fibrosis. CONCLUSIONS: Our findings suggest that endostatin treatment inhibits the increased MVD, inflammation and alveolar epithelial cell apoptosis, consequently ameliorating BLM-induced pulmonary fibrosis in rats. PMID- 23688087 TI - Route to pyrazolo[5,1-a]isoquinolines via a copper-catalyzed tandem reaction of 2 alkynylbromobenzene with pyrazole. AB - A copper-catalyzed tandem reaction of 2-alkynylbromobenzene and pyrazole is described that provides a facile route to pyrazolo[5,1-a]isoquinolines in good yields. During the reaction process, copper(I)-catalyzed hydroamination and C-H activation are involved. PMID- 23688088 TI - A pandemic of the poor: social disadvantage and the U.S. HIV epidemic. AB - The U.S. HIV/AIDS epidemic has evolved over the past 30 years and is now concentrated in socially marginalized and disenfranchised communities. The health disparities in this epidemic are striking, with most HIV infections occurring in sexual minorities and communities of color. While widely recognized, the health disparities in HIV and AIDS are not often discussed. In this article, we examine the factors underlying health disparities in the U.S. HIV epidemic. We first discuss the interlocking relationships between biological, social, and behavioral factors that drive HIV/AIDS epidemics. Guided by a well-established conceptual model of health disparities, we then describe the social positions of those most affected by HIV and AIDS, particularly racial and gender groups. Structural and economic conditions-including environmental resources, constraints, access to care, and psychosocial influences-are examined in relation to HIV disease trajectories. Greater attention to contextual factors and comorbidities is needed to reduce the health disparities in HIV/AIDS. PMID- 23688090 TI - Stigma and racial/ethnic HIV disparities: moving toward resilience. AB - Prior research suggests that stigma plays a role in racial/ethnic health disparities. However, there is limited understanding about the mechanisms by which stigma contributes to HIV-related disparities in risk, incidence and screening, treatment, and survival and what can be done to reduce the impact of stigma on these disparities. We introduce the Stigma and HIV Disparities Model to describe how societal stigma related to race and ethnicity is associated with racial/ethnic HIV disparities via its manifestations at the structural level (e.g., residential segregation) as well as the individual level among perceivers (e.g., discrimination) and targets (e.g., internalized stigma). We then review evidence of these associations. Because racial/ethnic minorities at risk of and living with HIV often possess multiple stigmas (e.g., HIV-positive, substance use), we adopt an intersectionality framework and conceptualize interdependence among co-occurring stigmas. We further propose a resilience agenda and suggest that intervening on modifiable strength-based moderators of the association between societal stigma and disparities can reduce disparities. Strengthening economic and community empowerment and trust at the structural level, creating common ingroup identities and promoting contact with people living with HIV among perceivers at the individual level, and enhancing social support and adaptive coping among targets at the individual level can improve resilience to societal stigma and ultimately reduce racial/ethnic HIV disparities. PMID- 23688091 TI - Opportunities for HIV combination prevention to reduce racial and ethnic health disparities. AB - Despite advances in HIV prevention and care, African Americans and Latino Americans remain at much higher risk of acquiring HIV, are more likely to be unaware of their HIV-positive status, are less likely to be linked to and retained in care, and are less likely to have suppressed viral load than are Whites. The first National HIV/AIDS Strategy (NHAS) has reducing these disparities as one of its three goals by encouraging the implementation of combination high-impact HIV intervention strategies. Federal agencies have expanded their collaborations in order to decrease HIV-related disparities through better implementation of data-driven decision making; integration and consolidation of the continuum of HIV care; and the reorganization of relationships among public health agencies, researchers, community-based organizations, and HIV advocates. Combination prevention, the integration of evidence-based and impactful behavioral, biomedical, and structural intervention strategies to reduce HIV incidence, provides the tools to address the HIV epidemic. Unfortunately, health disparities exist at every step along the HIV testing-to-care continuum. This provides an opportunity and a challenge to everyone involved in HIV prevention and care to understand and address health disparities as an integral part of ending the HIV epidemic in the United States. To further reduce health disparities, successful implementation of NHAS and combination prevention strategies will require multidisciplinary teams, including psychologists with diverse cultural backgrounds and experiences, to successfully engage groups at highest risk for HIV and those already infected with HIV. In order to utilize the comprehensive care continuum, psychologists and behavioral scientists have a role to play in reconceptualizing the continuum of care, conducting research to address health disparities, and creating community mobilization strategies. PMID- 23688092 TI - The intersection of gender and ethnicity in HIV risk, interventions, and prevention: new frontiers for psychology. AB - This article articulates a contextualized understanding of gender and ethnicity as interacting social determinants of HIV risk and acquisition, with special focus on African Americans and Hispanics/Latinos--2 ethnic groups currently at most risk for HIV/AIDS acquisition in the United States. First, sex and gender are defined. Second, a conceptual model of gender, ethnicity, and HIV risk and resilience is presented. Third, a historical backdrop of gender and ethnic disparities is provided, with attention to key moments in history when notions of the intersections between gender, ethnicity, and HIV have taken important shifts. Finally, new frontiers in psychology are presented, with recommendations as to how psychology as a discipline can better incorporate considerations of gender and ethnicity as not only HIV risk factors but also as potential avenues of resilience in ethnic families and communities. Throughout the article, we promulgate the notion of a syndemic intersectional approach, which provides a critical framework for understanding and building the conditions that create and sustain overall community health by locating gendered lived experiences and expectations within the layered conceptual model ranging from the biological self to broader societal structures that define and constrain personal decisions, behaviors, actions, resources, and consequences. For ethnic individuals and populations, health disparities, stress and depression, substance abuse, and violence and trauma are of considerable concern, especially with regard to HIV risk, infection, and treatment. The conceptual model poses new frontiers for psychology in HIV policy, research, interventions, and training. PMID- 23688093 TI - A holistic approach to addressing HIV infection disparities in gay, bisexual, and other men who have sex with men. AB - Gay, bisexual, and other men who have sex with men (MSM) have been disproportionately affected by HIV and AIDS since the beginning of the epidemic in the United States and in many other parts of the world. The HIV epidemic is inextricably tied to other health problems that disproportionately affect gay, bisexual, and other MSM including psychological comorbidities, substance use, sexual victimization, stigmatization, and multiple forms of discrimination. These interrelated health problems and social issues can be characterized as a syndemic of mutually reinforcing conditions or epidemics. Moreover, the syndemic is directed by biological, behavioral, psychosocial, and structural determinants. Addressing HIV within the context of a larger syndemic will require a more holistic approach to HIV prevention and treatment that recognizes the interplay between biological, behavioral, psychosocial, and structural factors that affect the health and well-being of sexual minority men. PMID- 23688089 TI - Neighborhoods and HIV: a social ecological approach to prevention and care. AB - Neighborhood factors have been linked to HIV risk behaviors, HIV counseling and testing, and HIV medical care. However, the social-psychological mechanisms that connect neighborhood factors to HIV-related behaviors have not been fully determined. In this article we review the research on neighborhood factors and HIV-related behaviors, approaches to measuring neighborhoods, and mechanisms that may help to explain how the physical and social environment within neighborhoods may lead to HIV-related behaviors. We then discuss organizational, geographic, and social network approaches to intervening in neighborhoods to reduce HIV transmission and facilitate HIV medical care with the goal of reducing morbidity and mortality and increasing social and psychological well-being. PMID- 23688094 TI - HIV infection among people who inject drugs: the challenge of racial/ethnic disparities. AB - Racial/ethnic disparities in HIV infection, with minority groups typically having higher rates of infection, are a formidable public health challenge. In the United States, among both men and women who inject drugs, HIV infection rates are elevated among Hispanics and non-Hispanic Blacks. A meta-analysis of international research concluded that among persons who inject drugs, racial and ethnic minorities were twice as likely to acquire an HIV infection, though there was great variation across the individual studies. To examine strategies to reduce racial/ethnic disparities among persons who inject drugs, we reviewed studies on injection drug use and its role in HIV transmission. We identified four sets of evidence-based interventions that may reduce racial/ethnic disparities among persons who inject drugs: HIV counseling and testing, risk reduction services, access to antiretroviral therapy, and drug abuse treatment. Implementation of these services, however, is insufficient in many countries, including the United States. Persons who inject drugs appear to be changing drug use norms and rituals to reduce their risks. The challenges are to (a) develop a validated model of how racial/ethnic disparities in HIV infection arise, persist, and are reduced or eliminated over time and (b) implement evidence-based services on a sufficient scale to eliminate HIV transmission among all persons who inject drugs. PMID- 23688096 TI - Vitamin E supplementation, superoxide dismutase status, and outcome of scaling and root planing in patients with chronic periodontitis: a randomized clinical trial. AB - BACKGROUND: This study investigates the levels of superoxide dismutase (SOD) activity in serum and saliva of patients with chronic periodontitis (CP). In addition, the outcome of scaling and root planing (SRP) with and without vitamin E supplementation is evaluated in terms of changes in periodontal parameters and SOD activity in patients with CP. METHODS: Serum and salivary SOD activity in 38 patients with CP were compared with those of 22 systemically and periodontally healthy individuals (control group). At periodontal examination, serum and saliva samples were obtained. Patients with CP were randomly divided into treatment groups 1 (TG-1) and 2 (TG-2). SRP was performed for both groups, and TG-2 also received 200 mg (300 IU) vitamin E every other day. Periodontal parameters and SOD activity were evaluated after 3 months. SOD activity was determined using an SOD assay and enzyme-linked immunosorbent assay reader at 450 nm. RESULTS: SOD activity in both serum (P <0.05) and saliva (P <0.001) was lower in patients with CP compared with controls. After 3 months of follow-up, SOD activity improved in both treatment groups; however, the improvement in TG-2 was higher than in TG-1, along with more improvement in periodontal parameters. Serum SOD levels in TG-2 increased even above the level of the control group. CONCLUSIONS: Systemic and local SOD levels are lowered in CP. Adjunctive vitamin E supplementation improves periodontal healing as well as antioxidant defense. PMID- 23688095 TI - Macro-level approaches to HIV prevention among ethnic minority youth: state of the science, opportunities, and challenges. AB - The HIV epidemic continues to disproportionately affect ethnic minority youth. These disconcerting health disparities indicate that although existing HIV preventive strategies for ethnic minority youth have been efficacious, they have not significantly reduced the impact of the epidemic in this population. Macro level interventions, such as structural or policy interventions, have the potential to impact the HIV epidemic at a population level, and thus reduce the HIV health disparities that exist among ethnic minority youth and other segments of the U.S. population. This article calls for a paradigm shift to develop, evaluate, and disseminate interventions that target upstream/macro-level factors or that, at a minimum, integrate both a macro and individual level perspective. The article also discusses the challenges in developing and evaluating such interventions. Psychologists and other behavioral scientists can play a critical role in reducing the impact of HIV on ethnic minority youth by integrating macro level approaches to future HIV prevention strategies. PMID- 23688097 TI - Antibiotic resistance in human chronic periodontitis microbiota. AB - BACKGROUND: Patients with chronic periodontitis (CP) may yield multiple species of putative periodontal bacterial pathogens that vary in their antibiotic drug susceptibility. This study determines the occurrence of in vitro antibiotic resistance among selected subgingival periodontal pathogens in patients with CP. METHODS: Subgingival biofilm specimens from inflamed deep periodontal pockets were removed before treatment from 400 adults with CP in the United States. The samples were cultured, and selected periodontal pathogens were tested in vitro for susceptibility to amoxicillin at 8 mg/L, clindamycin at 4 mg/L, doxycycline at 4 mg/L, and metronidazole at 16 mg/L, with a post hoc combination of data for amoxicillin and metronidazole. Gram-negative enteric rods/pseudomonads were subjected to ciprofloxacin disk-diffusion testing. RESULTS: Overall, 74.2% of the patients with CP revealed subgingival periodontal pathogens resistant to at least one of the test antibiotics. One or more test species, most often Prevotella intermedia/nigrescens, Streptococcus constellatus, or Aggregatibacter actinomycetemcomitans, were resistant in vitro to doxycycline, amoxicillin, metronidazole, or clindamycin, in 55%, 43.3%, 30.3%, and 26.5% of the patients with CP, respectively. Fifteen percent of patients harbored subgingival periodontal pathogens resistant to both amoxicillin and metronidazole, which were mostly either S. constellatus (45 individuals) or ciprofloxacin-susceptible strains of Gram-negative enteric rods/pseudomonads (nine individuals). CONCLUSIONS: Patients with CP in the United States frequently yielded subgingival periodontal pathogens resistant in vitro to therapeutic concentrations of antibiotics commonly used in clinical periodontal practice. The wide variability found in periodontal pathogen antibiotic-resistance patterns should concern clinicians empirically selecting antibiotic treatment regimens for patients with CP. PMID- 23688098 TI - Intracellular adhesion molecule-1 is regulated by porphyromonas gingivalis through nucleotide binding oligomerization domain-containing proteins 1 and 2 molecules in periodontal fibroblasts. AB - BACKGROUND: The mechanism by which Porphyromonas gingivalis regulates intracellular adhesion molecule 1 (ICAM-1) expression in human periodontal ligament cells (hPDLCs) and human gingival fibroblasts (hGFs) is unknown. The aim of this study is to investigate whether nucleotide binding oligomerization domain containing protein (NOD) 1 and NOD2 are involved in this process and the clinical significance of ICAM-1 in periodontitis. METHODS: hPDLCs and hGFs were treated with P. gingivalis, l-Ala-gamma-d-glutamyl-mesodiaminopimelic acid (an agonist for NOD1), and muramyl dipeptide (an agonist for NOD2). Alternatively, cells transfected with small interfering RNA targeting NOD1and NOD2 were treated with P. gingivalis. ICAM-1, NOD1, and NOD2 were detected at mRNA and protein levels. In addition, clinical examinations were performed in 30 healthy controls and 40 patients with chronic periodontitis (CP) before and after treatment, and serum soluble ICAM-1 (sICAM-1) levels in these individuals were detected by enzyme linked immunosorbent assay. RESULTS: This study shows that P. gingivalis caused an increase in ICAM-1, NOD1, and NOD2 expression in periodontal fibroblasts. There was a linear correlation between ICAM-1 and NOD1 and NOD2 levels. Activation of NOD1 and NOD2 by the specific agonist led to the upregulation of ICAM-1, whereas knocking down NOD1 and NOD2 caused a reduction in P. gingivalis induced ICAM-1 production. Furthermore, sICAM-1 levels were higher in patients with CP than in healthy controls and were positively related to the clinical periodontal parameters. After periodontal treatment, sICAM-1 levels decreased significantly. CONCLUSIONS: The present results indicate that sICAM-1 levels are correlated to the severity of periodontitis. NOD1 and NOD2 mediate P. gingivalis induced ICAM-1 production in periodontal fibroblasts. NOD1 and NOD2 could be considered potential targets for periodontal therapy. PMID- 23688099 TI - Tumor necrosis factor-alpha induces matrix metalloproteinases-3, -10, and -13 in human periodontal ligament cells. AB - BACKGROUND: Various biologic mediators, including matrix metalloproteinases (MMPs), that are implicated in periodontal tissue breakdown can be induced by cytokines. MMPs are known to degrade periodontal ligament attachment, and bone matrix proteins and tissue inhibitors of metalloproteinase (TIMPs) inhibit the activity of MMPs. The aim of this study is to investigate the effect of tumor necrosis factor (TNF)-alpha on the expression of MMPs in human periodontal ligament (PDL) cells in vitro and establish which MMPs are expressed specifically in response to that stimulus. METHODS: Cultured PDL cells were stimulated with TNF-alpha and analyzed with an MMP antibody array. Real-time polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), and western blot with cell lysate and zymography were used to measure messenger RNA (mRNA) and protein levels of MMP-3, -10, and -13. To examine TNF receptor (TNFR) expression, PDL cells were examined by flow cytometry, and expression of MMP-3, -10, and -13 was observed after blocking the TNFR with an antagonist. Results from real-time PCR, ELISA, and western blot were analyzed by paired t test. RESULTS: The antibody array showed that the protein most strongly upregulated by TNF-alpha stimulation was MMP-3, followed by MMP-13 and MMP-10. The TNF-alpha receptor blocker specifically inhibited expression of MMP-3 and -13. In addition, TNF-alpha increased levels of MMP mRNAs in MMP-3, -13, and -10 (in decreasing order). However, ELISAs showed that MMP-13 was the most upregulated protein, followed by MMP-10 and MMP-3. Western blotting indicated that TNF-alpha increased MMP-3 and 13 levels but had no significant effect on the level of MMP-10, and zymography showed that TNF-alpha increased the activities of all forms of MMP-3 and -13, but MMP-10 was not detected. Flow cytometry demonstrated that the majority of PDL cells expressed TNFR1. CONCLUSIONS: TNF-alpha (10 ng/mL) upregulates levels of MMP-3, -10, and -13 in human PDL cells. These results suggest that these proteins play an important role in the inflammation of PDLs. PMID- 23688100 TI - Early healing of hydroxyapatite-coated implants in grafted bone of zoledronic acid-treated osteoporotic rabbits. AB - BACKGROUND: Resorption of grafted bone and delayed osseointegration of implants are main problems associated with alveolar bone augmentation in dental implantology, especially for patients with osteoporosis. The aim of this study is to investigate the early healing response of implants to systemic treatment of zoledronic acid (ZA) in autogenous grafted iliac bone of osteoporotic rabbits. METHODS: Ovariectomy (OVX) or sham operation was performed in 46 rabbits, and osteoporotic changes were verified in animals receiving OVX 3 months later. The remaining animals were divided into three groups (n = 12): sham, OVX, and OVX with ZA treatment (ZA group). Autogenous iliac bone grafting was performed in bilateral tibiae, and hydroxyapatite-coated titanium implants were simultaneously placed into the grafted bone. The animals were sacrificed 2 and 8 weeks later for examination. RESULTS: At both time points, systemic treatment of ZA efficiently promoted bone healing of implants in grafted bone, and all histologic and microcomputed tomography bone indices, including mineralized bone volume, implant bone contact ratio, connectivity density, trabecular thickness, and trabecular number, were significantly increased in the ZA group compared with the OVX-only group (P <0.01); implant-bone contact rates in the ZA group were even restored to levels similar to those of sham-operated animals (P >0.05). Furthermore, biomechanical testing demonstrated that removal torque of implants was significantly increased in the ZA group compared with the OVX group (P <0.01). CONCLUSION: Systemic treatment with ZA could efficiently promote early bone healing of implants in autogenous grafted bone of osteoporotic rabbits by increasing early osseointegration and fixation of implants. PMID- 23688102 TI - Quantitative analysis of interdental Gingiva in patients with chronic periodontitis and transforming growth factor-beta1 29C/T gene polymorphisms. AB - BACKGROUND: The association of transforming growth factor (TGF)-beta1 29C/T gene polymorphisms with level of tissue breakdown and periodontal disease progression is not clear. In this study, quantitative parameters of interdental papilla are investigated in patients with chronic periodontitis (CP) and TGF-beta1 29C/T gene polymorphisms. METHODS: Sixty gingiva samples were included. After determination of TGF-beta1 29C/T gene polymorphisms using tetra-primer amplification refractory mutation system/polymerase chain reaction (T-ARMS-PCR), 15 gingival tissue samples from patients with CP in each genotype (TT, TC, and CC) were considered as case groups. Fifteen control samples were also collected from healthy individuals. After tissue processing, interdental gingiva tissues were exhaustively sectioned into 4-MUm-thick sections. Ten to 13 sections were sampled by systematic uniform random sampling and stained with Masson trichrome, and the volume density (Vv) of the gingival components was estimated using Cavalieri estimation. RESULTS: Statistically significant differences were found in Vv of epithelium, connective tissue, collagenous and non-collagenous matrix, and blood vessels between control and CP groups (P <0.0001). There was a corresponding decrease in the collagenous matrix Vv in patients with the TT genotype compared with those with CT and CC genotypes. Collagenous matrix and blood vessel Vv values were statistically correlated with the number of T alleles (r = -0.74, r(2) = 54.8%, P = 0.0001 and r = 0.84, r(2) = 70.6%, P = 0.0001, respectively). CONCLUSION: This study shows that there is a strong association between TGF-beta1 29C/T gene polymorphisms and quantitative parameters of interdental papilla in patients with CP. PMID- 23688101 TI - Distinctive tooth-extraction socket healing: bisphosphonate versus parathyroid hormone therapy. AB - BACKGROUND: Patients with osteoporosis who receive tooth extractions are typically on either oral bisphosphonate or parathyroid hormone (PTH) therapy. Currently, the consequence of these therapies on hard- and soft-tissue healing in the oral cavity is not clearly defined. The aim of this study is to determine the differences in the therapeutic effect on tooth-extraction wound healing between bisphosphonate and PTH therapies. METHODS: Maxillary second molars were extracted in Sprague Dawley rats (n = 30), and either bisphosphonate (zoledronate [Zol]), PTH, or saline (vehicle control [VC]) was administered for 10 days (n = 10 per group). Hard-tissue healing was evaluated by microcomputed tomography and histomorphometric analyses. Collagen, blood vessels, inflammatory cell infiltration, and cathepsin K expression were assessed in soft tissue using immunohistochemistry, quantitative polymerase chain reaction, and immunoblotting. RESULTS: Both therapies significantly increased bone fill and suppressed vertical bone loss. However, considerably more devital bone was observed in the sockets of rats on Zol versus VC. Although Zol increased the numbers of blood vessels, the total blood vessel area in soft tissue was significantly smaller than in VC. PTH therapy increased osteoblastic bone formation and suppressed osteoclasts. PTH therapy promoted soft-tissue maturation by suppressing inflammation and stimulating collagen deposition. CONCLUSION: Zoledronate therapy deters whereas PTH therapy promotes hard- and soft-tissue healing in the oral cavity, and both therapies prevent vertical bone loss. PMID- 23688103 TI - Extraction socket healing in humans after ridge preservation techniques: comparison between flapless and flapped procedures in a randomized clinical trial. AB - BACKGROUND: The preservation of hard and soft tissue volume, partially lost after tooth removal, can potentially reduce the need for the more demanding augmentation procedures used in implant-supported rehabilitation. The objective of this research study is to investigate the effect of filling with xenogeneic material the postextractive sockets of two surgical procedures (flapless versus flapped). METHODS: In this prospective randomized clinical survey, two types of socket preservation were performed on two groups of patients: the control, treated via full-thickness mucoperiosteal flap, and the test, via a flapless procedure. Anatomic measurements and related outcome variables at the third month were analyzed using multiway analysis of variance. Multiple comparison tests, using Tukey honestly significant difference test, and appropriate pairwise comparison tests for independent samples were carried out. RESULTS: Sixty-four patients were treated, 32 for each of the two socket preservation procedures. Statistically significant differences were registered for the output variables -- changes in width of keratinized gingiva, changes in bucco-lingual width, and vertical bone changes at four sites -- between the two socket preservation techniques, with P values of <0.001, <0.001, and 0.0105, respectively. CONCLUSIONS: A full-thickness mucoperiosteal flap gave significantly more negative results than that of the less-demanding flapless procedure, with an increased width resorption of the postextraction site. Moreover, the increased value of the keratinized gingival width attested to the positive outcome of a flapless procedure in terms of soft tissue preservation and improvement. On the other hand, the flapped technique seemed to show less vertical bone resorption on the buccal aspect than the flapless technique. PMID- 23688104 TI - Influence of tapered and external hexagon connections on bone stresses around tilted dental implants: three-dimensional finite element method with statistical analysis. AB - BACKGROUND: The purpose of this study is to analyze the tension distribution on bone tissue around implants with different angulations (0 degrees , 17 degrees , and 30 degrees ) and connections (external hexagon and tapered) through the use of three-dimensional finite element and statistical analyses. METHODS: Twelve different configurations of three-dimensional finite element models, including three inclinations of the implants (0 degrees , 17 degrees , and 30 degrees ), two connections (an external hexagon and a tapered), and two load applications (axial and oblique), were simulated. The maximum principal stress values for cortical bone were measured at the mesial, distal, buccal, and lingual regions around the implant for each analyzed situation, totaling 48 groups. Loads of 200 and 100 N were applied at the occlusal surface in the axial and oblique directions, respectively. Maximum principal stress values were measured at the bone crest and statistically analyzed using analysis of variance. Stress patterns in the bone tissue around the implant were analyzed qualitatively. RESULTS: The results demonstrated that under the oblique loading process, the external hexagon connection showed significantly higher stress concentrations in the bone tissue (P <0.05) compared with the tapered connection. Moreover, the buccal and mesial regions of the cortical bone concentrated significantly higher stress (P <0.005) to the external hexagon implant type. Under the oblique loading direction, the increased external hexagon implant angulation induced a significantly higher stress concentration (P = 0.045). CONCLUSIONS: The study results show that: 1) the oblique load was more damaging to bone tissue, mainly when associated with external hexagon implants; and 2) there was a higher stress concentration on the buccal region in comparison to all other regions under oblique load. PMID- 23688105 TI - How does investment in research training affect the development of research networks and collaborations? AB - BACKGROUND: Whether and how research training programs contribute to research network development is underexplored. The Fogarty International Center (FIC) has supported overseas research training programs for over two decades. FIC programs could provide an entry point in the development of research networks and collaborations. We examine whether FIC's investment in research training contributed to the development of networks and collaborations in two countries with longstanding FIC investments - Uganda and Kenya - and the factors which facilitated this process. METHODS: As part of two case studies at Uganda's Makerere University and Kenya's University of Nairobi, we conducted 53 semi structured in-depth interviews and nine focus group discussions. To expand on our case study findings, we conducted a focused bibliometric analysis on two purposively selected topic areas to examine scientific productivity and used online network illustration tools to examine the resulting network structures. RESULTS: FIC support made important contributions to network development. Respondents from both Uganda and Kenya confirmed that FIC programs consistently provided trainees with networking skills and exposure to research collaborations, primarily within the institutions implementing FIC programs. In both countries, networks struggled with inclusiveness, particularly in HIV/AIDS research. Ugandan respondents perceived their networks to be more cohesive than Kenyan respondents did. Network cohesiveness was positively correlated with the magnitude and longevity of FIC's programs. Support from FIC grants to local and regional research network development and networking opportunities, such as conferences, was rare. Synergies between FIC programs and research grants helped to solidify and maintain research collaborations. CONCLUSIONS: Networks developed where FIC's programs focused on a particular institution, there was a critical mass of trainees with similar interests, and investments for network development were available from early implementation. Networks were less likely to emerge where FIC efforts were thinly scattered across multiple institutions. The availability of complementary research grants created opportunities for researchers to collaborate in grant writing, research implementation, and publications. FIC experiences in Uganda and Kenya showcase the important role of research training programs in creating and sustaining research networks. FIC programs should consider including support to research networks more systematically in their capacity development agenda. PMID- 23688106 TI - The role of ubiquitin-proteasome system in glioma survival and growth. AB - High-grade gliomas represent a group of aggressive brain tumors with poor prognosis due to an inherent capacity of persistent cell growth and survival. The ubiquitin-proteasome system (UPS) is an intracellular machinery responsible for protein turnover. Emerging evidence implicates various proteins targeted for degradation by the UPS in key survival and proliferation signaling pathways of these tumors. In this review, we discuss the involvement of UPS in the regulation of several mediators and effectors of these pathways in malignant gliomas. PMID- 23688107 TI - 99mTc-NTP 15-5 assessment of the early therapeutic response of chondrosarcoma to zoledronic acid in the Swarm rat orthotopic model. AB - BACKGROUND: Since proteoglycans (PGs) appear as key partners in chondrosarcoma biology, PG-targeted imaging using the radiotracer 99mTc-N-(triethylammonium)-3 propyl-[15]ane-N5 (99mTc-NTP 15-5) developed by our group was previously demonstrated to be a good single-photon emission computed tomography tracer for cartilage neoplasms. We therefore initiated this new preclinical study to evaluate the relevance of 99mTc-NTP 15-5 imaging for the in vivo monitoring and quantitative assessment of chondrosarcoma response to zoledronic acid (ZOL) in the Swarm rat orthotopic model. FINDINGS: Rats bearing chondrosarcoma in the orthotopic paratibial location were treated by ZOL (100 MUg/kg, subcutaneously) or phosphate-buffered saline, twice a week, from day 4 to day 48 post-tumor implantation. 99mTc-NTP 15-5 imaging was performed at regular intervals with the target-to-background ratio (TBR) determined. Tumor volume was monitored using a calliper, and histology was performed at the end of the study. From day 11 to day 48, mean TBR values ranged from 1.7 +/- 0.6 to 2.3 +/- 0.6 in ZOL-treated rats and from 2.1 +/- 1.0 to 4.9 +/- 0.9 in controls. Tumor growth inhibition was evidenced using a calliper from day 24 and associated to a decrease in PG content in treated tumor tissues (confirmed by histology). CONCLUSIONS: This work demonstrated two proofs of concept: (1) biphosphonate therapy could be a promising therapeutic approach for chondrosarcoma; (2) 99mTc-NTP 15-5 is expected to offer a novel imaging modality for the in vivo evaluation of the extracellular matrix features of chondrosarcoma, which could be useful for the follow-up and quantitative assessment of proteoglycan 'downregulation' associated to the response to therapeutic attempts. PMID- 23688108 TI - Evaluation and development of a novel binocular treatment (I-BiTTM) system using video clips and interactive games to improve vision in children with amblyopia ('lazy eye'): study protocol for a randomised controlled trial. AB - BACKGROUND: Amblyopia (lazy eye) affects the vision of approximately 2% of all children. Traditional treatment consists of wearing a patch over their 'good' eye for a number of hours daily, over several months. This treatment is unpopular and compliance is often low. Therefore results can be poor. A novel binocular treatment which uses 3D technology to present specially developed computer games and video footage (I-BiTTM) has been studied in a small group of patients and has shown positive results over a short period of time. The system is therefore now being examined in a randomised clinical trial. METHODS/DESIGN: Seventy-five patients aged between 4 and 8 years with a diagnosis of amblyopia will be randomised to one of three treatments with a ratio of 1:1:1 - I-BiTTM game, non-I BiTTM game, and I-BiTTM DVD. They will be treated for 30 minutes once weekly for 6 weeks. Their visual acuity will be assessed independently at baseline, mid treatment (week 3), at the end of treatment (week 6) and 4 weeks after completing treatment (week 10). The primary endpoint will be the change in visual acuity from baseline to the end of treatment. Secondary endpoints will be additional visual acuity measures, patient acceptability, compliance and the incidence of adverse events. DISCUSSION: This is the first randomised controlled trial using the I-BiTTM system. The results will determine if the I-BiTTM system is effective in the treatment of amblyopia and will also determine the optimal treatment for future development. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01702727. PMID- 23688109 TI - Ethnic differences in grains consumption and their contribution to intake of B vitamins: results of the Multiethnic Cohort Study. AB - BACKGROUND: Research indicates that a diet rich in whole grains may reduce the risk of prevalent chronic diseases, including cardiovascular disease, diabetes, and some cancers, and that risk for these diseases varies by ethnicity. The objective of the current study was to identify major dietary sources of grains and describe their contribution to B vitamins in five ethnic groups. METHODS: A cross-sectional mail survey was used to collect data from participants in the Multiethnic Cohort Study in Hawaii and Los Angeles County, United States, from 1993 to 1996. Dietary intake data collected using a quantitative food frequency questionnaire was available for 186,916 participants representing five ethnic groups (African American, Latino, Japanese American, Native Hawaiian and Caucasian) aged 45-75 years. The top sources of grain foods were determined, and their contribution to thiamin, riboflavin, niacin, vitamin B6, and folic acid intakes were analyzed. RESULTS: The top source of whole grains was whole wheat/rye bread for all ethnic-sex groups, followed by popcorn and cooked cereals, except for Native Hawaiian men and Japanese Americans, for whom brown/wild rice was the second top source; major contributors of refined grains were white rice and white bread, except for Latinos. Refined grain foods contributed more to grain consumption (27.1-55.6%) than whole grain foods (7.4 30.8%) among all ethnic-sex groups, except African American women. Grain foods made an important contribution to the intakes of thiamin (30.2-45.9%), riboflavin (23.1-29.2%), niacin (27.1-35.8%), vitamin B6 (22.9-27.5%), and folic acid (23.3 27.7%). CONCLUSIONS: This is the first study to document consumption of different grain sources and their contribution to B vitamins in five ethnic groups in the U.S. Findings can be used to assess unhealthful food choices, to guide dietary recommendations, and to help reduce risk of chronic diseases in these populations. PMID- 23688110 TI - Effects of fiber orientation on the frictional properties and damage of regenerative articular cartilage surfaces. AB - Articular cartilage provides a low-friction, wear-resistant surface for diarthrodial joints. Due to overloading and overuse, articular cartilage is known to undergo significant wear and degeneration potentially resulting in osteoarthritis (OA). Regenerative medicine strategies offer a promising solution for the treatment of articular cartilage defects and potentially localized early OA. Such strategies rely on the development of materials to restore some aspects of cartilage. In this study, microfibrous poly(E-caprolactone) scaffolds of varying fiber orientations (random and aligned) were cultured with bovine chondrocytes for 4 weeks in vitro, and the mechanical and frictional properties were evaluated. Mechanical properties were quantified using unconfined compression and tensile testing techniques. Frictional properties were investigated at physiological compressive strains occurring in native articular cartilage. Scaffolds were sheared along the fiber direction, perpendicular to the fiber direction and in random orientation. The evolution of damage as a result of shear was evaluated via white light interferometry and scanning electron microscopy. As expected, the fiber orientation strongly affected the tensile properties as well as the compressive modulus of the scaffolds. Fiber orientation did not significantly affect the equilibrium frictional coefficient, but it was, however, a key factor in dictating the evolution of surface damage on the surface. Scaffolds shear tested perpendicular to the fiber orientation displayed the highest surface damage. Our results suggest that the fiber orientation of the scaffold implanted in the joint could strongly affect its resistance to damage due to shear. Scaffold fiber orientation should thus be carefully considered when using microfibrous scaffolds. PMID- 23688111 TI - An observational study of nutrition and physical activity behaviours, knowledge, and advice in pregnancy. AB - BACKGROUND: Maternal obesity, excess weight gain and lifestyle behaviours during pregnancy have been associated with future overweight and other adverse health outcomes for mothers and babies. This study compared the nutrition and physical activity behaviours of Australian healthy (BMI <= 25 k/m(2)) and overweight (BMI >= 25 kg/m(2)) pregnant women and described their knowledge and receipt of health professional advice early in pregnancy. METHODS: Pregnant women (n=58) aged 29+/ 5 (mean+/-s.d.) years were recruited at 16+/-2 weeks gestation from an Australian metropolitan hospital. Height and weight were measured using standard procedures and women completed a self administered semi-quantitative survey. RESULTS: Healthy and overweight women had very similar levels of knowledge, behaviour and levels of advice provided except where specifically mentioned. Only 8% and 36% of participants knew the correct recommended daily number of fruit and vegetable serves respectively. Four percent of participants ate the recommended 5 serves/day of vegetables. Overweight women were less likely than healthy weight women to achieve the recommended fruit intake (4% vs. 8%, p=0.05), and more likely to consume soft drinks or cordial (55% vs 43%, p=0.005) and take away foods (37% vs. 25%, p=0.002) once a week or more. Less than half of all women achieved sufficient physical activity. Despite 80% of women saying they would have liked education about nutrition, physical activity and weight gain, particularly at the beginning of pregnancy, less than 50% were given appropriate advice regarding healthy eating and physical activity. CONCLUSION: Healthy pregnancy behaviour recommendations were not being met, with overweight women less likely to meet some of the recommendations. Knowledge of dietary recommendations was poor and health care professional advice was limited. There are opportunities to improve the health care practices and education pregnant women received to improve knowledge and behaviours. Pregnant women appear to want this. PMID- 23688112 TI - Synthesis and electrophosphorescence of iridium complexes containing benzothiazole-based ligands. AB - Four heteroleptic bis-cyclometalated iridium(III) complexes containing 2-aryl benzothiazole ligands, in which the aryl is dibenzofuran-2-yl [Ir(O-bt)2(acac)], dibenzothiophene-2-yl [Ir(S-bt)2(acac)], dibenzothiophene-S,S-dioxide-2-yl [Ir(SO2-bt)2(acac)] and 4-(diphenylphosphoryl)phenyl [Ir(PO-bt)2(acac)], have been synthesized and characterized for use in organic light-emitting diodes (OLEDs). These complexes emit bright yellow (551 nm) to orange-red (598 nm) phosphorescence at room temperature, the peak wavelengths of which can be finely tuned depending upon the electronic properties of the aryl group in the 2 position of benzothiazole. The strong electron-withdrawing aryls such as dibenzothiophene-S,S-dioxide2-yl and 4-(diphenylphosphoryl)phenyl caused bathochromatic shift of the iridium complex phosphorescence. These iridium complexes were used as doped emitters to fabricate yellow to orange-red OLEDs and good performance was obtained. In particular, a maximum luminance efficiency of 58.4 cd A(-1) (corresponding to 30.6 lm W(-1) and 19%) with CIE coordinates of (0.45, 0.52) was achieved for Ir(O-bt)2(acac)-based yellow device. Furthermore, the yellow emitting Ir(S-bt)2(acac) was used to fabricate two-element white OLED that exhibited a high efficiency of 32.4 cd A(-1) with CIE coordinates of (0.28, 0.44). PMID- 23688113 TI - Crystal structure of putative CbiT from Methanocaldococcus jannaschii: an intermediate enzyme activity in cobalamin (vitamin B12) biosynthesis. AB - BACKGROUND: In the anaerobic pathway of cobalamin (vitamin B12) synthesis, the CbiT enzyme plays two roles, as a cobalt-precorrin-7 C15-methyltransferase and a C12-decarboxylase, to produce the intermediate, cobalt-precorrin 8. RESULTS: The primary structure of the hypothetical protein MJ0391, from Methanocaldococcus jannaschii, suggested that MJ0391 is a putative CbiT. Here, we report the crystal structure of MJ0391, solved by the MAD procedure and refined to final R-factor and R-free values of 19.8 & 27.3%, respectively, at 2.3 A resolution. The asymmetric unit contains two NCS molecules, and the intact tetramer generated by crystallographic symmetry may be functionally important. The overall tertiary structure and the tetrameric arrangements are highly homologous to those found in MT0146/CbiT from Methanobacterium thermoautotrophicum. CONCLUSIONS: The conservation of functional residues in the binding site for the co-factor, AdoMet, and in the putative precorrin-7 binding pocket suggested that MJ0391 may also possess CbiT activity. The putative function of MJ0391 is discussed, based on structural homology. PMID- 23688115 TI - Litter size determines circadian periodicity of nursing in rabbits. AB - Nursing in rabbits occurs inside the nest with circadian periodicity. To determine the contribution of suckling stimulation in regulating such periodicity, we varied the size of the litters provided (1, 2, 4, or 6-8 pups). Nursing does, kept under a 14:10 (L:D) photoperiod, were continuously videotaped from parturition into lactation day 15. Although parturitions occurred throughout the day, a significant negative linear correlation (p < 0.0001; r = -0.68) was evident between time of delivery and time of nursing on lactation day 1, regardless of newborn number: longer intervals between these two events were seen in does delivering in the early morning than in those that gave birth late in the day. In rabbits suckling 6-8 pups, a Rayleigh analysis revealed that the population vector best describing their nursing pattern (across lactation days 1 15) had a phase angle = 58 degrees (corresponding to solar time 0352 h and rho = 0.78; p < 0.001). In contrast, the nursing pattern of does nursing litters smaller than 6 pups did not show circadian periodicity; rather, mothers showed multiple entrances into the nest box throughout the day. Cluster analysis revealed that the main equilibrium point of intervals between suckling bouts shifted from 24 h (6-8 pups) to 6 h (4 and 2 pups) and to as low as 4 h with 1 pup. In the groups nursing 2, 4, or 6-8 pups, most nursing episodes were followed by food and water intake. Those mothers also showed self-grooming of the ventrum and nipples after nursing. The incidence of these behaviors was lower in does nursing 1 pup. In conclusion, nursing in rabbits spontaneously occurs with circadian periodicity, but it is largely modulated by a threshold of suckling stimulation. PMID- 23688114 TI - A prospective study of weight gain associated with chronotype among college freshmen. AB - A prospective study of chronotype as a predictor of increased weight gain and body mass index (BMI) among college freshman was undertaken. At baseline, 137 college freshmen were characterized as morning, neutral, or evening types using the reduced version of the Morningness-Eveningness Questionnaire. Additionally, information was collected regarding weight, BMI, and health habits (e.g., junk food and alcohol consumption). These additional measures consisted of a descriptive questionnaire, the Pittsburgh Sleep Quality Index, the International Physical Activity Questionnaire, the Gray-Donald Eating Patterns Questionnaire, and the Positive and Negative Affect Scale. Participants included 79 females and 80 males with a mean age of 18.25 (SD = 0.56) yrs. Eight weeks later, participants returned (N = 54) to complete follow-up measures, which were identical to baseline assessments with the exception of the descriptive questionnaire, in which demographic questions were removed. Evening types had a significantly greater BMI gain (p < 0.05) when compared with morning/neutral types. Health behaviors did not differ by chronotype. Future studies should seek to clarify the mechanisms underlying the chronotype-BMI/weight gain relationship. PMID- 23688116 TI - Reduced preprandial dipping accounts for rapid elevation of blood pressure and renal sympathetic nerve activity in rabbits fed a high-fat diet. AB - Consumption of a high-fat diet (HFD) by rabbits results in increased blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA) within 1 wk. Here, we determined how early this activation occurred and whether it was related to changes in cardiovascular and neural 24-h rhythms. Rabbits were meal-fed a HFD for 3 wks, then a normal-fat diet (NFD) for 1 wk. BP, HR, and RSNA were measured daily in the home cage via implanted telemeters. Baseline BP, HR, and RSNA over 24 h were 71 +/- 1 mm Hg, 205 +/- 4 beats/min and 7 +/- 1 normalized units (nu). The 24-h pattern was entrained to the feeding cycle and values increased from preprandial minimum to postprandial maximum by 4 +/- 1 mm Hg, 51 +/- 6 beats/min, and 1.6 +/- .6 nu each day. Feeding of a HFD markedly diminished the preprandial dip after 2 d (79-125% of control; p < 0.05) and this reduction lasted for 3 wks of HFD. Twenty-four-hour BP, HR, and RSNA concurrently increased by 2%, 18%, and 22%, respectively. Loss of preprandial dipping accounted for all of the BP increase and 50% of the RSNA increase over 3 wks and the 24-h rhythm became entrained to the light-dark cycle. Resumption of a NFD did not alter the BP preprandial dip. Thus, elevated BP induced by a HFD and mediated by increased sympathetic nerve activity results from a reduction in preprandial dipping, from the first day. Increased calories, glucose, insulin, and leptin may account for early changes, whereas long-term loss of dipping may be related to increased sensitivity of sympathetic pathways. PMID- 23688117 TI - Evening types are prone to depression. AB - Certain preferences for the timing of daily activities (chronotype) may predispose an individual to sleep problems and mood disorders. In this study, we have examined the link between chronotypes and depression. Participants (N = 6071) were recruited from a random sample of the general population aged 25 to 74 yrs living in defined geographical areas, as part of the National FINRISK Study in 2007 in Finland. Chronotype assessment was based on six items from the original Horne-Ostberg Morningness-Eveningness Questionnaire. Depression was assessed with four self-reported items, including two probes for a diagnosis of a major depressive episode, diagnosed or treated depression, and use of antidepressants. We also analyzed correlations between chronotype and several health indicators, such as systolic and diastolic blood pressures, resting heart rate, weight, and waist circumference. The odds ratios for a range of indicators of depression were higher for evening types (2.7- to 4.1-fold) and intermediate types (1.5- to 1.9-fold) than for morning types. Our results suggest that individuals having a preference for evening hours to carry out their daily activities are prone to depression. PMID- 23688118 TI - Daylight saving time transitions and acute myocardial infarction. AB - Most recently, the possible impact of transitions to and from daylight saving time (DST) on the increased incidence of acute myocardial infarction (AMI) has been suggested. The goal of this report was to analyze independent influence of DST transitions on the incidence of AMI with simultaneous control for the confounding presence of situational triggers such as physical exertion, emotional stress, heavy meals, and sexual intercourse, as well as for other clinical factors. Detailed information was obtained from 2412 patients and included baseline characteristics, working status, exact time of AMI, possible external triggers, cardiovascular risk factors, and prehospital medication. AMI incidence on days after the DST was compared with incidence during control periods and patient characteristics, cardiovascular medication, and circumstances of AMI were evaluated to identify potential risk modifiers. Relative risks of AMI and differences in patient characteristics were expressed through incidence ratios and odds ratios, respectively, with 95% confidence intervals (CIs). Multivariate analysis was performed by using a stepwise multiple regression to assess the independent predictive significance of the characteristics of patients for the AMI occurring in the posttransitional period. The incidence ratio for AMI for the first four workdays after the spring DST transition was 1.29 (95% CI: 1.09-1.49) and the excess was particularly prominent on Monday. In autumn, the incidence ratio for AMI for this 4-d period was 1.44 (95% CI: 1.19-1.69), with peaks on Tuesday and Thursday. The independent predictors for AMI during this period in spring were male sex (p = 0.03) and nonengagement in physical activity (p = 0.02) and there was a trend for the lower risk of incident among those taking calcium antagonists (p = 0.07). In autumn, the predictors were female sex (p = 0.04), current employment (p = 0.006), not taking beta-blocker (p = 0.03), and nonengagement in physical activity (p = 0.02). The present report supports the possibility that DST transitions represent additional chronobiological feature of AMI, and that risk of an onset varies according to sex, employment status, and the taking of cardiovascular medication. PMID- 23688119 TI - Light and feeding entrainment of the molecular circadian clock in a marine teleost (Sparus aurata). AB - Daily light and feeding cycles act as powerful synchronizers of circadian rhythmicity. Ultimately, these external cues entrain the expression of clock genes, which generate daily rhythmic behavioral and physiological responses in vertebrates. In the present study, we investigated clock genes in a marine teleost (gilthead sea bream). Partial cDNA sequences of key elements from both positive (Bmal1, Clock) and negative (Per2, Cry1) regulatory loops were cloned before studying how feeding time affects the daily rhythms of locomotor activity and clock gene expression in the central (brain) and peripheral (liver) oscillators. To this end, all fish were kept under a light-dark (LD) cycle and were divided into three experimental groups, depending on the time of their daily meal: mid-light (ML), mid-darkness (MD), or at random (RD) times. Finally, the existence of circadian control on gene expression was investigated in the absence of external cues (DD + RD). The behavioral results showed that seabream fed at ML or RD displayed a diurnal activity pattern (>91% of activity during the day), whereas fish fed at MD were nocturnal (89% of activity during the night). Moreover, seabream subjected to regular feeding cycles (ML and MD groups) showed food-anticipatory activity (FAA). Regardless of the mealtime, the daily rhythm of clock gene expression in the brain peaked close to the light-dark transition in the case of Bmal1 and Clock, and at the beginning of the light phase in the case of Per2 and Cry1, showing the existence of phase delay between the positive and negative elements of the molecular clock. In the liver, however, the acrophases of the daily rhythms differed depending on the feeding regime: the maximum expression of Bmal1 and Clock in the ML and RD groups was in antiphase to the expression pattern observed in the fish fed at MD. Under constant conditions (DD + RD), Per2 and Cry1 showed circadian rhythmicity in the brain, whereas Bmal1, Clock, and Per2 did in the liver. Our results indicate that the seabream clock gene expression is endogenously controlled and in liver it is strongly entrained by food signals, rather than by the LD cycle, and that scheduled feeding can shift the phase of the daily rhythm of clock gene expression in a peripheral organ (liver) without changing the phase of these rhythms in a central oscillator (brain), suggesting uncoupling of the light-entrainable oscillator (LEO) from the food-entrainable oscillator (FEO). These findings provide the basis and new tools for improving our knowledge of the circadian system and entraining pathways of this fish species, which is of great interest for the Mediterranean aquaculture. PMID- 23688120 TI - Diurnal redistribution of human lymphocytes and their temporal associations with salivary cortisol. AB - Immune cell trafficking is crucial for surveillance and effector functions of the immune system. Circadian rhythms of the hypothalamic-pituitary-adrenal (HPA) axis and of cortisol have been implicated in circadian redistribution of circulating lymphocytes and granulocytes. However, information regarding the diurnal redistribution of immune cells and their temporal correlations with cortisol is scarce. In this study, we investigated the diurnal redistribution of T, B, and natural killer (NK) cell subsets in relation to the endogenous cortisol rhythm. Saliva and blood samples were collected every 15 min over an 8-h period. Salivary free cortisol was measured by enzyme-linked immunosorbent assay (ELISA). Surface markers (CD3, CD19, CD8, CD56, CD16, KIR) were measured in whole blood samples by 6-color flow cytometry and cell subsets quantified as a percentage of the total lymphocyte population. To study associations between the diurnal cortisol rhythm and the redistribution of T, B, and NK cells, we calculated cross-correlations with lag periods of 15 min. The salivary cortisol levels showed the typical diurnal variations with a significant morning cortisol awakening response (CAR) peaking around 07:30 h followed by an afternoon nadir. Whereas B cells remained stable throughout the 8 h, T cells (CD3 + CD8+ and CD3 + CD8-) showed a significant positive cross-correlation with cortisol levels when a delay of 30 105 min was taken into account. This was followed by a negative correlation covering a period of 165-285 min after the cortisol peak. Conversely, NK cells showed an initial negative correlation at 45-105 min, followed by a positive correlation at 120-285 min. The major CD56 + CD16+ subset and the CD56 - CD16+ population showed similar temporal correlation profiles. The minor CD56 + CD16- NK cell subset showed no temporal changes. The major NK subset (CD56 + CD16+) contains cells with higher cytolytic activity (KIR+) cells, whereas the single positive subsets CD56 + CD16- and CD56 - CD16+ are mainly involved in cytokine production. Significant positive correlations were observed in KIR+ subsets coincident with this of NK cells covering a period of 105-300 min after the cortisol peak. In conclusion, our results suggest that cortisol and the HPA axis orchestrate tidal waves of immune cells that are alternatively based toward innate and acquired immune surveillance. PMID- 23688121 TI - Heterogeneous photooxidation of fluorotelomer alcohols: a new source of aerosol phase perfluorinated carboxylic acids. AB - Little is known of the atmospheric fate(s) of fluorotelomer alcohols (FTOHs), a class of high-production-volume chemicals used in the production of water- and oil-repelling surface coatings and which have been detected in a wide variety of urban and remote environmental matrices. In the present study, we investigated the uptake and photochemistry of FTOHs at the surface of TiO2, Fe2O3, Mauritanian sand, and Icelandic volcanic ash. Gas-phase 3,3,3-trifluoropropanol, 4:2 FTOH, and 6:2 FTOH exhibited significant uptake to each of the surfaces under study. The sand- and ash-catalyzed heterogeneous photooxidation of 6:2 FTOH resulted in the rapid production and subsequent slow degradation of surface-sorbed perfluorinated carboxylic acids (PFCAs). We suggest that this transformation, which proceeds via saturated and unsaturated fluorotelomer carboxylic acid intermediates (6:2 FTCA/FTUCA), is catalyzed by Fe and Ti contained within the samples. These results provide the first evidence that the heterogeneous oxidation of FTOHs at metal-rich atmospheric surfaces may provide a significant loss mechanism for these chemicals and also act as a source of aerosol-phase PFCAs close to source regions. Subsequent long-range transport of these aerosol sorbed PFCAs has the potential to join oceanic transport and local gas-phase FTOH oxidation as a source of PFCAs to Arctic regions. PMID- 23688122 TI - Theoretical and experimental studies of circular dichroism of mono- and diazonia[6]helicenes. AB - Combined experimental and theoretical studies revealed the characteristic circular dichroism (CD) spectral profiles of mono- and diazonia[6]helicenes, which were distinctly different from those reported for parent [6]helicene and neutral (di)aza-analogues. Aza[6]helicenes and [6]helicene showed bisignate Cotton effects (CEs) at the (1)Ba and (1)Bb bands, along with a weak CE at the (1)Lb band, where the signs of the former bands are responsible for the helical chirality of the helicenes while the sign of the latter is susceptive to the various factors such as electronic and steric effects. Protonation to monoaza[6]helicenes produces azonia[6]helicenes, showing dramatic changes in the CE pattern from the two bisignate to a three positive, two negative CE extremum series of comparable magnitudes, while dual protonation to diaza[6]helicenes forming diazonia[6]helicenes led to only nominal changes (slightly different rotational strength and excitation energy) in the CE pattern. Such rather complicated and contrasting CE behaviors of mono- versus diazoniahelicenes are derived mostly from the electronic effects of (unsymmetrical) protonation because the structures of neutral, mono-, and dicationic species are essentially identical to each other. Compared with those of neutral (di)aza[6]helicenes, the experimental CD spectra of (di)azonia[6]helicenes were less satisfactorily reproduced by the theoretical calculations at the state-of-the-art RI CC2/TZVPP//DFT-D2-B97-D/TZVP level, most probably due to the inadequate incorporation of the effects of solvation. Nevertheless, the bytheoretical predictions were reasonably accurate and highly valuable in assigning the observed CE and elucidating the origin of the elaborate CD spectral behaviors upon protonation through inspection of the molecular orbital configuration of each transition, encouraging the extended use of the present protocol for analyzing the CD spectral behavior of aza- and other heteroatom-incorporated helicenes upon protonation. The CD spectral behavior upon metal ligation will also be explained through further theoretical and experimental studies. PMID- 23688123 TI - Base-catalyzed bifunctional addition to amides and imides at low temperature. A new pathway for carbonyl hydrogenation. AB - Mono- or dideprotonation at the N-H groups of the Noyori ketone hydrogenation catalyst trans-[RuH2((R)-BINAP)((R,R)-dpen)] (1a) yields trans-M[RuH2((R,R) HNCH(Ph)CH(Ph)NH2)((R)-BINAP)], where M = K(+)(8-K) or Li(+) (8-Li), or trans M2[RuH2((R,R)-HNCH(Ph)CH(Ph)NH)((R)-BINAP)], where M = Li(+) (8-M'2), which have unprecedented activity toward the hydrogenation of amide and imide carbonyls at low temperatures in THF-d8. Details of the origins of the enantioselection for the desymmetrization of meso-cyclic imides by hydrogenation with 8-K are also described herein. PMID- 23688124 TI - Hypocrea jecorina cellobiohydrolase I stabilizing mutations identified using noncontiguous recombination. AB - Noncontiguous recombination (NCR) is a method to identify pieces of structure that can be swapped among homologous proteins to create new, chimeric proteins. These "blocks" are encoded by elements of sequence that are not necessarily contiguous along the polypeptide chain. We used NCR to design a library in which blocks of structure from Hypocrea jecorina cellobiohydrolase I (Cel7A) and its two thermostable homologues from Talaromyces emersonii and Chaetomium thermophilum are shuffled to create 531,438 possible chimeric enzymes. We constructed a maximally informative subset of 35 chimeras to analyze this library and found that the blocks contribute additively to the stability of a chimera. Within two highly stabilizing blocks, we uncovered six single amino acid substitutions that each improve the stability of H. jecorina cellobiohydrolase I by 1-3 degrees C. The small number of measurements required to find these mutations demonstrates that noncontiguous recombination is an efficient strategy for identifying stabilizing mutations. PMID- 23688125 TI - Utility of the PASE questionnaire, psoriatic arthritis (PsA) prevalence and PsA improvement with anti-TNF therapy: results from the PRISTINE trial. AB - OBJECTIVE: The authors tested the Psoriatic Arthritis Screening and Evaluation (PASE) to assess usefulness for psoriatic arthritis (PsA) screening before and after anti-TNF treatment in a clinical trial setting. METHODS: Participants of the PRISTINE trial (NCT0066305) were randomized to etanercept 50 mg once weekly or twice weekly. PASE was administered at baseline and 12 weeks of treatment. Scores were compared by a paired sample t-test. Logistic regression and receiver operating curves were used to compare disease assessments against the PASE scores. RESULTS: Participants (N = 273, once weekly, N = 137; twice weekly, N = 136) had a mean age of 44 years; 70% were male; mean PASI was 21. At baseline, 31% had a self-reported history of physician-diagnosed PsA (mean duration, 8 years); ~25% had a PASE total score >=47, indicating active PsA. At week 12, 14% had scores >=47 (p =. 0143). PASE scores correlated with subject global assessment of joint pain. CONCLUSIONS: The PASE was used in a randomized controlled clinical trial in a moderate to severe psoriasis population with a high prevalence of PsA. The findings also support the use of PASE as a tool to measure treatment response for PsA. PMID- 23688126 TI - Development of a proof of concept immunochromatographic lateral flow assay for point of care diagnosis of Mycobacterium tuberculosis. AB - BACKGROUND: Despite major public health initiatives and the existence of efficacious treatment regimes, tuberculosis (TB) remains a threat, particularly in resource-limited settings. A significant part of the problem is the difficulty of rapidly identifying infected individuals, and as a result, there has been renewed interest in developing better diagnostics for infection or disease caused by Mycobacterium tuberculosis. Many of the existing tools, however, have limitations such as poor sensitivity or specificity, or the need for well equipped laboratories to function effectively. Serodiagnostic approaches in particular have long drawn attention, due to their potential utility in large field studies, particularly in resource-poor settings. Unfortunately none of the serodiagnostic approaches have so far proven useful under field conditions. RESULTS: We screened a large panel of antigens with serodiagnostic potential by ELISA and selected a subpanel that was strongly and broadly recognised by TB patients, but not by controls. These antigens were then formulated into a simple immuno-chromatographic lateral flow assay format, suitable for field use, and tested against panels of plasma and blood samples from individuals with different clinical status (confirmed TB patients, household contacts, and apparently healthy community controls), recruited from Ethiopia (a highly TB-endemic country) and Turkey (a TB meso-endemic country). While specificity was good (97 100% in non TB-endemic controls), the sensitivity was not as high as expected (46 54% in pulmonary TB, 25-29% in extra-pulmonary TB). CONCLUSIONS: Though below the level of sensitivity the consortium had set for commercial development, the assay specifically identified M. tuberculosis-infected individuals, and provides a valuable proof of concept. PMID- 23688128 TI - Transition-metal-free arylations via photogenerated triplet 4-alkyl- and 4 trimethylsilylphenyl cations. AB - The irradiation in protic solvents of 4-chloroalkylbenzenes and 4 chlorophenyltrimethylsilane caused the heterolytic cleavage of aryl-chlorine bonds to give the corresponding triplet phenyl cations. These were exploited for transition-metal-free arylation reactions under mild conditions to give allylbenzenes, gamma-benzyl lactones, 3-arylacetals (ketals), and biaryls in moderate to good yields. The path followed was supported by DFT calculations at the UB3LYP/6-311+G(2d,p) level. PMID- 23688129 TI - Cytochrome P450s: new insights and relevance to medicinal chemistry and drug discovery. PMID- 23688127 TI - Protein complex detection using interaction reliability assessment and weighted clustering coefficient. AB - BACKGROUND: Predicting protein complexes from protein-protein interaction data is becoming a fundamental problem in computational biology. The identification and characterization of protein complexes implicated are crucial to the understanding of the molecular events under normal and abnormal physiological conditions. On the other hand, large datasets of experimentally detected protein-protein interactions were determined using High-throughput experimental techniques. However, experimental data is usually liable to contain a large number of spurious interactions. Therefore, it is essential to validate these interactions before exploiting them to predict protein complexes. RESULTS: In this paper, we propose a novel graph mining algorithm (PEWCC) to identify such protein complexes. Firstly, the algorithm assesses the reliability of the interaction data, then predicts protein complexes based on the concept of weighted clustering coefficient. To demonstrate the effectiveness of the proposed method, the performance of PEWCC was compared to several methods. PEWCC was able to detect more matched complexes than any of the state-of-the-art methods with higher quality scores. CONCLUSIONS: The higher accuracy achieved by PEWCC in detecting protein complexes is a valid argument in favor of the proposed method. The datasets and programs are freely available at http://faculty.uaeu.ac.ae/nzaki/Research.htm. PMID- 23688130 TI - CYP17A1: a biochemistry, chemistry, and clinical review. AB - Cytochrome P450 17A1 (CYP17A1; also P450c17and P450sccII) is a critically important enzyme in humans that catalyzes the formation of all endogenous androgens. It is an atypical cytochrome P450 enzyme in that it catalyzes two distinct types of substrate oxidation. Through its hydroxylase activity, it catalyzes the 17alpha-hydroxylation of pregnenolone to 17alpha-OH pregnenolone. Subsequently, through its C17,20lyase activity, it can further convert 17alpha-OH pregnenolone to the androgen dehydroepiandrosterone, which is a precursor to androstenedione, testosterone, and dihydrotestosterone. The importance of androgens in diseases such as prostate cancer has been appreciated for decades and the discovery of extra-testicular formation of androgens has helped clarify the pathology of the disease, especially the castrate- resistant disease. Therefore, specific inhibition of CYP17A1 by therapeutic intervention has been an area of considerable effort in several research laboratories. This basic research has led to the discovery of several promising drug candidates followed by the conduct of several clinical trials. Recently, all these efforts have culminated in the first approval by FDA of an inhibitor of CYP17A1 for the treatment of castrate-resistant prostate cancer. Ongoing clinical trials are now evaluating the agent in earlier stages of prostate cancer and even rare forms of androgen dependent breast cancer. Accordingly, this review focuses on the biochemistry, chemistry, and clinical inhibitors of CYP17A1. PMID- 23688131 TI - Progress towards clinically useful aldosterone synthase inhibitors. AB - Owing to the high degree of similarity between aldosterone synthase (CYP11B2) and cortisol synthase (CYP11B1), the design of selective inhibitors of one or the other of these two enzymes was, at one time, thought to be impossible. Through development of novel enzyme screening assays and significant medicinal chemistry efforts, highly potent inhibitors of CYP11B2 have been identified with selectivities approaching 1000-fold between the two enzymes. Many of these molecules also possess selectivity against other steroidogenic cytochromes P450 (e.g. CYP17A1 and CYP19A1) as well as hepatic drug metabolizing P450s. Though not as well developed or explored, inhibitors of CYP11B1, with selectivities approaching 50-fold, have also been identified. The therapeutic benefits of affecting the renin-angiotensin-aldosterone system have been well established with the therapeutically useful angiotensin-converting enzymes inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists. Data regarding the additional benefits of an aldosterone synthase inhibitor (ASi) are beginning to emerge from animal models and human clinical trials. Despite great promise and much progress, additional challenges still exist in the path towards development of a therapeutically useful ASi. PMID- 23688134 TI - Extra-hepatic isozymes from the CYP1 and CYP2 families as potential chemotherapeutic targets. AB - Cytochrome P450 isozymes (CYPs) from the CYP1 and CYP2 families located primarily in extra-hepatic tissues represent ideal candidates for chemotherapeutic drug development because: 1.) They are usually involved in the metabolism of endogenous substrates that are important for cell homeostasis and growth 2.) The over-expression of certain CYPs has been reported in various malignancies 3.) There has been much clinical success with inhibitors of CYPs involved in hormone synthesis. The most ideal candidates for chemotherapeutic drug development will be discussed in terms of their biological importance and relevant substrates. This review will focus on: 1.) CYP1A1 and CYP1B1 from the CYP1 family because of the dual role these enzymes play in the bioactivation of known carcinogens and endogenous compounds. 2.) The targeting of CYPs in hypoxic environments as a therapeutic strategy. 3.) CYP2J2 and its role in the metabolism of arachidonic acid to epoxyeicosatrienoic acids and angiogenesis will also be examined. While much progress has been made towards understanding the role of CYPs in extrahepatic tissue, future studies focused on the development of selective inhibitors coupled with appropriate delivery systems that would target the tumor micro-environments could lead to significant advancement in chemotherapeutic strategies. PMID- 23688133 TI - CYP4 enzymes as potential drug targets: focus on enzyme multiplicity, inducers and inhibitors, and therapeutic modulation of 20-hydroxyeicosatetraenoic acid (20 HETE) synthase and fatty acid omega-hydroxylase activities. AB - The Cytochrome P450 4 (CYP4) family of enzymes in humans is comprised of thirteen isozymes that typically catalyze the omega-oxidation of endogenous fatty acids and eicosanoids. Several CYP4 enzymes can biosynthesize 20- hydroxyeicosatetraenoic acid, or 20-HETE, an important signaling eicosanoid involved in regulation of vascular tone and kidney reabsorption. Additionally, accumulation of certain fatty acids is a hallmark of the rare genetic disorders, Refsum disease and X-ALD. Therefore, modulation of CYP4 enzyme activity, either by inhibition or induction, is a potential strategy for drug discovery. Here we review the substrate specificities, sites of expression, genetic regulation, and inhibition by exogenous chemicals of the human CYP4 enzymes, and discuss the targeting of CYP4 enzymes in the development of new treatments for hypertension, stroke, certain cancers and the fatty acid-linked orphan diseases. PMID- 23688136 TI - Cytochrome P450 bioreactors in the pharmaceutical industry: challenges and opportunities. AB - Cytochrome P450 (CYP) bioreactors play a major role in establishing the practical use of this enzyme family in academia and industry. The current demand for enzymatic hydroxylations of unactivated carbons in the parmaceutical industry includes the preparation of drug metabolites and various hydroxylated synthetic precursors as well as the enzyme mediated lead diversification and natural product synthesis, most of which require multigram scale synthesis. To date, the large scale application of CYPs in the synthesis of oxygenated compounds is limited by many challenges. This review describes relevant examples of CYP oxidations and also presents the strategies available to overcome such challenges. At present, P450 catalyzed reactions can only be performed at substrate concentrations ranging from 1-25 mM, unlike other biocatalytic redox reactions like ketone reductases, typically performed at substrate loads greater than 500 mM. The emergence of powerful expression methods and a large number of CYP mutants developed for specific applications holds the promise for future industrial applications. The search for higher volumetric productivities is however a task that needs to be addressed not only through the use of protein engineering as the primary tool but significant emphasis needs to be placed on process development through exploring multiple operating schemes, optimizing reaction media and modifying microbial strains needed for heterologous expression. PMID- 23688135 TI - CYP epoxygenase derived EETs: from cardiovascular protection to human cancer therapy. AB - Arachidonic acids are converted to eicosanoid mediators by the distinct enzyme systems: cyclooxygenase, lipoxygenase and cytochrome P450 (CYP) monooxygenase pathways (omega/omega-1-hydroxylases and epoxygenases). CYP2J2, CYP2C8 and CYP2C9 are the predominant epoxygenase isoforms abundantly expressed in the endothelium, myocardium, and kidney in human. The primary epoxidation products by epoxygenases are four regioisomers of cis-epoxyeicosatrienoic acids (EETs): 5,6-, 8,9-, 11,12 , and 14,15-EETs. Numerous studies demonstrated that the cardiovascular protective effects of CYP epoxygenases and EETs range from vasodilation, anti hypertension, pro-angiogenesis, anti-atherosclerosis, and anti-inflammation to anti-injury caused by ischemia-reperfusion. The roles of arachidonic acids and its metabolites in cancer biology have recently attracted great attentions. However, CYP epoxygenase derived EETs and cancer has received little attention. It was demonstrated that CYP epoxygenases and EETs are significantly upregulated in human tumors and promote tumor progression and metastasis. Additionally, specific inhibitors of CYP2J2, derived from terfenadine, exhibit strong anti tumor activity in vitro and in vivo. It is implicated that CYP2J2 may be a therapeutic target for treating human cancers. PMID- 23688132 TI - Therapeutic potential of the inhibition of the retinoic acid hydroxylases CYP26A1 and CYP26B1 by xenobiotics. AB - Retinoic acid (RA), the active metabolite of vitamin A, is an important endogenous signaling molecule regulating cell cycle and maintenance of epithelia. RA isomers are also used as drugs to treat various cancers and dermatological diseases. However, the therapeutic uses of RA isomers are limited due to side effects such as teratogenicity and resistance to treatment emerging mainly from autoinduction of RA metabolism. To improve the therapeutic usefulness of retinoids, RA metabolism blocking agents (RAMBAs) have been developed. These inhibitors generally target the cytochrome P450 (CYP) enzymes because RA clearance is predominantly mediated by P450s. Since the initial identification of inhibitors of RA metabolism, CYP26 enzymes have been characterized as the main enzymes responsible for RA clearance. This makes CYP26 enzymes an attractive target for the development of novel therapeutics for cancer and dermatological conditions. The basic principle of development of CYP26 inhibitors is that endogenous RA concentrations will be increased in the presence of a CYP26 inhibitor, thus, potentiating the activity of endogenous RA in a cell-type specific manner. This will reduce side effects compared to administration of RA and allow for more targeted therapy. In clinical trials, inhibitors of RA metabolism have been effective in treatment of psoriasis and other dermatological conditions as well as in some cancers. However, no CYP26 inhibitor has yet been approved for clinical use. This review summarizes the history of development of RAMBAs, the clinical and preclinical studies with the various structural series and the available knowledge of structure activity relationships of CYP26 inhibitors. PMID- 23688137 TI - Environmental enrichment as an effective treatment for autism: a randomized controlled trial. AB - Enriched sensorimotor environments enable rodents to compensate for a wide range of neurological challenges, including those induced in animal models of autism. Given the sensorimotor deficits in most children with autism, we attempted to translate that approach to their treatment. In a randomized controlled trial, 3 12 year-old children with autism were assigned to either a sensorimotor enrichment group, which received daily olfactory/tactile stimulation along with exercises that stimulated other paired sensory modalities, or to a control group. We administered tests of cognitive performance and autism severity to both groups at the initiation of the study and after 6 months. Severity of autism, as assessed with the Childhood Autism Rating Scale, improved significantly in the enriched group compared to controls. Indeed, 42% of the enriched group and only 7% of the control group had what we considered to be a clinically significant improvement of 5 points on that scale. Sensorimotor enrichment also produced a clear improvement in cognition, as determined by their Leiter-R Visualization and Reasoning scores. At 6 months, the change in average scores for the enriched group was 11.3 points higher than that for the control group. Finally, 69% of parents in the enriched group and 31% of parents in the control group reported improvement in their child over the 6-month study. Environmental enrichment therefore appears to be effective in ameliorating some of the symptoms of autism in children. PMID- 23688139 TI - Real-time observation of crystal evaporation in a metal phosphate at high temperature. AB - A number of experimental studies on crystal growth have been performed in connection with a variety of crystalline systems ranging from simple oxides to complex organic compounds. In contrast, little is known regarding how crystals evaporate. By using a combination of real-time high-resolution electron microscopy at high temperature, image simulations, and density functional theory calculations, we demonstrate the evaporation of metal-phosphate nanocrystals with flat surfaces at atomic resolution. In situ imaging and direct comparison with image simulation results reveal that, while a layer-by-layer lateral process is macroscopically maintained, the cations preferentially evaporate over the (PO4)(3 ) tetrahedral anions from shrinking ledges. The present observations provide the first atomic-scale experimental details of the evaporation of complex oxides, emphasizing the value of direct visualization in real time. PMID- 23688138 TI - The challenge of obtaining information necessary for multi-criteria decision analysis implementation: the case of physiotherapy services in Canada. AB - BACKGROUND: As fiscal constraints dominate health policy discussions across Canada and globally, priority-setting exercises are becoming more common to guide the difficult choices that must be made. In this context, it becomes highly desirable to have accurate estimates of the value of specific health care interventions.Economic evaluation is a well-accepted method to estimate the value of health care interventions. However, economic evaluation has significant limitations, which have lead to an increase in the use of Multi-Criteria Decision Analysis (MCDA). One key concern with MCDA is the availability of the information necessary for implementation. In the Fall 2011, the Canadian Physiotherapy Association embarked on a project aimed at providing a valuation of physiotherapy services that is both evidence-based and relevant to resource allocation decisions. The framework selected for this project was MCDA. We report on how we addressed the challenge of obtaining some of the information necessary for MCDA implementation. METHODS: MCDA criteria were selected and areas of physiotherapy practices were identified. The building up of the necessary information base was a three step process. First, there was a literature review for each practice area, on each criterion. The next step was to conduct interviews with experts in each of the practice areas to critique the results of the literature review and to fill in gaps where there was no or insufficient literature. Finally, the results of the individual interviews were validated by a national committee to ensure consistency across all practice areas and that a national level perspective is applied. RESULTS: Despite a lack of research evidence on many of the considerations relevant to the estimation of the value of physiotherapy services (the criteria), sufficient information was obtained to facilitate MCDA implementation at the local level. CONCLUSIONS: The results of this research project serve two purposes: 1) a method to obtain information necessary to implement MCDA is described, and 2) the results in terms of information on the benefits provided by each of the twelve areas of physiotherapy practice can be used by decision-makers as a starting point in the implementation of MCDA at the local level. PMID- 23688140 TI - Parent attendance and homework adherence predict response to a family-school intervention for children with ADHD. AB - This study examined the relative contribution of two dimensions of parent engagement, attendance and homework adherence, to parent and child treatment response and explored whether early engagement was a stronger predictor of outcomes than later engagement. The sample consisted of parents of participants (n = 92; M age = 9.4 years, SD = 1.27; 67% male, 69% White) in a 12-session evidence-based family-school intervention for children with attention deficit/hyperactivity disorder. Attendance was assessed using clinician records, and homework adherence was measured by rating permanent products. Outcomes included parent and teacher ratings of family involvement in education, parenting practices, and child functioning. Accounting for the contributions of baseline scores and attendance, homework adherence was a significant predictor of parental self-efficacy, the parent-teacher relationship, parenting through positive involvement, and the child's inattention to homework and homework productivity. Accounting for the contribution of baseline scores and homework adherence, attendance was a significant predictor of one outcome, the child's academic productivity. Early homework adherence appeared to be more predictive of outcomes than later adherence, whereas attendance did not predict outcomes during either half of treatment. These results indicate that, even in the context of evidence based practice, it is the extent to which parents actively engage with treatment, rather than the number of sessions they attend, that is most important in predicting intervention response. Because attendance is limited as an index of engagement and a predictor of outcomes, increased efforts to develop interventions to promote parent adherence to behavioral interventions for children are warranted. PMID- 23688141 TI - Resveratrol and analogues: a review of antioxidant activity and applications to human health. AB - Resveratrol has been extensively researched for its powerful antioxidant capacity and other biological effects. The number of patents involving this compound has been growing in recent years. However, the biggest problem associated with this molecule, a limited bioavailability due to its fast metabolism in the liver, has led to obtaining its analogues or derivatives. In this work, we selected patents which describe the application of the antioxidant activity of resveratrol and its analogues as food for the human segment. PMID- 23688142 TI - Effect of the processing steps on compositions of table olive since harvesting time to pasteurization. AB - Weight, oil, fatty acids, tocopherol, polyphenol, and sterol properties of 5 olive cultivars (Zard, Fishomi, Ascolana, Amigdalolia, and Conservalia) during crude, lye treatment, washing, fermentation, and pasteurization steps were studied. Results showed: oil percent was higher and lower in Ascolana (crude step) and in Fishomi (pasteurization step), respectively; during processing steps, in all cultivars, oleic, palmitic, linoleic, and stearic acids were higher; the highest changes in saturated and unsaturated fatty acids were in fermentation step; the highest and the lowest ratios of omega3 / omega6 were in Ascolana (washing step) and in Zard (pasteurization step), respectively; the highest and the lowest tocopherol were in Amigdalolia and Fishomi, respectively, and major damage occurred in lye step; the highest and the lowest polyphenols were in Ascolana (crude step) and in Zard and Ascolana (pasteurization step), respectively; the major damage among cultivars occurred during lye step, in which the polyphenol reduced to 1/10 of first content; sterol did not undergo changes during steps. Reviewing of olive patents shows that many compositions of fruits such as oil quality, fatty acids, quantity and its fraction can be changed by alteration in cultivar and process. PMID- 23688143 TI - Active ingredients are reported more often for pharmacologic than non pharmacologic interventions: an illustrative review of reporting practices in titles and abstracts. AB - Key components of healthcare interventions include 'active ingredients' (intervention components that can be specifically linked to effects on outcomes such that, were they omitted, the intervention would be ineffective). These should be reported in titles and abstracts of published reports of randomized controlled trials (RCTs). However, reporting of non-pharmacologic interventions (NPIs), particularly behaviour change interventions (BCIs), is difficult, owing to their complexity. This illustrative review compares how pharmacologic interventions (PIs), NPIs and BCIs are specified in titles and abstracts to clarify how reporting of NPIs and BCIs can be improved. MEDLINE and Embase were searched for RCTs published in the British Medical Journal, The Journal of the American Medical Association, The New England Journal of Medicine, The Lancet and Annals of Behavioral Medicine from 2009 to March 2011. All types of intervention, participant and outcome were included. A random sample of 198 studies (sampled proportionally from included journals) stratified by intervention type (PI/NPI) was taken: 98 evaluated PIs, 96 evaluated NPIs and four evaluated both. Studies were coded for the presence or absence of key components. The frequency data were analyzed using the chi-square test. Active ingredients were named in 88% titles and 95% abstracts of PI reports, and in 51% titles and 71% abstracts of NPI reports, with a significant association between intervention type and reporting of active ingredients in titles (chi2(1) = 28.90; P < 0.001) and abstracts (chi2(1) = 16.94; P < 0.001). Active ingredients were named in BCI reports in 37% titles and 56% abstracts, and in other NPI reports in 66% titles and 86% abstracts. There was also a significant association between intervention type and reporting of active ingredients in titles (chi2(1) = 6.68; P = 0.010) and abstracts (chi2(1) = 8.66; P = 0.003). Reporting practices also differed for such components as the trial setting and intervention provider. This review highlights the need for improved reporting of NPIs (particularly BCIs) and indicates that a set of agreed labels and definitions for complex NPIs could facilitate standardized reporting. This would ensure that interventions can be faithfully replicated and that evidence for interventions can be appropriately synthesized. PMID- 23688144 TI - Determinants of inter birth interval among married women living in rural pastoral communities of Southern Ethiopia: a case control study. AB - BACKGROUND: Though birth interval has beneficial effects on health status of the mother and their children, it is affected by range of factors some of which are rooted in social and cultural norms and the reproductive behaviors of individual women. However, there was limited data showed the determinants of birth intervals in rural pastoral communities of South Ethiopia. Therefore, the study was aimed to assess the determinants of inter birth interval among women's of child bearing age in Yaballo Woreda, Borena zone, Oromia Regional State, Ethiopia. METHODS: A community based unmatched case-control study with multi stage sampling technique was conducted from January to March 2012. Cases were women with two subsequent birth intervals of less than three years and controls were women with two subsequent birth intervals between three and above years. Simple random sampling technique was employed to select six hundred fifty two (326 cases and 326 controls) study subjects. All explanatory variables that were associated with the outcome variable (birth interval) during bivariate analysis were included in the final logistic model. Multivariable backward logistic regression when P values less than or equal to 0.05 and 95% CI were used to determine independent determinants for the outcome of interest. RESULTS: The median duration of birth interval was 31 & 40 months among cases and controls respectively. Variables such as number of children (AOR 3.73 95% CI: (1.50, 9.25), use of modern contraceptives (AOR 5.91 95% CI: (4.02, 8.69), mothers' educational status (AOR 1.89 95% CI: (1.15, 3.37), and sex of the child (AOR 1.72 95% CI: (1.17, 2.52) were significantly associated with birth intervals. CONCLUSIONS: Concerted efforts to encourage modern contraceptive use, women education, and breastfeeding should be made. PMID- 23688145 TI - Are the parts as good as the whole? A meta-analysis of component treatment studies. AB - OBJECTIVE: Component studies compare standard treatments to treatments with added components or dismantled components. A previous meta-analysis (Ahn & Wampold, 2001) failed to find any differences in outcome between treatments with more components and those with fewer components, leading the authors to conclude that common factors and not specific ingredients account for therapeutic change. METHOD: The current random effects model meta-analysis of psychotherapy component studies conducted between 1980 and 2010 included more than 3 times as many studies as Ahn and Wampold's (2001) meta-analysis (k = 66). Unlike the previous meta-analysis, this study conducted separate meta-analyses for additive and dismantling studies and also examined treatment outcomes at follow-up. RESULTS: For the dismantling studies, there were no significant differences between the full treatments and the dismantled treatments. For the additive studies, the treatment with the added component yielded a small, but significant, effect at completion (d = 0.14) and a slightly larger effect at follow-up (d = 0.28), but only for the specific problems that were targeted for treatment. Despite the diversity of populations studied, problems treated, and treatments examined, there was little heterogeneity among the results of these studies. CONCLUSION: These findings suggest that added specific ingredients may contribute modestly to treatment outcomes. PMID- 23688148 TI - Gas phase oxidation of monoethanolamine (MEA) with OH radical and ozone: kinetics, products, and particles. AB - Monoethanolamine (MEA) is currently the benchmark solvent in carbon capture and storage (CCS), a technology aimed at reducing CO2 emissions in large combustion industries. To accurately assess the environmental impact of CCS, a sound understanding of the fate of MEA in the atmosphere is necessary. Relative and absolute rate kinetic experiments were conducted in a smog chamber using online proton transfer reaction mass spectrometry (PTR-MS) to follow the decay of MEA. The room temperature (295 +/- 3K) kinetics of oxidation with hydroxyl radicals from light and dark sources yield an average value of (7.02 +/- 0.46) * 10(-11) cm(3) molec(-1) s(-1), in good agreement with previously published data. For the first time, the rate coefficient for MEA with ozone was measured: (1.09 +/- 0.05) * 10(-18) cm(3) molec(-1) s(-1). An investigation into the oxidation products was also conducted using online chemical ionization mass spectrometry (CI-TOFMS) where formamide, isocyanic acid as well as higher order products including cyclic amines were detected. Significant particle numbers and mass loadings were observed during the MEA oxidation experiments and accounted for over 15% of the fate of MEA-derived nitrogen. PMID- 23688146 TI - Anxiety and related outcomes in young adults 7 to 19 years after receiving treatment for child anxiety. AB - OBJECTIVE: This study evaluated follow-up outcomes associated with cognitive behavioral therapy (CBT) for childhood anxiety by comparing successfully and unsuccessfully treated participants 6.72 to 19.17 years after treatment. METHOD: Participants were a sample of 66 youths (ages 7-14 years at time of treatment, ages 18-32 years at present follow-up) who had been diagnosed with an anxiety disorder and randomized to treatment in a randomized clinical trial on average 16.24 (SD = 3.56, range = 6.72-19.17) years prior. The present follow-up included self-report measures and a diagnostic interview to assess anxiety, depression, and substance misuse. RESULTS: Compared with those who responded successfully to CBT for an anxiety disorder in childhood, those who were less responsive had higher rates of panic disorder, alcohol dependence, and drug abuse in adulthood. Relative to a normative comparison group, those who were less responsive to CBT in childhood had higher rates of several anxiety disorders and substance misuse problems in adulthood. Participants remained at particularly increased risk, relative to the normative group, for generalized anxiety disorder and nicotine dependence regardless of initial treatment outcome. CONCLUSIONS: The present study is the first to assess the long-term follow-up effects of CBT treatment for an anxiety disorder in youth on anxiety, depression, and substance abuse through the period of young adulthood when these disorders are often seen. Results support the presence of important long-term benefits of successful early CBT for anxiety. PMID- 23688147 TI - ENU-mutagenesis mice with a non-synonymous mutation in Grin1 exhibit abnormal anxiety-like behaviors, impaired fear memory, and decreased acoustic startle response. AB - BACKGROUND: The Grin1 (glutamate receptor, ionotropic, NMDA1) gene expresses a subunit of N-methyl-D-aspartate (NMDA) receptors that is considered to play an important role in excitatory neurotransmission, synaptic plasticity, and brain development. Grin1 is a candidate susceptibility gene for neuropsychiatric disorders, including schizophrenia, bipolar disorder, and attention deficit/hyperactivity disorder (ADHD). In our previous study, we examined an N ethyl-N-nitrosourea (ENU)-generated mutant mouse strain (Grin1(Rgsc174)/Grin1+) that has a non-synonymous mutation in Grin1. These mutant mice showed hyperactivity, increased novelty-seeking to objects, and abnormal social interactions. Therefore, Grin1(Rgsc174)/Grin1+ mice may serve as a potential animal model of neuropsychiatric disorders. However, other behavioral characteristics related to these disorders, such as working memory function and sensorimotor gating, have not been fully explored in these mutant mice. In this study, to further investigate the behavioral phenotypes of Grin1(Rgsc174)/Grin1+ mice, we subjected them to a comprehensive battery of behavioral tests. RESULTS: There was no significant difference in nociception between Grin1(Rgsc174)/Grin1+ and wild-type mice. The mutants did not display any abnormalities in the Porsolt forced swim and tail suspension tests. We confirmed the previous observations that the locomotor activity of these mutant mice increased in the open field and home cage activity tests. They displayed abnormal anxiety-like behaviors in the light/dark transition and the elevated plus maze tests. Both contextual and cued fear memory were severely deficient in the fear conditioning test. The mutant mice exhibited slightly impaired working memory in the eight-arm radial maze test. The startle amplitude was markedly decreased in Grin1(Rgsc174)/Grin1+ mice, whereas no significant differences between genotypes were detected in the prepulse inhibition (PPI) test. The mutant mice showed no obvious deficits in social behaviors in three different social interaction tests. CONCLUSIONS: This study demonstrated that the Grin1(Rgsc174)/Grin1+ mutation causes abnormal anxiety-like behaviors, a deficiency in fear memory, and a decreased startle amplitude in mice. Although Grin1(Rgsc174)/Grin1+ mice only partially recapitulate symptoms of patients with ADHD, schizophrenia, and bipolar disorder, they may serve as a unique animal model of a certain subpopulation of patients with these disorders. PMID- 23688149 TI - Odd-even effect in the elastic modulii of alpha,omega-alkanedicarboxylic acids. AB - Nanoindentation studies on alpha,omega-alkanedicarboxylic acids reveal that the elastic modulus, E, shows an odd-even alternation in exactly the same manner as the melting temperature, Tm. These results are consistent with the hypothesis that the strained molecular conformations in the odd diacids are the reasons for these alternations in Tm. The same packing features that lower Tm in the odd acids lead to easy accommodation of the deformation during nanoindentation and hence their low E. PMID- 23688150 TI - Estimation of ligand efficacies of metabotropic glutamate receptors from conformational forces obtained from molecular dynamics simulations. AB - Group 1 metabotropic glutamate receptors (mGluR) are G-protein coupled receptors with a large bilobate extracellular ligand binding region (LBR) that resembles a Venus fly trap. Closing of this LBR in the presence of a ligand is associated with the activation of the receptor. From conformational sampling of the LBR ligand complexes using all-atom molecular dynamics (MD) simulations, we characterized the conformational minima related to the hinge like motion associated with the LBR closing/opening in the presence of known agonists and antagonists. By applying a harmonic restraint on the LBR, we also determined the conformational forces generated by the different ligands. The change in the location of the minima and the conformational forces were used to quantify the efficacies of the ligands. This analysis shows that efficacies can be estimated from the forces of a single conformation of the receptor, indicating the potential of MD simulations as an efficient and useful technique to quantify efficacies, thereby facilitating the rational design of mGluR agonists and antagonists. PMID- 23688151 TI - Investigation of thrombin activity with PAR 1-based fluorogenic peptides. AB - Thrombin, a highly specific protease of blood coagulation, has two exosites that modulate its specificity. We designed two sets of synthetic substrate FRET peptides with 25- or 11- amino acids (aa) each, based on the PAR 1 sequence, to characterize the effect of exosite 1 engagement on substrate catalysis and preference. The 25-aa set encompassed a sequence binding to exosite 1, and structural modeling showed that binding to thrombin did not differ significantly from that of PAR 1 peptide. Modification at the P3'position of the 25 or 11-aa peptides resulted in small effect on kinetic parameters. Ionic strength higher than physiologic depressed thrombin action on the 25-aa peptides. Addition of ligands of the exosite 1 negatively modulated the catalysis of 25-aa substrates. In conclusion, we succeeded to mimic and study in real time, using these synthetic peptides, the influence of ligand binding to exosite 1 on thrombin activity. PMID- 23688152 TI - Incorporating secondary structural features into sequence information for predicting protein structural class. AB - Knowledge of structural classes is applied in numerous important predictive tasks that address structural and functional features of proteins, although the prediction accuracy of the protein structural classes is not high. In this study, 45 different features were rationally designed to model the differences between protein structural classes, among which, 30 of them reflect the combined protein sequence information. In terms of correlation function, the protein sequence can be converted to a digital signal sequence, from which we can generate 20 discrete Fourier spectrum numbers. According to the segments of amino with different characteristics occurring in protein sequences, the frequencies of the 10 kinds of segments of amino acid (motifs) in protein are calculated. Other features include the secondary structural information :10 features were proposed to model the strong adjacent correlations in the secondary structural elements and capture the long-range spatial interactions between secondary structures, other 5 features were designed to differentiate alpha/beta from alpha+beta classes , which is a major problem of the existing algorithm. The methods were proposed based on a large set of low-identity sequences for which secondary structure is predicted from their sequence (based on PSI-PRED). By means of this method, the overall prediction accuracy of four benchmark datasets were all improved. Especially for the dataset FC699, 25PDB and D1189 which are 1.26%, 1% and 0.85% higher than the best previous method respectively. PMID- 23688153 TI - Immunogenicity of a multiepitope plasmid DNA encoding T and B lymphocyte epitopes from latent membrane protein 2 (LMP2) of Epstein-Barr virus as a vaccine in mice. AB - Epstein-Barr virus (EBV) is a human oncogenic herpesvirus associating with several malignant diseases. Latent membrane protein 2 (LMP2) of EBV is considered to be an ideal candidate for immunotherapy or prophylactic EBV vaccine. We designed a LMP2 multiepitope containing T and B-cell epitope-rich peptides and constructed a recombinant plasmid containing mammalian codonoptimization EBV LMP2 multiepitope (pcDNA3.1+/EBV-LMP2 multiepitope). After pcDNA3.1+/EBV-LMP2 multiepitope was transfected into COS-7 cells, significant expression of the multiepitope in COS-7 cells was confirmed by RT-PCR and immunofluorescence assay. Western blot analysis indicated that serum from immunized mice could be discerned by the EBV-LMP2 protein and the EBV-LMP2 multiepitope specifically. The plasmid DNA of EBV-LMP2 multiepitope induced high levels anti-EBV membrane protein and anti-EBV LMP2 multiepitope IgG in mice. T lymphocytes from spleen of immunized mice showed a strong CTL activity. The present study suggested that plasmid DNA encoding EBV LMP2 multiepitope capable of stimulating enough cellular and humoral immunity could have potential for preventing or controlling EBV infection and EBV associated disease in mice. PMID- 23688154 TI - Plasma levels and potential roles of catestatin in patients with coronary heart disease. AB - OBJECTIVES: Catestatin (CST) is a new endogenous neuropeptide with a potent catecholamine release-inhibitory activity. This study was to investigate plasma CST levels in patients with coronary heart disease (CHD) and to determine the clinical significance of plasma CST in cardiovascular events. METHODS: A total of 120 CHD patients and 30 age/sex-matched healthy subjects were enrolled. Plasma CST level was measured using enzyme-linked immunosorbent assay (ELISA) and norepinephrine (NE) level was measured using high-performance liquid chromatography (HPLC). Clinical and laboratory data during hospitalization were collected, and a follow-up of 1045 days was carried out. RESULTS: Compared with controls, CHD patients had significantly higher plasma CST and NE levels on admission. ST segment elevation myocardial infarction (STEMI) patients had higher CST levels than angina pectoris patients had, but CST/NE ratios were unchanged among controls and different CHD subgroups. Plasma NE was the only independent factor associated with CST. As a dichotomous variable divided by the median value, plasma CST on admission was not associated with adverse cardiovascular events. CONCLUSIONS: Plasma CST level was positively correlated with that of NE and was elevated in parallel with that of NE in the different myocardial ischemia states. Plasma CST on admission was neither associated with adverse cardiac events nor was there any significant relationship between plasma CST and onset of new cardiovascular events. The pathophysiological role of CST in CHD needs further studies. PMID- 23688155 TI - Microporous "honeycomb" films support enhanced bone formation in vitro. AB - Substrate topography influences cell adhesion, proliferation, and differentiation. In this study, poly (epsilon-caprolactone) (PCL) films with a well-defined honeycomb structure of porosity 3-4, 5-6, 10-11, or 15-16 MUm were contrasted with flat surfaces for their ability to support primary rat osteoblast adhesion and mineralized extracellular matrix deposition in vitro. Immunofluorescent visualization of vinculin and rhodamine phalloidin binding of actin were used to investigate cell adhesion and morphology. Localization of the alkaline phosphatase activity and Alizarin Red staining were performed to assess the osteoblast activity and deposition of a mineralized matrix. Scanning electron microscopy together with energy-dispersive X-ray spectroscopy was used to provide morphological analysis of cell-film interactions, the deposited matrix, and elemental analysis of the mineralized structures. After 24 h of culture, there were no differences in cell numbers on porous or flat PCL surfaces, but there were changes in cell morphology. Osteoblasts on honeycomb films had a smaller surface area and were less circular than cells on flat PCL. Analysis of cells cultured for 35 days under osteogenic conditions revealed that osteoblasts on all substrates acquired alkaline phosphatase activity, but levels of mineralized matrix were increased on films with 3-4-MUm pore sizes. The bone-like matrix with a Ca:P ratio of 1.69+/-0.08 could be identified in larger areas often aligning with substrate topography. In addition, smaller spherical deposits (0.5-1 MUm in diameter) with a Ca:P ratio of 1.3+/-0.08 were observed at the surface and particularly within the pores of the PCL film. Localization of vinculin showed significant decreases in the number of focal adhesion structures per unit cell area on 5-6, 10-11, and 15-16-MUm surfaces compared to flat PCL, while focal complexes with a smaller area (0-2 MUm(2)) were more abundant on 3-4 and 5-6-MUm surfaces. Observation of cell interaction with these surfaces identified cytoplasmic protrusions that extended into and sealed the pores of these PCL films creating an extracellular space in which, the conditions could influence the deposition and formation of the mineralized matrix. PMID- 23688156 TI - Resonant states of the H3(-) molecule and its isotopologues D2H- and H2D-. AB - Using the ground potential energy surface [Ayouz, M.; etal. J. Chem. Phys. 2010, 132, 194309] of the H3(-) molecule, we have determined the energies and widths of the complex resonant levels of H3(-) located up to 4000 cm(-1) above the dissociation limit H- + H2(nud = 0,jd = 0). Bound and resonant levels of the H2D- and D2H- isotopologues have been also characterized within the same energy range. The method combines the hyperspherical adiabatic approach, slow variable discretization method, and complex absorbing potential. These results represent the first step for modeling the dynamics of the associated diatom-negative ion collision at low energy involving rotational quenching of the diatom and reactive nucleus exchange via the weak tunneling effect through the potential barrier of the potential energy surface. PMID- 23688158 TI - Microtube bundle carbon derived from Paulownia sawdust for hybrid supercapacitor electrodes. AB - The structure and capacitive properties of microtube bundle carbons (MTBCs) from carbonization of paulownia sawdust (PS) followed by NaOH activation were investigated. Morphology analyses indicated that MTBCs had abundant micropores and mesopores with a high specific surface area of about 1900 m(2) g(-1). Cyclic voltammetry, galvanostatic charge/discharge, and electrochemical impedance spectroscopy studies demonstrated the excellent charge storage, transfer capability, and low impedance of MTBCs. The specific capacitance of MTBCs-4 was as high as 227 F g(-1) at 2 mV s(-1). Experimental results indicated that MTBCs provide smooth charge-transfer pathways for the ions in electrolytes and gateways to micropores and mesopores in the bulk. The hybrid supercapacitor model of MTBCs based on electrical double-layer capacitors and electrostatic capacitors was discussed and demonstrated. MTBCs are electrostatic capacitors at low frequency current, and may provide the pathways for easy accessibility of efficient charge transmission and high energy storage. PMID- 23688157 TI - Measuring parent food practices: a systematic review of existing measures and examination of instruments. AB - During the last decade, there has been a rapid increase in development of instruments to measure parent food practices. Because these instruments often measure different constructs, or define common constructs differently, an evaluation of these instruments is needed. A systematic review of the literature was conducted to identify existing measures of parent food practices and to assess the quality of their development. The initial search used terms capturing home environment, parenting behaviors, feeding practices and eating behaviors, and was performed in October of 2009 using PubMed/Medline, PsychInfo, Web of knowledge (ISI), and ERIC, and updated in July of 2012. A review of titles and abstracts was used to narrow results, after which full articles were retrieved and reviewed. Only articles describing development of measures of parenting food practices designed for families with children 2-12 years old were retained for the current review. For each article, two reviewers extracted data and appraised the quality of processes used for instrument development and evaluation. The initial search yielded 28,378 unique titles; review of titles and abstracts narrowed the pool to 1,352 articles; from which 57 unique instruments were identified. The review update yielded 1,772 new titles from which14 additional instruments were identified. The extraction and appraisal process found that 49% of instruments clearly identified and defined concepts to be measured, and 46% used theory to guide instrument development. Most instruments (80%) had some reliability testing, with internal consistency being the most common (79%). Test retest or inter-rater reliability was reported for less than half the instruments. Some form of validity evidence was reported for 84% of instruments. Construct validity was most commonly presented (86%), usually with analysis of associations with child diet or weight/BMI. While many measures of food parenting practices have emerged, particularly in recent years, few have demonstrated solid development methods. Substantial variation in items across different scales/constructs makes comparison between instruments extremely difficult. Future efforts should be directed toward consensus development of food parenting practices constructs and measures. PMID- 23688159 TI - Patterns of genetic variation across inversions: geographic variation in the In(2L)t inversion in populations of Drosophila melanogaster from eastern Australia. AB - BACKGROUND: Chromosomal inversions are increasingly being recognized as important in adaptive shifts and are expected to influence patterns of genetic variation, but few studies have examined genetic patterns in inversion polymorphisms across and within populations. Here, we examine genetic variation at 20 microsatellite loci and the alcohol dehydrogenase gene (Adh) located within and near the In(2L)t inversion of Drosophila melanogaster at three different sites along a latitudinal cline on the east coast of Australia. RESULTS: We found significant genetic differentiation between the standard and inverted chromosomal arrangements at each site as well as significant, but smaller differences among sites in the same arrangement. Genetic differentiation between pairs of sites was higher for inverted chromosomes than standard chromosomes, while inverted chromosomes had lower levels of genetic variation even well away from inversion breakpoints. Bayesian clustering analysis provided evidence of genetic exchange between chromosomal arrangements at each site. CONCLUSIONS: The strong differentiation between arrangements and reduced variation in the inverted chromosomes are likely to reflect ongoing selection at multiple loci within the inverted region. They may also reflect lower effective population sizes of In(2L)t chromosomes and colonization of Australia, although there was no consistent evidence of a recent bottleneck and simulations suggest that differences between arrangements would not persist unless rates of gene exchange between them were low. Genetic patterns therefore support the notion of selection and linkage disequilibrium contributing to inversion polymorphisms, although more work is needed to determine whether there are spatially varying targets of selection within this inversion. They also support the idea that the allelic content within an inversion can vary between geographic locations. PMID- 23688160 TI - Ambient-processable high capacitance hafnia-organic self-assembled nanodielectrics. AB - Ambient and solution-processable, low-leakage, high capacitance gate dielectrics are of great interest for advances in low-cost, flexible, thin-film transistor circuitry. Here we report a new hafnium oxide-organic self-assembled nanodielectric (Hf-SAND) material consisting of regular, alternating pi-electron layers of 4-[[4-[bis(2-hydroxyethyl)amino]phenyl]diazenyl]-1-[4 (diethoxyphosphoryl) benzyl]pyridinium bromide) (PAE) and HfO2 nanolayers. These Hf-SAND multilayers are grown from solution in ambient with processing temperatures <=150 degrees C and are characterized by AFM, XPS, X-ray reflectivity (2.3 nm repeat spacing), X-ray fluorescence, cross-sectional TEM, and capacitance measurements. The latter yield the largest capacitance to date (1.1 MUF/cm(2)) for a solid-state solution-processed hybrid inorganic-organic gate dielectric, with effective oxide thickness values as low as 3.1 nm and have gate leakage <10(-7) A/cm(2) at +/-2 MV/cm using photolithographically patterned contacts (0.04 mm(2)). The sizable Hf-SAND capacitances are attributed to relatively large PAE coverages on the HfO2 layers, confirmed by X-ray reflectivity and X-ray fluorescence. Random network semiconductor-enriched single walled carbon nanotube transistors were used to test Hf-SAND utility in electronics and afforded record on-state transconductances (5.5 mS) at large on:off current ratios (I(ON):I(OFF)) of ~10(5) with steep 150 mV/dec subthreshold swings and intrinsic field-effect mobilities up to 137 cm(2)/(V s). Large-area devices (>0.2 mm(2)) on Hf-SAND (6.5 nm thick) achieve mA on currents at ultralow gate voltages (<1 V) with low gate leakage (<2 nA), highlighting the defect-free and conformal nature of this nanodielectric. High-temperature annealing in ambient (400 degrees C) has limited impact on Hf-SAND leakage densities (<10(-6) A/cm(2) at +/-2 V) and enhances Hf-SAND multilayer capacitance densities to nearly 1 MUF/cm(2), demonstrating excellent compatibility with device postprocessing methodologies. These results represent a significant advance in hybrid organic-inorganic dielectric materials and suggest synthetic routes to even higher capacitance materials useful for unconventional electronics. PMID- 23688162 TI - Confirmed efficacy of topical nifedipine in the treatment of facial wrinkles. AB - INTRODUCTION: Over the past two decades, there has been increasing demand for aesthetic procedures to reverse the effects of aging, particularly in the facial area. Recently, topical nifedipine has been proposed for its anti-wrinkle efficacy. OBJECTIVE: To confirm the anti-wrinkle efficacy of a 0.5% nifedipine based topical formulation. MATERIALS AND METHODS: A randomized study was conducted in 20 healthy female volunteers, aged between 45 and 60 years, with moderate to moderately severe facial wrinkles. 10 volunteers applied a 0.5% nifedipine cream and 10 volunteers applied a good moisturizer twice daily for 90 days. The aesthetic improvement was evaluated by a blinded investigator using the Wrinkle Severity Rating Scale (WSRS). Anti-wrinkles effectiveness was also objectively assessed by measuring transepidermal water loss (TEWL), moisture levels of the stratum corneum, skin viscoelasticity and skin folding capacity by instrumental analysis. RESULTS: Post-treatment WSRS score was significantly lower than the baseline WSRS score only in the nifedipine group. The mean WSRS score at T0 was 3.85 and at T3 1.84 in the nifedipine group, while the mean WSRS score at T0 was 3.78 and at T3 3.36 in the control group. Corneometry showed significant increases in measures of skin hydration and TEWL values decreased in all the patients of both groups, indicating a trend toward improved integrity of skin. Dermolab(r) recorded significant increases in measures of skin hydration in the nifedipine group and a lower increase in the control group. The colorimetric evaluation showed that use of the tested product resulted in significant overall lightening of the skin during use compared with baseline, while the moisturizer didn't produce any change of skin lightening parameters. CONCLUSION: The tested topical preparation is effective in reducing facial wrinkles' depth and in increasing skin hydration and elasticity. PMID- 23688161 TI - Social determinants of health and periodontal disease in Brazilian adults: a cross-sectional study. AB - BACKGROUND: Recently, increasing importance has been placed on the social determinants of health and disease. The present study aimed to determine the prevalence of periodontal disease in Brazilian adults and identify possible relationships with social determinants. METHODS: A cross-sectional study was performed using a sample of 743 adults (aged 35-49 years) living in an urban area of a large city in southeastern Brazil. The condition of the periodontium was assessed using the Community Periodontal Index (CPI) according to the diagnostic criteria established by the World Health Organization (WHO). The variables related to social determinants were collected using a structured questionnaire. A descriptive analysis of all study variables was performed. Multiple correspondence analysis was subsequently performed to identify relationships between periodontal disease and the social determinants of health. RESULTS: The periodontal exams showed that 36.5% of adults had a healthy periodontium, 2.0% had gingival bleeding, 47.1% had calculus and 9.5% had periodontal pockets of 4-5 mm. Periodontal pockets of 6 mm or more were the worst periodontal condition found (affecting only 2.1% of the participants). The correspondence analysis enabled us to form three groups with different profiles. The first group was distinguished by the presence of bleeding (gingivitis) or a healthy periodontium. The members of this group were typically aged 35 to 39 years and had 9-12 years or more than 12 years of education. The second group consisted of subjects with calculus and periodontal pockets of 4-5 mm. The members of this group were typically white men aged 40-44 years with incomes greater than $ 300.00. The third group was distinguished by the presence of periodontal pockets of 6 mm or more. The members of this group were typically adult females, black and mixed individuals who had 8 years or less of schooling, individuals with incomes <= $ 300.00 and widowers. CONCLUSION: The results suggest that periodontal health is worse in the group for which the social indicators are worse. Therefore, the social determinants of health also affect the severity of periodontal disease in adults Brazilian society. PMID- 23688163 TI - Concise synthesis of the isothiourea organocatalysts homobenzotetramisole and derivatives. AB - A concise approach to the synthesis of homobenzotetramisole and derivatives is described. Our strategy features a one-pot acylation-cyclization of 2 aminobenzothiazole with alpha,beta-unsaturated acid chlorides to afford annulated pyrimidones. Subsequent Grignard addition followed by acid-promoted dehydration and reduction provides good overall yields of the title compounds in three steps and in quantities up to 10 g. The synthesis employs low-cost and readily available starting materials and enables access to both optical antipodes of these increasingly useful nucleophilic catalysts following chiral separation. PMID- 23688164 TI - International Journal of Psychiatry in clinical practice. PMID- 23688166 TI - IWBDA 2012 Special Issue. PMID- 23688168 TI - The roles of Notch1 expression in the migration of intrahepatic cholangiocarcinoma. AB - BACKGROUND: Notch signaling, a critical pathway for tissue development, contributes to tumorigenesis in many tissues; however, the roles of Notch signaling in Intrahepatic Cholangiocarcinoma (ICC) remains unclear. In this study, we evaluated the expression and effects of Notch1 on cell migration in ICC. METHODS: Multiple cellular and molecular approaches were performed including gene transfection, siRNA transfection, RT-PCR, Western blotting, Rac activation assays and immunofluorescence. RESULTS: We found that Notch1 was up-regulated in ICC tissues and cell lines. The exogenous expression of Notch1 in glioma cells increased their migratory and invasive capacity. Similarly, the suppression of Notch1 expression inactivated Rac1 and inhibited ICC cell migration. Notch1 over expression induced an Epithelial-to-mesenchymal transition (EMT) phenotype that included enhanced expression of alpha-SMA and Vimentin, loss of E-cadherin expression, morphological changes and cytoskeletal reorganization in ICC cells. CONCLUSION: Notch1 may induce a migratory effect in ICC by causing an epithelial mesenchymal transition and activating Rac1 and could serve as a novel diagnostic and therapeutic target in patients with ICC. PMID- 23688169 TI - Capability of hypertonic saline cough provocation test to predict the response to inhaled corticosteroids in chronic cough: a prospective, open-label study. AB - BACKGROUND: Many patients with chronic cough respond to treatment with inhaled corticosteroids but it is difficult to predict which patients are likely to respond. The primary aim of the present study was to define the capability of hypertonic saline cough provocation test to predict the responsiveness to inhaled corticosteroids in chronic cough. The secondary aim was to assess the ability of the saline test to monitor the healing of cough during corticosteroid treatment. METHODS: Forty-three patients with chronic cough were recruited. Before therapy, spirometry, ambulatory peak flow monitoring, nitric oxide measurement, histamine airway challenge, and saline test were performed. Those responding to the first saline test repeated it and the nitric oxide measurement during the subsequent visits. The patients used inhaled budesonide, 400 ug twice daily, for twelve weeks. The treatment response was assessed by Leicester Cough Questionnaire at baseline, and at one, four, and twelve weeks. RESULTS: Seventy-seven % of the patients demonstrated the minimal important difference in the Leicester Cough Questionnaire indicating a symptomatic response. Neither the response magnitude nor the speed was predicted by the saline test. Histamine challenge showed the strongest predictive ability: The maximal improvement in Leicester Cough Questionnaire total score was 5.08 (3.76 - 6.40) points in the histamine positive and 2.78 (1.55 - 4.01) points in the histamine negative subjects (p = 0.006). Baseline nitric oxide level also associated with the improvement in Leicester Cough Questionnaire total score (p = 0.02). During the treatment, the cough sensitivity to saline gradually decreased among the budesonide responders but not in the non-responders. Nitric oxide levels decreased very rapidly among the responders. CONCLUSIONS: Saline test cannot predict the responsiveness to inhaled corticosteroids in chronic cough but it may be utilized to monitor the effect of this treatment. TRIAL REGISTRATION: The study was registered in ClinicalTrials.gov database (KUH5801112). ClinicalTrials.gov Identifier: NCT00859274. PMID- 23688170 TI - Meritocratic sharing is based on collaboration in 3-year-olds. AB - The present study investigated young preschoolers' proportional allocation of rewards in 2 different work contexts. We presented 32 pairs of 3.5-year-old peers with a collaborative task to obtain rewards by pulling ropes. In order to establish differences in work input, 1 child's rope was not immediately accessible but had to be retrieved from the apparatus by means of a specific tool, while the other child had no such additional work to do. The result of the game was that 1 individual received 1 toy and the other received 3 toys. In the Deserving condition, the working child received the 3 toys (thus work and reward matched), whereas in the Undeserving condition, the other child received the 3 toys (he or she was overpaid, and the working child was underpaid). Another 32 dyads participated in a noncollaborative, parallel work task, again in a Deserving condition and an Undeserving condition. On average, children with 3 toys shared with their partner more in the Undeserving condition than in the Deserving condition after collaboration but not in a parallel work setup. These results suggest that young children take merit into account in distributing resources at a much younger age than previously believed and that peer collaboration is an especially facilitative context for children's attention to norms of fairness. PMID- 23688171 TI - The role of popularity goal in early adolescents' behaviors and popularity status. AB - The effect of popularity goal on the use of 3 popularity-related behaviors and later popularity status was examined in a diverse sample of 314 6th-grade students (176 girls and 138 boys) in both fall (Time 1) and spring (Time 2) semesters. Popularity goal and the use of popularity-driven behaviors (e.g., "I change the way I dress in order to be more popular") were assessed by self-report survey items (Time 1). Physical aggression, social aggression (Time 1), and perceived popularity (Times 1 and 2) were assessed by peer nominations. Popularity goal was positively associated with popularity-driven behaviors, social aggression, and physical aggression. There was a significant interaction effect between popularity goal and popularity status on the use of concurrent social aggression at Time 1; a higher popularity goal was associated with greater usage of social aggression for high-popular adolescents. Popularity goal alone did not predict popularity status change at Time 2; rather, greater use of social aggression at Time 1 was associated with higher Time 2 popularity status for initially high-popular adolescents who had a high-popularity goal and for initially low-popular adolescents who had a low-popularity goal. A similar 3-way interaction effect was found for physical aggression. Results suggest that the adolescents' goal for popularity may help us better understand the functions of aggressive and popularity-driven behaviors in peer social networks. PMID- 23688172 TI - When will Little Red Riding Hood become scared? Children's attribution of mental states to a story character. AB - As children listen to a simple action-based narrative, they construct a dynamic representation of the protagonist's movements, visual perspective, and goal directed thoughts. We examined children's representations of more complex narratives in which the protagonist will encounter an unexpected outcome upon reaching his or her goal. Three studies involving 105 children between 3 and 6 years of age showed that children shifted in the mental states they attributed depending on the distance of the protagonist from the unexpected outcome. Even though children consistently recognized that the protagonist did not know about the surprise at any point, they increasingly attributed feelings and thoughts consistent with the surprise. The studies highlight the degree to which children's mental state attributions are dynamic rather than fixed by their current theory of mind. PMID- 23688173 TI - Working memory training and transfer in older adults: effects of age, baseline performance, and training gains. AB - Recent studies suggest that working memory training may benefit older adults; however, findings regarding training and transfer effects are mixed. The current study aimed to investigate the effects of a process-based training intervention in a diverse sample of older adults and explored possible moderators of training and transfer effects. For that purpose, 80 older adults (65-95 years) were assigned either to a training group that worked on visuospatial, verbal, and executive working memory tasks for 9 sessions over 3 weeks or to a control group. Performance on trained and transfer tasks was assessed in all participants before and after the training period, as well as at a 9-month follow-up. Analyses revealed significant training effects in all 3 training tasks in trained participants relative to controls, as well as near transfer to a verbal working memory task and far transfer to a fluid intelligence task. Encouragingly, all training effects and the transfer effect to verbal working memory were stable at the 9-month follow-up session. Further analyses revealed that training gains were predicted by baseline performance in training tasks and (to a lesser degree) by age. Gains in transfer tasks were predicted by age and by the amount of improvement in the trained tasks. These findings suggest that cognitive plasticity is preserved over a large range of old age and that even a rather short training regime can lead to (partly specific) training and transfer effects. However, baseline performance, age, and training gains moderate the amount of plasticity. PMID- 23688174 TI - Effectiveness of nutrition training of health workers toward improving caregivers' feeding practices for children aged six months to two years: a systematic review. AB - BACKGROUND: Nutrition training of health workers can help to reduce child undernutrition. Specifically, trained health workers might contribute to this end through frequent nutrition counseling of caregivers. This may improve child feeding practices and thus reduce the risk of undernutrition among children of counseled caregivers. Although studies have shown varied impacts of health workers' nutrition training on child feeding practices, no systematic review of the effectiveness of such intervention has yet been reported. Therefore, we conducted this study to examine the effectiveness of nutrition training for health workers on child feeding practices including feeding frequency, energy intake, and dietary diversity among children aged six months to two years. METHODS: We searched the literature for published randomized controlled trials (RCTs) and cluster RCTs using medical databases including PubMed/MEDLINE, CINAHL, EMBASE, and ISI Web of Knowledge, and through WHO regional databases. Our intervention of interest was nutrition training of health workers. We pooled the results of the selected trials, evaluated them using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) criteria, and calculated the overall effect size of the intervention in meta-analyses. RESULTS: Ten RCTs and cluster RCTs out of 4757 retrieved articles were eligible for final analyses. Overall, health workers' nutrition training improved daily energy intake of children between six months and two years of age. The pooled evidence from the three studies reporting mean energy intake per day revealed a standardized mean difference (SMD) of 0.76, 95% CI (0.63-0.88). For the two studies with median energy intake SMD was 1.06 (95% CI 0.87-1.24). Health workers' nutrition training also improved feeding frequency among children aged six months to two years. The pooled evidence from the three studies reporting mean feeding frequency showed an SMD of 0.48 (95% CI 0.38-0.58). Regarding dietary diversity, children in intervention groups were more likely to consume more diverse diets compared to their counterparts. CONCLUSION AND RECOMMENDATIONS: Nutrition training for health workers can improve feeding frequency, energy intake, and dietary diversity of children aged six months to two years. Scaling up of nutrition training for health workers presents a potential entry point to improve nutrition status among children. PMID- 23688175 TI - Economic and ecological costs and benefits of streamflow augmentation using recycled water in a California coastal stream. AB - Streamflow augmentation has the potential to become an important application of recycled water in water scarce areas. We assessed the economic and ecological merits of a recycled water project that opted for an inland release of tertiary treated recycled water in a small stream and wetland compared to an ocean outfall discharge. Costs for the status-quo scenario of discharging secondary-treated effluent to the ocean were compared to those of the implemented scenario of inland streamflow augmentation using recycled water. The benefits of the inland discharge scenario were greater than the increase in associated costs by US$1.8M, with recreational value and scenic amenity generating the greatest value. We also compared physical habitat quality, water quality, and benthic macroinvertebrate community upstream and downstream of the recycled water discharge to estimate the effect of streamflow augmentation on the ecosystem. The physical-habitat quality was higher downstream of the discharge, although streamflow came in unnatural diurnal pulses. Water quality remained relatively unchanged with respect to dissolved oxygen, pH, and ammonia-nitrogen, although temperatures were elevated. Benthic macroinvertebrates were present in higher abundances, although the diversity was relatively low. A federally listed species, the California red legged frog (Rana draytonii), was present. Our results may support decision making for wastewater treatment alternatives and recycled water applications in Mediterranean climates. PMID- 23688177 TI - Single-cell force spectroscopy, an emerging tool to quantify cell adhesion to biomaterials. AB - Cell adhesion receptors play a central role in sensing and integrating signals provided by the cellular environment. Thus, understanding adhesive interactions at the cell-biomaterial interface is essential to improve the design of implants that should emulate certain characteristics of the cell's natural environment. Numerous cell adhesion assays have been developed; among these, atomic force microscopy-based single-cell force spectroscopy (AFM-SCFS) provides a versatile tool to quantify cell adhesion at physiological conditions. Here we discuss how AFM-SCFS can be used to quantify the adhesion of living cells to biomaterials and give examples of using AFM-SCFS in tissue engineering and regenerative medicine. We anticipate that in the near future, AFM-SCFS will be established in the biomaterial field as an important technique to quantify cell-biomaterial interactions and thereby will contribute to the optimization of implants, scaffolds, and medical devices. PMID- 23688176 TI - Effect of Aedes aegypti exposure to spatial repellent chemicals on BG-SentinelTM trap catches. AB - BACKGROUND: An integrated approach to reduce densities of adult Aedes aegypti inside homes is currently being evaluated under experimentally controlled field conditions. The strategy combines a spatial repellent (SR) treatment (applied indoors) with the Biogents SentinelTM (BGS) mosquito trap positioned in the outdoor environment. In essence, when combined, the goal is to create a push-pull mechanism that will reduce the probability of human-vector contact. The current study measured BGS recapture rates of Ae. aegypti test cohorts that were exposed to either SR or control (chemical-free) treatments within experimental huts. The objective was to define what, if any, negative impact SR may have on BGS trap efficacy (i.e., reduced BGS collection). METHODS: Aedes aegypti females were exposed to SR compounds within experimental huts in the form of either treated fabric (DDT and transfluthrin) or mosquito coil (metofluthrin). Test cohorts were released within individual screen house cubicles, each containing 4 BGS traps, following SR exposure according to treatment. Two separate test cohorts were evaluated: (i) immediate release (IR) exposed from 06:00-12:00 hours and released at 12:00 hours and (ii) delayed release (DR) exposed from12:00-18:00 hours and released at 05:30 hours the following day. BGS recapture was monitored at 09:30, 13:30 and 15:30 hours and the cumulative recapture by time point quantified. RESULTS: Exposure of Ae. aegypti females to either DDT or metofluthrin did not significantly impact BGS capture as compared to cohorts of non-exposed females. This was true for both IR and DR exposure populations. IR cohorts exposed to transfluthrin resulted in significantly lower BGS recapture compared to matched controls but this effect was primarily due to high mosquito mortality during transfluthrin trials. CONCLUSION: Our data indicate no more than minor and short lived impacts (i.e., reduced attraction) on BGS trap catches following exposure to the pyrethroid compounds transfluthrin and metofluthrin and no change in recapture densities using DDT as compared to matched controls. These findings suggest a combined SR and BGS approach to vector control could function as a push pull strategy to reduce Ae. aegypti adults in and around homes. PMID- 23688179 TI - Constructing high-efficiency D-A-pi-A-featured solar cell sensitizers: a promising building block of 2,3-diphenylquinoxaline for antiaggregation and photostability. AB - Controlling the sensitizer morphology on a nanocrystalline TiO2 surface is beneficial to facilitating electron injection and suppressing charge recombination. Given that the grafted alkyl chain on a pi-bridge thiophene segment for preventing pi aggregation can deteriorate its intrinsic photostability, we incorporate a promising building block of 2,3 diphenylquinoxaline as the additional acceptor to construct a novel D-A-pi-A featured dye IQ4, which exhibits several characteristics: (i) efficiently decreasing the molecular HOMO-LUMO energy gap by extending its absorption bands; (ii) showing a moderate electron-withdrawing capability for an ideal balance in both promising photocurrent and photovoltage; (iii) endowing an ideal morphology control with strong capability of restraining the intermolecular aggregation and facilitating the formation of a compact sensitizer layer via two twisted phenyl groups grafted onto the quinoxaline unit. The coadsorbent-free dye-sensitized solar cell (DSSC) based on dye IQ4 exhibits very promising conversion efficiency as high as 9.24 +/- 0.05%, with a short-circuit current density (Jsc) of 17.55 mA cm(-2), an open-circuit voltage (Voc) of 0.74 V, and a fill factor (FF) of 0.71 under AM 1.5 illumination (100 mW cm(-2)). IQ4-based DSSC devices with an ionic liquid electrolyte can keep constant performance during a 1000 h aging test under 1 sun at 60 degrees C. Because of spatial restriction, the two phenyl groups grafted onto the additional electron-withdrawing quinoxaline are demonstrated as efficient building blocks, not only improving its photostability and thermal stability but also allowing it to be a successful antiaggregation functional unit. As a consequence, the incorporated 2,3-diphenylquinoxaline unit can realize a facile structural modification for constructing organic coadsorbent-free D-A-pi A-featured sensitizers, thus paving a way to replace the common, stability deleterious grafted alkyl chain on the thienyl bridge. PMID- 23688178 TI - County-level characteristics as predictors of dentists' ECC counseling in the USA: a survey study. AB - BACKGROUND: Transmission of Streptococcus mutans from mother-to-child can lead to Early Childhood Caries. A previous study identified characteristics and beliefs of general dentists about counseling pregnant women to reduce risk of infection and Early Childhood Caries. This study extends those findings with an analysis of county level factors. METHODS: In 2006, we surveyed 732 general dentists in Oregon, USA about dental care for pregnant women. Survey items asked about individual and practice characteristics. In the present study we matched those data to county level factors and used multinomial logistic regression to test the effects of the factors (i.e., dentist to population ratio, percentage of female dentists, percentage of females of childbearing age, and percentage of individuals living in poverty) on counseling behavior. RESULTS: County level factors were unrelated to counseling behavior when the models controlled for dentists' individual attitudes, beliefs, and practice level characteristics. The adjusted odds ratios for no counseling of pregnant patients (versus 100 percent counseling) were 1.1 (95% CI .8-1.7), 1.0 (1.0-1.1), 1.2 (.9-1.5), and 1.1 (1.0 1.2) for dentist/population ratio, percent female dentists, percent females of childbearing age, and percent in poverty, respectively Similar results were obtained when dentists who counseled some patients were compared to those counseling 100 percent of patients. CONCLUSIONS: Community level factors do not appear to impact the individual counseling behavior of general dentists in Oregon, USA regarding the risk of maternal transmission of Early Childhood Caries. PMID- 23688181 TI - Hydration of barium monohydroxide in (H2O)(1-3) clusters: theory and experiment. AB - The ionization energies (IEe's) of small BaOH(H2O)m clusters (m = 1-3), as generated in a laser vaporization-supersonic expansion source have been determined by laser photoionization experiments over the 3.65-4.55 eV energy range. Complementary ab initio studies show that the IEe's are in good agreement with computed adiabatic ionization energies and that BaOH(H2O)m structures with a direct coordination of the Ba atom to water molecules are favored over those that are characterized by H-bonded networks involving H2O molecules and the OH group of BaOH. Additional calculations have been performed on the hydration energies for the most stable isomers of the relevant BaOH(H2O)1-3 clusters. A comparison is made between the closed-shell title system and the results of related theoretical studies on the open-shell alkali monohydroxides, which allows for an interpretation of the opposite trends that are found in the cluster size dependence of the vertical ionization energies for both series of systems, and highlights the role of the BaOH unpaired electron in its ionization process. Altogether, the present evidence suggests for the initial steps of the BaOH hydration process to be dominated by electrostatic and polarization interactions between the Ba(+) and OH(-) ion cores, which become both increasingly solvated upon sequential addition of water molecules. PMID- 23688180 TI - Examination of mid-intervention mediating effects on objectively assessed sedentary time among children in the Transform-Us! cluster-randomized controlled trial. AB - BACKGROUND: The optimal targets and strategies for effectively reducing sedentary behavior among young people are unknown. Intervention research that explores changes in mediated effects as well as in outcome behaviors is needed to help inform more effective interventions. Therefore, the purpose of this study was to examine the mid-intervention mediating effects on children's objectively assessed classroom and total weekday sedentary time in the Transform-Us! intervention. METHODS: The results are based on 293 children, aged 7- to 9-years-old at baseline, from 20 schools in Melbourne, Australia. Each school was randomly allocated to one of four groups, which targeted reducing sedentary time in the school and family settings (SB; n = 74), increasing or maintaining moderate- to vigorous-intensity physical activity in the school and family settings (PA; n = 75), combined SB and PA (SB + PA; n = 80), or the current practice control (C; n = 64). Baseline and mid-intervention data (5-9 months) were collected in 2010 and analyzed in 2012. Classroom and total weekday sedentary time was objectively assessed using ActiGraph accelerometers. The hypothesized mediators including, child enjoyment, parent and teacher outcome expectancies, and child perceived access to standing opportunities in the classroom environment, were assessed by questionnaire. RESULTS: The SB + PA group spent 13.3 min/day less in weekday sedentary time at mid-intervention compared to the control group. At mid intervention, children in the SB group had higher enjoyment of standing in class (0.9 units; 5-unit scale) and all intervention groups had more positive perceptions of access to standing opportunities in the classroom environment (0.3 0.4 units; 3-unit scale), compared to the control group. However, none of the hypothesized mediator variables had an effect on sedentary time; thus, no mediating effects were observed. CONCLUSIONS: While beneficial intervention effects were observed on some hypothesized mediating variables and total weekday sedentary time at mid-intervention, no significant mediating effects were found. Given the dearth of existing information, future intervention research is needed that explores mediated effects. More work is also needed on the development of reliable mediator measures that are sensitive to change overtime. TRIAL REGISTRATION: ACTRN12609000715279. ISRCTN83725066. PMID- 23688182 TI - Reintroductions and genetic introgression from domestic pigs have shaped the genetic population structure of Northwest European wild boar. AB - BACKGROUND: Population genetic studies focus on natural dispersal and isolation by landscape barriers as the main drivers of genetic population structure. However, anthropogenic factors such as reintroductions, translocations and wild x domestic hybridization may also have strong effects on genetic population structure. In this study we genotyped 351 Single Nucleotide Polymorphism markers evenly spread across the genome in 645 wild boar (Sus scrofa) from Northwest Europe to evaluate determinants of genetic population structure. RESULTS: We show that wild boar genetic population structure is influenced by historical reintroductions and by genetic introgression from domestic pigs. Six genetically distinct and geographically coherent wild boar clusters were identified in the Netherlands and Western Germany. The Dutch Veluwe cluster is known to be reintroduced, and three adjacent Dutch and German clusters are suspected to be a result of reintroduction, based on clustering results, low levels of heterozygosity and relatively high genetic distances to nearby populations. Recent wild x domestic hybrids were found geographically widespread across clusters and at low frequencies (average 3.9%). The relationship between pairwise kinship coefficients and geographic distance showed male-biased dispersal at the population genetic level. CONCLUSIONS: Our results demonstrate that wildlife and landscape management by humans are shaping the genetic diversity of an iconic wildlife species. Historical reintroductions, translocation and recent restocking activities with farmed wild boar have all influenced wild boar genetic population structure. The current trend of wild boar population growth and range expansion has recently led to a number of contact zones between clusters, and further admixture between the different wild boar clusters is to be expected. PMID- 23688183 TI - Polymorphisms and high on-aspirin platelet reactivity after off-pump coronary artery bypass grafting. AB - OBJECTIVES: High on-aspirin residual platelet reactivity (RPR) after coronary artery bypass grafting (CABG) is a transient phenomenon with important implications for graft patency. This study was designed to determine the role of polymorphisms [TBXA2R (T924C), GPIIIa (Pl(A1/A2)), P2Y1 (A1622G), and GP1Balpha (C1018T)] on RPR in Chinese patients undergoing off-pump CABG (OPCAB). METHODS: Of 420 patients recruited to this study, 210 patients underwent primary OPCAB and 210 controls with ischemic heart disease received optimal medical therapy. Arachidonic acid-induced platelet aggregation and urinary 11-dehydro thromboxane B2 were measured at baseline and following aspirin administration on days 1, 4, 10, and on 6th month. Four polymorphisms were identified [TBXA2R (T924C), P2Y1 (A1622G), Pl(A1/A2) and GP1Balpha (C1018T)]. RESULTS: On the first post-operative day, 62 patients (29.5%) were with high RPR and 148 (70.5%) were with low RPR. Of the former, 33 (15.7%), 10 (4.6%), and 0 (0%) patients remained with high RPR on days 4, 10, and on 6 month, respectively. No individuals with high RPR was found in controls. Logistic regression identified TBXA2R-924TT (OR = 4.5; 95% CI, 1.8 11.1) and body mass index > 27 kg/m(2) (OR = 2.73; 95% CI, 1.1-7.0) as independent risk factors for high on-aspirin RPR. CONCLUSIONS: High on-aspirin RPR after OPCAB is associated with genetic polymorphism TBXA2R-924TT and obesity. PMID- 23688184 TI - Synthesis and structure of bull's horn-shaped oligothienoacene with seven fused thiophene rings. AB - A novel bull's horn-shaped oligothienoacene with seven fused thiophene rings (1) based on dithieno[2,3-b:2',3'-d]thiophene (2) was efficiently synthesized. X-ray diffraction data indicate that 1 possesses an extraordinary compressed sandwich herringbone arrangement and shows strong intermolecular S...C and S...S interactions. In addition, the UV/vis properties, theoretical calculations, and cyclic voltammetry behaviors of 1 are also described. PMID- 23688185 TI - Phototherapy trends in dermatology. AB - BACKGROUND: Use of phototherapy in the United States declined during the 1990s, largely due to unfavorable economic incentives. The trends in phototherapy since then are not well characterized. METHODS: We analyzed the National Ambulatory Medical Care Survey (NAMCS) data on quantity of phototherapy visits and associated diagnoses and payment sources. Trends were assessed by linear regression. RESULTS: There were an estimated 230 000 outpatient phototherapy visits per year, with an increasing trend over time (p = 0.03). Dermatologists managed 87% of the visits. Leading diagnoses associated with phototherapy included psoriasis (25%), dermatitis NOS (6%), vitiligo (6%), other dyschromia (6%), and actinic keratosis (5%). CONCLUSIONS: Use of phototherapy for psoriasis has remained relatively low up to 2010. However, phototherapy may be becoming more frequent for conditions other than psoriasis. PMID- 23688186 TI - Areca nut chewing and metabolic syndrome: evidence of a harmful relationship. AB - BACKGROUND: There is some evidence which suggests that areca nut chewing has a relationship with metabolic syndrome. Areca nut chewing is continue to increase and so is the metabolic syndrome which is a major cause of cardiovascular mortality in developing countries. The aim of this study was to determine the relationship of raw areca nut and areca nut chewing with tobacco additives and metabolic syndrome. METHODS: This cross sectional study was conducted on population of Karachi, Pakistan. Simple random sampling was implied using the voter list as a sampling frame. A detailed questionnaire about the demographic details of all subjects was filled and an informed consent obtained for blood sampling. Logistic regression analyses were carried out to investigate the relationship between areca nut chewing and metabolic syndrome. RESULTS: Of the 1070 individuals, 192(17.9%) had metabolic syndrome with significantly higher (p value <0.001) prevalence among females (26.3%) compared with males (11.4%). Eight individuals (11.1%) among non users had metabolic syndrome while significantly higher (p-value <0.001) proportion of both, raw areca nut users (n = 67, 29%) and areca users with tobacco additives (n = 45, 38.5%) had metabolic syndrome.The crude odds ratio for central obesity among raw areca nut users was 1.46 (95% CI 1.07-1.98) and among areca nut users with tobacco additives was 2.02 (95% CI 1.36 3.00), hypertension among raw areca nut users group was 1.31(0.96-1.78) and among areca nut users with tobacco additives group was 2.05 (95% CI 1.38-3.04). A significant positive association of raw areca nut chewing and metabolic syndrome was found among males (crude OR 2.74, 95% CI 1.52-4.95) and females (crude OR 3.80, 95% CI 2.32-6.20). Similarly, a significant positive association was found with regard to raw areca nut with tobacco additives chewing among males (crude OR 5.46, 95% CI 2.73-10.91) and females (crude OR 4.32, 95% CI 2.41-7.72). These associations remained significant adjustment for age, social class. CONCLUSIONS: This study suggests a harmful relationship between areca nut chewing and metabolic syndrome. The deleterious effects were even stronger among areca nut chewer with tobacco additives. Further research with longitudinal data might help to understand the temporal relationship between areca nut chewing and metabolic syndrome. PMID- 23688187 TI - Systematic analysis of proteomes with emphasis on insertions in malaria parasite Plasmodium falciparum. AB - Protein insertion sequences and their biological role in many organisms have been largely unknown. Here we study proteomes of 12 organisms of diverse genomes for insertion length and amino acid preferences. A total of 871 common proteins were catalogued amongst the 12 organisms for structure based sequence alignment. This underscores the key observations: (i) AT-richness seems to have no implication on the average protein length in an organism as only Dictyostelium discoideum and Plasmodium falciparum encode proteins of high average length (ii) all studied organisms possess insertion in their proteins, however > 40 residue length insertions and unique insertions were abundant in pathogen proteomes of Plasmodium falciparum followed by Toxoplasma gondii and Leishmania major, suggesting accessory structural and functional features that may favour evolutionary fitness. (iii) Glu and Asp residues are over-represented in most proteomes irrespective of AT/GC compositions or pathogenecity with an exception of Plasmodium falciparum where Asn dominates (iv) Abundance of Asn residues in Plasmodium falciparum is exceptional given that this feature is not common to other AT-rich genomes. In conclusion, this bioinformatics based study provides comprehensive knowledge of insertions and residue's preference among pathogen proteins, which can be exploited for further inhibitor studies. PMID- 23688188 TI - Analysis of proteins associated with ozone stress response in soybean cultivars. AB - Ozone stress induces leaf injuries and yield losses in soybean. To identify the proteins associated with the stress response, ozone tolerant and sensitive cultivars were analyzed by 2D-PAGE. After 11 days of ozone stress unifoliate leaves of tolerant soybean cv. Enrei developed 15% and sensitive cv. Nakasennari developed 52% leaf injury symptoms. Analysis of proteins in the unifoliate leaves identified six proteins in tolerant cv. Enrei and three proteins in sensitive cv. Nakasennari, responded significantly to ozone stress. The significantly responded proteins identified in this study were ATP synthase alpha-subunit, ATP synthase beta-subunit, phosphoglycerate kinase, aldo/ketoreductase, rubiscoactivase and glutamine synthetase. To understand that the differences in response of ATP synthase proteins were ultimately associated with extracellular ATP signaling response, ozone sensitive cv. Nakasennari was treated with 1 mM ATP. Unifoliate leaves of ATP treated plants have significantly reduced injury symptoms (20%) under ozone stress compare to control plants (47%). This confirms that extracellular ATP signaling in ATP synthase dependent manner is playing a pivotal role in inducing ozone stress tolerance and preventing injuries in soybean cultivars. PMID- 23688190 TI - Total synthesis of (+/-)-Gelsemoxonine. AB - Gelsemoxonine (1) is a Gelsemium alkaloid incorporating an unusual azetidine. Its total synthesis was achieved employing a novel ring contraction of a spirocyclopropane isoxazolidine to furnish a beta-lactam intermediate. This beta lactam ring was further elaborated into the azetidine of Gelsemoxonine. In addition, the synthesis includes a highly diastereoselective reductive Heck cyclization for the installation of the oxindole ring system as well as a directed hydrosilylation of an alkyne to access the ethyl ketone of the natural product. PMID- 23688189 TI - IR/IGF1R signaling as potential target for treatment of high-grade osteosarcoma. AB - BACKGROUND: High-grade osteosarcoma is an aggressive tumor most often developing in the long bones of adolescents, with a second peak in the 5th decade of life. Better knowledge on cellular signaling in this tumor may identify new possibilities for targeted treatment. METHODS: We performed gene set analysis on previously published genome-wide gene expression data of osteosarcoma cell lines (n=19) and pretreatment biopsies (n=84). We characterized overexpression of the insulin-like growth factor receptor (IGF1R) signaling pathways in human osteosarcoma as compared with osteoblasts and with the hypothesized progenitor cells of osteosarcoma - mesenchymal stem cells. This pathway plays a key role in the growth and development of bone. Since most profound differences in mRNA expression were found at and upstream of the receptor of this pathway, we set out to inhibit IR/IGF1R using OSI-906, a dual inhibitor for IR/IGF1R, on four osteosarcoma cell lines. Inhibitory effects of this drug were measured by Western blotting and cell proliferation assays. RESULTS: OSI-906 had a strong inhibitory effect on proliferation of 3 of 4 osteosarcoma cell lines, with IC50s below 100 nM at 72 hrs of treatment. Phosphorylation of IRS-1, a direct downstream target of IGF1R signaling, was inhibited in the responsive osteosarcoma cell lines. CONCLUSIONS: This study provides an in vitro rationale for using IR/IGF1R inhibitors in preclinical studies of osteosarcoma. PMID- 23688191 TI - Growth and the cancer caregiving experience: psychometric properties of the Portuguese Posttraumatic Growth Inventory. AB - The purpose of the present study was to investigate the psychometric properties of the Portuguese version of the Posttraumatic Growth Inventory (PTGI) and relate posttraumatic growth with psychological morbidity. This is a cross-sectional study with a sample of 214 adult children of cancer patients. Additionally, a comparison group was recruited with 78 participants without a chronically ill parent. Measures of distress, posttraumatic stress disorder (PTSD) symptoms, and posttraumatic growth were collected. The original five-factor structure of the PTGI was maintained, with satisfactory internal consistency. The reorganization of the items in five factors was similar to the solution found in the original PTGI study, except for four items. Positive correlations between posttraumatic growth and PTSD symptoms/distress were significant. Women showed significantly higher posttraumatic growth. Adult children with parental cancer, and with probable PTSD, showed higher scores on the PTGI. Regression analysis revealed that PTSD symptoms were associated with higher posttraumatic growth, after controlling for demographic and clinical variables. Analysis with the comparison group showed that differences in posttraumatic growth were observed as a function of a shattered experience. This study confirmed the multidimensionality of the posttraumatic growth construct, underscoring the importance of considering the subjective nature of the shattered event, and the experience of emotional distress with parental cancer. PMID- 23688192 TI - Porous substoichiometric TiO2 anodes as reactive electrochemical membranes for water treatment. AB - This research investigates the characterization and testing of an anodic reactive electrochemical membrane (REM) for water treatment. The REM consists of a porous substoichiometric titanium dioxide (Ti4O7) tubular, ceramic electrode operated in cross-flow filtration mode. Advection-enhanced mass transfer rates, on the order of a 10-fold increase, are obtained when the REM is operated in filtration-mode, relative to a traditional flow-through mode. Oxidation experiments with model organic compounds showed that the REM was active for both direct oxidation reactions and formation of hydroxyl radicals (OH(*)). Electrochemical impedance spectroscopy data interpreted by transmission line modeling determined that the electro-active surface area was 619 times the nominal geometric surface area. Results from filtration-mode experiments with p-methoxyphenol indicate that compound removal occurred by electro-assisted adsorption and subsequent oxidation. Electro-assisted adsorption was the primary removal mechanism at potentials where OH(*) did not form. At higher potentials (>2.0 V), where OH(*) concentrations were significant, p-methoxyphenol removal occurred by a combination of electro-assisted adsorption and OH(*) oxidation. These removal mechanisms resulted in 99.9% p-methoxyphenol removal in the permeate, with calculated current efficiencies >73% at applied current densities of 0.5-1.0 mA cm(-2). These results illustrate the extreme promise of the REM for water treatment. PMID- 23688193 TI - Transformation of a post-cesarean section placental site nodule into a coexisting epithelioid trophoblastic tumor and placental site trophoblastic tumor: a case report. AB - Placental site nodules (PSNs) and epithelioid trophoblastic tumors (ETTs) respectively represent non-neoplastic and neoplastic lesions of chorionic-type intermediate trophoblasts (ITs). Many patients with a PSN have a history of a cesarean section (CS) or therapeutic abortion. Recent evidence shows that a PSN may progress to an ETT. Herein, we describe a coexisting ETT and placental site trophoblastic tumor (PSTT) intimately associated with PSNs in the post-cesarean lower uterine segment of a 41-year-old woman. The patient presented with abnormal vaginal bleeding 1 year after a cesarean delivery for her most recent pregnancy. We speculated that the neoplasms had transformed from PSNs, the formation of which was related to faulty expulsion of the placental tissue or abnormal colonization of chorionic-type ITs during the CS. Neoplastic trophoblastic cells derived from PSNs displayed differentiation plasticity toward chorionic-type ITs and implantation site ITs that were respectively constituted of an ETT and PSTT. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1597949195882123. PMID- 23688195 TI - Detection of mRNA of the cyclin D1 breast cancer marker by a novel duplex-DNA probe. AB - Previously, we have described 5-((4-methoxy-phenyl)-trans-vinyl)-2'-deoxy uridine, 6, as a fluorescent uridine analogue exhibiting a 3000-fold higher quantum yield (Phi 0.12) and maximum emission (478 nm) which is 170 nm red shifted as compared to uridine. Here, we utilized 6 for preparation of labeled oligodeoxynucleotide (ODN) probes based on MS2 and cyclin D1 (a known breast cancer mRNA marker) sequences. Cyclin D1-derived labeled-ssODN showed a 9.5-fold decrease of quantum yield upon duplex formation. On the basis of this finding, we developed the ds-NIF (nucleoside with intrinsic fluorescence)-probe methodology for detection of cyclin D1 mRNA, by which the fluorescent probe is released upon recognition of target mRNA by the relatively dark NIF-duplex-probe. Indeed, we successfully detected, a ss-deoxynucleic acid (DNA) variant of cyclin D1 mRNA using a dark NIF-labeled duplex-probe, and monitoring the recognition process by fluorescence spectroscopy and gel electrophoresis. Furthermore, we successfully detected cyclin D1 mRNA in RNA extracted from cancerous human cells, using ds-NIF methodology. PMID- 23688194 TI - Diversity and function of bacterial microbiota in the mosquito holobiont. AB - Mosquitoes (Diptera: Culicidae) have been shown to host diverse bacterial communities that vary depending on the sex of the mosquito, the developmental stage, and ecological factors. Some studies have suggested a potential role of microbiota in the nutritional, developmental and reproductive biology of mosquitoes. Here, we present a review of the diversity and functions of mosquito associated bacteria across multiple variation factors, emphasizing recent findings. Mosquito microbiota is considered in the context of possible extended phenotypes conferred on the insect hosts that allow niche diversification and rapid adaptive evolution in other insects. These kinds of observations have prompted the recent development of new mosquito control methods based on the use of symbiotically-modified mosquitoes to interfere with pathogen transmission or reduce the host life span and reproduction. New opportunities for exploiting bacterial function for vector control are highlighted. PMID- 23688196 TI - The effects of vitamins C and B12 on human nasal ciliary beat frequency. AB - BACKGROUND: This study was designed to investigate the effects of the vitamins C and B12 on the regulation of human nasal ciliary beat frequency (CBF). METHODS: Human nasal mucosa was removed endoscopically and nasal ciliated cell culture was established. Changes of CBF in response to different concentrations of vitamin C or vitamin B12 were quantified by using high-speed (240 frames per second) digital microscopy combined with a beat-by-beat CBF analysis. RESULTS: At the concentrations of 0.01% and 0.10%, vitamin C induced an initial increase, followed by a gradual decrease of CBF to the baseline level, while 1.00% vitamin C induced a reversible decrease of CBF. Vitamin B12, at the concentrations of 0.01% and 0.10%, did not influence CBF during the 20-min observation period, while a 1.00% vitamin B12 treatment caused a time-dependent but reversible decrease of CBF. CONCLUSIONS: Treatment with vitamin C or vitamin B12 caused a concentration-dependent but reversible decrease of CBF in cultured human nasal epithelial cells. Therefore, it is necessary to choose a concentration that is safe, effective, and non-ciliotoxic when applying these drugs topically in the nasal cavity. PMID- 23688197 TI - The differential effects of PNF versus passive stretch conditioning on neuromuscular performance. AB - The effects of flexibility conditioning on neuromuscular and sensorimotor performance were assessed near to full knee extension (25 degrees ). Eighteen males who were randomly assigned into two groups underwent eight weeks (three times per week) of flexibility conditioning (hip region/knee flexor musculature; dominant limb) involving either proprioceptive neuromuscular facilitation (PNF) (n=9) or passive stretching (PASS) (n=9). Both modes of flexibility conditioning are popular within contemporary exercise and clinical settings and have demonstrated efficacy in improving range of motion. The contralateral limb and a prior 'no exercise' condition were used as controls. The PNF and PASS modes of conditioning improved passive hip flexibility to a similar extent (mean 19.3% vs. baseline, intervention limb, p<0.01) but did not alter knee flexor strength (overall mean 309.6+/-81 N) or sensorimotor performance (force and positional errors: 2.3+/-8.2% and 0.48+/-7.1%). Voluntary and magnetically evoked electromechanical delays (EMDV and EMDE, respectively) were increased but to a greater extent following PASS compared to PNF (PASS: 10.8% and 16.9% lengthening of EMDV and EMDE, respectively vs. PNF: 3.2% and 6.2%, p<0.01).The attenuated change to electromechanical delay (EMD) performance during PNF conditioning suggests a preserved capability for rapid muscle activation, which is important in the maintenance of dynamic joint stability. That PNF was also equally efficacious in flexibility conditioning would suggest that this mode of flexibility training should be used over passive to help preserve dynamic joint stability capabilities at this extended and vulnerable joint position. PMID- 23688198 TI - Two-photon induced photoluminescence and singlet oxygen generation from aggregated gold nanoparticles. AB - Metal nanoparticles have potential applications as bioimaging and photosensitizing agents. Aggregation effects are generally believed to be adverse to their biomedical applications. Here we have studied the aggregation effects on two-photon induced photoluminescence and singlet oxygen generation of Au nanospheres and Au nanorods of two different aspect ratios. Aggregated Au nanospheres and short Au nanorods were found to display enhanced two-photon induced photoluminescence and singlet oxygen generation capabilities compared to the unaggregated ones. The two-photon photoluminescence of Au nanospheres and short Au nanorods were enhanced by up to 15.0- and 2.0-fold upon aggregation, and the corresponding two-photon induced singlet oxygen generation capabilities were enhanced by 8.3 and 1.8-fold, respectively. The two-photon induced photoluminescence and singlet oxygen generation of the aggregated long Au nanorods were found to be lower than the unaggregated ones. These results support that the change in their two-photon induced photoluminescence and singlet oxygen generation originate from aggregation modulated two-photon excitation efficiency. This finding is expected to foster more biomedical applications of metal nanoparticles as Au nanoparticles normally exist in an aggregated form in the biological environments. Considering their excellent biocompatibility, high inertness, ready conjugation, and easy preparation, Au nanoparticles are expected to find more applications in two-photon imaging and two-photon photodynamic therapy. PMID- 23688199 TI - C-branched iminosugars: alpha-glucosidase inhibition by enantiomers of isoDMDP, isoDGDP, and isoDAB-L-isoDMDP compared to miglitol and miglustat. AB - The Ho crossed aldol condensation provides access to a series of carbon branched iminosugars as exemplified by the synthesis of enantiomeric pairs of isoDMDP, isoDGDP, and isoDAB, allowing comparison of their biological activities with three linear isomeric natural products DMDP, DGDP, and DAB and their enantiomers. L-IsoDMDP [(2S,3S,4R)-2,4-bis(hydroxymethyl)pyrrolidine-3,4-diol], prepared in 11 steps in an overall yield of 45% from d-lyxonolactone, is a potent specific competitive inhibitor of gut disaccharidases [K(i) 0.081 MUM for rat intestinal maltase] and is more effective in the suppression of hyperglycaemia in a maltose loading test than miglitol, a drug presently used in the treatment of late onset diabetes. The partial rescue of the defective F508del-CFTR function in CF-KM4 cells by L-isoDMDP is compared with miglustat and isoLAB in an approach to the treatment of cystic fibrosis. PMID- 23688200 TI - Are corticosteroids effective for prevention of scar formation after second degree skin burn? AB - BACKGROUND: Superficial second-degree skin burns only need re-epithelialization to heal without a scar. After re-epithelialization, inflammation in the dermis contributes to changes in skin architecture and scarring. Suppression of inflammation and fibroblast activation immediately after re-epithelialization may prevent scar formation. Corticosteroids are the mainstay of treatment for keloids and hypertrophic scars. OBJECTIVE: To assess the available data on use of corticosteroids for prevention of scars. METHODS: A review of literature was performed seeking clinical trials using corticosteroids for prevention of scars. RESULTS: Corticosteroids have been used to prevent recurrence after keloid or hypertrophic scar excision with variable success. We did not find any report involving the clinical use of corticosteroids for the prevention of scar formation in other settings, including after skin burns. CONCLUSION: Theoretically, topical corticosteroids can suppress inflammation and fibroblast activation after skin burn, decreasing the incidence of scar formation. However, there is no study evaluating this hypothesis. PMID- 23688201 TI - Expression of follicle-stimulating hormone receptor by the vascular endothelium in tumor metastases. AB - BACKGROUND: The Follicle Stimulating Hormone receptor (FSHR) is expressed by the vascular endothelium in a wide range of human tumors. It was not determined however if FSHR is present in metastases which are responsible for the terminal illness. METHODS: We used immunohistochemistry based on a highly FSHR-specific monoclonal antibody to detect FSHR in cancer metastases from 6 major tumor types (lung, breast, prostate, colon, kidney, and leiomyosarcoma ) to 6 frequent locations (bone, liver, lymph node, brain, lung, and pleura) of 209 patients. RESULTS: In 166 patients examined (79%), FSHR was expressed by blood vessels associated with metastatic tissue. FSHR-positive vessels were present in the interior of the tumors and some few millimeters outside, in the normally appearing tissue. In the interior of the metastases, the density of the FSHR positive vessels was constant up to 7 mm, the maximum depth available in the analyzed sections. No significant differences were noticed between the density of FSHR-positive vessels inside vs. outside tumors for metastases from lung, breast, colon, and kidney cancers. In contrast, for prostate cancer metastases, the density of FSHR-positive vessels was about 3-fold higher at the exterior of the tumor compared to the interior. Among brain metastases, the density of FSHR positive vessels was highest in lung and kidney cancer, and lowest in prostate and colon cancer. In metastases of breast cancer to the lung pleura, the percentage of blood vessels expressing FSHR was positively correlated with the progesterone receptor level, but not with either HER-2 or estrogen receptors. In normal tissues corresponding to the host organs for the analyzed metastases, obtained from patients not known to have cancer, FSHR staining was absent, with the exception of approx. 1% of the vessels in non tumoral temporal lobe epilepsy samples. CONCLUSION: FSHR is expressed by the endothelium of blood vessels in the majority of metastatic tumors. PMID- 23688202 TI - The role of microRNAs in the pathogenesis of MMPi-induced skin fibrodysplasia. AB - BACKGROUND: Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes involved in extracellular matrix (ECM) homeostasis. MMPs have been an attractive pharmacological target for a number of indications. However, development has been hampered by the propensity of compounds targeting these enzymes to cause connective-tissue pathologies. The broad-spectrum MMP-inhibitor (MMPi) AZM551248 has been shown to induce such effects in the dog. Histopathological changes were consistent with fibrodysplasia (FD), characterised by fibroblast proliferation and the deposition of collagen in the subcutaneous tissues. We conducted a time course study administering 20mg/kg/day AZM551248 between 4 and 17 days. Cervical subcutaneous tissue and plasma were sampled during the time-course. miRNA expression profiles in subcutaneous skin specimens following the administration of AZM551248 were determined by high-throughput-sequencing. RESULTS: An increasing number of miRNAs were differentially expressed compared with vehicle treated control animals as the study progressed. Several of these were members of the miR-200 family and were significantly attenuated in response to MMPi. As the severity of FD increased at the later time-points, other miRNAs associated with TGFbeta synthesis and regulation of the acute inflammatory response were modulated. Evidence indicative of epithelial to mesenchymal transition was present at all study time points. Receiver operator curve (ROC) analysis revealed that miR-21 expression in the cervical subcutaneous tissue was a sensitive and specific biomarker of FD incidence. CONCLUSIONS: Our data reveal significant perturbations in canine skin miRNA expression in response to MMPi administration. Furthermore, we have identified dysregulated miRNAs that are associated with processes relevant to the key histopathological events of MMPi-induced FD. PMID- 23688203 TI - Strong negative interference of ethamsylate (Dicynone(r)) in serum creatinine quantification via enzymatic assay using Trinder reaction. AB - BACKGROUND: With discrepancies encountered as early as the verification of enzymatic method for quantification of serum creatinine, our research pointed to a later confirmed interference caused by a compound called ethamsylate present in the commonly used antihemorrhagic drug Dicynone. METHODS: We measured concentrations of creatinine of 10 patients with blood taken before and 15 minutes after the intravenous administration of a 500 mg dose of Dicynone. The creatinine concentration was determined using Jaffe method and enzymatic method that utilize Trinder reaction (Roche) in analyzer Cobas c 501 (Roche AG, Basel, Switzerland). We also monitored concentration of blood creatinine in three patients before and 15 minutes after application of Dicynone (500 mg i.v.) and in the following 6th, 12th, 18th, and 24th hours. RESULTS: We discovered a significant negative bias in creatinine results using enzymatic assay with Trinder reaction in blood taken 15 min after i.v. application of 500 mg Dicynone to patients compared to their pre-application values (average decrease of 47%). Unlike this, the results of compensated Jaffe method yielded steady results in all samples (average deviation 0.6% from original values). However, 12 h after the drug administration comparable results were seen as before the administration. CONCLUSION: Considering the strong negative interference of ethamsylate in enzymatic assay using Trinder reaction for creatinine quantification, blood from patients with prescribed Dicynone should be taken at least 12 h after the last application of the drug for obtaining the correct creatinine values. PMID- 23688204 TI - Comparisons of maximum deformation and failure forces at the implant-abutment interface of titanium implants between titanium-alloy and zirconia abutments with two levels of marginal bone loss. AB - BACKGROUND: Zirconia materials are known for their optimal aesthetics, but they are brittle, and concerns remain about whether their mechanical properties are sufficient for withstanding the forces exerted in the oral cavity. Therefore, this study compared the maximum deformation and failure forces of titanium implants between titanium-alloy and zirconia abutments under oblique compressive forces in the presence of two levels of marginal bone loss. METHODS: Twenty implants were divided into Groups A and B, with simulated bone losses of 3.0 and 1.5 mm, respectively. Groups A and B were also each divided into two subgroups with five implants each: (1) titanium implants connected to titanium-alloy abutments and (2) titanium implants connected to zirconia abutments. The maximum deformation and failure forces of each sample was determined using a universal testing machine. The data were analyzed using the nonparametric Mann-Whitney test. RESULTS: The mean maximum deformation and failure forces obtained the subgroups were as follows: A1 (simulated bone loss of 3.0 mm, titanium-alloy abutment) = 540.6 N and 656.9 N, respectively; A2 (simulated bone loss of 3.0 mm, zirconia abutment) = 531.8 N and 852.7 N; B1 (simulated bone loss of 1.5 mm, titanium-alloy abutment) = 1070.9 N and 1260.2 N; and B2 (simulated bone loss of 1.5 mm, zirconia abutment) = 907.3 N and 1182.8 N. The maximum deformation force differed significantly between Groups B1 and B2 but not between Groups A1 and A2. The failure force did not differ between Groups A1 and A2 or between Groups B1 and B2. The maximum deformation and failure forces differed significantly between Groups A1 and B1 and between Groups A2 and B2. CONCLUSIONS: Based on this experimental study, the maximum deformation and failure forces are lower for implants with a marginal bone loss of 3.0 mm than of 1.5 mm. Zirconia abutments can withstand physiological occlusal forces applied in the anterior region. PMID- 23688206 TI - Placebo controlled, prospectively randomized, double-blinded study for the investigation of the effectiveness and safety of the acoustic wave therapy (AWT((r))) for cellulite treatment. AB - Placebo controlled double-blinded, prospectively randomized clinical trial with 17 patients (11 verum, 5 placebo) for evaluation of cellulite treatment with Acoustic Wave Therapy, (AWT((r))) was performed. The patients were treated once a week for 7 weeks, a total of 8 treatments with the D-ACTOR((r)) 200 by Storz Medical AG. Data were collected at baseline, before 8th treatment, at 1 month (follow-up 1) and at 3 months (follow-up 2) after the last treatment with a patients' questionnaire, weight control, measurement of circumference and standardized photography. Treatment progress was further documented using a specially designed 3D imaging system (SkinSCAN(3D), 3D-Shape GmbH) providing an objective measure of cellulite (primary efficacy criteria). Patient's questionnaire in the verum group revealed an improvement in number and depth of dimples, skin firmness and texture, in shape and in reduction of circumference. The overall result (of skin waviness, Sq and Sz, surface and volume of depressions and elevations, Vvv and Vmp) at two follow-up visits indicates a more than medium sized superiority (MW = 0.6706) and is statistically significant (pWei-Lachin = 0.0106). The placebo group revealed no statistical significance. No side effects were seen. This indicates the efficacy and safety of AWT((r)) for patients with cellulite. PMID- 23688205 TI - Environmental and social-motivational contextual factors related to youth physical activity: systematic observations of summer day camps. AB - BACKGROUND: Youth risk of obesity is high during the summer months. Summer day camps can be ideal settings for preventing obesity through reducing youth summer sedentary behaviors. However, with limited research on camp settings, the mechanisms by which these programs promote children's physical activity (PA) remains largely unknown. The current study was designed to take a first step in addressing this gap in research through systematic observations of 4 summer day camps. METHODS: Systematic observations of 4 summer day camps was conducted using the System for Observing Play and Leisure Activity in Youth (SOPLAY) and a social motivational climate supplemental observation tool founded on Self-Determination Theory and previous research developed by the authors. Teams of two coders observed daily activities for four days across two-week periods at each camp. On 15 minute intervals throughout each day, camps were assessed on level of youth PA (e.g., sedentary, moderate, vigorous), five physical features (e.g., equipment), eight staff interactions (e.g., encourage PA), and six social climate components (e.g., inclusive game). RESULTS: Across the sample, highly engaging games [F(1,329) = 17.68, p < .001], positive peer interactions [F(1,329) = 8.43, p < .01], and bullying [F(1,329) = 9.39, p < .01] were significantly related to higher PA participation rates, and clarity of rules [F(1,329) = 11.12, p < .001] was related to fewer youth participating in PA. Separate analyses for males and females indicated some sex differences with highly engaging games [F(1,329) = 23.10, p < .001] and bullying [F(1,329) = 10.00, p < .01] related to males' but not females' PA, and positive peer interactions related to only females' PA [F(1,329) = 9.58, p < .01]. Small, yet significant physical-environmental effects of temperature [F(1,328) = 1.54, p < .05] and equipment [F(1,328) = 4.34, p = .05] for girls also suggests that activities offered indoors (which was most common during high temperatures), and provision of equipment may also be important considerations for promoting girls' PA. Staff behaviors were minimally predictive of youth PA. CONCLUSIONS: This is the first study to conduct systematic observations of the physical and social resources of summer day camps and contributes to our understanding of the strengths and needs of camps to effectively promote PA in both boys and girls during the summer months when risks for obesity are high. PMID- 23688207 TI - Cancer T cell immunotherapy with bispecific antibodies and chimeric antigen receptors. AB - Solid tumors contain several different types of malignant cells. This cellular heterogeneity complicates therapy for at least two reasons. First, each subpopulation may respond differently to a given treatment. Second, cancer cells are plastic, and thus may convert from a therapy-sensitive to a therapy-resistant cell type represented by another subpopulation. Therefore, successful therapies will have to target numerous malignant cell types, not just the rapidly proliferating cells as most standard treatments do. Immunotherapies with T cells engineered to recognize cancer cells via bispecific antibodies (bsAbs) or chimeric antigen receptors (CARs) are particularly promising approaches with potential to ablate both dividing and non/slow-dividing subpopulations of cancer cells. Here, we discuss several patents associated with exceptionally effective bsAbs of the tandem single-chain variable fragment (taFv) class and untangle a part of the complex network of patents directly or indirectly related to CARs. Furthermore, we speculate on the future of bsAbs and CARs for both treatment and prevention of solid tumors such as prostate cancer. PMID- 23688208 TI - Enzyme-mediated methodology for the site-specific radiolabeling of antibodies based on catalyst-free click chemistry. AB - An enzyme- and click chemistry-mediated methodology for the site-selective radiolabeling of antibodies on the heavy chain glycans has been developed and validated. To this end, a model system based on the prostate specific membrane antigen-targeting antibody J591, the positron-emitting radiometal (89)Zr, and the chelator desferrioxamine has been employed. The methodology consists of four steps: (1) the removal of sugars on the heavy chain region of the antibody to expose terminal N-acetylglucosamine residues; (2) the incorporation of azide modified N-acetylgalactosamine monosaccharides into the glycans of the antibody; (3) the catalyst-free click conjugation of desferrioxamine-modified dibenzocyclooctynes to the azide-bearing sugars; and (4) the radiolabeling of the chelator-modified antibody with (89)Zr. The site-selective labeling methodology has proven facile, reproducible, and robust, producing (89)Zr-labeled radioimmunoconjguates that display high stability and immunoreactivity in vitro (>95%) in addition to highly selective tumor uptake (67.5 +/- 5.0%ID/g) and tumor to-background contrast in athymic nude mice bearing PSMA-expressing subcutaneous LNCaP xenografts. Ultimately, this strategy could play a critical role in the development of novel well-defined and highly immunoreactive radioimmunoconjugates for both the laboratory and clinic. PMID- 23688210 TI - Improvements of the recovery line of waste toner cartridges on environmental and safety performances. AB - A physical recovery line had been constructed in plant for the increasing waste toner cartridges in previous work. However, with the production, severe lacks of the line emerged: (1) there was little proper technology of treating the collected toner; (2) strong noise was produced from the line and influenced the health of worker. For disposing toner properly, a new collected system of toner was developed. An air current separator (ACS) was designed to separate organic materials from inorganic materials of toner. Then, the separated organic materials can be incinerated and the inorganic materials can be dumped. Movement behaviors of toner particles in the ACS were analyzed, and the optimized operation parameter (13.5 m/s) of air current speed was obtained by theory analysis and experiments. For controlling the noise, noise levels emitted from the different process of the line were measured. The results indicated noise levels emitted from crusher (95.2 dB(A)) and agitator/magnetic separator (AMS, 91.9 dB(A)) were greater than the permissible noise exposure level of the Occupational Safety and Health Standards (90 dB(A)). The noise levels of other processes of the line were relatively safe. An acoustic hood was developed to reduce the noise levels of the crusher and the AMS. Then, the noise levels were both decreased to 67.6 dB(A). This paper provided important data for the environment on the industrialization of waste toner cartridges recovery. PMID- 23688209 TI - Ulnar malignant peripheral nerve sheath tumour diagnosis in a mixed-breed dog as a model to study human: histologic, immunohistochemical, and clinicopathologic study. AB - Canine Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are uncommonly reported in the ulnar, since they are underestimated relative to the more common spindle cell tumours of soft tissue. In dogs, MPNST accounts for 27% of nervous system tumours. In man, MPNST represents 5-10% of all soft tissue sarcomas and is often associated with neurofibromatosis type 1 (NF-1).An 8-year-old, 9 kg, female mixed breed dog with a subcutaneous mass on the upper right side of the ulnar region was presented to the small animal research and teaching hospital of Tehran University. The dog was anorexic with general weakness. The mass (7 * 4 cm) was removed surgically and processed routinely. Microscopically, the mass was composed of highly cellular areas with a homogeneous population of round or spindle cells, high cellular pleomorphism, high mitotic index and various morphologic patterns. Furthermore, spindle cells arranged in densely or loosely sweeping fascicles, interlacing whorls, or storiform patterns together with wavy cytoplasm, nuclear palisades, and round cells were arranged in sheets or cords with a meshwork of intratumoral nerve fibers. In addition, in this case the presence of neoplastic cells within the blood vessels was observed. Immunohistochemically, tumor was positive for vimentin and S-100 protein. The histopathologic features coupled with the S-100 and vimentin immunoreactivity led to a diagnosis of malignant neurofibroma.To the best of our knowledge, primary ulnar MPNST has not been reported in animals. This is the first documentation of an ulnar malignant peripheral nerve sheath tumour in a dog. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1310907815984587. PMID- 23688211 TI - Attention-deficit/hyperactivity disorder (ADHD) and working memory in adults: a meta-analytic review. AB - OBJECTIVE: Within the last decade, working memory (WM) has garnered increased interest as a potential core deficit or endophenotype of attention deficit/hyperactivity disorder (ADHD). The current study is the first meta analytic review to examine several subject and task moderator variables' (e.g., percent female, diagnostic selection procedure, trials per set size, response demands, type of dependent variable, and central executive [CE] demands) effect on between-group phonological (PH) and visuospatial (VS) WM in adults with ADHD, relative to healthy controls. METHOD: Literature searches were conducted using the PsycINFO, Web of Science, and PubMed databases, and yielded 38 studies of WM in adults with ADHD. RESULTS: Results revealed moderate-magnitude between-group effect sizes (ESs) across both WM domains. In addition, several task-moderating variables explained significant ES variability among PH and VS studies. CONCLUSIONS: Collectively, these findings indicate that WM deficits persist into adulthood and suggest that methodological variability may explicate why WM deficits have not been uniformly detected in previous experimental studies. PMID- 23688212 TI - Working memory in Parkinson's disease: the effects of depression and side of onset of motor symptoms. AB - OBJECTIVE: Previous research has examined the neurocognitive effects of depression in Parkinson's disease (PD), finding worse performance on tests of cognitive functioning in PD patients with depression as compared to those without depression. However, this research has not considered the effect of side of onset of motor symptoms. Hence, we sought to investigate the interaction between depression and side of onset on working memory in patients with PD. METHOD: A total of 66 patients with PD completed the Digit Span Backward subtest of the Wechsler Memory Scale-III as well as two other tests of executive functioning. Groups of left hemibody onset (LHO) with and without depression and right hemibody onset (RHO) with and without depression were created. RESULTS: The results indicated significantly lower performance on the measure of working memory for the LHO with depression group, relative to both the LHO without depression and the RHO with depression groups. CONCLUSION: These findings indicate that working memory is worse in patients with LHO of motor symptoms who are also depressed, and they suggest that this group of patients might experience greater disability and lower quality of life. PMID- 23688213 TI - Implicit perceptual-motor skill learning in mild cognitive impairment and Parkinson's disease. AB - OBJECTIVE: Implicit skill learning is hypothesized to depend on nondeclarative memory that operates independent of the medial temporal lobe (MTL) memory system and instead depends on cortico striatal circuits between the basal ganglia and cortical areas supporting motor function and planning. Research with the Serial Reaction Time (SRT) task suggests that patients with memory disorders due to MTL damage exhibit normal implicit sequence learning. However, reports of intact learning rely on observations of no group differences, leading to speculation as to whether implicit sequence learning is fully intact in these patients. Patients with Parkinson's disease (PD) often exhibit impaired sequence learning, but this impairment is not universally observed. METHOD: Implicit perceptual-motor sequence learning was examined using the Serial Interception Sequence Learning (SISL) task in patients with amnestic Mild Cognitive Impairment (MCI; n = 11) and patients with PD (n = 15). Sequence learning in SISL is resistant to explicit learning and individually adapted task difficulty controls for baseline performance differences. RESULTS: Patients with MCI exhibited robust sequence learning, equivalent to healthy older adults (n = 20), supporting the hypothesis that the MTL does not contribute to learning in this task. In contrast, the majority of patients with PD exhibited no sequence-specific learning in spite of matched overall task performance. Two patients with PD exhibited performance indicative of an explicit compensatory strategy suggesting that impaired implicit learning may lead to greater reliance on explicit memory in some individuals. CONCLUSION: The differences in learning between patient groups provides strong evidence in favor of implicit sequence learning depending solely on intact basal ganglia function with no contribution from the MTL memory system. PMID- 23688214 TI - Cognitive consequences of high Abeta amyloid in mild cognitive impairment and healthy older adults: implications for early detection of Alzheimer's disease. AB - BACKGROUND: It has been proposed that only mild cognitive impairment (MCI) with high Abeta amyloid is indicative of incipient Alzheimer's disease (AD), yet MCI with low Abeta amyloid may reflect other neurodegenerative processes. We aimed to determine the extent to which high Abeta amyloid influenced cognitive function in healthy older adults and adults with MCI. METHOD: Healthy controls (HC; n = 178) and adults with MCI (n = 56) enrolled in the Australian Imaging, Biomarkers, and Lifestyle study, underwent positron emission tomography neuroimaging for Abeta amyloid and completed an extensive neuropsychological battery, assessing the cognitive domains of verbal and visual episodic memory, executive function, visuoconstruction, attention and processing speed, and language at baseline. RESULTS: MCI with low Abeta performed worse than MCI with high Abeta on measures of executive function, attention, visuoconstruction and language. No differences were observed between HC high and low Abeta groups. When compared with HC with low Abeta, both MCI high and low Abeta groups performed worse on measures of episodic memory. However, only the MCI low Abeta group performed worse than HC low Abeta on measures of executive function, attention, visuoconstruction, and language. CONCLUSIONS: When compared with HC with low Abeta amyloid, MCI with high Abeta amyloid present with impairments restricted to episodic memory, and the episodic memory impairments in MCI with low Abeta amyloid were accompanied by impairments in executive function, attention, visuoconstruction, and language, suggesting that MCI with high Abeta amyloid reflects prodromal AD, although further longitudinal data is required to confirm this. PMID- 23688215 TI - Recognition of famous names predicts cognitive decline in healthy elders. AB - OBJECTIVE: The ability to recognize familiar people is impaired in both Mild Cognitive Impairment (MCI) and Alzheimer's Dementia (AD). In addition, both groups often demonstrate a time-limited temporal gradient (TG) in which well known people from decades earlier are better recalled than those learned recently. In this study, we examined the TG in cognitively intact elders for remote famous names (1950-1965) compared to more recent famous names (1995-2005). We hypothesized that the TG pattern on a famous name recognition task (FNRT) would predict future cognitive decline, and also show a significant correlation with hippocampal volume. METHOD: Seventy-eight healthy elders (ages 65-90) with age-appropriate cognitive functioning at baseline were administered a FNRT. Follow-up testing 18 months later produced two groups: Declining (>= 1 SD reduction on at least one of three measures) and Stable (< 1 SD). RESULTS: The Declining group (N = 27) recognized fewer recent famous names than the Stable group (N = 51), although recognition for remote names was comparable. Baseline MRI volumes for both the left and right hippocampi were significantly smaller in the Declining group than the Stable group. Smaller baseline hippocampal volume was also significantly correlated with poorer performance for recent, but not remote famous names. Logistic regression analyses indicated that baseline TG performance was a significant predictor of group status (Declining vs. Stable) independent of chronological age and APOE epsilon4 inheritance. CONCLUSIONS: The TG for famous name recognition may serve as an early preclinical cognitive marker of cognitive decline in healthy older individuals. PMID- 23688217 TI - Association of serum dehydroepiandrosterone sulfate and cognition in older adults: sex steroid, inflammatory, and metabolic mechanisms. AB - OBJECTIVE: Dehydroepiandrosterone sulfate (DHEAS) levels and cognitive function decline with age, and a role for DHEAS in supporting cognition has been proposed. Higher DHEAS levels may be associated with better cognitive performance, although potential mechanisms for this relationship are not well established. METHOD: We performed a cross-sectional study of the relationship between serum DHEAS and three aspects of cognition--executive function, working memory, and processing speed--in 49 men and 54 women, aged 60-88 years, with low serum DHEAS levels. We examined three potential mechanisms of DHEAS action--sex hormone sufficiency, inflammatory status, and glucose regulation. RESULTS: After adjustment for multiple covariates, higher serum DHEAS levels were associated with better working memory (standardized beta coefficient 0.50, p < .05), with a trend toward better executive function (standardized beta coefficient 0.37, p < .10) in men only. There was a nonsignificant trend toward a negative association between levels of tumor necrosis factor alpha (TNFalpha) and working memory in the combined population (standardized beta coefficient -0.22, p < .10). None of the glucoregulatory measures was associated with cognitive function. CONCLUSIONS: The relationship between DHEAS and cognition is complex and differs by sex and cognitive domain. This study supports the need for further investigations of the sex-specific effects of DHEAS on cognition and its underlying mechanisms of action. PMID- 23688216 TI - Which neuropsychological tests predict progression to Alzheimer's disease in Hispanics? AB - OBJECTIVE: To investigate which neuropsychological tests predict eventual progression to Alzheimer's disease (AD) in both Hispanic and non-Hispanic individuals. Although our approach was exploratory, we predicted that tests that underestimate cognitive ability in healthy aging Hispanics might not be sensitive to future cognitive decline in this cultural group. METHOD: We compared first year data of 22 older adults (11 Hispanic) who were diagnosed as cognitively normal but eventually developed AD (decliners), to 60 age- and education-matched controls (27 Hispanic) who remained cognitively normal. To identify tests that may be culturally biased in our sample, we compared Hispanic with non-Hispanic controls on all tests and asked which tests were sensitive to future decline in each cultural group. RESULTS: Compared to age-, education-, and gender-matched non-Hispanic controls, Hispanic controls obtained lower scores on tests of language, executive function, and some measures of global cognition. Consistent with our predictions, some tests identified non-Hispanic, but not Hispanic, decliners (vocabulary, semantic fluency). Contrary to our predictions, a number of tests on which Hispanics obtained lower scores than non-Hispanics nevertheless predicted eventual progression to AD in both cultural groups (e.g., Boston Naming Test [BNT], Trails A and B). CONCLUSIONS: Cross-cultural variation in test sensitivity to decline may reflect greater resistance of medium difficulty items to decline and bilingual advantages that initially protect Hispanics against some aspects of cognitive decline commonly observed in non-Hispanics with preclinical AD. These findings highlight a need for further consideration of cross-cultural differences in neuropsychological test performance and development of culturally unbiased measures. PMID- 23688219 TI - Does executive control really play a crucial role in explaining age-related cognitive and neural differences? AB - OBJECTIVE: The present study investigated the role of executive control in accounting for the cognitive and electrophysiological alterations occurring in healthy aging. METHOD: Younger and older adults performed the inhibitory control task (ICT), a task composed of 3 types of trials that vary in the degree and kind of executive control subprocesses required. We analyzed event-related potentials (ERPs) elicited by these ICT trials and focused on the ERP components related to executive control subprocesses: P3b (updating), no-go P3 (inhibition), and reorienting negativity (RON; shifting). RESULTS: Compared with younger adults, older adults exhibited worse performance on the ICT and a delay in the latency of all the ERPs investigated. These age-related differences occurred regardless of the amount of executive control required because they were not influenced by the type of trial. The RON amplitude, an index of shifting, was found markedly attenuated in older adults relative to younger adults. CONCLUSIONS: Executive control, as a unitary function, cannot explain the age-related differences observed, which are more likely to reflect a general slowing of processes with aging. However, when we take into account the specific subprocesses of executive control, the one that seems to be particularly affected by aging is shifting, as revealed by the age-related alterations in the RON parameters. PMID- 23688220 TI - Pesticide in soil, fate and effects on environment. Foreword. PMID- 23688221 TI - European scenarios for exposure of soil organisms to pesticides. AB - Standardised exposure scenarios play an important role in European pesticide authorisation procedures (a scenario is a combination of climate, weather and crop data to be used in exposure models). The European Food Safety Authority developed such scenarios for the assessment of exposure of soil organisms to pesticides. Scenarios were needed for both the concentration in total soil and for the concentration in the liquid phase. The goal of the exposure assessment is the 90th percentile of the exposure concentration in the area of agricultural use of a pesticide in each of three regulatory European zones (North, Centre and South). A statistical approach was adopted to find scenarios that are consistent with this exposure goal. Scenario development began with the simulation of the concentration distribution in the entire area of use by means of a simple analytical model. In the subsequent two steps, procedures were applied to account for parameter uncertainty and scenario uncertainty (i.e. the likelihood that a scenario that is derived for one pesticide is not conservative enough for another pesticide). In the final step, the six scenarios were selected by defining their average air temperature, soil organic-matter content and their soil textural class. Organic matter of the selected scenarios decreased in the order North Centre-South. Because organic matter has a different effect on the concentration in total soil than it has on the concentration in the liquid phase, the concentration in total soil decreased in the order North-Centre-South whereas the concentration in the liquid phase decreased in the opposite order. The concentration differences between the three regulatory zones appeared to be no more than a factor of two. These differences were comparatively small in view of the considerable differences in climate and soil properties between the three zones. PMID- 23688218 TI - Relation of neural structure to persistently low academic achievement: a longitudinal study of children with differing birth weights. AB - OBJECTIVE: This study examined the relation of cerebral tissue reductions associated with VLBW to patterns of growth in core academic domains. METHOD: Children born <750 g, 750 to 1,499 g, or >2,500 g completed measures of calculation, mathematical problem solving, and word decoding at time points spanning middle childhood and adolescence. K. A. Espy, H. Fang, D. Charak, N. M. Minich, and H. G. Taylor (2009, Growth mixture modeling of academic achievement in children of varying birth weight risk, Neuropsychology, Vol. 23, pp. 460-474) used growth mixture modeling to identify two growth trajectories (clusters) for each academic domain: an average achievement trajectory and a persistently low trajectory. In this study, 97 of the same participants underwent magnetic resonance imaging (MRI) in late adolescence, and cerebral tissue volumes were used to predict the probability of low growth cluster membership for each domain. RESULTS: Adjusting for whole brain volume (wbv), each 1-cm(3) reduction in caudate volume was associated with a 1.7- to 2.1-fold increase in the odds of low cluster membership for each domain. Each 1-mm(2) decrease in corpus callosum surface area increased these odds approximately 1.02-fold. Reduced cerebellar white matter volume was associated specifically with low calculation and decoding growth, and reduced cerebral white matter volume was associated with low calculation growth. Findings were similar when analyses were confined to the VLBW groups. CONCLUSIONS: Reduced volume of structures involved in connectivity, executive attention, and motor control may contribute to heterogeneous academic trajectories among children with VLBW. PMID- 23688222 TI - The herbicide glyphosate and its metabolite AMPA in the Lavaux vineyard area, Western Switzerland: proof of widespread export to surface waters. Part I: method validation in different water matrices. AB - An analytical method for the quantification of the widely used herbicide, glyphosate, its main by-product, aminomethylphosphonic acid (AMPA) and the herbicide glufosinate at trace level was developed and tested in different aqueous matrices. Their derivatization with 9-fluorenylmethyl chloroformate (FMOC Cl) was done prior to their concentration and purification by solid phase extraction. The concentrated derivates were then analyzed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Spiking tests at three different concentrations were realized in several water matrices: ultrapure water, Evian((c)) mineral water, river water, soil solution and runoff water of a vineyard. Except for AMPA in runoff water, obtained regression curves for all matrices of interest showed no statistical differences of their slopes and intercepts, validating the method for the matrix effect correction in relevant environmental samples. The limits of detection and quantification of the method were as low as 5 and 10 ng/l respectively for the three compounds. Spiked Evian((c)) and river water samples at two different concentrations (30 and 130 ng/l) showed mean recoveries between 86 and 109%, and between 90 and 133% respectively. Calibration curves established in spiked Evian((c)) water samples between 10 and 1000 ng/l showed r(2) values above 0.989. Monitoring of a typical vineyard river showed peaks of pollution by glyphosate and AMPA during main rain events, sometimes above the legal threshold of 100 ng/l, suggesting the diffuse export of these compounds by surface runoff. The depth profile sampled in the adjacent lake near a waste water treatment plant outlet showed a concentration peak of AMPA at 25m depth, indicating its release with treated urban wastewater. PMID- 23688223 TI - The herbicide glyphosate and its metabolite AMPA in the Lavaux vineyard area, western Switzerland: proof of widespread export to surface waters. Part II: the role of infiltration and surface runoff. AB - Two parcels of the Lavaux vineyard area, western Switzerland, were studied to assess to which extent the widely used herbicide, glyphosate, and its metabolite aminomethylphosphonic acid (AMPA) were retained in the soil or exported to surface waters. They were equipped at their bottom with porous ceramic cups and runoff collectors, which allowed retrieving water samples for the growing seasons 2010 and 2011. The role of slope, soil properties and rainfall regime in their export was examined and the surface runoff/throughflows ratio was determined with a mass balance. Our results revealed elevated glyphosate and AMPA concentrations at 60 and 80 cm depth at parcel bottoms, suggesting their infiltration in the upper parts of the parcels and the presence of preferential flows in the studied parcels. Indeed, the succession of rainy days induced the gradual saturation of the soil porosity, leading to rapid infiltration through macropores, as well as surface runoff formation. Furthermore, the presence of more impervious weathered marls at 100 cm depth induced throughflows, the importance of which in the lateral transport of the herbicide molecules was determined by the slope steepness. Mobility of glyphosate and AMPA into the unsaturated zone was thus likely driven by precipitation regime and soil characteristics, such as slope, porosity structure and layer permeability discrepancy. Important rainfall events (>10 mm/day) were clearly exporting molecules from the soil top layer, as indicated by important concentrations in runoff samples. The mass balance showed that total loss (10-20%) mainly occurred through surface runoff (96%) and, to a minor extent, by throughflows in soils (4%), with subsequent exfiltration to surface waters. PMID- 23688224 TI - Modeling the influence of raindrop size on the wash-off losses of copper-based fungicides sprayed on potato (Solanum tuberosum L.) leaves. AB - Modeling the pesticide wash-off by raindrops is important for predicting pesticide losses and the subsequent transport of pesticides to soil and in soil run-off. Three foliar-applied copper-based fungicide formulations, specifically the Bordeaux mixture (BM), copper oxychloride (CO), and a mixture of copper oxychloride and propylene glycol (CO-PG), were tested on potato (Solanum tuberosum L.) leaves using a laboratory raindrop simulator. The losses in the wash-off were quantified as both copper in-solution loss and copper as particles detached by the raindrops. The efficiency of the raindrop impact on the wash-off was modeled using a stochastic model based on the pesticide release by raindrops. In addition, the influence of the raindrop size, drop falling height, and fungicide dose was analyzed using a full factorial experimental design. The average losses per dose after 14 mm of dripped water for a crop with a leaf area index equal to 1 were 0.08 kg Cu ha(-1) (BM), 0.3 kg Cu ha(-1) (CO) and 0.47 kg Cu ha(-1) (CO-PG). The stochastic model was able to simulate the time course of the wash-off losses and to estimate the losses of both Cu in solution and as particles by the raindrop impacts. For the Cu-oxychloride fungicides, the majority of the Cu was lost as particles that detached from the potato leaves. The percentage of Cu lost increased with the decreasing raindrop size in the three fungicides for the same amount of dripped water. This result suggested that the impact energy is not a limiting factor in the particle detachment rate of high doses. The dosage of the fungicide was the most influential factor in the losses of Cu for the three formulations studied. The results allowed us to quantify the factors that should be considered when estimating the losses by the wash-off of copper-based fungicides and the inputs of copper to the soil by raindrop wash-off. PMID- 23688225 TI - Environmental behavior of the fungicide metalaxyl in experimental tobacco field. AB - The loss of metalaxyl, a systemic fungicide, was determined in runoff water from loamy soil plots of various surface slopes cultivated with tobacco, over a period of 170 days. Conditions were selected to simulate agricultural practices employed in the Mediterranean region. The surface slopes of plots were 0, 2.5, 5, 7.5, 10% and both cultivated and uncultivated (control) areas were simultaneously monitored. The cumulative losses of metalaxyl in surface runoff from tilled and untilled plots with a slope of 10% were estimated at 0.469% and 0.740% of the initial applied active ingredient respectively, while for the plots with a slope 0% they were 0.033% and 0.044%. The dissipation in topsoil was studied for a period of 110 days. The half-lives that were calculated using first-order kinetics ranged from 13.7 to 16.6 days in tobacco soil and from 13.8 to 17 days in non-cropped soil. The dissipation of metalaxyl from the topsoil in cultivation of tobacco was higher in comparison with the untilled plots (46-62% and 52-69% respectively, of the applied dose in 23 days after the second application). The slope of soil surface, the compound solubility and sorption capacities are the main parameters that influenced the transport of metalaxyl residues via surface water in soil-water systems. PMID- 23688226 TI - Study of sorption of two sulfonylurea type of herbicides and their additives on soils and soil components. AB - The sorption of two sulfonylurea type herbicides (chlorsulfuron: (1-(2 chlorophenylsulfonyl)-3-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)urea; tribenuron methyl: (methyl-2-[N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-3-(methyl-ureido) sulfonyl]-benzoate) was studied on sand and chernozem soil adsorbents. Experimental results for solutions prepared from the pure ingredients were compared to those prepared from the appropriate formulated commercial products. At small concentrations, the extent of adsorption of the active ingredient was higher than from the formulation containing solutions. Environmental fate and effects of the forming agents are less investigated because they rarely have concentration limits recommended by authorities. In addition to the adsorption of active ingredients, therefore, the sorption behavior of a widely used additive Supragil WP (sodium diisopropyl naphthalene sulphonate) was also studied. This dispersant is an anionic forming agent applied in a lot of pesticide formulations. Using three different soils (sand, brown forest, chernozem) as adsorbents two-step isotherms were obtained. The role of the soil organic matter (OM) was significant in the adsorption mechanism because the adsorbed amounts of the dispersant correlated with the specific surface area as well as with the total organic carbon (TOC) content of the soils. The sorption behavior indicates the operation of hydrophobic interaction mechanism between the soil OM and the dispersant. These results are supported by our further sorption experiments on clays, too. Zeta potential measurements seem to be promising for the interpretation of multi-step isotherms. The application of this technique proved that higher concentrations of the anionic forming agent assisted the peptization of soil organic matter (SOM) resulting in stable colloidal solution dominated by negative charges. Since the pesticides investigated are also anionic at the studied pH (7 and 8.3) the dissolved organics lead to the enhancement of the mobility of both the sulfonylureas and dispersant. PMID- 23688227 TI - Impact of oiled and de-oiled olive mill waste amendments on the sorption, leaching, and persistence of S-metolachlor in a calcareous clay soil. AB - Agricultural practices based on periodic inputs of organic amendments are strongly recommended for Mediterranean agro-ecosystems. Such amendments can change the soil's properties and transport characteristics, and hence affect the behaviour and fate of pesticides. S-metolachlor is an herbicide commonly used in intensive crops. The aim of this study was to investigate the influence of fresh oiled (OW) and de-oiled two-phase olive mill waste (DW) amendments on the sorption, leaching, and persistence of the herbicide S-metolachlor in a calcareous clay soil. The soil was amended in the laboratory with OW and DW at the rates of 2.5% and 5% (w/w). Significant increases in S-metolachlor sorption were observed in all amended soils. The addition of OW and DW increased the herbicide half-life from 27 d for the original soil to 41 and 47 d at the higher application rate of OW and DW, respectively. There was a significantly greater retention of the herbicide at the higher OW and DW loading rate. However, whereas the amount of S-metolachlor in the leachate was reduced by increasing the amount of OW, it was unaffected by increasing the amount of DW. The results lend support to the potential of OW and DW amendments as an effective management practice to increase S-metolachlor persistence in soils. This increase does not necessarily ensure decreased leaching of the herbicide but it could also increase the risk of surface water contamination at higher application rate. PMID- 23688228 TI - Organically modified clays as binders of fumonisins in feedstocks. AB - This study reports an investigation on the ability of organically modified clays to bind mycotoxins, fumonisins B1 (FB1) and B2 (FB2). Organically modified clays are commercia materials prepared from natural clays, generally montmorillonite, by exchanging the inorganic cation with an ammonium organic cation. A screening experiment conducted on 13 organically modified clays and 3 nonmodified clays, used as controls, has confirmed that the presence of an organic cation in the clay interlayer promoted the adsorption of both fumonisins. On the basis of the results of the screening test, four modified clays and a Na-montmorillonite were selected for the determination of the adsorption kinetics and isotherms. On all the tested materials adsorption took place within one hour of contact with fumonisins solutions. Adsorption isotherms have pointed out that the modified clays exhibited a higher adsorptive capacity than the unmodified clay. It was also demonstrated that, notwithstanding the reduced structural difference between FB1 and FB2, they were differently adsorbed on the modified clays. Addition of 2% modified clays to contaminated maize allowed a reduction of more than 70% and 60% of the amount of FB1and FB2 released in solution. Although in vivo experiments are required to confirm the effectiveness of the organically modified clays, these preliminary results suggest that these materials are promising as fumonisins binders. PMID- 23688229 TI - Organo-clays and nanosponges for acquifer bioremediation: adsorption and degradation of triclopyr. AB - To avoid the problem of groundwater contamination, mitigation techniques have been proposed that consist of creating barriers made of suitable materials that can facilitate the adsorption and degradation of the pollutants. This study aims at evaluating the capacity of two organo-clays (Dellite 67 G and Dellite 43 B) and one nanosponge to adsorb the herbicide, triclopyr. Triclopyr was chosen because it is a good example of a moderately mobile, leacheable molecule. The rate of degradation of the molecule in the soil, both with and without the presence of the materials under examination, was also determined. Both the organo clays adsorbed more than 90% of the herbicide. The nanosponge and the soil adsorbed less than 10% triclopyr. When the soil was added with the two organoclays, adsorption increased to 92%. When added to the soil, the materials accelerated the degradation of triclopyr. The half-life in soil was 30 days, whereas in soil with Dellite 67 G and Dellite 43 B it was 10 and 6 days respectively. The addition of the nanosponge to the soil decreased the half life by 50%. These results lead us to suggest that they be used in creating reactive barriers for the remediation of soils and aquifers. PMID- 23688230 TI - Pesticides water decontamination in oxygen-limited conditions. AB - This study was undertaken to develop a laboratory bioreactor, with a functioning principle similar with that of biobed systems but working in oxygen-limited conditions, suitable for decontaminating wastewater mixtures with pesticides. The system is composed by two cylindrical plastic containers. The first one, where the pesticides solution is collected, is open, whereas the second one, where the biomass is disposed, is closed. The pesticides solution was pumped at the biomass surface and subsequently recollected and disposed in the first container. Four pesticides with different physical-chemical characteristics were tested. The results obtained showed a relatively good capacity of the developed prototype to decontaminate waste water containing the mixture of pesticides. The time of the experiment, the number of cycles that the solution made in the system and the environmental temperature have a significantly influence for the decontamination of acetochlor and chlorpyrifos whereas for the decontamination of terbuthylazine and metalaxyl no significant influence was observed. Even if the present prototype could represent a valid solution to manage the water pesticides residues in a farm and to increase the confidence of bystanders and residents, the practical difficulties when replacing the biomass could represent a limit of the system. PMID- 23688231 TI - Occurrence and removal of emerging pharmaceutical, personal care compounds and caffeine tracer in municipal sewage treatment plant in Western Greece. AB - A fourteen-month monitoring period (April 2007-May 2008) was realized to investigate the removal and occurrence of eight pharmaceutical and personal care compounds, two metabolites and caffeine across the municipal wastewater treatment plant (WWTP) of Agrinio city, located in Western Greece as well as in the discharging sampling point in Acheloos River, which receives the effluents of the plant. Solid-phase extraction (SPE) was used for the isolation and pre concentration of the target pollutants and gas chromatography mass spectrometry (GC-MS) for their detection and quantification. All the selected compounds were detected in the wastewater samples. The concentrations determined in the influent of the municipal WWTP ranged between 65.3 and 6679 ng L(-1) recorded for triclosan and caffeine respectively, while in the effluent ranged between 24.9 and 552 ng L(-1) observed for triclosan and carbamazepine, respectively. The detected concentration levels in Acheloos River ranged from 37.6 ng L(-1) for caffeine to 305 ng L(-1) for paracetamol. Mean total removal efficiencies ranged between 46.3% for carbamazepine and 96.8% for naproxen. The results of this study demonstrate that most of the compounds are being reduced in low levels by municipal wastewater treatment processes but quite significant levels of pharmaceuticals enter river waterways. PMID- 23688232 TI - Efficiency of advanced wastewater treatment plant system and laboratory-scale micelle-clay filtration for the removal of ibuprofen residues. AB - The efficiency of Al-Quds Waste Water Treatment Plant (WWTP), which includes sequential elements as activated sludge, ultrafiltration, activated carbon column and reverse osmosis, to remove spiked ibuprofen, a non steroid anti inflammatory drug (NSAID), was investigated. Kinetic studies in pure water and in the activated sludge indicated that the drug was stable during one month of observation. Besides, the overall performance of the integrated plant showed complete removal of ibuprofen from wastewater. Activated carbon column, which was the last element in the sequence before the reverse osmosis system, yielded 95.7% removal of ibuprofen. Batch adsorptions of the drug by using either activated charcoal or composite micelle-clay system were determined at 25 degrees C and well described by Langmuir isotherms. Octadecyltrimethylammonium (ODTMA) bromide and montmorillonite were used to prepare the micelle-clay adsorbent, for which the adsorption kinetics are much faster than activated charcoal. Results suggest that integrating clay-micelle complex filters within the existing WWTP may be promising in improving removal efficiency of the NSAID. PMID- 23688233 TI - Comparison of the standard WHO susceptibility tests and the CDC bottle bioassay for the determination of insecticide susceptibility in malaria vectors and their correlation with biochemical and molecular biology assays in Benin, West Africa. AB - BACKGROUND: The detection of insecticide resistance in natural populations of Anopheles vectors is absolutely necessary for malaria control. In the African region, the WHO insecticide susceptibility test is the most common method for assessing resistance status. In order to search for a simple, rapid and more reliable technique in the assessment of insecticide resistance in malaria vectors, we compared the WHO tests with the CDC bottle bioassay in the Oueme province of southern Benin where insecticide resistance has been widely reported. METHODS: Larvae and pupae of Anopheles gambiae s.l. mosquitoes were collected from the breeding sites in Oueme. WHO and CDC susceptibility tests were conducted simultaneously on unfed female mosquitoes aged 2-5 days old. WHO bioassays were performed with impregnated papers of deltamethrin (0.05%) and bendiocarb (0.1%), whereas CDC bioassays were performed with stock solutions of deltamethrin (12.5 MUg per bottle) and bendiocarb (12.5 MUg per bottle). PCR techniques were used to detect species, Kdr and Ace-1 mutations. CDC biochemical assays using synergists were also conducted to assess the metabolic resistance. RESULTS: A slight decrease in mortality rates was observed with 97.95% and 98.33% obtained from CDC and WHO bioassays respectively in populations of mosquitoes from Adjara and Dangbo. PCR revealed that all specimens tested were Anopheles gambiae s.s. The Kdr mutation was found at high frequency in all populations and both the Kdr mutation and mono-oxygenase enzymes were implicated as mechanisms of pyrethroid resistance in An. gambiae from Misserete. CONCLUSION: This study emphasizes that both WHO and CDC bioassays give similar results with regards to the susceptibility of mosquitoes to insecticides in southern Benin. There were complementarities between both methods, however, some specificity was noted for each of the two methods used. Both Kdr and metabolic mechanisms were implicated in the resistance. PMID- 23688236 TI - Fuzzy-TLX: using fuzzy integrals for evaluating human mental workload with NASA Task Load indeX in laboratory and field studies. AB - The aim of this study was to assess mental workload in which various load sources must be integrated to derive reliable workload estimates. We report a new algorithm for computing weights from qualitative fuzzy integrals and apply it to the National Aeronautics and Space Administration -Task Load indeX (NASA-TLX) subscales in order to replace the standard pair-wise weighting technique (PWT). In this paper, two empirical studies were reported: (1) In a laboratory experiment, age- and task-related variables were investigated in 53 male volunteers and (2) In a field study, task- and job-related variables were studied on aircrews during 48 commercial flights. The results found in this study were as follows: (i) in the experimental setting, fuzzy estimates were highly correlated with classical (using PWT) estimates; (ii) in real work conditions, replacing PWT by automated fuzzy treatments simplified the NASA-TLX completion; (iii) the algorithm for computing fuzzy estimates provides a new classification procedure sensitive to various variables of work environments and (iv) subjective and objective measures can be used for the fuzzy aggregation of NASA-TLX subscales. PRACTITIONER SUMMARY: NASA-TLX, a classical tool for mental workload assessment, is based on a weighted sum of ratings from six subscales. A new algorithm, which impacts on input data collection and computes weights and indexes from qualitative fuzzy integrals, is evaluated through laboratory and field studies. Pros and cons are discussed. PMID- 23688234 TI - Hit identification and optimization in virtual screening: practical recommendations based on a critical literature analysis. AB - A critical analysis of virtual screening results published between 2007 and 2011 was performed. The activity of reported hit compounds from over 400 studies was compared to their hit identification criteria. Hit rates and ligand efficiencies were calculated to assist in these analyses, and the results were compared with factors such as the size of the virtual library and the number of compounds tested. A series of promiscuity, druglike, and ADMET filters were applied to the reported hits to assess the quality of compounds reported, and a careful analysis of a subset of the studies that presented hit optimization was performed. These data allowed us to make several practical recommendations with respect to selection of compounds for experimental testing, definition of hit identification criteria, and general virtual screening hit criteria to allow for realistic hit optimization. A key recommendation is the use of size-targeted ligand efficiency values as hit identification criteria. PMID- 23688235 TI - Antimicrobial activity and cytotoxicity of triterpenes isolated from leaves of Maytenus undata (Celastraceae). AB - BACKGROUND: Plants of the genus Maytenus belong to the family Celastraceae and are widely used in folk medicine as anti-tumour, anti-asthmatic, analgesic, anti inflammatory, antimicrobial and anti-ulcer agents, and as a treatment for stomach problems. The aim of this study was to isolate and identify active compounds with antifungal activity from Maytenus undata after a preliminary study highlighted promising activity in crude extracts. METHODS: Sequential extracts of M. undata leaves prepared using hexane, dichloromethane (DCM), acetone and methanol (MeOH) were tested for activity against Cryptococcus neoformans, a fungal organism implicated in opportunistic infections. Bioassay-guided fractionation of the hexane extract using C. neoformans as test organism was carried out to isolate antifungal compounds. The cytotoxicity of compounds isolated in sufficient quantities was evaluated using a tetrazolium-based colorimetric cellular assay (MTT) and a haemagglutination assay (HA). RESULTS: The hexane extract was most active with an MIC of 20 MUg/ml against C. neoformans. The triterpene compounds friedelin (1), epifriedelanol (2), taraxerol (3), 3-oxo-11alpha-methoxyolean-12 ene-30-oic acid (4), 3-oxo-11alpha-hydroxyolean-12-ene-30-oic acid (5) and 3,11 dihydroxyolean-12-ene-30-oic acid (6) were isolated. Compound 6 was isolated for the first time from a plant species. The antimicrobial activity of compounds 1, 3, 5 and 6 was determined against a range of bacteria and fungi implicated in opportunistic and nosocomial infections. Compounds 5 and 6 were the most active against all the tested microorganisms with MIC values ranging between 24 and 63 MUg/ml, except against Staphylococcus aureus which was relatively resistant. Compounds 1 and 3 had a low toxicity with an LC50 > 200 MUg/ml towards Vero cells in the MTT assay. Compounds 5 and 6 were toxic with LC50 values of 6.03+/-0.02 and 2.98+/-0.01 MUg/ml, respectively. Compounds 1 and 3 similarly were not toxic to the red blood cells (RBCs) but compounds 5 and 6 were toxic, showing HA titer values of 1.33 and 0.67 respectively. CONCLUSIONS: Compounds 5 and 6 were the most active but were also relatively cytotoxic to monkey kidney cells and red blood cells, while the other isolated compounds were less active and less cytotoxic. PMID- 23688237 TI - Successful treatment of venous malformation located on glans penis with dual wavelength 595- and 1064-nm laser system. AB - The management of venous malformation (VM) located on genitalia is complex and challenging. Surgical excision and sclerotherapy are the first-lines therapeutic options, but in certain areas such as the genitalia can be too aggressive. We present a case of VM on the glans penis treated successfully with dual wavelength 595 and 1064 nm laser system. PMID- 23688238 TI - Deciphering teneurin domains that facilitate cellular recognition, cell-cell adhesion, and neurite outgrowth using atomic force microscopy-based single-cell force spectroscopy. AB - Teneurins are evolutionarily conserved transmembrane receptors that function as axon guidance and target selection molecules in the developing nervous system. How teneurins recognize each other, whether they establish neuronal adhesion, and which teneurin specific interactions guide neurons remains to be determined. To reveal insight into these pertinent questions we combine atomic force microscopy based single-cell force spectroscopy with genetic engineering and quantify the interactions teneurins establish between animal cells. Using a combinatorial approach of deletions and swaps of teneurin-1 and teneurin-2 domains, we unravel that teneurins use their NHL (NCL-1, HT2A, and Lin-41) domain to select homophilic teneurins from adjacent cells. This homophilic recognition of teneurins initiates cell-cell adhesion that, dependent on the intracellular domain, strengthens over time. Neurite outgrowth assays show that establishing and strengthening of teneurin-mediated homophilic cell-cell adhesion is required to stop outgrowth. On the basis of the results, we introduce a molecular model of teneurin domains that specify cellular recognition, adhesion strengthening, and neuronal pathfinding. The combined force spectroscopy and genetic approach can be applied to quantitatively decipher the contribution of any neuronal receptor domain and more generally of a given cell surface receptor domain to cell-cell recognition and adhesion. PMID- 23688239 TI - Synthesis and functionalization of BF2-complexes of meso-free 25-oxasmaragdyrin. AB - BF2-complex of meso-free 25-oxasmaragdyrin is synthesized under simple reaction conditions in high yield, and the reactivity of meso-free carbon atom was demonstrated by carrying out functionalization followed by coupling reactions. PMID- 23688240 TI - Proteomic analysis reveals novel extracellular virulence-associated proteins and functions regulated by the diffusible signal factor (DSF) in Xanthomonas oryzae pv. oryzicola. AB - Quorum sensing (QS) in Xanthomonas oryzae pv. oryzicola (Xoc), the causal agent of bacterial leaf streak, is mediated by the diffusible signal factor (DSF). DSF mediating QS has been shown to control virulence and a set of virulence-related functions; however, the expression profiles and functions of extracellular proteins controlled by DSF signal remain largely unclear. In the present study, 33 DSF-regulated extracellular proteins, whose functions include small-protein mediating QS, oxidative adaptation, macromolecule metabolism, cell structure, biosynthesis of small molecules, intermediary metabolism, cellular process, protein catabolism, and hypothetical function, were identified by proteomics in Xoc. Of these, 15 protein encoding genes were in-frame deleted, and 4 of them, including three genes encoding type II secretion system (T2SS)-dependent proteins and one gene encoding an Ax21 (activator of XA21-mediated immunity)-like protein (a novel small-protein type QS signal) were determined to be required for full virulence in Xoc. The contributions of these four genes to important virulence associated functions, including bacterial colonization, extracellular polysaccharide, cell motility, biofilm formation, and antioxidative ability, are presented. To our knowledge, our analysis is the first complete list of DSF regulated extracellular proteins and functions in a Xanthomonas species. Our results show that DSF-type QS played critical roles in regulation of T2SS and Ax21-mediating QS, which sheds light on the role of DSF signaling in Xanthomonas. PMID- 23688241 TI - The expression of cytoglobin as a prognostic factor in gliomas: a retrospective analysis of 88 patients. AB - BACKGROUND: Evidence suggests that cytoglobin (Cygb) may function as a tumor suppressor gene. METHODS: We immunohistochemically evaluated the expression of Cygb, phosphatidylinositol-3 kinase (PI-3K), phosphorylated (p)-Akt, Interleukin 6 (IL-6), tumor necrosis factor-alpha (TNFalpha) and vascular endothelial growth factor (VEGF) in 88 patients with 41 high-grade gliomas and 47 low-grade gliomas. Intratumoral microvessel density (IMD) was also determined and associated with clinicopathological factors. RESULTS: Low expression of Cygb was significantly associated with the higher histological grading and tumor recurrence. A significant negative correlation emerged between Cygb expression and PI3K, p-Akt, IL-6, TNFalpha or VEGF expression. Cygb expression was negatively correlated with IMD. There was a positive correlation between PI3K, p-Akt, IL-6, TNFalpha and VEGF expression with IMD.High histologic grade, tumor recurrence, decreased Cygb expression, increased PI3K expression, increased p-Akt expression and increased VEGF expression correlated with patients' overall survival in univariate analysis. However, only histological grading and Cygb expression exhibited a relationship with survival of patients as independent prognostic factors of glioma by multivariate analysis. CONCLUSIONS: Cygb loss may contribute to tumor recurrence and a worse prognosis in gliomas. Cygb may serve as an independent predictive factor for prognosis of glioma patients. PMID- 23688242 TI - Social capital in relation to alcohol consumption, smoking, and illicit drug use among adolescents: a cross-sectional study in Sweden. AB - BACKGROUND: Social capital has lately received much attention in public health research. However, few studies have examined the influence of social capital on alcohol consumption, smoking and drug use which have strong influence on public health. The present cross-sectional study investigated whether two measures of social capital were related to substance use in a large population of Swedish adolescents. METHODS: A total of 7757 13-18 year old students (participation rate: 78.2%) anonymously completed the Survey of Adolescent Life in Vestmanland 2008 which included questions on sociodemographic background, neighbourhood social capital, general social trust, alcohol consumption, smoking, and illicit drug use. RESULTS: Individuals within the group with low neighbourhood social capital had an approximately 60% increased odds of high alcohol consumption, more than three times increased odds of smoking and more than double the odds of having used illicit drugs compared with individuals with high neighbourhood social capital. Individuals within the group with low general social trust had approximately 50% increased odds of high alcohol consumption and double the odds of smoking and having used illicit drugs compared with individuals with high general social trust. However, social capital at the contextual level showed very weak effects on alcohol consumption, smoking, and illicit drug use. CONCLUSIONS: Social capital may be an important factor in the future development of prevention programs concerning adolescent substance use. However, further replications of the results as well as identifications of direction of causality are needed. PMID- 23688244 TI - Interface engineering to enhance the efficiency of conventional polymer solar cells by alcohol-/water-soluble C60 materials doped with alkali carbonates. AB - Two new C60-based n-type materials, EGMC-OH and EGMC-COOH, functionalized with hydrophilic triethylene glycol groups (TEGs), have been synthesized and employed in conventional polymer solar cells. With the assistance of the TEG-based surfactant, EGMC-OH and EGMC-COOH can be dissolved in highly polar solvents to implement the polar/nonpolar orthogonal solvent strategy, forming an electron modification layer (EML) without eroding the underlying active layer. Multilayer conventional solar cells on the basis of ITO/PEDOT:PSS/P3HT:PC61BM/EML/Ca/Al configuration with the insertion of the EGMC-OH and EGMC-COOH EML between the active layer and the electrode have thus been successfully realized by cost effective solution processing techniques. Moreover, the electron conductivity of the EML can be improved by incorporating alkali carbonates into the EGMC-COOH EML. Compared to the pristine device with a PCE of 3.61%, the devices modified by the Li2CO3-doped EGMC-COOH EML achieved a highest PCE of 4.29%. Furthermore, we demonstrated that the formation of the EGMC-COOH EML can be utilized as a general approach in the fabrication of highly efficient multilayer conventional devices. With the incorporation of the EGMC-COOH doped with 40 wt % Li2CO3, the PCDCTBT C8:PC71BM-based device exhibited a superior PCE of 4.51%, which outperformed the corresponding nonmodified device with a PCE of 3.63%. PMID- 23688243 TI - Mild therapeutic hypothermia is superior to controlled normothermia for the maintenance of blood pressure and cerebral oxygenation, prevention of organ damage and suppression of oxidative stress after cardiac arrest in a porcine model. AB - BACKGROUND: Mild therapeutic hypothermia (HT) has been implemented in the management of post cardiac arrest (CA) syndrome after the publication of clinical trials comparing HT with common practice (ie, usually hyperthermia). Current evidence on the comparison between therapeutic HT and controlled normothermia (NT) in CA survivors, however, remains insufficient. METHODS: Eight female swine (sus scrofa domestica; body weight 45 kg) were randomly assigned to receive either mild therapeutic HT or controlled NT, with four animals per group. Veno arterial extracorporeal membrane oxygenation (ECMO) was established and at minimal ECMO flow (0.5 L/min) ventricular fibrillation was induced by rapid ventricular pacing. After 20 min of CA, circulation was restored by increasing the ECMO flow to 4.5 L/min; 90 min of reperfusion followed. Target core temperatures (HT: 33 degrees C; NT: 36.8 degrees C) were maintained using the heat exchanger on the oxygenator. Invasive blood pressure was measured in the aortic arch, and cerebral oxygenation was assessed using near-infrared spectroscopy. After 60 min of reperfusion, up to three defibrillation attempts were performed. After 90 min of reperfusion, blood samples were drawn for the measurement of troponin I (TnI), myoglobin (MGB), creatine-phosphokinase (CPK), alanin-aminotransferase (ALT), neuron-specific enolase (NSE) and cystatin C (CysC) levels. Reactive oxygen metabolite (ROM) levels and biological antioxidant potential (BAP) were also measured. RESULTS: Significantly higher blood pressure and cerebral oxygenation values were observed in the HT group (P<0.05). Sinus rhythm was restored in all of the HT animals and in one from the NT group. The levels of TnI, MGB, CPK, ALT, and ROM were significantly lower in the HT group (P<0.05); levels of NSE, CysC, and BAP were comparable in both groups. CONCLUSIONS: Our results from animal model of cardiac arrest indicate that HT may be superior to NT for the maintenance of blood pressure, cerebral oxygenation, organ protection and oxidative stress suppression following CA. PMID- 23688245 TI - Ethnobotanic importance of plants used in pigeon-breeding in Eastern Spain. AB - BACKGROUND: The importance that birds of the Columbidae family have had throughout history is visible on the Mediterranean coast. Pigeon fancying is the art of breeding and training carrier pigeons and currently, several breeds exist. The sport of racing pigeons consists in covering a distance at maximum possible speed. However, pigeon breeding has another modality called "sport pigeon", where several males follow a female. This study focusses on ethnobotanical knowledge of native and exotic plant species that are used for diet, breeding, stimulation, healing illnesses and staining the plumage of pigeons bred in captivity. METHODS: Using semi-structured interviews, we gathered information about the different plant species traditionally used for pigeon-breeding in the region of Valencia. Background material on remedies for bird illnesses was gathered from folk botanical references, local books and journals.The plant species were collected in the study area, then identified in the laboratory using dichotomous keys and vouchered in the ABH (Herbarium of Alicante University). We used Excel ((r)) 2003 to perform a simple statistical analysis of the data collected. RESULTS: We collected 56 species of plants (and one variety) that included 29 botanical families. The total number of species was made up of 35 cultivated and 21 wild plants. The most common were Gramineae (14 species), Leguminosae (6 species), and Compositae (4 species). CONCLUSIONS: Pigeon breeding is an immensely popular activity in Eastern Spain, and ethnobiological knowledge about breeding pigeons and caring for them is considerable. The names and traditional uses of plants depend on their geographical location, vernacular names serve as an intangible heritage. Feeding, environmental features, and genetic makeup of individuals are relevant aspects in the maintenance of avian health. PMID- 23688246 TI - Mesenchymal stem cells for anti-cancer drug delivery. AB - Self renewal, extensive proliferation and multilineage differentiation ability in vitro and in vivo make mesenchymal stem cells (MSCs) powerful tools for tissue engineering. Beyond their potential uses in regenerative medicine, an emerging field of research aims to utilize MSCs for anti-cancer treatment. These strategies are based on the remarkable ability of MSCs to localize and integrate into tumor stroma and deliver anti-cancer agents (US20100055167, US20120207725, US20120010499). Genetically engineered MSCs can specifically target different tumor types and locally secrete therapeutic proteins such as interferons alpha and beta, interleukins 2 and 12 or chemokine CX3CL1 (US20110027239, US20120087901, WO2012071527). In addition, MSCs have also been engineered to deliver oncolytic viruses, for targeted chemotherapy using enzyme prodrug conversion or for inducing tumor cell apoptosis by delivering tumor necrosis factor-related apoptosis inducing ligand (TRAIL) (WO2012106281). The patent databases FPO and Delphion were used to locate patents that were published between 2005 and 2013. Here, we present the current progress and the most recent patents on MSC anti-cancer drug delivery systems and discuss future directions in the field. PMID- 23688247 TI - Friendly pathogens: prevent or provoke autoimmunity. AB - The gut microflora is an immense health asset for human beings. The mammalian gut harbors trillions of commensals. These microbes not only modulate local but also systemic immunity. Recently, various reports are evolving, which signify that the gut microbes can modulate, tune and tame the host immune response. Consequently, it advocates the significance of the microbial composition. Further, the microbiota provides a fine equilibrium to host by regulating immune homeostasis. Furthermore, disturbance in this population can incite imbalance in immune system, leading to molecular mimicry and therefore autoimmunity. Hence, it is imperative to understand the influence of these bugs in preventing or provoking immune system against the self-components. In this article, we highlight the interaction between different gut microbes and cells of immune system and the mechanism involved in controlling and curtailing various autoimmune diseases. PMID- 23688248 TI - Pathogenic, diagnostic and vaccine potential of leptospiral outer membrane proteins (OMPs). AB - Pathogenic Leptospira species are important human and animal pathogen that causes leptospirosis, with more than half a million cases reported annually but little is known regarding the true incidence of leptospirosis due to the limitations in diagnosis. Proteins embedded in the outer membrane are found to be prime drug targets due to its key role as receptors for cellular communication and gatekeepers for iron and substrate transport across cell membranes. The major key issues to be addressed to overcome the disease burden of leptospirosis are: need to identify the genes that turn on in vivo; development of rapid diagnostic methods to facilitate the early diagnosis and to develop a universal vaccine. Recent whole genome sequencing of Leptospira species and development of in silico analysis tools have led to the identification of a large number of leptospiral virulence genes, metabolic pathways and surface protein secretion systems that represent potential new targets for the development of anti-leptospiral drug, vaccine and diagnostic strategies. This review surveys the different types of outer membrane proteins (OMPs) of Leptospira and combines all the novel features of OMPs reported till date and put forth some views for future research. PMID- 23688249 TI - Managing work, family, and school roles: disengagement strategies can help and hinder. AB - The extent to which individuals manage multiple role domains has yet to be fully understood. We advance past research by examining the effect of interrole conflict among three very common and critically important life roles-work, family, and school-on three corresponding types of satisfaction. Further, we examine individual-based techniques that can empower people to manage multiple roles. In doing so, we integrate the disengagement strategies from the work recovery and coping literatures. These strategies focus on taking your mind off the problems at hand and include cognitive disengagement (psychological detachment, cognitive avoidance coping), as well as cognitive distortion (escape avoidance coping). We examine these strategies in a two-wave study of 178 individuals faced with the challenge of managing work, family, and school responsibilities. Findings demonstrated a joint offsetting effect of psychological detachment and cognitive avoidance coping on the relationship between work conflict and work satisfaction. Findings also indicated an exacerbating effect of escape avoidance coping on the relationship between work conflict and work satisfaction, school conflict and school satisfaction, and between family conflict and family satisfaction. Implications for theory and practice are discussed. PMID- 23688250 TI - Examining the nomological network of satisfaction with work-life balance. AB - This study expands on past work-life research by examining the nomological network of satisfaction with work-life balance-the overall appraisal or global assessment of how one manages time and energy across work and nonwork domains. Analyses using 456 employees at a midsized organization indicated expected relationships with bidirectional conflict, bidirectional facilitation, and satisfaction with work and nonwork life. Structural equation modeling supported the utility of satisfaction with balance as a unique component of work-life interface perceptions. Results also indicated that satisfaction with balance mediated the relationship between some conflict/facilitation and life satisfaction outcomes, though conflict and facilitation maintained unique predictive validity on domain specific outcomes (i.e., work-to-life conflict and facilitation with work life satisfaction; life-to-work conflict and facilitation with nonwork life satisfaction). PMID- 23688251 TI - Which hemostatic surgical devices should be used for thyroid surgery, or should we just continue to clamp and tie? PMID- 23688252 TI - Arsenic speciation and localization in horticultural produce grown in a historically impacted mining region. AB - A field and market basket study (~1300 samples) of locally grown fruits and vegetables from historically mined regions of southwest (SW) England (Cornwall and Devon), and as reference, a market basket study of similarly locally grown produce from the northeast (NE) of Scotland (Aberdeenshire) was conducted to determine the concentration of total and inorganic arsenic present in produce from these two geogenically different areas of the U.K. On average 98.5% of the total arsenic found was present in the inorganic form. For both the market basket and the field survey, the highest total arsenic was present in open leaf structure produce (i.e., kale, chard, lettuce, greens, and spinach) being most likely to soil/dust contamination of the open leaf structure. The concentration of total arsenic in potatoes, swedes, and carrots was lower in peeled produce compared to unpeeled produce. For baked potatoes, the concentration of total arsenic in the skin was higher compared to the total arsenic concentration of the potato flesh, this difference in localization being confirmed by laser ablation inductively coupled plasma mass spectroscopy (LA-ICP-MS). For all above ground produce (e.g., apples), peeling did not have a significant effect on the concentration of total arsenic present. PMID- 23688254 TI - Design, synthesis, and initial evaluation of a high affinity positron emission tomography probe for imaging matrix metalloproteinases 2 and 9. AB - The activity of matrix metalloproteinases (MMPs) is elevated locally under many pathological conditions. Gelatinases MMP2 and MMP9 are of particular interest because of their implication in angiogenesis, cancer cell proliferation and metastasis, and atherosclerotic plaque rupture. The aim of this study was to identify and develop a selective gelatinase inhibitor for imaging active MMP2/MMP9 in vivo. We synthesized a series of N-sulfonylamino acid derivatives with low to high nanomolar inhibitory potencies. (R)-2-(4-(4 Fluorobenzamido)phenylsulfonamido)-3-(1H-indol-3-yl)propanoic acid (7) exhibited the best in vitro binding properties: MMP2 IC50 = 1.8 nM, MMP9 IC50 = 7.2 nM. Radiolabeling of 7 with no carrier added (18)F-radioisotope was accomplished starting from iodonium salts as precursors. The radiochemical yield strongly depended on the iodonium counteranion (ClO4(-) > Br(-) > TFA(-) > tosylate). (18)F-7 was obtained in up to 20% radiochemical yield (decay corrected), high radiochemical purity, and >90 GBq/MUmol specific radioactivity. The radiolabeled compound showed excellent stability in vitro and in mice in vivo. PMID- 23688253 TI - Delta-like 1 regulates Bergmann glial monolayer formation during cerebellar development. AB - BACKGROUND: Bergmann glia (BG) are unipolar cerebellar astrocytes. The somata of mature BG reside in the Purkinje cell layer and extend radially arranged processes to the pial surface. BG have multiple branched processes, which enwrap the synapses of Purkinje cell dendrites. They migrate from the ventricular zone and align next to the Purkinje cell layer during development. Previously, we reported that Notch1, Notch2, and RBPj genes in the BG play crucial roles in the monolayer formation and morphogenesis of BG. However, it remains to be determined which ligand activates Nocth1 and Notch 2 on BG. Delta-like 1 (Dll1) is a major ligand of Notch receptors that is expressed in the developing cerebellum. RESULTS: In this study, we used human glial fibrillary acidic protein (hGFAP) promoter-driven Cre-mediated recombination to delete Dll1 in BG. Dll1-conditional mutant mice showed disorganization of Bergmann fibers, ectopic localization of BG in the molecular layer and a reduction in the number of BG. CONCLUSION: These results suggest that Dll1 is required for the formation of the BG layer and its morphological maturation, apparently through a Notch1/2-RBPj dependent signaling pathway. PMID- 23688255 TI - A study of general practitioners' perspectives on electronic medical records systems in NHSScotland. AB - BACKGROUND: Primary care doctors in NHSScotland have been using electronic medical records within their practices routinely for many years. The Scottish Health Executive eHealth strategy (2008-2011) has recently brought radical changes to the primary care computing landscape in Scotland: an information system (GPASS) which was provided free-of-charge by NHSScotland to a majority of GP practices has now been replaced by systems provided by two approved commercial providers. The transition to new electronic medical records had to be completed nationally across all health-boards by March 2012. METHODS: We carried out 25 in depth semi-structured interviews with primary care doctors to elucidate GPs' perspectives on their practice information systems and collect more general information on management processes in the patient surgical pathway in NHSScotland. We undertook a thematic analysis of interviewees' responses, using Normalisation Process Theory as the underpinning conceptual framework. RESULTS: The majority of GPs' interviewed considered that electronic medical records are an integral and essential element of their work during the consultation, playing a key role in facilitating integrated and continuity of care for patients and making clinical information more accessible. However, GPs expressed a number of reservations about various system functionalities - for example: in relation to usability, system navigation and information visualisation. CONCLUSION: Our study highlights that while electronic information systems are perceived as having important benefits, there remains substantial scope to improve GPs' interaction and overall satisfaction with these systems. Iterative user-centred improvements combined with additional training in the use of technology would promote an increased understanding, familiarity and command of the range of functionalities of electronic medical records among primary care doctors. PMID- 23688256 TI - Phosphoproteomic analysis of differentiating Leishmania parasites reveals a unique stage-specific phosphorylation motif. AB - Protists of the genus Leishmania are obligatory intracellular parasites that cause a wide range of cutaneous, mucocutaneous, and visceral diseases in humans. They cycle between phagolysosomes of mammalian macrophages and the sand fly midgut, proliferating as intracellular amastigotes and extracellular promastigotes, respectively. Exposure to a lysosomal environment, i.e. acidic pH and body temperature, signals promastigotes to differentiate into amastigotes. Time course analyses indicated that Leishmania differentiation is a highly regulated and coordinated process. However, the role of posttranslational events such as protein phosphorylation in this process is still unknown. Herein, we analyzed and compared the phosphoproteomes of L. donovani amastigotes and promastigotes using an axenic host-free system that simulates parasite differentiation. Shotgun phosphopeptide analysis revealed 1614 phosphorylation residues (p-sites) corresponding to 627 proteins. The analysis indicated that the majority of the p-sites are stage-specific. Serine phosphorylation in a previously identified trypanosomatid-specific "SF" motif was significantly enriched in amastigotes. We identified a few phosophotyrosines (pY), mostly in proteins known to participate in signal transduction pathways. The analysis indicated that Leishmania contains proteins with multiple p-sites that are phosphorylated at distinct stages of the life cycle. For over half of the phosphorylation events, changes in phosphoprotein abundance did not positively correlate with changes in protein abundance, suggesting functional regulation. This study compares, for the first time, the phosphoproteins of L. donovani axenic promastigotes and amastigotes and provides the largest data set of the Leishmania phosphoproteome to date. PMID- 23688257 TI - Magnetic hot spots in closely spaced thick gold nanorings. AB - Light-matter interaction at optical frequencies is mostly mediated by the electric component of the electromagnetic field, with the magnetic component usually being considered negligible. Recently, it has been shown that properly engineered metallic nanostructures can provide a magnetic response at optical frequencies originated from real or virtual flows of electric current in the structure. In this work, we demonstrate a magnetic plasmonic mode which emerges in closely spaced thick gold nanorings. The plasmonic resonance obtains a magnetic dipole character by sufficiently increasing the height of the nanorings. Numerical simulations show that a virtual current loop appears at resonance for sufficiently thick nanorings, resulting in a strong concentration of the magnetic field in the gap region (magnetic hot spot). We find that there is an optimum thickness that provides the maximum magnetic intensity enhancement (over 200-fold enhancement) and give an explanation of this observation. This strong magnetic resonance, observed both experimentally and theoretically, can be used to build new metamaterials and resonant loop nanoantennas at optical frequencies. PMID- 23688258 TI - GPER-1 expression decreases during breast cancer tumorigenesis. AB - GPER-1 protein expression was immunohistochemically examined in 164 primary breast cancer specimens and their matched normal breast epithelium. GPER-1 down regulation correlated significantly with increased histological grading (p = .015), lymph node metastases (p = .032), and negative estrogen receptor status (p = .018). The decrease of GPER-1 expression in breast cancer tissue, relative to normal tissue, was associated with poor overall survival (p = .043) and disease free survival (p = .037) and remained a significant unfavorable factor in multivariate analysis for DFS (HR = 1.569; 95% CI, 1.024-2.797; p = .041) and OS (HR = 2.082; 95% CI, 1.248-4.773; p = .039). Thus aberrant GPER-1 expression seems to be an important factor in breast cancer progression. PMID- 23688259 TI - Pragmatic controlled trial to prevent childhood obesity in maternity and child health care clinics: pregnancy and infant weight outcomes (the VACOPP Study). AB - BACKGROUND: According to current evidence, the prevention of obesity should start early in life. Even the prenatal environment may expose a child to unhealthy weight gain; maternal gestational diabetes is known to be among the prenatal risk factors conducive to obesity. Here we report the effects of antenatal dietary and physical activity counselling on pregnancy and infant weight gain outcomes. METHODS: The study was a non-randomised controlled pragmatic trial aiming to prevent childhood obesity, the setting being municipal maternity health care clinics. The participants (n = 185) were mothers at risk of developing gestational diabetes mellitus and their offspring. The children of the intervention group mothers were born between 2009 and 2010, and children of the control group in 2008. The intervention started between 10-17 gestational weeks and consisted of individual counselling on diet and physical activity by a public health nurse, and two group counselling sessions by a dietician and a physiotherapist. The expectant mothers also received a written information leaflet to motivate them to breastfeed their offspring for at least 6 months. We report the proportion of mothers with pathological glucose tolerance at 26-28 weeks' gestation, the mother's gestational weight gain (GWG) and newborn anthropometry. Infant weight gain from 0 to 12 months of age was assessed as weight-for-length standard deviation scores (SDS) and mixed effect linear regression models. RESULTS: Intervention group mothers had fewer pathological oral glucose tolerance test results (14.6% vs. 29.2%; 95% CI 8.9 to 23.0% vs. 20.8 to 39.4%; p-value 0.016) suggesting that the intervention improved gestational glucose tolerance. Mother's GWG, newborn anthropometry or infant weight gain did not differ significantly between the groups. CONCLUSION: Since the intervention reduced the prevalence of gestational diabetes mellitus, it may have the potential to diminish obesity risk in offspring. However, results from earlier studies suggest that the possible effect on the offspring's weight gain may manifest only later in childhood. TRIAL REGISTRATION: Clinical Trials gov: NCT00970710. PMID- 23688260 TI - Assessing equity of healthcare utilization in rural China: results from nationally representative surveys from 1993 to 2008. AB - BACKGROUND: The phenomenon of inequitable healthcare utilization in rural China interests policymakers and researchers; however, the inequity has not been actually measured to present the magnitude and trend using nationally representative data. METHODS: Based on the National Health Service Survey (NHSS) in 1993, 1998, 2003, and 2008, the Probit model with the probability of outpatient visit and the probability of inpatient visit as the dependent variables is applied to estimate need-predicted healthcare utilization. Furthermore, need-standardized healthcare utilization is assessed through indirect standardization method. Concentration index is measured to reflect income-related inequity of healthcare utilization. RESULTS: The concentration index of need-standardized outpatient utilization is 0.0486[95% confidence interval (0.0399, 0.0574)], 0.0310[95% confidence interval (0.0229, 0.0390)], 0.0167[95% confidence interval (0.0069, 0.0264)] and -0.0108[95% confidence interval (-0.0213, -0.0004)] in 1993, 1998, 2003 and 2008, respectively. For inpatient service, the concentration index is 0.0529[95% confidence interval (0.0349, 0.0709)], 0.1543[95% confidence interval (0.1356, 0.1730)], 0.2325[95% confidence interval (0.2132, 0.2518)] and 0.1313[95% confidence interval (0.1174, 0.1451)] in 1993, 1998, 2003 and 2008, respectively. CONCLUSIONS: Utilization of both outpatient and inpatient services was pro-rich in rural China with the exception of outpatient service in 2008. With the same needs for healthcare, rich rural residents utilized more healthcare service than poor rural residents. Compared to utilization of outpatient service, utilization of inpatient service was more inequitable. Inequity of utilization of outpatient service reduced gradually from 1993 to 2008; meanwhile, inequity of inpatient service utilization increased dramatically from 1993 to 2003 and decreased significantly from 2003 to 2008. Recent attempts in China to increase coverage of insurance and primary healthcare could be a contributing factor to counteract the inequity of outpatient utilization, but better benefit packages and delivery strategies still need to be tested and scaled up to reduce future inequity in inpatient utilization in rural China. PMID- 23688262 TI - Monoliths of semiconducting block copolymers by magnetic alignment. AB - Achieving highly ordered and aligned assemblies of organic semiconductors is a persistent challenge for improving the performance of organic electronics. This is an acute problem in macromolecular systems where slow kinetics and long-range disorder prevail, thus making the fabrication of high-performance large-area semiconducting polymer films a nontrivial venture. Here, we demonstrate that the anisotropic nature of semiconducting chromophores can be effectively leveraged to yield hierarchically ordered materials that can be readily macroscopically aligned. An n-type mesogen was synthesized based on a perylene diimide (PDI) rigid core coupled to an imidazole headgroup via an alkyl spacer. Supramolecular assembly between the imidazole and acrylic acid units on a poly(styrene-b-acrylic acid) block copolymer yielded self-assembled hexagonally ordered polystyrene cylinders within a smectic A mesophase of the PDI mesogen and poly(acrylic acid). We show that magnetic fields can be used to control the alignment of the PDI species and the block copolymer superstructure concurrently in a facile manner during cooling from a high-temperature disordered state. The resulting materials are monoliths, with a single well-defined orientation of the semiconducting chromophore and block copolymer microdomains throughout the sample. This synergistic introduction of both functional properties and the means of controlling alignment by supramolecular attachment of mesogenic species to polymer backbones offer new possibilities for the modular design of functional nanostructured materials. PMID- 23688261 TI - DNA-N-glycosylases process novel O-glycosidic sites in DNA. AB - After the hydrolysis of the N-glycosyl bond between a damaged base and C1' of a deoxyribosyl moiety of DNA, human alkyladenine DNA glycosylase (AAG) and Escherichia coli 3-methyladenine DNA glycosylase II (AlkA) bind tightly to their abasic DNA products, potentially protecting these reactive species. Here we show that both AAG and AlkA catalyze reactions between bound abasic DNA and small, primary alcohols to form novel DNA-O-glycosides. The synthesis reactions are reversible, as the DNA-O-glycosides are converted back into abasic DNA upon being incubated with AAG or AlkA in the absence of alcohol. AAG and AlkA are therefore able to hydrolyze O-glycosidic bonds in addition to N-glycosyl bonds. The newly discovered DNA-O-glycosidase activities of both enzymes compare favorably with their known DNA-N-glycosylase activities: AAG removes both methanol and 1,N(6) ethenoadenine (epsilonA) from DNA with single-turnover rate constants that are 2.9 * 10(5)-fold greater than the corresponding uncatalyzed rates, whereas the rate enhancement of 3.7 * 10(7) for removal of methanol from DNA by AlkA is 300 fold greater than its rate enhancement for removal of epsilonA from DNA. Although the biological significance of the DNA-O-glycosidase reactions is not known, the evolution of new DNA repair pathways may be aided by enzymes that practice catalytic promiscuity, such as these two unrelated DNA glycosylases. PMID- 23688263 TI - High-efficiency photoelectrochemical properties by a highly crystalline CdS sensitized ZnO nanorod array. AB - A ZnO nanorod array with comparatively long nanorods was successfully prepared on a Ti substrate by applying a hydrothermal method twice. CdS nanoparticles with high crystallinity were deposited onto the surface of ZnO nanorods through a galvanostatic electrodeposition method. CdS-sensitized ZnO nanorod arrays after being hydrothermally grown twice with the second growth time of 6 h possessed the best photoelectrochemical performance. The photoinduced current densities at a 0 V bias potential are 23.7 and 15.8 mA.cm(-2) under the illumination of simulated sunlight and visible light, respectively. The monochromatic incident photon-to electron conversion efficiency values at the wavelength of 380-520 nm are in the range of 50-60%, which indicated its high photoelectric conversion efficiency. The contribution from visible light is significantly higher than that from UV light. The prepared photoanodes in the present work exhibit a potential application in photoelectrochemical hydrogen production from water reduction under sunlight. PMID- 23688264 TI - Implementing the ten steps to successful breastfeeding in multiple hospitals serving low-wealth patients in the US: innovative research design and baseline findings. AB - BACKGROUND: The Ten Steps to Successful Breastfeeding are maternity practices proven to support successful achievement of exclusive breastfeeding. They also are the basis for the WHO/UNICEF Baby-Friendly Hospital Initiative (BFHI). This study explores implementation of these steps in hospitals that serve predominantly low wealth populations. METHODS: A quasi-experimental design with mixed methods for data collection and analysis was included within an intervention project. We compared the impact of a modified Ten Steps implementation approach to a control group. The intervention was carried out in hospitals where: 1) BFHI designation was not necessarily under consideration, and 2) the majority of the patient population was low wealth, i.e., eligible for Medicaid. Hospitals in the research aspect of this project were systematically assigned to one of two groups: Initial Intervention or Initial Control/Later Intervention. This paper includes analyses from the baseline data collection, which consisted of an eSurvey (i.e., Carolina B-KAP), Maternity Practices in Infant Nutrition and Care survey tool (mPINC), the BFHI Self-Appraisal, key informant interviews, breastfeeding data, and formatted feedback discussion. RESULTS: Comparability was ensured by statistical and non-parametric tests of baseline characteristics of the two groups. Additional findings of interest included: 1) a universal lack of consistent breastfeeding records and statistics for regular monitoring/review, 2) widespread misinterpretation of associated terminology, 3) health care providers' reported practices not necessarily reflective of their knowledge and attitudes, and 4) specific steps were found to be associated with hospital breastfeeding rates. A comprehensive set of facilitators and obstacles to initiation of the Ten Steps emerged, and hospital specific practice change challenges were identified. DISCUSSION: This is one of the first studies to examine introduction of the Ten Steps in multiple hospitals with a control group and in hospitals that were not necessarily interested in BFHI designation, where the population served is predominantly low wealth, and with the use of a mixed methods approach. Limitations including numbers of hospitals and inability to adhere to all elements of the design are discussed. CONCLUSIONS: For improvements in quality of care for breastfeeding dyads, innovative and site-specific intervention modification must be considered. PMID- 23688266 TI - Complete mitochondrial genome of the brain coral Platygyra carnosus. AB - Despite the importance of many species of Faviidae as structural-forming corals, only five species in three genera had a sequenced mitochondrial genome. We report the sixth complete mitochondrial genome in this family from the brain coral Platygyra carnosus, which is 16,463 bp in length and AT rich (67.0%). It has the typical coral mitochondrial gene arrangement, consisting of 13 protein-coding genes, 2 ribosomal RNA (rRNA) genes and 2 transfer RNA (tRNA) genes (tRNA-Met and tRNA-Trp). The ND5 gene is interrupted by a large group I intron which contains 10 protein-coding genes and 12S rRNA. Compared with related species from the same family, the three non-coding regions that are longer than 200 bp are less conserved in sequences than the coding regions, indicating potential markers for population genetic studies. PMID- 23688265 TI - Treatment of heart failure in adults with thalassemia major: response in patients randomised to deferoxamine with or without deferiprone. AB - BACKGROUND: Established heart failure in thalassaemia major has a poor prognosis and optimal management remains unclear. METHODS: A 1 year prospective study comparing deferoxamine (DFO) monotherapy or when combined with deferiprone (DFP) for patients with left ventricular ejection fraction (LVEF) <56% was conducted by the Thalassemia Clinical Research Network (TCRN). All patients received DFO at 50 60 mg/kg 12-24 hr/day sc or iv 7 times weekly, combined with either DFP 75 at mg/kg/day (combination arm) or placebo (DFO monotherapy arm). The primary endpoint was the change in LVEF by CMR. RESULTS: Improvement in LVEF was significant in both study arms at 6 and 12 months (p = 0.04), normalizing ventricular function in 9/16 evaluable patients. With combination therapy, the LVEF increased from 49.9% to 55.2% (+5.3% p = 0.04; n = 10) at 6 months and to 58.3% at 12 months (+8.4% p = 0.04; n = 7). With DFO monotherapy, the LVEF increased from 52.8% to 55.7% (+2.9% p = 0.04; n = 6) at 6 months and to 56.9% at 12 months (+4.1% p = 0.04; n = 4). The LVEF trend did not reach statistical difference between study arms (p = 0.89). In 2 patients on DFO monotherapy during the study and in 1 patient on combined therapy during follow up, heart failure deteriorated fatally. The study was originally powered for 86 participants to determine a 5% difference in LVEF improvement between treatments. The study was prematurely terminated due to slow recruitment and with the achieved sample size of 20 patients there was 80% power to detect an 8.6% difference in EF, which was not demonstrated. Myocardial T2* improved in both arms (combination +1.9 +/- 1.6 ms p = 0.04; and DFO monotherapy +1.9 +/- 1.4 ms p = 0.04), but with no significant difference between treatments (p = 0.65). Liver iron (p = 0.03) and ferritin (p < 0.001) both decreased significantly in only the combination group. CONCLUSIONS: Both treatments significantly improved LVEF and myocardial T2*. Although this is the largest and only randomized study in patients with LV decompensation, further prospective evaluation is needed to identify optimal chelation management in these high-risk patients. PMID- 23688267 TI - Complete mitochondrial genome of an Asian Lesser White-toothed Shrew, Crocidura shantungensis (Soricidae). AB - The complete mitochondrial genome was sequenced and annotated newly from an individual of Crocidura shantungensis (Soricidae) from Korea. The total length of the C. shantungensis genome is 17,160 bp, with a base composition of 32.5% A, 32.7% T, 21.6% C, and 13.1% G. PMID- 23688270 TI - Retraction: Profiling the different needs and expectations of patients for population-based medicine: a case study using segmentation analysis. PMID- 23688269 TI - Detection of E2A-PBX1 fusion transcripts in human non-small-cell lung cancer. AB - BACKGROUND: E2A-PBX1 fusion gene caused by t(1;19)(q23;p13), has been well characterized in acute lymphoid leukemia (ALL). There is no report on E2A-PBX1 fusion transcripts in non-small-cell lung cancer (NSCLC). METHODS: We used polymerase chain reaction (PCR) to detect E2A-PBX1 fusion transcripts in human NSCLC tissue specimens and cell lines. We analyzed correlation of E2A-PBX1 fusion transcripts with clinical outcomes in 76 patients with adenocarcinoma in situ (AIS) and other subgroups. We compared mutation status of k-ras, p53 and EGFR in 22 patients with E2A-PBX1 fusion transcripts. RESULTS: We detected E2A-PBX1 transcripts in 23 of 184 (12.5%) NSCLC tissue specimens and 3 of 13 (23.1%) NSCLC cell lines. Presence of E2A-PBX1 fusion transcripts correlated with smoking status in female patients (P=0.048), AIS histology (P=0.006) and tumor size (P=0.026). The overall survival was associated with gender among AIS patients (P=0.0378) and AIS patients without E2A-PBX1 fusion transcripts (P=0.0345), but not among AIS patients with E2A-PBX1 fusion transcripts (P=0.6401). The overall survival was also associated with status of E2A-PBX1 fusion transcripts among AIS stage IA patients (P=0.0363) and AIS stage IA female patients (P=0.0174). In addition, among the 22 patients with E2A-PBX1 fusion transcripts, 12 (54.5%) patients including all four non-smokers, showed no common mutations in k-ras, p53 and EGFR. CONCLUSIONS: E2A-PBX1 fusion gene caused by t(1;19)(q23;p13) may be a common genetic change in AIS and a survival determinant for female AIS patients at early stage. PMID- 23688271 TI - Non-FDG-avid primary papillary thyroid carcinoma may not differ from FDG-avid papillary thyroid carcinoma. AB - BACKGROUND: FDG (2-[(18)F]Fluoro-2-D-deoxyglucose-positron emission tomography (PET)/computed tomography (CT), which can detect a change in glucose metabolism in cancer cells, has been introduced as a diagnostic and prognostic tool in papillary thyroid carcinoma (PTC). However, differences in the clinicopathological and biological characteristics between primary PTCs with FDG uptake and those without FDG uptake are not well established. METHODS: A total of 188 patients with PTC who had preoperative PET/CT scans were enrolled to compare the differences of clinicopathological parameters between FDG-avid (F-PTC; n = 150) and non-FDG-avid tumors (FN-PTC; n = 38). Immunohistochemical staining for glucose transporter (GLUT)-1 and hypoxia-inducible factor-1 alpha (HIF-1alpha) was performed. RESULTS: FN-PTCs were smaller; had a lower incidence of lymphatic invasion, vascular invasion, multifocality, and central lymph node metastasis; and had a lower maximum standardized uptake value than F-PTCs. After exclusion of high-risk patients for recurrence, FN-PTCs remained smaller (p < 0.001) and had less lymphatic invasion (p = 0.061). Among tumors larger than the spatial resolution of the PET/CT scan, macrocalcification was more frequent in FN-PTC than in F-PTC (p = 0.043). While FN-PTC and F-PTC showed no difference in GLUT-1 expression (50% vs. 75%, p = 0.363), FN-PTC showed lower HIF-1alpha immunoreactivity than F-PTC (25.0% vs. 75.0%, p = 0.032). CONCLUSION: Tumor size and macrocalcification are clinicopathological differences between FN-PTC and F PTC. Biologically, HIF-1alpha may be responsible for increased FDG uptake in PTC. PMID- 23688272 TI - Transglutaminase inhibition as a possible therapeutical approach to protect cells from death in neurodegenerative diseases. AB - Transglutaminases are ubiquitous enzymes which catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross linking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted /crosslinked adducts) or -OH groups (to form ester linkages). In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Recently, "tissue" transglutaminase (transglutaminase 2), a member of the transglutaminase family of enzymes, has been shown to be involved in the molecular mechanisms responsible for some human pathologies, including celiac disease, a very widespread human pathology. Transglutaminase activity has also been hypothesized to be involved in the pathogenetic mechanisms responsible for other several human diseases, including neurodegenerative diseases, often associated to celiac disease. Neurodegenerative diseases, such as Alzheimer's Disease, Parkinson's Disease, supranuclear palsy, Huntington's Disease and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This review focuses on the possible therapeutic effects of selective transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity and on the strategies to design such transglutaminase inhibitors. In addition, the review also examines available patents that relates to cysteamine and derivatives. PMID- 23688273 TI - Adsorption of CO2, CH4, and N2 on ordered mesoporous carbon: approach for greenhouse gases capture and biogas upgrading. AB - Separation of CO2 and N2 from CH4 is significantly important in natural gas upgrading, and capture/removal of CO2, CH4 from air (N2) is essential to greenhouse gas emission control. Adsorption equilibrium and kinetics of CO2, CH4, and N2 on an ordered mesoporous carbon (OMC) sample were systematically investigated to evaluate its capability in the above two applications. The OMC was synthesized and characterized with TEM, TGA, small-angle XRD, and nitrogen adsorption/desorption measurements. Pure component adsorption isotherms of CO2, CH4, and N2 were measured at 278, 298, and 318 K and pressures up to 100 kPa, and correlated with the Langmuir model. These data were used to estimate the separation selectivities for CO2/CH4, CH4/N2, and CO2/N2 binary mixtures at different compositions and pressures according to the ideal adsorbed solution theory (IAST) model. At 278 K and 100 kPa, the predicted selectivities for equimolar CO2/CH4, CH4/N2, and CO2/N2 are 3.4, 3.7, and 12.8, respectively; and the adsorption capacities for CH4 and CO2 are 1.3 and 3.0 mmol/g, respectively. This is the first report of a versatile mesoporous material that displays both high selectivities and large adsorption capacities for separating CO2/CH4, CH4/N2, and CO2/N2 mixtures. PMID- 23688274 TI - Achieving a new controllable male contraception by the photothermal effect of gold nanorods. AB - During the process of human civilization, owning household pets has become increasingly popular. However, dogs and cats may be reservoirs or vectors of transmissible diseases to humans. Confronted with the overpopulation of pets, traditional contraception methods, surgical methods of sterilization, for animals are used, namely, ovariohysterectomy and orchidectomy. Therefore, a simple, nonsurgical, controllable, more effective and less expensive contraception method is highly desirable. In this study, we show that in situ testicular injection of methoxy poly(ethylene glycol)-modified gold nanorods with near-infrared irradiation in male mice can achieve short-lived or permanent male infertility. In a lower hyperthermia treatment, the morphology of testes and seminiferous tubules is only partly injured, and fertility indices are decreased to 10% at day 7, then recovered to 50% at day 60. In a higher hyperthermia treatment, the morphology of testes and seminiferous tubules are totally destroyed, and fertility indices are decreased to 0 at day 7. Overall, our results indicate a potential application of plasmonic nanomaterials for male contraception. PMID- 23688275 TI - Development of a prospective isopropyl alcohol-loaded pharmaceutical base using simultaneous in vitro/in vivo characterization methods of skin performance. AB - CONTEXT: Approaching of pharmaceutical and cosmetic industries in some aspects inevitably influence formulation of topical pharmaceuticals, urging researchers to introduce novel excipients with proven benefits over traditional ones. In that context, alkyl polyglucosides (APG) emerge as prominent natural-origin emulsifiers with numerous favorable features (biodegradability, dermatological acceptability, desirable sensory properties). OBJECTIVE: To evaluate APG stabilized bases (alone and upon addition of isopropyl alcohol) and their impact on skin performance. A simultaneous in vitro/in vivo skin absorption study was conducted to evaluate whether the tape stripping technique could be recommended as an in vivo tool for skin penetration assessment during formulation optimization process. MATERIALS AND METHODS: After a comprehensive physicochemical characterization, biopharmaceutical properties of APG-bases versus reference ones were assessed through a combined in vitro (release/permeation) and in vivo approach. RESULTS AND DISCUSSION: Physicochemical characterization revealed substantial difference in structural ordering due to the formation of various mesomorphic phases. The enhancer-loaded APG base resulted in significantly higher drug levels at all depths into the stratum corneum, indicating that the selected enhancer along with specific colloidal structure has increased the extent of drug delivery. CONCLUSION: Results recommend the investigated emulsifier for stabilization of topical drug delivery systems, not only for their ability to sustain the addition of isopropyl alcohol which proved to be a valuable enhancer, but also satisfactory skin absorption and tolerability when compared to samples stabilized by conventional emulsifier. Tape stripping proved to be a useful and yet inexpensive tool for in vivo trials, able to discriminate subtle differences in dermal availability. PMID- 23688276 TI - Three-ways crossover bioequivalence study of cephalexin in healthy Malay volunteers. AB - CONTEXT: Although the general pharmacokinetics of cephalexin is quite established up-to-date, however, no population-based study on Cephalexin pharmacokinetics profile in Malay population has been reported yet in the literature. OBJECTIVE: The objective of this study was to investigate the pharmacokinetics and to compare the bioavailability of three cephalexin products, Ospexin(r) versus MPI Cephalexin(r) tablet and MPI Cephalexin(r) capsule, in healthy Malay ethnic male volunteers in Malaysia. MATERIAL AND METHOD: A single dose, randomized, fasting, three-period, three-treatment, three-sequence crossover, open label bioequivalence study was conducted in 24 healthy Malay adult male volunteers, with 1 week washout period. The drug concentration in the sample was analyzed using high performance liquid chromatography. RESULT: The mean (SD) pharmacokinetic parameter results of Ospexin(r) were Cmax, 17.39 (4.15) MUg/mL; AUC0-6, 28.90 (5.70) ug/mL * h; AUC0-infinity, 30.07 (5.94) ug/mL * h; while, those of MPI Cephalexin(r) tablet were Cmax, 18.29 (3.01) MUg/mL; AUC0-6, 30.02 (4.80) ug/mL * h; AUC00-infinity, 31.33 (5.18) ug/mL * h and MPI Cephalexin(r) capsule were Cmax, 18.25 (3.92) MUg/mL; AUC0-6, 30.04 (5.13) ug/mL * h; AUC0 infinity, 31.22 (5.29) ug/mL * h. CONCLUSION: The 90% confidence intervals for the logarithmic transformed Cmax, AUC0-6 and AUC0-infinity, of Ospexin(r) versus MPI Cephalexin(r) tablet and Ospexin(r) versus MPI Cephalexin(r) capsule were between 0.80 and 1.25. Both Cmax and AUC met the predetermined criteria for assuming bioequivalence. The pharmacokinetic profile of cephalexin in Malay population does not vary much from other world population. PMID- 23688277 TI - Function of resistance conferring Plasmodium falciparum chloroquine resistance transporter isoforms. AB - The function of Plasmodium falciparum chloroquine resistance transporter (PfCRT) can be quantified using a Saccharomyces cerevisiae model system [Baro, N. K., Pooput, C., and Roepe, P. D. (2011) Biochemistry 50, 6701-6710]. We further optimized this system to distinguish PfCRT isoforms found in P. falciparum strains and isolates from across the globe. We created and expressed 13 naturally occurring pfcrt alleles associated with a range of chloroquine resistant (CQR) phenotypes. Using galactose induction of PfCRT, we quantified PfCRT and chloroquine (CQ)-dependent yeast growth inhibition and [3H]CQ transport specifically due to a given PfCRT isoform. Surprisingly, we found poor correlation between these parameters and the CQ IC50 observed in strains of malaria harboring the same isoforms. This suggested that an increased level of CQ transport due to PfCRT mutation is necessary, but not sufficient, for the range of CQ IC50 values observed in globally distributed CQR P. falciparum isolates. PMID- 23688278 TI - Assessing potential spatial accessibility of health services in rural China: a case study of Donghai County. AB - INTRODUCTION: There is a great health services disparity between urban and rural areas in China. The percentage of people who are unable to access health services due to long travel times increases. This paper takes Donghai County as the study unit to analyse areas with physician shortages and characteristics of the potential spatial accessibility of health services. We analyse how the unequal health services resources distribution and the New Cooperative Medical Scheme affect the potential spatial accessibility of health services in Donghai County. We also give some advice on how to alleviate the unequal spatial accessibility of health services in areas that are more remote and isolated. METHODS: The shortest traffic times of from hospitals to villages are calculated with an O-D matrix of GIS extension model. This paper applies an enhanced two-step floating catchment area (E2SFCA) method to study the spatial accessibility of health services and to determine areas with physician shortages in Donghai County. The sensitivity of the E2SFCA for assessing variation in the spatial accessibility of health services is checked using different impedance coefficient valuesa. Geostatistical Analyst model and spatial analyst method is used to analyse the spatial pattern and the edge effect of potential spatial accessibility of health services. RESULTS: The results show that 69% of villages have access to lower potential spatial accessibility of health services than the average for Donghai County, and 79% of the village scores are lower than the average for Jiangsu Province. The potential spatial accessibility of health services diminishes greatly from the centre of the county to outlying areas. Using a smaller impedance coefficient leads to greater disparity among the villages. The spatial accessibility of health services is greater along highway in the county. CONCLUSIONS: Most of villages are in underserved health services areas. An unequal distribution of health service resources and the reimbursement policies of the New Cooperative Medical Scheme have led to an edge effect regarding spatial accessibility of health services in Donghai County, whereby people living on the edge of the county have less access to health services. Comprehensive measures should be considered to alleviate the unequal spatial accessibility of health services in areas that are more remote and isolated. PMID- 23688279 TI - Manipulation of drugs to achieve the required dose is intrinsic to paediatric practice but is not supported by guidelines or evidence. AB - BACKGROUND: A lack of age-appropriate formulations can make it difficult to administer medicines to children. A manipulation of the dosage form may be required to achieve the required dose. This study aimed to describe medicines that are manipulated to achieve the required dose in paediatric practice. METHOD: A structured, undisguised observational study and postal survey. The observational study investigated drug manipulations occurring in clinical practice across three sites. The questionnaire, administered to a sample of paediatric nurses throughout the UK, surveyed manipulations conducted and nurses' experiences and views. RESULTS: The observational study identified 310 manipulations, of which 62% involved tablets, 21% were intravenous drugs and 10% were sachets. Of the 54 observed manipulations 40 involved tablets with 65% of the tablets being cut and 30% dispersed to obtain a smaller dose. 188 manipulations were reported by questionnaire respondents, of these 46% involved tablets, 12% were intravenous drugs, and 12% were nebuliser solutions. Manipulations were predominantly, but not exclusively, identified in specialist clinical areas with more highly dependent patients. Questionnaire respondents were concerned about the accuracy of the dose achieved following manipulations and the lack of practice guidance. CONCLUSION: Manipulations to achieve the required dose occur throughout paediatric in-patient settings. The impact of manipulations on the efficacy of the drugs, the accuracy of the dose and any adverse effects on patients is not known. There is a need to develop evidence based guidance for manipulations of medicines in children. PMID- 23688280 TI - Dynamic dosing assay relating real-time respiration responses of Staphylococcus aureus biofilms to changing microchemical conditions. AB - Bacterial biofilms are a metabolically heterogeneous community of bacteria distributed in an extracellular matrix comprised primarily of hydrated polysaccharides. Effective inhibitory concentrations measured under planktonic conditions are not applicable to biofilms, and inhibition concentrations measured for biofilms vary widely. Here, we introduce a novel microfluidic approach for screening respiration inhibition of bacteria in a biofilm array morphology. The device geometry and operating conditions allow antimicrobial concentration and flux to vary systematically and predictably with space and time. One experiment can screen biofilm respiratory responses to many different antimicrobial concentrations and dosing rates in parallel. To validate the assay, onset of respiration inhibition following NaN3 exposure is determined optically using an O2-sensing thin film. Onset of respiration inhibition obeys a clear and reproducible pattern based on time for diffusive transport of the respiration inhibitor to each biofilm in the array. This approach can be used for high throughput screening of antimicrobial effectiveness as a function of microbial characteristics, antimicrobial properties, or antimicrobial dosing rates. The approach may also be useful in better understanding acquired antimicrobial resistance or for screening antimicrobial combinations. PMID- 23688281 TI - Polydiacetylene-polymethylmethacrylate/graphene composites as one-shot, visually observable, and semiquantative electrical current sensing materials. AB - Aiming to develop pH-paper-like current sensing materials, we prepared irreversible electrochromic PDA-PMMA/graphene composites. The composites exhibited an excellent linear relationship between critical responsive currents and the amount of graphene in the system. In these composites, PDA acted as the electrochromic material and graphene as the conductive matrix. The presence of PMMA not only ensured mechanical performance but also made the color change more obvious to be observed by the naked eye. PMID- 23688283 TI - Nanopore detection of DNA molecules in magnesium chloride solutions. AB - High translocation speed of a DNA strand through a nanopore is a major bottleneck for nanopore detection of DNA molecules. Here, we choose MgCl2 electrolyte as salt solution to control DNA mobility. Experimental results demonstrate that the duration time for straight state translocation events in 1 M MgCl2 solution is about 1.3 ms which is about three times longer than that for the same DNA in 1 M KCl solution. This is because Mg(2+) ions can effectively reduce the surface charge density of the negative DNA strands and then lead to the decrease of the DNA electrophoretic speed. It is also found that the Mg(2+) ions can induce the DNA molecules binding together and reduce the probability of straight DNA translocation events. The nanopore with small diameter can break off the bound DNA strands and increase the occurrence probability of straight DNA translocation events. PMID- 23688282 TI - Improving the implementation of tailored expectant management in subfertile couples: protocol for a cluster randomized trial. AB - BACKGROUND: Prognostic models in reproductive medicine can help to identify subfertile couples who would benefit from fertility treatment. Expectant management in couples with a good chance of natural conception, i.e., tailored expectant management (TEM), prevents unnecessary treatment and is therefore recommended in international fertility guidelines. However, current implementation is not optimal, leaving room for improvement. Based on barriers and facilitators for TEM that were recently identified among professionals and subfertile couples, we have developed a multifaceted implementation strategy. The goal of this study is to assess the effects of this implementation strategy on the guideline adherence on TEM. METHODS/DESIGN: In a cluster randomized trial, 25 clinics and their allied practitioners units will be randomized between the multifaceted implementation strategy and care as usual. Randomization will be stratified for in vitro fertilization (IVF) facilities (full licensed, intermediate/no IVF facilities). The effect of the implementation strategy, i.e., the percentage guideline adherence on TEM, will be evaluated by pre- and post randomization data collection. Furthermore, there will be a process and cost evaluation of the strategy. The implementation strategy will focus on subfertile couples and their care providers i.e., general practitioners (GPs), fertility doctors, and gynecologists. The implementation strategy addresses three levels: patient level: education materials in the form of a patient information leaflet and a website; professional level: audit and feedback, educational outreach visit, communication training, and access to a digital version of the prognostic model of Hunault on a website; organizational level: providing a protocol based on the guideline. The primary outcome will be the percentage guideline adherence on TEM. Additional outcome measures will be treatment-, patient-, and process related outcome measures. DISCUSSION: This study will provide evidence about the effectiveness and costs of a multifaceted implementation strategy to improve guideline adherence on TEM. TRIAL REGISTRATION: http://www.trialregister.nlNTR3405. This study is sponsored by ZonMW. PMID- 23688284 TI - Transperitoneal laparoscopic renal denervation for the management of loin pain haematuria syndrome. AB - OBJECTIVES: To assess the role of laparoscopic renal denervation as a surgical option in loin pain-haematuria syndrome (LPHS), refractory to conservative treatment. MATERIAL AND METHODS: Nine patients between 2000 and 2010 with a diagnosis of LPHS following extensive investigations. The data collection from medical records and electronic databases included demographic details, details of surgical procedures, perioperative outcomes, pain recurrences and ongoing analgesia requirements. A telephone follow-up was conducted after at least one year after the procedure for each patient using the Pain Impact Questionnaire (PIQ-6TM) to assess impact of pain on their quality of life. RESULTS: Nine patients (nine women; median age 37 years) underwent 11 laparoscopic denervations. The median follow-up was 28 months. The median operative time was 150 min. There were no significant postoperative complications. In four patients (44%) laparoscopic denervation procedures were curative (median follow-up 70.5 months). The analgesic requirement was significantly reduced in 22% of patients. Telephone follow-up confirmed that 66.66% of the patients had better quality of life after the procedure. CONCLUSIONS: Laparoscopic renal denervation is a feasible and safe alternative to open procedures in patients with refractory LPHS, producing good outcomes in terms of pain-free rates and quality of life impact. PMID- 23688285 TI - Enhanced unblocking from sustained post-trial surprise. AB - Two appetitive conditioning experiments with rats investigated the mechanisms and properties of unblocking that results from the surprising omission of an expected post-trial unconditioned stimulus (US). Experiment 1 demonstrated unblocking under circumstances in which differences in the contribution of generalization decrement and within-compound associations are equated across experimental and control groups. Following Stage 1 training in which a conditioned stimulus (CS) A was followed by a US and a post-trial US, in Experiment 2 we arranged for the post-trial US to be present on some trials with AX but not others. Under these circumstances an enhancement of unblocking to X was observed, relative to a group who received standard unblocking by US omission. The implications of these results for attentional and US-processing theories of associative learning are discussed. PMID- 23688286 TI - Limoniastrum guyonianum aqueous gall extract induces apoptosis in human cervical cancer cells involving p16 INK4A re-expression related to UHRF1 and DNMT1 down regulation. AB - Several reports have described the potential effects of natural compounds as anti cancer agents in vitro as well as in vivo. The aim of this study was to evaluate the anti-cancer effect of Limoniastrum guyonianum aqueous gall extract (G extract) and luteolin in the human cervical cancer HeLa cell line, and, if so, to clarify the underlying mechanism. Our results show that G extract and luteolin inhibited cell proliferation and induced G2/M cell cycle arrest in a concentration and time-dependent manner. Both natural products induced programmed cell death as confirmed by the presence of hypodiploid G0/G1 cells. These effects are associated with an up-regulation of the expression of the tumor suppressor gene p16INK4A and a down-regulation of the expression of the anti-apoptotic actor UHRF1 and its main partner DNMT1. Moreover, G extract- and luteolin-induced UHRF1 and DNMT1 down-regulation is accompanied with a global DNA hypomethylation in HeLa cell line. Altogether our results show that G extract mediates its growth inhibitory effects on human cervical cancer HeLa cell line likely via the activation of a p16INK4A-dependent cell cycle checkpoint signalling pathway orchestrated by UHRF1 and DNMT1 down-regulation. PMID- 23688287 TI - The use of risk sharing tools for post adoption surveillance of a non pharmacological technology in routine practice: results after one year. AB - BACKGROUND: To report results obtained by combining risk sharing tools with post adoption surveillance mechanisms in order to control quality of care and implement a value-based reimbursement scheme for Neuro-reflexotherapy (NRT), a non-pharmacological treatment proven effective for neck pain (NP), thoracic pain (TP) and low back pain (LBP). METHODS: Pre-post prospective cohort study in routine clinical practice, carried out in primary care centers in the Spanish National Health Service in the Balearic Islands (Ib-Salut). Eight-hundred and seventy-one subacute and chronic NP, TP and LBP patients treated in Ib-Salut, who underwent NRT during 2011. A shared risk contract (SRC) was developed, where payments for NRT were linked to results on patients' clinical evolution, reduction in medication and proportion of patients undergoing spinal surgery. Main outcome measures were local pain (NP, TP or LBP), referred pain, LBP-related disability and NP-related disability, measured using previously validated instruments at referral and 3 months later, use of medication assessed at referral and discharge, and rates of spinal surgery prescription after undergoing NRT. RESULTS: Median improvements at discharge corresponded to 57.1% of baseline value for local pain, 75.0% for referred pain, 53.8% for LBP-related disability and 45.0% for NP-related disability. Patients taking medication at discharge represented 29.0% of those taking it at referral. The proportion of patients in whom spinal surgery was prescribed after undergoing NRT was 0%. These results were consistent with those from previous randomised controlled trials (RCTs) and studies in routine practice, and complied with the standards set in the SRC. CONCLUSIONS: It is feasible and effective to enhance post adoption surveillance methods with risk sharing tools to improve quality control and support value based reimbursement decisions for NRT. The feasibility of generalising this approach to other settings and to other non-pharmacological treatments should be explored. PMID- 23688289 TI - Supraicosahedral polyhedra in metallaboranes: synthesis and structural characterization of 12-, 15-, and 16-vertex rhodaboranes. AB - Syntheses and structural characterization of supraicosahedral rhodaborane clusters are reported. Reaction of [(Cp*RhCl2)2], (Cp* = eta(5)-C5Me5) with [LiBH4.thf] followed by thermolysis with excess of [BH3.thf] afforded 16-vertex closo-[(Cp*Rh)3B12H12Rh{Cp*RhB4H9}], 1, 15-vertex [(Cp*Rh)2B13H13], 2, 12-vertex [(Cp*Rh)2B10Hn(OH)m], (3a: n = 12, m = 0; 3b: n = 9, m = 1; 3c: n = 8, m = 2) and 10-vertex [(Cp*Rh)3B7H7], 4, and [(Cp*Rh)4B6H6], 5. Cluster 1 is the unprecedented 16-vertex cluster, consists of a sixteen-vertex {Rh4B12} with an exo-polyhedral {RhB4} moiety. Cluster 2 is the first example of a carbon free 15 vertex supraicosahedral metallaborane, exhibits icosihexahedron geometry (26 triangular faces) with three degree-six vertices. Clusters 3a-c have 12-vertex isocloso geometry, different from that of icosahedral one. Clusters 4 and 5 are attributed to the 10-vertex isocloso geometry based on 10-vertex bicapped square antiprism structure. In addition, quantum-chemical calculations with DFT methods at the BP86 level of theory have been used to provide further insight into the electronic structure and stability of the optimized structures which are in satisfactory agreement with the structure determinations. All the compounds have been characterized by IR, (1)H, (11)B, (13)C NMR spectroscopy in solution, and the solid state structures were established by crystallographic analysis of compounds 1-5. PMID- 23688288 TI - Analysing the visible conformational substates of the FK506-binding protein FKBP12. AB - The 1H-15N 2D NMR correlation spectrum of the widely studied FK506-binding protein FKBP12 (FK506-binding protein of 12 kDa) contains previously unreported peak doublings for at least 31 residues that arise from a minor conformational state (12% of total) which exchanges with the major conformation with a time constant of 3.0 s at 43 degrees C. The largest differences in chemical shift occur for the 80's loop that forms critical recognition interactions with many of the protein partners for the FKBP family. The residues exhibiting doubling extend into the adjacent strands of the beta-sheet, across the active site to the alpha helix and into the 50's loop. Each of the seven proline residues adopts a trans peptide linkage in both the major and minor conformations, indicating that this slow transition is not the result of prolyl isomerization. Many of the residues exhibiting resonance doubling also participate in conformational line-broadening transition(s) that occur ~105-fold more rapidly, proposed previously to arise from a single global process. The 1.70 A (1 A=0.1 nm) resolution X-ray structure of the H87V variant is strikingly similar to that of FKBP12, yet this substitution quenches the slow conformational transition throughout the protein while quenching the line-broadening transition for residues near the 80's loop. Line-broadening was also decreased for the residues in the alpha-helix and 50's loop, whereas line-broadening in the 40's loop was unaffected. The K44V mutation selectively reduces the line-broadening in the 40's loop, verifying that at least three distinct conformational transitions underlie the line-broadening processes of FKBP12. PMID- 23688290 TI - Photoelectron spectroscopy of CdSe nanocrystals in the gas phase: a direct measure of the evanescent electron wave function of quantum dots. AB - We present the first photoelectron spectroscopy measurements of quantum dots (semiconductor nanocrystals) in the gas phase. By coupling a nanoparticle aerosol source to a femtosecond velocity map imaging photoelectron spectrometer, we apply robust gas-phase photoelectron spectroscopy techniques to colloidal quantum dots, which typically must be studied in a liquid solvent or while bound to a surface. Working with a flowing aerosol of quantum dots offers the additional advantages of providing fresh nanoparticles for each laser shot and removing perturbations from bonding with a surface or interactions with the solvent. In this work, we perform a two-photon photoionization experiment to show that the photoelectron yield per exciton depends on the physical size of the quantum dot, increasing for smaller dots. Next, using effective mass modeling we show that the extent to which the electron wave function of the exciton extends from the quantum dot, the so-called "evanescent electron wavefunction", increases as the size of the quantum dot decreases. We show that the photoelectron yield is dominated by the evanescent electron density due to quantum confinement effects, the difference in the density of states inside and outside of the quantum dots, and the angle dependent transmission probability of electrons through the surface of the quantum dot. Therefore, the photoelectron yield directly reflects the fraction of evanescent electron wave function that extends outside of the quantum dot. This work shows that gas-phase photoelectron spectroscopy is a robust and general probe of the electronic structure of quantum dots, enabling the first direct measurements of the evanescent exciton wave function. PMID- 23688291 TI - One-pot microbial production, mechanical properties, and enzymatic degradation of isotactic P[(R)-2-hydroxybutyrate] and its copolymer with (R)-lactate. AB - P[(R)-2-hydroxybutyrate] [P((R)-2HB)] is an aliphatic polyester analogous to poly(lactic acid) (PLA). However, little has been known for its properties because of a high cost of commercially available chiral 2HB as a starting substance for chemical polymer synthesis. In this study, P[(R)-2HB] and P[(R)-2HB co-(R)-lactate] [P((R)-2HB-co-(R)-LA)] with a new monomer combination were successfully synthesized in recombinant Escherichia coli LS5218 from less expensive racemic 2HB using an R-specific polyester synthase. The cells expressing an engineered polyhydroxyalkanoate synthase from Pseudomonas sp. 61-3 and propionyl-CoA transferase from Megasphaera elsdenii were grown on LB medium containing 2HB and glucose in a shake flask and accumulated up to 17 wt % of P[(R)-2HB] with optical purity of >99.1%. In addition, the same cells cultured in a jar-fermentor produced P(86 mol % 2HB-co-LA) copolymer. Notably, the molecular weights (Mw) of P(2HB) (27000) and P(2HB-co-LA) (39000) were 2- and 3-fold higher than that of P(2HB) previously synthesized by chemical polycondensation. P(2HB) was processed into a transparent film by solvent-casting and it had flexible properties with elongation at break of 173%, which was contrast to the rigid PLA. Regarding mechanical properties, P(2HB-co-LA) was tougher but less stretchy than P(2HB). These results demonstrated that P(2HB) has useful properties and LA units in 2HB-based polymers can act as a controllable modulator of the material properties. In addition, P[(R)-2HB] was efficiently degraded by treatment of Novozym 42044 (lipase) but not Savinase 16L (protease), indicating that the degrading behavior of the polymer was similar to that of P[(R)-LA]. PMID- 23688292 TI - A novel parasternal transthoracic echocardiographic window for detecting coronary ostial dilation after modified Bentall surgery. AB - BACKGROUND: During the modified Bentall surgery (aortic root replacement), a cuff of native aorta is implanted, together with the coronary ostium, into the aortic graft. Multi-detector computed tomography (MDCT) imaging can accurately assess the coronary ostial anastomosis site post-surgery. In this study, we assessed the feasibility of imaging the coronary ostial anastomosis site using transthoracic echocardiography (TTE). METHODS: Patients (n = 14, mean age 65 +/- 12 years, 79% males) with previous Bentall surgery underwent TTE study, with MDCT (64-slice) as the reference standard. TTE used conventional and novel acoustic windows to interrogate the coronary ostia. RESULTS: All coronary ostia (n = 28) were well visualized with MDCT. The optimum TTE acoustic window for visualizing the coronary ostia was a superiorly positioned parasternal short-axis view with the probe tilted towards the left shoulder, medially angulated for the right coronary artery ostia (RCAos) and laterally angulated for the left main coronary artery (LMAos). In this off-axis position, 10 (71%) LMAos and 13 (93%) RCAos could be visualized. In the conventional parasternal views, only 5 (36%) RCAos and no LMAos could be visualized. TTE underestimated the diameter of the LMAos (10.0 +/- 2.4 mm TTE vs. 13.4 +/- 2.7 mm MDCT, p = 0.007), but was similar to MDCT for the RCAos (9.8 +/- 3.1 mm TTE vs. 11.1 +/- 3.2 mm MDCT, p = 0.10). CONCLUSIONS: We report a novel TTE acoustic window to image the coronary ostia of post-Bentall surgery patients. Although TTE underestimates the left coronary ostium size, recognition of the ostial dilation with TTE appears feasible in most patients. Those that cannot be imaged will require alternative imaging modality such as MDCT. PMID- 23688293 TI - (Un)doing gender in a rehabilitation context: a narrative analysis of gender and self in stories of chronic muscle pain. AB - PURPOSE: To explore how gender appears in the stories of self-told by men and women undergoing rehabilitation for chronic muscle pain. METHOD: The material, which consists of qualitative interviews with 10 men and 6 women with chronic neck pain, was analyzed from a gender sensitive perspective using narrative method. The analysis was inspired by Arthur Frank's typologies of illness narratives (restitution, chaos and quest). FINDINGS: The women's stories displayed selves that were actively trying to transcend their former identity and life conditions, in which their pain was embedded. Their stories tended to develop from "chaos", towards a quest narrative with a more autonomous self. The selves in the men's stories appeared to be actively seeking a solution to the pain within a medical context. Framed as a restitution narrative, rooted in a biomedical model of disease, the voice often heard in the men's stories was of a self-dependent on future health care. Our findings contribute greater nuance to a dominant cultural conception that men are more independent than women in relation to health care. CONCLUSION: Understanding the significance of gender in the construction of selves in stories of chronic pain may help to improve the health care offered to patients suffering from chronic pain. Implications for Rehabilitation Patients tell stories that powerfully communicate their particular illness experiences. Cultural expectations of femininity and masculinity play a significant role with regard to how the patients construct their stories, which may be important to health professionals' perceptions of the patients' problem. Health care professionals should listen carefully to the patient's own story and be sensitive to the significance of gender when trying to understand these people's health problem. PMID- 23688294 TI - The roles, barriers and experiences of rehabilitation therapists in disaster relief: post-earthquake Haiti 2010. AB - PURPOSE: This article describes the roles and experiences of rehabilitation therapists involved in disaster relief work (DRW) in Haiti after the 2010 earthquake. The results of a pilot study and phenomenological study are presented. METHOD: A phenomenological study of rehabilitation providers' experiences in post-disaster relief care is presented along with preliminary pilot study results. The phenomenological study explored the experiences of therapists from a lived experience perspective through the roles they played in DRW. RESULTS: Participants provided disaster relief through direct patient care, adaptive equipment sourcing and allocation, education and training, community outreach and logistic or administrative duties. Barriers and challenges included: (1) emotions: ups and downs; (2) challenges: working at the edge of practice; (3) education: key to success and sustainability; (4) lessons learned: social responsibility is why we go; and (5) difficulty coming home: no one understands. CONCLUSIONS: Therapists play a key role in disaster relief situations. Data presented should encourage organizations to include therapists from early planning to implementation of relief services. Further studies are needed to evaluate the impact of rehabilitation interventions in disaster settings. IMPLICATIONS FOR REHABILITATION: Understanding the roles and experiences of therapists in disaster relief setting is important Certain barriers to providing care in post-disaster settings exist Those participating in disaster response should be well prepared and aware of that they might be asked to do. PMID- 23688295 TI - Validation of the Episodic Disability Framework with adults living with HIV. AB - PURPOSE: To assess the validity of dimensions of disability in the Episodic Disability Framework, a conceptual framework derived from the perspective of adults living with HIV. METHODS: We conducted confirmatory factor analyses with 913 adults living with HIV in an observational cohort study called the Ontario HIV Treatment Network Cohort Study (OCS). We tested hypotheses that dimensions of disability in the Episodic Disability Framework were represented by a group of measured variables in the observational database. RESULTS: A model comprised of four latent variables and 43 indicator variables with one cross-loading was superior to models with fewer latent variables and more indicator variables and supported the validity of disability dimensions: physical health symptoms (represented by 21 indicator variables), mental health symptoms (10 variables), difficulties with day-to-day activities (5 variables) and challenges to social inclusion (8 variables). Overall goodness of fit statistics were chi(2 )= 2621.50 (p < 0.001), Comparative Fit Index = 0.912, Tucker Lewis Index = 0.907 and root mean square error of approximation = 0.048. Dimensions of disability correlated with each other ranging from r = 0.44 (between physical symptoms and challenges to social inclusion) to r = 0.81 (between physical symptoms and difficulties with day-to-day activities). CONCLUSIONS: This study supports the validity of four disability dimensions in the Episodic Disability Framework. This framework provides a new way to conceptualize disability and can lay the foundation for developing a future HIV disability measure for clinical and health services research. IMPLICATIONS FOR REHABILITATION: The Episodic Disability Framework is the first known conceptual framework of disability developed from the perspective of adults living with HIV. Results from this confirmatory factor analysis support the validity of four dimensions of disability experienced by adults living with HIV in the Episodic Disability Framework including: physical symptoms and impairments, mental health symptoms and impairments, difficulties carrying out day-to-day activities, and challenges to social inclusion. The Episodic Disability Framework provides a new way to conceptualize disability experienced by adults living with HIV. Clinicians can use this Framework to better understand episodic disability experienced by adults living with HIV. Clinicians can frame their assessments of disability to include physical and mental health symptoms and impairments as well as consider a patient's ability to participate in society, and indicate areas to apply interventions or strategies to prevent or mitigate disability experienced by adults living with HIV. PMID- 23688296 TI - Prevalence and socioeconomic and geographical inequalities of household food insecurity in the Paris region, France, 2010. AB - BACKGROUND: Food insecurity (FI) is the situation where people do not have, at all times, access to sufficient, safe and nutritious food that meets their dietary needs for an active and healthy life. The objectives of this study were to estimate the prevalence of FI in the Paris area by using, for the first time in France, a specific FI questionnaire and to identify the characteristics of food-insecure households, taking into account a potential neighbourhood effect. METHODS: This study is based on data from the third wave of the SIRS cohort study (a representative, population-based socioepidemiological study) that were analysed using a cross-sectional design. In 2010, 3000 individuals in the Paris metropolitan area (PMA) were interviewed. FI was investigated by means of the USDA's HFSSM. We used stratified multilevel models across three household income categories to identify populations at risk for FI. RESULTS: In 2010, 6.30% (95% CI = [4.99-7.97]) of the households in the PMA experienced FI (up to 13.59% in the most underprivileged neighbourhoods). About 2.50% of the households experienced severe FI and 2.85% of household living with an income above 1666 ? experienced food insecurity, whereas the percentage raises to 23.38% among those living below the poverty threshold (< 791 ?). Depending on the income level, different household characteristics emerged as being associated with FI. In the poorest households, the presence of a child under 3 years of age was associated with an increased risk of FI (OR = 2.11; p = 0.03). Among higher-income households, the household composition appeared to be strongly associated with FI. CONCLUSION: FI exists in several social groups in France. Its prevalence in the most underprivileged households should be considered an indicator of vulnerability, which could permit targeted social assistance policies. PMID- 23688297 TI - Glycomic analysis using glycoprotein immobilization for glycan extraction. AB - Glycosylation is one of the most common protein modifications and is involved in many functions of glycoproteins. Investigating aberrant protein glycosylation associated with diseases is useful in improving disease diagnostics. Due to the nontemplate nature of glycan biosynthesis, the glycans attached to glycoproteins are enormously complex; thus, a method for comprehensive analysis of glycans from biological or clinical samples is needed. Here, we describe a novel method for glycomic analysis using glycoprotein immobilization for glycan extraction (GIG). Proteins or peptides from complex samples were first immobilized on solid support, and other nonconjugated molecules were removed. Glycans were enzymatically or chemically modified on solid phase before releasing from glycoproteins/glycopeptides for mass spectrometry analysis. The method was applied to the glycomic analysis of both N- and O-glycans. PMID- 23688298 TI - Impact of very long time output variation in the treatment of total marrow irradiation with helical tomotherapy. AB - BACKGROUND: Beam-on time in Total Marrow Irradiation (TMI) delivery with helical tomotherapy is more than 30 minutes. The purpose of this study was to investigate extended time output variation in tomotherapy machine without dose servo system and its impact on the dosimetry of TMI planning. MATERIALS AND METHODS: The calibration procedures with 1800 seconds delivery were conducted. The slab and cylindrical phantoms were used for static and rotational output variation measurements, respectively. All measurements were performed in 0.1 second interval with an Exradin A1SL ionization chamber (Standard Imaging Inc., Madison, WI, USA) connected to the tomoelectrometer supplied by the manufacture. Simulated TMI treatment planning with a slab phantom was delivered and verified with ion chamber and EDR-2 films. RESULTS: The static output variations during 30 min averaged -2.9% +/- 0.2%, -3.4% +/- 0.3%, and -3.4% +/- 0.3% at 10 min, 20 min, and 30 min, respectively. The rotational output variations from start averaged 2.5% +/- 0.7%, -3.1% +/- 0.7%, and -3.5% +/- 0.8% at 10 min, 20 min, and 30 min, respectively. The maximum output variation was up to 4.5%. In a TMI planning model, in which beam-on time was over 30 min, planned dose and dose measured with ion chambers in both cranial and caudal sides agreed within 3%. Film measurements in cranial and caudal sides also showed the pass rates of 97.7% and 92.2% with the criteria of 3 mm/3% in gamma analysis. CONCLUSION: These results suggest that long TMI delivery by helical tomotherapy, even without dose servo system, does not pose a risk for significant deviations from the original treatment plan regardless of the output variation. However, very long time output variation should be checked before the first treatment. PMID- 23688299 TI - Noise and fluctuation relations of a spin diode. AB - : We consider fluctuation relations between the transport coefficients of a spintronic system where magnetic interactions play a crucial role. We investigate a prototypical spintronic device - a spin-diode - which consists of an interacting resonant level coupled to two ferromagnetic electrodes. We thereby obtain the cumulant generating function for the spin transport in the sequential tunnelling regime. We demonstrate the fulfilment of the nonlinear fluctuation relations when up and down spin currents are correlated in the presence of both spin-flip processes and external magnetic fields. PMID- 23688300 TI - In prone ventilation, one good turn deserves another. PMID- 23688301 TI - A randomized trial of nighttime physician staffing in an intensive care unit. AB - BACKGROUND: Increasing numbers of intensive care units (ICUs) are adopting the practice of nighttime intensivist staffing despite the lack of experimental evidence of its effectiveness. METHODS: We conducted a 1-year randomized trial in an academic medical ICU of the effects of nighttime staffing with in-hospital intensivists (intervention) as compared with nighttime coverage by daytime intensivists who were available for consultation by telephone (control). We randomly assigned blocks of 7 consecutive nights to the intervention or the control strategy. The primary outcome was patients' length of stay in the ICU. Secondary outcomes were patients' length of stay in the hospital, ICU and in hospital mortality, discharge disposition, and rates of readmission to the ICU. For length-of-stay outcomes, we performed time-to-event analyses, with data censored at the time of a patient's death or transfer to another ICU. RESULTS: A total of 1598 patients were included in the analyses. The median Acute Physiology and Chronic Health Evaluation (APACHE) III score (in which scores range from 0 to 299, with higher scores indicating more severe illness) was 67 (interquartile range, 47 to 91), the median length of stay in the ICU was 52.7 hours (interquartile range, 29.0 to 113.4), and mortality in the ICU was 18%. Patients who were admitted on intervention days were exposed to nighttime intensivists on more nights than were patients admitted on control days (median, 100% of nights [interquartile range, 67 to 100] vs. median, 0% [interquartile range, 0 to 33]; P<0.001). Nonetheless, intensivist staffing on the night of admission did not have a significant effect on the length of stay in the ICU (rate ratio for the time to ICU discharge, 0.98; 95% confidence interval [CI], 0.88 to 1.09; P=0.72), ICU mortality (relative risk, 1.07; 95% CI, 0.90 to 1.28), or any other end point. Analyses restricted to patients who were admitted at night showed similar results, as did sensitivity analyses that used different definitions of exposure and outcome. CONCLUSIONS: In an academic medical ICU in the United States, nighttime in-hospital intensivist staffing did not improve patient outcomes. (Funded by University of Pennsylvania Health System and others; ClinicalTrials.gov number, NCT01434823.). PMID- 23688304 TI - Levels of knowledge and deliberate practice. AB - This study examined the influence of deliberate practice, defined as practice specifically aimed at learners' weak areas and only their weak areas, on 8th graders performance in geometry. A control group had a choice over practice problems and their sequencing. Experiment 1 indicated a disordinal practice schedule by knowledge interaction. Simple effects tests indicated that the interaction was primarily caused by less knowledgeable learners benefiting more from a self-selected practice schedule than deliberate practice. Two subsequent experiments explored the cognitive mechanisms behind this effect by using learners with different levels of prior knowledge. Whereas the relatively more knowledgeable learners in Experiment 2 benefited by concentrating only on their weak areas during practice, the less knowledgeable learners in Experiment 3 improved their skills when they practiced on problem sets combining some of their weak and some of their strong areas or by concentrating on only a limited number of weak areas for a given problem area. These findings have important implications for the design of curriculum materials and implementation of deliberate practice techniques in secondary classrooms. Prior to attaining a sufficient level of familiarity with the subject matter, learners should be encouraged to continue practicing in areas in which they have some degree of competence. Only after competence is attained in several related areas should an exclusive emphasis be placed on practice in weak areas only. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23688305 TI - Photoluminescent 3D lanthanide-organic frameworks based on 2,5-dioxo-1,4 piperazinylbis(methylphosphonic) acid formed via in situ cyclodehydration of glyphosates. AB - Hydrothermal reactions of lanthanide nitrates with glyphosate have resulted three new isostructural 3D lanthanide-organic frameworks, Ln(NO3)(H2L) [Ln = Eu (1), Tb (2), Gd (3); H4L = 2,5-dioxo-1,4-piperazinylbis(methylphosphonic) acid], with good yields, where H4L as a new ligand was formed via in situ cyclodehydration of original ligand glyphosates during the hydrothermal reaction. The compounds were thoroughly characterized by IR, UV-vis, elemental analysis, single-crystal X-ray diffraction analysis, powder X-ray diffraction analysis, and thermogravimetric/differential thermal analysis (TG-DTA). Three compounds display 3D 6,6-connected open frameworks with 4(13).6(2) topology possessing 1D channels in which NO3(-) anions act as troglodytes by chelating Ln(3+) centers. The TG-DTA study of the compounds showed remarkable thermal stability up to 380 degrees C. Under room temperature UV-light irradiation, the Eu(3+) and Tb(3+) compounds showed the corresponding characteristic Ln(3+) intra 4f(n) emission peaks. The triplet energy level (21882 cm(-1)) of the ligand (H4L) was determined from the emission spectrum of its Gd(3+) compound at 77 K. The emission lifetimes (1.54 ms of (5)D0 for compound 1 and 1.98 ms of (5)D4 for compound 2) and absolute emission quantum yields (10.1% for compound 1 and 5.9% for compound 2) were also determined. PMID- 23688302 TI - Prone positioning in severe acute respiratory distress syndrome. AB - BACKGROUND: Previous trials involving patients with the acute respiratory distress syndrome (ARDS) have failed to show a beneficial effect of prone positioning during mechanical ventilatory support on outcomes. We evaluated the effect of early application of prone positioning on outcomes in patients with severe ARDS. METHODS: In this multicenter, prospective, randomized, controlled trial, we randomly assigned 466 patients with severe ARDS to undergo prone positioning sessions of at least 16 hours or to be left in the supine position. Severe ARDS was defined as a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (FiO2) of less than 150 mm Hg, with an FiO2 of at least 0.6, a positive end-expiratory pressure of at least 5 cm of water, and a tidal volume close to 6 ml per kilogram of predicted body weight. The primary outcome was the proportion of patients who died from any cause within 28 days after inclusion. RESULTS: A total of 237 patients were assigned to the prone group, and 229 patients were assigned to the supine group. The 28-day mortality was 16.0% in the prone group and 32.8% in the supine group (P<0.001). The hazard ratio for death with prone positioning was 0.39 (95% confidence interval [CI], 0.25 to 0.63). Unadjusted 90-day mortality was 23.6% in the prone group versus 41.0% in the supine group (P<0.001), with a hazard ratio of 0.44 (95% CI, 0.29 to 0.67). The incidence of complications did not differ significantly between the groups, except for the incidence of cardiac arrests, which was higher in the supine group. CONCLUSIONS: In patients with severe ARDS, early application of prolonged prone-positioning sessions significantly decreased 28-day and 90-day mortality. (Funded by the Programme Hospitalier de Recherche Clinique National 2006 and 2010 of the French Ministry of Health; PROSEVA ClinicalTrials.gov number, NCT00527813.). PMID- 23688303 TI - Genomics-driven discovery of the pneumocandin biosynthetic gene cluster in the fungus Glarea lozoyensis. AB - BACKGROUND: The antifungal therapy caspofungin is a semi-synthetic derivative of pneumocandin B0, a lipohexapeptide produced by the fungus Glarea lozoyensis, and was the first member of the echinocandin class approved for human therapy. The nonribosomal peptide synthetase (NRPS)-polyketide synthases (PKS) gene cluster responsible for pneumocandin biosynthesis from G. lozoyensis has not been elucidated to date. In this study, we report the elucidation of the pneumocandin biosynthetic gene cluster by whole genome sequencing of the G. lozoyensis wild type strain ATCC 20868. RESULTS: The pneumocandin biosynthetic gene cluster contains a NRPS (GLNRPS4) and a PKS (GLPKS4) arranged in tandem, two cytochrome P450 monooxygenases, seven other modifying enzymes, and genes for L-homotyrosine biosynthesis, a component of the peptide core. Thus, the pneumocandin biosynthetic gene cluster is significantly more autonomous and organized than that of the recently characterized echinocandin B gene cluster. Disruption mutants of GLNRPS4 and GLPKS4 no longer produced the pneumocandins (A0 and B0), and the Deltaglnrps4 and Deltaglpks4 mutants lost antifungal activity against the human pathogenic fungus Candida albicans. In addition to pneumocandins, the G. lozoyensis genome encodes a rich repertoire of natural product-encoding genes including 24 PKSs, six NRPSs, five PKS-NRPS hybrids, two dimethylallyl tryptophan synthases, and 14 terpene synthases. CONCLUSIONS: Characterization of the gene cluster provides a blueprint for engineering new pneumocandin derivatives with improved pharmacological properties. Whole genome estimation of the secondary metabolite-encoding genes from G. lozoyensis provides yet another example of the huge potential for drug discovery from natural products from the fungal kingdom. PMID- 23688306 TI - cWords - systematic microRNA regulatory motif discovery from mRNA expression data. AB - BACKGROUND: Post-transcriptional regulation of gene expression by small RNAs and RNA binding proteins is of fundamental importance in development of complex organisms, and dysregulation of regulatory RNAs can influence onset, progression and potentially be target for treatment of many diseases. Post-transcriptional regulation by small RNAs is mediated through partial complementary binding to messenger RNAs leaving nucleotide signatures or motifs throughout the entire transcriptome. Computational methods for discovery and analysis of sequence motifs in high-throughput mRNA expression profiling experiments are becoming increasingly important tools for the identification of post-transcriptional regulatory motifs and the inference of the regulators and their targets. RESULTS: cWords is a method designed for regulatory motif discovery in differential case control mRNA expression datasets. We have improved the algorithms and statistical methods of cWords, resulting in at least a factor 100 speed gain over the previous implementation. On a benchmark dataset of 19 microRNA (miRNA) perturbation experiments cWords showed equal or better performance than two comparable methods, miReduce and Sylamer. We have developed rigorous motif clustering and visualization that accompany the cWords analysis for more intuitive and effective data interpretation. To demonstrate the versatility of cWords we show that it can also be used for identification of potential siRNA off target binding. Moreover, cWords analysis of an experiment profiling mRNAs bound by Argonaute ribonucleoprotein particles discovered endogenous miRNA binding motifs. CONCLUSIONS: cWords is an unbiased, flexible and easy-to-use tool designed for regulatory motif discovery in differential case-control mRNA expression datasets. cWords is based on rigorous statistical methods that demonstrate comparable or better performance than other existing methods. Rich visualization of results promotes intuitive and efficient interpretation of data. cWords is available as a stand-alone Open Source program at Github https://github.com/simras/cWords and as a web-service at: http://servers.binf.ku.dk/cwords/. PMID- 23688307 TI - The polyserine domain of the lysyl-5 hydroxylase Jmjd6 mediates subnuclear localization. AB - Jmjd6 (jumonji-domain-containing protein 6) is an Fe(II)- and 2OG (2 oxoglutarate)-dependent oxygenase that catalyses hydroxylation of lysine residues in proteins involved in pre-mRNA splicing. Jmjd6 plays an essential role in vertebrate embryonic development and has been shown to modulate alternative splicing in response to hypoxic stress. In the present study we show that an alternatively spliced version of Jmjd6 lacking the polyS (polyserine) domain localizes to the nucleolus, predominantly in the fibrillar centre. Jmjd6 with the polyS domain deleted also interacts with nucleolar proteins. Furthermore, co immunoprecipitation experiments and F2H (fluorescent 2-hybrid) assays demonstrate that Jmjd6 homo-oligomerization occurs in cells. In correlation with the observed variations in the subnuclear distribution of Jmjd6, the structure of Jmjd6 oligomers in vitro changes in the absence of the polyS domain, possibly reflecting the role of the polyS domain in nuclear/nucleolar shuttling of Jmjd6. PMID- 23688308 TI - Instability and Structural Change of 4-Methylsulfinyl-3-butenyl Isothiocyanate in the Hydrolytic Process. AB - Sulforaphene (4-methylsulfinyl-3-butenyl isothiocyanate), which has significant chemopreventive activities, is an important phytochemical ingredient produced by myrosinase hydrolysis of glucoraphenin (4-methylsulfinyl-3-butenyl glucosinolate) found in radish seeds. In this research, we found that sulforaphene was unstable and converted rapidly to a water-soluble degradation product in the hydrolytic process. The degradation product was successfully purified by preparative high performance liquid chromatography on a C18 column using 10% methanol in water as the mobile phase. On the basis of MS and NMR spectroscopy data, the degradation product was identified to be 6-[(methylsulfinyl)methyl]-1,3-thiazinan-2-thione. The degradation pathway of sulforaphene was proposed in our study. Furthermore, low pH and metal ions were also found to have an effective inhibition to the degradation reaction of sulforaphene. Through adjusting the pH value of the system or adding metal ions after the content of sulforaphene has reached its maximum, the yield of sulforaphene increased significantly compared with that of the control. PMID- 23688309 TI - Molecular orbital gates for plasmon excitation. AB - Future combinations of plasmonics with nanometer-sized electronic circuits require strategies to control the electrical excitation of plasmons at the length scale of individual molecules. A unique tool to study the electrical plasmon excitation with ultimate resolution is scanning tunneling microscopy (STM). Inelastic tunnel processes generate plasmons in the tunnel gap that partially radiate into the far field where they are detectable as photons. Here we employ STM to study individual tris-(phenylpyridine)-iridium complexes on a C60 monolayer, and investigate the influence of their electronic structure on the plasmon excitation between the Ag(111) substrate and an Ag-covered Au tip. We demonstrate that the highest occupied molecular orbital serves as a spatially and energetically confined nanogate for plasmon excitation. This opens the way for using molecular tunnel junctions as electrically controlled plasmon sources. PMID- 23688310 TI - Sexual orientation change efforts and the search for authenticity. AB - This article is based on structured interviews of a sample of 15 former participants in sexual orientation change efforts (SOCE), who currently identify as gay or lesbian. The primary research question for this study was, "What was the experience of self-identified gay men and lesbians who went through some type of SOCE and eventually asserted themselves as gay or lesbian?" The research concludes that participants sometimes identified as heterosexual during SOCE, but never changed their underlying homosexual orientation, and that suppression, disconnection, and a sense of inauthenticity were significant phenomena of this process. PMID- 23688311 TI - Finding "safe" campuses: predicting the presence of LGBT student groups at North Carolina colleges and universities. AB - A key indicator of a supportive campus climate for lesbian, gay, bisexual, and transgender (LGBT) college students is the existence of an LGBT student organization. This article integrates the research on high school LGBT policies and programs with social movement studies of campus activism to examine the characteristics associated with the existence of university-approved LGBT groups on North Carolina campuses. Drawing on data from the National Center for Education Statistics, campus Web sites, and other sources, logistic regression is used to examine the importance of public opinion, campus and community resources, and the institutional context in predicting the location of these student groups. PMID- 23688312 TI - Forgive me Father for I have sinned: the role of a Christian upbringing on lesbian, gay, and bisexual identity development. AB - This study (n = 84) examined the extent to which a Christian upbringing may inhibit same-sex attracted individuals from accepting a lesbian, gay, and bisexual (LGB) identity. No significant differences were found between current and former Christians' positive or negative gay identities. Participants who had left Christianity were more liberal and viewed God as hostile. Participants' "outness" as LGB to their primary network was associated with a greater positive and lesser negative gay identity. Participants' LGB network size was not related to either their positive or negative gay identifications. Finally, the participants' sexual histories were not related to their negative identities, but were related to their positive identities. PMID- 23688313 TI - Are gay men and lesbians discriminated against when applying for jobs? A four city, Internet-based field experiment. AB - An Internet-based field experiment was conducted to examine potential hiring discrimination based on sexual orientation; specifically, the "first contact" between job applicants and employers was looked at. In response to Internet job postings on CareerBuilder.com(r), more than 4,600 resumes were sent to employers in 4 U.S. cities: Philadelphia, Chicago, Dallas, and San Francisco. The resumes varied randomly with regard to gender, implied sexual orientation, and other characteristics. Two hypotheses were tested: first, that employers' response rates vary by the applicants' assumed sexuality; and second, that employers' Response Rates by Sexuality vary by city. Effects of city were controlled for to hold constant any variation in labor market conditions in the 4 cities. Based on employer responses to the applications, it was concluded that there is no evidence that gay men or lesbians are discriminated against in their first encounter with employers, and no significant variation across cities in these encounters was found. Implications of these results for the literature on hiring discrimination based on sexual orientation, the strengths and limitations of the research, and the potential for the Internet-based field experiment design in future studies of discrimination are discussed. PMID- 23688314 TI - Measuring sexual prejudice against gay men and lesbian women: development of the Sexual Prejudice Scale (SPS). AB - The presence of bias against gay men and lesbian women remains an ongoing issue, and accurate measurement is essential to targeted intervention. A validation study of a new instrument, the Sexual Prejudice Scale, is reported. Students (N = 851) from 4 different universities participated in this study. An exploratory factor analysis and confirmatory factor analysis were conducted, and results of these analyses indicated a 3-factor solution (affective - valuation, stereotyping, and social equality beliefs) for each of the sex-specific scales. Evidence of validity and the results of the reliability analysis are reported. Implications for future research are discussed. PMID- 23688315 TI - The relationships between sense of belonging to the gay community, body image dissatisfaction, and self-esteem among Australian gay men. AB - Body image dissatisfaction has been linked to belonging to the gay community and poor self-esteem among gay men. This study was designed to explore the applicability of a moderation model and a mediation model in explaining the relations between sense of belonging to the gay community, body image dissatisfaction and self-esteem among 90 self-identified Australian gay men. Participants completed the psychological subscale of the Sense of Belonging Instrument, the Body Satisfaction Scale, and the Rosenberg Self-Esteem Scale. Results supported the moderation model; the relation between body image dissatisfaction and self-esteem was found to be statistically significant only at average and high levels of belonging to the gay community. The mediation model was also supported; body image dissatisfaction partially mediated the sense of belonging-self-esteem relation. Educating gay men and health professionals about the possible negative outcomes of "belonging" to an appearance-oriented community is important. PMID- 23688317 TI - Pharmacological primary and secondary cardiovascular prevention among diabetic patients in a multiethnic general practice population: still room for improvements. AB - BACKGROUND: Ethnic minority groups have higher prevalence of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). We assessed general practitioners' (GPs') performance with respect to the pharmacological prevention of CVD in patients with T2DM from different ethnic backgrounds in Oslo. METHODS: Of 1653 T2DM patients cared for by 49 GPs in 2005, 380 had a diagnosis of CVD. Ethnicity was categorized as Norwegian, South Asian and other. Risk factor levels, medication use, achievement of treatment targets (HbA1c <= 7.5%, systolic blood pressure (SBP) <= 140 mmHg, total cholesterol/HDL-cholesterol < 4) and therapeutic intensity (number of drugs targeting each risk factor) were recorded. Chi-square, Wald tests and multiple linear regression analyses were used. RESULTS: Of the 1273 patients receiving primary prevention, 1.5% had their Hb1Ac, 4.8% SBP and 12.7% lipids levels above treatment thresholds without relevant prescriptions. Among patients on pharmacological therapy, 66% reached the HbA1c, 62% SBP and 62% lipid target. Proportions not achieving the HbA1c target were 26% in Norwegians, 38% in South Asians and 29% in others (p = 0.008). Proportions not achieving the SBP target were 42% in Norwegians, 22% in South Asians and 25% in others (p <= 0.001). Of those not achieving the HbA1c and SBP targets, 43% and 35% respectively, used only one agent. CONCLUSIONS: Norwegian GPs comply reasonably well with guidelines for pharmacological prevention of CVD in T2DM patients across ethnic groups. However, lipid-lowering therapy was generally underused, and the achievement of treatment targets for HbA1c in ethnic minorities and for BP in Norwegians could be improved. PMID- 23688318 TI - Transient expansion of activated CD8(+) T cells characterizes tuberculosis associated immune reconstitution inflammatory syndrome in patients with HIV: a case control study. AB - BACKGROUND: CD4(+) T cell activation indicators have been reported to be a common phenomenon underlying diverse manifestations of immune reconstitution inflammatory syndrome (IRIS). However, we have found that a high frequency of circulating CD8(+) T cells is a specific risk factor for mycobacterial IRIS. Therefore, we investigated whether CD8(+) T cells from patients who develop TB IRIS were specifically activated. METHODS: We obtained PBMCs from HIV+ patients prior to and 4, 8, 12, 24, 52 and 104 weeks after initiating antiretroviral therapy. CD38 and HLADR expression on naive, central memory and effector memory CD8(+) and CD4(+) T cells were determined by flow cytometry. Absolute counts and frequencies of CD8(+) T cell subsets were compared between patients who developed TB IRIS, who developed other IRIS forms and who remained IRIS-free. RESULTS: TB IRIS patients showed significantly higher counts of naive CD8(+) T cells than the other groups at most time points, with a contraction of the effector memory subpopulation occurring later in the follow-up period. Activated (CD38(+) HLADR(+)) CD8(+) T cells from all groups decreased with treatment but transiently peaked in TB IRIS patients. This increase was due to an increase in activated naive CD8(+) T cell counts during IRIS. Additionally, the CD8(+) T cell subpopulations of TB IRIS patients expressed HLADR without CD38 more frequently and expressed CD38 without HLADR less frequently than cells from other groups. CONCLUSIONS: CD8(+) T cell activation is specifically relevant to TB IRIS. Different IRIS forms may involve different alterations in T cell subsets, suggesting different underlying inflammatory processes. PMID- 23688321 TI - Rozrolimupab, a first-in-class recombinant monoclonal antibody product for primary immune thrombocytopaenia. AB - INTRODUCTION: Over the last decade the field of medicine has dramatically changed with the introduction of biological therapies, among which monoclonal antibodies play a pivotal role in the management of many diseases. Rozrolimupab is the first of a new class of recombinant human monoclonal antibody mixtures, consisting of 25 genetically unique IgG1 antibodies, targeted against the RhD erythrocyte antigen. It is currently being investigated for its use in the treatment of primary immune thrombocytopenia. AREAS COVERED: This article outlines the impetus for the development of rozrolimupab in the treatment of ITP. In addition, the literature regarding the development of rozrolimupab and the recent clinical trials involving this agent are also reviewed. EXPERT OPINION: Although rozrolimupab is only in the very early phases of clinical development we believe that this agent represents a very interesting agent not only for its potential benefits in the management of ITP but potentially for the prevention of haemolytic disease of the foetus and newborn. PMID- 23688320 TI - Study protocol for "Moving Bright, Eating Smart"- A phase 2 clinical trial on the acceptability and feasibility of a diet and physical activity intervention to prevent recurrence in colorectal cancer survivors. AB - BACKGROUND: Colorectal cancer is the second most common cancer and cancer-killer in Hong Kong with an alarming increasing incidence in recent years. The latest World Cancer Research Fund report concluded that foods low in fibre, and high in red and processed meat cause colorectal cancer whereas physical activity protects against colon cancer. Yet, the influence of these lifestyle factors on cancer outcome is largely unknown even though cancer survivors are eager for lifestyle modifications. Observational studies suggested that low intake of a Western pattern diet and high physical activity level reduced colorectal cancer mortality. The Theory of Planned Behaviour and the Health Action Process Approach have guided the design of intervention models targeting a wide range of health related behaviours. METHODS/DESIGN: We aim to demonstrate the feasibility of two behavioural interventions intended to improve colorectal cancer outcome and which are designed to increase physical activity level and reduce consumption of a Western-pattern diet. This three year study will be a multicentre, randomised controlled trial in a 2x2 factorial design comparing the "Moving Bright, Eating Smart" (physical activity and diet) programme against usual care. Subjects will be recruited over a 12-month period, undertake intervention for 12 months and followed up for a further 12 months. Baseline, interim and three post intervention assessments will be conducted.Two hundred and twenty-two colorectal cancer patients who completed curative treatment without evidence of recurrence will be recruited into the study. Primary outcome measure will be whether physical activity and dietary targets are met at the end of the 12-month intervention. Secondary outcome measures include the magnitude and mechanism of behavioural change, the degree and determinants of compliance, and the additional health benefits and side effects of the intervention. DISCUSSION: The results of this study will establish the feasibility of targeting the two behaviours (diet and physical activity) and demonstrate the magnitude of behaviour change. The information will facilitate the design of a further larger phase III randomised controlled trial with colorectal cancer outcome as the study endpoint to determine whether this intervention model would reduce colorectal cancer recurrence and mortality. TRIAL REGISTRATION: ClinicalTrials.gov No: NCT01708824. PMID- 23688322 TI - Inhibiting interleukin-4 and interleukin-13 in difficult-to-control asthma. PMID- 23688319 TI - Maternal plasma soluble TRAIL is decreased in preeclampsia. AB - OBJECTIVE: Preeclampsia (PE) is characterized by systemic intravascular inflammation. Women who develop PE are at an increased risk for cardiovascular disease in later life. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) has anti-atherosclerotic effects in endothelial cells and can mediate neutrophil apoptosis. Low soluble TRAIL (sTRAIL) and high C-reactive protein (CRP) concentrations are associated with an increased risk of future cardiovascular disease in non-pregnant individuals. The aim of this study was to determine whether maternal plasma concentrations of sTRAIL and CRP differ between women with PE and those with uncomplicated pregnancies. METHOD: This cross sectional study included women with an uncomplicated pregnancy (n = 93) and those with PE (n = 52). Maternal plasma concentrations of sTRAIL and CRP concentrations were determined by ELISA. RESULTS: 1) The median plasma sTRAIL concentration (pg/mL) was significantly lower and the median plasma CRP concentration was significantly higher in women with PE than in those with an uncomplicated pregnancy (25.55 versus 29.17; p = 0.03 and 8.0 versus 4.1; p = 0.001, respectively); 2) the median plasma concentration sTRAIL/CRP ratio was two-fold lower in women with PE than in those with an uncomplicated pregnancy (p < 0.001); and 3) women with plasma sTRAIL and CRP ratio in the lowest quartile were 8 times more likely to have PE than women with concentrations in the upper three quartiles (OR 8.9; 95% CI: 2.8-27.8). CONCLUSION: Maternal plasma sTRAIL concentrations are lower (while those of CRP are higher) in women with PE than in those with uncomplicated pregnancies. These findings are consistent with the evidence of intravascular inflammation in this disorder. PMID- 23688323 TI - Dupilumab in persistent asthma with elevated eosinophil levels. AB - BACKGROUND: Moderate-to-severe asthma remains poorly treated. We evaluated the efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor, in patients with persistent, moderate-to-severe asthma and elevated eosinophil levels. METHODS: We enrolled patients with persistent, moderate-to-severe asthma and a blood eosinophil count of at least 300 cells per microliter or a sputum eosinophil level of at least 3% who used medium-dose to high-dose inhaled glucocorticoids plus long-acting beta-agonists (LABAs). We administered dupilumab (300 mg) or placebo subcutaneously once weekly. Patients were instructed to discontinue LABAs at week 4 and to taper and discontinue inhaled glucocorticoids during weeks 6 through 9. Patients received the study drug for 12 weeks or until a protocol defined asthma exacerbation occurred. The primary end point was the occurrence of an asthma exacerbation; secondary end points included a range of measures of asthma control. Effects on various type 2 helper T-cell (Th2)-associated biomarkers and safety and tolerability were also evaluated. RESULTS: A total of 52 patients were assigned to the dupilumab group, and 52 patients were assigned to the placebo group. Baseline characteristics were similar in the two groups. Three patients had an asthma exacerbation with dupilumab (6%) versus 23 with placebo (44%), corresponding to an 87% reduction with dupilumab (odds ratio, 0.08; 95% confidence interval, 0.02 to 0.28; P<0.001). Significant improvements were observed for most measures of lung function and asthma control. Dupilumab reduced biomarkers associated with Th2-driven inflammation. Injection-site reactions, nasopharyngitis, nausea, and headache occurred more frequently with dupilumab than with placebo. CONCLUSIONS: In patients with persistent, moderate to-severe asthma and elevated eosinophil levels who used inhaled glucocorticoids and LABAs, dupilumab therapy, as compared with placebo, was associated with fewer asthma exacerbations when LABAs and inhaled glucocorticoids were withdrawn, with improved lung function and reduced levels of Th2-associated inflammatory markers. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT01312961.). PMID- 23688324 TI - Deep sternal wound infection after cardiac surgery. AB - BACKGROUND: Deep sternal wound infection (DSWI) is a serious postoperative complication of cardiac surgery. In this study we investigated the incidence of DSWI and effect of re-exploration for bleeding on DSWI mortality. METHODS: We reviewed 73,700 cases registered in the Japan Adult Cardiovascular Surgery Database (JACVSD) during the period from 2004 to 2009 and divided them into five groups: 26,597 of isolated coronary artery bypass graft (CABG) cases, 23,136 valvular surgery cases, 17,441 thoracic aortic surgery cases, 4,726 valvular surgery plus CABG cases, and 1,800 thoracic aortic surgery plus CABG cases. We calculated the overall incidence of postoperative DSWI, incidence of postoperative DSWI according to operative procedure, 30-day mortality and operative mortality of postoperative DSWI cases according to operative procedure, 30-day mortality and operative mortality of postoperative DSWI according to whether re-exploration for bleeding, and the intervals between the operation and deaths according to whether re-exploration for bleeding were investigated. Operative mortality is defined as in-hospital or 30-day mortality. Risk factors for DSWI were also examined. RESULTS: The overall incidence of postoperative DSWI was 1.8%. The incidence of postoperative DSWI was 1.8% after isolated CABG, 1.3% after valve surgery, 2.8% after valve surgery plus CABG, 1.9% after thoracic aortic surgery, and 3.4% after thoracic aortic surgery plus CABG. The 30-day and operative mortality in patients with DSWI was higher after more complicated operative procedures. The incidence of re-exploration for bleeding in DSWI cases was 11.1%. The overall 30-day/operative mortality after DSWI with re-exploration for bleeding was 23.0%/48.0%, and it was significantly higher than in the absence of re-exploration for bleeding (8.1%/22.0%). The difference between the intervals between the operation and death according to whether re-exploration for bleeding had been performed was not significant. Age and cardiogenic shock were significant risk factors related to re-exploration for bleeding, and diabetes control was a significant risk factor related to DSWI for all surgical groups. Previous CABG was a significant risk factor related to both re-exploration for bleeding and DSWI for all surgical groups. CONCLUSIONS: The incidence of DSWI after cardiac surgery according to the data entered in the JACVSD registry during the period from 2004 to 2009 was 1.8%, and more complicated procedures were followed by higher incidence and mortality. When re-exploration for bleeding was performed, mortality was significantly higher than when it was not performed. Prevention of DSWI and establishment of an effective appropriate treatment for DSWI may improve the outcome of cardiac surgery. PMID- 23688325 TI - Stereochemical control of nonamphiphilic lyotropic liquid crystals: chiral nematic phase of assemblies separated by six nanometers of aqueous solvents. AB - Unlike conventional thermotropic and lyotropic liquid crystals, nonamphiphilic lyotropic liquid crystals consist of hydrated assemblies of nonamphiphilic molecules that are aligned with a separation of about 6 nm between assemblies in an aqueous environment. This separation raises the question of how chirality, either from chiral mesogens or chiral dopants, would impact the phase as the assemblies that need to interact with each other are about 6 nm apart. Here, we report the synthesis of three stereoisomers of disodium chromonyl carboxylate, 5'DSCG-diviol, and the correlation between the molecular structure, bulk assembly, and liquid crystal formation. We observed that the chiral isomers (enantiomers 5'DSCG-(R,R)-diviol and 5'DSCG-(S,S)-diviol) formed liquid crystals while the achiral isomer 5'DSCG-meso-diviol did not. Circular dichroism indicated a chiral conformation with bisignate cotton effect. The nuclear Overhauser effect in proton NMR spectroscopy revealed conformations that are responsible for liquid crystal formation. Cryogenic transmission electron microscopy showed that chiral 5'DSCG-diviols form assemblies with crossings. Interestingly, only planar alignment of the chiral nematic phase was observed in liquid crystal cells with thin spacers. The homeotropic alignment that permitted a fingerprint texture was obtained only when the thickness of the liquid crystal cell was increase to above ~500 MUm. These studies suggest that hydrated assemblies of chiral 5'DSCG-diviol can interact with each other across a 6 nm separation in an aqueous environment by having a twist angle of about 0.22 degrees throughout the sample between the neighboring assemblies. PMID- 23688326 TI - Morphology-dependent Li storage performance of ordered mesoporous carbon as anode material. AB - Rod-shaped ordered mesoporous carbons (OMCs) with different lengths, prepared by replication method using the corresponding size-tunable SBA-15 silicas with the same rodlike morphology as templates, are explored as anode material for Li-ion battery. All of the as-synthesized OMCs exhibit much higher Li storage capacity and better cyclability along with comparable rate capability as compared with commercial graphite. Particularly, the OMC-3 with the shortest length demonstrates the highest reversible discharge capacity of 1012 mAh g(-1) at 100 mA g(-1) and better cyclability with 86.6% retention of initial capacity after 100 cycles. Although the Coulombic efficiencies of all the OMCs are relatively low at the beginning, they improve promptly and after 10 cycles reach the level comparable to commercial graphite. Based on their specific capacity, cycle efficiency, and rate capability, the OMC-3 outperforms considerably its carbon peers, OMC-1 and OMC-2 with longer length. This behavior is mainly attributed to higher specific surface area, which provides more active sites for Li adsorption and storage along with the larger mesopore volume and shorter mesopore channels, which facilitate fast Li ion diffusion and electrolyte transport. The enhancement in reversible Li storage performance with decrease in the channel length is also supported by low solid electrolyte interphase resistance, contact resistance, and Warburg impedance in electrochemical impedance spectroscopy. PMID- 23688328 TI - Thoracoabdominal wall defect with complete ectopia cordis and gastroschisis: a case report and review of the literature. AB - Ventral wall defects are extremely rare anomalies that are likely caused by the failure of the ventral wall to close during week 4 of development. We report a case of severe thoracoabdominal wall defect including complete thoracic ectopia cordis and gastroschisis. This combination represents a novel constellation of findings in a single patient. This unique case further demonstrates an anatomically normal heart with age-appropriate development and an intact diaphragm. We review the literature of other reports and discussions of entities that share overlapping features with this case. PMID- 23688327 TI - Interferon-alpha (IFN-alpha) suppresses HTLV-1 gene expression and cell cycling, while IFN-alpha combined with zidovudine induces p53 signaling and apoptosis in HTLV-1-infected cells. AB - BACKGROUND: Human T-cell leukemia virus type-1 (HTLV-1) is the causative retrovirus of adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 gene expression is maintained at low levels in vivo by unknown mechanisms. A combination therapy of interferon-alpha (IFN-alpha) and zidovudin (AZT) shows therapeutic effects in ATL patients, although its mechanism is also obscure. We previously found that viral gene expression in IL-2-dependent HTLV-1-infected T-cells (ILTs) derived from ATL patients was markedly suppressed by stromal cells through a type I IFN response. Here, we investigated the effects of IFN-alpha with or without AZT on viral gene expression and cell growth in ILTs. RESULTS: ILTs expressed variable but lower amounts of HTLV-1 Tax protein than HTLV-1-transformed HUT102 cells. Following the addition of IFN-alpha, the amounts of HTLV-1 p19 in the supernatants of these cells decreased in three days, while HTLV-1 gene expression decreased only in ILTs but not HUT102 cells. IFN-alpha also suppressed the spontaneous HTLV-1 induction in primary ATL cells cultured for 24 h. A time course study using ILTs revealed that the levels of intracellular Tax proteins decreased in the first 24 h after addition of IFN-alpha, before the reduction in HTLV-1 mRNA levels. The initial decreases of Tax protein following IFN-alpha treatment were observed in 6 of 7 ILT lines tested, although the reduction rates varied among ILT lines. An RNA-dependent protein kinase (PKR)-inhibitor reversed IFN-mediated suppression of Tax in ILTs. IFN-alpha also induced cell cycle arrest at the G0/G1 phase and suppressed NF-kappaB activities in these cells. AZT alone did not affect HTLV-1 gene expression, cell viability or NF-kappaB activities. AZT combined with IFN alpha markedly induced cell apoptosis associated with phosphorylation of p53 and induction of p53-responsive genes in ILTs. CONCLUSIONS: IFN-alpha suppressed HTLV 1 gene expression at least through a PKR-mediated mechanism, and also induced cell cycle arrest in ILTs. In combination with AZT, IFN-alpha further induced p53 signaling and cell apoptosis in these cells. These findings suggest that HTLV-1 infected cells at an IL-2-dependent stage retain susceptibility to type I IFN mediated regulation of viral expression, and partly explain how AZT/IFN-alpha produces therapeutic effects in ATL. PMID- 23688329 TI - Pseudomonas fluorescens SBW25 produces furanomycin, a non-proteinogenic amino acid with selective antimicrobial properties. AB - BACKGROUND: Pseudomonas fluorescens SBW25 has been extensively studied because of its plant growth promoting properties and potential as a biocontrol agent. The genome of SBW25 has been sequenced, and among sequenced strains of pseudomonads, SBW25 appears to be most closely related to P. fluorescens WH6. In the authors' laboratories, WH6 was previously shown to produce and secrete 4 formylaminooxyvinylglycine (FVG), a non-proteinogenic amino acid with selective herbicidal and antimicrobial activity. Although SBW25 does not have the genetic capacity to produce FVG, we were interested in determining whether this pseudomonad might produce some other type of non-proteinogenic amino acid. RESULTS: P. fluorescens SBW25 was found to produce and secrete a ninhydrin reactive compound with selective antimicrobial properties. This compound was purified from SBW25 culture filtrate and identified as the non-proteinogenic amino acid L-furanomycin [2S,2'R,5'S)-2-amino-2-(5'methyl-2',5'-dihydrofuran-2' yl)acetic acid]. CONCLUSIONS: The identification of furanomycin as a secondary metabolite of SBW25 is the first report of the production of furanomycin by a pseudomonad. This compound was known previously only as a natural product produced by a strain of Streptomyces. This report adds furanomycin to the small list of non-proteinogenic amino acids that have been identified as secondary products of pseudomonads. This study also extends the list of bacteria that are inhibited by furanomycin to include several plant pathogenic bacteria. PMID- 23688330 TI - Build-up of auditory stream segregation induced by tone sequences of constant or alternating frequency and the resetting effects of single deviants. AB - A sequence of constant-frequency tones can promote streaming in a subsequent sequence of alternating-frequency tones, but why this effect occurs is not fully understood and its time course has not been investigated. Experiment 1 used a 2.0 s-long constant-frequency inducer (10 repetitions of a low-frequency pure tone) to promote segregation in a subsequent, 1.2-s test sequence of alternating low- and high-frequency tones. Replacing the final inducer tone with silence substantially reduced reported test-sequence segregation. This reduction did not occur when either the 4th or 7th inducer was replaced with silence. This suggests that a change at the induction/test-sequence boundary actively resets build-up, rather than less segregation occurring simply because fewer inducer tones were presented. Furthermore, Experiment 2 found that a constant-frequency inducer produced its maximum segregation-promoting effect after only three tones--this contrasts with the more gradual build-up typically observed for alternating frequency sequences. Experiment 3 required listeners to judge continuously the grouping of 20-s test sequences. Constant-frequency inducers were considerably more effective at promoting segregation than alternating ones; this difference persisted for ~10 s. In addition, resetting arising from a single deviant (longer tone) was associated only with constant-frequency inducers. Overall, the results suggest that constant-frequency inducers promote segregation by capturing one subset of test-sequence tones into an ongoing, preestablished stream, and that a deviant tone may reduce segregation by disrupting this capture. These findings offer new insight into the dynamics of stream segregation, and have implications for the neural basis of streaming and the role of attention in stream formation. PMID- 23688331 TI - Use of a Low-fidelity simulator to improve trans-nasal fibre-optic flexible laryngoscopy in the clinical setting: a randomized, single-blinded, prospective study. AB - BACKGROUND: Trans-nasal flexible fibre-optic laryngoscopy (TFFL) is an essential skill for otolaryngologists. There is evidence to suggest that simulators help residents acquire procedural skills. The objective of this study was to examine the effect of simulation on endoscopy skill acquistion. METHODS: A randomized controlled trial was conducted utilizing medical students and junior residents with limited experience in TFFL. Learners all performed a baseline endoscopy and were then randomized to receive either 45 minutes of simulation training or not. Following this, a second endoscopy was performed. Time to adequate visualization of the glottis, the percentage of time adequate visualization of the airway was maintained, and the number of collisions with mucosa were analyzed. Qualitative assessments were also obtained from the learner, patient, and staff laryngologist. RESULTS: Time to adequate visualization of the glottis and the number of mucosal collisions were significantly less during the second endoscopy, irrespective of the use of simulation (84.8 sec vs. 68 sec, p < 0.01; 5.0 vs. 3.2, p < 0.01, respectively). Analysis using a two-way ANOVA with interaction established that none of the quantitative measures analyzed in this study improved with the addition of simulation. CONCLUSION: Improvements in time to visualization of the glottis and number of mucosal contacts were seen between the first and second endoscopy irrespective of simulator use. No additional benefit was conferred with the use of a low-fidelity simulator. PMID- 23688332 TI - La3Ni2SbO9: a relaxor ferromagnet. AB - A polycrystalline sample of La3Ni2SbO9 has been synthesized using a standard ceramic method and characterized by neutron diffraction and magnetometry. The compound adopts a monoclinic, perovskite-like structure with space group P2(1)/n and unit cell parameters a = 5.0675(1), b = 5.6380(1), c = 7.9379(2) A, beta = 89.999(6) degrees at room temperature. The two crystallographically distinct six coordinate sites are occupied by Ni(2+) and a disordered distribution of Ni(2+)/Sb(5+), respectively; the Ni(2+) and Sb(5+) cations occupy the disordered site in a 1:2 ratio. Both ac and dc magnetometry indicate the presence of a spontaneous magnetization below 105 K. A magnetization of 1.5 MUB per formula unit was measured at 2 K in a field of 40 kOe. However, no magnetic scattering was observed in neutron diffraction data collected at 5 K. It is proposed that, as a consequence of the cation disorder, La3Ni2SbO9 behaves as a relaxor ferromagnet, analogous to a relaxor ferroelectric, with magnetic domains too small to be detected by neutron diffraction forming below 105 K. PMID- 23688333 TI - Application of propensity scores to estimate the association between government subsidy and injection use in primary health care institutions in China. AB - BACKGROUND: The problem posed by therapeutic injection is a clinical practice issue that influences health care quality and patient safety. Although sufficient government subsidy was one of the 12 key interventions to promote rational drug use initiated by WHO (World Health Organization), limited information is available about the association between government subsidy and injection use in primary health care institutions. In 2009, National Essential Medicines System (NEMS) was implemented in China. The subsidy policy plays an important role in maintaining primary health care institutions. This study explores the impact of government subsidies on the injection use in primary health care institutions in China. METHODS: 126 primary health institutions were included in this study. Institutions were divided into two groups (intervention and control groups) according to the median GS (General subsidy per personnel). Propensity score matching (PSM) was used to minimize the observed covariate differences in the characteristics of the primary institutions between the two groups. Kappa score was calculated to determine the consistency between the groups. Paired chi-square test and Relative Risk (RR) were calculated to compare the differences in injection use between the groups. RESULTS: Among all the investigated prescriptions, the overall percent of people who received an injection prescribed was 36.96% (n = 12600). PSM showed no significant covariate difference among the 34 groups obtained through this analysis. Kappa score (k = -0.082, p = 0.558) indicated an inconsistency between groups and paired chi-square test revealed a significant difference (p < 0.05) in injection use between the two groups. Relative Risk = 0.679 (95%CI [0.485, 0.950]) indicate that high General subsidy per personnel is a protective factor for primary health care institutions to prescribe injections properly. The intervention group obtained a higher possibility of using injection properly. CONCLUSIONS: The overall effect of government subsidy on the use of injection was positively significant. However, the mechanism by which government subsidy influence injection administration remains unclear, and thus requires further study. PMID- 23688334 TI - Effects of caloric intake timing on insulin resistance and hyperandrogenism in lean women with polycystic ovary syndrome. AB - In women with PCOS (polycystic ovary syndrome), hyperinsulinaemia stimulates ovarian cytochrome P450c17alpha activity that, in turn, stimulates ovarian androgen production. Our objective was to compare whether timed caloric intake differentially influences insulin resistance and hyperandrogenism in lean PCOS women. A total of 60 lean PCOS women [BMI (body mass index), 23.7+/-0.2 kg/m2] were randomized into two isocaloric (~1800 kcal; where 1 kcal~4.184 J) maintenance diets with different meal timing distribution: a BF (breakfast diet) (980 kcal breakfast, 640 kcal lunch and 190 kcal dinner) or a D (dinner diet) group (190 kcal breakfast, 640 kcal lunch and 980 kcal dinner) for 90 days. In the BF group, a significant decrease was observed in both AUC(glucose) (glucose area under the curve) and AUC(insulin) (insulin area under the curve) by 7 and 54% respectively. In the BF group, free testosterone decreased by 50% and SHBG (sex hormone-binding globulin) increased by 105%. GnRH (gonadotropin-releasing hormone)-stimulated peak serum 17OHP (17alpha-hydroxyprogesterone) decreased by 39%. No change in these parameters was observed in the D group. In addition, women in the BF group had an increased ovulation rate. In lean PCOS women, a high caloric intake at breakfast with reduced intake at dinner results in improved insulin sensitivity indices and reduced cytochrome P450c17alpha activity, which ameliorates hyperandrogenism and improves ovulation rate. Meal timing and distribution should be considered as a therapeutic option for women with PCOS. PMID- 23688335 TI - Chylous ascites after liver transplant: case report and review of literature. AB - CASE: A 62-year-old man with cirrhosis, hepatitis C, and hepatocellular carcinoma, underwent a liver transplant. On day 11 after surgery, a chylous leak from a partial wound dehiscence was noted. The leak did not respond to 2 weeks of uninterrupted, fat-free clear liquid diet and 12-hour total parenteral nutrition at night. The same treatment was continued for another 6 weeks with fatty meal challenge every weekend, which he failed. He was then given a fat-free clear liquid diet, 24-hour total parenteral nutrition, and octreotide 100 MUg subcutaneously every 8 hours for 14 days. A prompt response was noted. His recovery was excellent at the time of this writing (9 months' follow-up). DISCUSSION: Eleven major cases have been reported with 9 cases being managed conservatively. Four were given a diet plus total parenteral nutrition without octreotide producing a cure in 3 to 36 days. Two cases (including ours) were given the diet and total parenteral nutrition, which failed; octreotide was then added, and these cases were cured in 2 to 4 weeks. Therefore, diet with total parenteral nutrition failed in 33.3% of the cases (2/6). In 3 cases, octreotide was used from the outset. They were all cured in <= 2 weeks. One case was operated on for peritonitis; chylous ascites was found and a leak was ligated. One patient with congenital lymphatic disorder underwent peritoneovenous shunting. Octreotide was not used in any of the cases of chylous ascites that were treated surgically. CONCLUSIONS: If exploratory surgery is done for any other reason, it is best to identify a chylous leak and ligate it. Otherwise, we recommend octreotide combined with a fat-free, clear liquid diet, and supplementation with medium chain triglycerides and total parenteral nutrition from the outset. PMID- 23688336 TI - In-depth mass spectrometric mapping of the human vitreous proteome. AB - Mapping of proteins involved in normal eye functions is a prerequisite to identify pathological changes during eye disease processes. We therefore analysed the proteome of human vitreous by applying in-depth proteomic screening technologies. For ethical reasons human vitreous samples were obtained by vitrectomy from "surrogate normal patients" with epiretinal gliosis that is considered to constitute only negligible pathological vitreoretinal changes. We applied different protein prefractionation strategies including liquid phase isoelectric focussing, 1D SDS gel electrophoresis and a combination of both and compared the number of identified proteins obtained by the respective method. Liquid phase isoelectric focussing followed by SDS gel electrophoresis increased the number of identified proteins by a factor of five compared to the analysis of crude unseparated human vitreous. Depending on the prefractionation method proteins were subjected to trypsin digestion either in-gel or in solution and the resulting peptides were analysed on a UPLC system coupled online to an LTQ Orbitrap XL mass spectrometer. The obtained mass spectra were searched against the SwissProt database using the Mascot search engine. Bioinformatics tools were used to annotate known biological functions to the detected proteins. Following this strategy we examined the vitreous proteomes of three individuals and identified 1111 unique proteins. Besides structural, transport and binding proteins, we detected 261 proteins with known enzymatic activity, 51 proteases, 35 protease inhibitors, 35 members of complement and coagulation cascades, 15 peptide hormones, 5 growth factors, 11 cytokines, 47 receptors, 30 proteins of visual perception, 91 proteins involved in apoptosis regulation and 265 proteins with signalling activity. This highly complex mixture strikingly differs from the human plasma proteome. Thus human vitreous fluid seems to be a unique body fluid. 262 unique proteins were detected which are present in all three patient samples indicating that these might represent the constitutive protein pattern of human vitreous. The presented catalogue of human vitreous proteins will enhance our understanding of physiological processes in the eye and provides the groundwork for future studies on pathological vitreous proteome changes. PMID- 23688337 TI - Significantly improved long-cycle stability in high-rate Li-S batteries enabled by coaxial graphene wrapping over sulfur-coated carbon nanofibers. AB - Long-term instability of Li-S batteries is one of their major disadvantages compare to other secondary batteries. The reasons for the instability include dissolution of polysulfide intermediates and mechanical instability of the electrode film caused by volume changes during charging/discharging cycles. In this paper, we report a novel graphene-sulfur-carbon nanofibers (G-S-CNFs) multilayer and coaxial nanocomposite for the cathode of Li-S batteries with increased capacity and significantly improved long-cycle stability. Electrodes made with such nanocomposites were able to deliver a reversible capacity of 694 mA h g(-1) at 0.1C and 313 mA h g(-1) at 2C, which are both substantially higher than electrodes assembled without graphene wrapping. More importantly, the long cycle stability was significantly improved by graphene wrapping. The cathode made with G-S-CNFs with a initial capacity of 745 mA h g(-1) was able to maintain ~273 mA h g(-1) even after 1500 charge-discharge cycles at a high rate of 1C, representing an extremely low decay rate (0.043% per cycle after 1500 cycles). In contrast, the capacity of an electrode assembled without graphene wrapping decayed dramatically with a 10 times high rate (~0.40% per cycle after 200 cycles). These results demonstrate that the coaxial nanocomposites are of great potential as the cathode for high-rate rechargeable Li-S batteries. Such improved rate capability and cycle stability could be attributed to the unique coaxial architecture of the nanocomposite, in which the contributions from graphene and CNFs enable electrodes with improved electrical conductivity, better ability to trap soluble the polysulfides intermediate and accommodate volume expansion/shrinkage of sulfur during repeated charge/discharge cycles. PMID- 23688339 TI - Screening and X-ray crystal structure-based optimization of autotaxin (ENPP2) inhibitors, using a newly developed fluorescence probe. AB - Autotaxin (ATX), also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), was originally identified as a tumor cell autocrine motility factor and was found to be identical to plasma lysophospholipase D, which is the predominant contributor to lysophosphatidic acid (LPA) production from lysophospholipids. ATX is therefore considered to regulate the physiological and pathological roles of LPA, including angiogenesis, lymphocyte trafficking, tissue fibrosis, and cancer cell invasion and metastasis. Thus, it is a potential therapeutic target. Here, we first developed a sensitive and specific ATX fluorescence probe, TG-mTMP, and used it to screen ATX inhibitors in a large chemical library. This probe, which is superior to previously available probes FS-3 and CPF4 in terms of sensitivity or specificity, enabled us to identify several novel ATX inhibitor scaffolds. We solved the crystal structures of ATX complexes with the hit compounds at high resolution (1.75-1.95 A) and used this information to guide optimization of the structure of a selected inhibitor. The optimized compounds, 3BoA and its derivatives, exhibited potent ATX-inhibitory activity both in vitro and in vivo. These inhibitors are expected to be useful tools to understand the roles of ATX in vitro and in vivo and may also be candidate anti-ATX therapeutic agents. PMID- 23688341 TI - Transition-metal-free carbofluorination of TBS-protected nitrogen-containing cyclic enynols: synthesis of fluorinated azabicycles. AB - The synthesis of fluorinated azabicycles from tert-butyldimethylsilyl-protected N containing cyclic enynols using inexpensive BF3.OEt2 is described. In this reaction, BF3 reacts as both the Lewis acid and the fluoride source for cyclization/fluorination of the TBS-protected cyclic N-containing enynols. The method provides an easy access to fluorinated azabicycles where a new C(sp(2))-F bond and a new bicyclic skeleton are generated at ambient temperature within 1-13 min under metal-free reaction conditions. PMID- 23688340 TI - Lipid-lowering pharmacotherapy and socioeconomic status: Atherosclerosis Risk In Communities (ARIC) surveillance study. AB - BACKGROUND: Lipid-reduction pharmacotherapy is often employed to reduce morbidity and mortality risk for patients with dyslipidemia or established cardiovascular disease. Associations between socioeconomic factors and the prescribing and use of lipid-lowering agents have been reported in several developed countries. METHODS: We evaluated the association of census tract-level neighborhood household income (nINC) and lipid-lowering medications received during hospitalization or at discharge among 3,546 (5,335 weighted) myocardial infarction (MI) events in the United States (US) Atherosclerosis Risk In Communities (ARIC) surveillance study (1999-2002). Models included neighborhood household income, race, gender, age, study community, year of MI, hospital type (teaching vs. nonteaching), current or past history of hypertension, diabetes or heart failure, and presence of cardiac pain. RESULTS: About fifty-nine percent of patients received lipid-lowering pharmacotherapy during hospitalization or at discharge. Low nINC was associated with a lower likelihood (prevalence ratio 0.89, 95% confidence interval: 0.79, 1.01) of receiving lipid-lowering pharmacotherapy compared to high neighborhood household income, and no significant change in this association resulted when adjusted for the above mentioned covariates. CONCLUSION: Patient's socioeconomic status appeared to influence whether they were prescribed a lipid-lowering pharmacotherapy after hospitalization for myocardial infarction in the US ARIC surveillance study (1999 2002). PMID- 23688342 TI - Applications of poloxamers in ophthalmic pharmaceutical formulations: an overview. AB - INTRODUCTION: An ideal ophthalmic formulation is one that not only prolongs the contact time of the vehicle on the ocular surface but also slows down the drug elimination. The poor bioavailability and therapeutic response exhibited by the conventional ophthalmic solutions due to pre-corneal elimination of the drug may be overcome by the use of in situ gel forming systems. In situ gelling systems increase the viscosity by changing the pH or temperature in the pre-corneal region and lead to an increase of drug bioavailability by slowing drainage. Poloxamers are polyols with thermal gelling properties which are frequently included in ophthalmic formulations to improve the ocular bioavailability of drugs by increasing vehicle viscosity. AREAS COVERED: An overview on the unique physiological characteristics of ocular globe and the limitations and disadvantages of the conventional ophthalmic pharmaceutical formulations. Readers will appreciate the different strategies to improve the absorption of drugs in the ocular globe, especially the incorporation of poloxamers in ophthalmic formulations, understanding the main advantages of the poloxamers and also learning about the different examples of applications of these polymers in ophthalmic pharmaceutical formulations. EXPERT OPINION: Poloxamers offers a new strategy to improve bioavailability and decrease the side effects induced by the systemic absorption of topically applied ophthalmic drugs. PMID- 23688338 TI - Soluble ST2, a modulator of the inflammatory response, in preterm and term labor. AB - OBJECTIVE: Intra-amniotic infection/inflammation (IAI) is causally linked with spontaneous preterm labor and delivery. The ST2L receptor and its soluble form (sST2) are capable of binding to interleukin (IL)-33, a member of the IL-1 superfamily. Members of this cytokine family have been implicated in the onset of spontaneous preterm labor in the context of infection. Soluble ST2 has anti inflammatory properties, and plasma concentrations are elevated in systemic inflammation, such as sepsis, acute pyelonephritis in pregnancy and the fetal inflammatory response syndrome. The aims of this study were to examine: (1) whether amniotic fluid concentrations of sST2 change with IAI, preterm, and term parturition; and (2) if mRNA expression of ST2 in the chorioamniotic membranes changes with acute histologic chorioamnionitis in women who deliver preterm. METHOD: A cross-sectional study was conducted to determine amniotic fluid concentrations of sST2 in: (1) women with preterm labor (PTL) who delivered at term (n=49); (2) women with PTL who delivered preterm without IAI (n=21); (3) women with PTL who delivered preterm with IAI (n=31); (4) term pregnancies not in labor (n=13); and (5) term pregnancies in labor (n=43). The amniotic fluid concentration of sST2 was determined by ELISA. The mRNA expression of ST2 in the chorioamniotic membranes of women who delivered preterm with (n=24), and without acute histologic chorioamnionitis (n=19) was determined by qRT-PCR. RESULTS: (1) Patients with PTL who delivered preterm with IAI had a lower median amniotic fluid concentration of sST2 compared to those with PTL who delivered preterm without IAI [median 410 ng/mL, inter-quartile range (IQR) 152-699 ng/mL versus median 825 ng/mL, IQR 493-1216 ng/mL; p=0.0003] and those with PTL who delivered at term [median 410 ng/mL, IQR 152-699 ng/mL versus median 673 ng/mL, IQR 468 1045 ng/mL; p=0.0003]; (2) no significant differences in the median amniotic fluid concentration of sST2 were observed between patients with PTL who delivered at term and those who delivered preterm without IAI (p=0.4), and between women at term in labor and those at term not in labor (p=0.9); (3) the mean mRNA expression of ST2 was 4-fold lower in women who delivered preterm with acute histologic chorioamnionitis than in those without this lesion (p=0.008). CONCLUSIONS: The median sST2 amniotic fluid concentration and mRNA expression of ST2 by chorioamniotic membranes is lower in PTL associated with IAI and acute histologic chorioamnionitis than in PTL without these conditions. Changes in the median amniotic fluid sST2 concentration are not observed in preterm and term parturition without IAI. Thus, amniotic fluid sST2 in the presence of IAI behaves differently when compared to sST2 in the plasma of individuals affected by fetal inflammatory response syndrome, acute pyelonephritis in pregnancy, and adult sepsis. Decreased concentrations of sST2 in IAI are likely to promote a pro inflammatory response, which is important for parturition in the context of infection. PMID- 23688343 TI - High excitation energy quenching in fucoxanthin chlorophyll a/c-binding protein complexes from the diatom Chaetoceros gracilis. AB - The fucoxanthin chlorophyll (Chl) a/c-binding protein (FCP) is responsible for excellent light-harvesting strategies that enable survival in fluctuating light conditions. Here, we report the light-harvesting and quenching states of two FCP complexes, FCP-A and FCP-B/C, isolated from the diatom Chaetoceros gracilis. Pigment analysis revealed that FCP-A is enriched in Chl c, whereas FCP-B/C is enriched in diadinoxanthin, reflecting differences in low-temperature steady state absorption and fluorescence spectra of each FCP complex. Time-resolved fluorescence spectra were measured at 77 K, and the characteristic lifetimes were determined using global fitting analysis of the spectra. Tens of picosecond (ps) components revealed energy transfer to low-energy Chl a from Chls a and c, whereas the other components showed only fluorescence decay components with no concomitant rise components. The normalized amplitudes of hundreds of picosecond components were relatively 30% in the total fluorescence, whereas those of longest-lived components were 60%. The hundreds of picosecond components were assigned as excitation energy quenching, whereas the longest-lived components were assigned as fluorescence from the final energy traps. These results suggest that 30% of FCP complex forming quenching state and the other 60% of FCP complex forming light-harvesting state exist heterogeneously in each FCP fraction under continuous low-light condition. PMID- 23688344 TI - Tissue engineering rib with the incorporation of biodegradable polymer cage and BMSCs/decalcified bone: an experimental study in a canine model. AB - BACKGROUND: The reconstruction of large bone defects, including rib defects, remains a challenge for surgeons. In this study, we used biodegradable polydioxanone (PDO) cages to tissue engineer ribs for the reconstruction of 4cm long costal defects. METHODS: PDO sutures were used to weave 6cm long and 1cm diameter cages. Demineralized bone matrix (DBM) which is a xenograft was molded into cuboids and seeded with second passage bone marrow mesenchymal stem cells (BMSCs) that had been osteogenically induced. Two DBM cuboids seeded with BMSCs were put into the PDO cage and used to reconstruct the costal defects. Radiographic examination including 3D reconstruction, histologic examination and mechanical test was performed after 24 postoperative weeks. RESULTS: All the experimental subjects survived. In all groups, the PDO cage had completely degraded after 24 weeks and been replaced by fibrous tissue. Better shape and radian were achieved in PDO cages filled with DBM and BMSCs than in the other two groups (cages alone, or cages filled with acellular DBM cuboids). When the repaired ribs were subjected to an outer force, the ribs in the PDO cage/DBMs/BMSCs group kept their original shape while ribs in the other two groups deformed. In the PDO cage/DBMs/BMSCs groups, we also observed bony union at all the construct interfaces while there was no bony union observed in the other two groups. This result was also confirmed by radiographic and histologic examination. CONCLUSIONS: This study demonstrates that biodegradable PDO cage in combination with two short BMSCs/DBM cuboids can repair large rib defects. The satisfactory repair rate suggests that this might be a feasible approach for large bone repair. PMID- 23688345 TI - Population connectivity buffers genetic diversity loss in a seabird. AB - BACKGROUND: Ancient DNA has revolutionized conservation genetic studies as it allows monitoring of the genetic variability of species through time and predicting the impact of ecosystems' threats on future population dynamics and viability. Meanwhile, the consequences of anthropogenic activities and climate change to island faunas, particularly seabirds, remain largely unknown. In this study, we examined temporal changes in the genetic diversity of a threatened seabird, the Cory's shearwater (Calonectris borealis). FINDINGS: We analysed the mitochondrial DNA control region of ancient bone samples from the late-Holocene retrieved from the Canary archipelago (NE Atlantic) together with modern DNA sequences representative of the entire breeding range of the species. Our results show high levels of ancient genetic diversity in the Canaries comparable to that of the extant population. The temporal haplotype network further revealed rare but recurrent long-distance dispersal between ocean basins. The Bayesian demographic analyses reveal both regional and local population size expansion events, and this is in spite of the demographic decline experienced by the species over the last millennia. CONCLUSIONS: Our findings suggest that population connectivity of the species has acted as a buffer of genetic losses and illustrate the use of ancient DNA to uncover such cryptic genetic events. PMID- 23688346 TI - Disseminated nontuberculous mycobacterial infection in two children with different immune responses. AB - A diffuse, infiltrating abdominal mass accompanied with fever and anemia in a child raises the possibility of a benign or malignant tumor, pseudotumor, or infection. Herein, we describe a 9-year-old girl and a 14-year-old boy with multiple large abdominal masses, fever, weight loss, and anemia. During the evaluation of the children, the girl was found to be immunocompetent, while the boy was found to be immunocompromised. Computerized tomography of the abdomen in both cases demonstrated multiple large intra-abdominal masses. Tumors in the girl were composed of wide-spread necrotizing granulomas and necrosis with dystrophic calcifications. In the boy, non-necrotic, homogenous histiocytic infiltrates with rare multinucleated giant cells and lymphocytes were observed histologically. Review of histologic sections identified gram-positive, nonbranching acid-fast bacillary organisms in both cases. Diagnoses of Mycobacterium fortuitum (MF) and Mycobacterium avium-intracellulare complex (MAC) were confirmed by tissue microbiologic cultures in the girl and boy, respectively. The girl with MF infection was appropriately treated and is currently doing well. The boy with MAC was found to have human immunodeficiency virus infection/acquired immune deficiency syndrome (AIDS) and is currently undergoing AIDS treatment. These cases highlight the striking contrast between responses to nontuberculous mycobacteria infection based on immune status. PMID- 23688348 TI - The protein environment of the bacteriopheophytin anion modulates charge separation and charge recombination in bacterial reaction centers. AB - The kinetics and pathway of electron transfer has been explored in a series of reaction center mutants from Rhodobacter sphaeroides, in which the leucine residue at M214 near the bacteriopheophytin cofactor in the A-branch has been replaced with methionine, cysteine, alanine, and glycine. These amino acids have substantially different volumes, both from each other and, except for methionine, from the native leucine. Though the mutation site of M214 is close to the bacteriopheophytin cofactor, which is involved in the electron transfer, none of the mutations alter the cofactor composition of the reaction center and the primary charge separation reaction is essentially undisturbed. However, the kinetics of electron transfer from HA(-) -> QA becomes both slower and substantially heterogeneous in three of the four mutants. The decreased HA(-) -> QA electron transfer rate allows charge recombination between P(+) and HA(-) to compete with the forward reaction, resulting in a drop in the overall yield of charge separation. Both the yield change and the variation in kinetics correlate well with the volume of the mutant amino acid side chains. Analysis of the kinetics suggests that the introduction of a smaller side chain at M214 results in greater protein structural heterogeneity and dynamics on multiple time scales, resulting in perturbation of the electronic environment and its evolution in the vicinity of the early charge-separated radical pair, P(+)HA(-), and the subsequent acceptor QA, affecting both the extent and time scale of dielectric relaxation. It appears that the reaction center has been optimized not only in terms of its static structure-function relationships, but also finely tuned to favor particular reaction pathways on particular time scales by adjusting protein dynamics. PMID- 23688347 TI - Structure and thermodynamic insights on acetylaminofluorene-modified deletion DNA duplexes as models for frameshift mutagenesis. AB - 2-Acetylaminofluorene (AAF) is a prototype arylamine carcinogen that forms C8 substituted dG-AAF and dG-AF as the major DNA lesions. The bulky N-acetylated dG AAF lesion can induce various frameshift mutations depending on the base sequence around the lesion. We hypothesized that the thermodynamic stability of bulged-out slipped mutagenic intermediates (SMIs) is directly related to deletion mutations. The objective of the present study was to probe the structural/conformational basis of various dG-AAF-induced SMIs formed during translesion synthesis. We performed spectroscopic, thermodynamic, and molecular dynamics studies of several AAF-modified 16-mer model DNA duplexes, including fully paired and -1, -2, and -3 deletion duplexes of the 5'-CTCTCGATG[FAAF]CCATCAC-3' sequence and an additional 1 deletion duplex of the 5'-CTCTCGGCG[FAAF]CCATCAC-3' NarI sequence. Modified deletion duplexes existed in a mixture of external B and stacked S conformers, with the population of the S conformer being 'GC'-1 (73%) > 'AT'-1 (72%) > full (60%) > -2 (55%) > -3 (37%). Thermodynamic stability was in the order of -1 deletion > -2 deletion > fully paired > -3 deletion duplexes. These results indicate that the stacked S-type conformer of SMIs is thermodynamically more stable than the conformationally flexible external B conformer. Results from the molecular dynamics simulations indicate that perturbation of base stacking dominates the relative stability along with contributions from bending, duplex dynamics, and solvation effects that are important in specific cases. Taken together, these results support a hypothesis that the conformational and thermodynamic stabilities of the SMIs are critical determinants for the induction of frameshift mutations. PMID- 23688349 TI - Amidrazone complexes from a cascade platinum(II)-mediated reaction between amidoximes and dialkylcyanamides. AB - The aryl amidoximes R'C6H4C(NH2)?NOH (R' = Me, 2a; H, 2b; CN, 2c; NO2, 2d) react with the dialkylcyanamide platinum(II) complexes trans-[PtCl2(NCNAlk2)2] (Alk2 = Me2, 1a; C5H10, 1b) in a 1:1 molar ratio in CHCl3 to form chelated mono-addition products [3a-h]Cl, viz. [PtCl(NCNAlk2){NH?C(NR2)ON?C(C6H4R')NH2}]Cl (Alk2 = Me2; R' = Me, a; H, b; CN, c; NO2, d; Alk2 = C5H10; R' = Me, e; H, f; CN, g; NO2, h). In the solution, these species spontaneously transform to the amidrazone complexes [PtCl2{NH?C(NR2)NC(C6H4R')NNH2}] (7a-h; 36-47%); this conversion proceeds more selectively (49-60% after column chromatography) in the presence of the base (PhCH2)3N. The observed reactivity pattern is specific for NCNAlk2 ligands, and it is not realized for conventional alkyl- and arylnitrile ligands. The mechanism of the cascade reaction was studied by trapping the isocyanate intermediates [PtCl(NCO){NH?C(NR2)NC(C6H4R')NNH2}] (5a-h) and also by ESI-MS identification of the ammonia complexes [PtCl(NH3){NH?C(NR2)NC(C6H4R')NNH2}](+) ([6a-h](+)) in solution. The complexes [3a]Cl, [3c-h]Cl, 5a-h and 7a-h were characterized by elemental analyses, high resolution ESI-MS, IR, and (1)H NMR techniques, while 5b, 5d, 5g, 7b, and 7e were also studied using single-crystal X ray diffraction. PMID- 23688350 TI - Does a physically active lifestyle attenuate decline in all cognitive functions in old age? AB - In this study, the performance of a group of 20 physically active older adults was compared with that of a group of 20 sedentary healthy older adults while performing a series of cognitive tasks. These tasks were designed to assess processes that deteriorate most with age, namely executive control (assessed with the Wisconsin Card Sorting Task) and processing speed (simple and choice reaction time tasks). A repetition priming task that does not decline with age, involving attended and unattended picture outlines at encoding, was also included as a control task. The results show that a physically active lifestyle has a positive influence on executive control, processing speed, and controlled processing. As expected, a physically active lifestyle did not enhance repetition priming for attended stimuli, nor did it produce priming for unattended stimuli at encoding. Both groups exhibited robust priming for attended stimuli and no priming for unattended ones. Executive control functions are of vital importance for independent living in old age. These results have practical implications for enhancing the cognitive processes that decline most in old age. Promoting a physically active lifestyle throughout adulthood could significantly reduce the decline of effortful executive control functions in old age. PMID- 23688351 TI - Upregulation of myeloid cell leukemia-1 potentially modulates beclin-1-dependent autophagy in ischemic stroke in rats. AB - BACKGROUND: The mechanisms that underlie autophagy in cerebral ischemia remain poorly defined. Myeloid cell leukemia-1 (Mcl1), an anti-apoptotic member of the Bcl-2 family of proteins, regulates the balance between autophagy and apoptosis. However, little is known regarding its expression profile and contribution to cell fate in the brain following ischemic stroke. RESULTS: In this study, we investigated the expression profile and cellular distribution of Mcl1 in brains from transient middle cerebral artery occlusion (MCAO) model rats. Brain slices from sham-operated control rats showed minimal immunoreactivity for Mcl1. Mcl1 was mainly produced in neurons. Immunoreactivity for Mcl1 increased as early as 4 hours after MCAO, peaked at 24 hours, and then declined, but still remained high, at 72 hours. Mcl1 positive cells never colocalized with either cleaved caspase-3 or terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells. Both microtubule-associated protein 1 light chain 3 (LC3) and beclin-1 were evident in ischemic brain between 4 and 72 hours after MCAO. Most cells with strong LC3 staining were also labeled with beclin-1. Beclin-1 did colocalize with caspase-3 or Mcl1. Beclin-1/caspase-3 positive cells displayed the characteristic features of apoptosis including cell shrinkage and pyknotic nuclei, whereas beclin-1/Mcl1 positive cells had normal morphology. Pretreatment with 3 methyladenine attenuated autophagy without affecting the level of Mcl1 protein. CONCLUSIONS: These findings demonstrate that the expression of Mcl1 is involved in the survival of neuronal cells. In addition, the coexpression of Mcl1 with beclin-1 may attenuate beclin-1-dependent autophagy during ischemic stroke in rats. PMID- 23688353 TI - Mutation research/fundamental and molecular mechanisms of mutagenesis: special issue: DNA repair and genetic instability. PMID- 23688354 TI - A record number of fatalities in many categories of patients treated with deferasirox: loopholes in regulatory and marketing procedures undermine patient safety and misguide public funds? AB - A record 4113 fatalities were reported in 2012 in a postmarketing surveillance of patients treated with deferasirox, despite warnings of life-threatening toxic side effects, and the need for regular monitoring and prophylactic measures. In an EMA report, the mortality rate was estimated at 11.7% and a warning was issued for increasing the dose from 30 to 40 mg/kg/day. In an earlier FDA report of 2474 individual fatality cases, it was revealed that deferasirox was used in many categories of patients. Among the fatal cases reported were many young individuals and about 500 patients with normal iron stores such as cancer, leukaemia, cardiovascular and neurological diseases. The iron-loaded patient categories included myelodysplasia, sickle cell disease, haemochromatosis and thalassaemia. The rate of fatalities and the number of patient categories involved suggest that there has been an indiscriminate and uncontrollable use of deferasirox. These findings raise major concerns on patient safety and question the role, practices and procedures adopted by pharmaceutical companies, regulatory authorities, physicians, etc. in the development of new drugs and their safety. The generic drugs deferiprone, deferoxamine and their combination offer a safer, less expensive and complete treatment of iron overload in thalassaemia and other iron loading conditions. PMID- 23688355 TI - Pancreatic mucinous cystic neoplasm with sarcomatous stroma metastasizing to liver: a case report and review of literature. AB - We report a case of mucinous cystic neoplasm of pancreas with sarcomatous stroma metastasizing to the liver. The tumor occurred in a male patient aged 46 years. Symptoms included persistent epigastric and right upper quadrant pain. Radiographically, the pancreas contained four large cystic masses located in the neck, body, and tail. Histologically, the cysts were lined with benign, mucinous epithelium with underlying bland, storiform, ovarian-like stroma. An undifferentiated focally hyalinized, sarcomatous stroma composed of bland spindle cells showing short fascicular growth pattern and focal nuclear palisading was associated with the epithelial component in one of the cysts. These cells showed strong immunoreactivity with vimentin and inhibin (weak), they were negative for CD34, estrogen receptor, progesterone receptor, androgen, calretinin, S-100, CD117, melan A, chromogranin, and synaptophysin. A morphologically and immunohistochemically identical metastatic sarcomatous focus was identified in the liver without any glandular component. This case is unique in its clinically malignant behaviour and metastatic nature despite its morphologically benign epithelial and stromal components. PMID- 23688352 TI - Regenerative medicine for the kidney: stem cell prospects & challenges. AB - The kidney has key roles in maintaining human health. There is an escalating medical crisis in nephrology as growing numbers of patients suffer from kidney diseases that culminate in organ failure. While dialysis and transplantation provide life-saving treatments, these therapies are rife with limitations and place significant burdens on patients and healthcare systems. It has become imperative to find alternative ways to treat existing kidney conditions and preemptive means to stave off renal dysfunction. The creation of innovative medical approaches that utilize stem cells has received growing research attention. In this review, we discuss the regenerative and maladaptive cellular responses that occur during acute and chronic kidney disease, the emerging evidence about renal stem cells, and some of the issues that lie ahead in bridging the gap between basic stem cell biology and regenerative medicine for the kidney. PMID- 23688356 TI - Disease-modifying factors in hereditary angioedema: an RNA expression-based screening. AB - BACKGROUND: Hereditary Angioedema due to C1-Inhibitor deficiency (HAE types I and II) is a monogenic disease characterized by sudden, self-limited episodes of cutaneous and mucosal swelling due to local deregulation of vascular permeability. Despite its monogenic pattern of inheritance, HAE exhibits great clinical variability and low genotype/phenotype correlation among those affected, which ultimately hinders therapeutic approach and probably underlies yet unknown genetic and environmental factors. METHODS: We studied whole-genome RNA expression of PBMCs in three HAE type-I families (accounting for 40 individuals), 24 of which carry the same R472X mutation in the C1-Inhibitor gene and show large variability in terms of disease expression. Those included in this study were analyzed according to the presence of mutation and/or clinical symptoms. RESULTS: Instead of a single, common disease-associated expression pattern, we found different transcriptome signatures in two of the families studied. In one of them (referred to as DR family), symptoms correlate with the upregulation of 35 genes associated to the biological response to viral infections (including RSADs, OAS, MX and ISG pathway members) and immune response. In another pedigree (Q family), disease manifestation is linked to the upregulation of 43 genes with diverse functions, including transcription and protein folding. Moreover, symptoms-free members of the Q pedigree display relatively higher expression of 394 genes with a wide diversity of functions. CONCLUSION: We found no evidence for a common altered PBMC expression pattern linked to HAE symptoms in the three families analyzed. All the data considered, differential gene expression in PBMCs do not seem to play a significant role in the predisposition or protection against HAE in the basal -between crises- conditions analyzed. Although the RNA expression pattern associated to the response to viral infections observed in the DR family supports the idea of infectious diseases as a modifying factor for HAE severity, large-scale studies would be needed to statistically associate such expression pattern to the development of this rare disease. PMID- 23688358 TI - Effect of Au nanoparticle spatial distribution on the stability of thin polymer films. AB - The stability of thin poly(methyl-methacrylate) (PMMA) films of low molecular weight on a solid substrate is controlled by the areal coverage of gold nanoparticles (NPs) present at the air-polymer interface. As the polymer becomes liquid the Au NPs are free to diffuse, coalesce, and aggregate while the polymer film can change its morphology through viscous flow. These processes lead at the same time to the formation of a fractal network of Au NPs and to the development of spinodal instabilities of the free surface of the polymer films. For thinner films a single wavelength is observed, while for thicker films two wavelengths compete. With continued heating the aggregation process results in a decrease in coverage, the networks evolve into disordered particle assemblies, while the polymer films flatten again. The disordering occurs first on the smallest scales and coincides (in thicker films) with the disappearance of the smaller wavelength. The subsequent disordering on larger scales causes the films to flatten. PMID- 23688357 TI - Association between non-alcoholic fatty pancreatic disease (NAFPD) and the metabolic syndrome: case-control retrospective study. AB - BACKGROUND: Fatty liver is associated with insulin resistance, dyslipidemia, and obesity and is therefore considered a phenotype of metabolic syndrome. However, less is known regarding the metabolic abnormalities associated with non-alcoholic fatty pancreatic disease (NAFPD; fatty pancreas). The present study was performed to ascertain whether fatty pancreas is associated with specific metabolic risk factors and with metabolic syndrome as defined by the Adult Treatment Panel III. METHODS: Five-hundred-fifty-seven healthy and consecutive subjects without known hypertension or diabetes and who received a health investigation at the National Taiwan University Hospital Health Management Center were enrolled in this retrospective study. Fatty pancreas was diagnosed via trans-abdominal ultrasonographic findings. RESULTS: Seventy-two (12.9%) subjects diagnosed with fatty pancreas comprised the fatty pancreas group, and remaining subjects comprised the normal pancreas group. The presence of various demographic and metabolic risk factors was recorded for all subjects, and the two groups were examined for statistically significant differences in these factors. As compared to the absence of fatty pancreas, the presence of the disease was associated with older age and with higher values for each of the following: BMI, abdominal girth/height, abdominal girth (both genders), fasting and postprandial blood glucose, HbA1c, total cholesterol, triglycerides, LDL-cholesterol, systolic blood pressure, and platelet count. In contrast to previously reported findings, serum amylase values were lower in the fatty pancreas as compared to the control group. CONCLUSION: The presence of fatty pancreas represents a meaningful manifestation of metabolic syndrome together with obesity. PMID- 23688360 TI - The journey of the pain resource nurse in improving pain management practices: understanding role implementation. AB - Pain assessment and management continues to be challenging for many nurses. Single educational interventions have proven to be unsuccessful in knowledge retention. This study will assist leaders in nursing in understanding how a 4-day educational program delivered to self-selected pain resource nurses (PRNs) could improve pain assessment and management practices. A focus group study was undertaken at a trisite academic health science center to understand the role implementation of the PRNs and required resources to sustain the role at a unit level. To evaluate the PRN role, a qualitative descriptive study design using focus group interviews was used to answer the following questions: What was the experience of the PRN during role implementation? What barriers and enablers affected the implementation of this role? Organizational support, integration within the interdisciplinary team, and organizational role awareness were key themes highlighted in the focus group results. This article will describe how the three-site academic health science center used the PRN role to foster practice related change and enhance current knowledge of evidence-based pain management. PMID- 23688361 TI - Chronic pain patients--effects on mental health and pain after a 57-week multidisciplinary rehabilitation program. AB - Chronic musculoskeletal pain is a common health complaint in Norway and constitutes the largest proportion in terms of those who suffer long-term sickness and are in receipt of disability pensions. The aim of this study was to examine the relation between changes in pain and mental health among men and women with chronic musculoskeletal pain after a rehabilitation program. A total of 201 subjects (132 women and 63 men) with chronic pain (>6 months) and without any manifest organic diseases were referred to the 57-week multidisciplinary rehabilitation program. Measurements of pain (visual analog scale) and mental health (Hospital Anxiety and Depression Scale [HADS]), as well as sociodemographic data, were obtained before and after the rehabilitation period. At baseline, men showed higher HADS scores than women. Both women and men reported significant improvements in pain and mental health. The subjects scored higher on HADS both before and after the rehabilitation compared with a population-based study in the region. Older men and men with low education levels showed less improvement in HADS scores. In women, a significant association was found between change in pain and both change in anxiety and change in depression. The results support the hypothesis that there may be a strong association between change in chronic pain and psychologic factors, but there were gender differences. PMID- 23688362 TI - Predictors and use of nonpharmacologic interventions for procedural pain associated with turning among hospitalized adults. AB - Many hospitalized adults cannot reposition themselves in their beds. Therefore, they are regularly turned by their nurses, primarily to prevent pressure ulcer formation. Earlier research indicates that turning is painful and that patients are rarely premedicated with analgesics. Nonpharmacologic interventions may be used to help with this painful procedure. However, no published research was found on the use of nonpharmacologic interventions for turning of hospitalized patients. The objectives of this study were: 1) to describe patient pain characteristics during turning and their association with patient demographic and clinical characteristics; 2) to determine the frequency of use of various nonpharmacologic interventions for hospitalized adult patients undergoing the painful procedure of turning; and 3) to identify factors that predict the use of specific nonpharmacologic interventions for pain associated with turning. Hospitalized adult patients who experienced turning, the nurses caring for them, and others who were present at the time of turning were asked if they used various nonpharmacologic interventions to manage pain during the turning. Out of 1,395 patients, 92.5% received at least one nonpharmacologic intervention. Most frequently used were calming voice (65.7%), information (60.6%), and deep breathing (37.9%). Critical-care patients were more likely to receive a calming voice (odds ratio [OR] 1.66, p < .01), receive information (OR 1.62, p < .001), and use deep breathing (OR= 1.36, p < .05) than those who were not critical-care patients. Those reporting higher pain were consistently more likely to receive each of the three interventions (OR 1.01, p < .05 for all 3). In conclusion, nonpharmacologic interventions are used frequently during a turning procedure. The specific interventions used most often are ones that can be initiated spontaneously. Our data suggest that patients, nurses, and family members respond to patients' turning-related pain by using nonpharmacologic interventions. PMID- 23688363 TI - The management of HIV- and AIDS-related pain in a primary health clinic in Tshwane, South Africa. AB - Pain has been recognized as an important, highly prevalent, and debilitating symptom of HIV and AIDS. In South Africa, many people living with HIV and AIDS utilize primary health clinics for pain management. Primary health clinics are nurse led and face a variety of challenges pertaining to pain management. The purpose of this study was to explore if HIV and AIDS pain is effectively managed in a primary health clinic in Tshwane, South Africa. The study aimed to explore the level and characteristics of HIV- and AIDS-related pain, the pain-related experiences of patients and if pain was managed according to the applicable guidelines of the Department of Health. A quantitative survey was conducted. The target population was HIV and AIDS patients who had been using the primary health clinic for chronic pain management. The sampling method was convenience (n = 500). Data were gathered by means of structured interviews and structured observation. The data were analyzed using the SSPS 15 program and open coding. The study provided evidence that HIV- and AIDS-related pain is not managed effectively. Despite repeated visits to the primary health clinic, the overwhelming majority of patients still experienced pain. Nurses added to the suffering, because they lacked knowledge of pain and pain management. It is recommended that nurses practicing in primary health clinics should be trained and supervised to effectively manage the pain of people living with HIV and AIDS. PMID- 23688364 TI - Factors that influence pain intensity and fentanyl requirements after a gynecologic laparotomy. AB - The association between pain intensity and its control by intravenous patient controlled analgesia (IV-PCA) with fentanyl after a laparotomy for cystectomy/salphingoophorectomy, myomectomy, or hysterectomy was investigated. IV fentanyl infusion was administered to patients (n = 94) at 3 MUg/kg/h to provide intraoperative analgesia after induction of general anesthesia. Postoperative fentanyl requirements were quantified via IV-PCA, and the amounts of rescue fentanyl required both during and after surgery were recorded. Mean values for PCA use as well as the visual analog scores (VAS) for pain were documented for up to 24 hours. The association between postoperative fentanyl requirements and VAS were then analyzed by using Mann-Whitney or Kruskal-Wallis tests. Patients with lower midline incisions had greater degrees of pain (p < .05) during the first 16 hours after surgery but did not consume more fentanyl compared with patients with Pfannenstiel incisions. Subjects who underwent operations lasting >4 hours required more rescue fentanyl during surgery (p < .05). However, this group consumed less fentanyl during the first 4 hours after surgery (p < .05). The demand at the fourth 4-hour period was lower among subjects undergoing myomectomy compared with cystectomy/salphingoophorectomy or hysterectomy (p = .045). Only a poor correlation was observed between pain intensity and analgesic usage. Postoperative pain intensity is influenced by the type of surgical incision but not the type of gynecologic surgery nor the duration of surgery. The relationship between subjective pain ratings with analgesic consumption is weak. Prolonged intraoperative administration of continuous IV fentanyl infusion may reduce fentanyl requirements in the immediate postoperative period. PMID- 23688365 TI - Current knowledge of pain after breast cancer treatment: a systematic review. AB - Pain and functional compromise are reported as effects that can be expected after breast cancer treatment. The reported prevalence of pain after breast cancer treatment varies widely, ranging from 13% (n = 74) to 93% (n = 590). To date, pain after breast cancer treatment has not been the focus of a systematic review. The aim of this study was to present what is known about the prevalence, location, intensity, nature, and temporal factors of the pain experienced by patients after breast cancer treatment. Searches of the Pubmed, Embase, Scopus, Amed, and Cinhal databases identified 69 articles on the topic. Studies were methodologically assessed by two independent reviewers using a checklist of 18 criteria. Twenty-six of the articles were identified as meeting inclusion criteria. Findings related to research conducted on 15 patient cohorts. Pain is confirmed as a prevalent treatment-related symptom experienced by 13%-51% of women in several different anatomic locations. The onset is variable, ranging from immediate to 24 months, highlighting the need to assess for pain at every evaluation interval. Little is known about the nature of the pain, but descriptors used (tenderness, soreness) suggest that the type of pain may not be confined to neuropathic pain. Reported average numeric intensity is low, but no study measured the impact of pain on function. Incidence of posttreatment pain has yet to be established. Further exploration of the nature, temporal factors, and impact that the pain experienced after treatment has on function, activity, and participation is needed to guide intervention and test its efficacy. PMID- 23688366 TI - Prevalence of pain among residents in Japanese nursing homes: a descriptive study. AB - It is often observed that pain causes substantial problems for nursing home residents. However, there has been little research about the prevalence of pain for nursing home residents in Japan. This study aimed to examine the prevalence of pain in older adults living in nursing homes in Japan by using self-reporting and the Abbey Pain Scale-Japanese version (APS-J) and to explore factors related to pain. This is a descriptive study. Residents in two Special Nursing Homes for the Elderly in Tokyo, Japan, were asked to participate in this study, with the exclusion of short-term temporary residents. Data collected from participating residents included their demographics and the results from the Barthel Index, the Folstein Mini-Mental State Examination, the APS-J, and the Verbal Descriptor Scale for pain. The residents were divided into two groups: residents able to report their pain (self-report group) and residents not able to report their pain. The second group was assessed by using the APS-J (APS-J group). The Mann Whitney U test, the chi2 test, and logistic analyses were performed to derive factors related to pain prevalence. Data were obtained from 171 residents. The prevalence of pain in the self-report group (n = 96) was 41.7%. For the 75 residents unable to report their pain, 52.0% were assessed by the APS-J to have pain. The overall pain prevalence of all residents was 46.2%. Age, Barthel Index score, and length of time of institutionalization were significantly associated with residents' pain in the APS-J group. Logistic regression analysis showed that contracture (odds ratio 3.8) and previous injury (odds ratio 3.4) were associated with residents' pain in the self-report group, whereas only the length of nursing home stay (odds ratio 1.03) was a predictor for pain in the APS-J group. Nearly one-half of residents had pain when they moved or were moved. Pain assessment and management is needed for residents. PMID- 23688367 TI - Pain management for older persons living in nursing homes: a pilot study. AB - Because the prevalence of chronic pain among the elderly in nursing homes is high and decreases their quality of life, effective nonpharmacologic pain management should be promoted. The purpose of this quasiexperimental pretest and posttest control design was to enhance pain management in nursing homes via an integrated pain management program (IPMP) for staff and residents. Nursing staff and residents from the experimental nursing home were invited to join the 8-week IPMP, whereas staff and residents from the control nursing home did not receive the IPMP. Baseline data were collected from nursing staff and residents in both groups before and after the IPMP. The IPMP consisted of eight lectures on pain assessment, drug knowledge,and nondrug strategies for the nursing staff, and 8 weeks of activities, including gardening therapy and physiotherapy exercise, for the residents. There were 48 and 42 older people in the experimental and control groups, respectively. No significant differences were found in their educational level, sleep quality, bowel habits, past and present health conditions, pain conditions and psychologic well-being parameters (p > .05) at baseline. After the IPMP, the experimental nursing staff showed a significant improvement in their knowledge of and attitudes to pain management (p < .05), and the experimental residents reported significantly lower pain scores and used more nondrug strategies for pain relief compared with the control group (p < .05). Moreover, the psychologic well-being parameters, including happiness, loneliness, life satisfaction, and geriatric depression, had significantly improved among the experimental residents (p < .05). The IPMP was effective in enhancing the knowledge and attitudes of nursing staff, as well as reducing pain conditions and enhancing psychologic well-being for older persons in nursing homes. PMID- 23688368 TI - A pilot study to identify correlates of intentional versus unintentional nonadherence to analgesic treatment for cancer pain. AB - Existing studies of medication adherence treat "nonadherence" as a monolithic concept. The goal of this study was to isolate correlates of intentional versus unintentional nonadherence for analgesic treatment for cancer pain. Patients were recruited from outpatient oncology clinics in the middle Atlantic region, >=18 years old, and diagnosed with solid tumors, and had an active prescription of at least one around-the-clock analgesic. The Morisky Medication Adherence Scale (MMAS) was used to assesses "unintentional" (forgetfulness/carelessness) and "intentional" (stopping use of medication if feeling better or worse) dimensions of analgesic nonadherence. A visual analog scale was used to assess the percentage of analgesic doses taken in the preceding month. A majority of participants (85.5%) took prescribed analgesics in the index period. However, 51% reported taking only up to 60% of the analgesic doses prescribed to them. Stopping taking analgesics when feeling better was the most commonly reported nonadherence behavior (74%); those reporting "intentional" nonadherence when feeling better were more likely to report not using analgesics in the index week (100% vs. 67.7%; p = .029) and agree that pain medication can keep you from knowing what is going on in your body (p = .029) and were less likely to need stronger pain medication (33.3% vs. 81.5%; p = .003). "Unintentional" nonadherence, i.e., forgetfulness/carelessness, though associated with many analgesic beliefs, was not associated with measures of analgesic use in the index period. These preliminary data indicate that different heuristics underlie intentional versus unintentional nonadherence to analgesia and that intentional and unintentional nonadherence behaviors may have different implications for pain treatment outcomes. PMID- 23688369 TI - Nurses' opinions of pain and the assessed need for pain medication for the elderly. AB - The undertreatment of pain in the elderly living in nursing homes is a significant problem. In Swedish nursing homes, the registered nurse on duty is often responsible for 20-40 patients during the day with no daily contact from attending physicians. The aim of this study was to investigate the opinions of registered nurses regarding pain and the assessed need for pain medication for elderly patients using patient scenarios. Two patient scenarios were used in this study; a questionnaire and background information was provided. The scenarios consisted of one smiling patient and one grimacing patient, both with the same numeric rating scale value of pain, blood pressure, pulse rate, and respiration rate. Three questions regarding pain assessment and management followed the scenarios. The questionnaire was sent to all 128 registered nurses working daytime in elderly care in both municipal nursing homes and municipal home care in the mid-Sweden region. A total of 56 nurses participated, providing an answering frequency of 45%. Results showed that registered nurses with more experience did not have the same opinion about pain as the smiling patient and gave inadequate medication, which was not in accordance with recommendations from the county hospital and the World Health Organization. PMID- 23688370 TI - The seroprevalance of Crimean-Congo haemorrhagic fever in people living in the same environment with Crimean-Congo haemorrhagic fever patients in an endemic region in Turkey. AB - Crimean-Congo haemorrhagic fever (CCHF) is endemic in Turkey, and since 2004 many cases have been reported from different regions of Turkey. There are limited data about the seroprevalence of the disease in household members of patients or persons sharing the same environment. We evaluated seroprevalence of CCHF in the immediate neighbourhood and in household members of patients living in the same environment as confirmed cases of CCHF in an endemic area of Turkey. A total of 625 healthy subjects [mean (s.d.) age: 42.3 (18.4) years, 58.7% females] without a past history of CCHF infection included in this case-control, retrospective study were evaluated in terms of sociodemographic characteristics, risk factors for CCHF via a study questionnaire, while serum analysis for CCHF virus (CCHFV) IgG antibodies was performed by ELISA. Anti-CCHFV IgG antibodies were positive in 85 (13.6%) participants. None of the seropositive individuals had a history of symptomatic infection. Regression analysis revealed that animal husbandry [odds ratio (OR) 1.84, 95% confidence interval (CI) 1.09-3.11], contact with animals (OR 2.31, 95% CI 1.08-5.10), contact with ticks (OR 3.45, 95% CI 1.87-6.46), removing ticks from animals by hand (OR 2.48, 95% CI 1.48-4.18) and living in a rural area (OR 4.05, 95% CI 1.65-10.56) were associated with increased odds of having IgG seropositivity, while being a household member of a patient with prior CCHF infection had no influence on seropositivity rates. This result also supports the idea that CCHF is not transmitted person-to-person by the airborne route. PMID- 23688371 TI - Only distance matters - non-choosy females in a poison frog population. AB - BACKGROUND: Females have often been shown to exhibit preferences for certain male traits. However, little is known about behavioural rules females use when searching for mates in their natural habitat. We investigated mate sampling tactics and related costs in the territorial strawberry poison frog (Oophaga pumilio) possessing a lek-like mating system, where both sequential and simultaneous sampling might occur. We continuously monitored the sampling pattern and behaviour of females during the complete period between two successive matings. RESULTS: We found no evidence that females compared males by visiting them. Instead females mated with the closest calling male irrespective of his acoustic and physical traits, and territory size. Playback experiments in the natural home ranges of receptive females revealed that tested females preferred the nearest speaker and did not discriminate between low and high call rates or dominant frequencies. CONCLUSIONS: Our results suggest that females of O. pumilio prefer the closest calling male in the studied population. We hypothesize that the sampling tactic in this population is affected by 1) a strongly female biased sex ratio and 2) a low variance in traits of available males due to strong male male competition, preventing low quality males from defending a territory and mating. PMID- 23688372 TI - New and old predictive factors for breech presentation: our experience in 14 433 singleton pregnancies and a literature review. AB - OBJECTIVE: Breech presentation represents a common indication for primary cesarean section in women presenting for parturition. This study aims to investigate the presence of new and old risk factors for breech presentation and to provide a literature review. METHOD: In this population-based retrospective cohort study, we collected data from 14,433 consecutive singleton deliveries occurred in a 3rd level hospital setting of northeast Italy between January 2001 and July 2009. Related risk factors and trends in breech presentation prevalence were also considered. RESULTS: Mean maternal age was 31.78 years (+/-5.17) and mean gestational age at delivery 38.67 weeks (+/-2.54). Breech presentation prevalence in nullipara and pluripara was respectively 5.36% (415/7743) and 3.53% (236/6689; p<0.05), and was significantly lower among Sub-Saharan-African women 2.62% (14/535) versus 4.51% (651/14432; p<0.05). Also advanced maternal age, early gestational age at delivery, neonatal female gender and low weight at delivery resulted associated with a higher prevalence of breech presentation. By multivariate logistic regression, the breech presentation resulted independently predicted by maternal age, ethnicity, parity, gestational age and neonatal weight MoMs at delivery, and neonatal gender. CONCLUSIONS: Advanced maternal age, early gestational age, low neonatal weight MoMs at delivery and female gender resulted to be risk factors for fetal breech presentation at delivery, while multiparity and Sub-Saharan-African ethnicity resulted to be protective. PMID- 23688373 TI - SIU scholar: Dr. Husein Slaiman. PMID- 23688374 TI - Reverse mode of the sodium/calcium exchanger subtype 3 in interstitial cells of Cajal from rat bladder. AB - OBJECTIVE: To investigate how the sodium/calcium exchanger subtype 3 (NCX3) and its reverse mode contribute to the function of interstitial cells of Cajal (ICCs) from the rat bladder. METHODS: The study used 20 female Wistar rats. We observed the expression of the NCX3 expression in the bladder using reverse transcriptase polymerase chain reaction and Western blotting. The NCX3 in ICCs was also confirmed by double-labeled fluorescence. NCX3 functions in reverse mode of ICCs were observed using confocal microscopy with preload fluo-3AM, and its currents were evaluated using the whole-cell patch clamp technique, with or without the NCX3 inhibitor KB-R7943 (5 and 30MUM), with an afterward identification of ICCs using single-cell polymerase chain reaction. RESULTS: NCX3 was confirmed in rat bladder ICCs. The time required for the intracellular calcium concentration [Ca(2+)]i of NCX3 was enhanced by KB-R7943 (5MUM, P <=.01). Moreover, KB-R7943 (5 and 30MUM) significantly decreased the currents generated by the reverse mode of NCX3 from the ICCs (P <.05). CONCLUSION: NCX3 is expressed in rat bladder ICCs. The reverse mode of NCX3 can generate [Ca(2+)]i of the bladder ICCs. PMID- 23688375 TI - Sprouty2 is associated with prognosis and suppresses cell proliferation and invasion in renal cell carcinoma. AB - OBJECTIVE: To investigate the expression pattern of Sprouty2 (Spry2) and its clinicopathologic significance among patients with renal cell carcinoma (RCC) and to detect its role in proliferation and invasion of RCC in vitro. MATERIALS AND METHODS: The expression profile of Spry2 in RCC and matched adjacent noncancerous tissues were detected by immunohistochemistry and Western blot analysis. The expression of Spry2 was depleted by stably transfecting with small, interfering ribonucleic acid and the effects of Spry2 were assessed using the cell proliferation and transwell assay. RESULTS: We found Spry2 protein expressed at lower levels and modestly downregulated in cancerous RCC tissues compared with adjacent normal tissue (P <.001). We also measured the expression level of Spry2 in 103 archived RCC tissues by immunohistochemical staining and found its correlation with clinicopathologic findings such as tumor size (P = .002), pathologic TNM stage (P <.001), tumor grade (P <.001), lymph node metastasis (P = .001), distant metastasis (P <.001), and poor survival (P = .001). In addition, small interfering ribonucleic acid-induced depletion of Spry2 expression promoted proliferation and invasion in RCC cell lines. CONCLUSION: Collectively, our results have demonstrated for the first time, to our knowledge, that Spry2 might offer an attractive new target for prognostic and therapeutic intervention in RCC. PMID- 23688376 TI - Using Hounsfield unit measurement and urine parameters to predict uric acid stones. AB - OBJECTIVE: To determine the in vivo ability to predict uric acid stone composition by Hounsfield units (HU) with the addition of urine parameters. METHODS: We reviewed all consecutive stones sent for analysis during a 4-year period from our institution for patients with an in-house computed tomography (CT) scan within the prior 6 months and urinalysis within the prior week. CT scans were independently reviewed by a radiologist blinded to stone composition. RESULTS: Of the 507 patients with stones sent for analysis, 235 met the criteria for inclusion. Analysis showed 212 stones were predominantly calcium-based, and 22 were predominantly uric acid in composition. There was a significant difference between calcium stones and uric acid stones in mean HU (890 +/- 20 vs 484 +/- 44; P <.01) and urine pH (6.4 +/- 0.8 vs 5.1 +/- 0.2; P <.01). Receiver operating characteristic curve evaluation gave optimal predictive values of HU <=494 (rounded to 500) and pH of <=5.5 to predict uric acid stones. The combination of HU and pH criteria resulted in a sensitivity of 86% and a specificity of 98%, with a positive predictive value of 80%, which increased to 90% if we limited to stones >4 mm. CONCLUSION: Uric acid stones show a significant difference in HU and urine pH from calcium stones, and the use of both criteria is superior to either separately. For a stone >4 mm, a HU <=500 and pH <=5.5 has a positive predictive value of 90% for uric acid composition. Our prediction model gives a straightforward tool that can be easily measured to predict a uric acid stone. PMID- 23688377 TI - Percutaneous suprapubic stone extraction for posterior urethral stones in children: efficacy and safety. AB - OBJECTIVE: To evaluate the safety and efficacy of percutaneous suprapubic stone extraction (PSPSE) for pediatric posterior urethral stones. METHODS: Between July 2007 and June 2010, 54 boys presenting with acute urinary retention due to posterior urethral stones underwent PSPSE. Patients were a mean age of 66.4 months (range, 8-180 months). The stone size was 0.7-1.9 cm. Patients were placed under general anesthesia, and a 7F urethroscope was used to pushback the stone to the bladder. A 3-mm suprapubic puncture with a scalpel was performed, followed by insertion of a straight narrow hemostat through the puncture aided with cystoscopic guidance. The stone was grasped with the hemostat in its narrowest diameter and was extracted percutaneously or crushed if friable. The suprapubic puncture was closed with a single 4-0 Vicryl (Ethicon) suture. RESULTS: Intact stone retrieval was achieved in 45 patients, and the stone was crushed into minute fragments in 9 patients. Intraperitoneal extravasation developed in 1 patient that required open surgical intervention. Mean operative time was 22 minutes. Patients were monitored for up to 17 months, with complete resolution of symptoms and stone clearance. CONCLUSION: PSPSE provides a minimally invasive approach for the extraction of urethral and bladder stones in the pediatric population. The use of a straight hemostat for suprapubic stone extraction or crushing is a good alternative to suprapubic tract dilation, with minimal morbidity. PMID- 23688378 TI - Cystine nephrolithiasis. AB - Cystinuria is a rare etiology of nephroliathiasis but must be considered in the pediatric population and in those patients with recurrent nephrolithiasis. We describe a patient with an unusually large cystine stone burden and our successful multimodality therapy. PMID- 23688379 TI - Complicated sinusitis in a developing country, a retrospective review. AB - OBJECTIVES: The aim of our study was to assess the incidence rate, mode of presentation, treatment and outcome measures associated with complicated sinusitis in our developing world setting. Additionally we had hope to identify possible patterns or predisposing factors that may assist us in decreasing the significant morbidity and mortality associated with this serious disease. METHOD: A retrospective chart review was performed on all patients treated for complicated sinusitis at 3 referral hospitals in Durban South Africa between January 2006 and September 2009. RESULTS: A total of 220 patients were identified including 138 patients with orbital complications only and 82 with intracranial complications with or without orbital manifestations. We report on the demographics, mode of presentation, microbiology, impact on resources, management and mortality of the study group. The incidence rate was found to be 5.83 per million, the most common risk factors associated with intracranial complications, a persistent headache beyond 1 week and referral from a rural rather than urban area (OR 3.24). We found a high mortality rate of 20.7% in those patients with intracranial complications of their sinusitis. CONCLUSIONS: Complicated sinusitis is still far too common in the developing world with young adolescent males most at risk. A high index of suspicion must be maintained in detecting orbital as well as intracranial extension of disease and appropriate referral for investigation and management swift and aggressive in preventing extensive morbidity and mortality. PMID- 23688380 TI - Computed tomography supports histopathologic evidence of vestibulocochlear sexual dimorphism. AB - OBJECTIVE: To investigate whether the effects of sex (male/female) that have been demonstrated in the pathology literature using 0.1 mm histopathologic slices are measurable and statistically significant using high-resolution (0.625 mm slice) computed tomography (CT). METHODS: IRB-approved retrospective analysis of high resolution "normal" CT temporal bone images in pediatric subjects (0-18 years) using comparative anatomic measurements between males and females obtained from the semicircular canals, cochlea and vestibule as follows: (1) lateral semicircular canal (LSCC) bony island width, (2) superior semicircular canal (SSCC) bony island width, (3) central lucency of the LSCC bony island, (4) coronal cochlear height, (5) axial cochlear height, (6) cochlear length, (7) cochlea basal turn lumen width, (8) cochlear aperture width, (9) cochlear aperture height, (10) vestibular length, (11) vestibular width, and (12) coronal vestibule oblique diameter. RESULTS: Eighteen females (36 ears) and twenty males (36 ears) were included in the study. Independent-samples t-tests revealed statistically significant differences in measurements for females and males as follows (differences reported as a percentage and as an absolute difference (AD) in mm): (1) vestibular width was 4.2% (0.13 mm AD) smaller in females (mean +/- SD; 3.0 +/- 0.27) compared to males (mean +/- SD; 3.2 +/- 0.25) [t(70) = 2.083, p = 0.041]; (2) cochlear length was 3.9% (.23 mm AD) smaller in females (mean +/- SD; 5.8 +/- 0.32) compared to males (mean +/- SD; 6.0 +/- 0.40) [t(70)=2.660, p = 0.010]; (3) cochlear aperture height was 11.6% (0.13 mm AD) smaller in females (mean +/- SD; 1.0 +/- 0.18) compared to males (mean +/- SD; 1.2 +/- 0.22) [t(70)=2.549, p = 0.013]; and (4) coronal cochlear height was 11.4% (0.55 mm AD) smaller in females (mean +/- SD; 4.8 +/- 0.58) compared to males (mean +/- SD; 5.4 +/- 0.48) [t(68) = 4.270, p < 0.005]. CONCLUSION: Sexual dimorphism of inner ear structures may contribute to variability in reported normative and pathologic measurements of inner ear structures. This variability must be taken into consideration when designing future research studies to investigate inner ear structures and for drawing accurate conclusions about possible inner ear morphologic abnormalities associated with SNHL compared to controls. PMID- 23688381 TI - Rates of continuation and satisfaction of immediate intrauterine device insertion following first- or second-trimester surgical abortion: a French prospective cohort study. AB - BACKGROUND: Immediate postsurgical abortion insertion of intrauterine devices (IUDs) could substantially reduce the risk of repeat abortion. Studies have demonstrated efficacy and safety, and postabortum insertion would likely increase rates of usage. There are few data in the literature concerning rates of continuation and satisfaction after immediate postabortion IUD insertion. STUDY DESIGN: We performed a prospective cohort study of women undergoing surgical abortion and choosing immediate insertion of IUD for contraception. We followed at six months rates of continuation, expulsion, removal and pregnancy, and reasons for discontinuation of IUD postinsertion. RESULTS: 137 patients were included. At 6 months, we were able to contact 112 of them. The continuation rate was 78.6% (95% confidence intervals (CI) [69.8, 85.8]) and the satisfaction rate was high at 85.2% (95%CI [76.1, 91.1]). Three (2.7%) expulsions occurred. Removals occurred in 18.75%. CONCLUSIONS: We found that women choosing immediate postsurgical abortion IUD insertion had high rates of continuation and satisfaction. PMID- 23688382 TI - Brown-Vialetto-Van Laere syndrome: clinical and neuropathologic findings with immunohistochemistry for C20orf54 in three affected patients. AB - Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare degenerative neurological disorder characterized by pontobulbar palsy and sensorineural deafness. Since its initial description in 1894, fewer than 100 cases have been reported, and published neuropathological analyses of these cases are extremely rare. Recently, individuals with BVVLS have been found to carry mutations in the C20orf54 gene, which encodes the human homolog for a rat riboflavin transporter. We present the case of a male who presented at the age of 5 years with sensorineural deafness, as well as those of 2 infant sisters who presented at 11 and 13 months of age with weakness and ataxia, respectively. All cases were genetically confirmed. We include the 1st immunohistochemical characterization of C20orf54 expression in BVVLS and controls. Results showed punctate axonal staining in the control cases that was dramatically reduced in the 3 BVVLS cases compared to the 5 controls. This decreased staining was seen even in the neocortex, which was unaffected in the BVVLS cases by routine histology. While the implications of these results are far from definitive, and although the evaluation of more cases is needed, immunohistochemistry for the C20orf54 protein may eventually be useful, in the right clinical scenario, as a screening test when selecting cases for sequencing of the C20orf54 gene to diagnose BVVLS at autopsy. PMID- 23688383 TI - Centrosema is a promiscuous legume nodulated by several new putative species and symbiovars of Bradyrhizobium in various American countries. AB - Centrosema is an American indigenous legume that can be used in agroecosystems for recovery of acidic and degraded soils. In this study, a Centrosema-nodulating rhizobial collection of strains isolated in a poor acid savanna soil from Venezuela was characterized, and the members of the collection were compared to other Centrosema strains from America. The analysis of the rrs gene showed that the strains nodulating Centrosema in American countries were closely related to different species of the genus Bradyrhizobium. However, the analysis of the atpD and recA genes, as well as the 16S-23S ITS region, showed that they formed several new phylogenetic lineages within this genus. The Venezuela strains formed three lineages that were divergent among themselves and with respect to those formed by Centrosema strains isolated in other countries, as well as to the currently described species and genospecies of Bradyrhizobium. In addition, the symbiotic genes nodC and nifH carried by Centrosema-nodulating strains were analyzed for the first time, and it was shown that they belonged to three new phylogenetic lineages within Bradyrhizobium. The nodC genes of the Centrosema strains were divergent among themselves and with respect to the genistearum and glycinearum symbiovars, indicating that Centrosema is a promiscuous legume. According to these results, the currently known Centrosema-nodulating strains represent several new putative species and symbiovars of the genus Bradyrhizobium. PMID- 23688384 TI - Volume reductions in frontopolar and left perisylvian cortices in methamphetamine induced psychosis. AB - Consumption of methamphetamine disturbs dopaminergic transmission and sometimes provokes schizophrenia-like-psychosis, named methamphetamine-associated psychosis (MAP). While previous studies have repeatedly reported regional volume reductions in the frontal and temporal areas as neuroanatomical substrates for psychotic symptoms, no study has examined whether such neuroanatomical substrates exist or not in patients with MAP. Magnetic resonance images obtained from twenty patients with MAP and 20 demographically-matched healthy controls (HC) were processed for voxel-based morphometry (VBM) using Diffeomorphic Anatomical Registration using Exponentiated Lie Algebra. An analysis of covariance model was adopted to identify volume differences between subjects with MAP and HC, treating intracranial volume as a confounding covariate. The VBM analyses showed significant gray matter volume reductions in the left perisylvian structures, such as the posterior inferior frontal gyrus and the anterior superior temporal gyrus, and the frontopolar cortices, including its dorsomedial, ventromedial, dorsolateral, and ventrolateral portions, and white matter volume reduction in the orbitofrontal area in the patients with MAP compared with the HC subjects. The smaller regional gray matter volume in the medial portion of the frontopolar cortex was significantly correlated with the severe positive symptoms in the individuals with MAP. The volume reductions in the left perisylvian structure suggest that patients with MAP have a similar pathophysiology to schizophrenia, whereas those in the frontopolar cortices and orbitofrontal area suggest an association with antisocial traits or vulnerability to substance dependence. PMID- 23688385 TI - Synthesis of new gold(I) thiolates containing amino acid moieties with potential biological interest. AB - The reaction of the gold(I) complex [Au(SpyCOOH)(PPh3)], which contains nicotinic acid thiolate, with several amino acid esters such as glycine methyl ester or the enantiomerically pure L isomers of alanine methyl ester, phenylalanine methyl ester, valine methyl ester, methionine methyl ester, and proline methyl ester produces the gold(I) derivatives with the new thiolate containing amino acid ester ligands [Au{SpyCONHCH(R)COOMe}(PPh3)]. The reaction of these amino acid ester derivatives with LiOH in methanol and acidification with KHSO4 until pH 3-4 afford the corresponding acids, which are water-soluble species. These amino acid compounds can be further coupled with other amines, such as, for example, isopropylamine, to give the corresponding amide derivatives. The species with glycine methyl ester and valine methyl ester have been characterized by X-ray crystallography, showing, in the second case, only one of the enantiomers, which proves that retention of the configuration after reaction occurs. PMID- 23688387 TI - Editorial. PMID- 23688386 TI - A small cohort of FRU(M) and Engrailed-expressing neurons mediate successful copulation in Drosophila melanogaster. AB - BACKGROUND: In Drosophila, male flies require the expression of the male-specific Fruitless protein (FRU(M)) within the developing pupal and adult nervous system in order to produce male courtship and copulation behaviors. Recent evidence has shown that specific subsets of FRU(M) neurons are necessary for particular steps of courtship and copulation. In these neurons, FRU(M) function has been shown to be important for determining sex-specific neuronal characteristics, such as neurotransmitter profile and morphology. RESULTS: We identified a small cohort of FRU(M) interneurons in the brain and ventral nerve cord by their co-expression with the transcription factor Engrailed (En). We used an En-GAL4 driver to express a fru(M) RNAi construct in order to selectively deplete FRU(M) in these En/FRU(M) co-expressing neurons. In courtship and copulation tests, these males performed male courtship at wild-type levels but were frequently sterile. Sterility was a behavioral phenotype as these En-fru(M)RNAi males were less able to convert a copulation attempt into a stable copulation, or did not maintain copulation for long enough to transfer sperm and/or seminal fluid. CONCLUSIONS: We have identified a population of interneurons necessary for successful copulation in Drosophila. These data confirm a model in which subsets of FRU(M) neurons participate in independent neuronal circuits necessary for individual steps of male behavior. In addition, we have determined that these neurons in wild-type males have homologues in females and fru mutants, with similar placement, projection patterns, and neurochemical profiles. PMID- 23688388 TI - Possible mechanism of inotropic and chronotropic effects of Rosa damascena on isolated guinea pig heart. AB - BACKGROUND: The possible mechanism(s) of inotropic and chronotropic effects of the extract from Rosa damascena (R. damascena) on heart was examined. METHODS: Inotropic and chronotropic effects of four concentrations of the extract from R. damascena and isoprenaline were examined in isolated guinea-pig hearts perfused through aorta in a Langendorff model. All measurements were performed in three different groups: 1) In the presence and absence of propranolol, 2) In the presence and absence of methacholine and 3) In the presence of diltiazem (n = 12 for each group). RESULTS: In all groups both isoprenaline and the extract caused an increase in heart rate and contractility (p < 0.05 to p < 0.001). Only in group 1, the final concentration of isoprenaline in the absence of propranolol caused significant greater increase in heart rate compared to the extract (207.6 +/- 11.0 compared to 162.6 +/- 11.8, p < 0.01). The percent increase in heart contractility due to the final concentration of the extract in the absence (362.4 +/- 36.9 compared to 227.7 +/- 31.6, p < 0.01) and presence of propranolol (577.1 +/- 62.9 compared to 357.5 +/- 45.6, p < 0.001) in group 1 and absence (403.7 +/- 42.1 compared to 244.8 +/- 18.9, p < 0.005) and presence of methcholine (499.88 +/- 64.64 compared to 323.90 +/- 44.49, p < 0.05) in groups 2 was significantly greater than the increase caused by isoprenaline. CONCLUSIONS: The results of this study suggest that inotropic and chornotropic effect of R. damascena is possibly due to the stimulatory effect of this plant on beta-adrenoceptors. PMID- 23688389 TI - Impact of chemotherapy-induced amenorrhea in breast cancer patients: the evaluation of ovarian function by menstrual history and hormonal levels. AB - BACKGROUND: Chemotherapy-induced amenorrhea (CIA) is one of the most frequent therapy-related adverse events observed in breast cancer patients who have undergone chemotherapy. Although the characteristics of CIA have been studied in Western countries, little is known about CIA in Asian. We conducted a retrospective analysis to assess the characteristics and influencing factors of CIA and its association with menopause in Chinese women who underwent adjuvant chemotherapy for early-stage breast cancer. METHODS: Seventy-three premenopausal women who underwent adjuvant chemotherapy for early stage (stages I to III) breast cancer were analyzed. Patient clinical characteristics, treatment regimes, menstrual information, and serum hormone values were collected retrospectively. Characteristic factors relevant to the onset of CIA and menopause were also estimated. RESULTS: Approximately 83.6% of patients developed CIA. Older patients (>40 years old) had higher CIA incidence compared with younger patients (P <0.0001). The onset of menopause was correlated with age (P <0.0001) and tamoxifen use (P = 0.0313). On the basis of the Kaplan-Meier analysis, a significant difference was observed in the time of onset of permanent amenorrhea as determined by menstrual history and hormone levels (P = 0.0028). In women aged 46 to 49 years, the beginning of permanent amenorrhea was detected earlier via the clinical method than via the hormonal method (2 months versus 23 months, P <0.0001). In the analysis of patients >=50 years old, the median time to detection of permanent amenorrhea was 19 months in the hormonal test and 2 months in the clinical test (P = 0.0112). CONCLUSIONS: Age at diagnosis is a predictor of the onset of amenorrhea and transformation into menopause among premenopausal breast cancer patients. Adjuvant tamoxifen therapy substantially affects the onset of menopause. A delay of the onset of serum hormone postmenopausal status was observed compared with clinical symptoms. This interval was approximately 21 months in patients aged 46 to 49 years and 17 months in patients aged over 50 years. This interval is significant in the clinical estimate of the menstrual status. PMID- 23688391 TI - Role of environmental and antibiotic stress on Staphylococcus epidermidis biofilm microstructure. AB - Cellular clustering and separation of Staphylococcus epidermidis surface adherent biofilms were found to depend significantly on both antibiotic and environmental stress present during growth under steady flow. Image analysis techniques common to colloidal science were applied to image volumes acquired with high-resolution confocal laser scanning microscopy to extract spatial positions of individual bacteria in volumes of size ~30 * 30 * 15 MUm(3). The local number density, cluster distribution, and radial distribution function were determined at each condition by analyzing the statistics of the bacterial spatial positions. Environmental stressors of high osmotic pressure (776 mM NaCl) and sublethal antibiotic dose (1.9 MUg/mL vancomycin) decreased the average bacterial local number density 10-fold. Device-associated bacterial biofilms are frequently exposed to these environmental and antibiotic stressors while undergoing flow in the bloodstream. Characteristic density phenotypes associated with low, medium, and high local number densities were identified in unstressed S. epidermidis biofilms, while stressed biofilms contained medium- and low-density phenotypes. All biofilms exhibited clustering at length scales commensurate with cell division (~1.0 MUm). However, density phenotypes differed in cellular connectivity at the scale of ~6 MUm. On this scale, nearly all cells in the high- and medium-density phenotypes were connected into a single cluster with a structure characteristic of a densely packed disordered fluid. However, in the low-density phenotype, the number of clusters was greater, equal to 4% of the total number of cells, and structures were fractal in nature with d(f) =1.7 +/- 0.1. The work advances the understanding of biofilm growth, informs the development of predictive models of transport and mechanical properties of biofilms, and provides a method for quantifying the kinetics of bacterial surface colonization as well as biofilm fracture and fragmentation. PMID- 23688392 TI - Infant botulism with prolonged faecal excretion of botulinum neurotoxin and Clostridium botulinum for 7 months. AB - In Finland in April 2010, a 3-month old baby was diagnosed with type A infant botulism. He excreted botulinum neurotoxin and/or Clostridium botulinum in his faeces until November 2010. Five months of excretion was after clinical recovery and discharge from hospital. C. botulinum isolates recovered from the household dust in the patient's home were genetically identical to those found in the infant's stool samples. Long-term faecal excretion of C. botulinum may pose a possible health risk for the parents and others in close contact with the infant. PMID- 23688393 TI - Proteomic characterisation of toxins isolated from nematocysts of the South Atlantic jellyfish Olindias sambaquiensis. AB - Surprisingly little is known of the toxic arsenal of cnidarian nematocysts compared to other venomous animals. Here we investigate the toxins of nematocysts isolated from the jellyfish Olindias sambaquiensis. A total of 29 unique ms/ms events were annotated as potential toxins homologous to the toxic proteins from diverse animal phyla, including cone-snails, snakes, spiders, scorpions, wasp, bee, parasitic worm and other Cnidaria. Biological activities of these potential toxins include cytolysins, neurotoxins, phospholipases and toxic peptidases. The presence of several toxic enzymes is intriguing, such as sphingomyelin phosphodiesterase B (SMase B) that has only been described in certain spider venoms, and a prepro-haystatin P-IIId snake venom metalloproteinase (SVMP) that activates coagulation factor X, which is very rare even in snake venoms. Our annotation reveals sequence orthologs to many representatives of the most important superfamilies of peptide venoms suggesting that their origins in higher organisms arise from deep eumetazoan innovations. Accordingly, cnidarian venoms may possess unique biological properties that might generate new leads in the discovery of novel pharmacologically active drugs. PMID- 23688395 TI - Hippocampal hypoplasia in Smith-Lemli-Opitz syndrome. PMID- 23688396 TI - Cutaneous complications in hematopoietic cell transplant recipients: impact of biopsy on patient management. AB - The utility of cutaneous biopsies in directing the management of post hematopoietic cell transplantation (HCT) eruptions remains uncertain. We retrospectively analyzed 439 consecutive HCT procedures for malignant hematologic disorders performed at our institution between January 2005 and December 2012; 192 patients underwent 430 cutaneous biopsies. The clinical and dermatopathologic diagnosis differed in 240 cases (56%). Biopsy results led to a change in therapy in 69 (16%) episodes. Seventeen of 69 management changes occurred in response to a clinical diagnosis of graft-versus-host disease and resulted in augmentation of systemic immunosuppression. The management was modified with similar frequencies with respect to concordance or discordance between the clinical and histopathologic diagnosis (P = .51). We used classification and regression tree (CART) analysis, a decision-modeling technique, to predict the biopsy yield as expressed by impact on clinical management in the allogeneic and autologous setting. The models were cross-validated and then tested against a validation subset, and they maintained a high negative predictive value and high specificity. Although skin biopsies may not be mandatory for either diagnostic or therapeutic reasons, in carefully chosen circumstances, this procedure can yield extremely important data. We believe a prospective study should be undertaken to evaluate current practice data and to validate our decision tree models. PMID- 23688394 TI - Analysis of SARS-CoV E protein ion channel activity by tuning the protein and lipid charge. AB - A partial characterization of the ion channels formed by the SARS coronavirus (CoV) envelope (E) protein was previously reported (C. Verdia-Baguena et al., 2012 [12]). Here, we provide new significant insights on the involvement of lipids in the structure and function of the CoV E protein channel on the basis of three series of experiments. First, reversal potential measurements over a wide range of pH allow the dissection of the contributions to channel selectivity coming from ionizable residues of the protein transmembrane domain and also from the negatively charged groups of diphytanoyl phosphatidylserine (DPhPS) lipid. The corresponding effective pKas are consistent with the model pKas of the acidic residue candidates for titration. Second, the change of channel conductance with salt concentration reveals two distinct regimes (Donnan-controlled electrodiffusion and bulk-like electrodiffusion) fully compatible with the outcomes of selectivity experiments. Third, by measuring channel conductance in mixtures of neutral diphytanoyl phosphatidylcholine (DPhPC) lipids and negatively charged DPhPS lipids in low and high salt concentrations we conclude that the protein-lipid conformation in the channel is likely the same in charged and neutral lipids. Overall, the whole set of experiments supports the proteolipidic structure of SARS-CoV E channels and explains the large difference in channel conductance observed between neutral and charged membranes. PMID- 23688397 TI - PLANEX: the plant co-expression database. AB - BACKGROUND: The PLAnt co-EXpression database (PLANEX) is a new internet-based database for plant gene analysis. PLANEX (http://planex.plantbioinformatics.org) contains publicly available GeneChip data obtained from the Gene Expression Omnibus (GEO) of the National Center for Biotechnology Information (NCBI). PLANEX is a genome-wide co-expression database, which allows for the functional identification of genes from a wide variety of experimental designs. It can be used for the characterization of genes for functional identification and analysis of a gene's dependency among other genes. Gene co-expression databases have been developed for other species, but gene co-expression information for plants is currently limited. DESCRIPTION: We constructed PLANEX as a list of co-expressed genes and functional annotations for Arabidopsis thaliana, Glycine max, Hordeum vulgare, Oryza sativa, Solanum lycopersicum, Triticum aestivum, Vitis vinifera and Zea mays. PLANEX reports Pearson's correlation coefficients (PCCs; r-values) that distribute from a gene of interest for a given microarray platform set corresponding to a particular organism. To support PCCs, PLANEX performs an enrichment test of Gene Ontology terms and Cohen's Kappa value to compare functional similarity for all genes in the co-expression database. PLANEX draws a cluster network with co-expressed genes, which is estimated using the k-mean method. To construct PLANEX, a variety of datasets were interpreted by the IBM supercomputer Advanced Interactive eXecutive (AIX) in a supercomputing center. CONCLUSION: PLANEX provides a correlation database, a cluster network and an interpretation of enrichment test results for eight plant species. A typical co expressed gene generates lists of co-expression data that contain hundreds of genes of interest for enrichment analysis. Also, co-expressed genes can be identified and cataloged in terms of comparative genomics by using the 'Co expression gene compare' feature. This type of analysis will help interpret experimental data and determine whether there is a common term among genes of interest. PMID- 23688398 TI - Osteotropic cancer diagnosis by an osteocalcin inspired molecular imaging mimetic. AB - BACKGROUND: Although microcalcifications of hydroxyapatite can be found in both benign and malignant osteotropic tumors, they are mostly seen in proliferative lesions, including carcinoma. The aim of this present study is to develop a molecular imaging contrast agent for selective identification of hydroxyapatite calcification in human osteotropic tumor tissues ex vivo and in human osteosarcoma cells in vitro. METHODS: A bioinspired biomarker, hydroxyapatite binding peptide (HABP), was designed to mimic natural protein osteocalcin property in vivo. A fluorescein isothiocyanate dye conjugated HABP (HABP-19) was utilized to characterize hydroxyapatite on human osteotropic tumor tissue sections ex vivo and to selectively image hydroxyapatite calcifications in human osteosarcoma cells in vitro. RESULTS: Using a HABP-19 molecular imaging probe, we have shown that it is possible to selectively image hydroxyapatite calcifications in osteotropic cancers ex vivo and in human SaOS-2 osteosarcoma cells in vitro. CONCLUSION: Hydroxyapatite calcifications were selectively detected in osteotropic tissues ex vivo and in the early stage of the calcification process of SaOS-2 human osteosarcoma in vitro using our HABP-19 molecular imaging probe. This new target-selective molecular imaging probe makes it possible to study the earliest events associated with hydroxyapatite deposition in various osteotropic cancers at the cellular and molecular levels. GENERAL SIGNIFICANCE: It potentially could be used to diagnose and treat osteotropic cancer or to anchor therapeutic agents directing the local distribution of desired therapy at calcified sites. PMID- 23688399 TI - Difucosylation of chitooligosaccharides by eukaryote and prokaryote alpha1,6 fucosyltransferases. AB - BACKGROUND: The synthesis of eukaryotic N-glycans and the rhizobia Nod factor both involve alpha1,6-fucosylation. These fucosylations are catalyzed by eukaryotic alpha1,6-fucosyltransferase, FUT8, and rhizobial enzyme, NodZ. The two enzymes have similar enzymatic properties and structures but display different acceptor specificities: FUT8 and NodZ prefer N-glycan and chitooligosaccharide, respectively. This study was conducted to examine the fucosylation of chitooligosaccharides by FUT8 and NodZ and to characterize the resulting difucosylated chitooligosaccharides in terms of their resistance to hydrolysis by glycosidases. METHODS: The issue of whether FUT8 or NodZ catalyzes the further fucosylation of chitooligosaccharides that had first been monofucosylated by the other. The oligosaccharide products from the successive reactions were analyzed by normal-phase high performance liquid chromatography, mass spectrometry and nuclear magnetic resonance. The effect of difucosylation on sensitivity to glycosidase digestion was also investigated. RESULTS: Both FUT8 and NodZ are able to further fucosylate the monofucosylated chitooligosaccharides. Structural analyses of the resulting oligosaccharides showed that the reducing terminal GlcNAc residue and the third GlcNAc residue from the non-reducing end are fucosylated via alpha1,6-linkages. The difucosylation protected the oligosaccharides from extensive degradation to GlcNAc by hexosamidase and lysozyme, and also even from defucosylation by fucosidase. CONCLUSIONS: The sequential actions of FUT8 and NodZ on common substrates effectively produce site specific-difucosylated chitooligosaccharides. This modification confers protection to the oligosaccharides against various glycosidases. GENERAL SIGNIFICANCE: The action of a combination of eukaryotic and bacterial alpha1,6 fucosyltransferases on chitooligosaccharides results in the formation of difucosylated products, which serves to stabilize chitooligosaccharides against the action of glycosidases. PMID- 23688400 TI - PLIN2, the major perilipin regulated during sebocyte differentiation, controls sebaceous lipid accumulation in vitro and sebaceous gland size in vivo. AB - BACKGROUND: Lipid synthesis and storage are accomplished by lipid droplets (LDs). The perilipin family of LD-associated proteins, comprising 5 members (PLIN1 PLIN5), has been well characterized in adipocytes but not in sebocytes, epithelial cells in which LD formation is a key feature of the cellular differentiation. METHODS: Perilipin expression in the sebaceous gland cell line SZ95 and in human sebaceous glands was studied by qRT-PCR, Western blots, and immunohistochemistry. Lipid accumulation was evaluated by Nile red staining and mass spectrometry. RESULTS: PLIN2 and PLIN3 are the most abundant perilipins in undifferentiated sebocytes. Induction of lipogenesis by linoleic acid (LA) resulted in increased transcript levels of all perilipins except for PLIN3 and in a time-dependent increase of PLIN2 protein. Nile red staining revealed that siRNA mediated downregulation of PLIN2 significantly impaired basal and LA-induced lipid accumulation. Mass spectrometry revealed PLIN2 deficiency to cause a reduction in the amount of several specific lipid fractions, including di- and triacyl-glycerol esters, phosphatidylcholine lipids, and ceramides in sebocytes under basal conditions. In contrast, PLIN2 downregulation exerted a statistically significant inhibitory effect only on the accumulation of specific LA-induced triglycerides. PLIN2-deficient mice showed normal morphology of sebaceous glands. However, their sebaceous glands were significantly reduced in size and showed less cell proliferation. CONCLUSIONS: PLIN2 is the major perilipin regulated during sebocyte differentiation in vitro. PLIN2 is also important for sebaceous lipid accumulation in vitro and regulates sebaceous gland size in vivo. GENERAL SIGNIFICANCE: Our study provides the first systematic analysis of LD-associated proteins in sebocytes. PMID- 23688401 TI - Inhibition of non-target languages in multilingual word production: evidence from Uighur-Chinese-English trilinguals. AB - The present study examined the hypothesis whether non-target languages are inhibited during multilingual language production by examining the n-2 language repetition cost. In two experiments, Uighur-Chinese-English trilinguals named Arabic digits in one of their three languages according to a visually presented cue. Significant n-2 repetition costs were obtained in both experiments, which indicate that inhibition exists during multilingual word production. In addition, in Experiment 1, it was also found that the n-2 repetition cost was reduced when cues were highly compatible with the task, which means non-target languages are less inhibited. In Experiment 2, the n-2 repetition cost was increased at a shorter CSI. Taken together, these results indicate that inhibition of non-target languages occurs during multilingual language production, and that efficiency of establishing the target language task schema has an effect on the inhibitory control process. PMID- 23688402 TI - Risk assessments of human exposure to bioaccessible phthalate esters through market fish consumption. AB - The bioaccessibility of phthalate esters in 20 fish species collected from Hong Kong market was evaluated using an in vitro gastrointestinal model. The ?phthalate ester concentration detected in fresh water fish ranged from 1.66 to 3.14MUg/g wet weight (ww) and in marine fish ranged from 1.57 to 7.10MUg/g ww, respectively. di-2-Ethylhexyl phthalate (DEHP) and di-n-butyl phthalate (DBP) were the predominant compounds in both freshwater fish and marine fish. The digestible concentrations of phthalate esters ranged from 0.20 to 1.23MUg/g ww (mean 0.35MUg/g ww), and account for 2.44 to 45.5% (mean 16.8%) for raw concentrations of phthalate esters. In the present study, the accumulation ratio Rnn value of all phthalate esters was greater than 1 except for diisobutyl phthalate (DIBP), DBP and di-n-hexyl phthalate (DHP), suggesting that these phthalate esters could be accumulated during gastrointestinal digestion. Based on this health risk assessment, most of fish species were considered safe for consumption, however Hong Kong residents should take caution when consuming Mud carp and Bighead carp. PMID- 23688404 TI - Calcipotriol modulates IL-22 receptor expression and keratinocyte proliferation in IL-22-induced epidermal hyperplasia. PMID- 23688403 TI - Suppressive effects of antimycotics on thymic stromal lymphopoietin production in human keratinocytes. AB - BACKGROUND: Thymic stromal lymphopoietin (TSLP) is produced by epidermal keratinocytes, and it induces Th2-mediated inflammation. TSLP expression is enhanced in lesions with atopic dermatitis, and is a therapeutic target. Antimycotic agents improve the symptoms of atopic dermatitis. OBJECTIVE: The objective of this study was to examine whether antimycotics suppress TSLP expression in human keratinocytes. METHODS: Normal human keratinocytes were incubated with polyinosinic-polycytidylic acid (poly I:C) plus IL-4 in the presence of antimycotics. TSLP expression was analyzed by ELISA and real time PCR. Luciferase assays were performed to analyze NF-kappaB activity. IkappaBalpha degradation was analyzed by Western blot analysis. RESULTS: Poly I:C plus IL-4 increased the secretion and mRNA levels of TSLP, which was suppressed by an NF kappaB inhibitor, and also enhanced NF-kappaB transcriptional activities and induced the degradation of IkappaBalpha in keratinocytes. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine, and amorolfine suppressed the secretion and mRNA expression of TSLP, NF-kappaB activity, and IkappaBalpha degradation induced by poly I:C plus IL-4. These suppressive effects were similarly manifested by 15-deoxy-Delta-(12,14)-PGJ2 (15d-PGJ2), a prostaglandin D2 metabolite. Antimycotics increased the release of 15d-PGJ2 from keratinocytes and decreased the release of thromboxane B2, a thromboxane A2 metabolite. Antimycotic-induced suppression of TSLP production and NF-kappaB activity was counteracted by an inhibitor of lipocalin type-prostaglandin D synthase. CONCLUSIONS: Antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine, and amorolfine may suppress poly I:C plus IL-4-induced production of TSLP by inhibiting NF-kappaB via increasing 15d-PGJ2 production in keratinocytes. These antimycotics may block the overexpression of TSLP in lesions with atopic dermatitis. PMID- 23688405 TI - The largest family of the Americas with dominant dystrophic epidermolysis bullosa pruriginosa: a 18-year longitudinal genotype-phenotype study. PMID- 23688406 TI - Interaction of white matter hyperintensities (WMHs) and apolipoprotein E (APOE) genotypes on cognition in patients with amnestic mild cognitive impairment (aMCI). AB - The clinical implications of WMHs in aMCI are inconclusive. Moreover, clinical interactions between APOE genotypes and WMHs remain unclear. This study was conducted to investigate the relationship between WMHs and cognitive functions and how this relationship interacted with APOE genotype in people with aMCI. This study included a total of 1472 patients with aMCI from the Clinical Research Center for Dementia of South Korea (CREDOS) and divided them into 3 groups according to the severity of WMHs as assessed by visual ratings of brain magnetic resonance images. The associations of WMHs with the various cognitive domains and with APOE epsilon 4 (E4) status were evaluated. After multivariable adjustments, the severity of WMHs was independently associated with semantic/phonemic verbal fluency and Stroop test-color reading, while APOE E4 status was associated with verbal and visual memory-immediate, delayed recall, and recognition. Moreover, there were interaction between WMHs and APOE E4 status in semantic verbal fluency (animal, P=0.033; supermarket, P=0.047)/Stroop test-color reading (P=0.024). WMHs independently deleteriously affected frontal executive functions in aMCI patients, regardless of APOE E4 presence. Furthermore, APOE E4 possession caused a rapid decline in frontal executive functions with the increase in the WMHs severity (vs. absence), suggesting that WMHs and APOE E4 genotypes synergistically contribute to frontal executive dysfunctions in aMCI. PMID- 23688407 TI - Risk factors for contra-lateral hip fracture in elderly patients with previous hip fracture. AB - INTRODUCTION: Contra-lateral hip fractures in elderly patients with a previous hip fracture increase the incidence of complications and socioeconomic burden. The purpose of this study was to identify the risk factors that contribute to the occurrence of contra-lateral hip fracture in elderly patients. MATERIALS AND METHODS: Among 1093 patients treated for a hip fracture, 47 patients sustained a contra-lateral hip fracture. These patients were compared with 141 patients with a unilateral hip fracture (controls). RESULTS: The incidence of contra-lateral hip fracture was 4.3% among the 1093 patients treated for a hip fracture at our institute. A contra-lateral hip fracture occurred within 2 years of initial fracture in 66%, and subsequently, the annual incidence rate decreased. A similar fracture pattern was noted in 70% of patients who sustained an intertrochanteric fracture. In terms of preoperative factors, respiratory disease (OR 2.57, P=0.032) and visual impairment (OR 2.51, P=0.012) were higher in patients with a contra-lateral hip fracture than in controls, and for postoperative factors, the proportions of patients with postoperative delirium (OR 2.91, P=0.022), late onset of rehabilitation (OR 1.05, P=0.023), and poor ambulatory status at 3 months (OR 1.34, P=0.002) were also significantly higher in patients than in controls. CONCLUSIONS: Postoperative delirium and underlying visual impairment and respiratory disease could be risk factors of contra-lateral fracture in elderly patients. Early and active rehabilitation after surgery is important to prevent the occurrence of contra-lateral hip fracture in the elderly. PMID- 23688408 TI - Factors associated with participant compliance in studies using accelerometers. AB - Participant compliance is an important issue in studies using accelerometers. Some participants wear the accelerometer for the duration specified by the researchers but many do not. We investigated a range of demographic factors associated with participant compliance in obtaining analyzable accelerometer data. A total of 3601 participants (aged 47.6+/-13.1 years, 44.6% male) were included. They were asked to wear an accelerometer (ActiGraph) for four consecutive days after completing a household survey during March 2009-January 2011 in Hong Kong. Participants wore the accelerometer on average for 13.9h in a 24-h day. No significant difference was found between males and females (p=0.38). Using log-linear regression, it was found that older participants (0.5% more wearing hours for each year of age, p<0.001), those with full-time job (p<0.01), with tertiary education (p<0.01), non-smokers (p<0.01) and with high self reported health (p<0.05) wore the accelerometer for more hours. These results provide details for estimating compliance rates for samples with different characteristics and thus sample size calculation to account for participant compliance. PMID- 23688409 TI - Using Gd-EOB-DTPA-enhanced 3-T MRI for the differentiation of infiltrative hepatocellular carcinoma and focal confluent fibrosis in liver cirrhosis. AB - PURPOSE: The purpose of the study was to determine significant imaging features to differentiate between infiltrative hepatocellular carcinoma (HCC) and confluent fibrosis (CF) in liver cirrhosis using Gd-EOB-DTPA-enhanced 3-T magnetic resonance imaging. MATERIAL AND METHODS: Nineteen infiltrative HCCs and eight CFs were included. We evaluated the difference in imaging findings and apparent diffusion coefficient (ADC) between the two entities. We compared T2 weighted image (WI) and hepatobiliary phase (HBP) in terms of the clarity of the lesion outer margin. RESULTS: Seventeen infiltrative HCCs showed lobulated margin, while focal CFs showed either straight (n=3) or irregular margins (n=5) (P=.001). All infiltrative HCCs had intact or bulging contours, and all focal CFs showed capsular retraction (P=.001). Fourteen infiltrative HCCs and two focal CFs showed arterial enhancement (P=.035). The ADC of infiltrative HCCs was significantly lower than that of CFs (P=.001). Satellite nodules were noted in 10 infiltrative HCCs. In terms of outer margin clarity, infiltrative HCCs showed a more distinct margin on HBP than on T2-WI (P=.005), while these two sequences were not significantly different in focal CFs (P=1.000). CONCLUSION: HBP improved the imaging characteristics of infiltrative HCC, allowing it to be distinguished from focal CF. Infiltrative HCC showed lower ADC values than focal CF. Lobular configuration, contour bulging, enhancement pattern, associated satellite nodules and portal vein thrombosis were still found to be highly suggestive MR findings for infiltrative HCC. PMID- 23688410 TI - Diffusion pore imaging with generalized temporal gradient profiles. AB - In porous material research, one main interest of nuclear magnetic resonance diffusion (NMR) experiments is the determination of the shape of pores. While it has been a longstanding question if this is in principle achievable, it has been shown recently that it is indeed possible to perform NMR-based diffusion pore imaging. In this work we present a generalization of these previous results. We show that the specific temporal gradient profiles that were used so far are not unique as more general temporal diffusion gradient profiles may be used. These temporal gradient profiles may consist of any number of "short" gradient pulses, which fulfil the short-gradient approximation. Additionally, "long" gradient pulses of small amplitude may be present, which can be used to fulfil the rephasing condition for the complete profile. Some exceptions exist. For example, classical q-space gradients consisting of two short gradient pulses of opposite sign cannot be used as the phase information is lost due to the temporal antisymmetry of this profile. PMID- 23688411 TI - Delineation of malignant glioma by turbo spin echo multislice motion-sensitized driven-equilibrium (TSE-MSDE) with gadolinium-based contrast media: a case report. AB - T1-weighted images by turbo spin echo multislice motion-sensitized driven equilibrium with gadolinium-based contrast media clearly delineated the brainstem invasion of a malignant glioma in an 80-year-old woman compared with other magnetic resonance imaging sequences. PMID- 23688412 TI - Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production. AB - BACKGROUND: Cysteinyl leukotrienes (CysLTs) contribute to asthma pathogenesis, in part through cysteinyl leukotriene receptor 1 (CysLT1R). Recently discovered lineage-negative type 2 innate lymphoid cells (ILC2s) potently produce IL-5 and IL-13. OBJECTIVES: We hypothesized that lung ILC2s might be activated by leukotrienes through CysLT1R. METHODS: ILC2s (Thy1.2(+) lineage-negative lymphocytes) and CysLT1R were detected in the lungs of wild-type, signal transducer and activator of transcription 6-deficient (STAT6(-/-)), and recombination-activating gene 2-deficient (RAG2(-/-)) mice by means of flow cytometry. T(H)2 cytokine levels were measured in purified lung ILC2s stimulated with leukotriene D4 (LTD4) in the presence or absence of the CysLT1R antagonist montelukast. Calcium influx was measured by using Fluo-4 intensity. Intranasal leukotriene C4, D4, and E4 were administered to naive mice, and levels of ILC2 IL 5 production were determined. Finally, LTD4 was coadministered with Alternaria species repetitively to RAG2(-/-) mice (with ILC2s) and IL-7 receptor-deficient mice (lack ILC2s), and total ILC2 numbers, proliferation (Ki-67(+)), and bronchoalveolar lavage fluid eosinophil numbers were measured. RESULTS: CysLT1R was expressed on lung ILC2s from wild-type, RAG2(-/-), and STAT6(-/-) naive and Alternaria species-challenged mice. In vitro LTD4 induced ILC2s to rapidly generate high levels of IL-5 and IL-13 within 6 hours of stimulation. Interestingly, LTD4, but not IL-33, induced high levels of IL-4 by ILC2s. LTD4 administered in vivo rapidly induced ILC2 IL-5 production that was significantly reduced by montelukast before treatment. Finally, LTD4 potentiated Alternaria species-induced eosinophilia, as well as ILC2 accumulation and proliferation. CONCLUSIONS: We present novel data that CysLT1R is expressed on ILC2s and LTD4 potently induces CysLT1R-dependent ILC2 production of IL-4, IL-5, and IL-13. Additionally, LTD4 potentiates Alternaria species-induced eosinophilia and ILC2 proliferation and accumulation. PMID- 23688413 TI - De novo homozygous mutation of the C1 inhibitor gene in a patient with hereditary angioedema. PMID- 23688415 TI - SUDEP research: challenges for the future. PMID- 23688414 TI - Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis. AB - BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with TH2-dominant inflammation. Thymic stromal lymphopoietin (TSLP) is a cytokine that triggers dendritic cell-mediated TH2 inflammatory responses and that enhances IL 1-dependent TH2 cytokine production in mast cells. Although increased TSLP mRNA levels have been found in nasal polyps (NPs), expression of TSLP protein and its function in patients with chronic rhinosinusitis (CRS) have not been fully explored. OBJECTIVES: The objective of this study was to investigate the role of TSLP in patients with CRS. METHODS: We investigated the presence and stability of TSLP protein in NPs using ELISA and Western blotting and investigated the function of TSLP in nasal tissue extracts with a bioassay based on activation of human mast cells. RESULTS: Although TSLP mRNA levels were significantly increased in NP tissue from patients with CRSwNP compared with uncinate tissue from patients with CRS or control subjects, TSLP protein was significantly decreased in NP tissue, as detected by using the commercial ELISA kit. We found that recombinant TSLP was time-dependently degraded by NP extracts, and this degradation was completely inhibited by a protease inhibitor cocktail, suggesting that TSLP is sensitive to tissue proteases. Interestingly, NP extract-treated TSLP had higher activity in mast cells, although the amount of full-length TSLP was reduced up to 85%. NP extracts significantly enhanced IL-1beta-dependent IL-5 production in mast cells compared with uncinate tissue homogenates, and responses were significantly inhibited by anti-TSLP, suggesting that NPs contain biologically relevant levels of TSLP activity. CONCLUSION: TSLP and its metabolic products might play an important role in the inflammation seen in patients with CRSwNP. PMID- 23688416 TI - Probing the active site of cinnamoyl CoA reductase 1 (Ll-CCRH1) from Leucaena leucocephala. AB - Lack of three dimensional crystal structure of cinnamoyl CoA reductase (CCR) limits its detailed active site characterization studies. Putative active site residues involved in the substrate/NADPH binding and catalysis for Leucaena leucocephala CCR (Ll-CCRH1; GenBank: DQ986907) were identified by amino acid sequence alignment and homology modeling. Putative active site residues and proximal H215 were subjected for site directed mutagenesis, and mutated enzymes were expressed, purified and assayed to confirm their functional roles. Mutagenesis of S136, Y170 and K174 showed complete loss of activity, indicating their pivotal roles in catalysis. Mutant S212G exhibited the catalytic efficiencies less than 10% of wild type, showing its indirect involvement in substrate binding or catalysis. R51G, D77G, F30V and I31N double mutants showed significant changes in Km values, specifying their roles in substrate binding. Finally, chemical modification and substrate protection studies corroborated the presence Ser, Tyr, Lys, Arg and carboxylate group at the active site of Ll-CCRH1. PMID- 23688417 TI - Renaturation and one step purification of the chicken GIIA secreted phospholipase A2 from inclusion bodies. AB - The cDNA coding for a mature protein of 123 amino acids, containing all of the structural features of catalytically active group II sPLA2, has been amplified. The gene has been cloned into the bacterial expression vector pET-21a(+), which allows protein over-expression as inclusion bodies and enables about 3 mg per litre of pure refolded fully active enzyme to be obtained. Recombinant expression of chPLA2-IIA in Escherichia coli shows that the enzyme is Ca(2+) dependent, maximally active at pH 8-9, and hydrolyses phosphatidylglycerol versus phosphatidylcholine with a 15-fold preference. The ability to express reasonably large amounts of the sPLA2 Group IIA, compared to that obtained with the classical purification will provide a basis for future site directed mutagenesis studies of this important enzyme. PMID- 23688418 TI - The crystal structure of acidic beta-galactosidase from Aspergillus oryzae. AB - The crystal structure of the industrially important Aspergillus oryzae beta galactosidase has been determined at 2.60 A resolution. The Ao-beta-gal is a large (985 residues) monomeric multi-domain enzyme that has a catalytic (alpha/beta)8-barrel domain. An electron density map revealed extensive N glycosylation between the domain interfaces suggesting that the oligosaccharide chains would have a stabilizing role for the structure of Ao-beta-gal. Comparison of structure with other beta-galactosidase structures of glycoside hydrolase family 35 revealed a number of hydrophobic residues, which may contribute favorably to the stabilization of the structure. The role of a high number of acidic residues in Ao-beta-gal is also discussed. PMID- 23688419 TI - A rare case of renal dysplasia: prenatal and postnatal management. AB - The ultrasonographic detection of renal anomalies may modify obstetric management and facilitate pediatric care of the newborn. We performed prenatal differential diagnosis of an isolated unilateral cystic renal mass (71 * 74 * 82 mm) in a pregnant woman at 26 weeks of gestation. No other abnormalities were detected by ultrasonography, except for polyhydramnios. Repeated percutaneous cyst aspirations were required because of the increasing risk of vital organ damage. Postnatal nephroureterectomy was performed. Anatomopathologic analysis led to the diagnosis of segmental renal dysplasia, which could not be included in any of the four groups of Potter's classification of cystic renal dysplasia. PMID- 23688421 TI - Absent sella turcica: a case report and a review of the literature. AB - Absent sella turcica is an extremely rare and dramatic radiographic finding. It may be isolated or occur in the presence of other anomalies, often involving the adenohypophysis. Our evaluation of a female infant with multiple anomalies including absence of the sella turcica, a normal pituitary in the craniopharyngeal canal, normal pituitary function, choanal atresia and anomalies of the appendiceal skeleton prompted a review of the occurrence and biology of an absent sella turcica. PMID- 23688420 TI - Embryonal tumor with abundant neuropil and true rosettes with melanotic (retinal) differentiation. AB - Embryonal tumor with abundant neuropil and true rosettes (ETANTR) is a rare variant of central nervous system primitive neuroectodermal tumor occurring exclusively in the pediatric population. We report a unique case of a 6-month male child presenting with a large intraventricular lesion. Histological examination revealed a tumor composed of primitive neuroectodermal cells in dense aggregates, interspersed by hypocellular areas containing small round cells widely dispersed in neuropil-like material. Few ependymal and occasional ependymoblastic rosettes were appreciated. Focal melanotic neuroepithelium recapitulating retinal differentiation was also seen. Documentation of such cases may expand the neuroectodermal differentiation spectrum of ETANTR. PMID- 23688422 TI - Airway responsiveness to adenosine after a single dose of fluticasone propionate discriminates asthma from COPD. AB - BACKGROUND: Regular treatment with inhaled corticosteroids (ICS) is known to reduce airway hyperresponsiveness (AHR) to adenosine 5'-monophosphate (AMP) in asthma even after a single dose of fluticasone propionate (FP). AIM: To determine whether this rapid protective effect of a single dose of FP is also present in COPD. METHODS: 23 mild asthmatic and 24 COPD subjects with documented AHR to both AMP and methacholine took part in a randomized, double-blind, placebo-controlled, crossover study to measure AHR to inhaled AMP and methacholine 2 h after either 1000 MUg FP or matched placebo. RESULTS: In subjects with asthma, 1000 MUg FP in a single dose significantly attenuated the constrictor response to AMP, geometric mean (range) PC20AMP values increasing from a 19.2 (1.3-116.3) to 81.5 (9.6 1600.0) (p < 0.001; post-placebo vs post-FP) mg/ml. Change in the airways response to inhaled AMP after FP was well within test variability in patients with COPD, with PC20AMP values 59.6 (11.3-183.9) and 76.3 (21.0-445.3) (p = 0.022; post-placebo vs post-FP) mg/ml. Additionally, FP failed to significantly attenuate the bronchial response to methacholine in both asthma and COPD subjects. A change in doubling dilution, between placebo and following a single dose of FP, in AMP had a better sensitivity and specificity of 95.8% and 65.2%, compared to methacholine of 79.2% and 43.5% respectively in delineating between COPD and asthma. CONCLUSION: A single dose of 1000 MUg FP rapidly improves AHR to AMP in asthmatics but not in COPD subjects. This may provide a convenient way by which provocation challenge with inhaled AMP may help in discriminating asthma from COPD. PMID- 23688424 TI - Genetic deletion of Cxcl14 in mice alters uterine NK cells. AB - The uterine natural killer cells (uNK cells) are the major immune cells in pregnant uterus and the number of uNK cells is dramatically increased during placentation and embryo development. The uNK cells are necessary for the immune tolerance, cytokine secretion and angiogenesis of placenta. Former studies indicated that the population expansion of uNK cells was accomplished through recruitment of NK cell precursors from the spleen and bone marrow, but not proliferation of NK cells. However, the necessary molecules within this process were little understood. Here in our study, we found the co-localized expression of Cxcl14 protein with uNK cells in E13.5 pregnant uterus. Moreover, we used Cxcl14 knockout mice to examine uNK cells in mesometrial lymphoid aggregate of pregnancy (MLAp) and decidua basalis (DB) of E13.5 pregnant uterus and found significantly decreased uNK cells in Cxcl14(-/-) pregnant uteri compared with Cxcl14(+/-) pregnant uteri. To further explorer the molecular change in MLAp and DB after Cxcl14 knockout, we isolated the MLAp and DB from Cxcl14(+/+) and Cxcl14(-/-) pregnant uteri and performed microarray analysis. We found many genes were up and down regulated after Cxcl14 knockout. In conclusion, our results suggested the important function of Cxcl14 in uNK cells and the proper level of Cxcl14 protein were required to recruit NK cells to pregnant uterus. PMID- 23688423 TI - TNF-alpha and LPA promote synergistic expression of COX-2 in human colonic myofibroblasts: role of LPA-mediated transactivation of upregulated EGFR. AB - BACKGROUND: Enhanced EGF receptor (EGFR) signaling is a hallmark of many human cancers, though the role of enhanced EGFR signaling within the surrounding tumor stroma has not been well studied. The myofibroblast is an important stromal cell that demonstrates enhanced EGFR expression in the setting of inflammation, though the functional relevance is not known. We recently reported that TNF-alpha and the G protein-coupled receptor (GPCR) agonist lysophosphatidic acid (LPA) lead to synergistic cyclo-oxygenase-2 (COX-2) expression, an enzyme strongly associated with the development of colitis-associated cancer. Here, we investigate whether EGFR signaling plays a role in the synergistic COX-2 expression induced by LPA and TNF-alpha. METHODS: 18Co cells, a model of human colonic myofibroblasts, were grown to confluence on 35 * 10 mm cell culture dishes and were used from passages 10-14. 18Co cells were treated with TNF-alpha (8.3 ng/ml) and LPA (10 MUM). EGFR and COX-2 protein expression, Y1068 phosphorylation, and p42/44 MAPK phosphorylation were assessed by Western Blot, in the presence and absence of various inhibitors. RESULTS: Exposure of 18Co cells to either TNF-alpha or LPA alone had no effect on EGFR autophosphorylation at Y1068. However, chronic exposure to TNF-alpha led to upregulation of EGFR in association with sustained LPA-mediated EGFR phosphorylation at Y1068. TNF-alpha and LPA also led to sustained p42/44 MAPK phosphorylation and synergistic COX-2 expression, effects that were partially inhibited by the EGFR tyrosine kinase inhibitor AG1478. p42/44 MAPK phosphorylation and COX-2 expression were inhibited to the same degree by the MMP inhibitors GM6001 and BB-94, suggesting that LPA-mediated EGFR transactivation involved MMP-mediated release of EGFR ligands from the cell surface. The Src inhibitor SU6556 inhibited TNF-alpha/LPA-mediated EGFR phosphorylation at Y1068, p42/44 MAPK phosphorylation, and COX-2 expression in a dose-dependent fashion, suggesting an upstream role of Src in the transactivation of EGFR. CONCLUSION: Synergistic COX-2 expression induced by TNF-alpha and LPA involves Src/MMP-mediated transactivation of EGFR and downstream p42/44 MAPK activation in human colonic myofibroblasts. Enhanced EGFR expression induced by TNF-alpha promotes GPCR-mediated EGFR transactivation in colonic myofibroblasts, providing an important mechanism for stromal COX-2 over-expression that may predispose to the development of colitis-associated cancer. PMID- 23688425 TI - Changes of apoptosis in tumor tissues with time after irreversible electroporation. AB - Irreversible electroporation is a novel method of ablating living tissues through its non-thermal effects, unlike radiofrequency ablation which has a severe problem of heat sink. It is due to high-energy direct current which leads to permanent disruption of lipid bilayer integrity in terms of exchanges between intra- and extracellular components via nano-sized pores. That finally causes irreversible damage to cellular homeostasis. Irreversibly damaged cells may undergo apoptosis followed by necrosis with time after electroporation. This damage can make it possible to monitor the ablated area with time post-IRE through MR imaging and an ultrasound system. Most previous studies have investigated the immediate response of undesired tissue to IRE. In our study, we showed changes of tumor tissues with time post-IRE by histological analysis and MR imaging. Tissues under IRE ablation showed a peak apoptotic rate at 24 h after IRE ablation with viable tissues at the peripheral rim of treated tissues in histological analysis. This phenomenon was also observed with no enhancement on contrast-enhanced MR images due to devascularization of IRE ablated zones. PMID- 23688426 TI - Novel tamoxifen derivative Ridaifen-B induces Bcl-2 independent autophagy without estrogen receptor involvement. AB - Autophagy is a self-proteolysis process in eukaryotic cells that results in the sequestering of intracellular proteins and organelles in autophagosomes. Activation of autophagy progress continued growth of some tumors, instead extensive autophagy induces cell death. In a previous study, we synthesized a novel tamoxifen derivative, Ridaifen (RID)-B. RID-B induced mitochondria-involved apoptosis even in estrogen receptor (ER)-negative cells. Since tamoxifen induces autophagy other than apoptosis, we treated ER-negative Jurkat cells with RID-B in the present study. RID-B treatment induced apoptosis and LC3 and lysosome colocalization, which results in the formation of autolysosomes. Western blotting revealed that LC3 was converted to LC3-I to LC3-II with RID-B treatment, suggesting that RID-B induced autophagy without ER involvement. Moreover, overexpression of the anti-apoptotic protein Bcl-2 suppressed the RID-B-induced cell death, but not the induction of autophagy. These results presumed that RID-B induced autophagy is independent of Bcl-2, making RID-B-induced autophagy different from RID-B-induced apoptosis. Since Beclin 1 level is unchanged during RID-B treatment, RID-B induced autophagy pathway is Bcl-2/Beclin1 independent noncanonical pathway. PMID- 23688427 TI - A synthetic bivalent ligand of CXCR4 inhibits HIV infection. AB - G-protein-coupled receptors (GPCRs) are cell membrane protein receptors that transduce signals across the cell membrane and are important targets for therapeutic interventions. As members of the GPCR superfamily, chemokine receptors such as CXCR4 play critical roles in normal physiology as well as the pathology of many human diseases including cancer, inflammation, autoimmune diseases, and human immunodeficiency virus (HIV) infection. Here we report the discovery and study of a novel peptide ligand of CXCR4 using d-amino acids and bivalent ligand approach. This peptide, DV1-K-(DV3), shows very high affinity for CXCR4 with an IC50 of 4 nM in anti-CXCR4 monoclonal antibody (mAb) 12G5 competitive assay, which is more potent than full length natural ligand SDF 1alpha, even though the peptide is less than half of the number of residues of SDF-1alpha. This peptide can block the calcium influx stimulated by SDF-1alpha and inhibit cancer cell migration in vitro via CXCR4, thus functioning as a CXCR4 antagonist. Furthermore, DV1-K-(DV3) peptide displayed anti-HIV activity by inhibiting HIV-1 infection mediated by CXCR4. With its high receptor affinity and stability from D-amino acids, this peptide may be a new probe of CXCR4 functions in physiology and pathology and promising lead for therapeutic development. PMID- 23688428 TI - Recombinant disintegrin domain of ADAM15 inhibits the proliferation and migration of Bel-7402 cells. AB - ADAM15 (A Disintegrin And Metalloproteinase 15), a transmembrane protein containing seven domains, interacts with some integrins via its disintegrin domain and overexpresses in many solid tumors. In this study, the effect of the recombinant human disintegrin domain (rhddADAM15) on the proliferation and migration of Bel-7402 cells was evaluated in vitro and in vivo in zebrafish xenografts. rhddADAM15 (4 MUM) severely inhibited the proliferation and migration of Bel-7402 cells, inducing a partial G2/S arrest and morphological nucleus changes of apoptosis. Moreover, the activity of caspases 8, 9 and 3 in Bel-7402 cells was increased. In addition, the zebrafish was used as a model for apoptosis induction and tumor-xenograft. rhddADAM15 (1 pM) inhibited the growth and metastasis of Bel-7402 cell xenografts in zebrafish and a lower concentration (0.1 pM) induced severe apoptosis in the somatic cells of zebrafish. In conclusion, our data identified rhddADAM15 as a potent inhibitor of tumor growth and metastasis, making it a promising tool for use in anticancer treatment. PMID- 23688429 TI - A novel PGC-1alpha isoform in brain localizes to mitochondria and associates with PINK1 and VDAC. AB - Peroxisome proliferator-activated receptor-gamma co-activator 1alpha (PGC-1alpha) and PTEN-induced putative kinase 1 (PINK1) are powerful regulators of mitochondrial function. Here, we report that a previously unrecognized, novel 35 kDa PGC-1alpha isoform localizes to the mitochondrial inner membrane and matrix in brain as determined by protease protection and carbonate extraction assays, as well as by immunoelectron microscopy. Immunoelectron microscopy and import experiments in vitro revealed that 35 kDa PGC-1alpha colocalizes and interacts with the voltage-dependent anion channel (VDAC), and that its import depends on VDAC. Valinomycin treatment which depolarizes the membrane potential, abolished mitochondrial localization of the 35 kDa PGC-1alpha. Using blue native-PAGE, co immunoprecipitation, and immunoelectron microscopy analyses, we found that the 35 kDa PGC-1alpha binds and colocalizes with PINK1 in brain mitochondria. This is the first report regarding mitochondrial localization of a novel 35 kDa PGC 1alpha isoform and its association with PINK1, suggesting possible regulatory roles for mitochondrial function in the brain. PMID- 23688430 TI - Effects of bariatric surgery on cardiac remodeling: clinical and pathophysiologic implications. PMID- 23688431 TI - Prosthesis sizing for transcatheter aortic valve implantation--comparison of three dimensional transesophageal echocardiography with multislice computed tomography. AB - BACKGROUND: The complex anatomy of the aortic annulus warrants the use of three dimensional (3D) modalities for prosthesis sizing in transcatheter aortic valve implantation (TAVI). Multislice computed tomography (MSCT) has been used for this purpose, but its use may be restricted because of contrast administration. 3D transesophageal echocardiography (3D-TEE) lacks this limitation and data on comparison with MSCT is scarce. We compared 3D-TEE with MSCT for prosthesis sizing in TAVI. METHODS: Aortic annulus diameters in the sagittal and coronal plane and annulus areas in 3D-TEE and MSCT were compared in 57 patients undergoing TAVI. Final prosthesis size was left at the operator's discretion and the agreement with 3D-TEE and MSCT was calculated. RESULTS: Sagittal diameters on 3D-TEE and MSCT correlated well (r=.754, p<.0001) and means were comparable (22.3+/-2.1 vs. 22.5+/-2.3 mm; p=0.2; mean difference: -0.3 mm [-3.3-2.8]). On 3D TEE, coronal diameter and annulus area were significantly smaller (p<.0001 for both) with moderate correlation (r=0.454 and r=0.592). Interobserver variability was comparable for both modalities. TAVI was successful in all patients with no severe post-procedural insufficiency. Final prosthesis size was best predicted by sagittal annulus diameters in 84% and 79% by 3D-TEE and MSCT, respectively. Agreement between both modalities was 77%. CONCLUSIONS: Annulus diameters and areas for pre-procedural TAVI assessment by 3D-TEE are significantly smaller than MSCT with exception of sagittal diameters. Using sagittal diameters, both modalities predicted well final prosthesis size and excellent procedural results were obtained. 3D-TEE can thus be a useful alternative in patients with contraindications to MSCT. PMID- 23688432 TI - Comprehensive assessment of biomarkers in acutely decompensated heart failure: an in-depth look. PMID- 23688433 TI - Relation of the severity of contrast induced nephropathy to SYNTAX score and long term prognosis in patients treated with primary percutaneous coronary intervention. AB - BACKGROUND: SYNTAX score (SXscore) has been developed to assess the severity and complexity of coronary artery disease. The aim of this study was to evaluate whether baseline SXscore was associated with contrast induced nephropathy (CIN) after primary percutaneous coronary intervention (p-PCI) in patients with ST elevation myocardial infarction (STEMI). Secondarily we aimed to investigate the relation of the severity of CIN to long term prognosis. METHODS: We retrospectively enrolled 1893 patients with STEMI treated by p-PCI. We prospectively followed up the patients for a mean duration of 45 months. The patients were grouped according to the development of no nephropathy (grade 0, n: 1634), mild nephropathy (grade 1, n: 153) or severe nephropathy (grade 2, n: 106). RESULTS: SXscore was significantly higher (19.4+/-5.9 vs 15.6+/-4.8, p<0.001) in patients with CIN (grades 1 and 2) compared to those without CIN. SXscore was higher in patients with grade 2 CIN compared to those with grade 1 CIN (18.5+/-5.7 vs 20.7+/-5.9, p<0.001). In the multivariate analysis, SXscore was identified as an independent predictor of CIN (for one unit increment, OR: 1.06, 95% CI: 1.01-1.14, p=0.006). At long-term follow-up, death (p<0.001), stroke (p=0.006), reinfarction (p=0.024) and permanent HD requirement (p<0.001) were most frequent in grade 2 nephropathy group. HD was associated with very high in-hospital (60%) and long-term (83.3%) mortality rates. CONCLUSIONS: SXscore is an independent predictor of development and severity of CIN after p-PCI. CIN is associated with poor prognosis during both early and late postinfarction period. PMID- 23688434 TI - Are some of the last advances in cardiovascular therapeutics fighting against the historic evolution of the heart and the cardiovascular system? PMID- 23688435 TI - Left ventricle diastolic function in patients with polymyositis. PMID- 23688436 TI - Stimulus-driven attention modulates the release of anticipatory postural adjustments during step initiation. AB - OBJECTIVE: Step initiation can be modified by environmental stimulations, suggesting the involvement of stimulus-driven attention. Therefore, we assessed the influence of attentional status during step preparation. METHODS: Fourteen healthy, young subjects were presented with an auditory oddball paradigm in which an infrequent "target" stimulus was presented among frequent "standard" stimuli. An imperative visual "Go" signal for step initiation was presented 1.4s after the auditory stimulus. Both the P300 event-related potential (associated with the auditory attention task) and the trajectory of the centre of pressure (associated with step initiation) were recorded. RESULTS: When presented before the visual "Go" signal, the auditory stimuli prompted the early release of low-amplitude anticipatory postural adjustments, not followed by step execution. They occurred twice as frequently in the "target" condition as they did in the "standard" condition. P300 component was greater after presentation of the target stimulus than after presentation of the standard stimulus. CONCLUSION: Stimulus-driven attention can modify the release of anticipatory postural adjustments. SIGNIFICANCE: The cortical integration of an auditory stimulus (as evidenced by the P300 component) in a subject conditioned to initiate gait appears to release postural adjustments via two different attentional mechanisms: an "alerting effect" and an "orienting effect". PMID- 23688438 TI - A functional variant at miR-24 binding site in B7-H2 alters susceptibility to gastric cancer in a Chinese Han population. AB - A number of single nucleotide polymorphisms (SNPs) within the 3'-UTR of genes have been proved to be contributed to the risk of cancers. Here, we determined an SNP rs4819388 in the 3'-UTR of B7-H2 gene in 183 gastric cancer patients and 348 healthy controls by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Statistical analysis results showed that the rs4819388 genotypes were significantly related to the occurrence of gastric cancer. Compared with the GG homozygotes, the GA heterozygotes were significantly more prevalent in the patients (OR=1.60, 95%CI=1.08-2.37). In addition, the A allelic frequencies were significantly higher than that of the G allele in the patients with lymphatic metastasis (p=0.034) and/or advanced TNM stage (p=0.032). Dual-luciferase reporter assays showed that miR-24 inhibited the expression of B7 H2 through binding with the B7-H2 3'-UTR, and this inhibitory role of miR-24 was impacted by rs4819388. Our findings suggest that the SNP rs4819388 in B7-H2 3' UTR, through disrupting the regulatory role of miR-24 on B7-H2 expression, contributes to the occurrence of gastric cancer. PMID- 23688437 TI - Accurate structure prediction of peptide-MHC complexes for identifying highly immunogenic antigens. AB - Designing an optimal HIV-1 vaccine faces the challenge of identifying antigens that induce a broad immune capacity. One factor to control the breadth of T cell responses is the surface morphology of a peptide-MHC complex. Here, we present an in silico protocol for predicting peptide-MHC structure. A robust signature of a conformational transition was identified during all-atom molecular dynamics, which results in a model with high accuracy. A large test set was used in constructing our protocol and we went another step further using a blind test with a wild-type peptide and two highly immunogenic mutants, which predicted substantial conformational changes in both mutants. The center residues at position five of the analogs were configured to be accessible to solvent, forming a prominent surface, while the residue of the wild-type peptide was to point laterally toward the side of the binding cleft. We then experimentally determined the structures of the blind test set, using high resolution of X-ray crystallography, which verified predicted conformational changes. Our observation strongly supports a positive association of the surface morphology of a peptide MHC complex to its immunogenicity. Our study offers the prospect of enhancing immunogenicity of vaccines by identifying MHC binding immunogens. PMID- 23688440 TI - Computed tomography and magnetic resonance imaging in the study of joint development in the equine pelvic limb. AB - Osteochondrosis dissecans (OCD) is a focal failure of endochondral ossification of the epiphysis characterized by the presence of cartilage flaps and osteochondral fragments. The objective of this study was to image epiphyseal development in the equine pelvic limb to determine whether there was a variation in site maturation that could be a predisposing factor for OCD. Pelvic limbs (fetuses and foals) were studied post-mortem. The epiphyses of the distal femur, tibia and talus were scanned with computed tomography (CT) and 1.5T magnetic resonance imaging (MRI) to investigate the degree and pattern of ossification, the regularity of the ossification front and cartilage percentage (articular epiphyseal cartilage thickness as a percentage of total epiphyseal diameter) at predetermined sites. The secondary ossification centers (SOCs) were first identified in the femoral epiphyses at 7months, and both tibia and talus at 8months of gestation (MOG). At ?8 MOG the cartilage percentage was higher at the majority of OCD-susceptible sites when compared to control sites. At 8-9 MOG the lateral trochlear ridge of the femur, medial malleolus of the tibia (MM), cranial part of the distal intermediate ridge of the tibia (DIRT(Cr)), all OCD susceptible sites, had the greatest cartilage percentage compared to all other sites assessed. Post-partum, the cartilage percentage of the MM and DIRT(Cr), common sites of OCD, remained high. CT and MRI images illustrate equine epiphyseal development and provide additional evidence that greater cartilage thickness at specific joint sites could play a role in the development of OCD. PMID- 23688441 TI - The role of Stat3 in glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is the most common brain tumor and has the worst prognosis. Several signaling molecules have been clearly implicated in the development, progression, and aggressiveness of GBM. Here we review the role of signal transducer and activator of transcription-3 (Stat3) in GBM. We particularly focus on its expression in clinical GBM samples, its role in brain tumorigenicity in cell lines and animal models, and discuss possible therapeutic strategies targeting Stat3. This review also summarizes the current knowledge regarding the role of Stat3 regulation by upstream activators and repressors in promoting GBM progression in both translational and clinical studies. PMID- 23688439 TI - Trends in sugar-sweetened beverage and 100% fruit juice consumption among California children. AB - OBJECTIVE: To determine trends in the consumption of sugar-sweetened beverages (SSBs) and 100% fruit juice by California children ages 2 to 11 years from 2003 to 2009. METHODS: This analysis used serial cross-sectional data from the California Health Interview Survey, a telephone survey of households in California. Parents were asked how many servings of SSBs and 100% fruit juice the child consumed the day before. A test of trend was used to evaluate changes in consumption over time. Multivariate logistic regression was used to determine the independent effects of race/ethnicity, parental education, and household income on beverage consumption. RESULTS: The percentage of children consuming an SSB on the prior day declined from 40% in 2003 to 16% in 2009 (P < .001) among children ages 2 to 5 and from 54% in 2003 to 33% in 2009 (P < .001) among children ages 6 to 11. The percentage of children consuming any SSB decreased for all racial/ethnic groups, although there were disparities with higher consumption among Latinos. Among children ages 2 to 5, consumption of 2 or more servings of 100% fruit juice per day decreased among white children and increased among Latinos. For children ages 6 to 11, consumption of 2 or more servings of 100% fruit juice per day remained stable for white children and increased among Latinos and African Americans. CONCLUSIONS: The decrease in SSB consumption by California children from 2003 to 2009 is a promising trend. The increase in 100% fruit juice consumption among minority children during this period may be an unintended consequence of efforts to reduce SSB consumption. PMID- 23688442 TI - Ocular silicone oil in the lateral cerebral ventricle. AB - Silicone oil used for endotamponade of retinal detachment may migrate into the subarachnoid space of the brain, including the cerebral ventricles, presumably by extension through silicone oil-filled spaces in the optic nerve. Silicone oil has characteristic appearances on CT scans and MRI, which can be utilized to distinguish it from more ominous entities. We describe a case of intraventricular silicone in a patient who presented with seizures. PMID- 23688443 TI - MRI and magnetic resonance angiography findings in patients with multiple sclerosis mimicked by stroke. AB - We report a 45-year-old woman who presented with a first demyelinating event with abnormalities seen on both MRI and magnetic resonance angiography that were highly suggestive of acute ischemic stroke. This report highlights the problem of differential diagnosis of acute neurological symptoms in adult subjects. PMID- 23688444 TI - Intracerebral abscess with dissecting pneumocephalus caused by a gas-producing gram-positive rod following craniotomy for glioblastoma multiforme resection. AB - Propionibacterium acnes (P. acnes), an indolent and slow-growing anaerobic gram positive bacterium, has largely been known as a commensal organism of the normal skin flora. However, P. acnes is increasingly being recognized as the causative infectious organism complicating craniotomies and shunt insertions. To our knowledge, we present the first reported patient with an intracerebral abscess with dissecting pneumocephalus caused by P. acnes. A 58-year-old woman who was immunocompetent presented 3 weeks after a craniotomy for resection of a glioblastoma multiforme with worsening mental status, lethargy and left hemiparesis. Head CT scans and MRI demonstrated significant vasogenic edema and dissecting pneumocephalus in the resection cavity. A craniotomy was performed and purulent material was found in the subdural space and resection cavity. Cultures were positive for P. acnes. She completed a full course of intravenous antibiotics appropriate for the organism. The infection was eradicated and the patient survived albeit with persistent deficits. This case illustrates the importance of considering an underlying intracerebral abscess in patients with worsening neurological function and pneumocephalus on imaging several weeks after surgery. Our review of the literature underscores the great importance in early recognition and treatment with both surgical debridement and antibiotic therapy in achieving optimal patient recovery. PMID- 23688445 TI - Migraine variants--occurrence in pediatric neurology practice. AB - Migraine is common in pediatric neurology practice, while migraine variants are rare and pose diagnostic problems. OBJECTIVE: The aim was to establish the occurrence of migraine variants in pediatric neurology practice and among migraine, and to discuss their presentation. PATIENTS AND METHODS: The files of 2509 newly diagnosed patients, aged 0-18 years, treated as in- and out-patients in the Neuropediatric Ward at the Plovdiv Medical University Hospital between 2002 and 2006 were examined retrospectively. Migraine forms were diagnosed according to ICHD-II. Benign paroxysmal torticolis and alternating hemiplegia of childhood were also accepted as migraine variants according to proposed diagnostic criteria in the appendix of ICHD-II. Some specific forms like acute confusional migraine (ACM), Alice in wonderland syndrome (AWS), ophthalmoplegic migraine were also diagnosed although not included as migraine variants in the ICHD-II classification. RESULTS: 111 patients met diagnostic criteria for migraine. Patients with migraine variants comprised 24.3% of migrainous cases. Basilar type migraine was the most common (6.3% of all migrainous patients), followed by benign paroxysmal vertigo (5.4%), hemiplegic migraine (3.6%), ACM (2.7%), benign paroxysmal torticolis (2.7%), typical aura without headache (1.8%), abdominal migraine (1.8%), AWS (0.9%), ophthalmoplegic migraine (0.9%) and cyclical vomiting (0.9%). Alternating hemiplegia of childhood and retinal migraine was not found. Some patients either presented or were classified as different migraine variants. CONCLUSION: Basilar type migraine was the most common migraine variant. ACM and AWS should be regarded as distinct entities in the ICHD as migraine with complex aura. Benign paroxysmal torticollis also deserves its place as a migraine variant. Cases of ophthalmoplegic migraine with spontaneous remission and no cranial nerve enhancement on MRI should be considered as migraine form. Analyzing migraine variants will contribute to better awareness and adequate diagnosis. PMID- 23688446 TI - Adjacent segment degeneration at T1-T2: myth or reality? PMID- 23688447 TI - Development of flax/carbon fibre hybrid composites for enhanced properties. AB - Uni-directional (UD) and cross-ply (CP) cellulosic flax fibre epoxy composites were produced by hybridising UD carbon fibre prepreg onto flax system. A compression moulding technique was used to produce both flax and carbon/flax hybridised laminates. The effect of carbon fibre hybridisation on the water absorption behaviour, thermal and mechanical properties of both UD and CP flax specimens were investigated by means of water absorption, tensile, thermogravemetric analysis and flexural testing. The results showed that water absorption behaviour of hybrid samples are markedly improved compared to those without hybridisation. Similarly, the thermal stability, tensile and flexural properties of the hybrid composites are significantly improved in comparison with UD and CP flax composites without hybridisation. The experimental results suggest that cellulosic flax fibre reinforcement contributed to improve the toughness properties by promoting crack propagation whereas the carbon fibre contributed in improving thermal stability, water absorption behaviour and the overall strength and the stiffness of the hybrid composites. PMID- 23688448 TI - Purification and characterization of D-Gal-6-sulfurylase from Eucheuma striatum. AB - D-Gal-6-sulfurylase catalyzing the conversion of MU-carrageenan into kappa carrageenan was extracted from Eucheuma striatum and purified by ammonium sulfate precipitation, hydrophobic interaction chromatography and ion exchange chromatography. The purified enzyme was a monomeric protein with a molecular mass of about 65 kDa as shown in SDS-PAGE. The maximum activity of the enzyme was observed at pH 7.0 and temperature 40 degrees C. Km value for MU-carrageenan was 4.31 mM, and the corresponding Vmax was 0.17 mM min(-1). The carrageenan treated with 10 U of the purified enzyme exhibited 7.1-fold increase in gel strength with a removal of 30% sulfate groups. (1)H NMR spectral analysis of the control and enzyme treated carrageenan confirmed the conversion of MU- into kappa-carrageenan and highlighted the specificity of Gal-6-sulfurylase for MU-carrageenan. This Gal 6-sulfurylase provides an eco-friendly and alternative for alkali treatment method to produce high gel strength kappa-carrageenan. PMID- 23688449 TI - Hydrothermal synthesis, characterization, and bactericidal activities of hybrid from cellulose and TiO2. AB - The purpose of this study was to explore a new strategy to improve the high value added applications of biomass. Hybrid from cellulose and titanium dioxide (TiO2) was successfully prepared by using tetra-n-butyl titanate and cellulose solution via a hydrothermal method at 180 degrees C for 24h. The phase, microstructure, morphology, and thermal stability of the hybrid were characterized by X-ray powder diffraction (XRD), Fourier transform infrared spectrometry (FT-IR), thermogravimetric analysis (TGA), differential thermal analysis (DTA), and scanning electron microscopy (SEM). The influences of the tetra-n-butyl titanate concentration and the types of solvent on the products were investigated. The TiO2 nanoparticles were dispersed on the surface of cellulose and/or in the cellulose matrix. The hybrid possessed an antimicrobial activity against the model microbes Escherichia coli (Gram-negative) and Staphylococcus aureus (Gram positive), and were a promising antimicrobial material for the applications in the biomedical field. PMID- 23688450 TI - Ultrasound-assisted formation of the canthaxanthin emulsions stabilized by arabic and xanthan gums. AB - There is interest in incorporating canthaxanthin (CTX) into food emulsions due to its high potential health benefits. The used CTX in this study was produced by the bacterium of Dietzia natronolimnaea HS-1. Then, the influence of main emulsion components (gum arabic (GA), xanthan gum (XG) and coconut oil (CO)) on the surface-weighted mean diameter (D32), polydispersity index (PDI), specific surface area (SSA) of droplets and density of the emulsions containing CTX was optimized using response surface methodology (RSM). Polynomial equations between the responses and independent variables were derived. The linear effect of GA had a significant (p<0.0001) term in all reduced models. The optimal formulation for emulsions was composed of GA content of 9.85% (w/w), XG content of 0.13% (w/w) and CO concentration of 3.50% (w/w). This optimum formulation yielded D32 of 0.752 MUm, PDI of 1.533, SSA of 9.995 m(2)/ml and density of 1.0357 g/cm(3). PMID- 23688451 TI - Hydration and mechanical properties of arabinoxylans and beta-D-glucans films. AB - Arabinoxylans (AX) and (1->3)(1->4)-beta-d-glucans (BG) are the main components of the cell walls in the endosperm of wheat grain. The relative occurrence of these two polysaccharides and the fine structure of the AX are highly variable within the endosperm. Films of AX and BG were used as models of the cell wall to study the impact of polymer structure on the hydration and mechanical properties of the cell walls. Effective moisture diffusivities (Deff) of AX and BG films were determined from 0 to 95% relative humidity (RH) at 20 degrees C. Deff was influenced by the water content, and the structure of polysaccharides. Higher Deff was obtained for films made with highly substituted AX compared to values obtained for films made with BG or lowly substituted AX. Proton dipolar second moments M2 and water T2 relaxation times measured by TD-NMR, indicated that the highly branched AX films exhibited a higher nano-porosity, favoring water motions within films. Results from traction tests showed significant different mechanical properties between the AX and BG films. BG films exhibited much higher extensibility than AX films. Strength and extensibility of AX films decreased with increasing arabinose to xylose ratio. Our results show that the water motions and the mechanical properties of AX and BG films can be linked to the polysaccharide chains interactions that modulate the nanostructure of films. PMID- 23688452 TI - Effect of glycerol concentration on edible film production from cress seed carbohydrate gum. AB - In this study an edible film plasticized with glycerol was successfully prepared from cress seed gum (CSG). The physical, optical, water vapor permeability (WVP) and mechanical properties of CSG films incorporated with three levels of glycerol (25%, 35%, and 50% w/w) as plasticizer were determined. Dynamic mechanical thermal analysis was used to determine the glass transition temperature. WVP of the films was found to increase as the glycerol content increased from 25% to 50% w/w in the formulation, resulted in improvement of films flexibility and significantly lower tensile strength and higher elongation at break. The color measurement values showed that increasing the glycerol concentration in polymer matrix caused the b and L values increased while DeltaE value decreased. The electron scanning micrograph indicated smooth and uniform surface morphology without signs of phase separation between the film components. The results of the present study demonstrated that CSG can promisingly be used in producing edible films with improved quality characteristics. PMID- 23688453 TI - Synthesis and evaluation of novel water-soluble copolymers based on acrylamide and modular beta-cyclodextrin. AB - Mono-6-(allyl amino)-beta-cyclodextrin (N-beta-CD) and mono-2-O-(allyl oxygen radicals-2-hydroxyl propyl)-beta-cyclodextrin (O-beta-CD) were copolymerized with acrylamide (AM), acrylic acid (AA), and 1-llyl-3-oil acyloxyimidazole-1-ammonion bramide (AOAB) initiated by redox initiation system in an aqueous medium. The AM/AA/AOAB/N-beta-CD and AM/AA/AOAB/O-beta-CD were prepared by adjusting the reactive conditions, such as initiator concentration, pH, temperature, and monomer ratios. The obtained copolymers were characterized by means of infrared (IR) spectroscopy, (1)H NMR spectroscopy, scanning electron microscope (SEM), rotational rheometer, intrinsic viscosity, salt resistance, core flood test, etc. The temperature-tolerance, shear-tolerance, salt-resistance and thickening function of these copolymers are improved remarkably compared with partially hydrolyzed polyacrylamide (HPAM). About 18.3% and 12.5% oil recovery could be enhanced by 2000mg/L AM/AA/AOAB/N-beta-CD and AM/AA/AOAB/O-beta-CD comparing with water-flooding. In addition, the result of X-ray diffractometry (XRD) test showed that the solutions of obtained copolymers could remarkably reduce the crystalline interspace of sodium montmorillonite (from 18.9A to 15.3A). PMID- 23688454 TI - Effect of clay concentration on morphology and properties of hydroxypropylmethylcellulose films. AB - Hydroxypropylmethylcellulose (HPMC)/montmorillonite (MMT) nanocomposite films are prepared by solution intercalation method. Mechanical, thermal, moisture absorption, optical clarity and water vapor permeability of HPMC/MMT nanocomposite films are measured. X-ray diffraction (XRD) and transmission electron microscopic (TEM) results establish formation of partially intercalated and partially exfoliated HPMC/MMT nanocomposite films. In presence of MMT, the tensile strength, tensile modulus and elongation at break of HPMC films are improved. The thermal stability of HPMC/MMT nanocomposites is better than pure HPMC. The moisture absorption of HPMC film measured in 75% of constant relative humidity is reduced with loading of MMT. Optical clarity of HPMC film is almost unaffected in presence of MMT. Water vapor permeability of HPMC decreases in presence of nanoclay due to increasing tortuous path for diffusion. PMID- 23688455 TI - Amine salts-activated systems for one-step bleaching of cotton fabrics. AB - In this paper triethanolamine salt-catalyzed sodium chlorite bleaching system was used to bleach plain weave cotton fabric in one step. Different triethanolamine salts, including those derived from organic acids and mineral acids were tried for activating sodium chlorite decomposition during the bleaching reaction. All bleaching trials were carried out keeping fixed sodium chlorite concentration. The concentration of triethanolamine hydrochloride, as an example for the triethanolamine salts was varied to show the effect of the activator concentration on the final fabric degree of whiteness. The optimum triethanolamine hydrochloride concentration, required for activating sodium chlorite decomposition was found to be 10 mmol/l and based on that, this concentration was applied for other organic and inorganic triethanolamine salts to show the effect of nature of the activator on the final degree of whiteness. The results showed that salts prepared using mineral acids have activation potential better than those prepared using organic acids. PMID- 23688456 TI - Mechanical and water barrier properties of agar/kappa-carrageenan/konjac glucomannan ternary blend biohydrogel films. AB - Multicomponent hydrogel films composed of agar, kappa-carrageenan, konjac glucomannan powder, and nanoclay (Cloisite((r)) 30B) were prepared and their mechanical and water barrier properties such as water vapor permeability (WVP), water contact angle (CA), water solubility (WS), water uptake ratio (WUR), water vapor uptake ratio (WVUR) were determined. Mechanical, water vapor barrier, and water resistance properties of the ternary blend film exhibited middle range of individual component films, however, they increased significantly after formation of nanocomposite with the clay. Especially, the water holding capacity of the ternary blend biopolymer films increased tremendously, from 800% to 1681% of WUR for agar and kappa-carrageenan films up to 5118% and 5488% of WUR for the ternary blend and ternary blend nanocomposite films, respectively. Water vapor adsorption behavior of films was also tested by water vapor adsorption kinetics and water vapor adsorption isotherms test. Preliminary test result for fresh spinach packaging revealed that the ternary blend biohydrogel films had a high potential for the use as an antifogging film for packaging highly respiring agricultural produce. In addition, the ternary blend nanocomposite film showed an antimicrobial activity against Gram-positive bacteria, Listeria monocytogenes. PMID- 23688457 TI - Oil-in-water emulsions stabilized by sodium phosphorylated chitosan. AB - Oil-in-water (O/W) emulsions with sodium phosphorylated chitosan (PCTS) were obtained via simple emulsification. PCTS in aqueous solution was amphiphilic with a hydrophilic-lipophilic balance (HLB) of 19 and a critical aggregation concentration (CAC) of 0.13% w/v. The emulsifying efficiency and emulsion stability of PCTS over oil droplets were evaluated in terms of the droplet size, droplet size distribution and microscopic observation using confocal laser scanning microscopy. PCTS preferred to cover oil droplets to produce an O/W emulsion and formed long term stable particles (90 days storage at room temperature) when using PCTS concentrations from above the CAC to 3% w/v. However, emulsions formed from PCTS concentrations below the CAC or over 3% w/v were unstable with particle agglomeration by flocculation after only 7 days storage, although they reverted to individual droplets that retained their integrity in acidic conditions. Overall, PCTS forms effective stable O/W encapsulated particles with potential applications in lipophilic drug encapsulation via a simple emulsion system. PMID- 23688458 TI - Preparation and properties of blends composed of lignosulfonated layered double hydroxide/plasticized starch and thermoplastics. AB - Layered double hydroxide prepared with lignosulfonate (LDH/LS) can be easily dispersed down to the nanometric scale in thermoplastic starch, at concentration of 1 up to 4 wt% of LDH/LS. They can thus be used as a bio-based reinforcing agent of thermoplastic starch. Incorporation of LDH/LS in starch must be done using LDH/LS slurry instead of powder on order to avoid secondary particles aggregation, the water of the paste being used as the starch plasticizer. This reinforced starch was used for preparing a starch-polyolefine composite. LDH/LS starch nanocomposites were mixed in a random terpolymer of ethylene, butyl acrylate (6%) and maleic anhydride (3%) at concentrations of 20 wt% and 40 wt%. With a 20% loading of (1 wt% LDH/LS in thermoplastic starch), the ternary copolymer is partially bio-based while keeping nearly its original processability and mechanical properties and improving oxygen barrier properties. The use of layered double hydroxides is also removing most odours linked to the lignin phase. PMID- 23688460 TI - Thermo-molded biocomposite from cassava starch, natural fibers and lignin associated by laccase-mediator system. AB - Treatment of cellulose fibers and lignin by laccase-mediator system was conducted to enhance the binding efficiency of natural fibers and lignin compounds into cassava starch composite matrix. Violuric acid (VA) was tested for its effect as a mediator for laccase treatment. Influence of different fiber, lignin and water contents of biocomposite was statistically investigated. The results showed that adding 15% (w/w) fibers into biocomposite at 44% (w/w) water content increased flexural strength and modulus for 4 times compared with the control. A combination of fibers+VA gave the greatest enhancement of modulus for 1140% and flexural strength for 375.8% as much as neat starch biocomposite. The presence of fibers, lignin and VA as mediator for laccase treatment substantially enhanced water resistance of starch biocomposite detected by a change in water drop contact angle on biocomposite surface. PMID- 23688459 TI - Extraction, antioxidant and antimicrobial activities of Epimedium acuminatum Franch. polysaccharide. AB - Polysaccharides from Epimedium acuminatum were extracted by hot water and optimized with response surface methodology. The optimal conditions of the extraction were determined to be the ratio of water to raw material of 29.61, extraction temperature of 85.67 degrees C and extraction time of 3.57 h. Under these optimal conditions, the yield of polysaccharide was 8.21%, which was well matched with the predictive yield (8.23%). Moreover, three purified fractions (EAP40-1, EAP60-1 and EAP80-2) were obtained for further chemical analysis, antioxidant activity analysis and antimicrobial activity analysis. EAP40-1 with molecular weight of 138,884 Da showed the best radical scavenging activity. Meanwhile, EAP60-1 with molecular weight of 114,667 Da was found to exhibit significant antihemolytic activity and antimicrobial activity. PMID- 23688461 TI - Effects of the order of addition of reagents and catalyst on modification of maize starches. AB - The objective of this research was to determine if adding reactive reagents to starch granules before addition of alkali (TRF method) would produce products that are different than those obtained by adding alkali before addition of reagent. Normal (NMS) and waxy (WMS) maize starches were each reacted with acetic adipic mixed anhydride (AAMA), phosphoryl chloride (POCl3), sodium trimetaphosphate (STMP), acetic anhydride (AA), succinic anhydride (SA), and octenylsuccinic anhydride (OSA). Almost no or no starch polymer molecule modification occurred when the TRF method and AAMA, AA, or POCl3 were used; less than half as much reaction when SA was the reagent used, and about the same amount of reaction when STMP or OSA were the reagents used (for different reasons). It was concluded that most AAMA, AA, SA, and POCl3 reacted with surface protein molecules when the TRF method was used and that OSA molecules were driven into the structured internal water of granules. PMID- 23688462 TI - Bioactivity of selenium-enriched exopolysaccharides produced by Enterobacter cloacae Z0206 in broilers. AB - To investigate effects of Se-enriched exopolysaccharides (Se-ECZ-EPS) produced by Enterobacter cloacae Z0206 on growth performance, antioxidant status and immune function, 240 broilers were randomly assigned into five groups: the control group was fed a basal diet supplemented with 0.15 mg/kg Se (Na2SeO3), and the other four groups were fed with diets supplemented with Se-ECZ-EPS at 280, 560, 840 and 1120 mg/kg, respectively. Administration of Se-ECZ-EPS (840 and 1120 mg/kg) significantly increased average daily gain, decreased feed/gain ratio and enhanced antioxidant enzyme activities. Serum cytokine concentrations showed positive responses in birds treated with 560 and 1120 mg/kg Se-ECZ-EPS. Serum antibody titers against Newcastle disease virus in birds treated with 840 mg/kg Se-ECZ-EPS were significantly increased. These results suggested that Se-ECZ-EPS could enhance antioxidant status and immune function, and could be developed to a potentiator of the immune response in broilers, with the 840 mg/kg addition level being the most effective. PMID- 23688463 TI - The cold storage of green bananas affects the starch degradation during ripening at higher temperature. AB - The aim of this work was to investigate the starch degradation of bananas stored at low temperature (13 degrees C, cold-stored group) and bananas stored at 19 degrees C (control group) during ripening. The starch granules were isolated during different stages of banana ripening, and their structure was investigated using different techniques. The activities of alpha-amylase and beta-amylase associated to the starch granules were determined, and their presence was confirmed using immunolocalization assays. The increased molecular mobility likely facilitated the intake and action of alpha-amylase on the granule surface, where it was the prevalent enzyme in bananas stored at low temperature. The 10 days of storage at low temperature also influenced the sizes and shapes of the granules, with a predominance of rounded granules and pits on the surface along with superior amylose content, the higher amounts of amylopectin A-chains and the subtle increase in the A-type allomorph content. PMID- 23688464 TI - Extraction optimization of Bruguiera gymnorrhiza polysaccharides with radical scavenging activities. AB - Box-Behnken design including independent variables such as extraction temperature (60-80 degrees C), extraction time (20-40 min) and ratio of water to raw material (30-50 mL/g) was used to optimize the extraction process of Bruguiera gymnorrhiza polysaccharides (BGPs). The experimental data were fitted to a second-order polynomial equation using multiple regression analysis. The optimum conditions were predicted as follows: extraction temperature 71 degrees C, extracting time 31.4 min, and ratio of water to raw material 42. Under these conditions, the yield of BGPs obtained was (16.43 +/- 0.08)%, which was in good agreement with the predicted value 16.47%. Additionally, characterization of BGPs was obtained by FT-IR analysis. The antioxidant activities of BGPs were evaluated in vitro. BGPs demonstrated appreciable antioxidant potential on superoxide anion radical, ABTS radical, and hydroxyl radical scavenging. These may provide theoretical basis for further system research and rational development and utilization of mangrove resources. PMID- 23688465 TI - Preparation, characterization and in vitro release of microparticles based on dextran-rosuvastatin conjugate. AB - A novel conjugate for rosuvastatin has been prepared by a coupling reaction between rosuvastatin and dextran. The dextran-rosuvastatin conjugates (DRC) were characterized by FT-IR, NMR, and XRD. And the resulting DRC self-assembled into microparticles by controlled slow exchange of solvents applying dialysis. The size and morphology of DRC microparticles could be controlled through the solvents and pH selection. Particles with different shape and size of microspheres, micro-blocks, micro-flakes or three-dimensional network structure were obtained by adjusting the pH from 9.0 to 13.0. Multiple morphologies of nano or microparticles were collected in different organic solvents. In vitro release studies suggested that these DRC microparticles had a sustained release manner and the release behavior could be controlled by adjusting their morphology. PMID- 23688466 TI - Influence of the extraction process on the rheological and structural properties of agars. AB - Agars obtained by traditional hot-water (TWE) and microwave-assisted (MAE) extractions were compared in terms of their rheological and physicochemical properties and molecular self-association in solutions of low (0.05%, w/w) and high (1.5%, w/w) polymer concentrations. At low concentration, thin gelled layers were imaged by AFM. Slow or rapid cooling of the solutions influenced structure formation. In each case, TWE and MAE agar structures were different and apparently larger for MAE. At high concentration, progressive structural reinforcement was seen; while TWE agar showed a more open and irregular 3D network, MAE agar gel imaged by cryoSEM was denser and fairly uniform. The rheological (higher thermal stability and consistency) and mechanical (higher gel strength) behaviors of MAE agar seemed consistent with a positive effect of molecular mass and 3,6-anhydro-alpha-l-galactose content. MAE produced non degraded agar comparable with commercial ones and if properly monitored, could be a promising alternative to TWE. PMID- 23688467 TI - Development and characterization of cellulose-polymethacrylate mucoadhesive film for buccal delivery of carvedilol. AB - The aim of the present work was to develop and characterize mucoadhesive film of cellulose (methyl cellulose and hydroxy propyl methyl cellulose) and polymethacrylate (Eudragit RSPO) polymers for buccal delivery of carvedilol. Drug and polymers were found to be compatible as revealed by FTIR and DSC analysis. Mucoadhesive films were prepared by solvent casting technique. Swelling studies up to 4h did not show erosion of film, which was further confirmed by SEM analysis. New, simple and precise instrumental methods were established for the evaluation of mucoadhesive strength (33.8 +/- 0.37-38.4 +/- 0.24 g) and film strength (331.2 +/- 0.73-369.0 +/- 1.00 g) of developed films. Mucoadhesive film F5 showed 88 +/- 1.15% in vitro drug release and 80 +/- 2.30% ex vivo drug permeation through goat buccal mucosa in 12h. Drug release and permeation followed Higuchi's model and mechanism was found to be Fickian type diffusion controlled. PMID- 23688469 TI - Fabricating electroconductive cotton textiles using graphene. AB - In this work, design parameters were investigated for enhancing the conductivity of graphene-coated cotton textiles. Graphene oxide (GO) was immobilized on cotton fabric through a conventional "dip and dry" method. The GO-coated fabrics were then immersed in an aqueous solution of reducing agent, which converted the GO into graphene. The effect of various parameters such as type of reducing agent (NaBH4, N2H4, C6H8O6, Na2S2O4 and NaOH) and its concentration, reduction time and number of coating process on conductivity of the fabrics was studied. The mechanical performance of the fabrics was also investigated. The results showed that the best conductivity and mechanical performance were obtained using Na2S2O4 as a reducing agent. The reaction time of 30 min at 95 degrees C was enough for complete reduction of the GO. Electrical conductivity increased by approximately three orders of magnitude with the increase in the number of coating process from 1 to 20 cycles. PMID- 23688468 TI - Microencapsulated probiotics using emulsification technique coupled with internal or external gelation process. AB - Alginate-chitosan microcapsules containing probiotics (Yeast, Y235) were prepared by emulsification/external gelation and emulsification/internal gelation techniques respectively. The gel beads by external gelation showed asymmetrical structure, but those by internal gelation showed symmetrical structure in morphology. The cell viability was approximately 80% for these two techniques. However, during cell culture process, emulsification/internal gelation microcapsules showed higher cell growth and lower cell leakage. Moreover, the survival rate of entrapped low density cells with culture (ELDCwc) increased obviously than that directly entrapped high density cells (dEHDC) and free cells when keeping in simulated gastrointestinal conditions. It indicated the growth process of cells in microcapsule was important and beneficial to keep enough active probiotics under harmful environment stress. Therefore, the emulsification/internal gelation technique was the preferred method for application in food or biotechnological industries. PMID- 23688471 TI - Smart options for simultaneous functionalization and pigment coloration of cellulosic/wool blends. AB - The present innovative research work deals with the individual use of chitosan (2.5 g/kg), Aloe vera (10 g/kg), triclosan (10 g/kg), TiO2-nanoparticles (TiO2 NP's, 10 g/kg), silicon micro-emulsion (20 g/kg) or a water/oil-repellent agent (40 g/kg) for modifying the pigment print paste to produce functionalized cotton/wool and viscose/wool pigment prints in one step process. The imparted functional properties such as antibacterial, antibacterial/UV-protection, soft handle or water/oil-repellency together with the change in the printing properties were evaluated. Some of the obtained pigment prints were characterized by scanning electron microscope (SEM), and energy dispersive X-rays (EDX) to confirm deposition of certain functional additives on printed fabrics. The wide range of imparted functional properties together with the depth of the obtained pigment prints were maintained over 80% even after 15 consecutive laundering cycles. The extent of retention in functional and pigment printing properties is influenced by the type of functional additive as well as the kind of substrate. PMID- 23688470 TI - Inulinase production in a packed bed reactor by solid state fermentation. AB - In this work, production of inulinase was carried out in a packed bed reactor (PBR) under solid state fermentation. Kluyveromyces marxianus var. marxianus was used to produce the inulinase using pressmud as substrate. The parameters like air flow rate, packing density and particle size were optimized using response surface methodology (RSM) to maximize the inulinase production. The optimum conditions for the maximum inulinase production were: air flow rate - 0.82 L/min, packing density - 40 g/L and particle size - 0.0044 mm (mesh - 14/20). At these optimized conditions, the production of inulinase was found to be 300.5 unit/gram of dry substrate (U/gds). PMID- 23688472 TI - A thermosensitive carrageenan-based polymer: synthesis, characterization and interactions with a cationic surfactant. AB - Novel polyelectrolytes were obtained by grafting N-isopropylacrylamide (NIPAM) on the iota-carrageenan (CAR) chain. Two polymers with different grafting degrees were synthesized. The polymers were found to show the lower critical solution temperature (LCST) close to that of PNIPAM. The LCST values were dependent on the concentration of salt and cationic surfactant. The interactions of CAR-graft PNIPAM with a model cationic surfactant-dodecyltrimethyl ammonium chloride (DTAC) in water and 0.15M NaCl were studied. It was found that both iota-carrageenan and CAR-graft-PNIPAM polymers interact with DTAC. The presence of CAR-graft-PNIPAM in the solution of DTAC induces formation of surfactant aggregates at the critical aggregation concentration much lower than the cmc of the surfactant. Cac increased with ionic strength. The values of cac for CAR-graft-PNIPAM - DTAC system and standard free enthalpy changes attributed to the complexation process were determined. The results obtained for CAR-graft-PNIPAM were compared with these for the non-modified iota-carrageenan. The surfactant interactions with non modified and grafted polymers were found to be different in nature. PMID- 23688473 TI - Acetylation of rice straw for thermoplastic applications. AB - An inexpensive and biodegradable thermoplastic was developed through acetylation of rice straw (RS) with acetic anhydride. Acetylation conditions were optimized. The structure and properties of acetylated RS were characterized by fourier transform infrared (FTIR), solid-state (13)C NMR spectroscopy, X-ray diffractometer (XRD), scanning electron microscope (SEM), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The results showed that acetylation of RS has successfully taken place, and comparing with raw RS, the degree of crystallinity decreased and the decomposition rate was slow. The acetylated RS has got thermoplasticity when weight ratio of RS and acetic anhydride was 1:3, using sulphuric acid (9% to RS) as catalyst in glacial acetic acid 35 degrees C for 12h, and the dosage of solvent was 9 times RS, in which weight percent gain (WPG) of the modified RS powder was 35.5% and its percent acetyl content was 36.1%. The acetylated RS could be formed into transparent thin films with different amount of plasticizer diethyl phthalate (DEP) using tape casting technology. PMID- 23688474 TI - Activity of chitin deacetylase from Colletotrichum gloeosporioides on chitinous substrates. AB - Production of chitin deacetylases from the phytopathogenic fungus Colletotrichum gloeosporioides was successfully achieved by submerged fermentation. The highest specific activity of 0.018 U mg(-1) of protein was obtained after 96 h of cultivation at pH 6 and 28 degrees C. Two bands with molecular weights of 35 kDa and 170 kDa determined with SDS-PAGE displayed deacetylase activities as detected in the zymograms. Reacetylated commercial chitosan (52% acetylation degree) was used as substrate for the extracellular crude extract in order to estimate the kinetic parameters of acetate production as undirected deacetylation measurement. The highest acetate production of 12.8 MUmol mL(-1) was obtained using 7.5 mg mL( 1) of substrate. The produced enzyme from C. gloeosporioides achieved up to 25% deacetylation of a chitin substrate (hydrolyzed biological chitin) having 80% degree of acetylation, MW of 102*10(3) g mol(-1) and a crystallinity index of ca. 60%. PMID- 23688476 TI - Electrospun carboxymethyl cellulose acetate butyrate (CMCAB) nanofiber for high rate lithium-ion battery. AB - Cellulose derivative CMCAB was synthesized, and nanometer fiber composite material was obtained from lithium iron phosphate (LiFePO4, LFP)/CMCAB by electrospinning. Under the protection of inert gas, modified LFP/carbon nanofibers (CNF) nanometer material was obtained by carbonization in 600 degrees C. IR, TG-DSC, SEM and EDS were performed to characterize their morphologies and structures. LFP/CNF composite materials were assembled into lithium-ion battery and tested their performance. Specific capacity was increased from 147.6 mAh g( 1) before modification to 160.8 mAh g(-1) after modification for the first discharge at the rate of 2C. After 200 charge-discharge cycles, when discharge rate was increased from 2C to 5C to 10C, modified battery capacity was reduced from 152.4 mAh g(-1) to 127.9 mAh g(-1) to 106 mAh g(-1). When the ratio was reduced from 10C to 5C to 2C, battery capacity can be quickly approximate to the original level. Cellulose materials that were applied to lithium battery can improve battery performance by electrospinning. PMID- 23688475 TI - Preparation and characterization of bionanocomposite films filled with nanorod rich zinc oxide. AB - The effects of zinc oxide nanorods (ZnO-nr) incorporation on the physical, mechanical, heat sealability, barrier, thermal and antibacterial properties of sago starch and bovine gelatin bionanocomposites films were investigated. The ZnO was incorporated into the films at different concentrations (1-5%, w/w total solid). All films were plasticized with 40% (w/w of total solid) of a combination of sorbitol/glycerol at 3:1 ratio. Incorporation of 5% of ZnO-nr to starch and gelatin films decreased the permeability to oxygen by 40% and 55%, respectively. Moisture content and water absorption capacity of the films were decreased by increasing the ZnO-nr contents. Mechanical and heat seal properties of the films were increased more than 20%. The films exhibited UV absorption and displayed an excellent antimicrobial activity against the Escherichia coli. These properties suggest that bionanocomposites based on ZnO-nr have the potential as an active packaging material for food and pharmaceutical industries. PMID- 23688477 TI - Comprehensive analysis of the substituent distribution in 3-O-ethyl/propyl cellulose derivatives. AB - Two 3-O-ethyl-3-O-propyl celluloses of similar ethyl and propyl content prepared under different conditions were analyzed with respect to their substituent distribution in the glucosyl units and along the polymer chain by ESI-MS analysis of labeled oligosaccharides. Both samples showed similar regioselectivity of substitution and random distribution of ethyl and propyl groups over the 3-O positions. The distribution of all types of glucosyl residues identified by monomer analysis was also random over the cellulose molecules. Comparison of the substitution pattern in the glucosyl units with the pattern expected for the observed regioselectivity showed relative high 2-O-alkylation in spite of protecting group strategy, but no corresponding 2,3-di-O-substitution. This is probably the result of partial silyl migration under the alkaline alkylation conditions. PMID- 23688478 TI - Isolation and partial characterization of delayed releasing starches of Colocasia species from Jharkhand, India. AB - There is an increasing interest in starch manufactured from edible tubers for controlled delivery of drug. Starches of different cultivars of Colocasia from Jharkhand, North Eastern State of India, were isolated and their morphological, physicochemical, structural properties were studied. The yield of starches was estimated in the range of 6.46-13.75%. All the isolated starches revealed their irregular shape with a diameter of 5-10 MUm. There was considerable variation in amylose content, swelling and solubility power, water hydration capacity. FTIR spectra confirmed their carbohydrate nature. Powder studies revealed that these starches possess potential for pharmaceutical industries. In vitro release data revealed the delayed release of all tablets made by using Colocasia starches at pH 6.8 and 7.4 when compared with maize starch. Delayed release of all starches showed there is a great potential to be used these starches as pharmaceutical excipient in sustained release dosage form with minimum modification. PMID- 23688479 TI - Toward tunable amphiphilic copolymers via CuAAC click chemistry of oligocaprolactones onto starch backbone. AB - Starch-based tunable amphiphilic copolymers are easily obtained by grafting polycaprolactone chains via 1,3 dipolar Copper-Catalyzed Azide-Alkyne Cycloaddition (click chemistry CuAAC), starting from propargylated starch and azido oligocaprolactones with different chain lengths as the precursors. The copolymers are characterized by (1)H and (13)C NMR, from which a degree of substitution of starch can tentatively be deduced. Besides these bulk characterizations, the surface of the functionalized starch is also characterized by XPS which confirms the triazole formation, particularly through the deconvolution of the N 1s peak, and by ToF-SIMS which, not only confirms the surface modification, but also highlights the disappearance of the Cu(+) cations. The solubility and swelling behaviours of these copolymers have been investigated, which clearly show the dependence both on the solvent and the PCL chain length. These investigations highlight the swelling dependence on the deltad component of the Hansen solubility parameter of solvents. Finally, at low concentration, they present the capacity to organize themselves in aggregates in aqueous solutions, as seen from TEM and DLS investigations. PMID- 23688480 TI - Molecular structure of citric acid cross-linked starch films. AB - The effect of citric acid (CA) on starch films has been examined. A new method to detect cross-linking of starch by CA in solution-cast films by molecular weight measurements is described. Furthermore, we managed to distinguished between free, mono- and di-esterified CA and quantify di-ester content within starch films by using a modification in the method of complexometric titration with copper(II) sulfate. Cross-linking of starch by CA occurred at low temperature, 70 degrees C, which we assumed is so far the lowest temperature reported where cross-linking reaction occurred. This is essential for starch coating applications within paper industry since no high temperatures for curing will be required. However, curing at 150 degrees C and high CA concentrations, 30 pph, increased cross-linking reaction. Furthermore, the physical properties like water solubility, gel content and glass transition temperature, were highly reflected by changes in the molecular structure i.e. cross-linking and hydrolysis, as well as CA content and curing temperature. PMID- 23688481 TI - Use of pectin-thorium (IV) tungstomolybdate nanocomposite for photocatalytic degradation of methylene blue. AB - Pectin-thorium (IV) tungstomolybdate (Pc/TWM) nanocomposite was prepared by mixing biopolymer pectin with its inorganic counterpart thorium (IV) tungstomolybdate (TWM) using the sol-gel method. The nanocomposite was characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR). Distribution coefficient, thermal stability, pH titrations, elution and concentration behaviour were investigated to explore the ion exchange behaviour of nanocomposite material. Pc/TWM exhibited higher ion exchange capacity (1.10 mequiv/g) than its inorganic counterpart (0.62 mequiv/g). The Pc/TWM nanocomposite ion exchanger was thermally stable as it retained 59% of its ion exchange capacity upto 400 degrees C. The pH titrations study revealed the bifunctional nature of Pc/TWM. In order to explore the environmental applicability of the Pc/TWM nanocomposite material, its antibacterial and photocatalytic activities was investigated. 76% of methylene blue dye was photocatalytically degraded after five hours exposure. It also totally inhibited Escherichia coli at 400 MUg/ml concentration of Pc/TWM nanocomposite. PMID- 23688483 TI - Process optimization for bioscouring of cotton and lycra cotton weft knits by Box and Behnken design. AB - The aim of the study was to discover the effect of experimental parameters like pH, enzyme dosage and temperature, on the removal of natural and accidental impurities from cotton and lycra cotton weft knitted fabrics, to make them suitable for further processing like dyeing and finishing. The optimal experimental conditions and their effects have been ascertained by response surface methodology using the Box-Behnken model. The optimum values were found to be pH 8.5, enzyme dosage 0.4% on weight of fabric and temperature 55 degrees C. The r(2) values and the F values indicate that the effect of all the parameters taken together is significant. Based on the results of the study it can be understood that the bioscouring process performed with these optimal values is suitable for pretreatment of cotton and lycra cotton weft knitted fabrics. PMID- 23688482 TI - Characterization of water and alkali-soluble polysaccharides from Pleurotus tuber regium sclerotia. AB - Pleurotus tuber-regium sclerotia, an edible and medicinal mushroom, is a rich source of polysaccharides used as a functional food to promote health and longevity. The crude polysaccharides were isolated from the P. tuber-regium by hot aqueous and alkali extraction and then further purified by DEAE-52 cellulose chromatography and Sephadex G-100 chromatography. Two polysaccharides, water and alkaline extraction of polysaccharides (W-PTR and A-PTR), were obtained and their extraction process were optimized through orthogonal array design. Structure characteristics (physicochemical property analysis, molecular weight, monosaccharide composition, sulfate and uronic acid contents, triple helical structures, ultraviolet spectrum and infrared spectroscopy) of the two polysaccharides were investigated. Results showed that the main difference between the two polysaccharides is reflected in color, solubility, molecular weight and monosaccharide composition. Conformational analysis showed that both W PTP and A-PTP had triple-helix conformation. The 3D structure of the two polysaccharides and their structure-function relationship will be challenge in the future. PMID- 23688484 TI - Intrinsic intumescent-like flame retardant properties of DNA-treated cotton fabrics. AB - In the present work, the effect of different DNA add-ons (namely, 5, 10 and 19 wt.%) has been thoroughly investigated as far as the flammability and the resistance to an irradiating heat flux of 35 or 50 kW/m(2) are considered. The results have shown that 10 wt.% is the minimum amount that allows reaching the self-extinguishment of cotton when a methane flame is applied. Furthermore, only 19 wt.% is able to confer resistance to the fabric towards an irradiating heat flux of 35 kW/m(2): indeed, the specimens tested under the cone calorimetry do not burn. Measurements of temperature runs as a function of time have clearly indicated that cotton, instead of burning, pyrolyses: indeed, because of the protective role exerted by DNA molecules, the deposited coatings have turned out to absorb heat, form char and induce its formation on the fabric, and finally to release inert gases. PMID- 23688485 TI - Suitability of Confocal Raman microscopy for monitoring the penetration of PDMS compounds into cotton fibres. AB - PDMS compound was chosen as a molecule-model for investigating the diffusion of silicon products into cotton bulk. The study demonstrates the suitability of Confocal Raman microscopy (CRM) to monitor the distribution of poly(dimethylsiloxane) (PDMS) molecules into cotton fibres. Different molecular weights of PDMS compounds were used in two different solvents (water and hexane) at various temperatures (25, 50 and 60 degrees C). The surfaces of the fibres were studied with scanning electron microscopy and Confocal Raman microscopy was run to detect the PDMS on the surface and in the bulk of treated fabrics. We concluded that all PDMS compounds, irrespectively their molecular weights and the silicon oil infiltrate into cotton fibre. The penetration is strongly dependent on the solvent used. Water proved suitable for assisting the infiltration of low and medium molecular weight PDMS, at elevated temperatures. High molecular weight PDMS infiltrates better from hexane and at room temperature than from water. PMID- 23688486 TI - Biodegradation of (1->3)-beta-polyglucuronate prepared by TEMPO-mediated oxidation. AB - 2,2,6,6-Tetramethylpiperidine-1-oxyl radical (TEMPO)-mediated oxidation was applied to curdlan to prepare water-soluble sodium (1->3)-beta-polyglucuronate, and its biodegradation behavior was then investigated. A bacterial strain (EH621) having the ability to degrade (1->3)-beta-polyglucuronate was isolated from soil, and identified as Paenibacillus sp. Strain EH621 cultured with (1->3)-beta polyglucuronate decreased the initial total carbon in the supernatant by approximately 60% within 3 days, showing that (1->3)-beta-polyglucuronate can be readily degraded and metabolized by microorganisms present in the natural environment. Hydrolytic enzyme activity was detected in the cell-free extract of EH621, which was highly specific to (1->3)-beta-polyglucuronate. Analyses of the enzymatic degradation products revealed that (1->3)-beta-polyglucuronate was endolytically degraded to its monomeric unit, glucuronate, via some oligomers and dimers. PMID- 23688487 TI - Synthesis and adsorption performance of dithiocarbamate-modified glycidyl methacrylate starch. AB - The design of chelating polymers with fast complexation of the metal ions is particularly interest. In this work, the dithiocarbamate-modified glycidyl methacrylate starch was synthesized and characterized by FT-IR, (13)C NMR and XRD spectra. Its sorption performance for heavy metals fixation was studied. It was found that the removal process of metal ions involved a fast increase stage followed by a slower stage. There was a higher match between the pseudo-second order equation and the experimental data. The sorption rate constants were related to the substitution rates of hydrated metal ions in aqueous solutions, showing typical chemisorption. The Langmuir isotherm gave satisfying fits to equilibrium data of metals adsorption. And the capacities followed the sequence Cu(2+)>Cd(2+)>Co(2+)>Zn(2+)>Ni(2+)>Mn(2+), which could be well demonstrated with chelating interaction caused by sulfur atoms. Such understanding provides new insights as how to synthesize and use the dithiocarbamate-based polysaccharides. PMID- 23688488 TI - Antibacterial property and characterization of cotton fabric treated with chitosan/AgCl-TiO2 colloid. AB - The antibacterial activity of cotton fabric was studied by using chitosan/AgCl TiO2 colloid. Different blend ratios of chitosan to AgCl-TiO2 colloid were used to investigate the efficacy of antibacterial activity against Staphylococcus aureus (gram positive) and Escherichia coli (gram negative) and its effect on physical properties of cotton fabric. Our study shows that the combination of chitosan with AgCl-TiO2 colloid produced better antibacterial activity than the fabric treated without chitosan; 100% bacterial reduction against S. aureus and E. coli obtained with chitosan/AgCl-TiO2 colloid at concentrations of 4 g/L and 10 g/L respectively. Moreover, the treated cotton indicates improved tensile strength and wrinkle recovery angle (WRA). Increasing chitosan concentration slightly affected the fabric stiffness and whiteness. The treated cotton fabrics were further characterized by Fourier Transform Infrared spectroscopy (FTIR), Scanning Electron Microscopy (SEM), energy dispersive X-ray (EDX) and wide angle X-ray (WAXD). We can expect a direct industrial application of our proposed work because it is simple one go pad-dry-cure method and the low cost commercial grades of chitosan and AgCl-TiO2 are conveniently available in the market. PMID- 23688489 TI - Levansucrase optimization using solid state fermentation and levan biological activities studies. AB - Bacillus subtilis NRC1aza produced levansucrase under solid state fermentation using starch as support. A sequential optimization strategy, based on statistical experimental designs is employed to enhance enzyme productivity. First, a 2-level Plackett-Burman design was applied for bioprocess parameters screen that significantly increase levansucrase production. Second optimization step was performed using fractional factorial design in order to optimize the amounts of highest positive variables that had significant effect on levansucrase productivity. Maximal enzyme productivity of 170 U/gds was achieved in presence of glucose, yeast extract, and pH 8. In vitro, experiments confirmed that LevCR and LevQT had an antitumor activity against different animal and human cancer cell lines by demonstrating inhibitory effects on growth of Ehrlich ascites carcinoma cell line, human MCF-7 breast and liver HepG2 cancer cell lines, in particular LevQT was found to be efficacious compared to anticancer drug, cisplatin. Result focused in LevCR as strong fibrinolytic agent. PMID- 23688490 TI - Rapidly in situ forming chitosan/epsilon-polylysine hydrogels for adhesive sealants and hemostatic materials. AB - A novel in situ forming polysaccharides/polypeptide hydrogel composed of naturally derived materials for applications as adhesive sealant and hemostatic material was developed via Michael addition crosslinking, taking advantage of its mild condition. Thiol-modified chitosan (CSS) was fast in situ crosslinked by an efficient polypeptide crosslinker (EPLM) which was prepared by introducing maleimide groups onto epsilon-polylysine. Gelation can happen swiftly within 15 215s depending on the CSS concentration, the degree of substitution (DS) of maleimide groups, and the molar ratio of maleimide group to thiol group. Results indicated that storage modulus of the hydrogel increased dramatically with the increase of CSS concentration and DS of maleimide. The obtained adhesive hydrogel had an adhesion strength 4 times higher than that of the commercial fibrin glue. Notably, it is non-toxic to L929 cells and exhibits excellent prompt hemostatic property. Polysaccharides/polypeptide structure designed here facilitates to improve both the biocompatibility and the adhesive property. PMID- 23688491 TI - Calcium pectinate-fenugreek seed mucilage mucoadhesive beads for controlled delivery of metformin HCl. AB - Calcium pectinate-fenugreek seed mucilage (FSM) mucoadhesive beads containing metformin HCl was developed through ionic-gelation. Effects of pectin and FSM amounts on drug encapsulation efficiency (DEE) and cumulative drug release at 10h (R10 h) were optimized using 3(2) factorial design. The DEE (%) was within the range of 63.16 +/- 2.88 to 96.03 +/- 4.67% (w/w). The in vitro drug release from these beads (56.64 +/- 1.47 to 93.63 +/- 4.52% over 10h) was followed controlled release (zero-order) pattern (R(2)=0.993 to 0.997) with super case-II transport mechanism. The average size of beads was within 1.47 +/- 0.14 to 2.08 +/- 0.18 mm. The beads were also characterized by SEM and FTIR. The swelling and mucoadhesivity of these beads were influenced by pH of the medium. The optimized beads also exhibited good mucoadhesivity and significant hypoglycemic effect in alloxan-induced diabetic rats over prolonged period after oral administration. PMID- 23688492 TI - Influence of oxidized starch on the properties of thermoplastic starch. AB - Thermoplastic starch was prepared by adding oxidized starches and glycerol together into starch. The addition of oxidized starch improved the rheological properties and also increased the toughness of thermoplastic starch. Compared with TPS30, the elongation at break increased from 126.8% to 152.5% when 5wt% OS 117% was added. Good compatibility of thermoplastic starch between the matrix and oxidized starch was confirmed by SEM. The addition of oxidized starch lowered the storage modulus and glass transition temperature (Tg) of thermoplastic starch, decreasing Tg from 34.1 to 30 degrees C when 10 wt% OS117% was added. The thermal stability of blending was improved by adding oxidized starches, i.e. when 5 wt% OS70% was added, T5% increased from 134 to 156 degrees C. PMID- 23688493 TI - Studies on production of fructo-oligosaccharides (FOS) by gamma radiation processing of microbial levan. AB - Microbial levan, a natural polymer of fructose, was produced and purified by alcohol precipitation from culture supernatants of Bacillus megaterium type 1 grown in an optimized liquid sucrose medium. GPC analysis showed that the yield of the major fraction of levan having molecular weight ~5000 D increased with increase in sucrose concentration in the broth. Levan subjected to (60)Co-gamma radiation as well as acid hydrolysis was investigated by rheometry, UV-visible spectrophotometry and gel permeation chromatography (GPC) techniques. Unlike most of the polysaccharides, levan powder exhibited good radiation degradation stability up to 150 kGy. Gamma irradiation of 10% levan aqueous solution at 250 kGy yielded 63.0% fructo-oligosaccharide (FOS) with an average molecular weight of 1250 D. Acid hydrolysis of levan using 0.5 N HCl for 60 min treatment time gave rise to the desired FOS with lower yield (23.1%) as compared to that obtained in gamma radiolysis process. PMID- 23688494 TI - Advanced development in chemical analysis of Cordyceps. AB - Cordyceps sinensis, also called DongChongXiaCao (winter worm summer grass) in Chinese, is a well-known and valued traditional Chinese medicine. In 2006, we wrote a review for discussing the markers and analytical methods in quality control of Cordyceps (J. Pharm. Biomed. Anal. 41 (2006) 1571-1584). Since then this review has been cited by others for more than 60 times, which suggested that scientists have great interest in this special herbal material. Actually, the number of publications related to Cordyceps after 2006 is about 2-fold of that in two decades before 2006 according to the data from Web of Science. Therefore, it is necessary to review and discuss the advanced development in chemical analysis of Cordyceps since then. PMID- 23688495 TI - Prescribers and pharmacists requests for prescription monitoring program (PMP) data: does PMP structure matter? AB - Prescription monitoring programs (PMPs) have been purported to be an effective tool to combat prescription drug abuse. However, utilization rates of PMP data by health care providers (e.g., prescribers and pharmacists) is relatively low. The objectives of the study were to describe (1) PMP utilization (e.g., requested reports) by prescribers, pharmacists, and law enforcement for active state PMPs; (2) PMP utilization by health care providers with and without online access; (3) average annual operational costs for PMPs from 2008 to 2009; and (4) PMP requests based on PMP housing authority (law enforcement vs. non-law enforcement [e.g., board of pharmacy]). This was a cross-sectional study employing a Web-based survey. A 16-item questionnaire was e-mailed to the 33 operational state PMP administrators and responses were collected from January to March 2011. Descriptive statistics were used to describe PMP request rates and annual operating costs. The usable survey response rate was 45.5%. Among all authorized users, prescribers had higher mean (+/-SD) requests per 100,000 population (2198.2 +/- 3218.0) compared with pharmacists' requests (268.9 +/- 261.2). Online accessibility resulted in higher request rates per 100,000 population (2996.4 +/- 3021.5) compared with mail/fax access (14.6 +/- 2.8). On average, PMP annual costs were $12,515 +/- $14,911 per 100,000 population. In law enforcement governed PMPs, health care provider utilization was lower compared with PMPs under health or pharmacy boards. Prescriber request rates were higher than pharmacists and online access for providers (e.g., prescribers and pharmacists) resulted in higher request rates per 100,000 population. More research is needed to determine other factors that may be associated with PMP utilization by prescribers and pharmacists. PMID- 23688496 TI - The pharmacoeconomics of breakthrough cancer pain. AB - Breakthrough cancer pain (BTP) has a significant impact on patients' activities of daily living, family, and the society; however, the economic ramifications of BTP are largely unknown. This review aims to summarize the available pharmacoeconomics studies of BTP in the context of the availability of several formulations of rapid-onset opioids administered by various routes, which are significantly more expensive than oral opioids. A systematic literature search of PubMed and Tufts registry through August 2012 was conducted using key words including "breakthrough cancer pain" and "cost effectiveness." After exclusion of irrelevant articles, a total of six articles were included. Studies reviewed include two economic survey studies, two quality improvement projects, and two decision-analytic models. These studies demonstrate BTP causes significant financial burden to patients and society through increased hospitalization and health care utilization. Only one study comparing placebo with intranasal fentanyl spray, oral transmucosal fentanyl citrate, and oral transmucosal fentanyl buccal tablet has demonstrated the cost-effectiveness of these rapid onset opioids for the treatment of BTP. Overall, there is a lack of pharmacoeconomic studies for BTP management with rapid-onset opioids. Further study is warranted assessing the net benefit of rapid-onset opioids to oral opioids to assist decision-making by patients, clinicians, and payers. PMID- 23688497 TI - MicroRNA-15b contributes to ginsenoside-Rg1-induced angiogenesis through increased expression of VEGFR-2. AB - Ginsenoside-Rg1 (Rg1) has been identified as potent proangiogenic agent, which plays an important role in wound healing promotion or treatment of ischemic injury. We previously reported that miR-214/eNOS pathway was involved in Rg1 induced angiogenesis. Following the same microRNA microarray profiling data, we proposed miR-15b would be another microRNA candidate involved in Rg1-induced angiogenesis. Using human umbilical vein endothelial cells (HUVECs), it was showed that Rg1 could reduce miR-15b expression rapidly and steadily, leading to a temporal induction of vascular endothelial growth factor receptor-2 (VEGFR-2). The in vitro motility and tubulogenesis via VEGFR-2 in Rg1-treated HUVECs were also demonstrated. Besides, the reduction of VEGFR-2 3'-UTR reporter activity by miR-15b in the luciferase reporter gene assay clearly indicated that miR-15b could affect the VEGFR-2 transcript through targeting its 3'-UTR region. Diminishing expression of endogenous miR-15b could increase VEGFR-2 expression and HUVECs migration and tubulogenesis; while over-expression of miR-15b was found to associate with the reduction of VEGFR-2 expression as well as cellular migration and tubulogenesis. In vivo, artificial increment of miR-15b by injecting Pre-miR-15b precursor into zebrafish embryos was also found to significantly suppress the subintestinal vessels formation. In conclusion, our results further demonstrated the involvement of microRNAs in Rg1-induced angiogenesis. PMID- 23688498 TI - The suppression of thoc1 in cancer cell apoptosis mediated by activated macrophages is nitric oxide-dependent. AB - Activation of Toll-like receptor 4 (TLR4) triggers both innate and adaptive immunity. We previously identified a synthetic glycolipid, CCL-34, which can induce anticancer immunity in a TLR4-dependent manner. In the present study, we demonstrated the involvement of THO complex 1 (thoc1) in the CCL-34-induced anticancer mechanism. The expression of thoc1 was suppressed in bladder cancer cells (MBT-2) co-cultured with CCL-34-activated macrophages, whereas treatment with an iNOS inhibitor could restore the expression of thoc1. Direct treatment of MBT-2 cells with an NO donor also repressed thoc1 expression. Importantly, the thoc1-overexpressing MBT-2 cells (MBT/thoc1) exhibited greater resistance than the MBT-2 cells to cytotoxicity induced by the NO donor or the CCL-34-activated macrophages. In addition, treatments with CCL-34-activated macrophages or the NO donor resulted in the suppression of thoc1 promoter activity in MBT-2 cells, and mutations in the antioxidant response element (ARE) of the thoc1 promoter abolished the repression induced by these treatments. Furthermore, NO treatment increased the expression and nuclear localization of nuclear factor E2-related factor 2 (Nrf2) in MBT-2 cells. Overexpression of Nrf2 suppressed thoc1 promoter activity in an ARE-dependent manner, and knock-down of nrf2 reversed the suppression. Notably, Bcl-2 expression was suppressed in MBT-2 cells, but not in MBT-2/thoc1 cells, treated with CCL-34-activated macrophages or the NO donor. In summary, our results demonstrate that NO-mediated thoc1 downregulation, via Nrf2, is a key step in the cancer cell apoptosis induced by CCL-34-treated macrophages and that downregulated thoc1 could lead to Bcl-2 downregulation and subsequent cancer cell apoptosis. PMID- 23688499 TI - Pregnane X receptor dependent up-regulation of CYP2C9 and CYP3A4 in tumor cells by antitumor acridine agents, C-1748 and C-1305, selectively diminished under hypoxia. AB - Induction of proteins involved in drug metabolism and in drug delivery has a significant impact on drug-drug interactions and on the final therapeutic effects. Two antitumor acridine derivatives selected for present studies, C-1748 (9-(2'-hydroxyethylamino)-4-methyl-1-nitroacridine) and C-1305 (5 dimethylaminopropylamino-8-hydroxy-triazoloacridinone), expressed high and low susceptibility to metabolic transformations with liver microsomes, respectively. In the current study, we examined the influence of these compounds on cytochrome P450 3A4 (CYP3A4) and 2C9 (CYP2C9) enzymatic activity and gene expression in HepG2 tumor cells. Luminescence and HPLC examination, real-time RT-PCR and western blot analyses along with transfection of pregnane X receptor (PXR) siRNA and CYP3A4 reporter gene assays were applied. We found that both compounds strongly induced CYP3A4 and CYP2C9 activity and expression as well as expression of UGT1A1 and MDR1 in a concentration- and time-dependent manner. C-1748-mediated CYP3A4 and CYP2C9 mRNA induction equal to rifampicin occurred at extremely low concentrations (0.001 and 0.01MUM), whereas 10MUM C-1305 induced three-times higher CYP3A4 and CYP2C9 mRNA levels than rifampicin did. CYP3A4 and CYP2C9 expressions were shown to be PXR-dependent; however, neither compound influenced PXR expression. Thus, the observed drug-mediated induction of isoenzymes occurs on a PXR-mediated regulatory level. Furthermore, C-1748 and C-1305 were demonstrated to be selective PXR agonists. These effects are hypoxia-inhibited only in the case of C-1748, which is sensitive to P450 metabolism. In summary, PXR was found to be a new target of the studied compounds. Thus, possible combinations of these compounds with other therapeutics might lead to the PXR dependent enzyme-mediated drug-drug interactions. PMID- 23688500 TI - Inhibiting cancer metastasis via targeting NAPDH oxidase 4. AB - Cancer metastasis is a major cause for cancer-related death and inhibiting cancer metastasis is an alternative way to treat cancer. Several lines of reported evidence suggest that NADPH oxidase 4 (NOX4) is a potential target for intervention of cancer metastasis, as the reactive oxygen species (ROS) generated by this enzyme plays important roles in TGF-beta signaling, an important inducer of cancer metastasis. Here we show (1) that TGF-beta induces ROS production in breast cancer 4T1 cells and enhances cell migration and that the effect of TGF beta depends on NOX4 expression, (2) that knockdown of NOX4 via RNAi significantly decreases the migration ability of 4T1 cells in the presence or absence of TGF-beta and significantly attenuates distant metastasis of 4T1 cells to lung and bone, (3) that Schisandrin B (Sch B), a naturally occurring dibenzocyclooctadiene lignan with very low toxicity, is a novel NOX inhibitor and its IC50 toward NOX4 is 9.3MUM, and (4) that Sch B suppresses TGF-beta-induced and NOX4-associated ROS production in 4T1 cells and inhibits TGF-beta-enhanced cell migration. Similar to NOX4 knockdown observed in this study, Sch B significantly attenuated 4T1 cells distant metastasis to lung and bone in our recently published study. In line with previous reports, the study suggests that pharmacologically targeting NOX4 may be a potential approach to disrupt cancer metastasis. PMID- 23688501 TI - Role of AMPK activation in oxidative cell damage: Implications for alcohol induced liver disease. AB - Chronic alcohol consumption is a well-known risk factor for liver disease. Progression of alcohol-induced liver disease (ALD) is a multifactorial process that involves a number of genetic, nutritional and environmental factors. Experimental and clinical studies increasingly show that oxidative damage induced by ethanol contributes in many ways to the pathogenesis of alcohol hepatoxicity. Oxidative stress appears to activate AMP-activated protein kinase (AMPK) signaling system, which has emerged in recent years as a kinase that controls the redox-state and mitochondrial function. This review focuses on the most recent insights concerning the activation of AMPK by reactive oxygen species (ROS), and describes recent evidences supporting the hypothesis that AMPK signaling pathways play an important role in promoting cell viability under conditions of oxidative stress, such as during alcohol exposure. We suggest that AMPK activation by ROS can promote cell survival by inducing autophagy, mitochondrial biogenesis and expression of genes involved in antioxidant defense. Hence, increased intracellular concentrations of ROS may represent a general mechanism for enhancement of AMPK-mediated cellular adaptation, including maintenance of redox homeostasis. On the other hand, AMPK inhibition in the liver by ethanol appears to play a key role in the development of steatosis induced by chronic alcohol consumption. Although more studies are needed to assess the functions of AMPK during oxidative stress, AMPK may be a possible therapeutic target in the particular case of alcohol-induced liver disease. PMID- 23688502 TI - Indigenous plasmids of Bacillus megaterium WSH-002 involved in mutualism with Ketogulonicigenium vulgare WSH-001. AB - In the two-step vitamin C fermentation process, the precursor 2-keto-l-gulonic acid (2-KLG) was synthesized using a mixed culture of Ketogulonicigenium vulgare WSH-001 and Bacillus megaterium WSH-002, which contained three plasmids, pBME1, pBME2 and pBME3. The cell growth of B. megaterium was not affected by the elimination of these plasmids. However, elimination of pBME2 and pBME3 significantly affected l-sorbose uptake and 2-KLG production. Sequence analysis of the plasmids showed that many of the pBME2 and pBME3 genes were of unknown function or could not be assigned to a specific metabolic pathway. The current work showed that the indigenous plasmids pBME2 and pBME3 of B. megaterium WSH-002 involved in mutualism with K. vulgare WSH-001. The results provided a promising new route to further demonstrate the mutualism process between the two bacteria. PMID- 23688503 TI - Assessing hospital preparedness: comparison of an on-site survey with a self reported, internet-based, long-distance tabletop drill. AB - BACKGROUND: Methods of defining hospital disaster preparedness are poorly defined in the literature, leaving wide discrepancies between a hospital's self-reported preparedness and that assessed by an objective reviewer. OBJECTIVES: This study compared self-reported surge capacity data from individual hospitals, obtained from a previously reported long-distance tabletop drill (LDTT) prior to the 2010 FIFA World Cup tournament in Cape Town, South Africa, with surge capacity data assessed by an on-site survey inspection team. METHODS: In this prospective, observational study, contact persons used in the prior LDTT assessing hospital disaster preparedness in the lead-up to the 2010 FIFA World Cup made surge capacity assessments (licensed bed capacity plus surge capacity beds) for the respiratory intensive care unit (RICU), neonatal intensive care unit (NICU), medical intensive care unit (MICU), and general medical/surgical beds in each hospital. Following the 2010 World Cup, this data was then re-evaluated by an on site survey team consisting of two of the authors. RESULTS: The contact persons for the individual hospitals from the LDTT underreported their individual hospital's surge capacity in 86% (95% CI, 46%-99%) of RICU beds; 100% (95% CI, 63%-100%) of MICU beds; 75% (95% CI, 40%-94%) of NICU beds; and 71% (95% CI, 35% 92%) of medical/surgical beds compared with the on-site inspection team. CONCLUSIONS: The contact persons for the LDTT overwhelmingly underreported surge capacity beds compared with the surge capacity determined by the on-site inspection team. PMID- 23688504 TI - UCP4 expression changes in larval and pupal fat bodies of the beetle Zophobas atratus under adipokinetic hormone treatment. AB - We investigated the influence of adipokinetic hormone (AKH), an insect neurohormone, on uncoupling protein 4 (ZaUCP4) expression and activity in larval and pupal fat body mitochondria of the beetle Zophobas atratus in relation to intermediary metabolism. Homologous Tenmo-AKH was administered to the beetle larvae and pupae as either a single dose or as two doses of 20pmol during a 24h interval. In the larval and pupal fat bodies, downregulation of ZaUCP4 expression at the mRNA and protein levels was observed 24h and 48h after AKH treatment, respectively. In both developmental stages, ZaUCP4 activity was lowered in fat body mitochondria 48h after AKH treatment. In the AKH-injected larvae, changes in ZaUCP4 expression were accompanied by the mobilization of carbohydrate reserves, no change in the concentration of total lipids and an increase in the free fatty acid level. In contrast, AKH had no effect on carbohydrate metabolism in the pupal fat body but induced lipid mobilization. It seems that AKH influences ZaUCP4 expression by triggering multiple events and that it has different physiological roles in controlling intermediary metabolism in the fat body of the beetle larvae and pupae. PMID- 23688505 TI - Rapid effects of humidity acclimation on stress resistance in Drosophila melanogaster. AB - We tested the hypothesis whether developmental acclimation at ecologically relevant humidity regimes (40% and 75% RH) affects desiccation resistance of pre adults (3rd instar larvae) and adults of Drosophila melanogaster Meigen (Diptera: Drosophilidae). Additionally, we untangled whether drought (40% RH) acclimation affects cold-tolerance in the adults of D. melanogaster. We observed that low humidity (40% RH) acclimated individuals survived significantly longer (1.6-fold) under lethal levels of desiccation stress (0-5% RH) than their counter-replicates acclimated at 75% RH. In contrast to a faster duration of development of 1st and 2nd instar larvae, 3rd instar larvae showed a delayed development at 40% RH as compared to their counterparts grown at 75% RH. Rearing to low humidity conferred an increase in bulk water, hemolymph content and dehydration tolerance, consistent with increase in desiccation resistance for replicates grown at 40% as compared to their counterparts at 75% RH. Further, we found a trade-off between the levels of carbohydrates and body lipid reserves at 40% and 75% RH. Higher levels of carbohydrates sustained longer survival under desiccation stress for individuals developed at 40% RH than their congeners at 75% RH. However, the rate of carbohydrate utilization did not differ between the individuals reared at these contrasting humidity regimes. Interestingly, our results of accelerated failure time (AFT) models showed substantial decreased death rates at a series of low temperatures (0, -2, or -4 degrees C) for replicates acclimated at 40% RH as compared to their counter-parts at 75% RH. Therefore, our findings indicate that development to low humidity conditions constrained on multiple physiological mechanisms of water-balance, and conferred cross-tolerance towards desiccation and cold stress in D. melanogaster. Finally, we suggest that the ability of generalist Drosophila species to tolerate fluctuations in humidity might aid in their existence and abundance under expected changes in moisture level in course of global climate change. PMID- 23688506 TI - Fitting statistical models in bivariate allometry: scaling metabolic rate to body mass in mustelid carnivores. AB - The ongoing debate about methods for fitting the two-parameter allometric equation y=ax(b) to bivariate data seemed to be resolved recently when three groups of investigators independently reported that statistical models fitted by the traditional allometric method (i.e., by back-transforming a linear model fitted to log-log transformations) typically are superior to models fitted by standard nonlinear regression. However, the narrow focus for the statistical analyses in these investigations compromised the most important of the ensuing conclusions. All the investigations focused on two-parameter power functions and excluded from consideration other simple functions that might better describe pattern in the data; and all relied on Akaike's Information Criterion instead of graphical validation to identify the better statistical model. My re-analysis of data from one of the studies (BMR vs. body mass in mustelid carnivores) revealed (1) that the best descriptor for pattern in the dataset is a straight line and not a two-parameter power function; (2) that a model with additive, normal, heteroscedastic error is superior to one with multiplicative, lognormal, heteroscedastic error; and (3) that Akaike's Information Criterion is not a generally reliable metric for discriminating between models fitted to different distributions. These findings have apparent implications for interpreting the outcomes of all three of the aforementioned studies. Future investigations of allometric variation should adopt a more holistic approach to analysis and not be wedded to the traditional allometric method. PMID- 23688507 TI - Physiological functions of osmolality and calcium ions on the initiation of sperm motility and swimming performance in redside dace, Clinostomus elongatus. AB - Reproductive potential of fish stocks is critically dependent on sperm performance in an aquatic environment. The aim of this study is to test hypotheses, which govern the initiation of sperm motility and swimming performance, through physiological functions of osmolality and Ca(2+) ion, in a threatened species of freshwater fish, the redside dace, Clinostomus elongatus. Spermatozoa motility was activated in either ionic or non-ionic media spanning a range of osmolalities. The role of Ca(2+) channels on induction of spermatozoa motility and velocity was experimentally investigated by diluting sperm in media that contain various Ca(2+) channel blockers. Results show that initiation of spermatozoa motility is a hypo-osmolality dependent mechanism. Inhibitors for L type Ca(2+) channels partially prohibited initiation of spermatozoa motility, while velocity was significantly reduced in both L-type and T-type Ca(2+) channel blockers. Examination using W-7, an inhibitor for Ca(2+)-dependent calmodulin, showed significant decreases in spermatozoa motility and velocity. Involvement for Ca(2+) in axonemal beating was confirmed by significant increases in velocity after adding Ca(2+) into the activation media, while motility remained unchanged in Ca(2+) supplemented activation media. Together, these findings suggest the involvement of Ca(2+) in hypo-osmolality-dependent initiation of spermatozoa motility mediated by activation of Ca(2+) binding protein in the axoneme of a freshwater fish sperm. Blocking Ca(2+) exchange through L- or T-type Ca(2+) channel influences flagellar beating force and leads to decrease in spermatozoa velocity. PMID- 23688508 TI - [Chronic myeloid leukemia]. PMID- 23688509 TI - [Early initiation of breastfeeding is benefited by maternal education program]. AB - OBJECTIVE: To determine the influence of maternal education (ME) on early initiation of breastfeeding (BF) and its maintenance during the first two months of the infant's life, as well as to understand the influence of ME on the reasons for BF discontinuation. METHOD: This was a multicenter observational study carried out with primiparous women in four hospitals of Andalucia during 2011. Data was collected through interviews and from clinical charts. Raw and adjusted odds ratios were estimated during the analysis. RESULTS: Mothers who attended ME classes showed early initiation of BF (aOR = 1.78, 95% CI = 1.14-2.78) and maintenance of BF (aOR = 1.73, 95% CI = 1.15-2.61). There were no differences related to women's reasons to discontinue BF. CONCLUSIONS: ME positively impacts the initiation and maintenance of BF. PMID- 23688510 TI - Rectal forceps biopsy procedure in cystic fibrosis: technical aspects and patients perspective for clinical trials feasibility. AB - BACKGROUND: Measurements of CFTR function in rectal biopsies ex vivo have been used for diagnosis and prognosis of Cystic Fibrosis (CF) disease. Here, we aimed to evaluate this procedure regarding: i) viability of the rectal specimens obtained by biopsy forceps for ex vivo bioelectrical and biochemical laboratory analyses; and ii) overall assessment (comfort, invasiveness, pain, sedation requirement, etc.) of the rectal forceps biopsy procedure from the patients perspective to assess its feasibility as an outcome measure in clinical trials. METHODS: We compared three bowel preparation solutions (NaCl 0.9%, glycerol 12%, mannitol), and two biopsy forceps (standard and jumbo) in 580 rectal specimens from 132 individuals (CF and non-CF). Assessment of the overall rectal biopsy procedure (obtained by biopsy forceps) by patients was carried out by telephone surveys to 75 individuals who underwent the sigmoidoscopy procedure. RESULTS: Integrity and friability of the tissue specimens correlate with their transepithelial resistance (r = -0.438 and -0.305, respectively) and are influenced by the bowel preparation solution and biopsy forceps used, being NaCl and jumbo forceps the most compatible methods with the electrophysiological analysis. The great majority of the individuals (76%) did not report major discomfort due to the short procedure time (max 15 min) and considered it relatively painless (79%). Importantly, most (88%) accept repeating it at least for one more time and 53% for more than 4 times. CONCLUSIONS: Obtaining rectal biopsies with a flexible endoscope and jumbo forceps after bowel preparation with NaCl solution is a safe procedure that can be adopted for both adults and children of any age, yielding viable specimens for CFTR bioelectrical/biochemical analyses. The procedure is well tolerated by patients, demonstrating its feasibility as an outcome measure in clinical trials. PMID- 23688511 TI - An asparagine at position 417 of tissue-nonspecific alkaline phosphatase is essential for its structure and function as revealed by analysis of the N417S mutation associated with severe hypophosphatasia. AB - Various loss-of function mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene cause a rare genetic disorder called hypophosphatasia (HPP), which is characterized by defective mineralization in the bones and teeth and a deficiency in serum alkaline phosphatase. A point mutation (c.1250A>G), which leads to replacement of an asparagine at position 417 of TNSALP with serine [TNSALP (N417S)], has been reported in a patient diagnosed with perinatal HPP (Sergi C. et al. Am, J. Med. Genet. 103, 235-240, 2001). In order to characterize the molecular properties of TNSALP (N417S), we expressed and analyzed TNSALP (N417S) both in COS-1 cells (transient expression) and CHO K1 Tet-On cells (inducible cell system). In contrast to wild-type TNSALP [TNSALP (W)], cells expressing TNSALP (N417S) lacked its alkaline phosphatase activity. However, this mutant underwent N-linked oligosaccharide processing and appeared on the cell surface similar to TNSALP (W). Importantly, this mutant failed to assemble into a dimer structure, which is needed for the catalytic function of TNSALP, as evidenced by newly developed SDS-PAGE as well as sucrose-density-gradient centrifugation. Substitution of the asparagine at position 417 with structurally related amino acids such as an aspartate and a glutamine also abolished the dimerization of TNSALP without perturbing its cell surface localization. Taken together, the asparagine at position 417 is crucial for the assembly and function of TNSALP, which may explain the severity of the N417S mutation. PMID- 23688512 TI - English Pain Summit: a year on. AB - The English Pain Summit was held in Westminster, London on 22 November 2011. Dr. Martin Johnson explores its background, the meeting itself, and subsequent outputs. PMID- 23688513 TI - Managing surgical pain in long-term opioid patients. AB - The number of patients taking long-term opioid therapy for pain is increasing, with opioid use no longer being confined to advanced cancer patients. Challenges to peri- and postoperative pain management in chronic pain patients include complex existing drug regimens and problems arising from tolerance to opioid analgesia. Postoperatively, individualized, multimodal pain therapy involving a round-the-clock regimen of nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2) inhibitors, paracetamol, and regional blocks should be used. Other considerations may include patients receiving opioids by intrathecal drug delivery systems, spinal cord stimulator (SCS), and potential substance abusers. PMID- 23688514 TI - The importance of putting pain on the curricula in medical schools in Europe. AB - Pain continues to be underdiagnosed and undertreated in Europe. A lack of training in pain medicine among clinicians has been identified as a barrier to optimal pain management. Except for clinicians entering specialized training in pain medicine or a related field, inadequate or nonexistent pain management training is the norm in Europe. A multidisciplinary group of experts, including representatives from the European Federation of IASP (International Association for the Study of Pain) Chapters (EFIC), is launching a pan-European initiative aimed at raising the profile and importance of undergraduate pain education. PMID- 23688516 TI - We can make opioids safer. PMID- 23688518 TI - European pain management discussion forum. AB - A case of nerve injury pain is discussed to address whether it is more likely complex regional pain syndrome or neuropathic pain. PMID- 23688519 TI - P2X(7) inhibition in stellate ganglia prevents the increased sympathoexcitatory reflex via sensory-sympathetic coupling induced by myocardial ischemic injury. AB - Purinergic signaling has been found to participate in the regulation of cardiovascular function. In this study, using a rat myocardial ischemic injury model, the sympathoexcitatory reflex mediated by P2X7 receptor via sensory sympathetic coupling between cervical dorsal root ganglia (DRG) nerves and stellate ganglia (SG) nerves was explored. Our results showed that the systolic blood pressure, heart rate, serum cardiac enzymes concentrations, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) concentrations were increased, and the expression levels of P2X7 mRNA and protein in DRG and SG were up-regulated after myocardial ischemic injury. Administration of brilliant blue G (BBG), a selective P2X7 antagonist, decreased the elevation of systolic blood pressure, heart rate, serum cardiac enzyme, IL-6 and TNF-alpha, and inhibited the up-regulated expression of P2X7 mRNA and protein in DRG and SG after myocardial ischemic injury. Retrograde tracing test showed that there were calcitonin gene related peptide sensory nerves and substance P sensory nerves sprouting from DRG to SG, which played an important role in the development of myocardial ischemic injury. The up-regulated P2X7 receptor expression levels on the surface membrane of satellite glial cells contributed to the activation of sensory-sympathetic coupling, which in turn facilitated the sympathoexcitatory reflex. BBG can inhibit the activation of satellite glial cells and interrupt the generation of sensory-sympathetic coupling in the cervical sympathetic ganglia after the myocardial ischemic injury. Taken together, these findings may provide a new therapeutic approach for treating coronary heart disease, hypertension and other cardiovascular diseases. PMID- 23688520 TI - Multidrug-resistant tet(X)-containing hospital isolates in Sierra Leone. AB - The tet(X) gene encodes a flavin-dependent monooxygenase that confers resistance to all clinically relevant tetracycline antibiotics including tigecycline. It has only previously been identified in environmental and non-human pathogenic bacteria. To investigate levels of multidrug resistance in Bo, Sierra Leone, a molecular epidemiological study was conducted using an antimicrobial resistance determinant microarray (ARDM), PCR and DNA sequencing. The study found that 21% of isolates from Mercy Hospital (Bo, Sierra Leone) were tet(X)-positive, all of which originated from urinary specimens. Use of molecular epidemiological surveillance tools has provided the first evidence of tet(X)-containing multidrug resistant Gram-negative hospital isolates in a hospital in Sierra Leone. PMID- 23688521 TI - Characteristics of carbapenem-resistant Enterobacteriaceae isolates from Korea. AB - In this study, the characteristics of carbapenem-resistant Enterobacteriaceae (CRE) isolates from Korea was investigated. A total of 22 CRE isolates were investigated, and most were identified as Klebsiella pneumoniae (16 isolates). In vitro antimicrobial susceptibility testing, multilocus sequence typing, and pulsed-field gel electrophoresis were performed. Extended-spectrum beta-lactamase (ESBL) and carbapenemase genes were detected using gene amplification and sequencing. Efflux pump activity and inactivating mutations in OmpK35/36 were also investigated. Among 22 CRE isolates, only 5 produced metallo-beta-lactamases (3 NDM-1, one VIM-2 and one IMP-1). Four and 2 K. pneumoniae and Serratia marcescens isolates showed resistance to polymyxins, respectively, and 2 CRE isolates (1 K. pneumoniae and C. freundii) were resistant to tigecycline. The prevalent carbapenem resistance mechanism found in K. pneumoniae might be porin defects. The most prevalent clone of carbapenem-resistant K. pneumoniae was ST11 (56.3%), which is the most frequently identified clone among ESBL-producing K. pneumoniae isolates from Korea. Three NDM-1-producing K. pneumoniae isolates belonged to a single clone (ST340) despite their different antimicrobial susceptibilities. In the present study, the clonal dissemination of carbapenem resistant K. pneumoniae isolates (ST11) and NDM-1-producing K. pneumoniae isolates (ST340) was determined. Polymyxin- and tigecycline-resistant CRE isolates were also identified, which limits treatment options for infections causes by these organisms. PMID- 23688522 TI - Antibiotic resistance determinants of multidrug-resistant Acinetobacter baumannii clinical isolates in Algeria. AB - Antibiotic susceptibility testing was performed on 71 Acinetobacter baumannii clinical isolates, and presence of antibiotic resistance genes was screened for by PCR amplification and sequencing. Resistance rates were very high for aminoglycosides (22-80%), fluoroquinolones (>90%), and cephalosporins (>90%) but remained low for rifampin (2.8%) or null for colistin. Antibiotic resistance encoding genes detected were as follows: blaTEM-128 gene (74.6%), aph(3')-VI (50.7 %), aadA (63.4%), ant(2")-I (14.1%), aac(3)-Ia (91.1%), aac(6')-Ib (4.2%), mutation Ser83Leu in gyrA (94.4%), double mutations Ser83Leu and Ser80Leu (or Ser84Leu) in gyrA and parC (69.0%), and mutation I581N in RRDR of the rpoB gene. PMID- 23688523 TI - Lateral patellar retinaculum reconstruction for medial patellar instability following lateral retinacular release: a case report. AB - Lateral retinacular release is still being performed in patients with recurrent patellar dislocation as an additional procedure with distal realignment or medial patellofemoral ligament (MPFL) reconstruction. However, consensus remains lacking regarding suitable indications for lateral retinacular release. A 20-year-old woman presented with patellar instability in both medial and lateral directions after undergoing lateral retinacular release with MPFL reconstruction. She displayed inherent systemic joint laxity meeting all seven Carter-Wilkinson criteria. Simultaneous MPFL revision and lateral retinaculum reconstruction successfully improved patellar instability in both directions. This case provides an example of iatrogenic medial patellar instability after failed lateral retinacular release. PMID- 23688524 TI - Seasonal influenza vaccine effectiveness in pre- and full-term children aged 6-23 months over multiple seasons. AB - INTRODUCTION: This study aimed to determine the effectiveness of seasonal influenza vaccine in pre- and full-term children aged 6-23 months. METHODS: We examined a cohort of 683,354 young children (7.7% preterm) over five influenza seasons (2004-2005 to 2008-2009) in Ontario, Canada. Vaccine effectiveness was estimated using influenza-coded ambulatory visits during virologically-confirmed influenza season periods as the outcome and multivariable Cox proportional hazards modeling. RESULTS: Full vaccination was associated with a 19% reduction in influenza-coded ambulatory visits (HR=0.81; 95% CI, 0.68-0.97) in all children, and an 18% reduction in full-term children (HR=0.82; 95% CI, 0.68 0.99). We did not find significant vaccine effectiveness for preterm children. No benefit was found for partial vaccination. CONCLUSIONS: In children younger than two years, only full influenza vaccination is associated with reduced influenza coded ambulatory visits. Since the effectiveness of influenza vaccination in preterm children remains uncertain, further study of this highly vulnerable population is warranted. PMID- 23688525 TI - Influence of initial vaccination with 13-valent pneumococcal conjugate vaccine or 23-valent pneumococcal polysaccharide vaccine on anti-pneumococcal responses following subsequent pneumococcal vaccination in adults 50 years and older. AB - BACKGROUND: Unlike free polysaccharide vaccines, pneumococcal polysaccharide conjugate vaccines (PCVs) induce a T cell-dependent immune response and have the potential to provide an extended duration of protection with repeated vaccinations. METHODS: This was an extension of a previous study in pneumococcal vaccine-naive adults aged 50-64 years in which adults 60-64 years of age were given 13-valent PCV (PCV13) or 23-valent pneumococcal polysaccharide vaccine (PPSV23) and adults aged 50-59 were given PCV13. In this follow up study conducted about 4 years later, the 60-64 year olds initially given PCV13 received PCV13 or PPSV23, and those initially given PPSV23 received another PPSV23. All adults aged 50-59 years were re-vaccinated with PCV13. Anti-pneumococcal opsonophagocytic activity (OPA) titers were measured before and 1 month after vaccination. RESULTS: A second PCV13 given about 4 years after a first vaccination induced OPA titers that were significantly higher than those following the initial vaccination for 7 of 13 serotypes in the older group, and 6 of 13 serotypes in the younger group, and responses to the remaining serotypes were largely non-inferior. In contrast, OPA titers following revaccination with PPSV23 were statistically significantly lower for 9 of the 13 serotypes, and non inferior for the remaining serotypes, when compared to the responses to the first PPSV23. OPA titers in the older adults who received PPSV23 after initial PCV13 were significantly higher than those following a first PPSV23 for 10 of the 13 serotypes. CONCLUSION: In adults 50 to 64 years of age, initial vaccination with PCV13 establishes an immune state that results in recall anti-pneumococcal responses upon subsequent vaccination with either conjugated or free polysaccharide vaccine. In contrast, initial vaccination with PPSV23 results in an immune state in which subsequent PPSV23 administration yields generally lower responses compared with the initial responses. PMID- 23688526 TI - Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine compared to a 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine-naive adults. AB - BACKGROUND: Streptococcus pneumoniae is a major cause of morbidity and mortality among adults 50 years of age and older in the United States. Pneumococcal conjugate vaccines are efficacious against pneumococcal disease in children and may also offer advantages in adults. METHODS: We performed a randomized, modified double-blind trial that compared a single dose of 13-valent pneumococcal conjugate vaccine (PCV13) with 23-valent pneumococcal polysaccharide vaccine (PPSV23) in 831 pneumococcal vaccine naive adults 60-64 years of age. An additional group of 403 adults 50-59 years of age received open-label PCV13. Anti pneumococcal opsonophagocytic activity (OPA) titers were measured at baseline, and at 1 month and 1 year after vaccination. RESULTS: In the randomized trial, the month 1 post-vaccination OPA geometric mean titers in the PCV13 group were statistically significantly higher than in the PPSV23 group for 8 of the 12 serotypes common to both vaccines and for serotype 6A, a serotype unique to PCV13, and were comparable for the other 4 common serotypes. The immune response to PCV13 was generally greater in adults 50-59 years of age compared to adults 60 64 years of age. OPA titers declined from 1 month to 1 year after PCV13 administration but remained higher than pre-vaccination baseline titers. CONCLUSIONS: PCV13 induces a greater functional immune response than PPSV23 for the majority of serotypes covered by PCV13, suggesting that PCV13 could offer immunological advantages over PPSV23 for prevention of vaccine-type pneumococcal infection. PMID- 23688527 TI - Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine in adults 70 years of age and older previously vaccinated with 23-valent pneumococcal polysaccharide vaccine. AB - BACKGROUND: The currently recommended single dose of the 23-valent pneumococcal free polysaccharide vaccine (PPSV23) for adults 65 years of age and older does not provide extended protection into older age. This reflects a significant unmet medical need for alternative strategies to protect older adults against pneumococcal infection, which may be met by the 13-valent polysaccharide conjugate vaccine (PCV13). METHODS: We performed a randomized, modified double blind trial in 936 adults aged 70 years and older who had previously received PPSV23 at least 5 years before study entry and were now vaccinated with PCV13 or PPSV23. At 1 year after enrollment, all subjects received a follow-on dose of PCV13. Anti-pneumococcal opsonophagocytic activity (OPA) titers were measured before and at 1 month after each vaccination. RESULTS: Following the enrollment vaccination, OPA titers were significantly greater in the PCV13 group compared to the PPSV23 group for 10 of the 12 serotypes common to both vaccines and to serotype 6A which is unique to PCV13. Responses were noninferior for the other 2 common serotypes. Responses to PCV13 given at 1 year were generally lower in the group that received PPSV23 at enrollment. CONCLUSION: In adults aged 70 years and older previously vaccinated with PPSV23, PCV13 was significantly more immunogenic than PPSV23 for most of the common serotypes and for serotype 6A. The OPA responses after a follow-on dose of PCV13 one year later indicate that a prior dose of PPSV23, but not PCV13, diminishes the response to the subsequent administration of PCV13. PMID- 23688528 TI - Approaches to diabetes: empowerment, control or both? PMID- 23688529 TI - Birds of ill omen--is H7N9 the harbinger of the next pandemic? AB - In February 2013, a novel avian virus appeared in Humans in China and caused several fatalities since. The rapidity and efficiency of the organizations in charge led to the quick identification of H7N9 and the triggering of preventive measures. However, the sequencing of the viral genome holds good and bad news and it is not clear yet if we face an emerging pandemic. PMID- 23688530 TI - Okadaic acid induced neurotoxicity: an emerging tool to study Alzheimer's disease pathology. AB - Okadaic acid (OKA) is one of the main polyether toxins produced by marine microalgae which causes diarrhetic shellfish poisoning. It is a selective and potent inhibitor of serine/threonine phosphatases 1 and 2A induces hyperphosphorylation of tau in vitro and in vivo. The reduced activity of phosphatases like, protein phosphatase 2A (PP2A) has been implicated in the brain of Alzheimer's disease (AD) patients. It is reported that AD is a complex multifactorial neurodegenerative disorder and hyperphosphorylated tau proteins is a major pathological hallmark of AD. The molecular pathogenesis of AD includes an extracellular deposition of beta amyloid (Abeta), accumulation of intracellular neurofibrillary tangles (NFT), GSK3beta activation, oxidative stress, altered neurotransmitter and inflammatory cascades. Several lines of evidence suggested that the microinfusion of OKA into the rat brain causes cognitive deficiency, NFTs-like pathological changes and oxidative stress as seen in AD pathology via tau hyperphosphorylation caused by inhibition of protein phosphatases. So, communal data and information inferred that OKA induces neurodegeneration along with tau hyperphosphorylation; GSK3beta activation, oxidative stress, neuroinflammation and neurotoxicity which is a characteristic feature of AD pathology. Through this collected evidence, it is suggested that OKA induced neurotoxicity may be a novel tool to study Alzheimer's disease pathology and helpful in development of new therapeutic approach. PMID- 23688531 TI - On top of atopy. PMID- 23688532 TI - The relationship of autism and gluten. AB - BACKGROUND: Autism is now a common condition with a prevalence of 1 in 88 children. There is no known etiology. Speculation about possible treatments for autism or autism spectrum disorders (ASD) has included the use of various dietary interventions, including a gluten-free diet. OBJECTIVE: The goal of this article was to review the literature available evaluating the use of gluten-free diets in patients with autism to determine if diet should be instituted as a treatment. METHODS: A literature review was performed, identifying previously published studies in which a gluten-free diet was instituted as an autism treatment. These studies were not limited to randomized controlled trials because only 1 article was available that used a double-blind crossover design. Most publish reports were unblinded, observational studies. RESULTS: In the only double-blind, crossover study, no benefit of a gluten-free diet was identified. Several other studies did report benefit from gluten-free diet. Controlling for observer bias and what may have represented unrelated progress over time in these studies is not possible. There are many barriers to evaluating treatment benefits for patients with autism. Gluten sensitivity may present in a variety of ways, including gastrointestinal and neurologic symptoms. Although making a diagnosis of celiac disease is easier with new serology and genetic testing, a large number of gluten-sensitive patients do not have celiac disease. Testing to confirm non celiac gluten sensitivity is not available. CONCLUSIONS: A variety of symptoms may be present with gluten sensitivity. Currently, there is insufficient evidence to support instituting a gluten-free diet as a treatment for autism. There may be a subgroup of patients who might benefit from a gluten-free diet, but the symptom or testing profile of these candidates remains unclear. PMID- 23688533 TI - Is a subtype of autism an allergy of the brain? AB - BACKGROUND: Autism spectrum disorders (ASDs) are characterized by deficits in social communication and language and the presence of repetitive behaviors that affect as many as 1 in 50 US children. Perinatal stress and environmental factors appear to play a significant role in increasing the risk for ASDs. There is no definitive pathogenesis, which therefore significantly hinders the development of a cure. OBJECTIVE: We aimed to identify publications using basic or clinical data that suggest a possible association between atopic symptoms and ASDs, as well as evidence of how such an association could lead to brain disease, that may explain the pathogenesis of ASD. METHODS: PubMed was searched for articles published since 1995 that reported any association between autism and/or ASDs and any one of the following terms: allergy, atopy, brain, corticotropin-releasing hormone, cytokines, eczema, food allergy, food intolerance, gene mutation, inflammation, mast cells, mitochondria, neurotensin, phenotype, stress, subtype, or treatment. RESULTS: Children with ASD respond disproportionally to stress and also present with food and skin allergies that involve mast cells. Brain mast cells are found primarily in the hypothalamus, which participates in the regulation of behavior and language. Corticotropin-releasing hormone is secreted from the hypothalamus under stress and, together with neurotensin, stimulates brain mast cells that could result in focal brain allergy and neurotoxicity. Neurotensin is significantly increased in serum of children with ASD and stimulates mast cell secretion of mitochondrial adenosine triphosphate and DNA, which is increased in these children; these mitochondrial components are misconstrued as innate pathogens, triggering an autoallergic response in the brain. Gene mutations associated with higher risk of ASD have been linked to reduction of the phosphatase and tensin homolog, which inhibits the mammalian target of rapamycin (mTOR). These same mutations also lead to mast cell activation and proliferation. Corticotropin-releasing hormone, neurotensin, and environmental toxins could further trigger the already activated mTOR, leading to superstimulation of brain mast cells in those areas responsible for ASD symptoms. Preliminary evidence indicates that the flavonoid luteolin is a stronger inhibitor of mTOR than rapamycin and is a potent mast cell blocker. CONCLUSION: Activation of brain mast cells by allergic, environmental, immune, neurohormonal, stress, and toxic triggers, especially in those areas associated with behavior and language, lead to focal brain allergies and subsequent focal encephalitis. This possibility is more likely in the subgroup of patients with ASD susceptibility genes that also involve mast cell activation. PMID- 23688535 TI - Collaboration designed to increase translation of diabetes research outcomes into clinical practice. PMID- 23688534 TI - An open-label pilot study of a formulation containing the anti-inflammatory flavonoid luteolin and its effects on behavior in children with autism spectrum disorders. AB - BACKGROUND: Accumulating evidence suggests an association between autism spectrum disorders (ASD) and inflammation in brain regions related to cognitive function. The natural flavonoid luteolin has antioxidant, anti-inflammatory, mast cell blocking, and neuroprotective effects. It was shown to improve cognitive performance in a mouse model of ASD, but its effect in humans has not been adequately studied. OBJECTIVES: The goal of this study was to assess the effectiveness and tolerability in white children with ASD of a dietary supplement containing 2 flavonoids (>95% pure), luteolin (100 mg/capsule, from chamomile) and quercetin (70 mg/capsule), and the quercetin glycoside rutin (30 mg/capsule) from the Sophora japonica leaf, formulated in olive kernel oil to increase oral absorption. METHODS: Fifty children (4-10 years old; 42 boys and 8 girls) with ASD were enrolled in a 26-week, prospective, open-label trial at the 2nd University Department of Psychiatry at "Attikon" General Hospital, Athens, Greece. Children were referred for the study by their respective physicians or came from the practice of the senior author. ASD diagnosis by clinical assessment was based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, symptom list and corroborated by using the Autism Diagnostic Observation Schedule. The dose of the study formulation used was 1 capsule per 10 kg weight per day with food. The primary outcome measures were the age-equivalent scores in the Vineland Adaptive Behavior Scales domains. Secondary outcomes included the Aberrant Behavior Checklist, the Autism Treatment Evaluation Checklist, and the Clinical Global Impression-Improvement score. Data were measured at baseline, week 18, and week 26. Parents were interviewed for any possible improvements they noticed and instructed to report any unusual adverse events. RESULTS: A total of 40 children completed the protocol. There was a significant improvement in adaptive functioning as measured by using the VABS age equivalent scores (8.43 months in the communication domain, 7.17 months in daily living skills, and 8 months in the social domain; P < 0.005), as well as in overall behavior as indicated by the reduction (26.6%-34.8%) in Aberrant Behavior Checklist subscale scores. Age, sex, and history of allergies had no effect on the results, whereas the initial level of functioning or difficulty did predict the final outcome in most of the measures used. There was a transient (1-8 weeks) increased irritability in 27 of the 50 participants. CONCLUSIONS: These results are encouraging in that the combination of the flavonoids luteolin and quercetin seemed to be effective in reducing ASD symptoms, with no major adverse effects. ClinicalTrials.gov identifier: NCT01847521. PMID- 23688536 TI - Diabetes mellitus in the next decade: novel pipeline medications to treat hyperglycemia. AB - Despite a rapid increase in the number of drugs available to treat hyperglycemia there remain several unmet needs in the prevention and treatment of diabetes. There have also been tremendous advances in our understanding of the pathophysiology of type 2 diabetes, allowing the recognition of novel treatment targets. The purpose of this review is to highlight some of the novel approaches that are being developed to improve glucose control in patients with diabetes. PMID- 23688537 TI - Inpatient management of diabetes and hyperglycemia. AB - Illness, particularly when severe, leads to increased concentrations of counter regulatory factors which induce insulin resistance and predispose patients to stress hyperglycemia. Elevated glucose concentrations are common in hospitalized patients, both those with as well as without recognized diabetes. Substantial data has emerged over the past decade that quality glucose management in these individuals actually improves clinical outcomes. Controlling glucose in this setting is challenging, given the phenotypic variability amongst patients, with fluctuating courses of acute illnesses and unpredictable nutritional schedules. We review the evidence basis that has informed national standards and glucose targets in both critically and non-critically ill patients. In the intensive care setting, insulin infusions are now widely endorsed to quickly achieve and maintain glucose control. On the hospital wards, physiological subcutaneous insulin therapy, incorporating both basal and nutritional components, is emerging as the optimal treatment strategy. The transition to outpatient care is another important aspect of any hospital glycemic management program. PMID- 23688538 TI - Diabetes education: looking through the kaleidoscope. AB - BACKGROUND: Diabetes self-management education (DSME) is a critical element of care for all people with diabetes and those at risk for developing diabetes. In spite of growing evidence of the value of DSME in reducing hospitalization costs, improvement in glucose, weight and medication adherence, DSME remains an underutilized insurance benefit and access to qualified diabetes educators is problematic. PURPOSE: This paper reviews the current challenges, principles and evidence of DSME, importance of integration of diabetes education with clinical care, and the future of diabetes educators and education in the emerging health care delivery models. DATA SOURCES: Scientific literature review, Pub Med, EBP websites and other online literature databases and resources. LIMITATIONS: This is not a systematic literature review or meta-analysis of diabetes education. CONCLUSION: Because diabetes is a complex condition reaching pandemic proportions, which requires self-management of the chronic disease on a daily basis, the future of DSME faces challenges in the current fee for service environment. The National Standards for Diabetes self-management education and support and the American Association of Diabetes Educators Practice Guidelines offers new concepts for meeting the future demand of diabetes educators and education. PMID- 23688539 TI - Assessing the effect of providing a pharmacist with patient diagnosis on electronic prescription orders: a pilot study. AB - BACKGROUND: As a result of the US Omnibus Reconciliation Act of 1990 (OBRA '90), pharmacists have the obligation to ensure that prescription orders are appropriate and are not likely to cause adverse events. However, patient diagnosis information is not a requirement for a legal prescription order in any state in the US. OBJECTIVE: To compare a pharmacist's interventions before and after patient diagnosis is added by prescribers to their electronic prescription orders. METHODS: This prospective, pre-post study was conducted during two consecutive 4-week periods in a community health center pharmacy. During the first data collection period, the clinical pharmacist prospectively evaluated e prescriptions using a standard DUR protocol. All problematic prescriptions were documented using a medication intervention form. During the second data collection period, providers included the patient's diagnosis on each e prescription and the same clinical pharmacist again evaluated prescribed therapy and documented interventions. RESULTS: Pharmacist intervention rates on e prescription orders were significantly lower following addition of the patient diagnosis information to the e-prescription order (3.9% pre- vs. 1.0% post-, P < 0.001). CONCLUSIONS: While preliminary, the results of this pilot suggest that the addition of patient diagnosis to the e-prescription order can reduce confusion and uncertainty on the part of a DUR pharmacist, thereby decreasing the overall number of interventions and the subsequent number of contacts with prescribers. PMID- 23688540 TI - Pharmacists' performance of clinical interventions during adherence support medication reviews. AB - BACKGROUND: In New Zealand, pharmacists are funded to provide adherence support to their patients via a service called "Medicines Use Review" (MUR). The service is based on the assumption that the medication regimen is clinically appropriate and therefore does not include a clinical review. However, whether or not pharmacists make clinical recommendations to patients during MUR is unclear. OBJECTIVE: To identify the types of drug-related problems (DRPs) and interventions provided during MUR in order to understand whether clinical interventions occur. METHODS: A single district health board that funds MUR services was identified. The MUR providers that conducted MURs during the period (from 2007 - December 2011) were invited to participate. All MUR consultation records were reviewed and the data extracted were categorized according to the DRP Classification Scheme v6.2 by Pharmaceutical Care Network Europe (PCNE). DRPs that did not fit into the criteria were documented separately. RESULTS: Consultation records for 353 individual patients were obtained from five MUR providers. Of these patients, 56.4% were female and the median age was 73 years. A total of 886 DRPs were identified and resulted in a total of 844 interventions. During this period, 2718 medications were prescribed to these MUR patients. The most frequent DRPs identified were problems with "health literacy" and "non adherence" to medications. However 18.1% (n = 160) of the DRPs were perceived as a clinical review that went beyond the practice of MUR. The most common intervention was "patient counselling" (20%), "compliance packaging provided" (16%) and "recommendation to change medication" (11%). CONCLUSIONS: In this study, pharmacists perhaps based on ethical, legal and moral obligations provided clinical interventions that exceeded those expected and funded in a MUR. Since MUR detected a low number of clinical DRPs when compared to clinical medication review services conducted previously, a funding system that only supports MUR might not provide the important clinical support required by patients. Patients who receive only MUR may potentially be missing out on optimal care. PMID- 23688541 TI - RNA interference targeting alpha-synuclein attenuates methamphetamine-induced neurotoxicity in SH-SY5Y cells. AB - The protein alpha-synuclein (alpha-syn) is abundant in neurons and has been claimed to play critical roles in the pathophysiology of Parkinson's disease. Overexpression of alpha-syn has been shown to be toxicity in methamphetamine (METH)-induced model in vivo and in vitro which has Parkinson's-like pathology. However, the exact mechanisms underlying toxicity of alpha-syn mediated METH induced neuron remain unknown. In the present study, human dopaminergic-like neuroblastoma SH-SY5Y cells were used as METH-induced model in vitro. Cell viability was found to be dramatically increased after silencing alpha-syn expression followed by METH treatment compared with a-syn wild-type cells and the morphological damage to cells after METH treatment was abated through knockdown of alpha-syn expression in this model. The expression levels of tyrosine hydroxylase (TH), dopamine transporter (DAT) and vesicular monoamine transporter 2(VMAT-2) were significantly decreased and the activity/levels of reactive oxygen species (ROS), nitric oxide synthase (NOS) and nitrogen (NO) were notably increased after METH treatment. However, the changes of these expression levels were reversed in cells transfected with alpha-syn-shRNA. These results suggested that TH, DAT, VMAT-2, ROS and NOS maybe involved in alpha-syn mediated METH induced neuronal toxicity. PMID- 23688542 TI - Hydrogen peroxide-induced reduction of delayed rectifier potassium current in hippocampal neurons involves oxidation of sulfhydryl groups. AB - This study examined the effect of H2O2 on the delayed rectifier potassium current (IKDR) in isolated hippocampal neurons. Whole-cell voltage-clamp experiments were performed on freshly dissociated hippocampal CA1 neurons of SD rats before and after treatment with H2O2. To reveal the mechanism behind H2O2-induced changes in IKDR, cells were treated with different oxidizing and reducing agents. External application of membrane permeable H2O2 reduced the amplitude and voltage dependence of IKDR in a concentration dependent manner. Desferoxamine (DFO), an iron-chelator that prevents hydroxyl radical (OH) generation, prevented H2O2 induced reduction in IKDR. Application of the sulfhydryl-oxidizing agent 5,5 dithio-bis-nitrobenzoic acid (DTNB) mimicked the effect of H2O2. Sulfhydryl reducing agents dithiothreitol (DTT) and glutathione (GSH) alone did not affect IKDR; however, DTT and GSH reversed and prevented the H2O2-induced inhibition of IKDR, respectively. Membrane impermeable agents GSH and DTNB showed effects only when added intracellularly identifying intracellular sulfhydryl groups as potential targets for hydroxyl-mediated oxidation. However, the inhibitory effects of DTNB and H2O2 at the positive test potentials were completely and partially abolished by DTT, respectively, suggesting an additional mechanism of action for H2O2, that is not shared by DTNB. In summary, this study provides evidence for the redox modulation of IKDR, identifies hydroxyl radical as an intermediate oxidant responsible for the H2O2-induced decrease in current amplitude and identifies intracellular sulfhydryl groups as an oxidative target. PMID- 23688543 TI - Responses of single neurons and neuronal ensembles in frog first- and second order olfactory neurons. AB - A major challenge in sensory neuroscience is to elucidate the coding and processing of stimulus representations in successive populations of neurons. Here we recorded the spiking activity of receptor neurons (RNs) and mitral/tufted cells (MCs) in the frog olfactory epithelium and olfactory bulb respectively, in response to four odorants applied at precisely controlled concentrations. We compared how RN responses are translated in MCs. We examined the time course of the instantaneous firing frequency before and after stimulation in neuron ensembles and the dependency on odorant concentration of the number of action potentials fired in a preselected 5-s time window (dose-response curves) in both single neurons and neuron ensembles. In RNs and MCs, the dose-response curves typically increase then decrease and are well described by alpha functions. We established the main quantitative properties of these curves, including the distributions of concentrations at threshold and maximum responses. We showed that the main transformations occurring in the transition from RNs to MCs is the lowering of the firing threshold and a large decrease in the total number of spikes fired. We also found that the number of action potentials fired by recorded neurons and hence their energy consumption is independent of odorant concentration, and that this is a consequence of their time- and concentration dependent activities. This article is part of a Special Issue entitled Neural Coding 2012. PMID- 23688544 TI - Z-ligustilide activates the Nrf2/HO-1 pathway and protects against cerebral ischemia-reperfusion injury in vivo and in vitro. AB - Z-ligustilide (LIG), the main lipophilic component of Radix Angelica sinensis, has been shown to protect against brain ischemic damage in rodents by oral and intra-peritoneal treatments. The present study aimed to confirm the therapeutic effect of LIG administered intravenously on 2h middle cerebral artery occlusion (MCAO) and 22 h reperfusion injury in rats since oral administration has low bioavailability, slow absorption and distribution. Moreover, whether LIG activated the NF-E2-related factor 2/ heme oxygenase-1 (Nrf2/HO-1) pathway was also investigated in vivo and in vitro to further elucidate the precise protective mechanisms. In vivo, rats treated intravenously with LIG immediately after the surgery was finished had less neurological dysfunction and smaller infarct volume than that of the vehicle-treated rats. Additionally, LIG promoted Nrf2 nuclear translocation, and further remarkably increased Nrf2 and HO-1 protein expression. In vitro, LIG induced Nrf2 nuclear translocation and up regulated HO-1 expression in a time-dependent and concentration-dependent manner. Furthermore, LIG treatment reduced cell death induced by OGD, however, the protective action was abolished while Nrf2/HO-1 expression was knockdown by RNA interference. These results noted that intravenous post-treatment with LIG exhibits noticeable neuroprotective properties against brain damage by ischemia reperfusion and the ability of LIG to activate Nrf2/HO-1 pathway may be partly responsible for it. PMID- 23688545 TI - The glycolytic enzyme aldolase C is up-regulated in rat forebrain microsomes and in the cerebrospinal fluid after repetitive fluoxetine treatment. AB - The antidepressant drug fluoxetine is widely used for the treatment of a broad range of psychiatric disorders. Its mechanism of action is thought to involve cellular adaptations that are induced with a slow time course after initiation of treatment. To gain insight into the signaling pathways underlying such changes, the expression levels of proteins in a microsomal sub-fraction enriched in intracellular membranes from the rat forebrain was analyzed after two weeks of treatment with fluoxetine. Proteins were separated by two-dimensional gel electrophoresis, and the differentially regulated protein spots were identified by mass spectrometry. Protein network analysis suggested that most of the identified proteins could potentially be regulated by the insulin family of proteins. Among them, Fructose-bisphosphate aldolase C (AldoC), a glycolytic/gluconeogenic enzyme primarily expressed in forebrain astrocytes, was up-regulated 7.6-fold. An immunohistochemical analysis of the dorsal hippocampus revealed a robust decrease (43+/-2%) in the co-localization of AldoC and the astrocyte marker GFAP and a diffuse staining pattern, compatible with AldoC secretion into the extracellular space. Consistently, AldoC, contained in an exosome-like fraction in astrocyte conditioned medium, increased significantly in the cerebrospinal fluid. Our findings strongly favor a non-canonic signaling role for AldoC in cellular adaptations induced by repetitive fluoxetine treatment. PMID- 23688546 TI - Immunogenicity and safety of quadrivalent versus trivalent inactivated influenza vaccine: a randomized, controlled trial in adults. AB - BACKGROUND: Two phylogenetic lineages of influenza B virus coexist and circulate in the human population (B/Yamagata and B/Victoria) but only one B-strain is included in each seasonal vaccine. Mismatch regularly occurs between the recommended and circulating B-strain. Inclusion of both lineages in vaccines may offer better protection against influenza. METHODS: This study (NCT00714285) assessed the immunogenicity and safety of two candidate quadrivalent influenza vaccines (QIV) containing two A- and two B-strains (one from each lineage) in adults (18-60 years). Subjects were randomized and stratified by age to receive either QIV (non-adjuvanted or low-dose adjuvanted [LD QIV-AS]) or trivalent influenza vaccine (TIV, non-adjuvanted or low-dose adjuvanted [LD TIV-AS]), N = 105 in all treatment groups. The study evaluated the statistical non-inferiority of the immunological response elicited by QIV and LD QIV-AS versus TIV and LD TIV AS and the statistical superiority of the response elicited by the quadrivalent vaccines against the B-strain (B/Jiangsu) not included in the TIV. RESULTS: Pre defined non-inferiority and superiority criteria were reached for both QIVs compared to the TIVs. On Day 21 in all vaccine groups SCRs were >=54.8%, SPRs >=88.5% and SCFs >=5.4 for the A strains and B strain included in all vaccines (B/Malaysia). This fulfilled the European (CHMP) and the US (CBER) licensing criteria for the assessment of influenza vaccines in adults (CHMP criteria: SCR > 40%, SPR > 70%, SCF > 2; CBER criteria: LL of 95% CI for SPR >= 70% or SCR >= 40%). Only the QIVs met the CHMP and CBER criteria for the B/Jiangsu strain. In the QIV and LD-QIV-AS groups, the SCFs were 9.1 and 8.1, respectively and the SPRs were 98.1% and 95.2%, whereas for the TIV and LD-TIV-AS groups, the SCFs were 2.3 and 2.5, respectively, and the SPRs were 75.0% and 63.8%, with the LLs of the 95% CI <70% for SPR and <40% for SCR. CONCLUSIONS: Addition of a fourth strain did not impact the immune response elicited by the three original strains contained in the TIV. A clear immunological benefit was seen with the QIV formulation for the second B-strain, indicating that quadrivalent vaccines could provide broader protection against influenza. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00714285. PMID- 23688547 TI - Rotavirus genotype distribution during the pre-vaccine period in Bolivia: 2007 2008. AB - OBJECTIVES: Rotavirus is the most important etiology of severe diarrhea in Bolivia. The monovalent attenuated human oral rotavirus vaccine Rotarix((r)) was introduced in Bolivia in 2008. We describe the molecular epidemiology of circulating rotavirus strains before vaccine introduction. METHODS: Two thousand one hundred thirty-five diarrheal samples were collected from hospitals in four Bolivian cities during 2007-2008. Forty-three percent (445 of 1030 rotavirus positive samples) were analyzed for G and P genotypes. Among those, 331 were electropherotyped by polyacrylamide gel electrophoresis. Disease severity was quantified using a modified Vesikari scale. RESULTS: Among the 445 samples, five genotypes were found to be prevalent: G9P[8] (33%), G1P[6] (17%), G2P[4] (13%), G9P[6] (12%), and G1P[8] (4%). Co-infections with two or more strains accounted for 14% of samples. The most prevalent strain, G9, showed greater electropherotype diversity compared to other serogroups. Strain G1P[6] generally infected younger children and peaked later in the year than other strains. No particular genotype was associated with a higher severity score, though there was a significant difference in the duration of diarrhea between genotypes. CONCLUSIONS: During the 2-year pre-vaccine period, substantial diversity of rotavirus co-circulating strains was observed. These data constitute a baseline against which changes in circulating strains post-vaccine introduction can be monitored. PMID- 23688548 TI - Malignant syphilis. PMID- 23688549 TI - Deworming of intestinal helminths reduces HIV-1 subtype C viremia in chronically co-infected individuals. AB - OBJECTIVE: To define the impact of helminthic infestations and their treatment on viral load and T cell subsets in chronic HIV-1-infected patients. METHODS: Two hundred twenty chronic HIV-1-infected Ethiopian patients with (N = 87) and without (N = 133) helminthic infestations were included. To determine the impact of deworming on viral load and T cell subsets, a subset of these patients with (n = 23) and without (n = 20) helminthic infestations were followed longitudinally. Helminth egg loads, plasma HIV RNA levels, and peripheral blood CD4(+) and CD8(+) T cells were determined at baseline and at 12 weeks after antihelminthic treatment. RESULTS: At baseline, plasma viral load was significantly higher in individuals with (n = 87) than without (n = 133) a helminthic infestation (5.01 log10 vs. 3.41 log10, p < 0.001). Twelve weeks after antihelminthic treatment, plasma HIV RNA levels were reduced in the successfully treated group (p < 0.001). Twelve weeks after antihelminthic treatment, helminth infestations and their treatment had no significant effect on CD4(+) T cell counts. However, helminth infested individuals had a higher level of CD8(+) T cells at baseline (p < 0.001), which was significantly reduced (p < 0.01) at 12 weeks after antihelminthic treatment. CONCLUSIONS: Helminths were found to be associated with an increased HIV RNA level. Successful treatment of intestinal helminths reduced plasma HIV RNA levels in chronic HIV-1 subtype C infection. Considering the high endemicity of helminths in tropical settings, the management of chronically HIV infected individuals must include deworming. PMID- 23688550 TI - The putrescine biosynthesis pathway in Lactococcus lactis is transcriptionally regulated by carbon catabolic repression, mediated by CcpA. AB - Lactococcus lactis is the lactic acid bacterium most widely used by the dairy industry as a starter for the manufacture of fermented products such as cheese and buttermilk. However, some strains produce putrescine from agmatine via the agmatine deiminase (AGDI) pathway. The proteins involved in this pathway, including those necessary for agmatine uptake and conversion into putrescine, are encoded by the aguB, aguD, aguA and aguC genes, which together form an operon. This paper reports the mechanism of regulation of putrescine biosynthesis in L. lactis. It is shown that the aguBDAC operon, which contains a cre site at the promoter of aguB (the first gene of the operon), is transcriptionally regulated by carbon catabolic repression (CCR) mediated by the catabolite control protein CcpA. PMID- 23688551 TI - Assessment of the effect of stress-tolerance acquisition on some basic characteristics of specific probiotics. AB - The production of viable functional probiotics presupposes stability of strain features in the final product. We evaluated the impact of acquisition of heat tolerance and subsequent freeze-drying on the adhesion properties of Lactobacillus rhamnosus GG, Lactobacillus casei Shirota, Bifidobacterium lactis Bb-12 and Bifidobacterium animalis IF20/1 and on their ability to inhibit the adhesion of pathogens in a mucus model. Both fresh and freeze-dried cultures were evaluated. Significant differences were observed between fresh, freeze dried, fresh heat-tolerant and freeze dried heat-tolerant strains, especially in the ability of the freeze dried probiotics to exclude, displace or outcompete pathogens. Based on our study characterizing probiotic properties such as adhesion and competitive exclusion, it seems possible to adapt probiotics to processing stresses, such as heat, without significantly changing the probiotic properties of the strains assessed. This may provide new options for future probiotic production technology. However, our results also emphasize that the properties of the stress-adapted strains, as well as the effect of the production processes should always be assessed as these are strain-specific. PMID- 23688552 TI - Imaging cells at the nanoscale. AB - Recently developed super-resolution techniques in optical microscopy have pushed the length scale at which cellular structure can be observed down to tens of nanometres. A wide array of methods have been described that fall under the umbrella term of super-resolution microscopy and each of these methods has different requirements for acquisition speed, experimental complexity, fluorophore requirements and post-processing of data. For example, experimental complexity can be decreased by using a standard widefield microscope for acquisition, but this requires substantial processing of the data to extract the super-resolution information. These powerful techniques are bringing new insights into the nanoscale structure of sub-cellular assemblies such as podosomes, which are an ideal system to observe with super-resolution microscopy as the structures are relatively thin and they form and dissociate over a period of several minutes. Here we discuss the major classes of super-resolution microscopy techniques, and demonstrate their relative performance by imaging podosomes. PMID- 23688553 TI - beta-N-methylamino-l-alanine causes neurological and pathological phenotypes mimicking Amyotrophic Lateral Sclerosis (ALS): the first step towards an experimental model for sporadic ALS. AB - beta-N-methylamino-l-alanine (L-BMAA) is a neurotoxic amino acid that has been related to various neurodegenerative diseases. The aim of this work was to analyze the biotoxicity produced by L-BMAA in vivo in rats, trying to elucidate its physiopathological mechanisms and to search for analogies between the found effects and pathologies like Amyotrophic Lateral Sclerosis (ALS). Our data demonstrated that the neurotoxic effects in vivo were dosage-dependent. For evaluating the state of the animals, a neurological evaluation scale was developed as well as a set of functional tests. Ultrastructural cell analysis of spinal motoneurons has revealed alterations both in endoplasmic reticulum and mitochondria. Since GSK3beta could play a role in some neuropathological processes, we analyzed the alterations occurring in GSK3beta levels in L-BMAA treated rats, we have observed an increase in the active form of GSK3beta levels in lumbar spinal cord and motor cerebral cortex. On the other hand, (TAR)-DNA binding protein 43 (TDP-43) increased in L-BMAA treated animals. Our results indicated that N-acetylaspartate (NAA) declined in animals treated with L-BMAA, and the ratio of N-acetylaspartate/choline (NAA/Cho), N-acetylaspartate/creatine (NAA/Cr) and N-acetylaspartate/choline+creatine (NAA/Cho+Cr) tended to decrease in lumbar spinal cord and motor cortex. This project offers some encouraging results that could help establishing the progress in the development of an animal model of sporadic ALS and L-BMAA could be a useful tool for this purpose. PMID- 23688554 TI - Decision making by NICE: examining the influences of evidence, process and context. AB - The National Institute for Health and Clinical Excellence (NICE) provides guidance to the National Health Service (NHS) in England and Wales on funding and use of new technologies. This study examined the impact of evidence, process and context factors on NICE decisions in 2004-2009. A data set of NICE decisions pertaining to pharmaceutical technologies was created, including 32 variables extracted from published information. A three-category outcome variable was used, defined as the decision to 'recommend', 'restrict' or 'not recommend' a technology. With multinomial logistic regression, the relative contribution of explanatory variables on NICE decisions was assessed. A total of 65 technology appraisals (118 technologies) were analysed. Of the technologies, 27% were recommended, 58% were restricted and 14% were not recommended by NICE for NHS funding. The multinomial model showed significant associations (p ? 0.10) between NICE outcome and four variables: (i) demonstration of statistical superiority of the primary endpoint in clinical trials by the appraised technology; (ii) the incremental cost-effectiveness ratio (ICER); (iii) the number of pharmaceuticals appraised within the same appraisal; and (iv) the appraisal year. Results confirm the value of a comprehensive and multivariate approach to understanding NICE decision making. New factors affecting NICE decision making were identified, including the effect of clinical superiority, and the effect of process and socio economic factors. PMID- 23688555 TI - The contribution of platelet glycoproteins (GPIa C807T and GPIba C-5T) and cyclooxygenase 2 (COX-2G-765C) polymorphisms to platelet response in patients treated with aspirin. AB - OBJECTIVE: Aspirin is an antiplatelet agent commonly used in treatment of patients with high risk to develop stroke and myocardial infarction. However, inter-individual variability regarding the inhibition of platelet function by aspirin is well documented. In this study, the correlation between platelet glycoproteins (GPIa C807T and GPIba C-5T) and cyclooxygenase 2 (COX-2G-765C) polymorphisms and antiplatelet response in patients treated with aspirin was investigated. METHODS: Jordanian adult patients (n=584) who are taking aspirin as an antiplatelet agent participated in the study. Platelet aggregation response was measured using Multiplate Analyzer(r) system. Polymerase chain reaction restriction fragment length polymorphism assay (PCR-RFLP) was used for genotyping of the examined polymorphisms. RESULTS: Aspirin resistance was found in 15.8% of patients. Response to aspirin was significantly associated with GPIba C-5T polymorphism (P<0.05). However, the GPIa C807T and COX-2G-765C polymorphisms were not related to aspirin resistance (P>0.05). CONCLUSION: A considerable fraction of the Jordanian population is resistant to the antiplatelet effect of aspirin, which might be related to GPIba C-5T polymorphism. PMID- 23688556 TI - Characterization of genome-wide binding of NF-kappaB in TNFalpha-stimulated HeLa cells. AB - This study characterized the genome-wide binding of NF-kappaB RelA with ChIP-Seq and explored its effects on the gene transcription with DNA microarray. It was found that NF-kappaB showed several significant binding characteristics, including the inter- and intra-chromosomal differential high-fold enrichment binding, the dominant intronic binding to vast majority of target genes through multiple ChIP-seq peaks and kappaB sites, extensively binding to large number of genes in the human genome, and binding its target genes more broadly through noncanonical kappaB sites than canonical kappaB sites. These in vivo genome-wide binding characteristics exerted effects on the transcription of its direct target genes in genome, reflecting some important traits of this protein which acts as a stimulatory transcription factor involving in many biological processes and responding to various internal and external stimuli. PMID- 23688558 TI - Antagonism of L-type Ca2+ channels CaV1.3 and CaV1.2 by 1,4-dihydropyrimidines and 4H-pyrans as dihydropyridine mimics. AB - The L-type calcium channel (LTCC) CaV1.3 is regarded as a new potential therapeutic target for Parkinson's disease. Calcium influx through CaV1.3 LTCC during autonomous pacemaking in adult dopaminergic neurons of the substantia nigra pars compacta is related to the generation of mitochondrial oxidative stress in animal models. Development of a CaV1.3 antagonist selective over CaV1.2 is essential because CaV1.2 pore-forming subunits are the predominant form of LTCCs and are abundant in the central nervous and cardiovascular systems. We have explored 1,4-dihydropyrimidines and 4H-pyrans to identify potent and selective antagonists of CaV1.3 relative to CaV1.2 LTCCs. A library of 36 dihydropyridine (DHP)-mimic 1,4-dihydropyrimidines and 4H-pyrans was synthesized, and promising chiral compounds were resolved. The antagonism studies of CaV1.3 and CaV1.2 LTCCs using DHP mimic compounds showed that dihydropyrimidines and 4H-pyrans are effective antagonists of DHPs for CaV1.3 LTCCs. Some 1,4-dihydropyrimidines are more selective than isradipine for CaV1.3 over CaV1.2, shown here by both calcium flux and patch-clamp electrophysiology experiments, where the ratio of antagonism is around 2-3. These results support the hypothesis that the modified hydrogen bonding donor/acceptors in DHP-mimic dihydropyrimidines and 4H-pyrans can interact differently with DHP binding sites, but, in addition, the data suggest that the binding sites of DHP in CaV1.3 and CaV1.2 LTCCs are very similar. PMID- 23688559 TI - Development of time resolved fluorescence resonance energy transfer-based assay for FXR antagonist discovery. AB - FXR (farnesoid X receptor, NRIH4), a nuclear receptor, plays a major role in the control of cholesterol metabolism. FXR ligands have been investigated in preclinical studies for targeted therapy against metabolic diseases, but have shown limitations. Therefore, there is a need for new agonist or antagonist ligands of FXR, both for potential clinical applications, as well as to further elucidate its biological functions. Here we describe the use of the X-ray crystal structure of FXR complexed with the potent small molecule agonist GW4064 to design and synthesize a novel fluorescent, high-affinity probe (DY246) for time resolved fluorescence resonance energy transfer (TR-FRET) assays. We then used the TR-FRET assay for high throughput screening of a library of over 5000 bioactive compounds. From this library, we identified 13 compounds that act as putative FXR transcriptional antagonists. PMID- 23688560 TI - Demographic patterns of ED patients diagnosed as having corneal ulcer. AB - PURPOSE: This work aimed to study the demographic features of patients with emergency department (ED) visits for ulcerative keratitis, including information on insurance coverage and on-site consultant support. METHODS: Demographic features of corneal ulcers diagnosed in the ED were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes in Florida Agency of Health Care data sets for 2010. Patterns of patient encounters, including type of insurance coverage and consultant ED visits, were analyzed foremost descriptively. RESULT: In 2010, 2124 patients were evaluated in EDs in Florida with the primary diagnosis of corneal ulcer. Of these patients, 190 required hospital admission for further care. Thirty percent of patients discharged from the ED were seen on the weekend. About one-third of patients had no insurance (34.7%). Compared with outpatients, those hospitalized were older (54 years vs 39 years [P < .001]) and more often had insurance coverage (90.5% vs 65.3% [P < .001]). Ophthalmologists were associated with as many as 70.9% of outpatient encounters. The ratio of outpatients to those requiring hospitalization in urban areas ranged from 2.3 to 1 in counties on the west coast of Florida to 28.1 to 1 among counties in the southeast coast. CONCLUSION: Emergency department participation by ophthalmologist for ulcerative keratitis was relatively high. Whether the lack of health insurance affects the decision to hospitalize patients with corneal ulcers is a question that deserves further study. What influence the high proportion of uninsured ED patients will have on ophthalmologists coverage in the future may need to be addressed. PMID- 23688557 TI - Partial venom gland transcriptome of a Drosophila parasitoid wasp, Leptopilina heterotoma, reveals novel and shared bioactive profiles with stinging Hymenoptera. AB - Analysis of natural host-parasite relationships reveals the evolutionary forces that shape the delicate and unique specificity characteristic of such interactions. The accessory long gland-reservoir complex of the wasp Leptopilina heterotoma (Figitidae) produces venom with virus-like particles. Upon delivery, venom components delay host larval development and completely block host immune responses. The host range of this Drosophila endoparasitoid notably includes the highly-studied model organism, Drosophila melanogaster. Categorization of 827 unigenes, using similarity as an indicator of putative homology, reveals that approximately 25% are novel or classified as hypothetical proteins. Most of the remaining unigenes are related to processes involved in signaling, cell cycle, and cell physiology including detoxification, protein biogenesis, and hormone production. Analysis of L. heterotoma's predicted venom gland proteins demonstrates conservation among endo- and ectoparasitoids within the Apocrita (e.g., this wasp and the jewel wasp Nasonia vitripennis) and stinging aculeates (e.g., the honey bee and ants). Enzyme and KEGG pathway profiling predicts that kinases, esterases, and hydrolases may contribute to venom activity in this unique wasp. To our knowledge, this investigation is among the first functional genomic studies for a natural parasitic wasp of Drosophila. Our findings will help explain how L. heterotoma shuts down its hosts' immunity and shed light on the molecular basis of a natural arms race between these insects. PMID- 23688561 TI - Prognostic value of adrenomedullin in septic patients in the ED. AB - OBJECTIVE: The aims of the present study were to evaluate the prognostic value of adrenomedullin (AM) in septic patients in the emergency department (ED) and to compare it with procalcitonin (PCT) and Mortality in Emergency Department Sepsis (MEDS) score. METHODS: We enrolled 837 consecutive patients who fulfilled the systemic inflammatory response syndrome criteria and were admitted to the ED of Beijing Chaoyang Hospital and 100 age-matched healthy controls. Serum AM and PCT were determined, and MEDS score was calculated at enrollment. The prognostic value of AM was compared with PCT and MEDS score. Primary outcome was in-hospital mortality. RESULTS: On admission, mean levels of AM were 28.66 +/- 6.05 ng/L in 100 healthy controls, 31.65 +/- 6.47 ng/L in 153 systemic inflammatory response syndrome patients, 33.24 +/- 8.59 ng/L in 376 sepsis patients, 34.81 +/- 8.33 ng/L in 210 severe sepsis patients, and 45.15 +/- 9.87 ng/L in 98 septic shock patients. The differences between the 2 groups were significant. Adrenomedullin level was higher in nonsurvivors than in survivors in every group. The area under receiver operating characteristic curve of AM for predicting in-hospital mortality in septic patients was 0.773, which was better than PCT (0.701) and MEDS score (0.721). Combination of AM and MEDS score improved the accuracy of AM and MEDS score in predicting the risk of in-hospital mortality (area under receiver operating characteristic curve, 0.817). In logistic regression analysis, AM and MEDS score were independent predictors of in-hospital mortality. CONCLUSIONS: Adrenomedullin is valuable for prognosis in septic patients in the ED. PMID- 23688562 TI - A successful emergency management of spontaneous coronary artery dissection and review of the literature. AB - Spontaneous coronary artery dissection (SCAD) is a rare and lethal myocardial ischemic event, which usually causes acute coronary syndrome and sudden death. Emergency management of SCAD includes medical treatment, percutaneous coronary interventions, and coronary artery bypass grafting. Here, we report 1 case of 37 year-old young woman who was found to have a mid-distal SCAD of the left anterior descending artery, taking conservative management decision. In another case of a 50-year-old woman who was found to have a proximal-middle spiral SCAD of the right coronary artery, she underwent coronary angioplasty. After 6 months later at follow-up, 2 patients remained stable without symptom and in recovery of the left ventricular function; angiogram showed the SCAD healed. PMID- 23688563 TI - Painless aortic dissection: thrombolytic and antithrombotic vigilance. PMID- 23688564 TI - Troponin results definitively should be expressed in ng/L. PMID- 23688565 TI - Cytidine diphosphate choline improves the outcome of cardiac arrest vs epinephrine in rat model. AB - OBJECTIVES: Cytidine diphosphate choline (CDP-choline) is a cholinergic agent that can both stimulate the cholinergic pathway and increase blood pressure. We aimed to investigate the effects of CDP-choline on the outcome of cardiac arrest in comparison with epinephrine. METHODS: This was a randomized prospective animal study. Cardiac arrest was induced by asphyxia in 45 rats. After 7 minutes of asphyxia, resuscitation was attempted. The rats were allocated to different groups treated with 2 mL/kg saline, 100 MUg/kg epinephrine, or 250 mg/kg CDP choline. The hemodynamic parameters were monitored for 2 hours after resuscitation, and cardiac function was evaluated by echocardiography 2 hours after resuscitation. The hearts were harvested at the end of monitoring for histologic evaluation. RESULTS: Epinephrine and CDP-choline improved the rate of return of spontaneous circulation and blood pressure during cardiopulmonary resuscitation; however, postresuscitation cardiac function in the CDP-choline and placebo groups was better than in the epinephrine group. Compared with the epinephrine group, less myocardial and mitochondrial injury was observed by electron microscopy in the CDP-choline and placebo groups; the level of superoxide dismutase and malondialdehyde indicated less peroxidative injury in the CDP-choline and placebo groups. Cytidine diphosphate choline and placebo also preserved connexin 43 when compared with epinephrine. CONCLUSION: When administered during resuscitation, CDP-choline increased the rate of return of spontaneous circulation similarly to epinephrine. In addition, it did not increase the severity of myocardial injury and postresuscitation myocardial dysfunction, whereas epinephrine appeared to be harmful. PMID- 23688566 TI - LUCAS 2TM device, compression depth, and the 2010 cardiopulmonary resuscitation guidelines. AB - The 2010 guidelines for cardiopulmonary resuscitation recommends that the chest be compressed at least 5 cm, with evidence that depths exceeding 5 cm may further aid resuscitation. The current piston-based mechanical device LUCAS 2TM is programmed to deliver a compression depth of 5 cm. We report 2 cases in which the LUCAS 2TM device failed to generate physiological surrogates of blood flow (ie, end-tidal carbon dioxide tension and aortic diastolic blood pressure) at levels indicative of effective chest compressions. A switch to manual compressions allowing greater compression depth yielded higher end-tidal carbon dioxide tension and arterial blood pressure. These cases depict limitations of the LUCAS 2TM device and the importance of guiding chest compression by physiological parameters. Consideration should be given to modifications to the LUCAS 2TM, allowing rescuers to increase depth when required to optimize the hemodynamic efficacy of chest compression. PMID- 23688567 TI - Different duration of high-altitude pre-exposure associated with the incidence of acute mountain sickness on Jade Mountain. AB - OBJECTIVE: The objective of this study is to determine the association between the duration of high-altitude (>3000 m) pre-exposure and acute mountain sickness (AMS) incidence. METHODS: A prospective observational study was conducted on 2 random days each month from April 2007 to March 2008 at Paiyun Lodge (3402 m), Jade Mountain, Taiwan. Demographic data, prior AMS history, symptoms, and scores and the days and times of high-altitude pre-exposure within the preceding 2 months were obtained from lowland (<1500 m) trekkers. RESULTS: Totally, 1010 questionnaires were analyzed; 106, 76, and 828 trekkers had pre-exposure lasting at least 3 days (group 1), less than 3 days (group 2), and 0 days (group 3), respectively. Acute mountain sickness incidence was significantly higher in groups 2 and 3 than in group 1 (21.70%, 35.53%, 37.08%, respectively; P = .008). Logistic regression analysis indicated a significantly lower AMS risk in group 1 (group 1, P = .004; odds ratio [OR], 0.479; 95% confidence interval [CI], 0.290 0.791; group 2, P = .226; OR, 0.725; 95% CI, 0.430-1.221). In group 1, 28 and 78 trekkers had single and intermittent multiple pre-exposure, respectively. There was no difference in the incidence or severity of AMS symptoms between single and intermittent multiple pre-exposure (AMS, P = .838; headache, P = .891; dizziness or lightheadedness, P = .414; fatigue and/or weakness, P = .957; gastrointestinal symptoms, P = .257; difficulty sleeping, P = .804; AMS score, P = .796). CONCLUSIONS: High-altitude pre-exposure lasting at least 3 days within the preceding 2 months was associated with a significant lower AMS incidence during a subsequent ascent among Jade Mountain trekkers. PMID- 23688568 TI - High-sensitive troponin T levels and complex coronary lesions. PMID- 23688569 TI - Median arcuate ligament syndrome presenting as hemorrhagic shock. AB - The major symptoms of median arcuate ligament syndrome, celiac axis stenosis, or occlusion compressed by the median arcuate ligament include eating-associated abdominal pain and weight loss. Because celiac stenosis increases retrograde collateral blood flow from the superior mesenteric artery to the celiac artery via the pancreaticoduodenal arcade, a pancreaticoduodenal artery aneurysm could occur at a low incidence rate. Rupture of the pancreaticoduodenal artery aneurysm and hemorrhagic shock are rare. In this report, we present 3 cases of patients who had been well with no abdominal symptoms until the day of admission, when they experienced sudden-onset intra-abdominal hemorrhage and shock. These 3 patients were admitted to the emergency department, and contrast-enhanced computed tomography and radiographic selective catheter angiography revealed intra-abdominal hemorrhage, stenosis of the celiac arteries, and dilated pancreaticoduodenal arcade. Case 1 demonstrated severe hemorrhagic shock, whereas case 2 demonstrated moderate shock. We treated ruptured pancreaticoduodenal artery aneurysms with coil embolization. Case 3 demonstrated complete celiac occlusion and moderate hemorrhagic shock, and no aneurysm was detected. PMID- 23688570 TI - Non-invasive blood pressure and cardiac index measurements using the Finapres Portapres in an emergency department triage setting. AB - Emergency department (ED) patients are triaged to determine the urgency of care. The Finapres Portapres (FP) measures blood pressure (BP) and cardiac output (CO) non-invasively, and may be of added value in early detection of patients at risk for hemodynamic compromise. OBJECTIVES: Compare non-invasive BP measurements using FP and standard automated sphygmomanometry. Compare FP cardiac index (CI), CO corrected for body surface area, of normotensive patients, to chart-based physician estimate of shock, to discover if there is additional value in CI measurements in triage. METHODS: ED Patients requiring BP measurement in triage were included. Systolic (SBP) and diastolic (DBP) BP were measured using both devices during a two minutes measurement. Two physicians independently judged probability of shock, defined as estimated CI <=2.5 L min(-1) m(-2), based on chart review, three weeks after ED visit. RESULTS: Of a total of 112 patients 97 patients were included. Pearson's correlation coefficient was 0.50 for SBP, 0.53 for DBP, with a Blant-Altman mean bias of 11.3 (upper limit 65.3, lower limit 42.8) and 7.7 (39.2, -23.7) for SBP and DBP respectively. In normotensive patients, the group with low FP CI measurements had significantly more cases with physician-estimated shock, compared to the normal to high measurements (P = .036). CONCLUSIONS: When used as a triage device in the emergency department setting, non-invasive BP measurements using FP do not correlate well with automated sphygmomanometry. However, this study does indicate that use of the FP device in triage may aid physicians to recognize patients in early phases of shock. PMID- 23688571 TI - Can we predict arterial lactate from venous lactate in the ED? AB - OBJECTIVE: We aimed to generate equation to predict arterial lactate (a-Lac) using venous lactate (v-Lac) and other lab data. METHODS: A prospective cross sectional study was conducted on emergency patients in the emergency department for 6 months at a general hospital in Tokyo, Japan. We collected arterial and venous gas analysis data. Patients were eligible for entry into the study if an arterial blood gas analysis was required for appropriate diagnostic care by the treating physician. Univariate linear regression analysis was conducted to generate an equation to calculate a-Lac incorporating only v-Lac. A multivariate forward stepwise logistic regression model (p-value of 0.05 for entry, 0.1 for removal) was used to generate an equation including v-Lac and other potentially relevant variables. Bland-Altman plot was drawn and the two equations were compared for model fitting using R-squares. RESULTS: Seventy-two arterial samples from 72 participants (61% male; mean age, 58.2 years) were included in the study. An initial regression equation was derived from univariate linear regression analysis:"(a-Lac) = -0.259 + (v-Lac) * 0.996". Subsequent multivariate forward stepwise logistic regression analysis, incorporating v-Lac and Po2, generated the following equation:"(a-Lac) = -0.469+(venous Po2) * 0.005 + (v-Lac) * 0.997". Calculated R-squares by single and multiple regression were 0.94 and 0.96, respectively. CONCLUSION: v-Lac estimates showed a high correlation with arterial values and our data provide two clinically useful equations to calculate a-Lac from v-Lac data. Considering clinical flexibility, "Lac = -0.259 + v-Lac * 0.996" might be more useful while avoiding a time-consuming and invasive procedure. PMID- 23688572 TI - Haemophilus influenzae serotype f as a rare cause of septic arthritis. AB - Non-type B Haemophilus influenzae emerges as a new pathogen in the post H. influenzae serotype b vaccine era. We describe a case of polyarticular septic arthritis caused by H. influenzae serotype f in an adult. The patient was successfully treated with surgical debridement and antibiotic. To the best of our knowledge, this is the fourth reported case of H. influenzae serotype f septic arthritis in adults. PMID- 23688573 TI - Ultrasound elastography: a new modality in routine practice. PMID- 23688574 TI - Opioid MU-receptors as new target for insulin resistance. AB - Type-2 diabetes is one of the fastest growing public health problems worldwide resulting from both environmental and genetic factors. Activation of MU-opioid receptor (MOR) could result in reversal of the impairment of insulin-stimulated glucose disposal in genetically obese Zucker rats via exercise training. This improvement of insulin resistance was associated with an elevation of circulating beta-endorphin to ameliorate the post-receptor insulin signaling cascade, including downstream effectors of the phosphatidylinositol 3-kinase (PI3-kinase) signaling pathway. In insulin resistant rats, Loperamide treatment effected on the insulin receptor substrate (IRS)-1/PI3-kinase/Akt signaling cascade and subsequent insulin-stimulated glucose transport trafficking on skeletal muscle, which were all suppressed by MOR antagonism. In addition, induction of insulin resistance by the intake of high fructose is more rapid in MOR knockout mice than in wild-type mice. Improvements in insulin sensitivity through the peripheral MOR activation overcoming defects related to the post-receptor in IRS-1-associated PI3-kinase step have been defined. Opioid receptor activation, especially of the MU-subtype, may provide merits in the amelioration of defective insulin action. Atypical zeta (zeta) isoform of protein kinase C serves as a factor that integrates with peripheral MOR pathway and insulin signals for glucose utilization. The developments call new insights into the chemical compounds and/or herbal products that might enhance opioid peptide secretion and/or stimulate MOR in peripheral insulin-sensitive tissues to serve as potential agents or adjuvants for helping the glucose metabolism. In the present review, we update these topics and discuss the concept of targeting peripheral MOR pathway for the treatment of insulin resistance. PMID- 23688575 TI - Opioid use among low back pain patients in primary care: Is opioid prescription associated with disability at 6-month follow-up? AB - Opioid prescribing for chronic noncancer pain is increasing, but there is limited knowledge about longer-term outcomes of people receiving opioids for conditions such as back pain. This study aimed to explore the relationship between prescribed opioids and disability among patients consulting in primary care with back pain. A total of 715 participants from a prospective cohort study, who gave consent for review of medical and prescribing records and completed baseline and 6month follow-up questionnaires, were included. Opioid prescription data were obtained from electronic prescribing records, and morphine equivalent doses were calculated. The primary outcome was disability (Roland-Morris Disability Questionnaire [RMDQ]) at 6months. Multivariable linear regression was used to examine the association between opioid prescription at baseline and RMDQ score at 6months. Analyses were adjusted for potential confounders using propensity scores reflecting the probability of opioid prescription given baseline characteristics. In the baseline period, 234 participants (32.7%) were prescribed opioids. In the final multivariable analysis, opioid prescription at baseline was significantly associated with higher disability at 6-month follow-up (P<.022), but the magnitude of this effect was small, with a mean RMDQ score of 1.18 (95% confidence interval: 0.17 to 2.19) points higher among those prescribed opioids compared to those who were not. Our findings indicate that even after adjusting for a substantial number of potential confounders, opioids were associated with slightly worse functioning in back pain patients at 6-month follow-up. Further research may help us to understand the mechanisms underlying these findings and inform clinical decisions regarding the usefulness of opioids for back pain. PMID- 23688576 TI - Unobtrusive measurement of daily computer use to detect mild cognitive impairment. AB - BACKGROUND: Mild disturbances of higher order activities of daily living are present in people diagnosed with mild cognitive impairment (MCI). These deficits may be difficult to detect among those still living independently. Unobtrusive continuous assessment of a complex activity such as home computer use may detect mild functional changes and identify MCI. We sought to determine whether long term changes in remotely monitored computer use differ in persons with MCI in comparison with cognitively intact volunteers. METHODS: Participants enrolled in a longitudinal cohort study of unobtrusive in-home technologies to detect cognitive and motor decline in independently living seniors were assessed for computer use (number of days with use, mean daily use, and coefficient of variation of use) measured by remotely monitoring computer session start and end times. RESULTS: More than 230,000 computer sessions from 113 computer users (mean age, 85 years; 38 with MCI) were acquired during a mean of 36 months. In mixed effects models, there was no difference in computer use at baseline between MCI and intact participants controlling for age, sex, education, race, and computer experience. However, over time, between MCI and intact participants, there was a significant decrease in number of days with use (P = .01), mean daily use (~1% greater decrease/month; P = .009), and an increase in day-to-day use variability (P = .002). CONCLUSIONS: Computer use change can be monitored unobtrusively and indicates individuals with MCI. With 79% of those 55 to 64 years old now online, this may be an ecologically valid and efficient approach to track subtle, clinically meaningful change with aging. PMID- 23688577 TI - Glutathione relates to neuropsychological functioning in mild cognitive impairment. AB - BACKGROUND: Mild cognitive impairment (MCI) represents an at-risk state for Alzheimer's disease in which underlying pathophysiological mechanisms could be delineated. Oxidative stress has been implicated in Alzheimer's disease and can be measured by levels of the antioxidant glutathione. This study aims to assess in vivo levels of glutathione via proton magnetic resonance spectroscopy in patients with MCI and to determine how glutathione relates to cognitive decline. METHODS: Fifty-four patients with MCI and 41 healthy control subjects underwent proton magnetic resonance spectroscopy in conjunction with medical, psychiatric, and neuropsychological assessments. The concentration of glutathione was measured in the anterior and posterior cingulate, and ratios of glutathione were calculated relative to creatine. Neuropsychological performance was assessed across the domains of processing speed, learning, memory, and executive functions. RESULTS: In comparison with control subjects, patients with MCI had significantly elevated ratios of glutathione in the anterior (t = -2.2, P = .03) and posterior (t = -2.9, P = .005) cingulate. Higher levels of anterior cingulate glutathione were related to neuropsychological decrements on tests of executive functions. Elevated posterior cingulate glutathione was associated with poorer memory consolidation. CONCLUSION: This study has shown for the first time that MCI is associated with increased glutathione in the cingulate, which in turn relates to neuropsychological performance. This finding may be indicative of an early compensatory or neuroprotective response, and the role of glial cells and glutathione enzymes requires delineation. Longitudinal studies examining the utility of glutathione as a marker for cognitive decline are now required. PMID- 23688578 TI - Apolipoprotein E polymorphisms in frontotemporal lobar degeneration: a meta analysis. AB - OBJECTIVE: Case-control studies have not been consistent in showing association between apolipoprotein E (APOE) polymorphisms and frontotemporal lobar degeneration (FTLD), producing contradictory findings. The study objective was to define and quantify further the disease risk associated with the carriage of different APOE alleles to determine whether APOE gene polymorphism is a risk factor for FTLD. METHODS: A systematic review of all case-control studies investigating the association between the APOE gene and FTLD up to December 2011 was conducted. Case-control studies using clinical or pathological criteria for FTLD and reporting APOE allelic or genotypic data were included. Pooled odds ratios (ORs) were estimated using a random effects model, and 95% confidence intervals (CIs) were calculated. RESULTS: Twenty-eight case-control studies met the inclusion criteria. Carriage of the epsilon2 allele had no effect on disease risk. On the contrary, carriage of the epsilon4 allele was associated with a significantly increased disease risk (epsilon4 carriers vs non-epsilon4 carriers: OR, 1.94; 95% CI, 1.43-2.64; epsilon4 vs epsilon3 allele: OR, 1.83; 95% CI, 1.34 2.52). Furthermore, a gene-dosage effect for the epsilon4 allele was found. There was no evidence of publication bias, but heterogeneity between the studies was high. CONCLUSIONS: Our study provides evidence for an association between the APOE epsilon4 allele and frontotemporal lobar degeneration. PMID- 23688579 TI - The influence of environmental factors on the abundance and recruitment of the sand crab Emerita analoga (Stimpson 1857): source-sink dynamics? AB - The sandcrab Emerita analoga is the dominant species inhabiting sandy beaches along the Pacific coast of the American continent. In our study, 10 sandy beaches were sampled seasonally from 2006 to 2011, including coastal planktonic sampling from 2006 to 2008. Two major population cores were detected, the first one in the northern part of the study area and the second in the area immediately to the south of the Itata River mouth. Zoeal stages were found along the entire coastal zone. Highest densities and recruitment were found during spring and summer of each year. PLS regression indicated that source-sink habitat proxies correlated positively with morphodynamic parameters; while beach slope and total organic matter were negatively correlated. These results agree with the source-sink hypothesis, finding higher densities of adults, recruits and cohort recurrence on open coast beaches with milder physical dynamics. Furthermore, a hypoxic event and a mega-earthquake/tsunami negatively affected recruitment at the inter-annual scale. PMID- 23688580 TI - Disulfiram and its emerging role as an adjunctive anti-neoplastic agent. PMID- 23688581 TI - An unusual cause of foot clonus: spasticity of fibularis longus muscle. AB - The functional consequences of spasticity can be corrected by local, pharmacological or surgical treatments once the spastic muscle has been identified. However, this diagnosis can be tricky when the muscle in question is rarely involved in spasticity or when its mechanical action is unusual or poorly characterized. Here, we present the case of a man presenting with left hemiplegia after an ischaemic stroke. His gait was perturbed by foot clonus in the sagittal plan, which persisted after selective neurotomy of the gastrocnemius and soleus but disappeared after neurotomy of the peroneus longus. Clonus triggered by pushing up under the whole of the forefoot in the direction of dorsiflexion may not be related to spasticity of the triceps surae. We recommend screening for foot clonus by first pushing up on the sole of the foot under all five metatarsals. In a second step, selectively pushing up under the first metatarsal joint enables the physician to evidence spasticity of the peroneus longus. PMID- 23688582 TI - A hypervariable STR polymorphism in the CFI gene: southern origin of East Asian specific group H alleles. AB - Previous studies of four populations revealed that a hypervariable short tandem repeat (iSTR) in intron 7 of the human complement factor I (CFI) gene on chromosome 4q was unique, with 17 possible East Asian-specific group H alleles observed at relatively high frequencies. To develop a deeper anthropological and forensic understanding of iSTR, 1161 additional individuals from 11 Asian populations were investigated. Group H alleles of iSTR and c.1217A allele of a SNP in exon 11 of the CFI gene were associated with each other and were almost entirely confined to East Asian populations. Han Chinese in Changsha, southern China, showed the highest frequency for East Asian-specific group H alleles (0.201) among 15 populations. Group H alleles were observed to decrease gradually from south to north in 11 East Asian populations. This expansion of group H alleles provides evidence that southern China and Southeast Asia are a hotspot of Asian diversity and a genetic reservoir of Asians after they entered East Asia. The expected heterozygosity values of iSTR ranged from 0.927 in Thais to 0.874 in Oroqens, higher than those of an STR in the fibrinogen alpha chain (FGA) gene on chromosome 4q. Thus, iSTR is a useful marker for anthropological and forensic genetics. PMID- 23688583 TI - Parthenolide: from plant shoots to cancer roots. AB - Parthenolide (PTL), a sesquiterpene lactone (SL) originally purified from the shoots of feverfew (Tanacetum parthenium), has shown potent anticancer and anti inflammatory activities. It is currently being tested in cancer clinical trials. Structure-activity relationship (SAR) studies of parthenolide revealed key chemical properties required for biological activities and epigenetic mechanisms, and led to the derivatization of an orally bioavailable analog, dimethylamino parthenolide (DMAPT). Parthenolide is the first small molecule found to be selective against cancer stem cells (CSC), which it achieves by targeting specific signaling pathways and killing cancer from its roots. In this review, we highlight the exciting journey of parthenolide, from plant shoots to cancer roots. PMID- 23688584 TI - Measures of biosimilarity in monoclonal antibodies in oncology: the case of bevacizumab. AB - Biosimilars have been available on the European market since 2006 and experience with their use is increasing. The next wave of biopharmaceuticals that are about to lose patent protection consists of more-complicated products, including many monoclonal antibodies. Guidance has been released on the particulars of a biosimilarity exercise involving these products. Considerable challenges exist to establish biosimilarity for anticancer products. An especially challenging product is bevacizumab (Avastin((r))). On the basis of data available for the innovator product (bevacizumab) we will discuss strengths and weaknesses of preclinical and clinical models and explore the application of novel endpoints to the biosimilar comparability exercise. PMID- 23688585 TI - iPPI-DB: a manually curated and interactive database of small non-peptide inhibitors of protein-protein interactions. AB - The development of small molecule drugs targeting protein-protein interactions (PPI) represents a major challenge, in part owing to the misunderstanding of the PPI chemical space. To this end, we have manually collected the structures, the physicochemical and pharmacological profiles of 1650 PPI inhibitors across 13 families of PPI targets in a database named iPPI-DB. To access iPPI-DB, we propose a user-friendly web application (www.ippidb.cdithem.fr) with customizable queries and intuitive visualizing functionalities for associated properties of the compounds. This could assist scientists to design the next generation of PPI drugs. In this review, we describe iPPI-DB in the context of other low molecular weight molecule databases. PMID- 23688586 TI - Depletion of PHF14, a novel histone-binding protein gene, causes neonatal lethality in mice due to respiratory failure. AB - The plant homeodomain (PHD) finger is identified in many chromatin-binding proteins, and functions as a 'reader' that recognizes specific epigenetic marks on histone tails, bridging transcription factors and their associated complexes to chromatin, and regulating gene expression. PHD finger-containing proteins perform many biological functions and are involved in many human diseases including cancer. PHF14 is predicted to code for a protein with multiple PHD fingers. However, its function is unidentified. The aim of this study is to characterize PHF14 and investigate its biological significance by employing multiple approaches including mouse gene-targeting knockout, and molecular cloning and characterization. Three transcripts of PHF14 in human cell lines were identified by reverse transcriptase polymerase chain reaction. Two isoforms of PHF14 (PHF14alpha and PHF14beta) were cloned in this study. It was found that PHF14 was ubiquitously expressed in mouse tissues and human cell lines. PHF14alpha, the major isoform of PHF14, was localized in the nucleus and also bound to chromatin during cell division. Interestingly, co-immunoprecipitation results suggested that PHF14alpha bound to histones via its PHD fingers. Strikingly, gene-targeting knockout of PHF14 in mice resulted in a neonatal lethality due to respiratory failure. Pathological analysis revealed severe disorders of tissue and cell structures in multiple organs, particularly in the lungs. These results indicated that PHF14 might be an epigenetic regulator and play an important role in the development of multiple organs in mouse. PMID- 23688587 TI - Everolimus enhances the cytotoxicity of bendamustine in multiple myeloma cells through a network of pro-apoptotic and cell-cycle-progression regulatory proteins. AB - Bendamustine is a bifunctional alkylating agent with some efficacy in the treatment of newly diagnosed and relapsed/refractory multiple myeloma (MM). Everolimus, an mammalian target of rapamycin (mTOR) inhibitor, is a additional promising chemotherapeutic agent that has efficacy in a variety of cancers. We investigated the individual and combinational cytotoxic effects of these drugs in MM cell lines (RPMI8226 and MM1.S) and primary MM cells. Our results demonstrated a synergistic effect of these drugs, which was effective for both p53-wild-type and p-53-deleted MM cells, but was minimal in mononuclear cells from a healthy donor. Combination treatment with the two agents inhibited proliferation and promoted cytotoxicity and apoptosis as assessed by Annexin-V/PI staining, caspase 3 degradation, and PARP cleavage. Cell death was associated with the up regulation of the pro-apoptotic protein Bax and the down-regulation of the anti apoptotic proteins Mcl-1 and survivin. The combination drug treatment also promoted a decrease in the levels of the downstream target proteins of the mTOR pathway, p70s6k, and 4EBP-1, as well as an increase in the level of phosphorylation of the tumor suppressor protein p53 in MM1.S cells. p21 was also down-regulated upon treatment with the two drugs, suggesting a mechanism of sensitization through the release of cell cycle arrest. Our results demonstrate a network of regulatory factors that may contribute to the synergistic cytotoxicity of everolimus and bendamustine, and provide a rationale for application for the combinatorial treatment of MM with alkylating agents and mTOR inhibitors in future clinical practice. PMID- 23688588 TI - Study of the interaction of salmon sperm DNA with myricitrin-CPB based on the enhanced resonance light scattering signal and its potential application. AB - A new assay of salmon sperm DNA at nanogram level was established based on enhanced resonance light scattering (RLS) signals of DNA with myricitrin and cetylpyridinium bromide dihydrate (CPB). The RLS spectral characteristics of DNA with myricitrin-CPB and the optimum conditions for determination of DNA samples have been studied. At pH 7.4, myricitrin-CPB could enhance the intensity of RLS signal of DNA at 468 nm. The enhanced RLS intensity was directly proportional to DNA concentration in the range of 0.076-4.2 MUg mL(-1) with a good linear relationship (r=0.9944). The detection limit was 4.1 ng mL(-1). The synthetic samples were analyzed with satisfactory results that the recovery was 100.9 102.6% and RSD was 1.4-2.1%, which proved that the new method was reliable and applicable. PMID- 23688589 TI - Radical pleurectomy and chemoradiation for malignant pleural mesothelioma: the outcome of incomplete resections. AB - BACKGROUND: The type of surgery (radical pleurectomy (RP) vs. extrapleural pneumonectomy (EPP)) remains controversial for malignant pleural mesothelioma (MPM). Macroscopic complete resection (MCR) is a key prognostic factor. It is unclear, if patients undergoing incomplete RP within a standardized multimodality treatment protocols have any advantage in terms of survival and if EPP could theoretically have avoided incomplete resections (R2). METHODS: Eighty-eight patients underwent RP followed by chemoradiation from 2002 to 2011 within a prospective multimodality treatment study at a single institution. MCR were compared to R2 within this patient cohort retrospectively. EPP eligibility was assessed retrospectively based on preoperative cardiopulmonary testing and theoretical feasibility to achieve MCR. Kaplan-Meier analyses, log-rank test and Cox regression analyses were used to estimate survival and to determine predictors of survival. RESULTS: For the complete patient cohort, median survival (MS) was 26.3 months (mo). MCR could be achieved in 64.8% (57/88). Compared to MCR patients, R2-patients (n = 31, 35.2%) had an inferior overall survival (MS 13 vs. 33 mo, P < .0001), shorter progression-free-survival (MS 9 vs. 16 mo, P < .0001) and inferior survival after disease progression (MS 4 vs. 11 mo; P < .0001), respectively. R2 was associated with advanced p-T-Status (P < .0001), p-N Status (P = 0.046) and p-IMIG stage (P < .0001). No difference could be observed with regard to age, histology, laterality, surgical morbidity and mortality, respectively. Only 3 out of 88 patients (3.4%) would have been eligible for EPP to achieve MCR. Not resectable T4-disease and impaired cardiopulmonary reserves were the main reasons for ineligibility for EPP in 35.5% (11/31) and 48.4% (15/31), respectively. CONCLUSIONS: R2 in patients undergoing RP is associated with inferior outcomes. Only very selected cases would have qualified for EPP to achieve MCR. EPP might be an important surgical extension in selected patients to achieve MCR. There is a need for further investigation of effective intrapleural additive treatment options for patients undergoing R2. PMID- 23688590 TI - Informal payments for health care services in Russia: old issue in new realities. AB - Informal payments can be found across Europe, Africa, Asia and South America. Despite its hidden nature, they pose an important policy issue. Reported as being widespread, the true scale and scope of informal payment are unknown, and estimations differ among studies. We look at the Russian health care sector where the existence of informal payments has persisted for decades. We present the scale and scope of informal payments, as well as patterns of informal payments and their determinants. We discuss the reasons for discrepancies in estimations and implications for the ongoing reforms. PMID- 23688591 TI - Individual and combined effects of Fusarium toxins on the mRNA expression of pro inflammatory cytokines in swine jejunal epithelial cells. AB - Fusarium toxins have been arousing public interest in recent years because of their potential health hazards for humans and agricultural livestock. It was hypothesized that selected pro-inflammatory cytokines might serve as sensitive biomarkers of the predicted adverse effects of Fusarium toxins on the basis of their potential ability to induce immune and intestinal alterations comparable to those in human chronic inflammatory infection. Consequently, the aim of this study was to elucidate individual and combined effects of four common Fusarium toxins, deoxynivalenol (DON), nivalenol (NIV), zearalenone (ZEA) and fumonisin B1 (FB1) on the mRNA expression of pro-inflammatory cytokines (IL1alpha, IL1beta, IL6, IL8, TNFalpha and MCP-1) using a porcine jejunal epithelial cell line, IPEC J2. Based on a dose-response relationship between individual mycotoxins and cell viability (MTT assay) that was previously established, cytotoxic and non cytotoxic concentrations were selected to investigate combinations of two, three and all four of the mycotoxins. In general, up-regulation of pro-inflammatory cytokine mRNA expression occurred for both individual and mixtures of Fusarium toxins at cytotoxic concentrations, whereas significant up-regulation of pro inflammatory cytokine mRNA mostly obtained when the toxins existed in mixtures at non-cytotoxic concentrations and these mixtures were found to cause cytotoxicity from MTT assay determined previously. Therefore, it may be concluded that some of the changes in the mRNA expression of IL1alpha, IL1beta, IL6, IL8, TNFalpha and MCP-1 could be cytotoxicity-related. It was also noted that additive effects were not always observed for the mixtures. These data suggest that individual or mixtures of Fusarium toxins could cause or exacerbate intestinal inflammation. These also provide a better understanding of the possible effects of Fusarium toxins, alone or in combinations on the immunological defense mechanisms of IECs, which would contribute to the risk assessment of these toxins. PMID- 23688592 TI - One-step primary reconstruction for complex craniofacial resection with PEEK custom-made implants. AB - PURPOSE: Reconstruction of large craniofacial defects has largely improved since custom-made implants have been developed in the past decade. For large lesions in fronto-orbital region (such as osteomeningioma), we applied a simple and reliable protocol to perform optimal primary reconstruction with PEEK (polyetheretherketone) specific implant at the same time of the resection. MATERIAL AND METHODS: Our protocol is based on virtual preoperative surgery with a planned bone resection that allows engineering of a specific implant to accurately fit to the defect during the surgery. Thus tumour removal and optimal immediate reconstruction are performed easily in a single-step procedure. The use of navigation is required to perform accurate resection according to the planning. We report our experience in five patients requiring complex orbito frontal reconstruction. RESULTS: Planned resection was always achieved with accurate placement of the implant. Optimal orbital reconstruction is allowed and permits exophthalmos correction and orbital contour symmetry. No major complication was observed. CONCLUSION: We provide a simple one-step technique to reconstruct the orbit while achieving symmetric cosmetic and functional results, reducing operative time and avoiding donor site morbidity. PMID- 23688593 TI - Management of superolateral dislocation of the mandibular condyle: a retrospective study of 10 cases. AB - INTRODUCTION: Superolateral dislocation of the mandibular condyle (SDMC) is rarely described. The best treatment for superolateral dislocation of the fractured mandibular condyle (SDMC) is debated. This study investigated selection of the timing and techniques used in treating these fractures. PATIENTS AND METHODS: A retrospective clinical study was conducted on clinical data from 10 SDMC patients. Maximum mouth opening and occlusal relationships were compared following treatment using different techniques. RESULTS: The 10 patients were followed for 6-25 months. Patients who had dislocation for less than 1 week had condylar reduction and rigid internal fixation of the fractures. Mandibular sagittal split ramus osteotomy and articular reduction and fixation were performed in seven cases. Postoperative mouth opening and occlusal relationships were satisfactory in all patients with the exception of one case with mouth opening of only 27 mm. CONCLUSIONS: For all patients with superolateral dislocation, our first approach was to reduce the bone stump through surgery. When the dislocated joint had become adherent to the surrounding tissues and ankylosis developed, mandibular sagittal split ramus osteotomy was performed with good results. PMID- 23688594 TI - Endoscopic transmaxillary transMuller's muscle approach for decompression of superior orbital fissure: a cadaveric study with illustrative case. AB - BACKGROUND: In an effort to avoid the damage and inconvenience associated with transcranial approaches, we developed an endoscopic transmaxillary transMuller's muscle approach for decompression of the superior orbital fissure (SOF). METHODS: The endoscopic transmaxillary transMuller's muscle route was performed in ten cadaveric heads. We measured important anatomic landmarks, and angles radiographically. This approach was initially attempted in one patient with traumatic superior orbital fissure syndrome (tSOFS). RESULTS: A maxillary antrostomy was carried out with a buccal sulcus incision. The sinus ostium and the course of infraorbital nerve were used as endoscopic anatomic landmarks. Then the inferior orbital fissure was drilled out, followed by separating the Muller's muscle. The periorbita were peeled off from the lateral wall, followed by the endoscope going along the periorbital space, until the lateral aspect of the SOF could be visualized. Decompression was successfully performed in all specimens. The initial clinical application justified this approach. The patient had an uneventful postoperative course and satisfactory recovery. CONCLUSION: This approach offers sufficient endoscopic visualization and reliable decompression of SOF. It avoids the need for brain retraction, temporalis muscle manipulation, or any external incision, and appears to be able to deliver satisfying aesthetic results as well as favourable functional recovery. PMID- 23688595 TI - Extranodal lymphomas of head and neck with emphasis on NK/T-cell lymphoma, nasal type. AB - PURPOSE: To determine the occurrence, clinical course and outcome of our patients with natural killer/T-cell lymphoma (NKTCL), nasal type. The nasal type of natural killer/T-cell lymphoma (NKTCL), is rare in the European population but is more frequent in Asia, Central and South America where it accounts for 15-20% of all non-Hodgkin lymphomas (NHL). This type of lymphoma is characterized by tissue necrosis and destruction of the nasal cavity and upper aero-digestive tract. The disease is closely associated with Epstein-Barr virus (EBV) infection and has an aggressive clinical course, poor clinical outcome and high resistance to chemotherapy. PATIENTS: 63 patients with NHL were treated in our department between 2006 and 2011. Eleven patients were diagnosed with extranodal lymphoma, 6 in the area of head and neck. Three of them belonged to NKTCL, nasal type group (4.7%), 1 was diffuse large B cell lymphoma and 2 were marginal zone lymphomas. CONCLUSION: Two out of 3 patients with nasal type NKTCL, had extremely aggressive disease resistant to applied chemotherapy (anthracycline containing regimen), while 1 patient remains in complete remission 6 years after diagnosis. PMID- 23688596 TI - Monitoring the circadian rhythm of serum and salivary cortisol concentrations in the horse. AB - Daily fluctuations of cortisol concentration in the blood or saliva have been repeatedly reported. However, several contradictions in the existing literature appear on this subject. The present study was performed to definitively establish options for testing adrenocortical function. To the best of our knowledge, this is the first study to evaluate parallel circadian rhythms in salivary and serum cortisol concentrations during a 24-h period. Twenty horses were examined under the same conditions. Blood and saliva samples were taken every 2 h for 24 h to determine the daily changes in cortisol concentrations of saliva and serum at rest and to determine the relationship between salivary and serum cortisol levels. Cosinor analysis of group mean data confirmed a significant circadian component for both serum and salivary cortisol concentrations (P < 0.001 in both cases). The serum cortisol circadian rhythm had an acrophase at 10:50 AM (95% CI, 10:00 AM-11:40 AM), a MESOR of 22.67 ng/mL, and an amplitude of 11.93 ng/mL. The salivary cortisol circadian rhythm had an acrophase at 10:00 AM (95% CI, 9:00 AM 11:00 AM), a MESOR of 0.52 ng/mL, and an amplitude of 0.12 ng/mL. We found a significant but weak association between salivary and serum cortisol concentrations; the Pearson correlation coefficient was 0.32 (P < 0.001). The use of salivary cortisol level as an indicator of hypothalamic-pituitary-adrenal axis activity may be warranted. However, the salivary cortisol levels are more likely to be correlated with free plasma cortisol than with the total plasma cortisol concentration. PMID- 23688597 TI - Aseptic and alopecic nodules of the scalp. PMID- 23688598 TI - PDE2 and PDE10, but not PDE5, inhibition affect basic auditory information processing in rats. AB - Phosphodiesterase type 2 (PDE2), type 10 (PDE10), and type 5 (PDE5) have been considered as relevant targets for cognition enhancement. Although it is well established that PDE inhibitors (PDE-Is) improve memory functions in animals, the effects on auditory information processing are less clear. The aim of this study was to test the effects of PDE2 (BAY 60-7550), PDE5 (vardenafil) and PDE10 (PQ 10) inhibition on sensory gating in rats. Vehicle or 1mg/kg of a specific PDE-I was given orally 30min before testing. EEG was recorded from the hippocampus, striatum and vertex. Sensory gating was found for the N1 in the vertex and hippocampus, as revealed by diminished amplitudes to S2 compared to S1. Administration of PDE-Is did not affect sensory gating. However, PDE2 inhibition increased the P1 peak after presentation of S1 at the vertex and PQ-10 increased the N1 peak in general compared to vehicle treatment at the hippocampus. PDE2 and PDE10 inhibition affect auditory information processing in general, whereas PDE5 inhibition has no effect. These findings suggest that the positive effects of PDE5 inhibition on cognition previously found in animals are possibly the results of an effect on higher cognitive functioning specifically, whereas the cognition enhancing effects of PDE2 and PDE10 inhibition might also be influenced by effects on earlier stages of information processing. PMID- 23688599 TI - Interaction of light and surface plasmon polaritons in Ag islands studied by nonlinear photoemission microscopy. AB - Two photon photoemission microscopy was used to study the interaction of femtosecond laser pulses with Ag islands prepared using different strategies on Si(111) and SiO2. The femtosecond laser pulses initiate surface plasmon polariton (SPP) waves at the edges of the island. The superposition of the electrical fields of the femtosecond laser pulses with the electrical fields of the SPP results in a moire pattern that is comparable despite the rather different methods of preparation and that gives access to the wavelength and direction of the SPP waves. If the SPPs reach edges of the Ag islands, they can be converted back into light waves. The incident and refracted light waves result in an interference pattern that can again be described with a moire pattern, demonstrating that Ag islands can be used as plasmonic beam deflectors for light. PMID- 23688600 TI - Temporal and lateral electron pulse compression by a compact spherical electrostatic capacitor. AB - A novel solution for high intensity electron pulse compression in both space and time is proposed in this paper. Based on the unique properties of the central force electrostatic field of a spherical electrostatic capacitor, the newly developed alpha-Spherical Deflector Analyzer (alpha-SDA) with 2pi total deflection is utilized for the practical realization of femtosecond electron pulse compression. The mirror symmetry of the system at pi deflection causes not only the cancellation of the geometrical and chromatic aberrations at 2pi, but also leads to aberration-free time reversal of the electron pulse in the exit plane. As a consequence, the time-divergent electrons at the input are transformed to a time-convergent pulse at the output. In the symmetric case with the first time compression exactly at pi, the shortest electron pulse behind the alpha-SDA analyzer is a mirror symmetric to the original electron pulse at the photocathode. It results in extremely short final electron pulses that are limited only by the duration of the laser pulse, the emittance of the electron bunch, and by imperfections of the real system. PMID- 23688601 TI - Reverse hysterectomy: another technique for performing a laparoscopic hysterectomy. AB - STUDY OBJECTIVE: To show and evaluate outcomes of a modified laparoscopic hysterectomy technique (total reverse laparoscopic hysterectomy). DESIGN: Observational study (Canadian Task Force classification II-2). SETTING: Department of Women's and Children's Health, Obstetrics and Gynecology Clinic, University of Padova, Padova, Italy. PATIENTS: One hundred one women underwent total reverse laparoscopic hysterectomy for benign disease. Indications for surgery, patient characteristics, surgical data, complications, and patient satisfaction were recorded. INTERVENTIONS: Total reverse laparoscopic hysterectomy. MEASUREMENTS AND MAIN RESULTS: The modified procedure was performed starting with the incision of the vesicouterine fold and the pubocervical fascia followed by the dissection of only the anterior layer of the broad ligament, thus preserving the integrity of the posterior leaf (retrograde hysterectomy). This technique permits identification of the ureter until the cross with the uterine artery, creating a "safe triangle" for closure of the uterine vessels. The remaining surgical time did not differ from the standard technique. The average operating time was 112.1 +/- 35.6 minutes, and the average intraoperative mean blood loss was 79.5 +/- 138.4 mL. Ninety-one (90%) patients were very satisfied after surgery. No injuries to the ureter or bladder occurred in any patients. No other major complications were recorded. CONCLUSION: Reverse hysterectomy is another technique for performing laparoscopic hysterectomy, and it has been proven to be safe and efficient. PMID- 23688602 TI - Evaluation of a silver nitrate endometrial ablation fluid delivery system as a chemical treatment for menorrhagia. AB - STUDY OBJECTIVE: To explore the safety, feasibility, and effectiveness of silver nitrate-dextran paste delivered through the cervix as a simple and inexpensive endometrial ablation therapy for menorrhagia. DESIGN: Safety, feasibility, and effectiveness trials (Canadian Task Force classification II-3). SETTING: The trials were performed at the Whittington Hospital in London. PATIENTS: Seven women were treated for menorrhagia after prehysterectomy trials on 10 patients. Studies were first performed on rats and rabbits and human uterine specimens. INTERVENTION: We dissolved 10 g 75% silver nitrate/25% potassium nitrate and 15 g dextran 70 in 10 mL distilled water and delivered this paste through the cervix with a pressure-controlled syringe under fluroscopic monitoring. We planned silver nitrate doses of 500 mg in a 50-kg woman to remain in the uterus for 8 minutes after injection and then to be neutralized with normal saline and washed out. In uterine specimens, 8-minute treatment produced local necrosis to 4 mm. LD50 (lethal dose, 50%) studies in rats and mice ranged from 1100 to 2000 mg/kg. Prehysterectomy trials on 10 patients to evaluate safety revealed no penetration into the tubes and normal complete blood count, renal, cardiac, and liver tests with plasma silver rising to 20 to 30 MUmoles/L and returning to baseline after 4 weeks. Finally, 7 patients were treated and followed for 6 months. We followed blood values, complications, and degree of flow reduction. Six patients were well and discharged the same day; of those, all blood values were similar to the safety studies, 5 reported varying degrees of flow reduction, and 1 patient continued with menorrhagia. The seventh patient had passage of paste into the left fallopian tube and peritoneal cavity producing immediate pain. Laparoscopy showed several burns on the back of the uterus, sigmoid colon, and cul de sac. After neutralization with saline, she made a complete, uneventful recovery and became oligoamenorrheic. CONCLUSION: Silver nitrate could be a simple, inexpensive, safe, and potentially effective agent for endometrial ablation. However, to ensure safety, the fluid delivery system described herein must be abandoned. An alternative delivery system is needed, one which precisely controls the locus of caustic action, and further testing is required for effectiveness and safety. PMID- 23688603 TI - Combination therapy of human adipose-derived stem cells and basic fibroblast growth factor hydrogel in muscle regeneration. AB - Skeletal muscle regeneration after sport injury is inconsistent, and complete healing without fibrosis is very important. In this study, we determined whether the combination therapy using human adipose-derived stem cells (h-ADSCs) and basic fibroblast growth factor (bFGF) incorporated into hydrogel could enhance muscle regeneration in a muscle laceration animal model. The h-ADSCs and/or bFGF hydrogels were applied to the lacerated gastrocnemius muscle. Fast twitch muscle contraction improved significantly and fibrosis decreased significantly in combined h-ADSC and bFGF-hydrogel group compared to other experimental groups. Skeletal muscle differentiation of h-ADSCs was determined by immunohistochemistry (PKH-26/MyHC co-staining) and Western blot. Our data suggested that combination therapy of h-ADSCs and bFGF hydrogel resulted in functional recovery, revascularization and reinnervation with minimal fibrosis in lacerated muscle. A combination of h-ADSCs and bFGF hydrogel can be used as a promising therapy for skeletal muscle regeneration. PMID- 23688604 TI - Biodegradable polyglycerols with randomly distributed ketal groups as multi functional drug delivery systems. AB - Biodegradable multi-functional polymeric nanostructures that undergo controlled degradation in response to physiological cues are important in numerous biomedical applications including drug delivery, bio-conjugation and tissue engineering. In this paper, we report the development of a new class of water soluble multi-functional branched biodegradable polymer with high molecular weight and biocompatibility which demonstrates good correlation of in vivo biodegradation and in vitro hydrolysis. Main chain degradable hyperbranched polyglycerols (HPG) (20-100 kDa) were synthesized by the introduction of acid labile groups within the polymer structure by an anionic ring opening copolymerization of glycidol with ketal-containing epoxide monomers with different ketal structures. The water soluble biodegradable HPGs with randomly distributed ketal groups (RBHPGs) showed controlled degradation profiles in vitro depending on the pH of solution, temperature and the structure of incorporated ketal groups, and resulted in non-toxic degradation products. NMR studies demonstrated the branched nature of RBHPGs which is correlating with their smaller hydrodynamic radii. The RBHPGs and their degradation products exhibited excellent blood compatibility and tissue compatibility based on various analyses methods, independent of their molecular weight and ketal group structure. When administered intravenously in mice, tritium labeled RBHPG of molecular weight 100 kDa with dimethyl ketal group showed a circulation half life of 2.7 +/- 0.3 h, correlating well with the in vitro polymer degradation half life (4.3 h) and changes in the molecular weight profile during the degradation (as measured by gel permeation chromatography) in buffer conditions at 37 degrees C. The RBHPG degraded into low molecular weight fragments that were cleared from circulation rapidly. The biodistribution and excretion studies demonstrated that RBHPG exhibited significantly lower tissue accumulation and enhanced urinary and fecal excretion when compared to non-degradable HPG of similar molecular weight. Excellent biocompatibility together with in vivo degradability and clearance of RBHPGs make them attractive for the development of multi-functional drug delivery systems. PMID- 23688605 TI - First report of warfarin dose requirements in patients possessing the CYP2C9*12 allele. AB - BACKGROUND: Warfarin is the most frequently prescribed anticoagulant in North America and Europe. It is administered as a racemate, but S-warfarin is principally responsible for its anticoagulant activity. Cytochrome P450 (CYP) 2C9 is the enzyme primarily responsible for the metabolism of S-warfarin. Numerous variant alleles of CYP2C9 have been identified. The CYP2C9*12 (rs9332239) allele harbors a P489S substitution in CYP2C9 which has been shown to result in a 40% decline in catalytic activity in vitro. CASES: Four Caucasian patients with a low mean weekly warfarin dose (MWWD) were genotyped for CYP2C9, VKORC1 and APOE variant alleles. None of the four patients carried the common CYP2C9 variant alleles (*2, *3, *5, *6, *7, *8, *9, *11, *13) despite a relatively low MWWD (23.4+/-7.94 mg) compared to 208 patients carrying the CYP29C9*1 genotype (32.2+/ 12.65 mg). Given that CYP2C9*12 confers decreased in vitro activity to the enzyme, we investigated whether these patients carried this allele. All four patients were CYP2C9*12 CT heterozygotes. Individual comparisons with patients possessing the same VKORC1 and APOE genotypes also demonstrated lower dose requirements in the patients that possessed CYP2C9*12 allele. CONCLUSIONS: There are no reports of the clinical impact of rs9332239 on CYP2C9 substrates. This is the first report of patients with the rare CYP2C9*12 genotype and lower warfarin dose requirements. PMID- 23688606 TI - Label-free immunosensor for the detection of kanamycin using Ag@Fe3O4 nanoparticles and thionine mixed graphene sheet. AB - A highly sensitive label-free immunosensor for the detection of kanamycin had been developed using silver hybridized mesoporous ferroferric oxide nanoparticles (Ag@Fe3O4 NPs) and thionine mixed graphene sheet (TH-GS). TH was used as an electron transfer mediator. The electrical signal was greatly improved in the presence of GS due to its good electron-transfer ability. With the advantages of large specific surface area and excellent electrical conductivity, Ag@Fe3O4 NPs could immobilize more antibodies of kanamycin and promote the electron transfer. Cyclic voltammetry and square wave voltammetry were used to characterize the recognition of kanamycin. The proposed immunosensor showed good performances such as low detection limit (15 pg mL-1), wide linear range (from 0.050 to 16 ng mL 1), short analysis time (3 min), high stability, and good selectivity in the detection of kanamycin. The immunosensor was evaluated for pork meat sample, receiving satisfactory results. PMID- 23688607 TI - Novel functional variants locus in PLCE1 and susceptibility to esophageal squamous cell carcinoma: based on published genome-wide association studies in a central Chinese population. AB - A novel functional single nucleotide polymorphism (SNP) rs2274223 located in the phospholipase C epsilon 1 (PLCE1) gene was found to be associated with the risk of esophageal squamous cell carcinoma (ESCC) by three large-scale genome-wide association studies (GWAS) in Chinese populations. In the present study, we validated this finding and also explored the risk of ESCC associated with other two unreported potentially functional SNPs (rs17417407 G>T and rs2274224 C>G) of PLCE1 in a population-based case-control study to investigate the association between these three potentially functional SNPs in PLCE1 and susceptibility to ESCC. A total of 381 ESCC cases and 420 controls matched by age and sex were recruited and successfully genotyped for three SNPs (rs17417407, rs2274223 and rs2274224) of the PLCE1 in a central Chinese population. SNP rs2274223 was independently associated with increased risk of ESCC (adjusted odds ratio [OR], 2.80; 95% confidence interval [95% CI], 1.45-5.39 for GG vs. AA), and SNP rs2274224 was found to be associated with decreased risk of ESCC (adjusted OR, 0.65; 95% CI, 0.46-0.91 for CG vs. CC). The combined effects of risk alleles for three SNPs (rs17417407T, rs2274223G and rs2274224G) were found to be associated with elevated risk of ESCC in a dose-dependent effect manner (Ptrend=0.005). The Grs17417407Ars2274223Crs2274224 haplotype decreased the risk of ESCC (adjusted OR, 0.76; 95% CI, 0.62-0.93), meanwhile the Grs17417407Grs2274223Crs2274224 and Trs17417407Grs2274223Crs2274224 haplotypes could increase the risk of ESCC (adjusted OR, 1.75; 95% CI, 1.33-2.18 and OR, 2.51; 95% CI, 1.15-2.49). Gene environment interaction analysis presented a best model consisted of four factors (rs2274223, rs2274224, family history, and smoking) with testing balance accuracy (TBA): 0.66 and cross validation consistency (CVC): 7/10, which could increase the esophageal cancer risk in the "high risk group" with 3.67-fold (OR: 3.67, 95% CI: 2.74-4.92), compared to the "low risk group". Our results further confirmed that genetic variations in PLCE1 may contribute to ESCC risk associated with tobacco exposure in a central Chinese population. Further functional studies are needed to validate our results. PMID- 23688608 TI - A pulsatile blood vessel system for a femoral arterial access clinical simulation model. AB - The model-based, rapid-prototyping-enabled design and manufacture of a pulsatile blood vessel (PBV) for high-fidelity mannequin-based clinical simulations is presented. The PBV presented here is a pressurized, flexible tube with alternating fluid pressure created by a pump to mimic the behavior of a human vessel in response to pulsatile pressure. The use of PBVs is important for the fidelity of a clinical simulator that requires residents to palpate and/or access the vessel. In this study, a PBV is presented which features the integration of 3D modeling using patient-specific computed tomography (CT) data, mold fabrication using rapid-prototyping, and finite element method for estimating the required pumping pressure to generate the same level of force (about 1.5 N) experienced by the user through palpation. The relationship between this palpation force and the vessel pressure is studied using two strategies: finite element analysis (FEA) and experiments in a femoral arterial access simulator with a pump, artificial vessel, and surrounding phantom tissue. The experimental results show a discrepancy of 8.7% from the FEA-predicted value. Qualitative validation is done by exposing and surveying 19 interventional cardiology residents at four major educational institutions to the simulator for accuracy of its feel. The overall survey results are positive. PMID- 23688609 TI - Evaluation of carbohydrates and lignocellulosic biomass from different wood species as raw material for the synthesis of 5-bromomethyfurfural. AB - The influence of different parameters on the conversion of carbohydrates and biomass into the potential biofuel intermediate 5-bromomethylfurfural (BMF) has been studied. Our optimized conditions avoid the use of lithium salt additives, making this method cheaper and environmentally more benign compared to previously reported methods. Different wood species and their potential as a raw material in BMF and furfural production have also been evaluated. In addition, we report a very simple and efficient procedure for conversion of 5-hydroxymethylfurfural (HMF) into BMF or 5-chloromethylfurfural (CMF). PMID- 23688610 TI - [Unilateral optic neuritis and Miller Fisher syndrome]. AB - INTRODUCTION: Miller Fisher syndrome is an autoimmune neuropathy characterized by the clinical triad of ataxia, areflexia and external ophthalmoplegia. Ophthalmologic involvement in this syndrome is most often represented by motility disorders. The diagnosis is confirmed by the presence of anti-GQ1b antibodies. OBSERVATION: We report the case of a 65-year-old patient referred by his treating physician to the emergency department for ataxia, dizziness and decreased visual acuity in the left eye. In addition, the patient presented with clinical signs of subacute appendicitis for 2 weeks. After treatment with intravenous immunoglobulin, the patient complained of further decreased visual acuity and oculomotor disorders. On ophthalmological follow-up, he quickly recovered his initial visual acuity and more gradually his ocular motility. DISCUSSION: Unilateral optical neuropathy does not preclude the diagnosis of Miller Fisher syndrome. On the contrary, in the case of any rapidly progressive ophthalmologic involvement associated with peripheral neurological signs of ataxia, the diagnosis of Miller Fisher syndrome must be considered. CONCLUSION: Miller Fisher is a rare syndrome for which the diagnosis must be made quickly, so that the patient may benefit from urgent intravenous immunoglobulin therapy. In most cases, ophthalmologic recovery precedes peripheral neurologic recovery by 6 months to 1 year. PMID- 23688611 TI - Calcification of a hydrophilic acrylic intraocular lens: case report with laboratory analysis. AB - We analyzed a single-piece plate-type hydrophilic acrylic posterior chamber intraocular lens (IOL) that was explanted due to a progressive loss of vision, which occurred 6 years after uncomplicated phacoemulsification. Gross and light microscopy, as well as anterior segment optical coherence tomography (OCT) revealed granular deposits below the IOL surface. Light scattering, as measured with Scheimpflug photography and densitometry analyses was found to be increased; spectrophotometry demonstrated a decrease in the light transmittance of the explanted lens. The granular deposits within the IOL material were found to be composed of calcium by histochemical methods (alizarin red and Von Kossa stains). To our knowledge this is the only report of calcification of this IOL design. PMID- 23688612 TI - Ocular manifestations of the potentially lethal rheumatologic and vasculitic disorders. AB - Vision threatening ocular inflammation may occur in patients with any of the acquired connective tissue disorders and vasculitic diseases. Additionally, the ocular inflammation may be the presenting manifestation of the disease, which leads the patient to seek medical care. Other manifestations of the potentially lethal disease may be subtle or absent, presenting the thoughtful ophthalmologist with the opportunity to make life saving discoveries. Necrotizing scleritis, peripheral ulcerative keratitis, and retinal vasculitis are the ocular findings which should prompt the ophthalmologist to initiate very aggressive measures aimed at discovering any evidence of extra-ocular abnormalities, laboratory or otherwise. Appropriate therapy will be sight saving and may be life saving. PMID- 23688613 TI - [Secondary opacification of hydrophilic acrylic intraocular lenses: report of two cases]. AB - PURPOSE: To describe two cases of secondary opacification of hydrophilic acrylic IOLs after vitreoretinal surgery. METHODS: Analysis of IOL deposits with anterior segment optical coherence tomography (OCT Visante((r))) and high-frequency ultrasound biomicroscopy (CineScan HF, Quantel Medical((r))) was carried out preoperatively. The explanted IOLs were analyzed with optical and electron microscopy, and energy dispersive spectrometry (EDS). RESULTS: In both patients, the deposits were located on the surface and within the implant and were composed of calcium phosphate crystals. Vitreoretinal surgery performed a few months prior to the secondary opacification was identified as a risk factor. CONCLUSION: When a patient presents with a secondary opacification of the IOL involving the visual axis, explantation is sometimes necessary, fortunately with typically good functional recovery in the postoperative period. While this complication is rare and the exact pathophysiology poorly understood, it must be considered in a pseudophakic patient with an unexplained decrease in visual acuity who has undergone more than one intraocular procedure. PMID- 23688614 TI - Chromosome aberrations in normal human fibroblasts analyzed in G0/G1 and G2/M phases after exposure in G0 to radiation with different linear energy transfer (LET). AB - We have studied the induction of chromosome aberrations in human fibroblasts exposed in G0/G1 to X-rays or heavy ions to study the influence of G1 cell cycle arrest. Confluent normal fibroblasts were exposed to X-rays or accelerated particles with different LET values and chromosome aberrations were investigated in the first G0/G1 and G2//M phase. The particles used here were 490MeV/nucleon Si, 500MeV/nucleon Fe, and 200MeV/nucleon Fe ions. Cells were subcultured 24h after exposure and premature chromosome condensation (PCC) was performed by fusion-induced method for analysis of G0/G1 cells, and chemically-induced method for analysis of G2 and metaphase cells. Chromosome damage was assessed in chromosomes 1 and 3 using whole chromosome fluorescence in situ hybridization (FISH). Cell cycle was analyzed by flow cytometry at different incubation times following subculture. After irradiation with 2Gy of high-LET particles, the yields of chromosome aberrations and fragments were significantly higher in G0/G1 phase than in G2/M phase, whereas similar yields of damage were measured in both phases after exposure to X-rays. In contrast, the yield of misrepair, assessed by the number of color junctions, was similar in the G0/G1 and G2/M phases after exposure to either X-rays or high-LET particles. The yields of chromosome aberrations, fragments, and color junctions in both the G0/G1 and the G2/M phases, increased with LET up to 200keV/MUm, then decreased for 440keV/MUm Fe particles. A good correlation was found between chromosome aberrations in both G0/G1 and G2/M cells and survival fractions after 2Gy of different LET radiations, although the slopes were steeper for the G0/G1 cells. Flow cytometry analysis indicated that high-LET particles induce more non cycling G0/G1 cells within 48h of subculture than X-rays, suggesting that chromosome aberrations scored at the G2/M phase may not accurately describe the true radiation effect. PMID- 23688615 TI - Spatiotemporal dynamics of DNA repair proteins following laser microbeam induced DNA damage - when is a DSB not a DSB? AB - The formation of DNA lesions poses a constant threat to cellular stability. Repair of endogenously and exogenously produced lesions has therefore been extensively studied, although the spatiotemporal dynamics of the repair processes has yet to be fully understood. One of the most recent advances to study the kinetics of DNA repair has been the development of laser microbeams to induce and visualize recruitment and loss of repair proteins to base damage in live mammalian cells. However, a number of studies have produced contradictory results that are likely caused by the different laser systems used reflecting in part the wavelength dependence of the damage induced. Additionally, the repair kinetics of laser microbeam induced DNA lesions have generally lacked consideration of the structural and chemical complexity of the DNA damage sites, which are known to greatly influence their reparability. In this review, we highlight the key considerations when embarking on laser microbeam experiments and interpreting the real time data from laser microbeam irradiations. We compare the repair kinetics from live cell imaging with biochemical and direct quantitative cellular measurements for DNA repair. PMID- 23688616 TI - Antimutagenic and antioxidant properties of plumbagin and other naphthoquinones. AB - The structure-function relationships of the naphthoquinone phytochemicals, plumbagin, juglone, and menadione, have been studied with regard to antimutagenic and antioxidant activities. Antimutagenicity of these compounds was assessed by the Ames test and RNA polymerase B (rpoB)-based rifampicin resistance assay. Antioxidant potential was evaluated by radical scavenging assays and reducing power measurement. Protection of cells and DNA against gamma radiation-induced oxidative damage was assayed by survival analysis and gel electrophoresis profiling, respectively. On the 1,4-naphthoquinone nucleus, plumbagin possesses 5 hydroxyl and 2-methyl functional groups, whereas juglone has only the 5-hydroxyl and menadione only the 2-methyl group. Plumbagin showed strong antimutagenic (against ultraviolet and ethyl methanesulfonate) and antioxidant activities, whereas juglone displayed only strong antimutagenic, and menadione only strong antioxidant activities. Thus, these two functional groups (5-OH/2-CH3) play important roles in the differential bioactivity of naphthoquinones. Escherichia coli, microarray analysis showed upregulation of the genes rep (replication/repair), ybaK (tRNA editing), speE (spermidine synthesis), and yjfC (glutathionyl spermidine synthesis) by plumbagin or juglone, and sodC (superoxide dismutase), xthA (oxidative repair), hycB (electron carrier between hydrogenase 3 and fumarate dehydrogenase), and ligA (formation of phosphodiester bond in DNA) by plumbagin or menadione. Studies with E. coli single-gene knockouts showed that ybaK and speE, reported to prevent mistranslation, are likely to be involved in the antimutagenicity displayed by juglone, and sodC to be involved in the antioxidant activity of menadione. PMID- 23688617 TI - Delivery of definable numbers of PLGA microparticles within embryoid bodies. PMID- 23688618 TI - Selective JAK/STAT3 signalling regulates transcription of colony stimulating factor-2 and -3 in Concanavalin-A-activated mesenchymal stromal cells. AB - Human bone marrow-derived mesenchymal stromal cells (MSCs) express Toll-like receptors (TLRs) and produce cytokines and chemokines, all of which contribute to these cells' immunomodulatory and proangiogenic properties. Among the secreted cytokines, colony-stimulating factors (CSFs) regulate angiogenesis through activation of endothelial cell proliferation and migration. Since MSC are recruited within hypoxic tumors where they signal paracrine-regulated angiogenesis, the aim of this study was to evaluate which CSF members are expressed and are inducible in activated MSC. Furthermore, we investigated the JAK/STAT signal transducing pathway that may impact on CSF transcription. MSC were activated with Concanavalin-A (ConA), a TLR-2/6 agonist as well as a membrane type-1 matrix metalloproteinase (MT1-MMP) inducer, and we found increased transcription of granulocyte macrophage-CSF (GM-CSF, CSF-2), granulocyte CSF (G-CSF, CSF-3), and MT1-MMP. Gene silencing of either STAT3 or MT1-MMP prevented ConA-induced phosphorylation of STAT3, and reversed ConA effects on CSF-2 and CSF-3. Treatment with the Janus Kinase (JAK)2 inhibitor AG490 antagonized the ConA induction of MT1-MMP and CSF-2, while the pan-JAK inhibitor Tofacitinib reversed ConA-induced CSF-2 and -3 gene expression. Silencing of JAK2 prevented the ConA-mediated increase of CSF-2, while silencing of JAK1, JAK3 and TYK2 prevented the increase in CSF-3. Given that combined TLR activation and locally-produced CSF-2 and CSF-3 could regulate immunomodulation and neovascularization, pharmacological targeting of TLR-2/6-induced MT1 MMP/JAK/STAT3 signalling pathway may prevent MSC contribution to tumor development. PMID- 23688619 TI - Expression patterns of photoperiod and temperature regulated heading date genes in Oryza sativa. AB - In plants, flowering is a major biological phenomenon, which is regulated by an array of interactions occurring between biotic and abiotic factors. In our study, we have compared the expression profiles of flowering genes involved in the flowering pathway, which are influenced by conditions like photoperiod and temperature from seedling to heading developmental stages in two Oryza sativa indica varieties, viz., Zhenshan 97 and Minghui 63 using a expression network approach. Using the network expression approach, we found 17 co-expressed genes having the same expression profile pattern as three key photoperiod flowering genes Hd1, Ehd1 and Hd3a. We also demonstrated that these three co-expressed genes have a similar simulation pattern as temperature flowering genes. Based on our observations, we hypothesize that photoperiod and temperature regulate flowering pathways independently. The present study provides a basis for understanding the network of co-expressed genes involved in flowering pathway and presents a way to demonstrate the behavior of specific gene sets in specific cultivars. PMID- 23688620 TI - Influence of weaning regimen on intake, growth characteristics and plasma blood metabolites in male buffalo calves. AB - Experiment was conducted to evaluate the effect of weaning age on growth performance, feed intake, feed efficiency (FE) and blood metabolites in Nili-Ravi male buffalo (Bubalus bubalis) calves. Twenty-four male buffalo calves were assigned to one of the three treatment groups: continuous milk feeding (CMF), limited milk feeding (LMF) and early weaning (EW), and weaned off milk at 12, 10 and 8 weeks of age, respectively. For the first 3 days after birth, calves in all three treatments were fed colostrum, and were then moved to individual milk feeding at 10% of BW for the next 6 weeks. Thereafter, the provision of milk to the CMF group was gradually tapered to zero through week 12, using week 6 intakes as a base. The LMF calves were fed milk at 7.5%, 5.0%, 3.5%, and 1.5% of BW during weeks 7 to 10, respectively. Lastly, calves in the EW group were fed milk at 5.0% and 2.5% of BW at weeks 7 and 8, respectively. Calf starter (CS) feed was also provided ad libitum from weeks 2 to 12 and individual intakes were recorded on a daily basis. Blood samples were taken from weeks 6 to 12, on a weekly basis; whereas, the BW, heart girth, withers height and hip width were measured at the start of experiment and later on a weekly basis. Weight gain, average daily gain, and body measurements were the same across all three groups. Milk intake was lower (P < 0.05), whereas CS intake was greater (P < 0.05) in the EW calves compared with the other treatment groups. Dry matter intake was greater (P < 0.05) in the EW and LMF calves compared with the CMF calves. The FE was greater (P < 0.05) in the CMF calves compared with the LMF and EW treatment groups. Blood glucose concentration was similar among the treatments; however, blood urea nitrogen was greater (P < 0.05) in the EW calves compared with the CMF and LMF groups. Plasma concentration of non-esterified fatty acids was higher (P < 0.05) in the EW calves compared with the CMF calves. In light of these results, it is evident that buffalo calves can be successfully weaned as early as 8 weeks of age without negatively affecting their growth performance. PMID- 23688621 TI - Mesoporous carbon as a novel drug carrier of fenofibrate for enhancement of the dissolution and oral bioavailability. AB - The purpose of this study was to develop mesoporous carbon loaded with a poorly watersoluble drug to enhance the drug dissolution and improve the oral bioavailability. Mesoporous carbon was synthesized using Pluronic 127 triblock polymer (F127), TEOS and phenolic resins. Fenofibrate (FFB) was chosen as a model drug and loaded onto mesoporous carbon using three different loading methods involving incipient wetness impregnation, and the solvent and melting methods. The effect of the physical state and the specific surface area were investigated using nitrogen adsorption, transmission electron microscopy (TEM), powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC). It was found that the physicochemical properties of the drug as well as the drug loading methods had critical effects on the drug release rate. In vitro drug release studies showed that incorporation of FFB in mesoporous carbon greatly enhanced the dissolution rate in comparison with that of the pure crystalline drug. Moreover, the oral bioavailability of the drug from mesoporous carbon was higher than that of FFB commercial capsules. Furthermore, mesoporous carbon produced no irritation of the mucosa of the gastrointestinal tract as shown by gastric mucosa irritation test. PMID- 23688622 TI - Controlled release of cyclosporine A self-nanoemulsifying systems from osmotic pump tablets: near zero-order release and pharmacokinetics in dogs. AB - It is very important to enhance the absorption simultaneously while designing controlled release delivery systems for poorly water-soluble and poorly permeable drugs (BCS IV). In this study, controlled release of cyclosporine (CyA) was achieved by the osmotic release strategy taking advantage of the absorption enhancing capacity of self-nanoemulsifying drug delivery systems (SNEDDSs). The liquid SNEDDS consisting of Labrafil M 1944CS, Transcutol P and Cremophor EL was absorbed by the osmotic tablet core excipients (sucrose, lactose monohydrate, polyethylene oxide, and partly pregelatinized starch) and then transformed into osmotic tablets. Near zero-order release could be achieved for CyA-loaded nanoemulsions reconstituted from the SNEDDS. In general, the influencing factor study indicated that the release rate increased with increase of inner osmotic pressure, ratio of osmotic agent to suspending agent, content of pore-forming agent, and size of release orifice, whereas the thickness of the membrane impeded the release of CyA nanoemulsion. Pharmacokinetic study showed steady blood CyA profiles with prolonged Tmax and MRT, and significantly reduced Cmax for self nanoemulsifying osmotic pump tablet (SNEOPT) in comparison with highly fluctuating profiles of the core tablet and Sandimmune Neoral((r)). However, similar oral bioavailability was observed for either controlled release or non controlled release formulations. It was concluded that simultaneous controlling on CyA release and absorption-enhancing had been achieved by a combination of osmotic tablet and SNEDDS. PMID- 23688623 TI - Enhanced antitumor efficacy by methotrexate conjugated Pluronic mixed micelles against KBv multidrug resistant cancer. AB - A methotrexate (MTX) conjugated polymeric mixed micelles for MDR cancer therapy was developed in this study. To the best of our knowledge, MTX was firstly reported to be conjugated with Pluronic P105 (P105-MTX). The Pluronic F127 and P105-MTX polymeric mixed micelles (F127/P105-MTX) were fabricated by thin-film hydration technique, and performed superiority over physically entrapped MTX mixed micelles in drug loading capacity. The drug loading of MTX in F127/P105-MTX was found to be 3.42-fold higher than that of physically entrapped MTX mixed micelles. By conjugated to Pluronic, the amount of MTX in mixed micelles was increased 3.42-fold. In vitro cytotoxicity, cell apoptosis and cell cycle arrest studies also demonstrated that F127/P105-MTX had better antitumor efficacy in KBv MDR cells compared to that of physically entrapped mixed micelles. In comparison with MTX injection, F127/P105-MTX can significantly enhance blood circulation time of MTX in rats. Moreover, a much stronger antitumor efficacy in KBv xenografts mice was observed in F127/P105-MTX group than that of MTX. Therefore, MTX-conjugated mixed micelles might be an effective platform for delivering chemotherapeutic agents to MDR tumors. PMID- 23688624 TI - Is there a role for radiotherapy in the primary management of primary central nervous system lymphoma? A single-centre case series. AB - AIMS: In recent years, the optimum primary management of primary central nervous system lymphoma (PCNSL) has evolved from combined modality chemoradiotherapy to chemotherapy alone. We describe a single-centre case series of PCNSL with a view to assessing the role of radiotherapy in primary disease management. MATERIALS AND METHODS: West of Scotland PCNSL cases between 2001 and 2010 were identified by neuropathology. Observational data were collected retrospectively from case notes and electronic systems. RESULTS: Forty-nine patients fulfilled the eligibility criteria. The median age was 61 years. Chemotherapy with a view to consolidation radiotherapy on completion was delivered to 61% (n = 30). Regimens varied, but were generally methotrexate-based. Chemotherapy was discontinued prematurely in 80% (n = 24) due to progressive disease (n = 12), intolerable toxicity (n = 7) or death (n = 4). In all patients who progressed or did not tolerate chemotherapy, treatment was changed to immediate salvage radiotherapy; modal irradiation was 40 Gy. Radiotherapy alone was delivered to those not suitable for chemotherapy (18%, n = 9) and best supportive care to those with poor performance status (18%, n = 9). The overall median survival was 8 months. In those receiving single modality radiotherapy or chemotherapy, the median survival was 5 and 8 months, respectively. For those completing chemoradiotherapy in its entirety, 3 year survival was 100%; in groups receiving salvage radiotherapy despite progressive disease or chemotherapy toxicity, moderate survival was maintained with immediate radiotherapy with 3 year survival rates of 33 and 60%, respectively. CONCLUSIONS: Although chemotherapy alone remains the optimal treatment of PCNSL, out with clinical trials only a minority of patients complete chemotherapy due to toxicity and disease progression; in such patients, immediate salvage radiotherapy provides an effective and safe alternative with maintenance of good outcomes. PMID- 23688625 TI - Factors influencing overall survival specific to adult low-grade astrocytoma: a population-based study. AB - AIMS: We report a population-based overall survival and prognostic factor analysis specific to adult patients diagnosed with low-grade astrocytoma (LGA). MATERIALS AND METHODS: All histologically confirmed cases of LGA diagnosed between 1992 and 1996 in the province of Ontario, Canada, were identified from the Ontario Cancer Registry and reviewed. RESULTS: In total, 182 patients were identified; the mean age was 50 years and the mean survival time was 4.1 years (standard deviation = 5.1 years). Fifty-four per cent of patients had a surgical excision and 46% were biopsied alone. Both univariate and multivariate analyses showed that patients aged <30 years were significantly more likely to undergo an excision as compared with a biopsy alone (odds ratio = 4.26, 95% confidence interval 1.54-11.77). For the entire cohort, we observed a significant relationship between decreasing survival as a function of increasing age at diagnosis. In the biopsy sub-group, relative to patient's age <30 years, the hazard of dying increased significantly according to age when stratified by decade. However, in those patients having had a primary surgical excision, the hazard of dying relative to patient's age <30 years was similar for those aged 30 49 years and then significantly greater as patient age surpassed 50 years. CONCLUSIONS: Age is a significant prognostic factor for LGA. Our analysis suggests that in those patients amenable to a primary tumour excision, a survival benefit may be confined to those under age 50 years. PMID- 23688626 TI - Clinical effectiveness of secondary interventions for restenosis after renal artery stenting. AB - OBJECTIVE: Secondary interventions for renal artery restenosis (RAS) after renal artery stenting are common, despite limited data about their effectiveness. This study was designed to evaluate the outcomes of endovascular treatment of recurrent RAS. METHODS: We conducted a retrospective review of patients who underwent renal artery stenting between 2001 and 2011 at Dartmouth-Hitchcock Medical Center. Patients who required secondary interventions were compared with control patients who underwent only primary interventions for RAS. Multivariate regression models were used to identify factors associated with successful outcomes, as measured by changes in blood pressure, estimated glomerular filtration rate, and number of antihypertensive medications required. RESULTS: Sixty-five secondary (57 patients) renal interventions were undertaken for recurrent RAS associated with progressive hypertension or renal dysfunction and compared with outcomes after 216 primary (180 patients) renal artery stenting procedures. Patients undergoing primary vs secondary interventions did not differ significantly in the number of preoperative antihypertensive medications used, comorbid conditions, or blood pressure. All primary and secondary interventions were performed with stents and showed no difference in procedural complications. At a mean follow-up of 23 months (range, 1-128 months), similar improvements in renal function and blood pressure were found between patients undergoing primary and secondary interventions, and there was no difference in rates of restenosis or survival between cohorts. Regression models showed that the use of embolic protection devices was associated with improved renal function after primary (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.1-3.8; P < .05) and secondary (OR, 4.7; 95% CI, 1.7-12.5; P < .05) interventions, whereas statin therapy was associated with improved renal (OR, 2.0; 95% CI, 1.3-3.2; P < .05) and blood pressure response (OR, 4.1; 95% CI, 1.1-14.9; P < .05) after secondary interventions. CONCLUSIONS: Patients undergoing secondary interventions for recurrent RAS have outcomes that are comparable with those for primary interventions. These data suggest that repeated endovascular procedures for RAS can be undertaken with similar expectations for clinical improvement and may be further improved by routine use of embolic protection devices and statin therapy. PMID- 23688627 TI - Outcomes of endovascular aneurysm repair on renal function compared with open repair. AB - OBJECTIVE: Recent studies have shown that progressive renal dysfunction may develop in patients after endovascular aneurysm repair (EVAR). Data are conflicting about the effect of EVAR on renal function compared with open repair (OR). The purpose of this study was to compare the effects of EVAR, both with transrenal fixation (TRF) and infrarenal fixation (IRF), vs OR on renal function detected with renal perfusion scintigraphy (RPS). METHODS: A prospective study was carried out from January 2003 to December 2007. Exclusion criteria included factors that could influence post-procedural renal function as: preoperative creatinine clearance level <65 mL/min for men and 60 mL/min for women, renal artery stenosis >60%, renal accessory artery planned to be covered by the endograft, single functioning kidney, hemodialysis, and kidney transplant. To evaluate renal function, an RPS was performed preoperatively, at 30 days, at 6 and 12 months, and then yearly. The glomerular filtration rate (GFR) was estimated with the Gates method. RESULTS: During the study period, 403 patients were enrolled; 243 (60%) had OR and 160 (40%) EVAR; among these, 83 (51%) had a TRF and 77 (48%) an IRF; 55 patients were excluded from the study. No statistical differences were observed between groups for demographics and risk factors. Statistically significant differences emerged between OR and EVAR for early postoperative death (4% vs 0%; P = .01). Follow-up ranged from 54 to 126 months (mean, 76 months) for OR and from 54 to 124 months (mean, 74 months) for EVAR (P = NS). Kaplan-Meier analysis survival rate at 9 years was 70% for OR and 58% for EVAR with a risk of secondary procedure of 9% and 34%, respectively (P < .0001). A deterioration of the GFR was observed during the follow-up in both groups with a decrease after 9 years of 11% in the EVAR group and 3% in the OR group respective to baseline (P < .001). A remarkable difference emerged on renal function between EVAR patients who required a secondary procedure compared with the other EVAR patients (P < .005). No significant differences emerged between TFR and IRF for GFR decline during the follow-up period. CONCLUSIONS: After EVAR, there is a continuous decline in renal function with respect to OR, regardless of fixation level and independently of pre-existing renal insufficiency. The risk of GFR impairment after EVAR should be taken into consideration in selecting patients with preoperative renal insufficiency. PMID- 23688628 TI - Surgeon education decreases radiation dose in complex endovascular procedures and improves patient safety. AB - OBJECTIVE: Complex endovascular procedures such as fenestrated endovascular aneurysm repair (FEVAR) are associated with higher radiation doses compared with other fluoroscopically guided interventions (FGIs). The purpose of this study was to determine whether surgeon education on radiation dose control can lead to lower reference air kerma (RAK) and peak skin dose (PSD) levels in high-dose procedures. METHODS: Radiation dose and operating factors were recorded for FGI performed in a hybrid room over a 16-month period. Cases exceeding 6 Gy RAK were investigated according to institutional policy. Information obtained from these investigations led to surgeon education focused on reducing patient dose. Points addressed included increasing table height, utilizing collimation and angulation, decreasing magnification modes, and maintaining minimal patient-to-detector distance. Procedural RAK doses and operating factors were compared 8 months pre- (group A) and 8 months post- (group B) educational intervention using analysis of variance with Tukey pairwise comparisons and t-tests. PSD distributions were calculated using custom software employing input data from fluoroscopic machine logs. RESULTS: Of 447 procedures performed, 300 FGIs had sufficient data to be included in the analysis (54% lower extremity, 11% thoracic endovascular aneurysm repair, 10% cerebral, 8% FEVAR, 7% endovascular aneurysm repair, 5% visceral, and 5% embolization). Twenty-one cases were investigated for exceeding 6 Gy RAK. FEVAR comprised 70% of the investigated cases and had a significantly higher median RAK dose compared with all other FGIs (P < .0001). There was no difference in body mass index between groups A and B; however, increasing body mass index was an indicator for increased RAK. PSD calculations were performed for the 122 procedures that focused on the thorax and abdomen (group A, 80 patients; group B, 42 patients). Surgeon education most strongly affected table height, with an average table height elevation of 10 cm per case after education (P < .0001). The dose index (PSD/RAK ratio) was used to track changes in operating practices, and it decreased from 1.14 to 0.79 after education (P < .0001). These changes resulted in an estimated 16% reduction in PSD. There was a trend toward a decrease in patient to detector distance, and the use of collimation increased from 25% to 40% (P < .001) for all cases; however, these did not result in a decrease in PSD. The number of cases that exceeded 6 Gy RAK did not change after education; however, the proportion of non-FEVAR cases that exceeded 6 Gy decreased from 40% to 20%. CONCLUSIONS: Surgeon education on the appropriate use of technical factors during FGIs improved operating practice, reduced patient radiation dose, and decreased the number of non-FEVAR cases that exceeded 6 Gy. It is essential that vascular surgeons be educated in best operating practices to lower PSD; nonetheless, FEVAR remains a high-dose procedure. PMID- 23688629 TI - Plasma metabolomic profiles predict near-term death among individuals with lower extremity peripheral arterial disease. AB - BACKGROUND: Individuals with peripheral arterial disease (PAD) have a nearly two fold increased risk of all-cause and cardiovascular disease mortality compared to those without PAD. This pilot study determined whether metabolomic profiling can accurately identify patients with PAD who are at increased risk of near-term mortality. METHODS: We completed a case-control study using (1)H NMR metabolomic profiling of plasma from 20 decedents with PAD, without critical limb ischemia, who had blood drawn within 8 months prior to death (index blood draw) and within 10 to 28 months prior to death (preindex blood draw). Twenty-one PAD participants who survived more than 30 months after their index blood draw served as a control population. RESULTS: Results showed distinct metabolomic patterns between preindex decedent, index decedent, and survivor samples. The major chemical signals contributing to the differential pattern (between survivors and decedents) arose from the fatty acyl chain protons of lipoproteins and the choline head group protons of phospholipids. Using the top 40 chemical signals for which the intensity was most distinct between survivor and preindex decedent samples, classification models predicted near-term all-cause death with overall accuracy of 78% (32/41), a sensitivity of 85% (17/20), and a specificity of 71% (15/21). When comparing survivor with index decedent samples, the overall classification accuracy was optimal at 83% (34/41) with a sensitivity of 80% (16/20) and a specificity of 86% (18/21), using as few as the top 10 to 20 chemical signals. CONCLUSIONS: Our results suggest that metabolomic profiling of plasma may be useful for identifying PAD patients at increased risk for near-term death. Larger studies using more sensitive metabolomic techniques are needed to identify specific metabolic pathways associated with increased risk of near-term all-cause mortality among PAD patients. PMID- 23688630 TI - The toe-brachial index in the diagnosis of peripheral arterial disease. AB - BACKGROUND: Peripheral arterial disease (PAD) can be diagnosed noninvasively by segmental blood pressure measurement and calculating an ankle-brachial index (ABI) or toe-brachial index (TBI). The ABI is known to be unreliable in patients with vascular stiffness and fails to detect the early phase of arteriosclerotic development. The toe vessels are less susceptible to vessel stiffness, which makes the TBI useful. However, the diagnostic limits used in guidelines, clinical settings, and experimental studies vary substantially. This review provides an overview of the evidence supporting the clinical use of the TBI. METHODS: A review of the literature identified studies reporting the use of the TBI regarding guideline recommendations, normal populations, correlations to angiographic findings, and prognostic implications. RESULTS: Eight studies conducted in a normal population were identified, of which only one study used imaging techniques to rule out arterial stenosis. A reference value of 0.71 was estimated as the lowest limit of normal based on the weighted average in studies with preheating of the limbs. A further seven studies showed correlations of the TBI with angiographic findings. The TBI had a sensitivity of 90% to 100% and a specificity of 65% to 100% for the detection of vessel stenosis. Few studies investigated the value of the TBI as a prognostic marker for cardiovascular mortality and morbidity, and no firm conclusions could be made. Studies have, however, shown correlation between the TBI and comorbidities such as kidney disease, diabetes, and microvasculature disease. CONCLUSIONS: In contrast to the well-defined and evidence-based limits of the ABI, the diagnostic criteria for a pathologic TBI remain ambiguous. Although several guidelines and reviews of PAD diagnostics recommend a TBI <0.70 as cutoff, it is not strictly evidence-based. The current literature is not sufficient to conclude a specific cutoff as diagnostic for PAD. The current studies in normal populations and the correlation with angiography are sparse, and additional trials are needed to further validate the limits. Large-scale trials are needed to establish the risk of morbidity and mortality for the various diagnostic limits of the TBI. PMID- 23688631 TI - Binding of heavy metals by algal biosorbents. Theoretical models of kinetics, equilibria and thermodynamics. AB - Biosorption is an extensively studied technology applied for the removal of heavy metal ions and other pollutants from aqueous solutions. Most biosorption research is focused on the experimentally measured sorption isotherms, kinetics and thermodynamics. The aim of this paper is to review a class of theoretical models developed for the interpretation of such experimental data related to biosorption of metal cations by alginate-containing sorbents (e.g. algal biosorbents). The focus is put on: (i) modeling the biosorption equilibrium isotherms (including the description of the pH and ionic strength effects); (ii) thermodynamics of biosorption; (iii) kinetics of biosorption; and (iv) metal ion binding modes. This review facilitates the choice of the model suitable for the given type of data and describes the most common mistakes made during the data analysis (e.g. the use of incorrect or oversimplified models). PMID- 23688633 TI - Activation of autophagy by globular adiponectin attenuates ethanol-induced apoptosis in HepG2 cells: involvement of AMPK/FoxO3A axis. AB - Hepatocellular apoptosis is an important pathological entity of alcoholic liver disease. Previously, we have shown that globular adiponectin (gAcrp) protects liver cells from ethanol-induced apoptosis by modulating an array of signaling pathways. In the present study, we investigated the role of autophagy induction by gAcrp in the suppression of ethanol-induced apoptosis and its potential mechanism(s) in liver cells. Here, we demonstrated that gAcrp significantly restores ethanol-induced suppression of autophagy-related genes, including Beclin 1 and microtubule-associated protein light chain (LC3B) both in primary rat hepatocytes and human hepatoma cell line (HepG2). Globular adiponectin also restored autophagosome formation suppressed by ethanol treatment in HepG2. Furthermore, inhibition of gAcrp-induced autophagic process by knock-down of LC3B prevented protection from ethanol-induced apoptosis. In particular, the autophagic process induced by gAcrp was involved in the suppression of ethanol induced activation of caspase-8 and expression of Bax. Moreover, knock-down of AMPK by small interfering RNA (siRNA) blocked gAcrp-induced expression of genes related to autophagy, which in turn prevented protection from ethanol-induced apoptosis, suggesting that AMPK plays an important role in the induction of autophagy and protection of liver cells by gAcrp. Finally, we also showed that gAcrp treatment induces translocation of the forkhead box O member protein, FoxO3A, into the nucleus, which may play a role in the induction of autophagy related genes. Taken together, our data demonstrated that gAcrp protects liver cells from ethanol-induced apoptosis via induction of autophagy. Further, the AMPK-FoxO3A axis plays a cardinal role in gAcrp-induced autophagy and subsequent inhibition of ethanol-induced apoptosis. PMID- 23688632 TI - Membrane mimetic surface functionalization of nanoparticles: methods and applications. AB - Nanoparticles (NPs), due to their size-dependent physical and chemical properties, have shown remarkable potential for a wide range of applications over the past decades. Particularly, the biological compatibilities and functions of NPs have been extensively studied for expanding their potential in areas of biomedical application such as bioimaging, biosensing, and drug delivery. In doing so, surface functionalization of NPs by introducing synthetic ligands and/or natural biomolecules has become a critical component in regard to the overall performance of the NP system for its intended use. Among known examples of surface functionalization, the construction of an artificial cell membrane structure, based on phospholipids, has proven effective in enhancing biocompatibility and has become a viable alternative to more traditional modifications, such as direct polymer conjugation. Furthermore, certain bioactive molecules can be immobilized onto the surface of phospholipid platforms to generate displays more reminiscent of cellular surface components. Thus, NPs with membrane-mimetic displays have found use in a range of bioimaging, biosensing, and drug delivery applications. This review herein describes recent advances in the preparations and characterization of integrated functional NPs covered by artificial cell membrane structures and their use in various biomedical applications. PMID- 23688634 TI - Downregulation of Ezh2 methyltransferase by FOXP3: new insight of FOXP3 into chromatin remodeling? AB - Transcription factor FOXP3 (forkhead box P3) is found initially as a key regulator in regulatory T cells. Recently its expression has been demonstrated in some non-lymphoid normal and cancerous cells. Now FOXP3 has been proven to regulate cancer-related genes, especially suppressor genes in breast cancer. But the mechanisms by which FOXP3 regulates suppressor genes are not fully determined. In this study, we found the inverse correlation between FOXP3 and Ezh2, an enzyme for histone H3K27 trimethylation (H3K27me3) and a central epigenetic regulator in cancer. The overexpression of FOXP3 weakened Ezh2's enhancement on the mammosphere formation, cell proliferation, directional migration, and colony forming ability of T47D cells. We demonstrated that FOXP3 could downregulate Ezh2 protein level and this depended on not only the FOXP3 expression amount, but also the nuclear localization of FOXP3. More importantly, we demonstrated FOXP3 accelerated Ezh2 protein degradation through the polyubiquitination-proteasome pathway by enhancing the transcription of E3 ligase Praja1 directly. These results provided a new mechanism for FOXP3 in histone modifications as an Ezh2 suppressor and supported new evidence for FOXP3 as a tumor suppressor in breast cancer. PMID- 23688636 TI - Alginate beads as a tool to handle, cryopreserve and culture isolated human primordial/primary follicles. AB - BACKGROUND: One major concern of grafting cryopreserved ovarian tissue to restore fertility in cancer patients is the possibility of reintroducing tumor cells. Cryopreservation of isolated primordial/primary follicles (PFs) may circumvent this problem. The aim of our work was to compare dimethyl sulfoxide (ME2SO) and ethylene glycol (EG) as cryoprotectants (CPAs) for slow-freezing of isolated human PFs in alginate. METHODS: Ovarian biopsies from four women were processed for follicle isolation. PFs were embedded in alginate (5-15 per group). Follicles were frozen-thawed using 1.4M ME2SO or 1.5M EG as CPAs. Fresh and cryopreserved isolated follicles were in vitro cultured (IVC) for 7 days. At different time periods (after isolation, cryopreservation and IVC), follicles were evaluated with live/dead assay (using fluorescent probes) and diameter measurement. Follicle viability was calculated according to the percentage of dead follicular cells and the presence of a live/dead oocyte. RESULTS: A total of 841 PFs were isolated, embedded in alginate and cryopreserved with ME2SO (n=424) or EG (n=259), or used as controls (n=158). After 7 days of IVC, a significant increase in follicle size was observed in the fresh and ME2SO groups, but not in the EG group. The percentage of totally viable PFs was not significantly different before or after seven days of culture in fresh (100% and 82%) or ME2SO (93.2% and 85.1%) tissue. The EG group showed significantly lower viability before (63.9%) and after IVC (66.2%) than the fresh and ME2SO groups. CONCLUSIONS: Our results show that 1.4M ME2SO yields better preservation of isolated PF viability after thawing and 7 days of IVC than 1.5M EG. Alginate constitutes an easy, safe hydrogel matrix to handle and cryopreserve isolated human follicles using ME2SO as a CPA. PMID- 23688635 TI - Nucleoid localization of Hsp40 Mdj1 is important for its function in maintenance of mitochondrial DNA. AB - Faithful replication and propagation of mitochondrial DNA (mtDNA) is critical for cellular respiration. Molecular chaperones, ubiquitous proteins involved in protein folding and remodeling of protein complexes, have been implicated in mtDNA transactions. In particular, cells lacking Mdj1, an Hsp40 co-chaperone of Hsp70 in the mitochondrial matrix, do not maintain functional mtDNA. Here we report that the great majority of Mdj1 is associated with nucleoids, DNA-protein complexes that are the functional unit of mtDNA transactions. Underscoring the importance of Hsp70 chaperone activity in the maintenance of mtDNA, an Mdj1 variant having an alteration in the Hsp70-interacting J-domain does not maintain mtDNA. However, a J-domain containing fragment expressed at the level that Mdj1 is normally present is not competent to maintain mtDNA, suggesting a function of Mdj1 beyond that carried out by its J-domain. Nevertheless, loss of mtDNA function upon Mdj1 depletion is retarded when the J-domain, is overexpressed. Analysis of Mdj1 variants revealed a correlation between nucleoid association and DNA maintenance activity, suggesting that localization is functionally important. We found that Mdj1 has DNA binding activity and that variants retaining DNA binding activity also retained nucleoid association. Together, our results are consistent with a model in which Mdj1, tethered to the nucleoid via DNA binding, thus driving a high local concentration of the Hsp70 machinery, is important for faithful DNA maintenance and propagation. PMID- 23688637 TI - Echinococcus multilocularis and Trichinella spiralis in golden jackals (Canis aureus) of Hungary. AB - Over the last decades the distribution area of the golden jackal (Canis aureus) has increased significantly in Europe, particularly in the Balkan Peninsula and in Central Europe. Vagrant individuals were described in many European countries. Herein, we report Echinococcus multilocularis (total worm count: 412) and Trichinella spiralis (101 larvae/g for muscles of the lower forelimb) infections in two golden jackals shot in Hungary. It is a new host record of E. multilocularis and T. spiralis in Europe and Hungary, respectively. As jackals migrate for long distances through natural ecological corridors (e.g., river valleys), they may play a significant role in the long distance spread of zoonotic parasites into non-endemic areas of Europe. Therefore, monitoring zoonotic parasites in this host species can be recommended in the European Union. PMID- 23688638 TI - In vitro and in vivo evaluation of the activity of pineapple (Ananas comosus) on Haemonchus contortus in Santa Ines sheep. AB - The development of resistance to anthelmintics has prompted research into alternative methods of controlling intestinal nematodes in ruminants. This study aimed to assess the activity of Ananas comosus on Haemonchus contortus in Santa Ines sheep. The aqueous extract of pineapple skin (AEPS), bromelain from pineapple stems (B4882) and residue from pineapple processing was evaluated in in vitro and in vivo tests. The enzymatic activity of substances was analyzed by the azocasein method. The egg hatch test (EHT) and larval development test (LDT) were performed using the Embrapa2010 isolate of H. contortus. In the in vivo test, 36 sheep artificially infected with H. contortus were divided into six groups: G1: 2 g/kg BW of the aqueous extract administered for three days; G2: 2 g/kg BW of the industrial pineapple residue for 60 days; G3: 180 mg/animal of bromelain in a single dose; G4: negative control I; G5: positive control (levamisole phosphate); and G6: negative control II. The eggs per gram (EPG) in the feces were counted till 28 days after treatment. LC50 and LC90 were obtained by the probit procedure, while the in vivo test results were analyzed by GLM. The aqueous extract in the in vitro and in vivo test, the bromelain and industrial residue presented 0.102, 0.157, 1.864 and 0.048 enzyme units/mL, respectively. In the egg hatch test, the LC50 and LC90 were respectively 31 and 81 mg/mL for the aqueous extract and 0.50 and 2 mg/mL for bromelain. In the larval development test, the LC50 and LC90 were respectively 1.7 and 7.3 mg/mL for the aqueous extract and 0.019 and 0.086 mg/mL for bromelain. In the in vivo test, the general efficacies of the treatments in relation to the negative control were 22.6%, 42.2%, 3.65% and 89% for the aqueous extract, industrial pineapple residue, bromelain and positive control respectively. The transformed EPG values were 3.19 +/- 0.59, 3.32 +/- 0.25, 2.85 +/- 0.66, 3.44 +/- 0.50, 2.28 +/- 0.93 and 2.75 +/- 0.94 for the aqueous extract, industrial residue, bromelain, negative control I, positive control and negative control II respectively. The results for all the treated groups differed significantly (p<0.05) from the positive control, and although the residue presented efficacy of 42.2%, there was no statistical difference (p>0.05) in relation to the negative control. Therefore, both the aqueous extract and bromelain were effective in vitro, but showed reduced anthelmintic efficacy in vivo. For the pineapple residue, the 42.2% in vivo efficacy in reducing the EPG and the possibility of reducing environmental contamination through reuse of industrial residue indicate it can also be useful for control of this parasite. PMID- 23688639 TI - Can we change patient behaviors to improve urological health? PMID- 23688640 TI - Early detection of prostate cancer continues to support rational, limited screening. PMID- 23688641 TI - Turning on the lights: new technologies in optical diagnostics and therapeutics. PMID- 23688642 TI - Balancing process and risk: standardizing posttreatment surveillance for renal cell carcinoma. PMID- 23688644 TI - Editorial comment. PMID- 23688645 TI - Adjuvant versus salvage post-prostatectomy radiation therapy: a critical review of the evidence. PMID- 23688646 TI - Surgeon responsibility. PMID- 23688648 TI - What's in a link: associative and taxonomic priming effects in the infant lexicon. AB - Infants develop a lexical-semantic system of associatively and semantically related words by the end of the second year of life. However, the precise nature of the lexical relationships that underpin the structure-building process remains under-determined. We compare two types of lexical-semantic relationship, associative and taxonomic, using a lexical-priming adaption of the intermodal preferential looking task with 21- and 24-month-olds. Prime-target word pairs were either associatively or taxonomically related or unrelated. A further control condition evaluated the facility of a prime word, in the absence of a target word, to promote target preferences. Twenty-four-month-olds, but not 21 month-old infants, exhibited a priming effect in both associative and taxonomic conditions, pointing to the formation of a lexical-semantic network driven by both associative and taxonomic relatedness late in the second year. The pattern of priming in 24-month-olds indicates the operation of inhibitory processes: unrelated primes interfere with target recognition whereas related primes do not. We argue that taxonomic and associative relationships between words are integral to the emergence of a structured lexicon and discuss the importance of inhibitory mechanisms in shaping early lexical-semantic memory. PMID- 23688649 TI - Blinded by an error. AB - Errors are typically followed by a series of behavioural changes. Although most of these changes are well understood, accuracy changes following errors are not. A new paradigm is presented where participants performed a flanker task followed by a rapid serial visual presentation (RSVP) of numbers (1-9). In most trials, a letter was presented on three possible positions of the RSVP (1-3-6). This was done with and without immediate feedback on the flanker task. In both experiments participants had worse target detection after an error in the flanker task. These findings support non-functional accounts for error monitoring that predict decreased post-error performance (Dudschig & Jentzsch, 2009; Jentzsch & Dudschig, 2009; Notebaert et al., 2009). In a third experiment we tried to dissociate between a bottleneck and an orienting account and showed decreased target detection after irrelevant red signals, irrespective of frequency. This result is interpreted in support for the bottleneck account (Dudschig & Jentzsch, 2009; Jentzsch & Dudschig, 2009). PMID- 23688647 TI - Differential activation of neuronal cell types in the basolateral amygdala by corticotropin releasing factor. AB - Enhanced corticotropin releasing factor (CRF) release in the basolateral amygdala (BLA) is strongly associated with the generation of behavioral stress responses through activation of the CRF-R1 receptor subtype. Stress and anxiety-like behavior are modulated in part by the balance of peptide actions such as excitatory CRF and inhibitory neuropeptide Y (NPY) receptor activation in the BLA. While the actions of CRF are clear, little is known about the cell type influenced by CRF receptor stimulation. These studies were designed to identify the cell types within the BLA activated by intra-BLA administration of CRF using multi-label immunohistochemistry for cFos and markers for pyramidal (CaMKII immunopositive) and interneuronal [glutamic acid decarboxylase (GAD65)] cell populations. Administration of CRF into the BLA produced a dose-dependent increase in the expression of cFos-ir. Intra-BLA injection of CRF induced significant increases in cFos-ir in the CaMKII-ir population. Although increases in cFos-ir in GAD65-ir cells were observed, this did not reach statistical significance perhaps in part due to the decreased numbers of GAD65-ir cells within the BLA after CRF treatment. These findings demonstrate that CRF, when released into the BLA, activates projection neurons and that the activity of GABAergic interneurons is also altered by CRF treatment. Decreases in the number of GAD65-ir neurons could reflect either increased or decreased activity of these cells and future studies will more directly address these possibilities. The expression of cFos is associated with longer term regulation of gene expression which may be involved in the profound long term effects of neuropeptides, such as CRF, on the activity and plasticity of BLA pyramidal neurons. PMID- 23688650 TI - Zinc deficiency and its management in the pediatric population: a literature review and proposed etiologic classification. AB - Zinc is a trace element essential to the gastrointestinal, immune, integumentary, reproductive, and central nervous systems. Zinc deficiency is prevalent in many areas of the world and is a diagnostically challenging condition. Cutaneous manifestations typically occur in moderate to severe zinc deficiency and present as alopecia and dermatitis in the perioral, acral, and perineal regions. Zinc deficiency is a potentially fatal disease process. The aim of this review is to focus on the cutaneous manifestations, diagnosis, and treatment of zinc deficiency in children, and to propose an etiologic classification system. PMID- 23688652 TI - Overview of cytokine and growth factor review focus on Australia. Preface. PMID- 23688651 TI - Comparative effectiveness of nonpurpuragenic 595-nm pulsed dye laser and microsecond 1064-nm neodymium:yttrium-aluminum-garnet laser for treatment of diffuse facial erythema: A double-blind randomized controlled trial. AB - BACKGROUND: Facial erythema is a common symptom that responds to vascular laser treatment, but there are few comparative studies. OBJECTIVE: We sought to compare the effectiveness of microsecond 1064-nm neodymium:yttrium-aluminum-garnet (Nd:YAG) laser with nonpurpuragenic 595-nm pulsed dye laser (PDL) for diffuse facial erythema. METHODS: This was a split-face, double-blind randomized controlled trial. Bilateral cheeks received 4 treatments each at one month intervals with PDL or Nd:YAG. Spectrophotometer measurements, digital photographs, pain scores, and patient preferences were recorded. RESULTS: Sixteen patients enrolled and 2 dropped out. Fourteen patients, all skin types I to III, 57% women, mean age 42 years, completed the study and were analyzed. Spectrophotometer readings changed after both PDL (8.9%) and Nd:YAG (2.5%), but varied by treatment type, with PDL reducing facial redness 6.4% more from baseline than Nd:YAG (P = .0199; 95% confidence interval -11.6 to -1.2). Pain varied (P = .0028), with Nd:YAG associated with less pain, at 3.07, than PDL at 3.87. Subjects rated redness as improved by 52% as a result of PDL, and 34% as a result of Nd:YAG (P = .031; 95% confidence interval -34.6 to -1.94). No serious adverse events were observed. LIMITATIONS: Lasers settings are not standardized across devices. CONCLUSION: Facial erythema is safely and effectively treated with PDL and Nd:YAG. Nonpupuragenic PDL may be more effective for lighter-skinned patients, but microsecond Nd:YAG may be less painful. PMID- 23688653 TI - Manipulating T cell-mediated pathology: targets and functions of monoclonal antibody immunotherapy. AB - Monoclonal antibody (mAb) technology has revolutionized treatment options for T cell mediated diseases. However, a safe, clinically available anti-T cell antibody (ab) remains elusive. Experience with anti-T cell agents and their propensity for causing immune-mediated toxicities have hampered the development of anti-T cell mAb's. Furthermore, misunderstanding regarding mechanism(s) of action of particular antibodies can influence development and clinical prescription habits. For example, the anti-CD3 Ab OKT3 is consistently described as a depleting Ab even though original studies showed the mechanism to be non lytic. Future anti-T cell mAbs are likely to be non-depletional and focused on the expansion of regulatory T cells. This review discusses how the properties of Abs can be exploited for manipulating pathological T cell responses in the clinic. PMID- 23688654 TI - Protocells for DNA cargo delivery to the spinal cord. PMID- 23688655 TI - Senescence-associated secretory phenotype in a mouse model of bleomycin-induced lung injury. AB - Bleomycin produces DNA damage, apoptosis and senescence, all of which play crucial roles in the development of pulmonary fibrosis. Recently, close attention has been paid to a DNA damage-induced phenotypic change (senescence-associated secretory phenotype; SASP) as a trigger for the secretion of various mediators which modify the processes of tissue injury, inflammation, repair and fibrosis. We characterized the SASP in a murine model of bleomycin-induced lung injury. Mice were intratracheally administered bleomycin or control saline, and the lungs were obtained on days 7, 14 and 21. The occurrence of DNA damage and the SASP in the lungs was examined by immunostaining. gammaH2AX immunostaining of the bleomycin-treated lungs revealed double-strand breaks (DSBs), largely within E cadherin-positive, beta4-integirn-positive alveolar epithelial cells. The DSBs were associated with phosphorylation of ATM/ATR, a central signal transducer mediating the DNA damage response, and upregulation of the cyclin-dependent kinase inhibitor p21(CIP1). The DSBs persisted for at least 21 days after the bleomycin exposure, although it began to wane after 7 days. A subpopulation of the gammaH2AX-positive, DNA-damaged cells exhibited the SASP, characterized by overexpression of IL-6, TNFalpha, MMP-2 and MMP-9, in association with the phosphorylation of IKKalpha/beta and p38 MAPK. Persistent DNA damage and the SASP are induced in the process of bleomycin-induced lung injury and repair, suggesting that these events play an important role in the regulation of inflammation and tissue remodeling in bleomycin-induced pneumopathy. PMID- 23688656 TI - Gene expression changes in rat brain after short and long exposures to particulate matter in Los Angeles basin air: Comparison with human brain tumors. AB - Air pollution negatively impacts pulmonary, cardiovascular, and central nervous systems. Although its influence on brain cancer is unclear, toxic pollutants can cause blood-brain barrier disruption, enabling them to reach the brain and cause alterations leading to tumor development. By gene microarray analysis validated by quantitative RT-PCR and immunostaining we examined whether rat (n=104) inhalation exposure to air pollution particulate matter (PM) resulted in brain molecular changes similar to those associated with human brain tumors. Global brain gene expression was analyzed after exposure to PM (coarse, 2.5-10MUm; fine, <2.5MUm; or ultrafine, <0.15MUm) and purified air for different times, short (0.5, 1, and 3 months) and chronic (10 months), for 5h per day, four days per week. Expression of select gene products was also studied in human brain (n=7) and in tumors (n=83). Arc/Arg3.1 and Rac1 genes, and their protein products were selected for further examination. Arc was elevated upon two-week to three-month exposure to coarse PM and declined after 10-month exposure. Rac1 was significantly elevated upon 10-month coarse PM exposure. On human brain tumor sections, Arc was expressed in benign meningiomas and low-grade gliomas but was much lower in high-grade tumors. Conversely, Rac1 was elevated in high-grade vs. low-grade gliomas. Arc is thus associated with early brain changes and low-grade tumors, whereas Rac1 is associated with long-term PM exposure and highly aggressive tumors. In summary, exposure to air PM leads to distinct changes in rodent brain gene expression similar to those observed in human brain tumors. PMID- 23688658 TI - ["The only thing worse than being talked about is not being talked about" (Oscar Wilde)]. PMID- 23688657 TI - Endoscopic endonasal management of congenital intranasal meningocele in a 2-month old infant. AB - INTRODUCTION: Nasal meningocele, which is usually congenital, is a rare anomaly resulting from meningeal herniation into the nasal cavities through a bone defect in the skull base. CASE REPORT: An 8-day-old boy was referred with respiratory disturbance and nasal obstruction. Examination showed a cyst-like grayish swelling filling the right nasal cavity. CT scan showed opacity, of fluid-like density, filling the right nasal fossa, in contact with a small bony defect in the right cribriform plate. MRI ruled out herniated brain parenchyma and enabled diagnosis of meningocele. The patient was operated on at the age of 2 months through a transnasal endoscopic approach. Immediate postoperative course was favorable. MRI control at 8 months was normal. DISCUSSION: Modern imaging (CT scan and MRI) is of paramount importance in the preoperative evaluation of nasal meningocele. Endoscopic endonasal (EE) surgery is currently the treatment of choice. CONCLUSION: Steady progress in instrumentation, technique and skills will increase the feasibility of skull-base surgery using an endonasal approach in the pediatric population. PMID- 23688659 TI - [Spinal anesthesia in pediatric surgical campaigns]. PMID- 23688660 TI - External factors impacting hospital evacuations caused by Hurricane Rita: the role of situational awareness. AB - INTRODUCTION: The 2005 Gulf Coast hurricane season was one of the most costly and deadly in US history. Hurricane Rita stressed hospitals and led to multiple, simultaneous evacuations. This study systematically identified community factors associated with patient movement out of seven hospitals evacuated during Hurricane Rita. METHODS: This study represents the second of two systematic, observational, and retrospective investigations of seven acute care hospitals that reported off-site evacuations due to Hurricane Rita. Participants from each hospital included decision makers that comprised the Incident Management Team (IMT). Investigators applied a standardized interview process designed to assess evacuation factors related to external situational awareness of community activities during facility evacuation due to hurricanes. The measured outcomes were responses to 95 questions within six sections of the survey instrument. RESULTS: Investigators identified two factors that significantly impacted hospital IMT decision making: (1) incident characteristics affecting a facility's internal resources and challenges; and (2) incident characteristics affecting a facility's external evacuation activities. This article summarizes the latter and reports the following critical decision making points: (1) Emergency Operations Plans (EOP) were activated an average of 85 hours (3 days, 13 hours) prior to Hurricane Rita's landfall; (2) the decision to evacuate the hospital was made an average of 30 hours (1 day, 6 hours) from activation of the EOP; and (3) the implementation of the evacuation process took an average of 22 hours. Coordination of patient evacuations was most complicated by transportation deficits (the most significant of the 11 identified problem areas) and a lack of situational awareness of community response activities. All evacuation activities and subsequent evacuation times were negatively impacted by an overall lack of understanding on the part of hospital staff and the IMT regarding how to identify and coordinate with community resources. CONCLUSION: Hospital evacuation requires coordinated processes and resources, including situational awareness that reflects the condition of the community as a result of the incident. Successful hospital evacuation decision making is influenced by community-wide situational awareness and transportation deficits. Planning with the community to create realistic EOPs that accurately reflect available resources and protocols is critical to informing hospital decision making during a crisis. Knowledge of these factors could improve decision making and evacuation practices, potentially reducing evacuation times in future hurricanes. PMID- 23688661 TI - Resident recruitment costs: a national survey of internal medicine program directors. PMID- 23688662 TI - Temporal trends in hospitalization rates for older adults with chronic obstructive pulmonary disease. AB - BACKGROUND: Over the last 15 years, substantial advances have been made in the treatment of chronic obstructive pulmonary disease (COPD). Little information is available, however, on whether these treatments have resulted in reduced rates of hospitalization and acute exacerbations among COPD patients. This retrospective cohort study examined changes in hospitalization rates among Medicare beneficiaries with COPD from 1999 to 2008. METHODS: We analyzed data from 424,418 fee-for-service Medicare beneficiaries enrolled between 1999 and 2008 who were diagnosed with COPD. We examined temporal changes in the frequency of hospitalization and acute exacerbations among Medicare beneficiaries with COPD. RESULTS: Over the 10-year study period, the hospitalization rates for COPD patients--adjusted for age, sex, race, socioeconomic status, region, and number of comorbidities--decreased: from 131 to 107 per 100 person-years for all causes (P <.001); from 58 to 44 per 100 person-years for all respiratory causes (P <.001); and from 73 to 63 per 100 person-years for nonrespiratory causes (P <.001). There was no change in prevalence of COPD in the Medicare population over this time. Additionally, the percentage of COPD patients hospitalized with 2 or more acute exacerbations decreased from 5.5% to 4.3% over the 10-year study period (P <.001). CONCLUSION: Between 1999 and 2008, hospitalization rates decreased substantially among Medicare beneficiaries diagnosed with COPD. PMID- 23688663 TI - Premature aging of cardiovascular/platelet function in polycystic ovarian syndrome. AB - OBJECTIVE: The objective of this study was to compare the impact of aging on nitric oxide (NO) modulation of platelet and vascular function in healthy women and women with polycystic ovary syndrome. METHODS AND RESULTS: A case-control study of women ages 18 to 60 years, comparing women with polycystic ovarian syndrome against age-matched healthy controls, was performed. A total of 242 women, of whom 109 had polycystic ovarian syndrome (based on Rotterdam criteria), participated in the study. Women who were pregnant or on clopidogrel were excluded from the study. Inhibition of platelet aggregation by nitric oxide (primary outcome measure), vascular endothelial function, plasma concentrations of N(G), N(G)-dimethyl-L-arginine (ADMA), endothelial progenitor cell count, and high-sensitivity C-reactive protein (markers of endothelial dysfunction and inflammation) were assessed. With increasing age in control women, there was progressive attenuation of platelet responses to NO, impairment of endothelial function, and elevation of ADMA levels (P <=.001). Irrespective of age, women with polycystic ovarian syndrome exhibited greater impairment of all these parameters (all P <.05, 2-way analysis of variance) and demonstrated these anomalies earlier in life. CONCLUSIONS: Normal aging in women is associated with attenuation of NO-based signaling in platelets and blood vessels. In women with polycystic ovarian syndrome, these changes are present from early adult life and may contribute to premature atherogenesis. PMID- 23688664 TI - Naming right: gnostic nomenclature vs useful names. PMID- 23688665 TI - Novel bisabolane derivative from "arnica-da-serra" (Vernonieae: Asteraceae) reduces pro-nociceptive cytokines levels in LPS-stimulated rat macrophages. AB - ETHNOPHARMACOLOGY RELEVANCE: Hydro alcoholic leaves extracts (HALE) of Lychnophora ericoides Mart. ("false arnica" or "arnica-da-serra") had been popularly used against pain and inflammatory process. AIM: The present work aimed to look for possible active volatile compounds that could be found in HALE of Lychnophora ericoides among the non volatile anti-inflammatory and analgesic compounds previously reported. METHODS: Harvests were performed during the end of the wet summer season (April) when scented branches were instantly collected and frozen. HALE's were simulated at the lab by following the procedures lectured by the locals. Mass Spectrometry experiments suggested structural information when using both EI-MS and ESI-MS/MS. After isolation through classical thin layer chromatography (TLC) procedures, the NMR experiments and signals assignments were carried out. The effects on the cytokines or nitric oxide (NO) production were assessed at in vitro assays that had monitored the levels of these substances on the supernatant of LPS-stimulated macrophage primary cell culture. RESULTS: The major metabolite from HALE was isolated from the essential oil and the major compound had its molecular formulae established by Mass Spectrometry (High Resolution) and its structure by NMR. Literature-based investigation enables us to define the structure of the new metabolite as 6-methyl-2-(4-methylcyclohex-4 enyl-2-acetyloxy) hept-5-en-2-ol and its name as orto-acetoxy-bisabolol. In vitro assay of interleukins release inhibition was carried out using rat peritoneal macrophages cultures. IL-1beta and TNF-alpha levels were significantly reduced when cells were previously treated with low doses of orto-acetoxy-bisabolol, but neither IL-6 nor NO levels have their levels reduced. Results suggest that ethnical knowledge of anti-inflammatory and analgesic effects of the "arnica-da serra" HALE may be associated to the orto-acetoxy-bisabolol ability on synthesis inhibition of the key inflammatory/hypernociceptive mediators. CONCLUSIONS: Phytochemical investigation of the volatile active compounds in Lychnophora ericoides HALE allows us to isolate a new bisabolane derivative (orto-acetoxy bisabolol) and to infer that this compound inhibits the synthesis of TNF-alpha and IL-1beta, two important inflammatory mediators in the hypernociception. Our present data, in addition to literature's data, furnish scientific support to folk's use of Lychnophora ericoides as an endemic wound healer. PMID- 23688666 TI - Efficient bifunctional catalyst lipase/organophosphonic acid-functionalized silica for biodiesel synthesis by esterification of oleic acid with ethanol. AB - An efficient bifunctional catalyst lipase/organophosphonic acid-functionalized silica (SG-T-P-LS) has been successfully developed, and biodiesel production of fatty acid ethyl ester (FAEE) from free fatty acid (FFA) oleic acid with short chain alcohol ethanol catalyzed by SG-T-P-LS was investigated. The process optimization using response surface methodology (RSM) was performed and the interactions between the operational variables were elucidated, and it was found that the molar ratio of alcohol to acid was the most significant factor. The optimum values for maximum conversion ratio can be obtained by using a Box Behnken center-united design, and the conversion ratio could reach 89.94 +/- 0.42% under the conditions that ethanol/acid molar ratio was 1.05:1 and SG-T-P-LS to FFA weight ratio was 14.9 wt.% at 28.6 degrees C. The research results show that SG-T-P and LS-20 could work cooperatively to promote the esterification reaction, and the bifunctional catalyst SG-T-P-LS is a potential catalyst for biodiesel production. PMID- 23688667 TI - Scenedesmus incrassatulus CLHE-Si01: a potential source of renewable lipid for high quality biodiesel production. AB - The potential of microalgal oil from Scenedesmus incrassatulus as a feedstock for biodiesel production was studied. Cell concentration of S. incrassatulus and lipid content obtained during mixotrophic growth were 1.8 g/L and 19.5 +/- 1.5% dry cell weight, respectively. The major components of biodiesel obtained from S. incrassatulus oil were methyl palmitate (26%) and methyl linoleate (49%), which provided a strong indication of high quality biodiesel. Fuel properties were determined by empirical equations and found to be within the limits of biodiesel standard ASTM D6751 and EN 14214. The quality properties of the biodiesel were high cetane number (62), low density (803 kg/m(3)), low viscosity (3.78 mm(2)/s), oxidation stability (9h) and cold filter plugging point (-4 degrees C). Hence, S. incrassatulus has potential as a feedstock for the production of excellent quality biodiesel. PMID- 23688668 TI - Quantitative evaluation of the ease of rupture of industrially promising microalgae by high pressure homogenization. AB - The susceptibility to rupture of the microalgae Nannochloropsis sp., Chlorella sp. and Tetraselmis suecica by high pressure homogenization was compared quantitatively to the yeast Saccharomyces cerevisiae. Methods for quantifying cell rupture were investigated including cell counting, turbidity, metabolite release and particle sizing. Cell counting was the only reliable method for quantitative comparisons of all microalgae, with turbidity complicated by agglomeration of cell debris for T. suecica, and measurement of metabolite release affected by degradation occurring for all microalgae after significant rupture. The rupture of all microalgae followed exponential decay as a function of number of passes. The pressure required to achieve rupture of 50% of the cells per pass was determined to be 170, 1070, 1380, and ca. 2000 bar for Tetraselmis sp., Chlorella sp., S. cerevisiae, and Nannochloropsis sp., respectively. These results extend the criteria for selecting microalgae for industrial applications beyond consideration of growth and compositional attributes. PMID- 23688669 TI - Purification of triacylglycerols for biodiesel production from Nannochloropsis microalgae by membrane technology. AB - Triacylglycerols recovery from wet microalgae is a key aspect of biodiesel production, because of the energetic balance gained from avoiding biomass drying. In order to isolate TAG from Nannochloropsis cells, the possibility to concentrate biomass and to recover TAG in a single step by membrane process was studied. Different polymeric membranes were selected and screened on the basis of adsorption test and permeation flux. Results showed that membrane of regenerated cellulose (RC) with nominal molecular weight cutoff of 100 kDa and 30 kDa gave the best performance. Indeed, permeate flux was stable during ultrafiltration experiment in concentration mode and no severe fouling/cake deposition was observed. Both membranes allowed to recover permeates with high content of triacylglicerols. However, a more purity of the triacylglicerols from the other co-products was only obtained with the 30 kDa RC membrane because the retention of the unwanted proteins was in the range of 89%. PMID- 23688670 TI - Microalgae harvesting and subsequent biodiesel conversion. AB - Chlorella vulgaris ESP-31 containing 22.7% lipid was harvested by coagulation (using chitosan and polyaluminium chloride (PACl) as the coagulants) and centrifugation. The harvested ESP-31 was directly employed as the oil source for biodiesel production via transesterification catalyzed by immobilized Burkholderia lipase and by a synthesized solid catalyst (SrO/SiO2). Both enzymatic and chemical transesterification were significantly inhibited in the presence of PACl, while the immobilized lipase worked well with wet chitosan coagulated ESP-31, giving a high biodiesel conversion of 97.6% w/w oil, which is at a level comparable to that of biodiesel conversion from centrifugation harvested microalgae (97.1% w/w oil). The immobilized lipase can be repeatedly used for three cycles without significant loss of its activity. The solid catalyst SrO/SiO2 worked well with water-removed centrifuged ESP-31 with a biodiesel conversion of 80% w/w oil, but the conversion became lower (55.7-61.4% w/w oil) when using water-removed chitosan-coagulated ESP-31 as the oil source. PMID- 23688671 TI - Alkaline post-treatment for improved sludge anaerobic digestion. AB - Alkaline post-treatment was tested in order to improve sludge anaerobic digestion. Between the 8th and the 12th hour of a 24-h digestion cycle, 5% of sludge was extracted from a semi-continuous digester with a sludge retention time of 20 days. The sludge was then disintegrated with 0.1 mol/L NaOH and returned to the digester after neutralization. The results showed that alkaline post treatment increased the level of soluble organic substances in the extracted sludge, particularly of volatile fatty acids and polysaccharides. This process resulted in a 33% enhancement of biogas production in comparison with the control. When the ratio of the recycled sludge was further increased to 10% or 15%, the increment of biogas yield was reduced, due to excessive inactivation of anaerobic bacteria in the digester. Alkaline post-treatment had a minimal impact on the dewaterability of digested sludge. PMID- 23688672 TI - Amygdala responses to Valence and its interaction by arousal revealed by MEG. AB - It is widely accepted that the amygdala plays a crucial role in the processing of emotions. The precise nature of its involvement is however unclear. We hypothesized that ambivalent findings from neuroimaging studies that report amygdala's activity in emotions, are due to distinct functional specificity of amygdala's sub-divisions and specifically to differential reactivity to arousal and valence. The goal of the present study is to characterize the amygdala response to affective stimuli by disentangling the contributions of arousal and valence. Our hypothesis was prompted by recent reports claiming anatomical sub divisions of amygdala based on cytoarchitecture and the functional maps obtained from diverse behavioral, emotional, and physiological stimulation. We measured magnetoencephalography (MEG) recordings from 12 healthy individuals passively exposed to affective stimuli from the International Affective Picture System (IAPS) collection using a 2 (Valence levels)* 2 (Arousal levels) design. Source power was estimated using a beamformer technique with the activations referring to the amygdala sub-divisions defined through probabilistic cytoarchitectonic maps. Right laterobasal amygdala activity was found to mediate negative valence (elicited by unpleasant stimuli) while left centromedial activity was characterized by an interaction of valence by arousal (arousing pleasant stimuli). We did not find a main effect for amygdala activations in any of its sub-divisions for arousal modulation. To the best of our knowledge, our findings from non-invasive MEG data indicate for the first time, a distinct functional specificity of amygdala anatomical sub-divisions in the emotional processing. PMID- 23688673 TI - EEG beta band activity is related to attention and attentional deficits in the visual performance of elderly subjects. AB - We have previously shown that beta-band EEG activity is related to attentional modulation in the visual system of cats and humans. In a separate experiment we also observed that some elderly subjects expressed beta-band power decreases during a simple visual attention task, an effect which was accompanied by low behavioral accuracy in this subgroup. Here, we conducted a detailed examination of beta power deficits in elderly subjects in comparison to young controls. In order to do so, we equalized the subjective level of task difficulty by adjusting visual stimuli presentation duration in such a way that elderly and young subjects achieved similar behavioral results. We found that: (1) beta-band power of EEG signals recorded over occipital regions in elderly and young groups is related to visual attention, as judged from increases in beta power preceding correct responses and lack of beta activity change before erroneous responses; (2) despite forming a homogeneous group when screened for dementia (MMSE), age, education level, visual correction, and speed-accuracy trade-off strategy, elderly subjects could be assigned into one of the two subgroups: high performers, who did not differ from young performers in terms of beta-band power increases, and low performers, whose beta power decreased during the most difficult attentional conditions (shortest - 3s and longest - 11s cue-target delays). These findings posit that the beta-band activity decrease recorded in low performing elderly subjects reflects difficulty in activation and deficits in sustaining attentional processes. PMID- 23688674 TI - Genetic deletion of uncoupling protein 3 exaggerates apoptotic cell death in the ischemic heart leading to heart failure. AB - BACKGROUND: Uncoupling protein 3 (ucp3) is a member of the mitochondrial anion carrier superfamily of proteins uncoupling mitochondrial respiration. In this study, we investigated the effects of ucp3 genetic deletion on mitochondrial function and cell survival under low oxygen conditions in vitro and in vivo. METHODS AND RESULTS: To test the effects of ucp3 deletion in vitro, murine embryonic fibroblasts and adult cardiomyocytes were isolated from wild-type (WT, n=67) and ucp3 knockout mice (ucp3(-/-), n=70). To test the effects of ucp3 genetic deletion in vivo, myocardial infarction (MI) was induced by permanent coronary artery ligation in WT and ucp3(-/-) mice. Compared with WT, ucp3(-/-) murine embryonic fibroblasts and cardiomyocytes exhibited mitochondrial dysfunction and increased mitochondrial reactive oxygen species generation and apoptotic cell death under hypoxic conditions in vitro (terminal deoxynucleotidyl transferase-dUTP nick end labeling-positive nuclei: WT hypoxia, 70.3 +/- 1.2%; ucp3(-/-) hypoxia, 85.3 +/- 0.9%; P<0.05). After MI, despite similar areas at risk in the 2 groups, ucp3(-/-) hearts demonstrated a significantly larger infarct size compared with WT (infarct area/area at risk: WT, 48.2 +/- 3.7%; ucp3(-/-), 65.0 +/- 2.9%; P<0.05). Eight weeks after MI, cardiac function was significantly decreased in ucp3(-/-) mice compared with WT (fractional shortening: WT MI, 42.7 +/- 3.1%; ucp3(-/-) MI, 24.4 +/- 2.9; P<0.05), and this was associated with heightened apoptotic cell death (terminal deoxynucleotidyl transferase-dUTP nick end labeling-positive nuclei: WT MI, 0.7 +/- 0.04%; ucp3(-/ ) MI, 1.1 +/- 0.09%, P<0.05). CONCLUSIONS: Our data indicate that ucp3 levels regulate reactive oxygen species levels and cell survival during hypoxia, modulating infarct size in the ischemic heart. PMID- 23688675 TI - T-helper type 1 bias in healthy people is associated with cytomegalovirus serology and atherosclerosis: the Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND: Although T-helper type 1 (Th1) cells are considered important in atherosclerosis, the relationships between Th1 and Th2 cells and atherosclerosis have not been examined in population-based studies. METHODS AND RESULTS: We measured Th cells as a percentage of lymphocytes by flow cytometry using CD4 staining (%CD4) in 917 participants of the Multi-Ethnic Study of Atherosclerosis. We also measured interferon gamma-positive and interleukin-4-positive CD4(+) cells, representing Th1 and Th2 subpopulations (%Th1 and %Th2), respectively. We found that %CD4 was 1.5% lower per 10 years of age (P<0.0001). Whites had higher %CD4 and lower %Th1 and %Th2 values than other race/ethnic groups. Body mass index (BMI) and blood pressure were associated with %CD4, but no traditional cardiovascular disease (CVD) risk factors were associated with %Th1 or %Th2. In multivariable models, the major independent variable associated with %Th1 was cytomegalovirus (CMV) antibody titer, with minor contributions from age, sex, seasonality, and interleukin-6. In models with coronary artery calcification level as the outcome, significant independent variables included age, sex, smoking status, and %Th1 (beta=0.25; P <= 0.01). Both %Th1 and %Th2 were associated with common carotid intimal media thickness (beta=0.02 and -0.02, respectively; both P<0.05), as were age, sex, race/ethnicity, blood pressure, and BMI. CONCLUSIONS: Th1 bias is associated with subclinical atherosclerosis in a multiethnic population. The main Th1 correlate was CMV infectious burden. These findings are consistent with a role of Th1 cells in atherosclerosis and suggest the importance of prospective studies of T-helper cell biasing in CVD. PMID- 23688676 TI - Naming outcome after left or right temporal lobectomy in patients with bilateral language representation by Wada testing. AB - OBJECTIVE: This study aimed to examine language outcome after left or right anterior temporal lobectomy (ATL) in patients with epilepsy with bilateral language representation on intracarotid sodium amobarbital (Wada) testing. METHODS: Twenty-two patients with epilepsy with bilateral language (Wada laterality index between -50 and 50) underwent right ATL (RATL, n=10) or left ATL (LATL, n=12). All the patients were administered the Boston Naming Test preoperatively and six months postoperatively. RESULTS: Left anterior temporal lobectomy patients showed greater postoperative naming decline than RATL patients. Group differences were also observed on subtests of the Wada test. Performance on the Wada naming and comprehension subtests was better in the nonsurgical hemisphere than in the surgical hemisphere in the RATL group, but there was no difference between the nonsurgical and the surgical hemisphere naming and comprehension performance in the LATL group. CONCLUSIONS: Left anterior temporal lobectomy patients with bilateral language are at greater risk for naming decline than RATL patients with bilateral language. This difference may be due to relatively better naming and comprehension abilities in the nonsurgical hemisphere in the RATL group. PMID- 23688677 TI - Marital adjustment for patients with epilepsy in China. AB - Marriage is a major source of social support and a predictor of health; however, marriages that involve people with epilepsy are more likely to fail. To explore this issue in China, we compared the marital adjustment of patients with epilepsy to control subjects using the Dyadic Adjustment Scale (DAS). A total of 136 married persons with epilepsy and 145 healthy control subjects were recruited. The DAS score was significantly lower in people with active epilepsy than in the controls (102.0+/-17.8 vs. 109.2+/-15.8, p<0.001). A hierarchical regression showed that depression and social support satisfaction were significant predictors for DAS. Psychosocial variables accounted for 24.0% of the variance in DAS after control for demographic and seizure-related factors in patients with active epilepsy. The result suggests that people with active epilepsy in our sample encountered more marital discord than controls. Treatment to control mood disorder and support intervention might be important for their marital adjustment. PMID- 23688678 TI - Overview of ocular complications in patients with electrical burns: an analysis of 102 cases across a 7-year period. AB - BACKGROUND: Ocular complications from electrical burns are uncommon. Thus far, there has been no systematic review on ocular electrical trauma with emphasis on patients' ophthalmic complications and visual symptoms. Herein, we retrospectively analyzed records of patients with electrical injuries to summarize the ophthalmic characteristics and explore their relationships with visual symptoms. METHODS: We collected the medical records of 102 patients who consulted from 557 electrical burn patients between 2004 and 2010. Ophthalmic, systemic and demographic factors associated with electrical burns were identified in the patient who underwent the ophthalmic consultations. Two sets of comparisons were used to determine the demographic and systemic factors that were related to ophthalmic complications and the subjective outcome of visual impairment. RESULTS: There were 53 eyes (29 patients) with ophthalmic complication were identified. Corneal epithelial erosion was the most common ocular electrical injury and the primary reason for subjective visual symptoms. Electrical burns affecting the head and neck were significantly related to subjective symptoms of visual disturbances. CONCLUSION: Present study indicates that earlier involvement of ophthalmologists in the case of any patient who has suffered a facial burn is advisable. Appropriate management would be helpful to prevent future complications and alleviate visual symptoms. PMID- 23688679 TI - Neurofascin 186 specific autoantibodies induce axonal injury and exacerbate disease severity in experimental autoimmune encephalomyelitis. AB - Axonal injury is considered the major cause of chronic disability in multiple sclerosis (MS) patients, however the mechanisms behind remain still unclear. Recently, it was demonstrated that autoantibodies against Neurofascin, a cell adhesion molecule within the adult nervous system, can contribute to the development of axonal pathology in some patients. We compared the ability of the two different isoforms of Neurofascin, Nfasc155 and Nfasc186, to induce a pathogenic antibody response in the Dark Agouti (DA) rat. Animals were immunized with recombinant proteins prior to induction of experimental autoimmune encephalomyelitis (EAE) by adoptive transfer of activated MOG-specific T cells. Only Nfasc186 induced an axopathic autoantibody response in vivo, despite extensive cross reactivity between the two isoforms as shown by ELISA and flow cytometry. In this case, using transfected cell lines failed to differentiate between pathogenic and non-pathogenic responses. These findings have important implications with respect to the usage of cell based assays as an approach to detect pathologically relevant autoantibodies in clinical samples. PMID- 23688681 TI - Development of solvent micro-extraction combined with derivatization. AB - Solvent microextraction (SME), such as single-drop microextraction (SDME), hollow fiber liquid-phase microextraction (HF-LPME) and dispersive liquid-liquid microextraction (DLLME), has been explored for its ability to cover a wide range of analytes. Microextraction, combined microextraction with derivatization can greatly improve separation, detectability and compound identification, expand its scope of application, and improve the effect of analysis. In this view, the article not only highlights the development of the microextraction technology such as SDBE, HF-LPME and DLLME, but also improves the key strategies of microextraction coupled to derivatization in analytical chemistry. In order to encourage further development of microextraction-derivatization, its coupling with different analytical techniques such as GC or GC-MS, HPLC, and the other technique has also been discussed. PMID- 23688680 TI - Effect of methysergide on pudendal inhibition of micturition reflex in cats. AB - The role of 5-HT2 and opioid receptors in pudendal inhibition of bladder activity induced by intravesical infusion of saline or 0.25% acetic acid (AA) was investigated in anesthetized cats using methysergide (a 5-HT2 receptor antagonist) and naloxone (an opioid receptor antagonist). AA irritated the bladder and significantly (P<0.0001) reduced bladder capacity to 27.0 +/- 7.4% of saline control capacity. Pudendal nerve stimulation (PNS) at multiples of the threshold (T) intensity for inducing anal sphincter twitching restored bladder capacity to 60.1 +/- 8.0% at 1-2T (P<0.0001) and 92.2 +/- 14.1% at 3-4T (P=0.001) of the saline control capacity. Methysergide (0.03-1mg/kg, i.v.) suppressed low intensity (1-2T) PNS inhibition but not high intensity (3-4T) inhibition, and also significantly (P<0.05) increased control bladder capacity at the dosage of 0.3-1mg/kg. During saline infusion without AA irritation, PNS significantly increased bladder capacity to 150.8 +/- 9.9% at 1-2T (P<0.01) and 180.4 +/- 16.6% at 3-4T (P<0.01) of the saline control capacity. Methysergide (0.1-1 mg/kg) significantly (P<0.05) increased saline control bladder capacity and suppressed PNS inhibition at the dosage of 0.03-1mg/kg. After methysergide treatment (1 mg/kg), naloxone significantly (P<0.05) reduced control bladder capacity during AA infusion but had no effect during saline infusion. Naloxone also had no influence on PNS inhibition. These results suggest that 5-HT2 receptors play a role in PNS inhibition of reflex bladder activity and interact with opioid mechanisms in micturition reflex pathway. Understanding neurotransmitter mechanisms underlying pudendal neuromodulation is important for the development of new treatments for bladder disorders. PMID- 23688682 TI - Effect of mobile phase additives on qualitative and quantitative analysis of ginsenosides by liquid chromatography hybrid quadrupole-time of flight mass spectrometry. AB - This study was to systematically investigate the effect of mobile phase additives, including ammonia water, formic acid, acetic acid, ammonium chloride and water (as a control), on qualitative and quantitative analysis of fifteen representative ginsenosides based on liquid chromatography hybrid quadrupole-time of flight mass spectrometry (LC-Q-TOF/MS). To evaluate the influence of mobile phase additives on qualitative performance, the quality of the negative mode MS/MS spectra of ginsenosides produced by online LC-Q-TOF/MS analyses, particularly the numbers and intensities of fragment ions, were compared under different adduct ion states, and found to be strongly affected by the mobile phase additives. When 0.02% acetic acid was added in the mobile phase, the deprotonated ginsenosides ions produced the most abundant product ions, while almost no product ion was observed for the chlorinated ginsenoside ions when 0.1mM ammonium chloride was used as the mobile phase additive. On the other hand, sensitivity, linear range and precision were adopted to investigate the quantitative performance affected by different mobile phase additives. Validation results of the LC-Q-TOF/MS-based quantitative performance for ginsenosides showed that ammonium chloride not only provided the highest sensitivity for all the target analytes, but also dramatically improved the linear ranges, the intra-day and inter-day precisions comparing to the results obtained using other mobile phase additives. Importantly, the validated method, using 0.1mM ammonium chloride as the mobile phase additive, was successfully applied to the quantitative analysis of ginsenosides in rat plasma after intragastric administration of Ginsenoside Extract at 200mg/kg. In conclusion, 0.02% acetic acid was deemed to be the most suitable mobile phase additive for qualitative analysis of ginsenosides, and 0.1mM ammonium chloride in mobile phase could lead to the best quantitative performance. Our results reveal that choosing the appropriate mobile phase additive is an important step in optimizing the analytical conditions, and the best quantitative method may not be suitable for the qualitative analysis. PMID- 23688683 TI - Combination of graphene oxide-based solid phase extraction and electro membrane extraction for the preconcentration of chlorophenoxy acid herbicides in environmental samples. AB - Combination of different extraction methods is an interesting and debatable work in the field of sample preparation. In the current study, for the first time, solid phase extraction combined with electro membrane extraction (SPE-EME) was developed for ultra-preconcentration and determination of chlorophenoxy acid herbicides in environmental samples using capillary electrophoresis (CE). In the mentioned method, first, a 100mL of chlorophenoxy acid herbicides (2-methyl-4 chlorophenoxyacetic acid (MCPA), 2-(2,4-dichlorophenoxy) propanoic acid (2,4-DP) and 2-(4-chloro-2-methylphenoxy) propanoic acid (MCPP)) was passed through a column of graphene oxide as a solid phase, and then the adsorbed herbicides were eluted by 4.0mL of 8% acetic acid (HOAC) in methanol. Then, the elution solvent was evaporated and the herbicides residue was dissolved in 4.0mL of double distilled water (pH 9.0). Afterwards, the herbicides in 4.0mL of the aqueous solution were transferred to an EME glass vial. In the EME step, the herbicides were extracted from the sample solution into the basic acceptor solution (pH 13.0) under electrical potential, which was held inside the lumen of the fiber with 1-octanol as the supported liquid membrane (SLM). Under the optimized conditions, high enrichment factors were obtained in the range of 1950-2000. The limits of quantification (LOQs) and method detection limits (MDLs) were obtained in the range of 1.0-1.5 and 0.3-0.5ngmL(-1), respectively. Finally, the performance of the present method was evaluated for extraction and determination of chlorophenoxy acid herbicides in environmental samples. PMID- 23688685 TI - Aptamer-protein binding detected by asymmetric flow field flow fractionation. AB - Asymmetric flow field flow fractionation (AF4) should be suitable for the study of aptamer-target binding, because its gentle separation would impose little disturbance to the complex structure, and it can use carrier solutions with high salt concentrations to provide the most optimal interaction environment to the complex. However, no report has been found for such applications. Herein, we investigated the utility of AF4 as an effective tool for detection of the aptamer protein complex. With the model system of human immunoglobulin E (IgE) and its aptamer, impacts on aptamer binding from the incubation and AF4 carrier solutions, as well as the flow conditions used during the sample focusing step, were studied. We found that the composition of the carrier solution, in particular, the presence of Mg(2+), strongly influenced the complex's integrity in AF4. Also, the focusing conditions during sample injection in AF4 affected the binding equilibrium. Our findings highlight the necessity of maintaining the optimal binding environment during the time course of complex measurement; and demonstrated the good compatibility of AF4 with salty buffers and its high simplicity in conducting on-channel incubation. With its capability to carry out size-based separation of analytes with a wide range of dimensions, AF4 can be employed for detection of large proteins and even biological particles using aptamers. AF4 is also valuable for study of aptamer-target binding under different buffer environments for better understanding of the structure-function relationship of aptamers. PMID- 23688684 TI - Influence of a strong sample solvent on analyte dispersion in chromatographic columns. AB - In chromatographic columns, when the eluting strength of the sample solvent is larger than that of the carrier liquid, a deformation of the analyte zone occurs because its frontal part moves at a relatively high velocity due to a low retention factor in the sample solvent while the rear part of the analyte zone is more retained in the carrier liquid and hence moves at a lower velocity. The influence of this solvent strength effect on the separation of analytes is studied here theoretically using a mass balance model describing the spatio temporal evolution of the eluent, the sample solvent and the analyte. The viscosity of the sample solvent and carrier fluid is supposed to be the same (i.e. no viscous fingering effects are taken into account). A linear isotherm adsorption with a retention factor depending upon the local concentration of the liquid phase is considered. The governing equations are numerically solved by using a Fourier spectral method and parametric studies are performed to analyze the effect of various governing parameters on the dispersion and skewness of the analyte zone. The distortion of this zone is found to depend strongly on the difference in eluting strength between the mobile phase and the sample solvent as well as on the sample volume. PMID- 23688686 TI - Influence of phase type and solute structure on changes in retention with pressure in reversed-phase high performance liquid chromatography. AB - The influence of pressure on the retention of several types of solute, including acids, bases and neutrals, was studied by the use of restriction capillaries added to the end of various monomeric and polymeric octadecylsilyl-modified 5MUm particle size columns. Although it appeared that certain polymeric columns could give somewhat greater increases in retention with pressure, differences in behaviour between these different C18 columns were rather small. Differences in solute molecular size were most important in determining increases in retention with pressure. However, solute structure such as polarity and planarity were also influential. A prototype C30 column gave interesting selectivity changes between planar and non-planar solutes as a function of pressure. Considerable selectivity differences with pressure were shown when diverse mixtures of solutes were analysed. For the solutes studied, only minor effects of increased pressure on column efficiency and peak shape were noted. PMID- 23688687 TI - Neuropsychiatric symptom assessments in toxic exposure. AB - The goal of this review is to provide guidelines for evaluating psychiatric and mood changes that result from neurotoxicity. Mood changes that are often seen to varying degrees in neurotoxicity include increased anxiety, depression, irritability, impulsiveness, and psychosis. Some common agents that induce neurotoxicity include drugs, heavy metals, and organophosphates with presentations varying somewhat depending upon the mechanism of toxicity. The authors discuss in detail psychiatric assessment for patients with suspected of having neurotoxicologic syndrome. PMID- 23688688 TI - Emerging toxic neuropathies and myopathies. AB - Psychiatrists in practice encounter patients abusing alcohol and street drugs such as cocaine that can lead to toxic myopathies or neuropathies. Psychiatrists also encounter patients with neuropsychiatric systemic lupus erythematosus who are treated with myotoxic medications (e.g., Hydroxychloroquine). Thus a well rounded knowledge of toxic myopathies and neuropathies is extremely useful. The differential diagnosis of toxic myopathies and neuropathies is expanding rapidly and practical knowledge of these entities is becoming important. PMID- 23688689 TI - Neurotoxic emergencies. AB - This article is intended for clinicians treating neurotoxic emergencies. Presented are causative agents of neurotoxic emergencies, many of which are easily mistaken for acute psychiatric disorders. Understanding the wide variety of agents responsible for neurotoxic emergencies and the neurotransmitter interactions involved will help the psychiatrist identify and treat this challenging population. PMID- 23688690 TI - Antidepressant overdose-induced seizures. AB - Treating patients with psychiatric problems can present numerous challenges for clinicians. The deliberate self-ingestion of antidepressants is one such challenge frequently encountered in hospitals throughout the United States. This review focuses on 1) the classes of antidepressants, their pharmacologic properties, and some of the proposed mechanism(s) for antidepressant overdose induced seizures; 2) the evidence for seizures caused by antidepressants in overdose; 3) management strategies for patients who have intentionally or unintentionally overdosed on an antidepressant, or who have experienced an antidepressant overdose-induced seizure. PMID- 23688692 TI - Toxic leukoencephalopathies. AB - Leukoencephalopathy is a syndrome of neurologic deficits, including alteration of mental status, caused by pathologic changes in the cerebral white matter. The term, toxic leukoencephalopathy, encompasses a wide variety of exposures and clinical presentations. The diagnosis in these Frontiers in Clinical Neurotoxicology syndromes is made by careful attention to the history, clinical features, and radiologic findings. This article details three of the best-defined toxic leukoencephalopathies: delayed posthypoxic leukoencephalopathy, including delayed neurologic sequelae after carbon monoxide poisoning; heroin inhalation leukoencephalopathy; and posterior reversible encephalopathy syndrome. PMID- 23688691 TI - Neurologic manifestations of chronic methamphetamine abuse. AB - The drug with perhaps the greatest impact on the practice of Psychiatry is Methamphetamine. By increasing the extracellular concentrations of dopamine while slowly damaging the dopaminergic neurotransmission, Meth is a powerfully addictive drug whose chronic use preferentially causes psychiatric complications. Chronic Meth users have deficits in memory and executive functioning as well as higher rates of anxiety, depression, and most notably psychosis. It is because of addiction and chronic psychosis from Meth abuse that the Meth user is most likely to come to the attention of the practicing Psychiatrist/Psychologist. Understanding the chronic neurologic manifestations of Meth abuse will better arm practitioners with the diagnostic and therapeutic tools needed to make the Meth epidemic one of historical interest only. PMID- 23688693 TI - Toluene abuse and white matter: a model of toxic leukoencephalopathy. AB - The brain is the primary target of toluene (methylbenzene), the major solvent in spray paint and a constituent of many other easily obtained commercial and industrial products. The effects of acute intoxication can be dramatic and the lasting adverse effects of inhalants may be highly injurious. Mental status alterations range from acute confusional state to coma. Toluene abuse effects on white matter are demonstrable neuroradiologically and neuropathologically, and have important neurobehavioral consequences. PMID- 23688694 TI - Neurotoxicology: the ties that bind us. PMID- 23688695 TI - Synthesis of pyrazolo[1,5-a][1,3,5]triazine derivatives as inhibitors of thymidine phosphorylase. AB - Thymidine phosphorylase (TP) is an enzyme that promotes tumor growth and metastasis and therefore is an attractive druggable target. Using a reported TP inhibitor, 7-deazaxanthine (7DX), as the lead compound; this study was set up to evaluate whether pyrazolo[1,5-a][1,3,5]triazin-2,4-diones and pyrazolo[1,5 a][1,3,5]triazin-2-thioxo-4-ones would exhibit TP inhibitory activity. The pyrazolo[1,5-a][1,3,5]triazine nucleus was constructed using a reaction that annulated the 1,3,5-triazine ring onto a pyrazole scaffold. Among the 52 compounds synthesized and tested, it was found that 1,3-dihydro-pyrazolo[1,5 a][1,3,5]triazin-2-thioxo-4-ones exhibited various extent of inhibitory activity against TP. The best compound 17p, which bears a para-substituted pentafluorosulfur group, showed an IC50 value of 0.04 MUM, which was around 800 times more potent than the 7DX (IC50 = 32 MUM) under the same bioassay conditions. The results of the study suggested that a substituent with +sigma and +pi properties inserted at position 4 of a phenyl ring that is attached to position 8 of the pyrazolo[1,5-a][1,3,5]triazin-2-thioxo-4-one scaffold would give excellent TP inhibitory action. In addition, 17p was found to be a non competitive inhibitor thus suggested that it might interact with TP at a position different from the substrate binding site. PMID- 23688696 TI - Synthesis and biological evaluation of newly designed phosphonate based bone seeking agent. AB - A cyclic tetraaza based bifunctional triphosphonate ligand 10-(2-aminoethyl) 1,4,7,10-tetraazacyclododecane-1,4,7-tris(methylenephosphonic acid) (DO3MP-EA) was synthesized as bone-seeking theranostic agent. The compound was characterized by spectroscopic techniques and labelled with (99m)Tc with more than 97% purity. Blood clearance of 99mTc labelled compound a quick wash out from the circulation. The compound was excreted mainly via kidneys and accumulation of (99m)Tc-DO3MP-EA in bone was 9.53 +/- 1.06% of injected dose per gram of bone at 1 h. The preliminary CADD analysis confirms the efficacy of DO3MP-EA (G Score -7.005) as better binding agent for osteocalcin (pdb 1Q8H) rather than other known clinical agents. Subsequently stability constant of chelate with Ga(III) was found to be 18.6 which confirms its efficacy as (68)Ga labelled PET radiopharmaceutical for bone. PMID- 23688697 TI - Synthesis and structure--activity relationships of N2-alkylated quaternary beta carbolines as novel antitumor agents. AB - A series of novel N(2)-alkylated quaternary beta-carbolines was synthesized by modification of position-1, 2, 7 and 9 of beta-carboline nucleus with various alkyl and arylated alkyl substituents, and their cytotoxic activities in vitro and antitumor potencies in mice were evaluated. Compound 3m was found to be the most potent antitumor agent. SARs analysis revealed that (1) the substituents in position-2 and 9 of beta-carboline nucleus played a vital role in modulation of antitumor activity; (2) the benzyl and 3-phenylpropyl substituents in position-2 and 9 of beta-carboline ring were the optimal substituents giving rise to significant antitumor agent. These compounds might be a novel promising class of antitumor agents with clinical development potential. PMID- 23688698 TI - Synthesis and pharmacological evaluation of 2-aryloxy/arylamino-5 cyanobenzenesulfonylureas as novel thromboxane A2 receptor antagonists. AB - New series of original 2-aryloxy/arylamino-5-cyanobenzenesulfonylureas were synthesized and evaluated as thromboxane A2 receptor (TP receptor) antagonists. A functional pharmacological test was used, which consisted of measuring the inhibition of intracellular calcium mobilization in a model of mammalian cell line that specifically over-expressed the individual TPalpha or TPbeta isoforms. 2-Arylamino-5-cyanobenzenesulfonylureas exhibited virtually identical affinity and/or functional activity than 2-aryloxy-5-cyanobenzenesulfonylureas for both TPalpha and TPbeta, but some 2-aryloxy-substituted compounds showed increased selectivity for TPbeta relative to TPalpha. Several compounds were found to be as potent as the 2-arylamino-5-nitrobenzenesulfonylurea reference compound BM-573, supporting the view that the bioisosteric replacement of the nitro group by a cyano group was tolerated. TP receptor antagonist activity of the most promising molecules was confirmed in a platelet aggregation assay using the TP receptor agonist U-46619 as a proaggregant. Three compounds (7e, 7h and 8h) were identified as leads for further non-clinical pharmacological and toxicological studies. PMID- 23688699 TI - Evaluation of adenine as scaffold for the development of novel P2X3 receptor antagonists. AB - Ligands that selectively block P2X3 receptors localized on nociceptive sensory fibres may be useful for the treatment of chronic pain conditions including neuropathic pain, migraine, and inflammatory pain. With the aim at exploring the suitability of adenine moiety as a scaffold for the development of antagonists of this receptor, a series of 9-benzyl-2-aminoadenine derivatives were designed and synthesized. These new compounds were functionally evaluated at rat or human P2X3 receptors expressed in human embryonic kidney (HEK) cells and on native P2X3 receptors from mouse trigeminal ganglion sensory neurons using patch clamp recording under voltage clamp configuration. The new molecules behaved as P2X3 antagonists, as they rapidly and reversibly inhibited (IC50 in the low micromolar range) the membrane currents induced via P2X3 receptor activation by the full agonist alpha,beta-methyleneATP. Introduction of a small lipophilic methyl substituent at the 6-amino group enhanced the activity, in comparison to the corresponding unsubstituted derivative, resulting in the 9-(5-iodo-2-isopropyl-4 methoxybenzyl)-N(6)-methyl-9H-purine-2,6-diamine (24), which appears to be a good antagonist on recombinant and native P2X3 receptors with IC50 = 1.74 +/- 0.21 MUM. PMID- 23688701 TI - [Disseminated salmonella infection with aortic mycotic aneurysm in a ulcerative colitis patient treated with infliximab]. PMID- 23688700 TI - Design, synthesis and characterization of peptidomimetic conjugate of BODIPY targeting HER2 protein extracellular domain. AB - Among the EGFRs, HER2 is a major heterodimer partner and also has important implications in the formation of particular tumors. Interaction of HER2 protein with other EGFR proteins can be modulated by small molecule ligands and, hence, these protein-protein interactions play a key role in biochemical reactions related to control of cell growth. A peptidomimetic (compound 5-1) that binds to HER2 protein extracellular domain and inhibits protein-protein interactions of EGFRs was conjugated with BODIPY (4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s indacene). Conjugation of BODIPY to the peptidomimetic was investigated by different approaches. The conjugate was characterized for its ability to bind to HER2 overexpressing SKBR-3 and BT-474 cells. Furthermore, cellular uptake of conjugate of BODIPY was studied in the presence of membrane tracker and Lyso tracker using confocal microscopy. Our results suggested that fluorescently labeled compound 5-7 binds to the extracellular domain and stays in the membrane for nearly 24 h. After 24 h there is an indication of internalization of the conjugate. Inhibition of protein-protein interaction and downstream signaling effect of compound 5-1 was also studied by proximity ligation assay and Western blot analysis. Results suggested that compound 5-1 inhibit protein-protein interactions of HER2-HER3 and phosphorylation of HER2 in a time-dependent manner. PMID- 23688702 TI - [Reversible acute heart failure]. PMID- 23688703 TI - Successful pregnancy and delivery in a patient with Parkinson's disease under pramipexole treatment. PMID- 23688704 TI - [Disseminated intravascular coagulation associated with pancytopenia]. PMID- 23688705 TI - [Letter on the article "depression in general practitioner"]. PMID- 23688706 TI - [Pemphigus vegetants]. PMID- 23688707 TI - Lipoxin A(4) promotes more complete inflammation resolution in sepsis compared to stable lipoxin A(4) analog. AB - In sepsis, excessive inflammation may lead to organ injury or a paradoxical immunosuppressed state where the host is unable to clear preexisting infection. Resolution of inflammation is the process which restores tissue homeostasis and ensures that a chronic cycle of infection/inflammation does not occur. Lipoxin A4 (LXA4) is one of a family of lipid mediators with novel inflammation resolution activity. We compared the actions of LXA4 to the stable 15-epi-16-(para fluorophenoxy)-lipoxin A4 methyl ester (LXA4 analog) in the cecal ligation and puncture (CLP) model of sepsis. Both LXA4 compounds (at 7 MUg/kg; i.v.) reduced plasma TNFalpha and IL-6 concentrations compared to rats given vehicle saline. Neither treatment altered plasma IL-10 compared to CLP given saline, but LXA4 analog, increased plasma IL-10 concentrations compared to rats given LXA4. LXA4 reduced blood bacterial load but the LXA4 analog did not. LXA4 increased 8 day survival and the LXA4 analog did not have a significant effect. To examine possible mechanisms for the differences, we investigated peritoneal leukocyte gene expression of iNOS and macrophage phagocytic ability. Only LXA4 increased the percentage of phagocytic peritoneal macrophages. LXA4 reduced neutrophil gene expression of iNOS compared to CLP rats given vehicle, while the LXA4 analog did not. Our results suggest that at doses which reduced systemic inflammation, only LXA4 inhibited bacterial spread and increased survival. This difference may be due to the shorter-lived compound being able to increase macrophage phagocytosis and reduce neutrophil iNOS expression. PMID- 23688708 TI - Humans, 'things' and space: costing hospital infection control interventions. AB - BACKGROUND: Previous attempts at costing infection control programmes have tended to focus on accounting costs rather than economic costs. For studies using economic costs, estimates tend to be quite crude and probably underestimate the true cost. One of the largest costs of any intervention is staff time, but this cost is difficult to quantify and has been largely ignored in previous attempts. AIM: To design and evaluate the costs of hospital-based infection control interventions or programmes. This article also discusses several issues to consider when costing interventions, and suggests strategies for overcoming these issues. METHODS: Previous literature and techniques in both health economics and psychology are reviewed and synthesized. FINDINGS: This article provides a set of generic, transferable costing guidelines. Key principles such as definition of study scope and focus on large costs, as well as pitfalls (e.g. overconfidence and uncertainty), are discussed. CONCLUSION: These new guidelines can be used by hospital staff and other researchers to cost their infection control programmes and interventions more accurately. PMID- 23688709 TI - Visual impairment and subsequent use of support services among older people: longitudinal findings from the Blue Mountains Eye Study. AB - PURPOSE: To assess the impact of visual impairment and blindness on the incident use of community support services in the Blue Mountains Eye Study. DESIGN: Population-based cohort. METHODS: Of 3654 baseline participants (1992-1994), 2334, 1952, and 1149 were re-examined after 5, 10, and 15 years, respectively. Incident visual impairment was defined as subsequent development of visual impairment (visual acuity <20/40) in the better eye of subjects with best corrected visual acuity >=20/40 at baseline. Community support service use included regular use of Meals on Wheels, Home Care, or community nurse services. Informal support included assistance from family or friends. Discrete logistic regression models with time-dependent study and outcome variables were used to assess associations between visual impairment and subsequent use of support, adjusted for potential confounders. RESULTS: Among participants with bilateral visual impairment at baseline, incident use of community services over 5-15 years was 41.7% compared to 19.4% in those without visual impairment at baseline (odds ratio, 1.39; 95% confidence interval, 0.54-3.60). Persons with incident bilateral visual impairment were more likely to subsequently need community support (odds ratio, 3.32; confidence interval 1.96-5.59) in 5 years, compared to persons without visual impairment during the entire follow-up period. Baseline older age, walking disability, receiving pension, and having 2+ hospital admissions within 12 months were also significantly associated with incident use of support services. CONCLUSIONS: Development of bilateral visual impairment in this cohort was associated with greater likelihood of subsequent use of community or informal support services in 5 years, independent of physical comorbidities. PMID- 23688710 TI - Outcomes of outpatient fluid-gas exchange for open macular hole after vitrectomy. AB - PURPOSE: To report the efficacy and safety of outpatient fluid-gas exchange for open macular hole after primary vitrectomy. DESIGN: Retrospective interventional case series. METHODS: setting: Institutional. patients: Thirty-six patients with primary failed closure or reopened holes after primary vitrectomy. intervention: Fluid-gas excahnge with 15% perfluoropropane (C3F8) or 20% sulfur hexafluoride (SF6) was performed to reclose the hole under topical anesthesia. main outcome measures: The hole closure rate and type, pre- and postexchange best-corrected visual acuity (BCVA), and complication rates were assessed. RESULTS: Thirty-two eyes (89%) achieved anatomic success from 1-3 weeks after the fluid-gas exchange. Twenty-two eyes (61%) achieved type 1 closure, 10 eyes (28%) achieved type 2 closure, and 4 eyes (11%) did not achieve closure. The BCVA for type 1 closure improved significantly from logarithm of the minimal angle of resolution (logMAR) 1.66 +/- 0.41 to 0.84 +/- 0.41, with a P value <.001. The BCVA for type 2 closure improved from logMAR 1.77 +/- 0.41 to 1.52 +/- 0.41, with a P value of .05. All patients with an unclosed hole after fluid-gas exchange had a stage IV macular hole before the primary vitrectomy and a hole size larger than 1000 MUm. The complication related to fluid-gas exchange procedure was transient high intraocular pressure, which responded well to topical antiglaucoma medications. There were 2 retinal detachment cases following the exchange; surgery to reattach the retina was performed, with visual acuity recovery. CONCLUSION: Outpatient fluid-gas exchange is an effective treatment option for eyes with open holes following vitrectomy. PMID- 23688711 TI - Enhanced depth imaging optical coherence tomography of the choroid in central retinal vein occlusion. AB - PURPOSE: To evaluate subfoveal choroidal thickness in patients with central retinal vein occlusion (CRVO) using enhanced depth imaging optical coherence tomography. DESIGN: Retrospective observational study. METHODS: We measured bilateral subfoveal choroidal thickness, averaged for 100 scans, in 36 patients (mean age, 66 +/- 15 years; 26 women and 10 men) with unilateral CRVO by using the enhanced depth imaging methods of the Spectralis optical coherence tomography system. Twenty-two patients were treated with intravitreal bevacizumab (1.25 mg/0.05 mL), and subfoveal choroidal thickness was measured before and after treatment. Statistical analysis was performed to compare subfoveal choroidal thickness of CRVO and fellow eyes and to compare subfoveal choroidal thickness before and after intravitreal bevacizumab. RESULTS: Mean subfoveal choroidal thickness measured in 36 eligible eyes of 36 patients was 257.1 +/- 83.2 MUm, which was significantly greater than that in fellow eyes (222.6 +/- 67.8 MUm; P < .01, paired t test). There was strong correlation between CRVO eyes and fellow eyes (r = 0.79, P < .01). Mean subfoveal choroidal thickness after intravitreal bevacizumab was 227.7 +/- 65.1 MUm, which was significantly thinner than that before intravitreal bevacizumab therapy (266.9 +/- 79.0 MUm; P < .01, paired t test). CONCLUSIONS: Subfoveal choroidal thickness of CRVO eyes was significantly greater than that of fellow eyes and decreased significantly after intravitreal bevacizumab treatment. Enhanced depth imaging optical coherence tomography can be used to evaluate choroidal involvement in CRVO and may assist noninvasive diagnosis and management of this disease. PMID- 23688712 TI - Hunger, overconsumption and youth: future directions for research in school-based public health nutrition strategies. PMID- 23688713 TI - School food and nutrition: developing the evidence base for policy. PMID- 23688714 TI - School food research: building the evidence base for policy. AB - OBJECTIVE: Following an international workshop on developing the evidence base for policy relating to school food held in London, UK, in January 2012, the objectives of the present paper were (i) to outline a rationale for school food research, monitoring and evaluation in relation to policy and (ii) to identify ways forward for future working. DESIGN: The authors analysed presentations, summaries of evidence, and notes from discussions held at the international workshop in London in 2012 to distil common themes and make recommendations for the development of coherent research programmes relating to food and nutrition in schools. SETTING: International, with an emphasis on middle- and high-income countries. RESULTS: Overviews of existing school food and nutrition programmes from the UK, Hungary, Sweden, the USA, Australia, Brazil, China, Mexico and other countries were presented, along with information on monitoring, evaluation and other research to demonstrate the impact of school feeding on health, attainment, food sourcing, procurement and finances, in the context of interactions between the evidence base and policy decisions. This provided the material which, together with summaries and notes of discussions, was used to develop recommendations for the development and dissemination of robust approaches to sustainable and effective school food and nutrition programmes in middle- and high-income countries, including policy guidelines, standards, cost-effectiveness measures and the terms of political engagement. CONCLUSIONS: School food and nutrition can provide a cohesive core for health, education and agricultural improvement provided: (i) policy is appropriately framed and includes robust monitoring and evaluation; and (ii) all stakeholders are adequately engaged in the process. International exchange of information will be used to develop a comprehensive guide to the assessment of the impact of school food and nutrition policy and supporting infrastructure. PMID- 23688715 TI - Improvement of brain uptake for in vivo PET imaging of astrocytic oxidative metabolism using benzyl [1-(11)C]acetate. AB - Brain uptake of acetate is insufficient for obtaining a quantitative image of astrocytic oxidative metabolism. To improve the brain uptake of [1-(11)C]acetate, we synthesized benzyl [1-(11)C]acetate ([1-(11)C]BA) and conducted a positron emission tomography (PET) study assessing astrocytic oxidative metabolism. The brain uptake of [1-(11)C]BA was markedly higher compared with [1-(11)C]acetate, and disappeared with a half-life of 20 min in all regions studied. The brain uptake of [1-(11)C]BA was significantly decreased by fluorocitrate. The results indicate that [1-(11)C]BA could be a useful PET probe for assessing astrocytic oxidative metabolism. PMID- 23688716 TI - Deep sequencing of Trichomonas vaginalis during the early infection of vaginal epithelial cells and amoeboid transition. AB - The human pathogen Trichomonas vaginalis has the largest protozoan genome known, potentially encoding approximately 60,000 proteins. To what degree these genes are expressed is not well known and only a few key transcription factors and promoter domains have been identified. To shed light on the expression capacity of the parasite and transcriptional regulation during phase transitions, we deep sequenced the transcriptomes of the protozoan during two environmental stimuli of the early infection process: exposure to oxygen and contact with vaginal epithelial cells. Eleven 3' fragment libraries from different time points after exposure to oxygen only and in combination with human tissue were sequenced, generating more than 150 million reads which mapped onto 33,157 protein coding genes in total and a core set of more than 20,000 genes represented within all libraries. The data uncover gene family expression regulation in this parasite and give evidence for a concentrated response to the individual stimuli. Oxygen stress primarily reveals the parasite's strategies to deal with oxygen radicals. The exposure of oxygen-adapted parasites to human epithelial cells primarily induces cytoskeletal rearrangement and proliferation, reflecting the rapid morphological transition from spindle shaped flagellates to tissue-feeding and actively dividing amoeboids. PMID- 23688717 TI - Evolution of microstructure in mixed niobia-hybrid silica thin films from sol-gel precursors. AB - The evolution of structure in sol-gel derived mixed bridged silsesquioxane niobium alkoxide sols and drying thin films was monitored in situ by small-angle X-ray scattering. Since sol-gel condensation of metal alkoxides proceeds much faster than that of silicon alkoxides, the incorporation of d-block metal dopants into silica typically leads to formation of densely packed nano-sized metal oxide clusters that we refer as metal oxide building blocks in a silica-based matrix. SAXS was used to study the process of niobia building block formation while drying the sol as a thin film at 40-80 degrees C. The SAXS curves of mixed niobia hybrid silica sols were dominated by the electron density contrast between sol particles and surrounding solvent. As the solvent evaporated and the sol particles approached each other, a correlation peak emerged. Since TEM microscopy revealed the absence of mesopores, the correlation peak was caused by a heterogeneous system of electron-rich regions and electron poor regions. The regions were assigned to small clusters that are rich in niobium and which are dispersed in a matrix that mainly consisted of hybrid silica. The correlation peak was associated with the typical distances between the electron dense clusters and corresponded with distances in real space of 1-3 nm. A relationship between the prehydrolysis time of the silica precursor and the size of the niobia building blocks was observed. When 1,2-bis(triethoxysilyl)ethane was first hydrolyzed for 30 min before adding niobium penta-ethoxide, the niobia building blocks reached a radius of 0.4 nm. Simultaneous hydrolysis of the two precursors resulted in somewhat larger average building block radii of 0.5-0.6 nm. This study shows that acid-catalyzed sol-gel polymerization of mixed hybrid silica niobium alkoxides can be rationalized and optimized by monitoring the structural evolution using time-resolved SAXS. PMID- 23688718 TI - One-pot synthesis of Aluminum-containing ordered mesoporous silica MCM-41 using coal fly ash for phosphate adsorption. AB - The present study offers an economic one-pot synthesis of Al-containing ordered mesoporous silica MCM-41 from the coal fly ash. The samples were characterized by small-angle XRD, N2 adsorption, TEM, mapping, (27)Al MAS NMR, EDX, and NH3-TPD. The effects of pH values to the final mesostructures have also been investigated. The results show that the material prepared at the pH value of 10 displays the largest pore volume of 0.98 cm(3)/g, the highest BET surface area of 1020 m(2)/g, and the lowest Si/Al molar ratio of 2. Using this material as adsorbent for phosphates, the adsorption capacity reaches 64.2mg/g at 298 K, which is much higher than that of large pore mesoporous silica SBA-15 (53.5mg/g), diatomite (62.7 mg/g), and MCM-41 (31.1 mg/g). In addition, the thermodynamics and kinetics for the phosphate adsorption were also investigated. Our present study shows an economic way to treat phosphates using the industrial solid waste of coal fly ash. PMID- 23688719 TI - Implementation of permutation testing to determine clustering of social and behavioral risk factors for coronary heart disease, National Health and Nutrition Examination Survey 2001-2004. AB - PURPOSE: To determine whether social and behavioral risk factors for coronary heart disease, including education, physical activity, fruit/vegetable intake, and smoking, cluster (i.e., co-occur more than expected as the result of chance) in U.S. adults. METHODS: The study included 4305 male and 4673 female subjects aged >=20 years from the National Health and Nutrition Examination Survey. Risk factors included: <=high school diploma/general educational development certificate; <150 minutes of moderate/vigorous physical activity per week; <3 or <2 servings of vegetables and fruit, respectively, per day; and smoking cigarettes. Indicator variables were summed into a sociobehavioral risk index (SRI, range 0 [no risk factors] to 4 [all risk factors]). Ratios of observed-to expected prevalence (under the assumption of independence) of the SRI were assessed. Statistical significance was evaluated by the use of randomly permuted average observed-to-expected SRI ratios and 95% confidence intervals (95% CIs). RESULTS: In male subjects, the ratio of observed-to-expected prevalence of SRI = 0 was 1.70 (permuted ratio = 1.00; 95% CI: 0.92-1.08), and SRI = 4 was 2.10 (permuted ratio = 1.00, 95% CI: 0.86-1.14), demonstrating significant clustering. In females, the ratio of observed-to-expected prevalence of SRI = 0 was 1.67 (permuted ratio = 1.00, 95% CI: 0.92-1.08), and SRI = 4 was 1.86 (permuted ratio = 1.00, 95% CI: 0.85-1.15). CONCLUSIONS: Social and behavioral risk factors for coronary heart disease cluster in this sample of U.S. adults. PMID- 23688720 TI - Physical health indicators among lesbian, gay, and bisexual U.S. veterans. AB - PURPOSE: To provide information about lesbian, gay, and bisexual (LGB) veterans' health status, diagnoses, and health screening behaviors compared with heterosexual veterans. METHODS: Data are from 10 states' 2010 Behavioral Risk Factor Surveillance System surveys that contained sexual orientation data for veterans (n = 11,665). chi(2) tests and multiple logistic regression were used to examine outcomes among LGB and heterosexual veterans. RESULTS: More LGB than heterosexual veterans reported current smoking, not seeking medical care owing to cost, and activity limitations. Compared with heterosexual veterans, LGB veterans had greater odds of ever having an human immunodeficiency virus test (odds ratio [OR], 5.42; 95% confidence interval [CI], 3.28-8.96) but lower odds of diabetes diagnosis (OR, 0.55; 95% CI, 0.34-0.89). CONCLUSIONS: Findings from this sample suggest patterns of health behaviors and outcomes among LGB veterans that are both unique from and similar to results from general samples of LGB persons. With the formal end of the "Don't Ask, Don't Tell" policy that discriminated against LGB people in the military, institutions such as the Department of Veterans Affairs are likely to see an increase in its current population of LGB veterans. The Department of Veterans Affairs stands in a unique place to meet the health equity needs of this minority population. PMID- 23688721 TI - [The acute respiratory distress syndrome in malaria: is it always the prerogative of Plasmodium falciparum?]. AB - Severe malaria causes nearly one million deaths annually in endemic areas and is a public health priority worldwide. Severity associated with the occurrence of acute respiratory distress syndrome (ARDS) is a well-known complication of infection with Plasmodium falciparum and can reach 25% of infected adults. However, ARDS is less often described with other Plasmodium species. We report the case of a young Moroccan soldier who died in an array of ARDS related to malaria of Plasmodium ovale 7 months after his return from an endemic country. PMID- 23688722 TI - [Varicella pneumonia associated with bilateral pleurisy in an immunocompetent adult]. AB - Chickenpox is a viral infection usually benign and practically mandatory of the childhood. In the adult, it may know multivisceral complications as pneumonia in relationship with chickenpox which is the most frequent. One case of varicella pneumonia with a bilateral pleurisy has been noticed in a 38-year-old adult. The definite diagnosis has been based on clinical, biological and radiological arguments. Under an antiviral treatment, the evolution is favourable. PMID- 23688723 TI - [Lymphangioma and lymphangiectasia]. AB - Primary thoracic lymphatic diseases are both infrequent and probably under diagnosed. The two major forms are lymphangiomas and lymphangiectasias. Lymphangiomas are focal proliferation of well-differentiated lymphatic vessels. Childhood lymphangiomas may follow embryologic disorders. Adult lymphangiomas are more likely secondary to lymphatic obstruction. When associated with typical CT and MRI features, their surgical resection is not mandatory, whereas in case of diagnostic difficulties or related complications, surgical resection is the rule. Lymphangiectasias are congenital or acquired pathologic lymphatic dilatation from pleura and interlobular septa without any proliferation. These diseases can be limited to one pulmonary lobe, or can involve the whole lymphatic network. In case of communication between the lymphangiectasias and the thoracic duct, symptoms may include chyloptysis, chylothorax, and chylopericardium. Lymphangio MRI allows visualisation of the lymphangiectasis and thoracic duct. Surgical treatment may be required in case of resistance to medical treatment. PMID- 23688724 TI - Generation of HIV-1 Gag VLPs by transient transfection of HEK 293 suspension cell cultures using an optimized animal-derived component free medium. AB - Virus-like particles (VLPs) offer great promise as candidates for new vaccine strategies. Large-scale approaches for the manufacturing of HIV-1 Gag VLPs have mainly focused on the use of the baculovirus expression system. In this work, the development and optimization of an HIV-1 Gag VLP production protocol by transient gene expression in mammalian cell suspension cultures is reported. To facilitate process optimization, a Gag-GFP fusion construct enabling the generation of fluorescent VLPs was used. The great majority of Gag-GFP present in cell culture supernatants was shown to be correctly assembled into virus-like particles of the expected size and morphology consistent with immature HIV-1 particles. Medium optimization was performed using design of experiments (DoE). Culture medium supplementation with non-animal derived components including recombinant proteins and lipids of synthetic or non-animal-derived origin resulted in improved HEK 293 cell growth and VLP production. The maximum cell density attained using the optimized Freestyle culture medium was 5.4*10(6)cells/mL in batch mode, almost double of that observed using the unsupplemented medium (2.9*10(6)cells/mL). Best production performance was attained when cells were transfected at mid-log phase (2-3*10(6)cells/mL) with medium exchange at the time of transfection using standard amounts of plasmid DNA and polyethylenimine. By using an optimized production protocol, VLP titers were increased 2.4-fold obtaining 2.8MUg of Gag GFP/mL or 2.7*10(9)VLPs/mL according to ELISA and nanoparticle tracking quantification analyses, respectively. PMID- 23688725 TI - Iron-induced oxidation of (all-E)-beta-carotene under model gastric conditions: kinetics, products, and mechanism. AB - The stability of (all-E)-beta-carotene toward dietary iron was studied in a mildly acidic (pH 4) micellar solution as a simple model of the postprandial gastric conditions. The oxidation was initiated by free iron (Fe(II), Fe(III)) or by heme iron (metmyoglobin, MbFe(III)). Fe(II) and metmyoglobin were much more efficient than Fe(III) at initiating beta-carotene oxidation. Whatever the initiator, hydrogen peroxide did not accumulate. Moreover, beta-carotene markedly inhibited the conversion of Fe(II) into Fe(III). beta-Carotene oxidation induced by Fe(II) or MbFe(III) was maximal with 5-10 eq Fe(II) or 0.05-0.1 eq MbFe(III) and was inhibited at higher iron concentrations, especially with Fe(II). UPLC/DAD/MS and GC/MS analyses revealed a complex distribution of beta-carotene derived products including Z-isomers, epoxides, and cleavage products of various chain lengths. Finally, the mechanism of iron-induced beta-carotene oxidation is discussed. Altogether, our results suggest that dietary iron, especially free (loosely bound) Fe(II) and heme iron, may efficiently induce beta-carotene autoxidation within the upper digestive tract, thereby limiting its supply to tissues (bioavailability) and consequently its biological activity. PMID- 23688727 TI - Flowering plants under global pollinator decline. AB - There is now compelling evidence of a reduction of pollinator richness and density at a global scale. In this opinion article, we argue that such pollinator decline intensifies pollen limitation and reduces plant reproductive success, threatening natural populations of extinction. We use genetic architecture and selection experiments on floral traits and evaluate the potential for plant reproductive strategies to adapt rapidly to new pollination environments. We propose that plant reproductive strategies could adapt to the current pollinator decline by decreasing or increasing their reliance to pollinators, for example, increasing autonomous selfing or reinforcing interactions with pollinators. We further discuss if and how adaptation of plant reproductive strategies can buffer the demographic consequences of pollinator decline, and possibly rescue plant populations from extinction. PMID- 23688726 TI - Genetic variation in antioxidant enzymes, cigarette smoking, and longitudinal change in lung function. AB - Antioxidant enzymes play an important role in the defense against oxidative stress in the lung and in the pathogenesis of chronic obstructive pulmonary disease (COPD). Sequence variation in genes encoding antioxidant enzymes may alter susceptibility to COPD by affecting longitudinal change in lung function in adults. We genotyped 384 sequence variants in 56 candidate genes in 1281 African American and 1794 European American elderly adults in the Health, Aging, and Body Composition study. Single-marker associations and gene-by-smoking interactions with rate of change in FEV1 and FEV1/FVC were evaluated using linear mixed effects models, stratified by race/ethnicity. In European Americans, rs17883901 in GCLC was statistically significantly associated with rate of change in FEV1/FVC; the recessive genotype (TT) was associated with a 0.9% per year steeper decline (P = 4.50 * 10(-5)). Statistically significant gene-by-smoking interactions were observed for variants in two genes in European Americans: the minor allele of rs2297765 in mGST3 attenuated the accelerated decline in FEV1/FVC in smokers by 0.45% per year (P = 1.13 * 10(-4)); for participants with greater baseline smoking pack-years, the minor allele of rs2073192 in IDH3B was associated with an accelerated decline in FEV1/FVC (P = 2.10 * 10(-4)). For both genes, nominally significant interactions (P < 0.01) were observed at the gene level in African Americans (P = 0.007 and 4.60 * 10(-4), respectively). Nominally significant evidence of association was observed for variants in SOD3 and GLRX2 in multiple analyses. This study identifies two novel genes associated with longitudinal lung function phenotypes in both African and European Americans and confirms a prior finding for GCLC. These findings suggest novel mechanisms and molecular targets for future research and advance the understanding of genetic determinants of lung function and COPD risk. PMID- 23688728 TI - Transit peptide design and plastid import regulation. AB - Import of most nuclear encoded proteins into plastids is directed by an N terminal transit peptide. Early studies suggested that transit peptides are interchangeable between precursor proteins. However, emerging evidence shows that different transit peptides contain different motifs specifying their preference for certain plastid types or ages. In this opinion article, we propose a 'multi selection and multi-order' (M&M) model for transit peptide design, describing each transit peptide as an assembly of motifs for interacting with selected translocon components. These interactions determine the preference of the precursor for a particular plastid type or age. Furthermore, the order of the motifs varies among transit peptides, explaining why no consensus sequences have been identified through linear sequence comparison of all transit peptides as one group. PMID- 23688729 TI - Assessment of semi-volatile organic compounds in drinking water sources in Jiangsu, China. AB - Many xenobiotic compounds, especially organic pollutants in drinking water, can cause threats to human health and natural ecosystems. The ability to predict the level of pollutants and identify their source is crucial for the design of pollutant risk reduction plans. In this study, 25 semi-volatile organic compounds (SVOCs) were assessed at 16 monitoring sites of drinking water sources in Jiangsu, east China, to evaluate water quality conditions and source of pollutants. Four multivariate statistical techniques were used for this analysis. The correlation test indicated that 25 SVOCs parameters variables had a significant spatial variability (P<0.05). The results of correlation analysis, principal component analysis (PCA) and cluster analysis (CA) suggested that at least four sources, i.e., agricultural residual pesticides, industrial sewage, water transportation vehicles and miscellaneous sources, were responsible for the presence of SVOCs in the drinking water sites examined, accounting for 89.6% of the total variance in the dataset. The analysis of site similarity showed that 16 sites could be divided into high, moderate, and low pollutant level groups at (D(link)/D(max))*25<10, and each group had primary typical SVOCs. These results provide useful information for developing appropriate strategies for contaminants control in drinking water sources. PMID- 23688730 TI - Modulation of antioxidant defense system after long term arsenic exposure in Zantedeschia aethiopica and Anemopsis californica. AB - Zantedeschia aethiopica (calla lily) and Anemopsis californica (yerba mansa) are plant species capable of accumulating arsenic (As) and therefore proposed as phytoremediation for removal of As from drinking water. The effects of a continuous 6 month As exposure (34+/-11 MUg/L) from local contaminated groundwater on the antioxidant response of Z. aethiopica and A. californica were evaluated in leaves and stems of the plants bimonthly in a subsurface flow constructed wetland. As increased the activities of the antioxidant enzymes ascorbate peroxidase, glutathione reductase and catalase where higher levels were observed in Z. aethiopica than A. californica. No significant differences were detected on lipid peroxidation levels or antioxidant capacity evaluated by ORAC and DPPH assays or total phenol contents in any part of the plant, although in general the leaves of both plants showed the best antioxidant defense against the metal. In conclusion, Z. aethiopica and A. californica were able to cope to As through induction of a more sensitive enzymatic antioxidant response mechanism. PMID- 23688731 TI - Comparison of early (60 min) and delayed (180 min) acquisition of 18F-FDG PET/CT in large vessel vasculitis. AB - PURPOSE: To compare the contribution of the (18)F-FDG-PET/CT acquisition at 180 min and at 60 min in suspicion of large vessel vasculitis (LVV). MATERIAL AND METHODS: A prospective study including 23 patients was performed. PET/CT was acquired at 60 and 180 min (early and delayed scan) after (18)F-FDG injection. A visual analysis was performed at the supra-aortic trunks (SAT), thoracic aorta (TA), abdominal aorta (AA), iliac arteries (IA) and femoral/tibioperoneal arteries (FTA). Intensity (0-3) and uptake pattern (diffuse/linear) were assessed in the 115 vascular regions. RESULTS: There was no FDG uptake in the early and delayed acquisition in 20/115 vascular regions (17.4%). Of the 95 regions (82.6%) showing FDG uptake at the early, delayed or both acquisitions, intensity did not change in the delayed acquisition in 46 and changed in 49. Of the 49 regions in which the intensity changed, it decreased in 36 and increased in 13 (TA:8, SAT:5). AA, IA and FTA intensity did not increase in any of the cases. Uptake pattern at the TA in the early acquisition was diffuse in 16 patients. In 7, it changed to linear and in 9 the uptake disappeared. The early pattern was linear in 7 patients and 6 of them showed increased intensity in the delayed acquisition and in 1 remained the same. CONCLUSION: The 180 min delayed FDG-PET/CT acquisition provides a more detailed visualized of the vessel wall, showing the washout of the blood pool activity. Therefore, it may contribute to a more accurate diagnosis of LVV. PMID- 23688732 TI - Tracing decadal environmental change in ombrotrophic bogs using diatoms from herbarium collections and transfer functions. AB - Central European mountain bogs, among the most valuable and threatened of habitats, were exposed to intensive human impact during the 20th century. We reconstructed the subrecent water chemistry and water-table depths using diatom based transfer functions calibrated from modern sampling. Herbarium Sphagnum specimens collected during the period 1918-1998 were used as a source of historic diatom samples. We classified samples into hummocks and hollows according to the identity of dominant Sphagnum species, to reduce bias caused by uneven sampling of particular microhabitats. Our results provide clear evidence for bog pollution by grazing during the period 1918-1947 and by undocumented aerial liming in the early 90-ies. We advocate use of herbarized epibryon as a source of information on subrecent conditions in recently polluted mires. PMID- 23688733 TI - Arsenic transport in irrigation water across rice-field soils in Bangladesh. AB - Experiments were conducted to analyze processes impacting arsenic transport in irrigation water flowing over bare rice-field soils in Bangladesh. Dissolved concentrations of As, Fe, P, and Si varied over space and time, according to whether irrigation water was flowing or static. Initially, under flowing conditions, arsenic concentrations in irrigation water were below well-water levels and showed little spatial variability across fields. As flowing-water levels rose, arsenic concentrations were elevated at field inlets and decreased with distance across fields, but under subsequent static conditions, concentrations dropped and were less variable. Laboratory experiments revealed that over half of the initial well-water arsenic was removed from solution by oxidative interaction with other water-column components. Introduction of small quantities of soil further decreased arsenic concentrations in solution. At higher soil-solution ratios, however, soil contributed arsenic to solution via abiotic and biotic desorption. Collectively, these results suggest careful design is required for land-based arsenic-removal schemes. PMID- 23688734 TI - Nitrogen deposition effects on plant species diversity; threshold loads from field data. AB - National-scale plant species richness data for Great Britain in 1998 were related to modelled contemporary N deposition (N(dep)) using a broken stick median regression, to estimate thresholds above which N(dep) definitely has had an effect. The thresholds (kg N ha-1 a-1) are 7.9 for acid grassland 14.9 for bogs, 23.6 for calcareous grassland, 7.8 for deciduous woodland and 8.8 for heath. The woodland and heath thresholds are not significantly greater than the lowest N(dep), which implies that species loss may occur over the whole range of contemporary N(dep). This also applies to acid grassland if it is assumed that N(dep) has substituted for previous N fixation. The thresholds for bog and calcareous grassland are both significantly above the lowest N(dep). The thresholds are lower than the mid-range empirical Critical Loads for acid grassland, deciduous woodland and heath, higher for bogs, and approximately equal for calcareous grassland. PMID- 23688735 TI - Application of fingerprint-based multivariate statistical analyses in source characterization and tracking of contaminated sediment migration in surface water. AB - This study investigates the suitability of multivariate techniques, including principal component analysis and discriminant function analysis, for analysing polycyclic aromatic hydrocarbon and heavy metal-contaminated aquatic sediment data. We show that multivariate "fingerprint" analysis of relative abundances of contaminants can characterize a contamination source and distinguish contaminated sediments of interest from background contamination. Thereafter, analysis of the unstandardized concentrations among samples contaminated from the same source can identify migration pathways within a study area that is hydraulically complex and has a long contamination history, without reliance on complex hydrodynamic data and modelling techniques. Together, these methods provide an effective tool for drinking water source monitoring and protection. PMID- 23688736 TI - Assessing ecotoxicity and uptake of metals and metalloids in relation to two different earthworm species (Eiseina hortensis and Lumbricus terrestris). AB - Due to diffuse atmospheric fallouts of process particles enriched by metals and metalloids, polluted soils concern large areas at the global scale. Useful tools to assess ecotoxicity induced by these polluted soils are therefore needed. Earthworms are currently used as biotest, however the influence of specie and earthworm behaviour, soil characteristics are poorly highlighted. Our aim was therefore to assess the toxicity of various polluted soils with process particles enriches by metals and metalloids (Pb, Cd, Cu, Zn, As and Sb) collected from a lead recycling facility on two earthworm species belonging to different ecological types and thus likely to have contrasted behavioural responses (Eiseina hortensis and Lumbricus terrestris). The combination of behavioural factors measurements (cast production and biomass) and physico-chemical parameters such as metal absorption, bioaccumulation by earthworms and their localization in invertebrate tissues provided a valuable indication of pollutant bioavailability and ecotoxicity. Soil characteristics influenced ecotoxicity and metal uptake by earthworms, as well as their soil bioturbation. PMID- 23688738 TI - Is type 1 diabetes a food-induced disease? AB - The incidence of type 1 diabetes among children has almost doubled during the last decades in Sweden. Type 1 diabetes is considered as an autoimmune disease with unknown aetiology. Here we propose that the immune reaction may be initiated by food-derived mechanisms. The incidence of diabetes parallels an increased consumption of pasta, white bread, meat, cheese, low-fat milk, exotic fruits, soda, and snacks. Simultaneously, the consumption of potatoes, butter, high-fat milk, and domestic fruit has decreased. Three categories of food related reaction mechanisms are discussed against the following items (1) proteins from wheat, meat, and milk, (2) fat from processed food, and (3) exotic fruits. The current food consumption is suggested to initiate a pro-inflammatory reaction in the intestine and thereby reduce the intestinal barrier function. This may influence tolerance development and thus pave the way for an autoimmune attack on pancreatic beta cells. PMID- 23688737 TI - Dynamic regulation of Bcl6 in follicular helper CD4 T (Tfh) cells. AB - Our bodies are continuously exposed to various types of infectious pathogens. Vaccinations are the most cost effective way to protect our bodies against a variety of infectious microbes. The efficacy of most vaccines relies on protective antibody production and generation of memory B cells. These two key components develop mostly from B cells that participate in germinal center reactions. Recent efforts have highlighted the critical role of follicular helper CD4 T (Tfh) cells in the generation of germinal centers. Given that Bcl6 is a major transcription factor for Tfh differentiation, here we review recent developments in the understanding of signaling molecules that regulate Bcl6 expression in CD4 T cells, as a potential target for development of more efficacious vaccines. PMID- 23688739 TI - Self-cutting versus intentional overdose: psychological risk factors. AB - Individuals who present to emergency departments with self-harm are at elevated risk of further self-harm and suicide, and these risks are yet higher among patients who self-cut. Repetitive self-injury has previously been explained using a behaviourist approach focussing on operant conditioning, but we propose that the increased risk of self-harm repetition among those who present with self cutting is at least partly mediated by pre-existing psychological risk factors. Several studies show that those who present with self-cutting differ from intentional overdose patients on demographic, psychiatric and social factors, but, based on findings from community-based studies, we hypothesise that there may be additional psychological differences that may also be associated with increased repetition risk. We conducted a small-scale cohort study of 29 self harm patients presenting to A&E and compared theoretically-derived psychological variables between 8 self-cutting and 21 overdose patients. Those presenting with self-cutting scored significantly higher on hopelessness and lower on non reactivity to inner experience and generally had a more vulnerable profile than those presenting with overdose. These findings support our hypothesis that the association between self-cutting and prospective repetition is at least partly due to pre-existing psychological vulnerabilities that increase both the likelihood of engaging in self-cutting as a method of self-harm and the likelihood of subsequent repetition of self-harm. Existing evidence suggests that self-cutting is a risk factor for repetition of self-harm, and it is possible that reducing and preventing repetition among these patients can be achieved by implementing psychological interventions to reduce hopelessness and increase tolerance of emotional distress. PMID- 23688740 TI - Atherosclerotic plaques: is endothelial shear stress the only factor? AB - Initiation and development of atherosclerosis has largely been attributed to irregular shear stress patterns and values, in the current literature. Abnormalities such as low shear stress, reversing and oscillatory shear force patterns, as well as temporal variations of shear stress are the most cited factors. However, clinical findings have further indicated that plaques have still been formed and developed in arterial sites that possess relatively more steady and higher shear stresses than those observed in studies correlating low or oscillatory shear stresses with atherosclerosis. These data imply that deviations in shear stress from its normal physiological pattern alone may not be the only factor inducing atherosclerosis, and additional haemodynamics parameter other then shear stress may also contribute to the initiation and development of plaques. In this paper, we hypothesise that the combined effect of wall shear stress and circumferential stress waves, in the form of angular phase difference between the two waves at each cardiac cycle, may be a more accurate determinant of plaque formation and growth. Furthermore, arterial sites that possess more positive values of this angular phase difference may be more prone to plaque formation or development. If proved correct, this theory can transform our understanding of endothelial cell mechanotransduction and mechanobiology, and may lead to design and utilisation of new diagnostic procedures and equipment as predictive and preventive clinical tools for patients with abnormal arterial blood pressure. PMID- 23688741 TI - A case for optimising fracture healing through inverse dynamization. AB - The mechanical conditions in the repair tissues are known to influence the outcome of fracture healing. These mechanical conditions are determined by the stiffness of fixation and limb loading. Experimental studies have shown that there is a range of beneficial fixation stiffness for timely healing and that fixation stiffness that is either too flexible or too stiff impairs callus healing. However, much less is known about how mechanical conditions influence the biological processes that make up the sequence of bone repair and if indeed mechanical stimulation is required at all stages of repair. Secondary bone healing occurs through a sequence of events broadly characterised by inflammation, proliferation, consolidation and remodelling. It is our hypothesis that a change in fixation stiffness from very flexible to stiff can shorten the time to healing relative to constant fixation stiffness. Flexible fixation has the benefit of promoting greater callus formation and needs to be applied during the proliferative stage of repair. The greater callus size helps to stabilize the fragments earlier allowing mineralization to occur faster. Together with stable/rigid fixation applied during the latter stage of repair to ensure mineralization of the callus. The predicted benefits of inverse dynamization are shortened healing in comparison to very flexible fixation and healing time comparable or faster than stable fixation with greater callus stiffness. PMID- 23688742 TI - Does spironolactone ameliorate trastuzumab-induced cardiac toxicity? AB - The ErbB2 receptor is a proto-oncogene associated with a poor prognosis in breast cancer. Trastuzumab, a humanized anti-ErbB2 antibody currently in clinical use, has proven to be an essential tool in the immunotherapy of breast carcinoma. Additionally, ErbB2 is involved in the growth and survival pathway of adult cardiomyocytes which accounts for the trastuzumab-induced cardiotoxicity. Moreover, in metastatic breast cancer patients treated with trastuzumab, endomyocardial biopsy documented focal vacuolar changes, pleomorphic mitochondria, myocardial cell hypertrophy, and mild interstitial fibrosis on electron microscopy without accompanying light microscopic abnormalities, a finding consistent with a reversible pattern of cardiac injury. On the other hand, aldosterone and mineralocorticoid receptor (MR) researches have experienced a revival after the discovery that aldosterone and MR are not only involved in the electrolyte and volume balance but also in the pathophysiological processes of the reno-cardiovascular system. Aldosterone has both genomic and nongenotropic effects on epidermal growth factor receptor (EGFR) expression. Genomic effect induces genomic up-regulation of the EGFR protein expression via EGFR promoter, whereas nongenotropic effect leads to the EGFR transactivation resulting in persistent pathophysiological effects including formation of extracellular matrix and myocardial hypertrophy. Spironolactone, an aldosterone receptor antagonist, is known to ameliorate the cardiac damage. The underlying mechanism for the genomic interactions seem to be the stimulation of the EGFR promoter by aldosterone-bound MR, which then dose-dependently enhances the EGFR protein levels, which may be successively inhibited by spironolactone. By the light of these findings, we hypothesize that spironolactone may ameliorate trastuzumab induced cardiotoxicity via inhibition of transactivation of the EGFR by aldosterone and reversing myocardial hypertrophy. This issue warrants further studies. PMID- 23688743 TI - Long non-coding RNAs as potential biomarkers and therapeutic targets for gliomas. AB - Gliomas are the most malignant and common primary brain tumors, accounting for 50 60%. Despite all surgical efforts in combination with intense chemoradiotherapy, gliomas still have a dismal prognosis. The early screening and identification of patients with gliomas could improve their prognosis by allowing proactive medical treatment. Traditionally, gliomas of varying subtypes and grades are diagnosed based on histopathological features, but this can be challenging, particularly in cases that lack the typical features. Molecular expression profiles using microarray analyses have provided additional information to help distinguish between glioma subtypes, which correlate well with histological profiles. Various molecular biomarkers and therapeutic targets for gliomas are currently available, including genes and miRNAs, but all remain in preclinical studies. Certain specific lncRNAs involved in gliomas have been identified in surgical brain biopsies, which may be involved in brain development and the pathogenesis of gliomas; these can also be detected in peripheral blood. Therefore, we postulate that these specific lncRNAs may be both potential biomarkers and therapeutic targets for gliomas. PMID- 23688744 TI - The role of retinoic acid receptors in activated hepatic stellate cells. AB - Hepatic stellate cells (HSCs), also known as Ito cells, fat-storing cells, vitamin A-storing cells or lipocytes, reside in the spaces between hepatocytes and liver sinusoids. Vitamin A storage within the HSCs is achieved through the cooperative action of two proteins, cellular retinol-binding protein (CRBP) I and lecithin:retinol acyltransferase (LRAT). After the discovery that HSCs are responsible not only for the storage of vitamin A, but also for the development of liver fibrosis and subsequent liver cirrhosis, HSCs have been considered a therapeutic target for prevention or reversal of liver fibrogenesis. We have reported that HSCs acquire retinoid responsiveness after in vitro activation by post-transcriptional upregulation of retinoic acid receptor alpha gene expression. Here we extend this observation in relation to the functions of CRBP I and LRAT, and propose a hypothesis that increased retinoid signaling in activated HSCs forms a feedback loop toward vitamin A restoration in the liver. PMID- 23688745 TI - [Clinicopathological features and prognostic factors of 216 cases with primary gastrointestinal tract non-Hodgkin's lymphoma]. AB - OBJECTIVE: To investigate the clinicopathological features of primary gastrointestinal non-Hodgkin's lymphomas (PGI-NHL) and their prognostic values. METHODS: The clinical and pathological data of 216 patients diagnosed as PGI-NHL from Zhejiang Cancer Hospital were analyzed retrospectively. chi2 test, log-liner model analysis, COX proportional hazard regression analysis and Life-table survival analysis were used to analyze the survival status of the patients by SAS 8.2 software, and Log-rank test was performed to couple the overall survival rates with different prognostic factors. RESULTS: Totally, the age of onset was 8 to 89 years with the median age of 56.5 years. Male versus female was 1.27?1(121?95). The most frequently involved location was stomach (147 cases, 68.1%), followed by ileocecus (25 cases, 11.6%), large intestine (20 cases, 9.3%), small intestine (17 cases, 7.9%) and multiple GI involvement (5 cases, 2.3%). 182 cases were classified as B cell lymphomas, 22 cases as T cell lymphomas, and 12 cases not classified exactly due to insufficient data. The 3 year and 5-year survival rates of the patients were 69.4% and 53.3%, respectively. Univariate analysis revealed that age>60 years, ECOG>=2, high LDH level, stage III-IV, IPI>=2, T cell type and intestinal involvement were predictors for poor prognosis. IPI>=2, T cell type and intestinal involvement were independent adverse predictors for prognosis by multiple COX proportional hazard regression analysis. Among different treatment groups, cases received chemotherapy combined with local radiotherapy gained the best survival status. CONCLUSION: B-cell lymphoma was the main pathological type in PGI-NHL; IPI>=2, T cell type and intestinal involvement are independent adverse predictors for prognosis; chemotherapy combined with local radiotherapy might be the choice of approach for advanced stage and aggressive PGI-HNL. PMID- 23688746 TI - [Clinical efficacy and safety of chemoimmunotherapy with rituximab,fludarabine and cyclophosphamide for chronic lymphocytic leukemia]. AB - OBJECTIVE: To evaluate the efficacy and safety of a chemoimmunotherapy regimen of rituximab, fludarabine and cyclophosphamide (FCR) for patients with chronic lymphocytic leukemia(CLL). METHODS: The clinical data of 26 CLL patients receiving FCR regimen in our hospital from April 2003 to January 2012 were analyzed retrospectively. Patients were grouped according to indicators including Rai risk stratification, beta(2)-MG, LDH, ZAP-70, CD38, cytogenetics and immunoglobulin heavy chain variable region gene (IgVH) mutation status. Therapy efficacy and survival were evaluated and the safety of FCR regimen was assessed. RESULTS: Among 26 patients, the overall response rate ( ORR ) was 76.9%, 10 patients (38.5%) achieved complete remission(CR) and 10(38.5%) partial remission(PR). With a median follow-up time of 30 ( 3-98 ) months, the median estimated progression-free survival(PFS) for all patients was 42(16-68) months and median overall survival(OS) was 63(41-85)months. Clinical parameters associated with higher CR rates were <2 courses of prior treatment regimens, proportions of bone marrow lymphocytes declining >= 50% after 2 courses of FCR, low LDH, low beta(2)-MG and ZAP-70 negative (P = 0.014, 0.008, 0.027, 0.035 and 0.013, retrospectively). PFS and OS time in minimal residual disease(MRD) negative, normal LDH and proportions of bone marrow lymphocytes declining >= 50% after 2 courses of FCR patients were significantly better than that of the control group (P<0.05), PFS in the non-high-risk genetics group was significantly better than that in the high-risk genetics group (P = 0.005), while OS between two groups showed no statistically significant difference. The most common toxicities were gastrointestinal reactions (88.5%), followed by bone marrow suppression (80.8%): including neutropenia, anemia and thrombocytopenia. Infections accounted for 30.8%, mainly lung infection. CONCLUSION: FCR is an effective and well-tolerated therapy for patients with CLL. Patients with MRD positive, elevated LDH, proportions of bone marrow lymphocytes declining<50% after 2 courses of FCR and high risk genetics patients are suitable for more effective treatment after achieving treatment response. PMID- 23688747 TI - [Comparison of clinical implications of p16 deletion in childhood and adult B lineage acute lymphoblastic leukemia]. AB - OBJECTIVE: To investigate and compare the clinical implications of p16 deletion in childhood and adult B-lineage acute lymphoblastic leukemia (B-ALL). METHODS: A total of 129 cases of de novo childhood (73 cases) and adult (56 cases) B-ALL were examined genetically and immunologically using G-banding techniqhe, interphase fluorescence in situ hybridization (I-FISH) and immunophenotyping by flow cytometry, and their clinical data were retrospectively analyzed. RESULTS: Of 73 childhood cases, the prevalences of homozygous deletion, hemizygous deletion and no deletion of p16 were 24.7% (18 cases), 6.8% (5 cases) and 68.5% (50 cases) respectively, and of 56 adult cases, the incidences as of 14.3% (8 cases), 8.9% (5 cases) and 76.8% (43 cases) respectively. The incidence of p16 deletion between the two groups had no significant difference (P = 0.338). In both groups, patients with or without p16 deletion had no significant difference in terms of white blood cells (WBC) count at diagnosis, BM blast percentage, chromosome karyotype, extra-infiltration and CR1 rate. Of note, there were 2 cases, each in childhood and adult, showed no deletion at the time of diagnosis, their p16 deletions occurred at relapse. The deletion of p16 was associated with poor overall survival and event-free survival (EFS) in both childhood and adults. According to the standard of NCI risk stratification, we divided patients of two groups into standard and high risk category respectively, and performed further analysis. The significance of different risk category in children and adults was disparity. The overall survival (OS) rates of deletion and no deletion of p16 were 45.3% and 79.8% (P = 0.006) in children, and 7.7% and 22.6% (P = 0.002) in adults, respectively. EFS rates of deletion and no deletion of p16 were 33.5% and 58.1% (P = 0.008) in children, and 0 and 10.9% (P < 0.01) in adults, respectively. Of the standard risk category in children, OS rates of deletion and no deletion of p16 were 46.8% and 89.3% (P = 0.015) respectively, and EFS rates of deletion and no deletion of p16 as of 40.9% and 82.1% (P = 0.007) respectively. Of the high risk category in children, OS rates of deletion and no deletion of p16 were 41.7% and 67.4% (P = 0.193) respectively, and EFS rates of deletion and no deletion of p16 were 25.0% and 25.6% (P = 0.305) respectively. Of the standard risk category in adults, OS rates of deletion and no deletion of p16 were 20.0% and 46.9% (P = 0.092) respectively, and EFS rates of deletion and no deletion of p16 were 0 and 25.0% (P = 0.062) respectively. Of the high risk category in adults, OS rates of deletion and no deletion of p16 were 0 and 12.4% (P < 0.001) respectively, and EFS rate of deletion and no deletion of p16 was 0 and 4.8%(P < 0.001), respectively. CONCLUSION: This study indicated that deletion of p16 was associated with poor prognosis in both childhood and adult B-ALL, which highlighted an important significance to define the status of p16 in both childhood and adult B-ALL for predicting prognosis and guiding clinical intervention. PMID- 23688748 TI - [Multivariate analysis of imatinib resistance-related factors during the treatment of chronic myeloid leukemia]. AB - OBJECTIVE: To explore efficacy of imatinib for patients with chronic myeloid leukemia(CML) and its resistance-related factors during the treatment. METHODS: The clinical data of 214 CML patients received imatinib were analyzed respectively in our hospital from April 2005 to December 2010. The therapy history and efficacy of regular follow-up and factors influencing drug resistance were analyzed. COX regression analysis was used to perform the univariate and multivariate analysis. RESULTS: Until the end of follow up, thirty-one patients (14.5%) occurred drug resistance. One of them was in accelerated phase(AP), and two in blast phase(BP); 69.2% of patients achieved a complete cytogenetic response(CCyR), and 31.3% of patients achieved a major molecular response(MMR). COX analysis was performed in 207 chronic phase(CP) patients. Univariate analysis showed that the course of disease before treatment, the hemoglobin count, the white blood cell count, whether achieved CCyR or not and whether achieved MMR or not were the influencing factors for imatinib resistance. Multivariate analysis showed that whether achieved CCyR or not was the independent factor for drug resistance. CONCLUSION: Whether achieved CCyR or not is an independent factor and also a protective factor for imatinib resistance in patients with CML. PMID- 23688749 TI - [Outcomes of 104 children with B-cell non-Hodgkin lymphoma]. AB - OBJECTIVE: To analyze outcomes and prognostic factors of children with B-cell non Hodgkin lymphoma (B-NHL). METHODS: One hundred and four newly diagnosed B-NHL children were enrolled in protocol of B-NHL 2001. The statistics were performed by SPSS 13.0. RESULTS: Of 104 children (79 males, the median age of 7.1 years), 60, 32 and 4 patients were diagnosed with Burkitt lymphoma, diffuse large B-cell lymphoma and unclassifiable B-cell lymphoma, respectively. Four patients were in stage I, 27 stage II, 55 stage III and 18 stage IV; 1, 26 and 77 patients were allocated into R1, R2 and R3 risk groups, respectively. Three patients never got complete remission (CR), 9 patients relapsed after CR with the duration of relapse from 1 to 7 months after chemotherapy. The estimated 5-year EFS of 104 patients was (86.7 +/- 3.5)%. Univariable analyses identified that risk factors for recurrence were of higher staging, elevated LDH, serum ferritin and poor early response. Age, sex, pathologic diagnosis, original tumor, bone or marrow involvement, C-MYC and risk group were not found to be associated with the risk of failure to treatment. Multivariable COX regression models confirmed serum ferritin as a significant independent prognostic marker. CONCLUSION: B-NHL 2001 protocol was reasonable for B-NHL children. Higher staging, elevated LDH, serum ferritin and poor early response increased risk for recurrence. PMID- 23688750 TI - [Expression of interleukin-6 and its clinicopathological significance in Castleman's disease]. AB - OBJECTIVE: To evaluate the expression of interleukin-6 (IL-6) and its clinicopathological significance in Castleman's disease (CD). METHODS: Clinical data and paraffin blocks of 92 CD patients and 20 cases of lymph node reactive hyperplasia (LRH) as a control group were collected from department of pathology of Peking University Health Science Center. The expression of IL-6 was detected by using immunohistochemical method. RESULTS: The 92 patients were composed of 42 multicentric variant (MCDs) and 50 unicentric variant (UCDs) clinically, and 30 hyaline-vascular variant (HV-CDs) and 62 plasma cell variant (PC-CDs) morphologically. None of them was positive for HIV tests. There were 56 males and 36 females, and their ages ranged from 4 years to 90 years with the median 41 years. IL-6 was expressed in 77 (83.7%) of 92 CD cases and 1 (5.0%) of 20 LRH cases. The expression rate of IL-6 was 90.5% in MCDs, 78.0% in UCDs, 93.6% in PC CDs and 63.4% in HV-CDs, respectively. PC-CD cases showed a significantly higher expression rate of IL-6 than HV-CD cases (P = 0.001). All cases with positive IL 6 expression in plasmacytes were PC-CDs, showing obviously higher expression in MCDs than that in UCDs (P = 0.003). Compared with HV-CD cases, much more PC-CD cases showed IL-6 positivity in endothelial cells (P = 0.008). However, IL-6 was rarely expressed by both FDCs and macrophages, with only 3.3% and 10.9% positive cases, respectively. There are 53.2% (41/77) of the IL-6 positive cases and 20.0% (3/15) of IL-6 negative cases suffered from systemic symptoms, showing a significant difference between the two groups (P = 0.018). Cases with IL-6 expression in plasmacytes and macrophages were more likely to suffer from systemic symptoms, especially B type symptoms (P < 0.05). CONCLUSION: There is a high expression rate of IL-6 in CD, which is different from LRH. The expression of IL-6 has close relationship with CD subtypes and the presence of systemic symptoms. In all, the evaluation of interleukin-6 is of great value to guide the diagnosis and therapy of CD. PMID- 23688751 TI - [Efficacy and safety of low-dose rituximab combined with different dosage of glucocorticoids for immune thrombocytopenia]. AB - OBJECTIVE: To compare the efficacy and safety of low-dose rituximab combined with different dosage of glucocorticoids for immune thrombocytopenia (ITP). METHODS: Seventy-four patients (35 male, median age 34 years, range 18-70 years) including 60 newly-diagnosed, 6 persistent, 5 chronic and 3 refractory patients were enrolled in this study, and separated into control (36 cases) and experimental (38 cases) groups according to the dosage of glucocorticoids. Patients in both groups received dexamethasone 40 mg/day on days 1-4, followed by rituximab 100 mg on days 7, 14, 21, 28. The patients in experimental group also received decrements of prednisone 60, 30, 20, 10 mg/day on days 5-7, 8-14, 15-21, 22-28. The initial, long-term efficacy and safety were evaluated. RESULTS: Platelet counts of all patients at day 4 remarkably increased, with the median platelet count from 11(1-26) * 109/L to 84(23-132) * 109/L in control group, and 10(2-20) * 109/L to 80(22-115) * 109/L in experimental group; the platelet counts of patients at day 14 in experimental group [163(19-262) * 109/L] was higher than that of control group [98(18-238) * 109/L] (P<0.05). The overall response (OR) rates at day 28 in experimental group (84.21%) was significantly higher than that of control group (66.67%, P = 0.03). There was no significant difference of sustained response (SR) rates in two groups (63.89%vs 65.79%, 58.33%vs 60.53%, P > 0.05) at six and twelve months follow-up points. Both groups showed similar incidence of adverse events, and no patients discontinued the treatment due to side effects. CONCLUSION: Low-dose rituximab and glucocorticoids was an effective method for ITP patients, and maintenance treatment with decrements of prednisone contributed to improving earlier CR rate. PMID- 23688752 TI - [Itraconazole for secondary prophylaxis of invasive fungal infection in patients undergoing chemotherapy and stem cell transplantation]. AB - OBJECTIVE: To evaluate the efficacy and safety of itraconazole for secondary prophylaxis of previous proven or probable invasive fungal infection (IFI) in patients undergoing chemotherapy or allogeneic hematopoietic stem cell transplantation (HSCT) in agranulocytosis state. METHODS: A phase IV prospective, open-label, multicenter trial was conducted to evaluate itraconazole (200 mg q12h intravenously d1-2, 200 mg/d) as secondary antifungal prophylaxis in patients (18 65 years old) undergoing chemotherapy or HSCT with previous proven or probable IFI. Itraconazole was started when patients' neutrophils<1.5 * 109/L, and stopped when chemotherapy patients' neutrophils >0.5 * 109/L and stem cell transplant recipients' neutrophils>1.0 * 109/L. The primary end-point of the study was the incidence of proven, probable or possible IFI. RESULTS: Seventy one patients from November 2008 to September 2010 were enrolled in the trial. The median duration of itraconazole prophylaxis was 14 (4-35) days. No patients died of drug-related toxicity within trial. Five cases occurred IFI during the trial. The cumulative incidence of invasive fungal disease was 7.0%. One patient was withdrawn from the study due to treatment-related adverse events (liver malfunction and severe phlebitis). CONCLUSION: Itraconazole appears to be safe and effective for secondary prophylaxis of systemic fungal infection after chemotherapy and allogeneic HSCT. The observed incidence of 7.0% is considerably lower than the relapse rate reported in historical controls, suggesting that itraconazole is a promising prophylactic agent in this population. PMID- 23688753 TI - [Effect of TAK1 gene silencing on the apoptosis of Kasumi-1 cells induced by arsenic trioxide]. AB - OBJECTIVE: To study the effect of transforming growth factor-beta activated kinase-1 (TAK1) gene silencing on the proliferation and apoptosis of Kasumi-1 cells induced by arsenic trioxide (As2O3). METHODS: Acute myeloid leukemia with t(8;21) cell line Kasumi-1 cells were treated with As2O3 or in combination with TAK1 siRNA interference technology. The experiment was divided into four groups: Kasumi-1 cells without any treatment, TAK1 specific siRNA transfection alone, Kasumi-1 cells treated with different concentration of As2O3, TAK1siRNA transfection combined with As2O3. CCK-8 was used to detect the cell viability. The expression of phosphorylated c-Jun N-terminal kinase (P-JNK) was determined by Western Blot. Cell apoptosis and growth were examined by morphological and colony formation assay. RESULTS: After Kasumi-1 cells were treated with As2O3, the rate of cell inhibition was concentration-dependent, and the 50% inhibitory concentration was 3.5 MUmol/L. The highest expression level of P-JNK appeared in 30 minutes after cells were treated with As2O3. The apoptosis rates of Kasumi-1 cells without any treatment, TAK1 siRNA interference alone group, As2O3 alone group and the combined group were (5.02 +/- 1.13)%, (6.18 +/- 0.28)%, (48.33 +/- 2.70)% and (86.07 +/- 2.21)%; colony formation rates were (73.83 +/- 2.78)%, (76.03 +/- 1.46)%, (55.07 +/- 1.50)% and (22.20 +/- 1.15)%; apoptosis rate of TAK1 siRNA group and the untreated group has no significant difference (P = 0.052); colony formation rate between TAk1 siRNA group and the untreated group has no significant difference (P = 0.179), but the difference in other groups was significant (P = 0.000). CONCLUSION: Silencing the expression of TAK1 can enhance the anti-proliferative and pro-apoptotic effect of As2O3 on Kasumi-1 cells, and its mechanism may be through the TAK1 downstream JNK signal pathway. PMID- 23688754 TI - [A novel modi cation of real-time AS-qPCR by using locked nucleic acid-modified oligonucleotide probe as wild type allele amplification blockers for quantitative detection of the JAK2 V617F mutation]. AB - OBJECTIVE: To develop a novel real-time PCR for sensitively quantitative detection of JAK2 V617F allele burden in peripheral blood. METHODS: Based on the real-time allele-specific PCR (AS-qPCR), the locked nucleic acid (LNA)-modified oligonucleotide probe was used for selectively blocking amplification of wild type alleles in AS-qPCR, and then a novel AS-LNA-qPCR method was established. The percentages of sample JAK2 V617F alleles were directly calculated by its threshold cycle (Ct) values according to the standard curve which generated by JAK2 V617F alleles with its Ct values. We validated intra- and inter-assay variability for quantifying JAK2 V617F. We also assayed 623 apparent healthy donors by our method to validate its clinical application value. RESULTS: The quantitative lower limit of this method for JAK2 V617F was 0.01%, and the intra- and inter-assay average variability for quantifying percentage of JAK2 V617F in total DNA was 6.3% and 8.6%, respectively. Nineteen JAK2 V617F-positive individuals were identified using AS-LNA-qPCR in blood of 623 apparently healthy donors, and the range of percentages of JAK2 V617F alleles were 0.01%-5.49%. CONCLUSION: The AS-LNA-qPCR with highly sensitive and reproducible quantification of JAK2 V617F mutant burden can be used clinically for diagnosis as well as evaluation of disease prognosis and efficacy of therapy in patients with myeloproliferative neoplasms. PMID- 23688755 TI - [Study on serum protein mass spectrometric characteristics of acute leukemia]. AB - OBJECTIVE: To study the serum protein differential expression in acute leukemia patients and healthy control by differential protein mass spectrometry. METHODS: Serum proteins of 51 acute leukemia (AL) patients and 10 healthy donors were extracted from their peripheral blood. After removing high abundance protein, serum low abundance proteins were separated by two dimensional gel electrophoresis, the differences of serum proteins in AL patients and healthy human were identified. The protein spots with differential expression were cut out and then undergone bleaching, gel digestion and peptide extraction. The peptide mass fingerprint analysis was performed by using MALDI TOF/TOF MS. The protein database MSDB Masort retrieval program was used to evaluate the results. RESULTS: Using Student's t test,19 statistically significant abnormal expression proteins in the serum of AL patients were found compared with the healthy controls (P < 0.05). The expression of alpha1-trypsin inhibitor (P < 0.01), prealbumin (P < 0.01), trypsin inhibitor (P < 0.01), apolipoprotein E (P < 0.01) and apolipoprotein A-IV (P < 0.01) decreased, while retinol binding protein (P < 0.05), globin HP2 (P < 0.05), serum lectin (P < 0.05), H factor homologue protein (P < 0.05) and serum amyloid A1 (P < 0.01) increased. Further stratified analysis found that high serum lectin expression in AL patient resulted in poor outcomes. CONCLUSION: There are a variety of serum proteins with differential expression in peripheral blood of AL patients. The differential expression of serum lectin is related to the therapeutic effect. The differential expression of these proteins can be used as a new diagnosis marker or prognostic indicator for acute leukemia. PMID- 23688756 TI - [The mechanisms underlying bone marrow damage by iron overload in pancytopenic patients with positive BMMNC-Coombs test]. AB - OBJECTIVE: To investigate the mechanisms underlying bone marrow damage by iron overload in pancytopenic patients with positive BMMNC-Coombs test (IRP). METHODS: Twenty-one iron overloading, 26 non-iron overloading IRP patients and 10 normal controls were enrolled in this study. The expressions of ROS, Bcl-2, Caspase-3 and apoptosis of BMMNC were analyzed by flow cytometry (FCM). Antioxidants were added to iron overloading IRP BMMNC, and then the changes of indices above were detected by FCM. The number and apoptosis of T lymphocytes of IRP patients were also detected. RESULTS: ROS and apoptosis of BMMNC, myelocytes, erythrocytes and stem cells of iron overloading IRP patients were significantly higher than that of non-iron overloading IRP ones and normal controls (P < 0.05). The expressions of Bcl-2 on BMMNC, erythrocytes and stem cells of iron overloading IRP patients were significantly lower than those of non-iron overloading IRP ones (P < 0.05). The levels of Caspase-3 on myelocytes, erythrocytes and stem cells of iron overloading IRP patients were significantly higher than those of non-iron overloading IRP ones and normal controls (P < 0.05). After treatment with antioxidants, the expressions of ROS, Caspase-3 and apoptosis of iron overloading IRP BMMNC significantly decreased, but opposite for Bcl-2. The percentages of CD4(+) lymphocytes [ ( 40.86 +/- 8.74)%] and CD4(+)/CD8(+) (1.44 +/- 0.36) in PB of iron overloading IRP patients were significantly higher than that of non-iron overloading IRP ones [(35.96 +/- 7.03)% and 1.14 +/- 0.37] and normal controls [(28.00 +/- 6.73)% and 0.79 +/- 0.21], respectively (P < 0.05), as opposite for CD8(+) lymphocytes (P < 0.05). The apoptosis of CD8(+) lymphocytes [(27.35 +/- 10.76)%] and the ratio of CD8(+) apoptosis/CD4(+) apoptosis (2.51 +/- 0.81) in BM of iron overloading IRP patients were significantly higher than those of non-iron overloading IRP ones [(15.47 +/- 8.99)%] and normal controls (1.39 +/- 0.47), respectively (P < 0.05). The apoptosis of erythrocytes and stem cells coated with auto-antibodies in BM of iron overloading IRP patients were significantly higher than those of non-iron overloading IRP and normal controls. CONCLUSION: Mechanisms underlying bone marrow damage by iron overload might be through the follows: 1The increased ROS induced by excessive iron deposition affected the expressions of Caspase-3 and Bcl-2, which caused more BMMNC apoptosis; 2The abnormal number and ratio of T lymphocytes caused by iron overload aggravated the abnormality of immunity of IRP; 3Iron overload may increase the damage to erythrocytes and stem cells coated with auto-antibodies. PMID- 23688757 TI - [Effects of ICAM-1 gene transfection on the adipogenic differentiation of MSCs]. AB - OBJECTIVE: To explore the effects of ICAM-1 gene transfection on the differentiation of MSCs to adipocytes. METHODS: The recombinant retroviral expression plasmid MIGR1-ICAM-1 containing full length of mouse ICAM-1 gene was constructed. The constructed plasmid MIGR1-ICAM-1, empty plasmid MIGR1 and packaging plasmid ECOS were transfected into T293 cell lines and then the supernatant generated from T293 cells were used to infect mouse MSCs cell line C3H10T 1/2. The transfective efficiency was determined by inverted fluorescence microscope, real-time PCR and flow cytometry. Furthermore, ICAM-1 overexpressing MSCs (C3H10T 1/2-ICAM-1) and empty vector transfection MSCs (C3H10T 1/2-MIGR1) were cultured in medium with or without induction reagents, Oil-red-O staining was used to detect the lipid accumulation, and the expression of transcriptional factors C/EBPalpha and PPARgamma, which were key factors in the differentiation of MSCs to adipocytes, were tested by real-time-PCR. RESULTS: The recombinant retrovirus vector containing mouse ICAM-1 gene was successful constructed. After transfection into MSCs cell line C3H10T 1/2, the overexpression ICAM-1 MSCs cell line (C3H10T 1/2-ICAM-1) and control cell line (C3H10T 1/2-MIGR1) were obtained. Furthermore, these two cell lines were treated without or with adipocytic induction reagents, C3H10T 1/2-ICAM-1 showed significantly lower mRNA expression level for C/EBPalpha [(1.2 +/- 0.7), (2.9 +/- 0.9)] and PPARgamma [(1557.6 +/- 70.2), (7547.0 +/- 442.2)] when compared with C3H10T 1/2-MIGR1 [(5.8 +/- 0.5), (23.0 +/- 2.3) and (2453.0 +/- 215.6), (9856.3 +/- 542.2)](P < 0.05). Moreover, little lipid droplet and decreased quantity of adipocytes were detected in C3H10T 1/2-ICAM-1 [(3.2 +/- 0.5)/well, (12.2 +/- 3.8)/well] than that in C3H10T 1/2 MIGR1 [(11.2 +/- 0.4)/well, (51.3 +/- 2.8)/well] (P < 0.05). CONCLUSION: Overexpression of ICAM-1 in MSCs can inhibit its adipocytic differentiation. PMID- 23688758 TI - [Effect of CXCR4 gene overexpression mediated by lentiviral vector on the biological characteristics of mesenchymal stem cells]. AB - OBJECTIVE: To construct mouse CXC chemokine receptor type 4 (Cxcr4) gene overexpressing lentiviral vector and to evaluate its biological effect on mouse mesenchymal stem cells (MSCs). METHODS: Cxcr4 gene was amplified and subcloned into pCR-Blunt vector. Cxcr4 gene and enhanced green fluorescent protein (EGFP) gene expressed bicistronic recombinant lentiviral vector LV-CXCR4-IRES-EGFP and control vector LV-IRES-EGFP were constructed, respectively. Both plasmids were co transfected into 293FT packaging cell line with packaging plasmid pSPAX2 and enveloping plasmid pMD.2G using Lipofectamine 2000 to produce lentiviral virus, respectively. The recombinant viruses were harvested and the virus titer was determined by limiting dilution. Mouse MSCs were infected with viral supernatant. EGFP expression was visualized using fluorescence microscope and efficiency of infection was determined by flow cytometry (FCM). Cell counting kit-8 (CCK-8) was applied in mixed lymphocyte reaction (MLR) to evaluate the suppressive effect of MSCs on mice splenocyte proliferation in vitro. Wound healing ability of MSCs was measured by scratch experiment and migration capacity by a chemotaxis assay using a transwell assay. RESULTS: The Cxcr4 fragment was amplified by reverse transcription polymerase chain reaction (RT-PCR) and verified by DNA sequencing. The restriction enzyme digestion experiment demonstrated that the recombinant lentiviral vector LV-CXCR4-IRES-EGFP and the control vector LV-IRES-EGFP were successfully constructed. Expression of CXCR4 was detected by fluorescence microscopy, which indicated that the lentiviral particles expressing CXCR4 were packaged. Furthermore, expression of EGFP were detected by fluorescence microscopy in MSCs after infection and the expression of CXCR4 protein on MSCs surface in CXCR4-MSC group was significantly increased comparing to those in the control group(P < 0.05).CXCR4-MSCs group and the control group were (90.3 +/- 3.37)% and (1.53 +/- 0.34)%, respectively. Meanwhile, overexpression of CXCR4 had no effect on their capacity of immune regulation when co-cultured with splenocyte(P > 0.05). Moreover, overexpression of CXCR4 can not only accelerated the wound healing after scratch, but also enhanced the migration ability of cells in the transwell induced by high concentration of SDF-1 in a dose-dependent manner compared with the EGFP control group. CONCLUSION: The CXCR4 expressing lentiviral vector LV-CXCR4-IRES-EGFP was successfully constructed. The lentiviral vector can not only efficiently infect mouse MSCs, but also stably express CXCR4 in MSCs. The MSCs modified with CXCR4 have biological characteristic in vitro. PMID- 23688759 TI - [Acute leukemia child with ocular Kaposi's sarcoma after hematopoietic stem cell transplantation: a case report and literatures review]. AB - OBJECTIVE: To summarize clinical features of eye Kaposis' sarcoma ( KS ) in leukemia child after peripheral blood stem cell transplantation (PBSCT). METHODS: One 13 years-old child with acute lymphoblastic leukemia (ALL) and negative HIV test who developed KS restricted in right conjunctiva, cornea and sclera after successful allogeneic PBSCT was reviewed retrospectively. RESULTS: The child suffered from T cell type ALL. He received immunosuppressive treatment after PBSCT, and had once extensive herpes zoster restricted in skin. Seven months after PBSCT, he had blurred vision with right eye and slowly neoplasm formed in cornea and conjunctiva. Pathological examination confirmed KS with changes like capillary hemangioma, atypical fusiform cell, typical immunochemistry and positive immunofluorescent result of HHV8. He received excision of lump of cornea, conjunctiva, sclera and transplantation of cornea and sclera. Antiviral therapy was given together with anti-infection, prevention of cornea rejection and biotherapy. He kept right eye and hand-move eyesight, survived without GVHD or recurrence of ALL and KS. CONCLUSION: This was the first ocular KS case in ALL child after PBSCT, without correlation with HIV infection. Complete excision combined with biotherapy was safe and effective for single ocular lesions. PMID- 23688760 TI - [Study on NPM1 and IDH mutations in childhood acute myeloid leukemia]. PMID- 23688761 TI - [Nontuberculous mycobacteria bacteremia after hematopoietic stem cell transplantation: a case report and literature review]. PMID- 23688763 TI - [Progress in diagnosis and treatment of diffuse large B cell lymphoma]. PMID- 23688762 TI - [Effect of flavonoids of puerarin on the proliferation and apoptosis of retinoic acid resistant acute promyelocytic leukemia cell line NB4-R1 cells]. PMID- 23688764 TI - [Consensus of Chinese experts on diagnosis and treatment of hemophilia(2013)]. PMID- 23688765 TI - [Guideline for management of chronic myeloid leukemia(2013)]. PMID- 23688766 TI - [Hotspot report of 54th American Society of Hematology Annual Meeting--the principle and clinical application of Bruton tyrosine kinase inhibitor]. PMID- 23688767 TI - Evaluating the in vivo Th2 priming potential among common allergens. AB - Exposure to allergens, both man-made and from our environment is increasingly associated with the development of significant human health issues such as allergy and asthma. Allergen induced production of the cytokine interleukin (IL )4 by Th2 cells is central to the pathogenesis of allergic disease (Gavett et al., 1994). The development of the G4 mouse, that expresses green fluorescent protein (GFP) as a surrogate for IL-4 protein expression has made it possible to directly track the immune cells that produce IL-4. By combining a reliable intradermal immunisation technique with the transgenic G4 mouse we have been able to develop a novel & unique in vivo primary Th2 immune response model (PTh2). When allergens relevant to human disease are evaluated using the PTh2 assay a dose dependent hierarchy of allergenicity is revealed with environmental allergens (cockroach, house dust mite) the most potent and food allergens being the least. In addition, the PTh2 assay is extremely sensitive to the immunoregulatory effects of Mycobacterial extracts and immunosuppressive drugs on primary Th2 cell development. Taken together, this assay provides a standardised method for the identification of the structural and functional properties of proteins relevant to allergenicity, and is a powerful screening tool for novel lead compounds that are effective at inhibiting the primary Th2 response in allergic diseases. PMID- 23688768 TI - ST-elevation and non-ST-elevation acute coronary syndromes: should the guidelines be changed? AB - The 12 lead surface electrocardiogram (ECG) is an indispensable tool to identify acute coronary syndromes and the patient at high risk. Acute coronary syndromes are classified according to the presence or absence of ST elevation (ST Elevation Myocardial Infarction or Acute Coronary Syndrome, STEMI or STEACS and Non ST Elevation Myocardial Infarction). NonSTEMI or nonSTEACS is approached by less invasive and frequently delayed treatment strategies. Because also nonSTEACS comprises severe and/or extensive coronary artery disease undertreatment may occur of these patient categories. Therefore better identification of those patients is needed. In the current guidelines the ischemic ECG changes are incompletely described. Improved description and understanding of the ECG in ACS will lead to better recognition of the patient at risk by emergency physicians and cardiologists. PMID- 23688769 TI - Screening for at-risk alcohol use and drug use in an emergency department: integration of screening questions into electronic triage forms achieves high screening rates. AB - STUDY OBJECTIVE: Previous studies have shown that brief interventions for at-risk alcohol and drug use are significantly more likely to occur if patients are screened with a standardized, validated instrument, but high screening rates have traditionally been difficult to attain. Use of very brief screens can enable brief intervention specialists to focus their efforts on assessing and assisting patients most likely to need a brief intervention or more intensive treatment. This study describes the results of integrating brief substance abuse screens into an urban emergency department's (ED's) triage process. METHODS: As part of a comprehensive initiative to increase alcohol and drug screening, brief intervention, and referral to treatment (SBIRT), 3 single-item screening questions were programmed into the electronic triage tool used in the ED to detect tobacco use, at-risk alcohol use, illicit drug use, or prescription drug misuse. Project staff conducted training sessions with nurses to ensure the questions were asked properly and ED supervisors provided ongoing performance feedback. Names of patients with positive responses to the alcohol or drug questions automatically populated a list forwarded to health education specialists, who provided assessments, brief interventions, and referrals. RESULTS: Screening was conducted with 145,394 of 151,597 eligible patients, a 96% screening rate. Electronic reports revealed an 89% screening rate 30 days postimplementation and gradually increasing and stabilizing at approximately 97%. The overall percentage of patients screening positive for alcohol or drug use was similar to that of other ED-based studies (22%) but varied substantially by patient demographics. CONCLUSION: High rates of screening can be achieved if properly integrated into a clinical setting's existing patient care processes with well-planned information technology support. PMID- 23688770 TI - Comparison of electronic pharmacy prescription records with manually collected medication histories in an emergency department. AB - STUDY OBJECTIVE: Medication history is an essential part of patient assessment in emergency care. Patient-reported medication history can be incomplete. We study whether an electronic pharmacy-sourced prescription record can supplement the patient-reported history. METHODS: In a community hospital, we compared the patient-reported history obtained by triage nurses to a proprietary electronic pharmacy record in all emergency department (ED) patients during 3 months. RESULTS: Of 9,426 triaged patients, 5,001 (53%) had at least 1 (mean 7.7) prescription medication in the full-year electronic pharmacy record. Counting only recent prescription medications (supply lasting to at least 7 days before the ED visit), 3,688 patients (39%) had at least 1 (mean 4.0) recent medication. After adjustment for possible false-positive results, recent electronic prescription medication record enriched the patient-reported history by 28% (adding 1.1 drugs per patient). However, only 60% of patients with any active prescription medications from either source had any recent prescription medications in their electronic pharmacy record. CONCLUSION: The electronic pharmacy prescription record augments the manually collected history. PMID- 23688771 TI - Hypertension, obesity, and coronary artery disease in the survivors of congenital heart disease. AB - Obesity, hypertension, and coronary artery disease are prevalent in the general population and well recognized as contributors to cardiac morbidity and mortality. With surgical and medical advances, there is a growing and aging population with congenital heart disease who are also at risk of developing these comorbidities. In addition, some congenital cardiac lesions predispose patients to conditions such as hypertension or coronary artery disease. The effect of these comorbidities on the structurally abnormal heart is not well understood, but might be very important, especially in those with residual abnormalities. Thus, in addition to surveillance for and treatment of late complications it is important for the congenital cardiologist to consider and aggressively manage acquired comorbidities. In this review we explore the prevalence of hypertension, obesity, and coronary artery disease, discuss congenital lesions that predispose to these conditions and review management strategies for this unique population. PMID- 23688772 TI - Bacterial-directed enzyme prodrug therapy. AB - Current conventional treatments for cancer lack tumour selectivity resulting in the destruction of healthy tissue and severe adverse effects to the patient in addition to limiting the administration dose and efficacy. Hence, it is imperative that we seek alternative approaches to treat cancer that localise therapeutic agents to the site of the tumour and spare normal tissue. The use of bacteria in cancer therapy represents one such approach. Bacteria were first used as anti-cancer agents over a century ago. Today, this field has re-emerged from the past and is progressing at a rapid rate. Bacteria are used as anticancer agents either alone or in combination with conventional treatments and have been armed with an arsenal of therapeutic genes, which enhance their efficacy. Bacterial directed enzyme prodrug therapy (BDEPT) is one of the most promising approaches, which harnesses the tumour-specific location of bacteria to locally activate systemically administered 'prodrugs' within the tumour in order to induce selective tumour destruction. BDEPT is a relatively new concept. It was originally conceived more than 10years ago but it is only until recently that we witness a surge in activity in this field. In this review, we provide a full account of developments in the field of BDEPT since its inception. We share technical knowhow and discuss optimization strategies for vector and enzyme combinations, provide a clear view of the research landscape and suggest possible directions for the field. PMID- 23688773 TI - Multi-level control of actin dynamics by protein kinase D. AB - Dynamic actin remodeling is fundamental to processes such as cell motility, vesicle trafficking, and cytokinesis. Protein kinase D (PKD) is a serine threonine kinase known to be involved in diverse biological functions ranging from vesicle fission at the Golgi complex to regulation of cell motility and invasion. This review addresses the role of PKD in the organization of the actin cytoskeleton with a particular emphasis on the substrates associated with this function. We further highlight the multi-level control of actin dynamics by PKD and suggest that the tight spatio-temporal control of PKD activity is critical for the coordination of directed cell migration. PMID- 23688774 TI - The benefit of pretreatment esophageal screening with image-enhanced endoscopy on the survival of patients with hypopharyngeal cancer. AB - BACKGROUND: Synchronous esophageal cancers can suppress the survival of patients with hypopharyngeal cancers. Esophageal screening with the image-enhanced endoscopy may identify more synchronous cancers while there is no evidence to support its benefit on survival. METHODS: A total of 281 and 320 patients were diagnosed with hypopharyngeal cancer before and after the policy of routine esophageal screening. Primary outcome measures were overall survival. RESULTS: Among those who received screening, 49 patients (49/180, 27.2%) had synchronous esophageal cancers; treatment planning was changed in 42 (23.3%). Before and after the policy, percentages of stage I-II synchronous cancers were 20% (3/15) and 53.1% (26/49), respectively. Adjunctive therapies for synchronous cancers have led to a better survival after the policy than before (P = 0.002). The Cox regression model quantified a survival benefit of 29% (95% CI: 11-43%) when adjusting for TNM stage of hypopharyngeal cancer. In post-policy period, the survival was better for those who chose screening than those who did not (HR: 0.57, 95% CI: 0.41-0.79). Among those without screening, there was no difference between the pre- and post-policy periods (HR: 0.96, 95% CI: 0.74-1.26). CONCLUSIONS: Patients with hypopharyngeal cancers may benefit from the esophageal screening with image-enhanced endoscopy through the better detection of early stage synchronous cancers. PMID- 23688775 TI - Simultaneous wide and narrow QRS complex tachycardia: what is the mechanism? AB - We present the case of a 50-year-old patient with several episodes of syncope and documented simultaneous wide and narrow QRS complex tachycardia. We then review this tacharrhythmia, focusing on electrophysiological findings and pathophysiology, diagnosis and treatment. PMID- 23688776 TI - Promoter regions of potato vacuolar invertase gene in response to sugars and hormones. AB - Potato vacuolar acid invertase (StvacINV1) (beta-fructofuranosidase; EC 3.2.1.26) has been confirmed to play an important role in cold-induced sweetening of potato tubers. However, the transcriptional regulation mechanisms of StvacINV1 are largely unknown. In this study, the 5'-flanking sequence of StvacINV1 was cloned and the cis-acting elements were predicted. Histochemical assay showed that the StvacINV1 promoter governed beta-glucuronidase (GUS) expression in potato leaves, stems, roots and tubers. Quantitative analysis of GUS expression suggested that the activity of StvacINV1 promoter was suppressed by sucrose, glucose, fructose, and cold, while enhanced by indole-3-acetic acid (IAA), and gibberellic acid (GA3). Further deletion analysis clarified that the promoter regions from -118 to -551, -551 to -1021, and -1021 to -1521 were required for responding to sucrose/glucose, GA3, and IAA, respectively. These findings provide essential information regarding transcriptional regulation mechanisms of StvacINV1. PMID- 23688777 TI - Walking kinematics and kinetics following eccentric exercise-induced muscle damage. AB - The goal of this investigation was to investigate how walking patterns are affected following muscle-damaging exercise by quantifying both lower limb kinematics and kinetics. Fifteen young women conducted a maximal isokinetic eccentric exercise (EE) muscle damage protocol (5*15) of the knee extensors and flexors of both legs at 60 degrees /s. Three-dimensional motion data and ground reaction forces (GRFs) were collected 24h pre-EE while the participants walked at their preferred self-selected walking speed (SWS). Participants were asked to perform two gait conditions 48h post-EE. The first condition (COND1) was to walk at their own speed and the second condition (COND2) to maintain the SWS (+/-5%) they had 24h pre-EE. Walking speed during COND1 was significantly lower compared to pre-exercise values. When walking speed was controlled during COND2, significant effects of muscle damage were noticed, among other variables, for stride frequency, loading rate, lateral and vertical GRFs, as well as for specific knee kinematics and kinetics. These findings provide new insights into how walking patterns are adapted to compensate for the impaired function of the knee musculature following muscle damage. The importance to distinguish the findings caused by muscle damage from those exhibited in response to changes in stride frequency is highlighted. PMID- 23688778 TI - Diagnosis of antigenic markers of acute toxoplasmosis by IgG avidity immunoblotting. AB - To perform IgG avidity immunoblotting assay for detection of acute toxoplasmosis, 100 serum samples were collected from Tehran, Iran. The presence of Toxoplasma specific IgG and IgM antibodies were checked by commercial Trinity kit. Samples were categorized in acute and chronic phases of Toxoplasma gondii infection according to IgG avidity ELISA. IgG avidity immunoblotting was performed, and antigenic bands with molecular weights of 22, 25, 28, 30, 32, 42, 44, 49, 55, 60, 66, 69, 88, 106, 130 and 157 kDa were recognized as low avidity markers. The most prevalent antigen for low avidity was p22. It is concluded that IgG avidity immunoblotting could distinguish acute and chronic phases of T. gondii infection. PMID- 23688779 TI - ADAM17 silencing by adenovirus encoding miRNA-embedded siRNA revealed essential signal transduction by angiotensin II in vascular smooth muscle cells. AB - Small interfering RNA (siRNA) mediated gene silencing has been utilized as a powerful molecular tool to study the functional significance of a specific protein. However, due to transient gene silencing and insufficient transfection efficiency, this approach can be problematic in primary cell culture such as vascular smooth muscle cells. To overcome this weakness, we utilized an adenoviral-encoded microRNA (miRNA)-embedded siRNA "mi/siRNA"-based RNA interference. Here, we report the results of silencing a disintegrin and metalloprotease 17 (ADAM17) in cultured rat vascular smooth muscle cells and its functional mechanism in angiotensin II signal transduction. 3 distinct mi/siRNA sequences targeting rat ADAM17 were inserted into pAd/CMV/V5-DEST and adenoviral solutions were obtained. Nearly 90% silencing of ADAM17 was achieved when vascular smooth muscle cells were infected with 100 multiplicity of infection of each ADAM17 mi/siRNA encoding adenovirus for 3days. mi/siRNA-ADAM17 but not mi/siRNA-control inhibited angiotensin II-induced epidermal growth factor receptor trans-activation and subsequent extracellular signal-regulated kinase activation and hypertrophic response in the cells. mi/siRNA-ADAM17 also inhibited angiotensin II-induced heparin-binding epidermal growth factor-like factor shedding. This inhibition was rescued with co-infection of adenovirus encoding mouse ADAM17 but not by its cytosolic domain deletion mutant or cytosolic Y702F mutant. As expected, angiotensin II induced tyrosine phosphorylation of ADAM17 in the cells. In conclusion, ADAM17 activation via its tyrosine phosphorylation contributes to heparin-binding epidermal growth factor-like factor shedding and subsequent growth promoting signals induced by angiotensin II in vascular smooth muscle cells. An artificial mi/siRNA-based adenoviral approach appears to be a reliable gene-silencing strategy for signal transduction research in primary cultured vascular cells. PMID- 23688780 TI - Sequencing of mRNA identifies re-expression of fetal splice variants in cardiac hypertrophy. AB - Cardiac hypertrophy has been well-characterized at the level of transcription. During cardiac hypertrophy, genes normally expressed primarily during fetal heart development are re-expressed, and this fetal gene program is believed to be a critical component of the hypertrophic process. Recently, alternative splicing of mRNA transcripts has been shown to be temporally regulated during heart development, leading us to consider whether fetal patterns of splicing also reappear during hypertrophy. We hypothesized that patterns of alternative splicing occurring during heart development are recapitulated during cardiac hypertrophy. Here we present a study of isoform expression during pressure overload cardiac hypertrophy induced by 10 days of transverse aortic constriction (TAC) in rats and in developing fetal rat hearts compared to sham-operated adult rat hearts, using high-throughput sequencing of poly(A) tail mRNA. We find a striking degree of overlap between the isoforms expressed differentially in fetal and pressure-overloaded hearts compared to control: forty-four percent of the isoforms with significantly altered expression in TAC hearts are also expressed at significantly different levels in fetal hearts compared to control (P<0.001). The isoforms that are shared between hypertrophy and fetal heart development are significantly enriched for genes involved in cytoskeletal organization, RNA processing, developmental processes, and metabolic enzymes. Our data strongly support the concept that mRNA splicing patterns normally associated with heart development recur as part of the hypertrophic response to pressure overload. These findings suggest that cardiac hypertrophy shares post-transcriptional as well as transcriptional regulatory mechanisms with fetal heart development. PMID- 23688781 TI - linc-UBC1 physically associates with polycomb repressive complex 2 (PRC2) and acts as a negative prognostic factor for lymph node metastasis and survival in bladder cancer. AB - OBJECTIVES: The human genome encodes many long intergenic noncoding RNAs (lincRNAs). However, their biological functions, molecular mechanisms and prognostic values associated with bladder cancer remain to be elucidated. Here we investigated a lincRNA termed linc-UBC1 (Up-regulated in bladder cancer 1) and evaluated its prognostic value in bladder cancer patients. MATERIALS AND METHODS: Expression of linc-UBC1 was evaluated by quantitative reverse transcription PCR (qRT-PCR) in 102 bladder cancer tissue samples and normal adjacent tissues. The functions of linc-UBC1 on cell proliferation, migration, invasion, colony formation, tumorigenicity and metastatic potential were evaluated by knockdown strategy in vitro and in vivo. RNA immunoprecipitation (RIP) was performed to confirm that linc-UBC1 physically associates with EZH2 and SUZ12, core components of polycomb repressive complex 2 (PRC2). Chromatin immunoprecipitation (ChIP) was conducted to examine histone modification status. RESULTS: qRT-PCR confirmed that linc-UBC1 expression is up-regulated in 60 cases (58.8%) in bladder cancer tissues compared with normal adjacent tissues, and its overexpression correlates with lymph node metastasis and poor survival. Further functional analysis demonstrated that knockdown of linc-UBC1 attenuates bladder cancer cell proliferation, motility, invasion, colony formation ability, tumorigenicity and metastatic potential. Importantly, the inhibitory effect of linc-UBC1 on cell proliferation was also observed in primary bladder cancer cells obtained from patients. RIP and ChIP assay confirmed that linc-UBC1 physically associates with PRC2 complex and regulates histone modification status of target genes. CONCLUSIONS: Frequently overexpressed linc-UBC1 physically associates with PRC2 complex, and acts as a negative prognostic factor for lymph node metastasis and survival in bladder cancer. PMID- 23688782 TI - Role of adipose specific lipid droplet proteins in maintaining whole body energy homeostasis. AB - Excess or insufficient lipid storage in white adipose tissue lipid droplets is associated with dyslipidemia, insulin resistance and increased risk for diabetes type 2. Thus, maintenance of adipose lipid droplet growth and function is critical to preserve whole body insulin sensitivity and energy homeostasis. Progress in understanding biology of lipid droplets has underscored the role of proteins that interact with lipid droplets. Here, we review the current knowledge of adipose specific lipid droplet proteins, which share unique functions controlling adipocyte lipid storage, limiting lipid spill-over and lipotoxic effects thought to contribute to disease. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. PMID- 23688784 TI - Different unequal cross-over events between NCF1 and its pseudogenes in autosomal p47(phox)-deficient chronic granulomatous disease. AB - Chronic granulomatous disease (CGD) is a rare congenital disorder in which phagocytes cannot generate superoxide (O2(-)) and other microbicidal oxidants due to mutations in one of the five components of the O2(-)-generating NADPH oxidase complex. The most common autosomal subtype of CGD is caused by mutations in NCF1, encoding the NADPH subunit p47(phox). Usually, these mutations are the result of unequal exchange of chromatid between NCF1 and one of its two pseudogenes. We have now investigated in detail the breakpoints within or between these (pseudo) NCF1 genes in 43 families with p47(phox)-deficient CGD by means of multiplex ligase-dependent probe amplification (MLPA). In 24 families the patients totally lacked NCF1 sequences, indicating that in these families the cross-over points are located between NCF1 and its pseudogenes. Six other families were compound heterozygous for a total NCF1 deletion and another mutation in NCF1 on the other allele. In 8 families, the patients lacked NCF1 exons 1-4 but had retained NCF1 exons 6-10, indicating that a cross-over point is located within NCF1 between exons 4 and 6. Similarly, in 4 families a cross-over point was located within NCF1 between exons 2 and 4. Similar cross-overs, in heterozygous form, were observed in family members of the patients. Several patients were compound heterozygous for total and partial NCF1 deletions. Thus, at least three different cross-over points exist within the NCF1 gene cluster, indicating that autosomal p47(phox)-deficient CGD is genetically heterogeneous but can be dissected in detail by MLPA. PMID- 23688785 TI - Delivery of biopharmaceuticals: advanced analytical and biophysical methods. PMID- 23688786 TI - Sartorius transposition during inguinal lymphadenectomy for melanoma. AB - BACKGROUND: Inguinal lymph node dissection (ILND) for melanoma has been associated with high rates of wound complication (WC). Sartorius transposition (ST) is a technique that has been proposed to minimize morbidity. We report the frequency of utilization of ST and associated clinical outcomes in a national sample. MATERIALS AND METHODS: Patients undergoing ILND for melanoma were identified in the American College of Surgeons National Surgical Quality Improvement Program Participant Use File (2005-2011). ST status was determined. Univariate logistic regression analyses were performed. Propensity score matching was used to control for operative time. Conditional logistic regression was used to determine the likelihood of a WC following ST in the matched cohort. RESULTS: Of the 381 patients identified, 13% had a WC. By univariate analysis, increasing body mass index (P = 0.006), diabetes (P = 0.02), and longer operative time (P = 0.005) were associated with WC. Sixty-three patients received a prophylactic ST (16.5%). ST use was significantly associated with deep nodal dissection (P = 0.03) and increased operative time (P < 0.0001) but not with any preoperative risk factors. WC rates were similar between ST and non-ST patients (10% versus 14%, P = 0.39). In the multivariate analysis of patients matched for operative time, ST was the only factor significantly associated with lower WC rate. The WC rate was 23% in non-ST compared with 8% in ST patients (P = 0.05). CONCLUSIONS: Nationally, ST is used infrequently at the time of ILND. Moreover, patients undergoing ST do not appear to be selected based on the patient factors associated with increased risk of WC. Risk factors for wound complication should be considered in the selective use of ST. PMID- 23688787 TI - Vascular endothelial growth factor receptor-2 inhibition in experimental murine colitis. AB - BACKGROUND: In the setting of inflammatory bowel disease, inflammation is associated with a simultaneous increase in angiogenesis; moreover, elevated vascular endothelial growth factor (VEGF) levels implicate angiogenesis as a pathologic contributor to disease severity. We hypothesize that selectively inhibiting vascular endothelial growth factor receptor-2 (VEGFR2) in a model of murine colitis will reduce angiogenesis, resulting in decreased inflammation and disease severity, providing mechanistic insight into the role of pathologic angiogenesis in IBD. MATERIALS AND METHODS: In a dextran sodium sulfate model of murine colitis, anti-VEGFR2 monoclonal antibody (DC101) or placebo was administered. Clinical assessments followed by histologic and molecular tissue analysis were performed to quantify inflammation, microvessel density (MVD), VEGF and VEGFR2 gene expression, and phosphorylated mitogen-activated protein kinase protein expression. RESULTS: Weight loss began after d 6 with the treatment group demonstrating a more favorable percent weight change. Inflammation and MVD were similar between cohorts, both increasing in parallel toward a plateau. VEGF and VEGFR2 messenger RNA expression were not significantly different, but phosphorylated mitogen-activated protein kinase was elevated in the DC101 cohort (P = 0.03). CONCLUSIONS: Despite a more favorable weight change profile in the treated group, no difference was observed between cohorts regarding clinical disease severity. However, a parallel rise in inflammation and MVD was observed coinciding with weight loss, suggesting their relationship in IBD. VEGFR2 downstream signaling was significantly elevated in the treated cohort, possibly by VEGF-independent signal transduction. Early and effective inhibition of angiogenesis by limiting downstream VEGF signaling or targeting multiple angiogenic pathways may block angiogenesis, thereby reducing disease severity and provide evidence toward the mechanism and clinical benefit of antiangiogenics in the setting of IBD. PMID- 23688788 TI - Unilateral thyroidectomy for the treatment of benign multinodular goiter. AB - BACKGROUND: Benign multinodular goiter (MNG) is one of the most commonly treated thyroid disorders. Although bilateral resection is the accepted surgical treatment for bilateral MNG, the appropriate surgical resection for unilateral MNG continues to be debated. Bilateral resection generally has lower recurrence rates but higher complication rates than unilateral resection. Therefore, the purpose of this study was to define the recurrence and complication rates of unilateral and bilateral resections to determine the appropriate intervention for patients with unilateral, benign MNG. METHODS: We reviewed a prospectively maintained database of all patients who underwent a thyroidectomy for treatment of benign MNG at a single institution between May 1994 and December 2011. All patients with bilateral MNG were treated with bilateral resection. Surgical treatment for unilateral MNG was determined by surgeon preference, with all but one surgeon opting for unilateral resection to treat unilateral MNG. Data were reported as means +/- standard error of the mean. Chi-squared analysis was used to determine statistical significance at a level of P < 0.05. RESULTS: A total of 683 patients underwent thyroidectomy for MNG. Of these patients, 420 (61%) underwent unilateral resection and 263 patients (39%) underwent total thyroidectomy. The mean age was 52 +/- 17 y, and 542 patients (79%) were female. The mean follow-up time was 46.1 +/- 1.9 mo. The rate of recurrent disease was similar between unilateral (2%, n = 10) and bilateral (1%, n = 3) resections (P = 0.248). Unilateral resection patients had a lower total complication rate than patients with bilateral resections (8% versus 26%, P < 0.001); however, there was no difference in the rate of permanent complications (0.2% versus 1%, P = 0.133). Thyroid hormone replacement was rare in unilateral resection patients but necessary in all patients with bilateral resection (19% versus 100%, P < 0.001). CONCLUSIONS: Patients that had unilateral resections endured less overall morbidities than those who had bilateral resections, and their risk of recurrent disease was similar. They were also significantly less likely to require lifelong hormone replacement therapy postoperatively. Although bilateral resection remains the recommended treatment for bilateral MNG, these data strongly support the use of unilateral thyroidectomy for the treatment of unilateral, benign MNG. PMID- 23688789 TI - Does the volume of ductal carcinoma in situ impact the positive margin rate in patients undergoing breast conservation for invasive breast cancer? AB - BACKGROUND: We sought to investigate whether the volume of ductal carcinoma in situ (DCIS) impacts margin status in patients undergoing lumpectomy for invasive breast cancer. METHODS: We identified 358 patients with stages I-III invasive breast cancer and associated DCIS who were treated with breast-conserving therapy from 1999 to 2009. Data included patient and tumor characteristics, percentage of DCIS (<25%, 26%-50%, or >50%), and pathologic outcomes. Data were compared using chi-square and Fisher exact tests. A two-tailed P value of <0.05 was considered significant. RESULTS: The 358 patients had a mean age of 58 +/- 13 y; 260 (72%) patients were >50 y. The volume of DCIS in lumpectomy specimens was <25% in 296 (83%) patients, 26%-50% in 29 (8%) patients, and >50% in 33 (9%) patients. Tumors with decreasing DCIS volume were more likely to be estrogen receptor positive (239 [82%] with <25% DCIS, 21 [72%] with 26%-50% DCIS, 22 [67%] with >50% DCIS; P=0.026). DCIS volume was not significantly associated with patient age, tumor size, grade, and stage, nodal status, progesterone receptor status, or Her2 status (P>0.05). Overall, 137 (38%) patients had one or more positive margins, including 97 of 296 (33%) with <25% DCIS volume, 17 of 29 (59%) with 26%-50% DCIS volume, and 23 of 33 (70%) with >50% DCIS volume (P<0.0001). CONCLUSIONS: The volume of DCIS associated with an invasive breast cancer in the final lumpectomy specimen is a strong predictor of positive surgical margins. Future analyses will focus on the ability of core pathology to provide this information for intraoperative surgical decision making. PMID- 23688783 TI - Adipose tissue plasticity from WAT to BAT and in between. AB - Adipose tissue plays an essential role in regulating energy balance through its metabolic, cellular and endocrine functions. Adipose tissue has been historically classified into anabolic white adipose tissue and catabolic brown adipose tissue. An explosion of new data, however, points to the remarkable heterogeneity among the cells types that can become adipocytes, as well as the inherent metabolic plasticity of mature cells. These data indicate that targeting cellular and metabolic plasticity of adipose tissue might provide new avenues for treatment of obesity-related diseases. This review will discuss the developmental origins of adipose tissue, the cellular complexity of adipose tissues, and the identification of progenitors that contribute to adipogenesis throughout development. We will touch upon the pathological remodeling of adipose tissue and discuss how our understanding of adipose tissue remodeling can uncover new therapeutic targets. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. PMID- 23688790 TI - Is chronic kidney disease an independent risk factor for mortality in breast cancer? AB - BACKGROUND: Chronic kidney disease (CKD) is an independent risk factor for morbidity and mortality in multiple disease processes. However, not much is known about the relationship between breast cancer and CKD. CKD is associated with increased difficulty in breast cancer screening or surveillance due to increased calcifications on mammography. In addition, there is concern regarding the optimization of serum levels of chemotherapeutics in patients with CKD or on hemodialysis. We hypothesized that CKD is an independent risk factor for mortality in patients with breast cancer. METHODS: A case-matched, retrospective review of a prospectively maintained database was conducted on patients treated for breast cancer at an academic medical center between 1998 and 2011. Glomerular filtration rates (GFRs) were calculated for each patient at the time of diagnosis, and patients with CKD (GFR <60 mL/min) were matched in a 1:2 ratio with patients with GFR >60 mL/min, controlling for age, stage at diagnosis, and race. Primary end points measured were disease-free survival and overall survival. Statistical analysis was performed using Student t-test and Kaplan Meier. RESULTS: Of the 1223 total patients, 54 (4%) had CKD. One hundred five patients without CKD were matched for age, stage at diagnosis, and race. Mean GFR among patients with and without CKD were 47.6 and 83.2 mL/min, respectively (P < 0.001). The 5-y overall survival was 77% for patients with CKD and 86% for patients without CKD (P = 0.47). Disease-free survival was 64% and 81%, respectively (P = 0.45). CONCLUSION: Based on our data, CKD does not appear to have a significant impact on outcomes in patients with breast cancer. PMID- 23688791 TI - A short-stay unit for thyroidectomy patients increases discharge efficiency. AB - BACKGROUND: Patients traditionally recover overnight on a general surgery ward after a thyroidectomy; however, these units often lack the efficiency and focus for rapid discharge, which is the goal of a short-stay (SS) unit. Using an SS unit for thyroidectomy patients, who are often discharged in <24 h, may reduce the duration of hospital stay and subsequently decrease associated costs and increase hospital bed and resource availability. METHODS: A retrospective review of 400 patients undergoing thyroidectomy at a single academic hospital. We analyzed postoperative discharge information and hospital cost data. Adult patients who stayed a single night in the hospital were included. We compared patients staying on a designated SS unit versus a general surgery (GS) ward. RESULTS: A total of 223 patients were admitted to SS, and 177 to GS. Trends of admission location were blocked based on time period, with most patients per time period going to the same location. Discharge times were significantly quicker for patients admitted to SS (P < 0.001). A total of 70% of SS patients were discharged before noon, versus 40% of GS patients (P < 0.001). Many variances were identified to account for these differences. Direct costs were significantly lower with SS, owing to savings in pharmacy, recovery room, and nursing expenses (all P < 0.01). CONCLUSIONS: A designated short-stay hospital unit is an effective model for increasing the efficiency of discharge for thyroidectomy patients compared with those admitted to a general surgery ward. It also serves to increase bed availability, which decreases hospital cost and may improve patient flow. PMID- 23688792 TI - Tonometry as a predictor of inadequate splanchnic perfusion in an intra-abdominal hypertension animal model. AB - BACKGROUND: The gastrointestinal system is the most sensitive to the presence of intra-abdominal hypertension. We aimed to assess the early prognostic value of gastric air tonometry as a predictor of inadequate splanchnic perfusion and determine its relation with abdominal perfusion pressure (APP). METHODS: Twenty five Large White swine were used for this study. A control group and two study groups were included, in which intra-abdominal pressure (IAP) was elevated with Co2 to 20 and 30 mmHg during 5 h. We measured the intramucosal gastric pH (pHim) and determined gastric luminal PCO2 (PgCO2) and PgCO2gap (gastric luminal CO2 arterial CO2) to evaluate gastric acidity. APP was indirectly obtained through IAP and mean arterial pressure. Additionally, histopathologic samples of small intestine were obtained and analyzed. RESULTS: pHim showed a decrease in IAP groups, with statistical significance in the 30 mmHg group, 90 min after stabilization period (P < 0.01). Serum lactate showed delayed alteration when compared with pHim, with significant increase, 180 min after stabilization (P < 0.05). The values of PgCO2 and PCO2gap were increased in IAP groups, being statistically significant in the 30 mmHg group, 120 and 150 min, respectively, after stabilization. In increased IAP groups, there was a time progressive decrease of APP, with statistically significant differences observed between groups at 20 min (P < 0.001). The histopathology study revealed parenchymal injury of the intestine at 30 mmHg. CONCLUSIONS: Tonometry is sensitive to the increase in IAP and relates to the reduction of APP generated by splanchnic hypoperfusion. PMID- 23688793 TI - Ghost publications in the pediatric surgery match. AB - INTRODUCTION: Pediatric surgery fellowship is considered one of the most competitive subspecialties in medicine. With fierce competition increasing the stakes, publications and first authorship are paramount to the success rate of matching. We analyzed Electronic Residency Application Service applications for verification of authorship to determine rate of misrepresentation. METHODS: After institutional review board approval, the bibliographies of fellowship applications from 2007-2009 were reviewed to allow time for publication. Only peer-reviewed journal articles were evaluated. A Medline search was conducted for the article, by author or by title. If the article could not be found, other authors and journal were used as search parameters. If the article was still not found, the website for the journal was searched for abstract or manuscript. Finally, an experienced medical sciences librarian was consulted for remaining unidentified articles. Differences between misrepresented and accurate applications were analyzed, including: age, gender, medical and undergraduate school parameters, advanced degrees, other fellowships, number of publications, first author publications, American Board of Surgery In-Training Examination scores, and match success. RESULTS: There were 147 applications reviewed. Evidence of misrepresentation was found in 17.6% of the applicants (24/136), with 34 instances in 785 manuscripts (4.3%). Manuscripts classified as published were verified 96.7% of the time, were not found in 1.4%, and had incorrect authors or journal in less than 1% each. "In press" manuscripts were verified 88.3% of the time, 6.4% could not be found, and 4.3% had an incorrect journal listing. Number of publications (P = 0.026) and first author publications (P = 0.037) correlated with misrepresentation. None of the remaining variables was significant. CONCLUSIONS: The pediatric surgical pool has a very low incidence of suspicious citations; however, authorship claims should be verified. PMID- 23688794 TI - A new liver graft preparation method for uncontrolled non-heart-beating donors, combining short oxygenated warm perfusion and prostaglandin E1. AB - BACKGROUND: To resolve the shortage of donors associated with liver transplantation, the potential uncontrolled non-heart-beating donor (UNHBD) pool is expected to increase. However, warm ischemia-reperfusion injury leads to inferior survival in transplantation using the grafts from UNHBD compared with those from heart-beating donors. To overcome this problem, we developed a new method for preparation of liver grafts from UNHBDs consisting of a combination of short oxygenated warm perfusion (SOWP) and prostaglandin E1 (PGE1). METHODS: Using an ex vivo perfusion rat model, we examined the effectiveness of this new method. RESULTS: Using SOWP and PGE1 treatment, the total amount of bile production during reperfusion in UNHBD grafts was increased to the same level as that in the heart-beating donor grafts. The addition of PGE1 to SOWP buffer decreased aspartate aminotransferase/alanine aminotransferase and tumor necrosis factor alpha levels during 1 h of reperfusion. Necrosis and apoptosis were significantly decreased by SOWP + PGE1 treatment. SOWP + PGE1 ameliorated induction of mitochondrial permeability transition, and the total amount of mitochondrial cytochrome c in the SOWP + PGE1 group after reperfusion was kept significantly higher than that in the no treatment group. Cytosolic c-Jun N terminal protein kinase activation was significantly suppressed by SOWP + PGE1. Decrease in mitochondrial Bcl-2 was suppressed by SOWP alone and SOWP + PGE1 treatment, and Bax in the mitochondria was significantly suppressed by SOWP + PGE1. CONCLUSION: SOWP and PGE1 prior to cold preservation significantly improved the function of liver grafts that underwent warm ischemia-reperfusion injury. Therefore, this method might be useful in liver transplantation using UNHBD grafts. PMID- 23688795 TI - Constructal law: pleasure, golden ratio, animal locomotion and the design of pedestrian evacuation: comment on "The emergence of design in pedestrian dynamics: locomotion, self-organization, walking paths and the constructal law" by A. Miguel. PMID- 23688796 TI - Novel aspects of health promoting compounds in meat. AB - Meat is an integral part of the human diet. Besides essential amino acids and nutritive factors of high quality and availability, meat provides often overlooked components of importance for human health. These are amino acids and bioactive compounds that may be very important in i) preventing muscle wasting diseases, such as in sarcopenia, ii) reducing food and caloric intake to prevent metabolic syndrome, iii) blood pressure homeostasis via ACE-inhibitory components from connective tissue, and iv) maintaining functional gut environment through meat-derived nucleotides and nucleosides. In addition, meat could be an important source of phytanic acid, conjugated linoleic acids and antioxidants. Further, it becomes increasingly apparent that design of in vitro meat will be possible, and that this development may lead to improved health benefits from commercially viable and sustainable meat products. PMID- 23688798 TI - Quantifying and predicting meat and meat products quality attributes using electromagnetic waves: an overview. AB - The meat industry needs reliable meat quality information throughout the production process in order to guarantee high-quality meat products for consumers. Besides laboratory researches, food scientists often try to adapt their tools to industrial conditions and easy handling devices useable on-line and in slaughterhouses already exist. This paper overviews the recently developed approaches and latest research efforts related to assessing the quality of different meat products by electromagnetic waves and examines the potential for their deployment. The main meat quality traits that can be assessed using electromagnetic waves are sensory characteristics, chemical composition, physicochemical properties, health-protecting properties, nutritional characteristics and safety. A wide range of techniques, from low frequency, high frequency impedance measurement, microwaves, NMR, IR and UV light, to X-ray interaction, involves a wide range of physical interactions between the electromagnetic wave and the sample. Some of these techniques are now in a period of transition between experimental and applied utilization and several sensors and instruments are reviewed. PMID- 23688797 TI - Microbial pathogen control in the beef chain: recent research advances. AB - Within a recent EU research project ("ProSafeBeef"), research on foodborne pathogens in the beef chain was conducted by using a longitudinally integrated (fork-to-farm) approach. There is not any "single intervention-single chain point" combination by which the pathogens would be reliably and entirely eliminated from the chain resulting in total prevention of pathogens in beef and products thereof at the consumption time. Rather, a range of control interventions have to be applied at multiple points of the chain, so to achieve an acceptable, ultimate risk reduction. Various novel interventions were developed and evaluated during the project, and are briefly summarized in this paper. They include on-farm measures, risk categorisation of cattle presented for slaughter, hygiene-based measures and antimicrobial treatments applied on hides and/or carcasses during cattle slaughter, those applied during beef processing storage-distribution, use of Time Temperature Integrator-based indicators of safety, and effective sanitation of surfaces. PMID- 23688799 TI - Effects of low protein diets on pigs with a lean genotype 2. Compositional traits measured with computed tomography (CT). AB - The effects on compositional changes across the growing-finishing period (40-115 kg) of feeding pig diets with different protein and amino acid levels were investigated using CT scanning (at 60, 85 and 115 kg live weight). Pigs of a lean commercial genotype were fed a commercial control regime (C), or a low protein regime with either high (LP1) or low (LP2) essential amino acid levels, all balanced for net energy. In vivo CT measurements agreed well with post-slaughter sample joint dissection results for carcass tissue weights/proportions, and CT measured muscle density predicted intramuscular fat accurately. Pigs on C and LP1 regimes did not differ significantly in composition during growth. However, pigs on the LP2 regime had significantly more fat (in carcass, internal and intra muscular depots) and less muscle, from 85 kg onwards. Although fat levels differed depending on diet regime (LP2>others), proportions of fat in different body depots were unaffected. PMID- 23688800 TI - Credence quality coordination and consumers' willingness-to-pay for certified halal labelled meat. AB - This paper reports on halal credence quality coordination and Muslim consumers' willingness to buy and pay for certified halal labelled meat at the supermarket and the Islamic butcher. Cross-sectional data were collected through a survey with 202 Muslim consumers in Belgium. Findings indicate that more acculturated and female consumers are more in favour of purchasing certified halal labelled meat in a supermarket. Important conditions are that supermarkets can provide a guarantee of separating halal from non-halal meat and of the organisation of adequate verification and control. Results further show that more Muslim consumers are willing to pay a price premium (of 13% on average) for halal labelled meat at the Islamic butcher shop than at the supermarket. The higher the importance attached to a certified halal label and the more distrust in the actual halal meat status, the higher the likelihood that a Muslim consumer is willing to pay a higher price for certified halal labelled meat at the Islamic butcher shop. Gender and generation determine the actual premium Muslim consumers are willing to pay. PMID- 23688801 TI - Symptoms and treatment of mental illness among prisoners: a study of Michigan state prisons. AB - This study reports on a representative sample of prisoners in Michigan correctional facilities to determine the prevalence of psychiatric illness and the delivery of mental health (MH) services. Mental health assessments were conducted with 618 incarcerated subjects using the interRAI Correctional Facilities (interRAI CF). Subjects were randomly sampled based on four strata: males in the general population, males in administrative segregation, males in special units, and females. The interRAI CF assessments were merged with secondary data provided by the Michigan Department of Corrections (MDOC) containing information on MH diagnoses or services that the subjects were receiving within the facilities, demographics, and sentencing. Study results show that 20.1% of men and 24.8% of women in Michigan prisons have a substantial level of MH symptoms and that 16.5% and 28.9%, respectively, are receiving MH services. However, when compared with Michigan Department of Corrections MH care records, 65.0% of prisoners who are experiencing symptoms of mental illness are not currently receiving any psychiatric services. The mis-match between symptoms and service delivery suggests the need for improved procedures for identifying and measuring psychiatric symptoms within Michigan correctional facilities to ensure that appropriate individuals receive needed care. It is recommended that a standardized assessment process be implemented and conducted at regular intervals for targeting and improving psychiatric care in the prison system. PMID- 23688802 TI - What are we to make of the concept of race? Thoughts of a philosopher-scientist. AB - Discussions about the biological bases (or lack thereof) of the concept of race in the human species seem to be never ending. One of the latest rounds is represented by a paper by Neven Sesardic, which attempts to build a strong scientific case for the existence of human races, based on genetic, morphometric and behavioral characteristics, as well as on a thorough critique of opposing positions. In this paper I show that Sesardic's critique falls far short of the goal, and that his positive case is exceedingly thin. I do this through a combination of analysis of the actual scientific findings invoked by Sesardic and of some philosophical unpacking of his conceptual analysis, drawing on a dual professional background as an evolutionary biologist and a philosopher of science. PMID- 23688803 TI - A sensitive and specific PCR assay for the detection of Baylisascaris schroederi eggs in giant panda feces. AB - Baylisascaris schroederi is one of the most common intestinal nematodes in giant pandas. It can cause severe baylisascariasis which is highly infectious in its natural hosts. A rapid and reliable diagnosis of parasite infections is crucial to protect giant pandas, as well as for environmental monitoring and disease surveillance. Here, we established a specific PCR assay for B. schroederi detection which was targeting a 331-bp long fragment of the mitochondrial cytochrome c oxidase subunit II (COII) gene. Fifty fresh fecal samples collected from captive giant pandas were tested by the established PCR assay and the traditional flotation technique. DNA extracted from a single B. schroederi egg could be successfully amplified, while no cross-reactivity was found with DNA from Ancylostoma caninum eggs. The detection rate of the PCR assay was 68%, which was higher than that of the traditional egg flotation (46%). Our findings demonstrated that the PCR assay is sensitive and specific for the detection and identification of B. schroederi eggs. Therefore, it could become a useful tool for the investigation of B. schroederi infections in giant pandas. PMID- 23688804 TI - Characterization of Plasmodium falciparum cdc2-related kinase and the effects of a CDK inhibitor on the parasites in erythrocytic schizogony. AB - The cell cycle of Plasmodium is unique among major eukaryotic cell cycle models. Cyclin-dependent kinases (CDKs) are thought to be the key molecular switches that regulate cell cycle progression in the parasite. However, little information is available about Plasmodium CDKs. The present study was performed to investigate the effects of a CDK inhibitor, olomoucine, on the erythrocytic growth of Plasmodium falciparum. This agent inhibited the growth of the parasite at the trophozoite/schizont stage. Furthermore, we characterized the Plasmodium CDK homolog, P. falciparum cdc2-related kinase-1 (Pfcrk-1), which is a potential target of olomoucine. We synthesized a functional kinase domain of Pfcrk-1 as a GST fusion protein using a wheat germ protein expression system, and examined its phosphorylation activity. The activity of this catalytic domain was higher than that of GST-GFP control, but the same as that of a kinase-negative mutant of Pfcrk-1. After the phosphatase treatment, the labeling of [gamma-(32)P]ATP was abolished. Recombinant human cyclin proteins were added to these kinase reactions, but there were no differences in activity. This report provides important information for the future investigation of Plasmodium CDKs. PMID- 23688805 TI - Silver sulfadiazine based cubosome hydrogels for topical treatment of burns: development and in vitro/in vivo characterization. AB - The present study is concerned with the development and characterization of a novel nanaoparticulate system; cubosomes, loaded with silver sulfadiazine (SSD), which is the metallic salt of a sulfonamide derivative, and is considered as the drug of choice for topical treatment of infected burns. Cubosome dispersions were formulated by an emulsification technique using different concentrations of a lipid phase monoolein and the nonionic surfactant, Poloxamer 407, with or without polyvinyl alcohol. The prepared cubosomal dispersions were characterized regarding physical morphology, dimensional distribution, particle size, and in vitro drug release. The optimum formulae were incorporated in a chitosan, carbopol 940 or chitosan/carbopol mixture based hydrogels, to form cubosomal hydrogels (cubogels). The cubogels were characterized regarding in vitro release of SSD, rheological properties, pH, and mucoadhesion. For the optimal cubogel formulae, an in vivo histopathological study was conducted on rats to predict the effectiveness of the newly prepared cubogels in comparison with the commercially available cream (Dermazin(r)). In vivo histopathological study results showed that prepared cubogels were successful in the treatment of deep second degree burn which may result in better patient compliance and excellent healing results with least side effects in comparison with the commercially available product. PMID- 23688806 TI - Drug solubilisation in lipid nanoparticles containing high melting point triglycerides. AB - The effect of lipid (either the triglyceride trilaurin or tripalmitin, melting points of 43 and 64 degrees C, respectively) on the properties of lipid nanoparticles (LN) stabilised by the surfactant, polyoxyethylene-10-oleyl ether (C18:1E10) at a temperature of 22 degrees C, has been determined. LN were prepared by heating lipid, surfactant and water to 70 degrees C and cooling to ambient temperature with constant stirring. While lipid type influenced LN formation in that trilaurin-containing LN formed over the greatest range of compositions, phase inversion studies suggested that both lipids formed a core within the LN while light scattering studies indicated that the size of both types of LN varied with lipid concentration: in an approximately linear fashion for clear or opalescent LN and exponentially for cloudy LN. Additionally, both types of preformed LN exhibited an increase in solubilisation capacity of the hydrophobic drug, testosterone propionate compared to C18:1E10 micelles, although the trilaurin-containing LN exhibited the greatest increase. Differential scanning calorimetry studies demonstrated that trilaurin formed a 'fluid-like' core and therefore liquefied-lipid nanoparticles, which allowed dissolution of testosterone propionate in the lipid core. In contrast, tripalmitin was present in a 'solid-like' state forming solid lipid nanoparticles which did not allow testosterone propionate dissolution in the core. PMID- 23688807 TI - Impact of gluten-free diet on cardiovascular risk factors. A retrospective analysis in a large cohort of coeliac patients. AB - BACKGROUND: Concerns have been raised on whether a gluten-free diet affects the cardiovascular risk profile of coeliac patients. AIMS: To assess changes of multiple cardiovascular risk factors in coeliac patients evaluated before and during a gluten-free diet. METHODS: Retrospective analysis of the effects of 1-5 years of gluten-free diet on indicators of cardiovascular risk and on distribution in cardiovascular risk categories in 715 coeliac patients. RESULTS: Compared to baseline, significant increases were found in body mass index (21.4+/ 3.4 vs. 22.5+/-3.5; p<0.0001), total cholesterol (171.2+/-37.4mg/dL vs. 181.4+/ 35.1mg/dL; p<0.0001), and gamma-glutamyl transpeptidase (16.5+/-14.9 vs. 19.5+/ 19.2U/L; p<0.0001). Significant reductions were found in serum triglycerides (87.9+/-49.5 vs. 80.2+/-42.8mg/dL; p<0.0001) and homocysteine (16.9+/-9.6 vs. 13.3+/-8.0MUmol/L; p=0.018) during gluten-free diet. The proportion of patients included in an arbitrarily defined category of "lowest cardiovascular risk profile" decreased from 58% at baseline to 47% during gluten-free diet. CONCLUSIONS: A gluten-free diet significantly affects cardiovascular risk factors in coeliac patients, but changes do not consistently point towards worse or better risk profiles, thus suggesting that the diet is unlikely to be atherogenic. PMID- 23688808 TI - [An umbilical nodule]. PMID- 23688809 TI - HeartWare ventricular assist system for bridge to transplant: the new kid on the block. PMID- 23688810 TI - The origins of Penrose diagrams in physics, art, and the psychology of perception, 1958-62. AB - Penrose diagrams gave mid-twentieth century physicists studying General Relativity (GR) a new tool for understanding Einstein's theory of gravity. Starting in 1962 they allowed new understandings and conceptualizations of the mathematical objects of theoretical physics. One origin of the diagrams is found in Roger Penrose's engagement with the art of "impossible objects". These new understandings contributed to the "renaissance" GR experienced starting in the late 1950s. By following the diagrams through the GR community, the interrelation of research and pedagogy is explicated. This interrelation rapidly disseminated the tools to new workers in the field, further amplifying the effect of this new theoretical tool on disciplinary growth. PMID- 23688811 TI - Management of respiration-induced motion with 4-dimensional computed tomography (4DCT) for pancreas irradiation. AB - PURPOSE: The purposes of this study were to quantify respiration-induced organ motions for pancreatic cancer patients and to explore strategies to account for these motions. METHODS AND MATERIALS: Both 3-dimensional computed tomography (3DCT) and 4-dimensional computed tomography (4DCT) scans were acquired sequentially for 15 pancreatic cancer patients, including 10 randomly selected patients and 5 patients selected from a subgroup of patients with large tumor respiratory motions. 3DCTs were fused with 2 sets of 4DCT data at the end of exhale phase (50%) and the end of inhale phase (0%). The target was delineated on the 50% and 0% phase CT sets, and the organs at risk were drawn on the 3DCT. These contours were populated to the CT sets at other respiratory phases based on deformable image registration. Internal target volumes (ITV) were generated by tracing the target contours of all phases (ITV10), 3 phases of 0%, 20% and 50% (ITV3), and 2 phases of 0% and 50% (ITV2). ITVs generated from phase images were compared using percentage of volume overlap, Dice coefficient, geometric centers, and average surface distance. RESULTS: Volume variations of pancreas, kidneys, and liver as a function of respiratory phases were small (<5%) during respiration. For the 10 randomly selected patients, peak-to-peak amplitudes of liver, left kidney, right kidney, and the target along the superior-inferior (SI) direction were 7.9 +/- 3.2 mm, 7.1 +/- 3.1 mm, 5.7 +/- 3.2 mm, and 5.9 +/- 2.8 mm, respectively. The percentage of volume overlap and Dice coefficient were 92% +/- 1% and 96% +/- 1% between ITV10 and ITV2 and 96% +/- 1% and 98% +/- 1% between ITV10 and ITV3, respectively. The percentage of volume overlap between ITV10 and ITV3 was 93.6 +/- 1.1 for patients with tumor motion >8 mm. CONCLUSIONS: Appropriate motion management strategies are proposed for radiation treatment planning of pancreatic tumors based on magnitudes of tumor respiratory motions. PMID- 23688812 TI - Statistical assessment of proton treatment plans under setup and range uncertainties. AB - PURPOSE: To evaluate a method for quantifying the effect of setup errors and range uncertainties on dose distribution and dose-volume histogram using statistical parameters; and to assess existing planning practice in selected treatment sites under setup and range uncertainties. METHODS AND MATERIALS: Twenty passively scattered proton lung cancer plans, 10 prostate, and 1 brain cancer scanning-beam proton plan(s) were analyzed. To account for the dose under uncertainties, we performed a comprehensive simulation in which the dose was recalculated 600 times per given plan under the influence of random and systematic setup errors and proton range errors. On the basis of simulation results, we determined the probability of dose variations and calculated the expected values and standard deviations of dose-volume histograms. The uncertainties in dose were spatially visualized on the planning CT as a probability map of failure to target coverage or overdose of critical structures. RESULTS: The expected value of target coverage under the uncertainties was consistently lower than that of the nominal value determined from the clinical target volume coverage without setup error or range uncertainty, with a mean difference of -1.1% (-0.9% for breath-hold), -0.3%, and -2.2% for lung, prostate, and a brain cases, respectively. The organs with most sensitive dose under uncertainties were esophagus and spinal cord for lung, rectum for prostate, and brain stem for brain cancer. CONCLUSIONS: A clinically feasible robustness plan analysis tool based on direct dose calculation and statistical simulation has been developed. Both the expectation value and standard deviation are useful to evaluate the impact of uncertainties. The existing proton beam planning method used in this institution seems to be adequate in terms of target coverage. However, structures that are small in volume or located near the target area showed greater sensitivity to uncertainties. PMID- 23688813 TI - Predictive models for regional hepatic function based on 99mTc-IDA SPECT and local radiation dose for physiologic adaptive radiation therapy. AB - PURPOSE: High-dose radiation therapy (RT) for intrahepatic cancer is limited by the development of liver injury. This study investigated whether regional hepatic function assessed before and during the course of RT using 99mTc-labeled iminodiacetic acid (IDA) single photon emission computed tomography (SPECT) could predict regional liver function reserve after RT. METHODS AND MATERIALS: Fourteen patients treated with RT for intrahepatic cancers underwent dynamic 99mTc-IDA SPECT scans before RT, during, and 1 month after completion of RT. Indocyanine green (ICG) tests, a measure of overall liver function, were performed within 1 day of each scan. Three-dimensional volumetric hepatic extraction fraction (HEF) images of the liver were estimated by deconvolution analysis. After coregistration of the CT/SPECT and the treatment planning CT, HEF dose-response functions during and after RT were generated. The volumetric mean of the HEFs in the whole liver was correlated with ICG clearance time. Three models, dose, priori, and adaptive models, were developed using multivariate linear regression to assess whether the regional HEFs measured before and during RT helped predict regional hepatic function after RT. RESULTS: The mean of the volumetric liver HEFs was significantly correlated with ICG clearance half-life time (r=-0.80, P<.0001), for all time points. Linear correlations between local doses and regional HEFs 1 month after RT were significant in 12 patients. In the priori model, regional HEF after RT was predicted by the planned dose and regional HEF assessed before RT (R=0.71, P<.0001). In the adaptive model, regional HEF after RT was predicted by regional HEF reassessed during RT and the remaining planned local dose (R=0.83, P<.0001). CONCLUSIONS: 99mTc-IDA SPECT obtained during RT could be used to assess regional hepatic function and helped predict post-RT regional liver function reserve. This could support individualized adaptive radiation treatment strategies to maximize tumor control and minimize the risk of liver damage. PMID- 23688814 TI - DNA ploidy measured on archived pretreatment biopsy material may correlate with prostate-specific antigen recurrence after prostate brachytherapy. AB - PURPOSE: To explore whether DNA ploidy of prostate cancer cells determined from archived transrectal ultrasound-guided biopsy specimens correlates with disease free survival. METHODS AND MATERIALS: Forty-seven failures and 47 controls were selected from 1006 consecutive low- and intermediate-risk patients treated with prostate (125)I brachytherapy (July 1998-October 2003). Median follow-up was 7.5 years. Ten-year actuarial disease-free survival was 94.1%. Controls were matched using age, initial prostate-specific antigen level, clinical stage, Gleason score, use of hormone therapy, and follow-up (all P nonsignificant). Seventy eight specimens were successfully processed; 27 control and 20 failure specimens contained more than 100 tumor cells were used for the final analysis. The Feulgen Thionin stained cytology samples from archived paraffin blocks were used to determine the DNA ploidy of each tumor by measuring integrated optical densities. RESULTS: The samples were divided into diploid and aneuploid tumors. Aneuploid tumors were found in 16 of 20 of the failures (80%) and 8 of 27 controls (30%). Diploid DNA patients had a significantly lower rate of disease recurrence (P=.0086) (hazard ratio [HR] 0.256). On multivariable analysis, patients with aneuploid tumors had a higher prostate-specific antigen failure rate (HR 5.13). Additionally, those with "excellent" dosimetry (V100 >90%; D90 >144 Gy) had a significantly lower recurrence rate (HR 0.25). All patients with aneuploid tumors and dosimetry classified as "nonexcellent" (V100 <90%; D90 <144 Gy) (5 of 5) had disease recurrence, compared with 40% of patients with aneuploid tumors and "excellent" dosimetry (8 of 15). In contrast, dosimetry did not affect the outcome for diploid patients. CONCLUSIONS: Using core biopsy material from archived paraffin blocks, DNA ploidy correctly classified the majority of failures and nonfailures in this study. The results suggest that DNA ploidy can be used as a useful marker for aggressiveness of localized prostate cancer. A larger study will be necessary to further confirm our hypothesis. PMID- 23688816 TI - Prevalence and clinical features of lymphedema in patients with lymphangioleiomyomatosis. AB - BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease predominantly affecting young women. Some of these patients develop lymphedema of the lower extremities and buttocks; however, neither the exact frequency of LAM associated lymphedema nor the clinical features of such patients is well delineated. OBJECTIVES: To document the frequency, features, and treatment of LAM associated lymphedema. METHODS: We reviewed all medical records of patients listed in the Juntendo University LAM registry for the 30 years preceding August 2010. RESULTS: Of 228 patients registered with a diagnosis of LAM, eight (3.5%) had LAM-associated lymphedema of the lower extremities. All were females with sporadic LAM, and their mean age when diagnosed was 32.5 years (range 23-44). Lymphedema of the lower extremities was the chief or a prominent presenting feature in five of these LAM patients. CT scans showed that all eight patients had enlarged lymph nodes (lymphangioleiomyomas) in the retroperitoneum and/or pelvic cavity. Yet, cystic destruction of the lungs was mild in four patients, moderate in two and severe only in two. Seven of these patients were treated by administering a fat-restricted diet and complex decongestive physiotherapy, and four received a gonadotropin-releasing hormone analog. With this combined protocol, all eight patients benefitted from complete relief or good control of the lymphedema. CONCLUSIONS: Lymphedema is a rare complication of LAM and may be associated with axial lymphatic involvement or dysfunction rather than severe cystic lung destruction. The combined multimodal treatments used here effectively resolved or controlled LAM-associated lymphedema. PMID- 23688815 TI - Phase 1 study of dose escalation in hypofractionated proton beam therapy for non small cell lung cancer. AB - BACKGROUND: Many patients with locally advanced non-small cell lung cancer (NSCLC) cannot undergo concurrent chemotherapy because of comorbidities or poor performance status. Hypofractionated radiation regimens, if tolerable, may provide an option to these patients for effective local control. METHODS AND MATERIALS: Twenty-five patients were enrolled in a phase 1 dose-escalation trial of proton beam therapy (PBT) from September 2010 through July 2012. Eligible patients had histologically documented lung cancer, thymic tumors, carcinoid tumors, or metastatic thyroid tumors. Concurrent chemotherapy was not allowed, but concurrent treatment with biologic agents was. The dose-escalation schema comprised 15 fractions of 3 Gy(relative biological effectiveness [RBE])/fraction, 3.5 Gy(RBE)/fraction, or 4 Gy(RBE)/fraction. Dose constraints were derived from biologically equivalent doses of standard fractionated treatment. RESULTS: The median follow-up time for patients alive at the time of analysis was 13 months (range, 8-28 months). Fifteen patients received treatment to hilar or mediastinal lymph nodes. Two patients experienced dose-limiting toxicity possibly related to treatment; 1 received 3.5-Gy(RBE) fractions and experienced an in-field tracheoesophageal fistula 9 months after PBT and 1 month after bevacizumab. The other patient received 4-Gy(RBE) fractions and was hospitalized for bacterial pneumonia/radiation pneumonitis 4 months after PBT. CONCLUSION: Hypofractionated PBT to the thorax delivered over 3 weeks was well tolerated even with significant doses to the lungs and mediastinal structures. Phase 2/3 trials are needed to compare the efficacy of this technique with standard treatment for locally advanced NSCLC. PMID- 23688817 TI - New insights into replication clamp unloading. AB - The sliding clamp protein proliferating cell nuclear antigen (PCNA) is situated at the core of the eukaryotic replisome, where it acts as an interaction scaffold for numerous replication and repair factors and coordinates DNA transactions ranging from Okazaki fragment maturation to chromatin assembly and mismatch repair. PCNA is loaded onto DNA by a dedicated complex, the replication factor C, whose mechanism has been studied in detail. Until recently, however, it was unclear how PCNA is removed from DNA upon completion of DNA synthesis. Two complementary studies now present data strongly implicating the replication factor C-like complex, Elg1/ATAD5-RLC, in the unloading of PCNA during replication in yeast and human cells. They indicate that an appropriate control over PCNA's residence on the chromatin is important for maintaining genome stability. At the same time, they suggest that the interaction of Elg1/ATAD5 with SUMO, which was also reported to contribute to its role in genome maintenance, affects aspects of its function distinct from its unloading activity. PMID- 23688819 TI - Tuberculosis screening and treatment compliance in human immunodeficiency virus patients. AB - This study aims to evaluate compliance of HIV patients to TB screening and treatment, identifying determinants for non-compliance. We reviewed clinical records of all HIV infected patients first attended in a Portuguese-Infectious Unit from 2007-2010 (152 patients). Screening included: symptom inquiry, chest x ray, TST/IGRA. In 2008 a protocol was established with a TB outpatient clinic allowing patients to choose where to perform screening (decentralization). All patients were offered screening, 69 (45.4%) accepted. Before decentralization, out of 78 patients, 20 (25%) accepted screening. After decentralization, out of 64 patients, 49 (76.6%) accepted screening. Decentralization was associated with higher levels of acceptance (p<0.001), having an AIDS-defining-disease (p=0.002) and being older (p=0.04) was associated with lower screening acceptance. LTBI was diagnosed in 14 and active-TB in 18 cases; 14 cases of active-TB were later diagnosed during hospital appointments. For active-TB, being on HAART was related with treatment adherence (p=0.03). In this population, improving health care access was important for screening compliance. PMID- 23688820 TI - Structure-based histidine substitution for optimizing pH-sensitive Staphylococcus protein A. AB - Optimizing antibody purification is crucial to overcoming a bottleneck in the costly manufacturing process for antibody therapy. To address this issue, we designed a pH-sensitive Staphylococcus aureus protein A variant that retained its innate stability and affinity toward antibody. On the basis of structural information and mutation analysis data, we identified candidate positions for accumulative histidine substitutions to cause electrostatic repulsion under acidic conditions. The histidine substitutions effectively decreased the dissociation rate under acidic conditions by three orders of magnitude. Avoiding deleterious effects of the substitutions, we successfully engineered a protein A variant that exhibited high pH sensitivity and maintained affinity, thermal stability, and alkaline tolerance. The variant was capable of serving as an affinity ligand that made affinity chromatography under milder acidic conditions possible; the elution peak shifted from pH 4.2 to 5.6. Only two substitutions were needed to achieve this pH sensitivity. This structure-based approach is applicable to other protein-based ligands. PMID- 23688818 TI - Functional domains of the HK97 capsid maturation protease and the mechanisms of protein encapsidation. AB - Tailed double-stranded DNA bacteriophages and herpesviruses build capsids by co assembling a major capsid protein with an internal scaffolding protein that then exits from the assembled structure either intact or after digestion in situ by a protease. In bacteriophage HK97, the 102-residue N-terminal delta domain of the major capsid protein is also removed by proteolysis after assembly and appears to perform the scaffolding function. We describe the HK97 protease that carries out these maturation cleavages. Insertion mutations at seven sites in the protease gene produced mutant proteins that assemble into proheads, and those in the N terminal two-thirds were enzymatically inactive. Plasmid-expressed protease was rapidly cleaved in vivo but was stabilized by co-expression with the delta domain. Purified protease was found to be active during the assembly of proheads in vitro. Heterologous fusions to the intact protease or to C-terminal fragments targeted fusion proteins into proheads. We confirm that the catalytic activity resides in the N-terminal two-thirds of the protease polypeptide and suggest that the C-terminal one-fifth of the protein contains a capsid targeting signal. The implications of this arrangement are compared to capsid targeting systems in other phages, herpesviruses, and encapsulins. PMID- 23688821 TI - Effects of dietary fatty acid composition from a high fat meal on satiety. AB - The composition of fats within a high-fat (HF) meal may differentially affect hunger and satiety. PURPOSE: Compare HF meals rich in either monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs), or saturated fatty acids (SFAs) on the satiety hormone, peptide YY (PYY), and subjective feelings of hunger and fullness. METHODS: Fifteen normal weight women (18-45 year) were randomized in a crossover design to complete three study visits. The three treatments (three visits) were HF meals (70% of energy from fat) rich in MUFAs (42% of total energy), PUFAs (42% of total energy), or SFAs (45% of total energy). At each visit, subjects consumed a HF meal and eight blood draws were collected over a 5 h period. A visual analog scale (VAS) was completed at the same time as each blood draw for subjective feelings of hunger and fullness. RESULTS: The postprandial PYY response (area under the curve) was significantly lower (p<0.05) for the MUFA-rich meal (MUFA: 534.5+/-27.2 pg/mL/5 h) vs. the SFA rich or PUFA-rich meals (SFA: 607.3+/-51.6 pg/mL/5h, PUFA: 633.1+/-35.8 pg/mL/5 h). The SFA-rich meal elicited greater subjective feelings of fullness compared to MUFA- and PUFA-rich meals (288.1+/-9.6 vs. 236.8+/-7.9 and 220.9+/-7.4 mm/5 h; p=0.04, for 5h AUC for SFA, MUFA, and PUFA, respectively). The only significant correlations between PYY levels and VAS measures were found with the SFA-rich meal. CONCLUSION: Our data shows that liquid meals rich in MUFAs may elicit a weaker satiety response based on PYY levels compared to liquid meals rich in PUFAs or SFAs in normal weight women. PMID- 23688823 TI - Robust tests for one or more allometric lines. AB - In allometry, the study of how size variables scale against each other, it is often of interest to fit lines to bivariate data and test hypotheses about slope and elevation about one or several lines. The nature of the problem suggests that bivariate techniques related to principal component analysis are more appropriate than linear regression. Inference methods have been developed for this problem and are in widespread use, however, we demonstrate that such methods are not robust to bivariate contamination, and propose alternative approaches which are. The new approaches use Huber's M-estimator via a plug-in approach, where robust test procedures have the same form as classical ones, but where we plug in robust estimators of parameters and standard errors in place of classical estimators. Simulations demonstrate that these new procedures are robust against bivariate contamination, and can make accurate inferences even from small samples. PMID- 23688822 TI - Optimizing prediction of back pain outcomes. AB - An accurate means of identifying patients at high risk for chronic disabling pain could lead to more cost-effective care, with more intensive interventions targeted to those likely to benefit most. The Chronic Pain Risk Score is a tool developed to predict risk for chronic pain. The aim of this study was to examine whether its predictive ability could be enhanced by: (1) improved measures of the constructs it assesses (Improved Chronic Pain Risk Model); and (2) adding other predictors (Expanded Chronic Pain Risk Model). Patients initiating primary care for back pain (N=571) completed measures used in the Chronic Pain Risk Score, Improved Model, and Expanded Model, then completed the Graded Chronic Pain Scale (GCPS) 4 months later (n=521; 91% response rate). In predicting 4-month GCPS grade III or IV (moderate or severe pain-related activity interference), the Improved Model performed better than did the Chronic Pain Risk Score (Net Reclassification Index [NRI]=0.32, P=0.003). The Expanded Model improved significantly on the prediction of the Improved Model (NRI=0.56, P<0.001) and demonstrated excellent discriminative ability (AUC=0.84, 95% CI=0.79-0.88). The Improved Model (AUC=0.79, 95% CI=0.75-0.84) and the Chronic Pain Risk Score (AUC=0.76, 95% CI=0.71-0.81) showed acceptable discriminative ability. A limited set of measures may be used to predict risk for future clinically significant pain in patients initiating primary care for back pain, but further evaluation of prognostic models is needed. PMID- 23688824 TI - Model the evolution of protein interaction network assisted with protein age. AB - Understanding the dynamic evolutionary process of protein interaction network is fundamental to study cell's activity. As an important attribute of proteins, their age can provide heuristic information for studying the evolution of protein interaction network. In this paper an age-dependent duplication-divergence model (ADD) is proposed to model the evolutionary process of protein interaction network, which integrates the age information of proteins into duplication divergence (DD) model. Moreover, we also reverse protein interaction network with our model, which is named as inverse age-dependent duplication-divergence model (IADD). The results show that the network built by ADD model conforms to the yeast protein interaction network in the interaction density pattern and other topological properties. The protein age groups predicted by IADD model also show a high agreement with existing research results. PMID- 23688825 TI - Protandry, sexual size dimorphism, and adaptive growth. AB - Adaptive growth refers to the strategic adjustment of growth rate by individuals to maximize some component of fitness. The concept of adaptive growth proliferated in the 1990s, in part due to an influential theoretical paper by Peter Abrams and colleagues. In their 1996 paper, Abrams et al. explored the effects of time stress on optimal growth rate, development time, and adult size in seasonal organisms. In this review, I explore how the concept of adaptive growth informs our understanding of protandry (the earlier arrival of males to sites of reproduction than females) and sexual size dimorphism in seasonal organisms. I conclude that growth rate variation is an important mechanism that helps to conserve optimal levels of protandry and sexual size dimorphism in changing environments. PMID- 23688827 TI - With how many users should you test a medical infusion pump? Sampling strategies for usability tests on high-risk systems. AB - Usability testing is recognized as an effective means to improve the usability of medical devices and prevent harm for patients and users. Effectiveness of problem discovery in usability testing strongly depends on size and representativeness of the sample. We introduce the late control strategy, which is to continuously monitor effectiveness of a study towards a preset target. A statistical model, the LNB(zt) model, is presented, supporting the late control strategy. We report on a case study, where a prototype medical infusion pump underwent a usability test with 34 users. On the data obtained in this study, the LNB(zt) model is evaluated and compared against earlier prediction models. The LNB(zt) model fits the data much better than previously suggested approaches and improves prediction. We measure the effectiveness of problem identification, and observe that it is lower than is suggested by much of the literature. Larger sample sizes seem to be in order. In addition, the testing process showed high levels of uncertainty and volatility at small to moderate sample sizes, partly due to users' individual differences. In reaction, we propose the idiosyncrasy score as a means to obtain representative samples. Statistical programs are provided to assist practitioners and researchers in applying the late control strategy. PMID- 23688826 TI - New index based on the physical separation of motion into three categories for characterizing the effect of cocaine in mice. AB - Characterization of open-field behavior and locomotor activity is widely used to assess the influence of a drug on mouse or rat behavior. In this study, we developed an index for characterizing the behavior of cocaine-administered mice (C57BL/6, DBA/2, and BALB/c). Because a three-exponential-model exhibited the best fit to the obtained data among the different probability density functions, we divided each walking episode into three categories according to the duration of movement. We found a significant difference in decay variation of mean speed with time in the case of long walking duration. To clarify this difference quantitatively, we developed an index for the changes in locomotion control, based on a heuristic argument regarding the ratio of the coefficients of the drag term obtained by the biphasic motion-equation model. The index had a significant dose-related effect in each strain and a significant strain effect in high concentration drug. Therefore, it would thus be useful for examining the effect of the drug on locomotor activity in mice. Moreover, evaluating other characters suggested previously, the proposed index had good advantage to differentiate the dose-related response in the three species of inbred mice. PMID- 23688829 TI - Sickness absence due to musculoskeletal diagnoses and risk of diagnosis-specific disability pension: a nationwide Swedish prospective cohort study. AB - Musculoskeletal disorders constitute major public health problems. Few studies have, however, examined risk of disability pension among persons sickness absent due to musculoskeletal diagnoses. Thus, we constructed a prospective nationwide population-based cohort study based on Swedish registers, consisting of all 4,687,756 individuals living in Sweden December 31, 2004/2005, aged 20-64 years, who were not on disability or old-age pension. Those individuals who were sickness absent in 2005 due to musculoskeletal diagnoses were compared to those sickness absent due to non-musculoskeletal diagnoses and those with no sickness absence. Musculoskeletal diagnoses were categorized as follows: 1) artropathies/systemic connective tissue disorders, 2) dorsopathies, and 3) soft tissue disorders/osteopathies/chondropathies/other musculoskeletal disorders. All cause and diagnosis-specific incident disability pension were followed from 2006 to 2009. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards regression. In models adjusted for socio demographic factors and morbidity, sickness absence due to all categories of musculoskeletal diagnoses was associated with 12- to 18-fold increased risks of all-cause disability pension (adjusted model, category 2 diagnoses, IRR = 18.57, 95% CI = 18.18-18.97). Similar associations were observed among both women and men sickness absent due to all 3 musculoskeletal diagnostic categories. Moreover, increased risks of disability pension because of cancer, mental, circulatory and musculoskeletal diagnoses were observed among individuals sickness absent because of any musculoskeletal diagnostic category (disability pension due to musculoskeletal diagnoses, adjusted model, category 2 diagnoses, IRR = 50.66, 95% CI = 49.06-52.32). In conclusion, this nationwide cohort study reveals strongly increased risks of all-cause and diagnosis-specific disability pension among those sickness absent due to musculoskeletal diagnoses. PMID- 23688828 TI - Disabling musculoskeletal pain in working populations: is it the job, the person, or the culture? AB - To compare the prevalence of disabling low back pain (DLBP) and disabling wrist/hand pain (DWHP) among groups of workers carrying out similar physical activities in different cultural environments, and to explore explanations for observed differences, we conducted a cross-sectional survey in 18 countries. Standardised questionnaires were used to ascertain pain that interfered with everyday activities and exposure to possible risk factors in 12,426 participants from 47 occupational groups (mostly nurses and office workers). Associations with risk factors were assessed by Poisson regression. The 1-month prevalence of DLBP in nurses varied from 9.6% to 42.6%, and that of DWHP in office workers from 2.2% to 31.6%. Rates of disabling pain at the 2 anatomical sites covaried (r = 0.76), but DLBP tended to be relatively more common in nurses and DWHP in office workers. Established risk factors such as occupational physical activities, psychosocial aspects of work, and tendency to somatise were confirmed, and associations were found also with adverse health beliefs and group awareness of people outside work with musculoskeletal pain. However, after allowance for these risk factors, an up-to 8-fold difference in prevalence remained. Systems of compensation for work-related illness and financial support for health-related incapacity for work appeared to have little influence on the occurrence of symptoms. Our findings indicate large international variation in the prevalence of disabling forearm and back pain among occupational groups carrying out similar tasks, which is only partially explained by the personal and socioeconomic risk factors that were analysed. PMID- 23688830 TI - The Pain Course: a randomised controlled trial of a clinician-guided Internet delivered cognitive behaviour therapy program for managing chronic pain and emotional well-being. AB - The present study evaluated the efficacy of a clinician-guided Internet-delivered cognitive behaviour therapy (iCBT) program, the Pain Course, to reduce disability, anxiety, and depression associated with chronic pain. Sixty-three adults with chronic pain were randomised to either a Treatment Group or waitlist Control Group. Treatment consisted of 5 iCBT-based lessons, homework tasks, additional resources, weekly e-mail or telephone contact from a Clinical Psychologist, and automated e-mails. Twenty-nine of 31 Treatment Group participants completed the 5 lessons during the 8-week program, and posttreatment and 3-month follow-up data were collected from 30/31 and 29/31 participants, respectively. Treatment Group participants obtained significantly greater improvements than Control Group participants in levels of disability, anxiety, depression, and average pain levels at posttreatment. These improvements corresponded to small to large between-groups effect sizes (Cohen's d) at posttreatment for disability (d = .88), anxiety (d = .38), depression (d = .66), and average pain (d = .64), respectively. These outcomes were sustained at follow up and participants rated the program as highly acceptable. Overall, the clinician spent a total mean time of 81.54 minutes (SD 30.91 minutes) contacting participants during the program. The results appear better than those reported in iCBT studies to date and provide support for the potential of clinician-guided iCBT in the treatment of disability, anxiety, and depression for people with chronic pain. PMID- 23688831 TI - Nutrition screening tools: does one size fit all? A systematic review of screening tools for the hospital setting. AB - BACKGROUND & AIMS: Numerous nutrition screening tools for the hospital setting have been developed. The aim of this systematic review is to study construct or criterion validity and predictive validity of nutrition screening tools for the general hospital setting. METHODS: A systematic review of English, French, German, Spanish, Portuguese and Dutch articles identified via MEDLINE, Cinahl and EMBASE (from inception to the 2nd of February 2012). Additional studies were identified by checking reference lists of identified manuscripts. Search terms included key words for malnutrition, screening or assessment instruments, and terms for hospital setting and adults. Data were extracted independently by 2 authors. Only studies expressing the (construct, criterion or predictive) validity of a tool were included. RESULTS: 83 studies (32 screening tools) were identified: 42 studies on construct or criterion validity versus a reference method and 51 studies on predictive validity on outcome (i.e. length of stay, mortality or complications). None of the tools performed consistently well to establish the patients' nutritional status. For the elderly, MNA performed fair to good, for the adults MUST performed fair to good. SGA, NRS-2002 and MUST performed well in predicting outcome in approximately half of the studies reviewed in adults, but not in older patients. CONCLUSIONS: Not one single screening or assessment tool is capable of adequate nutrition screening as well as predicting poor nutrition related outcome. Development of new tools seems redundant and will most probably not lead to new insights. New studies comparing different tools within one patient population are required. PMID- 23688832 TI - Substance, structure and stigma: parents in the UK accounting for opioid substitution therapy during the antenatal and postnatal periods. AB - BACKGROUND: Parenting and pregnancy in the context of drug use is a contentious topic, high on the policy agenda. Providing effective support to parents who are opioid dependent, through early intervention, access to drug treatment and parenting skills training, is a priority. However, little is known about opioid dependent parents' experiences and understanding of parenting support during the antenatal and postnatal periods. This paper focuses on the position and impact of opioid substitution therapy (OST) in the accounts of parents who were expecting, or who had recently had, a baby in the UK. METHODS: Semi-structured qualitative interviews were held with a purposive sample of 19 opioid dependent service users (14 female, 5 male). Longitudinal data was collected across the antenatal and postnatal (up to 1 year) periods, with participants interviewed up to three times. Forty-five interviews were analysed thematically, using a constant comparison method, underpinned by a sociologically informed narrative approach. RESULTS: Participants' accounts of drug treatment were clearly oriented towards demonstrating that they were doing 'the best thing' for their baby. For some, OST was framed as a route to what was seen as a 'normal' family life; for others, OST was a barrier to such normality. Challenges related to: the physiological effects of opioid dependence; structural constraints associated with treatment regimes; and the impact of negative societal views about drug-using parents. CONCLUSION: Parents' accounts of OST can be seen as a response to socio-cultural ideals of a 'good', drug-free parent. Reflecting the liminal position parents engaged in OST found themselves in, their narratives entailed reconciling their status as a 'drug-using parent' with a view of an 'ideal parent' who was abstinent. PMID- 23688833 TI - miR-210 suppresses BNIP3 to protect against the apoptosis of neural progenitor cells. AB - MiR-210 is a hypoxia-inducible factor (HIF)-1 target gene and is the most consistently and predominantly upregulated miRNA in response to hypoxia in various cancer cell lines. Our recent study shows that hypoxia increased miR-210 expression in neural progenitor cells (NPCs) in a time-dependent manner. However, the role of miR-210 in NPCs remains unknown. Following the identification of the miR-210 putative target genes, we demonstrated that the Bcl-2 adenovirus E1B 19kDa-interacting protein 3 (BNIP3), which is regulated by HIF-1 and activates cell death, is regulated by miR-210 in NPCs under hypoxia. Moreover, the over expression of miR-210 decreased apoptosis in NPCs, and the inhibition of miR-210 expression remarkably increased the number of TUNEL-positive NPCs by 30% in response to hypoxia. Importantly, miR-210 mimics reduced both BNIP3 protein expression and the translocation of AIF into the nucleus, which reduced cell death, whereas miR-210 inhibitors reversed this process, leading to cell death during hypoxia. Taken together, we report a novel feedback loop of BNIP3 regulation in NPCs under hypoxia. HIF-1 is activated under hypoxia and then induces the expression of both BNIP3 and miR-210. The upregulation of miR-210 then directly suppresses BNIP3 expression to maintain the survival of NPCs under hypoxia. This negative feedback regulation might partially contribute to protection against hypoxia-induced cell death via the inhibition of AIF nuclear translocation. PMID- 23688834 TI - Use of remote sensing techniques and aeromagnetic data to study episodic oil seep discharges along the Gulf of Suez in Egypt. AB - Four successive oil discharges were observed during the last 2 years following the recording of the earthquake events. Oil slicks were clearly observed in the thermal band of the Enhanced Thematic Mapper images acquired during the discharge events. Lineaments were extracted from the ETM+ image data and SRTM (DEM). The seismic activity is conformable in time and spatially related to active major faults and structural lineaments. The concerned site was subjected to a numerous earthquakes with magnitudes ranging from 3 to 5.4 Mb. Aeromagnetic field data analyses indicated the existence of deep major faults crossing the Gebel El-Zeit and the Mellaha basins (oil reservoirs). The magnetic field survey showed major distinctive fault striking NE-SW at 7000 m depth. Occurrence of these faults at great depth enables the crude oil to migrate upward and appear at the surfaces as oil seeps onshore and as offshore slicks in the Gemsa-Hurghada coastal zone. PMID- 23688835 TI - In silico methods in the discovery of endocrine disrupting chemicals. AB - The prevalence of sex hormone-dependent cancers, reproductive problems, obesity, and cardiovascular complications has risen especially in the Western world. It has been suggested, that the exposure to various endocrine disrupting chemicals (EDCs) contributes to the development and progression of these diseases. EDCs can interfere with various proteins: nuclear steroid hormone receptors, such as estrogen-, androgen-, glucocorticoid- and mineralocorticoid receptors (ER, AR, GR, MR), and enzymes that are involved in steroid hormone synthesis and metabolism, for example hydroxysteroid dehydrogenases (HSDs). Numerous chemicals are known as endocrine disruptors. However, the mechanism of action for most of these EDCs is still unknown. It is exhaustive and time consuming to test in vitro all chemicals - potential EDCs - used in industry, agriculture or as food preservatives against their effects on the endocrine system. Computational methods, such as virtual screening, quantitative structure activity relationships and docking, are already well recognized and used in drug development. The same methods could also aid the research on EDCs. So far, the computational methods in the search of EDCs have been retrospective. There are, however, some prospective studies reporting the use of in silico methods: five studies reporting the identification of previously unknown 17beta-HSD3 inhibitors, MR agonists, and ER antagonists/agonists. This review provides an overview of case studies and in silico methods that are used in the search of EDCs. This article is part of a Special Issue entitled 'CSR 2013'. PMID- 23688836 TI - Steroidal 5alpha-reductase and 17alpha-hydroxylase/17,20-lyase (CYP17) inhibitors useful in the treatment of prostatic diseases. AB - The role of steroidal inhibitors of androgen biosynthesis as potential weapons in the treatment of prostatic diseases, such as benign prostatic hyperplasia and prostatic cancer will be reviewed. Two enzymes have been targeted in the development of inhibitors that potentially could be useful in the management of such conditions. 5alpha-Reductase is primarily of interest in benign prostatic disease, though some role in the chemoprevention of prostatic carcinoma have been considered, whereas the 17alpha-hydroxylase/17,20-lyase (CYP17) enzyme is of interest in the treatment of malignant disease. An overview of the main achievements obtained during the past years will be presented, however special focus will be made on steroidal molecules that reached clinical trials or have been commercially launched. Relevant examples of such drugs are finasteride, dutasteride, abiraterone acetate and galeterone (TOK-001, formerly known as VN/124-1). This article is part of a Special Issue entitled "Synthesis and biological testing of steroid derivatives as inhibitors". PMID- 23688837 TI - The anti-proliferative effect of 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl] 2H-benzo(b) pyran is potentiated via induction of estrogen receptor beta and p21 in human endometrial adenocarcinoma cells. AB - In an effort to develop novel therapeutic agents for endometrial cancer, benzopyran derivatives synthesized at our institute display significant inhibitory activity on cellular growth in uterine cancer cells. The current study was undertaken to demonstrate and explore the estrogen receptor (ER) subtype mediated mechanism of action of benzopyran derivative 2-[piperidinoethoxyphenyl] 3-[4-hydroxyphenyl]-2H-benzo(b) pyran (K-1) in human endometrial cancer cells. K 1 competitively inhibited the estradiol binding to human ERalpha and ERbeta and showed growth inhibitory activity in human endometrial Ishikawa, HEC1B and primary endometrial adenocarcinoma cells. Transient transactivation assays carried out in COS-1 cells have demonstrated the diminished ERalpha-ERE mediated- and induced the ERbeta-ERE mediated-transactivation triggered by compound. It also induced ER-mediated transactivation of the cyclin-dependent kinase inhibitor (CDKI) p21(WAF-1) in both COS-1 cells and in Ishikawa cells. ERbeta inducing effects of compound were blocked by ICI182,780. In endometrial adenocarcinoma cells, it induced ERbeta and p21 expression significantly whereas the expression of fos, jun and ERalpha were significantly reduced. In addition, compound promoted ERalpha-beta heterodimerization as observed in Ishikawa cells. These results demonstrate that the benzopyran compound suppressed the cellular growth via ERbeta agonism, induction of p21 and via promoting the ERalpha-beta heterodimerization, in addition to its antagonistic effects exerted on ERalpha, in human endometrial cancer cells. The study suggests that the dual action of benzopyran molecule may be of significant therapeutic value in ERalpha/beta positive cases of endometrial cancer. PMID- 23688838 TI - Melatonin attenuates dexamethasone toxicity-induced oxidative stress, calpain and caspase activation in human neuroblastoma SH-SY5Y cells. AB - Glucocorticoids (GCs) have a significant role in the adaptive response of the brain to stress. Increasing evidence has demonstrated that an increase of GC levels may induce neuronal cell death via apoptotic pathways. There is a correlation between over-production of reactive oxygen species (ROS) and an elevation in cytosolic calcium that causes a subsequent increase in the calcium dependent death-process activation in GC-induced toxicity. Consequently, melatonin, via its antioxidant activity, exhibits a neuroprotective effect against apoptosis induced by intracellular calcium overload. Therefore, in the present study, we explored the protective effect of melatonin in GC-induced toxicity in dopaminergic SH-SY5Y cells. Cellular treatment with the synthetic GCs, dexamethasone (DEX), resulted in a marked decrease in cell viability and in the level of the calpain-inhibitor protein, calpastatin. DEX-induced toxicity also caused an increase in ROS production and the activation of the calcium dependent cysteine protease, calpain, along with an increase in caspase-3 activation. Pretreatment of the cells with melatonin substantially prevented the decrease in cell viability, over-production of ROS and the activation of calpain and caspase-3, and reversed the depletion in calpastatin levels. These results suggest that melatonin may exert its protective effects against the calpain- and caspase-dependent death process in DEX-induced neurotoxicity. PMID- 23688839 TI - Aortic valve and ascending aorta guidelines for management and quality measures. PMID- 23688840 TI - The second generation of iodido complexes: trans-[PtI2(amine)(amine')] bearing different aliphatic amines. AB - The antitumoral potential for a series of platinum iodido complexes, all bearing the same aliphatic amines (first iodido complexes generation), was demonstrated in a previous study. Concretely, cis complexes were shown to have a peculiar and different reactivity compared to cisplatin with sulfur donors models and Cyt C. In this work we have synthesized and studied iodido complexes bearing different aliphatic amines in trans configuration (the second generation) to investigate their potential antitumor activity in a panel of cell lines. Their interaction with biological models such as pBR322 and smaller biomolecules (5'-GMP, 9EtG, N AcMet and N-AcCys) have been studied and compared to cisplatin and to the first iodido series. Their cytotoxicity, on the other hand, turned out to be especially active towards cell lines where cisplatin has no effect. PMID- 23688841 TI - Potentially mutagenic impurities: analysis of structural classes and carcinogenic potencies of chemical intermediates in pharmaceutical syntheses supports alternative methods to the default TTC for calculating safe levels of impurities. AB - Potentially mutagenic impurities in new pharmaceuticals are controlled to levels with negligible risk, the TTC (threshold of toxicological concern, 1.5 MUg/day for a lifetime). The TTC was based on the more potent rodent carcinogens, excluding the highly potent "cohort of concern" (COC; for mutagenic carcinogens these are N-nitroso, Aflatoxin-like, and azoxy structures). We compared molecules with DEREK "structural alerts" for mutagenicity used in drug syntheses with the mutagenic carcinogens in the Gold Carcinogenicity Potency Database. Data from 108 diverse synthetic routes from 13 companies confirm that many "alerting" or mutagenic chemicals are in structural classes with lower carcinogenic potency than those used to derive the TTC. Acceptable daily intakes can be established that are higher than the default TTC for many structural classes (e.g., mono functional alkyl halides and certain aromatic amines). Examples of ADIs for lifetime and shorter-term exposure are given for chemicals of various potencies. The percentage of chemicals with DEREK alerts that proved mutagenic in the Ames test ranged from 36% to 83%, depending on structural class, demonstrating that such SAR analysis to "flag" potential mutagens is conservative. We also note that aromatic azoxy compounds need not be classed as COC, which was based on alkyl azoxy chemicals. PMID- 23688842 TI - A national study of substance use behaviors among NCAA male athletes who use banned performance enhancing substances. AB - BACKGROUND: Reports of illicit substance use by college athletes have become commonplace in recent years, yet comparatively little effort has been put forth by the research community to understand these behaviors. METHODS: Data for this study came from a large, national dataset collected by the National Collegiate Athletic Association (NCAA). This study compared substance use behaviors of male undergraduate student athletes who reported using ergogenic performance enhancing substances (e.g., anabolic steroids and peptide hormones) during college (PES users) to those who did not (PES non-users). RESULTS: A consistent pattern of higher substance use rates was observed among PES users compared to non-users, including heavier drinking, higher prevalence rates of cigarettes, marijuana, amphetamines, narcotics, and a variety of permissible and impermissible dietary supplements. An unexpected finding was that there were large discrepancies in reported prevalence rates between similar or overlapping survey items (e.g., past year use of "narcotics" versus "I have taken Vicodin, Oxycontin or Percocet with/without a prescription"). CONCLUSIONS: These findings suggest that male college athletes who use PES while in college demonstrate a general tendency to engage in alcohol and drug use behaviors, regardless of whether these behaviors improve or impede athletic performance. The results further suggest that college athletes may not fully appreciate drug categorizations that are commonly employed to gauge substance use behaviors. Changes to drug education and prevention programs may be needed to enhance understanding of drug properties and actions. PMID- 23688844 TI - Quality of care standards for nursing clinics in rheumatology. AB - BACKGROUND: Nursing clinics in rheumatology (NCR) are organizational models in the field of nursing care. There are various NCR models, but there is no consensus on its operational definition. Our objective is to develop quality standards to define and characterize a NCR. METHOD: Two-round Delphi method. The panel consisted of 67 experts: Rheumatologists and nurses of the nursing working group of the Spanish Society of Rheumatology (SSR). The Delphi questionnaire was developed after a literature and experience review from previous SSR projects. The questionnaire consists of 7 sections: general considerations, standards of structure, process, treatment and monitoring, health education, training and research and quality of care. Each item was scored from 1 (least important) to 9 (most important) or by assigning a number (e.g., waiting days). The degree of agreement among the experts was categorized according to the coefficient of variation (CoV) between very high (CoV<=25%) and very low (CoV>100%). RESULTS: The second round questionnaire (182 items) was answered by 46 panelists (34 rheumatologists and 12 nurses). A very important agreement was reached on the general standards of structure, process, treatment and monitoring, health education and quality of care. Less agreement was observed on standards related to training time, number of recommended nurses' research projects and publications. CONCLUSION: The standards developed in this study would be useful for establishing desirable quality standards of structure and process, and criteria for clinical work, research and teaching that can be used to develop and evaluate the NCRs. PMID- 23688843 TI - Benzodiazepine use during buprenorphine treatment for opioid dependence: clinical and safety outcomes. AB - BACKGROUND: Prescribing benzodiazepines during buprenorphine treatment is a topic of active discussion. Clinical benefit is unclear. Overdose, accidental injury, and benzodiazepine misuse remain concerns. We examine the relationship between benzodiazepine misuse history, benzodiazepine prescription, and both clinical and safety outcomes during buprenorphine treatment. METHODS: We retrospectively examined outpatient buprenorphine treatment records, classifying patients by past year benzodiazepine misuse history and approved benzodiazepine prescription at intake. Primary clinical outcomes included 12-month treatment retention and urine toxicology for illicit opioids. Primary safety outcomes included total emergency department (ED) visits and odds of an ED visit related to overdose or accidental injury during treatment. RESULTS: The 12-month treatment retention rate for the sample (N=328) was 40%. Neither benzodiazepine misuse history nor benzodiazepine prescription was associated with treatment retention or illicit opioid use. Poisson regressions of ED visits during buprenorphine treatment revealed more ED visits among those with a benzodiazepine prescription versus those without (p<0.001); benzodiazepine misuse history had no effect. The odds of an accidental injury-related ED visit during treatment were greater among those with a benzodiazepine prescription (OR: 3.7, p<0.01), with an enhanced effect among females (OR: 4.7, p<0.01). Overdose was not associated with benzodiazepine misuse history or prescription. CONCLUSIONS: We found no effect of benzodiazepine prescriptions on opioid treatment outcomes; however, benzodiazepine prescription was associated with more frequent ED visits and accidental injuries, especially among females. When prescribing benzodiazepines during buprenorphine treatment, patients need more education about accidental injury risk. Alternative treatments for anxiety should be considered when possible, especially among females. PMID- 23688845 TI - Septic arthritis of the shoulder due to Corynebacterium striatum. PMID- 23688846 TI - The interplay between global standards and local practice in nursing. AB - PURPOSE: The paper assesses the extent, form, and transformation of global nursing classifications (NANDA) in a nursing practice during a period of 5 years. METHOD: A longitudinal case study was used to trace implementation, adoption and use of nursing classifications as an integral part of an electronic nursing module. A mixed method of data collection was used, including semi-structured interviews, observation and document analysis. RESULTS: A surprisingly high proportion of nursing diagnoses was consistent with the global standard, in spite of a gradual increase of user-generated concepts. This is elaborated more thoroughly through a co-constructing perspective, emphasizing how the global standard and the practice mutually shaped each other over several years. CONCLUSION: Standardization is an iterative process that is performed in close relationship with practice. The mutual interrelation between formal classifications (NANDA) and local practices are co-constructed in a dynamic interplay that evolves over time. In such a process, the use of local classifications and local strategies can be a means to bridge the gap between these two extreme points. PMID- 23688847 TI - Risk of incisional hernia after minimally invasive and open radical prostatectomy. AB - PURPOSE: The number of radical prostatectomies has increased. Many urologists have shifted from the open surgical approach to minimally invasive techniques. It is not clear whether the risk of post-prostatectomy incisional hernia varies by surgical approach. MATERIALS AND METHODS: In the linked Surveillance, Epidemiology and End Results (SEER)-Medicare data set we identified men 66 years old or older who were treated with minimally invasive or open radical prostatectomy for prostate cancer diagnosed from 2003 to 2007. The main study outcome was incisional hernia repair, as identified in Medicare claims after prostatectomy. We also examined the frequency of umbilical, inguinal and other hernia repairs. RESULTS: We identified 3,199 and 6,795 patients who underwent minimally invasive and open radical prostatectomy, respectively. The frequency of incisional hernia repair was 5.3% at a median 3.1-year followup in the minimally invasive group and 1.9% at a 4.4-year median followup in the open group, corresponding to an incidence rate of 16.1 and 4.5/1,000 person-years, respectively. Compared to the open technique, the minimally invasive procedure was associated with more than a threefold increased risk of incisional hernia repair when controlling for patient and disease characteristics (adjusted HR 3.39, 95% CI 2.63-4.38, p<0.0001). Minimally invasive radical prostatectomy was associated with an attenuated but increased risk of any hernia repair compared with open radical prostatectomy (adjusted HR 1.48, 95% CI 1.29-1.70, p<0.0001). CONCLUSIONS: Minimally invasive radical prostatectomy was associated with a significantly increased risk of incisional hernia compared with open radical prostatectomy. This is a potentially remediable complication of prostate cancer surgery that warrants increased vigilance with respect to surgical technique. PMID- 23688848 TI - Outcomes of intralesional interferon-alpha2B for the treatment of Peyronie disease. AB - PURPOSE: We evaluated the efficacy of intralesional interferon-alpha2b for Peyronie disease, reviewed the impact of the timing of therapy from disease onset and identified variables predictive of a response. MATERIALS AND METHODS: We retrospectively reviewed the charts of patients treated with intralesional interferon-alpha2b from 2001 to 2012. Demographic information, disease characteristics, pretreatment and posttreatment penile duplex ultrasound findings, and objective measures were analyzed. Response was defined as a 20% or greater improvement in curvature. Statistical analysis was done to identify significant changes in variables and identify predictive factors. RESULTS: A total of 127 patients with a mean age of 55 years (range 25 to 76) and a mean+/ SD pretreatment curvature of 42.4+/-18.6 degrees underwent a median of 12 biweekly interferon-alpha2b injections (range 6 to 24). The median history of Peyronie disease was 2.0 years (range 0.5 to 23). Of the patients 54% responded to therapy with an overall mean improvement of 9.0 degrees (p<0.001). Patients with less than 30-degree curvature were most likely to experience a 20% or greater improvement with interferon-alpha2b (86% response, p<0.001). However, similar overall improvement in pretreatment curvature was noted in all cases. No statistically significant improvement was observed in penile vascular status or ultrasound parameters. The duration of Peyronie disease did not impact the change in curvature. Age, pretreatment curvature, vascular status, penile ultrasound findings, curvature site and International Index of Erectile Function (IIEF) score did not predict the response to therapy. CONCLUSIONS: Intralesional therapy with interferon-alpha2b resulted in significantly improved curvature without impacting penile vascular parameters. The absolute improvement in curvature was independent of pretreatment curvature or Peyronie disease duration. PMID- 23688849 TI - Acute traumatic hallux valgus. AB - Post-traumatic hallux valgus is an uncommon condition with sporadic reports. The deformity usually develops in a gradual manner following direct injury to the first ray; including injury to the first metatarsophalangeal joint, the first metatarsal bone or the first metatarsal-cuneiform joint. A case of acute traumatic hallux valgus following metatarsal neck fractures of the lesser rays is reported. We believe that understanding the importance of the transverse 'tie bar' system in the pathogenesis of post-traumatic hallux valgus deformity avoids unnecessary surgery to the great toe. PMID- 23688851 TI - Joint awareness in different types of knee arthroplasty evaluated with the Forgotten Joint score. AB - The purpose of this study was to validate the 'Forgotten Joint' score (FJS-12), a 12-item questionnaire designed to analyze the patient's ability to forget the joint in everyday life, in French and to compare the results of this Patient Reported Outcome (PRO) score in patients who had other than total joint arthroplasties. The score was compared in 122 patients that had either medial unicompartmental (N=51), patellofemoral (N=21) or total knee arthroplasty (N=50). After having validated the FJS-12 in French, a similar PRO was observed in unicompartmental and postero-stabilized total knee arthroplasty. Patellofemoral resurfacing had a significantly lower score than the two other types of arthroplasty, which can be explained by a significantly younger and smaller patient group. PMID- 23688850 TI - Relation between HLA genes, human skin volatiles and attractiveness of humans to malaria mosquitoes. AB - Chemical cues are considered to be the most important cues for mosquitoes to find their hosts and humans can be ranked for attractiveness to mosquitoes based on the chemical cues they emit. Human leukocyte antigen (HLA) genes are considered to be involved in the regulation of human body odor and may therefore affect human attractiveness to mosquitoes, and hence, affect the force of malaria transmission. In the present study the correlations between HLA profiles, human skin volatiles and human attractiveness to the malaria mosquito Anopheles gambiae Giles sensu stricto were examined. Skin emanations of 48 volunteers were collected by rubbing a foot over glass beads. Previously the attractiveness of these emanations to An. gambiae was determined. In this study, the chemical composition of these emanations was determined by gas chromatography-mass spectroscopy (GC-MS) and blood samples of all volunteers were taken for HLA analysis. Hierarchical cluster analysis (HCA), partial least squares discriminant analysis (PLS-DA), Fisher's exact test and random forest regression were used to test for correlations between individuals classified as either highly or poorly attractive to mosquitoes and their HLA profile and volatile composition. HLA profiling suggests that people carrying HLA gene Cw*07 are more attractive to mosquitoes. GC-MS revealed that limonene, 2-phenylethanol and 2-ethyl-1-hexanol were associated with individuals that were poorly attractive to An.gambiae and lactic acid, 2-methylbutanoic acid, tetradecanoic acid and octanal with individuals that were highly attractive. Such compounds offer potential for disruption of mosquito behavior in malaria intervention programs. PMID- 23688853 TI - Influence of gap balance on the sagittal movement of a specific mobile bearing floating platform design in total knee arthroplasty. AB - We analyzed 119 knees implanted with mobile bearing floating platform prostheses using the navigation-assisted gap balancing technique to analyze the relationship between intraoperative sagittal movement of floating platforms and soft tissue balancing. The 95 (79.8%) knees were classified into the positive rollback group (mean insert posterior rollback 5.86 +/- 1.24 mm), and the remaining 24 (20.2%) into the negative rollback group. Lateral flexion gap (LFG) differed significantly between knees with positive and negative rollback (20.5 +/- 1.7 mm vs 22.1 +/- 1.7 mm, P = .021). Only LFG significantly influenced the occurrence of bearing sagittal movement. Sagittal translation of the insert occurred in about 80% of knees implanted with mobile bearing floating platforms in TKA, and was affected by flexion gaps, especially on the lateral side. PMID- 23688852 TI - Rotational alignment of the femoral component using trochlear navigation during total knee arthroplasty: a dual-center study of 145 cases. AB - Rotational alignment of the femoral component during TKA is critical. Here we propose a technique using navigation of the femoral trochlea to determine the rotation of the femoral component. The rotation is considered "ideal" when the component position leads to the arthroplasty trochlea being perfectly superimposed over the native trochlea. Thus the arthroplasty trochlea will be aligned on the trochlear groove axis, which itself is perpendicular to the transepicondylar axis. This was a prospective, non-randomized, dual-center study involving 145 knees. In all knees, the rotation of the femoral component was determined intraoperatively by trochlear navigation. The alpha angle obtained with this method was compared to the one calculated on a preoperative or postoperative CT scan. There was excellent agreement between the results obtained with the CT scan method and the ones obtained with trochlear navigation. PMID- 23688854 TI - Challenges for taking primary and stem cells into clinical neurotransplantation trials for neurodegenerative disease. AB - We review the first generations of clinical trials of novel cell therapies applied to a range of neurodegenerative diseases in the context of mechanisms of functional efficacy. This in turn helps to determine the best strategies to be adopted and the potential chances for success in developing new cell therapies to clinical application in different conditions. We then consider the scientific, technical, ethical, regulatory and logistic issues to be resolved in translating effective laboratory cell-based protocols to patients in clinical trials. We draw optimistic conclusions about the likelihood of success in developing radical new approaches to a range of devastating, and currently untreatable, neurodegenerative conditions, but caution that the problems are complex and the solutions are likely to be slow and costly to achieve in order to overcome significant ethical and regulatory as well as scientific challenges. PMID- 23688855 TI - Human amniotic fluid-derived and dental pulp-derived stem cells seeded into collagen scaffold repair critical-size bone defects promoting vascularization. AB - INTRODUCTION: The main aim of this study is to evaluate potential human stem cells, such as dental pulp stem cells and amniotic fluid stem cells, combined with collagen scaffold to reconstruct critical-size cranial bone defects in an animal model. METHODS: We performed two symmetric full-thickness cranial defects on each parietal region of rats and we replenished them with collagen scaffolds with or without stem cells already seeded into and addressed towards osteogenic lineage in vitro. After 4 and 8 weeks, cranial tissue samples were taken for histological and immunofluorescence analysis. RESULTS: We observed a new bone formation in all of the samples but the most relevant differences in defect correction were shown by stem cell-collagen samples 4 weeks after implant, suggesting a faster regeneration ability of the combined constructs. The presence of human cells in the newly formed bone was confirmed by confocal analysis with an antibody directed to a human mitochondrial protein. Furthermore, human cells were found to be an essential part of new vessel formation in the scaffold. CONCLUSION: These data confirmed the strong potential of bioengineered constructs of stem cell-collagen scaffold for correcting large cranial defects in an animal model and highlighting the role of stem cells in neovascularization during skeletal defect reconstruction. PMID- 23688856 TI - The effect of school status and academic skills on the reporting of premarital sexual behavior: evidence from a longitudinal study in rural Malawi. AB - PURPOSE: Reliable data on sexual behavior are needed to identify adolescents at risk of acquiring human immunodeficiency virus or other sexually transmitted diseases, as well as unintended pregnancies. This study aimed to investigate whether schooling status and literacy and numeracy skills affect adolescents' reports of premarital sex, collected using audio computer-assisted self interviews. METHODS: We analyzed data on 2,320 participants in the first three rounds of the Malawi Schooling and Adolescent Study to estimate the level of inconsistency in reporting premarital sex among rural Malawian adolescents. We used multivariate logistic regressions to examine the relationships between school status and academic skills and premarital sexual behavior reports. RESULTS: Males were more likely than females to report premarital sex at baseline, whereas females were more likely than males to report sex inconsistently within and across rounds. School-going females and males were more likely to report never having had sex at baseline and to retract reports of ever having sex across rounds than were their peers who had recently left school. School-going females were also more likely to report sex inconsistently at baseline. Literate and numerate respondents were less likely to report sex inconsistently at baseline; however, they were more likely to retract sex reports across rounds. CONCLUSIONS: The level of inconsistency both within a survey round and across rounds reflects the difficulties in collecting reliable sexual behavior data from young people in settings such as rural Malawi, where education levels are low and sex among school-going females is not socially accepted. PMID- 23688857 TI - Psychiatric disorder prevalence among deaf and hard-of-hearing outpatients. AB - OBJECTIVES: To contribute to the dearth of literature on the prevalence rates of psychiatric disorders in deaf adults, this study examined the diagnostic and clinical characteristics of deaf psychiatric outpatients in comparison to hearing psychiatric outpatients. METHODS: Archival clinical data for deaf adults (N=241), treated at a specialized, linguistically and culturally affirmative outpatient community mental health program from 2002 to 2010, was compared to data from a random sample of hearing adult outpatients (N=345) who were treated at the same community mental health center. RESULTS: In various diagnostic categories, significant differences were seen between the deaf and hearing groups: bipolar disorders (3.7% versus 14.2%), impulse control disorders (15.8% versus 5.2%), anxiety disorders (18.7% versus 30.1%), attention deficit hyperactivity disorder (11.2% versus 4.9%), pervasive developmental disorders (3.3% versus 0.3%), substance use disorders (27.8% versus 48.4%), and intellectual disabilities (10.4% versus 2.9%). CONCLUSIONS: The deaf outpatient group evidenced a different diagnostic profile than the hearing sample. It is suggested that the use of culturally competent and fluent ASL-signing clinicians provides more diagnostic clarity and is encouraged as a best practice for the care of deaf individuals. PMID- 23688858 TI - Liver cirrhosis treated by living donor liver transplantation in a patient with AGL mutation c.2607-2610delATTC and c.1672dupA. AB - Glycogen storage disease type III (GSD III) is an inherited disorder characterized by the accumulation of abnormal glycogen in the liver. Hepatic manifestations were considered as improving with age; however, patients live longer and liver cirrhosis is being recognized. We report a patient of GSD IIIa with liver cirrhosis, which was treated successfully by living donor liver transplantation. The patient proved to be a compound heterozygote for a novel small deletion c.2607-2610delATTC and a known duplication c.1672dupA in AGL, a gene coding glycogen debranching enzyme responsible for GSD III. Molecular diagnosis helped clinical decision-making. PMID- 23688860 TI - Cognitive-enhancing effects of Rhus verniciflua bark extract and its active flavonoids with neuroprotective and anti-inflammatory activities. AB - The neuroprotective potential of flavonoids within the brain comprises anti apoptosis of neuronal cells, anti-neuroinflammation and enhancement of cognitive function. We reported that Rhus vernciflua inhibits glutamate-induced neurotoxicity in primary cultured rat cortical cells. Here we narrowed it down to get neuroprotective fractions from the plant yielding flavonoid-rich ethyl acetate fraction (PREF). Among its active flavonoids, fisetin exhibited not only inhibitory effect against lipopolysaccharide (LPS)-induced neuroinflammation by suppressing inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 but also memory enhancing effects via reactivation of cAMP responsive element binding protein (CREB)-brain derived neurotrophic factor (BDNF) pathway in memory impaired mice by scopolamine. Butein also showed a similar activity to fisetin even though to a lesser extent. The neuroprotection by PREF and selected flavonoids may involve maintenance of antioxidant defense mechanism including glutathione peroxidase (GSH-Px), glutathione reductase (GR) and superoxide dismutase (SOD). Conclusively, we demonstrate the R. vernciflua bark extract and its active flavonoids with potent neuroprotective and anti-inflammatory effects might be good therapeutic candidates as cognitive-enhancers. PMID- 23688859 TI - Effects of exposure to thin-ideal media images on body dissatisfaction: testing the inclusion of a disclaimer versus warning label. AB - The current study was designed to determine whether the inclusion of a disclaimer (i.e., "Retouched photograph aimed at changing a person's physical appearance.") or warning (i.e., "Warning: Trying to look as thin as this model may be dangerous to your health.") added to images of thin/attractive models would affect body dissatisfaction and intent to diet in female undergraduate students (n=342). Participants were randomly assigned to one of four groups: (a) disclaimer, (b) warning, (c) model control, or (d) car control. Results revealed a significant interaction between group and time, whereby only the car control group reported a significant change (i.e., decrease) in body dissatisfaction over time. Groups did not differ on intent to diet measured at post-exposure. The results largely replicate other findings in this area and call into question advocacy efforts to label media images as a strategy to decrease women's identification with the stimuli. PMID- 23688861 TI - Brucine, an effective natural compound derived from nux-vomica, induces G1 phase arrest and apoptosis in LoVo cells. AB - Brucine is an alkaloid from nux vomica, has been shown various pharmacological actions. To study the possible anti-cancer mechanisms on LoVo cells, effects of Brucine on cell viability, cell cycle and apoptosis were investigated. The results showed that Brucine revealed strong growth inhibitory effect on LoVo cells, and caused LoVo cell shrinkage and membrane blobbing, induced cellular and DNA morphological changes. Cell cycle and apoptosis analysis documented that Brucine could change cell cycle and induce cell apoptosis. Brucine-mediated cell cycle arrest in G1 phase was associated with a marked increase of protein levels of CCND1 and decrease in CCNB1, cyclin E and CDC2. In addition, Brucine dose dependently caused LoVo cells apoptosis evidenced by Annexin V/PI staining Brucine-induced apoptosis was mediated via up-regulation of Bax and down regulation of Bcl-2. Furthermore, proteins Erk1/2, p38 and Akt phosphorylation were down regulated by Brucine in a dose-dependent manner. In summary, this paper indicates Brucine is effective against LoVo cells proliferation, and promotes LoVo cells death via apoptosis. These results reveal functional interplay among a series of pathway that are deregulated in cancer and suggest that their simultaneous targeting by Brucine could result in efficacious inhibition on cancer cells. PMID- 23688862 TI - Pesticide exposure and genetic variation in xenobiotic-metabolizing enzymes interact to induce biochemical liver damage. AB - Metabolic activation of pesticides in the liver may result in highly reactive intermediates capable of impairing various cellular functions. Nevertheless, the knowledge about the effect of pesticide exposure on liver function is still limited. This study assessed whether exposure to pesticides elicits early biochemical changes in biomarkers of liver function and looked for potential gene environmental interactions between pesticide exposure and polymorphisms of pesticide-metabolizing genes. A longitudinal study was conducted in farm-workers from Andalusia (South Spain), during two periods of the same crop season with different degree of pesticide exposure. Blood samples were taken for the measurement of serum and erythrocyte cholinesterase activities as well as for determining clinical chemistry parameters as biomarkers of liver function. Serum lipid levels were also measured as they may help to monitor the progress of toxic liver damage. A reduction in serum cholinesterase was associated with decreased levels of all clinical chemistry parameters studied except HDL-cholesterol. Conversely, a decreased erythrocyte cholinesterase (indicating long-term pesticide exposure) was associated with increased levels of aspartate aminotransferase and alkaline phosphatase and increased levels of triglycerides, total cholesterol and LDL-cholesterol, but reduced levels of HDL-cholesterol. Changes in liver biomarkers were particularly associated with the PON155M/192R haplotype. The obtained results therefore support the hypothesis that pesticide exposure results in subtle biochemical liver toxicity and highlight the role of genetic polymorphisms in pesticide-metabolizing enzymes as biomarkers of susceptibility for developing adverse health effects. PMID- 23688864 TI - Extended treatment duration overcomes the requirement for profound week-4 interferon responsiveness in order for hepatitis C genotype 1 patients with unfavorable IL-28B genotype to achieve sustained virologic response. PMID- 23688863 TI - Emergence of antiviral resistance during oral valganciclovir treatment of an infant with congenital cytomegalovirus (CMV) infection. AB - Congenital infection with human cytomegalovirus (CMV) is a major cause of morbidity, including sensorineural hearing loss (SNHL), in newborns. Antiviral therapy with ganciclovir (GCV) and its oral prodrug, valganciclovir (VAL-GCV) are increasingly being administered to infected infants, toward the goal of improving neurodevelopmental and auditory outcomes. In this case report, we describe a symptomatic congenitally infected infant treated with VAL-GCV in whom GCV resistance was suspected, based on a 50-fold increase in viral load after 6 weeks of oral therapy. Analyses of CMV sequences from both blood and urine demonstrated populations of viruses with M460V and L595F mutations in the UL97 phosphotransferase gene. In contrast, analysis of viral DNA retrieved from the newborn dried blood spot demonstrated wild-type UL97 sequences. DNAemia resolved after the discontinuation of VAL-GCV. Long-term VAL-GCV therapy in congenitally infected infants can select for resistant viral variants, and anticipatory virological monitoring may be warranted. PMID- 23688865 TI - Antioxidant effect of quercetin against acute spinal cord injury in rats and its correlation with the p38MAPK/iNOS signaling pathway. AB - AIMS: The present study aimed to investigate the correlation between quercetin (Que) and the p38 mitogen-activated protein kinase (p38MAPK)/inducible nitric oxide synthase (iNOS) signaling pathway and to explore its regulating effect on secondary oxidative stress following acute spinal cord injury (SCI), so as to elucidate the protective effects and mechanism associated with Que treatment during acute SCI. MAIN METHODS: Sprague-Dawley rats were randomly divided into sham-surgery, SCI, Que, methylprednisolone (MP), and specific p38MAPK inhibitor SB203580 treatment groups. Acute SCI models were established in rats by a modified Allen's method. Real-time PCR analysis, western blot assay and immunohistochemistry for molecular changes in the p38MAPK/iNOS signaling pathway, determination of malondialdehyde (MDA) content and superoxide dismutase (SOD) activity, reflecting the levels of secondary oxidative stress, and functional or behavioral data, reflecting changes induced by Que and control treatments post SCI were performed. KEY FINDINGS: Que significantly increased Basso, Beattie and Bresnahan scores and inclined plane test scores in SCI rats similar to the positive control drug, MP. Que significantly inhibited increases in phosphorylated-p38MAPK (p-p38MAPK) and iNOS expression and reduced the rate of iNOS-positive cells in rats with SCI, similar to the effects of SB203580. In addition, both Que and SB203580 reduced MDA content and enhanced SOD activity in SCI rats, with Que effects being stronger. SIGNIFICANCE: These experimental findings indicate that in SCI rats, Que has protective effects on the spinal cord by the potential mechanism of inhibiting the activation of p38MAPK/iNOS signaling pathway and thus regulating secondary oxidative stress. PMID- 23688866 TI - Effects of cilnidipine on sympathetic outflow and sympathetic arterial pressure and heart rate regulations in rats. AB - AIMS: Cilnidipine is a unique Ca(2+) channel blocker that inhibits both L-type and N-type Ca(2+) channels. The present study aimed to assess the effects of intravenous cilnidipine on sympathetic outflow and sympathetic arterial pressure (AP) and heart rate (HR) regulations. MAIN METHODS: Carotid sinus baroreceptor regions were isolated from the systemic circulation in anesthetized and vagotomized Wistar Kyoto rats. Changes in efferent sympathetic nerve activity (SNA), AP and HR in response to a stepwise input of carotid sinus pressure were examined before and during intravenous cilnidipine administration (30 MUg/kg bolus+100 MUg kg(-1)h(-1) infusion, n=6). KEY FINDINGS: Cilnidipine significantly reduced the AP response range (from 68.0 +/- 10.2 to 34.6 +/- 4.1 mmHg, P=0.007) but did not affect the SNA response range (from 90.4 +/- 10.3 to 84.7 +/- 9.5%, P=0.297) or the HR response range (from 50.4 +/- 10.1 to 48.1 +/- 6.2 beats/min, P=0.719). SIGNIFICANCE: Cilnidipine, at a depressor dose used in the present study, does not acutely suppress sympathetic outflow from the central nervous system. Also, it spared the sympathetic HR response, suggesting that N-type Ca(2+) channel blocking action at the cardiac sympathetic nerve endings may be a modest one. PMID- 23688867 TI - Transgenic human programmed cell death 5 expression in mice suppresses skin cancer development by enhancing apoptosis. AB - AIMS: We sought to probe the role of human programmed cell death 5 (PDCD5) in vivo and to understand its mechanisms. MAIN METHODS: A transgenic mouse model of human PDCD5 was generated by pronuclear microinjection. Apoptosis in tissues of three independent transgenic mouse lines was quantified by terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling (TUNEL) and compared to wild type littermates. Their lifespan was compared. 8-Week PDCD5 mice and wild type mice (at a group of 5) were treated with carcinogen 3-methylcholanthrene (3 MC) at 5 MUg per week to induce skin cancer. Cancer development was measured by examining hematoxylin and eosin (H&E) stained skin sections after 5 weeks and 10 weeks treatment. Protein expression was determined by Western blot and apoptosis of skin cells was quantified by TUNEL. KEY FINDINGS: Starting from 5 months after birth, significant autonomous apoptosis was observed in multiple tissues of transgenic mice including skin, liver, spleen, adrenal gland and thyroid gland comparing to their wild type littermates. The average lifespan of PDCD5 mice was reduced to 9.75 months (normally 24-30 months). Moreover, carcinogen 3-MC induced skin cancer development was attenuated in the lesion of PDCD5 transgenic mice by enhancing apoptosis. Pro-apoptotic protein Bax expression was up-regulated in the 3-MC treated skin of transgenic mice. SIGNIFICANCE: These results suggest PDCD5 plays an antitumor role by enhancing apoptosis in animal physiological settings. Therefore, PDCD5 is a potential target for cancer therapy. PMID- 23688868 TI - Blocking the light. PMID- 23688869 TI - Modified implantation of black diaphragm intraocular lens in traumatic aniridia. AB - We describe a modified technique of black diaphragm intraocular lens (IOL) implantation in eyes with traumatic aniridia, aphakia, and previous vitrectomy. During black diaphragm IOL implantation, a double-armed 10-0 polypropylene suture is used to fixate the IOL in the ciliary sulcus. Two 10-0 polypropylene sutures are subsequently placed in front of the IOL to block its forward displacement and thus prevent its contact with the anterior chamber angle and corneal endothelium. This modified implantation technique reduces long-term complications following black diaphragm IOL implantation in patients with traumatic aniridia. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23688870 TI - Retrochop technique for rock-hard cataracts. AB - We describe a recently developed chopper, the retrochopper, and a technique for managing black and brunescent cataracts. The technique enables the surgeon to effectively disassemble the nucleus and perform a safe procedure with a short learning curve. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23688871 TI - Binocular visual function with a diffractive multifocal intraocular lens in patients with unilateral cataract. AB - PURPOSE: To compare binocular visual function in patients with unilateral cataract after monocular implantation of a multifocal intraocular lens (IOL) and after monocular implantation of a monofocal IOL. SETTING: Hayashi Eye Hospital, Fukuoka, Japan. DESIGN: Nonrandomized comparative study. METHODS: Patients with unilateral cataract scheduled for implantation of a diffractive multifocal IOL and age-matched patients scheduled for implantation of a monofocal IOL were recruited. Three months postoperatively, binocular visual acuity from far to near distances, binocular photopic or mesopic high- to low-contrast visual acuity with and without glare, and stereoacuity were examined. RESULTS: The mean binocular uncorrected near visual acuity or corrected near visual acuity at 0.3 m and uncorrected or corrected intermediate visual acuity at 0.5 m were significantly better in the multifocal group than in the monofocal group (P<=.0196), although there was no significant difference in uncorrected or corrected visual acuity at other distances. Binocular photopic contrast visual acuity and glare visual acuity at low contrasts and mesopic glare visual acuity were significantly worse in the multifocal group than in the monofocal group (P<=.0147). Near stereoacuity was similar between groups. Spectacle independence was significantly better in the multifocal group than in the monofocal group (P<=.0006). CONCLUSION: Monocular implantation of a diffractive multifocal IOL in patients with unilateral cataract provided better binocular near and intermediate visual acuity and spectacle independence than monocular implantation of a monofocal IOL, although distance contrast sensitivity was worse with the multifocal IOL. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23688872 TI - Outcomes and complications of a multifocal toric intraocular lens with a surface embedded near section. AB - PURPOSE: To evaluate the refractive outcomes and rotational stability after implantation of a multifocal toric intraocular lens (IOL) with a surface-embedded near section. SETTING: Private center, London, United Kingdom. DESIGN: Case series. METHODS: This study evaluated eyes with more than 1.50 diopters (D) of preexisting corneal astigmatism. After phacoemulsification, Lentis Mplus toric IOLs were implanted in all cases. The main outcome measures were refraction, uncorrected (UDVA) and corrected (CDVA) distance visual acuities, uncorrected near visual acuity (UNVA), keratometry, and IOL position. Three-month postoperative data are presented. RESULTS: The study enrolled 89 eyes (58 patients). The mean monocular postoperative UDVA and UNVA were 0.03 logMAR +/- 0.11 (SD) and 0.17 +/- 0.14 logMAR, respectively. The mean refractive cylinder decreased from 2.90 +/- 1.31 D preoperatively to 0.50 +/- 0.39 D postoperatively (P<.001). The mean difference between the planned axis of implantation and the actual axis postoperatively was 2.53 +/- 2.27 degrees. CONCLUSION: The multifocal toric IOL with a surface-embedded near section effectively corrected preexisting corneal astigmatism. The IOL was stable in the capsular bag, there were no visually significant complications, and there was no significant rotation out to 3 months postoperatively. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 23688873 TI - Intraocular lens calculation for aspheric intraocular lenses. AB - PURPOSE: To evaluate the possible benefits of biometry and ray-tracing intraocular lens (IOL) calculation for aspheric aberration-correcting IOLs. SETTING: Private eye clinic in Germany. DESIGN: Retrospective consecutive case series. METHODS: Eyes with 3 different aberration-correcting IOLs were reviewed. Before surgery, the axial length, corneal thickness, anterior chamber depth, crystalline lens thickness, and corneal radii were measured with the Lenstar biometer. Subjective refraction was taken 1 month after surgery. Okulix ray tracing software (version 8.79) and the Hoffer Q, Holladay, and SRK/T formulas were used to calculate a prediction error based on preoperative biometry data, the given IOL, and the manifest refraction. RESULTS: The study evaluated 308 eyes of 185 patients. The median absolute error was 0.28 diopters (D) for the Hoffer Q, 0.27 D for the Holladay, 0.28 D for the SRK/T, and 0.24 D for ray-tracing calculation. Using ray-tracing calculation, 95% of eyes were within +/-0.71 D of the predicted refraction as opposed to +/-0.85 D with the Hoffer Q, +/-0.82 D with the Holladay, and +/-0.84 D with the SRK/T. CONCLUSIONS: Ray tracing based on biometry data improved IOL prediction accuracy over conventional formulas in normal eyes implanted with aberration-correcting IOLs. The number of outliers can also be reduced significantly. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 23688874 TI - Exploring the optimum step size for defocus curves. AB - PURPOSE: To evaluate the effect of reducing the number of visual acuity measurements made in a defocus curve on the quality of data quantified. SETTING: Midland Eye, Solihull, United Kingdom. DESIGN: Evaluation of a technique. METHODS: Defocus curves were constructed by measuring visual acuity on a distance logMAR letter chart, randomizing the test letters between lens presentations. The lens powers evaluated ranged between +1.50 diopters (D) and -5.00 D in 0.50 D steps, which were also presented in a randomized order. Defocus curves were measured binocularly with the Tecnis diffractive, Rezoom refractive, Lentis rotationally asymmetric segmented (+3.00 D addition [add]), and Finevision trifocal multifocal intraocular lenses (IOLs) implanted bilaterally, and also for the diffractive IOL and refractive or rotationally asymmetric segmented (+3.00 D and +1.50 D adds) multifocal IOLs implanted contralaterally. Relative and absolute range of clear-focus metrics and area metrics were calculated for curves fitted using 0.50 D, 1.00 D, and 1.50 D steps and a near add-specific profile (ie, distance, half the near add, and the full near-add powers). RESULTS: A significant difference in simulated results was found in at least 1 of the relative or absolute range of clear-focus or area metrics for each of the multifocal designs examined when the defocus-curve step size was increased (P<.05). CONCLUSION: Faster methods of capturing defocus curves from multifocal IOL designs appear to distort the metric results and are therefore not valid. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23688875 TI - Comparison of intraocular pressures after myopic laser-assisted subepithelial keratectomy: tonometry-pachymetry, Goldmann applanation tonometry, dynamic contour tonometry, and noncontact tonometry. AB - PURPOSE: To compare intraocular pressure (IOP) measurements using a new tonometer pachymeter device (Tonopachy), Goldmann applanation tonometry (GAT), dynamic contour tonometry (DCT), and noncontact tonometry (NCT) before and after myopic laser-assisted subepithelial keratectomy (LASEK). SETTING: Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, South Korea. DESIGN: Prospective comparative observational study. METHODS: Nine IOP values were measured using 4 tonometers (6 IOPs by tonometer-pachymeter and 1 each by GAT, DCT, and NCT) and compared preoperatively and 3 months postoperatively. Of the 6 IOP values measured by the tonometer-pachymeter, 1 showed uncorrected IOP and 5 indicated central corneal thickness (CCT)-corrected IOPs through different formulas. RESULTS: Preoperatively and postoperatively, the means of 9 IOP values measured by 4 tonometers were statistically different. The IOP measurements by the tonometer-pachymeter correlated with all other IOP values preoperatively; however, there was no correlation with IOP measurements using DCT postoperatively. Some IOPs using the tonometer-pachymeter were interchangeable with those using GAT preoperatively, but not with DCT preoperatively or postoperatively. The corrected IOP values of the tonometer-pachymeter formula 3 and DCT did not change after surgery. The percentage change in CCT and corneal curvature and change in diopters correlated with the percentage change in IOP measurements by GAT and NCT but not with those using DCT and the tonometer pachymeter. CONCLUSION: Among the 9 IOP values, corrected IOP using the tonometer pachymeter formula 3 showed similar IOP values after LASEK, as did DCT. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23688876 TI - Small-aperture corneal inlay implantation to treat presbyopia after laser in situ keratomileusis. AB - PURPOSE: To evaluate the visual outcomes after implantation of a Kamra small aperture corneal inlay into a femtosecond-created corneal pocket to treat presbyopia in patients who had previous laser in situ keratomileusis (LASIK). SETTING: Private center, Tokyo, Japan. DESIGN: Prospective interventional case series. METHODS: Post-LASIK presbyopic patients had inlay implantation into a corneal pocket created by a femtosecond laser at a depth of 200 MUm or 250 MUm a minimum of 80 MUm below the previous LASIK flap interface in the nondominant eye. Uncorrected and corrected distance visual acuities, near visual acuity, and a patient questionnaire on satisfaction, the use of reading glasses, and visual symptoms were evaluated. RESULTS: The study enrolled 223 eyes (223 patients) with a mean age of 53.6 years (range 44 to 65 years) and a mean manifest spherical equivalent of -0.18 diopter (D) (range -1.00 to +0.50 D). The mean uncorrected distance visual acuity in the operated eye decreased 1 line from 20/16 preoperatively to 20/20 6 months postoperatively (P<.001). The mean uncorrected near visual acuity improved 4 lines from Jaeger (J) 8 to J2 (P<.001). At 6 months, significant improvements were observed in patient dependence on reading glasses and patient satisfaction with vision without reading glasses. CONCLUSION: The 6-month results suggest that implantation of a small-aperture inlay in post LASIK presbyopic patients improves near vision with a minimal effect on distance vision, resulting in high patient satisfaction and less dependence on reading glasses. FINANCIAL DISCLOSURE: Drs. Tomita and Waring are consultants to Acufocus, Inc. Dr. Tomita is a consultant to Ziemer Group AG. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 23688877 TI - Visual performance of 2 aspheric toric intraocular lenses: comparative study. AB - PURPOSE: To compare the visual and aberrometric outcomes of 2 aspheric toric intraocular lenses (IOLs). SETTING: Fatebenefratelli e Oftalmico Hospital, Milan, Italy. DESIGN: Prospective randomized comparative study. METHODS: Astigmatic patients had cataract surgery with implantation of an Acrysof SN6AT IOL (Group A) or an AT Torbi 709M IOL (Group B). The uncorrected (UDVA) and corrected (CDVA) distance visual acuities, net refractive astigmatism, spherical equivalent (SE), IOL misalignment, and optical quality were evaluated 3 months postoperatively. RESULTS: The study included 72 eyes. No statistically significant difference was found in UDVA, CDVA, residual refractive astigmatism, intraocular or total higher order aberrations (Z(n,i) (order of aberrations calculated: 3<=n<=8), coma Z(3,+/ 1), or trefoil Z(3,+/-2). The UDVA was 0.3 logMAR or better in all eyes and 0.1 logMAR or better in 55.5% of eyes in Group A and in 61.1% of eyes in Group B. Considering polar value analysis, 94.4% of eyes in both groups had a refractive astigmatism value within +/-0.50 diopter at KP90 (polar value along 90-degree meridian). The SE was closer to emmetropia in Group A (P=.01). Intraocular lens misalignment of less than 5 degrees was present in 61.1% of cases in Group A (maximum 9 degrees) and in 66.6% in Group B (maximum 11 degrees). Spherical aberration Z(4,0) was significantly lower in Group B. CONCLUSIONS: Both IOLs had similar clinical effectiveness in term of astigmatism correction, rotational stability, and optical quality. Eyes in Group A appeared significantly nearer to emmetropia, while the IOL in Group B induced significantly less spherical aberration. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23688878 TI - Clinical outcomes after implantation of a posterior chamber collagen copolymer phakic intraocular lens with a central hole for myopic correction. AB - PURPOSE: To evaluate the efficacy, predictability, safety, and stability of a new model posterior chamber Implantable Collamer Lens phakic intraocular lens (pIOL) (V4c Visian) to correct myopia. SETTING: Private practice, Oviedo, Spain. DESIGN: Case series. METHODS: This study enrolled patients who had implantation of a new pIOL design with a central hole for more natural aqueous flow, eliminating the need for neodymium:YAG iridotomy or peripheral iridectomy. The uncorrected (UDVA) and corrected (CDVA) distance visual acuities, refractive error, intraocular pressure (IOP), endothelial cell count, central vault, and adverse events were evaluated 6 months postoperatively. RESULTS: The study enrolled 138 eyes (70 patients). The mean spherical equivalent decreased from -8.73 diopters (D) +/- 2.54 (SD) preoperatively to -0.03 +/- 0.19 D 6 months postoperatively; 98.5% of eyes were within +/-0.50 D and 100% of eyes were within +/-1.00 D. The mean UDVA and CDVA were 20/20 or better in 92.1% and 95.0% of eyes, respectively, at 6 months. The safety and efficacy indices were 1.01 and 1.00, respectively. Postoperatively, the IOP remained stable over time. No significant rises in IOP (including pupillary block) and no secondary cataract were found. After 6 months, the mean vault was 482.7 +/- 210.5 MUm (range 90 to 970 MUm) and the mean endothelial cell loss was 8.5%. CONCLUSIONS: Implantation of the pIOL was effective, predictable, safe, and stable for the correction of moderate to high myopic errors. This design, which avoids iridotomy or iridectomy, provided good IOP outcomes. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23688879 TI - Comparison of 2 femtosecond lasers for laser in situ keratomileusis flap creation. AB - PURPOSE: To compare the morphology of laser in situ keratomileusis (LASIK) flaps created by 2 femtosecond lasers. SETTING: Ophthalmic Center, Beijing Tongren Hospital, Capital Medical University, Beijing Ophthalmology & Visual Sciences Key Lab, Beijing, China. DESIGN: Comparative case series. METHODS: The RTVue optical coherence tomography (OCT) device was used to measure the morphology of LASIK flaps created with an Intralase FS60 (Group 1) or Femto LDV (Group 2) femtosecond laser 1 week postoperatively. Nominal flap thickness was 110 MUm for both devices. RESULTS: Group 1 comprised 408 flaps and Group 2, 408 flaps. The mean central flap thickness was 109.34 MUm +/- 7.57 (SD) in Group 1 and 103.91 +/- 6.07 MUm in Group 2 (P<.001). The mean flap thickness in Group 2 (105.37 +/- 4.56 MUm) was significantly thinner than in Group 1 (110.29 +/- 6.95 MUm) (P<.001). Corneal flaps in the 2 groups were uniform and regular, showing an almost planar configuration. The 2 groups had similar predictability; the mean deviation in flap thickness was 6.59 MUm in Group 1 and 6.56 MUm in Group 2 (P=.877). The maximum deviation from the intended 110 MUm thickness of 18 measurements was 7.1 MUm in Group 1 and 7.6 MUm in Group 2. CONCLUSIONS: The flaps in Group 2 were thinner than in Group 1. The 2 groups had similar predictability and uniformity in flap creation. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23688880 TI - In vitro optical quality differences between multifocal apodized diffractive intraocular lenses. AB - PURPOSE: To compare the in vitro optical quality of multifocal apodized intraocular lenses (IOLs) at different focal points. SETTING: University of Valencia, Valencia, Spain. DESIGN: Experimental study. METHODS: The Acrysof Restor +3.0 diopter (D) multifocal IOL with 2 main foci (bifocal IOL) and the Finevision multifocal IOL with 3 main foci (trifocal IOL) were evaluated. The optical quality was quantified using the modulation transfer function (MTF) at 7 focal points and for 3.0 mm and 4.5 mm apertures. The through-focus MTF at 10 focal points of the IOLs was also recorded. RESULTS: For the 0.0 D and -2.5 D focal points, the bifocal IOL showed the highest MTF values for pupil sizes as well as for the -3.0 D focal point for a 3.0 mm aperture. For the -1.5 D and -3.5 D focal points, the trifocal IOL provided better MTF values, whereas for -2.0 D and -4.0 D both IOLs provided comparable results for both apertures. The through focus MTF curves showed 3 and 2 peaks for the trifocal IOL and the bifocal IOL, respectively. With the bifocal IOL, better peak values were obtained at the 0.0 D, -2.0 D, -2.5 D, and -3.0 D focal points, while the trifocal IOL yielded better peak values at the -1.5 D and -3.5 D focal points. CONCLUSION: The bifocal IOL is likely to provide a greater range of vision from distance to near than the trifocal IOL; however, at the intermediate focal point (-1.5 D), the trifocal IOL will probably yield better optical quality. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23688882 TI - Refractive changes after vitrectomy and phacovitrectomy for macular hole and epiretinal membrane. AB - Several studies have described changes in refraction toward myopia in eyes having vitrectomy and phacovitrectomy. This article reviews studies of the refractive outcome in phakic and pseudophakic eyes after vitrectomy and phacovitrectomy for macular hole or epiretinal membrane. Several factors play a role in refraction, including measurement of the axial length, changes in the effective lens position and the anterior chamber depth, the use of intraocular gas tamponade, the formula for intraocular lens (IOL) power calculation, and the IOL type. Most phakic eyes with macular hole or epiretinal membrane that have vitrectomy will develop cataract. Therefore, the sequence of surgery has to be considered; ie (1) performing combined phacovitrectomy, (2) vitrectomy and subsequent cataract surgery, or (3) cataract surgery and subsequent vitrectomy. Most studies reviewed in this article found a myopic shift regardless of the sequence of the surgery. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 23688881 TI - Cytotoxicity of cannulas for ophthalmic surgery after cleaning and sterilization: evaluation of the use of enzymatic detergent to remove residual ophthalmic viscosurgical device material. AB - PURPOSE: To evaluate the cytotoxicity of reusable cannulas for ophthalmic surgery after the cannulas were filled with an ophthalmic viscosurgical device (OVD) and cleaned with an enzymatic detergent. SETTING: Microbiological Testing Laboratory, Department of Medical-Surgical Nursing, University of Sao Paulo School of Nursing, and Cell Culture Section, Adolfo Lutz Institute, Sao Paulo, Brazil. DESIGN: Experimental study. METHODS: The sample consisted of 30 reusable 25-gauge injection cannulas, 20.0 mm in length, whose lumens were filled with an OVD solution for 50 minutes. The following steps were used to process the cannulas: (1) presoaking, (2) washing the lumen using a high-pressure water jet, (3) backwashing with enzymatic detergent in ultrasonic cleaner, (4) preliminary rinsing with tap water, (5) final rinsing with sterile distilled water, (6) drying with compressed filtered air, (7) wrapping in surgical-grade paper, and (8) steam sterilization at 134 degrees C for 4 minutes. The cannulas were then tested for cytotoxicity according to the United States Pharmacopeia 32. RESULTS: The cleaning protocol used in this study removed residues of OVD solution and enzymatic detergent as shown by the lack of cytotoxicity of all sample extracts. CONCLUSION: This cleaning protocol has the potential to minimize the occurrence of toxic anterior segment syndrome associated with residues of OVD solutions and enzymatic detergents. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23688883 TI - Irregular astigmatism after femtosecond laser refractive lenticule extraction. AB - We report a case of irregular corneal astigmatism after refractive lenticule extraction. A refractive lenticule was created using a femtosecond laser and then extracted through a small arcuate incision. One day postoperatively, the corneal findings by slitlamp biomicroscopy indicated mild corneal edema. Corneal topography demonstrated an area of steepened corneal surface inferiorly, and corneal thickness was relatively thicker in this area than in others. At 5 months, the corneal findings were normal by slitlamp biomicroscopy but corneal topography results remained unchanged. Fourier-domain optical coherence tomography examination showed remnant intrastromal lenticule tissue in this affected area. To our knowledge, this is the first case of residue intrastromal lenticule after refractive lenticule extraction. To prevent this complication, we believe it is important to completely dissect the lenticule and carefully examine the intactness of the lenticule during the surgery. FINANCIAL DISCLOSURE: Neither author has a financial or proprietary interest in any material or method mentioned. PMID- 23688884 TI - Nonarteritic ischemic optic neuropathy secondary to severe ocular hypertension masked by interface fluid in a post-LASIK eye. AB - We report a case of ischemic optic neuropathy arising from elevated intraocular pressure (IOP) masked by interface fluid in a post-laser in situ keratomileusis (LASIK) eye. A 51-year-old man, who had had LASIK 6 years prior to presentation, sustained blunt trauma to the left eye that resulted in a hyphema and ocular hypertension. Elevated IOP resulted in accumulation of fluid in the stromal bed LASIK flap interface, leading to underestimation of IOP when measured centrally over the flap. After days of unrecognized ocular hypertension, ischemic optic neuropathy developed. To our knowledge, this is the first reported case of ischemic optic neuropathy resulting from underestimated IOP measurements in a post-LASIK patient. It highlights the inaccuracy of IOP measurements in post LASIK eyes and a vision-threatening potential complication. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23688885 TI - Refractive surgical problem: June consultation. PMID- 23688896 TI - Comments on corneal astigmatic marking methods. PMID- 23688897 TI - Potential effects of laterality and learning on misalignment in marking horizontal meridian. PMID- 23688898 TI - A simple technique for corneal marking before toric intraocular lens implantation. PMID- 23688899 TI - Reply: a simple technique for corneal marking before toric intraocular lens implantation. PMID- 23688900 TI - Pellucid marginal degeneration and keratoconus; differential diagnosis by corneal topography. PMID- 23688901 TI - Reply: pellucid marginal degeneration and keratoconus; differential diagnosis by corneal topography. PMID- 23688902 TI - Comparing visual function of accommodating IOLs versus mini-monovision with a nonaccommodating monofocal IOL. PMID- 23688903 TI - Reply: comparing visual function of accommodating IOLs versus mini-monovision with a nonaccommodating monofocal IOL. PMID- 23688904 TI - Retropupillary iris-claw intraocular lens in aphakic eyes. PMID- 23688905 TI - Mitochondrial respiration in blood platelets of depressive patients. AB - Recent evidences include mitochondrial dysfunctions in pathophysiology of mood disorders. We examined association between depressive disorders and mitochondrial respiration using both intact and permeabilized blood platelets. In intact platelets, physiological respiration, maximal capacity of electron transport system and respiratory rate after complex I inhibition were decreased in depressive patients, who reached partial remission, compared to healthy controls. Respiratory rates were unchanged in several respiratory states in permeabilized platelets. Results indicate that changes in respiratory rate in intact platelets can be used as biological marker of depressive disorder. The hypothesis that decreased mitochondrial respiratory rate participate in pathophysiology of depression was supported. PMID- 23688906 TI - Phenotype and genotype of deaf patients with combined genomic and mitochondrial inheritance models. AB - In most studies, sensorineural hearing loss is reported as a single-gene disease with autosomal dominant or autosomal recessive or with X-linked or maternal inheritance. It is uncommon that the hearing impairment is caused by a combined inheritance model including genomic and mitochondrial models. Here, we report six patients with sensorineural hearing loss caused by co-existing mutations in GJB2 or SLC26A4 and the mitochondrial gene. And there was no significant difference in hearing phenotypes between the six patients and the controls. The results indicate the complicated genetic etiology of, and may impact the diagnostic strategy for, hereditary hearing impairment. All patient siblings will carry mitochondrial DNA A1555G or C1494T mutations, and 25% of siblings may carry the same homozygous or compound heterozygote mutations in GJB2 or SLC26A4. Although this combined inheritance is not common in the Chinese deaf population (0.10%), our findings will have great impact in genetic counseling and risk prediction for deafness. PMID- 23688907 TI - Purple drank prevalence and characteristics of misusers of codeine cough syrup mixtures. AB - A mixture of codeine cough syrup with alcohol and/or a soft drink known as "purple drank" has gained media attention in recent years as a drug associated with professional athletes and southern rap music. The existing research on purple drank consumption has primarily utilized samples of African Americans residing in the Houston, Texas area. This is the first scholarly study of purple drank use outside of the Houston, Texas area among a general population of young adults, and indicates that purple drank use is not limited to African American males. The findings depict higher odds of the use of purple drank among other racial and ethnic groups, males, and homosexual, bisexual, and transgender college students from urban areas. PMID- 23688908 TI - Age of first cigarette, alcohol, and marijuana use among U.S. biracial/ethnic youth: a population-based study. AB - This study examines age of first cigarette, alcohol, and marijuana use among self identified biracial youth, using data from the National Longitudinal Study of Adolescent Health (Add Health). We found an intermediate biracial phenomenon in which some biracial youth initiate substance use at ages that fall between the initiation ages of their 2 corresponding monoracial groups. When controlling for the covariates, our findings show that White-Asian biracial youth begin smoking marijuana and drinking alcohol at earlier ages than Whites and engaging in all forms of substance use at earlier ages than Asian youth. Results indicate that White-American Indian youth start smoking cigarettes at earlier ages than all biracial and monoracial groups. Our findings underscore the need for future research to examine substance-use initiation and progression among biracial/ethnic youth. PMID- 23688909 TI - Odorant receptor gene choice and axonal wiring in mice with deletion mutations in the odorant receptor gene SR1. AB - In the mouse, a mature olfactory sensory neuron (OSN) of the main olfactory epithelium (MOE) expresses one allele of one of the 1200 odorant receptor (OR) genes in the genome. The mechanisms that underlie the one receptor-one neuron rule remain poorly understood. A popular experimental paradigm for OR gene choice is to delete an OR coding region by gene targeting or in a transgene. Here we have applied this ?OR paradigm to SR1, also known as MOR256-3 or Olfr124. This gene is expressed in OSNs of the MOE, and in ~50% of the OSNs of the septal organ. In heterozygous ?SR1 mice, we observe an unprecedented biallelic expression rate of 30% at the SR1 locus. In homozygous ?SR1 mice, we find a significant increase in the number of septal organ OSNs that undergo apoptosis. As a population, ?SR1 OSNs project their axons to 81-85 glomeruli in each half of the OB, and coexpress at least 77 OR genes as evaluated by single-cell molecular analysis. There are no obvious or simple rules for the set of OR genes that are coexpressed with the ?SR1 allele. The frequencies of coexpression are different for ?SR1 OSNs in the septal organ compared to those in the MOE. We propose that there are as many as five scenarios for the fate of individual ?SR1 OSNs. PMID- 23688910 TI - Early venous manifestation of Ehlers-Danlos syndrome Type IV through a novel mutation in COL3A1. AB - Ehlers-Danlos syndrome (EDS) leads to abnormalities in the synthesis of collagen and complications involving arterial vessels. We describe here a mutation in the intron 14 of the COL3A1 gene leading to EDS Type IV (EDS IV) associated with venous manifestations only. The patient, an 18-year-old male, suffered from truncal varicosity of the long saphenous vein on both sides. Conventional stripping surgery of the left saphenous vein revealed an extremely vulnerable ectatic superficial femoral vein. An inserted vein graft occluded, and venous thrombectomy was unsuccessful. A conservative anticoagulant and compression therapy finally succeeded. This is the first report describing EDS IV due to a mutation in intron 14 of the COL3A1 gene leading to venous manifestations without affecting arterial vessels at clinical presentation. Our findings imply that molecular genetic analysis should be considered in patients with unusual clinical presentation and that conservative therapy should be applied until a suspected clinical diagnosis has been secured. PMID- 23688911 TI - Reduced plakoglobin immunoreactivity in arrhythmogenic cardiomyopathy: methodological considerations. AB - BACKGROUND: Arrhythmogenic cardiomyopathy (AC) primarily is considered to be a desmosomal disease with a predominant right ventricular phenotype. Reduced signal intensity for junctional plakoglobin (JUP) at the intercalated disks has been proposed as a marker that contributes to diagnosis of the disease. In this technical study, we investigated how methodology-related differences caused by tissue preservation and antibody dilutions affect an appropriate diagnosis. METHODS: Autopsy and biopsy material was available from a total of 7 control and 25 AC patients that fulfilled the diagnostic Task Force Criteria as proposed in 2010. Immunohistochemical analysis was performed on cryosections and formalin fixed material using antibodies against JUP and N-Cadherin. RESULTS: Immunohistochemistry (1:1000 antibody dilution) on formalin-fixed material showed a reduced signal for JUP in 7/10 AC patients in a bidirectional, double-blinded exchange experiment in which 77% of individuals were correctly classified. Unmasking this disturbed JUP pattern was highly dependent on tissue preservation and antibody dilution since on cryosections the disturbed pattern in patients could only be unmasked at a very strong antibody dilution of 1:100000. CONCLUSIONS: Reduced immunoreactive signal of JUP at the intercalated disks can be observed in a majority of AC patients. These changes can comparably be detected on both cryo- (74%) and formalin-fixed material (70%) but demand a different, highly defined, and uniformly used approach. PMID- 23688912 TI - Entry into motherhood among adolescent girls in two informal settlements in Nairobi, Kenya. AB - The contribution of adolescents' childbearing to total fertility rates in many sub-Saharan African countries is higher than in other parts of the world. In this paper, data collected from 897 female adolescents aged 15-19 years are analysed to investigate patterns and determinants of entry into motherhood in two informal settlements in Nairobi, Kenya, using Kaplan-Meier estimates and Cox regression models. About 15% of these adolescents have had a child. The findings show that marriage, being out of school and having negative models in peer, family and school contexts are associated with early childbearing among females aged 15-17 years. For adolescents aged 18-19 years, school attendance considerably delays entry into motherhood while marriage hastens its timing. Furthermore, older adolescents with high levels of social controls (parental monitoring or perceived peer orientation to or approval of prosocial behaviours) and individual controls (high religiosity and positive orientation to schooling) are likely to delay childbearing. Programmes aiming to reduce risky sexual behaviours that could lead to childbearing among adolescents should be introduced very early, and before the onset of sexual activity. Also, the findings underscore the need to identify and address the risky factors and reinforce the protective ones in order to improve sexual and reproductive health outcomes of adolescent girls in Nairobi slum settlements. PMID- 23688913 TI - Life stressors and resources and the 23-year course of depression. AB - BACKGROUND: Life stressors and personal and social resources are associated with depression in the short-term, but little is known about their associations with the long-term course of depression. The current paper presents results of a 23 year study of community adults who were receiving treatment for depression at baseline (N=382). METHODS: Semi-parametric group-based modeling was used to identify depression trajectories and determine baseline predictors of belonging to each trajectory group. RESULTS: There were three distinct courses of depression: high severity at baseline with slow decline, moderate severity at baseline with rapid decline, and low severity at baseline with rapid decline. At baseline, individuals in the high-severity group had less education than those in the moderate-severity group, and more medical conditions than those in the moderate- and low-severity groups. Individuals in the high- and moderate-severity groups evidenced less psychological flexibility, and relied more on avoidance coping than individuals in the low-severity group. LIMITATIONS: Results are limited by use of self-report and lack of information about depression status and life events in the periods between follow-ups. CONCLUSIONS: These results assist in identifying groups at high risk for a long-term course of depression, and will help in selecting appropriate interventions that target depression severity, coping skills and management of stressors. PMID- 23688914 TI - Increased resting-state functional connectivity between the anterior cingulate cortex and the precuneus in panic disorder: resting-state connectivity in panic disorder. AB - BACKGROUND: The structural and functional abnormalities of the anterior cingulate cortex (ACC) have been reported in panic disorder (PD). Patients with PD have shown decreased gamma-aminobutyric acid (GABA) concentration in the ACC. The GABA concentration in the ACC was found to be associated with default mode network (DMN) activity in normal human subjects. Therefore, it was hypothesized that the DMN would show abnormal activity in PD. METHODS: We identified and compared the functional connectivity maps with seed region of interest (ROI) located in the perigenual area of ACC between the 11 patients with panic disorder and age- and sex-matched normal control subjects. Combining magnetic resonance spectroscopy (MRS) and resting fMRI, we investigated the correlation between the GABA concentration in the seed ROI and the index of functional connectivity between ACC and the area showing group differences. RESULTS: The patients with PD showed increased functional connectivity between ACC and precuneus compared to control subjects. The functional connectivity between the ACC and the precuneus negatively correlated with the GABA concentration of the ACC. LIMITATIONS: The relatively small sample size and seed based analysis with the selection of a single ROI limits the generalizability of the result. CONCLUSIONS: Increased functional connectivity in the two medial nodes of the resting-state default mode network, the ACC and the precuneus, might play an important role in the pathophysiology of panic disorder. The treatment aimed to normalize the functional connectivity between ACC and precuneus might have clinical benefits in PD. PMID- 23688915 TI - Cognitive-behavioural interventions for mood and anxiety disorders in HIV: a systematic review. AB - BACKGROUND: Mood and anxiety disorders are highly prevalent and comorbid with HIV/AIDS. However, there is a paucity of research on the effectiveness of cognitive-behavioural interventions (CBI) for common mental disorders in HIV infected adults. The present study sought to review the existing literature on the use of CBI for depression and anxiety in HIV-positive adults and to assess the effect size of these interventions. METHODS: We did duplicate searches of databases (from inception to 17-22 May 2012). The following online databases were searched: PubMed, The Cochrane Central Register of Controlled Trials and PsychArticles. RESULTS: We identified 20 studies suitable for inclusion. A total of 2886 participants were enroled in these studies, of which 2173 participants completed treatment. The present review of the literature suggests that CBI may be effective in the treatment of depression and anxiety in individuals living with HIV/AIDS. Significant reductions in depression and anxiety were reported in intervention studies that directly and indirectly targeted depression and/or anxiety. Effect sizes ranged from 0.02 to 1.02 for depression and 0.04 to 0.70 for anxiety. LIMITATIONS: Some trials included an immediate postintervention assessment but no follow-up assessments of outcome. This omission makes it difficult to determine whether the intervention effects are sustainable over time. CONCLUSION: The present review of the literature suggests that CBI may have a positive impact on the treatment of depression and anxiety in adults living with HIV/AIDS. PMID- 23688916 TI - Major depressive episode among Brazilian adults: a cross-sectional population based study. AB - BACKGROUND: Despite the fact that there is extensive scientific research on depression very few population-based studies have been conducted in Brazilian cities. METHODS: A sampling design of two-stage conglomerates with probability proportional to size. All adults aged 20 or more living in the selected households were invited to participate in the study. Depression was assessed using the Patient Health Questionnaire-9 (PHQ-9) with a cutoff >=9. RESULTS: The study sample comprised 2925 respondents. The prevalence of depression in the sample studied was 20.4% (95% CI 18.9;21.8). After adjustment for confounding factors according to a conceptual analysis model the following variables were associated with a higher prevalence of depression: female gender; younger age; white skin color; lower socioeconomic condition; lower education; smoking; being single or separated; being unemployed; and reporting a heart condition. Alcohol use, arterial hypertension, and diabetes mellitus were not found to be associated with depression. LIMITATIONS: The difference in the proportion of males among losses and refusals compared to that in the sample analyzed. Another limitation is reverse causality bias that is a problem inherent to cross-sectional studies. CONCLUSIONS: Our findings support the relevance of depression as a prevalent condition among adults. It also provided evidence of the factors associated with depression, and that some are potentially modifiable risk factors may have implications for policy and health service planning. PMID- 23688917 TI - The Australian public's beliefs about the causes of depression: associated factors and changes over 16 years. AB - BACKGROUND: Biological conceptualisations of depression are increasingly prevalent. The current study aimed to investigate the current prevalence of causal beliefs about depression in the Australian public, the factors associated with these beliefs, and changes over time. METHOD: A nationally representative sample of Australian adults was surveyed as part of the 2011 National Mental Health Literacy and Stigma Survey. Beliefs about the causes of depression were assessed based on responses to vignettes depicting a person with either depression (n=893) or depression with suicidal thoughts (n=903). Socio demographic characteristics, personal and professional experience with depression, and correct recognition of depression were investigated as predictors of causal beliefs about depression using binary logistic regression. Comparisons were made between the Australian public's current causal beliefs and data obtained in national surveys conducted in 1995 and 2003/4. RESULTS: Over 80% of the Australian public attributed depression to day to day problems, death of a close friend or relative, a recent traumatic event, childhood problems, and a chemical imbalance in the brain. People who correctly labelled the disorder in the vignettes were more likely to attribute depression to psychosocial reasons and less likely to attribute it to an allergic reaction, a virus, or an infection. Belief in psychosocial and genetic causes has increased over time, whereas belief in infection, allergy and weakness of character has decreased. LIMITATIONS: Comparisons between the 1995, 2003/4 and 2011 surveys were limited by the differences in the survey methodology at each time point, and by low response rates to the 2003/4 and 2011 surveys. The survey design prevented insight into the reasoning underlying individuals' responses, and lacked sufficient power to explore the beliefs of Australians from cultural minorities. CONCLUSIONS: The majority of the Australian public believe that both psychosocial and biological factors cause depression. PMID- 23688919 TI - Effects of water immersion on short- and long-latency afferent inhibition, short interval intracortical inhibition, and intracortical facilitation. AB - OBJECTIVE: The aim of the present study was to investigate the effect of water immersion (WI) on short- and long-latency afferent inhibition (SAI and LAI), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). METHODS: Motor evoked potentials (MEPs) were measured from the first dorsal interosseous (FDI) muscle of fifteen healthy males before, during, and after a 15-min WI at 30 degrees C up to the axilla. Both SAI and LAI were evaluated by measuring MEPs in response to transcranial magnetic stimulation (TMS) of the left motor cortex following electrical stimulation of the right median nerve (fixed at about three times the sensory threshold) at interstimulus intervals (ISIs) of 20 ms to assess SAI and 200 ms to assess LAI. The paired pulse TMS paradigm was used to measure SICI and ICF. RESULTS: Both SAI and LAI were reduced during WI, while SICI and ICF were not significantly different before, during, and after WI. CONCLUSIONS: WI decreased SAI and LAI by modulating the processing of afferent inputs. SIGNIFICANCE: Changes in somatosensory processing and sensorimotor integration may contribute to the therapeutic benefits of WI for chronic pain or movement disorders. PMID- 23688918 TI - Gamma activity modulated by picture and auditory naming tasks: intracranial recording in patients with focal epilepsy. AB - OBJECTIVE: We measured the spatial, temporal and developmental patterns of gamma activity augmented by picture- and auditory-naming tasks and determined the clinical significance of naming-related gamma-augmentation. METHODS: We studied 56 epileptic patients (age: 4-56 years) who underwent extraoperative electrocorticography. The picture-naming task consisted of naming of a visually presented object; the auditory-naming task consisted of answering an auditorily presented sentence question. RESULTS: Naming-related gamma-augmentation at 50-120 Hz involved the modality-specific sensory cortices during stimulus presentation and inferior-Rolandic regions during responses. Gamma-augmentation in the bilateral occipital and inferior/medial-temporal regions was more intense in the picture-naming than auditory-naming task, whereas that in the bilateral superior temporal, left middle-temporal, left inferior-parietal, and left frontal regions was more intense in the auditory-naming task. Patients above 10 years old, compared to those younger, showed more extensive gamma-augmentation in the left dorsolateral-premotor region. Resection of sites showing naming-related gamma augmentation in the left hemisphere assumed to contain essential language function was associated with increased risk of post-operative language deficits requiring speech therapy (p < 0.05). CONCLUSIONS: Measurement of gamma augmentation elicited by either naming task was useful to predict postoperative language deficits. SIGNIFICANCE: A smaller degree of frontal engagement in the picture-naming task can be explained by no requirement of syntactic processing or less working memory load. More extensive gamma-augmentation in the left dorsolateral-premotor region in older individuals may suggest more proficient processing by the mature brain. PMID- 23688920 TI - Neonatal NMDA receptor blockade alters anxiety- and depression-related behaviors in a sex-dependent manner in mice. AB - There is increasing evidence that N-methyl-D-aspartate (NMDA) receptor blockade in the neonatal period has a long-lasting influence on brain and behavior development and has been linked to an increased risk for neuropsychiatric disorders in later life. We sought to determine whether postnatal NMDA receptor blockade can affect normal development of body weight, corticosterone levels, anxiety- and depression-related behaviors in male and female mice in adulthood. For this purpose, male and female NMRI mice were treated with either saline or phencyclidine (PCP; 5 and 10 mg/kg, s.c.) on postnatal days (PND) 7, 9, and 11, and then subjected to different behavioral tests, including open field, elevated plus-maze, elevated zero-maze, light-dark box, tail suspension test and forced swimming test in adulthood. The results indicated that neonatal PCP treatment reduced body weight during neonatal and adulthood periods, and did not alter baseline corticosterone levels in both male and female mice. Moreover, this study obtained some experimental evidence showing the PCP at dose of 10 mg/kg increases stress-induced corticosterone levels, anxiety- and depression-related behaviors in males, while decreasing levels of anxiety without any significant effect on depression in female mice in adulthood. These data support the argument that neonatal NMDA receptor blockade can lead to behavioral abnormalities and psychiatric diseases in adulthood. Collectively, our findings suggest that neonatal exposure to PCP may have profound effects on the development of anxiety- and depression-related behaviors in a sex- and dose-dependent manner in mice. PMID- 23688921 TI - MK-801 disrupts and nicotine augments 40 Hz auditory steady state responses in the auditory cortex of the urethane-anesthetized rat. AB - Patients with schizophrenia show marked deficits in processing sensory inputs including a reduction in the generation and synchronization of 40 Hz gamma oscillations in response to steady-state auditory stimulation. Such deficits are not readily demonstrable at other input frequencies. Acute administration of NMDA antagonists to healthy human subjects or laboratory animals is known to reproduce many sensory and cognitive deficits seen in schizophrenia patients. In the following study, we tested the hypothesis that the NMDA antagonist MK-801 would selectively disrupt steady-state gamma entrainment in the auditory cortex of urethane-anesthetized rat. Moreover, we further hypothesized that nicotinic receptor activation would alleviate this disruption. Auditory steady state responses were recorded in response to auditory stimuli delivered over a range of frequencies (10-80 Hz) and averaged over 50 trials. Evoked power was computed under baseline condition and after vehicle or MK-801 (0.03 mg/kg, iv). MK-801 produced a significant attenuation in response to 40 Hz auditory stimuli while entrainment to other frequencies was not affected. Time-frequency analysis revealed deficits in both power and phase-locking to 40 Hz. Nicotine (0.1 mg/kg, iv) administered after MK-801 reversed the attenuation of the 40 Hz response. Administered alone, nicotine augmented 40 Hz steady state power and phase locking. Nicotine's effects were blocked by simultaneous administration of the alpha4beta2 antagonist DHbetaE. Thus we report for the first time, a rodent model that mimics a core neurophysiological deficit seen in patients with schizophrenia and a pharmacological approach to alleviate it. PMID- 23688923 TI - Connexin43 confers Temozolomide resistance in human glioma cells by modulating the mitochondrial apoptosis pathway. AB - Glioblastoma multiforme (GBM) is the most aggressive astrocytoma, and therapeutic options are generally limited to surgical resection, radiotherapy, and Temozolomide (TMZ) chemotherapy. TMZ is a DNA alkylating agent that causes DNA damage and induces cell death. Unfortunately, glioma cells often develop resistance to TMZ treatment, with DNA de-methylation of the MGMT promoter identified as the primary reason. However, the contributions from proteins that normally protect cells against cytotoxic stress in TMZ-induced apoptosis have not been extensively explored. Here, we showed that increasing the level of the gap junction protein, Cx43, in human LN18 and LN229 glioma cells enhances resistance to TMZ treatment while knockdown of Cx43 in these same cells sensitizes them to TMZ treatment. By expressing a channel-dead or a C-terminal truncation mutant of Cx43, we show that Cx43-mediated TMZ resistance involves both channel dependent and independent functions. Expression of Cx43 in LN229 cells decreases TMZ induced apoptosis, as determined by Annexin V staining. Cx43-mediated chemoresistance appears to be acting via a mitochondrial apoptosis pathway as manifested by the reduction in Bax/Bcl-2 ratio and the release of cytochrome C. Our findings highlight additional mechanisms and proteins that contribute to TMZ resistance, and raise the possibility of increasing TMZ efficiency by targeting Cx43 protein. This article is part of the Special Issue Section entitled 'Current Pharmacology of Gap Junction Channels and Hemichannels'. PMID- 23688922 TI - A role for alpha4(non-alpha6)* nicotinic acetylcholine receptors in motor behavior. AB - Nicotinic acetylcholine receptors (nAChRs) containing either the alpha4 and/or alpha6 subunit are robustly expressed in dopaminergic nerve terminals in dorsal striatum where they are hypothesized to modulate dopamine (DA) release via acetylcholine (ACh) stimulation from cholinergic interneurons. However, pharmacological blockade of nAChRs or genetic deletion of individual nAChR subunits, including alpha4 and alpha6, in mice, yields little effect on motor behavior. Based on the putative role of nAChRs containing the alpha4 subunit in modulation of DA in dorsal striatum, we hypothesized that mice expressing a single point mutation in the alpha4 nAChR subunit, Leu9'Ala, that renders nAChRs hypersensitive to agonist, would exhibit exaggerated differences in motor behavior compared to WT mice. To gain insight into these differences, we challenged WT and Leu9'Ala mice with the alpha4beta2 nAChR antagonist dihydro beta-erythroidine (DHbetaE). Interestingly, in Leu9'Ala mice, DHbetaE elicited a robust, reversible motor impairment characterized by hypolocomotion, akinesia, catalepsy, clasping, and tremor; whereas the antagonist had little effect in WT mice at all doses tested. Pre-injection of nicotine (0.1 mg/kg) blocked DHbetaE induced motor impairment in Leu9'Ala mice confirming that the phenotype was mediated by antagonism of nAChRs. In addition, SKF82958 (1 mg/kg) and amphetamine (5 mg/kg) prevented the motor phenotype. DHbetaE significantly activated more neurons within striatum and substantia nigra pars reticulata in Leu9'Ala mice compared to WT animals, suggesting activation of the indirect motor pathway as the circuit underlying motor dysfunction. ACh evoked DA release from Leu9'Ala striatal synaptosomes revealed agonist hypersensitivity only at alpha4(non alpha6)* nAChRs. Similarly, alpha6 nAChR subunit deletion in an alpha4 hypersensitive nAChR (Leu9'Ala/alpha6 KO) background had little effect on the DHbetaE-induced phenotype, suggesting an alpha4(non-alpha6)* nAChR-dependent mechanism. Together, these data indicate that alpha4(non-alpha6)* nAChR have an impact on motor output and may be potential molecular targets for treatment of disorders associated with motor impairment. PMID- 23688925 TI - BDNF and memory processing. AB - Brain-derived neurotrophic factor has emerged as one of the most important molecules involved in memory. Its wide role in different types of memories that depend on different structures as well as its involvement in distinct memory stages points at BDNF as one likely target to treat cognitive impairments and anxiety-related memory disorders. However, regulation of BDNF expression is very complex as well as its modes of action. Here we describe the latest research carried out on the function of BDNF in memory to illustrate such complexity. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'. PMID- 23688924 TI - Cocaine represses protein phosphatase-1Cbeta through DNA methylation and Methyl CpG Binding Protein-2 recruitment in adult rat brain. AB - Repeated cocaine exposure induces epigenetic factors such as DNA methyl-binding proteins, indicating that resulting changes in gene expression are mediated by alterations in brain DNA methylation. While the activity of protein phosphatase type-1 (PP1) is involved in cocaine effects and in brain plasticity, the expression of the PP1Cbeta catalytic subunit gene was identified here as modulated by cocaine. Its expression was induced together with that of PP1Cgamma in the brain of Methyl-CpG Binding Protein-2 (Mecp2) mutant mice, whereas PP1Calpha expression was not affected, illustrating a different regulation of PP1C isoforms. Repeated cocaine administration was found to increase DNA methylation at the PP1Cbeta gene together with its binding to Mecp2 in rat caudate putamen, establishing a link between two genes involved in cocaine related effects and in learning and memory processes. Cocaine also increased DNMT3 expression, resulting in PP1Cbeta repression that did not occur in the presence of DNMT inhibitor. Cocaine-induced PP1Cbeta repression was observed in several brain structures, as evaluated by RT-qPCR, immunohistochemistry and Western blot, but did not occur after a single cocaine injection. Our data demonstrate that PP1Cbeta is a direct MeCP2-target gene in vivo. They suggest that its repression may participate to behavioral adaptations triggered by the drug. PMID- 23688926 TI - The function of BDNF in the adult auditory system. AB - The inner ear of vertebrates is specialized to perceive sound, gravity and movements. Each of the specialized sensory organs within the cochlea (sound) and vestibular system (gravity, head movements) transmits information to specific areas of the brain. During development, brain-derived neurotrophic factor (BDNF) orchestrates the survival and outgrowth of afferent fibers connecting the vestibular organ and those regions in the cochlea that map information for low frequency sound to central auditory nuclei and higher-auditory centers. The role of BDNF in the mature inner ear is less understood. This is mainly due to the fact that constitutive BDNF mutant mice are postnatally lethal. Only in the last few years has the improved technology of performing conditional cell specific deletion of BDNF in vivo allowed the study of the function of BDNF in the mature developed organ. This review provides an overview of the current knowledge of the expression pattern and function of BDNF in the peripheral and central auditory system from just prior to the first auditory experience onwards. A special focus will be put on the differential mechanisms in which BDNF drives refinement of auditory circuitries during the onset of sensory experience and in the adult brain. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'. PMID- 23688928 TI - Squamous suture--a rare case of asymmetrical closure with review of literature. AB - Cranial sutures give a wide estimate of age and asymmetric closure of sutures is likely to further complicate the process of age estimation from the closure of cranial sutures. Literature on the estimation of age from squamous suture is limited. A rare case of asymmetric closure of squamous suture is reported along with a review of literature. The reported case highlights on the fact that asymmetric closure of the sutures may cause inaccuracies in age estimation when only one half of the skull is available for forensic examination. Asymmetric closure of sutures may also lead to erroneous opinion on the number of individuals in cases when fragments of skull are brought for medicolegal investigation. PMID- 23688929 TI - Fever after therapeutic hypothermia - does rebound pyrexia matter? PMID- 23688930 TI - MicroRNAs linking inflamm-aging, cellular senescence and cancer. AB - Epidemiological and experimental data demonstrate a strong correlation between age-related chronic inflammation (inflamm-aging) and cancer development. However, a comprehensive approach is needed to clarify the underlying molecular mechanisms. Chronic inflammation has mainly been attributed to continuous immune cells activation, but the cellular senescence process, which may involve acquisition of a senescence-associated secretory phenotype (SASP), can be another important contributor, especially in the elderly. MicroRNAs (miRs), a class of molecules involved in gene expression regulation, are emerging as modulators of some pathways, including NF-kappaB, mTOR, sirtuins, TGF-beta and Wnt, that may be related to inflammation, cellular senescence and age-related diseases, cancer included. Interestingly, cancer development is largely avoided or delayed in centenarians, where changes in some miRs are found in plasma and leukocytes. We identified miRs that can be considered as senescence-associated (SA-miRs), inflammation-associated (inflamma-miRs) and cancer-associated (onco-miRs). Here we review recent findings concerning three of them, miR-21, -126 and -146a, which target mRNAs belonging to the NF-kappaB pathway; we discuss their ability to link cellular senescence, inflamm-aging and cancer and their changes in centenarians, and provide an update on the possibility of using miRs to block accumulation of senescent cells to prevent formation of a microenvironment favoring cancer development and progression. PMID- 23688931 TI - Epigenetic mechanisms in Alzheimer's disease: implications for pathogenesis and therapy. AB - The vast majority of Alzheimer's disease (AD) are late-onset forms (LOAD) likely due to the interplay of environmental influences and individual genetic susceptibility. Epigenetic mechanisms, including DNA methylation, histone modifications and non-coding RNAs, constitute dynamic intracellular processes for translating environmental stimuli into modifications in gene expression. Over the past decade it has become increasingly clear that epigenetic mechanisms play a pivotal role in aging the pathogenesis of AD. Here, we provide a review of the major mechanisms for epigenetic modification and how they are reportedly altered in aging and AD. Moreover, we also consider how aberrant epigenetic modifications may lead to AD pathogenesis, and we review the therapeutic potential of epigenetic treatments for AD. PMID- 23688932 TI - Theory and simulation. PMID- 23688927 TI - Addiction science: Uncovering neurobiological complexity. AB - Until very recently addiction-research was limited by existing tools and strategies that were inadequate for studying the inherent complexity at each of the different phenomenological levels. However, powerful new tools (e.g., optogenetics and designer drug receptors) and high throughput protocols are starting to give researchers the potential to systematically interrogate "all" genes, epigenetic marks, and neuronal circuits. These advances, combined with imaging technologies (both for preclinical and clinical studies) and a paradigm shift toward open access have spurred an unlimited growth of datasets transforming the way we investigate the neurobiology of substance use disorders (SUD) and the factors that modulate risk and resilience. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23688933 TI - Computational methods for high resolution prediction and refinement of protein structures. AB - We review advances in implicit solvation and sampling algorithms which have resulted in enhanced capabilities in predicting and refining localized protein structures (e.g. loop regions) to high resolution. Improvements in the generalized Born model and hydrophobicity term yield significantly more accurate energetics; specialized sampling algorithms allow complex local structures, such as a loop-helix-loop region, to be reliably predicted. A novel penalty term is added for loops containing patterns of dihedrals seldom found in experimental structures. We show prediction of diverse sets of large loops, in the native backbone environment, to subangstrom accuracy. The methodology offers the promise of addressing the refinement problem in homology modeling if an approach can be devised to handle delocalized errors in the structure. PMID- 23688934 TI - Six-month IVUS and two-year clinical outcomes in the EVOLVE FHU trial: a randomised evaluation of a novel bioabsorbable polymer-coated, everolimus-eluting stent. AB - Aims: The EVOLVE FHU trial demonstrated non-inferiority of six-month late loss with two dose formulations of SYNERGY, a novel bioabsorbable polymer everolimus eluting stent (EES) compared with the durable polymer PROMUS Element (PE) EES. The current analysis describes the six-month IVUS and clinical results through two years from the EVOLVE FHU trial. Methods and results: EVOLVE recruited 291 patients from 29 centres. At six months, IVUS-assessed in-stent net volume obstruction was 3.40+/-5.06% for PROMUS Element (PE) vs. 2.68+/-4.60% for SYNERGY (p=0.34) and 3.09+/-4.29% for SYNERGY 1/2 dose (p=0.68 vs. PE). There were no significant differences between groups for any other measured IVUS parameter including resolved, persistent, and late-acquired incomplete stent apposition (ISA). At two years, target lesion failure (TLF) was 6.1% for PE vs. 5.5% for SYNERGY (p=0.87) and 5.2% for SYNERGY 1/2 dose (p=0.81). There were no significant differences between groups for cardiac death, repeat revascularisation, MI or stent thrombosis through two years. Conclusions: At six months, everolimus delivered from an ultrathin bioabsorbable abluminal polymer resulted in equivalent net volume obstruction and ISA compared with a permanent polymer EES. There were no significant differences between PE and either SYNERGY stent for any major cardiac endpoint through two years. Clinical trials number: NCT01135225. PMID- 23688935 TI - Performing native mass spectrometry analysis on therapeutic antibodies. AB - Since the introduction of "soft" ionization techniques, the role of mass spectrometry (MS) in the field of structural biology has increasingly expanded. With the incorporation of volatile buffers as electrospray ionization (ESI) solvents, non-covalent protein complexes could be efficiently transferred to the gas phase for mass analysis. While native MS has not become a technique used for standard characterization of therapeutic proteins in an industrial setting, it is increasingly used to probe the structural heterogeneity of these complex biomolecules. Here, we describe a detailed sample protocol for the analysis of monoclonal antibodies (mAbs) by native MS and highlight some recent applications of native MS in the analysis of intact mAbs and mAb-based therapeutics. PMID- 23688936 TI - Comparison of the effects of extracts from three Vitex plant species on Anopheles gambiae s.s. (Diptera: Culicidae) larvae. AB - Acetone and methanol extracts of different parts of three Vitex species (leaves and stem bark of Vitex trifolia, leaves, stem bark and root bark of Vitex schiliebenii and stem and root bark of Vitex payos) were evaluated for their potential to control Anopheles gambiae Giles s.s. larvae (Diptera: Culicidae). The extracts gave different levels and rate of mortality of the larvae. Some (methanol extract of V. trifolia leaves, acetone extracts of stem bark and leaves of V. schiliebenii, acetone extract of root bark of V. payos) caused 100% mortality at 100 ppm in 72 h, with those of V. schiliebenii and V. payos showing faster rate of mortality (LT50=8 h) than that of V. trifolia (LT50=14 h). At lower doses of these extracts (<=50 ppm), most of the larvae failed to transform to normal pupae but gave larval-pupal intermediates between 4 and 14 days of exposure. Some pupated normally but the adults that emerged appeared to be weak and died within 48 h. Extracts of the stem bark of V. payos showed interesting effects on the larvae. Initially, the larvae were relatively hyperactive compared to those in control treatments. Later, the ones that did not transform to larval pupal intermediates became stretched and inactive and died and floated in clusters on the surface. These observations suggest some interesting growth disrupting constituents in the plants, with possible application in the practical control of mosquito larvae in aquatic ecosystems. PMID- 23688937 TI - Diagnosis and management of life-threatening cardiac malformations in the newborn. AB - Approximately 1-2 per 1000 newborn babies have a cardiac defect that is potentially life-threatening usually because either the systemic or the pulmonary blood flow is dependent on a patent ductus arteriosus. A significant proportion of newborns with such cardiac defects are being discharged from well-baby nurseries without a diagnosis and therefore risk circulatory collapse and death. This risk is greatest for defects with duct-dependent systemic circulation, notably aortic arch obstruction, but is also significant in transposition of the great arteries, for example. The solution to this problem, apart from improving prenatal detection rates, is to introduce effective neonatal screening including routine pulse oximetry. PMID- 23688939 TI - Feeding the immune system. AB - A well-functioning immune system is key to providing good defence against pathogenic organisms and to providing tolerance to non-threatening organisms, to food components and to self. The immune system works by providing an exclusion barrier, by identifying and eliminating pathogens and by identifying and tolerating non-threatening sources of antigens, and by maintaining a memory of immunological encounters. The immune system is complex involving many different cell types distributed throughout the body and many different chemical mediators some of which are involved directly in defence while others have a regulatory role. Babies are born with an immature immune system that fully develops in the first few years of life. Immune competence can decline with ageing. The sub optimal immune competence that occurs early and late in life increases susceptibility to infection. Undernutrition decreases immune defences, making an individual more susceptible to infection. However, the immune response to an infection can itself impair nutritional status and alter body composition. Practically all forms of immunity are affected by protein-energy malnutrition, but non-specific defences and cell-mediated immunity are most severely affected. Micronutrient deficiencies impair immune function. Here, vitamins A, D and E, and Zn, Fe and Se are discussed. The gut-associated lymphoid tissue is especially important in health and well-being because of its close proximity to a large and diverse population of organisms in the gastrointestinal tract and its exposure to food constituents. Certain probiotic bacteria which modify the gut microbiota enhance immune function in laboratory animals and may do so in human subjects. PMID- 23688938 TI - Newly emerging therapies for neonatal seizures. AB - The treatment of neonatal seizures has not changed significantly over the last 50 years despite advances in antiepileptic drug (AED) development for older children and adults. Recently new drugs have emerged some of which address age-specific challenges or mechanisms and will be discussed in this review. The loop diuretic bumetanide blocks the neuronal NKCC1 co-transporter and is thought specifically to supress seizures in the immature brain. Levetiracetam has been used in children and infants with good efficacy, an excellent safety profile, and near ideal pharmacokinetic characteristics. Randomised controlled trials are now underway to test the efficacy of some newer AEDs for neonatal seizures. Topiramate has been shown to have neuroprotective properties in addition to its antiepileptic action and trials in babies with hypoxic-ischaemic encephalopathy are now planned. There is an urgent need to develop age-specific AEDs for preterm and term babies. These drugs must be evaluated with multicentre, collaborative trials using innovative methods and high ethical standards to overcome age specific challenges with the ultimate aim of improving the outcome for neonates with seizures. PMID- 23688940 TI - Catheter-based bailout techniques for an interrupted deployment of the excluder endograft due to broken deployment string. AB - In this report we describe catheter-based bailout techniques for when the distal end of the ipsilateral leg of an Excluder endograft has remained undeployed due to a broken deployment string. We attempted to advance a percutaneous transluminal angioplasty (PTA) balloon into an undeployed leg via the brachial artery, but were unable to do so. The delivery catheter was then pulled out through the undeployed leg while the main body was supported by a dilated touch up balloon to prevent stent graft migration, which subsequently enabled insertion of the balloon via the ipsilateral femoral artery. Complete deployment was accomplished by balloon dilation. Although this is situation is extremely rare, it should be recognized and catheter-based strategies should be known for dealing with this complication. PMID- 23688941 TI - A novel strategy of vascular reconstruction after radical resection of an inferior vena cava leiomyosarcoma. AB - BACKGROUND: Vascular reconstruction after resection of a inferior vena cava (IVC) leiomyosarcoma remains a major challenge. In this study we describe a case of successful vascular reconstruction using a novel approach. METHODS: A patient underwent the surgical resection of an IVC tumor. The caudal stump of the IVC was then anastomosed to an 18-mm Dacron graft with bilateral 8-mm arms, which were anastomosed to the bilateral renal veins, respectively. RESULTS: Complete resolution of abdominal pain was achieved and the patient did well throughout the 12-month follow-up. No recurrent clinical symptoms were observed. Renal function was well maintained. CONCLUSIONS: This novel vascular reconstruction approach may be a feasible, effective surgical strategy for preservation of renal function for IVC leiomyosarcoma. PMID- 23688942 TI - Successful endovascular treatment of a bronchial artery aneurysm refractory to transcatheter embolization. AB - Bronchial artery aneurysm (BAA) is a rare entity, detected in <1% of all patients who undergo selective bronchial arteriography. BAAs are potentially life threatening when untreated. We describe the first BAA case, in the English language, treated only by thoracic aorta endografting, with an uneventful postoperative course with exclusion and thrombosis of the BAA. The endovascular stent graft provides a safe, reliable tool complementing the armamentarium of surgical and percutaneous techniques in the treatment of patients with BAA. PMID- 23688943 TI - Spontaneous femoral artery pseudoaneurysm in a young patient. AB - Spontaneous femoral artery pseudoaneurysm is a rare disease and reported cases are very rare. Most of them are related to an underlying pathology of either atherosclerotic disease or connective tissue disease. We present a healthy, 29 year-old man with 2-month history of a painful pulsating mass at the level of the lower right thigh with no previous history of trauma, surgery, or puncture of the femoral artery. An angiogram revealed a right superficial femoral artery pseudoaneurysm. It was treated surgically by resection of the aneurysm and reconstruction with an interpositional saphenous vein graft. We report this case because of the rarity of this condition in a young patient with no underlying pathology. PMID- 23688944 TI - A patient with narcolepsy with cataplexy and multiple sclerosis: two different diseases that may share pathophysiologic mechanisms? PMID- 23688945 TI - Relationship of depression, stress and endothelial function in stable angina patients. AB - Endothelial dysfunction has been considered as one of potential mechanisms by which depression and stress might contribute to the development of coronary artery disease (CAD). Recent studies suggest that circulating endothelial progenitor cells (EPCs) and brachial artery flow-mediated dilation (FMD) are related to endothelial function and progression of CAD. We investigated the relationships between the level of circulating CD34/KDR(+) EPCs and CD133/KDR(+) EPCs, brachial FMD, and scores of depression and stress measured with the Depression Anxiety Stress Scales in 288 stable angina patients without major psychiatric disorders. As defined by the >=75th percentile, 100 (35%) subjects had high depression score (>=8), and 84 (29%) subjects had high stress score (>=10). Subjects with high depression or stress score had significantly lower FMD (1.86+/-0.14 vs. 3.63+/-0.17%, p<0.001; 2.05+/-0.18 vs. 3.48+/-0.17%, p<0.001) and percentage of circulating CD34/KDR(+) EPCs (0.97+/-0.11 vs. 1.94+/-0.17%, p<0.001; 1.09+/-0.13 vs. 1.68+/-0.16%, p=0.005), but not CD133/KDR(+) EPCs (0.52+/-0.04 vs. 0.66+/-0.06%, p=0.057; 0.61+/-0.05 vs. 0.59+/-0.05%, p=0.833), as compared with subjects with normal depression or stress score. Multivariate regression analysis indicated that high depression score (OR 1.09, 95% CI: 1.04 1.15, p<0.001), but not stress score or percentage of circulating EPCs, independently predicted impaired brachial FMD. In conclusions, our results demonstrated that in stable angina patients without major psychiatric disorders, a high depression or stress score was related to attenuated brachial FMD and depletion of circulating EPCs. However, only the depression score, but not the stress score or the level of EPCs, was an independent predictor for decreased brachial FMD. PMID- 23688946 TI - Tenuigenin ameliorates learning and memory impairments induced by ovariectomy. AB - Estrogen deficiency is associated with cognitive impairment. Hormone replacement therapy (HRT) has proven to be effective in preventing and reversing the memory and learning deficiencies. However, conventional estrogenic treatment could increase the risks of breast cancer and venous thromboembolism. Tenuigenin (TEN) is putatively believed as the active component extracted from a Chinese herb Polygala tenuifolia root. Although TEN has been shown to enhance learning and memory in healthy mice, it remains unknown whether or not TEN could ameliorate learning and memory impairments. In the present study, mice were divided into four groups: sham-operated (sham), ovariectomized (OVX), OVX+estradiol benzoate (EB) and OVX+TEN groups. Step-through passive avoidance and Y-maze tests were used to assess learning and memory abilities, and the number of nitric oxide synthase (NOS) positive neurons and the synaptic measurement of hippocampal CA1 area were examined. The results showed that TEN was given orally to OVX mice, leading to the improvement of learning and memory in step-through passive avoidance and Y-maze tests. TEN could reduce the loss of NOS positive neurons and prevent the synaptic morphological changes induced by ovariectomy. Our results suggest that TEN may exert a potential therapeutic value for menopause cognitive dysfunction. PMID- 23688947 TI - Inducing physiological stress recovery with sounds of nature in a virtual reality forest--results from a pilot study. AB - Experimental research on stress recovery in natural environments is limited, as is study of the effect of sounds of nature. After inducing stress by means of a virtual stress test, we explored physiological recovery in two different virtual natural environments (with and without exposure to sounds of nature) and in one control condition. Cardiovascular data and saliva cortisol were collected. Repeated ANOVA measurements indicated parasympathetic activation in the group subjected to sounds of nature in a virtual natural environment, suggesting enhanced stress recovery may occur in such surroundings. The group that recovered in virtual nature without sound and the control group displayed no particular autonomic activation or deactivation. The results demonstrate a potential mechanistic link between nature, the sounds of nature, and stress recovery, and suggest the potential importance of virtual reality as a tool in this research field. PMID- 23688948 TI - Effect of chronic administration of tamoxifen and/or estradiol on feeding behavior, palatable food and metabolic parameters in ovariectomized rats. AB - Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) used in the treatment of breast cancer; however many women complain of weight gain during TAM treatment. The anorectic effects of estradiol (E) and TAM are well known, although the effects of E on the consumption of palatable food are controversial and there is no information regarding the effects of TAM on palatable food consumption. The aim of this study was to investigate the effects of chronic treatment with estradiol and/or tamoxifen on feeding behavior in ovariectomized rats exposed to standard chow and palatable foods (Froot Loops(r) or chocolate). Additionally, parameters such as body weight, uterine weight, lipid profile and plasma glucose were also measured. Wistar rats were ovariectomized (OVX) and subsequently injected (ip.) for 40 days with: E, TAM, E+TAM or vehicle (OVX and SHAM - controls). Behavioral tests were initiated 25 days after the start of treatment. Froot Loops(r) consumption was evaluated in a novel environment for 3 min. Standard chow intake was evaluated for two days and chocolate intake for 7 days in the home cage in a free choice model (chocolate or standard chow). Rats injected with E, TAM and E+TAM groups showed a reduction in body weight and standard chow intake, compared with control groups. With regard to palatable food intake, the E, TAM and E+TAM groups demonstrated increased consumption of Froot Loops(r), compared with the SHAM and OVX groups. In contrast, all groups increased their consumption of chocolate, compared with standard chow; however the E group consumed more chocolate than the OVX, TAM and E+TAM groups. Despite these differences in chocolate consumption, all groups showed the same caloric intake during the chocolate exposure period; however the TAM and E+TAM groups presented decreased body weight. Treatment with estradiol and tamoxifen showed a favorable lipid profile with low levels of TC, LDL, LDL/HDL ratio and lower levels of plasma glucose. The E group presented high levels of TG and HDL, when compared with the TAM and E+TAM groups. Taken together, results suggest that TAM acted in an estrogen-like manner on the majority of parameters analyzed. However, tamoxifen acts in a different manner depending on the type of palatable food and the exposure. In addition, the TAM group demonstrated weight loss, compared with other groups independently of the type of food presented (palatable food or standard chow), showing a low caloric efficiency. PMID- 23688949 TI - Protein and lipid oxidative damage in healthy students during and after exam stress. AB - Oxidative damage at cellular level is thought to be one of the mechanisms in the pathogenesis of psychological stress (anxiety). The aim of this study was to investigate lipid and protein oxidative damage in exam anxiety conditions. Blood samples were collected in two stages (during the exam period and post vacation) from 51 healthy female students after responding to Beck Anxiety Inventory (BAI) and test anxiety questionnaire. Protein carbonyl, total thiol and malondialdehyde (MDA) levels were determined in serum. Participants reported significantly higher levels of subjective anxiety during the exam period than post vacation. Also the level of total thiol was significantly lower during the exam period compared with post vacation (p<0.001). Meanwhile, protein carbonyl and MDA levels during the exams were significantly higher than those in post-exam period (p<0.01). During the exam period, there was a negative correlation between serum total thiol levels and the severity of anxiety (r=-0.45, p<0.01). A significant positive correlation between the changes in serum protein carbonyl and MDA levels, also between those markers and anxiety score was found during the exam period. The high level of protein carbonyl and MDA, also low level of total thiol during the exam period demonstrated an oxidative damage to proteins and lipids in stress conditions. Our results suggest that oxidative damage to cellular compounds may be one of the mechanisms involved in the pathogenesis of anxiety. PMID- 23688950 TI - The effect of cocaine on rotarod performance in male C57BL/6J mice. AB - There is surprisingly little research examining the effect of cocaine on motor learning. Given that changes in motor activity can confound behavioral assays of learning and memory a direct assessment of cocaine on motor learning seems warranted. The present study was conducted to examine the effect of cocaine on motor learning using an accelerating rotarod test in adult male C57BL/6J mice. Mice were given an injection of either saline or cocaine (10mg/kg, i.p.) for 6 consecutive days prior to rotarod training (Pre-exposure). In the first phase of training (Phase I), mice were given an injection of either saline or cocaine 10min prior to the start of each day's training on the rotarod for 6 consecutive days. In the second phase (Phase II), half the animals continued to receive the same drug during training, while the other half were switched from saline to cocaine or from cocaine to saline. All mice exhibited motor learning as evidenced by an increased latency to fall across days. Animals that received cocaine injections exhibited significantly longer latencies to fall on days 3-6 compared to those mice receiving saline. This enhanced performance was lost when cocaine injected animals were switched to saline on day 7. It is hypothesized that the performance enhancing effects of cocaine are due to the increased stamina and/or psychomotor stimulation and not the result of enhanced motor learning as the increment in performance was lost when the drug was discontinued. PMID- 23688951 TI - A review of metal (Pb and Zn) sensitive and pH tolerant bioassay organisms for risk screening of metal-contaminated acidic soils. AB - To improve risk estimates at the screening stage of Ecological Risk Assessment (ERA), short duration bioassays tailored to undisturbed soil cores from the contaminated site could be useful. However, existing standardized bioassays use disturbed soil samples and often pH sensitive organisms. This is a problem as naturally acidic soils are widespread. Changing soil properties to suit the test organism may change metal bioavailability, leading to erroneous risk estimates. For bioassays in undisturbed soil cores to be effective, species able to withstand natural soil properties must be identified. This review presents a critical examination of bioassay species' tolerance of acidic soils and sensitivity to metal contaminants such as Pb and Zn. Promising organisms include; Dendrobaena octaedra, Folsomia candida, Caenorhabditis elegans, Oppia nitens, Brassica rapa, Trifolium pratense, Allium cepa, Quercus rubra and Acer rubrum. The MetSTICK test and the Bait lamina test were also identified as suitable microorganism tests. PMID- 23688952 TI - Kinetic control of contaminant release from NAPLs--information potential of concentration time profiles. AB - Release of contaminants from non-aqueous phase liquids (NAPLs) is often limited by the dynamic exchange with aqueous solutions governed by a priori unknown kinetic laws. Release experiments require a thorough evaluation of the potential and limitations of kinetic models to reveal release processes. In this study, we investigated the characteristic concentration-time profiles of various models for the release of contaminants from an organic phase into an aqueous solution under no flow conditions. Criteria have been tested that allow for distinction of a first order one domain, a first order two domain, a spherical diffusion model, a spherical diffusion model with a time variable diffusion coefficient, a model for diffusion in a sphere with organic film, and a model for diffusion in a sphere with an aqueous film. The results can serve to evaluate the processes potentially governing release of organic contaminants from non-aqueous liquid phases. PMID- 23688954 TI - Rearranged limonoids and chromones from Harrisonia perforata and their anti inflammatory activity. AB - Two new rearranged limonoids, harperforatin (1) and harperfolide (2), and a new chromone, harperamone (3), were isolated from fruits and roots of Harrisonia perforata, together with eight known compounds. Their structures were elucidated on the basis of spectroscopic data. Harperfolide (2) exhibited potent anti inflammatory activity by suppressing nitric oxide (NO) production from activated macrophages with IC50 value of 6.51 MUM. Furthermore, its effect is mediated by reduction of iNOS protein expression, attributable to the inhibitory action of LPS-induced NO production. PMID- 23688955 TI - Metabolomics in rheumatic diseases: the potential of an emerging methodology for improved patient diagnosis, prognosis, and treatment efficacy. AB - Metabolomics belongs to the family of "-omics" sciences, also comprised of genomics, transcriptomics, and proteomics, all of which share the advantage of a non-targeted approach for identifying biomarkers and profiling the patient. This means that they do not require a preliminary knowledge of the substances to be studied. Moreover, even small quantities of biological fluids or tissues may be utilized for analysis. Metabolomic procedure has become feasible only recently with the advent and accessibility of new high-throughput technologies, including mass spectrometry and nuclear magnetic resonance. The methodology generally involves three defining steps: 1) the acquisition of experimental data, 2) the multivariate statistical analysis, and 3) the projection of the acquired information (profiles) to construct the patient map. Metabolomic analysis has been applied to several disorders: as far as rheumatic diseases are concerned, a few studies have focused on rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, and osteoarthritis. Both murine models and clinical data have shown the potential of this novel tool to contribute to deciding a diagnosis, discriminate between patients based on disease activity, and even predict the response to a particular treatment. The present review fully reports these findings and offers a critical view of the challenges still to be met. PMID- 23688957 TI - Pediatric thoracic paravertebral block: roentgenologic evidence for extensive dermatomal coverage. AB - A case of a 10 year old boy who underwent a T10 continuous thoracic paravertebral block (TPVB) using a standard technique for postoperative pain management is reported. In the postoperative recovery area, 10 mL of Omnipaque contrast dye was injected through the catheter and an anteroposterior chest radiograph was performed. The radiograph showed longitudinal spread of contrast parallel to the spine from the T(4)-T(5) intervertebral disc to the T(10)-T(11) intervertebral disc with clear lateral extension of contrast along the fifth through the tenth intercostal nerves. PMID- 23688956 TI - Clathrin-coated vesicles from brain have small payloads: a cryo-electron tomographic study. AB - Clathrin coats, which stabilize membrane curvature during endocytosis and vesicular trafficking, form highly polymorphic fullerene lattices. We used cryo electron tomography to visualize coated particles in isolates from bovine brain. The particles range from ~66 to ~134nm in diameter, and only 20% of them (all ?80nm) contain vesicles. The remaining 80% are clathrin "baskets", presumably artifactual assembly products. Polyhedral models were built for 54 distinct coat geometries. In true coated vesicles (CVs), most vesicles are offset to one side, leaving a crescent of interstitial space between the coat and the membrane for adaptor proteins and other components. The latter densities are fewer on the membrane-proximal side, which may represent the last part of the vesicle to bud off. A small number of densities - presumably cargo proteins - are associated with the interior surface of the vesicles. The clathrin coat, adaptor proteins, and vesicle membrane contribute almost all of the mass of a CV, with most cargoes accounting for only a few percent. The assembly of a CV therefore represents a massive biosynthetic effort to internalize a relatively diminutive payload. Such a high investment may be needed to overcome the resistance of membranes to high curvature. PMID- 23688958 TI - A case of cerebrospinal fluid leak in an infant after spinal anesthesia. AB - A 2 month old, 51 kg female infant underwent neuraxial anesthesia for repair of a right inguinal hernia. After two unsuccessful attempts at obtaining free-flowing cerebrospinal fluid (CSF) in the L(3)-L(4) lumbar interspace with a 25-gauge (G) neonatal spinal needle, clear CSF was obtained using a Quincke 22-G needle. After easy aspiration, a total of 0.7 mL of 0.75% hyperbaric bupivicaine was injected intrathecally. Immediately after the spinal block, a caudal epidural block was placed by injecting 2 mL of 0.25% bupivacaine with 1:200,000 using a 22-G Quincke spinal needle. Surgery and recovery were uneventful. Two days later, after a crying spell, a bulging, grape size swelling was noted in the infant's lumbar region. Examination was normal except that her fontanel was mildly depressed when she was upright, and a 1 - 1.5 cm soft, nontender swelling in her lumbar area bulged out when she strained. The bulge resolved over the next 48 hours. In the majority of neonates, CSF leaks into the epidural space after lumbar puncture. In our case, the patient showed CSF accumulation at the site of puncture. PMID- 23688959 TI - Anesthetic evaluation and management of a patient with thoracic endometriosis syndrome presenting for elective surgery. AB - Thoracic endometriosis syndrome is a relatively uncommon disorder characterized by recurrent pneumothoraces, hemothorax, chest pain, dyspnea, and hemoptysis within 48 to 72 hours of menstruation. A 34 year old, ASA physical status 2 woman with recurrent catamenial pneumothoraces due to thoracic endometriosis syndrome is presented. After treatment with video-assisted thoracoscopic surgery, she underwent successful elective diagnostic abdominal laparoscopy without incident. The presence of parenchymal injury and damage predisposes these patients to ventilator-induced lung injury. Postponement of surgery until the intermenstrual period, with lung protective ventilation, allows patients with this disease to successfully undergo general anesthesia and surgery. PMID- 23688960 TI - Perioperative management of a patient scheduled for bilateral hand transplant. AB - The perioperative management of a patient receiving a bilateral hand transplant is presented. The anesthetic management required careful fluid administration, homeothermic temperature maintenance, and postoperative analgesia. The role of different anesthesia subspecialties is highlighted. PMID- 23688961 TI - Perioperative management of a neurosurgical patient with a meningioma and recent coronary artery stent. AB - Patients who undergo placement of a drug-eluting coronary artery stent are prescribed dual antiplatelet therapy for one year. Early cessation of this therapy is a risk factor for a major adverse cardiac event, especially in high risk patients. The perioperative physician team must evaluate the risk of surgical bleeding relative to the thrombotic risk during the perioperative period in patients taking dual antiplatelet therapy who must undergo intracranial neurosurgery. A 67 year old woman presented with right-sided hearing loss. Neurologic examination was significant for early papilledema and decreased hearing in the right ear. Magnetic resonance imaging showed a > 5 cm contrast enhancing mass within her right-middle fossa with surrounding vasogenic edema and midline shift. Additional medical history was significant for diabetes, hypertension, and placement of a drug-eluting stent for coronary artery disease three months before her initial presentation. Medications included aspirin and clopidogrel. She underwent embolization of the middle meningeal arterial supply to the meningioma, then was admitted to the hospital for perioperative management of her antiplatelet therapy and telemetry monitoring. Her clopidogrel was stopped and aspirin continued perioperatively. An intravenous infusion of the antiplatelet drug, eptifibatide, replaced clopidogrel and was continued until 8 hours prior to surgical incision. During resection of the meningioma, no unusual surgical bleeding was noted. The patient was discharged on postoperative day 3 with satisfactory recovery. PMID- 23688962 TI - Do persons with schizophrenia who have better metacognitive capacity also have a stronger subjective experience of recovery? AB - Research suggests that persons with schizophrenia experience deficits in the ability to synthesize complex and integrated representations of themselves and others. While impairments in these metacognitive capacities are hypothetically related to the ability to make sense of the challenges of schizophrenia, little is known about their relationship with the subjective experience of recovery from mental illness. To examine this question, this study investigated whether persons with stronger self-reported recovery had better metacognitive capacity, after controlling for severity of psychiatric symptoms. Forty-six outpatients with schizophrenia spectrum disorders who were taking part in a study of the Illness Management and Recovery program were concurrently administered the Recovery Assessment Scale, the Positive and Negative Syndrome Scale, and the Indiana Psychiatric Illness Interview which was scored using the Abbreviated Metacognitive Assessment Scale. Analysis of covariance revealed that metacognitive capabilities reflecting self-reflectivity and decentration were differentially related to several components of recovery beyond the effects of psychiatric symptoms. The metacognitive abilities to think about oneself in a sophisticated way and form integrated ideas about oneself and others within the larger world, understanding that none are the metaphorical center are present in individuals holding strong perceptions of recovery. PMID- 23688963 TI - Identification, expression and bioactivity of Paramisgurnus dabryanus beta defensin that might be involved in immune defense against bacterial infection. AB - beta-defensins are a large family of multi-disulfide-bonded peptides with broad spectrum antimicrobial activities that contribute to innate host defense in many organisms, but little information is available about beta-defensins produced by freshwater fish lacking scales. We therefore cloned and identified a beta defensin gene from Chinese loach (Paramisgurnus dabryanus) by designing degenerate primers and using thermal asymmetric interlaced PCR. This gene is the first defensin gene ever identified in a non-scaled freshwater fish. Annotation of the protein domain architecture showed that the putative Chinese loach beta defensin contains the signature motif of six conserved cysteines within the mature peptide, an aspect similar to beta-defensins of other marine fish. We also used quantitative real-time PCR to investigate the expression pattern of the Chinese loach beta-defensin gene, mRNA of which could be observed in various tissues. After challenge with the pathogenic bacterium Aeromonas hydrophila, beta defensin expression was induced in the eye, gill, skin, and spleen of the adult loach. The bioactivity of the recombinant P. dabryanus beta-defensin was examined against pathogenic bacteria, and the results suggest that this class 2 beta defensin has potential applications for treatment of bacterial infections. PMID- 23688964 TI - Characterization of MIF family proteins: MIF and DDT from rock bream, Oplegnathus fasciatus. AB - Macrophage migration inhibitory factor (MIF) is a pleiotropic molecule playing vital roles in various signaling cascades, including cell proliferation, and activation of immune responses against infections. It is well known as a pivotal regulator of innate immunity. In this study, we have rescued and characterized two members of the MIF family, macrophage migration inhibitory factor (OfMIF) and D-Dopachrome tautomerase (OfDDT) from rock bream, Oplegnathus fasciatus. The deduced OfMIF and OfDDT protein sequences revealed the presence of the catalytic oxidoreductase (CXXC), motif. They also possessed highly conserved proline (P(2)) and lysine residues (K(33)), responsible for their isomerase and tautomerase functions. Rock bream MIF and DDT homologues shared higher identity with fish homologues and also with mammals and occupied a distinct position in the phylogenetic tree, depicting their evolutionary conservation. The spatial expression analysis revealed the highest expression of both OfMIF and OfDDT in liver, while portraying constitutive expression in other tissues. The recombinant proteins purified using the Escherichia coli system revealed potent oxidoreductase activity against insulin with both dithiothreitol and glutathione as reducing agents. Stimulation of rock bream head kidney cells with recombinant OfMIF and OfDDT proteins induced the expression of proinflammatory cytokines like tumor necrosis factor alpha (TNF-alpha), interleukin-8 (IL-8) and interleukin 1beta (IL-1beta). These results together suggest their involvement in rock bream immune defense and this study on the novel MIF family member DDT from rock bream will pave the way for further studies of this homologue in other teleosts and delineate its multiple functions. PMID- 23688965 TI - A fluorescence-based assay for the apurinic/apyrimidinic-site cleavage activity of human tyrosyl-DNA phosphodiesterase 1. AB - Tyrosyl-DNA phosphodiesterase 1 (Tdp1) catalyzes the hydrolysis of phosphodiester bonds between the DNA 3'-phosphate and tyrosine residues and plays a major role in the repair of stalled topoisomerase I-DNA covalent complexes. Given this role, Tdp1 is of interest as a potential target for anticancer therapy. Inhibiting Tdp1 in combination with clinically used Top1 inhibitors may potentiate the effects of the latter and help to overcome some of the chemoresistance issues currently observed. In addition, Tdp1 can function during DNA repair to remove a variety of other 3' adducts from DNA such as phosphoglycolates and abasic or apurinic/apyrimidinic (AP) sites. Here we describe a new mix-and-read homogeneous fluorogenic assay for the measurement of the AP-site cleavage activity of Tdp1 that is compatible with high-throughput screening. The application of such an assay will open up further avenues for the discovery of novel Tdp1 inhibitors. PMID- 23688966 TI - Plane thinking: mental representations in number line estimation as a function of orientation, scale, and counting proficiency. AB - Young children typically show strong biases when estimating the placement of numbers on or along a scale. Number line estimation changes in accuracy and linearity across development. However, existing research is almost entirely based on a horizontal number line, which presupposes that numbers are scaled on a horizontal plane only. We present data that broaden our understanding of number line estimation by also including vertically oriented scales. This study presented 4- to 7-year-olds with the number line estimation task presented in both horizontal and vertical orientations and on different scales. Our results suggest that children store numbers as accurately in the vertical plane as in the horizontal plane, although some developmental changes are observed. Our results highlight how even simple experimental manipulations can reveal the complexities of internal representations of number. PMID- 23688967 TI - Study on the leaching of phthalates from polyethylene terephthalate bottles into mineral water. AB - Carbonated and non-carbonated mineral water samples bottled in 0.5-L, 1.5-L and 2.0-L polyethylene terephthalate (PET) containers belonging to three different water brands commercialized in Hungary were studied in order to determine their phthalate content by gas chromatography-mass spectrometry. Among the six investigated phthalates, diisobutyl phthalate, di-n-butyl-phthalate, benzyl-butyl phthalate and di(2-ethyl-hexyl) phthalate (DEHP) were determined in non carbonated samples as follows: <3.0 ng L(-1)-0.2 MUg L(-1), <6.6 ng L(-1)-0.8 MUg L(-1), <6.0 ng L(-1)-0.1 MUg L(-1) and <16.0 ng L(-1)-1.7 MUg L(-1), respectively. Any of the above-mentioned phthalate esters could be detected in carbonated mineral water samples. DEHP was the most abundant phthalate in the investigated samples. It could be detected after 44 days of storage at 22 degrees C and its leaching was the most pronounced when samples were stored over 1200 days. Mineral water purchased in PET bottles of 0.5L had the highest phthalate concentrations compared to those obtained for waters of the identical brand bottled in 1.5-L or 2.0-L PET containers due to the higher surface/volume ratio. No clear trend could be established for phthalate leaching when water samples were kept at higher temperatures (max. 60 degrees C) showing improper storage conditions. Phthalate determination by pyrolysis-gas chromatography/mass spectrometric measurements in the plastic material as well as in the aqueous phase proved the importance of the quality of PET raw material used for the production of the pre-form (virgin vs. polymer containing recycled PET). PMID- 23688968 TI - Local vs. external contribution to the budget of pollutants in the Po Valley (Italy) hot spot. AB - Numerical experiments using both passive tracers and full chemistry were performed to investigate the budget of pollutants in the Po Valley hot spot, using the BOLCHEM integrated model of atmospheric dynamics and composition. A one year run was undertaken over the European domain, with a resolution of 50*50 km(2). Sources internal and external to the Po Valley were treated in separated runs. For the tracer experiment, the ratio between total masses of locally and externally emitted tracers showed that for half of the year the contribution from remote sources exceeds the local one. Although local sources prevailed at the ground level, external contribution exceedance was observed 15% of the time. Since the Po Valley is mostly surrounded by high mountains, vertical mixing and entrainment at the boundary layer top were found to be more effective than the advection at low levels. As the concentration of reacting species is affected by the nonlinearity of the transport-reaction mechanism, the results of the full chemistry runs with internal and external sources can be compared only in cases where this effect is weak. In these cases, the results for tracers were broadly confirmed for the less reacting species (CO, PM10) and, to some extent, also for more reactive ones (NO2, O3) for which more pronounced seasonal and diurnal cycles were found due to photochemical reactivity. PMID- 23688969 TI - Laryngeal sarcoidosis: a case report presenting transglottic involvement. AB - Isolated laryngeal sarcoidosis is a very rare disease. In most cases, it will present as a supraglottic pale edematous swelling. In our case, the patient presented with hoarseness and dyspnea during exertion. Laryngeal examination did show not only supraglottic edema but also prominent subglottic swelling and edematous true vocal folds. Histology showed noncaseating granulomas. After excluding other causes and localizations, the patient was diagnosed with laryngeal sarcoidosis and treated with systemic corticosteroid with good result. We describe our case of isolated transglottic sarcoidosis and discuss the disease, its presentation, diagnosis, and therapeutic options. PMID- 23688970 TI - Cytotoxic 9,11-secosteroids from the South China Sea gorgonian Subergorgia suberosa. AB - Ten new 9,11-secosteroids, subergorgols A-J (1-10), including two pairs of epimers (3/4, and 6/7), along with three known analogues (11-13) were isolated from the South China Sea gorgonian Subergorgia suberosa. The structures of these compounds were elucidated on the basis of extensive spectroscopic analyses and comparison with the literature data. The cytotoxicities in vitro against three selected human tumor cell lines for all the compounds were evaluated. Compound 9 showed significant cytotoxicities toward both K562 and MDA-MB-231 cell lines with IC50 values of 5.5 and 6.2MUM, respectively, and compound 10 also showed inhibitory activity against K562 cell line with an IC50 value of 6.5MUM. PMID- 23688971 TI - Overestimation of salivary 25-hydroxyvitamin D3 level when using stimulated saliva with gum-chewing. AB - BACKGROUND: The measurement of 25-hydroxyvitamin D3 [25(OH)D3] in whole saliva can be a noninvasive tool for assessing vitamin D status. Gum-chewing increases salivation and is often used to collect an adequate sample volume of saliva within a shorter time. The aim of this study was to clarify whether the concentration of 25(OH)D3 in whole saliva is influenced by gum-chewing. METHODS: Stimulated saliva was collected from healthy volunteers chewing a tasteless and flavorless chewing gum after unstimulated saliva was collected without gum chewing. The salivary 25(OH)D3 and albumin concentrations were measured. RESULTS: The salivary 25(OH)D3 concentration was reproducibly measured when saliva was collected without gum-chewing, whereas the concentration was significantly increased by gum-chewing (p<0.05, paired t-test). One of the causes for the gum chewing-induced increase in the 25(OH)D3 concentration may be the increased amount of protein-bound 25(OH)D3 in whole saliva. CONCLUSION: Stimulated saliva by gum-chewing should be used with caution in the measurement of 25(OH)D3. The protein binding rate in plasma is a significant consideration when predicting whether the salivary concentration of a compound is varied by gum-chewing. PMID- 23688972 TI - Quinine sulfate as a therapeutic option in a patient with slow channel congenital myasthenic syndrome. AB - Slow channel congenital myasthenic syndrome is caused by a genetically determined kinetic anomaly of the acetylcholine receptor at the neuromuscular junction leading to its prolonged open state. Patients typically present with fatigability and static weakness of neck, hand and finger extensors. The open-channel blockers fluoxetine and quinidine have been used as standard treatment, although the former is limited by its side effects. We describe a patient with a novel "de novo" mutation in the alpha subunit of acetylcholine receptor with clinical and electrophysiological hallmarks of the disease. The patient showed marked treatment response to fluoxetine as well as quinine, a stereoisomer of quinidine, expanding the treatment options for this hereditary disorder. PMID- 23688973 TI - Seizure outcomes of lesionectomy in pediatric lesional epilepsy with brain tumor - single institute experience. AB - PURPOSE: To determine the clinical characteristics, surgical strategy, and outcome in pediatric lesional epilepsy patients younger than 5years of age undergoing surgery in a single institute. METHOD: Retrospective data were collected and analyzed on patients younger than 5years of age who underwent lesionectomy for lesional epilepsy at single institute from January 2001 to August 2010. Fourteen pediatric lesional epilepsy patients were enrolled in this study. Engel classification was used to classify seizure outcome. RESULTS: Median preoperative seizure period was 1month (range, 1-21). Median post-operative follow up period was 35months (range 13-84). Ten patients who underwent gross total resection of tumor showed Engel class Ia seizure outcome without any antiepileptic drug (AED). Subtotal resection was performed in four patients to avoid eloquent area injury. Two of these four patients with subtotal removal became seizure-free (Engel class Ia) without AED, while two were in Engel class Ib with AED medication. There was no significant surgical morbidity or mortality. CONCLUSION: Lesionectomy in children younger than 5years of age is relatively safe and effective in controlling seizures. Short preoperative seizure periods and total removal of tumor might be associated with good outcome. Therefore, early and complete lesionectomy alone may help allow for seizure freedom and optimal brain development in pediatric patients. PMID- 23688974 TI - Free pre-expanded lateral circumflex femoral artery perforator flap for extensive resurfacing and reconstruction of the hand. AB - Resurfacing and reconstruction of extensive scars, severe contractures and deformities of the hand are still challenging cases for plastic surgeons. Treatments usually necessitate thin, pliable and broad flaps. Additionally, minimising the donor-site morbidity is an indisputable requisite. The pre expanded perforator flap technique has been shown to provide extensive, thin and pliable skin with increased vascularity while reducing the donor-site morbidity. Utilisation of free pre-expanded lateral circumflex femoral artery perforator flap in an aesthetic and functional reconstruction of severe post-burn hand deformity is demonstrated. The successful functional and aesthetic outcome that was achieved in the early postoperative period and which still persists after 23 months of follow-up indicates that our technique could be preferably used in the extensive coverage of the hand. PMID- 23688975 TI - Margins of excision and prognostic factors for cutaneous eyelid melanomas. AB - BACKGROUND: Guidelines for wide excision of cutaneous melanomas according to Breslow thickness are impractical when considering melanomas arising on eyelid skin. No consensus exists regarding appropriate excision margins for these tumours. This study sought to determine whether excision margins influenced locoregional recurrence, and to identify prognostic factors for survival in these patients. METHODS: Fifty-six cases of invasive cutaneous eyelid melanomas diagnosed between 1985 and 2011 were identified from the database of Melanoma Institute Australia. Clinical and pathological factors were assessed for their associations with recurrence and survival. RESULTS: Local recurrence occurred in 12 patients (21%), nodal metastasis in 6 (11%) and distant metastasis in 2 (4%). Pathological margins>2 mm from the in situ component of the tumour were associated with increased disease-free survival (P=0.029) compared with margins<=2 mm but there was no statistically significant benefit for a pathological margin>2 mm from the invasive component. Lower eyelid melanomas were found to have a significantly higher local recurrence rate than upper eyelid melanomas (P=0.044). CONCLUSIONS: This series of cutaneous eyelid melanomas is the largest yet reported. The results suggest that, as a minimum, an in vivo surgical margin of 3 mm (corresponding to a 2 mm pathological margin after tissue fixation) is desirable for eyelid melanomas. We recommend a surgical excision margin of 3 mm for eyelid melanomas<=1 mm in Breslow thickness. However, for melanomas>1 mm in thickness, the current practice of aiming to achieve 5 mm margins would seem reasonable. Patients with lower eyelid melanomas warrant particularly close follow-up given their higher local recurrence rate. PMID- 23688976 TI - Role of alpha-toxin-induced apoptosis of umbilical vein endothelial cells in vertical infection of Staphylococcus aureus L-form. AB - OBJECTIVE: To investigate alpha-toxin-induced apoptosis of umbilical vein endothelial cells and explore its role in vertical infection of Staphylococcus aureus L-form. METHODS: HUV-EC-C cells exposed to different concentrations (0, 10, 30, 90, and 270 ng/ml) of alpha-toxin for different time lengths (0, 2, 4, 6, and 8 h) were examined for apoptosis using flow cytometry with Annexin V-PI staining. The levels of tumor necrosis factor-alpha (TNF-alpha) and the activities of, caspase-3 and caspase-8 in the cell culture were detected by ELISA and colorimetric method, respectively. alpha-Toxin-induced cell apoptosis was also analyzed in HUV-EC-C cells treated with a neutralizing antibody of TNF-alpha or with the inhibitory peptides of caspase-3 (zDEVD-FMK) and caspase-8 (zIETD fmk). RESULTS: alpha-Toxin induced apoptosis of HUV-EC-C cells in a dose- and time-dependent manner and caused significantly enhanced expression of TNF-alpha and the activation of both caspase-3 and caspase-8. Inhibition of TNF-alpha with its neutralizing antibody and the inhibitory peptides of caspase-3 or -8 all significantly decreased alpha-toxin-induced cell apoptosis, and the caspase-3 inhibitor completely blocked alpha-toxin-induced cell apoptosis. CONCLUSION: alpha-Toxin-induced apoptosis is partially mediated by the extrinsic cell death pathway of TNF-alpha and caspase-8 and plays an important role in the vertical infection of S. aureus L-form to affect fetal growth and development. PMID- 23688977 TI - Protective mechanisms of sevoflurane against one-lung ventilation-induced acute lung injury: role of cyclooxygenase-2 and 5-lipoxygenase pathways. AB - OBJECTIVE: To explore the protective mechanisms of sevoflurane against acute lung injury (ALI) induced by one-lung ventilation (OLV) in view of cyclooxygenase-2 (COX2) and 5-lipoxygenase (5-LOX) pathways. METHOD: Eighteen healthy Japanese white rabbits were randomized into sham-operated group (S group), OLV group (O group) and OLV + sevoflurane group (OS group). COX2 and 5-LOX protein and mRNA expressions in the lungs were detected by Western blotting and real-time PCR, respectively. Prostaglandin I2 (PGI2), thromboxane A2 (TXA2) and leukotrienes B2 (LTB2) in the lung tissues were quantified with ELISA. Histological scores and lung wet/dry weight (W/D) ratios were determined for lung injury assessment. RESULTS: COX2 and 5-LOX protein and mRNA expressions and the contents of LTB2, TXA2 and PGI2 in the lungs, lung W/D ratio and histological scores were significantly higher while PGI2/TXA2 ratio was significantly lower in O group and OS group than in S group (P<0.05). Compared with those in O group, COX2 and 5-LOX expressions, pulmonary contents of LTB2, TXA2 and PGI2, and lung W/D ratio all decreased significantly but PGI2/TXA2 ratio was significantly elevated in OS group (P<0.05). CONCLUSION: OLV may activate COX2 and 5-LOX pathways to result in increased production of arachidonic acid metabolites. Sevoflurane protects against OLV-induced ALI probably by reducing AA metabolites and regulating PGI2/TXA2 ratio through inhibitions of COX2 and 5-LOX pathways. PMID- 23688978 TI - Transforming growth factor-beta1 level in tears and corneal haze formation following flap-on or flap-off epi-LASIK. AB - OBJECTIVE: To observe the influence of flap-on or flap-off Epipolis laser in situ keratomileusis (epi-LASIK) on the release of transforming growth factor-beta1 (TGF-beta1) in tear fluid and corneal haze formation. METHODS: Thirty patients (60 eyes) with myopia underwent epi-LASIK surgery with epithelial flap repositioning (flap-on) in the right eyes and epithelial flap removal (flap-off) in the left eyes. The level of TGF-beta1 in tears was measured preoperatively and on days 1, 3, and 7 postoperatively. Corneal haze was graded at 1, 3 and 6 months after surgery. RESULTS: The mean preoperative spherical equivalent refraction was -4.98?2.28 D (-2.50 to -7.25 D) in flap-on group and -5.20?4.02 D (-1.75 to -7.00 D) in flap-off group, showing no significant difference between the two groups (P=0.80). TGF-beta1 levels in the tear fluid were similar in the two groups preoperatively (P=0.11) and at 1, 3, and 7 days postoperatively (P=0.55, 0.45, 0.19, respectively). TGF-beta1 levels in tears gradually decreased after the first postoperative day in both groups, but were still higher than the preoperative value till the 7th postoperative day. Corneal haze scores in the two groups were similar at 1 month (P=0.98), 3 months (P=0.52), and 6 months (P=0.72) after the operation. CONCLUSION: Flap-on and flap-off epi-LASIK surgeries do not differ significantly in postoperative TGF-beta1 levels in the tear fluid or in the postoperative haze scores. TGF-beta1 may play a role in corneal wound healing. PMID- 23688980 TI - [An inverted-repeat RNA construct for silencing dengue virus type 2 pre-membrane gene suppresses viral replication in BHK-21 cells]. AB - OBJECTIVE: To evaluate the anti-viral effects of a plasmid expressing an inverted repeat RNA targeting dengue virus type-2 (DENV-2) pre-membrane (prM) gene. METHOD: Suckling mice were inoculated with live DENV-2 in the brain. The total RNA was extracted from the brain tissue of the infected mice, and the prM gene fragments were amplified by RT-PCR and then subcloned into XhoI/EcoR I of the pcDNA3.1(+) plasmid in antisense orientation to construct the plasmid pcDNA asprM. DENV-2 prM sequences were also subcloned into pMD18-T-vector in sense orientation to construct the plasmid pMD18-T- prM. pcDNA-irRNA was constructed by inserting in sense orientation the prM fragment isolated from pMD18-T-prM into the NheI/Kpn I of pcDNA-asprM. The plasmid pcDNA-irRNA was transfected into BHK 21 cells and the anti-viral effects were analyzed by semi-quantitative PCR and real-time PCR. RESULTS: Transfection with the plasmid pcDNA-irRNA caused a reduction of NS3 mRNA expression level by 28% in BHK-21 cells following a 96-h challenge with DENV-2 as compared to the cells without plasmid transfection (positive control). The viral copies in pcDNA-irRNA-transfected cells was 1.44 fold lower than those in the positive control cells following a 72-h virus challenge, and the mRNA expression levels of NS1 were also significantly lower in the transfected cells at 96 h after viral challenge (P<0.05) as shown by real time quantitative PCR. CONCLUSION: The inverted-repeat RNA for DENV-2 prM gene silencing can suppress DENV-2 replication in BHK-21 cells, which provides a basis for developing dengue virus gene vaccine. PMID- 23688979 TI - [Effects of TIMP-1 on PTEN expression on renal tubular epithelial cells]. AB - OBJECTIVE: To investigate the role of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in regulating both angiogenesis and the expressions of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and vascular endothelial growth factor (VEGF)/Flk-1 expression in human proximal tubular epithelial cells (HKC). METHODS: HKC cells were transfected with two recombinant plasmids containing sense and antisense full-length TIMP-1 cDNA (TIMP-1S-pcDNA3.0 and TIMP-1AS-pcDNA3.0, respectively) constructed previously, or treated with 100 umol/L MMP-2/MMP-9 inhibitor III (with similar cellular enzyme suppression activity with sense TIMP-1 plasmid). The mRNA expression of TIMP-1, MMP-2, MMP-9, PTEN, VEGF and Flk-1 were examined by RT-PCR. In each group, the expression of PTEN, VEGF and Flk-1 were also detected using an indirect immunofluorescence assay. RESULTS: Compared with non-transfected cells and cells transfected with the empty vector, sense TIMP-1-transfected cells showed obviously upregulated PTEN expression (P<0.05) and significantly lowered gelatinase activity (P<0.05) and VEGF and Flk-1 expressions (P<0.05). Transfection with the antisense TIMP-1 plasmid produced the reverse results (P<0.05). MMP-2/MMP-9 inhibitor III did not obviously affected the expression of PTEN, VEGF or Flk-1 as compared with the non transfected or empty vector-transfected cells. CONCLUSION: In the aging progress, the renal tissues express high levels of TIMP-1 to upregulate PTEN expression via a MMP-independent pathway, and subsequently down-regulates the expression of VEGF and Flk-1 to cause aging-related impairment of renal angiogenesis. These findings provide new evidence for understanding the role of TIMP-1 in renal aging. PMID- 23688981 TI - [CaMKIIgamma promotes in vitro and in vivo growth of colorectal cancer cells by upregulating nuclear factor-kappaB signaling pathway]. AB - OBJECTIVE: To investigate the effects of the gamma isoform of Ca(2+)/calmodulin dependent protein kinase II (CaMKIIgamma) on colorectal cancer (CRC) cell growth in vitro and in vivo and explore the mechanisms. METHODS: The mRNA levels of CaMKIIgamma in 5 CRC cell lines, tumor tissues and matched adjacent tissues from 20 CRC patients were examined by semi-quantitative RT-PCR. The lentiviral vector pLenti6.3-MCS-IRES2-eGFP was used to generate the lentivirus particle Lenti CaMKIIgamma for transfecting SW620 cells. The proliferation ability of the transfected SW620-CaMKIIgamma cells was assessed by growth curve and colony formation assay. The expression of IKKalpha, IKKbeta, IKKgamma, p-IKKalpha/beta, p-IkappaB andIkappaB of the transfected cells were determined by Western blotting, and the expression and localization of nuclear factor-kappaB (NF kappaB) p65 were detected by immunofluorescence. In nude mouse models bearing the transfected SW620-CaMKIIgamma cell xenograft, the tumor volume was measured twice a week. RESULTS: CaMKIIgamma mRNA showed high expressions in the 5 colorectal cancer cell lines. Eighteen of the 20 tumor tissues showed higher expressions of CaMKIIgamma than the adjacent non-tumor tissues. The proliferation of transfected SW620-CaMKIIgamma cells was enhanced significantly. CaMKIIgamma activated NF kappaB signaling pathway and led to NF-kappaB p65 nuclear translocation. In the tumor-bearing mouse model, the volume of the tumors generated by the transfected SW620-CaMKIIgamma cells was 1.46- and 1.68-fold higher than that of the tumors with the control cells at the 8th and 12th day, respectively. CONCLUSION: CaMKIIgamma can effectively promote the growth of colorectal cancer cells in vitro and in vivo by activating NF-kappaB signaling pathway. PMID- 23688982 TI - [Expression of hsa-miR-186 and its role in human colon carcinoma cells]. AB - OBJECTIVE: To explore the expression of hsa-mir-186 in colorectal cancer and study its role in regulating the biological behaviors of human colorectal cancer SW620 cells in vitro. METHODS: The expression of hsa-miR-186 in colon cancer tissue and the adjacent tissues as well as 5 colon carcinoma cells were analyzed using real-time quantitative RT-PCR. The precursor sequence of miR-186 gene was amplified from the genomic DNA by PCR and cloned into the lentiviral vector PLVTHM labeled with GFP. The colorectal cancer cell line SW620 was transfected with PLVTHM-miR186 vector and the lentivirus-infected cells were sorted with flow cytometry. Cell counting kit-8 (CCK-8) assay was used to detect the proliferation of the cells. The migration and invasion of SW620 cells were investigated using Transwell assay and scratch test. Western blotting was used to detect the expression of YY1 protein in SW620 cell lines. RESULTS: The relative expression of miR-186 in the cancer tissues was 0.0024?0.0027, significantly lower than that in the adjacent tissues (0.066?0.068, P=0.008); the relative expression level of hsa-miR-186 in SW620 and LoVo cells with a high metastatic potential was 0.118?0.138 and 0.157?0.001, respectively, significantly lower than that in HT-29 cells with a low metastatic potential (1.000?0.00, P<0.05). The recombinant lentiviral vector PLVTHM-miR186, verified by enzyme digestion, sequencing and qPCR, caused significant inhibition of cell proliferation, migration and invasion and suppressed the expression of YY1 protein in SW620 cells. CONCLUSION: As a tumor suppressor gene, Hsa-miR-186 is down-regulated in colon carcinoma tissues and in highly metastatic SW620 and LoVo cells. Has-miR-186 can inhibit the cell proliferation, migration and invasion of colon carcinoma cells in vitro possibly by suppressing YY1 expression. PMID- 23688983 TI - [Expression pattern of hsa-miR-9 and its association with BCL6 in EBV-positive and EBV-negative Burkitt lymphoma cell lines]. AB - OBJECTIVE: To investigate the differential expression pattern of hsa-miR-9 between EBV-positive and -negative Burkitt lymphoma cell lines and its association with BCL-6. METHODS: The expression of hsa-miR9 and BCL-6 mRNAs in EBV(+) Raji and EBV-Ramous cells in mRNA levels were detected using fluorescence quantitative PCR (QRT-PCR). The two cells lines were transiently transfected with hsa-mir9-inhibitor and hsa-mir9-minicsvia Oligofectamine 2000, and the changes in BCL6 expressions was detected using QRT-PCR and Western blotting. Annexin V/PI staining was used to analyze the apoptosis and morphological changes of the transfected cells. RESULTS: The expression of Hsa-miR9 and BCL-6 was significantly higher in EBV(+) Raji cells than EBV(-) Ramous cells (P<0.01). BCL 6 mRNA and protein expression was reduced in EBV(+) Raji cells after transfection with hsa-miR9-inhibitor but up-regulated in EBV(-) Ramous cells transfected with hsa-miR9-minics. Flow cytometry revealed a significantly decreased apoptosis rate in EBV(+) Raji cells transfected with hsa-miR9-inhibitor but an increased rate in EBV(-) Ramous cells transfected with hsa-miR9-minics, and the results were confirmed by microscopic observations. CONCLUSION: Hsa-miR9 positively regulate the expression of BCL-6 and apoptosis of EBV(+) Raji cells and EBV(-) Ramous cells. PMID- 23688984 TI - [Changes in gene expression profiles in multiple myeloma cells after knocking down SNF5, a core subunit of SWI/SNF complex]. AB - OBJECTIVE: To investigate the changes in the gene expression profiles in a multiple myeloma cell line after knocking-down the expression of SNF5, a core component of the SWI/SNF chromatin remodeling complex. METHODS: The total RNA were extracted from tetracycline-inducible SNF5 knockdown (KD) cell line derived from KM3 cells for gene expression profiling by affymetrix microarray and bioinformatic analysis. RESULTS: Knockdown of SNF5 inhibited KM3 cell proliferation. A total of 545 genes were found to be differentially expressed in the cells with SNF5 knockdown, among which 214 were up-regulated and 331 were down-regulated. CONCLUSIONS: SNF5 is essential for the growth of multiple myeloma cells and can regulate the expression of the genes associated with cell growth and apoptosis. PMID- 23688985 TI - [Illumina sequencing 16S rRNA tagging reveals diverse vaginal microbiomes associated with bacterial vaginosis]. AB - OBJECTIVE: To analyze and compare vaginal microbiomes in healthy women at child bearing ages and patients with bacterial vaginosis (BV). METHODS: A total of 74 vaginal swabs of the vaginal fornix were collected from 37 BV patients and 37 healthy women. BV status was assessed according to Amsels clinical criteria for all the subjects and confirmed using Gram-stain criteria (Nugent scores). Genomic DNA of the samples was extracted for amplifying the 16S rRNA V6 hypervariable region by PCR and pyrosequencing by Illumina. BIPES, UCHIME, TSC and GAST were employed to analyze the information of the species from the samples. RESULTS: Lactobacillus was the predominant species in healthy women (more than 95%), including mainly L. iners and L. crispatus, with a small quantity of Gardnerella, Granulicatella, Streptococcus, Prevotella, Escherichia and other genus. The alpha diversity was significantly increased in 30 BV patients (P<0.001), and beta diversity also changed obviously shown by decreased Lactobacillus (varying from 45% to 1%, consisting mainly of L. iners) or even absence Lactobacillus in 6 cases, with increased relative abundance of Gardnerella, Prevotella, Granulicatella, Anaerococcus, Parvimonas, Peptoniphilus.harei, Peptostreptococcus, and Dialister. Different from previous data, 7 BV cases showed a predominance of the rare species L.gasseri and L.acidophilus (75% to 50%). CONCLUSION: Lactobacillus is the predominant vaginal species in healthy women (mainly L. iners and L. crispatus) co-existing with many other bacteria and a variety of microorganisms. Lactobacillus is significantly decreased and even absent in most of BV patients, and some cases show the predominance of the rare species L.gasseri and L.acidophilus. PMID- 23688986 TI - [Effect of blocking endogenous miR-23a on the proliferation and invasion in gastric adenocarcinoma cell line MGC803]. AB - OBJECTIVE: To investigate the effect of functional blocking of endogenous miR-23a with a specific antisense oligonucleotide (ASO) on the proliferation and invasiveness of gastric adenocarcinoma cell line MGC803 in vitro. METHODS: A specific ASO targeting miR-23a, namely ASO-23a, was transfected into MGC803 cells to block endogenous miR-23a. The mRNA level of miR-23a in the transfected cells was detected with quantitative real-time PCR. The changes of cell proliferation following the transfection were detected with MTT assay and colony formation assay, and TUNEL assay and Transwell assay were employed to evaluate the changes in cell apoptosis and invasiveness, respectively. RESULTS: Quantitative real-time PCR demonstrated efficient functional blocking of endogenous miR-23a in MGC803 cells by ASO-23a. Suppression of miR-23a with ASO-23a obviously inhibited cell growth, colony formation and invasiveness of MGC803 cells and significantly enhanced the cell apoptosis. CONCLUSION: ASO-23a can efficiently block the function of endogenous miR-23a in MGC803 cells to inhibit cell proliferation and invasion and promote cell apoptosis. PMID- 23688987 TI - [Construction of full-length human bladder cancer-specific antibody libraries based on mammalian display technology]. AB - OBJECTIVE: To construct full-length human bladder cancer-specific antibody libraries for efficient display of full-length antibodies on the surface of mammalian cells. METHODS: The total RNA was isolated from peripheral blood mononuclear cells from patients with bladder cancer. The repertoires of IgG1 heavy chain variable region (VH) and Kappa light chain were amplified by RT-PCR using specific primers. The antibody genes were inserted into the vector pDGB-HC TM to construct the bladder-cancer-specific antibody libraries of heavy chains and light chains. Ten clones from each library were randomly picked for gene sequencing and transient transfection into FCHO cells to analyze antibody display on mammalian cell surface by flow cytometry after staining with corresponding fluorescent labeled antibodies. RESULTS: The libraries of bladder-cancer-specific antibody heavy chain (IgG1) and light chain (LCk) were successfully constructed. Seven out of the 10 clones randomly selected from the heavy chain library and 9 out of the 10 clones from the light chain library showed correct open reading frame, coding for 7 unique VH and 9 unique LCk. The combinatory library size reached 3.32*10(11). CONCLUSION: We have successfully constructed a full-length human bladder-cancer-specific antibody library with a combinatory diversity of 3.32*10(11) based on mammalian display technology, which can be used for screening monoclonal antibodies against bladder-cancer-associated antigens. PMID- 23688988 TI - [Expression of long noncoding RNA MALAT1 gene in human nasopharyngeal carcinoma cell lines and its biological significance]. AB - OBJECTIVE: To explore the expression of MALAT 1 in nasopharyngeal carcinoma (NPC) and its biological function. METHOD: Real-time PCR was used to detect the expression of MALAT1 in 5-8F, C666-1, CNE-1, CNE-2, HONE-1, 6-10B and NP69 cell lines. CNE-1 cells engineered with MALAT1 RNA interference (RNAi) and RNA activation (RNAa) techniques were examined for changes in cell proliferation, invasion and metastasis using CCK8 assay, colony formation assay, Transwell in vitro invasion assay and wound-healing assay ability. RESULTS: MALAT1 was highly expressed in 5-8F cells with a high metastatic potential, and lowly expressed in normal nasopharyngeal epithelium cells. Overexpression of MALAT1 by RNAa suppressed the expression of E-cadherin, promoted the expression of vimentin and enhanced the proliferation, invasion, and metastasis of CNE-1 cells. CONCLUSION: MALAT1 can enhance the proliferation, invasion, and metastasis of CNE-1 cells. PMID- 23688989 TI - [Extraction of cytoskeletons and associated proteins using subcellular proteome fractionation technique]. AB - OBJECTIVE: To develop a method for extracting cytoskeletons and cytoskeleton associated proteins for proteomic analysis. METHODS: A subcellular sequential proteome extraction method was exploited. The extraction procedure was optimized and controlled according to observed cell morphology changes and one- and two dimensional electrophoresis images. The extraction efficiency and selectivity were evaluated by Western blotting and mass spectrometry. RESULTS: Four extracted fractions clearly displayed distinct patterns. Western blotting detected the fraction-marker proteins FAK, integrin-beta1, histone H1 and cytokeratin 19 only in their expected fractions. About 90% of the protein spots in the cytoskeleton fraction were identified by mass spectrometry as cytoskeleton and/or its associated proteins. CONCLUSION: The subcellular proteome sequential fractionation method facilitates the detection of proteins of low abundance and shows a high reproducibility and selectivity, and thus can serve as an ideal pre fractionation method prior to two-dimensional electrophoresis. PMID- 23688990 TI - [Screening of differential proteins binding to Nox1 promoter in A549 cell model of inflammation and oxidative stress]. AB - OBJECTIVE: To screen the regulatory proteins involved in Nox1 promoter activation in a cell model of inflammation and oxidative stress. METHODS: A cell model of inflammation and oxidative stress was established by stimulating A549 cells with tumor necrosis factor-alpha (TNF-alpha). The differential proteins binding to Nox1 promoter were screened by DNA pull-down and the binding proteins were separated by 2D electrophoresis and selected according to the their differential expression levels (with over 1.5-fold changes relative to the control level). The screened proteins were finally identified by MALDI-TOF/TOF-MS. RESULTS: Seven differentially expressed protein spots (all upregulated in the cell model) were obtained, among which GLE1, DDX19A, KRT1 and KRT10 were identified by mass spectrometry. CONCLUSION: GLE1, DDX19A, KRT1 and KRT10 participate in the activation of Nox1 promoter in TNF-alpha-induced A549 cells, and this result provides new insights into the biological roles of the regulatory proteins of Nox1 promoter in inflammation and oxidative stress. PMID- 23688992 TI - [Neurolinguistic features during recovery of a Chinese patient with pure alexia]. AB - OBJECTIVE: To analyze the neurolinguistic features of a Chinese patient with pure alexia in acute and convalescent stages. METHODS: We assessed the reading and writing abilities of the patient with the Aphasia Battery of Chinese (ABC), the reading examination of Chinese characters (1999, Lin) and the Chinese agraphia battery (CAB). RESULTS: In the ABC examination in the acute phase, the patient performed well in oral expression and comprehension, and the prominent linguistic abnormalities were alexia and merging agraphia; in the convalescent phase, the recovery of alexia was better than that of agraphia. In reading examination of Chinese characters, shape errors were the main reading disorders in the acute phase with a few semantic errors, regularization errors and mistakes in pronunciation, but only shape errors reappeared in the recovery period. CAB examination showed impairment of writing for pictures and dictation abilities in the recovery period but recovery of other writing abilities. The writing disorder was manifested as aphasic agraphia, with obvious dysorthography and lexical errors; the patient was capable of spontaneous writing only after spontaneous speech, and was able to read the written words. CONCLUSION: The linguistic components of the Chinese patient with pure alexia showed different patterns of damage and recovery, suggesting the difference in their respective neuropsychological pathways. PMID- 23688991 TI - [Ventricular and subventricular zones under the frontal cortex of human fetus: development and distribution of nestin-positive cells]. AB - OBJECTIVE: To observe the morphological changes during development of the ventricular zone (VZ) and subventricular zone (SVZ) of human fetus and the distribution pattern of neural stem cells in the VA and SVZ. METHODS: Human fetuses at the gestational ages of 9-11 weeks, 14-16 weeks, 22-24 weeks and 32-36 weeks were collected, and the brain sections of the VZ/SVZ under the frontal lobe were examined for cytoarchitecture and distribution of nestin-positive cells with HE staining, immunohistochemistry or immunofluorescence. RESULTS: The thickness of VZ underwent no significant changes at the gestational ages of 9-24 weeks (P>0.05) and became obviously thinner at 32 weeks (P<0.05), while the thickness of SVZ increased during 9-24 weeks (P<0.05) without obvious thinning at 32 weeks (P>0.05). VZ was thicker than SVZ at 9-11 weeks but became markedly thinner than SVZ after 14 weeks (P<0.05). The VZ contained denser cells than SVZ and showed a distinct boundary between the VZ and SVZ. Large numbers of nestin-positive cells were detected in the VZ and SVZ, and nestin immunoreactivity was found primarily in the cell processes and occasionally in the soma. Some nestin-positive cells in the SVZ had 1-3 processes. Nestin immunoreactivity in the VZ and SVZ gradually grew weak with development. The cells positive for both nestin and Ki67 were located mainly in the inner zone of the VZ and throughout the SVZ, where some nestin-positive but Ki67-negative cells were also found. CONCLUSION: The SVZ fully extends and the neural stem cells in the VZ/SVZ can be morphologically heterogeneous during the development of fetal human brain. PMID- 23688993 TI - [Eradication of H.pylori may cause gastroesophageal reflux disease: a meta analysis]. AB - OBJECTIVE: To confirm whether eradication of H. pylori is associated with the occurrence of gastroesophageal reflux disease (GERD). METHODS: We searched multiple medical databases for published randomized controlled trials (RCTs) from 2000 to 2012 comparing the incidence of GERD in adult patients receiving H. pylori treatment and those without treatment. The effects of H. pylori eradication were analyzed by calculating the pooled estimates for the number of new cases of GERD. Each racial subgroup of patients was analyzed using risk ratio (RR) by fixed effects models. The publication bias was assessed with funnel plot, Egger and Begg's test. RESULTS: Sixteen eligible RCTs were finally included in the analysis. Statistically analysis suggested H. pylori eradication was significantly correlated with the occurrence of GERD (RR 1.89, 95% CI 1.50-2.40). Funnel plot, Egger or Begg's test revealed no publication bias. CONCLUSION: H. pylori may have a positive effect on GERD especially in Asian patients and those with long-term follow-up, and eradication of H. pylori may cause GERD. PMID- 23688994 TI - [HAND system-based four multiplex RT-PCR for simultaneous detection of four diarrhea viruses]. AB - OBJECTIVE: To establish a one-step four multiplex reverse transcription polymerase chain reaction (RT-PCR) method based on Homo-Tag Assisted Non-Dimer System (HAND) system for simultaneous detection of 4 diarrhea viruses of rotavirus, astrovirus, norovirus and sapovirus. METHODS: Primers were designed according to the conserved genome sequence of the 4 viruses and the homologous tail sequences were added to the 5' end. The multiplex RT-PCR system was constructed by optimizing the PCR parameters such as the concentration of universal tag primer and genome-specific Homo-Tailed primers. The specificity, stability and sensitivity of the method were evaluated systematically. RESULTS: The 4 multiplex RT-PCR methods based on HAND system was established successfully. Specificity analysis showed no cross reaction between the 4 diarrhea viruses. The sensitivity analysis showed detection limits for rotavirus, astrovirus, norovirus and sapovirus of 48, 1.92, 9.6 and 48 pg per reaction, respectively. CONCLUSION: The established HAND system-based multiplex RT-PCR assay allows simple, rapid, specific, sensitive, and stable for detection of the 4 common diarrhea viruses at low costs and is suitable for application in general medical laboratories. PMID- 23688995 TI - [Anti-microRNA-221 enhances radiosensitivity of colorectal carcinoma cells by up regulating PTEN]. AB - OBJECTIVE: To investigate the effect of knocking-down microRNA-221 (miR-221) expression on the radiosensitivity of human colorectal carcinoma cells. METHODS: Human colorectal carcinoma-derived cell line Caco2 was transfected with miR-221 antisense oligonucleotides (anti-miR-221) via Lipofectamine 2000. Real-time quantitative PCR was performed to detect the expression of miR-221 and PTEN mRNA in Caco2 cells. The changes in the protein expression of PTEN in the transfected cells were detected by Western blotting. The cell death after transfection and irradiation was detected by flow cytometry. RESULTS: Transfection with anti-miR 221 caused a significant reduction in miR-221 expression (P<0.05) and up regulated PTEN protein expression (P<0.05) in Caco2 cells. The percentage of cell death was significantly increased in anti-miR-221 group and anti-miR-221 with irradiation group (P<0.01). Anti-miR-221 significantly enhanced the radiosensitivity of Caco2 cells, which was partially reversed by PTEN-siRNA. CONCLUSION: Anti-miR-221 can enhance the radiosensitivity of colorectal carcinoma cells by up-regulating the expression of PTEN. PMID- 23688996 TI - [Expression of epithelial-mesenchymal transition markers in tumor tissues generated by side population and non-side population of A431 cells in NOD/SCID mice]. AB - OBJECTIVE: To isolate the side population (SP) and non-side population (NSP) cells from A431 cells and compare their difference in tumorigenicity in mice and the expression profiles of epithelial-mesenchymal transition (EMT) markers. METHODS: A431 cells stained with Hoechst 33342 were sorted with flow cytometry. The isolated SP cells and NSP cells were inoculated into NOD/SCID mice and the tumorigenicity of the cells was observed. EMT markers E-cadherin, beta-catenin, vimentin, AXL, and Erbb3 in the tumor tissues were detected by immunohisto staining. RESULTS: The tumors generated by SP cells were larger than those by NSP cells in NOD/SCID mice. Compared with the tumors generated by NSP cells, the cells in the periphery of tumors generated by SP cells showed up-regulated expressions of AXL, vimentin and beta-catenin and down-regulated ERBB3 and E cadherin. CONCLUSION: The SP cells in A431 cells have a strong tumorigenicity and show more EMT phenotypes in tissues. PMID- 23688997 TI - [Selection and identification of ssDNA aptamers specific to clinical isolates of Streptococcus mutans strains with different cariogenicity]. AB - OBJECTIVE: To select and identify ssDNA aptamers specific to Streptococcus mutans strains with different cariogenicity isolated from clinical specimens. METHODS: Subtractive SELEX technology targeting the whole intact cells was used to screen for ssDNA aptamers specific to the clinical isolates Streptococcus mutans strains with different cariogenicity. Radioactive isotope, flow cytometry, gene cloning and sequencing, MEME online software and RNA structure analysis software were employed to analyze the first and secondary structures of the aptamers and identify the screened aptamers. RESULTS: Detection by radioactive isotope showed sufficient pool enrichment after 9 rounds of subtractive SELEX. Flow cytometry showed that the selected aptamers H1, H16, H4, L1, L10 and H19 were capable of binding specifically with highly cariogenic Streptococcus mutans strains but not with strains with a low cariogenicity. The aptamer H19 had the strongest binding capacity to highly cariogenic Streptococcus mutans strains, with a dissociation constant of 69.45?38.53 nmol/L. CONCLUSION: We have obtained the ssDNA aptamers specific to the clinical isolates of highly cariogenic Streptococcus mutans strains. PMID- 23688998 TI - [Effect of dexamethasone on expression of interleukin-21 and phospho-STAT3 in a murine model of chronic asthma]. AB - OBJECTIVE: To investigate the effects of dexamethasone on the expression of interleukin-21 (IL-21) and phospho- STAT3 (p-STAT3) in a murine model of chronic asthma. METHODS: Thirty-three female BALB/C mice were randomly divided into control group, asthmatic group and dexamethasone-treated group (n=11). In the latter two groups, asthmatic models were established by ovalbumin administration. The cells in the broncho-alveolar lavage fluid (BALF) were counted and classified. The airway inflammation was evaluated by HE staining, and the expressions of IL-21 and p-STAT3 in the lung tissue were detected by immunohistochemistry and Western blotting. RESULTS: The total cell number and lymphocyte number in the BALF were significantly higher in asthmatic group than in the control group and dexamethasone group (P/0.01). Compared with the control group, the asthmatic group showed significantly increased protein expressions of IL-21 and p-STAT3 (P<0.05), which were reduced by dexamethasone intervention (P/0.05). CONCLUSION: Dexamethasone can inhibit the expression of IL-21 and p STAT3 in the murine model of chronic asthma, suggesting the importance of IL 21/STAT3 signaling pathway in the therapeutic mechanisms of dexamethasone for asthma. PMID- 23688999 TI - [Ultrasound-assisted ex vivo transdermal test of glucosamine sulfate solution]. AB - OBJECTIVE: To evaluate the transdermal permeability of glucosamine sulfate solution across ex vivo rabbit dermis under ultrasound and optimize the ultrasound conditions. METHODS: The ultrasound-assisted transdermal permeation of glucosamine sulfate solution across ex vivo rabbit dermis was tested using a simple Franz diffuse. The transdermal permeation volume and rate were calculated by measuring the concentration of glucosamine sulfate in the receptor fluid with ultraviolet spectrophotometry, and the impact of different sound intensities, irradiation time and solution concentration on solution permeation was analyzed. RESULTS: At the ultrasound intensity of 0.2 W/cm(2), the permeation volume and rate of glucosamine sulfate both reached the maximum; no glucosamine sulfate was detected in the receptor fluid after a 5-min ultrasound irradiation. The permeation volume and rate of glucosamine sulfate increased as the irradiation time prolonged and also with increased glucosamine sulfate concentration. The dorsal and lateral skin thickness (2.0?0.1 and 1.2?0.1 mm, respectively) did not significantly affect the transdermal permeation of glucosamine sulfate (P>0.05). CONCLUSION: Ultrasound irradiation at 1.0 MHz for over 5 min allows glucosamine sulfate to permeate rabbit dermis, and the volume and rate of permeation increase with the irradiation time and concentration of the solution and are not affected by variations of the dermal thickness. PMID- 23689000 TI - [Prognostic value of B lymphocyte infiltration in breast cancer]. AB - OBJECTIVE: To assess the prognostic value of CD20(+) tumor-infiltrating lymphocytes (TILs) in early-stage breast cancer. METHODS: Paraffin sections were collected from 130 cases of stage I-III breast cancer undergoing surgery between January, 2000 and December, 2002 in our hospital. Immunohistochemistry was used to analyze mesenchymal CD20(+) TILs infiltration in the tumor and evaluate its association with the density of CD4(+) and CD8(+) TILs. The association of CD20(+) TILs was evaluated with the histopathologic features, overall survival (OS), distant disease-free survival (DDFS), and disease-free survival (DFS) of the patients. RESULTS: Aggregations of CD20(+) lymphocytes were observed in 37.69% (49/130) of the cases. CD3(+) T cells were found to aggregate around CD20(+) B cell aggregations to form lymphoid follicle-like structures. The aggregations of CD20(+) TILs were positively correlated with the densities of mesenchymal CD8+ and CD4(+) TILs. Overall, CD20(+) TIL aggregations were not significantly correlated with the outcomes of the patients, but multivariate COX regressions suggested that CD20(+) TIL aggregations were positively correlated with DDFS (HR=0.251, 95% CI=0.071-0.894, P=0.033) and OS (HR=0.325, 95% CI=0.103 1.028, P=0.056) in hormone receptor-negative patients but not in the positive patients. Further analysis suggested that post-operative adjuvant endocrine therapy significantly improved the OS of patients positive for hormone receptors without CD20(+) TIL aggregations (P=0.001). CONCLUSION: The long-term therapeutic effects of adjuvant endocrine therapy are correlated with CD20(+) TIL aggregations to affect prognostic value of CD20(+) TIL aggregations in early stage breast cancer patients. PMID- 23689001 TI - [Laryngeal mask anesthesia in video-assisted thoracoscopic surgery for pulmonary bulla: comparison with intubation anesthesia]. AB - OBJECTIVE: To assess the feasibility and safety of thoracoscopic bulla resection under laryngeal mask anesthesia with low tidal volume high-frequency lung ventilation. METHODS: Sixty patients with pulmonary bulla were randomized into two groups (n=30) to undergo video-assisted thoracoscopic surgery (VATS) for bulla resection with laryngeal mask anesthesia and high-frequency low tidal volume lung ventilation general anesthesia and or with intubation anesthesia and one-lung ventilation through double-lumen endotracheal intubation. RESULTS: No significant differences were found in anesthesia time, surgery time, intraoperative lowest SpO2, intraoperative highest PetCO2, operative field, anesthetic effects, or blood loss between the two groups. The post-operative WBC and NEU% showed significantly smaller increments in the mask anesthesia group than in the intubation group, and the postoperative awake time, initial eating time, ambulation time, in-hospital stay, and drainage time were significantly shortened in the former group with also lower incidences of gastrointestinal reactions, throat discomfort and hoarseness. CONCLUSION: Thoracoscopic bulla resection under laryngeal mask anesthesia with low tidal volume high-frequency lung ventilation is safe and feasible and results in better patient satisfaction and shorter in-hospital stay than procedures performed under intubation anesthesia with one-lung ventilation. PMID- 23689002 TI - [Changes of systemic and local myeloperoxidase and tumor necrosis factor-alpha in rats with myocardial injury induced by hind-limb ischemia-reperfusion]. AB - OBJECTIVE: To explore the role of myeloperoxidase (MPO) and tumor necrosis factor alpha (TNF-alpha) in myocardial injury induced by hind-limb ischemia-reperfusion (IR) in rats. METHODS: Rat models of bilateral hindlimb IR established using a tourniquet were randomized into 9 groups, including a normal control group normal, 2 ischemic groups with hindlimb ischemia for 2 and 4 h, and 6 IR groups with a 4-h ischemia followed by reperfusion for 0.5, 2, 4, 6, 12, and 24 h. The plasma and myocardial levels of MPO and TNF-alpha in each group were measured, and the myocardial expression of TNF-alpha was determined with immunohistochemistry. RESULTS: Compared with the normal control group, the rats with a 2-h ischemia showed significantly increased levels of MPO and TNF-alpha in the plasma and myocardium. Compared with those in rats with a 4-h ischemia, the plasma and myocardial MPO levels increased significantly at 0.5 and 2 h of reperfusion, respectively; the plasma TNF-alpha level increased significantly at 4 h of reperfusion and myocardial TNF-alpha level decreased obviously at 12 h; plasma levels of MPO and TNF-alpha both significantly decreased at 24 h. The plasma MPO and TNF-alpha and myocardial TNF-alpha reached the peak levels at 4 h of reperfusion, and the peak myocardial MPO level occurred at 6 h. Immunohistochemistry showed that TNF-alpha positivity moderately increased after hindlimb ischemia, and further increased at 4 h of reperfusion but obviously reduced at 24 h. CONCLUSION: The activation of systemic and local neutrophils and inflammatory cytokines may play an important role in myocardial injury induced by hindlimb IR in rats. PMID- 23689003 TI - [Mechanism of cytoprotective effect of thyroid hormone on the hippocampus of rats with chronic cerebral ischemia]. AB - OBJECTIVE: To investigate the role of Bcl-2 in the cytoprotective effect of thyroid hormone against hippocampal cell apoptosis in rats with chronic cerebral ischemia. METHODS: Fifty adult male SD rats were randomized into sham-operated group, 2-vessel occlusion (2VO) group and triiodothyronine (T3) treatment group. At 7 and 14 days after the operation, the tissue structure of the CA1 region was observed with Nissl staining, and TUNEL staining was used to determine the apoptosis index (AI) in the dentate gyrus; Western blotting was performed to detect the expression level of Bcl-2 in the hippocampus. RESULTS: In the 2VO group, the CA1 region of the hippocampus showed obvious structural damages with reduced number of neurons, and these changes were significantly improved in T3 treatment group. At 7 days after the operation, no significant difference was found in AI between the sham-operated group (17.714?2.553), 2VO group (20.868?2.090) and T3 group (20.365?1.055) (P=0.060); the expression level of Bcl 2 was higher in T3 group than in 2VO group. On day 14, AI was 66.532?3.249 in 2VO group, significantly higher than that in T3 treatment group (56.153?4.556, P=0.001); Bcl-2 expression was the highest in T3 group and the lowest in 2VO group. CONCLUSION: Thyroid hormone can reduce cell apoptosis in the hippocampus of rats with chronic cerebral ischemia possibly by up-regulating the expression of Bcl-2. PMID- 23689004 TI - [Association between APOBEC3G polymorphisms and susceptibility to chronic hepatitis B]. AB - OBJECTIVE: To investigate the association between rs185983011 single-nucleotide polymorphisms (SNP) of apolipoprotein B mRNA editing enzyme catalytic polypeptide like 3G (APOBEC3G) and the susceptibility to chronic hepatitis B. METHODS: The blood samples were collected from 186 healthy subjects and 159 patients with chronic hepatitis B. The rs185983011 SNP was detected and genotyped by sequencing with Sanger's method to analyze the relationship between rs185983011 SNP and chronic hepatitis B. RESULTS: Only C/C and C/T genotypes of the alleles of rs185983011 SNP were found in the tested subjects, and the C/C genotype was predominant (97.7%). The distribution frequencies of rs185983011 SNP genotypes and alleles showed no significant difference between healthy subjects and patients with chronic hepatitis B (P>0.05). CONCLUSION: The predominant genotype of rs185983011 SNP of APOBEC3G is C/C in the tested subjects, and rs185983011 SNP does not appear to associate with the susceptibility to chronic hepatitis B. PMID- 23689005 TI - [A meta-analysis of fish intake and the risk of renal cell cancer]. AB - OBJECTIVE: To explore the association of fish intake with the risk of renal cancer. METHODS: PubMed, Embase, CNKI and CA databases were searched for case control studies or cohort studies examining the relationship between fish or fish products intake and renal cancer. Heterogeneity among the selected studies was assessed using I2 score, and the publication bias was assessed using funnel plots. RESULTS: Seventeen articles were included in the analysis with a heterogeneity across the studies (P=0.003, I(2)=52.3%). A random-effects model was used to generate the pooled risk ratio (RR) and 95% confidence interval (CI), and no statistically significant association was found between the risk of renal cancer and fish intake (RR=0.90; 95% CI, 0.78-1.02). In subgroup analysis, no evidence was found that the study design, study region or publication date influenced the results; but in the gender subgroup analysis, fish intake we found to decrease the risk of renal cancer in men but not in women. CONCLUSION: The results of meta-analysis do not support an association between fish intake and a lowered risk of renal cancer. PMID- 23689006 TI - [Effect of revascularization treatment of immature permanent teeth with endodontic infection]. AB - OBJECTIVE: To observe the effect of revascularization for treatment of immature teeth with endodontic infection mediated by calcium hydroxide. METHODS: Seventeen pediatric patients with endodontic infections of the permanent teeth were treated with routine root canal and pulp cavity irrigation and disinfection followed by application of calcium hydroxide paste to the root canal orifice to induce revascularization. Another 17 patients received conventional apexification procedures to serve as the control group. The patients were followed up to observe the therapeutic effect of the treatments. RESULTS: In the revascularization treatment group, 4 cases showed healed periapical lesions 6 to 18 months after the surgery with thickened root canal walls and closure of the apical foramen; in 10 cases, the periapical lesions healed 12 to 18 months postoperatively with lengthened root, thickened root canal wall, and narrowed apical foramen. One patient reported pain and swelling at 2 months, and 2 patients showed the formation of gum fistula and ceased development of the roots at 7 and 8 months. In the control group, the periapical lesions healed in 1 cases at 12 months postoperatively with apical foramen closure; in 11 cases, hard tissues formed in the root apex without obviously lengthened roots 6 to 8 months after the surgery; in 5 cases, no apical barrier formed even 12 to 18 months after the surgery. The overall effective rates were similar between the two groups (P>0.05). CONCLUSIONS: Revascularization by calcium hydroxide sealing can promote root development of immature permanent teeth with pulpitis or periradicular periodontitis. PMID- 23689007 TI - Unknown in vivo factors influencing the oxygen dissociation curve? PMID- 23689008 TI - Respiratory muscle function during a six-week period of normocapnic hyperpnoea training. AB - Respiratory muscle endurance training (normocapnic hyperpnoea, RMET) improves maximal volitional ventilation (MVV) and respiratory muscle endurance while volitionally-assessed respiratory muscle strength remains unchanged (prior-to post comparison). What remains unclear is how respiratory muscle function changes/adapts during a defined period of RMET in highly-trained subjects. This study assessed respiratory muscle function during a six-week period of RMET in 13 highly-trained, healthy subjects. Weekly-assessed twitch mouth pressure (prior/post 2.20 +/- 0.41 kPa vs. 2.43 +/- 0.61 kPa; p=0.14); twitch transdiaphragmatic pressure (prior/post 3.04 +/- 0.58 kPa vs. 3.13 +/- 0.48 kPa; p=0.58) and maximal inspiratory pressure (prior/post 12.6 +/- 3.6 kPa vs. 13.9 +/ 3.8 kPa; p=0.06) did not increase. MVV (prior/post 175 +/- 18 l/min vs. 207 +/- 30 l/min; p=0.001), sniff nasal pressure (prior/post 11.8 +/- 2.8 kPa vs. 14.0 +/ 2.9 kPa; p=0.003) and maximal expiratory pressure (prior/post 16.9 +/- 5.8 kPa vs. 20.9 +/- 4.9 kPa; p=0.006) each increased. In conclusion, non-volitionally assessed diaphragmatic strength does not increase during six weeks of RMET in highly-trained subjects, while expiratory muscle strength and MVV rose. Future studies should clarify if these findings apply when assessed during respiratory muscle strength rather than endurance training. PMID- 23689009 TI - 2-Arachidonoylglycerol is a substrate for butyrylcholinesterase: A potential mechanism for extracellular endocannabinoid regulation. AB - 2-Arachidonoylglycerol (2-AG) is a component of the endocannabinoid receptor pathway and is primarily hydrolyzed by monoacylglycerol lipase (MAGL) in vivo. We found that the non-specific serine esterase, butyrylcholinesterase (BChE), can hydrolyze 2-AG with reasonable affinity and may present a new compensatory mechanism for endocannabinoid regulation. In vitro hydrolysis reactions of 2-AG with equine BChE were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) positive/negative electrospray ionization (ESI+/-) to measure the formation of arachidonic acid (AA) and the loss of 2-AG over time (min). The resulting Michaelis-Menten approximations reveal that BChE has affinity towards 2 AG in phosphate buffer at neutral pH (7.4). The calculated Vmax, Km and kcat were 12.1nmols(-1), 57.5MUM, and 0.074s(-1), respectively, which produced a diffusion controlled rate of association (kcat/Km) of 1.3*10(3)M(-1)s(-1). Human BChE 2-AG hydrolysis was measured by immunoprecipitating BChE from fresh plasma and monitoring 2-AG loss and AA formation over time. These findings show that BChE can hydrolyze 2-AG which may be evidence of a more specific role for BChE in endocannabinoid regulation. PMID- 23689010 TI - The nemaline myopathy-causing E117K mutation in beta-tropomyosin reduces thin filament activation. AB - The effect of the nemaline myopathy-causing E117K mutation in beta-tropomyosin (TM) on the structure and function of this regulatory protein was studied. The E117K mutant was found to have indistinguishable actin affinity compared with wild-type (WT) and similar secondary structure as measured by circular dichroism. However the E117K mutation significantly lowered maximum activation of actomyosin ATPase. To explain the molecular mechanism of impaired ATPase activation, WT and E117K TMs were covalently labeled at Cys-36 with 5-iodoacetimido-fluorescein and incorporated into ghost muscle fibers. The changes in the position and flexibility of tropomyosin strands on the thin filaments were observed at simulation of weak and strong binding states of actomyosin at high or low Ca(2+) by polarized fluorescence techniques. The E117K mutation was found to shift the tropomyosin strands towards the closed position and restrict the tropomyosin displacement during the transformation of actomyosin from weak to strong binding state thus leading to a reduction in thin filament activation. PMID- 23689011 TI - Swine, human or avian influenza viruses differentially activates porcine dendritic cells cytokine profile. AB - Swine influenza virus (SwIV) is considered a zoonosis and the fact that swine may act as an intermediate reservoir for avian influenza virus, potentially infectious for humans, highlights its relevance and the need to understand the interaction of different influenza viruses with the porcine immune system. Thus, in vitro porcine bone marrow-derived dendritic cell (poBMDCs) were infected with a circulating SwIV A/Swine/Spain/SF32071/2007(H3N2), 2009 human pandemic influenza virus A/Catalonia/63/2009(H1N1), low pathogenic avian influenza virus (LPAIV) A/Anas plathyrhynchos/Spain/1877/2009(aH7N2) or high pathogenic avian influenza virus (HPAIV) A/Chicken/Italy/5093/1999(aH7N1). Swine influenza virus H3N2 infection induced an increase of SLA-I and CD80/86 at 16 and 24h post infection (hpi), whereas the other viruses did not. All viruses induced gene expression of NF-kappaB, TGF-beta, IFN-beta and IL-10 at the mRNA level in swine poBMDCs to different extents and in a time-dependent manner. All viruses induced the secretion of IL-12 mostly at 24hpi whereas IL-18 was detected at all tested times. Only swH3N2 induced IFN-alpha in a time-dependent manner. Swine H3N2, aH7N2 and aH7N1 induced secretion of TNF-alpha also in a time-dependent manner. Inhibition of NF-kappaB resulted in a decrease of IFN-alpha and IL-12 secretion by swH3N2-infected poBMDC at 24hpi, suggesting a role of this transcription factor in the synthesis of these cytokines. Altogether, these data might help in understanding the relationship between influenza viruses and porcine dendritic cells in the innate immune response in swine controlled through soluble mediators and transcription factors. PMID- 23689012 TI - Validation of an eight parameter immunophenotyping panel in adult canines for assessment of immunotoxicity. AB - Analysis of peripheral blood leukocyte populations by flow cytometry in adult beagles is a critical component of immunotoxicity assessment in regulated pre clinical toxicology studies. In this study, data is presented utilizing a single panel, six-color method to simultaneously enumerate absolute cell counts and determine the relative percentage of leukocytes. A GLP validation was performed to determine intra- and inter-assay variance, inter-instrument variance, and pre- and post-fixation stability for the target populations. The results demonstrated all samples met acceptance criteria, CV values less than 25%, for all precision and stability intervals assessed. The intra and inter-assay data demonstrated the single panel method generated acceptable precision. Furthermore, stability results indicated whole blood samples and processed samples may be stored without a statistically significant difference in the data compared to samples immediately processed and analyzed after blood collection. This assay will provide researchers a more precise and efficient tool to evaluate the immunotoxic effects of a test article on canine peripheral blood leukocytes during pre clinical drug testing. PMID- 23689013 TI - Magnetic source imaging (MSI) in children with neocortical epilepsy: surgical outcome association with 3D post-resection analysis. AB - OBJECTIVE: To investigate the validity of magnetic source imaging (MSI) to localize seizure-onset zone using 3D analysis of pre-operative MSI source imaging coregistered to post-resection MRI following neocortical epilepsy surgery. METHODS: Twenty-two children who had MSI and epilepsy surgery were studied (median age=11 years, 1 year 2 months-22 years). Only seven (31.8%) had localized lesions on pre-operative conventional brain MRIs. Sixteen (72.7%) underwent intracranial EEG monitoring. Mean post-operative follow-up was 4.7 years (1 year 3 months-8 years 2 months). Fifteen patients (68%) were seizure-free. MEG spike dipole sources were superimposed onto post-operative MRIs. The number and proportion of spike dipoles within resection volume were calculated and compared between seizure free and non-free groups. RESULTS: Both number of dipole clusters and proportion of dipoles in resection volume were not associated with seizure free outcome (p>0.05). In seven cases with MRI lesions, six of these with a >=70% dipoles within the resection margin were seizure-free, while one with the proportion <70% was not seizure-free. Further, among the 15 cases with non localized or normal MRI, five with both the proportion <70% and multiple dipoles clusters were post-operatively seizure free. CONCLUSION: Number and density of clustered spike dipole sources within the surgical resection volume is not associated with postoperative seizure-free outcome. MSI successfully localized the perilesional epileptogenic zone in cases with localized MRI lesions, but not in cases with normal MRI in this study. Even if MEG localizes spikes to a single focal region, confirmation of epilepsy localization with intracranial EEG is still recommended in cases with non-lesional MRI. PMID- 23689014 TI - Orientation pop-out processing in human visual cortex. AB - Visual stimuli can "pop out" if they are different to their background. There has been considerable debate as to the role of primary visual cortex (V1) versus higher visual areas (esp. V4) in pop-out processing. Here we parametrically modulated the relative orientation of stimuli and their backgrounds to investigate the neural correlates of pop-out in visual cortex while subjects were performing a demanding fixation task in a scanner. Whole brain and region of interest analyses confirmed a representation of orientation contrast in extrastriate visual cortex (V4), but not in striate visual cortex (V1). Thus, although previous studies have shown that human V1 can be involved in orientation pop-out, our findings demonstrate that there are cases where V1 is "blind" and pop-out detection is restricted to higher visual areas. Pop-out processing is presumably a distributed process across multiple visual regions. PMID- 23689015 TI - Impartiality in humans is predicted by brain structure of dorsomedial prefrontal cortex. AB - The moral force of impartiality (i.e. the equal treatment of all human beings) is imperative for providing justice and fairness. Yet, in reality many people become partial during intergroup interactions; they demonstrate a preferential treatment of ingroup members and a discriminatory treatment of outgroup members. Some people, however, do not show this intergroup bias. The underlying sources of these inter-individual differences are poorly understood. Here we demonstrate that the larger the gray matter volume and thickness of the dorsomedial prefrontal cortex (DMPFC), the more individuals in the role of an uninvolved third-party impartially punish outgroup and ingroup perpetrators. Moreover, we show evidence for a possible mechanism that explains the impact of DMPFC's gray matter volume on impartiality, namely perspective-taking. Large gray matter volume of DMPFC seems to facilitate equal perspective-taking of all sides, which in turn leads to impartial behavior. This is the first evidence demonstrating that brain structure of the DMPFC constitutes an important source underlying an individual's propensity for impartiality. PMID- 23689017 TI - Temporally-structured acquisition of multidimensional optical imaging data facilitates visualization of elusive cortical representations in the behaving monkey. AB - Fundamental understanding of higher cognitive functions can greatly benefit from imaging of cortical activity with high spatiotemporal resolution in the behaving non-human primate. To achieve rapid imaging of high-resolution dynamics of cortical representations of spontaneous and evoked activity, we designed a novel data acquisition protocol for sensory stimulation by rapidly interleaving multiple stimuli in continuous sessions of optical imaging with voltage-sensitive dyes. We also tested a new algorithm for the "temporally structured component analysis" (TSCA) of a multidimensional time series that was developed for our new data acquisition protocol, but was tested only on simulated data (Blumenfeld, 2010). In addition to the raw data, the algorithm incorporates prior knowledge about the temporal structure of the data as well as input from other information. Here we showed that TSCA can successfully separate functional signal components from other signals referred to as noise. Imaging of responses to multiple visual stimuli, utilizing voltage-sensitive dyes, was performed on the visual cortex of awake monkeys. Multiple cortical representations, including orientation and ocular dominance maps as well as the hitherto elusive retinotopic representation of orientation stimuli, were extracted in only 10s of imaging, approximately two orders of magnitude faster than accomplished by conventional methods. Since the approach is rather general, other imaging techniques may also benefit from the same stimulation protocol. This methodology can thus facilitate rapid optical imaging explorations in monkeys, rodents and other species with a versatility and speed that were not feasible before. PMID- 23689018 TI - Emotion regulation by cognitive reappraisal - the role of frontal theta oscillations. AB - The regulation of emotion by cognitive reappraisal has attracted a lot of attention over the last decade. Studies using functional magnetic resonance imaging (fMRI) revealed a wide-spread network of multiple prefrontal and sub cortical brain regions involved in the successful decrease of negative emotions. However, less is known about the temporal dynamics and the physiological mechanisms underlying these regulation processes. Synchronization of neural oscillations in specific frequency bands plays a key-role in the long-range interaction of different brain regions and oscillatory coupling in the theta frequency range was recently identified to play an important role in the interaction of prefrontal structures, the amygdala and the hippocampus in animal models. Accordingly, we investigated the role of prefrontal theta oscillations during the cognitive reappraisal of aversive pictures in humans. We hypothesized an increase in frontal theta oscillations during emotion regulation and a relationship between frontal theta power and the subjective success of emotion regulation. EEG from 30 healthy participants was recorded while they were asked to passively watch or reappraise the content of pictures with negative content. As expected, we found a significant increase in frequencies around 4Hz at electrode Fz during the regulation condition 'decrease' compared to the 'maintain' condition (p=.006) as well as for the regulation condition 'increase' compared to the 'maintain' condition (p=.017). Additionally, the strength of theta power was positively correlated with the regulation success as reported by the participants (r=0.463, p<.05). The estimation of possible generators of the theta oscillations was done using standardized low resolution electromagnetic tomography (sLORETA). Results suggested the left middle/inferior frontal gyrus as a possible generator. The results of the present study are in line with previous findings of fMRI studies suggesting the same regions as part of the regulation network and provide a first direct link between the imaging based knowledge of emotion regulation and a possible physiological mechanism. PMID- 23689016 TI - Characterization of the temporo-parietal junction by combining data-driven parcellation, complementary connectivity analyses, and functional decoding. AB - The right temporo-parietal junction (RTPJ) is consistently implicated in two cognitive domains, attention and social cognitions. We conducted multi-modal connectivity-based parcellation to investigate potentially separate functional modules within RTPJ implementing this cognitive dualism. Both task-constrained meta-analytic coactivation mapping and task-free resting-state connectivity analysis independently identified two distinct clusters within RTPJ, subsequently characterized by network mapping and functional forward/reverse inference. Coactivation mapping and resting-state correlations revealed that the anterior cluster increased neural activity concomitantly with a midcingulate-motor-insular network, functionally associated with attention, and decreased neural activity concomitantly with a parietal network, functionally associated with social cognition and memory retrieval. The posterior cluster showed the exact opposite association pattern. Our data thus suggest that RTPJ links two antagonistic brain networks processing external versus internal information. PMID- 23689019 TI - [Anesthesia-related cardiac arrest in children. Data from a tertiary referral hospital registry]. AB - OBJECTIVES: The aim of this study is to analyze the cardiac arrests related to anesthesia in a tertiary children's hospital, in order to identify risk factors that would lead to opportunities for improvement. METHODS: A 5-year retrospective study was conducted on anesthesia related cardiac arrest occurring in pediatric patients. All urgent and elective anesthetic procedures performed by anesthesiologists were included. Data collected included patient characteristics, the procedure, the probable cause, and outcome of the cardiac arrest. Odds ratio was calculated by univariate analysis to determine the clinical factors associated with cardiac arrest and mortality. RESULTS: There were a total of 15 cardiac arrests related to anesthesia in 43,391 anesthetic procedures (3.4 per 10,000), with an incidence in children with ASA I-II versus ASA>=III of 0.28 and 19.27 per 10,000, respectively. The main risk factors were children ASA>=III (P<.001), less than one month old (P<.001), less than one year old (P<.001), emergency procedures (P<.01), cardiac procedures (P<.001) and procedures performed in the catheterization laboratory (P<.05). The main causes of cardiac arrest were cardiovascular (53.3%), mainly due to hypovolemia, and cardiovascular depression associated with induction of anesthesia, followed by respiratory causes (20%), and medication causes (20%). The incidence of mortality and neurological injury within the first 24h after the cardiac arrest was 0.92 and 1.38 per 10,000, respectively. The mortality in the first 3 months was 1.6 per 10,000. The main causes of death were ASA>=III, age under one year, pulmonary arterial hypertension, cardiac arrest in areas remote from the surgery area, a duration of cardiopulmonary resuscitation over 20min, and when hypothermia was not applied after cardiac arrest. CONCLUSION: The main risk factors for cardiac arrest were ASA>=III, age under one year, emergency procedures, cardiology procedures and procedures performed in the catheterization laboratory. The main cause of the cardiac arrest was due mainly to cardiovascular hypovolemia. All patients who died or had neurological injury were ASA>=III. Pulmonary arterial hypertension is a risk of anesthesia-related mortality. PMID- 23689020 TI - The adaptive invasion of epialleles in a heterogeneous environment. AB - The evolution of transgenerational epigenetic adaptation is driven by the invasion and stable inheritance of epialleles. Here, we describe a population genetic model subject to environmentally-induced epigenetic effects in order to investigate the conditions under which an epigenetically modifiable allele (epiallele) can invade a population insensitive to such cues. Here, epigenetically modifiable individuals have the potential to develop a phenotype that is suitable for their predicted future environment and, provided this prediction is correct, possess a biological advantage compared to their non modifiable counterpart. However, when individuals experience an environment that 'mismatches' their phenotype, an advantage over unmodifiable individuals may be precluded and instead they experience a decrease in fitness. These epigenetic modifications are then inherited by the next generation which are either epigenetically reset to match their environment or, by resisting environmental cues, maintain their epigenetic status. We found that when environmental cues were common, a severe fitness cost of mismatch between environment and phenotype meant that the disadvantage was too costly and epialleles were less likely to invade. Moreover, for a wide range of parameters, a higher rate of germline epigenetic resetting decreased the likelihood of epiallele invasion. Accordingly, we found that both the frequency of environmental influences and the rate of resetting were central parameters in this system. PMID- 23689021 TI - Taylor's power law of fluctuation scaling and the growth-rate theorem. AB - Taylor's law (TL), a widely verified empirical relationship in ecology, states that the variance of population density is approximately a power-law function of mean density. The growth-rate theorem (GR) states that, in a subdivided population, the rate of change of the overall growth rate is proportional to the variance of the subpopulations' growth rates. We show that continuous-time exponential change implies GR at every time and, asymptotically for large time, TL with power-law exponent 2. We also show why diverse population-dynamic models predict TL in the limit of large time by identifying simple features these models share: If the mean population density and the variance of population density are (exactly or asymptotically) non-constant exponential functions of a parameter (e.g., time), then the variance of density is (exactly or asymptotically) a power law function of mean density. PMID- 23689022 TI - A dynamic model of the marriage market-Part 2: simulation of marital states and application to empirical data. AB - A dynamic, two-sex, age-structured marriage model is presented. Part 1 focused on first marriage only and described a marriage market matching algorithm. In Part 2 the model is extended to include divorce, widowing, and remarriage. The model produces a self-consistent set of marital states distributed by age and sex in a stable population by means of a gender-symmetric numerical method. The model is compared with empirical data for the case of Zambia. Furthermore, a dynamic marriage function for a changing population is demonstrated in simulations of three hypothetical scenarios of elevated mortality in young to middle adulthood. The marriage model has its primary application to simulation of HIV-AIDS epidemics in African countries. PMID- 23689023 TI - Stochastic gene expression in mammals: lessons from olfaction. AB - One of the remarkable characteristics of higher organisms is the enormous assortment of cell types that emerge from a common genome. The immune system, with the daunting duty of detecting an astounding number of pathogens, and the nervous system with the equally bewildering task of perceiving and interpreting the external world, are the quintessence of cellular diversity. As we began to appreciate decades ago, achieving distinct expression programs among similar cell types cannot be accomplished solely by deterministic regulatory systems, but by the involvement of some type of stochasticity. In the last few years our understanding of these non-deterministic mechanisms is advancing, and this review will provide a brief summary of the current view of stochastic gene expression with focus on olfactory receptor (OR) gene choice, the epigenetic underpinnings of which recently began to emerge. PMID- 23689025 TI - Comparative analysis of nucleosides and nucleobases from different sections of Elaphuri Davidiani Cornu and Cervi Cornu by UHPLC-MS/MS. AB - A rapid and sensitive hydrophilic interaction liquid chromatography method was developed for the identification and quantitative determination of 17 nucleosides and nucleobases by using ultra-high performance liquid chromatography separation system coupled to triple quadrupole mass spectrometer. Sufficient separation of the target compounds was achieved on an Acquity BEH Amide column (2.1 mm * 100 mm, 1.7 MUm) in a single run of 9 min. The LOD and LOQ were in the range of 0.017 50.00 ng ml(-1) and 0.056-146.00 ng ml(-1), respectively. Then, the method was applied for the analysis of nucleosides and nucleobases in Elaphuri Davidiani Cornu and Cervi Cornu. Multivariate statistical analysis was also used to investigate the differences in the nucleosides and nucleobases profiles among the samples. The present study also provided helpful information for quality control of Elaphuri Davidiani Cornu and Cervi Cornu. PMID- 23689026 TI - Cobalt complexes as artificial hydrogenases for the reductive side of water splitting. AB - The generation of H2 from protons and electrons by complexes of cobalt has an extensive history. During the past decade, interest in this subject has increased as a result of developments in hydrogen generation that are driven electrochemically or photochemically. This article reviews the subject of hydrogen generation using Co complexes as catalysts and discusses the mechanistic implications of the systems studied for making H2. This article is part of a Special Issue entitled: Metals in Bioenergetics and Biomimetics Systems. PMID- 23689027 TI - The validation and application of a finite element human head model for frontal skull fracture analysis. AB - Traumatic head injuries can result from vehicular accidents, sports, falls or assaults. The current advances in computational methods and the detailed finite element models of the human head provide a significant opportunity for biomechanical study of human head injuries. The biomechanical characteristics of the human head through head impact scenarios can be studied in detail by using the finite element models. Skull fracture is one of the most frequent occurring types of head injuries. The purpose of this study is to analyse the experimental head impacts on cadavers by means of the Strasbourg University Finite Element Head Model (SUFEHM). The results of the numerical model and experimental data are compared for validation purpose. The finite element model has also been applied to predict the skull bone fracture in frontal impacts. The head model includes the scalp, the facial bone, the skull, the cerebral spinal fluid, the meninges, the cerebrum and the cerebellum. The model is used to simulate the experimental frontal head impact tests using a cylindrical padded impactor. Results of the computational simulation shows that the model correlated well with a number of experimental data and a global fracture pattern has been predicted well by the model. Therefore the presented numerical model could be used for reconstruction of head impacts in different impact conditions also the forensic application of the head model would provide a tool for investigation of the causes and mechanism of head injuries. PMID- 23689028 TI - On a staggered iFEM approach to account for friction in compression testing of soft materials. AB - An inverse finite element method (iFEM) to estimate material parameters from compression tests of soft materials is presented, where alginate hydrogel was used as a phantom material. The method applies if the boundary conditions at the loaded surfaces are not ideal, i.e. neither free of friction nor fully constrained, as it may be the case in most realistic testing set-ups. Assuming a linear friction law, the friction coefficient MU was considered unknown and estimated in a first step by minimising the difference between the contours of the sample, obtained by optical measurements, and the simulated shape. Force displacement data were used in a second step to determine the parameters of the constitutive law. Staggering these two steps, both friction and material parameters were identified by optimisation. Skipping the first step and predefining MU instead, a unique parameter set could only be clearly identified if the deviations of the contours were considered in addition to the deviations in the force-displacement data. Finally, forward FEM calculations with differently shaped specimens were used to verify the goodness of the obtained parameter sets. PMID- 23689029 TI - Development of a risk-adjustment model for antimicrobial utilization data in 21 public hospitals in Queensland, Australia (2006-11). AB - OBJECTIVES: Making valid comparisons of antimicrobial utilization between hospitals requires risk adjustment for each hospital's case mix. Data on individual patients may be unavailable or difficult to process. Therefore, risk adjustment for antimicrobial usage frequently needs to be based on a hospital's services. This study evaluated such a strategy for hospital antimicrobial utilization. METHODS: Data were obtained on five broad subclasses of antibiotics [carbapenems, beta-lactam/beta-lactamase inhibitor combinations (BLBLIs), fluoroquinolones, glycopeptides and third-generation cephalosporins] from the Queensland pharmacy database (MedTrx) for 21 acute public hospitals (2006-11). Eleven clinical services and a variable for hospitals from the tropical region were employed for risk adjustment. Multivariable regression models were used to identify risk and protective services for these antibiotics. Funnel plots were used to display hospitals' antimicrobial utilization. RESULTS: Total inpatient antibiotic utilization for these antibiotics increased from 130.6 defined daily doses (DDDs)/1000 patient-days in 2006 to 155.8 DDDs/1000 patient-days in 2011 (P < 0.0001). Except for third-generation cephalosporins, the average utilization rate was higher for intensive care, renal/nephrology, cardiac, burns/plastic surgery, neurosurgery, transplant and acute spinal services than for the respective reference group (no service). In addition, oncology, high-activity infectious disease and coronary care services were associated with higher utilization of carbapenems, BLBLIs and glycopeptides. CONCLUSIONS: Our model predicted antimicrobial utilization rates by hospital services. The funnel plots displayed hospital utilization data after adjustment for variation among the hospitals. However, the methodology needs to be validated in other populations, ideally using a larger group of hospitals. PMID- 23689030 TI - The neuropeptides alpha-MSH and NPY modulate phagocytosis and phagolysosome activation in RAW 264.7 cells. AB - Within the immunosuppressive ocular microenvironment, there are constitutively present the immunomodulating neuropeptides alpha-melanocyte stimulating hormone (alpha-MSH) and neuropeptide Y (NPY) that promote suppressor functionality in macrophages. In this study, we examined the possibility that alpha-MSH and NPY modulate phagocytic activity in macrophages. The macrophages treated with alpha MSH and NPY were significantly suppressed in their capacity to phagocytize unopsonized Escherichia coli and Staphylococcus aureus bioparticles, but not antibody-opsonized bioparticles. The neuropeptides significantly suppressed phagolysosome activation, and the FcR-associated generation of reactive oxidative species as well. This suppression corresponds to neuropeptide modulation of macrophage functionality within the ocular microenvironment to suppress the activation of immunogenic inflammation. PMID- 23689031 TI - Effects of hyperhomocysteinemia and betaine-homocysteine S-methyltransferase inhibition on hepatocyte metabolites and the proteome. AB - Both cardiovascular disease and liver injury are major public health issues. Hyperhomocysteinemia has been linked to cardiovascular diseases, and defects in methyl group metabolism, often resulting in hyperhomocysteinemia, are among the key molecular events postulated to play a role in liver injury. We employed proteomics and metabolomics analyses of human hepatocytes in primary cell culture to explore the spectrum of proteins and associated metabolites affected by the disruption of methyl group metabolism. We treated the hepatocytes with homocysteine (Hcy, 0.1mM and 2mM) to follow the impact of hyperhomocysteinemia, and in parallel, we used a specific inhibitor of betaine-homocysteine S methyltransferase (BHMT) to extend our understanding of the physiological functions of the enzyme. The major effect of BHMT inhibition was a 50% decrease in S-adenosylmethionine levels. The treatments with Hcy resulted in multiple changes in the metabolite levels depending on the treatment modality. The BHMT inhibition and 0.1mM Hcy treatment induced only moderate changes in the hepatocyte proteome and secretome, while the changes induced by the 2mM Hcy treatment were extensive. Phosphatidylethanolamine carboxykinase and ornithine aminotransferase were up-regulated about two fold indicating an intervention into metabolism. Cellular proliferation was suspended, secretome composition was changed and signs of apoptosis were discernible. We have detected fibrinogen gamma dimers, which might have a role as a potentially new biomarker of early liver injury. Finally, we have demonstrated the failed maturation of apolipoprotein A1, which might be a new mechanism of disruption of cholesterol efflux from tissues. PMID- 23689032 TI - [Opsoclonus-myoclonus syndrome associated with leptospirosis]. PMID- 23689033 TI - Preclinical QT safety assessment: cross-species comparisons and human translation from an industry consortium. AB - INTRODUCTION: In vivo models have been required to demonstrate relative cardiac safety, but model sensitivity has not been systematically investigated. Cross species and human translation of repolarization delay, assessed as QT/QTc prolongation, has not been compared employing common methodologies across multiple species and sites. Therefore, the accurate translation of repolarization results within and between preclinical species, and to man, remains problematic. METHODS: Six pharmaceutical companies entered into an informal consortium designed to collect high-resolution telemetered data in multiple species (dog; n=34, cynomolgus; n=37, minipig; n=12, marmoset; n=14, guinea pig; n=5, and man; n=57). All animals received vehicle and varying doses of moxifloxacin (3-100 mg/kg, p.o.) with telemetered ECGs (>=500 Hz) obtained for 20-24h post-dose. Individual probabilistic QT-RR relationships were derived for each subject. The rate-correction efficacies of the individual (QTca) and generic correction formulae (Bazett, Fridericia, and Van de Water) were objectively assessed as the mean squared slopes of the QTc-RR relationships. Normalized moxifloxacin QTca responses (Veh Delta%/MUM) were derived for 1h centered on the moxifloxacin Tmax. RESULTS: All QT-RR ranges demonstrated probabilistic uncertainty; slopes varied distinctly by species where dog and human exhibited the lowest QT rate dependence, which was much steeper in the cynomolgus and guinea pig. Incorporating probabilistic uncertainty, the normalized QTca-moxifloxacin responses were similarly conserved across all species, including man. DISCUSSION: The current results provide the first unambiguous evidence that all preclinical in vivo repolarization assays, when accurately modeled and evaluated, yield results that are consistent with the conservation of moxifloxacin-induced QT prolongation across all common preclinical species. Furthermore, these outcomes are directly transferable across all species including man. The consortium results indicate that the implementation of standardized QTc data presentation, QTc reference cycle lengths, and rate-correction coefficients can markedly improve the concordance of preclinical and clinical outcomes in most preclinical species. PMID- 23689034 TI - Surgical management of breast deformity in a young patient with localized scleroderma: a case report and literature review. AB - Localized scleroderma in the chest region of adolescent girls leads to incomplete breast development and breast asymmetry, for which patients may require treatment. The site of localized scleroderma, its activity, the surgeon, and the patient's desires influence the selection of treatment method. There have been few reports on surgical treatment of this disease. In the current report, we present a case in which improved breast asymmetry was achieved through multiphased surgery, and we review treatment methods and indications of this disease. PMID- 23689035 TI - Interplay effects in proton scanning for lung: a 4D Monte Carlo study assessing the impact of tumor and beam delivery parameters. AB - Relative motion between a tumor and a scanning proton beam results in a degradation of the dose distribution (interplay effect). This study investigates the relationship between beam scanning parameters and the interplay effect, with the goal of finding parameters that minimize interplay. 4D Monte Carlo simulations of pencil beam scanning proton therapy treatments were performed using the 4DCT geometry of five lung cancer patients of varying tumor size (50.4 167.1 cc) and motion amplitude (2.9-30.1 mm). Treatments were planned assuming delivery in 35 * 2.5 Gy(RBE) fractions. The spot size, time to change the beam energy (taues), time required for magnet settling (tauss), initial breathing phase, spot spacing, scanning direction, scanning speed, beam current and patient breathing period were varied for each of the five patients. Simulations were performed for a single fraction and an approximation of conventional fractionation. For the patients considered, the interplay effect could not be predicted using the superior-inferior motion amplitude alone. Larger spot sizes (sigma ~ 9-16 mm) were less susceptible to interplay, giving an equivalent uniform dose (EUD) of 99.0 +/- 4.4% (1 standard deviation) in a single fraction compared to 86.1 +/- 13.1% for smaller spots (sigma ~ 2-4 mm). The smaller spot sizes gave EUD values as low as 65.3% of the prescription dose in a single fraction. Reducing the spot spacing improved the target dose homogeneity. The initial breathing phase can have a significant effect on the interplay, particularly for shorter delivery times. No clear benefit was evident when scanning either parallel or perpendicular to the predominant axis of motion. Longer breathing periods decreased the EUD. In general, longer delivery times led to lower interplay effects. Conventional fractionation showed significant improvement in terms of interplay, giving a EUD of at least 84.7% and 100.0% of the prescription dose for the small and larger spot sizes respectively. The interplay effect is highly patient specific, depending on the motion amplitude, tumor location and the delivery parameters. Large degradations of the dose distribution in a single fraction were observed, but improved significantly using conventional fractionation. PMID- 23689036 TI - Effects of pre-exercise sucralose ingestion on carbohydrate oxidation during exercise. AB - Recent studies have demonstrated a direct link between increased exogenous CHO oxidation (CHOexog) and enhanced performance. The limiting factor for CHOexog appears to be at the level of intestinal transporters, with sodium/glucose cotransporter 1 (SGLT1) and glucose transporter Type 5 (GLUT5) responsible for glucose and fructose transport, respectively. Studies in animal models have shown that SGLT1 and intestinal glucose uptake are up-regulated by high carbohydrate diets or noncaloric sweeteners. The aim of this study was to determine the effect of preexercise ingestion of noncaloric sweeteners on CHOexog during exercise in athletes. In a randomized, crossover, double-blind fashion twenty-three healthy male cyclists (age = 29 +/- 7 yrs, mass = 73.6 +/- 7.4 kg, VO2peak = 68.3 +/- 9.3 ml/kg/min) consumed 8 * 50 ml doses of either placebo (CON) or 1mM sucralose (SUCRA) every 15 min starting 120 min before the onset of exercise. This was followed by 2h of cycling at 48.5 +/- 8.6% of VO2peak with continual ingestion of a maltodextrin drink (1.2 g/min; 828 ml/ hr). Average CHOexog during the first hour of exercise did not differ between SUCRA and CON conditions (0.226 +/- 0.081 g/min vs. 0.212 +/- 0.076 g/min, Delta =0.015 g/min, 95% CI -0.008 g/min, 0.038 g/min, p = .178). Blood glucose, plasma insulin and lactate, CHO and fat substrate utilization, heart rate, ratings of perceived exertion, and gastrointestinal symptoms did not differ between conditions. Our data suggest that consumption of noncaloric sweeteners in the immediate period before exercise does not lead to a significant increase in CHOexog during exercise. PMID- 23689037 TI - Anaplastic ganglioglioma in the spinal cord: case report and literature review. AB - Anaplastic ganglioglioma (AGG) is a rare tumor. A PubMed database search yielded only a few case reports and fewer case series. An even rarer entity is AGG arising in the spinal cord. We present a case of a pediatric patient with a pathological diagnosis of spinal AGG. PMID- 23689039 TI - Nevin Stewart Scrimshaw, PhD, MD, MPH, 1918-2013. PMID- 23689038 TI - Crowdsourcing a normative natural language dataset: a comparison of Amazon Mechanical Turk and in-lab data collection. AB - BACKGROUND: Crowdsourcing has become a valuable method for collecting medical research data. This approach, recruiting through open calls on the Web, is particularly useful for assembling large normative datasets. However, it is not known how natural language datasets collected over the Web differ from those collected under controlled laboratory conditions. OBJECTIVE: To compare the natural language responses obtained from a crowdsourced sample of participants with responses collected in a conventional laboratory setting from participants recruited according to specific age and gender criteria. METHODS: We collected natural language descriptions of 200 half-minute movie clips, from Amazon Mechanical Turk workers (crowdsourced) and 60 participants recruited from the community (lab-sourced). Crowdsourced participants responded to as many clips as they wanted and typed their responses, whereas lab-sourced participants gave spoken responses to 40 clips, and their responses were transcribed. The content of the responses was evaluated using a take-one-out procedure, which compared responses to other responses to the same clip and to other clips, with a comparison of the average number of shared words. RESULTS: In contrast to the 13 months of recruiting that was required to collect normative data from 60 lab sourced participants (with specific demographic characteristics), only 34 days were needed to collect normative data from 99 crowdsourced participants (contributing a median of 22 responses). The majority of crowdsourced workers were female, and the median age was 35 years, lower than the lab-sourced median of 62 years but similar to the median age of the US population. The responses contributed by the crowdsourced participants were longer on average, that is, 33 words compared to 28 words (P<.001), and they used a less varied vocabulary. However, there was strong similarity in the words used to describe a particular clip between the two datasets, as a cross-dataset count of shared words showed (P<.001). Within both datasets, responses contained substantial relevant content, with more words in common with responses to the same clip than to other clips (P<.001). There was evidence that responses from female and older crowdsourced participants had more shared words (P=.004 and .01 respectively), whereas younger participants had higher numbers of shared words in the lab-sourced population (P=.01). CONCLUSIONS: Crowdsourcing is an effective approach to quickly and economically collect a large reliable dataset of normative natural language responses. PMID- 23689040 TI - Concurrent chemoradiotherapy with a novel fluoropyrimidine, S-1, and cisplatin for locally advanced esophageal cancer: long-term results of a phase II trial. AB - OBJECTIVES: A phase II study was performed to investigate the safety and efficacy of concurrent chemoradiotherapy (CCRT) combined with an orally active fluoropyrimidine, S-1, plus cisplatin for locally advanced esophageal cancer (LAEC). METHODS: CCRT comprised 2 courses, a 30-Gy radiotherapy over 3 weeks plus daily oral S-1 (80 mg/m(2)/day) for 2 weeks and a 24-hour cisplatin infusion (70 mg/m(2)) on day 8, and an identical course administered after a 2-week break. RESULTS: One hundred and sixteen patients, 12 with stage II, 71 with stage III, and 33 with stage IVa LAEC participated, and 106 of them (91.4%) completed the CCRT course. The most serious toxicity was myelosuppression: grade 3 and 4 neutropenia occurred in 28.4 and 9.5% of patients, respectively. Nonhematologic toxicity was moderate. Complete response rates in patients with stage II, III, and IVa LAEC were 91.7, 67.6, and 36.4%, respectively. The overall median survival time was 2.3 years and that of patients with stage II, III, and IVa cancer was 7.0, 2.6, and 1.3 years, respectively. CONCLUSIONS: CCRT combined with S-1 plus cisplatin showed promising safety and efficacy. Potentially, this combination therapy could become a baseline medication for patients with LAEC. PMID- 23689041 TI - Phasing-in plasma metanephrines determination. AB - OBJECTIVES: We set up plasma normetanephrine (pNMA) and metanephrine (pMA) assays as they demonstrated their usefulness for diagnosing phaeochromocytomas. Our scope is to describe some practical laboratory aspects and the clinical relevance of these assays in our endocrinological or cardiological departments. METHODS: We retrospectively reviewed the results of MA from a population of in- and outpatients over a 7-year period. Subjects (n=2536) from endocrinological or cardiological departments were investigated (66 phaeochromocytomas). Urinary NMA (uNMA) and pNMA, and urinary MA (uMA) and pMA were assayed by HPLC with electrochemical detection. RESULTS: pNMA and pMA assays are now more frequently requested than uNMA and uMA. This changed our laboratory work load with improved delivery, sensitivity and reliability of plasma assays as well as reduced apparatus maintenance time. The pNMA and pMA upper reference limits (URLs) of subjects with no phaeochromocytoma were 1040 and 430 pmol/l respectively. Sensitivity and specificity based on receiver operating characteristic curves optimal points were 83 and 93% for pNMA at 972 pmol/l and 67 and 98% for pMA at 638 pmol/l. Sensitivity and specificity of paired tests of pMA (positive test: at least one analyte above its URLs) were 100 and 91% respectively. CONCLUSION: The very low concentration of analytes requires a sustained very good apparatus analytical sensitivity. This can be obtained in an up-to-date laboratory. In terms of clinical performances, assays in plasma or urine are equivalent. Depending on local preferences, populations, strategies or departments, requests for one or the other assay may sustain the need for specifically defined reference ranges. PMID- 23689042 TI - New advances in the integrated management of food processing by-products in Europe: sustainable exploitation of fruit and cereal processing by-products with the production of new food products (NAMASTE EU). AB - By-products generated every year by the European fruit and cereal processing industry currently exceed several million tons. They are disposed of mainly through landfills and thus are largely unexploited sources of several valuable biobased compounds potentially profitable in the formulation of novel food products. The opportunity to design novel strategies to turn them into added value products and food ingredients via novel and sustainable processes is the main target of recently EC-funded FP7 project NAMASTE-EU. NAMASTE-EU aims at developing new laboratory-scale protocols and processes for the exploitation of citrus processing by-products and wheat bran surpluses via the production of ingredients useful for the formulation of new beverage and food products. Among the main results achieved in the first two years of the project, there are the development and assessment of procedures for the selection, stabilization and the physical/biological treatment of citrus and wheat processing by-products, the obtainment and recovery of some bioactive molecules and ingredients and the development of procedures for assessing the quality of the obtained ingredients and for their exploitation in the preparation of new food products. PMID- 23689043 TI - Uranium removal from a contaminated effluent using a combined microbial and nanoparticle system. AB - Reduction of soluble uranium(VI) to insoluble uranium(IV) for remediating a uranium-contaminated effluent (EF-03) was examined using a biotic and abiotic integrated system. Shewanella putrefaciens was first used and reduced U(VI) in a synthetic medium but not in the EF-03 effluent sample. Subsequently the growth of autochthonous microorganisms was stimulated with lactate. When lactate was supported on active carbon 77% U(VI) was removed in 4 days. Separately, iron nanoparticles that were 50 nm in diameter reduced U(VI) by 60% in 4 hours. The efficiency of uranium(VI) removal was improved to 96% in 30 min by using a system consisting of lactate and iron nanoparticles immobilized on active carbon. Lactate also stimulated the growth of potential uranium-reducing microorganisms in the EF-03 sample. This system can be efficiently used for the bioremediation of uranium-contaminated effluents. PMID- 23689044 TI - Patient and societal value functions for the testing morbidities index. AB - BACKGROUND: We developed preference-based and summated scale scoring for the Testing Morbidities Index (TMI) classification, which addresses short-term effects on quality of life from diagnostic testing before, during, and after testing procedures. METHODS: The two TMI preference functions use multiattribute value techniques; one is patient-based and the other has a societal perspective, informed by 206 breast biopsy patients and 466 (societal) subjects. Because of a lack of standard short-term methods for this application, we used the visual analog scale (VAS). Waiting tradeoff (WTO) tolls provided an additional option for linear transformation of the TMI. We randomized participants to 1 of 3 surveys: The first derived weights for generic testing morbidity attributes and levels of severity with the VAS; a second developed VAS values and WTO tolls for linear transformation of the TMI to a "dead-healthy" scale; the third addressed initial validation in a specific test (breast biopsy). The initial validation included 188 patients and 425 community subjects. Direct VAS and WTO values were compared with the TMI. Alternative TMI scoring as a nonpreference summated scale was included, given evidence of construct and content validity. RESULTS: The patient model can use an additive function, whereas the societal model is multiplicative. Direct VAS and the VAS-scaled TMI were correlated across modeling groups (r = 0.45-0.62). Agreement was comparable to the value function validation of the Health Utilities Index 2. Mean absolute difference (MAD) calculations showed a range of 0.07-0.10 in patients and 0.11-0.17 in subjects. MAD for direct WTO tolls compared with the WTO-scaled TMI varied closely around 1 quality adjusted life day. CONCLUSIONS: The TMI shows initial promise in measuring short term testing-related health states. PMID- 23689045 TI - A standardized technique for the blood sedimentation test. 1935. PMID- 23689046 TI - Large paraesophageal varices causing recurrent hepatic encephalopathy. PMID- 23689047 TI - Effect of oxygen-driven nebulization at different oxygen flows in acute exacerbation of chronic obstructive pulmonary disease patients. AB - OBJECTIVES: The aim of this study was to study the effect of oxygen-driven nebulization (ODN) at different oxygen flows on heart rate, respiratory rate, SpO2, SaO2, PaO2, PaCO2 and pH of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients. METHODS: According to random number table, 9 AECOPD patients were randomly divided into 3 groups, numbered A, B and C and treated with ODN. Oxygen flow of groups A, B and C was 4-5, 6-7 and 8-9 L/min, respectively. Heart rate, respiratory rate, SpO2, SaO2, PaO2, PaCO2 and pH were recorded before ODN and 30 minutes after ODN. Statistical differences of data before or after ODN were analyzed by analysis of variance and F-test, whereas data before and after ODN were tested by paired t test. RESULTS: There was no significant difference of heart rate, respiratory rate, SpO2, PaO2, PaCO2, SaO2 and pH among 3 groups before ODN or after ODN. The heart rate was increased in all groups after ODN. But significant increase was only present in groups A and C but not in group B. SaO2 was significantly increased in group C after ODN but no statistical difference was observed between before and after ODN in groups A and B. There was no significant change in respiratory rate, SpO2, PaO2, PaCO2, SaO2 and pH between before and after ODN in all groups. CONCLUSIONS: Optimal oxygen flow in ODN-treating AECOPD patients may be 6-7 L/min. PMID- 23689049 TI - Community-acquired methicillin-resistant Staphylococcus aureus prostatic abscesses. AB - We describe 2 men with prostatic abscesses due to community-acquired methicillin resistant Staphylococcus aureus. Neither of them had diabetes mellitus, prior prostate disease, recent health care exposure or urinary instrumentation and had no evidence of bloodstream infection at the time of presentation. Both were treated with surgical drainage and prolonged antibiotics. PMID- 23689050 TI - Sepsis-associated cholestasis in adult patients: a prospective study. AB - BACKGROUND: Sepsis-associated cholestasis is a common problem in neonatal patients. However, there are limited data related to sepsis-associated cholestasis in adults. In this study, the authors assessed the clinical characteristics, risk factors and outcome of adult patients with sepsis associated cholestasis. METHODS: An observational prospective single-center study was conducted. A total of 608 patients with sepsis (66 patients with cholestasis and 542 without evidence of cholestasis) from January 1, 2005, to December 31, 2011, were included from the infectious disease unit. Demographic, clinical and laboratory information were recorded on admission for all patients. Additional data were also collected on the day of the 1st episode of bacteremia for patients who developed cholestasis. Accordingly, the organ dysfunction scores (Acute Physiology and Chronic Health Evaluation [APACHE] II and Sequential Organ Failure Assessment [SOFA]) were assessed on the same day. RESULTS: The mean age of the 608 patients was 49.3 +/- 11.4 years (range, 22-83 years); 312 (51.3%) patients were men, 296 (48.7%) were women. The mean APACHE II and SOFA score were 15.2 +/- 6 and 5.6 +/- 2.3, respectively. Sepsis-associated cholestasis was strongly associated with older age, biomarkers of organ dysfunction and clinical composite scores (APACHE II and SOFA). Mortality was higher in patients with sepsis associated cholestasis (10.6%) compared with subjects with sepsis without cholestasis (1.5%) (P < 0.05). CONCLUSIONS: The authors found that sepsis associated cholestasis affects the outcome of patients with sepsis in the infectious disease unit. Additional clinical studies are necessary to elucidate the pathology and pathophysiology of sepsis-associated cholestasis. PMID- 23689051 TI - Risk of death and need for transplantation in chronic pulmonary hypertension. AB - BACKGROUND: Echo-Doppler parameters that exemplify right ventricular (RV) outflow dynamics and measures of annular tissue Doppler imaging to assess left ventricular (LV) and RV diastolic function, known to be affected in chronic pulmonary hypertension (cPH), have never been studied to determine if they could be predictive of mortality or need for transplantation 1-year after follow-up. METHODS: Numerous echo-Doppler parameters of RV and LV performance were recorded from 120 patients. This patient population was divided into 3 groups. Group I had no PH, group II had cPH but no documented death or need for either lung or heart transplantation, at 1-year follow-up after their initial echocardiogram whereas group III had cPH and patients had either died or required heart and/or lung transplantation during the same time period. RESULTS: Analysis of variance was first used to identify which echo-Doppler variables were significant among the studied groups. A logistic regression analysis was then performed to identify predictive variables of the occurrence death and need for transplantation. Finally, a multiple regression analysis was used between groups II and III to identify which echo-Doppler variables were most useful in identifying severe cPH patients at risk of the prespecified events. CONCLUSIONS: Even though older patients with worse RV fractional area change might be considered at risk of worse prognosis in patients with severe cPH, only a low mitral annular early diastolic velocity was useful in identifying which of those individuals were at highest risk of death or in need of transplantation. PMID- 23689052 TI - Preliminary case-control study to evaluate diagnostic values of C-reactive protein and erythrocyte sedimentation rate in differentiating active Crohn's disease from intestinal lymphoma, intestinal tuberculosis and Behcet's syndrome. AB - BACKGROUND: There are few evidences of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and white blood cell (WBC) in differentiating active Crohn's disease (CD) from intestinal lymphoma (IL), intestinal tuberculosis (ITB) and Behcet's syndrome (BD). This study is designed to investigate potential differential capacity of the 3 biomarkers between these disorders. METHODS: A hospital-based case-control study was performed. A total of 29 active CD, 25 IL, 30 ITB and 17 BD patients were collected. Laboratory parameters were drawn from the first blood test results on admission. RESULTS: In active CD group, the level of CRP was 20.2 +/- 4.26 mg/dL, which was statistically lower than IL (59.9 +/- 10.8 mg/dL, P < 0.0001). Similarly, the level of ESR reached its lowest point in active CD group (23.8 +/- 3.18 mm/hr), compared with 46.6 +/- 6.46 mm/hr in IL group (P = 0.0002). CRP showed a possible diagnostic value in differentiation of IL from active CD (odds ratio = 1.028, P = 0.046). CRP also exhibited a superior ability (area under curve [AUC] = 0.821) than ESR (AUC = 0.797) and CRP+ESR (AUC = 0.800) in distinguishing active CD from IL. The optimal cutoff value was 19.7 mg/dL, and the sensitivity and specificity were 62.1% and 96.0%, respectively. CONCLUSIONS: A significant decreased level of CRP and ESR was confirmed in active CD compared with IL. Current study demonstrated a possible differential value of CRP between active CD and IL. Further studies would be performed to validate their clinical significances. PMID- 23689054 TI - Genetic polymorphisms of 9 non-CODIS short tandem repeat loci in two ethnic minority populations in Southern China. PMID- 23689053 TI - Predictors of long-term mortality after severe sepsis in the elderly. AB - BACKGROUND: Mortality rates after severe sepsis are extremely high, and the main focus of most research is short-term mortality, which may not be associated with long-term outcomes. The purpose of this study was to examine long-term mortality after a severe sepsis and identify factors associated with this mortality. METHODS: The authors performed a population-based study using Veterans' Affairs administrative data of patients aged 65 years and older. The outcome of interest was mortality > 90 days following hospitalization. Our primary analyses were Cox proportional hazard models to examine specific risk factors for long-term mortality. RESULTS: There were 2,727 patients that met the inclusion criteria. Overall mortality was 55%, and 1- and 2-year mortality rates were 31% and 43%, respectively. Factors significantly associated with long-term mortality included congestive heart failure, peripheral vascular disease, dementia, diabetes with complications and use of mechanical ventilation. Smoking cessation and cardiac medications were associated with decreased long-term mortality rates. CONCLUSIONS: The authors identified several factors, including receipt of mechanical ventilation, which were significantly associated with increased long term mortality for survivors of severe sepsis. This information will help clinicians discuss prognosis with patients and their families. PMID- 23689055 TI - Nasopharyngeal tuberculosis: CT and MRI findings in thirty-six patients. AB - PURPOSE: Tuberculosis is uncommon in the nasopharynx. The purpose of this study was to investigate the CT and MRI features of 36 cases of tuberculosis in this area. MATERIALS AND METHODS: CT (n=15) and MRI (n=21) scans from 36 patients with histologically proved tuberculosis of the nasopharynx were reviewed by two experienced radiologists, paying particular attention to the lesions' distribution, location, extent, size, internal architecture, pattern, and degree of enhancement, and cervical lymphadenopathy. RESULTS: Twenty-nine patients exhibited a polypoid mass pattern and seven had diffuse mucosal thickening. The roof of the nasopharynx was involved in all cases. The mean size of the lesions was 11.4mm. Striped pattern was detected in 19 cases. Adjacent muscle invasion or bone destruction was not detected. Heterogeneous enhancement was detected in all patients, and necrosis in the nasopharyngeal lesions was detected in 16 cases. Poor, moderate, and marked enhancement was detected in one, 27, and eight cases, respectively. Thirty-four patients had involvement of the cervical lymph nodes. Twenty-two and 28 cases were associated with bilateral lymphadenopathy or necrosis, respectively. The retropharyngeal lymph node was the most commonly involved site (94.1%). CONCLUSION: The presence of necrosis and striped pattern in nasopharyngeal lesions, site predilection, no invasion of regional structures, and central necrosis with peripheral rim enhancement of cervical lymphadenopathy may suggest the diagnosis of nasopharyngeal tuberculosis. PMID- 23689057 TI - Intranasal, liposome-adjuvanted cockroach allergy vaccines made of refined major allergen and whole-body extract of Periplaneta americana. AB - BACKGROUND: Cockroach (CR) allergens frequently cause severe asthma in CR sensitized subjects. Allergen-specific immunotherapy causes a shift of allergic Th2 responses towards Th1 and/or regulatory T cell (Treg) responses which reduce airway inflammation and prevent disease progression. Data are relatively limited on immunotherapy via CR allergy vaccine. METHODS: The therapeutic efficacy of an intranasal liposome-adjuvant vaccine made of a refined Periplaneta americana arginine kinase (AK) was compared to the liposome-entrapped P. americana crude extract (CRE) vaccine. Adult BALB/c mice were rendered allergic to CRE. Three allergic mouse groups were immunized intranasally on alternate days with 8 doses of liposome-entrapped CRE (L-CRE), liposome-entrapped AK and placebo, respectively. One week later, all mice received a nebulized CRE provocation. Evaluation of vaccine efficacy was performed 1 day after provocation. RESULTS: Liposome-entrapped native AK attenuated airway inflammation after the CRE provocation and caused a shift of allergic Th2 to Th1 and Treg responses. The L CRE also induced a shift from the Th2 to the Th1 response but did not induce a Treg response and could not attenuate the airway inflammation upon allergen reexposure. CONCLUSIONS: Intranasal liposome-adjuvant CR allergy vaccine containing native AK (Per a 9) is better than L-CRE in attenuating allergic airway inflammation. The findings of this study not only document a more comprehensive and beneficial immune response induced by the refined allergen vaccine but also raise the point that the shift from the Th2 to the Th1 response alone might not correlate with improved airway histopathology, clinical outcome and quality of life. PMID- 23689058 TI - Associations between pituitary imaging abnormalities and clinical and biochemical phenotypes in children with congenital growth hormone deficiency: data from an international observational study. AB - BACKGROUND/AIMS: Magnetic resonance imaging (MRI) is used to investigate the etiology of growth hormone deficiency (GHD). This study examined relationships between MRI findings and clinical/hormonal phenotypes in children with GHD in the observational Genetics and Neuroendocrinology of Short Stature International Study, GeNeSIS. METHODS: Clinical presentation, hormonal status and first-year GH response were compared between patients with pituitary imaging abnormalities (n = 1,071), patients with mutations in genes involved in pituitary development/GH secretion (n = 120) and patients with idiopathic GHD (n = 7,039). RESULTS: Patients with hypothalamic-pituitary abnormalities had more severe phenotypes than patients with idiopathic GHD. Additional hormonal deficiencies were found in 35% of patients with structural abnormalities (thyroid-stimulating hormone > adrenocorticotropic hormone > luteinizing hormone/follicle-stimulating hormone > antidiuretic hormone), most frequently in patients with septo-optic dysplasia (SOD). Patients with the triad [ectopic posterior pituitary (EPP), pituitary aplasia/hypoplasia and stalk defects] had a more severe phenotype and better response to GH treatment than patients with isolated abnormalities. The sex ratio was approximately equal for patients with SOD, but there was a significantly higher proportion of males (approximately 70%) in the EPP, pituitary hypoplasia, stalk defects, and triad categories. CONCLUSION: This large, international database demonstrates the value of classification of GH-deficient patients by the presence and type of hypothalamic-pituitary imaging abnormalities. This information may assist family counseling and patient management. PMID- 23689059 TI - Partial virological response to adefovir add-on lamivudine rescue therapy in patients with lamivudine-resistant chronic hepatitis B. AB - BACKGROUND/AIMS: In patients with lamivudine (LAM)-resistant chronic hepatitis B (CHB) receiving adefovir (ADV) add-on LAM therapy, insufficient viral suppression or the appearance of additional ADV resistance has remained unresolved. This study determined the partial virological response (PVR) criteria to predict a virological response (VR) at week 96 in these patients. METHODS: 96 patients with LAM-resistant CHB (ADV add-on LAM therapy >2 years) were analyzed. For predicting VR at week 96, the area under the receiver operating characteristic curve values at different time points were compared to establish the optimal time point, and the maximal Youden index was calculated to determine the optimal cut-off hepatitis B virus (HBV) DNA level. RESULTS: 50 (52.1%) patients achieved VR at 2 years after ADV add-on LAM therapy. The optimal PVR criteria were determined to be HBV DNA 500 IU/ml at week 48. 44 (45.8%) patients who met optimal PVR criteria showed a significantly higher risk for detectable HBV DNA levels at week 96 than those with a favorable VR (HBV DNA <500 IU/ml) at week 48. CONCLUSIONS: This study suggested optimal PVR criteria in patients with LAM-resistant CHB receiving ADV add-on LAM therapy. Modification of the antiviral agent regimen should be considered if the serum HBV DNA level exceeds 500 IU/ml at week 48. PMID- 23689060 TI - Correction for 'artificial' electron disequilibrium due to cone-beam CT density errors: implications for on-line adaptive stereotactic body radiation therapy of lung. AB - Cone-beam computed tomography (CBCT) has rapidly become a clinically useful imaging modality for image-guided radiation therapy. Unfortunately, CBCT images of the thorax are susceptible to artefacts due to scattered photons, beam hardening, lag in data acquisition, and respiratory motion during a slow scan. These limitations cause dose errors when CBCT image data are used directly in dose computations for on-line, dose adaptive radiation therapy (DART). The purpose of this work is to assess the magnitude of errors in CBCT numbers (HU), and determine the resultant effects on derived tissue density and computed dose accuracy for stereotactic body radiation therapy (SBRT) of lung cancer. Planning CT (PCT) images of three lung patients were acquired using a Philips multi-slice helical CT simulator, while CBCT images were obtained with a Varian On-Board Imaging system. To account for erroneous CBCT data, three practical correction techniques were tested: (1) conversion of CBCT numbers to electron density using phantoms, (2) replacement of individual CBCT pixel values with bulk CT numbers, averaged from PCT images for tissue regions, and (3) limited replacement of CBCT lung pixels values (LCT) likely to produce artificial lateral electron disequilibrium. For each corrected CBCT data set, lung SBRT dose distributions were computed for a 6 MV volume modulated arc therapy (VMAT) technique within the Philips Pinnacle treatment planning system. The reference prescription dose was set such that 95% of the planning target volume (PTV) received at least 54 Gy (i.e. D95). Further, we used the relative depth dose factor as an a priori index to predict the effects of incorrect low tissue density on computed lung dose in regions of severe electron disequilibrium. CT number profiles from co-registered CBCT and PCT patient lung images revealed many reduced lung pixel values in CBCT data, with some pixels corresponding to vacuum (-1000 HU). Similarly, CBCT data in a plastic lung phantom were reduced by 200 HU compared with known CT number values. For the three patients, dose results using the CBCT number data registered with PCT showed a prescription dose reduction ranging from 4 to 13% (D95 = 47 Gy). Therefore, accurate determination of lung density, especially for very low lung density (<0.2 g cm(-3)) is essential, but difficult to achieve using the CBCT data. Applying corrective techniques (1) and (2) to CBCT patient data produced unacceptable dose differences. For one typical VMAT SBRT patient, the D95 for the corrected CBCT and BCT image-based plans differed by -4% (D95 = 52 Gy) and 9% (D95 = 59 Gy) compared to the co-registered PCT image-based plan. However, corrective technique (3) produced negligible dose differences comparing LCT and PCT image-based plans. With regard to implementing on-line DART, dose errors must be minimized because they affect re-optimization decisions, and prevent accurate accumulation of the dose distribution. PMID- 23689061 TI - Nuclear import of influenza B virus nucleoprotein: involvement of an N-terminal nuclear localization signal and a cleavage-protection motif. AB - The nucleoprotein of influenza B virus (BNP) shares several characteristics with its influenza A virus counterpart (ANP), including localization in the host's nucleus. However, while the nuclear localization signal(s) (NLS) of ANP are well characterized, little is known about those of BNP. In this study, we showed that the fusion protein bearing the BNP N-terminus fused with GFP (N70-GFP) is exclusively nuclear, and identified a highly conserved KRXR motif spanning residues 44-47 as a putative NLS. In addition, we demonstrated that residues 3-15 of BNP, though not an NLS, are also crucial for nuclear import. Results from mutational analyses of N70-GFP and the full-length BNP suggest that this region may be required for protection of the N-terminus from proteolytic cleavage. Altogether, we propose that the N-terminal region of BNP contains the NLS and cleavage-protection motif, which together drive its nuclear localization. PMID- 23689063 TI - Surgical approach to the management of medullary thyroid cancer: when is lymph node dissection needed? AB - OBJECTIVE: Medullary thyroid cancer (MTC) is a rare and particularly aggressive type of thyroid cancer of neuroendocrine origin. It occurs in hereditary and sporadic forms and its aggressiveness is related to the clinical presentation and the type of RET mutation. METHODS: In this article, we present the criteria, as reviewed in contemporary literature, regarding lymph node dissection and radical neck dissection in patients with either sporadic or hereditary MTC. RESULTS: Early diagnosis and treatment remains the key to a 100% cure rate. CONCLUSIONS: Routine central lymph node dissection is the minimum procedure recommended for all sporadic and hereditary MTCs. Routine lateral lymph node dissection on either side is necessary when lymph node metastases are found in the central neck compartment. PMID- 23689065 TI - Dietary intakes and familial correlates of overweight/obesity: a four-cities study in India. AB - BACKGROUND: The prevalence of overweight and obesity among children is increasing in India. However, knowledge of, attitude towards and practice of health and nutrition in mothers and children have not been researched. OBJECTIVE: To assess knowledge of, attitude towards and practice of nutrition, physical activity and other lifestyle practices in a nationally representative sample of urban children and mothers in India. METHODS: A cross-sectional observational study of 1,800 children aged 9-18 years and their mothers, using qualitative (focus group) and quantitative (semi-structured survey) data. RESULTS: The overall prevalence of overweight/obesity among the children was 19.2% in males and 18.1% in females; 64.8% of mothers were either overweight [body mass index (BMI) 23.0-24.9; 23.3%] or obese (BMI >25.0; 41.5%). Household family income, related socioeconomic factors, and overweight in mothers were most significantly associated with obesity in children (all p <= 0.001). Dietary consumption patterns (snacking, fast food etc.) showed a marked association between mothers and children (all p <= 0.000). Focus group discussion revealed several interesting attitudes and misconceptions among children ('home-cooked food is old fashioned') and mothers ('a child with chubby cheeks is healthy, not fat'). Importantly, only a few mothers understood that excess weight or diets are contributory factors of morbidities in children or themselves. CONCLUSIONS: This study highlights the poor knowledge, faulty attitudes and practices of urban Asian Indian mothers and their children in a highly correlated manner. These knowledge gaps must be addressed to formulate effective strategies for the prevention of obesity and related metabolic disorders. PMID- 23689062 TI - L2, the minor capsid protein of papillomavirus. AB - The capsid protein L2 plays major roles in both papillomavirus assembly and the infectious process. While L1 forms the majority of the capsid and can self assemble into empty virus-like particles (VLPs), L2 is a minor capsid component and lacks the capacity to form VLPs. However, L2 co-assembles with L1 into VLPs, enhancing their assembly. L2 also facilitates encapsidation of the ~8 kbp circular and nucleosome-bound viral genome during assembly of the non-enveloped T=7d virions in the nucleus of terminally differentiated epithelial cells, although, like L1, L2 is not detectably expressed in infected basal cells. With respect to infection, L2 is not required for particles to bind to and enter cells. However L2 must be cleaved by furin for endosome escape. L2 then travels with the viral genome to the nucleus, wherein it accumulates at ND-10 domains. Here, we provide an overview of the biology of L2. PMID- 23689064 TI - Prospective inter-relationships between late adolescent personality and major depressive disorder in early adulthood. AB - BACKGROUND: A well-established body of literature demonstrates concurrent associations between personality traits and major depressive disorder (MDD), but there have been relatively few investigations of their dynamic interplay over time. METHOD: Prospective inter-relationships between late-adolescent personality and MDD in early adulthood were examined in a community sample of male and female twins from the Minnesota Twin Family Study (MTFS; n = 1252). Participants were classified into naturally occurring MDD groups based on the timing (adolescent versus adult onset) and course (chronic/recurrent versus remitting) of MDD. MDD diagnoses were assessed at ages 17, 20, 24 and 29 years, and personality traits [negative emotionality (NEM), positive emotionality (PEM) and constraint (CON)] were assessed at ages 17, 24 and 29 years. RESULTS: Multilevel modeling (MLM) analyses indicated that higher age-17 NEM was associated with the subsequent development of MDD, and any MDD, regardless of onset or course, was associated with higher NEM up to age 29. Moreover, the chronic/recurrent MDD groups failed to show the normative decrease in NEM from late adolescence to early adulthood. Lower age-17 PEM was also associated with the subsequent development of MDD but only among the chronic/recurrent MDD groups. Finally, the adolescent-onset MDD groups reported lower age-17 CON relative to the never-depressed and adult-onset MDD groups. CONCLUSIONS: Taken together, the results speak to the role of personality traits for conferring risk for the onset of MDD in late adolescence and early adulthood, in addition to the pernicious implications of chronic/recurrent MDD, particularly when it onsets during adolescence, for adaptive personality development. PMID- 23689066 TI - Substantia nigra hyperechogenicity as a marker for Parkinson's disease: a population-based study. AB - BACKGROUND: The clinical diagnosis of Parkinson's disease (PD) is currently anchored in its cardinal motor symptoms. According to hospital-based studies, an enlarged echogenicity in the area of the substantia nigra (SN) assessed with transcranial sonography (TCS) may represent a useful biomarker in the diagnosis of PD. OBJECTIVE: To evaluate SN hyperechogenicity as a marker for PD in the Bruneck Study cohort, which is representative of the general elderly community. METHODS: The diagnostic accuracy of TCS in distinguishing clinically diagnosed PD from nonparkinsonian subjects was assessed in 574 subjects from this cohort. RESULTS: There was a good diagnostic accuracy of TCS in distinguishing PD subjects from nonparkinsonian subjects with an area under the curve value of 0.82. At a receiver-operating characteristic curve analysis-based cutoff value for SN hyperechogenicity of 0.18 cm(2), TCS had a sensitivity of 88.2% (95% confidence interval, CI, 64.4-98.0), a specificity of 77.0% (95% CI 72.8-80.6), a positive predictive value of 12.7% (95% CI 7.8-20.0) and a negative predictive value of 99.4% (95% CI 97.8-100.0) for subjects with clinically definite PD at baseline. When analyzing the same population after 5 years with regard to the presence of known and newly diagnosed PD cases, baseline TCS yielded very similar diagnostic accuracy values. CONCLUSION: SN hyperechogenicity may represent a useful biomarker for PD not only in a hospital-based setting but also in the general community. PMID- 23689067 TI - Stress coping strategies in patients with psychogenic non-epileptic seizures and how they relate to trauma symptoms, alexithymia, anger and mood. AB - PURPOSE: The purpose of the present study was to assess stress coping strategies employed by patients with psychogenic non-epileptic seizures (PNES) and determine whether these approaches were associated with other psychopathological features. Ineffective stress coping strategies can have a variety of unhealthy consequences fueling psychopathology just as psychopathology can also have an impact on stress coping. Because of this, the study of stress coping has the potential to inform our understanding of the PNES condition and underscore a potential target for psychological treatment. METHODS: Eighty-two consecutive patients with PNES were studied using the Coping Inventory for Stressful Situations (CISS). The CISS is a self-rating coping strategies scale that has three main subscales (Task-Oriented, Emotion-Focused, and Avoidance-Oriented). Other psychological variables that were thought to potentially influence the chosen coping mechanisms including alexithymia, symptoms of post-traumatic stress disorder, anger expression and select scales from the Minnesota Multiphasic Personality Inventory 2-RF (MMPI 2 RF) were also evaluated. RESULTS: Fifty patients (60.9%) endorsed using at least one coping strategy that was 1.5 standard deviations or more away from the normal adult mean. Over 30% of the participants endorsed using elevated Emotion-Focused coping strategies (T score >= 65), and just over 25% endorsed underusing Task Oriented coping strategies (T score <= 35). Elevations in avoidance strategies were endorsed by only 15.9% of the respondents. ANOVA comparing T scores between the coping strategies was significant (F=13.4, p=.0001) with a significantly lower Task-Oriented strategy than Emotion-Focused (p=.001) and Avoidance (p=.005) strategies. Patients with high scores of Emotion-Focused coping strategies also had significantly high scores on diverse psychopathology factors including elevations on depressive mood, intrusive experiences, anger state, and general anger scores. In contrast, those who used Task-Oriented strategies and who used Avoidance-Focused strategies had less psychopathology including low positive emotion scores (RC2). CONCLUSION: Nearly one-third of patients with PNES tended to use the less effective Emotion-Oriented coping strategies and one fourth reported underusing the more effective Task-focused strategies. Substantial differences were noted between coping strategies with a significantly lower Task Oriented strategy than Emotion-Focused and Avoidance strategies. In addition, high Emotion-Focused coping was seen in patients with underlying psychological symptoms that were not observed in other coping strategies. This information supports the relevance of assessing stress coping in patients with PNES because it allows the identification of useful behavioral targets for the psychotherapist. PMID- 23689068 TI - The impact of early dementia diagnosis and intervention on informal caregivers. AB - In the absence of disease modifying therapies for dementia, the question rises what the benefits are of an early dementia diagnosis for patients and their caregivers. This paper reviews the caregiver perspective in dementia and addresses the question what the consequences are of promoting earlier dementia diagnosis. An early diagnosis offers caregivers the opportunity to advance the process of adaptation to the caregiver role. Caregivers that are better able to adapt to the changes that characterize dementia, feel more competent to care and experience less psychological problems. However, drawbacks of an early diagnosis may outweigh the benefits if people are left with a diagnosis but little support. There is convincing evidence that multicomponent caregiver interventions in the mild to moderate dementia stages are effective to improve caregiver well-being and delay institutionalization. However, there still exist a gap between the improved possibilities to diagnose people in the predementia stage versus the scarce knowledge on intervention effects in this very early stage. This stresses the urgent need for more research on early caregiver interventions that enhance role adaptation and that include long-term follow-up and cost-effectiveness evaluation. Early interventions may help caregivers in anticipating and accepting the future care role and transitions, with the increased possibility that caregivers can still involve the patient in the decision making process. As levels of stress and burden are still low in the predementia stage it provides excellent opportunities to empower the resources of caregivers. PMID- 23689069 TI - Drug susceptibility distributions in slowly growing non-tuberculous mycobacteria using MGIT 960 TB eXiST. AB - In general, uniform clinical antibiotic susceptibility breakpoints (CBPs) for slowly growing nontuberculous mycobacteria (NTM) have not been established. The aim of this study was to determine wild-type drug susceptibility distributions for relevant antibiotics using Bactec MGIT 960 equipped with EpiCenter TB eXiST and to derive epidemiological cut-offs (ECOFFs) from semi quantitative drug susceptibility measurements. One hundred and twenty-six NTM clinical isolates (Mycobacterium avium n=58, Mycobacterium intracellulare n=18, Mycobacterium kansasii n=50) were investigated in this study. Drug susceptibility distributions and MIC90 values were determined for clarithromycin, ethambutol, rifampicin, rifabutin, ofloxacin, moxifloxacin, and amikacin using Bactec MGIT 960/EpiCenter TB eXiST. For most species/drug combinations ECOFFs were determined. For some species/drug combinations ECOFFs were not defined as either the isolates were susceptible to the lowest drug concentration tested or because isolates, in part, had MIC levels exceeding the highest drug concentration tested. This study describes drug susceptibility distributions and MIC90 values of M. avium, M. intracellulare, and M. kansasii that may aid the definition of CBPs when correlating in vitro drug susceptibility with clinical outcomes in future studies. PMID- 23689070 TI - A Norwegian study of the suitability of hair samples in epidemiological research of alcohol, nicotine and drug use. AB - A feasibility study was performed to examine the effectiveness of hair testing in determining the prevalence of drug use in a young adult population. The study included 200 randomly selected young adults in Norway. It was designed to make the collection, preparation and analysis of the samples as little resource demaning as possible. Full anonymity was provided for the participants. In total, 23.5% of the samples were positive for one or more substances (14.5%, excluding the nicotine metabolite cotinine). Of the samples, 5% were positive for at least one illegal drug, 9.5% for a medicinal drug, 11.5% for cotinine and 2.5% for the alcohol metabolite ethyl glucuronide. The preliminary findings suggest that the study protocol used to collect and analyze the samples was unable to produce results that could be generalized to the young adult population in Norway. Analysis of hair samples may underestimate the use of cannabis, alcohol, amphetamine and methamphetamine. It may, however, be done to estimate cocaine and general drug use if a sample-collection procedure different from that described in our study is used and includes information about hair length, sample length, length from the scalp, cosmetic treatment, washing and whether the samples always get washed/decontaminated prior to analysis. PMID- 23689074 TI - Prediction models for assessing long-term outcome in Alzheimer's disease: a review. AB - In Alzheimer's disease (AD), placebo-controlled long-term studies of cholinesterase inhibitors (ChEIs) are not permitted for ethical reasons. Therefore, in these studies, patients' outcomes on cognitive and functional assessment scales must be compared with mathematical models or historical data from untreated cohorts. PubMed and previously published long-term extensions of clinical trials and naturalistic studies of ChEIs were examined to identify empirical statistical models and other approaches, such as use of data from historical cohorts or extrapolated changes from extension studies, that were used to draw comparisons between ChEI-treated and untreated patients. The models and methods were described. It is essential to be aware of the limitations of comparisons made with these approaches. Prediction models based on ChEI-treated patients can be used in the studies of new treatments when those treatments are added to ChEIs. More sophisticated models that also accommodate patient-specific characteristics should be developed for comparisons in future long-term AD studies. PMID- 23689073 TI - Clinical experience with a novel glaucoma drainage implant. AB - PURPOSE: To retrospectively evaluate the safety and efficacy of an Ahmed glaucoma valve (AGV) modified with a polyethylene shell (M4) to reduce the fibrotic reaction around the drainage plate compared with the S2 and FP7 models in patients with glaucoma. METHODS: The medical records of patients who underwent implantation of the AGV FP7, S2, and M4 were reviewed. The primary outcome measure was cumulative probability of success, defined as an intraocular pressure (IOP) between 5 and 18 mm Hg and >20% reduction of IOP without loss of light perception, need for additional IOP-lowering surgical procedures, or removal of AGV. RESULTS: Seventy-six, 38, and 40 eyes received the FP7, S2, and M4 with a mean follow-up time of 578+/-157, 662+/-186, and 504+/-158 days, respectively. The mean IOP was reduced from 31.0+/-10.6 to 13.9+/-5.5 mm Hg in the FP7 group, 33.5+/-12.1 to 15.8+/-8.1 mm Hg in the S2 group, and 27.0+/-12.0 to 15.0+/-4.0 mm Hg in the M4 group at 1 year (P=0.31). At 1 year, the cumulative probability of success was 70%, 66%, and 80% and at 18 months, 61%, 53%, and 52% in the FP7, S2, and M4 groups, respectively (P=0.99). Complications were similar among groups. CONCLUSIONS: No significant difference was observed between the AGV M4, FP7, and S2 at 1 year. Additional follow-up is required to determine its long-term safety profile and efficacy. PMID- 23689072 TI - Stromal EGF and igf-I together modulate plasticity of disseminated triple negative breast tumors. AB - The causes for malignant progression of disseminated tumors and the reasons recurrence rates differ in women with different breast cancer subtypes are unknown. Here, we report novel mechanisms of tumor plasticity that are mandated by microenvironmental factors and show that recurrence rates are not strictly due to cell-intrinsic properties. Specifically, outgrowth of the same population of incipient tumors is accelerated in mice with triple-negative breast cancer (TNBC) relative to those with luminal breast cancer. Systemic signals provided by overt TNBCs cause the formation of a tumor-supportive microenvironment enriched for EGF and insulin-like growth factor-I (IGF-I) at distant indolent tumor sites. Bioavailability of EGF and IGF-I enhances the expression of transcription factors associated with pluripotency, proliferation, and epithelial-mesenchymal transition. Combinatorial therapy with EGF receptor and IGF-I receptor inhibitors prevents malignant progression. These results suggest that plasticity and recurrence rates can be dictated by host systemic factors and offer novel therapeutic potential for patients with TNBC. PMID- 23689075 TI - The role of Beta-adrenergic receptor blockers in Alzheimer's disease: potential genetic and cellular signaling mechanisms. AB - According to genetic studies, Alzheimer's disease (AD) is linked to beta adrenergic receptor blockade through numerous factors, including human leukocyte antigen genes, the renin-angiotensin system, poly(adenosine diphosphate-ribose) polymerase 1, nerve growth factor, vascular endothelial growth factor, and the reduced form of nicotinamide adenine dinucleotide phosphate. Beta-adrenergic receptor blockade is also implicated in AD due to its effects on matrix metalloproteinases, mitogen-activated protein kinase pathways, prostaglandins, cyclooxygenase-2, and nitric oxide synthase. Beta-adrenergic receptor blockade may also have a significant role in AD, although the role is controversial. Behavioral symptoms, sex, or genetic factors, including Beta 2-adrenergic receptor variants, apolipoprotein E, and cytochrome P450 CYP2D6, may contribute to beta-adrenergic receptor blockade modulation in AD. Thus, the characterization of beta-adrenergic receptor blockade in patients with AD is needed. PMID- 23689076 TI - Current incidence of active tuberculosis in IBD patients treated with anti-TNF agents: still room for improvement. PMID- 23689077 TI - An evaluation of a child welfare training program on the commercial sexual exploitation of children (CSEC). AB - With the growing awareness of the nature and scope of the commercial sexual exploitation of children (CSEC) in the United States, a few state child welfare agencies have started to develop and implement training on CSEC for their social service staff. Since other state child welfare agencies may adopt a similar training model, it is important to evaluate the effectiveness of these CSEC trainings. Therefore, in the present study, we used a randomized, control group design to evaluate the effectiveness of a CSEC webinar training program for child protective service (CPS) employees. We discuss our findings and make recommendations for child welfare agencies interested in providing CSEC training to their staff. Given the lack of sophisticated research evaluating the effectiveness of child welfare training programs, in general, and CSEC training programs, more specifically, this study fills a gap in the literature and offers a training model that could be replicated with child protection systems in other states. PMID- 23689078 TI - Humor and aging - a mini-review. AB - Humor is one of the most important human activities, one that is enjoyed daily by people in every culture and at every age. However, very little is known about how aging affects humor experiences. Research suggests that elderly people enjoy humor more than younger people, but they have increasing difficulties in understanding jokes. Several cognitive mechanisms that may help explain this trend are discussed. Also, the amount of laughter exhibited by the elderly is smaller compared to young adults. In addition, the older population seems not to enjoy aggressive types of humor as much as the younger ones, and the elderly are especially sensitive to jokes referring to old age. Because most studies are cross-sectional, we cannot ignore possible cohort effects that might influence age differences in humor production and humor appreciation. Several future directions are mentioned with the hope for further research on the subject to follow. PMID- 23689079 TI - Gastrointestinal bleeding: Matters of life and death: long-term mortality after nonvariceal upper gastrointestinal bleeding. PMID- 23689080 TI - Viral hepatitis: Carjacking HBV therapy. PMID- 23689082 TI - Colorectal cancer: Is the new era of colorectal cancer classification finally here? PMID- 23689083 TI - Proteomic quantification and identification of carbonylated proteins upon oxidative stress and during cellular aging. AB - Increased protein carbonyl content is a hallmark of cellular and organismal aging. Protein damage leading to the formation of carbonyl groups derives from direct oxidation of several amino acid side chains but can also derive through protein adducts formation with lipid peroxidation products and dicarbonyl glycating compounds. All these modifications have been implicated during oxidative stress, aging and age-related diseases. However, in most cases, the proteins targeted by these deleterious modifications as well as their consequences have not yet been clearly identified. Indeed, this is essential to determine whether and how these modified proteins are impacting on cellular function, on the development of the senescent phenotype and the pathogenesis of age-related diseases. In this context, protein modifications occurring during aging and upon oxidative stress as well as main proteomic methods for detecting, quantifying and identifying oxidized proteins are described. Relevant proteomics studies aimed at monitoring the extent of protein carbonylation and identifying the targeted proteins in the context of aging and oxidative stress are also presented. Proteomics approaches, i.e. fluorescent based 2D-gel electrophoresis and mass spectrometry methods, represent powerful tools for monitoring at the proteome level the extent of protein oxidative and related modifications and for identifying the targeted proteins. BIOLOGICAL SIGNIFICANCE: Accumulation of damaged macromolecules, including oxidatively damaged (carbonylated) proteins, is a hallmark of cellular and organismal aging. Since protein carbonyls are the most commonly used markers of protein oxidation, different methods have been developed for the detection and quantification of carbonylated proteins. The identification of these protein targets is of valuable interest in order to understand the mechanisms by which damaged proteins accumulate and potentially affect cellular functions during oxidative stress, cellular senescence and/or aging in vivo. The specificity of hydrazide derivatives to carbonyl groups and the presence of a wide range of functional groups coupled to the hydrazide, allowed the design of novel strategies for the detection and quantification of carbonylated proteins. Of note is the importance of fluorescent probes for monitoring carbonylated proteins. Proteomics approaches, i.e. fluorescent based 2D-gel electrophoresis and mass spectrometry methods, represent powerful tools for monitoring at the proteome level the extent of protein oxidative and related modifications and for identifying the targeted proteins. This article is part of a Special Issue entitled: Posttranslational Protein modifications in biology and Medicine. PMID- 23689084 TI - Comparative proteomic analyses reveal that FlbA down-regulates gliT expression and SOD activity in Aspergillus fumigatus. AB - FlbA is a regulator of G-protein signaling protein that plays a central role in attenuating heterotrimeric G-protein mediated vegetative growth signaling in Aspergillus. The deletion of flbA (?flbA) in the opportunistic human pathogen Aspergillus fumigatus results in accelerated cell death and autolysis in submerged culture. To further investigate the effects of ?flbA on intracellular protein levels we carried out 2-D proteome analyses of 2-day old submerged cultures of ?flbA and wild type (WT) strains and observed 160 differentially expressed proteins. Via nano-LC-ESI-MS/MS analyses, we revealed the identity of 10 and 2 proteins exhibiting high and low level accumulation, respectively, in ?flbA strain. Notably, the GliT protein is accumulated at about 1800-fold higher levels in ?flbA than WT. Moreover, GliT is secreted at high levels from ?flbA strain, whereas Sod1 (superoxide dismutase) is secreted at a higher level in WT. Northern blot analyses reveal that ?flbA results in elevated accumulation of gliT mRNA. Consequently, ?flbA strain exhibits enhanced tolerance to gliotoxin toxicity. Finally, ?flbA strain displayed enhanced SOD activity and elevated resistance to menadione and paraquat. In summary, FlbA-mediated signaling control negatively affects cellular responses associated with detoxification of reactive oxygen species and of exogenous gliotoxin in A. fumigatus. BIOLOGICAL SIGNIFICANCE: Regulator of G protein Signaling (RGS) proteins play crucial roles in fundamental biological processes in filamentous fungi. FlbA is the first studied filamentous fungal RGS protein, yet much remains to be understood about its roles in the opportunistic human pathogen Aspergillus fumigatus. In the present study, we examined the effects of the deletion of flbA using comprehensive analyses of the intra- and extracellular proteomes of A. fumigatus wild type and the flbA deletion mutant. Via MS analyses, we identified 10 proteins exhibiting high level accumulation in the flbA deletion mutant and 8 proteins differentially secreted in wild type and the flbA mutant. Based on proteomic analyses, we further examined the role of FlbA and found that FlbA down regulates gliT expression and SOD activity. Our results proposed that FlbA mediated signaling control negatively affects cellular responses associated with detoxification of reactive oxygen species and exogenous gliotoxin in A. fumigatus. PMID- 23689081 TI - MicroRNAs in liver disease. AB - Small, noncoding microRNAs (miRNAs) regulate diverse biological functions in the liver and increasing evidence suggests that they have a role in liver pathology. This Review summarizes advances in the field of miRNAs in liver diseases, inflammation and cirrhosis. MicroRNA-122, the most abundant miRNA in hepatocytes, has well-defined roles in HCV replication, and data indicate that it also serves as a viable therapeutic target. The role of miR-122 is also emerging in other liver diseases. Ample evidence exists for the important regulatory potential of other miRNAs in conditions associated with liver inflammation related to alcohol use, the metabolic syndrome or autoimmune processes. In addition, a broad array of miRNAs have been associated with the development of liver fibrosis both in animal models and human studies. The significance of the function and cellular distribution of miRNAs in the liver and the potential of miRNAs as a means of communication between cells and organs is discussed as well as the emerging utility of circulating miRNAs as biomarkers of different forms of liver damage and as early markers of disease and progression in hepatocellular carcinoma. Importantly, miRNA modulation in the liver represents a new therapeutic approach in the treatment armamentarium of hepatologists in the future. PMID- 23689085 TI - A randomized, open-label study of sirolimus versus cyclosporine in primary de novo renal allograft recipients. AB - BACKGROUND: Despite a decreased incidence of acute rejection and early renal allograft loss due to calcineurin inhibitors (CNIs) in transplant recipients, nephrotoxicity associated with long-term CNI use remains an important issue. This study evaluated whether a CNI-free regimen, including sirolimus, mycophenolate mofetil, corticosteroids, and anti-interleukin-2 receptor antibody induction, results in improved long-term renal function. METHODS: This open-label, randomized, parallel group, comparative study in primary de novo renal transplant recipients was planned for 48 months but terminated early because of high acute rejection rates in the sirolimus arm. RESULTS: Enrollment was stopped after ~12 months, with 475 transplanted patients randomized (2:1) to sirolimus (n=314) or cyclosporine A (CsA) treatment (n=161). Mean length of follow-up after transplantation was 190 days; this article focuses on available data through 6 months. Mean+/-SD on-therapy Nankivell-calculated glomerular filtration rate was not significantly different between the sirolimus (69.1+/-18.7 mL/min) and CsA (66.0+/-15.2 mL/min) treatment groups. Occurrence and length of delayed graft function was not significantly different between groups. Patients in the sirolimus group experienced numerically lower survival rates (96.9% vs. 99.4%; P=0.14), with nine deaths reported with sirolimus and one with CsA; higher rates of biopsy-confirmed acute rejection (21.4% vs. 6.1%; P<0.001); and higher rates of discontinuations due to adverse events (17.4% vs. 6.8%; P=0.001). CONCLUSION: A sirolimus-based, CNI-free immunosuppressive regimen, when used with mycophenolate mofetil, corticosteroids, and anti-interleukin-2 receptor antibody induction, was associated with high rates of biopsy-confirmed acute rejection compared with CsA-based immunosuppression and is not recommended. PMID- 23689086 TI - Cotransplantation of MSCs and HSCs. PMID- 23689087 TI - Severe encapsulating peritoneal sclerosis after renal transplantation in the United States: first case report. PMID- 23689088 TI - An uncommon presentation of non-Hodgkin's lymphoma in a renal transplant recipient. PMID- 23689089 TI - Clinical Trials: Spline Modeling is Wonderful for Nonlinear Effects. AB - Traditionally, nonlinear relationships like the smooth shapes of airplanes, boats, and motor cars were constructed from scale models using stretched thin wooden strips, otherwise called splines. In the past decades, mechanical spline methods have been replaced with their mathematical counterparts. The objective of the study was to study whether spline modeling can adequately assess the relationships between exposure and outcome variables in a clinical trial and also to study whether it can detect patterns in a trial that are relevant but go unobserved with simpler regression models. A clinical trial assessing the effect of quantity of care on quality of care was used as an example. Spline curves consistent of 4 or 5 cubic functions were applied. SPSS statistical software was used for analysis. The spline curves of our data outperformed the traditional curves because (1) unlike the traditional curves, they did not miss the top quality of care given in either subgroup, (2) unlike the traditional curves, they, rightly, did not produce sinusoidal patterns, and (3) unlike the traditional curves, they provided a virtually 100% match of the original values. We conclude that (1) spline modeling can adequately assess the relationships between exposure and outcome variables in a clinical trial; (2) spline modeling can detect patterns in a trial that are relevant but may go unobserved with simpler regression models; (3) in clinical research, spline modeling has great potential given the presence of many nonlinear effects in this field of research and given its sophisticated mathematical refinement to fit any nonlinear effect in the mostly accurate way; and (4) spline modeling should enable to improve making predictions from clinical research for the benefit of health decisions and health care. We hope that this brief introduction to spline modeling will stimulate clinical investigators to start using this wonderful method. PMID- 23689090 TI - Recent Advances in the Pharmacological Management of Atrial Fibrillation. AB - Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia that leads to hospitalizations for complications and adverse events each year. Despite significant improvement in our therapeutic approaches in the past decade, management of AF remains a difficult task. Novel therapies have failed to terminate AF and prevent its recurrence, and patients with AF continue to have thromboembolic complications. With the increasingly aging population and associated conditions, the prevalence of AF is expected to progressively increase, becoming a public health problem. Most patients with AF have multiple comorbidities and are of advanced age, making long-term anticoagulation challenging. This article provides an overview of the current pharmacological therapies for the management of AF, with particular emphasis on the emerging agents. PMID- 23689091 TI - Pulmonary collision tumor consisting of adenocarcinoma and typical carcinoid--a case report and review of literature. AB - Collision tumors are rare in nature. We report a case of a 70-year-old woman who was found to have a new mass in the right lung. Right upper and middle lobectomies with a mediastinal lymph node sampling were performed. Pathological examination of the mass revealed a collision tumor composed of micropapillary adenocarcinoma and typical carcinoid. The neoplastic cells were not intimately admixed with one another. To the best of our knowledge, this case is the first report in the English medical literature of a primary pulmonary collision tumor consisting of micropapillary adenocarcinoma and typical carcinoid. PMID- 23689092 TI - Combination of capecitabine and phenytoin may cause phenytoin intoxication: a case report. AB - Capecitabine is an oral antineoplastic agent, and phenytoin is an anticonvulsant drug with a narrow therapeutic index. Although the interaction between capecitabine and phenytoin is rare, it may be potentially fatal. This interaction is thought to be at the level of CYP2C9 isoenzyme system in the liver. Here, we present a patient with metastatic breast cancer who developed phenytoin intoxication when using capecitabine and phenytoin together. Closely monitoring plasma phenytoin levels is essential if capecitabine is used with phenytoin concurrently. PMID- 23689093 TI - Trimethoprim-sulfamethoxazole induced rhabdomyolysis. AB - Empiric antibiotic usage is very common in clinical practice and Trimethoprim Sulfamethoxazole (TMP-SMX) is one such antibiotic used extensively in primary care practice. Some patients experience serious adverse effects to the antibiotics that markedly increase the morbidity and the cost of medical care. We describe one such patient, a previously healthy 40-year-old Hispanic female who developed myositis and rhabdomyolysis secondary to TMP-SMX. To the best of our knowledge, this is the first report of TMP-SMX-induced rhabdomyolysis in an immunocompetent host. PMID- 23689094 TI - Patterns of cyanide antidote use since regulatory approval of hydroxocobalamin in the United States. AB - Sodium nitrite and sodium thiosulfate are common cyanide antidotes. Hydroxocobalamin was approved for use in the United States in 2006. Our objective was to determine the frequency of antidote use as reported to the US poison centers from 2005 to 2009 and describe which antidotes were used in critically ill cyanide toxic patients. We performed a retrospective review over 5 years (2005-2009) from 61 US poison centers. We identified all cyanide-exposed cases that received a cyanide antidote. Variables collected included demographics, gastric decontamination, antidote used, predefined serious clinical effects (hypotension, cardiac arrest, respiratory arrest, and coma), and predefined serious therapies (cardiopulmonary resuscitation, vasopressors, atropine, anticonvulsant, antidysrhythmic, and intubation/ventilation). One trained abstractor abstracted each chart to a standardized electronic form. Another investigator audited 20% of the charts. Kappa values were calculated. One hundred sixty-five exposures were identified. Mean age was 42 years (range, 3-93 years). Seventy-one percent were male. Exposures were 27% ingestion and 53% inhalation. Thirty-two percent of the ingestions were suicide attempts. Twenty percent (32 of 157) of all cases died. Over all years reported, hydroxocobalamin was administered to 29% (45 of 157) of patients, sodium nitrite to 25%, and sodium thiosulfate to 46%. Hydroxocobalamin use increased from 24% to 54% from 2007 to 2009, respectively (P = 0.024). Sodium thiosulfate use decreased from 73% to 31% (P = 0.002) and sodium nitrite use decreased from 26% to 14% (P = 0.39). The proportion of cases with serious clinical effects that received hydroxocobalamin increased each year, and the proportion that received other antidotes decreased. Hydroxocobalamin was also administered more often in cases that required serious therapies and increased each year. Hydroxocobalamin use for cyanide toxicity increased each year as reported to the US poison centers. Reported use of sodium thiosulfate and sodium nitrite decreased over the same years. In addition, hydroxocobalamin was used more often each year in critically ill cyanide toxic patients than were sodium nitrite or sodium thiosulfate. PMID- 23689095 TI - Quantitative and qualitative differences in the metabolism of pesticides in biobed substrates and soil. AB - Biobed substrates commonly exhibit high degradation capacity. However, degradation does not always lead to detoxification and information on the metabolic pathways of pesticides in biobeds is scarce. We studied the degradation and metabolism of three pesticides in selected biomixtures and soil. Biomixtures stimulated degradation of terbuthylazine and metribuzin, whereas chlorpyrifos degraded faster in soil. The latter was attributed to the lipophilicity of chlorpyrifos which increased adsorption and limited biodegradation in organic rich biomixtures. Although the same metabolites were detected in all substrates, qualitative and quantitative differences in the metabolic routes of pesticides in the various substrates were observed. Chlorpyrifos was hydrolyzed to 3,5,6 tricholorpyridinol (TCP) which was further degraded only in compost-biomixture CBX1. Metabolism of terbuthylazine in compost biomixtures (BX) and soil resulted in the formation of desethyl-terbuthylazine (DES) which was fully degraded only in the compost-biomixture CBX2, whereas peat-based biomixture (OBX) promoted the hydroxylation of terbuthylazine. Desamino- (DA) (dominant) and diketo- (DK) metribuzin appear as intermediate metabolites in all substrates and were further transformed to desamino-diketo-metribuzin (DADK) which was fully degraded only in compost-biomixture GSBX. Overall, lower amounts of metabolites were accumulated in biomixtures compared to soil stressing the higher depuration efficiency of biobeds. PMID- 23689096 TI - Aquatic toxicity of four veterinary drugs commonly applied in fish farming and animal husbandry. AB - Doramectin (DOR), metronidazole (MET), florfenicol (FLO), and oxytetracycline (OXT) are among the most widely used veterinary drugs in animal husbandry or in aquaculture. Contamination of the environment by these pharmaceuticals has given cause for concern in recent years. Even though their toxicity has been thoroughly analyzed, knowledge of their ecotoxicity is still limited. We investigated their aquatic toxicity using tests with marine bacteria (Vibrio fischeri), green algae (Scenedesmus vacuolatus), duckweed (Lemna minor) and crustaceans (Daphnia magna). All the ecotoxicological tests were supported by chemical analyses to confirm the exposure concentrations of the pharmaceuticals used in the toxicity experiments, since deviations from the nominal concentration can result in underestimation of biological effects. It was found that OXT and FLO have a stronger adverse effect on duckweed (EC50=3.26 and 2.96mgL(-1) respectively) and green algae (EC50=40.4 and 18.0mgL(-1)) than on bacteria (EC50=108 and 29.4mgL(-1)) and crustaceans (EC50=114 and 337mgL(-1)), whereas MET did not exhibit any adverse effect in the tested concentration range. For DOR a very low EC50 of 6.37*10(-5)mgL(-1) towards D. magna was determined, which is five orders of magnitude lower than values known for the toxic reference compound K2Cr2O7. Our data show the strong influence of certain veterinary drugs on aquatic organisms and contribute to a sound assessment of the environmental hazards posed by commonly used pharmaceuticals. PMID- 23689098 TI - Photolysis of RDX and nitroglycerin in the context of military training ranges. AB - Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and nitroglycerin (NG) are two energetic materials commonly found in the environment on military training ranges. They are deposited on the ground in the form of solid particles, which can then dissolve in infiltration water or in surface water bodies. The objective of this study was to evaluate whether photolysis by sunlight can significantly contribute to the natural attenuation of RDX and NG (as solid particles or dissolved in surface water) at mid-northern latitudes, where training ranges of Canada and many European countries are located. Experiments conducted at 46.9 degrees N show that both compounds are degraded by sunlight when dissolved in water, with half-lives between 1 and 120d, depending on the compound and time of year. Numerical models may be useful in predicting such photolysis rates, but the models should take into account current ozone levels, as older radiation datasets, collected before the ozone depletion observed since the late 1970s, underestimate the RDX/NG photolysis rate. For solid RDX or NG-bearing particles, photolysis is slower (half-lives of 2-4months), but the degradation rate is still rapid enough to make this process significant in a natural attenuation context. However, photolysis of NG embedded within solid propellant particles cannot proceed to completion, due to the stable nitrocellulose matrix of the propellant. Nonetheless, photolysis clearly constitutes an important attenuation mechanism that should be considered in conceptual models and included in numerical modeling efforts. PMID- 23689097 TI - Neonatal-maternal factors and perfluoroalkyl substances in cord blood. AB - Perfluoroalkyl substances (PFASs) can cross the placenta, enter fetal circulation, and were found to correlate with adverse fetal growth. However, determinants of cord blood PFASs are not fully characterized. The study aimed to explore the association between PFASs and neonatal-maternal factors within a Taiwanese birth cohort. We selected subjects from Taiwan Birth Panel Study, which enrolled 486 infant-mother pairs in 2004-2005. We collected cord blood and analyzed perfluorooctanoic acid (PFOA), perfluorooctanyl sulfonate (PFOS), perfluorononanoic acid (PFNA) and perfluoroundecanoic acid (PFUA) using a simple protein precipitation and an ultra-high performance liquid chromatography/tandem mass spectrometry. We retrieved information pertaining to maternal socio demographics, lifestyle- and dietary-related factors through structured questionnaires during the postpartum hospital stay. A total of 439 subjects, with 90% response rate, have completed serum analysis and questionnaire survey. The median concentrations for PFOA, PFOS, PFNA, and PFUA in cord blood were 1.86, 5.67, 3.00, and 13.5ngmL(-1), respectively. After adjusting for potential confounders, multiple linear regression models revealed that log10-PFOA was positively associated with maternal age (beta=0.011) and negatively associated with multiparity (beta=-0.044). Log10-PFOS was negatively correlated with birth weight (beta=-0.011) and higher maternal education (senior high school: beta= 0.067; university: beta=-0.088). Log10-PFUA tended to negatively associate with gender, male infants (beta=-0.075), and using cosmetics during pregnancy (beta= 0.065). Interestingly, presence of cockroaches in the home was positively associated with log10-PFOA (beta=0.041) and 1og10-PFNA (beta=0.123). In conclusion, this study demonstrated several factors to correlate with cord blood PFASs and further investigation are still needed for confirmation of exposure routes. PMID- 23689099 TI - Electron donor capacity of reducing dissolved organic matter from crop residue decomposition as probed by chronoamperometry. AB - Reducing dissolved organic matters (RDOMs) from the anaerobic decomposition of crop residue can greatly affect the physicochemical and biological properties of soils. Electrochemical methods that can effectively protect them from oxidation and rapidly obtain results, such as differential pulse voltammetry (DPV), have been applied to qualitatively analyzing properties of RDOMs. However, the donated amount of electrons from RDOMs as a capacity factor may be more crucial for evaluating their important roles. For the first time, matured chronoamperometry (CA) was applied to quantitatively determining the electron donor capacities of RDOMs in crop residue management. The electron donor capacities of RDOMs from green manure were much higher than those from rice straw, which indicated that the former had greater effect on the redox status and reactions of soil. Chronoamperometry was proposed as a practical and effective method to quantitatively characterize RDOMs from residue decomposition. PMID- 23689100 TI - Electrochemical mineralization of pentachlorophenol (PCP) by Ti/SnO2-Sb electrodes. AB - Electrochemical degradation of pentachlorophenol (PCP) in aqueous solution was investigated over Ti/SnO2-Sb electrodes prepared by sol-gel method. X-ray diffraction (XRD), scanning electron microscopy (SEM) and electrochemical measurements were used to characterize the physicochemical properties of the electrodes. The electrochemical degradation of PCP followed pseudo-first-order kinetics. The main influencing factors, including the types of supporting electrolyte (i.e., NaClO4, Na2SO4, Na2SO3, NaNO3, and NaNO2), initial concentrations of PCP (5-1000mgL(-1)), pH values (3.0-11.0), and current densities (5-40mAcm(-2)) were evaluated. The degradation and mineralization ratios of 100mgL(-1) of PCP achieved >99.8% and 83.0% after 30min electrolysis with a 10mmolL(-1) Na2SO4 at a current density of 10mAcm(-2), respectively. The corresponding half-life time (t1/2) was 3.94min. The degradation pathways that were involved in dechlorination, protons generation, and mineralization processes were proposed based on the determination of total organic carbon, chloride, and intermediate products (i.e., low chlorinated phenol and some organic acids). The toxicity of PCP and its intermediates could be reduced effectively by electrolysis. These results showed that electrochemical technique could achieve a significant mineralization rate in a short time (<30min), which provided an efficient way for PCP elimination from wastewater. PMID- 23689102 TI - A tailored ML-EM algorithm for reconstruction of truncated projection data using few view angles. AB - Dedicated cardiac single photon emission computed tomography (SPECT) systems have the advantage of high speed and sensitivity at no loss, or even a gain, in resolution. The potential drawbacks of these dedicated systems are data truncation by the small field of view (FOV) and the lack of view angles. Serious artifacts, including streaks outside the FOV and distortion in the FOV, are introduced to the reconstruction when using the traditional emission data maximum likelihood expectation-maximization (ML-EM) algorithm to reconstruct images from the truncated data with a small number of views. In this note, we propose a tailored ML-EM algorithm to suppress the artifacts caused by data truncation and insufficient angular sampling by reducing the image updating step sizes for the pixels outside the FOV. As a consequence, the convergence speed for the pixels outside the FOV is decelerated. We applied the proposed algorithm to truncated analytical data, Monte Carlo simulation data and real emission data with different numbers of views. The computer simulation results show that the tailored ML-EM algorithm outperforms the conventional ML-EM algorithm in terms of streak artifacts and distortion suppression for reconstruction from truncated projection data with a small number of views. PMID- 23689103 TI - Universal hepatitis B vaccination in Belgium: impact on serological markers 3 and 7 years after implementation. AB - Hepatitis B virus (HBV) can be eliminated by effective universal vaccination. In Belgium, a free-of-charge HBV vaccination programme in infants with catch-up in adolescents was introduced in 1999. To evaluate the effects in <20-year-olds, seroprotection (anti-HBs >11 mIU/ml, according to the assay) and markers of infection (anti-HBc, HBsAg) were assessed in 2443 residual sera collected 7-8 years after implementation of the programme. The maximal prevalence of a solely anti-HBs seroprotective ('vaccinated') serostatus was 82.9% at age 1 year and 60.5% at age 13 years. A clear increase was found in age cohorts targeted by the campaign after a similar serosurvey conducted 4 years earlier. The prevalence of HBV infection remained unchanged at a low level (1.8% in 2006) similar to pre vaccination data (1993-1994). We conclude that universal HBV vaccination has achieved overall high levels of vaccine-induced immunity, despite regional variations, which may give rise to pockets of susceptible young adults in the future. PMID- 23689104 TI - Greater chance of high core temperatures with modified pacing strategy during team sport in the heat. AB - OBJECTIVES: To measure the activity profile, hydration status and core temperature of elite team sport athletes during matches in hot and cool conditions. DESIGN: Thirty-five professional Australian footballers (age 25.9 +/- 3.5 yrs; height 188.4 +/- 7.8 cm; body mass 90.6 +/- 8.8 kg), gave informed consent to participate in this study. Core temperature (T(c)), hydration and running performance were compared in eight hot and eight cool matches classified via a rating of the risk of heat illness from the Wet Bulb Globe Temperature (WBGT). METHODS: Core temperature was measured via an ingestible sensor before matches and after each quarter and player movement was recorded by 5 Hz GPS and expressed per period of the match (rotation), for distance; high-intensity running (HIR, 4.17-10.00 m s(-1)), sprinting (>4.17 m s(-1)) and maximal accelerations (2.78-10.00 m s(-2)). All data was compared for hot and cool matches and the magnitude of effects was analysed with the effect size (ES) statistic. RESULTS: Core temperature was elevated from rest at all time-points during matches (37.3-39.4 degrees C), with small additional elevations after the first and third quarters in hot matches (ES: 0.39 +/- 0.40 and 0.37 +/- 0.42 respectively). In hot matches 12 players had T(c)>40 degrees C but only one in cool matches. Total distance was reduced in the latter parts of each half (-6.5%, -0.49 +/- 0.58; and -6.7%, -0.57 +/- 0.59), yet the high intensity tasks of sprinting and accelerating were preserved. CONCLUSIONS: Players tolerated core temperatures up to 40.5 degrees C during hot matches but reduced the volume of running undertaken, thus preserving the ability to undertake high intensity activities. PMID- 23689105 TI - Return-to-play probabilities following new versus recurrent ankle sprains in high school athletes. AB - OBJECTIVES: Although ankle sprains have the highest recurrence rate of any musculoskeletal injury, objective estimates of when an athlete is likely to return-to-play (RTP) are unknown. The purpose was to compare time to return-to play probability timelines for new and recurrent ankle sprains in interscholastic athletes. DESIGN: Observational. METHODS: Ankle sprain data were collected at seven high schools during the 2007-2008 and 2008-2009 academic years. Ankle sprains were categorized by time lost from participation (same day return, next day return, 3-day return, 7-day return, 10-day return, >22-day return, no return [censored data]). Time-to-event analyses were used to determine the influence of ankle injury history on return-to-play after an ankle sprain. RESULTS: 204 ankle sprains occurred during 479,668 athlete-exposures, 163 were new (4 censored) and 35 recurrent (1 censored). There was no significant difference (p=0.89) between the time-to-event curves for new and recurrent ankle sprains. The median (inter quartile rage) time to return-to-play for new sprains (inter-quartile range)=3 days (same day to 7 day return); recurrent sprains=next day return (next day to 7 day return). Noteworthy probabilities [95% CIs] include: same day return (new=25.2[18.7, 31.9], recurrent=17.1[6.6, 30.3]); next-day return (new=43.6[35.3, 52.7], recurrent=51.4[32.5, 67.5]); and 7-day return (new=85.9[73.8, 94.4], recurrent=94.3[47.8, 99.5]). CONCLUSIONS: Previous injury history did not affect time until return-to-play probabilities for ankle sprains. Time until return-to-play analyses that describe the likelihood of return-to-play are useful to clinicians by providing prognostic guidelines and can be used for educating athletes, coaches, and parents about the likely timeframe of being withheld from play. PMID- 23689106 TI - ACTN3 R577X polymorphism and explosive leg-muscle power in elite basketball players. AB - PURPOSE: To determine the association of the ACTN3 R577X polymorphism with leg muscle explosive power in Spanish (white) elite basketball players and controls. PARTICIPANTS: 100 (60 men) elite basketball players (cases) and 283 nonathletic controls. METHODS: The authors assessed power performance by means of the vertical-squat and countermovement-jump tests. RESULTS: Genotype distributions did not differ between groups (cases: 37.0% [RR], 42.0% [RX], and 21.0% [XX]; controls: 31.8% [RR], 49.8% [RX], and 18.4% [XX]; P = .353). The authors did not observe any effect of the ACTN3 R577X polymorphism on study phenotypes in either group, including when they performed the analyses separately in men and women. They found no association between the ACTN3 R577X polymorphism and the likelihood of being an elite basketball player using the dominant or the recessive model, and the results remained unaltered when the analyses were adjusted for sex, weight, height, and age or when performed for men and women separately. CONCLUSIONS: Although the ACTN3 R577X is associated with explosive muscle performance and this phenotype is important in the sport of basketball (ie, during jumps), the authors found no association with leg explosive power in elite basket players or with the status of being this type of athlete. PMID- 23689108 TI - Zinc. Editorial. PMID- 23689109 TI - Update on zinc biology. AB - Zinc has become a prominent nutrient of clinical and public health interest in the new millennium. Functions and actions for zinc emerge as increasingly ubiquitous in mammalian anatomy, physiology and metabolism. There is undoubtedly an underpinning in fundamental biology for all of the aspects of zinc in human health (clinical and epidemiological) in pediatric and public health practice. Unfortunately, basic science research may not have achieved a full understanding as yet. As a complement to the applied themes in the companion articles, a selection of recent advances in the domains homeostatic regulation and transport of zinc is presented; they are integrated, in turn, with findings on genetic expression, intracellular signaling, immunity and host defense, and bone growth. The elements include ionic zinc, zinc transporters, metallothioneins, zinc metalloenzymes and zinc finger proteins. In emerging basic research, we find some plausible mechanistic explanations for delayed linear growth with zinc deficiency and increased infectious disease resistance with zinc supplementation. PMID- 23689110 TI - Update on zinc deficiency and excess in clinical pediatric practice. AB - The critical importance of adequate zinc status to human health, including normal growth and development, is indisputable. The high prevalence of zinc deficiency on a global basis and its importance to public health have been well documented through large-scale randomized controlled zinc supplementation trials. Similar evidence in the clinical setting, however, is much less widely available due to the nonspecific features of zinc deficiency and to the lack of sensitive biomarkers to detect zinc deficiency, especially that of a mild degree of severity. The current understanding of zinc homeostasis indicates that the primary determinants of zinc absorption are the amount of zinc ingested and dietary phytate, the latter having a major effect on zinc bioavailability. In normal as well as in many pathologic conditions, the gastrointestinal tract is the major site of zinc losses resulting from secretion of endogenous zinc into the lumen and subsequent excretion in the feces. The amount excreted is dependent on host status, the amount reabsorbed, and sometimes the presence of pathophysiologic conditions, including diarrhea and steatorrhea. Assessment in the clinical setting dictates that the clinician obtain a careful medical and diet history, recognize clinical presentations in which zinc adequacy may be compromised, and link this risk with nonspecific but plausible manifestations of deficiency. Examples discussed in this article include primary zinc deficiency due to dietary inadequacy (older breastfed infants or toddlers without zinc-rich complementary foods); genetically based deficiency (acrodermatitis enteropathica, acquired zinc deficiency of lactogenic origin), and acquired secondary deficiency in low birth weight and prematurity, gastrointestinal and hepatic disease, and cystic fibrosis. Evidence for efficacy of zinc therapy with pharmacologic doses for two conditions, Wilson's disease and viral upper respiratory infections, is also discussed. PMID- 23689111 TI - Zinc supplementation in public health. AB - Zinc is necessary for physiological processes including defense against infections. Zinc deficiency is responsible for 4% of global child morbidity and mortality. Zinc supplements given for 10-14 days together with low-osmolarity oral rehydration solution (Lo-ORS) are recommended for the treatment of childhood diarrhea. In children aged >= 6 months, daily zinc supplements reduce the duration of acute diarrhea episodes by 12 h and persistent diarrhea by 17 h. Zinc supplements could reduce diarrhea mortality in children aged 12-59 months by an estimated 23%; they are very safe but are associated with an increase in vomiting especially with the first dose. Heterogeneity between the results of trials is not understood but may be related to dose and the etiology of the diarrhea infection. Integration of zinc and Lo-ORS into national programs is underway but slowly, procurement problems are being overcome and the greatest challenge is changing health provider and caregiver attitudes to diarrhea management. Fewer trials have been conducted of zinc adjunct therapy in severe respiratory tract infections and there is as yet insufficient evidence to recommend addition of zinc to antibiotic therapy. Daily zinc supplements for all children >12 months of age in zinc deficient populations are estimated to reduce diarrhea incidence by 11-23%. The greatest impact is in reducing multiple episodes of diarrhea. The effect on duration of diarrheal episodes is less clear, but there may be up to 9% reduction. Zinc is also efficacious in reducing dysentery and persistent diarrhea. Zinc supplements may also prevent pneumonia by about 19%, but heterogeneity across studies has not yet been explained. When analyses are restricted to better quality studies using CHERG (Child Health Epidemiology Reference Group) methodology, zinc supplements are estimated to reduce diarrheal deaths by 13% and pneumonia deaths by 20%. National-level programs to combat childhood zinc deficiency should be accelerated. PMID- 23689112 TI - Systematic review of zinc fortification trials. AB - Zinc is one of the essential trace elements required by the human body as it is present in more than a hundred specific enzymes and serves as an important structural ion in transcription factors. Around one third of the world population lives in countries with a high prevalence of zinc deficiency. Food fortification with zinc seems to be an attractive public health strategy and a number of programs have been initiated, especially in developing countries. We conducted a systematic review to assess the efficacy of zinc fortification. A total of 11 studies with 771 participants were included in our analysis. Zinc fortification was associated with significant improvements in plasma zinc concentrations [standard mean difference (SMD) 1.28, 95% CI 0.56, 2.01] which is a functional indicator of zinc status. Significant improvement was observed for height velocity (SMD 0.52, 95% CI 0.01, 1.04); however, this finding was weak and based on a restricted analysis. Further subgroup analysis showed significant improvement in height velocity among very-low-birth-weight infants (SMD 0.70, 95% CI 0.02, 1.37), while for healthy newborns, the impact was insignificant. Zinc fortification had insignificant impacts on serum alkaline levels, serum copper levels, hemoglobin and weight gain. Although the findings highlight that zinc fortification is associated with an increased serum concentration of the micronutrient, overall evidence of the effectiveness of this approach is limited. Data on pregnant and lactating women is scarce. Large-scale fortification programs with robust impact assessment should be initiated to cover larger populations in all age groups. Mass fortification of zinc may be a cost-effective strategy to overcome zinc deficiency. PMID- 23689113 TI - In vivo and in vitro liver cancer metabolism observed with hyperpolarized [5 (13)C]glutamine. AB - Glutamine metabolism is, with its many links to oncogene expression, considered a crucial step in cancer metabolism and it is thereby a key target for alteration in cancer development. In particular, strong correlations have been reported between oncogene expression and expression and activity of the enzyme glutaminase. This mitochondrial enzyme, which is responsible for the deamidation of glutamine to form glutamate, is overexpressed in many tumour tissues. In animal models, glutaminase expression is correlated with tumour growth rate and it is readily possible to limit tumour growth by suppression of glutaminase activity. In principle, hyperpolarized (13)C MR spectroscopy can provide insight to glutamine metabolism and should hence be a valuable tool to study changes in glutaminase activity as tumours progress. However, no such successful in vivo studies have been reported, even though several good biological models have been tested. This may, at least partly, be due to problems in preparing glutamine for hyperpolarization. This paper reports a new and improved preparation of hyperpolarized [5-(13)C]glutamine, which provides a highly sensitive (13)C MR marker. With this preparation of hyperpolarized [5-(13)C]glutamine, glutaminase activity in vivo in a rat liver tumour was investigated. Moreover, this marker was also used to measure response to drug treatment in vitro in cancer cells. These examples of [5-(13)C]glutamine used in tumour models warrant the new preparation to allow metabolic studies with this conditionally essential amino acid. PMID- 23689114 TI - Correlating infarct size and patient prognosis: are cardiac biomarkers truly insufficient? PMID- 23689115 TI - Structural and functional assessment of macula in patients with high-risk proliferative diabetic retinopathy submitted to panretinal photocoagulation and associated intravitreal bevacizumab injections: a comparative, randomised, controlled trial. AB - PURPOSE: To compare the efficacy of therapy with panretinal photocoagulation (PRP) and intravitreal bevacizumab (IVB) injections versus PRP alone in patients with high-risk proliferative diabetic retinopathy (HR-PDR) with a 6-month follow up. METHODS: Forty-two patients with HR-PDR were prospectively studied in a randomised, masked, controlled trial. Both eyes of each patient were randomised either to the study group (SG) receiving PRP plus IVB injections or the control group (CG) receiving PRP alone. Mean change in visual acuity (VA), optical coherence tomography-measured foveal thickness (FT) and macular volume (MV) were compared. RESULTS: Intergroup comparisons showed no significant difference in VA while FT exhibited a significant (p < 0.05) difference at 1 month of follow-up and MV was significantly reduced at the 1- and 3-month follow-up. Compared to baseline, VA was significantly worse at all follow-ups in the CG and was stable in the SG. FT increased significantly in the CG from baseline to the 1- and 6 month follow-ups and in the SG, no significant difference was observed. MV was significantly increased in the CG during all follow-up periods. CONCLUSION: In HR PDR, using IVB injections as adjuvant treatment to PRP reduces the VA deterioration and results in decreased FT and MV measurements compared to PRP alone. PMID- 23689116 TI - In patients with colorectal cancer, preoperative serum interleukin-6 level and granulocyte/lymphocyte ratio are clinically relevant biomarkers of long-term cancer progression. AB - OBJECTIVE: To investigate the clinical significance of the serum inflammatory cytokines and the blood granulocytes/lymphocytes (G/L) ratio in patients with colorectal cancer. METHODS: Forty-six patients underwent surgery for colorectal cancer. The G/L ratio and serum inflammatory cytokines including interleukin (IL) 1beta, IL-6, IL-8, tumour necrosis factor-alpha (TNF-alpha), granulocyte colony stimulating factor and macrophage colony-stimulating factor (M-CSF) were measured before surgery and correlated with the Tumour Node Metastasis classification and overall survival. RESULTS: Serum IL-6 in T3-4, N1-2, M1 cases and cancer stages III-IV sub-groups was significantly higher than in Tis-2, N0, M0 and cancer stages 0-II sub-groups. The G/L ratio, serum M-CSF and TNF-alpha in T3-4 cases were significantly higher than in Tis-2 cases. Furthermore, the G/L ratio and serum IL-6 showed a significant inverse correlation with the overall survival, while the G/L ratio showed a significant positive correlation with serum IL-6, TNF-alpha and M-CSF. Multivariate analysis showed that the serum IL-6 level and G/L ratio were independent risk factors for poor prognosis. CONCLUSIONS: In this investigation, a pre-operative high level of serum IL-6 and the G/L ratio appeared to be significant predictive factors for cancer progression and poor prognosis. Accordingly, these variables might be clinically relevant biomarkers in patients with colorectal cancer. PMID- 23689117 TI - Clinical routine utility of basophil activation testing for diagnosis of hymenoptera-allergic patients with emphasis on individuals with negative venom specific IgE antibodies. AB - BACKGROUND: Previous reports suggest the usefulness of basophil activation testing (BAT) in Hymenoptera-allergic patients with negative venom-specific IgE antibodies. We sought to evaluate the diagnostic utility of this testing in a routine clinical laboratory setting. MATERIALS AND METHODS: Twenty-one patients with anaphylactic reactions to Hymenoptera sting (median grade III) and negative venom-specific IgE were routinely and prospectively tested with BAT. RESULTS: We were able to diagnose 81% (17 of 21) of patients with BAT and 57% (12 of 21) with intradermal skin testing. Three wasp venom-allergic patients showed IgE positivity to rVes v 5. Four patients (19%) were negative for all tests. In the case of double-positive BAT, the culprit insect correlated with the venom that induced a significantly higher basophil response. CONCLUSIONS: BAT allows the identification of severe Hymenoptera-allergic patients with negative specific IgE and skin tests. The routine use of this cellular test should facilitate prescription of venom immunotherapy in complex cases with inconclusive diagnostic results. PMID- 23689118 TI - Rapid complete donor lymphoid chimerism and graft-versus-leukemia effect are important in early control of chronic lymphocytic leukemia. AB - Eradication of minimal residual disease (MRD) after allotransplantation in persons with chronic lymphocytic leukemia (CLL) is associated with lower rates of relapse. Rapid engraftment of donor lymphocyte elements can contribute to MRD control, but it remains unclear whether this strategy will benefit patients. In this study, we report the incidence of MRD eradication and graft-versus-host disease (GvHD) in persons with rapid versus later donor T lymphocyte engraftment after lymphodepleting chemotherapy and reduced intensity conditioning (RIC) allotransplantation. Twenty-seven subjects received lymphodepleting chemotherapy to facilitate donor engraftment followed by fludarabine and cyclophosphamide RIC and a blood cell allograft. MRD was monitored by multicolor flow cytometry after transplantation. Complete donor T lymphoid chimerism (TLC) and myeloid chimerism (MC) were achieved in 25 subjects at a median of 28 days (range, 14-60 days) and 21 days (range, 14-180 days), respectively. Achieving complete donor TLC by day 14 versus day 28 or later correlated with occurrence of grade 2 or higher acute GvHD (90% [95% confidence interval {CI}, 78-100%] versus 35% [95% CI, 16-54%]; p = 0.014) and better control of MRD in the bone marrow at day 100, median 0% (range, 0-0.1%) versus 8.5% (range, 0-92%; p = 0.016). Among 11 persons with early donor TLC, none had progressive disease, and seven died of treatment related mortality (TRM). In persons with later development of TLC, 8 of 16 had progressive disease and 2 died of TRM. Time to donor myeloid chimerism had no effect on outcomes. Rapid establishment of donor TLC resulted in more complete eradication of early MRD, but greater incidence of acute GvHD and TRM in persons with CLL undergoing RIC allotransplantation. PMID- 23689120 TI - Nephrotic syndrome: Genetic screening in steroid-resistant nephrotic syndrome. PMID- 23689121 TI - Dialysis: Decrease in mortality among US children starting dialysis. PMID- 23689071 TI - Differences between office and 24-hour blood pressure control in hypertensive patients with CKD: A 5,693-patient cross-sectional analysis from Spain. AB - BACKGROUND: Previous studies have examined control rates of office blood pressure (BP) in chronic kidney disease (CKD). However, recent evidence suggests major discrepancies between office and 24-hour BP values in hypertensive populations. This study examined concordance/discordance between office- and ambulatory-based BP control in a large cohort of patients with CKD. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 5,693 hypertensive individuals with CKD stages 1-5 from the Spanish ABPM (ambulatory BP monitoring) Registry. PREDICTORS: Thresholds of 140/90 and 130/80 mm Hg for office BP and 24-hour ambulatory BP, respectively. Age, sex, body mass index, waist circumference, hypertension duration, kidney measures, diabetes, dyslipidemia, target-organ damage, and cardiovascular comorbid conditions. OUTCOMES: Misclassification of BP control as "white-coat" hypertension (office BP >=140/90 mm Hg, 24-hour BP <130/80 mm Hg) or masked hypertension (office BP <140/90 mm Hg, 24-hour BP >=130/80 mm Hg). MEASUREMENTS: Standardized office-based BP and 24-hour ABPM. RESULTS: Mean age was 61.0 +/- 13.9 (SD) years and 52.6% were men. The proportion with white-coat hypertension was 28.8% (36.8% of patients with office BP >=140/90 mm Hg) and that of masked hypertension was 7.0% (but 32.1% of patients with office BP <140/90 mm Hg). Female sex, aging, obesity, and target-organ damage were associated with white coat hypertension; aging and obesity were associated with masked hypertension. Only 21.7% and 8.1% of the CKD population had office BP <140/90 and <130/80 mm Hg, respectively. In contrast, 43.5% of individuals had average 24-hour BP <130/80 mm Hg. LIMITATIONS: Cross-sectional design, longitudinal associations cannot be established. CONCLUSIONS: Misclassification of BP control at the office was observed in 1 of 3 hypertensive patients with CKD. Ambulatory-based control rates were far better than office-based rates. Nevertheless, the burden of uncontrolled ambulatory BP and misclassification of BP control at the office constitutes a call for wider use of ABPM to evaluate the success of hypertension treatment in patients with CKD. PMID- 23689124 TI - Pancreaticojejunostomy versus pancreaticogastrostomy after pancreaticoduodenectomy: a systematic review and meta-analysis. AB - BACKGROUND AND OBJECTIVES: The method of pancreatic reconstruction after pancreaticoduodenectomy (PD) is closely associated with postoperative morbidity, mortality, and patient's quality of life. The objective of this study is to evaluate which anastomosis approach - pancreaticogastrostomy (PG) or pancreaticojejunostomy (PJ) is a better option of choice in terms of postoperative complications. METHODS: Articles comparing PG and PJ that were published by July 2011 were retrieved and subjected to a systematic review and meta-analysis. RESULTS: Four randomized controlled trials (RCTs) and 22 observational clinical studies (OCSs) were included. RCTs showed that the PG group had significantly lower incidence rates of postoperative intra-abdominal fluid collection (p = 0.003, relative risk (RR) 0.50, 95% CI 0.31-0.79) and multiple intra-abdominal complications (p = 0.0007, RR 0.26, 95% CI 0.12-0.56) than the PJ group. OCSs demonstrated significant differences between PG and PJ in terms of frequencies of postoperative biliary fistula, intra-abdominal fluid collection, pancreatic fistula, morbidity, and mortality. The overall analysis revealed significant differences in frequencies of intra-luminal hemorrhage (p = 0.03, OR 2.82, 95% CI 1.08-7.33) and grade B/C pancreatic fistula (p = 0.002, OR 0.42, 95% CI 0.24-0.73) between the two groups. CONCLUSIONS: Current literature has no adequate evidence to prove that PG is superior to PJ for patients undergoing PD in terms of postoperative complications. A standardized classification of pancreatic fistula and other intra-abdominal complications may enable an objective, valid comparison between PG and PJ. PMID- 23689122 TI - Peritoneal dialysis--current status and future challenges. AB - Peritoneal dialysis is now a well established, mature treatment modality for advanced chronic kidney disease. The medium term (at least 5 year) survival of patients on peritoneal dialysis is currently equivalent to that of those on haemodialysis, and is particularly good in patients who are new to renal replacement therapy and have less comorbidity. Nevertheless the modality needs to keep pace with the constantly evolving challenges associated with the provision and delivery of health care. These challenges, which are gradually converging at a global level, include ageing of the population, multimorbidity of patients, containment of cost, increasing self care and environmental issues. In this context, peritoneal dialysis faces particular challenges that include multiple barriers to the therapy and unsatisfactory and poorly defined technique survival as well as limitations relating to intrinsic aspects of the therapy, such as peritoneal membrane longevity and hypoalbuminaemia. To move the therapy forward and favourably influence health-care policy, the peritoneal dialysis community needs to integrate their research effort more effectively by undertaking clinically meaningful studies-with a strong focus on technique survival--that are supported by multidisciplinary expertise in patient-centred outcomes, study design and analysis. PMID- 23689125 TI - Indices of insulin resistance and dyslipidemia are correlated with lymphocyte proneness to apoptosis in obese or overweight low birth weight children. AB - AIMS: Our aim was to study the relationship between markers of cell proneness to apoptosis and indices of insulin resistance and dyslipidemia in children born with low birth weight (LBW). METHODS: The study comprised 177 prepubertal children stratified by birth weight and their nutritional status into LBW (n = 138) and normal birth weight (NBW; n = 39) groups. We analyzed DNA from peripheral blood lymphocytes, separated by pulsed-field gel electrophoresis (PFGE), as well as the serum levels of cholesterol, HDL-cholesterol, triglycerides, fasting insulin and glucose, caspase 3, and BCL2. RESULTS: LBW children with a BMI SDS >1.55 demonstrated increased content of the large fragments of the lymphocyte DNA [300-500 kb (DNA300-500 kb)] in electrophoretic slides (a marker of decreased chromatin stability and susceptibility of cells to apoptosis) compared to the NBW group. In these children the level of DNA300-500 kb exhibited a strong negative correlation with the serum level of antiapoptotic protein of BCL2 (r = -0.901). DNA300-500 kb significantly correlated with calculated indices of insulin resistance: HOMA-IR and QUICKI as well as with the indices of lipid homeostasis (Castelli and AIP). CONCLUSIONS: Increased susceptibility of lymphocytes to apoptosis correlated with a higher risk of insulin resistance and lipid disturbance in overweight or obese LBW children. A comprehensive study of the proneness of cells to apoptosis should be implemented to further investigate the pathomechanism of the metabolic syndrome in these children. PMID- 23689126 TI - New molecular targets for the treatment of medulloblastoma. PMID- 23689123 TI - Neuropilin-2 promotes extravasation and metastasis by interacting with endothelial alpha5 integrin. AB - Metastasis, the leading cause of cancer death, requires tumor cell intravasation, migration through the bloodstream, arrest within capillaries, and extravasation to invade distant tissues. Few mechanistic details have been reported thus far regarding the extravasation process or re-entry of circulating tumor cells at metastatic sites. Here, we show that neuropilin-2 (NRP-2), a multifunctional nonkinase receptor for semaphorins, vascular endothelial growth factor (VEGF), and other growth factors, expressed on cancer cells interacts with alpha5 integrin on endothelial cells to mediate vascular extravasation and metastasis in zebrafish and murine xenograft models of clear cell renal cell carcinoma (RCC) and pancreatic adenocarcinoma. In tissue from patients with RCC, NRP-2 expression is positively correlated with tumor grade and is highest in metastatic tumors. In a prospectively acquired cohort of patients with pancreatic cancer, high NRP-2 expression cosegregated with poor prognosis. Through biochemical approaches as well as Atomic Force Microscopy (AFM), we describe a unique mechanism through which NRP-2 expressed on cancer cells interacts with alpha5 integrin on endothelial cells to mediate vascular adhesion and extravasation. Taken together, our studies reveal a clinically significant role of NRP-2 in cancer cell extravasation and promotion of metastasis. PMID- 23689127 TI - Blue water sailing and neurosurgery: a natural fit? "Uma vida so se vive". PMID- 23689128 TI - The fuzzy logic of degenerative disc disease: from a Lorenz attractor to a percolation threshold model. PMID- 23689129 TI - No treatment for small unruptured intracranial aneurysm: is this the right way to go? PMID- 23689130 TI - Rpd3- and spt16-mediated nucleosome assembly and transcriptional regulation on yeast ribosomal DNA genes. AB - Ribosomal DNA (rDNA) genes in eukaryotes are organized into multicopy tandem arrays and transcribed by RNA polymerase I. During cell proliferation, ~50% of these genes are active and have a relatively open chromatin structure characterized by elevated accessibility to psoralen cross-linking. In Saccharomyces cerevisiae, transcription of rDNA genes becomes repressed and chromatin structure closes when cells enter the diauxic shift and growth dramatically slows. In this study, we found that nucleosomes are massively depleted from the active rDNA genes during log phase and reassembled during the diauxic shift, largely accounting for the differences in psoralen accessibility between active and inactive genes. The Rpd3L histone deacetylase complex was required for diauxic shift-induced H4 and H2B deposition onto rDNA genes, suggesting involvement in assembly or stabilization of the entire nucleosome. The Spt16 subunit of FACT, however, was specifically required for H2B deposition, suggesting specificity for the H2A/H2B dimer. Miller chromatin spreads were used for electron microscopic visualization of rDNA genes in an spt16 mutant, which was found to be deficient in the assembly of normal nucleosomes on inactive genes and the disruption of nucleosomes on active genes, consistent with an inability to fully reactivate polymerase I (Pol I) transcription when cells exit stationary phase. PMID- 23689131 TI - Phospholipase D1 has a pivotal role in interleukin-1beta-driven chronic autoimmune arthritis through regulation of NF-kappaB, hypoxia-inducible factor 1alpha, and FoxO3a. AB - Interleukin-1beta (IL-1beta) is a potent proinflammatory and immunoregulatory cytokine playing an important role in the progression of rheumatoid arthritis (RA). However, the signaling network of IL-1beta in synoviocytes from RA patients is still poorly understood. Here, we show for the first time that phospholipase D1 (PLD1), but not PLD2, is selectively upregulated in IL-1beta-stimulated synoviocytes, as well as synovium, from RA patients. IL-1beta enhanced the binding of NF-kappaB and ATF-2 to the PLD1 promoter, thereby enhancing PLD1 expression. PLD1 inhibition abolished the IL-1beta-induced expression of proinflammatory mediators and angiogenic factors by suppressing the binding of NF kappaB or hypoxia-inducible factor 1alpha to the promoter of its target genes, as well as IL-1beta-induced proliferation or migration. However, suppression of PLD1 activity promoted cell cycle arrest via transactivation of FoxO3a. Furthermore, PLD1 inhibitor significantly suppressed joint inflammation and destruction in IL 1 receptor antagonist-deficient (IL-1Ra(-/-)) mice, a model of spontaneous arthritis. Taken together, these results suggest that the abnormal upregulation of PLD1 may contribute to the pathogenesis of IL-1beta-induced chronic arthritis and that a selective PLD1 inhibitor might provide a potential therapeutic molecule for the treatment of chronic inflammatory autoimmune disorders. PMID- 23689132 TI - Regulation of focal adhesion kinase activation, breast cancer cell motility, and amoeboid invasion by the RhoA guanine nucleotide exchange factor Net1. AB - Net1 is a RhoA guanine nucleotide exchange factor (GEF) that is overexpressed in a subset of human cancers and contributes to cancer cell motility and invasion in vitro. However, the molecular mechanism accounting for its role in cell motility and invasion has not been described. In the present work, we show that expression of both Net1 isoforms in breast cancer cells is required for efficient cell motility. Although loss of Net1 isoform expression only partially blocks RhoA activation, it inhibits lysophosphatidic acid (LPA)-stimulated migration as efficiently as knockdown of RhoA itself. However, we demonstrate that the Net1A isoform predominantly controls myosin light-chain phosphorylation and is required for trailing edge retraction during migration. Net1A interacts with focal adhesion kinase (FAK), localizes to focal adhesions, and is necessary for FAK activation and focal adhesion maturation during cell spreading. Net1A expression is also required for efficient invasion through a Matrigel matrix. Analysis of invading cells demonstrates that Net1A is required for amoeboid invasion, and loss of Net1A expression causes cells to shift to a mesenchymal phenotype characterized by high beta1-integrin activity and membrane type 1 matrix metalloproteinase (MT1-MMP) expression. These results demonstrate a previously unrecognized role for the Net1A isoform in controlling FAK activation during planar cell movement and amoeboid motility during extracellular matrix (ECM) invasion. PMID- 23689133 TI - Impaired epidermal permeability barrier in mice lacking elovl1, the gene responsible for very-long-chain fatty acid production. AB - The sphingolipid backbone ceramide (Cer) is a major component of lipid lamellae in the stratum corneum of epidermis and has a pivotal role in epidermal barrier formation. Unlike Cers in other tissues, Cers in epidermis contain extremely long fatty acids (FAs). Decreases in epidermal Cer levels, as well as changes in their FA chain lengths, cause several cutaneous disorders. However, the molecular mechanisms that produce such extremely long Cers and determine their chain lengths are poorly understood. We generated mice deficient in the Elovl1 gene, which encodes the FA elongase responsible for producing C20 to C28 FAs. Elovl1 knockout mice died shortly after birth due to epidermal barrier defects. The lipid lamellae in the stratum corneum were largely diminished in these mice. In the epidermis of the Elovl1-null mice, the levels of Cers with >=C26 FAs were decreased, while those of Cers with <=C24 FAs were increased. In contrast, the levels of C24 sphingomyelin were reduced, accompanied by an increase in C20 sphingomyelin levels. Two ceramide synthases, CerS2 and CerS3, expressed in an epidermal layer-specific manner, regulate Elovl1 to produce acyl coenzyme As with different chain lengths. Elovl1 is a key determinant of epidermal Cer chain length and is essential for permeability barrier formation. PMID- 23689134 TI - Interaction and antagonistic roles of NF-kappaB and Hes6 in the regulation of cortical neurogenesis. AB - The involvement of nuclear factor kappa B (NF-kappaB) in several processes in the postnatal and adult brain, ranging from neuronal survival to synaptogenesis and plasticity, has been documented. In contrast, little is known about the functions of NF-kappaB during embryonic brain development. It is shown here that NF-kappaB is selectively activated in neocortical neural progenitor cells in the developing mouse telencephalon. Blockade of NF-kappaB activity leads to premature cortical neuronal differentiation and depletion of the progenitor cell pool. Conversely, NF-kappaB activation causes decreased cortical neurogenesis and expansion of the progenitor cell compartment. These effects are antagonized by the proneuronal transcription factor Hes6, which physically and functionally interacts with RelA containing NF-kappaB complexes in cortical progenitor cells. In turn, NF-kappaB exerts an inhibitory effect on the ability of Hes6 to promote cortical neuronal differentiation. These results reveal previously uncharacterized functions and modes of regulation for NF-kappaB and Hes6 during cortical neurogenesis. PMID- 23689135 TI - Insights into the mechanism of ribosomal incorporation of mammalian L13a protein during ribosome biogenesis. AB - In contrast to prokaryotes, the precise mechanism of incorporation of ribosomal proteins into ribosomes in eukaryotes is not well understood. For the majority of eukaryotic ribosomal proteins, residues critical for rRNA binding, a key step in the hierarchical assembly of ribosomes, have not been well defined. In this study, we used the mammalian ribosomal protein L13a as a model to investigate the mechanism(s) underlying eukaryotic ribosomal protein incorporation into ribosomes. This work identified the arginine residue at position 68 of L13a as being essential for L13a binding to rRNA and incorporation into ribosomes. We also demonstrated that incorporation of L13a takes place during maturation of the 90S preribosome in the nucleolus, but that translocation of L13a into the nucleolus is not sufficient for its incorporation into ribosomes. Incorporation of L13a into the 90S preribosome was required for rRNA methylation within the 90S complex. However, mutations abolishing ribosomal incorporation of L13a did not affect its ability to be phosphorylated or its extraribosomal function in GAIT element-mediated translational silencing. These results provide new insights into the mechanism of ribosomal incorporation of L13a and will be useful in guiding future studies aimed at fully deciphering mammalian ribosome biogenesis. PMID- 23689136 TI - Testosterone-dependent interaction between androgen receptor and aryl hydrocarbon receptor induces liver receptor homolog 1 expression in rat granulosa cells. AB - Androgens play a major role in the regulation of normal ovarian function; however, they are also involved in the development of ovarian pathologies. These contrasting effects may involve a differential response of granulosa cells to the androgens testosterone (T) and dihydrotestosterone (DHT). To determine the molecular pathways that mediate the distinct effects of T and DHT, we studied the expression of the liver receptor homolog 1 (LRH-1) gene, which is differentially regulated by these steroids. We found that although both T and DHT stimulate androgen receptor (AR) binding to the LRH-1 promoter, DHT prevents T-mediated stimulation of LRH-1 expression. T stimulated the expression of aryl hydrocarbon receptor (AHR) and its interaction with the AR. T also promoted the recruitment of the AR/AHR complex to the LRH-1 promoter. These effects were not mimicked by DHT. We also observed that the activation of extracellular regulated kinases by T is required for AR and AHR interaction. In summary, T, but not DHT, stimulates AHR expression and the interaction between AHR and AR, leading to the stimulation of LRH-1 expression. These findings could explain the distinct response of granulosa cells to T and DHT and provide a molecular mechanism by which DHT negatively affects ovarian function. PMID- 23689137 TI - Immune mediators regulate CFTR expression through a bifunctional airway-selective enhancer. AB - An airway-selective DNase-hypersensitive site (DHS) at kb -35 (DHS-35kb) 5' to the cystic fibrosis transmembrane conductance regulator (CFTR) gene is evident in many lung cell lines and primary human tracheal epithelial cells but is absent from intestinal epithelia. The DHS-35kb contains an element with enhancer activity in 16HBE14o- airway epithelial cells and is enriched for monomethylated H3K4 histones (H3K4me1). We now define a 350-bp region within DHS-35kb which has full enhancer activity and binds interferon regulatory factor 1 (IRF1) and nuclear factor Y (NF-Y) in vitro and in vivo. Small interfering RNA (siRNA) mediated depletion of IRF1 or overexpression of IRF2, an antagonist of IRF1, reduces CFTR expression in 16HBE14o- cells. NF-Y is critical for maintenance of H3K4me1 enrichment at DHS-35kb since depletion of NF-YA, a subunit of NF-Y, reduces H3K4me1 enrichment at this site. Moreover, depletion of SETD7, an H3K4 monomethyltransferase, reduces both H3K4me1 and NF-Y occupancy, suggesting a requirement of H3K4me1 for NF-Y binding. NF-Y depletion also represses Sin3A and reduces its occupancy across the CFTR locus, which is accompanied by an increase in p300 enrichment at multiple sites. Our results reveal that the DHS-35kb airway selective enhancer element plays a pivotal role in regulation of CFTR expression by two independent regulatory mechanisms. PMID- 23689138 TI - Pathogenic role of Epstein-Barr virus latent membrane protein-1 in the development of nasopharyngeal carcinoma. AB - Undifferentiated nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus associated malignant tumor. A consistent elevation in EBV antibody titers is a well-established risk factor for the development of NPC. The pathophysiological relationship and molecular mechanisms of EBV-mediated carcinogenesis have not been fully elucidated. While NPC tumors are known to express three EBV-encoded proteins, EBNA1, LMP1, and LMP2, they also express a large number of virus encoded small RNAs (EBERs) and microRNAs (miRNAs). Among them, LMP1 may be a central player in the development of NPC. LMP1, an EBV-encoded primary oncogene, functions as a viral mimic of the TNFR family member, CD40, and engages in a number of signaling pathways that induce morphological and phenotypic alterations in epithelial cells. LMP1 upregulates EMT, and contributes to the highly metastatic features of NPC. Moreover, LMP1-associated EMT is accompanied by the expression of cancer stem cell (CSC)/cancer progenitor cell (CPC) markers (CD44high/CD24low) and the acquisition of stem cell/progenitor cell-like properties. BART miRNAs, encoded from the BamHI-A region of the viral genome, are the most abundant transcripts. They modulate apoptosis and host innate immune defense mechanisms. Some BART1 miRNAs are considered to negatively regulate LMP1 protein expression. LMP1 is secreted via exosomes, is incorporated into EBV uninfected cells by endocytosis, and affects the environment surrounding the tumor. Here we reviewed the contribution of EBV gene products to NPC pathogenesis in relation with LMP1. PMID- 23689140 TI - Feedback loop between p66(Shc) and Nrf2 promotes lung cancer progression. AB - p66(Shc), one of the SHC1 gene encoding proteins, promotes cell death and reports cell anchorage status, mediating anoikis in vitro and functioning as a metastasis suppressor in vivo. However, very little is known about p66(Shc) gene regulation in cancer cells. Here, we show that methylation of a specific CpG site in the early post-transcriptional region correlates with p66(Shc) repression in clinical human lung cancer samples and cancer cell lines. We also find that the stress related transcription factor Nrf2 associates with p66(Shc) gene promoter in the methylated region, and promotes p66(Shc) transcription. However, p66(Shc) induction by Nrf2 requires demethylation of the Nrf2 binding site in p66(Shc) promoter. Knock-down of p66(Shc) leads to a positive feedback upregulation of Nrf2 expression and accordingly, Nrf2 is found to be highly expressed in tumors with low p66(Shc) expression. Further, Nrf2 expression level positively correlates with tumor grade of patients. Thus, we propose that epigenetic repression of p66(Shc) in cancer cells might be a key factor leading to Nrf2 upregulation, increased cell survival, and tumor progression. PMID- 23689139 TI - Quantitative high-throughput efficacy profiling of approved oncology drugs in inflammatory breast cancer models of acquired drug resistance and re sensitization. AB - Although there is no standard treatment protocol for inflammatory breast cancer (IBC), multi-modality treatment has improved survival. In this study we profiled the NCI approved oncology drug set in a qHTS format to identify those that are efficacious in basal type and ErbB2 overexpressing IBC models. Further, we characterized the sensitivity of an acquired therapeutic resistance model to the oncology drugs. We observed that lapatinib-induced acquired resistance in SUM149 cells led to cross-resistance to other targeted- and chemotherapeutic drugs. Removal of the primary drug to which the model was developed led to re sensitization to multiple drugs to a degree comparable to the parental cell line; this coincided with the cells regaining the ability to accumulate ROS and reduced expression of anti-apoptotic factors and the antioxidant SOD2. We suggest that our findings provide a unique IBC model system for gaining an understanding of acquired therapeutic resistance and the effect of redox adaptation on anti-cancer drug efficacy. PMID- 23689141 TI - On the holotype and original description of the pliopithecid Plesiopliopithecus lockeri (). PMID- 23689142 TI - CD271 as a marker for mesenchymal stem cells in bone marrow versus umbilical cord blood. AB - CD271 has been applied to isolate mesenchymal stem cells (MSCs) from bone marrow and other tissues. Umbilical cord blood is a unique resource of stem cells and endothelial progenitor cells. Isolation of MSCs from umbilical cord blood, however, has been inefficient and inconsistent. This study was designed to examine the potential application of CD271 as a marker for the isolation of MSCs from umbilical cord blood. CD271+ cells were isolated from umbilical cord blood and bone marrow using CD271 antibody-conjugated microbeads, and characterized in osteogenic, chondrogenic and adipogenic differentiation. CD271+ cells from umbilical cord blood were slow to proliferate compared with those isolated from bone marrow. While CD271+ cells from bone marrow differentiated into osteogenic, chondrogenic and adipogenic lineages, there were no sound indications of differentiation by CD271+ cells from umbilical cord blood under the same differentiation conditions applied to the CD271+ cells from bone marrow. The study also found that bone marrow CD271+ cells remarkably upregulated the expression of chondrogenic genes under chondrogenic differentiation induction. When implanted into bone defects in mice, CD271+ cells from bone marrow regenerated significant bone, but the counterparts in umbilical cord blood formed little bone in the bone defects. In conclusion, CD271 is an efficient marker for MSC isolation from bone marrow but has failed to isolate MSCs from umbilical cord blood. CD271+ cells in bone marrow are particularly chondrogenic. The property of CD271+ cells is unique but varies from different tissues. PMID- 23689143 TI - Microalbuminuria and left ventricular hypertrophy in essential hypertension: consequence or cause. PMID- 23689144 TI - Postmenopausal osteoporosis treatment and risk of urinary calculus development. PMID- 23689145 TI - Immunoglobulin M nephropathy: not uncommon but still a controversial entity. PMID- 23689146 TI - Does kidney retransplantation have a favorable outcome? PMID- 23689147 TI - Microalbuminuria: a useful marker of cardiovascular disease. AB - Leakage of small amounts of proteins in urine has been considered since 1980s a crucial sign of early kidney disease, especially in diabetic patients. An increasing interest in microalbuminuria as a cardiovascular risk marker has been more recently considered. Many studies linked microalbuminuria to early cardiovascular disease, as a marker of endothelial dysfunction, not only in diabetic patients, but also in hypertensive patients and in general population. Microalbuminuria is considered nowadays by guidelines as a cost-effective marker of subclinical organ damage in hypertensive patients and should be checked routinely in hypertensive patients. Assessing subclinical organ damage is recommended not only at the level of screening, but also during treatment. Microalbuminuria is also considered as a treatment outcome marker and useful for understanding the ability of a given therapeutic intervention to regress organ damage or slow down its progression. PMID- 23689148 TI - Seroepidemiology of human T-cell lymphotropic virus 1 infection in hemodialysis patients: should we be concerned about it? AB - Human T-cell lymphotropic virus 1 (HTLV1) is a lymphotropic virus which can be transmitted through unprotected sexual activity, breast feeding, and blood transfusion. Although most of HTLV1-infected individuals remain asymptomatic carriers, 1% to 5% and 3% to 5% develop adult T-cell leukemia and HTLV1 associated myelopathy/tropical spastic paraparesis, respectively. The aim of this study was to determine the prevalence of HTLV1 infection in hemodialysis patients in Sari and Ghaemshahr. This cross-sectional study was conducted on160 patients using random samples selection, and included 80 men and 80 women (mean age, 59.1 ± 14.7 years). All the samples were screened for HTLV1 antibody by enzyme linked immunosorbent assay and positive samples were confirmed by Western blot assay. Only 1 patient had a positive anti-HTLV1 enzyme-linked immunosorbent assay test, which was confirmed by Western blot. The overall prevalence of HTLV1 seropositivity was 0.6%. The patient was a 21-year-old woman with a history of multiple blood transfusions. She had a history of unsuccessful kidney transplantation and had been on hemodialysis before transplant, too. This study suggests that HTLV1 infection may not be prevalent in high-risk patients in Mazandaran province, and there is no need for HTLV1 screening of blood samples. PMID- 23689149 TI - Skin ulcerations in a lupus hemodialysis patient with hepatitis C infection: what is your diagnosis? PMID- 23689150 TI - Left ventricular hypertrophy and microalbuminuria in patients with essential hypertension. AB - INTRODUCTION: Microalbuminuria and left ventricular hypertrophy (LVH) have both been shown to predict increased cardiovascular morbidity and mortality, especially in diabetic patients. The present study investigated the relationship between microalbuminuria and LVH in patients with essential hypertension. MATERIALS AND METHODS: After a primary workup to rule out secondary hypertension, 110 essential hypertensive patients with LVH (mean age, 62.97 +/- 11.02 years) and 10 essential hypertensive patients without LVH (mean age, 65.13 +/- 10.15 years) were enrolled in this case-control study. Spot urine sample was collected for the assessment of microalbuminuria and creatinine concentrations in the two groups. Smoking status, blood pressure, and serum levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and creatinine were evaluated. RESULTS: Patients with LVH had significantly higher microalbuminuria level compared with those without LVH (mean urine albumin creatinine ratio, 54.4 +/- 39.48 MUg/mg versus 33.56 +/- 21.73 MUg/mg; P < .001). Multivariable regression analysis showed that the patients with a higher urine albumin-creatinine ratio were more likely to have LVH (OR, 1.028; 95% CI, 1.015 to 1.041; P < .001). Other significant predictive factors for LVH in the model were diastolic blood pressure, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and serum creatinine. CONCLUSIONS: Left ventricular hypertrophy is associated with microalbuminuria in patients with essential hypertension. These data are strengthening the role of microalbuminuria as an indicator of high cardiovascular risk. PMID- 23689151 TI - Ki-67 proliferation index in renal biopsy samples of patients with systemic lupus erythematosus and its correlation with clinical findings. AB - INTRODUCTION: Systemic lupus erythematosus is an autoimmune disease that may affect almost all organ systems. Renal involvement is the most significant prognostic factor. Renal biopsy findings play an important role in treatment decision. Ki-67 is a monoclonal antibody that is only found in proliferative cells. This study aimed to investigate the proliferative activity in renal biopsy specimens of patients with lupus nephritis using the Ki-67 monoclonal antibody, and to compare the proliferative index between different subgroups of patients. MATERIALS AND METHODS: Renal biopsy specimens of 29 patients with systemic lupus erythematosus were retrospectively evaluated. Type of lupus nephritis and activity and chronicity indexes were determined. Ki-67 immunostaining was performed. For each patient, 1000 cells were counted and the number of Ki-67 positive cells was determined. The Ki-67 activity index was compared between different subgroups of lupus nephritis and correlated with systemic lupus erythematosus disease activity index, serum creatinine, proteinuria, anticardiolipin antibodies, and complement levels. RESULTS: A positive correlation between Ki-67 proliferation index, serum creatinine levels, and systemic lupus erythematosus disease activity index were found. Although conventional activity indexes were low, in 3 of 9 patients with class II lupus nephritis, Ki-67 proliferation indexes were high, indicating proliferation. CONCLUSIONS: Ki-67 can be used as a proliferation marker in renal biopsy specimens for patients diagnosed with systemic lupus erythematosus. PMID- 23689152 TI - Correlation between ankle-brachial index and microalbuminuria in type 2 diabetes mellitus. AB - INTRODUCTION: Microalbuminuria is a reliable marker of diabetic nephropathy. Establishment of peripheral vascular complications leads to early diagnosis, prevention, and treatment of renal and cardiovascular complications. This study investigated the value of ankle-brachial index (ABI) for prediction of microalbuminuria in type 2 diabetic patients. MATERIALS AND METHODS: Measurement of ABI with color Doppler ultrasonography was carried out for 206 patients with type 2 diabetes mellitus. An ABI Index less than 0.9 was defined as a predictive marker for atherosclerosis. Microalbuminuria and risk factors of atherosclerosis were compared between the patients categorized based on the ABI values. RESULTS: The mean ABI was 1.1 +/- 0.2 (range, 0.052 to 1.6), and 41 (20%) had an abnormal ABI (< 0.9). The correlations were significant between abnormal ABI and duration of disease (P = .04), cardiovascular event and cardiac care unit admission (P = .001), hypertension (P = .01), and dyslipidemia (P = .01). There was a significant correlation between ABI and microalbuminuria (odds ratio, 0.05; 95% confidence interval, 0.038 to 0.630; P < .001). A cutoff point of an ABI less than or equal to 1.04 had a sensitivity of 71.6% and a specificity of 64.2% for prediction of microalbuminuria. CONCLUSIONS: The ABI is a noninvasive and reliable assay for detection of peripheral and cardiovascular complications, and also early stage of nephropathy in diabetic patients. In patients with an abnormal ABI, long-term follow-up for earlier detection and prevention of complications is helpful. PMID- 23689153 TI - Calcium and vitamin D supplementation and risk of kidney stone formation in postmenopausal women. AB - INTRODUCTION: Calcium and vitamin D are essential structural components of the skeletal system, which prevent osteoporosis after menopause. However, there is a controversial debate on the association between the intake of calcium and vitamin D supplements and the increased risk of formation of kidney calculi in postmenopausal women. which yet have to be confirmed. This study aimed to compare the metabolic changes after supplementation of calcium and vitamin D and examine the risk of stone formation. MATERIALS AND METHODS: Fifty-three postmenopausal women referred to rheumatology clinic who had no history of kidney calculi, bone diseases (apart from osteoporosis), metabolic, and rheumatic disorders and had not been receiving calcium, diuretics and calcitonin were investigated. Renal ultrasonography and blood tests were performed and the urine calcium levels were measured for a period of 24 hours for all patients. The examinations were repeated after a 1- year period of treatment with supplemental calcium (100 mg/d) and vitamin D (400 IU/d) and compared with the data before the treatment. RESULTS: After 1 year, asymptomatic lithiasis was confirmed in 1 of 53 patients (1.9%) using ultrasonographic examination. No significant differences were found between the 24-hour urine and blood calcium levels before and after the treatment. CONCLUSIONS: Our findings showed that oral intake of calcium and vitamin D after 1 year has no effect on the urinary calcium excretion rate and the formation of kidney calculi in postmenopausal women. PMID- 23689154 TI - Immunoglobulin M nephropathy in adults: a clinicopathological study. AB - INTRODUCTION: There is no data specifically on the clinical and immunopathologic features of Immunoglobulin M nephropathy (IgMN) in adults with kidney diseases in Pakistan. MATERIALS AND METHODS: We retrospectively reviewed our adult native renal biopsy records from May 2001 to April 2010 and identified 57 cases out of a total of 1,753 records labeled as IgMN on final histopathological analysis. Among these, 41 cases were included in the present analysis. Their relevant data items were collected from the case files and biopsy reports. RESULTS: The mean age of this cohort was 30.21 +/- 10.12 years. The male-female ratio was 1.15:1. The most common presentation was idiopathic nephrotic syndrome. Hematuria and hypertension at presentation were noted in 24 (58.5%) and 10 (24.4%) patients, respectively. The most common morphologic change was glomerular mesangial cell proliferation, found in 28 biopsies (68.3%). Mesangial matrix expansion was noted in 16 (39%). Minor glomerular alterations were noted in 5 cases (12.2%) and focal segmental glomerulosclerosis in 4 (9.8%). Immunofluorescence microscopy showed diffuse mesangial positivity of IgM in all specimens. Subdominant IgA was noted in 6 cases (14.6%). Complements C3 and C1q were found in 28 (68.3%) and 21 (51.2%) patients, respectively. CONCLUSIONS: Our results show that IgMN is not very common in adults. Its clinicopathological spectrum is similar to that described from the neighboring countries, showing a spectrum of morphologic changes ranging from minor changes to focal segmental glomerulosclerosis. PMID- 23689155 TI - Blood pressure increase after erythropoietin injection in hemodialysis and predialysis patients. AB - INTRODUCTION: Anemia is among the most important complications of chronic kidney disease (CKD) and a lot of symptoms and signs are due to this problem. Erythropoietin injection may improve anemia, but it may cause hypertension in these patients. The aim of this study is to evaluate erythropoietin injection effects on blood pressure of hemodialysis and predialysis patients. MATERIALS AND METHODS: Forty hemodialysis patients and 40 predialysis patients with end-stage renal disease were enrolled in the study. The studied patients were comparable in terms of age, sex, hemoglobin, serum calcium, and baseline blood pressure. Erythropoietin was injected for all of the patients with anemia (4000 U, twice weekly). The effect of erythropoietin on their blood pressure was evaluated for each group by comparison of systolic, diastolic, and mean arterial blood pressure values before and 1 hour after the injection. RESULTS: After erythropoietin injection, systolic, diastolic, and mean arterial blood pressure values increased significantly in the hemodialysis group, and the increases were significantly greater in this group than the predialysis group (P = .02, P = .01, and P = .02, respectively). Blood pressure increase was significant only for the systolic component in the predialysis group. CONCLUSIONS: Erythropoietin injection increases blood pressure levels in both groups. However, this is more significant in the hemodialysis patients as compared with patients with end-stage renal disease who have not started dialysis. Monitoring of blood pressure after erythropoietin injection is recommended. PMID- 23689156 TI - Hyperglycemia after kidney transplantation: frequency and risk factors. AB - INTRODUCTION: Kidney transplantation and its conventional treatment can lead to increased risk of diabetes mellitus outbreak in normoglycemic recipients. Also, uncontrolled hyperglycemia may increase allograft loss and decrease patient survival. We aimed to assess the frequency of hyperglycemia in transplant patients and its risk factors. MATERIALS AND METHODS: A retrospective study was performed on 3342 adult kidney transplant recipients between 2008 and 2010. Demographic and laboratory data were collected. All laboratory tests were done in a one laboratory, and hyperglycemia was defined as a fasting plasma glucose level greater than 125 mg/dL. Univariable and multivariable logistic regression analyses were used to determine the risk factors of hyperglycemia following kidney transplantation. RESULTS: There were 2120 men (63.4%) and 1212 women (36.3%) included in the study. The prevalence of hyperglycemia was 22.5%. Hyperglycemia was significantly higher in patients with cytomegalovirus infection (P = .001), elevated serum creatinine (P < .001), low high-density lipoprotein cholesterol (P = .01), and increased blood levels of cyclosporine (P < .001). After adjusting for covariates by multivariate logistic regression, the hyperglycemia rate was significantly higher for patients with a cyclosporine trough level greater than 250 ng/mL (P < .001), a serum creatinine level greater than 1.5 mg/dL (P < .001), and a high-density lipoprotein cholesterol less than 45 mg/dL (P = .03). CONCLUSIONS: This study indicated that hyperglycemia is a common metabolic disorder in Iranian kidney transplant patients. Risk factors for hyperglycemia were higher cyclosporine level, impaired kidney function, and reduced high-density lipoprotein cholesterol values. PMID- 23689157 TI - Nephrotic syndrome due to immunoglobulin M mesangial glomerulonephritis preceding juvenile idiopathic arthritis. AB - The association between nephrotic syndrome and juvenile idiopathic arthritis have rarely been described in pediatric patients. We report a child with steroid responsive nephrotic syndrome, with frequent relapses, who presented with a new relapse of nephrotic syndrome associated with arthritis and uveitis at 21 months in remission after treatment with chlorambucil. Juvenile idiopathic arthritis was diagnosed and kidney biopsy examination showed mesangial glomerulonephritis with immunoglobulin M deposits. To our knowledge, only 2 cases of nephrotic syndrome preceding juvenile idiopathic arthritis have been reported, one without histopathology assessment and the other with minimal change disease. Although mesangial glomerulonephritis with nephrotic syndrome and juvenile idiopathic arthritis could have been coincidental, the immune pathogenic mechanism accepted for both diseases suggests they could be related. PMID- 23689158 TI - Severe high anion gap metabolic acidosis in pregnancy. AB - Ketoacidosis can occur most often as a result of uncontrolled diabetes mellitus. However, it can be seen with fasting and alcohol consumption, as well. Ketoacidosis in association with fasting has less severity, and ketoacid levels do not exceed 10 mEq/L. In the literature, there are a few reports about severe high anion gap acidosis that were associated with fasting. We report a case of pregnancy associated with high anion gap acidosis as a result of fasting. PMID- 23689159 TI - Successful 4th kidney transplantation: a case report from Iran. AB - Kidney transplantation is generally considered the best option for most patients with end-stage renal disease requiring renal replacement therapy, even for patients with graft failure. Here, we describe a case of a 49-year-old man who received his 1st kidney transplant the United Kingdom from his brother when he was 18 years old in. Thirty-one year after the first transplant, he underwent successful 4th living-unrelated kidney transplantation with no serious complications at our transplant center. He continued to have excellent allograft function and his latest serum creatinine 33 months after his 4th transplant was 1.2 mg/dL. To our knowledge, this is the first case of 4th kidney transplantation from Iran. PMID- 23689160 TI - Re: prevalence of pulmonary hypertension in patients undergoing hemodialysis: evaluation all affecting factors otherwise freak of nature! PMID- 23689161 TI - Re: association between serum magnesium and risk factors of cardiovascular disease in hemodialysis patients. PMID- 23689163 TI - Preconditioning strategies to enhance physical performance on the day of competition. AB - Sports scientists and strength and conditioning professionals spend the majority of the competition season trying to ensure that their athletes' training and recovery strategies are appropriate to ensure optimal performance on competition day. However, there is an additional window on the day of competition where performance can be acutely enhanced with a number of preconditioning strategies. These strategies include appropriately designed warm-up, passive heat maintenance, postactivation potentiation, remote ischemic preconditioning, and, more recently, prior exercise and hormonal priming. The aim of this review was to explore the potential practical use of these strategies and propose a theoretical timeline outlining how they may be incorporated into athlete's precompetition routine to enhance performance. For the purpose of this review the discussion is confined to strategies that may enhance performance of short-duration, high intensity sports (eg, sprinting, jumping, throwing). PMID- 23689164 TI - AUStralian Indigenous Chronic Disease Optimisation Study (AUSI-CDS) prospective observational cohort study to determine if an established chronic disease health care model can be used to deliver better heart failure care among remote Indigenous Australians: Proof of concept-study rationale and protocol. AB - BACKGROUND: The congestive heart failure syndrome has increased to epidemic proportions and is cause for significant morbidity and mortality. Indigenous patients suffer a greater prevalence with greater severity. Upon diagnosis patients require regular follow-up with medical and allied health services. Patients are prescribed life saving, disease modifying and symptom relieving therapies. This can be an overwhelming experience for patients. To compound this, remoteness, differentials in conventional health care and services pose special problems for Indigenous clients in accessing care. Additional barriers of language, culture, socio-economic disadvantage, negative attitudes towards establishment, social stereotyping, stigma and discrimination act as barriers to improved care. Recent focus supported by clinical evidence support the role of chronic disease self-management programs. A patient focused, problem identification, goal setting and psychosocial modification based program should in principal highlight these issues and help tailor a patient focused comprehensive care plan to complement guideline based care. At present there are no Indigenous focused chronic disease self-management programs. There is a need for research on ways to provide chronic disease management to this group. We therefore designed a study to assess a model of patient focussed comprehensive care for Indigenous Australians with heart failure. STUDY DESIGN: AUSI-CDS is a prospective, cohort, observational study to evaluate the efficacy of the standard "Flinders Program of Chronic Condition Management" for Indigenous patients with chronic heart failure. Eligible patients will be Indigenous, suffering from chronic heart failure, in the Northern Territory. The primary end-point is the satisfaction score based on the PACIC. The study will recruit 20 patients and is expected to last 12 months. SUMMARY: The rationale and design of the AUSI-CDS using the Flinders Model is described. PMID- 23689165 TI - Intracellular ATP-binding cassette transporter A3 is expressed in lung cancer cells and modulates susceptibility to cisplatin and paclitaxel. AB - Patients with advanced-stage bronchial cancer benefit from systemic cytostatic therapy, in particular from regimens integrating cisplatin and taxanes. However, eventual disease progression leads to a fatal outcome in most cases, originating from tumor cells resisting chemotherapy. We here show that the intracellular ATP binding cassette transporter A3 (ABCA3), previously recognized as critical for the secretion of surfactant components from type 2 pneumocytes, is expressed in non-small-cell lung cancer (NSCLC) cells. With some heterogeneity in a given specimen, expression levels detected immunohistochemically in primary cancer tissue were highest in adenocarcinomas and lowest in small cell lung cancers. Genetic silencing of ABCA3 in the NSCLC cell line models A549, NCI-H1650 and NCI H1975 significantly increased tumor cell susceptibility to the cytostatic effects of both cisplatin (in all cell lines) and paclitaxel (in two of three cell lines). Taken together, ABCA3 emerges as a modulator of NSCLC cell susceptibility to cytostatic therapy. PMID- 23689166 TI - Chronic hepatitis E infection: risks and controls. AB - Very recently, an unusual clinical presentation with an altered natural history associated with hepatitis E virus (HEV) infection has emerged in high-income industrialized nations. Although HEV infection does not develop into chronicity in general, viremia can persist for long periods of time in immunocompromised solid organ, bone marrow and stem cell transplant patients. Conceivably, the atypical clinical and virological outcomes in these cases could be related to immunosuppressive chemotherapy, resulting in suboptimal HEV-specific immune responses. In the absence of travel to endemic regions, foodborne autochthonous HEV infection due to viral genotypes 3 and 4 has been implicated in the chronic cases. Presently, pegIFN-alpha-2a and ribavirin, the commonly used drugs to treat chronic viral hepatitis, are proving very promising in hepatitis E patients. Nevertheless, the most-awaited HEV vaccine could be protective in naive travelers or high-risk group populations. The mechanisms of establishing chronic HEV infection and the disease severity have hitherto not been clearly understood. Therefore, a comprehensive clinical, virological and molecular study is needed to understand and control the disease. PMID- 23689167 TI - Improving the uptake of long acting reversible contraception: a review. AB - Across the world rates of unintended pregnancy are high. Unintended pregnancy not only results in substantial costs to health services, it can lead to personal distress for women experiencing this. Whilst a large number of unintended pregnancies occur in those not using any method of contraception, a proportion occur in women using a contraceptive method incorrectly or inconsistently. Long acting reversible methods of contraception such as the IUD, IUS, contraceptive implant and contraceptive injectables are the most effective methods of contraception. In spite of this, they are under-utilized by women in developed countries. Educating women and health professionals, and dispelling myths about these methods may improve their acceptability. Furthermore, facilitating uptake by ensuring that a range of contraceptive providers are trained and able to provide to women without undue delay, particularly in the immediate post abortion and postpartum period, may also be effective strategies to improve uptake, and prevent more unintended pregnancies. PMID- 23689168 TI - Preconception care and fertility. AB - Preconceptional health has been shown to be an important determinant of fertility, fecundity and perinatal outcomes. In recent years the impact of periconceptional factors on developmental programming, and the health of the resultant child have become increasingly clear. Since fertility specialists care for couples during this critical phase, they have a unique opportunity to collaborate with the couple to optimise preconceptional health and thus fertility and pregnancy outcomes. In this review article, the current evidence available for the importance of preconceptional health care is considered, specific lifestyle and dietary interventions are described and the care of the medically complicated patient prior to fertility treatment is discussed. Finally strategies for overcoming challenges in implementing preconceptional care into the fertility clinic are addressed. PMID- 23689169 TI - Long-acting reversible contraception: a practical solution to reduce unintended pregnancy. AB - Unintended pregnancy remains a significant global public health problem; 41% of all pregnancies worldwide in 2008 were unintended. The unintended pregnancy rate is greater in less developed regions (57 per 1000 women aged 15-44 years) than in more developed regions (42 per 1000), with the United States a notable exception at a rate of 52 per 1000 women. Among US women, nearly half of unintended pregnancies are due to incorrect or inconsistent use of a contraceptive method. Long-acting reversible contraception (LARC) includes the intrauterine device and subdermal implant and offers the potential to address the problem of unintended pregnancy. LARC is extremely safe and over 99% effective at preventing pregnancy. In real-world tests LARC methods were over 20 times more effective at preventing unintended pregnancy (HRadj=21.8, 95% confidence interval, 13.7 to 34.9) compared to the contraceptive pill, patch, or ring. Despite their level of effectiveness, less than 15% of contracepting women worldwide use LARC. LARC are only infrequently contraindicated, even among younger and nulliparous women. Instead education, access, and cost are the primary barriers. In a US study of nearly 10000 women aged 14-45 years, when the three barriers were removed 75% of study participants chose a LARC method. As a result, the study reported an 80% reduction in teen births and 75% reduction in abortions among women in the cohort compared to national statistics. If we are serious about reducing unintended pregnancy, we need to be serious about increasing the use of methods that we know work. Greater LARC use and continuation has been proven to effectively reduce unintended pregnancy, including abortion and teen pregnancy. PMID- 23689170 TI - Obesity and contraception: metabolic changes, risk of thromboembolism, use of emergency contraceptives, and role of bariatric surgery. AB - Rates of obesity are increasing worldwide. Due to the medical consequences of obesity, routine health care like family planning becomes complicated. Conflicting data exists regarding efficacy of hormonal contraceptives in obese women, while little data on efficacy of emergency contraception in obese women exists. Much of what is available suggests lower serum hormonal levels in obese women with little effect on ovulation inhibition. Contraceptive steroids can cause a number of deteriorating metabolic changes, particularly in obese women; whether these changes are clinically significant is unknown. Venous thromboembolic risk is increased with both obesity and use of hormonal contraceptives; however the question remains if the risk is additive or multiplicative. Bariatric surgery can lead to digestive changes which may affect absorption of contraceptive hormones. While long acting reversible contraceptives may be the best option in the post operative obese patient, little data, beyond a simple recommendation to avoid pregnancy for at least one year, exists to help guide appropriate contraceptive choice. PMID- 23689171 TI - New surgical trends in breast cancer treatment: conservative interventions and oncoplastic breast surgery. AB - AIM: From radical mastectomy by Halstedt to quadrantectomy by Veronesi, surgical treatment of breast cancer has become more and more conservative in order to preserve women quality of life. We analyzed the evolution of breast interventions through a nine-year period. METHODS: We collected data about all breast surgery interventions performed between 2002 and 2010 in our Department Of Surgery, focusing on patients' age, tumor histology, TNM classification, hormonal status, intervention radicality on the breast and axilla, and eventual plastic surgery. Data were analyzed by R (version 2.14.2), considering significant P<0.05. RESULTS: A total of 3320 breast surgery interventions were performed on 2300 patients. Absolute yearly number of interventions has strongly increased with the introduction of the mammography screening (291 to 430). Conservative breast surgery (55% to 62%) and skin-sparing mastectomy (1% to 8%) have been performed more frequently in premenopausal patients, and significantly increased in time, with a consequent decrease of classical radical mastectomy (38 to 15%) but an increase of margins widening after primary surgery (2% to 6%). Sentinel lymph node biopsy is mostly replacing complete axillary lymph node dissection (93% to 31%). Skin-glandular reshaping progressively increased (up to 20%) as also breast reconstruction (23% to 40%), which since 2008 has been performed also in women older than 75 years, while flaps have been used in strictly selected patients. CONCLUSION: Conservative surgery represents the target of current breast cancer treatment where possible, and skin-sparing mastectomy an interesting alternative to classical one when radicality is required. Sentinel lymph node biopsy has replaced complete axillary lymph node dissection by clinically negative nodal status. Breast reshaping and reconstruction are increasing in every age group, including women older than 75 years. PMID- 23689172 TI - Endogenous sex hormones are not associated with subclinical atherosclerosis in menopausal women. AB - AIM: The aim of this paper was to compare the carotid intima-media thickness (IMT) in pre- and postmenopausal women and to evaluate the association between endogenous sex hormones, body fat distribution, and insulin resistance and the IMT. METHODS: This cross-sectional study included 145 women aged 45-65 yr, comprising 56 premenopausal (FSH<20IU/mL and regular menstrual cycles) and 89 postmenopausal (FSH>40IU/ml and amenorrheic). All patients were evaluated for lipid profile, estradiol and testosterone, insulin ratio (G/I), HOMA-IR, and ultrasound measurement of IMT. Each variable was assessed for correlation with IMT using the univariate model. RESULTS: No difference was observed in IMT between pre- and postmenopausal women. A positive and statistically significant correlation was found between IMT and FSH levels (rs=0.21, P<0.009) and HOMA (rs=0.16, P<0.04). A positive and statistically significant correlation was observed between testosterone and waist (rs=0.3, P<0.04). No correlation was found between IMT and time of menopause (r=0.02, P=0.19). CONCLUSION: Estradiol and testosterone are not associated with subclinical atherosclerosis in menopausal women. A positive correlation between IMT and FSH may reflect an association between low estrogen and IMT. Abdominal fat can be an important link between androgenic levels and cardiovascular risk. PMID- 23689173 TI - Association of pregnancy and Candida vaginal colonization in women with or without symptoms of vulvovaginitis. AB - AIM: Candida infection is one of the main causes of vulvovaginitis. The experience of symptoms of vulvovaginitis during pregnancy changes in relation to clinical, behavioral, and demographic factors. Candidiasis is associated with an increased risk of delivery complications. In some studies pregnant women are found more symptomatic than non-pregnant women, but in others a higher prevalence of asymptomatic infections is described during pregnancy. The aims of this study were to evaluate the prevalence of Candida vaginal colonization in pregnant women, and investigate if the occurrence of symptoms is influenced by pregnancy, in a population of Italian native and immigrant women. METHODS: A total of 344 outpatients, who visited the laboratory for routine genital examination, independently of pregnancy or presence or absence of symptoms of vulvovaginitis, were evaluated. RESULTS: Colonization by Candida spp. was significantly higher in pregnant than non-pregnant patients (31.4% vs. 19.9%; chi2=5.59; P=0.018), nevertheless pregnant women were significantly more often asymptomatic compared to non-pregnant (46.5% vs. 16%; chi2=42.31; P<0.0001). In the sub-group of women colonized by Candida spp., pregnancy resulted significantly associated to asymptomatic infection (58.1% vs. 30.8%; chi2 =6.18; P=0.013). A binary logistic regression analysis showed pregnancy or lactobacilli colonization independently associated to a lower probability of experiencing symptoms of vulvovaginitis (respectively: P<0.0001 and P=0.008). CONCLUSION: Pregnancy seems to be independently associated to Candida spp. asymptomatic vaginal infection. Given that candidiasis has been associated with possible delivery complications, these results suggest to screen for Candida spp. vaginal colonization asymptomatic women during pregnancy. PMID- 23689174 TI - The cycle characteristics of clomiphene with clomiphene and menotropins in polycystic ovary syndrome and non polycystic ovary syndrome infertile patients. AB - AIM: This study compares the cycle characteristics of clomiphene (CC) with CC+HMG (Human Menopausal Gonadotropin or Menotropins) in Polycystic Ovary Syndrome (PCOS) and non-PCOS infertile patients. METHODS: Patients were treated by CC + minimal HMg protocol. The cancellation rate, the mean number of different follicle sizes and endometrial thickness and pattern were compared. RESULTS: The cancelled cycles due to non-responsiveness were significantly higher in CC compared to CC+ minimal HMg protocol. PCOS patients are significantly nonresponsive in CC cycle and hyperresponsive in CC+ minimal HMg cycles. The mean number of different sizes of follicles and the endometrial thickness were significantly higher in CC+ minimal HMg. PCOS patients were significantly different from non-PCOS regarding the number of mature follicle and endometrial thickness. The pregnancy rate was 11% (10.2% in non-PCOS and 12.2% in PCOS). CONCLUSION: CC+ minimal HMg is a viable alternative to HMg /FSH only protocol in CC failure or resistant patients, and its efficacy can be mostly attributed to improvement of endometrial quality and increase in follicle number. Moreover, due to high cancellation of PCOS patients treated by this protocol, seemingly other alternatives should be found; perhaps sequential letrozole+HMg/FSH that have been shown to improve the ovarian response in this group of patients. PMID- 23689175 TI - Use of a preventive sling surgery for the simultaneous correction of latent stress urinary incontinence during the cystocele repair: two year follow-up. AB - AIM: The aim of this paper was to assess the feasibility and utility of adding a preventive trans obturatory tape (TOT) during the same intervention for anterior prolapse repair, in patients with masked urinary incontinence and massive cystocele. METHODS: A retrospective trial was conducted in a Tertiary care University Hospital. Ninety-nine women with a massive cystocele (Ba >=2 cm of pelvic organ prolapse quantification) and an occult stress urinary incontinence were recruited from 2004 to 2010: 53 women were subjected to an anterior fascial reconstruction alone while 46 underwent the same intervention with the addition of TOT. Patients were also asked to rate their overall quality of life, using the International Consultation on Incontinence Modular Questionnaire-Lower Urinary Tract Symptoms Quality Of Life (ICIQ-LUTSqol). All patients were assessed at one, six, twelve and twenty-four months of follow-up. Statistical analysis was performed with SPSS 15.0 software; SPSS inc., Chicago IL, USA was performed using the Chi-square test with Fisher's post-hoc correction. RESULTS: At 24 month follow-up the rate of appearance of stress urinary incontinence at the urogynecological examination, was higher in the group without TOT (81% vs. 19%, P=0.004). In terms of overall quality of life, significantly higher rates of satisfaction have been reported by the group treated with additional TOT (P=0.006). CONCLUSION: The addition of TOT during the anterior prolapse correction seems to give a greater durability to the correction, resulting, in the long term, in a lower rate of urinary symptoms onset (first latency) and in a better quality of life compared to the traditional anterior colporrhaphy alone. PMID- 23689176 TI - [Effectiveness of a new cervicometer in evaluating the risk of preterm delivery]. AB - AIM: The ultrasound measurement of the cervix is the gold standard for assessing the risk of preterm delivery. We compared the accuracy of this technique with measurements obtained by the cervicometer Cervilenz(r). The purpose was to show that this device can be used as a screening tool, low cost, in the diagnosis of preterm labor. METHODS: Fifty patients were included in the study at gestational age between 21+0 and 26 +0 or weeks. The study was blinded between the two performers utilizing the cervicometer and the transvaginal ultrasound. RESULTS: The study showed 100% concordance and a correlation between the two techniques of 0.94. CONCLUSION: The cervicometer proved to be a reliable and easy to use device to detect a normal or short cervix, with contained healthcare costs. PMID- 23689177 TI - [Indications and controindications of hormone replacement therapy in menopause]. AB - Menopause is a physiological event of women's life that is the end of menstrual cycles and the end of the fertile period. Normally the age at which women reach menopause is between 50 and 52 years, as the world average. Menopause occurs when the functional ovarian reserve is exhausted or can be induced by surgical removal of the ovaries. What follows, however, is the establishment of a state of hypoestrogenism, which potentially affects various organs and systems (genito urinary system, cardiovascular system, skeleton, skin, brain) and quality of life of women (varying degrees of vasomotor symptoms, vaginal atrophy, osteoporosis). Hormone replacement therapy (HRT), it is based on estrogen or estrogen and progesterone, can be used to compensate for estrogen deficiency and to prevent or limit the damages that may result. During the years, there have been several observational studies designed to identify the risks and benefits arising from the use of postmenopausal hormone replacement therapy, in spontaneous and surgical menopause. In fact, although several studies have shown that women treated with estrogen enjoyed a better overall level of health, over the last decade have raised doubts about the safety of hormone replacement therapy long term. In our study we try to discuss, based on a review of the literature and evidence available to date, what are the present indications and controindications to the use of hormone replacement therapy. PMID- 23689178 TI - Prediction of preterm birth. AB - Preterm delivery is birth occurring before 37 completed weeks of gestation. Preterm birth is the primary cause of morbidity and mortality in children especially if this occurs before 34 weeks of gestation. If preterm birth could be predicted and treated accordingly, this would greatly reduce mortality, morbidity and associated costs. There have been many attempts to develop an accurate and efficient method to predict preterm premature rupture of membranes (PPROM) and preterm labor that leads to spontaneous preterm birth (SPB). However, the initial signs and symptoms are most often mild and may even occur in normal pregnancies, making early detection rather difficult. The aim of this paper is to provide an overview of the current methods employed in predicting preterm birth occurring due to preterm labor and PPROM. Among these methods are risk scoring systems, cervical/vaginal screening for fetal fibronectin, cervical assessment by ultrasonography, uterine activity monitoring, biomarkers such as endocrine factors, cytokines and enzymes, fetal DNA and genetic polymorphism. SPB is multifactorial, and so it is highly unlikely that a single test can accurately predict SPB. A combination of biological markers is also reviewed in the estimation of the risk of preterm delivery. PMID- 23689179 TI - Arylsulphatase A activity in human endometrial polyps inversely correlates with aging. PMID- 23689180 TI - Should the frequency of surveillance of a small abdominal aortic aneurysm be reduced? PMID- 23689181 TI - The contextual influence of coal abandoned mine lands in communities and type 2 diabetes in Pennsylvania. AB - Coal abandoned mine lands (AMLs), persistent and prevalent across Pennsylvania, offer an instructive evaluation of potential contextual influences of chronic environmental contamination (CEC) on individual health. We evaluated associations between the burden of AMLs, represented by 10 contextual metrics at the community level, and individual-level type 2 diabetes using hemoglobin A1c (HbA1c) as a biomarker. Cross-sectional and longitudinal multilevel analyses were conducted with over 28,000 diabetic primary care patients of the Geisinger Clinic. Adjusted models revealed five AML burden measures were associated (p<0.05), and three additional were borderline associated (0.05<=p<=0.10), with higher and/or change in HbA1c levels. This study provides key empirical evidence of adverse impacts of CEC in communities on an important chronic disease, illustrating the contextual effects of living in long-term degraded landscapes and communities. PMID- 23689183 TI - Mediterranean foods on health and disease. Abstracts of the World Forum for Nutrition Research Conference. May 20-21, 2013. Reus, Spain. PMID- 23689186 TI - Neurodegenerative disease: Oxidative stress in cells near amyloid plaques linked to neuronal death. PMID- 23689185 TI - Differential airway inflammatory responses in asthma exacerbations induced by respiratory syncytial virus and influenza virus a. AB - BACKGROUND: Although respiratory viral infections cause acute exacerbations of asthma, the inflammatory responses vary depending on the causative virus. The purpose of this study was to compare the inflammatory responses in the airways of acute exacerbations of asthma induced by respiratory syncytial virus (RSV) and influenza A virus. METHODS: Sputum induction was performed in asthmatic patients with acute exacerbations induced by RSV (n = 6), influenza A (n = 7), and non upper respiratory infection (URI)-related factors (n = 8). Sputum concentrations of cysteinyl leukotrienes (cysLTs), TNF-alpha and IFN-gamma were measured. RESULTS: Sputum cysLTs were significantly higher in RSV-induced exacerbations than in influenza A- and non-URI-induced exacerbations. Sputum TNF-alpha was significantly higher in influenza A-induced exacerbations than in RSV- and non URI-induced exacerbations. Sputum IFN-gamma was significantly lower in RSV induced exacerbations than in the others. CONCLUSIONS: RSV and influenza A cause acute exacerbations and have different effects on airway inflammation in asthmatic patients. RSV significantly increased cysLTs, while influenza A significantly increased TNF-alpha in the airway. The underlying mechanism in virus-induced asthma might depend on the viral species. PMID- 23689188 TI - Motor neuron disease: Two new ALS susceptibility loci identified in Han Chinese. PMID- 23689192 TI - Epilepsy: Implantable device advises patients with epilepsy of seizure likelihood. PMID- 23689193 TI - Sleep-disordered breathing and periodic limb movements in narcolepsy with cataplexy: a systematic analysis of 35 consecutive patients. AB - BACKGROUND: Disturbed sleep is a core feature of narcolepsy with cataplexy (NC). Few studies have independently assessed sleep-disordered breathing (SDB) and periodic limb movements (PLMs) in non-homogeneous series of patients with and without cataplexy. We systematically assessed both SDB and PLMs in well-defined NC patients. METHODS: We analyzed the clinical and polysomnographic features of 35 consecutive NC patients (mean age 40 +/- 16 years, 51% males, 23/23 hypocretin deficient) to assess the prevalence of SDB (apnea-hypopnea index >5) and PLMs (periodic leg movements in sleep (PLMI) >15) together with their impact on nocturnal sleep and daytime sleepiness using the multiple sleep latency test. RESULTS: 11 (31%) and 14 (40%) patients had SDB and PLMs, respectively. SDB was associated with older age (49 +/- 16 vs. 35 +/- 13 years, p = 0.02), higher BMI (30 +/- 5 vs. 27 +/- 6, p = 0.05), and a trend towards higher PLMI (25 +/- 20 vs. 12 +/- 23, p = 0.052), whereas PLMs with older age (50 +/- 16 vs. 33 +/- 11 years, p = 0.002) and reduced and fragmented sleep (e.g. sleep efficiency of 82 +/- 12% vs. 91 +/- 6%, p = 0.015; sleep time of 353 +/- 66 vs. 395 +/- 28, p = 0.010). SDB and PLMs were also mutually associated (p = 0.007), but not correlated to daytime sleepiness. CONCLUSIONS: SDB and PLMs are highly prevalent and associated in NC. Nevertheless, SDB and PLMs are rarely severe, suggesting an overall limited effect on clinical manifestations. PMID- 23689194 TI - Implicit attitudes, emotions, and helping intentions of mental health workers toward their clients. AB - The attitudes of mental health care workers toward their clients may influence the quality of care they provide. There is growing recognition of the role of implicit attitudes in behavior toward people with stigmatized illnesses, such as mental illness, and of the need to measure these separately from explicit attitudes. Seventy-four mental health workers completed implicit and explicit measure of attitudes toward people with mental illness. The participants were also asked about their intention to help people with mental illness and their emotional reactions toward people with a mental illness. The findings show that the implicit attitudes of the health workers toward clients with a mental illness are somewhat negative despite the fact that their explicit attitudes are somewhat positive. Although both implicit and explicit attitudes predicted negative emotions, only implicit attitudes were related to helping intentions. This study highlights the association between implicit attitudes and behavioral intentions and confirms the importance of addressing implicit attitudes in mental health research. PMID- 23689195 TI - No association between cumulative traumatic experiences and sex in risk for posttraumatic stress disorder among human immunodeficiency virus-positive adults. AB - This study examined the association between the type and number of traumatic experiences and the conditional risk for posttraumatic stress disorder (PTSD), stratified by sex, in human immunodeficiency virus (HIV). We evaluated 465 (114 male and 350 female) HIV-positive adults attending HIV clinics in Cape Town, South Africa. Demographic and clinical data were collected, and the participants were screened for current PTSD and traumatic event exposure using the Mini International Neuropsychiatric Interview and the Life Events Checklist, respectively. The highest attributable risk for PTSD was derived from sexual assault (17.4%) and transport accidents (16.9%). Only sexual assault was significantly (p = 0.002) associated with current PTSD. Although sex had no effect on the prediction of current PTSD, HIV-infected men tended to experience more lifetime traumas than HIV-infected women, with the men having significantly higher rates of exposure than women to physical assault (p = 0.018) and assault with a weapon (p = 0.001). These data highlight the importance of considering trauma type in contributing to the burden of PTSD in HIV-infected adults. PMID- 23689196 TI - Working with Asian American youth at clinical high risk for psychosis: a case illustration. AB - The idea of a clinical high risk (CHR) for psychosis has focused attention on early intervention to prevent or attenuate psychosis. However, many clinicians may still not be very familiar with the concept of CHR. Current studies have not allowed for an in-depth examination of the challenges and the strategies of working with youth from the range of racial/ethnic minority families, Asian American families in particular. The purpose of this article was three-fold. First, we critically review Asian cultural values and beliefs about mental illness, psychosis in particular, while highlighting specific challenges that Asian American families encounter. Second, we provide a clinical case to illustrate these challenges and inform clinical practice when working with Asian youth at risk for psychosis and their families. Third, practical and easy-to follow clinical strategies are provided. Implications for clinical practice and directions for future research are presented. PMID- 23689198 TI - X-linked thrombocytopenia in a female with a complex familial pattern of X chromosome inactivation. AB - The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia, eczema and various degrees of immune deficiency caused by mutations in the WAS gene, which encodes the WASP protein, the expression of which is restricted to haematopoietic cells. Mild allelic variants are associated with X-linked thrombocytopenia (XLT). Female carriers tend in general to be asymptomatic as a consequence of a positive selection of cells with an active normal X chromosome, which results in a non-random inactivation of the mutated gene in affected cell lineages. We report on six female members of the same family carrying the mutated WAS allele p.V332A, which is known to be associated with XLT. One of them had presented severe thrombocytopenia from birth. Western blotting showed the WASP protein in peripheral blood cells to be normal in size and expression, and scanning electron microscopy revealed a normal distribution of microvilli on T cells. X-chromosome inactivation-pattern analysis showed total inactivation of the non-mutated paternal X chromosome in the patient's peripheral blood cells. All the other female family members were healthy and presented varying X-chromosome inactivation patterns, ranging from random X chromosome inactivation to total X chromosome inactivation of the mutated chromosome. Our results in these female carriers of p.V332A show that manifestation of the disease requires a total inactivation of the non-mutated X chromosome and allow us to confirm that clinical manifestations in female carriers are highly dependent not only on the mutation characteristics but also on the X-chromosome inactivation pattern of affected line. PMID- 23689197 TI - Distribution of thalassemias and associated hemoglobinopathies identified by prenatal diagnosis in Taiwan. AB - BACKGROUND: Hemoglobin (Hb) gene disorders are common hereditary disorders in Taiwan, and alpha- and beta-thalassemias are among the well-known Hb disorders here. Our study provides a primary reference for designing a locally relevant antenatal diagnostic test to control the spread of thalassemia. METHODS: Between 1998 and 2011, prenatal diagnoses for identifying thalassemia and hemoglobinopathies were performed on 1240 fetuses at risk for alpha-hydrops and beta-thalassemia major. RESULTS: Of 1240 specimens analyzed, 1082 (87%) were obtained by amniocentesis; 125 (10%), by chorionic villus sampling; and 33 (3%), by cordocentesis. Prenatal diagnoses revealed that 21.5% of these fetuses as thalassemia major (including alpha-thalassemia hydrops, beta-thalassemia major, and Hb E/beta-thalassemia); 50.2%, for thalassemia minor (include alpha thalassemia carrier, beta-thalassemia carrier, and alpha-thalassemia combined beta-thalassemia carrier); and 28.3% for normal type (include non-alpha, beta thalassemia). The most common alpha-hydrops were SEA (Southeast Asian) and Philippine type (frequencies of 74.91 and 5.24%, respectively). The frequency of the IVS-II-654 combined codons 41/42 mutation, the most common beta-thalassemia major mutation in this region, was 5.24%. Two fetuses were found with E/beta thalassemia (HbE/IVS-II-654 and HbE/codons 41/42, respectively). Since 1993, Taiwan's Department of Health adopted a national program for screening pregnancies to control spread of thalassemia. In the last 10years, less than 3 such cases have occurred per year. After 2003, this number was 0 for a total of 4years (2003, 2004, 2007, and 2008). CONCLUSION: In Taiwan, incidence and frequency of thalassemia genotypes were similar to those previously reported. The national program for screening pregnancies to control spread of thalassemia that resulted in a marked decline in the number of newborns with thalassemia major. Interestingly, prenatal diagnoses revealed 21.5% for thalassemia major, 50.2% for thalassemia minor, 28.3% normal comparison of thalassemia type distribution showed normal type increasing by 13.2% and major type decreasing by 14%. This unique and significant finding needs further clinical studies and discussion to explain such a phenomenon. PMID- 23689199 TI - Reproducibility of pacing profiles in elite swimmers. AB - PURPOSE: To analyze the reproducibility of pacing in elite swimmers during competitions and to compare heats and finals within 1 event. METHODS: Finals and heats of 158 male swimmers (age 22.8 +/- 2.9 y) from 29 nations were analyzed in 2 competitions (downloaded from swimrankings.net). Of these, 134 were listed in the world's top 50 in 2010; the remaining 24 were finalists of the Pan Pacific Games or European Championships. The level of both competitions for the analysis had to be at least national championships (7.7 +/- 5.4 wk apart). Standard error of measurement expressed as percentage of the subject's mean score (CV) with 90% confidence limits (CL) for each 50-m split time and for total times were calculated. In addition, mixed general modeling was used to determine standard deviations between and within swimmers. RESULTS: CV for total time in finals ranged between 0.8% and 1.3% (CL 0.6-2.2%). Regarding split times, 200-m freestyle showed a consistent pacing over all split times (CV 0.9-1.6%). During butterfly, backstroke, and 400-m freestyle, CVs were low in the first 3 and 7 sections, respectively (CV 0.9-1.7%), with greater variability in the last section (1.9-2.2%). In breaststroke, values were higher in all sections (CV 1.2 2.3%). Within-subject SDs for changes between laps were between 0.9% and 2.6% in all finals. Split-time variability for finals and heats ranged between 0.9% and 2.5% (CL 0.3-4.9%). CONCLUSION: Pacing profiles are consistent between different competitions. Variability of pacing seems to be a result of the within-subject variation rather than a result of different competitions. PMID- 23689200 TI - Risky driving behavior among university students and staff in the Sultanate of Oman. AB - BACKGROUND: There is a well developed literature on research investigating the relationship between various driving behaviors and road crash involvement. However, this research has predominantly been conducted in developed economies dominated by western types of cultural environments. To date no research has been published that has empirically investigated this relationship within the context of the emerging economies such as Oman. OBJECTIVE: The present study aims to investigate driving behavior as indexed in the driving behavior questionnaire (DBQ) among a group of Omani university students and staff. METHODS: A convenience non-probability self-selection sampling approach was utilized with Omani university students and staff. RESULTS: A total of 1003 Omani students (n=632) and staff (n=371) participated in the survey. Factor analysis of the BDQ revealed four main factors that were errors, speeding violation, lapses and aggressive violation. In the multivariate logistic backward regression analysis, the following factors were identified as significant predictors of being involved in causing at least one crash: driving experience, history of offenses and two DBQ components, i.e., errors and aggressive violation. CONCLUSION: This study indicates that errors and aggressive violation of the traffic regulations as well as history of having traffic offenses are major risk factors for road traffic crashes among the sample. While previous international research has demonstrated that speeding is a primary cause of crashing, in the current context, the results indicate that an array of factors is associated with crashes. Further research using more rigorous methodology is warranted to inform the development of road safety countermeasures in Oman that improves overall Traffic Safety Culture. PMID- 23689201 TI - Which visual measures affect change in driving difficulty after first eye cataract surgery? AB - OBJECTIVE: To investigate self-reported driving difficulty before and after first eye cataract surgery and determine which visual measures are associated with changes in self-reported driving difficulty after surgery. METHODS: A cohort of 99 older drivers with bilateral cataract were assessed the week before and 12 weeks after first eye cataract surgery. Visual measures including visual acuity, contrast sensitivity, stereopsis and useful field of view were assessed. Self reported driving difficulty was measured via the Driving Habits Questionnaire. Cognitive status was assessed using the Mini Mental State Examination. Regression analysis was undertaken to determine the association between changes in visual measures and self-reported driving difficulty after first eye cataract surgery. RESULTS: Overall, self-reported driving difficulty improved after first eye cataract surgery. However, 16% of participants did not improve and driving difficulty worsened in 11% following surgery. Improvement in driving difficulty score after first eye cataract surgery was associated with improved contrast sensitivity in the operated eye (p<0.001), new glasses after surgery (p<0.001), and fewer chronic health conditions (p=0.016). CONCLUSION: Contrast sensitivity rather than visual acuity was a significant factor affecting change in self reported driving difficulty after first eye cataract surgery for bilateral patients. This has implications for driver licensing authorities worldwide that rely heavily on visual acuity as a measure of visual fitness to drive. PMID- 23689202 TI - How similar are two-unit bicycle and motorcycle crashes? AB - This paper explores the similarities and differences between bicycle and motorcycle crashes with other motor vehicles. If similar treatments can be effective for both bicycle and motorcycle crashes, then greater benefits in terms of crash costs saved may be possible for the same investment in treatments. To reduce the biases associated with under-reporting of these crashes to police, property damage and minor injury crashes were excluded. The most common crash type for both bicycles (31.1%) and motorcycles (24.5%) was intersection from adjacent approaches. Drivers of other vehicles were coded most at fault in the majority of two-unit bicycle (57.0%) and motorcycle crashes (62.7%). The crash types, patterns of fault and factors affecting fault were generally similar for bicycle and motorcycle crashes. This confirms the need to combat the factors contributing to failure of other drivers to yield right of way to two-wheelers, and suggest that some of these actions should prove beneficial to the safety of both motorized and non-motorized two-wheelers. In contrast, child bicyclists were more often at fault, particularly in crashes involving a vehicle leaving the driveway or footpath. The greater reporting of violations by riders and drivers in motorcycle crashes also deserves further investigation. PMID- 23689203 TI - The effect of external non-driving factors, payment type and waiting and queuing on fatigue in long distance trucking. AB - INTRODUCTION: The aim of this study was to explore the effects of external influences on long distance trucking, in particular, incentive-based remuneration systems and the need to wait or queue to load or unload on driver experiences of fatigue. METHODS: Long distance truck drivers (n=475) were recruited at truck rest stops on the major transport corridors within New South Wales, Australia and asked to complete a survey by self-administration or interview. The survey covered demographics, usual working arrangements, details of the last trip and safety outcomes including fatigue experiences. RESULTS: On average drivers' last trip was over 2000 km and took 21.5 h to complete with an additional 6h of non driving work. Incentive payments were associated with longer working hours, greater distances driven and higher fatigue for more drivers. Drivers required to wait in queues did significantly more non-driving work and experienced fatigue more often than those who did not. Drivers who were not paid to wait did the longest trips with average weekly hours above the legal working hours limits, had the highest levels of fatigue and the highest levels of interference by work with family life. In contrast, drivers who were paid to wait did significantly less work with shorter usual hours and shorter last trips. Multivariate analysis showed that incentive-based payment and unpaid waiting in queues were significant predictors of driver fatigue. CONCLUSIONS: The findings suggest that mandating payment of drivers for non-driving work including waiting would reduce the amount of non-driving work required for drivers and reduce weekly hours of work. In turn this would reduce driver fatigue and safety risk as well as enhancing the efficiency of the long distance road transport industry. PMID- 23689204 TI - Injury incidence rates of cyclists compared to pedestrians, car occupants and powered two-wheeler riders, using a medical registry and mobility data, Rhone County, France. AB - PURPOSE: In France, the bicycle's modal share is stabilizing after a decline; in some of France's major cities, it has even increased since the 1990s. It is hence relevant to improve the knowledge of the injury risk associated with cycling, compared with other means of transport such as car, walking and powered two wheeler (PTW) riding. METHODS: The injury incidence rates were estimated by the ratio between accident data and mobility (exposure) data. Two accident data sources were used: police data and hospital-based data (outpatients and inpatients) from the Rhone road trauma Registry. This provides four injury categories: all-injury, hospitalization, serious-injury and fatal-injury. Exposure data were estimated from a regional household travel survey (RTS), using three measures of mobility: number of trips, distance traveled and time spent traveling. The survey was carried out from November 2005 to April 2006, on weekdays, outside school and public holidays; this seasonality was corrected using the 2007-2008 national household travel survey (NTS) that covered an entire year. Only information involving accidents and trips in, and residents of, the Rhone County (1.6 million inhabitants, including the city Lyon) were included in our study. Trends of injury rates were also evaluated in Greater Lyon, using previous travel surveys. RESULTS: The PTW riders had the highest all-injury, hospitalization, serious-injury and fatal-injury rates, followed by cyclists, and lastly by pedestrians and car occupants. The rates between men and women seemed similar among pedestrians and among car occupants. For car occupants, pedestrians and cyclists, the age group 18-25 years had higher all-injury rate compared with the age group 25-65 years. On the contrary, the age group>=65 years seemed to have higher hospitalization and serious-injury rates, compared with the age group 25-65 years. For cyclists, the injury rates seemed higher in non-dense areas than in dense areas. Between 1996-1997 and 2005-2006 and with regards to time spent traveling, the all-injury, serious-injury and fatal-injury rates seemed to have decreased for car occupants and cyclists. CONCLUSION: The higher risk for PTW riders is confirmed and quantified; it is very high. Decrease in injury rates seems more marked for cyclists; this may indicate the "safety in numbers" effect. Countermeasures for improving road safety could be implemented, especially for vulnerable road user types. However, they will not be sufficient to fill in the gap between the much higher risk for PTW riders and that of car occupants. Exposure-based injury rates can be a tool for monitoring and evaluating the effectiveness of policies and programs, and for comparisons between countries. PMID- 23689205 TI - The relationship between vehicle roof crush and head, neck and spine injury in rollover crashes. AB - BACKGROUND: It is well established that rollover crashes are associated with a higher risk of serious injury and death than other types of crashes. Some of the most serious injuries that can result from a rollover crash are those to the head, neck and spine. The mechanism of injury to these body parts in a rollover is a matter of dispute in the literature. Some authors have concluded that the magnitude of vehicle roof deformation or vertical roof crush resulting from a rollover crash is not causally associated with head and neck injury severity, while others offer support for a causal association between roof crush and the degree of injury. A better understanding of the cause of serious injuries resulting from rollover crashes is important for improving injury prevention. METHODS: This study utilized data from the National Automotive Sampling System- Crashworthiness Data System (NASS-CDS) for the years 1997 through 2007. Both cross-sectional and matched case-control designs along with a new composite injury metric termed the Head, Neck and Spine New Injury Severity Score (HNS NISS) were used to analyze these data. RESULTS: The cross-sectional analysis demonstrated a 64% (95% CI: 26-114%) increase in the odds of a life-threatening injury as estimated by the HNS-NISS with every 10 cm of increased roof crush. The results of the matched case-control analysis demonstrated a 44% (95% CI: 8-91%) increase in the odds of sustaining any injury to the head, neck or spine with every 10 cm increase in roof crush. CONCLUSION: These results lend statistical support to a causal association between roof crush and head, neck and spine injury severity. Though they do not constitute definitive proof, they do contradict previously published theories suggesting that roof deformation is unrelated to such injuries. PMID- 23689207 TI - Acceleration of drug development: a collaboration of many stakeholders. AB - Modern drugs are used to treat and prevent diseases that previously led to morbidity and mortality. There is a high cost to this achievement--investment for each successful drug can exceed $1.8 billion. Late-phase drug candidate failure decreases efficiency of drug development because each failure represents lost or delayed opportunity to develop successful drugs. Collaboration of stakeholders and the use of new science and knowledge management can reduce late-phase failure and accelerate drug development. PMID- 23689211 TI - The role of product development partnerships in advancing the development of drugs for unmet needs. PMID- 23689212 TI - Office of clinical pharmacology science day: a forum to stimulate innovation in clinical pharmacology. AB - The Office of Clinical Pharmacology (OCP) of the US Food and Drug Administration (FDA) has hosted an office-wide event called Science Day (SD) since 1999. SD 2012 included presentations on physiologically based pharmacokinetic models, exposure response analyses, and other research projects. SD provides a forum for showcasing clinical pharmacology (CP) research within the OCP and provides an opportunity for professional development. This article discusses the evolution of Science Day and then focuses on SD 2012 as an example platform for promotion of regulatory research. PMID- 23689213 TI - Advancing the science of pharmacovigilance. AB - The importance of detecting postmarketing safety signals earlier and with a high degree of fidelity is increasingly important and of great interest to industry, regulators, and the public. This issue of Clinical Pharmacology & Therapeutics contains two companion articles that represent exciting new advances in the field of pharmacovigilance and postmarketing safety signal detection. Given that drug safety evaluation and pharmacovigilance science are core competencies in the discipline of clinical pharmacology, these articles should be of interest to clinical pharmacologists as well as drug safety professionals. PMID- 23689214 TI - Development of structure-activity relationship for metal oxide nanoparticles. AB - Nanomaterial structure-activity relationships (nano-SARs) for metal oxide nanoparticles (NPs) toxicity were investigated using metrics based on dose response analysis and consensus self-organizing map clustering. The NP cellular toxicity dataset included toxicity profiles consisting of seven different assays for human bronchial epithelial (BEAS-2B) and murine myeloid (RAW 264.7) cells, over a concentration range of 0.39-100 mg L(-1) and exposure time up to 24 h, for twenty-four different metal oxide NPs. Various nano-SAR building models were evaluated, based on an initial pool of thirty NP descriptors. The conduction band energy and ionic index (often correlated with the hydration enthalpy) were identified as suitable NP descriptors that are consistent with suggested toxicity mechanisms for metal oxide NPs and metal ions. The best performing nano-SAR with the above two descriptors, built with support vector machine (SVM) model and of validated robustness, had a balanced classification accuracy of ~94%. An applicability domain for the present data was established with a reasonable confidence level of 80%. Given the potential role of nano-SARs in decision making, regarding the environmental impact of NPs, the class probabilities provided by the SVM nano-SAR enabled the construction of decision boundaries with respect to toxicity classification under different acceptance levels of false negative relative to false positive predictions. PMID- 23689215 TI - Low serum vitamin D is not associated with an increase in mortality in oldest old subjects: the Octabaix three-year follow-up study. AB - BACKGROUND: Poor vitamin D status, i.e. low serum levels of 25-hydroxyvitamin D [25(OH)D], is common in the general population. Prospective epidemiologic data on the association between vitamin D and mortality in oldest old subjects are limited. OBJECTIVE: This study aimed to determine whether 25(OH)D concentrations were prospectively and independently associated with cardiovascular disease (CVD) mortality and all-cause mortality in oldest old subjects. METHODS: A total of 312 subjects aged 85 years old at baseline (Octabaix study) were followed for 3 years. Sociodemographic and overall geriatric assessment data were collected. Serum 25(OH)D concentrations were used to assess vitamin D status. Data on overall and cardiovascular mortality were collected. RESULTS: The mean serum 25(OH)D levels were 28 +/- 30 ng/ml. During the follow-up period, 58 subjects (18.5%) died. Twenty-five of the deaths (8%) were related to CVD. There were no differences in mortality rates according to the different quartiles of vitamin D (p = 0.41 for total mortality and p = 0.86 for CVD mortality). CONCLUSION: In community-dwelling oldest old subjects, serum 25(OH)D levels were not associated with overall or CVD mortality after a 3-year follow-up. PMID- 23689216 TI - A rhodamine based "turn-on" chemodosimeter for monitoring gold ions in synthetic samples and living cells. AB - A rhodamine-based fluorescent probe, functionalized with an alkyne moiety, shows highly selective recognition towards Au(i) and Au(iii) ions over other metal ions. Probe is successfully employed for the determination of residual gold species in synthetic samples and monitoring the accumulation of gold ions in living cells. PMID- 23689217 TI - Effect of belly board with bladder compression device on small bowel displacement from the radiotherapy field for rectal cancer. AB - BACKGROUND: The aim of this study was to investigate the effect of a belly board (BB) with the addition of a bladder compression device (BCD) for small bowel (SB) displacement from the radiotherapy field for rectal cancer. PATIENTS AND METHODS: Computed tomography (CT) scans of 38 rectal cancer patients positioned on a BB were analyzed and compared with CT scans from the same patients after the addition of a BCD. The BCD moves the inferior border of the BB from the pubic symphysis to the lumbosacral junction. The treated and irradiated volumes of the SB and bladder were compared. The irradiated volume ratio of SB to abdominopelvic cavity (APC) and that of bladder to APC were analyzed. RESULTS: With the BCD, the treated and irradiated volumes of SB decreased significantly (49.1 +/- 48.0 vs. 60.9 +/- 50.9 cc, p = 0.006 and 207.5 +/- 140.8 vs. 482.8 +/- 214.2 cc, p < 0.001, respectively). The irradiated volume ratio of bladder to APC with the BCD increased considerably compared to that without the BCD (25.2 +/- 11.5 vs. 18.7 +/- 10.5%, p < 0.001), and the ratio of irradiated volume of SB to APC decreased significantly with the BCD (18.8 +/- 12.4 vs. 31.8 +/- 12.1%, p < 0.001). CONCLUSION: This study showed that the addition of a BCD to the BB could effectively provide further displacement of SB from the rectal cancer radiotherapy field. PMID- 23689218 TI - Clinical characteristics of 274 non-small cell lung cancer patients in China. AB - BACKGROUND: The mortality from non-small cell lung cancer (NSCLC) in China is increasing, and studies about clinical characteristics of recent NSCLC are rare. The primary objective of this study was to explore clinical features in a large general hospital in Northwest China, and to determine risk factors for stage, pathology and survival, with a view to prevention and treatment of NSCLC as well as establishment and improvement of national medical insurance policies. PATIENTS AND METHODS: We retrospectively analyzed the characteristics of NSCLC patients (n = 274), as well as risk factors for advanced stage and squamous cell carcinoma (SCC). Survival features in different groups were analyzed, as well as risk factors of survival. Follow-up was at least 3 years. RESULTS: 179 were male (65.3%); 136 had adenocarcinoma (49.6%) and 109 had SCC (39.8%); 186 (67.9%) had advanced-stage disease (IIIB-IV); 130 (47.4%) had smoking habits; 195 came from an urban area (71.2%); 69 had local urban resident basic medical insurance; 58% were younger than 60 years. Female, adenocarcinoma, rural patients were significantly younger than male, SCC, and urban patients. Pathology was the only independent risk factor for advanced stage. Age, sex, and smoking status were independent prognostic factors for SCC. The proportion of male SCC was higher than female SCC even without the influence of smoking. Without local urban resident basic medical insurance, higher stage and not having surgery, but not smoking status, were independent risk factors for lower median progression-free survival (PFS). Patients with adenocarcinoma and SCC in advanced stage accepting EGFR-TKI during treatment had a higher 1-year survival rate and longer overall survival (OS) compared with those never accepting EGFR-TKI. EGFR-TKI treatment and chemotherapy regimen numbers were independent risk factor for median OS in advanced adenocarcinoma and SCC patients. CONCLUSION: More prevention and screening should be carried out for the female and rural population. EGFR-TKI could benefit advanced NSCLCs. China's medical insurance policy has some adverse effect on NSCLC survival calling for further improvement. PMID- 23689219 TI - Matrix metalloproteinase activity in early-stage lung cancer. AB - BACKGROUND: The matrix metalloproteinases (MMPs)-2, -9 and -7 are thought to be associated with tumor invasion, metastasis, and angiogenesis. However, their possible roles in early-stage lung cancer are not clear. We measured the activity of MMP-2, -7 and -9 in early-stage lung cancer tissues. MATERIAL AND METHODS: Normal lung tissues and cancer tissues were collected from 60 consecutive stage-I non-small cell lung cancer (NSCLC) patients. The activities of MMP-2 and MMP-9 were determined by gelatin zymography, and the activity of MMP-7 was determined by casein zymography. Furthermore, the ratio of the active form of MMP-2 in tumor tissue (T) compared with normal tissue (N) was determined, and the survival in the groups with different MMP-2 T:N ratio was compared. RESULTS: The activity of both MMP-2 and MMP-9 was detected in all cancer and normal tissues. Interestingly, MMP-9 activity was significantly reduced, whereas MMP-2 activity was significantly increased, in cancer tissues compared to normal tissues. The survival rate of the MMP-2 T:N ratio > 2.5 group was 57.45%, which was significantly reduced compared with that of the T:N ratio <= 2.5 group (86.78%). CONCLUSION: Our findings suggest that MMP-2, but not MMP-9 and MMP-7, may be implicated in early-stage tumor invasion, metastasis, and angiogenesis in NSCLC. PMID- 23689220 TI - Thyroid incidentalomas on FDG PET/CT in patients with non-thyroid cancer - a large retrospective monocentric study. AB - BACKGROUND: The purpose of this study was to compare the incidence of thyroid cancer among patients with primary non-thyroid cancer, who showed focal thyroid uptake in (18)F-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography/computed tomography (PET/CT). MATERIAL AND METHODS: We reviewed a total of 22,674 FDG PET/CTs performed at our institution between March 2005 and June 2011. A retrospective review was conducted on 433 non-thyroid cancer patients (male: n = 90, female: n = 343) who had thyroid incidentaloma on FDG PET/CT. In 286 patients, diagnostic confirmation was done by ultrasound-guided fine needle aspiration biopsy (FNAB). RESULTS: Among 22,674 FDG PET/CT scans, 483 subjects (2.1%) showed focal thyroid uptake. Among the 286 patients who underwent FNAB, 280 were included in the study. Of those, 68 patients (24.3%) demonstrated papillary thyroid carcinoma on the final pathologic findings. We divided patients into 7 groups depending on the primary cancer. CONCLUSION: In patients with cancer of non-thyroid origin, incidental FDG uptake in the thyroid gland was observed in 2.1% and associated with a 24.3% risk for well-differentiated thyroid carcinoma. However, there was no statistically significant difference in the malignant risk of focal FDG uptake of the thyroid gland according to the underlying primary non-thyroid cancer type. PMID- 23689221 TI - Treatment of cancer-associated anaemia: results from a two-day cross-sectional survey in Germany. AB - BACKGROUND: The aim was to re-evaluate the current prevalence and management of cancer-associated anaemia as defined by the World Health Organisation (WHO) and related risk factors. PATIENTS AND METHODS: This was a prospective, 2-day web based cross-sectional survey in cancer patients with non-myeloid malignancies in German outpatient clinics. RESULTS: 89 centres collected data from 3,867 patients, of whom 74% received active cancer therapy. The median age was 65 years (range 19-99 years) and almost two-thirds were women; 68% of the patients had solid tumours (breast 34%, colorectal 17%, lung 8%), with 56% of them being metastatic; 73% had a WHO performance score of <= 1. The mean haemoglobin level was 12.0 +/- 1.7 g/dl (+/- standard deviation; range 4.3-17.8 g/dl); the prevalence of levels below 12.0 g/dl was 49%. Two-thirds of these patients were not treated for anaemia; one-third received erythropoiesis-stimulating agents (12.6%), iron therapy (8.1%), transfusions (7.5%) or combinations thereof (8.0%) during the 4 weeks before evaluation. Chemotherapy, female sex, age and poor performance status were identified as significant anaemia-associated factors. CONCLUSIONS: The prevalence of untreated anaemia and the decreased performance status of cancer patients in Germany have hardly changed since the European Cancer Anaemia Survey (ECAS) in 2001. The treatment practice may not only be driven by guidelines and does not yet reflect new concepts of anaemia management. PMID- 23689222 TI - Online information on complementary and alternative medicine for cancer patients: evidence-based recommendations. AB - BACKGROUND: Many cancer patients use complementary and alternative medicine (CAM). Most websites offering online information on CAM are not helpful for them. METHODS: We extracted decisive elements for online information on CAM by analyzing the literature on the information needs of cancer patients and on counseling cancer patients on CAM. RESULTS: Key issues for online information on CAM are the qualification of the authors, transparency and accountability of the information, description of the aims, a scientific approach, description of treatment alternatives, support for the patient-physician relationship, individualized information, a summary of the information, disclosure of funding, and the privacy policy. CONCLUSIONS: The communicative challenge will be to convey information without destroying hope and motivation. We suggest that CAM topics should be integrated into broader information provided on cancer (etiology, conventional treatment). By also providing information for physicians, such a website could promote shared decision-making. Online information will gain the status of independent expert knowledge if provided by a well-known scientific organization as, e.g., a national cancer society. PMID- 23689223 TI - Overexpression of the Hedgehog signalling pathway in head and neck squamous cell carcinoma. AB - BACKGROUND: Overexpression of the Hedgehog (HH) signalling pathway has been described in several malignancies and is associated with a poor prognosis. HH signalling blockade reduces tumour growth in vitro and in vivo. We aimed to determine whether head and neck squamous cell carcinomas (HNSCCs) express HH proteins in comparison to healthy mucosa. PATIENTS AND METHODS: Formalin-fixed and paraffin-embedded tissue sections of 10 patients with HNSCC were stained with fluorescence-labelled antibodies for cytokeratin and HH proteins (SHH, PTCH1/2, SMO, Gli1-3) and photographs were taken with a laser scanning microscope. The pixel count and colour intensity were analysed in RGB (red/green/blue) colour mode, and expression levels were compared to healthy mucosa. RESULTS: Image analysis in RGB mode provided objective evidence for the over-expression of HH signalling components in HNSCC, particularly with regard to the transcription factors Gli1 (10-fold) and SHH (5-fold) in comparison with healthy mucosa. The lowest levels were found for Gli3 in HNSCC. CONCLUSIONS: We postulate pivotal roles of Gli1 and SHH expression in the carcinogenesis of HNSCC. HH pathway overexpression appears to be involved in the initiation of tumour growth and spread due to its stem cell-modulating properties. Detection of HH pathway components, and especially Gli1 and SHH, in HNSCC might offer a promising target for further anticancer research in HNSCC. PMID- 23689224 TI - Bortezomib in plasmablastic lymphoma: a case report and review of the literature. AB - BACKGROUND: Plasmablastic lymphoma (PBL) is an aggressive subtype of non Hodgkin's lymphoma (NHL). While classically associated with the human immunodeficiency virus (HIV), cases of PBL in immunocompetent patients have been increasingly described. PBL shares common morphological and immunohistochemical features with diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). Due to the rarity of PBL, there is no current consensual standard therapy available. As a result, PBL treatment is mirrored after aggressive NHL regimens. One of the newly emerged therapeutic options for PBL is bortezomib, which is a proteasome inhibitor and a cornerstone in MM therapy. In recently published cases, bortezomib has shown promising results in PBL. CASE REPORT: In this report, we describe a patient with HIV-negative PBL who dramatically responded to bortezomib after failing several other lines of therapy. We also review 4 other, similar cases reported in the literature. RESULTS AND CONCLUSION: We conclude that bortezomib resulted in rapid and dramatical responses regardless of the line of therapy. Although most of these responses were not sustained, bortezomib represents a new therapeutic option for PBL that should be further explored in larger clinical trials. PMID- 23689225 TI - Severe disseminated coagulopathy caused by adenocarcinoma with bone marrow metastasis. AB - BACKGROUND: Patients with mucin-producing adenocarcinoma have an increased risk for venous and arterial thrombosis. When these patients present with thrombocytopenia, disseminated intravascular coagulopathy (DIC) is often the underlying cause. CASE REPORT: We report 2 patients who were admitted due to bleeding symptoms of unknown cause, in whom further workup revealed adenocarcinoma-induced DIC. CONCLUSION: In elderly patients presenting with signs of DIC, such as reduced fibrinogen levels, elevated prothrombin time, elevated D dimer, and thrombocytopenia, without any obvious reason (e.g., sepsis), adenocarcinoma-associated coagulopathy should be considered as the underlying cause. Paradoxically, in these patients bleeding symptoms improve when the patient is sufficiently anti-coagulated with low molecular weight heparin. Treatment of the underlying disease is of central importance in controlling acute or chronic DIC associated with malignant diseases and chemotherapy should be started as soon as possible. PMID- 23689226 TI - Practical management of everolimus-related toxicities in patients with advanced solid tumors. AB - Everolimus is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), an intracellular protein kinase downstream of the phosphatidylinositol 3-kinase/AKT pathway involved in key components of tumorigenesis, including cell growth, proliferation, and angiogenesis. In the advanced cancer setting, based on favorable results from phase III trials, everolimus is indicated for the treatment of advanced renal cell carcinoma, advanced neuroendocrine tumors of pancreatic origin, and advanced hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Additional oncology indications for everolimus include renal angiomyolipoma with tuberous sclerosis complex and subependymal giant-cell astrocytoma. Although it is generally well tolerated, with most adverse events of mild to moderate severity and manageable, everolimus exhibits a distinct adverse event profile that warrants guidance for proper diagnostic and medical management. This guidance is particularly important given the potential for widespread long-term use of everolimus. This review will focus on the most relevant toxicities associated with mTOR inhibitors and on their management. Practical treatment recommendations are presented for stomatitis, noninfectious pneumonitis, rash, selected metabolic abnormalities, and infections. Provided these events are rapidly identified and treated, the vast majority should resolve with minimal effect on treatment outcomes and patients' quality of life. PMID- 23689227 TI - Use of inherent anteversion of an intramedullary nail to avoid malrotation in femur fractures. AB - Rotational malalignment after intramedullary (IM) nailing of femoral fractures remains a significant problem. A technique using intraoperative fluoroscopy and the anteversion inherent to the IM nail for obtaining appropriate femoral rotational alignment is presented. The technique is advocated as a simple alternative to more complex methods for estimation of femoral anteversion during placement of femoral IM nails. This method is simple and requires intraoperative fluoroscopy on the injured extremity alone. It reliably sets the femoral anteversion within a normal physiologic range with minimal additional intraoperative steps and without preoperative measurements. PMID- 23689228 TI - Transglutaminase-1 mutations in Omani families with lamellar ichthyosis. AB - OBJECTIVE: To determine the molecular basis of familial ichthyosis in three Omani families. SUBJECTS AND METHODS: Nine patients from three consanguineous families, A, B, and C, were born with typical features of lamellar ichthyosis subtype including collodion membrane and maintained ectropion, and epidermal scaling through their childhood. The 4 patients from family B had more severe symptoms requiring neonatal critical care and subsequent regular treatment with emollients, eye lubricants, and low-dose acitretin. DNA was extracted from peripheral blood by standard methods. The samples were initially genotyped to screen known loci linked to recessive ichthyosis on chromosomes 2q33-32 (ABCA12), 14q11 (TGM1), and 19p12-q12 using commercially supplied polymorphic fluorescent microsatellite markers. TGM1 was analyzed by direct sequencing for disease associated mutations. RESULTS: Two known pathogenic mutations in TGM1 were detected: p.Gly278Arg in families A and B and p.Arg396His in family C. These two mutations were segregating in an autosomal recessive mode of inheritance. CONCLUSION: Two known pathogenic TGM1 mutations were detected in three large consanguineous Omani families with lamellar ichthyosis. This study confirmed the geographic distribution of known mutations to an apparently unrelated population. PMID- 23689229 TI - Surgery: Preserving shoulder movement in advanced OA--yes we CAM! PMID- 23689230 TI - Rheumatoid arthritis: MRI points to inflammation as source of cartilage damage. PMID- 23689233 TI - Graphene oxide grafted with Pd17Se15 nano-particles generated from a single source precursor as a recyclable and efficient catalyst for C-O coupling in O arylation at room temperature. AB - The Pd17Se15 nanoparticles, synthesized for the first time from a single source precursor [Pd(L)Cl2] {L = 1,3-bis(phenylselenyl)propan-2-ol} and grafted onto graphene oxide, show high catalytic activity in C-O coupling between aryl/heteroaryl chlorides/bromides and phenol at room temperature (Pd loading 1 mol%; yield up to 94%). PMID- 23689232 TI - Musculoskeletal ultrasonography in patients with rheumatoid arthritis. AB - In the current paradigm for management of patients with rheumatoid arthritis (RA), obtaining clinical remission of symptoms remains the most important aim, but achieving radiographic remission is another key goal of treatment. Several parameters detectable by musculoskeletal ultrasonography can predict the development of severe RA, as well as monitor patients' responses to treatment; thus, musculoskeletal ultrasonography is widely used for evaluating patients with RA, both in clinical trials and in clinical practice. This Review describes the applications of musculoskeletal ultrasonography in patients with RA, focusing on the identification of ultrasonographic features that predict the development of erosions. Such predictive markers include high vascularity of synovitis, persistent synovitis, tenosynovitis of the extensor carpi ulnaris tendon, and erosive changes in the distal ulna. This article also describes ultrasonographic scores that could feasibly be integrated into daily rheumatology practice for the evaluation of patients with RA. PMID- 23689231 TI - Post-traumatic osteoarthritis: from mouse models to clinical trials. AB - Osteoarthritis (OA), the most common of all arthropathies, is a leading cause of disability and has a large (and growing) worldwide socioeconomic cost. Despite its burgeoning importance, translation of disease-modifying OA therapies from the laboratory into clinical practice has slowed. Differences between the OA models studied preclinically and the disease evaluated in human clinical trials contribute to this failure. Most animal models of OA induce disease through surgical or mechanical disruption of joint biomechanics in young individuals rather than the spontaneous development of age-associated disease. This instability-induced joint disease in animals best models the arthritis that develops in humans after an injurious event, known as post-traumatic OA (PTOA). Studies in genetically modified mice suggest that PTOA has a distinct molecular pathophysiology compared with that of spontaneous OA, which might explain the poor translation from preclinical to clinical OA therapeutic trials. This Review summarizes the latest data on potential molecular targets for PTOA prevention and modification derived from studies in genetically modified mice, and describes their validation in preclinical therapeutic trials. This article focuses on how these findings might best be translated to humans, and identifies the potential challenges to successful implementation of clinical trials of disease-modifying drugs for PTOA. PMID- 23689235 TI - Patient-reported problems after office procedures. PMID- 23689237 TI - Recent advances in hereditary angioedema self-administration treatment: summary of an International Hereditary Angioedema Expert Meeting. PMID- 23689234 TI - Core-shell structured luminescent and mesoporous beta-NaYF4:Ce3+/Tb3+@mSiO2-PEG nanospheres for anti-cancer drug delivery. AB - Multifunctional nanocomposites integrating mesoporous and luminescence properties into a single entity are synthesized via a facile and effective approach. Oleic acid capped beta-NaYF4:Ce(3+)/Tb(3+) nanoparticles (NPs) are transferred into aqueous solution by cetyltrimethylammonium bromide (CTAB) surfactants, and further encapsulated with uniform mesoporous silica shell followed by the surface modification with poly(ethylene glycol) (PEG), leading to the formation of water dispersible and biocompatible core-shell structured beta NaYF4:Ce(3+)/Tb(3+)@mSiO2-PEG (denoted as NPs@mSiO2-PEG) nanospheres. The as synthesized nanospheres show a typical mesoporous structure and a green emission under UV irradiation. Doxorubicin hydrochloride (DOX), a widely used anti-cancer drug, is used as a model drug to evaluate the loading and controlled release behaviors of the NPs@mSiO2-PEG in phosphoric acidic buffer solutions (PBS) at different pH values (pH = 7.4 and 5.0). The composite carriers provide a pH sensitive drug release pattern and the drug releases faster under lower pH value. The endocytosis process of fluorescein isothiocyanate (FITC)-labelled nanospheres is characterized using flow cytometry and confocal laser scanning microscopy (CLSM) against A549 cells. The in vitro cytotoxic effect against A549 cells of the DOX-loaded carriers is investigated in detail. In addition, the extent of drug release can be monitored by the variation of photoluminescence (PL) intensity of beta-NaYF4:Ce(3+)/Tb(3+). Considering the good biocompatibility and pH-dependent drug release pattern, such core-shell structured luminescent NPs@mSiO2-PEG nanospheres have potential applications in controlled drug delivery. PMID- 23689238 TI - Review of recent guidelines and consensus statements on hereditary angioedema therapy with focus on self-administration. AB - Consensus meetings and the resulting recommendations shape treatment choices in rare diseases such as hereditary angioedema (HAE) because they combine the experience of prescribing physicians and the patients who are receiving therapy. Self-administration of HAE therapy was recognised as a potential treatment option in the first consensus publication in 2003. Recent studies have confirmed that self-administration of therapy resolves attacks quickly, safely and minimises burden of disease; however, the discovery of inconsistent treatment approaches is a concern and warrants investigation into the barriers that prevent adherence with current recommendations. PMID- 23689239 TI - Current status of implementation of self-administration training in various regions of Europe, Canada and the USA in the management of hereditary angioedema. AB - Results from a 16-question survey about self-administration of hereditary angioedema (HAE) therapy, administered in Europe, Canada and the USA, were used to guide discussion at an international HAE expert meeting. The aim was to capture information about current practice in self-administered HAE therapy in these countries, including self-administration training, the key benefits of switching to self-administration, the barriers to self-administration and trends in self-administration. Overall, switching to self-administration therapy is looked upon favourably from both patient and clinician perspectives by virtue of the potential improvement in quality of life arising from optimisation of therapy and early intervention. The recent changes to product licences allowing self administration provide additional options for the management of HAE. PMID- 23689240 TI - Practical approach to self-administration of intravenous C1-INH concentrate: a nursing perspective. AB - At an international hereditary angioedema (HAE) expert meeting, results from a survey were used to guide discussion on how best to advise patients on self administering intravenous C1 esterase inhibitor therapy. Treatment differences across Europe were highlighted, together with the practicalities of self administration and useful resources for patients in the future. The international HAE experts noted an increase in the uptake of self-administration, with patients being trained by nursing staff. All patients who are willing and able to self administer should be offered this treatment option and patients should be encouraged to treat attacks early. Several initiatives were suggested regarding support for patients who self-administer therapy, including a 24-hour helpline and home care agencies. PMID- 23689241 TI - Challenges of C1-inhibitor concentrate self-administration. AB - Self-administration of therapy can help hereditary angioedema (HAE) patients regain control of their disease or reduce its impact and improve the quality of their lives. However, data from a self-administration survey, and subsequent discussion at an international HAE expert meeting, identified several barriers to self-administration therapy. These barriers include difficulty in administration technique, availability of nursing resources and the mental capacity of the patient. Encouragingly, international HAE experts identified that once a patient has acquired self-administration skills, they generally retain them in the long term. As patient uptake increases, it was recommended that follow-up management plans should be established to address any issues from the patient's perspective. PMID- 23689242 TI - Recent advances in hereditary angioedema self-administration treatment: summary of an International Hereditary Angioedema Expert Meeting. PMID- 23689244 TI - Sensory conduction study in fisher syndrome: patterns of abnormalities and their clinical correlation. AB - OBJECTIVE: To report sensory conduction findings in patients with typical Fisher syndrome (FS) and to determine if a specific pattern of sensory conduction abnormalities was present in such patients. METHODS: We retrospectively reviewed results of sensory conduction studies of 55 FS patients and compared them with those obtained from 83 age- and sex-matched healthy volunteers. RESULTS: Mean median and ulnar sensory nerve action potential (SNAP) amplitudes were lower in FS patients than in normal subjects, whereas sural SNAP amplitudes were not different between the two groups. Abnormal median/ulnar sensory responses (reduced SNAP amplitude or absent response) were more frequently observed than abnormal sural response. Normal sensory conduction results were found in 31 (56%) patients. Of the 24 (44%) patients with abnormal sensory findings, 18 (33%) had a sural-sparing pattern of abnormalities. Patients with impaired sensation had lower median and ulnar SNAP amplitudes than those without. CONCLUSIONS: Abnormal median and ulnar sensory responses were the most frequent sensory findings in FS. Findings of the sural-sparing pattern of abnormalities suggest distal sensory nerve involvement in these patients. PMID- 23689245 TI - Differences in active commuting among younger and older adults. AB - The demonstrated health benefits of active commuting (AC) and low participation rates among older adults indicate a need to examine the socioecological correlates of AC by age category. An online survey of employed U.S. adults examined AC participation and individual, employment-related, community, and environmental variables. Participants were dichotomized by age (younger: 18-49 yr; n = 638, 64% and older: >= 50 yr; n = 359, 36%). Logistic-regression analyses examined differences in AC correlates by age. Older adults were less likely to be active commuters (13.4%) than younger adults (27.9%; p < .001) For older adults, analyses yielded a Nagelkerke R2 = .76, with perceived behavioral control, behavioral beliefs, household cars, and walking distance as predictors. Analyses for younger adults resulted in a Nagelkerke R2 = .79, with perceived behavioral control, coworker normative beliefs, parking problems at work, greater employer and community support for AC, and bad weather as predictors. Findings suggest age should be considered when examining and targeting AC behaviors. PMID- 23689247 TI - Development of quantitative real-time PCR primers for detecting 42 oral bacterial species. AB - In this study, we introduced species-specific quantitative real-time PCR (qPCR) primers designed based on a DNA-dependent RNA polymerase beta-subunit gene (rpoB) for detecting 42 oral bacterial species. The specificity of the qPCR primers was confirmed by conventional PCR with the genomic DNAs of 73-79 strains regarding 73 75 bacterial species including the type strain for the target species. The standard curves revealed the lower detection limits of 42 bacterial species specific qPCR primers ranged from 4 to 40 fg below a cycle threshold (C T) value of 35, except Atopobium rimae, Fusobacterium nucleatum, Neisseria meningitidis, and Porphyromonas asaccharolytica which were 400 fg. These results suggest that 42 bacterial species-specific qPCR primers are suitable for applications in epidemiological studies related to oral infectious diseases such as periodontal diseases, endodontic infection, and dental caries. PMID- 23689248 TI - Inhibition of EphA4 expression promotes Schwann cell migration and peripheral nerve regeneration. AB - Erythropoietin-producing hepatocellular carcinoma receptors (Ephs) and their ligands Ephrins can affect axon growth. To evaluate the efficacy of EphA4 knockdown on Schwann cell migration and peripheral nerve regeneration, we detected EphA4 levels in Schwann cells. To knock down the expression of EphA4 in Schwann cell, two independent small interfering RNAs (siRNAs) were designed, and Schwann cell migration was examined. Four days after surgery, sciatic nerve sections of wild-type (WT) and EphA4(-/-) rats were examined by immunofluorescence, and axonal outgrowth was analyzed. The EphA4 protein could be detected in Schwann cells from intact nerves. EphA4 mediates the inhibitory effect on Schwann cell migration, and EphA4 knock-down can strongly increase Schwann cell migration and peripheral nerve regeneration. Knocking-down the expression of EphA4 promotes peripheral axon growth in vivo. It may provide a potential strategy for the recovery of peripheral nerve injury. PMID- 23689249 TI - A flexion period for attachment formation in isolated chicks to unfamiliar peers visualized in a developmental trajectory space through behavioral multivariate correlation analysis. AB - Attachment formation is crucial for social animals to survive in natural environments. Predisposition and imprinting mechanisms have been well documented as a process of con-specific affiliation development. However, it is unclear how neonatal stage attachment formation leads to juvenile peer sociality. Here we have developed an animal model (Gallus gallus domesticus) and a method of quantitative behavioral analysis, to study the developmental trajectory from postnatal day (P) 3 through to P21. Domestic chicks were raised in either group or isolated conditions and we focused on social behavior during a two-minute meeting context with unfamiliar group peers at P3, 7, 13, 16, and 21. Results showed that relative to isolated chicks, group reared chicks were more active behaviorally, when facing peers at P3 and that this activity declined slightly over development, up to P13. Isolated chicks that had not met any animals except humans, exhibited a major change in social behavior around P7, in particular, with increasing activity (head moving velocity and rotation velocity) and distress calls. This modulation disappeared after P13, suggesting the existence of a sensitive window for behavior toward peers around P7. These findings in isolated chicks suggest the maturation of new neuronal substrates for peer-social emotion and cognition, resulting in a new combination of behavioral modules. PMID- 23689250 TI - Picomolar inhibition of cholera toxin by a pentavalent ganglioside GM1os calix[5]arene. AB - Cholera toxin (CT), the causative agent of cholera, displays a pentavalent binding domain that targets the oligosaccharide of ganglioside GM1 (GM1os) on the periphery of human abdominal epithelial cells. Here, we report the first GM1os based CT inhibitor that matches the valency of the CT binding domain (CTB). This pentavalent inhibitor contains five GM1os moieties linked to a calix[5]arene scaffold. When evaluated by an inhibition assay, it achieved a picomolar inhibition potency (IC50 = 450 pM) for CTB. This represents a significant multivalency effect, with a relative inhibitory potency of 100,000 compared to a monovalent GM1os derivative, making GM1os-calix[5]arene one of the most potent known CTB inhibitors. PMID- 23689251 TI - Turn-on selective vitamin B6 derivative fluorescent probe for histidine detection in biological samples. AB - A new compound L soluble in water derived from vitamin B6 was successfully synthesized and characterized. The complex LAl(3+) is a turn-on selective fluorescent probe for histidine in HEPES buffer, with detection and quantification limits of 0.3 MUM and 0.6 MUM, respectively. The application of the complex LAl(3+) in real urine samples is reported. PMID- 23689252 TI - Prostate cancer: to EBRT or not to EBRT: surgery or radiotherapy for localized prostate cancer? That is the question. PMID- 23689253 TI - Prostate cancer: does a negative second biopsy give patients false hope? PMID- 23689254 TI - Quality of life: validated PROM for urethral stricture. PMID- 23689255 TI - Kidney cancer: Stearoyl-CoA desaturase: a novel therapeutic target for RCC. PMID- 23689256 TI - Bladder cancer: Towards risk stratification in bladder cancer. PMID- 23689257 TI - Crosstalk between intracellular and extracellular salicylic acid signaling events leading to long-distance spread of signals. AB - It is well recognized that salicylic acid (SA) acts as a natural signaling molecule involved in both local and systemic plant defense responses upon attacks by pathogens. Recently, cellular SA receptors and a number of SA-related phloem mobile signals were identified. Here, we compare the old and up-to-date concepts of plant defense signaling events involving SA. Finally, the crosstalk between intracellular and extracellular SA signaling events leading to long-distance spread of signals was outlined by focusing on the modes of both the short- and long-distance signaling events involving the actions of SA. For the above purpose, two distinct conceptual models for local SA perception and signaling mechanisms in the intracellular and extracellular paths (referred to as models i and ii, respectively) were proposed. In addition to two local SA perception models, we propose that the long-distance SA action could be attributed to three different modes, namely, (iii) local increase in SA followed by transport of SA and SA intermediates, (iv) systemic propagation of SA-derived signals with both chemical and electrical natures without direct movement of SA, and (v) integrated crosstalk allowing alternately repeated secondary signal propagation and biosynthesis of SA and/or conversion of inert SA intermediates to free SA finally contributing to the systemic spread of SA-derived signals. We review here that the long-distance SA signaling events (models iii-v), inevitably involve the mechanisms described in the local signaling models (models i and ii) as the key pieces of the crosstalk. PMID- 23689258 TI - A chloroplast membrane protein LTO1/AtVKOR involving in redox regulation and ROS homeostasis. AB - KEY MESSAGE: The role of LTO1/ At VKOR-DsbA in ROS homeostasis and in redox regulation of cysteine-containing proteins in chloroplast was studied in lto1 - 2 mutant, and a potential target of LTO1 was captured. A chloroplast membrane protein LTO1/AtVKOR-DsbA encoded by the gene At4g35760 was recently found to be an oxidoreductase and involved in assembly of PSII. Here, the growth of a mutant lto1-2 line of Arabidopsis was found to be severely stunted and transgenic complementation ultimately demonstrated the phenotype changes were due to this gene. A proteomic experiment identified 23 proteins presenting a differential abundance in lto1-2 compared with wild-type plants, including components in PSII and proteins scavenging active oxygen. Three scavengers of active oxygen, L ascorbate peroxidase 1, peroxisomal catalase 2, dehydroascorbate reductase 1, are reduced in lto1-2 plants, corresponding to high levels of accumulation of reactive oxygen species (ROS). The photosynthetic activities of PSII and the quantity of core protein D1 decreased significantly in lto1-2. Further investigation showed the synthesis of D1 was not affected in mutants both at transcription and translation levels. The soluble DsbA-like domain of LTO1 was found to have reduction, oxidation and isomerization activities, and could promote the formation of disulfide bonds in a lumenal protein, FKBP13. A potential target of LTO1 was captured which was involving in chlorophyll degradation and photooxidative stress response. Experimental results imply that LTO1 plays important roles in redox regulation, ROS homeostasis and maintenance of PSII. PMID- 23689259 TI - Fine mapping of BH1, a gene controlling lemma and palea development in rice. AB - KEY MESSAGE: A new rice floral organ mutant bh1 , had a negative effect on grain yield. BH1 was fine mapped to 87.5 kb on chr2. A 55 kb chromosome segment was deleted in bh1. The cereal spikelet is enclosed by the lemma and palea. The lemma and palea of the floral mutant designated bh1, a selection from a T-DNA library generated from the rice cultivar Asominori, takes on an abnormal curve-shaped appearance only late in floral development, finally forming a beak-shaped hull. The mutation had a negative effect on thousand grain weight, seed set rate and germination rate. Genetic analysis indicated that the mutant phenotype was determined by a single recessive gene. Through map-based approach, BH1 gene was finally located to a ~87.5-kbp region on the long arm of chromosome 2. An analysis of the gene content of this region indicated that the mutation involves the loss of a 55-kbp stretch, harboring four open reading frames. Transcription profiling based on qRT-PCR revealed that the genes OsMADS1, OsMADS14, OsMADS15, OsMADS18, REP1, CFO1, and DL, all of which are also involved in lemma and palea development and identity specification, were down-regulated in the bh1 mutant. BH1 is therefore an important floral organ development gene. PMID- 23689261 TI - Normal and proton pump inhibitor-mediated gastrin levels in infants 1 to 11 months old. AB - BACKGROUND: Scant data exist on the normal range of serum gastrin in infants. In phase I and III trials of rabeprazole in gastroesophageal reflux disease, we studied serum gastrin levels in infants 1 to 11 months old, and assessed normal ranges and the effect of acid-suppressive drugs. METHODS: Overall, 349 treatment naive or treatment-experienced (previously exposed to proton pump inhibitors and/or H2-receptor antagonists) infants with gastroesophageal reflux disease were screened for baseline serum gastrin. Repeat gastrin was monitored at early termination or end of study, allowing assessment of 1 to 8 week daily rabeprazole (5- or 10-mg) treatment on gastrin levels. RESULTS: Median (5%-95% range) baseline gastrin was 118 ng/L (39-315) in the treatment-naive group (n = 251), driven mostly by high levels (121.5 [48-326] ng/L) in the 1- to <4-month-old subgroup. Treatment-experienced infants (n = 98) had elevated baseline gastrin levels (152 [48-487] ng/L; P = 0.0011) with no clear difference between previously proton pump inhibitor-exposed and H2-receptor antagonist-exposed groups. At the end of study, mean (standard deviation) levels were unchanged from baseline in infants withdrawn from rabeprazole to placebo (124 [94] ng/L), but elevated from baseline in those continuing treatment with 5-mg (245 [151] ng/L) and 10-mg (332 [222] ng/L) rabeprazole during the study. CONCLUSIONS: Gastrin levels in treatment-naive infants were elevated through 8 months of age. Between 8 and 12 months of age, they declined so that the median level was within the upper limit of the normal adult range (<100 ng/L). Previous exposure to acid suppressive medications and short-term exposure to rabeprazole significantly increased gastrin levels in infants younger than 1 year. PMID- 23689262 TI - Vascular malformation as a cause of occult gastrointestinal bleeding. PMID- 23689260 TI - Effects of ex vivo gamma-tocopherol on airway macrophage function in healthy and mild allergic asthmatics. AB - Elevated inflammation and altered immune responses are features found in atopic asthmatic airways. Recent studies indicate gamma-tocopherol (GT) supplementation can suppress airway inflammation in allergic asthma. We studied the effects of in vitro GT supplementation on receptor-mediated phagocytosis and expression of cell surface molecules associated with innate and adaptive immunity on sputum-derived macrophages. Cells from nonsmoking healthy (n = 6) and mild house dust mite sensitive allergic asthmatics (n = 6) were treated ex vivo with GT (300 uM) or saline (control). Phagocytosis of opsonized zymosan A bioparticles (Saccharomyces cerevisiae) and expression of surface molecules associated with innate and adaptive immunity were assessed using flow cytometry. GT caused significantly decreased (p < 0.05) internalization of attached zymosan bioparticles and decreased (p < 0.05) macrophage expression of CD206, CD36 and CD86 in allergic asthmatics but not in controls. Overall, GT caused downregulation of both innate and adaptive immune response elements, and atopic status appears to be an important factor. PMID- 23689264 TI - Breast milk is better than formula milk in preventing parenteral nutrition associated liver disease in infants receiving prolonged parenteral nutrition. AB - BACKGROUND AND AIM: Breast milk has been shown to be associated with greater success with regard to weaning children with intestinal failure off parenteral nutrition (PN). There are only a few studies investigating the role of breast milk in decreasing PN-associated liver disease (PNALD). The aim of our study was to determine whether breast milk is better than formula milk in preventing PNALD in infants receiving PN for >4 weeks. METHODS: We conducted a retrospective analysis of newborns requiring prolonged parenteral nutrition. We divided the sample into 3 different groups (exclusive breast-feeding, exclusive formula feeding, and mixed feeding. We compared baseline characteristics, feeding profiles and liver function tests, and liver enzymes among the 3 groups. RESULTS: Among infants receiving PN for >4 weeks, we found that infants who were fed only breast milk were significantly less likely to develop PNALD (34.6%) compared with those who were fed only formula milk (72.7%; P = 0.008). The mean maximum conjugated bilirubin (P = 0.03) and the mean maximum aspartate aminotransferase were significantly lower in the breast-fed group (P = 0.04) compared with the formula-fed group. Among the mixed-feeding group, infants who received a higher percentage of breast milk showed a significant negative correlation with the mean maximum conjugated bilirubin. (Pearson correlation -0.517, P = 0.027). The mean number of days receiving PN and the average daily lipid intake in the 2 groups was not significantly different. CONCLUSIONS: As a modality for early enteral nutrition, breast milk is protective against the development of PNALD in infants receiving PN for >4 weeks. PMID- 23689263 TI - Associations between intestinal mucosal function and changes in plasma zinc concentration following zinc supplementation. AB - OBJECTIVES: Subclinical environmental enteropathy is associated with malabsorption of fats, carbohydrates, and vitamins A, B12, and folate; however, little information is available on mineral absorption. We therefore investigated the relation between intestinal mucosal function (measured by the lactulose:mannitol permeability test and plasma citrulline concentration), and zinc (Zn) absorption, as estimated by the change in plasma Zn concentration (PZC) following short-term Zn or placebo supplementation. METHODS: We conducted a randomized, partially masked, placebo-controlled trial among 282 apparently healthy children 6 to 23 months of age in Burkina Faso. After completing baseline intestinal function tests, participants received either 5 mg Zn, as zinc sulfate, or placebo, daily for 21 days. RESULTS: At baseline, mean +/- standard deviation PZC was 62.9 +/- 11.9 MUg/dL; median (interquartile range) urinary lactulose:mannitol (L:M) recovery ratio and plasma citrulline concentrations were 0.04 (0.03-0.07) and 11.4 (9.0-15.6) MUmol/L, respectively. Change in PZC was significantly greater in the Zn-supplemented versus placebo group (15.6 +/- 13.3 vs 0.02 +/- 10.9 MUg/dL; P < 0.0001), and was negatively associated with initial urinary L:M recovery ratio (-1.1 MUg/dL per 50% increase in urinary L:M recovery ratio; P = 0.014); this latter relation did not differ between supplementation groups (P = 0.26). Baseline plasma citrulline concentration was not associated with change in PZC. CONCLUSIONS: Although altered intestinal permeability may reduce dietary Zn absorption, it likely does not undermine the efficacy of Zn supplementation, given the large increases in PZC following short-term Zn supplementation observed in this study, even among those with increased urinary L:M recovery ratios. PMID- 23689265 TI - Development and validation of a celiac disease quality of life instrument for North American children. AB - OBJECTIVE: Given the social constraints imposed by a gluten-free diet, it can be hypothesized that children with celiac disease (CD) living in the United States have a reduced health-related quality of life (HRQOL); however, there is no validated CD-specific HRQOL instrument for children living in the United States. The goals of this study were to develop and validate a CD-specific HRQOL instrument for children 8 to 18 years of age with CD and to report HRQOL in these children using both generic- and disease-specific instruments. METHODS: This was a prospective study using focus group methodology to develop a CD-specific HRQOL instrument that was then administered to children 8 to 18 years of age with CD living throughout the United States. Instrument validation methods included construct, convergent, and divergent validities. RESULTS: Two instruments were developed: CD-specific pediatric HRQOL instrument (CDPQOL) 8 to 12 and CDPQOL 13 to 18. A total of 181 children with CD completed the CDPQOL as well as a comparator generic instrument. Exploratory factor analysis restructured the CDPQOL and reduced the total number of items. The CDPQOL showed a moderate agreement with the Psychosocial dimensions of the generic instrument confirming convergent validity and low-to-moderate agreement with the Physical Health Summary dimension of the generic instrument confirming divergent validity. CONCLUSIONS: The CDPQOL, consisting of 13 to 17 questions, is a validated instrument for the measurement of HRQOL in children 8 to 18 years of age with CD living in the United States. PMID- 23689266 TI - Benzyl alcohol-based synthesis of oxide nanoparticles: the perspective of S(N)1 reaction mechanism. AB - In this paper, we describe a class of benzyl alcohol-based reactions for the synthesis of a series of inorganic oxide nanoparticles. Benzyl alcohol served as both the solvent and the reagent to interact with various metal chlorides for the synthesis of a series of metal oxides and compound oxides. Typical metal(IV) oxides, like TiO2, metal(III) oxides, like Fe2O3, and metal(II) oxides, like ZnO, with uniform size and special dispersibility, have been prepared through these reactions. The reaction can be illustrated from the perspective of S(N)1 reaction mechanism attributed to the easier formation of benzyl carbocation and unique reactivity of benzyloxy group with nucleophilic agents. By adjusting the experimental conditions, it was found that this type of reaction is available for the synthesis of many inorganic oxides. PMID- 23689267 TI - Results of intravenous thrombolysis within 4.5 to 6 hours and updated results within 3 to 4.5 hours of onset of acute ischemic stroke recorded in the Safe Implementation of Treatment in Stroke International Stroke Thrombolysis Register (SITS-ISTR): an observational study. AB - IMPORTANCE: Pooled analysis of randomized controlled trials of intravenous thrombolysis shows no statistically significant benefit beyond 4.5 hours, with the possible advantage perhaps offset by risk. OBJECTIVE: To compare the outcomes of patients who were treated within 4.5 to 6 hours or within 3 to 4.5 hours of the onset of an ischemic stroke with the outcomes of patients who were treated within 3 hours in the SITS-ISTR. DESIGN: An observational study based on SITS ISTR data during the period from 2002 to 2011. SETTING: Acute and emergency care. PARTICIPANTS: Of 29 618 patients with acute ischemic stroke, 283 (1.0%) were treated within 4.5 to 6 hours of onset, 4056 (13.7%) were within 3 to 4.5 hours of onset, and 25 279 (85.4%) were treated within 3 hours of onset, in compliance with other European Union approval criteria. EXPOSURE: Intravenous thrombolysis with alteplase. MAIN OUTCOMES AND MEASURES: Functional independence (modified Rankin Scale score of 0-2) and mortality at 3 months and symptomatic intracerebral hemorrhage (SICH). P values are based on comparisons between patients treated within 4.5 to 6 hours or within 3 to 4.5 hours of onset against patients treated within 3 hours of onset. RESULTS: Results are presented as within 4.5 to 6 hour vs within 3 to 4.5 hours vs within 3 hours. Median time from stroke onset to treatment was 295 vs 210 minutes vs 138 minutes (P < .01), median age was 65 vs 67 vs 68 years (P < .01), and median baseline National Institutes of Health Stroke Scale score was 9 vs 9 vs 12 (P < .01). Rate of functional independence was 61.3% (P = .40) vs 62.7% (P < .01) vs 58.4%; mortality rate was 11.8% (P = .99) vs 11.1% (P = .21) vs 11.8%; and rate of SICH was 2.6% (P = .17) vs 1.8% (P = .27) vs 1.5%. Multivariate analysis detected no significant difference in SICH (P > .05), mortality (P > .05), or independence (P > .05). Time from stroke onset to treatment as a continuous variable was significantly associated with higher rates of SICH and poor 3-month outcome after adjustment for age and National Institutes of Health Stroke Scale score. CONCLUSIONS AND RELEVANCE: The treatment remains safe and effective for patients treated within 3 to 4.5 hours compared with patients treated within 3 hours. Our selected group of patients treated within 4.5 to 6 hours of stroke onset did not have worse outcomes than patients treated within 3 hours. An inevitable limitation of our observational study is the possible nonequivalence of the cohorts, particularly the 4.5- to 6-hour cohort relative to the other 2 cohorts. PMID- 23689268 TI - Unique karyotype: mos 46,X,dic(X;Y)(p22.33;p11.32)/ 45,X/45,dic(X;Y)(p22.33;p11.32) in an Egyptian patient with Ovotesticular disorder of sexual development. AB - Ovotesticular disorder of sexual development (OT-DSD) is an unusual form of DSD, characterized by the coexistence of testicular and ovarian tissue in the same individual. In this report, we present clinical, cytogenetic and molecular data of an Egyptian patient with ambiguous genitalia and OT-DSD, who had a unique karyotype comprising 3 different cell lines: mos 46,X,dic(X;Y)(p22.33;p11.32)/45,X/ 45,dic(X;Y)(p22.33;p11.32). This mosaic karyotype probably represents 2 different events: abnormal recombination between the X and Y chromosomes during paternal meiosis and postzygotic abnormality in mitotic segregation of the dic(X;Y) chromosome, resulting in a mosaic karyotype. The presence of the sex-determining region Y (SRY) gene explains the development of testicular tissue. On the other hand, other factors, including the presence of a 45,X cell line, partial SRY deletion, X inactivation pattern, and position effect, could be contributed to genital ambiguity. Explanation of the patient's phenotype in relation to the genotype is discussed with a literature review. We conclude that FISH analysis with X- and Y-specific probes and molecular analysis of the SRY gene are highly recommended and allow accurate diagnosis for optimal management of cases with ambiguous genitalia. PMID- 23689269 TI - Direct electron transfer between Cyt c and heme-Abeta relevant to Alzheimer's disease. AB - Partially reduced oxygen species (PROS), produced by reduced heme bound Abeta peptides, can cause oxidative stress and synaptic damage in the brain, which is one of the key pathological features of Alzheimer's disease. In situ oxidation of the heme center by a physiological redox agent like Cytochrome c (Cyt c) can significantly suppress neurotoxic PROS formation. Thus, Cyt c can potentially act as a neuroprotective agent against AD. PMID- 23689271 TI - Evaluating health system processes with randomized controlled trials. PMID- 23689270 TI - Freely-available, true-color volume rendering software and cryohistology data sets for virtual exploration of the temporal bone anatomy. AB - BACKGROUND: Cadaveric dissection of temporal bone anatomy is not always possible or feasible in certain educational environments. Volume rendering using CT and/or MRI helps understanding spatial relationships, but they suffer in nonrealistic depictions especially regarding color of anatomical structures. Freely available, nonstained histological data sets and software which are able to render such data sets in realistic color could overcome this limitation and be a very effective teaching tool. METHODS: With recent availability of specialized public-domain software, volume rendering of true-color, histological data sets is now possible. We present both feasibility as well as step-by-step instructions to allow processing of publicly available data sets (Visible Female Human and Visible Ear) into easily navigable 3-dimensional models using free software. RESULTS: Example renderings are shown to demonstrate the utility of these free methods in virtual exploration of the complex anatomy of the temporal bone. After exploring the data sets, the Visible Ear appears more natural than the Visible Human. CONCLUSION: We provide directions for an easy-to-use, open-source software in conjunction with freely available histological data sets. This work facilitates self-education of spatial relationships of anatomical structures inside the human temporal bone as well as it allows exploration of surgical approaches prior to cadaveric testing and/or clinical implementation. PMID- 23689272 TI - Mean platelet volume is not associated with platelet reactivity and the extent of coronary artery disease in diabetic patients. AB - Platelets play a central role in the pathogenesis of coronary artery disease (CAD). Mean platelet volume (MPV) is an indicator of platelet activation, and has been demonstrated to be correlated with platelet reactivity. Diabetic patients have been shown to have larger MPV, that may contribute to higher platelet reactivity and atherothrombotic complications observed in these patients. Therefore, the aim of the current study was to investigate whether MPV is associated with platelet reactivity and the extent of CAD among diabetic patients. We performed a cohort study including 1016 consecutive diabetic patients undergoing coronary angiography at the University Hospital 'Maggiore della Carita', Novara, Italy. CAD is defined as stenosis above 50% in at least one coronary vessel at coronary angiography. Platelet reactivity was evaluated in 50 diabetic patients without history of CAD and who were free (in the past month) from medications which may affect platelet aggregation. Platelet aggregation was evaluated by light transmission aggregometry after stimulation with 1 MUg/ml collagen type I. We additionally evaluated platelet surface expression of P selectin after stimulation with U46619 (a stable synthetic analogue of the prostaglandin PGH2) and plasma concentration of thromboxane B2 (TxB2). Patients were grouped according to tertile values of MPV (<10.6 fl, group 1; 10.6-11.3 fl, group 2; >11.4 fl, group 3). MPV was associated with age (P=0.011), baseline fasting glucose (P=0.044), glycosylated haemoglobin (P=0.005), creatinine (P=0.052) and haemoglobin (P=0.003), but inversely related to platelet count (P<0.001) and triglycerides (P=0.031). Larger MPV was associated with therapy with statins (P=0.012) and diuretics (P=0.021). CAD was observed in 826 patients (81.3%). MPV was not associated with the prevalence of CAD [odds ratio (OR), 0.85 (0.7-1.03), P=0.11]. The results were confirmed in terms of severe CAD [OR, 1.03 (0.88-1.21), P=0.7]. The absence of any significant relationship between MPV and CAD was confirmed after correction for baseline confounding factors [OR, 0.9 (0.75-1.08), P=0.19]. Finally, MPV was not related to platelet reactivity. This is the first study showing that in diabetic patients MPV is not related to platelet reactivity and the prevalence and extent of CAD. Therefore, MPV may not be considered a risk factor for CAD among diabetic patients. PMID- 23689273 TI - Molecular characterization of 16 hemophilia B families in Aragon, Spain. AB - Molecular characterization of hemophilia B at gene level has become an indispensable tool for a proper genetic counseling in carriers and for a closer surveillance of inhibitor development in several severe forms. Our study was aimed at characterizing the molecular defects in the factor IX (FIX) gene in hemophilia B families in Aragon, a center-east region of Spain. Direct sequencing of all regions of likely functional significance of the FIX gene was performed in the screened 18 hemophilia B families. Quantitative techniques, such as multiplex ligation-dependent prove amplification reaction, were carried out only in patients in whom no mutation was found. We have identified the molecular events responsible for hemophilia B in 16 unrelated families (eight with mild hemophilia B and eight with severe hemophilia B). Out of all families studied, we have found 14 missense mutations and two nonsense mutations; still we were unsuccessful in determining the genetic defects in two severe and unrelated families. Of the 16 characterized mutations, 14 of them lie in the protease domain in which one mutation, A233T, was surprisingly found in three unrelated families. We also report and discuss the pathogenicity of F314L, a novel mutation found in the protease domain. Our molecular data reflect a notable heterogeneity of the mutational spectrum mainly in the protease domain of FIX. This is the first mutation report on the disease in Aragon, Spain. PMID- 23689274 TI - "Fit and fabulous": mixed-methods research on processes, perceptions, and outcomes of a yearlong gym program with assisted-living residents. AB - This study's mixed-methods design sought to understand how to encourage assisted living (AL) residents to initiate and continue exercise in a gym setting. Ten residents participated in this yearlong program. Processes developed and perceived benefits were understood through interviews and observations. Changes in active time, lower body strength, and workload were evaluated using direct measures. Findings indicated that AL residents regularly used exercise machines (mean participation = 53.8%) and increased active time and lower body strength (p = .02) when adequately prepared and supported. Participants prioritized gym time and developed pride and ownership in the program. They described themselves as exercisers and developed a sense of belonging to their new home. Friendships with one another, staff, and university partners were nurtured in the gym setting. When provided space, equipment, trained staff, and additional resource support, AL residents' quality of life and life satisfaction were enhanced in several domains. PMID- 23689275 TI - Bilateral thalamic lesions in a child. PMID- 23689276 TI - Chemical-genetic identification of the biochemical targets of polyalkyl guanidinium biocides. AB - Alkylated guanidinium compounds exhibit microbiocidal activity in marine environments, yet the mode of action of these compounds has not been defined. A comprehensive chemical-genetic approach in budding yeast was used to define the biological processes affected by these compounds. N-Butyl-N'-decylguanidinium and N-hexyl-N'-(3-hydroxypropyl)-N''-octylguanidinium chlorides were shown to prevent yeast growth in a dose-dependent manner. All non-essential genes required for tolerance of sub-lethal amounts of these biocides were identified. These unbiased and systematic screens reveal the two related guanidinium compounds have a non overlapping spectrum of targets in vivo. A functional tryptophan biosynthetic pathway is essential for tolerance of both biocides, which identifies tryptophan amino acid import as one process affected by these compounds. Further analysis of hypersensitive gene lists demonstrates that the substitutions on alkylated guanidiums confer important functional differences in vivo: one derivative renders the ability to generate acidic vacuoles essential, while the other is synthetically lethal with mutants in the transcriptional response to chemical stress. Altogether the results define the common and distinct biological processes affected by biocidal alkylated guanidinium salts. PMID- 23689278 TI - RhoGTPases--NODes for effector-triggered immunity in animals. AB - A recent study published in Nature by Keestra and colleagues addresses how the immune system detects the pathogenic potential of microbes and provides evidence that one strategy involves NOD1, which monitors the activation state of the RhoGTPases that are targeted by virulence effectors produced by pathogenic microbes. Interestingly, their findings reveal striking similarities with previous observations made in flies and plants, establishing the evolutionary conservation of this detection system in the innate immune arsenal in many taxa. PMID- 23689277 TI - Sirtuin deacetylases in neurodegenerative diseases of aging. AB - Sirtuin enzymes are a family of highly conserved protein deacetylases that depend on nicotinamide adenine dinucleotide (NAD+) for their activity. There are seven sirtuins in mammals and these proteins have been linked with caloric restriction and aging by modulating energy metabolism, genomic stability and stress resistance. Sirtuin enzymes are potential therapeutic targets in a variety of human diseases including cancer, diabetes, inflammatory disorders and neurodegenerative disease. Modulation of sirtuin activity has been shown to impact the course of several aggregate-forming neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and spinal and bulbar muscular atrophy. Sirtuins can influence the progression of neurodegenerative disorders by modulating transcription factor activity and directly deacetylating proteotoxic species. Here, we describe sirtuin protein targets in several aggregate-forming neurodegenerative diseases and discuss the therapeutic potential of compounds that modulate sirtuin activity in these disorders. PMID- 23689280 TI - Does a positive Pittsburgh Compound B scan in a patient with dementia equal Alzheimer disease? AB - IMPORTANCE: The clinical role of amyloid brain positron emission tomographic imaging in the diagnosis of Alzheimer disease is currently being formulated. The specificity of a positive amyloid scan is a matter of contention. OBSERVATIONS: An 83-year-old Canadian man presented with a 5-year history of predominantly short-term memory loss and functional impairment. Clinical evaluation revealed significant, gradually progressive short-term memory loss in the absence of any history of strokes or other neuropsychiatric symptoms. The patient met clinical criteria for probable Alzheimer disease but had a higher than expected burden of white matter disease on magnetic resonance imaging. A positron emission tomographic Pittsburgh Compound B scan was highly positive in typical Alzheimer disease distribution. The patient died of an intracerebral hemorrhage 6 months after the assessment. Autopsy revealed cerebral amyloid angiopathy in the complete absence of amyloid plaques or neurofibrillary tangles. CONCLUSIONS AND RELEVANCE: This patient demonstrates that a positive Pittsburgh Compound B scan in a patient with clinical dementia meeting criteria for probable Alzheimer disease is not proof of an Alzheimer disease pathophysiological process. A positive Pittsburgh Compound B scan in typical Alzheimer disease distribution in a patient with dementia can be secondary to cerebral amyloid angiopathy alone. PMID- 23689279 TI - ALDH2 protects against stroke by clearing 4-HNE. AB - Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that metabolizes ethanol and toxic aldehydes such as 4-hydroxy-2-nonenal (4-HNE). Using an unbiased proteomic search, we identified ALDH2 deficiency in stroke-prone spontaneously hypertensive rats (SHR-SP) as compared with spontaneously hypertensive rats (SHR). We concluded the causative role of ALDH2 deficiency in neuronal injury as overexpression or activation of ALDH2 conferred neuroprotection by clearing 4-HNE in in vitro studies. Further, ALDH2-knockdown rats revealed the absence of neuroprotective effects of PKCepsilon. Moderate ethanol administration that is known to exert protection against stroke was shown to enhance the detoxification of 4-HNE, and to protect against ischemic cerebral injury through the PKCepsilon-ALDH2 pathway. In SHR-SP, serum 4-HNE level was persistently elevated and correlated inversely with the lifespan. The role of 4 HNE in stroke in humans was also suggested by persistent elevation of its plasma levels for at least 6 months after stroke. Lastly, we observed that 21 of 1 242 subjects followed for 8 years who developed stroke had higher initial plasma 4 HNE levels than those who did not develop stroke. These findings suggest that activation of the ALDH2 pathway may serve as a useful index in the identification of stroke-prone subjects, and the ALDH2 pathway may be a potential target of therapeutic intervention in stroke. PMID- 23689281 TI - Differentiation of Chinese liquors by using ambient glow discharge ionization mass spectrometry. AB - Chinese liquors are often a very important part of social event in China. Driven by high profit, some illegal traders often use inferior liquors instead of the products with high quality to cheat the customer. Therefore, it is highly required to authenticate Chinese liquors. In this paper a novel method based on ambient glow discharge ionization mass spectrometry has been developed to differentiate Chinese liquors. Volatile components from liquor samples were ionized by the plasma generated by glow discharge and then detected by a commercial linear ion trap mass spectrometer. Consequently, the fingerprint mass spectra of several Chinese liquors were obtained. Combined with principal component analysis, this new method was successfully applied to differentiate different brands of Chinese liquors without any sample pretreatment. Compared with conventional methods, this novel method has the advantages of easy operation, high speed, and high efficiency, which make it a potential tool in the fields of food safety, atmosphere chemistry. PMID- 23689282 TI - Smartphone-based hearing test as an aid in the initial evaluation of unilateral sudden sensorineural hearing loss. AB - Sudden sensorineural hearing loss (SSNHL) can cause significant morbidity. Treatment with steroids can improve outcome. Delay in initiation of treatment reduces the chance to regain hearing. For this reason SSNHL is considered an emergency. Diagnosis is based on history, physical examination and a standard audiogram, the latter requiring specialized equipment and personnel. Standard audiogram may not be available at the time and place of patient presentation. A smartphone or tablet computer-based hearing test may aid in the decision to prescribe steroids in this setting. In this study the uHearTM hearing test application was utilized. The output of this ear-level air conduction hearing test is reported in hearing grades for 6 frequencies ranging from 250 to 6000 Hz. A total of 32 patients with unilateral SSNHL proven by a standard audiogram were tested. The results of standard and iPod hearing tests were compared. Based on the accepted criterion of SSNHL (at least 30 dB loss - or 2 hearing grades - in 3 consecutive frequencies) the test had a sensitivity of 0.76 and specificity of 0.91. Using a less stringent criterion of a loss of 2 hearing grades over at least 2 frequencies the sensitivity was 0.96 and specificity 0.86. The correlation coefficient for the comparison of the average hearing grade across the 6 measured frequencies of the study and standard audiogram was 0.83. uHear more accurately reflected hearing thresholds at mid and high tones. Similarly to previously published data, low frequency thresholds could be artificially elevated. In conclusion, uHear can be useful in the initial evaluation of patients with single-sided SSNHL by providing important information guiding the decision to initiate treatment before a standard audiogram is available. PMID- 23689284 TI - A combined approach of quantitative interaction proteomics and live-cell imaging reveals a regulatory role for endoplasmic reticulum (ER) reticulon homology proteins in peroxisome biogenesis. AB - Peroxisome biogenesis initiates at the endoplasmic reticulum (ER) and maturation allows for the formation of metabolically active organelles. Yet, peroxisomes can also multiply by growth and division. Several proteins, called peroxins, are known to participate in these processes but little is known about their organization to orchestrate peroxisome proliferation. Here, we demonstrate that regulation of peroxisome proliferation relies on the integrity of the tubular ER network. Using a dual track SILAC-based quantitative interaction proteomics approach, we established a comprehensive network of stable as well as transient interactions of the peroxin Pex30p, an integral membrane protein. Through association with merely ER resident proteins, in particular with proteins containing a reticulon homology domain, and with other peroxins, Pex30p designates peroxisome contact sites at ER subdomains. We show that Pex30p traffics through the ER and segregates in punctae to which peroxisomes specifically append, and we ascertain its transient interaction with all subunits of the COPI coatomer complex suggesting the involvement of a vesicle-mediated transport. We establish that the membrane protein Pex30p facilitates the connection of peroxisomes to the ER. Taken together, our data indicate that Pex30p-containing protein complexes act as focal points from which peroxisomes can form and that the tubular ER architecture organized by the reticulon homology proteins Rtn1p, Rtn2p and Yop1p controls this process. PMID- 23689286 TI - Effects of age, sex, body mass index and APOE genotype on cardiovascular biomarker response to an n-3 polyunsaturated fatty acid supplementation. AB - OBJECTIVES: To test whether age, sex, body mass index (BMI), and the apolipoprotein E (APOE) genotype are associated with the metabolic response to an n-3 polyunsaturated fatty acid (PUFA) supplementation. METHODS: 210 subjects followed a 2-week run-in period based on Canada's Food Guide and underwent a 6 week 5 g/day fish oil supplementation (1.9 g of eicosapentaenoic acid and 1.1 g of docosahexaenoic acid). Cardiovascular disease risk factors were measured. RESULTS: n-3 PUFA supplementation was associated with a decrease of plasma triglyceride levels (p = 0.0002) as well as with an increase of fasting glucose (FG) levels (p = 0.02). Age was associated with post-intervention plasma total cholesterol (p = 0.01), low-density lipoprotein cholesterol (p = 0.007), apolipoprotein B (p = 0.04), and insulin (p = 0.002) levels. Sex was associated with post-intervention plasma high-density lipoprotein cholesterol levels (p = 0.02). BMI was associated with plasma FG (p = 0.02) and insulin levels (p < 0.0001) after the supplementation. APOE genotype was associated with FG (p = 0.001) and C-reactive protein levels (p = 0.03) after the supplementation. CONCLUSION: Results suggest that age, sex, BMI, and the APOE genotype contribute to the inter-individual variability observed in the metabolic response to an n-3 PUFA supplementation. PMID- 23689285 TI - Design, implementation and multisite evaluation of a system suitability protocol for the quantitative assessment of instrument performance in liquid chromatography-multiple reaction monitoring-MS (LC-MRM-MS). AB - Multiple reaction monitoring (MRM) mass spectrometry coupled with stable isotope dilution (SID) and liquid chromatography (LC) is increasingly used in biological and clinical studies for precise and reproducible quantification of peptides and proteins in complex sample matrices. Robust LC-SID-MRM-MS-based assays that can be replicated across laboratories and ultimately in clinical laboratory settings require standardized protocols to demonstrate that the analysis platforms are performing adequately. We developed a system suitability protocol (SSP), which employs a predigested mixture of six proteins, to facilitate performance evaluation of LC-SID-MRM-MS instrument platforms, configured with nanoflow-LC systems interfaced to triple quadrupole mass spectrometers. The SSP was designed for use with low multiplex analyses as well as high multiplex approaches when software-driven scheduling of data acquisition is required. Performance was assessed by monitoring of a range of chromatographic and mass spectrometric metrics including peak width, chromatographic resolution, peak capacity, and the variability in peak area and analyte retention time (RT) stability. The SSP, which was evaluated in 11 laboratories on a total of 15 different instruments, enabled early diagnoses of LC and MS anomalies that indicated suboptimal LC-MRM MS performance. The observed range in variation of each of the metrics scrutinized serves to define the criteria for optimized LC-SID-MRM-MS platforms for routine use, with pass/fail criteria for system suitability performance measures defined as peak area coefficient of variation <0.15, peak width coefficient of variation <0.15, standard deviation of RT <0.15 min (9 s), and the RT drift <0.5min (30 s). The deleterious effect of a marginally performing LC-SID MRM-MS system on the limit of quantification (LOQ) in targeted quantitative assays illustrates the use and need for a SSP to establish robust and reliable system performance. Use of a SSP helps to ensure that analyte quantification measurements can be replicated with good precision within and across multiple laboratories and should facilitate more widespread use of MRM-MS technology by the basic biomedical and clinical laboratory research communities. PMID- 23689287 TI - Overexpression of miR-26a-2 in human liposarcoma is correlated with poor patient survival. AB - Approximately 90% of well-differentiated/de-differentiated liposarcomas (WDLPS/DDLPS), the most common LPS subtype, have chromosomal amplification at 12q13-q22. Many protein-coding genes in the region, such as MDM2 and , have been studied as potential therapeutic targets for LPS treatment, with minimal success. In the amplified region near the MDM2 gene, our single nucleotide polymorphism (SNP) array analysis of 75 LPS samples identified frequent amplification of miR 26a-2. Besides being in the amplicon, miR-26a-2 was overexpressed significantly in WDLPS/DDLPS (P<0.001), as well as in myxoid/round cell LPS (MRC) (P<0.05). Furthermore, Kaplan-Meier survival analysis showed that overexpression of miR-26a 2 significantly correlated with poor patient survival in both types of LPS (P<0.05 for WDLPS/DDLPS; P<0.001 for MRC). Based on these findings, we hypothesized that miR-26a-2 has an important role in LPS tumorigenesis, regardless of LPS subtypes. Overexpression of miR-26a-2 in three LPS cell lines (SW872, LPS141 and LP6) enhanced the growth and survival of these cells, including faster cell proliferation and migration, enhanced clonogenicity, suppressed adipocyte differentiation and/or resistance to apoptosis. Inhibition of miR-26a-2 in LPS cells using anti-miR-26a-2 resulted in the opposite responses. To explain further the effect of miR-26a-2 overexpression in LPS cells, we performed in silico analysis and identified 93 candidate targets of miR 26a-2. Among these genes, RCBTB1 (regulator of chromosome condensation and BTB domain-containing protein 1) is located at 13q12.3-q14.3, a region of recurrent loss of heterozygosity (LOH) in LPS. Indeed, either overexpression or inhibition of RCBTB1 made LPS cells more susceptible or resistant to apoptosis, respectively. In conclusion, our study for the first time reveals the contribution of miR-26a-2 to LPS tumorigenesis, partly through inhibiting RCBTB1, suggesting that miR-26a-2 is a novel therapeutic target for human LPS. PMID- 23689288 TI - Analysis of immunoglobulin heavy chain rearrangement in a child with recurrent Burkitt lymphoma to determine clonality. AB - BACKGROUND: Burkitt lymphoma (BL) is an aggressive, rapidly proliferating neoplasm of B-cell origin. A late recurrence should be investigated to differentiate whether it is a true relapse or a de novo lymphoma as this has therapeutic implications. OBSERVATIONS: We report an HIV-negative white male individual, who at the age of 14 presented with recurrent BL in the abdomen occurring 6 years after successful treatment. Analysis of VDJ rearrangement showed marked dissimilarity in clonal peaks between the 2 tumors, suggesting that each tumor was associated with separate origins. The second tumor was treated as a de novo BL, and the patient remained in complete remission 2 years from recurrence without any evidence of the disease. CONCLUSION: We present a case with 2 distinct BLs verified by the VDJ rearrangement analysis in a non-HIV infected individual. Our case supports the finding that a genetically discrete BL can be treated as if it were a new tumor, thereby reducing chemotherapeutic burden and treatment-related morbidity associated with the regimens for relapsed or refractory disease. Analysis of VDJ rearrangement seems to be a reliable assessment of tumor clonality. PMID- 23689289 TI - Monitoring of anti-L-asparaginase antibody and L-asparaginase activity levels in a pediatric patient with acute lymphoblastic leukemia and hypersensitivity to native Escherichia coli L-asparaginase during desensitization courses. AB - A patient with acute lymphoblastic leukemia who was hypersensitive to native Escherichia coli L-asparaginase (L-asp) underwent readministration of the L-asp without serious adverse effects for 11 doses using a desensitization protocol every time. Monitoring of anti-L-asp antibody and L-asp activity levels revealed that the serum L-asp activity was below the effective levels during the administration of first 6 to 7 doses because of extremely high levels of anti-L asp IgG. Sustained L-asp activity was attained since the eighth dose was administered, when the antibody levels were <5 U/mL. L-asp activity levels in patients with L-asp hypersensitivity should be monitored during the desensitization courses to ensure a sufficient L-asp activity. PMID- 23689290 TI - Graphene oxide as a recyclable phase transfer catalyst. AB - We demonstrated a simple and green chemical method to obtain Michael adducts and their derivatives by using GO as a phase transfer catalyst with different kinds of bases in water and dichloromethane, and we also used GO multiple cycles almost without reduction in reaction yields. PMID- 23689292 TI - Talofibular interval changes after acute ankle sprain: a stress ultrasonography study of ankle laxity. AB - INTRODUCTION: Quantifying talocrural joint laxity after ankle sprain is problematic. Stress ultrasonography (US) can image the lateral talocrural joint and allow the measurement of the talofibular interval, which may suggest injury to the anterior talofibular ligament (ATFL). The acute talofibular interval changes after lateral ankle sprain are unknown. METHODS: Twenty-five participants (9 male, 16 female; age 21.8 +/- 3.2 y, height 167.8 +/- 34.1 cm, mass 72.7 +/- 13.8 kg) with 27 acute, lateral ankle injuries underwent bilateral stress US imaging at baseline (<7 d) and on the affected ankle at 3 wk and 6 wk from injury in 3 ankle conditions: neutral, anterior drawer, and inversion. Talofibular interval (mm) was measured using imaging software and self-reported function (activities of daily living [ADL] and sports) by the Foot and Ankle Ability Measure (FAAM). RESULTS: The talofibular interval increased with anterior-drawer stress in the involved ankle (22.65 +/- 3.75 mm; P = .017) over the uninvolved ankle (19.45 +/- 2.35 mm; limb * position F1,26 = 4.9, P = .035) at baseline. Inversion stress also resulted in greater interval changes (23.41 +/- 2.81 mm) than in the uninvolved ankles (21.13 +/- 2.08 mm). A main effect for time was observed for inversion (F2,52 = 4.3, P = .019, 21.93 +/- 2.24 mm) but not for anterior drawer (F2,52 = 3.1, P = .055, 21.18 +/- 2.34 mm). A significant reduction in the talofibular interval took place between baseline and week 3 inversion measurements only (F1,26 = 5.6, P = .026). FAAM-ADL and sports results increased significantly from baseline to wk 3 (21.9 +/- 16.2, P < .0001 and 23.8 +/- 16.9, P < .0001) and from wk 3 to wk 6 (2.5 +/- 4.4, P = .009 and 10.5 +/- 13.2, P = .001). CONCLUSIONS: Stress US methods identified increased talofibular interval changes suggestive of talocrural laxity and ATFL injury using anterior drawer and inversion stress that, despite significant improvements in self reported function, only marginally improved during the 6 wk after ankle sprain. Stress US provides a safe, repeatable, and quantifiable method of measuring the talofibular interval and may augment manual stress examinations in acute ankle injuries. PMID- 23689293 TI - Cationic D4R zinc phosphate-anionic polyoxometalate hybrids: synthesis, spectra, structure and catalytic studies. AB - A facile synthetic strategy for the generation of a new class of inorganic organic-inorganic hybrids is reported. Replacement of labile DMSO ligands from the preformed Double-Four-Ring (D4R) zinc phosphate cluster [Zn(dipp){(CH3)2SO}]4 by the addition of 4-aminopyridine (4-ampyr) results in the isolation of another discrete D4R cluster [Zn(dipp)(4-ampyr)]4 (1), which forms a hydrogen-bonded framework in solid-state. If 1-methyl-4,4'-bipyridinium salts are employed instead, tetra-cationic D4R cluster [Zn(dipp)(L)]4[PF6]4 (2) and [Zn(dipp)(L)]4[ClO4]4 (3) (L = 1-methyl-4,4'-bipyridinium, dipp = 2,6-di-iso propylphenylphosphate) are isolated. Compound 2 was reacted with three different polyoxometalates, [TBA]4[Mo8O26] (POM-1), [TBA]4[PMo11VO40] (POM-2), and [TBA]4[SiMo12O40] (POM-3) to obtain amorphous hybrids, [Zn(dipp)(L)]4[Mo8O26] (4), [Zn(dipp)(L)]4[PMo11VO40] (5), and [Zn(dipp)(L)]4[SiMo12O40] (6), respectively. All the hybrid materials have been characterized by analytical and spectroscopic studies. The molecular structure of 1 has also been determined by single-crystal XRD measurements. N2 gas sorption analyses show moderate BET surface area and also establish the mesoporous nature of the hybrids 4-6. The catalytic potential of hybrids 4, 5 and 6 has been explored towards epoxidation of cyclohexene. PMID- 23689294 TI - Passive stiffness of the gastrocnemius muscle in athletes with spastic hemiplegic cerebral palsy. AB - The passive properties of the muscle-tendon unit are regularly assessed in individuals with cerebral palsy (CP). However, no information is available on the passive properties of adult muscle, and whether any differences exist between the paretic and control muscles. Eleven ambulant male athletes with spastic hemiplegic CP (21.2 +/- 3.0 years) and controls without neurological impairment (age = 21.8 +/- 2.2 years) completed two and one passive stretch session, respectively. During each session, the ankle was passively dorsiflexed until end range of motion (ROM), whilst recording passive ankle angle, torque and gastrocnemius medialis (GM) myotendinous junction (MTJ) displacement. In addition, GM cross-sectional area (CSA) and length were measured. Subsequently, in vivo stress and strain were determined to calculate elastic modulus. Passive stiffness, MTJ displacement and ROM of the paretic GM were not different from the control muscles. However, the elastic modulus of the paretic GM was two times stiffer than the control GM muscles. In conclusion, athletes with CP exhibit absolute passive muscle stiffness similar to the controls; however, the elastic modulus of the CP muscle was significantly greater. Therefore, throughout the same ROM a smaller GM CSA in CP athletes has to dissipate larger relative torque compared to the control muscles, consequently causing the muscle to elongate to the same extent as the non-paretic muscle under stretch. PMID- 23689295 TI - Assessment of an in vitro transport model using BeWo b30 cells to predict placental transfer of compounds. AB - The human ex vivo placental perfusion model has regularly been used to study the transplacental transport of compounds. However, this method is laborious and dependent on the presence of fresh human placenta, hampering its use for the assessment of large numbers of compounds. An in vitro model for the placental barrier using BeWo b30 cells may provide an alternative to the ex vivo system. The present study aims to assess whether such an in vitro model could be used to reliably predict placental transfer. To this end, BeWo b30 cells, derived from a human choriocarcinoma, were grown on transwell insert to form a cell layer, separating an apical maternal compartment from a basolateral fetal compartment. For a set of nine selected model compounds, including the reference compound antipyrine, the transport velocity from the apical to the basolateral compartment was determined. Relative transport rates obtained were compared with the transfer indices (a measure for the transport relative to antipyrine) of these compounds obtained in ex vivo placental perfusion studies as reported in the literature. The relative transport rates in the in vitro BeWo model were in good correlation (R2 = 0.95) with the transfer indices reported for the ex vivo model. This indicates that the BeWo model could be a valuable in vitro model for prediction of placental transfer of compounds. PMID- 23689296 TI - Noise and health in vulnerable groups: a review. AB - Vulnerable or susceptible groups are mentioned in most reviews and documents regarding noise and health. But only a few studies address this issue in a concrete and focused way. Groups at risk most often mentioned in the literature are children, the elderly, the chronically ill and people with a hearing impairment. The other categories encountered are those of sensitive persons, shiftworkers, people with mental illness (e.g., schizophrenia or autism), people suffering from tinnitus, and fetuses and neonates. The mechanism for this vulnerability has not been clearly described and relevant research has seldom focused on the health effects of noise in these groups in an integrated manner. This paper summarizes the outcomes and major conclusions of a systematic, qualitative review of studies over the past 5 years. This review was prepared for the 10 th Conference on Noise as a Public Health Problem (ICBEN, 2011). Evidence is reviewed describing effects, groups assumed to be at risk, and mechanisms pertaining to noise sensitivity and learned helplessness. PMID- 23689297 TI - Interleukin-1beta gene polymorphism and hearing loss related to the history of occupational noise exposure in Brazilian elderly. AB - Hearing loss is the most common sensory impairment in older people, and may have social and psychological consequences, such as social isolation, frustration and depression. Noise-induced hearing loss (NIHL) is an interaction of both genetic and environmental factors. Some studies have led to the identification of possible NIHL susceptibility genes. The aim of the present study was to investigate whether the polymorphism of the interleukin (IL)-1beta gene at position + 3954 was associated with complaints of hearing loss due to occupational exposure. The sample was composed of elderly people with hearing loss (age >= 60 years) divided into two groups: 99 with occupational exposure to noise and 193 without exposure. Information on occupational exposure to noise was obtained through interviews using a semi-structured questionnaire. Hearing acuity was measured from 500 to 6000 Hz and the IL-1beta genotype was obtained by the polymerase chain reaction- restriction fragment length polymorphism technique. Differences in allelic and genotypic frequencies, and the association between genotypic frequencies and complaints of hearing loss due to occupational exposure, were analyzed by the Chi-square test at the 5% significance level. Fifty-one percent of the elderly were homozygous for the ancestral allele (C), 17.2% were homozygous for the polymorphic allele (T) and 31.8% were heterozygous. The frequency was found to be 67-33% C to allele T. There was no significant association between polymorphism in gene IL-1beta and hearing loss associated with occupational exposure (chi2 = 0.538; P = 0.676). No association was found with the polymorphism of the IL-1beta +3954 C/T gene and hearing loss associated with the occupational noise exposure history. PMID- 23689298 TI - The association between road traffic noise exposure and blood pressure among children in Germany: the GINIplus and LISAplus studies. AB - Studies examining the association between road traffic noise and blood pressure in children are scarce. Nighttime noise levels and window orientations have not been considered in most previous studies. Investigate the association between road traffic noise exposure and blood pressure among children, and investigate the impact of bedroom window direction on this association. We measured blood pressure in 605 children aged 10 years from two Munich cohorts. Demographic and health information was collected by parent completed questionnaires. Road traffic noise levels were assessed by day-evening-night noise indicator "Lden" and night noise indicator "Lnight". Minimum and maximum levels within a 50 m buffer around child's home address were derived. Generalized additive models were applied to explore effect of noise levels on systolic and diastolic blood pressure (SBP and DBP). The orientation of child's bedroom window was considered in sensitivity analyses. DBP was significantly associated with the minimum level of noise during 24 h (Lden_min) and nightime (Lnight_min). Specifically, DBP increased by 0.67 and 0.89 mmHg for every 5 A-weighted decibels increase in Lden_min and Lnight_min. After adjusting for Lden_min (Lnight_min), DBP of children whose bedroom window faced the street was 1.37 (1.28) mmHg higher than those whose bedroom window did not, these children showed statistically significant increased SBP for Lden_min (3.05 mmHg) and Lnight_min (3.27 mmHg) compared to children whose bedroom window did not face the street. Higher minimum levels of weighted day-evening-night noise and nighttime noise around the home residence may increase a child's blood pressure. PMID- 23689299 TI - Stress and odor sensitivity in persons with noise sensitivity. AB - Previous research has indicated that sensory sensitivity/intolerance to a specific modality may be part of a more general environmental hypersensitivity, and possibly mediated by stress. This study investigated the relationship between noise sensitivity, perceived stress, and odor sensitivity in a group of men. A quasi-experimental design was used. One-hundred and thirty-four male undergraduate students completed Weinstein's noise sensitivity scale from which a low-sensitivity group (n = 16) and a high-sensitivity (n = 16) group were formed. These two groups were screened for loss in auditory and olfactory detection sensitivity, and completed the perceived stress questionnaire (PSQ) and the chemical sensitivity scale (CSS). One-way analysis of variance and Spearman correlational analyses were performed. Significantly higher scores on the PSQ (P < 0.05) and the CSS (P < 0.05) were found in the high noise-sensitivity group compared to the low noise-sensitivity group. These findings raise the question of whether the relation between noise and odor sensitivity reflects a general environmental sensitivity. PMID- 23689300 TI - Evaluation of speech perception in competing noise conditions for normally hearing children. AB - Evaluation of speech perception in noisy environments for normally hearing children was conducted in order to provide normal data for speech perception testing in children with hearing impairments thus improving early intervention alternatives for Mandarin-speaking children with hearing impairments. The speech perception abilities of 174 developmentally normal children ranging aged 2-5 years, in four age groups, were evaluated in environments that were quiet or with high levels of competing noise using the Mandarin pediatric speech intelligibility (MPSI) test. The mean score of MPSI between the four age groups showed notable statistical differences, including a variation in mean score between the four age groups, clearly indicating that the speech perception abilities of young children in noisy environments improved greatly with age, most notably between the ages of 3 and 4 years old. Speech perception ability in noisy environments was shown to be significantly, but weakly, related to age, implying the presence of other, possibly environment factors, in speech perception development. Furthermore, no statistically significant difference between boys and girls was noted in the experimental MPSI scores. The ability of children to increasingly perceive speech in environments containing high competing noise levels was shown to gradually and progressively increase with age. These results indicated that the developing Mandarin speech perception abilities in noisy environments in normal hearing children develops substantially after the age of 3 4 years, suggesting that similar age ranges may be even more critical intervention points for children with hearing impairments. More studies are still needed to confirm that. PMID- 23689301 TI - An analysis of roadway noise at residential estates in close proximity to expressways in Singapore. AB - Singapore is a city-state of 5 million people. The entire urban population has expanded from 4.4 million to 5 million in a matter of 5 years. Because of the scarcity of land available, more major roads and expressways are being run close to residential developments, exposing the residents to expressway noise. Recognizing the problems of noise in a high-density urban society such as Singapore, the National Environmental Agency of Singapore (NEA) has set prescribed noise limits for residential areas. The purpose of this paper is to analyze the noise level in one such development that is adjacent to an expressway, examine the effect of building height on noise and to compare the results with the NEA standards. The paper concludes with the implications of the results and a discussion on the solution to the problem. PMID- 23689302 TI - Comparison of anxiety levels associated with noise in the dental clinic among children of age group 6-15 years. AB - Fear or anxiety due to noise produced in the dental clinic is rated third among the reasons to avoid dental visits. The aim of the present study was to determine anxiety levels associated with noise in a dental clinic. The study was done using a survey questionnaire containing 10 questions and was divided into two parts. The first part included demographic information such as name, age, gender, and school; the second half included questions regarding patient's feelings toward noise in the dental clinic and its possible link to dental anxiety. Two-hundred and fifty children and adolescents of age group 6-15 years participated in the study. Results of the study showed that 50% of females, 29% males avoided a visit to the dentist because of anxiety and fear, 38% subjects of age group 6-11 years reported that sound of the drill makes them uncomfortable, followed by having to wait in the reception area. Gender gap was also observed with more females feeling annoyed than males on the 1-10 annoyance level scale. More than 60% felt "annoyed" to "extremely annoyed" by noise in the dental clinic. 45% of subjects preferred watching television to cope with such noise. This study concludes that the noise produced in dental clinic is anxiety provoking and significantly contributes to avoidance of dental treatment and the best way opted by the majority of subjects to overcome this anxiety was audiovisual distraction method. PMID- 23689303 TI - Effect of administration of vitamins C and E on fertilization capacity of rats exposed to noise stress. AB - The aims of this study were to evaluate the effects of administration of Vitamins C and E on fertilization capacity in rats exposed to noise stress. 40 adult male rats were randomly divided into 5 equal groups. Group 1 as controls who were not exposed to noise and groups 2-5 exposed to noise with 90-120 dB intensity and 300 350 Hz frequency from 7 pm to 7 am everyday for 50 days. Group 2 exposed to noise and did not receive Vitamins. Group 3 received vitamin C, Group 4 received Vitamin E. Group 5 received Vitamins C and E concomitantly. After 50 days, serum Follicle-stimulating hormone (FSH), Luteinizing hormone (LH) and testosterone were calculated. Then each rat was left with three female rats for mating. Pregnant females were sacrificed on the 19 th day of pregnancy and evaluated for the presence and number of viable, dead and absorbed fetuses. The level of FSH, LH and testosterone significantly decreased in rats exposed to noise (P < 0.05). By administration of Vitamins in groups 3-5 we observed that the level of hormones significantly increased in compared to group 2 (P < 0.05). The fertilization capacity of male rats in groups 3-5 significantly increased in compared to group 2 (P < 0.05). There was significant difference between groups 1 and 2 in case of fertilization capacity (P = 0.001). The data in this study strongly suggests a negative role for noise stress on level of FSH, LH and testosterone level and also fertilization capacity of male rats. To complement the information it is suggested that this research be done on human samples. PMID- 23689304 TI - Musicians' ability to judge the risk of acquiring noise induced hearing loss. AB - The objective of this research was to study musicians' abilities to estimate the risk to obtain a hearing loss. Twenty-two professional musicians mainly playing classical music wore dosimeters during 2 working weeks. They also wrote a diary describing all their musical activities and tried to judge the percentage of time that every activity was harmful to their hearing. Half of the musicians seemed to be capable to reasonably judge the harmfulness of the music that they were exposed to. They started to judge the levels to be risky at 80 dB(A) and regarded themselves as slightly more susceptible to noise induced hearing loss than normal. PMID- 23689306 TI - Breakdown of immune homeostasis in the testis of mice lacking Tyro3, Axl and Mer receptor tyrosine kinases. AB - Tyro3, Axl and Mer (TAM) receptor tyrosine kinases triple knockout (TAM(-/-)) mice are male infertile due to impaired spermatogenesis. However, the mechanism by which TAM receptors regulate spermatogenesis remains unclear. In this study, we demonstrate that the testicular immune homeostasis was impaired in TAM(-/-) mice. As development after the onset of sexual maturity, germ cells were progressively degenerated. Macrophages and lymphocytes infiltrated into the testis as TAM(-/-) mice aged. Moreover, the integrity of blood-testis barrier was impaired, and the autoantibodies against germ cell antigens were produced. Major inflammatory cytokines, including tumor necrosis factor-alpha, interleukin-6 and monocyte chemotactic protein 1 were upregulated in the testis of TAM(-/-) mice, and predominantly located in Sertoli cells (SCs). In vitro assays showed that TAM(-/-) SCs secrete significantly high levels of inflammatory cytokines compared with wild-type SCs after coculture with apoptotic germ cells. These results suggest that TAM receptors are important in the maintenance of the immune homeostasis in the testis. PMID- 23689305 TI - Pathogenesis of allergen-induced eosinophilic esophagitis is independent of interleukin (IL)-13. AB - Several studies have shown that interleukin (IL)-13 is induced in the esophageal biopsies of eosinophilic esophagitis (EoE) patients and promotes esophageal eosinophilia in mice, following an IL-13 challenge. However, the role of IL-13 has not been clearly investigated in allergen-induced EoE. Accordingly, we tested the hypothesis that IL-13 is required in allergen-induced EoE. Mice deficient in IL-13, STAT (signal transducer and activator of transcription)6 and both IL-4/IL 13 genes with their respective controls were challenged with Aspergillus extract, and IL-5 gene deficient with their control were challenged with recombinant IL 13, intranasally. The lung and esophageal eosinophils, mast cells and collagen accumulation were examined. Herein, we report that intranasal delivery of IL-13 promotes IL-5-dependent esophageal eosinophilia. However, allergen-induced EoE is not impaired in the IL-13 gene-deficient mice. In addition, wild-type and IL-13 gene-deficient mice demonstrated a comparable level of mast cells and collagen accumulation in the esophagus, following allergen-induced experimental EoE. Similarly, we found that esophageal eosinophilia in IL-4/IL-13 double gene deficient and STAT6 gene-deficient mice were also not reduced following allergen induced experimental EoE. In contrast, lung eosinophilia was significantly reduced in mice deficient in IL-13, both IL-4/IL-13 and STAT6 genes following allergen challenge. In conclusion, our data establish that allergen-induced EoE pathogenesis is independent of IL-13, whereas IL-13 is required for allergen induced lung eosinophilia. PMID- 23689307 TI - Swiss analysis of multiple sclerosis: a multicenter, non-interventional, retrospective cohort study of disease-modifying therapies. AB - BACKGROUND: There is a scarcity of reports comparing efficacy and tolerability of the multiple sclerosis (MS) disease-modifying therapies [DMTs; intramuscular interferon-beta1a (IM IFNbeta-1a), subcutaneous (SC) IFNbeta-1a, SC IFNbeta-1b, SC glatiramer acetate (GA)] in a real-world setting. METHODS: This multicenter, non-interventional, retrospective cohort study analyzed data from 546 patients with clinically isolated or relapsing-remitting MS constantly treated with one DMT for 2 years. Annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) scores, and DMT tolerability were assessed. RESULTS: Demographic data were comparable across DMTs. There were no significant differences between DMT groups in ARR during study year 1 (p = 0.277) or study year 2 (p = 0.670), or in EDSS change between years 1 and 2 (p = 0.624). Adverse events were frequent (39-56%) in all groups. Flu-like symptoms were less frequent with GA treatment (2.3% vs. IM IFNbeta-1a, 46.7%; SC IFNbeta-1a, 39.8%; SC IFNbeta-1b, 25.8%; p < 0.05). Injection site reactions were less often reported with IM IFNbeta-1a (10.5% vs. SC IFNbeta-1a, 33.9%; SC IFNbeta-1b, 38.3%; GA, 26.1%; p < 0.05). CONCLUSIONS: All DMTs showed comparable effects on MS relapse rate and EDSS change, with IM IFNbeta-1a and GA being more tolerable with respect to injection site reactions and flu-like symptoms, respectively. PMID- 23689308 TI - Technical and clinical breast cancer screening performance indicators for computed radiography versus direct digital radiography. AB - OBJECTIVES: To compare technical and clinical screening performance parameters between computed radiography (CR) and direct digital radiography (DR) systems. METHODS: The number of women screened with CR was 73,008 and with DR 116,945. Technical and patient dose survey data of 25 CR and 37 DR systems were available. Technical performance was expressed by threshold thickness values at the mean glandular dose (MGD) level of routine practice. Clinical indicators included recall rate (RR), cancer detection rate (CDR), percentage of ductal carcinoma in situ (DCIS), percentage of cancers with T-scores smaller than 1 cm and positive predictive value (PPV). RESULTS: Contrast threshold values for the 0.1-mm gold disk were 1.44 MUm (SD 0.13 MUm) for CR and 1.20 MUm (SD 0.13 MUm for DR). MGD was 2.16 mGy (SD 0.36 mGy) and 1.35 mGy (SD 0.32 mGy) for CR and DR respectively. We obtained for CR, respectively DR, the following results: RR in the first round of 5.48 % versus 5.61 %; RR in subsequent rounds of 2.52 % versus 2.65 %; CDR of 0.52 % versus 0.53 %; DCIS of 0.08 % versus 0.11 %; a rate of cancers with T scores smaller than 1 cm of 0.11 % versus 0.11 %; PPV of 18.45 % versus 18.64 %; none of them was significantly different. CONCLUSION: Our screening indicators are reassuring for the use of CR and DR, with CR operating at 60 % higher MGD. KEY POINTS: * Breast cancer screening can employ both computed (CR) and direct digital radiography (DR). * Screening performance parameters for CR and DR technology are not significantly different. * Screening parameters are in accordance with European Guidelines. * Radiation doses employed for CR are generally 60 % greater than for DR. PMID- 23689310 TI - Relapse of scrotal calcinosis 7 years after primary excision. AB - Idiopathic scrotal calcinosis is a rare, benign condition characterized by progressive calcification of the scrotal skin. A 29-year-old man who had undergone primary surgical excision of idiopathic scrotal calcinosis 7 years previously presented with recurrence that he had first noticed 3 years after surgery. Multiple yellowish nodules were observed in the scrotal skin and were confirmed by computed tomography. He underwent repeat resection without any postoperative complications. Histological examination of the surgical specimens revealed diffusely calcified areas within and beneath the squamous epithelium, some of which were associated with epithelial cysts. Immunopathological stains for antibodies against carcinoembryonic antigen, epithelial membrane antigen, and gross cystic disease fluid protein-15 were negative. This is the first reported case of recurrence of scrotal calcinosis. One possible reason for the relapse is that there were remnant seeds of calcification after the primary surgery. This case demonstrates the importance of careful identification and resection of all calcified areas, and of counseling patients about the possibility of relapse after surgical treatment. PMID- 23689309 TI - Safety and effectiveness of percutaneous sacroplasty: a single-centre experience in 58 consecutive patients with tumours or osteoporotic insufficient fractures treated under fluoroscopic guidance. AB - OBJECTIVE: To report our experience in percutaneous sacroplasty (PSP) for tumours and insufficiency fractures of the sacrum. METHODS: Single-centre retrospective analysis of 58 consecutive patients who underwent 67 PSPs for intractable pain from sacral tumours (84.5 %) or from osteoporotic fractures (15.5 %). The following data were assessed: visual analogue scale (VAS) before and after the procedure for global pain; short-term (1-month) clinical follow-up using a four grade patient satisfaction scale (worse, unchanged, mild improvement and significant improvement); modification in analgesics consumption; referred short term walking mobility. Minor and major complications were systematically assessed. RESULTS: The mean VAS score was 5.3 +/- 2.0 in pre-procedure and 1.7 +/ 1.8 in post-procedure. At 1-month follow-up, 34/58 (58.5 %) patients experienced a mild improvement; 15/58 (26 %) presented a significant improvement while 4/58 (7 %) and 5/58 (8.5 %) patients had unchanged or worse pain, respectively. Decreased analgesic consumption was observed in 34 % (20/58) of the patients. Eighty percent of patients with walking limitation experienced improvement, 16 % remained unchanged and 4 % were worse. We noted minor complications in 2/58 patients (3.4 %) and major complications in 2/58 patients (3.4 %). CONCLUSION: Percutaneous sacroplasty for metastatic and osteoporotic fractures is a safe and effective technique in terms of pain relief and functional outcome. KEY POINTS: * Percutaneous sacroplasty provides pain relief and functional improvement for insufficiency sacral fractures. * Percutaneous sacroplasty provides pain relief and function improvement for sacral tumours. * The major complication rate is acceptable (3.4 %), and is higher in sacral tumours. * Posterior wall/cortical sacral bone disruption is not statistically associated with more complications. * However, osteolytic tumours seem to be associated with higher risk of complications. PMID- 23689311 TI - The photoinduced transformation of fluorescent DNA base analogue tC triggers DNA melting. AB - While fluorescent analogues of the canonical nucleobases have proven to be highly valuable in a large number of applications, up until today, fluorescent DNA base analogues remain virtually inapplicable for single-molecule fluorescence experiments which require extremely bright and photostable dyes. Insight into the photodegradation processes of these fluorophores is thus a key step in the continuous development towards dyes with improved performances. Here, we show that the commercially available fluorescent nucleobase analogue tC under intense long-term illumination and in the presence of O2 is degraded to form a single photoreaction product which we suggest to be the sulfoxide form of tC. The photoproduct is characterized by a blue-shifted absorption and a less intense fluorescence compared to that of tC. Interestingly, when tC is positioned inside double-stranded DNA this photodriven conversion of tC to its photoproduct greatly reduces the duplex stability of the overall double helix in which the probe is positioned. Since tC can be excited selectively at 400 nm, well outside the absorption band of the natural DNA bases, this observation points towards the application of tC as a general light-triggered switch of DNA duplex stability. PMID- 23689312 TI - The development of lateralization abilities in children with bilateral cochlear implants. AB - OBJECTIVES: The purpose of this study was to investigate the development of lateralization skills in children who received bilateral cochlear implants (CIs) in sequential operations. METHODS: The lateralization skills of 9 children with a mean age of 4.1 years at the first surgery and 5.5 years at the second surgery were assessed at 3 time intervals. Children were assessed with a 3-loudspeaker setup (front, left and right) at 0.9 years (interval I) and 1.6 years (interval II) after the second implantation, and after 5.3 years of bilateral implant use (interval III) with a 9-loudspeaker setup in the frontal horizontal plane between -90 degrees and 90 degrees azimuth. RESULTS: With bilateral implants, a significant decrease in lateralization error was noted between test interval I (45.0 degrees ) and II (23.3 degrees ), with a subsequent significant decrease at test interval III (4.7 degrees ). Unilateral performance with the CI did not improve significantly between the first 2 intervals; however, there was a bias of responses towards the unilateral side by test interval III. CONCLUSIONS: The lateralization abilities of children with bilateral CIs develop in a relatively short period of time (1-2 years) after the second implant. Children appear to be able to acquire binaural skills after bilateral cochlear implantation. PMID- 23689313 TI - Perinatal infections and neurodevelopmental outcome in very preterm and very low birth-weight infants: a meta-analysis. AB - IMPORTANCE: Perinatal infections are commonly present in preterm and very low birth-weight (VLWB) infants and might contribute to adverse neurodevelopmental outcome. OBJECTIVE: To summarize studies evaluating the effect of perinatal infections on neurodevelopmental outcome in very preterm/VLBW infants. EVIDENCE REVIEW: On December 12, 2011, we searched Medline, PsycINFO, Embase, and Web of Knowledge for studies on infections and neurodevelopmental outcome. All titles and abstracts were assessed for eligibility by 2 independent reviewers. We also screened the reference lists of identified articles to search for additional eligible studies. Preselected criteria justified inclusion in this meta-analysis: (1) the study included infants born very preterm (<=32 weeks) and/or with VLBW (<=1500 g); (2) the study compared infants with and without perinatal infection; (3) there was follow-up using the Bayley Scales of Infant Development 2nd edition; and (4) results were published in an English-language peer-reviewed journal. The quality of each included study was assessed using the Newcastle Ottawa Scale. FINDINGS: This meta-analysis includes 18 studies encompassing data on 13.755 very preterm/VLBW infants. Very preterm/VLBW infants with perinatal infections had poorer mental (d = -0.25; P < .001) and motor (d = -0.37; P < .001) development compared with very preterm/VLBW infants without infections. Mental development was most impaired by necrotizing enterocolitis (d = -0.40; P < .001) and meningitis (d = -0.37; P < .001). Motor development was most impaired by necrotizing enterocolitis (d = -0.66; P < .001). Chorioamnionitis did not affect mental (d = -0.05; P = .37) or motor (d = 0.19; P = .08) development. CONCLUSIONS AND RELEVANCE: Postnatal infections have detrimental effects on mental and motor development in very preterm/VLBW infants. PMID- 23689314 TI - Benign paroxysmal positional vertigo in the elderly. AB - BACKGROUND: Benign paroxysmal positional vertigo (BPPV) is the most frequent peripheral vertigo in the elderly. It is a well-characterized entity and generally easy to treat. OBJECTIVE: To evaluate the main symptoms, time to consult for the problem, vertigo characteristics, treatment and follow-up in patients over 70 with BPPV. METHODS: This was a retrospective cohort study. Four hundred and four patients were diagnosed to have BPPV (between January 2006 and December 2012); 211 of them were >=70 years old (mean 77.7 years) and 193 <70 years old (mean 53.82 years). RESULTS: Patients over 70 with BPPV took longer to consult for the problem (Spearman rho, p = 0.01). The frequency of a clinical presentation consisting of unsteadiness or imbalance without vertigo sensation is higher among elderly patients (chi(2), p = 10(-6)). The effectiveness of the repositioning maneuver is lower than in patients under 70 (chi(2), p = 0.002), and the recurrences are more frequent (chi(2), p = 0.04). CONCLUSION: BPPV is a frequent entity in the elderly, and it is necessary to take it into account when older patients complain about imbalance. An appropriate treatment with repositioning maneuvers and prolonged follow-up are required in order to detect recurrences. PMID- 23689315 TI - Techniques of DNA methylation analysis with nutritional applications. AB - Epigenetic mechanisms are likely to play an important role in the regulation of metabolism and body weight through gene-nutrient interactions. This review focuses on methods for analyzing one of the most important epigenetic mechanisms, DNA methylation, from single nucleotide to global measurement depending on the study goal and scope. In addition, this study highlights the major principles and methods for DNA methylation analysis with emphasis on nutritional applications. Recent developments concerning epigenetic technologies are showing promising results of DNA methylation levels at a single-base resolution and provide the ability to differentiate between 5-methylcytosine and other nucleotide modifications such as 5-hydroxymethylcytosine. A large number of methods can be used for the analysis of DNA methylation such as pyrosequencingTM, primer extension or real-time PCR methods, and genome-wide DNA methylation profile from microarray or sequencing-based methods. Researchers should conduct a preliminary analysis focused on the type of validation and information provided by each technique in order to select the best method fitting for their nutritional research interests. PMID- 23689316 TI - (C^C*) Cyclometalated binuclear N-heterocyclic biscarbene platinum(II) complexes- highly emissive phosphorescent emitters. AB - A series of bimetallic N-heterocyclic carbene (NHC) platinum(II) complexes with the general formula [Pt(NHC)(L)]2Ph were synthesized, which are composed of two [Pt(NHC)(L)] (L = acetylacetone, dipivaloylmethane or dimesitoylmethane; NHC = 3 methylimidazole or 3-benzylimidazole) fragments. Both fragments are cyclometalated to the same central phenyl ring in the para- or meta-position. All complexes have been fully characterized by standard techniques, two of them additionally by solid-state structures. Photoluminescence properties were investigated and very high quantum yields of 76-93% at room temperature have been observed. For a single-matrix device with an emitter concentration of 30%, a current efficiency of 25 cd A(-1), an external quantum efficiency of 8.5%, and a luminance efficiency of 10 lm W(-1) were achieved at 300 cd m(-2). Density functional theory (DFT) calculations were performed to support experimental data and gain further insight into the photoluminescence behaviour. PMID- 23689317 TI - The calcineurin inhibitor cyclosporine A improves lipopolysaccharide-induced vascular dysfunction but does not rescue from cardiovascular collapse in endotoxemic mice. AB - The calcineurin inhibitor cyclosporine A (CsA) improves survival in endotoxemic mice. It was hypothesized that CsA counteracts the bradycardia and hypotension characteristic of endotoxemia. Vascular reactivity was determined in lipopolysaccharide (LPS; 50 MUg/mL)-treated mouse aortic rings suspended in a myograph. Arterial blood pressure and heart rate were measured continuously with indwelling catheters in conscious mice treated with CsA and a bolus injection of LPS (2 mg/kg). The alpha1-adrenoceptor agonist phenylephrine induced stable tension of aortic rings that were attenuated significantly by LPS. Co-incubation of rings with LPS and CsA (1 * 10(-7) mol/L-1 * 10(-5) mol/L) restored vascular reactivity to phenylephrine. Intravenous administration of CsA (20 and 40 mg/kg/day) to mice induced a significant increase (by approximately 10 mmHg) in mean arterial blood pressure (MAP), with no effect on heart rate. An LPS bolus led to significant decreases in MAP (by approximately 30 mmHg) and heart rate (to 50 % of baseline). CsA-treated LPS-mice exhibited higher MAP at some (20 mg/kg) or all (40 mg/kg) time points after LPS. The decrease in MAP (Delta pressure) was similar between vehicle- and CsA-treated groups. The 50 % decrease in heart rate was not affected by CsA. Inducible nitric oxide synthase (iNOS) mRNA and protein levels in LPS-treated mice organs and plasma NO x concentration were significantly reduced by CsA. It is concluded that in a murine model of endotoxemia, increased peripheral vascular resistance and suppression of systemic NO formation by cyclosporine A are not sufficient to prevent cardiovascular collapse, which is caused primarily by compromised cardiac function. PMID- 23689318 TI - Hospitalization and mortality in hemodialysis patients: association with hemoglobin variability. AB - BACKGROUND/AIMS: Hemodialysis patients show complications associated with low or high hemoglobin (Hb), which occur frequently in clinical practice. We sought to determine the clinical importance of these changes in Hb levels. METHODS: From our clinic cohorts, we identified 1,634 who met inclusion criteria for analysis of hospitalization frequency and 1,953 analysis of mortality; many patients were in both groups. Hb excursions outside the target range (11-12.5 g/dl) were studied in relation to patient outcomes. RESULTS: Hb measures below range were associated with more frequent hospitalization (p < 0.001), increased length of stay (p < 0.001), and increased mortality (p < 0.01), whereas Hb above range was associated with a reduced frequency of hospitalization (p < 0.01) and shorter length of stay (p < 0.01), and tended to be associated with reduced mortality. CONCLUSIONS: Excursions below range were associated with negative outcomes, but excursions above range were either beneficial or neutral. Our findings indicate that clinicians should focus on low Hb as a negative indicator of patient status, whereas transient Hb above range is a marker for patient health and well-being. PMID- 23689337 TI - Double-edged sword? PMID- 23689338 TI - The acute effect of a plyometric stimulus on jump performance in professional rugby players. AB - Post-activation potentiation (PAP) is the elevation of motor performance to a higher level in response to a conditioning stimulus. Extensive research exists examining the PAP effect after a heavy resistance exercise. However, there is limited research examining the PAP effect after a plyometric stimulus. This study was designed to examine whether a plyometric stimulus could produce a PAP effect comparable to that typically reported with a heavy resistance protocol. Importantly, it was hypothesized that the PAP effect would exist without the same levels of acute fatigue resulting from a heavy stimulus, thus allowing improvement in performance within a short rest interval range. Twenty professional rugby players were recruited for the study. Subjects performed 2 countermovement jumps (CMJs) at baseline and at 1, 3, and 5 minutes after a plyometric stimulus consisting of 40 jumps. Two separate 1-way repeated-measures analyses of variance were conducted to compare the dependent variables CMJ height and peak force at the 4 time points. Results of the Bonferroni adjusted pairwise comparisons indicated that jump height and peak force before plyometric exercises were significantly lower than all other time points (p < 0.01). The main finding of this study indicates that a series of plyometric exercises causes a significant acute enhancement in CMJ height (p < 0.01) and peak force (p < 0.01) throughout the rest interval range of 1-5 minutes. The plyometric series induced an improvement in CMJ height comparable to that reported elsewhere after a heavy lifting stimulus but without the need for a prolonged rest interval. Performing repeated series of plyometric jumps appears to be an efficient method of taking advantage of the PAP phenomenon, thus possibly eliminating the need for a complex training protocol. PMID- 23689339 TI - The concurrent validity and reliability of a low-cost, high-speed camera-based method for measuring the flight time of vertical jumps. AB - Flight time is the most accurate and frequently used variable when assessing the height of vertical jumps. The purpose of this study was to analyze the validity and reliability of an alternative method (i.e., the HSC-Kinovea method) for measuring the flight time and height of vertical jumping using a low-cost high speed Casio Exilim FH-25 camera (HSC). To this end, 25 subjects performed a total of 125 vertical jumps on an infrared (IR) platform while simultaneously being recorded with a HSC at 240 fps. Subsequently, 2 observers with no experience in video analysis analyzed the 125 videos independently using the open-license Kinovea 0.8.15 software. The flight times obtained were then converted into vertical jump heights, and the intraclass correlation coefficient (ICC), Bland Altman plot, and Pearson correlation coefficient were calculated for those variables. The results showed a perfect correlation agreement (ICC = 1, p < 0.0001) between both observers' measurements of flight time and jump height and a highly reliable agreement (ICC = 0.997, p < 0.0001) between the observers' measurements of flight time and jump height using the HSC-Kinovea method and those obtained using the IR system, thus explaining 99.5% (p < 0.0001) of the differences (shared variance) obtained using the IR platform. As a result, besides requiring no previous experience in the use of this technology, the HSC Kinovea method can be considered to provide similarly valid and reliable measurements of flight time and vertical jump height as more expensive equipment (i.e., IR). As such, coaches from many sports could use the HSC-Kinovea method to measure the flight time and height of their athlete's vertical jumps. PMID- 23689340 TI - The acute effects of conventional, complex, and contrast protocols on lower-body power. AB - This study compared conventional, complex, and contrast protocols on peak power (PP) output. Static vs. dynamic contractions were also manipulated to determine the effect of these confounding variables. Eighteen recreationally trained men [age, 21.1 +/- 3.3 years; body mass, 81.7 +/- 15.9 kg; height, 182.8 +/- 6.2 cm; 5 repetition maximum (5RM) half back squat, 119.2 +/- 25.4 kg; 5RM/BW, 1.5 +/- 0.2 kg] involved in sports including Australian Rules football, basketball, soccer, and rugby participated in this investigation. Five protocols were executed in a randomized order, a conventional protocol in which 3 sets of 4 countermovement jumps (CMJs) were performed 2 minutes apart. Contrast protocols using a heavy resistance conditioning action of either 4 repetitions with a 5RM load or a 5-second static back squat were alternated with sets of 4 CMJs. Complex conditions with 3 sets of 4 repetitions of a 5RM back squat or a 5-second static back squat were performed before the 3 sets of CMJs. In all conditions, 4 minutes of rest followed sets of heavy resistance exercises and 2 minutes of rest followed each set of CMJs. Individual set means and a total session mean were calculated from each CMJ performed during the session. Results showed that the conventional protocol produced significantly greater PP than all conditions except for the dynamic complex and the static contrast. Results suggest that the use of the complex and contrast protocols used in this investigation should not be used for acute increases in lower-body PP in recreationally trained individuals. PMID- 23689341 TI - Kinetic comparison of the power development between power clean variations. AB - The purpose of this study was to compare the power production of the hang clean (HC), jump shrug (JS), and high pull (HP) when performed at different relative loads. Seventeen men with previous HC training experience, performed 3 repetitions each of the HC, JS, and HP at relative loads of 30, 45, 65, and 80% of their 1 repetition maximum (1RM) HC on a force platform over 3 different testing sessions. Peak power output (PPO), peak force (PF), and peak velocity (PV) of the lifter plus bar system during each repetition were compared. The JS produced a greater PPO, PF, and PV than both the HC (p < 0.001) and HP (p < 0.001). The HP also produced a greater PPO (p < 0.01) and PV (p < 0.001) than the HC. Peak power output, PF, and PV occurred at 45, 65, and 30% 1RM, respectively. Peak power output at 45% 1RM was greater than PPO at 65% (p = 0.043) and 80% 1RM (p = 0.004). Peak force at 30% was less than PF at 45% (p = 0.006), 65% (p < 0.001), and 80% 1RM (p = 0.003). Peak velocity at 30 and 45% was greater than PV at 65% (p < 0.001) and 80% 1RM (p < 0.001). Peak velocity at 65% 1RM was also greater than PV at 80% 1RM (p < 0.001). When designing resistance training programs, practitioners should consider implementing the JS and HP. To optimize PPO, loads of approximately 30 and 45% 1RM HC are recommended for the JS and HP, respectively. PMID- 23689343 TI - The effect of pelvic position on popliteal angle achieved during 90:90 hamstring length test. AB - CONTEXT: Hamstring muscle length is commonly measured because of its perceived relationship to injury of both the hamstrings themselves and the pelvis and lumbar spine. The popliteal (knee-extension) angle measured from the starting position hip and knee at 90 degrees is a commonly used indirect measure of hamstring muscle length. When this measure has been undertaken in the literature previously, little attention was paid to the position of the pelvis, which may significantly influence measurements taken. DESIGN: Repeated-measures. SETTING: University human performance laboratory. PARTICIPANTS: 60 healthy physically active males (mean age 20.1 +/- 1.8 y, range 18-24 y). INTERVENTION: The 2 extremes of pelvic position (anterior and posterior). MAIN OUTCOME MEASURE: Popliteal angle (with maximal knee extension) was measured in 2 positions, 1 of full anterior and 1 of full posterior pelvic tilt. RESULTS: The mean difference in popliteal angle between anterior to posterior pelvic positions was 13.4 degrees +/- 9 degrees (range 0-26 degrees ); this was statistically significant (P = .0001). CONCLUSION: The findings of the study indicate that pelvic position has a significant effect on popliteal angle and therefore should be taken into account when measuring hamstring muscle length. PMID- 23689345 TI - Ureteral endometriosis: proposal for a diagnostic and therapeutic algorithm with a review of the literature. AB - INTRODUCTION: The ureteral involvement in deep pelvic endometriosis in usually asymptomatic and might lead to a silent loss of renal function. As a matter of fact, the diagnosis and the treatment modalities are still a matter of debate. MATERIALS AND METHODS: We performed a literature review by searching the MEDLINE database for articles published in English between 1996 and 2010, using the key words urinary tract endometriosis, ureteral endometriosis, diagnosis and treatment. We found more than 200 cases of ureteral endometriosis (UE). RESULTS: The disease most commonly affects a single distal segment of the ureter, with a left predisposition in most of the patients. Two major pathological types of UE may be distinguished: intrinsic and extrinsic. The symptoms are usually nonspecific and owing to secondary obstruction. The diagnosis has to be considered as a step- by-step procedure, starting from physical examination to highly detailed imaging methods. Nowadays, the treatment is usually chosen according to the type of UE, the site lesion and the distance to the ureteral orifice, with the use of JJ stents remaining a matter of debate. CONCLUSIONS: A close collaboration between the gynecologist and the urologist is advisable, especially in referral centers. Surgical treatment can lead to good results in terms of both patient compliance and prognosis. PMID- 23689346 TI - The influence of growth hormone/insulin-like growth factor deficiency on prostatic dysplasia in pbARR2-Cre, PTEN knockout mice. AB - BACKGROUND: Elevated insulin-like growth factor-I (IGF-I) serum levels and phosphatase and tensin homolog (PTEN) loss are prostate cancer (PCa) risk factors that enhance androgen-responsive and castration-resistant PCa xenografts growth. METHODS: The impact of suppressed growth hormone (GH)/IGF-I levels on neoplastic initiation of PTEN-deficient prostate epithelia was assessed histologically and by epithelial-to-mesenchymal marker expression in Ghrhr D60G homozygous (lit/lit) and heterozygous (lit/+) pbARR2-Cre, PTEN(fl/fl) (PTEN-/-) mice. How suppressed GH/IGF-I levels impacted growth of PTEN-/- mouse-derived prostate cells (MPPK) was examined by growth and survival signaling of cells cultured in lit/+ or lit/lit serum. RESULTS: Body weight, prostate weight and serum GH and IGF-I levels were reduced in lit/lit relative to lit/+ PTEN-/- littermates. While the anterior lobes of lit/+ PTEN-/- prostates consistently presented swollen, indicative of ductal blockage, the degree of prostatic dysplasia in 15- and 20 week-old lit/lit and lit/+ PTEN-/- mice was indistinguishable as measured by normalized prostatic weight, tissue histology, or probasin, PSP94, E-cadherin, N cadherin and vimentin expression. However, growth and AKT activation of MPPK cells was decreased when cultured in lit/lit serum as compared with lit/+ serum and restored in lit/lit serum supplemented with IGF-I and, to a lesser extent, GH. CONCLUSIONS: These results suggest that initiation of prostate carcinogenesis by loss of PTEN is not influenced by germline variation of genes encoding signaling molecules in the GH/IGF-I axis, but suggests that these factors may affect the progression of dysplastic phenotype and supports previous studies, indicating that the GH/IGF milieu does impact the growth of PTEN-deficient dysplastic prostatic cells once transformed. PMID- 23689347 TI - Determination of trans fat in edible oils: current official methods and overview of recent developments. AB - The adverse effects of dietary trans fat on biomarkers of chronic disease are well documented. Regulatory authorities in many countries have enacted legislation aimed at reducing trans fat content of their food supplies, either by requiring trans fat labeling on pre-packaged foods or by limiting the amount of trans fat in oils used for food production. Increased use by the food industry of oils with a low trans fat content necessitates reevaluation of official methods used by the food industry and regulatory agencies for the determination of total trans fat. Attenuated total reflection-Fourier-transform infrared (ATR-FTIR) spectroscopy and gas chromatography with flame ionization detection (GC-FID) are two techniques used in official methods approved by method-endorsing organizations, for example AOAC International and the American Oil Chemists' Society. Here, we review current official ATR-FTIR and GC-FID methods for determination of trans fat, with a focus on factors affecting quantification of low levels of trans fat. We include new data on method performance that have only recently become available, and provide an overview of notable recent developments in lipid analysis (e.g. IR spectroscopy procedures, ionic-liquid GC columns, and multidimensional chromatographic techniques) that have the potential to substantially improve the accuracy, sensitivity, and/or speed of trans fat determination. PMID- 23689348 TI - Application of normal-phase high-performance liquid chromatography followed by gas chromatography for analytics of diesel fuel additives. AB - The paper presents the results of investigations on new procedures of determination of selected cleaning additives in diesel fuel. Two procedures: one step analysis using gas chromatography with flame ionization detection (GC-FID) or mass spectrometry (GC-MS) and a two-step procedure in which normal-phase high performance liquid chromatography (NP-HPLC) was used for preliminary separation of the additives, were compared. The additive fraction was collected using either simple elution or eluent backflush. Final determinations were performed by GC-FID and GC-MS. The studies revealed that it was impossible to determine the investigated analytes by one-step procedures, i.e. by using solely HPLC or GC. On the other hand, the use of a two-step procedure ensures reproducible results of determinations, and the limits of quantitation are, depending on the method of fraction collection by HPLC, from 1.4-2.2 ppm (GC-MS in SIM mode) to 9.6-24.0 ppm (GC-FID). Precision and accuracy of the developed procedures are compared, and possible determination errors and shortcomings discussed. PMID- 23689349 TI - Slothful gelation of a dipolar building block by "top-down" morphology transition from microparticles to nanofibres. AB - An amide-functionalized dipolar building block showed spontaneous self-assembly to micro-particles predominately by H-bonding. Possibly due to inefficient dipolar interaction, it gradually adopted an alternate mode of assembly by anti parallel dimerization and H-bonding in orthogonal directions leading to a strikingly different nano-fibrillar morphology resulting in unusually slow gelation after 80 h. PMID- 23689350 TI - Objective measurement of tissue tension in myofascial trigger point areas before and during the administration of anesthesia with complete blocking of neuromuscular transmission. AB - OBJECTIVES: Myofascial trigger points (MTPs) are extremely frequent in the human musculoskeletal system. Despite this, little is known about their etiology. Increased muscular tension in the trigger point area could be a major factor for the development of MTPs. To investigate the impact of muscular tension in the taut band with an MTP and thereby, the spinal excitability of associated segmental neurons, we objectively measured the tissue tension in MTPs before and during the administration of anesthesia using a transducer. METHODS: Three target muscles (m. temporalis, upper part of m. trapezius, and m. extensor carpi radialis longus) with an MTP and 1 control muscle without an MTP were examined in 62 patients scheduled for an operation. RESULTS: We found significant 2-way interactions (ANOVA, P<0.05) between the analyzed regions of the target muscles dependent on the time of measurement, that is, before and during a complete blocking of neuromuscular transmission. These effects could be demonstrated for each target muscle separately. DISCUSSION: An increased muscle tension in MTPs, and not a primary local inflammation with enhanced viscoelasticity, was the main result of our investigation. We interpret this increased muscular tension in the taut band with an MTP as increased spinal segmental excitability. In line with this, we assume a predominant, but not unique, impact of increased spinal excitability resulting in an augmented tension of segmental-associated muscle fibers for the etiology of MTP. Consequently, postisometric relaxation might be a promising therapeutic option for MTPs. PMID- 23689351 TI - Ecological momentary assessment of smoking behavior in persistent pain patients. AB - OBJECTIVES: Smoking is associated with chronic pain and pain-related functional impairment. Some studies suggest that pain activates smoking urges and others suggest that smoking is analgesic. We evaluated these associations using ecological momentary assessment, a method for real-time measurement of health related phenomena. METHODS: For 1 week, 36 chronic pain patients who smoked a mean of 17.5 (SD=9.4) cigarettes per day completed multiple daily assessments on a handheld computer. RESULTS: The sample included 67% women and 39% whites; 67% had back pain, with an average (SD) worst pain severity during the past week of 8.6 (1.5) on a 0 to 10 numeric rating scale. Patients completed an average (SD) of 44 (24) random assessments. At each assessment, the patient recorded pain "right now" on a 0 to 10 scale, whether he/she was "about to smoke," and if he/she had "just smoked in the past 30 minutes," pain before smoking. After controlling for other significant correlates of pain, patients who were about to smoke had more pain than at other times (M [SD]=6.5 [2.3] vs. 5.2 [2.4]; P<0.01), but pain before and after smoking was not different (M [SD]=6.1 [2.2] vs. 5.9 [2.3]; P=0.18). DISCUSSION: These findings support the hypothesis that smoking behavior is triggered by pain, but smoking is not analgesic. Future studies should clarify potential explanatory mechanisms for this pain-related trigger and evaluate tailored cessation strategies for pain patients. PMID- 23689352 TI - The antipsychotic agent chlorpromazine induces autophagic cell death by inhibiting the Akt/mTOR pathway in human U-87MG glioma cells. AB - 2-Chloro-10-[3(-dimethylamino)propyl]phenothiazine mono hydrochloride (chlorpromazine; CPZ) is an antipsychotic agent that was originally developed to control psychotic disorders. The cytotoxic properties of the CPZ are well known, but its mechanism of action is poorly understood. In this study, we investigated the role of apoptosis and autophagy in CPZ-induced cytotoxicity in U-87MG glioma cells. CPZ treatment inhibited cell proliferation and long-term clonogenic survival. Additionally, CPZ triggered autophagy, as indicated by electron microscopy and accumulation of the membrane form of microtubule-associated protein 1 light chain 3 (LC3-II); however, CPZ did not induce apoptosis. Inhibition of autophagy by expression of Beclin 1 small interfering RNA (siRNA) in U-87MG cells attenuated CPZ-induced LC3-II formation. Furthermore, U-87MG cells expressing Beclin 1 siRNA attenuated CPZ-induced cell death. CPZ inhibited phosphatidylinositol 3-kinase (PI3K)/AKT/ mTOR pathway in U-87MG cells. Treatment with LY294002, a PI3K inhibitor, alone increased the accumulation of LC3-II and potentiated the effect of CPZ. In contrast, exogenous expression of AKT partially inhibited CPZ-induced LC3-II formation. When U-87MG cells were implanted into the brain of athymic nude mouse, CPZ triggered autophagy and inhibited xenograft tumor growth. These results provided the first evidence that CPZ-induced cytotoxicity is mediated through autophagic cell death in PTEN (phosphatase and tensin homolog deleted on chromosome 10)-null U-87MG glioma cells by inhibiting PI3K/AKT/mTOR pathway. PMID- 23689353 TI - Aneuploidy facilitates oncogenic transformation via specific genetic alterations, including Twist2 upregulation. AB - Aneuploidy, deviation from the normal chromosome number, and other chromosomal aberrations are commonly observed in cancer. Integrin-mediated adhesion and dynamic turnover of adhesion sites are required for successful cytokinesis of normal adherent cells and impaired cell division can lead to the generation of cells with abnormal chromosome contents. We find that repeated cytokinesis failure, due to impaired integrin traffic alone, is sufficient to induce chromosome aberrations resulting in the generation of aneuploid cells with malignant properties. Here, we have compared isogenic aneuploid and euploid cell lines with unravel aneuploidy-induced changes in cellular signaling. Euploid, non transformed, and aneuploid, transformed, cell lines were investigated using genome-wide gene expression profiling, analysis of deregulated biological pathways and array-comparative genomic hybridization. We find that aneuploidy drives malignancy via inducing marked changes in gene and micro RNA expression profiles and thus imposing specific growth and survival promoting alterations in cellular signaling. Importantly, we identify Twist2 as a key regulator of survival, invasion and anchorage-independent growth in the aneuploid cells. In addition, alterations in lipid biosynthetic pathways and miR-10b upregulation are likely contributors to the malignant phenotype. PMID- 23689354 TI - Sulindac inhibits pancreatic carcinogenesis in LSL-KrasG12D-LSL-Trp53R172H-Pdx-1 Cre mice via suppressing aldo-keto reductase family 1B10 (AKR1B10). AB - Sulindac has been identified as a competitive inhibitor of aldo-keto reductase 1B10 (AKR1B10), an enzyme that plays a key role in carcinogenesis. AKR1B10 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and exhibits lipid substrate specificity, especially for farnesyl and geranylgeranyl. There have been no studies though showing that the inhibition of PDAC by sulindac is via inhibition of AKR1B10, particularly the metabolism of farnesyl/geranylgeranyl and Kras protein prenylation. To determine the chemopreventive effects of sulindac on pancreatic carcinogenesis, 5-week-old LSL-Kras(G12D)-LSL-Trp53(R172H)-Pdx-1-Cre mice (Pan(kras/p53) mice) were fed an AIN93M diet with or without 200 p.p.m. sulindac (n = 20/group). Kaplan-Meier survival analysis showed that average animal survival in Pan(kras/p53) mice was 143.7 +/- 8.8 days, and average survival with sulindac was increased to 168.0 +/- 8.8 days (P < 0.005). Histopathological analyses revealed that 90% of mice developed PDAC, 10% with metastasis to the liver and lymph nodes. With sulindac, the incidence of PDAC was reduced to 56% (P < 0.01) and only one mouse had lymph node metastasis. Immunochemical analysis showed that sulindac significantly decreased Ki-67 labeled cell proliferation and markedly reduced the expression of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Raf and mitogen activated protein kinase kinase 1 and 2. In in vitro experiments with PDAC cells from Pan(kras/p53) mice, sulindac exhibited dose-dependent inhibition of AKR1B10 activity. By silencing AKR1B10 expression through small interfering RNA or by sulindac treatment, these in vitro models showed a reduction in Kras and human DNA-J homolog 2 protein prenylation, and downregulation of phosphorylated C-raf, ERK1/2 and MEK1/2 expression. Our results demonstrate that sulindac inhibits pancreatic carcinogenesis by the inhibition of Kras protein prenylation by targeting AKR1B10. PMID- 23689356 TI - Response to 'Area-level deprivation and adiposity in children: is the relationship linear?'. PMID- 23689355 TI - Obesity development in caspase-1-deficient mice. AB - Caspase-1 is a member of the intracellular cysteine protease family that mediates inflammation through the activation of the cytokines interleukin-1beta (IL-1beta) and interleukin-18 (IL-18). As mice lacking IL-18 become obese and insulin resistant, and both IL-18 and IL-1beta have a role in overall energy balance, we sought to determine whether caspase-1 deficiency also causes obesity. Male and female caspase-1-deficient (caspase-1-/-) and control (wild-type (WT)) mice were fed either a high-fat (HF, 45% of kcal) or a low-fat (LF, 10% of kcal) synthetic diet starting at 6 weeks of age. Caspase-1-/- mice maintained lower but detectable levels of IL-18 compared with WT mice. Plasma IL-1beta levels were below the detection limit for both KO and WT mice. Male caspase-1-/- mice gained extra fat mass by 16 weeks on the HF diet, but not until 40 weeks on the LF diet. Female capase-1-/- mice gained more fat by 28 weeks but only on the HF diet. These data indicate that caspase-1-/- mice develop obesity with an age and sex dependent differences, and only male mice display obesity on LF diet. Overall, this study suggests that the lower level of IL-18 in caspase-1-/- mice might be causing obesity development similarly to IL-18-deficient mice. PMID- 23689357 TI - Reply to 'Area-level deprivation and adiposity in children: is the relationship linear?'. PMID- 23689358 TI - Noninvasive identification and assessment of functional brown adipose tissue in rodents using hyperpolarized 13C imaging. AB - OBJECTIVE: The recent identification of functional depots of brown adipose tissue (BAT) in adult humans has potential implications for the treatment of obesity. In order to evaluate new therapies aimed at inducing the production of more BAT or activating BAT in humans, it will be important to develop noninvasive methods to assess the functional state of the tissue in vivo. In this study, we investigate the feasibility of using hyperpolarized (13)C imaging to noninvasively identify functional, activated BAT in an in vivo rodent model, in less than 1 min, following an infusion of pre-polarized [1-(13)C] pyruvate. DESIGN: Hyperpolarized (13)C imaging was used to monitor BAT metabolic conversion of pre-polarized [1 (13)C] pyruvate in rats during baseline and norepinephrine (NE)-stimulated conditions. RESULTS: Activated BAT, stimulated by NE injection, can be detected in rats by increased conversion of pre-polarized [1-(13)C] pyruvate into its downstream products (13)C bicarbonate and [1-(13)C] lactate. The colocalization of the (13)C signal to interscapular BAT was validated using hematoxylin-eosin histological staining. CONCLUSION: The radiation-free nature and recent translation into the clinic of the hyperpolarized (13)C-imaging test may potentially facilitate trials of therapeutics targeting BAT activation in humans. PMID- 23689360 TI - Impairment in natural killer cells editing of immature dendritic cells by infection with a virulent Trypanosoma cruzi population. AB - Early interactions between natural killer (NK) and dendritic cells (DC) shape the immune response at the frontier of innate and adaptive immunity. Activated NK cells participate in maturation or deletion of DCs that remain immature. We previously demonstrated that infection with a high virulence (HV) population of the protozoan parasite Trypanosoma cruzi downmodulates DC maturation and T-cell activation capacity. Here, we evaluated the role of NK cells in regulating the maturation level of DCs. Shortly after infection with HV T. cruzi, DCs in poor maturation status begin to accumulate in mouse spleen. Although infection induces NK cell cytotoxicity and cytokine production, NK cells from mice infected with HV T. cruzi exhibit reduced ability to lyse and fail to induce maturation of bone marrow-derived immature DCs (iDCs). NK-mediated lysis of iDCs is restored by in vitro blockade of the IL-10 receptor during NK-DC interaction or when NK cells are obtained from T. cruzi-infected IL-10 knockout mice. These results suggest that infection with a virulent T. cruzi strain alters NK cell-mediated regulation of the adaptive immune response induced by DCs. This regulatory circuit where IL 10 appears to participate might lead to parasite persistence but can also limit the induction of a vigorous tissue-damaging T-cell response. PMID- 23689359 TI - Chronic carbon monoxide treatment attenuates development of obesity and remodels adipocytes in mice fed a high-fat diet. AB - OBJECTIVE: Induction of heme oxygenase-1 (HO-1) has been demonstrated to result in chronic weight loss in several rodent models of obesity. However, the specific contribution of the HO metabolite, carbon monoxide (CO) to this response remains unknown. In this study, we determined the effect of chronic low level administration of a specific CO donor on the progression of obesity and its effects on metabolism and adipocyte biology in mice fed a high-fat diet. DESIGN: Experiments were performed on C57BL/6J mice fed a high-fat diet (60%) from 4 weeks until 30 weeks of age. Mice were administered either the CO donor, carbon monoxide releasing molecules (CORM)-A1 (5 mg kg(-1), intraperitoneally every other day) or the inactive form of the drug (iCORM-A1). Body weights were measured weekly and fasted blood glucose, insulin as well as body composition were measured every 6 weeks. Food intake, O2 consumption, CO2 production, activity and body heat production were measured at 28 weeks after start of the experimental protocol. RESULTS: Chronic CORM-A1 attenuated the development of high fat induced obesity from 18 weeks until the end of the study. Chronic CORM A1 treatment in mice fed a high-fat diet resulted in significant decreases in fasted blood glucose, insulin and body fat and increased O2 consumption and heat production as compared with mice treated with iCORM-A1. Chronic CORM-A1 treatment also resulted in a significant decrease in adipocyte size and an increase in adipocyte number and in NRF-1, PGC-1alpha and UCP1 protein levels in epidydmal fat. CONCLUSION: Our results demonstrate that chronic CO treatment prevents the development of high-fat diet induced obesity via stimulation of metabolism and remodeling of adipocytes. PMID- 23689361 TI - Targeting CD30 in malignant tissues: challenges in detection and clinical applications. AB - The CD30 transmembrane receptor from the tumor necrosis factor receptor family is expressed in a distinct, yet diverse set of lymphoproliferative disorders and a small subset of normal activated lymphocytes. Therefore, detection of CD30 expression when performed properly according to the standardized methods facilitates diagnosis of Hodgkin lymphoma, anaplastic large cell lymphoma, and other disorders expressing the receptor. More recently, CD30 has also become an attractive therapeutic target. The preliminary observations indicate that the methods currently used to detect CD30 expression, typically immunohistochemistry performed on formalin-fixed, paraffin-embedded tissues, may be suboptimal in regard to identifying CD30 as a therapeutic target since only a limited number of CD30 receptor molecules per cell may be sufficient to achieve therapeutic effect. PMID- 23689363 TI - Sleep-deprived young drivers and the risk for crash: the DRIVE prospective cohort study. AB - IMPORTANCE: Short sleep duration is common in adolescents and young adults, and short sleep duration is a risk factor for motor vehicle crash. OBJECTIVE: To assess the association between hours of sleep and the risk for motor vehicle crash, including the time of day of crash and types of crash (single, multiple vehicle, run off road, and intersection). DESIGN: Prospective cohort study. SETTING: New South Wales, Australia. PARTICIPANTS: Questionnaire responses were obtained from 20,822 newly licensed drivers aged 17 to 24 years. Participants held a first-stage provisional license between June 2003 and December 2004 prospectively linked to licensing and police-reported crash data, with an average of 2 years of follow-up. Analyses were conducted on a subsample of 19,327 participants for which there was full information. EXPOSURE: Sleeping 6 or fewer hours per night. MAIN OUTCOMES AND MEASURES: The main outcome variable was police reported crash. Multivariable Poisson regression models were used to investigate the role of sleep duration on the risk for crash. RESULTS: On average, those who reported sleeping 6 or fewer hours per night had an increased risk for crash compared with those who reported sleeping more than 6 hours (relative risk [RR], 1.21; 95% CI, 1.04-1.41). Less weekend sleep was significantly associated with an increased risk for run-off-road crashes (RR, 1.55; 95% CI, 1.21-2.00). Crashes for individuals who had less sleep per night (on average and on weekends) were significantly more likely to occur between 8 pm and 6 am (RR, 1.86; 95% CI, 1.11 3.13, for midnight to 5:59 am and RR, 1.66; 95% CI, 1.15-2.39, for 8:00 pm to 11:59 pm). CONCLUSIONS AND RELEVANCE: Less sleep per night significantly increased the risk for crash for young drivers. Less sleep on weekend nights increased the risk for run-off-road crashes and crashes occurring in the late night hours. This provides rationale for governments and health care providers to address sleep-related crashes among young drivers. PMID- 23689364 TI - Factors associated with hospices' provision of complementary and alternative medicine. AB - There is limited research about the provision of complementary and alternative (CAM) in US hospices. The purpose of this study was to assess the factors that influence hospices' likelihood of providing CAM therapies. Mail surveys were sent to 369 hospices in Texas; 61 were returned undelivered, yielding a total usable response rate of 35.7% (n = 110) after an initial and one follow-up mail out. Binary logistic regression was used to assess whether the likelihood of offering CAM is related to hospice's age, geographic location, agency type, profit orientation, Medicare certification, and number of patients served annually. Results showed that profit orientation and the number of patients served by hospices were significantly related to the probability that hospices will offer CAM. Specifically, the odds of offering CAM in not-for-profit hospices were approximately 4 times higher than that in for-profit hospices (odds ratio [OR] = 3.77, P = .022, 95% confidence interval [CI] = 1.2, 11.8). In addition, for every 100 patients served by the hospices, the odds of offering CAM increases by 13% (OR = 1.13, P = .015, 95% CI = 1.02, 1.25). In conclusion, CAM offering by hospices is related to hospices' profit orientation status and number of patients served but is not related to other measured characteristics of hospices. PMID- 23689362 TI - TRPV1 gates tissue access and sustains pathogenicity in autoimmune encephalitis. AB - Multiple sclerosis (MS) is a chronic progressive, demyelinating condition whose therapeutic needs are unmet, and whose pathoetiology is elusive. We report that transient receptor potential vanilloid-1 (TRPV1) expressed in a major sensory neuron subset, controls severity and progression of experimental autoimmune encephalomyelitis (EAE) in mice and likely in primary progressive MS. TRPV1-/- B6 congenics are protected from EAE. Increased survival reflects reduced central nervous systems (CNS) infiltration, despite indistinguishable T cell autoreactivity and pathogenicity in the periphery of TRPV1-sufficient and deficient mice. The TRPV1+ neurovascular complex defining the blood-CNS barriers promoted invasion of pathogenic lymphocytes without the contribution of TRPV1 dependent neuropeptides such as substance P. In MS patients, we found a selective risk-association of the missense rs877610 TRPV1 single nucleotide polymorphism (SNP) in primary progressive disease. Our findings indicate that TRPV1 is a critical disease modifier in EAE, and we identify a predictor of severe disease course and a novel target for MS therapy. PMID- 23689365 TI - Palliative care knowledge and attitudes among oncology nurses in Qatar. AB - OBJECTIVES: Formal palliative care (PC) education is lacking in the middle eastern state of Qatar. This study was done to assess the need for PC education among oncology nurses in Qatar. METHODS: In March 2012, a self-constructed questionnaire was distributed to 115 nurses at the Qatar National Center for Cancer Care and Research. RESULTS: A total of 115 nurses responded to the questionnaire. The majority (87.8%) were female. Although 60% had more than 10 years of work experience, only 31% had received formal training in PC, with only 6.1% having completed postgraduate training. The majority (63%) of responders attributed this issue to unavailability of PC courses rather than lack of time, interest, or financial issues. Currently, only 16.7% did not express interest in the field, with 56% showing some kind of interest. In terms of knowledge, 54% of the responders were familiar with the World Health Organization ladder for pain relief. Only 43.6% know about Palliative Performance Scale, and half of the nurses know the Edmonton Symptom Assessment System. Overall, 56% of the nurses indicated a need for training in more than 1 aspect. These aspects included training in care of the dying patients (14.6%), communication strategies (22%), caregiver support (10.6%), psychosocial care (15%), pain management (10.2%), other symptom management (13%), and other ethical/spiritual issues (14.2%). CONCLUSIONS: There is a clear deficiency in formal PC education among the nurses at the National Center for Cancer Care and Research, in Qatar. This is reflected by their lack of experience and exposure to PC and their mediocre knowledge in the field. This could be attributed to the fact that formal PC service was established only recently in Qatar (2008). Formal training courses in PC nursing are required. PMID- 23689366 TI - A pilot study of adaptation of the transtheoretical model to narratives of bereaved family members in the bereavement life review. AB - This study aimed to examine the possibility of adaptation of the transtheoretical model (TTM) to narratives from the Bereavement Life Review. Narratives from 19 bereaved family members were recorded, transcribed into sentences, and allocated into stages based on the TTM criteria. Those who lived in fantasy were allocated to the precontemplation stage and who recognized the patient's death but could not adjust to the death were allocated to the contemplation stage. Those who understood the need for changes and had new plans were allocated to the preparation stage, and those who were coping were allocated to the action stage, and those who had confidence to remember the loved one who died were allocated to the maintenance stage. These results provide deeper understanding of a bereaved family member and suggest that a different intervention method may be useful in each stage. PMID- 23689367 TI - Health care interactional suffering in palliative care. AB - A secondary analysis of 2 qualitative studies was conducted to explore the experiences of suffering caused by interactions with health care providers in the hospital setting. Interview transcripts from 20 palliative care patients and 15 palliative care informal caregivers in University Malaya Medical Centre were thematically analyzed. The results of health care interactional suffering were associated with themes of attention, understanding, communication, competence, and limitation. These 5 themes may serve as a framework for the improvement in interaction skills of health care providers in palliative care. PMID- 23689368 TI - Predictive role of different dimensions of burden for risk of complicated grief in caregivers of terminally ill patients. AB - The aim of the study was to test whether high levels of caregiver burden, as other confirmed predictors, are associated with the risk of prolonged grief disorder in caregivers of terminally ill patients. A predictive study was carried out in order to test the hypothesis. A demographic schedule, the Prolonged Grief 12 (PG-12), the Toronto Alexithymia Scale, Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, and Caregiver Burden Inventory were administered to 60 caregivers of 51 patients who were admitted in Hospice. In the regression analysis, difficulty in recognizing emotions, total burden, depression, and developmental burden dimension were significant predictors of PG 12 levels. Findings showed that feeling of deprivation of existential expectations represents the greater risk factor for the prolonged grief disorder, among the burden dimensions. PMID- 23689369 TI - The lectin domain of the polypeptide GalNAc transferase family of glycosyltransferases (ppGalNAc Ts) acts as a switch directing glycopeptide substrate glycosylation in an N- or C-terminal direction, further controlling mucin type O-glycosylation. AB - Mucin type O-glycosylation is initiated by a large family of polypeptide GalNAc transferases (ppGalNAc Ts) that add alpha-GalNAc to the Ser and Thr residues of peptides. Of the 20 human isoforms, all but one are composed of two globular domains linked by a short flexible linker: a catalytic domain and a ricin-like lectin carbohydrate binding domain. Presently, the roles of the catalytic and lectin domains in peptide and glycopeptide recognition and specificity remain unclear. To systematically study the role of the lectin domain in ppGalNAc T glycopeptide substrate utilization, we have developed a series of novel random glycopeptide substrates containing a single GalNAc-O-Thr residue placed near either the N or C terminus of the glycopeptide substrate. Our results reveal that the presence and N- or C-terminal placement of the GalNAc-O-Thr can be important determinants of overall catalytic activity and specificity that differ between transferase isoforms. For example, ppGalNAc T1, T2, and T14 prefer C-terminally placed GalNAc-O-Thr, whereas ppGalNAc T3 and T6 prefer N-terminally placed GalNAc O-Thr. Several transferase isoforms, ppGalNAc T5, T13, and T16, display equally enhanced N- or C-terminal activities relative to the nonglycosylated control peptides. This N- and/or C-terminal selectivity is presumably due to weak glycopeptide binding to the lectin domain, whose orientation relative to the catalytic domain is dynamic and isoform-dependent. Such N- or C-terminal glycopeptide selectivity provides an additional level of control or fidelity for the O-glycosylation of biologically significant sites and suggests that O glycosylation may in some instances be exquisitely controlled. PMID- 23689370 TI - Single cell analysis of RNA-mediated histone H3.3 recruitment to a cytomegalovirus promoter-regulated transcription site. AB - Unlike the core histones, which are incorporated into nucleosomes concomitant with DNA replication, histone H3.3 is synthesized throughout the cell cycle and utilized for replication-independent (RI) chromatin assembly. The RI incorporation of H3.3 into nucleosomes is highly conserved and occurs at both euchromatin and heterochromatin. However, neither the mechanism of H3.3 recruitment nor its essential function is well understood. Several different chaperones regulate H3.3 assembly at distinct sites. The H3.3 chaperone, Daxx, and the chromatin-remodeling factor, ATRX, are required for H3.3 incorporation and heterochromatic silencing at telomeres, pericentromeres, and the cytomegalovirus (CMV) promoter. By evaluating H3.3 dynamics at a CMV promoter regulated transcription site in a genetic background in which RI chromatin assembly is blocked, we have been able to decipher the regulatory events upstream of RI nucleosomal deposition. We find that at the activated transcription site, H3.3 accumulates with sense and antisense RNA, suggesting that it is recruited through an RNA-mediated mechanism. Sense and antisense transcription also increases after H3.3 knockdown, suggesting that the RNA signal is amplified when chromatin assembly is blocked and attenuated by nucleosomal deposition. Additionally, we find that H3.3 is still recruited after Daxx knockdown, supporting a chaperone-independent recruitment mechanism. Sequences in the H3.3 N terminal tail and alphaN helix mediate both its recruitment to RNA at the activated transcription site and its interaction with double-stranded RNA in vitro. Interestingly, the H3.3 gain-of-function pediatric glioblastoma mutations, G34R and K27M, differentially affect H3.3 affinity in these assays, suggesting that disruption of an RNA-mediated regulatory event could drive malignant transformation. PMID- 23689371 TI - Structural transformation of the amyloidogenic core region of TDP-43 protein initiates its aggregation and cytoplasmic inclusion. AB - TDP-43 (TAR DNA-binding protein of 43 kDa) is a major deposited protein in amyotrophic lateral sclerosis and frontotemporal dementia with ubiquitin. A great number of genetic mutations identified in the flexible C-terminal region are associated with disease pathologies. We investigated the molecular determinants of TDP-43 aggregation and its underlying mechanisms. We identified a hydrophobic patch (residues 318-343) as the amyloidogenic core essential for TDP-43 aggregation. Biophysical studies demonstrated that the homologous peptide formed a helix-turn-helix structure in solution, whereas it underwent structural transformation from an alpha-helix to a beta-sheet during aggregation. Mutation or deletion of this core region significantly reduced the aggregation and cytoplasmic inclusions of full-length TDP-43 (or TDP-35 fragment) in cells. Thus, structural transformation of the amyloidogenic core initiates the aggregation and cytoplasmic inclusion formation of TDP-43. This particular core region provides a potential therapeutic target to design small-molecule compounds for mitigating TDP-43 proteinopathies. PMID- 23689372 TI - Dismantling promoter-driven RNA polymerase II transcription complexes in vitro by the termination factor Rat1. AB - Proper RNA polymerase II (Pol II) transcription termination is essential to generate stable transcripts, to prevent interference at downstream loci, and to recycle Pol II back to the promoter (1-3). As such, termination is an intricately controlled process that is tightly regulated by a variety of different cis- and trans-acting factors (4, 5). Although many eukaryotic termination factors have been identified to date, the details of the precise molecular mechanisms governing termination remain to be elucidated. We devised an in vitro transcription system to study specific Pol II termination. We show for the first time that the exonucleolytic Rat1.Rai1 complex can elicit the release of stalled Pol II in vitro and can do so in the absence of other factors. We also find that Rtt103, which interacts with the Pol II C-terminal domain (CTD) and with Rat1, can rescue termination activity of an exonucleolytically deficient Rat1 mutant. In light of our findings, we posit a model whereby functional nucleolytic activity is not the feature of Rat1 that ultimately promotes termination. Degradation of the nascent transcript allows Rat1 to pursue Pol II in a guided fashion and arrive at the site of RNA exit from Pol II. Upon this arrival, however, it is perhaps the specific and direct contact between Rat1 and Pol II that transmits the signal to terminate transcription. PMID- 23689373 TI - Comparison of predicted epimerases and reductases of the Campylobacter jejuni D altro- and L-gluco-heptose synthesis pathways. AB - Uniquely modified heptoses found in surface carbohydrates of bacterial pathogens are potential therapeutic targets against such pathogens. Our recent biochemical characterization of the GDP-6-deoxy-D-manno- and GDP-6-deoxy-D-altro-heptose biosynthesis pathways has provided the foundation for elucidation of the more complex L-gluco-heptose synthesis pathway of Campylobacter jejuni strain NCTC 11168. In this work we use GDP-4-keto,6-deoxy-D-lyxo-heptose as a surrogate substrate to characterize three enzymes predicted to be involved in this pathway: WcaGNCTC (also known as Cj1427), MlghB (Cj1430), and MlghC (Cj1428). We compare them with homologues involved in d-altro-heptose production: WcaG81176 (formerly WcaG), DdahB (Cjj1430), and DdahC (Cjj1427). We show that despite high levels of similarity, the enzymes have pathway-specific catalytic activities and substrate specificities. MlghB forms three products via C3 and C5 epimerization activities, whereas its DdahB homologue only had C3 epimerase activity along its cognate pathway. MlghC is specific for the double C3/C5 epimer generated by MlghB and produces L-gluco-heptose via stereospecific C4 reductase activity. In contrast, its homologue DdahC only uses the C3 epimer to yield d-altro-heptose via C4 reduction. Finally, we show that WcaGNCTC is not necessary for L-gluco-heptose synthesis and does not affect its production by MlghB and MlghC, in contrast to its homologue WcaG81176, that has regulatory activity on d-altro-heptose synthesis. These studies expand our fundamental understanding of heptose modification, provide new glycobiology tools to synthesize novel heptose derivatives with biomedical applications, and provide a foundation for the structure function analysis of these enzymes. PMID- 23689374 TI - Simultaneous surface display and secretion of proteins from mammalian cells facilitate efficient in vitro selection and maturation of antibodies. AB - A mammalian expression system has been developed that permits simultaneous cell surface display and secretion of the same protein through alternate splicing of pre-mRNA. This enables a flexible system for in vitro protein evolution in mammalian cells where the displayed protein phenotype remains linked to genotype, but with the advantage of soluble protein also being produced without the requirement for any further recloning to allow a wide range of assays, including biophysical and cell-based functional assays, to be used during the selection process. This system has been used for the simultaneous surface presentation and secretion of IgG during antibody discovery and maturation. Presentation and secretion of monomeric Fab can also be achieved to minimize avidity effects. Manipulation of the splice donor site sequence enables control of the relative amounts of cell surface and secreted antibody. Multi-domain proteins may be presented and secreted in different formats to enable flexibility in experimental design, and secreted proteins may be produced with epitope tags to facilitate high-throughput testing. This system is particularly useful in the context of in situ mutagenesis, as in the case of in vitro somatic hypermutation. PMID- 23689375 TI - The molecular chaperone apolipoprotein J/clusterin as a sensor of oxidative stress: implications in therapeutic approaches - a mini-review. AB - BACKGROUND: Organisms are constantly exposed to physiological and environmental stresses and therefore require an efficient surveillance of genome and proteome quality in order to prevent disruption of homeostasis. Central to the intra- and extracellular proteome surveillance system are the molecular chaperones that contribute to both proteome maintenance and clearance. The conventional protein product of the apolipoprotein J/clusterin (CLU) gene is a heterodimeric secreted glycoprotein (also termed as sCLU) with a ubiquitous expression in human tissues. CLU exerts a small heat shock protein-like stress-induced chaperone activity and has been functionally implicated in numerous physiological processes as well as in ageing and most age-related diseases including tumorigenesis, neurodegeneration, and cardiovascular and metabolic syndromes. OBJECTIVE: The CLU gene is differentially regulated by a wide variety of stimuli due to the combined presence of many distinct regulatory elements in its promoter that make it an extremely sensitive cellular biosensor of environmental and/or oxidative stress. Downstream to CLU gene induction, the CLU protein seems to actively intervene in pathological states of increased oxidative injury due to its chaperone-related property to inhibit protein aggregation and precipitation (a main feature of oxidant injury), as well as due to its reported distribution in both extra- and, most likely, intracellular compartments. CONCLUSION: On the basis of these findings, CLU has emerged as a unique regulator of cellular proteostasis. Nevertheless, it seemingly exerts a dual function in pathology. For instance, in normal cells and during early phases of carcinogenesis, CLU may inhibit tumor progression as it contributes to suppression of proteotoxic stress. In advanced neoplasia, however, it may offer a significant survival advantage in the tumor by suppressing many therapeutic stressors and enhancing metastasis. This review will critically present a synopsis of recent novel findings that relate to the function of this amazing molecule and support the notion that CLU is a biosensor of oxidative injury; a common link between ageing and all pathologies where CLU has been implicated. Potential future perspectives, implications and opportunities for translational research and the development of new therapies will be discussed. PMID- 23689376 TI - The rs9939609 polymorphism in the FTO gene is associated with fat and fiber intakes in patients with type 2 diabetes. AB - BACKGROUND/AIMS: The common polymorphism in the FTO gene (rs9939609) has been associated with obesity, type 2 diabetes, and appetite regulation. The aim of this study was to evaluate possible associations of FTO rs9939609 with dietary factors in patients with type 2 diabetes. METHODS: This was a cross-sectional study of 236 patients with type 2 diabetes (age 60.0 +/- 10.3 years; diabetes duration 12.7 +/- 8.2 years; 53.4% females) who were genotyped for FTO rs9939609. Patients underwent clinical and laboratory evaluations and 3-day weighed diet records. Data on dietary intake were categorized as high or low, based on median values. RESULTS: The AA genotype in the FTO gene was positively associated with high fat (>34% energy; OR = 2.17; 95% CI 1.02-4.63) and low fiber intakes (<16 g/day; OR = 2.42; 95% CI 1.05-5.57), adjusted for gender, BMI, total energy intake, systolic blood pressure, and HbA1c. When gender was taken into account, AA females had higher fat (37.4 +/- 5.3 vs. 32.6 +/- 7.5 and 32.2 +/- 6.2% energy; p = 0.005) and lower fiber intakes (12.4 +/- 4.4 vs. 15.1 +/- 6.3 and 16.7 +/- 5.6 g/day; p = 0.023) than patients with TT and AT genotypes. Multiple logistic regression models confirmed female associations for high fat (OR = 9.73; 95% CI 2.12-44.66) and low fiber intakes (OR = 4.28; 95% CI 1.14-16.06; p < 0.05 for all models). CONCLUSIONS: Patients with type 2 diabetes, who were carriers of the AA genotype of the FTO rs9939609, had increased fat and decreased fiber consumption, independently of BMI. PMID- 23689377 TI - A basic helix-loop-helix transcription factor DvIVS determines flower color intensity in cyanic dahlia cultivars. AB - The study was aimed to identify the factors that regulate the intensity of flower color in cyanic dahlia (Dahlia variabilis), using fifteen cultivars with different color intensities in their petals. The cultivars were classified into three groups based on their flavonoid composition: ivory white cultivars with flavones; purple and pink cultivars with flavones and anthocyanins; and red cultivars with flavones, anthocyanins, and chalcones. Among the purple, pink, and ivory white cultivars, an inverse relationship was detected between lightness, which was used as an indicator for color intensity and anthocyanin content. A positive correlation was detected between anthocyanin contents and the expression of some structural genes in the anthocyanin synthesis pathway that are regulated by DvIVS, a basic helix-loop-helix transcription factor. A positive correlation between anthocyanin content and expression of DvIVS was also found. The promoter region of DvIVS was classified into three types, with cultivars carrying Type 1 promoter exhibited deep coloring, those carrying Type 2 and/or Type 3 exhibited pale coloring, and those carrying Type 1 and Type 2 and/or Type 3 exhibited medium coloring. The transcripts of the genes from these promoters encoded full length predicted proteins. These results suggested that the genotype of the promoter region in DvIVS is one of the key factors determining the flower color intensity. PMID- 23689378 TI - Zwitterionic {Fe(I)Pc(-2)-}.(TMP+) assemblies comprising anionic iron(I) phthalocyanines and coordinating N,N,N'-trimethylpiperazinium cations. AB - {[Fe(I)Pc(-2)(-)].(TMP(+))}.0.5C6H14 (1) and {Co(i)Pc(-2)(-)}.(TMP(+)) (2) salts containing iron(I) and cobalt(I) phthalocyanine anions and N,N,N' trimethylpiperazinium cations (TMP(+)) have been obtained as single crystals. The TMP(+) cations coordinate to the iron(I) centers in 1 by free nitrogen atoms to form a weak N(TMP(+))-Fe bond of 2.568(3) and 2.553(3) A length at 150 and 105 K, respectively. This is the first zwitterionic assembly containing anions and cations in one neutral coordination {[Fe(I)Pc(-2)(-)].(TMP(+))} unit. The Fe(I)Pc(-2)(-) anions manifest strongly asymmetric EPR signals in the spectrum of 1 which can be fitted well by four components at 298 K with g1 = 2.1770, g2 = 2.1681, g3 = 2.1425 and g4 = 2.0708. The signal is attributed to the low-spin (S = 1/2) Fe(I) with the d(7) configuration. The EPR spectrum of 1 does not change qualitatively upon slow cooling from 298 down to 4 K. Quenching of the sample for seconds produces a different EPR spectrum at 4 K. This spectrum can be attributed to the frozen metastable state of Fe(I)Pc(-2)(-) which exists only at low temperatures and transfers to the spectrum observed for the slowly cooled sample above 70 K. Salt 2 contains EPR silent cobalt(I) with the d(8) configuration and in this case the TMP(+) cations do not coordinate to the cobalt(I) atoms. PMID- 23689379 TI - Impact of low- or high-flux haemodialysis and online haemodiafiltration on inflammatory markers and lipid profile in chronic haemodialysis patients. AB - BACKGROUND/AIMS: We aimed to evaluate the impact of low- or high-flux haemodialysis (HD) and online haemodiafiltration (OL-HDF) on inflammation and the lipid profile in HD patients. METHODS: 50 HD patients were assigned to two groups for HD with low-flux (n = 25) or high-flux (n = 25) polysulphone dialysers for 6 weeks. Subsequently, all patients were haemodialysed with a low-flux polysulphone dialyser for 6 weeks, then transferred to OL-HDF for another 6 weeks. Blood samples for lipids and inflammatory markers (IL-6, IL-8, TNF-alpha, hs-CRP) were obtained at baseline and every 6 weeks. RESULTS: Changes in inflammatory markers and lipids from baseline to the 6-week dialysis period did not differ between low and high-flux groups. When patients were transferred from low-flux HD to OL-HDF, IL-6, IL-8, and TNF-alpha levels significantly decreased whereas HDL and LDL cholesterol significantly increased. CONCLUSION: Low- and high-flux polysulphone membranes had similar effects on lipids and inflammatory markers, whereas OL-HDF potently reduced pro-inflammatory cytokines. PMID- 23689380 TI - Thermoregulation in African Green Pigeons (Treron calvus) and a re-analysis of insular effects on basal metabolic rate and heterothermy in columbid birds. AB - Columbid birds represent a useful model taxon for examining adaptation in metabolic and thermal traits, including the effects of insularity. To test predictions concerning the role of insularity and low predation risk as factors selecting for the use of torpor, and the evolution of low basal metabolic rate in island species, we examined thermoregulation under laboratory and semi-natural conditions in a mainland species, the African Green Pigeon (Treron calvus). Under laboratory conditions, rest-phase body temperature (T b) was significantly and positively correlated with air temperature (T a) between 0 and 35 degrees C, and the relationship between resting metabolic rate (RMR) and T a differed from typical endothermic patterns. The minimum RMR, which we interpret as basal metabolic rate (BMR), was 0.825 +/- 0.090 W. Green pigeons responded to food restriction by significantly decreasing rest-phase T b, but the reductions were small (at most ~5 degrees C below normothermic values), with a minimum T b of 33.1 degrees C recorded in a food-deprived bird. We found no evidence of the large reductions in T b and metabolic rate and the lethargic state characteristic of torpor. The absence of torpor in T. calvus lends support to the idea that species restricted to islands that are free of predators are more likely to use torpor than mainland species that face the risk of predation during the rest phase. We also analysed interspecific variation in columbid BMR in a phylogenetically informed framework and verified the conclusions of an earlier study which found that BMR is significantly lower in island species compared to those that occur on mainlands. PMID- 23689381 TI - Aggressive fluid and sodium restriction in acute decompensated heart failure: a randomized clinical trial. AB - IMPORTANCE: The benefits of fluid and sodium restriction in patients hospitalized with acute decompensated heart failure (ADHF) are unclear. OBJECTIVE: To compare the effects of a fluid-restricted (maximum fluid intake, 800 mL/d) and sodium restricted (maximum dietary intake, 800 mg/d) diet (intervention group [IG]) vs a diet with no such restrictions (control group [CG]) on weight loss and clinical stability during a 3-day period in patients hospitalized with ADHF. DESIGN: Randomized, parallel-group clinical trial with blinded outcome assessments. SETTING: Emergency room, wards, and intensive care unit. PARTICIPANTS: Adult inpatients with ADHF, systolic dysfunction, and a length of stay of 36 hours or less. INTERVENTION: Fluid restriction (maximum fluid intake, 800 mL/d) and additional sodium restriction (maximum dietary intake, 800 mg/d) were carried out until the seventh hospital day or, in patients whose length of stay was less than 7 days, until discharge. The CG received a standard hospital diet, with liberal fluid and sodium intake. MAIN OUTCOMES AND MEASURES: Weight loss and clinical stability at 3-day assessment, daily perception of thirst, and readmissions within 30 days. RESULTS: Seventy-five patients were enrolled (IG, 38; CG, 37). Most were male; ischemic heart disease was the predominant cause of heart failure (17 patients [23%]), and the mean (SD) left ventricular ejection fraction was 26% (8.7%). The groups were homogeneous in terms of baseline characteristics. Weight loss was similar in both groups (between-group difference in variation of 0.25 kg [95% CI, -1.95 to 2.45]; P = .82) as well as change in clinical congestion score (between-group difference in variation of 0.59 points [95% CI, -2.21 to 1.03]; P = .47) at 3 days. Thirst was significantly worse in the IG (5.1 [2.9]) than the CG (3.44 [2.0]) at the end of the study period (between-group difference, 1.66 points; time * group interaction; P = .01). There were no significant between group differences in the readmission rate at 30 days (IG, 11 patients [29%]; CG, 7 patients [19%]; P = .41). CONCLUSIONS AND RELEVANCE: Aggressive fluid and sodium restriction has no effect on weight loss or clinical stability at 3 days and is associated with a significant increase in perceived thirst. We conclude that sodium and water restriction in patients admitted for ADHF are unnecessary. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01133236. PMID- 23689382 TI - Wnt signalling in pituitary development and tumorigenesis. AB - Wnt signalling is activated in both pituitary organogenesis and its mature function. Wnt ligands and Wnt signalling pathways are critical for the regulation of the formation of the pituitary. In the mature pituitary, Wnt signalling pathways control cell activity and may stimulate cell proliferation in both physiological and pathological processes. This review compares Wnt signalling pathways active in the developing and mature pituitary and explores how this gives us further insight into the development of pituitary adenomas. PMID- 23689383 TI - Defining left ventricular noncompaction using cardiac computed tomography. AB - PURPOSE: Left ventricular noncompaction (LVNC) is a cardiomyopathy characterized by a distinctive 2-layered appearance of the myocardium because of increased trabeculation and deep intertrabecular recesses. Echocardiography serves as the initial noninvasive diagnostic test. Currently, magnetic resonance imaging (MRI) is increasingly being used to diagnose LVNC because of its improved temporal and spatial resolution. So far, no criteria have been proposed to define pathologic LVNC with the use of computed tomography (CT). MATERIALS AND METHODS: We analyzed CT images using an American Heart Association 17-segment model in 8 patients previously diagnosed with LVNC by clinical diagnosis, echocardiography, and/or MRI, as well as in 11 patients with nonischemic dilated cardiomyopathy, 11 patients with hypertrophic cardiomyopathy, 10 patients with severe aortic stenosis, 9 patients with severe aortic regurgitation, 10 patients with left ventricular hypertrophy due to essential hypertension, and, additionally, in a control group of 20 patients who had normal CT scans without a history of cardiovascular disease. The distribution of LVNC was assessed by qualitative analysis of 17 myocardial segments for the presence or absence of any degree of noncompaction. Each segment was analyzed in each of the 3 end-diastolic long-axis views for the presence or absence of noncompaction, and the most prominent trabeculation was chosen for measurement. The left ventricular apex was excluded. Thickness of noncompacted and compacted myocardium was measured perpendicular to the compacted myocardium. The ratio of noncompacted to compacted (NC:C) myocardium was calculated for each segment. Receiver operating characteristics were used to generate cutoff values with sensitivity and specificity to distinguish the LVNC group from other groups. RESULTS: An end-diastolic NC:C ratio >2.3 distinguished pathologic LVNC with 88% sensitivity and 97% specificity; positive and negative predictive values were 78% and 99%, respectively. CONCLUSIONS: CT using the standard MRI NC:C ratio cutoff >2.3 accurately characterizes pathologic LVNC. PMID- 23689384 TI - Concise solid-phase synthesis of inverse poly(amidoamine) dendrons using AB2 building blocks. AB - A concise solid-phase synthesis of inverse poly(amidoamine) dendrons was developed. Upon introduction of AB2-type monomers, each dendron generation was constructed via one reaction. G2 to G5 dendrons were constructed in a peptide synthesizer in 93%, 89%, 82%, and 78% yields, respectively, within 5 days. PMID- 23689385 TI - Comparison of patient and proxy reporting of health-related quality of life in adolescent athletes who suffer a sports-related injury and require orthopaedic consultation. AB - CONTEXT: Accurate assessment of health-related quality of life (HRQoL) is important for quality patient care. Evaluation of HRQoL typically occurs with patient self-report, but some instruments, such as the Pediatric Quality of Life Inventory (PedsQL), allow for proxy reporting. Limited information exists comparing patient and proxy reports of HRQoL after sport-related injury in adolescent athletes. OBJECTIVE: To compare patient ratings and parent-proxy ratings of HRQoL in adolescent athletes who suffer musculoskeletal injuries requiring orthopedic consultation. The authors hypothesized poor agreement between patient and parent-proxy ratings of HRQoL. DESIGN: Cross-sectional study. SETTING: Orthopedic practice. PATIENTS: Thirteen adolescent patients with a sport related musculoskeletal injury requiring orthopedic consultation and 1 of their parents participated. INTERVENTIONS: During the initial visit to the physician's office, each patient was asked to complete the PedsQL, and the patient's parent was asked to complete the parent-proxy version of the PedsQL. MAIN OUTCOME MEASUREMENTS: The PedsQL is a pediatric generic outcome measure that consists of a total score and 4 subscale scores: physical, emotional, social, and school functioning. Means and standard deviations were calculated for all scores, and comparisons between patient-self report and parent-proxy ratings of HRQoL were made for the PedsQL total score and subscale scores using Pearson product-moment correlations (r). RESULTS: Pearson product-moment correlations showed little to fair insignificant relationships between patient self-report and parent-proxy report of the PedsQL for the total score (r = -.1) and all subscales (range r = .1 to .4). CONCLUSIONS: Our results suggest a lack of agreement between patient and parent-proxy ratings of HRQoL, with patients rating their HRQoL lower than their parent. Patient perception of HRQoL may be more accurate than proxy report, which supports the use of patient-rated HRQoL in patient evaluation. Assessments of HRQoL made by proxies, even those close to the patient, may not represent patient health status. PMID- 23689387 TI - Heparin for venous thromboembolism prophylaxis in patients with acute spinal cord injury: a systematic review and meta-analysis. AB - OBJECTIVE: The objective of this study is to systematically review and estimate the effect of heparin for thromboprophylaxis in patients with acute spinal cord injury (SCI). METHODS: We searched the PubMed database up to February 2013. Only randomized control trials (RCTs), quasi-RCTs, cohorts, case-control and cross sectional studies were included. The incidence of venous thromboembolism (VTE) and major bleeding complication were recorded as the endpoints. The summary relative risks (RR) were calculated by meta-analysis. RESULTS: A total of 18 studies with 2578 patients were included. Four studies evaluated the effects of low-dose unfractionated heparin (LDUH) compared placebo or untreated. No significant differences were observed, with the summary RR 0.661 (95% confidence interval (CI) 0.365-1.199; Z=1.36, P=0.173) for VTE. Only one RCT compared fixed dose LDUH with adjusted-dose LDUH, which showed lower VTE incidence but higher bleeding incidence for adjusted dose. Nine trials have compared LDUH with low molecular-weight heparin (LMWH). No significant differences were observed for VTE with the summary RR 1.633 (95% CI 0.822-3.243; Z=1.40, P=0.162). But major bleeding was lower with LMWH (summary RR=2.034, 95% CI 1.018-4.063; Z=2.01, P=0.044). Three studies compared different LMWHs, which included one for enoxaparin versus tinzaparin and two for enoxaparin versus dalteparin. No significant differences were observed with the summary RR 0.694 (95% CI 0.336 1.434; Z=0.99, P=0.324) for VTE. Three studies compared different dose of LMWH. No differences were observed. CONCLUSION: Our meta-analysis showed that in patients with acute SCI, LDUH have no thromboprophylaxis effect compared with placebo or untreated; LMWH seems only can reduce bleeding incidence, but not prophylaxis thromboembolism compared with LDUH. Because of no good quality studies existed in this setting, well-designed RCTs are urgently needed. PMID- 23689386 TI - Physical activity classification utilizing SenseWear activity monitor in manual wheelchair users with spinal cord injury. AB - STUDY DESIGN: Validation. OBJECTIVES: The primary aim of this study was to develop and evaluate activity classification algorithms for a multisensor-based SenseWear (SW) activity monitor that can recognize wheelchair-related activities performed by manual wheelchair users (MWUs) with spinal cord injury (SCI). The secondary aim was to evaluate how the accuracy in activity classification affects the estimation of energy expenditure (EE) in MWUs with SCI. SETTING: University based laboratory. METHODS: Forty-five MWUs with SCI wore a SW on their upper arm and participated in resting, wheelchair propulsion, arm-ergometery and deskwork activities. The investigators annotated the start and end of each activity trial while the SW collected multisensor data and a portable metabolic cart collected criterion EE. Three methods including linear discriminant analysis, quadratic discriminant analysis (QDA), and Naive Bayes (NB) were used to develop classification algorithms for four activities based on the training data set from 36 subjects. RESULTS: The classification accuracy was 96.3% for QDA and 94.8% for NB when the classification algorithms were tested on the validation data set from nine subjects. The average EE estimation errors using the activity-specific EE prediction model were 5.3+/-21.5% and 4.6+/-22.8% when the QDA and NB classification algorithms were applied, respectively, as opposed to 4.9+/-20.7% when 100% classification accuracy was assumed. CONCLUSION: The high classification accuracy and low EE estimation errors suggest that the SW can be used by researchers and clinicians to classify and estimate the EE for the four activities tested in this study among MWUs with SCI. PMID- 23689388 TI - Brain activation in the acute phase of traumatic spinal cord injury. AB - STUDY DESIGN: Prospective clinical study. BACKGROUND: The aim of the study was to investigate cortical reorganisation after traumatic spinal cord injury (TSCI) using functional magnetic resonance imaging (fMRI). SETTING: Tartu University Hospital, Tartu, Estonia. METHODS: We studied six right-handed tetraplegic TSCI patients at 1, 3 and 12 months after the injury and 12 age- and gender-matched healthy controls. Individuals performed simple test-rest cycles of flexion/extension of the right-hand fingers and flexion/extension of the right ankle during fMRI. The volumes of activation (VOA), maximum t-values, centres of gravity (COG) and weighted laterality indexes were calculated. RESULTS: There was no recovery of neurologic function in three patients and, according to the American Spinal Injury Association (ASIA) Impairment Scale the remaining three recovered. A positive correlation between the VOA in the primary motor cortex and the ASIA impairment scale (1 month: r=0.82, P=0.002; 3 Month: r=0.63, P=0.03; 12 Month: r=0.23, P=0.52) was found. The study also revealed a pattern of cortical activation that was increased among the patients who recovered (in Brodmann area 4 (BA 4), P=0.06; BA 1-2-3-5, P=0.08; BA 6, P=0.05). During the hand task there was an expansion of COG laterally, anteriorly and inferiorly among the patients who recovered. During the hand movement the cortical activation was less lateralised among the patients compared with the controls (P<0.05). CONCLUSION: Our study has found broadening of cortical activation and shift of COG during the first year after TSCI, depending on the recovery. PMID- 23689389 TI - Assessment of in vivo spinal cord conduction velocity in rats in an experimental model of ischemic spinal cord injury. AB - STUDY DESIGN: Experimental laboratory investigation of spinal cord conductivity alterations in a rat model of ischemic spinal cord injury (SCI). OBJECTIVE: To observe the epidural spinal cord stimulation-induced electromyography responses, and to investigate the possible alterations of spinal cord conduction velocity (SCCV) and compound muscle action potentials (CMAPs) after ischemic SCI in rats. SETTINGS: Adnan Menderes University, Institute of Health Science, Aydin, Turkey. METHODS: SCI was induced by transient occlusion of the abdominal aorta in male Sprague-Dawley rats. Spinal cord histopathology was examined to determine neuronal damage and Tarlov scale was used to grade locomotor functions. Epidural electrical stimulation of spinal cord was performed by monopolar needle electrodes sequentially at L1-L2 and L5-L6 levels, and CMAPs were recorded from the left gastrocnemius muscle by surface electrodes. Amplitudes and durations of CMAPs were evaluated and SCCVs were calculated by analyzing the latency difference of CMAPs. RESULTS: Ischemia-induced SCI resulted in significant reduction of Tarlov scores and a significant decline in number of viable neurons. Similarly, a significant decrement was observed in SCCV following spinal cord ischemia. CONCLUSION: This study demonstrated that measurement of SCCV via epidural electrical stimulation is possible and displays a significant decline after spinal cord ischemia in rats. We suggest that this method can be beneficial to quantify neuronal damage after experimental ischemic SCI. PMID- 23689390 TI - The use of oxybutynin in patients treated by means of botulinum neurotoxin A for neurogenic detrusor overactivity: an observational study. AB - STUDY DESIGN: This is an observational prospective noncontrolled study. We enrolled 105 patients affected by neurogenic detrusor overactivity (NDO) who underwent botulinum neurotoxin A (BONT-A) intradetrusor injection and were followed-up for 270 days. OBJECTIVES: To investigate the use of oxybutynin after BONT-A administration in NDO patients. SETTING: Careggi University Hospital in Florence and Tor Vergata University Hospital in Rome. METHODS: Prospective data from two Italian centers were collected in 1 year. Patients showing limited efficacy but good tolerability and adherence to oxybutynin 5 mg three times a day (t.i.d.). were enrolled in the study. Patients received BONT-A intradetrusor injection (onabotulinumtoxinA, 300 U) with a trigone-sparing technique, and the use of oxybutynin was registered at every visit. RESULTS: 105 patients were included. At visit 1, only 30 patients (28.6%) used oxybutynin t.i.d., whereas 47 (45,2%) used a lower dosage and 28 (26.7%) stopped the therapy. At visit 2, 77.3% of patients who had reduced oxybutynin intake, maintained the dosage decided at visit 1. At visit 3, 51.9% returned to oxybutynin t.i.d.; 44.8% were on a reduced dosage and only 3 (2.9%) were not taking the drug. At visit 4, only 37.5% of patients were taking less than oxybutynin t.i.d. CONCLUSION: This study provides some important insights on the use of oral antimuscarinics in patients treated by means of BONT-A intradetrusor administration for NDO; in particular, it suggests that, after an initial reduction in the use of oxybutynin, patients tend to increase the dosage of this drug during the follow-up after the BONT-A treatment. PMID- 23689391 TI - Examining factors that contribute to the process of resilience following spinal cord injury. AB - STUDY DESIGN: Cross-sectional survey. OBJECTIVE: To examine factors that contribute to the process of positive adjustment, or resilience, in an adult community sample with spinal cord injury (SCI). SETTING: South Australian Spinal Cord Injury Service, Hampstead Rehabilitation Centre, South Australia, Australia METHODS: A postal survey comprising standardised measures of resilience (Connor Davidson Resilience Scale-10 item), self-efficacy (Moorong Self-Efficacy Scale), locus of control (Locus of Control of Behaviour Scale) and psychological distress (Depression Anxiety Stress Scale--21 item). RESULTS: Of 60 respondents, 58% reported moderate to high levels of resilience. Resilience correlated significantly with high self-efficacy (r=0.68, P<0.01), internal locus of control (r=-0.52, P<0.01) and low psychological distress (depression r=-0.68, P<0.01; anxiety r=-0.55, P<0.01; stress r=-0.67, P<0.01). In comparison, resilience was not significantly influenced by degree of neuropathic pain (r=-0.23, P>0.05), time since injury (r=-0.14, P>0.05), gender (t(58)=-0.92, P>0.05), lesion completeness (t(57)=-0.86, P>0.05), or SCI diagnosis (t(58)=-1.21, P>0.05). A multiple regression indicated that psychological distress and self-efficacy were the only two variables that uniquely contributed to resilient behaviour. CONCLUSION: Resilience is an important psychological process in the longer-term management of SCI which can be promoted by targeting rehabilitation interventions towards mood management in addition to self efficacy beliefs. Larger-scale research will help to validate these results. PMID- 23689392 TI - Neglected traumatic spinal cord injuries: experience sharing from Pakistan. PMID- 23689393 TI - Permanent mechanical deformation of an intrathecal baclofen pump secondary to scuba diving: a case report. AB - STUDY DESIGN: Case report. OBJECTIVES: To describe the case of a spinal cord injury patient that went scuba diving resulting in a mechanical deformation of his intrathecal baclofen pump. SETTING: University Hospitals Leuven, Belgium. METHODS: Case report. RESULTS: Diving below 10 meters of depth can result in irreversible mechanical damage of the drug reservoir of an intrathecal baclofen pump. CONCLUSION: Patients with an intrathecal baclofen pump should be warned for the risks associated with scuba diving and should not dive more than 10 meters below sea level. PMID- 23689394 TI - Testicular sperm retrieval and intra cytoplasmic sperm injection provide favorable outcome in spinal cord injury patients, failing conservative reproductive treatment. AB - STUDY DESIGN: Retrospective cohort analysis. OBJECTIVES: The objective of this study was to determine the in vitro fertilization (IVF) outcome after testicular sperm extraction (TESE) in a group of spinal cord injury (SCI) male patients not compatible with conservative fertility treatment. SETTING: University-affiliated medical center. METHODS: Thirty two SCI patients (C2 to L2) were referred to IVF after repeated trials of electroejaculation (EEJ) or penile vibratory stimulation (PVS), and full andrological evaluation. Testicular sperm aspiration (TESA) was the method of choice for sperm extraction. Open TESE was performed only after a negative TESA attempt. Clinical pregnancy and live birth rates were determined. RESULTS: A total of 106 testicular procedures were performed. Sperm was found in 95 cycles (89.6%). The average metaphase II (MII) oocyte number was 11.0+/-4.2, an average of 5.1+/-2.3 oocytes became normally fertilized after Intra Cytoplasmic Sperm Injection (ICSI) (fertilization rate 57.1%). On average, 2.7+/ 1.2 embryos were replaced. The clinical pregnancy rate was 32/106 (30.2%) per cycle and 19/32 (59.3%) per couple. Live birth rate was 62.5% (20/32). CONCLUSIONS: TESA/E and IVF can provide excellent prognosis for SCI patients that cannot be treated by EEJ or PVS. PMID- 23689395 TI - Poly(propylene imine) dendrimer caps on mesoporous silica nanoparticles for redox responsive release: smaller is better. AB - To elucidate the importance of the size of capping agents in stimulus-induced release systems from mesoporous silica nanoparticles (MSNs), the effectiveness of poly(propylene imine) dendrimers in controlling the model drug release was studied. MCM-41-type MSNs were synthesized and characterized. Fluorescent compounds (fluorescein disodium salt and carboxyfluorescein) were loaded in the porous structure of the MSNs and entrapped in the silica matrix with the dendrimers of generations I through V by anchoring dendrimers on the MSN surface through disulfide bonds. Stimulus-induced release of the cargo was studied in the presence of dithiothreitol (DTT). Dendrimers of generations I and II were found to be more effective in model drug retention and subsequent release than higher generations. Moreover, MSNs modified with larger amounts of dendrimers lowered the cargo release in the presence of DTT. These findings are of importance for optimizing drug delivery systems based on responsive MSNs as they enable tuning of the amount of the released cargo by choosing the capping agent of appropriate size. PMID- 23689396 TI - Extradural hematoma in children: case series of 33 patients. AB - BACKGROUND: Conservative management of extradural hematomas (EDH) is relatively recent in the literature and there are few papers reporting on the pediatric population. OBJECTIVE: We conduct a 20-month assessment of the treatment administered for EDH at a pediatric intensive care unit (PICU). METHODS: A retrospective case series in the period described above. The main variables studied were the weight and age of the patients, the Pediatric Trauma Score, the mechanism of injury, clinical features, CT findings and the Glasgow Coma Scale score on arrival, and after 12 and 24 h. Also analyzed was whether during primary care either surgical intervention or initial conservative management was recommended. RESULTS: In the 20 months analyzed, 33 EDH patients were admitted to the PICU. Patients had a mean age of 7.42 +/- 4.66 years, mean weight of 31.16 +/ 16.16 kg and mean Pediatric Trauma Scores of 7.03 +/- 3.71. Out of the total sample, surgery was indicated in 12 patients (36.4%) in primary care and 21 patients (63.6%) were treated with initial conservative management. Most of the patients who were given conservative treatment had a Glasgow Coma Scale score of 15 on arrival and maintained this level throughout the hospital stay. The most prevalent sites of the hematomas were the temporal and parietal regions and the most common associated injury was skull fracture. CONCLUSION: In this case series, conservative treatment of EDH was most frequent; however, which factors are involved in this decision has to be better studied. PMID- 23689398 TI - A novel mutation in two families with pycnodysostosis. PMID- 23689397 TI - A postural reflex evoked by brief axial accelerations. AB - Impulsive stimuli were used to evoke postural reflexes in healthy subjects (n = 10) and avestibular patients (n = 2). Electromyographic (EMG) activity was recorded with subjects standing erect, feet together with eyes closed and leaning forward to activate their leg muscles. EMG was recorded bilaterally from over the soleus muscles, rectified and averaged. The evoked response was biphasic and consisted of a short latency (SL) and a smaller medium latency (ML) response, at approximately 60 and 80 ms post-stimulus, respectively. Reflex amplitude was expressed as a percentage of the prestimulus level. Stimulus rise times of 10 and 14 ms evoked the largest responses. SL responses were largest when stimulating at the vertebra prominens (C7) or over the mid-thoracic region (C7: 56 +/- 42%, mid thoracic: 56 +/- 51%). Positive (push) stimuli evoked larger responses than negative stimuli which evoked an initial inhibition (C7 positive: 56 +/- 42%, C7 negative: -12 +/- 5%). Similarly, increasing intensity also produced larger responses (standard intensity: 56 +/- 42%; increased intensity: 80 +/- 53%). There was no apparent EMG response in the sitting condition, despite activation of calf muscles, indicating the reflex was dependent on posture. Avestibular patients had well-formed responses similar to normals (patients: SL = 137.5 and 84.5%, ML = -11.6 and -16.2%) with mildly prolonged latencies. This study has described the basic properties of a reflex evoked by impulsive accelerations of the trunk that we propose is not primarily dependent upon vestibular afferents and is likely to have a role in normal postural stability. A truncal origin of the receptors mediating the response best fits our observations and is an alternative explanation for some previous reports about postural reflexes in response to limb displacements. PMID- 23689399 TI - Syndromic congenital diarrhea because of the SPINT2 mutation showing enterocyte tufting and unique electron microscopy findings. PMID- 23689402 TI - Comparing neuromyelitis optica and multiple sclerosis severity: is there a difference? PMID- 23689403 TI - Pompe disease: further challenges to pursue. PMID- 23689401 TI - Antimicrobial autophagy: a conserved innate immune response in Drosophila. AB - Autophagy is a highly conserved degradative pathway that has rapidly emerged as a critical component of immunity and host defense. Studies have implicated autophagy genes in restricting the replication of a diverse array of pathogens, including bacteria, viruses and protozoans. However, in most cases, the in vivo role of antimicrobial autophagy against pathogens has been undefined. Drosophila provides a genetically tractable model system that can be easily adapted to study autophagy in innate immunity, and recent studies in flies have demonstrated that autophagy is an essential antimicrobial response against bacteria and viruses in vivo. These findings reveal striking conservation of antimicrobial autophagy between flies and mammals, and in particular, the role of pathogen-associated pattern recognition in triggering this response. This review discusses our current understanding of antimicrobial autophagy in Drosophila and its potential relevance to human immunity. PMID- 23689404 TI - Patients with neuromyelitis optica have a more severe disease than patients with relapsingremitting multiple sclerosis, including higher risk of dying of a demyelinating disease. AB - Although neuromyelitis optica (NMO) is known to be a more severe disease than relapsing-remitting multiple sclerosis (RRMS), few studies comparing both conditions in a single center have been done. METHODS: Comparison of our previously published cohort of 41 NMO patients with 177 RRMS patients followed in the same center, from 1994 to 2007. RESULTS: Mean age of onset was 32.6 for NMO and 30.2 for RRMS (p=0.2062) with mean disease duration of 7.4 years for NMO and 10.3 years for RRMS. Patients with NMO had a higher annualized relapse rate (1.0 versus 0.8, p=0.0013) and progression index (0.9 versus 0.6, p<0.0001), with more patients reaching expanded disability status scale (EDSS) 6.0 (39 versus 17%, p=0.0036). The odds ratio for reaching EDSS 6.0 and being deceased due to NMO in comparison to RRMS were, respectively, 3.14 and 12.15. CONCLUSION: Patients with NMO have a more severe disease than patients with RRMS, including higher risk of dying of a demyelinating disease. PMID- 23689405 TI - Muscle biopsy in Pompe disease. AB - Pompe disease (PD) can be diagnosed by measuring alpha-glucosidase levels or by identifying mutations in the gene enzyme. Muscle biopsies can aid diagnosis in doubtful cases. METHODS: A review of muscle biopsy from 19 cases of PD (infantile, 6 cases; childhood, 4 cases; and juvenile/adult, 9 cases). RESULTS: Vacuoles with or without glycogen storage were found in 18 cases. All cases had increased acid phosphatase activity. The vacuole frequency varied (almost all fibers in the infantile form to only a few in the juvenile/adult form). Atrophy of type 1 and 2 fibers was frequent in all forms. Atrophic angular fibers in the NADH-tetrazolium reductase and nonspecific esterase activity were observed in 4/9 of the juvenile/adult cases. CONCLUSION: Increased acid phosphatase activity and vacuoles were the primary findings. Most vacuoles were filled with glycogen, and the adult form of the disease had fewer fibers with vacuoles than the infantile or childhood forms. PMID- 23689406 TI - Prevalence and risk factors for stroke in a population of Southern Brazil. AB - Stroke is the leading cause of death in many countries of Latin America. Population studies are necessary in this region. OBJECTIVES: To evaluate the prevalence of stroke and its risk factors in a population of vulnerable communities of southern Brazil. METHODS: Population-based crosssectional study with systematic sampling. Individuals aged 20 and over were included (n=3,391). Individuals with previous diagnosis of stroke or identified by a validate stroke questionnaire were compared with those without stroke in many variables. RESULTS: 285 individuals (8.4%) had previous stroke. The group without stroke showed greater average of years of study than the group with stroke (p<0.001). Multivariable analysis identified as risk factors for stroke (p<0.05): age from 40 to 59, age from 60 to 79, widowhood, present smoking, previous smoking, hypertension and ischemic heart disease. CONCLUSION: The findings in this population indicate the need of preventive cost-effective public health policies in Brazil. PMID- 23689407 TI - Microsurgical ressection for parasagittal meningiomas with preservation of the parasagittal sinus and excelent neurovascular control. AB - OBJECTIVE: It was to observe whether a microsurgical gross total removal (GTR) of a parasagittal meningioma (PSM) outside the sinus is a safe and efficient procedure. METHOD: We identify 58 parasagittal meningiomas patients. Medical charts, operative reports, imaging studies and clinical follow-up evaluations were reviewed. RESULTS: GTR of the mass was achieved in 45 (77.7%) instances. The surgical mortality rate was 1.7%. The median follow-up time was 63 months. CONCLUSION: The surgical approach used in this group of patients afford that the great majority of tumors could be totally removed with low mortality, proving to be safe and effective. PMID- 23689408 TI - Clinical and laboratorial characterization and post-surgical follow-up of 87 patients with non-functioning pituitary macroadenomas. AB - OBJECTIVE: It was to assess the main characteristics of patients undergoing pituitary tumor surgery. METHOD: Eighty-seven patients (44 men; 44.8+/-13 years old) were included. RESULTS: The main symptoms were visual alterations (87.3%), headache (70.1%), diminished libido (34.4%), galactorrhea (22.9%) and hair loss (19.5%). The axes affected were gonadotropic (72.6%), thyrotropic (48.4%) and corticotropic (38.7%), without significant changes after surgery. The average largest tumor diameter was 3.1 cm before surgery and 1.56 cm after surgery. The most frequent postoperative complications were hydro-electrolyte and acid-base disorders (12%), diabetes insipidus (9%), visual field alterations (9%), liquoric fistula (8%) and nasal obstruction (7%). The patients were affected by more than one complication. CONCLUSION: Although a decrease in tumor volume was achieved through surgery, hormonal deficiencies persisted in most of the patients and new surgical approaches were necessary for dealing with tumor recurrence or persistence. PMID- 23689409 TI - Brain tissue oxidative damage as a possible mechanism for the deleterious effect of a chronic high dose of estradiol on learning and memory in ovariectomized rats. AB - In addition to antioxidative effects, estrogens also exert pro-oxidative actions. The effect of chronic administration of a high dose of estradiol valerate on Morris water maze tasks and brain tissues oxidative damage was investigated. The Sham-Est and OVX-Est groups were treated with estradiol valerate (4 mg/kg) for 12 weeks. Escape latency and traveled path in the Sham-Est and OVX-Est groups were significantly higher than in the Sham and OVX groups (p<0.01 and p<0.001). In the probe trial, the animals of the Sham-Est and OVX-Est groups spent lower time in Q1 compared to Sham and OVX groups (p<0.05 and p<0.001). In Sham-Est and OVX-Est groups, the brain tissue total thiol concentration was significantly lower, and malondialdehyde (MDA) concentrations were higher than in the Sham and OVX groups (p<0.05 and p<0.001). It is concluded that administration of high exogenous levels of estradiol impairs performance and enhances oxidative stress. PMID- 23689410 TI - Is there a consistent association between coronary heart disease and ischemic stroke caused by intracranial atherosclerosis? AB - Coronary heart disease and ischemic stroke are frequent coexistent conditions that share risk factors and pose major burdens to global health. Even though a clear relation has been established between extracranial internal carotid artery atherosclerosis and symptomatic or asymptomatic coronary heart disease, there is a gap in knowledge about the association between intracranial atherosclerosis and coronary heart disease. Intracranial atherosclerosis is associated with high risks of stroke recurrence and vascular death. More research and clinical trials are needed to answer whether early diagnosis of asymptomatic coronary heart disease and aggressive treatment can decrease the risk of vascular death in patients with ischemic stroke caused by intracranial atherosclerosis. PMID- 23689411 TI - Where is Gilles? Or, the little mistake in a copy of Brouillet's painting: "a clinical lesson at the Salpetriere". AB - Professor Jean-Martin Charcot is considered the most important professor of Neurology and also the head of the Salpetriere School of Neurology. In a famous picture painted by Andre Brouillet and presented at the Salon of 1887, under the title "A clinical lesson at the Salpetriere", Professor Charcot presents a case of hysteria to a large audience of physicians and renowned intellectuals. Copies of this guided picture are also available for sale at the shop of the Museum of the School of Medicine of Paris and are frequently used in lectures by neurologists worldwide. However, in these reproductions, Gilles de la Tourette's and Charles Fere's positions are inverted. This historical note sheds some light on this little mistake in some of the reproductions of Brouillet's famous painting, so that further confusion can be avoided. PMID- 23689412 TI - Expanded endonasal approach to skull base meningiomas. PMID- 23689413 TI - Proptosis in a family with the p16 Leuc-to-Prol mutation in the PMP22 gene (CMT 1E). PMID- 23689414 TI - Pseudotumoral presentation of primary central nervous system vasculitis. PMID- 23689415 TI - SMART syndrome: a late reversible complication of radiotherapy. PMID- 23689416 TI - Surgical treatment of an anterior cranial fossa dural fistula. PMID- 23689417 TI - Prognosis of dialysed patients after kidney transplant failure. AB - BACKGROUND/AIMS: Patients with a failed kidney transplant represent a unique, high-risk chronic kidney disease population that is increasing in number, and may be sub-optimally managed. Our aim was to compare the survival of patients with failed allografts to patients with native kidney failure and to assess whether their survival is affected by the graft resection. METHODS: Kaplan-Meier and Cox regression survival analyses were performed on the data of 57 patients with graft failure and of 123 transplant-naive haemodialysed patients. RESULTS: After adjustment for age and gender, there was no statistically significant difference in the mortality of patients in the two groups. The 43 patients, who had a transplanted kidney nephrectomy had a statistically not significant survival benefit over non-nephrectomised patients (age and gender adjusted hazard ratio: 0.56 95 % confidence interval: 0.24-1.58, p-value: 0.18). CONCLUSION: Elective graft resection is a safe, effective alternative for both the treatment and the prevention of the chronic inflammatory state associated with a failed kidney transplant. PMID- 23689418 TI - Stunting the growth of child health research: a need to reframe "children are not small adults". PMID- 23689419 TI - Human papillomavirus 16-positive uterine cervical squamous cell carcinoma with coinfection with human papillomavirus 34 has a lower incidence in lymph node metastasis than that without coinfection with human papillomavirus 34. AB - Our earlier study demonstrated high prevalence of multiple human papillomavirus (HPV) infection in patients with invasive uterine cervical cancer, including squamous cell carcinoma (SCC). HPV 16 is the most predominant genotype related to SCC of the uterine cervix. The aim of this study was to reveal the biological significance of multiple HPV infection concerning the tumor progression of invasive uterine cervical SCC. In the present study, the effects of coinfection with genotypes other than HPV 16 on tumor growth and lymph node metastasis of invasive uterine cervical SCC with HPV 16 infection were examined. Although coinfection with most genotypes did not influence tumor progression, the clinical stage of patients coinfected with HPV 16 and HPV 34 was significantly lower than that of those without HPV 34 coinfection (p = 0.0038). Moreover, no patient coinfected with HPV 16 and HPV 34 manifested lymph node metastasis, but about half of the patient population without HPV 34 coinfection did (p = 0.0299). These findings suggested that coinfection with HPV 34 could prevent the tumor progression of invasive uterine cervical SCC with HPV 16 infection. PMID- 23689421 TI - Unconscious relational traumatic memory and its relevance to 'everyday' clinical psychiatry. AB - OBJECTIVE: The aim of this paper is to demonstrate the relevance of the concept of unconscious relational traumatic memory to 'everyday' clinical psychiatry. METHOD: One clinical vignette and concepts from the Conversational Model of Psychotherapy are used to consider the potential relevance of this type of memory. CONCLUSIONS: The influence of modern classification systems and the dominance of the paradigm of 'biological psychiatry' over the last 30 years have together led to an emphasis on diagnosis and treatment by symptom cluster. This perspective may overlook both the patient's current psycho-social context and their personal history. An understanding of unconscious relational traumatic memory may assist in both the conceptualisation and the treatment of many patients, particularly those adults who have been abused in childhood, where the link between the early experiences and the late manifestations are frequently lost. PMID- 23689422 TI - Formation of ternary CaUO2(CO3)3(2-) and Ca2UO2(CO3)3(aq) complexes under neutral to weakly alkaline conditions. AB - The chemical behavior of ternary Ca-UO2-CO3 complexes was investigated by using time-resolved laser fluorescence spectroscopy (TRLFS) in combination with EDTA complexation at pH 7-9. A novel TRLFS revealed two distinct fluorescence lifetimes of 12.7 +/- 0.2 ns and 29.2 +/- 0.4 ns for uranyl complexes which were formed increasingly dependent upon the calcium ion concentration, even though nearly indistinguishable fluorescence peak shapes and positions were measured for both Ca-UO2-CO3 complexes. For identifying the stoichiometric number of complexed calcium ions, slope analysis in terms of relative fluorescence intensity versus calcium concentration was employed in a combination with the complexation reaction of CaEDTA(2-) by adding EDTA. The formation of CaUO2(CO3)3(2-) and Ca2UO2(CO3)3(aq) was identified under given conditions and their formation constants were determined at I = 0.1 M Na/HClO4 medium, and extrapolated to infinitely dilute solution using specific ion interaction theory (SIT). As a result, the formation constants for CaUO2(CO3)3(2-) and Ca2UO2(CO3)3(aq) were found to be log beta113(0) = 27.27 +/- 0.14 and log beta213(0) = 29.81 +/- 0.19, respectively, providing that the ternary Ca-UO2-CO3 complexes were predominant uranium(vi) species at neutral to weakly alkaline pH in the presence of Ca(2+) and CO3(2-) ions. PMID- 23689420 TI - A zebrafish model for uremic toxicity: role of the complement pathway. AB - Many organic solutes accumulate in end-stage renal disease (ESRD) and some are poorly removed with urea-based prescriptions for hemodialysis. However, their toxicities have been difficult to assess. We have employed an animal model, the zebrafish embryo, to test the toxicity of uremic serum compared to control. Serum was obtained from stable ESRD patients predialysis or from normal subjects. Zebrafish embryos 24 h postfertilization were exposed to experimental media at a water:human serum ratio of 3:1. Those exposed to serum from uremic subjects had significantly reduced survival at 8 h (19 +/- 18 vs. 94 +/- 6%, p < 0.05, uremic serum vs. control, respectively). Embryos exposed to serum from ESRD subjects fractionated at 50 kDa showed significantly greater toxicity with the larger molecular weight fraction (83 +/- 11 vs. 7 +/- 17% survival, p < 0.05, <50 vs. >50 kDa, respectively). Heating serum abrogated its toxicity. EDTA, a potent inhibitor of complement by virtue of calcium chelation, reduced the toxicity of uremic serum compared to untreated uremic serum (96 +/- 5 vs. 28 +/- 20% survival, p < 0.016, chelated vs. nonchelated serum, respectively). Anti-factor B, a specific inhibitor of the alternative complement pathway, reduced the toxicity of uremic serum, compared to untreated uremic serum (98 +/- 6 vs. 3 +/- 9% survival, p < 0.016, anti-factor B treated vs. nontreated, respectively). Uremic serum is thus more toxic to zebrafish embryos than normal serum. Furthermore, this toxicity is associated with a fraction of large size, is inactivated by heat, and is reduced by both specific and nonspecific inhibitors of complement activation. Together these data lend support to the hypothesis that at least some uremic toxicities may be mediated by complement. PMID- 23689423 TI - MicroRNA profiling in chemoresistant and chemosensitive acute myeloid leukemia. AB - MicroRNA (miRNA) deregulation is associated with progression and treatment outcome in various types of cancers. To identify miRNAs related to therapeutic response, we applied an miRNA microarray followed by PCR verification of 33 available diagnostic bone marrow core biopsies from 33 acute myeloid leukemia patients including 15 chemoresistant and 18 chemosensitive patients. We found 3 significantly upregulated miRNAs, miR-363, miR-532-5p and miR-342-3p, related to therapeutic response (q < 0.05). Further validation of miR-532-5p and miR-363 expression by quantitative RT-PCR confirmed microarray analysis results. Genes targeted by miR-363 include RGS17 and HIPK3, both reported to be associated with drug response. PMID- 23689424 TI - Effect of oxide supports in stabilizing desirable Pt-Ni bimetallic structures for hydrogenation and reforming reactions. AB - Previous surface science studies have shown that bimetallic surfaces often show unique activity for reactions involving the consumption and production of hydrogen, such as hydrogenation and reforming reactions, respectively. These two types of reactions require different bimetallic configurations. For example, for the Pt-Ni bimetallic system, the desirable structure is Pt-terminated for hydrogenation while Ni-terminated for reforming. In the current study, 1,3 butadiene hydrogenation and ethanol reforming were used as probe reactions to investigate the effect of oxide supports (gamma-Al2O3 and TiO2) on the structural and catalytic properties of Pt-Ni catalysts. The supported catalysts were characterized by transmission electron microscopy (TEM) and extended X-ray absorption fine structure (EXAFS). The reactions were carried out in a batch reactor equipped with a Fourier transform infrared (FTIR) spectrometer. For ethanol reforming, Pt-Ni/TiO2 showed higher activity than Pt-Ni/gamma-Al2O3, and the Pt-Ni bimetallic catalyst outperformed the monometallic catalysts on TiO2 but not on gamma-Al2O3. In contrast, for 1,3-butadiene hydrogenation, Pt-Ni/TiO2 showed much lower activity than Pt-Ni/gamma-Al2O3. Density functional theory (DFT) calculations of Pt-Ni nanoparticles on gamma-Al2O3 and TiO2 were performed to provide possible explanations for the different modification effects of the two oxide supports. PMID- 23689425 TI - Identification and functional characterization of a Ku-binding motif in aprataxin polynucleotide kinase/phosphatase-like factor (APLF). AB - Aprataxin polynucleotide kinase/phosphatase-like factor (APLF) facilitates nonhomologous end joining (NHEJ) and associates with the core NHEJ components XRCC4-DNA ligase IV and Ku. The APLF forkhead-associated (FHA) domain directs interactions with XRCC4, but the APLF-Ku interaction has not been well characterized. Here we describe an evolutionarily conserved amino acid motif within APLF that is required for mediating the physical interaction between APLF and Ku. This APLF Ku-binding motif possesses a similarity to regions identified in other NHEJ factors, WRN and XLF, which also direct interactions with Ku. Indeed, peptides derived from the Ku-binding region of APLF, WRN, or XLF were sufficient to reconstitute the interaction with Ku in vitro. Although APLF is localized predominantly to the nucleus, it does not possess a nuclear localization signal (NLS). Interestingly, the disruption of the APLF-Ku interaction by substituting key residues in the APLF Ku-binding motif was associated with increased relocalization of APLF to the cytoplasm and reduced association with XRCC4, which was rescued by the introduction of an NLS onto APLF. When human cells stably depleted of APLF were reconstituted with APLF Ku binding mutants, or with an APLF FHA mutant that is known to disrupt interactions with XRCC4, APLF-dependent NHEJ and the retention of APLF at sites of laser generated DNA damage were impaired. These data suggest functional requirements for Ku and XRCC4 in APLF-dependent NHEJ and a unique role for Ku as a factor required to facilitate the nuclear retention of APLF. PMID- 23689426 TI - Plasmon-enhanced light harvesting of chlorophylls on near-percolating silver films via one-photon anti-Stokes upconversion. AB - There exists a wealth of means of efficient utilization of solar energy in nature, with photosynthesis of chlorophylls as a prime example. Separately, artificially structured plasmonic materials are versatile in light harvesting and energy conversion. Using a simple and scalable design of near-percolating silver nanostructures, we demonstrate that the light-harvesting efficiency of chlorophylls can be drastically enhanced by tuning the plasmon frequency of the constituent silver nanoparticles to coincide with the maximal photon flux of sunlight. In particular, we show that the photon upconversion efficiency can be readily enhanced by over 20 folds, with the room-temperature fluorescence quantum yield increased by a factor of 2.63. The underlying mechanism for the upconversion enhancement is attributed to a one-electron-per-photon anti-Stokes process, involving absorption of a characteristic phonon mode of the chlorophylls. These findings suggest that chlorophylls can serve as molecular building blocks for high-efficiency light harvesting and solar energy conversion. PMID- 23689427 TI - Estimating quality of life in acute venous thrombosis. AB - IMPORTANCE: Future funding for new treatments in venous thromboembolism will be guided by cost-utility analyses. There is little available information on the utility of acute venous thromboembolism, limiting the validity of economic analyses. OBJECTIVE: To measure the quality of life in the health states relating to thromboembolism cost-utility analyses. DESIGN: A prospective cohort study. SETTING: A single-center, university-affiliated thrombosis clinic. PARTICIPANTS: Two hundred sixteen thrombosis clinic patients with a history of lower limb deep vein thrombosis (DVT) or pulmonary embolism (PE). EXPOSURES: Participants consented to take a standard gamble interview. Each participant rated the quality of life in acute DVT, acute PE, and bleeding complication health states. MAIN OUTCOMES AND MEASURES: The standard gamble measured quality of life (utility value) for acute DVT, acute PE, major intracranial bleeding event, minor intracranial bleeding event, and gastrointestinal bleeding event. RESULTS: Two hundred fifteen responses were included in the analysis. Twenty-six percent had experienced both PE and DVT; 54%, DVT alone; and 20%, PE alone. Forty-two percent had experienced more than 1 episode of thrombosis, and 23% had had cancer associated thrombosis. We found the median utility for acute DVT was 0.81 (interquartile range [IQR], 0.55-0.94); acute PE, 0.75 (IQR, 0.45-0.91); major intracranial bleeding event, 0.15 (IQR, 0.00-0.65); minor intracranial bleeding event, 0.75 (IQR, 0.55-0.92); and gastrointestinal bleeding event, 0.65 (IQR, 0.15-0.86). The median length of symptoms for DVT or PE was 1 week (IQR, <1-3 weeks). CONCLUSIONS AND RELEVANCE: To our knowledge, this is the largest published study on utilities in which the participants had personal experience of venous thromboembolism. We present unique information for economic analyses but have also identified future challenges for research in this area. Our summary results differ from those previously published, and we found wide variation in individual responses. PMID- 23689428 TI - Cerebral and hepatic inflammatory response after neonatal hypoxia-ischemia in newborn rats. AB - BACKGROUND: Neonatal encephalopathy induced by perinatal asphyxia is a serious condition associated with high mortality and morbidity. Inflammation after the insult is thought to contribute to brain injury. This inflammatory response to hypoxia-ischemia (HI) may not only occur in the brain but also in peripheral organs. The aim of the present study was to investigate the effect of neonatal HI on the inflammatory response in the liver in comparison to inflammation in the brain. METHODS: HI was induced in P7 Wistar rats by unilateral carotid artery occlusion and hypoxia. Cytokine and chemokine mRNA levels were determined in the brain and liver by quantitative PCR. Polarization of brain macrophages to the M1/M2-like phenotype and infiltration of neutrophils were characterized by immunohistochemistry. RESULTS: 3 h after HI, an upregulation of the proinflammatory cytokines TNF-alpha and IL-1beta and anti-inflammatory IL-10 was observed in the ipsilateral hemisphere of the brain compared to mRNA levels in sham-operated animals. Additionally, cerebral CINC-1 and MCP-1 mRNA expressions were increased. We also observed increased numbers of macrophages/microglia of the M1-like phenotype as well as a small increase in granulocyte influx in the ipsilateral hemisphere. Conversely, in the liver 3 h after HI, a downregulation of TNF-alpha, IL-1beta, and MCP-1 and a trend towards an upregulation of IL-10 were observed compared to mRNA levels of sham-operated animals. However, hepatic CINC-1 expression was increased compared to levels in sham-operated animals. Following systemic hypoxia only, no significant changes in the expression of TNF alpha, CINC-1 or MCP-1 were observed in the liver compared to sham-operated littermates, except for an upregulation in hepatic IL-1beta expression 3 h after hypoxia. Twenty-four hours after insult, cerebral ipsilateral TNF-alpha, MCP-1 and CINC-1 mRNA expression was still increased, together with an increase in TGF beta expression. Moreover, an increase in macrophages/microglia of the M1-like phenotype was observed together with the appearance of macrophages/microglia of the M2-like phenotype around the cerebral lesion as well as an increase in granulocyte influx in comparison to 3 h after HI. In the liver, 24 h after HI, cytokine and chemokine responses were similar to mRNA levels in sham-operated animals except for a decrease in IL-10 and MCP-1. CONCLUSION: We describe for the first time that brain damage following neonatal HI induces an early downregulation of the proinflammatory response in the liver. HI induces an early proinflammatory response in the brain with a concomitant increase in influx of neutrophils and polarization of macrophages/microglia to the M1-like phenotype starting at 3 h and increasing up to 24 h after HI. The inflammatory state of the brain changes after 24 h, with an increase in the anti-inflammatory cytokine TGF beta together with the appearance of macrophages/microglia of the M2-like phenotype. The downregulation of proinflammatory cytokines in the liver is not due to systemic hypoxia only, but is induced by the cerebral damage. PMID- 23689429 TI - Detection of ALK-positive non-small-cell lung cancers on cytological specimens: high accuracy of immunocytochemistry with the 5A4 clone. AB - INTRODUCTION: Lung cancer is often diagnosed by cytology, necessitating predictive molecular marker analyses on cytological specimens. The gold standard for detection of predictive anaplastic lymphoma kinase (ALK)-rearrangements is fluorescence in situ hybridization (FISH), but FISH is both expensive and often challenging to interpret. The aim of our study was to investigate the accuracy of ALK immunocytochemistry (ICC) on cytological specimens of non-small-cell lung cancers (NSCLCs). METHODS: Forty-one cytological specimens with available ALK FISH results were retrospectively analyzed with the 5A4 monoclonal antibody (Novocastra; Leica Biosystems) on a fully automated slide stainer. The specimens were enriched for ALK FISH-positive NSCLCs (14 of 41; 34.1%). Evaluation of the ICC staining was performed blinded to the FISH results. The staining intensity and the percentage of stained cancer cells were recorded. Any ICC staining was regarded as a positive result. The ALK ICC results were compared with the FISH results. In case of a discrepancy the ICC-stained slide and the FISH signals were reviewed. RESULTS: ICC was evaluable on 40 of 41 specimens. Fifteen of 40 NSCLCs (37.5%) were ALK ICC-positive, with staining of the majority of cancer cells (median 100%; mean 82.3%). Twelve of the ICC-positive NSCLCs (80.0%) showed an intense staining (3+). Compared with the ALK FISH results, only one NSCLC was false-negative, and one false-positive by ICC, respectively. The sensitivity, specificity, and positive and negative predictive values for ALK ICC compared with ALK FISH were 93.3%, 96.0%, 93.3%, and 96%, respectively. CONCLUSION: ALK ICC is highly accurate for detecting ALK-rearranged NSCLCs. PMID- 23689430 TI - Vandetanib plus chemotherapy for induction followed by vandetanib or placebo as maintenance for patients with advanced non-small-cell lung cancer: a randomized phase 2 PrECOG study (PrE0501). AB - INTRODUCTION: After early reports of vandetanib's efficacy in the induction setting, we evaluated the effect of combination docetaxel, carboplatin, and vandetanib, followed by maintenance therapy with either vandetanib, or placebo on progression-free survival (PFS) in patients with advanced non-small-cell lung cancer. METHODS: Patients with advanced non-small-cell lung cancer were randomized to induction docetaxel (75 mg/m) + carboplatin (area under the curve of 6) on day 1 of a 21-day cycle, and daily vandetanib (100 mg/day orally) for four cycles, followed by daily vandetanib (300 35 mg/day orally) or placebo until progression. Eligible patients had measurable disease, Eastern Cooperative Oncology Group performance status 0 of 1, and no prior cytotoxic or targeted agents for advanced disease. RESULTS: One hundred sixty-two patients were randomized; 158 began induction treatment. Fifty-eight patients began maintenance vandetanib or placebo (median, 3.5 cycles). Median PFS for patients randomized to maintenance vandetanib was 4.5 months (95% confidence interval, 3.3-5.8 months), and for patients randomized to maintenance placebo was 4.2 months (95% confidence interval, 2.8-4.9 months). An exploratory analysis showed prolonged PFS for patients randomized to vandetanib maintenance (stratified log-rank p= 0.07) as also in a multivariate model adjusting for sex and stage (p= 0.02). Differences in PFS were not observed among patients who began maintenance therapy. Toxicities were similar to other studies of these agents. CONCLUSION: Neither arm showed improvement over historical median PFS of 4.6 months, although patients who began maintenance and were randomized to vandetanib had somewhat better outcomes than those randomized to placebo. Given its acceptable toxicity profile, there may be a role for vandetanib in maintenance. PMID- 23689431 TI - Young drivers and the risk for drowsy driving. PMID- 23689432 TI - [Posttraumatic stress symptoms, dysfunctional attitudes and ways of coping in a clinical sample of PTSD patients]. AB - INTRODUCTION: In the present study specific characteristics of PTSD patients were explored in a clinical sample with particular regard to dysfunctional attitudes and coping strategies. The purpose was to draw attention to this rarely investigated but presumably prevalent psychiatric disorder in the Hungarian population. METHOD: Twenty-two PTSD patients' retrospective data was analyzed who presented at our clinic for outpatient psychotherapy treatment. Patients were assessed on depressive, anxiety, hopelessness, and posttraumatic stress symptoms, as well as dysfunctional attitudes and coping strategies. RESULTS: Thirty-two percent (n=7) of the sample is male and 68% (n=15) is female, the mean age is 34.77 years. Based on trauma type 40.9% (n=9) had a motor vehicle accident, 18.2% (n=4) lost a close relative, 18.2% (n=4) was a victim of sexual or physical assault. There is great variance in the duration since the trauma (2 months to 10 years). The results suggest that posttraumatic stress symptoms (PTSSs) are associated with the dysfunctional attitudes of need for achievement and external control, and with avoidant and conforming coping styles. Additionally, PTSSs were highly comorbid with depressive and anxiety symptoms. CONCLUSION: The results imply that PTSD patients in Hungary have similar characteristics as international findings indicate. PMID- 23689433 TI - [Problems of aggressive behaviour and its measurement in various age levels. Introduction of two questionnaires]. AB - Authors give a detailed overview on aspects of aggressive behaviour in childhood and adolescence especially on the basis of the literature of the last two decades, then. the measurement opportunities of aggression is discussed. The Children's Aggression Scale- parent version (Halperin et al 2002) rated by parents is presented and Hungarian validity data are published. In the second part of the publication, authors focus on the viewpoints of differences between aggressiveness of IQ deficit people and those of having normal intelligence, preliminary experiences are reported about the behavioural dimensions of intellectually disabled (ID) patients rated by the Behaviour Problem Inventory (BPI, Rojahn et al, 2001) suitable for measuring frequency and severity of behavioural qualities of both ID adolescents and adults. PMID- 23689434 TI - [Methodological background and descriptive features of the ESPAD 2011 Study (European School Survey Project on Alcohol and other Drugs) in Hungary]. AB - BACKGROUND AND AIMS: The aim of the ESPAD (European School Survey Project on Alcohol and other Drugs) study - launched in 1995 and repeated in every four years - is to collect representative data on alcohol and drug consumption patterns of the 16 year old population, in as many European countries as possible. METHOD: The survey followed standardized methodology to gain comparable data in every participating country. Students fill in the self-report questionnaire during a school lesson. Beside the compulsory core-question blocks, the Hungarian survey in 2011 contained questions on behavioral addictions (online gaming, internet, eating disorders and gambling) as well. All classes were included into the sample pool, where at least 10% of the students were born in 1995. Data collection took place between 1-20 March 2011. The sample was representative in terms of type of school; class and geographic location. RESULTS: Data was gathered from 370 classes and resulted in 8570 questionnaires. Only 0,96 percent of the total collected data was unreliable. Obtained data is valid and reliable; and can be compared to data from previous years, as well as to data from other ESPAD countries. Representative data on behavioral addictions is highly valuable, because our current knowledge is limited on this domain. PMID- 23689435 TI - [Erotica in the arts and brain]. AB - Erotic arts express the relation of a person to his or her sexual orientation. Scrutinizing works of arts of that kind could explore unanswered questions about 'normal' and 'perverse' sexuality. Beyond the possibilities of forensic psychiatry the ethical, legal, and social consequences should be more intensely studied. At the same time the employment of modern functional brain imaging techniques is also warranted in the research of eroticism. PMID- 23689436 TI - [The relationship between reactive/proactive aggression, callous/unemotional traits and behavioural problems in Hungarian adolescents]. AB - INTRODUCTION: The relationship between the type of physical aggressive behavior, callous/unemotional traits and behavioral problems was extensively studied in the literature, but no similar data exist in Hungarian adolescents. AIM: In the present study, the type of aggressive behavior was assessed in adolescents on a normative sample to study its relationship with callous/unemotional traits and behavioral problems. SAMPLE: 223 students were participated in the study after informed consent (girls, n=106, age: 14.2+/-1.5 years; boys, n=117, age: 13.9+/ 1.6 years) from primary and secondary schools in Miskolc and adjacent areas. METHODS: The Reactive/Proactive Aggression Questionnaire was used to assess the level of aggressive behavior, the Inventory of Callous Unemotional Traits was used to measure callous/unemotional traits, while behavioral problems were established by the means of the Strengths and Difficulties Questionnaire. RESULTS: In the present non-clinical sample, the level of reactive aggression was higher than the level of proactive aggressive behavior. In boys, proactive and total aggression measures were significantly higher compared to girls. In both genders, reactive aggression was specifically associated with emotional and peer related problems. Proactive aggression was correlated positively with callous traits in both genders, while self-reported prosocial behavior had an inverse correlation with proactive aggressive behavior in boys. Self reported conduct- and hyperactivity problems were positively correlated with both types of aggressive behavior in both genders. The strongest positive correlation was observed between self-reported conduct symptoms and both types of aggressive behavior. CONCLUSIONS: Callous/unemotional traits were related with proactive forms of aggression, similar to literature data. Reactive aggressive behavior was related to peer-related and emotional problems, thus our data outlined the importance of the distinction between the two main types of aggression. PMID- 23689437 TI - [The pictorial expression of aggression in the drawings of adolescents between the ages of 14 and 16]. AB - The visual expression of adolescent and preadolescent people including their representation of aggression is a neglected field of both the child psychology's and pedagogy's research. The author offers a survey of pubescent people's portrayal of aggression based upon the data of the scientific literature and her own pedagogical experience. The representation of aggression is strongly influenced by the young people's cultural background and the media (history, literature, religion, the traditions of the different nations, and gender too) concerning both form and content. Aggression can appear directly or in a hidden, symbolic way. Pictorial expression aggression is closely bound up with depressed feelings, congestion and humour and can also refer to the fact that the drawing person was sexually, physically or psychologically abused. The survey is completed with a case study that shows the connection between the aggressive content and the anxiety. The case study also calls our attention to the weakness of the pedagogical practice in making use of the self-expressive aspect of visual communication. PMID- 23689438 TI - [Beauticians' eating attitudes and body attitudes]. AB - Some professional groups (models, actresses, ballet dancers, jockeys and athletes) are considered as risk populations for eating disorders and body image disorders. Beauticians may be a possible risk group, as their work is closely related to beauty and fashion. MEASURES: Eating disorders were assessed using the Eating Attitudes Test and the Eating Behaviour Severity Scale, body image measures included the Human Figure Drawings Test, the Body Dissatisfaction Subscale of the Eating Disorders Inventory, the Body Attitudes Test, and the Body Investment Scale. RESULTS: Questionnaire data of 276 subjects were analysed. The study sample comprised 128 beauticians from Transylvania (5 males, 123 females). This group was compared with a control group consisting of 148 subjects (25 males, 123 females). Such weight reducing methods as dieting, exercise, the use of appetite suppressants and diuretics were significantly more prevalent in the beautician group. Mean total score and the scores of the Dieting subscale of the Eating Disorders Inventory were significantly (p < 0.02) higher in the beautician group in comparison with the control group. The prevalence of clinical and subclinical eating disorders (2.4% subclinical bulimia nervosa and 1.6% subclinical anorexia nervosa) was significantly higher in the beautician group. Beauticians invest significantly (p < 0.0001) more money and time for body care. CONCLUSION: The above results suggest that working in the beauty industry may represent an increased risk of developing eating disorders. PMID- 23689439 TI - Expression of insulin-like growth factor 1 and insulin-like growth factor 1 receptor is associated with the favorable clinicopathologic parameters in small intestinal carcinomas. AB - OBJECTIVE: The insulin-like growth factor (IGF) system has been known to play a critical role in tumor development and progression in many human cancers. However, the role of the IGF system in small intestinal carcinoma (SIC) has not been studied yet. METHODS: We evaluated the expression of IGF1 and IGF1 receptor (IFG1R) in a total of 194 cases of SIC. RESULTS: IGF1 expression was associated with well/moderate differentiation, better survival, lower pT, lower stage and no lymph node metastasis. IGF1R was more diffusely and strongly expressed in tumors with lower pT and lower stage. CONCLUSIONS: IGF1 and IGF1R expression is associated with favorable clinicopathologic parameters and may involve early carcinogenesis of SICs. Target therapy for the IGF1R signaling pathway may not have a major therapeutic role in treating SIC. PMID- 23689440 TI - To treat or not to treat? Cost-effectiveness of ace inhibitors in non-diabetic advanced renal disease - a Dutch perspective. AB - BACKGROUND: Treating non-diabetic proteinuric patients with advanced renal disease with an angiotensin-converting enzyme (ACE) inhibitor is still subject to discussion. This study aims to determine the cost-effectiveness of ACE inhibitor therapy in this patient population in the Netherlands. METHODS: We compared two strategies: first, treating patients with advanced renal disease with an ACE inhibitor and no-treatment. A lifetime Markov decision model was developed simulating the progression of renal disease and using published data on costs and health outcomes. A health care perspective was adopted. RESULTS: In the base-case analysis, treatment with ACE inhibitors leads to higher benefits and lower costs and dominates the no-treatment strategy. Sensitivity analysis shows that the probability of savings is 83%. CONCLUSION: ACE inhibitor treatment for non diabetic patients with advanced renal disease in the Netherlands is highly cost effective and should therefore be considered. PMID- 23689442 TI - Bioengineered kidneys at work in rats. PMID- 23689443 TI - Protein directs brain folding during development. PMID- 23689445 TI - Relying on chimpanzees for hepatitis research. PMID- 23689446 TI - Thousands rally for medical research. PMID- 23689447 TI - Synthetic research tools as alternatives to animal models. PMID- 23689449 TI - AACR annual meeting 2013. PMID- 23689450 TI - The simplicity of sea slugs. PMID- 23689451 TI - Federal court dismisses challenge to Animal Enterprise Terrorism Act. PMID- 23689452 TI - Response to protocol review scenario: Experience is not evidence. PMID- 23689453 TI - Scientific justification for exemptions. PMID- 23689454 TI - Response to protocol review scenario: Review institutional policies. PMID- 23689455 TI - Response to protocol review scenario: Scientific justification needed. PMID- 23689456 TI - Response to protocol review scenario: A word from OLAW. PMID- 23689457 TI - Electroejaculation of chimeric rats. AB - With the advent of genetic engineering of rodents came the need to assess fertility and germline competency, especially in chimeric rodents generated using embryonic stem cells. Traditional methods rely on natural mating and progeny testing, which is time- and cost-intensive. Electroejaculation is a faster method of collecting sperm for genetic analysis and offers the additional benefit of using fewer animals. This column describes a refined electroejaculation technique for chimeric rats using light gas anesthesia and a custom-made platform for sperm collection. PMID- 23689459 TI - Abdominal distention in an inbred mouse. PMID- 23689460 TI - Challenges in oral administration of metronidazole dissolved in drinking water to rhesus monkeys (Macaca mulatta). AB - Intestinal pathogens such as Entamoeba spp. and Giardia spp. protozoans are not uncommon among rhesus macaques (Macaca mulatta) in research facilities. These infections affect the health of the macaques, potentially causing severe diarrhea, and also pose a risk of zoonotic transmission to human caretakers. Infections must therefore be treated, but no standard treatment for intestinal protozoans in macaques has been developed. Metronidazole is commonly used to treat infections with Giardia spp. and Entamoeba spp. in veterinary medicine, but evidence-based information on effectiveness and dosages for nonhuman primates is lacking, and administration of drugs to nonhuman primates is challenging. The authors designed a study to determine whether oral administration of metronidazole dissolved in drinking water would be successful in rhesus macaques. They monitored daily fluid intake of macaques given water with or without metronidazole and with or without flavored syrup. Metronidazole addition, with or without flavored syrup, resulted in a decrease in fluid intake. Although it was possible to administer metronidazole in drinking water to some macaques, the authors conclude that this strategy is not a practical clinical method because of variation in the amount of water and metronidazole ingested by the macaques. PMID- 23689462 TI - Transparency in training. PMID- 23689463 TI - Serendipity and targeted hope. PMID- 23689461 TI - Estimation of rat mammary tumor volume using caliper and ultrasonography measurements. AB - Mammary tumors similar to those observed in women can be induced in rats by intraperitoneal administration of N-methyl-N-nitrosourea. Determining tumor volume is a useful and quantitative way to monitor tumor progression. In this study, the authors measured dimensions of rat mammary tumors using a caliper and using real-time compound B-mode ultrasonography. They then used different formulas to calculate tumor volume from these tumor measurements and compared the calculated tumor volumes with the real tumor volume to identify the formulas that gave the most accurate volume calculations. They found that caliper and ultrasonography measurements were significantly correlated but that tumor volumes calculated using different formulas varied substantially. Mammary tumors seemed to take on an oblate spheroid geometry. The most accurate volume calculations were obtained using the formula V = (W(2) * L)/2 for caliper measurements and the formula V = (4/3) * pi * (L/2) * (L/2) * (D/2) for ultrasonography measurements, where V is tumor volume, W is tumor width, L is tumor length and D is tumor depth. PMID- 23689464 TI - Cultivating a positive culture of compliance. PMID- 23689465 TI - Ab initio insight into ultrafast nonadiabatic decay of hypoxanthine: keto-N7H and keto-N9H tautomers. AB - Nonadiabatic dynamics simulations at the SA-CASSCF level were performed for the two most stable keto-N7H and keto-N9H tautomers of hypoxanthine in order to obtain deep insight into the lifetime of the optically bright S1((1)pipi*) excited state and the relevant decay mechanisms. Supporting calculations on the ground-state (S0) equilibrium structures and minima on the crossing seams of both tautomers were carried out at the MR-CIS and CASSCF levels. These studies indicate that there are four slightly different kinds of conical intersections in each tautomer, exhibiting a chiral character, each of which dominates a barrierless reaction pathway. Moreover, both tautomers reveal the ultrafast S1-> S0 decay, in which the S1 state of keto-N9H in the gas phase has a lifetime of 85.5 fs, whereas that of keto-N7H has a longer lifetime of 137.7 fs. An excellent agreement is found between the present results and the experimental value of 130 +/- 20 fs in aqueous solution (Chen and Kohler, Phys. Chem. Chem. Phys., 2012, 14, 10677-10689). PMID- 23689466 TI - Palladium-catalyzed asymmetric coupling cyclization of terminal gamma-allenols with aryl iodides. AB - A Pd-catalyzed asymmetric coupling cyclization of gamma-allenols has been developed. Styrenyl derivatives can be prepared in 60-86% yields with ee values ranging from 85-92%. PMID- 23689467 TI - The role of the serum vitamin D binding protein in the actions of the vitamin D analog eldecalcitol (ED-71) on bone and mineral metabolism. AB - The vitamin D analog ED-71 (eldecalcitol) has been shown to be superior to calcitriol and its precursor alfacalcidol in maintaining or increasing bone mass in women and animal models with osteoporosis. The mechanism for the greater effectiveness of ED-71 is unknown. In the present study, we tested the hypothesis that the higher activity of ED-71 is due to its higher affinity for the serum vitamin D binding protein (DBP) by comparing the activities of orally administered ED-71, calcitriol and 22-oxacalcitriol (OCT) in wild type (WT) and DBP-ablated (DBPko) mice. In 8-week-old male WT mice, the effects of the analogs on serum and urinary calcium and phosphate were ED-71 > calcitriol > OCT. The results in DBPko mice were identical to those of the WT mice for all parameters tested. In ovariectomized mice, ED-71 was more effective than calcitriol in increasing bone mineral density, but again, there were no differences in the responses of the WT versus DBPko OVX mice. This lack of an effect of DBP ablation on the activities of oral ED-71 occurred despite the finding that peak circulating levels of ED-71 were 100 times lower and disappeared quickly in the DBPko mice while the peak levels at 1 h in WT mice were maintained for at least 24 h. These findings indicate that although DBP has a major influence on circulating levels of vitamin D compounds, it is not responsible for the greater efficacy of ED-71 on bone and mineral metabolism. PMID- 23689468 TI - A comparative analysis of the quality of patient education materials from medical specialties. PMID- 23689469 TI - Perinatal factors associated with developmental defects of enamel in primary teeth: a case-control study. AB - The present study was designed to evaluate associations between developmental defects of enamel (DDE) in the primary dentition and aspects related to mothers and preschoolers in the city of Diamantina, Brazil. A case-control study was carried out involving children aged three to five years. The case group was composed of 104 children with at least one dental surface affected by DDE. The control group comprised 105 children without DDE, matched for gender and age. The diagnosis of enamel defects was performed using the Developmental Defects of Enamel Index. Information was collected through interviews investigating socio demographic aspects, gestation, birth weight, prematurity and breastfeeding. Simple and multiple regression analyses were performed, providing unadjusted and adjusted prevalence ratios (Poisson regression). DDE were more prevalent among children who had not been breastfed (PR=1.57; 95% CI: 1.1-2.2) and those whose mothers were under 24 years of age at the birth of the child (PR=1.41; 95% CI: 1.1-1.9). The prevalence of DDE in the primary dentition was higher among children who had not been breastfed and those whose mothers were under 24 years of age at the birth of the child. PMID- 23689470 TI - N-heterocyclic carbenes--catalysts for the preparation of polyhedral silsesquioxanes. AB - N-Heterocyclic carbenes could be used as powerful catalysts for the preparation of various polyhedral silsesquioxanes. NHCs also catalyze a rearrangement of existing cages and a scrambling between two different cages at a concentration as low as 1 mol%. PMID- 23689471 TI - Post-dilution high convective transport improves microinflammation and endothelial dysfunction independently of the technique. AB - BACKGROUND/AIMS: We examined the effects of different online hemodiafiltration techniques on microinflammation and endothelial damage/repair. METHODS: The study was designed as a prospective crossover study. Flow cytometry was used to measure CD14(+)CD16(+) monocytes, apoptotic endothelial microparticles (EMPs), and endothelial progenitor cells (EPCs). RESULTS: Patients treated with high-flux hemodialysis showed a marked chronic inflammatory state (HF-HD 11 +/- 2) versus healthy subjects (HS 3.9 +/- 2.3; p < 0.05). High convective transport, independent of the technique used, improves microinflammatory parameters (OL-HDF 7.3 +/- 2.1 or MID 6.5 +/- 3.4; p < 0.05) and the endothelial damage/repair balance compared to HF-HD (EPCs HF-HD 0.3 +/- 0.2), with no differences found between the two modalities (EPCs OL-HDF 0.6 +/- 0.1, MID 0.6 +/- 0.2; p < 0.05). CONCLUSION: An increase in convective transport improves the microinflammatory state and the endothelial damage/repair of these patients independently of the technique used. PMID- 23689472 TI - Noninvasive ventilation to breathe but not to leak: that is the question! PMID- 23689473 TI - Bilateral lambdoid and posterior sagittal craniosynostosis--management, evolution, and outcome. PMID- 23689474 TI - Electrochemical formation of Mn(III)-peroxo complexes supported by pentadentate amino pyridine and imidazole ligands. AB - A novel and efficient method for preparing [Mn(III)(O2)(L)](+) complexes using electrochemically generated superoxide is reported, with the reaction probed by low temperature electronic absorption and electron paramagnetic resonance spectroscopic techniques. PMID- 23689475 TI - The effect of increased coverage of participatory women's groups on neonatal mortality in Bangladesh: A cluster randomized trial. AB - IMPORTANCE: Community-based interventions can reduce neonatal mortality when health systems are weak. Population coverage of target groups may be an important determinant of their effect on behavior and mortality. A women's group trial at coverage of 1 group per 1414 population in rural Bangladesh showed no effect on neonatal mortality, despite a similar intervention having a significant effect on neonatal and maternal death in comparable settings. OBJECTIVE: To assess the effect of a participatory women's group intervention with higher population coverage on neonatal mortality in Bangladesh. DESIGN: A cluster randomized controlled trial in 9 intervention and 9 control clusters. SETTING: Rural Bangladesh. PARTICIPANTS: Women permanently residing in 18 unions in 3 districts and accounting for 19 301 births during the final 24 months of the intervention. INTERVENTIONS: Women's groups at a coverage of 1 per 309 population that proceed through a participatory learning and action cycle in which they prioritize issues that affected maternal and neonatal health and design and implement strategies to address these issues. MAIN OUTCOMES AND MEASURES: Neonatal mortality rate. RESULTS: Analysis included 19 301 births during the final 24 months of the intervention. More than one-third of newly pregnant women joined the groups. The neonatal mortality rate was significantly lower in the intervention arm (21.3 neonatal deaths per 1000 live births vs 30.1 per 1000 in control areas), a reduction in neonatal mortality of 38% (risk ratio, 0.62 [95% CI, 0.43-0.89]) when adjusted for socioeconomic factors. The cost-effectiveness was US $220 to $393 per year of life lost averted. Cause-specific mortality rates suggest reduced deaths due to infections and those associated with prematurity/low birth weight. Improvements were seen in hygienic home delivery practices, newborn thermal care, and breastfeeding practices. CONCLUSIONS AND RELEVANCE: Women's group community mobilization, delivered at adequate population coverage, is a highly cost-effective approach to improve newborn survival and health behavior indicators in rural Bangladesh. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN01805825. PMID- 23689476 TI - Reduced habituation to angry faces: increased attentional capture as to override inhibition of return. AB - The aim of this paper was to study whether real angry faces do capture attention to the extent of overcoming the inhibition of return (IOR) effect and whether the anxiety level of participants modulates this effect by stressing biases toward threatening stimuli. With this purpose, participants categorized the emotional valence of face targets in a standard spatial cueing procedure suitable to measure IOR. In Experiment 1, participants were selected according to their high vs. low-trait anxiety, whereas in Experiment 2 participants were induced a positive vs. anxiety mood state. The typical IOR effect was observed with neutral and happy face targets, which disappeared with angry face targets. Similar results were observed for all anxiety groups and in both experiments. The results indicate that IOR is overridden when the target is a biologically relevant angry face, as highly relevant targets should suffer less from habituation to attentional capture regardless of anxiety. We suggest that these data show that attentional capture is less likely to habituate for threatening information, so that no cost is measured in detecting new threatening information appearing at recently cued locations. PMID- 23689477 TI - Under-water superoleophobic glass: unexplored role of the surfactant-rich solvent. AB - Preparing low energy liquid-repellant surfaces (superhydrophobic or superoleophobic) have attracted tremendous attention of late. In all these studies, the necessary liquid repellency is achieved by irreversible micro-nano texturing of the surfaces. Here we show for the first time that a glass surface, placed under water, can be made superoleophobic (with unprecedented contact angles close to 180 degrees and roll off angles only a few fractions of 1 degree) by merely changing the surfactant content of the water medium in which the oil (immiscible in water) has been dispersed. Therefore, we propose a paradigm shift in efforts to achieve liquid-repellant systems, namely, altering the solvent characteristics instead of engineering the surfaces. The effect occurs for a surfactant concentration much larger than the critical micelle concentration, and is associated to strong adsorption of surfactant molecules at the solid surface, triggering an extremely stable Cassie-Baxter like conformation of the oil droplets. PMID- 23689478 TI - Adverse reactions after tattooing: review of the literature and comparison to results of a survey. AB - The number of tattooed people has substantially increased in the past years. Surveys in different countries reveal this to be up to 24% of the population. The number of reported adverse reactions after tattooing has also increased including infections, granulomatous and allergic reactions and tumors. However, the case reports do not reflect the frequency of adverse reactions. This review compares the medically documented adverse reactions published in 1991-2011 with the findings of a nation-wide survey that recently revealed the features and health problems associated with tattoos. To compare the data with the survey, the sex of patients was reported and the location and color of tattoos were evaluated. The results show clearly that colored tattoo inks are mainly responsible for adverse skin reactions and that tattoos on the extremities are involved most. PMID- 23689479 TI - A novel correlation of vibrational circular dichroism spectra with the electronic ground state for Delta-SAPR-8-cesium-tetrakis((+)-heptafluorobutyryl camphorato)lanthanide(III) complexes. AB - For Delta-SAPR-8-Cs[Ln((+)-hfbc)4]((+)-hfbc = (+)-heptafluoro-butyrylcamphorate; Cs-Ln), the vibrational circular dichroism pattern and intensity of Cs-La, Cs-Nd, Cs-Gd, Cs-Ho, Cs-Er, Cs-Lu and Cs-Sm, Cs-Eu, Cs-Tb, Cs-Dy, Cs-Tm, Cs-Yb, respectively, are correlated with the even and the odd parity of total orbital angular momentum in the ground state terms. PMID- 23689480 TI - Early morbidity and mortality in childhood acute lymphoblastic leukemia with very high white blood cell count. PMID- 23689481 TI - Use of narratives to assess language disorders in an inpatient pediatric psychiatric population. AB - A large proportion of child psychiatry patients have undiagnosed language disorders. Adequately developed language is critical for psychotherapy and cognitive-behavioral therapies. This study investigated (1) whether assessment of oral narratives would identify language impairments in this population undetected by assessment of only core language abilities, and (2) the extent to which measures of cognition, working memory, emotional distress, and social function differentially predict core language and narrative development. Results showed that (1) more than twice as many children were identified with language impairment when both narrative and core language assessment were used, and (2) core language comprehension and complex verbal working memory were the strongest predictors of narrative production, while core language comprehension, a less complex working-memory task, and social skills best predicted narrative comprehension. Emotional distress did not predict either. The results emphasize the importance of evaluating child psychiatry patients' language, using both core language and narrative measures. PMID- 23689484 TI - 18th international congress of cytology paris, france, may 26-30, 2013. PMID- 23689482 TI - Nephronectin expression in glomeruli of renal biopsy specimens from various kidney diseases: nephronectin is expressed in the mesangial matrix expansion of diabetic nephropathy. AB - BACKGROUND: In a previous proteomic study, we detected increased expression of nephronectin in the glomeruli from patients with diabetic nephropathy (DN). The aim of the present study was to clarify the usefulness of determining glomerular expression of nephronectin in kidney disease. METHODS: We performed immunohistochemical staining for nephronectin in renal biopsy specimens from patients with a variety of kidney diseases (n = 190). The percentage of nephronectin-positive areas in the glomeruli was analyzed using an image analyzer. RESULTS: Nephronectin immunoreactivity was clearly, strongly positive in the mesangial expansion and nodular lesions of DN (n = 18), whereas nephronectin immunoreactivity was negative in IgA glomerulonephritis, membranoproliferative glomerulonephritis, lupus nephritis, membranous glomerulonephritis, minor glomerular abnormalities, crescentic glomerulonephritis, and other kidney diseases, such as amyloidosis and light chain deposition disease. Nephronectin was stained weakly in sclerotic lesions, such as focal segmental glomerulosclerosis and hypertensive nephropathy. The percentage of nephronectin-positive areas in the glomeruli from DN patients [15.1 +/- 4.7% (n = 18)] was significantly higher than that for other kidney diseases [5.5 +/- 3.6% (n = 172)] (p < 0.001). In multiple regression analyses, fasting plasma glucose and hemoglobin A1c were significantly associated with the increase in the percentage of nephronectin-positive areas in the glomeruli (beta = 0.23, p < 0.001 and beta = 0.16, p = 0.045, respectively). CONCLUSIONS: The expression of nephronectin was sufficient to discriminate DN from other kidney diseases with mesangial matrix expansion and nodular lesions. We consider that nephronectin staining could be helpful in the diagnosis of DN. PMID- 23689485 TI - Regular atrial tachycardias developing after cryoballoon pulmonary vein isolation: incidence, characteristics, and predictors. AB - AIMS: Cryoballoon ablation (CBA) is a well-used technique when performing pulmonary vein (PV) isolation in patients with paroxysmal atrial fibrillation (AF). Our aim is to describe incidence, characteristics, and clinical predictors for developing atrial tachycardias (ATs) after cryoballoon PV isolation in patients with paroxysmal AF. METHODS AND RESULTS: The study population consisted of 181 consecutive patients undergoing a first CBA. All patients received an event-recorder before cryoablation and transmitted daily electrocardiogram (ECG) during 1 month before ablation and 3 months after. Further follow-up consisted of 24 h Holter monitoring and ECG registration every 3 months and also in patients presenting with symptoms. A mean follow-up period was 497.9 +/- 283.9 days, and 175 patients completed follow-up. In 14 (8%) patients regular ATs were registered. In multivariate logistic regression model, the following parameters were independently associated with ATs after ablation: an additional right PV, treatment with beta-blockers, and presence of AT on event-recording strips before ablation. Seven (4%) patients with registered AT underwent a redo procedure. In two (1.1%) patients ATs were originated in reconnected PVs. In other patients no left AT was induced. No macro re-entrant left AT was documented in any patient. During follow-up, after a redo ablation, no AT was registered. CONCLUSION: The incidence of left AT after CBA is low, and no left atrial macro re-entrant tachycardia was found. The following independent predictors of AT development have been identified: an additional right PV, regular AT registered before ablation, and the use of beta-blockers. PMID- 23689486 TI - Progressive endothelial damage revealed by multilevel von Willebrand factor plasma concentrations in atrial fibrillation patients. AB - AIMS: Abnormal plasma concentrations of von Willebrand factor (vWF), a marker of prothrombotic risk, have been found in atrial fibrillation (AF) patients, but the extent of this variation is not clear. This study aimed to investigate the effect of different clinical forms of AF on plasma concentrations of vWF at different levels of the circulatory tree, both intracardiac and extracardiac. METHODS AND RESULTS: Peripheral (Pf), left atrial (LA), and coronary sinus (CS) blood samples were obtained during cardiac catheterization from 52 patients with paroxysmal AF (PAF), 36 with persistent AF (PsAF), and 17 control subjects (Ct) with left-sided accessory pathway Wolff-Parkinson-White syndrome. Plasma concentrations of vWF were determined by immunoturbidimetry. Compared with Ct, patients with PAF had higher LA plasma levels of vWF (P = 0.004), but similar Pf and CS levels (both P > 0.30). In contrast, patients with PsAF had higher plasma concentrations of vWF in Pf (P = 0.04), LA (P < 0.001), and CS (P = 0.04) samples compared with Ct. Left atrial plasma concentrations of vWF in patients with PsAF were also higher than in the PAF group (P = 0.04). CONCLUSION: Regardless of the clinical form of the arrhythmia, AF patients presented significantly higher plasma concentrations of vWF compared with sinus rhythm controls. Multilevel vWF plasma concentration assessment suggests an association between the clinical evolution of AF and the progression of endothelial dysfunction. Further studies will have to establish the exact mechanisms that link endothelial dysfunction and stroke in the context of AF. PMID- 23689487 TI - Expanding utilization of intensity-modulated radiotherapy for prostate cancer: soaring costs, dubious benefits: comment on "Comparative effectiveness of intensity-modulated radiotherapy and conventional conformal radiotherapy in the treatment of prostate cancer after radical prostatectomy". PMID- 23689488 TI - An ATP-selective, lanthanide complex luminescent probe. AB - A luminescent probe based on a europium complex is developed, which effectively distinguishes adenosine-5'-triphosphate (ATP) from adenosine diphosphate (ADP) and adenosine monophosphate (AMP) in pure water at pH 6.8. With a longer lifetime (in ms range), the probe is prospectively applied to biological systems to monitor ATP levels by completely removing the background fluorescence of other molecules. PMID- 23689489 TI - Risk factors for the development of prolonged post-operative ileus following elective colorectal surgery. AB - PURPOSE: Prolonged post-operative ileus (PPOI) increases post-operative morbidity and prolongs hospital stay. An improved understanding of the elements which contribute to the genesis of PPOI is needed in the first instance to facilitate accurate risk stratification and institute effective preventive measures. The aim of this retrospective cohort study was to therefore determine the perioperative risk factors associated with development of PPOI. METHODS: All elective intra abdominal operations undertaken by the Colorectal Unit at Auckland District Health Board from 1 January to 31 December 2011 were accessed. Data were extracted for an assortment of patient characteristics and perioperative variables. Cases were stratified by the occurrence of clinician-diagnosed PPOI. Univariate and regression analyses were performed to identify correlates and independent risk factors, respectively. RESULTS: Two hundred and fifty-five patients were identified of whom 50 (19.6%) developed PPOI. The median duration for PPOI was 4 days with 98% resolving spontaneously with conservative measures. Univariate analysis identified increasing age; procedure type; increasing opiate consumption; elevated preoperative creatinine; post-operative haemoglobin drop, highest white cell count and lowest sodium; and increasing complication grade as significant correlates. Logistic regression found increasing age (OR 1.032, 95% CI 1.004-1.061; p = 0.026) and increasing drop in pre- to post-operative haemoglobin (OR 1.043, 95% CI 1.002-1.085; p = 0.037) as the only independent predictors for developing PPOI. An important limitation of this study was its retrospective nature. CONCLUSIONS: Increasing age and increasing drop in haemoglobin are independent predictors for developing PPOI. Prospective assessment is required to facilitate more accurate risk factor analysis. PMID- 23689490 TI - Treating symptomatic adhesions to the sigmoid colon: colectomy improves quality of life. AB - INTRODUCTION: When severe chronic pelvic pain, constipation, and bloating are due to dense pelvic adhesions fixing the sigmoid loops, patients may be offered the option of sigmoid colectomy. This study examines the effectiveness of colectomy in the treatment of such patients. METHODS: Patients were identified from a surgical database, demographic data were abstracted, and charts were reviewed. Patients were interviewed postoperatively. Primary end points were morbidity, length of stay, change in bowel habit, and patient satisfaction. RESULTS: There were 46 patients (44 women) with a mean age of 54.7 years (+/-14.3). Forty-three had a history of prior pelvic surgery (93%), including 30 (65%) with hysterectomy. One quarter had been diagnosed with irritable bowel syndrome. Surgery revealed adhesive tethering of the sigmoid colon in 43 patients (94%). Mean length of stay was 6.5 days (+/-2.5), and complications occurred in eight (17.3%) patients. There were no deaths, and no patients required a stoma. Follow up in 37 patients after mean of 7.2(+/-5.0) years showed significant reductions in abdominal pain and bloating postoperatively, with normalization of bowel function and increase in quality of life. CONCLUSION: When severe lower abdominal pain and bloating in women who have had pelvic surgery are reproduced by colonoscopy, and there is an obvious kink in the bowel, sigmoid colectomy is worth considering. PMID- 23689491 TI - Varicella pneumonia in an immunocompetent adult. PMID- 23689493 TI - The Mediterranean diet as prevention strategy for dementia as a multicausal geriatric syndrome. PMID- 23689492 TI - Every cockroach is beautiful to its mother. PMID- 23689494 TI - Self-report-based estimates of energy intake offer an inadequate basis for scientific conclusions. PMID- 23689495 TI - PUFAs in sickle cell disease. PMID- 23689497 TI - Mechanisms of the protective effects of curcumin against indomethacin-induced gastric ulcer in rats. AB - BACKGROUND/AIMS: Curcumin, a naturally occurring polyphenolic compound, exhibits anti-inflammatory and antioxidant properties that render it an attractive candidate for protection against gastric ulcer. The aim of this study is therefore to evaluate the protective effects of curcumin against indomethacin induced gastric ulcer in rats. METHODS: Gastric ulceration was induced by a single intraperitoneal injection of indomethacin (30 mg/kg). Curcumin (50 mg/kg, p.o.) was administered 30 min before ulcer induction. RESULTS: Curcumin showed gastroprotective effects as evidenced by significant decreases in ulcer index, total acid output and pepsin activity in gastric juice in addition to gastric mucosal malondialdehyde concentration, and concomitant increases in gastric juice mucin concentration, gastric mucosal nitric oxide level and catalase and superoxide dismutase activities as compared to the indomethacin-induced ulcer group. Moreover, immunohistochemical investigations demonstrated that curcumin treatment markedly decreased expression of inducible nitric oxide synthase, nuclear factor-kappaB, and caspase-3. CONCLUSION: Curcumin protected the rats' gastric mucosa against indomethacin-induced gastric ulceration possibly, at least in part, by enhancement of the gastric mucosal barrier and reduction in acid secretory parameters in addition to antioxidant and antiapoptotic activities. PMID- 23689498 TI - Rapid synthesis of unsaturated alcohols under mild conditions by highly selective hydrogenation. AB - Ir-ReOx/SiO2 acted as a highly active and selective heterogeneous catalyst for the hydrogenation of unsaturated aldehydes to unsaturated alcohols in water at low H2 pressure (0.8 MPa) and low temperature (303 K). The catalysis is derived from the synergy between Ir metal and ReOx. PMID- 23689499 TI - Nutritional and metabolic alterations during continuous renal replacement therapy. AB - Adequate feeding of critically ill patients under continuous renal replacement therapy (CRRT) remains a challenging issue. We performed a systematic search of the literature published between 1992 and 2012 using the quorum guidelines regarding nutrition in intensive care unit patients treated with CRRT. Daily recommended energy requirements during CRRT are between 25 and 35 kcal/kg with carbohydrates and lipids accounting for 60-70% and 30-40% of calorie intake, respectively. Daily protein needs range from 1.5 to 1.8 g/kg. Indirect calorimetry corrected for CRRT-induced CO2 diversion should be used to more correctly match calorie intake to the real needs. This type of tool is not yet available but hopefully soon. Electrolyte deficit as well as overload have been described during CRRT but, in general, can be easily controlled. Although not strongly evidenced, consensus exists to supplement important micronutrients such as amino acids (glutamine), water-soluble vitamins and trace elements. PMID- 23689500 TI - An MRI atlas of the mouse basal ganglia. AB - The basal ganglia are a group of subpallial nuclei that play an important role in motor, emotional, and cognitive functions. Morphological changes and disrupted afferent/efferent connections in the basal ganglia have been associated with a variety of neurological disorders including psychiatric and movement disorders. While high-resolution magnetic resonance imaging has been used to characterize changes in brain structure in mouse models of these disorders, no systematic method for segmentation of the C57BL/6 J mouse basal ganglia exists. In this study we have used high-resolution MR images of ex vivo C57BL/6 J mouse brain to create a detailed protocol for segmenting the basal ganglia. We created a three dimensional minimum deformation atlas, which includes the segmentation of 35 striatal, pallidal, and basal ganglia-related structures. In addition, we provide mean volumes, mean T2 contrast intensities and mean FA and ADC values for each structure. This MR atlas is available for download, and enables researchers to perform automated segmentation in genetic models of basal ganglia disorders. PMID- 23689501 TI - Phenotypic characterization of C57BL/6J mice carrying the Disc1 gene from the 129S6/SvEv strain. AB - Disruption of disrupted-in-schizophrenia 1 (DISC1), a candidate susceptibility gene for schizophrenia, was first identified in a large Scottish family in which many members suffered from various psychiatric disorders, including schizophrenia. To model the Scottish DISC1 truncation, we established a Disc1 mutant mouse line in which the 129S6/SvEv 25-bp deletion variant was transferred into the C57BL/6J strain by backcrossing. A battery of behavioral tasks was conducted to evaluate the basic behaviors and cognitive function of these mice. In heterozygote and homozygote Disc1 mutant (Het and Homo) mice, behavioral impairments were noted in working memory test which is thought to be mediated by the function of the medial prefrontal cortex (mPFC). The properties of mPFC neurons were characterized in both morphological and physiological aspects. The dendritic diameters were decreased in layer II/III mPFC pyramidal neurons of Het and Homo mice, whereas a significant reduction in spine density was observed in Homo mice. Neuronal excitability was declined in layer II/III mPFC pyramidal neurons of Het and Homo mice, yet increased transmitter release was identified in Homo mice. Thus, the structural and functional alterations of the mPFC in Het and Homo mice might account for their cognitive impairment. Since most of the gene knockout mice are generated from 129 substrain-derived embryonic stem cells, potential Disc1 deficiency should be considered. PMID- 23689503 TI - Psychometric evidence of spasticity measurement tools in cerebral palsy children and adolescents: a systematic review. AB - OBJECTIVE: To conduct a systematic review using validated critical appraisal scales to analyze both the quality and content of the psychometric evidence of spasticity measurement tools in cerebral palsy children and adolescents. DATA SOURCES: The literature search was performed in 3 databases (Pubmed, CINAHL, Embase) up to March 2012. STUDY SELECTION: To be retained for detailed review, studies had to report on at least one psychometric property of one or many spasticity assessment tool(s) used to evaluate cerebral palsy children and adolescents. DATA EXTRACTION: Two raters independently reviewed admissible articles using a critical appraisal scale and a structured data extraction form. DATA SYNTHESIS: A total of 19 studies examining 17 spasticity assessment tools in cerebral palsy children and adolescents were reviewed. None of the reviewed tools demonstrated satisfactory results for all psychometric properties evaluated, and a major lack of evidence concerning responsiveness was emphasized. However, neurophysiological tools demonstrated the most promising results in terms of reliability and discriminating validity. CONCLUSIONS: This systematic review revealed insufficient psychometric evidence for a single spasticity assessment tool to be recommended over the others in pediatric and adolescent populations. PMID- 23689502 TI - A functional model of cortical gyri and sulci. AB - Diffusion tensor imaging (DTI) and high angular resolution diffusion imaging (HARDI) have been broadly used in the neuroimaging field to investigate the macro scale fiber connection patterns in the cerebral cortex. Our recent analyses of DTI and HARDI data demonstrated that gyri are connected by denser, streamlined fibers than sulci are. Inspired by this finding and motivated by the fact that DTI-derived fibers provide the structural substrates for functional connectivity, we hypothesize that gyri are global functional connection centers and sulci are local functional units. To test this functional model of gyri and sulci, we examined the structural and functional connectivity among the landmarks on the selected gyral/sulcal areas in the frontal/parietal lobe and in the whole cerebral cortex via multimodal DTI and resting state fMRI (R-fMRI) datasets. Our results demonstrate that functional connectivity is strong among gyri, weak among sulci, and moderate between gyri and sulci. These results suggest that gyri are functional connection centers that exchange information among remote structurally connected gyri and neighboring sulci, while sulci communicate directly with their neighboring gyri and indirectly with other cortical regions through gyri. This functional model of gyri and sulci has been supported by a series of experiments, and provides novel perspectives on the functional architecture of the cerebral cortex. PMID- 23689504 TI - Stability and structural phase transitions of cobalt porphyrin adlayers on Au(100) surfaces. AB - The stability and phase transitions of adlayers of two cobalt(II) porphyrins, 5,10,15,20-tetraphenyl-21H,23H-porphine cobalt(II) (CoTPP) and 2,3,7,8,12,13,17,18-octaethyl-21H,23H-porphine cobalt(II) (CoOEP), formed on Au(100) were investigated under electrochemical conditions. In situ scanning tunneling microscopy (STM) was employed to investigate the structure of CoTPP and CoOEP adlayers in 0.1 M HClO4. The CoTPP and CoOEP adlayer structures were varied with the modification time and the concentration. The in situ STM observations showed that the underlying reconstructed atomic structure was lifted to a (1 * 1) atomic arrangement by either the adsorption of CoTPP/CoOEP during modification in a benzene solution or positive potential manipulation in 0.1 M HClO4. Ordered CoTPP arrays with two different hexagonal and square packing arrangements were found on an Au(100)-(1 * 1) surface, along with characteristic Au islands. The CoOEP molecules also formed a close-packed hexagonal structure on an Au(100) (hex) surface; CoOEP molecules were arranged in a semi-square structure on the Au(100)-(1 * 1) surface by the lifting of reconstruction. The results of this study showed that the interaction between the cobalt porphyrins and the Au(100) substrate depended on the modification conditions and the electrochemical potential. PMID- 23689505 TI - Rapid single cell detection of Staphylococcus aureus by aptamer-conjugated gold nanoparticles. AB - Staphylococcus aureus is one of the most important human pathogens, causing more than 500,000 infections in the United States each year. Traditional methods for bacterial culture and identification take several days, wasting precious time for patients who are suffering severe bacterial infections. Numerous nucleic acid based detection methods have been introduced to address this deficiency; however, the costs and requirement for expensive equipment may limit the widespread use of such technologies. Thus, there is an unmet demand of new platform technology to improve the bacterial detection and identification in clinical practice. In this study, we developed a rapid, ultra-sensitive, low cost, and non-polymerase chain reaction (PCR)-based method for bacterial identification. Using this method, which measures the resonance light-scattering signal of aptamer-conjugated gold nanoparticles, we successfully detected single S. aureus cell within 1.5 hours. This new platform technology may have potential to develop a rapid and sensitive bacterial testing at point-of-care. PMID- 23689506 TI - Succinylated octopamine ascarosides and a new pathway of biogenic amine metabolism in Caenorhabditis elegans. AB - The ascarosides, small-molecule signals derived from combinatorial assembly of primary metabolism-derived building blocks, play a central role in Caenorhabditis elegans biology and regulate many aspects of development and behavior in this model organism as well as in other nematodes. Using HPLC-MS/MS-based targeted metabolomics, we identified novel ascarosides incorporating a side chain derived from succinylation of the neurotransmitter octopamine. These compounds, named osas#2, osas#9, and osas#10, are produced predominantly by L1 larvae, where they serve as part of a dispersal signal, whereas these ascarosides are largely absent from the metabolomes of other life stages. Investigating the biogenesis of these octopamine-derived ascarosides, we found that succinylation represents a previously unrecognized pathway of biogenic amine metabolism. At physiological concentrations, the neurotransmitters serotonin, dopamine, and octopamine are converted to a large extent into the corresponding succinates, in addition to the previously described acetates. Chemically, bimodal deactivation of biogenic amines via acetylation and succinylation parallels posttranslational modification of proteins via acetylation and succinylation of L-lysine. Our results reveal a small-molecule connection between neurotransmitter signaling and interorganismal regulation of behavior and suggest that ascaroside biosynthesis is based in part on co-option of degradative biochemical pathways. PMID- 23689507 TI - Analysis of polymorphic residues reveals distinct enzymatic and cytotoxic activities of the Streptococcus pyogenes NAD+ glycohydrolase. AB - The Streptococcus pyogenes NAD(+) glycohydrolase (SPN) is secreted from the bacterial cell and translocated into the host cell cytosol where it contributes to cell death. Recent studies suggest that SPN is evolving and has diverged into NAD(+) glycohydrolase-inactive variants that correlate with tissue tropism. However, the role of SPN in both cytotoxicity and niche selection are unknown. To gain insight into the forces driving the adaptation of SPN, a detailed comparison of representative glycohydrolase activity-proficient and -deficient variants was conducted. Of a total 454 amino acids, the activity-deficient variants differed at only nine highly conserved positions. Exchanging residues between variants revealed that no one single residue could account for the inability of the deficient variants to cleave the glycosidic bond of beta-NAD(+) into nicotinamide and ADP-ribose; rather, reciprocal changes at 3 specific residues were required to both abolish activity of the proficient version and restore full activity to the deficient variant. Changing any combination of 1 or 2 residues resulted in intermediate activity. However, a change to any 1 residue resulted in a significant decrease in enzyme efficiency. A similar pattern involving multiple residues was observed for comparison with a second highly conserved activity deficient variant class. Remarkably, despite differences in glycohydrolase activity, all versions of SPN were equally cytotoxic to cultured epithelial cells. These data indicate that the glycohydrolase activity of SPN may not be the only contribution the toxin has to the pathogenesis of S. pyogenes and that both versions of SPN play an important role during infection. PMID- 23689508 TI - Impact of peripheral ketolytic deficiency on hepatic ketogenesis and gluconeogenesis during the transition to birth. AB - Preservation of bioenergetic homeostasis during the transition from the carbohydrate-laden fetal diet to the high fat, low carbohydrate neonatal diet requires inductions of hepatic fatty acid oxidation, gluconeogenesis, and ketogenesis. Mice with loss-of-function mutation in the extrahepatic mitochondrial enzyme CoA transferase (succinyl-CoA:3-oxoacid CoA transferase, SCOT, encoded by nuclear Oxct1) cannot terminally oxidize ketone bodies and develop lethal hyperketonemic hypoglycemia within 48 h of birth. Here we use this model to demonstrate that loss of ketone body oxidation, an exclusively extrahepatic process, disrupts hepatic intermediary metabolic homeostasis after high fat mother's milk is ingested. Livers of SCOT-knock-out (SCOT-KO) neonates induce the expression of the genes encoding peroxisome proliferator-activated receptor gamma co-activator-1a (PGC-1alpha), phosphoenolpyruvate carboxykinase (PEPCK), pyruvate carboxylase, and glucose-6-phosphatase, and the neonate's pools of gluconeogenic alanine and lactate are each diminished by 50%. NMR-based quantitative fate mapping of (13)C-labeled substrates revealed that livers of SCOT-KO newborn mice synthesize glucose from exogenously administered pyruvate. However, the contribution of exogenous pyruvate to the tricarboxylic acid cycle as acetyl-CoA is increased in SCOT-KO livers and is associated with diminished terminal oxidation of fatty acids. After mother's milk provokes hyperketonemia, livers of SCOT-KO mice diminish de novo hepatic beta-hydroxybutyrate synthesis by 90%. Disruption of beta-hydroxybutyrate production increases hepatic NAD(+)/NADH ratios 3-fold, oxidizing redox potential in liver but not skeletal muscle. Together, these results indicate that peripheral ketone body oxidation prevents hypoglycemia and supports hepatic metabolic homeostasis, which is critical for the maintenance of glycemia during the adaptation to birth. PMID- 23689511 TI - How provocative is provocative testing?: comment on "Yield of routine provocative cardiac testing among patients in an emergency department-based chest pain unit. PMID- 23689509 TI - COP9 signalosome subunit Csn8 is involved in maintaining proper duration of the G1 phase. AB - The COP9 signalosome (CSN) is a conserved protein complex known to be involved in developmental processes of eukaryotic organisms. Genetic disruption of a CSN gene causes arrest during early embryonic development in mice. The Csn8 subunit is the smallest and the least conserved subunit, being absent from the CSN complex of several fungal species. Nevertheless, Csn8 is an integral component of the CSN complex in higher eukaryotes, where it is essential for life. By characterizing the mouse embryonic fibroblasts (MEFs) that express Csn8 at a low level, we found that Csn8 plays an important role in maintaining the proper duration of the G1 phase of the cell cycle. A decreased level of Csn8, either in Csn8 hypomorphic MEFs or following siRNA-mediated knockdown in HeLa cells, accelerated cell growth rate. Csn8 hypomorphic MEFs exhibited a shortened G1 duration and affected expression of G1 regulators. In contrast to Csn8, down-regulation of Csn5 impaired cell proliferation. Csn5 proteins were found both as a component of the CSN complex and outside of CSN (Csn5-f), and the amount of Csn5-f relative to CSN was increased in the Csn8 hypomorphic cells. We conclude that CSN harbors both positive and negative regulators of the cell cycle and therefore is poised to influence the fate of a cell at the crossroad of cell division, differentiation, and senescence. PMID- 23689510 TI - Structural and pharmacological characterization of novel potent and selective monoclonal antibody antagonists of glucose-dependent insulinotropic polypeptide receptor. AB - Glucose-dependent insulinotropic polypeptide (GIP) is an endogenous hormonal factor (incretin) that, upon binding to its receptor (GIPr; a class B G-protein coupled receptor), stimulates insulin secretion by beta cells in the pancreas. There has been a lack of potent inhibitors of the GIPr with prolonged in vivo exposure to support studies on GIP biology. Here we describe the generation of an antagonizing antibody to the GIPr, using phage and ribosome display libraries. Gipg013 is a specific competitive antagonist with equally high potencies to mouse, rat, dog, and human GIP receptors with a Ki of 7 nm for the human GIPr. Gipg013 antagonizes the GIP receptor and inhibits GIP-induced insulin secretion in vitro and in vivo. A crystal structure of Gipg013 Fab in complex with the human GIPr extracellular domain (ECD) shows that the antibody binds through a series of hydrogen bonds from the complementarity-determining regions of Gipg013 Fab to the N-terminal alpha-helix of GIPr ECD as well as to residues around its highly conserved glucagon receptor subfamily recognition fold. The antibody epitope overlaps with the GIP binding site on the GIPr ECD, ensuring competitive antagonism of the receptor. This well characterized antagonizing antibody to the GIPr will be useful as a tool to further understand the biological roles of GIP. PMID- 23689512 TI - Abiotic photophosphorylation model based on abiogenic flavin and pteridine pigments. AB - A model for abiotic photophosphorylation of adenosine diphosphate by orthophosphate with the formation of adenosine triphosphate was studied. The model was based on the photochemical activity of the abiogenic conjugates of pigments with the polymeric material formed after thermolysis of amino acid mixtures. The pigments formed showed different fluorescence parameters depending on the composition of the mixture of amino acid precursors. Thermolysis of the mixture of glutamic acid, glycine, and lysine (8:3:1) resulted in a predominant formation of a pigment fraction which had the fluorescence maximum at 525 nm and the excitation band maxima at 260, 375, and 450 nm and was identified as flavin. When glycine in the initial mixture was replaced with alanine, a product formed whose fluorescence parameters were typical to pteridines (excitation maximum at 350 nm, emission maximum at 440 nm). When irradiated with the quasi-monochromatic light (over the range 325-525 nm), microspheres in which flavin pigments were prevailing showed a maximum photophosphorylating activity at 375 and 450 nm, and pteridine-containing chromoproteinoid microspheres were most active at 350 nm. The positions and the relative height of maxima in the action spectra correlate with those in the excitation spectra of the pigments, which point to the involvement of abiogenic flavins and pteridines in photophosphorylation. PMID- 23689513 TI - Selection shapes the robustness of ligand-binding amino acids. AB - The phenotypes of biological systems are to some extent robust to genotypic changes. Such robustness exists on multiple levels of biological organization. We analyzed this robustness for two categories of amino acids in proteins. Specifically, we studied the codons of amino acids that bind or do not bind small molecular ligands. We asked to what extent codon changes caused by mutation or mistranslation may affect physicochemical amino acid properties or protein folding. We found that the codons of ligand-binding amino acids are on average more robust than those of non-binding amino acids. Because mistranslation is usually more frequent than mutation, we speculate that selection for error mitigation at the translational level stands behind this phenomenon. Our observations suggest that natural selection can affect the robustness of very small units of biological organization. PMID- 23689515 TI - Leukemia-initiating cell activity requires calcineurin in T-cell acute lymphoblastic leukemia. AB - Despite their initial efficient response to induction chemotherapy, relapse remains frequent in patients with T-cell acute lymphoblastic leukemia (T-ALL), an aggressive malignancy of immature T-cell progenitors. We previously reported sustained calcineurin (Cn) activation in human lymphoid malignancies, and showed that Cn inhibitors have antileukemic effects in mouse models of T-ALL. It was unclear, however, from these studies whether these effects resulted from Cn inhibition in leukemic cells themselves or were an indirect consequence of impaired Cn function in the supportive tumor microenvironment. We thus generated a Notch (intracellular Notch 1, ICN1)-induced T-ALL mouse model, in which conditional Cn genetic deletion is restricted to leukemic cells. Ex vivo, Cn deletion altered the adhesive interactions between leukemic cells and their supportive stroma, leukemic cell survival, proliferation, migration and clonogenic potential. In vivo, Cn activation was found to be critical for leukemia initiating/propagating cell activity as demonstrated by the failure of Cn-deficient leukemic cells to transplant the disease to syngeneic recipient mice. Importantly, combination of vincristine treatment with Cre-mediated Cn ablation cooperated to induce long-term remission of ICN1-induced T-ALL. These findings indicate that Cn is a promising target in T-ALL relapse prevention, and call for clinical trials incorporating Cn inhibitors during consolidation therapy. PMID- 23689514 TI - JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma. AB - Extranodal, nasal-type natural killer (NK)/T-cell lymphoma (NKCL) is an aggressive malignancy with poor prognosis in which, usually, signal transducer and activator of transcription 3 (STAT3) is constitutively activated and oncogenic. Here, we demonstrate that STAT3 activation mostly results from constitutive Janus kinase (JAK)3 phosphorylation on tyrosine 980, as observed in three of the four tested NKCL cell lines and in 20 of the 23 NKCL tumor samples under study. In one of the cell lines and in 4 of 19 (21%) NKCL primary tumor samples, constitutive JAK3 activation was related to an acquired mutation (A573V or V722I) in the JAK3 pseudokinase domain. We then show that constitutive activation of the JAK3/STAT3 pathway has a major role in NKCL cell growth and survival and in the invasive phenotype. Indeed, NKCL cell growth was slowed down in vitro by targeting JAK3 with chemical inhibitors or small-interfering RNAs. In a human NKCL xenograft mouse model, tumor growth was significantly delayed by the JAK3 inhibitor CP-690550. Altogether, the constitutive activation of JAK3, which can result from JAK3-activating mutations, is a frequent feature of NKCL that deserves to be tested as a therapeutic target. PMID- 23689516 TI - Improving the quality of telephone-delivered health care: a national quality improvement transformation initiative. AB - BACKGROUND: Many Veterans Affairs (VA) primary care (PC) patients prefer telephone-delivered care to other health care delivery modalities. OBJECTIVE: To evaluate PC patients' telephone experiences and outcomes before and after a national telephone transformation quality improvement (QI) collaborative. METHODS: Cross-sectional surveys were conducted pre- and post-collaborative. We used bivariate analyses to assess differences in pre/post outcomes and multivariate regression to identify variables associated with patients' perceptions of poor quality care. RESULTS: Patients from 13 VA facilities participated (n = 730; pre-intervention = 314, post-intervention = 416); most of them were males (90%) with a mean age of 62 years. After the collaborative (versus pre-collaborative), few experienced transfers (52% versus 62%, P = 0.0006) and most reported timely call answer (88% versus 80%, P = 0.003). Improvements in staff understanding why patients were calling and providing needed medical information were also found. There were measurable improvements in patient satisfaction (87% versus 82% very/mostly satisfied, P = 0.04) and perceived quality of telephone care (85% versus 78% excellent/good quality, P = 0.01) post- collaborative. The proportion of veterans who reported delayed care due to telephone access issues decreased from 41% to 15% after the collaborative, P < 0.0001. Perceptions of poor quality care were higher when calls were for urgent care needs did not result in receipt of needed information and included a transfer or untimely answer. CONCLUSIONS: The QI collaborative led to improvements in timeliness of answering calls, patient satisfaction and perceptions of high-quality telephone care and fewer reports of health care delays. Barriers to optimal telephone care 'quality' include untimely answer, transfers, non-receipt of needed information and urgent care needs. PMID- 23689517 TI - Neurosurgeons were indeed promoting evidence-based, ethical, and multidisciplinary psychiatric surgery! PMID- 23689518 TI - Tolerogenic dendritic cells: key regulators of peripheral tolerance in health and disease. AB - Dendritic cells (DCs) as professional antigen-presenting cells are able to induce immunity and tolerance in different conditions, which leads to strong immune responses against hostile agents or tolerance to self-antigens. Although for subsets of DCs, a regulatory function has been shown, the role of the microenvironment is momentous to generate tolerogenic DCs (tDCs). Different microorganisms and tumor cells escape from immune responses by producing mediators and components that influence DCs to show tolerogenic characteristics. In this review, tDC induction was explained in steady state and disease conditions. Moreover, an overview was presented on the efforts to generate in vitro tDCs, their clinical applications and the problems which remain to be solved in this field. PMID- 23689519 TI - Pediatric left renal vein entrapment syndrome diagnosed by 99mTc-albumin conjugate scintigraphy. AB - BACKGROUND/AIMS: Procedures for diagnosis of left renal vein entrapment syndrome (LRVES) in children have been either invasive or limited in accuracy. We examined scintigraphy with (99m)Tc-diethylene triamine pentaacetic acid-conjugated human serum albumin ((99m)Tc-HSA-D) scintigraphy in childhood LRVES, demonstrating selective left renal nuclides excretion. We also measured peak velocity using pulse Doppler ultrasonography, calculating pressure differences between inferior vena cava and left renal vein using a simplified Bernoulli equation. METHODS: Thirteen patients provisionally diagnosed with LRVES by ultrasonography combined with other imaging such as magnetic resonance angiography and three-dimensional computer tomography (CT) were examined. RESULTS: Four children showing repeated gross hematuria all showed pressure differences exceeding 3.0 mm Hg. Selective left renal albumin excretion was demonstrated by (99m)Tc-HSA-D scintigraphy. Single-photon emission CT also showed accumulation in a site consistent with the left renal pelvis. Among 9 children manifesting mainly orthostatic proteinuria, selective left renal albumin excretion examined by (99m)Tc-HSA-D scintigraphy was demonstrated only in those with proteinuria exceeding 1 g/g Cr after standing in a lordotic position. Pressure differences in patients with orthostatic proteinuria were unrelated to proteinuria severity. CONCLUSIONS: Combining pulse Doppler ultrasonography with (99m)Tc-HSA-D scintigraphy, both noninvasive and safe in children, may suffice for diagnosis of LRVES, especially with gross hematuria. PMID- 23689520 TI - Syntheses of normal, expanded, strapped and N-confused calixbenzophyrins from a single starting material. AB - The syntheses and spectral and structural characterization of hitherto unknown p benzene incorporated normal, expanded, strapped and N-confused calixbenzophyrins are achieved; altogether five new macrocycles from a single starting material are reported. The binding studies of the strapped macrocycle revealed that the molecule is selective towards Fe(III) ions. PMID- 23689521 TI - The pulsed Doppler and tissue Doppler-derived septal E/e' ratio is significantly related to invasive measurement of ventricular end-diastolic pressure in biventricular rather than univentricular physiology in patients with congenital heart disease. AB - OBJECTIVES: The value of conventional non-invasive Doppler parameters to predict ventricular end-diastolic pressure (EDP) and diastolic function in congenital heart diseases is limited. The aim of our prospective study was to investigate whether the ratio of mitral early blood inflow velocity to early diastolic velocity of the mitral annulus (E/e') as assessed by pulsed tissue Doppler is related to EDP in patients with different congenital heart disease (CHD) undergoing left heart catheterization. METHODS: A total of 115 hospital inpatients (64 male) with different CHD referred for cardiac catheterization were simultaneously examined by echocardiography for non-invasive estimation of ventricular EDP during heart catheterization. The mean age at catheterization was 8.71 years (range 3 days to 18 years). These patients were divided into two groups according to the different hemodynamic and morphology conditions: group A consisted of patients with biventricular heart and group B of patients with univentricular heart. RESULTS: For all the studied patients, a significant positive correlation was found between E/e' and EDP (r = 0.54, P < 0.001). EDP correlated rather weakly with combined measurements E/global LV early diastolic velocity (r = 0.27, P = 0.02). A significant relationship was also found between ventricular EDP and early mitral inflow velocity E (r = 0.36, P = 0.001). The ratio of pulmonary venous flow velocities s/d was not found to be related to invasively measured EDP (r = -0.16, P = 0.13). Group A (n = 96) had similar results, but for group B (n = 19), these parameters did not show a relationship to EDP. The analysis of these parameters showed that the larger area under the curve (AUC) was found for the ratio of E/e' (AUC = 0.77) compared with E/global e' (AUC = 0.57). E/e' > 10.7 had 69 % sensitivity and 81 % specificity for EDP > 10 mmHg. CONCLUSION: Doppler and tissue Doppler-derived E/e' ratio is related to simultaneous invasive measurement of EDP in a heterogeneous group of patients with CHD and may provide an additional surrogate non-invasive estimation of ventricular diastolic performance in the routine follow-up of these patients. PMID- 23689522 TI - Inflammasomes in inflammatory bowel disease pathogenesis. AB - PURPOSE OF REVIEW: Inflammasomes are molecular platforms assembled in response to infection or danger signals, and they regulate the activation of caspase-1 and the maturation of the inflammatory cytokines IL-1beta and IL-18. In this review, we will summarize the centrality of Nod-like receptor proteins that assemble inflammasomes and regulate intestinal homeostasis by controlling host defense responses, microbiota composition, intestinal inflammation and tissue damage. RECENT FINDINGS: In the intestine, the innate immune system evolved to tolerate commensal microorganisms while maintaining the capacity to trigger host defense responses to invading pathogens. Recent findings suggest that inflammasomes play a critical role in the intricate interplay between the local microbial community and the mucosal immune system by sensing commensal bacteria, regulating microbial ecology, establishing the host defense response that discriminates pathogenic from commensal microbes and preventing the emergence of pathobionts. A model to reconcile the conflicting results in the literature on the role of inflammasomes in experimental colitis will be discussed. SUMMARY: A better understanding of the relationship between inflammasome signaling and the intestinal microbiota might provide insight into the complex interaction of the innate immune system with the intestinal environment, and identify new approaches for the treatment of inflammatory bowel disease and gastrointestinal cancer. PMID- 23689523 TI - Molecular markers for Barrett's esophagus and its progression to cancer. AB - PURPOSE OF REVIEW: There is a clinical need for biomarkers that can improve diagnostic accuracy and risk stratification of esophageal lesions. Here we review the current literature and highlight the most important, recent advancements in biomarkers as a supplement to histopathology for management of patients with Barrett's esophagus. RECENT FINDINGS: A prospective cohort study in Northern Ireland shows that a small panel of biomarkers (low-grade dysplasia, abnormal DNA ploidy and Aspergillus oryzae lectin) can identify patients at high risk for developing high-grade dysplasia or cancer. Recent research in molecular imaging shows promise for molecular probes in endoscopy, using fluorescently labeled peptides or lectins to identify dysplastic areas of Barrett's epithelium. Based on the current literature, p53 immunostaining is starting to be adopted by some centers as an adjunct to histopathology diagnosis for dysplasia. SUMMARY: The evidence base for the use of biomarkers is increasing and it appears that panels may have superior diagnostic and predictive power over single, candidate biomarkers. Prior to clinical implementation, biomarkers must overcome significant barriers including the need for large-scale prospective validation trials, and the limited ability of clinical laboratories to process and analyze complex biomarker assays. PMID- 23689524 TI - Diet therapy for eosinophilic esophagitis: when, why and how. AB - PURPOSE OF REVIEW: With the increasing recognition of eosinophilic esophagitis (EoE) over the past two decades, pharmacologic and dietary therapies have emerged as primary management options. The effectiveness of the elimination dietary therapy supports the conceptual definition of EoE as an antigen/immune-mediated esophageal disease. This manuscript reviews the three types of dietary therapy: an elemental formula diet with complete elimination of table foods, an allergy testing-directed elimination diet and an empiric elimination diet based on common food allergens. RECENT FINDINGS: Recent prospective studies have demonstrated symptomatic and histologic response to an elimination diet in adults with EoE that is comparable with response rates previously reported in children. Retrospective, comparative data in pediatric EoE have identified the elemental diet as offering the greatest likelihood of histologic disease remission compared with either allergy testing-directed or empiric elimination diets. The long-term goal of each dietary approach is the eventual identification of a single or limited number of trigger foods, thereby allowing a return to as regular a diet as possible. SUMMARY: Studies continue to support dietary therapy as an important and effective therapy for EoE. Although topical steroids continue to be a mainstay of therapy, none are presently Food and Drug Administration-approved for EoE. In addition, many patients are reluctant to utilize pharmacologic therapy on a chronic basis. Further research is necessary to better understand and optimize the use of diet therapy for EoE. PMID- 23689525 TI - Reduction of lymphocyte G protein-coupled receptor kinase-2 (GRK2) after exercise training predicts survival in patients with heart failure. AB - BACKGROUND: Increased cardiac G protein-coupled receptor kinase-2 (GRK2) expression has a pivotal role at inducing heart failure (HF)-related beta adrenergic receptor (betaAR) dysfunction. Importantly, abnormalities of betaAR signalling in the failing heart, including GRK2 overexpression, are mirrored in circulating lymphocytes and correlate with HF severity. Exercise training has been shown to exert several beneficial effects on the failing heart, including normalization of cardiac betaAR function and GRK2 protein levels. In the present study, we evaluated whether lymphocyte GRK2 levels and short-term changes of this kinase after an exercise training programme can predict long-term survival in HF patients. METHODS: For this purpose, we prospectively studied 193 HF patients who underwent a 3-month exercise training programme. Lymphocyte GRK2 protein levels, plasma N-terminal pro-brain natriuretic peptide, and norepinephrine were measured at baseline and after training along with clinical and functional parameters (left ventricular ejection fraction, NYHA class, and peak-VO2). Cardiac-related mortality was evaluated during a mean follow-up period of 37 +/- 20 months. RESULTS: Exercise was associated with a significant reduction of lymphocyte GRK2 protein levels (from 1.29 +/- 0.52 to 1.16 +/- 0.65 densitometric units, p < 0.0001). Importantly, exercise related changes of GRK2 (delta values) robustly predicted survival in our study population. Interestingly, HF patients who did not show reduced lymphocyte GRK2 protein levels after training presented the poorest outcome. CONCLUSIONS: Our data offer the first demonstration that changes of lymphocyte GRK2 after exercise training can strongly predict outcome in advanced HF. PMID- 23689527 TI - Environmental fate of processed natural rubber latex. AB - In this study, processed natural rubber latex was degraded in outdoor aquatic microcosms, under a number of treatment scenarios for 200 days. The analytical strategy adopted aimed to characterise a range of volatile, semi-volatile and non volatile substances. Zinc, was shown to migrate from the latex into solution and increase in concentration over time. Dissolved compounds for which predicted formulas were generated largely consisted of oxygen containing compounds, and are potential oxidised polyisoprene oligomers of various chain lengths. A classification of samples based on principal component analysis showed a clear separation of the degraded latex samples from the representative controls. This technique identified an increase in the complexity of the substances produced and showed that these substances undergo further degradation and transformation processes. A number of volatile substances were also identified indicating the atmosphere to be a potential receiving environmental compartment for polymer degradates. Overall, the results show that complex mixtures of substances are produced when polymer-based materials degrade under environmental conditions. PMID- 23689528 TI - Developmental disturbances of a maxillary central incisor due to trauma to its predecessor: a case report. AB - OBJECTIVE: To report the effects of a primary tooth trauma on the underlying permanent tooth germ. CLINICAL PRESENTATION AND INTERVENTION: A 12-year-old girl was referred to our clinic with a complaint of poor aesthetic appearance. The crown of the permanent maxillary left central tooth exhibited an increased clinical crown height with an 'enamel hyperplasia' in the cervical third and had hypoplastic enamel with yellowish-brown discoloration extending from the middle third to the incisal edge. Radiographic examination revealed that the permanent maxillary left central tooth had abnormal root morphology with root dilaceration. The patient revealed a history of trauma at the age of 4 years. An aesthetic restoration with light-curing resin composite was performed on the vestibular surface of the maxillary left permanent central tooth. CONCLUSION: Sequelae of a primary tooth trauma on the permanent tooth were restored. We recommend that parents should be aware of the consequences of untreated trauma to a primary tooth. Educational and preventive programmes on dental trauma are required to educate parents about emergency knowledge and sequelae of dental trauma. PMID- 23689526 TI - Computed tomography-derived cardiovascular risk markers, incident cardiovascular events, and all-cause mortality in nondiabetics: the Multi-Ethnic Study of Atherosclerosis. AB - AIM: We assess the improvement in discrimination afforded by the addition of the computed tomography risk markers thoracic aorta calcium (TAC), aortic valve calcification (AVC), mitral annular calcification (MAC), pericardial adipose tissue volume (PAT), and liver attenuation (LA) to the Framingham risk score (FRS) + coronary artery calcium (CAC) for incident coronary heart disease (CHD) and incident cerebrovascular disease (CVD) in a multiethnic cohort. METHODS AND RESULTS: A total of 5745 participants were enrolled, with 2710 at intermediate Framingham risk, 210 CVD events, and 155 CHD events). Over 9 years of follow up, 251 had adjudicated CHD, 346 had CVD events, and 321 died. The data were analysed using Cox proportional hazard, receiver operator curve (ROC), and net reclassification improvement (NRI) analyses. In the whole cohort and also when the analysis was restricted to only the intermediate-risk participants, CAC, TAC, AVC, and MAC were all significantly associated with incident CVD, incident CHD, and mortality, and CAC had the strongest association. When added to the FRS, CAC had the highest area under the curve (AUC) for the prediction of incident CVD and incident CHD; LA had the least. The addition of TAC, AVC, MAC, PAT, and LA to FRS + CAC all resulted in a significant reduction in AUC for incident CHD (0.712 vs. 0.646, 0.655, 0.652, 0.648, and 0.569; all p < 0.01, respectively) in participants with intermediate FRS. The addition of CAC to FRS resulted in an NRI of 0.547 for incident CHD in the intermediate-risk group. The NRI when TAC, AVC, MAC, PAT, and LA were added to FRS + CAC were 0.024, 0.026, 0.019, 0.012, and 0.012, respectively, for incident CHD in the intermediate-risk group. Similar results were obtained for incident CVD in the intermediate-risk group and also when the whole cohort was used instead of the intermediate FRS group. CONCLUSIONS: The addition of CAC to the FRS provides superior discrimination especially in intermediate-risk individuals compared with the addition of TAC, AVC, MAC, PAT, or LA for incident CVD and incident CHD. Compared with FRS + CAC, the addition of TAC, AVC, MAC, PAT, or LA individually to FRS + CAC worsens the discrimination for incident CVD and incident CHD. These risk markers are unlikely to be useful for improving cardiovascular risk prediction. PMID- 23689529 TI - A novel electrochemical membrane bioreactor as a potential net energy producer for sustainable wastewater treatment. AB - One possible way to address both water and energy shortage issues, the two of major global challenges, is to recover energy and water resource from wastewater. Herein, a novel electrochemical membrane bioreactor (EMBR) was developed to recover energy from wastewater and meantime harvest clean water for reuse. With the help of the microorganisms in the biocatalysis and biodegradation process, net electricity could be recovered from a low-strength synthetic wastewater after estimating total energy consumption of this system. In addition, high-quality clean water was obtained for reuse. The results clearly demonstrate that, under the optimized operating conditions, it is possible to recover net energy from wastewater, while at the same time to harvest high-quality effluent for reuse with this novel wastewater treatment system. PMID- 23689531 TI - Androgenic hormone profile of adult women with acne. AB - Acne in adult women is a hard-to-manage frequent disease with many relapse cases. It mostly interferes with quality of life and causes major social and metabolic losses for patients. This is a transversal retrospective study and the aim was to standardize the research on circulating androgenic hormone levels and to detect hyperandrogenic states early, showing the frequency and the pattern of the altered hormones, useful resources to correctly evaluate each patient. In this study 835 women above 15 years of age, with acne or aggravation cases, were analyzed. The aim was to verify the percentage of androgen examinations with levels above normal. The levels of the hormones dehydroepiandrosterone sulfate, dehydroepiandrosterone (DHEA), dehydrotestosterone, androstenedione and total testosterone were measured in all patients. The evaluation of the hormone profile showed that 54.56% of the patients had hyperandrogenism, and the levels of DHEA were most frequently elevated. Therefore, in the face of the importance of hyperandrogenism in the pathogenesis of acne, standardizing the research of the hormone profile is paramount for the treatment and control of relapses in case of a surge of acne breakouts during a woman's adult life. PMID- 23689532 TI - Current approaches for the treatment of autoimmune hemolytic anemia. AB - Autoimmune hemolytic anemia (AIHA) is an infrequent group of diseases defined by autoantibody mediated red blood cell destruction. Correct diagnosis and classification of this condition are essential to provide appropriate treatment. AIHA is divided into warm and cold types according to the characteristics of the autoantibody involved and by the presence of an underlying or associated disorder into primary and secondary AIHA. Due to its low frequency, treatment for AIHA is largely based on small prospective trials, case series, and empirical observations. This review describes in detail the different treatment approaches for autoimmune hemolytic anemia. Warm antibody type AIHA should be treated with steroids, to which most patients respond, although relapse can occur and maintenance doses are frequently required. Splenectomy is an effective second line treatment and can provide long-term remission without medication. Rituximab is a useful alternative for steroid refractory patients, those requiring high maintenance doses and unfavorable candidates for surgery. Promising therapeutic modifications with this monoclonal antibody are emerging including drug combinations, lower doses, and long-term use. Primary cold agglutinin disease has been recognized as having a lymphoproliferative monoclonal origin. It is unresponsive to both steroids and splenectomy. Rituximab is currently the best therapeutic alternative for this condition, and several treatment regimens are available with variable responses. PMID- 23689533 TI - Childhood maltreatment and obesity: systematic review and meta-analysis. AB - Obesity is a prevalent global-health problem associated with substantial morbidity, impairment and economic burden. Because most readily available forms of treatment are ineffective in the long term, it is essential to advance knowledge of obesity prevention by identifying potentially modifiable risk factors. Findings from experimental studies in non-human primates suggest that adverse childhood experiences may influence obesity risk. However, observations from human studies showed heterogeneous results. To address these inconsistencies, we performed Medline, PsycInfo and Embase searches till 1 August 2012 for articles examining the association between childhood maltreatment and obesity. We then conducted a meta-analysis of the identified studies and explored the effects of various possible sources of bias. A meta-analysis of 41 studies (190 285 participants) revealed that childhood maltreatment was associated with elevated risk of developing obesity over the life-course (odds ratio=1.36; 95% confidence interval=1.26-1.47). Results were not explained by publication bias or undue influence of individual studies. Overall, results were not significantly affected by the measures or definitions used for maltreatment or obesity, nor by confounding by childhood or adult socioeconomic status, current smoking, alcohol intake or physical activity. However, the association was not statistically significant in studies of children and adolescents, focusing on emotional neglect, or adjusting for current depression. Furthermore, the association was stronger in samples including more women and whites, but was not influenced by study quality. Child maltreatment is a potentially modifiable risk factor for obesity. Future research should clarify the mechanisms through which child maltreatment affects obesity risk and explore methods to remediate this effect. PMID- 23689534 TI - Antenatal prediction of postpartum depression with blood DNA methylation biomarkers. AB - Postpartum depression (PPD) affects ~10-18% of women in the general population and results in serious consequences to both the mother and offspring. We hypothesized that predisposition to PPD risk is due to an altered sensitivity to estrogen-mediated epigenetic changes that act in a cell autonomous manner detectable in the blood. We investigated estrogen-mediated epigenetic reprogramming events in the hippocampus and risk to PPD using a cross-species translational design. DNA methylation profiles were generated using methylation microarrays in a prospective sample of the blood from the antenatal period of pregnant mood disorder patients who would and would not develop depression postpartum. These profiles were cross-referenced with syntenic locations exhibiting hippocampal DNA methylation changes in the mouse responsive to long term treatment with 17beta-estradiol (E2). DNA methylation associated with PPD risk correlated significantly with E2-induced DNA methylation change, suggesting an enhanced sensitivity to estrogen-based DNA methylation reprogramming exists in those at risk for PPD. Using the combined mouse and human data, we identified two biomarker loci at the HP1BP3 and TTC9B genes that predicted PPD with an area under the receiver operator characteristic (ROC) curve (area under the curve (AUC)) of 0.87 in antenatally euthymic women and 0.12 in a replication sample of antenatally depressed women. Incorporation of blood count data into the model accounted for the discrepancy and produced an AUC of 0.96 across both prepartum depressed and euthymic women. Pathway analyses demonstrated that DNA methylation patterns related to hippocampal synaptic plasticity may be of etiological importance to PPD. PMID- 23689535 TI - High rate of disease-related copy number variations in childhood onset schizophrenia. AB - Copy number variants (CNVs) are risk factors in neurodevelopmental disorders, including autism, epilepsy, intellectual disability (ID) and schizophrenia. Childhood onset schizophrenia (COS), defined as onset before the age of 13 years, is a rare and severe form of the disorder, with more striking array of prepsychotic developmental disorders and abnormalities in brain development. Because of the well-known phenotypic variability associated with pathogenic CNVs, we conducted whole genome genotyping to detect CNVs and then focused on a group of 46 rare CNVs that had well-documented risk for adult onset schizophrenia (AOS), autism, epilepsy and/or ID. We evaluated 126 COS probands, 69 of which also had a healthy full sibling. When COS probands were compared with their matched related controls, significantly more affected individuals carried disease related CNVs (P=0.017). Moreover, COS probands showed a higher rate than that found in AOS probands (P<0.0001). A total of 15 (11.9%) subjects exhibited at least one such CNV and four of these subjects (26.7%) had two. Five of 15 (4.0% of the sample) had a 2.5-3 Mb deletion mapping to 22q11.2, a rate higher than that reported for adult onset (0.3-1%) (P<0.001) or autism spectrum disorder and, indeed, the highest rate reported for any clinical population to date. For one COS subject, a duplication found at 22q13.3 had previously only been associated with autism, and for four patients CNVs at 8q11.2, 10q22.3, 16p11.2 and 17q21.3 had only previously been associated with ID. Taken together, these findings support the well-known pleiotropic effects of these CNVs suggesting shared abnormalities early in brain development. Clinically, broad CNV-based population screening is needed to assess their overall clinical burden. PMID- 23689536 TI - Microbiota is essential for social development in the mouse. PMID- 23689537 TI - Rapid antidepressant effects: moving right along. AB - Available treatments for depression have significant limitations, including low response rates and substantial lag times for response. Reports of rapid antidepressant effects of a number of compounds, including the glutamate N-methyl D-aspartate receptor antagonist ketamine, have spurred renewed translational neuroscience efforts aimed at elucidating the molecular and cellular mechanisms of action that result in rapid therapeutic response. This perspective provides an overview of recent advances utilizing compounds with rapid-acting antidepressant effects, discusses potential mechanism of action and provides a framework for future research directions aimed at developing safe, efficacious antidepressants that achieve satisfactory remission not only by working rapidly but also by providing a sustained response. PMID- 23689538 TI - Tuberin and p27 expression in breast cancer patients with or without BRCA germline mutations. AB - BACKGROUND: Tuberin, the protein product of tuberous sclerosis gene 2 (TSC2), is the functional component of the TSC1/TSC2 complex and regulates cell cycle through activation of the cyclin-dependent kinase inhibitor p27. The transcriptional regulation of p27 is, however, also linked to a functional BRCA protein, since in BRCA1 mutant breast cancer cells, which lack the ability to repair DNA damages by homologous recombination, p27 is down-regulated. We have therefore investigated the expression of both tuberin and p27 in normal breast tissue, and in malignant epithelium from women with and without a BRCA mutation. MATERIALS AND METHODS: immunohistochemistry was used to compare p27 and tuberin protein expression in 26 BRCA1 and 2 mutation carriers, in 53 matched breast cancer patients without a family history, and in 74 benign breast tissues in a case-control study. RESULTS: Tuberin and p27 protein expression were significantly more common in benign when compared to malignant breast tissue (p = 0.01 and p = 0.03), but no difference was observed when sporadic and BRCA-mutated breast cancer specimen were compared. Tuberin and p27 were positively correlated with each other (p = 0.0017, r = 0.2527). Furthermore, p27 expression was positively correlated with ER and PR, and negatively correlated with tumor size. The expression of tuberin and p27 in breast cancer was not correlated with clinical outcome. CONCLUSION: Our results suggest that tuberin and p27 are aberrantly expressed in malignant tissue, but their expression does not appear to be dependent on the BRCA mutation state of a breast cancer patient. PMID- 23689539 TI - Tandem therapy for retinoblastoma: immunotherapy and chemotherapy enhance cytotoxicity on retinoblastoma by increasing apoptosis. AB - PURPOSE: The goal of this study was to provide an experimental basis for the clinical application of cell immunotherapy on RB in combination with chemotherapy treatment and to explore the mechanism of their combined cytotoxicity. METHODS: We investigated the antitumor effect of cytokine-induced killer cells (CIK), co cultivated with dendritic cells pulsed with tumor antigens (DC-Ag) and/or with carboplatin. Cytotoxicity was evaluated on a retinoblastoma cell line (RB-Y79) by FCM and immunofluorescence microscopy. Time-lapse video microscopy was used to follow the sequence of events during the carboplatin and CIK cytotoxicity. RESULTS: Our results showed that a small proportion of RB-Y79 cells died after a low-dose carboplatin application. The cell population recovered 5 days after carboplatin was removed from the culture medium. Three times fewer normal epithelium retina cell lines (hTERT-RPE1) died at the same carboplatin dose. CIK achieved 5 times more cytotoxicity against RB cells pre-treated with low dose of carboplatin, showing the highest antitumor activity in the tandem carboplatin-DC Ag-CIK-carboplatin treatment. Time-lapse video microscopy revealed that carboplatin-preconditioned RB cells are more avidly engaged by CIK cells, increasing RB mortality and resulting in an overall increment in apoptosis. CONCLUSION: This study provides evidence that carboplatin combined with cell immunotherapy is superior to carboplatin alone to kill RB cells in vitro. We propose that a primary application of a low dose of a chemotherapeutic drug that is able to attack the tumor, and a subsequent treatment with highly effective immunotherapy based on DC-Ag-CIK cells could be a safe and selective treatment for RB. PMID- 23689540 TI - Defensive medicine--legally necessary but ethically wrong?: Inpatient stress testing for chest pain in low-risk patients. PMID- 23689541 TI - Waldenstrom's macroglobulinemia associated with serum amyloid A protein amyloidosis: pitfalls in diagnosis and successful treatment with melphalan-based autologous stem cell transplant. AB - Waldenstrom's macroglobulinemia (WM) is increasingly being associated with amyloidosis particularly of the amyloid light-chain variety. We report on one of the few cases of WM associated with serum amyloid A protein (AA) amyloidosis. Autologous stem cell transplant (ASCT) is now being increasingly used for the treatment of amyloidosis, but most studies are small case series. Traditionally AA amyloid is associated with connective tissue disorders and periodic fever syndromes and has been treated by addressing the underlying condition. We present the first case of serum amyloid A being treated with melphalan-based ASCT to deal with the underlying WM and thereby control the amyloid, thus demonstrating the viability of this novel approach for the treatment of this disorder. PMID- 23689542 TI - Adsorption of nucleobase pairs on hexagonal boron nitride sheet: hydrogen bonding versus stacking. AB - The adsorption of hydrogen-bonded and stacked nucleobase pairs on the hexagonal boron nitride (h-BN) surface was studied by density functional theory and molecular dynamics methods. Eight types of nucleobase pairs (i.e., GG, AA, TT, CC, UU, AT, GC, and AU) were chosen as the adsorbates. The adsorption configurations, interaction energies, and electronic properties of the nucleobase pair on the h-BN surface were obtained and compared. The density of states analysis result shows that both the hydrogen-bonded and stacked nucleobase pairs were physisorbed on h-BN with minimal charge transfer. The hydrogen-bonded base pairs lying on the h-BN surface are significantly more stable than the stacked forms in both the gas and water phase. The molecular dynamics simulation result indicates that h-BN possessed high sensitivity for the nucleobases and the h-BN surface adsorption could revert the base pair interaction from stacking back to hydrogen bonding in aqueous environment. The h-BN surface could immobilize the nucleobases on its surface, which suggests the use of h-BN has good potential in DNA/RNA detection biosensors and self-assembly nanodevices. PMID- 23689543 TI - Design and validation of a multi-electrode bioimpedance system for enhancing spatial resolution of cellular impedance studies. AB - This paper reports the design and evaluation of a multi-electrode design that improves upon the statistical significance and spatial resolution of cellular impedance data measured using commercial electric cell-substrate impedance sensing (ECIS) systems. By evaluating cellular impedance using eight independent sensing electrodes, position-dependent impedance measurements can be recorded across the device and compare commonly used equivalent circuit and mathematical models for extraction of cell parameters. Data from the 8-electrode device was compared to data taken from commercial electric cell-substrate impedance sensing (ECIS) system by deriving a relationship between equivalent circuit and mathematically modelled parameters. The impedance systems were evaluated and compared by investigating the effects of arsenic trioxide (As2O3), a well established chemotherapeutic agent, on ovarian cancer cells. Impedance spectroscopy, a non-destructive, label-free technique, was used to continuously measure the frequency-dependent cellular properties, without adversely affecting the cells. The importance of multiple measurements within a cell culture was demonstrated; and the data illustrated that the non-uniform response of cells within a culture required redundant measurements in order to obtain statistically significant data, especially for drug discovery applications. Also, a correlation between equivalent circuit modelling and mathematically modelled parameters was derived, allowing data to be compared across different modelling techniques. PMID- 23689545 TI - Epidemiology of alcohol and drug use in the elderly. AB - PURPOSE OF REVIEW: Alcohol and drug abuse among older adults is a topic of growing public health concern. The authors review the recent epidemiological surveys of this emerging trend and outline some public health challenges for the coming future. RECENT FINDINGS: Relevant studies showed that prevalence of substance use disorders is increasing among American and European elders. Although treatment admissions involving use of alcohol have slightly decreased, rates involving misuse of prescription medications and illicit drugs have increased. As older adults were less likely than younger adults to recognize substance use as problematic or to use treatment services, elders were as likely to benefit from treatment as younger people. Healthcare settings should be prepared to treat this population. SUMMARY: There is robust epidemiological evidence showing that alcohol and drug abuse among the elderly are current health problems in developed regions. The number of older adults will increase in less developed regions in the next decades, but it is unclear whether this population subgroup will also seek treatment for substance use to a greater extent. Investigations of the sexual difference and cross-cultural variation can help tailor effective interventions. Routine screening programmes to address the needs of the ageing substance-using population are recommended. PMID- 23689546 TI - Mental health services for parents affected by mental illness. AB - PURPOSE OF REVIEW: Despite an increasing awareness of support needs of families affected by parental mental illness, there is a lack of adequate mental healthcare provision for parents. As contemporary mental health services are both user-focused and evidence based, the present review focuses on knowledge regarding the subjective perspective on parenting issues among affected parents and the evidence base for parenting programs. RECENT FINDINGS: There has been a shift in the research focus from adverse effects of parental mental illness on children toward inclusion and the subjective perspective in affected mothers and, more recently, fathers with mental health problems. Parents report on role conflicts, parenting difficulties, and stigma. Despite a broad spectrum of parental needs, many parents are reluctant to use services. There is an increasing evidence base for intervention programs. SUMMARY: Adequate care for parents affected by mental illness requires sensitivity for parents' subjective perspective, interagency collaboration, standard intake practice, high level of professional knowledge and skills, provision of family-friendly environments, evidence-based parenting programs comprising both individual and group approaches and peer support. There is a lack of research on other parenting needs such as desire for children, coping with custody loss, and childlessness related to mental illness. PMID- 23689544 TI - Comparison of bioimpedance and dual-energy x-ray absorptiometry for measurement of fat mass in hemodialysis patients. AB - BACKGROUND: Fat mass (FM) is measured with dual-energy X-ray absorptiometry (DXA), but is expensive and not portable. Multifrequency bioimpedance spectroscopy (BIS) measures total body water (TBW), intracellular water (ICW) and extracellular water (ECW). FM is calculated by subtracting fat-free mass (FFM) from weight assuming a fractional hydration of FFM of 0.73. Hemodialysis (HD) patients, however, have nonphysiologic expansion of ECW. Our aim was to apply a model to estimate FM in HD patients and controls. METHODS: We estimated the hydration of FFM in healthy subjects and HD patients with BIS (Impedimed multifrequency) assuming a hydration of 0.73 or using a model allowing ECW and ICW to vary, deriving a value for FM accounting for variances in ECW and ICW. FM was measured by DXA (Hologic Discovery W) in 25 controls and in 11 HD patients. We measured TBW, ECW and ICW with BIS and calculated FM using either weight - TBW/0.73 or with a model accounting for variations in ECW/ICW to estimate FM. RESULTS: ECW/ICW was greater in HD patients than in controls (0.83 +/- 0.08 vs. 0.76 +/- 0.04; p = 0.001). FM (kg) measured by DXA or estimated from TBW using constant hydration or accounting for variations in ECW/ICW was not significantly different in controls or in HD patients. Values obtained by all methods correlated (p < 0.001) and none of the Bland-Altman plots regressed (r(2) = 0.00). FM measured by DXA and by BIS in both controls and HD patients combined correlated (r(2) = 0.871). CONCLUSION: Expansion of ECW in HD patients is statistically significant; however, the effect on hydration of FFM was insufficient to cause significant deviation from values derived using a hydration value of 0.73 within the range of expansion of ECW in the HD patient population studied here. PMID- 23689547 TI - How did we arrive at burden of disease estimates for mental and illicit drug use disorders in the Global Burden of Disease Study 2010? AB - PURPOSE OF REVIEW: The Global Burden of Disease study 2010 (GBD 2010) estimated regional and global burden of 291 diseases and 67 risk factors. Here, we provide an overview of the methodological approach taken to this work, as well as the challenges and limitations encountered in deriving the burden of mental and drug use disorders. RECENT FINDINGS: GBD 2010 estimated the burden of 11 mental disorders and four drug use disorders for 21 regions. This involved a systematic literature search for epidemiological data; setting lay case definitions; synthesizing available epidemiological data into an internally consistent disease model; and quantifying the associated disability and health outcomes, to derive region, sex, year and age-specific burden estimates. Notable challenges included the difficulty in deriving culturally comparable case definitions for mental and drug use disorders, the paucity of epidemiological data and the difficulty in capturing disability associated with mental and drug use disorders. SUMMARY: GBD 2010 findings demonstrated the major public health importance of mental and drug use disorders. The methodology used to estimate burden was more sophisticated than previous GBD studies, with some restrictions required in order to achieve defensible numerical measures of burden for mental and drug use disorders. PMID- 23689548 TI - Engaging young people who misuse substances in treatment. AB - PURPOSE OF REVIEW: The focus of this review is to examine service utilization, treatment effectiveness, and future directions for adolescents who misuse substances. RECENT FINDINGS: Although the effectiveness of treatments has improved in the last two decades, young people's utilization of services has remained relatively stable. This is disconcerting because early intervention improves outcomes and deterioration is associated with physical, psychological, and social problems. The requirement for coordinated service provision across a wide range of treatment agencies cannot be emphasized enough, because young substance misusers come to services with a variety of symptoms and problems. It is encouraging that, to date, treatment studies indicate that adolescents in almost all types of treatment reduce their use of substances. The greatest reductions are shown for family therapy, followed by cognitive behavior therapy (CBT), motivational enhancement therapy (MET)/CBT, MET behavior therapy, and pharmacological treatment. Despite the developing treatment literature, important methodological limitations restrict comparability between studies. SUMMARY: The requirement for holistic, systematic assessments should include adolescents' social contexts, trauma, and psychiatric and physical illnesses because they are the cornerstones to understanding engagement and retention. Our review shows the importance of coordinating primary healthcare, mental health, and substance abuse treatment facilities, and highlights networking between other providers as integral to providing an optimal response to this unpredictable, often marginalized, group. PMID- 23689549 TI - Changes in cannabis use among young people: impact on mental health. AB - PURPOSE OF REVIEW: The aim of this review was to examine current trends in cannabis use and cannabis use disorder (CUD) among youth, and to investigate recent findings concerning the relationship between cannabis use and mental health concerns, with a focus on how use during adolescence may interact with related mental health disorders. RECENT FINDINGS: Current data indicate that cannabis use among adolescents has shown both marginal increases and decreases, depending on global location; however, the profile of cannabinoids in cannabis may now be biased toward those that promote psychotogenic and memory-impairing effects. CUD has been found most prevalent among youth. After controlling for multiple confounders, longitudinal research suggests that cannabis use predicts the development of anxiety disorders, depression, suicidal ideation, certain personality disorders, and interpersonal violence. Further, associations have been found stronger in adolescents relative to adults, and younger age of initiation increases the risk of developing mental health disorders. SUMMARY: Cannabis use among youth remains prevalent, and recent studies are consolidating previous findings that adolescents are especially vulnerable to mental health disorders associated with cannabis. This suggests that cannabis involvement requires increased prominence in research, prevention initiatives, routine screening, and interventions to improve adolescent mental health. PMID- 23689550 TI - Ethical issues in obtaining collateral information on alcohol and drug use: experience from Asia and Africa. AB - PURPOSE OF REVIEW: In many regions of the world, wives of alcohol and drug-using men are at an increased risk for HIV/AIDS because of their husbands' high-risk behaviours. These women also tend to be poor, illiterate and dependent on their husbands. Few interventions are designed exclusively for these women. Furthermore, these interventions have had to obtain permission from the husbands to recruit the wives. This article discusses the ethical concerns in obtaining husbands' permission to recruit their wives, with examples taken from India and other countries in Asia and Africa. RECENT FINDINGS: Studies indicate that married women are recruited for interventions only with their husbands' consent. Researchers reported that this strategy was acceptable to the local culture, increased acceptance of the research by family and community and improved the participation rate of married women. However, this strategy conflicts with the ethical principles of individual autonomy and voluntariness. SUMMARY: Designing research processes according to the local cultural norms is important. However, it is a researcher's ethical duty to ensure that every individual of the society, irrespective of sex, race or marital status, gets equal opportunities to make health-related decisions. This article suggests alternate strategies to directly approach and recruit monogamous wives of alcohol and drug-using men; further research is required to test the feasibility of suggested strategies. PMID- 23689554 TI - Rapid electrochemical detection on a mobile phone. AB - We present a compact mobile phone platform for rapid, quantitative biomolecular detection. This system consists of an embedded circuit for signal processing and data analysis, and disposable microfluidic chips for fluidic handling and biosensing. Capillary flow is employed for sample loading, processing, and pumping to enhance operational portability and simplicity. Graphical step-by-step instructions displayed on the phone assists the operator through the detection process. After the completion of each measurement, the results are displayed on the screen for immediate assessment and the data is automatically saved to the phone's memory for future analysis and transmission. Validation of this device was carried out by detecting Plasmodium falciparum histidine-rich protein 2 (PfHRP2), an important biomarker for malaria, with a lower limit of detection of 16 ng mL(-1) in human serum. The simple detection process can be carried out with two loading steps and takes 15 min to complete each measurement. Due to its compact size and high performance, this device offers immense potential as a widely accessible, point-of-care diagnostic platform, especially in remote and rural areas. In addition to its impact on global healthcare, this technology is relevant to other important applications including food safety, environmental monitoring and biosecurity. PMID- 23689555 TI - Effects of pre- and post-treatment with plant polyphenols on human keratinocyte responses to solar UV. AB - BACKGROUND: The understanding of the anti-inflammatory mechanisms of action of plant polyphenols (PPs) and clarification of the relationship between their anti inflammatory and antioxidant properties may result in a new therapeutic approach to skin cancers. OBJECTIVE: To elucidate the underlying mechanism, we analyzed the ability of PPs to attenuate inflammatory, metabolic and oxidative cellular responses to UV irradiation. METHODS: Normal human epidermal keratinocytes (NHEK) were exposed to physiologically relevant dose of solar-simulated UV irradiation. Effects of pre- and post-treatment with PPs on the overproduction of peroxides and inflammatory mediators (mRNA and protein) were analyzed using real-time RT PCR, enzyme-linked immunosorbent and fluorometric techniques. RESULTS: Differences between the effectiveness of pre- and post-treatment with polyphenols was found. In particular, PPs post-treatment, but not pretreatment, completely abolished overexpression of Cyp1a1 and Cyp1b1 genes and elevation of intracellular peroxides in NHEK irradiated by UV. Post-treatment with PPs also more efficiently than pretreatment prevented UV-induced overexpression of IL-1 beta, IL-6 and COX2 mRNAs. CONCLUSION: Our data strongly suggest that PPs predominantly affect delayed molecular and cellular events initiated in NHEK by solar UV rather than primary photochemical reactions. PPs may be important component in cosmetic formulations for post-sun skin care. PMID- 23689556 TI - Role of staphylococcal superantigens in airway disease. AB - Staphylococcus aureus is a common human pathogen, which is regularly part of the normal microflora found in the nose and skin. It represents a significant threat to human health, not in the least because of its capability to produce exotoxins, which have superantigenic properties. These exotoxins, in particular the staphylococcal enterotoxins (SEs), are known to be involved in the modulation and aggravation of airway inflammation. Indeed, recent studies show an important impact of SEs on the natural course of allergic rhinitis, nasal polyposis, asthma and COPD. This review outlines the current knowledge on the influence of SEs on airway inflammation. We highlight, in particular, the recent evidence on their role in asthma. PMID- 23689557 TI - Sequence of synaptogenesis in the fetal and neonatal cerebellar system - part 1: Guillain-Mollaret triangle (dentato-rubro-olivo-cerebellar circuit). AB - Precise temporal and spatial sequences of synaptogenesis occur in the cerebellar system, as in other synaptic circuits of the brain. In postmortem brain sections of 172 human fetuses and neonates, synaptophysin immunoreactivity was studied in nuclei of the Guillain-Mollaret triangle: dentato-olivo-rubro-cerebellar circuit. Synaptophysin demonstrates not only progressive increase in synaptic vesicles in each structure, but also shows the development of shape from amorphous globular neuronal aggregates to undulated nuclei. Intensity of synaptophysin reactivity is strong before the mature shape of these nuclei is achieved. Accessory olivary and deep cerebellar nuclei are intensely stained earlier than the principal olivary and dentate nuclei. The dorsal blades of both form earlier than the ventral, with reactivity initially peripheral. Initiation of synaptophysin reactivity is at 13 weeks in the inferior olive (r6, r7) and at 16 weeks in the dentate (r2). Initial synaptic vesicles are noted at 13 weeks in the red nucleus (r0); synapses form initially on the small neurons at 13 weeks but thereafter simultaneously on small and large neurons. Form and reactivity follow caudorostral, dorsoventral and mediolateral gradients in the axes of the rhombencephalon. This study provides control data to serve as a basis for interpreting aberrations in synaptogenesis in malformations of the cerebellar system, genetic disorders and acquired insults to the cerebellum and brainstem during fetal life, applicable to tissue sections and complementing biochemical and molecular techniques. PMID- 23689558 TI - Inflammation and spontaneous stone expulsion rate. PMID- 23689559 TI - Hydroxylated derivatives of dimethoxy-1,4-benzoquinone as redox switchable earth alkaline metal ligands and radical scavengers. AB - Benzoquinones (BQ) have important functions in many biological processes. In alkaline environments, BQs can be hydroxylated at quinoid ring proton positions. Very little is known about the chemical reaction leading to these structural transformations as well as about the properties of the obtained hydroxyl benzoquinones. We analyzed the behavior of the naturally occurring 2,6-dimethoxy 1,4-benzoquinone under alkaline conditions and show that upon substitution of methoxy-groups, poly-hydroxyl-derivatives (OHBQ) are formed. The emerging compounds with one or several hydroxyl-substituents on single or fused quinone rings exist in oxidized or reduced states and are very stable under physiological conditions. In comparison with the parent BQs, OHBQs are stronger radical scavengers and redox switchable earth-alkaline metal ligands. Considering that hydroxylated quinones appear as biosynthetic intermediates or as products of enzymatic reactions, and that BQs present in food or administered as drugs can be hydroxylated by enzymatic pathways, highlights their potential importance in biological systems. PMID- 23689560 TI - Cucurbit[8]uril-based supramolecular polymers: promoting supramolecular polymerization by metal-coordination. AB - Linear supramolecular polymers were obtained in aqueous solution by employing cucurbit[8]uril-based host-guest interaction as the driving force. Water-soluble monomers were prepared through direct metal-coordination. The rigid and bulky terpyridine-Fe linker can effectively enhance the monomer's solubility and suppress its cyclization, thereby promoting supramolecular polymerization. PMID- 23689562 TI - Primary glomerulonephritis in mainland China: an overview. AB - Chronic kidney disease (CKD) has received increased attention as a global health problem because of its increasing incidence and prevalence, poor outcome and high associated costs. Primary glomerulonephritis (GN) is the leading cause of CKD and end-stage renal disease in China. Immunoglobulin A nephropathy (IgAN) is the most common type of primary GN and accounts for 40-50% of the adult patients undergoing renal biopsy. Interestingly, the reported prevalence of focal segmental glomerulosclerosis (FSGS) in China varies by geographical region, and the prevalence of membranous nephropathy is increasing. Familial FSGS and IgAN are common in China, suggesting that genetic factors are involved in their pathogenesis. The evidence to guide the treatment of these glomerular diseases is limited. Most Chinese nephrologists follow the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines during their practice. Here, we review the current prevalence, etiology, clinicopathological features and treatment of primary GN in China. PMID- 23689561 TI - Calcium co-ingestion augments postprandial glucose-dependent insulinotropic peptide(1-42), glucagon-like peptide-1 and insulin concentrations in humans. AB - PURPOSE: This study determined whether calcium co-ingestion potentiates postprandial GIP(1-42) and GLP-1 concentrations in humans and the concomitant impact on insulin, appetite sensations and substrate metabolism. METHODS: Ten healthy males consumed two energy- and macronutrient-matched meals in a double blind, randomized, crossover design. The calcium content of the control meal was 3 mg/kg body mass, which was increased to 15 mg/kg body mass with calcium co ingestion. Circulating concentrations of GIP(1-42), GLP-1 and insulin were determined over a 180-min postprandial period, followed by 60 min of exercise. Visual analogue scales were used to determine subjective appetite sensations. Rates of energy expenditure and substrate (lipid and carbohydrate) oxidation were estimated using indirect calorimetry. RESULTS: Calcium co-ingestion resulted in a 47% increase in GIP(1-42), a 22% increase in GLP-1 and a 19% increase in insulin areas under the curve for the 120 min following consumption (all P < 0.05). Furthermore, appetite sensations were suppressed by calcium co-ingestion by 12% (P = 0.034). No differences, however, were observed in substrate metabolism (P > 0.05). CONCLUSION: Ingestion of a high-calcium meal potentiates postprandial GIP(1-42), GLP-1 and insulin concentrations in humans. Subjective appetite is also temporarily suppressed, although substrate metabolism is unaffected. PMID- 23689563 TI - Advances in the pathology of glomerular diseases. AB - Glomerular injury can be caused by numerous insults including hemodynamics, infections and immunity, hereditary and metabolic diseases, and toxicity. Basic and translational experimental studies in combination with clinical research in patients with renal disease have advanced our understanding of the etiology and pathogenesis of many forms of glomerulonephritis. This new knowledge has facilitated classification and treatment and has contributed to a better outcome of patients with renal disease. Since renal disease almost without exception leads to systemic cardiovascular complications, these advances are also of general health interest. Here, we shall briefly review general principles in the pathology of glomerular injury and discuss recent developments in the study of podocytopathies; membranous glomerulopathy; ANCA-associated vasculitis; C3 glomerulopathies and the role of complement in endothelial injury; and the prognostic value of the renal biopsy in predicting long-term outcome in lupus nephritis, vasculitis and IgA nephropathy. PMID- 23689564 TI - Changing spectrum of biopsy-proven primary glomerular diseases over the past 15 years: a single-center study in China. AB - The prevalence of chronic kidney disease (CKD) is reported to be 10.8-11.8% of the Chinese population. With economic development and longer life expectancy, the spectrum of CKD etiology has kept changing. Primary glomerular diseases (PGD) are still the most common renal diseases in China. To investigate the changing pattern of PGD in China, we retrospectively analyzed consecutive native renal biopsies performed in our hospital from 1997 to 2011. The patients were grouped according to a 3-year interval, 1997-1999 (period 1), 2000-2002 (period 2), 2003 2005 (period 3), 2006-2008 (period 4), 2009-2011 (period 5), and divided into three age groups (<20, 20-59, and >=60 years old). 8,909 qualified cases were enrolled in this study. Among 8,909 specimens, 6,337 (71.13%) were diagnosed as PGD, while this prevalence decreased significantly from 77.61% in 1997-1999 to 66.73% in 2006-2008. IgA nephropathy (IgAN) was the most common PGD (36.66%), without any significant difference in the 5 periods (p = 0.185). IgAN was the most common PGD both in patients between the 20- to 59-year-old group (45.58%) and <20-year-old group (19.29%) as well. Membranous nephropathy (MN) was the most frequently found PGD in patients at age >=60 years (39.64%). The frequency of MN was increased significantly from 6.48% in 1997-1999 to 22.79% in 2009-2011 (p < 0.001). The proportion of elderly patients increased significantly from 3.18% in 1997-1999 to 15.21% in 2009-2011 (p < 0.001). The prevalence of endocapillary proliferative glomerulonephritis (EnPGN) has decreased since 1997. PGD has remained the most common renal disease in China, although with a descending trend. The spectrum of PGD is different in different age groups. The frequency of EnPGN has decreased significantly, while that of MN has increased significantly. PMID- 23689565 TI - Evaluation of anemia and serum iPTH, calcium, and phosphorus in patients with primary glomerulonephritis. AB - Glomerulonephritis (GN) remains a major cause of morbidity and mortality in chronic kidney disease (CKD). Our study aimed to investigate the prevalence of anemia, abnormal serum intact parathyroid hormone (iPTH), calcium, and phosphorus in a Chinese patient population with primary GN. Medical histories and laboratory test results were collected from 2,924 patients with primary GN hospitalized in Ruijin Hospital of Shanghai between January 2003 and August 2009. The leading cause of CKD was primary glomerular diseases, which were responsible for up to 53.5% of all cases. IgA nephropathy was the most common cause, accounting for 38.7%, followed by focal segmental glomerulosclerosis (FSGS). The anemia rate of GN patients in early stages of CKD (stages 1-2 and 3) was 16-36%, and rapidly accelerated to 65.8 and 80.2% in advanced CKD stage 4 and stage 5, respectively. There was no significant decline observed in the level of serum calcium in patients with CKD stages 1-4 (p > 0.05). However, in patients with CKD stage 5 the prevalence of hypocalcaemia increased significantly (13.7%, p = 0.000). The prevalence of hyperphosphatemia did not significantly increase in patients with CKD stages 1-3 (p < 0.05), but was much higher in patients with CKD stages 4 and 5 (p = 0.001 and p = 0.021, respectively) and showed a negative correlation with renal function. Serum iPTH levels did not increase significantly in GN patients with CKD stages 1-2. The median iPTH levels were 54.7, 88.6, and 289.2 pg/ml (p = 0.000) for CKD stages 3-5, respectively, all of which showed negative correlation with renal function. The proportion of vitamin D insufficiency and deficiency increased to 29.3 and 11.2%, respectively, as the glomerular filtration rate fell below 15 ml/min/1.73 m(2). Primary glomerular disease remains the major cause of CKD in China, and complications such as anemia and metabolic bone disease are frequently present in GN patients. PMID- 23689566 TI - Role of podocyte injury in IgA nephropathy. AB - IgA nephropathy (IgAN) encompasses different pathological entities, all of which are characterized by the mesangial deposition of IgA. Aberrantly glycosylated IgA molecules appear to play a major role in the pathogenesis of IgAN. Both genetic and environmental factors contribute to the formation of IgG antibodies that binds to aberrantly glycosylated IgA molecules and the glomerular deposition of circulating polymeric IgA complexes. Mesangial cells serve as primary glomerular cell type injured in IgAN with a variety of pathological changes leading to progressive renal dysfunction. Recent evidence suggests that indirect podocyte injury also contributes to glomerular damage observed in IgAN. These mechanisms were demonstrated in cultured podocytes exposed to mesangial cell-conditioned medium of human IgAN. Large-scale biopsy series of human kidneys also suggest that podocyte injury plays a role in IgAN. In this review, we discuss the recent advances that have helped elucidate the mechanisms of podocyte injury in IgAN and how these mechanisms correlate with clinically important outcomes in human studies. PMID- 23689568 TI - Immunopathological predictors of prognosis in IgA nephropathy. AB - IgA nephropathy (IgAN) is characterized by the expansion of the glomerular mesangial matrix with mesangial cell proliferation and/or mononuclear cell infiltration. Glomeruli typically contain generalized diffuse granular mesangial deposits of IgA (mainly galactose-deficient polymeric IgA1), IgG and C3. Electron dense deposits are observed in the glomerular mesangial area and glomerular basement membrane. Therefore, this disease is considered to be an immune complex mediated glomerulonephritis. The detailed observations of electron-dense deposits are of value for the evaluation of the disease activity. The evidence- and lumped system-based histological classification can identify the magnitude of the risk of disease progression and is useful for predicting long-term renal outcome in this disease. A study of IgAN patients showed that the number of angiotensin-II positive cells was correlated with mast cells containing both tryptase and chymase and containing only tryptase in the interstitial lesions with the most severe pathological changes. Hypercomplementemia occurs in the progression of IgAN and is controlled by an increase of complement regulatory proteins. The measurement of urinary levels of membrane attack complex and factor H and extraglomerular C3 deposition could be useful indicators of renal injury in patients with IgAN. Development of glomerulosclerosis in IgAN patients is associated with podocytopenia and the alteration of the podocyte components, i.e. podocalyxin and dendrin. It appears that the number of urinary podocytes and levels of urinary podocalyxin are useful for predicting histological changes in IgAN patients. A positive correlation was observed between acute extracapillary changes and the number of dendrin-positive nuclei per glomerulus in patients with IgAN. It is concluded that there are many immunopathological predictors of prognosis, including genetic background, in this disease. Thus, the early diagnostic screening of prognosis predictors and subsequent intervention are important for the good prognosis in this disease. PMID- 23689567 TI - Genetic studies of IgA nephropathy: what have we learned from genome-wide association studies. AB - Primary IgA nephropathy (IgAN) is the most common glomerulonephritis in the world. It is most common in Asian populations, followed by Caucasians, yet relatively infrequent amongst African populations. The striking difference in the prevalence of IgAN between world populations, together with the known familial aggregation of disease, suggests an inherited mechanism. Recently three genome wide association studies (GWAS) of IgAN have identified seven susceptibility loci, providing initial insight into the genetic architecture of this trait. While genetic studies of complex traits are challenging, applying new techniques and methods of analysis, especially Next-Generation Sequencing, will push the genetic studies of IgAN forward. PMID- 23689569 TI - Treatment of progressive IgA nephropathy: an update. AB - IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. About 25-30% of IgAN patients will progress to end-stage kidney disease in 20-25 years. Early-onset symptoms that are highly suggestive of progressive IgAN include massive proteinuria, hypertension, renal damage, glomerular sclerosis, crescent formation, and tubulointerstitial fibrosis. Progressive IgAN may progress to renal failure in a short time. Optimized supportive therapy is the fundamental treatment for progressive IgAN patients, and includes renin angiotensin system blockers, blood pressure control, antiplatelet and anticoagulant drugs, statins, and allopurinol. In progressive IgAN patients whose clinical and pathological manifestations are more severe, active therapy may be considered including glucocorticoid therapy, cyclophosphamide, azathioprine, mycophenolate mofetil, tacrolimus, and other immunosuppressants. However, there are currently controversies on the definition and treatment of progressive IgAN. PMID- 23689570 TI - Different targets for treating focal segmental glomerular sclerosis. AB - Various drugs have been used for the treatment of focal segmental glomerular sclerosis (FSGS) or minimal change disease (idiopathic nephrotic syndrome, INS) including methylprednisolone pulses, alkylating agents and calcineurin inhibitors, often without a strong rationale. For some drugs the rationale has been recently provided by the identification of mechanisms regulating proteinuria. The characterization of molecules acting as permeability factors, including hemopexin, soluble urokinase receptor and cardiotrophin-like cytokine 1, supports plasma exchange in severe cases of INS, particularly in patients at high risk of recurrence of FSGS after transplantation. The collaboration of B and T cells for the production of permeability factors has provided a rationale for targeting B cells using rituximab. Several studies in children and adults, mostly in steroid-dependent cases, or after recurrence in grafted kidneys, have reported improved outcomes after rituximab. Podocyte actin cytoskeleton is a new target for therapy. Calcineurin inhibitors block the dephosphorylation of the cytoskeleton component synaptopodin, and steroids increase actin polymerization and stability. High doses of methylprednisolone and cyclosporine proved to be beneficial in patients with a high risk of FSGS recurrence. An interesting new target for blunting the INS pathogenetical mechanisms is the transcription factor nuclear factor-kappaB (NF-kappaB) which was reported to be activated in circulating mononuclear cells of these patients. NF-kappaB is regulated by the proteasome and saquinavir, a HIV protease inhibitor, is provided with antiproteasome activity. Using saquinavir associated with small doses of calcineurin inhibitors, we treated a small series of very difficult cases of INS with insufficient response to steroid therapy and multiple immunosuppressive drugs. Saquinavir allowed a significant reduction of steroid cumulative doses and disappearance of features of steroid toxicity. In conclusion, recent reports have allowed a new insight into the pathogenetical mechanism regulating proteinuria in INS, offering new targets for treating severe cases. PMID- 23689571 TI - Screening of ACTN4 and TRPC6 mutations in a Chinese cohort of patients with adult onset familial focal segmental glomerulosclerosis. AB - OBJECTIVES: Familial focal segmental glomerulosclerosis (FSGS) has been widely reported as having an underlining genetic component to its pathogenesis. Recently, mutations in TRPC6 and ACTN4 were identified to be associated with familial FSGS, however few studies have reported the mutation rates of these two genes in Chinese familial FSGS patients. The aim of this study was to determine the prevalence of TRPC6 and ACTN4 mutations in Chinese adult-onset familial FSGS. METHODS: 80 FSGS pedigrees with Chinese ancestry who were admitted to our hospital from September 1997 to January 2012 were screened for TRPC6 and ACTN4 mutations. There was at least one biopsy-proven FSGS in each family. An additional family member with renal function insufficiency, obvious proteinuria, or end-stage renal disease was required if there was only 1 biopsy-proven FSGS case in the family. FSGS secondary to systemic diseases, such as obesity, hypertension, diabetes, or virus infection, were excluded. Other hereditary renal diseases, such as Alport's disease and Fabry disease, were also excluded by related tests. Genomic DNA was extracted from peripheral blood cells, and Sanger sequencing was performed for all exons and exon-intron boundaries of TRPC6 and ACTN4 in the probands of all FSGS pedigrees enrolled in this study. RESULTS: Of the total index patients, 33 were female and 47 were male. The median age at disease onset was 39 years (range 15-67). The median proteinuria level was 1,324 mg/day and the median serum creatinine level was 114.5 MUmol/l (range 41-1,040) at diagnosis. A missense mutation (Q889K) of TRPC6 was found in two independent families. No mutation was found in ACTN4. Accordingly, the mutation rate of TRPC6 was 2.5% and of ACTN4 it was 0%. CONCLUSION: Mutations of TRPC6 and ACTN4 occur in only a minor portion of Chinese familial FSGS patients. Further genetic studies conducted in these patients will be helpful to increase our understanding of the pathogenesis of FSGS. PMID- 23689572 TI - Increased risk of treatment failure and end-stage renal disease in familial focal segmental glomerular sclerosis. AB - OBJECTIVE: Focal segmental glomerular sclerosis (FSGS) is one of the most important causes of end-stage renal disease (ESRD). The pathogenesis, clinical manifestation, pathological changes and treatment of FSGS differ in patients with and without a family history of the disease. Few studies have compared familial FSGS (FFSGS) and sporadic FSGS (SFSGS). The aim of this study was to assess the clinical and pathological features and the prognosis of FSGS in patients with and without a family history of the disease. METHODS: We enrolled 124 FFSGS patients and 124 age- and sex-matched SFSGS patients in the study. All patients underwent a renal biopsy to determine FSGS. The mean follow-up time was 28.3 +/- 12.5 months for the FFSGS group and 26.5 +/- 19.5 months for the SFSGS group (p > 0.05). Baseline clinical characteristics were recorded for all participants. The primary outcomes of the study were ESRD and remission of proteinuria (defined as a 50% reduction of the baseline urine protein level). The pathological changes were assessed by focal/global glomerulosclerosis and the tubulointerstitial lesion score. RESULTS: There were no age or gender differences between the two groups. A total of 43.75% of the FFSGS patients and 35.16% of the SFSGS patients had high blood pressure, but the difference was not statistically significant (p = 0.079). In addition, patients in the FFSGS group had a lower urine protein excretion rate (1.4 +/- 1.4 vs. 2.0 +/- 1.8 g/24 h) and a higher serum albumin value (3.6 +/- 6.2 vs. 3.0 +/- 1.1 g/dl) than patients in the SFSGS group (p < 0.01). A total of 62.9% of the FFSGS patients and 22.9% of the SFSGS patients had hematuria, and the difference was statistically significant (p = 0.0001). Nephrotic syndrome occurred less frequently in the FFSGS group than in the SFSGS group (13.3 vs. 22.6%, p = 0.003). The baseline serum creatinine, uric acid and eGFR values were similar in the two groups. When pathological changes were examined, the FFSGS patients showed more severe global glomerulosclerosis and tubular interstitial injury than the SFSGS patients. During the follow-up period, the FFSGS group had a lower proteinuria remission rate (23.08 vs. 48.39%, p = 0.006) and a lower median renal survival time (96 vs. 72 months, p = 0.04) than the SFSGS group. CONCLUSIONS: Compared to SFSGS patients, FFSGS patients displayed distinct clinicopathological features that were associated with less response to treatment and worse renal outcomes. PMID- 23689573 TI - Treatment and prognosis of primary focal segmental glomerulosclerosis. AB - This study aimed to analyze the treatment, clinical outcomes, and risk factors that affect the prognosis of patients with primary focal segmental glomerulosclerosis (FSGS) and to provide theoretical evidence for various treatment options in these patients. The study reviewed the clinical, laboratory, and pathological data of 168 patients with primary FSGS treated at Ruijin Hospital between January 2002 and October 2011. Of these patients, 108 were male (64.3%) and 60 were female (35.7%). The median age of disease onset was 38 years (range 12-78 years). The median case history was 10 months (range 4 days to 30 years). The mean proteinuria level was 2.3 +/- 0.6 g/day. 75 (44.6%) patients had nephrotic syndrome. The mean serum creatinine was 108.1 +/- 8.9 MUmol/l. Over a follow-up period of 25.3 +/- 11.4 months, end-stage renal failure occurred in 4 patients, and all 4 survived. In the group treated with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, the following factors were identified as risk factors for experiencing a 50% increase in serum creatinine over the baseline: a baseline eGFR <60 ml/min, proteinuria >1 g/day during the follow-up period, glomerular sclerosis >grade 1, and tubulointerstitial lesions >stage 1. In the group treated with steroids, patients who achieved a stable remission had better preserved renal function and milder glomerular sclerosis than steroid-dependent patients (p < 0.01). Steroid-resistant FSGS patients had a worse histological severity of glomerular sclerosis than steroid-dependent patients (p < 0.01). The prognosis of FSGS was correlated with the amount of proteinuria, the level of serum creatinine, and the severity of glomerular sclerosis and tubulointerstitial lesions. Steroids may be more effective in those who have better preserved renal function and milder glomerular sclerosis. PMID- 23689574 TI - New insights into treatment of nephrotic syndrome in children. AB - Primary nephrotic syndrome (PNS) is the most common glomerular disease seen in children. The pathogenic basis of PNS, in context of witnessed immunological dysfunction and its relationship with slit diaphragm and the podocyte cytoskeleton, has been explored for years. The outcome and management of PNS in children is determined by the response to corticosteroids and the frequency of relapses. The first episode of nephrotic syndrome should be treated adequately, both in terms of dose and duration of steroids, aiming at reducing the risk for subsequent relapses. While patients with steroid-sensitive nephrotic syndrome have a favorable long-term outcome, almost half of them relapse frequently and are at risk of adverse effects of steroids. Immunosuppressive agents are suggested for patients with frequently relapsing nephrotic syndrome or steroid dependent nephrotic syndrome. Calcineurin inhibitors are strongly recommended for patients who show resistance to steroids. Rituximab is a new therapy that could be a potential area but still requires further trials. The aim of therapy is to induce and maintain remission of proteinuria while avoiding medication-related adverse effects. PMID- 23689575 TI - Pathogenesis of membranous nephropathy: a new paradigm in evolution. AB - Membranous nephropathy (MN) has been recognized as a distinct morphological entity for over 50 years, but it is only recently that the underlying pathogenesis of the primary form of the disorder has been elucidated. This brief overview catalogues recent advances in understanding the pathogenesis of MN, focused mainly on its primary form. These studies have enumerated and identified several autologous podocyte antigens that serve as targets of autoantibody responses in primary MN. The dominant autoantigen is M-type phospholipase A2 receptor protein (PLA2R1) expressed on the surface of native glomerular podocytes. Autoantibodies to PLA2R1, usually of IgG4 subclass, are found in about 80% of patients with primary MN. These autoantibodies bind to genetically determined, conformational epitopes on PLA2R1, form immune complexes in situ and induce proteinuria, mostly likely via local activation of complement via the mannose-binding lectin pathway. The autoimmune response is modulated by genes at the HLA-DQA1 locus. The level of autoantibody to PLA2R correlates with the severity of the clinical disease and may predict recurrences in renal allografts, at least in some patients. Most forms of secondary MN appear to be due to distinctly different pathogenetic mechanisms. PMID- 23689576 TI - Short-term complications of membranous nephropathy. AB - Short-term complications of membranous nephropathy (MN) are important components of the process and their proper management can significantly alter the outcomes of patients with this disease. These complications vary from the non-specific ones associated with many types of chronic kidney disease such as hypertension, proteinuria and the symptoms associated with the nephrotic syndrome including edema and dyslipidemia. These are briefly discussed in the chapter. In addition, there are some specific issues more commonly associated with MN than other types of glomerulonephritis. This includes a hypercoagulable state and the associated thromboembolism. There is more recent information in this domain and this is included in the chapter. The associated increased risk of infection in MN patients is the final chapter component. This section is included to remind us not only of the direct impact of that disease process on reducing resistance to infection, but also to indicate the need to consider prophylactic antibiotics when the addition of potent immunosuppressive drug treatment is required for these patients. PMID- 23689577 TI - Tacrolimus combined with corticosteroids in idiopathic membranous nephropathy: a randomized, prospective, controlled trial. AB - Although idiopathic membranous nephropathy (IMN) is the most common cause of adult-onset nephrotic syndrome, the management of IMN remains controversial. The aim of this prospective study was to compare the efficacy and drug safety of tacrolimus with that of cyclophosphamide (CTX; control group) in IMN patients receiving corticosteroid therapy. A total of 100 IMN patients with nephrotic syndrome were randomly assigned to receive a combination of corticosteroid therapy and either CTX or tacrolimus. During a follow-up period of at least 18 months, the remission rate after 2 months in the tacrolimus group was 65.1%, which was higher than that of the CTX group (44.2%) (p = 0.02). The mean time to partial or complete remission was 2.20 months in the tacrolimus group and 3.92 months in the CTX group (p < 0.001). We also found significantly greater improvements in the serum albumin levels in the tacrolimus group compared with the CTX group at the 2-month (p = 0.003) and 3-month time points (p = 0.01). The serum creatinine levels remained stable in both groups. Although remission was quicker and more common in the tacrolimus group (compared with the CTX group) before 3 months, there was no superiority of tacrolimus after 6 months. Glucose intolerance, urinary tract infections, and pneumonia were the major side effects observed in this study. All of the side effects were mild and controlled, and there were fewer side effects in the tacrolimus group compared with the CTX group, indicating a better treatment tolerance in the tacrolimus group. PMID- 23689578 TI - Membranoprolferative glomerulonephritis - mechanisms and treatment. AB - Membranoproliferative glomerulonephritis (MPGN) is a histologic pattern of glomerular damage with many etiologies. In the past, it was divided into secondary and primary, or idiopathic forms. In turn, the idiopathic forms were labeled MPGN types I, II, and III based on ultrastructural localization of the electron-dense 'deposits'. A recent major change in classification relies on the presence of immunoglobulins and complement to determine etiologies that are more in line with the pathogenesis of the disease. Idiopathic MPGN II, now called dense deposit disease and C3 glomerulonephritis, are now recognized as diseases of the alternate complement pathway. They are caused by a variety of alternate complement pathway defects including genetic forms and those due to autoantibodies that either activate accelerators of the pathway or block inhibitors of the cascade. These patients need to be evaluated in a different fashion and receive different therapy than those patients with MPGN forms associated with immunoglobulin deposition. PMID- 23689579 TI - Re-evaluation of the classification system for membranoproliferative glomerulonephritis. AB - In recent years, significant advances have been made in understanding the pathogenesis and etiology of membranoproliferative glomerulonephritis (MPGN). A new classification system based on pathological immunofluorescence findings has been proposed to replace the traditional clinical classification system in order to better identify the underlying causes of MPGN and to provide guidance for more individualized treatment. We conducted a retrospective survey of the MPGN patients treated in our hospital from 2000 to 2012 and report here the validation of this new classification system in this cohort. A total of 34 patients were diagnosed with MPGN, including 25 males and 9 females. There were 3 cases of secondary MPGN, including 1 case due to monoclonal gammopathy of undetermined significance (MGUS) and 2 cases related to hepatitis B virus (HBV) infection. Clinical presentations included nephrotic syndrome (76.5%), microscopic hematuria (79.4%), hypocomplementemia (58.8%), renal insufficiency (82.4%), hypertension (100%), and peripheral edema (100%). All patients were treated with prednisone and immunosuppressive agents, mainly cyclophosphamide. During follow-up (median 6 months, range 3-47 months), 4 patients were lost to follow-up and 2 patients progressed to end-stage renal disease. In Western countries the main cause of secondary MPGN was hepatitis C virus or HBV infection, here however we report 2 cases related to HBV infection. MGUS-associated MPGN was less frequent in the Chinese cohort. Future studies should be designed to evaluate the association of the new classification system and clinical outcomes of MPGN. PMID- 23689580 TI - C3 glomerulopathy. AB - C3 glomerulopathy is a recent disease classification comprising several rare types of glomerulonephritis, including dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The most common histological feature in these diseases is the presence of glomerular deposition of C3 within the mesangium and along the glomerular basement membrane (GBM) in the subendothelial area or within the GBM. The key role of complement alternative pathway (AP) in these disorders has been recently shown with the identification of acquired or genetic abnormalities. Low serum C3 level but normal C4 is a common finding. The acquired AP dysregulation in DDD and C3GN may be first induced by C3 nephritic factor (C3NeF). C3NeF activity is found in approximately 80% of patients with DDD and in 45% of patients with C3GN. The correlation with the complement is further supported by the detection of homozygous or heterozygous mutations in the regulatory complement proteins factor H (CFH), factor I (CFI), or C3. The genetic background of the patients may also influence the disease manifestation since common genetic variants including single nucleotide polymorphisms in the CFH, C3 and CFHR5 genes are associated with DDD and one at-risk MCP haplotype have been found to be significantly increased in C3GN. C3 glomerulopathies can present over a broad age range. DDD is more often diagnosed in children and age at diagnosis is significantly higher for patients with C3GN. Presenting features comprise any of proteinuria, hematuria, hypertension and renal failure. These glomerulonephritides are associated with chronic deterioration of renal function, leading to ESRD within 10 years of the diagnosis in 36-50% of patients. Outcomes of renal transplantation are characterized by histological recurrence which may contribute to increased rates of allograft failure. Administration of recombinant FH if it becomes available or replacement of FH via plasma exchange may be efficacious in the cases of FH deficiency. However, therapeutic inhibition of complement C3 and C5 is the main perspective. PMID- 23689581 TI - Hepatitis C virus-associated glomerulonephritis. AB - Hepatitis C virus (HCV) infection remains a major global health burden. In addition to liver-related morbidity and mortality due to hepatic decompensation and development of hepatocellular carcinoma, extrahepatic manifestations of hepatitis C are frequent. Type I membranoproliferative glomerulonephritis associated with type II cryoglobulinemia is the most frequent association. The pathogenesis of the renal lesions is related to glomerular deposition of immune complexes. International guidelines recommend that patients with HCV-related glomerulopathies should be treated with antiviral therapy in the form of standard or pegylated interferon-alpha and ribavirin. The recent development of direct acting antiviral agents that inhibit the various steps of the viral life cycle represents a major milestone for the treatment of chronic HCV infection. Initial reports suggest that they are safe in ESRD subjects. However, data is lacking on their efficacy and safety in HCV-related glomerulonephritis. PMID- 23689582 TI - Pathogenesis of rapidly progressive glomerulonephritis: what do we learn? AB - Rapidly progressive glomerulonephritis (RPGN) is a life-threatening disease with a poor prognosis. In this review, the pathogenesis of RPGN owing to antineutrophil cytoplasmic antibody-associated crescentic glomerulonephritis and anti-GBM diseases is discussed. By the model of nephrotoxic nephritis, T cells, dendritic cells and toll-like receptors are involved in podocyte activation and parietal epithelial cell proliferation which contribute to the crescent formation and glomerular injury. Furthermore, growth factors and Goodpasture autoantigen are also involved in the onset of the disease. In the study of ANCA-associated glomerulonephritis, the role of lysosome-associated membrane protein (LAMP)-2 and neutrophil extracellular traps is well studied. However, the role of LAMP-2 in the disease pathogenesis remains uncertain. We hope this review can help us to further understand the pathogenesis of the disease. PMID- 23689583 TI - ANCA-associated renal vasculitis - an update. AB - ANCA-associated vasculitis (AAV) is a potentially life-threatening disease with frequent and often severe kidney involvement which may result in end-stage renal disease. Anti-PR3 and anti-MPO disease are genetically distinct diseases and may have a different pathogenesis. Recent discovery of new autoantibodies (anti-LAMP 2) and the role of complement activation in the pathogenesis of AAV could result in better monitoring of the activity of the disease and identification of new treatment targets. The outcome of patients with AAV has dramatically improved, but long-term mortality still remains relatively high partly due to effective but relatively toxic immunosuppressive treatment. Recent studies demonstrated that B cell depletion with rituximab is comparable to cyclophosphamide as induction treatment in newly diagnosed AAV patients and better than cyclophosphamide in relapsing patients. Rituximab-based maintenance treatment is superior to standard treatment with azathioprine. The use of more targeted treatment will hopefully be translated into a better long-term outcome of AAV patients. PMID- 23689584 TI - Management of crescentic glomerulonephritis: what are the recent advances? AB - Crescentic glomerulonephritis (GN) is a life-threatening clinical syndrome characterized by crescents which are morphological manifestations of severe glomerular injury. Immunologically, crescentic GN are classified as anti glomerular basement membrane nephritis, immune complex-mediated GN and pauci immune GN. Conventional treatment for crescentic GN mainly consists of corticosteroids, immunosuppressants and plasma exchange. Plasmapheresis is beneficial for patients with Goodpasture's syndrome and those with severe pauci immune GN. Recently, new therapeutic agents have emerged, such as monoclonal antibodies to T cells, B cells and cytokines (e.g. anti-CD20 antibodies and TNF alpha inhibitors) and signal transduction inhibitors, which may provide satisfactory alternatives. However, most of these treatments have only been established in experimental crescentic GN, described in single cases or reported in open-label trials; thus, the safety and efficacy of these agents remain to be investigated via controlled clinical trials. PMID- 23689585 TI - Plasma exchange in the treatment of rapidly progressive glomerulonephritis. AB - Plasma exchange has been used for the treatment of rapidly progressive glomerulonephritis (RPGN) for more than 40 years. Its main application has been the rapid removal of special pathogenic factors that are of great importance for treatment of antiglomerular basement membrane disease, antineutrophil cytoplasmic antibody-associated vasculitis, and immune complex-mediated crescentic nephritis. Although the number of controlled trials is increasing, evidence for the benefit of plasma exchange in RPGN has varied in quality and the results are controversial. Moreover, its efficacy appears to depend on the type and duration of crescentic nephritis. Patients with pulmonary hemorrhage need plasma exchange to alleviate their symptoms and improve their chance of survival. Further trials are needed to ascertain the optimal dose, frequency and number of plasma exchange sessions, long-term outcomes, as well as the role of plasma exchange in the treatment of RPGN. PMID- 23689586 TI - Role of 18F-FDG PET CT as an independent prognostic indicator in patients with hepatocellular carcinoma. AB - OBJECTIVES: The aim of the study was to evaluate the role of F-fluorodeoxyglucose PET computed tomography (F-FDG PET CT) as an independent prognostic indicator in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: PET contrast enhanced CT scans of 100 consecutive patients with HCC were reviewed retrospectively. Patients were asked to fast for 6 h before the study and blood glucose levels were monitored and ensured to be less than 200 mg/dl before injection of F-FDG. After administering the F-FDG injection (370-550 MBq) patients were instructed to rest comfortably for 45-60 min. All images were acquired using a dedicated GE Discovery PET/CT scanner. The PET CT scans of all the patients were reported separately by two nuclear medicine physicians. A stage wise analysis of the compiled data was carried out. Lesions that showed standardized uptake values greater than background activity (activity in adjacent normal liver tissue) were defined as having increased F-FDG uptake. Pearson's chi -test or the Kruskal-Wallis test was used to assess statistical significance. A P value less than 0.05 was taken as significant. RESULTS: In this retrospective study of 100 HCC patients, a radiologically higher-stage disease was found more commonly in patients with F-FDG-avid primary tumors (P<0.001), whereas a lower stage disease was found in patients with non-F-FDG-avid primary tumors. The non-F FDG-avid tumors also showed lower incidence of metastatic disease and portal vein thrombosis (P<0.001). The histopathological findings of the patients who underwent liver transplantation demonstrated that a higher-grade tumor was more common in the F-FDG-avid tumor group than in the non-F-FDG-avid tumor group (P<0.05). CONCLUSION: An F-FDG PET CT scan can be used not only for staging but also as a tool for preoperative prediction of cellular differentiation in patients with HCC. The F-FDG uptake seen on a PET scan can serve as a molecular signature for management decisions and can be used as an independent and significant prognostic factor in patients with HCC. PMID- 23689587 TI - Fred Neufeld and pneumococcal serotypes: foundations for the discovery of the transforming principle. AB - During the first decade of the twentieth century, the German bacteriologist Fred Neufeld, later Director of the Robert Koch-Institute in Berlin, first described the differentiation of pneumococci into serotypes on the basis of type-specific antisera. This finding was essential for subsequent research at the Rockefeller Institute of Medical Research (RIMR) in New York, and elsewhere, aiming for the conquest of human pneumococcal pneumonia, including antiserum therapy, the discovery that the type-specific antigens were carbohydrates, and the development of effective multivalent pneumococcal polysaccharide vaccines. Moreover, on the basis of pneumococcal serotypes Fred Griffith, in 1928 in London, discovered pneumococcal transformation, and Oswald T. Avery and coworkers, in 1944 at RIMR, identified DNA as the transforming substance. This sequence of events, leading to today's knowledge that genes consist of DNA, was initiated by a farsighted move of Simon Flexner, first Director of the RIMR, who asked Neufeld to send his pneumococcal typing strains, thus setting the stage for pneumococcal research at RIMR. Here, we describe Fred Neufeld's contributions in this development, which have remained largely unknown. PMID- 23689589 TI - Transcription factor Snail is a novel regulator of adipocyte differentiation via inhibiting the expression of peroxisome proliferator-activated receptor gamma. AB - Snail belongs to the superfamily of zinc-finger transcription factors and plays a crucial role in processes regulating cell fate, such as the formation of mesoderm and initiation of epithelial-mesenchymal transition. We have previously discovered that Snail modulates adiponectin expression in 3T3-L1 cells during adipogenesis. In the present study, we elucidated the functional role of Snail in adipocyte differentiation and its underlying molecular mechanism. Snail expression was dramatically decreased during adipogenesis in 3T3-L1 cells. Overexpression of Snail blocked adipocyte differentiation by suppressing the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT-enhancer-binding protein alpha, while knockdown of Snail expression stimulated adipogenesis in 3T3-L1 cells. Chromatin immunoprecipitation assay and luciferase assay showed that Snail inhibits the transcriptional activity of the PPARgamma gene by directly binding to the E-box motifs in the PPARgamma promoter. Wnt10b induced phosphorylation of glycogen synthase kinase 3 beta (GSK3beta), leading to inhibition of adipogenesis in 3T3-L1 cells in accordance with increased expression of Snail, whereas adipogenic capacity was restored in Snail siRNA-transfected preadipocytes. LiCl (a GSK3beta inhibitor)-treated cells also showed increased expression of Snail, with a reduced adipogenic potential. Snail overexpressing 3T3-F442A cells did not differentiate into mature adipocytes in immunodeficient nude mice. Taken together, Snail is a novel regulator of adipocyte differentiation, which acts by direct suppression of PPARgamma expression. Our data also indicate that the expression of Snail is mediated by the Wnt-GSK3beta signaling pathway. PMID- 23689592 TI - Neuroepidemiology: a brighter look for the future. PMID- 23689588 TI - Bacterial serine proteases secreted by the autotransporter pathway: classification, specificity, and role in virulence. AB - Serine proteases exist in eukaryotic and prokaryotic organisms and have emerged during evolution as the most abundant and functionally diverse group. In Gram negative bacteria, there is a growing family of high molecular weight serine proteases secreted to the external milieu by a fascinating and widely employed bacterial secretion mechanism, known as the autotransporter pathway. They were initially found in Neisseria, Shigella, and pathogenic Escherichia coli, but have now also been identified in Citrobacter rodentium, Salmonella, and Edwardsiella species. Here, we focus on proteins belonging to the serine protease autotransporter of Enterobacteriaceae (SPATEs) family. Recent findings regarding the predilection of serine proteases to host intracellular or extracellular protein-substrates involved in numerous biological functions, such as those implicated in cytoskeleton stability, autophagy or innate and adaptive immunity, have helped provide a better understanding of SPATEs' contributions in pathogenesis. Here, we discuss their classification, substrate specificity, and potential roles in pathogenesis. PMID- 23689593 TI - Measurement of thrombin in different matrices: whole blood, platelet-rich and platelet-poor plasma using fluorogenic substrate ZGGR-AMC. PMID- 23689594 TI - Tunneled pleural catheters in the management of chylothorax from central venous catheter-related superior vena cava obstruction. AB - Chylothorax is characterized by the accumulation of chyle in the pleural space, of which the most common cause is trauma or neoplasm. Although chylothorax accounts for a small proportion of clinical pleural effusions, prompt recognition is needed to avoid malnutrition, immunodeficiency, and fibrothorax. We report 2 patients with superior vena cava obstruction caused by tunneled venous catheters resulting in chylothorax and demonstrate the potential safety of tunneled pleural catheters for prolonged chylothorax drainage in an outpatient setting with rigorous follow-up. Changes in pleural fluid chemistries of the effusions and the possible pathophysiology were assessed with a review of the literature on pleural fluid chemistries in superior vena cava obstruction. PMID- 23689590 TI - Regulation of oligodendrocyte precursor migration during development, in adulthood and in pathology. AB - Oligodendrocytes are the myelin-forming cells in the central nervous system (CNS). These cells originate from oligodendrocyte precursor cells (OPCs) during development, and they migrate extensively from oligodendrogliogenic niches along the neural tube to colonise the entire CNS. Like many other such events, this migratory process is precisely regulated by a battery of positional and signalling cues that act via their corresponding receptors and that are expressed dynamically by OPCs. Here, we will review the cellular and molecular basis of this important event during embryonic and postnatal development, and we will discuss the relevance of the substantial number of OPCs existing in the adult CNS. Similarly, we will consider the behaviour of OPCs in normal and pathological conditions, especially in animal models of demyelination and of the demyelinating disease, multiple sclerosis. The spontaneous remyelination observed after damage in demyelinating pathologies has a limited effect. Understanding the cellular and molecular mechanisms underlying the biology of OPCs, particularly adult OPCs, should help in the design of neuroregenerative strategies to combat multiple sclerosis and other demyelinating diseases. PMID- 23689596 TI - Ocular protection in facial paralysis. AB - PURPOSE OF REVIEW: Facial nerve paralysis has a profound impact on patients' quality of life, of which one of the most important sequelae is a risk of corneal surface disease. Herein, we discuss methods to protect the eye following insult to the facial nerve. RECENT FINDINGS: Protection of the ocular surface in patients with facial nerve injury is of paramount importance to prevent corneal injury and potential blindness. Many interventions on the eye are temporary and therefore easily reversible. A systematic approach to managing the eye is required in these patients. SUMMARY: This article provides a review of current methods used for ocular protection in patients with facial nerve paralysis. PMID- 23689595 TI - Dose-dependent vitamin C uptake and radical scavenging activity in human skin measured with in vivo electron paramagnetic resonance spectroscopy. AB - Vitamin C is a potent radical scavenger and a physiological part of the antioxidant system in human skin. The aim of this study was to measure changes in the radical-scavenging activity of human skin in vivo due to supplementation with different doses of vitamin C and at different time points. Therefore, 33 volunteers were supplemented with vitamin C or placebo for 4 weeks. The skin radical-scavenging activity was measured with electron paramagnetic resonance spectroscopy. After 4 weeks, the intake of 100 mg vitamin C/day resulted in a significant increase in the radical-scavenging activity by 22%. Intake of 180 mg/day even resulted in a significant increase of 37%. No changes were found in the placebo group. A part of the study population was additionally measured after 2 weeks: in this group radical scavenging had already reached maximal activity after 2 weeks. In conclusion, orally administered vitamin C increases the radical scavenging activity of the skin. The effect occurs fast and is enhanced with higher doses of vitamin C. PMID- 23689597 TI - BCL-2 inhibitors sensitize therapy-resistant chronic lymphocytic leukemia cells to VSV oncolysis. AB - Many primary cancers including chronic lymphocytic leukemia (CLL) are resistant to vesicular stomatitis virus (VSV)-induced oncolysis due to overexpression of the antiapoptotic and antiautophagic members of the B-cell lymphoma-2 (BCL-2) family. In the present study, we investigated the mechanisms of CLL cell death induced as a consequence of VSV infection in the presence of BCL-2 inhibitors, obatoclax, and ABT-737 in primary ex vivo CLL patient samples. Microarray analysis of primary CD19+ CD5+ CLL cells treated with obatoclax and VSV revealed changes in expression of genes regulating apoptosis, the mechanistic target of rapamycin (mTOR) pathway, and cellular metabolism. A combined therapeutic effect was observed for VSV and BCL-2 inhibitors in cells from untreated patients and from patients unresponsive to standard of care therapy. In addition, combination treatment induced several markers of autophagy--LC3-II accumulation, p62 degradation, and staining of autophagic vacuoles. Inhibition of early stage autophagy using 3-methyladenine (3-MA) led to increased apoptosis in CLL samples. Mechanistically, a combination of BCL-2 inhibitors and VSV disrupted inhibitory interactions of Beclin-1 with BCL-2 and myeloid cell leukemia-1 (MCL-1), thus biasing cells toward autophagy. We propose a mechanism in which changes in cellular metabolism, coupled with pharmacologic disruption of the BCL-2-Beclin-1 interactions, facilitate induction of apoptosis and autophagy to mediate the cytolytic effect of VSV. PMID- 23689598 TI - Genetically engineered human islets protected from CD8-mediated autoimmune destruction in vivo. AB - Islet transplantation is a promising therapy for type 1 diabetes, but graft function and survival are compromised by recurrent islet autoimmunity. Immunoprotection of islets will be required to improve clinical outcome. We engineered human beta cells to express herpesvirus-encoded immune-evasion proteins, "immunevasins." The capacity of immunevasins to protect beta cells from autoreactive T-cell killing was evaluated in vitro and in vivo in humanized mice. Lentiviral vectors were used for efficient genetic modification of primary human beta cells without impairing their function. Using a novel beta-cell-specific reporter gene assay, we show that autoreactive cytotoxic CD8(+) T-cell clones isolated from patients with recent onset diabetes selectively destroyed human beta cells, and that coexpression of the human cytomegalovirus-encoded US2 protein and serine proteinase inhibitor 9 offers highly efficient protection in vitro. Moreover, coimplantation of these genetically modified pseudoislets with beta-cell-specific cytotoxic T cells into immunodeficient mice achieves preserved human insulin production and C-peptide secretion. Collectively, our data provide proof of concept that human beta cells can be efficiently genetically modified to provide protection from killing mediated by autoreactive T cells and retain their function in vitro and in vivo. PMID- 23689600 TI - Selective forelimb impairment in rats expressing a pathological TDP-43 25 kDa C terminal fragment to mimic amyotrophic lateral sclerosis. AB - Pathological inclusions containing transactive response DNA-binding protein 43 kDa (TDP-43) are common in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). TDP-43 normally localizes predominantly to the nucleus, but during disease progression, it mislocalizes to the cytoplasm. We expressed TDP-43 in rats by an adeno-associated virus (AAV9) gene transfer method that transduces neurons throughout the central nervous system (CNS). To mimic the aberrant cytoplasmic TDP-43 found in disease, we expressed a form of TDP-43 with mutations in the nuclear localization signal sequence (TDP-NLS). The TDP-NLS was detected in both the cytoplasm and the nucleus of transduced neurons. Unlike wild type TDP-43, expression of TDP-NLS did not induce mortality. However, the TDP-NLS induced disease-relevant motor impairments over 24 weeks. We compared the TDP-NLS to a 25 kDa C-terminal proaggregatory fragment of TDP-43 (TDP-25). The clinical phenotype of forelimb impairment was pronounced with the TDP-25 form, supporting a role of this C-terminal fragment in pathogenesis. The results advance previous rodent models by inducing cytoplasmic expression of TDP-43 in the spinal cord, and the non-lethal phenotype enabled long-term study. Approaching a more relevant disease state in an animal model that more closely mimics underlying mechanisms in human disease could unlock our ability to develop therapeutics. PMID- 23689599 TI - Therapeutic response in feline sandhoff disease despite immunity to intracranial gene therapy. AB - Salutary responses to adeno-associated viral (AAV) gene therapy have been reported in the mouse model of Sandhoff disease (SD), a neurodegenerative lysosomal storage disease caused by deficiency of beta-N-acetylhexosaminidase (Hex). While untreated mice reach the humane endpoint by 4.1 months of age, mice treated by a single intracranial injection of vectors expressing human hexosaminidase may live a normal life span of 2 years. When treated with the same therapeutic vectors used in mice, two cats with SD lived to 7.0 and 8.2 months of age, compared with an untreated life span of 4.5 +/- 0.5 months (n = 11). Because a pronounced humoral immune response to both the AAV1 vectors and human hexosaminidase was documented, feline cDNAs for the hexosaminidase alpha- and beta-subunits were cloned into AAVrh8 vectors. Cats treated with vectors expressing feline hexosaminidase produced enzymatic activity >75-fold normal at the brain injection site with little evidence of an immune infiltrate. Affected cats treated with feline-specific vectors by bilateral injection of the thalamus lived to 10.4 +/- 3.7 months of age (n = 3), or 2.3 times as long as untreated cats. These studies support the therapeutic potential of AAV vectors for SD and underscore the importance of species-specific cDNAs for translational research. PMID- 23689602 TI - Quality of life, utilities, quality-adjusted life-years, and health care decision making: comment on "Estimating quality of life in acute venous thrombosis". PMID- 23689601 TI - Minicircle DNA is superior to plasmid DNA in eliciting antigen-specific CD8+ T cell responses. AB - Clinical trials reveal that plasmid DNA (pDNA)-based gene delivery must be improved to realize its potential to treat human disease. Current pDNA platforms suffer from brief transgene expression, primarily due to the spread of transcriptionally repressive chromatin initially deposited on plasmid bacterial backbone sequences. Minicircle (MC) DNA lacks plasmid backbone sequences and correspondingly confers higher levels of sustained transgene expression upon delivery, accounting for its success in preclinical gene therapy models. In this study, we show for the first time that MC DNA also functions as a vaccine platform. We used a luciferase reporter transgene to demonstrate that intradermal delivery of MC DNA, relative to pDNA, resulted in significantly higher and persistent levels of luciferase expression in mouse skin. Next, we immunized mice intradermally with DNA encoding a peptide that, when presented by the appropriate major histocompatibility complex class I molecule, was recognized by endogenous CD8(+) T cells. Finally, immunization with peptide-encoding MC DNA, but not the corresponding full-length (FL) pDNA, conferred significant protection in mice challenged with Listeria monocytogenes expressing the model peptide. Together, our results suggest intradermal delivery of MC DNA may prove more efficacious for prophylaxis than traditional pDNA vaccines. PMID- 23689603 TI - Enhanced field emission characteristics in metal-coated Si-nanocones. AB - Metallic gold (Au) and platinum (Pt) thin films were deposited on silicon nanocones (Si-NCs) by sputtering to elucidate the effects of work function and conductivities on the field electron emission characteristics of surface-modified Si-NCs. The results showed that for Pt/Si-NCs and Au/Si-NCs, although the turn-on field defined at a corresponding current density of 10 MUA cm(-2) only improved from 4.20 V MUm(-1) for bare Si-NCs to 3.65 and 2.90 V MUm(-1), respectively, the emission current density measured at 5.00 V MUm(-1) was enhanced by orders of magnitude, reaching 1.82 mA cm(-2) for Au/Si-NCs. Compared to those obtained from various surface-modified Si-nanostructures, such as ZnO/Si-nanopillars and ferroelectrics/Si-nanotips, the current results represent an interesting alternative route for producing surface-modified Si-NCs that might be useful for optical and electronic applications. PMID- 23689604 TI - Molecular identification of Theileria and Babesia in sheep and goats in the Black Sea Region in Turkey. AB - This study was carried out to investigate presence and distribution of Theileria and Babesia species via microscopic examination and reverse line blotting (RLB) techniques in sheep and goats in the Black Sea region of Turkey. For this purpose, 1,128 blood samples (869 sheep and 259 goats) were collected by active surveillance from sheep and goats in different provinces of various cities in the region in the years 2010 and 2011. Smears were prepared from the blood samples, stained with Giemsa, and examined under the light microscope for Theileria and Babesia piroplasms. The genomic DNAs were extracted from blood samples. The length of 360-430-bp fragment in the variable V4 region of 18S SSU rRNA gene of Theileria and Babesia species was amplified using the gDNAs. The polymerase chain reaction products were hybridized to the membrane-connected species-specific probes. A total of 38 animals (3.37%) including 34 sheep (3.91%) and 4 goats (1.54%) were found to be positive for Theileria spp. piroplasms in microscopic examination of smears while Babesia spp. piroplasm could not detected. Infection rates were 34.64% in sheep, 10.04% in goats, and totally 28.99% for Theileria ovis while 0.58% in sheep and totally 0.44% for Babesia ovis. However, Theileria sp. OT3 was detected in 2.65% of sheep and 2.04% of all animals; besides Theileria sp., MK had 0.58% prevalence in sheep and 0.77% in goats, with a total 0.62% with RLB. Although T. ovis and Theileria sp. MK were determined in both sheep and goats, B. ovis and Theileria sp. OT3 were observed only in the sheep. These results provide the first detailed molecular data for sheep and goat theileriosis and babesiosis in the region. PMID- 23689605 TI - Anthelmintic efficacy of Santalum album (Santalaceae) against monogenean infections in goldfish. AB - Dactylogyrus spp. and Gyrodactylus spp. are helminth ectoparasites that are a significant threat to the aquaculture industry. Existing treatments could cause the threats of anthelmintic resistance, risk of residues, environmental contamination, and toxicity to fish. Importantly, there is no report on a treatment against these two parasites. This study explored the possibility of using the extracts of Santalum album to treat Dactylogyrus sp. and Gyrodactylus sp. infections in goldfish. Results showed that among the four extracts (chloroform, methanol, ethyl acetate, and water) of S. album, the chloroform extract is the most effective and 40 mg/L is a safe and the lowest effective dosage. In addition, we found that Gyrodactylus elegans is more sensitive than Dactylogyrus intermedius when exposed to the extract of the medicinal plant. Finally, it is substantiated that bath treatment with long duration and multiple administrations could eliminate a greater proportion of monogenean infections. These findings show the potential for the development of effective and safe therapy to treat Dactylogyrus sp. and Gyrodactylus sp. infections of fishes. PMID- 23689607 TI - Retraction note to: Continuous cerebral and myocardial perfusion during one-stage repair for aortic coarctation with ventricular septal defect. PMID- 23689606 TI - Functional specific roles of FADD: comparative proteomic analyses from knockout cell lines. AB - Fas-associated death domain (FADD) is a classical adaptor protein involved in tumor necrosis factor receptor family-mediated apoptosis. Besides being an essential instrument in cell death, it also plays key roles in cell proliferation and survival. The current study shows for the first time that FADD is probably associated with energy metabolism and proteolysis. It has been reported that embryonic death caused by FADD deficiency in mice was not attributable to impaired apoptosis. Furthermore, mice bearing the substitution in FADD of serine 191 to aspartic acid exhibited leaner body size than both wild-type control and serine 191 to alanine mutant mice, indicating metabolic disorders. To study these non-apoptotic effects of FADD, a comprehensive strategy of proteomics identification combined with bioinformatic analyses and further cell biology validation was utilized to identify differentially-expressed proteins in FADD deficient mouse embryonic fibroblasts (MEFs). A total of 45 unique proteins were determined to be significantly changing due to FADD deficiency. Network analysis of these proteins using MetaCoreTM suggested induction of transcriptional factors that are too low to be detected by two-dimensional gels and identified an enriched cluster of changed proteins that are involved in cellular metabolic processes, including lipid metabolism, fatty acids metabolism, glycolysis, tricarboxylic acid (TCA) cycle, and oxidative phosphorylation. Fatty acids beta oxidation was found to be enhanced in FADD-deficient cells. In addition, five proteins related to the ubiquitin-proteasome (UP) pathway were also specifically up-regulated in the FADD(-/-) MEFs. Finally, the c-Myc gene represents a convergent hub lying at the center of dysregulated pathways, and was up-regulated in FADD knockout cells. Taken together, these studies show that impaired mitochondrial function and proteolysis may play pivotal roles in the dysfunction associated with FADD deficiency-induced disorders, probably including embryonic lethality. The link between FADD and cell metabolism may provide us new insight for understanding the crosstalk of independent cell signaling pathways. PMID- 23689608 TI - Double-outlet left ventricle with L-malposition of the great arteries and subpulmonary ventricular septal defect. PMID- 23689609 TI - Sociodemographic correlates of four indices of blood pressure and hypertension among older persons in Japan. AB - BACKGROUND: High blood pressure is a significant risk factor for cardiovascular disease and mortality. Japan has traditionally had higher levels of measured blood pressure than many Western countries, and reducing levels of hypertension has been a major focus of Japanese health policy over recent decades. In the West, hypertension is strongly associated with sociodemographic and behavioral (smoking and body mass index, BMI) factors; studies of the association between sociodemographic factors and biological indicators have not been fully explored in the elderly population of Japan using nationally representative survey data. OBJECTIVE: To describe hypertension prevalence rates with increasing age and to examine the link between sociodemographic and behavioral factors (including age, gender, education, residence, smoking, and BMI) and measures of blood pressure and overall hypertension in the Japanese population aged >=68 years. METHODS: Data were collected in 2006 during the fourth wave of the Nihon University Japanese Longitudinal Study of Aging, a nationally representative sample of those >=68. The analytic sample includes 2,634 participants. Pulse pressure, systolic, diastolic, and mean blood pressure, as well as hypertension, were regressed on sociodemographic and behavioral factors. RESULTS: There is no significant difference in the prevalence of overall hypertension by age for men and women from ages 68-69 to 90+. Higher BMI and older age were linked to higher blood pressure and higher chance of having hypertension. More years of education and being female were associated with a lower likelihood of measured hypertension. Smoking, rural residence, and living alone were not significantly associated with the outcome measures. CONCLUSION: The increase in hypertension with higher BMI raises concerns about future health in Japan as BMI increases. The lack of a relationship between smoking and any measure of blood pressure or hypertension is an indicator that smoking may have different effects in Japan than in other countries. Because there is no effect of living alone on blood pressure, compliance with drug regimes may not be enhanced by living with others in Japan. PMID- 23689610 TI - Controlled scalable synthesis of uniform, high-quality monolayer and few-layer MoS2 films. AB - Two dimensional (2D) materials with a monolayer of atoms represent an ultimate control of material dimension in the vertical direction. Molybdenum sulfide (MoS2) monolayers, with a direct bandgap of 1.8 eV, offer an unprecedented prospect of miniaturizing semiconductor science and technology down to a truly atomic scale. Recent studies have indeed demonstrated the promise of 2D MoS2 in fields including field effect transistors, low power switches, optoelectronics, and spintronics. However, device development with 2D MoS2 has been delayed by the lack of capabilities to produce large-area, uniform, and high-quality MoS2 monolayers. Here we present a self-limiting approach that can grow high quality monolayer and few-layer MoS2 films over an area of centimeters with unprecedented uniformity and controllability. This approach is compatible with the standard fabrication process in semiconductor industry. It paves the way for the development of practical devices with 2D MoS2 and opens up new avenues for fundamental research. PMID- 23689611 TI - Variation in host resistance could limit the spread of more broadly virulent pathogens. PMID- 23689612 TI - A synthetic approach to GFP chromophore analogs from 3-azidocinnamates. Role of methyl rotors in chromophore photophysics. AB - We have suggested a novel combinatorial approach for synthesis of otherwise inaccessible GFP chromophore analogs, and studied the influence of aliphatic substituents on their pH-dependent spectral properties. We found that the demethylation at C or N positions of the imidazolone ring leads to a decrease in the excited state lifetime. PMID- 23689613 TI - Insulin signaling controls the expression of O-GlcNAc transferase and its interaction with lipid microdomains. AB - Lipid microdomains (rafts) are cholesterol-enriched dynamic ordered lipid domains belonging to cell membranes involved in diverse cellular functions, including signal transduction, membrane trafficking, and infection. Many studies have reported relationships between insulin signaling and lipid rafts. Likewise, links between insulin signaling and O-GlcNAcylation have also been described. However, the potential connection between O-GlcNAc and raft dynamics remains unexplored. Here we show that O-GlcNAc and the enzyme that creates this modification, O GlcNAc transferase (OGT), are localized in rafts. On insulin stimulation, we observe time-dependent increases in OGT expression and localization within rafts. We show that these processes depend on activation of the phosphatidylinositol 3 kinase (PI3K) pathway. Inhibition of OGT does not significantly affect cholesterol synthesis and raft building but decreases insulin receptor expression and PI3K and mitogen-activated protein kinase pathway activation. Taken together, these findings indicate that O-GlcNAcylation, lipid rafts, and signaling pathways are spatiotemporally coordinated to enable fundamental cellular functions. PMID- 23689614 TI - Identification of novel allergenic components from German cockroach fecal extract by a proteomic approach. AB - BACKGROUND: Cockroaches produce potent allergens, and cockroach feces are known to be especially rich in allergens. In this study, we analyze the allergenic components from cockroach feces and evaluate allergenicity of recombinant alpha amylase identified from fecal extract. METHODS: IgE-reactive proteins from German cockroach fecal extract were analyzed by proteomic analysis and immunoblotting. Recombinant alpha-amylase was produced and its allergenicity was evaluated by ELISA. RESULTS: Analysis of German cockroach fecal extracts identified 12 IgE reactive components. Most of these allergens were found to be digestive enzymes such as alpha-amylase, trypsin, chymotrypsin, metalloprotease, and midgut carboxypeptidase A, but the identity of 3 IgE-reactive proteins is still unknown. Glycinin-like proteins, which were likely derived from the cockroach diet, were also identified. German cockroach alpha-amylase shares the highest identity with pig alpha-amylase (55.8%), followed by mite group 4 allergens (Blo t 4, 50.4%; Der p 4, 49.8%; Eur m 4, 47.4%). In this study, recombinant alpha-amylase from German cockroach was expressed, and its allergenicity was examined by ELISA. Specific IgE against recombinant amylase was detected in 41.4% (12/29) of serum samples from German cockroach-sensitized subjects. Recombinant alpha-amylase was able to inhibit 55% of specific IgE to German cockroach whole-body extract. CONCLUSIONS: Amylase was found to be an important novel allergen in cockroach feces. It is hoped that recombinant alpha-amylase will be useful for further studies and clinical applications. PMID- 23689615 TI - Mycophenolate as maintenance therapy for lupus nephritis with impaired renal function. AB - BACKGROUND: Mycophenolate (MF) is effective as a maintenance therapy after induction therapy in patients with lupus nephritis (LN). However, little is known about its role in patients with impaired renal function. The purpose of this study was to evaluate the efficacy and safety of MF as a maintenance therapy for LN and its association with renal function. METHODS: Data were obtained for 56 Spanish patients who were receiving MF as a maintenance therapy for LN. Patients were classified into two groups according to renal function at the initiation of MF treatment: group 1 [estimated glomerular filtration rate (eGFR) >=60 ml/min/1.73 m(2)] and group 2 (eGFR <60 ml/min/1.73 m(2)). The primary endpoints of the study were the rates of renal relapse and responses, and their relationship with baseline renal function. Secondary outcomes were the appearance of side effects during treatment. RESULTS: At initiation of MF treatment, the only differences between the groups were for age, hemoglobin levels, anti-DNA antibody titer, proteinuria, and renal function. In group 1 (n = 38), the eGFR was 98 +/- 34 ml/min/1.73 m(2) and in group 2 (n = 18) the eGFR was 43 +/- 14 ml/min/1.73 m(2). Only 3 cases had an eGFR <30 ml/min/1.73 m(2). No significant differences were observed in the rate of relapse at 6 months (group 1: 20%; group 2: 23%) or at 12 months (group 1: 25%; group 2: 17%). Response rates were also similar in both groups. Side effects were unremarkable. CONCLUSIONS: MF is effective and safe as a maintenance therapy for LN both in patients with normal renal function and in those with renal impairment. PMID- 23689616 TI - Refined brain tumor diagnostics and stratified therapies: the requirement for a multidisciplinary approach. AB - Individualized therapies are popular current concepts in oncology and first steps towards stratified medicine have now been taken in neurooncology through implementation of stratified therapeutic approaches. Knowledge about the molecular basis of brain tumors has expanded greatly in recent years and a few molecular alterations are studied routinely because of their clinical relevance. However, no single targeted agent has yet been fully approved for the treatment of glial brain tumors. In this review, we argue that multidisciplinary and integrated approaches are essential for translational research and the development of new treatments for patients with malignant gliomas, and we present a conceptual framework in which to place the components of such an interdisciplinary approach. We believe that this ambitious goal can be best realized through strong cooperation of brain tumor centers with local hospitals and physicians; such an approach enables close dialogue between expert subspecialty clinicians and local therapists to consider all aspects of this increasingly complex set of diseases. PMID- 23689617 TI - Codeletion of 1p and 19q determines distinct gene methylation and expression profiles in IDH-mutated oligodendroglial tumors. AB - Oligodendroglial tumors (OTs) are primary brain tumors that show variable clinical and biological behavior. The 1p/19q codeletion is frequent in these tumors, indicating a better prognosis and/or treatment response. Recently, the prognostically favorable CpG island methylator phenotype (CIMP) in gliomas (G CIMP+) was associated with mutations in the isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH) genes, as opposed to G-CIMP- tumors, highlighting the relevance of epigenetic mechanisms. We performed a whole-genome methylation study in 46 OTs, and a gene expression study of 25 tumors, correlating the methylation and transcriptomic profiles with molecular and clinical variables. Here, we identified two different epigenetic patterns within the previously described main G-CIMP+ profile. Both IDH mutation-associated methylation profiles featured one group of OTs with 1p/19q loss (CD-CIMP+), most of which were pure oligodendrogliomas, and a second group with intact 1p/19q and frequent TP53 mutation (CIMP+), most of which exhibited a mixed histopathology. A third group of OTs lacking the CIMP profile (CIMP-), and with a wild-type IDH and an intact 1p/19q, similar to the G-CIMP- subgroup, was also observed. The three CIMP groups presented a significantly better (CD-CIMP+), intermediate (CIMP+) or worse (CIMP-) prognosis. Furthermore, transcriptomic analyses revealed CIMP specific gene expression signatures, indicating the impact of genetic status (IDH mutation, 1p/19q codeletion, TP53 mutation) on gene expression, and pointing to candidate biomarkers. Therefore, the CIMP profiles contributed to the identification of subgroups of OTs characterized by different prognoses, histopathologies, molecular features and gene expression signatures, which may help in the classification of OTs. PMID- 23689618 TI - Atmospheric reactions on electrically charged surfaces. AB - It is proposed that tropospheric NO2 at concentrations in the parts-per-billion range can be efficiently converted to HONO in a dust storm, by a process that is initiated by electron capture by NO2 from a negatively-charged dust particle. The electron capture is visualized as a harpoon-type process that does not require the NO2 to be adsorbed on the particle. The resulting electronically excited [NO2(-)]* ion reacts with water to form an HONO molecule plus an OH(-).(H2O)n cluster ion. It is suggested that analogous processes can occur on other atmospheric aerosol particles with both positive and negative charges, with other molecules of high electron affinity such as SO2, and also, because the earth's surface is effectively the negative plate of a planet-sized capacitor, at the surfaces of terrestrial solids, lakes and oceans. PMID- 23689619 TI - Equity in public health: an epigenetic perspective. AB - Evidence emerging from the study of epigenetics and epigenomics challenges notions of health by enhancing understanding of disease etiologies and improving awareness of new health risks. New paradigms arising from epigenetic and epigenomic research present challenging cases through which to debate theories of justice in health because they expand the concept of health and, controversially, place value on what was previously assumed to be 'healthy' individual variance. Discoveries of the dynamic nature of the epigenome and its variable sensitivity towards change in numerous phenomena add further complexity to the assessment of health inequalities. Such evidence can cast doubt on perceptions of justice in health, which in turn raises questions over the suitability of actions taken in pursuit of equity. This article discusses how recent developments in epigenetics and epigenomics may impact upon assessments of equity in health. A review of literature discussing possible health risks associated with acquired yet heritable epigenetic variance is used to highlight the diversity of possible pathways through which health may be influenced. From this context, the consideration of health risk with respect to epigenetics, it is argued, demands a more inclusive concept of health when used in discussions of inequities. PMID- 23689620 TI - Facilitating reproducibility. PMID- 23689630 TI - Cancer therapeutics: Pulling the plug on BCL-X(L). PMID- 23689635 TI - The structure of pairwise correlation in mouse primary visual cortex reveals functional organization in the absence of an orientation map. AB - Neural responses to sensory stimuli are not independent. Pairwise correlation can reduce coding efficiency, occur independent of stimulus representation, or serve as an additional channel of information, depending on the timescale of correlation and the method of decoding. Any role for correlation depends on its magnitude and structure. In sensory areas with maps, like the orientation map in primary visual cortex (V1), correlation is strongly related to the underlying functional architecture, but it is unclear whether this correlation structure is an essential feature of the system or arises from the arrangement of cells in the map. We assessed the relationship between functional architecture and pairwise correlation by measuring both synchrony and correlated spike count variability in mouse V1, which lacks an orientation map. We observed significant pairwise synchrony, which was organized by distance and relative orientation preference between cells. We also observed nonzero correlated variability in both the anesthetized (0.16) and awake states (0.18). Our results indicate that the structure of pairwise correlation is maintained in the absence of an underlying anatomical organization and may be an organizing principle of the mammalian visual system preserved by nonrandom connectivity within local networks. PMID- 23689637 TI - Hip disease in ankylosing spondylitis. AB - PURPOSE OF REVIEW: Hip disease occurs in about one-third of patients with ankylosing spondylitis (AS) and can often be disabling, necessitating total hip replacement in young adults. There have been recent articles on a number of aspects of this problem, including the epidemiology and pathology. The most recent studies on diagnosis, prognosis and therapeutic management are reviewed here. RECENT FINDINGS: Several large studies have evaluated the prevalence and outcome of hip involvement in AS. Hip involvement can be diagnosed clinically, radiologically, by MRI or by ultrasonography. These examinations highlight different aspects of hip disease in AS. Hip disease is more prevalent in patients with a younger disease onset and seems to be associated with more severe axial disease. Antitumour necrosis factor (TNF) agents are helpful for pain relief and improvement of function in patients with active axial and active hip disease. However, it is not clear whether this treatment option can prevent progression of structural damage. In case of end-stage hip disease, total hip replacement should be considered. SUMMARY: In patients with AS, the hips should be routinely assessed, at least by clinical examination. Anti-TNF therapy should be considered in patients with NSAID-resistant active axial disease who have concomitant hip disease. PMID- 23689638 TI - Autoimmunity: an infection-related risk? PMID- 23689636 TI - Impact of sex and gonadal steroids on neonatal brain structure. AB - There are numerous reports of sexual dimorphism in brain structure in children and adults, but data on sex differences in infancy are extremely limited. Our primary goal was to identify sex differences in neonatal brain structure. Our secondary goal was to explore whether brain structure was related to androgen exposure or sensitivity. Two hundred and ninety-three neonates (149 males) received high-resolution structural magnetic resonance imaging scans. Sensitivity to androgen was measured using the number of cytosine, adenine, guanine (CAG) triplets in the androgen receptor gene and the ratio of the second to fourth digit, provided a proxy measure of prenatal androgen exposure. There was a significant sex difference in intracranial volume of 5.87%, which was not related to CAG triplets or digit ratios. Tensor-based morphometry identified extensive areas of local sexual dimorphism. Males had larger volumes in medial temporal cortex and rolandic operculum, and females had larger volumes in dorsolateral prefrontal, motor, and visual cortices. Androgen exposure and sensitivity had minor sex-specific effects on local gray matter volume, but did not appear to be the primary determinant of sexual dimorphism at this age. Comparing our study with the existing literature suggests that sex differences in cortical structure vary in a complex and highly dynamic way across the human lifespan. PMID- 23689640 TI - Counterintuitive evidence concerning salt and water restriction in acute decompensated heart failure patients: comment on "Aggressive fluid and sodium restriction in acute decompensated heart failure". PMID- 23689639 TI - IRGM1 regulates oxidized LDL uptake by macrophage via actin-dependent receptor internalization during atherosclerosis. AB - Macrophage derived foam cells are actively involved in the initial phase of atherosclerosis. Uptake of modified lipoprotein such as oxidized LDL (oxLDL) is a critical step for foam cell formation. CD36 is the major receptor mediating oxLDL uptake by macrophage. However, the molecular mechanism underlying CD36 mediated oxLDL uptake remains unclear. Here we reported that IRGM1 (IRGM in human), a member of immunity-related small GTPase family, is essential for the actin dependent CD36 mediated oxLDL uptake by macrophage. IRGM/IRGM1 was highly expressed by macrophage around the atherosclerotic plaque and was up-regulated by oxLDL both in vitro and in vivo. Moreover loss of IRGM/IRMG1 significantly decreased oxLDL uptake in both mouse and human. Furthermore, the IRGM1 knock-out mice displayed impaired CD36 internalization in macrophage, which was associated with the deficiency of F-actin polymerization. These results revealed a novel function of IRGM1 in regulating oxLDL uptake by macrophage during atherosclerosis. PMID- 23689642 TI - Seliciclib inhibits renal hypertrophy but not fibrosis in the rat following subtotal nephrectomy. AB - BACKGROUND: 5/6 subtotal nephrectomy (SNx) is a non-immune stimulus used to induce renal fibrosis. The ability of seliciclib, a cyclin-dependent kinase inhibitor, to reduce kidney hypertrophy and extracellular matrix (ECM) deposition has been examined in the SNx rat. METHODS: Wistar rats were subjected to SNx under isoflurane anaesthesia. The acute effect of seliciclib 28 mg/kg (5 days) on compensatory renal growth (CRG), kidney protein and DNA was determined. In chronic studies albuminuria, hypertension and GFR were monitored. Ki67, apoptag and alpha-smooth muscle actin were determined by immunohistochemistry together with Masson's trichrome staining. The effect of a maximum non-hypotensive dose of seliciclib 28 mg/kg (8 weeks) was determined. RESULTS: Acutely, the remnant kidney developed CRG. Seliciclib 28 mg/kg inhibited both CRG by 45% and increased kidney protein by 48% without affecting increased kidney DNA. Chronically, SNx rats developed albuminuria, hypertension, low GFR with increased tubulointerstitial cell proliferation, apoptosis, myofibroblast accumulation and enhanced ECM deposition. Seliciclib 28 mg/kg (8 weeks) had no effect on either renal function or renal pathology. Plasma concentrations of seliciclib exceeded 5 uM throughout the study. CONCLUSIONS: Despite inhibition of early renal hypertrophy, a maximum non-hypotensive dose of seliciclib 28 mg/kg had no impact on the progression of kidney fibrosis in the SNx rat. PMID- 23689643 TI - Treating gynecologic malignancies in elderly patients. AB - AIM: To determine the relative benefits of full and partial treatment for gynecologic malignancies in elderly patients. METHODS: A retrospective cohort study of all consecutive patients (n=169) aged 79 and older (median age 82 y; range, 79 to 94 y), diagnosed between 1971 and 2007 with various types of gynecologic malignancies (endometrial, 52%; ovarian, 26%; vulvar, 11%; cervical, 5%; other, 6%) was conducted. Stages were I to II (47%), III to IV (35.5%), and unknown (17.5%). Major comorbidities were hypertension (51%), diabetes (17%), cardiac diseases (34%), and other malignancy (12%). Regardless of age or chronic illnesses, patients were grouped on the basis of having been treated optimally (100 patients; 59.2%), defined as the accepted standard for each diagnosis and stage including surgery and adjuvant radiation or chemotherapy as indicated; or suboptimally (69 patients; 40.8%), that is, no or only partial treatment. Kaplan Meier survival analysis and Cox proportional hazard models, univariate and multivariable were conducted. RESULTS: For all patients with suboptimal treatment, the age-and-stage-adjusted hazard ratio for death was 1.76 (95% CI, 1.203-2.570; P=0.004) compared with optimal treatment. Age-adjusted hazard ratio was 2.15 (95% CI, 1.127-4.114; P=0.02) and 2.3 (95% CI, 1.415-3.779; P=0.001) for ovarian and endometrial cancer patients, respectively. Age-adjusted and stage adjusted hazard ratio was 2.8 (95% CI, 1.099-5.157; P=0.028) and 1.53 (95% CI, 0.867-2.702; P=0.1420) for ovarian and endometrial cancer patients, respectively. CONCLUSIONS: Optimal treatment in patients with gynecologic malignancies evidently improves survival in elderly patients at any age, and in patients with ovarian cancer at any stage. Regardless of chronological age, the aim should be to deliver optimal treatment. PMID- 23689641 TI - Novel POMGnT1 mutations cause muscle-eye-brain disease in Chinese patients. AB - Muscle-eye-brain (MEB) disease is a congenital muscular dystrophy (CMD) phenotype characterized by hypotonia at birth, brain structural abnormalities and ocular malformations. To date, few MEB cases have been reported in China where clinical recognition and genetic confirmatory testing on a research basis are recent developments. Here, we report the clinical and molecular genetics of three MEB disease patients. The patients had different degrees of muscle, eye and brain symptoms, ranging from congenital hypotonia, early-onset severe myopia and mental retardation to mild weakness, independent walking and language problems. This confirmed the expanding phenotypic spectrum of MEB disease with varying degrees of hypotonia, myopia and cognitive impairment. Brain magnetic resonance imaging showed cerebellar cysts, hypoplasia and characteristic brainstem flattening and kinking. Four candidate genes (POMGnT1, FKRP, FKTN and POMT2) were screened, and six POMGnT1 mutations (four novel) were identified, including five missense and one splice site mutation. Pathogenicity of the two novel variants in one patient was confirmed by POMGnT1 enzyme activity assay, protein expression and subcellular localization of mutant POMGnT1 in HeLa cells. Transfected cells harboring this patient's L440R mutant POMGnT1 showed POMGnT1 mislocalization to both the Golgi apparatus and endoplasmic reticulum. We have provided clinical, histological, enzymatic and genetic evidence of POMGnT1 involvement in three unrelated MEB disease patients in China. The identification of novel POMGnT1 mutations and an expanded phenotypic spectrum contributes to an improved understanding of POMGnT1 structure-function relationships, CMD pathophysiology and genotype-phenotype correlations, while underscoring the need to consider POMGnT1 in Chinese MEB disease patients. PMID- 23689644 TI - Clinical Significance of ABCG2 Haplotype-tagging Single Nucleotide Polymorphisms in Patients With Unresectable Non-Small Cell Lung Cancer Treated With First-line Platinum-based Chemotherapy. AB - OBJECTIVES: The ATP-binding cassette (ABC) ABCG2, involved in multidrug resistance (MDR) in cancer cells, plays an integral role in drug resistance. Single nucleotide polymorphisms (SNPs) have been identified in many MDR associated ABC genes that seem to influence drug sensitivity/resistance through various mechanisms. Therefore, we investigated whether ABCG2 haplotype-tagging SNPs (htSNPs) were associated with clinical outcomes in patients with unresectable non-small cell lung cancer (NSCLC) treated with front-line platinum based chemotherapy. PATIENTS AND METHODS: We genotyped 4 ABCG2 htSNPs for 129 unresectable NSCLC cases treated with first-line platinum-based chemotherapy. Clinical characteristics, treatment outcomes, and predictive value of the htSNPs in patient response, survival, and adverse events related to platinum-based chemotherapy were analyzed according to each ABCG2 htSNP using the chi test, Kaplan-Meier method, and Cox proportional hazard model. RESULTS: The rs2725264 was significantly related to overall survival (OS) (P=0.018, log-rank test). The median survival duration (in months) for patients with the rs2725264 T/T, T/C, and C/C genotypes was 35.75 (95% confidence interval [CI], 24.25-47.25), 34.25 (hazard ratio [HR] 1.27 [0.68 to 2.35]; 95% CI, 27.16-41.34), and 14.89 (HR 3.22 [1.26 to 8.24], 95% CI, 13.86-15.92), respectively. The rs2725264 was identified as an independent factor by Cox proportional hazard model analysis (P=0.028). In the taxane-based groups, OS was associated with rs2725264 (P=0.041), whereas in the gemcitabine-based groups, OS was associated with rs4148149 (P=0.014). CONCLUSIONS: Our data suggest ABCG2 htSNPs rs2725264 (overall group and taxane platinum combination group) and rs4148149 (gemcitabine-platinum combination group) were associated with OS in unresectable NSCLC patients treated with first line platinum-based chemotherapy. Thus, the ABCG2 htSNP rs2725264 may be independently associated with OS in unresectable NSCLC patients treated with first-line platinum-based chemotherapy. PMID- 23689645 TI - C-F bond formation with fluoride anions--highly selective iodofluorination of simple allenes. AB - A highly regioselective (up to 99 : 1) iodofluorination reaction of simple allenes occurs under mild conditions with Et3N.3HF or Py.9HF to afford 2 iodoalken-3-yl fluorides. PMID- 23689646 TI - Impact of diabetes on treatment outcomes and long-term survival in multidrug resistant tuberculosis. AB - BACKGROUND: Few studies have investigated the impact of diabetes mellitus (DM), a globally increasing metabolic disease, on treatment outcomes and long-term survival in patients with multidrug-resistant forms of tuberculosis (MDR-TB). OBJECTIVES: We analyzed outcomes in a large cohort to assess the impact of DM on treatment outcomes of patients with MDR-TB. METHODS: MDR-TB patients newly diagnosed or retreated between 2000 and 2002 and followed for 8-11 years were retrospectively analyzed with respect to the effect of DM as a comorbidity on their treatment outcome and long-term survival. RESULTS: Of 1,407 patients with MDR-TB, 239 (17.0%) had coexisting DM. The mean age and body mass index were higher in MDR-TB patients with DM [MDR-TBDM(+)] than in those without DM [MDR TBDM(-)]. Patients with MDR-TB and a comorbidity of DM had a significantly lower treatment success rate than those without a history of DM (36.0 vs. 47.2%, p = 0.002). In addition, DM was the negative predictor for MDR-TB treatment success in multivariate analyses [odds ratio 0.51, 95% confidence interval (CI) 0.26 0.99]. Mean survival times were also lower in MDR-TBDM(+) than in MDR-TBDM(-) patients (102 vs. 114 months, p = 0.001), with DM as a significant predictor of poor long-term survival in multivariate analyses (hazard ratio 1.59, 95% CI 1.01 2.50). CONCLUSIONS: Among MDR-TB patients, DM was a relatively common comorbidity. In patients undergoing treatment for MDR-TB and followed for 8-11 years, it was found to be independently associated with an increased risk of both treatment failure and death. PMID- 23689647 TI - Hollow fiber culture accelerates differentiation of Caco-2 cells. AB - Caco-2 cells usually require 21 days of culture for developing sufficient differentiation in traditional two-dimensional Transwell culture, deviating far away from the quick differentiation of enterocytes in vivo. The recently proposed three-dimensional cultures of Caco-2 cells, though imitating the villi/crypt-like microstructure of intestinal epithelium, showed no effect on accelerating the differentiation of Caco-2 cells. In this study, a novel culture of Caco-2 cells on hollow fiber bioreactor was applied to morphologically mimic the human small intestine lumen for accelerating the expression of intestine functions. The porous hollow fibers of polyethersulfone (PES), a suitable membrane material for Caco-2 cell culture, successfully promoted cells to form confluent monolayer on the inner surface. The differentiated functions of Caco-2 cells, represented by alkaline phosphatase, gamma-glutamyltransferase, and P-glycoprotein activity, were greatly higher in a 10-day hollow fiber culture than in a 21-day Transwell culture. Moreover, the Caco-2 cells on PES hollow fibers expressed higher F-actin and zonula occludens-1 protein than those on Transwell culture, indicative of an increased mechanical stress in Caco-2 cells on PES hollow fibers. The accelerated differentiation of Caco-2 cells on PES hollow fibers was unassociated with membrane chemical composition and surface roughness, but could be stimulated by hollow fiber configuration, since PES flat membranes with either rough or smooth surface failed to enhance the differentiation of Caco-2. Therefore, the accelerated expression of Caco-2 cell function on hollow fiber culture might show great values in simulation of the tissue microenvironment in vivo and guide the construction of intestinal tissue engineering apparatus. PMID- 23689648 TI - Early dysphagia complicating anterior cervical spine surgery: incidence and risk factors. AB - BACKGROUND: Dysphagia is a common complication of anterior cervical spine surgery, and most of them occurred in the early postoperative period. This study aimed to determine the incidence of early dysphagia after anterior cervical spine surgery and to identify its risk factors. METHODS: A review of 186 consecutive patients undergoing anterior cervical spine surgeries in a 3-year period was performed. Dysphagia at postoperative 1 month was surveyed, and the severity of dysphagia was evaluated. Demographic information and procedural characters were collected to determine their relationships to dysphagia. RESULTS: A total of 50 patients developed early postoperative dysphagia, including 23 males and 27 females. The incidence of early dysphagia after anterior cervical spine surgery was 26.9 % in this study. Mild, moderate, and severe dysphagia were found in 30, 14, and 6 patients, respectively. Female, advanced age, multi-levels surgery, use of plate, and a big protrusion of plate were found to be significantly increased early dysphagia after anterior cervical spine surgery. CONCLUSION: There is a relatively high incidence of early dysphagia after anterior cervical spine surgery, which may be attributable to multiple factors. PMID- 23689649 TI - Midterm results after modified Epping procedure for trapeziometacarpal osteoarthritis. AB - BACKGROUND AND PURPOSE: Various surgical procedures have been proposed for the treatment of trapeziometacarpal joint (TMJ) osteoarthritis. Despite an overall satisfactory outcome in most cases, some patients complain about inadequate performance at work, due to instability of the TMJ. We present a cross-sectional study of patients with TMJ arthritis who underwent a modified Epping procedure for increased TMJ stability. METHODS: 71 patients underwent a modified Epping procedure with a flexor carpi radialis tendon sling stabilizer. 59 patients were followed up after a mean time of 38 months. Residual pain was evaluated by visual analog scale. Functional outcome was quantified by pinch and grip strength, static two-point discrimination test, as well as DASH outcome scoring. Quality of life measures included patients' perceived satisfaction, activities of daily living (ADL), grip/pinch force and manual performance at work. RESULTS: 85 % of the patients regained full or partial manual performance during labor. Strength and ADL improved or remained the same in 81 %. In cases of a unilateral treatment, no difference in grip between the operated and nonoperated hand was observed. Mean tip pinch strength was 2.8 kg for the operated and 3.6 kg for the nonoperated hand. Mean pain level during rest was 0.98, 0.95 during mild activity, and 3.70 during strenuous activity. Mean DASH score was 26.6. CONCLUSION: The great majority of patients who underwent this novel procedure benefited from an unaffected or improved work performance, due to good TMJ stability combined with adequate motion for ADL. Less favorable results were seen in patients with accompanying hand pathologies. PMID- 23689650 TI - Osteitis pubis and adductor tendinopathy in athletes: a novel arthroscopic pubic symphysis curettage and adductor reattachment. AB - INTRODUCTION: Various surgical treatment options have been described in athletes with degenerative osteitis pubis who fail to respond to conservative treatment modalities. Although adductor longus tendinopathy often represents an additional pain generator in chronic groin pain associated with osteitis pubis, this has not been acknowledged in the surgical literature, to our knowledge. We present the results of a novel surgical technique for combined degenerative lesions of the pubic symphysis joint and the adjacent adductor longus tendon in a series of athletes with osteitis pubis. METHODS: During 2009 and 2010, five competitive non professional soccer players with considerable groin and pubic pain were referred to our clinic, after conservative therapy over a period of at least 12 months had failed. According to our clinical protocol for patients with groin pain, physical examination, pelvic radiographs and arthrography of the pubic symphysis to detect microlesions of the adjacent adductor longus tendons were performed. The patients diagnosed with degenerative osteitis pubis and concomitant lesion of the adductor longus origin were indicated for surgery. Surgery consisted of resection of the degenerative soft and bone tissue and subsequent reattachment with suture anchors. With regard to stability of the symphysis pubis, a two-portal arthroscopic curettage of the degenerative fibrocartilaginous disc tissue was performed. The patients were followed prospectively at medium term with assessment of general pain level (VAS score) and sport activity with pain (NIPPS score) pre- and postoperatively. RESULTS: All patients recovered to full activity sports after an average period of 14.4 weeks. VAS and NIPPS scores markedly improved and overall satisfaction with the postoperative result was high. One intraoperative bleeding occurred, needing revision surgery. None of the patients developed pubic instability due to pubic symphysis curettage in the sequel. CONCLUSIONS: This novel surgical technique combines successfully stability preserving arthroscopic pubic symphysis curettage with adductor debridement and reattachment in well-selected cases of athletes suffering from degenerative osteitis pubis and concomitant adductor pathology, being refractory to conservative treatment. Diligent preoperative evaluation of the specific pathology will lead to successful outcome. PMID- 23689651 TI - Acute Dialysis Quality Initiative (ADQI). AB - ADQI0--Acute Dialysis Quality Initiative--is a process that was created seeking consensus and evidence-based recommendations in the field of acute kidney injury. This organization gave birth to important classifications such as the RIFLE and the cardiorenal syndrome. Several conferences were organized in the last 10 years. Today, ADQI is a well-known initiative and it provides useful information to the physicians and nurses interested in acute kidney injury. PMID- 23689652 TI - Implementation of novel biomarkers in the diagnosis, prognosis, and management of acute kidney injury: executive summary from the tenth consensus conference of the Acute Dialysis Quality Initiative (ADQI). AB - Detection of acute kidney injury is undergoing a dynamic revolution of biomarker technology allowing greater, earlier, and more accurate determination of diagnosis, prognosis, and with powerful implication for management. Biomarkers can be broadly considered as any measurable biologic entity or process that allows differentiation between normal function and injury or disease. The ADQI (Acute Dialysis Quality Initiative) had its Ninth Consensus Conference dedicated to synthesis and formulation of the existing literature on biomarkers for the detection of acute kidney injury in a variety of settings. In the papers that accompany this summary, ADQI workgroups fully develop key concepts from a summary of the literature in the domains of early diagnosis, differential diagnosis, prognosis and management, and concurrent physiologic and imaging measures. PMID- 23689653 TI - Diagnosis of acute kidney injury using functional and injury biomarkers: workgroup statements from the tenth Acute Dialysis Quality Initiative Consensus Conference. AB - Acute kidney injury (AKI) commonly occurs in hospitalized patients and is independently and strongly associates with morbidity and mortality. The clinical benefits of a timely and definitive diagnosis of AKI have not been fully realized due to limitations imposed by the use of serum creatinine and urine output to fulfill diagnostic criteria. These restrictions often lead to diagnostic delays, potential misclassification of actual injury status, and provide little information regarding underlying cause. Novel biomarkers of damage have shown ability to reflect ongoing kidney injury and help further refine existing Risk, Injury, Failure, Loss, End-stage kidney disease (RIFLE) and Acute Kidney Injury Network (AKIN) diagnostic criteria. A comprehensive review of the published literature to date was performed using previously published methodology of the Acute Dialysis Quality Initiative (ADQI) working group to establish consensus statements regarding (i) the overall implementation of injury biomarkers in the concept of AKI diagnosis, (ii) their clinical use, and (iii) future research. On the basis of published data on the ability of novel damage biomarkers to provide diagnostic and prognostic information on AKI, we recommend that novel damage biomarkers may, in the appropriate clinical setting and context (situation consistent with AKI), be used to diagnose AKI even in the absence of changes in serum creatinine or the presence of oliguria as described in the existing RIFLE/AKIN criteria for diagnosis of AKI. Adding injury biomarkers as a criterion for AKI will complement the ability of RIFLE/AKIN to define AKI. Promising diagnostic injury markers include neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), interleukin 18 (IL-18) and liver-type fatty acid binding protein (L-FABP). However, there are currently insufficient data on damage biomarkers to support their use for AKI staging. Rigorous validation studies measuring the association between the novel damage biomarker(s) and clinically relevant outcomes are needed. PMID- 23689654 TI - Differential diagnosis of AKI in clinical practice by functional and damage biomarkers: workgroup statements from the tenth Acute Dialysis Quality Initiative Consensus Conference. AB - Acute kidney injury (AKI) is a common but complex clinical syndrome with multiple etiologies. These etiologies target different sites and pathways within the kidney. Novel biomarkers of 'kidney damage' (which can be tubular or glomerular) can be used to diagnose AKI, even in the absence of an increase in serum creatinine or oliguria. These biomarkers of kidney damage can be combined with biomarkers of kidney function to facilitate classification of AKI. A comprehensive review of the literature was performed using the published methodology of the Acute Dialysis Quality Initiative (ADQI) working group and used to establish consensus statements regarding the use of biomarkers in the differential diagnosis of AKI. We recommend that the pathophysiological terms 'functional change' and 'kidney damage' be used in preference to the anatomical classification using the terms pre-renal, renal and post-renal AKI. We further recommend the use of both renal and non-renal biomarkers in establishing the specific cause of AKI as soon as possible after diagnosis. The presence of underlying CKD or of sepsis poses additional challenges in differential diagnosis, since these conditions alter both baseline biomarker excretion and biomarker performance. We recommend that biomarkers be validated within the clinical context in which they are to be used. Within that context, combinations of biomarkers may, in the future, allow differentiation of the site, mechanism and phase of injury. PMID- 23689655 TI - Use of biomarkers to assess prognosis and guide management of patients with acute kidney injury. AB - Several new biomarkers of kidney damage have been characterized and are being validated in clinical studies. These damage biomarkers complement existing conventional biomarkers of kidney function (e.g. serum creatinine, serum urea, and urine output) that are currently utilized to diagnose and stage acute kidney injury (AKI). Both functional and damage biomarkers provide an opportunity to identify patients with AKI who are at risk for a less favorable prognosis in terms of worsening damage or further declines in kidney function and likelihood of need for renal replacement. We performed a systemic search and review of the available literature pre-conference. Our workgroup presented the findings in multiple rounds to the ADQI conference members and a final summary and review was refined in an iterative approach. The specific clinical situations of renal or liver transplantation, or cirrhosis/hepatorenal syndrome were not included. Overall, multiple AKI biomarkers have been well characterized for utilization for AKI prognosis. These functional and damage markers can be used to assist in decisions related to triage of patients with AKI and identifying patients with who are at risk for progression. Set cut-offs for various biomarkers and their bedside utility are forthcoming and will be in part determined by regulatory intended use guidelines, platform standardization, and inter-laboratory calibration. There remain many unresolved areas of AKI biomarker use in selected syndromes of AKI (e.g. cardiorenal syndrome, hepatorenal syndrome). As clinicians gain experience with AKI biomarkers, clinical care plans that incorporate them into routine care will shortly follow. PMID- 23689656 TI - Physiological biomarkers of acute kidney injury: a conceptual approach to improving outcomes. AB - The past 5-10 years have brought significant advances in the identification and validation of novel biochemical biomarkers in the prevention and treatment of acute kidney injury (AKI). These biochemical biomarkers remain research tools but we anticipate that soon they will be employed in clinical practice. A Consensus Conference held by the Acute Dialysis Quality Initiative (ADQI) recently reviewed the evidence, and identified gaps and a research agenda. Furthermore, at this meeting was the birth of an initiative to comprehensively identify new opportunities to characterize the physiological changes during the course of AKI based upon a conceptual framework for the detection and monitoring of renal ischemia-reperfusion injury. This framework includes a transition from monitoring physiological biomarkers of adequate renal perfusion, to pathophysiologic biomarkers of renal hypoperfusion, and finally biomarkers of kidney cell structural injury/damage. Techniques to measure physiological changes in AKI include several physiological variables that might be used in an interactive way to supplement clinical information and biochemical damage biomarkers in the diagnosis and management of AKI. This review summarizes the spectrum of physiological parameters and potential new physiological methods that enable identification of high-risk patients for AKI, facilitate early diagnosis, and differential diagnosis to guide therapeutic management and prognostication. Finally, we propose a research agenda for the next 5 years to facilitate the development and validation of physiological biomarkers in AKI. PMID- 23689657 TI - Pathophysiology of the cardiorenal syndromes: executive summary from the eleventh consensus conference of the Acute Dialysis Quality Initiative (ADQI). AB - Cardiorenal syndromes (CRS) have been recently classified into five distinct entities, each with different major pathophysiologic mechanisms. CRS type 1 most commonly occurs in the setting of acutely decompensated heart failure where approximately 25% of patients develop a rise in serum creatinine and a reduction of urine output after the first several doses of intravenous diuretics. Altered cardiac and renal hemodynamics are believed to be the most important determinants of CRS type 1. CRS type 2 is the hastened progression of chronic kidney disease (CKD) in the setting of chronic heart failure. Accelerated renal cell apoptosis and replacement fibrosis is considered to be the dominant mechanism. CRS type 3 is acutely decompensated heart failure after acute kidney injury from inflammatory, toxic, or ischemic insults. This syndrome is precipitated by salt and water overload, acute uremic myocyte dysfunction, and neurohormonal dysregulation. CRS type 4 is manifested by the acceleration of the progression of chronic heart failure in the setting of CKD. Cardiac myocyte dysfunction and fibrosis, so-called 'CKD cardiomyopathy', is believed to be the predominant pathophysiologic mechanism. Type 5 CRS is simultaneous acute cardiac and renal injury in the setting of an overwhelming systemic insult such as sepsis. In this scenario, the predominant pathophysiological disturbance is microcirculatory dysfunction as a result of acutely abnormal immune cell signaling, catecholamine cellular toxicity, and enzymatic activation which result in simultaneous organ injury often extending beyond both the heart and the kidneys. This paper will summarize these and other key findings from an international consensus conference on the spectrum of pathophysiologic mechanisms at work in the CRS. PMID- 23689658 TI - Pathogenesis of cardiorenal syndrome type 1 in acute decompensated heart failure: workgroup statements from the eleventh consensus conference of the Acute Dialysis Quality Initiative (ADQI). AB - Pathophysiological mechanisms of cardiorenal syndromes (CRS) types 1-5 are still sparsely characterized. In an attempt to address this issue, a consensus conference on CRS was held in Venice, Italy, in November 2012 under the auspices of the Acute Dialysis Quality Initiative (ADQI). Working group 1 discussed monodirectional mechanisms of CRS type 1 which is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Pre conference we performed a systematic search and review of the available literature using a modified Delphi analysis. Hereby identified and in this review discussed questions were: (i) What are the predominant pathophysiologic mechanisms of CRS type 1 in acute decompensated heart failure? (ii) Could biomarker profiling identify pathomechanisms or hemodynamic phenotype of patients with CRS type 1? Could predictive biomarkers improve renal safety of therapy in CRS type 1? (iii) How do the timing, severity and duration relate to the mechanisms and outcomes of CRS type 1? In summary, after discussion and appraisal of the best available evidence, working group 1 makes consensus recommendations for future research on pathologic mechanisms of CRS type 1 and recommendations for clinical practice where treatment is in either proof or disproof of a mechanism. PMID- 23689660 TI - Cardiorenal syndrome type 3: pathophysiologic and epidemiologic considerations. AB - Cardiorenal syndrome (CRS) type 3 is a subclassification of the CRS whereby an episode of acute kidney injury (AKI) precipitates and contributes to the development of acute cardiac injury. There is limited understanding of the pathophysiologic mechanisms of how AKI contributes to acute cardiac injury and/or dysfunction. An episode of AKI may have effects that depend on the severity and duration of AKI and that both directly and indirectly predispose to an acute cardiac event. Moreover, baseline susceptibility will modify the subsequent risk for cardiac events associated with AKI. Experimental data suggest cardiac injury may be directly induced by inflammatory mediators, oxidative stress, apoptosis and activation of neuroendocrine systems early after AKI. Likewise, AKI may be associated with physiologic derangements (i.e. volume overload; metabolic acidosis, retention of uremic toxins, hyperkalemia; hypocalcemia), alterations to coronary vasoreactivity, and ventricular remodeling and fibrosis that indirectly exert negative effects on cardiac function. AKI may also adversely impact cardiac function by contributing to alternations in drug pharmacokinetics and pharmacodynamics. Additional experimental and translational investigations coupled with epidemiologic surveys are needed to better explore that pathophysiologic mechanisms underpinning acute cardiac events associated with AKI and their impact on outcomes. PMID- 23689659 TI - Pathophysiology of cardiorenal syndrome type 2 in stable chronic heart failure: workgroup statements from the eleventh consensus conference of the Acute Dialysis Quality Initiative (ADQI). AB - In cardiorenal syndrome (CRS) type 2, chronic heart failure (HF) results in the onset or progression of chronic kidney disease (CKD). Examples of CRS type 2 (CRS2) include progressive CKD resulting from chronic HF in congenital or acquired heart disease or from repeated bouts of acute decompensated HF. Animal data and clinical studies indicate that extended periods of chronic HF result in altered renal hemodynamics followed by progressive renal pathology. Experimental and clinical data indicate that CRS2 is characterized by mild to moderate proteinuria, a progressive decline of glomerular filtration rate, and an elevated expression of renal injury biomarkers. Important pathophysiological triggers of renal disease progression include chronic increases in renal venous pressure, maladaptive activation of the renin-angiotensin-aldosterone axis and the sympathetic nervous system, as well as a chronic inflammatory state. Intrarenal oxidative stress and proinflammatory signaling precipitate structural injury, including glomerulosclerosis and tubulointerstitial fibrosis. Yet, clinical interventional trials that directly test the impact of renin-angiotensin system antagonists and beta-blockers on the progression of CKD in CRS2 are lacking. Secondary analyses of trials designed to assess the impact of these agents on cardiovascular endpoints have failed to show a consistent benefit regarding renal functional parameters. In contrast, left ventricular assist device placement and cardiac resynchronization therapy in HF patients consistently improved renal function, suggesting a marked potential for reversibility in many cases of CRS2. Future research should be directed towards the evaluation of novel biomarkers to improve the diagnosis, severity grading as well as our understanding of the pathophysiology of CRS2. In addition, there is a need for interventional trials in HF patients to address long-term renal endpoints incorporating clinical information and measures of renal function as well as renal injury. PMID- 23689661 TI - Cardiorenal syndrome type 4: insights on clinical presentation and pathophysiology from the eleventh consensus conference of the Acute Dialysis Quality Initiative (ADQI). AB - In developed countries, the continuing rise in the prevalence of hypertension, hyperlipidemia and diabetes has contributed to an overall increase in the incidence of both cardiovascular disease (CVD) and chronic kidney disease (CKD). The observation that even modest reductions in renal function correlate with increased CVD morbidity and mortality has led to the recognition that CKD is an independent risk factor for CVD. Conversely, there is a growing recognition that many pathologic conditions that contribute to CVD, including coronary artery disease, left ventricular hypertrophy and diastolic dysfunction, can accelerate the decline in renal function. In addition, physiologic mechanisms designed to compensate for reduced glomerular filtration rate including activation of the renin-angiotensin-aldosterone axis, the release of fibroblastic growth factor 23 and other mechanisms for calcium-phosphate homeostasis as well as and the pathophysiologic effects of uremic toxins can also directly contribute to CVD. The end result of the interaction between changes in pressure and volume overload and the physiologic compensation for the loss of function in both the heart and the kidney leads to accelerated decline in both organ systems. This complex physiologic and pathophysiologic interplay between the cardiovascular and renal systems is collectively referred to as the cardiorenal syndrome. The discussion which follows is aimed at outlining the pathophysiologic mechanisms linking advanced CKD (4 and 5) to the development of cardiac abnormalities which occur with unique frequency and severity in patients with severe impairment of renal function. PMID- 23689662 TI - Cardiorenal syndrome type 5: clinical presentation, pathophysiology and management strategies from the eleventh consensus conference of the Acute Dialysis Quality Initiative (ADQI). AB - Cardiorenal syndrome type 5 (CRS-5) includes conditions where there is a simultaneous involvement of the heart and kidney from a systemic disorder. Given the wide spectrum of diseases that contribute to CRS-5, several pathophysiological mechanisms are invoked representing the response of the heart and kidney to the contributing disorder that is ongoing. The nature, duration and the underlying condition of the heart and kidney strongly influence the clinical course of CRS-5. In this paper we discuss the pathophysiology of CRS-5 in the setting of sepsis as a model system for CRS-5 providing a brief overview of strategies for monitoring and therapeutic intervention. We offer a framework for reference for considering other disorders leading to CRS-5 where the development of cardiac and renal dysfunction is more insidious. PMID- 23689668 TI - Trans-generational impact of cerium oxide nanoparticles on tomato plants. AB - Cerium oxide nanoparticles (CeO2-NPs) are increasingly used in polishing, engine enhancement agents and many other products. Even though the acute toxicity of CeO2-NPs to plants has been investigated, the long-term effects of CeO2-NPs in the environment are still unknown. The main objective of this study was to investigate whether the treatment of tomato plants with relatively low concentrations of CeO2-NPs (10 mg L(-1)) through their lifecycle would affect the seed quality and the development of second generation seedlings. The results indicated that second generation seedlings grown from seeds collected from treated parent plants with CeO2-NPs (treated second generation seedlings) were generally smaller and weaker, as indicated by their smaller biomass, lower water transpiration and slightly higher reactive oxygen species content. An interesting phenomenon noticed in the study was that the second generation seedlings grown from treated seeds developed extensive root hairs compared with the control second generation seedlings (seedlings grown from seeds collected from untreated parent plants) regardless of the treatment. Treated second generation seedlings also accumulate a higher amount of ceria than control second generation seedlings under the same treatment conditions even though such differences are not statistically significant. PMID- 23689669 TI - Immunotherapy with a recombinant hybrid molecule alleviates allergic responses more efficiently than an allergenic cocktail or pollen extract in a model of chenopodium album allergy. AB - BACKGROUND: The aim of this study is to assess the therapeutic potential of a recombinant hybrid molecule (rHM) alongside an allergenic cocktail from recombinant wild-type allergens as well as pollen extract on Chenopodium album allergy, using a BALB/c mouse model. METHODS: The BALB/c mice had already been sensitized to C. album via intraperitoneal injections of alum-adsorbed allergenic cocktail and immunotherapy procedure was followed by subcutaneous injections of the rHM, allergenic cocktail and pollen extract at weekly intervals. Humoral immune responses were determined via measurement of specific antibodies in serum. Splenocytes of immunized mice were stimulated in vitro and then proliferation responses, cytokine secretion and mRNA expression of genes involved in immunotherapy were examined by ELISA and real-time PCR. RESULTS: Sensitized mice were identified with high specific IgE against allergenic cocktail when compared with healthy mice. Immunotherapy with the rHM induced the highest ratio of the IgG2a/IgG1 levels compared to allergenic cocktail or C. album pollen extract. The rHM was able to induce proliferative responses as well as the allergenic cocktail in cultured splenocytes. Immunotherapy with the rHM significantly improved secretion of IFN-gamma and IL-10, while secretion of IL-13 rapidly diminished. Interestingly, mRNA expression of GATA3 was strongly decreased in rHM-treated mice whereas mRNA expression of T-bet and Foxp3 was significantly increased. CONCLUSION: Our results prove that immunotherapy with the rHM effectively controlled allergic responses by shifting from a Th2-like immune response to a Th1-dominated immune response. PMID- 23689671 TI - Directly measuring reaction kinetics of QOOH--a crucial but elusive intermediate in hydrocarbon autoignition. AB - Hydrocarbon autoignition has long been an area of intense fundamental chemical interest, and is a key technological process for emerging clean and efficient combustion strategies. Carbon-centered radicals containing an -OOH group, commonly denoted QOOH radicals, are produced by isomerization of the alkylperoxy radicals that are formed in the first stages of oxidation. These QOOH radicals are among the most critical species for modeling autoignition, as their reactions with O2 are responsible for chain branching below 1000 K. Despite their importance, no QOOH radicals have ever been observed by any means, and only computational and indirect experimental evidence has been available on their reactivity. Here, we directly produce a QOOH radical, 2-hydroperoxy-2-methylprop 1-yl, and experimentally determine rate coefficients for its unimolecular decomposition and its association reaction with O2. The results are supported by high-level theoretical kinetics calculations. Our experimental strategy opens up a new avenue to study the chemistry of QOOH radicals in isolation. PMID- 23689670 TI - Oral activated charcoal adsorbent (AST-120) ameliorates chronic kidney disease induced intestinal epithelial barrier disruption. AB - BACKGROUND: Chronic kidney disease (CKD) impairs intestinal barrier function which by allowing influx of noxious products causes systemic inflammation. We have recently shown that intestinal barrier dysfunction in CKD is due to degradation of epithelial tight junction (TJ) which is, in part, mediated by influx of urea and its conversion to ammonia by microbial urease. We hypothesized that by adsorbing urea and urea-derived ammonia, oral activated charcoal (AST 120) may ameliorate CKD-induced intestinal epithelial barrier disruption and systemic inflammation. METHODS: Rats were randomized to the CKD or control groups. The CKD group was fed a chow containing 0.7% adenine for 2 weeks. They were then randomized to receive a chow with or without AST-120 (4 g/kg/day) for 2 weeks. Rats consuming regular diet served as controls. Animals were then euthanized, colons were removed and processed for Western blot and immunohistology, and plasma was used to measure endotoxin and oxidative and inflammatory markers. RESULTS: Compared with the controls, the untreated CKD rats showed elevated plasma endotoxin, IL-6, TNF-alpha, MCP-1, CINC-3, L-selectin, ICAM-1, and malondialdehyde, and depletions of colonic epithelial TJ proteins, claudin-1, occludin, and ZO1. Administration of AST-120 resulted in partial restoration of the epithelial TJ proteins and reduction in plasma endotoxin and markers of oxidative stress and inflammation. CONCLUSIONS: CKD animals exhibited depletion of the key protein constituents of the colonic epithelial TJ which was associated with systemic inflammation, oxidative stress and endotoxemia. Administration of AST-120 attenuated uremia-induced disruption of colonic epithelial TJ and the associated endotoxemia, oxidative stress and inflammation. PMID- 23689672 TI - Sex-biased expression of sex-differentiating genes FOXL2 and FGF9 in American alligators, alligator Mississippiensis. AB - Across amniotes, sex-determining mechanisms exhibit great variation, yet the genes that govern sexual differentiation are largely conserved. Studies of evolution of sex-determining and sex-differentiating genes require an exhaustive characterization of functions of those genes such as FOXL2 and FGF9. FOXL2 is associated with ovarian development, and FGF9 is known to play a role in testicular organogenesis in mammals and other amniotes. As a step toward characterization of the evolutionary history of sexual development, we measured expression of FOXL2 and FGF9 across 3 developmental stages and 8 juvenile tissue types in male and female American alligators, Alligator mississippiensis. We report surprisingly high expression of FOXL2 before the stage of embryonic development when sex is determined in response to temperature, and sustained and variable expression of FGF9 in juvenile male, but not female tissue types. Novel characterization of gene expression in reptiles with temperature-dependent sex determination such as American alligators may inform the evolution of sex determining and sex-differentiating gene networks, as they suggest alternative functions from which the genes may have been exapted. Future functional profiling of sex-differentiating genes should similarly follow other genes and other species to enable a broad comparison across sex-determining mechanisms. PMID- 23689673 TI - Dissociable effects of kappa-opioid receptor activation on impulsive phenotypes in wistar rats. AB - The kappa-opioid receptor (KOR) is the primary target for the endogenous opioid peptide dynorphin (DYN), and KORs reside within brain circuitry underlying the complex integration of information related to different behavioral domains such as motivation, negative affect, and decision-making. Alterations in extended amygdala DYNs and KOR function following chronic alcohol exposure have been shown to mediate escalated alcohol self-administration during acute withdrawal. In addition to excessive alcohol consumption and increased negative affect, other symptoms of alcohol dependence include compromised impulse control. Given that DYN and KOR expressions are dysregulated within prefrontal brain circuitry associated with decision-making and impulse control in alcohol-dependent humans and rodents, and have been shown to modify multiple neurotransmitter systems associated with impulse-control disorders, we hypothesized that KOR activation could contribute to impulsive phenotypes. To test this hypothesis, separate cohorts of male Wistar rats were trained in one of the two animal models of impulsivity: delay-discounting (DD) or stop-signal reaction time (SSRT) tasks, and once stable responding was observed, received intracerebroventricular (ICV) infusions of the KOR agonist U50,488 (0-50 MUg) according to a within-subject dosing regimen. The results demonstrated a dissociable effect of U50,488 on impulsive phenotypes related to intolerance to delay or response inhibition, with selective effects in the SSRT. Furthermore, the pro-impulsive effects of KOR activation were rescued by pretreatment with the KOR antagonist nor binaltorphimine (nor-BNI). Therefore, KOR activation was shown to induce an impulsive phenotype that was nor-BNI-sensitive. Dysregulation of impulsive behavior by increased DYN/KOR activity could serve to increase vulnerability for the initiation, or perpetuate existing patterns of excessive alcohol abuse and can enhance the probability of relapse in dependent individuals. Furthermore, KOR mediated impulsivity has implications for numerous neuropsychiatric disorders. PMID- 23689674 TI - BDNF overexpression in the ventral tegmental area prolongs social defeat stress induced cross-sensitization to amphetamine and increases DeltaFosB expression in mesocorticolimbic regions of rats. AB - Social defeat stress induces persistent cross-sensitization to psychostimulants, but the molecular mechanisms underlying the development of cross-sensitization remain unclear. One candidate is brain-derived neurotrophic factor (BDNF). The present research examined whether ventral tegmental area (VTA) BDNF overexpression would prolong the time course of cross-sensitization after a single social defeat stress, which normally produces transient cross sensitization lasting <1 week. DeltaFosB, a classic molecular marker of addiction, was also measured in mesocorticolimbic terminal regions. Separate groups of intact male Sprague-Dawley rats underwent a single episode of social defeat stress or control handling, followed by amphetamine (AMPH) challenge 3 or 14 days later. AMPH cross-sensitization was apparent 3, but not 14, days after stress. Intra-VTA infusion of adeno-associated viral (AAV-BDNF) vector resulted in a twofold increase of BDNF level in comparison to the group receiving the control virus (AAV-GFP), which lasted at least 45 days. Additionally, overexpression of BDNF in the VTA alone increased DeltaFosB in the nucleus accumbens (NAc) and prefrontal cortex. Fourteen days after viral infusions, a separate group of rats underwent a single social defeat stress or control handling and were challenged with AMPH 14 and 24 days after stress. AAV-BDNF rats exposed to stress showed prolonged cross-sensitization and facilitated sensitization to the second drug challenge. Immunohistochemistry showed that the combination of virally enhanced VTA BDNF, stress, and AMPH resulted in increased DeltaFosB in the NAc shell compared with the other groups. Thus, elevation of VTA BDNF prolongs cross-sensitization, facilitates sensitization, and increases DeltaFosB in mesocorticolimbic terminal regions. As such, elevated VTA BDNF may be a risk factor for drug sensitivity. PMID- 23689675 TI - Genetic risk for nicotine dependence in the cholinergic system and activation of the brain reward system in healthy adolescents. AB - Genetic variation in a genomic region on chromosome 15q25.1, which encodes the alpha5, alpha3, and beta4 subunits of the cholinergic nicotinic receptor genes, confers risk to smoking and nicotine dependence (ND). Neural reward-related responses have previously been identified as important factors in the development of drug dependence involving ND. Applying an imaging genetics approach in two cohorts (N=487; N=478) of healthy non-smoking adolescents, we aimed to elucidate the impact of genome-wide significant smoking-associated variants in the CHRNA5 CHRNA3-CHRNB4 gene cluster on reward-related neural responses in central regions such as the striatum, orbitofrontal and anterior cingulate cortex (ACC), and personality traits related to addiction. In both samples, carriers of the rs578776 GG compared with AG/AA genotype showed a significantly lower neural response to reward outcomes in the right ventral and dorsal ACC but not the striatum or the orbitofrontal cortex. Rs578776 was unrelated to neural reward anticipation or reward magnitude. Significantly higher scores of anxiety sensitivity in GG compared with AG/AA carriers were found only in sample 1. Associations with other personality traits were not observed. Our findings suggest that the rs578776 risk variant influences susceptibility to ND by dampening the response of the ACC to reward feedback, without recruiting the striatum or orbitofrontal cortex during feedback or anticipation. Thus, it seems to have a major role in the processing of and behavioral adaptation to changing reward outcomes. PMID- 23689677 TI - Clinical evaluation of accuracy of horizontal meridian limbal marking. AB - PURPOSE: To assess the horizontal meridian misalignment of limbal marking under a slit lamp microscope by means of anterior segmental image assessment. METHODS: A consecutive series of the 32 eyes of 16 subjects (7 males and 9 females) aged 29 +/- 6 years (range, 23-44 years), who had refractive errors but were otherwise healthy, were used in this study. With each subject seated at the slit lamp and a coaxial slit turned to the horizontal meridian, we aligned the subject's head vertically and placed two reference marks aligned with the 3- and 9-o'clock positions on the limbal conjunctiva, using a marker pen or a toric marker. We quantitatively evaluated the accuracy of axis aliment by determining deviation from the horizontal reference line using a corneal topographer with an anterior segment image. RESULTS: The amount of the axis misalignment was 3.4 degrees +/- 2.2 degrees (range, 0 degrees -8 degrees ) when the marker pen was used, and 6.9 degrees +/- 5.0 degrees (range, 0-24 degrees ) when the toric marker was used. Location identification using the toric marker showed a significantly larger deviation in axis alignment than that using the marker pen (Wilcoxon sign rank test, p < 0.001). CONCLUSIONS: Horizontal limbal marking using a slit lamp microscope showed the axis misalignment by an average of 3.4 degrees to 6.9 degrees . These alignment errors led to a reduction of the effectiveness of astigmatism correction by an average of 10% to 20%, which was not necessarily negligible when we aim to correct astigmatism completely, if possible. For successful astigmatic surgical procedures, increased accuracy of preoperative limbal marking by decreased misalignment of the astigmatism axis is essential. PMID- 23689676 TI - Comparison of progressive addition lenses by direct measurement of surface shape. AB - PURPOSE: To compare the optical properties of five state-of-the-art progressive addition lenses (PALs) by direct physical measurement of surface shape. METHODS: Five contemporary freeform PALs (Varilux Comfort Enhanced, Varilux Physio Enhanced, Hoya Lifestyle, Shamir Autograph, and Zeiss Individual) with plano distance power and a +2.00-diopter add were measured with a coordinate measuring machine. The front and back surface heights were physically measured, and the optical properties of each surface, and their combination, were calculated with custom MATLAB routines. Surface shape was described as the sum of Zernike polynomials. Progressive addition lenses were represented as contour plots of spherical equivalent power, cylindrical power, and higher order aberrations (HOAs). Maximum power rate, minimum 1.00-DC corridor width, percentage of lens area with less than 1.00 DC, and root mean square of HOAs were also compared. RESULTS: Comfort Enhanced and Physio Enhanced have freeform front surfaces, Shamir Autograph and Zeiss Individual have freeform back surfaces, and Hoya Lifestyle has freeform properties on both surfaces. However, the overall optical properties are similar, regardless of the lens design. The maximum power rate is between 0.08 and 0.12 diopters per millimeter and the minimum corridor width is between 8 and 11 mm. For a 40-mm lens diameter, the percentage of lens area with less than 1.00 DC is between 64 and 76%. The third-order Zernike terms are the dominant high-order terms in HOAs (78 to 93% of overall shape variance). Higher order aberrations are higher along the corridor area and around the near zone. The maximum root mean square of HOAs based on a 4.5-mm pupil size around the corridor area is between 0.05 and 0.06 um. CONCLUSIONS: This nonoptical method using a coordinate measuring machine can be used to evaluate a PAL by surface height measurements, with the optical properties directly related to its front and back surface designs. PMID- 23689679 TI - Patterns of abnormal visual attention in myalgic encephalomyelitis. AB - PURPOSE: To experimentally assess visual attention difficulties commonly reported by those with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). METHODS: Twenty-nine ME/CFS patients and 29 controls took part in the study. Performance was assessed using the Useful Field of View (UFOV), a spatial cueing task and visual search. RESULTS: Patients and controls performed similarly on the processing speed subtest of the UFOV. However, patients exhibited marginally worse performance compared with controls on the divided attention subtest and significantly worse performance on the selective attention subtest. In the spatial cueing task, they were slower than controls to respond to the presence of the target, particularly when cues were invalid. They were also impaired, relative to controls, on visual search tasks. CONCLUSIONS: We have provided experimental evidence for ME/CFS-related difficulties in directing visual attention. These findings support the subjective reports of those with ME/CFS and could represent a potential means to improve diagnosis. PMID- 23689678 TI - Hemolacria in a patient with severe systemic diseases. AB - PURPOSE: Hemolacria is a rare phenomenon of bloody tears caused by various ocular and systemic conditions, as well as psychological, pharmacologic, and idiopathic etiologies. Hemolacria is typically a benign process; however, serious systemic associations can exist. It is predominantly unilateral and self-limiting, but because of limited literature, its prevalence and predilection toward a specific gender, race, or age is not known. CASE REPORT: An 82-year-old Caucasian male presented for an emergent eye examination with an acute onset of hemolacria of the right eye (OD). Patient medical history was extensive with coronary artery disease, atrial fibrillation, lipidemia, insulin-dependent diabetes, uncontrolled hypertension, and untreated severe renal failure. Before the incident, patient medication included warfarin, 81 mg of aspirin, insulin, glipizide, and blood pressure regime with which the patient was noncompliant. The patient was forwarded to urgent care to address his stage 2 hypertension and referred for a medical evaluation, which included a complete blood count, an International Normalized Ratio, a prothrombin time, and a glycated hemoglobin. CONCLUSIONS: Spontaneous resolution of the hemolacria occurred within 24 hr after evaluation and restoration of blood pressure to normal range. Before follow-up, the patient died because of kidney failure. After a review of pertinent laboratory results and literature, the etiology of this patient's hemolacria could be attributed to either uncontrolled hypertension, chronic renal failure, aggressive anticoagulant therapy, and/or diabetes. An extensive literature review of documented etiologies and management is included. PMID- 23689680 TI - Antioxidant promotion of tyrosine nitration in the presence of copper(II). AB - Copper(II) is known to catalyze the generation of reactive nitrogen species in the presence of hydrogen peroxide, nitrite or nitric oxide, leading to tyrosine nitration, a biomarker for free radical species associated diseases. Here, we find that biological antioxidants such as ascorbic acid can promote tyrosine nitration in the presence of copper(II) and nitrite under aerobic and weak acidic conditions. Tyrosine nitration is demonstrated on both the beta-amyloid peptide and angiotensin I. These studies show that (i) ascorbic acid works as a pro oxidant in the presence of copper(II) to induce oxidation and nitration on peptides, (ii) both free and coordinated copper(II) can catalyze peptide oxidation and nitration, (iii) nitration occurs under mild acidic conditions (pH = 6.0-6.5). PMID- 23689681 TI - A general strategy for obtaining biodegradable polymer shelled microbubbles as theranostic devices. AB - Fabrication of multifunctional ultrasound contrast agents (UCAs) has been recently addressed by several research groups. A versatile strategy for the synthesis of UCA precursors in the form of biodegradable vesicles with a biocompatible crosslinked polymer shell is described. Upon ultrasound irradiation, acoustic droplet vaporization transforms such particles into microbubbles behaving as UCAs. This proof of concept entails the features of a potential theranostic microdevice. PMID- 23689682 TI - Role of regulatory T cells in patients with acute herpes zoster and relationship to postherpetic neuralgia. AB - This study is to analyze distribution of peripheral T cell subsets including regulatory T cells in patients with acute herpes zoster (AHZ) and investigate its relationship to the development of postherpetic neuralgia (PHN). T lymphocyte subsets in peripheral blood from 76 patients with AHZ and 38 normal controls were analyzed using flow cytometry. According to the visual analogue scales in the acuter phase and followed up by PHN for 3 months, patients with herpes zoster (HZ) were divided into different patient groups. The results demonstrated a significant decrease in the percentage of CD4 lymphocytes and CD4/CD8 ratios in each patient group as compared with normal controls, and the CD4+ subsets in the severe group were significantly decreased as compared with mild group and moderate group (p < 0.01). Moreover, there seemed a relationship between severity of acute pain during zoster and PHN. The proportions of regulatory T cells (Treg; CD4+CD25+FoxP3+ T cells) were significantly elevated from AHZ patients as compared with normal controls, and CD4+ T cells were inversely correlated with Treg cells (p < 0.01). Furthermore, FoxP3 expression was significantly increased by CD4+CD25(high) T cells in the severe group as compared with mild group, moderate group and normal controls. These results indicated that T cellular immunity in AHZ patients was impaired and suggested increased activation of Treg cells may suppress anti-viral CD4+ T cells immune responses, especially in the severe HZ patients. Treg cells may play an important role in the pathogenesis of AHZ and progression toward PHN. PMID- 23689683 TI - siRNA-Act1 inhibits the function of IL-17 on lung fibroblasts via the NF-kappaB pathway. AB - BACKGROUND: Interleukin (IL)-17-producing T lymphocytes play a role in pulmonary fibrosis, but the possible mechanism of IL-17 on lung fibroblasts remains uncertain. OBJECTIVES: To explore the role and possible mechanism of IL-17 on lung fibroblasts. METHODS: A mouse model of pulmonary fibrosis was established by intratracheal administration of 5 mg/kg bleomycin. At 14 days following bleomycin administration the pulmonary fibroblasts were isolated, cultured and identified. siRNA for activator 1 (Act1) were transfected into lung fibroblasts, which were cocultured with IL-17. The NF-kappaB pathway was detected for IL-17 on the lung fibroblasts. RESULTS: IL-17R was increased significantly at 14 days in the bleomycin-induced pulmonary fibroblast model, exogenous IL-17 significantly promoted the proliferation of the pulmonary fibroblasts in primary culture and obviously increased the expression of alpha-smooth muscle actin and type I and type III collagen in the fibroblasts. We found that IL-17 rapidly activated the NF-kappaB signaling pathway through activated phosphorylated p65 and IkappaB, and all roles of IL-17 on lung fibroblasts were inhibited under the interference for the expression of Act1 in lung fibroblasts. CONCLUSION: IL-17 may directly promote the proliferation, transformation and collagen synthesis of lung fibroblasts via the NF-kB signaling pathway, which can be inhibited by the interference for the expression of Act1. PMID- 23689686 TI - Slow dynamics of water molecules in an aqueous solution of lithium chloride probed by neutron spin-echo. AB - Aqueous solutions of lithium chloride are uniquely similar to pure water in the parameters such as glass transition temperature, Tg, yet they could be supercooled without freezing down to below 200 K even in the bulk state. This provides advantageous opportunity to study low-temperature dynamics of water molecules in water-like environment in the bulk rather than nano-confined state. Using high-resolution neutron spin-echo data, we argue that the critical temperature, Tc, which is also common between lithium chloride aqueous solutions and pure water, is associated with the split of a secondary relaxation from the main structural relaxation on cooling down. Our results do not allow distinguishing between a well-defined separate secondary relaxation process and the "excess wing" scenario, in which the temperature dependence of the secondary relaxation follows the main relaxation. Importantly, however, in either of these scenarios the secondary relaxation is associated with density-density fluctuations, measurable in a neutron scattering experiment. Neutron scattering could be the only experimental technique with the capability of providing information on the spatial characteristics of the secondary relaxation through the dependence of the signal on the scattering momentum transfer. We propose a simple method for such analysis. PMID- 23689684 TI - Transmembrane protein PERP is a component of tessellate junctions and of other junctional and non-junctional plasma membrane regions in diverse epithelial and epithelium-derived cells. AB - Protein PERP (p53 apoptosis effector related to PMP-22) is a small (21.4 kDa) transmembrane polypeptide with an amino acid sequence indicative of a tetraspanin character. It is enriched in the plasma membrane and apparently contributes to cell-cell contacts. Hitherto, it has been reported to be exclusively a component of desmosomes of some stratified epithelia. However, by using a series of newly generated mono- and polyclonal antibodies, we show that protein PERP is not only present in all kinds of stratified epithelia but also occurs in simple, columnar, complex and transitional epithelia, in various types of squamous metaplasia and epithelium-derived tumors, in diverse epithelium-derived cell cultures and in myocardial tissue. Immunofluorescence and immunoelectron microscopy allow us to localize PERP predominantly in small intradesmosomal locations and in variously sized, junction-like peri- and interdesmosomal regions ("tessellate junctions"), mostly in mosaic or amalgamated combinations with other molecules believed, to date, to be exclusive components of tight and adherens junctions. In the heart, PERP is a major component of the composite junctions of the intercalated disks connecting cardiomyocytes. Finally, protein PERP is a cobblestone-like general component of special plasma membrane regions such as the bile canaliculi of liver and subapical-to-lateral zones of diverse columnar epithelia and upper urothelial cell layers. We discuss possible organizational and architectonic functions of protein PERP and its potential value as an immunohistochemical diagnostic marker. PMID- 23689685 TI - Association between dietary sodium and potassium intake with chronic kidney disease in US adults: a cross-sectional study. AB - BACKGROUND/AIMS: Clinical guidelines recommend a diet low in sodium and high in potassium to reduce blood pressure and cardiovascular events. Little is known about the relationship between dietary sodium and potassium intake and chronic kidney disease (CKD). METHODS: 13,917 participants from the National Health and Nutrition Examination Survey (2001-2006) were examined. Sodium and potassium intake were calculated from 24-hour recall and evaluated in quartiles. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2) or eGFR >=60 ml/min/1.73 m(2) with albuminuria (>30 mg/g creatinine). RESULTS: The mean (SE) age and eGFR of participants were 45.0 +/- 0.4 years and 88.0 +/- 0.60 ml/min/1.73 m(2), respectively. 2,333 (14.2%) had CKD: 1,146 (7.3%) had an eGFR <60 ml/min/1.73 m(2) and 1,514 (8.4%) had an eGFR >=60 ml/min/1.73 m(2) and albuminuria. After adjustment for age, sex, race, BMI, diabetes, hypertension, cardiovascular disease and congestive heart failure, subjects in the highest quartile of sodium intake had lower odds of CKD compared to subjects in the lowest quartile (adjusted OR: 0.79; 95% CI: 0.66-0.96; p < 0.016). Compared to the highest quartile, the odds of CKD increased 44% for participants in the lowest quartile of potassium intake (adjusted OR: 1.44; 95% CI: 1.16-1.79; p = 0.0011). CONCLUSIONS: Higher intake of sodium and potassium is associated with lower odds of CKD among US adults. These results should be corroborated through longitudinal studies and clinical trials designed specifically to examine the effects of dietary sodium and potassium intake on kidney disease and its progression. PMID- 23689687 TI - The concept of the immune-pineal axis tested in patients undergoing an abdominal hysterectomy. AB - OBJECTIVE: Activation of the immune-pineal axis induces a transient reduction in nocturnal melatonin in the plasma during the proinflammatory phase of an innate immune response to allow the proper migration of leukocytes to the lesion site. This transient reduction should be regulated by inflammatory mediators, which are responsible for the fine-tuning of the process. In the present study, we measured the pre- and postoperative serum concentrations of melatonin, tumor necrosis factor (TNF) and cortisol in women who underwent an elective hysterectomy and correlated the variation in melatonin with postoperative pain. METHODS: We evaluated 12 women who had an abdominal hysterectomy. Blood was collected at 10.00 and 22.00 h 1 week and 1 day before the surgery, on the 1st and 2nd days after the surgery and at 22.00 h on the day of the surgery. RESULTS: On the night after the surgery, there was no melatonin detected at 22.00 h. High TNF levels were accompanied by a lower nocturnal melatonin output, higher postoperative pain according to a visual analog scale and the request of higher doses of analgesics. In addition, low cortisol levels were accompanied by a lower nocturnal melatonin output. CONCLUSION: Our results confirm that the same antagonistic pattern between TNF and glucocorticoids observed in cultured pineal glands also occurs in humans. This integrative pattern suggests that the cross talk between the immune and endocrine system orchestrates longitudinal changes in pineal activity, reinforcing the hypothesis of an immune-pineal axis. PMID- 23689688 TI - MPR realignment increases accuracy when measuring femoral neck anteversion angle. AB - OBJECTIVE: To compare two methods of measuring femoral neck anteversion angle (FNA): A 2D method used at Odense University Hospital until 2010, and a method labeled 3D-OUH. The latter method makes corrections to compensate for errors introduced by the individual placement of patients in the CT scanner. MATERIALS AND METHODS: Twenty-six CT-examined patients were included: nine men and 17 women. The right side FNA was measured twice with each method by one observer, measuring intraobserver variability. Both methods are based on the following anatomy: femoral head center, center at the level of lesser trochanter and posterior apex of the femoral condyles. The 3D-OUH method corrects for the individual orientation of femur by realigning it prior to measurement, in accordance to Murphy et al.'s original definition of FNA. The intercondylar notch center of the knee and center at lesser trochanter was used in the realignment. RESULTS: The 2D method significantly overestimated FNA compared to 3D-OUH by 4.2 degrees (95 % CI: 2.8 degrees ; 5.6 degrees ), p < 0.0001. All measurements with the 3D method needed clock-wise correction in the coronal plane, suggesting patient positioning as a consistent source of overestimation by the 2D method. The 3D-OUH method had a lower intraobserver variability with a limit of agreement (LOA) of -2.4 degrees to 2.1 degrees against that of the 2D method of -3.4 degrees to 3.8 degrees CONCLUSIONS: Mean anteversion was 4.2 degrees (95 % CI: 2.8 degrees ; 5.6 degrees ) lower with the 3D-OUH method than with the 2D method. The 3D-OUH method eliminated an obvious source of error, namely the individual orientation of femur during CT-examination. Moreover, intraobserver variability was improved with the 3D-OUH method. PMID- 23689690 TI - Yield of routine provocative cardiac testing among patients in an emergency department-based chest pain unit. AB - IMPORTANCE: The American Heart Association recommends routine provocative cardiac testing in accelerated diagnostic protocols for coronary ischemia. The diagnostic and therapeutic yield of this approach are unknown. OBJECTIVE: To assess the yield of routine provocative cardiac testing in an emergency department-based chest pain unit. DESIGN AND SETTING: We examined a prospectively collected database of patients evaluated for possible acute coronary syndrome between March 4, 2004, and May 15, 2010, in the emergency department-based chest pain unit of an urban academic tertiary care center. PARTICIPANTS: Patients with signs or symptoms of possible acute coronary syndrome and without an ischemic electrocardiography result or a positive biomarker were enrolled in the database. EXPOSURES: All patients were evaluated by exercise stress testing or myocardial perfusion imaging. MAIN OUTCOMES AND MEASURES: Demographic and clinical features, results of routine provocative cardiac testing and angiography, and therapeutic interventions were recorded. Diagnostic yield (true-positive rate) was calculated, and the potential therapeutic yield of invasive therapy was assessed through blinded, structured medical record review using American Heart Association designations (class I, IIa, IIb, or lower) for the potential benefit from percutaneous intervention. RESULTS: In total, 4181 patients were enrolled in the study. Chest pain was initially reported in 93.5%, most (73.2%) were at intermediate risk for coronary artery disease, and 37.6% were male. Routine provocative cardiac testing was positive for coronary ischemia in 470 (11.2%), of whom 123 underwent coronary angiography. Obstructive disease was confirmed in 63 of 123 (51.2% true positive), and 28 (0.7% overall) had findings consistent with the potential benefit from revascularization (American Heart Association class I or IIa). CONCLUSIONS AND RELEVANCE: In an emergency department-based chest pain unit, routine provocative cardiac testing generated a small therapeutic yield, new diagnoses of coronary artery disease were uncommon, and false-positive results were common. PMID- 23689689 TI - Prevalence and clinical significance of chondromalacia isolated to the anterior margin of the lateral femoral condyle as a component of patellofemoral disease: observations at MR imaging. AB - OBJECTIVE: To determine the prevalence of chondromalacia isolated to the anterior margin of the lateral femoral condyle as a component of patellofemoral disease in patients with anterior knee pain and to correlate it with patient demographics, patellar shape, and patellofemoral alignment. MATERIALS AND METHODS: Retrospective study over a 1-year period reviewing the MR knee examinations of all patients who were referred for assessment of anterior knee pain. Only patients with isolated lateral patellofemoral disease were included. Age, gender, distribution of lateral patellofemoral chondromalacia, and grade of cartilaginous defects were documented for each patient. Correlation between the distribution of lateral patellofemoral chondromalacia and patient demographics, patellar shape, and indices of patellar alignment (femoral sulcus angle and modified Q angle) was then ascertained. RESULTS: There were 50 patients (22 males, 28 females) with anterior knee pain and isolated patellofemoral disease. The majority of the patients (78 %) had co-existent disease with grade 1 chondromalacia. No significant correlation was found between patients with chondromalacia isolated to the anterior margin of the lateral femoral condyle and age, gender, patellar shape, or modified Q angle (p > 0.05). However, patients with chondromalacia isolated to the anterior margin of the lateral femoral condyle had a shallower femoral sulcus angle (mean 141.8 degrees ) compared to the patients with lateral patellar facet disease (mean 133.8 degrees ) (p = 0.002). CONCLUSIONS: A small percentage of patients with anterior knee pain have chondromalacia isolated to the anterior margin of the lateral femoral condyle. This was associated with a shallower femoral sulcus angle. PMID- 23689691 TI - Anaplastic lymphoma kinase (ALK1) immunohistochemistry in diagnostic dermatopathology; an update. AB - The use of anaplastic lymphoma kinase antibodies (ALK1) as a diagnostic aid has expanded since becoming a routinely available immunohistochemical stain. Because the skin may be the site of a wide variety of hematolymphoid and fibroblastic proliferations, dermatopathologists commonly use ALK1 as part of a broader staining panel in diagnosing soft tissue and cutaneous hematolymphoid neoplasms. Furthermore, new entities and differential diagnostic contexts are emerging, which broaden the utility of ALK1 immunohistochemistry. We review the expanding role of ALK1 immunohistochemistry in contemporary dermatopathology. PMID- 23689692 TI - Angiosarcoma: a tissue microarray study with diagnostic implications. AB - BACKGROUND: Angiosarcoma (AS) is a rare soft tissue sarcoma showing endothelial differentiation as indicated by morphology and expression of CD31 (blood), D2-40 (lymphatic), factor VIII, and CD34 (both). We sought to examine the pattern of immunohistochemical markers of differentiation in AS and correlate these with outcome. DESIGN: An AS tissue microarray (n = 70 specimens) was constructed for immunohistochemical analysis of CD31, CD34, factor VIII, D2-40, and pan cytokeratin. Samples on this array were linked to clinicopathologic and outcome data for these patients. Univariate analyses were used to explore disease specific survival (DSS) factors. RESULTS: Nine metastatic, 23 localized, and 4 recurrent cases were included. Information about the tissue status (ie, primary or metastasis) was unavailable in 4 patients. Primary sites for the tumor included bone (n = 1), breast parenchyma (n = 11), breast skin (n = 4), heart (n = 5), skin (n = 8), soft tissue (n = 7), and unknown (n = 3). Three patients presented with multifocal disease (primary sites in these patients included breast, skin, and soft tissue). Metastatic sites included lung, bone, lymph nodes, brain, liver, and parotid. Of the 40 cases, 8 (20%) showed a pure or predominant epithelioid histology. Of the biomarkers evaluated by tissue microarray, 92% of tumors expressed at least one endothelial marker (factor VIII = 83%, CD31 = 80%, CD34 = 63%, and D2-40 = 43%) with 88% expressing 2 or more markers. Eighty-eight percent of tumors expressing D2-40 coexpressed CD31, an unusual combination in normal vessels. No endothelial marker clearly associated with disease-specific survival. Fifty percent (4/8) of epithelioid cases and 9% (3/32) of nonepithelioid cases showed keratin expression. CONCLUSIONS: Unusual patterns and loss of endothelial markers are common in AS, suggesting use of multiple markers in challenging cases and perhaps indicating important biologic characteristics. PMID- 23689693 TI - Direct immunofluorescence on hair follicles--present and future perspectives. AB - Direct immunofluorescence (DIF) is an important tool for evaluating bullous autoimmune and connective tissue disorders. We report 21 cases of pemphigus vulgaris, bullous pemphigoid and lupus erythematosus that were investigated by performing DIF on scalp hair follicles. The study was done using a simplified technique of preparing the hairs for DIF testing. The anagen hairs tested positive in pemphigus vulgaris patients while the telogen hairs were negative. In bullous pemphigoid and lupus erythematosus cases hair DIF presented negative results.Hair DIF has the potential of taking the place of skin or mucosal DIF in pemphigus patients if performed on anagen hair follicles. The technique used to perform hair DIF is important in obtaining reliable results and eliminating the possibility of generating false-negative testing. Larger studies are needed in order to validate this method. PMID- 23689694 TI - Keratotic papules in a 6-year-old girl. PMID- 23689695 TI - Uveitis and desquamating rash of the palms and soles. AB - Syphilis, a sexually transmitted disease caused by the spirochete Treponema pallidum, can affect nearly every organ system in the body. In particular, skin manifestations of secondary syphilis are common but nonspecific and can be a true masquerader of other skin disorders. Concomitant infection with HIV has been increasing and may cause even more unusual skin presentations. We present a patient with the atypical combination of palmoplantar keratoderma and ocular symptoms that closely resembled reactive arthritis (or Reiter's syndrome). When evaluating patients with HIV infection, clinicians should maintain a high level of suspicion for syphilis to accurately diagnose and treat this curable but potentially fatal disease. PMID- 23689696 TI - Controversial concepts: infundibular squamous cell carcinoma and tricholemmal carcinoma. PMID- 23689698 TI - Down-regulation of Na/K+ atpase activity by human parvovirus B19 capsid protein VP1. AB - BACKGROUND/AIMS: Human parvovirus B19 (B19V) may cause inflammatory cardiomyopathy (iCMP) which is accompanied by endothelial dysfunction. The B19V capsid protein VP1 contains a lysophosphatidylcholine producing phospholipase A2 (PLA) sequence. Lysophosphatidylcholine has in turn been shown to inhibit Na(+)/K(+) ATPase. The present study explored whether VP1 modifies Na(+)/K(+) ATPase activity. METHODS: Xenopus oocytes were injected with cRNA encoding VP1 isolated from a patient suffering from fatal B19V-iCMP or cRNA encoding PLA2 negative VP1 mutant (H153A) and K(+) induced pump current (I(pump)) as well as ouabain-inhibited current (I(ouabain)) both reflecting Na(+)/K(+)-ATPase activity were determined by dual electrode voltage clamp. RESULTS: Injection of cRNA encoding VP1, but not of VP1(H153A) or water, was followed by a significant decrease of both, I(pump) and I(ouabain) in Xenopus oocytes. The effect was not modified by inhibition of transcription with actinomycin (10 uM for 36 hours) but was abrogated in the presence of PLA2 specific blocker 4-bromophenacylbromide (50 uM) and was mimicked by lysophosphatidylcholine (0.5 - 1 ug/ml). According to whole cell patch clamp, lysophosphatidylcholine (1 ug /ml) similarly decreased I(pump) in human microvascular endothelial cells (HMEC). CONCLUSION: The B19V capsid protein VP1 is a powerful inhibitor of host cell Na(+)/K(+) ATPase, an effect at least partially due to phospholipase A2 (PLA2) dependent formation of lysophosphatidylcholine. PMID- 23689699 TI - Vertebral anomalies in siblings with Fanconi anemia. PMID- 23689700 TI - Soluble CD23 levels are inversely associated with atopy and parasite-specific IgE levels but not with polyclonal IgE levels in people exposed to helminth infection. AB - BACKGROUND: Protective acquired immunity against helminths and allergic sensitisation are both characterised by high IgE antibody levels. Levels of IgE antibodies are naturally tightly regulated by several mechanisms including binding of the CD23 receptor. Following observations that helminth infections and allergic sensitisation may co-present, the current study aims to investigate the relationship between the soluble CD23 (sCD23) receptor, parasite-specific IgE responses and allergic sensitisation in people exposed to the helminth parasite Schistosoma haematobium. METHODS: A cohort of 434 participants was recruited in two villages with different levels of S. haematobium infection in Zimbabwe. Serum levels of the 25-kDa fragment of sCD23 were related to levels of schistosome infection intensity, allergen (house dust mite, HDM) and schistosome-specific IgE, total IgE and skin sensitisation to HDM. RESULTS: sCD23 levels rose significantly with schistosome infection intensity but declined significantly with schistosome-specific IgE levels. Furthermore, sCD23 levels were negatively associated with skin sensitisation and IgE reactivity against HDM, but showed no relationship with total IgE. CONCLUSION: The results are consistent with the suppression of parasite and allergen-specific IgE levels by sCD23. Further mechanistic studies will determine the relevance of this potential regulatory mechanism in the development of helminth-specific immune responses in atopic individuals. PMID- 23689701 TI - Arrhythmias: CPAP with ablation reduces AF in OSA. PMID- 23689704 TI - Intravenous colistin for multidrug-resistant gram-negative infections in critically ill pediatric patients. AB - OBJECTIVES: Nosocomial infection due to multidrug-resistant Gram-negative pathogens in ICUs is a challenge for clinicians and microbiologists and has led to the resurgence of IV colistin use in the last decade. The aim of this study was to assess the efficacy of IV colistin in the treatment of critically ill children with multidrug-resistant Gram-negative infections. DESIGN AND SETTING: Retrospective descriptive study conducted in the PICU of Maulana Azad Medical College and associated Chacha Nehru Bal Chikitsalaya, Delhi, India, during the period of January 2010 to December 2011. PATIENTS: The records of critically ill children with multidrug-resistant Gram-negative infections treated with IV colistin were reviewed. RESULTS: Fifty critically ill children received IV colistin; their median age was 36 months (range: 1 mo-12 yr), with male:female ratio of 3:2. The isolated pathogens were Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae. Mean duration of colistin therapy was 14.3 days (range, 7-21). A favorable clinical outcome occurred in 36 children (72%), and 14 children (28%) died due to severe sepsis with multiple-organ dysfunction syndrome. Renal toxicity occurred in five children and was associated with multiple-organ dysfunction syndrome in three and coadministration of vancomycin in two. No neurotoxic adverse effects due to colistin therapy were reported. CONCLUSION: Our study suggests that IV colistin may have a role in the treatment of infections caused by multidrug resistant Gram-negative bacteria in critically ill children, but further prospective and randomized control trials are needed to confirm its efficacy and safety in children. PMID- 23689703 TI - Oral anticoagulants in the management of venous thromboembolism. AB - Despite advances in diagnosis, prevention, and management, venous thromboembolism (VTE) remains a common cause of morbidity and mortality. For decades, antithrombotic therapy for prevention and treatment of VTE was limited to parenteral agents related to heparin and oral vitamin K antagonists (VKAs). Both classes of anticoagulants are effective, but have limitations, including considerable variability in dose-response, narrow therapeutic margins between the risks of thrombosis and bleeding, and the need to monitor anticoagulation intensity. Over the past decade, the introduction of new oral anticoagulants that specifically inhibit coagulation factors IIa (thrombin) or Xa has changed practice in a variety of clinical situations, including VTE prophylaxis and treatment. In this Review, we outline the use of the novel oral anticoagulants apixaban, dabigatran, edoxaban, and rivaroxaban in the prevention and treatment of VTE, and discuss practical considerations for choosing the appropriate drug for each patient. Although the introduction of novel anticoagulant drugs is promising, selecting the optimum strategy for an individual patient requires an understanding of the specific circumstances associated with thrombus formation and the pharmacological properties of each agent. PMID- 23689702 TI - Small-diameter vascular tissue engineering. AB - Vascular occlusion remains the leading cause of death in Western countries, despite advances made in balloon angioplasty and conventional surgical intervention. Vascular surgery, such as CABG surgery, arteriovenous shunts, and the treatment of congenital anomalies of the coronary artery and pulmonary tracts, requires biologically responsive vascular substitutes. Autografts, particularly saphenous vein and internal mammary artery, are the gold-standard grafts used to treat vascular occlusions. Prosthetic grafts have been developed as alternatives to autografts, but their low patency owing to short-term and intermediate-term thrombosis still limits their clinical application. Advances in vascular tissue engineering technology-such as self-assembling cell sheets, as well as scaffold-guided and decellularized-matrix approaches-promise to produce responsive, living conduits with properties similar to those of native tissue. Over the past decade, vascular tissue engineering has become one of the fastest growing areas of research, and is now showing some success in the clinic. PMID- 23689705 TI - The effect of atropine on rhythm and conduction disturbances during 322 critical care intubations. AB - OBJECTIVES: Our objectives were to describe the prevalence of arrhythmia and conduction abnormalities before critical care intubation and to test the hypothesis that atropine had no effect on their prevalence during intubation. DESIGN: Prospective, observational study. SETTING: PICU and pediatric/neonatal intensive care transport. SUBJECTS: All children of age less than 8 years intubated September 2007-2009. Subgroups of intubations with and without atropine were analyzed. INTERVENTION: None. MEASUREMENT AND MAIN RESULTS: A total of 414 intubations were performed in the study period of which 327 were available for analysis (79%). Five children (1.5%) had arrhythmias prior to intubation and were excluded from the atropine analysis. Atropine was used in 47% (152/322) of intubations and resulted in significant acceleration of heart rate without provoking ventricular arrhythmias. New arrhythmias during intubation were related to bradycardia and were less common with atropine use (odds ratio, 0.14 [95% CI, 0.06-0.35], p < 0.001). The most common new arrhythmia was junctional rhythm. Acute bundle branch block was observed during three intubations; one Mobitz type 2 rhythm and five ventricular escape rhythms occurred in the no-atropine group (n = 170). Only one ventricular escape rhythm occurred in the atropine group (n = 152) in a child with an abnormal heart. One child died during intubation who had not received atropine. CONCLUSIONS: Atropine significantly reduced the prevalence of new arrhythmias during intubation particularly for children over 1 month of age, did not convert sinus tachycardia to ventricular tachycardia or fibrillation, and may contribute to the safety of intubation. PMID- 23689706 TI - Intraocular penetration of intravenous micafungin in inflamed human eyes. AB - Eight eyes of 7 patients with fungal disease received intravenous injections of 150 to 300 mg micafungin, and samples of blood, cornea, retina-choroid, aqueous humor, and vitreous humor were collected. The micafungin levels in all collected samples exceeded the MICs; however, the levels in the vitreous and aqueous humors were lower. Our findings suggest that intravenous micafungin should be given in combination with intravitreal antifungal agents after vitrectomy in severe cases of intraocular fungal diseases. PMID- 23689707 TI - Maculatin 1.1 disrupts Staphylococcus aureus lipid membranes via a pore mechanism. AB - Maculatin 1.1 (Mac1) showed potent activity against Staphylococcus aureus with an MIC of 7 MUM. The mode of action of Mac1 was investigated by combining assays with S. aureus cells and lipid vesicles mimicking their membrane composition. A change in Mac1 conformation was monitored by circular dichroism from random coil to ca. 70% alpha-helix structure in contact with vesicles. Electron micrographs of S. aureus incubated with Mac1 showed rough and rippled cell surfaces. An uptake of 65% of small (FD, 4 kDa [FD-4]) and 35% of large (RD, 40 kDa [RD-40]) fluorescent dextrans by S. aureus was observed by flow cytometry and indicate that Mac1 formed a pore of finite size. In model membranes with both dyes encapsulated together, the full release of FD-4 occurred, but only 40% of RD-40 was reached, supporting the flow cytometry results, and indicating a pore size between 1.4 and 4.5 nm. Finally, solid-state nuclear magnetic resonance showed formation of an isotropic phase signifying highly mobile lipids such as encountered in a toroidal pore structure. Overall, Mac1 is a promising antimicrobial peptide with the potent capacity to form pores in S. aureus membranes. PMID- 23689708 TI - Coadministration of atazanavir-ritonavir and zinc sulfate: impact on hyperbilirubinemia and pharmacokinetics. AB - Atazanavir (ATV) causes an elevation of unconjugated hyperbilirubinemia (HBR) as a result of UDP glucuronyltransferase (UGT) 1A1 inhibition. Zinc sulfate (ZnSO4) reduces unconjugated hyperbilirubinemia in individuals with Gilbert's syndrome. We assessed the changes in total, conjugated, and unconjugated bilirubin and the effect on ATV pharmacokinetics (PK) after single and 14-day dosing of ZnSO(4). HIV patients, stable on ATV/ritonavir (ATV/r)-containing regimens with a total bilirubin level of >25 mmol/liter received 125 mg daily of ZnSO(4) as Solvazinc tablets for 14 days. ATV/r and bilirubin concentrations were measured pre-ATV/r dose and 2, 4, 6, 8, and 24 h post-ATV/r dose; before ZnSO4 initiation (phase 1), after a single dose (phase 2) and after 14 days (phase 3). Changes in bilirubin and ATV/r concentrations in the absence or presence of ZnSO4 were evaluated by geometric mean ratios (GMRs) and 90% confidence intervals (CIs; we used phase 1 as a reference). Sixteen male patients completed the study maintaining virologic suppression; ZnSO(4) was well tolerated. Statistically significant declines in total bilirubin C(max) and AUC(0-24) of 16 and 17% were seen in phase2 and 20% in phase 3. Although there were no significant changes in conjugated bilirubin, unconjugated bilirubin Cmax and AUC(0-24) of were lower (17 and 19%, phase 2; 20 and 23% during phase 3). The ATV GMRs (90% CI) for C(trough), C(max), and AUC(0 24) were 0.74 (0.62 to 0.89), 0.82 (0.70 to 0.97), and 0.78 (0.70 to 0.88). Intake of ZnSO(4) decreases total and unconjugated bilirubin and causes modest declines in ATV exposure. ZnSO(4) supplementation may be useful in management of ATV-related HBR in selected patients. PMID- 23689709 TI - Evaluation of antimicrobial susceptibility of Enterobacteriaceae causing urinary tract infections in Africa. AB - Our objective was to evaluate the antimicrobial susceptibility of Enterobacteriaceae causing urinary tract infections (UTIs) in adults in Africa. The PubMed database was systematically searched to identify relevant studies published after 2000. Google, World Health Organization, and African Field Epidemiology networks were also searched. Twenty-eight studies, accounting for 381,899 urine isolates from 14 African countries, met the inclusion criteria. Escherichia coli, Klebsiella spp., and Proteus spp. were the most commonly encountered uropathogens. Cefotaxime, imipenem, fosfomycin, and ciprofloxacin were the antibiotics with the highest activity against E. coli isolates from outpatients, with susceptibility being 92 to 99, 100, 100, and 68 to 91%, respectively. The susceptibility among Klebsiella spp. isolates from outpatients varied from 80 to 100% for amikacin and from 53 to 100% for ciprofloxacin, while susceptibility was 74 to 78, 97, and 77% for ciprofloxacin, amikacin, and fosfomycin, respectively, among Klebsiella species isolates from inpatients or patients with hospital-acquired UTIs. With regard to Proteus spp., the highest activity was observed among fluoroquinolones; 71 to 100% of the P. mirabilis isolates were susceptible to ciprofloxacin in four studies, and 74 to 100% of the P. vulgaris isolates were susceptible to ofloxacin in two studies. The currently available evidence suggests that the antimicrobial susceptibility patterns of Enterobacteriaceae uropathogens in African countries were similar to those in countries of southeast Europe. Further original studies are warranted from African countries for which there is limited published data. PMID- 23689710 TI - HIV-1 resistance mechanism to an electrostatically constrained peptide fusion inhibitor that is active against T-20-resistant strains. AB - T-20EK is a novel fusion inhibitor designed to have enhanced alpha-helicity over T-20 (enfuvirtide) through engineered electrostatic interactions between glutamic acid (E) and lysine (K) substitutions. T-20EK efficiently suppresses wild-type and T-20-resistant variants. Here, we selected T-20EK-resistant variants. A combination of L33S and N43K substitutions in gp41 were required for high resistance to T-20EK. While these substitutions also caused resistance to T-20, they did not cause cross-resistance to other known fusion inhibitors. PMID- 23689711 TI - Broad-spectrum antimalarial activity of peptido sulfonyl fluorides, a new class of proteasome inhibitors. AB - Despite declining numbers of cases and deaths, malaria remains a major public health problem in many parts of the world. Today, case management relies heavily on a single class of antimalarial compounds: artemisinins. Hence, development of resistance against artemisinins may destroy current malaria control strategies. Beyond malaria control are elimination and eradication programs that will require drugs with good activity against acute infection but also with preventive and transmission-blocking properties. Consequently, new antimalarials are needed not only to ensure malaria control but also for elimination and eradication efforts. In this study, we introduce peptido sulfonyl fluorides (PSF) as a new class of compounds with antiplasmodial activity. We show that PSF target the plasmodial proteasome and act on all asexual stages of the intraerythrocytic cycle and on gametocytes. PSF showed activities at concentrations as low as 20 nM against multidrug-resistant and chloroquine-sensitive Plasmodium falciparum laboratory strains and clinical isolates from Gabon. Structural requirements for activity were identified, and cytotoxicity in human HeLa or HEK 293 cells was low. The lead PSF PW28 suppressed growth of Plasmodium berghei in vivo but showed signs of toxicity in mice. Considering their modular structure and broad spectrum of activity against different stages of the plasmodial life cycle, proteasome inhibitors based on PSF have a great potential for further development as preclinical candidate compounds with improved species-specific activity and less toxicity. PMID- 23689712 TI - Antibiotic administration routes significantly influence the levels of antibiotic resistance in gut microbiota. AB - This study examined the impact of oral exposure to antibiotic-resistant bacteria and antibiotic administration methods on antibiotic resistance (AR) gene pools and the profile of resistant bacteria in host gastrointestinal (GI) tracts using C57BL/6J mice with natural gut microbiota. Mice inoculated with a mixture of tet(M)-carrying Enterococcus spp. or blaCMY-2-carrying Escherichia coli were treated with different doses of tetracycline hydrochloride (Tet) or ampicillin sodium (Amp) and delivered via either feed or intravenous (i.v.) injection. Quantitative PCR assessment of mouse fecal samples revealed that (i) AR gene pools were below the detection limit in mice without prior inoculation of AR gene carriers regardless of subsequent exposure to corresponding antibiotics; (ii) oral exposure to high doses of Tet and Amp in mice inoculated with AR gene carriers led to rapid enrichment of corresponding AR gene pools in feces; (iii) significantly less or delayed development of AR in the GI tract of the AR carrier inoculated mice was observed when the same doses of antibiotics were administered via i.v. injection rather than oral administration; and (iv) antibiotic dosage, and maybe the excretion route, affected AR in the GI tract. The shift of dominant AR bacterial populations in the gut microbiota was consistent with the dynamics of AR gene pools. The emergence of endogenous resistant bacteria in the gut microbiota corresponding to drug exposure was also observed. Together, these data suggest that oral administration of antibiotics has a prominent effect on AR amplification and development in gut microbiota, which may be minimized by alternative drug administration approaches, as illustrated by i.v. injection in this study and proper drug selection. PMID- 23689714 TI - Linezolid resistance in Brazilian Staphylococcus hominis strains is associated with L3 and 23S rRNA ribosomal mutations. PMID- 23689713 TI - Discovery of antivirulence agents against methicillin-resistant Staphylococcus aureus. AB - Antivirulence agents inhibit the production of disease-causing virulence factors but are neither bacteriostatic nor bactericidal. Antivirulence agents against methicillin-resistant Staphylococcus aureus (MRSA) strain USA300, the most widespread community-associated MRSA strain in the United States, were discovered by virtual screening against the response regulator AgrA, which acts as a transcription factor for the expression of several of the most prominent S. aureus toxins and virulence factors involved in pathogenesis. Virtual screening was followed by similarity searches in the databases of commercial vendors. The small-molecule compounds discovered inhibit the production of the toxins alpha hemolysin and phenol-soluble modulin alpha in a dose-dependent manner without inhibiting bacterial growth. These antivirulence agents are small-molecule biaryl compounds in which the aromatic rings either are fused or are separated by a short linker. One of these compounds is the FDA-approved nonsteroidal anti inflammatory drug diflunisal. This represents a new use for an old drug. Antivirulence agents might be useful in prophylaxis and as adjuvants in antibiotic therapy for MRSA infections. PMID- 23689715 TI - Efficacy of AiiM, an N-acylhomoserine lactonase, against Pseudomonas aeruginosa in a mouse model of acute pneumonia. AB - Quorum sensing (QS) in Pseudomonas aeruginosa regulates the production of many virulence factors and plays an important role in the pathogenesis of P. aeruginosa infection. N-acyl homoserine lactones (AHL) are major QS signal molecules. Recently, a novel AHL-lactonase enzyme, AiiM, has been identified. The aim of this study was to evaluate the effect of AiiM on the virulence of P. aeruginosa in a mouse model of acute pneumonia. We developed a P. aeruginosa PAO1 strain harboring an AiiM-expressing plasmid. The production of several virulence factors by the AiiM-expressing strain was examined. Mice were intratracheally infected with an AiiM-expressing PAO1 strain. Lung histopathology, bacterial burden, and bronchoalveolar lavage (BAL) fluid were assessed at 24 h postinfection. AiiM expression in PAO1 reduced production of AHL-mediated virulence factors and attenuated cytotoxicity against human lung epithelial cells. In a mouse model of acute pneumonia, AiiM expression reduced lung injury and greatly improved the survival rates. The levels of proinflammatory cytokines and myeloperoxidase activity in BAL fluid were significantly lower in mice infected with AiiM-expressing PAO1. Thus, AiiM can strongly attenuate P. aeruginosa virulence in a mammalian model and is a potential candidate for use as a therapeutic agent against P. aeruginosa infection. PMID- 23689716 TI - MBX-500 is effective for treatment of Clostridium difficile infection in gnotobiotic piglets. AB - The novel antibiotic MBX-500, dosed at 100, 200, or 400 mg/kg twice daily for 7 days, was evaluated for the treatment of Clostridium difficile infection (CDI) in the gnotobiotic pig model. MBX-500 increased survival at all doses and at high doses improved clinical signs and reduced lesion severity, similar to vancomycin. Our results show that MBX-500 is an effective antibiotic for the treatment of diarrhea associated with CDI and prevents severe systemic disease. PMID- 23689717 TI - Identification and mechanism of action of the plant defensin NaD1 as a new member of the antifungal drug arsenal against Candida albicans. AB - In recent decades, pathogenic fungi have become a serious threat to human health, leading to major efforts aimed at characterizing new agents for improved treatments. Promising in this context are antimicrobial peptides produced by animals and plants as part of innate immune systems. Here, we describe an antifungal defensin, NaD1, with activity against the major human pathogen Candida albicans, characterize the mechanism of killing, and identify protection strategies used by the fungus to survive defensin treatment. The mechanism involves interaction between NaD1 and the fungal cell surface followed by membrane permeabilization, entry into the cytoplasm, hyperproduction of reactive oxygen species, and killing induced by oxidative damage. By screening C. albicans mutant libraries, we identified that the high-osmolarity glycerol (HOG) pathway has a unique role in protection against NaD1, while several other stress responsive pathways are dispensable. The involvement of the HOG pathway is consistent with induction of oxidative stress by NaD1. The HOG pathway has been reported to have a major role in protection of fungi against osmotic stress, but our data indicate that osmotic stress does not contribute significantly to the adverse effects of NaD1 on C. albicans. Our data, together with previous studies with human beta-defensins and salivary histatin 5, indicate that inhibition of the HOG pathway holds promise as a broad strategy for increasing the activity of antimicrobial peptides against C. albicans. PMID- 23689718 TI - Evaluation of pharmacokinetic interaction between PA-824 and midazolam in healthy adult subjects. AB - This study assessed the safety, tolerability, and pharmacokinetic interaction between PA-824, a novel antitubercular nitroimidazo-oxazine, and midazolam, a CYP3A4 substrate, in 14 healthy adult male and female subjects. The study followed up on observations in vitro that PA-824 caused weak and time-dependent inhibition of CYP3A4. Subjects received a single oral dose of midazolam (2 mg), followed by a 2-day washout. After the washout, all subjects received PA-824 (400 mg) once daily for 14 consecutive days. On day 14, all subjects received the final PA-824 dose coadministered with a 2-mg oral dose of midazolam. The pharmacokinetic endpoints AUC0-t, AUC(0-infinity), and C(max) for midazolam and 1 hydroxy midazolam were compared between midazolam administered alone versus midazolam coadministered with PA-824. Statistical analysis demonstrated that the mean midazolam values of C(max), AUC(0-t), and AUC(0-infinity) parameters were reduced by ca. 16, 15, and 15%, respectively, when PA-824 was coadministered with midazolam. The total exposure (AUC) of 1-hydroxy midazolam was 13 to 14% greater when coadministered with PA-824 compared to midazolam administered alone. The Cmax of 1-hydroxy midazolam was similar between treatments. Based on these results, PA-824 does not inhibit or induce CYP3A4 to a clinically meaningful extent and is not likely to markedly affect the pharmacokinetics of CYP3A4 metabolized drugs. PMID- 23689719 TI - High-throughput screening of a collection of known pharmacologically active small compounds for identification of Candida albicans biofilm inhibitors. AB - Candida albicans is the most common etiologic agent of systemic fungal infections with unacceptably high mortality rates. The existing arsenal of antifungal drugs is very limited and is particularly ineffective against C. albicans biofilms. To address the unmet need for novel antifungals, particularly those active against biofilms, we have screened a small molecule library consisting of 1,200 off patent drugs already approved by the Food and Drug Administration (FDA), the Prestwick Chemical Library, to identify inhibitors of C. albicans biofilm formation. According to their pharmacological applications that are currently known, we classified these bioactive compounds as antifungal drugs, as antimicrobials/antiseptics, or as miscellaneous drugs, which we considered to be drugs with no previously characterized antifungal activity. Using a 96-well microtiter plate-based high-content screening assay, we identified 38 pharmacologically active agents that inhibit C. albicans biofilm formation. These drugs were subsequently tested for their potency and efficacy against preformed biofilms, and we identified three drugs with novel antifungal activity. Thus, repurposing FDA-approved drugs opens up a valuable new avenue for identification and potentially rapid development of antifungal agents, which are urgently needed. PMID- 23689720 TI - Cationic antimicrobial peptides and biogenic silver nanoparticles kill mycobacteria without eliciting DNA damage and cytotoxicity in mouse macrophages. AB - With the emergence of multidrug-resistant mycobacterial strains, better therapeutic strategies are required for the successful treatment of the infection. Although antimicrobial peptides (AMPs) and silver nanoparticles (AgNPs) are becoming one of the popular antibacterial agents, their antimycobacterial potential is not fully evaluated. In this study, we synthesized biogenic-silver nanoparticles using bacterial, fungal, and plant biomasses and analyzed their antibacterial activities in combination with AMPs against mycobacteria. Mycobacterium smegmatis was found to be more susceptible to AgNPs compared to M. marinum. We found that NK-2 showed enhanced killing effect with NP 1 and NP-2 biogenic nanoparticles at a 0.5-ppm concentration, whereas LLKKK-18 showed antibacterial activity only with NP-2 at 0.5-ppm dose against M. smegmatis. In case of M. marinum NK-2 did not show any additive activity with NP 1 and NP-2 and LLKKK-18 alone completely inhibited the bacterial growth. Both NP 1 and NP-2 also showed increased killing of M. smegmatis in combination with the antituberculosis drug rifampin. The sizes and shapes of the AgNPs were determined by transmission electron microscopy and dynamic light scattering. AgNPs showed no cytotoxic or DNA damage effects on macrophages at the mycobactericidal dose, whereas treatment with higher doses of AgNPs caused toxicity and micronuclei formation in cytokinesis blocked cells. Macrophages actively endocytosed fluorescein isothiocyanate-labeled AgNPs resulting in nitric oxide independent intracellular killing of M. smegmatis. Apoptosis and cell cycle studies showed that treatment with higher dose of AgNPs arrested macrophages at the G1-phase. In summary, our data suggest the combined effect of biogenic-AgNPs and antimicrobial peptides as a promising antimycobacterial template. PMID- 23689721 TI - Induction of plasmid-carried qnrS1 in Escherichia coli by naturally occurring quinolones and quorum-sensing signal molecules. AB - Naturally occurring quinolone and quinolone-like compounds, such as quinine, 2 hydroxyquinoline, 4-hydroxyquinoline, and 2-heptyl-3-hydroxy-4(1H)-quinolone, increased expression of qnrS1 in Escherichia coli 2.3- to 11.2-fold, similar to the synthetic quinolone ciprofloxacin. In contrast, chromosomal qnrVS1 of Vibrio splendidus was not induced by these compounds. Molecules associated with quorum sensing, such as N-3-hydroxybutyryl-homoserine lactone (HSL), N-hexanoyl-HSL, and N-3-(oxododecanoyl)-HSL, did not show an induction effect on either qnrS1 or qnrVS1 at the tested concentrations. PMID- 23689722 TI - Clinical validation of the analysis of linezolid and clarithromycin in oral fluid of patients with multidrug-resistant tuberculosis. AB - Linezolid plays an increasingly important role in the treatment of multidrug resistant tuberculosis (MDR-TB). However, patients should be carefully monitored due to time- and dose-dependent toxicity. Clarithromycin plays a more modest role. Therapeutic drug monitoring may contribute to assessment of treatment regimens, helping to reduce toxicity while maintaining adequate drug exposure. Oral fluid sampling could provide a welcome alternative in cases where conventional plasma sampling is not possible or desirable. The aim of this study was to clinically validate the analysis of linezolid and clarithromycin and its metabolite hydroxyclarithromycin in oral fluid of patients with multidrug resistant tuberculosis. Serum and oral fluid samples were simultaneously obtained and analyzed by using validated methods, after extensive cross-validation between the two matrices. Passing-Bablok regressions and Bland-Altman analysis showed that oral fluid analysis of linezolid and clarithromycin appeared to be suitable for therapeutic drug monitoring in MDR-TB patients. No correction factor is needed for the interpretation of linezolid oral fluid concentrations with a ratio of the linezolid concentration in serum to that in oral fluid of 0.97 (95% confidence interval [CI], 0.92 to 1.02). However, the clarithromycin concentration serum/clarithromycin concentration in oral fluid ratio is 3.07 (95% CI, 2.45 to 3.69). Analysis of hydroxyclarithromycin in oral fluid was not possible in this study due to a nonlinear relationship between the concentration in serum and that in oral fluid. In conclusion, the analysis of linezolid (no correction factor) and clarithromycin (correction factor of 3) in oral fluid is applicable for therapeutic drug monitoring in cases of multidrug-resistant tuberculosis as an alternative to conventional serum sampling. Easy sampling using a noninvasive technique may facilitate therapeutic drug monitoring for specific patient categories. PMID- 23689723 TI - Identification of cell-penetrating peptides that are bactericidal to Neisseria meningitidis and prevent inflammatory responses upon infection. AB - Meningococcal disease is characterized by a fast progression and a high mortality rate. Cell-penetrating peptides (CPPs), developed as vectors for cargo delivery into eukaryotic cells, share structural features with antimicrobial peptides. A screen identified two CPPs, transportan-10 (TP10) and model amphipathic peptide (MAP), with bactericidal action against Neisseria meningitidis. Both peptides were active in human whole blood at micromolar concentrations, while hemolysis remained negligible. Additionally, TP10 exhibited significant antibacterial activity in vivo. Uptake of SYTOX green into live meningococci was observed within minutes after TP10 treatment, suggesting that TP10 may act by membrane permeabilization. Apart from its bactericidal activity, TP10 suppressed inflammatory cytokine release from macrophages infected with N. meningitidis as well as from macrophages stimulated with enterobacterial and meningococcal lipopolysaccharide (LPS). Finally, incubation with TP10 reduced the binding of LPS to macrophages. This novel endotoxin-inhibiting property of TP10, together with its antimicrobial activity in vivo, indicates the possibility to design peptide-based therapies for infectious diseases. PMID- 23689724 TI - Potentiation of azole antifungals by 2-adamantanamine. AB - Azoles are among the most successful classes of antifungals. They act by inhibiting alpha-14 lanosterol demethylase in the ergosterol biosynthesis pathway. Oropharyngeal candidiasis (OPC) occurs in about 90% of HIV-infected individuals, and 4 to 5% are refractory to current therapies, including azoles, due to the formation of resistant biofilms produced in the course of OPC. We reasoned that compounds affecting a different target may potentiate azoles to produce increased killing and an antibiofilm therapeutic. 2-Adamantanamine (AC17) was identified in a screen for compounds potentiating the action of miconazole against biofilms of Candida albicans. AC17, a close structural analog to the antiviral amantadine, did not affect the viability of C. albicans but caused the normally fungistatic azoles to become fungicidal. Transcriptome analysis of cells treated with AC17 revealed that the ergosterol and filamentation pathways were affected. Indeed, cells exposed to AC17 had decreased ergosterol contents and were unable to invade agar. In vivo, the combination of AC17 and fluconazole produced a significant reduction in fungal tissue burden in a guinea pig model of cutaneous candidiasis, while each treatment alone did not have a significant effect. The combination of fluconazole and AC17 also showed improved efficacy (P value of 0.018) compared to fluconazole alone when fungal lesions were evaluated. AC17 is a promising lead in the search for more effective antifungal therapeutics. PMID- 23689725 TI - Isoniazid, rifampin, and pyrazinamide plasma concentrations in relation to treatment response in Indonesian pulmonary tuberculosis patients. AB - Numerous studies have reported low concentrations of antituberculosis drugs in tuberculosis (TB) patients, but few studies have examined whether low drug concentrations affect TB treatment response. We examined steady-state plasma concentrations of isoniazid, rifampin, and pyrazinamide at 2 h after the administration of drugs (C(2 h)) among 181 patients with pulmonary tuberculosis in Indonesia and related these to bacteriological response during treatment. C(2 h) values below reference values for either isoniazid, rifampin, or pyrazinamide were found in 91% of patients; 60% had at least two low C(2 h) concentrations. The isoniazid C2 h was noticeably lower in fast versus slow acetylators (0.9 mg/liter versus 2.2 mg/liter, P < 0.001). At the end of treatment, 82% of the patients were cured, whereas 30 patients (17%) had dropped out during the study, and 2 patients (1%) failed treatment. No association was found between C(2 h) concentrations and sputum culture results at 8 weeks of treatment. Post hoc analysis showed that patients with low pyrazinamide C2 h (P = 0.01) and patients with large extensive lung lesions (P = 0.01) were at risk of at least one positive culture at week 4, 8, or 24/32. Antituberculosis drug concentrations were often low, but treatment response was nevertheless good. No association was found between drug concentrations and 8 weeks culture conversion, but low pyrazinamide drug concentrations may be associated with a less favorable bacteriological response. The use of higher doses of pyrazinamide may warrant further investigation. PMID- 23689726 TI - A mouse model of Acinetobacter baumannii-associated pneumonia using a clinically isolated hypervirulent strain. AB - Acinetobacter baumannii is an important emerging pathogen in health care-acquired infections and is responsible for severe nosocomial and community-acquired pneumonia. Currently available mouse models of A. baumannii pneumonia show poor colonization with little to no extrapulmonary dissemination. Here, we describe a mouse model of A. baumannii pneumonia using a clinical isolate (LAC-4 strain) that reliably reproduces the most relevant features of human pulmonary A. baumannii infection and pathology. Using this model, we have shown that LAC-4 infection induced rapid bacterial replication in the lungs, significant extrapulmonary dissemination, and severe bacteremia by 24 h postintranasal inoculation. Infected mice showed severe bronchopneumonia and dilatation and inflammatory cell infiltration in the perivascular space. More significantly, 100% of C57BL/6 and BALB/c mice succumbed to 10(8) CFU of LAC-4 inoculation within 48 h. When this model was used to assess the efficacy of antimicrobials, all mice treated with imipenem and tigecycline survived a lethal intranasal challenge, with minimal clinical signs and body weight loss. Moreover, intranasal immunization of mice with formalin-fixed LAC-4 protected 40% of mice from a lethal (100* 100% lethal dose) intraperitoneal challenge. Thus, this model offers a reproducible acute course of A. baumannii pneumonia without requiring additional manipulation of host immune status, which will facilitate the development of therapeutic agents and vaccines against A. baumannii pneumonia in humans. PMID- 23689728 TI - Treatment of high-level gentamicin-resistant Enterococcus faecalis endocarditis with daptomycin plus ceftaroline. AB - A recurrent case of left-sided endocarditis caused by high-level aminoglycoside resistant Enterococcus faecalis was successfully treated with ceftaroline and daptomycin. This combination demonstrated excellent synergy in vitro. Mechanistically, ceftaroline enhanced binding of daptomycin to the cell membrane and sensitized E. faecalis to killing by human cathelicidin LL-37, a cationic innate host defense peptide. Daptomycin plus ceftaroline may be considered in salvage therapy in E. faecalis endovascular infections and requires further study. PMID- 23689727 TI - Epidemiology of isoniazid resistance mutations and their effect on tuberculosis treatment outcomes. AB - Isoniazid resistance is highly prevalent in Vietnam. We investigated the molecular and epidemiological characteristics and the association with first-line treatment outcomes of the main isoniazid resistance mutations in Mycobacterium tuberculosis in codon 315 of the katG and in the promoter region of the inhA gene. Mycobacterium tuberculosis strains with phenotypic resistance to isoniazid from consecutively diagnosed smear-positive tuberculosis patients in rural Vietnam were subjected to Genotype MTBDRplus testing to identify katG and inhA mutations. Treatment failure and relapse were determined by sputum culture. In total, 227 of 251 isoniazid-resistant strains (90.4%) had detectable mutations: 75.3% in katG codon 315 (katG315) and 28.2% in the inhA promoter region. katG315 mutations were significantly associated with pretreatment resistance to streptomycin, rifampin, and ethambutol but not with the Beijing genotype and predicted both unfavorable treatment outcome (treatment failure or death) and relapse; inhA promoter region mutations were only associated with resistance to streptomycin and relapse. In tuberculosis patients, M. tuberculosis katG315 mutations but not inhA mutations are associated with unfavorable treatment outcome. inhA mutations do, however, increase the risk of relapse, at least with treatment regimens that contain only isoniazid and ethambutol in the continuation phase. PMID- 23689729 TI - A novel inhibitor of proteasome deubiquitinating activity renders tumor cells sensitive to TRAIL-mediated apoptosis by natural killer cells and T cells. AB - The proteasome inhibitor bortezomib simultaneously renders tumor cells sensitive to killing by natural killer (NK) cells and resistant to killing by tumor specific T cells. Here, we show that b-AP15, a novel inhibitor of proteasome deubiquitinating activity, sensitizes tumors to both NK and T cell-mediated killing. Exposure to b-AP15 significantly increased the susceptibility of tumor cell lines of various origins to NK (p < 0.0002) and T cell (p = 0.02)-mediated cytotoxicity. Treatment with b-AP15 resulted in increased tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptor-2 expression (p = 0.03) and decreased cFLIP expression in tumor cells in vitro. In tumor-bearing SCID/Beige mice, treatment with b-AP15 followed by infusion of either human NK cells or tumor-specific T cells resulted in a significantly delayed tumor progression compared with mice treated with NK cells (p = 0.006), T cells (p < 0.0001) or b AP15 alone (p = 0.003). Combined infusion of NK and T cells in tumor-bearing BALB/c mice following treatment with b-AP15 resulted in a significantly prolonged long-term survival compared with mice treated with b-AP15 and NK or T cells (p <= 0.01). Our findings show that b-AP15-induced sensitization to TRAIL-mediated apoptosis could be used as a novel strategy to augment the anticancer effects of adoptively infused NK and T cells in patients with cancer. PMID- 23689730 TI - Transgenerational effects and the cost of ant tending in aphids. AB - In mutualistic interactions, partners obtain a net benefit, but there may also be costs associated with the provision of benefits for a partner. The question of whether aphids suffer such costs when attended by ants has been raised in previous work. Transgenerational effects, where offspring phenotypes are adjusted based on maternal influences, could be important in the mutualistic interaction between aphids and ants, in particular because aphids have telescoping generations where two offspring generations can be present in a mature aphid. We investigated the immediate and transgenerational influence of ant tending on aphid life history and reproduction by observing the interaction between the facultative myrmecophile Aphis fabae and the ant Lasius niger over 13 aphid generations in the laboratory. We found that the effect of ant tending changes dynamically over successive aphid generations after the start of tending. Initially, total aphid colony weight, aphid adult weight and aphid embryo size decreased compared with untended aphids, consistent with a cost of ant association, but these differences disappeared within four generations of interaction. We conclude that transgenerational effects are important in the aphid-ant interactions and that the costs for aphids of being tended by ants can vary over generations.